WO2018229543A2

WO2018229543A2 - Therapeutic inhibitory compounds

Info

Publication number: WO2018229543A2
Application number: PCT/IB2018/000702
Authority: WO
Inventors: Andrew Mcdonald; Shawn QIAN
Original assignee: Lifesci Pharmaceuticals, Inc.
Priority date: 2017-06-14
Filing date: 2018-06-14
Publication date: 2018-12-20
Also published as: WO2018229543A3

Abstract

Provided herein are heterocyclic derivative compounds and pharmaceutical compositions comprising said compounds which are complement factor D inhibitors. Such compounds are useful for treating complement related disorders including, but are not limited to, autoimmune, inflammatory, and neurodegenerative diseases.

Description

THERAPEUTIC INHIBITORY COMPOUNDS

CROSS-REFERENCE

[0001] This application claims benefit of U.S. Provisional Patent Application No. 62/519,755 filed on June 14, 2017, and U.S. Provisional Patent Application No. 62/520,951 filed on June 16, 2017, each incorporated herein by reference in its entirety.

BACKGROUND

[0002] A need exists in the medicinal arts for the effective treatment of diseases and disorders mediated by complement factor D. Such diseases and disorders include, but are not limited to, autoimmune, inflammatory, and neurodegenerative diseases.

BRIEF SUMMARY OF THE INVENTION

[0003] Provided herein are heterocyclic derivative compounds and pharmaceutical compositions comprising said compounds. The subject compounds and compositions are useful for inhibiting complement factor D activity.

[0004] One embodiment provides a compound, or a pharmaceutically acceptable salt thereof, having the structure of Formula (I :

wherein,

W, X, and Z are each independently selected from N or C-R¹;

each Pv¹ is independently selected from hydrogen, cyano, halo, hydroxy, azido, amino, nitro, -

20 20 20

C0₂H, -S(0)-Pv , -S-R , -S(0)₂-R , optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted (heterocyclyl)-O-, optionally substituted alkyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted alkenyl, optionally substituted

21 20 20 aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, -N(R ), -CO-R , -C0₂-R , - CO(NR²¹)₂, -NR²¹CO-R²⁰, -NR²¹C0₂-R²⁰, -S0₂(NR²¹)₂, -C(=NR²²)-(NR²¹)₂, -NR²¹CO-R²⁰, -NR²¹C0₂-R²⁰, - NR²¹CO-N(R²⁰)₂, -NR²¹SO₂-N(R²⁰)₂;

each R²⁰ is independently optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; each R²¹ is independently hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;

R² is optionally substituted aryl, or optionally substituted heteroaryl;

R³ is selected from NH₂, optionally substituted alkylamino, optionally substituted dialkylamino, optionally substituted alkyl, optionally substituted carbocyclyl, or optionally substituted heterocyclyl;

R⁴ is selected from hydrogen, -CN, -(CH₂)_n-C0₂H, -(CH₂)_n-CO(NR²¹)₂, -(CH₂)_n-C0₂-R²⁰, - (CH₂)_n-NR²¹CO-R²⁰, -(CH₂)_n-NR²¹C0₂-R²⁰, -(CH₂)_n-S0₂(NR²¹)₂, -(CH₂)_n-OH, -(CH₂)_n-NH₂;

R⁵ is selected from -NRⁿCO-R¹⁰, -NRⁿC0₂-R¹⁰, -NR¹ CO-N(R¹²)₂, -NR¹ S0₂-N(R¹²)₂, -O- CO-R¹⁰, -O-CO-R²⁰, -0-C0₂-R¹⁰, -0-C0₂-R²⁰, optionally substituted aralkoxy, optionally substituted heteroarylalkoxy, optionally substituted (carbocyclyl)-O-, optionally substituted heterocyclylalkoxy;

R¹⁰ is optionally substituted carbocyclylalkyl, optionally substituted aralkyl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl;

R¹¹ is independently hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, or optionally, R¹⁰ and R¹¹ join to form a ring;

each R¹² is independently hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted

carbocyclylalkyl, optionally substituted aralkyl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl; or two R¹² groups join to form a N-linked heterocyclyl;

R¹³ is independently hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; or optionally, one R¹² and R¹³ join to form a ring;

each R⁶ is independently selected from hydrogen, cyano, halo, hydroxy, amino, optionally substituted alkylamino, optionally substituted dialkylamino, or optionally substituted alkoxy;

n is 0, 1, or 2; and m is 0, 1, 2, or 3.

[0005] One embodiment provides a compound, or a pharmaceutically acceptable salt thereof, having the structure of Formula (II):

(II)

wherein,

U is NH and V is CH, or U is CH₂ and V is N;

W, X, and Z are each independently selected from N or C-R¹;

each R¹ is independently selected from hydrogen, cyano, halo, hydroxy, azido, amino, nitro, -

C0₂H, -S(0)-R , -S-R , -S(0)₂-R , optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted (heterocyclyl) -0-, optionally substituted alkyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted alkenyl, optionally substituted

each R²⁰ is independently optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;

each R²¹ is independently hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;

R² is optionally substituted aryl, or optionally substituted heteroaryl;

R¹¹ is independently hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, or optionally, R¹⁰ and R¹¹ join to form a ring; each R¹² is independently hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted

n is 0, 1, or 2; and m is 0, 1, 2, or 3.

[0006] One embodiment provides a compound, or a pharmaceutically acceptable salt thereof, having the structure of Formula III):

V is N, T is N, and U is C; or V is C, T is CH, and U is N;

W, X, and Z are each independently selected from N or C-R¹;

20 20 20

R² is optionally substituted aryl, or optionally substituted heteroaryl; R³ is selected from NH₂, optionally substituted alkylamino, optionally substituted dialkylamino, optionally substituted alkyl, optionally substituted carbocyclyl, or optionally substituted heterocyclyl;

n is 0, 1, or 2; and m is 0, 1, 2, or 3.

[0007] One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof.

[0008] One embodiment provides a method of treating an autoimmune, inflammatory, or neurodegenerative disease in a patient in need thereof comprising administering to the patient a

pharmaceutical composition comprising a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof.

INCORPORATION BY REFERENCE

[0009] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference for the specific purposes identified herein.

DETAILED DESCRIPTION OF THE INVENTION

[0010] As used herein and in the appended claims, the singular forms "a," "and," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "an agent" includes a plurality of such agents, and reference to "the cell" includes reference to one or more cells (or to a plurality of cells) and equivalents thereof known to those skilled in the art, and so forth. When ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formulae, all combinations and subcombinations of ranges and specific embodiments therein are intended to be included. The term "about" when referring to a number or a numerical range means that the number or numerical range referred to is an approximation within experimental variability (or within statistical experimental error), and thus the number or numerical range, in some instances, will vary between 1% and 15% of the stated number or numerical range. The term "comprising" (and related terms such as "comprise" or "comprises" or "having" or "including") is not intended to exclude that in other certain embodiments, for example, an embodiment of any composition of matter, composition, method, or process, or the like, described herein, "consist of or "consist essentially of the described features.

Definitions

[0011] As used in the specification and appended claims, unless specified to the contrary, the following terms have the meaning indicated below.

[0012] "Amino" refers to the -NH₂ radical.

[0013] "Cyano" refers to the -CN radical.

[0014] "Nitro" refers to the -N0₂ radical.

[0015] "Oxa" refers to the -O- radical.

[0016] "Oxo" refers to the =0 radical.

[0017] "Thioxo" refers to the =S radical.

[0018] "Imino" refers to the =N-H radical.

[0019] "Oximo" refers to the =N-OH radical.

[0020] "Hydrazino" refers to the =N-NH₂ radical.

[0021] "Alkyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to fifteen carbon atoms (e.g., C1-C15 alkyl). In certain embodiments, an alkyl comprises one to thirteen carbon atoms (e.g., C1-C13 alkyl). In certain embodiments, an alkyl comprises one to eight carbon atoms (e.g., Ci-C₈ alkyl). In other embodiments, an alkyl comprises one to five carbon atoms (e.g., Ci-C₅ alkyl). In other embodiments, an alkyl comprises one to four carbon atoms (e.g., C1-C4 alkyl). In other embodiments, an alkyl comprises one to three carbon atoms (e.g., C1-C3 alkyl). In other embodiments, an alkyl comprises one to two carbon atoms (e.g., Ci-C₂ alkyl). In other embodiments, an alkyl comprises one carbon atom (e.g., Ci alkyl). In other embodiments, an alkyl comprises five to fifteen carbon atoms (e.g., C₅-Ci₅ alkyl). In other embodiments, an alkyl comprises five to eight carbon atoms (e.g., C₅-C₈ alkyl). In other embodiments, an alkyl comprises two to five carbon atoms (e.g., C₂-C₅ alkyl). In other embodiments, an alkyl comprises three to five carbon atoms (e.g., C₃-C₅ alkyl). In other embodiments, the alkyl group is selected from methyl, ethyl, 1 -propyl (^-propyl), 1-methylethyl (zso-propyl), 1 -butyl («-butyl), 1-methylpropyl (sec-butyl), 2-methylpropyl (/so-butyl), 1, 1-dimethylethyl (fert-butyl), 1-pentyl («-pentyl). The alkyl is attached to the rest of the molecule by a single bond. Unless stated otherwise specifically in the specification, an alkyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR^a, -SR^a, -OC(0)-R^a, -N(R^a)₂, -C(0)R^a, -C(0)OR^a, -C(0)N(R^a)₂, -N(R^a)C(0)OR^a, -OC(0)-N(R^a)₂, -N(R^a)C(0)R^a, -N(R^a)S(0),R^a (where t is 1 or 2), -S(0)_tOR^a (where t is 1 or 2), -S(0)_tR^a (where t is 1 or 2) and -S(0)_tN(R^a)₂ (where t is 1 or 2) where each R^a is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or

trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[0022] "Alkoxy" refers to a radical bonded through an oxygen atom of the formula -O-alkyl, where alkyl is an alkyl chain as defined above.

[0023] "Alkenyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon double bond, and having from two to twelve carbon atoms. In certain embodiments, an alkenyl comprises two to eight carbon atoms. In other embodiments, an alkenyl comprises two to four carbon atoms. The alkenyl is attached to the rest of the molecule by a single bond, for example, ethenyl (i.e., vinyl), prop-l-enyl (i.e., allyl), but-l-enyl, pent-l-enyl, penta-l,4-dienyl, and the like. Unless stated otherwise specifically in the specification, an alkenyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR^a, -SR^a, -OC(0)-R^a, -N(R^a)₂, -C(0)R^a, -C(0)OR^a, -C(0)N(R^a)₂, -N(R^a)C(0)OR^a, - OC(0)-N(R^a)₂, -N(R^a)C(0)R^a, -N(R^a)S(0),R^a (where t is 1 or 2), -S(0),OR^a (where t is 1 or 2), -S(0),R^a (where t is 1 or 2) and -S(0)_tN(R^a)₂ (where t is 1 or 2) where each R^a is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[0024] "Alkynyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon triple bond, having from two to twelve carbon atoms. In certain embodiments, an alkynyl comprises two to eight carbon atoms. In other embodiments, an alkynyl comprises two to six carbon atoms. In other embodiments, an alkynyl comprises two to four carbon atoms. The alkynyl is attached to the rest of the molecule by a single bond, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Unless stated otherwise specifically in the specification, an alkynyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR^a, -SR^a, -OC(0)-R^a, -N(R^a)₂, -C(0)R^a, - C(0)OR^a, -C(0)N(R^a)₂, -N(R^a)C(0)OR^a, -OC(0)-N(R^a)₂, -N(R^a)C(0)R^a, -N(R^a)S(0),R^a (where t is 1 or 2), -S(0),OR^a (where t is 1 or 2), -S(0)_tR^a (where t is 1 or 2) and -S(0)_tN(R^a)₂ (where t is 1 or 2) where each R^a is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or

trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or

[0025] "Alkylene" or "alkylene chain" refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing no unsaturation and having from one to twelve carbon atoms, for example, methylene, ethylene, propylene, «-butylene, and the like. The alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkylene chain to the rest of the molecule and to the radical group is through one carbon in the alkylene chain or through any two carbons within the chain. In certain embodiments, an alkylene comprises one to eight carbon atoms (e.g., Ci-C₈ alkylene). In other embodiments, an alkylene comprises one to five carbon atoms (e.g., Ci-C₅ alkylene). In other embodiments, an alkylene comprises one to four carbon atoms (e.g., Ci-C₄ alkylene). In other embodiments, an alkylene comprises one to three carbon atoms (e.g., Ci-C₃ alkylene). In other embodiments, an alkylene comprises one to two carbon atoms (e.g., Ci-C₂ alkylene). In other embodiments, an alkylene comprises one carbon atom (e.g., Ci alkylene). In other embodiments, an alkylene comprises five to eight carbon atoms (e.g., C₅-C₈ alkylene). In other embodiments, an alkylene comprises two to five carbon atoms (e.g., C₂-C₅ alkylene). In other embodiments, an alkylene comprises three to five carbon atoms (e.g., C₃-C₅ alkylene). Unless stated otherwise specifically in the specification, an alkylene chain is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, - OR^a, -SR^a, -OC(0)-R^a, -N(R^a)₂, -C(0)R^a, -C(0)OR^a, -C(0)N(R^a)₂, -N(R^a)C(0)OR^a, -OC(0)-N(R^a)₂, - N(R^a)C(0)R^a, -N(R^a)S(0)_tR^a (where t is 1 or 2), -S(0)_tOR^a (where t is 1 or 2), -S(0)_tR^a (where t is 1 or 2) and -S(0),N(R^a)₂ (where t is 1 or 2) where each R^a is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[0026] "Alkynylene" or "alkynylene chain" refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one carbon-carbon triple bond, and having from two to twelve carbon atoms. The alkynylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. In certain embodiments, an alkynylene comprises two to eight carbon atoms (e.g., C₂-C₈ alkynylene). In other embodiments, an alkynylene comprises two to five carbon atoms (e.g., C₂-C₅ alkynylene). In other embodiments, an alkynylene comprises two to four carbon atoms (e.g., C₂-C₄ alkynylene). In other embodiments, an alkynylene comprises two to three carbon atoms (e.g., C₂-C₃ alkynylene). In other embodiments, an alkynylene comprises two carbon atom (e.g., C₂ alkylene). In other embodiments, an alkynylene comprises five to eight carbon atoms (e.g., C₅-C₈ alkynylene). In other embodiments, an alkynylene comprises three to five carbon atoms (e.g., C₃-C₅ alkynylene). Unless stated otherwise specifically in the specification, an alkynylene chain is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR^a, -SR^a, -OC(0)-R^a, -N(R^a)₂, -C(0)R^a, - C(0)OR^a, -C(0)N(R^a)₂, -N(R^a)C(0)OR^a, -OC(0)-N(R^a)₂, -N(R^a)C(0)R^a, -N(R^a)S(0),R^a (where t is 1 or 2), - S(0)_tOR^a (where t is 1 or 2), -S(0)_tR^a (where t is 1 or 2) and -S(0)_tN(R^a)₂ (where t is 1 or 2) where each R^a is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or

trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[0027] "Aryl" refers to a radical derived from an aromatic monocyclic or multicyclic

hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom. The aromatic monocyclic or multicyclic hydrocarbon ring system contains only hydrogen and carbon from five to eighteen carbon atoms, where at least one of the rings in the ring system is fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2) π-electron system in accordance with the Hiickel theory. The ring system from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin and naphthalene. Unless stated otherwise specifically in the specification, the term "aryl" or the prefix "ar-" (such as in "aralkyl") is meant to include aryl radicals optionally substituted by one or more substituents independently selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R^b- OR^a, -R^b-OC(0)-R^a, -R^b-OC(0)-OR^a, -R^b-OC(0)-N(R^a)₂, -R^b-N(R^a)₂, -R^b-C(0)R^a, -R^b-C(0)OR^a, -R^b- C(0)N(R^a)₂, -R^b-0-R^c-C(0)N(R^a)₂, -R^b-N(R^a)C(0)OR^a, -R^b-N(R^a)C(0)R^a, -R^b-N(R^a)S(0),R^a (where t is 1 or 2), -R^b-S(0),R^a (where t is 1 or 2), -R^b-S(0),OR^a (where t is 1 or 2) and -R^b-S(0),N(R^a)₂ (where t is 1 or 2), where each R^a is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or

trifluoromethyl), each R^b is independently a direct bond or a straight or branched alkylene or alkenylene chain, and R^c is a straight or branched alkylene or alkenylene chain, and where each of the above substituents is unsubstituted unless otherwise indicated.

[0028] "Aralkyl" refers to a radical of the formula -R^c-aryl where R^c is an alkylene chain as defined above, for example, methylene, ethylene, and the like. The alkylene chain part of the aralkyl radical is optionally substituted as described above for an alkylene chain. The aryl part of the aralkyl radical is optionally substituted as described above for an aryl group.

[0029] "Aralkenyl" refers to a radical of the formula -R^d-aryl where R^d is an alkenylene chain as defined above. The aryl part of the aralkenyl radical is optionally substituted as described above for an aryl group. The alkenylene chain part of the aralkenyl radical is optionally substituted as defined above for an alkenylene group.

[0030] "Aralkynyl" refers to a radical of the formula -R^e-aryl, where R^e is an alkynylene chain as defined above. The aryl part of the aralkynyl radical is optionally substituted as described above for an aryl group. The alkynylene chain part of the aralkynyl radical is optionally substituted as defined above for an alkynylene chain.

[0031] "Aralkoxy" refers to a radical bonded through an oxygen atom of the formula -0-R^c-aryl where R^c is an alkylene chain as defined above, for example, methylene, ethylene, and the like. The alkylene chain part of the aralkyl radical is optionally substituted as described above for an alkylene chain. The aryl part of the aralkyl radical is optionally substituted as described above for an aryl group.

[0032] "Carbocyclyl" refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, which includes fused or bridged ring systems, having from three to fifteen carbon atoms. In certain embodiments, a carbocyclyl comprises three to ten carbon atoms. In other embodiments, a carbocyclyl comprises five to seven carbon atoms. The carbocyclyl is attached to the rest of the molecule by a single bond. Carbocyclyl is saturated (i.e., containing single C-C bonds only) or unsaturated (i.e., containing one or more double bonds or triple bonds). A fully saturated carbocyclyl radical is also referred to as "cycloalkyl." Examples of monocyclic cycloalkyls include, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. An unsaturated carbocyclyl is also referred to as "cycloalkenyl." Examples of monocyclic cycloalkenyls include, e.g., cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Polycyclic carbocyclyl radicals include, for example, adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptanyl), norbornenyl, decalinyl,

7,7-dimethyl-bicyclo[2.2. l]heptanyl, and the like. Unless otherwise stated specifically in the specification, the term "carbocyclyl" is meant to include carbocyclyl radicals that are optionally substituted by one or more substituents independently selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R^b-OR^a, -R^b-OC(0)-R^a, -R^b-OC(0)-OR^a, -R^b-OC(0)-N(R^a)₂, -R^b-N(R^a)₂, -R^b- C(0)R^a, -R^b-C(0)OR^a, -R^b-C(0)N(R^a)₂, -R^b-0-R^c-C(0)N(R^a)₂, -R^b-N(R^a)C(0)OR^a, -R^b-N(R^a)C(0)R^a, -R^b- N(R^a)S(0),R^a (where t is 1 or 2), -R^b-S(0),R^a (where t is 1 or 2), -R^b-S(0),OR^a (where t is 1 or 2) and -R^b- S(0)_tN(R^a)₂ (where t is 1 or 2), where each R^a is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or

trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), each R^b is independently a direct bond or a straight or branched alkylene or alkenylene chain, and R^c is a straight or branched alkylene or alkenylene chain, and where each of the above substituents is unsubstituted unless otherwise indicated.

[0033] "Carbocyclylalkyl" refers to a radical of the formula -R^c-carbocyclyl where R^c is an alkylene chain as defined above. The alkylene chain and the carbocyclyl radical is optionally substituted as defined above.

[0034] "Carbocyclylalkynyl" refers to a radical of the formula -R^c-carbocyclyl where R^c is an alkynylene chain as defined above. The alkynylene chain and the carbocyclyl radical is optionally substituted as defined above.

[0035] "Carbocyclylalkoxy" refers to a radical bonded through an oxygen atom of the formula -

0-R^c-carbocyclyl where R^c is an alkylene chain as defined above. The alkylene chain and the carbocyclyl radical is optionally substituted as defined above.

[0036] As used herein, "carboxylic acid bioisostere" refers to a functional group or moiety that exhibits similar physical, biological and/or chemical properties as a carboxylic acid moiety. Examples of

and the like.

[0037] "Halo" or "halogen" refers to bromo, chloro, fluoro or iodo substituents.

[0038] "Fluoroalkyl" refers to an alkyl radical, as defined above, that is substituted by one or more fluoro radicals, as defined above, for example, trifluoromethyl, difluoromethyl, fluoromethyl,

2,2,2-trifluoroethyl, 1 -fluoromethyl -2 -fluoroethyl, and the like. In some embodiments, the alkyl part of the fluoroalkyl radical is optionally substituted as defined above for an alkyl group.

[0039] "Heterocyclyl" refers to a stable 3- to 18-membered non-aromatic ring radical that comprises two to twelve carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen and sulfur. Unless stated otherwise specifically in the specification, the heterocyclyl radical is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which optionally includes fused or bridged ring systems. The heteroatoms in the heterocyclyl radical are optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heterocyclyl radical is partially or fully saturated. The heterocyclyl is attached to the rest of the molecule through any atom of the ring(s). Examples of such heterocyclyl radicals include, but are not limited to, dioxolanyl, thienyl[l,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1, 1-dioxo-thiomorpholinyl. Unless stated otherwise specifically in the specification, the term "heterocyclyl" is meant to include heterocyclyl radicals as defined above that are optionally substituted by one or more substituents selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R^b-OR^a, -R^b-OC(0)-R^a, -R^b-OC(0)-OR^a, -R^b-OC(0)-N(R^a)₂, -R^b- N(R^a)₂, -R^b-C(0)R^a, -R^b-C(0)OR^a, -R^b-C(0)N(R^a)₂, -R^b-0-R^c-C(0)N(R^a)₂, -R^b-N(R^a)C(0)OR^a, -R^b- N(R^a)C(0)R^a, -R^b-N(R^a)S(0),R^a (where t is 1 or 2), -R^b-S(0),R^a (where t is 1 or 2), -R^b-S(0),OR^a (where t is 1 or 2) and -R^b-S(0)_tN(R^a)₂ (where t is 1 or 2), where each R^a is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), each R^b is independently a direct bond or a straight or branched alkylene or alkenylene chain, and R^c is a straight or branched alkylene or alkenylene chain, and where each of the above substituents is unsubstituted unless otherwise indicated.

[0040] "N-heterocyclyl" or "N-attached heterocyclyl" refers to a heterocyclyl radical as defined above containing at least one nitrogen and where the point of attachment of the heterocyclyl radical to the rest of the molecule is through a nitrogen atom in the heterocyclyl radical. An N-heterocyclyl radical is optionally substituted as described above for heterocyclyl radicals. Examples of such N-heterocyclyl radicals include, but are not limited to, 1-morpholinyl, 1 -piperidinyl, 1-piperazinyl, 1-pyrrolidinyl, pyrazolidinyl, imidazolinyl, and imidazolidinyl.

[0041] "C-heterocyclyl" or "C-attached heterocyclyl" refers to a heterocyclyl radical as defined above containing at least one heteroatom and where the point of attachment of the heterocyclyl radical to the rest of the molecule is through a carbon atom in the heterocyclyl radical. A C-heterocyclyl radical is optionally substituted as described above for heterocyclyl radicals. Examples of such C-heterocyclyl radicals include, but are not limited to, 2-morpholinyl, 2- or 3- or 4-piperidinyl, 2-piperazinyl, 2- or 3-pyrrolidinyl, and the like.

[0042] "Heterocyclylalkyl" refers to a radical of the formula -R^c -heterocyclyl where R^c is an alkylene chain as defined above. If the heterocyclyl is a nitrogen -containing heterocyclyl, the heterocyclyl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heterocyclylalkyl radical is optionally substituted as defined above for an alkylene chain. The heterocyclyl part of the heterocyclylalkyl radical is optionally substituted as defined above for a heterocyclyl group.

[0043] "Heterocyclylalkoxy" refers to a radical bonded through an oxygen atom of the formula -

0-R^c-heterocyclyl where R^c is an alkylene chain as defined above. If the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heterocyclylalkoxy radical is optionally substituted as defined above for an alkylene chain. The heterocyclyl part of the heterocyclylalkoxy radical is optionally substituted as defined above for a heterocyclyl group.

[0044] "Heteroaryl" refers to a radical derived from a 3 - to 18-membered aromatic ring radical that comprises two to seventeen carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen and sulfur. As used herein, the heteroaryl radical is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, wherein at least one of the rings in the ring system is fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2) π-electron system in accordance with the Hiickel theory. Heteroaryl includes fused or bridged ring systems. The heteroatom(s) in the heteroaryl radical is optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heteroaryl is attached to the rest of the molecule through any atom of the ring(s). Examples of heteroaryls include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzooxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[6][l,4]dioxepinyl, benzo[b][l,4]oxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl,

benzo[4,6]imidazo[l,2-a]pyridinyl, carbazolyl, cinnolinyl, cyclopenta[d]pyrimidinyl,

6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl, 5,6-dihydrobenzo[h]quinazolinyl,

5,6-dihydrobenzo[h]cinnolinyl, 6,7-dihydro-5H-benzo[6,7]cyclohepta[l,2-c]pyridazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, furo[3,2-c]pyridinyl, 5,6,7,8,9, 10-hexahydrocycloocta[d]pyrimidinyl, 5,6,7,8,9, 10-hexahydrocycloocta[d]pyridazinyl, 5,6,7,8,9, 10-hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, 5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl, 1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 5,6,6a,7,8,9, 10, 10a-octahydrobenzo[h]quinazolinyl, 1 -phenyl- lH-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl,

pyrazolo[3,4-d]pyrimidinyl, pyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl,

5.6.7.8- tetrahydroquinazolinyl, 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl,

6.7.8.9- tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl, 5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pridinyl, and thiophenyl (i.e. thienyl). Unless stated otherwise specifically in the specification, the term "heteroaryl" is meant to include heteroaryl radicals as defined above which are optionally substituted by one or more substituents selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R^b-OR^a, -R^b-OC(0)-R^a, -R^b-OC(0)-OR^a, -R^b- OC(0)-N(R^a)₂, -R^b-N(R^a)₂, -R^b-C(0)R^a, -R^b-C(0)OR^a, -R^b-C(0)N(R^a)₂, -R^b-0-R^c-C(0)N(R^a)₂, -R^b- N(R^a)C(0)OR^a, -R^b-N(R^a)C(0)R^a, -R^b-N(R^a)S(0)_tR^a (where t is 1 or 2), -R^b-S(0)_tR^a (where t is 1 or 2), -R^b- S(0),OR^a (where t is 1 or 2) and -R^b-S(0),N(R^a)₂ (where t is 1 or 2), where each R^a is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), each R^b is independently a direct bond or a straight or branched alkylene or alkenylene chain, and R^c is a straight or branched alkylene or alkenylene chain, and where each of the above substituents is unsubstituted unless otherwise indicated.

[0045] "N-heteroaryl" refers to a heteroaryl radical as defined above containing at least one nitrogen and where the point of attachment of the heteroaryl radical to the rest of the molecule is through a nitrogen atom in the heteroaryl radical. An N-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.

[0046] "C-heteroaryl" refers to a heteroaryl radical as defined above and where the point of attachment of the heteroaryl radical to the rest of the molecule is through a carbon atom in the heteroaryl radical. A C-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.

[0047] "Heteroarylalkyl" refers to a radical of the formula -R^c-heteroaryl, where R^c is an alkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heteroarylalkyl radical is optionally substituted as defined above for an alkylene chain. The heteroaryl part of the heteroarylalkyl radical is optionally substituted as defined above for a heteroaryl group.

[0048] "Heteroarylalkoxy" refers to a radical bonded through an oxygen atom of the formula -O-

R^c-heteroaryl, where R^c is an alkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heteroarylalkoxy radical is optionally substituted as defined above for an alkylene chain. The heteroaryl part of the heteroarylalkoxy radical is optionally substituted as defined above for a heteroaryl group.

[0049] The compounds disclosed herein, in some embodiments, contain one or more asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that are defined, in terms of absolute stereochemistry, as (R)- or (S)-. Unless stated otherwise, it is intended that all stereoisomeric forms of the compounds disclosed herein are contemplated by this disclosure. When the compounds described herein contain alkene double bonds, and unless specified otherwise, it is intended that this disclosure includes both E and Z geometric isomers (e.g., cis or trans) Likewise, all possible isomers, as well as their racemic and optically pure forms, and all tautomeric forms are also intended to be included. The term "geometric isomer" refers to E or Z geometric isomers (e.g., cis or trans) of an alkene double bond. The term "positional isomer" refers to structural isomers around a central ring, such as ortho-, meta-, and para- isomers around a benzene ring.

[0050] A "tautomer" refers to a molecule wherein a proton shift from one atom of a molecule to another atom of the same molecule is possible. The compounds presented herein, in certain embodiments, exist as tautomers. In circumstances where tautomerization is possible, a chemical equilibrium of the tautomers will exist. The exact ratio of the tautomers depends on several factors, including physical state, temperature, solvent, and pH. Some examples of tautomeric equilibrium include:

[0051] The compounds disclosed herein, in some embodiments, are used in different enriched isotopic forms, e.g., enriched in the content of 2 H, 3 H, 11 C, 13 C and/or 14 C. In one particular embodiment, the compound is deuterated in at least one position. Such deuterated forms can be made by the procedure described in U.S. Patent Nos. 5,846,514 and 6,334,997. As described in U.S. Patent Nos. 5,846,514 and 6,334,997, deuteration can improve the metabolic stability and or efficacy, thus increasing the duration of action of drugs.

[0052] Unless otherwise stated, structures depicted herein are intended to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by ¹ C- or ¹⁴C-enriched carbon are within the scope of the present disclosure.

[0053] The compounds of the present disclosure optionally contain unnatural proportions of atomic isotopes at one or more atoms that constitute such compounds. For example, the compounds may be labeled with isotopes, such as for example, deuterium ( 2 H), tritium ( 3 H), iodine-125 ( 125 I) or carbon-14 ( 14 C). Isotopic substitution with ²H, ⁿC, ¹³C, ¹⁴C, ¹⁵C, ¹²N, ¹³N, ¹⁵N, ¹⁶N, ¹⁶0, ¹⁷0, ¹⁴F, ¹⁵F, ¹⁶F, ¹⁷F, ¹⁸F, ³³S, ³⁴S, ³⁵S,

36 35 37 79 81 125

S, CI, CI, Br, Br, I are all contemplated. All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.

[0054] In certain embodiments, the compounds disclosed herein have some or all of the ^l atoms replaced with ²H atoms. The methods of synthesis for deuterium -containing compounds are known in the art and include, by way of non-limiting example only, the following synthetic methods.

[0055] Deuterium substituted compounds are synthesized using various methods such as described in: Dean, Dennis C; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [In: Curr., Pharm. Des., 2000; 6(10)] 2000, 110 pp;

George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic

Intermediates, Tetrahedron, 1989, 45(21), 6601-21; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64(1-2), 9-32.

[0056] Deuterated starting materials are readily available and are subjected to the synthetic methods described herein to provide for the synthesis of deuterium-containing compounds. Large numbers of deuterium-containing reagents and building blocks are available commerically from chemical vendors, such as Aldrich Chemical Co.

[0057] Deuterium-transfer reagents suitable for use in nucleophilic substitution reactions, such as iodomethane-d₃ (CD₃I), are readily available and may be employed to transfer a deuterium-substituted carbon atom under nucleophilic substitution reaction conditions to the reaction substrate. The use of CD₃I is illustrated, by way of example only, in the reaction schemes below.

^ base ^ D

[0058] Deuterium-transfer reagents, such as lithium aluminum deuteride (LiAlD₄), are employed to transfer deuterium under reducing conditions to the reaction substrate. The use of LiAlD₄ is illustrated, by way of example only, in the reaction schemes below.

^R ¾N ^LiAID4. ^{R AI P}4 , ^Dv^R'

D D^Nh2 ρΌ¾Η

R V^OH R A ^Li

R' " _R^_{O H}

[0059] Deuterium gas and palladium catalyst are employed to reduce unsaturated carbon-carbon linkages and to perform a reductive substitution of aryl carbon-halogen bonds as illustrated, by way of example onl in the reaction schemes below.

[0060] In one embodiment, the compounds disclosed herein contain one deuterium atom. In another embodiment, the compounds disclosed herein contain two deuterium atoms. In another embodiment, the compounds disclosed herein contain three deuterium atoms. In another embodiment, the compounds disclosed herein contain four deuterium atoms. In another embodiment, the compounds disclosed herein contain five deuterium atoms. In another embodiment, the compounds disclosed herein contain six deuterium atoms. In another embodiment, the compounds disclosed herein contain more than six deuterium atoms. In another embodiment, the compound disclosed herein is fully substituted with deuterium atoms and contains no non-exchangeable ^l hydrogen atoms. In one embodiment, the level of deuterium incorporation is determined by synthetic methods in which a deuterated synthetic building block is used as a starting material.

[0061] "Pharmaceutically acceptable salt" includes both acid and base addition salts. A pharmaceutically acceptable salt of any one of the kallikrein inhibitory compounds described herein is intended to encompass any and all pharmaceutically suitable salt forms. Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0062] "Pharmaceutically acceptable acid addition salt" refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, and the like. Also included are salts that are formed with organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and. aromatic sulfonic acids, etc. and include, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethane sulfonic acid, p -toluene sulfonic acid, salicylic acid, and the like. Exemplary salts thus include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates,

monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinate suberates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates,

methanesulfonates, and the like. Also contemplated are salts of amino acids, such as arginates, gluconates, and galacturonates (see, for example, Berge S.M. et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 66: 1-19 (1997)). Acid addition salts of basic compounds are, in some embodiments, prepared by contacting the free base forms with a sufficient amount of the desired acid to produce the salt according to methods and techniques with which a skilled artisan is familiar.

[0063] "Pharmaceutically acceptable base addition salt" refers to those salts that retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid.

Pharmaceutically acceptable base addition salts are, in some embodiments, formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, for example, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol,

2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, NN- dibenzylethylenediamine, chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline, N-methylglucamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like. See Berge et al., supra.

[0064] As used herein, "treatment" or "treating," or "palliating" or "ameliorating" are used interchangeably. These terms refer to an approach for obtaining beneficial or desired results including but not limited to therapeutic benefit and/or a prophylactic benefit. By "therapeutic benefit" is meant eradication or amelioration of the underlying disorder being treated. Also, a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the patient, notwithstanding that the patient is still afflicted with the underlying disorder. For prophylactic benefit, the compositions are, in some embodiments, administered to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease has not been made.

[0065] "Prodrug" is meant to indicate a compound that is, in some embodiments, converted under physiological conditions or by solvolysis to a biologically active compound described herein. Thus, the term "prodrug" refers to a precursor of a biologically active compound that is pharmaceutically acceptable. A prodrug is typically inactive when administered to a subject, but is converted in vivo to an active compound, for example, by hydrolysis. The prodrug compound often offers advantages of solubility, tissue compatibility or delayed release in a mammalian organism (see, e.g., Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam).

[0066] A discussion of prodrugs is provided in Higuchi, T., et al., "Pro-drugs as Novel Delivery

Systems," A.C.S. Symposium Series, Vol. 14, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987.

[0067] The term "prodrug" is also meant to include any covalently bonded carriers, which release the active compound in vivo when such prodrug is administered to a mammalian subject. Prodrugs of an active compound, as described herein, are prepared by modifying functional groups present in the active compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent active compound. Prodrugs include compounds wherein a hydroxy, amino or mercapto group is bonded to any group that, when the prodrug of the active compound is administered to a mammalian subject, cleaves to form a free hydroxy, free amino or free mercapto group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol or amine functional groups in the active compounds and the like.

Complement Factor D Inhibitory Compounds

[0068] Provided herein are heterocyclic derivative compounds and pharmaceutical compositions comprising said compounds. The subject compounds and compositions are useful for inhibiting complement factor D activity.

[0069] One embodiment provides a compound, or a pharmaceutically acceptable salt thereof, having the structure of Formula (I):

wherein,

W, X, and Z are each independently selected from N or C-R¹;

20 20 20

R² is optionally substituted aryl, or optionally substituted heteroaryl;

n is 0, 1, or 2; and m is 0, 1, 2, or 3.

[0070] Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein W, X, and Z are C-R¹ and each R¹ is independently selected from hydrogen, halogen, optionally substituted alkyl, optionally substituted carbocyclyl, or optionally substituted alkoxy. Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein W, X, and Z are C-R¹ and each R¹ is hydrogen. Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein X is N; W and Z are C-R¹; and each R¹ is independently selected from hydrogen, halogen, optionally substituted alkyl, optionally substituted carbocyclyl, or optionally substituted alkoxy. Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein X is N; W and Z are C-H. Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein W is N; X and Z are C- R¹; and each R¹ is independently selected from hydrogen, halogen, optionally substituted alkyl, optionally substituted carbocyclyl, or optionally substituted alkoxy. Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein W is N; X and Z are C-H. Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein both X and W are N; Z is C-H. Another embodiment provides the compound of Formula (I), or a

pharmaceutically acceptable salt thereof, wherein both Z and W are N; W is C-H. Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Z is N or C-H. Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Z is C-H.

[0071] Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R² is optionally substituted aryl. Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R² is optionally substituted heteroaryl. Another embodiment provides the compound, or a pharmaceutically acceptable salt thereof, wherein the optionally substituted heteroaryl is an optionally substituted pyridine.

[0072] Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R³ is NH₂. Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R³ is optionally substituted alkyl. [0073] Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein m is 0.

[0074] Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein m is 1.

[0075] Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R⁴ is hydrogen.

[0076] Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein each R⁶ is hydrogen.

[0077] Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R⁵ is -NRⁿCO-R¹⁰. Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R⁵ is -NRⁿC0₂-R¹⁰. Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R¹¹ is hydrogen. Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R⁵ is -NR¹ CO-N(R¹²)₂. Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R⁵ is -NR¹ S0₂-N(R¹²)₂. Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R¹³ is hydrogen. Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R⁵ is -O-CO- R¹⁰. Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R⁵ is -O-CO-R²⁰. Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R⁵ is -0-C0₂-R¹⁰. Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R⁵ is -0-C0₂-R²⁰. Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R⁵ is optionally substituted aralkoxy. Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R⁵ is optionally substituted heteroarylalkoxy. Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R⁵ is optionally substituted (carbocyclyl)-O-. Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R⁵ is optionally substituted heterocyclylalkoxy.

[0078] Another embodiment provides a compound, or a pharmaceutically acceptable salt thereof, of Formula (I) having the structure of Formula (la):

wherein,

each R 31 , R 32 , or R 33 is independently selected from hydrogen, cyano, -CF₃, or halogen; each R³⁶ or R³⁷ is independently hydrogen, halogen, cyano, or optionally substituted alkyl;

R⁵ is selected from -NRⁿCO-R¹⁰, -NRⁿC0₂-R¹⁰, -NR¹ CO-N(R¹²)₂, -NR¹ S0₂-N(R¹²)₂;

R¹³ is independently hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; or optionally, one R¹² and R¹³ join to form a ring.

[0079] One embodiment provides a compound, or a pharmaceutically acceptable salt thereof, having the structure of Formula (II):

wherein,

U is NH and V is CH, or U is CH₂ and V is N;

W, X, and Z are each independently selected from N or C-R¹;

20 20 20

C0₂H, -S(0)-R , -S-R , -S(0)₂-R , optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted (heterocyclyl)-O-, optionally substituted alkyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted alkenyl, optionally substituted

R² is optionally substituted aryl, or optionally substituted heteroaryl;

each R⁶ is independently selected from hydrogen, cyano, halo, hydroxy, amino, optionally substituted alkylamino, optionally substituted dialkylamino, or optionally substituted alkoxy; n is 0, 1, or 2; and m is 0, 1, 2, or 3.

[0080] Another embodiment provides the compound, or a pharmaceutically acceptable salt thereof, of Formula (II) wherein U is NH and V is CH.

[0081] Another embodiment provides the compound, or a pharmaceutically acceptable salt thereof, of Formula (II) wherein U is CH₂ and V is N.

[0082] Another embodiment provides the compound of Formula (II), or a pharmaceutically acceptable salt thereof, wherein W, X, and Z are C-R¹ and each R¹ is independently selected from hydrogen, halogen, optionally substituted alkyl, optionally substituted carbocyclyl, or optionally substituted alkoxy. Another embodiment provides the compound of Formula (II), or a pharmaceutically acceptable salt thereof, wherein W, X, and Z are C-R¹ and each R¹ is hydrogen. Another embodiment provides the compound of Formula (II), or a pharmaceutically acceptable salt thereof, wherein X is N; W and Z are C-R¹; and each R¹ is independently selected from hydrogen, halogen, optionally substituted alkyl, optionally substituted carbocyclyl, or optionally substituted alkoxy. Another embodiment provides the compound of Formula (II), or a pharmaceutically acceptable salt thereof, wherein X is N; W and Z are C-H. Another embodiment provides the compound of Formula (II), or a pharmaceutically acceptable salt thereof, wherein W is N; X and Z are C- R¹; and each R¹ is independently selected from hydrogen, halogen, optionally substituted alkyl, optionally substituted carbocyclyl, or optionally substituted alkoxy. Another embodiment provides the compound of Formula (II), or a pharmaceutically acceptable salt thereof, wherein W is N; X and Z are C-H. Another embodiment provides the compound of Formula (II), or a pharmaceutically acceptable salt thereof, wherein both X and W are N; Z is C-H. Another embodiment provides the compound of Formula (II), or a pharmaceutically acceptable salt thereof, wherein both Z and W are N; W is C-H. Another embodiment provides the compound of Formula (II), or a pharmaceutically acceptable salt thereof, wherein Z is N or C-H. Another embodiment provides the compound of Formula (II), or a pharmaceutically acceptable salt thereof, wherein Z is C-H.

[0083] Another embodiment provides the compound of Formula (II), or a pharmaceutically acceptable salt thereof, wherein R² is optionally substituted aryl. Another embodiment provides the compound of Formula (II), or a pharmaceutically acceptable salt thereof, wherein R² is optionally substituted heteroaryl. Another embodiment provides the compound, or a pharmaceutically acceptable salt thereof, wherein the optionally substituted heteroaryl is an optionally substituted pyridine.

[0084] Another embodiment provides the compound of Formula (II), or a pharmaceutically acceptable salt thereof, wherein R³ is NH₂. Another embodiment provides the compound of Formula (II), or a pharmaceutically acceptable salt thereof, wherein R³ is optionally substituted alkyl.

[0085] Another embodiment provides the compound of Formula (II), or a pharmaceutically acceptable salt thereof, wherein m is 0.

[0086] Another embodiment provides the compound of Formula (II), or a pharmaceutically acceptable salt thereof, wherein m is 1.

[0087] Another embodiment provides the compound of Formula (II), or a pharmaceutically acceptable salt thereof, wherein R⁴ is hydrogen.

[0088] Another embodiment provides the compound of Formula (II), or a pharmaceutically acceptable salt thereof, wherein each R⁶ is hydrogen.

[0089] Another embodiment provides the compound of Formula (II), or a pharmaceutically acceptable salt thereof, wherein R⁵ is -NRⁿCO-R¹⁰. Another embodiment provides the compound of Formula (II), or a pharmaceutically acceptable salt thereof, wherein R⁵ is -NRⁿC0₂-R¹⁰. Another embodiment provides the compound of Formula (II), or a pharmaceutically acceptable salt thereof, wherein R¹¹ is hydrogen.

Another embodiment provides the compound of Formula (II), or a pharmaceutically acceptable salt thereof, wherein R⁵ is -NR¹ CO-N(R¹²)₂. Another embodiment provides the compound of Formula (II), or a pharmaceutically acceptable salt thereof, wherein R⁵ is -NR¹ S0₂-N(R¹²)₂. Another embodiment provides the compound of Formula (II), or a pharmaceutically acceptable salt thereof, wherein R¹³ is hydrogen. Another embodiment provides the compound of Formula (II), or a pharmaceutically acceptable salt thereof, wherein R⁵ is -O-CO-R¹⁰. Another embodiment provides the compound of Formula (II), or a pharmaceutically acceptable salt thereof, wherein R⁵ is -O-CO-R²⁰. Another embodiment provides the compound of Formula (II), or a pharmaceutically acceptable salt thereof, wherein R⁵ is -0-C0₂-R¹⁰. Another embodiment provides the compound of Formula (II), or a pharmaceutically acceptable salt thereof, wherein R⁵ is -0-C0₂-R²⁰. Another embodiment provides the compound of Formula (II), or a pharmaceutically acceptable salt thereof, wherein R⁵ is optionally substituted aralkoxy. Another embodiment provides the compound of Formula (II), or a pharmaceutically acceptable salt thereof, wherein R⁵ is optionally substituted heteroarylalkoxy. Another embodiment provides the compound of Formula (II), or a pharmaceutically acceptable salt thereof, wherein R⁵ is optionally substituted (carbocyclyl)-O-. Another embodiment provides the compound of Formula (II), or a pharmaceutically acceptable salt thereof, wherein R⁵ is optionally substituted heterocyclylalkoxy.

[0090] One embodiment provides a compound, or a pharmaceutically acceptable salt thereof, having the structure of Formula III):

V is N, T is N, and U is C; or V is C, T is CH, and U is N;

W, X, and Z are each independently selected from N or C-R¹ each R¹ is independently selected from hydrogen, cyano, halo, hydroxy, azido, amino, nitro, -

20 20 20

R² is optionally substituted aryl, or optionally substituted heteroaryl;

n is 0, 1, or 2; and m is 0, 1, 2, or 3.

[0091] Another embodiment provides the compound, or a pharmaceutically acceptable salt thereof, of Formula (III) wherein V is N, T is N, and U is C. [0092] Another embodiment provides the compound, or a pharmaceutically acceptable salt thereof, of Formula (III) wherein V is C, T is CH, and U is N.

[0093] Another embodiment provides the compound of Formula (III), or a pharmaceutically acceptable salt thereof, wherein W, X, and Z are C-R¹ and each R¹ is independently selected from hydrogen, halogen, optionally substituted alkyl, optionally substituted carbocyclyl, or optionally substituted alkoxy. Another embodiment provides the compound of Formula (III), or a pharmaceutically acceptable salt thereof, wherein W, X, and Z are C-R¹ and each R¹ is hydrogen. Another embodiment provides the compound of Formula (III), or a pharmaceutically acceptable salt thereof, wherein X is N; W and Z are C-R¹; and each R¹ is independently selected from hydrogen, halogen, optionally substituted alkyl, optionally substituted carbocyclyl, or optionally substituted alkoxy. Another embodiment provides the compound of Formula (III), or a pharmaceutically acceptable salt thereof, wherein X is N; W and Z are C-H. Another embodiment provides the compound of Formula (III), or a pharmaceutically acceptable salt thereof, wherein W is N; X and Z are C-R¹; and each R¹ is independently selected from hydrogen, halogen, optionally substituted alkyl, optionally substituted carbocyclyl, or optionally substituted alkoxy. Another embodiment provides the compound of Formula (III), or a pharmaceutically acceptable salt thereof, wherein W is N; X and Z are C-H. Another embodiment provides the compound of Formula (III), or a pharmaceutically acceptable salt thereof, wherein both X and W are N; Z is C-H. Another embodiment provides the compound of Formula (III), or a pharmaceutically acceptable salt thereof, wherein both Z and W are N; W is C-H. Another embodiment provides the compound of Formula (III), or a pharmaceutically acceptable salt thereof, wherein Z is N or C-H. Another embodiment provides the compound of Formula (III), or a pharmaceutically acceptable salt thereof, wherein Z is C-H.

[0094] Another embodiment provides the compound of Formula (III), or a pharmaceutically acceptable salt thereof, wherein R² is optionally substituted aryl. Another embodiment provides the compound of Formula (III), or a pharmaceutically acceptable salt thereof, wherein R² is optionally substituted heteroaryl. Another embodiment provides the compound, or a pharmaceutically acceptable salt thereof, wherein the optionally substituted heteroaryl is an optionally substituted pyridine.

[0095] Another embodiment provides the compound of Formula (III), or a pharmaceutically acceptable salt thereof, wherein R³ is NH₂. Another embodiment provides the compound of Formula (III), or a pharmaceutically acceptable salt thereof, wherein R³ is optionally substituted alkyl.

[0096] Another embodiment provides the compound of Formula (III), or a pharmaceutically acceptable salt thereof, wherein m is 0.

[0097] Another embodiment provides the compound of Formula (III), or a pharmaceutically acceptable salt thereof, wherein m is 1.

[0098] Another embodiment provides the compound of Formula (III), or a pharmaceutically acceptable salt thereof, wherein R⁴ is hydrogen.

[0099] Another embodiment provides the compound of Formula (III), or a pharmaceutically acceptable salt thereof, wherein each R⁶ is hydrogen. [00100] Another embodiment provides the compound of Formula (III), or a pharmaceutically acceptable salt thereof, wherein R⁵ is -NRⁿCO-R¹⁰. Another embodiment provides the compound of Formula (III), or a pharmaceutically acceptable salt thereof, wherein R⁵ is -NRⁿC0₂-R¹⁰. Another embodiment provides the compound of Formula (III), or a pharmaceutically acceptable salt thereof, wherein R¹¹ is hydrogen. Another embodiment provides the compound of Formula (III), or a pharmaceutically acceptable salt thereof, wherein R⁵ is -NR¹ CO-N(R¹²)₂. Another embodiment provides the compound of Formula (III), or a pharmaceutically acceptable salt thereof, wherein R⁵ is -NR¹ S0₂-N(R¹²)₂. Another embodiment provides the compound of Formula (III), or a pharmaceutically acceptable salt thereof, wherein R¹³ is hydrogen.

