Tyrosine kinase 2 inhibitor and application thereof

Abstract

Provided are compounds of Formula (I): # imgabs0 #, or a pharmaceutically acceptable salt thereof, which are useful in the inhibition of TYK2 and in the treatment of a variety of TYK2-mediated conditions or diseases.

Description

[0001] Related applications

[0002] This application claims priority to U.S. Provisional Application No. 63 / 354,914, filed on June 23, 2022. The entire contents of the aforementioned application are expressly incorporated herein by reference. Technical Field

[0003] The present disclosure relates to inhibitors of tyrosine kinase 2 (TYK2) and pharmaceutically acceptable salts thereof, compositions of these compounds, methods for their preparation, their use in the treatment of diseases, their use, optionally in combination with a pharmaceutically acceptable carrier, for the manufacture of pharmaceutical preparations, the use of such pharmaceutical preparations in the treatment of diseases, and methods for treating diseases comprising administering a TYK2 inhibitor to a warm-blooded animal, especially a human. Background Art

[0004] Cytokines are small secretory proteins released by cells that have specific effects on cell-to-cell interactions and communication. Cytokine pathways mediate a wide range of biological functions, including many aspects of inflammation and immunity, primarily through extracellular signaling.

[0005] Tyrosine kinase 2 (TYK2) is a member of the Janus kinase (JAK) family of cytoplasmic protein kinases associated with cytokine receptors and 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 cytokines with cognate receptors triggers activation of JAK-associated receptors, which leads to tyrosine phosphorylation of JAK-mediated signal transducers and activators of transcription (STAT) proteins, and ultimately to transcriptional activation of specific gene sets (Schindler et al., 2007, J. Biol. Chem. 282: 20059-63). Many cytokines are known to activate the JAK family, including the interferon (IFN) family (IFN-α, IFN-β, IFN-ω, Limitin, IFN-γ, 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 γC 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), receptor tyrosine kinases (EGF, PDGF, CSF-1, HGF), and the G protein-coupled receptor (AT1).

[0006] TYK2 is important in the signaling of type I interferons (e.g., IFN-α), IL-6, IL-10, IL-12, and IL-23 (Liang, Y. et al., Expert Opinion on Therapeutic Targets, 2014, 18, 5, 571-580; Kisseleva et al., 2002, Gene 285: 1-24; and Watford, WT and O'Shea, JJ, 2006, Immunity 25: 695-697). Consistent with this, primary cells derived from TYK2-deficient humans are defective in type I interferon, IL-6, IL-10, IL-12, and IL-23 signaling. TYK2 signals with other members of the JAK family in the following combinations: TYK2 / JAK1, TYK2 / JAK2, TYK2 / JAK1 / JAK2.

[0007] Studies have shown that inappropriate JAK activity can be caused by mutation, overexpression or inappropriate regulation, abnormal or dysregulated regulation, and excessive or insufficient production of growth factors or cytokines, thereby triggering a variety of 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 nervous system and neurodegenerative disorders such as Alzheimer's disease.

[0008] 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 entered the development stage are active site-directed inhibitors that bind to the adenosine triphosphate (ATP) site of the catalytic domain of the JAK protein (also known as the JH1 or "Janus homology 1" domain), which prevents the catalytic activity of the kinase by blocking ATP, downstream phosphorylation, and the resulting pathway signal transduction (Bryan et al., J. Med. Chem. 2018, 61, 9030-9058).

[0009] Because the ATP active site is highly homologous across the kinome and specifically within the JAK family, achieving high selectivity for specific JAK family members while also maintaining selectivity within the kinome is a major challenge. Consequently, many JAK inhibitors that have been developed are pan-JAK inhibitors or have modest selectivity for one or more JAK family members. While these inhibitors have shown encouraging results in the treatment of autoimmune diseases, adverse side effects have been observed that result in a narrow therapeutic index, indicating a need for improved treatments.

[0010] TYK2 has been shown to be important in the differentiation and function of multiple cell types that are important in inflammatory and autoimmune diseases, including natural killer cells, B cells, and T helper cell types. Aberrant TYK2 expression is associated with a variety of autoimmune or inflammatory conditions.

[0011] There remains a need for effective compounds that exhibit 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

[0012] The present disclosure provides compounds that are TYK2 inhibitors. In a first aspect, the present disclosure relates to compounds having Formula I:

[0013]

[0014] or a pharmaceutically acceptable salt thereof, wherein:

[0015] Ring A is an aromatic or heteroaromatic ring fused to Ring B which is a 5-membered heterocyclic ring;

[0016] X 1 N or CH;

[0017] Ring C represents phenyl, 5 to 10 membered monocyclic or bicyclic heteroaryl, 3 to 7 membered monocyclic carbocyclyl or 4 to 7 membered monocyclic heterocyclyl, each of which is optionally substituted by one or more R C replace;

[0018] Each R C are independently halo, –CN, –NR N1 R N2 ,–NR N3 –C(O)–R 7 、-C(O)–NR N3 R N4 ,–NR N4 –SO2–R 7 ,–C(O)–R 7 、-C(O)-OH、-C(O)-OR 7 、-SR 7 ,–SO2–R 7 、–OR O1 、C 1-6 Alkyl, C 2-6 alkenyl, phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered monocyclic carbocyclic group or 4- to 9-membered monocyclic or bicyclic heterocyclic group, wherein R C The C 1-6 Alkyl, C 1-6 Alkenyl, phenyl, 5 to 6 membered heteroaryl, 3 to 7 membered monocyclic carbocyclyl and 4 to 9 membered monocyclic or bicyclic heterocyclyl are each optionally substituted by one or more R C1 replace;

[0019] Each R C1 are independently halo, oxo, –CN, –OR O1 ,–NR N3 R N4 ,–C(O)-R 7 、–C(O)-OR O3 、–SO2-R 7 、C 1-6 alkyl, phenyl, 3 to 7 membered monocyclic carbocyclic group, 5 to 6 membered heteroaryl or 4 to 7 membered monocyclic heterocyclic group, wherein R C1 The C 1-6Alkyl, phenyl, 5- to 6-membered heteroaryl, and 4- to 7-membered monocyclic heterocyclyl are each optionally substituted with one or more substituents independently selected from the group consisting of halo, oxo, -CN, -OR O1 ,–NR N3 R N4 、C 1-6 Alkyl, C 1-4 haloalkyl, phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 8-membered monocyclic heterocyclyl;

[0020] R 1 H, C 1-6 Alkyl, -OR 2 、-NR 2 R 4 , 3 to 7 membered monocyclic carbocyclic group or 4 to 7 membered monocyclic heterocyclic group, wherein R 1 The C 1-6 Alkyl, 3 to 7 membered monocyclic carbocyclyl and 4 to 7 membered monocyclic heterocyclyl are each optionally substituted by one or more R 8 replace;

[0021] R 1A H or C 1-3 alkyl;

[0022] Each R 2 and R 4 Independently H, C 1-4 Alkyl or 3- to 4-membered monocyclic carbocyclic group;

[0023] Each R 3 are independently H, halo or C 1-3 alkyl;

[0024] Alternatively, two R 3 Together with the atoms to which they are attached, they form a 3- to 7-membered monocyclic carbocyclyl or a 4- to 9-membered monocyclic heterocyclyl, each of which is optionally substituted by one or more R 5 replace;

[0025] Each R 5 are independently H, halo, -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 、SO2-R 7, phenyl, 5 to 6 membered heteroaryl or 3 to 7 membered monocyclic carbocyclic group or 4 to 7 membered monocyclic heterocyclic group, wherein R 5 The C 1-6 Alkyl, phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 7-membered monocyclic heterocyclyl are each optionally substituted with one or more substituents independently selected from the group consisting of halo, oxo, -CN, -OR O1 ,–NR N1 R N2 、C 1-6 Alkyl, C 1-4 haloalkyl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 7-membered monocyclic heterocyclyl;

[0026] Each R 7 Independently C 1-6 alkyl, phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered monocyclic carbocyclic group or 4- to 7-membered monocyclic heterocyclic group; wherein R 7 The C 1-6 Alkyl, phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 7-membered monocyclic heterocyclyl are each optionally substituted with one or more substituents independently selected from the group consisting of halo, oxo, -CN, -OR O1 ,–NR N3 R N4 、C 1-6 Alkyl, C 1-4 haloalkyl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 7-membered monocyclic heterocyclyl;

[0027] Each R 8 are 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 carbocyclyl, or 4- to 7-membered monocyclic heterocyclyl;

[0028] Each R O1 Independently H, C 1-6 alkyl, phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered monocyclic carbocyclic group or 4- to 8-membered monocyclic or bicyclic heterocyclic group, wherein R O1 The C 1-6 Alkyl, phenyl, 5 to 6 membered heteroaryl, 3 to 8 membered monocyclic carbocyclyl and 4 to 7 membered monocyclic or bicyclic heterocyclyl are each optionally substituted by one or more R O2 replace;

[0029] Each R O2 are independently halo, OH, -CN, C 1-4 Alkoxy, C1-4 Alkyl, C 1-4 Alkyl-C 1-4 Alkoxy, C 1-4 haloalkyl, phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered monocyclic carbocyclyl, or 4- to 7-membered monocyclic or bicyclic heterocyclyl, wherein the 4- to 7-membered monocyclic or bicyclic heterocyclyl is optionally C 1-4 Alkyl or C 1-4 Alkoxy substitution;

[0030] Each R O3 Independently H, C 1-6 Alkyl, C 1-4 haloalkyl, phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered monocyclic carbocyclic group or 4- to 7-membered monocyclic heterocyclic group, wherein R O3 The C 1-6 Alkyl, phenyl, 5 to 6 membered heteroaryl, 3 to 7 membered monocyclic carbocyclyl and 4 to 7 membered monocyclic heterocyclyl are each optionally substituted by one or more R O2 replace;

[0031] R O4 H, C 1-6 alkyl, phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered monocyclic carbocyclic group or 4- to 7-membered monocyclic heterocyclic group, wherein R O4 The C 1-6 Alkyl, phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 7-membered monocyclic heterocyclyl are each optionally substituted with one or more substituents independently selected from the group consisting of 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 carbocyclyl, and 4- to 7-membered monocyclic heterocyclyl;

[0032] R N1 and R N2 Each independently is H or C 1-6 Alkyl, wherein R N1 and R N2 The C 1-6 Each alkyl group is optionally substituted with a halo group, a C 1-4 Alkoxy or –NR N3 R N4 Replace, or

[0033] R N1 H or C 1-3 Alkyl and R N2 Ring D or –C 1-3 Alkylene-ring D;

[0034] Ring D is a 3- to 7-membered monocyclic or bicyclic carbocyclyl or a 4- to 7-membered monocyclic heterocyclyl, wherein the 3- to 7-membered monocyclic carbocyclyl and the 4- to 7-membered monocyclic heterocyclyl represented by ring D are each optionally substituted with one or two substituents independently selected from the group consisting of halo, C 1-6 Alkyl and C 1-4 alkoxy;

[0035] Each R N3 are independently H or C 1-6 alkyl; and

[0036] Each R N4 are independently H or C 1-6 alkyl.

[0037] 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.

[0038] In yet another aspect, the present disclosure provides a method of treating a disease or condition 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.

[0039] 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 treating a disease or condition responsive to inhibition of TYK2. Also provided is a compound described herein, or a pharmaceutically acceptable salt thereof, for use in treating a disease or condition responsive to inhibition of TYK2. The present disclosure also encompasses the use of a compound described herein, or a pharmaceutically acceptable salt thereof, for treating a disease or condition responsive to inhibition of TYK2. DETAILED DESCRIPTION

[0040] The present disclosure provides compounds and pharmaceutical compositions thereof, which can be used to treat diseases or conditions mediated by TYK2. In some embodiments, the compounds of the present disclosure are TYK2 inhibitors.

[0041] Compounds and compositions

[0042] In a first embodiment, the present disclosure provides a compound of formula (I):

[0043]

[0044] or a pharmaceutically acceptable salt thereof, wherein:

[0045] Ring A is an aromatic or heteroaromatic ring fused to Ring B which is a 5-membered heterocyclic ring;

[0046] X 1N or CH;

[0047] Ring C represents phenyl, 5 to 10 membered monocyclic or bicyclic heteroaryl, 3 to 7 membered monocyclic carbocyclyl or 4 to 7 membered monocyclic heterocyclyl, each of which is optionally substituted by one or more R C replace;

[0048] Each R C are independently halo, –CN, –NR N1 R N2 ,–NR N3 –C(O)–R 7 、-C(O)–NR N3 R N4 ,–NR N4 –SO2–R 7 ,–C(O)–R 7 、-SR 7 ,–SO2–R 7 、–OR O1 、C 1-6 alkyl, phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered monocyclic carbocyclic group or 4- to 9-membered monocyclic or bicyclic heterocyclic group, wherein R C The C 1-6 Alkyl, phenyl, 5 to 6 membered heteroaryl, 3 to 7 membered monocyclic carbocyclyl and 4 to 9 membered monocyclic or bicyclic heterocyclyl are each optionally substituted by one or more R C1 replace;

[0049] Each R C1 are independently halo, oxo, –CN, –OR O1 ,–NR N3 R N4 ,–C(O)-R 7 、–C(O)-OR O3 、–SO2-R 7 、C 1-6 alkyl, phenyl, 3 to 7 membered monocyclic carbocyclic group, 5 to 6 membered heteroaryl or 4 to 7 membered monocyclic heterocyclic group, wherein R C1 The C 1-6 Alkyl, phenyl, 5- to 6-membered heteroaryl, and 4- to 7-membered monocyclic heterocyclyl are each optionally substituted with one or more substituents independently selected from the group consisting of halo, oxo, -CN, -OR O1 ,–NR N3 R N4 、C 1-6 Alkyl, C 1-4 haloalkyl, phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 8-membered monocyclic heterocyclyl;

[0050] R 1 H, C1-6 Alkyl, -OR 2 、-NR 2 R 4 , 3 to 7 membered monocyclic carbocyclic group or 4 to 7 membered monocyclic heterocyclic group, wherein R 1 The C 1-6 Alkyl, 3 to 7 membered monocyclic carbocyclyl and 4 to 7 membered monocyclic heterocyclyl are each optionally substituted by one or more R 8 replace;

[0051] R 1A H or C 1-3 alkyl;

[0052] Each R 2 and R 4 Independently H, C 1-4 Alkyl or 3- to 4-membered monocyclic carbocyclic group;

[0053] Each R 3 are independently H, halo or C 1-3 alkyl;

[0054] Alternatively, two R 3 Together with the atoms to which they are attached, they form a 3- to 7-membered monocyclic carbocyclyl or a 4- to 9-membered monocyclic heterocyclyl, each of which is optionally substituted by one or more R 5 replace;

[0055] Each R 5 are independently H, halo, -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 、SO2-R 7 , phenyl, 5 to 6 membered heteroaryl or 3 to 7 membered monocyclic carbocyclic group or 4 to 7 membered monocyclic heterocyclic group, wherein R 5 The C 1-6 Alkyl, phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 7-membered monocyclic heterocyclyl are each optionally substituted with one or more substituents independently selected from the group consisting of halo, oxo, -CN, -OR O1 ,–NR N1 R N2 、C 1-6 Alkyl, C 1-4 haloalkyl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 7-membered monocyclic heterocyclyl;

[0056] Each R 7 Independently C 1-6 alkyl, phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered monocyclic carbocyclic group or 4- to 7-membered monocyclic heterocyclic group; wherein R 7 The C 1-6 Alkyl, phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 7-membered monocyclic heterocyclyl are each optionally substituted with one or more substituents independently selected from the group consisting of halo, oxo, -CN, -OR O1 ,–NR N3 R N4 、C 1-6 Alkyl, C 1-4 haloalkyl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 7-membered monocyclic heterocyclyl;

[0057] Each R 8 are 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 carbocyclyl, or 4- to 7-membered monocyclic heterocyclyl;

[0058] Each R O1 Independently H, C 1-6 alkyl, phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered monocyclic carbocyclic group or 4- to 7-membered monocyclic or bicyclic heterocyclic group, wherein R O1 The C 1-6 Alkyl, phenyl, 5 to 6 membered heteroaryl, 3 to 7 membered monocyclic carbocyclyl and 4 to 7 membered monocyclic or bicyclic heterocyclyl are each optionally substituted by one or more R O2 replace;

[0059] Each R O2 are independently halo, OH, -CN, C 1-4 Alkoxy, C 1-4 haloalkyl, phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered monocyclic carbocyclyl, or 4- to 7-membered monocyclic heterocyclyl;

[0060] Each R O3 Independently H, C 1-6 Alkyl, C 1-4 haloalkyl, phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered monocyclic carbocyclic group or 4- to 7-membered monocyclic heterocyclic group, wherein R O3 The C 1-6 Alkyl, phenyl, 5 to 6 membered heteroaryl, 3 to 7 membered monocyclic carbocyclyl and 4 to 7 membered monocyclic heterocyclyl are each optionally substituted by one or more RO2 replace;

[0061] R O4 H, C 1-6 alkyl, phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered monocyclic carbocyclic group or 4- to 7-membered monocyclic heterocyclic group, wherein R O4 The C 1-6 Alkyl, phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 7-membered monocyclic heterocyclyl are each optionally substituted with one or more substituents independently selected from the group consisting of 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 carbocyclyl, and 4- to 7-membered monocyclic heterocyclyl;

[0062] R N1 and R N2 Each independently is H or C 1-6 Alkyl, wherein R N1 and R N2 The C 1-6 Each alkyl group is optionally substituted with a halo group, a C 1-4 Alkoxy or –NR N3 R N4 Replace, or

[0063] R N1 H or C 1-3 Alkyl and R N2 Ring D or –C 1-3 Alkylene-ring D;

[0064] Ring D is a 3- to 7-membered monocyclic or bicyclic carbocyclyl or a 4- to 7-membered monocyclic heterocyclyl, wherein the 3- to 7-membered monocyclic carbocyclyl and the 4- to 7-membered monocyclic heterocyclyl represented by ring D are each optionally substituted with one or two substituents independently selected from the group consisting of halo, C 1-6 Alkyl and C 1-4 alkoxy;

[0065] Each R N3 are independently H or C 1-6 alkyl; and

[0066] Each R N4 are independently H or C 1-6 alkyl.

[0067] In a second embodiment, for a compound of formula (I) or a pharmaceutically acceptable salt thereof, R 1A is H or -CH3; and the remaining variables are as described in the first aspect or first embodiment.

[0068] In a third embodiment, for a compound of Formula (I) or a pharmaceutically acceptable salt thereof, each R 3 are independently H or -CH3; and the remaining variables are as described in the first aspect or the first or second embodiment.

[0069] In a fourth embodiment, for the compound of formula (I) or a pharmaceutically acceptable salt thereof, both R 3 Together with the atoms to which it is attached, it forms C 3-6 Cycloalkyl or 5- to 6-membered monocyclic heterocyclic group, each of which is optionally substituted by one to three R 5 and the remaining variables are as described in the first aspect or the first or second embodiment.

[0070] In a fifth embodiment, for the compound of formula (I) or a pharmaceutically acceptable salt thereof, both R 3 Together with the atoms to which they are attached, they form cyclopropane, cyclobutane, cyclopentane, tetrahydropyran or piperidine, each of which is optionally substituted with one to three R 5 and the remaining variables are as described in the first aspect or the first, second or fourth embodiment.

[0071] In a sixth embodiment, for the compound of formula (I) or a pharmaceutically acceptable salt thereof, both R 3 Together with the atoms to which they are attached, they form:

[0072]

[0073] where m is 0, 1, 2, or 3, and represents a bond within Ring B; and the remaining variables are as described in the first aspect or the first, second or fourth embodiment.

[0074] In a seventh embodiment, the compounds of the present disclosure are represented by formula (III), (IV), (V), (VI), (VII), (VIII), or (IX):

[0075]

[0076]

[0077] or a pharmaceutically acceptable salt thereof, wherein the variables in Formula (III), (IV), (V), (VI), (VII), (VIII) or (IX) are as defined above in the first embodiment.

[0078] In an eighteenth embodiment, for a compound of Formula (I), (III), (IV), (V), (VI), (VII), (VIII), or (IX), or a pharmaceutically acceptable salt thereof, each R 5 is independently H, -CN or CH3; and the remaining variables are as described in the first aspect or the first, second, fourth, fifth, sixth or seventh embodiment.

[0079] In a ninth embodiment, for compounds of Formula (I), (III), (IV), (V), (VI), (VII), (VIII), or (IX), or pharmaceutically acceptable salts thereof, Ring C is optionally substituted with one to three R C substituted 5- to 9-membered monocyclic or bicyclic heteroaryl; and the remainder of the variables are as described in the first aspect or the first, second, third, fourth, fifth, sixth, seventh or eighth embodiment.

[0080] In a tenth embodiment, for compounds of Formula (I), (III), (IV), (V), (VI), (VII), (VIII), or (IX), or pharmaceutically acceptable salts thereof, Ring C is pyrazine, pyrazolo[1,5-a]pyrimidine, pyridine, pyrimidine, pyrimidinone, or thiazole, each of which is optionally substituted with one or three R C and the remaining variables are as described in the first aspect or the first, second, third, fourth, fifth, sixth, seventh, eighth or ninth embodiment.

[0081] 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 selected from

[0082]

[0083] And among them represents a bond to Ring B, and n is 0, 1, 2 or 3; and the remaining variables are as described in the first aspect or the first, second, third, fourth, fifth, sixth, seventh, eighth or ninth embodiment.

[0084] In a twelfth embodiment, for a compound of Formula (I), (III), (IV), (V), (VI), (VII), (VIII), or (IX), or a pharmaceutically acceptable salt thereof, Ring C is selected from:

[0085] And among them represents a bond to ring B, and one to three R in ring C CThe groups may be the same or different; and the remaining variables are as described in the first aspect, or the first, second, third, fourth, fifth, sixth, seventh, eighth, or ninth embodiment.

[0086] In a thirteenth embodiment, for a compound of Formula (I), (III), (IV), (V), (VI), (VII), (VIII), or (IX), or a pharmaceutically acceptable salt thereof, each R C are 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, 4 to 9 membered monocyclic or bicyclic heterocyclic group, phenyl or 5 to 6 membered heteroaryl, wherein R C C 1-3 Alkyl, C 3-6 Cycloalkyl, 4 to 9 membered monocyclic or bicyclic heterocyclyl, phenyl and 5 to 6 membered heteroaryl are each optionally substituted by one to three R C1 replace;

[0087] R 7 C 1-3 alkyl;

[0088] R O1 H, C 1-4 Alkyl, C 1-4 Alkyl, C 3-6 Cycloalkyl, 4- to 6-membered monocyclic heterocyclic group, 5- to 6-membered heteroaryl, wherein R O1 C 1-4 Alkyl is optionally substituted with one to three substituents independently selected from the group consisting of halo, CN, C 1-3 Alkoxy, C 3-6 Cycloalkyl, 4 to 6 membered monocyclic heterocyclic group, and wherein R O1 C 3-6 Cycloalkyl, 4- to 6-membered monocyclic heterocyclyl, and 5- to 6-membered heteroaryl are each optionally substituted with one to two substituents independently selected from the group consisting of halo, C 1-3 Alkyl, CN, OH and C 1-3 alkoxy;

[0089] R N1 H or C 1-3 Alkyl and R N2 Ring D or –C 1-3 Alkylene-ring D;

[0090] Ring D is a 3- to 7-membered monocyclic or bicyclic carbocyclyl or a 4- to 7-membered monocyclic heterocyclyl, wherein the 3- to 7-membered monocyclic carbocyclyl and the 4- to 7-membered monocyclic heterocyclyl represented by ring D are each optionally substituted with one or two substituents independently selected from the group consisting of halo, C 1-6 Alkyl and –C 1-4 Alkoxy; R N1 and R N2 Each independently is H or C 1-4 Alkyl, wherein R N1 and R N2 The C 1-4 Each alkyl group is optionally substituted with a halo group, a C 1-3 Alkoxy or –NR N3 R N4 Replace, or

[0091] R N1 H or C 1-2 Alkyl and R N2 Ring D or –C 1-2 Alkylene-ring D;

[0092] Ring D is a 3- to 6-membered monocyclic or bicyclic carbocyclyl or a 4- to 6-membered monocyclic heterocyclyl, wherein the 3- to 6-membered monocyclic carbocyclyl and the 4- to 6-membered monocyclic heterocyclyl represented by ring D are each optionally substituted with one or two substituents independently selected from the group consisting of halo, C 1-3 Alkyl and C 1-3 alkoxy;

[0093] Each R N3 are independently H or C 1-3 alkyl;

[0094] Each R N4 are independently H or C 1-3 alkyl; and the remainder of the variables are as described in the first aspect or the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh or twelfth embodiment.

[0095] Alternatively, as part of a thirteenth embodiment, for a compound of Formula (I), (III), (IV), (V), (VI), (VII), (VIII), or (IX), or a pharmaceutically acceptable salt thereof, each R C are 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, 4 to 9 membered monocyclic or bicyclic heterocyclic group, phenyl or 5 to 6 membered heteroaryl, wherein R C The C 1-6 Alkyl, C 2-4 Alkenyl, C 3-6 Cycloalkyl, 4 to 9 membered monocyclic or bicyclic heterocyclyl, phenyl and 5 to 6 membered heteroaryl are each optionally substituted by one to three R C1 replace;

[0096] R 7 C 1-3 alkyl;

[0097] R O1 H, C 1-4 Alkyl, C 1-4 Alkyl, C 3-6 Cycloalkyl, 4 to 8-membered monocyclic or bicyclic heterocyclic group, 5 to 6-membered heteroaryl, wherein R O1 C 1-4 The alkyl group is optionally substituted with one to three substituents independently selected from the group consisting of halo, OH, CN, C 1-3 Alkoxy, C 3-6 Cycloalkyl and optionally C 1-3 Alkyl or C 1-3 4 to 6 membered monocyclic heterocyclic group substituted by alkoxy, wherein R O1 C 3-6 Cycloalkyl, 4 to 8 membered monocyclic or bicyclic heterocyclyl and 5 to 6 membered heteroaryl are each optionally substituted with one to two substituents independently selected from the group consisting of halo, C 1-3 Alkyl, C 1-3 Alkyl-C 1-3 Alkoxy, CN, OH and C 1-3 alkoxy;

[0098] R N1 and R N2 Each independently is H or C 1-6 Alkyl, wherein R N1 and R N2 The C 1-6 Each alkyl group is optionally substituted with a halo group, a C 1-4 Alkoxy or –NR N3 R N4 Replace, or

[0099] R N1 H or C 1-3 Alkyl and R N2Ring D or –C 1-3 Alkylene-ring D;

[0100] Ring D is a 3- to 7-membered monocyclic or bicyclic carbocyclyl or a 4- to 7-membered monocyclic heterocyclyl, wherein the 3- to 7-membered monocyclic carbocyclyl and the 4- to 7-membered monocyclic heterocyclyl represented by ring D are each optionally substituted with one or two substituents independently selected from the group consisting of halo, C 1-6 Alkyl and –C 1-4 Alkoxy; R N1 and R N2 Each independently is H or C 1-4 Alkyl, wherein R N1 and R N2 The C 1-4 Each alkyl group is optionally substituted with a halo group, a C 1-3 Alkoxy or –NR N3 R N4 Replace, or

[0101] Each R N3 are independently H or C 1-3 alkyl; and

[0102] Each R N4 are independently H or C 1-3 alkyl; and the remainder of the variables are as described in the first aspect or the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh or twelfth embodiment.

[0103] In a fourteenth embodiment, for 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 remainder of the variables are as described in the first aspect or the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth or thirteenth embodiment.

[0104] In a fifteenth embodiment, for a compound of Formula (I), (III), (IV), (V), (VI), (VII), (VIII), or (IX), or a pharmaceutically acceptable salt thereof, Ring D is each of which is optionally substituted with one or two substituents independently selected from: F, -CH3, and -OCH3; and the remainder of the variables are as described in the first aspect or the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, or fourteenth embodiment.

[0105] In a sixteenth embodiment, for a compound of Formula (I), (III), (IV), (V), (VI), (VII), (VIII) or (IX), or a pharmaceutically acceptable salt thereof, R O1 The 4 to 6 membered monocyclic heterocyclic group represented by R O1 C 1-4 The alkyl substituent is oxetane, azetidine or tetrahydrofuran, each of which is optionally substituted with one to two substituents independently selected from the group consisting of: C 1-3 Alkyl, halo, CN, OH or C 1-3 Alkoxy; and R O1 The 5- to 6-membered heteroaryl represented by is pyrazole, triazole, pyridine, pyrazine, pyrimidine or pyridazine, each of which is optionally substituted with one to two substituents independently selected from the following: C 1-3 Alkyl, halo, CN, OH or C 1-3 and the remaining variables are as described in the first aspect or the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth or thirteenth embodiment. Alternatively, as part of a sixteenth embodiment, for a compound of Formula (I), (III), (IV), (V), (VI), (VII), (VIII) or (IX), or a pharmaceutically acceptable salt thereof, R O1 The 4 to 8 membered monocyclic or bicyclic heterocyclic group represented by R O1 C 1-4 The substituent of the alkyl group is oxetane, azetidine, pyrrolidine, 2-oxaspiro[3.3]heptyl or tetrahydrofuran, each of which is optionally substituted with one to two substituents independently selected from the group consisting of: C 1-3 Alkyl, halo, CN, OH, C 1-3 Alkyl-C 1-3 Alkoxy or C 1-3 Alkoxy; and R O1 The 5- to 6-membered heteroaryl represented by is pyrazole, triazole, pyridine, pyrazine, pyrimidine or pyridazine, each of which is optionally substituted with one to two substituents independently selected from the following: C 1-3 Alkyl, halo, CN, OH or C 1-3alkoxy; and the remaining variables are as described in the first aspect or the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth or thirteenth embodiment.

[0106] In a seventeenth embodiment, for the compound 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 each of which is optionally substituted with one or two substituents independently selected from the group consisting of F, -CN, -CH3, -CH2CH3, OH, and -OCH3;

[0107] The 5- to 6-membered heteroaryl group is:

[0108] each of which is optionally substituted with one or two substituents independently selected from F, -CN, -CH3, -CH2CH3, OH, and -OCH3; and the remainder of the variables are as described in the first aspect or the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, or sixteenth embodiment.

[0109] Alternatively, as part of a seventeenth embodiment, for compounds of Formula (I), (III), (IV), (V), (VI), (VII), (VIII) or (IX), or pharmaceutically acceptable salts thereof, the 4- to 6-membered monocyclic heterocyclyl is:

[0110] each of which is optionally substituted with one or two substituents independently selected from the group consisting of F, -CN, -CH3, -CH2CH3, OH, -CH2OCH3, and -OCH3; and

[0111] The 5- to 6-membered heteroaryl group is:

[0112] each of which is optionally substituted with one or two substituents independently selected from F, -CN, -CH3, -CH2CH3, OH, and -OCH3; and the remaining variables are as described in the first aspect or the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, or sixteenth embodiment.

[0113] In an eighteenth embodiment, for a compound of Formula (I), (III), (IV), (V), (VI), (VII), (VIII), or (IX), or a pharmaceutically acceptable salt thereof, each R cIndependently selected from F, -CH3, -CHF2, -CF3, -CH2CH3, -CH2CH2CH3, -CH2CH2CH2CH3, -CF2CH3, -CF2CFH2, -C FHCFH2, -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, -OCH2CH2OCH 3. -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, -NH CH(CH3)2, -N(CH3)2, -N(CH3)CH(CH3)2, -NHCH2CH2CH2F, -NHCH2CHF2, -NHCH2C(F)CH3, -N HCH2CH2OCH3, -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, and the remaining variables are as described in the first aspect or the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth or thirteenth embodiment. Alternatively, as part of an eighteenth embodiment, for a compound of Formula (I), (III), (IV), (V), (VI), (VII), (VIII) or (IX), or a pharmaceutically acceptable salt thereof, each R CIndependently selected from F, -Cl, -CH3, -CHF2, -CF3, -CH2CH3, -CH2CH2CH3, -CH2CH2CH2CH3, -CH2CH2CH2CH2CH3, -CF2CH3, -CF2CFH2, -CFHCFH2, -CF2CH2CH3, -CF2CH2OH, -CF2CH2OCH3, -CH(CH3)2, -CF(CH3)2, -C(CH3)3, -CF2C(O)OCH2CH3, -CH2OH, -CH(OH)CH3, -CH2OCH3, -CH2CH2CH2OH, -CH2CH2OCH2CH3, -CH2CH2CH2OCH3, -CH2CH2C(CH3)(OH)CH2CH3, -CH2CH2CH2OC(CH3)3, -CH2CH2C(CH3)2OH, -CH(CH3)OCH3, -C(CH3)2OCH3, -CH2OCH2CH3, -CH2-cyclopropyl, -CH(CH3)-SO2CH3, -CH2CH2-SO2CH3, -CH2NHCH3, -CH2CN, -CH(CH3)CN, -CH=CH-OCH2CH3, OH, -OCH3, -OCH2CH3, -OCH(CH3)2, -OCH2CF3, -OCH2CF2CH3, -OCH2CH2OCH3, -OCH2CH2F, -OCH2CH2CH2OCH3, -OCH2CH2N(CH3)2, -OCH(CH3)CH2OCH3, -OCH(CH3)CN, -OCH2C(CH3)2OH, -OCH2C(CH3)2OCH3, -OCH(cyclopropyl)(CN), -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -C(O)H, -C(O)CH3, -C(O)OH, -C(O)OCH2CH3, -NH2, -NHCH3, -NHCH2CH3, -NHCH2CH2CH3, -NHCH(CH3)2, -N(CH3)2, -N(CH3)CH(CH3)2, -NHCH2CH2CH2F, -NHCH2CHF2, -NHCH2C(F)CH3, -NHCH2CH2OCH3, -NHCH(CH3)CH2OCH3, -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,

[0114] and the remaining variables are as described in the first aspect or the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth or thirteenth embodiment.

[0115] In a nineteenth embodiment, for a compound of Formula (I), (III), (IV), (V), (VI), (VII), (VIII) or (IX), or a pharmaceutically acceptable salt thereof, R C Each C 3-6 Cycloalkyl is selected from cyclobutane, cyclopentane and cyclopropane;

[0116] By R C Each 4- to 9-membered monocyclic or bicyclic heterocyclic group 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;

[0117] By R C Each of the 5- to 6-membered heteroaryl groups represented by is independently selected from oxazole, pyrazole, pyridine, pyrimidine and thiazole;

[0118] Among them C 3-6 Each of the cycloalkyl, 4- to 9-membered monocyclic or bicyclic heterocyclyl, and 5- to 6-membered heteroaryl is optionally substituted by one to three R C1 and the remaining variables are as described in the first aspect or the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth or thirteenth embodiment.

[0119] Alternatively, as part of a nineteenth embodiment, for a compound of Formula (I), (III), (IV), (V), (VI), (VII), (VIII) or (IX), or a pharmaceutically acceptable salt thereof, R C Each C 3-6 Cycloalkyl is selected from cyclobutane, cyclopentane and cyclopropane;

[0120] By R C Each 4- to 9-membered monocyclic or bicyclic heterocyclic group 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; and

[0121] By R C Each of the 5- to 6-membered heteroaryl groups represented by is independently selected from oxazole, pyrazole, pyridine, pyrimidine, triazole, and thiazole;

[0122] And wherein said C 3-6 Each of the cycloalkyl, 4- to 9-membered monocyclic or bicyclic heterocyclyl, and 5- to 6-membered heteroaryl is optionally substituted by one to three R C1 and the remaining variables are as described in the first aspect or the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth or thirteenth embodiment.

