Heterocyclic compounds as NRAS inhibitors

Abstract

Disclosed herein are compounds, and salts thereof, which inhibit targeted NRAS mutants, pharmaceutical formulations, and methods of treatment of NRAS-mediated diseases, such as certain cancers.

Description

HETEROCYCLIC COMPOUNDS AS NRAS INHIBITORS

[0001] This application claims the benefit of United States Provisional Application No. 63 / 632,694, which was filed April 11, 2024, the disclosure of which hereby incorporated by reference in its entirety.

[0002] RAS proteins serve a critical role in cell proliferation as they regulate signal transduction received from extracellular stimuli to downstream pathways such as MAPK, PI3K-AKT and Ral-GDS. These pathways are involved in cellular events such as cell cycle, cell differentiation and cell survival. Dysregulation in RAS signaling is most often associated with activating mutations in the RAS protein typically found at codons 12,13 and 61. Such activating mutations break down the cycling between active (GTP-bound) and inactive (GDP-bound) RAS leading to cancer.

[0003] Approximately 20% of all human cancers present with mutations in RAS proteins. KRAS mutations are responsible for 75% of these cases and are predominantly found in PDAC, colorectal cancer and adenocarcinoma, followed by NRAS (17%) in hematopoietic cancers and malignant melanoma and HRAS (7%) in head and neck squamous cell carcinomas and bladder tumors. NRAS mutant-driven acute myeloid leukemia (AML) accounts for 11-30% of all AML patients. 44% of occurring mutation in AML is observed at codon 12 (NRAS G12D represents 30%) followed by codon 13 and 61. In contrast, in melanoma, NRAS mutations are predominantly observed at codon 61 and to a lesser extent at codons 12 and 13.

[0004] Targeting RAS mutant cancers has been historically challenging. After the initial failed attempts to prevent KRAS attachment and activation in the membrane by using famesyl transferase inhibitors, focus has shifted to upstream and downstream targets in the RAS signaling pathway. Inhibition of RTKs (receptor tyrosine kinases), SHP2 and SOS, all found upstream of RAS, has shown limited impact on RAS driven cancers, while regulation of downstream proteins such as MEK, RAF and PI3K are often plagued by toxicity issues. However, it has been discovered that directly targeting the mutant RAS proteins offers new possibilities for inhibiting the main oncogene. The direct targeting of KRAS G12C mutant tumors has been demonstrated in the clinic to be an effective mode of treatment of NSCLC (non-small cell lung cancer), resulting in the FDA approval of sotorasib. Others have shown that KRAS G12D mutant cancers can also be targeted with non-covalent inhibitors, with the non-conserved KRAS residue H95 theorized to play a significant role in binding selectivity.

[0005] Despite the significant attention focused on targeting RAS mutants, there exists a need for compounds and methods for the treatment of RAS G12D-mediated diseases, specifically NRAS G12D-mediated diseases. The present disclosure fulfills these and other needs, as evident in reference to the following disclosure.SUMMARY

[0006] Provided in Embodiment 1 is a compound of Formula I,or a salt or tautomer thereof, whereinQ is chosen fromJ1, J2and J3are independently chosen from CR12and N;J4is chosen from N, NR12, CH and S;X is chosen from CR5and NR5;Y is chosen from CR6, N, and NR6;Z is chosen from CR7, N, and NR7;R1is chosen from H, alkyl, halo, OH, and NH2;R2is chosen from H, alkyl, and halo;R3is chosen from H, alkyl, alkoxy, haloalkyl, haloalkoxy, halo, and -SF5;R4is chosen from H, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, aryl, heteroaryl, alkoxy, amino, alkylamino, and dialkylamino, wherein alkyl, cycloalkyl, heterocycloalkyl, alkenyl, aryl, heteroaryl, alkoxy, amino, alkylamino, and dialkylamino may be optionally substituted by one or more R8; or R4and R12, taken together, form a 5- membered heteroaryl;R5is chosen fromeither of which may be optionally substituted by one or more R9;R6is chosen from H, amino, alkyl, alkynyl, heteroaryl, and cyano, wherein alkyl and alkynyl may be optionally substituted by one or more groups chosen from hydroxy, cyano, -N(R13)2, -NHC(O)-R14, -C(O)N(R15)2, -NHS(O)2-alkyl, heteroaryl, heterocycloalkyloxy, and heterocycloalkylamino, wherein heteroaryl, heterocycloalkyloxy, and heterocycloalkylamino are optionally substituted with halo or alkyl, or R6and R7, taken together, form a 6-membered heterocycloalkyl optionally substituted with one or more R16; or R6and R9, taken together, form - CH2O(CH2)4OCH2O-;R7is chosen from H, alkyl, amino, alkylamino, dialkylamino, alkoxy, heteroalkyl, cycloalkyl, heterocycloalkyl, haloalkyl, sulfoxyalkyl, aryl, and heteroaryl, wherein alkyl, amino, alkylamino, dialkylamino, alkoxy, heteroalkyl, cycloalkyl, heterocycloalkyl, haloalkyl, sulfoxyalkyl, aryl, and heteroaryl may be optionally substituted by one or more R10; each R8is independently chosen from halo, alkyl, alkoxy, cyano, hydroxy, haloalkyl, - C(O)NH2, and oxo; each R9is independently chosen from alkyl, amido, -C(O)O-alkyl, -C(O)O- cycloalkyl, -C(O)N(R13)2, and heteroaryl, wherein alkyl may be optionally substituted by R11; each R10is independently chosen from alkyl, amino, alkylamino, dialkylamino, halo, cyano, -C(O)NH2, and hydroxy;R11is chosen from alkoxy, hydroxy, oxo, amino, alkylamino, dialkylamino, and halo; each R12is independently chosen from H, halo, alkyl, amino, and cyano; each R13is independently chosen from H, alkyl, and haloalkyl;R14is chosen from alkyl, cyanoalkyl, hydroxyalkyl, alkoxy, and heteroaryl; each R15is independently chosen from H and alkyl; and each R16is independently chosen from halo and alkyl.

[0007] Also provided is a compound as disclosed herein, or a pharmaceutically acceptable salt thereof.

[0008] Also provided is a pharmaceutical formulation comprising a compound as disclosed herein, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier.

[0009] Also provided is a method for treating a disease or condition that benefits from or is treatable by inhibition of NR AS G12D, comprising the administration of a therapeuticallyeffective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, to a subject in need thereof.

[0010] Also provided are methods of inhibiting at least one NR AS GI2D function comprising the step of contacting NRAS G12D with a compound as described herein, or a pharmaceutically acceptable salt thereof. The cell phenotype, cell proliferation, activity of NRAS G12D, change in biochemical output produced by active NRAS G12D, expression of NRAS G12D, or binding of NRAS G12D with a natural binding partner may be monitored. Such methods may be modes of treatment of disease, biological assays, cellular assays, biochemical assays, or the like.[Oi l] Also provided are methods of treatment of an NRAS G12D-mediated disease comprising the administration of a therapeutically effective amount of a compound as disclosed herein, or a pharmaceutically acceptable salt thereof, to a patient in need thereof.

[0012] Also provided is a method of inhibition of NRAS G12D comprising contacting NRAS G12D with a compound as disclosed herein, or a pharmaceutically acceptable salt thereof.|013 ] Also provided is a method of modulation of an NRAS G12D-mediated function in a subject comprising the administration of a therapeutically effective amount of a compound as disclosed herein, or a pharmaceutically acceptable salt thereof.

[0014] These and other aspects of the invention will be apparent upon reference to the following detailed description.DETAILED DESCRIPTION

[0015] As used in the present specification, the following words and phrases are generally intended to have the meanings as set forth below, except to the extent that the context in which they are used indicates otherwise.

[0016] In the following description, certain specific details are set forth in order to provide a thorough understanding of various embodiments. However, one skilled in the art will understand that the invention may be practiced without these details. In other instances, well-known structures have not been shown or described in detail to avoid unnecessarily obscuring descriptions of the embodiments. Unless the context requires otherwise, throughout the specification and claims which follow, the word “comprise” and variations thereof, such as, “comprises” and “comprising” are to be construed in an open, inclusive sense, that is, as “including, but not limited to.” Further, headings provided herein are for convenience only and do not interpret the scope or meaning of the claimed invention.

[0017] Reference throughout this specification to “one embodiment” or “an embodiment” or “some embodiments” or “a certain embodiment” means that a particular feature, structure or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, the appearances of the phrases “in one embodiment” or “in an embodiment” or “in some embodiments” or “in a certain embodiment” in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.

[0018] Also, as used in this specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the content clearly dictates otherwise.

[0019] When ranges of values are disclosed, and the notation “from m ... to m” or “between m . . . and ” is used, where m and n2 are the numbers, then unless otherwise specified, this notation is intended to include the numbers themselves and the range between them. This range may be integral or continuous between and including the end values. By way of example, the range “from 2 to 6 carbons” is intended to include two, three, four, five, and six carbons, since carbons come in integer units. Compare, by way of example, the range “from 1 to 3 pM (micromolar),” which is intended to include 1 pM, 3 pM, and everything in between to any number of significant figures (e.g., 1.255 pM, 2.1 pM, 2.9999 pM, etc.).

[0020] As used herein, “about” means ± 20% of the stated value, and includes more specifically values of ± 10%, ± 5%, ± 2% and ± 1% of the stated value.

[0021] The term “alkenyl,” as used herein, refers to a straight-chain or branched-chain hydrocarbon radical having one or more double bonds and containing from 2 to 20 carbon atoms. In certain embodiments, said alkenyl will comprise from 2 to 6 carbon atoms.

[0022] The term “alkoxy”, and, interchangeably, “(alkyl)oxy”, as used herein, refers to an alkyl radical attached to a molecule by oxygen.

[0023] The term “alkyl,” as used herein, refers to a straight-chain or branched-chain saturated, hydrocarbon radical containing from 1 to 20 carbon atoms. In some embodiments, alkyl will comprise from 1 to 10 carbon atoms. In some embodiments, alkyl will comprise from 1 to 8 carbon atoms.

[0024] The term “alkylamino,” as used herein, refers to an alkyl group attached to the parent molecular moiety through an amino group. The term “dialkylamino,” as used herein, refers to two alkyl groups attached to the parent molecular moiety through an amino group.

[0025] The terms “amido” and “carbamoyl,” as used herein, refer to an amino or alkylamino group as described below attached to the parent molecular moiety through a carbonyl group, or vice versa.

[0026] The term “amino,” as used herein, refers to -NH2.

[0027] The term "aryl," as used herein, means a carbocyclic aromatic system containing one, two or three rings wherein such polycyclic ring systems are fused together.

[0028] The term “cyano,” as used herein, refers to -CN.

[0029] The term “cycloalky],” or, alternatively, “carbocycle,” as used herein, refers to a saturated monocyclic, bicyclic or tricyclic alkyl group wherein each cyclic moiety contains from 3 to 12 carbon atom ring members. In some embodiments, cycloalkyl will comprise from 5 to 7 carbon atoms. In some embodiments, cycloalkyl will comprise a spirocyclic ring system. “Bicyclic” and “tricyclic” as used herein are intended to include both fused ring systems, as well as the multicyclic (multicentered) saturated type.

[0030] The term “halo,” or “halogen,” as used herein, refers to fluorine, chlorine, bromine, or iodine.|031 ] The term “haloalkyl,” as used herein, refers to an alkyl radical having the meaning as defined above wherein one or more hydrogens are replaced with a halogen. Specifically embraced are monohaloalkyl, dihaloalkyl and polyhaloalkyl radicals. Dihalo and polyhaloalkyl radicals may have two or more of the same halo atoms or a combination of different halo radicals.

[0032] The term "heteroaryl," as used herein, refers to a 3 to 15 membered unsaturated heteromonocyclic ring, or a fused monocyclic, bicyclic, or tricyclic ring system in which at least one of the fused rings is aromatic, which contains at least one atom chosen from N, O, and S. In some embodiments, heteroaryl will comprise from 1 to 4 heteroatoms as ring members. In some embodiments, heteroaryl will comprise from 1 to 2 heteroatoms as ring members. In some embodiments, heteroaryl will comprise from 5 to 7 atoms. The term also embraces fused polycyclic groups wherein heterocyclic rings are fused with aryl rings wherein heteroaryl rings are fused with other heteroaryl rings wherein heteroaryl rings are fused with heterocycloalkyl rings, or wherein heteroaryl rings are fused with cycloalkyl rings.

[0033] The terms “heterocycloalkyl” and, interchangeably, “heterocycle,” as used herein, refers to a saturated, partially unsaturated, or fully unsaturated (but nonaromatic) monocyclic; saturated, partially unsaturated, or fully unsaturated (but not fully aromatic) bridged; saturated, partially unsaturated, or fully unsaturated (but not fully aromatic) bicyclic; or saturated, partially unsaturated, or fully unsaturated (but not fully aromatic) tricyclicheterocyclic group containing at least one heteroatom as a ring member wherein each heteroatom may be independently chosen from nitrogen, oxygen, and sulfur.

[0034] In some embodiments, heterocycloalkyl will comprise a spirocyclic ring system. In some embodiments, heterocycloalkyl will comprise from 1 to 4 heteroatoms as ring members. In some embodiments, heterocycloalkyl will comprise from 1 to 2 heteroatoms as ring members. In some embodiments, heterocycloalkyl will comprise from 3 to 8 ring members in each ring. In some embodiments, heterocycloalkyl will comprise from 3 to 7 ring members in each ring. In some embodiments, heterocycloalkyl will comprise from 5 to 6 ring members in each ring. “Heterocycloalkyl” and “heterocycle” are intended to include sulfones, sulfoxides, N-oxides of tertiary nitrogen ring members, and carbocyclic fused and benzo fused ring systems; additionally, both terms also include systems where a heterocycle ring is fused to an aryl or heteroaryl group, as defined herein, or an additional heterocycle group.

[0035] The terms “hydroxy” and, interchangeably, “hydroxyl,” as used herein, refers to - OH.

[0036] The term “oxo,” as used herein, refers to =0.|037 ] Any definition herein may be used in combination with any other definition to describe a composite structural group. By convention, the trailing element of any such definition is that which attaches to the parent moiety. For example, the composite group alkylamido would represent an alkyl group attached to the parent molecule through an amido group, and the term alkoxyalkyl would represent an alkoxy group attached to the parent molecule through an alkyl group.

[0038] Asymmetric centers exist in the compounds and pharmaceutically acceptable salts thereof, disclosed herein. These centers are designated by the symbols “R” or “S,” depending on the configuration of substituents around the chiral carbon atom. It should be understood that the disclosure encompasses all stereochemical isomeric forms, including diastereomeric, enantiomeric, and epimeric forms, as well as d-isomers and 1 -isomers, and mixtures thereof. Individual stereoisomers of compounds, and pharmaceutically acceptable salts thereof, can be prepared synthetically from commercially available starting materials which contain chiral centers or by preparation of mixtures of enantiomeric products followed by separation such as conversion to a mixture of diastereomers followed by separation or recrystallization, chromatographic techniques, direct separation of enantiomers on chiral chromatographic columns, or any other appropriate method known in the art. Starting compounds, and pharmaceutically acceptable salts thereof, of particular stereochemistry are either commercially available or can be made and resolved by techniques known in the art.Additionally, the compounds, and pharmaceutically acceptable salts thereof, disclosed herein may exist as geometric isomers. The present disclosure includes all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers as well as the appropriate mixtures thereof.

[0039] Additionally, the compounds disclosed herein can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. In general, the solvated forms are considered equivalent to the unsolvated forms.

[0040] As used herein, "administering to a patient" refers to the process of introducing a composition or dosage form into the patient via an art-recognized means of introduction.

[0041] The term “disease” as used herein is intended to be generally synonymous, and is used interchangeably with, the terms “disorder,” “syndrome,” and “condition” (as in medical condition), in that all reflect an abnormal condition of the human or animal body or of one of its parts that impairs normal functioning, is typically manifested by distinguishing signs and symptoms, and causes the human or animal to have a reduced duration or quality of life.

[0042] The term "combination therapy" means the administration of two or more therapeutic agents to treat a therapeutic condition or disorder described in the present disclosure. Such administration encompasses co- administration of these therapeutic agents in a substantially simultaneous manner, such as in a single capsule having a fixed ratio of active ingredients or in multiple, separate capsules for each active ingredient. In addition, such administration also encompasses use of each type of therapeutic agent in a sequential manner. In either case, the treatment regimen will provide beneficial effects of the drug combination in treating the conditions or disorders described herein.

[0043] The phrase "therapeutically effective" is intended to qualify the amount of active ingredients used in the treatment of a disease or disorder or on the effecting of a clinical endpoint. The precise therapeutically effective amount for a subject may depend upon, e.g., the subject’s size and health, the nature and extent of the condition, the therapeutics or combination of therapeutics selected for administration, and other variables known to those of skill in the art. The effective amount for a given situation is determined by routine experimentation and is within the judgment of the clinician.

[0044] As used herein, the term “treat,” “treating”, or “treatment” means the administration of therapy to an individual who already manifests at least one symptom of a disease or condition or who has previously manifested at least one symptom of a disease or condition. For example, “treating” can include alleviating, abating or ameliorating a disease or condition symptoms, preventing additional symptoms, ameliorating the underlying metabolic causes of symptoms, inhibiting the disease or condition, e.g., arresting thedevelopment of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition. For example, the term “treating” in reference to a disorder means a reduction in severity of one or more symptoms associated with that particular disorder. Therefore, treating a disorder does not necessarily mean a reduction in severity of all symptoms associated with a disorder and does not necessarily mean a complete reduction in the severity of one or more symptoms associated with a disorder.

[0045] The term “patient” is generally synonymous with the term “subject” and includes all mammals including humans. Examples of patients include humans, livestock such as cows, goats, sheep, pigs, and rabbits, and companion animals such as dogs, cats, rabbits, and horses. Preferably, the patient is a human.

[0046] Those skilled in the art will appreciate that the invention(s) described herein is susceptible to variations and modifications other than those specifically described. It is to be understood that the invention(s) includes all such variations and modifications. The invention(s) also includes all the steps, features, compositions and compounds referred to or indicated in this specification, individually or collectively, and any and all combinations or any two or more of steps or features unless specifically stated otherwise.

[0047] The present invention(s) is not to be limited in scope by the specific embodiments described herein, which are intended for the purpose of exemplification only. Functionally equivalent products, compositions, and methods are clearly within the scope of the invention(s), as described herein.

[0048] It is appreciated that certain features of the invention(s), which are, for clarity, described in the context of separate embodiments, can also be provided in combination in a single embodiment. Conversely, various features of the invention(s), which are, for brevity, described in the context of a single embodiment, can also be provided separately or in any suitable subcombination.

[0049] Embodiment 2 - The compound of embodiment 1, or a salt or tautomer thereof, wherein

[0050] Embodiment 3 - The compound of embodiment 2, or a salt or tautomer thereof, wherein J2is N and J3is CH.

[0051] Embodiment 4 - The compound of embodiment 2, or a salt or tautomer thereof, wherein J2is CH and J3is N.

[0052] Embodiment 5 - The compound of embodiment 2, or a salt or tautomer thereof, wherein J2is CF and J3is N.

[0053] Embodiment 6 - The compound of embodiment 2, or a salt or tautomer thereof, wherein J2and J3are CH.

[0054] Embodiment 7 - The compound of embodiment 2, or a salt or tautomer thereof, wherein R1is NH?.

[0055] Embodiment 8 - The compound of embodiment 2, or a salt or tautomer thereof, wherein R1is OH.

[0056] Embodiment 9 - The compound of embodiment 2, or a salt or tautomer thereof, wherein R2is chosen from H, methyl, fluoro, and chloro.

[0057] Embodiment 10 - The compound of embodiment 2, or a salt or tautomer thereof, wherein R3is chosen from trifluoromethyl, trifluoromethoxy, chloro, and -SFs.

[0058] Embodiment 11 - The compound of embodiment 2, or a salt or tautomer thereof,

[0059] Embodiment 12 - The compound of embodiment 11 , or a salt or tautomer thereof, wherein

[0060] Embodiment 13 - The compound of embodiment 11 , or a salt or tautomer

[0062] Embodiment 15 - The compound of embodiment 14, or a salt or tautomer thereof, wherein J2is CR12, wherein R12is -NH2.

[0063] Embodiment 16 - The compound of embodiment 14, or a salt or tautomer thereof, wherein J2is N.

[0064] Embodiment 17 - The compound of embodiment 14, or a salt or tautomer thereof, wherein J3is CR12, wherein R12is cyano.

[0065] Embodiment 18 - The compound of embodiment 14, or a salt or tautomer thereof, wherein J3is N.

[0066] Embodiment 19 - The compound of embodiment 14, or a salt or tautomer thereof, wherein J4is CH.

[0067] Embodiment 20 - The compound of embodiment 14, or a salt or tautomer thereof, wherein J4is S.

[0068] Embodiment 21 - The compound of embodiment 14, or a salt or tautomer thereof, wherein J4is N.

[0069] Embodiment 22 - The compound of embodiment 14, or a salt or tautomer thereof, wherein R2is chosen from H and fluoro.

[0070] Embodiment 23 - The compound of embodiment 14, or a salt or tautomer thereof, wherein R1is chosen from H and methyl.

[0071] Embodiment 24 - The compound of embodiment 14, or a salt or tautomer thereof, wherein R3is chosen from H and chloro.

[0072] Embodiment 25 - The compound of embodiment 14, or a salt or tautomer thereof, wherein Q is chosen from

[0073] Embodiment 26 - The compound of embodiment 25, or a salt or tautomer thereof, wherein

[0074] Embodiment 27 - The compound of any one of embodiments 1 to 26, or a salt or tautomer thereof, wherein R4is chosen from H, ethyl, isopropyl, isobutyl, isopropoxy, cyclopropyl, 1 -methylcyclopropyl, tetrahydrofuran-2-ol, propylnitrile, propan- l-ol, trifluoroprop- l-en-2-yl, phenyl, propenyl, cyclopentenyl, 1-methylpyrazolyl, dimethylamino, isobutanol, aminoethanol, isobutanone, acetonitrile, isobutylnitrile, methoxyisopropyl,

[0075] Embodiment 28 - The compound of any one of embodiments 1 to 26, or a salt or tautomer thereof, wherein R4is chosen from alkyl, cycloalkyl, and cyanoalkyl.

[0076] Embodiment 29 - The compound of embodiment 28, wherein R4is chosen from isopropyl, cyclopropyl, and propylnitrile.

[0077] Embodiment 30 - The compound of embodiment 29, wherein R4is isopropyl.

[0078] Embodiment 31 - The compound of embodiment 29, wherein R4is cyclopropyl.

[0079] Embodiment 32 - The compound of embodiment 29, wherein R4is propylnitrile.

[0080] Embodiment 33 - The compound of any one of embodiments 1 to 32, or a salt or tautomer thereof, wherein J1is N.

[0081] Embodiment 34 - The compound of any one of embodiments 1 to 33, or a salt or tautomer thereof, wherein X is CR5.

[0082] Embodiment 35 - The compound of embodiment 34, or a salt or tautomer

[0083] Embodiment 36 - The compound of embodiment 35, or a salt or tautomer thereof, wherein R5is chosen from

[0084] Embodiment 37 - The compound of embodiment 36, or a salt or tautomer thereof, wherein

[0085] Embodiment 38 - The compound of embodiment 36, or a salt or tautomer thereof, wherein

[0086] Embodiment 39 - The compound of embodiment 36, or a salt or tautomer thereof, wherein

[0087] Embodiment 40 - The compound of any one of embodiments 1 to 39, or a salt or tautomer thereof, wherein Y is CR6.

[0088] Embodiment 41 - The compound of embodiment 40, or a salt or tautomer thereof, wherein R6is chosen from hydroxyalkynyl and -alkyl-NHC(O)-R14.

[0089] Embodiment 42 - The compound of embodiment 41 , or a salt or tautomer thereof, wherein R6is hydroxyalkynyl.

[0090] Embodiment 43 - The compound of embodiment 42, or a salt or tautomer thereof, wherein

[0091] Embodiment 44 - The compound of embodiment 41 , or a salt or tautomer thereof, wherein R6is chosen from hydroxyalkynyl and -alkyl-NHC(O)-R14.

[0092] Embodiment 45 - The compound of embodiment 44, or a salt or tautomer thereof, wherein

[0093] Embodiment 46 - The compound of any one of embodiments 1 to 39, or a salt or tautomer thereof, wherein Y is N.

[0094] Embodiment 47 - The compound of any one of embodiments 1 to 46, or a salt or tautomer thereof, wherein Z is NR7.

[0095] Embodiment 48 - The compound of embodiment 47, or a salt or tautomer thereof, wherein R7is cyclopropyl optionally substituted with R10.

[0096] Embodiment 49 - The compound of embodiment 48, or a salt or tautomer thereof, wherein R7is cyclopropyl.

[0097] Embodiment 50 - The compound of embodiment 48, or a salt or tautomer thereof, wherein

[0098] Embodiment 51 - The compound of any one of embodiments 1 to 50, or a salt or tautomer thereof, whereinJ1is N;X is CR5;Y is CR6; andZ is NR7.

[0099] Embodiment 52 - The compound of any one of embodiments 1 to 50, or a salt or tautomer thereof, whereinJ1is N;X is CR5;Y is N; and Z is NR7.

[0100] Embodiment 53 - The compound of embodiment 1 , or a salt or tautomer thereof, having a structural formula of Formula II:wherein n is 0, 1 , or 2J2and J3are independently chosen from CR12and N;Y is chosen from CR6, N, and NR6;R1is chosen from H, alkyl, halo, OH, and NH2;R2is chosen from H, alkyl, and halo;R3is chosen from H, alkyl, alkoxy, haloalkyl, haloalkoxy, halo, and -SB;R4is chosen from H, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, aryl, heteroaryl, alkoxy, amino, alkylamino, and dialkylamino, wherein alkyl, cycloalkyl, heterocycloalkyl, alkenyl, aryl, heteroaryl, alkoxy, amino, alkylamino, and dialkylamino may be optionally substituted by one or more R8; or R4and R12, taken together, form a 5 -membered heteroaryl;R6is chosen from H, amino, alkyl, alkynyl, heteroaryl, and cyano, wherein alkyl and alkynyl may be optionally substituted by one or more groups chosen from hydroxy, cyano, -N(R13)2, -NHC(O)-R14, -C(O)N(R1S)2, alkyl-S(O)2NH-, heteroaryl, heterocycloalkyloxy, and heterocycloalkylamino, wherein heteroaryl, heterocycloalkyloxy, and heterocycloalkylamino are optionally substituted with halo or alkyl; or R6and R9, taken together, form -CH2O(CH2)4OCH2O-;R7is chosen from H, alkyl, amino, alkylamino, dialkylamino, alkoxy, heteroalkyl, cycloalkyl, heterocycloalkyl, haloalkyl, sulfoxyalkyl, aryl, and heteroaryl, wherein alkyl, amino, alkylamino, dialkylamino, alkoxy, heteroalkyl, cycloalkyl,heterocycloalkyl, haloalkyl, sulfoxyalkyl, aryl, and heteroaryl may be optionally substituted by one or more R10; each R8is independently chosen from halo, alkyl, alkoxy, cyano, hydroxy, haloalkyl, -C(0)NH2, and oxo; each R9is independently chosen from alkyl, amido, -C(O)O-alkyl, -C(O)O- cycloalkyl, -C(O)N(R13)2, and heteroaryl, wherein alkyl may be optionally substituted by R11; each R12is independently chosen from H, halo, alkyl, amino, and cyano; each R13is independently chosen from H, alkyl, and haloalkyl;R14is chosen from alkyl, cyanoalkyl, hydroxyalkyl, alkoxy, and heteroaryl; each R15is independently chosen from H and alkyl; and each R16is independently chosen from halo and alkyl.

[0101] Embodiment 54 - The compound of embodiment 1, or a salt or tautomer thereof, having a structural formula of Formula III:wherein n is 0, 1 , or 2J2and J3are independently chosen from CR12and N;Y is chosen from CR6, N, and NR6;R1is chosen from H, alkyl, halo, OH, and NH2;R2is chosen from H, alkyl, and halo;R3is chosen from H, alkyl, alkoxy, haloalkyl, haloalkoxy, halo, and -SFs;R4is chosen from H, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, aryl, heteroaryl, alkoxy, amino, alkylamino, and dialkylamino, wherein alkyl, cycloalkyl, heterocycloalkyl, alkenyl, aryl, heteroaryl, alkoxy, amino, alkylamino, and dialkylamino may be optionally substituted by one or more R8; or R4and R12, taken together, form a 5 -membered heteroaryl;R6is chosen from H, amino, alkyl, alkynyl, heteroaryl, and cyano, wherein alkyl and alkynyl may be optionally substituted by one or more groups chosen fromhydroxy, cyano, -N(R13)2, -NHC(O)-R14, -C(O)N(R15)2, alkyl-S(O)2NH-, heteroaryl, heterocycloalkyloxy, and heterocycloalkylamino, wherein heteroaryl, heterocycloalkyloxy, and heterocycloalkylamino are optionally substituted with halo or alkyl; or R6and R9, taken together, form -CH2O(CH2)4OCH2O-;R7is chosen from H, alkyl, amino, alkylamino, dialkylamino, alkoxy, heteroalkyl, cycloalkyl, heterocycloalkyl, haloalkyl, sulfoxyalkyl, aryl, and heteroaryl, wherein alkyl, amino, alkylamino, dialkylamino, alkoxy, heteroalkyl, cycloalkyl, heterocycloalkyl, haloalkyl, sulfoxyalkyl, aryl, and heteroaryl may he optionally substituted by one or more R10; each R8is independently chosen from halo, alkyl, alkoxy, cyano, hydroxy, haloalkyl, -C(0)NH2, and oxo; each R9is independently chosen from alkyl, amido, -C(O)O-alkyl, -C(O)O- cycloalkyl, -C(O)N(R13)2, and heteroaryl, wherein alkyl may be optionally substituted by R11; each R12is independently chosen from H, halo, alkyl, amino, and cyano; each R13is independently chosen from H, alkyl, and haloalkyl;R14is chosen from alkyl, cyanoalkyl, hydroxyalkyl, alkoxy, and heteroaryl; each R15is independently chosen from H and alkyl; and each R16is independently chosen from halo and alkyl.

[0102] Embodiment 55 - The compound of embodiment 1, or a salt or tautomer thereof, having a structural formula of Formula IV :wherein:A is a 6-membered heterocycloalkyl; m is 0, 1, 2, 3, 4; n is 0, 1, or 2;J2and J3are independently chosen from CR12and N;Y is chosen from CR6, N, and NR6;R1is chosen from H, alkyl, halo, OH, and NH2;R2is chosen from H, alkyl, and halo;R3is chosen from H, alkyl, alkoxy, haloalkyl, haloalkoxy, halo, and -SB;R4is chosen from H, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, aryl, heteroaryl, alkoxy, amino, alkylamino, and dialkylamino, wherein alkyl, cycloalkyl, heterocycloalkyl, alkenyl, aryl, heteroaryl, alkoxy, amino, alkylamino, and dialkylamino may be optionally substituted by one or more R8; or R4and R12, taken together, form a 5 -membered heteroaryl; each R8is independently chosen from halo, alkyl, alkoxy, cyano, hydroxy, haloalkyl, -C(O)NH2, and oxo; each R9is independently chosen from alkyl, amido, -C(O)O-alkyl, -C(O)O- cycloalkyl, -C(O)N(R13)2, and heteroaryl, wherein alkyl may be optionally substituted by R11; each R12is independently chosen from H, halo, alkyl, amino, and cyano; and each R16is independently chosen from halo and alkyl.|0103 | Embodiment 56 - The compound of embodiment 55, or a salt or tautomer thereof, wherein

[0104] Embodiment 57 - The compound of embodiment 1, or a salt or tautomer thereof, wherein the compound of Formula I has a structural formula chosen from:

[0105] Embodiment 58 - The compound of embodiment 57, or a salt or tautomer thereof, wherein the compound of Formula I has a structural formula chosen from:

[0106] Embodiment 59 - A pharmaceutical formulation comprising a compound as recited in any one of embodiments 1-58, or a salt or tautomer thereof, together with a pharmaceutically acceptable carrier.

[0107] Embodiment 60 - The pharmaceutical formulation as recited in embodiment 59, formulated for oral administration.

[0108] Embodiment 61 - The pharmaceutical formulation as recited in embodiment 59 or 60, additionally comprising another therapeutic agent.

[0109] Embodiment 62 - A method of inhibition of NRAS G12D, comprising contacting NRAS G12D with a compound as recited in any one of embodiments 1-58, or a salt or tautomer thereof, or a pharmaceutical composition as recited in any one of embodiments 59- 61.

[0110] Embodiment 63 - A method of treatment of an NRAS G12D-mediated disease, comprising the administration of a therapeutically effective amount of a compound as recited in any one of embodiments 1-58, or a salt or tautomer thereof, or a pharmaceutical composition as recited in any one of embodiments 59-61, to a patient in need thereof.

[0111] Embodiment 64 - The method as recited in embodiment 63, wherein the NRAS G12D-mediated disease is cancer.

[0112] Embodiment 65 - The method as recited in embodiment 64, wherein the cancer is chosen from Melanoma, Malignant Solid Tumors, Colorectal Carcinoma, Non-Small Cell Lung Carcinoma, Acute Myeloid Leukemia, Myelodysplastic Syndromes, Chronic Myelomonocytic Leukemia, Colorectal Adenocarcinoma, Multiple Myeloma, Non-Hodgkin Lymphoma, Pancreatic Carcinoma, Cutaneous Melanoma, Ovarian Carcinoma, Pancreatic Ductal Adenocarcinoma, Acute Lymphoblastic Leukemia, Thyroid Gland Carcinoma, Glioma, Neurofibromatosis, Poorly Differentiated Thyroid Gland Carcinoma, Myelodysplastic Syndrome With Excess Blasts, Juvenile Myelomonocytic Leukemia, Histiocytic And Dendritic Cell Neoplasm, Head And Neck Squamous Cell Carcinoma, Small Cell Lung Carcinoma, Low Grade Glioma, Squamous Cell Lung Carcinoma, Breast Carcinoma, Chronic Myelomonocytic Leukemia, Thyroid Gland Undifferentiated (Anaplastic) Carcinoma, Embryonal Rhabdomyosarcoma, Thyroid Gland Follicular Carcinoma, T-Cell Acute Lymphoblastic Leukemia, Mucosal Melanoma, Low Grade Ovarian Serous Adenocarcinoma, Thyroid Gland Papillary Carcinoma, Refractory Anemia With Excess Blasts, Myeloid Neoplasm, Myelodysplastic / Myeloproliferative Neoplasm, Rectal Carcinoma, Colon Carcinoma, Malignant Peripheral Nerve Sheath Tumor, Cholangiocarcinoma, Endometrial Carcinoma, Mantle Cell Lymphoma, Secondary Myelodysplastic Syndrome, Therapy-Related Myelodysplastic Syndrome, Lymphoma, Neuronal And Mixed Neuronal-Glial Tumors, Ganglioglioma, Soft Tissue Sarcoma, Bladder Carcinoma, Esophageal Carcinoma, Sarcoma, Thymic Carcinoma, Lung Adenocarcinoma, Lung Carcinoma, Uveal Melanoma, Head And Neck Carcinoma, Diffuse Glioma, Squamous Cell Carcinoma, Chronic Myeloid Leukemia, Adenocarcinoma of the GastroesophagealJunction, Glioblastoma, Neuroblastoma, Astrocytic Tumor, Hepatocellular Carcinoma, Pancreatic Adenocarcinoma, Diffuse Large B-Cell Lymphoma, Anaplastic Astrocytoma, Gastric Adenocarcinoma, Gastric Carcinoma, Prostate Carcinoma, Renal Cell Carcinoma, B- Cell Acute Lymphoblastic Leukemia, Double-Hit Lymphoma, Dysembryoplastic Neuroepithelial Tumor, Gangliocytoma, Low-Grade Neuroepithelial Tumor, Peripheral T- Cell Lymphoma, Pilocytic Astrocytoma, Pilomyxoid Astrocytoma, Rhabdoid Tumor, and Schwannoma.

[0113] Embodiment 66 - A compound of Formula I,J1, J2and J3are independently chosen from CR12and N;J4is chosen from N, CH and S;X is chosen from CR5and NR5;Y is chosen from CR6, N, and NR6;Z is chosen from CR7, N, and NR7;R1is chosen from H, alkyl, halo, OH and NH2;R2is chosen from H, alkyl, and halo;R3is chosen from H, alkyl, alkoxy, haloalkyl, haloalkoxy, and halo;R4is chosen from H, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, aryl, heteroaryl, alkoxy, amino, alkylamino, and dialkylamino, wherein alkyl, cycloalkyl, heterocycloalkyl, alkenyl, aryl, heteroaryl, alkoxy, amino, alkylamino, and dialkylamino may be optionally substituted by one or more Rs;R5is chosen fromeither of which may be optionally substituted by one or more R9;R6is chosen from H, alkyl, and cyano, wherein alkyl may be optionally substituted by one or more groups chosen from hydroxy, amino, alkylamino, and dialkylamino;R7is chosen from H, alkyl, amino, alkylamino, dialkylamino, alkoxy, heteroalkyl, cycloalkyl, heterocycloalkyl, haloalkyl, sulfoxyalkyl, aryl, and heteroaryl, wherein alkyl, amino, alkylamino, dialkylamino, alkoxy, heteroalkyl, cycloalkyl, heterocycloalkyl, haloalkyl, sulfoxyalkyl, aryl, and heteroaryl may be optionally substituted by one or moreR10; each R8is independently chosen from alkyl, alkoxy, cyano, hydroxy, haloalkyl, - C(O)NH2, and oxo; each R9is independently chosen from alkyl, amido, and -C(O)OCH3, wherein alkyl may be optionally substituted by R11; each R10is independently chosen from alkyl, amino, alkylamino, dialkylamino, halo, cyano, -C(O)NH2, and hydroxy; andR11is chosen from alkoxy, hydroxy, amino, alkylamino, dialkylamino, and halo; and each R12is independently chosen from H, alkyl, amino, and cyano.

[0114] Embodiment 67 - In some embodiments,

[0115] Embodiment 68 - In some embodiments,

[0116] Embodiment 69 - In some embodiments, J2is CH.

[0117] Embodiment 70 - In some embodiments, J3is N.

[0118] Embodiment 71 - In some embodiments, J3is CH.

[0119] Embodiment 72 - In some embodiments, R1is NH2.

[0120] Embodiment 73 - In some embodiments, R1is OH.

[0121] Embodiment 74 - In some embodiments, R2is chosen from H, methyl, fluoro, and chloro.

[0122] Embodiment 75 - In some embodiments, R3is chosen from trifluoromethyl, trifluoromethoxy, and chloro.

[0123] Embodiment 76 - In some embodiments,R1is NH2;R2is methyl; andR is trifluoromethyl.

[0124] Embodiment 77 - In some embodiments, Q is chosen from

[0126] Embodiment 79 - In some embodiments,

[0127] Embodiment 80 - In some embodiments, J2is CR12, wherein R12is -NH2.

[0128] Embodiment 81 - In some embodiments, J2is N.

[0129] Embodiment 82 - In some embodiments, J3is CR12, wherein R12is cyano.

[0130] Embodiment 83 - In some embodiments, J3is N.

[0131] Embodiment 84 - In some embodiments, J4is CH.

[0132] Embodiment 85 - In some embodiments, J4is S.

[0133] Embodiment 86 - In some embodiments, J4is N.

[0134] Embodiment 87 - In some embodiments, R2is chosen from H and fluoro.

[0135] Embodiment 88 - In some embodiments, R1is chosen from H and methyl

[0136] Embodiment 89 - In some embodiments, R3is chosen from H and chloro.

[0139] Embodiment 92 - In some embodiments, R4is chosen from H, ethyl, isopropyl, isobutyl, isopropoxy, cyclopropyl, tetrahydrofuran-2-ol, propylnitrile, propan- l-ol, trifluoroprop- l-en-2-yl, phenyl, propenyl, cyclopentenyl, 1-methylpyrazolyl, dimethylamino, isobutanol, aminoethanol, isobutanone, isobutylnitrile, methoxyisopropyl, and pentyldinitrile.

[0140] Embodiment 93 - In some embodiments, R4is chosen from propylnitrile and isopropyl.

[0141] Embodiment 94 - In some embodiments, J1is CH.

[0142] Embodiment 95 - In some embodiments, J1is N.

[0143] Embodiment 96 - In some embodiments, X is CR5.

[0144] Embodiment 97 - In some embodiments, R5is chosen from

[0145] Embodiment 98 - In some embodiments,

[0146] Embodiment 99 - In some embodiments, Y is CR6.

[0147] Embodiment 100 - In some embodiments, R6is H.

[0148] Embodiment 101 - In some embodiments, Y is N.

[0149] Embodiment 102 - In some embodiments, Z is NR7.

[0150] Embodiment 103 - In some embodiments, R7is chosen from methyl, cyclopropyl, cyclopropylcarboxamide, and cyclopropylnitrile.

[0151] Embodiment 104 - In some embodiments, R7is cyclopropyl.

[0152] Embodiment 105 - In some embodiments,I1is N;X is CR5;Y is N; andZ is NR7.

[0153] Embodiment 106 - In some embodiments, the compound has a structural formula of Formula II:or a salt or tautomer thereof, wherein n is 0, 1, or 2 and wherein Y, J2, J3, R1, R2, R3, R4, R7, and R9are as defined herein.

[0154] Embodiment 107 - The compound of embodiment 1 , or a salt or tautomer thereof, having a structural formula of Formula III:or a salt or tautomer thereof,wherein n is 0, 1, or 2 and wherein Y, J2, J3, R1, R2, R3, R4, R7, and R9are as defined herein.

[0155] The compounds disclosed herein can exist as pharmaceutically acceptable salts. The present disclosure includes compounds listed herein in the form of salts, including acid addition salts. Suitable salts include those formed with both organic and inorganic acids. Such acid addition salts will normally be pharmaceutically acceptable. However, salts of non- pharmaceutically acceptable salts may be of utility in the preparation and purification of the compound in question. Basic addition salts may also be formed and be pharmaceutically acceptable. For a more complete discussion of the preparation and selection of salts, refer to Pharmaceutical Salts: Properties, Selection, and Use (Stahl, P. Heinrich. Wiley-VCHA, Zurich, Switzerland, 2002).

[0156] The term “pharmaceutically acceptable salt,” as used herein, represents salts or zwitterionic forms of the compounds disclosed herein. The salts can be prepared during the final isolation and purification of the compounds or separately by reacting the appropriate compound in the form of the free base with a suitable acid. Representative acid addition salts include acetate, adipate, alginate, L-ascorbate, aspartate, benzoate, benzenesulfonate (besylate), bisulfate, butyrate, camphorate, camphorsulfonate, citrate, digluconate, formate, fumarate, gentisate, glutarate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hippurate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethansulfonate (isethionate), lactate, maleate, malonate, DL-mandelate, mesitylenesulfonate, methanesulfonate, naphthylenesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylproprionate, phosphonate, picrate, pivalate, propionate, pyroglutamate, succinate, sulfonate, tartrate, L-tartrate, trichloroacetate, trifluoroacetate, phosphate, glutamate, bicarbonate, para-toluenesulfonate (p-tosylate), and undecanoate. Also, basic groups in the compounds disclosed herein can be quatemized with methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dimethyl, diethyl, dibutyl, and diamyl sulfates; decyl, lauryl, myristyl, and steryl chlorides, bromides, and iodides; and benzyl and phenethyl bromides. Examples of acids which can be employed to form pharmaceutically acceptable addition salts include inorganic acids such as hydrochloric, hydrobromic, sulfuric, and phosphoric, and organic acids such as oxalic, maleic, succinic, and citric. Salts can also be formed by coordination of the compounds with an alkali metal or alkaline earth ion. Hence, the present disclosure contemplates sodium, potassium, magnesium, and calcium salts of the compounds disclosed herein, and the like.

[0157] Basic addition salts can be prepared during the final isolation and purification of the compounds by reacting a carboxy group with a suitable base such as the hydroxide, carbonate, or bicarbonate of a metal cation or with ammonia or an organic primary, secondary, or tertiary amine. The cations of pharmaceutically acceptable salts include lithium, sodium, potassium, calcium, magnesium, and aluminum, as well as nontoxic quaternary amine cations such as ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, tributylamine, pyridine, Mdimelhylaniline, Mmethylpiperidine, Wmethylmorpholine, dicyclohexylamine, procaine, dibenzylamine, JV.JV-dibenzylphenethylamine, 1 -ephenamine, and Ar-dibenzylethylenediamine. Other representative organic amines useful for the formation of base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, and piperazine.

[0158] While it may be possible for the compounds, and pharmaceutically acceptable salts thereof, of the subject disclosure to be administered as the raw chemical, it is also possible to present them as a pharmaceutical formulation.|0159| Also provided is a pharmaceutical formulation comprising a compound as disclosed herein, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Typically, these methods include the step of bringing into association a compound, or pharmaceutically acceptable salts thereof, of the subject disclosure or a pharmaceutically acceptable salt thereof ("active ingredient") with the carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.

[0160] Preferred unit dosage formulations are those containing an effective dose, or an appropriate fraction thereof, of the active ingredient.

[0161] Compounds, or pharmaceutically acceptable salts thereof, may be administered at a dose of from 0.1 to 500 mg / kg per day. The dose range for adult humans is generally from 5 mg to 2 g / day. The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.

[0162] The compounds, or pharmaceutically acceptable salts thereof, can be administered in various modes. In some embodiments, the pharmaceutical formulation is formulated for oral administration.

[0163] In certain instances, it may be appropriate to administer at least one of the compounds described herein (or a pharmaceutically acceptable salt thereof) in combination with another therapeutic agent. By way of example only, if one of the side effects experienced by a patient upon receiving one of the compounds herein, or pharmaceutically acceptable salt thereof, is hypertension, then it may be appropriate to administer an antihypertensive agent in combination with the initial therapeutic agent. Or, by way of example only, the therapeutic effectiveness of one of the compounds described herein, or pharmaceutically acceptable salts thereof, may be enhanced by administration of an adjuvant (i.e., by itself the adjuvant may only have minimal therapeutic benefit, but in combination with another therapeutic agent, the overall therapeutic benefit to the patient is enhanced). Or, by way of example only, the benefit of experienced by a patient may be increased by administering one of the compounds described herein, or pharmaceutically acceptable salts thereof, with another therapeutic agent (which also includes a therapeutic regimen) that also has therapeutic benefit. In any case, regardless of the disease, disorder or condition being treated, the overall benefit experienced by the patient may simply be additive of the two therapeutic agents or the patient may experience a synergistic benefit.

[0164] In any case, the multiple therapeutic agents (at least one of which is a compound disclosed herein, or a pharmaceutically acceptable salt thereof) may be administered in any order or even simultaneously. If simultaneously, the multiple therapeutic agents may be provided in a single, unified form, or in multiple forms (by way of example only, either as a single pill or as two separate pills). One of the therapeutic agents may be given in multiple doses, or both may be given as multiple doses. If not simultaneous, the timing between the multiple doses may be any duration of time ranging from a few minutes to four weeks.

[0165] Also provided is a method for treating a disease or condition that benefits from or is treatable by inhibition of NRAS G12D, comprising the administration of a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, to a subject in need thereof.

[0166] Also provided are methods of inhibiting at least one NRAS G12D function comprising the step of contacting NRAS G12D with a compound as described herein, or a pharmaceutically acceptable salt thereof. The cell phenotype, cell proliferation, activity of NRAS G12D, change in biochemical output produced by active NRAS G12D, expression ofNRAS G12D, or binding of NRAS G12D with a natural binding partner may be monitored. Such methods may be modes of treatment of disease, biological assays, cellular assays, biochemical assays, or the like.

[0167] Also provided are methods of treatment of an NRAS G12D-mediated disease comprising the administration of a therapeutically effective amount of a compound as disclosed herein, or a pharmaceutically acceptable salt thereof, to a patient in need thereof.

[0168] Also provided is a method of inhibition of NRAS G12D comprising contacting NRAS G12D with a compound as disclosed herein, or a pharmaceutically acceptable salt thereof.

[0169] Also provided is a method of modulation of an NRAS G12D-mediated function in a subject comprising the administration of a therapeutically effective amount of a compound as disclosed herein, or a pharmaceutically acceptable salt thereof.

[0170] In some embodiments, the NRAS G12D-mediated disease is cancer.

[0171] In some embodiments, the cancer is chosen from Melanoma, Malignant SolidTumors, Colorectal Carcinoma, Non-Small Cell Lung Carcinoma, Acute Myeloid Leukemia, Myelodysplastic Syndromes, Chronic Myelomonocytic Leukemia, Colorectal Adenocarcinoma, Multiple Myeloma, Non-Hodgkin Lymphoma, Pancreatic Carcinoma, Cutaneous Melanoma, Ovarian Carcinoma, Pancreatic Ductal Adenocarcinoma, Acute Lymphoblastic Leukemia, Thyroid Gland Carcinoma, Glioma, Neurofibromatosis, Poorly Differentiated Thyroid Gland Carcinoma, Myelodysplastic Syndrome With Excess Blasts, Juvenile Myelomonocytic Leukemia, Histiocytic And Dendritic Cell Neoplasm, Head And Neck Squamous Cell Carcinoma, Small Cell Lung Carcinoma, Low Grade Glioma, Squamous Cell Lung Carcinoma, Breast Carcinoma, Chronic Myelomonocytic Leukemia, Thyroid Gland Undifferentiated (Anaplastic) Carcinoma, Embryonal Rhabdomyosarcoma, Thyroid Gland Follicular Carcinoma, T-Cell Acute Lymphoblastic Leukemia, Mucosal Melanoma, Low Grade Ovarian Serous Adenocarcinoma, Thyroid Gland Papillary Carcinoma, Refractory Anemia With Excess Blasts, Myeloid Neoplasm, Myelodysplastic / Myeloproliferative Neoplasm, Rectal Carcinoma, Colon Carcinoma, Malignant Peripheral Nerve Sheath Tumor, Cholangiocarcinoma, Endometrial Carcinoma, Mantle Cell Lymphoma, Secondary Myelodysplastic Syndrome, Therapy-Related Myelodysplastic Syndrome, Lymphoma, Neuronal And Mixed Neuronal-Glial Tumors, Ganglioglioma, Soft Tissue Sarcoma, Bladder Carcinoma, Esophageal Carcinoma, Sarcoma, Thymic Carcinoma, Lung Adenocarcinoma, Lung Carcinoma, Uveal Melanoma, Head And Neck Carcinoma, Diffuse Glioma, Squamous Cell Carcinoma, Chronic Myeloid Leukemia,Adenocarcinoma of the Gastroesophageal Junction, Glioblastoma, Neuroblastoma, Astrocytic Tumor, Hepatocellular Carcinoma, Pancreatic Adenocarcinoma, Diffuse Large B-Cell Lymphoma, Anaplastic Astrocytoma, Gastric Adenocarcinoma, Gastric Carcinoma, Prostate Carcinoma, Renal Cell Carcinoma, B-Cell Acute Lymphoblastic Leukemia, Double-Hit Lymphoma, Dysembryoplastic Neuroepithelial Tumor, Gangliocytoma, Low-Grade Neuroepithelial Tumor, Peripheral T-Cell Lymphoma, Pilocytic Astrocytoma, Pilomyxoid Astrocytoma, Rhabdoid Tumor, and Schwannoma.