Another embodiment provides the compound of Formula (III), or a pharmaceutically acceptable salt thereof, wherein R⁵ is -O-CO-R¹⁰. Another embodiment provides the compound of Formula (III), or a

pharmaceutically acceptable salt thereof, wherein R⁵ is -O-CO-R²⁰. Another embodiment provides the compound of Formula (III), or a pharmaceutically acceptable salt thereof, wherein R⁵ is -0-C0₂-R¹⁰. Another embodiment provides the compound of Formula (III), or a pharmaceutically acceptable salt thereof, wherein R⁵ is -0-C0₂-R²⁰. Another embodiment provides the compound of Formula (III), or a pharmaceutically acceptable salt thereof, wherein R⁵ is optionally substituted aralkoxy. Another embodiment provides the compound of Formula (III), or a pharmaceutically acceptable salt thereof, wherein R⁵ is optionally substituted heteroarylalkoxy. Another embodiment provides the compound of Formula (III), or a pharmaceutically acceptable salt thereof, wherein R⁵ is optionally substituted (carbocyclyl)-O-. Another embodiment provides the compound of Formula (III), or a pharmaceutically acceptable salt thereof, wherein R⁵ is optionally substituted heterocyclylalkoxy.

[00101] One embodiment provides a compound, or a pharmaceutically acceptable salt thereof, having the structure of Formula (IV :

W, X, Y and Z are each independently selected from N, C-R¹, or C-R⁵, provided that at least one of W, X, Y, and Z is C-R⁵;

20 20 20

21 20 20 aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, -N(R ), -CO-R , -C0₂-R , - CO(NR²¹)₂, -NR²¹CO-R²⁰, -NR²¹C0₂-R²°, -S0₂(NR²¹)₂, -C(=NR²²)-(NR²¹)₂, -NR²¹CO-R²⁰, -NR²¹C0₂-R²⁰, - NR²¹CO-N(R²⁰)₂, -NR²¹SO₂-N(R²⁰)₂;

R² is optionally substituted aryl, or optionally substituted heteroaryl;

n is 0, 1, or 2; and m is 0, 1, 2, or 3.

[00102] Another embodiment provides the compound, or a pharmaceutically acceptable salt thereof, having the structure of Formula (IV), wherein only one of W, X, Y and Z is C-R⁵.

[00103] Another embodiment provides the compound of Formula (IV), or a pharmaceutically acceptable salt thereof, wherein only X is C-R⁵. Another embodiment provides the compound of Formula (IV), or a pharmaceutically acceptable salt thereof, wherein X is C-R⁵, and W, Y, and Z are C-R¹. [00104] Another embodiment provides the compound of Formula (IV), or a pharmaceutically acceptable salt thereof, wherein R² is optionally substituted aryl. Another embodiment provides the compound of Formula (IV), or a pharmaceutically acceptable salt thereof, wherein R² is optionally substituted heteroaryl. Another embodiment provides the compound, or a pharmaceutically acceptable salt thereof, wherein the optionally substituted heteroaryl is an optionally substituted pyridine.

[00105] Another embodiment provides the compound of Formula (IV), or a pharmaceutically acceptable salt thereof, wherein R³ is NH₂. Another embodiment provides the compound of Formula (IV), or a pharmaceutically acceptable salt thereof, wherein R³ is optionally substituted alkyl.

[00106] Another embodiment provides the compound of Formula (IV), or a pharmaceutically acceptable salt thereof, wherein m is 0.

[00107] Another embodiment provides the compound of Formula (IV), or a pharmaceutically acceptable salt thereof, wherein m is 1.

[00108] Another embodiment provides the compound of Formula (IV), or a pharmaceutically acceptable salt thereof, wherein R⁴ is hydrogen.

[00109] Another embodiment provides the compound of Formula (IV), or a pharmaceutically acceptable salt thereof, wherein each R⁶ is hydrogen.

[00110] Another embodiment provides the compound of Formula (IV), or a pharmaceutically acceptable salt thereof, wherein R⁵ is -NRⁿCO-R¹⁰. Another embodiment provides the compound of Formula (IV), or a pharmaceutically acceptable salt thereof, wherein R⁵ is -NRⁿC0₂-R¹⁰. Another embodiment provides the compound of Formula (IV), or a pharmaceutically acceptable salt thereof, wherein R¹¹ is hydrogen. Another embodiment provides the compound of Formula (IV), or a pharmaceutically acceptable salt thereof, wherein R⁵ is -NR¹ CO-N(R¹²)₂. Another embodiment provides the compound of Formula (IV), or a pharmaceutically acceptable salt thereof, wherein R⁵ is -NR¹ S0₂-N(R¹²)₂. Another embodiment provides the compound of Formula (IV), or a pharmaceutically acceptable salt thereof, wherein R¹³ is hydrogen.

Another embodiment provides the compound of Formula (IV), or a pharmaceutically acceptable salt thereof, wherein R⁵ is -O-CO-R¹⁰. Another embodiment provides the compound of Formula (IV), or a

pharmaceutically acceptable salt thereof, wherein R⁵ is -O-CO-R²⁰. Another embodiment provides the compound of Formula (IV), or a pharmaceutically acceptable salt thereof, wherein R⁵ is -0-C0₂-R¹⁰. Another embodiment provides the compound of Formula (IV), or a pharmaceutically acceptable salt thereof, wherein R⁵ is -0-C0₂-R²⁰. Another embodiment provides the compound of Formula (IV), or a pharmaceutically acceptable salt thereof, wherein R⁵ is optionally substituted aralkoxy. Another embodiment provides the compound of Formula (IV), or a pharmaceutically acceptable salt thereof, wherein R⁵ is optionally substituted heteroarylalkoxy. Another embodiment provides the compound of Formula (IV), or a pharmaceutically acceptable salt thereof, wherein R⁵ is optionally substituted (carbocyclyl)-O-. Another embodiment provides the compound of Formula (IV), or a pharmaceutically acceptable salt thereof, wherein R⁵ is optionally substituted heterocyclylalkoxy.

[00111] One embodiment provides a compound, or a pharmaceutically acceptable salt thereof, having the structure of Formula (V):

U is NH and V is CH, or U is CH₂ and V is N;

20 20 20

R² is optionally substituted aryl, or optionally substituted heteroaryl;

R¹⁰ is optionally substituted carbocyclylalkyl, optionally substituted aralkyl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl; R¹¹ is independently hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, or optionally, R¹⁰ and R¹¹ join to form a ring;

n is 0, 1, or 2; and m is 0, 1, 2, or 3.

[00112] Another embodiment provides the compound, or a pharmaceutically acceptable salt thereof, of Formula (V) wherein U is NH and V is CH.

[00113] Another embodiment provides the compound, or a pharmaceutically acceptable salt thereof, of Formula (V) wherein U is CH₂ and V is N.

[00114] Another embodiment provides the compound, or a pharmaceutically acceptable salt thereof, having the structure of Formula (V), wherein only one of W, X, Y and Z is C-R⁵.

[00115] Another embodiment provides the compound of Formula (V), or a pharmaceutically acceptable salt thereof, wherein only X is C-R⁵. Another embodiment provides the compound of Formula (V), or a pharmaceutically acceptable salt thereof, wherein X is C-R⁵, and W, Y, and Z are C-R¹.

[00116] Another embodiment provides the compound of Formula (V), or a pharmaceutically acceptable salt thereof, wherein R² is optionally substituted aryl. Another embodiment provides the compound of Formula (V), or a pharmaceutically acceptable salt thereof, wherein R² is optionally substituted heteroaryl.

Another embodiment provides the compound, or a pharmaceutically acceptable salt thereof, wherein the optionally substituted heteroaryl is an optionally substituted pyridine.

[00117] Another embodiment provides the compound of Formula (V), or a pharmaceutically acceptable salt thereof, wherein R³ is NH₂. Another embodiment provides the compound of Formula (V), or a pharmaceutically acceptable salt thereof, wherein R³ is optionally substituted alkyl.

[00118] Another embodiment provides the compound of Formula (V), or a pharmaceutically acceptable salt thereof, wherein m is 0.

[00119] Another embodiment provides the compound of Formula (V), or a pharmaceutically acceptable salt thereof, wherein m is 1.

[00120] Another embodiment provides the compound of Formula (V), or a pharmaceutically acceptable salt thereof, wherein R⁴ is hydrogen.

[00121] Another embodiment provides the compound of Formula (V), or a pharmaceutically acceptable salt thereof, wherein each R⁶ is hydrogen.

[00122] Another embodiment provides the compound of Formula (V), or a pharmaceutically acceptable salt thereof, wherein R⁵ is -NRⁿCO-R¹⁰. Another embodiment provides the compound of Formula (V), or a pharmaceutically acceptable salt thereof, wherein R⁵ is -NRⁿC0₂-R¹⁰. Another embodiment provides the compound of Formula (V), or a pharmaceutically acceptable salt thereof, wherein R¹¹ is hydrogen.

Another embodiment provides the compound of Formula (V), or a pharmaceutically acceptable salt thereof, wherein R⁵ is -NR¹ CO-N(R¹²)₂. Another embodiment provides the compound of Formula (V), or a pharmaceutically acceptable salt thereof, wherein R⁵ is -NR¹ S0₂-N(R¹²)₂. Another embodiment provides the compound of Formula (V), or a pharmaceutically acceptable salt thereof, wherein R¹³ is hydrogen. Another embodiment provides the compound of Formula (V), or a pharmaceutically acceptable salt thereof, wherein R⁵ is -O-CO-R¹⁰. Another embodiment provides the compound of Formula (V), or a pharmaceutically acceptable salt thereof, wherein R⁵ is -O-CO-R²⁰. Another embodiment provides the compound of Formula (V), or a pharmaceutically acceptable salt thereof, wherein R⁵ is -0-C0₂-R¹⁰. Another embodiment provides the compound of Formula (V), or a pharmaceutically acceptable salt thereof, wherein R⁵ is -0-C0₂-R²⁰. Another embodiment provides the compound of Formula (V), or a pharmaceutically acceptable salt thereof, wherein R⁵ is optionally substituted aralkoxy. Another embodiment provides the compound of Formula (V), or a pharmaceutically acceptable salt thereof, wherein R⁵ is optionally substituted heteroarylalkoxy. Another embodiment provides the compound of Formula (V), or a pharmaceutically acceptable salt thereof, wherein R⁵ is optionally substituted (carbocyclyl)-O-. Another embodiment provides the compound of Formula (V), or a pharmaceutically acceptable salt thereof, wherein R⁵ is optionally substituted heterocyclylalkoxy.

[00123] One embodiment provides a compound, or a pharmaceutically acceptable salt thereof, having the structure of Formula (VI :

wherein,

V is N, T is N, and U is C; or V is C, T is CH, and U is N;

20 20 20

R² is optionally substituted aryl, or optionally substituted heteroaryl;

n is 0, 1, or 2; and m is 0, 1, 2, or 3.

[00124] Another embodiment provides the compound, or a pharmaceutically acceptable salt thereof, of Formula (VI) wherein V is N, T is N, and U is C.

[00125] Another embodiment provides the compound, or a pharmaceutically acceptable salt thereof, of Formula (VI) wherein V is C, T is CH, and U is N. [00126] Another embodiment provides the compound, or a pharmaceutically acceptable salt thereof, having the structure of Formula (VI), wherein only one of W, X, Y and Z is C-R⁵.

[00127] Another embodiment provides the compound of Formula (VI), or a pharmaceutically acceptable salt thereof, wherein only X is C-R⁵. Another embodiment provides the compound of Formula (VI), or a pharmaceutically acceptable salt thereof, wherein X is C-R⁵, and W, Y, and Z are C-R¹.

[00128] Another embodiment provides the compound of Formula (VI), or a pharmaceutically acceptable salt thereof, wherein R² is optionally substituted aryl. Another embodiment provides the compound of Formula (VI), or a pharmaceutically acceptable salt thereof, wherein R² is optionally substituted heteroaryl. Another embodiment provides the compound, or a pharmaceutically acceptable salt thereof, wherein the optionally substituted heteroaryl is an optionally substituted pyridine.

[00129] Another embodiment provides the compound of Formula (VI), or a pharmaceutically acceptable salt thereof, wherein R³ is NH₂. Another embodiment provides the compound of Formula (VI), or a pharmaceutically acceptable salt thereof, wherein R³ is optionally substituted alkyl.

[00130] Another embodiment provides the compound of Formula (VI), or a pharmaceutically acceptable salt thereof, wherein m is 0.

[00131] Another embodiment provides the compound of Formula (VI), or a pharmaceutically acceptable salt thereof, wherein m is 1.

[00132] Another embodiment provides the compound of Formula (VI), or a pharmaceutically acceptable salt thereof, wherein R⁴ is hydrogen.

[00133] Another embodiment provides the compound of Formula (VI), or a pharmaceutically acceptable salt thereof, wherein each R⁶ is hydrogen.

[00134] Another embodiment provides the compound of Formula (VI), or a pharmaceutically acceptable salt thereof, wherein R⁵ is -NRⁿCO-R¹⁰. Another embodiment provides the compound of Formula (VI), or a pharmaceutically acceptable salt thereof, wherein R⁵ is -NRⁿC0₂-R¹⁰. Another embodiment provides the compound of Formula (VI), or a pharmaceutically acceptable salt thereof, wherein R¹¹ is hydrogen. Another embodiment provides the compound of Formula (VI), or a pharmaceutically acceptable salt thereof, wherein R⁵ is -NR¹ CO-N(R¹²)₂. Another embodiment provides the compound of Formula (VI), or a pharmaceutically acceptable salt thereof, wherein R⁵ is -NR¹ S0₂-N(R¹²)₂. Another embodiment provides the compound of Formula (VI), or a pharmaceutically acceptable salt thereof, wherein R¹³ is hydrogen.

Another embodiment provides the compound of Formula (VI), or a pharmaceutically acceptable salt thereof, wherein R⁵ is -O-CO-R¹⁰. Another embodiment provides the compound of Formula (VI), or a

pharmaceutically acceptable salt thereof, wherein R⁵ is -O-CO-R²⁰. Another embodiment provides the compound of Formula (VI), or a pharmaceutically acceptable salt thereof, wherein R⁵ is -0-C0₂-R¹⁰. Another embodiment provides the compound of Formula (VI), or a pharmaceutically acceptable salt thereof, wherein R⁵ is -0-C0₂-R²⁰. Another embodiment provides the compound of Formula (VI), or a pharmaceutically acceptable salt thereof, wherein R⁵ is optionally substituted aralkoxy. Another embodiment provides the compound of Formula (VI), or a pharmaceutically acceptable salt thereof, wherein R⁵ is optionally substituted heteroarylalkoxy. Another embodiment provides the compound of Formula (VI), or a pharmaceutically acceptable salt thereof, wherein R⁵ is optionally substituted (carbocyclyl)-O-. Another embodiment provides the compound of Formula (VI), or a pharmaceutically acceptable salt thereof, wherein R⁵ is optionally substituted heterocyclylalkoxy.

[00135] One embodiment provides a compound, or a pharmaceutically acceptable salt thereof, having the structure of Formula (VII :

wherein,

Ring A is an optionally substituted bicyclic heteroaryl;

U is C(R⁷⁰)(R⁷¹), or NH;

R² is optionally substituted aryl, or optionally substituted heteroaryl;

R⁶¹, R⁶², R⁶³, R⁶⁴, R⁶⁵, R⁶⁶, R⁶⁷, R⁶⁸, and R⁶⁹ are independently selected from hydrogen, cyano, halo, hydroxy, amino, optionally substituted alkylamino, optionally substituted dialkylamino, optionally substituted alkyl, optionally substituted carbocyclyl or optionally substituted alkoxy;

each R⁷⁰ or R⁷¹ is independently selected from hydrogen, cyano, optionally substituted alkyl, hydroxy, amino, optionally substituted alkylamino, optionally substituted dialkylamino, optionally substituted carbocyclyl or optionally substituted alkoxy;

n is 0, 1, or 2; and m is 0, 1, 2, or 3.

[00136] Another embodiment provides the compound, or a pharmaceutically acceptable salt thereof, of Formula (VII), wherein Ring A is an optionally substituted 10-membered bicyclic heteroaryl.

[00137] Another embodiment provides the compound, or a pharmaceutically acceptable salt thereof, of Formula (VII), wherein Ring A is an optionally substituted 9-membered bicyclic heteroaryl.

[00138] Another embodiment provides the compound, or a pharmaceutically acceptable salt thereof, of Formula (VII), wherein Ring A is an optionally substituted bicyclic heteroaryl ring selected from optionally substituted quinolyl, optionally substituted indolyl, optionally substituted indazolyl, optionally substituted benzimidazolyl, optionally substituted isoquinolyl, optionally substituted cinnolinyl, optionally substituted phthalazinyl, optionally substituted quinazolinyl, optionally substituted naphthyridinyl, or optionally substituted benzoisoxazolyl.

[00139] Another embodiment provides the compound, or a pharmaceutically acceptable salt thereof, of Formula (VII), wherein Ring A is optionally substituted isoquinolyl.

[00140] Another embodiment provides the compound, or a pharmaceutically acceptable salt thereof, of Formula (VII), wherein U is C(R⁷⁰)(R⁷¹), and Ring A has the structure of Formula (Vila):

wherein,

20 20 20

carbocyclylalkyl, optionally substituted aralkyl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl; or two R¹² groups join to form a N-linked heterocyclyl; and

[00141] Another embodiment provides the compound, or a pharmaceutically acceptable salt thereof, of Formula (VII), wherein Ring A has the structure of Formula (Vllb):

wherein,

U is NH and V is CH, or U is C(R⁷⁰)(R⁷¹) and V is N;

20 20 20

[00142] Another embodiment provides the compound, or a pharmaceutically acceptable salt thereof, of Formula (VII), wherein Ring A is Formula (Vllb), U is NH and V is CH.

[00143] Another embodiment provides the compound, or a pharmaceutically acceptable salt thereof, of Formula (VII), wherein Ring A is Formula (Vllb), U is C(R⁷⁰)(R⁷¹) and V is N.

[00144] Another embodiment provides the compound, or a pharmaceutically acceptable salt thereof, of Formula (VII), wherein U is C(R⁷⁰)(R⁷¹), and Ring A has the structure of Formula (VIIc):

wherein,

V is N, T is N, and Q is C; or V is C, T is CH, and Q is N;

20 20 20

each R²¹ is independently hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; R³ is selected from NH₂, optionally substituted alkylamino, optionally substituted dialkylamino, optionally substituted alkyl, optionally substituted carbocyclyl, or optionally substituted heterocyclyl;

[00145] Another embodiment provides the compound, or a pharmaceutically acceptable salt thereof, of Formula (VII), wherein U is C(R⁷⁰)(R⁷¹), and Ring A has the structure of Formula (VIIc) wherein

V is N, T is N, and Q is C.

[00146] Another embodiment provides the compound, or a pharmaceutically acceptable salt thereof, of Formula (VII), wherein U is C(R⁷⁰)(R⁷¹), and Ring A has the structure of Formula (VIIc) wherein

V is C, T is CH, and Q is N.

[00147] Another embodiment provides the compound, or a pharmaceutically acceptable salt thereof, having the structure of Formula (VII), wherein Ring A has the structure of Formula (Vila), (Vllb), or (VIIc), wherein only one ofW, X, Y and Z is C-R⁵.

[00148] Another embodiment provides the compound, or a pharmaceutically acceptable salt thereof, having the structure of Formula (VII), wherein Ring A has the structure of Formula (Vila), (Vllb), or (VIIc), wherein only X is C-R⁵. Another embodiment provides the compound, or a pharmaceutically acceptable salt thereof, having the structure of Formula (VII), wherein Ring A has the structure of Formula (Vila), (Vllb), or (VIIc), wherein X is C-R⁵, and W, Y, and Z are C-R¹.

[00149] Another embodiment provides the compound, or a pharmaceutically acceptable salt thereof, having the structure of Formula (VII), wherein R² is optionally substituted aryl. Another embodiment provides the compound, or a pharmaceutically acceptable salt thereof, having the structure of Formula (VII), wherein R² is optionally substituted heteroaryl. Another embodiment provides the compound, or a pharmaceutically acceptable salt thereof, wherein the optionally substituted heteroaryl is an optionally substituted pyridine.

[00150] Another embodiment provides the compound, or a pharmaceutically acceptable salt thereof, having the structure of Formula (VII), wherein Ring A has the structure of Formula (Vila), (Vllb), or (VIIc), wherein R³ is NH₂. Another embodiment provides the compound, or a pharmaceutically acceptable salt thereof, having the structure of Formula (VII), wherein Ring A has the structure of Formula (Vila), (Vllb), or (VIIc), or a pharmaceutically acceptable salt thereof, wherein R³ is optionally substituted alkyl.

[00151] Another embodiment provides the compound, or a pharmaceutically acceptable salt thereof, having the structure of Formula (VII), wherein m is 0.

[00152] Another embodiment provides the compound, or a pharmaceutically acceptable salt thereof, having the structure of Formula (VII), wherein m is 1.

[00153] Another embodiment provides the compound, or a pharmaceutically acceptable salt thereof, having the structure of Formula (VII), wherein R⁴ is hydrogen.

[00154] Another embodiment provides the compound, or a pharmaceutically acceptable salt thereof, having the structure of Formula (VII), wherein Ring A has the structure of Formula (Vila), (Vllb), or (VIIc), wherein R⁵ is -NRⁿCO-R¹⁰. Another embodiment provides the compound, or a pharmaceutically acceptable salt thereof, having the structure of Formula (VII), wherein Ring A has the structure of Formula (Vila), (Vllb), or (VIIc), wherein R⁵ is -NRⁿC0₂-R¹⁰. Another embodiment provides the compound, or a pharmaceutically acceptable salt thereof, having the structure of Formula (VII), wherein Ring A has the structure of Formula (Vila), (Vllb), or (VIIc), wherein R¹¹ is hydrogen. Another embodiment provides the compound, or a pharmaceutically acceptable salt thereof, having the structure of Formula (VII), wherein Ring A has the structure of Formula (Vila), (Vllb), or (VIIc), wherein R⁵ is -NR¹ CO-N(R¹²)₂. Another embodiment provides the compound, or a pharmaceutically acceptable salt thereof, having the structure of Formula (VII), wherein Ring A has the structure of Formula (Vila), (Vllb), or (VIIc), wherein R⁵ is - NR¹ S0₂-N(R¹²)₂. Another embodiment provides the compound, or a pharmaceutically acceptable salt thereof, having the structure of Formula (VII), wherein Ring A has the structure of Formula (Vila), (Vllb), or (VIIc), wherein R¹³ is hydrogen. Another embodiment provides the compound, or a pharmaceutically acceptable salt thereof, having the structure of Formula (VII), wherein Ring A has the structure of Formula (Vila), (Vllb), or (VIIc), wherein R⁵ is -O-CO-R¹⁰. Another embodiment provides the compound, or a pharmaceutically acceptable salt thereof, having the structure of Formula (VII), wherein Ring A has the structure of Formula (Vila), (Vllb), or (VIIc), wherein R⁵ is -O-CO-R²⁰. Another embodiment provides the compound, or a pharmaceutically acceptable salt thereof, having the structure of Formula (VII), wherein Ring A has the structure of Formula (Vila), (Vllb), or (VIIc), wherein R⁵ is -0-C0₂-R¹⁰. Another embodiment provides the compound, or a pharmaceutically acceptable salt thereof, having the structure of Formula (VII), wherein Ring A has the structure of Formula (Vila), (Vllb), or (VIIc), wherein R⁵ is -0-C0₂-R²⁰. Another embodiment provides the compound, or a pharmaceutically acceptable salt thereof, having the structure of Formula (VII), wherein Ring A has the structure of Formula (Vila), (Vllb), or (VIIc), wherein R⁵ is optionally substituted aralkoxy. Another embodiment provides the compound, or a pharmaceutically acceptable salt thereof, having the structure of Formula (VII), wherein Ring A has the structure of Formula (Vila), (Vllb), or (VIIc), wherein R⁵ is optionally substituted heteroarylalkoxy. Another embodiment provides the compound, or a

pharmaceutically acceptable salt thereof, having the structure of Formula (VII), wherein Ring A has the structure of Formula (Vila), (Vllb), or (VIIc), wherein R⁵ is optionally substituted (carbocyclyl)-O-. Another embodiment provides the compound, or a pharmaceutically acceptable salt thereof, having the structure of Formula (VII), wherein Ring A has the structure of Formula (Vila), (Vllb), or (VIIc), wherein R⁵ is optionally substituted heterocyclylalkoxy.

[00155] In some embodiments, the complement factor D inhibitory compound described herein has a structure provided in Table 1.

TABLE 1

Preparation of Compounds

[00156] The compounds used in the reactions described herein are made according to organic synthesis techniques known to those skilled in this art, starting from commercially available chemicals and/or from compounds described in the chemical literature. "Commercially available chemicals" are obtained from standard commercial sources including Acros Organics (Pittsburgh, PA), Aldrich Chemical (Milwaukee, WI, including Sigma Chemical and Fluka), Apin Chemicals Ltd. (Milton Park, UK), Avocado Research (Lancashire, U.K.), BDH Inc. (Toronto, Canada), Bionet (Cornwall, U.K.), Chemservice Inc. (West Chester, PA), Crescent Chemical Co. (Hauppauge, NY), Eastman Organic Chemicals, Eastman Kodak Company (Rochester, NY), Fisher Scientific Co. (Pittsburgh, PA), Fisons Chemicals (Leicestershire, UK), Frontier Scientific (Logan, UT), ICN Biomedicals, Inc. (Costa Mesa, CA), Key Organics (Cornwall, U.K.), Lancaster Synthesis (Windham, NH), Maybridge Chemical Co. Ltd. (Cornwall, U.K.), Parish Chemical Co. (Orem, UT), Pfaltz & Bauer, Inc.

(Waterbury, CN), Polyorganix (Houston, TX), Pierce Chemical Co. (Rockford, IL), Riedel de Haen AG

(Hanover, Germany), Spectrum Quality Product, Inc. (New Brunswick, NJ), TCI America (Portland, OR), Trans World Chemicals, Inc. (Rockville, MD), and Wako Chemicals USA, Inc. (Richmond, VA).

[00157] Suitable reference books and treatise that detail the synthesis of reactants useful in the preparation of compounds described herein, or provide references to articles that describe the preparation, include for example, "Synthetic Organic Chemistry", John Wiley & Sons, Inc., New York; S. R. Sandler et al., "Organic Functional Group Preparations," 2nd Ed., Academic Press, New York, 1983; H. O. House, "Modern Synthetic Reactions", 2nd Ed., W. A. Benjamin, Inc. Menlo Park, Calif. 1972; T. L. Gilchrist, "Heterocyclic Chemistry", 2nd Ed., John Wiley & Sons, New York, 1992; J. March, "Advanced Organic Chemistry:

Reactions, Mechanisms and Structure", 4th Ed., Wiley-Interscience, New York, 1992. Additional suitable reference books and treatise that detail the synthesis of reactants useful in the preparation of compounds described herein, or provide references to articles that describe the preparation, include for example, Fuhrhop, J. and Penzlin G. "Organic Synthesis: Concepts, Methods, Starting Materials", Second, Revised and Enlarged Edition (1994) John Wiley & Sons ISBN: 3-527-29074-5; Hoffman, R.V. "Organic Chemistry, An

Intermediate Text" (1996) Oxford University Press, ISBN 0-19-509618-5; Larock, R. C. "Comprehensive Organic Transformations: A Guide to Functional Group Preparations" 2nd Edition (1999) Wiley -VCH, ISBN: 0-471-19031-4; March, J. "Advanced Organic Chemistry: Reactions, Mechanisms, and Structure" 4th Edition (1992) John Wiley & Sons, ISBN: 0-471-60180-2; Otera, J. (editor) "Modern Carbonyl Chemistry" (2000) Wiley-VCH, ISBN: 3-527-29871-1; Patai, S. "Patai's 1992 Guide to the Chemistry of Functional Groups" (1992) Interscience ISBN: 0-471-93022-9; Solomons, T. W. G. "Organic Chemistry" 7th Edition (2000) John Wiley & Sons, ISBN: 0-471-19095-0; Stowell, J.C., "Intermediate Organic Chemistry" 2nd Edition (1993) Wiley-Interscience, ISBN: 0-471-57456-2; "Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann's Encyclopedia" (1999) John Wiley & Sons, ISBN: 3-527-29645-X, in 8 volumes; "Organic Reactions" (1942-2000) John Wiley & Sons, in over 55 volumes; and "Chemistry of Functional Groups" John Wiley & Sons, in 73 volumes.

[00158] Specific and analogous reactants are optionally identified through the indices of known chemicals prepared by the Chemical Abstract Service of the American Chemical Society, which are available in most public and university libraries, as well as through on-line databases (contact the American Chemical Society, Washington, D.C. for more details). Chemicals that are known but not commercially available in catalogs are optionally prepared by custom chemical synthesis houses, where many of the standard chemical supply houses (e.g. , those listed above) provide custom synthesis services. A reference for the preparation and selection of pharmaceutical salts of the kallikrein inhibitory compound described herein is P. H. Stahl & C. G. Wermuth "Handbook of Pharmaceutical Salts", Verlag Helvetica Chimica Acta, Zurich, 2002.

Pharmaceutical Compositions

[00159] In certain embodiments, the complement factor D inhibitory compound as described herein is administered as a pure chemical. In other embodiments, the complement factor D inhibitory compound described herein is combined with a pharmaceutically suitable or acceptable carrier (also referred to herein as a pharmaceutically suitable (or acceptable) excipient, physiologically suitable (or acceptable) excipient, or physiologically suitable (or acceptable) carrier) selected on the basis of a chosen route of administration and standard pharmaceutical practice as described, for example, in Remington: The Science and Practice of Pharmacy (Gennaro, 21^st Ed. Mack Pub. Co., Easton, PA (2005)).

[00160] Provided herein is a pharmaceutical composition comprising at least one complement factor D inhibitory compound, or a stereoisomer, pharmaceutically acceptable salt, hydrate, solvate, or N- oxide thereof, together with one or more pharmaceutically acceptable carriers. The carrier(s) (or excipient(s)) is acceptable or suitable if the carrier is compatible with the other ingredients of the composition and not deleterious to the recipient (i.e., the subject) of the composition.

[00161] One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of any one of Formula (I)-(VII), or a pharmaceutically acceptable salt thereof.

[00162] In certain embodiments, the complement factor D inhibitory compound as described by

Formula (I)-(VII) is substantially pure, in that it contains less than about 5%, or less than about 1%, or less than about 0.1%, of other organic small molecules, such as unreacted intermediates or synthesis by-products that are created, for example, in one or more of the steps of a synthesis method.

[00163] Suitable oral dosage forms include, for example, tablets, pills, sachets, or capsules of hard or soft gelatin, methylcellulose or of another suitable material easily dissolved in the digestive tract. In some embodiments, suitable nontoxic solid carriers are used which include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium carbonate, and the like. (See, e.g. , Remington: The Science and Practice of Pharmacy (Gennaro, 21^st Ed. Mack Pub. Co., Easton, PA (2005)).

[00164] The dose of the composition comprising at least one complement factor D inhibitory compound as described herein differ, depending upon the patient's (e.g., human) condition, that is, stage of the disease, general health status, age, and other factors.

[00165] Pharmaceutical compositions are administered in a manner appropriate to the disease to be treated (or prevented). An appropriate dose and a suitable duration and frequency of administration will be determined by such factors as the condition of the patient, the type and severity of the patient's disease, the particular form of the active ingredient, and the method of administration. In general, an appropriate dose and treatment regimen provides the composition(s) in an amount sufficient to provide therapeutic and/or prophylactic benefit (e.g., an improved clinical outcome, such as more frequent complete or partial remissions, or longer disease-free and/or overall survival, or a lessening of symptom severity. Optimal doses are generally determined using experimental models and/or clinical trials. The optimal dose depends upon the body mass, weight, or blood volume of the patient.

[00166] Oral doses typically range from about 1.0 mg to about 1000 mg, one to four times, or more, per day. Complement Factor D and Methods of Treatment

[00167] Complement Factor D (also referred to as C3 proactivator convertase, properdin factor D esterase, factor D (complement), CFD, or adipsin) is a protein which in humans is encoded by the CFD gene. Factor D is involved in the alternative complement pathway of the complement system where it cleaves factor B.

[00168] The complement factor D inhibitory compounds described herein function to modulate in vivo complement activation and/or the alternative complement pathway. In some embodiments, the complement factor D inhibitory compounds described herein function to inhibit in vivo complement activation and/or the alternative complement pathway. Accordingly, provided herein is a method of treating a disease or disorder associated with increased complement activity, the method comprising administering to a subject in need thereof a complement factor D inhibitory compound described herein. In some embodiments, the disease or disorder associated with increased complement activity is a disease or disorder associated with increased activity of the C3 amplification loop of the complement pathway.

[00169] Exemplary complement related diseases and disorders include, but are not limited to, autoimmune, inflammatory, and neurodegenerative diseases. In certain instances, the complement related diseases and disorder is paraoxysmal nocturnal hemoglobinuria. In certain instances, the complement related diseases and disorder is C3 glomerulopathy. One embodiment provides a method for treating paraoxysmal nocturnal hemoglobinuria in a patient in need thereof, comprising administering to the patient a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof. One embodiment provides a method for treating paraoxysmal nocturnal hemoglobinuria in a patient in need thereof, comprising administering to the patient a composition comprising a compound of Formula (II), or a pharmaceutically acceptable salt thereof. One embodiment provides a method for treating paraoxysmal nocturnal

hemoglobinuria in a patient in need thereof, comprising administering to the patient a composition comprising a compound of Formula (III), or a pharmaceutically acceptable salt thereof. One embodiment provides a method for treating paraoxysmal nocturnal hemoglobinuria in a patient in need thereof, comprising administering to the patient a composition comprising a compound of Formula (IV), or a pharmaceutically acceptable salt thereof. One embodiment provides a method for treating paraoxysmal nocturnal

hemoglobinuria in a patient in need thereof, comprising administering to the patient a composition comprising a compound of Formula (V), or a pharmaceutically acceptable salt thereof. One embodiment provides a method for treating paraoxysmal nocturnal hemoglobinuria in a patient in need thereof, comprising administering to the patient a composition comprising a compound of Formula (VI), or a pharmaceutically acceptable salt thereof. One embodiment provides a method for treating paraoxysmal nocturnal

hemoglobinuria in a patient in need thereof, comprising administering to the patient a composition comprising a compound of Formula (VII), or a pharmaceutically acceptable salt thereof.

[00170] One embodiment provides a method for treating C3 glomerulopathy in a patient in need thereof, comprising administering to the patient a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof. One embodiment provides a method for treating C3 glomerulopathy in a patient in need thereof, comprising administering to the patient a composition comprising a compound of Formula (II), or a pharmaceutically acceptable salt thereof. One embodiment provides a method for treating C3 glomerulopathy in a patient in need thereof, comprising administering to the patient a composition comprising a compound of Formula (ΠΙ), or a pharmaceutically acceptable salt thereof. One embodiment provides a method for treating C3 glomerulopathy in a patient in need thereof, comprising administering to the patient a composition comprising a compound of Formula (IV), or a pharmaceutically acceptable salt thereof. One embodiment provides a method for treating C3 glomerulopathy in a patient in need thereof, comprising administering to the patient a composition comprising a compound of Formula (V), or a pharmaceutically acceptable salt thereof. One embodiment provides a method for treating C3 glomerulopathy in a patient in need thereof, comprising administering to the patient a composition comprising a compound of Formula (VI), or a pharmaceutically acceptable salt thereof. One embodiment provides a method for treating C3

glomerulopathy in a patie t in need thereof, comprising administering to the patient a composition comprising a compound of Formula (VII), or a pharmaceutically acceptable salt thereof.

[00171] Other embodiments and uses will be apparent to one skilled in the art in light of the present disclosures. The following examples are provided merely as illustrative of various embodiments and shall not be construed to limit the invention in any way.

EXAMPLES

I. Chemical Synthesis

[00172] Unless otherwise noted, reagents and solvents were used as received from commercial suppliers. Anhydrous solvents and oven -dried glassware were used for synthetic transformations sensitive to moisture and/or oxygen. Yields were not optimized. Reaction times are approximate and were not optimized. Column chromatography and thin layer chromatography (TLC) were performed on silica gel unless otherwise noted. Spectra are given in ppm (δ) and coupling constants, J are reported in Hertz. For proton spectra the solvent peak was used as the reference peak.

[00173] The following abbreviations and terms have the indicated meanings throughout:

AcOH = acetic acid

B₂pin₂ = bis(pinacolato)diboron

Boc = tert- butoxycarbonyl

DCC = dicyclohexylcarbodiimide

DIEA = N,N-diisopropylethylamine

DMAP = 4-dimethylaminopyridine

EDC = l-ethyl-3-(3-dimethylaminopropyl) carbodiimide

eq = equivalent(s)

Et = ethyl

EtOAc or EA = ethyl acetate

EtOH = ethanol

g = gram h or hr = hour

HBTU 0-(benzotriazol-l-yl)-N,N,N',N'-tetramethyluroniui

hexafluorophosphate

HOBt hydroxybenzotriazole

HPLC high pressure liquid chromatography

kg or Kg kilogram

L or l liter

LC/MS or LCMS = liquid chromatography-mass spectrometry

LRMS low resolution mass spectrometry

m/z = mass-to-charge ratio

Me methyl

MeOH methanol

mg milligram

min = minute

mL = milliliter

mmol = millimole

NaOAc sodium acetate

PE petroleum ether

Ph phenyl

Prep = preparative

quant. = quantitative

RP-HPLC reverse phase-high pressure liquid chromatography

rt or RT room temperature

THF tetrahydrofuran

UV ultraviolet

Preparation of 2-(3-carbamoyl-lH-indazol-l

2-(3-carbamoyl-1 H-indazol-1 -yl)acetic acid

[00174] To a solution of indazole 3-carboxylic acid (2.0 g, 12.4 mmol, 1.0 eq.) in anhydrous THF

(30 mL) were added isobutyl chloroformate (2.6 g, 19.6 mmol, 1.5 eq.) and N-methylmorpholine (2.0 g, 19.6 mmol, 1.5 eq.) under nitrogen protection at -20° C. The mixture was stirred for 2 h, then 3.4 mL of

NH₄OH was added. After the addition was complete, the mixture was stirred at r.t. for 1 h, then quenched by water. The mixture was extracted with EtOAc (2 x 50 mL). The combined organic layers were dried over anhydrous Na₂S0₄ and concentrated under vacuum. The residue was purified by column chromatography (CH₂Cl₂/MeOH=20: l) to provide isobutyl 3-carbamoyl-lH-indazole-l-carboxylate as a white solid (1.7 g, 52.4%).

[00175] To a solution of isobutyl 3 -carbamoyl -lH-indazole-l-carboxylate (1.7 g, 6.5 mmol, 1.0 eq.) in MeOH (20 mL) was added K₂C0₃ (1.8 g, 13.0 mmol, 2.0 eq.). The mixture was stirred at 80 °C for 2 h, cooled, then quenched by water. The mixture was extracted with EtOAc (2 x 50 mL). The combined organic layers were dried over anhydrous Na₂S0₄ and concentrated under vacuum. The residue was purified by column chromatography (CH₂Cl₂/MeOH= 20: 1) to provide lH-indazole-3-carboxamide as a white solid (1.0 g, 94.8%).

[00176] To a suspension of 1 H-indazole-3-carboxamide (1.0 g, 6.2 mmol, 1.0 eq.) and potassium carbonate (2.1 g, 14.9 mmol, 2.4 eq.) in CH₃CN (30 mL) was added tert-butyl bromoacetate (1.1 mL, 7.4 mmol, 1.2 eq.) dropwise at r.t.. After the addition was complete, the resulting mixture was heated under reflux for 16 h, then cooled and filtered. The filtrate was concentrated under vacuum and the residue was purified by column chromatography (PE/EA=20: 1) to provide tert-butyl 2-(3-carbamoyl-lH-indazol-l-yl)acetate (1.6 g, 93.6%).

[00177] To a solution of tert-butyl 2 -(3 -carbamoyl- 1 H-indazol-l-yl)acetate (1.6 g, 5.8 mmol) in

CH₂CI₂ (16 mL) was added TFA (4 mL). The resulting mixture was stirred at r.t. for 16 h, then concentrated under vacuum and the residual was triturated in methanol and filtered to provide 2-(3-carbamoyl-lH-indazol- l-yl)acetic acid (1.0 g, 78.0%) which was used in the next step without any further purification.

Preparation of 2-(3-carbamoyl-5-chloro-lH- ic acid

2-(3-carbamoyl-5-chloro-1 H-indazol-1 -yl)acetic acid

[00178] To a mixture of 5-chloro-lH-indazole (2.0 g, 13.1 mmol, 1.0 eq.), KOH (2.4 g, 45.8 mmol) in DMF was added I₂ (6.6 g, 26.1 mmol, 2.0 eq.). The mixture was stirred at r.t. overnight, then quenched by aqueous Na₂S₂0₄ solution. The mixture was extracted with EtOAc (2 x 50 mL). The combined organic layers were dried over anhydrous Na₂S0₄ and concentrated. The residue was purified by column chromatography (PE/EA =10: 1) to provide 5-chloro-3-iodo-lH-indazole (3.1 g, 85.3%).

[00179] To a suspension of 5-chloro-3-iodo-lH-indazole (3.1 g, 11.2 mmol, 1.0 eq.) and potassium carbonate (3.1 g, 22.3 mmol, 2.0 eq.) in CH₃CN (50 mL) was added tert-butyl bromoacetate (2.6 g, 13.4 mmol, 1.2 eq.) dropwise at r.t. The resulting mixture was heated under reflux for 16 h, then cooled and filtered. The filtrate was concentrated under vacuum and the residue was purified by column chromatography (PE/EA =20: 1) to provide tert-butyl 2-(5-chloro-3-iodo-lH-in .7 g, 84.1%).

[00180] To a suspension of tert-butyl 2-(5-chloro-3-iodo-lH-indazol-l-yl)acetate (3.5 g, 8.9 mmol, 1.0 eq.) in MeOH (30 mL) was added Et₃N (2.24 g, 22.2 mmol) and Pd(dppf)Cl₂ (612 mg, 0. 9 mmol, 0.1 eq.) under N₂ protection. After the addition was complete, the mixture was degassed, stirred at 100°C overnight under CO atmosphere, then cooled, diluted with water and extracted with EtOAc (2 x 30 mL). The combined organic layers were dried over anhydrous Na₂S0₄ and concentrated under vacuum. The residue was purified by column chromatography (PE/EA=10: 1) and to provide methyl l-((tert-butoxycarbonyl)methyl)-5- chloro-lH-indazole-3-carboxyl

[00181] To a solution of methyl l-((tert-butoxycarbonyl)methyl)-5-chloro-lH-indazole-3- carboxylate (410 mg, 1.3 mmol) in DCM (16.0 mL) was added TFA (4.0 mL) and the resulting mixture was stirred at r.t. for 16 h, then concentrated under vacuum. The residual was used in the next step without any further purification.

[00182] A solution of the above obtained 2-(3-(methoxycarbonyl)-5-chloro-lH-indazol-l-yl)acetic acid in NH₃/H₂0 (16 mL) was stirred at 50°C in a sealed tube for 16 h, then cooled and acidified with 3N HCl to pH=2. The precipitate was filtered and dried to provide 2-(3-carbamoyl-5-chloro-lH-indazol-l-yl)acetic acid (250 mg,78.0%) as a white solid. Preparation 2-(3-carbanioyl-5-c cSoprop S-lH-indazoS-l-y!)acetic acid

2-(3-oarbamoyl-5-cyclopropyl-1 H-i acid

[00183] To a solution of 5-bromo-lH-indazole (5.0 g, 25.4 mmol, 1.0 eq.) in anhydrous DMF

(15.0 mL) was added KOH (4.3 g, 76.1 mmol, 3.0 eq.) and I₂ (12.9 g, 50.75 mmol, 2.0 eq.) under nitrogen. The mixture was stirred at r.t. for 2 h, then diluted with ice water, extracted with EA (50 mL x 2). The combined organic layers were washed with aqueous Na₂S₂0₃ solution and brine, dried over anhydrous Na₂S0₄ and concentrated under vacuum to provide 5-bromo-3-iodo-lH-indazole (8.0 g, 97.9%) which was used in the next step without further purification.

[00184] To a solution of 5-bromo-3-iodo-lH-indazole (4.0 g, 12.4 mmol, 1.0 eq.) and potassium carbonate (4.5 g, 32.3 mmol, 2.6 eq,) in CH₃CN (100 mL) was added tert-butyl bromoacetate (2.9 g, 14.9 mmol, 1.2 eq.) dropwise at r.t.. After the addition was complete, the resulting mixture was heated under reflux for 16 h, then cooled and filtered. The filtrate was concentrated under vacuum to provide crude tert-butyl 2-(5- bromo-3-iodo-lH-indazol-l-yl)acetate which was used directly in the next step without further purification.

H-

[00185] To a solution of tert-butyl 2-(5-bromo-3-iodo-lH-indazol-l-yl)acetate (2.0 g, 4.6 mmol,

1.0 eq.) in CH₃OH (50 mL) were added Pd(dppf)Cl₂ (340 mg, 0. 5 mmol, 0.1 eq.) and TEA (1.4 g, 1.4 mmol, 3.0 eq.). The resulting mixture was stirred at 80°C under CO atmosphere for 16 h, then cooled and concentrated under vacuum. The residue was purified by column chromatography (PE/EA=10: 1) to provide methyl 5-bromo-l-(2-(tert-butoxy)-2-oxoethyl)-lH-indazole-3-carboxylate (400 mg, 23.7%).

[00186] To a solution of methyl 5-bromo-l-(2-(tert-butoxy)-2-oxoethyl)-lH-indazole-3- carboxylate (1.0 g , 2.8 mmol, 1.0 eq.) in toluene/H₂0 (4: 1, 50 mL) were added cyclopropylboronic acid (265 mg , 3.1 mmol, 1.1 eq.), K₃P0₄ ( 1.8 g , 8.4 mmol, 3.0 eq.) . After purged with argon for 15 mins, the mixture was and then added Pd(OAc)₂ (130 mg , 0.56 mmol, 0.2 eq.) and Pcy₃ (310 mg , 1.12 mmol, 0.4 eq.). The resulting mixture was stirred at 100 °C for 16 h under argon atmosphere, then cooled and concentrated under vacuum. The residue was purified by column chromatography (PE/EA= 10: 1) to provide methyl l -(2-(tert- butoxy)-2-oxoethyl)-5-cyclopropyl-lH-indazole-3-carboxylate (650 mg, 70.0%)

[00187] A solution of methyl l-(2-(tert-butoxy)-2-oxoethyl)-5-cyclopropyl-lH-indazole-3- carboxylate (397 mg , 1.2 mmol, 1.0 eq.) in TFA/DCM(1 :3, 8 mL) was stirred at r.t. for 3 h, then

concentrated under cacuum. The resulting residue was used directly in the next reaction step without further purification.

[00188] A suspension of 2-(5-cyclopropyl-3-(methoxycarbonyl)-lH-indazol-l-yl)acetic acid (330 mg, 1.2 mmol) in NH₄OH(10 mL) was stirred at r.t. in a sealed tube for 16 h, then diluted with H₂0 (10 mL). The mixture was adjusted to pH 5-7 with HCl and the resulting precipitate was filtered and dried to provide 2-(3-carbamoyl-5-cyclopropyl-lH-indazol-l-yl)acetic acid (140 mg, 44.7%). i-NMR (DMSO-d6, 400 MHz) δ= 13.24 (s, 1 H), 7.88 (s, 1 H), 7.64 (s, 1 H), 7.61 (d, 1 H), 7.35 (s, 1 H), 7.18 (d, 1 H), 5.28 (s, 2 H), 2.06- 2.10 (m, 1 H), 0.97 (q, 2 H), 0.685 (q, 2 H).

Preparation of 2-(3-carbamoyl-6-(methoxy ol-l-yl)acetic acid

2-(3-carbamoyl-6-(methoxycarbonyl)-1 H-indazol-1 -yl)acetic acid

[00189] A solution of methyl 6-bromo-l-(2-(tert-butoxy)-2-oxoethyl)-lH-indazole -3- carboxylate (3.0 g , 8.2 mmol) in TFA/DCM (1 :3, 40 mL) was stirred at r.t. for 3 h, then concentrated. The residue was used directly in the next reaction step without further purification.

[00190] A suspension of 2-(6-bromo-3-(methoxycarbonyl)-lH-indazol-l-yl)acetic acid (2.5 g, 8.0 mmol) in NH₄OH (40 mL) was stirred at r.t. in a sealed vessel for 24 h, then concentrated. The residue was used directly in the next step without further purification.

[00191] To a solution of 2-(6-bromo-3-carbamoyl-lH-indazol-l-yl)acetic acid (1.0 g, 3.4 mmol,

1.0 eq.) in CH₃OH (50 mL) and DMF (15 mL) was added Pd(dppf)Cl₂ (250 mg, 0.34 mmol, O. leq.) and TEA (1.0 g, 10.1 mmol, 3.0eq.). The resulting mixture was stirred at 70°C under CO atmosphere for 16 h, then concentrated in vacuo. The residue was dissolved in H₂0 (50 mL), washed with EA (50 mL x 2), adjusted to pH 3-5 until the white precipitate was formed. The solid was collected by filtration and washed with PE to provide 2-(3-carbamoyl-6-(methoxycarbonyl)-lH-indazol-l-yl)acetic acid (450 mg, 48.2%).