[0123] In a twentieth embodiment, for a compound of Formula (I), (III), (IV), (V), (VI), (VII), (VIII) or (IX), or a pharmaceutically acceptable salt thereof, R C C 3-6 Each of the cycloalkyl groups is independently selected from

[0124] By R C Each of the 4 to 9 membered monocyclic heterocyclic groups represented by is independently selected from

[0125]

[0126] By R C Each of the phenyl groups represented by

[0127] By R C Each of the 5- to 6-membered heteroaryl groups represented by is independently selected from in represents a bond to Ring C, and n is 0, 1, 2, or 3, as valence permits; and the remaining variables are as described in the first aspect or the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, or thirteenth embodiment.

[0128] Alternatively, as part of the twentieth embodiment, for a compound of Formula (I), (III), (IV), (V), (VI), (VII), (VIII) or (IX), or a pharmaceutically acceptable salt thereof, R C C 3-6 Each of the cycloalkyl groups is independently selected from

[0129]

[0130] By R CEach of the 4 to 9 membered monocyclic heterocyclic groups represented by is independently selected from

[0131]

[0132] By R C Each of the phenyl groups represented by and

[0133] By R C Each of the 5- to 6-membered heteroaryl groups represented by is independently selected from And among them represents a bond to Ring C, and n is 0, 1, 2, or 3, as valence permits; and the remaining variables are as described in the first aspect or the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, or thirteenth embodiment.

[0134] In a twenty-first embodiment, for a compound of Formula (I), (III), (IV), (V), (VI), (VII), (VIII) or (IX), or a pharmaceutically acceptable salt thereof, R C C 3-6 Each of the cycloalkyl groups is independently selected from:

[0135]

[0136] By R C Each of the 4 to 6-membered monocyclic heterocyclic groups represented by is independently selected from:

[0137]

[0138] and

[0139] By R C Each of the phenyl groups represented by

[0140] By R C Each of the 5- to 6-membered heteroaryl groups represented by is independently selected from

[0141]

[0142] in represents a bond to Ring C; and the remaining variables are as described in the first aspect or the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth or thirteenth embodiment.

[0143] Alternatively, as part of the twenty-first embodiment, for a compound of Formula (I), (III), (IV), (V), (VI), (VII), (VIII) or (IX), or a pharmaceutically acceptable salt thereof, R C C 3-6 Each of the cycloalkyl groups is independently selected from:

[0144]

[0145] By R C Each of the 4 to 6-membered monocyclic heterocyclic groups represented by is independently selected from:

[0146]

[0147]

[0148] and

[0149] By R C Each of the phenyl groups represented by

[0150]

[0151] By R C Each of the 5- to 6-membered heteroaryl groups represented by is independently selected from

[0152] in represents a bond to Ring C; and the remaining variables are as described in the first aspect or the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth or thirteenth embodiment.

[0153] In a twenty-second embodiment, for a compound of Formula (I), (III), (IV), (V), (VI), (VII), (VIII) or (IX), or a pharmaceutically acceptable salt thereof, each R C1 independently selected from halo, OH, –NR N3 R N4 ,–CN,–C(O)-R 7 、–SO2-R 7 、C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 3-6 Cycloalkyl, 4 to 6 membered monocyclic heterocyclic group and C 1-4 Alkyl, wherein R C1 The C 1-4Alkyl is optionally substituted with one to three independently selected C 3-5 Cycloalkyl, C 1-3 Alkoxy, OH and halo substituents, and R C1 C 1-3 Alkoxy is optionally substituted by one to three independently selected 1-3 and the remaining variables 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 compound of Formula (I), (III), (IV), (V), (VI), (VII), (VIII) or (IX), or a pharmaceutically acceptable salt thereof, each R C1 independently selected from halo, OH, –NR N3 R N4 ,–CN,–C(O)-R 7 、–SO2-R 7 、C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 3-6 Cycloalkyl, 4 to 6 membered monocyclic heterocyclic group and C 1-4 Alkyl, wherein R C1 The C 1-4 Alkyl is optionally substituted with one to three independently selected C 3-5 Cycloalkyl, 4 to 8 membered monocyclic heterocyclic group, C 1-3 Alkoxy, OH, CN, -NR N3 R N4 and substituted by a halo substituent, and R C1 The C 1-3 Alkoxy is optionally substituted by one to three independently selected 1-3 and the remaining variables 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.

[0154] In a twenty-third embodiment, for a compound of Formula (I), (III), (IV), (V), (VI), (VII), (VIII) or (IX), or a pharmaceutically acceptable salt thereof, each R C1independently 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、- C H2CH2OH, -CH2CH2OCH3, -CH2-cyclopropyl, -CH2F, -CHF2, -CF3, cyclobutyl, cyclopropyl, and the remaining variables 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 or twenty-second embodiment. Alternatively, as part of the twenty-third embodiment, for a compound of Formula (I), (III), (IV), (V), (VI), (VII), (VIII) or (IX), or a pharmaceutically acceptable salt thereof, each R C1 independently selected 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, and the remaining variables 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 or twenty-second embodiment.

[0155] In a 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 optionally substituted by one to three independently selected R 8 Substituted C 1-4 Alkyl: halo, -CN, C 1-3 Alkoxy, C 1-3 Alkyl and C 1-3and the remaining variables 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 optionally substituted by one to three independently selected R 8 Substituted C 1-4 Alkyl: halo, -CN, -NR 2 R 4 、C 1-3 Alkoxy, C 1-3 Alkyl and C 1-3 haloalkyl, and R 2 and R 4 Each independently is H or C 1-3 and the remaining variables 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.

[0156] In a twenty-fifth embodiment, for a compound 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 variables 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 a compound 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 variables 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.

[0157] In a twenty-sixth embodiment, for a compound of Formula (I), (III), (IV), (V), (VI), (VII), (VIII), or (IX), or a pharmaceutically acceptable salt thereof, each R O1 Independently H, C 1-3 Alkyl or C 3-6 Cycloalkyl, wherein R O1 The C 1-3 Alkyl and C 3-6 The cycloalkyl group is optionally C 1-3 and the remainder of the variables 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, twenty-third, twenty-fourth or twenty-fifth embodiment.

[0158] In a twenty-seventh embodiment, for a compound of Formula (I), (III), (IV), (V), (VI), (VII), (VIII), or (IX), or a pharmaceutically acceptable salt thereof, each R O1 are independently H, -CH3, -CH2-CH2-OCH3, and the remaining variables 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, twenty-third, twenty-fourth, twenty-fifth or twenty-sixth embodiment.

[0159] In a twenty-eighth embodiment, for a 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 or optionally C 1-3 Alkoxy-substituted C 1-3 and the remaining variables 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, twenty-third, twenty-fourth, twenty-fifth, twenty-sixth or twenty-seventh embodiment.

[0160] In a twenty-ninth embodiment, for a 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 variables 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, twenty-third, twenty-fourth, twenty-fifth, twenty-sixth, twenty-seventh or twenty-eighth embodiment.

[0161] In a thirtieth embodiment, the compounds of the present disclosure are represented by formula (X) or (XI):

[0162]

[0163] or a pharmaceutically acceptable salt thereof, wherein:

[0164] n is 1, 2, or 3;

[0165] Each R C Independently –NR N1 R N2 、–OR O1 or C 1-6 Alkyl, 4 to 6 membered monocyclic heterocyclic group, wherein R C The C 1-6 The alkyl group and the 4 to 6 membered monocyclic heterocyclic group are each optionally substituted by one to three R C1 replace;

[0166] Each R C1 are independently halo;

[0167] R 1 C 1-3 alkyl;

[0168] R O1 Optionally, R O2 Substituted C 3-4 Cycloalkyl;

[0169] R O2 C 1-3 alkoxy; and

[0170] R N1 and R N2 are each independently H or optionally C 1-3 Alkoxy-substituted C 1-3 alkyl.

[0171] In a thirty-first embodiment, the compound of the present disclosure is represented by Formula (XA), (XIA), (XIB), (XIC), or (XID):

[0172]

[0173]

[0174] or a pharmaceutically acceptable salt thereof, wherein the variables in Formula (III), (IV), (V), (VI), (VII), (VIII) or (IX) are as defined above in the thirtieth embodiment.

[0175] In a thirty-second embodiment, for a compound of Formula (X), (XI), (XA), (XIA), (XIB), (XIC), or (XID), or a pharmaceutically acceptable salt thereof, each R C are independently -NHCH3, -NHCH2CH2OCH3, -CH3, -CH2CH3, -CH(CH3)2, -CF2CH3, -CF(CH3)2, R 1 is CH3; and the remaining variables are as described in the thirtieth or thirty-first embodiment.

[0176] In a thirty-third embodiment, for a compound of Formula (X), (XI), (XA), (XIA), (XIB), (XIC), or (XID), or a pharmaceutically acceptable salt thereof, R C is a 4- to 6-membered monocyclic heterocyclic group independently selected from tetrahydrofuran and tetrahydropyran, each of which is optionally substituted by one to three R C1 and the remaining variables are as described in the thirtieth or thirty-first embodiment.

[0177] In a thirty-fourth embodiment, for a compound of Formula (X), (XI), (XA), (XIA), (XIB), (XIC), or (XID), or a pharmaceutically acceptable salt thereof, R C Independently selected from in represents a bond to Ring C; and the remaining variables are as described in the thirtieth or thirty-first embodiment.

[0178] In a thirty-fifth embodiment, for a compound of Formula (X), (XI), (XA), (XIA), (XIB), (XIC), or (XID), or a pharmaceutically acceptable salt thereof, R C Independently selected from in represents a bond to Ring C; and the remaining variables are as described in the thirtieth or thirty-first embodiment.

[0179] In a thirty-sixth embodiment, 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 variables are as described in the thirtieth, thirty-first, thirty-second, thirty-third or thirty-fourth embodiment.

[0180] In another embodiment, the compounds of the present disclosure are represented by formula (XII):

[0181]

[0182] or a pharmaceutically acceptable salt thereof, wherein:

[0183] Each R C Independently C 1-3 Alkyl, C 1-3 Haloalkyl or –NR N1 R N2 ;

[0184] R N1 and R N2 Each independently is H or C 1-3 alkyl; and the remaining variables are as described above in the first aspect or first embodiment.

[0185] In some embodiments, for compounds of Formula (XII), each R C is independently -CH3, -CH2CH3, -CF2CH3 or -NHCH3; and the remaining variables are as described above for compounds of Formula (XII).

[0186] In a thirty-seventh embodiment, the disclosure provides a compound described herein (e.g., a compound of any one of Examples 1 to 411), or a pharmaceutically acceptable salt thereof.

[0187] In a thirty-eighth embodiment, the present disclosure provides a compound selected from the group consisting of:

[0188] N-(1'-(2-(1,1-difluoroethyl)-6-methoxypyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-6'-yl)acetamide;

[0189] N-(1'-(4-(1,1-difluoroethyl)-6-methoxypyrimidin-2-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-6'-yl)acetamide;

[0190] N-(1'-(2-(oxetan-3-yl)pyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-6'-yl)acetamide;

[0191] 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;

[0192] N-(1'-(2-(1,1-difluoroethyl)-6-(3-methoxycyclobutyloxy)pyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin-6'-yl)acetamide;

[0193] N-(1'-(6-cyclopropyloxy-2-(1,1-difluoroethyl)pyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin-6'-yl)acetamide;

[0194] N-(1'-(6-(1,1-difluoroethyl)-5-fluoropyridin-2-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin-6'-yl)acetamide;

[0195] N-(1'-(6-(1,1-difluoroethyl)-5-methoxypyridin-2-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin-6'-yl)acetamide;

[0196] N-(1'-(6-(1,1-difluoroethyl)-4-methoxypyridin-2-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin-6'-yl)acetamide;

[0197] N-(1'-(2-(1,1-difluoroethyl)-6-(methylamino)pyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin-6'-yl)acetamide;

[0198] N-(1'-(2-(1,1-difluoroethyl)-6-ethylpyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin-6'-yl)acetamide;

[0199] N-(1'-(6-(1,1-difluoroethyl)pyridin-2-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin]-6'-yl)acetamide;

[0200] N-(1'-(2-(1,1-difluoroethyl)pyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin-6'-yl)acetamide;

[0201] N-(1'-(4-(1,1-difluoroethyl)pyrimidin-2-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin-6'-yl)acetamide;

[0202] N-(1′-(6-acetamido-2-(1,1-difluoroethyl)pyrimidin-4-yl)-1′,2′-dihydrospiro[cyclopropane-1,3′-pyrrolo[3,2-c]pyridin-6′-yl)acetamide;

[0203] N-(1'-(6-(tetrahydrofuran-3-yl)pyridin-2-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin-6'-yl)acetamide;

[0204] N-(1'-(2-(2-fluoropropan-2-yl)pyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-6'-yl)acetamide;

[0205] N-(1'-(6-(3-methoxytetrahydrofuran-3-yl)pyridin-2-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin-6'-yl)acetamide;

[0206] N-(1'-(6-(3-hydroxytetrahydrofuran-3-yl)pyridin-2-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin-6'-yl)acetamide;

[0207] N-(1'-(2-(1,1-difluoroethyl)-6-(dimethylamino)pyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin-6'-yl)acetamide;

[0208] N-(1'-(6-cyclopropyl-2-(1,1-difluoroethyl)pyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin-6'-yl)acetamide;

[0209] 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;

[0210] N-(1'-(2-(1,1-difluoroethyl)-6-(3-methoxycyclobutyl)pyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin-6'-yl)acetamide;

[0211] N-(1'-(6-cyclobutyl-2-(1,1-difluoroethyl)pyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin-6'-yl)acetamide;

[0212] 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;

[0213] 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;

[0214] N-(1'-(6-methylpyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin-6'-yl)acetamide;

[0215] N-(1'-(2,5-dimethylpyrazolo[1,5-a]pyrimidin-7-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin-6'-yl)acetamide;

[0216] N-(1'-(6-methyl-2-(methylthio)pyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-6'-yl)acetamide;

[0217] N-(1-(2-(1,1-difluoroethyl)pyrimidin-4-yl)-2,3-dihydro-1H-pyrrolo[3,2-c]pyridin-6-yl)acetamide;

[0218] N-(1-(4-(1,1-difluoroethyl)pyrimidin-2-yl)-2,3-dihydro-1H-pyrrolo[3,2-c]pyridin-6-yl)acetamide;

[0219] N-(1-(6-(1,1-difluoroethyl)pyridin-2-yl)-2,3-dihydro-1H-pyrrolo[3,2-c]pyridin-6-yl)acetamide;

[0220] N-(1-(6-(tetrahydrofuran-3-yl)pyridin-2-yl)-2,3-dihydro-1H-pyrrolo[3,2-c]pyridin-6-yl)acetamide;

[0221] N-(1-(2-(1,1-difluoroethyl)-6-methoxypyrimidin-4-yl)-2,3-dihydro-1H-pyrrolo[3,2-c]pyridin-6-yl)acetamide;

[0222] N-(1-(2-(1,1-difluoroethyl)-6-(methylamino)pyrimidin-4-yl)-2,3-dihydro-1H-pyrrolo[3,2-c]pyridin-6-yl)acetamide;

[0223] N-(1'-(4-(1,1-difluoroethyl)pyrimidin-2-yl)-2-methyl-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin-6'-yl)acetamide;

[0224] N-(1'-(2-(1,1-difluoroethyl)pyrimidin-4-yl)-2-methyl-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin-6'-yl)acetamide;

[0225] N-(1-(2-(1,1-difluoroethyl)pyrimidin-4-yl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-c]pyridin-6-yl)acetamide;

[0226] N-(1-(4-(1,1-difluoroethyl)pyrimidin-2-yl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-c]pyridin-6-yl)acetamide;

[0227] N-(1'-(4-(1,1-difluoroethyl)pyrimidin-2-yl)-1',2'-dihydrospiro[cyclobutane-1,3'-pyrrolo[3,2-c]pyridin-6'-yl)acetamide;

[0228] N-(1'-(2-(1,1-difluoroethyl)pyrimidin-4-yl)-1',2'-dihydrospiro[cyclobutane-1,3'-pyrrolo[3,2-c]pyridin-6'-yl)acetamide;

[0229] N-(1'-(6-(1,1-difluoroethyl)pyridin-2-yl)-1',2'-dihydrospiro[cyclobutane-1,3'-pyrrolo[3,2-c]pyridin-6'-yl)acetamide;

[0230] N-(1'-(4-(1,1-difluoroethyl)pyrimidin-2-yl)-1',2'-dihydrospiro[cyclopentane-1,3'-pyrrolo[3,2-c]pyridin-6'-yl)acetamide;

[0231] N-(1'-(2-(1,1-difluoroethyl)pyrimidin-4-yl)-1',2'-dihydrospiro[cyclopentane-1,3'-pyrrolo[3,2-c]pyridin-6'-yl)acetamide;

[0232] N-(1'-(6-(1,1-difluoroethyl)pyridin-2-yl)-1',2'-dihydrospiro[cyclopentane-1,3'-pyrrolo[3,2-c]pyridin]-6'-yl)acetamide;

[0233] N-(1'-(4-(1,1-difluoroethyl)pyrimidin-2-yl)-1',2,2',3,5,6-hexahydrospiro[pyran-4,3'-pyrrolo[3,2-c]pyridin-6'-yl)acetamide;

[0234] N-(1'-(2-(1,1-difluoroethyl)pyrimidin-4-yl)-1',2,2',3,5,6-hexahydrospiro[pyran-4,3'-pyrrolo[3,2-c]pyridin-6'-yl)acetamide;

[0235] N-(1'-(6-(1,1-difluoroethyl)pyridin-2-yl)-1',2,2',3,5,6-hexahydrospiro[pyran-4,3'-pyrrolo[3,2-c]pyridin]-6'-yl)acetamide;

[0236] 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;

[0237] 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;

[0238] 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;

[0239] N-(1'-(2-(1,1-difluoroethyl)-6-morpholinopyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-6'-yl)acetamide;

[0240] N-(1'-(2-(1,1-difluoroethyl)-6-isopropylpyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-6'-yl)acetamide;

[0241] N-(1'-(2-cyclopropyl-6-methylpyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin-6'-yl)acetamide;

[0242] N-(1'-(2-(tert-Butyl)-6-methylpyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-6'-yl)acetamide;

[0243] N-(1'-(2-methoxy-6-methylpyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin-6'-yl)acetamide;

[0244] N-(1'-(2-(methoxymethyl)-6-methylpyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-6'-yl)acetamide;

[0245] N-(1'-(2-butyl-6-methylpyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-6'-yl)acetamide;

[0246] N-(1'-(2-(ethoxymethyl)-6-methylpyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-6'-yl)acetamide;

[0247] N-(1'-(2-cyclobutyl-6-methylpyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-6'-yl)acetamide;

[0248] N-(1'-(6-methyl-2-(trifluoromethyl)pyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin-6'-yl)acetamide;

[0249] N-(1'-(2-(cyclopropylmethyl)-6-methylpyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-6'-yl)acetamide;

[0250] N-(1'-(2-(difluoromethyl)-6-methylpyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-6'-yl)acetamide;

[0251] N-(1'-(2-ethyl-6-methylpyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin-6'-yl)acetamide;

[0252] N-(1'-(6-methyl-2-propylpyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-6'-yl)acetamide;

[0253] N-(1'-(2-isopropyl-6-methylpyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin-6'-yl)acetamide;

[0254] N-(1'-(5-fluoro-2,6-dimethylpyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin-6'-yl)acetamide;

[0255] N-(1'-(2,6-dimethylpyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin-6'-yl)acetamide;

[0256] N-(1'-(6-methyl-2-(1-methylcyclopropyl)pyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-6'-yl)acetamide;

[0257] 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;

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

[0259] 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;

[0260] 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;

[0261] N-(1′-(6-(3-cyanocyclobutyl)-2-(1,1-difluoroethyl)pyrimidin-4-yl)-1′,2′-dihydrospiro[cyclopropane-1,3′-pyrrolo[3,2-c]pyridin-6′-yl)acetamide;

[0262] 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;

[0263] 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;

[0264] N-(1-(6-(1,1-difluoroethyl)pyridin-2-yl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-c]pyridin-6-yl)acetamide;

[0265] N-(1'-(thiazol-2-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridinyl]-6'-yl)acetamide;

[0266] N-(1'-(5-methylthiazol-2-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridinyl]-6'-yl)acetamide;

[0267] N-(1'-(4-(1,1-difluoroethyl)thiazol-2-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridinyl]-6'-yl)acetamide;

[0268] N-(1'-(4,5-dimethylthiazol-2-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridinyl]-6'-yl)acetamide;

[0269] N-(1'-(4-(tetrahydro-2H-pyran-3-yl)thiazol-2-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin-6'-yl)acetamide;

[0270] N-(1'-(5-methyl-4-(tetrahydrofuran-3-yl)thiazol-2-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridinyl]-6'-yl)acetamide;

[0271] N-(1'-(4-(1,1-difluoroethyl)-6-methylpyrimidin-2-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin-6'-yl)acetamide;

[0272] N-(1'-(6-(oxetan-3-yl)pyridin-2-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin-6'-yl)acetamide;

[0273] N-(1'-(6-(3-fluorooxetan-3-yl)pyridin-2-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin-6'-yl)acetamide;

[0274] N-(1'-(6-(1,1-difluoroethyl)-4-(2-methoxyethoxy)pyridin-2-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin]-6'-yl)acetamide;

[0275] N-(1'-(6-(3-methoxyoxetan-3-yl)pyridin-2-yl)-1',2',5',7a'-tetrahydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin-6'-yl)acetamide;

[0276] N-(1'-(2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin-6'-yl)acetamide;

[0277] N-(1'-(2-(1,1-difluoroethyl)pyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin-6'-yl)propanamide;

[0278] N-(1'-(6-(1,1-difluoroethyl)pyridin-2-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin-6'-yl)propanamide;

[0279] N-(1'-(2-(1,1-difluoroethyl)pyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-6'-yl)-3-methoxypropionamide;

[0280] N-(1'-(6-(1,1-difluoroethyl)-4-((1r,3r)-3-methoxycyclobutyloxy)pyridin-2-yl)-1',2',4',7'-tetrahydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin]-6'-yl)acetamide;

[0281] N-(1'-(6-(methylsulfonyl)pyridin-2-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin-6'-yl)acetamide;

[0282] N-(1'-(pyridin-2-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin]-6'-yl)acetamide;

[0283] N-(1'-(6-(3-hydroxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin]-6'-yl)acetamide;

[0284] N-(1'-(6-(3-methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin]-6'-yl)acetamide;

[0285] N-(1′-(6-methyl-2-(1-(methylsulfonyl)ethyl)pyrimidin-4-yl)-1′,2′-dihydrospiro[cyclopropane-1,3′-pyrrolo[3,2-c]pyridin-6′-yl)acetamide;

[0286] N-(1'-(2-(1,1-dioxoanionyltetrahydrothiophen-3-yl)-6-methylpyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-6'-yl)acetamide;

[0287] N-(1'-(4-(2-methoxyethoxy)pyrimidin-2-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin-6'-yl)acetamide;

[0288] 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;

[0289] N-(1'-(6-(1,1-difluoroethyl)pyrazin-2-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin-6'-yl)acetamide;

[0290] N-(1′-(2-(7-oxabicyclo[2.2.1]hept-2-yl)-6-methylpyrimidin-4-yl)-1′,2′-dihydrospiro[cyclopropane-1,3′-pyrrolo[3,2-c]pyridine]-6′-yl)acetamide;

[0291] 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;

[0292] N-(1'-(2-(1-methoxycyclobutyl)-6-methylpyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-6'-yl)acetamide;

[0293] N-(1'-(6-methyl-2-phenylpyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin-6'-yl)acetamide;

[0294] 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;

[0295] 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;

[0296] N-(1'-(6-methyl-[2,2'-bipyrimidinyl]-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridinyl]-6'-yl)acetamide;

[0297] 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;

[0298] 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;

[0299] N-(1'-(2-(3-fluorophenyl)-6-methylpyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin-6'-yl)acetamide;

[0300] 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;

[0301] 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;

[0302] 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;

[0303] N-(1'-(2-(Isopropyl(methyl)amino)-6-methylpyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin-6'-yl)acetamide;

[0304] N-(1'-(2-(dimethylamino)-6-methylpyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-6'-yl)acetamide;

[0305] 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;

[0306] 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;

[0307] 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;

[0308] 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;

[0309] 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;

[0310] 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;

[0311] N-(1'-(6-methyl-2-(2-methylcyclopropyl)pyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-6'-yl)acetamide;

[0312] N-(1'-(2-(2,2-dimethylcyclopropyl)-6-methylpyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-6'-yl)acetamide;

[0313] N-(1'-(2-(3,3-difluorocyclopentyl)-6-methylpyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-6'-yl)acetamide;

[0314] N-(1'-(2-(hydroxymethyl)-6-methylpyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-6'-yl)acetamide;

[0315] N-(1'-(2-(1,1-difluoroethyl)-5-fluoro-6-methylpyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin-6'-yl)acetamide;

[0316] N-(1'-(2-(1,1-difluoroethyl)-5-fluoropyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin]-6'-yl)acetamide;

[0317] 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;

[0318] N-(1'-(2-(1-methoxyethyl)-6-methylpyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-6'-yl)acetamide;

[0319] N-(1'-(2-(1-methoxyethyl)pyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin-6'-yl)acetamide;

[0320] N-(1'-(2-(2-methoxypropan-2-yl)pyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-6'-yl)acetamide;

[0321] N-(1'-(2-(1,1-difluoroethyl)-6-hydroxypyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin-6'-yl)acetamide;

[0322] 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;

[0323] N-(1'-(4-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin-6'-yl)acetamide;

[0324] N-(1'-(6-methyl-2-(methylsulfonyl)pyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin-6'-yl)acetamide;

[0325] 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;

[0326] N-(1'-(2-cyclobutoxy-6-methylpyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin-6'-yl)acetamide;

[0327] 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;

[0328] N-(1'-(2-(1,1-difluoroethyl)-6-(2-(dimethylamino)ethoxy)pyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin-6'-yl)acetamide;

[0329] 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;

[0330] 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;

[0331] 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]pyridin-6′-yl)acetamide;

[0332] N-(1'-(6-(1-cyanocyclopropyloxy)-2-(1,1-difluoroethyl)pyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin-6'-yl)acetamide;

[0333] 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]pyridin-6′-yl)acetamide;

[0334] N-(1'-(2-(1,1-difluoroethyl)-6-(pyrazin-2-yloxy)pyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin-6'-yl)acetamide;

[0335] 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;

[0336] 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;

[0337] 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;

[0338] 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;

[0339] N-(1'-(6-(1-cyanoethoxy)-2-(1,1-difluoroethyl)pyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin-6'-yl)acetamide;

[0340] N-(1′-(6-(Cyano(cyclopropyl)methoxy)-2-(1,1-difluoroethyl)pyrimidin-4-yl)-1′,2′-dihydrospiro[cyclopropane-1,3′-pyrrolo[3,2-c]pyridin-6′-yl)acetamide;

[0341] N-(1'-(2-(1,1-difluoroethyl)-6-(isopropylamino)pyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin-6'-yl)acetamide;

[0342] N-(1'-(6-((cyclopropylmethyl)amino)-2-(1,1-difluoroethyl)pyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin-6'-yl)acetamide;

[0343] 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;

[0344] 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;

[0345] N-(1'-(6-(cyclobutylamino)-2-(1,1-difluoroethyl)pyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin-6'-yl)acetamide;

[0346] 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;

[0347] 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]pyridin-6′-yl)acetamide;

[0348] 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;

[0349] 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;

[0350] 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;

[0351] 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;

[0352] 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;

[0353] 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;

[0354] N-(1'-(2-(1,1-difluoroethyl)-6-(thietan-3-ylamino)pyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin-6'-yl)acetamide;

[0355] N-(1'-(2-(1,1-difluoroethyl)-6-(ethylamino)pyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin-6'-yl)acetamide;

[0356] 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]pyridin-6′-yl)acetamide;

[0357] 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;

[0358] N-(1′-(2-(1,1-difluoroethyl)-6-((3-fluorobutyl)amino)pyrimidin-4-yl)-1′,2′-dihydrospiro[cyclopropane-1,3′-pyrrolo[3,2-c]pyridin-6′-yl)acetamide;

[0359] 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;

[0360] 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;

[0361] 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;

[0362] 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;

[0363] 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]pyridin-6'-yl)acetamide;

[0364] 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]pyridin-6′-yl)acetamide;

[0365] 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;

[0366] 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;

[0367] 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;

[0368] 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;

[0369] 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;

[0370] 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;

[0371] N-(1'-(6-(3-(difluoromethyl)-4-methylpiperazin-1-yl)-4-methylpyridin-2-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin]-6'-yl)acetamide;

[0372] N-(1'-(6-(3,3-difluoropyrrolidin-1-yl)-4-methylpyridin-2-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin]-6'-yl)acetamide;

[0373] N-(1'-(6-(3-(2-methoxyethoxy)pyrrolidin-1-yl)-4-methylpyridin-2-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin]-6'-yl)acetamide;

[0374] N-(1'-(6-(3-hydroxy-3-(trifluoromethyl)pyrrolidin-1-yl)-4-methylpyridin-2-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin]-6'-yl)acetamide;

[0375] N-(1'-(6-(3,4-dihydroxypyrrolidin-1-yl)-4-methylpyridin-2-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin]-6'-yl)acetamide;

[0376] 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;

[0377] N-(1'-(6-(3-hydroxypyrrolidin-1-yl)-4-methylpyridin-2-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin]-6'-yl)acetamide;

[0378] N-(1'-(6-(dimethylamino)-4-methylpyridin-2-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin-6'-yl)acetamide;

[0379] N-(1'-(6-((2-methoxyethyl)amino)-4-methylpyridin-2-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin]-6'-yl)acetamide;

[0380] N-(1'-(6-(3-(dimethylamino)pyrrolidin-1-yl)-4-methylpyridin-2-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin]-6'-yl)acetamide;

[0381] 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;

[0382] 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;

[0383] 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;

[0384] 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;

[0385] N-(1′-(6-(3-cyano-3-ethylazetidin-1-yl)-4-methylpyridin-2-yl)-1′,2′-dihydrospiro[cyclopropane-1,3′-pyrrolo[3,2-c]pyridin-6′-yl)acetamide;

[0386] 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;

[0387] 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;

[0388] 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;

[0389] 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;

[0390] 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;

[0391] N-(1'-(4-methyl-6-(3-(methylsulfonyl)azetidin-1-yl)pyridin-2-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin-6'-yl)acetamide;

[0392] N-(1′-(6-(3-(ethylsulfonyl)azetidin-1-yl)-4-methylpyridin-2-yl)-1′,2′-dihydrospiro[cyclopropane-1,3′-pyrrolo[3,2-c]pyridin]-6′-yl)acetamide;

[0393] 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;

[0394] N-(1'-(4-methyl-6-morpholinopyridin-2-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin-6'-yl)acetamide;

[0395] N-(1'-(4-methyl-6-(4-methylpiperazin-1-yl)pyridin-2-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin]-6'-yl)acetamide;

[0396] N-(1'-(4-methyl-6-(2-oxa-7-azaspiro[3.5]non-7-yl)pyridin-2-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin-6'-yl)acetamide;

[0397] 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;

[0398] 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]pyridin]-6'-yl)acetamide;

[0399] N-(1'-(4-methyl-6-(piperazin-1-yl)pyridin-2-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin]-6'-yl)acetamide;

[0400] N-(1'-(6-(3-(2-hydroxyethyl)piperazin-1-yl)-4-methylpyridin-2-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin]-6'-yl)acetamide;

[0401] N-(1'-(6-methyl-2-morpholinopyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-6'-yl)acetamide;

[0402] 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;

[0403] 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;

[0404] N-(1'-(2-(3-cyanoazetidin-1-yl)-6-methylpyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-6'-yl)acetamide;

[0405] 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;

[0406] N-(1'-(2-(3-cyano-3-(fluoromethyl)azetidin-1-yl)-6-methylpyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-6'-yl)acetamide;

[0407] 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;

[0408] 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;

[0409] 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;

[0410] 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;

[0411] 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;

[0412] 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;

[0413] 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;

[0414] 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;

[0415] 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;

[0416] N-(1′-(6-methyl-2-(2-oxa-7-azaspiro[3.5]non-7-yl)pyrimidin-4-yl)-1′,2′-dihydrospiro[cyclopropane-1,3′-pyrrolo[3,2-c]pyridine]-6′-yl)acetamide;

[0417] 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;

[0418] 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;

[0419] N-(1'-(2-(4-(cyclopropanecarbonyl)-4-methoxypiperidin-1-yl)-6-methylpyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-6'-yl)acetamide;

[0420] 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;

[0421] 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;

[0422] 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;

[0423] 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;

[0424] 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;

[0425] 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;

[0426] 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]pyridin-6′-yl)acetamide;

[0427] N-(1′-(2-(1,1-difluoroethyl)-6-(1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-1′,2′-dihydrospiro[cyclopropane-1,3′-pyrrolo[3,2-c]pyridin-6′-yl)acetamide;

[0428] 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;

[0429] 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]pyridin-6′-yl)acetamide;

[0430] 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;

[0431] N-(1'-(2-(1,1-difluoroethyl)-6-(6-methoxypyridin-3-yl)pyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin]-6'-yl)acetamide;

[0432] 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;

[0433] 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;

[0434] 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;

[0435] 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;

[0436] 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;

[0437] 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;

[0438] 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;

[0439] 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;

[0440] 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;

[0441] 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;

[0442] N-(1'-(2-(6-methoxypyridin-3-yl)-6-methylpyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-6'-yl)acetamide;

[0443] 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;

[0444] N-(1′-(4-methyl-6-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)-1′,2′-dihydrospiro[cyclopropane-1,3′-pyrrolo[3,2-c]pyridin]-6′-yl)acetamide;

[0445] N-(1′-(4-methyl-6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-1′,2′-dihydrospiro[cyclopropane-1,3′-pyrrolo[3,2-c]pyridin]-6′-yl)acetamide;

[0446] N-(1′-(4-methyl-6-(1-(methylsulfonyl)-1H-pyrazol-4-yl)pyridin-2-yl)-1′,2′-dihydrospiro[cyclopropane-1,3′-pyrrolo[3,2-c]pyridin]-6′-yl)acetamide;

[0447] 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;

[0448] N-(1′-(6-(1-ethyl-1H-pyrazol-4-yl)-4-methylpyridin-2-yl)-1′,2′-dihydrospiro[cyclopropane-1,3′-pyrrolo[3,2-c]pyridin-6′-yl)acetamide;

[0449] 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]pyridin]-6′-yl)acetamide;

[0450] 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]pyridin-6′-yl)acetamide;

[0451] N-(1′-(6-(1-isopropyl-1H-pyrazol-4-yl)-4-methylpyridin-2-yl)-1′,2′-dihydrospiro[cyclopropane-1,3′-pyrrolo[3,2-c]pyridin-6′-yl)acetamide;

[0452] N-(1′-(6-(1-cyclopropyl-1H-pyrazol-4-yl)-4-methylpyridin-2-yl)-1′,2′-dihydrospiro[cyclopropane-1,3′-pyrrolo[3,2-c]pyridin-6′-yl)acetamide;

[0453] 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]pyridin]-6'-yl)acetamide;

[0454] 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;

[0455] N-(1'-(6'-methoxy-4-methyl-[2,3'-bipyridyl]-6-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridinyl]-6'-yl)acetamide;

[0456] 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;

[0457] 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;

[0458] N-(1'-(4-(1,1-difluoroethyl)pyrimidin-2-yl)-1',2'-dihydrospiro[piperidin-4,3'-pyrrolo[3,2-c]pyridin]-6'-yl)acetamide;

[0459] N-(1'-(2-(1,1-difluoroethyl)pyrimidin-4-yl)-1',2'-dihydrospiro[piperidin-4,3'-pyrrolo[3,2-c]pyridin]-6'-yl)acetamide;

[0460] N-(1'-(6-(1,1-difluoroethyl)pyridin-2-yl)-1',2'-dihydrospiro[piperidin-4,3'-pyrrolo[3,2-c]pyridin]-6'-yl)acetamide;