[0172] Further embodiments include the embodiments disclosed in the following Schemes, which are not to be construed as limiting in any way.SCHEMES101 102 Formula I

[0173] Referring to Scheme I, Step 1, to a suspension of a compound of Formula 101 in a polar solvent, such as dioxane, is added a palladium catalyst, such as tris(dibenzylideneacetone)dipalladium(0), a ligand, such as tricyclohexylphosphine, a Lewis acid, such as lithium chloride, and tributyl(tributylstannyl)stannane. The mixture is stirred, optionally at elevated temperatures. In some embodiments, the mixture is stirred for 24-48 h. The product, a compound of Formula 102, is isolated and purified using methods known in the art.

[0174] Referring to Scheme I, Step 2, to a solution of a compound of Formula 102 in a polar solvent, such as dioxane, is added a palladium catalyst, such as tris(dibenzylideneacetone)dipalladium(0), a ligand, such as tricyclohexylphosphine, a Lewis acid, such as lithium chloride, and a compound of Formula Q-X (Q as defined herein; and X = halogen). The mixture is stirred, optionally at elevated temperatures. In some embodiments, the mixture is stirred for 16-24 h. Optionally, the product may be subsequently subjected to any set of deprotection conditions known in the art. The product, a compound of Formula I, isisolated and purified using methods known in the art. Individual enantiomers can be separated by using methods known in the art, such as chiral chromatography.Scheme IIOR '201 202 Formula I

[0175] Referring to Scheme II, Step 1 , to a suspension of a compound of Formula 201 in a polar solvent, such as tetrahydrofuran, is added a base, such as potassium phosphate or cesium carbonate, a compound of R4-X (R4is as defined herein; and X = a boronate ester such as pinacol borane or other group to facilitate a metal-catalyzed cross-coupling), and a metal catalyst, such as cataCXium Pd G3 or tris(dibenzylideneacetone)dipalladium(0). The mixture is stirred, optionally at elevated temperatures. In some embodiments, the mixture is stirred for 16-48 h. The product, a compound of Formula 202, is isolated and purified using methods known in the art.

[0176] Referring to Scheme II, Step 2, to a solution of a compound of Formula 202 in a polar solvent, such as a mixture of dioxane and water, is added a base, such as potassium phosphate, a compound of Formula 203 (R = alkyl, such as methyl, or hydrogen, or in combination with a second R group forms a heterocycloalkyl, such as pinacol borane), and a metal catalyst, such as cataCXium Pd G3. The mixture is stirred, optionally at elevated temperatures. In some embodiments, the mixture is stirred for 16-24 h. Optionally, the product may be subsequently subjected to any set of deprotection conditions known in the art. The product, a compound of Formula I, is isolated and purified using methods known in the art. Individual enantiomers can be separated by using methods known in the art, such as chiral chromatography.Scheme III307

[0177] A compound of Formula 301 in a polar solvent, such as tetrahydrofuran, is reacted with a metalating agent, such as lithium chloro-(2,2,6,6-tetramethyl-l-piperidyl)magnesium chloride, and a brominating agent such as l ,2-dibromo- l ,l ,2,2-tetrachloro-ethane to give a compound of Formula 302. The compound of Formula 302 in a polar solvent, such as a mixture of 1 ,4-dioxane and water, is reacted with a compound of Formula 303 in the presence of a catalyst, such as 1 , 1 ’-bis(diphenylphosphino)ferrocene]palladium(II) dichloride, and a base, such as cesium carbonate, to give a compound of Formula 305. Alternatively, The compound of Formula 302 in a polar solvent such as 1 ,4-dioxane, is reacted with a compound of Formula 304 in the presence of a catalyst, such as a combination of [4,4'-bis( 1 , 1 - dimethylethyl)-2,2'-bipyridine] nickel (II) dichloride, 4,4'-£>A(l,l-dimethylethyl)-2,2’- bipyridine-Al,Ain A[3,5-difhioro-2-[5-(trifluoromethyl)-2-pyridinyl-A]phenyl- C]iridium(III) hexafluorophosphate, tris (trimethylsilyl)silane, and a base, such as sodium carbonate, in the presence of 455 nm blue LED light, to give a compound of Formula 305. The compound of Formula 305 in a polar solvent such as tetrahydrofuran is reacted with a compound of Formula 306 in the presence of a catalyst, such as [(di(l-adamantyl)- butylphosphine)-2-(2'-amino-l,l'-biphenyl)]palladium(II) methanesulfonate (cataCXium Pd G3), and a base, such as tripotassium phosphate, to give a compound of Formula 307.

[0178] Optionally, the product may be subsequently subjected to any set of deprotection conditions known in the art. The product is isolated and purified using methods known in theart. Individual enantiomers can be separated by using methods known in the art, such as chiral chromatography.Scheme IV

[0179] The compound of Formula 401 in a polar solvent, such as a mixture of tetrahydrofuran and water, is reacted with a compound of Formula 402 in the presence of a catalyst, such as [(di(l-adamantyl)-butylphosphine)-2-(2'-arnino-l,l'-biphenyl)]palladium(II) methanesulfonate (cataCXium Pd G3), and a base, such as tripotassium phosphate, to give a compound of Formula 403.Scheme Vj 504 506lr[dF(CF3)ppy]2(dtbpy)(PF6), Cu(OAc)2,[2,2]bipyridinyl,NiCI2dtbbpy, TTMSS, Na2CO3, DME, Na2CO3, DCE, 70 °C 25 °C, blue LED (455 nm)507

[0180] The compound of Formula 501 in a polar solvent, such as dichloromethane, is reacted with a protecting agent, such as dihydropyran, in the presence of an acid catalyst, such as pyridinium p-toluenesulfonate, to give a compound of Formula 502. A compound of Formula 502 in a polar solvent, such as tetrahydrofuran, is reacted with a metalating agent, such as lithium chloro-(2,2,6,6-tetramethyl-l-piperidyl)magnesium chloride, and a brominating agent such as l,2-dibromo-l,l,2,2-tetrachloro-ethane to give a compound of Formula 503. The compound of Formula 503 in a polar solvent such as 1 ,2-dimethoxyethane, is reacted with a compound of Formula 504 in the presence of a catalyst, such as acombination of [4,4'-bis(l,l-dimethylethyl)-2,2'-bipyridine] nickel (II) dichloride, 4,4'- / ? / .$( ! . 1 -dimethylethyl )-2,2’-bipyridine-Arl ,Vl']Z>A[3,5-difluoro-2-[5-(trifluoromethyl)-2- pyridinyl-.V]phenyl-C]iridium(III) hexafluorophosphate, tris (trimethylsilyl)silane, and a base, such as sodium carbonate, in the presence of 455 nm blue LED light, to give a compound of Formula 505. The compound of Formula 505 in a polar solvent such as dichloroethane, is reacted with a compound of Formula 506 in the presence of a catalyst, such as Cu(OAc)2,[2,2]bipyridinyl, and a base, such as sodium carbonate, to give a compound of Formula 507.Scheme VI

[0181] A compound of Formula 601 in a polar solvent, such as tetrahydrofuran, is reacted with a metalating agent, such as lithium chloro-(2,2,6,6-tetramethyl-l-piperidyl)magnesium chloride, and a brominating agent such as l,2-dibromo-l,l,2,2-tetrachloro-ethane to give a compound of Formula 602. The compound of Formula 602 in a polar solvent, such as a mixture of 1 ,4-dioxane and water, is reacted with a compound of Formula 603 in the presence of a catalyst, such as l,l’-bis(diphenylphosphino)ferrocene]palladium(II) dichloride, and abase, such as potassium carbonate, to give a compound of Formula 604. The compound of Formula 604 in a polar solvent, such as dichloromethane, is reacted with a compound of Formula 605 in the presence of a catalyst, such as 1,1’- bis(diphenylphosphino)ferrocene]palladium(II) dichloride, and a base, such as tripotassium phosphate, to give a compound of Formula 606. The compound of Formula 606 in a polar solvent, such as a mixture of tetrahydrofuran and water, is reacted with a compound of Formula 607 in the presence of a catalyst, such as [(di(l-adamantyl)-butylphosphine)-2-(2'- amino- l , r-biphenyl)]palladium(II) methanesulfonate (cataCXium Pd G3), and a base, such as tripotassium phosphate, to give a compound of Formula 608. The compound of Formula 608 in a polar solvent, such as ethanol, is reacted with hydrogen gas in the presence of a catalyst, such as a combination of palladium on carbon and palladium hydroxide, to give a compound of Formula 609.Scheme VII

[0182] A compound of Formula 701 in a polar solvent, such as N,N-dimethylformamide, is reacted with an iodinating agent, such as N-iodosuccinimide, to give a compound of Formula 702. The compound of Formula 702 in a polar solvent, such as N,N- dimethylformamide, is reacted with a protecting agent, such as 2- (trimethylsilyl)ethoxymethyl chloride, in the presence of a base, such as sodium hydride, to give a compound of Formula 703. The compound of Formula 703 in a polar solvent, such as a mixture of 1 ,4-dioxane and water, is reacted with a compound of Formula 704 in the presence of a catalyst, such as [(di(l -adamantyl)-butylphosphine)-2-(2'-amino-l ,1'- biphenyl)]palladium(II) methanesulfonate (cataCXium Pd G3), and a base, such as tripotassium phosphate, to give a compound of Formula 705. A compound of Formula 705 in a polar solvent, such as tetrahydrofuran, is reacted with a metalating agent, such as lithium chloro-(2,2,6,6-tetramethyl-l-piperidyl)magnesium chloride, and a brominating agent, such as 1 ,2-dibromo- 1 , 1 ,2,2-tetrachloro-ethane, to give a compound of Formula 706. The compound of Formula 706 in a polar solvent, such as tetrahydrofuran, is reacted with a compound of Formula 707 in the presence of a catalyst, such as 1,1’- bis(diphenylphosphino)ferrocene Ipalladium(ll) dichloride, and a base, such as tripotassium phosphate, to give a compound of Formula 708. The compound of Formula 708 in a polar solvent, such as dichloromethane, is reacted with a deprotecting agent, such as trifluoroacetic acid, to give a compound of Formula 709. The compound of Formula 709 in a polar solvent, such as dichloromethane, is reacted with a compound of Formula 710 in the presence of a base, such as potassium hydroxide, to give a compound of Formula 711.EXAMPLES

[0183] Examples of embodiments of the present disclosure are provided in the following examples. The following examples are presented only by way of illustration and to assist one of ordinary skill in using the disclosure. The examples are not intended in any way to otherwise limit the scope of the disclosure.EXAMPLE 12-amino-4-[3-(3-azabicyclo[3.1.0]hexan-6-yl)-l-cyclopropyl-7-fluoro-4-isopropyl- pyrazolo[4,3-c]pyridin-6-yl]-7-fluoro-benzothiophene-3-carbonitrileStep 1 tert-butyl 6-[6-[2-(tert-butoxycarbonylamino)-3-cyano-7-fluoro-benzothiophen-4-yl]-l- cyclopropyl-7-fluoro-4-isopropyl-pyrazolo[4,3-c]pyridin-3-yl]-3- azabicyclo[3.1.0]hexane-3-carboxylate

[0184] To a mixture of tert-butyl 6-(6-chloro-l-cyclopropyl-7-fluoro-4-isopropyl- pyrazolo[4,3-c]pyridin-3-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (100 mg, 229.92 pmol, 1 eq) and tert-butyl N-[3-cyano-7-fluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)benzothiophen-2-yl]carbamate (144.26 mg, 344.88 pmol, 1.5 eq) in THF (1.6 mL) and H2O (0.4 mL) were added DIEA (89.15 mg, 689.76 pmol, 120.14 pL, 3 eq) and ditertbutyl (cyclopenta- l,4-dien-l-yl)phosphane;dichloropalladium;iron (14.98 mg, 22.99 pmol, 0.1 eq) at 25 °C under N2. The resulting mixture was stirred at 70 °C for 4 h under N2. LCMS showed the tert-butyl 6-(6-chloro-l-cyclopropyl-7-fluoro-4-isopropyl-pyrazolo[4,3-c]pyridin- 3-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate was consumed completely and a peak (42%) with desired mass. The mixture was diluted with ethyl acetate (20 mL) and dried with anhydrous Na2SC>4, filtered and the filtrate was concentrated in vacuum. The residue was purified by flash silica gel chromatography (10 g SepaFlash® Silica Flash Column, Eluent of 2-16% Ethyl acetate / Petroleum ether gradient @ 100 mL / min) to afford tert-butyl 6-[6-[2- (tert-butoxycarbonylamino)-3-cyano-7-fluoro-benzothiophen-4-yl]-l-cyclopropyl-7-fluoro-4-isopropyl-pyrazolo[4,3-c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate (131 mg, 180.15 pmol, 78.35% yield, 95% purity) as yellow solid.MS (ES+) C36H4ON6F2S04 requires: 690, found: 691 [M+H]+Step 22-amino-4-[3-(3-azabicyclo[3.1.0]hexan-6-yl)-l-cyclopropyl-7-fluoro-4-isopropyl- pyrazoIo[4,3-c]pyridin-6-yl]-7-fluoro-benzothiophene-3-carbonitrile

[0185] To a solution of tert-butyl 6-[6-[2-(tert-butoxycarbonylamino)-3-cyano-7-fluoro- benzothiophen-4-yl]-l-cyclopropyl-7-fluoro-4-isopropyl-pyrazolo[4,3-c]pyridin-3-yl]-3- azabicyclo[3.1.0]hexane-3-carboxylate (131 mg, 189.63 pmol, 1 eq) in DCM (1 mL) was added TFA (767.50 mg, 6.73 mmol, 0.5 mL) at 25 °C. Then the mixture was stirred at 25 °C for 20 min. LCMS showed one main peak with desired mass. The mixture was concentrated in vacuum. The residue was purified by prep-HPLC(column: Welch Xtimate Cl 8 150*25mm*5um; mobile phase: [water(FA)- ACN] ; gradient: 18%-48% B over 10 min) and lyophilized to afford 2-amino-4-[3-(3-azabicyclo[3.1.0]hexan-6-yl)-l-cyclopropyl-7-fluoro- 4-isopropyl-pyrazolo[4,3-c]pyridin-6-yl]-7-fluoro-benzothiophene-3-carbonitrile (48.2 mg, 78.93 pmol, 41.62% yield, 99% purity, TFA) as white solid.

[0186] MS (ES+) C26H24F2N6S requires: 490, found: 491 [M+H]+

[0187] 'H NMR (400 MHz, CD3OD) 8.51 (s, 0.1H),7.37 (dd, J = 5.3, 8.4 Hz, 1H), 7.08 - 6.99 (m, 1H), 3.94 - 3.77 (m, 2H), 3.67 - 3.50 (m, 4H), 2.55 - 2.39 (m, 3H), 1.50 - 1.36 (m, 6H), 1.34 - 1.19 (m, 2H), 1.16 - 1.08 (m, 2H).EXAMPLE 23-[3-(3-azabicyclo[3.1.0]hexan-6-yl)-l-cydopropyl-7-fluoro-4-isopropyl-pyrazoIo[4,3- c]pyridin-6-yl]-5-methyl-4-(trifluoromethyl)phenoIStep 1 tert-butyl 6-[l-cyclopropyl-7-fluoro-6-[5-hydroxy-3-methyl-2-(trifluoromethyl)phenyl]-4-isopropyl-pyrazolo[4,3-c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate

[0188] A mixture of tert-butyl 6-(6-chloro-l-cyclopropyL7-fluoro-4-isopropyl- pyrazolo[4,3-c]pyridin-3-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (30.00 mg, 68.98 pmol, 1 eq), 3-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)phenol (41.67 mg, 137.95 pmol, 2 eq), CataCXium A Pd G3 (25.12 mg, 34.49 pmol, 0.5 eq) and K3PO4 (1.5 M, 137.95 pL, 3 eq) in THF (1 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 60 °C for 16 h under N2 atmosphere. LCMS showed a peak (71%) with desired mass. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with bine (10 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (10 g SepaFlash® Silica Flash Column, Eluent of 0~80%Ethylacetate / Petroleum ether gradient @ 40 mL / min) to afford tert-butyl 6-[l- cyclopropyl-7-fluoro-6-[5-hydroxy-3-methyl-2-(trifluoromethyl)phenyl]-4-isopropyl-pyrazolo[4,3-c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate (50 mg, crude) as a brown oil.MS (ES+) C30H 4F4N4O3 requires: 574, found: 575 [M+H]+.Step 23-[3-(3-azabicyclo[3.1.0]hexan-6-yl)-l-cyclopropyl-7-fluoro-4-isopropyl-pyrazolo[4,3- c]pyridin-6-yl]-5-methyl-4-(trifluoromethyl)phenol

[0189] To a solution of tert-butyl 6-[l-cyclopropyl-7-fluoro-6-[5-hydroxy-3-methyl-2- (trifluoromethyl)phenyl]-4-isopropyl-pyrazolo[4,3-c]pyridin-3-yl]-3- azabicyclo|3.1.0|hexane-3-carboxylate (45 mg, 78.31 pmol, 1 eq) in DCM (2 mL) was added HCl / dioxane (2 M, 2 mL, 51.08 eq). The mixture was stirred at 25 °C for 1 h. LCMS showed a peak (71%) with desired mass. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Welch Xtimate C18 150*25 mm*5um;mobile phase: [water (FA) -ACN];gradient:20%-50% B over 10 min). The eluent was lyophilized under reduced pressure to afford 3-[3-(3-azabicyclo[3.1.0]hexan- 6-yl)-l-cyclopropyl-7-fluoro-4-isopropyl-pyrazolo[4,3-c]pyridin-6-yl]-5-methyl-4- (trifhioromethyl)phenol (10.2 mg, 19.40 pmol, 24.77% yield, 99% purity, FA) as a red solid.

[0190] MS (ES+) C25H26F4N4O requires: 474, found: 475 [M+H]+.6-[3-(3-azabicyclo[3.1.0]hexan-6-yl)-l-cydopropyl-7-fluoro-4-isopropyl-pyrazolo[4,3- c]pyridin-6-yl]-4-methyl-5-(trifluoromethyl)pyridin-2-amineStep 1 tert-butyl 6-(l-cydopropyl-7-fluoro-4-isopropyl-6-tributylstannyl-pyrazolo[4,3- c]pyridin-3-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate

[0191] To a solution of tert-butyl 6-(l-cyclopropyl-7-fluoro-4-isopropyl-6- tributylstannyl-pyrazolo[4,3-c]pyridin-3-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (150 mg, 344.88 pmol, 1 eq) in dioxane (3 mL) were added tributyl(tributylstannyl)stannane (1.98 g, 3.41 mmol, 1.71 mL, 9.90 eq), P(Cy)3 (19.34 mg, 68.98 pmol, 22.36 pL, 0.2 eq), LiCl (73.10 mg, 1 .72 mmol, 35.35 pL, 5 eq) and Pd2(dbah (31 .58 mg, 34.49 pmol, 0.1 eq) under the protection of N2. Then the mixture was stirred at 100 °C for 16 h under the protection of N2. LCMS showed 36% of tert-butyl 6-(l-cyclopropyl-7-fluoro-4-isopropyl-6- tributylstannyl-pyrazolo[4,3-c]pyridin-3-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate remained and the desired mass. Then tributyl(tributylstannyl)stannane (1.41 g, 2.43 mmol, 1.22 mL, 7.05 eq) was added into the mixture under N2, the mixture was stirred at 100 °C for 16 hr under the protection of N2. LCMS showed a peak (65%) with the mass of tert-butyl 6- (l-cyclopropyl-7-fluoro-4-isopropyl-6-tributylstannyl-pyrazolo[4,3-c]pyridin-3-yl)-3- azabicyclo[3.1.0]hexane-3-carboxylate and product. The reaction was diluted with water (20 mL), extracted with ethyl acetate (20 mL x 3), the organic layer was washed with brine (20 mL x 3), dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (20 g SepaFlash® Silica Flash Column, Eluent of 0-20% Ethyl acetate / Petroleum ether gradient @ 100 mL / min) to afford tert-butyl 6-( l-cyclopropyl-7-fluoro-4-isopropyl-6-tributylstannyl-pyrazolo[4, 3-c]pyridin-3- yl) -3-azabicyclo[3.1.0]hexane-3-carboxylate (70 mg, 101.52 pmol, 29.44% yield) as colorless oil.

[0192] MS (ES+) C34H55N4FSnO2 requires: 690 found 691 [M+H]+Step 2tert-butyl 6-[6-[6-amino-4-methyl-3-(trifluoromethyl)-2-pyridyl]-l-cyclopropyl-7- fluoro-4-isopropyl-pyrazolo[4,3-c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate

[0193] To a solution of tert-butyl 6-(l-cyclopropyl-7-fluoro-4-isopropyl-6- tributylstannyl-pyrazolo[4,3-c]pyridin-3-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (50 mg, 72.51 pmol, 1 eq) in dioxane (1 mL) were added 6-bromo-4-methyl-5-(trifluoromethyl) pyridin-2-amine (36.99 mg, 145.03 pmol, 2 eq), LiCl (9.22 mg, 217.54 pmol, 4.46 pL, 3 eq), Cui (2.76 mg, 14.50 pmol, 0.2 eq) and Pd(PPhs)4 (8.38 mg, 7.25 pmol, 0.1 eq) under the protection of N , the mixture was stirred at 100 °C for 16 hr. LCMS showed 26% of tert-butyl 6-(l-cyclopropyl-7-fluoro-4-isopropyl-6-tributylstannyl-pyrazolo[4,3-c]pyridin-3-yl)-3- azabicyclo[3.1.0]hexane-3-carboxylate remained and a peak (25%) with desired mass. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by prep-TLC (Ethyl acetate: Petroleum ether= 2: 1 ) to afford tert-butyl 6-[6-[6-amino-4-methyl-3-(trifluoromethyl)-2-pyridyl]-l-cyclopropyl-7-fluoro-4-isopropyl- pyrazolo[4,3-c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate (20 mg, 34.81 pmol, 48.00% yield) as brown oil.MS (ES+) C29H34N6F4O2 requires: 574 found 575 [M+H]+Step 3 6-[3-(3-azabicyclo[3.1.0]hexan-6-yl)-l-cyclopropyl-7-fluoro-4-isopropyl-pyrazolo[4,3- c]pyridin-6-yl]-4-methyl-5-(trifluoromethyl)pyridin-2-amine

[0194] To a solution of tert-butyl 6-[6-[6-amino-4-methyl-3-(trifluoromethyl)-2-pyridyl]- 1 -cyclopropyl-7-fluoro-4-isopropyl-pyrazolo[4,3 -c]pyridin-3 -y 1] -3 -azabicyclo[3.1.0]hexane- 3-carboxylate (20 mg, 34.81 pmol, 1 eq) in DCM (0.2 mL) was added TFA (0.1 mL), the mixture was stirred at 25 °C for 0.5 hr. LCMS showed a peak (94%) with desired mass. The mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Welch Xtimate C18 150*25 mm*5um; mobile phase: [water (FA) -ACN]; gradient: 14%-44% B over 10 min), the eluent was lyophilized under reduced pressure to afford 6-[3- (3-azabicyclo[3.1.0]hexan-6-yl)-l-cyclopropyl-7-fluoro-4-isopropyl-pyrazolo[4,3-c]pyridin- 6-yl]-4-methyl-5-(trifluoromethyl)pyridin-2-amine (8.5 mg, 17.91 pmol, 51.47% yield) as a white solid.MS (ES+) C24H26N6F4 requires: 474, found 475.’H NMR (400 MHz, CD3OD) 5 = 6.61 (s, 1H), 3.90 - 3.79 (m, 2H), 3.60 - 3.54 (m, 2H), 3.53 - 3.47 (m, 2H), 2.49 - 2.43 (m, 5H), 2.43 - 2.39 (m, 1H), 1.38 (d, J = 6.7 Hz, 6H), 1.25 - 1.18 (m, 2H), 1.17 - 1.09 (m, 2H).4-[3-(3-azabicyclo[3.1.0]hexan-6-yl)-l,4-dicyclopropyl-7-fluoro-pyrazolo[4,3-c]pyridin-6-yl]-6-metliyl-5-(trifluoromethyl)pyridin-2-amineStep 1tert-butyl 6-(6-chloro-l,4-dicyclopropyl-7-fluoro-pyrazoIo[4,3-c]pyridin-3-yl)-3- azabicyclo[3.1.0]hexane-3-carboxylate

[0195] To a solution of tert-butyl 6-(4-bromo-6-chloro-l-cyclopropyl-7-fluoro- pyrazolo[4,3-c]pyridin-3-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (100 mg, 211.98 pmol, 1 eq) in toluene (2 mL) and H2O (0.2 mL) were added potassium cyclopropyl(trifluoro)boranuide (37.64 mg, 254.37 pmol, 1.2 eq), Pd(OAc)2 (4.76 mg, 21.20 pmol, 0.1 eq), bis(l-adamantyl)-butyl-phosphane (11.40 mg, 31.80 pmol, 0.15 eq) and CS2CO3 (207.20 mg, 635.93 pmol, 3 eq) under N2 atmosphere. The mixture was stirred at 80 °C forl6h. LCMS showed tert-butyl 6-(4-bromo-6-chloro-l-cyclopropyl-7-fluoro- pyrazolo[4,3-c]pyridin-3-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate consumed completely and a peak (56%) with desired mass. The mixture was diluted with water (10 mL), extracted with ethyl acetate (10 mL x 3), the organic layers were washed with brine (10 mL), dried over Na2SC>4, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (10 g SepaFlash® Silica Flash Column, Eluent of 0-20% Ethyl acetate / Petroleum ether gradient @ 100 mL / min) to afford tert-butyl 6-(6-chloro-l,4-dicyclopropyl-7-fluoro-pyrazolo[4,3-c]pyridin-3-yl)-3- azabicyclo[3.1.0]hexane-3-carboxylate (190 mg, crude) as light yellow oil.Step 2 tert-butyl 6-[6-[6-amino-2-methyl-3-(trifluoromethyl)-4-pyridyl]-l,4-dicyclopropyl-7- fluoro-pyrazolo[4,3-c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate

[0196] To a solution of tert-butyl 6-(6-chloro- 1 ,4-dicyclopropyl-7-fluoro-pyrazolo[4,3- c]pyridin-3-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (60 mg, 138.59 pmol, 1 eq) in dioxane (1.5 mL) were added 6-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-5- (trifluoromethyl)pyridin-2-amine (83.74 mg, 277.19 pmol, 2 eq), K3PO4 (1.5 M in H2O, 277.19 pL, 3 eq) and CATACXIUM (R) A PD CL (10.09 mg, 13.86 pmol, 0.1 eq) under N2, the mixture was stirred at 100 °C for 16 hr. LCMS showed tert-butyl 6-(6-chloro-l ,4- dicyclopropyl-7-fluoro-pyrazolo[4,3-c]pyridin-3-yl)-3-azabicyclo[3.1.0]hexane-3- carboxylate was consumed completely and a peak (58%) with desired mass. The reaction mixture was diluted with water (10 mL), extracted with ethyl acetate (10 mL x 3), the organic layers were washed with brine (10 mL x 3), dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by prep-TLC (Petroleum ether: Ethyl acetate— 1 :1) to afford tert-butyl 6-[6-[6-amino-2-methyl-3-(trifluoromethyl)-4- pyridyl]-l,4-dicyclopropyl-7-fluoro-pyrazolo[4,3-c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate (32 mg, 55.89 pmol, 40.32% yield) as a white solid.MS (ES+) C29H32N6F4O2 requires: 572 found 573 [M+H]+.Step 34-[3-(3-azabicydo[3.1.0]hexan-6-yl)-l,4-dicydopropyl-7-fluoro-pyrazolo[4,3-c]pyridin- 6-yl]-6-methyl-5-(trifluoromethyI)pyridin-2-amine

[0197] To a solution of tert-butyl 6-[6-[6-amino-2-methyl-3-(trifluoromethyl)-4-pyridyl]- l,4-dicyclopropyl-7-fluoro-pyrazolo[4,3-c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-3- carboxylate (30 mg, 52.39 pmol, 1 eq) in DCM (0.4 mL) was added TFA (0.2 mL), the mixture was stirred at 25 °C for 25 min. LCMS showed a peak (95%) with desired mass. The mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex luna C 18 150*25mm* lOum; mobile phase: [water(FA)- ACN] ; gradient: 12%-42% B over 10 min). The eluent was lyophilized under reduced pressure to afford 4-[3-(3-azabicyclo[3.1.0]hexan-6-yl)-l ,4-dicyclopropyl-7-fluoro-pyrazolo[4,3- c]pyridin-6-yl]-6-methyl-5-(trifluoromethyl)pyridin-2-amine (18 mg, 34.72 pmol, 66.26% yield, 100% purity, FA) as a white solid.

[0198] MS (ES+) C24H24F4N6 requires: 472, found 473.

[0199] 1H NMR (400 MHz, CDsOD) 5 = 8.52 (s, 0.3H), 6.35 (s, 1H), 3.86 - 3.76 (m, 1H),3.55 - 3.48 (m, 2H), 3.44 - 3.38 (m, 2H), 2.75 - 2.66 (m, 1H), 2.58 - 2.51 (m, 3H), 2.51 - 2.45 (m, 1H), 2.49 - 2.38 (m, 2H), 1.26 - 1.02 (m, 8H).EXAMPLE 53-[6-[5-amino-3-methyl-2-(trifluoromethyl)phenyl]-3-(3-azabicyclo[3.1.0]hexan-6-yl)-l- cyclopropyl-7-fluoro-pyrazolo[4,3-c]pyridin-4-yI]propanenitrileStep 1 tert-butyl 6-[6-chloro-4-(2-cyanoethyl)-l-cyclopropyl-7-fluoro-pyrazolo[4,3-c]pyridin-3- yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate

[0200] To a solution of tert-butyl 6-(4-bromo-6-chloro-l-cyclopropyl-7-fluoro- pyrazolo[4,3-c]pyridin-3-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (220 mg, 466.35 pmol, 1 eq) and 3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)propanenitrile (92.87 mg, 512.98 pmol, 1.1 eq) in THF (9 mL) were added CATACXIUM (R) A PD G3(33.96 mg, 46.63 pmol, 0.1 eq) and K3PO4 (1.5 M in H2O, 932.70 pL, 3 eq). The mixture was stirred at 60 °C for 16 h under N2. LCMS showed 29% of tert-butyl 6-(4-bromo-6-chloro-l-cyclopropyl-7- fluoro-pyrazolo[4,3-c]pyridin-3-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate remained and a peak (29%) with desired mass. 3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)propanenitrile (42.21 mg, 233.17 pmol, 0.5 eq) was added into the mixture. The mixture was stirred at 60 °C for 4 h under N2. LCMS showed 30% of tert-butyl 6-(4-bromo-6-chloro-l-cyclopropyl-7- fluoro-pyrazolo[4,3-c]pyridin-3-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate remained and a peak (34%) with desired mass. The reaction mixture was diluted with water (10 mL), extracted with ethyl acetate (10 mL x 3), the organic layers were washed with brine (10 mL x 3), dried over NaiSO-i, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by prep-TLC (Petroleum ether: Ethyl acetate=3: l) to afford tert-butyl 6- [6-chloro-4-(2-cyanoethyl)-l-cyclopropyl-7-fluoro-pyrazolo[4,3-c]pyridin-3-yl]-3- azabicyclo[3.1.0]hexane-3-carboxylate (50 mg, 112.13 pmol, 24.04% yield) as a white solid.

[0201] MS (ES+) C22H25N5FCIO2 requires: 445 found 446 [M+H]+.Step 2 tert-butyl 6-[6-[5-amino-3-methyl-2-(trifluoromethyl)phenyl]-4-(2-cyanoethyl)-l- cyclopropyI-7-fluoro-pyrazolo[4,3-c]pyridin-3-yI]-3-azabicycIo[3.1.0]hexane-3- carboxylate

[0202] To a solution of tert-butyl 6-[6-chloro-4-(2-cyanoethyl)-l -cyclopropyl-7-fluoro- pyrazolo[4,3-c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate (20 mg, 44.85 pmol, 1 eq) in THF (0.9 mL) were added 3-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-4- (trifluoromethyl) aniline (27.01 mg, 89.70 pmol, 2 eq), CATACXIUM (R) A PD G3 (6.53 mg, 8.97 pmol, 0.2 eq) and K3PO4 (1.5 M, 89.70 pL, 3 eq) under N2. The mixture was stirred at 60 °C for 16 h. LCMS showed tert-butyl 6-[6-chloro-4-(2-cyanoethyl)-l-cyclopropyl-7- fluoro-pyrazolo[4,3-c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate was consumed completely and a peak (54%) with desired mass. The residue was diluted with water (10 mL), extracted with ethyl acetate (10 mL x 3), the organic layers were dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by prep- TLC (Petroleum ether: Ethyl acetate=l:l) to afford tert-butyl 6-[6-[5-amino-3-methyl-2- (trifluoromethyl)phenyl]-4-(2-cyanoethyl)-l-cyclopropyl-7-fluoro-pyrazolo[4,3-c]pyridin-3- yl] -3 -azabicyclo [3.1.0]hexane-3 -carboxylate (20 mg, 34.21 pmol, 76.28% yield) was a white solid.MS (ES+) C30H32N6F4O2 requires: 584 found 585 [M+H]+.Step 3 3-[6-[5-amino-3-methyl-2-(trifluoromethyI)phenyl]-3-(3-azabicyclo[3.1.0]hexan-6-yl)-l- cydopropyl-7-fluoro-pyrazolo[4,3-c]pyridin-4-yl]propanenitrile

[0203] To a solution of tert-butyl 6-[6-[5-amino-3-methyl-2-(trifluoromethyl)phenyl]-4- (2-cyanoethyl)-l-cyclopropyl-7-fluoro-pyrazolo[4,3-c]pyridin-3-yl]-3- azabicyclo[3.1.0]hexane-3-carboxylate (20 mg, 34.21 pmol, 1 eq) in DCM (0.3 mL) was added TFA (234.05 mg, 2.05 mmol, 152.48 pL, 60 eq) at 25 °C, the mixture was stirred 15 min. LCMS showed tert-butyl 6-[6-[5-amino-3-methyl-2-(trifluoromethyl)phenyl]-4-(2- cyanoethyl)-l-cyclopropyl-7-fluoro-pyrazolo[4,3-c]pyridin-3-yl]-3-azabicyclo[3.L0]hexane- 3-carboxylate was consumed completely and a peak (63%) with desired mass. The mixture was diluted with dichloromethane (20 mL), quench with saturated NaHCCL aqueous solution (20 mL), the organic phase was dried over NaiSCU, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Welch Xtimate C18 150*25mm*5um; mobile phase: [water(FA)-ACN]; gradient: 16%-46% B over 10 min), the eluent was lyophilized under reduced pressure to afford 3-[6-[5-amino-3- methyl-2-(trifluoromethyl)phenyl]-3-(3-azabicyclo[3.L0]hexan-6-yl)-l-cyclopropyl-7-fluoro- pyrazolo[4,3-c]pyridin-4-yl]propanenitrile (7.1 mg, 13.38 pmol, 39.12% yield, 100% purity, FA) as a white solid.

[0204] MS (ES+) C25H24F4N6 requires: 484, found 485.

[0205] ’H NMR (400 MHz, CD3OD) 5 = 8.52 (s, 0.7H), 6.70 (s, 1H), 6.47 (d, J = 2.2 Hz, 1H), 3.85 (It, J= 3.6, 7.2 Hz, 1H), 3.65 - 3.52 (m, 4H), 3.48 - 3.40 (m, 2H), 3.09 - 2.91 (m, 2H), 2.56 - 2.49 (m, 5H), 2.35 - 2.23 (m, 1H), 1.32 -1.26 (m, 2H), 1.17 - 1.05 (m, 2H).EXAMPLE 62-amino-4-[3-(3-azabicyclo[3.1.0]hexan-6-yl)-4-(2-cyanoethyl)-l-cydopropyl-7-fluoro- pyrazolo[4,3-c]pyridin-6-yl]-7-fluoro-benzothiophene-3-carbonitrileStep 1 tert-butyl 6-[6-[2-(tert-butoxycarbonylamino)-3-cyano-7-fluoro-benzothiophen-4-yl]-4-(2-cyanoethyl)-l-cyclopropyl-7-fluoro-pyrazoIo[4,3-c]pyridin-3-yl]-3- azabicyclo[3.1.0]hexane-3-carboxylate

[0206] To a solution of tert-butyl 6-[6-chloro-4-(2-cyanoethyl)-l-cyclopropyl-7-fluoro- pyrazolo[4,3-c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate (25 mg, 56.06 pmol, 1 eq) in THF (1 mL) and H2O (0.25 mL) were added tert-butyl N-[3-cyano-7-fluoro-4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)benzothiophen-2-yl]carbamate (35.18 mg, 84.10 pmol,I.5 eq), ditert-butyl(cyclopenta-l,4-dien-l-yl)phosphane;dichloropalladium;iron (7.31 mg,I I.21 pmol, 0.2 eq) and DIEA (21.74 mg, 168.19 pmol, 29.30 pL, 3 eq) under N2. The mixture was stirred at 70 °C for 4 hr. LCMS showed 23% of tert-butyl 6-[6-chloro-4-(2- cyanoethyl)-l-cyclopropyl-7-fluoro-pyrazolo[4,3-c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane- 3-carboxylate remained and a peak (31%) with desired mass. The mixture was diluted with water (10 mL), extracted with ethyl acetate (10 mL), the organic layers were dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by prep-TLC (Petroleum ether: Ethyl acetate= 2: 1) to afford tert-butyl 6-[6-[2-(tert- butoxycarbonylamino)-3-cyano-7-fluoro-benzothiophen-4-yl]-4-(2-cyanoethyl)-l- cyclopropyl-7-fluoro-pyrazolo[4,3-c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate (15 mg, 21.37 pmol, 38.12% yield) as brown oil. MS (ES+) C36H37N7F2SO4 requires: 701 found 702 [M+H]+.Step 2 2-ainino-4-[3-(3-azabicydo[3.1.0]hexan-6-yl)-4-(2-cyanoethyl)-l-cyclopropyl-7-fluoro- pyrazolo[4,3-c]pyridin-6-yl]-7-fluoro-benzothiophene-3-carbonitrile

[0207] To a solution of tert-butyl 6-[6-[2-(tert-butoxycarbonylamino)-3-cyano-7-fluoro- benzothiophen-4-yl]-4-(2-cyanoethyl)-l-cyclopropyl-7-fluoro-pyrazolo[4,3-c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate (15 mg, 21.37 pmol, 1 eq) in DCM (0.3 mL) was added TFA (243.71 mg, 2.14 mmol, 158.77 pL, 100 eq) , the mixture was stirred at 25 °C for 15 min. LCMS showed tert-butyl 6-[6-[2-(tert-butoxycarbonylamino)-3-cyano-7-fluoro- benzothiophen-4-yl]-4-(2-cyanoethyl)-l-cyclopropyl-7-fluoro-pyrazolo[4,3-c]pyridin-3-yl]- 3-azabicyclo[3.1.0]hexane-3-carboxylate was consumed completely and a peak (47%) with desired mass. The mixture was diluted with dichloromethane (20 mL), neutralized with saturated NaHCCL aqueous solution (20 mL), the organic phase was dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Welch Xtimate C 18 150*25mm*5um; mobile phase: [water(FA)- ACN]; gradient: 14%-44% B over 10 min), the eluent was lyophilized under reduced pressure to afford 2-amino-4-[3-(3-azabicyclo[3.1.0]hexan-6-yl)-4-(2-cyanoethyl)-l-cyclopropyl-7- fluoro-pyrazolo[4,3-c]pyridin-6-yl]-7-fluoro-benzothiophene-3-carbonitrile (2.5 mg, 4.43 pmol, 20.72% yield, 97% purity, FA) as a white solid.

[0208] MS (ES+) C26H21F2N7S requires: 501, found 502.

[0209] ’H NMR (400 MHz, CD3OD) 6 = 8.53 (s, 0.6H), 7.44 (dd, J = 5.1, 8.4 Hz, 1H), 7.09 - 6.99 (m, 1H), 3.88 - 3.81 (m, 1H), 3.62 (t, J = 7.2 Hz, 2H), 3.56 - 3.46 (m, 2H), 3.41 - 3.34 (m, 2H), 3.05 (t, J = 7.3 Hz, 2H), 2.43 - 2.30 (m, 3H), 1.33 - 1.25 (m, 2H), 1.18 - 1.09 (m, 2H).4-[3-(3-azabicyclo[3.1.0]hexan-6-yI)-l-cyclopropyl-7-fluoro-4-isobutyl-pyrazolo[4,3- c]pyridin-6-yl]-6-methyl-5-(trifluoromethyl)pyridin-2-amineStep 1 tert-butyl 6-(6-chloro-l-cyclopropyl-7-fluoro-4-isobutyl-pyrazolo[4,3-c]pyridin-3-yl)-3- azabicyclo[3.1.0]hexane-3-carboxylate

[0210] A mixture of tert-butyl 6-(4-bromo-6-chloro-l-cyclopropyl-7-fluoro-pyrazolo[4,3- c]pyridin-3-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (200 mg, 423.95 pmol, 1 eq), 1- iodo-2-methyl-propane (156.03 mg, 847.91 pmol, 97.58 pL, 2 eq), Ir[dF (CF3) ppy]2 (dtbpy) (PF6) (4.76 mg, 4.24 pmol, 0.01 eq), NiCh’dtbpy (843.66 pg, 2.12 pmol, 0.005 eq), TTMSS (105.42 mg, 423.95 pmol, 130.79 pL, 1 eq) and Na2C0a (89.87 mg, 847.91 pmol, 2 eq) in DME (8 mL) was degassed and purged with N2, and then the mixture was stirred at 25 °C for 16 h irradiated with a 455nm blue LED. TLC (Petroleum ether: Ethyl acetate= 5: 1) showed tert-butyl 6-(4-bromo-6-chloro-l-cyclopropyl-7-fluoro-pyrazolo[4,3-c]pyridin-3-yl)-3- azabicyclo[3.1.0]hexane-3-carboxylate was consumed completely and a new spot with lower polarity. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (10 g SepaFlash® Silica Flash Column, Eluent of 0-15% Ethyl acetate / Petroleum ether gradient @ 100 mL / min) to afford tert-butyl 6-(6-chloro-l-cyclopropyl-7-fluoro-4-isobutyl-pyrazolo[4,3-c]pyridin-3-yl)-3- azabicyclo[3.1.0]hexane-3-carboxylate (160 mg, 356.38 pmol, 84.06% yield) as a colorless oil. MS (ES+) C23H30N4FCIO2 requires: 448 found 448 [M+H]+.Step 2 tert-butyl 6-[6-[6-amino-2-methyl-3-(trifluoromethyl)-4-pyridyl]-l-cyclopropyl-7- fluoro-4-isobutyI-pyrazolo[4,3-c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate

[0211] To a solution of tert-butyl 6-(6-chloro-l-cyclopropyl-7-fluoro-4-isobutyl- pyrazolo[4,3-c]pyridin-3-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (50 mg, 111.37 pmol, 1 eq) in THF (2.2 mL) were added 6-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)- 5-(trifluoromethyl)pyridin-2-amine (67.29 mg, 222.74 pmol, 2 eq), CATACXIUM (R) A PD G3 (8.11 mg, 11.14 pmol, 0.1 eq) and K3PO4 (1.5 M, 222.74 pL, 3 eq) under N2, the mixture was stirred at 60 °C for 16 hr. LCMS showed tert-butyl 6-(6-chloro-l-cyclopropyl-7-fluoro- 4-isobutyl-pyrazolo[4,3-c]pyridin-3-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate was consumed completely and a peak (50%) with desired mass. The mixture was diluted with water (10 mL), the mixture was extracted with ethyl acetate (10 mL x 3), and the organic layers were concentrated under reduced pressure. The residue was purified by prep-TLC (Petroleum ether: Ethyl acetate= 1: 1) to afford tert-butyl 6-[6-[6-amino-2-methyl-3- (trifhioromethyl)-4-pyridyl]-l-cyclopropyl-7-fluoro-4-isobutyl-pyrazolo[4,3-c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate (40 mg, 67.95 pmol, 61.02% yield) as colorless oil. MS (ES+) C30H36N6F4O2 requires: 588 found 589 [M+H]+Step 34-[3-(3-azabicydo[3.1.0]hexan-6-yl)-l-cydopropyl-7-fluoro-4-isobutyI-pyrazolo[4,3- c]pyridin-6-yl]-6-methyl-5-(trifluoromethyl)pyridin-2-amine

[0212] To a solution of tert-butyl 6-[6-[6-amino-2-methyl-3-(trifluoromethyl)-4-pyridyl]- l-cyclopropyl-7-fluoro-4-isobutyl-pyrazolo[4,3-c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-3- carboxylate (40 mg, 67.95 pmol, 1 eq) in DCM (0.4 mL) was added TFA (309.93 mg, 2.72 mmol, 201.91 pL, 40 eq). The mixture was stirred at 25 °C for 20 min. LCMS showed a peak (76%) with desired mass. The mixture was diluted with dichloromethane (20 mL), neutralized with saturated NaHCCh aqueous solution (20 mL), the organic phase was dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Welch Xtimate C18 150*25mm*5um; mobile phase: [water(FA)-ACN]; gradient: 16%-36% B over 10 min), the eluent was lyophilized underreduced pressure to afford 4-[3-(3-azabicyclo[3.1.0]hexan-6-yl)-l-cyclopropyl-7-fluoro-4- isobutyl-pyrazolo[4,3-c]pyridin-6-yl]-6-methyl-5-(trifluoromethyl)pyridin-2-amine (5.3 mg, 9.91 pmol, 14.59% yield, 100% purity, FA) as a white solid.

[0213] MS (ES+) C25H28F4N6 requires: 488, found 489.

[0214] ’H NMR (400 MHz, CD3OD) 5 = 8.49 (s, 0.2H), 6.37 (s, 1H), 3.92 - 3.79 (m, 1H), 3.62 - 3.48 (m, 4H), 3.15 - 2.97 (m, 2H), 2.56 (d, J= 2.2 Hz, 3H), 2.52 - 2.46 (m, 2H), 2.41 - 2.35 (m, 1H), 2.30 - 2.18 (m, 1H), 1.27 - 1.20 (m, 2H), 1.17 - 1.09 (m, 2H), 0.99 (d, J= 6.6 Hz, 6H).3-[6-[6-amino-2-methyl-3-(trifluoromethyI)-4-pyridyl]-3-(3-azabicyclo[3.1.0]hexan-6-yl)- l-cyclopropyl-7-fluoro-pyrazolo[4,3-c]pyridin-4-yI]propenamide andEXAMPLE 533-(6-(6-amino-2-methyI-3-(trifluoromethyl)pyridin-4-yl)-3-((lR,5S,6r)-3- azabicydo[3.1.0]hexan-6-yl)-l-cyclopropyl-7-fluoro-lH-pyrazolo[4,3-c]pyridin-4- yl)propanenitrileStep 1tert-butyl 6-[6-chloro-4-(2-cyanoethyl)-l-cyclopropyl-7-fluoro-pyrazolo[4,3-c]pyridin-3- yl]-3-azabicyclo[3.1.0]hexane-3-carboxyIate

[0215] To a solution of tert-butyl 6-(4-bromo-6-chloro-l-cyclopropyl-7-fluoro- pyrazolo[4,3-c]pyridin-3-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (150 mg, 317.96 pmol, 1 eq) and 3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)propanenitrile (63.32 mg, 349.76 pmol, 1.1 eq) in THF (6 mL) were added CATACXIUM(R) A PD G3 (23.16 mg, 31.80 pmol, 0.1 eq) and K3PO4 (1.5 M, 635.93 pL, 3 eq). The mixture was stirred at 60 °C for 16 h under N2. LCMS showed 29% of tert-butyl 6-(4-bromo-6-chloro-l-cyclopropyl-7-fluoro- pyrazolo[4,3-c]pyridin-3-yl)-3-azabicyclo[3. 1.0]hexane-3-carboxylate remained, several peaks and 38% of desired mass. The mixture was diluted with 8 mL of water and extracted with 8 mL x 2 of ethyl acetate. The combined organic layers were washed with 8 mL of brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to afford crude residue. The residue was purified by prep-TLC (Petroleum ether : Ethyl acetate=2:l) to afford tert-butyl 6-[6-chloro-4-(2-cyanoethyl)-l-cyclopropyl-7-fluoro- pyrazolo[4,3-c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate (83 mg, 173.10 pmol, 54.44% yield, 93% purity) as yellow oil.

[0216] MS (ES+) C22H25CIFN5O2 requires:445, found:446 [M+H]+.Step 2 tert-butyl 6-[6-[6-amino-2-inethyl-3-(trifluoromethyl)-4-pyridyl]-4-(2-cyanoethyl)-l- cyclopropyl-7-fluoro-pyrazolo[4,3-c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-3- carboxylate

[0217] To a solution of tert-butyl 6-[6-chloro-4-(2-cyanoethyl)-l-cyclopropyl-7-fluoro- pyrazolo[4,3-c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate (83 mg, 186.13 pmol, 1 eq) and 6-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-5- (trifluoromethyl)pyridin-2-amine (112.46 mg, 372.27 pmol, 2 eq) in THF (4 mL) were added CATACXIUM(R) A PD G3 (13.56 mg, 18.61 pmol, 0.1 eq) and K3PO4 (1.5 M, 372.27 pL, 3 eq). The mixture was stirred at 60 °C for 16 h under N2. LCMS showed the reaction was completed, several peaks and 52% of desired mass. The mixture was diluted with 5 mL of water and extracted with 5 mL x 2 of ethyl acetate. The combined organic layers were washed with 5 mL of brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to afford crude residue. The residue was purified by prep-TLC (Petroleum ether : Ethyl acetate=l: l) to afford tert-butyl 6-[6-[6-amino-2-methyl-3-(trifluoromethyl)-4- pyridyl]-4-(2-cyanoethyl)-l-cyclopropyl-7-fluoro-pyrazolo[4,3-c]pyridin-3-yl]-3- azabicyclo[3.1.0]hexane-3-carboxylate (54 mg, 78.38 pmol, 42.11% yield, 85% purity) as yellow oil.