Preparation of 2-(3-carbamoyI-lH-pyrazoSol3,4-c]pyridm-l-yl)ac6tic acid!

2-(3-c -yl)acetic acid

[00192] To a solution of lH-pyrazolo[3,4-c]pyridine (4.0 g, 33.6 mmol, 1.0 eq.) in DMF (40 mL) were added K₂C0₃ (9.3 g, 100.8 mmol, 3.0 eq.), I₂ (7.9 g, 33.6 mmol, 1.0 eq.). The resulting mixture was stirred at r.t. for 3 hr, then diluted by H₂0 and filtered. The collected solid was dried to give 3-iodo-lH- pyrazolo[3,4-c]pyridine (6.0 g, 73.0 % yield).

[00193] To a solution of 3-iodo-lH-pyrazolo[3,4-c]pyridine (6.0 g, 24.5 mmol, 1.0 eq.) and

K₂C0₃ (4.0 g, 29.4 mmol, 1.2 eq.) in DMF (40 mL) was added tert-butyl 2-bromoacetate (4.78 g, 24.5 mmol, 1.0 eq.). The resulting mixture was stirred at r.t. for 2 h, then poured into water (200 mL), extracted with EtOAc (200 mL x 3). The combined organic layers were dried and concentrated under vacuum. The residue was purified by column chromatography (PE/EtOAc=3: l) to provide tert-butyl 2-(3-iodo-lH-pyrazolo[3,4- c]pyridin-l-yl)acetate as a yellow oil (6.0 g, 68.0% yield).

[00194] To a solution of tert-butyl 2-(3-iodo-lH-pyrazolo[3,4-c]pyridin-l-yl)acetate (6.0 g, 16.7 mmol, 1.0 eq.) and Zn(CN)₂ (2.3 g, 20.0 mmol, 1.2 eq.) in H₂0/DMF (5/35 ml) were added Pd(dppf)C12 (1.2 g, 1.6 mmol, 0.1 eq.), Pd2(dba)3 (1.5 g, 1.6 mmol, 0.1 eq.). The resulting mixture was stirred at 80°C for lh, then cooled and poured into water (200 ml), extracted with EtOAc (200 ml x 3). The combined organic layers were dried over anhydrous Na₂S0₄ and evaporated. The residue was purified by column chromatography (PE/EtOAc=5: l) to provide tert-butyl 2-(3-cyano-lH-pyrazolo[3,4-c]pyridin-l-yl)acetate (3.5 g, 81.0 % yield).

[00195] A solution of tert-butyl 2-(3-cyano-lH-pyrazolo[3,4-c]pyridin-l-yl)acetate (500 mg, 2.0 mmol) in TFA (2 mL) was stirred at 120 °C for 3 h under microwave irradiation, then cooled and concentrated under vacuum to provide crude 2-(3-carbamoyl-lH-pyrazolo[3,4-c]pyridin-l-yl)acetic acid (450 mg, ca. 100 % yield) which was used in the next step without further purification.

Preparation of 2-(3-carbamoyl-lH-pyrazolo[4, -b]pyridin-l-yl)acetic acid

2-(3-carbamoyl-1 H-pyrazolo[4,3-i>]pyridin-1 -yl)acetic acid

[00196] To a solution of lH-pyrazolo[4,3-b] pyridine (800.0 mg, 6.7 mmol, 1.0 eq.) in anhydrous

DMF (10 mL) were added KOH (1.1 g, 20.2 mmol, 3.0 eq.) and I₂ (3.4 g, 13.4 mmol, 2.0 eq.) under nitrogen at r. . The mixture was stirred for 2 h, then diluted with ice water, extracted with EA (30 mL χ 3). The combined organic layer was washed with aqueous Na₂S₂0₃ and brine, dried over anhydrous Na₂S0₄, concentrated under vacuum. The residue was purified by column chromatography (DCM/MeOH = 40: 1) to provide 3-iodo-lH-pyrazolo[4,3-b]py

[00197] To a solution of 3-iodo-lH-pyrazolo[4,3-b] pyridine (500 mg, 2.0 mmol, 1.0 eq.) and potassium carbonate (845 mg, 6.1 mmol, 3.0 eq,) in CH₃CN (10 mL) was added tert-butyl bromoacetate (398 mg, 2.04 mmol, l .Oeq.) dropwise at r.t., The resulting mixture was heated under reflux for 16 h, then cooled and diluted with H₂0 (20 mL), extracted with EA (20 mL χ 3). The combined organic layers were washed with brine, dried over Na₂S0₄, concentrated under vacuum and purified by column (DCM/MeOH = 100: 1) to provide tert-butyl 2-(3-iodo-lH-pyrazolo[4,3-b]pyridin-l-yl)acetate (350 mg, 47.8%).

[00198] To a solution of tert-butyl 2-(3-iodo-lH-pyrazolo[4,3-b] pyridin-l-yl) acetate (76 mg, 0.2 mmol, 1.0 eq.) in CH₃OH (5 mL) were added Pd(dppf)Cl₂ (15 mg, 0. 02 mmol, 0.1 eq.) and TEA (64 mg, 0.6 mmol, 3.0 eq.). The resulting mixture was stirred at 60°C under CO atmosphere for 16 h. Then cooled and concentrated in vacuo and the residue was purified by prep-TLC (DCM/MeOH = 20: 1) to provide methyl 1- (2-(tert-butoxy)-2-oxoethyl)-lH- 45 mg, 73.8%) as a yellow solid.

[00199] A solution of methyl l-(2-(tert-butoxy)-2-oxoethyl)-lH-pyrazolo [4,3-b]pyridine-3- carboxylate (45 mg , 0.155 mmol) in TFA/DCM(1 :2, 6 mL) was stirred at r.t. for 3 h, then concentrated. The residue was used directly in the next without further purification.

[00200] A suspension of 2-(3-(methoxycarbonyl)-lH-pyrazolo[4,3-b]pyridin-l-yl)acetic acid (36 mg, 0.155 mmol) in NH₄OH (10 mL) was stirred at r.t. in a sealed vessel for 16 h. The reaction mixture was concentrated to provide crude 2-(3-carbamoyl-lH-pyrazolo [4,3-b]pyridin-l-yl)acetic acid (34 mg, ca. 100% yield) which was used directly in the next step without further purification.

Preparation of 2-amino-6-chloronicotinonitrile

2-amino-6-chloronicotinonitrile

[00201] To a solution of 2,6-dichloronicotinonitrile (2.0 g, 11.6 mmol, 1.0 eq.) in NMP (50 mL) was added PMBNH₂ (2.4 g, 17.3 mmol, 1.5 eq.) and DIEA (3.0 g, 23.1 mmol, 2.0 eq.). The mixture was stirred at 120°C under N₂ atmosphere overnight until TLC showed that the reaction was completed, then cooled and concentrated. The residue was quenched with H₂0 (200 mL), extracted with EA (80 mL x 3). The combined organic layer was washed with brine (80 mL x 2), dried over anhydrous Na₂S0₄, concentrated. The resulting residue was purified by column chromatography (PE/EA = 10: 1) to provide 6-chloro-2-((4- methoxybenzyl) amino)nicotinonitrile (2.3 g, 72.9%) as yellow solid.

^NC X- ^X. TFA,r.,.,2h ^NC

PMBNH N CI NH₂ N CI

[00202] A solution of 6-chloro-2-((4-methoxybenzyl)amino)nicotinonitrile (2.2 g, 8.1 mmol) in

TFA (20 mL) was stirred at r.t. for 45 minutes until TLC showed that the reaction was completed, then concentrated to provide crude 2-amino-6-chloronicotinonitrile (1.2 g, ca. 99% yield) which was used directly in the next step without further purification.

Preparation of (5-bromo-3-chloro-2-fluorophenyl)methanamine

[00203] To a solution of dissoprppylamine (5.1 mL, 36.0 mmol, 1.5 eq.) in anhydrous THF (15 mL) was added n-BuLi (19.2 mL, 28.8 mmol, 1.2eq.) dropwise at -78°C under N₂ atmosphere, then was added the 4-bromo-2-chloro-l-fluorobenzene (5 g, 24.0 mmol, 1.0 eq.) at -78°C 1 h later. The mixture was stirred at -78°C for 45 minutes, then was added DMF (2.8 mL, 36.0 mmol, 1.5 eq. ), warmed to -30°C until TLC showed that the reaction was completed. The reaction was quenched with H₂0 (100 mL), then adjusted to pH 2-3, extracted with EA (50 mLx3). The combined organic layers were washed with brine, dried over anhydrous Na₂S0₄ and evaporated. The residue was purified by column chromatography (PE/EA=100: 1) to provide 5-bromo-3-chloro-2-fluoroben low solid.

[00204] To a solution of 5-bromo-3-chloro-2-fluorobenzaldehyde (4.7 g, 19.9 mmol, 1.0 eq.) in

CH₃OH (30 mL) was added NaBH₄ (2.3 g, 59.7 mmol, 3.0eq,) in portions. The mixture was stirred at r.t. for 2 h until TLC showed that the reaction was completed, then concentrated under reduced pressure. The residue was dissolved in EA (60 mL), washed with brine (60 mLx3), dried over anhydrous Na₂S0₄ and concentrated to provide (5-bromo-3-chloro-2

[00205] To a solution of (5 -bromo-3-chloro-2 -fluorophenyl) methanol (4.6 g, 19.3 mmol, 1.0 eq.) in dry THF (200 mL) was added isoindoline-l,3-dione (3.7 g, 25.1 mmol, 1.3 eq.) and PPh₃ (10.1 g, 38.6 mmol, 2.0eq.). The resulting mixture was stirred at 0°C under N₂ atmosphere for 30 mins, then was added DIAD (7.8 g, 38.6 mmol, 2.0 eq.) dropwise. The mixture was stirred at r.t. overnight until the reaction was completed, then concentrated under reduced pressure. The resulting residue was purified by column chromatography (PE/EA=10: 1) to provide 2-(5-bromo-3-chloro-2-fluorobenzyl) isoindoline-l,3-dione (4.0 g, 43.4%). ^-NMR (CDC1₃, 400 MH (s, 2 H), 7.77 (s, 2 H), 7.48 (s, 1 H), 7.35 (s, 1 H), 4.90 (s, 2 H).

a suspension of 2-(5-bromo-3-chloro-2-fluorobenzyl)isoindoline-l,3-dione (1.0 g, 2.7 mmol, 1.0 eq.) in CH₃OH (50 mL) was added N₂H₄ .H₂0 (85%, 1.6 mL, 27.2 mmol, 10.0 eq.). The resulting mixture was stirred at 70°C for 4 h until the reaction was completed monitored by LCMS, then cooled to r. , and adjusted to pH 4-5 until white precipitate was formed. The mixture was concentrated under reduced pressure and the residue was dissolved in H₂0, filtered. The filtrate was adjusted to pH 8-12, extracted with EA (50 mL x 5). The combined organic layer was added HCl/dioxane (4 N) to pH 4-5, and concentrated to provide (5-bromo-3-chloro-2-fluorophenyl)methanamine hydrochloride (750 mg, ca. 100%).

Preparation of 2-(3-carbamoyl-7-chloro-lH-i cetic acid

2-(3-carbamoyl-7-chloro-1 H-indazol-1 -yl)acetic acid

[00207] To a mixture of 7-chloro-lH-indazole (0.6 g, 3.93mmol, 1.0 eq.), KOH (0.55 g, 9.8 mmol) in DMF was added I₂ (1.02g, 4.01 mmol, 1.02 eq.). The mixture was stirred at r.t. overnight, then quenched by aqueous Na₂S₂0₄ solution. The mixture was extracted with EtOAc (2 x 50 mL). The combined organic layers were dried over anhydrous Na₂S0₄ and concentrated. The resulting residue was purified by column chromatography (PE/EA =10: 1) to provide 7-chloro-3-iodo-lH-indazole (0.96 g, 87.8%).

[00208] To a suspension of 7-chloro-3-iodo-lH-indazole (0.96 g, 3.45 mmol, 1.0 eq.) and potassium carbonate (953 mg, 6.90 mmol, 2.0 eq.) in CH₃CN (20 mL) was added tert-butyl bromoacetate (807 mg, 4.14 mmol, 1.2 eq.) dropwise at r.t.. The resulting mixture was heated under reflux for 16 h, then cooled and filtered. The filtrate was concentrated under vacuum and the residue was purified by column

chromatography (PE/EA =20: 1) to provide tert-butyl 2-(7-chloro-3-iodo-lH-indazol-l-yl)acetate (1.1 g, 81.5%) as a yellow solid.

[00209] To a suspension of tert-butyl 2-(7-chloro-3-iodo-lH-indazol-l-yl)acetate (1.1 g, 2.81 mmol, 1.0 eq.) in MeOH/DMF (10 mL/10mL) was added Et₃N (567 mg, 5.62 mmol, 2.0eq.) and Pd(dppf)Cl₂ (229 mg, 0.281 mmol, 0.1 eq.) under N₂ protection. After the addition was complete, the mixture was degassed, stirred at 100°C overnight under CO atmosphere, then cooled, diluted with water and extracted with EtOAc (2 x 30 mL). The combined organic layers were dried over anhydrous Na₂S0₄ and concentrated under vacuum. The residue was purified by column chromatography (PE/EA=10: 1) and to provide methyl l-(2-(tert- butoxy)-2-oxoethyl)-7-chloro-lH 00 mg, 88.0%).

[00210] To a solution of methyl l-(2-(tert-butoxy)-2-oxoethyl)-7-chloro-lH-indazole-3- carboxylate (800 mg, 2.47 mmol) in DCM (16.0 mL) was added TFA (4.0 mL) and the resulting mixture was stirred at r.t. for 16 h, then concentrated under vacuum. The residual was used in the next step without any further purification.

[00211] A solution of the above obtained 2-(7-chloro-3-(methoxycarbonyl)-lH-indazol-l -yl)acetic acid (662mg, 2.47 mmol) in NH₃/H₂0 (16 mL) was stirred at 50°C in a sealed tube for 16 h, then cooled and acidified with 3N HCl to pH 2. The precipitate was filtered and dried to provide 2-(3-carbamoyl-7-chloro-lH- indazol-l-yl)acetic acid (480 mg,76.8%) as a white solid.

Example 1: Preparation of 7-chloro-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carb

azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-l -indazole-3-carboxamide

7-chloro-1 -(2-((1 R,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1 ]heptan-2-yl)-2-oxoethyl)-1 H-indazole-3-carboxamide

[00212] A solution of (lR,3S,4S)-2-(tert-butoxycarbonyl)-2-azabicyclo[2.2. l]heptane-3- carboxylic acid (400 mg , 1.7 mmol, 1.0 eq.) in dry DMF (6 mL) was cooled to 0 °C. TEA (168 mg , 1.7 mmol, 1.0 eq.) and isobutyl carbonochloridate (272 mg , 2.0 mmol, 1.2 eq.) were added the above mixture and the resulting mixture was stirred at 0 °C for 3 h to provide (lR,3S,4S)-2-(tert-butoxycarbonyl)-2- azabicyclo[2.2.1]heptane-3-carboxylic (isobutyl carbonic) anhydride which was used in the next step directly without further purification.

[00213] 6-Chloropyridin-2 -amine (320 mg , 2.5 mmol) and TEA (168 mg , 1.660 mmol) were added to above solution, then the resulting mixture was heated at 120 °C overnight, then cooled and concentrated under vacuum. The residue was purified by column chromatography (EA/PE= 1:25) to provide (lR,3S,4S)-tert-butyl 3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptane-2-carboxylate. (185 mg, 31.0 % yield).

[00214] TFA (1.5 mL) was added dropwise to a solution of (lR,3S,4S)-tert-butyl 3-((6- chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptane-2-carboxylate (100 mg , 0.3 mmol) in DCM (3.5 mL) at 0 °C. After the addition was complete, the resulting mixture was stirred at 0 °C overnight, then diluted with DCM (10 mL) and neutralized by the addition of saturated aqueous NaHC0₃ (10 mL). The bi-layers were separated and the organic layer was dried over anhydrous Na₂S0₄ and concentrated under vacuum to provide (lR,3S,4S)-N-(6-chloropyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3-carboxamide (70 mg, ca. 100% yield) which was used in next step without further purification.

[00215] To a solution of 2-(3-carbamoyl-lH-indazol-l-yl)acetic acid (25 mg , 0.1 mmol, 1.0 eq.),

HATU (65 mg , 0.2 mmol, 2.0 eq.) and DIPEA (40 mg , 0.3 mmol, 3.0 eq.) in DMF (1.5 mL) was added (lR,3S,4S)-N-(6-chloropyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3-carboxamide (35 mg , 0.1 mmol, 1.0 eq). After the addition was complete, the resulting mixture was stirred at r.t. for 4 h, then concentrated under vacuum. The resulting residue was purified by Prep-HPLC to provide 7-chloro-l-(2-((lR,3S,4S)-3-((6- chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-lH-indazole-3-carboxamide (12.0 mg, 24.6%).1H NMR (CD30D, 400 MHz) δ 8.19 (d, 1 H), 8.00 (d, 1 H), 7.69 (t, 1 H), 7.44 (d, 1 H), 7.21 (t, 1 H), 7.08 (d, IH), 5.84 (d, IH), 5.75 (d, 1 H), 4.60 (s, 2 H), 4.15 (s, 1 H), 2.81 (s, 1 H), 2.19 (d, 1 H), 1.87-1.92 (m, 3 H), 1.56 (m, 1 H). LCMS (M+H⁺) m/z calculated 487.1, found 487.1.

Example 2: Preparation of l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-7-methyl-lH-indazole-3-carboxamide

1 -(2-((1 R,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1 ]heptan-2-yl)-2-oxoethyl)-7-methyl-1 H-indazole-3<arboxamide

[00216] l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- oxoethyl)-7-methyl-lH-indazole-3-carboxamide (44.9 mg) was prepared as described for7-chloro-l-(2- ((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-lH ndazol^ carboxamide. lH NMR (DMSO, 400 MHz) δ 10.89 (s, 1 H), 7.97-8.04 (m, 2 H), 7.80-7.84 (m, 1 H), 7.60 (s, 1 H), 7.36 (s, 1 H), 7.13-7.18 (m, 3H), 5.84 (d, 1H), 5.42 (d, 1 H), 4.63 (s, 1 H), 4.11 (s, 1 H), 2.69 (s, 1 H), 2.62 (s, 3 H), 2.06-2.08 (m, 1 H), 1.72-1.81 (m, 3 H), 1.42-1.58 (m, 2 H). LCMS (M+H⁺) m/z calculated 467.2, found 467.2.

Example 3: Preparation of l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-7- ole-3-carboxamide

1 -(2-((1 R,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1 ]h.8ptan-2-yl)-2-oxoethyl)-7-f luoro-1 H-indazole-3-carboxamide

[00217] l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- oxoethyl)-7-fluoro-lH-indazole-3-carboxamide (51.4 mg) was prepared as described for 7-chloro-l-(2- ((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-lH-indazole-3- carboxamide. lH NMR (CD₃OD, 400 MHz) δ 8.01 (t, 2 H), 7.70 (t, 1 H), 7.15-7.22 (m, 2 H), 7.09 (d, 1 H), 5.69 (d, 1 H), 5.54 (d, 1 H), 4.59 (s, 1 H), 4.16 (s, 1 H) 2.82 (s, 1 H), 2.19 (d, 1 H), 1.87-1.94 (m, 3 H), 1.66 (t, 1 H), 1.57 (d, 1 H). LCMS (M+H⁺) m/z calculated 471.1, found 471.2.

Example 4: Preparation of l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-7- ole-3-carboxamide

1 -(2-((1 ?,3S,4S)-3-((6-chlorapyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1 ]heptan-2-yl)-2-oxoethyl)-7-cyano-1 H-indazole-3-carboxamide [00218] l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- oxoethyl)-7-cyano-lH-indazole-3-carboxamide (8.2 mg) was prepared as described for 7-chloro-l-(2- ((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-lH ndazol^ carboxamide. lH NMR (CD₃OD, 400 MHz) δ 8.57 (d, 1 H), 8.00 (d, 1 H), 7.88 (t, 1 H), 7.69 (t, 1 H), 7.41 (t, 1 H), 7.08 (d, 1 H), 5.91 (d, 1 H), 5.73 (d, 1H), 4.60 (d, 1 H), 4.18 (s, 1 H), 2.83 (d, 1 H), 2.18 (t, 2 H), 1.89-1.93 (m, 2 H), 1.67-1.70 (m, 1 H), 1.58 (d, 1 H). LCMS (M+H⁺) m/z calculated 478.1, found 478.2.

Example 5: Preparation of 7-(aminomethyl)-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-lH-indazole-3-carboxamide

7-(aminomethyl)-1-(2-((1R,3S,4S)-3-((6-chloropyridi^

carboxamide

[00219] 7-(aminomethyl)-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-lH-indazole-3-carboxamide (6.6 mg) was prepared as described for 7-chloro-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- oxoethyl)-lH-indazole-3-carboxamide. lH NMR (CDC13, 400 MHz) δ 9.05 (s, 1 H), 8.38 (d, 1 H), 8.12 (d, 1 H), 7.60-7.64 (m, 1 H), 7.28 (d, 2 H), 7.21 (t, 1 H), 7.14 (s, 1 H), 7.02-7.05 (m, 1H), 6.36 (d, 1 H), 5.45-5.56 (m,3 H), 4.21-4.25 (m, 4 H), 3.02 (d, 1 H), 1.86-1.99 (m, 5 H), 1.51 (d, 1 H). LCMS (M+H⁺) m/z calculated 482.2, found 482.3.

Example 6: Preparation of methyl 3-carbamoyl-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-l oxylate

methyl 3-carbamoyl-1-(2-((1R,3S,4S)-3-((6-chloropyridin-2-yl)^

carboxylate

[00220] Methyl 3-carbamoyl-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-lH-indazole-7-carboxylate (12.1 mg) was prepared as described for 7-chloro-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- oxoethyl)- lH-indazole-3 -carboxamide. lH NMR (CD₃OD, 400 MHz) δ 8.53-8.55 (m, 1 H), 8.00-8.07 (m, 2 H), 7.68 (t, 1 H), 7.32-7.36 (m, 1 H), 7.08 (d, 1 H), 5.98 (d, 1 H), 5.75 (d, 1H), 4.58 (s, 1 H), 4.09 (s, 1 H), 3.97 (d, 3 H), 2.83 (d, 1 H), 2.17 (t, 2 H), 1.88-1.95 (m, 2 H), 1.65 (t, 1 H), 1.58 (d, 1 H). LCMS (M+H⁺) m/z calculated 511.1, found 511.2.

Example 7: Preparation of methyl 7-chloro-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-lH boxylate

methyl 7 hloro-1-(2-((1R,3S,4S)^-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-^

[00221] Methyl 7-chloro-l-(2 -((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-lH-indazole-3-carboxylate (49.0 mg) was prepared as described for 7-chloro-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- oxoethyl)-lH-indazole-3-carboxamide. lH NMR (CD30D, 400 MHz) δ 8.09-8.13 (m, 1 H), 7.99 (d, 1 H), 7.68 (t, 1 H), 7.46 (d, 1 H), 7.25(t, 1 H), 7.06 (d, 1 H), 5.92 (d, IH), 5.70(d, IH), 4.59 (s, IH), 4.14 (s, 1 H), 3.99 (s, 3 H), 2.80 (s, 1 H), 2.18 (d, 1 H), 2.02 (s, 1 H), 1.90-1.94 (m, 2 H), 1.62-1.70 (m, 1 H), 1.55 (d, 1 H). LCMS (M+H⁺) m/z calculated 502.1, found 502.1.

Example 8: Preparation of l-(2-((lR,3S,4S)-3-((7-chloro-l,6-naphthyridin-5-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-l oxamide

1 -(2-((1 R,3S,4S)-3-((7-chloro-1 ,6-naphthyridin-5-yl)carbamoyl)-2-azabicyclo[2.2.1 ]heptan-2-yl)-2-oxoethyl)-1 H-indazole-3-carboxamide

[00222] l-(2-((lR,3S,4S)-3-((7-chloro-l,6-naphthyridin-5-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-lH-indazole-3-carboxamide (22.0 mg) was prepared as described for 7-chloro-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- oxoethyl)-lH-indazole-3-carboxamide. lH NMR (CD₃OD, 400 MHz) δ 9.01-9.02 (m, 1 H), 8.40 (d, 1 H), 8.25 (d, 1 H), 7.85 (d, 1 H), 7.61 (d, 1 H), 7.42-7.47 (m, 2 H), 7.30 (t, 1 H), 5.47-5.64 (m, 2 H), 4.68 (s, 1 H), 4.30 (s, 1 H), 2.99 (d, 1 H), 2.28 (d, 1 H), 1.60-1.98 (m, 5 H). LCMS (M+H⁺) m/z calculated 504.1, found 504.2. Example 9: Preparation of l-(2-((lR,3S,4S)-3-((7-chloro-l,6-naphthyridin-5-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-lH-indazole-3-carboxamide

1 -(2-((1 R,3S,4S)-3-((6-chloro-3H-imidazo[4,5-c]pyridin-4-yl)carbamoyl)-2-azabicyclo[2.2.1 ]heptan-2-yl)-2-oxoethyl)-1 H-indazole-3-carboxamide

[00223] l-(2-((lR,3S,4S)-3-((6-chloro-3H-imidazo[4,5-c]pyridin-4-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-lH-indazole-3-carboxamide (32.9 mg) was prepared as described for 7-chloro-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- oxoethyl)-lH-indazole-3-carboxamide. lH NMR (CD30D, 400 MHz) δ 9.01-9.02 (m, 1 H), 8.40 (d, 1 H), 8.25 (d, 1 H), 7.85 (d, 1 H), 7.61 (d, 1 H), 7.42-7.47 (m, 2 H), 7.30 (t, 1 H), 5.47-5.64 (m, 2 H), 4.68 (s, 1 H), 4.30 (s, 1 H), 2.99 (d, 1 H), 2.28 (d, 1 H), 1.60-1.98 (m, 5 H). LCMS (M+H+) m/z calculated 504.1, found 504.2.

Example 10: Preparation of l-(2-((lR,3S,4S)-3-((6-chloro-5-cyanopyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-lH-indazole-3-carboxamide

1-(2-((1R,3S,4S)-3-((6-chloro-5-cyanopyridin-2-yl)carbam

[00224] 1 -(2-(( 1R,3 S,4S)-3 -((6-chloro-5 -cyanopyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-lH-indazole-3-carboxamide (77.3 mg) was prepared as described for 7-chloro-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- oxoethyl)-lH-indazole-3-carboxamide. lH NMR (CD₃OD, 400 MHz) δ 8.20 (t, 2 H), 8.10 (d, 1 H), 7.59 (d, 1 H), 7.44 (t, 1 H), 7.27 (t, 1 H), 5.57 (d, 1 H), 5.43 (d, 1 H), 4.63 (s, 1 H), 4.14 (s, 1 H), 2.78 (s, 1 H), 2.17 (d, 1 H), 1.81-1.88 (m, 2 H), 1.67-1.70 (m, 1 H), 1.60-1.62 (m, 1 H), 1.52-1.54 (m, 1 H). LCMS (M+H⁺) m/z calculated 478.1, found 478.1.

Example 11: Preparation of l-(2-((lR,3S,4S)-3-((6-chloro-5-(trifluoromethyl)pyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-lH-indazole-3-carboxamide

1 -(2-((1 R,3S,4S)-3-((6-chloro-5-(trif luorome^

[00225] 1 -(2-(( 1R,3 S,4S)-3 -((6-chloro-5 -(trifluoromethyl)pyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-lH-indazole-3-carboxamide (123.1 mg) was prepared as described for 7-chloro-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- oxoethyl)-lH-indazole-3-carboxamide. lH NMR (CD₃OD, 400 MHz) δ 8.18-8.23 (m, 2 H), 8.11 (d, 1 H), 7.61

(d, 1 H), 7.46 (t, 1 H), 7.28 (t, 1 H), 5.43-5.61 (m, 2 H), 4.65 (s, 1 H), 4.15 (s, 1 H), 2.81 (s, 1 H), 2.18 (t, 1 H),

1.81-1.92 (m, 2 H), 1.54-1.73 (m, 3 H). LCMS (M+H⁺) m/z calculated 521.1, found 521.1.

Example 12: Preparation of l-(2-((lR,3S,4S)-3-((6-chloro-3-(trifluoromethyl)pyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-lH-indazole-3-carboxamide

1 -(2-((1 3S,4S)-3-((6-chlorcH3-(trifluoromethyl)pyridin-2-yl)carbamoyl)-2-azabic clo[2.2.1 ]heptan-2-yl)-2-oxoethyl)-1 H-indazole-3-carboxamide

[00226] 1 -(2-(( 1R,3 S,4S)-3 -((6-chloro-3 -(trifluoromethyl)pyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-lH-indazole-3-carboxamide (10.2 mg) was prepared as described for 7-chloro-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- oxoethyl)-lH-indazole-3-carboxamide. lH NMR (CD₃OD, 400 MHz) δ 8.14-8.27 (m, 2 H), 7.52-7.67 (m, 2

H), 7.45 (t, 1 H), 7.28 (t, 1 H), 5.35-5.58 (m, 2 H), 4.64 (s, 1 H), 4.22 (s, 1 H), 2.90-3.04 (m, 1 H), 2.18 (t, 1

H), 1.82-1.95 (m, 2 H), 1.58-1.72 (m, 3 H). LCMS (M+H⁺) m/z calculated 521.1, found 521.1.

Example 13: Preparation of l-(2-((lR,3S,4S)-3-((6-chloro-3-(trifluoromethyl)pyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-l boxamide

1 -(2-((1 R,3S,4S)^-((3-chloroisoquinolin-1 -yl)carbamoy^

[00227] l-(2-((lR,3S,4S)-3-((3-chloroisoquinolin-l-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2- yl)-2-oxoethyl)-lH-indazole-3-carboxamide (28.0 mg) was prepared as described for 7-chloro-l-(2- ((lI^3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-lH-indazole-3- carboxamide. lH NMR (MeOD-d4, 400 M Hz) δ 8.26 (d, 1 H, J= 8.0 Hz), 8.02 (d, 1 H, J= 8.4 Hz), 7.87 (d, 1 H, J= 8.0 Hz), 7.79 (s, 1 H), 7.72-7.76 (td, 1 H), 7.64 (d, 1 H, J= 8.4 Hz), 7.43-7.49 (m, 2 H), 7.32 (t, 1 H), 5.63 (d, 1 H, J= 16.8 Hz), 5.50 (d, 1 H, J= 17.2 Hz), 4.69 (s, 1 H), 4.34 (s, 1 H), 3.04 (s, 1 H), 2.34 (d, 1 H, J= 10.4 Hz), 1.90-1.99 (m, 2 H), 1.70-1.79 (m, 2 H), 1.63 (d, 1 H, J= 10.4 Hz) ; LRMS (M+H⁺) m/z calculated 502.2, found 503.2.

Example 14: Preparation of l-(2-((lR,3S,4S)-3-((6-chloro-5-fluoropyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-l boxamide

1-(2-((1R,3S,4S)-3-((6-chloro-5-fluoropyridin-2-yl)carb^

[00228] l-(2-((lR,3S,4S)-3-((6-chloro-5-fluoropyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-lH-indazole-3-carboxamide (2.9 mg) was prepared as described for 7-chloro-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- oxoethyl)- lH-indazole-3 -carboxamide. lH NMR (CD₃OD, 400 MHz) 8.22 (d, 1 H), 8.08-8.06 (m, 1 H), 7.66- 7.60 (m, 2H), 7.47-7.43 (m, 1 H), 7.28(t,lH), 5.59-5.41 (q, 2 H), 4.62 (s, 1 H), 4.12 (s, 1 H), 2.78 (s, 1 H), 2.18 (d, 1 H), 1.89-1.59 (m, 4 H), 1.53 (d,lH). LRMS (M+H⁺) m/z calculated 471.1, found 471.1.

Example 15: Preparation of l-(2-((lR,3S,4S)-3-((7-chloropyrido[3,4-b]pyrazin-5-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-l boxamide

1 -(2-((1 R,3S,4S)-3-((7-chlorapyrido[3,4-i)]pyrazin-5-yl)carbamoyl)-2-azabicyclo[2.2.1 ]heptan-2-yl)-2-oxoethyl)-1 H-indazole-3-carboxamide

[00229] l-(2-((lR,3S,4S)-3-((7-chloropyrido[3,4-b]pyrazin-5-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-lH-indazole-3-carboxamide (12.6 mg) was prepared as described for 7-chloro-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- oxoethyl)- lH-indazole-3 -carboxamide. lH NMR (CD₃OD, 400 MHz) δ 9.05 (d, 1 H), 8.82 (d, 1 H),8.21 (d, 1 H), 7.70 (t, 1H), 7.61 (d, 1 H), 7.42(t,lH), 7.26(t, lH), 5.66-5.45 (q, 2 H), 4.71 (s, 1 H), 4.52 (s, 1 H), 3.01 (s, 1 H), 2.23(d, 1 H), 1.98-1.73 (m, 4 H), 1.60 (d,lH). LCMS (M+H⁺) m/z calculated 505.2, found 505.2. Example 16: Preparation of l-(2-((lR,3S,4S)-3-((5-chloro-lH-pyrazolo[3,4-c]pyridin-7-yl)carb azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-lH-indazole-3-carboxamide

1 -(2-((1 R,3S,4S)-3-((5-chloro-1 H-pyrazolo[3^-c]pyrid^^

[00230] l-(2-((lR,3S,4S)-3-((5-chloro-lH-pyrazolo[3,4-c]pyridin-7-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-lH-indazole-3-carboxamide (4.8 mg) was prepared as described for 7-chloro-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- oxoethyl)-lH-indazole-3-carboxamide. lH NMR (CD30D, 400 MHz) δ 8.32 (s, 1 H), 8.22 (d, 1 H), 7.64 (d, 1 H), 7.47 (t, 1H), 7.35-7.24(m, 2 H), 5.64-5.46 (q, 2 H), 4.67 (s, 1 H), 2.90 (s, 1 H), 1.93-1.83(m, 2 H), 1.76- 1.67 (m, 2 H), 1.57 (d, 1 H), 1.37-1.31 (m, 2 H). LRMS (M+H⁺) m/z calculated 493.1, found 493.1.

Example 17: Preparation of l-(2-((lR,3S,4S)-3-((3-chloronaphthalen-l-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-lH-indazole-3-carboxamide

1 -(2-((1 R,3S,4S)-3-((3-chloronaphthalen-1 -yl)carbamoyl)-2-azabicyclo[2.2.1 ]heptan-2-yl)-2-oxoethyl)-1 H-indazole-3-carboxamide

[00231] l-(2-((lR,3S,4S)-3-((3-chloronaphthalen-l-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2- yl)-2-oxoethyl)-lH-indazole-3-carboxamide (4.1 mg) was prepared as described for 7-chloro-l-(2- ((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-lH-indazole-3- carboxamide. lH NMR (DMSO-d6, 400 MHz) δ 8.25 (d, 1 H), 7.90-7.30 (m, 9 H), 5.65-5.47 (q, 2 H), 4.67 (s, 1 H), 4.29 (s, 1 H), 2.98 (s, 1 H), 2.28(d, 1 H), 1.97-1.64 (m,5H). LRMS (M+H⁺) m/z calculated 502.2, found 502.2.

Example 18: Preparation of l-(2-((lR,3S,4S)-3-((5-chloro-lH-indazol-7-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-lH-indazole-3-carboxamide

1 -(2-((1 R S^S)-3-((5-chloro-1 H-indazol-7-yl)carbamo

[00232] l-(2-((lR,3S,4S)-3-((5-chloro-lH-indazol-7-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2- yl)-2-oxoethyl)-lH-indazole-3-carboxamide (34.2 mg) was prepared as described for 7-chloro-l-(2- ((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo^

carboxamide. lH NMR (CD₃OD, 400 MHz) δ 8.22 (d, 1 H), 8.03 (s, 1 H), 7.61-7.64 (m, 2 H), 7.44-7.48 (m, 2 H), 7.29 (t, 1 H), 5.62 (d, 1H), 5.50 (d, 1 H), 4.68 (s, 1 H), 4.18 (s, 1 H), 2.93 (s, 1 H), 2.29 (d, 1 H), 1.88-1.96 (m, 2 H), 1.76 (d, 1 H), 1.65 (d, 1 H), 1.59 (d, 1 H). LCMS (M+H⁺) m/z calculated 492.1, found 492.2.

Example 19: Preparation of 5-acetamido-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-lH-indazole-3-carboxamide

5-acetamido-1-(2-((1R,3S,4S)-3-((6-chloropyridin-2-yl)c^

[00233] 5-Acetamido-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-lH-indazole-3-carboxamide (6.8 mg) was prepared as described for 7-chloro-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- oxoethyl)-lH-indazole-3-carboxamide. lH NMR (CD30D, 400 MHz) δ 8.33 (d, 1 H), 8.01 (d, 1 H), 7.66-7.73 (m, 1 H), 7.56 (d, 1 H), 7.08-7.17(m, 1 H), 6.74-6.80 (m, 1 H), 5.55(d, 1H), 5.41 (d, 1H), 4.59 (s, 1 H), 4.13 (s, 1 H), 2.79 (s, 1 H), 2.18 (d, 1 H), 2.13(s, lH), 1.82-1.90 (m, 1 H), 1.61-1.70 (m, 2 H), 1.28-1.34 (m, 2 H). LCMS (M+H⁺) m/z calculated 510.2, found 510.3.

Example 20: Preparation of 5-benzamido-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-lH-indazole-3-carboxamide

54)enzamido-1-(2-((1R,3S,4S)-3-((6^hloropyridin-2-yl)carbamoyl)-2-az^ [00234] 5-Benzamido-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-lH-indazole-3-carboxamide (12.0 mg) was prepared as described for 7-chloro-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- oxoethyl)-lH-indazole-3-carboxamide. lH NMR (CD30D, 400 MHz) δ 8.45 (d, 1 H), 8.02 (d, 1 H), 7.94-7.96 (m, 2 H), 7.80-7.84 (m, 1 H), 7.71(t, 1 H), 7.62 (d, 1 H), 7.55-7.59 (m, 1H), 7.49-7.51 (m, 2H), 7.09(d, 1H), 5.58(d, 1H), 5.44 (d, 1H), 4.63 (s, 1 H), 4.14 (s, 1 H), 2.80 (s, 1 H), 2.19 (d, 1 H), 1.81-1.93 (m, 1 H), 1.60- 1.74 (m, 1 H), 1.55 (d, 1 H), 1.25-1.304 (m, 2 H). LCMS (M+H⁺) m/z calculated 572.2, found 572.3.

Example 21: Preparation of l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethy dazole-3-carboxamide

1 -(2-((1 R,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1 ]heptan-2-yl)-2-oxoethyl)-5-(nicotinamido)-1 H-indazole-3-carboxamide

[00235] l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- oxoethyl)-5-(nicotinamido)-lH-indazole-3-carboxamide (10.9 mg) was prepared as described for 7-chloro-l- (2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-lH- indazole-3-carboxamide. lH NMR (CD30D, 400 MHz) δ 9.10 (d, 1 H), 8.72 (d, 1 H), 8.49 (d, 1 H), 8.36-8.39 (m, 1 H), 8.02(d, 1H), 7.78-7.86(m, 1 H), 7.71 (t, 1 H), 7.64 (d, 1H), 7.57-7.60 (m, 1H), 7.11(d, 1H), 5.60(d, 1H), 5.46 (d, 1H), 4.65 (s, 1 H), 4.15 (s, 1 H), 2.80 (s, 1 H), 2.19 (d, 1 H), 1.85-1.93 (m, 2 H), 1.63-1.76 (m, 1 H), 1.55 (d, 1 H), 1.27 (d, 1 H). LCMS (M+H⁺) m/z calculated 573.2, found 573.3.

Example 22: Preparation of l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethy lH-indazole-3-carboxamide

1-(2-((1R,3S,4S)-3-((6-chloropyridin-2-yl (carbamoyl )-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxo8thyl)-5-(2-phenylacetamido)-1H-indazole-3-carboxamide

[00236] l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- oxoethyl)-5-(2-phenylacetamido)-lH-indazole-3-carboxamide (13.4 mg) was prepared as described for 7- chloro-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)- lH-indazole-3-carboxamide. lH NMR (CDC13, 400 MHz) δ 8.83 (d, 1 H), 8.05 (d, 1 H), 7.97(d, 1 H), 7.88 (s, 1 H), 7.56(t, 1H), 7.32-7.37(m, 4 H), 7.22-7.29 (m, 2 H), 7.11-7.12 (m, 1H), 6.96-7.01 (m, 1H), 5.41-5.5 l(m, 1H), 5.17-5.23(m, 1H), 5.08 (d, 1H), 4.14 (s, 1 H), 4.02 (s, 1 H), 3.69 (s, 2 H), 3.56-3.62(m, 1 H), 2.92 (s, 1 H), 1.89-1.91 (m, 1 H), 1.61-1.79 (m, 1 H), 1.18 (s, 1 H), 1.08-1.14 (m, 1 H), 0.96 (d, 1 H), 0.78 (m, 1 H). LCMS (M+H⁺) m/z calculated 586.2, found 586.3.

Example 23: Preparation of l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-7- -lH-indazole-3-carboxamide

1 -(2-((1 R,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1 ]heptan-2-yl)-2-oxoethyl)-7-(1 -hydraxyethyl)-1 H-indazole-3- carboxamide

[00237] l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- oxoethyl)-7-(l-hydroxyethyl)-lH-indazole-3-carboxamide (46.0 mg) was prepared as described for 7-chloro- l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-lH- indazole-3-carboxamide. lH NMR (CD₃OD, 400 MHz) δ 8.21 (d, 1 H), 8.02 (d, 1 H), 7.70 (t, 1 H), 7.49-7.51 (m, 1 H), 7.24 (t, 1 H), 7.08-7.10 (m, 1 H), 5.90 (d, 1 H), 5.29-5.34 (m, 1 H), 5.20-5.25 (m, 1 H), 4.60 (s, 1 H), 4.14 (s, 1 H), 2.82 (s, 1 H), 2.21 (t, 1 H), 1.93 (t, 3 H), 1.72-1.75 (m, 1 H), 1.67 (d, 3 H), 1.56 (d, 1 H). LCMS (M+H⁺) m/z calculated 497.2, found 497.2.

Example 24: Preparation of (lR,3S,4S)-N-(6-chloropyridin-2-yl)-2-(2-(3-methoxy-lH-indazol-l- yl)acetyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide

(1 R,3S,4S)-N-(6-chloropyridin-2-yl)-2-(2-(3-methoxy-1 ^

[00238] (lR,3S,4S)-N-(6-chloropyridin-2-yl)-2-(2-(3-methoxy-lH-indazol-l-yl)acetyl)-2- azabicyclo[2.2.1]heptane-3-carboxamide (57.0 mg) was prepared as described for 7-chloro-l-(2-((lR,3S,4S)- 3 -((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo [2.2.1 ]heptan-2-yl)-2-oxoethyl)- lH-indazole-3 - carboxamide. lH NMR (CD30D, 400 MHz) δ 8.02 (d, 1 H), 7.71 (t, 1 H), 7.58 (d, 1 H), 7.39 (t, 2 H), 7.03- 7.14 (m, 2 H), 5.25 (d, 1H), 5.12 (d, 1H), 4.59 (s, 1H), 4.12 (s, 1 H), 4.05 (s, 3 H), 2.78 (m, 1 H), 2.15 (d, 1 H), 1.70-1.88 (m, 3 H), 1.60-1.63 (m, 1 H), 1.52 (d, 1 H). LCMS (M+H⁺) m/z calculated 440.1, found 440.3. Example 25: Preparation of 7-acetyl-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-lH-indazole-3-carboxamide

7-a∞tyl-1 -(2-((1 R,3S,4S)-3-((6 hloropyridin-2-yl)∞ifcam

[00239] 7-acetyl-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-lH-indazole-3-carboxamide (13.0 mg) was prepared as described for 7-chloro-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- oxoethyl)-lH-indazole-3-carboxamide. lH NMR (CD30D, 400 MHz) δ 8.53 (t, 1 H), 8.00 (d, 2 H), 7.69 (t, 1 H), 7.34-7.39 (m, 1 H), 7.08 (d, 1 H), 5.87 (d, 1H), 5.61(d, 1H), 4.56 (s, 1H), 4.09 (t, 1 H), 2.82 (s, 1 H), 2.70 (s, 3 H), 2.18 (d, 1 H), 1.88-1.95 (m, 2 H), 1.56-1.67 (m, 2 H), 1.24 (t, 1 H). LCMS (M+H⁺) m/z calculated 495.1, found 495.2.

Example 26: Preparation of l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-7-(2-hydroxypropan-2-yl)-lH-indazole-3-carboxamide

1 -(2-((1 R,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl^

[00240] l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- oxoethyl)-7-(2-hydroxypropan-2-yl)-lH-indazole-3-carboxamide (17.0 mg) was prepared as described for 7- chloro-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)- lH-indazole-3-carboxamide. lH NMR (CD30D, 400 MHz) δ 8.25 (d, 1 H), 8.01 (t, 1 H), 7.68-7.72 (m, 1 H), 7.44 (d, 1 H), 7.19 (t, 1 H), 7.09 (d, 1 H), 6.28 (d, 1 H), 6.16 (d, 1 H), 4.51 (s, 1 H), 4.11 (s, 1 H), 2.80 (s, 1 H), 2.69 (s, 1 H), 2.17 (d, 1 H), 2.03 (t, 3 H), 1.85-1.95 (m, 2 H), 1.73 (d, 6 H), 1.65 (s, 1 H), 1.53 (d, 1 H), LCMS (M+H+) m/z calculated 511.2, found 511.2.

Example 27: Preparation of l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-lH-indole-3-carboxamide

1-(2-((1R,3S,4S 3-((6 hloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-o oethyl)-1H^

[00241] l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- oxoethyl)-lH-indole-3-carboxamide (34.0 mg) was prepared as described for 7-chloro-l-(2-((lR,3S,4S)-3-((6- chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-lH-indazole-3-carboxamide. lH NMR (CD₃OD, 400 MHz) δ 8.11 (d, 1 H), 8.02 (d, 1 H), 7.88 (s, 1 H), 7.71 (t, 1 H), 7.42(d, 1 H), 7.24 (t, 1 H), 7.15-7.20 (m, 1H), 7.09(d, 1H), 5.29 (d, 1H), 5.14 (d, 1 H), 4.59 (s, 1 H), 4.14 (s, 1 H), 2.79 (s, 1 H), 2.18 (d, 1 H), 1.85-1.90 (m, 2 H), 1.71-1.74 (m, 1 H), 1.62-1.69 (m, 1 H), 1.53 (d, 1 H). LCMS (M+H⁺) m/z calculated 452.1, found 452.2.

Example 28: Preparation of l-(2-((lR,3S,4S)-3-((3-chloro-2-fluorophenyl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-lH-indole-3-carboxamide

1 -(2-((1 R,3S,4S)-3-((3-chloro-2-f luorophenyl)carbamoyl)-2-azabicyclo[2.2.1 ]heptan-2-yl)-2-oxoethyl)-1 H-indole-3-carboxamide

[00242] l-(2-((lR,3S,4S)-3-((3-chloro-2-fluorophenyl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2- yl)-2-oxoethyl)-lH-indole-3-carboxamide (40.2 mg) was prepared as described for 7-chloro-l-(2-((lR,3S,4S)- 3 -((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo [2.2.1 ]heptan-2-yl)-2-oxoethyl)- lH-indazole-3 - carboxamide. lH NMR (CD30D, 400 MHz) δ 8.10 (d, 1 H), 7.84 (s, 1 H), 7.7.74 (t, 1 H), 7.36 (d, 1 H), 7.15- 7.22(m, 3 H), 7.04 (t, 1 H), 5.14 (d, 1H), 5.04(d, 1H), 4.51 (s, 1H), 4.15 (s, 1 H), 2.78 (s, 1 H), 2.17 (d, 1 H), 1.82-1.86 (m, 1 H), 1.66-1.73 (m, 2 H), 1.51-1.59 (m, 2 H). LCMS (M+H⁺) m/z calculated 469.1, found 469.1. Example 29: Preparation of methyl (3-carbamoyl-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)- 2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-lH-indazol-5-yl)carbamate

methyl (3-carbamoyl-1-(2-((1 ,3S^S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoe

yl)carbamate

[00243] Methyl (3-carbamoyl-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-lH-indazol-5-yl)carbamate (20.0 mg) was prepared as described for 7-chloro-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- oxoethyl)-lH-indazole-3 -carboxamide. IH NMR. (CD₃OD, 400 MHz) δ 8.01 (d, 1 H), 7.86 (s, 1 H), 7.70- 7.72(m, 3 H), 7.49-7.51 (m, 2 H), 7.39-7.44(m, 2H), 7.29(d, IH), 7.10(d, IH), 5.52(d, 1 H), 5.37 (d, 1 H), 4.58 (s, I H), 4.12 (s, I H), 3.74 (s, 3 H), 2.79(s, 1 H), 2.16 (d, 1 H), 1.81-1.89(m, 2 H), 1.60-1.69 (m, 2 H), 1.53 (d, 1 H). LCMS (M+H⁺) m/z calculated 526.2, found 526.3.