[0461] N-(1'-(6-amino-2-(1,1-difluoroethyl)pyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin-6'-yl)acetamide;

[0462] N-(1'-(4-(1,1-difluoroethyl)pyrimidin-2-yl)-1-methyl-1',2'-dihydrospiro[piperidin-4,3'-pyrrolo[3,2-c]pyridin]-6'-yl)acetamide;

[0463] N-(1'-(2-(1,1-difluoroethyl)pyrimidin-4-yl)-1-methyl-1',2'-dihydrospiro[piperidin-4,3'-pyrrolo[3,2-c]pyridin]-6'-yl)acetamide;

[0464] N-(1'-(6-(1,1-difluoroethyl)pyridin-2-yl)-1-methyl-1',2'-dihydrospiro[piperidin-4,3'-pyrrolo[3,2-c]pyridin]-6'-yl)acetamide;

[0465] 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]pyridin]-6′-yl)acetamide;

[0466] 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;

[0467] N-(1'-(6-(1-fluorocyclopropyl)-4-methylpyridin-2-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin-6'-yl)acetamide;

[0468] N-(1'-(6-(1,1-difluoroethyl)pyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin-6'-yl)acetamide;

[0469] Ethyl 2-(4-(6'-acetamidospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-1'(2'H)-yl)-6-methylpyrimidin-2-yl)-2,2-difluoroacetate;

[0470] N-(1'-(2-chloro-6-(1,1-difluoroethyl)pyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin-6'-yl)acetamide;

[0471] 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;

[0472] N-(1'-(6-(cyclopropylamino)-2-(1,1-difluoroethyl)pyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin-6'-yl)acetamide;

[0473] 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;

[0474] 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;

[0475] N-(1'-(6-(1,1-difluoroethyl)-2-(2-methoxyethoxy)pyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-6'-yl)acetamide;

[0476] N-(1'-(2-(2-fluoroethoxy)-6-methylpyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin-6'-yl)acetamide;

[0477] 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;

[0478] N-(1'-(6-(1,1-difluoro-2-hydroxyethyl)-4-methylpyridin-2-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin]-6'-yl)acetamide;

[0479] 6-(6'-acetamidospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin]-1'(2'H)-yl)-2-(1,1-difluoroethyl)pyrimidine-4-carboxylic acid ethyl ester;

[0480] N-(1'-(2-(1,1-difluoroethyl)-6-(hydroxymethyl)pyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin-6'-yl)acetamide;

[0481] N-(1'-(2-(1,1-difluoroethyl)-6-(1-hydroxyethyl)pyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin-6'-yl)acetamide;

[0482] 6-(6'-acetamidospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridinyl]-1'(2'H)-yl)-2-(1,1-difluoroethyl)pyrimidine-4-carboxylic acid;

[0483] N-(1'-(2-(1,1-difluoroethyl)-6-(3-hydroxypropyl)pyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin-6'-yl)acetamide;

[0484] N-(1'-(2-(1,1-difluoroethyl)-6-(4,5-dihydrofuran-3-yl)pyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-6'-yl)acetamide;

[0485] (S)-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;

[0486] N-(1'-(2-(1,1-difluoroethyl)-6-((methylamino)methyl)pyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin-6'-yl)acetamide;

[0487] N-(1′-(6-(azetidin-1-ylmethyl)-2-(1,1-difluoroethyl)pyrimidin-4-yl)-1′,2′-dihydrospiro[cyclopropane-1,3′-pyrrolo[3,2-c]pyridine]-6′-yl)acetamide;

[0488] N-(1′-(2-(1,1-difluoroethyl)-6-(1-methyl-1H-1,2,4-triazol-3-yl)pyrimidin-4-yl)-1′,2′-dihydrospiro[cyclopropane-1,3′-pyrrolo[3,2-c]pyridine]-6′-yl)acetamide;

[0489] N-(1′-(2-(1,1-difluoroethyl)-6-(1-ethyl-5-fluoro-1H-pyrazol-4-yl)pyrimidin-4-yl)-1′,2′-dihydrospiro[cyclopropane-1,3′-pyrrolo[3,2-c]pyridine]-6′-yl)acetamide;

[0490] N-(1'-(6-(1-cyanoethyl)-2-(1,1-difluoroethyl)pyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin-6'-yl)acetamide;

[0491] N-(1'-(6-(cyanomethyl)-2-(1,1-difluoroethyl)pyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin-6'-yl)acetamide;

[0492] N-(1'-(2-(1,1-difluoropropyl)-6-methylpyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-6'-yl)acetamide;

[0493] N-(1'-(2-(1,1-difluoroethyl)-6-fluoropyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-6'-yl)acetamide;

[0494] 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]pyridin-6′-yl)acetamide;

[0495] 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;

[0496] 1-(1'-(2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin]-6'-yl)urea;

[0497] 1-(1'-(2-(1,1-difluoroethyl)-6-ethylpyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin]-6'-yl)urea;

[0498] 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]pyridin-6′-yl)acetamide;

[0499] Methyl (1'-(2-(1,1-difluoroethyl)-6-ethylpyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin-6'-yl)carbamate;

[0500] 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;

[0501] N-(1'-(6-methoxypyridin-2-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin]-6'-yl)acetamide;

[0502] N-(1'-(6-ethyl-2-methylpyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin-6'-yl)acetamide;

[0503] N-(1'-(6-(1,1-difluoro-2-methoxyethyl)-4-methylpyridin-2-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin]-6'-yl)acetamide;

[0504] N-(1'-(4-methyl-6-(1,1,2-trifluoroethyl)pyridin-2-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin-6'-yl)acetamide;

[0505] N-(1'-(2-(3-methoxycyclobutyl)-6-methylpyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-6'-yl)acetamide;

[0506] 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]pyridin-6'-yl)acetamide;

[0507] N-(1′-(6-methyl-2-(2-(methylsulfonyl)ethyl)pyrimidin-4-yl)-1′,2′-dihydrospiro[cyclopropane-1,3′-pyrrolo[3,2-c]pyridin-6′-yl)acetamide;

[0508] 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]pyridin-6′-yl)acetamide;

[0509] (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;

[0510] 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]pyridin-6′-yl)acetamide;

[0511] 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;

[0512] (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]pyridin-6'-yl)acetamide;

[0513] N-(1′-(6-(3-(tert-Butoxy)propyl)-2-(1,1-difluoroethyl)pyrimidin-4-yl)-1′,2′-dihydrospiro[cyclopropane-1,3′-pyrrolo[3,2-c]pyridin-6′-yl)acetamide;

[0514] 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;

[0515] N-(1'-(2-(1,1-difluoroethyl)-6-(3-hydroxy-3-methylbutyl)pyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin-6'-yl)acetamide;

[0516] N-(1'-(2-(1,1-difluoroethyl)-6-pentylpyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-6'-yl)acetamide;

[0517] (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;

[0518] N-(1'-(2-(1,1-difluoroethyl)-6-(2-ethoxyethyl)pyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin-6'-yl)acetamide;

[0519] N-(1'-(4-fluoro-6-methylpyrimidin-2-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin-6'-yl)acetamide;

[0520] N-(1'-(2-fluoro-6-methylpyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin-6'-yl)acetamide;

[0521] N-(1'-(4-methyl-6-(2,2,2-trifluoroethoxy)pyridin-2-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin]-6'-yl)acetamide;

[0522] N-(1'-(6-isopropoxy-4-methylpyridin-2-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin-6'-yl)acetamide;

[0523] N-(1'-(6-ethoxy-4-methylpyridin-2-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin-6'-yl)acetamide;

[0524] N-(1'-(6-(2-methoxy-2-methylpropoxy)-4-methylpyridin-2-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin]-6'-yl)acetamide;

[0525] N-(1'-(6-(((1R,3S)-3-hydroxycyclopentyl)oxy)-4-methylpyridin-2-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin]-6'-yl)acetamide;

[0526] N-(1'-(6-(((1R,3S)-3-methoxycyclopentyl)oxy)-4-methylpyridin-2-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin]-6'-yl)acetamide;

[0527] (R)-N-(1'-(4-methyl-6-((tetrahydrofuran-3-yl)oxy)pyridin-2-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin]-6'-yl)acetamide;

[0528] N-(1'-(6-cyclobutoxy-4-methylpyridin-2-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin-6'-yl)acetamide;

[0529] N-(1'-(4-methyl-6-(oxetan-3-yloxy)pyridin-2-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin]-6'-yl)acetamide;

[0530] N-(1′-(6-((1s,3s)-3-hydroxycyclobutyloxy)-4-methylpyridin-2-yl)-1′,2′-dihydrospiro[cyclopropane-1,3′-pyrrolo[3,2-c]pyridin]-6′-yl)acetamide;

[0531] N-(1′-(6-((1s,3s)-3-methoxycyclobutyloxy)-4-methylpyridin-2-yl)-1′,2′-dihydrospiro[cyclopropane-1,3′-pyrrolo[3,2-c]pyridin-6′-yl)acetamide;

[0532] N-(1′-(6-((1s,3s)-3-cyanocyclobutyloxy)-4-methylpyridin-2-yl)-1′,2′-dihydrospiro[cyclopropane-1,3′-pyrrolo[3,2-c]pyridin-6′-yl)acetamide;

[0533] N-(1′-(6-((1s,3s)-3-(methoxymethyl)cyclobutyloxy)-4-methylpyridin-2-yl)-1′,2′-dihydrospiro[cyclopropane-1,3′-pyrrolo[3,2-c]pyridin-6′-yl)acetamide;

[0534] N-(1′-(6-((1r,3r)-3-fluorocyclobutyloxy)-4-methylpyridin-2-yl)-1′,2′-dihydrospiro[cyclopropane-1,3′-pyrrolo[3,2-c]pyridin]-6′-yl)acetamide;

[0535] N-(1'-(4-methyl-6-((1s,3s)-3-methylcyclobutyloxy)pyridin-2-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin]-6'-yl)acetamide;

[0536] N-(1′-(6-((1s,3s)-3-fluorocyclobutyloxy)-4-methylpyridin-2-yl)-1′,2′-dihydrospiro[cyclopropane-1,3′-pyrrolo[3,2-c]pyridin]-6′-yl)acetamide;

[0537] 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]pyridin-6′-yl)acetamide;

[0538] N-(1′-(6-(((1s,3s)-3-methoxycyclobutyl)methoxy)-4-methylpyridin-2-yl)-1′,2′-dihydrospiro[cyclopropane-1,3′-pyrrolo[3,2-c]pyridin]-6′-yl)acetamide;

[0539] N-(1′-(6-((1-methoxycyclobutyl)methoxy)-4-methylpyridin-2-yl)-1′,2′-dihydrospiro[cyclopropane-1,3′-pyrrolo[3,2-c]pyridin]-6′-yl)acetamide;

[0540] N-(1'-(6-(cyclopropylmethoxy)-4-methylpyridin-2-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin-6'-yl)acetamide;

[0541] N-(1′-(6-(((1R,3S)-3-fluorocyclopentyl)oxy)-4-methylpyridin-2-yl)-1′,2′-dihydrospiro[cyclopropane-1,3′-pyrrolo[3,2-c]pyridin]-6′-yl)acetamide;

[0542] N-(1'-(6-(cyclopentyloxy)-4-methylpyridin-2-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin-6'-yl)acetamide;

[0543] N-(1'-(6-(2-fluoroethoxy)-4-methylpyridin-2-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin-6'-yl)acetamide;

[0544] N-(1'-(6-(2,2-difluoropropoxy)-4-methylpyridin-2-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin]-6'-yl)acetamide;

[0545] N-(1'-(6-(2-methoxyethoxy)-4-methylpyridin-2-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin]-6'-yl)acetamide;

[0546] (R)-N-(1'-(4-methyl-6-(oxetan-2-ylmethoxy)pyridin-2-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin]-6'-yl)acetamide;

[0547] (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]pyridin-6'-yl)acetamide;

[0548] N-(1'-(2-(2-methoxyethoxy)-6-methylpyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-6'-yl)acetamide;

[0549] 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;

[0550] N-(1'-(2-isopropoxy-6-methylpyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin-6'-yl)acetamide;

[0551] N-(1'-(2-(3,3-difluorocyclobutyloxy)-6-methylpyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin-6'-yl)acetamide;

[0552] N-(1′-(2-((2-oxaspiro[3.3]hept-6-yl)oxy)-6-methylpyrimidin-4-yl)-1′,2′-dihydrospiro[cyclopropane-1,3′-pyrrolo[3,2-c]pyridin-6′-yl)acetamide;

[0553] N-(1'-(6-methyl-2-((3-methyloxetan-3-yl)oxy)pyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin-6'-yl)acetamide;

[0554] 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;

[0555] N-(1′-(6-methyl-2-((1s,3s)-3-methylcyclobutyloxy)pyrimidin-4-yl)-1′,2′-dihydrospiro[cyclopropane-1,3′-pyrrolo[3,2-c]pyridine]-6′-yl)acetamide;

[0556] N-(1′-(2-((1s,3s)-3-cyano-3-fluorocyclobutyloxy)-6-methylpyrimidin-4-yl)-1′,2′-dihydrospiro[cyclopropane-1,3′-pyrrolo[3,2-c]pyridine]-6′-yl)acetamide;

[0557] N-(1'-(2-(cyclopropylmethoxy)-6-methylpyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-6'-yl)acetamide;

[0558] N-(1′-(2-((1s,3s)-3-fluorocyclobutyloxy)-6-methylpyrimidin-4-yl)-1′,2′-dihydrospiro[cyclopropane-1,3′-pyrrolo[3,2-c]pyridine]-6′-yl)acetamide;

[0559] 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;

[0560] 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;

[0561] 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;

[0562] (R)-N-(1'-(6-methyl-2-((tetrahydrofuran-3-yl)oxy)pyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin-6'-yl)acetamide;

[0563] N-(1′-(2-((1s,3s)-3-cyanocyclobutyloxy)-6-methylpyrimidin-4-yl)-1′,2′-dihydrospiro[cyclopropane-1,3′-pyrrolo[3,2-c]pyridine]-6′-yl)acetamide;

[0564] N-(1′-(2-((1s,3s)-3-(methoxymethyl)cyclobutyloxy)-6-methylpyrimidin-4-yl)-1′,2′-dihydrospiro[cyclopropane-1,3′-pyrrolo[3,2-c]pyridine]-6′-yl)acetamide;

[0565] N-(1′-(2-((1r,3r)-3-fluorocyclobutyloxy)-6-methylpyrimidin-4-yl)-1′,2′-dihydrospiro[cyclopropane-1,3′-pyrrolo[3,2-c]pyridine]-6′-yl)acetamide;

[0566] N-(1′-(2-((1-methoxycyclobutyl)methoxy)-6-methylpyrimidin-4-yl)-1′,2′-dihydrospiro[cyclopropane-1,3′-pyrrolo[3,2-c]pyridine]-6′-yl)acetamide;

[0567] N-(1'-(2-(cyclopentyloxy)-6-methylpyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin-6'-yl)acetamide;

[0568] (R)-N-(1'-(6-methyl-2-(oxetan-2-ylmethoxy)pyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin-6'-yl)acetamide;

[0569] 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;

[0570] 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;

[0571] 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;

[0572] 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;

[0573] 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]pyridin-6′-yl)acetamide;

[0574] 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;

[0575] 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;

[0576] 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;

[0577] 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;

[0578] 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]pyridin-6′-yl)acetamide;

[0579] 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;

[0580] 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;

[0581] 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;

[0582] 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]pyridin-6'-yl)acetamide;

[0583] N-(1'-(2-(1,1-difluoroethyl)-6-(1-fluoroethyl)pyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin-6'-yl)acetamide;

[0584] 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;

[0585] N-(1'-(2-(1,1-difluoroethyl)-6-(methoxymethyl)pyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin-6'-yl)acetamide;

[0586] 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;

[0587] 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;

[0588] N-(1′-(2-(1,1-difluoroethyl)-6-(1H-pyrazol-4-yl)pyrimidin-4-yl)-1′,2′-dihydrospiro[cyclopropane-1,3′-pyrrolo[3,2-c]pyridin-6′-yl)acetamide;

[0589] 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;

[0590] (S)-N-(1'-(6-(3-cyanopyrrolidin-1-yl)-4-methylpyridin-2-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin]-6'-yl)acetamide;

[0591] (R)-N-(1'-(6-(3-cyanopyrrolidin-1-yl)-4-methylpyridin-2-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin]-6'-yl)acetamide;

[0592] (S)-N-(1'-(6-(3-cyano-3-methylpyrrolidin-1-yl)-4-methylpyridin-2-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin]-6'-yl)acetamide;

[0593] (S)-N-(1'-(6-(3-hydroxy-3-methylpyrrolidin-1-yl)-4-methylpyridin-2-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin]-6'-yl)acetamide;

[0594] N-(1'-(6-(4-(2-hydroxyethyl)piperazin-1-yl)-4-methylpyridin-2-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin]-6'-yl)acetamide;

[0595] (R)-N-(1'-(2-(3-cyanopyrrolidin-1-yl)-6-methylpyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin]-6'-yl)acetamide;

[0596] (S)-N-(1'-(2-(3-cyanopyrrolidin-1-yl)-6-methylpyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin]-6'-yl)acetamide;

[0597] (R)-N-(1'-(2-(3-cyano-3-methylpyrrolidin-1-yl)-6-methylpyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin]-6'-yl)acetamide;

[0598] 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

[0599] 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;

[0600] or a pharmaceutically acceptable salt thereof.

[0601] In a thirty-ninth embodiment, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure (eg, according to any one of the preceding embodiments) or a pharmaceutically acceptable salt thereof.

[0602] The compounds and intermediates described herein can be isolated and used as the compounds themselves. Alternatively, when there is a portion capable of forming a salt, the compound or intermediate can be isolated and used as its corresponding salt. As used herein, the term "salt" refers to an acid addition salt or a base addition salt of the compound described herein. "Salt" particularly includes "pharmaceutically acceptable salts". The term "pharmaceutically acceptable salt" refers to a salt that retains the biological effectiveness and properties of the compound described herein and is generally not biologically or otherwise undesirable. In many cases, the compounds of the present disclosure can form acid salts and / or basic salts by virtue of the presence of amino and / or carboxyl groups or groups similar thereto.

[0603] Pharmaceutically acceptable acid addition salts can be formed with inorganic or organic acids, for example, acetate, aspartate, benzoate, benzenesulfonate, bromide / hydrobromide, bicarbonate / carbonate, bisulfate / sulfate, camphorsulfonate, chloride / hydrochloride, chlortheophyllonate, citrate, edisylate, fumarate, glucoheptonate, gluconate, glucuronate, hippurate, hydroiodide / iodide, isethionate, lactate, lactobionate, lauryl sulfate, malate, maleate, malonate, mandelate, methanesulfonate, methylsulfate, naphthoate, naphthylate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate / hydrogenphosphate / dihydrogenphosphate, polygalacturonate, propionate, stearate, succinate, sulfate, sulfosalicylate, tartrate, tosylate, and trifluoroacetate.

[0604] Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.

[0605] 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.

[0606] Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.

[0607] Inorganic bases from which salts can be derived include, for example, ammonium salts and metals from columns I to XII of the Periodic Table. In certain embodiments, salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include ammonium, potassium, sodium, calcium, and magnesium salts.

[0608] Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines; substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like. Certain organic amines include isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine, and tromethamine.

[0609] The salt can be synthesized from a compound containing an alkaline or acidic part by conventional chemical methods. Generally speaking, such salts can be prepared by reacting the free acid form of these compounds with a stoichiometric amount of a suitable base (such as hydroxides, carbonates, bicarbonates of Na, Ca, Mg or K), or by reacting the free base form of these compounds with a stoichiometric amount of a suitable acid. Such reactions are usually carried out in water or an organic solvent or a mixture of the two. Generally, where feasible, it is desirable to use a non-aqueous medium such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile. Additional lists of suitable salts can be found in, for example, "Remington's Pharmaceutical Sciences", 20th edition, Mack Publishing Company, Easton, Pa., (1985); and Stahl and Wermuth's "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" (Wiley-VCH, Weinheim, Germany, 2002).

[0610] Isotopically labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by methods analogous to those described in the accompanying examples and preparations using an appropriate isotopically labeled reagent in place of the unlabeled reagent previously employed. In one embodiment, the present disclosure provides a deuterated compound as described herein or a pharmaceutically acceptable salt thereof.

[0611] Pharmaceutically acceptable solvates according to the present invention include those wherein the solvent of crystallization may be isotopically substituted, for example D2O, d6-acetone, d6-DMSO.

[0612] Those skilled in the art will recognize that the compounds of the present invention may contain chiral centers and, therefore, may exist in different stereoisomeric forms. As used herein, the term "optical isomer" or "stereoisomer" refers to any of the various stereoisomeric configurations that may exist for a given compound of the present disclosure. It should be understood that substituents may be attached at chiral centers of carbon atoms. Therefore, the present disclosure includes enantiomers, diastereomers, or racemates of the compounds.

[0613] "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. Where appropriate, the terms "racemic" or "rac" are used to specify a racemic mixture. When specifying the stereochemistry of the compound of the present invention, a single stereoisomer (e.g., (1S, 2S)) with the relative and absolute configuration of two known chiral centers is specified using the conventional RS system. "Diastereomers" are stereoisomers that have at least two asymmetric atoms but are not mirror images of each other. Absolute stereochemistry is specified according to the Cahn-Ingold-Prelog R-S system. When a compound is a pure enantiomer, the stereochemistry of each chiral carbon can be specified by R or S. The unknown splitting compound of absolute configuration can be specified as (+) or (-) according to the direction (right-handed or left-handed) of their rotation of plane polarized light at the sodium D line wavelength. Alternatively, the splitting compound can be defined by the respective retention times of the corresponding enantiomers / diastereomers via chiral HPLC.

[0614] Certain of the compounds described herein contain one or more asymmetric centers or axes and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that can be defined, in terms of absolute stereochemistry, as (R)- or (S)-.

[0615] Unless otherwise indicated, the compounds of the present disclosure are intended to include all such possible stereoisomers, including racemic mixtures, optically pure forms, and intermediate mixtures. Optically active (R)- and (S)-stereoisomers can be prepared using chiral synthons or chiral reagents, or can be separated using conventional techniques (e.g., on chiral SFC or HPLC columns (such as CHIRALPAKRTM and CHIRALCELRTM available from DAICEL Corp.) using appropriate solvents or solvent mixtures to achieve good separation). If the compound contains a double bond, the substituent can be in E or Z configuration. If the compound contains a disubstituted cycloalkyl, the cycloalkyl substituent can have a cis or trans configuration. All tautomeric forms are also intended to be included.

[0616] How to use

[0617] 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., a decrease in TYK2 activity of at least 10% as measured by a given assay (such as a bioassay described in the Examples and known in the art)).

[0618] In certain embodiments, the present disclosure provides a method for treating a disease or condition responsive to inhibition of TYK2 activity (referred to herein as a "TYK2-mediated disease or condition" or a "disease or condition mediated by TYK2") in a subject in need of treatment. The method comprises administering to the subject a compound described herein (e.g., a compound of Formula (I) according to any one of Embodiments 1 to 38) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0619] In certain embodiments, the present disclosure provides the use of a compound described herein (e.g., a compound of Formula (I) according to any one of Embodiments one to thirty-eight) 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 treating a TYK2-mediated disorder or disease in a subject in need of treatment.

[0620] In certain embodiments, the present disclosure provides a compound described herein (e.g., a compound of Formula (I) according to any one of Embodiments one to thirty-eight) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound described herein or a pharmaceutically acceptable salt thereof, for use in treating a TYK2-mediated disorder or disease in a subject in need thereof.

[0621] In some embodiments, the disease or condition responsive to inhibition of TYK2 activity is inflammation, autoimmune disease, neuroinflammation, arthritis, rheumatoid arthritis, spondyloarthropathies, systemic lupus erythematosus, cutaneous lupus erythematosus, lupus nephritis, arthritis, osteoarthritis, gouty arthritis, pain, fever, pulmonary sarcoma, silicosis, cardiovascular disease, atherosclerosis, myocardial infarction, thrombosis, congestive heart failure and cardiac reperfusion injury, cardiomyopathy, stroke, ischemia, reperfusion injury, cerebral edema, brain 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 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, hair loss, Alzheimer's disease, skin flushing, eczema, psoriasis, atopic dermatitis, or sunburn.

[0622] In certain embodiments, the present disclosure relates to the aforementioned methods, wherein the subject is a mammal. In certain embodiments, the subject is a primate. In certain embodiments, the subject is a human.

[0623] As used herein, "effective amount" and "therapeutically effective amount" are used interchangeably. It means an amount that is effective to treat one or more of the diseases, conditions, or disorders described herein or to lessen their severity. In some embodiments, the effective dose may be between 10 μg and 500 mg.

[0624] According to the methods of the present disclosure, the compounds and compositions may be administered using any amount and any route of administration effective for treating or lessening the severity of one or more of the above-mentioned diseases, conditions, or disorders.

[0625] In certain embodiments, the present disclosure relates to the aforementioned methods, wherein the compound is administered parenterally. In certain embodiments, the present disclosure relates to the aforementioned methods, wherein the compound is administered intramuscularly, intravenously, subcutaneously, orally, pulmonary, rectal, intrathecal, topically, or intranasally. In certain embodiments, the present disclosure relates to the aforementioned methods, wherein the compound is administered systemically.

[0626] The compound of the present invention can be used as a pharmaceutical composition (for example, a compound of the present invention and at least one pharmaceutically acceptable carrier). As used herein, the term "pharmaceutically acceptable carrier" includes generally recognized as safe (GRAS) solvents, dispersion media, surfactants, antioxidants, preservatives (for example, antibacterial agents, antifungal agents), isotonic agents, salts, preservatives, pharmaceutical stabilizers, buffers (for example, maleic acid, tartaric acid, lactic acid, citric acid, acetic acid, sodium bicarbonate, sodium phosphate, etc.) and combinations thereof, as known to those skilled in the art (see, for example, Remington's Pharmaceutical Sciences, 18th edition Mack Printing Company, 1990, pages 1289-1329). Except for the case where any conventional carrier is incompatible with the active ingredient, its use in treatment or pharmaceutical compositions is considered. For the purposes of this disclosure, solvates and hydrates are considered to be pharmaceutical compositions comprising the compound of the present invention and solvent (that is, solvate) or water (that is, hydrate).

[0627] The formulations can be prepared using conventional dissolution and mixing procedures. For example, the raw 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 above-mentioned excipients. The compounds of the present invention are typically formulated into pharmaceutical dosage forms to provide a readily controllable drug dosage and provide patients with an elegant and easy-to-handle product.

[0628] The pharmaceutical composition (or preparation) for application can be packaged in a variety of ways according to the method for administering the drug. Generally speaking, the article for distribution includes a container in which a pharmaceutical preparation in an appropriate form is placed. Suitable containers are well known to those skilled in the art and include materials such as bottles (plastic and glass), pouches, ampoules, plastic bags, metal cylinders, etc. The container can also include a tamper-proof component to prevent inadvertent contact with the contents of the package. In addition, a label describing the contents of the container is also placed on the container. The label can also include appropriate warnings.

[0629] Pharmaceutical compositions containing compounds of the present disclosure are typically formulated for use as suppositories for parenteral or oral administration or alternatively.

[0630] For example, the pharmaceutical oral compositions of the present disclosure can be prepared into solid forms (including but not limited to capsules, tablets, pills, granules, powders or suppositories) or liquid forms (including but not limited to solutions, suspensions or emulsions). The pharmaceutical compositions can be subjected to conventional pharmaceutical operations, such as sterilization, and / or can contain conventional inert diluents, lubricants or buffers and adjuvants, such as preservatives, stabilizers, wetting agents, emulsifiers and buffers, etc.

[0631] Typically, the pharmaceutical composition is a tablet or gelatin capsule containing the active ingredient together with

[0632] a) diluents, such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine;

[0633] b) lubricants, for example silicon dioxide, talc, stearic acid, its magnesium or calcium salts and / or polyethylene glycol; for tablets, also

[0634] c) binders, such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone; and, if desired,

[0635] d) disintegrants, for example starch, agar, alginic acid or its sodium salt or effervescent mixtures; and / or

[0636] e) absorbents, colorants, flavorings and sweeteners.

[0637] Tablets may be film coated or enteric coated according to methods known in the art.

[0638] Suitable compositions for oral administration include compounds of the present disclosure in the form of tablets, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use are prepared according to any method known in the art for manufacturing pharmaceutical compositions, and such compositions may contain one or more agents selected from the group consisting of sweeteners, flavorings, colorants, and preservatives to provide pharmaceutically elegant and palatable preparations. Tablets may contain active ingredients mixed with non-toxic, pharmaceutically acceptable excipients suitable for making tablets. These excipients are, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate; granulating agents and disintegrants such as corn starch or alginic acid; binders such as starch, gelatin, or gum arabic; and lubricants such as magnesium stearate, stearic acid, or talc. Tablets are uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained effect over a longer period of time. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. Formulations for oral use may be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent (e.g. calcium carbonate, calcium phosphate or kaolin), or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium (e.g. peanut oil, liquid paraffin or olive oil).

[0639] Parenteral compositions (e.g., intravenous (IV) formulations) are aqueous isotonic solutions or suspensions. Parenteral compositions can be sterilized and / or contain adjuvants such as preservatives, stabilizers, wetting agents or emulsifiers, solution promoters, salts for regulating osmotic pressure, and / or buffers. In addition, they can also contain other therapeutically valuable substances. Said compositions are typically prepared according to conventional mixing, granulation, or coating methods, respectively, and contain about 0.1-75% or about 1-50% active ingredient.

[0640] The compounds of the present disclosure or their pharmaceutical compositions for subjects (e.g., people) are typically administered orally or parenterally in therapeutic doses. When administered intravenously via infusion, the dosage may depend on the infusion rate of the IV preparation. Generally speaking, the therapeutically effective dose of a compound, pharmaceutical composition, or its combination depends on the species, body weight, age, and individual condition of the subject, the disorder or disease being treated, or its severity. A physician, pharmacist, clinician, or veterinarian of ordinary skill can easily determine the effective amount of each active ingredient required for preventing, treating, or suppressing disorder or disease progression.

[0641] The above-mentioned dosage characteristics can be demonstrated by in vitro and in vivo tests, advantageously using mammals, such as mice, rats, dogs, monkeys or their isolated organs, tissues and preparations. The compounds of the present invention can be applied in vitro in the form of solutions, such as aqueous solutions, and can be applied in vivo enterally, parenterally, advantageously intravenously, for example as a suspension or in the form of an aqueous solution. In vitro dosages may range from about 10<-3 > molar to 10<-9 > molar concentrations.

[0642] definition

[0643] As used herein, "patient," "subject," or "individual" are used interchangeably and refer to a human or non-human animal. The terms include mammals, such as humans. Typically, the animal is a mammal. Subject also refers to, for example, primates (e.g., humans, male or female), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, etc. In certain embodiments, the animal is a primate. Preferably, the subject is a human.

[0644] As used herein, the terms "inhibit," "inhibition," or "inhibiting" refer to a reduction or suppression of a given condition, symptom, disorder, or disease, or a significant decrease in the baseline activity of a biological activity or process.

[0645] As used herein, the terms "treat," "treating," or "treatment" of any disease, disorder, or condition refer to the management and care of a patient for the purpose of combating the disease, disorder, or condition, and include the administration of a compound of the present invention to obtain the desired pharmacological and / or physiological effect. The effect may be therapeutic, including partially or substantially achieving one or more of the following results: partially or completely reducing the extent of the disease, disorder, or condition; improving or ameliorating clinical symptoms, complications, or indicators associated with the disease, disorder, or condition; or delaying, inhibiting, or reducing the likelihood of progression of the disease, disorder, or condition; or eliminating the disease, disorder, or condition. In certain embodiments, the effect may be preventing the onset of symptoms or complications of the disease, disorder, or condition.

[0646] As used herein, the term "cancer" has the meaning generally accepted in the art. The term can broadly refer to abnormal cell growth.

[0647] As used herein, the term "autoimmune disease" has the meaning generally accepted in the art. The term can broadly refer to a disease in which the host's immune system targets or attacks the host's normal or healthy tissues.

[0648] As used herein, the term "myelination" has the meaning generally accepted in the art. The term can broadly refer to the process of myelin production.

[0649] As used herein, the terms "myelin-related diseases or disorders," "demyelinating disorders," or "demyelinating disorders" have the meanings generally accepted in the art. These terms broadly refer to diseases or disorders involving myelin damage.

[0650] As used herein, a subject (preferably a human) is "in need of" treatment if the subject would benefit biologically, medically, or in quality of life from such treatment.

[0651] As used herein, the phrase "optionally substituted" is used interchangeably with the phrase "substituted or unsubstituted". In general, the term "optionally substituted" refers to the replacement of hydrogen radicals in a given structure by the group of a specified substituent. Specific substituents are described in the definitions and in the description of compounds and examples thereof. Unless otherwise indicated, an optionally substituted group may have a substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted by more than one substituent selected from a specified group, the substituent at each position may be the same or different. In some embodiments, an optionally substituted group may be substituted with one or more substituents, each of which may be the same or different. In some embodiments, "one or more" substituents may be 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.

[0652] As used herein, the term "alkyl" refers to a fully saturated branched or unbranched hydrocarbon moiety. 1-4 "Alkyl" refers to an alkyl group having 1 to 4 carbon atoms. The term "C 1-3 Alkyl" and "C 1-2 Alkyl" should be interpreted accordingly. 1-4 Representative examples of "alkyl" include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, and tert-butyl. Similarly, the alkyl portion of an alkoxy group (i.e., alkyl moiety) has the same definition as above. When indicated as "optionally substituted," the alkane group or alkyl moiety may be unsubstituted or substituted with one or more substituents (generally one to three substituents, except in the case of halogen substituents such as perchloro or perfluoroalkyl groups).

[0653] As used herein, the term "alkoxy" refers to a fully saturated branched or unbranched alkyl moiety attached through an oxygen bridge (ie, --O--C 1-4 Alkyl, where C 1-4Alkyl is as defined herein). Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, and the like. Preferably, the alkoxy has about 1-4 carbon atoms, more preferably about 1-2 carbon atoms. The term "C 1-2 "Alkoxy" should be interpreted accordingly.

[0654] As used herein, the term "C 1-4 Alkoxy C 1-4 "Alkyl" means a C 1-4 Alkyl groups in which at least one of the hydrogen atoms is replaced by a C 1-4 Alkoxy substitution. C 1-4 Alkoxy C 1-4 The alkyl group is attached to the rest of the molecule described herein through the alkyl group.

[0655] The number of carbon atoms in a 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.

[0656] "Halogen" or "halo" may be fluorine, chlorine, bromine or iodine.

[0657] As used herein, the term "halo-substituted C 1-4 Alkyl" or "C 1-4 "Haloalkyl" refers to a C 1-4 Alkyl group in which at least one of the hydrogen atoms is replaced by a halogen atom. 1-4 The haloalkyl group may be a monohalogenated-C 1-4 Alkyl, dihalogenated-C 1-4 Alkyl or polyhalogenated-C 1-4 Alkyl (including perhalogenated-C 1-4 alkyl). Monohalogenated-C 1-4 The alkyl group may have one iodine, bromine, chlorine or fluorine within the alkyl group. 1-4 Alkyl and polyhalogenated-C 1-4 An alkyl group may have two or more of the same halogenated atoms or a combination of different halogenated groups within the alkyl group. 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. 1-4 Non-limiting examples of haloalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, and dichloropropyl. 1-4 Alkyl refers to a C-H group in which all hydrogen atoms are replaced by halogen atoms. 1-4 Alkyl group.

[0658] The term "aryl" refers to an aromatic carbocyclic monocyclic ring or two fused ring systems containing 6 to 10 carbon atoms. Examples include phenyl and naphthyl.