[0218] MS (ES+) C29H31F4N7O2 requires:585, found:586[M+H]+.Step 3 3-[6-[6-amino-2-methyl-3-(trifluoroinethyl)-4-pyridyl]-3-(3-azabicyclo[3.1.0]hexan-6-yl)- l-cycIopropyl-7-fluoro-pyrazolo[4,3-c]pyridin-4-yl]propenamide

[0219] To a solution of tert-butyl 6-[6-[6-amino-2-methyl-3-(trifluoromethyl)-4-pyridyl]- 4-(2-cyanoethyl)-l-cyclopropyl-7-fhioro-pyrazolo[4,3-c]pyridin-3-yl]-3- azabicyclo[3.1.0]hexane-3-carboxylate (54 mg, 92.21 pmol, 1 eq) in DCM (1 mL) was added TFA (767.50 mg, 6.73 mmol, 0.5 mL, 72.99 eq). The mixture was stirred at 20 °C for 20 min. LCMS showed 89% of desired mass. The mixture was concentrated to afford crude residue. The residue was purified by prep-HPLC (column: Phenomenex luna Cl 8 150*25mm* lOum; mobile phase: [water(TFA)-ACN]; gradient:9%-39% B over 12 min). The eluent was concentrated and freeze-dried to afford the compounds of Example 61 and Example XX.

[0220] Example 52 - 3-[6-[6-amino-2-methyl-3-(trifluoromethyl)-4-pyridyl]-3-(3- azabicyclo[3.1.0]hexan-6-yl)-l-cyclopropyl-7-fluoro-pyrazolo[4,3-c]pyridin-4- yl]propanamide (13.9 mg, 22.51 pmol, 24.41% yield, 100% purity, TFA) as a white solid.

[0221] MS (ES+) C24H25F4N7O requires:503, found: 504 [M+H]+.

[0222] ’H NMR (400 MHz, CD3OD) 5 = 6.80 (s, 1H), 3.91 - 3.82 (m, 1H), 3.76 (d, J = 11.9 Hz, 2H), 3.61 (d, J = 12.0 Hz, 2H), 3.52 (t, J = 7.6 Hz, 2H), 2.79 (t, J= 7.6 Hz, 2H), 2.74 - 2.65 (m, 3H), 2.62 - 2.55 (m, 1H), 2.55 - 2.50 (m, 2H), 1.27 - 1.10 (m, 4H).

[0223] Example 53 - 3-(6-(6-amino-2-methyl-3-(trifluoromethyl)pyridin-4-yl)-3-((lR,5S,6r)-3-azabicyclo[3.1.0]hexan-6-yl)-l-cyclopropyl-7-fluoro-lH-pyrazolo[4,3- c]pyridin-4-yl)propanenitrile

[0224] MS (ES+) C24H23F4N7 requires:485, found: 486 [M+H]+.

[0225] 1H NMR (400 MHz, CD3OD) 5 = 6.41 (s, 1H), 3.87 - 3.79 (m, 1H), 3.59 (t, J =7.1 Hz, 2H), 3.29 - 3.26 (m, 1H), 3.26 - 3.23 (m, 1H), 3.07 - 2.95 (m, 4H), 2.59 - 2.53 (m, 3H), 2.25 - 2.20 (m, 1H), 2.20 - 2.15 (m, 2H), 1.27 - 1.18 (m, 2H), 1.18 - 1.09 (m, 2H).2-[6-[5-amino-3-fluoro-2-(trifluoromethoxy)phenyl]-3-(3-azabicyclo[3.1.0]hexan-6-yl)-7- fluoro-4-isopropyl-pyrazolo[4,3-c]pyridin-l-yl]-N-methyl-cyclopropanecarboxamide Step 1 tert-butyl 6-(6-chloro-7-fluoro-l-tetrahydropyran-2-yl-pyrazolo[4,3-c]pyridin-3-yl)-3- azabicyclo[3.1.0]hexane-3-carboxy!ateBoc /

[0226] To a solution of tert-butyl 6-(6-chloro-7-fluoro-lH-pyrazolo[4,3-c]pyridin-3-yl)- 3-azabicyclo[3.1.0]hexane-3-carboxylate (1 g, 2.83 mmol, 1 eq) in DCM (5 mL) were added 3,4-dihydro-2H-pyran (715.33 mg, 8.50 mmol, 777.53 pL, 3 eq) and 4- methylbenzenesulfonic acid;pyridine (14.25 mg, 56.69 pmol, 0.02 eq) at 20 °C, then the mixture was stirred at 20 °C for 16 h. LCMS showed two peaks (38%, 56%) with the desired mass. The mixture was diluted with water (5 mL), then extracted with ethyl acetate (5 mL x 3), the combined organic phase was dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by flash silica gel chromatography (25 g SepaFlash® Silica Flash Column, Eluent of 20-60% Ethyl acetate / Petroleum ether gradient @ 100 mL / min) to afford tert-butyl 6-(6-chloro-7-fluoro-l-tetrahydropyran-2-yLpyrazolo[4,3- c]pyridin-3-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (1.2 g, 2.75 mmol, 96.90% yield) as a yellow oil.

[0227] MS (ES+) C21H26N4FCIO3 requires:436, found: 437 [M+H]+.Step 2 tert-butyl 6-(4-bromo-6-chloro-7-fluoro-l-tetrahydropyran-2-yl-pyrazolo[4,3-c]pyridin- 3-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate

[0228] To a solution of tert-butyl 6-(6-chloro-7-fluoro-l-tetrahydropyran-2-yl- pyrazolo[4,3-c]pyridin-3-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (1.5 g, 3.43 mmol, 1 eq) in THF (15 mL) was added lithium;chloro-(2,2,6,6-tetramethyl-l- piperidyl)magnesium;chloride (1 M, 17. 17 mL, 5 eq) at 0 °C under N2, the mixture was stirred at 0 °C for 1 h, then l,2-dibromo-l,l,2,2-tetrachloro-ethane (5.59 g, 17.17 mmol, 2.06mL, 5 eq) in THF (5 mL) was added to the mixture, and stirred at 0 °C stirred for 1 h. LCMS showed a peak (55%) with the desired mass. The reaction mixture was quenched with Sat.aq.NH4Cl (25 mL), then extracted with ethyl acetate (20 mL x 3), the combined organic phase was dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by flash silica gel chromatography (20g SepaFlash® Silica Flash Column, Eluent of 20-70% Ethyl acetate / Petroleum ether gradient @ 100 mL / min) to afford tert-butyl 6-(4-bromo-6-chloro-7-fluoro-l-tetrahydropyran-2-yl-pyrazolo[4,3-c]pyridin-3-yl)-3- azabicyclo[3.1 .0]hexane-3-carboxylate (1.1 g, 2.13 mmol, 62.12% yield) as a yellow oil.

[0229] MS (ES+) C2iH25N4FClBrO3 requires:514, found: 515 [M+H]+.Step 3 tert-butyl 6-(6-chloro-7-fluoro-4-isopropyI-l-tetrahydropyran-2-yl-pyrazolo[4,3- c]pyridin-3-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate

[0230] A solution of tert-butyl 6-(4-bromo-6-chloro-7-fluoro-l-tetrahydropyran-2-yl- pyrazolo[4,3-c]pyridin-3-yl)-3-azabicyclo[3.1 .0]hexane-3-carboxylate (450.00 mg, 872.43 pmol, 1 eq), 2-iodopropane (988.70 mg, 5.82 mmol, 580.56 pL, 3 eq), bis[3,5-difluoro-2-[5- (trifhioromethyl)-2-pyridyl]phenyl]iridium(l-i-);4-tert-butyl-2-(4-tert-butyl-2- pyridyl)pyridine;hexafluorophosphate (21.75 mg, 19.39 pmol, 0.01 eq), dichloronickel;3- diphenylphosphanylpropyl(diphenyl)phosphane (5.25 mg, 9.69 pmol, 0.005 eq), Na2CO3 (616.46 mg, 5.82 mmol, 3 eq) and TTMSS (482.08 mg, 1.94 mmol, 598.12 pL, 1 eq) in DME (50 mL) was degassed and purged with N2, and then the mixture was stirred at 25 °C for 16 h irradiated with a 455 nm blue LED. TLC (Petroleum ether : Ethyl acetate=3: l) indicated tertbutyl 6-(4-bromo-6-chloro-7-fluoro- 1 -tetrahydropyran-2-yl-pyrazolo[4,3-c]pyridin-3-yl)-3- azabicyclo[3.1.0]hexane-3-carboxylate was remained and one major new spot with lower polarity. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (40 g SepaFlash® Silica Flash Column, Eluent of 25-60% Ethyl acetate / Petroleum ether gradient @ 100 mL / min) to afford tert-butyl 6-(6-chloro-7-fluoro-4-isopropyl- 1 -tetrahydropyran-2-yl-pyrazolo[4,3-c]pyridin-3-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (800 mg, 1.67 mmol, 86.15% yield) as a yellow solid.

[0231] MS (ES+) C24H 2N4FCIO requires:478, found: 479[M+H]+.Step 4 tert-butyl 6-(6-chloro-7-fluoro-4-isopropyl-lH-pyrazolo[4,3-c]pyridin-3-yl)-3- azabicyclo[3.1.0]hexane-3-carboxylate

[0232] To a solution of tert-butyl 6-(6-chloro-7-fluoro-4-isopropyl-l-tetrahydropyran-2- yl-pyrazolo[4,3-c]pyridin-3-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (800 mg, 1.67 mmol, 1 eq) in DCM (2 mL) was added HCl / dioxane (2 M, 8.00 mL) at 20 °C, then the mixture was stirred at 20 °C for 2 h. LCMS showed a peak (40%) with the desired mass. The reaction mixture was concentrated under reduced pressure to give a residue. To the mixture were added DCM (5 mL), DIEA (647.57 mg, 5.01 mmol, 872.73 pL, 3 eq) and BOC2O (364.52 mg, 1.67 mmol, 383.71 pL, 1 eq) at 20 °C, then the mixture was stirred at 20 °C for 10 mins. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (25 g SepaFlash® Silica Flash Column, Eluent of 10-60% Ethyl acetate / Petroleum ether gradient @ 50 mL / min) to afford tert-butyl 6-(6-chloro-7-fluoro-4-isopropyl-lH-pyrazolo[4,3-c]pyridin-3-yl)-3- azabicyclo[3.1.0]hexane-3-carboxylate (300 mg, 759.74 pmol, 45.49% yield,) as a yellow solid.

[0233] MS (ES+) C19H24N4FCIO2 requires: 394, found: 395[M+H]+.Step 5 tert-butyl 6-[6-chloro-7-fluoro-4-isopropyI-l-(2- methoxycarbonylcyclopropyl)pyrazolo[4,3-c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-3- carboxylate

[0234] To a solution of tert-butyl 6-(6-chloro-7-fluoro-4-isopropyl-lH-pyrazolo[4,3- c]pyridin-3-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (300 mg, 759.74 pmol, 1 eq) and (2- methoxycarbonylcyclopropyl)boronic acid (218.70 mg, 1.52 mmol, 2 eq) in DCE (5 mL) were added Cu(OAc)2 (13.80 mg, 75.97 pmol, 0.1 eq), 2-(2-pyridyl)pyridine (23.73 mg, 151.95 pmol, 0.2 eq) and Na2CCh (241.58 mg, 2.28 mmol, 3 eq), O2 was bubbled into the solution, the mixture was stirred at 70 °C for 16 h. LCMS showed a peak (91%) with the desired mass. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (20 g SepaFlash® Silica Flash Column, Eluent of 0-100% Ethyl acetate / Petroleum ether gradient @ 100 mL / min) to afford tert-butyl 6-[6-chloro-7-fluoro-4-isopropyl-l -(2- methoxycarbonylcyclopropyl)pyrazolo[4,3-c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-3- carboxylate (370 mg, 750.55 pmol, 98.79% yield) as a yellow solid.

[0235] MS (ES+) C24H30N4FCIO4 requires:492, found: 493[M+H]+.Step 6 2-[3-(3-tert-butoxycarbonyl-3-azabicyclo[3.1.0]hexan-6-yl)-6-chloro-7-fluoro-4- isopropyl-pyrazolo[4,3-c]pyridin-l-yl]cyclopropanecarboxylic acid

[0236] To a solution of tert-butyl 6-[6-chloro-7-fluoro-4-isopropyl-l-(2- methoxycarbonylcyclopropyl)pyrazolo[4,3-c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-3- carboxylate (300 mg, 608.56 pmol, 1 eq) in THF (3 mL), H2O (3 mL) and MeOH (0.3 mL)was added LiOH.I LO (76.61 mg, 1.83 mmol, 3 eq), then the mixture was stirred at 40 °C for 0.5 h. LCMS showed a peak (97%) with the desired mass. The mixture was adjusted pH to pH = 6 by added aq.HCl(lM), extracted with ethyl acetate (5 mL x 3), the combined organic phase was dried with anhydrous Na2SC>4, filtered and concentrated in vacuum to afford 2-[3- (3-tert-butoxycarbonyl-3-azabicyclo[3.1.0]hexan-6-yl)-6-chloro-7-fluoro-4-isopropyl- pyrazolo[4,3-c]pyridin-l-yl]cyclopropanecarboxylic acid (290 mg, crude) as a yellow solid.

[0237] MS (ES+) C23H28N4FO4CI requires: 478, found: 479[M+H]+.Step 7 tert-butyl 6-[6-chloro-7-fluoro-4-isopropyl-l-[2- (methylcarbamoyl)cyclopropyl]pyrazolo[4,3-c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane- 3-carboxylate

[0238] To a solution of 2-[3-(3-tert-butoxycarbonyl-3-azabicyclo[3.1.0]hexan-6-yl)-6- chloro-7-fhioro-4-isopropyl-pyrazolo[4,3-c]pyridin-l-yl]cyclopropanecarboxylic acid (150 mg, 313.19 pmol, 1 eq) and methanamine;hydrochloride (169.17 mg, 2.51 mmol, 8 eq) in DMF (2 mL) were added DIEA (323.82 mg, 2.51 mmol, 436.41 pL, 8 eq) and HATU (178.63 mg, 469.78 pmol, 1.5 eq) at 20 °C, then the mixture was stirred at 20 °C for 1 h. LCMS showed a peak (87%) with the desired mass. The reaction mixture was diluted with water (5 mL), then extracted with ethyl acetate (5 mL x 3), washed with brine (5 mL x 3), the combined organic phase was dried with anhydrous NaoSCL, filtered and concentrated in vacuum. The residue was purified by flash silica gel chromatography (4 g SepaFlash® Silica Flash Column, Eluent of 60-80% Ethyl acetate / Petroleum ether gradient @ 50 mL / min) to afforded tert-butyl 6-[6-chloro-7-fluoro-4-isopropyl-l-[2- (methylcarbamoyl)cyclopropyl]pyrazolo[4,3-c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-3- carboxylate (120 mg, 243.91 pmol, 77.88% yield) as a yellow solid.

[0239] MS (ES+) C24H31N5FO3CI requires: 491, found: 492[M+H]+.Step 8tert-butyl 6-[6-[5-amino-3-fluoro-2-(trifluoromethoxy)phenyl]-7-fluoro-4-isopropyl-l-[2- (methyIcarbamoyl)cyclopropyl]pyrazolo[4,3-c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane- 3-carboxylate

[0240] To a solution of tert-butyl 6-[6-chloro-7-fluoro-4-isopropyl-l-[2- (methylcarbamoyl)cyclopropyl]pyrazolo[4,3-c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-3- carboxylate (120 mg, 243.91 pmol, 1 eq) and 3-fhjoro-5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-4-(trifluoromethoxy)aniline (117.47 mg, 365.86 pmol, 1.5 eq) in THF (3 mL) were added K3PO4 (1.5 M, 487.82 pL, 3 eq) and CATACXIUM(R) A PD G3(17.76 mg, 24.39 pmol, 0. 1 eq) at 20 °C under N3, then the mixture was stirred at 60 °C for 16 h. LCMS showed a peak (46%) with the desired mass. The reaction mixture was diluted with water (2 mL), then extracted with ethyl acetate (2 mL x 3), the combined organic phase was dried with anhydrous NazSCU, filtered and concentrated in vacuum. The residue was purified by flash silica gel chromatography (12 g SepaFlash® Silica Flash Column, Eluent of 50-80% Ethyl acetate / Petroleum ether gradient @ 80 mL / min) to afford tert-butyl 6-[6-[5-amino-3-fhioro-2- (trifluoromethoxy)phenyl] -7 -fluoro-4-isopropyl- 1 - [2- (methylcarbamoyl)cyclopropyl]pyrazolo[4,3-c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-3- carboxylate (120 mg, 184.43 pmol, 75.62% yield) as yellow oil.

[0241] MS (ES+) C3IH35N6F5O4 requires:650, found: 651[M+H]+. Step 9 2-[6-[5-amino-3-fluoro-2-(trifluoromethoxy)phenyl]-3-(3-azabicyclo[3.1.0]hexan-6-yl)-7- fluoro-4-isopropyl-pyrazolo [4,3-c] pyridin- 1 -yl] -N-methyl-cyclopropanecarboxamide

[0242] To a solution of tert-butyl 6-[6-[5-amino-3-fluoro-2-(trifluoromethoxy)phenyl]-7- fluoro-4-isopropyl-l-[2-(methylcarbamoyl)cyclopropyl]pyrazolo[4,3-c]pyridin-3-yl]-3- azabicyclo[3.1.0]hexane-3-carboxylate (100 mg, 153.70 pmol, 1 eq) in DCM (2 mL) was added TFA (6.14 g, 4.00 mL) at 20 °C, then the mixture was stirred at 20 °C for 0.5 h. LCMS showed a peak (87%) with the desired mass. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C 18 150*25mm* lOum; mobile phase: [water(FA)-ACN]; gradient: 14%- 44% B over 10 min) and lyophilized to afforded 2-[6-[5-amino-3-fluoro-2- (trifluoromethoxy)phenyl]-3-(3-azabicyclo[3.1.0]hexan-6-yl)-7-fluoro-4-isopropyl- pyrazolo[4,3-c]pyridin-l-yl]-N-methyl-cyclopropanecarboxamide (50.5 mg, 83.81 pmol. 54.53% yield, 99% purity, FA) as a yellow solid.102431 MS (ES+) C26H27F5N6O2 requires: 550, found: 551.

[0244] 1H NMR (400 MHz, CD3OD) 5 = 8.51 (s, 1H), 6.66 - 6.61 (m, 2H), 4.22 - 4.14(m, 1H), 3.84 (q, 7 = 6.9 Hz, 1H), 3.59 - 3.52 (m, 2H), 3.51 - 3.44 (m, 2H), 2.78 (s, 3H), 2.47 - 2.39 (m, 3H), 2.34 - 2.22 (m, 1H), 1.86 - 1.78 (m, 1H), 1.69 - 1.62 (m, 1H), 1.40 (d, 7 = 6.7 Hz, 6H).2-[6-[6-amino-2-methyl-3-(trifluoromethyl)-4-pyridyl]-3-(3-azabicyclo[3.1.0]hexan-6-yl)-7-fluoro-4-isopropyl-pyrazolo[4,3-c]pyridin-l-yl]cyclopropanecarbonitriIeStep 1 tert-butyl 6-[6-chloro-l-(2-cyanocyclopropyI)-7-fluoro-4-isopropyI-pyrazolo[4,3- c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate

[0245] To a solution of tert-butyl 6-[l-(2-carbamoylcyclopropyl)-6-chloro-7-fluoro-4- isopropyl-pyrazolo[4,3-c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate (50 mg, 104.61 pmol, 1 eq) in DCM (3 mL) were added TEA (105.86 mg, 1.05 mmol, 145.61 pL, 10 eq) and TFAA (65.92 mg, 313.83 pmol, 43.62 pL, 3 eq) at 0 °C, then the mixture was stirred at 20 °C for 1 h. LCMS showed a peak (47%) with the desired mass. The mixture was concentrated in vacuum. The residue was purified by prep-TLC (SiCh, Petroleum ether : Ethyl acetate= 2: 1) to afford tert-butyl 6-[6-chloro-l-(2-cyanocyclopropyl)-7-fluoro-4- isopropyl-pyrazolo[4,3-c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate (30 mg, 65.23 pmol, 62.35% yield) as a yellow solid.

[0246] MS (ES+) C23H27N5FCIO2 requires:459, found: 460[M+H]+.Step 2 2-[6-[6-amino-2-methyl-3-(trifluoromethyI)-4-pyridyl]-3-(3-azabicyclo[3.1.0]hexan-6-yl)- 7-fluoro-4-isopropyl-pyrazolo[4,3-c]pyridin-l-yl]cyclopropanecarbonitriIe

[0247] Prepared from tert-butyl 6-[6-chloro-l-(2-cyanocyclopropyl)-7-fluoro-4- isopropyl-pyrazolo[4,3-c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate via Suzuki coupling / TFA deprotection as described for Example 67.

[0248] MS (ES+) C25H25F4N7 requires:499, found: 500[M+H]+

[0249] 1H NMR (400 MHz, CD3OD) 5 = 8.55 - 8.47 (m, 0.05H), 6.44 (s, 1H), 4.58 - 4.49 (m, 1H), 3.89 - 3.77 (m, 1H), 3.62 - 3.55 (m, 2H), 3.54 - 3.49 (m, 2H), 2.70 - 2.59 (m, 3H), 2.49 - 2.43 (m, 3H), 2.42 - 2.36 (m, 1H), 2.15 - 2.06 (m, 1H), 1.92 - 1.83 (m, 1H), 1.40 (d, J = 6.7 Hz, 6H).3- [3-(3-azabicydo[3.1.0]hexan-6-yl)- 1- [2- [(dimethylamino)methyl]cyclopropyl] -7 -fluoro- 4-isopropyl-pyrazolo[4,3-c]pyridin-6-yl]-5-fluoro-4-(trifluoromethoxy)anilineStep 1 tert-butyl 6-[6-chloro-l-[2-[(dimethylamino)methyl]cyclopropyl]-7-fluoro-4-isopropyl- pyrazoIo[4,3-c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxyIate

[0250] To a solution of tert-butyl 6-[6-chloro-l-[2-(dimethylcarbamoyl)cyclopropyl]-7- fluoro-4-isopropyl-pyrazolo[4,3-c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate (120 mg, 237.15 pmol, 1 eq) in THF (1 mL) was added BH3.THF (1 M, 1.19 mL, 5 eq) at 0 °C, then the mixture was stirred at 60 °C for 16 h. LCMS showed a peak (74%) with the desired mass. The mixture was slowly quenched with MeOH (10 mL), then stirred at 0 °C for30 mins, dried with anhydrous NaiSCU, filtered and concentrated in vacuum. The residue was purified by flash silica gel chromatography (12 g SepaFlash® Silica Flash Column, Eluent of 100% Methanol ether gradient @ 100 mL / min) to afford tert-butyl 6-[6-chloro-l-[2- [(dimethylamino)methyl]cyclopropyl]-7-fluoro-4-isopropyl-pyrazolo[4,3-c]pyridin-3-yl]-3- azabicyclo[3.1.0]hexane-3-carboxylate (100 mg, 203.24 pmol, 85.70% yield) as a yellow solid.

[0251] MS (ES+) C25H35N5FC1O2requires:491, found: 492 [M+H]+.Step 23- [3-(3-azabicyclo[3.1.0]hexan-6-yl)- 1- [2- [(dimethylamino)methyl]cyclopropyl] -7 -fhioro-4-isopropyl-pyrazolo[4,3-c]pyridin-6-yl]-5-fluoro-4-(trifluoromethoxy)aniline

[0252] Prepared via Suzuki coupling / TFA deprotection as described for Example 67.

[0253] MS (ES+) C27H3iF5N6O requires: 550, found: 551 [M+H]+.

[0254] 1H NMR (400 MHz, CD OD) 5 = 8.48 (s, 1H), 6.72 - 6.57 (m, 2H), 4.01 - 3.90(m, 1H), 3.83 - 3.73 (m, 1H), 3.67 - 3.50 (m, 4H), 3.25 - 3.12 (m, 2H), 2.92 (s, 6H), 2.54 - 2.44 (m, 3H), 2.07 - 1.93 (m, 1H), 1.72 - 1.62 (m, 1H), 1.46 - 1.28 (m, 7H).(lR,2S,5S,6R)-6-[6-[6-amino-2-methyl-3-(trifluoromethyl)-4-pyridyl]-l-cyclopropyl-7- fluoro-4-isopropyl-pyrazolo[4,3-c]pyridin-3-yl]-N-methyl-3-azabicyclo[3.1.0]hexane-2- carboxamideStep 1O3-tert-butyl O2-methyl (lS,2S,5R,6R)-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yI)-3-azabicyclo[3.1.0]hexane-2,3-dicarboxylateBoc

[0255] To a solution of dichlorochromium (37.86 g, 308.02 mmol, 7 eq) in THF (300 mL) was added TMEDA (35.80 g, 308.02 mmol, 46.49 L, 7 eq) at 20 °C and stirred for 0.5 h under N2. Then a solution of Ol-tert-butyl O2-methyl (2S)-2,5-dihydropyrrole-l,2- dicarboxylate (10 g, 44.00 mmol, 1 eq) in THF (150 mL) was added to Lil (23.56 g in 6.75 mL THF , 176.01 mmol, 4 eq) was slowly added into THF (150 mL) (exothermic reaction) and followed by addition of 2-(dichloromethyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (18.56 g, 88.01 mmol, 2 eq) to prepare the solution A, the solution A was added to above mixture at 20 °C and stirred at 40 °C for 96 h. TLC (Petroleum ether : Ethyl acetate=5:l) indicated the material remained and one new spot formed. The mixture was diluted with EtOAc (500 mL), filtered through diatomite and silica gel, the filtrate was poured into water (800 mL). The aqueous phase was extracted with ethyl acetate (300 mL x 3). The combined organic phase was washed with brine (100 mL), dried over anhydrous NazSCL, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (120 g SepaFlashSSilica Flash Column, Eluent of 0-20% Ethyl acetate / Petroleum ether gradient @ 100 mL / min) to afford 03 -tert-butyl O2-methyl (lS,2S,5R,6R)-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3-azabicyclo[3.1.0]hexane- 2,3-dicarboxylate (4.1 g, 11.16 mmol, 25.37% yield) as a colorless oil.

[0256] ’H NMR (400 MHz, CD3OD) 6 = 4.29 (d, J = 9.9 Hz, 1H), 3.76 (d, 7 = 4.4 Hz, 3H), 3.59 - 3.49 (m, 2H), 1.80 - 1.65 (m, 2H), 1.48 - 1.35 (m, 9H), 1.22 (s, 12H), -0.12 - -0.27 (m, 1H).Step 24-bromo-6-chloro-l-cyclopropyl-7-fluoro-3-iodo-pyrazolo[4,3-c]pyridine

[0257] To a solution of 6-chloro-l-cyclopropyl-7-fluoro-3-iodo-pyrazolo[4,3-c]pyridine (1 g, 2.90 mmol, 1 eq) in THF (10 mL) was added lithium;chloro-(2,2,6,6-tetramethyl-l- piperidyl)magnesium;chloride (1 M, 14.52 mL, 5 eq) . Then l,2-dibromo-l,l,2,2-tetrachloro- ethane (4.73 g, 14.52 mmol, 1.74 mL, 5 eq) was added to the mixture after 0.5 h. The mixture was stirred at -60 °C for 1 h under N2. TLC (Petroleum ether: Ethyl acetate= 10: 1) indicated many new spots formed. The reaction mixture was quenched with saturated NH4CI (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over NazSC and concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography (40 g SepaFlash® Silica Flash Column, Eluent of 0~5% petroleum ether / ethyl acetate gradient @ 90mL / min) to afford 4- bromo-6-chloro-l-cyclopropyl-7-fluoro-3-iodo-pyrazolo[4,3-c]pyridine (1.08 g, 2.57 mmol, 88.43% yield, 99% purity) as a yellow solid.

[0258] ' H NMR (400 MHz, DMSO-t / 6) 5 = 4.00 - 3.88 (m, 1H), 1.27- 1.23 (m, 2H), 1.22- 1.06 (m, 2H).Step 3O3-tert-butyl O2-methyl (lR,2S,5S,6R)-6-(4-bromo-6-chloro-l-cyclopropyl-7-fluoro- pyrazoIo[4,3-c]pyridin-3-yl)-3-azabicyclo[3.1.0]hexane-2,3-dicarboxyIate

[0259] To a solution of 4-bromo-6-chloro-l-cyclopropyl-7-fluoro-3-iodo-pyrazolo[4,3- c]pyridine (900 mg, 2.16 mmol, 1 eq) in THF (30 mL) and HiO (10 mL) were added 03-tert- butyl O2-methyl (lS,2S,5R,6R)-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3- azabicyclo[3.1.0]hexane-2,3-dicarboxylate (476.24 mg, 1.30 mmol, 0.6 eq), K2CO3 (896.11 mg, 6.48 mmol, 3 eq) and Pd(dppf)CL (158.14 mg, 216.13 pmol, 0.1 eq) under N2, the mixture was stirred at 90 °C for 16 hr. LCMS showed 54% of 4-bromo-6-chloro-l-cyclopropyl-7-fluoro-3-iodo-pyrazolo[4,3-c]pyridine remained and a peak (21%) with desired mass. The mixture was diluted with water (10 mL), extracted with ethyl acetate (10 mL x 3), dried over Na2SC>4, filtered and concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography (40 g SepaFlash® Silica Flash Column, Eluent of 0~20%Ethylacetate / Petroleum ether gradient @ 100 mL / min) to afford 03-tert- butyl 02-methyl (lR,2S,5S,6R)-6-(4-bromo-6-chloro-l-cyclopropyl-7-fluoro-pyrazolo[4,3- c]pyridin-3-yl)-3-azabicyclo[3.1.0]hexane-2,3-dicarboxylate (100 mg, 188.76 pmol, 8.73% yield) as brown oil.

[0260] MS (ES+) C2iH23N4FClBrO4 requires: 530, found: 531 [M+H]+.Step 403-tert-butyl O2-methyl (lR,2S,5S,6R)-6-(6-chIoro-l-cyclopropyl-7-fluoro-4- isopropenyl-pyrazolo[4,3-c]pyridin-3-yl)-3-azabicyclo[3.1.0]hexane-2,3-dicarboxylate

[0261] To a solution of 03-tert-butyl 02-methyl (lR,2S,5S,6R)-6-(4-bromo-6-chloro-l- cyclopropyl-7-fluoro-pyrazolo[4,3-c]pyridin-3-yl)-3-azabicyclo[3.1.0]hexane-2,3- dicarboxylate (0.1 g, 188.76 pmol, 1 eq) and potassium;trifluoro(isopropenyl)boranuide (41.90 mg, 283.13 pmol, 1.5 eq) in THF (2.5 mL) were added Pd(dppf)C12*CH2C12 (30.83 mg, 37.75 pmol, 0.2 eq) and K3PO4 (1.5 M, 377.51 pL, 3 eq) under N2. The mixture was stirred at 60 °C for 16 hours. LCMS showed 03-tert-butyl 02-methyl (lR,2S,5S,6R)-6-(4- bromo-6-chloro-l-cyclopropyl-7-fluoro-pyrazolo[4,3-c]pyridin-3-yl)-3- azabicyclo[3.1.0]hexane-2,3-dicarboxylate was consumed and main peak with desired mass. The reaction mixture was diluted with EtOAc (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography (5 g SepaFlash® Silica Flash Column, Eluent of 0-30% Ethyl acetate / Petroleum ether gradient @ 35 mL / min) to afford 03-tert-butyl 02-methyl (lR,2S,5S,6R)-6-(6-chloro-l-cyclopropyl-7-fluoro-4-isopropenyl-pyrazolo[4,3-c]pyridin-3- yl)-3-azabicyclo[3.1.0]hexane-2,3-dicarboxylate (120 mg, 183.32 pmol, 97.12% yield, 75% purity) as green oil.

[0262] MS (ES+) C24H28CIFN4O4 requires: 490, found: 491 [M+H]+.Step 5O3-tert-butyl O2-methyl (lR,2S,5S,6R)-6-[6-[6-amino-2-methyl-3-(trifluoromethyl)-4- pyridyl]-l-cyclopropyI-7-fluoro-4-isopropenyl-pyrazolo[4,3-c]pyridin-3-yl]-3- azabicyclo[3.1.0]hexane-2,3-dicarboxylate

[0263] To a solution of 6-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-5- (trifluoromethyl)pyridin-2-amine (101.53 mg, 336.08 pmol, 1.5 eq) and 03-tert-butyl 02- methyl (lR,2S,5S,6R)-6-(6-chloro-l-cyclopropyl-7-fluoro-4-isopropenyl-pyrazolo[4,3- c]pyridin-3-yl)-3-azabicyclo[3.1.0]hexane-2,3-dicarboxylate (0.11 g, 224.05 pmol, 1 eq) in THF (4.48 mF) were added K3PO4 ( 1 .5 M, 448. 11 pL, 3 eq) and CataCXium A Pd G3(16.32 mg, 22.41 pmol, 0.1 eq) under N2. The mixture was stirred at 60 °C for 16 hours. LCMS showed 03-tert-butyl O2-methyl (lR,2S,5S,6R)-6-(6-chloro-l-cyclopropyl-7-fluoro-4- isopropenyl-pyrazolo[4,3-c]pyridin-3-yl)-3-azabicyclo[3.1.0]hexane-2,3-dicarboxylate was still remained and main peak with desired mass. The reaction mixture was diluted with EtOAc (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography (5g SepaFlash® Silica Flash Column, Eluent of 0-25% Ethyl acetate / Petroleum ether gradient @35 mL / min) to afford 03-tert-butyl O2-methyl (lR,2S,5S,6R)-6-| 6-|6-amino-2-methyl-3-(trifluoromethyl)-4- pyridyl]-l-cyclopropyl-7-fluoro-4-isopropenyl-pyrazolo[4,3-c]pyridin-3-yl]-3- azabicyclo[3.1.0]hexane-2,3-dicarboxylate (0.083 g, 131.61 pmol, 58.74% yield) as yellow oil.

[0264] MS (ES+) C31H34F4N6O4 requires: 630, found: 631 [M+H]+.Step 603-tert-butyl O2-methyl (lR,2S,5S,6R)-6-[6-[6-amino-2-methyl-3-(trifluoromethyI)-4- pyridyl]-l-cyclopropyl-7-fluoro-4-isopropyl-pyrazolo[4,3-c]pyridin-3-yl]-3- azabicyclo[3.1.0]hexane-2,3-dicarboxylate

[0265] To a suspension of Pd / C (0.03 g, 28.19 pmol, 10% purity, 2.14e-l eq) and Pd(OH)2 (0.03 g, 42.72 pmol, 20% purity, 3.25e-l eq) in EtOH (5 mL) was added 03-tert- butyl O2-methyl (lR,2S,5S,6R)-6-[6-[6-amino-2-methyl-3-(trifluoromethyl)-4-pyridyl]-l- cyclopropy l-7-fluoro-4-isopropenyl-pyrazolo[4,3 -c]pyridin-3 -y 1] -3 -azabicyclo [3.1.0]hexane- 2,3-dicarboxylate (0.083 g, 131.61 pmol, 1 eq), the suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred under H2 (45psi) at 25°C for 16 hours. LCMS showed 03-tert-butyl O2-methyl (lR,2S,5S,6R)-6-[6-[6-amino-2-methyl-3- (trifluoromethyl)-4-pyridyl]-l-cyclopropyl-7-fluoro-4-isopropenyl-pyrazolo[4,3-c]pyridin-3- yl]-3-azabicyclo[3.1.0]hexane-2,3-dicarboxylate was consumed and one main peak with desired mass. The reaction mixture was filtered and concentrated under reduced pressure to give 03-tert-butyl O2-methyl (lR,2S,5S,6R)-6-[6-[6-amino-2-methyl-3-(trifluoromethyl)-4- pyridyl]-l-cyclopropyl-7-fluoro-4-isopropyl-pyrazolo[4,3-c]pyridin-3-yl]-3- azabicyclo[3.1.0]hexane-2,3-dicarboxylate (0.083 g, 131.19 pmol, 99.68% yield) as colorless oil.

[0266] MS (ES+) C31H36F4N6O4 requires: 632, found: 633 [M+H]+.Step 7 (lR,2S,5S,6R)-6-[6-[6-amino-2-methyl-3-(trifluoromethyl)-4-pyridyl]-l-cydopropyl-7- fluoro-4-isopropyl-pyrazolo[4,3-c]pyridin-3-yI]-3-tert-butoxycarbonyI-3- azabicydo[3.1.0]hexane-2-carboxylic add

[0267] To a solution of 03-tert-butyl O2-methyl (lR,2S,5S,6R)-6-[6-[6-amino-2-methyl- 3-(trifhioromethyl)-4-pyridyl]-l-cyclopropyl-7-fluoro-4-isopropyl-pyrazolo[4,3-c]pyridin-3- yl]-3-azabicyclo[3.1.0]hexane-2,3-dicarboxylate (0.083 g, 131.19 pmol, 1 eq) in THF (0.8 mL) was added a solution of LiOlW-hO (13.76 mg, 327.99 pmol, 2.5 eq) in H2O (0.8 mL) at 0 °C. The mixture was stirred at 25 °C for 1 hour. LCMS showed 03-tert-butyl O2-methyl (lR,2S,5S,6R)-6-[6-[6-amino-2-methyl-3-(trifluoromethyl)-4-pyridyl]-l-cyclopropyl-7- fluoro-4-isopropyl-pyrazolo[4,3-c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-2,3-dicarboxylate was consumed and one main peak with desired mass. To the mixture was added HC1 (0.5 N), the pH was adjusted to 6, extracted with EtOAc (5 mL x 3), dried over NazSO4, filtered and concentrated under reduced pressure to give (lR,2S,5S,6R)-6-[6-[6-amino-2-methyl-3- (trifhioromethyl)-4-pyridyl]-l-cyclopropyl-7-fluoro-4-isopropyl-pyrazolo[4,3-c]pyridin-3- yl]-3-tert-butoxycarbonyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (0.075 g, 121.24 pmol, 92.41% yield) as a white solid.

[0268] MS (ES+) C30H34F4N6O4 requires: 618, found: 619 [M+H]+.Step 8 tert-butyl (lR,2S,5S,6R)-6-[6-[6-amino-2-methyl-3-(trifluoromethyl)-4-pyridyl]-l- cyclopropyI-7-fluoro-4-isopropyl-pyrazoIo[4,3-c]pyridin-3-yl]-2-(methyIcarbamoyl)-3- azabicyclo[3.1.0]hexane-3-carboxylate

[0269] To a solution of (lR,2S,5S,6R)-6-[6-[6-amino-2-methyl-3-(trifluoromethyl)-4- pyridyl]-l-cyclopropyl-7-fluoro-4-isopropyl-pyrazolo[4,3-c]pyridin-3-yl]-3-tert- butoxycarbonyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (0.015 g, 24.25 pmol, 1 eq) in DMF (1 mL) were added HATU (23.05 mg, 60.62 pmol, 2.5 eq) and DIPEA (18.80 mg, 145.48 pmol, 25.34 pL, 6 eq), to the mixture was added methanamine;hydrochloride (1.64 mg, 24.25 pmol, 1 eq). The mixture was stirred at 25 °C for 1 hour. LCMS showed (lR,2S,5S,6R)-6-[6-[6-amino-2-methyl-3-(trifluoromethyl)-4-pyridyl]-l-cyclopropyl-7- fluoro-4-isopropyl-pyrazolo[4,3-c]pyridin-3-yl]-3-tert-butoxycarbonyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid was consumed and main peak with desired mass. The reaction mixture was diluted with EtOAc (5 mL), washed with HC1 (0.1 N, 5 mL x 2) and saturated NaHCOr(5 mL x 3), dried over Na2SC>4, filtered and concentrated under reduced pressure to give tert-butyl (lR,2S,5S,6R)-6-[6-[6-amino-2-methyl-3- (trifluoromethyl)-4-pyridyl]-l-cyclopropyl-7-fluoro-4-isopropyl-pyrazolo[4,3-c]pyridin-3- yl]-2-(methylcarbamoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (0.02 g, 21.21 pmol, 87.49% yield, 67% purity) as a yellow solid.

[0270] MS (ES+) C31 H37F4N7O3 requires: 631 , found: 632 [M+H]+.Step 9 (lR,2S,5S,6R)-6-[6-[6-amino-2-methyl-3-(trifluoromethyl)-4-pyridyl]-l-cyclopropyl-7- fluoro-4-isopropyl-pyrazolo[4,3-c]pyridin-3-yl]-N-methyI-3-azabicyclo[3.1.0]hexane-2- carboxamide

[0271] To a solution of tert-butyl (lR,2S,5S,6R)-6-[6-[6-amino-2-methyl-3- (trifluoromethyl)-4-pyridyl]-l-cyclopropyl-7-fluoro-4-isopropyl-pyrazolo[4,3-c]pyridin-3- yl]-2-(methylcarbamoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (0.02 g, 31.66 pmol, 1 eq) in DCM (0.6 mL) was added TFA (460.50 mg, 4.04 mmol, 0.3 mL, 127.55 eq) at 0 °C, the mixture was stirred at 25 °C for 0.25 hour. LCMS showed tert-butyl (lR,2S,5S,6R)-6-[6-[6- amino-2-methyl-3-(trifluoromethyl)-4-pyridyl]-l-cyclopropyl-7-fluoro-4-isopropyl- pyrazolo[4,3-c]pyridin-3-yl]-2-(methylcarbamoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate was consumed and main peak with desired mass. The reaction mixture was added into saturated NaHCChf 10 mL), extracted with EtOAc (10 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue which was purified by prep-HPLC (column: Phenomenex luna C 18 150*25mm* lOum; mobile phase: [water(FA)- ACN] ; gradient: 12%-42% B over 10 min), the eluent was freeze dried over to afford (1R,2S,5S,6R)- 6-[6-[6-amino-2-methyl-3-(trifluoromethyl)-4-pyridyl]-l-cyclopropyl-7-fluoro-4-isopropyl-pyrazolo[4,3-c]pyridin-3-yl]-N-methyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (2.4 mg, 4.52 pmol, 14.26% yield) as a white solid.

[0272] MS (ES+) C26H29F4N7O requires: 531, found: 532 [M+H]+.

[0273] 'H NMR (400 MHz, CD3OD) 5 = 6.41 (s, 1H), 4.03 - 3.77 (m, 3H), 3.30 - 3.21 (m, 2H), 2.79 (s, 3H), 2.64 - 2.49 (m, 4H), 2.30 - 2.23 (m, 1H), 2.20 - 2.09 (m, 1H), 1.45 - 1.32 (m, 6H), 1.28 - 1.18 (m, 2H), 1.15 - 1.06 (m, 2H).cyclopropyl (lR,2S,5S,6R)-6-[6-[6-amino-2-methyl-3-(trifluoromethyl)-4-pyridyl]-l- cyclopropyl-7-fhioro-4-isopropyl-pyrazoIo[4,3-c]pyridin-3-yl]-3- azabicyclo[3.1.0]hexane-2-carboxylateStep 1O3-tert-butyl O2-cyclopropyl (lR,2S,5S,6R)-6-[6-[6-amino-2-methyl-3-(trifluoromethyl)-4-pyridyl]-l-cyclopropyl-7-fluoro-4-isopropyl-pyrazolo[4,3-c]pyridin- 3-yl]-3-azabicyclo[3.1.0]hexane-2,3-dicarboxylate

[0274] To a solution of (lR,2S,5S,6R)-6-[6-[6-amino-2-methyl-3-(trifluoromethyl)-4- pyridyl]-l-cyclopropyl-7-fluoro-4-isopropyl-pyrazolo[4,3-c]pyridin-3-yl]-3-tert- butoxycarbonyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (0.02 g, 32.33 pmol, 1 eq) in DCM (0.5 mL) were added cyclopropanol (5.63 mg, 96.99 Limol, 3 eq), DCC (8.00 mg, 38.80pmol, 7.85 pL, 1.2 eq) and DMAP (394.97 pg, 3.23 pmol, 0.1 eq). The mixture was stirred at 25 °C for 2 hours. LCMS showed (lR,2S,5S,6R)-6-[6-[6-amino-2-methyl-3- (trifluoromethyl)-4-pyridyl]-l-cyclopropyl-7-fluoro-4-isopropyl-pyrazolo[4,3-c]pyridin-3- yl]-3-tert-butoxycarbonyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid was consumed and main peak with desired mass. The reaction mixture was diluted with EtOAc (5 mL), filtered and concentrated under reduced pressure to give 03-tert-butyl 02-cyclopropyl (lR,2S,5S,6R)-6-[6-[6-amino-2-methyl-3-(trifluoromethyl)-4-pyridyl]-l-cyclopropyl-7- fluoro-4-isopropyl-pyrazolo[4,3-c]pyridin-3-yl]-3-azabicyclo[3.1 .0]hexane-2,3-dicarboxylate (0.03 g, crude) as colorless oil.

[0275] MS (ES+) C33H38F4N6O4 requires: 658, found: 659 [M+H]+.Step 2 cyclopropyl (lR,2S,5S,6R)-6-[6-[6-ainino-2-methyl-3-(trifluoromethyl)-4-pyridyl]-l- cyclopropyl-7-fluoro-4-isopropyl-pyrazolo[4,3-c]pyridin-3-yl]-3- azabicyclo[3.1.0]hexane-2-carboxylate

[0276] To a solution of 03-tert-butyl 02-cyclopropyl (lR,2S,5S,6R)-6-[6-[6-amino-2- methyl-3-(trifhioromethyl)-4-pyridyl]-l-cyclopropyl-7-fluoro-4-isopropyl-pyrazolo[4,3- c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-2,3-dicarboxylate (0.03 g, 45.55 pmol, 1 eq) in DCM (1 mL) were added TFA (5.19 mg, 45.55 pmol, 3.38 pL, 1 eq). The mixture was stirred at 25 °C for 0.25 hour. LCMS showed 03-tert-butyl 02-cyclopropyl (lR,2S,5S,6R)-6-[6-[6- amino-2-methyl-3-(trifluoromethyl)-4-pyridyl]-l-cyclopropyl-7-fluoro-4-isopropyl- pyrazolo[4,3-c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-2,3-dicarboxylate was consumed and main peak with desired mass. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by prep-HPLC (column: Phenomenex luna C18 150*25mm* 10um;mobile phase: [water(FA)-ACN]; gradient: 16%-46% B over 10 min), the eluent was freeze dried over to afford cyclopropyl (lR,2S,5S,6R)-6-[6-[6-amino-2-methyl-3- (trifluoromethyl)-4-pyridyl]-l-cyclopropyl-7-fluoro-4-isopropyl-pyrazolo[4,3-c]pyridin-3-yl] -3 -azabicyclo [3.1.0]hexane-2-carboxylate (5.7 mg, 10.20 pmol, 22.41% yield) as a white solid.

[0277] MS (ES+) C28H 0F4N6O2 requires: 558, found: 559 [M+H]+.

[0278] 'H NMR (400 MHz, CD3OD) 5 = 6.41 (s, 1H), 4.25 - 4.17 (m, 1H), 3.95 (s, 1H), 3.93 - 3.77 (m, 2H), 3.30 - 3.19 (m, 2H), 2.58 - 2.54 (m, 3H), 2.38 - 2.31 (m, 2H), 2.19 - 2.12 (m, 1H), 1.36 (dd, 7 = 2.4, 6.7 Hz, 6H), 1.26 - 1.18 (m, 2H), 1.16 - 1.09 (m, 2H), 0.76 (d, J = 5.3 Hz, 4H).[(lR,2S,5S,6R)-6-[6-[6-amino-2-methyl-3-(trifluoromethyl)-4-pyridyl]-l-cyclopropyl-7- fluoro-4-isopropyl-pyrazolo[4,3-c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexan-2-yl]methanoI Step 1 tert-butyl (lR,2S,5S,6R)-6-(6-chloro-l-cycIopropyl-7-fluoro-pyrazolo[4,3-c]pyridin-3- yl)-2-(hydroxymethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate

[0279] To a solution of(lR,2S,5S,6R)-3-tert-butoxycarbonyl-6-(6-chloro-l-cyclopropyl- 7-fluoro-pyrazolo[4,3-c]pyridin-3-yl)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (1.6 g, 3.66 mmol, 1 eq) in THF (20 mL) was added NMM (555.67 mg, 5.49 mmol, 603.99 pL, 1.5 eq) and isobutyl carbonochloridate (750.31 mg, 5.49 mmol, 718.69 pL, 1.5 eq) at -10 °C under N2.The mixture was stirred at -10 °C for 0.5 hr. Then the mixture was added dropwise into a solution of NaBH4 (415.68 mg, 10.99 mmol, 3 eq) in H2O (10 mL) at 0°C underN2. The resulting mixture was stirred at 0°C for 0.5 h under N2. LCMS showed a peak (86%) with desired mass. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with water (30 mL), dried over Na2SC>4, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (20 g SepaFlash® Silica Flash Column, Eluent of 0-30% Ethyl acetate / Petroleum ether gradient @ 100 mL / min) to afford tert-butyl (lR,2S,5S,6R)-6-(6-chloro-l-cyclopropyl-7-fluoro-pyrazolo[4,3-c]pyridin-3-yl)-2- (hydroxymethyl)-3-azabicyclo[3.1 .0]hexane-3-carboxylate (400 mg, 945.89 pmol, 25.83% yield) as a white solid.

[0280] MS(ES+) C20H24N4FCIO3 requires: 422, found 423 [M+H]+.Step 2 tert-butyl (lR,2S,5S,6R)-2-[[tert-butyl(dimethyl)silyl]oxymethyl]-6-(6-chloro-l- cyclopropyl-7-fluoro-pyrazolo[4,3-c]pyridin-3-yl)-3-azabicyclo[3.1.0]hexane-3- carboxylate

[0281] To a solution of tert-butyl (lR,2S,5S,6R)-6-(6-chloro-l-cyclopropyl-7-fluoro pyrazolo[4,3-c]pyridin-3-yl)-2-(hydroxymethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (400 mg, 945.89 pmol, 1 eq) in DCM (4 mL) were added imidazole (193.18 mg, 2.84 mmol, 3 eq) and TBSC1 (171.08 mg, 1.14 mmol, 139.66 pL, 1.2 eq) , the mixture was stirred at 25 °C for 16 hr. LCMS showed 23% of tert-butyl (lR,2S,5S,6R)-6-(6-chloro-l-cyclopropyl-7- fluoro pyrazolo[4,3-c]pyridin-3-yl)-2-(hydroxymethyl)-3-azabicyclo[3.1.0]hexane-3 carboxylate remained and a peak (63%) with desired mass. The mixture was diluted with H2O (10 mL), extracted with dichloromethane (10 mL x 3), the organic layers was combined together, dried over Na2SO4 filtered and the filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (20 g SepaFlash® Silica Flash Column, Eluent of 0-30% Ethyl acetate / Petroleum ether gradient @ 100 mL / min) to afford tert-butyl (lR,2S,5S,6R)-2-[[tert-butyl(dimethyl)silyl]oxymethyl]-6-(6-chloro-l-cyclopropyl-7-fluoro-pyrazolo[4,3-c]pyridin-3-yl)-3-azabicyclo[3.L0]hexane-3-carboxylate (410 mg, 763.30 pmol, 80.70% yield) as colorless oil.