Example 30: Preparation of l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)- )acetamido)-lH-indazole-3-carboxamide

[00244] l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- oxoethyl) -5 -(2 -(dimethylamino)acetamido)-lH-indazole -3 -carboxamide (9.4 mg) was prepared as described for 7-chloro-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- oxoethyl)-lH-indazole-3 -carboxamide. ¾NMR. (CD₃OD, 400 MHz) δ 8.37 (s, 1 H), 8.02 (d, 1 H), 7.69- 7.79(m, 2 H), 7.59 (d, 1 H), 7.09(d, IH), 5.56(d, 1 H), 5.42 (d, 1 H), 4.63 (s, IH), 4.14 (s, IH), 3.17(s, 2 H), 2.80(s, IH), 2.39 (s, 6H), 2.18 (s, 1 H), 1.83-1.93(m, 2 H), 1.62-1.70 (m, 2 H), 1.54 (d, 1 H). LCMS (M+H⁺) m/z calculated 553.2, found 553.3.

Example 31: Preparation of l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(2-morpholinoacetamido)-lH-indazole-3-carboxamide

1-(2-((1R,3S,4S)-3-((6-chloropyridin-2-yl)cait>amoyl)-2-azabi^^

[00245] l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- oxoethyl)-5-(2-moφholinoacetamido)-lH-indazole-3-carboxamide (11.9 mg) was prepared as described for 7- chloro-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl) lH-indazole-3-carboxamide. ¾NMR. (CD₃OD, 400 MHz) δ 8.36 (d, 1 H), 8.00 (d, 1 H), 7.67-7.71(m, 2 H), 7.57 (d, 1 H), 7.08(d, IH), 5.55(d, 1 H), 5.40 (d, 1 H), 4.59 (s, IH), 4.13 (s, IH), 3.75-3.77(m, 4 H),3.18(s, 2 H), 2.78(s, IH), 2.59-2.61(m, 4 H), 2.17 (m, 1 H), 1.81-1.87(m, 2 H), 1.67-1.72 (m, 1 H), 1.59-1.62 (m, 1 H), 1.53 (d, 1 H). LCMS (M+H⁺) m/z calculated 595.2, found 595.3.

Example 32: Preparation of l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(2-(4-methylpiperazin-l-yl)acetamido)-lH-indazole-3- carboxamide

1 -(2-((1 R,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-ara^

1 H-indazole-3-carboxamide

[00246] l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- oxoethyl)-5-(2-(4-methylpiperazin-l-yl)acetamido)-lH-indazole-3-carboxamide (11.7 mg) was prepared as described for 7-chloro-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2- yl)-2-oxoethyl)-lH-indazole-3-carboxamide. ¾NMR. (CD₃OD, 400 MHz) δ 8.37 (s, 1 H), 8.01-8.02 (m, 1 H), 7.68-7.79(m, 2 H), 7.58 (d, 1 H), 7.09(d, IH), 5.54-5.57(m, 1 H), 5.39-5.42 (m, 1 H), 4.61 (s, IH), 4.14 (s, IH), 3.30(s, 2 H), 2.92(s, 1 H), 2.79(s, 7H), 2.47(s, 4 H), 2.18 (d, 1 H), 1.80-1.93(m, 2 H), 1.69-1.71 (m, 1 H), 1.59-1.64 (m, 1 H), 1.53 (d, 1 H). LCMS (M+H⁺) m/z calculated 608.2, found 608.3.

Example 33: Preparation of l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(phenylsulfonamido)-lH-indazole-3-carboxamide

1-(2-((1R,3S,₄S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoet^

indazole-3-carboxamide

[00247] l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- oxoethyl)-5-(phenylsulfonamido)-lH-indazole-3-carboxamide (11.7 mg) was prepared as described for 7- chloro-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)- lH-indazole-3-carboxamide. ¾NMR. (CD₃OD, 400 MHz) δ 8.01 (d, 1 H), 7.86 (s, 1 H), 7.70-7.72(m, 3 H), 7.49-7.51 (m, 2 H), 7.39-7.44(m, 2H), 7.29(d, IH), 7.10(d, lH), 5.52(d, 1 H), 5.37 (d, l H), 4.58 (s, 1 H), 4.12 (s, 1 H), 2.79(s, 1 H), 2.16 (d, 1 H), 1.81-1.89(m, 2 H), 1.60-1.69 (m, 2 H), 1.53 (d, 1 H). LCMS (M+H⁺) m/z calculated 608.1, found 608.3.

Example 34: Preparation of (lR,3S,4S)-N-(6-chloropyridin-2-yl)-2-(2-(l-methoxyisoquinolin-3- yl)acetyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide

(1 R,3S,4S)-W-(6-chloropyridin- -methoxyiso

[00248] To a solution of 1,3-dibromoisoquinoline (200 mg, 0.70 mmol, 1.0 eq) in toluene (10 mL) was added MeONa (56 mg, 1.05 mmol, 1.5 eq). The resulting mixture was stirred at 110 °C for 1.5 h. The mixture was washed with water and saturated aq. NaCl. The organic layer was dried over Na₂S0₄, filtered and concentrated under vacuum. The resulting residue was purified by column chromatography (PE/EA = 50/1, v/v) to afford 3-bromo-l-methoxyisoquinoline (165 mg, 99%) as a white solid.

[00249] To a solution of 3-bromo-l-methoxyisoquinoline (165 mg, 0.70 mmol, 1.0 eq), Pd₂(dba)₃

(160 mg, 0.175 mmol, 0.25 eq) and X-phos (66 mg, 0.14 mmol, 0.2 eq) in THF (15 mL) was added (2-(tert- butoxy)-2-oxoethyl)zinc(II) bromide (544 mg, 2.10 mmol, 3.0 eq). The mixture was stirred at 70 °C overnight. After the reaction completed, the reaction was cooled to r. . The mixture was washed with water and saturated aq. NaCl, the organic layer was dried over Na₂S0₄, filtered and concentrated under vacuum. The resulting residue was purified by column chromatography (PE/EA = 50/1, v/v) to afford tert-butyl 2-(l- methoxyisoquinolin-3-yl)acetate (60 mg, 31%).

[00250] To a solution of tert-butyl 2-(l-methoxyisoquinolin-3-yl)acetate (60 mg, 0.22 mmol, 1.0 eq) in DCM (3 mL) was added TFA (1.5 mL). The mixture was stirred at rt for 2h. The mixture was concentrated under vacuum to afford 2-(l-methoxyisoquinolin-3-yl)acetic acid (48 mg, crude) as a white solid which used in the next step directly.

[00251] To a solution of 2-(l-methoxyisoquinolin-3-yl)acetic acid (48 mg, 0.22 mmol, l .Oeq),

(lR,3S,4S)-N-(6-chloropyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3-carboxamide (15 mg, 0.22 mmol, l .Oeq) and HATU (101 mg, 0.33mmol, 1.5 eq) in DMF (3 mL) was added DIEA (86 mg, 0.66 mmol, 3.0 eq). The reaction mixture was stirred at rt for 1 h. Water was added, and the mixture was extracted with EA. The organic layer was washed with saturated aq. NaCl, dried over Na₂S0₄, filtered and concentrated. The resulting residue was purified by prep-HPLC to give (lR,3S,4S)-N-(6-chloropyridin-2-yl)-2-(2-(l-methoxyisoquinolin- 3-yl)acetyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide as a white solid (35.0 mg, 35.3%).1H NMR (CD₃0D, 400 MHz) δ 8.19 (d, 1 H), 8.04 (d, 1 H), 7.67-7.78 (m, 3 H), 7.36 (d, 1 H), 7.52(t, 1 H), 7.33 (s, 1 H), 7.09 (d, 1 H), 4.73 (s, 1 H), 4.17(s, 1H), 4.11 (s, 3H), 4.01 (d, 1 H), 3.92 (d, 1 H), 2.81 (s, 1 H), 2.14 (d, 1 H), 1.82- 1.88 (m, 1 H), 1.69-1.76 (m, 2 H), 1.59-1.63 (m, 1 H), 1.49 (d, 1 H). LCMS (M+H⁺) m/z calculated 451. 1, found 451.2.

Example 35: Preparation of l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)isoq oxamide

1 -(2-((1 R S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-aza [00252] l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- oxoethyl)isoquinoline-3-carboxamide (6.0 mg) was prepared as described for (lR,3S,4S)-N-(6-chloropyridin- 2-yl)-2-(2-(l-methoxyisoquinolin-3-yl)acetyl)-2-azabicyclo[2.2. l]heptane-3-carboxamide. 1H NMR

(CD30D, 400 MHz) δ 8.50 (s, 1 H), 8.32 (d, 1 H), 8.12 (t, 2 H), 7.80-7.87 (m, 2 H), 7.74 (t, 1 H), 7.1 l(d, 1 H), 4.91 (t, 2 H), 4.38 (s, 1 H), 4.20 (s, 1 H), 2.79 (d, 1 H), 2.27 (d, 1 H), 1.84-1.88 (m, 1 H), 1.64-1.74 (m, 3 H), 1.43 (d, 1 H). LCMS (M+H⁺) m/z calculated 464.1, found 464.2.

Example 36: Preparation of isopropyl (3-carbamoyl-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2- yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-lH-indazol-5-yl)carbamate

isopropyl (3-carbamoyl-1-(2-((1R,3S,4S)-3-((6-chloropyridin-2^

[00253] Isopropyl(3-carbamoyl-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1] heptan-2-yl)-2-oxoethyl)-lH-indazol-5-yl)carbamate (22.2 mg) was prepared as described for 7-chloro-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- oxoethyl)-lH-indazole-3-carboxamide. ¾ NMR (CD₃OD, 400 MHz) δ 8.23 (s, 1 H), 8.00 (d, 1 H), 7.693(t, 1 H), 7.45-7.56 (m, 2 H), 7.08(d, 1 H), 5.52(d, 1 H), 5.38 (d, 1 H), 4.90-4.98 (m, 1 H), 4.57-4.58(m, 1 H), 4.12 (s, l H), 2.77(s, l H), 2.16 (d, 1 H), 1.79-1.87(m, 2 H), 1.56-1.69 (m, 2 H), 1.51 (d, 1 H), 1.29 (d, 6 H). LCMS (M+H⁺) m/z calculated 554.2, found 554.3.

Example 37: Preparation of l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(tetrahydrofuran-3-carboxamido)-lH-indazole-3- carboxamide

[00254] l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- oxoethyl)-5-(tetrahydrofuran-3-carboxamido)-lH-indazole-3-carboxamide (26.1 mg) was prepared as described for 7-chloro-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2- yl)-2-oxoethyl)-lH-indazole-3-carboxamide. ¾ NMR (CD₃OD, 400 MHz) δ 8.34 (d, 1 H), 8.02 (d, 1 H), 7.69-7.73(m, 2 H), 7.57 (d, 1 H), 7.09(d, 1 H), 5.54(d, 1 H), 5.42 (d, 1 H), 4.61 (s, 1 H), 4.13(s, 1 H), 4.05 (t, 1 H), 3.88-3.94(m, 2H), 3.81-3.85(m, 1 H), 3.18-3.22(m, 1H ), 2.79(s, 1 H), 2.17-2.24 (m, 4 H), 1.83-1.89(m, 2 H), 1.61-1.71 (m, 2 H), 1.53 (d, 1H). LCMS (M+H⁺) m/z calculated 566.2, found 566.3. Example 38: Preparation of l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)- oxamido)-lH-indazole-3-carboxamide

1-(2-((1 3S,4S)-3-((6 :hloropyridin-2-yl)carbamoy1)-2^

[00255] l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- oxoethyl)-5-(cyclopentanecarboxamido)-lH-indazole-3-carboxamide (30.1 mg) was prepared as described for 7-chloro-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)- lH-indazole-3-carboxamide. ¾NMR (CD₃OD, 400 MHz) δ 8.32 (s, 1 H), 8.01 (d, 1 H), 7.68-7.72(m, 2 H), 7.55 (d, 1 H), 7.09(d, 1 H), 5.54(d, 1 H), 5.42 (d, 1 H), 4.61 (s, 1 H), 4.13(s, 1 H), 2.78-3.84(m, 2H), 2.17(d, 1 H), 1.93-1.96(m, 2 H ), 1.76-1.89(m, 5 H), 1.61-1.69 (m, 5 H), 1.53 (d, 1H). LCMS (M+H⁺) m/z calculated 564.2, found 564.3.

Example 39: Preparation of l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5 do)-lH-indazole-3-carboxamide

1-(2-((1 ,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-az^^

[00256] l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- oxoethyl)-5-(methylsulfonamido)-lH-indazole-3-carboxamide (5.9 mg) was prepared as described for 7- chloro-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)- lH-indazole-3-carboxamide. ¾NMR (CD₃OD, 400 MHz) δ 8.08 (s, 1 H), 8.01 (d, 1 H), 7.72(t, 1 H), 7.62 (d, 1 H), 7.42 (d, 1 H),7.10(d, 1 H), 5.59(d, 1 H), 5.43 (d, 1 H), 4.56 (s, 1 H), 4.14(s, 1 H), 2.93(s, 3 H), 2.08(s, 1 H), 2.02(d, 1 H), 1.85-1.93(m, 2 H ), 1.63-1.77(m, 2 H), 1.55 (d, 1H). LCMS (M+H⁺) m/z calculated 564.1, found 546.2.

Example 40: Preparation of l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)- acetamido)-lH-indazole-3-carboxamide

1-(2-((1R,3S,4S)-3-((6-c loropyridin-2-yl)carbamoyl)-2-az^ [00257] l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- oxoethyl)-5-(2-(2-fluorophenyl)acetamido)-lH-indazole-3-carboxamide (16.1 mg) was prepared as described for 7-chloro-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- oxoethyl)-lH-indazole-3-carboxamide. ¾ NMR (CD₃OD, 400 MHz) δ 8.32 (d, 1 H), 8.01(d, 1 H), 7.69-7.75 (m, 2 H), 7.58(d, 1 H) , 7.39 (d, 1 H), 7.27-7.32(m, 1 H) , 7.07-7.17 (m, 3 H), 5.56 (d, 1 H), 5.43 (d, 1 H), 4.62 (s, 1 H), 4.14 (s, 1 H), 3.78 (s, 2 H), 2.80 (s, 1 H), 2.18 (d, 1 H), 1.83-1.91(m, 2 H), 1.70 (t, 1 H), 1.63 (d, 1 H), 1.54 (d, 1 H).LCMS (M+H⁺) m/z calculated 604.2, found 604.3.

Example 41: Preparation of l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)- acetamido)-lH-indazole-3-carboxamide

1-(2-((1R3S,4S)-3-((6-chloropyridin-2-yl)caifcamoyl)-2-_^

[00258] l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- oxoethyl)-5-(2-(3-fluorophenyl)acetamido)-lH-indazole-3-carboxamide (16.6 mg) was prepared as described for 7-chloro-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- oxoethyl)-lH-indazole-3-carboxamide. ¾ NMR (CD₃OD, 400 MHz) δ 8.31-8.33 (m, 1 H), 8.02(d, 1 H), 7.71 (d, 2 H), 7.58(d, 1 H) , 7.31-7.37 (m, 1 H), 7.19(d, 1 H) , 7.09-7.14 (m, 2 H), 6.99 (t, 1 H), 5.56 (d, 1 H), 5.42 (d, 1 H), 4.62 (s, l H), 4.13 (s, 1 H), 3.71 (s, 2 H), 2.79 (s, l H), 2.18 (d, 1 H), 1.83-1.91(m, 2 H), 1.68-1.73 (m, 1 H), 1.62 (t, 1 H), 1.54 (d, 1 H).LCMS (M+H⁺) m/z calculated 604.2, found 604.3.

Example 42: Preparation of l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl) acetamido)-lH-indazole-3-carboxamide

1-(2-((1R,3S,4S)-3-((6-chloropyridin-2-yl)∞rbamoyl)-2-azabicyd^

[00259] l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- oxoethyl)-5-(2-(4-fluorophenyl)acetamido)-lH-indazole-3-carboxamide (35.5 mg) was prepared as described for 7-chloro-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- oxoethyl)-lH-indazole-3-carboxamide. ¾ NMR (CD₃OD, 400 MHz) δ 8.30-8.33 (m, 1 H), 8.02(d, 1 H), 7.69- 7.73 (m, 2 H), 7.57(d, 1 H) , 7.36-7.40 (m, 2 H), 7.03-7.11 (m, 3 H), 6.99 (t, 1 H), 5.56 (d, 1 H), 5.42 (d, 1 H), 4.61 (s, 1 H), 4.13 (s, 1 H), 3.68 (s, 2 H), 2.80 (s, 1 H), 2.18 (d, 1 H), 1.83-1.90(m, 2 H), 1.62-1.73 (m, 2 H), 1.53 (d, 1 H).LCMS (M+H⁺) m/z calculated 604.2, found 604.3. Example 43: Preparation of 5-(2-(4-chlorophenyl)acetamido)-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2- yl)carbamoyl)-2-azabicyclo[2.2.1]heptan dazole-3-carboxamide

5-(2-(4-chlorophenyl)a ^mido)-1-(2-((1R,3S,4S)-3-((e-chloropyridin-2-yl)carbamoyl)-2-azabi^

[00260] 5-(2-(4-Chlorophenyl)acetamido)-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)- 2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-lH-indazole-3-carboxamide (45.9 mg) was prepared as described for 7-chloro-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- oxoethyl)-lH-indazole-3-carboxamide. ¾ NMR (CD₃OD, 400 MHz) δ 8.33 (d, 1 H), 8.02(d, 1 H), 7.69-7.74 (m, 2 H), 7.57(d, 1 H) , 7.31-7.37 (m, 4 H), 7.09-7.15(m, 1 H), 5.56 (d, 1 H), 5.42 (d, 1 H), 4.61 (s, 1 H), 4.13 (s, I H), 3.69 (s, 2 H), 2.80 (s, 1 H), 2.18 (d, 1 H), 1.83-1.90(m, 2 H), 1.62-1.70 (m, 2 H), 1.54 (d, 1 H).LCMS (M+H⁺) m/z calculated 620.2, found 620.3.

Example 44: Preparation of l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo

[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(2-(4- lH-indazole-3-carboxamide

1-(2-((1R,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azab^

[00261] l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- oxoethyl)-5-(2-(4-cyanophenyl)acetamido)-lH-indazole-3-carboxamide (38.0 mg) was prepared as described for 7-chloro-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- oxoethyl)-lH-indazole-3-carboxamide. ¾ NMR (DMSO, 400 MHz) δ 10.83 (s, 1 H), 10.34 (s, 1 H), 8.41 (d, 1 H), 7.98(d, 1 H), 7.80 (d, 2 H), 7.54-7.67 (m, 4 H) , 7.34 (s, 1 H), 7.19 (t, 1 H) , 7.08 (s, 1 H), 6.95 (s, 1 H), 5.62 (d, 1 H), 5.33 (d, 1 H), 4.60 (s, 1 H), 4.07 (s, 1 H), 3.79 (s, 2 H), 2.67 (s, 1 H), 2.06 (d, 1 H), 1.77 (s, 3 H), 1.49 (d, 1 H), 1.42 (d, 1 H).LCMS (M+H⁺) m/z calculated 611.2, found 611.3

Example 45: Preparation of l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(2-(m-tolyl)acetamido)-lH-indazole-3-carboxamide

1 -(2-((1 R3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl^2-aza

[00262] l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- oxoethyl)-5-(2-(m-tolyl)acetamido)-lH-indazole-3-carboxamide (41.0 mg) was prepared as described for 7- chloro-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoeth^ lH-indazole-3-carboxamide. ¾ NMR (CD₃OD, 400 MHz) δ 8.30-8.32 (m, 1 H), 8.02(d, 1 H), 7.69-7.73 (m, 2 H), 7.57(d, 1 H) , 7.06-7.20(m, 5 H), 5.55 (d, 1 H), 5.42 (d, 1 H), 4.61 (s, 1 H), 4.13 (s, 1 H), 3.65 (s, 2 H), 2.80 (s, 1 H), 2.18 (d, 1 H), 1.83-1.90(m, 2 H), 1.61-1.70 (m, 2 H), 1.54 (d, 1 H).LCMS (M+H⁺) m/z calculated 600.2, found 600.3

Example 46: Preparation of 5-(4-chlorobenzamido)-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2- yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-lH-indazole-3-carboxamide

5-(4-chlorobenzamido)-1 -(2-((1 ,3S,4S)-3-((6-chloro

[00263] 5-(4-Chlorobenzamido)-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-lH-indazole-3-carboxamide (49.0mg) was prepared as described for 7-chloro-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- oxoethyl)-lH-indazole-3-carboxamide. ¾ NMR (DMSO-d6, 400 MHz) δ 10.84 (s, 1 H), 10.42 (s, 1 H), 8.58 (d, 1 H), 7.98-8.05(m, 3 H), 7.81-7.85 (m, 2 H), 7.60-7.65 (m, 4 H) , 7.36 (s, 1 H), 7.18 (d, 1 H) , 5.65 (d, 1 H), 5.36 (d, 1 H), 4.62 (s, 1 H), 4.09 (s, 1 H), 2.68 (s, 1 H), 2.08 (d, 1 H), 1.78 (s, 3 H), 1.50 (d, 1 H), 1.43 (d, 1 H).LCMS (M+H⁺) m/z calculated 606.1, found 606.2

Example 47: Preparation of l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(4-cyanobenzamido)-lH-indazole-3-carboxamide

1-(2-((1 ,3S^S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclop_^ [00264] l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- oxoethyl)-5-(4-cyanobenzamido)-lH-indazole-3-carboxamide (55.0 mg) was prepared as described for 7- chloro-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl) lH-indazole-3-carboxamide. ¾NMR (CD₃OD, 400 MHz) δ 8.49 (t, 1 H), 8.02-8.17(m, 3 H), 7.78-7.90 (m, 3 H), 7.55-7.74(m, 2 H) , 7.09-7.17(m, 1 H), 5.60 (d, 1 H), 5.45 (d, 1 H), 4.64(s, l H), 4.15 (s, l H), 2.81 (s, 1 H), 2.20 (d, 1 H), 1.82-1.94(m, 2 H), 1.61-1.77 (m, 2 H), 1.56 (d, 1 H).LCMS (M+H⁺) m/z calculated 597.2, found 597.3

Example 48: Preparation of l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(cyclopropanecarboxamido)-lH-indazole-3-carboxamide

1 -(2-((1 R,3S,4S)-3-((6-chloropyridin-2-yl)rarbamoyl)-2-arabic^^

[00265] l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- oxoethyl)-5-(cyclopropanecarboxamido)-lH-indazole-3-carboxamide (33.1 mg) was prepared as described for 7-chloro-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)- lH-indazole-3-carboxamide. ¾NMR (CD30D, 400 MHz) δ 8.36 (s, 1 H), 8.01 (d, 1 H), 7.79-7.47 (m, 3 H), 7.10 (d, 1 H), 5.50 (dd, 2 H), 4.64 (s, 1 H), 4.15 (s, 1 H), 2.80 (s, l H), 2.18 (d, 1 H), 1.90-1.53 (m, 6 H), 0.98- 0.94 (m, 2 H), 0.87-0.81 (m, 1 H).LCMS (M+H⁺) m/z calculated 536.2, found 536.3.

Example 49: Preparation of l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(piperazine-2-carboxamido)-lH-indazole-3-carboxamide

1-(2-((1R,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azaW

[00266] l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- oxoethyl)-5-(piperazine-2-carboxamido)-lH-indazole-3-carboxamide (33.0 mg) was prepared as described for 7-chloro-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)- lH-indazole-3-carboxamide. ¾NMR (CD30D, 400 MHz) δ 8.56 (d, 1 H), 8.04-7.96 (m, 1 H), 7.72-7.62 (m, 1 H), 7.54-7.43 (m, 2 H),7.08 (d, 1 H), 5.68-5.54 (m, 1 H), 5.40 (d, 1 H), 4.78-4.63 (m, 2 H), 4.27-4.11 (m, 2 H), 3.94-3.43 (m, 5 H), 2.84 (s, 1 H), 2.18 (d, 1 H), 1.93-1.51 (m, 5 H).LCMS (M+H⁺) m/z calculated 580.2, found 536.3. Example 50: Preparation of l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(picolinamido)-lH-indazole-3-carboxamide

[00267] l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- oxoethyl)-5-(picolinamido)-lH-indazole-3-carboxamide (40.0 mg) was prepared as described for 7-chloro-l- (2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-lH- indazole-3-carboxamide. ¾ NMR (CD₃OD, 400 MHz) δ 8.71 (t, 1 H), 8.62(t, 1 H), 8.22(d, 1 H), 8.00-8.04 (m, 2 H), 7.88-7.90 (m, 1 H) , 7.58-7.74 (m, 3 H), 7.09-7.16 (m, 1 H), 5.60 (d, 1 H), 5.46 (d, 1 H), 4.64 (s, 1 H), 4.15 (s, 1 H), 2.81 (s, 1 H), 2.20 (d, 1 H), 1.82-1.92 (m, 2 H), 1.61-1.75 (m, 2 H), 1.55 (d, 1 H).LCMS (M+H⁺) m/z calculated 573.2, found 573.3

Example 51: Preparation of l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo

[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(pyrimidine-4-carboxamido)-lH-indazole-3-carboxamide

1 -(2-((1 R,3S^S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabic^ ^

[00268] l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- oxoethyl)-5-(pyrimidine-4-carboxamido)-lH-indazole-3-carboxamide (45.0 mg) was prepared as described for 7-chloro-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- oxoethyl)-lH-indazole-3-carboxamide. ¾ NMR (CD₃OD, 400 MHz) δ 9.36 (s, 1 H), 9.08(d, 1 H), 8.67(d, 1 H), 8.21 (d, 1 H), 8.02-8.04 (m, 1 H) , 7.89-7.91 (m, 1 H), 7.66-7.74 (m, 2 H), 7.09-7.16 (m, 1 H), 5.61 (d, 1 H), 5.46 (d, 1 H), 4.64 (s, 1 H), 4.15 (s, 1 H), 2.81 (s, 1 H), 2.20 (d, 1 H), 1.85-1.93 (m, 2 H), 1.62-1.76 (m, 2 H), 1.56 (d, 1 H).LCMS (M+H⁺) m/z calculated 574.2, found 574.3

Example 52: Preparation of N-(3-carbamoyl-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-lH-indazol-5-yl)morpholine-2-carboxamide

W-(3-carbamoy1-1-(2-((1R,3S,4S)-3-((6^

[00269] N-(3-carbamoyl-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1] heptan-2-yl)-2-oxoethyl)-lH-indazol-5-yl)mo holine-2-carboxamide (11.7 mg) was prepared as described for 7-chloro-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-lH-indazole-3-carboxamide. ¾NMR (CD30D, 400 MHz) δ 8.38 (d, 1 H), 8.02 (d, 1 H), 7.73-7.58 (m, 3 H), 7.09 (d, 1 H), 5.49 (dd, 2 H), 4.64 (t, 1 H), 4.15-4.02 (m, 2 H), 3.74-3.68 (m, 1 H), 2.97-2.70 (m, 5 H), 2.17 (d, 1 H), 1.92-1.49 (m, 6 H). LCMS (M+H⁺) m/z calculated 581.2, found 581.3.

Example 53: Preparation of l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl) boxamido)-lH-indazole-3-carboxamide

1-(2-((1R,3S,4S)-3-((6-chloropyridin-2-yl)rarbamoyl^

[00270] l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- oxoethyl)-5-(lH-pyrazole-4-carboxamido)-lH-indazole-3-carboxamide (7.0 mg) was prepared as described for 7-chloro-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- oxoethyl)-lH-indazole-3-carboxamide. ¾NMR (CD₃OD, 400 MHz) δ 8.41 (d, 1 H), 8.21(s, 2 H), 8.03 (d, 1 H), 7.84(d, 1 H) , 7.72 (t, 1 H), 7.62(d, 1 H), 7.09-7.17 (m, 1 H), 5.59 (d, 1 H), 5.45 (d, 1 H), 4.64 (s, 1 H), 4.15 (s, 1 H), 2.81(s, 1 H), 2.19 (t, 1 H), 1.85-1.92(m, 2 H), 1.61-1.74 (m, 2 H), 1.55 (d, 1 H).LCMS (M+H⁺) m/z calculated 562.2, found 562.3

Example 54: Preparation of 5-((S)-2-amino-3-methylbutanamido)-l-(2-((lR,3S,4S)-3-((6-chloropyridin- 2-yl)carbamoyl)-2-azabicyclo[2.2.1]he H-indazole-3-carboxamide

5-((S)-2-amino-3-methylbutanamido)-1-(2-((1R,3S,4S)-3-((6-^

[00271] 5-((S)-2-amino-3-methylbutanamido)-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2- yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-lH-indazole-3-carboxamide (55.7 mg) was prepared as described for 7-chloro-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-lH-indazole-3-carboxamide. ¾NMR (DMSO-d6, 400 MHz) δ 10.85 (s, 1 H), 10.16 (s, 1 H), 8.47 (s, 1 H), 7.99 (d, 1 H), 7.80 (t, 1 H), 7.72-7.52 (m, 4 H), 7.35 (s, 1 H), 7.17 (d, 1 H), 5.63 (d, 1 H), 5.34 (d, 1 H), 4.61 (s, 1 H), 4.08 (s, 1 H), 3.13 (d, 1 H), 2.95-2.90 (m, 1 H), 2.68 (s,l H), 2.06 (d, 1 H), 1.99-1.88 (m, 1 H), 1.59-1.23(m, 4 H), 0.94 (d, 3 H), 0.88 (d, 3 H). LCMS (M+H⁺) m/z calculated 567.2, found 567.3.

Example 55: Preparation of 5-(2-(2-chlorophenyl)acetamido)-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2- yl)carbamoyl)-2-azabicyclo[2.2.1]heptan- indazole-3-carboxamide

5-(2-(2-chlorophenyl)acetamido)-1-(2-((1R,3S,4S)-3-((6-chloropyri^

[00272] 5-(2-(2-Chlorophenyl)acetamido)-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)- 2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-lH-indazole-3-carboxamide (33.0 mg) was prepared as described for 7-chloro-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- oxoethyl)-lH-indazole-3-carboxamide. ¾ NMR (CD₃OD, 400 MHz) δ 8.30-8.33 (m, 1 H), 8.02(d, 1 H), 7.69- 7.76 (m, 2 H), 7.58(d, 1 H) , 7.40-7.42 (m, 2 H), 7.26-7.31(m, 2 H), 7.09-7.16 (m, 1 H), 5.56 (d, 1 H), 5.43 (d, 1 H), 4.62 (s, 1 H), 4.14 (s, 1 H), 3.90 (s, 2 H), 2.80 (s, 1 H), 2.18 (d, 1 H), 1.82-1.91(m, 2 H), 1.62-1.73 (m, 2 H), 1.54 (d, 1 H).LCMS (M+H⁺) m/z calculated 620.2, found 620.3

Example 56: Preparation of 5-(2-(3-chlorophenyl)acetamido)-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2- yl)carbamoyl)-2-azabicyclo[2.2.1]heptan ndazole-3-carboxamide

5-(2-(3-chlorophenyl)acetamido)-1 -(2-((1 R,3S,4S)-3-((6^

[00273] 5-(2-(3-chlorophenyl)acetamido)-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)- 2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-lH-indazole-3-carboxamide (45.0 mg) was prepared as described for 7-chloro-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- oxoethyl)-lH-indazole-3-carboxamide. ¾ NMR (CD₃OD, 400 MHz) δ 8.33 (t, 1 H), 8.02(d, 1 H), 7.69-7.74 (m, 2 H), 7.58(d, 1 H) , 7.41 (s, 1 H), 7.27-7.32(m, 3 H), 7.09-7.14(m, 1 H), 5.56 (d, 1 H), 5.42 (d, 1 H), 4.62 (s, I H), 4.14 (s, I H), 3.70 (s, 2 H), 2.80 (s, 1 H), 2.18 (d, 1 H), 1.80-1.93(m, 2 H), 1.60-1.73 (m, 2 H), 1.54 (d, 1 H).LCMS (M+H⁺) m/z calculated 620.2, found 620.3. Example 57: Preparation of l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoet o)-lH-indazole-3-carboxamide

1 -(2-((1 R,3S,4S)-3-((6-c loropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1 ]heptan-2-yl)-2-oxoethyl)-5-(2-(o-tolyl)acetamido)-1 H-indazole-3-carboxamide

[00274] l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- oxoethyl)-5-(2-(o-tolyl)acetamido)-lH-indazole-3-carboxamide (37.0 mg) was prepared as described for 7- chloro-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)- lH-indazole-3-carboxamide. ¾ NMR (DMSO, 400 MHz) δ 10.83 (s, 1 H), 10.23 (s, 1 H), 8.42 (s, 1 H), 7.98(d, 1 H) , 7.81 (t, 1 H), 7.66-7.68 (m, 1 H), 7.58 (d, 2 H), 7.33 (s, 1 H), 7.26 (t, 1 H), 7.13-7.19 (m, 4 H), 5.62 (d, 1 H), 5.33 (d, 1 H), 4.60 (s, 1 H), 4.07 (s, 1 H), 3.69 (s, 2 H), 2.67 (s, 1 H), 2.32 (s, 3 H), 2.07 (d, 1 H), 1.77 (t, 3 H), 1.48 (d, 1 H), 1.42 (d, 1 H).LCMS (M+H⁺) m/z calculated 600.2, found 600.4.

Example 58: Preparation of N-(3-carbamoyl-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)- pholine-3-carboxamide

/V-(3^rbamoyl-1-(2-((1 3S,4S)-3-((6-chloropyridin-2^

[00275] N-(3-carbamoyl-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1] heptan-2-yl)-2-oxoethyl)-lH-indazol-5-yl)mo holine-3-carboxamide (37.0 mg) was prepared as described for 7-chloro-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-lH-indazole-3-carboxamide. ¾ NMR (DMSO-d6, 400 MHz) δ 10.87 (s, 1 H), 9.89 (s, 1 H), 8.49 (s, 1 H), 7.99 (d, 1 H), 7.82 (t, 1 H), 7.68-7.55 (m, 3 H), 7.36 (s, 1 H), 7.19 (d, 1 H), 5.63 (d, 1 H), 5.34 (d, 1 H), 4.62 (s, 1 H), 4.08 (s, 1 H), 3.86 (d, 1 H), 3.67-3.61 (m, 1 H), 3.57-3.40 (m, 3 H), 2.94-2.71 (m, 3 H), 2.68 (s, l H), 2.06 (d, 1 H), 1.85-1.69 (m, 3 H), 1.61-1.38 (m, 2 H). LCMS (M+H⁺) m/z calculated 581.2, found 581.3.

Example 59: Preparation of 5-(3-aminopropanamido)-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2- yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-lH-indazole-3-carboxamide

5-(3-aminopropanamido)-1-(2-((1R,3S,4S)-3-((6-chloropyridin-2-yl)carb^

[00276] 5-(3-Aminopropanamido)-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-lH-indazole-3-carboxamide (35.8 mg) was prepared as described for 7-chloro-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- oxoethyl)-lH-indazole-3-carboxamide. ¾ NMR (DMSO-d6, 400 MHz) δ 10.81 (s, 1 H), 10.14 (s, 1 H), 8.44 (s, 1 H), 7.97 (d, 1 H), 7.81 (t, 1 H), 7.65-7.47 (m, 3 H), 7.31 (s, 1 H), 7.18 (d, 1 H), 5.62 (d, 1 H), 5.33 (d, 1 H), 4.60 (s, 1 H), 4.08 (s, 1 H), 2.91 (t, 2 H), 2.67 (s, 1 H), 2.47 (t, 2 H), 2.06 (d, 1 H), 1.84-1.70 (m, 3 H), 1.53-1.38 (m, 2 H). LCMS (M+H⁺) m/z calculated 539.2, found 539.4.

Example 60: Preparation of l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)- rboxamido)-lH-indazole-3-carboxamide

1-(2-((1/?,3S,4S)-3-((6-chloropyridin-2-yl)caitamoyl)-2-az^^

[00277] l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- oxoethyl)-5-(lH-imidazole-4-carboxamido)-lH-indazole-3-carboxamide (12.0 mg) was prepared as described for 7-chloro-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- oxoethyl)-lH-indazole-3-carboxamide. ¾ NMR (CD₃OD, 400 MHz) δ 8.39-8.56 (m, 2 H), 8.01-8.10(m, 2 H), 7.64-7.79 (m, 3 H), 7.09-7.17 (m, 1 H), 5.61 (d, 1 H), 5.45 (d, 1 H), 4.64 (s, 1 H), 4.15 (s, 1 H), 2.82 (s, 1 H), 2.20 (d, 1 H), 1.83-1.93(m, 2 H), 1.62-1.78 (m, 2 H), 1.56 (d, 1 H).LCMS (M+H⁺) m/z calculated 562.2, found 562.3.

Example 61: Preparation of l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoet H-indazole-3-carboxamide

1-(2-((1R,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(isoni [00278] l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- oxoethyl)-5-(isonicotinamido)-lH-indazole-3-carboxamide (48.0 mg) was prepared as described for 7-chloro- l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-lH^ indazole-3-carboxamide. ¾ NMR (DMSO, 400 MHz) δ 10.85 (s, 1 H), 10.61 (s, 1 H), 8.79 (t, 2 H), 8.61(s, 1 H) , 7.99 (d, 1 H), 7.91 (t, 2 H), 7.79-7.86 (m, 2 H), 7.66 (d, 2 H), 7.38 (s, 1 H), 7.17-7.27 (m, 1 H), 5.66 (d, 1 H), 5.37 (d, 1 H), 4.62 (s, 1 H), 4.09 (s, 1 H), 2.68 (s, 1 H), 2.08 (d, 1 H), 1.78 (s, 3 H), 1.50 (d, 1 H), 1.43 (d, 1 H).LCMS (M+H⁺) m/z calculated 573.2, found 573.3

Example 62: Preparation of l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)- oxamido)-lH-indazole-3-carboxamide

1-(2-((1R,3S^S)-3-((6<;hloropyridin-2-yl)ca*amoyl)-2-azabicyclo[2^

[00279] l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- oxoethyl)-5-(lH-pyrrole-3-carboxamido)-lH-indazole-3-carboxamide (19.0 mg) was prepared as described for 7-chloro-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- oxoethyl)-lH-indazole-3-carboxamide. ¾ NMR (CD₃OD, 400 MHz) δ 8.37 (d, 1 H), 8.03(d, 1 H), 7.83-7.86 (m, 1 H), 7.72(d, 1 H) , 7.60 (d, 1 H), 7.52(d, 1 H), 7.09-7.17(m, 1 H), 6.80 (d, 1 H), 6.72(d, 1 H), 5.57 (d, 1 H), 5.44 (d, 1 H), 4.63 (s, 1 H), 4.15 (s, 1 H), 2.80 (s, 1 H), 2.19 (d, 1 H), 1.84-1.93(m, 2 H), 1.60-1.73 (m, 2 H), 1.54 (d, 1 H).LCMS (M+H⁺) m/z calculated 561.2, found 561.4

Example 63: Preparation of 5-((S)-2-amino-4-methylpentanamido)-l-(2-((lR,3S,4S)-3-((6- chloropyridin-2-yl)carbamoyl)-2-azabicy -2-oxoethyl)-lH-indazole-3-carboxamide

5-((S)-2-amino^-methylpentanamido)-1-(2-((1R,^

[00280] 5-((S)-2-amino-4-methylpentanamido)-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2- yl)carbamoyl)-2-azabicyclo[2.2. l]heptan-2-yl)-2-oxoethyl)-lH-indazole-3-carboxamide (50.2 mg) was prepared as described for 7-chloro-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-lH-indazole-3-carboxamide. ¾ NMR (DMSO-d6, 400 MHz) δ 10.83 (s, 1 H), 8.46 (d, 1 H), 7.98 (d, 1 H), 7.81 (t, 1 H), 7.70-7.50 (m, 4 H), 7.34 (s, 1 H), 7.18 (d, 1 H), 5.62 (d, 1 H), 5.33 (d, 1 H), 4.61 (s, 1 H), 4.08 (s, 1 H), 3.45-3.39 (m, 2 H), 2.67 (s, 1 H), 2.06 (d, 1 H), 1.84-1.69 (m, 5 H), 1.60-1.34 (m, 4 H), 0.90 (t, 6 H). LCMS (M+H⁺) m/z calculated 581.2, found 581.3. Example 64: Preparation of l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(3-cyanobenzamido)-lH-indazole-3-carboxamide

l-^-^IR^S^SJ-S-fte^hloropyridin^-ylJcarbamoy^

[00281] l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- oxoethyl)-5-(3-cyanobenzamido)-lH-indazole-3-carboxamide (31.0 mg) was prepared as described for 7- chloro-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)- lH-indazole-3-carboxamide. ¾NMR (CD₃OD, 400 MHz) δ 8.49 (t, 1 H), 8.33 (s, 1 H), 8.25 (d, 1 H), 8.03(d, 1 H) , 7.94 (d, 1 H), 7.85 (d, 1 H),7.64-7.74 (m, 3 H), 7.09-7.17(m, 1 H), 5.60 (d, 1 H), 5.46 (d, 1 H), 4.64 (s, 1 H), 4.15 (s, 1 H), 2.81 (s, 1 H), 2.20 (d, 1 H), 1.85-1.93(m, 2 H), 1.61-1.76 (m, 2 H), 1.55 (d, 1 H).LCMS (M+H⁺) m/z calculated 597.2, found 597.3.

Example 65: Preparation of 5-(3-chlorobenzamido)-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2- yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-lH-indazole-3-carboxamide

5-(3n;hlorobenzamido)-1-(2-((1R,3S,4S)-3-((6-chloropyridin-2-yl^

[00282] 5-(3-Chlorobenzamido)-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo [2.2.1]heptan-2-yl)-2-oxoethyl)-lH-indazole-3-carboxamide (58.0 mg) was prepared as described for 7-chloro-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- oxoethyl)-lH-indazole-3-carboxamide. ¾NMR (CD₃OD, 400 MHz) δ 8.46 (t, 1 H), 8.03(d, 1 H) , 7.98 (s, 1 H), 7.82-7.90 (m, 2 H),7.49-7.74 (m, 4 H), 7.09-7.17(m, 1 H), 5.59 (d, 1 H), 5.45 (d, 1 H), 4.64 (s, 1 H), 4.15 (s, 1 H), 2.81 (s, 1 H), 2.20 (d, 1 H), 1.84-1.92(m, 2 H), 1.61-1.75 (m, 2 H), 1.55 (d, 1 H).LCMS (M+H⁺) m/z calculated 606.2, found 606.4.

Example 66: Preparation of l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(2-cyanobenzamido)-lH-indazole-3-carboxamide

1-(2-((1R,3S,4S)-3-((6-chloropyridin-2-yl)ca*amoyl)-2-azaW

[00283] l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- oxoethyl)-5-(2-cyanobenzamido)-lH-indazole-3-carboxamide (55.0 mg) was prepared as described for 7- chloro-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-y^

lH-indazole-3-carboxamide. ¾ NMR (CD₃OD, 400 MHz) δ 8.48 (t, 1 H), 8.10 (d, 2 H), 8.03(d, 1 H) , 7.83- 7.90 (m, 3 H),7.64-7.74 (m, 2 H), 7.09-7.16(m, 1 H), 5.60 (d, 1 H), 5.45 (d, 1 H), 4.64 (s, 1 H), 4.15 (s, 1 H), 2.81 (s, 1 H), 2.20 (d, 1 H), 1.82-1.93(m, 2 H), 1.62-1.76 (m, 2 H), 1.55 (d, 1 H).LCMS (M+H⁺) m/z calculated 597.2, found 597.4.

Example 67: Preparation of 5-(2-aminoacetamido)-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2- yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-lH-indazole-3-carboxamide

5-(2-aminoacetamido)-1-(2-((1R,3S,4S)-3-((6-chloropyridin-2-yl)ra^

[00284] 5-(2-Aminoacetamido)-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-lH-indazole-3-carboxamide (53.6 mg) was prepared as described for 7-chloro-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- oxoethyl)-lH-indazole-3-carboxamide. ¾ NMR (DMSO-d6, 400 MHz) δ 10.83 (s, 1 H), 8.47 (s, 1 H), 7.98 (d, 1 H), 7.81 (t, 1 H), 7.68-7.56 (m, 3 H), 7.31 (s, 1 H), 7.18 (d, 1 H), 5.62 (d, 1 H), 5.33 (d, 1 H), 4.61 (s, 1 H), 4.08 (s, 1 H), 3.41 (s, 2 H), 2.67 (s, 1 H), 2.06 (d, 1 H), 1.84-1.70 (m, 3 H), 1.53-1.38 (m, 2 H). LCMS (M+H⁺) m/z calculated 525.2, found 525.3.

Example 68: Preparation of 5-((S)-2-aminopropanamido)-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2- yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-lH-indazole-3-carboxamide

5-((S)-2 )-1-(2-((1 7,3S,4S)-3-((6 -2 )-2 [2.2.1

[00285] 5-((S)-2-aminopropanamido)-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-lH-indazole-3-carboxamide (47.1 mg) was prepared as described for 7-chloro-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- oxoethyl)-lH-indazole-3-carboxamide. ¾ NMR (DMSO-d6, 400 MHz) δ 10.83 (s, 1 H), 8.47 (s, 1 H), 7.98 (d, 1 H), 7.81 (t, 1 H), 7.69-7.56 (m, 2 H), 7.31 (s, 1 H), 7.18 (d, 1 H), 5.62 (d, 1 H), 5.33 (d, 1 H), 4.61 (s, 1 H), 4.08 (s, 1 H), 3.51-3.42 (m, 1 H), 2.67 (s, 1 H), 2.06 (d, 1 H), 1.84-1.70 (m, 3 H), 1.53-1.38 (m, 2 H). LCMS (M+H⁺) m/z calculated 539.2, found 539.3.

Example 69: Preparation of l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo

[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(piperidine-3-carboxamido)-lH-indazole-3-carboxamide

1-(2-((1 3S,4S)-3-((6-chloropyridin-2-yl)cart)amoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2K)xoethyl)-5-(p

[00286] l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- oxoethyl)-5-(piperidine-3-carboxamido)-lH-indazole-3-carboxamide (63.0 mg) was prepared as described for 7-chloro-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)- lH-indazole-3-carboxamide. ¾NMR (CD₃OD, 400 MHz) 8.33 (d, 1 H), 8.03(d, 1 H) , 7.68-7.74 (m, 2 H), 7.57(d, 1 H) , 7.09-7.17(m, 1 H), 5.56 (d, 1 H), 5.42 (d, 1 H), 4.63 (s, 1 H), 4.15 (s, 1 H), 3.14(d, 1 H), 3.0 (d, 1 H), 2.59-2.93(m, 4 H), 2.18 (d, 1 H), 2.03 (d, 1 H), 1.53-1.93 (m, 8 H). LCMS (M+H⁺) m/z calculated 579.2, found 579.4

Example 70: Preparation of l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(piperidine-2-carboxamido)-lH-indazole-3-carboxamide

1 -(2-((1 3S,4S)-3-((6-chloropyridin-2-yl)rarbamoyl)-2-azati

[00287] l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- oxoethyl)-5-(piperidine-2-carboxamido)-lH-indazole-3-carboxamide (60.0 mg) was prepared as described for 7-chloro-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)- lH-indazole-3-carboxamide. ¾ NMR (CD₃OD, 400 MHz) 8.41 (d, 1 H), 8.01(d, 1 H) , 7.67-7.73 (m, 2H), 7.61 (d, 1 H) , 7.09-7.17(m, 1 H), 5.59 (d, 1 H), 5.43 (d, 1 H), 4.63 (s, 1 H), 4.14 (s, 1 H), 3.72 (t, 1 H), 2.93- 2.98 (m, 1 H), 2.81 (s, 4 H), 2.21 (t, 2 H), 1.82-1.99 (m, 4 H), 1.54-1.76 (m, 7 H). LCMS (M+H⁺) m/z calculated 579.3, found 579.5

Example 71: Preparation of l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(2-hydroxyacetamido)-lH-indazole-3-carboxamide

1-(2-((1 3S,4S)-3-((6-chloropyridin-2-yl)carbamoy1)-2-a^

[00288] l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- oxoethyl)-5-(2-hydroxyacetamido)-lH-indazole-3-carboxamide (45.7 mg) was prepared as described for 7- chloro-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl^ lH-indazole-S-carboxamide^ NMR (CD30D, 400 MHz) δ 8.41 (s, 1 H), 8.02 (d, 1 H), 7.77-7.62 (m, 2 H), 7.60 (d, 1 H), 7.10 (d, 1 H), 5.57 (d, 1 H), 5.43 (d, 1 H), 4.14 (s, 2 H), 2.80 (s, 1H), 2.18 (d, 1 H), 1.99-1.79 (m, 2 H), 1.75-1.50 (m, 4 H). LCMS (M+H⁺) m/z calculated 526.2, found 526.3.