[0659] The term "heteroaryl" refers to a 5 to 12 membered aromatic group containing 1 to 4 heteroatoms selected from N, O and S. In some cases, the nitrogen atom in the heteroaryl group can be quaternized. The term "heteroaryl" can be used interchangeably with the terms "heteroaryl ring," "heteroaryl group," or "heteroaromatic." A heteroaryl group can be monocyclic or bicyclic. Monocyclic heteroaryls include, for example, pyrazolyl, imidazolyl, oxazolyl, pyridyl, furyl, oxadiazolyl, thienyl, etc. Bicyclic heteroaryls include groups in which a monocyclic heteroaryl ring is fused to one or more aryl or heteroaryl rings. Non-limiting examples include pyrazolopyridyl, pyrazolopyridyl, benzotriazolyl, imidazopyridyl, and indolyl.

[0660] The term "carbocycle" or "carbocyclyl" refers to a 4 to 12-membered saturated or partially unsaturated hydrocarbon ring and can exist as a monocycle, a bicyclic ring (including a fused, spiral or bridged carbocycle) or a spirocycle. Bicyclic carbocyclyl groups include, for example, unsaturated carbocyclic groups fused to another unsaturated carbocyclic group, a cycloalkyl group or an aryl group, such as 2,3-dihydroindenyl, decahydronaphthyl and 1,2,3,4-tetrahydronaphthyl. Unless otherwise indicated, carbocycles typically contain 4 to 10 ring members.

[0661] The term "C 3-6 "Cycloalkyl" refers to a fully saturated carbocyclic ring (eg, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl).

[0662] The term "heterocycle" or "heterocyclyl" refers to a 4 to 12-membered saturated or partially unsaturated heterocycle containing 1 to 4 heteroatoms independently selected from N, O and S. The heterocyclyl group can be a monocyclic or bicyclic ring (for example, bridged, fused or spiral bicyclic). The example of a monocyclic saturated or partially unsaturated heterocyclyl includes but is not limited to oxetane, tetrahydrofuranyl, tetrahydropyranyl and piperidinyl. Bicyclic heterocyclyl groups include, for example, unsaturated heterocyclyls fused to another unsaturated heterocyclyl, cycloalkyl, aryl or heteroaryl ring, such as tetrahydro-3H-[1,2,3]triazolo[4,5-c]pyridyl, 2-oxa-6-azaspiro[3.3]heptyl, 5-oxabicyclo[2.1.1]hexyl and 9-azabicyclo[3.3.1]nonyl. 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.

[0663] As used herein, the term "spiro" ring refers to a bicyclic ring system in which the two rings share one common atom. Examples of spiro rings include 2-oxa-6-azaspiro[3.3]heptyl and the like.

[0664] The term "fused" ring refers to two ring systems that share two adjacent ring atoms. A fused heterocycle 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).

[0665] As used herein, the term "bridged" refers to a 5- to 10-membered cyclic moiety that is linked at two non-adjacent ring atoms (eg, 5-oxabicyclo[2.1.1]hexane).

[0666] The language "pharmaceutically acceptable" means that the substance, composition or dosage form must be compatible chemically and / or toxicologically with the other ingredients comprising the formulation and / or the mammal to be treated therewith.

[0667] Unless otherwise indicated, the term "compound of the present disclosure" refers to a compound of formula (I) and all stereoisomers (including diastereomers and enantiomers), rotamers, tautomers, isotope-labeled compounds (including deuterium substitution). When there is a moiety capable of forming a salt, the salt (particularly a pharmaceutically acceptable salt) is also included.

[0668] 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) should be interpreted as covering both the singular and the plural, unless otherwise indicated herein or clearly contradicted by the context. The use of any and all examples or exemplary language (e.g., "such as") provided herein is intended only to better illustrate the present invention and does not limit the scope of the invention as originally claimed.

[0669] The intermediates and compounds of the present invention may also exist in different tautomeric forms, and all such forms are included within the scope of the present invention. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that can be interconverted via a low energy barrier. For example, proton tautomers (also referred to as prototropic tautomers) include interconversions via the migration of a proton, such as keto-enol and imine-enamine isomerizations. The specific example of a proton tautomer is an imidazole moiety in which a proton can migrate between two ring nitrogens. Valence tautomers include interconversions by reorganization of some bonding electrons.

[0670] In one embodiment, the present disclosure relates to a compound of formula (I) as defined herein in free form. In another embodiment, the present disclosure relates to a compound of formula (I) as defined herein in salt form. In another embodiment, the present disclosure relates to a compound of formula (I) as defined herein in acid addition salt form. In yet another embodiment, the present disclosure relates to a compound of formula (I) as defined herein in pharmaceutically acceptable salt form. In yet another embodiment, the present disclosure relates to a compound of formula (I) as defined herein in pharmaceutically acceptable acid addition salt form. In yet another embodiment, the present disclosure relates to any one of the compounds in the Examples in free form. In yet another embodiment, the present disclosure relates to any one of the compounds in the Examples in salt form. In yet another embodiment, the present disclosure relates to any one of the compounds in the Examples in acid addition salt form. In yet another embodiment, the present disclosure relates to any one of the compounds in the Examples in pharmaceutically acceptable salt form. In yet another embodiment, the present disclosure relates to any one of the compounds in the Examples in pharmaceutically acceptable acid addition salt form.

[0671] The compounds of the present disclosure can be synthesized by synthetic routes including methods analogous to those well known in the chemical arts, particularly in light of the description contained herein. Starting materials are generally available from commercial sources such as Sigma-Aldrich, or are readily prepared using methods well known to those skilled in the art (e.g., by methods generally described in Louis F. Fieser and Mary Fieser, Reagents for Organic Synthesis, Vols. 1-19, Wiley, New York (1967-1999 editions) or Beilsteins Handbuch der organischen Chemie, 4, Aufl. ed. Springer-Verlag, Berlin, including supplements (also available via the Beilstein online database)).

[0672] For illustrative purposes, the reaction scheme described below provides a possible approach for synthesizing compounds disclosed herein and key intermediates. For a more detailed description of each reaction step, see the Examples section below. Although specific parent material and reagent are described and discussed below in the scheme, other parent material and reagent can be easily replaced to provide multiple derivatives and / or reaction conditions.

[0673] According to the first method, the compound of formula (I) can be prepared from the compounds of formula (II') and (III'), as shown in Scheme 1

[0674]

[0675] Hal is a halogen, usually Cl or Br.

[0676] Compounds of formula (I) can be prepared from compounds of formula (II') and (III') by a Buchwald-Hartwig cross-coupling reaction according to process step (a). Typical conditions include reacting an amide of formula (III') with a halide of formula (II') in the presence of a suitable inorganic base, a suitable palladium catalyst, in the presence of a suitable phosphine ligand, in a suitable solvent at elevated temperature, optionally under microwave irradiation. Preferred conditions include reacting compounds of formula (II') and (III') in the presence of Brettphos Pd G3, Xantphos Pd G3, Xantphos Pd G4, RuPhos Pd G3, CPhos Pd G3, Josiphos or a combination of Xantphos and Pd2(dba)3 in the presence of a suitable base such as Cs2CO3, NaOtBu, Zn(OAc)2 or K3PO4 in a suitable solvent such as dioxane, DMF or THF at between 70°C and 120°C.

[0677] According to the second method, the compound of formula (I) can be prepared from the compounds of formula (IV') and (V'), as shown in Scheme 2

[0678]

[0679] Hal is a halogen, usually Cl or Br.

[0680] Compounds of formula (I) can be prepared from compounds of formula (IV') and halide of formula (V') according to process step (a) Buchwald-Hartwig reaction as previously described in Scheme 1 .

[0681] Alternatively, compounds of formula (I) can be prepared from compounds of formula (IV') and halides of formula (V') by process step (b) alkylation reaction in the presence of a suitable inorganic or organic base and a suitable aprotic polar solvent at temperatures between rt and elevated temperatures. Preferred conditions include reacting compounds of formula (IV') with compounds of formula (V') in the presence of NaH, KHMDS, KOtBu, K3PO4, Cs2CO3 or K2CO3 in DMSO, DMF or THF at temperatures between rt and 100°C.

[0682] Alternatively, the compound of formula (I) can be prepared from the compound of formula (IV') and the halide of formula (V') by a Ullmann-type copper-mediated coupling reaction in process step (c). Typical conditions include reacting the compound of formula (IV') with the halide of formula (V'), a copper catalyst, optionally in the presence of a suitable ligand, in the presence of a suitable inorganic or organic base in a suitable solvent at elevated temperature. Preferred conditions include reacting the compound of formula (IV') with the halide of formula (V'), a copper catalyst, optionally in the presence of a suitable ligand, in the presence of a suitable inorganic or organic base in a suitable solvent at elevated temperature. 1 ,N 2 -dimethylethane-1,2-diamine or L-proline, a suitable inorganic base such as K2CO3 or K3PO4, optionally in a solvent such as dioxane or DMSO, at 40°C to 120°C, the compound of formula (IV') is reacted with a halide of formula (V').

[0683] According to a third method, compounds of formula (II') and (IV') can be prepared from compounds of formula (III'), (V'), (VI'), (VII') and (VIII'), as shown in Scheme 3.

[0684]

[0685] Hal is a halogen, preferably Br or Cl.

[0686] PG is a suitable N-protecting group, typically carbamate, and preferably Boc.

[0687] Compounds of formula (II') can be prepared from compounds of formula (VI') and formula (V') according to process steps (a), (b) or (c) as previously described in Schemes 1 and 2.

[0688] Compounds of formula (VII') can be prepared from compounds of formula (VI') according to the protection of the N atom in process step (d). Typical conditions include reacting compounds of formula (VI') with Boc2O in the presence of a coupling agent (e.g. DMAP) in a suitable solvent (e.g. THF) at about rt.

[0689] Compounds of formula (VIII') can be prepared from compounds of formula (VII') and (III') according to process step (a) as previously described in Scheme 1 .

[0690] Compounds of formula (IV') can be prepared from compounds of formula (VIII') according to process step (e) deprotection reaction. Typical conditions include reacting compounds of formula (VIII') with a suitable acid (eg TFA or HCl) in DCM at rt.

[0691] According to a fourth method, compounds of formula (VI') can be prepared from compounds of formula (IX'), (X'), (XI') and (XII') as shown in Scheme 4.

[0692]

[0693] Hal is a halogen, preferably Br or Cl.

[0694] LG is a leaving group, usually a halide or sulfonate

[0695] Compounds of formula (X') can be prepared from compounds of formula (IX') by addition reaction according to process step (f). Preferred conditions include reacting compounds of formula (IX') with a suitable halogenating agent (e.g., pyridinium tribromide) in a suitable alcohol solvent (e.g., t-BuOH) at rt.

[0696] Compounds of formula (XI') can be prepared from compounds of formula (X') according to process step (g) reduction reaction. Preferred conditions include reacting the compound of formula (X') in the presence of zinc and acetic acid at rt.

[0697] Compounds of formula (XII') can be prepared from compounds of formula (XI') according to the alkylation reaction of process step (h). Typical conditions include reacting a compound of formula (XI') with R 3 LG is reacted in the presence of a strong organic or inorganic base (such as NaH, n-BuLi, LiHMDS or TMEDA) in a suitable solvent (such as DMF or THF) at rt.

[0698] Compounds of formula (VI') can be prepared from compounds of formula (XII') according to the carbonyl reduction reaction of process step (i). Preferred conditions include reacting the compound of formula (XII') with a reducing agent (typically LiAlH4 or NaBH4 in combination with BF3.Et2O) in a suitable solvent (e.g. THF) at a temperature between rt and 60°C.

[0699] The compound of formula (III'), (V'), (IX') and R 3 LG is commercially available or can be prepared analogously to methods known in the literature or as described in the experimental section below.

[0700] Compounds of Formula (I), (II'), (IV'), (VI') and (VIII') can 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 such transformations include, but are not limited to:

[0701] Reaction of aryl or heteroaryl halides with amines or alcohols (optionally in the presence of a suitable base) to give aryl or heteroaryl amines or ethers,

[0702] • Reaction of an aryl or heteroaryl halide with an amine or alcohol according to process step (a) Buchwald-Hartwig reaction as previously described in Scheme 1 to give an aryl or heteroaryl amine or ether,

[0703] Using Suzuki reaction conditions, aryl or heteroaryl halides react with alkyl or aryl borate esters or acids to give alkyl or aryl substituted aryl or heteroaryl groups,

[0704] Using Negishi reaction conditions, aryl or heteroaryl halides react with alkyl or aryl zinc reagents to give alkyl or aryl substituted aryl or heteroaryl groups,

[0705] Using Sonogashira-type reaction conditions, aryl or heteroaryl halides react with substituted alkynes to give alkenyl-substituted aryl or heteroaryl groups.

[0706] The aryl or heteroaryl halide reacts with a halide substituted with a cycloalkyl or 4- to 7-membered monocyclic heterocyclic group or 1,3-dioxoisoindolinate in a transition metal photocatalytic reaction to obtain an aryl or heteroaryl compound substituted with a 4- to 7-membered monocyclic heterocyclic group.

[0707] · Reaction of aryl or heteroaryl halides with alkylthiolates to obtain alkylthio-substituted aryl or heteroaryl groups,

[0708] Reduction of alkenes or alkynes under hydrogenation conditions to give the corresponding alkyl compounds,

[0709] Oxidation of the alkoxyvinyl group using a suitable oxidizing agent (e.g., KMnO4) to give an ester,

[0710] Cleavage of vinyl ethers under acidic conditions to give methyl ketones,

[0711] Ketones react with Grignard reagents to give tertiary alcohols.

[0712] Using MCPBA or trichlororuthenium hydrate and IO4, alkylthio groups are oxidized to give alkylsulfonyl groups.

[0713] As previously described in Scheme 2, alkylation of an aryl alcohol or heteroaryl alcohol according to process step (b) alkylation reaction,

[0714] Alkylation of heteroatoms (e.g., O or N) with alkyl halides in the presence of inorganic bases to give secondary amines or ethers,

[0715] C-H alkylation of heteroaryls with 4- to 7-membered monocyclic or heterocyclic halides using redox catalysis to give 4- to 7-membered monocyclic or heterocyclic heteroaryls,

[0716] Reductive amination of the N atom with a secondary amine to give a secondary amine,

[0717] Fluorination of alcohols or carbonyl groups using fluorinating agents (e.g. DAST),

[0718] Fluorination of aryl or heteroaryl chlorides using TBAF to give aryl or heteroaryl fluorides,

[0719] Chlorination of primary alcohols with chlorinating agents (such as SOCl2) to obtain alkyl chlorides,

[0720] Hydrolysis of carboxylic acid esters to give carboxylic acids, or

[0721] Dehalogenation of heteroaryl halides using palladium catalysts to give heteroaryls.

[0722] Those skilled in the art will appreciate that it may be necessary to utilize an appropriate protecting group strategy to prepare compounds of formula (I). Typical protecting groups may include 2,4-dimethoxybenzyl or carbamate groups, preferably Boc for protecting amines, or benzyl for protecting phenolic OH.

[0723] It will also be appreciated that it may be necessary or desirable to perform the transformations in an order different from that depicted in the schemes, or to modify one or more transformations, to provide the desired compounds of the present invention.

[0724] example

[0725] abbreviation:

[0726] AcOH = acetic acid;

[0727] AIBN = 2,2'-azobis(2-methylpropionitrile);

[0728] Aq.=water;

[0729] BF3.Et2O = Boron trifluoride etherate;

[0730] Bn = benzyl;

[0731] BnOH = benzyl alcohol;

[0732] Boc = tert-butyloxycarbonyl;

[0733] Boc2O = di-tert-butyl dicarbonate;

[0734] br = broad peak;

[0735] 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;

[0736] t-BuOH = tert-butyl alcohol;

[0737] t-BuONa = sodium tert-butoxide;

[0738] n-BuLi = n-butyllithium;

[0739] ℃ = degrees Celsius;

[0740] CDCl3 = deuterated chloroform;

[0741] CS2 = carbon disulfide;

[0742] Cs2CO3 = cesium carbonate;

[0743] CuI = copper (I) iodide;

[0744] δ = chemical shift;

[0745] d = doublet;

[0746] DAST = (diethylamino)sulfur trifluoride;

[0747] dd = doublet;

[0748] DCM = dichloromethane;

[0749] DIPEA = N-ethyldiisopropylamine or N,N-diisopropylethylamine;

[0750] DMAP = 4-(dimethylamino)pyridine;

[0751] DME = 1,2-dimethoxyethane;

[0752] DMF = N,N-dimethylformamide;

[0753] DMSO = dimethyl sulfoxide;

[0754] DMSO-d6 = hexadeuterated dimethyl sulfoxide;

[0755] dtbbpy = 4-tert-butyl-2-(4-tert-butylpyridin-2-yl)pyridine;

[0756] Et = ethyl;

[0757] EtOH = ethanol;

[0758] EtOAc = ethyl acetate;

[0759] Eq. = equivalent;

[0760] FeSO4 = ferrous (II) sulfate;

[0761] g = grams;

[0762] HCl = hydrochloric acid;

[0763] HCO2H = formic acid;

[0764] 1 H NMR = proton nuclear magnetic resonance;

[0765] H2O = water;

[0766] HPLC = high pressure liquid chromatography;

[0767] h = hour;

[0768] IPA = 2-propanol;

[0769] K2CO3 = potassium carbonate;

[0770] KF = potassium fluoride;

[0771] KHMDS = potassium hexamethyldisilazide;

[0772] KOH = potassium hydroxide;

[0773] KOtBu = potassium tert-butoxide;

[0774] K3PO4 = tripotassium phosphate;

[0775] L = liter;

[0776] LCMS = liquid chromatography mass spectrometry;

[0777] LiAlH4 = lithium aluminum hydride;

[0778] NaHMDS = lithium hexamethyldisilazide;

[0779] m = multiplet;

[0780] M = mole;

[0781] MCPBA = 3-chloroperoxybenzoic acid;

[0782] Me = methyl;

[0783] MeCN = acetonitrile;

[0784] MeI = methyl iodide;

[0785] MeOH = methanol;

[0786] MeOH-d4 = deuterated methanol;

[0787] mg = milligram;

[0788] MgSO4 = magnesium sulfate;

[0789] Mhz = megahertz;

[0790] mins = minutes;

[0791] mL = milliliters;

[0792] mmol = millimole;

[0793] MS m / z = mass spectrum peak;

[0794] N2 = nitrogen;

[0795] NaBH4 = sodium borohydride;

[0796] NaBH3CN = sodium cyanoborohydride;

[0797] Na2CO3 = sodium carbonate;

[0798] NaH = sodium hydride;

[0799] NaHCO3 = sodium bicarbonate;

[0800] NaOH = sodium hydroxide;

[0801] NaOtBu = sodium tert-butoxide;

[0802] NaOMe = sodium methoxide;

[0803] Na2SO3 = sodium thiosulfate;

[0804] Na2SO4 = sodium sulfate;

[0805] NBS = N-bromosuccinimide;

[0806] NH3 = ammonia;

[0807] NH4Cl = ammonium chloride;

[0808] NH4OH is ammonium hydroxide;

[0809] NiCl 2. Glyme = dichloro(dimethoxyethane)nickel;

[0810] PE = petroleum ether;

[0811] Pd(dppf)Cl2=[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II);

[0812] Pd(DPEPhos)Cl2 = dichloro[bis(2-(diphenylphosphino)phenyl)ether]palladium(II);

[0813] Pd(OAc)2 = palladium(II) acetate;

[0814] Pd2(dba)3=tris(dibenzylideneacetone)dipalladium(0);

[0815] POCl3 = phosphorus oxychloride (V);

[0816] q = quartet;

[0817] rt = room temperature;

[0818] RT = retention time;

[0819] RuPhos Pd G3 = methanesulfonic acid (2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl) [2-(2′-amino-1,1′-biphenyl)] palladium (II);

[0820] s = singlet;

[0821] sat.=saturated;

[0822] soln.=solution;

[0823] t = triplet;

[0824] TEA = triethylamine;

[0825] TFA = trifluoroacetic acid;

[0826] THF = tetrahydrofuran;

[0827] TLC = thin layer chromatography;

[0828] TMEDA = 1,2-bis(dimethylamino)ethane;

[0829] μL=microliter;

[0830] μmol = micromole;

[0831] Xantphos = 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene;

[0832] Xantphos Pd G3 = [(4,5-bis(diphenylphosphino)-9,9-dimethylxanthene)-2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate;

[0833] Zn(OAc)2 = zinc acetate.

[0834] General approach

[0835] Preparation 1

[0836] 3,3-Dibromo-6-chloro-1,3-dihydro-2H-pyrrolo[3,2-c]pyridin-2-one

[0837]

[0838] 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 min. The reaction mixture was stirred at 25 ° C for 16 h. The mixture was diluted with water (400 mL) and extracted with EtOAc (100 mL x 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 H NMR: (400MHz, CDCl3) δ: ppm 9.07 (s, 1H), 8.56 (s, 1H), 7.01 (s, 1H).

[0839] Alternative synthesis

[0840] 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 rt. After stirring for 20 min, NBS (6.346 kg, 35.65 mol) was added in portions at 20-25 ° C over 4 h, and after the addition was complete, the reaction was stirred for another 2 h. 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 h to give 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(400MHz,DMSO-d6)δ(ppm):12.01(brs,1H),8.58(s,1H),7.05(d,1H)

[0841] Preparation 2

[0842] 6-Chloro-1,3-dihydro-2H-pyrrolo[3,2-c]pyridin-2-one

[0843]

[0844] To a solution of 3,3-dibromo-6-chloro-1,3-dihydro-2H-pyrrolo[3,2-c]pyridin-2-one (preparation 1,16.5g, 50.6mmol) in AcOH (150mL) was added zinc (33.1g, 506mmol) and the reaction mixture was stirred at rt for 50min. The mixture was filtered and concentrated under vacuum, diluted with saturated NaHCO3 (150mL) and extracted with EtOAc (200mL x 5). The combined organic layer was washed with H2O (200mL x 3) and brine (100mL x 2). The organic layer was dried over Na2SO4, filtered and concentrated under vacuum to give 6-chloro-1,3-dihydro-2H-pyrrolo[3,2-c]pyridin-2-one (7.0g, 82.1% yield) as a yellow solid. 1 H NMR: (400MHz, DMSO-d6) δ: ppm 10.95 (s, 1H), 8.03 (s, 1H), 6.82 (s, 1H), 3.52 (s, 2H).

[0845] Alternative synthesis

[0846] To a stirred 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 HO (20 L) was added a solution of NaSO (5.252 kg, 41.67 mol) in HO (15 L) at rt over 1.5 h. The mixture was stirred at 25 °C for 2 h and then filtered. The resulting solid was washed with HO and dried at 45-50 °C for 24 h to afford 6-chloro-1,3-dihydro-2H-pyrrolo[3,2-c]pyridin-2-one (1.70 kg, 96.8%) as an off-white solid. 1HNMR(400MHz,DMSO-d6)δ(ppm):10.99(brs,lH),8.06(s,1H),6.86(s,lH),3.56(s,2H)

[0847] Preparation 3

[0848] 6'-Chlorospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin]-2'(1'H)-one

[0849]

[0850] 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, 60% purity) in DMF (30 mL) under N₂ at 0°C. The reaction mixture was stirred for 15 min, after which a solution of 1,2-dibromoethane (6.7 g, 35.6 mmol) in anhydrous DMF (4.0 mL) was added dropwise. The brown reaction mixture was stirred at room temperature for 18 h, then filtered and concentrated under vacuum. H₂O (400 mL) was then added and extracted with EtOAc (200 mL x 5). The combined organic layers were washed with H₂O (200 mL x 3) and brine (100 mL x 2), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The crude product was slurried in EtOAc and PE, filtered and dried to afford 6'-chlorospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin]-2'(1'H)-one as a yellow solid (1 g, 43.3% yield). 1 H NMR: (500MHz, 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).

[0851] Alternative synthesis

[0852] A mixture of THF (7.0 L), 6-chloro-1,3-dihydro-2H-pyrrolo[3,2-c]pyridin-2-one (prepared 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 30-35°C for 48 hours. The reaction mixture was quenched with 4 Naq. HCl (30 L) and the pH was adjusted to 8-9 with saturated aqueous Na2CO3. The mixture was filtered and the resulting solid was dried to afford 6'-chlorospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin]-2'(1'H)-one (650 g, 86.6%) as a yellow solid. 1 HNMR(400MHz,DMSO-d6)δ(ppm):11.20(brs,lH),7.93(s,1H),6.96(s,lH),1.77-1.74(m,2H),1.57-1.54(m,2H)

[0853] Preparation 4

[0854] 6'-Chloro-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]

[0855]

[0856] A solution of 6'-chlorospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-2'(1'H)-one (preparation 3,850mg, 4.37mmol) and LiAlH4(547mg, 14.4mmol) in THF (40mL) was stirred at 60°C for 10min. The mixture was diluted with water (70mL) and extracted with EtOAc (60mL x 3). The combined organic layers were washed with brine (40mL), dried over Na2SO4, filtered and concentrated under vacuum to give a crude product, which was purified by silica gel chromatography (PE / EtOAc 1 / 0 to 2 / 1) to give 6'-chloro-1', 2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine] (470mg, 59.6% yield) as a yellow solid. 1 H NMR: (500MHz, DMSO-d6)δ: ppm7.32(s,1H),6.91(s,1H),6.31(s,1H),3.60(s,2H),1.02-1.01(m,2H),1.01-0.98(m,2H).

[0857] Alternative synthesis

[0858] 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 portionwise NaBH4 (466.55 g, 12.33 mol) at 25°C over a period of 20 min. BF3.Et2O (2.45 kg, 17.265 mol) was then added dropwise at 20°C under an N2 atmosphere over 5 h. After the addition was complete, the reaction was stirred for another 2 h. The reaction mixture was quenched with 6N aq. HCl (20 L) and stirred vigorously at 25°C for 16 h. The mixture was basified to pH = 9 with 6N aq. NaOH under ice cooling and then filtered. The filter cake was dissolved in 2N aq. HCl (7 L), and the solution was stirred at 25°C for 2 h. The solution was then basified to pH 9 with 6N aq. NaOH under ice-cooling. The resulting solid was filtered and dried to afford 6'-chloro-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine] (974.50 g, 87.50%) as a yellow solid. 1HNMR(400MHz,DMSO-d6)δ(ppm):7.32(s,lH),6.92(brs,1H),6.30(s,lH),3.59(s,2H),1.01-0.98(m,4H)

[0859] Preparation 5

[0860] tert-Butyl 6'-chlorospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-1'(2'H)-carboxylate

[0861]

[0862] 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) was 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 silica gel chromatography (PE / EtOAc 15 / 1 to 3 / 1) to give tert-butyl 6'-chlorospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-1'(2'H)-carboxylate (274 mg, 58.8% yield) as a white solid. 1 H NMR: (400MHz, CDCl3) δ: ppm7.84-7.71(m,1H),7.59(s,1H),3.97(s,2H),1.63(s,9H),1.18-1.10(m,4H).

[0863] Alternative synthesis

[0864] 6'-Chloro-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine] (Preparation 4,800g, 4.43mol) was dissolved in THF (5L). DMAP (541.6g, 4.43mol) and Boc2O (2.416kg, 11.072mol) were added and the mixture was stirred at 20°C for 5h. EtOAc (4L) was added and the mixture was washed with saturated aqueous NH4Cl solution (2L x 5). The organic phase was dried over anhydrous MgSO4, filtered, and concentrated under vacuum. The crude product was triturated with n-heptane (1L) at ambient temperature for 0.5h, then filtered to give tert-butyl 6'-chlorospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-1'(2'H)-carboxylate (900g, 72.38%) as an off-white solid.

[0865] 1HNMR(400MHz,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)

[0866] Preparation 6

[0867] tert-Butyl 6'-acetamidospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-1'(2'H)-carboxylate

[0868]

[0869] To a solution of tert-butyl 6'-chlorospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-1'(2'H)-carboxylate (Preparation 5, 274 mg, 0.976 mmol) in dioxane (3 mL) was added acetamide (86.5 mg, 1.46 mmol), Cs2CO3 (954 mg, 2.93 mmol), Xantphos (113 mg, 0.195 mmol) and Pd2(dba)3 (89.4 mg, 0.0976 mmol). The reaction mixture was stirred at 100 ° C. under N2 for 16 h. The mixture was treated with H2O (10 mL) and extracted with EtOAc (15 mL x 3). The organic layer was washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (PE / EtOAc 15 / 1 to 0 / 1) to give tert-butyl 6'-acetamidospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-1'(2'H)-carboxylate (269 mg, 90.7% yield) as a yellow solid. LCMS m / z = 304.1 [M+H] + . 1 H NMR: (400MHz, CDCl3) δ: ppm 8.49-8.35(m,2H),7.39(s,1H),3.97(s,2H),2.15(s,3H),1.62(s,9H),1.09-1.04(m,4H).

[0870] Alternative synthesis

[0871] 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) was 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. The mixture was filtered through a pad of 4% paraffin wax. The filtrate was washed with water (3 L x 3), and 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 afford tert-butyl 6'-acetamidospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-1'(2'H)-carboxylate as a yellow solid. 1 HNMR(400MHz,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)

[0872] Preparation 7

[0873] N-(1',2'-Dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridinyl]-6'-yl)acetamide

[0874]

[0875] To a solution of tert-butyl 6'-acetamidospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-1'(2'H)-carboxylate (Preparation 6, 248 mg, 0.818 mmol) in DCM (25 mL) was added TFA (5 mL). The mixture was stirred at 25°C for 2 h. The pH of the solution was adjusted to 7-8 with NH4OH. The mixture was concentrated and purified by prep-HPLC (column: Boston Green ODS150*30mm*5um; conditions: water (NH4HCO3)-MeCN; start B: 15; end B: 45; gradient time (min): 11; flow rate (ml / min): 25) to afford N-(1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-6'-yl)acetamide (60 mg, 36.1% yield) as a white solid. LCMS m / z=204.1[M+H] + . 1H NMR: (500MHz, CDCl3)δ: ppm7.98(s,1H),7.37(s,1H),7.03(s,1H),4.32(s,1H),3.72-3.62(m,2H),2.10(s,3H),1.03-0.94(m,4H).

[0876] Alternative synthesis

[0877] To a solution of tert-butyl 6'-acetamidospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-1'(2'H)-carboxylate (preparation 6,800g, 2.637mol) in DCM (3.0L) was added TFA (3.007kg, 26.372mol) at rt and the reaction was stirred at 25 °C for 15h. The mixture was concentrated and the residue was diluted with H2O (3.0L). The solution was basified to pH=9 with saturated Na2CO3 aqueous solution. After filtration, the filter cake was washed with saturated Na2CO3 aqueous solution (2.0L). After drying at 45-50 °C for 24h, the solid was slurried with DCM / n-heptane (1.0L / 1.0L) at rt. The solid was collected by filtration and dried to give N-(1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin]-6'-yl)acetamide (510.4 g, 95.2%) as a yellow solid. 1 HNMR(400MHz,DMSO-d6)δ(ppm):10.01(brs,lH),7.28(s,1H),7.20(s,1H),6.64(s,lH),3.54(s,2H),2.01(s,3H),0.96-0.92(m,4H)

[0878] Preparation 8

[0879] 6'-Chloro-2-methylspiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin]-2'(1'H)-one

[0880]

[0881] To a solution of 6-chloro-1,3-dihydro-2H-pyrrolo[3,2-c]pyridin-2-one (preparation 2,500 mg, 2.97 mmol) in THF (20 mL) was added butyl lithium (2.5 M, 2.97 mL) at -78 ° C. The reaction mixture was stirred at -78 ° C for 1 h, followed by the addition of 4-methyl-1,3,2-dioxathiolane 2,2-dioxide (451 mg, 3.26 mmol) while maintaining the temperature below -50 ° C. The reaction was allowed to warm to rt overnight, then quenched with water and partitioned between EtOAc and water. The aqueous solution was extracted with EtOAc and the combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by silica gel chromatography (0-80% EtOAc-EtOH 3:1 (containing 2% NH4OH) in heptane) to give 6'-chloro-2-methylspiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin]-2'(1'H)-one (115 mg, 19% yield). LCMS m / z = 209.1 [M+H] + .

[0882] Preparation 9

[0883] 6'-Chlorospiro[cyclobutane-1,3'-pyrrolo[3,2-c]pyridin]-2'(1'H)-one

[0884]

[0885] To a solution of 6-chloro-1,3-dihydro-2H-pyrrolo[3,2-c]pyridin-2-one (preparation 2,1.0 g, 5.93 mmol) and TMEDA (1.72 g, 14.8 mmol) in THF (40 mL) was added butyl lithium (2.5 M, 5.93 mL) dropwise at -78 ° C. The mixture was stirred at -78 ° C for 10 min and then stirred at rt for 30 min. 1,3-diiodopropane (4.4 g, 14.8 mmol) was added dropwise at -50 ° C to -30 ° C. The reaction was allowed to warm to rt overnight and then filtered. The filtrate was concentrated under reduced pressure and diluted with EtOAc. The precipitate was filtered and rinsed with EtOAc to give a solid (304 mg). The filtrate was concentrated under reduced pressure and then purified by silica gel chromatography (0-80% EtOAc-EtOH 3:1 (containing 2% NH4OH) in heptane) to give 242 mg of 6-chlorospiro[1H-pyrrolo[3,2-c]pyridin-3,1'-cyclobutane]-2-one as a white powder (546 mg total, 44% yield). LCMS m / z = 209.1 [M+H] + .

[0886] Preparation 10

[0887] 6'-Chlorospiro[cyclopentane-1,3'-pyrrolo[3,2-c]pyridin]-2'(1'H)-one

[0888]

[0889] To a solution of LiHMDS (1.0 M, 14.8 mL) in THF (10 mL) was added 6-chloro-1,3-dihydro-2H-pyrrolo[3,2-c]pyridin-2-one (Preparation 2, 1.0 g, 5.93 mmol) at -78 ° C. The reaction mixture was stirred at -78 ° C for 5 min, then warmed to -50 ° C and stirred for 30 min. 1,4-dichlorobutane (829 mg, 6.5 mmol) was added dropwise at 0 ° C. The reaction mixture was allowed to warm to rt and heated to reflux overnight. The mixture was concentrated under reduced pressure and partitioned between diethyl ether and saturated NH4Cl aqueous solution. The ether layer was concentrated under reduced pressure and purified by silica gel chromatography (0-100% EtOAc in heptane) to give 6'-chlorospiro[cyclopentane-1,3'-pyrrolo[3,2-c]pyridin]-2'(1'H)-one (696 mg, 53% yield) as a light brown powder. LCMS m / z = 223.0 [M+H] + .

[0890] Preparation 11

[0891] 6'-Chloro-2,3,5,6-tetrahydrospiro[pyran-4,3'-pyrrolo[3,2-c]pyridin]-2'(1'H)-one

[0892]

[0893] 6'-Chloro-2,3,5,6-tetrahydrospiro[pyran-4,3'-pyrrolo[3,2-c]pyridin]-2'(1'H)-one (286 mg, 20.2% yield) was obtained as a white powder from 6-chloro-1,3-dihydro-2H-pyrrolo[3,2-c]pyridin-2-one (Preparation 2) and 1-iodo-2-(2-iodoethoxy)ethane using a method similar to that described in Preparation 9. LCMS m / z = 239.1 [M+H] + .

[0894] Preparation 12

[0895] 6'-Chloro-2-methyl-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine] trifluoroacetate

[0896]

[0897] To a suspension of 6'-chloro-2-methylspiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-2'(1'H)-one (preparation 8, 110 mg, 527 μmol) in THF (4 mL) was added LiAlH4 (2M, 923 μL) and the reaction mixture was heated to 60 ° C and maintained for 1 h. The reaction was quenched by dropwise addition of aqueous potassium sodium tartrate. The mixture was filtered, the filtrate was diluted with EtOAc, washed with aqueous NaHCO3 solution and brine. The organic layer was separated, dried and concentrated under reduced pressure. The crude material was purified by HPLC, eluting with MeCN, water (+0.1% TFA modifier) ​​to give 6'-chloro-2-methyl-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine] (83 mg, 51% yield). LCMS m / z=195.1[M+H] + .