[0282] MS(ES+) C26H3SN4FC103Si requires: 536, found 537 [M+H]+.Step 3 tert-butyl (lR,2S,5S,6R)-6-(4-bromo-6-chloro-l-cyclopropyl-7-fluoro-pyrazolo[4,3- c]pyridin-3-yl)-2-[[tert-butyl(dimethyl)silyl]oxymethyl]-3-azabicyclo[3.1.0]hexane-3- carboxylate

[0283] To TMPMgCFLiCl (1 M, 2.98 mL, 4 eq) was added a solution of tert-butyl (lR,2S,5S,6R)-2-[[tert-butyl(dimethyl)silyl]oxymethyl]-6-(6-chloro-l-cyclopropyl-7-fluoro- pyrazolo[4,3-c]pyridin-3-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (400 mg, 744.68 (imol, 1 eq) in THF (2 mL) was added under N2 at 0 °C. The mixture was stirred at 0 °C for 1 hr. Then a solution of 1 ,2-dibromo- 1 , 1 ,2,2-tetrachloro-ethane (970.00 mg, 2.98 mmol, 357.54 pL, 4 eq) in THF (2 mL) was added into the mixture at 0 °C. The mixture was stirred at 0 °C for 2 h. LCMS showed tert-butyl 6-[6-[6-amino-2-methyl-3-(trifluoromethyl)-4-pyridyl]-l- cyclopropyL7-fluoro-4-[l-(hydroxymethyl)cyclopropyl]pyrazolo[4,3-c]pyridin-3-yl]-3- azabicyclo[3.1.0]hexane-3-carboxylate was consumed completely and a peak (41%) with desired mass. The mixture was poured into water (20 mL), extracted with ethyl acetate (20 mL x 3), the organic layer was combined together, dried over NasSCU, filtered and filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (20 g SepaFlash® Silica Flash Column, Eluent of 0~25%Ethylacetate / Petroleum ether gradient @ 100 mL / min) to afford tert-butyl (lR,2S,5S,6R)-6-(4-bromo-6-chloro-l-cyclopropyl-7-fluoro-pyrazolo[4,3-c]pyridin-3-yl)-2- [[tert-butyl (dimethyl)silyl]oxymethyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate (300 mg, 486.98 pmol, 65.39% yield) as colourless oil.

[0284] MS(ES+) C26H3?N4FClBrO3Si requires: 616 found 561 [M-isobutene+H]+.Step 4tert-butyl (lR,2S,5S,6R)-2-[[tert-butyl(dimethyl)silyl]oxymethyl]-6-(6-chloro-l- cydopropyl-7-fluoro-4-isopropyl-pyrazolo[4,3-c]pyridin-3-yl)-3- azabicydo[3.1.0]hexane-3-carboxylate

[0285] A mixture of tert-butyl (lR,2S,5S,6R)-6-(4-bromo-6-chloro-l-cyclopropyl-7- fluoro-pyrazolo[4,3-c]pyridin-3-yl)-2-[[tert-butyl(dimethyl)silyl]oxymethyl]-3- azabicyclo[3.1.0]hexane-3-carboxylate (300 mg, 486.98 pmol, 1 eq), 2-iodopropane (165.57 mg, 973.97 pmol, 97.22 pL, 2 eq), fr[dF(CF3)ppy]2(dtbpy)(PF6) (5.46 mg, 4.87 pmol, 0.01 eq), NiCh^dtbbpy (969.09 pg, 2.43 pmol, 0.005 eq), bis(trimethylsilyl)silyl-trimethyl-silane (121.09 mg, 486.98 pmol, 150.24 pL, 1 eq) and Na2CO3(103.23 mg, 973.97 pmol, 2 eq) in DME (12 mL) was degassed and purged with N2, and then the mixture was stirred at 25 °C for 16 h irradiated with a 455 nm blue LED. TLC (Petroleum ether : Ethyl acetate=5:l) showed tert-butyl (lR,2S,5S,6R)-6-(4-bromo-6-chloro-l-cyclopropyl-7-fluoro-pyrazolo[4,3- c]pyridin-3-yl)-2-[[tert-butyl(dimethyl)silyl]oxymethyl]-3-azabicyclo[3.1.0]hexane-3- carboxylate remained and a new spot with lower polarity. The mixture was filtered and filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0-10% Ethyl acetate / Petroleum ether gradient @ 100 mL / min) to afford tert-butyl (lR,2S,5S,6R)-2-[[tert- butyl(dimethyl)silyl]oxymethyl]-6-(6-chloro-l-cyclopropyl-7-fluoro-4-isopropyl- pyrazolo[4,3-c]pyridin-3-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (170 mg, 293.50 pmol, 60.27% yield) as a white solid.

[0286] MS(ES+) C29H 4N4FC103Si requires: 578, found 579 [M+H]+Step 5 tert-butyl (lR,2S,5S,6R)-6-[6-[6-ainino-2-methyI-3-(trifluoromethyl)-4-pyridyl]-l- cyclopropyl-7-fluoro-4-isopropyl-pyrazolo[4,3-c]pyridin-3-yl]-2-[[tert- butyl(dimethyI)silyl]oxymethyl]-3-azabicydo[3.1.0]hexane-3-carboxylate

[0287] To a solution of tert-butyl (lR,2S,5S,6R)-2-[[tert- butyl(dimethyl)silyl]oxymethyl]-6-(6-chloro-l-cyclopropyl-7-fluoro-4-isopropyl- pyrazolo[4,3-c]pyridin-3-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (50 mg, 86.32 pmol, 1 eq) in THF (1.7 mL) were added 6-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-5- (trifluoromethyl)pyridin-2-amine (52.16 mg, 172.65 pmol, 2 eq), CataCXium A Pd G3 (6.29 mg, 8.63 pmol, 0.1 eq) and K3PO4 (1.5 M, 172.65 pL, 3 eq) under N2, the mixture was stirred at 60 °C for 16 hr. LCMS showed 11% of tert-butyl (lR,2S,5S,6R)-2-[[tert- butyl(dimethyl)silyl]oxymethyl]-6-(6-chloro-l-cyclopropyl-7-fluoro-4-isopropyl- pyrazolo[4,3-c]pyridin-3-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate remained and a peak (64%) with desired mass. The mixture was diluted with water (10 mL), the mixture was extracted with ethyl acetate (10 mL x 3), and the organic layers were concentrated under reduced pressure. The residue was purified by prep-TLC (Petroleum ether: Ethyl acetate=2:l) to afford tert-butyl (lR,2S,5S,6R)-6-[6-[6-amino-2-methyl-3-(trifluoromethyl)-4-pyridyl]-l- cyclopropyl-7-fluoro-4-isopropyl-pyrazolo[4,3-c]pyridin-3-yl]-2-[[tert- butyl(dimethyl)silyl]oxymethyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate (40 mg, 55.64 pmol, 64.46% yield) as colourless oil.

[0288] MS(ES+) C36H5oN6F403Si requires: 718, found 719 [M+H]+.Step 6 [(lR,2S,5S,6R)-6-[6-[6-amino-2-methyl-3-(trifluoromethyl)-4-pyridyl]-l-cyclopropyl-7- fluoro-4-isopropyl-pyrazolo[4,3-c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexan-2-yI]methanol

[0289] To a solution of tert-butyl (lR,2S,5S,6R)-6-[6-[6-amino-2-methyl-3- (trifluoromethyl)-4-pyridyl]-l-cyclopropyl-7-fluoro-4-isopropyl-pyrazolo[4,3-c]pyridin-3- yl]-2-[[tert-butyl(dimethyl)silyl]oxymethyl]-3-azabicyclo[3.1 ,0]hexane-3-carboxylate (40 mg, 55.64 pmol, 1 eq) in HCl / dioxane (2 mL) and TFA (0.5 mL) was stirred at 25 °C for 0.5 hr. LCMS showed tert-butyl (lR,2S,5S,6R)-6-[6-[6-amino-2-methyl-3-(trifluoromethyl)-4- pyridyl]-l-cyclopropyl-7-fluoro-4-isopropyl-pyrazolo[4,3-c]pyridin-3-yl]-2-[[tert- butyl(dimethyl)silyl]oxymethyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate was consumed completely and a peak with desired mass. The mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Unisil 3-100 Cl 8 Ultra 150*50mm*3 um;mobile phase: [water(FA)-ACN];gradient:10%-40% B over 10 min), the eluent was lyophilized under reduced pressure to afford [(lR,2S,5S,6R)-6-[6-[6-amino-2- methyl-3-(trifhioromethyl)-4-pyridyl |- 1 -cyclopropyl-7-fluoro-4-isopropyl-pyrazolo| 4,3- c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexan-2-yl]methanol (5.5 mg, 9.99 pmol, 17.95% yield, FA) as white solid.

[0290] MS (ES+) C25H28F4N6O requires: 504, found: 505 [M+H]+,

[0291] 1H NMR (400 MHz,CD3OD) 5 = 8.44 (s, 1H), 6.40 (s, 1H), 3.98 - 3.93 (m, 1H),3.91 - 3.80 (m, 3H), 3.76 -3.71 (m, 1H), 3.71 - 3.63 (m, 1H), 3.61 - 3.52 (m, 1H), 2.59 - 2.54 (m, 3H), 2.53 - 2.45 (m, 2H), 2.42 - 2.35 (m, 1H), 1.38 (d, J= 6.8 Hz, 6H), 1.27 - 1.18 (m, 2H), 1.17 - 1.08 (m, 2H).EXAMPLE 60l-[(lR,2S,5S,6R)-6-[6-[5-amino-3-fluoro-2-(trifluoromethoxy)phenyl]-l-cyclopropyl-7- fluoro-4-isopropyl-pyrazolo[4,3-c]pyridin-3-yI]-3-azabicycIo[3.1.0]hexan-2-yl]ethanol Step 1 tert-butyl (lR,2S,5S,6R)-6-[6-[5-(tert-butoxycarbonylamino)-3-fluoro-2- (trifluoromethoxy)phenyl]-l-cyclopropyl-7-fluoro-4-isopropyl-pyrazolo[4,3-c]pyridin-3- yl]-2-formyl-3-azabicyclo[3.1.0]hexane-3-carboxylate

[0292] tert-butyl (lR,2S,5S,6R)-6-[6-[5-(tert-butoxycarbonylamino)-3-fluoro-2- (trifluoromethoxy)phenyl]-l-cyclopropyl-7-fluoro-4-isopropyl-pyrazolo[4,3-c]pyridin-3-yl]- 2-(hydroxymethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate was prepared similarly to Example 59 via Suzuki coupling of tert-butyl (3-fluoro-5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-4-(trifluoromethoxy)phenyl)carbamate.

[0293] To a solution of oxalyl dichloride (52.62 mg, 414.52 pmol, 36.29 pL, 3 eq) in DCM (1 mL) was added DMSO (34.55 mg, 442.15 pmol, 34.55 pL, 3.2 eq) at -70 °C, the mixture was stirred at -70 °C for 15 mins, to the mixture was added as solution of tert-butyl (lR,2S,5S,6R)-6-[6-[5-(tert-butoxycarbonylamino)-3-fluoro-2-(trifluoromethoxy)phenyl]-l- cyclopropyl-7-fluoro-4-isopropyl-pyrazolo[4,3-c]pyridin-3-yl]-2-(hydroxymethyl)-3- azabicyclo[3.1.0]hexane-3-carboxylate (0.1 g, 138.17 pmol, 1 eq) in DCM (0.2 mL), the mixture was stirred at -70 °C for 15 mins, to the mixture was added TEA (90.88 mg, 898.13 pmol, 125.01 pL, 6.5 eq), the mixture was stirred at -70 °C for 15 min and stirred at 0 °C for1 hour. LCMS showed tert-butyl (lR,2S,5S,6R)-6-[6-[5-(tert-butoxycarbonylamino)-3- fluoro-2-(trifluoromethoxy)phenyl]-l-cyclopropyl-7-fluoro-4-isopropyl-pyrazolo[4,3- c]pyridin-3-yl]-2-(hydroxymethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate still remained and one peak with desired mass. To the mixture was added water (5 mL) and extracted with DCM (5 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (4 g SepaFlash® Silica Flash Column, Eluent of 0-50% Ethyl acetate / Petroleum ether gradient @ 34 mL / min) to afford tert-butyl (lR,2S,5S,6R)-6-[6-[5-(tert-butoxycarbonylamino)-3-fluoro-2- (trifluoromethoxy)phenyl]-l-cyclopropyl-7-fluoro-4-isopropyl-pyrazolo[4,3-c]pyridin-3-yl]- 2-formyl-3-azabicyclo[3.1.0]hexane-3-carboxylate (0.095 g, 131.63 pmol, 95.27% yield) as colorless oil.

[0294] MS (ES+) C35H40F N5O6 requires: 721 , found: 722 [M+H]+.Step 2 tert-butyl (lR,2S,5S,6R)-6-[6-[5-(tert-butoxycarbonylamino)-3-fluoro-2- (trifluoromethoxy)phenyl]-l-cyclopropyl-7-fluoro-4-isopropyl-pyrazolo[4,3-c]pyridin-3- yl]-2-(l-hydroxyethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate

[0295] To a solution of tert-butyl (lR,2S,5S,6R)-6-[6-[5-(tert-butoxycarbonylamino)-3- fluoro-2-(trifluoromethoxy)phenyl]- l-cyclopropyl-7-fluoro-4-isopropyl-pyrazolo[4,3- c]pyridin-3-yl]-2-formyl-3-azabicyclo[3.1.0]hexane-3-carboxylate (0.095 g, 131.63 pmol, 1 eq) in THF (1 mL) was added MeMgBr (3 M, 131.63 pL, 3 eq) at -70 °C under the protection of N2, the mixture was stirred at -70 °C for 1 hour. LCMS showed mass of tert-butyl (lR,2S,5S,6R)-6-[6-[5-(tert-butoxycarbonylamino)-3-fluoro-2-(trifluoromethoxy)phenyl]-l- cyclopropyl-7-fluoro-4-isopropyl-pyrazolo[4,3-c]pyridin-3-yl]-2-formyl-3- azabicyclo[3.1.0]hexane-3-carboxylate and desired mass in the same peak, the mixture was stirred at 0 °C for another 1 hour, LCMS showed mass of tert-butyl (lR,2S,5S,6R)-6-[6-[5- (tert-butoxycarbonylamino)-3-fluoro-2-(trifluoromethoxy)phenyl]-l-cyclopropyl-7-fluoro-4-isopropyl-pyrazolo[4,3-c]pyridin-3-yl]-2-formyl-3-azabicyclo[3.1.0]hexane-3-carboxylate and product in the same peak. To the mixture was added water (5 mL) and extracted with EtOAc (5 mL x 3), dried over Na2SC>4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (Si O2, Petroleum ether / Ethyl acetate = 1:1) to afford tert-butyl (lR,2S,5S,6R)-6-[6-[5-(tert-butoxycarbonylamino)-3-fluoro-2- (trifluoromethoxy)phenyl]-l-cyclopropyl-7-fluoro-4-isopropyl-pyrazolo[4,3-c]pyridin-3-yl]- 2-(l-hydroxyethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (50 mg, 67.77 pmol, 51.49% yield) as colorless oil.

[0296] MS (ES+) C36H44F5N5O6 requires: 737, found: 738 [M+H]+.Step 3 l-[(lR,2S,5S,6R)-6-[6-[5-amino-3-fluoro-2-(trifluoromethoxy)phenyl]-l-cyclopropyl-7- fluoro-4-isopropyl-pyrazolo[4,3-c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexan-2-yl]ethanol

[0297] To a solution of tert-butyl (lR,2S,5S,6R)-6-[6-[5-(tert-butoxycarbonylamino)-3- fluoro-2-(trifluoromethoxy)phenyl]-l-cyclopropyl-7-fluoro-4-isopropyl-pyrazolo[4,3- c]pyridin-3-yl]-2-(l-hydroxyethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (0.02 g, 27.11 pmol, 1 eq) in DCM (0.6 mL) was added TFA (614.00 mg, 5.38 mmol, 400.00 pL, 198.64 eq) , the mixture was stirred at 25 °C for 0.25 hour. LCMS showed tert-butyl (1R,2S,5S,6R)- 6-[6-[5-(tert-butoxycarbonylamino)-3-fluoro-2-(trifluoromethoxy)phenyl]-l-cyclopropyl-7- fluoro-4-isopropyl-pyrazolo[4,3-c]pyridin-3-yl]-2-(l-hydroxyethyl)-3- azabicyclo[3.1.0]hexane-3-carboxylate was consumed and main peak with desired mass. To the mixture was added saturated NaHCCh and the pH was adjusted to 8, extracted with EtOAc (10 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Luna Cl 8 150*25mm*10um; mobile phase: [H2O(0.225% FA)-ACN]; gradient: 19%-49% B over 10.0 min), the eluent was freeze dried over to afford l-[(lR,2S,5S,6R)-6-[6-[5-amino-3-fluoro-2- (trifhioromethoxy)phenyl]-l-cyclopropyl-7-fluoro-4-isopropyl-pyrazolo[4,3-c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexan-2-yl]ethanol (4.6 mg, 7.88 pmol, 29.08% yield, FA) as a white solid.

[0298] MS (ES+) C26H28F N5O2 requires: 537, found: 538 [M+H]+.

[0299] 'H NMR (400 MHz, CD3OD) 5 = 8.54 (s, 1H), 6.68 - 6.58 (m, 2H), 3.98 - 3.87 (m, 1H), 3.86 - 3.74 (m, 1H), 3.70 - 3.59 (m, 1H), 3.27 - 3.12 (m, 3H), 2.32 - 2.10 (m, 3H), 1.39 (d, J= 6.7 Hz, 6H), 1.26 (d, J= 6.5 Hz, 3H), 1.24 - 1.18 (m, 2H), 1.16 - 1.10 (m, 2H).l-[(lR,2S,5S,6R)-6-[6-[5-amino-3-fluoro-2-(trifluoromethoxy)phenyl]-l-cycIopropyl-7- fluoro-4-isopropyl-pyrazolo[4,3-c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexan-2-yl]ethanone Step 1 tert-butyl (lR,2S,5S,6R)-2-acetyl-6-[6-[5-(tert-butoxycarbonylamino)-3-fluoro-2- (trifluoromethoxy)phenyl]-l-cydopropyl-7-fluoro-4-isopropyl-pyrazolo[4,3-c]pyridin-3- yl]-3-azabicyclo[3.1.0]hexane-3-carboxyIate

[0300] To a solution of oxalyl dichloride (28.90 mg, 227.72 pmol, 19.93 pL, 3 eq) in DCM (1 mL) was added DMSO (18.98 mg, 242.90 pmol, 18.98 pL, 3.2 eq) at -70 °C, the mixture was stirred at -70 °C for 15 mins, to the mixture was added as solution of tert-butyl (lR,2S,5S,6R)-6-[6-[5-(tert-butoxycarbonylamino)-3-fluoro-2-(trifluoromethoxy)phenyl]-l- cyclopropyl-7-fluoro-4-isopropyl-pyrazolo[4,3-c]pyridin-3-yl]-2-(l-hydroxyethyl)-3- azabicyclo[3.1.0]hexane-3-carboxylate (0.056 g, 75.91 pmol, 1 eq) in DCM (0.3 mL), themixture was stirred at -70 °C for 15 mins, to the mixture was added TEA (49.93 mg, 493.39 pmol, 68.67 pL, 6.5 eq), the mixture was stirred at -70 °C for 15 min and stirred at 0 °C for 1 hour. LCMS showed tert-butyl (lR,2S,5S,6R)-6-[6-[5-(tert-butoxycarbonylamino)-3-fluoro-2-(trifluoromethoxy)phenyl]-l-cyclopropyl-7-fluoro-4-isopropyl-pyrazolo[4,3-c]pyridin-3- yl]-2-(l-hydroxyethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate still remained and one peak with desired mass. To the mixture was added water (5 mL) and extracted with DCM (5 mL x 3), dried over NazSC , filtered and concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography (4 g SepaFlash® Silica Flash Column, Eluent of 0-50% Ethyl acetate / Petroleum ether gradient @ 34 mL / min) to afford tert-butyl (lR,2S,5S,6R)-2-acetyl-6-[6-[5-(tert-butoxycarbonylamino)-3-fluoro-2- (trifhioromethoxy)phenyl]-l-cyclopropyl-7-fluoro-4-isopropyl-pyrazolo[4,3-c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate (27 mg, 36.70 pmol, 48.35% yield) as colorless oil.

[0301] MS (ES+) C36H42F5N5O6 requires: 735, found: 736 [M+H]+.Step 2 l-[(lR,2S,5S,6R)-6-[6-[5-amino-3-fluoro-2-(trifluoromethoxy)phenyl]-l-cyclopropyl-7- fluoro-4-isopropyl-pyrazolo[4,3-c]pyridin-3-yI]-3-azabicydo[3.1.0]hexan-2-yI]ethanone

[0302] To a solution of tert-butyl (lR,2S,5S,6R)-2-acetyl-6-[6-[5-(tert- butoxycarbonylamino)-3-fluoro-2-(trifluoromethoxy)phenyl]-l-cyclopropyl-7-fluoro-4- isopropyl-pyrazolo[4,3-c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate (0.027 g, 36.70 pmol, 1 eq) in DCM (1 mL) was added TFA (767.50 mg, 6.73 mmol, 0.5 mL, 183.42 eq), the mixture was stirred at 20 °C for 15 mins. LCMS showed tert-butyl (lR,2S,5S,6R)-2- acetyl-6-[6-[5-(tert-butoxycarbonylamino)-3-fluoro-2-(trifluoromethoxy)phenyl]-l- cyclopropyl-7-fluoro-4-isopropyl-pyrazolo[4,3-c]pyridin-3-yl]-3-azabicyclo[3. L0]hexane-3- carboxylate was consumed and one peak with desired mass. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by prep-HPLC (column: Phenomenex Luna C18 150*25mm*10um; mobile phase: [H2O(0.225% FA)- ACN]; gradient: 21 %-51 % B over 10.0 min), to the eluent was freeze dried over to afford 1-[(lR,2S,5S,6R)-6-[6-[5-amino-3-fluoro-2-(trifluoromethoxy)phenyl]-l-cyclopropyl-7-fluoro- 4-isopropyl-pyrazolo[4,3-c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexan-2-yl]ethanone (2.1 mg, 3.57 pmol, 9.72% yield, 91% purity) as a white solid.

[0303] MS (ES+) C26H26F5N5O2 requires: 535, found: 536 [M+H]+.

[0304] ’H NMR (400 MHz, CD3OD) 5 = 6.66 - 6.61 (m, 2H), 4.07 (s, IH), 3.96 - 3.88 (m, IH), 3.86 - 3.81 (m, IH), 3.27 - 3.23 (m, 2H), 2.44 (dd, J= 3.4, 6.4 Hz, IH), 2.39 - 2.36 (m, IH), 2.30 (s, 3H), 2.22 - 2.17 (m, IH), 1.41 (dd, J = 6.8, 8.9 Hz, 6H), 1.23 - 1.20 (m, 2H), 1.16 - 1.12 (m, 2H).2-[(lR,2R,5S,6R)-6-[6-[5-amino-3-fluoro-2-(trifluoromethoxy)phenyl]-l-cyclopropyl-7- fluoro-4-isopropyl-pyrazolo[4,3-c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexan-2-yl]ethanol Step 1 tert-butyl (lR,2R,5S,6R)-6-[6-[5-(tert-butoxycarbonylamino)-3-fluoro-2- (trifluoromethoxy)phenyl]-l-cyclopropyl-7-fluoro-4-isopropyl-pyrazolo[4,3-c]pyridin-3- yl]-2-vinyl-3-azabicyclo[3.1.0]hexane-3-carboxylate

[0305] To a solution of methyl(triphenyl)phosphonium;bromide (55.68 mg, 155.88 pmol, 1.5 eq) in THF (1 mL) was added [bis(trimethylsilyl)amino]potassium (1 M, 155.88 LIL, 1.5 eq) at 0 °C, the mixture was stirred at 25 °C for Ih, to the mixture was added as solution oftert-butyl (lR,2S,5S,6R)-6-[6-[5-(tert-butoxycarbonylamino)-3-fluoro-2- (trifluoromethoxy)phenyl]-l-cyclopropyl-7-fluoro-4-isopropyl-pyrazolo[4,3-c]pyridin-3-yl]- 2-formyl-3-azabicyclo[3.1.0]hexane-3-carboxylate (0.075 g, 103.92 pmol, 1 eq) in THF (0.5 mL) at -70 °C, the mixture was stirred at -10 °C for 1 hour. LCMS showed tert-butyl (lR,2S,5S,6R)-6-[6-[5-(tert-butoxycarbonylamino)-3-fluoro-2-(trifluoromethoxy)phenyl]-l- cyclopropyl-7-fluoro-4-isopropyl-pyrazolo[4,3-c]pyridin-3-yl]-2-formyl-3- azabicyclo[3.1.0]hexane-3-carboxylate was consumed and main peak with desired mass. To the mixture was added water (5 mL) and extracted with EtOAc (5 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography (5 g SepaFlash® Silica Flash Column, Eluent of 0-25% Ethyl acetate / Petroleum ether gradient @ 45 mL / min) to afford tert- butyl (lR,2R,5S,6R)-6-[6-[5-(tert-butoxycarbonylamino)-3-fluoro-2-(trifluoromethoxy)phenyl]-l- cyclopropyl-7-fluoro-4-isopropyl-pyrazolo[4,3-c]pyridin-3-yl]-2-vinyl-3- azabicyclo[3.1.0]hexane-3-carboxylate (40 mg, 55.58 pmol, 53.48% yield) as yellow oil.

[0306] MS (ES+) C36H42F5N5O5 requires: 719, found: 720 [M+H]+.Step 2 tert-butyl (lR,2R,5S,6R)-6-[6-[5-(tert-butoxycarbonylamino)-3-fluoro-2- (trifluoromethoxy)phenyl]-l-cyclopropyl-7-fluoro-4-isopropyl-pyrazolo[4,3-c]pyridin-3- yl]-2-(2-hydroxyethyl)-3-azabicydo[3.1.0]hexane-3-carboxylate

[0307] To a solution of tert-butyl (lR,2R,5S,6R)-6-[6-[5-(tert-butoxycarbonylamino)-3- fluoro-2-(trifluoromethoxy)phenyl]-l-cyclopropyl-7-fluoro-4-isopropyl-pyrazolo[4,3- c]pyridin-3-yl]-2-vinyl-3-azabicyclo[3.1.0]hexane-3-carboxylate (40.00 mg, 55.58 pmol, 1 eq) in THF (0.5 mL) was added BH3*THF (1 M, 166.73 pL, 3 eq) at 0 °C under the protection of N2, the mixture was stirred at 25 °C for 2 hours, to the mixture was added a solution of NaOH (11.12 mg, 277.88 pmol, 5 eq) in H2O (20.03 mg, 1.11 mmol, 20.03 pL, 20 eq) at 0 °C dropwise slowly and followed by H2O2 (31.50 mg, 277.88 pmol, 26.70 pL, 30%purity, 5 eq) , the mixture was stirred at 40 °C for 2 hours. LCMS showed tert-butyl (lR,2R,5S,6R)-6-[6-[5-(tert-butoxycarbonylamino)-3-fluoro-2-(trifluoromethoxy)phenyl]-l- cyclopropyl-7-fluoro-4-isopropyl-pyrazolo[4,3-c]pyridin-3-yl]-2-vinyl-3- azabicyclo[3.1.0]hexane-3-carboxylate was consumed and main peak with desired mass. To the mixture was added saturated Na2SO3(10 mL), the mixture was stirred at 25 °C for 15 mins, extracted with EtOAc (10 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give tert-butyl (lR,2R,5S,6R)-6-[6-[5-(tert-butoxycarbonylamino)-3- fluoro-2-(trifluoromethoxy)phenyl]- l-cyclopropyl-7-fluoro-4-isopropyl-pyrazolo[4,3- c]pyridin-3-yl]-2-(2-hydroxyethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (40 mg, 54.22 pmol, 97.56% yield) as colorless oil.

[0308] MS (ES+) C36H44F5N5O6 requires: 737, found: 738 [M+H]+.Step 3 2-[(lR,2R,5S,6R)-6-[6-[5-amino-3-fluoro-2-(trifluoromethoxy)phenyl]-l-cyclopropyl-7- fluoro-4-isopropyl-pyrazolo[4,3-c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexan-2-yI]ethanol

[0309] To a solution of tert-butyl (lR,2R,5S,6R)-6-[6-[5-(tert-butoxycarbonylamino)-3- fluoro-2-(trifluoromethoxy)phenyl]-l-cyclopropyl-7-fluoro-4-isopropyl-pyrazolo[4,3- c]pyridin-3-yl]-2-(2-hydroxyethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (0.04 g, 54.22 pmol, 1 eq) in DCM (0.5 mL) was added TFA (383.75 mg, 3.37 mmol, 0.25 mL, 62.07 eq) , the mixture was stirred at 25 °C for 0.25 hour. LCMS showed tert-butyl (lR,2R,5S,6R)-6-[6- [5-(tert-butoxycarbonylamino)-3-fluoro-2-(trifluoromethoxy)phenyl]-l-cyclopropyl-7-fluoro- 4-isopropyl-pyrazolo[4,3-c]pyridin-3-yl]-2-(2-hydroxyethyl)-3-azabicyclo[3.1.0]hexane-3- carboxylate was consumed and main peak with desired mass. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by prep-HPLC (column: Phenomenex Luna Cl 8 150*25mm*10um; mobile phase: [H2O(0.225% FA)- ACN]; gradient: 20%-50% B over 10.0 min), the eluent was freeze dried over to afford 2- [(lR,2R,5S,6R)-6-[6-[5-amino-3-fluoro-2-(trifluoromethoxy)phenyl]-l-cyclopropyl-7 -fluoro-4-isopropyl-pyrazolo[4,3-c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexan-2-yl]ethanol (8.1 mg, 13.88 pmol, 25.60% yield, FA) as a white solid.

[0310] MS (ES+) C26H28F5N5O2 requires: 537, found: 538 [M+H]+.

[0311] 'H NMR (400 MHz, CD3OD) 5 = 8.53 (s, 1H), 6.70 - 6.58 (m, 2H), 4.01 - 3.77 (m, 4H), 3.59 - 3.32 (m, 4H), 2.41 - 2.22 (m, 3H), 1.91 - 1.80 (m, 1H), 1.45 - 1.34 (m, 6H), 1.34 - 1.27 (m, 1H), 1.24 - 1.17 (m, 2H), 1.17 - 1.10 (m, 2H).3- [l-cyclopropyl-7 -fluoro-4-isopropyl-3- [( lR,2S,5S,6R)-2-oxazol-2-yl-3- azabicyclo[3.1.0]hexan-6-yl]pyrazolo[4,3-c]pyridin-6-yl]-5-fluoro-4- (trifluoromethoxy)anilineStep 1 tert-butyl (lR,2S,5S,6R)-6-[6-[5-(tert-butoxycarbonylamino)-3-fluoro-2- (trifluoromethoxy)phenyl]-l-cydopropyI-7-fluoro-4-isopropyl-pyrazoIo[4,3-c]pyridin-3- yl]-2-(2-hydroxyethylcarbamoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate

[0312] Isobutyl carbonochloridate (22.22 mg, 162.67 pmol, 21.28 pL, 1 eq) was added dropwise to a solution of (lR,2S,5S,6R)-3-tert-butoxycarbonyl-6-[6-[5-(tert- butoxycarbonylamino)-3-fluoro-2-(trifluoromethoxy)phenyl]-l-cyclopropyl-7-fluoro-4- isopropyl-pyrazolo[4,3-c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (120 mg, 162.67 pmol, 1 eq) and DIPEA (23.13 mg, 178.93 pmol, 31.17 pL, 1.1 eq) in DCM (1 mL) at0 °C. After 1 h at 25 °C, the mixture was cooled to -15 °C and then DIPEA (23.13 mg, 178.93 pmol, 31.17 pL, 1.1 eq) and 2- aminoethanol (10.93 mg, 178.93 pmol, 10.80 pL, 1.1 eq) were added in one portion. The mixture stirred to 25 °C for 16 h. LCMS showed 12% of (lR,2S,5S,6R)-3-tert-butoxycarbonyl-6-[6-[5-(tert-butoxycarbonylamino)-3-fluoro-2- (trifluoromethoxy)phenyl]-l-cyclopropyl-7-fluoro-4-isopropyl-pyrazolo[4,3-c]pyridin-3-yl]- 3-azabicyclo[3.1.0]hexane-2-carboxylic acid remained and 76% of peak with desired mass. To the mixture was added water (10 mL) and extracted with EtOAc (10 mL x 3), the combined organic phase was washed with brine (15 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography (4 g SepaFlash® Silica Flash Column, Eluent of 0-75% Ethyl acetate / Petroleum ether gradient @ 50 mL / min) to afford tert-butyl (lR,2S,5S,6R)-6-[6-[5- (tert-butoxycarbonylamino)-3-fluoro-2-(trifluoromethoxy)phenyl]-l-cyclopropyl-7-fluoro-4- isopropyl-pyrazolo[4,3-c]pyridin-3-yl]-2-(2-hydroxyethylcarbamoyl)-3- azabicyclo[3.1.0]hexane-3-carboxylate (120 mg, 146.01 pmol, 89.76% yield, 95% purity) as yellow oil.|0313 | MS (ES+) C37H45F5N6O7 requires: 780, found 781 |M+H|+.Step 2 tert-butyl (lR,2S,5S,6R)-6-[6-[5-(tert-butoxycarbonylamino)-3-fluoro-2- (trifluoromethoxy)phenyl]-l-cydopropyl-7-fluoro-4-isopropyl-pyrazolo[4,3-c]pyridin-3- yl]-2-(2-oxoethylcarbamoyl)-3-azabicyclo[3.1.0]hexane-3-carboxyIate

[0314] A suspension of tert-butyl (lR,2S,5S,6R)-6-[6-[5-(tert-butoxycarbonylamino)-3- fluoro-2-(trifluoromethoxy)phenyl]-l-cyclopropyl-7-fluoro-4-isopropyl-pyrazolo[4,3- c]pyridin-3-yl]-2-(2-hydroxyethylcarbamoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (120 mg, 153.69 pmol, 1 eq) in DCM (1 mL) was added in small portions to a solution of DMP (78.22 mg, 184.43 pmol, 57.14 pL, 1.2 eq) and t-BuOH (12.53 mg, 169.06 pmol, 16.17 pL, 1. 1 eq) in DCM (1 mL) at 0 °C. Then the mixture was allowed to warm to 25 °C for 1 h. LCMS showed 54% of peak with desired mass. The reaction mixture was quenched withNaHCOs (8 mL) and extracted with EtOAc (8 mL x 3), the combined organic phase was washed with brine (10 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give tert-butyl (lR,2S,5S,6R)-6-[6-[5-(tert-butoxycarbonylamino)-3-fluoro-2- (trifluoromethoxy)phenyl]-l-cyclopropyl-7-fluoro-4-isopropyl-pyrazolo[4,3-c]pyridin-3-yl]- 2-(2-oxoethylcarbamoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (120 mg, crude) as yellow oil.

[0315] MS (ES+) C37H43F5N6O7 requires: 778, found 779 [M+H]+.Step 3 tert-butyl (lR,2S,5S,6R)-6-[6-[5-(tert-butoxycarbonylamino)-3-fluoro-2- (trifluoromethoxy)phenyl]-l-cydopropyl-7-fluoro-4-isopropyl-pyrazolo[4,3-c]pyridin-3- yl]-2-oxazol-2-yl-3-azabicyclo[3.1.0]hexane-3-carboxylate

[0316] To a solution of PPI13 (121.25 mg, 462.27 pmol, 3 eq) and 1, 1,1, 2,2,2- hexachloroethane (109.44 mg, 462.27 pmol, 52.34 pL, 3 eq) in ACN (1 mL) was added TEA (93.55 mg, 924.54 pmol, 128.68 pL, 6 eq) at 0 °C, the mixture was stirred at 0 °C for 10 min. Added tert-butyl (1 R,2S,5S,6R)-6-[6-[5-(tert-butoxycarbonylamino)-3-fluoro-2- (trifluoromethoxy)phenyl]-l-cyclopropyl-7-fluoro-4-isopropyl-pyrazolo[4,3-c]pyridin-3-yl]- 2-(2-oxoethylcarbamoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (120 mg, 154.09 pmol, 1 eq) in ACN (0.5 mL) to mixture at 0 °C, the mixture was stirred at 20 °C for 16 h. LCMS showed 6% of peak with desired mass. The reaction mixture was filtered, the combined organic phase was washed with brine (5 mL x 3), dried over Na^SCA, filtered and concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography (4 g SepaFlash® Silica Flash Column, Eluent of 0-60% Ethyl acetate / Petroleum ether gradient @ 50 mL / min) and purified by prep-TLC ( Si O2, Petroleum ether: Ethyl acetate= 2: 1) to afford tert-butyl (lR,2S,5S,6R)-6-[6-[5-(tert- butoxycarbonylamino)-3-fluoro-2-(trifluoromethoxy)phenyl]-l-cyclopropyl-7-fluoro-4- isopropyl-pyrazolo[4,3-c]pyridin-3-yl]-2-oxazol-2-yl-3-azabicyclo[3.1.0]hexane-3- carboxylate (20 mg, 26.29 pmol, 17.06% yield) as yellow oil.

[0317] MS (ES+) C37H41F5N6O6 requires: 760, found 761 [M+H]+.Step 43-[l-cyclopropyl-7-fluoro-4-isopropyl-3-[(lR,2S,5S,6R)-2-oxazol-2-yl-3- azabicyclo[3.1.0]hexan-6-yl]pyrazolo[4,3-c]pyridin-6-yl]-5-fluoro-4-(trifluoromethoxy)aniline

[0318] To a solution of tert-butyl (lR,2S,5S,6R)-6-[6-[5-(tert-butoxycarbonylamino)-3- fluoro-2-(trifluoromethoxy)phenyl]-l-cyclopropyl-7-fluoro-4-isopropyl-pyrazolo[4,3- c]pyridin-3-yl]-2-oxazol-2-yl-3-azabicyclo[3.1.0]hexane-3-carboxylate (20 mg, 26.29 Limo I, 1 eq) in DCM (0.5 mL) was added TFA (383.75 mg, 3.37 mmol, 0.25 mL). The mixture was stirred at 20 °C for 20 min. LCMS showed 40% of peak with desired mass. The reaction mixture was concentrated in vacuum to give a residue which was purified by prep-HPLC (column: Phenomenex Luna C 18 150*25mm*10um; mobile phase: [H2O(0.1%TFA)-ACN]; gradient: 15%-45% B over 15.0 min) and lyophilized to afford 3-[l-cyclopropyl-7-fluoro-4- isopropy]-3-[(lR,2S,5S,6R)-2-oxazol-2-yl-3-azabicyclo[3.L0]hexan-6-yl]pyrazolo[4,3- c]pyridin-6-yl]-5-fluoro-4-(trifluoromethoxy)aniline (1.1 mg, 1.58 pmol, 6.02% yield, 97% purity, TFA) as a yellow solid.

[0319] MS (ES+) C27H25F N6O2 requires: 560, found 561 [M+H]+.

[0320] 1H NMR (400 MHz, CD3OD) 5 = 8.09 (d, J = 0.7 Hz, 1H), 7.33 (d, J = 0.6 Hz,1H), 6.67 - 6.61 (m, 2H), 5.35 (s, 1H), 3.95 - 3.75 (m, 4H), 2.88 - 2.83 (m, 1H), 2.74 - 2.68 (m, 2H), 1.46 - 1.41 (m, 6H), 1.24 - 1.19 (m, 2H), 1.18 - 1.12 (m, 2H).EXAMPLE 642-[6-[6-amino-2-methyl-3-(trifluoromethyI)-4-pyridyl]-3-(3-azabicyclo[3.1.0]hexan-6-yl)- l-cyclopropyl-7-fluoro-pyrazolo[4,3-c]pyridin-4-yl]acetonitrileStep 1 tert-butyl 6-(6-chloro-l-cydopropyl-7-fluoro-4-isoxazoI-4-yl-pyrazolo[4,3-c]pyridin-3- yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate

[0321] A solution of Tert-butyl 6-(4-bromo-6-chloro-l-cyclopropyl-7-fluoro- pyrazolo[4,3-c]pyridin-3-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (300 mg, 635.93 pmol, 1 eq), 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)isoxazole (148.82 mg, 763.12 pmol, 1.2 eq), Pd(dppf)Ch (46.53 mg, 63.59 pmol, 0.1 eq) and K2CO3 (263.67 mg, 1.91 mmol, 3 eq) in H2O (1 mL) and dioxane (5 mL) was de-gassed with N2 and then heated to 130 °C for 16 hours. LCMS showed tert-butyl 6-(4-bromo-6-chloro-l-cyclopropyl-7-fluoro-pyrazolo[4,3- c]pyridin-3-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate was consumed completely and a peak (29%) with desired mass. The mixture was diluted with water (10 mL), extracted with ethyl acetate (10 mL x 3), washed with brine (10 mL x 3), the organic layers were combined together, dried over Na2SC>4, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (8 g SepaFlash® Silica Flash Column, Eluent of 0~100%Ethylacetate / Petroleum ether gradient @ 100 mL / min) to afford tert-butyl 6-(6-chloro-l-cyclopropyl-7-fluoro-4-isoxazol-4-yl-pyrazolo[4,3-c]pyridin- 3-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (160 mg, 347.90 pmol, 54.71% yield) as brown oil.

[0322] MS (ES+) C22H23N5FCIO3 requires: 459 and 461, found: 404 and 406 [M+H- isobutene]+.Step 2 tert-butyl 6-[6-[6-amino-2-methyI-3-(trifluoromethyl)-4-pyridyl]-4-(cyanomethyl)-l- cydopropyl-7-fluoro-pyrazolo[4,3-c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-3- carboxylate

[0323] To a solution of tert-butyl 6-(6-chloro-l-cyclopropyl-7-fluoro-4-isoxazol-4-yl- pyrazolo[4,3-c]pyridin-3-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (120 mg, 260.93 pmol, 1 eq) in THF (5.2 mL) were added 6-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)- 5-(trifluoromethyl)pyridin-2-amine (157.65 mg, 521.85 pmol, 2 eq), K3PO4 (1.5 M, 521.85 pL, 3 eq) and CataCXium A Pd G3 (19.00 mg, 26.09 pmol, 0.1 eq) under N2. The mixture was stirred at 60 °C for 16 hr. LCMS showed 32% of tert-butyl 6-(6-chloro-l-cyclopropyl-7- fluoro-4-isoxazol-4-yl-pyrazolo[4,3-c]pyridin-3-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate remained and a peak (10%) with desired mass. The mixture was diluted with water (10 mL), extracted with ethyl acetate (10 mL x 3), the organic layers were combined together, dried over SkoSCL. filtered and filtrate was concentrated under reduced pressure. Theresidue was purified by prep-HPLC (column: Welch Xtimate C18 150*25mm*5um;mobile phase: |water(FA)-ACN |;gradient:42%-72% B over 10 min), the eluent was lyophilized under reduced pressure to afford tert-butyl 6-[6-[6-amino-2-methyl-3-(trifluoromethyl)-4-pyridyl]- 4-(cyanomethyl)-l-cyclopropyl-7-fluoro-pyrazolo[4,3-c]pyridin-3-yl]-3- azabicyclo[3.1.0]hexane-3-carboxylate (5 mg, 8.75 pmol, 3.35% yield) was a white solid.

[0324] MS (ES+) C28H29N7F4O2 requires: 571, found: 572 [M+H]+.Step 3 2-[6-[6-amino-2-methyl-3-(trifluoromethyI)-4-pyridyl]-3-(3-azabicyclo[3.1.0]hexan-6-yl)- l-cyclopropyl-7-fluoro-pyrazolo[4,3-c]pyridin-4-yl]acetonitrile

[0325] To a solution of tert-butyl 6-[6-[6-amino-2-methyl-3-(trifluoromethyl)-4-pyridyl]- 4-(cyanomethyl)-l-cyclopropyl-7-fluoro-pyrazolo[4,3-c]pyridin-3-yl]-3- azabicyclo[3.1.0]hexane-3-carboxylate (10 mg, 17.50 pmol, 1 eq) in DCM (0.4 mL) was added TFA (299.24 mg, 2.62 mmol, 194.94 pL, 150 eq), the mixture was stirred at 25 °C for 15 min. LCMS showed tert-butyl 6-[6-[6-amino-2-methyl-3-(trifluoromethyl)-4-pyridyl]-4- (cyanomethyl)-l-cyclopropyl-7-fluoro-pyrazolo[4,3-c]pyridin-3-yl]-3- azabicyclo[3.1.0]hexane-3-carboxylate was consumed completely and a peak (80%) with desired mass. The mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Welch Xtimate C18 150*25mm*5um;mobile phase: [water(FA)-ACN] gradient: 16%-46% B over 10 min), the eluent was concentrated and lyophilized under reduced pressure to afford 2-[6-[6-amino-2-methyl-3-(trifhioromethyl)-4- pyridyl]-3-(3-azabicyclo[3.1.0]hexan-6-yl)-l-cyclopropyl-7-fluoro-pyrazolo[4,3-c]pyridin-4- yl] acetonitrile (2.6 mg, 5.02 pmol, 28.72% yield, FA) as a white solid.

[0326] MS (ES+) C23H21N7F4 requires: 471, found: 472 [M+H]+,

[0327] ’H NMR (400 MHz, CD3OD) 5 = 6.40 (s, 1H), 4.61 - 4.46 (m, 2H), 3.94 - 3.85 (m, 1H), 3.78 - 3.67 (m, 2H), 3.65 - 3.52 (m, 2H), 2.60 - 2.54 (m, 3H), 2.54 - 2.46 (m, 3H), 1.28 - 1.21 (m, 2H), 1.20 - 1.11 (m, 2H).4-[3-(3-azabicyclo[3.1.0]hexan-6-yl)-l-cyclopropyl-7-fluoro-4-(l- methyIcyclopropyl)pyrazoIo[4,3-c]pyridin-6-yl]-6-methyl-5-(trifluoromethyl)pyridin-2- amineStep 1 tert-butyl 6-[6-chloro-l-cyclopropyl-7-fluoro-4-(l-methylcyclopropyl)pyrazolo[4,3- c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate

[0328] To a solution of tert-butyl 6-(4-bromo-6-chloro-l-cyclopropyl-7-fluoro- pyrazolo[4,3-c]pyridin-3-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (200 mg, 423.95 pmol, 1 eq) in dioxane (4 mL) and H2O (0.4 mL) were added 4,4,5,5-tetramethyl-2-(l- methylcyclopropyl)-l,3,2-dioxaborolane (77.19 mg, 423.95 pmol, 1 eq), CS2CO3 (414.40 mg, 1.27 mmol, 3 eq) and Pd(dppf)C12 (31.02 mg, 42.40 pmol, 0.1 eq) under N2. The mixture was stirred at 100 °C for 16 hr. LCMS showed 12% of tert-butyl 6-(4-bromo-6-chloro-l- cyclopropyl-7-fluoro-pyrazolo[4,3-c]pyridin-3-yl)-3-azabicyclo[3.1 .0]hexane-3-carboxylate remained and a peak (46%) with desired mass. The mixture was diluted with water (10 mL), the mixture was extracted with ethyl acetate (10 mL x 3), and the organic layer was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography ( 20 g SepaFlash® Silica Flash Column, Eluent of 0-50% Ethyl acetate / Petroleum ether gradient @ 100 mL / min) to afford tert-butyl 6-[6-chloro-l- cyclopropyl-7-fluoro-4-(l-methylcyclopropyl)pyrazolo[4,3-c]pyridin-3-yl]-3- azabicyclo[3.1.0]hexane-3-carboxylate (80 mg, 178.99 pmol, 42.22% yield, 100% purity) as colourless oil.

[0329] MS(ES+) C23H28N4FCIO2 requires: 446 and 448, found 447 and 449.Step 2 tert-butyl 6-[6-[6-amino-2-methyl-3-(trifluoromethyl)-4-pyridyl]-l-cyclopropyl-7- fluoro-4-(l-methyIcyclopropyl)pyrazoIo[4,3-c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-3- carboxylateBoc

[0330] To a solution of tert-butyl 6-[6-chloro-l-cyclopropyl-7-fluoro-4-(l- methylcyclopropyl)pyrazolo[4,3-c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate (30 mg, 67.12 pmol, 1 eq) in THF (1.5 mL) were added 6-methyL4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-5-(trifluoromethyl)pyridin-2-amine (40.56 mg, 134.24 ymol, 2 eq) , K3PO4 (1.5 M, 134.24 pL, 3 eq) and CataCXium A Pd G3 (4.89 mg, 6.71 pmol, 0.1 eq) under N2, the mixture was stirred at 60 °C for 16 h. LCMS showed tert-butyl 6-[6-chloro-l- cyclopropyl-7-fluoro-4-(l-methylcyclopropyl)pyrazolo[4,3-c]pyridin-3-yl]-3- azabicyclo[3.1.0]hexane-3-carboxylate was consumed completely and a peak (23%) with desired mass. The mixture was diluted with water (10 mL), the mixture was extracted with ethyl acetate (10 mL x 3), and the organic layers were concentrated under reduced pressure. The residue was purified by prep-TLC (Petroleum ether: Ethyl acetate=l:l) to afford tertbutyl 6-[6-[6-amino-2-methyl-3-(trifluoromethyl)-4-pyridyl]-l-cyclopropyl-7-fluoro-4-(l- methylcyclopropyl)pyrazolo[4,3-c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate (20 mg, 34.09 (imol, 50.79% yield) as colourless oil.

[0331] MS(ES+) C30H34N6F4O2 requires: 586, found 587.Step 34-[3-(3-azabicycIo[3.1.0]hexan-6-yl)-l-cyclopropyl-7-fluoro-4-(l- methylcyclopropyl)pyrazolo[4,3-c]pyridin-6-yI]-6-inethyl-5-(trifluoromethyl)pyridin-2- amine

[0332] To a solution of tert-butyl 6-[6-[6-amino-2-methyl-3-(trifluoromethyl)-4-pyridyl]- l-cyclopropyl-7-fhioro-4-(l-methylcyclopropyl)pyrazolo[4,3-c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate (20 mg, 34.09 pmol, 1 eq) in DCM (0.5 mb) was added TFA (388.74 mg, 3.41 mmol, 253.25 pL, 100 eq), the mixture was stirred at 25 °C for 20 min. LCMS showed tert-butyl 6-[6-[6-amino-2-methyl-3-(trifluoromethyl)-4-pyridyl]-l- cyclopropyl-7-fluoro-4-(l-methylcyclopropyl)pyrazolo[4,3-c]pyridin-3-yl]-3- azabicyclo[3.1.0]hexane-3-carboxylate was consumed completely and a peak (100%) with desired mass. The mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Welch Xtimate C18 150*25mm*5um;mobile phase: [water(FA)-ACN];gradient:8%-38% B over 10 min), the eluent was lyophilized under reduced pressure to afford 4-[3-(3-azabicyclo[3.1.0]hexan-6-yl)-l-cyclopropyl-7-fluoro-4-(l- methylcyclopropyl)pyrazolo[4,3-c]pyridin-6-yl]-6-methyl-5-(trifluoromethyl)pyridin-2- amine (3.6 mg, 6.62 pmol, 19.43% yield, 98% purity, FA) as white solid.