Example 72: Preparation of l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl) amido)-lH-indazole-3-carboxamide

1-(2-((1 3S,4S)-3-((6-chloropyridin-2-yl)cart}amoyl)-2-az^^

[00289] l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- oxoethyl)-5-(piperidine-4-carboxamido)-lH-indazole-3-carboxamide (36.0 mg) was prepared as described for 7-chloro-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)- lH-indazole-3-carboxamide. ¾NMR (CD30D, 400 MHz) δ 8.38 (d, 1 H), 8.01 (d, 1 H), 7.74-7.56 (m, 3 H), 7.09 (d, 1 H), 5.58 (d, 1 H), 5.42 (d, 1 H), 4.63 (s, 1 H), 4.14 (s, 1 H), 3.53-3.44 (m, 2 H), 3.14-3.02 (m, 2 H), 2.82 (s, 1H), 2.78-2.68 (m, 1 H), 2.22-1.53 (m, 10 H),. LCMS (M+H⁺) m/z calculated 579.2, found 579.4. Example 73: Preparation of l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl) -lH-indazole-3-carboxamide

1-(2-((1R,3S,4S)-3-((6-chloropyridin-2-yl)caitiamoyl)-2-azaW^

[00290] l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- oxoethyl)-5-(3-fluorobenzamido)-lH-indazole-3-carboxamide (57.8 mg) was prepared as described for 7- chloro-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)- lH-indazole-3-carboxamide. ¾NMR (CD30D, 400 MHz) δ 8.47 (s, 1 H), 8.02 (d, 1 H), 7.86-7.50 (m, 5 H),

7.32 (t, 1 H), 7.10 (d, 1 H), 5.59 (d, 1 H), 5.47 (d, 1 H), 4.64 (s, 1 H), 4.15 (s, 1 H), 2.81 (s, 1H), 2.17 (d, 1 H),

1.95-1.52 (m, 5 H),. LCMS (M+H⁺) m/z calculated 590.2, found 590.3.

Example 74: Preparation of l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(thiophene-2-carboxamido)-lH-indazole-3-carboxamide

1-(2-((1R,3S,4S)-3-((6-c loropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethy^

[00291] l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- oxoethyl)-5-(thiophene-2-carboxamido)-lH-indazole-3-carboxamide (43.2 mg) was prepared as described for 7-chloro-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)- lH-indazole-3-carboxamide. ¾NMR (CD30D, 400 MHz) δ 8.41 (d, 1 H), 8.02 (d, 1 H), 7.91 (d, 1 H), 7.86- 7.81 (m, 1 H), 7.74-7.69 (m, 2 H), 7.63 (d, 1 H), 7.21-7.15 (m, 1 H), 7.10 (d, 1 H), 5.58 (d, 1 H), 5.45 (d, 1 H), 4.64 (s, 1 H), 4.15 (s, 1 H), 2.81 (s, 1H), 2.19 (d, 1 H), 1.95-1.52 (m, 5 H),. LCMS (M+H⁺) m/z calculated 578.1, found 578.3.

Example 75: Preparation of l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo

[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(2-(2- -lH-indazole-3-carboxamide

1-(2-((1R,3S,4S)-3-((6-*loropyridin-2-yl)carbamoy1)-2-aza^^

[00292] l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- oxoethyl)-5-(2-(2-cyanophenyl)acetamido)-lH-indazole-3-carboxamide (36.0 mg) was prepared as described for 7-chloro-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- oxoethyl)-lH-indazole-3-carboxamide. ¾NMR (CD₃OD, 400 MHz) δ 8.34 (d, 1 H), 8.02 (d, 1 H), 7.63-7.75 (m, 4 H), 7.54-7.60 (m, 2 H), 7.45 (t, 1 H), 7.09-7.16(m, 1 H), 5.56 (d, 1 H), 5.43 (d, 1 H), 4.62 (s, 1 H), 4.14 (s, 1 H), 4.01 (s, 2 H), 2.80 (s, 1 H), 2.18 (d, 1 H), 1.80-1.93 (m, 2 H), 1.60-1.75 (m, 2 H), 1.54 (d, 1 H). LCMS (M+H⁺) m/z calculated 611.2, found 611.3.

Example 76: Preparation of 5-(2-chlorobenzamido)-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2- yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-lH-indazole-3-carboxamide

5-(2-chlorobenzamido)-1-(2-((1R,3S,4S 3-((6→;hloropyrM

[00293] 5-(2-Chlorobenzamido)-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-lH-indazole-3-carboxamide (20.0 mg) was prepared as described for 7-chloro-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- oxoethyl)-lH-indazole-3-carboxamide. ¾ NMR (CD₃OD, 400 MHz) δ 8.46-8.48 (m, 1 H), 8.02 (d, 1 H), 7.82 (t, 1 H), 7.71 (t, 1 H), 7.58-7.64 (m, 2 H), 7.41-7.53 (m, 2 H), 7.09-7.17(m, 1 H), 5.58 (d, 1 H), 5.44 (d, 1 H), 4.63 (s, 1 H), 4.15 (s, 1 H), 2.80 (s, 1 H), 2.19 (d, 1 H), 1.84-1.90 (m, 2 H), 1.62-1.74 (m, 2 H), 1.54 (d, 1 H). LCMS (M+H⁺) m/z calculated 606.2, found 606.4.

Example 77: Preparation of l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(2-fluorobenzamido)-lH-indazole-3-carboxamide

1-(2-((1R,3S^S)-3-((6-chloropyridin-2-yl)ca*amoyl^

[00294] l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- oxoethyl)-5-(2-fluorobenzamido)-lH-indazole-3-carboxamide (33.0 mg) was prepared as described for 7- chloro-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)- lH-indazole-3-carboxamide. ¾ NMR (CD₃OD, 400 MHz) δ 8.49 (t, 1 H), 8.03 (d, 1 H), 7.70-7.84 (m, 3 H), 7.56-7.65 (m, 3 H), 7.23-7.34 (m, 2 H),7.09-7.17(m, 1 H), 5.59 (d, 1 H), 5.46 (d, 1 H), 4.64 (s, 1 H), 4.15 (s, 1 H), 2.81 (s, 1 H), 2.20 (d, 1 H), 1.85-1.99 (m, 2 H), 1.60-1.75 (m, 2 H), 1.56 (d, 1 H). LCMS (M+H⁺) m/z calculated 590.2, found 590.3.

Example 78: Preparation of l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(2-(3-cyanophenyl)acetamido)-lH-indazole-3-carboxamide

H ftSS^SJ-S-tte-chloropyridin^-ylJcarbamoyl^-a^

[00295] l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- oxoethyl)-5-(2-(3-cyanophenyl)acetamido)-lH-indazole-3-carboxamide (43.0 mg) was prepared as described for 7-chloro-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- oxoethyl)-lH-indazole-3-carboxamide. ¾ NMR (CD₃OD, 400 MHz) δ 8.32-8.34 (m, 1 H), 8.02 (d, 1 H), 7.68-7.72 (m, 4 H), 7.50-7.65 (m, 3 H), 7.09-7.14(m, 1 H), 5.56 (d, 1 H), 5.42 (d, 1 H), 4.62 (s, 1 H), 4.14 (s, 1 H), 3.78 (s, 2 H), 2.80 (s, 1 H), 2.18 (d, 1 H), 1.80-1.91 (m, 2 H), 1.60-1.73 (m, 2 H), 1.54 (d, 1 H). LCMS (M+H⁺) m/z calculated 611.2, found 611.3.

Example 79: Preparation of l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(2-(p-tolyl)acetamido)-lH-indazole-3-carboxamide

1-(2-((1 ,3S,4S)-3-((6-chloropyridin-2-yl)rarbamoyl^

[00296] l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- oxoethyl)-5-(2-(p-tolyl)acetamido)-lH-indazole-3-carboxamide (43.0 mg) was prepared as described for 7- chloro-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)- lH-indazole-3-carboxamide. ¾ NMR (CD₃OD, 400 MHz) δ 8.29-8.31 (m, 1 H), 8.02(d, 1 H), 7.70-7.73(m, 2 H), 7.56 (d, 1 H), 7.25(d, 2 H) , 7.09-7.15(m, 3 H), 5.55 (d, 1 H), 5.42 (d, 1 H), 4.61 (s, 1 H), 4.13 (s, 1 H), 3.64 (s, 2 H), 2.80 (s, 1 H), 2.18 (d, 1 H), 1.82-1.90(m, 2 H), 1.62-1.72 (m, 2 H), 1.53 (d, 1 H). LCMS (M+H⁺) m/z calculated 600.2, found 600.4.

Example 80: Preparation of l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(4-fluorobenzamido)-lH-indazole-3-carboxamide

1-(2-((1R,3S,4S)-3-((6-chloropyridin-2-yl)cai amoyl)-2-ara^

[00297] l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- oxoethyl)-5-(4-fluorobenzamido)-lH-indazole-3-carboxamide (48.0 mg) was prepared as described for 7- chloro-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)- lH-indazole-3-carboxamide. ¾ NMR (CD₃OD, 400 MHz) δ 8.43 (d, 1 H), 8.00-8.04(m, 3 H), 7.80-7.84 (m, 1 H), 7.70-7.73(m, 1 H), 7.60-7.64 (m, 1 H), 7.24(t, 2 H) , 7.09-7.16(m, 1 H), 5.59 (d, 1 H), 5.45 (d, 1 H), 4.63 (s, 1 H), 4.15 (s, 1 H), 2.80 (s, 1 H), 2.19 (d, 1 H), 1.85-1.90(m, 2 H), 1.63-1.73 (m, 2 H), 1.55 (d, 1 H).

LCMS (M+H⁺) m/z calculated 590.2, found 590.3. Example 81: Preparation of N-(3-carbamoyl-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)- ole-5-carboxamide

N-(3-ca*amoyl-1-(2-((1R3S,4S)-3-((6-*loropyridin-2-^

[00298] N-(3-carbamoyl-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1] heptan-2-yl)-2-oxoethyl)-lH-indazol-5-yl)oxazole-5-carboxamide (50.0 mg) was prepared as described for 7-chloro-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2. l]heptan-2- yl)-2-oxoethyl)-lH-indazole-3-carboxamide. ¾ NMR (CD₃OD, 400 MHz) δ 8.46-8.48 (m, 1 H), 8.39(s, 1 H), 8.02(d, 1 H),7.88 (s, 1 H), 7.78-7.84(m, 1 H), 7.72 (t, 1 H), 7.64(d, 1 H) , 7.09-7.16(m, 1 H), 5.60 (d, 1 H), 5.45 (d, 1 H), 4.64 (s, l H), 4.15 (s, 1 H), 2.81 (s, l H), 2.19 (d, 1 H), 1.85-1.91(m, 2 H), 1.61-1.76 (m, 2 H), 1.56 (d, 1 H). LCMS (M+H⁺) m/z calculated 563.2, found 563.3.

Example 82: Preparation of l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl) do)-lH-indazole-3-carboxamide

1-(2-((1R,3S,4S)-3-((6-chloropyridin-2-yl)ca*amoyl^^

[00299] l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- oxoethyl)-5-(2-methoxyacetamido)-lH-indazole-3-carboxamide(30.0 mg) was prepared as described for 7- chloro-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)- lH-indazole-3-carboxamide. ¾ NMR (CD₃OD, 400 MHz) δ 8.37-8.39 (m, 1 H), 8.02(d, 1 H), 7.70-7.74(m, 2 H), 7.60(d, 1 H) , 7.09-7.16(m, 1 H), 5.57 (d, 1 H), 5.43 (d, 1 H), 4.62 (s, 1 H), 4.14 (s, 1 H), 4.06 (s, 2 H), 3.50 (s, 3 H), 2.80 (s, l H), 2.19 (d, 1 H), 1.83-1.91(m, 2 H), 1.60-1.74 (m, 2 H), 1.54 (d, 1 H). LCMS (M+H⁺) m/z calculated 540.2, found 540.3

Example 83: Preparation of 5-((S)-2-aminobutanamido)-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2- yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-lH-indazole-3-carboxamide

[00300] 5-((S)-2-aminobutanamido)-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-lH-indazole-3-carboxamide (33.0 mg) was prepared as described for 7-chloro-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- oxoethyl)-lH-indazole-3-carboxamide. ¾ NMR (CD₃OD, 400 MHz) δ 8.38 (t, 1 H), 8.02(d, 1 H), 7.70- 7.75(m, 2 H), 7.59(d, 1 H) , 7.09-7.17(m, 1 H), 5.57 (d, 1 H), 5.43 (d, 1 H), 4.62 (s, 1 H), 4.14 (s, 1 H), 3.41 (t, 1 H), 2.80 (s, 1 H), 2.19 (d, 1 H), 1.78-1.91(m, 3 H), 1.60-1.73 (m, 3 H), 1.54 (d, 1 H), 1.01 (t, 3 H). LCMS (M+H⁺) m/z calculated 553.2, found 553.3.

Example 84: Preparation of 5-((S)-2-amino-3-hydroxypropanamido)-l-(2-((lR,3S,4S)-3-((6- chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-lH-indazole-3-carboxamide

[00301] -amino-3-hydroxypropanamido)-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2- yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-lH-indazole-3-carboxamide (18.0 mg) was prepared as described for 7-chloro-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-lH-indazole-3-carboxamide. ¾ NMR (CD₃OD, 400 MHz) δ 8.38- 8.41(m, 1 H), 8.02(d, 1 H), 7.70-7.76(m, 2 H), 7.59(d, 1 H) , 7.09-7.17(m, 1 H), 5.57 (d, 1 H), 5.43 (d, 1 H), 4.62 (s, I H), 4.14 (s, 1 H), 3.80 (t, 2 H), 3.58 (t, l H), 2.81 (s, l H), 2.19 (d, 1 H), 1.81-1.91(m, 2 H), 1.62- 1.73 (m, 2 H), 1.54 (d, 1 H).LCMS (M+H⁺) m/z calculated 555.2, found 555.3.

Example 85: Preparation of l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-ureido-lH-indazole-3-carboxamide

1-(2-((1R,3S,4S)-3-((6-chloropyridin-2-y1)ca*am

[00302] l-(2-((lR,3S,4S)-3-((3-chlorophenyl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- oxoethyl)-5-nitro-lH-indazole-3-carboxamide (1.5 g, 3.02 mmol) was dissolved in a mixture of CH30H (100.0 mL), NH3.H20 (50.0 mL). Raney-Ni (300 mg) was added and the reaction mixture was stirred at rt under H2 atmosphere (1 atm) for 2 hours. LC-MS confirmed that the reaction was finished. The mixture was filtered and concentrated to provide 5-amino-l-(2-((lR,3S,4S)-3-((3-chlorophenyl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-lH-indazole-3-carboxamide (1.4 g, 99.3%) which was used in the next step without further purification.

[00303] 5-Amino-l-(2-((lR,3S,4S)-3-((3-chlorophenyl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2- yl)-2-oxoethyl)-lH-indazole-3-carboxamide (1.4 g, 3.01 mmol) was dissolved in pyridine (50.0 mL), then phenyl carbonochloridate ( 706.7 mg, 4.53 mmol) was added dropwise in lOmin. The reaction mixture was stirred at rt for 1 hour. LC-MS confirmed that the reaction was finished. The mixture was then concentrated to remove the solvent and the residue was purified by silica gel column (DCM:MeOH=10: 1, v:v) to provide phenyl (3-carbamoyl-l-(2-((lR,3S,4S)-3-((3-chlorophenyl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- oxoethyl)-lH-indazol-5-yl)carbamate (901.0 mg, 51.1%).

[00304] A mixture of phenyl (3-carbamoyl-l-(2-((lR,3S,4S)-3-((3-chlorophenyl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-lH-indazol-5-yl)carbamate (90.0 mg, 0.153 mmol) in

NH₃/THF(4N, 5 mL) was heated at 70 °C in a sealed-tube for 12 hr. LC-MS confirmed that the reaction was finished. The mixture was concentrated, and the resulting residue was purified by prep-HPLC to provide l-(2- ((lR,3S,4S)-3-((3-chlorophenyl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-ureido-lH- indazole-3-carboxamide (44.8 mg, 52.9%). ¾NMR (CD₃OD, 400 MHz) δ 8.09-8.02 (m, 2 H), 7.72(t, 3 H), 7.62-7.54 (m, 2 H), 7.10(d, 2H) , 5.54(d, 1 H), 5.42 (d, 1 H), 4.61 (s, 1 H), 4.14 (s, 1 H), 2.80 (s, 1 H), 2.18 (d, 1 H), 1.89-1.82(m, 2 H), 1.69-1.62 (m, 2 H), 1.54 (d, 1 H). LCMS (M+H⁺) m/z calculated 511.2, found 511.1. Example 86: Preparation of N-(3-carbamoyl-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)- pholine-4-carboxamide

[00305] N-(3-carbamoyl-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1] heptan-2-yl)-2-oxoethyl)-lH-indazol-5-yl)mo holine-4-carboxamide (7.7 mg) was prepared as described for l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2- yl)-2-oxoethyl)-5-ureido-lH-indazole-3-carboxamide. ¾ NMR (CD₃OD, 400 MHz) δ 8.08 (t, 1 H), 8.03 (d, 1 H), 7.72(t, 3 H), 7.49-7.51 (m, 2 H), 7.11(d, 2H) , 5.55(d, 1 H), 5.42 (d, 1 H), 4.62 (s, 1 H), 4.14 (s, 1 H), 3.72 (t,4 H), 3.52 (t,4 H), 2.80 (s, 1 H), 2.19 (d, 1 H), 1.83-1.91(m, 2 H), 1.62-1.70 (m, 2 H), 1.54 (d, 1 H). LCMS (M+H⁺) m/z calculated 581.2, found 581.2.

Example 87: Preparation of l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(4-methylpiperazine-l-carboxamido)-lH-indazole-3- carboxamide

1 -(2-((1 R,3S,4S)-3-((6→*loropyridin-2-yl)carbamoy ^

[00306] l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- oxoethyl)-5-(4-methylpiperazine-l-carboxamido)-lH-indazole-3-carboxamide (21.9 mg) was prepared as described for l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- oxoethyl)-5-ureido-lH-indazole-3-carboxamide. ¾ NMR (CD₃OD, 400 MHz) δ 8.07-8.02 (m, 2 H), 7.72(t, 3 H), 7.47-7.54 (m, 2 H), 7.10(d, 2H) , 5.54(d, 1 H), 5.42 (d, 1 H), 4.61 (s, 1 H), 4.13 (s, 1 H), 3.58 (t,4 H), 2.79 (s, 1 H), 2.50(t,4H), 2.34(s, 3 H), 2.18 (d, 1 H), 1.82-1.91(m, 2 H), 1.59-1.68 (m, 2 H), 1.53 (d, 1 H). LCMS (M+H⁺) m/z calculated 594.2, found 594.3. Example 88: Preparation of l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoet )-lH-indazole-3-carboxamide

1 -(2-((1 R,3S,4S)-3-((6-c loropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1 ]heptan-2-yl)-2-oxoethyl)-5-(3-isopropylureido)-1 H-indazole-3-carboxamide

[00307] l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- oxoethyl)-5-(3-isopropylureido)-lH-indazole-3-carboxamide (15.4 mg) was prepared as described for l-(2- ((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-ureido-lH- indazole-3-carboxamide. ¾ NMR (CD₃OD, 400 MHz) δ 8.06-8.01 (m, 2 H), 7.72(t, 3 H), 7.61-7.51 (m, 2 H), 7.10(d, 2H) , 5.53(d, 1 H), 5.40 (d, 1 H), 4.61 (s, 1 H), 4.13 (s, 1 H), 3.91-3.87 (m,lH), 2.79 (s, 1 H), 2.17 (d, 1 H), 1.89-1.85(m, 2 H), 1.69-1.62 (m, 2 H), 1.54 (d, 1 H), 1.18 (d, 6 H).LCMS (M-H⁺) m/z calculated 551.2, found 551.2.

Example 89: Preparation of l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoet o)-lH-indazole-3-carboxamide

1 -(2-((1 R,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1 ]heptan-2-yl)-2-oxoethyl)-5-(3-cyclopentylureido)-1 H-indazole-3-carboxamide

[00308] l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- oxoethyl)-5-(3-cyclopentylureido)-lH-indazole-3-carboxamide (19.6 mg) was prepared as described for l-(2- ((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-ureido-lH- indazole-3-carboxamide. ¾ NMR (CD₃OD, 400 MHz) δ 8.06-8.04 (m, 2 H), 7.72(t, 3 H), 7.60-7.52 (m, 2 H), 7.10(d, 2H) , 5.53(d, 1 H), 5.41 (d, 1 H), 4.61 (s, 1 H), 4.14 (s, 1 H), 4.05(t, lH), 2.80 (s, 1 H), 2.18 (d, 1 H), 1.98-1.92(m, 2 H), 1.90-1.85(m,2 H),1.72-1.61(m,6 H), 1.53(d,lH), 1.50-1.42 (m, 2 H). LCMS (M-H⁺) m/z calculated 577.2, found 577.2. Example 90: Preparation of l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoet )ureido)-lH-indazole-3-carboxamide

1 -(2-((1 R,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1 ]heptan-2-yl)-2-oxoethyl)-5-(3-(2-f luorophenyl)ureido)-1 H-indazole-3-carboxamide

[00309] l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- oxoethyl)-5-(3-(2-fluorophenyl)ureido)-lH-indazole-3-carboxamide (6.5 mg) was prepared as described for 1- (2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-ureido- lH-indazole-3-carboxamide. ¾NMR (CD₃OD, 400 MHz) δ 8.21-8.17 (m, 1 H),8.1 l-8.02(m, 2 H), 7.74-7.65 (m, H), 7.59-7.57(m, lH) , 7.15-7.10(m,3H), 5.56 (d, 1 H), 5.43(d,l H), 4.63(s, 1 H), 4.14(s,lH), 2.80 (s, 1 H), 2.18 (d, 1 H), 1.93-1.88(m, 2 H), 1.70-1.62 (m, 2 H), 1.54 (d, 1 H). LCMS (M+H⁺) m/z calculated 605.2, found 605.2.

Example 91: Preparation of l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl) o)-lH-indazole-3-carboxamide

1 -(2-((1 R,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1 ]heptan-2-yl)-2-oxoethyl)-5-(3-cyclopropylureido)-1 H-indazole-3-carboxamide

[00310] l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- oxoethyl)-5-(3-cyclopropylureido)-lH-indazole-3-carboxamide (10.9 mg) was prepared as described for l-(2- ((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-ureido-lH- indazole-3-carboxamide. ¾ NMR (CD₃OD, 400 MHz) δ 8.10-8.01 (m, 2 H), 7.71(t, 3 H), 7.63-7.52 (m, 2 H), 7.10(d, 2H) , 5.53(d, 1 H), 5.41 (d, 1 H), 4.61 (s, 1 H), 4.13 (s, 1 H), 2.79 (s, 1 H), 2.60-2.57 (m, l H), 2.18 (d, 1 H), 1.90-1.81(m, 2 H), 1.69-1.61 (m, 2 H), 1.53 (d, 1 H), 0.76-0.71 (m, 1 H), 0.53-0.50 (m, 2 H).LCMS (M+H⁺) m/z calculated 551.2, found 551.2. Example 92: Preparation of 5-(3-(2-aminoethyl)ureido)-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2- yl)carbamoyl)-2-azabicyclo[2.2.1]hep ndazole-3-carboxamide

5-(3-(2-aminoethyl)ureido)-1 -(2-((1 R,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1 ]heptan-2-yl)-2-oxoethyl)-1 H-indazole-3-carboxamide

[00311] 5-(3-(2-Aminoethyl)ureido)-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-lH-indazole-3-carboxamide (9.3 mg) was prepared as described for l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5- ureido-lH-indazole-3-carboxamide. ¾ NMR (CD₃OD, 400 MHz) δ 8.11 (s, 1 H), 8.02(d, lH), 7.72(t, 3 H), 7.59-7.52 (m, 2 H), 7.10(d, 2H) , 5.54(d, 1 H), 5.41 (d, 1 H), 4.62 (s, 1 H), 4.14 (s, 1 H), 2.82-2.80 (m, 3 H), 2.18 (d, 1 H), 1.90-1.83(m, 3 H), 1.69-1.62(m,3 H), 1.54(d,lH). LCMS (M+H⁺) m/z calculated 554.2, found 554.3.

Example 93: Preparation of l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(3-(tetrahydrofuran-3-yl)ureido)-lH-indazole-3- carboxamide

1-(2-((1R,3S,4S)-3-((6<hloropyridin-2-yl)cart)amoyl)-2-azabioyolo[2.2.1]heptan-2-yl)-2-oxoeth

[00312] l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- oxoethyl)-5-(3-(tetrahydrofuran-3-yl)ureido)-lH-indazole-3-carboxamide (33.2mg) was prepared as described for l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5- ureido-lH-indazole-3-carboxamide. ¾ NMR (CD₃OD, 400 MHz) δ 8.08-8.01 (m, 2 H), 7.71(t, 3 H), 7.60- 7.52 (m, 2 H), 7.10(d, 2H) , 5.53(d, 1 H), 5.40 (d, 1 H), 4.61 (s, 1 H), 4.33 (t, 1 H), 4.14(s, lH), 3.93-3.81 (m,3H), 3.65-3.62(m,lH), 2.79 (s, 1 H), 2.25-2.17 (m, 2 H), 1.89-1.82(m, 3 H), 1.68-1.61(m,2 H), 1.53(d,lH). LCMS (M-H⁺) m/z calculated 581.2, found 581.3.

Example 94: Preparation of 5-(3-(4-chlorophenyl)ureido)-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2- yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-lH-indazole-3-carboxamide

5-(3-(4-chlorophenyl)ureido)-1 -(2-((1 R,3S,4S)-3-((6^

[00313] 5-(3-(4-chlorophenyl)ureido)-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-lH-indazole-3-carboxamide (18.2 mg) was prepared as described for l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5- ureido-lH-indazole-3-carboxamide. ¾ NMR (CD₃OD, 400 MHz) δ 8.17 (s, 1 H),8.02(d, 1 H), 7.71 (t, 1H), 7.66-7.56(m, 2H) , 7.43 (d, 2H), 7.26 (d, 2H),7.10 (d,lH), 5.56 (d, 1 H), 5.43(d,l H), 4.62(s, 1 H), 4.14(s,lH), 2.80 (s, 1 H), 2.20 (d, 1 H), 1.90-1.83(m, 2 H), 1.70-1.67 (m, 2 H), 1.54 (d, 1 H). LCMS (M+H⁺) m/z calculated 621.1, found 621.2.

Example 95: Preparation of l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl lH-indazole-3-carboxamide

1 -(2-((1 R,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl^

[00314] l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- oxoethyl)-5-(3-(m-tolyl)ureido)-lH-indazole-3-carboxamide (42.4 mg) was prepared as described for l-(2- ((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-ureido-lH- indazole-3-carboxamide. ¾ NMR (CD₃OD, 400 MHz) δ 8.15 (d, 1 H),8.02(d, 1 H), 7.73-7.65 (m, 2H), 7.26- 7.09(m, 4H) , 6.84 (d, 1H), 5.55 (d, 1 H), 5.42(d,l H), 4.62(s, 1 H), 4.14(s,lH), 2.79 (s, 1 H), 2.31 (s, 3H), 2.18 (d, 1 H), 1.90-1.83(m, 2 H), 1.70-1.62 (m, 2 H), 1.54 (d, 1 H). LCMS (M+H⁺) m/z calculated 601.2, found 601.2.

Example 96: Preparation of l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl amido)-lH-indazole-3-carboxamide

1-(2-((1R,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabi^ [00315] l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- oxoethyl)-5-(piperazine-l-carboxamido)-lH-indazole-3-carboxamide (16.0 mg) was prepared as described for l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-ure lH-indazole-3-carboxamide. ¾ NMR (DMSO-d6, 400 MHz) δ 10.84 (s, 1 H), 9.17(s, 2 H), 8.86 (s, 1 H), 8.18 (s, 1H) , 7.98(d, 1 H), 7.81 (t, 1 H), 7.60-7.52 (m, 3 H), 7.30 (s, 1 H), 7.18 (d, 1 H), 5.61 (d, 1 H), 5.31(d, 1 H), 4.61(s, 1 H), 4.08(s, 1 H), 3.70(t, 4 H), 3.13(s, 4H),2.67(s, 1H), 2.06 (d, 1 H), 1.77(s, 3 H), 1.53-1.44 (m, 2 H). LCMS (M-H⁺) m/z calculated 580.2, found 580.3.

Example 97: Preparation of l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(3-(2-hydroxyethyl)ureido)-lH-indazole-3-carboxamide

1-(2-((1 ,3S,4S)-3-((6-chloropyridin-2-yl)oarbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(3-(2-hydroxyethyl)ureid

[00316] l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- oxoethyl)-5-(3-(2-hydroxyethyl)ureido)-lH-indazole-3-carboxamide (44.8 mg) was prepared as described for l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-ureido- lH-indazole-3-carboxamide. ¾ NMR (DMSO-d6, 400 MHz) δ 10.82 (s, 1 H), 8.64(s, 1 H), 8.17 (s, 1 H), 7.98 (d, 1H) , 7.81 (t, 1 H), 7.52-7.44(m, 3 H), 7.26 (s, 1 H), 7.18 (d, 1 H), 6.11(t, l H), 5.58 (d, 1 H), 5.30 (d, 1 H), 4.73 (t,l H), 4.60 (s, 1 H), 4.08(s, 1 H), 3.45(q, 2 H), 3.16(q, 2H),2.67(s, 1H), 2.05 (d, 1 H), 1.76(s, 3 H), 1.43- 1.40 (m, 2 H). LCMS (M-H⁺) m/z calculated 555.2, found 555.2.

Example 98: Preparation of l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(3-(2-methoxyethyl)ureido)-lH-indazole-3-carboxamide

1 -(2-((1 R,3 S)-3-((6-chloropyridin-2-yl)carbamoy ^

[00317] l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- oxoethyl)-5-(3-(2-methoxyethyl)ureido)-lH-indazole-3-carboxamide (60.8 mg) was prepared as described for l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-ureido- lH-indazole-3-carboxamide. ¾ NMR (DMSO-d6, 400 MHz) δ 10.83 (s, 1 H), 8.61(s, 1 H), 8.18 (s, 1 H), 7.98 (d, 1H) , 7.81 (t, 1 H), 7.52-7.42(m, 3 H), 7.27 (s, 1 H), 7.18 (d, 1 H), 6.11(t, l H), 5.58 (d, 1 H), 5.30 (d, 1 H), 4.60 (s, 1 H), 4.07(s, 1 H), 3.39(q, 2 H), 3.28-3.24(m, 5H),2.67(s, 1H), 2.06 (d, 1 H), 1.76(s, 3 H), 1.47-1.40 (m, 2 H). LCMS (M-H⁺) m/z calculated 569.2, found 569.3.

Example 99: Preparation of l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoeth -indazole-3-carboxamide

1 -(2-((1 R,3S^S)-3-((6-chloropyridin-2-yl (carbamoyl)^

[00318] l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- oxoethyl)-5-(3-(p-tolyl)ureido)-lH-indazole-3-carboxamide (42.0 mg) was prepared as described for l-(2- ((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-ureido-lH- indazole-3-carboxamide. ¾ NMR (CD₃OD, 400 MHz) δ 8.14 (d, 1 H),8.02(d, 1 H), 7.73-7.64 (m, 2H), 7.56(d, 1H) , 7.29 (d, 2 H), 7.10(d,2 H), 5.55 (d, 1 H), 5.42(d,l H), 4.62(s, 1 H), 4.14(s,lH), 2.80 (s, 1 H), 2.28 (s, 3H), 2.18 (d, 1 H), 1.89-1.82(m, 2 H), 1.71-1.62 (m, 2 H), 1.54 (d, 1 H). LCMS (M+H⁺) m/z calculated 601.2, found 601.3.

Example 100: Preparation of l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl reido)-lH-indazole-3-carboxamide

1-(2-((1R,3S,4S)-3-((6-ohloropyridin-2- l)cariDamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(3-(4-fluorophenyl)ureid

[00319] l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- oxoethyl)-5-(3-(4-fluorophenyl)ureido)-lH-indazole-3-carboxamide (41.6 mg) was prepared as described for l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-ureido- lH-indazole-3-carboxamide. ¾ NMR (CD₃OD, 400 MHz) δ 8.15 (d, 1 H),8.01 (d, 1 H), 7.71 (t, 1 H), 7.66- 7.63 (m, 1H) , 7.58-7.56 (m, l H), 7.44-7.40 (m,2H),7.11 (d, l H), 7.02(t,2H), 5.55 (d, 1 H), 5.42(d,l H), 4.62(s, 1 H), 4.14(s, lH), 2.80 (s, 1 H), 2.18 (d, 1 H), 1.92-1.80(m, 2 H), 1.72-1.60 (m, 2 H), 1.54 (d, 1 H). LCMS (M+H⁺) m/z calculated 605.2, found 605.3.

Example 101: Preparation of l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(3-(pyridin-3-yl)ureido)-lH-indazole-3-carboxamide

1-(2-((1R,3S tS)-3-((6-chloropyridin-2-yl)carbam

[00320] l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- oxoethyl)-5-(3-(pyridin-3-yl)ureido)-lH-indazole-3-carboxamide (19.0 mg) was prepared as described for 1- (2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-ureido lH-indazole-3-carboxamide. ¾NMR (CD₃OD, 400 MHz) δ 8.62 (d, 1 H),8.20-8.17 (m, 2 H), 8.03(d,2 H), 7.72 (t, 1 H), 7.68-7.65 (m, 1H) , 7.60-7.58 (m,l H), 7.38-7.35 (m, lH),7.10 (d,l H), 5.57 (d, 1 H), 5.43(d, l H), 4.63 (s, 1 H), 4.15 (s,lH), 2.81 (s, l H), 2.19 (d, 1 H), 1.93-1.84(m, 2 H), 1.73-1.62 (m, 2 H), 1.55 (d, 1 H). LCMS (M+H⁺) m/z calculated 588.2, found 588.3.

Example 102: Preparation of l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl reido)-lH-indazole-3-carboxamide

[00321] l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- oxoethyl)-5-(3-(4-cyanophenyl)ureido)-lH-indazole-3-carboxamide (29.7 mg) was prepared as described for l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-ureido- lH-indazole-3-carboxamide. ¾NMR (DMSO-d6, 400 MHz) δ 10.83 (s, 1 H), 8.74 (s, 1 H), 8.29 (s, 1H) , 7.99(d, 1 H), 7.82 (t, 1 H), 7.59-7.52 (m, 4 H), 7.31 (s, 1 H), 7.18 (d, 1 H), 5.62 (d, 1 H), 5.33(d, 1 H), 4.61(s, 1 H), 4.09(s, 1 H), 2.67(s, 2H), 2.07 (d, 1 H), 1.77(s, 5 H), 1.51-1.42 (m, 3 H). LCMS (M-H⁺) m/z calculated 612.2, found 612.3.

Example 103: Preparation of 5-(3-(3-chlorophenyl)ureido)-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2- yl)carbamoyl)-2-azabicyclo[2.2.1]hep indazole-3-carboxamide

5-(3-(3^hlorophenyl)ureido)-1 -(2-((1 R,3S,4S)-3-((6-^ [00322] 5-(3-(3-Chlorophenyl)ureido)-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-lH-indazole-3-carboxamide (11.8 mg) was prepared as described for 7-chloro-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- oxoethyl)-lH-indazole-3-carboxamide. ¾NMR (DMSO-d6, 400 MHz) δ 10.84 (s, 1 H), 8.86 (d, 2 H), 8.30 (s, IH) , 7.99(d, 1 H), 7.81(t, 1 H), 7.73 (s, 1 H),7.59-7.46 (m,4 H), 7.32-7.29(m,4 H), 7.18 (d, 1 H), 7.02-7.00 (m, 1 H), 5.62 (d, 1 H), 5.33(d, 1 H), 4.61(s, 1 H), 4.08 (s, 1 H), 2.67(s, IH), 2.07 (d, 1 H), 1.77(s, 3 H), 1.49- 1.42 (m, 2 H). LCMS (M-H⁺) m/z calculated 621.1, found 621.3.

Example 104: Preparation of 5-(4-acetylpiperazine-l-carboxamido)-l-(2-((lR,3S,4S)-3-((6- chloropyridin-2-yl)carbamoyl)-2-azabic -oxoethyl)-lH-indazole-3-carboxamide

5-(4-acet lpiperazine-1-cartoxamido)-1-(2-((1R,3S,4S)-3-^

[00323] 5-(4-acetylpiperazine-l-carboxamido)-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2- yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-lH-indazole-3-carboxamide (11.7 mg) was prepared as described for 7-chloro-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-lH-indazole-3-carboxamide. ¾NMR (DMSO-d6, 400 MHz) δ 10.84 (s, 1 H), 8.71 (s, 1 H), 7.98(d, 1 H), 7.81(t, 1 H), 7.60-7.50 (m,3 H), 7.30 (s,l H), 7.18 (d, 1 H), 5.60 (d, 1 H), 5.31(d, 1 H), 4.61(s, 1 H), 4.08 (s, 1 H), 2.67(s, IH), 2.07-2.04 (m, 4 H), 1.77(s, 3 H), 1.50-1.41 (m, 2 H). LCMS (M+H⁺) m/z calculated 622.2, found 622.3.

Example 105: Preparation of l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoeth ido)-lH-indazole-3-carboxamide

1 -(2-((1 R,3S,4S)-3-((6-chloropyridin-2-yl)carbamo

[00324] l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- oxoethyl)-5-(3-(3-cyanophenyl)ureido)-lH-indazole-3-carboxamide (6.0 mg) was prepared as described for 7- chloro-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)- lH-indazole-3-carboxamide. ¾NMR (DMSO-d6, 400 MHz) δ 10.83 (s, 1 H), 8.97 (s, 2 H), 8.30 (S, l H), 7.98(d, 2 H), 7.81(t, 1 H), 7.59-7.47 (m, 4 H), 7.41 (d, 1 H), 7.32(s, 1 H), 7.18 (d, 1 H), 5.62 (d, 1 H), 5.33(d, 1 H), 4.61(s, 1 H), 4.08 (s, 1 H), 2.67(s, IH), 2.06 (d, 1 H), 1.77(s, 3 H), 1.51-1.42 (m, 2 H). LCMS (M+H⁺) m/z calculated 612.2, found 612.3. Example 106: Preparation of l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(3-(pyridin-2-yl)ureido)-lH-indazole-3-carboxamide

1-(2-((1R,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabi(yclo[2.2.1]heptan-2-yl)-2-oxoeth

[00325] l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- oxoethyl)-5-(3-(pyridin-2-yl)ureido)-lH-indazole-3-carboxamide (8.7 mg) was prepared as described for 7- chloro-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)- lH-indazole-3-carboxamide. ¾ NMR (DMSO-d6, 400 MHz) δ 10.83 (s, 1 H), 10.57 (s, 1 H), 9.41(s,l H), 8.38 (d, 1 H), 8.30 (d,l H), 7.99 (d, 1 H), 7.84-7.73 (m,2 H), 7.62-7.50 (m,4 H), 7.34 (s, 1 H), 7.18 (d,lH), 7.01(t, lH), 5.63 (d, 1 H), 5.35(d, 1 H), 4.62(s, 1 H), 4.09 (s, 1 H), 2.68(s, 1H), 2.07 (d, 1 H), 1.78(s, 3 H), 1.49-1.42 (m, 2 H). LCMS (M+H⁺) m/z calculated 588.2, found 588.3.

Example 107: Preparation of l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(3-methylureido)-lH-indazole-3-carboxamide

1 -(2-((1 R,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl^

[00326] l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- oxoethyl)-5-(3-methylureido)-lH-indazole-3-carboxamide (43.1 mg) was prepared as described for 7-chloro- l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-lH- indazole-3-carboxamide. ¾ NMR (DMSO-d6, 400 MHz) δ 10.83 (s, 1 H), 8.58 (s, 1 H), 8.15 (s, l H), 7.98 (d, 1 H), 7.81 (t,l H), 7.52-7.49 (m, 3 H), 7.26 (s, 1 H), 7.18 (d,lH), 5.92(d, lH), 5.58 (d, 1 H), 5.29(d, 1 H), 4.60(s, 1 H), 4.07 (s, 1 H), 2.65(d, 4H), 2.06 (d, 1 H), 1.76(s, 3 H), 1.48-1.41 (m, 2 H). LCMS (M+H⁺) m/z calculated 525.2, found 525.3.

Example 108: Preparation of l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(3-(thiazol-2-yl)ureido)-lH-indazole-3-carboxamide

1-(2-((1R,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azab^

[00327] l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- oxoethyl)-5-(3-(thiazol-2-yl)ureido)-lH-indazole-3-carboxamide (18.6 mg) was prepared as described for 7- chloro-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)^ lH-indazole-3-carboxamide. ¾ NMR (DMSO-d6, 400 MHz) δ 10.83 (s, 1 H), 10.45 (s, 1 H), 9.06 (s, l H), 8.35 (s, 1 H), 7.99(d, l H), 7.81 (t,l H), 7.60 (d, 2 H), 7.48-7.35 (m, 3 H), 7.18 (d,lH), 7.12 (s, lH), 5.63(d, lH), 5.34 (d, 1 H), 4.62(s, 1 H), 4.09 (s, 1 H), 2.67(s, 1H), 2.07 (d, 1 H), 1.77(s, 3 H), 1.51-1.42 (m, 2 H). LCMS (M+H⁺) m/z calculated 594.1, found 594.2.

Example 109: Preparation of l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(3-(3-fluorophenyl)ureido)-lH-indazole-3-carboxamide

1 -(2-((1 R.SS^SJ-S-tie^hloropyridin^-yOcarbam

[00328] l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- oxoethyl)-5-(3-(3-fluorophenyl)ureido)-lH-indazole-3-carboxamide (10.4 mg) was prepared as described for 7-chloro-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)- lH-indazole-3-carboxamide. ¾ NMR (DMSO-d6, 400 MHz) δ 10.83 (s, 1 H), 9.16 (s, 1 H), 9.10 (s, l H), 8.31 (s, 1 H), 7.99(d,l H), 7.81 (t,l H), 7.58-7.45 (m, 4 H), 7.32-7.26 (m, 2 H), 7.18 (d,lH), 7.13 (d,lH), 6.76 (t, lH), 5.61(d, lH), 5.33 (d, 1 H), 4.61 (s, 1 H), 4.09 (s, 1 H), 2.67(s, 2H), 2.07 (d, 1 H), 1.77(s, 3 H), 1.49-1.41 (m, 2 H). LCMS (M+H⁺) m/z calculated 605.2, found 605.3.

Example 110: Preparation of l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl indazole-3-carboxamide

1 -(2-((1 R,3S,4S)-3-((6-chloropyridin-2-yl)carbam [00329] l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- oxoethyl)-5-(3-phenylureido)-lH-indazole-3-carboxamide (30.9 mg) was prepared as described for 7-chloro- l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-lH- indazole-3-carboxamide. ¾ NMR (CD₃OD, 400 MHz) δ 8.16 (d, 1 H),8.01 (d, 1 H), 7.73-7.65 (m, 2 H), 7.57 (d, 1H) , 7.42 (d, 2H),7.28 (t,l H), 7.10(d,l H),7.00(t,l H), 5.55 (d, 1 H), 5.42(d,l H), 4.62(s, 1 H),

4.15(s,lH), 2.80 (s, 1 H), 2.18 (d, 1 H), 1.91-1.83(m, 2 H), 1.70-1.62 (m, 2 H), 1.54 (d, 1 H). LCMS (M+H⁺) m/z calculated 587.2, found 587.3.

Example 111: Preparation of l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(3-(2-(dimethylamino)ethyl)ureido)-lH-indazole-3- carboxamide

1 -(2-((1 R,3S,4S)-3-((6^loropyridin-2-yl)ca*amoyl)^

[00330] l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- oxoethyl)-5-(3-(2-(dimethylamino)ethyl)ureido)-lH-indazole-3-carboxamide (32.9 mg) was prepared as described for 7-chloro-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2- yl)-2-oxoethyl)-lH-indazole-3-carboxamide. ¾ NMR (DMSO-d6, 400 MHz) δ 10.82 (s, 1 H), 8.67 (s, 1 H), 8.19 (s,l H), 7.98 (d, 1 H), 7.81 (t,l H), 7.51-7.42 (m, 3 H), 7.26 (s, 1 H), 7.18 (d,lH), 6.00 (t, 1 H), 5.57 (d, 1 H), 5.29(d, 1 H), 4.60(s, 1 H), 4.08 (s, 1 H),3.18 (q, 2 H), 2.67(s, 1H), 2.33(t, 2 H), 2.17 ( s, 6 H), 2.06 (d, 1 H), 1.76(s, 3 H), 1.48-1.41 (m, 2 H). LCMS (M+H⁺) m/z calculated 582.2, found 582.3.

Example 112: Preparation of l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl ido)-lH-indazole-3-carboxamide

1 -(2-((1 R,3S,4SJ-3-((6-chloropyridin-2-yl)ca*amoyl^

[00331] l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- oxoethyl)-5-(3-(pyridin-4-yl)ureido)-lH-indazole-3-carboxamide (6.2 mg) was prepared as described for 7- chloro-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)- lH-indazole-3-carboxamide. ¾ NMR (DMSO-d6, 400 MHz) δ 10.83 (s, 1 H),9.03 (d, 2 H), 8.35-8.32 (m, 2 H), 7.98 (d, 1 H), 7.81(t, l H), 7.60-7.54 (m, 2 H), 7.48-7.45( m, 3 H), 7.32 (s, 1 H), 7.18 (d, lH), 5.62 (d, 1 H), 5.33 (d, 1 H), 4.61 (s, 1 H), 4.08 (s, 1 H), 2.67(s, 1H), 2.07 (d, 1 H), 1.77(s, 3 H), 1.49-1.42 (m, 2 H). LCMS (M+H⁺) m/z calculated 588.2, found 588.3.

Example 113: Preparation of l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(3-(2-(methylamino)ethyl)ureido)-lH-indazole-3- carboxamide

1-(2-((1fi,3S,4S)-3-((6<hloropyridin-2-yl)∞rbamoyl)-2-az^

[00332] l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- oxoethyl)-5-(3-(2-(methylamino)ethyl)ureido)-lH-indazole-3-carboxamide (35.3 mg) was prepared as described for 7-chloro-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2- yl)-2-oxoethyl)-lH-indazole-3-carboxamide. ¾ NMR (DMSO-d6, 400 MHz) δ 10.83 (s, 1 H), 9.02-9.97 (m, 1 H), 8.58-8.53 (m,2 H), 8.26 (d, 1 H), 7.97 (d, 1 H), 7.81 (t, l H), 7.54-7.44 (m, 3 H), 7.26 (s, 1 H), 7.18 (d, lH), 6.51-6.44 (m, 1 H), 5.59 (d, 1 H), 5.30(d, 1 H), 4.61 (s, 1 H), 4.07 (s, 1 H),3.38 (d, 2 H), 3.00(d, 2H), 2.67(s, 1 H), 2.58 ( s, 3 H), 2.06 (d, 1 H), 1.77 (s, 3 H), 1.50-1.41 (m, 2 H). LCMS (M+H⁺) m/z calculated 568.2, found 568.4.

Example 114: Preparation of 5-(3-(lH-imidazol-2-yl)ureido)-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2- yl)carbamoyl)-2-azabicyclo[2.2.1]heptan- ndazole-3-carboxamide

5-(3-(1H-imidazol-2-yl)ureido)-1-(2-((1fi,3S,4S)-3-((6-chloro^

[00333] 5-(3-(lH-imidazol-2-yl)ureido)-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-lH-indazole-3-carboxamide (10.2 mg) was prepared as described for 7-chloro-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- oxoethyl)-lH-indazole-3-carboxamide. ¾ NMR (DMSO-d6, 400 MHz) δ 10.83 (s, 1 H), 9.77 (s, 1 H), 8.40 (s, 2 H), 7.98 (d, 1 H), 7.81 (t,l H), 7.61-7.59 (m, 2 H), 7.45(d, 1 H), 7.32 (s, l H), 7.18 (d,lH), 6.84(s,2H), 6.51-6.44 (m, 1 H), 5.63 (d, 1 H), 5.34(d, 1 H), 4.61 (s, 1 H), 4.08 (s, 1 H), 2.68(s, 3 H), 2.32 ( s, 1 H), 2.06 (d, 1 H), 1.75 (s, 3 H), 1.51-1.41 (m, 2 H). LCMS (M+H⁺) m/z calculated 577.2, found 577.4.

Example 115: Preparation of 5-(3-(lH-imidazol-5-yl)ureido)-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2- yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-lH-indazole-3-carboxamide

5-(3-(1H-imidazol-5-yl)ureido 1-(2-((1R,3S,4S)-3-((6-chloro^^

[00334] 5-(3-(lH-imidazol-5-yl)ureido)-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-lH-indazole-3-carboxamide (10.4 mg) was prepared as described for 7-chloro-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- oxoethyl)-lH-indazole-3-carboxamide. ¾ NMR (DMSO-d6, 400 MHz) δ 11.84 (s, 1 H), 10.83(s,l H), 9.77 (s, 1 H), 8.61 (s, 1 H), 8.28 (s, 1 H), 7.98(d, l H), 7.81 (t,l H), 7.56-7.54 (m, 2 H), 7.46-7.43(m, 2 H), 7.30 (s, l H), 7.18 (d,lH), 6.91(s, l H), 5.60 (d, 1 H), 5.32(d, 1 H), 4.61 (s, 1 H), 4.08 (s, 1 H), 2.67(s, 3 H), 2.32 ( s, 1 H), 2.06 (d, 1 H), 1.75 (s, 3 H), 1.49-1.41 (m, 2 H). LCMS (M+H⁺) m/z calculated 577.2, found 577.4. Example 116: Preparation of l-(2-((li?,35',45)-3-((6-bromopyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)- -(pyrimidin-5-yl)-lH-indazole-3-carboxamide

1-(2-((1R,3S,4S)-3-((6-bromopyridin-2-y1)carbamoyl)-2-azabicyclo[2.2.1]heptan-2- yl)-2-oxoethyl)-5-(pyrimidin-5-yl)-1H-indazole-3-carboxamide

[00335] A mixture of 2-aza-bicyclo[2.2. l]heptane-2,3-dicarboxylic acid 2-fert-butyl ester (2.0 g,

8.3 mmol, 1.0 eq) , 6-bromo-pyridin-2-ylamine (1.4 g, 8.3 mmol, 1.0 eq), EEDQ (4.1 g, 16.6 mmol, 2.0 eq) and DIEA (3.2 g, 24.9 mmol, 3.0 eq) in 100 mL of DCE was heated to 90 °C overnight. LCMS montired this reaction was completeand DCE was concentrated in vacuo. The resulting residue was dissolved in 100 mL of DCM, and the mixture was heated to reflux for 1 h before slowly cooled to 0 °C. The precipitate was collected by filtration to give pure 3-(6-bromo-pyridin-2-ylcarbamoyl)-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid fert-butyl ester as a yellow solid. Then 20 mL of TFA was added with stirring. After reacting at rt for 3 h, the reaction mixture was concentrated in vacuo to give 2-aza-bicyclo[2.2.1]heptane-3-carboxylic acid (6-bromo- pyridin-2-yl)-amide (2.3 g, 70%) as a yellow solid. LRMS (M+H⁺) m/z calculated 296.03, found 296.12.