[0898] Preparation 13

[0899] 6'-Chloro-1',2'-dihydrospiro[cyclobutane-1,3'-pyrrolo[3,2-c]pyridine]

[0900]

[0901] To a suspension of 6'-chlorospiro[cyclobutane-1,3'-pyrrolo[3,2-c]pyridine]-2'(1'H)-one (preparation 9, 530 mg, 2.3 mmol) in THF (20 mL) was added LiAlH4 (2M, 3.77 mL). After stirring at rt, the reaction mixture was heated to 60 ° C and maintained for 1 h. The mixture was quenched by dropwise addition of aqueous potassium sodium tartrate. The formed precipitate was filtered and the filtrate was diluted with EtOAc. The organic layer was separated, dried and concentrated under reduced pressure. The solid formed was triturated with heptane / ether (1: 1) to give 6'-chloro-1', 2'-dihydrospiro[cyclobutane-1,3'-pyrrolo[3,2-c]pyridine] (194 mg, 43% yield) as a white solid. LCMS m / z=195.1[M+H] + .

[0902] Preparation 14

[0903] 6'-Chloro-1',2'-dihydrospiro[cyclopentane-1,3'-pyrrolo[3,2-c]pyridine]

[0904]

[0905] 6'-Chloro-1',2'-dihydrospiro[cyclopentane-1,3'-pyrrolo[3,2-c]pyridine] was prepared from 6'-chlorospiro[cyclopentane-1,3'-pyrrolo[3,2-c]pyridine]-2'(1'H)-one (Preparation 10) using a method similar to that described in Preparation 13. LCMS m / z = 209.1 [M+H] + .

[0906] Preparation 15

[0907] 6'-Chloro-1',2,2',3,5,6-hexahydrospiro[pyrano-4,3'-pyrrolo[3,2-c]pyridine]

[0908]

[0909] 6'-Chloro-1',2,2',3,5,6-hexahydrospiro[pyran-4,3'-pyrrolo[3,2-c]pyridine] was prepared from 6'-chloro-2,3,5,6-tetrahydrospiro[pyran-4,3'-pyrrolo[3,2-c]pyridine]-2'(1'H)-one (Preparation 11) using a method similar to that described in Preparation 4. LCMS m / z = 225.1 [M+H] + .

[0910] Preparation 16

[0911] 1-(6-chloro-4-(2-methoxyethoxy)pyridin-2-yl)ethan-1-one

[0912]

[0913] To a solution of 2-chloro-4-(2-methoxyethoxy)pyridine (17 g, 90.6 mmol) in MeCN (100 mL) was added acetaldehyde (5 M, 181 mL), 2-hydroperoxy-2-methyl-propane (16.3 g, 181 mmol), TFA (11.4 g, 99.7 mmol) and FeSO4 (25.2 g, 90.6 mmol) at 25 ° C. The reaction mixture was stirred at 80 ° C and N2 for 24 h. The mixture was concentrated in vacuo, diluted with H2O (200 mL) and extracted with EtOAc (150 mL x 3). The organic layer was washed with brine (300 mL), dried over Na2SO4, filtered, concentrated, and purified by silica gel chromatography (PE / EtOAc 5 / 1 to 1 / 1) to give 1-(6-chloro-4-(2-methoxyethoxy)pyridin-2-yl)ethan-1-one (1.7 g, 8.2% yield) as a yellow oil. 1H NMR: (400MHz, CDCl3) δ: ppm 7.51 (d, J = 2.4Hz, 1H), 7.04 (d, J = 2.0Hz, 1H), 4.25-4.22 (m, 2H), 3.82-3.79 (m, 2H), 3.47 (s, 3H), 2.70 (s, 3H).

[0914] Preparation 17

[0915] 4-(Benzyloxy)-2-chloro-5-fluoro-6-methylpyrimidine

[0916]

[0917] A solution of BnOH (5.8 g, 53.9 mmol) and t-BuONa (5.2 g, 53.9 mmol) in toluene (100 mL) was stirred at 0°C for 10 min. 2,4-Dichloro-5-fluoro-6-methylpyrimidine (9.8 g, 53.9 mmol) was added and the reaction mixture was stirred at 20°C for 1 h. The mixture was diluted with H₂O (150 mL) and extracted with EtOAc (100 mL x 3). The organic layer was washed with brine (200 mL), dried over Na₂SO₄, filtered, concentrated, and then purified by silica gel chromatography (PE / EtOAc 20 / 1 to 5 / 1) to give 4-(benzyloxy)-2-chloro-5-fluoro-6-methylpyrimidine (7.9 g, 58.2% yield) as a colorless oil. 1 H NMR: (500MHz, CDCl3) δ: ppm 7.48-7.46 (m, 2H), 7.42-7.36 (m, 3H), 5.48 (s, 2H), 2.44 (d, J = 3.0Hz, 3H).

[0918] Preparation 18

[0919] Methyl 4-(benzyloxy)-5-fluoro-6-methylpyrimidine-2-carboxylate

[0920]

[0921] To a solution of 4-(benzyloxy)-2-chloro-5-fluoro-6-methylpyrimidine (Preparation 17, 7.9 g, 31.3 mmol) in MeOH (80 mL) was added TEA (6.4 g, 62.7 mmol) and Pd(dppf)Cl2 (459 mg, 0.627 mmol). The reaction mixture was stirred at 80 ° C and CO (50 psi) for 16 h. The mixture was concentrated and purified by silica gel chromatography (PE / EtOAc 20 / 1 to 5 / 1) to give methyl 4-(benzyloxy)-5-fluoro-6-methylpyrimidine-2-carboxylate (3.1 g, 35.8% yield) as a yellow oil. 1HNMR: (500MHz, CDCl3) δ: ppm 7.53-7.51 (m, 2H), 7.40-7.35 (m, 3H), 5.58 (s, 2H), 4.03 (s, 3H), 2.55 (d, J = 2.8Hz, 3H).

[0922] Preparation 19

[0923] 1-(4-(Benzyloxy)-5-fluoro-6-methylpyrimidin-2-yl)ethan-1-one

[0924]

[0925] 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) was slowly added dropwise MeMgBr (3 M, 3.8 mL) 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 (30.0 mL), treated with H2O (20 mL), and extracted with EtOAc (40 mL x 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 HNMR: (500MHz, 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 = 3.2Hz, 3H).

[0926] Preparation 20

[0927] 1-(2-Chloro-6-methylpyrimidin-4-yl)ethan-1-one

[0928]

[0929] At 0 ° C and N2 atmosphere, MeMgBr (3M, 1.76mL, 5.28mmol) is added to a solution of 2-chloro-6-methylpyrimidine-4-formic acid methyl ester (985mg, 5.28mmol) in THF (10mL) and stirred for 5h. The reaction mixture is quenched with H2O (30mL) and extracted with EtOAc (20mL x 3). The combined organic layer is dried (Na2SO4), evaporated to dryness and the residue is purified by silica gel chromatography (PE / EtOAc=5 / 1) to give 1- (2-chloro-6-methylpyrimidin-4-yl) second -1- ketone (147mg, 16%) as a white solid. 1 H NMR (400MHz, CDCl3) δ: 7.69 (s, 1H), 2.70 (s, 3H), 2.63 (s, 3H).

[0930] Preparation 21

[0931] 2,4-Dichloro-6-(1,1-difluoroethyl)pyridine

[0932]

[0933] To a solution of 1-(4,6-dichloropyridin-2-yl)ethan-1-one (4.8 g, 25.3 mmol) in DCM (50 mL) was added DAST (20.36 g, 126 mmol) and the reaction mixture was stirred at 25 ° C for 12 h. The mixture was added dropwise to H2O (40 mL) and extracted with DCM (50 mL x 3). The combined organic layer was washed with brine (60 mL), dried over Na2SO4, filtered and concentrated to give a residue, which was purified by silica gel chromatography (PE) to give 2,4-dichloro-6-(1,1-difluoroethyl)pyridine (4.9 g, 91.5% yield) as a colorless oil. 1 H NMR: (500MHz, CDCl3) δ: ppm 7.59 (s, 1H), 7.43 (s, 1H), 2.00 (t, J = 18.5Hz, 3H).

[0934] Preparation 22 to 26

[0935] The compounds in the table below were prepared using procedures similar to those described in Preparation 21 from the corresponding ketones and DAST.

[0936]

[0937]

[0938] Preparation 27

[0939] 2-Chloro-6-(1,1-difluoroethyl)-4-methoxypyridine

[0940]

[0941] To a solution of 2,4-dichloro-6-(1,1-difluoroethyl)pyridine (preparation 21,2g, 9.43mmol) in MeOH (20mL) was added NaOMe (561mg, 10.4mmol). The reaction mixture was stirred at 50°C for 5h. The mixture was diluted with H2O (20mL) and extracted with EtOAc (20mL x 2). The combined organic layer was washed with brine (20mL x 2), dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography (PE / EtOAc 3 / 1) to give 2-chloro-6-(1,1-difluoroethyl)-4-methoxypyridine (1.3g, 66.4% yield) as a yellow solid. 1 H NMR: (500MHz, CDCl3) δ: ppm7.13-7.09(m,1H),6.88-6.87(m,1H),3.90(s,3H),2.02-1.94(m,3H).

[0942] Preparation 28

[0943] 2-Chloro-4-(1,1-difluoroethyl)-6-methoxypyrimidine

[0944]

[0945] 2-Chloro-4-(1,1-difluoroethyl)-6-methoxypyrimidine was obtained from yellow oily 2,4-dichloro-6-(1,1-difluoroethyl)pyrimidine (Preparation 22) (110 mg, 65.7% yield) following a procedure similar to that described in Preparation 27. 1 H NMR: (500MHz, CDCl3) δ: ppm 6.94 (s, 1H), 4.05 (s, 3H), 1.99-1.91 (m, 3H).

[0946] Preparation 29

[0947] 2-(1,1-difluoroethyl)pyrimidine-4,6-diol

[0948]

[0949] To a solution of malonamide (15.0 g, 147 mmol) in EtOH (500 mL) was added t-BuONa (49.4 g, 514 mmol) and the solution was stirred at 25 ° C for 30 min. Ethyl 2,2-difluoropropionate (50.7 g, 367 mmol) was added and the reaction was stirred at reflux and 100 ° C for 16 h. The reaction was cooled, 4N HCl (75 mL) was added and the mixture was concentrated under reduced pressure. The resulting solid was collected and dried to give 2-(1,1-difluoroethyl)pyrimidine-4,6-diol (20.0 g, 77.3% yield) as a yellow solid. LCMS m / z=177.0[M+H] + .

[0950] Preparation 30

[0951] 4,6-Dichloro-2-(1,1-difluoroethyl)pyrimidine

[0952]

[0953] A solution of 2-(1,1-difluoroethyl)pyrimidine-4,6-diol (Preparation 29, 20.0 g, 113.56 mmol) in POCl3 (200 mL, 2.15 mol) was stirred at 100 ° C for 8 h. The mixture was evaporated to dryness, the residue was diluted with DCM (150 mL) and slowly added to water. The mixture was extracted with DCM (200 mL x 3), and the combined organic phases were washed with brine (300 mL), dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by column chromatography (EtOAc in PE 0% to 10%) to give 4,6-dichloro-2-(1,1-difluoroethyl)pyrimidine (23.0 g, 95.1% yield) as a yellow liquid. LCMS m / z=213.0[M+H] + .

[0954] Preparation 31

[0955] 4-Chloro-2-(1,1-difluoroethyl)-6-methoxypyrimidine

[0956]

[0957] To a solution of 4,6-dichloro-2-(1,1-difluoroethyl)pyrimidine (Preparation 30, 300 mg, 1.41 mmol) in MeOH (5.0 mL) was added NaOMe (76.1 mg, 1.41 mmol) at 0°C. The reaction was stirred at 25°C for 2 h. The mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography (PE / EtOAc 15 / 1 to 5 / 1) to give 4-chloro-2-(1,1-difluoroethyl)-6-methoxypyrimidine (260 mg, 88.5% yield) as a colorless oil. 1 H NMR: (400MHz, CDCl3) δppm: 6.81 (s, 1H), 2.02 (t, J = 18.5Hz, 1H).

[0958] Preparation 32

[0959] 4-((1r,3r)-3-(benzyloxy)cyclobutyloxy)-2-chloro-6-(1,1-difluoroethyl)pyridine

[0960]

[0961] A solution of (1r,3r)-3-(benzyloxy)cyclobutan-1-ol in THF (5 mL) and NaH (90.6 mg, 2.26 mmol, 60% purity) was stirred at 25°C for 0.5 h, followed by the addition of 2,4-dichloro-6-(1,1-difluoroethyl)pyridine (Preparation 21, 400 mg, 1.89 mmol). The reaction mixture was stirred at 25°C for 5 h. The mixture was treated with H2O (10 mL) and extracted with EtOAc (10 mL x 3). The organic layer was washed with brine (15 mL), dried over Na2SO4, filtered, concentrated, and purified by silica gel chromatography (PE / EtOAc 10 / 1 to 5 / 1) to give 4-((1r,3r)-3-(benzyloxy)cyclobutoxy)-2-chloro-6-(1,1-difluoroethyl)pyridine (350 mg, 52.4% yield) as a yellow oil. 1 H NMR: (400MHz, CDCl3) δ: ppm 7.38-7.30(m,5H),7.00(d,J=2.4Hz,1H),6.75(d,J=2.0Hz,1H),4.46(s,2H),4.38-4.35 (m,1H),3.88-3.82(m,1H),2.93-2.89(m,2H),2.25-2.21(m,2H),1.97(t,J=18.8Hz,3H).

[0962] Preparation 33

[0963] (1r,3r)-3-((2-chloro-6-(1,1-difluoroethyl)pyridin-4-yl)oxy)cyclobutan-1-ol

[0964]

[0965] A solution of 4-((1r,3r)-3-(benzyloxy)cyclobutoxy)-2-chloro-6-(1,1-difluoroethyl)pyridine (Preparation 32, 350 mg, 0.989 mmol) in TFA (5 mL) was stirred at 100° C. for 3 h. The mixture was concentrated under reduced pressure and purified by silica gel chromatography (PE / EtOAc 10 / 1 to 3 / 1) to give (1r,3r)-3-((2-chloro-6-(1,1-difluoroethyl)pyridin-4-yl)oxy)cyclobutan-1-ol (250 mg, 95.8% yield) as a yellow oil. LCMS m / z=264.0 [M+H] +

[0966] Preparation 34

[0967] 2-Chloro-6-(1,1-difluoroethyl)-4-((1r,3r)-3-methoxycyclobutyloxy)pyridine

[0968]

[0969] To a solution of (1r,3r)-3-((2-chloro-6-(1,1-difluoroethyl)pyridin-4-yl)oxy)cyclobutan-1-ol (Preparation 33, 250 mg, 0.948 mmol) in THF (5 mL) was added NaH (37.9 mg, 0.948 mmol, 60% purity) and MeI (202 mg, 1.42 mmol). The reaction mixture was stirred at 25 ° C for 2 h. The mixture was treated with H2O (20 mL) and extracted with EtOAc (15 mL x3). The organic layer was washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give 2-chloro-6-(1,1-difluoroethyl)-4-((1r,3r)-3-methoxycyclobutyloxy)pyridine (190 mg, 72.2% yield) as a white solid. 1 H NMR: (500MHz, CDCl3) δ: ppm7.00 (d, J=2.0Hz, 1H), 6.76 (d, J=2.0Hz, 1H), 4.42-4.36 (m, 1H), 3 .70-3.67(m,1H),3.27(s,3H),2.94-2.91(m,2H),2.18-2.14(m,2H),1.97(t,J=19.0Hz,3H).

[0970] Preparation 35

[0971] 2-(1,1-difluoroethyl)-5-fluoro-6-methylpyrimidin-4-ol

[0972]

[0973] 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, then at 100 ° C. for 3 h. The mixture was concentrated under reduced pressure and purified by silica gel chromatography (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 H NMR: (500MHz, CDCl3) δ: ppm 2.40 (d, J = 3.5 Hz, 3H), 2.02 (t, J = 18.5 Hz, 3H).

[0974] Preparation 36

[0975] 4-Chloro-2-(1,1-difluoroethyl)-5-fluoro-6-methylpyrimidine

[0976]

[0977] 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 x 10). The combined organic layers were dried over Na2SO4, filtered, concentrated and purified by silica gel chromatography (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] + .

[0978] Preparation 37

[0979] Methyl 4-(benzyloxy)-6-methylpyrimidine-2-carboxylate

[0980]

[0981] Following a procedure similar to that described in Preparation 18, methyl 4-(benzyloxy)-6-methylpyrimidine-2-carboxylate was obtained as a green oil from 4-(benzyloxy)-2-chloro-6-methylpyrimidine, 2.8 g, 56%. 1H NMR(500MHz,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).

[0982] Preparation 38

[0983] 1-(4-(Benzyloxy)-6-methylpyrimidin-2-yl)ethan-1-one

[0984]

[0985] Following a procedure similar to that described in Preparation 20, 1-(4-(Benzyloxy)-6-methylpyrimidin-2-yl)ethan-1-one was obtained as a yellow oil, 312 mg, 13% yield, from methyl 4-(benzyloxy)-6-methylpyrimidine-2-carboxylate (Preparation 37). LCMS m / z = 243.0 [M+H] + .

[0986] Preparation 39

[0987] 4-(Benzyloxy)-2-(1,1-difluoroethyl)-6-methylpyrimidine

[0988]

[0989] 4-(Benzyloxy)-2-(1,1-difluoroethyl)-6-methylpyrimidine (208 mg, 61.1% yield) was obtained as a yellow oil from 1-(4-(benzyloxy)-6-methylpyrimidin-2-yl)ethan-1-one (Preparation 38) following a procedure similar to that described in Preparation 21. LCMS m / z = 265.1 [M+H] + .

[0990] Preparation 40

[0991] 2-(1,1-difluoroethyl)-6-methylpyrimidin-4-ol

[0992]

[0993] A mixture of 4-(benzyloxy)-2-(1,1-difluoroethyl)-6-methylpyrimidine (Preparation 39, 208 mg, 0.8 mmol) and TFA (1 mL) was stirred for 12 h at 100° C. The mixture was concentrated under reduced pressure to give a residue, which was purified on silica gel column chromatography (DCM / MeOH 19 / 1) to give 2-(1,1-difluoroethyl)-6-methylpyrimidin-4-ol (124 mg, 90%) as a yellow solid. 1HNMR(500MHz,MeOH-d4)δ:6.37(s,1H),2.34(s,3H),1.98(t,3H).

[0994] Preparation 41

[0995] 4-Chloro-2-(1,1-difluoroethyl)-6-methylpyrimidine

[0996]

[0997] A mixture of 2-(1,1-difluoroethyl)-6-methylpyrimidin-4-ol (Preparation 40, 124 mg, 0.7 mmol) and POCl3 (1 mL) was stirred at 100 ° C for 1 h. The reaction mixture was added dropwise to ice water (5 mL) and extracted with EtOAc (10 mL x 3). The combined organics were washed with brine (15 mL), dried (Na2SO4) and evaporated to dryness in vacuo to give 4-chloro-2-(1,1-difluoroethyl)-6-methylpyrimidine (86 mg, 63%) as a brown oil. LCMS m / z=193.1[M+H] + .

[0998] Preparation 42

[0999] 4-(Benzyloxy)-2-chloro-5-fluoropyrimidine

[1000]

[1001] A solution of BnOH (6.5 g, 59.9 mmol) and t-BuONa (5.8 g, 59.9 mmol) in toluene (150 mL) was stirred at 0 ° C for 10 min. 2,4-dichloro-5-fluoropyrimidine (10.0 g, 59.9 mmol) was slowly added and the resulting mixture was stirred at 20 ° C for 1 h. The mixture was poured into H2O (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (PE / EtOAc 20 / 1 to 5 / 1) to give 4-(benzyloxy)-2-chloro-5-fluoropyrimidine (12.5 g, 87.5% yield) as a white solid. 1 H NMR: (500MHz, CDCl3) δ: ppm 8.21 (s, 1H), 7.49-7.42 (m, 2H), 7.41-7.38 (m, 3H), 5.51 (s, 2H).

[1002] Preparation 43

[1003] Methyl 4-(benzyloxy)-5-fluoropyrimidine-2-carboxylate

[1004]

[1005] Following a procedure similar to that described in Preparation 18, methyl 4-(benzyloxy)-5-fluoropyrimidine-2-carboxylate was obtained from 4-(benzyloxy)-2-chloro-5-fluoropyrimidine (Preparation 42) as a white solid, 12 g, 42% yield. 1 H NMR: (400MHz, CDCl3) δ: ppm 8.44 (d, J=2.0Hz, 1H), 7.53-7.39 (m, 2H), 7.38-7.35 (m, 3H), 5.61 (s, 2H), 4.03 (s, 3H).

[1006] Preparation 44

[1007] 1-(4-(Benzyloxy)-5-fluoropyrimidin-2-yl)ethan-1-one

[1008]

[1009] To a solution of methyl 4-(benzyloxy)-5-fluoropyrimidine-2-carboxylate (preparation 43, 12.0 g, 45.76 mmol) in THF (120 mL) was added MeMgBr (3 M, 18.3 mL, 54.9 mmol) dropwise at -78 ° C and the reaction mixture was stirred under N2 for 2 h. The mixture was quenched with saturated NH4Cl (30 mL) at -78 ° C, poured into H2O (60 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (PE / EtOAc 20 / 1 to 3 / 1) to give 1-(4-(benzyloxy)-5-fluoropyrimidine-2-yl) ethyl-1-one (7.3 g, 64.8% yield) as a white solid. 1 H NMR: (400MHz, CDCl3) δ: ppm 8.45 (d, J=2.0Hz, 1H), 7.52-7.49 (m, 2H), 7.42-7.37 (m, 3H), 5.60 (s, 2H), 2.73 (s, 3H).

[1010] Preparation 45

[1011] 4-(Benzyloxy)-2-(1,1-difluoroethyl)-5-fluoropyrimidine

[1012]

[1013] Following a procedure similar to that described in Preparation 21, 4-(benzyloxy)-2-(1,1-difluoroethyl)-5-fluoropyrimidine was obtained from 1-(4-(benzyloxy)-5-fluoropyrimidin-2-yl)ethan-1-one (Preparation 44) as a colorless oil, 6.7 g, 84% yield. 1 HNMR: (400MHz, CDCl3) δ: ppm8.38 (d, J = 2.4Hz, 1H), 7.51-7.40 (m, 2H), 7.39-7.36 (m, 3H), 5.56 (s, 2H), 2.02 (t, J = 18.4Hz, 3H).

[1014] Preparation 46

[1015] 2-(1,1-difluoroethyl)-5-fluoropyrimidin-4-ol

[1016]

[1017] A solution of 4-(benzyloxy)-2-(1,1-difluoroethyl)-5-fluoropyrimidine (Preparation 45, 6.7 g, 24.9 mmol) in TFA (40 mL) was stirred at 100° C. for 12 h. The reaction was concentrated under reduced pressure and the residue was purified by silica gel chromatography (PE / EtOAc 20 / 1 to 3 / 1) to give 2-(1,1-difluoroethyl)-5-fluoropyrimidin-4-ol (3.2 g, 72.1% yield) as a white solid. 1 H NMR: (400MHz, CDCl3) δ: ppm 11.61 (br s, 1H), 7.93 (d, J = 2.4Hz, 1H), 2.03 (t, J = 18.8Hz, 3H).

[1018] Preparation 47

[1019] 4-Chloro-2-(1,1-difluoroethyl)-5-fluoropyrimidine

[1020]

[1021] A solution of 2-(1,1-difluoroethyl)-5-fluoropyrimidin-4-ol (Preparation 46, 3.2 g, 18 mmol) in POCl3 (20.0 mL) was stirred at 100 ° C for 2 h. The mixture was slowly poured into ice / water (50 mL) and extracted with EtOAc (60 mL x 3). The combined organic phase was washed with brine (50 mL x 2), dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography (PE / EtOAc 20 / 1 to 5 / 1) to give 4-chloro-2-(1,1-difluoroethyl)-5-fluoropyrimidine (2.3 g, 65.1% yield) as a colorless oil. LCMS m / z=197.1[M+H]+

[1022] Preparation 48

[1023] 2-Bromo-6-(oxetan-3-yl)pyridine

[1024]

[1025] To a solution of 2,6-dibromopyridine (1.0 g, 4.22 mmol) and 3-iodooxetane (1.6 g, 8.44 mmol) in DME (10 mL) was added Ir[dF(CF3)ppy]2(dtbbpy)PF6 (47.4 mg, 0.422 mmol), LiOH (202 mg, 8.44 mmol), NiCl2. Glyme (92.5 mg, 0.422 mmol), tris(trimethylsilyl)silane (1.1 g, 4.22 mmol) and dtbbpy (113 mg, 0.422 mmol). The reaction mixture was stirred and irradiated with a blue LED at 25 ° C and N2 for 12 h. The mixture was concentrated and diluted with H2O (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layer was washed with brine (20 mL x 2), dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography (PE / EtOAc 10 / 1 to 3 / 1) to give 2-bromo-6-(oxetan-3-yl)pyridine (250 mg, 27.7% yield) as a yellow oil. 1 HNMR: (500MHz, CDCl3) δ: ppm 7.54(t,J=8.0Hz,1H),7.40(d,J=7.5Hz,1H),7.28(d,J=7.5Hz,1H),5.05-5.02(m,2H),4.91-4.89(m,2H),4.40-4.35(m,1H).

[1026] Preparation 49

[1027] 3-(4-chloropyrimidin-2-yl)oxetan-3-ol

[1028]

[1029] Under N2 at -70 DEG C over 30min to a solution of 2-bromo-4-chloropyrimidine (2g, 10.3mmol) in toluene (20mL) n-BuLi (2.5M, 4.34mL) was added dropwise, followed by addition of oxetane-3-one (820mg, 11.4mmol). The reaction mixture was allowed to warm to room temperature and maintained for 3h. The mixture was quenched with H2O (10mL) and extracted with EtOAc (20mL x 2). The combined organic layer was washed with brine (10mL x 2), dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography (PE / EtOAc 1 / 1 to 0 / 1) to give 3- (4-chloropyrimidine-2-yl) oxetane-3-ol (800mg, 41.5% yield) as a yellow oil. 1 H NMR: (400MHz, CDCl3) δ: ppm 8.71 (d, J = 5.2 Hz, 1H), 7.36 (d, J = 5.2 Hz, 1H), 5.04-5.02 (m, 2H), 4.99-4.97 (m, 2H), 4.92 (s, 1H).

[1030] Preparation 50

[1031] S-Methyl O-(3-(4-chloropyrimidin-2-yl)oxetan-3-yl)dithiocarbonate

[1032]

[1033] To a solution of 3-(4-chloropyrimidin-2-yl)oxetane-3-ol (Preparation 49, 800 mg, 4.29 mmol) in THF (10 mL) was added NaH (514 mg, 12.9 mmol, 60% purity), followed by the addition of MeI (608 mg, 4.29 mmol) and CS2 (326 mg, 4.29 mmol). The reaction mixture was stirred at 50 ° C for 3 h. The reaction was quenched with NH4Cl (10 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (10 mL x 2), dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography (PE / EtOAc 5 / 1) to give S-methyldithiocarbonate O-(3-(4-chloropyrimidin-2-yl)oxetane-3-yl) ester (450 mg, 37.9% yield) as a yellow oil. 1 H NMR: (400MHz, CDCl3) δ: ppm 8.55 (d, J = 5.6 Hz, 1H), 7.21 (d, J = 5.2 Hz, 1H), 5.20-5.18 (m, 2H), 5.13-5.11 (m, 2H), 2.59 (s, 3H).

[1034] Preparation 51

[1035] 4-Chloro-2-(oxetan-3-yl)pyrimidine

[1036]

[1037] A mixture of S-methyl dithiocarbonic acid O-(3-(4-chloropyrimidin-2-yl)oxetane-3-yl) ester (Preparation 50, 450 mg, 1.63 mmol), tributyltin (946 mg, 3.25 mmol) and AIBN (26.7 mg, 163 μmol) in toluene (5 mL) was stirred at 125 ° C and N2 for 1 h. The mixture was quenched with KF (5 mL), filtered and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL x 2), dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography (petroleum ether / EtOAc 3 / 1) to give 4-chloro-2-(oxetane-3-yl)pyrimidine (105 mg, 37.8% yield) as a yellow oil. 1 H NMR: (400MHz, CDCl3) δ: ppm 8.63 (d, J = 5.6Hz, 1H), 7.27-7.26 (m, 1H), 5.07-5.01 (m, 4H), 4.52-4.46 (m, 1H).

[1038] Preparation 52

[1039] 3-(6-Bromopyridin-2-yl)oxetan-3-ol

[1040]

[1041] To a solution of 2,6-dibromopyridine (1.0 g, 4.22 mmol) in DCM (20 mL) was added n-BuLi (2.5 M, 1.5 mL) at -70 ° C over 30 min, followed by addition of oxetane-3-one (304 mg, 4.22 mmol) at -70 ° C over 1 h. The mixture was quenched with saturated NH4Cl (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography (PE / EtOAc 5 / 1) to give 3- (6-bromopyridin-2-yl) oxetane-3-ol (430 mg, 44.3% yield) as a white solid. 1HNMR: (400MHz, CDCl3) δ: ppm 7.93 (d, J = 7.6 Hz, 1H), 7.75-7.71 (m, 1H), 7.50 (d, J = 8.0 Hz, 1H), 5.26 (s, 1H), 5.08-5.06 (m, 2H), 4.72-4.69 (m, 2H).

[1042] Preparation 53

[1043] 2-Bromo-6-(3-hydroxytetrahydrofuran-3-yl)-4-methyl-pyridine

[1044]

[1045] 2-Bromo-6-(3-hydroxytetrahydrofuran-3-yl)-4-methyl-pyridine was obtained as a yellow solid, 570 mg, 55.4% yield, from 2,6-dibromo-4-methylpyridine and dihydrofuran-3(2H)-one following a procedure similar to that described in Preparation 52. LCMS m / z = 258.0 [M+H] +

[1046] Preparation 54

[1047] 2-Bromo-6-(3-methoxyoxetan-3-yl)pyridine

[1048]

[1049] NaH (149 mg, 3.74 mmol, 60% purity) was added to a mixture of 3-(6-bromopyridin-2-yl)oxetane-3-ol (Preparation 52, 430 mg, 1.87 mmol) in THF (8 mL) at 0 ° C. After 10 min, iodomethane (398 mg, 2.81 mmol) was added and the reaction mixture was stirred at 30 ° C for 2 h. The mixture was quenched with saturated NH4Cl (10 mL), poured into H2O (10 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were dried over Na2SO4, filtered, concentrated under reduced pressure and purified by column silica gel chromatography (PE / EtOAc 5 / 1) to give 2-bromo-6-(3-methoxyoxetane-3-yl)pyridine (416.3 mg, 91.2% yield) as a colorless oil. 1 H NMR: (400MHz, CDCl3) δ: ppm 7.61-7.58(m,1H),7.46-7.41(m,1H),7.40-7.39(m,1H),5.05-5.04(m,2H),4.86-4.84(m,2H),3.24(s,3H).

[1050] Preparation 55

[1051] 2-Fluoro-6-(3-methoxytetrahydrofuran-3-yl)pyridine

[1052]

[1053] 2-Fluoro-6-(3-methoxytetrahydrofuran-3-yl)pyridine was obtained as a colorless oil from 3-(6-fluoro-2-pyridyl)tetrahydrofuran-3-ol and iodomethane following a procedure similar to that described in Preparation 54, 327 mg, 38%. LCMS m / z = 198.1 [M+H] +

[1054] Preparation 56

[1055] 2-Bromo-6-(3-methoxytetrahydrofuran-3-yl)-4-methyl-pyridine

[1056]

[1057] Following a procedure similar to that described in Preparation 54, 2-bromo-6-(3-hydroxytetrahydrofuran-3-yl)-4-methyl-pyridine was obtained as a brown oil from 2-bromo-6-(3-hydroxytetrahydrofuran-3-yl)-4-methyl-pyridine (Preparation 53) and iodomethane, 500 mg, 94.9% yield. LCMS m / z = 272.1 [M+H] +

[1058] Preparation 57

[1059] 2-Bromo-6-(3-fluorooxetan-3-yl)pyridine

[1060]

[1061] To a solution of 3-(6-bromopyridin-2-yl)oxetane-3-ol (preparation 52, 680 mg, 2.96 mmol) in DCM (15 mL) was added DAST (715 mg, 4.43 mmol) at 0 ° C. The reaction mixture was stirred at 25 ° C for 4 h. The mixture was quenched with a Na2CO3 aqueous solution (15 mL), poured into H2O (20 mL) and extracted with EtOAc (20 mL x 2). The combined organic layer was washed with brine (20 mL x 2), dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography (PE / EtOAc 3 / 1) to give 2-bromo-6-(3-fluorooxetane-3-yl)pyridine (493 mg, 71.9% yield) as a white solid. 1H NMR: (400MHz, CDCl3) δ: ppm 7.62-7.58(m,1H), 7.49-7.45(m,2H), 5.19-5.11(m,2H), 5.01-4.94(m,2H).

[1062] Preparation 58

[1063] 6'-Chloro-1'-(2-(1,1-difluoroethyl)-6-methoxypyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]

[1064]

[1065] To a solution of 6'-chloro-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine] (Preparation 4, 80.0 mg, 0.443 mmol), 4-chloro-2-(1,1-difluoroethyl)-6-methoxypyrimidine (111 mg, 0.531 mmol), and K3PO4 (132 mg, 0.620 mmol) in DMF (2 mL) was added Xantphos (25.7 mg, 0.0443 mmol) and Pd2(dba)3 (40.6 mg, 0.0443 mmol). The reaction mixture was stirred at 70°C under N2 for 5 h. The mixture was diluted with water (60 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated in vacuo to afford the crude product, which was purified by silica gel chromatography (PE / EtOAc 1 / 0 to 3 / 1) to afford 6'-chloro-1'-(2-(1,1-difluoroethyl)-6-methoxypyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine] (150 mg, 96.0% yield) as a white solid. LCMS m / z = 353.0 [M+H] + . 1 H NMR: (500MHz, CDCl3) δ: ppm8.32(s,1H),7.58(s,1H),5.90(s,1H),4.03(s,3H ), 3.99 (s, 2H), 2.07 (t, J = 18.5Hz, 3H), 1.26-1.22 (m, 2H), 1.21-1.19 (m, 2H).

[1066] Preparations 59 to 66

[1067] The compounds in the table below were prepared following procedures analogous to those described in Preparation 58 from 6'-chloro-l',2'-dihydrospiro[cyclopropane-l,3'-pyrrolo[3,2-c]pyridine] (Preparation 4) and the appropriate heterocycle.

[1068]

[1069]

[1070]

[1071] A=Use K2CO3 instead of K3PO4

[1072] B=Use Cs2CO3 instead of K3PO4

[1073] C = using dioxane as the reaction solvent

[1074] Preparation 67

[1075] 6'-Chloro-1'-(2-(1,1-difluoroethyl)pyrimidin-4-yl)-1',2'-dihydrospiro[cyclopentane-1,3'-pyrrolo[3,2-c]pyridine]

[1076]

[1077] 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 CsCO (125 mg, 383 μmol) in dioxane (2 mL) was heated at 100° C. under N for 2 h. The mixture was filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel chromatography (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] + .