[0333] MS(ES+) C25H26N6F4 requires: 486, found 487[M+H]+.

[0334] 1H NMR (400 MHz, CD3OD) 5 = 8.52 (s, 0.5H),6.39 (s, 1H), 3.92 -3.82 (m, 1H), 3.59 - 3.47 (m, 4H), 2.64 (t, J = 3.5 Hz, 1H), 2.56 (d, J = 2.1 Hz, 3H), 2.54 - 2.47 (m, 2H), 1.55 (s, 3H), 1.28 - 1.20 (m, 2H), 1.17 - 1.07 (m, 4H), 1.02 - 0.92 (m, 2H).EXAMPLE 664-[3-(3-azabicyclo[3.1.0]hexan-6-yl)-l-cyclopropyl-7-fluoro-4-isobutyl-pyrazolo[4,3- c]pyridin-6-yl]-6-methyl-5-(trifluoromethyl)pyridin-2-amineStep 1 tert-butyl 6-(6-chloro-l-cydopropyl-7-fluoro-4-isobutyI-pyrazolo[4,3-c]pyridin-3-yl)-3- azabicyclo[3.1.0]hexane-3-carboxyIate

[0335] A mixture of tert-butyl 6-(4-bromo-6-chloro-l-cyclopropyl-7-fluoro-pyrazolo[4,3- c]pyridin-3-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (200 mg, 423.95 pmol, 1 eq), 1- iodo-2-methyl-propane (156.03 mg, 847.91 pmol, 97.58 pL, 2 eq), Ir[dF (CF3) ppy]2 (dtbpy) (PF6) (4.76 mg, 4.24 pmol, 0.01 eq), NiCh’dtbpy (843.66 pg, 2.12 pmol, 0.005 eq), TTMSS (105.42 mg, 423.95 pmol, 130.79 pL, 1 eq) and Na2C0a (89.87 mg, 847.91 pmol, 2 eq) in DME (8 mL) was degassed and purged with N2, and then the mixture was stirred at 25 °C for 16 h irradiated with a 455nm blue LED. TLC (Petroleum ether: Ethyl acetate= 5: 1) showed tert-butyl 6-(4-bromo-6-chloro-l-cyclopropyl-7-fluoro-pyrazolo[4,3-c]pyridin-3-yl)-3- azabicyclo[3.1.0]hexane-3-carboxylate was consumed completely and a new spot with lower polarity. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (10 g SepaFlash® Silica Flash Column, Eluent of 0-15% Ethyl acetate / Petroleum ether gradient @ 100 mL / min) to afford tert-butyl 6-(6-chloro-l-cyclopropyl-7-fluoro-4-isobutyl-pyrazolo[4,3-c]pyridin-3-yl)-3- azabicyclo[3.1.0]hexane-3-carboxylate (160 mg, 356.38 pmol, 84.06% yield) as a colourless oil.

[0336] MS (ES+) C23H30N4FCIO2 requires: 448 found 448 [M+H]+.Step 2 4-[3-(3-azabicyclo[3.1.0]hexan-6-yl)-l-cyclopropyl-7-fluoro-4-isobutyl-pyrazolo[4,3- c]pyridin-6-yl]-6-methyl-5-(trifluoromethyl)pyridin-2-amine

[0337] Prepared from tert-butyl 6-(6-chloro-l-cyclopropyl-7-fluoro-4-isobutyl- pyrazolo[4,3-c]pyridin-3-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate similarly to Example 65.

[0338] MS (ES+) C25H28F4N6 requires: 488, found 489.

[0339] ’H NMR (400 MHz, CD3OD) 5 = 6.37 (s, 1H), 3.92 - 3.79 (m, 1H), 3.62 - 3.48 (m, 4H), 3.15 - 2.97 (m, 2H), 2.56 (d, J= 2.2 Hz, 3H), 2.52 - 2.46 (m, 2H), 2.41 - 2.35 (m, 1H), 2.30 - 2.18 (m, 1H), 1.27 - 1.20 (m, 2H), 1.17 - 1.09 (m, 2H), 0.99 (d, J = 6.6 Hz, 6H).EXAMPLE 67[6-[5-amino-3-fluoro-2-(trifluoromethoxy)phenyl]-3-(3-azabicyclo[3.1.0]hexan-6-yl)-l- cyclopropyl-7-fluoro-4-isopropyl-pyrrolo[3,2-c]pyridin-2-yl]methanolStep 1 tert-butyl 6-[4-bromo-6-chloro-l-cyclopropyl-7-fluoro-2-(tetrahydropyran-2- yloxymethyl)pyrrolo[3,2-c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate

[0340] Tert-butyl 6-[6-chloro-l-cyclopropyl-7-fluoro-2-(tetrahydropyran-2- yloxymethyl)pyrrolo[3,2-c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate was prepared as described in WO 2024 / 215862 A2.

[0341] To a solution of tert-butyl 6-[6-chloro-l-cyclopropyl-7-fluoro-2-(tetrahydropyran- 2-yloxymethyl)pyrrolo[3,2-c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate (1.3 g, 2.57 mmol, 1 eq) in THF (2 mL) was added lithium; chloro-(2, 2,6, 6-tetramethyl-l-piperidyl)magnesium;chloride (1 M, 12.85 mL, 5 eq) at 0 °C under N2. The mixture was stirred at 0 °C for 1 h under N2. The 1 ,2-dibromo- 1 , 1 ,2,2-tetrachloro-ethane (4.18 g, 12.85 mmol, 1.54 mL, 5 eq in THF (5 mL) was added to the mixture at 0 °C under N2. The resulting mixture was stirred at 0 °C for 1 h under N2. LCMS showed the tert-butyl 6-[6- chloro-l-cyclopropyl-7-fluoro-2-(tetrahydropyran-2-yloxymethyl)pyrrolo[3,2-c]pyridin-3- yl]-3-azabicyclo[3.1.0]hexane-3 -carboxylate was still remained and a peak (20%) with the desired mass. The mixture was quenched by sat. aq. NH4CI (50 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phase was dried with anhydrous Na3SO4, filtered and concentrated in vacuum. The residue was purified by flash silica gel chromatography (40 g SepaFlash® Silica Flash Column, Eluent of 5-25% Ethyl acetate / Petroleum ether gradient @ 100 mL / min) to afford tert-butyl 6-[4-bromo-6-chloro-l-cyclopropyl-7-fluoro-2- (tetrahydropyran-2-yloxymethyl)pyrrolo[3,2-c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-3- carboxylate (290 mg, 456.14 pmol, 17.75% yield, 92% purity) as yellow solid.

[0342] MS (ES+) C26H32N3FClBrO4 requires: 583, found: 584 [M+H]+.Step 2 tert-butyl 6-[6-chloro-l-cydopropyl-7-fluoro-4-isopropyl-2-(tetrahydropyran-2- yloxymethyl)pyrrolo[3,2-c]pyridin-3-yl]-3-azabicydo[3.1.0]hexane-3-carboxylate

[0343] To a solution of tert-butyl 6-[4-bromo-6-chloro-l-cyclopropyl-7-fluoro-2- (tetrahydropyran-2-yloxymethyl)pyrrolo[3,2-c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-3- carboxylate (250 mg, 427.42 pmol, 1 eq), 2-iodopropane (290.63 mg, 1.71 mmol, 170.66 pL, 4 eq) and bis(trimethylsilyl)silyl-trimethyl-silane (106.28 mg, 427.42 pmol, 131.86 pL, 1 eq), Na3CO3(90.60 mg, 854.84 pmol, 2 eq) in DME (5 mL) were added bis[3,5-difluoro-2-[5- (trifluoromethyl)-2-pyridyl]phenyl]iridium(l-i-);4-tert-butyl-2-(4-tert-butyl-2- pyridyl)pyridine;hexafluorophosphate (4.80 mg, 4.27 pmol, 0.01 eq) and 4-tert-butyl-2-(4- tert-butyl-2-pyridyl)pyridine;dichloronickel (850.56 pg, 2.14 pmol, 0.005 eq) under N2. The mixture was stirred at 25 °C for 16 h under N2 irradiated with a 455nm blue LED. LCMS showed the tert-butyl 6-[4-bromo-6-chloro-l-cyclopropyl-7-fluoro-2-(tetrahydropyran-2-yloxymethyl)pyrrolo[3,2-c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate was consumed completely and a peak (64%) with desired mass. The mixture was filtered and the filtrate was concentrated in vacuum. The residue was purified by prep-TLC (Petroleum ether : Ethyl acetate = 3: 1) to afford tert-butyl 6-[6-chloro-l-cyclopropyl-7-fluoro-4- isopropyl-2-(tetrahydropyran-2-yloxymethy l)pyrrolo [3 ,2-c]pyridin-3 -yl] -3 - azabicyclo[3.1.0]hexane-3-carboxylate (17 mg, 30.09 pmol, 7.04% yield, 97% purity) as colorless oil.

[0344] MS (ES+) C29H39N3FCIO4 requires: 547, found: 548 [M+H]+.Step 3 tert-butyl 6-[6-[5-amino-3-fhioro-2-(trifluoromethoxy)phenyl]-l-cydopropyl-7-fluoro-4- isopropyI-2-(tetrahydropyran-2-yloxymethyl)pyrrolo[3,2-c]pyridin-3-yI]-3- azabicyclo[3.1.0]hexane-3-carboxylate

[0345] To a solution of tert-butyl 6-[6-chloro-l-cyclopropyl-7-fluoro-4-isopropyl-2- (tetrahydropyran-2-yloxymethyl)pyrrolo[3,2-c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-3- carboxylate (17 mg, 31.02 pmol. 1 eq), 3-fluoro-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)-4-(trifluoromethoxy)aniline (12.95 mg, 40.32 pmol, 1.3 eq) and K3PO4 (1.5 M, 62.03 pL, 3 eq) in THF (1 mL) was added AdinBuP Pd G3(cataCXium® A Pd G3 ) (2.26 mg, 3.10 pmol, 0.1 eq) under N2, the mixture was stirred at 60 °C for 16 h under N2. LCMS showed the tert-butyl 6-[6-chloro-l-cyclopropyl-7-fluoro-4-isopropyl-2-(tetrahydropyran-2- yloxymethyl)pyrrolo[3,2-c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate was still remained and a peak (28 %) with the desired mass. The mixture was diluted with water (2 mL) and extracted with ethyl acetate (2 mL x 3). The combined organic phase was dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by prep- TLC (SiO2, Dichloromethane : Methanol = 10: 1) to afford tert-butyl 6-[6-[5-amino-3-fluoro- 2-(trifluoromethoxy)phenyl]-l-cyclopropyl-7-fluoro-4-isopropyl-2-(tetrahydropyran-2-yloxymethyl)pyrrolo[3,2-c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate (16 mg, 7.47 pmol, 24.09% yield, 33% purity) as white solid.

[0346] MS (ES+) C36H43N4F5O5 requires: 706, found: 707 [M+H]+.Step 4[6-[5-amino-3-fluoro-2-(trifluoromethoxy)phenyl]-3-(3-azabicyclo[3.1.0]hexan-6-yI)-l- cydopropyl-7-fluoro-4-isopropyl-pyrrolo[3,2-c]pyridin-2-yl]methanol

[0347] To a solution of tert-butyl 6-[6-[5-amino-3-fluoro-2-(trifluoromethoxy)phenyl]-l- cyclopropyl-7-fhioro-4-isopropyl-2-(tetrahydropyran-2-yloxymethyl)pyrrolo[3,2-c]pyridin-3- yl] -3 -azabi cyclo [3.1.0]hexane-3 -carboxylate (16 mg, 22.64 pmol, 1 eq) in DCM (0.6 mL) as added TFA (460.50 mg, 4.04 mmol, 0.3 mL) at 20 °C. The mixture was stirred at 20 °C for 10 min. LCMS showed the starting material was consumed completely and a peak (53%) with desired mass. The mixture was concentrated in vacuum. The residue was purified by prep-HPLC(column: Phenomenex luna C18 150*25mm* 10um;mobile phase: [water(FA)- ACN];gradient:7%-37% B over 10 min) and lyophilized to afford [6-[5-amino-3-fluoro-2- (trifluoromethoxy)phenyl]-3-(3-azabicyclo[3.1.0]hexan-6-yl)-l-cyclopropyl-7-fluoro-4- isopropyl-pyrrolo[3,2-c]pyridin-2-yl]methanol (2.9 mg, 5.10 pmol, 22.53% yield, 100% purity, FA) as yellow solid.

[0348] MS (ES+) C26H27F5N4O2 requires: 522, found: 523 [M+H]+.

[0349] 1H NMR (400 MHz, CD3OD) 5 = 6.66 - 6.56 (m, 2H), 5.00 (s, 2H), 4.12 - 4.01(m, 1H), 3.67 - 3.51 (m, 4H), 3.50 - 3.41 (m, 1H), 2.33 (s, 2H), 2.05 - 1.99 (m, 1H), 1.37 (d, J = 6.7 Hz, 6H), 1.25 - 1.10 (m, 4H).EXAMPLE 683-[2-(aminomethyl)-3-(3-azabicyclo[3.1.0]hexan-6-yl)-l-cyclopropyl-7-fluoro-4- isopropyl-pyrrolo[3,2-c]pyridin-6-yl]-5-fluoro-4-(trifluoromethoxy)aniline Step 1 (6-chIoro-l-cyclopropyl-7-fluoro-3-iodo-pyrrolo[3,2-c]pyridin-2-yI)methanol

[0350] To a solution of 6-chloro-l-cyclopropyL7-fluoro-3-iodo-2-(tetrahydropyran-2- yloxymethyl)pyrrolo[3,2-c]pyridine (27.7 g, 61.46 mmol, 1 eq) in DCM (40 mL) was added TFA (33.48 g, 293.62 mmol, 21.81 mL) at 20 °C. The mixture was stirred at 20°C for 6 h. TLC (Petroleum ether : Ethyl acetate = 4:1) showed the starting material was still remained and two new spots were formed. The mixture was adjusted pH to pH = 9 by sat. aq. NaHCCL. The mixture was extracted with ethyl acetate (200 mL x 3). The combined organic phase was washed with brine (300 mL), dried with anhydrous \Ia2SO4, filtered and concentrated in vacuum. The crude product was triturated with (Petroleum ether : Ethyl acetate = 3: 1, 40 mL) at 20 C for 10 min. The mixture was filtered and the filtered cake was dried under vacuum to afford (6-chloro-l-cyclopropyl-7-fluoro-3-iodo-pyrrolo[3,2-c]pyridin-2-yl)methanol (10.1 g, 25.62 mmol, 41.69% yield, 93% purity) as white solid.

[0351] MS (ES+) C11H9N2CIFIO requires: 366, found: 367 [M+H]+.|0352| 1H NMR (400 MHz, CDCh) 5 = 8.23 (s, 1H), 5.08 - 4.90 (m, 2H), 3.59 - 3.42 (m, 1H), 1.32 - 1.22 (m, 4H).Step 2 tert-butyl-[(6-chloro-l-cyclopropyl-7-fhioro-3-iodo-pyrrolo[3,2-c]pyridin-2- yl)methoxy] -dimethyl-silane

[0353] To a solution of (6-chloro-l-cyclopropyl-7-fluoro-3-iodo-pyrrolo[3,2-c]pyridin-2- yl)methanol (10.1 g, 27.55 mmol, 1 eq) in DCM (100 mL) were added IMIDAZOLE (3.75 g, 55.11 mmol, 2 eq), DMAP (673.25 mg, 5.51 mmol, 0.2 eq) and TBSC1 (4.98 g, 33.06 mmol, 4.07 mL, 1.2 eq) at 20 °C. The mixture was stirred at 20 °C for 16h. LCMS showed the starting material was consumed completely and one main peak with desired mass. The mixture was concentrated in vacuum. The residue was purified by flash silica gel chromatography (80 g SepaFlash® Silica Flash Column, Eluent of 0~9% Ethyl acetate / Petroleum ether gradient @ 100 mL / min) to afford tert-butyl- [(6-chloro-l- cyclopropyl-7-fluoro-3-iodo-pyrrolo[3,2-c]pyridin-2-yl)methoxy]-dimethyl-silane (10.7 g, 22.25 mmol, 80.77% yield, 100% purity) as white solid.

[0354] MS (ES+) Ci7H23N2ClFIOSi requires: 480, found: 481 [M+H]+.

[0355] 1H NMR (400 MHz, CDCh) 8 = 8.24 (s, 1H), 4.93 (s, 2H), 3.55 - 3.41 (m, 1H),1.26 - 1.19 (m, 4H), 0.96 - 0.89 (m, 9H), 0.19 - 0.14 (m, 6H).Step 3 tert-butyl 6-[2-[[tert-butyl(dimethyl)silyl]oxymethyI]-6-chloro-l-cyclopropyl-7-fluoro- pyrrolo[3,2-c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate|0356| To a solution of tert-butyl-|(6-chloro-l-cyclopropyl-7-fluoro-3-iodo-pyrrolo| 3,2- c]pyridin-2-yl)methoxy]-dimethyl-silane (11.8 g, 24.54 mmol, 1 eq), tert-butyl 6-(4, 4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (9.44 g, 30.53 mmol, 1.24 eq) and K3PO4 (1.5 M, 49.08 mL, 3 eq) in Dioxane (245 mL) was added Ad2nBuP Pd G3(cataCXium® A Pd G3 ) (1.79 g, 2.45 mmol, 0.1 eq) at 25 °C under N2. The mixture was stirred at 100 °C for 16 h under N2. LCMS showed the starting material was consumed completely and a peak (49%) with desired mass. The mixture was diluted withethyl acetate (100 mL) and the aqueous phase was extracted with ethyl acetate (20 mL x 3). The combined organic phase was dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by flash silica gel chromatography (120 g SepaFlash® Silica Flash Column, Eluent of 1~11% Ethyl acetate / Petroleum ether gradient @ 200 mL / min) to afford tert-butyl 6-[2-[[tert-butyl(dimethyl)silyl]oxymethyl]-6-chloro-l- cyclopropyl-7-fluoro-pyrrolo[3,2-c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate (6.5 g, 11.27 mmol, 45.94% yield, 93% purity) as yellow solid.

[0357] MS (ES+) C27H39N3FC103Si requires: 535, found: 536 [M+H]+.Step 4 tert-butyl 6-[4-bromo-2-[[tert-butyl(dimethyl)silyl]oxymethyl]-6-chloro-l-cyclopropyl- 7-fluoro-pyrrolo[3,2-c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate

[0358] To a solution of lithium;chloro-(2,2,6,6-tetramethyl-l- piperidyl)magnesium;chloride (1 M, 109.67 mL, 7 eq) was added tert-butyl 6-[2-[[tert- butyl(dimethyl)silyl]oxymethyl]-6-chloro-l-cyclopropyl-7-fluoro-pyrrolo[3,2-c]pyridin-3- yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate (8.4 g, 15.67 mmol, 1 eq) in THF (20 mL) at 0 °C under N2. The mixture was stirred at 0 °C for 1 h under N2. The l,2-dibromo-l,l,2,2- tetrachloro-ethane (25.51 g, 78.34 mmol, 9.40 mL, 5 eq) in THF (20 mL) was added to the mixture at 0 °C under N2. The resulting mixture was stirred at 0 °C for 1 h under N2. LCMS showed the tert-butyl 6-[2-[[tert-butyl(dimethyl)silyl]oxymethyl]-6-chloro-l-cyclopropyl-7- fluoro-pyrrolo[3,2-c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate was still remained and a peak (27%) with desired mass. The mixture was quenched by sat.aq.NH4Q (200 mL) at 0 °C. The mixture was extracted with ethyl acetate (200 mL x 3). The combined organic phase was washed with brine (200 mL), dried with anhydrous Na SO4, filtered and concentrated in vacuum. The residue was purified by flash silica gel chromatography (120 g SepaFlash® Silica Flash Column, Eluent of 0~5~9% Ethyl acetate / Petroleum ether gradient @ 150 mL / min) to afford tert-butyl 6-[4-bromo-2-[[tert-butyl(dimethyl)silyl]oxymethyl]-6-chloro-l-cyclopropyl-7-fluoro-pyrrolo[3,2-c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-3- carboxylate (4.1 g, 6.33 mmol, 40.42% yield, 95% purity) as yellow solid.

[0359] MS (ES+) C27H3sN3FClBrOrSi requires: 613, found: 615 [M+H]+.

[0360] 1H NMR (400 MHz, CDC13) 8 = 4.91 (d, J = 4.4 Hz, 2H), 3.98 - 3.77 (m, 2H), 3.59 - 3.46 (m, 2H), 3.41 - 3.28 (m, 1H), 2.03 - 1.86 (m, 2H), 1.48 (s, 9H), 1.32 - 1.07 (m, 7H), 0.93 (s, 9H), 0.19 (s, 6H).Step 5 tert-butyl 6-[2-[[tert-butyl(dimethyl)silyl]oxymethyI]-6-chloro-l-cycIopropyl-7-fluoro-4- isopropenyl-pyrrolo[3,2-c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate

[0361] To a solution of tert-butyl 6-[4-bromo-2-[[tert-butyl(dimethyl)silyl]oxymethyl]-6- chloro-l-cyclopropyl-7-fluoro-pyrrolo[3,2-c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-3- carboxylate (4.1 g, 6.67 mmol, 1 eq), potassium;trifluoro(isopropenyl)boranuide (1.18 g, 8.00 mmol, 1.2 eq) and K3PO4 (1.5 M, 13.33 mL, 3 eq) in THF (130 mL) was added Pd(dppf)C12.CH2C12 (544.38 mg, 666.61 pmol, 0.1 eq) under N2. The mixture was stirred at 60 °C for 16 h under N2. LCMS showed the starting material was consumed completely and a peak (76%) with the desired mass. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 2). The combined organic phase was dried with anhydrous Na2SC>4, filtered and concentrated in vacuum. The residue was purified by flash silica gel chromatography (40 g SepaFlash® Silica Flash Column, Eluent of 0-9% Ethyl acetate / Petroleum ether gradient @ 100 mL / min) to afford tert-butyl 6- [2- [[tert- butyl(dimethyl)silyl]oxymethyl]-6-chloro-l-cyclopropyl-7-fluoro-4-isopropenyl-pyrrolo[3,2- c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate (3.3 g, 5.27 mmol, 79.04% yield, 92% purity) as yellow solid.

[0362] MS (ES+) C3oH43N3FC103Si requires: 575, found: 576 [M+H]+.

[0363] 1H NMR (400 MHz, CDCI3) 6 = 5.54 - 5.45 (m, 1H), 5.00 - 4.88 (m, 3H), 3.84 - 3.62 (m, 2H), 3.50 - 3.32 (m, 3H), 2.27 (s, 2H), 1.59 (s, 3H), 1.52 - 1.45 (m, 9H), 1.28 - 1.11 (m, 5H), 0.93 (s, 9H), 0.19 (s, 6H).Step 6 tert-butyl 6-[6-[5-amino-3-fluoro-2-(trifluoromethoxy)phenyl]-2-[[tert- butyl(dimethyl)silyl]oxymethyl]-l-cyclopropyl-7-fluoro-4-isopropenyl-pyrrolo[3,2- c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate

[0364] To a solution of tert-butyl 6-[2-[[tert-butyl(dimethyl)silyl]oxymethyl]-6-chloro-l- cyclopropyl-7-fluoro-4-isopropenyl-pyrrolo[3,2-c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-3- carboxylate (3.3 g, 5.73 mmol, 1 eq), 3-fluoro-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)-4-(trilluoromethoxy)aniline (2.39 g, 7.45 mmol, 1.3 eq) and K3PO4 (1.5 M, 11.45 mL, 3 eq) in THF (55 mL) was added Ad2nBuP Pd Gs(cataCXium® A Pd G3 ) (417.08 mg, 572.70 pmol, 0.1 eq) under N2. The mixture was stirred at 60 °C for 16 h under N2. LCMS showed the starting material was consumed completely and a peak (53%) with the desired mass. The mixture was diluted with water (5 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phase was dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by flash silica gel chromatography (80 g SepaFlash® Silica Flash Column, Eluent of 0~16~25% Ethyl acetate / Petroleum ether gradient @ 200 mL / min) to afford tert-butyl 6-[6-[5-amino-3-fluoro-2-(trifluoromethoxy)phenyl]-2-[[tert- butyl(dimethyl)silyl]oxymethyl]-l-cyclopropyl-7-fluoro-4-isopropenyl-pyrrolo[3,2-c]pyridin- 3-yl|-3-azabicyclo|3.1.0|hexane-3-carboxylate (3.3 g, 4.31 mmol,yield, 96% purity) as yellow oil.

[0365] MS (ES+) C37H47N4F5O4Si requires: 734, found: 735 [M+H]+.Step 3 tert-butyl 6-[6-[5-(tert-butoxycarbonyIamino)-3-fluoro-2-(trifluoromethoxy)phenyl]-2- [[tert-butyl(diiuethyl)silyl]oxymethyl]-l-cyclopropyl-7-fluoro-4-isopropyl-pyrrolo[3,2- c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate

[0366] To a solution of Pd / C (330.00 mg, 310.09 pmol, 10% purity) and Pd(OH)2 (330.00 mg, 469.97 pmol, 20% purity) in EtOH (30 mL) was added tert-butyl 6-[6-[5-amino- 3-fluoro-2-(trifluoromethoxy)phenyl]-2-[[tert-butyl(dimethyl)silyl]oxymethyl]-l- cyclopropyl-7-fluoro-4-isopropenyl-pyrrolo[3,2-c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-3- carboxylate (3.3 g, 4.49 mmol, 1 eq) and BOC2O (2.16 g, 9.88 mmol, 2.27 mL, 2.2 eq) in EtOH (10 mL) under N2. The suspension was degassed under vacuum and purged with H2 (50Psi) several times. The mixture was stirred under H2 (50 psi) at 25 °C for 32 hours. LCMS showed the starting material was consumed completely and a peak (62%) with desired mass. The mixture was filtered through celite and the filtrate was concentrated in vacuum. The residue was purified by flash silica gel chromatography (40 g SepaFlash® Silica Flash Column, Eluent of 0~9% Ethyl acetate / Petroleum ether gradient @ 100 mL / min) to afford tert-butyl 6-[6-[5-(tert-butoxycarbonylamino)-3-fluoro-2-(trifluoromethoxy)phenyl]-2-[[tert- butyl(dimethyl)silyl]oxymethyl]-l-cyclopropyl-7-fluoro-4-isopropyl-pyrrolo[3,2-c]pyridin-3- yl] -3 -azabicyclo [3.1.0]hexane-3 -carboxylate (2.2 g, 2.05 mmol, 45.65% yield, 78% purity)as colorless oil.

[0367] MS (ES+) C42H57N4F5O6Si requires: 836, found: 837 [M+H]+.

[0368] 1H NMR (400 MHz, CDCh) 5 = 7.81 - 7.63 (m, 1H), 7.05 (s, 1H), 6.74 (s, 1H),4.95 (s, 2H), 4.10 - 4.03 (m, 1H), 3.87 (d, J = 10.9 Hz, 1H), 3.74 (d, 7 = 10.9 Hz, 1H), 3.62 - 3.48 (m, 2H), 3.39 - 3.29 (m, 1H), 2.04 - 1.94 (m, 2H), 1.53 (s, 9H), 1.50 (s, 9H), 1.35 (d, J = 6.8 Hz, 6H), 1.21 - 1.09 (m, 4H), 0.95 (s, 9H), 0.21 (s, 6H).Step 7 tert-butyl 6-[6-[5-(tert-butoxycarbonylamino)-3-fluoro-2-(trifluoromethoxy)phenyl]-l- cydopropyl-7-fluoro-2-(hydroxymethyl)-4-isopropyl-pyrrolo[3,2-c]pyridin-3-yl]-3- azabicyclo[3.1.0]hexane-3-carboxyIate

[0369] To a solution of tert-butyl 6-[6-[5-(tert-butoxycarbonylamino)-3-fluoro-2- (trifluoromethoxy)phenyl]-2-[[tert-butyl(dimethyl)silyl]oxymethyl]-l-cyclopropyl-7-fluoro- 4-isopropyl-pyrrolo[3,2-c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate (2.2 g, 2.63 mmol, 1 eq) in THF (10 mL) was added TBAF (1 M, 5.26 mL, 2 eq) at 20 °C. The mixture was stirred at 20 °C for 1 h. TLC (Plate 1 Petroleum ether : Ethyl acetate = 4:1) showed the starting material was consumed completely and a peak (70%) with desired mass. The mixture was quenched by sat.aq.NH4O (50 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phase was dried with anhydrous NazSCU, filtered and concentrated in vacuum. The residue was purified by flash silica gel chromatography (20 g SepaFlash® Silica Flash Column, Eluent of 0-33% Ethyl acetate / Petroleum ether gradient @ 100 mL / min) to afford tert-butyl 6-[6-[5-(tert-butoxycarbonylamino)-3-fluoro-2- (trifluoromethoxy)phenyl]-l-cyclopropyl-7-fluoro-2-(hydroxymethyl)-4-isopropyl- pyrrolo[3,2-c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate (1.7 g, 2.16 mmol, 82.33% yield, 92% purity) as colorless oil.

[0370] MS (ES+) C36H43N4F5O6 requires: 722, found: 723 [M+H]+.Step 8 tert-butyl 6-[6-[5-(tert-butoxycarbonylamino)-3-fluoro-2-(trifluoromethoxy)phenyl]-2- (chloromethyl)-l-cyclopropyl-7-fluoro-4-isopropyl-pyrrolo[3,2-c]pyridin-3-yl]-3- azabicyclo[3.1.0]hexane-3-carboxylate

[0371] To a solution of tert-butyl 6-[6-[5-(tert-butoxycarbonylamino)-3-fluoro-2- (trifluoromethoxy)phenyl]-l-cyclopropyl-7-fluoro-2-(hydroxymethyl)-4-isopropyl- pyrrolo[3,2-c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate (300 mg, 415.09 ymol, 1 eq) in DCM (6 mL) was added DIEA (160.94 mg, 1.25 mmol, 216.90 pL, 3 eq) and ethanesulfonyl chloride (106.74 mg, 830.17 prnol, 78.66 pL, 2 eq) at 0 °C. The mixture was stirred at 0 °C for 0.5 h. TLC (Plate 1 Petroleum ether : Ethyl acetate = 3: 1) showed the starting material was consumed completely and one new spot was formed. The mixture was added water (5 mL) and extracted with Dichloromethane (5 mL x 3). The combined organic phase was washed with brine (10 mL x 2), dried with anhydrous NazSCL, filtered and concentrated in vacuum to afford tert-butyl 6-[6-[5-(tert-butoxycarbonylamino)-3-fluoro-2- (trifluoromethoxy)phenyl]-2-(chloromethyl)-l-cyclopropyl-7-fluoro-4-isopropyl-pyrrolo[3,2- c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate (330 mg, 409.61 pmol, 98.68% yield, 92% purity) as brown solid.

[0372] MS (ES+) C36H42N4F5O5CI requires: 740, found: 741 [M+H]+.Step 9 tert-butyl 6-[2-(aminomethyl)-6-[5-(tert-butoxycarbonylamino)-3-fluoro-2- (trifluoromethoxy)phenyl]-l-cyclopropyl-7-fluoro-4-isopropyl-pyrrolo[3,2-c]pyridin-3- yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate

[0373] To a solution of tert-butyl 6-[6-[5-(tert-butoxycarbonylamino)-3-fluoro-2- (trifhioromethoxy)phenyl]-2-(chloromethyl)-l-cyclopropyl-7-fluoro-4-isopropyl-pyrrolo[3,2- c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate (200 mg, 269.84 pmol, 1 eq) in MeCN (5 mL) was added K2CO3 (111.88 mg, 809.51 pmol. 3 eq) and NH3.H2O (94.57 mg, 809.51 pmol, 103.92 pL, 3 eq). The mixture was stirred at 60 °C for 16 h. LCMS showed the starting material was consumed completely and a peak (38%) with desired mass. The mixture was filtered and the filtrate was concentrated in vacuum. The residue was purified by flash silica gel chromatography (4 g SepaFlash® Silica Flash Column, Eluent of 10-100% Ethyl acetate / Petroleum ether to 20-100% Ethyl acetate : Methanol gradient @ 100 mL / min) to afford tert-butyl 6-[2-(aminomethyl)-6-[5-(tert-butoxycarbonylamino)-3-fluoro-2- (trifhioromethoxy)phenyl]-l-cyclopropyl-7-fluoro-4-isopropyl-pyrrolo[3,2-c]pyridin-3-yl]-3- azabicyclo[3.1.0]hexane-3-carboxylate (130 mg, 136.89 pmol, 50.73% yield, 76% purity) as yellow oil.

[0374] MS (ES+) C36H44N5F5O5 requires: 721, found: 722 [M+H]+.Step 10 3-[2-(aininomethyI)-3-(3-azabicyclo[3.1.0]hexan-6-yl)-l-cyclopropyl-7-fluoro-4- isopropyl-pyrrolo[3,2-c]pyridin-6-yl]-5-fluoro-4-(trifluoromethoxy)aniline

[0375] To a solution of tert-butyl 6-[2-(aminomethyl)-6-[5-(tert-butoxycarbonylamino)- 3-fluoro-2-(trifluoromethoxy)phenyl]-l-cyclopropyl-7-fluoro-4-isopropyl-pyrrolo[3,2- c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate (65 mg, 90.06 pmol, 1 eq) in DCM (0.6 mL) was added TFA (332.74 mg, 2.92 mmol, 0.3 mL) at 25 °C. The mixture was stirred at 25 °C for 10 min. LCMS showed the starting material was consumed completely and one main peak with desired mass. The mixture was concentrated in vacuum. The residue was purified by prep-HPLC(column: Phenomenex luna C 18 150*25mm* 10um;mobile phase: [water(FA)-ACN];gradient:7%-27% B over 10 min) and lyophilized to afford 3-[2- (aminomethyl)-3-(3-azabicyclo[3.1.0]hexan-6-yl)-l-cyclopropyl-7-fluoro-4-isopropyl-pyrrolo[3,2-c]pyridin-6-yl]-5-fluoro-4-(trifluoromethoxy)aniline (9.9 mg, 15.58 pmol, 17.30% yield, 100% purity, TFA) as white solid.

[0376] MS (ES+) C26H28F N5O requires: 521 , found: 522 [M+H]+.

[0377] 1H NMR (400 MHz, CD3OD) 8 = 6.66 - 6.57 (m, 2H), 4.57 - 4.47 (m, 2H), 4.12 - 3.99 (m, 1H), 3.74 - 3.62 (m, 2H), 3.62 - 3.50 (m, 3H), 2.21 (s, 2H), 2.16 - 2.09 (m, 1H), 1.36 (d, J= 6.8 Hz, 6H), 1.33 - 1.27 (m, 2H), 1.12 - 1.04 (m, 2H).EXAMPLE 69N-[[6-[5-amino-3-fluoro-2-(trifluoromethoxy)phenyl]-3-(3-azabicycIo[3.1.0]hexan-6-yI)- l-cyclopropyl-7-fluoro-4-isopropyl-pyrrolo[3,2-c]pyridin-2-yl]methyl]-2-cyano- acetamideStep 1 tert-butyl 6-[6-[5-(tert-butoxycarbonylamino)-3-fluoro-2-(trifluoromethoxy)phenyI]-2-[[(2-cyanoacetyl)amino]methyl]-l-cyclopropyl-7-fluoro-4-isopropyl-pyrrolo[3,2- c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate

[0378] To a solution of tert-butyl 6-[2-(aminomethyl)-6-[5-(tert-butoxycarbonylamino)- 3-fluoro-2-(trifluoromethoxy)phenyl]-l-cyclopropyl-7-fluoro-4-isopropyl-pyrrolo[3,2- c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate (50 mg, 69.28 pmol, 1 eq) and 2- cyanoacetic acid (8.84 mg, 103.91 pmol, 1.5 eq) in DMF (1 mL) were added HATU (39.51mg, 103.91 pmol, 1.5 eq) and DIEA (26.86 mg, 207.83 pmol, 36.20 pL, 3 eq). The mixture was stirred at 20 °C for 16 hours. LCMS showed tert-butyl 6-[2-(aminomethyl)-6-[5-(tert- butoxycarbonylamino)-3-fluoro-2-(trifluoromethoxy)phenyl]-l-cyclopropyl-7-fluoro-4- isopropyl-pyrrolo[3,2-c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate was consumed completely and one main peak (47%) with desired mass. The mixture was added H2O (3 mL) and extracted with ethyl acetate (3 mL x 3). The combined organic phase was washed with brine (10 mL x 3), dried over Na2SO4, filtered and concentrated in vacuum to afford a residue which was purified by prep-TLC (SiCL. Petroleum ether: Ethyl acetate= 1 : 1 ) to afford tert-butyl 6-[6-[5-(tert-butoxycarbonylamino)-3-fluoro-2- (trifhioromethoxy)phenyl]-2-[[(2-cyanoacetyl)amino]methyl]-l-cyclopropyl-7-fluoro-4- isopropyl-pyrrolo[3,2-c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate (30 mg, 38.03 pmol, 54.90% yield) as a yellow oil.

[0379] MS (ES+) C39H45F5N6O6 requires: 788, found: 789 [M+H]+.Step 2 N-[[6-[5-amino-3-fluoro-2-(trifluoromethoxy)phenyl]-3-(3-azabicycIo[3.1.0]hexan-6-yl)- l-cydopropyl-7-fluoro-4-isopropyl-pyrrolo[3,2-c]pyridin-2-yl]methyl]-2-cyano- acetamide

[0380] To a solution of tert-butyl 6-[6-[5-(tert-butoxycarbonylamino)-3-fluoro-2- (trifhioromethoxy)phenyl]-2-[[(2-cyanoacetyl)amino]methyl]-l-cyclopropyl-7-fluoro-4- isopropyl-pyrrolo[3,2-c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate (30 mg, 38.03 pmol, 1 eq) in DCM (1 mL) was added TFA (767.50 mg, 6.73 mmol, 0.5 mL). The mixture was stirred at 25 °C for 10 min. LCMS showed tert-butyl 6-[6-[5-(tert- butoxycarbonylamino)-3-fluoro-2-(trifluoromethoxy)phenyl]-2-[[(2- cyanoacetyl)amino]methyl]-l-cyclopropyl-7-fluoro-4-isopropyl-pyrrolo[3,2-c]pyridin-3-yl]- 3-azabicyclo[3.1.0]hexane-3-carboxylate was consumed completely and 65% of desired compound. The mixture was added NaHCCh (5 mL) and extracted with DCM (5 mL x 3).The combined organic phase was dried over NaiSC , filtered and concentrated in vacuum to afford a residue which was purified by reversed- phase HPLC(column: Phenomenex luna C18 150*25mm* lOum; mobile phase: [H2O(0.225% FA)-ACN]; gradient: 7%-37% B over 10.0 min) and eluent was lyophilized to afford N-[[6-[5-amino-3-fluoro-2- (trifhioromethoxy)phenyl]-3-(3-azabicyclo[3.1.0]hexan-6-yl)-l-cyclopropyl-7-fluoro-4- isopropyl-pyrrolo[3,2-c]pyridin-2-yl]methyl]-2-cyano-acetamide (6.6 mg, 10.30 Limo I, 27.07% yield, 99% purity, FA) as a white solid.

[0381] MS (ES+) C29H29F5N6O2 requires: 588, found: 589 [M+H]+.

[0382] 'H NMR (400 MHz, CD3OD) 5 = 8.49 (s, 0.9 H), 6.66 - 6.57 (m, 2H), 4.92 (s, 2H), 4.13 - 3.99 (m, 1H), 3.73 - 3.64 (m, 2H), 3.63 - 3.53 (m, 2H), 3.51 - 3.34 (m, 3H), 2.26 - 2.16 (m, 2H), 2.07 - 1.98 (m, 1H), 1.36 (d, J= 6.8 Hz, 6H), 1.29 - 1.19 (m, 2H), 1.12 - 1.01 (m, 2H).[6-[5-amino-3-chloro-2-(trifluoromethyl)phenyl]-3-(3-azabicyclo[3.1.0]hexan-6-yl)-l,4- dicydopropyl-7-fluoro-pyrrolo[3,2-c]pyridin-2-yl]methanolStep 1 tert-butyl 6-[2-[[tert-butyl(dimethyl)silyl]oxymethyl]-6-chloro-l,4-dicyclopropyl-7- fluoro-pyrrolo[3,2-c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate

[0383] To a solution of tert-butyl 6-[4-bromo-2-[[tert-butyl(dimethyl)silyl]oxymethyl]-6- chloro-l-cyclopropyl-7-fluoro-pyrrolo[3,2-c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate (300 mg, 487.77 pmol, 1 eq), potassium;cyclopropyl(trifluoro)boranuide (86.61 mg, 585.32 pmol, 1.2 eq), CS2CO3 (476.77 mg, 1.46 mmol, 3 eq) and bis(l-adamantyl)-butyl- phosphane (26.23 mg, 73.16 pmol, 0.15 eq) in toluene (3 mL) and H2O (0.3 mL) was added Pd(OAc)2 (10.95 mg, 48.78 pmol, 0.1 eq) under N2. The mixture was stirred at 80 °C for 16 h under N2. LCMS showed the starting material was consumed completely and a peak (63%) with desired mass. The mixture was diluted with ethyl acetate (20 mL) and dried with anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuum. The residue was purified by flash silica gel chromatography (12 g SepaFlash® Silica Flash Column, Eluent of 0~9% Ethyl acetate / Petroleum ether gradient @ 100 mL / min) to afford tert-butyl 6-[2-[[tert- butyl(dimethyl)silyl]oxymethyl]-6-chloro-l,4-dicyclopropyl-7-fluoro-pyrrolo[3,2-c]pyridin- 3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate (210 mg, 291.56 pmol, 59.77% yield, 80% purity) as yellow solid.

[0384] MS (ES+) C3oH43N3FC103Si requires: 575, found: 576 [M+H]+.Step 2 tert-butyl 6-[6-[5-amino-3-chIoro-2-(trifluoromethyl)phenyl]-2-[[tert- butyl(dimethyI)silyl]oxymethyl]-l,4-dicyclopropyl-7-fluoro-pyrroIo[3,2-c]pyridin-3-yl]- 3-azabicyclo[3.1.0]hexane-3-carboxylate

[0385] To a solution of tert-butyl 6-[2-[[tert-butyl(dimethyl)silyl]oxymethyl]-6-chloro- l,4-dicyclopropyl-7-fluoro-pyrrolo[3,2-c]pyridin-3-yl]-3-azabicyclo[3.L0]hexane-3- carboxylate (100 mg, 173.55 pmol, 1 eq), 3-chloro-5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-4-(trifluoromethyl)aniline (139.50 mg, 433.87 pmol, 2.5 eq) and K3PO4 (1.5 M, 347.09 pL, 3 eq) in THF (1.5 mL) was added Ad2nBuP Pd G3(cataCXium® A Pd G3) (12.64 mg, 17.35 pmol, 0.1 eq) under N2. The mixture was stirred at 60 °C for 16 h under N2. LCMS showed the starting material was consumed completely and a peak (15%) with desired mass. The mixture was added water (2 mL) and extracted with ethyl acetate (2 mL x 3). The combined organic phase was dried with anhydrous Na2SO4, filtered and concentratedin vacuum. The residue was purified by prep-TLC (Petroleum ether : Ethyl acetate - 3:1) to afford tert-butyl 6-[6-[5-amino-3-chloro-2-(trifhioromethyl)phenyl]-2-[[tert- butyl(dimethyl)silyl]oxymethyl]-l,4-dicyclopropyl-7-fluoro-pyrrolo[3,2-c]pyridin-3-yl]-3- azabicyclo[3.1.0]hexane-3-carboxylate (30 mg, 30.19 pmol, 17.40% yield, 74% purity) as yellow solid.

[0386] MS (ES+) C37H47N4F4C103Si requires: 734, found: 735 [M+H]+.Step 3 [6-[5-amino-3-chIoro-2-(trifluoromethyl)phenyl]-3-(3-azabicycIo[3.1.0]hexan-6-yI)-l,4- dicyclopropyl-7-fluoro-pyrrolo[3,2-c]pyridin-2-yl]methanol

[0387] To a solution of tert-butyl 6-[6-[5-amino-3-chloro-2-(trifluoromethyl)phenyl]-2- [[tert-butyl(dimethyl)silyl]oxymethyl]-l,4-dicyclopropyl-7-fluoro-pyrrolo[3,2-c]pyridin-3- yl] -3 -azabicyclo [3.1.0]hexane-3 -carboxylate (30 mg, 40.80 pmol, 1 eq) in DCM (0.5 mL) was added HCl / dioxane (2 M, 1 mL) at 25 °C. The mixture was stirred at 25 °C for 0.5 h. LCMS showed the starting material was consumed completely and a peak (67%) with desired mass. The mixture was adjust pH to pH = 8 by sat. aq. NaHCCL at 0°C.The mixture was extracted with ethyl acetate (5 mL x 3). The combined organic phase was dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by prep- HPLC(column: Phenomenex luna C18 150*25mm* 10um;mobile phase: [water(FA)- ACN] gradient: 10%-40% B over 10 min) and lyophilized to afford [6-[5-amino-3-chloro-2- (trifluoromethyl)phenyl]-3-(3-azabicyclo[3.L0]hexan-6-yl)-l,4-dicyclopropyl-7-fluoro- pyrrolo[3,2-c]pyridin-2-yl]methanol (3 mg, 5.24 pmol, 12.84% yield, 99% purity, FA) as white solid.

[0388] MS (ES+) C26H25C1F4N4O requires: 520, found: 521 [M+H]+.

[0389] 1H NMR (400 MHz, CD3OD) 5 = 6.84 (s, 1H), 6.49 (s, 1H), 5.01 (s, 2H), 3.61 -3.37 (m, 5H), 2.88 - 2.77 (m, 1H), 2.35 - 2.22 (m, 2H), 2.10 - 2.02 (m, 1H), 1.24 - 1.07 (m, 6H), 1.03 - 0.92 (m, 2H).EXAMPLE 713-[6-[5-amino-3-fluoro-2-(trifluoromethoxy)phenyl]-3-(3-azabicydo[3.1.0]hexan-6-yl)- l,4-dicyclopropyl-7-fluoro-pyrrolo[3,2-c]pyridin-2-yl]prop-2-yn-l-olStep 1 tert-butyl 6-[6-chloro-l,4-dicyclopropyl-7-fluoro-2-(hydroxymethyl)pyrrolo[3,2- c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate

[0390] To a solution of tert-butyl 6-[2-[[tert-butyl(dimethyl)silyl]oxymethyl]-6-chloro-1.4-dicyclopropyl-7-fluoro-pyrrolo[3,2-c]pyridin-3-yl]-3-azabicyclo[3. L0]hexane-3- carboxylate (0.884 g, 1.53 mmol, 1 eq) in THF (8 mL) was added TBAF (1 M, 8 mL, 5.21 eq), the mixture was stirred at 25 °C for 1 hour. LCMS showed one main peak with desired mass. To the mixture was added saturated NFLCIQO mL) and extracted with EtOAc (10 mL x 3), the combined organic phase was washed with saturated NH4C1(3O mL x 2), dried over Na2SC>4, filtered and concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography (10 g SepaFlash® Silica Flash Column, Eluent of 0-50% Ethyl acetate / Petroleum ether gradient @ 40 mL / min) to afford tert-butyl 6-[6-chloro-1.4-dicyclopropyl-7-fluoro-2-(hydroxymethyl)pyrrolo[3,2-c]pyridin-3-yl]-3- azabicyclo[3.1.0]hexane-3-carboxylate (0.611 g, 1.32 mmol, 86.21% yield) as a yellow solid.

[0391] MS (ES+) C24H29CIFN3O3 requires: 461 , found: 462 [M+H]+.Step 2 tert-butyl 6-(6-chloro-l,4-dicyclopropyl-7-fluoro-2-formyl-pyrrolo[3,2-c]pyridin-3-yl)-3- azabicyclo[3.1.0]hexane-3-carboxyIate

[0392] To a solution of tert-butyl 6-[6-chloro-l,4-dicyclopropyl-7-fluoro-2- (hydroxymethyl)pyrrolo[3,2-c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate (0.611 g, 1.32 mmol, 1 eq) in DCE (6 mL) was added MnCL (2.30 g, 26.45 mmol, 20 eq), the mixtrue was stirred at 60 °C for 16 hours. LCMS showed main peak with desired mass and tert-butyl 6-[6-chloro-l,4-dicyclopropyl-7-fluoro-2-(hydroxymethyl)pyrrolo[3,2-c]pyridin-3- yl] -3 -azabicyclo [3.1.0]hexane-3 -carboxylate was consumed. The reaction mixture was filtered and concentrated under reduced pressure to give tert-butyl 6-(6-chloro-l,4- dicyclopropyl-7-fluoro-2-formyl-pyrrolo[3,2-c]pyridin-3-yl)-3-azabicyclo[3. 1.0]hexane-3- carboxylate (0.6 g, 1.30 mmol, 98.63% yield) as a yellow solid.

[0393] MS (ES+) C24H27CIFN3O3 requires: 459, found: 460 [M+H]+.Step 3 tert-butyl 6-(6-chloro-l,4-dicyclopropyl-2-ethynyl-7-fluoro-pyrrolo[3,2-c]pyridin-3-yl)- 3-azabicyclo[3.1.0]hexane-3-carboxylate

[0394] To a solution of tert-butyl 6-(6-chloro-l,4-dicyclopropyl-7-fluoro-2-formyl- pyrrolo[3,2-c]pyridin-3-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (0.6 g, 1.30 mmol, 1 eq) in MeOH (6 mL) was added K2CO3 (360.60 mg, 2.61 mmol, 2 eq) and 1-diazo-l- dimethoxyphosphoryl-propan-2-one (300.73 mg, 1.57 mmol, 1.2 eq) at 0 °C, the mixture was stirred at 25 °C for 16 hours. LCMS showed tert-butyl 6-(6-chloro-l,4-dicyclopropyl-7- fluoro-2-formyl-pyrrolo[3,2-c]pyridin-3-yl)-3-azabicyclo[3.L0]hexane-3-carboxylate still remained and one peak with desired mass and reactant was consumed. The reaction mixture was diluted with EtOAc (15 mL), filtered and concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography (5 g SepaFlash® Silica FlashColumn, Eluent of 0-10% Ethyl acetate / Petroleum ether gradient @ 35 mL / min) to afford tert-butyl 6-(6-chloro-l,4-dicyclopropyl-2-ethynyl-7-fluoro-pyrrolo[3,2-c]pyridin-3-yl)-3- azabicyclo[3.1.0]hexane-3-carboxylate (0.3 g, 657.97 pmol, 50.44% yield) as colorless oil.