[00336] To a mixture of 5-bromo-lH-indazole (50.0 g, 254.0 mmol, 1.0 eq), KOH (43.0 g, 768.0 mmol, 3.0 eq) in DMF (150 mL) was added I₂ (129 g, 507.8 mmol, 2.0 eq). The result mixture was stirred at 30 °C for 1 h. The mixture was poured into aqueous Na₂S0₃ solution and stirred for 30 min. The resulting solid was collected to give 5-bromo-3-iodo-lH-indazole (80.5 g, 98%) as an off-white solid. LRMS (M+H⁺) m/z calculated 322.9, found 322.

[00337] To a suspension of 5-bromo-3-iodo-lH-indazole (80.0 g, 247.7 mmol, 1.0 eq) and potassium carbonate (68.3 g, 495.4 mmol, 2.0 eq) in DMF (1.2 L) was added tert-butyl bromoacetate (58.0 g, 297.3 mmol, 1.2 eq) dropwise at rt. The mixture was stirred at rt for 3 h. The mixture was diluted with EA (2 L) and washed with brine (1 L x 4), dried over Na₂S0₄, filtered and concentrated to give a crude product. The resulting crude was washed with PE (1 L) to afford tert-butyl 2-(5-bromo-3-iodo-lH-indazol-l-yl)acetate (101.0 g, 94%) as an off-white solid. LRMS (M-56+H⁺) m/z calculated 380.9, found 380.7 and 382.7.

[00338] To a solution of (5-bromo-3-iodo-indazol-l-yl)-acetic acid tert-butyl ester (5.0 g, 11.5 mmol, 1.0 eq) in DMF (50 mL) was added Zn (450.0 mg, 6.9 mmol, 0.6 eq), Zn(CN)₂ (2.7 g, 23.0 1.0 eq). The reaction mixture was stirred at 120 °C overnight under nitrogen atmosphere. After cooled to rt, water (200 mL) was added and extracted with EA (200 mL x 3). The combined organic layers were washed with water (300 mL), dried over Na₂S0₄, filtered and concentrated. The resulting residue was purified by

chromatography on silica gel column (PE/EA = 5/1, v/v) to give tert-butyl 2-(5-bromo-3-cyano-lH-indazol-l- yl)acetate (1.4 g, 34.6%) as a yellow solid.

[00339] To a solution of tert-butyl 2-(5-bromo-3-cyano-lH-indazol-l-yl)acetate (1.4 g, , 4.2 mmol, 1.0 eq) in DMSO (20 mL) was added K2C03 (86.5 mg, 0.63 mmol, 0.15 eq) and 30% H202 (2.37 g, 20.9 mmol, 5.0 eq) at 0 °C. The reaction mixture was stirred at rt for 2 h. After that, water (100 mL) was added and extracted with EA (100 mL x 3). The combined organic layers were washed with water (300 mL), dried over Na2S04, filtered and concentrated to give tert-butyl 2-(5-bromo-3-carbamoyl-lH-indazol-l-yl)acetate (1.2 g, 80.0%) as a white solid. LRMS (M+H+) m/z calculated 354.0, found 354.1.

[00340] A mixture of fert-butyl 2-(5-bromo-3-carbamoyl-lH-indazol-l-yl)acetate (1.17 g, 3.3 mmol, 1.0 eq), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (1.26 g, 4.96 mmol, 1.5 eq), KOAc (0.97 g, 9.9 mmol, 3.0 eq) and Pd(dppf)Cl₂.DCM (0.27 g, 0.33 mmol, 0.1 eq) in dioxane (20 mL) was stirred at 120 °C for 4 h under nitrogen atmosphere. After cooling to rt, the reaction mixture was concentrated and the resulting residue was purified by chromatography on silica gel column (PE/EA = 1/1, v/v) to give fert-butyl 2- (3-carbamoyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-indazol-l-yl)acetate (1.2 g, 90.2%) as a yellow solid. LRMS (M+H⁺)

[00341] To a solution of fert-butyl 2-(3-carbamoyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)-lH-indazol-l-yl)acetate (250 mg, 0.62 mmol, 1.0 eq) in dioxane/H₂0 (10 mL/1 mL) were added 5- bromopyrimidine (118 mg, 0.75 mmol, 1.2 eq), K₂C0₃ (129 mg, 0.94 mmol, 1.5 eq) and Pd(PPh₃)₄ (36 mg, 0.031 mmol, 0.05 eq). The resulting mixture was stirred at 100 °C overnight under nitrogen atmosphere. After that, water (20 mL) was added and extracted with EA (20 mL x 2). The organic layer was dried over Na₂S0₄, filtered and concentrated. The resulting residue was purified chromatography on silica gel column (PE/EA = 1/2, v/v) to give fert-butyl 2-(3-carbamoyl-5-(pyrimidin-5-yl)-lH-indazol-l-yl)acetate (110 mg, 50%) as a white solid. LRMS (M+H⁺)

[00342] To a solution of fert-butyl 2-(3-carbamoyl-5-(pyrimidin-5-yl)-lH-indazol-l-yl)acetate

(110 mg, 0.31 mmol, 1.0 eq) in DCM (3 mL) was added TFA (3 mL ) at rt. The mixture was stirred at rt overnight. The resulting solution was concentrated to give TFA salt of 2-(3-carbamoyl-5-(pyrimidin-5-yl)-lH- indazol-l-yl)acetic acid (130 mg, 100%) as a yellow oil. LRMS (M+H⁺) m/z calculated 298.1, found 298.0

[00343] A mixture of ( li?,35',45)-N-(6-bromopyridin-2-yl)-2-azabicyclo[2.2. l]heptane-3- carboxamide (69.0 mg, 0.233 mmol, 1.0 eq), 2-(3-carbamoyl-5-(pyrimidin-5-yl)-lH-indazol-l-yl)acetic acid (90.0 mg, 0.303 mmol, 1.3 eq), HATU (133.0 mg, 0.350 mmol, 1.5 eq) and DIEA (120.0 mg, 0.932 mmol, 4.0 eq) in DMF (5.0 mL) was stirred at 35 °C for 2 h. DMF was concentrated in vacuo, The resulting mixture was purified by Pre-HPLC to give l-(2-((li?,35',45)-3-((6-bromopyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(pyrimidin-5-yl)-lH-indazole-3-carboxamide (34.5 mg, 26%) as a white solid. LRMS (M+H⁺) m/z calculated 575.1, found 574.9.¹H NMR (DMSO- ₆, 400 MHz) δ 10.87 (s, 1H), 9.20 (s, 1H), 9.15 (s, 2H) > 8.46 (s, 1H), 8.00-8.02 (d, 1H), 7.68-7.85 (m, 4H), 7.48 (s, 1H), 7.30-7.32 (d, 1H), 5.72-5.76 (d, 1H), 5.41-5.46 (d, 1H), 4.64 (s, 1H), 4.10 (s, 1H) > 2.68 (s, 1H), 2.08-2.10 (d, 1H), 1.78- 1.84 (t, 3H), 1.43-1.50 (m, 2H).

Example 117: Preparation of l-(2-((li?,35',45)-3-((6-bromopyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5- -methylpyrimidin-5-yl)-lH-indazole-3-carboxamide

[00344] A mixture of [3-carbamoyl-5-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-indazol-l- yl]-acetic acid fert-butyl ester (200.0 mg , 0.498 mmol, 1.0 eq), 5-bromo-2-methyl-pyrimidine (103.5 mg, 0.6 mmol, 1.52 eq), Pd(PPh₃)₄ (29.0 mg, 0.025 mmol, 0.05 eq) and K₂C0₃ (103.0 mg, 0.75 mmol, 1.5 eq) in 1,4- dioxane (10 mL) was stirred at 100 °C for 2 h. The mixture was concentrated and The resulting residue was purified by chromatography on silica gel column (PE/EA = 9/1, v/v) to give the fert-butyl 2-(3-carbamoyl-5- (2-methylpyrimidin-5-yl)-lH-indazol-l-yl)acetate (110 mg, 48%). LRMS (M+H⁺) m/z calculated 368.16, found 368.1.

[00345] To a solution of [3-carbamoyl-5-(2-methyl-pyrimidin-5-yl)-indazol-l-yl]-acetic acid tert- butyl ester (110.0 mg, 0.299 mmol, 1.0 eq) in DCM (3 mL) was added TFA (3 mL ) at rt. The mixture was stirred at 30 °C for 16 h. The solution was concentrated to give crude [3-carbamoyl-5-(2-methyl-pyrimidin-5- yl)-indazol-l-yl]-acetic acid (110.0 mg ). LRMS (M+H⁺) m/z calculated 312.1, found 312.0.

[00346] A mixture of 2-(3-carbamoyl-5-(2-methylpyrimidin-5-yl)-lH-indazol-l-yl)acetic acid

(100.0 mg, 0.25 mmol, 1.0 eq), (li?,3S,4¾-N-(6-bromopyridin-2-yl)-2-azabicyclo [2.2.1]heptane-3- carboxamide trifluoroacetate (123.0 mg, 0.29 mmol, 1.2 eq), HATU (112.0 mg, 0.29 mmol, 1.2 eq) and DIEA (95.0 mg, 0.74 mmol, 3.0 eq) in DMF (6 mL) was stirred at rt overnight. The mixture was concentrated and the resulting residue was purified by prep-HPLC to afford l-(2-((li?,35',45)-3-((6-bromopyridin-2- yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(2-methylpyrimidin-5-yl)-lH-indazole-3- carboxamide (72.0 mg, 50%) as a white solid. LRMS (M+H⁺) m/z calculated 589.1, found 588.9. ¾NMR (DIVISOR, 400 MHz) δ 10.88 (s, IH), 9.03 (s, 2H), 8.42 (s, IH), 8.0-8.02 (d, IH), 7.83 (s, 2H), 7.68-7.80 (m, 2H), 7.48 (s, IH), 7.30-7.33 (d, IH), 5.71-5.76 (d, IH), 5.40-5.45 (d, IH), 4.64 (s, IH), 4.09 (s, IH), 2.68 (s, 4H), 2.07-2.09 (d, IH), 1.78-1.83 (m, 3H), 1.43-1.49 (m, 2H).

Example 118: Preparation of l-(2-((lR,3S,4S)-3-((6-bromopyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(2-methoxypyrimidin-5-yl)-lH-indazole-3-carboxamide

1-(2-((1R,3S,4S)-3-((6-bramopyridin-2-yl (carbamoyl )-2-azabicyclo[2.2.1]heptan-2-yl)

-2-oxoethyl)-5-(2-methoxypyrimidin-5-yl)-1H-indazole-3-carb«)xamide

[00347] To a solution of fert-butyl 2-(3-carbamoyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)-lH-indazol-l-yl)acetate (300 mg, 0.75 mmol, 1.0 eq) in dioxane/H₂0 (15 ml/lml) were added 5-bromo-2- methoxypyrimidine (168 mg, 0.9 mmol, 1.2 eq), K₂C0₃ (155 mg, 1.12 mmol, 1.5 eq) and Pd(PPh₃)₄ (43.2mg, 0.037 mmol, 0.05 eq). The mixture was stirred at 100 °C overnight under nitrogen atmosphere. After that, water (20 mL) was added and extracted with EA (20 mL x 2). The combined organic layers were dried over Na₂S0₄, filtered and concentrated. The resulting residue was purified by chromatography on silica gel column (PE/EA = 1/2, v/v) to give fert-butyl 2-(3-carbamoyl-5-(2-methoxypyrimidin-5-yl)-lH-indazol-l-yl)acetate (200 mg, 60%) as a yellow solid. LRMS (M+H⁺) m/z calculated 384.2, found 384.1.

[00348] To a solution of fert-butyl 2-(3-carbamoyl-5-(2-methoxypyrimidin-5-yl)-lH-indazol-l- yl)acetate (180 mg, 0.47 mmol, 1.0 eq) in DCM (3 mL) was added TFA (3 mL ) at rt. The mixture was stirred at rt overnight. Then the resulting solution was concentrated to give crude TFA salt of 2-(3-carbamoyl-5-(2- methoxypyrimidin-5-yl)-lH-indazol-l-yl)acetic acid (210 mg, 100%). LRMS (M+H⁺) m/z calculated 328.1, found 328.0

[00349] A mixture of 2-aza-bicyclo[2.2. l]heptane-3-carboxylic acid (6-bromo-pyridin-2-yl)- amide (100.0 mg, 0 25 mmol, 1.0 eq) , [3-carbamoyl-5-(2-methoxy-pyrimidin-5-yl)-indazol-l-yl]-acetic acid (119 mg, 0.28 mmol, 1.1 eq), HATU (106.0 mg, 0.28 mmol, 1.1 eq) and DIEA (161. Omg, 1.25 mmol, 5.0 eq) in 10 mL of DMF was stirred at rt for 5 h. The reaction mixture was quenched with aqueous NH₄C1, extracted with EA. The organic layer was concentrated and the resulting residue was purified by prep-HPLC to give 1 - (2-((lR,3S,4S)-3-((6-bromopyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(2- methoxypyrimidin-5-yl)-lH-indazole-3-carboxamide (28.5 mg, 19%) as a white solid. LRMS (M+H⁺) m/z calculated 605.1, fownd 604.9. ¾ NMR (DMSO- ₆, 400 MHz) δ 10.87 (s, 1H), 8.93 (s, lH), 8.37 (s, 1H) > 8.01 (d, 1H), 7.82-7.68 (m, 4H), 7.46 (s, lH), 7.31 (d, 1H), 5.72 (d, 1H), 5.42 (d, 1H), 4.64 (s, lH), 4.10 (s, 1H), 3.98 (s, 3H), 2.68 (s, 1H), 2.08 (d, 1H), 1.43-1.50 (m, 2H), 1.79 (s, 3H), 1.49-1.43 (m, 2H)

Example 119: Preparation of l-(2-((lR,3S,4S)-3-((6-bromopyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)- -(2-cyanopyrimidin-5-yl)-lH-indazole-3-carboxamide

l^-iflR.SS^SJ-S-ite-bromopyridin^-ylJcarbamoyl^-azabioyclop^.llheptan^-yl)

-2 >xoethyl)-5-(2-cyanopyrimidin-5-yl)-1H-indazole-3-carboxamide

[00350] A mixture of fert-butyl 2-(3-carbamoyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)- lH-indazol-l-yl)acetate (250 mg , 0.623 mmol, 1.0 eq), 5-bromopyrimidine-2-carbonitrile (138 mg, 0.748 mmol, 1.2eq), Pd(PPh₃)₄ (36 mg, 0.031 mmol, 0.05 eq) and K₂C0₃ (129 mg, 0.935 mmol, 1.5 eq) in 1,4- dioxane (15 mL) was stirred at 100 °C for 2 h. The mixture was concentrated and the resulting residue was purified by chromatography on silica gel column (PE/EA = 9/1, v/v) to give the fert-butyl 2-(3-carbamoyl-5- (2-cyanopyrimidin-5-yl)-l -indazol-l-yl)acetate (160 mg, 68%).

[00351] To a solution of fert-butyl 2-(3 -carbamoyl -5 -(2-cyanopyrimidin-5-yl)-lH-indazol-l- yl)acetate (160 mg, 0.423 mmol, 1.0 eq) in DCM (6 mL) was added TFA (2 mL ) at rt. The mixture was stirred at 30 °C for 16 h. The reaction mixture was concentrated to give crude 2-(3-carbamoyl-5-(2- cyanopyrimidin-5-yl)-lH-indazol-l-yl)acetic acid (170 mg ), which was used in the next step without further purification.

[00352] A mixture of 2-aza-bicyclo[2.2. l]heptane-3-carboxylic acid (6-bromo-pyridin-2-yl)- amide (70.0 mg, 0.24 mmol, 1.0 eq) , [3-carbamoyl-5-(2-cyano-pyrimidin-5-yl)-indazol-l-yl]-acetic acid (84 mg, 0.26 mmol, 1.1 eq), HATU (99.0 mg, 0.26 mmol, 1.1 eq) and DIEA (93.0 mg, 0.72 mmol, 3 eq) in 10 mL of DMF was stirred at rt for 4 h.The reaction was monitored by LCMS. After completion, DMF was concentrated in vacuo, and the resulting residue was purified by prep-HPLC to give l-(2-((li?,3S,4S)-3-((6- bromopyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(2-cyanopyrimidin-5-yl)-lH- indazole-3-carboxamide (21.0 mg, 16%) as a white solid. LRMS (M+H⁺) m/z calculated 600.10, found 602.1. 'HNMR (DMSO-£¾, 400 MHz) δ 10.87 (s, 1H), 9.40 (s, 2H), 8.59 (s, 1H), 8.01 (d, 1Η),7.96-7.94 (m, 2H), 7.90 (s, 1H), 7.79 (t, 1H), 7.52 (s, 1H), 7.31 (d, 1H), 5.60 (dd, 2H), 4.64 (s, 1H), 4.09 (s, 1H), 2.68 (s, 1H), 2.09 (d, 1H), 1.78-1.84 (t, 3H), 1.43-1.50 (m, 2H).

Example 120: Preparation of methyl (l-(2-((lR,3S,4S)-3-((6-bromopyridin-2-yl)carbamoyl)-2- azabicyclo [2.2.1 ]heptan-2-yl)-2-oxoethyl)-3 -carbamoyl- lH-indazol-5 -yl)carbamate

methyl (l^-ftlR.SS^SJ-S-tte-bromopyridin^-ylJcarbamoyl^-azabic olop^.llheptan^-yl)-

[00353] To a solution of fert-butyl 2-(5-bromo-3-cyano-lH-indazol-l-yl)acetate ( 18.0 g, 53.6 mmol, 1.0 eq) in dioxane ( 150 mL) were added Pd₂(dba)₃ (4.9 g, 5.4 mmol, 0.1 eq), Xantphos (3.1 g, 5.4 mmol, 0.1 eq) and Cs₂C0₃ (35.0 g, 107.2 mmol , 2.0 eq) carefully. The result mixture was stirred at 80 °C for 2 h under N₂ protected. The reaction mixture was concentrated, and the resulting residue was purified by chromatography on silica gel column (EA/PE = 1/5, v/v) to afford fert-butyl 2-(5 -((tert- butoxycarbonyl)amino)-3-cyano-lH-indazol-l -yl)acetate ( 15.3 g, 77%) as a yellow solid. LRMS (M+H⁺) m/z calculated 373.2, found 373.1.

[00354] To a solution of fert-butyl 2-(5-((teri-butoxycarbonyl)amino)-3-cyano-lH-indazol-l- yl)acetate (1 1.3 g, 30.4 mmol, 1.0 eq) in DMSO (100 mL) at 0 °C was added a solution of K₂C0₃ (635 mg, 4.6 mmol, 0.15 eq) in H₂0₂ (17.2 g, 152.0 mmol, 5.0 eq). The reaction mixture was stirred at rt for 2 h, then quenched with water (300 mL), extracted with EA ( 150 mL x 2 ). The organic layer was concentrated, and the resulting residue was purified by prep-HPLC to give fert-butyl 2-(5-((fert-butoxycarbonyl)amino)-3- carbamoyl-lH-indazol-l-yl)acetate (1 1.5 g, 97%) as a white solid. LRMS (M+H⁺) m/z calculated 391.2, found 391.0.

[00355] To a solution of fert-butyl 2-(5-((teri-butoxycarbonyl)amino)-3-carbamoyl-lH-indazol-l - yl)acetate (1 1.5 g, 29.5 mmol, 1.0 eq) in THF (60 mL) at rt was added a solution of NaOH (2.4 g, 59.0 mmol, 2.0 eq) in H₂0 (15 mL). The result mixture was stirred at rt overnight. The reaction mixture was purified by prep-HPLC to give the target compound (9.1 g, 92%) as a white solid. LRMS (M+H⁺) m/z calculated 335.1, found 335.0.

[00356] To a mixture of ( li?,35',45)-N-(6-bromopyridin-2-yl)-2-azabicyclo[2.2. l]heptane-3- carboxamide (1.07 g, 3.60 mmol, 1.0 eq), 2-(5-((tert-butoxycarbonyl)amino)-3-carbamoyl-lH-indazol-l- yl)acetic acid (1.20 g, 3.59 mmol, 1.0 eq) in DMF (10 mL) were added HATU (1.36 g, 3.59 mmol, 1.2 eq) and DIEA (581 mg, 4.50 mmol, 1.5 eq) at 0 °C. The reaction mixture was stirred at rt for 3 h. DMF was removed in vacuo, the resulting residue was purified by prep-HPLC to give fert-butyl (l-(2-((lR,3S,4S)-3-((6- bromopyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-3-carbamoyl-lH-indazol-5- yl)carbamate (2.3 g, 91%) as a pale yellow solid. LRMS (M+H⁺) m/z calculated 612.2, found 611.9 and 613.9

[00357] To a cooled solution of fert-butyl (l-(2-((lR,3S,4S)-3-((6-bromopyridin-2- yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-3-carbamoyl-lH-indazol-5-yl)carbamate (2.28 g, 3.72 mmol) in DCM (10 mL) was addeded TFA (5 mL). The mixture was stirred at rt for 2 h. The reaction mixture was neutralized with ammonia and extracted with DCM (70 mL x 4). The combined organic layers were dried over anhydrous Na₂S0₄ and concentrated. The resulting residue was purified by chromatography on silica gel column (PE/EA = 20/1, v/v) to give 5-amino-l-(2-((lR,3S,4S)-3-((6-bromopyridin-2- yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-lH-indazole-3-carboxamide (1.43 g, 75%) as a pale yellow solid. LRMS (M+ ⁺) m/z calculated 512.1, found 511.9 and 513.9.

[00358] To a cooled solution of 5-amino-l-(2-((lR,3S,4S)-3-((6-bromopyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-lH-indazole-3-carboxamide (280 mg, 0.547 mmol, 1.0 eq) and DIEA (143 mg, 1.09 mmol, 2.0 eq) in NMP (1.5 mL) was added dropwise methyl carbonochloridate (77 mg, 0.82 mmol, 1.5 eq). The resulting mixture was stirred at 0°C for 30 min. The mixture was purified by prep- HPLC to give methyl (l-(2-((lR,3S,4S)-3-((6-bromopyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2- yl)-2-oxoethyl)-3-carbamoyl-lH-indazol-5-yl)carbamate (242.2 mg, 77%) as a white solid. LRMS (M+H⁺) m/z calculated 560.2, found 559.9. ¾ NMR (DMSO- ₆, 400 MHz) δ 11.26 (s, 0.15H), 10.85 (s, 0.85H), 9.64 (s, 1H), 8.29 (s, 1H), 8.14 (d, 0.15H), 8.01 (d, 0.85H), 7.79 (t, 0.15H), 7.70 (t, 0.85H), 7.62-7.42 (m, 3H), 7.38 (d, 0.15H),7.35-7.24 (m, 1.85H), 5.60 (d, 0.85H), 5.31 (d, 0.85H), 5.27 (d, 0.15H), 4.83 (d, 0.15H), 4.60 (s, 0.85H), 4.48 (s, 0.15H), 4.45 (s, 0.15H), 4.08 (s, 0.85H), 3.67 (s, 3H), 2.91 (d, 0.15H), 2.67 (s, 0.85H), 2.06 (d, 0.85H), 1.84-1.36 (m, 5.15 H).

Example 121: Preparation of l-(2-((lR,3S,4S)-3-((6-bromopyridin-2-yl)carbamoyl)-2-

[00359] To a mixture of 5-amino-l-(2-((lR,3S,4S)-3-((6-bromopyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-lH-indazole-3-carboxamide (380 mg, 0.742mmol, 1.0 eq), nicotinic acid (100 mg, 0.816 mmol, 1.1 eq) in NMP (2.5 mL) were added HATU (338 mg, 0.890 mmol, 1.2 eq) and DIEA (143 mg, 1.1 1 mmol, 1.5 eq) at 0 °C. The reaction mixture was stirred at rt for 3 h. The resulting residue was purified by prep-HPLC to give l-(2-((lR,3S,4S)-3-((6-bromopyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(nicotinamido)-lH-indazole-3-carboxamide (225.5 mg, 49%) as a white solid. LRMS (M+H⁺) m/z calculated 617.1, found 616.9 and 618.9. ¾ NMR (DMSO- ₆, 400 MHz) δ 11.30 (s, 0.15H), 10.90 (s, 0.85H), 10.56 (s, 1H), 9.16 (d, 1H), 8.77 (d, 1H), 8.60 (s, 1H), 8.35 (d, 1H), 8.16 (d, 0.15H), 8.02 (d, 0.85H), 7.89-7.54 (m, 5H), 7.39 (s, 1H), 7.54 (d, 1H) 5.66 (d, 0.85H), 5.37 (d, 0.85H), 5.33 (d, 0.15H), 4.87 (d, 0.15H), 4.63 (s, 0.85H), 4.50 (s, 0.15H), 4.46 (s, 0.15H), 4.09 (s, 0.85H), 2.93 (d, 0.15H), 2.68 (s, 0.85H), 2.07 (d, 0.85H), 1.89-1.27 (m, 5.15H).

Example 122: Preparation of l-(2-((lR,3S,4S)-3-((6-bromopyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)- -(2-chlorobenzamido)-lH-indazole-3-carboxamide

1 -(2-((1 R,3S,4S)-3-((6-bromopyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1 ]heptan-2-yl)

-2-oxoethyl)-5-(2-chlorobenzamido)-1H-indazole-3-carboxamide

[00360] To a mixture of 5-amino-l-(2-((li?,35',45)-3-((6-bromopyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-lH-indazole-3-carboxamide (430 mg, 0.84 mmol, 1.0 eq) and 2- chlorobenzoic acid (145 mg, 0.924 mmol, 1.1 eq) in NMP (2.5 mL) were added HATU (383 mg, 1.01 mmol, 1.2 eq) and DIEA (162 mg, 1.26 mmol, 1.5 eq) at 0 °C. The reaction mixture was stirred at rt for 3 h.Water (10 mL) was added, and the precipitate was collected by filtration. The filter cake was purified by prep-HPLC to give l-(2-((lR,3S,4S)-3-((6-bromopyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(2- chlorobenzamido)-lH-indazole-3-carboxamide (280 mg, 51%) as a white solid. LRMS (M+H⁺) m/z calculated 650.1, found 650.1 and 652.0. ¾ NMR (DMSO- ₆, 400 MHz) δ 11.30 (s, 0.15H), 10.89 (s, 0.85H), 10.58 (s, 1H), 8.64 (s, 1.0H), 8.15 (d, 0.15H), 8.02 (d, 0.85H), 7.80 (t, 0.15H), 7.74-7.55 (m, 5.85H), 7.54- 7.42 (m, 2H), 7.39 (d, 0.15H), 5.65 (d, 0.85H), 5.36 (d, 0.85H), 5.32 (d, 0.15H), 4.86 (d, 0.15H), 4.62 (s, 0.85H), 4.50 (s, 0.15H), 4.46 (s, 0.15H), 4.09 (s, 0.85H), 2.92 (d, 0.15H), 2.68 (s, 0.85H), 2.06 (d, 0.85H), 1.85-1.27 (m, 515H).

Example 123: Preparation of l-(2-((lR,3S,4S)-3-((6-bromopyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5- -methylureido)-lH-indazole-3-carboxamide

1-(2-((1R,3S,4S)^-((6-bromopyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heplan-2-yl)

-2-oxoethyl)-5-(3-methylureido)-1H-indazole-3-carboxamide

[00361] To a cooled solution of CDI (3.26 g, 20.0 mmol) in THF (30 mL) was added dropwise a solution of methanamine (2.0 M in THF, 10 mL) at 0 °C. The resulting mixture was stirred at rt for 2 h to give a solution of N-methyl-lH-imidazole-l-carboxamide in THF (0.5 M). A mixture of 5-amino-l-(2- ((lR,3S,4S)-3-((6-bromopyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-lH-indazole-3- carboxamide (922 mg, 1.80 mmol, 1.0 eq), N-methyl-lH-imidazole-l-carboxamide (0.5 M in THF, 18 mL, 9 mmol, 5.0 eq), DIEA (464 mg, 3.60 mmol, 2.0 eq) in NMP (7 mL) was stirred at 90 °C for 24 h. Water (10 mL) was added, and the resulting precipitate was collected. The resulting residue was purified by prep-HPLC to give l-(2-((lR,3S,4S)-3-((6-bromopyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5- (3 -methylureido)-lH-indazole -3 -carboxamide (211.9 mg, 21%) as a white solid. LRMS (M+H⁺) m/z calculated 569.1, found 568.8 and 570.8. ¾ NMR (DMSO- ₆, 400 MHz) δ 11.30 (s, 0.15H), 10.89 (s, 0.85H), 8.61 (s, 1H), 8.16 (m, 1.15H), 8.01 (d, 0.85H), 7.83-7.21 (m, 6H), 5.94 (s, 1H), 5.59 (d, 0.85H), 5.30 (d, 0.85H), 5.26 (d, 0.15H), 4.80 (d, 0.15H), 4.60 (s, 0.85H), 4.50 (s, 0.15H), 4.45 (s, 0.15H), 4.07 (s, 0.85H), 2.91 (d, 0.15H), 2.65 (s, 3.85H), 2.06 (d, 0.85H), 1.83-1.17 (m, 5.15H).

Example 124: Preparation of l-(2-((li?,35',45)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(2-methylpyrimidin-5-yl)-lH-indazole-3-carboxamide

[00362] To a cooled mixture of 6-chloropyridin-2-amine (5.33 g, 41.5 mmol, 1.0 eq), (1R,3S,4S)-

2-(teri-butoxycarbonyl)-2-azabicyclo[2.2.1]heptane-3-carboxylic acid (10 g, 41.5 mmol, 1.0 eq) in pyridine (20 mL) was added POCl₃ (6.36 g, 41.5 mmol, 1.0 eq) slowly. The reaction mixture was stirred at rt for 2 h. The reaction mixture was poured into a cooled aqueous solution of HQ (2.0 M, 150 mL). The resulting precipitate was collected to give (lR,3S,4S)-fert-butyl 3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptane-2-carboxylate (10. lg, 68%) as an off-white solid. LRMS (M+H⁺) m/z calculated 352.1, found 352.0.

[00363] To a cooled slurry of (lR,3S,4S)-tert-butyl 3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptane-2-carboxylate (10.1 g, 28.7mmol) in DCM (50 mL) was added TFA (25 mL). The reaction mixture was stirred at rt for 4 h. The reaction mixture was neutralized with ammonia and extracted with DCM (80 mL x 3). The combined organic layers were dried over anhydrous Na₂S0₄ and concentrated to give (lR,3S,4S)-N-(6-chloropyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3-carboxamide (7.10 g, 98%) as an off- white solid. LRMS (M+H⁺

[00364] A mixture of 2-aza-bicyclo[2.2. l]heptane-3-carboxylic acid (6-chloro-pyridin-2-yl)-amide

(58 mg, 0.231 mmol, 1.0 eq), [3-carbamoyl-5-(2-methyl-pyrimidin-5-yl)-indazol-l -yl]-acetic acid (93 mg, 0.3 mmol, 1.3 eq), HATU (132 mg, 0.347 mmol, 1.5 eq) and DIEA ( 120 mg, 0.924 mmol, 4.0 eq) in DMF (4 mL) was stirred at 30 °C for 3 h. The resulting mixture was purified by prep-HPLC to give \-(2-((\R,3S,4S)-3-((6- chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(2-methylpyrimidin-5-yl)-lH- indazole-3-carboxamide (58 mg, 46%) as a white solid. LRMS (M+H⁺) m/z calculated 545.2, found 545.2. ¾ NMR (DIVISOR, 400 MHz) δ 10.88 (s, 1H), 9.03 (s, 2H), 8.42 (s, 1H), 7.98-8.00 (m, 1H), 7.78-7.84 (m, 4H), 7.50 (m, 1H), 7.18-7.20 (t, 1H), 5.72-5.76 (d, 1H), 5.41-5.45 (d, 1H), 4.65 (s, 1H), 4.09 (s, 1H), 2.68 (s, 4H).2.07-2.09 (m, 1H), 1.78-1.81 (t, 3H), 1.43-1.49 (t, 2H).

Example 125: Preparation of l-(2-((li?,35',45)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)- -(2-cyanopyrimidin-5-yl)-lH-indazole-3-carboxamide

1-(2-((1R,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyolo[2.2.1]heptan-2-yl)-2- 1H-indazole-3-carboxamide

[00365] A mixture of 2-aza-bicyclo[2.2. l]heptane-3-carboxylic acid (6-chloro-pyridin-2-yl)-amide

(41 mg, 0.163 mmol, 1.0 eq), 2-(3-carbamoyl-5-(2-cyanopyrimidin-5-yl)-lH-indazol-l -yl)acetic acid (68 mg, 0.212 mmol, 1.3 eq), HATU (93 mg, 0.245 mmol, 1.5 eq) and DIEA (84 mg, 0.652 mmol, 4.0 eq) in DMF (4 mL) was stirred at 30 °C for 3 h. The resulting mixture was purified by prep-HPLC to give \-(2-(( \R,3S,4S)-3- ((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(2-cyanopyrimidin-5-yl)- lH-indazole-3-carboxamide (23.4 mg, 26%) as a white solid. LRMS (Μ+Η ) m/z calculated 556.2, found SSe.O/H NMR DMSO-de, 400 MHz) δ 10.89 (s, IH), 9.41 (s, 2H), 8.59 (s, IH), 7.79-7.98 (m, 5H), 7.54 (s, IH), 7.18-7.20 (d, IH), 5.75-5.79 (d, IH), 5.43-5.47 (d, IH), 4.65 (s, IH), 4.09 (s, IH), 2.68 (s, IH), 2.07-2.09 (d, IH), 1.80-1.82 (t, 3H), 1.43-1.46 (t, 2H).

Example 126: Preparation of l-(2-((li?,35',45)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)- -(2-methoxypyrimidin-5-yl)-lH-indazole-3-carboxamide

1 -(2-((1 R,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1 ]heptan-

[00366] A mixture of (l i^.S^^-N-ie-chloropyridin^-y ^-azabicycloP^. l]heptane-3- carboxamide (59 mg, 0.236 mmol, 1.0 eq), 2-(3-carbamoyl-5-(2-methoxypyrimidin-5-yl)-lH-indazol-l- yl)acetic acid (100 mg, 0.306 mmol, 1.3 eq), HATU (135 mg, 0.354 mmol, 1.5 eq) and DIEA (122 mg, 0.944 mmol, 4.0 eq) in DMF (5 mL) was stirred at 35 °C for 2 h. The resulting mixture was purified by prep-HPLC to give l-(2-((li?,35',45)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5- (2-methoxypyrimidin-5-yl)-lH-indazole-3-carboxamide (21 mg, 16%) as a white solid. LRMS (M+H⁺) m/z calculated 561.2, found 561.2. ¾NMR (DMSO- ₆, 400 MHz) δ 10.86 (s, IH), 8.93 (s, 2H), 8.37 (s, IH), 7.98-8.00 (d, IH), 7.74-7.83 (m, 4H), 7.46 (s, IH), 7.17-7.19 (d, IH), 5.70-5.75 (d, IH), 5.40-5.44 (d, IH), 4.64 (s, IH), 3.98 (s, 3H), 2.68 (s, IH), 2.08-2.10 (d, IH), 1.80 (s, 3H), 1.43-1.49 (m, 2H).

Example 127: Preparation of l-(2-((li?,35',45)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5- azole-3-carboxamide

1-(2-((1 ,3S,4S 3-((6-chloropyridin-2-yl)rarbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)- 2-oxoethyl)-5-(pyrimidin-5-yl)-1H-indazole-3-carboxamide

[00367] A mixture of (l i^^^-N-ie-chloropyridin^-y ^-azabicycloP^- llheptane-S- carboxamide (59 mg, 0.233 mmol, 1.0 eq), 2-(3-carbamoyl-5-(pyrimidin-5-yl)-lH-indazol-l-yl)acetic acid (90 mg, 0.303 mmol, 1.3 eq), HATU (133 mg, 0.350 mmol, 1.5 eq) and DIEA (120 mg, 0.932 mmol, 4.0 eq) in DMF (5 mL) was stirred at 35 °C for 2 h. The resulting mixture was purified by prep-HPLC to give l-(2- ((li?,3^,4¾-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(pyrimidin-5- yl)-lH-indazole-3-carboxamide (61.6 mg, 50%) as a white solid. LRMS (M+H⁺) m/z calculated 531.2, found 530.9. 'H NMR (DMSO-£¾, 400 MHz) δ 10.85 (s, IH), 9.20 (s, IH), 9.15 (s, 2H) > 8.46 (s, IH), 7.98-8.00 (d, IH), 7.76-7.85 (m, 4H), 7.48 (s, IH), 7.17-7.19 (d, IH), 5.72-5.76 (d, IH), 5.41-5.46 (d, IH), 4.65 (s, IH), 4.10 (s, IH), 2.69 (s, IH), 2.08-2.10 (d, IH), 1.78-1.84 (t, 3H), 1.43-1.50 (m, 2H).

Example 128: Preparation of 1 l-(2-((li?,35',45)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo [2.2.1 ]heptan-2-yl)-2-oxoethyl) -5 -(piperidin- 1 -yl) - lH-indazole -3 -carboxamide

1-(2-((1 3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)- 2-oxoethyl)-5-(piperidin-1 -yl)-1 H-indazole-3-carboxamide

[00368] To a solution of fert-butyl 2-(3-carbamoyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)-lH-indazol-l-yl)acetate (300 mg, 0.75 mmol, 1.0 eq) in MeCN (40 mL) was added piperidine (180 mg, 2.2 mol, 3.0 eq), Cu(OAc)₂ (135 mg, 0.75 mmol, 1.0 eq) and TEA (151 mg, 1.5 mmol, 2.0 eq). The reaction mixture was stirred at 40 °C overnight. The mixture was allowed to cool to ambient temperature, treated with brine (20 mL) and extracted with EA (30 mL x 3). The organic layer was dried over Na₂S0₄, filtered and concentrated. The resulting residue was purified by chromatography on silica gel column (EA/PE = 1/1, v/v) to afford fert-butyl 2-(3-carbamoyl-5-(piperidin-l-yl)-lH-indazol-l-yl)acetate (80 mg, 31%) as a yellow oil.

[00369] To a solution of fert-butyl 2-(3-carbamoyl-5-(piperidin-l-yl)-lH-indazol-l-yl)acetate (80 mg, 0.22 mmol, 1.0 eq) in DCM (10 ml) was added TFA (3 mL). The reaction mixture was stirred at rt overnight. The mixture was concentrated to afford the TFA salt of 2-(3-carbamoyl-5-(piperidin-l-yl)-lH- indazol-l-yl)acetic acid (100 mg, 100%) as a brown solid.

[00370] To a solution of the TFA salt of 2-(3-carbamoyl-5-(piperidin-l-yl)-lH-indazol-l-yl)acetic acid (100 mg, 0.22 mmol, 1.0 eq) in DMF (10 mL) were added HATU (100 mg, 0.26 mol, 1.2 eq), DIEA (85 mg, 0.66 mmol, 3.0 eq) and the TFA salt of (lR,3S,4S)-N-(6-chloropyridin-2-yl)-2-azabicyclo[2.2.1]heptane- 3-carboxamide (120 mg, 0.33 mmol, 1.5 eq).The reaction mixture was stirred at rt overnight. The mixture was treated with brine (20 mL) and extracted with EA (30 mL x 3). The organic layer was dried over Na₂S0₄, filtered and concentrated. The resulting residue was purified by prep-HPLC to afford 1 \-(2-((\R,3S,4S)-3-((6- chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(piperidin-l-yl)-lH-indazole-3- carboxamide (20 mg, 17%) as a white solid. LRMS (M+H⁺) m/z calculated 535.2, found 536.2. ^l NMR (DMSO- ;, 400 MHz) δ 11.22 (s, 0.1H), 10.83 (s, 0.8H), 7.97-8.09 (m, IH), 7.79-7.89 (m, IH), 7.43-7.50 (m, 3H), 7.23-7.25 (m, 2H), 7.17-7.19 (m, IH), 5.57 (d, IH), 5.28 (d, IH), 4.59 (s, IH), 4.02-4.07 (m, IH), 3.05- 3.07 (m, 4H), 2.50 (s, IH), 2.06 (d, IH), 1.98 (s, IH), 1.67-1.75 (m, 2H), 1.53-1.61 (m, 4H), 1.40-1.47 (m, 2H), 1.23-1.29 (m, IH), 1.15-1.19 (m, IH).

Example 129: Preparation of l-(2-((li?,35',45)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo [2.2.1 ]heptan-2-yl)-2-oxoethyl)-5 -morpholino- lH-indazole-3 -carboxamide

1-(2-((1 3S^S)-3-((e-chloropyridin-2-yl)caitamoyl)-2-azabic clo[2.2.1]he

2-oxoethyl

[00371] To a solution of fert-butyl 2-(3-carbamoyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)-lH-indazol-l-yl)acetate (400 mg,1.0 mmol, 1.0 eq) in MeCN (40 ml) was added morpholine (261 mg, 3.0 mol, 3.0 eq), Cu(OAc)₂ (181 mg, 1.0 mmol, 1.0 eq) and TEA (202 mg, 2.0 mmol, 2.0 eq). The reaction mixture was stirred at rt overnight. The mixture was treated with brine (20 mL) and extracted with EA (30 mL x 3). The organic layer was dried over Na₂S0₄, filtered and concentrated. The resulting residue was purified by chromatography on silica gel column (EA/PE = 1/1, v/v) to afford fert-butyl 2-(3-carbamoyl-5- moφholino-lH-indazol-

[00372] To a solution of fert-butyl 2-(3-carbamoyl-5-morpholino-lH-indazol-l-yl)acetate (50 mg,

0.13 mmol, 1.0 eq) in DCM (10 ml) was added TFA (3 mL) The reaction mixture was stirred at rt overnight. The mixture was concentrated to afford the TFA salt of 2-(3-carbamoyl-5-morpholino-lH-indazol-l-yl)acetic acid (60 mg, 100%) as a brown solid.

[00373] To a solution of the TFA salt of 2-(3-carbamoyl-5-morpholino-lH-indazol-l-yl)acetic acid (60 mg, 0.13 mmol, 1.0 eq) in DMF (10 ml) was added HATU (59 mg, 0.15 mol, 1.2 eq), DIEA (50 mg, 0.39mmol, 3.0 eq) and the TFA salt of (li?,35',45)-N-(6-chloropyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3- carboxamide (71 mg, 0.19mmol, 1.5 eq). The reaction mixture was stirred at rt overnight. Then the mixture was treated with brine (20 mL) and extracted with EA (30 mL x 3). The organic layer was dried over Na₂S0₄, filtered and concentrated. The resulting residue was purified by prep-HPLC to afford \-(2-((\R,3S,4S)-3-((6- chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-moφholino-lH-indazole-3- carboxamide (10 mg, 14%) as a white solid. LRMS (M+H⁺) m/z calculated 537.2, found 538.2. ^l NMR DMSO-d₆, 400 MHz) δ 11.22 (s, 0.1H), 10.83 (s, 0.8H), 7.97-8.11 (m, 1H), 7.79-7.91 (m, 1H), 7.46-7.55 (m, 3H), 7.24-7.30 (m, 2H), 7.18 (s, 1H), 5.58 (d, 1H), 5.23-5.32 (m, 1H), 4.59 (s, 1H), 4.45 (s, 1H), 4.07 (s, 4H), 3.08 (t, 4H), 2.67 (s, 1H), 2.06 (d, lH), 1.71-1.76 (m, 3H), 1.41-1.49 (m, 2H).

Example 130: Preparation of l-(2-((li?,35',45)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(pyrrolidin-l-yl)-lH-indazole-3-carboxamide

1 -(2-((1 R,3S,4S)-3-((6-chloropyridin-2-yl)car amoyl)-2-azabicyclo[2.2.1 ]

[00374] To a solution of fert-butyl 2-(3-cyano-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan -2-yl)- lH-indazol-l-yl)acetate (500 mg, 1.3mmol, 1.0 eq), Cu(OAc)₂ (272 mg, 39 mmol, 3 eq) and TEA (132 mg, 1.3 mmol, 1.0 eq) in ACN (10 mL) was added pyrrolidine (277 mg, 3.9 mmol, 3 eq). The mixture was stirred at rt overnight. After concentrated, the resulting residue was purified by chromatography on silica gel column (PE/EA = 10/1, v/v) to give fert-butyl 2-(3-cyano-5-(pyrrolidin-l-yl)-lH-indazol-l-yl)acetate (220 mg, 51%) as a yellow oil. LRMS (M+ ⁺) m/z calculated 327.3, found 327.1.

[00375] To a solution of fert-butyl 2-(3-cyano-5-(pyrrolidin-l-yl)-lH-indazol-l-yl)acetate (220 mg, 0.675 mmol, 1.0 eq) in DMSO (5 mL) was added K₂C0₃ (14 mg, 0.1 mmol, 0.15 eq) in Η₂0₂/Η₂0 (405 mg, 3.37 mmol, 5 eq). The mixture was stirred at rt overnight. Then water (25 mL) was added and extracted with EA ( 20 mL x 2). The resulting organic layers were concentrated to give fert-butyl 2-(3-carbamoyl-5- (pyrrolidin-l-yl)-lH-indazol-l-yl)acetate (200 mg, 87%) as a yellow solid. LRMS (M+H⁺) m/z calculated 345.2, found 345.1.

[00376] To a solution of fert-butyl 2-(3-carbamoyl-5-(pyrrolidin-l-yl)-lH-indazol- l-yl)acetate

(200 mg, 0.58 mmol, 1.0 eq) in DCM (6 mL) was added TFA (2 mL ) at rt. The mixture was stirred at rt overnight. The solution mixture was concentrated to give 2-(3-carbamoyl-5-(pyrrolidin-l-yl)-lH-indazol-l- yl)acetic acid trifluoroacetate (200 mg, 87%) as a yellow oil. LRMS (M+H⁺) m/z calculated 289.1, found 289.3.

[00377] A mixture of 2-(3-carbamoyl-5-(pyrrolidin-l-yl)-lH-indazol-l-yl)acetic acid

trifluoroacetate ( 180 mg, 0.447 mmol, 1.0 eq), (li?,3S,4¾-N-(6-chloropyridin-2-yl)-2- azabicyclo[2.2.1]heptane-3-carboxamide trifluoroacetate (164 mg, 0.447 mmol, 1.0 eq), HATU (204 mg, 0.536 mmol, 1.2 eq) and DIEA ( 173 mg, 1.34 mmol, 3.0 eq) in DMF (8 mL) was stirred at rt overnight. The mixture was concentrated, and the resulting residue was purified by prep-HPLC to afford \-(2-(( \R,3S,4S)-3- ((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(pyrrolidin-l-yl)-lH- indazole-3-carboxamide (25 mg, 10%) as a white solid. LRMS (M+H⁺) m/z calculated 521.2, found 522.2. ¾ NMR (DMSO-£/₆, 400 MHz) δ 10.82 (s, 1H), 7.98-8.0 (m, 1H), 7.79-7.83 (m, 1H), 7.46-7.48 (d, 1H), 7..39- 7.42 (m, 1H), 7.18-7.19 (d, 2H), 7.08-7.09 (d, 1H), 6.91-6.94 (m, 1H), 5.51-5.55 (d, 1H), 5.25-5.29 (d, 1H), 4.59 (s, 1H), 4.07 (s, 1H), 3.26 (s,4H), 2.66 (s, lH), 2.05-2.07(d, 1H), 1.96-1.98 (m, 4H), 1.70-1.78 (m, 3H), 1.40-1.47 (m, 2H).

Example 131 : Preparation of l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-( -pyrazol-l-yl)-lH-indazole-3-carboxamide

1-(2-((1R,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)

[00378] A mixture of fert-butyl 2-(5-bromo-3-cyano-lH-indazol-l-yl)acetate (900 mg, 2.68 mmol,

1.0 eq), lH-pyrazole (273 mg, 4.02 mmol, 1.5 eq), Cul ( 102.0 mg, 0.0.535 mmol, 0.2 eq), K₂C0₃ (924.3 mg, 6.69 mmol, 2.5 eq) and 1, 2-diaminocyclohexane (92.4 mg, 0.81 mmol, 0.3 eq) in DMF (6 mL) was stirred in a sealed tube at 90 °C under N₂ for 16 h. The reaction mixture was diluted with EA ( 150 mL), washed with brine ( 100 mL), dried over Na₂S0₄, filtered and concentrated. The resulting residue was purified by chromatography on silica gel column (PE/EA = 7/1, v/v) to give fert-butyl 2-(3-cyano-5-(lH-pyrazol-l -yl)- lH-indazol-l -yl)acetate (212.0 mg, 24.5%) as a white solid. LRMS (M+H⁺) m/z calculated 324.1, found 324.0

[00379] To a mixture of fert-butyl 2-(3-cyano-5-(lH-pyrazol-l-yl)-lH-indazol-l-yl)acetate (115 mg, 0.356 mmol, 1.0 eq) in DMSO (1.5 mL) at 0 °C was added a solution of K₂C0₃ (22.0 mg, 0.16 mmol, 0.45 eq) in H₂0₂ (968.0 mg, 8.544 mmol, 24.0 eq). The result mixture was stirred at rt for 10 h. The reaction mixture was purified by prep-HPLC to give fert-butyl 2-(3-carbamoyl-5-(lH-pyrazol-l-yl)-lH-indazol-l- yl)acetate (91.5 mg, 75.2%) as a white solid. LRMS M-56+H⁺ m/z calculated 286.1, found 286.0.