[1078] Preparation 68

[1079] 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 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), Xantphos Pd G4 (59 mg, 62 μmol) in dioxane (6 mL) was heated at 110 °C under N2 for 1 h. The mixture was filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel chromatography (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 as a white powder (116 mg, 40% yield). LCMS m / z = 466.2 [M+H] + .

[1080] Preparation 69

[1081] 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

[1082]

[1083] 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 analogous to that described in Preparation 68. LCMS m / z = 466.2 [M+H] + .

[1084] Preparation 70

[1085] 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

[1086]

[1087] 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 (252 mg, 88% yield) was prepared from tert-butyl 6'-chloro-1',2'-dihydrospiro[piperidine-4,3'-pyrrolo[3,2-c]pyridine]-1-carboxylate and 2-bromo-6-(1,1-difluoroethyl)pyridine in a manner analogous to that described in Preparation 68. LCMS m / z = 465.2 [M+H] + .

[1088] Preparation 71

[1089] 6'-Chloro-1'-(6-chloro-2-(1,1-difluoroethyl)pyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]

[1090]

[1091] A mixture of 6'-chloro-1', 2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine] (preparation 4, 1.1 g, 6.09 mmol), Cs2CO3 (3.97 g, 12.2 mmol) and 4,6-dichloro-2-(1,1-difluoroethyl) pyrimidine (preparation 32, 1.32 g, 6.2 mmol) in DMF (22 mL) was stirred at rt for 1 h. The reaction mixture was diluted with EtOAc and washed with water. The organic layer was separated, dried and concentrated under reduced pressure. The residue was filtered and washed with cold MeOH to give 6'-chloro-1'-(6-chloro-2-(1,1-difluoroethyl) pyrimidin-4-yl)-1', 2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine] (1.86 g, 85% yield). LCMS m / z=357.0[M+H] + .

[1092] Preparation 72

[1093] 6-Chloro-1-(6-chloro-2-(1,1-difluoroethyl)pyrimidin-4-yl)-2,3-dihydro-1H-pyrrolo[3,2-c]pyridine

[1094]

[1095] By 6- chloro-2,3-dihydro-1H-pyrrolo [3,2-c] pyridine (300mg, 1.94mmol), Cs2CO3 (1.26g, 3.88mmol) and 4,6- dichloro-2- (1,1- difluoroethyl) pyrimidine (preparation 30,420mg, 1.97mmol) in DMF (5mL) mixture was stirred at rt for 1h. The reaction mixture was diluted with EtOAc and washed with water (x 5). The organic layer was separated, dried and concentrated under reduced pressure. The crude material was purified by silica gel chromatography (0-80% EtOAc in heptane) to obtain 6- chloro-1- (6- chloro-2- (1,1- difluoroethyl) pyrimidin-4-yl) -2,3- dihydro -1H- pyrrolo [3,2-c] pyridine (358mg, 56% yield). LCMS m / z=331.0[M+H] + .

[1096] Preparation 73

[1097] 6'-Chloro-1'-(2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]

[1098]

[1099] A mixture of 4-chloro-2-(1,1-difluoroethyl)-6-methylpyrimidine (Preparation 41, 1.7 g, 8.83 mmol), CsCO (8.6 g, 26.5 mmol) and 6'-chloro-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine] (Preparation 4, 1.6 g, 8.83 mmol) in DMF (15 mL) was stirred at 80 ° C for 3 h. The mixture was poured into H O (50 mL) and extracted with EtOAc (50 mL x 3). The organic layer was washed with brine (50 mL x 2), dried over Na SO and filtered. The filtrate was concentrated and the residue was purified by silica gel chromatography (PE / EtOAc 20 / 1 to 3 / 1) to give 6'-chloro-1'-(2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine] (2.15 g, 72.3% yield) as a yellow solid. 1 H NMR: (400MHz, CDCl3) δ: ppm 8.35 (s, 1H), 7.60 (s, 1H), 6.44 (s, 1H), 4.09 (s, 2H), 2.56 (s, 3H), 2.09 (t, J = 18.5Hz, 3H), 1.26-1.21 (m, 4H).

[1100] Preparation 74

[1101] 6'-Chloro-1'-(4-(1,1-difluoroethyl)-6-methoxypyrimidin-2-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]

[1102]

[1103] To a solution of 2-chloro-4-(1,1-difluoroethyl)-6-methoxypyrimidine (Preparation 28, 70 mg, 0.336 mmol) in DMF (2 mL) was added 6'-chloro-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine] (Preparation 4, 60.6 mg, 0.336 mmol) and CsCO (219 mg, 0.671 mmol). The reaction mixture was stirred at 100°C for 16 h. The mixture was concentrated and the residue was purified by silica gel chromatography (PE / EtOAc 10 / 1) to afford 6'-chloro-1'-(4-(1,1-difluoroethyl)-6-methoxypyrimidin-2-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine] (50 mg, 42.2% yield) as a yellow solid. 1 H NMR: (400MHz, CDCl3) δ: ppm8.16(s,1H),7.57(s,1H),6.61(s,1H),4.29(s,2H),4.07(s,3H),2.01-1.92(m,3H),1.20(s,4H).

[1104] Preparation 75

[1105] 6'-Chloro-1'-(4-(1,1-difluoroethyl)-6-methylpyrimidin-2-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]

[1106]

[1107] 6'-Chloro-1'-(4-(1,1-difluoroethyl)-6-methylpyrimidin-2-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine] (167 mg, 89.4% yield) was obtained as a yellow solid from 6'-chloro-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine] (Preparation 4) and 2-chloro-4-(1,1-difluoroethyl)-6-methylpyrimidine (Preparation 26). 1H NMR: (500MHz, CDCl3) δ: ppm 8.22 (s, 1H), 7.57 (s, 1H), 7.04 (s, 1H), 4.30 (s, 2H), 2.57 (s, 3H), 2.00 (t, J = 19.0Hz, 3H), 1.19-1.18 (m, 4H).

[1108] Preparation 76

[1109] 6'-Chloro-1'-(6-(3-methoxyoxetan-3-yl)pyridin-2-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]

[1110]

[1111] To a mixture of 2-bromo-6-(3-methoxyoxetan-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) was added 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). The reaction mixture was stirred at 100 ° C. under N2 for 3 h. The mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography (PE / EtOAc 3 / 1) to give 6'-chloro-1'-(6-(3-methoxyoxetan-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 H NMR: (400MHz, CDCl3) δ: ppm 8.28(s,1H),7.73(t,J=8.0Hz,1H),7.53(s,1H),7.08(d,J=7.6Hz,1H),6.67(d,J=8.0Hz,1H ),5.06(d,J=6.8Hz,2H),4.96(d,J=6.8Hz,2H),4.14(s,2H),3.31(s,3H),1.22-1.18(m,4H).

[1112] Preparations 77 to 83

[1113] The compounds in the following table were prepared following procedures analogous to those described in Preparation 76 from the appropriate pyrrolo[3,2-c]pyridine and the appropriate heterocycle listed below.

[1114] Heterocycle 1: 2-bromo-6-(1,1-difluoroethyl)pyridine

[1115] Heterocycle 2: 2-bromo-6-(tetrahydrofuran-3-yl)pyridine

[1116]

[1117]

[1118]

[1119] Preparation 84

[1120] 6-Chloro-1-(6-(1,1-difluoroethyl)pyridin-2-yl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-c]pyridine

[1121]

[1122] 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), KCO (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 N and then heated at 110 ° C for 1 h. The reaction was cooled, filtered, and the filtrate was diluted with EtOAc and washed with brine. The organic layer was separated, dried, and concentrated in vacuo. The crude material was purified by silica gel chromatography (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] +

[1123] Preparation 85

[1124] 6'-Chloro-1'-(2-(1,1-difluoroethyl)pyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]

[1125]

[1126] To a solution of 6'-chloro-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine] (Preparation 4 45 mg, 249 μmol) in DMF (1 mL) was added NaH (15 mg, 374 μmol, 60% in mineral oil) and the mixture was stirred at rt for 10 min. 4-Chloro-2-(1,1-difluoroethyl)pyrimidine (49 mg, 274 μmol) was added and the reaction was stirred at 60 ° C for 2 h. The mixture was diluted with EtOAc and washed with water (× 2). The organic layer was separated, dried, and concentrated under reduced pressure. The crude material was purified by silica gel chromatography (0-80% EtOAc in heptane) to give 6-chloro-1-[2-(1,1-difluoroethyl)pyrimidin-4-yl]spiro[2H-pyrrolo[3,2-c]pyridine-3,1′-cyclopropane] (78 mg, 97% yield) as a white powder. LCMS m / z = 323.1 [M+H] + .

[1127] Preparation 86 to 99

[1128] The compounds in the following table were prepared following procedures analogous to those described in Preparation 85 from 6'-chloro-l',2'-dihydrospiro[cyclopropane-l,3'-pyrrolo[3,2-c]pyridine] (Preparation 4) and the appropriate heterocycle listed below.

[1129] Heterocycle 3: 2-chloro-4-(1,1-difluoroethyl)pyrimidine

[1130] Heterocycle 4: 4-chloro-2-(2-fluoroprop-2-yl)pyrimidine

[1131] Heterocycle 5: 2-fluoro-6-(3-methoxytetrahydrofuran-3-yl)pyridine (Preparation 57)

[1132] Heterocycle 6: 3-(6-fluoropyridin-2-yl)tetrahydrofuran-3-ol (commercially available)

[1133]

[1134]

[1135]

[1136]

[1137]

[1138]

[1139] A=THF was used as the reaction solvent

[1140] Preparation 100

[1141] 2-(6'-chlorospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-1'(2'H)-yl)thiazole

[1142]

[1143] To a cooled solution of 6'-chloro-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine] (Preparation 4, 45 mg, 249.1 μmol) in DMF (2.03 mL) was added NaH (14.95 mg, 373.7 μmol, 60% purity). The solution was stirred at rt for 20 min, 2-bromothiazole (49.0 mg, 299 μmol) was added, and the reaction was stirred at 60 ° C overnight. The mixture was diluted with EtOAc, washed with NaHCO 3, H 2 O, and brine. The organic layer was dried over Na 2 SO 4 and the solvent was removed in vacuo to give 2-(6'-chlorospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-1'(2'H)-yl)thiazole. LCMS m / z=264[M+H] +

[1144] Preparation 101

[1145] 6'-Chloro-1'-(6-methylpyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]

[1146]

[1147] To a solution of 6'-chloro-1', 2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine] (preparation 4,50 mg, 277 μmol) in DMSO (2 mL) was added KOtBu (62.1 mg, 554 μmol) and 4-chloro-6-methylpyrimidine (71 mg, 553.6 μmol). The reaction mixture was stirred at rt for 20 min. The mixture was diluted with EtOAc and washed with water (x 3) and brine. The organic layer was separated, dried and concentrated under reduced pressure to give 6'-chloro-1'-(6-methylpyrimidin-4-yl)-1', 2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine] (81 mg), which was used without further purification. LCMS m / z=273.0[M+H] + .

[1148] Preparation 102 to 120

[1149] The compounds in the following table were prepared following the procedure described in Preparation 101 from 6'-chloro-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine] (Preparation 4) and the appropriate heterocycle.

[1150]

[1151]

[1152]

[1153]

[1154]

[1155]

[1156] Preparation 121

[1157] 6'-Chloro-1'-(6-methyl-2-(methylthio)pyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]

[1158]

[1159] To a solution of 6'-chloro-1', 2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine] (preparation 4, 100 mg, 554 μmol) in THF (5 mL) was added KOtBu (1M in THF, 1.11 mL) and 4-chloro-6-methyl-2-(methylthio)pyrimidine. The reaction mixture was stirred at rt for 30 min. The mixture was diluted with EtOAc and washed with brine. The organic layer was separated, dried and concentrated, and then diluted with EtOAc. The precipitate was filtered and dried to give 80 mg of 6'-chloro-1'-(6-methyl-2-(methylthio)pyrimidin-4-yl)-1', 2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]. The mother liquor was evaporated and purified by column silica gel chromatography (0-80% EtOAc-EtOH 3:1 (containing 2% NH4OH) in heptane) to give an additional 38 mg of the title compound (total 138 mg, 78% yield) LCMS m / z = 319.0 [M+H] + .

[1160] Preparation 122

[1161] 2-(6'-chlorospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-1'(2'H)-yl)-5-methylthiazole

[1162]

[1163] A solution of 6'-chloro-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine] (Preparation 4, 60 mg, 332.2 μmol) in THF (2.70 mL) was purged with N2. KOtBu (1 M, 398.6 μL) was added and the reaction mixture was stirred at rt for 20 min. 2-bromo-5-methyl-thiazole (70.97 mg, 398.6 μmol) was then added and the reaction was stirred at 60 ° C overnight. The mixture was diluted with EtOAc and washed with NaHCO3, H2O and brine. The organic layer was dried over Na2SO4 and the solvent was removed in vacuo to give 2-(6'-chlorospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-1'(2'H)-yl)-5-methylthiazole. LCMS m / z=278[M+H] +

[1164] Preparation 123

[1165] 2-(6'-chlorospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-1'(2'H)-yl)-4-(1,1-difluoroethyl)thiazole

[1166]

[1167] 2-(6'-Chlorospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-1'(2'H)-yl)-4-(1,1-difluoroethyl)thiazole was prepared from 6'-chloro-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine] (Preparation 4) and 2-bromo-4-(1,1,-difluoroethyl)thiazole following the procedure described in Preparation 122. LCMS m / z = 328 [M+H] +

[1168] Preparation 124

[1169] 2-(6'-chlorospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-1'(2'H)-yl)-4,5-dimethylthiazole

[1170]

[1171] 2-(6'-Chlorospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-1'(2'H)-yl)-4,5-dimethylthiazole was prepared from 6'-chloro-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine] (Preparation 4) and 2-bromo-4,5-dimethylthiazole following the procedure described in Preparation 122. LCMS m / z = 292 [M+H]+

[1172] Preparation 125

[1173] 2-(6'-chlorospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-1'(2'H)-yl)-4-(tetrahydro-2H-pyran-3-yl)thiazole

[1174]

[1175] 2-(6'-Chlorospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-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) following the procedure described in Preparation 122. LCMS m / z = 348 [M+H] +

[1176] Preparation 126

[1177] 2-(6'-chlorospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-1'(2'H)-yl)-5-methyl-4-(tetrahydrofuran-3-yl)thiazole

[1178]

[1179] 2-(6'-Chlorospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-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 following the procedure described in Preparation 122. LCMS m / z = 348 [M+H] +

[1180] Preparation 127

[1181] 6'-Chloro-1'-(2-(1,1-difluoroethyl)-6-(2-methoxyethoxy)pyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]

[1182]

[1183] 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-methoxyethan-1-ol (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 x 3) and brine (30 mL), dried over Na2SO4, filtered and concentrated under vacuum to give the crude product, which was purified by silica gel chromatography (PE / EtOAc 1 / 0 to 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. 1 H NMR: (400MHz, 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=18.5Hz,3H),1.25-1.22(m,2H),1.21-1.17(m,2H).

[1184] Preparation 128

[1185] 6'-Chloro-1'-(2-(1,1-difluoroethyl)-6-(3-methoxycyclobutyloxy)pyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]

[1186]

[1187] 6'-Chloro-1'-(2-(1,1-difluoroethyl)-6-(3-methoxycyclobutyloxy)pyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine] (80.0 mg, 52.0% yield) was obtained as a white solid 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 3-methoxycyclobutan-1-ol following a procedure similar to that described in Preparation 127. LCMS m / z = 423.1 [M+H] + .

[1188] Preparation 129

[1189] 6'-Chloro-1'-(6-cyclopropyloxy-2-(1,1-difluoroethyl)pyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]

[1190]

[1191] 6'-Chloro-1'-(6-cyclopropyloxy-2-(1,1-difluoroethyl)pyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine] (80.0 mg, 68.6% yield) was obtained as a white solid 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 cyclopropanol. 1 H NMR: (400MHz, 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. 4Hz,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).

[1192] Preparation 130

[1193] 6-(6'-chlorospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-1'(2'H)-yl)-2-(1,1-difluoroethyl)-N,N-dimethylpyrimidin-4-amine

[1194]

[1195] 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] (prepared 71, 50 mg, 140 μmol) and N-methylmethanamine (2M in THF, 2 mL) was stirred for 1 h at rt. The solvent was evaporated and the residue was diluted with EtOAc and washed with water and brine. The organic layer was dried and concentrated to give 6-(6'-chlorospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-1'(2'H)-yl)-2-(1,1-difluoroethyl)-N,N-dimethylpyrimidin-4-amine (49 mg, 95.7% yield) as a white powder, which was used without further purification. LCMS m / z=366.1[M+H] + .

[1196] Preparation 131

[1197] 6-(6'-chlorospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-1'(2'H)-yl)-2-(1,1-difluoroethyl)-N-methylpyrimidin-4-amine

[1198]

[1199] 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 methylamine (2M, 2.0 mL) was stirred overnight at rt. The solvent was removed and the crude was diluted with EtOAc and washed with water followed by 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 HNMR(400MHz, CDCl3)δ8.32(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=5.0Hz),2.05(t,3H,J=18.6Hz),1.30-1.20(m,4H)

[1200] Preparation 132 to 135

[1201] The compounds in the following table were prepared following the procedure described in Preparation 131 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.

[1202]

[1203]

[1204] Preparation 136

[1205] 6'-Chloro-1'-(6-(1,1-difluoroethyl)-5-fluoropyridin-2-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]

[1206]

[1207] A solution of 1-(6-(6'-chlorospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin]-1'(2'H)-yl)-3-fluoropyridin-2-yl)ethan-1-one (Preparation 64, 120.0 mg, 0.378 mmol) in DAST (1 mL) was stirred at 60° C. for 4 h. The mixture was diluted with DCM (30 mL) and treated with H 2 O (50 mL). The organic layer was washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under vacuum to give the crude product, which was purified by silica gel chromatography (PE / EtOAc 1 / 0 to 1 / 1) to give 6'-chloro-1'-(6-(1,1-difluoroethyl)-5-fluoropyridin-2-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine] (80.0 mg, 62.3% yield) as a white solid. 1 H NMR: (400MHz, CDCl3) δ: ppm 8.02(s,1H),7.50-7.44(m,2H),6.72-6.68(m,1H),4.03(s,2H),2.07(t,J=19.6Hz,3H),1.17-1.15(m,2H),1.13-1.11(m,2H).

[1208] Preparation 137

[1209] 6'-Chloro-1'-(2-(1,1-difluoroethyl)-6-ethylpyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]

[1210]

[1211] 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, 50 mg, 140 μmol) and Pd(DPEPhos)Cl2 (1.0 mg, 1.40 μmol) in THF (2 mL) was added ethylzinc bromide (0.5 M, 336 μL) under N2. The reaction mixture was stirred at rt overnight. The mixture was treated with water and evaporated to dryness. The residue was dry loaded onto silica gel and purified by silica gel chromatography (0-60% EtOAc in heptane) to give 6'-chloro-1'-(2-(1,1-difluoroethyl)-6-ethylpyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine] (38 mg, 77% yield). LCMS m / z = 351.1 [M+H] + . 1 H NMR: (400MHz, CDCl3) δ: ppm8.39(s,1H),7.62(s,1H),6.45(s,1H),4.13(s,2H),2.8 3(q,2H,J=7.7Hz),2.10(t,3H,J=18.4Hz),1.34(t,3H,J=7.7Hz),1.30-1.20(m,4H).

[1212] Preparation 138

[1213] 6'-Chloro-1'-(2-(1,1-difluoroethyl)-6-isopropylpyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]

[1214]

[1215] 6'-Chloro-1'-(2-(1,1-difluoroethyl)-6-isopropylpyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine] (Preparation 71) and bromo(isopropyl)zinc were prepared in a manner analogous to that of Preparation 137. LCMS m / z = 365.1 [M+H] +

[1216] Preparation 139

[1217] 6'-Chloro-1'-(6-cyclopropyl-2-(1,1-difluoroethyl)pyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]

[1218]

[1219] 6'-Chloro-1'-(6-cyclopropyl-2-(1,1-difluoroethyl)pyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine] (Preparation 71) and cyclopropylzinc bromide were prepared using a similar method as described in Preparation 137. LCMS m / z = 363.1 [M+H] + .

[1220] Preparation 140

[1221] 6'-Chloro-1'-(6-cyclobutyl-2-(1,1-difluoroethyl)pyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]

[1222]

[1223] 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 were prepared using a similar method as described in Preparation 137. LCMS m / z = 377.2 [M+H] + .

[1224] Preparation 141

[1225] 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]

[1226]

[1227] 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, 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) was added DME (2 mL) 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 crystal mixture was sonicated and added to the reaction vial. The reaction mixture was stirred and irradiated with a blue LED at rt overnight. The mixture was concentrated under vacuum, diluted with water and extracted with EtOAc (x 3). The combined organic layer was washed with brine, dried and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel chromatography (0-80% EtOAc in heptane) to give 6'-chloro-1'-(2-(1,1-difluoroethyl)-6-(oxetanes-3-yl)pyrimidin-4-yl)-1', 2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine] (11 mg, 10.4% yield). LCMSm / z=379.2[M+H] + .

[1228] Preparation 142 to 144

[1229] The compounds in the following table were prepared following procedures analogous to those described in Preparation 147 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.

[1230]

[1231]

[1232] Preparation 145

[1233] 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]

[1234]

[1235] 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, 150 mg, 420 μmol), tetrahydrofuran-2-carboxylic acid (146 mg, 1.26 mmol), and CsCO (410 mg, 1.26 mmol) in DMF (10 mL) was stirred under N2. In a separate vial, NiCl2 glyme (9.2 mg, 42 μmol), dtbbpy (16.9 mg, 63.0 μmol), and Ir[dF(CF3)ppy]2(dtbpy)PF6 (4.71 mg, 4.20 μmol) were combined in DMF (10 mL) under N2. The crystal mixture was sonicated and added to the reaction vial. The reaction mixture is stirred and irradiated with a blue LED (450 nm) at rt for 72 h under N2. The mixture is diluted with EtOAc, washed with water (x 5) and brine. The organic layer is separated, dried, and filtered. The filtrate is concentrated and the crude product is purified by silica gel chromatography (0-80% EtOAc in heptane) to give 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] (26 mg, 16% yield) as a white powder. LCMSm / z=393.1[M+H] + .

[1236] Preparation 146

[1237] 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

[1238]

[1239] To 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, 50 mg, 140 μmol) and 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropane-1-carbonitrile (32.4 mg, 168 μmol) in dioxane (2 mL) were added Cs2CO3 (2 M in water, 140 μL), Pd(OAc)2 (1.6 mg, 7 μmol) and A (2.5 mg, 7 μmol). The reaction mixture was heated at 90 ° C for 2 h. The mixture was diluted with EtOAc and washed with aqueous NaHCO3. The organic layer was dried and concentrated under vacuum. The crude material was purified by silica gel chromatography (0-90% EtOAc in heptane) to give 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 (32 mg, 59% yield). LCMS m / z=388.1[M+H] + .

[1240] Preparation 147

[1241] 6'-Chloro-1'-(2-(1,1-difluoroethyl)-6-(methylsulfonyl)pyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]

[1242]

[1243] To 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 an aqueous solution of sodium thiomethoxide (2.14 M, 785 μL, 90% purity, 15% w / w) at 0 ° C. The reaction mixture was stirred at 0 ° C to rt for 4 h. The mixture was quenched with water and extracted with EtOAc. The organic layer was separated, dried and concentrated under reduced pressure and used without further purification. LCMS m / z = 369.1 [M + H] + .

[1244] The crude material 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 rt for 16 h and then treated with saturated Na2S2O3 aqueous solution. The mixture was extracted with DCM, washed with saturated NaHCO3 aqueous solution, water and brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel chromatography (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] + .

[1245] Preparation 148

[1246] 6-Chloro-1-(2-(1,1-difluoroethyl)-6-methoxypyrimidin-4-yl)-2,3-dihydro-1H-pyrrolo[3,2-c]pyridine

[1247]

[1248] To a solution 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) in MeOH (2 mL) was added NaOMe (0.5 M, 302 μL) at rt. The reaction mixture was stirred at 60 ° C for 1 h. The mixture was concentrated and purified by silica gel chromatography (0-90% EtOAc in heptane) to give 6-chloro-1-(2-(1,1-difluoroethyl)-6-methoxypyrimidin-4-yl)-2,3-dihydro-1H-pyrrolo[3,2-c]pyridine (21 mg, 43% yield). LCMS m / z=327.0[M+H] + .

[1249] Preparation 149

[1250] 6-(6-chloro-2,3-dihydro-1H-pyrrolo[3,2-c]pyridin-1-yl)-2-(1,1-difluoroethyl)-N-methylpyrimidin-4-amine

[1251]

[1252] A mixture of 6-chloro-1-(6-chloro-2-(1,1-difluoroethyl)pyrimidin-4-yl)-2,3-dihydro-1H-pyrrolo[3,2-c]pyridine (prepared 72, 50 mg, 151 μmol) and methylamine (2M in THF, 2 mL) was stirred overnight at rt. The mixture was concentrated under reduced pressure and purified by silica gel chromatography (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] + .

[1253] Preparation 150

[1254] 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

[1255]

[1256] 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 analogous to that described in Example 12. LCMS m / z = 489.2 [M+H] + .

[1257] Preparation 151

[1258] 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

[1259]

[1260] 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 analogous to that described in Example 12. LCMS m / z = 489.2 [M+H] + .

[1261] Preparation 152

[1262] 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

[1263]

[1264] 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 was prepared from 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 (Preparation 70) and acetamide using a method analogous to that described in Example 12. LCMS m / z = 488.2 [M+H] + .

[1265] Preparation of 153 and 154

[1266] N-(1'-(2-chloro-6-methylpyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin]-6'-yl)acetamide and N-(1'-(4-chloro-6-methylpyrimidin-2-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin]-6'-yl)acetamide

[1267]

[1268] A mixture of N-(1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-6'-yl)acetamide (Preparation 7, 2g, 9.84mmol), NaOtBu (2.84g, 29.52mmol) and Xantphos Pd G3 (491.17mg, 492μmol) in dioxane (100mL) was purged with N2. 2,4-dichloro-6-methyl-pyrimidine (3.21g, 19.68mmol) was added and the reaction was stirred at 90 °C for 1h. The mixture was quenched with 1M NaOH, diluted with brine and extracted with EtOAc. The solid formed in the organic layer was separated by filtration and washed with EtOAc to give 1.32g of solid product 1, Preparation 153. The filtrate was washed with water, dried and concentrated. The crude material was purified by silica gel chromatography (0-80% EtOAc-EtOH 3:1 (containing 2% NH4OH) in heptane) to provide another 710 mg of N-(1'-(2-chloro-6-methylpyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin]-6'-yl)acetamide and 71 mg of N-(1'-(4-chloro-6-methylpyrimidin-2-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin]-6'-yl)acetamide as a white powder. Regioisomers were confirmed by 2D-NMR.

[1269] 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 H NMR (DMSO-d6, 400MHz) δ10.30(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).

[1270] Preparation 154: N-(1'-(4-chloro-6-methylpyrimidin-2-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin]-6'-yl)acetamide. (71 mg, 2% yield). LCMS m / z = 330.0 [M+H] +1 H NMR(DMSO-d6,400MHz)δ10.27(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)

[1271] Preparation 155

[1272] 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

[1273]

[1274] A solution of N-(1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin]-6'-yl)acetamide (Preparation 7, 5 g, 24.60 mmol), 4,6-dichloro-2-(1,1-difluoroethyl)pyrimidine (Preparation 30, 6.55 g, 30.75 mmol), and K3PO4 (10.44 g, 49.20 mmol) in DMF (50 mL) was stirred overnight at 70° C. The cooled mixture was diluted with DMF (10 mL) followed by water (100 mL), and the resulting solid was filtered and dried to afford 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 as a tan solid, 5.9 g. The aqueous layer was extracted with EtOAc, and the combined organic extracts were filtered through silica gel and concentrated in vacuo to provide more title compound. LCMS m / z = 380 [M+H] + ;

[1275] Preparation 156

[1276] N-(1'-(2-(1,1-difluoroethyl)-6-((2,4-dimethoxybenzyl)amino)pyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin-6'-yl)acetamide

[1277]

[1278] To a vial was added 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, 150 mg, 395 μmol), (2,4-dimethoxyphenyl)methanamine (79.25 mg, 474 μmol), K2CO3 (163.75 mg, 1.18 mmol), and DMF (3 mL), and the reaction mixture was stirred at 60°C overnight. The mixture was diluted with EtOAc and washed with aqueous NaHCO3, H2O, and brine. The organic layer was dried over Na2SO4 and the solvent was removed in vacuo. The residue was purified by column chromatography (0 to 100% EtOAc:heptane) to afford 253 mg of N-(1′-(2-(1,1-difluoroethyl)-6-((2,4-dimethoxybenzyl)amino)pyrimidin-4-yl)-1′,2′-dihydrospiro[cyclopropane-1,3′-pyrrolo[3,2-c]pyridin]-6′-yl)acetamide as a yellow oil. LCMS m / z = 511 [M+H] +

[1279] Preparation 157

[1280] N-(1'-(6-Bromo-4-methylpyridin-2-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin-6'-yl)acetamide

[1281]

[1282] A solution of N-(1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-6'-yl)acetamide (prepared 7,5 g, 24.6 mmol) in THF (250 mL) was purged with N2, KHMDS (1 M, 54 mL) was added and the solution was stirred for 20 min. 2,6-dibromo-4-methyl-pyridine (6.2 g, 24.6 mmol) was added and the reaction was stirred at rt overnight. The mixture was quenched with 1 M NaOH, diluted with brine and extracted with EtOAc. The organic layer was separated, dried and concentrated. The crude material was purified by silica gel chromatography (0-80% EtOAc-EtOH 3:1 (containing 2% NH4OH) in heptane) to give N-(1'-(6-bromo-4-methylpyridin-2-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin]-6'-yl)acetamide as a white powder (2.8 g, 30% yield). LCMS m / z = 373.0, 375.0 [M+H] + .

[1283] Preparation 158

[1284] Ethyl 2-(4-chloro-6-methylpyrimidin-2-yl)-2,2-difluoroacetate

[1285]

[1286] A mixture of 2-bromo-2,2-difluoro-ethyl acetate (978 mg, 4.82 mmol) and copper (613 mg, 9.64 mmol) in DMSO (8 mL) was purged with N2 and stirred at rt for 1 h. To this was added a solution of 2-bromo-4-chloro-6-methyl-pyrimidine (500 mg, 2.41 mmol) in DMSO (2 mL) and the resulting mixture was stirred at 40 ° C overnight. The reaction was diluted with water and extracted with EtOAc (x2). The combined organics were dried and concentrated and the residue was purified by silica gel chromatography (0-40% EtOAc / heptane) to give 2- (4-chloro-6-methylpyrimidin-2-yl) -2,2-difluoroethyl acetate (440 mg, 72%) as a colorless oil: LCMS m / z=251[M+H] + .

[1287] Preparation 159

[1288] Ethyl 2-(6-chloro-4-methylpyridin-2-yl)-2,2-difluoroacetate

[1289]

[1290] The title compound was prepared as a yellow oil (585 mg, 63%) from ethyl 2-bromo-2,2-difluoro-acetate and 2-bromo-6-chloro-4-methylpyridine using a method similar to that described for Preparation 158. LCMS m / z = 250 [M+H] + .

[1291] Preparation 160

[1292] 2-(6-chloro-4-methylpyridin-2-yl)-2,2-difluoroethan-1-ol

[1293]

[1294] To a solution of ethyl 2-(6-chloro-4-methylpyridin-2-yl)-2,2-difluoroacetate (Preparation 159, 500 mg, 2.0 mmol) in EtOH (9 mL) was added NaBH4 (152 mg, 4.0 mmol) and the mixture was stirred at room temperature for 1 h. The reaction was neutralized with 2M HCl and evaporated to remove the solvent. The residue was purified by silica gel chromatography (0-80% [(3:1 EtOAc / EtOH) + 2% NH4OH] / heptane) to afford 2-(6-chloro-4-methylpyridin-2-yl)-2,2-difluoroethan-1-ol (305 mg, 73%) as a white solid. LCMS m / z = 208 [M+H] + .

[1295] Preparation 161

[1296] 2-Chloro-6-(1,1-difluoro-2-methoxyethyl)-4-methylpyridine

[1297]

[1298] To a mixture of 2-(6-chloro-4-methylpyridin-2-yl)-2,2-difluoroethane-1-ol (Preparation 160, 140 mg, 0.674 mmol) in DMF (3 mL) was added NaH (54 mg, 1.35 mmol, 60% in mineral oil) at 0 ° C. and stirred for 5 min, followed by addition of MeI (957 mg, 6.74 mmol) and stirring the reaction mixture at rt for 1 h. The reaction mixture was diluted with EtOAc, washed with water (3x) and brine. The organic layer was separated, dried and evaporated to dryness and the residue was purified by silica gel chromatography (0-100% EtOAc / heptane) to give 2-chloro-6-(1,1-difluoro-2-methoxyethyl)-4-methylpyridine (91 mg, 61%). LCMS m / z=222[M+H] + .

[1299] Preparation 162

[1300] 2-Chloro-4-methyl-6-(1,1,2-trifluoroethyl)pyridine

[1301]

[1302] To a solution of 2-(6-chloro-4-methylpyridin-2-yl)-2,2-difluoroethane-1-ol (Preparation 160, 150 mg, 0.72 mmol) in DCM (4 mL) was added DAST (191 mL, 1.45 mmol) at 0 ° C and the resulting mixture was stirred at 60 ° C for 3 h. The reaction was cooled to 0 ° C, quenched with MeOH, solid NaHCO 3 was slowly added, the mixture was diluted with water and extracted with DCM. The organic layer was separated, dried and evaporated to dryness to give 2-chloro-4-methyl-6-(1,1,2-trifluoroethyl)pyridine (94 mg), which was used without further purification. LCMS m / z = 210 [M + H] +

[1303] Preparation 163

[1304] 2-(1,1-difluoropropyl)pyrimidine-4,6-diol

[1305]

[1306] To a solution of malonamide (210 mg, 2.06 mmol) in EtOH (5 mL) was added sodium tert-butoxide (692 mg, 7.20 mmol) and the mixture was stirred at 25 ° C for 30 min. To this was added ethyl 2,2-difluorobutyrate (642 mg, 4.22 mmol) and the reaction was heated under reflux for 24 h. The reaction mixture was cooled to rt, HCl (4N, 2.57 mL) was added and the precipitate was removed by filtration. The filtrate was concentrated under reduced pressure and the residue was partitioned between EtOAc and H2O (very little) and separated. The combined organics were dried (MgSO4) and evaporated to dryness. The residue was purified by silica gel chromatography (0-100% EtOAc / EtOH (3: 1) in heptane) to give 2-(1,1-difluoropropyl)pyrimidine-4,6-diol (104 mg, 27%) as a white solid. LCMS m / z=191[M+H] + .

[1307] Preparation 164

[1308] 4,6-Dichloro-2-(1,1-difluoropropyl)pyrimidine

[1309]

[1310] The title compound was prepared as a colorless oil (200 mg, 62%) from 2-(1,1-difluoropropyl)pyrimidine-4,6-diol (Preparation 163) using a method analogous to that described for Preparation 30. 1 H NMR (500MHz, CDCl3) δppm 7.50 (s, 1H), 2.29-2.42 (m, 2H), 1.08 (t, J = 7.48Hz, 3H).