[0395] MS (ES+) C25H27CIFN3O2 requires: 455, found: 456 [M+H]+.Step 4 tert-butyl 6-[6-chloro-l,4-dicyclopropyl-7-fluoro-2-(3-hydroxyprop-l-ynyl)pyrrolo[3,2- c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylateBoc

[0396] To a solution of tert-hutyl 6-(6-chloro- 1 ,4-dicyclopropyl-2-ethynyl-7-fluoro- pyrrolo[3,2-c]pyridin-3-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (0.1 g, 219.32 pmol, 1 eq) in DMSO (1 mL) were added TEA (1.33 mg, 13.16 pmol, 1.83 pL, 0.06 eq), HCHO (26.34 mg, 438.64 pmol, 24.17 pL, 50% purity, 2 eq) and CS2CO3 (50.02 mg, 153.53 pmol, 0.7 eq) at 0 °C, the mixture was stirred at 25 °C for 16 hours. LCMS showed tert-butyl 6-(6- chloro- 1 ,4-dicyclopropyl-2-ethynyl-7 -fluoro-pyrrolo [3 ,2-c]pyri din-3 -yl) -3 - azabicyclo[3.1.0]hexane-3-carboxylate was consumed and main peak with desired mass. The reaction mixture was diluted with THF(10 mL) and HC1(1N, 10 mL), stirred at 20 °C for 0.5 hour, extracted with EtOAc (10 mL x 3), the combined organic phase was washed with saturated NaHCO3(30 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography (5 g SepaFlash® Silica Flash Column, Eluent of 0-50% Ethyl acetate / Petroleum ether gradient @ 40 mL / min) to afford tert-butyl 6-[6-chloro-l,4-dicyclopropyl-7-tluoro-2-(3-hydroxyprop-l- ynyl)pyrrolo[3,2-c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate (85 mg, 174.91 pmol, 79.75% yield) as yellow oil.

[0397] MS (ES+) C26H29CIFN3O3 requires: 485, found: 486 [M+H]+.Step 5 tert-butyl 6-[6-[5-(tert-butoxycarbonyIamino)-3-fluoro-2-(trifluoromethoxy)phenyl]-l,4- dicyclopropyI-7-fluoro-2-(3-hydroxyprop-l-ynyI)pyrroIo[3,2-c]pyridin-3-yl]-3- azabicyclo[3.1.0]hexane-3-carboxylate

[0398] To a solution of tert-butyl 6-[6-chloro- 1 ,4-dicyclopropyl-7-fluoro-2-(3- hydroxyprop-l-ynyl)pyrrolo[3,2-c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate (0.085 g, 174.91 pmol, 1 eq) and tert-butyl N-[3-fluoro-5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-4-(trifluoromethoxy)phenyl]carbamate (110.50 mg, 262.36 pmol, 1.5 eq) in THF (0.8 mL) were added K PO4 (1.5 M, 349.81 pL, 3 eq) and CataCXium A Pd Gj (12.74 mg, 17.49 pmol, 0.1 eq) under N2. The mixture was stirred at 60 °C for 3 hour. LCMS showed tert-butyl 6-[6-chloro-l,4-dicyclopropyl-7-fluoro-2-(3-hydroxyprop-l- ynyl)pyrrolo[3,2-c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate was consumed and one peak with desired mass. The reaction mixture was diluted with EtOAc (10 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography (5 g SepaFlash® Silica Flash Column, Eluent of 0-50% Ethyl acetate / Petroleum ether gradient @ 50 mL / min) to afford tert-butyl 6-[6-[5- (tert-butoxycarbonylamino)-3-fluoro-2-(trifluoromethoxy)phenyl]-l,4-dicyclopropyl-7- fluoro-2-(3-hydroxyprop-l-ynyl)pyrrolo[3,2-c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-3- carboxylate (0.1 g, 134.27 pmol, 76.77% yield) as yellow oil.

[0399] MS (ES+) C38H41F5N4O requires: 744, found: 745 [M+H]+.Step 6 3-[6-[5-amino-3-fluoro-2-(trifluoromethoxy)phenyl]-3-(3-azabicyclo[3.1.0]hexan-6-yI)- l,4-dicyclopropyI-7-fluoro-pyrrolo[3,2-c]pyridin-2-yl]prop-2-yn-l-oI

[0400] To a solution of tert-butyl 6-[6-[5-(tert-butoxycarbonylamino)-3-fluoro-2- (trifluoromethoxy)phenyl]- 1 ,4-dicyclopropyl-7-fluoro-2-(3-hydroxyprop- 1 -ynyl)pyrrolo[3,2- c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate (100.00 mg, 134.27 pmol, 1 eq) in DCM (1 mL) were added TFA (767.50 mg, 6.73 mmol, 0.5 mL, 50.13 eq), The mixture was stirred at 20 °C for 0.25 hour. LCMS showed tert-butyl (lR,5S)-6-[6-[5-(tert- butoxycarbonylamino)-3-fluoro-2-(trifluoromethoxy)phenyl]-l,4-dicyclopropyl-7-fluoro-2- (3-hydroxyprop-l-ynyl)pyrrolo[3,2-c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate was consumed and main peak with desired mass. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by prep-HPLC (column: Phenomenex Luna C18 150*25mm*10um; mobile phase: [H2O(0.225% FA)-ACN]; gradient: 19%-49% B over 10.0 min), the eluent was freeze dried over to afford 3-[6- [5- amino-3-fluoro-2-(trifluoromethoxy)phenyl]-3-(3-azabicyclo[3.1.0]hexan-6-yl)-l,4- dicyclopropyl-7-fluoro-pyrrolo[3,2-c]pyridin-2-yl]prop-2-yn-l-ol (11.8 mg, 18.38 pmol, 13.69% yield, 92% purity, FA) as a white solid.

[0401] MS (ES+) C28H25F5N4O2 requires: 544, found: 545 [M+H]+.|0402| 'H NMR (400 MHz, CD3OD) 5 = 8.56 (s, 1H), 6.64 - 6.53 (m, 2H), 4.60 (s, 2H), 3.55 - 3.47 (m, 2H), 3.47 - 3.38 (m, 3H), 2.89 - 2.79 (m, 1H), 2.38 (s, 2H), 2.13 - 2.06 (m, 1H), 1.26 - 1.17 (m, 4H), 1.12- 1.08 (m, 2H), 1.07 - 1.00 (m, 2H).EXAMPLE 723-[3-(3-azabicyclo[3.1.0]hexan-6-yl)-l-cyclopropyl-7-fluoro-2-(lH-imidazol-2-yl)-4- isopropyl-pyrrolo[3,2-c]pyridin-6-yl]-5-fluoro-4-(trifluoromethoxy)anilineStep 1 tert-butyl 6-[6-[5-(tert-butoxycarbonylamino)-3-fluoro-2-(trifluoromethoxy)phenyl]-l- cycIopropyl-2-(4,5-dihydro-lH-imidazol-2-yl)-7-fluoro-4-isopropyl-pyrrolo[3,2- c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate

[0403] Ethane- 1 ,2-diamine (83.39 mg, 1.39 mmol, 92.86 pL, 10 eq) was added to a mixture of tert-butyl 6-[6-[5-(tert-butoxycarbonylamino)-3-fluoro-2- (trifluoromethoxy)phenyl]-l-cyclopropyl-7-fluoro-2-formyl-4-isopropyl-pyrrolo[3,2- c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate (100 mg, 138.75 pmol, 1 eq) and 4A MS (50 mg) in t-BuOH (1 mL). The mixture was stirred at 25 °C for 12.5 h under N2 atmosphere. To the mixture was added I2 (35.22 mg, 138.75 pmol, 27.95 pL, 1 eq) and K2CO3 (57.53 mg, 416.25 pmol, 3 eq), the reaction mixture was stirred at 70 °C for 3 h. LCMS showed 10% of desired compound. To the mixture was added saturated Na2SOa (5mL) and extracted with ethyl acetate (5 mL x 3). The combined organic phase was dried over Na2SO4, filtered and concentrated in vacuum to give a residue which was purified by prep-TLC (SiCL, Dichloromethane: Ethyl acetate= 3: 1) to afford tert-butyl 6-[6-[5-(tert- butoxycarbonylamino)-3-fluoro-2-(trifluoromethoxy)phenyl]-l-cyclopropyl-2-(4,5-dihydro- lH-imidazol-2-yl)-7-fluoro-4-isopropyl-pyrrolo[3,2-c]pyridin-3-yl]-3- azabicyclo[3.1.0]hexane-3-carboxylate (60 mg, crude) as a yellow solid.

[0404] MS (ES+) C38H45EN6O5 requires: 760, found: 761 [M+H]+. Step 2 tert-butyl 6-[6-[5-(tert-butoxycarbonylamino)-3-fluoro-2-(trifluoromethoxy)phenyl]-l- cydopropyl-7-fluoro-2-(lH-imidazol-2-yl)-4-isopropyl-pyrrolo[3,2-c]pyridin-3-yl]-3- azabicyclo[3.1.0]hexane-3-carboxyIate

[0405] To a solution of tert-butyl 6-[6-[5-(tert-butoxycarbonylamino)-3-fluoro-2- (trifluoromethoxy)phenyl]-l-cyclopropyl-2-(4,5-dihydro-lH-imidazol-2-yl)-7-fluoro-4- isopropyl-pyrrolo[3,2-c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate (40 mg, 52.58 pmol, 1 eq) and [acetoxy(phenyl)-iodanyl] acetate (25.40 mg, 78.87 pmol, 1.5 eq) in DMSO (0.5 mL) was added K2CO3 (10.90 mg, 78.87 pmol, 1.5 eq). The mixture was stirred at 25 °C for 2 h in darkness. LCMS showed tert-butyl 6-[6-[5-(tert-butoxycarbonylamino)-3-fluoro-2- (trifluoromethoxy)phenyl]-l -cyclopropyl-2-(4,5-dihydro- lH-imidazol-2-yl)-7-fluoro-4- isopropyl-pyrrolo[3,2-c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate was consumed completely and 17% of desired mass. The mixture was quenched by H2O (5 mL) and extracted with ethyl acetate (5 mL x 3). The combined organic phase was washed with saturate N2SO3 (20 mL x 2), dried over NaiSOa, filtered and concentrated in vacuum to give tert-butyl 6-[6-[5-(tert-butoxycarbonylamino)-3-fluoro-2-(trifluoromethoxy)phenyl]-l- cyclopropyl-7-fluoro-2-(lH-imidazol-2-yl)-4-isopropyl-pyrrolo[3,2-c]pyridin-3-yl]-3- azabicyclo[3.1.0]hexane-3-carboxylate (20 mg, 26.36 pmol, 50.13% yield) as a yellow solid.

[0406] MS (ES+) C38H43F5N6O5 requires: 758, found: 759 [M+H]+.Step 3 3-[3-(3-azabicyclo[3.1.0]hexan-6-yl)-l-cyclopropyl-7-fluoro-2-(lH-imidazol-2-yl)-4- isopropyl-pyrrolo[3,2-c]pyridin-6-yl]-5-fluoro-4-(trifluoromethoxy)aniline

[0407] To a solution of tert-butyl 6-[6-[5-(tert-butoxycarbonylamino)-3-fluoro-2- (trifluoromethoxy)phenyl]-l-cyclopropyl-7-fluoro-2-(lH-imidazol-2-yl)-4-isopropyl- pyrrolo[3,2-c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate (20 mg, 26.36 pmol, 1 eq) in DCM (2 mL) was added TFA (1.54 g, 13.46 mmol, 1 mL). The mixture was stirred at 25 °C for 10 min. LCMS showed tert-butyl 6-[6-[5-(tert-butoxycarbonylamino)-3-fluoro-2- (trifluoromethoxy)phenyl]-l-cyclopropyl-7-fluoro-2-(lH-imidazol-2-yl)-4-isopropyl- pyrrolo[3,2-c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate was consumed completely and one main peak (42%) with desired mass. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by reversed-phase HPLC(column: Phenomenex Luna Cl 8 150*25mm*10um; mobile phase: [HzO(0. 1% TFA)- ACN]; gradient:5%-35% B over 15.0 min) to afford crude product. The crude product was purified by reversed-phase HPLC(column: Waters Xbridge C18 150*25mm*5um;mobile phase: [FLOQOmM NFLHCC^-ACN]; gradient: 35%-65% B over 10.0 min) to afford 3-[3- (3-azabicyclo[3.1.0]hexan-6-yl)-l-cyclopropyl-7-fluoro-2-(lH-imidazol-2-yl)-4-isopropyl- pyrrolo[3,2-c]pyridin-6-yl]-5-fluoro-4-(trifluoromethoxy)aniline (1.3 mg, 2.26 pmol, 8.57% yield, 97% purity) as a white solid.

[0408] MS (ES+) CsslWsNeO requires: 558, found: 559 [M+H]+.

[0409] 'H NMR (400 MHz, CD3OD) 5 = 7.46 - 7.20 (m, 2H), 6.72 - 6.55 (m, 2H), 4.39 -4.11 (m, 1H), 3.53 (s, 3H), 3.12 - 2.94 (m, 2H), 2.93 - 2.70 (m, 2H), 1.97 - 1.86 (m, 1H), 1.45 - 1.33 (m, 6H), 0.96 - 0.81 (m, 2H), 0.72 - 0.51 (m, 2H).EXAMPLE 73N-[[6-[5-amino-3-fluoro-2-(trifluoromethoxy)phenyl]-3-(3-azabicyclo[3.1.0]hexan-6-yI)- l-cyclopropyI-7-fluoro-4-isopropyl-pyrrolo[3,2-c]pyridin-2- yl]methyl]methanesulfonamideStep 1tert-butyl 6-[2-(acetamidomethyl)-6-[5-(tert-butoxycarbonylamino)-3-fluoro-2-(trifluoromethoxy)phenyl]-l-cyclopropyl-7-fluoro-4-isopropyl-pyrrolo[3,2-c]pyridin-3- yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate[041 OJ To a solution of tert-butyl 6-[2-(aminomethyl)-6-[5-(tert-butoxycarbonylamino)-3-fluoro-2-(trifluoromethoxy)phenyl]-l-cyclopropyl-7-fluoro-4-isopropyl-pyrrolo[3,2- c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate (65 mg, 90.06 pmol, 1 eq) in DCM (2 mL) was added DIEA (23.28 mg, 180.12 pmol, 31.37 pL, 2 eq) and acetyl chloride (3.53 mg, 45.03 pmol, 3.20 pL, 0.5 eq) at 0 °C. The mixture was stirred at 25 °C for 1 h. LCMS showed the starting material was consumed completely and a peak (76%) with desired mass. The mixture was concentrated in vacuum. The residue was purified by flash silica gel chromatography (4 g SepaFlash® Silica Flash Column, Eluent of 3-75% Ethyl acetate / Petroleum ether gradient @ 100 mL / min) to afford tert-butyl 6-[2-(acetamidomethyl)- 6-[5-(tert-butoxycarbonylamino)-3-fluoro-2-(trifluoromethoxy)phenylJ-l-cyclopropyl-7- fluoro-4-isopropyl-pyrrolo[3,2-c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate (27 mg, 31.81 pmol, 35.33% yield, 90% purity) as colorless oil.

[0411] MS (ES+) C38H46N5F5O6 requires: 763, found: 764 [M+H]+.Step 2 N-[[6-[5-amino-3-fluoro-2-(trifluoromethoxy)phenyl]-3-(3-azabicydo[3.1.0]hexan-6-yl)- l-cycIopropyl-7-fluoro-4-isopropyl-pyrrolo[3,2-c]pyridin-2-yl]methyl]acetamide

[0412] To a solution of tert-butyl 6-[2-(acetamidomethyl)-6-[5-(tert- butoxycarbonylamino)-3-fluoro-2-(trifluoromethoxy)phenyl]-l-cyclopropyl-7-fluoro-4- isopropyl-pyrrolo[3,2-c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate (27 mg, 35.35 pmol, 1 eq) in DCM (0.6 mL) was added TFA (1.21 mg, 10.60 pmol, 0.3 mL) at 25 °C. The mixture was stirred at 25 °C for 10 min. LCMS showed the starting material was consumed completely and one main peak with desired mass. The mixture was concentrated in vacuum. The residue was purified by prep-HPLC(column: Phenomenex luna C18 150*25mm* 10um;mobile phase: [water(FA)-ACN];gradient:7%-38% B over 6 min) and lyophilized to afford N-[[6-[5-amino-3-fluoro-2-(trifluoromethoxy)phenyl]-3-(3-azabicyclo[3.1.0]hexan-6- yl)-l-cyclopropyl-7-fluoro-4-isopropyl-pyrrolo[3,2-c]pyridin-2-yl]methyl]acetamide (11 mg, 18.05 pmol, 51.05% yield, 100% purity, FA) as white solid.

[0413] MS (ES+) C2SH 0F N5O2 requires: 563, found: 564 [M+H]+.

[0414] 1H NMR (400 MHz, CD3OD) 5 = 6.64 - 6.57 (m, 2H), 4.83 (s, 2H), 4.16 - 4.06(m, 1H), 3.55 - 3.48 (m, 2H), 3.47 - 3.36 (m, 3H), 2.10 (s, 2H), 2.00 (s, 3H), 1.97 - 1.92 (m, 1H), 1.36 (d, 7= 6.7 Hz, 6H), 1.27 - 1.19 (m, 2H), 1.08 - 1.02 (m, 2H).Step 3N-[[6-[5-amino-3-fluoro-2-(trifluoromethoxy)phenyl]-3-(3-azabicydo[3.1.0]hexan-6-yl)- l-cydopropyl-7-fluoro-4-isopropyl-pyrrolo[3,2-c]pyridin-2- yl]methyl]methanesulfonamide

[0415] Prepared similarly to Example 73.

[0416] MS (ES+) C27H3OF5N503S requires: 599, found: 600 [M+H]+.

[0417] ’H NMR (400 MHz, CD3OD) 6 = 6.69 - 6.57 (m, 2H), 4.75 (s, 2H), 4.12 - 4.01 (m, 1H), 3.72 - 3.62 (m, 2H), 3.61 - 3.48 (m, 3H), 2.94 (s, 3H), 2.26 (s, 2H), 2.07 - 2.02 (m, 1H), 1.37 (d, 7= 6.8 Hz, 6H), 1.30 - 1.25 (m, 2H), 1.11 - 1.02 (m, 2H).EXAMPLE 743-[3-(3-azabicyclo[3.1.0]hexan-6-yl)-l-cyclopropyl-7-fluoro-4-isopropyl-2-(pyrrolidin-3- yloxymethyl)pyrrolo[3,2-c]pyridin-6-yl]-5-fluoro-4-(trifluoromethoxy)anilineStep 1 tert-butyl 6-[6-[5-(tert-butoxycarbonyIamino)-3-fluoro-2-(trifluoromethoxy)phenyl]-2-[(l-tert-butoxycarbonylpyrrolidin-3-yl)oxymethyI]-l-cycIopropyl-7-fluoro-4-isopropyl- pyrrolo[3,2-c]pyridin-3-yI]-3-azabicycIo[3.1.0]hexane-3-carboxylate

[0418] To a solution of tert-butyl 3-hydroxypyrrolidine-l -carboxylate (15.16 mg, 80.95 pmol, 2 eq) in DMF (0.5 mL) was added NaH (4.05 mg, 101.19 pmol, 60% purity, 2.5 eq) at 0 °C under the protection of N , the mixture was stirred at 0 °C for 10 min, to the mixture was added tert-butyl 6-[6-[5-(tert-butoxycarbonylamino)-3-fluoro-2- (trifluoromethoxy)phenyl]-2-(chloromethyl)-l-cyclopropyl-7-fluoro-4-isopropyl-pyrrolo[3,2- c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate (30.00 mg, 40.48 pmol, 1 eq) the mixture was stirred at 0 °C for 1 hour. LCMS showed tert-butyl (lS,5R)-6-[6-[5-(tert- butoxycarbonylamino)-3-fluoro-2-(trifluoromethoxy)phenyl]-2-(chloromethyl)-l- cyclopropyl-7-fhioro-4-isopropyl-pyrrolo[3,2-c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-3- carboxylate was consumed and main peak with desired mass. To the mixture was added saturated NH4CI (5 mL) and extracted with EtOAc (5 mL x 3), dried over NaiSCL, filtered and concentrated under reduced pressure to give tert-butyl 6-[6-[5-(tert- butoxycarbonylamino)-3-fluoro-2-(trifluoromethoxy)phenyl]-2-[(l-tert-butoxycarbonylpyrrolidin-3 -yl)oxymethyl]- 1 -cyclopropyl-7 -fluoro-4-isopropyl-pyrrolo [3 ,2- c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate (70 mg, crude) as yellow oil.

[0419] MS (ES+) C45H5SF5N5O8 requires: 891 , found: 892 [M+H]+.Step 23-[3-(3-azabicyclo[3.1.0]hexan-6-yl)-l-cyclopropyl-7-fluoro-4-isopropyl-2-(pyrrolidin-3- yloxymethyl)pyrrolo[3,2-c]pyridin-6-yl]-5-fluoro-4-(trifluoromethoxy)aniline

[0420] To a solution of tert-butyl 6-[6-[5-(tert-butoxycarbonylamino)-3-fluoro-2- (trifluoromethoxy)phenyl]-2-[(l-tert-butoxycarbonylpyrrolidin-3-yl)oxymethyl]-l- cyclopropyl-7-fluoro-4-isopropyl-pyrrolo[3,2-c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-3- carboxylate (0.07 g, 78.48 pmol. 1 eq) in DCM (1 mL) was added TFA (767.50 mg, 6.73 mmol, 0.5 mL, 85.77 eq), the mixture was stirred at 20 °C for 15 mins. LCMS showed tertbutyl 6-[6-[5-(tert-butoxycarbonylamino)-3-fluoro-2-(trifluoromethoxy)phenyl]-2-[(l-tert- butoxycarbonylpyrrolidin-3-yl)oxymethyl]-l-cyclopropyl-7-fluoro-4-isopropyl-pyrrolo[3,2- c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate was consumed and main peak with desired mass. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by prep-HPLC (column: Phenomenex Luna C18 150*25mm*10um; mobile phase: [H2O(0.225% FA)-ACN]; gradient:5%-35% B over 10.0 min), the eluent was freeze dried over to afford 3-[3-(3-azabicyclo[3.1.0]hexan-6-yl)-l-cyclopropyl-7-fluoro-4- isopropyl-2-(pyrrolidin-3-yloxymethyl)pyrrolo[3,2-c]pyridin-6-yl]-5-fluoro-4- (trifluoromethoxy) aniline (6 mg, 8.34 pmol, 10.62% yield, 95% purity, 2FA) as a yellow solid.

[0421] MS (ES+) C30H34F N5O2 requires: 591 , found: 592 [M+H]+.

[0422] 'H NMR (400 MHz, CD3OD) 5 = 8.49 (s, 2H), 6.67 - 6.55 (m, 2H), 5.00 - 4.95 (m, 2H), 4.54 - 4.50 (m, 1H), 4.15 - 3.96 (m, 1H), 3.74 - 3.63 (m, 2H), 3.62 - 3.53 (m, 2H), 3.50 - 3.37 (m, 5H), 2.45 - 2.33 (m, 1H), 2.27 - 2.14 (m, 3H), 2.11 - 2.06 (m, 1H), 1.36 (dd, J = 1.3, 6.7 Hz, 6H), 1.26 - 1.20 (m, 2H), 1.14 - 1.06 (m, 2H).EXAMPLE 75N-[[6-[5-amino-3-fluoro-2-(trifluoromethoxy)phenyl]-3-(3-azabicyclo[3.1.0]hexan-6-yI)- l-cyclopropyl-7-fluoro-4-isopropyl-pyrrolo[3,2-c]pyridin-2-yl]methyl]-3-methyl-oxetan-3-amineStep 1 tert-butyl 6-[6-[5-(tert-butoxycarbonyIamino)-3-fluoro-2-(trifluoromethoxy)phenyl]-l- cyclopropyl-7-fluoro-4-isopropyl-2-[[(3-methyloxetan-3-yl)amino]methyl]pyrrolo[3,2- c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate

[0423] To a solution of tert-butyl 6-[6-[5-(tert-butoxycarbonylamino)-3-fluoro-2- (trifhioromethoxy)phenyl]-l-cyclopropyl-7-fluoro-2-formyl-4-isopropyl-pyrrolo[3,2- c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate (80 mg, 111.00 pmol, 1 eq) and 3- methyloxetan-3-amine;hydrochloride (20.58 mg, 166.50 pmol, 1.5 eq) in DCE (2 mL) was added TEA (5.62 mg, 55.50 pmol, 7.72 pL, 0.5 eq). The mixture was stirred at 25 °C for 0.25 hour. AcOH (6.67 mg, 111.00 pmol, 6.35 pL, 1 eq) was added to the mixture. The mixture was stirred at 25 °C for 1 hour. To the mixture was added NaBH(OAc)3 (70.58 mg, 333.00 pmol, 3 eq), the mixture was stirred at 25 °C for 12 hours. LCMS showed tert-butyl 6- [6- [5- (tert-butoxycarbonylamino)-3-fhioro-2-(trifluoromethoxy)phenyl]-l-cyclopropyl-7-fluoro-2- formyl-4-isopropyl-pyrrolo[3,2-c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate wasconsumed completely and one main peak (66%) with desired mass. The mixture was quenched by NaHCCL (5 mL) and extracted with DCM (5 mL x 3). The combined organic phase was dried over Na2SO4, filtered and concentrated in vacuum to afford a residue which was purified by prep-TLC (SiCF, Petroleum ether: Ethyl acetate= 1: 1) to afford tert-butyl 6- [6-[5-(tert-butoxycarbonylamino)-3-fluoro-2-(trifluoromethoxy)phenyl]-l-cyclopropyl-7- fluoro-4-isopropyl-2-[[(3-methyloxetan-3-yl)amino]methyl]pyrrolo[3,2-c]pyridin-3-yl]-3- azabicyclo[3.1.0]hexane-3-carboxylate (60 mg, 75.77 pmol, 68.26% yield) as a white solid.

[0424] MS (ES+) C40H50F5N5O6 requires: 791 , found: 792 [M+H]+.Step 2N-[[6-[5-amino-3-fluoro-2-(trifluoromethoxy)phenyl]-3-(3-azabicydo[3.1.0]hexan-6-yl)- l-cydopropyl-7-fluoro-4-isopropyl-pyrrolo[3,2-c]pyridin-2-yl]methyl]-3-methyl-oxetan- 3-amine

[0425] To a solution of tert-butyl 6-[6-[5-(tert-butoxycarbonylamino)-3-fluoro-2- (trifluoromethoxy)phenyl]-l-cyclopropyl-7-fluoro-4-isopropyl-2-[[(3-methyloxetan-3- yl)amino]methyl]pyrrolo[3,2-c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-3 -carboxylate (60 mg, 75.77 pmol, 1 eq) in DCM (0.5 mL) was added TFA (1.54 g, 13.46 mmol, 1 mL, 177.67 eq). The mixture was stirred at 25 °C for 0.5 hour. LCMS showed tert-butyl 6- [6-[5-(tert- butoxycarbonylamino)-3-fluoro-2-(trifluoromethoxy)phenyl]-l-cyclopropyl-7-fluoro-4- isopropyl-2-[[(3-methyloxetan-3-yl)amino]methyl]pyrrolo[3,2-c]pyridin-3-yl]-3- azabicyclo[3.1.0]hexane-3-carboxylate was consumed completely and one main peak with desired mass. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by prep-HPLC(column: Phenomenex Luna Cl 8 150*25mm*10um; mobile phase: [HzO(0.225% FA)-ACN]; gradient: 6%-36% B over 10.0 min) and eluent was lyophilized to afford N-[[6-[5-amino-3-fluoro-2-(trifluoromethoxy)phenyl]-3-(3- azabicyclo[3.1.0]hexan-6-yl)-l-cyclopropyl-7-fluoro-4-isopropyl-pyrrolo[3,2-c]pyridin-2-yl]methyl]-3-methyl-oxetan-3-amine (16.2 mg, 25.15 pmol. 33.19% yield, 99% purity, FA) as a white solid.

[0426] MS (ES+) C30H 4F5N5O2 requires: 591 , found: 592 [M+H]+.

[0427] 'H NMR (400 MHz, CD3OD) 5 = 6.68 - 6.57 (m, 2H), 4.64 (d, J = 6.4 Hz, 2H), 4.44 (d, J= 6.4 Hz, 2H), 4.18 (s, 2H), 4.12 - 3.99 (m, 1H), 3.63 - 3.55 (m, 3H), 3.53 - 3.46 (m, 2H), 2.25 (s, 2H), 2.06 - 1.97 (m, 1H), 1.62 (s, 3H), 1.36 (d, J = 6.8 Hz, 6H), 1.31 - 1.20 (m, 2H), 1.15 - 1.03 (m, 2H).2-[6-[5-amino-3-fluoro-2-(trifluoromethoxy)phenyl]-3-(3-azabicyclo[3.1.0]hexan-6-yl)-l- cyclopropyl-7-fluoro-4-isopropyl-pyrrolo[3,2-c]pyridin-2-yl]acetonitrileStep 1 tert-butyl 6-[6-[5-(tert-butoxycarbonylamino)-3-fluoro-2-(trifluoromethoxy)phenyl]-2-(cyanomethyl)-l-cyclopropyl-7-fluoro-4-isopropyl-pyrrolo[3,2-c]pyridin-3-yl]-3- azabicyclo[3.1.0]hexane-3-carboxylate

[0428] To a solution of tert-butyl 6-[6-[5-(tert-butoxycarbonylamino)-3-fluoro-2- (trifluoromethoxy)phenyl]-l-cyclopropyl-7-fluoro-2-(hydroxymethyl)-4-isopropyl- pyrrolo[3,2-c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate (0.5 g, 691.81 pmol, 1 eq) and 2-hydroxy-2-methyl-propanenitrile (176.63 mg, 2.08 mmol, 189.52 pL, 3 eq) in THF(10 mL) was added PPI13 (453.63 mg, 1.73 mmol, 2.5 eq) at 25 °C. Then DIAD (349.72 mg, 1.73 mmol, 335.31 pL, 2.5 eq) was added dropwised to the mixture at 25 °C. The resulting mixture was stirred at 25 °C for 3 h. LCMS showed the starting material was consumed completely and a peak (31%) with desired mass. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (5 mL x 3). The combined organic phase was dried with anhydrous N zSCU, filtered and concentrated in vacuum. The residue was purified by flash silica gel chromatography (40 g SepaFlash® Silica Flash Column, Eluent of 0-25-33-50% Ethyl acetate / Petroleum ether gradient @ 50 mL / min) to afford tert-butyl 6-[6-[5-(tert- butoxycarbonylamino)-3-fluoro-2-(trifluoromethoxy)phenyl]-2-(cyanomethyl)-l- cyclopropyl-7-fluoro-4-isopropyl-pyrrolo[3,2-c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-3- carboxylate (240 mg, 295.18 pmol, 42.67% yield, 90% purity) as yellow oil.

[0429] MS (ES+) C37H42N5E5O5 requires: 731 , found: 732 [M+H]+.Step 2 2-[6-[5-amino-3-fluoro-2-(trifluoromethoxy)phenyl]-3-(3-azabicyclo[3.1.0]hexan-6-yl)-l- cydopropyl-7-fluoro-4-isopropyl-pyrrolo[3,2-c]pyridin-2-yl]acetonitrile

[0430] To a solution of tert-butyl 6-[6-[5-(tert-butoxycarbonylamino)-3-fluoro-2- (trifhioromethoxy)phenyl]-2-(cyanomethyl)-l-cyclopropyl-7-fluoro-4-isopropyl-pyrrolo[3,2- c]pyridin-3-yl]-3-azabicyclo[3.1 .0]hexane-3-carboxylate (50 mg, 68.33 pmol, 1 eq) in DCM (0.6 mL) was added TFA (460.50 mg, 4.04 mmol, 0.3 mL) at 25 °C. The mixture was stirred at 25 °C for 10 min. LCMS showed the starting material was consumed completely and a peak (62%) with desired mass. The mixture was adjusted to pH = 8 by sat. aq. NaHCCh at 0 °C. The mixture was extracted with ethyl acetate (5 mL x 3). The combined organic phase was dried with anhydrous NazSCU, filtered and concentrated in vacuum. The residue was purified by prep-HPLC(column: Phenomenex luna C 18 150*25mm* 10um;mobile phase: [water(FA)-ACN] gradient: 16%-36% B over 10 min) and lyophilized to afford 2-[6-[5- amino-3-fluoro-2-(trifluoromethoxy)phenyl]-3-(3-azabicyclo[3.L0]hexan-6-yl)-l-cyclopropyl-7-fluoro-4-isopropyl-pyrrolo[3,2-c]pyridin-2-yl]acetonitrile (6.1 mg, 10.25 pmol, 14.99% yield, 97% purity, FA) as white solid.

[0431] MS (ES+) C27H26F N5O requires: 531, found: 532 [M+H]+.

[0432] 1H NMR (400 MHz, CD3OD) 8 = 8.45 (s, 1H), 6.67 - 6.58 (m, 2H), 4.39 (s, 2H), 4.08 - 3.97 (m, 1H), 3.81 - 3.60 (m, 4H), 3.54 - 3.45 (m, 1H), 2.33 - 2.22 (m, 2H), 2.16 - 2.06 (m, 1H), 1.38 (d, J= 6.7 Hz, 6H), 1.34 - 1.26 (m, 2H), 1.09 - 1.00 (m, 2H).l-[6-[5-amino-3-fluoro-2-(trifluoromethoxy)phenyl]-3-(3-azabicyclo[3.1.0]hexan-6-yl)-l- cyclopropyl-7-fluoro-4-isopropyl-pyrrolo[3,2-c]pyridin-2-yl]-2-methyl-propan-2-olStep 1 tert-butyl 6-[6-[5-(tert-butoxycarbonyIamino)-3-fluoro-2-(trifluoromethoxy)phenyl]-l- cydopropyI-7-fluoro-4-isopropyl-2-(oxiran-2-yl)pyrrolo[3,2-c]pyridin-3-yl]-3- azabicyclo[3.1.0]hexane-3-carboxylate

[0433] To a solution of trimethylsulfonium;iodide (750.35 mg, 3.68 mmol, 5 eq) in DMSO (5.3 mL) was added t-BuOK (412.58 mg, 3.68 mmol, 5 eq) at 0 °C. The mixture was stirred at 20 °C for 0.5 h. tert-butyl 6-[6-[5-(tert-butoxycarbonylamino)-3-fluoro-2- (trifluoromethoxy)phenyl]-l-cyclopropyl-7-fluoro-2-formyl-4-isopropyl-pyrrolo[3,2- c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate (530 mg, 735.37 pmol, 1 eq) inDMSO (7.5 mL) was added to the mixture at 0 °C. The resulting mixture was stirred at 20 °C for 1 h. LCMS showed the starting material was consumed completely and a peak (55%) with desired mass. The mixture was quenched by water (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed with brine (30 mL x 2), dried with anhydrous NazSCL, filtered and concentrated in vacuum. The residue was purified by flash silica gel chromatography (10 g SepaFlash® Silica Flash Column, Eluent of 0-20% Ethyl acetate / Petroleum ether gradient @ 100 mL / min) to afford tert-butyl 6- [6- [5-(tert- butoxycarbonylamino)-3-fluoro-2-(trifluoromethoxy)phenyl]-l -cyclopropyl -7-fluoro-4- isopropyl-2-(oxiran-2-yl)pyrrolo[3,2-c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-3- carboxylate (270 mg, 213.13 pmol, 28.98% yield, 58% purity) as yellow solid.

[0434] MS (ES+) C37H43N4F5O6 requires: 734, found: 735 [M+H]+.Step 2 tert-butyl 6-[6-[5-(tert-butoxycarbonylamino)-3-fluoro-2-(trifluoromethoxy)phenyl]-l- cydopropyl-7-fluoro-2-(2-hydroxyethyl)-4-isopropyl-pyrrolo[3,2-c]pyridin-3-yl]-3- azabicyclo[3.1.0]hexane-3-carboxylate

[0435] To a solution of tert-butyl 6-[6-[5-(tert-butoxycarbonylamino)-3-fluoro-2- (trifluoromethoxy)phenyl]-l-cyclopropyl-7-fluoro-4-isopropyl-2-(oxiran-2-yl)pyrrolo[3,2- c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate (270 mg, 213.13 pmol, 1 eq) in THF (1 mL) were added l-[6-(2,5-dioxopyrrol-l-yl)hexyl]pyrrole-2, 5-dione (22.61 mg, 81.84 pmol, 3.84e-l eq) and diethyloxonio(trifluoro)boranuide (95.93 mg, 189.26 pmol, 83.13 pL, 28% purity) at 20 °C. The mixture was stirred at 20 °C for 1 h. LCMS showed the starting material was consumed completely and a peak (79%) with desired mass. The mixture was quenched by MeOH (5 mL) and stirred at 25 °C for 20 min. The mixture was concentrated in vacuum. The residue was purified by flash silica gel chromatography (4 g SepaFlash® Silica Flash Column, Eluent of 0-33% Ethyl acetate / Petroleum ether gradient @ 100 mL / min) to afford tert-butyl 6-[6-[5-(tert-butoxycarbonylamino)-3-fhioro-2-(trifhioromethoxy)phenyl]-l-cyclopropyl-7-fluoro-2-(2-hydroxyethyl)-4-isopropyl-pyrrolo[3,2-c]pyridin-3-yl]-3- azabicyclo[3.1.0]hexane-3-carboxylate (100 mg, 126.23 pmol, 59.22% yield, 93% purity) as yellow solid.

[0436] MS (ES+) C37H45N4F5O6 requires: 736, found: 737 [M+H]+.Step 3 tert-butyl 6-[6-[5-(tert-butoxycarbonylamino)-3-fluoro-2-(trifluoromethoxy)phenyl]-l- cycIopropyl-7-fluoro-4-isopropyl-2-(2-oxoethyl)pyrrolo[3,2-c]pyridin-3-yI]-3- azabicyclo[3.1.0]hexane-3-carboxylate

[0437] To a solution of tert-butyl 6-[6-[5-(tert-butoxycarbonylamino)-3-fluoro-2- (trifluoromethoxy)phenyl]-l-cyclopropyl-7-fluoro-2-(2-hydroxyethyl)-4-isopropyl- pyrrolo[3,2-c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate (120 mg, 162.87 ymol, 1 eq) in DCM (2 mL) was added DMP (103.62 mg, 244.31 pmol, 75.69 pL, 1.5 eq) at 0 °C. The mixture was stirred at 0 °C for 20 min and 0°C for 20 min. LCMS showed the starting material was consumed completely and a peak (53%) with desired mass. The mixture was diluted with DCM (1 mL) and was purified by flash silica gel chromatography (4 g SepaFlash® Silica Flash Column, Eluent of 2-33% Ethyl acetate / Petroleum ether gradient @ 100 mL / min) to afford tert-butyl 6-[6-[5-(tert-butoxycarbonylamino)-3-fluoro-2- (trifluoromethoxy)phenyl]-l-cyclopropyl-7-fluoro-4-isopropyl-2-(2-oxoethyl)pyrrolo[3,2- c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate (94 mg, 106.19 pmol, 65.20% yield, 83% purity) as yellow solid.

[0438] MS (ES+) C37H43N4F5O6 requires: 734, found: 735 [M+H]+.Step 4 tert-butyl 6-[6-[5-(tert-butoxycarbonylamino)-3-fluoro-2-(trifluoromethoxy)phenyl]-l- cydopropyl-7-fluoro-2-(2-hydroxypropyl)-4-isopropyl-pyrrolo[3,2-c]pyridin-3-yl]-3- azabicyclo[3.1.0]hexane-3-carboxylate

[0439] To a solution of MeMgBr (3 M, 426.45 pL, 10 eq) was added dropwised slowly tert-butyl 6-[6-[5-(tert-butoxycarbonylamino)-3-fluoro-2-(trifluoromethoxy)phenyl]-l- cyclopropyl-7-fluoro-4-isopropyl-2-(2-oxoethyl)pyrrolo[3,2-c]pyridin-3-yl]-3- azabicyclo[3.1.0]hexane-3-carboxylate (94 mg, 127.93 pmol, 1 eq) in THF (2 mL) at 50 °C under N2. The mixture was stirred at 50 °C for 15 min under N2. LCMS showed the starting material was consumed completely and a peak (83%) with desired mass. The mixture was quenched by sat. aq. NH4CI (5 mL) and extracted with ethyl acetate (3 mL x 3). The combined organic phase was washed with brine (5 mL), dried with anhydrous ISfeSCU, filtered and concentrated in vacuum. The residue was purified by flash silica gel chromatography (4 g SepaFlash® Silica Flash Column, Eluent of 2-43% Ethyl acetate / Petroleum ether gradient @ 80 mL / min) to afford tert-butyl 6-[6-[5-(tert- butoxycarbonylamino)-3-fhioro-2-(trifhioromethoxy)phenyl]-l-cyclopropyl-7-fluoro-2-(2- hydroxypropyl)-4-isopropyl-pyrrolo[3,2-c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-3- carboxylate (56 mg, 64.89 pmol. 50.72% yield, 87% purity) as yellow solid.

[0440] MS (ES+) C38H47N4F5O6 requires: 750, found: 751 [M+H]+.Step 5 tert-butyl 6-[2-acetonyl-6-[5-(tert-butoxycarbonyIamino)-3-fluoro-2- (trifluoromethoxy)phenyl]-l-cyclopropyl-7-fluoro-4-isopropyl-pyrrolo[3,2-c]pyridin-3- yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate

[0441] To a solution of tert-butyl 6-[6-[5-(tert-butoxycarbonylamino)-3-fluoro-2- (trifluoromethoxy)phenyl]-l-cyclopropyl-7-fluoro-2-(2-hydroxypropyl)-4-isopropyl- pyrrolo[3,2-c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate (40 mg, 53.28 pmol, 1 eq) in DCM (2 mL) was added DMP (33.90 mg, 79.92 pmol, 24.76 pL, 1.5 eq) at 0 °C. The mixture was stirred at 25 °C for 4 h. LCMS showed the starting material was consumed completely and a peak (45%) with desired mass. The mixture was filtered. The filtrate was purified by flash silica gel chromatography (4 g SepaFlash® Silica Flash Column, Eluent of2-66% Ethyl acetate / Petroleum ether gradient @ 80 mL / min) to afford tert-butyl 6-[2- acetonyl-6-[5-(tert-butoxycarbonylamino)-3-fluoro-2-(trifluoromethoxy)phenyl]-l- cyclopropyl-7-fluoro-4-isopropyl-pyrrolo[3,2-c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-3- carboxylate (36 mg, 26.44 pmol, 49.63% yield, 55% purity) as yellow solid.

[0442] MS (ES+) C38H45N4F5O6 requires: 748, found: 749 [M+H]+.Step 6 tert-butyl 6-[6-[5-(tert-butoxycarbonylamino)-3-fluoro-2-(trifluoromethoxy)phenyl]-l- cydopropyl-7-fluoro-2-(2-hydroxy-2-methyl-propyl)-4-isopropyl-pyrrolo[3,2-c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxyIate

[0443] A solution of tert-butyl 6-[2-acetonyl-6-[5-(tert-butoxycarbonylamino)-3-fluoro-2-(trifluoromethoxy)phenyl]-l-cyclopropyl-7-fluoro-4-isopropyl-pyrrolo[3,2-c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate (36 mg, 48.08 pmol, 1 eq) in THF (1 mL) was added dropwise slowly to MeMgBr (3 M, 0.5 mL) at 50 °C under N2. The mixture was stirred at 50 °C for 15 min under N2. LCMS showed the starting material was consumed completely and a peak(68%) with desired mass. The mixture was quenched by sat. aq. NH4CI (10 mL) and extracted with ethyl acetate (5 mL x 3). The combined organic phase was washed with brine (10 mL), dried with anhydrous Na2SOr, filtered and concentrated in vacuum. The residue was purified by prep-TLC (Commercial hexanes : Ethyl acetate = 1: 1) to afford tert-butyl 6-[6-[5- (tert-butoxycarbonylamino)-3-fluoro-2-(tri fluoromethoxy )pheny]]-l-cyclopropyl-7-fluoro-2- (2-hydroxy-2-methyl-propyl)-4-isopropyl-pyrrolo[3,2-c]pyridin-3-yl]-3- azabicyclo[3.1.0]hexane-3-carboxylate (12 mg, 14.43 pmol, 30.02% yield, 92% purity) as yellow solid.

[0444] MS (ES+) C39H49N4F5O6 requires: 764, found: 765 [M+H]+Step 7 l-[6-[5-amino-3-fluoro-2-(trifluoromethoxy)phenyl]-3-(3-azabicyclo[3.1.0]hexan-6-yl)-l- cydopropyl-7-fluoro-4-isopropyl-pyrrolo[3,2-c]pyridin-2-yl]-2-methyl-propan-2-ol

[0445] To a solution of tert-butyl 6-[6-[5-(tert-butoxycarbonylamino)-3-fluoro-2- (trifluoromethoxy)phenyl]-l-cyclopropyl-7-fluoro-2-(2-hydroxy-2-methyl-propyl)-4- isopropyl-pyrrolo[3,2-c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate (12 mg, 15.69 pmol, 1 eq) in DCM (0.6 mL) was added TFA (460.50 mg, 4.04 mmol, 0.3 mL) at 25 °C. The mixture was stirred at 25 °C for 20 min. LCMS showed the starting material was consumed completely and one main peak with desired mass. The mixture was concentrated in vacuum. The residue was purified by prep-HPLC(column: Phenomenex luna Cl 8 150*25mm* 10um;mobile phase: [H2O(0.225% FA)- ACN] gradient: 10%-40% B over 10.0 min) and lyophilized to afford l-[6-[5-amino-3-fhioro-2-(trifluoromethoxy)phenyl]-3-(3- azabicyclo[3.1.0]hexan-6-yl)-l-cyclopropyl-7-fluoro-4-isopropyl-pyrrolo[3,2-c]pyridin-2-yl]- 2-methyl-propan-2-ol (3 mg, 4.91 pmol, 31.31% yield, 100% purity, FA) as white solid.

[0446] MS (ES+) C29H33F5N4O2 requires: 564, found: 565 [M+H]+.

[0447] 1H NMR (400 MHz, CD3OD) 5 = 8.58 - 8.51 (m, 0.3H), 6.67 - 6.56 (m, 2H), 4.18 - 4.06 (m, 1H), 3.60 - 3.48 (m, 3H), 3.47 - 3.40 (m, 2H), 3.37 - 3.32 (m, 1H), 3.30 - 3.24 (m, 1H), 2.27 - 1.90 (m, 3H), 1.37 (d, J = 5.4 Hz, 6H), 1.30 (s, 6H), 1.26 - 1.19 (m, 2H), 1.01 - 0.79 (m, 2H).[5-fluoro-6-[7-fluoro-3-(methoxymethoxy)-8-(2-triisopropylsilylethynyl)-l-naphthyI]-4- methyl-l-[(3R)-3-methyI-3-tetrahydropyran-2-yloxy-l-piperidyl]-2,7-naphthyridin-3- yl] methyl methanesulfonateStep 1 tert-butyl 6-[6-[5-(tert-butoxycarbonylamino)-3-fluoro-2-(trifluoromethoxy)phenyl]-l- cydopropyl-7-fluoro-2-(2-hydroxyethyl)-4-isopropyl-pyrrolo[3,2-c]pyridin-3-yl]-3- azabicyclo[3.1.0]hexane-3-carboxylate

[0448] To a solution of 2-[6-[5-amino-3-fluoro-2-(trifluoromethoxy)phenyl]-3-(3- azabicyclo[3.1.0]hexan-6-yl)-l-cyclopropyl-7-fluoro-4-isopropyl-pyrrolo[3,2-c]pyridin-2- yl]ethanol (50.00 mg, 93.19 pmol, 1 eq) in EtOH (0.5 mL) was added BOC2O (24.41 mg, 111.83 pmol, 25.69 pL, 1.2 eq). The mixture was stirred at 20 °C for 15.5 hours. LCMS showed 2- [6- [5-amino-3 -fluoro-2-(trifluoromethoxy)phenyl] -3 -(3 -azabicyclo[3.1.0]hexan-6-yl)-l-cyclopropyl-7-fluoro-4-isopropyl-pyrrolo[3,2-c]pyridin-2-yl]ethanol was consumed completely and 73% of desired compound. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography (4 g SepaFlash® Silica Flash Column, Eluent of 0-50% Ethyl acetate / Petroleum ether gradient @ 50 mL / min) to afford tert-butyl 6-[6-[5-(tert-butoxycarbonylamino)-3-fluoro-2- (trifluoromethoxy)phenyl]-l-cyclopropyl-7-fluoro-2-(2-hydroxyethyl)-4-isopropyl- pyrrolo[3,2-c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate (30 mg, 40.72 pmol, 43.69% yield) as yellow oil.

[0449] MS (ES+) C37H45F5N4O6 requires: 736, found: 737 [M+H]+.Step 2 tert-butyl 6-[6-[5-(tert-butoxycarbonyIamino)-3-fluoro-2-(trifluoromethoxy)phenyl]-l- cyclopropyl-2-(2-ethylsulfonyloxyethyl)-7-fluoro-4-isopropyl-pyrrolo[3,2-c]pyridin-3- yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate

[0450] To a solution of tert-butyl 6-[6-[5-(tert-butoxycarbonylamino)-3-fluoro-2- (trifhioromethoxy)phenyl]-l-cyclopropyl-7-fluoro-2-(2-hydroxyethyl)-4-isopropyl- pyrrolo[3,2-c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate (30.00 mg, 40.72 pmol,1 eq) in DCM (0.5 mL) was added ethanesulfonyl chloride (10.47 mg, 81.44 pmol, 7.72 pL, 2 eq) and DIEA (15.79 mg, 122.16 pmol, 21.28 pL, 3 eq). The mixture was stirred at 0 °C for 0.5 hours. LCMS showed tert-butyl 6-[6-[5-(tert-butoxycarbonylamino)-3-fluoro-2- (trifluoromethoxy)phenyl]-l-cyclopropyl-7-fluoro-2-(2-hydroxyethyl)-4-isopropyl- pyrrolo[3,2-c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate was consumed completely and 81% of desired compound. The mixture was quenched by H2O (5 mL) and extracted with DCM (5 mL x 3). The combined organic phase was dried over Na2SO4, filtered and concentrated in vacuum to afford tert-butyl 6-|6-|5-(tert-butoxycarbonylamino)- 3-fluoro-2-(trifluoromethoxy)phenyl]-l-cyclopropyl-2-(2-ethylsulfonyloxyethyl)-7-fluoro-4-isopropyl-pyrrolo[3,2-c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate (40 mg, crude) as a yellow oil.