[00380] To a solution of fert-butyl 2-(3-carbamoyl-5-(lH-pyrazol-l-yl)-lH-indazol-l-yl)acetate

(91.5 mg, 0.27 mmol, 1.0 eq) in DCM (3.0 mL) was added TFA (2.0 mL) slowly at 0 °C. The mixture was stirred at rt for 1 h. The mixture was diluted with MeOH(100 mL) and concentrated to give 2-(3-carbamoyl-5- (lH-pyrazol-l-yl)-lH-indazol-l-yl)acetic acid (77.0 mg, 95%) as a white solid. LRMS (M+H⁺) m/z calculated 286.0, found 286.0.

[00381] A mixture of (lR,3S,4S)-N-(6-chloropyridin-2-yl)-2-azabicyclo[2.2. l]heptane-3- carboxamide (35.8 mg 0.10 mmol, 1.0 eq), 2-(3-carbamoyl-5-(lH-pyrazol-l-yl)-lH-indazol-l-yl)acetic acid (35.0 mg, 0.12 mmol, 1.2 eq), HATU (74.0 mg, 0.20 mmol, 2.0 eq) and DIEA (75.0 mg, 0.59 mmol, 6.0 eq) in dry DMF (1.5 mL) was stirred at rt for 2 h. The resulting mixture was purified by prep-HPLC to afford l-(2- ((lP 3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(lH-pyrazol- l-yl)-lH-indazole-3-carboxamide (16.2 mg, 32%) as a white solid. LRMS (M+H⁺) m/z calculated 519.1, found 519.2. ¾ NMR (CD₃OD, 400 MHz) δ 8.48 (s, 1H), 8.23 (s, 1H), 8.13-7.45 (m, 2H), 7.81-7.66 (m, 3H), 7.14 (d,0.21H), 7.09 (d, 0.81H), 6.54 (s, 1H), 5.64 (d, 0.85H), 5.48 (d, 0.85H), 5.31 (t, 0.23H), 5.10 (d, 0.2H), 4.65 (d, 1H), 4.35 (s, 0.18H), 4.16 (s, 0.82H), 2.95 (s, 0.15H), 2.81 (s, 0.85H), 2.20 (d, 1H), 1.98-1.86 (m, 2H), 1.81-1.52 (m, 3H).

Example 132: Preparation of l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(lH-imidazol-l-yl)-lH-indazole-3-carboxamide

1-(2-((1R,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyolo[2.2.1]heptan-2-yl)

[00382] To a mixture of fert-butyl 2-(5-bromo-3-cyano-lH-indazol-l-yl)acetate (1.0 g, 3.0 mmol,

1.0 eq), lH-imidazole (408.0 mg, 6.0 mmol, 2.0 eq), Cul (570.0 mg, 3.0 mmol, 1.0 eq) in NMP (15 mL) were added K₂C0₃ (1.24 g, 9.0 mmol, 3.0 eq) and L-proline (379.0 mg, 3.3 mmol, 1.1 eq). The reaction mixture was stirred in a sealed tube at 90 °C under N₂ for 48 h. The result mixture was diluted with EA (150 mL), washed with brine (100 mL), dried over Na₂S0₄, filtered and concentrated. The resulting residue was purified by prep-HPLC to give fert-butyl 2-(3-cyano-5-(lH-imidazol-l-yl)-lH-indazol-l-yl)acetate (143 mg, 14.9%) as a white solid. LRMS (M ⁺) m/z calculated 324.1, found 324.0.

[00383] To a solution of fert-butyl 2-(3-cyano-5-(lH-imidazol-l-yl)-lH-indazol-l- yl)acetate( 143.0 mg, 0.44 mmol, 1.0 eq) in DMSO (1.5 mL) was added a solution of K₂C0₃ (27.5 mg, 0.20 mmol, 0.45 eq) in H₂0₂ (1.2 g, 10.62 mmol, 24.0 eq) at 0 °C. The result mixture was stirred at rt for 2.5 h. The resulting mixture was purified by prep-HPLC to give fert-butyl 2-(3-carbamoyl-5-(lH-imidazol-l-yl)-lH- indazol-l-yl)acetate (112.0 a yellow oil. LRMS (M-56+H⁺) m/z calculated 286.1, found 286.0.

[00384] To a solution of fert-butyl 2-(3-carbamoyl-5-(lH-imidazol-l-yl)-lH-indazol-l- yl)acetate( 112.0 mg, 0.33 mmol, 1.0 eq) in DCM (3 mL) was added TFA (2 mL) slowly at 0 °C. The reaction mixture was stirred at rt for 1 h. The reaction mixture was diluted with MeOH (100 mL) and concentrated to give 2-(3-carbamoyl-5-(lH-imidazol-l-yl)-lH-indazol-l-yl)acetic acid (90.0 mg, 96%) as a white solid. LRMS (M+H⁺) m/z calculated 286.0, found 286.0.

[00385] A mixture of (lR,3S,4S)-N-(6-chloropyridin-2-yl)-2-azabicyclo[2.2. l]heptane-3- carboxamide (43.0 mg 0.12 mmol, 1.0 eq),2-(3-carbamoyl-5-(lH-imidazol-l-yl)-lH-indazol-l-yl)acetic acid (40.0 mg, 0.14 mmol, 1.2 eq), HATU (89.0 mg, 0.23 mmol, 2.0 eq) and DIEA (90.0 mg, 0.70 mmol, 6.0 eq) in dry DMF (1.5 mL) was stirred at rt for 2.5 h. The resulting mixture was purified by prep-HPLC to afford l-(2- ((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(lH- imidazol-l-yl)-lH-indazole -3 -carboxamide (10.8 mg, 17.8%) as a white solid. LRMS (M+H⁺) m/z calculated 519.1, found 519.2. ¾ NMR (CD₃OD, 400 MHz) δ 8.32 (d,lH), 8.17-7.69 (m, 2H),7.83-7.75 (m, IH), 7.74- 7.63 (m, 2H), 7.63-7.56 (m, IH), 7.16 (t, IH), 7.10 (t, IH), 5.68 (d, 0.81H), 5.49 (d, 0.81H), 5.32 (d, 0.21H), 5.12 (d, 0.22H), 4.65 (s, IH), 4.34 (s, 0.15H), 4.16 (s, 0.85H), 2.96 (s, 0.15H), 2.19 (s, 0.85H), 2.20 (d, IH), 1.94-1.76 (m, 3H), 1.74-1.54 (m, 2H).

Example 133: Preparation of l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5 ole-3-carboxamide

1-(2-((1R,3S,4S)-3-((6-chloTOpyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- oxoethyl)-5-(oxazol-2-yl)-1H-indazole-3-carb

[00386] A mixture of fert-butyl 2-(5-bromo-3-carbamoyl-lH-indazol-l-yl)acetate (531 mg, 1.50 mmol, 1.0 eq), 2-(tri-n-butylstannyl)oxazole (840 mg, 2.25 mmol, 1.5 eq), LiCl (65 mg, 1.50 mmol, 1.5 eq) and Pd(PPh₃)₄ (210 mg, 0.15 mmol, 0.1 eq) in toluene (23 mL) was stirred at 100 °C for 5 h under nitrogen. The cooled mixture was partitioned between EA (50 mL) and water (20 ml). The organic layer was separated, dried over Na₂S0₄ and concentrated. The resulting residue was purified by chromatography on silica gel column (EA/PE = 1/2, v/v) to give fert-butyl 2-(3-carbamoyl-5-(oxazol-2-yl)-lH-indazol-l-yl)acetate (240 mg, 47%) as an off-white solid. LRMS M+H⁺) m/z calculated 343.1, found 343.0.

[00387] To a cooled solution of fert-butyl 2-(3-carbamoyl-5-(oxazol-2-yl)-lH-indazol-l-yl)acetate

(206 mg, 0.6 mmol) in DCM (2 mL) was added dropwise TFA (2 mL). The result mixture was stirred at rt for 5 h. The reaction mixture was concentrated and the resulting residue was purified by prep-HPLC to give (lR,3S,4S)-N-(6-chloropyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3-carboxamide (102 mg, 50%) as a white solid. LRMS (M+

[00388] A mixture of (lR,3S,4S)-N-(6-chloropyridin-2-yl)-2-azabicyclo[2.2. l]heptane-3- carboxamide (50 mg, 0.137 mmol, 1.0 eq), 2-(3-carbamoyl-5-(oxazol-2-yl)-lH-indazol-l-yl)acetic acid (45 mg, 0.157 mmol, 1.2 eq), HATU (65 mg, 0.171 mmol, 1.3 eq) and DIEA (88 mg, 0.685 mmol, 5.0 eq) in DMF (1.5 mL) was stirred at rt for 16 h. The resulting mixture was purified by prep-HPLC to give l-(2- ((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(oxazol-2- yl)-lH-indazole-3-carboxamide (27.0 mg, 37%) as a white solid. LRMS (M+H⁺) m/z calculated 520.1, found 519.9. 'H NMR (CD₃OD, 400 MHz) δ 8.93-8.86 (m, 1H), 8.16-7.95 (m, 3H), 7.80-7.65 (m, 2H), 7.29 (d, 1H), 7.15-7.07 (m, 1H), 5.66 (d, 0.85H), 5.48 (d, 0.85H), 5.31 (d, 0.15H), 5.11 (d, 0.15H), 4.67 (s, 0.15H), 4.65 (s, 0.85H), 4.32 (s, 0.15H), 4.16 (s, 0.85H), 2.94 (d, 0.15H), 2.81(s, 0.85H), 2.20(s, 0.85 H), 1.96-1.27 (m, 5.15 H).

Example 134: Preparation of l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5- -imidazol-2-yl)-lH-indazole-3-carboxamide

1 -(2-((1 ?,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1 ]heptan-2-yl)-2-

[00389] A mixture of fert-butyl 2-(3-carbamoyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)- lH-indazol-l-yl)acetate (200 mg, 0.499 mmol, 1.0 eq), 2-bromo-l-((2-(trimethylsilyl)ethoxy)methyl)-lH- imidazole (153.5 mg, 0.550 mmol, 1.1 eq), K₃P0₄ (212 mg, 1.00 mmol, 2.0 eq ) and Pd(dppf)Cl₂ (40.8 mg, 0.05 mmol, 0.1 eq) in dixoane(10 mL)/water (2 mL) was stirred at 100 °C for 5 h under nitrogen. The reaction mixture was concentrated and the resulting residue was purified by chromatography on silica gel column (EA/PE = 1/2, v/v) to give fert-butyl 2-(3-carbamoyl-5-(l-((2-(trimethylsilyl)ethoxy)methyl)-lH-imidazol-2- yl)-lH-indazol-l-yl)acetate (100 mg, 43%) as a brown oil. LRMS (M-56+H⁺) m/z calculated 472.2, found 471.8.

[00390] To a cooled solution of fert-butyl 2-(3 -carbamoyl -5 -(l-( (2 -(trimethylsilyl)ethoxy)methyl)- lH-imidazol-2-yl)-lH-indazol-l-yl)acetate (100 mg, 0.212 mmol) in DCM (2 mL) was added dropwise TFA (2 mL). The result mixture was stirred at rt for 6 h. The reaction mixture was concentrated and the resulting residue was purified by prep-HPLC to give 2-(3-carbamoyl-5-(lH-imidazol-2-yl)-lH-indazol-l-yl)acetic acid (86.9 mg, 100%) as a brown gel. LRMS (M+H⁺) m/z calculated 286.1, found 285.8.

[00391] A mixture of (lR,3S,4S)-N-(6-chloropyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3- carboxamide (73 mg, 0.199 mmol, 1.0 eq), 2-(3-carbamoyl-5-(lH-imidazol-2-yl)-lH-indazol-l-yl)acetic acid (86.9 mg, 0.219 mmol, 1.1 eq), HATU (113 mg, 0.299 mmol, 1.5 eq) and DIEA (155 mg, 1.20 mmol, 6.0 eq) in DMF (1.5 mL) were stirred at rt for 16 h. The resulting mixture was purified by prep-HPLC to give l-(2- ((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(lH- imidazol-2-yl)-lH-indazole-3-carboxamide (8.0 mg, 8%) as a white solid. LRMS (M+H⁺), m/z calculated 519.2, found 519.1. ¾ NMR (CD₃OD, 400 MHz) δ 8.70-8.64 (m, 1H), 8.12-7.95 (m, 2H), 7.80-7.63 (m, 2H), 7.18 (s, 2H), 7.14 (d, 0.15H), 7.09 (d, 0.85H), 5.64 (d, 0.85H), 5.47 (d, 0.85H), 5.30 (d, 0.15H), 5.09 (d, 0.15H), 4.66 (s, 0.15H), 4.64 (s, 0.85H), 4.37 (s, 0.15H), 4.16 (d, 0.85H), 2.96(d, 0.15H), 2.81(s, 0.85 H), 2.20 (d, 0.85), 1.96-1.27 (m, 5.15 H)

Example 135: Preparation of l-(2-((li?,35',45)-3-((3-chloro-2-fluorobenzyl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)- -(2-methoxypyrimidin-5-yl)-lH-indazole-3-carboxamide

1-(2-((1R,3S,4S)-3-((3-chlora-2-fluorobenzyl)carbamoyl)-2-a^bicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)

-5-(2-methoxypyrimidin-5-yl)-1H-indazole-3-carboxamide

[00392] A mixture of (^^^^^-(tert-butoxycarbony^^-azabicycloP^. lJheptane-S-carboxylic acid (2.0 g , 8.2 mmol, 1.0 eq), (3-chloro-2-fluorophenyl)methanamine hydrochloride (2.4 g, 12.3 mmol, 1.5 eq), HATU (4.7g, 12.3 mmol, 1.5 eq) and TEA (2.5 g, 24.6 mmol, 3.0 eq) in DMF (20 mL) was stirred at rt overnight. The reaction mixture was concentrated and the resulting residue was purified by prep-HPLC to give (\R,3S,4S)-tert-butyl 3-((3-chloro-2-fluorobenzyl)carbamoyl)-2-azabicyclo[2.2.1]heptane-2-carboxylate (1.1 g, 34.7% yield) as a white solid. LRMS (M+H⁺) m/z calculated 383.1, found 383.2.

[00393] A solution of (\R,3S,4S)-tert-butyl 3-((3-chloro-2-fluorobenzyl)carbamoyl)-2- azabicyclo[2.2.1]heptane-2-carboxylate (1.1 g, 3.1 mmol, 1.0 eq) in HCl/dioxane (20 mL) was stirred at rt for 2 h. Then the resulting solution was concentrated to give (li?,35',45)-N-(3-chloro-2-fluorobenzyl)-2- azabicyclo[2.2.1]heptane-3-carboxamide hydrochloride (1.2, 100% yield) as a white solid. LRMS (M+H⁺) m/z calculated 282.1, found

[00394] A mixture of TFA salt of 2-(3-carbamoyl-5-(2-methoxypyrimidin-5-yl)-lH-indazol-l- yl)acetic acid (210 mg, 0.48 mmol, 1.0 eq), (li?,3S,4¾-N-(3-chloro-2-fluorobenzyl)-2- azabicyclo[2.2.1]heptane-3-carboxamide hydrochloride (205 mg, 0.64 mmol, 1.3 eq), HATU (282 mg, 0.74 mmol, 1.5 eq) and DIEA (255 mg, 1.98 mmol, 3.0 eq) in DMF (10 mL) was stirred at rt overnight. The reaction mixture was concentrated and the resulting residue was purified by prep-HPLC to give l-(2- ((li?,35',45)-3-((3-chloro-2-fluorobenzyl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(2- methoxypyrimidin-5-yl)-lH-indazole-3-carboxamide (50 mg, 17.8%) as a white solid. LRMS (M+H⁺) m/z calculated 592.2, found 592.3. ¾NMR (DMSO- ₆, 400 MHz) δ 8.94(s, 2H), 8.45-8.48(m, 1H), 8.37-8.38 (m, 1H), 7.64-7.78 (m, 3H), 7.38-7.49 (m, 2H), 7.17-7.20 (m, 1H), 7.03-7.07 (m, 1H), 5.66-5.70 (d, 1H), J=17.2Hz, 5.35-5.45 (m, 1H), 4.57 (s, 1H), 4.23-4.49 (m, 2H), 3.99 (s, 3H), 3.84 (s, 1H), 2.80 (s, 1H),2.02- 2.04 (m, 1H), 1.44-1.78 (m, 5H). Example 136: Preparation of l-(2-((li?,35',45)-3-((3-chloro-2-fluorobenzyl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(2-cyanopyrimidin-5-yl)-lH-indazole-3-carboxami

6-(2-rarbamoylpyrimidin-5-yl)-1-(2-((1R,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-1H-indazole-3-carboxamide

[00395] A mixture of (l i^^^^-N-iS-cliloro^-fluorobenzy^^-azabicycloP^. lJheptane-S- carboxamide (52 mg, 0.163 mmol, 1.0 eq), 2-(3-carbamoyl-5-(2-cyanopyrimidin-5-yl)-lH-indazol-l-yl)acetic acid (68 mg, 0.212 mmol, 1.3 eq), HATU (93 mg, 0.245 mmol, 1.5 eq) and DIEA (105 mg, 0.815 mmol, 5.0 eq) in DMF (4 mL) was stirred at 30 °C for 3 h. The resulting mixture was purified by prep-HPLC to give 1- (2-((li?,35',45)-3-((3-chloro-2-fluorobenzyl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(2- cyanopyrimidin-5-yl)-lH-indazole-3-carboxamide (37 mg, 39%) as a white solid. LRMS (M+H⁺) m/z calculated 587.2, found 587.0. 'HNMR (DMSO- ₆, 400 MHz) δ 9.42 (s, 2H), 8.59-8.60 (d, 1H), 8.45-8.48 (t, 3H), 7.81-7.92 (m, 3H), 7.55 (s, IH), 7.41-7.44 (t, 1H), 7.17-7.18 (t, 1H), 7.02-7.06 (t, 1H), 5.69-5.74 (d, 1H), 5.37-5.42 (d, IH), 4.57 (s, IH), 4.26-4.47 (m, 3H), 3.84 (s, IH), 2.59 (s, IH), 2.02-2.04 (d, IH), 1.75-1.78 (d, 2H), 1.44-1.49 (t, 2H).

Example 137: Preparation of l-(2-((li?,35',45)-3-((3-chloro-2-fluorobenzyl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5- -methylpyrimidin-5-yl)-lH-indazole-3-carboxamide

1-(2-((1R,3S,4S)^-((3-chloro-2-fluorabenzyl)carbamoyl)-2-a2abiC Clo[2.2.1]heptan-2-yl)-2-oxoethyl)- 5-(2-methylpyrimidin-5-yl)-1H-indazole-3-carboxamide

[00396] A mixture of TFA salt of 2-(3-carbamoyl-5-(2-methylpyrimidin-5-yl)-lH-indazol-l- yl)acetic acid (100 mg, 0.27 mmol, 1.0 eq), (li?,3S,4¾-N-(3-chloro-2-fluorobenzyl)-2- azabicyclo[2.2.1]heptane-3-carboxamide hydrochloride (94.3 mg, 0.30 mmol, 1.1 eq), HATU (153.6 mg, 0.40 mmol, 1.5 eq) and DIEA (208.6 mg, 1.62 mmol, 6.0 eq) in DMF (10 mL) was stirred at rt overnight. The reaction mixture was concentrated, and the resulting residue was purified by prep-HPLC to give l-(2- ((li?,35',45)-3-((3-chloro-2-fluorobenzyl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(2- methylpyrimidin-5-yl)-lH-indazole-3-carboxamide (28.0 mg, 18.1%) as a yellow solid. LRMS (M+H⁺) m/z calculated 576.2, found 576.2. ¾NMR (DMSO- ₆, 400 MHz) δ 9.04 (s, 2H), 8.44-8.48 (m, 2H), 7.64-7.81 (m, 3H), 7.74-7.49 (m, 2H), 7.15-7.19 (m, 1H), 7.14-7.16 (m, 1Η),5.67-5.68 (m, 1H), 5.36 -5.42 (m, 1H), 4.57 (s, 1H), 4.1 -4.39 (m, 2H), 3.84 (s, 1H), 2.69 (s, 3H), 2.59 (s, 1H), 2.03-2.06 (m, 1H), 1.72-1.78 (m, 3H),1.23- 1.58(m, 2H).

Example 138: Preparation of l-(2-((li?,35',45)-3-((3-chloro-2-fluorobenzyl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5 indazole-3-carboxamide

1-(2-((1fi,3S,4S)-3-((3-tfiloro-2-fluorobenzyl)ca^^

-5-(pyrimidin-5-yl)-1H-indazole-3-carboxamide

[00397] A mixture of TFA salt of 2-(3-carbamoyl-5-(pyrimidin-5-yl)-lH-indazol-l-yl)acetic acid

(130 mg, 0.32 mmol, 1.0 eq), (l i^^^^-N-iS-chloro^-fluorobenzy^^-azabicycloP^. lJheptane-S- carboxamide hydrochloride (129 mg, 0.41 mmol, 1.3 eq), HATU (178.5 mg, 0.47 mmol, 1.5 eq) and DIEA (161.6 mg, 1.25 mmol, 4.0 eq) in DMF (10 mL) was stirred at rt overnight. The reaction mixture was concentrated, and the resulting residue was purified by prep-HPLC to give l-(2-((li?,35^*,45)-3-((3-chloro-2- fluorobenzyl)carbamoyl) -2 -azabicyclo [2.2.1] heptan-2 -yl) -2 -oxoethyl)-5 -(pyrimidin-5 -yl) - lH-indazole -3 - carboxamide (26.8 mg, 15.1%) as a white solid. LRMS (M+H⁺) m/z calculated 562.2, found 562.3. ¾ NMR DMSO-d₆, 400 MHz) δ 9.21 (s, 1H), 9.17 (s, 2H), 8.47-8.48 (m, 2H), 7.82-7.85(m, 2H), 7.69-7.78 (m, 1H), 7.51 (s, 1H), 7.43-7.45 (m, 1H),7.19-7.19 (m, 1H), 7.04-7.06 (t, 1H), 5.66-5.72 (m, 1H), 5.34-5.49 (m, 1H), 4.57 (s, 1H), 4.27-4.43 (m, 2H), 3.84 (s, 1H),2.59 (s, 1H), 2.05-2.08 (m, 1H), 1.78(s, 3H), 1.399-1.55 (m, 2H). Example 139: Preparation of l-(2-((lR,3S,4S)-3-((3-chloro-2-fluorobenzyl)carbamoyl)-2- azabicyclo [2.2.1 ]heptan-2-yl)-2-oxoethyl)- lH-indazole-3 -carboxamide

1-(2-((1R,3S,4S)-3-((3-chloro-2-fluorobenzyl)carbamoyl)-2-azabic clo[2.2.1]

heptan-2-yl)-2-oxo8thyl)-5-(nicotinamido)-1H-inclazol8-3-ca

[00398] To a mixture of 2-(5-((teri-butoxycarbonyl)amino)-3-carbamoyl-lH-indazol-l-yl)acetic acid (500 mg 1.5 mmol, 1.0 eq) and (lR,3S,4S)-N-(3-chloro-2-fluorobenzyl)-2-azabicyclo[2.2.1]heptane-3- carboxamide (508 mg, 1.8 mmol, 1.2 eq) in NMP (5 mL) were added HATU (1.14 g, 3.0 mmol, 2.0 eq) and DIEA (580 mg, 4.5 mmol, 3.0 eq) at 0 °C. The reaction mixture was stirred at rt for 2 h. The resulting residue was purified by prep-HPLC to afford fert-butyl (3-carbamoyl-l-(2-((lR,3S,4S)-3-((3-chloro-2- fluorobenzyl)carbamoyl)-2-azabicyclo[2.2. l]heptan-2-yl)-2-oxoethyl)-lH-indazol-5-yl)carbamate (810 mg, 90%) as a white solid. LR 599.2, found 599.0.

[00399] To a solution of fert-butyl (3-carbamoyl-l-(2-((lR,3S,4S)-3-((3-chloro-2- fluorobenzyl)carbamoyl)-2-azabicyclo[2.2. l]heptan-2-yl)-2-oxoethyl)-lH-indazol-5-yl)carbamate (810 mg, 1.35 mmol) in DCM (2 mL) at 0 °C was added TFA (2 mL) slowly. The mixture was concentrated and the resulting residue was purified by prep-HPLC to afford the target compound (600 mg, 89%) as a white solid. LRMS (M+H⁺) m/z calculated 499.2, found 498.7.

[00400] A mixture of 5-amino-l-(2-((lR,3S,4S)-3-((3-chloro-2-fluorobenzyl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-lH-indazole-3-carboxamide (150 mg, 0.30 mmol, 1.0 eq), nicotinic acid (45 mg, 0.36 mmol, 1.2 eq), HATU (240 mg, 0.60 mmol, 2.0 eq) and DIEA (115 mg, 0.90 mmol, 3.0 eq) in NMP (2 mL) was stirred at rt for 2 h. The mixture was concentrated, and the resulting residue was purified by prep-HPLC to afford l-(2-((lR,3S,4S)-3-((3-chloro-2-fluorobenzyl)carbamoyl)-2-azabicyclo[2.2.1]heptan- 2-yl)-2-oxoethyl)-5-(nicotinamido)-lH-indazole-3-carboxamide (166.6 mg, 92%) as a white solid. LRMS (M+H⁺) m/z calculated 604.2, found 604.0. ¾ NMR (DMSO- ₆, 400 MHz) δ 10.57 (s, IH), 9.17 (s, IH), 8.94 - 8.35 (m, 4H), 7.83 - 7.80 (m, IH), 7.64 - 7.05 (m, 6H), 5.62 (d, 0.85H), 5.35 - 5.30 (m, IH), 4.80 (d, 0.15H), 4.55 - 4.27 (s, 3.15H), 3.85 (s, 0.85H), 2.79 (d, 0.15H), 2.59 (s, IH), 2.03 (d, 0.85H), 1.79 - 1.29 (m, 5H). Example 140: Preparation of l-(2-((lR,3S,4S)-3-((3-chloro-2-fluorobenzyl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)- -(2-chlorobenzamido)-lH-indazole-3-carboxamide

1

[00401] A mixture of 5-amino-l-(2-((lR,3S,4S)-3-((3-chloro-2-fluorobenzyl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-lH-indazole-3-carboxamide (150 mg, 0.30 mmol, 1.0 eq), 2- chlorobenzoic acid (55 mg, 0.36 mmol, 1.2 eq), HATU (240 mg, 0.60 mmol, 2.0 eq) and DIEA (1 15mg, 0.90 mmol, 3.0 eq) in NMP (2 mL) was stirred at rt for 2 h. The mixture was concentrated, and the resulting residue was purified by prep-HPLC to afford l-(2-((lR,3S,4S)-3-((3-chloro-2-fluorobenzyl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(2-chlorobenzamido)-lH ndazole-3-carboxamide (140.5 mg, 74%) as a white solid. LRMS (M+H⁺) m/z calculated 637.2, found 637.1. 1H NMR (DMSO- ₆, 400 MHz) δ 10.57 (s, 1H), 8.92 - 8.89 (m, 0.15H), 8.64 (s, 1H), 8.44 - 8.42 (m, 1H), 7.21 - 7.18 (m, 1H), 7.08 - 7.04 (m, 1H), 5.60 (d, 0.85H), 5.35 - 5.29 (m, 1H), 4.81 (d, 0.15H), 4.54 - 4.27 (m, 3.15H), 3.85 (s, 0.85H), 2.79 (d, 0.15H), 2.59 (s, 1H), 2.02 (d, 0.85H), 1.78 - 1.28 (m, 5H).

Example 141: Preparation of methyl (3-carbamoyl-l-(2-((lR,3S,4S)-3-((3-chloro-2-fluorobenzyl)carbamoyl)- 2-azabicyclo [2.2.1] heptan-2-yl) -2 -oxoethyl) - 1 H-indazol-5 -yl)carbamate

[00402] To a solution of 5-amino-l-(2-((lR,3S,4S)-3-((3-chloro-2-fluorobenzyl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-lH-indazole-3-carboxamide (150 mg, 0.30 mmol, 1.0 eq) and DIEA (155 mg, 1.2 mmol, 4.0 eq) in NMP (2 mL) was added methyl carbonochloridate (57 mg, 0.6 mmol, 2.0 eq) at 0 °C under N₂. The result mixture was stirred at 0 °C for 1 h. The resulting mixture was purified by prep-HPLC to give methyl (3-carbamoyl-l-(2-((lR,3S,4S)-3-((3-chloro-2-fluorobenzyl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-lH-indazol-5-yl)carbamate (145 mg, 87%) as a white solid. LRMS (M+H⁺) m/z calculated 556.2, found 557.1. ¾ NMR (400 MHz, DMSO- ₆) δ 9.68 (s, 1H), 8.45(s, 1H), 8.31 (s, 1H), 7.59-7.34 (m, 5.20H), 7.19-7.17 (m, 1H), 7.07-7.05 (m, 0.80H), 5.58 (d, 1H), 5.27 (d, 1H), 4.53-4.27 (m, 3.20H), 3.83 (s, 0.80H), 3.68 (s, 3H), 2.58 (s, 1H), 2.01 (d, 0.80H), 1.77-1.42 (m, 5.20 H).

Example 142: Preparation of l-(2-((lR,3S,4S)-3-((3-chloro-2-fluorobenzyl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(lH-pyrazol-l-yl)-lH-indazole-3-carboxamide

[00403] A mixture of (lR,3S,4S)-N-(3-chloro-2-fluorobenzyl)-2-azabicyclo[2.2.1]heptane-3- carboxamide (62.7 mg 0.11 mmol, 1.0 eq), 2-(3-carbamoyl-5-(lH-pyrazol-l-yl)-lH-indazol-l-yl)acetic acid (38.0 mg, 0.13 mmol, 1.2 eq), HATU (83.6 mg, 0.22 mmol, 2.0 eq) and DIEA (86.0 mg, 0.66 mmol, 6.0 eq) in dry DMF (1.5 mL) was stirred at rt for 2 h. The reaction mixture was purified by prep-HPLC to afford l-(2- ((lR,3S,4S)-3-((3-chloro-2-fluorobenzyl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(lH- pyrazol-l-yl)-lH-indazole -3 -carboxamide (17.8 mg, 46.3%) as a white solid. LRMS (M+H⁺) m/z calculated 550.1, found 550.0. ¾ NMR (CD₃OD, 400 MHz) δ 8.48 (d, IH), 8.23 (d, IH), 7.87 (dd, IH), 7.71 (t, 0.8H), 7.58 (d, 0.2H), 7.39-7.17 (m, 2H), 7.08 (t, 0.2H), 6.99 (t, 0.8H), 6.55 (t, IH), 5.59 (d, 0.81H), 5.44 (d, 0.81H), 5.30 (d, 0.21H), 4.95 (d, 0.22H), 5.64-4.35 (m, 3H), 4.22 (s, 0.19H), 3.99 (s, 0.81H), 2.85 (s, 0.19H), 2.71 (s, 0.82H), 2.14 (d, IH), 1.95-1.71 (m, 3H), 1.93-1.52 (m, 2H).

Example 143: Preparation of l-(2-((lR,3S,4S)-3-((3-chloro-2-fluorobenzyl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-( -imidazol-l-yl)-lH-indazole-3-carboxamide

1-(2-((1R,3S,4S)-3-((3-chlora-2-fluorabenzyl)carbamoyl)-2-azabicyclo[2.2.1]heptan

^-ylJ^-oxoethylJ-S- H-imidazol-1 -yl)-1 H-indazole-3-carboxamide

[00404] A mixture of (lR,3S,4S)-N-(3-chloro-2-fluorobenzyl)-2-azabicyclo[2.2. l]heptane-3- carboxamide (65.0 mg 0.12 mmol, 1.0 eq), 2-(3-carbamoyl-5-(lH-imidazol-l-yl)-lH-indazol-l-yl)acetic acid (40.0 mg, 0.14 mmol, 1.2 eq), HATU (89.0 mg, 0.23 mmol, 2.0 eq) and DIEA (90.0 mg, 0.7 mmol, 6.0 eq) in dry DMF (1.5 mL) was stirred at rt for 2.5 h. The resulting mixture purified by prep-HPLC to afford l-(2- ((lR,3S,4S)-3-((3-chloro-2-fluorobenzyl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(lH- imidazol-l-yl)-lH-indazole-3-carboxamide. LRMS (M+H⁺) m/z calculated 550.1, found 550.0. ¾ NMR (CD₃OD, 400 MHz) δ 8.32 (d,lH), 8.13 (s, 1Η),7.77-7.56 (m, 3H), 7.38-7.28 (m, 1H), 7.28-7.19 (m, 1H), 7.17 (t, 1H), 7.11-6.95 (m, 1H), 5.62 (d, 0.81H), 5.45 (d, 0.81H), 5.31 (d, 0.21H), 4.96 (d, 0.20H), 4.60 (s, 1H), 4.56-4.37 (m, 2H), 4.23 (s, 0.21H), 3.99 (s, 0.82H), 2.88-2.68 (m, 1H), 2.96 (s, 0.15H), 2.19 (s, 0.85H), 1.97- 1.73 (m, 3H), 1.72-1.51 (m, 2H).

Example 144: Preparation of l-(2-((li?,35',45)-3-((3-chloro-2-fluorobenzyl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)- xamide

1-(2-((1R ptan-2-yl)

[00405] A mixture of (l i^^^^-N-iS-chloro^-fluorobenzy ^-azabicycloP^. l]heptane-3- carboxamide (740 mg, 1.947 mmol, 1.0 eq), 2-(5-bromo-3-carbamoyl-lH-indazol-l-yl)acetic acid (1.0 g, 2.531 mmol, 1.3eq), HATU (1.11 g, 2.92 mmol, 1.5 eq) and DIEA (1.26 g, 9.735 mmol, 5.0 eq) in DMF (30 mL) was stirred at 35 °C for 16 h. The resulting mixture was purified by chromatography on silica gel column (DCM/MeOH = 97/3, v/v) to give 5-bromo-l-(2-((li?,3,S',4₁S)-3-((3-chloro-2-fluorobenzyl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2- -2-oxoethyl)-lH-indazole-3-carboxamide as a brown solid (220 mg, 20%).

[00406] A mixture of 5-bromo-l-(2-((li?,3₁S',4₁S)-3-((3-chloro-2-fluorobenzyl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-lH-indazole-3-carboxamide as a brown solid (100 mg, 0.178 mmol, 1.0 eq), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (68 mg, 0.266 mmol, 1.5eq), Pd(dppf)Cl₂ DCM (15 mg, 0.018 mmol, 0.1 eq) and KOAc (52 mg, 0.534 mmol, 3.0 eq) in dioxane (5 mL) was stirred at 100 °C for 16 h. The resulting mixture was purified by chromatography on silica gel column (DCM/MeOH = 49/1, 1/1) to give l-(2-((li?,3,S^*,4₁S)-3-((3-chloro-2-fluorobenzyl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-indazole-3- carboxamide as a light yellow solid (60 mg, 56%).

[00407] To a solution of l-(2-((li?,3,S^*,4₁S)-3-((3-chloro-2-fluorobenzyl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-indazole-3- carboxamide (60 mg, 0.10 mmol, 1.0 eq) in dioxane/H₂0 (40 mL, v/v = 1/1) were added 2-bromothiazole (24 mg, 0.15 mol, 1.5 eq), Pd(PPh₃)₄ (23 mg, 0.02 mmol, 0.2 eq) and K₃P0₄ (64 mg, 0.3 mmol, 3.0 eq). The mixture was stirred at 100° C overnight under N₂. Then the mixture was allowed to cool to ambient temperature, treated with brine (10 mL) and extracted with EA (30 mL x 3). The organic layer was dried over Na₂S0₄, filtered and concentrated. The resulting residue was purified by prep-HPLC to afford tl-(2- ((l i^^^^-S-iiS-chloro^-fluorobenzy^carbamoy^^-azabicycloP^. ^heptan^-y^^-oxoethy^-S-ithiazol- 2-yl)-lH-indazole-3 -carboxamide (8 mg, 14%) as a white solid. LRMS (M+H⁺) m/z calculated 566.1, found 566.9. 'H NMR DMSO-d₆, 400 MHz) δ 8.93 (t, 0.2H), 8.74-8.76 (m, 1H), 8.44 (t, 0.8H), 7.99-8.05 (m, 1H), 7.93 (d, 1H), 7.71-7.78 (m, 2H), 7.59-7.68 (m, 1H), 7.51 (m, 1H), 7.35-7.47 (m, 1H), 7.15-7.21 (m, 1H), 7.02 (t, 1H), 5.68 (d, 0.7H), 5.42 (d, 0.2H), 5.36 (d, 0.7H), 4.85 (d, 0.2H), 4.55 (s, 1H), 4.37-4.52 (m, 1H), 4.22- 4.30 (m, 1H), 3.85 (m, 1H), 2.68 (m, 1H), 1.97-2.04 (m, 1H), 1.68-1.77 (m, 3H), 1.43-1.63 (m, 2H).

Example 145: Preparation of methyl (3-carbamoyl-l-(2-oxo-2-((lR,3S,4S)-3-((6-(trifluoromethyl)pyridin-2- yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)ethyl)-lH-indazol-5-yl)carbamate

[00408] To a cooled mixture of 6-(trifluoromethyl)pyridin-2 -amine (2.43 g, 15.0 mmol, 1.0 eq) and (lR,3S,4S)-2-(teri-butoxycarbonyl)-2-azabicyclo[2.2.1]heptane-3-carboxylic acid (3.62 g, 15.0 mmol, 1.0 eq) in pyridine (10 mL) was dropped POCl₃ (2.30 g, 15.0 mmol, 1.0 eq) at 0 °C. The result mixture was stirred at rt for 2 h. The mixture was poured into a cooled aqueous solution of HQ (2.0 N, 40 mL). The resulting precipitate was collected to give (lR,3S,4S)-fert-butyl 3-((6-(trifluoromethyl)pyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptane-2-carboxylate (4.82 g, 69%) as a white solid. LRMS (M+H⁺) m/z calculated 386.2, found 386.0

[00409] To a cooled solution of (lR,3S,4S)-fert-butyl 3-((6-(trifluoromethyl)pyridin-2- yl)carbamoyl)-2-azabicyclo[2.2.1]heptane-2-carboxylate (3.46 g, 8.95 mmol) in DCM (18 mL) was added dropwise TFA (9 mL). The result mixture was stirred at rt for 4 h. The reaction mixture was neutralized with ammonia and extracted with DCM (50 mL x 3). The combined layers were dried over anhydrous Na₂S0₄ and concentrated to give (lR,3S,4S)-N-(6-(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3- carboxamide (2.44 g, 95 , found 286.0.

[00410] To a mixture of (lR,3S,4S)-N-(6-(trifluoromethyl)pyridin-2-yl)-2- azabicyclo[2.2.1]heptane-3-carboxamide (856 mg, 2.99 mmol, 1.0 eq), 2-(5-((fert-butoxycarbonyl)amino)-3- carbamoyl-lH-indazol-l-yl)acetic acid (1.0 g, 2.99 mmol, 1.0 eq) in DMF (10 mL) were added HATU (1.36 g, 3.59 mmol, 1.2 eq) and DIEA (581 mg, 4.50 mmol, 1.5 eq). The reaction mixture was stirred at rt for 3 h. The resulting mixture was purified by prep-HPLC to give fert-butyl (3-carbamoyl-l-(2-oxo-2-((lR,3S,4S)-3- ((6-(trifluoromethyl)pyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)ethyl)-lH-indazol-5- yl)carbamate (1.70 g, 94%) as an off-white solid. LRMS (M+H⁺) m/z calculated 602.2, found 602.0.

[00411] To a cooled solution of fert-butyl (3-carbamoyl-l-(2-oxo-2-((lR,3S,4S)-3-((6-

(trifluoromethyl)pyridin-2 -yl)carbamoyl) -2 -azabicyclo [2.2.1] heptan-2 -yl)ethyl) - 1 H-indazol-5 -yl)carbamate (1.70 g, 2.82 mmol) in DCM (10 mL) was added dropwise TFA (5 mL). The reaction mixture was neutralized with ammonia and extracted with DCM (70 mL x 3). The combined layers were dried over anhydrous Na₂S0₄ and concentrated to give 5-amino-l-(2-oxo-2-((lR,3S,4S)-3-((6-(trifluoromethyl)pyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)ethyl)-lH-indazole-3-carboxamide (1.30 g, 92%) as a pale yellow solid. LRMS (M+H⁺) m/z calculated 502.2

[00412] To a cooled mixture of 5-amino-l-(2-oxo-2-((lR,3S,4S)-3-((6-(trifluoromethyl)pyridin-2- yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)ethyl)-lH-indazole-3-carboxamide (213 mg, 0.424 mmol, 1.0 eq) and DIEA (82 mg, 0.636 mmol, 1.5 eq) in NMP (2 mL) was added dropwise methyl carbonochloridate (60 mg, 0.636 mmol, 1.5 eq). The reaction mixture was stirred at 0 °C for 0.5 h. The resulting mixture was purified by prep-HPLC to give methyl (3-carbamoyl-l-(2-oxo-2-((lR,3S,4S)-3-((6-(trifluoromethyl)pyridin-2- yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)ethyl)-lH-indazol-5-yl)carbamate (119.7 mg, 51%) as a white solid. LRMS (M+H⁺) m/z calculated 560.2, found 559.9. ¾ NMR (DMSO- ₆, 400 MHz) δ 11.39 (s, 0.15H), 11.01 (s, 0.85H), 9.66 (s, 1H), 8.43 (d, 0.15H), 8.29 (d, 1.85H), 8.13 (t, 0.15H), 8.04 (t, 0.85H), 7.70-7.42 (m, 4H), 7.33 (s, 1H), 5.62 (d, 0.85H), 5.33 (d, 0.85H), 5.30 (d, 0.15H), 4.86 (d, 0.15H), 4.62 (s, 0.85H), 4.53 (s, 0.15H), 4.46 (s, 0.15H), 4.14 (s, 0.85H), 3.67 (s, 3H), 2.94 (d, 0.15H), 2.70 (s, 0.85H), 2.09 (d, 0.85H), 1.85- 1.27 (m, 5.15H).

Example 146: Preparation of 5-(2-chlorobenzamido)-l-(2-oxo-2-((lR,3S,4S)-3-((6-(trifluoromethyl)pyridin- 2-yl)carbamoyl)-2 -azabicyclo [2.2.1 ]heptan-2-yl)ethyl)- lH-indazole-3 -carboxamide 5-(2-chl )-2-

[00413] To a mixture of 5-amino-l-(2-oxo-2-((lR,3S,4S)-3-((6-(trifluoromethyl)pyridin-2- yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)ethyl)-lH-indazole-3-carboxamide (208 mg, 0.40 mmol, 1.0 eq) and 2-chlorobenzoic acid (69 mg, 0.44 mmol, 1.1 eq) in NMP (1.5 mL) were added HATU (182 mg, 0.48 mmol, 1.2 eq) and DIEA (77 mg, 0.60 mmol, 1.5 eq) at 0 °C. The reaction mixture was stirred at rt for 3 h. The resulting mixture was purified by prep-HPLC to give 5-(2-chlorobenzamido)-l-(2-oxo-2-((lR,3S,4S)-3- ((6-(trifluoromethyl)pyridin-2-yl)carbamoyl)-2-azabicyclo [2.2.1 ]heptan-2-yl)ethyl)- 1 H-indazole-3 - carboxamide (127 mg, 50%) as a white solid. LRMS (M+H⁺) m/z calculated 640.2, found 639.9. ¾ NMR (DMSO- ₆, 400 MHz) δ 11.39 (s, 0.15H), 11.01 (s, 0.85H), 10.56 (s, 1H), 8.63 (s, l .OH), 8.43 (d, 0.15H), 8.29 (d, 0.85H), 8.13 (t, 0.15H), 8.04 (t, 0.85H), 7.70-7.42 (m, 8H), 7.36 (s, 1H), 5.65 (d, 0.85H), 5.36 (d, 0.85H), 5.32 (d, 0.15H), 4.89 (d, 0.15H), 4.63 (s, 0.85H), 4.55 (s, 0.15H), 4.48 (s, 0.15H), 4.15 (s, 0.85H), 2.94 (d, 0.15H), 2.70 (s, 0.85H), 2.09 (d, 0.85H), 1.85-1.27 (m, 5.15H).

Example 147: Preparation of 5-(nicotinamido)-l-(2-oxo-2-((lR,3S,4S)-3-((6-(trifluoromethyl)pyridin-2- yl)carbamoyl)-2-azabicyclo[2.2.1]heptan- -yl)ethyl)-lH-indazole-3-carboxamide

5-(ni∞tinamido)-1-(2-oxo-2-((1R,3S,4S^3-((6-(trifluoramethyl)pyridin-2-yl)carbamoyl)

-2-azabicyclo[2.2.1]heptan-2-yl)ethyl)-1H-indazole-3-carboxamide

[00414] To a mixture of 5-amino-l-(2-oxo-2-((lR,3S,4S)-3-((6-(trifluoromethyl)pyridin-2- yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)ethyl)-lH-indazole-3-carboxamide (208 mg, 0.40 mmol, 1.0 eq) and nicotinic acid (54 mg, 0.44 mmol, 1.1 eq) in NMP (1.5 mL) were added HATU (182 mg, 0.48 mmol, 1.2 eq) and DIEA (77 mg, 0.60 mmol, 1.5 eq) at 0 °C. The reaction mixture was stirred at rt for 3 h. The resulting mixture was purified by prep-HPLC to give 5-(nicotinamido)-l-(2-oxo-2-((lR,3S,4S)-3-((6- (trifluoromethyl)pyridin-2 -yl)carbamoyl) -2 -azabicyclo [2.2.1] heptan-2 -yl)ethyl) - 1 H-indazole -3 -carboxamide (118 mg, 49%) as a white solid. LRMS (M+H⁺) m/z calculated 607.2, found 607.0. ¾ NMR (DMSO- ₆, 400 MHz) δ 11.39 (s, 0.15H), 11.01 (s, 0.85H), 10.56 (s, 1H), 9.16 (d, 1H), 8.80-8.72 (m, 1H), 8.60 (d, 1H), 8.44 (d, 0.15H), 8.38-8.23 (m, 1.85H), 8.14 (t, 0.15H), 8.05 (t, 0.85H), 7.88-7.80 (m, 1H), 7.70-7.51 (m, 4H), 7.37 (s, 1H), 5.66 (d, 0.85H), 5.37 (d, 0.85H), 5.33 (d, 0.15H), 4.90 (d, 0.15H), 4.64 (s, 0.85H), 4.54 (s, 0.15H), 4.48 (s, 0.15H), 4.16 (s, 0.85H), 2.94 (d, 0.15H), 2.70 (s, 0.85H), 2.09 (d, 0.85H), 1.89-1.27 (m, 5.15H). Example 148: Preparation of 5-(3-methylureido)-l-(2-oxo-2-((lR,3S,4S)-3-((6-(trifluoromethyl)pyridin-2- yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2 3-carboxamide

5-(3-methylureido)-1-(2-oxo-2-((1R,3S,4S)-3-((6-(trifluoromethyl)pyridin-2-yl)carbamoyl)-2-

[00415] To a cooled solution of CDI (3.26 g, 20.0 mmol) in THF (30 mL) was added dropwise a solution of methanamine (2.0 M in THF, 10 mL) at 0 °C. The result mixture was stirred at rt for 2 h to give a solution of N-methyl-lH-imidazole-l-carboxamide in THF (0.5 M). A mixture of 5-amino-l-(2-oxo-2- ((lR,3S,4S)-3-((6-(trifluoromethyl)pyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)ethyl)-lH- indazole -3 -carboxamide (312 mg, 0.600 mmol, 1.0 eq), N-methyl-lH-imidazole-1 -carboxamide (0.5 M in THF, 6.0 mL, 3.0 mmol, 5.0 eq) and DIEA (156 mg, 1.20 mmol, 2.0 eq) in DMF (2 mL) was stirred at 90 °C for 48 h. The resulting mixture was purified by prep-HPLC to give 5-(3-methylureido)-l-(2-oxo-2- ((lP 3S,4S)-3-((6-(trifluoromethyl)pyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)ethyl)-lH- indazole-3-carboxamide (167.3 mg, 50%) as a white solid. LRMS (M+H⁺) m/z calculated 559.2, found 559.0. ¾ NMR (DMSO-<i₆, 400 MHz) δ 11.39 (s, 0.15H), 11.01 (s, 0.85H), 8.60 (s, 1H), 8.43 (d, 0.15H), 8.29 (d, 1.85H), 8.16 (s, 1H), 8.13 (t, 0.15H), 8.04 (t, 0.85H), 7.72-7.36 (m, 4H), 7.29 (s, 1H), 6.00-5.80 (m, 1H), 5.59 (d, 0.85H), 5.33 (d, 0.85H), 5.26 (d, 0.15H), 4.83 (d, 0.15H), 4.62 (s, 0.85H), 4.54 (s, 0.15H), 4.46 (s, 0.15H), 4.14 (s, 0.85H), 2.94 (d, 0.15H), 2.70 (s, 0.85H), 2.65 (d, 3H), 2.08 (d, 0.85H), 1.89-1.27 (m, 5.15H).