[1311] Preparation 165

[1312] 1-Methyl-2-oxabicyclo[2.1.1]hexane-4-carboxylic acid 1,3-dioxoisoindolin-2-yl ester

[1313]

[1314] To a mixture of 1-methyl-2-oxabicyclo[2.1.1]hexane-4-carboxylic acid (145 mg, 1.02 mmol), DMAP (6.23 mg, 0.051 mmol) and 2-hydroxyisoindoline-1,3-dione (166.4 mg, 1.02 mmol) in DCM (5 mL) was added a solution of DCC (253 mg, 1.22 mmol) in DCM (2 mL) and the mixture was stirred overnight at 40° C. The solids were removed by filtration and the filtrate was concentrated to give 1,3-dioxoisoindolin-2-yl 1-methyl-2-oxabicyclo[2.1.1]hexane-4-carboxylate as an off-white powder (303 mg, crude), which was used without further purification. 1 H NMR (500MHz, DMSO-d6) δ8.00-7.90 (m, 4H), 3.98 (s, 2H), 2.26 (br d, 2H, J = 4.3Hz), 1.93 (br d, 2H, J = 4.1Hz), 1.42 (s, 3H).

[1315] Preparation 166

[1316] 1-Fluorocyclopropane-1-carboxylic acid 1,3-dioxoisoindolin-2-yl ester

[1317]

[1318] N, N'-diisopropylmethanediimide (133.4 mg, 1.06 mmol) was added to a solution of 1-fluorocyclopropanecarboxylic acid (100 mg, 0.961 mmol) and 2-hydroxyisoindolin-1,3-dione (196 mg, 1.20 mmol) in THF (3 mL) and the mixture was stirred at rt for 1.5 h. The reaction mixture was evaporated to dryness under reduced pressure and the residue was purified by column chromatography (heptane) to give 1,3-dioxoisoindolin-2-yl 1-fluorocyclopropane-1-carboxylate (183 mg, 79%).

[1319] Preparation 167

[1320] 6'-Chloro-1'-(6-methyl-2-(oxetan-3-yl)pyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]

[1321]

[1322] A solution of 6'-chloro-1'-(6-methylpyrimidin-4-yl)-1',2'-dihydrospiro[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, additional portions of ferrous sulfate heptahydrate and hydrogen peroxide (74.8 mg, 2.20 mmol) were added, and the reaction mixture was stirred at 60°C for 1 hour. The cooled mixture was poured into 0.2M NaOH (saturated with NaCl) and extracted with EtOAc (2x). The combined organics were dried and concentrated, and the residue was purified by silica gel chromatography (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'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine] (24 mg, 10%). LCMS m / z = 329 [M+H] + .

[1323] Preparation 168

[1324] 1'-(2-Bromopyrimidin-4-yl)-6'-chloro-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]

[1325]

[1326] To a solution of 6'-chloro-1', 2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine] (prepared 4,600 mg, 3.32 mmol) in THF (24 mL) was added potassium tert-butoxide (2M in THF, 3.32 mL) and the reaction mixture was stirred at rt for 30 min. The reaction mixture was diluted with EtOAc and washed with brine. The combined organics were dried, concentrated, and the residue was purified by silica gel chromatography (0-80% (3:1 EtOAc / EtOH+2% NH4OH) in heptane) to give 1'-(2-bromopyrimidin-4-yl)-6'-chloro-1', 2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine] (121 mg, 11%). LCMSm / z=337 / 339[M+H] + .

[1327] Preparation 169

[1328] Ethyl 2-(4-(6'-chlorospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-1'(2'H)-yl)pyrimidin-2-yl)-2,2-difluoroacetate

[1329]

[1330] A mixture of ethyl 2-bromo-2,2-difluoroacetate (144.3 mg, 0.711 mmol) and copper (90.4 mg, 1.42 mmol) in DMSO (2 mL) was stirred at 40° C. for 30 min. A solution of 1'-(2-bromopyrimidin-4-yl)-6'-chloro-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine] (Preparation 168, 120 mg, 0.355 mmol) in DMSO (2 mL) was added and the mixture was stirred at 40° C. overnight. The reaction mixture was diluted with EtOAc and washed with water (3x) and brine. The combined organics were dried and evaporated to dryness and the residue was purified by silica gel chromatography (0-100% EtOAc / heptane) to give ethyl 2-(4-(6'-chlorospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin]-1'(2'H)-yl)pyrimidin-2-yl)-2,2-difluoroacetate (94 mg, 69%) as a white powder. LCMS m / z = 381 [M+H] + .

[1331] Preparation 170

[1332] 2-(4-(6'-chlorospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-1'(2'H)-yl)pyrimidin-2-yl)-2,2-difluoroethan-1-ol

[1333]

[1334] NaBH4 (36 mg, 0.945 mmol) was added to a solution of ethyl 2-(4-(6'-chlorospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-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 rt for 1 h. The reaction was quenched with 2M HCl and concentrated to remove volatiles. The residue was diluted with NaHCO3 / brine and extracted with EtOAc (3x). 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 (78 mg, crude) as a white powder, which was used without further purification. LCMS m / z = 339 [M+H]+ .

[1335] Preparation 171

[1336] 6'-Chloro-1'-(2-(1,1-difluoro-2-methoxyethyl)pyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]

[1337]

[1338] 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 rt overnight. The solid was removed by filtration and the filtrate was evaporated to dryness. The residue was purified by silica gel chromatography (0-100% EtOAc / heptane) to afford 6'-chloro-1'-(2-(1,1-difluoro-2-methoxyethyl)pyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine] (46 mg, 59%) as a white solid. LCMS m / z = 353 [M+H] + .

[1339] Preparation 172

[1340] 6'-Chloro-1'-(2-(1,1-difluoroethyl)-6-(1-ethoxyvinyl)pyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]

[1341]

[1342] 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 71,2g, 5.60mmol) and Pd(PPh3)4Cl2 (393mg, 0.56mmol) in DMF (20mL) was added tributyl(1-ethoxyvinyl)stannane (2.22g, 6.16mmol) at rt. The reaction mixture was purged with N2 and then heated at 70°C for 2h. After cooling, the reaction was quenched with saturated KF aqueous solution and diluted with EtOAc. The precipitate was filtered off and the filtrate was collected and washed with water (3x) 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] + .

[1343] Preparation 173

[1344] Ethyl 6-(6'-chlorospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-1'(2'H)-yl)-2-(1,1-difluoroethyl)pyrimidine-4-carboxylate

[1345]

[1346] 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 overnight at rt. The reaction mixture was extracted with EtOAc, and the organic layer was separated, washed with water, brine, then dried and concentrated. The crude material was purified by silica gel chromatography (0-60% EtOAc in heptane) to give ethyl 6-(6'-chlorospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin]-1'(2'H)-yl)-2-(1,1-difluoroethyl)pyrimidine-4-carboxylate (122 mg, 20% yield). LCMS m / z = 395 [M+H] + .

[1347] Preparation 174

[1348] (6-(6'-Chlorospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin-1'(2'H)-yl)-2-(1,1-difluoroethyl)pyrimidin-4-yl)methanol

[1349]

[1350] 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 rt 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)pyrimidine-4-yl)methanol (106 mg, 98% yield), which was used in the next step without further purification. LCMS m / z=353[M+H] + .

[1351] Preparation 175

[1352] 6'-Chloro-1'-(2-(1,1-difluoroethyl)-6-(methoxymethyl)pyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]

[1353]

[1354] To a solution of (6-(6'-chlorospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-1'(2'H)-yl)-2-(1,1-difluoroethyl)pyrimidin-4-yl)methanol (Preparation 174, 90 mg, 0.255 mmol) in DMF (2 mL) was added CsCO (166 mg, 0.510 mmol) and MeI (217 mg, 1.53 mmol), and the mixture was stirred at rt overnight. The reaction mixture was diluted with EtOAc and washed with water (3x) and brine. The combined organics were dried and evaporated to dryness and the residue was purified by silica gel chromatography (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] + .

[1355] Preparation 176

[1356] 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

[1357]

[1358] 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 aq. HCl (2M, 1.91 mL) and the reaction mixture was stirred at rt for 2 h. The mixture was concentrated in vacuo and the residue was diluted with diethyl ether, and the solid formed was filtered, rinsed with diethyl 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] + .

[1359] Preparation 177

[1360] 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

[1361]

[1362] A solution of 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 (Preparation 176, 200 mg, 0.548 mmol) in THF (6 mL) was cooled to 0° C., methylmagnesium chloride (3M in THF, 0.2 mL) was added dropwise, and the resulting mixture was stirred from 0° C. to rt for 1 h. The reaction was quenched with water and extracted with EtOAc. The combined organics were washed with brine, dried, and evaporated to dryness to give 2-(6-(6'-chlorospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin]-1'(2'H)-yl)-2-(1,1-difluoroethyl)pyrimidin-4-yl)propan-2-ol (208 mg, crude) which was used without further purification. LCMS m / z = 381 [M+H] + .

[1363] Preparation 178

[1364] 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]

[1365]

[1366] 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) and N,N-triethylamine trihydrofluoride (42 mg, 0.263 mmol) were added sequentially under N2 and the reaction mixture was stirred at 0 ° C. for 1 h. The reaction was quenched with aqueous NaHCO3 and the mixture was extracted with EtOAc. The combined organics were dried and evaporated to dryness. The residue was purified by silica gel chromatography (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] + .

[1367] Preparation 179

[1368] 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

[1369]

[1370] 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 method similar to that described for Preparation 174. LCMS m / z = 367 [M+H] + .

[1371] Preparation 180

[1372] 6'-Chloro-1'-(2-(1,1-difluoroethyl)-6-(1-fluoroethyl)pyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]

[1373]

[1374] 6'-Chloro-1'-(2-(1,1-difluoroethyl)-6-(1-fluoroethyl)pyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine] (73 mg, 60%) 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-ol (Preparation 179) using a method similar to that described for Preparation 178. LCMS m / z = 369 [M+H] + .

[1375] Preparation 181

[1376] Ethyl 2-(4-(6'-chlorospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-1'(2'H)-yl)-6-methylpyrimidin-2-yl)-2,2-difluoroacetate

[1377]

[1378] A mixture of 6'-chloro-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine] (Preparation 4, 450 mg, 2.49 mmol), ethyl 2-(4-chloro-6-methylpyrimidin-2-yl)-2,2-difluoroacetate (Preparation 158, 892 mg, 2.49 mmol), and CsCO (1.62 g, 4.98 mmol) in DMF (10 mL) was heated at 40° C. overnight. The reaction was partitioned between water and EtOAc, and the organic layer was separated. The combined organics were washed with H O (3×) followed by brine, dried, and evaporated to dryness. The residue was purified by silica gel chromatography (0-80% (3:1 EtOAc / EtOH (+2% NH4OH) in heptane) to afford ethyl 2-(4-(6'-chlorospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin]-1'(2'H)-yl)-6-methylpyrimidin-2-yl)-2,2-difluoroacetate (303 mg, 31%) as a white solid. LCMS m / z = 395.1 [M+H] + .

[1379] Preparation 182

[1380] 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

[1381]

[1382] NaBH4 (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 rt for 1 h. The reaction mixture was quenched with 2M HCl and concentrated to remove volatiles. The residue was diluted with saturated aqueous NaHCO3 solution, brine, and extracted with EtOAc (2x). The combined organics were dried and evaporated to dryness to give 2-(4-(6'-chlorospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin-1'(2'H)-yl)-6-methylpyrimidin-2-yl)-2,2-difluoroethan-1-ol (66 mg, 53%) as a white solid. LCMS m / z = 353.0 [M+H] +

[1383] Preparation 183

[1384] 6'-Chloro-1'-(2-(1,1-difluoro-2-methoxyethyl)-6-methylpyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]

[1385]

[1386] To a mixture of 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 (Preparation 182, 33 mg, 0.094 mmol) and MeI (58 μL, 0.940 mmol) in THF (1.5 mL) was added NaH (7 mg, 0.20 mmol, 60% purity) and the reaction was stirred at rt for 24 h before additional NaH (7 mg, 0.20 mmol, 60% purity) was added. After 3 h, the mixture was heated to 60 ° C and maintained for 2.5 h. The mixture was cooled to rt and quenched with saturated NaHCO 3 and extracted with EtOAc (×2). The combined organics were concentrated under reduced pressure and the residue was purified by silica gel chromatography (0-100% EtOAc / heptane) to afford 6'-chloro-1'-(2-(1,1-difluoro-2-methoxyethyl)-6-methylpyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine] (16 mg, 48%) as a white solid. LCMS m / z = 367.0 [M+H] +

[1387] Preparation 184

[1388] N-(1'-(6-Fluoro-4-methylpyridin-2-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin-6'-yl)acetamide

[1389]

[1390] A mixture of N-(1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-6'-yl)acetamide (preparation 7,4g, 19.7mmol), 2-bromo-6-fluoro-4-methylpyridine (11.22g, 59mmol), Cs2CO3 (12.82g, 39.4mmol) and BrettPhos Pd G3 (892mg, 0.984mmol) in dioxane (160mL) was heated at 100°C for 2h. Josiphos (545mg, 0.984mmol) was added and the reaction was stirred at 90°C overnight. The mixture was diluted with EtOAc and washed with brine. The organic layer was separated and evaporated to dryness and the residue was diluted with MeOH. The solid formed was collected by filtration, washed with MeOH, water and then dried. The resulting solid was dissolved in DCM and filtered. The filtrate was then concentrated and recrystallized from MeCN to give N-(1'-(6-fluoro-4-methylpyridin-2-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin]-6'-yl)acetamide (3.86 g, 63%) as a white powder. LCMS m / z = 313 [M+H] +

[1391] Preparation 185

[1392] Ethyl 2-(6-(6'-acetamidospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-1'(2'H)-yl)-4-methylpyridin-2-yl)-2,2-difluoroacetate

[1393]

[1394] Ethyl 2-(6-(6'-acetamidospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-1'(2'H)-yl)-4-methylpyridin-2-yl)-2,2-difluoroacetate (83 mg, 28%) was prepared from ethyl 2-(6-chloro-4-methylpyridin-2-yl)-2,2-difluoroacetate (Preparation 159) and N-(1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin]-6'-yl)acetamide (Preparation 7) using a similar method as described for Example 93. LCMS m / z = 417 [M+H] + .

[1395] Preparation 186

[1396] 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

[1397]

[1398] N-(1'-(6-Chloro-2-(1,1-difluoropropyl)pyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin]-6'-yl)acetamide (Preparation 7) was obtained as a white solid (24 mg, 40%) from 4,6-dichloro-2-(1,1-difluoropropyl)pyrimidine (Preparation 164) and N-(1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin]-6'-yl)acetamide (Preparation 7) following a procedure analogous to that described in Preparation 72. LCMS m / z = 394.0 [M+H] + .

[1399] Preparation 187

[1400] 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

[1401]

[1402] To a mixture of 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 (Preparation 155, 2 g, 5.27 mmol) and Pd(PPh3)4Cl2 (370 mg, 0.527 mmol) in DMF (20 mL) was added tributyl(1-ethoxyvinyl)stannane (2.28 g, 6.32 mmol) at rt. The mixture was purged with N2 and then heated at 80°C for 30 min. After cooling, the mixture was diluted with EtOAc and the solid was removed by filtration. The filtrate was stirred with KF-alumina (3 g, 40% w) for 30 min. The mixture was filtered and the filtrate was washed with water (3x) and brine. The combined organics were dried and evaporated to dryness under reduced pressure. The resulting solid was collected and rinsed with heptane to give N-(1'-(2-(1,1-difluoroethyl)-6-(1-ethoxyvinyl)pyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin]-6'-yl)acetamide (1.40 g, 64%). LCMS m / z = 416 [M+H] + .

[1403] Preparation 188

[1404] N-(1'-(6-Acetyl-2-(1,1-difluoroethyl)pyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin-6'-yl)acetamide

[1405]

[1406] 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]pyridin]-6'-yl)acetamide (Preparation 187, 110 mg, 0.265 mmol) in acetone (2 mL) was added HCl (2M, 0.4 mL) and the mixture was stirred at rt for 3 h. The reaction mixture was evaporated to dryness under reduced pressure and the residue was diluted with EtOAc and made slightly basic with aqueous Na2CO3. The organics were dried and evaporated to dryness and the residue was purified by silica gel chromatography (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]pyridin]-6'-yl)acetamide (37 mg, 36%). LCMS m / z = 388 [M+H] +

[1407] Preparation 189

[1408] N-(1'-(6-(Chloromethyl)-2-(1,1-difluoroethyl)pyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin-6'-yl)acetamide

[1409]

[1410] To 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 added SOCl2 (222 mg, 1.86 mmol) and the reaction was stirred at rt overnight. The reaction mixture was evaporated to dryness under reduced pressure and the residue was dissolved in EtOAc and washed with NaHCO3 aqueous solution. The combined organics were dried and concentrated to give 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] + .

[1411] Preparation 190

[1412] 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

[1413]

[1414] To 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 sodium tert-butoxide (101 mg, 1.05 mmol) at rt and the mixture was heated at 80° C. for 1 h. Most of the volatiles were removed under reduced pressure and 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]pyridine]-1'(2'H)-yl)-2-(1,1-difluoroethyl)pyrimidin-4-yl)-2-cyanoacetate (145 mg, 60%). LCMS m / z = 457 [M+H] + .

[1415] Preparation 191

[1416] 1-Methyl-2-oxabicyclo[2.1.1]hexane-4-carboxamide

[1417]

[1418] 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 uL) under N2 and the solution was stirred at rt 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 slowly added and the mixture was stirred at rt for 2 h. The solid formed was filtered off and rinsed with MeOH. The filtrate was concentrated, diluted with MeCN, the solid formed was collected by filtration and washed with cold 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] +

[1419] Preparation 192

[1420] 6-Methyl-2-(1-methyl-2-oxabicyclo[2.1.1]hexan-4-yl)pyrimidin-4(3H)-one

[1421]

[1422] A mixture of NaOMe (2.32 mL, 25% in MeOH) and n-BuOH (3.0 mL) was heated to 105°C in a 20 mL sealed vial (punctured with a needle to expose to air) while removing the solvent. To this was slowly added a suspension of (E)-methyl 3-aminobut-2-enoate (300 mg, 2.61 mmol) and 1-methyl-2-oxabicyclo[2.1.1]hexane-4-carboxamide (919.6 mg, 6.51 mmol) in n-BuOH (6.0 mL) and MeOH (6.0 mL). The temperature was raised to 110°C while continuing to remove the solvent and heating the reaction for another 2 h. The cooled reaction mixture was neutralized with concentrated sulfuric acid, the resulting precipitate was filtered off, and the filtrate was concentrated under reduced pressure. The filtrate was concentrated and purified by silica gel chromatography (EtOAc / 0-60% EtOAc-EtOH 3:1+2% AcOH) to give the title compound as a yellow oil (178 mg, 33% yield). LCMS m / z=207 [M+H] +

[1423] Preparation 193

[1424] 4-Chloro-6-methyl-2-(1-methyl-2-oxabicyclo[2.1.1]hexan-4-yl)pyrimidine

[1425]

[1426] A mixture of 6-methyl-2-(1-methyl-2-oxabicyclo[2.1.1]hexan-4-yl)pyrimidin-4(3H)-one (Preparation 192, 170 mg, 824 umol), DMF (64 uL) and POCl3 (253 mg, 1.65 mmol) in toluene (5 mL) was stirred at rt for 2 h. The mixture was concentrated under reduced pressure, EtOAc was added and the mixture was neutralized with NaHCO3(aq). The organic layer was separated, washed with brine, then dried and concentrated to give 4-chloro-6-methyl-2-(1-methyl-2-oxabicyclo[2.1.1]hexan-4-yl)pyrimidine (90 mg, 48% yield) as a yellow oil. LCMS m / z=225[M+H] +

[1427] Preparation 194

[1428] 2-Oxabicyclo[2.1.1]hexane-4-carboxamide

[1429]

[1430] 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 following a procedure analogous to that 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).

[1431] Preparation 195

[1432] 2-(2-Oxabicyclo[2.1.1]hexan-4-yl)-6-methylpyrimidin-4(3H)-one

[1433]

[1434] 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 (E)-3-aminobut-2-enecarboxylate following a procedure similar to that described in Preparation 192. LCMS m / z = 193 [M+H] +

[1435] Preparation 196

[1436] 2-(2-oxabicyclo[2.1.1]hexan-4-yl)-4-chloro-6-methylpyrimidine

[1437]

[1438] Following a procedure similar to that described in Preparation 193, 2-(2-oxabicyclo[2.1.1]hexan-4-yl)-6-methylpyrimidine was obtained as an oil, 715 mg, crude, from 2-(2-oxabicyclo[2.1.1]hexan-4-yl)-6-methylpyrimidin-4(3H)-one. LCMS m / z = 211 [M+H] +

[1439] Preparation 197

[1440] 2-(2-Oxabicyclo[2.1.1]hexan-4-yl)-6-ethylpyrimidin-4(3H)-one

[1441]

[1442] 2-(2-Oxabicyclo[2.1.1]hexan-4-yl)-6-ethylpyrimidin-4(3H)-one was obtained as a crude solid from (E)-3-aminopent-2-enoic acid methyl ester and 2-oxabicyclo[2.1.1]hexane-4-carboxamide following a procedure similar to that described in Preparation 192. LCMS m / z = 207 [M+H] +

[1443] Preparation 196

[1444] 2-(2-oxabicyclo[2.1.1]hexan-4-yl)-4-chloro-6-ethylpyrimidine

[1445]

[1446] 2-(2-Oxabicyclo[2.1.1]hexan-4-yl)-4-chloro-6-ethylpyrimidine was obtained as an oil from 2-(2-oxabicyclo[2.1.1]hexan-4-yl)-6-ethylpyrimidin-4(3H)-one (Preparation 197) following a procedure similar to that described in Preparation 193. LCMS m / z = 255 [M+H] + .

[1447] Example 1

[1448] N-(1'-(2-(1,1-difluoroethyl)-6-methoxypyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin-6'-yl)acetamide

[1449]

[1450] To 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. under N2 for 1 h. 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 under vacuum to give the crude product, which was purified by prep-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]pyridin]-6'-yl)acetamide (29.5 mg, 18.5% yield) as a white solid. LCMS m / z = 376.1 [M+H] + . 1 HNMR: (500MHz, DMSO-d6)δ: ppm10.88(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).

[1451] Examples 2 to 9

[1452] The compounds in the following table were prepared from the appropriate pyrrolo[3,2-c]pyridine and acetamide following a procedure similar to that described in Example 1. The crude product was purified by Prep-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.

[1453]

[1454]

[1455]

[1456]

[1457] A=DMF was used as the reaction solvent

[1458] Example 10

[1459] N-(1'-(2-(1,1-difluoroethyl)-6-(methylamino)pyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin-6'-yl)acetamide

[1460]

[1461] A mixture of 6-(6'-chlorospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin]-1'(2'H)-yl)-2-(1,1-difluoroethyl)-N-methylpyrimidin-4-amine (Preparation 131, 50 mg, 142.1 μmol), acetamide (41.98 mg, 710.7 μmol), Cs2CO3 (92.62 mg, 284.3 μmol) and Brettphos Pd G3 (6.44 mg, 7.11 μmol) in dioxane (2 mL) was purged with N2 and then heated in a sealed tube at 110°C for 1 h. The cooled mixture was filtered and the resulting solid was dry-loaded onto silica gel and purified by silica gel chromatography (0-80% EtOAc-EtOH 3:1 (containing 2% NH4OH) in heptane) to give N-(1'-(2-(1,1-difluoroethyl)-6-(methylamino)pyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin]-6'-yl)acetamide as a white powder (40 mg, 75.2% yield). LCMS m / z = 375.2 [M+H] +1 H NMR(400MHz,MeOH-d4)δ9.00-8.70(m,1H),7.52(s,1H),5.69(s,1H),4.08(s,2H),2.92(s,3H),2.16(s,3H),2.10-2.00(m,3H),1.18(br d,4H,J=2.5Hz)

[1462] Example 11

[1463] N-(1'-(2-(1,1-difluoroethyl)-6-ethylpyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin-6'-yl)acetamide

[1464]

[1465] A mixture of 6'-chloro-1'-(2-(1,1-difluoroethyl)-6-ethylpyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine] (Preparation 137, 35 mg, 100 μmol), acetamide (30 mg, 500 μmol), Cs2CO3 (65 mg, 200 μmol) and BrettPhos Pd G3 (4.5 mg, 5 μmol) in dioxane (1 mL) was purged with N2 and then heated in a sealed tube at 110°C for 1 h. The cooled mixture was filtered, the filtrate was concentrated, and the crude product was purified by silica gel chromatography (0-70% EtOAc-EtOH 3:1 (containing 2% NH4OH) in heptane) to give N-(1'-(2-(1,1-difluoroethyl)-6-ethylpyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin]-6'-yl)acetamide as a white powder (29 mg, 77% yield). LCMS m / z = 374.2 [M+H] + . 1 H NMR: (400MHz, CDCl3) δ: ppm 9.03 (br s, 1H), 8.14 (br s,1H),7.51(s,1H),6.59(s,1H),4.14(s,2H),2.84(q,2H,J=7.6Hz),2.30-2.10(m,6H),1.35(t,3H,J=7.5Hz),1.20-1.10(m,4H).

[1466] Example 12

[1467] N-(1'-(6-(1,1-difluoroethyl)pyridin-2-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin-6'-yl)acetamide

[1468]

[1469] 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 in a sealed tube at 110 °C for 1 h. The cooled mixture was filtered and the crude material was purified by silica gel chromatography (0-80% EtOAc-EtOH 3:1 (containing 2% NH4OH) in heptane) to give N-[1-[6-(1,1-difluoroethyl)-2-pyridinyl]spiro[2H-pyrrolo[3,2-c]pyridin-3,1'-cyclopropane]-6-yl]acetamide as a white powder (37 mg, 49% yield). LCMS m / z = 345.1 [M+H] +

[1470] 1H NMR(CDCl3,400MHz)δ8.86(s,1H),8.05(br s,1H),7.78(t,1H,J=7.9Hz),7.45(s,1H),7.29(d,1H,J=7.5Hz),6.90-6.80(m,1H),4.14(s,2H),2.30-2.10(m,6H),1.20-1.10(m,4H)

[1471] Examples 13 to 71

[1472] Following procedures analogous to those described in Example 12, the compounds in the following table were prepared from acetamide and the appropriate chloride.

[1473]

[1474]

[1475]

[1476]

[1477]

[1478]

[1479]

[1480]

[1481]

[1482]

[1483]

[1484]

[1485]

[1486]

[1487]

[1488]

[1489]

[1490]

[1491]

[1492]

[1493] Examples 72 and 73

[1494] 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

[1495]

[1496] trans-rac-N-(1'-(6-(2-cyanocyclopropyl)-2-(1,1-difluoroethyl)pyrimidin-4-yl)cyclopropane-1-carbonitrile) was prepared following a procedure analogous to that described in Example 12 from 2-(6-(6'-chlorospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin-1'(2'H)-yl)-2-(1,1-difluoroethyl)pyrimidin-4-yl)cyclopropane-1-carbonitrile (Preparation 146) and acetamide. 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.

[1497] 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]pyridin-6'-yl)acetamide or 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, 13 mg, LCMS m / z=411.2 [M+H] + . 1 H NMR: (400MHz, 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=4.3,5.8,8.7Hz),2.30-2.20(m,4H ),2.13(t,3H,J=18.7Hz),1.85(ddd,1H,J=4.8,5.8,9.0Hz),1.67(ddd,1H,J=4.8,6.0,8.8Hz),1.22(br d,4H,J=4.3Hz).

[1498] 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]pyridin-6'-yl)acetamide or 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, 2 mg, LCMS m / z = 411.2 [M+H] + . 1 H NMR: (400MHz, 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=3.4,8.4Hz),1.21(br s,4H).

[1499] Examples 74 and 75

[1500] N-(1'-(6-((1s,3s)-3-cyanocyclobutyl)-2-(1,1-difluoroethyl)pyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin-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]pyridin-6'-yl)acetamide

[1501]

[1502] N-(1'-(6-((1s,3s)-3-cyanocyclobutyl)-2-(1,1-difluoroethyl)pyrimidin-4-yl)cyclobutane-1-carbonitrile was prepared following a procedure analogous to that described in Example 12 from 3-(6-(6'-chlorospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin-1'(2'H)-yl)-2-(1,1-difluoroethyl)pyrimidin-4-yl)cyclobutane-1-carbonitrile (Preparation 143) and acetamide.

[00145] N-(1'-(6-((1r,3r)-3-cyanocyclobutyl)-2-(1,1-difluoroethyl)pyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin]-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]pyridin]-6'-yl)acetamide. Isomer 1, 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 or 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, 11 mg, LCMS m / z=425.3 [M+H] + . 1 H NMR: (400MHz, CDCl3) δ: ppm 9.20-8.90(m,1H),8.07(br s,1H),7.52(s,1H),6.55(br s,1H),4.13(s,2H),3.90-3.80(m,1H),3.50-3.40(m,1H),2.90-2.70(m,4H),2.30-2.10(m,7H),1.21-1.18(m,4H). Isomer 2, 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 or 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, 16 mg, LCMS m / z=425.3 [M+H] + . 1H NMR: (400 MHz, CDCl3) δ: ppm 9.10-8.90 (m, 1H), 8.50-8.20 (m, 1H), 7.50 (s, 1H), 6.64 (s, 1H), 4.18 (s, 2H), 3.66 (quintet, 1H, J = 9.0 Hz), 3.20-3.10 (m, 1H), 2.83-2.80 (m, 4H), 2.20-2.10 (m, 7H), 1.21 (s, 4H).

[1503] Example 76

[1504] 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

[1505]

[1506] A mixture of 6-chloro-1-(6-(1,1-difluoroethyl)pyridin-2-yl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-c]pyridine (Preparation 84, 30 mg, 92.7 μmol), acetamide (27.37 mg, 463.3 μmol), Cs2CO3 (60.38 mg, 185.3 μmol) and BrettPhos Pd G3 (4.20 mg, 4.63 μmol) in dioxane (1 mL, 11.74 mmol) was purged with N2 and then heated in a sealed tube at 110°C for 1 h. The cooled mixture was filtered and the resulting crude solid was purified by HPLC using MeCN and water (+0.1% TFA modifier) ​​to afford 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 (5 mg, 12% yield) as a white powder. LCMS m / z = 347.2 [M+H] + ; 1 H NMR (400MHz, CDCl3) δ12.35(br d,1H,J=2.5Hz),9.20-9.00(m,1H),8.00-7.90(m,1H),7.68(s,1H),7.60-7.40(m,1H),7.06(br d,1H,J=7.3Hz),4.06(s,2H),2.34(s,3H),2.18(br t,3H,J=18.9Hz),1.49(s,6H).

[1507] Example 77

[1508] N-(1'-(Thiazol-2-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin-6'-yl)acetamide trifluoroacetate

[1509]

[1510] To a mixture of 2-(6'-chlorospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin]-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), purged with N2, and 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 was removed in vacuo. The crude mixture was purified by reverse phase HPLC (Sunfire Prep C18 OBD 5um 30x50mm, gradient: 5-40% MeCN in water, modifier 0.1% TFA, flow rate: 50ml / min) to afford N-(1'-(thiazol-2-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin]-6'-yl)acetamide trifluoroacetate, 2.5 mg. LCMS m / z = 287 [M+H] +

[1511] Examples 78 to 82

[1512] The compounds in the following table were prepared following the procedure described in Example 77 from the appropriate chloro compound and acetamide.

[1513]

[1514]

[1515] The crude material was purified by HPLC (column: XSelect CSH Prep C18 5um OBD 30x50mm, gradient: 5-70 MeCN in water, modifier 0.2% NH4OH, flow rate: 50ml / min)

[1516] Example 83

[1517] N-(1'-(4-(1,1-difluoroethyl)-6-methylpyrimidin-2-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin-6'-yl)acetamide

[1518]

[1519] To a solution of 6'-chloro-1'-(4-(1,1-difluoroethyl)-6-methylpyrimidin-2-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine] (Preparation 75, 130 mg, 0.386 mmol) in dioxane (3 mL) was added acetamide (34.2 mg, 0.579 mmol), Cs2CO3 (252 mg, 0.772 mmol), Pd2(dba)3 (70.7 mg, 0.077 mmol) and Xantphos (89.3 mg, 0.154 mmol). The reaction mixture was stirred at 100° C. under N2 for 3 h. The mixture was concentrated and purified by Prep-HPLC (Welch Xtimate C18 150*25mm*5um; conditions: water (10mM NH4HCO3)-MeCN; start B: 40; end B: 70; gradient time (min): 11; flow rate (ml / min): 25) to give N-(1'-(4-(1,1-difluoroethyl)-6-methylpyrimidin-2-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin]-6'-yl)acetamide (37.1 mg, 26.7% yield) as a yellow solid. LCMS m / z = 360.2 [M+H] + . 1 H NMR: (400MHz, CDCl3) δ: ppm 9.13(s,1H),7.89(s,1H),7.47(s,1H),7.03(s,1H),4.29(s,2H),2.57(s,3H),2.20(s,3H),2.12(t,J=18.8Hz,3H),1.14(s,4H).

[1520] Examples 84 to 87

[1521] The compounds in the following table were prepared following procedures analogous to those described in Example 83 from the appropriate chloro compound and acetamide.

[1522]

[1523]

[1524] Example 88

[1525] N-(1'-(2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin-6'-yl)acetamide

[1526]

[1527] 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) was 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. under N2 for 12 h. The mixture was poured into H2O (50 mL) and extracted with EtOAc (50 mL x 3). The organic phase was washed with brine (50 mL x 2), dried over Na2SO4 and filtered. The filtrate was concentrated and the residue was purified by silica gel chromatography (PE / EtOAc=20 / 1 to 0 / 1) to give a crude product, which was treated with PE (20 mL) and MeOH (5 mL) to give N-(1'-(2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin]-6'-yl)acetamide (1.21 g, 52.7% yield) as a white solid. LCMS m / z=360.2 [M+H] + . 1 H NMR: (400MHz, DMSO-d6)δ: ppm10.30(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=19.2Hz,3H),2.07(s,3H),1.18-1.16(m,4H).

[1528] Example 89

[1529] N-(1'-(2-(1,1-difluoroethyl)pyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-6'-yl)propanamide

[1530]

[1531] To 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 CsCO (363 mg, 1.12 mmol) in dioxane (10 mL) was added BrettPhos Pd G (33.8 mg, 0.0372 mmol). The reaction mixture was stirred at 100° C. under N for 2 h. The mixture was treated with H O (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 give the crude product, which was purified by prep-HPLC (column: Boston Prime C18 150*30mm*5um; conditions: water (NH3·H2O+NH4HCO3)-ACN; start B: 41; end B: 71; gradient time (min): 10; flow rate (ml / min): 25) to give N-(1'-(2-(1,1-difluoroethyl)pyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin]-6'-yl)propanamide (56 mg, 41.9% yield) as a white solid. LCMS m / z = 360.1 [M+H] + . 1 H NMR: (500MHz, CDCl3) δ: ppm 8.97(s,1H),8.61(d,J=6.0Hz,1H),7.86(s,1H),7.53(s,1H),6.82(d,J=5.5Hz,1H),4.16(s,2H),2. 46-2.41(m,2H),2.19(t,J=19.0Hz,3H),1.27(t,J=7.5Hz,3H),1.22-1.21(m,2H),1.20-1.18(m,2H).

[1532] Example 90

[1533] N-(1'-(6-(1,1-difluoroethyl)pyridin-2-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin-6'-yl)propanamide

[1534]

[1535] N-(1'-(6-(1,1-difluoroethyl)pyridin-2-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin]-6'-yl)propanamide was obtained from 6'-chloro-1'-(6-(1,1-difluoroethyl)pyridin-2-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridinamide (Preparation 77) and propanamide following the procedure described in Example 12, 20 mg. LCMS m / z = 359.2 [M+H] + . 1 HNMR: (400MHz, CDCl3) δ: ppm 8.81 (s, 1H), 7.99 (br s,1H),7.78(t,1H,J=7.9Hz),7.44(s,1H),7.30-7.28(m,1H),7.00-6.90(m,1H),4.16(s,2 H), 2.42 (q, 2H, J = 7.5Hz), 2.19 (t, 3H, J = 18.9Hz), 1.26 (t, 3H, J = 7.5Hz), 1.20-1.10 (m, 4H).