[0451] MS (ES+) C39H49F5N4O8S requires: 828, found: 829 [M+H]+.Step 3 tert-butyl 6-[6-[5-(tert-butoxycarbonylamino)-3-fluoro-2-(trifluoromethoxy)phenyl]-l- cydopropyl-2-[2-(dimethylamino)ethyl]-7-fluoro-4-isopropyl-pyrrolo[3,2-c]pyridin-3- yl]-3-azabicyclo[3.1.0]hexane-3-carboxyIate

[0452] To a solution of tert-butyl 6-[6-[5-(tert-butoxycarbonylamino)-3-fluoro-2- (trifluoromethoxy)phenyl]-l-cyclopropyl-2-(2-ethylsulfonyloxyethyl)-7-fluoro-4-isopropyl- pyrrolo[3,2-c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate (40.00 mg, 48.26 pmol, 1 eq) in ACN (1 mL) were added Me2NH (2 M, 120.64 pL, 5 eq) and K2CO3 (20.01 mg, 144.77 pmol, 3 eq). The mixture was stirred at 60 °C for 12 hours. LCMS showed 20% of tert-butyl 6-[6-[5-(tert-butoxycarbonylamino)-3-fluoro-2-(trifluoromethoxy)phenyl]-l- cyclopropyl-2-(2-ethylsulfonyloxyethyl)-7-fluoro-4-isopropyl-pyrrolo[3,2-c]pyridin-3-yl]-3- azabicyclo[3.1.0]hexane-3-carboxylate remained and 68% of desired compound. The reaction mixture was added ethyl acetate (20 mL) and dried over Na2SO4, filtered and concentrated in vacuum to afford tert-butyl 6-[6-[5-(tert-butoxycarbonylamino)-3-fluoro-2- (trifhioromethoxy)phenyl]-l-cyclopropyl-2-[2-(dimethylamino)ethyl]-7-fluoro-4-isopropyl- pyrrolo[3,2-c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate (40 mg, crude) as a yellow oil.

[0453] MS (ES+) C39H50F5N5O5 requires: 763, found: 764 [M+H]+.Step 4 [5-fhioro-6-[7-fluoro-3-(methoxymethoxy)-8-(2-triisopropylsilylethynyl)-l-naphthyl]-4- methyl-l-[(3R)-3-methyl-3-tetrahydropyran-2-yloxy-l-piperidyI]-2,7-naphthyridin-3- yl]methyl methanesulfonate

[0454] To a solution of tert-butyl 6-[6-[5-(tert-butoxycarbonylamino)-3-fluoro-2- (trifluoromethoxy)phenyl]-l-cyclopropyl-2-[2-(dimethylamino)ethyl]-7-fluoro-4-isopropyl- pyrrolo[3,2-c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate (40.00 mg, 52.37 pmol, 1 eq) in DCM (0.5 mL) was added TFA (2.05 g, 17.95 mmol, 1.33 mL). The mixture was stirred at 25 °C for 0.5 hr. LCMS showed tert-butyl 6-[6-[5-(tert-butoxycarbonylamino)-3- fluoro-2-(trifluoromethoxy)phenyl]-l-cyclopropyl-2-[2-(dimethylamino)ethyl]-7-fluoro-4- isopropyl-pyrrolo[3,2-c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate was consumed completely and 54% of desired compound. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by reversed-phase HPLC (column: Phenomenex luna C18 150*25mm* lOum; mobile phase: [water (FA)-ACN]; gradient: 3 %-33% B over 10 min) to afford crude product which was purified by reversed- phase HPLC(column: Phenomenex luna Cl 8 150*25 mm* lOum; mobile phase: [water(TFA)-ACN]; gradient: 0%-25% B over 10 min) to afford 3-[3-(3- azabicyclo[3.1.0]hexan-6-yl)-l-cyclopropyl-2-[2-(dimethylamino)ethyl]-7-fluoro-4- isopropyl-pyrrolo[3,2-c]pyridin-6-yl]-5-fluoro-4-(trifluoromethoxy)aniline (6.8 mg, 10.04 pmol, 19.16% yield, TFA) as yellow oil.

[0455] MS (ES+) C29H34F5N5O requires: 563, found: 564 [M+H]+.

[0456] 1H NMR (400 MHz, CD3OD) 5 = 6.79 - 6.66 (m, 2H), 4.32 - 4.20 (m, 1H), 3.82(d, J = 12 Hz, 2H), 3.70 - 3.62 (M, 5H), 3.58 - 3.51 (m, 2H), 3.05 (s, 6H), 2.32 (s, 2H), 2.28 - 2.19 (m, 1H), 1.49 (d, J = 6.8 Hz, 6H), 1.43 - 1.33 (m, 2H), 1.16 (s, 2H).EXAMPLE 793-[3-(3-azabicyclo[3.1.0]hexan-6-yl)-l-cyclopropyl-7-fluoro-2-(lH-imidazol-2-ylmethyl)-4-isopropyl-pyrrolo[3,2-c]pyridin-6-yI]-5-fluoro-4-(trifluoromethoxy)anilineStep 1 tert-butyl 6-[6-[5-(tert-butoxycarbonyIamino)-3-fluoro-2-(trifluoromethoxy)phenyl]-l- cyclopropyl-7-fluoro-2-[hydroxy-[l-(2-trimethylsilylethoxymethyl)imidazol-2- yl]methyl]-4-isopropyI-pyrroIo[3,2-c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-3- carboxylate104571 To a solution of 2-(imidazol-l-ylmethoxy)ethyl-trimethyl-silane (275.19 mg, 1.39 mmol, 10 eq) in THF (2 mL) was added n-BuLi (2.5 M, 832.50 pL, 15 eq) at -70 °C under the protection of N2, the mixture was stirred at -70 °C for 20 min, the mixture was added into a solution of tert-butyl 6-[6-[5-(tert-butoxycarbonylamino)-3-fluoro-2- (trifhioromethoxy)phenyl]-l-cyclopropyl-7-fluoro-2-formyl-4-isopropyl-pyrrolo[3,2- c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate (0.1 g, 138.75 pmol, 1 eq) in THF (1 mL) under the protection of N2 at -70 °C, the mixture was allowed to warmed to 20 °C slowly and stirred at 20 °C for 1 hour. LCMS showed tert-butyl 6-[6-[5-(tert- butoxycarbonylamino)-3-fluoro-2-(trifluoromethoxy)phenyl]-l-cyclopropyl-7-fluoro-2- formyl-4-isopropyl-pyrrolo[3,2-c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate was consumed and main peak with desired mass. To the mixture was added saturated NH4CI (2 mL) and extracted with EtOAc (2 mL x 3), dried over Na2SO4, filtered and concentratedunder reduced pressure to give a residue which was purified by flash silica gel chromatography (5 g SepaFlash® Silica Flash Column, Eluent of 0-100% Ethyl acetate / Petroleum ether gradient @ 40 mL / min) to afford tert-butyl 6-[6-[5-(tert- butoxycarbonylamino)-3-fluoro-2-(trifluoromethoxy)phenyl]-l-cyclopropyl-7-fluoro-2- [hydroxy-[l-(2-trimethylsilylethoxymethyl)imidazol-2-yl]methyl]-4-isopropyl-pyrrolo[3,2- c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate (0.08 g, 87.05 pmol, 62.74% yield) as colorless oil.

[0458] MS (ES+) C45H59F5N6O7Si requires: 918, found: 919 [M+H]+.Step 2 tert-butyl 6-[6-[5-(tert-butoxycarbonylamino)-3-fluoro-2-(trifluoromethoxy)phenyl]-2- [chloro-[l-(2-trimethylsilylethoxymethyI)imidazol-2-yl]methyl]-l-cydopropyl-7-fluoro- 4-isopropyl-pyrrolo[3,2-c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate

[0459] To a solution of tert-butyl 6-[6-[5-(tert-butoxycarbonylamino)-3-fluoro-2- (trifluoromethoxy)phenyl] - 1 -cyclopropyl-7 -fluoro-2- [hydroxy- [ 1 -(2- trimethylsilylethoxymethyl)imidazol-2-yl]methyl]-4-isopropyl-pyrrolo[3,2-c]pyridin-3-yl]-3- azabicyclo[3.1 .0]hexane-3-carboxylate (0.13 g, 141.45 pmol, 1 eq) in DCM (1 mb) was added SOCh (50.48 mg, 424.35 pmol, 30.82 pL, 3 eq) at 0 °C, the mixture was stirred at 20 °C for 2 hours. The reaction mixture was concentrated under reduced pressure to afford tertbutyl 6-[6-[5-(tert-butoxycarbonylamino)-3-fluoro-2-(trifluoromethoxy)phenyl]-2-[chloro-[l- (2-trimethylsilylethoxymethyl)imidazol-2-yl]methyl]-l-cyclopropyl-7-fluoro-4-isopropyl- pyrrolo[3,2-c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate (0.132 g, 140.80 pmol, 99.54% yield) as yellow oil.Step 3 tert-butyl 6-[6-[5-(tert-butoxycarbonyIamino)-3-fluoro-2-(trifluoromethoxy)phenyl]-l- cyclopropyl-7-fluoro-4-isopropyl-2-[[l-(2-trimethylsilylethoxymethyl)imidazol-2- yl]methyl]pyrrolo[3,2-c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate

[0460] To a solution of tert-butyl 6-[6-[5-(tert-butoxycarbonylamino)-3-fluoro-2- (trifluoromethoxy)phenyl]-2-[chloro-[l-(2-trimethylsilylethoxymethyl)imidazol-2- yl]methyl]-l-cyclopropyl-7-fluoro-4-isopropyl-pyrrolo[3,2-c]pyridin-3-yl]-3- azabicyclo[3.1.0]hexane-3-carboxylate (0.132 g, 140.80 pmol, 1 eq) in EtOAc (2 mL) was added Pd / C (52.80 mg, 49.61 pmol, 10% purity, 3.52e-l eq) under N2. The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred under H2 (15 psi) at 20°C for 16 hours. LCMS showed tert-butyl 6-[6-[5-(tert-butoxycarbonylamino)- 3-fluoro-2-(trifluoromethoxy)phenyl]-2-[chloro-[l-(2-trimethylsilylethoxymethyl)imidazol-2- yl]methyl]-l-cyclopropyl-7-fluoro-4-isopropyl-pyrrolo[3,2-c]pyridin-3-yl]-3- azabicyclo[3.1.0]hexane-3-carboxylate was consumed and one peak with desired mass. The reaction mixture was filtered and concentrated under reduced pressure to give a residue which was purified by prep-HPLC (column: Phenomenex Luna C18 150*25mm* lOum; mobile phase: [H2O(0.1% TFA)-ACN]; gradient: 40%-70% B over 15.0 min) to afford tertbutyl 6-[6-[5-(tert-butoxycarbonylamino)-3-fluoro-2-(trifluoromethoxy)phenyl]-l- cyclopropyl-7-fhioro-4-isopropyl-2-[[l-(2-trimethylsilylethoxymethyl)imidazol-2- yl]methyl]pyrrolo[3,2-c]pyridin-3-yl]-3-azabicyclo[3.1 .0]hexane-3-carboxylate (25 mg, 27.68 pmol, 19.66% yield) as a white solid.

[0461] MS (ES+) C45H59F5N6O6Si requires: 902, found: 903 [M+H]+.Step 43-[3-(3-azabicyclo[3.1.0]hexan-6-yl)-l-cydopropyl-7-fluoro-2-(lH-imidazol-2-ylmethyl)-4-isopropyl-pyrrolo[3,2-c]pyridin-6-yl]-5-fluoro-4-(trifluoromethoxy)aniline

[0462] To a flask was added tert-butyl 6-[6-[5-(tert-butoxycarbonylamino)-3-fluoro-2- (trifluoromethoxy)phenyl]-l-cyclopropyl-7-fluoro-4-isopropyl-2-[[l-(2- trimethylsilylethoxymethyl)imidazol-2-yl]methyl]pyrrolo[3,2-c]pyridin-3-yl]-3- azabicyclo[3.1.0]hexane-3-carboxylate (25 mg, 27.68 pmol, 1 eq) and HCl / dioxane (2 M, 1 mL, 72.24 eq), The mixture was stirred at 60°C for 1 hour. LCMS showed tert-butyl 6-[6-[5- (tert-butoxycarbonylamino)-3-fluoro-2-(trifluoromethoxy)phenyl]-l-cyclopropyl-7-fluoro-4- isopropyl-2-[[l-(2-trimethylsilylethoxymethyl)imidazol-2-yl]methyl]pyrrolo[3,2-c]pyridin-3- yl] -3 -azabicyclo [3.1.0]hexane-3 -carboxylate was consumed and one peak with desired mass. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by prep-HPLC (column: Phenomenex Luna C18 150*25mm*10um; mobile phase: [H2O(0.1% TFA)-ACN]; gradient: 0%-30% B over 15.0 min), the eluent was freeze dried over to afford 3-[3-(3-azabicyclo[3.1.0]hexan-6-yl)-l-cyclopropyl-7-fluoro-2-(lH-imidazol- 2-ylmethyl)-4-isopropyl-pyrrolo[3,2-c]pyridin-6-yl]-5-fluoro-4-(trifluoromethoxy)aniline (5 mg, 7.28 pmol, 26.31% yield, TFA) as a white solid.

[0463] MS (ES+) C29H29F5N6O requires: 572, found: 573 [M+H]+.

[0464] ’H NMR (400 MHz, CD3OD) 8 = 7.53 (s, 2H), 7.52 - 7.33 (m, 1H), 6.74 - 6.68 (m, 1H), 6.65 (s, 1H), 5.01 - 4.95 (m, 2H), 4.26 - 4.11 (m, 1H), 3.65 - 3.47 (m, 4H), 3.23 - 3.15 (m, 1H), 2.34 - 2.24 (m, 2H), 2.11 - 1.99 (m, 1H), 1.52 - 1.39 (m, 6H), 1.27 - 1.17 (m, 2H), 1.16 - 1.07 (m, 2H).EXAMPLE 80l-[6-[5-amino-3-fluoro-2-(trifluoromethoxy)phenyl]-3-(3-azabicyclo[3.1.0]hexan-6-yl)-l- cyclopropyl-7-fhioro-4-isopropyl-pyrrolo[3,2-c]pyridin-2-yl]ethanolStep 1 tert-butyl 6-[6-[5-(tert-butoxycarbonyIamino)-3-fluoro-2-(trifluoromethoxy)phenyl]-l- cyclopropyI-7-fluoro-2-(l-hydroxyethyl)-4-isopropyl-pyrrolo[3,2-c]pyridin-3-yI]-3- azabicyclo[3.1.0]hexane-3-carboxylate

[0465] To a solution of tert-butyl 6-[6-[5-(tert-butoxycarbonylamino)-3-fluoro-2- (trifhioromethoxy)phenyl]-l-cyclopropyl-7-fluoro-2-formyl-4-isopropyl-pyrrolo[3,2- c]pyridin-3-yl]-3-azabicyclo[3.1 .0]hexane-3-carboxylate (50 mg, 69.37 pmol, 1 eq) in THF (1 mb) was added MeMgBr (3 M, 69.37 pL, 3 eq) at -78 °C under N2. The mixture was stirred at -78 °C for 1 h under N2. LCMS showed the starting material remained and a peak (77%) with desired mass. The mixture was quenched by sat. aq. NH4CI (4 mL) and extracted with ethyl acetate (3 mL x 2). The combined organic phase was dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by flash silica gel chromatography (4 g SepaFlash® Silica Flash Column, Eluent of 0-25% Ethyl acetate / Petroleum ether gradient @ 80 mL / min) to afford tert-butyl 6-[6-[5-(tert- butoxycarbonylamino)-3-fluoro-2-(trifluoromethoxy)phenyl |- 1 -cyclopropyl-7 -fluoro-2-( 1 - hydroxyethyl)-4-isopropyl-pyrrolo[3,2-c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-3- carboxylate (27 mg, 31.15 pmol, 44.90% yield, 85% purity) as colorless oil.

[0466] MS (ES+) C37H45N4F5O6 requires: 736, found: 737 [M+H]+.Step 2 l-[6-[5-amino-3-fluoro-2-(trifluoromethoxy)phenyl]-3-(3-azabicyclo[3.1.0]hexan-6-yl)-l- cyclopropyI-7-fluoro-4-isopropyl-pyrrolo[3,2-c]pyridin-2-yl]ethanol

[0467] To a solution of tert-butyl 6-[6-[5-(tert-butoxycarbonylamino)-3-fluoro-2- (trifluoromethoxy)phenyl]-l-cyclopropyl-7-fluoro-2-(l-hydroxyethyl)-4-isopropyl- pyrrolo[3,2-c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate (27 mg, 36.65 jxmol, 1 eq) in DCM (0.6 mL) was added TFA (460.50 mg, 4.04 mmol, 0.3 mL) at 25 °C. The mixture was stirred at 25 °C for 10 min. LCMS showed the starting material was consumed completely and a peak (84%) with the desired mass. The mixture was concentrated in vacuum. The residue was purified by prep-HPLC(column: Phenomenex luna Cl 8 150*25mm* 10um;mobile phase: [water(FA)-ACN];gradient:8%-38% B over 10 min) and lyophilized to afford l-[6-[5-amino-3-fhioro-2-(trifluoromethoxy)phenyl]-3-(3- azabicyclo[3.1.0]hexan-6-yl)-l-cyclopropyl-7-fluoro-4-isopropyl-pyrrolo[3,2-c]pyridin-2- yl]ethanol (15.5 mg, 26.61 pmol, 72.60% yield, 100% purity, FA) as white solid.

[0468] MS (ES+) C27H29F5N4O2 requires: 536, found: 537 [M+H]+.

[0469] 1H NMR (400 MHz, CD3OD) 5 = 6.67 - 6.56 (m, 2H), 5.72 - 5.63 (m, 1H), 4.16 -4.06 (m, 1H), 3.63 - 3.54 (m, 2H), 3.53 - 3.43 (m, 3H), 2.81 - 2.73 (m, 1H), 2.17 - 2.11 (m, 1H), 2.00 - 1.95 (m, 1H), 1.80 (d, 7= 6.8 Hz, 3H), 1.36 (dd, 7 = 6.8, 16.0 Hz, 6H), 1.26 - 1.12 (m, 4H)EXAMPLE 812-[6-[5-amino-3-fluoro-2-(trifluoromethoxy)phenyl]-3-(3-azabicyclo[3.1.0]hexan-6-yl)-l- cyclopropyl-7-fluoro-4-isopropyl-pyrrolo[3,2-c]pyridin-2-yl]-N-methyl-acetamideStep 12-[6-[5-(tert-butoxycarbonylamino)-3-fluoro-2-(trifluoromethoxy)phenyl]-3-(3-tert- butoxycarbonyl-3-azabicyclo[3.1.0]hexan-6-yl)-l-cyclopropyl-7-fluoro-4-isopropyl- pyrrolo[3,2-c]pyridin-2-yl]acetic acid

[0470] To a solution of tert-butyl 6-[6-[5-(tert-butoxycarbonylamino)-3-fluoro-2- (trifluoromethoxy)phenyl]-2-(cy anomethyl)- 1 -cyclopropyl-7-fluoro-4-isopropyl-pyrrolo [3,2- c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate (190 mg, 259.65 pmol, 1 eq) in MeOH (2 mL) was added NaOH (5 M, 778.95 pL, 15 eq) at 25 °C. The mixture was stirred at 60 °C for 4 h. LCMS showed the starting material was consumed completely and a peak(12%) with desired mass. The mixture was concentrated in vacuum and diluted with water (5 mL). The mixture was extracted with ethyl acetate (5 mL x 3). The combined organic phase was dried with anhydrous N toSCL, filtered and concentrated in vacuum. The residue was purified by flash silica gel chromatography (4 g SepaFlash® Silica Flash Column, Eluent of 2-100% Ethyl acetate / Petroleum ether gradient @ 60 mL / min) and prep- TLC (Petroleum ether : Ethyl acetate = 0:1) to afford 2-[6-[5-(tert-butoxycarbonylamino)-3- fhioro-2-(trifluoromethoxy)phenyl]-3-(3-tert-butoxycarbonyl-3-azabicyclo[3.1.0]hexan-6-yl)-l-cyclopropyl-7-fluoro-4-isopropyl-pyrrolo[3,2-c]pyridin-2-yl]acetic acid (12 mg, 14.07 pmol, 5.42% yield, 88% purity) as yellow solid.

[0471] MS (ES+) C37H43N4F5O7 requires: 750, found: 751 [M+H]+Step 2 tert-butyl 6-[6-[5-(tert-butoxycarbonylamino)-3-fluoro-2-(trifluoromethoxy)phenyl]-l- cycIopropyl-7-fluoro-4-isopropyl-2-[2-(methylamino)-2-oxo-ethyl]pyrrolo[3,2-c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxyIate z Boc

[0472] To a solution of 2-[6-[5-(tert-butoxycarbonylamino)-3-fluoro-2- (trifluoromethoxy)phenyl]-3-(3-tert-butoxycarbonyl-3-azabicyclo[3.1.0]hexan-6-yl)-l- cyclopropyl-7-fluoro-4-isopropyl-pyrrolo[3,2-c]pyridin-2-yl]acetic acid (12 mg, 15.98 pmol, 1 eq) in DMF (1 mL) was added DIEA (16.53 mg, 127.87 pmol, 22.27 pL, 8 eq) and methanamine;hydrochloride (5.40 mg, 79.92 pmol, 5 eq), HATU (12.16 mg, 31.97 pmol, 2 eq) at 25 °C. The mixture was stirred at 25 °C for 1 h. LCMS showed the starting material was consumed completely and a peak (86%) with desired mass. The mixture was diluted with ethyl acetate (5 mL) and washed with brine (6 mL x 3), dried with anhydrous NaiSCh, filtered and concentrated in vacuum. The residue was purified by prep-TLC(Petroleum ether : Ethyl acetate = 0: 1) to afford tert-butyl 6-[6-[5-(tert-butoxycarbonylamino)-3-fluoro-2- (trifluoromethoxy)phenyl]-l-cyclopropyl-7-fluoro-4-isopropyl-2-[2-(methylamino)-2-oxo- ethyl]pyrrolo[3,2-c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate (10 mg, 11.91 pmol, 74.54% yield, 91% purity) as white solid.

[0473] MS (ES+) C38H46N5F5O6 requires: 763, found: 764 [M+H]+Step 3 2-[6-[5-amino-3-fluoro-2-(trifluoromethoxy)phenyl]-3-(3-azabicycIo[3.1.0]hexan-6-yI)-l- cyclopropyl-7-fluoro-4-isopropyl-pyrrolo[3,2-c]pyridin-2-yl]-N-methyl-acetamide

[0474] To a solution of tert-butyl 6-[6-[5-(tert-butoxycarbonylamino)-3-fluoro-2- (trifluoromethoxy)phenyl]-l-cyclopropyl-7-fluoro-4-isopropyl-2-[2-(methylamino)-2-oxo- ethyl]pyrrolo[3,2-c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate (10 mg, 13.09 pmol, 1 eq) in DCM (0.5 mL) was added TFA (383.75 mg, 3.37 mmol, 0.25 mL) at 25 °C. The mixture was stirred at 25 °C for 10 min. LCMS showed the starting material was consumed completely and a peak (43%) with desired mass. The mixture was concentrated in vacuum. The residue was purified by prep-HPLC(column: Phenomenex Luna Cl 8 150*25mm*10um;mobile phase: [H2O(0.225% FA)-ACN];gradient:6%-36% B over 10.0 min) and lyophilized to afford 2-[6-[5-amino-3-fluoro-2-(trifluoromethoxy)phenyl]-3-(3- azabicyclo[3.1.0]hexan-6-yl)-l-cyclopropyl-7-fluoro-4-isopropyl-pyrrolo[3,2-c]pyridin-2-yl]- N-methyl-acetamide (1.1 mg, 1.80 pmol, 13.78% yield, 100% purity, FA) as white solid.

[0475] MS (ES+) C28H30F5N5O2 requires: 563, found: 564 [M+H]+.

[0476] 1H NMR (400 MHz, CD3OD) 5 = 6.65 - 6.56 (m, 2H), 4.16 - 4.07 (m, 1H), 4.05(s, 2H), 3.54 - 3.46 (m, 3H), 3.44 - 3.40 (m, 2H), 2.84 - 2.78 (m, 3H), 2.11 (s, 2H), 1.94 - 1.87 (m, 1H), 1.36 (d, J = 6.8 Hz, 6H), 1.25 - 1.16 (m, 2H), 1.06 - 0.99 (m, 2H)6-[5-amino-3-fluoro-2-(trifluoromethoxy)phenyl]-3-(3-azabicyclo[3.1.0]hexan-6-yl)-l- cyclopropyl-7-fluoro-4-isopropyl-pyrrolo[3,2-c]pyridin-2-amineStep 16-[5-(tert-butoxycarbonylamino)-3-fluoro-2-(trifluoromethoxy)phenyl]-3-(3-tert- butoxycarbonyl-3-azabicyclo[3.1.0]hexan-6-yI)-l-cydopropyl-7-fluoro-4-isopropyl- pyrrolo[3,2-c]pyridine-2-carboxylic acid[0477 J To a solution of tert-butyl 6-[6-[5-(tert-butoxycarbonylamino)-3-fluoro-2- (trifluoromethoxy)phenyl]-l-cyclopropyl-7-fluoro-2-formyl-4-isopropyl-pyrrolo[3,2- c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate (130 mg, 180.37 pmol, 1 eq) in t- BuOH (1 mL) and 2-methylbut-2-ene (1 mL) were added a mixture of sodium;dihydrogen phosphate;hydrate (149.34 mg, 1.08 mmol, 6 eq) and sodium;chlorite (48.94 mg, 541.12 (imol, 3 eq) in H2O (0.3 mL) at 0 °C, then the mixture was stirred at 20 °C for 2 h. LCMS showed 71% peak with desired mass. The mixture was cooled to 25 °C and poured into a mixture of saturated Na^SCF (10 mL) and water (10 mL). The aqueous phase was extracted with ethyl acetate (10 mL x 2). The combined organic phase was washed with brine (20 mL x 2), dried over anhydrous NasSCU, filtered and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography (4 g SepaFlash® Silica Flash Column, Eluent of 0-100% Ethyl acetate / Petroleum ether gradient @ 80 mL / min) to afford 6-[5-(tert- butoxycarbonylamino)-3-fluoro-2-(trifluoromethoxy)phenyl]-3-(3-tert-butoxycarbonyl-3- azabicyclo[3.1.0]hexan-6-yl)-l-cyclopropyl-7-fluoro-4-isopropyl-pyrrolo[3,2-c]pyridine-2- carboxylic acid (85 mg, 103.84 pmol, 57.57% yield, 90% purity) as white oil.

[0478] MS (ES+) C36H41N4F5O7 requires: 736, found: 737 [M+H]+.Step 2 tert-butyl 6-[2-(tert-butoxycarbonylamino)-6-[5-(tert-butoxycarbonyIamino)-3-fluoro-2- (trifluoromethoxy)phenyl]-l-cydopropyl-7-fluoro-4-isopropyl-pyrrolo[3,2-c]pyridin-3- yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate

[0479] To a solution of 6-[5-(tert-butoxycarbonylamino)-3-fluoro-2- (trifluoromethoxy)phenyl]-3-(3-tert-butoxycarbonyl-3-azabicyclo[3.L0]hexan-6-yl)-l- cyclopropyl-7-fluoro-4-isopropyl-pyrrolo[3,2-c]pyridine-2-carboxylic acid (75 mg, 101.80 pmol, 1 eq) in t-BuOH (2 mL) were added DPPA (36.42 mg, 132.34 pmol, 28.57 pL, 1.3 eq) and TEA (20.60 mg, 203.60 pmol, 28.34 pL, 2 eq) at 20 °C under N2, then the mixture was stirred at 85 °C for 16 h. LCMS showed 18% of peak with desired mass. The reaction mixture was washed with saturated citric acid. (10 mL x 3) and saturated NaHCOs (10 mL x 3), dried over NtoSCL. filtered and concentrated under reduced pressure to give a residue which was purified by prep-TLC (SiCL, Petroleum ether: Ethyl acetate= 1: 1) to afford tertbutyl 6-[2-(tert-butoxycarbonylamino)-6-[5-(tert-butoxycarbonylamino)-3-fluoro-2- (trifluoromethoxy)phenyl]-l-cyclopropyl-7-fluoro-4-isopropyl-pyrrolo[3,2-c]pyridin-3-yl]-3- azabicyclo[3.1.0]hexane-3-carboxylate (14 mg, 16.46 pmol, 16.17% yield, 95% purity) as yellow oil.

[0480] MS (ES+) C35H42F5N5O5 requires: 707, found: 708 [M+H]+.Step 3 6-[5-amino-3-fluoro-2-(trifluoromethoxy)phenyl]-3-(3-azabicyclo[3.1.0]hexan-6-yl)-l- cydopropyl-7-fluoro-4-isopropyl-pyrrolo[3,2-c]pyridin-2-amine

[0481] To a solution of tert-butyl 6-[2-(tert-butoxycarbonylamino)-6-[5-(tert- butoxycarbonylamino)-3-fluoro-2-(trifluoromethoxy)phenyl]-l-cyclopropyl-7-fluoro-4- isopropyl-pyrrolo[3,2-c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate (14 mg, 17.33pmol, 1 eq) in DCM (0.2 mL) was added TFA (307.00 mg, 2.69 mmol, 0.2 mL). The mixture was stirred at 25 °C for 20 min. LCMS showed 75% of peak with desired mass. The reaction mixture was concentrated in vacuum to give a residue which was purified by prep-HPLC (column: Phenomenex luna C18 150*25mm* lOum; mobile phase: [H2O(0.2%FA)-ACN]; gradient: 8%-38% B over 10.0 min) and lyophilized to afford 6-[5-amino-3-fluoro-2- (trifluoromethoxy)phenyl]-3-(3-azabicyclo[3.L0]hexan-6-yl)-l-cyclopropyl-7-fluoro-4- isopropyl-pyrrolo[3,2-c]pyridin-2-amine (4.4 mg, 7.71 pmol, 44.49% yield, 97% purity, FA) as a white solid.

[0482] MS (ES+) C25H26F5N5O requires: 507, found 508[M+H]+.

[0483] ’H NMR (400 MHz, CD3OD) 8 = 8.56 - 8.40 (m, 0.3H), 6.69 - 6.49 (m, 2H), 3.66 - 3.36 (m, 5H), 2.96 - 2.86 (m, 1H), 2.40 - 2.28 (m, 1H), 1.37 - 1.22 (m, 7H), 1.20 - 1.04 (m, 3H), 0.93 - 0.79 (m, 2H).6-[5-amino-3-fluoro-2-(trifluoromethoxy)phenyl]-3-[(lR,5S)-3-azabicyclo[3.1.0]hexan-6- yl]-l-cyclopropyl-7-fluoro-4-isopropyl-N-methyl-pyrrolo[3,2-c]pyridine-2-carboxamide Step 1 tert-butyl (lR,5S)-6-[6-[5-(tert-butoxycarbonylamino)-3-fluoro-2- (trifluoromethoxy)phenyl]-l-cyclopropyl-7-fluoro-4-isopropyl-2- (methylcarbamoyl)pyrrolo[3,2-c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate

[0484] To a solution of 6-[5-(tert-butoxycarbonylamino)-3-fluoro-2- (trifluoromethoxy)phenyl]-3-[(lR,5S)-3-tert-butoxycarbonyl-3-azabicyclo[3.1.0]hexan-6-yl]- l-cyclopropyl-7-fluoro-4-isopropyl-pyrrolo[3,2-c]pyridine-2-carboxylic acid (50 mg, 67.87 pmol, 1 eq) and methanamine;hydrochloride (22.91 mg, 339.34 pmol, 5 eq) in DMF (0.5 mL) were added DIEA (70.17 mg, 542.94 pmol, 94.57 pL, 8 eq) and HATU (38.71 mg, 101.80 pmol, 1.5 eq). The mixture was stirred at 25 °C for 1 h. LCMS showed 100% of peak with desired mass. To the mixture was added water (5 mL) and extracted with EtOAc (5 mL x 3), the combined organic phase was washed with brine (8 mL x 3), dried over Na2SOa, filtered and concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography (4 g SepaFlash® Silica Flash Column, Eluent of 0-60% Ethyl acetate / Petroleum ether gradient @ 50 mL / min) to afford tert-butyl (lR,5S)-6-[6-[5-(tert- butoxycarbonylamino)-3-fluoro-2-(tri fluoromethoxy )phenyl |- 1 -cyclopropyl-7-fluoro-4- isopropyl-2-(methylcarbamoyl)pyrrolo[3,2-c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-3- carboxylate (40 mg, 52.82 pmol, 77.82% yield, 99% purity) as yellow oil.

[0485] MS (ES+) C37H44N5F5O6 requires: 749, found 750 [M+H]+.Step 2 6-[5-amino-3-fluoro-2-(trifluoromethoxy)phenyI]-3-[(lR,5S)-3-azabicycIo[3.1.0]hexan-6- yl]-l-cyclopropyl-7-fluoro-4-isopropyl-N-methyl-pyrrolo[3,2-c]pyridine-2-carboxamide

[0486] To a solution of tert-butyl (lR,5S)-6-[6-[5-(tert-butoxycarbonylamino)-3-fluoro-2- (trifluoromethoxy)phenyl]-l-cyclopropyl-7-fluoro-4-isopropyl-2- (methylcarbamoyl)pyrrolo[3,2-c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate (40 mg, 53.35 pmol, 1 eq) in DCM (0.4 mL) was added TFA (307.00 mg, 2.69 mmol, 0.2 mL). The mixture was stirred at 25 °C for 20 min. LCMS showed 94% of peak with desired mass. The reaction mixture was concentrated in vacuum to give a residue which was purified by prep-HPLC (column: Phenomenex luna C18 150*25mm* lOum; mobile phase: [water(FA)- ACN]; gradient: 13%-43% B over 10 min) and lyophilized to afford 6-[5-amino-3-fluoro-2- (trifluoromethoxy)phenyl]-3-[(lR,5S)-3-azabicyclo[3.1.0]hexan-6-yl]-l-cyclopropyl-7-fluoro-4-isopropyl-N-methyl-pyrrolo[3,2-c]pyridine-2-carboxamide (19.6 mg, 32.58 pmol, 61.07% yield, 99% purity, FA) as a white solid.

[0487] MS (ES+) C27H2SF5N5O2 requires: 549, found 550[M+H]+.

[0488] 'H NMR (400 MHz, CD3OD) 5 = 6.70 - 6.56 (m, 2H), 4.11 - 3.96 (m, 1H), 3.65 - 3.52 (m, 1H), 3.50 - 3.35 (m, 4H), 3.02 (s, 3H), 2.07 - 1.97 (m, 3H), 1.37 (d, J= 6.8 Hz, 6H), 1.16 - 1.04 (m, 2H), 1.00 - 0.90 (m, 2H).EXAMPLE 84[6-[5-amino-3-fluoro-2-(trifluoroinethoxy)phenyl]-l-cyclopropyl-7-fluoro-3- [(lS,2S,5R,6R)-2-(hydroxymethyI)-3-azabicycIo[3.1.0]hexan-6-yl]-4-isopropyI- pyrrolo[3,2-c]pyridin-2-yl]methanoIStep 1O3-tert-butyI O2-methyl (lS,2S,5R,6R)-6-[6-chIoro-l-cyclopropyl-7-fluoro-2-(tetrahydropyran-2-yloxymethyl)pyrrolo[3,2-c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane- 2,3-dicarboxylate

[0489] To a solution of 6-chloro-l-cyclopropyl-7-fluoro-3-iodo-2-(tetrahydropyran-2- yloxymethyl)pyrrolo[3,2-c]pyridine (2 g, 4.44 mmol, 1 eq) and 03-tert-butyl O2-methyl (lS,2S,5R,6R)-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3-azabicyclo[3.1.0]hexane- 2,3-dicarboxylate (1.63 g, 4.44 mmol, 1 eq) in dioxane (44.4 mL) were added cataCXium® A Pd G3 (323.19 mg, 443.78 pmol, 0.1 eq) and K3PO4 (1.5 M, 8.88 mL, 3 eq). The mixture wasstirred at 100 °C for 3 h under N2. LCMS showed 60% of peak with desired mass. To the mixture was added water (30 mL) and extracted with EtOAc (20 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give 03-tert-butyl 02-methyl (lS,2S,5R,6R)-6-[6-chloro-l-cyclopropyl-7-fluoro-2-(tetrahydropyran-2- yloxymethyl)pyrrolo[3,2-c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-2,3-dicarboxylate (2.5 g, crude) as yellow oil.

[0490] MS (ES+) C28H35N3FCIO6 requires: 563, found 564 [M+H]+.Step 2 (lS,2S,5R,6R)-3-tert-butoxycarbonyl-6-[6-chloro-l-cyclopropyl-7-fluoro-2- (tetrahydropyran-2-yIoxymethyl)pyrrolo[3,2-c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane- 2-carboxylic acid

[0491] To a solution of 03-tert-butyl 02-methyl (lS,2S,5R,6R)-6-[6-chloro-l- cyclopropyl-7-fluoro-2-(tetrahydropyran-2-yloxymethyl)pyrrolo[3,2-c]pyridin-3-yl]-3- azabicyclo[3.1.0]hexane-2,3-dicarboxylate (2.5 g, 4.43 mmol, 1 eq) in THF (10 mL) was added LiOH-HzO (464.99 mg, 11.08 mmol, 2.5 eq) in H2O (10 mL) at 0 °C. The mixture was stirred at 25 °C for 1 h. LCMS showed 65% of peak with desired mass. To the mixture was added water (20 mL) and extracted with EtOAc (20 mL), the aqueous phase was adjusted to pH= 6 with HC1 (1 N) and was extracted with ethyl acetate (30 mL x 2), dried over Na2SO4, filtered and concentrated under vacuum to afford (lS,2S,5R,6R)-3-tert-butoxycarbonyl-6-[6- chloro-l-cyclopropyl-7-fluoro-2-(tetrahydropyran-2-yloxymethyl)pyrrolo[3,2-c]pyridin-3- yl] -3 -azabicyclo [3.1.0]hexane-2-carboxy lie acid (2.1 g, 3.67 mmol, 82.70% yield, 96% purity) as yellow oil.

[0492] MS (ES+) C27H33N3FCIO6 requires: 549, found 550 [M+H]+.Step 3 tert-butyl (lS,2S,5R,6R)-6-[6-chloro-l-cyclopropyl-7-fluoro-2-(tetrahydropyran-2- yloxymethyl)pyrrolo[3,2-c]pyridin-3-yI]-2-(hydroxymethyI)-3-azabicydo[3.1.0]hexane- 3-carboxylate

[0493] To a solution of (lS,2S,5R,6R)-3-tert-butoxycarbonyl-6-[6-chloro-l-cyclopropyl- 7-fluoro-2-(tetrahydropyran-2-yloxymethyl)pyrrolo[3,2-c]pyridin-3-yl]-3- azabicyclo[3.1.0]hexane-2-carboxylic acid (1.9 g, 3.45 mmol, 1 eq) in THF (19 mL) was added BH3-Me2S (10 M, 1.73 mL, 5 eq) at 0 °C. The mixture was stirred at 25 °C for 16 h under N2. LCMS showed 89% of peak with desired mass. The mixture was quenched by methanol (5 ml) at 0 °C dropwise under nitrogen atmosphere and stirred for 20 min. Then the mixture was concentrated under reduced pressure to give tert-butyl (lS,2S,5R,6R)-6-[6- chloro-l-cyclopropyl-7-fluoro-2-(tetrahydropyran-2-yloxymethyl)pyrrolo[3,2-c]pyridin-3- yl]-2-(hydroxymethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (1.85 g, crude) as yellow oil.

[0494] MS (ES+) C27H35N3FCIO5 requires: 535, found 536 [M+H]+.Step 4 tert-butyl (lS,2S,5R,6R)-2-[[tert-butyl(dimethyl)silyl]oxymethyl]-6-[6-chloro-l- cycIopropyl-7-fluoro-2-(tetrahydropyran-2-yloxymethyl)pyrrolo[3,2-c]pyridin-3-yl]-3- azabicyclo[3.1.0]hexane-3-carboxylate

[0495] To a solution of tert-butyl (lS,2S,5R,6R)-6-[6-chloro-l-cyclopropyl-7-fluoro-2- (tetrahydropyran-2-yloxymethyl)pyrrolo[3,2-c]pyridin-3-yl]-2-(hydroxymethyl)-3- azabicyclo[3.1.0]hexane-3-carboxylate (2.02 g, 3.77 mmol, 1 eq) in DCM (20 mL) were added TBSC1 (681.58 mg, 4.52 mmol, 556.39 pL, 1.2 eq) and imidazole (513.09 mg, 7.54 mmol, 2 eq). The mixture was stirred at 25 °C for 16 h. LCMS showed 19% of tert-butyl (lS,2S,5R,6R)-6-[6-chloro-l-cyclopropyl-7-fluoro-2-(tetrahydropyran-2-yloxymethyl)pyrrolo[3,2-c]pyridin-3-yl]-2-(hydroxymethyl)-3-azabicyclo[3.1.0]hexane-3- carboxylate remained and 68% of peak with desired mass. To the mixture was added water (30 mL) and extracted with EtOAc (30 mL x 3), the combined organic phase was washed with brine (50 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography (20 g SepaFlash® Silica Flash Column, Eluent of 0-15% Ethyl acetate / Petroleum ether gradient @ 100 mL / min) to afford tert-butyl (lS,2S,5R,6R)-2-[[tert-butyl(dimethyl)silyl]oxymethyl]-6-[6- chloro-l -cyclopropyl-7-fluoro-2-(tetrahydropyran-2-yloxymethy])pyrrolo[3,2-c]pyridin-3- yl] -3 -azabicyclo [3.1.0]hexane-3 -carboxylate (1.5 g, 2.12 mmol, 56.31% yield, 92% purity) as yellow oil.

[0496] MS (ES+) C33H49N3FC105Si requires: 649, found 650 [M+H]+.Step 5 tert-butyl (lS,2S,5R,6R)-6-[4-bromo-6-chloro-l-cyclopropyl-7-fluoro-2- (tetrahydropyran-2-yloxymethyl)pyrrolo[3,2-c]pyridin-3-yl]-2-[[tert- butyl(dimethyI)silyl]oxymethyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate

[0497] To a solution of lithium;chloro-(2,2,6,6-tetramethyl-l- piperidyl)magnesium;chloride (1 M, 8.46 mL, 5 eq) was added tert-butyl (lS,2S,5R,6R)-2- [[tert-butyl(dimethyl)silyl]oxymethyl]-6-[6-chloro-l-cyclopropyl-7-fluoro-2- (tetrahydropyran-2-yloxymethyl)pyrrolo[3,2-c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-3- carboxylate (1.1 g, 1.69 mmol, 1 eq) in THF (2 mL) at 0 °C under N2, then the mixture was stirred at 0 °C for 1 h, then l,2-dibromo-l,l,2,2-tetrachloro-ethane (2.75 g, 8.46 mmol, 1.02 mL, 5 eq) in THF ( 1 mL) was added to the mixture, and stirred at 0 °C stirred for 1 h under N2. LCMS showed 19% of peak with desired mass. The reaction mixture was quenched with NH4CI (20 mL) and extracted with EtOAc (20 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography (12 g SepaFlash® Silica Flash Column, Eluent of 0-30% Ethyl acetate / Petroleum ether gradient @ 120 mL / min) to afford crude product which was purifiedby prep-HPLC (column: Phenomenex luna C18 150*40mm* 15um; mobile phase: [water(FA)-ACN]; gradient: 90%-100% B over 15 min) and concentrated under reduced pressure to tert-butyl (lS,2S,5R,6R)-6-[4-bromo-6-chloro-l-cyclopropyl-7-fluoro-2- (tetrahydropyran-2-yloxymethyl)pyrrolo[3,2-c]pyridin-3-yl]-2-[[tert- butyl(dimethyl)silyl]oxymethyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate (200 mg, 266.05 pmol, 15.73% yield, 97% purity) as yellow oil and tert-butyl (lS,2S,5R,6R)-2-[[tert- butyl(dimethyl)silyl]oxymethyl]-6-[6-chloro-l-cyclopropyl-7-fluoro-2-(tetrahydropyran-2- yloxymethyl)pyrrolo[3,2-c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate (700 mg, 1.04 mmol, 61.73% yield, 97% purity) was obtained as yellow oil.

[0498] MS (ES+) C33H48N3FClBrO5Si requires: 727, found 730[M+H]+.

[0499] MS (ES+) C33H49N3FC105Si requires: 649, found 650[M+H]+.Step 6 tert-butyl (lS,2S,5R,6R)-2-[[tert-butyl(dimethyl)silyl]oxymethyl]-6-[6-chloro-l- cydopropyl-7-fluoro-4-isopropenyl-2-(tetrahydropyran-2-yloxymethyl)pyrrolo[3,2- c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate

[0500] To a solution of tert-butyl (lS,2S,5R,6R)-6-[4-bromo-6-chloro-l-cyclopropyl-7- fluoro-2-(tetrahydropyran-2-yloxymethyl)pyrrolo[3,2-c]pyridin-3-yl]-2-[[tert- butyl(dimethyl)silyl]oxymethyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate (160 mg, 219.42 pmol, 1 eq) and potassium;trifluoro(isopropenyl)boranuide (35.72 mg, 241.36 pmol, 1.1 eq) in THF (4.4 mL) were added Pd(dppf)Ch- CH2CI2 (35.84 mg, 43.88 pmol, 0.2 eq) and K3PO4 (1.5 M, 438.84 pL. 3 eq). The mixture was stirred at 60 °C for 16 h under N2. LCMS showed 74% of peak with desired mass. To the mixture was added water (6 mL) and extracted with EtOAc (6 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography (4 g SepaFlash® Silica Flash Column, Eluent of 0-8% Ethyl acetate / Petroleum ether gradient @ 80 mL / min) to afford tert-butyl (lS,2S,5R,6R)-2-[[tert-butyl(dimethyl)silyl]oxymethyl]-6-[6-chloro-l- cyclopropyl-7-fhioro-4-isopropenyl-2-(tetrahydropyran-2-yloxymethyl)pyrrolo[3,2-c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate (150 mg, 210.76 pmol, 96.05% yield, 97% purity) as yellow oil.

[0501] MS (ES+) C36H.53N3FClO.5Si requires: 689, found 690 [M+H]+.Step 7 tert-butyl (lS,2S,5R,6R)-6-[6-[5-(tert-butoxycarbonylamino)-3-fluoro-2-(trifluoromethoxy)phenyl]-l-cyclopropyl-7-fluoro-4-isopropenyl-2-(tetrahydropyran-2- yloxymethyl)pyrrolo[3,2-c]pyridin-3-yl]-2-[[tert-butyl(dimethyl)silyl]oxymethyl]-3- azabicyclo[3.1.0]hexane-3-carboxylate

[0502] To a solution of tert-butyl (lS,2S,5R,6R)-2-[[tert- butyl(dimethyl)silyl]oxymethyl]-6-[6-chloro-l-cyclopropyl-7-fluoro-4-isopropenyl-2- (tetrahydropyran-2-yloxymethyl)pyrrolo[3,2-c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-3- carboxylate (285 mg, 412.83 pmol, 1 eq) and tert-butyl N-[3-fluoro-5-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)-4-(trifluoromethoxy)phenyl]carbamate (260.82 mg, 619.24 pmol, 1.5 eq) in THF (4.1 mb) were added cataCXium® A Pd G3 (30.07 mg, 41.28 pmol, 0.1 eq) and K3PO4 (1.5 M, 825.66 pL, 3 eq). The mixture was stirred at 60 °C for 16 h under N2. LCMS showed 65% of peak with desired mass. To the mixture was added water (8 mL) and extracted with EtOAc (8 mL x 3), dried over Na^SO i, filtered and concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography (4 g SepaFlash® Silica Flash Column, Eluent of 0-30% Ethyl acetate / Petroleum ether gradient @ 80 mL / min) and purified by prep-TLC (SiCb, Petroleum ether: Ethyl acetate= 2: 1) to afford tert-butyl (lS,2S,5R,6R)-6-[6-[5-(tert-butoxycarbonylamino)-3-fluoro-2- (trifluoromethoxy)phenyl]-l-cyclopropyl-7-fluoro-4-isopropenyl-2-(tetrahydropyran-2- yloxymethyl)pyrrolo[3,2-c]pyridin-3-yl]-2-[[tert-butyl(dimethyl)silyl]oxymethyl]-3- azabicyclo[3.1.0]hexane-3-carboxylate (180 mg, 178.27 pmol, 43.18% yield, 94% purity) as yellow oil.

[0503] MS (ES+) C48H65N4F5O8Si requires: 948, found 949[M+H]+.Step 8 tert-butyl (lS,2S,5R,6R)-6-[6-[5-(tert-butoxycarbonylamino)-3-fluoro-2-(trifluoromethoxy)phenyl]-l-cyclopropyl-7-fluoro-4-isopropyl-2-(tetrahydropyran-2- yloxymethyl)pyrrolo[3,2-c]pyridin-3-yl]-2-[[tert-butyl(dimethyl)silyl]oxymethyl]-3- azabicyclo[3.1.0]hexane-3-carboxylate

[0504] To a suspension of Pd / C (100 mg, 93.97 pmol, 10% purity, 4.95e-l eq) and Pd(OH)2 (100 mg, 142.41 pmol, 20% purity) in EtOH (2 mL) was added tert-butyl (lS,2S,5R,6R)-6-[6-[5-(tert-butoxycarbonylamino)-3-fluoro-2-(trifluoromethoxy)phenyl]-l- cyclopropyl-7-fluoro-4-isopropenyl-2-(tetrahydropyran-2-yloxymethyl)pyrrolo[3,2-c]pyridin- 3-yl]-2-[[tert-butyl(dimethyl)silyl]oxymethyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate (180 mg, 189.65 pmol, 1 eq) in EtOH (2 mL) under N2. The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred at 25 °C for 16 h under H2 (45 psi). LCMS showed 95% of peak with desired mass. The reaction mixture was added EtOH (150 mL) filtered and concentrated under reduced pressure to give tert-butyl (lS,2S,5R,6R)-6-[6-[5-(tert-butoxycarbonylamino)-3-fluoro-2-(trifluoromethoxy)phenyl]-l- cyclopropyl-7-fluoro-4-isopropyl-2-(tetrahydropyran-2-yloxymethyl)pyrrolo[3,2-c]pyridin-3- yl]-2-[[tert-butyl(dimethyl)silyl]oxymethyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate (185 mg, 184.78 pmol, 97.43% yield, 95% purity) as yellow oil.

[0505] MS (ES+) C48H67N4F5O8Si requires: 950, found 951 [M+H]+.Step 9 tert-butyl (lS,2S,5R,6R)-6-[6-[5-(tert-butoxycarbonylamino)-3-fluoro-2- (trifluoromethoxy)phenyl]-l-cyclopropyl-7-fluoro-4-isopropyl-2-(tetrahydropyran-2- yloxymethyl)pyrrolo[3,2-c]pyridin-3-yl]-2-(hydroxymethyI)-3-azabicycIo[3.1.0]hexane- 3-carboxylate

[0506] To a solution of tert-butyl (lS,2S,5R,6R)-6-[6-[5-(tert-butoxycarbonylamino)-3- fluoro-2-(trifluoromethoxy)phenyl]-l-cyclopropyl-7-fluoro-4-isopropyl-2-(tetrahydropyran-2-yloxymethyl)pyrrolo[3,2-c]pyridin-3-yl]-2-[[tert-butyl(dimethyl)silyl]oxymethyl]-3- azabicyclo[3.1.0]hexane-3-carboxylate (180 mg, 189.25 pmol, 1 eq) in THF (1.5 mL) was added TBAF (I M, 378.49 pL, 2 eq). The mixture was stirred at 25 °C for 1 h under N2. LCMS showed 89% of peak with desired mass. The reaction mixture was quenched with NH4CI (8 mL) and extracted with EtOAc (8 mL x 3), dried over NazSCU, filtered and concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography (4 g SepaFlash® Silica Flash Column, Eluent of 0-70% Ethyl acetate / Petroleum ether gradient @ 50 mL / min) to afford tert-butyl (lS,2S,5R,6R)-6-[6-[5- (tert-butoxycarbonylamino)-3-fhioro-2-(trifluoromethoxy)phenyl]-l-cyclopropyl-7-fluoro-4- isopropyl-2-(tetrahydropyran-2-yloxymethyl)pyrrolo[3,2-c]pyridin-3-yl]-2-(hydroxymethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (103 mg, 119.38 pmol, 63.08% yield, 97% purity) as yellow oil.

[0507] MS (ES+) C42H53N4F5O8 requires: 836, found 837[M+H]+.Step 10 [6-[5-amino-3-fluoro-2-(trifluoromethoxy)phenyl]-l-cyclopropyl-7-fluoro-3- [(lS,2S,5R,6R)-2-(hydroxymethyl)-3-azabicyclo[3.1.0]hexan-6-yl]-4-isopropyl- pyrrolo[3,2-c]pyridin-2-yl]methanol

[0508] To a solution of tert-butyl (lS,2S,5R,6R)-6-[6-[5-(tert-butoxycarbonylamino)-3- fluoro-2-(trifluoromethoxy)phenyl]-l-cyclopropyl-7-fluoro-4-isopropyl-2-(tetrahydropyran- 2-yloxymethyl)pyrrolo[3,2-c]pyridin-3-yl]-2-(hydroxymethyl)-3-azabicyclo[3.1.0]hexane-3- carboxylate (20 mg, 23.90 pmol. 1 eq) in DCM (0.4 mL) was added TFA (307.00 mg, 2.69 mmol, 0.2 mL). The mixture was stirred at 25 °C for 20 min. LCMS showed 80% of peak with desired mass. The reaction mixture was concentrated in vacuum to give a residue which was purified by prep-HPLC (column: Phenomenex Luna C18 150*25mm*10um; mobile phase: [FLO (0.225% FA)-ACN]; gradient: 8%-38% B over 10.0 min) and lyophilized to afford [6-[5-amino-3-fluoro-2-(trifluoromethoxy)phenyl]-l-cyclopropyl-7-fluoro-3- [(lS,2S,5R,6R)-2-(hydroxymethyl)-3-azabicyclo[3.1.0]hexan-6-yl]-4-isopropyl-pyrrolo[3,2- c]pyridin-2-yl]methanol (3.5 mg, 5.85 pmol, 24.47% yield, 100% purity, FA) as a white solid.

[0509] MS (ES+) C27H29F5N4O3 requires: 552, found 553[M+H]+.

[0510] 'H NMR (400 MHz, CD3OD) 6 = 6.65 - 6.57 (m, 2H), 5.01 (s, 2H), 4.19 - 4.05 (m, 1H), 3.90 - 3.75 (m, 2H), 3.72 - 3.63 (m, 1H), 3.59 - 3.43 (m, 3H), 2.34 - 2.25 (m, 1H), 2.16 - 2.07 (m, 1H), 2.06 - 1.96 (m, 1H), 1.41 - 1.33 (m, 6H), 1.27 - 1.10 (m, 4H).(lS,2S,5R,6R)-6-[6-[5-amino-3-fluoro-2-(trifluoromethoxy)phenyI]-l-cyclopropyl-7- fluoro-2-(hydroxymethyl)-4-isopropyl-pyrrolo[3,2-c]pyridin-3-yl]-N,N-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamideStep 1(6-chloro-l-cyclopropyl-7-fluoro-3-iodo-pyrrolo[3,2-c]pyridin-2-yI)methanol

[0511] To a solution of 6-chloro-l-cyclopropyl-7-fluoro-3-iodo-2-(tetrahydropyran-2- yloxymethyl)pyrrolo[3,2-c]pyridine (49.7 g, 110.28 mmol, 1 eq) in DCM (70 mL) was added TFA (53.73 g, 471.19 mmol, 35 mL, 4.27 eq). The mixture was stirred at 30 °C for 6 h. LCMS showed 51% of 6-chloro-l-cyclopropyl-7-fluoro-3-iodo-2-(tetrahydropyran-2- yloxymethyl)pyrrolo[3,2-c]pyridine remained and 34% of peak with desired mass. To the mixture was added saturated N'aHCCh and the pH was adjusted to 9, extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with brine (30 mL), dried over Na2SOr, filtered and concentrated in vacuum to give a residue which was triturated with (Petroleum ether: Ethyl acetate— 3: 1, 50 mL) at 20 °C for 10 min. The mixture was filtered and the filtered cake was dried under vacuum to afford (6-chloro-l-cyclopropyl-7-fluoro-3- iodo-pyrrolo|3,2-c|pyridin-2-yl)methanol (9.9 g, 24.85 mmol, 22.53% yield, 92% purity) as a yellow solid

[0512] MS (ES+) C11H9N2CIFIO requires: 366, found 367 [M+H]+.

[0513] ’H NMR (400 MHz, CDCh) 5 = 8.21 (s, 1H), 4.98 (s, 2H), 3.57 - 3.43 (m, 1H), 1.35 - 1.19 (m, 5H).Step 2 tert-butyI-[(6-ch!oro-l-cyclopropyl-7-fluoro-3-iodo-pyrrolo[3,2-c]pyridin-2- yl)methoxy] -dimethyl-silane

[0514] To a solution of (6-chloro-l-cyclopropyl-7-fluoro-3-iodo-pyrrolo[3,2-c]pyridin-2- yljmethanol (13 g, 28.37 mmol, 1 eq) and TBSC1 (5.13 g, 34.05 mmol, 4.19 mL, 1.2 eq) in DCM (130 mL) were added imidazole (3.86 g, 56.74 mmol, 2 eq) and DMAP (693.24 mg, 5.67 mmol, 0.2 eq). The mixture was stirred at 20 °C for 16 h. LCMS showed starting material was consumed completely and 94% of peak with desired mass. The reaction mixture was concentrated in vacuum to give a residue which was purified by flash silica gel chromatography (120 g SepaFlash® Silica Flash Column, Eluent of 0~8% Ethylacetate / Petroleum ether gradient @ 200 mL / min) to afford tert-butyl- [(6-chloro-l- cyclopropyl-7-fhioro-3-iodo-pyrrolo[3,2-c]pyridin-2-yl)methoxy]-dimethyl-silane (11.6 g, 23.64 mmol, 83.33% yield, 98% purity) as a white solid.

[0515] MS (ES+) Ci7H23N2ClFIOSi requires: 480, found 481 [M+H]+.

[0516] ’H NMR (400 MHz, CDC13) 5 = 8.24 (s, 1H), 4.93 (s, 2H), 3.53 - 3.43 (m, 1H), 1.26 - 1.21 (m, 4H), 0.95 - 0.92 (m, 9H), 0.19 - 0.15 (m, 6H).Step 3(4-bromo-6-chloro- 1 -cyclopropyl-7 -fluoro-3-iodo-pyrrolo[3,2-c]pyridin-2-yI)methoxy- tert-butyl-dimethyl-silane and (4-bromo-6-chloro-l-cyclopropyl-7-fluoro-3-iodo- pyrrolo[3,2-c]pyridin-2-yl)methoxy-tert-butyl-dimethyl-silane

[0517] To a solution of lithium;chloro-(2,2,6,6-tetramethyl-l- piperidyl)magnesium;chloride (1 M, 62.39 mL, 5 eq) was added tert-butyl- [(6-chloro-l- cyclopropyl-7-fhioro-3-iodo-pyrrolo[3,2-c]pyridin-2-yl)methoxy]-dimethyl-silane (6 g, 12.48 mmol, 1 eq) in THF (10 mL) at -20 °C under N2, then the mixture was stirred at -20 °C for 1 h, then l,2-dibromo-l,l,2,2-tetrachloro-ethane (20.32 g, 62.39 mmol, 7.49 mL, 5 eq) in THF (10 mL) was added to the mixture, and stirred at -20 °C stirred for 1 h under N2. LCMS showed 15% of tert-butyl-[(6-chloro-l-cyclopropyl-7-fluoro-3-iodo-pyrrolo[3,2-c]pyridin-2- yl)methoxy]-dimethyl-silane remained and 36% peak with desired mass. The reaction mixture was quenched with NH4CI (100 mL) and extracted with EtOAc (100 mL x 3), dried over Na2SC>4, filtered and concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography (120 g SepaFlash® Silica Flash Column, Eluent of 0~5% Ethyl acetate / Petroleum ether gradient @ 200 mL / min) to afford (4-bromo-6-chloro- l -cyclopropyl-7-fluoro-3-iodo-pyrrolo[3,2-c]pyridin-2-yl)methoxy-tert-buty]-dimethyl-silane (3.5 g, 6.07 mmol, 48.61% yield, 97% purity) as a white solid.

[0518] MS (ES+) Ci7H22N2ClFIBrOSi requires: 560, found 561[M+H]+.Step 4O3-tert-butyl O2-methyl (lS,2S,5R,6R)-6-[4-bromo-2-[[tert- butyl(dimethyl)silyl]oxymethyl]-6-chloro-l-cyclopropyl-7-fluoro-pyrrolo[3,2-c]pyridin- 3-yl]-3-azabicyclo[3.1.0]hexane-2,3-dicarboxylate

[0519] To a solution of (4-bromo-6-chloro-l-cyclopropyl-7-fluoro-3-iodo-pyrrolo[3,2- c]pyridin-2-yl)methoxy-tert-butyl-dimethyl-silane (2 g, 3.57 mmol, 1 eq) and 03-tert-butyl O2-methyl (lS,2S,5R,6R)-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3- azabicyclo[3.1.0]hexane-2,3-dicarboxylate (1.31 g, 3.57 mmol, 1 eq) in THF (60 mL) and H2O (20 mL) were added Pd(dppf)CL (522.91 mg, 714.65 pmol, 0.2 eq) and K2CO3 (1.48 g, 10.72 mmol, 3 eq). The mixture was stirred at 90 °C for 16 h under N2. LCMS showed 13% of peak with desired mass. To the mixture was added water (50 mL) and extracted with EtOAc (50 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography (40 g SepaFlash® Silica Flash Column, Eluent of 0~8% Ethyl acetate / Petroleum ether gradient @ 120 mL / min) to afford 03-tert-butyl O2-methyl (lS,2S,5R,6R)-6-[4-bromo-2-[[tert- butyl(dimethyl)silyl]oxymethyl]-6-chloro-l-cyclopropyl-7-fluoro-pyrrolo[3,2-c]pyridin-3- yl]-3-azabicyclo[3.1.0]hexane-2,3-dicarboxylate (380 mg, 513.75 pmol, 14.38% yield, 91% purity) as yellow oil.

[0520] MS (ES+) C29H4oN3ClFBr05Si requires: 673, found 674 [M+H]+.Step 503-tert-butyl O2-methyl (lS,2S,5R,6R)-6-[2-[[tert-butyl(dimethyl)silyl]oxymethyl]-6- chloro-l-cyclopropyl-7-fluoro-4-isopropenyl-pyrrolo[3,2-c]pyridin-3-yl]-3- azabicyclo[3.1.0]hexane-2,3-dicarboxylate

[0521] To a solution of 03-tert-butyl O2-methyl (lS,2S,5R,6R)-6-[4-bromo-2-[[tert- butyl(dimethyl)silyl]oxymethyl]-6-chloro-l-cyclopropyl-7-fluoro-pyrrolo[3,2-c]pyridin-3- yl]-3-azabicyclo[3.1.0]hexane-2,3-dicarboxylate (380 mg, 564.57 pmol, 1 eq) and potassium;trifluoro(isopropenyl)boranuide (66.83 mg, 451.65 pmol, 0.8 eq) in THF (5.5 mL) were added Pd(dppf)C12-CH2C12 (46.10 mg, 56.46 pmol, 0.1 eq) and K3PO4 (1.5 M, 1.13 mL, 3 eq). The mixture was stirred at 60 °C for 16 h under N2. LCMS showed 56% of peak with desired mass. To the mixture was added water (10 mL) and extracted with EtOAc (10 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography (12 g SepaFlash® Silica Flash Column, Eluent of 0-20% Ethyl acetate / Petroleum ether gradient @ 80 mL / min) to afford 03-tert-butyl O2-methyl (lS,2S,5R,6R)-6-[2-[[tert-butyl(dimethyl)silyl]oxymethyl]-6- chloro- 1 -cyclopropyl-7-fluoro-4-isopropenyl-pyrrolo [3 ,2-c]pyridin-3 -yl] -3 - azabicyclo[3.1.0]hexane-2,3-dicarboxylate (240 mg, 310.29 pmol, 54.96% yield, 82% purity) as yellow oil.

[0522] MS (ES+) C32H45N3FC105Si requires: 633, found 634 [M+H]+.Step 6 03-tert-butyl O2-methyl (lS,2S,5R,6R)-6-[6-[5-(tert-butoxycarbonylamino)-3-fluoro-2- (trifluoromethoxy)phenyl]-2-[[tert-butyl(dimethyl)silyl]oxymethyl]-l-cyclopropyl-7- fluoro-4-isopropenyl-pyrrolo[3,2-c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-2,3- dicarboxylate

[0523] To a solution of 03-tert-butyl O2-methyl (lS,2S,5R,6R)-6-[2-[[tert- butyl(dimethyl)silyl]oxymethyl]-6-chloro-l-cyclopropyl-7-fluoro-4-isopropenyl-pyrrolo[3,2- c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-2,3-dicarboxylate (240 mg, 378.40 pmol, 1 eq) and tert-butyl N-[3-fluoro-5-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)-4-(trifhioromethoxy)phenyl]carbamate (239.07 mg, 567.60 pmol, 1.5 eq) in THF (3.8 mL) were added cataCXium® A Pd G3 (27.56 mg, 37.84 pmol, 0.1 eq) and K3PO4 (1.5 M, 756.80 pL, 3eq). The mixture was stirred at 60 °C for 16 h under N2. LCMS showed 42% of peak with desired mass. To the mixture was added water (10 mL) and extracted with EtOAc (10 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography (12 g SepaFlash® Silica Flash Column, Eluent of 0-30% Ethyl acetate / Petroleum ether gradient @ 80 mL / min) to afford crude product which was purified by prep-HPLC (column: Phenomenex luna Cl 8 150*40mm* 15um; mobile phase: [H2O(0.225% FA)-ACN]; gradient: 95%-100% B over 15.0 min) and concentrated under reduced pressure to give 03-tert-butyl O2-methyl (lS,2S,5R,6R)-6-[6-[5-(tert-butoxycarbonylamino)-3-fluoro-2-(trifluoromethoxy)phenyl]-2- [[tert-butyl(dimethyl)silyl]oxymethyl]-l-cyclopropyl-7-fluoro-4-isopropenyl-pyrrolo[3,2- c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-2,3-dicarboxylate (120 mg, 134.38 pmol, 35.51% yield) as yellow oil.

[0524] MS (ES+) C44HS7N4F5O8Si requires: 892, found 893 [M+H]+.Step 703-tert-butyl O2-methyl (lS,2S,5R,6R)-6-[6-[5-(tert-butoxycarbonylamino)-3-fhioro-2- (trifluoromethoxy)phenyl]-2-[[tert-butyl(diinethyl)silyl]oxymethyI]-l-cydopropyl-7- fluoro-4-isopropyl-pyrrolo[3,2-c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-2,3- dicarboxylate

[0525] To a solution of Pd(OH)2 (96.30 mg, 137.14 pmol, 20% purity) and Pd / C (96.30 mg, 90.49 pmol, 10% purity) in EtOH (3 mL) was added a solution of 03-tert-butyl 02- methyl (lS,2S,5R,6R)-6-[6-[5-(tert-butoxycarbonylamino)-3-fluoro-2- (trifluoromethoxy)phenyl]-2-[[tert-butyl(dimethyl)silyl]oxymethyl]-l-cyclopropyl-7-fluoro- 4-isopropenyl-pyrrolo[3,2-c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-2,3-dicarboxylate (260 mg, 291.15 pmol, 1 eq) in EtOH (3 mL) under N2. The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred at 25 °C for 16 h under H2 (45 psi). LCMS showed starting material was consumed completely and 48% of peak withdesired mass. The reaction mixture was added EtOH (150 mL) filtered and concentrated under reduced pressure to give 03-tert-butyl O2-methyl (lS,2S,5R,6R)-6-[6-[5-(tert- butoxycarbonylamino)-3-fluoro-2-(trifluoromethoxy)phenyl]-2-[[tert- butyl(dimethyl)silyl]oxymethyl]-l-cyclopropyl-7-fluoro-4-isopropyl-pyrrolo[3,2-c]pyridin-3- yl]-3-azabicyclo[3.1.0]hexane-2,3-dicarboxylate (260 mg, 290.49 pmol, 99.77% yield) as yellow oil.

[0526] MS (ES+) C44H59N4F5O8Si requires: 894, found 895[M+H]+.Step 8(lS,2S,5R,6R)-3-tert-butoxycarbonyl-6-[6-[5-(tert-butoxycarbonylamino)-3-fluoro-2-(trifluoromethoxy)phenyl]-2-[[tert-butyl(dimethyl)silyl]oxymethyl]-l-cyclopropyl-7- fluoro-4-isopropyl-pyrrolo[3,2-c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-2-carboxylic acid

[0527] To a solution of 03-tert-butyl O2-methyl (lS,2S,5R,6R)-6-[6-[5-(tert- butoxycarbonylamino)-3-fluoro-2-(trifluoromethoxy)phenyl]-2-[[tert- butyl(dimethyl)silyl]oxymethyl]-l-cyclopropyl-7-fluoro-4-isopropyl-pyrrolo[3,2-c]pyridin-3- yl]-3-azabicyclo[3.1 .0]hexane-2,3-dicarboxylate (260 mg, 290.49 pmol, 1 eq) in THF (0.7 mL) was added a solution of LiOH FFO (30.48 mg, 726.23 pmol, 2.5 eq) in H2O (0.7 mL) at 0 °C. The mixture was stirred at 35 °C for 17 h. MeOH (0.7 mL) was added to the mixture, the mixture was stirred at 35 °C for 1 h. LCMS showed 52% of peak with desired mass. To the mixture was added water (5 mL), the aqueous phase was adjusted to pH=6 with IN HC1 and extracted with ethyl acetate (5 mL x 2), dried over Na SO^ filtered and concentrated under reduced pressure to give (lS,2S,5R,6R)-3-tert-butoxycarbonyl-6-[6-[5-(tert- butoxycarbonylamino)-3-fluoro-2-(trifluoromethoxy)phenyl]-2-[[tert- butyl(dimethyl)silyl]oxymethyl]-l-cyclopropyl-7-fluoro-4-isopropyl-pyrrolo|3,2-c|pyridin-3- yl]-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (220 mg, 249.71 pmol, 85.96% yield) as yellow oil.

[0528] MS (ES+) C43H57N4F5O8Si requires: 880, found 881 [M+H]+.Step 9 tert-butyl (lS,2S,5R,6R)-6-[6-[5-(tert-butoxycarbonylamino)-3-fluoro-2-(trifluoromethoxy)phenyl]-2-[[tert-butyl(dimethyl)silyl]oxymethyl]-l-cyclopropyl-7- fluoro-4-isopropyl-pyrrolo[3,2-c]pyridin-3-yl]-2-(dimethylcarbamoyl)-3- azabicyclo[3.1.0]hexane-3-carboxylate

[0529] To a solution of (lS,2S,5R,6R)-3-tert-butoxycarbonyl-6-[6-[5-(tert- butoxycarbonylamino)-3-fluoro-2-(trifluoromethoxy)phenyl]-2-[[tert- butyl(dimethyl)silyl]oxymethyl]-l-cyclopropyl-7-fluoro-4-isopropyl-pyrrolo[3,2-c]pyridin-3- yl] -3 -azabicyclo [3.1.0]hexane-2-carboxy lie acid (30 mg, 34.05 pmol, 1 eq) and methanamine;hydrochloride (11.50 mg, 170.26 pmol, 5 eq) in DMF (0.5 mL) were added DIEA (35.21 mg, 272.41 pmol, 47.45 pL, 8 eq) and HATU (19.42 mg, 51.08 pmol, 1.5 eq). The mixture was stirred at 25 °C for 1 h. LCMS showed 57% of peak with desired mass. To the mixture was added water (3 mL) and extracted with EtOAc (3 mL x 3), the combined organic phase was washed with brine (5 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography (4 g SepaFlash® Silica Flash Column, Eluent of 0-100% Ethyl acetate / Petroleum ether gradient @ 50 mL / min) to afford tert-butyl (lS,2S,5R,6R)-6-[6-[5- (tert-butoxycarbonylamino)-3-fluoro-2-(trifluoromethoxy)phenyl]-2-[[tert- butyl(dimethyl)silyl]oxymethyl]-l-cyclopropyl-7-fluoro-4-isopropyl-pyrrolo[3,2-c]pyridin-3- yl]-2-(dimethylcarbamoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (41 mg, 26.64 pmol, 78.23% yield, 59% purity) as yellow oil.

[0530] MS (ES+) C45H62N5F5O7Si requires: 907, found 908[M+H]+.Step 10(lS,2S,5R,6R)-6-[6-[5-amino-3-fluoro-2-(trifluoromethoxy)phenyl]-l-cydopropyl-7- fluoro-2-(hydroxymethyl)-4-isopropyl-pyrrolo[3,2-c]pyridin-3-yl]-N,N-dimethyl-3- azabicydo[3.1.0]hexane-2-carboxamide[05311 To a solution of tert-butyl (lS,2S,5R,6R)-6-[6-[5-(tert-butoxycarbonylamino)-3- fluoro-2-(trifluoromethoxy)phenyl]-2-[[tert-butyl(dimethyl)silyl]oxymethyl]-l -cyclopropyl- 7-fluoro-4-isopropyLpyrrolo[3,2-c]pyridin-3-yl]-2-(dimethylcarbamoyl)-3- azabicyclo[3.1.0]hexane-3-carboxylate (41 mg, 45.15 pmol, 1 eq) in DCM (0.3 mL) was added HCl / dioxane (2 M, 0.3 mL). The mixture was stirred at 20 °C for 1 h. LCMS showed 36% of peak with desired mass. The reaction mixture was concentrated in vacuum to give a residue which was purified by prep-HPLC (column: Phenomenex luna C18 150*25mm* lOum; mobile phase: [H2O(0.225% FA)-ACN]; gradient: 19%-39% B over 10.0 min) and lyophilized to afford (lS,2S,5R,6R)-6-[6-[5-amino-3-fluoro-2-(trifluoromethoxy)phenyl]-l- cyclopropyl-7-fluoro-2-(hydroxymethyl)-4-isopropyl-pyrrolo[3,2-c]pyridin-3-yl]-N,N- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (4 mg, 6.00 pmol, 13.30% yield, 96% purity, FA) as a white solid.

[0532] MS (ES+) C29H32F5N5O3 requires: 593, found 594[M+H]+.

[0533] ‘H NMR (400 MHz, CD3OD) 5 = 8.62 - 8.41 (m, 1H), 6.66 - 6.53 (m, 2H), 5.05 (s, 2H), 4.04 - 3.92 (m, 1H), 3.67 - 3.58 (m, 1H), 3.50 - 3.37 (m, 2H), 3.19 (s, 3H), 3.00 (s, 3H), 2.69 - 2.62 (m, 1H), 2.59 - 2.50 (m, 1H), 2.37 - 2.25 (m, 1H), 1.57 - 1.44 (m, 6H), 1.26 - 1.19 (m, 2H), 1.18 - 1.10 (m, 2H).EXAMPLE 863-[8-(3-azabicyclo[3.1.0]hexan-6-yI)-3-fluoro-6-isopropyI-ll-oxa-l,5- diazatricyclo[7.4.0.02,7]trideca-2,4,6,8-tetraen-4-yl]-5-fluoro-4- (trifluoromethoxy)anilineStep 16-chloro-7-fluoro-3-iodo-2-(tetrahydropyran-2-yloxymethyl)-lH-pyrrolo[3,2-c]pyridine

[0534] To a solution of 6-chloro-7-fluoro-2-(tetrahydropyran-2-yloxymethyl)- 1H- pyrrolo[3,2-c]pyridine (12 g, 29.92 mmol, 1 eq) in DMF (125 mL) was added NIS (6.73 g, 29.92 mmol, 1 eq) at 25 °C. Then the mixture was stirred at 25 °C for 1 hour. TLC (Petroleum ether: Ethyl acetate— 3:1) indicated 6-chloro-7-fluoro-2-(tetrahydropyran-2-yloxymethyl)- lH-pyrrolo[3,2-c]pyridine was consumed completely and many new spots formed. The mixture was diluted with ethyl acetate (240 mL) and washed with brine (300 mL x 1). The organic phase was washed with IskhSCE (240 mL x 1) and then washed with brine (300 ml x 3). The combined organic phase washed with anhydrous Na2SO4, filtered and concentrated in vacuum to afford crude product which was triturated with MeCN (10 mL) at 25 °C for 5 min. The mixture was filtered and filter cake was dried in vacuum to afford 6-chloro-7-fluoro-3- iodo-2-(tetrahydropyran-2-yloxymethyl)-lH-pyrrolo[3,2-c]pyridine (4.22 g, 10.28 mmol, 34.34% yield) as a white solid.

[0535] MS (ES+) C13H13CIFIN2O2 requires: 409, found: 410 [M+H]+.

[0536] ’H NMR (400 MHz, DMSO-de) 5 = 13.02 (s, 1H), 8.30 - 8.15 (m, 1H), 4.77 (d, J = 12.6 Hz, 1H), 4.73 - 4.70 (m, 1H), 4.60 (d, J = 12.6 Hz, 1H), 3.85 - 3.77 (m, 1H), 3.57 - 3.44 (m, 1H), 1.77 - 1.58 (m, 2H), 1.58 - 1.41 (m, 4H).Step 22-[[6-chloro-7-fluoro-3-iodo-2-(tetrahydropyran-2-yloxymethyl)pyrrolo[3,2-c]pyridin-l- yl]methoxy]ethyl-trimethyl-silane

[0537] To a solution of 6-chloro-7-fluoro-3-iodo-2-(tetrahydropyran-2-yloxymethyl)-lH- pyrrolo[3,2-c]pyridine (3.5 g, 8.52 mmol, 1 eq) in DMF (30 mL) was added NaH (511.39 mg, 12.79 mmol, 60% purity, 1.5 eq) at 0 °C under N2 and stirred at 0 °C for 0.5 h, then added SEM-C1 (1.71 g, 10.23 mmol, 1.81 mL, 1.2 eq) at 0 °C under N2, stirred at 25 °C for 1 hour. LCMS showed 6-chloro-7-fluoro-3-iodo-2-(tetrahydropyran-2-yloxymethyl)-lH-pyrrolo[3,2- c] pyridine was consumed completely and 96% of desired compound. The mixture was added H2O (50 mL) at 0 °C. The mixture was extracted with ethyl acetate (60 mL x 3). The combined organic phase was washed with brine (200 mL x 3), dried with anhydrous Na2SC>4, filtered and concentrated in vacuum to afford residue which was purified by flash silica gel chromatography (40 g SepaFlash® Silica Flash Column, Eluent of 0-20% Ethyl acetate / Petroleum ether gradient @ 80 mL / min) to afford 2-[[6-chloro-7-fhioro-3-iodo-2- (tetrahydropyran-2-yloxymethyl)pyrrolo[3,2-c]pyridin-l-yl]methoxy]ethyl-trimethyl-silane (4 g, 7.40 mmol, 86.76% yield) as yellow oil.

[0538] MS (ES+) Ci9H27ClFIN2O3Si requires: 540, found: 541 [M+H]+.

[0539] ’H NMR (400 MHz, DMSO-O 5 = 8.29 (s, 1H), 5.74 - 5.61 (m, 2H), 4.93 (d, J = 12.6 Hz, 1H), 4.80 - 4.64 (m, 2H), 3.92 - 3.77 (m, 1H), 3.63 - 3.44 (m, 3H), 1.77 - 1.59 (m, 2H), 1.55 - 1.43 (m, 4H), 0.89 - 0.75 (m, 2H), -0.11 (s, 9H).Step 3 tert-butyl 6-[6-chloro-7-fluoro-2-(tetrahydropyran-2-yloxymethyl)-l-(2- trimethyIsilylethoxymethyl)pyrrolo[3,2-c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-3- carboxylate

[0540] A mixture of 2-[[6-chloro-7-fluoro-3-iodo-2-(tetrahydropyran-2- yloxymethyl)pyrrolo[3,2-c]pyridin-l-yl]methoxy]ethyl-trimethyl-silane (2 g, 3.70 mmol, 1 eq), tert-butyl 6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3-azabicyclo[3.1.0]hexane-3- carboxylate (1.14 g, 3.70 mmol, 1 eq), cataCXium® A Pd G3 (269.30 mg, 369.78 pmol, 0.1 eq), K3PO4 (1.5 M, 7.40 mL, 3 eq) in dioxane (37 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 100 °C for 3 hours under N2 atmosphere. LCMS showed 2-[[6-chloro-7-fluoro-3-iodo-2-(tetrahydropyran-2-yloxymethyl)pyrrolo[3,2- c]pyridin-l -yl]methoxy]ethyl-trimethyl-silane was consumed completely and 53% of desired compound.

[0541] The reaction mixture was added Ethyl acetate (50 mL) and dried over NaiSCU, filtered and concentrated under reduced pressure to afford residue which was purified by flash silica gel chromatography (20 g SepaFlash® Silica Flash Column, Eluent of 0-11% Ethyl acetate / Petroleum ether gradient @ 60 mL / min) to afford tert-butyl 6-[6-chloro-7- fluoro-2-(tetrahydropyran-2-yloxymethyl)-l-(2-trimethylsilylethoxymethyl)pyrrolo[3,2- c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate (1.18 g, 1.98 mmol, 53.52% yield) as yellow oil.

[0542] MS (ES+) C29H43ClFN3O5Si requires: 595, found: 596 [M+H]+.Step 4 tert-butyl 6-[4-bromo-6-chloro-7-fluoro-2-(tetrahydropyran-2-yloxymethyl)-l-(2- trimethyIsilylethoxymethyl)pyrrolo[3,2-c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-3- carboxylate

[0543] To a solution of lithium;chloro-(2,2,6,6-tetramethyl-l- piperidyl)magnesium;chloride (1 M, 19.96 mL, 7 eq) was added tert-butyl 6-[6-chloro-7- fluoro-2-(tetrahydropyran-2-yloxymethyl)-l-(2-trimethylsilylethoxymethyl)pyrrolo[3,2- c]pyridin-3-yl]-3-azabicyclo[3.1 .0]hexane-3-carboxylate (1.7 g, 2.85 mmol, 1 eq) in THF (5 mL) at 0 °C under N2. The mixture was stirred at 0 °C for 1 hour under N2. Then 1 ,2- dibromo-l,l,2,2-tetrachloro-ethane (4.64 g, 14.26 mmol, 1.71 mL, 5 eq) in THF (5 mL) was added to the mixture...

Claims

CLAIMSWhat is claimed is:1 . A compound of Formula I:or a salt or tautomer thereof, whereinQ is chosen fromJ1, J2and J3are independently chosen from CR12and N;J4is chosen from N, NR12, CH and S;X is chosen from CR5and NR5;Y is chosen from CR6, N, and NR6;Z is chosen from CR7, N, and NR7;R1is chosen from H, alkyl, halo, OH, and NH2;R2is chosen from H, alkyl, and halo;R3is chosen from H, alkyl, alkoxy, haloalkyl, haloalkoxy, halo, and -SF5;R4is chosen from H, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, aryl, heteroaryl, alkoxy, amino, alkylamino, and dialkylamino, wherein alkyl, cycloalkyl, heterocycloalkyl, alkenyl, aryl, heteroaryl, alkoxy, amino, alkylamino, and dialkylamino may be optionally substituted by one or more R8; or R4and R12, taken together, form a 5- membered heteroaryl;R5is chosen fromeither of which may be optionally substituted by one or more R9;R6is chosen from H, amino, alkyl, alkynyl, heteroaryl, and cyano, wherein alkyl and alkynyl may be optionally substituted by one or more groups chosen from hydroxy, cyano, -N(R13)2, -NHC(O)-R14, -C(O)N(R15)2, -NHS(O)2-alkyl, heteroaryl, heterocycloalkyloxy, and heterocycloalkylamino, wherein heteroaryl,heterocycloalkyloxy, and heterocycloalkylamino are optionally substituted with halo or alkyl, or R6and R7, taken together, form a 6-membered heterocycloalkyl optionally substituted with one or more R16; or R6and R9, taken together, form -CH2O(CH2)4OCH2O-;R7is chosen from H, alkyl, amino, alkylamino, dialkylamino, alkoxy, heteroalkyl, cycloalkyl, heterocycloalkyl, haloalkyl, sulfoxyalkyl, aryl, and heteroaryl, wherein alkyl, amino, alkylamino, dialkylamino, alkoxy, heteroalkyl, cycloalkyl, heterocycloalkyl, haloalkyl, sulfoxyalkyl, aryl, and heteroaryl may he optionally substituted by one or moreR10; each R8is independently chosen from halo, alkyl, alkoxy, cyano, hydroxy, haloalkyl, - C(O)NH2, and oxo; each R9is independently chosen from alkyl, amido, -C(O)O-alkyl, -C(O)O- cycloalkyl, -C(O)N(R13)2, and heteroaryl, wherein alkyl may be optionally substituted byR11; each R10is independently chosen from alkyl, amino, alkylamino, dialkylamino, halo, cyano, -C(O)NH2, and hydroxy;R11is chosen from alkoxy, hydroxy, oxo, amino, alkylamino, dialkylamino, and halo; each R12is independently chosen from H, halo, alkyl, amino, and cyano; each R1is independently chosen from H, alkyl, and haloalkyl;R14is chosen from alkyl, cyanoalkyl, hydroxyalkyl, alkoxy, and heteroaryl; each R15is independently chosen from H and alkyl; and each R16is independently chosen from halo and alkyl.

2. The compound of claim 1, or a salt or tautomer thereof, wherein3. The compound of claim 2, or a salt or tautomer thereof, wherein4. The compound of claim 2, or a salt or tautomer thereof, wherein J2is CH and J3is N.

5. The compound of claim 2, or a salt or tautomer thereof, wherein J2is CF and J3is N.

6. The compound of claim 2, or a salt or tautomer thereof, wherein J2and J3are CH.

7. The compound of claim 2, or a salt or tautomer thereof, wherein R1is NH2.

8. The compound of claim 2, or a salt or tautomer thereof, wherein R1is OH.

9. The compound of claim 2, or a salt or tautomer thereof, wherein R2is chosen from H, methyl, fluoro, and chloro.

10. The compound of claim 2, or a salt or tautomer thereof, wherein R3is chosen from trifluoromethyl, trifluoromethoxy, chloro, and -SFs.

11. The compound of claim 2, or a salt or tautomer thereof, wherein Q is chosen from12. The compound of claim 11, or a salt or tautomer thereof, wherein13. The compound of claim 11 , or a salt or tautomer thereof, wherein14. The compound of claim 1 , or a salt or tautomer thereof, wherein15. The compound of claim 14, or a salt or tautomer thereof, whereinR12is -NH2.

16. The compound of claim 14, or a salt or tautomer thereof, wherein J2is N.

17. The compound of claim 14, or a salt or tautomer thereof, wherein J3is CR12, wherein R12is cyano.

18. The compound of claim 14, or a salt or tautomer thereof, wherein J3is N.

19. The compound of claim 14, or a salt or tautomer thereof, wherein J4is CH.

20. The compound of claim 14, or a salt or tautomer thereof, wherein J4is S.

21. The compound of claim 14, or a salt or tautomer thereof, wherein J4is N.

22. The compound of claim 14, or a salt or tautomer thereof, wherein R2is chosen from H and fluoro.

23. The compound of claim 14, or a salt or tautomer thereof, wherein R1is chosen from H and methyl.

24. The compound of claim 14, or a salt or tautomer thereof, wherein R3is chosen from H and chloro.

25. The compound of claim 14, or a salt or tautomer thereof, wherein Q is chosen from26. The compound of claim 25, or a salt or tautomer thereof, wherein27. The compound of any one of claims 1 to 26, or a salt or tautomer thereof, wherein R4is chosen from H, ethyl, isopropyl, isobutyl, isopropoxy, cyclopropyl, 1- methylcyclopropyl, tetrahydrofuran-2-ol, propylnitrile, propan-l-ol, trifluoroprop- 1- en-2-yl, phenyl, propenyl, cyclopentenyl, 1 -methylpyrazolyl, dimethylamino, isobutanol, aminoethanol, isobutanone, acetonitrile, isobutylnitrile, methoxyisopropyl,28. The compound of any one of claims 1 to 26, or a salt or tautomer thereof, wherein R4is chosen from alkyl, cycloalkyl, and cyanoalkyl.

29. The compound of claim 28, wherein R4is chosen from isopropyl, cyclopropyl, and propylnitrile.

30. The compound of claim 29, wherein R4is isopropyl.

31. The compound of claim 29, wherein R4is cyclopropyl.

32. The compound of claim 29, wherein R4is propylnitrile.

33. The compound of any one of claims 1 t< > 32, or a salt or tautomer thereof, wherein J1is N.

34. The compound of any one of claims 1 to 33, or a salt or tautomer thereof, wherein X is CR5.

35. The compound of claim 34, or a salt or tautomer thereof, wherein R5is chosen from36. The compound of claim 35, or a salt or tautomer thereof, wherein R5is chosen from37. The compound of claim 36, or a salt or tautomer thereof, wherein38. The compound of claim 36, or a salt or tautomer thereof, wherein39. The compound of claim 36, or a salt or tautomer thereof, wherein R5is40. The compound of any one of claims 1 to 39, or a salt or tautomer thereof, wherein Y is CR6.

41. The compound of claim 40, or a salt or tautomer thereof, wherein R6is chosen from hydroxyalkynyl and -alkyl-NHC(O)-R14.

42. The compound of claim 41, or a salt or tautomer thereof, wherein R6is hydroxyalkynyl.

43. The compound of claim 42, or a salt or tautomer thereof, wherein R6is OH .

44. The compound of claim 41, or a salt or tautomer thereof, wherein R6is chosen from hydroxyalkynyl and -alkyl-NHC(O)-R14.O45. The compound of claim 44, or a salt or tautomer thereof, wherein R6is H46. The compound of any one of claims 1 to 39, or a salt or tautomer thereof, wherein Y is N.

47. The compound of any one of claims 1 to 46, or a salt or tautomer thereof, wherein Z is NR7.

48. The compound of claim 47, or a salt or tautomer thereof, wherein R7is cyclopropyl optionally substituted with R10.

49. The compound of claim 48, or a salt or tautomer thereof, wherein R7is cyclopropyl.

50. The compound of claim 48, or a salt or tautomer thereof, wherein R7is51. The compound of any one of claims 1 to 50, or a salt or tautomer thereof, whereinJ1is N;X is CR5;Y is CR6; andZ is NR7.

52. The compound of any one of claims 1 to 50, or a salt or tautomer thereof, whereinJ1is N;X is CR5;Y is N; and Z is NR7.

53. The compound of claim 1, or a salt or tautomer thereof, having a structural formula of Formula II:wherein n is 0, 1 , or 2J2and J3are independently chosen from CR12and N;Y is chosen from CR6, N, and NR6;R1is chosen from H, alkyl, halo, OH, and NH2;R2is chosen from H, alkyl, and halo;R3is chosen from H, alkyl, alkoxy, haloalkyl, haloalkoxy, halo, and -SF5;R4is chosen from H, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, aryl, heteroaryl, alkoxy, amino, alkylamino, and dialkylamino, wherein alkyl, cycloalkyl, heterocycloalkyl, alkenyl, aryl, heteroaryl, alkoxy, amino, alkylamino, and dialkylamino may be optionally substituted by one or more R8; or R4and R12, taken together, form a 5-membered heteroaryl;R6is chosen from H, amino, alkyl, alkynyl, heteroaryl, and cyano, wherein alkyl and alkynyl may be optionally substituted by one or more groups chosen from hydroxy, cyano, -N(R13)2, -NHC(O)-R14, -C(O)N(R15)2, alkyl-S(O)2NH-, heteroaryl, heterocycloalkyloxy, and heterocycloalkylamino, wherein heteroaryl, heterocycloalkyloxy, and heterocycloalkylamino are optionally substituted with halo or alkyl; or R6and R9, taken together, form -CH2O(CH2)4OCH2O-;R7is chosen from H, alkyl, amino, alkylamino, dialkylamino, alkoxy, heteroalkyl, cycloalkyl, heterocycloalkyl, haloalkyl, sulfoxyalkyl, aryl, and heteroaryl, wherein alkyl, amino, alkylamino, dialkylamino, alkoxy, heteroalkyl, cycloalkyl, heterocycloalkyl, haloalkyl, sulfoxyalkyl, aryl, and heteroaryl may be optionally substituted by one or more R10;each R8is independently chosen from halo, alkyl, alkoxy, cyano, hydroxy, haloalkyl, -C(0)NH2, and oxo; each R9is independently chosen from alkyl, amido, -C(O)O-alkyl, -C(O)O- cycloalkyl, -C(O)N(R13)2, and heteroaryl, wherein alkyl may be optionally substituted by R11; each R12is independently chosen from H, halo, alkyl, amino, and cyano; each R13is independently chosen from H, alkyl, and haloalkyl;R14is chosen from alkyl, cyanoalkyl, hydroxyalkyl, alkoxy, and heteroaryl; each R15is independently chosen from H and alkyl; and each R16is independently chosen from halo and alkyl.

54. The compound of claim 1 , or a salt or tautomer thereof, having a structural formula of Formula III:wherein n is 0, 1 , or 2J2and J3are independently chosen from CR12and N;Y is chosen from CR6, N, and NR6;R1is chosen from H, alkyl, halo, OH, and NH2;R2is chosen from H, alkyl, and halo;R3is chosen from H, alkyl, alkoxy, haloalkyl, haloalkoxy, halo, and -SF5;R4is chosen from H, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, aryl, heteroaryl, alkoxy, amino, alkylamino, and dialkylamino, wherein alkyl, cycloalkyl, heterocycloalkyl, alkenyl, aryl, heteroaryl, alkoxy, amino, alkylamino, and dialkylamino may be optionally substituted by one or more R8; or R4and R12, taken together, form a 5-membered heteroaryl;R6is chosen from H, amino, alkyl, alkynyl, heteroaryl, and cyano, wherein alkyl and alkynyl may be optionally substituted by one or more groups chosen from hydroxy, cyano, -N(R13)2, -NHC(O)-R14, -C(O)N(R15)2, alkyl-S(O)2NH-, heteroaryl, heterocycloalkyloxy, and heterocycloalkylamino, wherein heteroaryl,heterocycloalkyloxy, and heterocycloalkylamino are optionally substituted with halo or alkyl; or R6and R9, taken together, form -CH2O(CH2)4OCH2O-;R7is chosen from H, alkyl, amino, alkylamino, dialkylamino, alkoxy, heteroalkyl, cycloalkyl, heterocycloalkyl, haloalkyl, sulfoxyalkyl, aryl, and heteroaryl, wherein alkyl, amino, alkylamino, dialkylamino, alkoxy, heteroalkyl, cycloalkyl, heterocycloalkyl, haloalkyl, sulfoxyalkyl, aryl, and heteroaryl may be optionally substituted by one or more R10; each R8is independently chosen from halo, alkyl, alkoxy, cyano, hydroxy, haloalkyl, -C(0)NH2, and oxo; each R9is independently chosen from alkyl, amido, -C(O)O-alkyl, -C(O)O- cycloalkyl, -C(O)N(R13)2, and heteroaryl, wherein alkyl may be optionally substituted by R11; each R12is independently chosen from H, halo, alkyl, amino, and cyano; each R13is independently chosen from H, alkyl, and haloalkyl;R14is chosen from alkyl, cyanoalkyl, hydroxyalkyl, alkoxy, and heteroaryl; each R15is independently chosen from H and alkyl; and each R16is independently chosen from halo and alkyl.

55. The compound of claim 1, or a salt or tautomer thereof, having a structural formula of Formula IV :wherein:A is a 6- membered heterocycloalkyl; m is 0, 1, 2, 3, 4; n is 0, 1, or 2;J2and J3are independently chosen from CR12and N;Y is chosen from CR6, N, and NR6;R1is chosen from H, alkyl, halo, OH, and NH2;R2is chosen from H, alkyl, and halo;R3is chosen from H, alkyl, alkoxy, haloalkyl, haloalkoxy, halo, and -SF5;R4is chosen from H, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, aryl, heteroaryl, alkoxy, amino, alkylamino, and dialkylamino, wherein alkyl, cycloalkyl, heterocycloalkyl, alkenyl, aryl, heteroaryl, alkoxy, amino, alkylamino, and dialkylamino may be optionally substituted by one or more R8; or R4and R12, taken together, form a 5-membered heteroaryl; each R8is independently chosen from halo, alkyl, alkoxy, cyano, hydroxy, haloalkyl, -C(0)NH2, and oxo; each R9is independently chosen from alkyl, amido, -C(O)O-alkyl, -C(O)O- cycloalkyl, -C(O)N(R13)2, and heteroaryl, wherein alkyl may be optionally substituted by R11; each R12is independently chosen from H, halo, alkyl, amino, and cyano; and each R16is independently chosen from halo and alkyl.

56. The compound of claim 55, or a salt or tautomer thereof, wherein A is.

57. The compound of claim 1, or a salt or tautomer thereof, wherein the compound of Formula I has a structural formula chosen from:

58. The compound of claim 57, or a salt or tautomer thereof, wherein the compound ofFormula I has a structural formula chosen from:

59. A pharmaceutical formulation comprising a compound as recited in any one of claims 1-58, or a salt or tautomer thereof, together with a pharmaceutically acceptable carrier.

60. The pharmaceutical formulation as recited in claim 59, formulated for oral administration.

61. The pharmaceutical formulation as recited in claim 59 or 60, additionally comprising another therapeutic agent.

62. A method of inhibition of NRAS G12D, comprising contacting NRAS G12D with a compound as recited in any one of claims 1-58, or a salt or tautomer thereof, or a pharmaceutical composition as recited in any one of claims 59-61.

63. A method of treatment of an NRAS G12D-mediated disease, comprising the administration of a therapeutically effective amount of a compound as recited in any one of claims 1 -58, or a salt or tautomer thereof, or a pharmaceutical composition as recited in any one of claims 59-61, to a patient in need thereof.

64. The method as recited in claim 63, wherein the NRAS G12D-mediated disease is cancer.

65. The method as recited in claim 64, wherein the cancer is chosen from Melanoma, Malignant Solid Tumors, Colorectal Carcinoma, Non-Small Cell Lung Carcinoma, Acute Myeloid Leukemia, Myelodysplastic Syndromes, Chronic Myelomonocytic Leukemia, Colorectal Adenocarcinoma, Multiple Myeloma, Non-Hodgkin Lymphoma, Pancreatic Carcinoma, Cutaneous Melanoma, Ovarian Carcinoma, Pancreatic Ductal Adenocarcinoma, Acute Lymphoblastic Leukemia, Thyroid Gland Carcinoma, Glioma, Neurofibromatosis, Poorly Differentiated Thyroid Gland Carcinoma, Myelodysplastic Syndrome With Excess Blasts, Juvenile Myelomonocytic Leukemia, Histiocytic And Dendritic Cell Neoplasm, Head And Neck Squamous Cell Carcinoma, Small Cell Lung Carcinoma, Low Grade Glioma, Squamous Cell Lung Carcinoma, Breast Carcinoma, Chronic Myelomonocytic Leukemia, Thyroid Gland Undifferentiated (Anaplastic) Carcinoma, Embryonal Rhabdomyosarcoma, Thyroid Gland Follicular Carcinoma, T-Cell Acute Lymphoblastic Leukemia, Mucosal Melanoma, Low Grade Ovarian Serous Adenocarcinoma, Thyroid Gland Papillary Carcinoma, Refractory Anemia With Excess Blasts, Myeloid Neoplasm, Myelodysplastic / Myeloproliferative Neoplasm, Rectal Carcinoma, Colon Carcinoma, Malignant Peripheral Nerve Sheath Tumor, Cholangiocarcinoma, Endometrial Carcinoma, Mantle Cell Lymphoma, Secondary Myelodysplastic Syndrome, Therapy-Related Myelodysplastic Syndrome, Lymphoma, Neuronal And Mixed Neuronal-Glial Tumors, Ganglioglioma, Soft Tissue Sarcoma, Bladder Carcinoma, Esophageal Carcinoma, Sarcoma, Thymic Carcinoma, Lung Adenocarcinoma, Lung Carcinoma, Uveal Melanoma, Head And Neck Carcinoma, Diffuse Glioma, Squamous Cell Carcinoma, Chronic MyeloidLeukemia, Adenocarcinoma of the Gastroesophageal Junction, Glioblastoma, Neuroblastoma, Astrocytic Tumor, Hepatocellular Carcinoma, Pancreatic Adenocarcinoma, Diffuse Large B-Cell Lymphoma, Anaplastic Astrocytoma, Gastric Adenocarcinoma, Gastric Carcinoma, Prostate Carcinoma, Renal Cell Carcinoma, B- Cell Acute Lymphoblastic Leukemia, Double-Hit Lymphoma, Dysembryoplastic Neuroepithelial Tumor, Gangliocytoma, Low-Grade Neuroepithelial Tumor, Peripheral T-Cell Lymphoma, Pilocytic Astrocytoma, Pilomyxoid Astrocytoma, Rhabdoid Tumor, and Schwannoma.

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