[1536] Example 91

[1537] N-(1'-(2-(1,1-difluoroethyl)pyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-6'-yl)-3-methoxypropionamide

[1538]

[1539] To 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, 110 mg, 0.341 mmol), 3-methoxypropionamide (70.3 mg, 0.682 mmol), and Cs2CO3 (333 mg, 1.02 mmol) in dioxane (10 mL) was added BrettPhos Pd G3 (30.9 mg, 0.0341 mmol). The reaction mixture was stirred at 100° C. 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 give the crude product, which was purified by prep-HPLC (column: Welch Xtimate C18 150*25mm*5um; conditions: water (NH4HCO3)-ACN; start B: 26; end B: 60; gradient time (min): 11; flow rate (ml / min): 25) to give N-(1'-(2-(1,1-difluoroethyl)pyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin]-6'-yl)-3-methoxypropanamide (32.0 mg, 24.1% yield) as a white solid. LCMS m / z = 390.1 [M+H] + . 1 H NMR: (500MHz, CDCl3) δ: ppm 9.02(s,1H),8.88(s,1H),8.61(d,J=6.0Hz,1H),7.54(s,1H),6.78(d,J=5.5Hz,1H),4.14(s,2H ),3.76-3.73(m,2H),3.45(s,3H),2.69-2.66(m,2H),2.19(d,J=18.5Hz,3H),1.20-1.18(m,4H).

[1540] Example 92

[1541] N-(1'-(6-(1,1-difluoroethyl)-4-((1r,3r)-3-methoxycyclobutyloxy)pyridin-2-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin-6'-yl)acetamide

[1542]

[1543] 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) was added 2-chloro-6-(1,1-difluoroethyl)-4-((1r,3r)-3-methoxycyclobutyloxy)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. under N2 for 1 h. The mixture was concentrated and purified by prep-HPLC (column: Boston Green ODS150*30mm*5um; conditions: water (10mM 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-methoxycyclobutyloxy)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 H NMR: (500MHz, 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).

[1544] Example 93

[1545] N-(1'-(6-(Methylsulfonyl)pyridin-2-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin-6'-yl)acetamide

[1546]

[1547] N-(1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin]-6'-yl)acetamide

[1548] To a mixture of (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 Cs 2 CO 3 (192.38 mg, 0.59 mmol) was added dioxane (2.5 mL) and the reaction was heated at 90° C. for 1 h and then stirred at rt 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 and dry loaded and purified by silica gel chromatography (20-100% EtOAc-EtOH 3:1 in heptane) to afford N-(1′-(6-(methylsulfonyl)pyridin-2-yl)-1′,2′-dihydrospiro[cyclopropane-1,3′-pyrrolo[3,2-c]pyridin]-6′-yl)acetamide (15 mg, 14.2% yield) as a white solid. LCMS m / z = 359.1 [M+H] + . 1 H NMR (400MHz, CDCl3): δ (ppm) 9.16 (s, 1H), 8.13-8.07 (m, 1H), 7.94 (d, J = 7.5Hz, 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)

[1549] ...

Claims

1. A compound of formula (I): or a pharmaceutically acceptable salt thereof, wherein: Ring A is an aromatic or heteroaromatic ring fused to Ring B which is a 5-membered heterocyclic ring; X 1 N or CH; Ring C represents phenyl, 5- to 10-membered monocyclic or bicyclic heteroaryl, 3- to 7-membered monocyclic carbocyclic group or 4- to 7-membered monocyclic heterocyclic group, each of which is optionally substituted by one or more R C replace; Each R C are independently halo, –CN, –NR N1 R N2 ,–NR N3 –C(O)–R 7 、-C(O)–NR N3 R N4 ,–NR N4 –SO2–R 7 ,–C(O)–R 7 、-C(O)-OH、-C(O)-OR 7 、-SR 7 , –SO2–R 7 ,–OR O1 , C 1-6 Alkyl, C 2-6 alkenyl, phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered monocyclic carbocyclic group or 4- to 9-membered monocyclic or bicyclic heterocyclic group, wherein R C The C 1-6 Alkyl, C 1-6 alkenyl, phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 9-membered monocyclic or bicyclic heterocyclyl are each optionally substituted by one or more R C1 replace; Each R C1 are independently halo, oxo, –CN, –OR O1 ,–NR N3 R N4 , –C(O)-R 7 , –C(O)-OR O3 、–SO2-R 7 , C 1-6 alkyl, phenyl, 3- to 7-membered monocyclic carbocyclic group, 5- to 6-membered heteroaryl, or 4- to 7-membered monocyclic heterocyclic group, wherein R C1 The C 1-6 Alkyl, phenyl, 5- to 6-membered heteroaryl, and 4- to 7-membered monocyclic heterocyclyl are each optionally substituted with one or more substituents independently selected from the group consisting of halo, oxo, -CN, -OR O1 ,–NR N3 R N4 , C 1-6 Alkyl, C 1-4 haloalkyl, phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 8-membered monocyclic heterocyclyl; R 1 H, C 1-6 Alkyl, -OR 2 、-NR 2 R 4 , a 3- to 7-membered monocyclic carbocyclic group or a 4- to 7-membered monocyclic heterocyclic group, wherein R 1 The C 1-6 The alkyl, 3- to 7-membered monocyclic carbocyclic group and 4- to 7-membered monocyclic heterocyclic group are each optionally substituted by one or more R 8 replace; R 1A H or C 1-3 alkyl; Each R 2 and R 4 Independently H, C 1-4 Alkyl or 3- to 4-membered monocyclic carbocyclic group; Each R 3 are independently H, halo or C 1-3 alkyl; Alternatively, two R 3 Together with the atoms to which they are attached, they form a 3- to 7-membered monocyclic carbocyclyl or a 4- to 9-membered monocyclic heterocyclyl, each of which is optionally substituted by one or more R 5 replace; Each R 5 are independently H, halo, -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 、 SO2-R 7 , phenyl, 5- to 6-membered heteroaryl or 3- to 7-membered monocyclic carbocyclic group or 4- to 7-membered monocyclic heterocyclic group, wherein R 5 The C 1-6 Alkyl, phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 7-membered monocyclic heterocyclyl are each optionally substituted with one or more substituents independently selected from the group consisting of halo, oxo, -CN, -OR O1 ,–NR N1 R N2 , C 1-6 Alkyl, C 1-4 haloalkyl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 7-membered monocyclic heterocyclyl; Each R 7 Independently for C 1-6 alkyl, phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered monocyclic carbocyclic group or 4- to 7-membered monocyclic heterocyclic group; wherein R 7 The C 1-6 Alkyl, phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 7-membered monocyclic heterocyclyl are each optionally substituted with one or more substituents independently selected from the group consisting of halo, oxo, -CN, -OR O1 ,–NR N3 R N4 , C 1-6 Alkyl, C 1-4 haloalkyl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 7-membered monocyclic heterocyclyl; Each R 8 are 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 carbocyclyl, or 4- to 7-membered monocyclic heterocyclyl; Each R O1 Independently H, C 1-6 alkyl, phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered monocyclic carbocyclic group, or 4- to 8-membered monocyclic or bicyclic heterocyclic group, wherein R O1 The C 1-6 Alkyl, phenyl, 5- to 6-membered heteroaryl, 3- to 8-membered monocyclic carbocyclic group and 4- to 7-membered monocyclic or bicyclic heterocyclic group are each optionally substituted by one or more R O2 replace; Each R O2 are independently halo, OH, -CN, C 1-4 Alkoxy, C 1-4 Alkyl, C 1-4 Alkyl-C 1-4 Alkoxy, C 1-4 haloalkyl, phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered monocyclic carbocyclyl, or 4- to 7-membered monocyclic or bicyclic heterocyclyl, wherein the 4- to 7-membered monocyclic or bicyclic heterocyclyl is optionally C 1-4 Alkyl or C 1-4 Alkoxy substitution; Each R O3 Independently H, C 1-6 Alkyl, C 1-4 haloalkyl, phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered monocyclic carbocyclic group or 4- to 7-membered monocyclic heterocyclic group, wherein R O3 The C 1-6 Alkyl, phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered monocyclic carbocyclic group and 4- to 7-membered monocyclic heterocyclic group are each optionally substituted by one or more R O2 replace; R O4 H, C 1-6 alkyl, phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered monocyclic carbocyclic group or 4- to 7-membered monocyclic heterocyclic group, wherein R O4 The C 1-6 Alkyl, phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 7-membered monocyclic heterocyclyl are each optionally substituted with one or more substituents independently selected from the group consisting of 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 carbocyclyl, and 4- to 7-membered monocyclic heterocyclyl; R N1 and R N2 Each independently is H or C 1-6 Alkyl, wherein R N1 and R N2 The C 1-6 The alkyl groups are each optionally substituted with a halo group, a C 1-4 Alkoxy or –NR N3 R N4 Replace, or R N1 H or C 1-3 Alkyl and R N2 For ring D or –C 1-3 Alkylene-ring D; Ring D is a 3- to 7-membered monocyclic or bicyclic carbocyclic group or a 4- to 7-membered monocyclic heterocyclic group, wherein the 3- to 7-membered monocyclic carbocyclic group and the 4- to 7-membered monocyclic heterocyclic group represented by ring D are each optionally substituted with one or two substituents independently selected from the following: halo, C 1-6 Alkyl and C 1-4 Alkoxy; Each R N3 are independently H or C 1-6 Alkyl; and Each R N4 are independently H or C 1-6 alkyl.

2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein: Ring A is an aromatic or heteroaromatic ring fused to Ring B which is a 5-membered heterocyclic ring; X 1 N or CH; Ring C represents phenyl, 5- to 10-membered monocyclic or bicyclic heteroaryl, 3- to 7-membered monocyclic carbocyclic group or 4- to 7-membered monocyclic heterocyclic group, each of which is optionally substituted by one or more R C replace; Each R C are independently halo, –CN, –NR N1 R N2 ,–NR N3 –C(O)–R 7 、-C(O)–NR N3 R N4 ,–NR N4 –SO2–R 7 ,–C(O)–R 7 、-SR 7 , –SO2–R 7 ,–OR O1 , C 1-6 alkyl, phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered monocyclic carbocyclic group, or 4- to 9-membered monocyclic or bicyclic heterocyclic group, wherein R C The C 1-6 Alkyl, phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered monocyclic carbocyclic group and 4- to 9-membered monocyclic or bicyclic heterocyclic group are each optionally substituted by one or more R C1 replace; Each R C1 are independently halo, oxo, –CN, –OR O1 ,–NR N3 R N4 , –C(O)-R 7 , –C(O)-OR O3 、–SO2-R 7 , C 1-6 alkyl, phenyl, 3- to 7-membered monocyclic carbocyclic group, 5- to 6-membered heteroaryl, or 4- to 7-membered monocyclic heterocyclic group, wherein R C1 The C 1-6 Alkyl, phenyl, 5- to 6-membered heteroaryl, and 4- to 7-membered monocyclic heterocyclyl are each optionally substituted with one or more substituents independently selected from the group consisting of halo, oxo, -CN, -OR O1 ,–NR N3 R N4 , C 1-6 Alkyl, C 1-4 haloalkyl, phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 8-membered monocyclic heterocyclyl; R 1 H, C 1-6 Alkyl, -OR 2 、-NR 2 R 4 , a 3- to 7-membered monocyclic carbocyclic group or a 4- to 7-membered monocyclic heterocyclic group, wherein R 1 The C 1-6 The alkyl, 3- to 7-membered monocyclic carbocyclic group and 4- to 7-membered monocyclic heterocyclic group are each optionally substituted by one or more R 8 replace; R 1A H or C 1-3 alkyl; Each R 2 and R 4 Independently H, C 1-4 Alkyl or 3- to 4-membered monocyclic carbocyclic group; Each R 3 are independently H, halo or C 1-3 alkyl; Alternatively, two R 3 Together with the atoms to which they are attached, they form a 3- to 7-membered monocyclic carbocyclyl or a 4- to 9-membered monocyclic heterocyclyl, each of which is optionally substituted by one or more R 5 replace; Each R 5 are independently H, halo, -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 、 SO2-R 7 , phenyl, 5- to 6-membered heteroaryl or 3- to 7-membered monocyclic carbocyclic group or 4- to 7-membered monocyclic heterocyclic group, wherein R 5 The C 1-6 Alkyl, phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 7-membered monocyclic heterocyclyl are each optionally substituted with one or more substituents independently selected from the group consisting of halo, oxo, -CN, -OR O1 ,–NR N1 R N2 , C 1-6 Alkyl, C 1-4 haloalkyl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 7-membered monocyclic heterocyclyl; Each R 7 Independently for C 1-6 alkyl, phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered monocyclic carbocyclic group or 4- to 7-membered monocyclic heterocyclic group; wherein R 7 The C 1-6 Alkyl, phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 7-membered monocyclic heterocyclyl are each optionally substituted with one or more substituents independently selected from the group consisting of halo, oxo, -CN, -OR O1 ,–NR N3 R N4 , C 1-6 Alkyl, C 1-4 haloalkyl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 7-membered monocyclic heterocyclyl; Each R 8 are 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 carbocyclyl, or 4- to 7-membered monocyclic heterocyclyl; Each R O1 Independently H, C 1-6 alkyl, phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered monocyclic carbocyclic group or 4- to 7-membered monocyclic or bicyclic heterocyclic group, wherein R O1 The C 1-6 Alkyl, phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered monocyclic carbocyclic group and 4- to 7-membered monocyclic or bicyclic heterocyclic group are each optionally substituted by one or more R O2 replace; Each R O2 are independently halo, OH, -CN, C 1-4 Alkoxy, C 1-4 haloalkyl, phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered monocyclic carbocyclyl, or 4- to 7-membered monocyclic heterocyclyl; Each R O3 Independently H, C 1-6 Alkyl, C 1-4 haloalkyl, phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered monocyclic carbocyclic group or 4- to 7-membered monocyclic heterocyclic group, wherein R O3 The C 1-6 Alkyl, phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered monocyclic carbocyclic group and 4- to 7-membered monocyclic heterocyclic group are each optionally substituted by one or more R O2 replace; R O4 H, C 1-6 alkyl, phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered monocyclic carbocyclic group or 4- to 7-membered monocyclic heterocyclic group, wherein R O4 The C 1-6 Alkyl, phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 7-membered monocyclic heterocyclyl are each optionally substituted with one or more substituents independently selected from the group consisting of 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 carbocyclyl, and 4- to 7-membered monocyclic heterocyclyl; R N1 and R N2 Each independently is H or C 1-6 Alkyl, wherein R N1 and R N2 The C 1-6 The alkyl groups are each optionally substituted with a halo group, a C 1-4 Alkoxy or –NR N3 R N4 Replace, or R N1 H or C 1-3 Alkyl and R N2 For ring D or –C 1-3 Alkylene-ring D; Ring D is a 3- to 7-membered monocyclic or bicyclic carbocyclic group or a 4- to 7-membered monocyclic heterocyclic group, wherein the 3- to 7-membered monocyclic carbocyclic group and the 4- to 7-membered monocyclic heterocyclic group represented by ring D are each optionally substituted with one or two substituents independently selected from the following: halo, C 1-6 Alkyl and C 1-4 Alkoxy; Each R N3 are independently H or C 1-6 Alkyl; and Each R N4 are independently H or C 1-6 alkyl.

3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R 1A is H or –CH3.

4. The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein each R 3 are independently H or –CH3.

5. The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein two R 3 Together with the atoms to which it is attached, it forms C 3-6 cycloalkyl or 5- to 6-membered monocyclic heterocyclic group, each of which is optionally substituted by one to three R 5 replace.

6. The compound according to claim 5, or a pharmaceutically acceptable salt thereof, wherein two R 3 Together with the atoms to which they are attached, they form cyclopropane, cyclobutane, cyclopentane, tetrahydropyran or piperidine, each of which is optionally substituted with one to three R 5 replace.

7. The compound according to claim 5, or a pharmaceutically acceptable salt thereof, wherein two R 3 Together with the atoms to which they are attached, they form: where m is 0, 1, 2, or 3, and represents a bond within ring B.

8. The compound of claim 1 or 2, wherein the compound is represented by formula (III), (IV), (V), (VI), (VII), (VIII) or (IX): or a pharmaceutically acceptable salt thereof.

9. The compound of any one of claims 1, 2, 3 and 5-8, or a pharmaceutically acceptable salt thereof, wherein each R 5 are independently H, -CN or CH3.

10. The compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein ring C is optionally substituted with one to three R C Substituted 5- to 9-membered monocyclic or bicyclic heteroaryl.

11. The compound according to claim 10, or a pharmaceutically acceptable salt thereof, wherein Ring C is pyrazine, pyrazolo[1,5-a]pyrimidine, pyridine, pyrimidine, pyrimidone or thiazole, each of which is optionally substituted by one or three R C replace.

12. The compound according to claim 10, or a pharmaceutically acceptable salt thereof, wherein Ring C is selected from: And among them represents a bond to ring B, and n is 0, 1, 2 or 3.

13. The compound according to claim 10, or a pharmaceutically acceptable salt thereof, wherein Ring C is selected from: And among them represents a bond to ring B, and the one to three R in ring C C The groups may be the same or different.

14. The compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, wherein: Each R C are 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, 4 to 9-membered monocyclic or bicyclic heterocyclic group, phenyl or 5 to 6-membered heteroaryl, wherein R C The C 1-6 Alkyl, C 2-4 Alkenyl, C 3-6 Cycloalkyl, 4 to 9 membered monocyclic or bicyclic heterocyclic group, phenyl and 5 to 6 membered heteroaryl are each optionally substituted by one to three R C1 replace; R 7 C 1-3 alkyl; R O1 H, C 1-4 Alkyl, C 1-4 Alkyl, C 3-6 Cycloalkyl, 4- to 8-membered monocyclic or bicyclic heterocyclic group, 5- to 6-membered heteroaryl, wherein R O1 C 1-4 The alkyl group is optionally substituted with one to three substituents independently selected from the group consisting of halo, OH, CN, C 1-3 Alkoxy, C 3-6 Cycloalkyl and optionally C 1-3 Alkyl or C 1-3 alkoxy-substituted 4- to 6-membered monocyclic heterocyclic group, wherein R O1 C 3-6 The cycloalkyl, 4- to 8-membered monocyclic or bicyclic heterocyclyl, and 5- to 6-membered heteroaryl are each optionally substituted with one to two substituents independently selected from the group consisting of 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 Each independently is H or C 1-6 Alkyl, wherein R N1 and R N2 The C 1-6 The alkyl groups are each optionally substituted with a halo group, a C 1-4 Alkoxy or –NR N3 R N4 Replace, or R N1 H or C 1-3 Alkyl and R N2 For ring D or –C 1-3 Alkylene-ring D; Ring D is a 3- to 7-membered monocyclic or bicyclic carbocyclic group or a 4- to 7-membered monocyclic heterocyclic group, wherein the 3- to 7-membered monocyclic carbocyclic group and the 4- to 7-membered monocyclic heterocyclic group represented by ring D are each optionally substituted with one or two substituents independently selected from the following: halo, C 1-6 Alkyl and –C 1-4 Alkoxy; R N1 and R N2 Each independently is H or C 1-4 Alkyl, wherein R N1 and R N2 The C 1-4 The alkyl groups are each optionally substituted with a halo group, a C 1-3 Alkoxy or –NR N3 R N4 Replace, or Each R N3 independently H or C 1-3 Alkyl; and Each R N4 are independently H or C 1-3 alkyl.

15. The compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, wherein: Each R C are 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, 4 to 9-membered monocyclic or bicyclic heterocyclic group, phenyl or 5 to 6-membered heteroaryl, wherein R C The C 1-3 Alkyl, C 3-6 Cycloalkyl, 4 to 9 membered monocyclic or bicyclic heterocyclic group, phenyl and 5 to 6 membered heteroaryl are each optionally substituted by one to three R C1 replace; R 7 C 1-3 alkyl; R O1 H, C 1-4 Alkyl, C 1-4 Alkyl, C 3-6 Cycloalkyl, 4- to 6-membered monocyclic heterocyclic group, 5- to 6-membered heteroaryl, wherein R O1 C 1-4 The alkyl group is optionally substituted with one to three substituents independently selected from the group consisting of halo, CN, C 1-3 Alkoxy, C 3-6 cycloalkyl, 4 to 6 membered monocyclic heterocyclic group, and wherein R O1 C 3-6 The cycloalkyl, 4- to 6-membered monocyclic heterocyclyl, and 5- to 6-membered heteroaryl are each optionally substituted with one to two substituents independently selected from the group consisting of halo, C 1-3 Alkyl, CN, OH and C 1-3 Alkoxy; R N1 H or C 1-3 Alkyl and R N2 For ring D or –C 1-3 Alkylene-ring D; Ring D is a 3- to 7-membered monocyclic or bicyclic carbocyclic group or a 4- to 7-membered monocyclic heterocyclic group, wherein the 3- to 7-membered monocyclic carbocyclic group and the 4- to 7-membered monocyclic heterocyclic group represented by ring D are each optionally substituted with one or two substituents independently selected from the following: halo, C 1-6 Alkyl and –C 1-4 Alkoxy; R N1 and R N2 Each independently is H or C 1-4 Alkyl, wherein R N1 and R N2 The C 1-4 alkyl; Each R N3 are independently H or C 1-3 Alkyl; and Each R N4 independently H or C 1-3 alkyl.

16. The compound of claim 14, or a pharmaceutically acceptable salt thereof, wherein 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 the group consisting of halo, C 1-2 Alkyl and C 1-2 Alkoxy.

17. The compound of claim 16, or a pharmaceutically acceptable salt thereof, wherein ring D is one of the following: Each of which is optionally substituted with one or two substituents independently selected from F, -CH3 and -OCH3.

18. The compound of claim 14, or a pharmaceutically acceptable salt thereof, wherein R O1 The 4 to 8-membered monocyclic or bicyclic heterocyclic group represented by R O1 C 1-4 The alkyl substituent is oxetane, azetidine, pyrrolidine, 2-oxaspiro[3.3]heptyl or tetrahydrofuran, each of which is optionally substituted with one to two substituents independently selected from the following: 1-3 Alkyl, halo, CN, OH, C 1-3 Alkyl-C 1-3 Alkoxy or C 1-3 Alkoxy; and R O1 The 5- to 6-membered heteroaryl represented by is pyrazole, triazole, pyridine, pyrazine, pyrimidine or pyridazine, each of which is optionally substituted with one to two substituents independently selected from the following: 1-3 Alkyl, halo, CN, OH or C 1-3 Alkoxy.

19. The compound according to claim 15, or a pharmaceutically acceptable salt thereof, wherein R O1 The 4- to 6-membered monocyclic heterocyclic group represented by R O1 C 1-4 The alkyl substituent is oxetane, azetidine or tetrahydrofuran, each of which is optionally substituted with one to two substituents independently selected from the following: 1-3 Alkyl, halo, CN, OH or C 1-3 Alkoxy; and R O1 The 5- to 6-membered heteroaryl represented by is pyrazole, triazole, pyridine, pyrazine, pyrimidine or pyridazine, each of which is optionally substituted with one to two substituents independently selected from the following: 1-3 Alkyl, halo, CN, OH or C 1-3 Alkoxy.

20. The compound of claim 19, or a pharmaceutically acceptable salt thereof, wherein the 4- to 6-membered monocyclic heterocyclic group is: each of which is optionally substituted with one or two substituents independently selected from the group consisting of F, -CN, -CH3, -CH2CH3, OH, -CH2OCH3, and -OCH3; and The 5- to 6-membered heteroaryl group is: Each of which is optionally substituted with one or two substituents independently selected from F, -CN, -CH3, -CH2CH3, OH, and -OCH3.

21. The compound of claim 15, or a pharmaceutically acceptable salt thereof, wherein: Each R C is independently selected from F, -Cl, -CH3, -CHF2, -CF3, -CH2CH3, -CH2CH2CH3, -CH2CH2CH2CH3, -CH2CH2CH2CH2CH3, -CF2CH3, -CF2CFH2, -CFHCFH2, -CF2CH2CH3, -CF2CH2OH, -CF2CH2OCH3, -CH(CH3)2, -CF(CH3)2, -C(CH3)3, -CF2C(O)OCH2CH3, -CH2OH, -CH(OH)CH3, -CH2OCH3, -CH2CH2CH2OH, -CH2CH2OCH2CH3, -CH2CH2CH2OCH3, -CH2CH2C(CH3)(OH)CH2CH3, -CH2CH2CH2OC(CH3)3, -CH2CH2C(CH3)2OH, -CH(CH3)OCH3, -C(CH3)2OCH3, -CH2OCH2CH3, -CH2-cyclopropyl, -CH(CH3)-SO2CH3, -CH2CH2-SO2CH3, -CH2NHCH3, -CH2CN, -CH(CH3)CN, -CH=CH-OCH2CH3, OH, -OCH3, -OCH2CH3, -OCH(CH3)2, -OCH2CF3, -OCH2CF2CH3, -OCH2CH2OCH3, -OCH2CH2F, -OCH2CH2CH2OCH3, -OCH2CH2N(CH3)2, -OCH(CH3)CH2OCH3, -OCH(CH3)CN, -OCH2C(CH3)2OH, -OCH2C(CH3)2OCH3, -OCH(cyclopropyl)(CN), -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -C(O)H, -C(O)CH3, -C(O)OH, -C(O)OCH2CH3, -NH2, -NHCH3, -NHCH2CH3, -NHCH2CH2CH3, -NHCH(CH3)2, -N(CH3)2, -N(CH3)CH(CH3)2, -NHCH2CH2CH2F, -NHCH2CHF2, -NHCH2C(F)CH3, -NHCH2CH2OCH3, -NHCH(CH3)CH2OCH3, -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, 22. The compound of claim 15, or a pharmaceutically acceptable salt thereof, wherein: Each R C is 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, 23. The compound of claim 15, or a pharmaceutically acceptable salt thereof, wherein: By R C Each C 3-6 Cycloalkyl is selected from cyclobutane, cyclopentane and cyclopropane; By R C each 4- to 9-membered monocyclic or bicyclic heterocyclic group 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; and By R C Each of the 5- to 6-membered heteroaryl groups represented by is independently selected from oxazole, pyrazole, pyridine, pyrimidine, triazole and thiazole; And wherein the C 3-6 Each of the cycloalkyl, 4- to 9-membered monocyclic or bicyclic heterocyclyl, and 5- to 6-membered heteroaryl is optionally substituted by one to three R C1 replace.

24. The compound of claim 15, or a pharmaceutically acceptable salt thereof, wherein: By R C Each C 3-6 Cycloalkyl is selected from cyclobutane, cyclopentane and cyclopropane; By R C Each 4- to 9-membered monocyclic or bicyclic heterocyclic group 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; and By R C Each of the 5- to 6-membered heteroaryl groups represented by is independently selected from oxazole, pyrazole, pyridine, pyrimidine and thiazole; And wherein the C 3-6 Each of the cycloalkyl, 4- to 9-membered monocyclic or bicyclic heterocyclyl, and 5- to 6-membered heteroaryl is optionally substituted by one to three R C1 replace.

25. The compound of claim 15, or a pharmaceutically acceptable salt thereof, wherein: By R C The C 3-6 Each of the cycloalkyl groups is independently selected from By R C Each of the 4 to 9 membered monocyclic heterocyclic groups represented by is independently selected from By R C Each of the phenyl groups represented by and By R C Each of the 5- to 6-membered heteroaryl groups represented by is independently selected from And among them represents a bond to ring C, and n is 0 if valence permits, 1, 2, or 3.

26. The compound of claim 15, or a pharmaceutically acceptable salt thereof, wherein: By R C The C 3-6 Each of the cycloalkyl groups is independently selected from By R C Each of the 4 to 9 membered monocyclic heterocyclic groups represented by is independently selected from By R C Each of the phenyl groups represented by and By R C Each of the 5- to 6-membered heteroaryl groups represented by is independently selected from And among them represents a bond to Ring C, and n is 0, 1, 2 or 3 as valency permits.

27. The compound of claim 15, or a pharmaceutically acceptable salt thereof, wherein: By R C The C 3-6 Each of the cycloalkyl groups is independently selected from: By R C Each of the 4 to 6-membered monocyclic heterocyclic groups represented by is independently selected from: and By R C Each of the phenyl groups represented by By R C Each of the 5- to 6-membered heteroaryl groups represented by is independently selected from And among them represents the bond to Ring C.

28. The compound of claim 15, or a pharmaceutically acceptable salt thereof, wherein: By R C The C 3-6 Each of the cycloalkyl groups is independently selected from: By R C Each of the 4 to 6-membered monocyclic heterocyclic groups represented by is independently selected from: and By R C Each of the phenyl groups represented by By R C Each of the 5- to 6-membered heteroaryl groups represented by is independently selected from And among them represents the bond to Ring C.

29. The compound of any one of claims 1 to 28, or a pharmaceutically acceptable salt thereof, wherein each R C1 are independently selected from halo, OH, –NR N3 R N4 , –CN, –C(O)-R 7 、–SO2-R 7 , C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 3-6 Cycloalkyl, 4- to 6-membered monocyclic heterocyclic group and C 1-4 Alkyl, wherein R C1 The C 1-4 The alkyl group is optionally substituted with one to three substituents independently selected from the group consisting of: 3-5 Cycloalkyl, 4- to 8-membered monocyclic heterocyclic group, C 1-3 Alkoxy, OH, CN, -NR N3 R N4 and halo, and R C1 The C 1-3 Alkoxy is optionally substituted by one to three independently selected 1-3 Substituents of the alkoxy and halo groups are substituted.

30. The compound of any one of claims 1-28, or a pharmaceutically acceptable salt thereof, wherein each R C1 are independently selected from halo, OH, –NR N3 R N4 , –CN, –C(O)-R 7 、–SO2-R 7 , C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 3-6 Cycloalkyl, 4- to 6-membered monocyclic heterocyclic group and C 1-4 Alkyl, wherein R C1 The C 1-4 Alkyl is optionally substituted with one to three independently selected 3-5 Cycloalkyl, C 1-3 Alkoxy, OH and halo substituents, and R C1 The C 1-3 Alkoxy is optionally substituted by one to three independently selected 1-3 Substituents of the alkoxy and halo groups are substituted.

31. The compound of claim 29, or a pharmaceutically acceptable salt thereof, wherein each R C1 independently selected 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, 32. The compound of claim 30, or a pharmaceutically acceptable salt thereof, wherein each R C1 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, 33. A compound as described in any one of claims 1 to 31, or a pharmaceutically acceptable salt thereof, wherein R 1 is optionally selected from one to three R 8 Substituted C 1-4 Alkyl: halo, -CN, -NR 2 R 4 , C 1-3 Alkoxy, C 1-3 Alkyl and C 1-3 haloalkyl, and R 2 and R 4 Each independently is H or C 1-3 alkyl.

34. A compound as described in any one of claims 1 to 32, or a pharmaceutically acceptable salt thereof, wherein R 1 is optionally selected from one to three R 8 Substituted C 1-4 Alkyl: halo, -CN, C 1-3 Alkoxy, C 1-3 Alkyl and C 1-3 Halogenated alkyl.

35. A compound as described in any one of claims 1 to 33, or a pharmaceutically acceptable salt thereof, wherein R 1 It is –CH3, –CH2CH3, –NH2, –NHCH3, –N(CH3)2, –OCH3 or –CH2CH2OCH3.

36. A compound as described in any one of claims 1 to 35, or a pharmaceutically acceptable salt thereof, wherein R 1 It is –CH3, –CH2CH3 or –CH2CH2OCH3.

37. The compound of any one of claims 1 to 36, or a pharmaceutically acceptable salt thereof, wherein each R O1 Independently H, C 1-3 Alkyl or C 3-6 Cycloalkyl, wherein R O1 The C 1-3 Alkyl and C 3-6 The cycloalkyl group is optionally C 1-3 Alkoxy substitution.

38. The compound of claim 37, or a pharmaceutically acceptable salt thereof, wherein each R O1 are independently H, -CH3, -CH2-CH2-OCH3, 39. The compound of any one of claims 1 to 38, or a pharmaceutically acceptable salt thereof, wherein R N1 and R N2 Each independently represents H or optionally C 1-3 Alkoxy substituted C 1-3 alkyl.

40. The compound of claim 39, or a pharmaceutically acceptable salt thereof, wherein R N1 and R N2 Each independently represents H, -CH3 or -CH2-CH2-OCH3.

41. The compound of claim 1, wherein the compound is represented by formula (X) or (XI): or a pharmaceutically acceptable salt thereof, wherein: n is 1, 2 or 3; Each R C Independently for –NR N1 R N2 ,–OR O1 or C 1-6 alkyl, 4 to 6-membered monocyclic heterocyclic group, wherein R C The C 1-6 The alkyl group and the 4- to 6-membered monocyclic heterocyclic group are each optionally substituted by one to three R C1 replace; Each R C1 are independently halo; R 1 C 1-3 alkyl; R O1 Optionally, R O2 Substituted C 3-4 Cycloalkyl; R O2 C 1-3 alkoxy; and R N1 and R N2 are each independently H or optionally C 1-3 Alkoxy substituted C 1-3 alkyl.

42. The compound of claim 41, wherein the compound is represented by formula (XA), (XIA), (XIB), (XIC) or (XID): or a pharmaceutically acceptable salt thereof.

43. The compound of claim 41 or 42, or a pharmaceutically acceptable salt thereof, wherein: Each R C are independently -NHCH3, -NHCH2CH2OCH3, -CH3, -CH2CH3, -CH(CH3)2, -CF2CH3, -CF(CH3)2, and R 1 For CH3.

44. The compound of claim 41 or 42, or a pharmaceutically acceptable salt thereof, wherein R C is a 4- to 6-membered monocyclic heterocyclic group independently selected from tetrahydrofuran and tetrahydropyran, each of which is optionally substituted by one to three R C1 replace.

45. The compound of claim 41 or 42, or a pharmaceutically acceptable salt thereof, wherein R C Independently selected from And among them represents the bond to Ring C.

46. ​​The compound of claim 41 or 42, or a pharmaceutically acceptable salt thereof, wherein R C Independently selected from And among them represents the bond to Ring C.

47. A compound as described in any one of claims 41 to 45, or a pharmaceutically acceptable salt thereof, wherein each R C1 For F.

48. The compound of claim 1, wherein the compound is represented by formula (XII): or a pharmaceutically acceptable salt thereof, wherein: Each R C Independently for C 1-3 Alkyl, C 1-3 Haloalkyl or –NR N1 R N2 ; R N1 and R N2 Each independently is H or C 1-3 alkyl.

49. The compound of claim 48, or a pharmaceutically acceptable salt thereof, wherein each R C are independently -CH3, -CH2CH3, -CF2CH3 or -NHCH3.

50. A pharmaceutical composition comprising the compound according to any one of claims 1 to 49 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

51. A method of inhibiting tyrosine kinase 2 (TYK2) activity in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 49 or a pharmaceutical composition according to claim 50.

52. A method of treating a disease or condition responsive to inhibition of tyrosine kinase 2 (TYK2) in a subject, the method comprising administering to the subject an effective amount of a compound of any one of claims 1 to 49 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 50.

53. The method of claim 52, wherein the disease or condition is inflammation, autoimmune disease, neuroinflammation, arthritis, rheumatoid arthritis, spondyloarthropathies, systemic lupus erythematosus, cutaneous lupus erythematosus, lupus nephritis, arthritis, osteoarthritis, gouty arthritis, pain, fever, pulmonary sarcoma, silicosis, cardiovascular disease, atherosclerosis, myocardial infarction, thrombosis, congestive heart failure and cardiac reperfusion injury, cardiomyopathy, stroke, ischemia, reperfusion injury, cerebral edema, brain 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 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.

Images