Example 149: Preparation of (li?,35',45)-2-(2-(3-acetyl-5-(2-methylpyrimidin-5-yl)-lH-indazol-l-yl)acetyl)- N-(6 -bromopyridin-2-yl) -2-azabicyclo [2.2.1 ]heptane -3 -carboxamide

(1R,3S,4S)-2-(2-(3-acetyl-5-(2-met ylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)- -2-yl)-2-azabicyclo[2.2.1]heptan

[00416] To a solution of fert-butyl 2-(5-bromo-3-iodo-lH-indazol-l-yl)acetate (1.0 g, 2.3 mol, 1.0 eq) in DMF (12 mL) was added Pd(PPh₃)₄ (39.7 mg, 0.034 mmol, 0.015 eq) under nitrogen atmosphere with stirring at rt for 15 min. Then tributyl( 1 -ethoxyvinyl)stannane (909 mg, 2.5 mmol, 1.1 eq) was added to this mixture. The resulting mixture was stirred at 100 °C for 4 h. The reaction mixture was quenched with water (20 mL), extracted with EA (30 mL x 2). The combined organic layers were dried and concentrated to give fert-butyl 2-(5-bromo-3-(l-ethoxyvinyl)-lH-indazol-l-yl)acetate as a oil.

To this oil in THF (10 mL) was added 4 Ν HC1 (1 mL) slowly. The reaction mixture was stirred at rt for 0.5 h and then diluted with water (20 mL), extracted with EA (30 mL x 2). The organic layer was concentrated, and the resulting residue was purified by chromatography on silica gel column (PE/EA = 30/1, v/v) to give tert- butyl 2-(3-acetyl-5-bromo-lH-indazol-l-yl)acetate (600 mg, 75%) as a white solid. LCMS (M+H⁺) m/z calculated 353.0, found 352

[00417] A mixture of fert-butyl 2-(3-acetyl-5-bromo-lH-indazol-l-yl)acetate (500 mg, 1.42 mmol,

1.0 eq), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (540 mg, 2.12 mmol, 1.5 eq) KOAc (337 mg, 3.44 mmol, 3.0 eq) and Pd(dppf)Cl₂.DCM (116 mg, 0.142 mmol, 0.1 eq) in dioxane (20 mL) was stirred at 120 °C for 4 h under nitrogen atmosphere. The mixture was concentrated, and the resulting residue was purified by chromatography on silica gel column (PE/EA = 10/1, v/v) to give fert-butyl 2-(3-acetyl-5-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-indazol -l-yl)acetate (640 mg, 94%) as a yellow solid. LCMS (M+H⁺) m/z calculated 401.2, found 401.1.

[00418] To a solution of fert-butyl 2-(3-acetyl-5-(2-methylpyrimidin-5-yl)-lH-indazol- 1- yl)acetate (200 mg, 0.5 mmol, 1.0 eq) and 5-bromo-2-methylpyrimidine (104 mg, 0.6 mmol, 1.2 eq) in dioxane (5 mL) were added K₂C0₃ (103.5 mg, 0.75 mmol, 1.5 eq) in H₂0 (0.75 mL) and Pd(PPh₃)₄ (29 mg, 0.025 mmol, 0.05 eq). The mixture was stirred at 100 °C under nitrogen atmosphere overnight. After that, water (5 mL) was added and extracted with EA (10 mL x 2). The organic layer was dried over Na₂S0₄, filtered and concentrated. The resulting residue was purified by chromatography on silica gel column (PE/EA = 10/1, v/v) to give fert-butyl 2-(3-acetyl-5-(2-methylpyrimidin-5-yl)-lH-indazol-l-yl)acetate (130 mg, 71%) as a yellow solid. LCMS (M ⁺) m/z calculated 367.2, found 367.1.

[00419] To a solution of fert-butyl 2-(3-acetyl-5-(2-methylpyrimidin-5-yl)-lH-indazol- 1- yl)acetate (130 mg, 0.355 mmol, 1.0 eq) in DCM (3 mL) was added TFA (3 mL ) at rt. The mixture was stirred at rt overnight. Then the solution was concentrated to give 2-(3-acetyl-5-(2-methylpyrimidin-5-yl)-lH- indazol-l-yl)acetic acid (120 mg, 100%) as a yellow oil. LCMS (M+H⁺) m/z calculated 311.3, found 311.1.

[00420] A mixture of 2-(3-acetyl-5-(2-methylpyrimidin-5-yl)-lH-indazol-l-yl)acetic acid (400 mg, 0.33 mmol, 1.0 eq), (li?,35',45)-N-(6-bromopyridin-2-yl)-2-azabicyclo[2.2.1] heptane -3 -carboxamide trifluoroacetate (166 mg, 0.40 mmol, 1.2 eq), HATU (150 mg, 0.40 mmol, 1.2 eq) and DIEA (129 mg, 1.0 mmol, 3.0 eq) in DMF (6 mL) was stirred at rt overnight. The mixture was concentrated, and the resulting residue was purified by prep-HPLC to give (li?,35',45)-2-(2-(3-acetyl-5-(2-methylpyrimidin-5-yl)-lH-indazol- l-yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3-carboxamide (26 mg, 13%) as a white solid. LCMS (M+H⁺) m/z calculated 588.1, found 588.2. ¾ NMR DMSO-d₆, 400 MHz) δ 10.87 (s, 1H), 9.04 (s, 2H), 8.43 (s, 1H), 8.0-8.03 (d, 1H), 7.87 (s, 2H), 7.68-7.73 (m, 1H), 7.31-7.33 (d, 1H), 5.83-5.88 (d, IH), 5.51-5.56 (d, IH), 4.67 (s, IH), 4.10 (s, IH), 2.68 (s, 3H), 2.65(s, IH), 2.62 (s, 3H), 2.08-2.11 (d, IH), 1.78-1.83 (m, 3H), 1.44-1.51 (m, 2H).

Example 150: Preparation of (li?,35',45)-2-(2-(3-acetyl-5-(pyrimidin-5-yl)-lH-indazol-l-yl)acetyl)-N-(6- bromopyridin-2 -yl) -2 -azabicyclo [2.2.1 ]heptane -3 -carboxamide

(1 R,3S,4S)-2-(2-(3-acetyl-5-(pyrimidin-5-yl)-1 H-in^

-2-azabicyclo[2.2.1]heptane-3-carboxamide

[00421] A mixture of fert-butyl 2-(3-acetyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH- indazol-l-yl)acetate (1.0 g , 2.5 mmol, 1.0 eq), 5-bromopyrimidine (437.0 mg, 2.8 mmol, l . leq), Pd(PPh₃)₄ (144.0 mg, 0.13 mmol, 0.05 eq) and K₂C0₃ (517.0 mg, 3.75 mmol, 1.5 eq) in dioxane (25 mL) was stirred at 100 °C overnight under N₂. The reaction mixture was concentrated, and the resulting residue was purified by silica gel column (PE/EA = 2/1, v/v) to give fert-butyl 2-(3-acetyl-5-(pyrimidin-5-yl)-lH-indazol-l-yl)acetate (800 mg, 91%) as a white solid. LRMS (M+H⁺) m/z calculated 352.2, found 354.2.

[00422] To a solution of fert-butyl 2-(3-acetyl-5-(pyrimidin-5-yl)-lH-indazol-l-yl)acetate (800 mg, 2.27 mmol, 1.0 eq) in DCM (5 mL) was added TFA (3 mL) . The mixture was stirred at 30 °C overnight

The resulting mixture was concentrated to give the TFA salt of 2-(3-carbamoyl-5-(pyrimidin-5-yl)-lH- indazol-l-yl)acetic acid (930 mg , 100%). LRMS (M+H⁺) m/z calculated 297.1, found 297.0.

[00423] A mixture of the TFA salt of 2-(3-carbamoyl-5-(pyrimidin-5-yl)-lH-indazol-l-yl)acetic acid (1 : 1) (140 mg, 0.34 mmol, 1.0 eq), (l i^.S'^^-N-ie-bromopyridin^-y ^-azabicycloP^. llheptane-S- carboxamide (140 mg, 0.34 mmol, 1.0 eq), HATU (150 mg, 0.40 mmol, 1.2 eq) and DIEA (260 mg, 2.0 mmol, 6.0 eq) in DMF (10 mL) was stirred at 35 °C overnight. The mixture was concentrated and the resulting residue was purified by prep-HPLC to give ( li?,35',45)-2-(2-(3-acetyl-5-(pyrimidin-5-yl)-lH-indazol-l- yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3-carboxamide (91.6 mg, 47%) as a white solid. LRMS (M+H⁺) m/z calculated 574.1, found 574.9. ¾ NMR DMSO-d₆, 400 MHz) δ 1 1.31 (s, 0.16H), 10.89 (s, 0.86H), 9.21-9.22 (d, 1H), 9.18 (s, 2H), 8.47 (s, 1H), 8.01-8.17 (d, 1H), 7.90-7.92 (s, 2H), 7.69-7.73 (d, 1H), 7.31-7.33 (d, 1H), 5.85-5.89 (d, 1H), 5.53-5.57 (m, 1H), 4.68 (s, 1H),4.10 (s, 1H), 2.63-2.69 (m, 1H), 2.66 (s, 3H), 2.08-2.1 1 (m, 1H), 1.79-1.89 (m, 3H), 1.51-1.54 (m, 1H), 1.44-1.46 (m, 1H).

Example 151 : Preparation of ( li?,35',45)-2-(2-(3-acetyl-5-(2-methoxypyrimidin-5-yl)-lH-indazol-l - yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabi oxamide

(1 R,3S,4S)-2-(2-(3-acetyl-5-(2-methoxypyrimidin-5-yl)-1 H-indazol-1 -yl)acetyl)

-A/- 6-bromopyridin-

[00424] To a solution of fert-butyl 2-(3-acetyl-5-(2-methylpyrimidin-5-yl)-lH-indazol- 1 - yl)acetate (500 mg, 1.25 mmol, 1.0 eq) and 5-bromo-2-methoxypyrimidine (282 mg, 1.5 mmol, 1.2 eq) in dioxane/H₂0 (10 mL/1 mL) was added K₂C0₃ (259 mg, 1.88 mmol, 1.5 eq) and Pd(PPh₃)₄ (72 mg, 0.063 mmol, 0.05 eq). The mixture was stirred at 100 °C under nitrogen atmosphere overnight. After that, water (50 mL) was added and the mixture was extracted with EA (50 mL x 2). The organic layer was dried over Na₂S0₄, filtered and concentrated. The resulting residue was purified by chromatography on silica gel column (PE/EA = 1/1, v/v) to give fert-butyl 2-(3-acetyl-5-(2-methoxypyrimidin-5-yl)-lH-indazol-l -yl)acetate (590 mg, 61.8%) as a white solid. ⁺) m/z calculated 383.2, found 383.1.

[00425] To a solution of fert-butyl 2-(3-acetyl-5-(2-methoxypyrimidin-5-yl)-lH-indazol-l - yl)acetate (590 mg, 1.54 mmol, 1.0 eq) in DCM (8 mL) was added TFA (8 mL ) at rt. The mixture was stirred at rt overnight. Then the solution was concentrated to give 2-(3-acetyl-5-(2-methoxypyrimidin-5-yl)-lH- indazol-l -yl)acetic acid ( 1.0 g, 100%) as a yellow oil. LRMS (M+H⁺) m/z calculated 327.1, found 327.0.

[00426] A mixture of 2-(3-acetyl-5-(2-methoxypyrimidin-5-yl)-lH-indazol-l-yl)acetic acid trifluoroacetate (100 mg, 0.24 mmol, 1.0 eq), (l ^SS^^-N-^-bromopyridin^-yl) -2-azabicyclo[2.2.1] heptane -3 -carboxamide trifluoroacetate (116 mg, 0.28 mmol, 1.2 eq), HATU (150 mg, 0.28 mmol, 1.2 eq) and DIEA (91 mg, 0.71 mmol, 3.0 eq) in DMF (5 mL) was stirred at rt overnight. The mixture was concentrated and the resulting residue was purified by prep-HPLC to afford (li?,35^*,45)-2-(2-(3-acetyl-5-(2- methoxypyrimidin-5-yl)-lH-indazol-l-yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3- carboxamide (25 mg, 18%) as a white solid. LRMS (M+H⁺) m/z calculated 604.1, found 604.1.

¾ NMR (DMSO-£/₆, 400 MHz) δ 10.86 (s, 1H), 8.95 (s, 2H), 8.37 (s, 1H), 8.0-8.03 (d, 1H), 7.79-7.84 (m, 2H), 7.68-7.73 (m, 1H), 7.31-7.32 (d, 1H), 5.82-5.86 (d, 1H), 5.50-5.55 (d, 1H), 4.67 (s, 1H), 4.10 (s, 1H), 3.98 (s, 3H), 2.69 (s, 1H), 2.65 (s, 3H), 2.07-2.11 (d, 1H), 1.78-1.80 (m, 3H), 1.44-1.51 (m, 2H).

Example 152: Preparation of 2-{2-[3-Acetyl-5-(2-cyano-pyrimidin-5-yl)-indazol-l-yl]-acetyl}-2-aza- bicyclo[2.2. l]heptane-3-carboxylic acid (6-bromo-pyridin-2-yl)-amide

2-{2-[3-Acetyl-5-(2-cyano-pyrimidin-5-yl)-indazol-1 -yl]-acetyl}-2-aza-bicyclo[2.2.1 ]heptane

-3-carboxylic acid (6-bromo-pyridin-2-yl)-amide

[00427] To a solution of fert-butyl 2-(3-acetyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)- lH-indazol-l-yl)acetate (700 mg, 1.75 mmol, 1.0 eq) in DCM (25 mL) was added TFA (25 mL). The mixture was stirred at rt overnight. The resulting mixture was concentrated to give the TFA salt of 2 -(3 -acetyl -5- (4,4,5, 5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-indazol-l-yl)acetic acid (700 mg , 100%) as an off-white solid. LRMS (M+H⁺) m/z calculated 401.2, found 401.2.

[00428] A mixture of TFA salt of 2-(3-acetyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH- indazol-l -yl)acetic acid ( 170 mg, 0.5 mmol, 1.0 eq), (lR,3S,4S)-N-(6-bromopyridin-2-yl)-2- azabicyclo[2.2.1]heptane-3-carboxamide (205.0 mg, 0.5 mmol, l .Oeq), HATU (230 mg, 0.6 mmol, 1.2 eq) and DIEA (468 mg, 3.6 mmol, 6.0 eq) in DMF (10 mL) was stirred at rt overnight. The reaction mixture was concentrated and the resulting residue was purified by prep-HPLC to give

(li?,3^,4^-2^2^3-acetyl-5 4,4,5,5 etramethyl-l,3,2-dioxaborolan-2-yl)-lH ndazol-l-yl)acetyl)-N-(6^ bromopyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3-carboxamide (170 mg, 54.0%) as a white solid. LRMS (M+H⁺) m/z calculated

[00429] A mixture of (li?,35',45)-2-(2-(3-acetyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)- lH-indazol-l -yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3-carboxamide ( 170 mg , 0.27 mmol, 1.0 eq), 5-bromopyrimidine-2-carbonitrile (50 mg, 0.27 mmol, 1.0 eq), Pd(dppf)Cl₂.DCM (20.0 mg, 0.027 mmol, 0.1 eq) and K₂C0₃ (75.0 mg, 0.54 mmol, 2.0 eq) in THF/H₂0 (10 mL/1 mL) was stirred at 90 °C overnight under N₂. The reaction mixture was concentrated and the resulting residue was purified by prep- HPLC to give (li?,3^,4,S)-2-(2-(3-acetyl-5-(2-cyanopyrimidin-5-yl)-lH-indazol-l -yl)acetyl)-N-(6- bromopyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3-carboxamide (41.8 mg, 26%) as a white solid. LRMS (M+H⁺) m/z calculated 599.1, found 598.9. ¾ NMR DMSO-d₆, 400 MHz) δ 10.86 (s, 1H), 9.41 (s, 2H), 8.59 (s, 1H), 7.92-8.02 (m, 3H), 7.68-7.72 (t, 1H), 7.30-7.32 (m, 1H), 5.85-5.89 (d, 1H), 5.53-5.57 (d, 1H), 4.67 (s, 1H), 4.1 1 (s, 1H), 2.64-2.70 (m, 1H), 2.66 (s, 3H), 2.07-2.1 1 (m, 1H), 1.79-1.89 (m, 3H), 1.44-1.54 (m, 2H). Example 153: Preparation of methyl (3-acetyl-l -(2-(( lR,3S,4S)-3-((6-bromopyridin-2-yl)carbamoyl)-2- azabicyclo [2.2.1 ]heptan-2-yl)-2-oxoethyl)- lH-indazol-5 -yl)carbamate

[00430] A mixture of (lR,3S,4S)-N-(6-bromopyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3- carboxamide (888 mg, 3.00 mmol, 1.0 eq), 2-(3-acetyl-5-((tert-butoxycarbonyl)amino)-lH-indazol-l-yl)acetic acid (1.00 g, 3.00 mmol, 1.0 eq), HATU (1.36 g, 3.59 mmol, 1.2 eq) and DIEA (581 mg, 4.50 mmol, 1.5 eq) in DMF (6 mL) was stirred at rt for 3 h. The reaction mixture was purified by prep-HPLC to give fert-butyl (3-acetyl-l-(2-((lR,3S,4S)-3-((6-bromopyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)- lH-indazol-5-yl)carbamate (1.70 g, 92%) as a white solid. LRMS (M+H⁺) m/z calculated 611.2, found 610.9 and 612.9.

[00431] To a solution of fert-butyl (3-acetyl-l-(2-((lR,3S,4S)-3-((6-bromopyridin-2- yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-lH-indazol-5-yl)carbamate(1.45 g,2.37 mmol,l eq) in DCM (16 mL) was added TFA slowly at 0 °C. The resulting mixture was stirred at rt for 1 h and concentrated. The resulting residue was purified by prep-HPLC to give (lR,3S,4S)-2-(2-(3-acetyl-5-amino- lH-indazol-1 -yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[2.2.1] heptane -3 -carboxamide ( 1.06 g,87%) as a yellow solid LCMS (M+H⁺) m/z calculated 511.1, found 511.0.

[00432] To a mixture of (lR,3S,4S)-2-(2-(3-acetyl-5-amino-lH-indazol-l-yl)acetyl)-N-(6- bromopyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3-carboxamide (200.0 mg,0.4 mmol, 1.0 eq), methyl carbonochloridate (57.0 mg, 0.6 mmol, 1.5 eq) in NMP (1.5 mL) was added DIEA (155.0 mg, 1.2 mmol, 3.0 eq) at 0 °C. The result mixture was stirred at rt fori h. The resulting mixture was purified by prep-HPLC to afford methyl (3-acetyl-l-(2-((lR,3S,4S)-3-((6-bromopyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2- yl)-2-oxoethyl)-lH-indazol-5-yl)carbamate (160.0 mg, 72%) as a white solid. LRMS (M+H⁺) m/z calculated 569.1, found 569.0. ¾ NMR (DMSO- ₆, 400 MHz) δ 11.2 (s, 0.19H), 10.84 (s,0.73H), 9.73 (s, l .OH), 8.15 (s, 1H), 8.13 (d, 0.21H), 8.01 (d, 0.78H), 7.80-7.68 (m, 1H), 7.61 (d, 0.83H),7.54-7.51 (m, 1.16H), 7.37 (d, 0.16H), 7.31 (d, 0.82H), 5.29 (d, 0.85H), 5.44-5.36 (m, 1H), 4.89 (d, 0.15H), 4.60 (s, 0.83H), 4.47 (s, 0.17H), 4.38 (s, 0.17H), 4.08 (s, 0.93H), 3.68 (s, 3H), 2.68 (s, 1H), 2.67 (d, 3H), 2.03 (d, 1H) 1.90-1.66 (m,3H), 1.59- 1.43 (m, 2H).

Example 154: Preparation of (lR,3S,4S)-2-(2-(3-acetyl-5-(2-chlorobenzamido)-lH-indazol-l-yl)acetyl)-N- (6-bromopyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3-carboxamide

[00433] To a mixture of (lR,3S,4S)-2-(2-(3-acetyl-5-amino-lH-indazol-l-yl)acetyl)-N-(6- bromopyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3-carboxamide (200.0 mg, 0.4 mmol, 1.0 eq), 2-chlorobenzoic acid (94.4 mg, 0.60 mmol, 1.5 eq), HATU (297.2 mg, 0.78 mmol, 2.0 eq) in NMP (1.5 mL) was added DIEA (155.0 mg, 1.2 mmol, 3.0 eq) at 0 °C. The reaction mixture was stirred at rt for 1 h. The resulting mixture was purified by prep-HPLC to afford (lR,3S,4S)-2-(2-(3-acetyl-5-(2-chlorobenzamido)-lH-indazol-l-yl)acetyl)- N-(6-bromopyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3-carboxamide (160 mg, 63%) as a white solid. LRMS (M+H⁺) m/z calculated 649.1, found 648.8. ¾ NMR (DMSO- 6, 400 MHz) δ 11.2 (s, 0.15H), 10.84 (s,0.85H), 10.64 (s, 0.97H), 8.68 (s, 1H), 8.15 (d, 0.17H), 8.06 (d, 0.83H), 7.80-7.44 (m, 7H), 7.38 (d, 0.17H),7.32 (m, 0.84H), 5.77 (d, 0.87H), 5.48-5.41 (m, 1H), 4.93 (d, 0.15H), 4.65 (s, 0.81H), 4.48 (s, 0.16H), 4.38 (s, 0.17H), 4.09 (s, 0.93H), 2.73 (s, 1H), 2.62 (d, 3H), 2.07 (d, 1H), 1.91-1.52 (m, 3H), 1.31-1.23 (m, 2H).

Example 155: Preparation of (lR,3S,4S)-2-(2-(3-acetyl-5-(nicotinamido)-lH-indazol-l-yl)acetyl)-N-(6- bromopyridin-2 -yl) -2 -azabicyclo [2.2.1 ]heptane -3 -carboxamide

(1 R,3S,4S)-2-(2-(3-acetyl-5-(nicotinamido)-1 H-indazol-1 -yl)acetyl)-N-(6-bromopyridin

[00434] To a mixture of (lR,3S,4S)-2-(2-(3-acetyl-5-amino-lH-indazol-l-yl)acetyl)-N-(6- bromopyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3-carboxamide (204 mg, 0.40 mmol, 1.0 eq), nicotinic acid (49 mg, 0.40 mmol, 1.0 eq) in NMP (1.5 mL) were added HATU (182 mg, 0.48 mmol, 1.2 eq) and DIEA (77 mg, 0.60 mmol, 1.5 eq) at 0 °C. The reaction mixture was stirred at rt for 3 h. The resulting mixture was purified by prep-HPLC to give (lR,3S,4S)-2-(2-(3-acetyl-5-(nicotinamido)-lH-indazol-l-yl)acetyl)-N-(6- bromopyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3-carboxamide (126.3 mg, 51%) as a pale yellow solid. LRMS (M+H⁺) m/z calculated 616.1, found 616.1. ¾ NMR (DMSO- ₆, 400 MHz) δ 11.28 (s, 0.15H), 10.89 (s, 0.85H), 10.61 (s, 1H), 9.15 (d, 1H), 8.77 (dd, 1H), 8.66 (d, lH), 8.38-8.32 (m, 1H), 8.15 (d, 0.15H), 8.02 (m, 0.85H), 7.90-7.85 (m, 1H), 7.79 (t, 0.15H), 7.75-7.67 (m, 1.70H), 7.63 (d, 0.15H), 7.58 (dd, lH), 7.38 (d, 0.15H), 7.32 (d, 0.85H), 5.78 (d, 0.85H), 5.47 (d, 0.85H), 5.45 (d, 0.15H), 4.94 (d, 0.15H), 4.66 (s, 0.85H), 4.49 (s, 0.15H), 4.41 (s, 0.15H), 4.10 (s, 0.85H), 2.93 (d, 0.15H), 2.69 (s, 0.85H), 2.63 (s, 2.55H), 2.59 (s, 0.45H), 2.09 (d, 0.85H), 1.89-1.20 (m, 5.15H).

Example 156: Preparation of (lR,3S,4S)-2-(2-(3-acetyl-5-(3-methylureido)-lH-indazol-l-yl)acetyl)-N-(6- bromopyridin-2 -yl) -2 -azabicyclo [2.2.1 ]heptane -3 -carboxamide

[00435] To a cooled solution of CDI (3.26 g, 20.0 mmol) in THF (30 mL) was added dropwise a solution of methanamine (2.0 M in THF, 10 mL) at 0 °C. The reaction mixture was stirred at rt for 2 h to give a solution of N-methyl-lH-imidazole-l-carboxamide in THF (0.5 M). A mixture of (lR,3S,4S)-2-(2-(3-acetyl- 5-amino-lH-indazol-l-yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3-carboxamide (320.0 mg, 0.63 mmol, 1.0 eq), N-methyl-lH-imidazole-l-carboxamide (0.5 M in THF, 2.6 mL, 1.3 mmol, 2.1 eq) and DIEA (169.0 mg, 1.31 mmol, 2.1 eq) in NMP (2 mL) was stirred at 80 °C for 36 h under N₂. The resulting mixture was purified by prep-HPLC to afford (lR,3S,4S)-2-(2-(3-acetyl-5-(3-methylureido)-lH-indazol-l- yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3-carboxamide (116.0 mg, 32.8%) as a white solid. LRMS (M+H⁺) m/z calculated 568.1, found 568.0. ¾ NMR DMSO-d₆, 400 MHz) δ 11.28 (s, 0.15H), 11.01 (s, 0.85H), 8.69 (s, 1H), 8.23 (s, 1H), 8.15 (d, 0.15H), 8.01 (d, 0.85H), 7.78 (t, 0.17H), 7.70 (t, 0.83H), 7.56-7.48 (m, 2H), 7.38 (d, 0.15H), 7.32 (d, 0.85H), 5.97 (s, 1H), 5.71 (d, 0.82H), 5.39 (t, 1H), 4.90 (d, 0.15H), 4.65 (s, 0.86H), 4.49 (s, 0.14H), 4.42 (s, 0.16H), 4.15 (s, 0.87H), 2.93 (s, 0.12H), 2.70 (s, 0.91H), 2.65 (s, 3H), 2.58 (s, 2.41H), 2.54 (s, 0.65H), 2.10 (d, 1H), 1.89-1.68 (m, 3H), 1.62-1.40 (m, 2H).

Example 157: Preparation of (li?,35',45)-2-(2-(3-acetyl-5-(2-methylpyrimidin-5-yl)-lH-indazol-l-yl)acetyl)- N-(6 -chloropyridin-2-yl) -2 -azabicyclo [2.2.1] heptane -3 -carboxamide

a

[00436] A mixture of 2-(3-acetyl-5-(2-methylpyrimidin-5-yl)-lH-indazol-l-yl)acetic acid (120 mg, 0.30 mmol, 1.0 eq), (l i^^^-N-ie-chloropyridin^-y^^-azabicyclo [2.2.1]heptane-3-carboxamide (89 mg, 0.36 mmol, 1.2 eq), HATU (135 mg, 0.36 mmol, 1.2 eq) and DIEA (114 mg, 0.9 mmol, 3.0 eq) in DMF (5 mL) was stirred at rt overnight. The mixture was concentrated and the resulting residue was purified by prep-HPLC to afford (lR,3S,4S)-2-(2-(3 -acetyl-5-(2-methylpyrimidin-5 -yl)-lH-indazol- 1 -yl)acetyl)-N-(6- chloropyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3-carboxamide (24 mg, 15%) as a white solid. LCMS (M+H⁺) m/z calculated 544.2, found 544.0. ¾ NMR DMSO-d₆, 400 MHz) δ 10.85 (s, IH), 9.04 (s, 2H), 8.43 (s, IH), 7.98-8.0 (d, IH), 7.87 (s, 2H), 7.80-7.83 (m, IH), 7.18-7.20 (d, IH), 5.84-5.88 (d, IH), 5.52-5.56 (d, IH), 4.67 (s, lH), 4.10 (s, IH), 2.68 (s, 3H), 2.65 (s, IH), 2.62 (s, 3H), 2.08-2.11 (d, IH), 1.78-1.80 (m, 3H), 1.44-1.46 (m, 2H).

Example 158: Preparation of (li?,35',45)-2-(2-(3-acetyl-5-(2-methoxypyrimidin-5-yl)-lH-indazol-l- yl)acetyl)-N-(6-chloropyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3-carboxamide

(1 R,3S,4S)-2-(2-(3-aoetyl-5-(2-methox pyrimidin-5-yl)-1 H-indazol-1 - yl)acetyl)-N-(6-chloropyridin-2-yl)-2-azabicyclo|2.2.1]heptane-3-carboxamide

[00437] A mixture of (l i^^^^-N-ie-chloropyridin^-y ^-azabicycloP^. l]heptane-3- carboxamide (59.4 mg, 0.236 mmol, 1.0 eq), 2-(3-acetyl-5-(2-methoxypyrimidin-5-yl)-lH-indazol-l-yl)acetic acid (100 mg, 0.306 mmol, 1.3 eq), HATU (135 mg, 0.354 mmol, 1.5 eq) and DIEA (122 mg, 0.944 mmol, 4.0 eq) in DMF (5 mL) was stirred at 35 °C for 1.5 h. The resulting mixture was purified by prep-HPLC to give (li?,3^,4^-2-(2-(3-acetyl-5-(2-methoxypyrimidin-5-yl)-lH-indazol-l-yl)acetyl)-N-(6-chloropyridin-2- yl)-2-azabicyclo[2.2.1]heptane-3-carboxamide (49.1 mg, 37%) as a white solid. LRMS (M+H⁺) m/z calculated 560.2, found 560.0. ¾NMR (DMSO- ₆, 400 MHz) δ 10.87 (s, IH), 8.95 (s, 2H), 8.38 (s, IH), 7.98-8.00 (d, IH), 7.80-7.87 (m, 3H), 7.18-7.20 (d, IH), 5.83-5.87 (d, IH), 5.51-5.55 (d, IH), 4.67 (s, IH), 4.10 (s, IH), 3.99 (s, 3H), 2.69 (s, IH), 2.65 (s, 3H), 2.07-2.08 (d, IH), 1.78-1.88 (m, 3H), 1.44-1.46 (d, 2H) Example 159: Preparation of (li?,35',45)-2-(2-(3-acetyl-5-(pyrimidin-5-yl)-lH-indazol-l-yl)acetyl)-N-(6- chloropyridin-2-yl)-2-azabicyclo [2.2.1 ]heptane-3 -carboxamide

(1R,3S,4S)-2-(2-(3-acetyl-5-(pyrimidin-5-yl)-1H-indazol-1-yl)acetyl)-W-(6-chloropyridin-2-yl^

[00438] A mixture of fert-butyl 2-(3-acetyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH- indazol-l-yl)acetate (1.0 g , 2.5 mmol, 1.0 eq), 5-bromopyrimidine (437.0 mg, 2.8 mmol, l . leq), Pd(PPh₃)₄ (144.0 mg, 0.13 mmol, 0.05 eq) and K₂C0₃ (517.0 mg, 3.75 mmol, 1.5 eq) in dioxane (25 mL) was stirred at 100 °C overnight under N₂. The reaction mixture was concentrated and The resulting residue was purified by chromatography on silica gel column (PE/EA = 2/1, v/v) to give fert-butyl 2-(3-acetyl-5-(pyrimidin-5-yl)-lH- indazol-l-yl)acetate (800 mg, 91%) as a white solid. LRMS (M+H⁺) m/z calculated 352.2, found 354.2.

[00439] To a solution of fert-butyl 2-(3-acetyl-5-(pyrimidin-5-yl)-lH-indazol-l-yl)acetate (800 mg, 2.27 mmol, 1.0 eq) in DCM (5 mL) was added TFA (3 mL). The mixture was stirred at 30 °C overnight. The resulting mixture was concentrated to give the TFA salt of 2-(3-carbamoyl-5-(pyrimidin-5-yl)-lH- indazol-l-yl)acetic acid (930 mg , 100%) as an off white solid. LRMS (M+H⁺) m/z calculated 297.1, found 297.0.

[00440] A mixture of the TFA salt of 2-(3-carbamoyl-5-(pyrimidin-5-yl)-lH-indazol-l-yl)acetic acid (140 mg, 0.34 mmol, 1.0 eq), (l i^.S'^^-N-ie-chloropyridin^-y ^-azabicycloP^. llheptane-S- carboxamide (85 mg, 0.34 mmol, 1.0 eq), HATU (150 mg, 0.40 mmol, 1.2 eq) and DIEA (260 mg, 2.0 mmol, 6.0 eq) in DMF (10 mL) was stirred at 35 °C overnight. The mixture was concentrated, and the resulting residue was purified by prep-HPLC to give (li?,35',45)-2-(2-(3-acetyl-5-(pyrimidin-5-yl)-lH-indazol-l- yl)acetyl)-N-(6-chloropyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3-carboxamide (62.6 mg, 31.3%) as a white solid. LRMS (M+H⁺) m/z calculated 530.2, found 530.2. ¾ NMR DMSO-d₆, 400 MHz) δ 11.29 (s, 0.16H), 10.87 (s, 0.86H), 9.21-9.22 (d, IH), 9.18 (s, 2H), 8.47 (s, IH), 7.98-8.11 (d, IH), 7.90-7.92 (s, 2H), 7.79-7.84 (d, IH), 7.18-7.26 (d, IH), 5.85-5.89 (d, IH), 5.53-5.57 (m, IH), 4.68 (s, IH), 4.10 (s, IH), 2.63-2.69 (m, IH), 2.66 (s, 3H), 2.08-2.11 (m, IH), 1.79-1.89 (m, 3H), 1.51-1.54 (m, IH), 1.44-1.47 (m, IH).

Example 160: Preparation of (li?,35',45)-2-(2-(3-acetyl-5-(2-cyanopyrimidin-5-yl)-lH-indazol-l-yl)acetyl)- N-(6 -chloropyridin-2-yl) -2 -azabicyclo [2.2.1] heptane -3 -carboxamide

[00441] A mixture of TFA salt of 2-(3-acetyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH- indazol-l-yl)acetic acid (180 mg, 0.39 mmol, 1.0 eq), (li?,3S,4,S)-N-(6-chloropyridin-2-yl)-2- azabicyclo[2.2.1]heptane-3-carboxamide hydrochloride (108.5 mg, 0.43 mmol, 1.1 eq), HATU (224.0 mg, 0.59 mmol, 1.5 eq) and DIEA (304.2 mg, 2.36 mmol, 6.0 eq) in DMF (10 mL) was stirred at rt overnight. After that, water (20 mL) was added and the mixture was extracted with EA (20 mL x 3). The combined organic layers were washed with water(50 mL), dried over Na₂S0₄, filtered and concentrated. The resulting residue was purified by cchromatography on silica gel column (EA) to give (li?,35^*,45)-2-(2-(3-acetyl-5- (4,4,5, 5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-indazol-l-yl)acetyl)-N-(6-chloropyridin-2-yl)-2- azabicyclo[2.2.1]heptane-3-carboxamide (200 mg, 88%) as a white solid. LCMS (M+H⁺) m/z calculated 578.2 found 578.1

[00442] To a solution of (li?,35',45)-2-(2-(3-acetyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)-lH-indazol-l-yl)acetyl)-N-(6-chloropyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3-carboxamide (200 mg, 0.35 mmol, 1.0 eq) in dioxane/H₂0 (10 mL/1 mL) were added 5-bromopyrimidine-2-carbonitrile (63.4 mg, 0.35 mmol, 1.0 eq), K₂C0₃ (71.8 mg, 0.52 mmol, 1.5 eq) and Pd(PPh₃)₄ (20.0 mg, 0.017 mmol, 0.05 eq). The reaction mixture was stirred at 100 °C overnight under nitrogen atmosphere. The mixture was concentrated and the resulting residue was purified by prep-HPLC to give (\R,3S,4S)-2-(2-(3 -acetyl -5 -(2-cyanopyrimidin- 5-yl)-lH-indazol-l-yl)acetyl)-N-(6-chloropyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3-carboxamide (42.9mg, 22.3%) as a white solid. LRMS (M+H⁺) m/z calculated 555.2, found 555.2. ¾ NMR DMSO-d₆, 400 MHz) δ 10.90 (s, 1H), 9.43 (s, 2H),4.59 (s, 1H), 7.93-8.01 (m, 3H), 7.80-7.82 (m, 1H), 7.18-7.20 (m, 1H), 5.88-5.92 (d, 1H), 5.54-5.59 (d, 1H), 4.68 (s, 1H), 4.10 (s, 1H), 2.64-2.69 (m, 4H), 2.08-2.11 (m, 1H), 1.79-1.81 (m, 3H), 1.44-1.51 (m, 2H).

Example 161: Preparation of methyl (3-acetyl-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo [2.2.1 ]heptan-2-yl)-2-oxoethyl)- lH-indazol-5 -yl)carbamate

methyl

-2-azab

[00443] To a mixture of 5-nitro-lH-indazole (20.0 g, 69.2 mmol, 1.0 eq), KOH (7.7 g, 138.4 mmol, 2.0 eq) in DMF (250 mL) was added I₂ (31.6 g, 124.6 mmol, 1.8 eq). The reaction mixture was stirred at 30 °C for 2 h. The reaction was poured into aqueous Na₂S0₃ solution and stirred for 30 min. The resulting solid was collected to give 3-iodo-5-nitro-lH-indazole (32.0 g, 90%). LRMS (M+H⁺) m/z calculated 289.9, found 289.8.

[00444] To a suspension of 5-bromo-3-iodo-lH-indazole (32.0 g, 110.7 mmol, 1.0 eq) and potassium carbonate (30.5 g, 221.4 mmol, 2.0 eq) in DMF (400 mL) was added fert-butyl bromoacetate (25.9 g, 132.8 mmol, 1.2 eq) dropwise at rt. The resulting mixture was stirred at rt for 2 h. The mixture was diluted with EA (2 L) and washed with brine (1 L x 4), dried over Na₂S0₄, filtered and concentrated. The resulting residue was washed with PE (200 mL) to afford fert-butyl 2-(3-iodo-5-nitro-lH-indazol-l-yl)acetate (37.6 g, 83.0%) as a yellow solid. ⁺) m/z calculated 404.0, found 347.8 (M-56+H⁺).

[00445] To a mixture of fert-butyl 2-(3-iodo-5-nitro-lH-indazol-l-yl)acetate (9.0 g, 22.3 mmol,

1.0 eq) and tetrakis(triphenylphosphine)palladium (386.0 mg, 0.33 mmol, 0.015 eq) in DMF (90.0 mL) was added tributyl(l-ethoxyvinyl)stannane (8.9 g, 24.6 mmol, 1.1 eq). The resulting mixture was stirred at 100 °C for 5.5 h under N₂. After the reaction mixture was cooled to rt, 4 N HC1 (9 mL) was added. The mixture was stirred at rt for 30 min. The mixture was diluted with EA (500 mL) and washed with brine (500 mL x 3), dried over Na₂S0₄, filtered and concentrated. The resulting crude was purified by chromatography on silica gel column (PE/EA = 5/1, v/v) to give fert-butyl 2-(3-acetyl-5-nitro-lH-indazol-l-yl)acetate (6.8 g, 95.4%) as a brown solid. LRMS (M+H⁺ -56+H⁺).

[00446] To a mixture of fert-butyl 2-(3-acetyl-5-nitro-lH-indazol-l-yl)acetate (7.0 g, 21.9 mmol,

1.0 eq) in DCM (70 mL) was added TFA (18 mL) slowly at 0 °C. The result mixture was stirred at rt for 6 h. The mixture was concentrated and the resulting residue was treated with MeOH (50 mL). The mixture was concentrated to afford 2-(3-acetyl-5-nitro-lH-indazol-l-yl)acetic acid (5.3 g, 92.0%) as a yellow solid. LRMS (M+H⁺) m/z calculated 264.0, found 264.1

[00447] To a mixture of (lR,3S,4S)-N-(6-chloropyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3- carboxamide (3.7 g,14.9 mmol, 1.0 eq), 2-(3-acetyl-5-nitro-lH-indazol-l-yl)acetic acid (4.6 g,17.6 mmol, 1.2 eq) and HATU (6.8 g, 17.9 mmol, 1.2 eq) in DMF (37 mL) was added DIEA (2.9 g, 22.3 mmol, 1.5 eq) slowly at 0 °C. The result mixture was stirred at rt for 3.5 h. The reaction mixture was treated with EA (500 mL) and washed with brine (500 mL x 3), dried over Na₂S0₄, filtered and concentrated. The resulting residue was purified by chromatography on silica gel column (DCM/MeOH = 100/1, v/v) to give (lR,3S,4S)-2-(2-(3- acetyl-5-nitro-lH-indazol-l-yl)acetyl)-N-(6-chloropyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3-carboxami (7.3 g, 98.6%) as a yello ⁺) m/z calculated 497.1, found 496.9.

[00448] A mixture of (lR,3S,4S)-2-(2-(3-acetyl-5-nitro-lH-indazol-l-yl)acetyl)

chloropyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3-carboxamide (7.3 g, 14.7 mmol, 1.0 eq), Fe (4.1 g,73.4 mmol, 5.0 eq) and NH₄C1 (3.9 g, 73.4 mmol, 5.0 eq) in EtOH (138 mL) and H₂0 (69 mL) was stirred at 80 °C for 1.5 h under N₂. The mixture was diluted with EA (1 L) and filtered by Celite. The filtrate was washed with brine (500 mL x 3), dried over Na₂S0₄, filtered and concentrated to give (lR,3S,4S)-2-(2-(3-acetyl-5-amino- lH-indazol-l-yl)acetyl)-N-(6-chloropyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3-carboxamide (6.3 g, 92.5%) as a yellow solid. LRM ⁺) m/z calculated 467.1, found 466.9.

[00449] To a mixture of (lR,3S,4S)-2-(2-(3-acetyl-5-amino-lH-indazol-l-yl)acetyl)-N-(6- chloropyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3-carboxamide (200.0 mg, 0.43 mmol, 1.0 eq) and methyl carbonochloridate (81.0 mg, 0.86 mmol, 2.0 eq) in NMP (1.5 mL) at 0 °C was added slowly DIEA (110.5 mg, 0.86 mmol, 2.0 eq). The mixture was stirred at 0 °C for 1 h and purified by prep-HPLC to afford methyl (3- acetyl-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)- lH-indazol-5-yl)carbamate(103.7 mg, 46.1%) as a white solid. LRMS (M+H⁺) m/z calculated 525.1, found 525.1. ¾ NMR DMSO-d₆, 400 MHz) δ 11.23 (s, 0.15H), 10.82 (s, 0.85H), 9.79 (s, 1H), 8.34 (s, 1H), 8.09 (d, 0.21H), 7.98 (d, 0.81H), 7.92-7.75 (m, 1H), 7.70-7.46 (m, 2H), 7.32-7.07 (m, 1H), 5.72 (d, 0.83H), 5.42 (d, 1H), 4.90 (d, 0.15H), 4.64 (s, 0.86H), 4.48 (s, 0.18H), 4.38 (s, 0.16H), 4.09 (s, 0.87H), 3.68 (s, 3H), 2.91 (s, 0.22H), 2.68 (s, 0.80H), 2.59 (s, 2.70H), 2.56 (s, 0.35H), 2.07 (d, 1H), 1.91-1.65 (m, 3H), 1.64-1.35 (m, 2H). Example 162: Preparation of (lR,3S,4S)-2-(2-(3-acetyl-5-(nicotinamido)-lH-indazol-l-yl)acetyl)-N-(6- chloropyridin-2-yl)-2-azabicyclo [2.2.1 ]heptane-3 -carboxamide

(1 R,3S,4S)-2-(2-(3-acetyl-5-(nicotinamido)-1 H-indazol-1 -yl)acetyl)

-W-(6-chloropyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3-carboxamide

[00450] To a mixture of (lR,3S,4S)-2-(2-(3-acetyl-5-amino-lH-indazol-l-yl)acetyl)-N-(6- chloropyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3-carboxamide (200.0 mg, 0.43 mmol, 1.0 eq), HATU (196.1 mg, 0.52 mmol, 1.2 eq) and nicotinic acid (58.2 mg, 0.47 mmol, 1.1 eq) in NMP (1.5 mL) was added DIEA (83.2 mg, 0.64 mmol, 1.5 eq) slowly at 0 °C. The reaction mixture was stirred at rt for 1 h. The resulting mixture was purified by prep-HPLC to afford (lR,3S,4S)-2-(2-(3-acetyl-5-(nicotinamido)-lH-indazol-l- yl)acetyl)-N-(6-chloropyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3-carboxamide (119.2 mg, 51.5%) as a white solid. LRMS (M+H⁺) m/z calculated 572.2, found 572.1. ¾ NMR DMSO-d₆, 400 MHz) δ 11.24 (s, 0.15H), 10.84 (s, 0.85H), 10.60 (s, 1H), 9.15 (d, 1H), 8.77 (dd, 1H), 8.65 (d, 1H), 8.37-8.30 (m, 1H), 8.12 (d, 0.15H), 7.99 (d, 0.85H), 7.92-7.79 (m, 2H), 7.70 (d, 0.85H), 7.63 (d, 0.15H), 7.59-7.56 (m, 1H), 7.23 (d, 0.15H), 7.18 (d, 0.85H), 5.78 (d, 0.85H), 5.50-5.42 (m, 1H), 4.94 (d, 0.15H), 4.65 (s, 0.85H), 4.49 (s, 0.15H), 4.41 (s, 0.15H), 4.10 (s, 0.85H), 2.92 (s, 0.20H), 2.69 (s, 0.81H), 2.63 (s, 2.70H), 2.59 (s, 0.35H), 2.08 (d, 1H), 1.91- 1.65 (m, 3H), 1.64-1.35 (m, 2H).

Example 163: Preparation of (lR,3S,4S)-2-(2-(3-acetyl-5-(2-chlorobenzamido)-lH-indazol-l-yl)acetyl)-N- (6 -chloropyridin-2 -yl) -2 -azabicyclo [2.2.1 ]heptane -3 -carboxamide

(1R,3S,4S)-2-(2-(3-acetyl-5-(2-chlorobenzamido)-1H-indazol-1-yl)acetyl)

-N-(6-chloropyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3-carboxamide

[00451] To a mixture of (lR,3S,4S)-2-(2-(3-acetyl-5-amino-lH-indazol-l-yl)acetyl)-N-(6- chloropyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3-carboxamide (200.0 mg, 0.43 mmol, 1.0 eq), HATU (196.1 mg, 0.52 mmol, 1.2 eq) and 2-chlorobenzoic acid (73.6 mg, 0.47 mmol, 1.1 eq) in NMP (1.5 mL) was added DIEA (83.2 mg, 0.64 mmol, 1.5 eq) slowly at 0 °C. The result mixture was stirred at rt for 1 h. The reaction mixture was purified by prep-HPLC to afford (lR,3S,4S)-2-(2-(3-acetyl-5-(2-chlorobenzamido)-lH-indazol- l-yl)acetyl)-N-(6-chloropyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3-carboxamide (107.0 mg, 45.9%) as a white solid. LRMS (M+H⁺) m/z calculated 605.1, found 604.9. ¾ NMR (DMSO- ₆, 400 MHz) δ 11.24 (s, 0.15H), 10.83 (s, 0.85H), 10.68 (s, IH), 8.12 (d, 0.15H), 7.99 (d, 0.85H), 7.89 (t, 0.15H), 7.81 (t, 0.85H), 7.76- 7.64 (m, 2H), 7.64-7.56 (m, 2H), 7.25 (d, 0.15H), 7.18 (d, 0.85H), 5.76 (d, 0.85H), 5.50-5.41 (m, IH), 4.93 (d, 0.15H), 4.65 (s, 0.85H), 4.49 (s, 0.15H), 4.40 (s, 0.15H), 4.10 (s, 0.85H), 2.92 (s, 0.2H), 2.69 (s, 0.8 IH), 2.62 (s, 2.7H), 2.58 (s, 0.35H), 2.08 (d, IH), 1.90-1.63 (m, 3H), 1.63-1.35 (m, 2H)

Example 164: Preparation of (lR,3S,4S)-2-(2-(3-acetyl-5-(3-methylureido)-lH-indazol-l-yl)acetyl)-N-(6- chloropyridin-2-yl)-2-azabicyclo [2.2.1 ]heptane-3 -carboxamide

(1 ,3S,4S)-2-(2-(3-acetyl-5-(3-methylureido)-1H-indazol-1-yl)acetyl)

-N-(6-chloropyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3-carboxamide

[00452] To a cooled solution of CDI (3.26 g, 20.0 mmol) in THF (30 mL) was added dropwise a solution of methanamine (2.0 M in THF, 10 mL) at 0 °C. The result mixture was stirred at rt for 2 h to give a solution of N-methyl-lH-imidazole-l-carboxamide in THF (0.5 M). A mixture of (lR,3S,4S)-2-(2-(3-acetyl- 5-amino-lH-indazol-l-yl)acetyl)-N-(6-chloropyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3-carboxamide (340 mg, 0.728 mmol, 1.0 eq), N-methyl-lH-imidazole-l-carboxamide (0.5 M in THF, 8 mL, 4 mmol, 5.5 eq ) and DIEA (188 mg, 1.46 mmol, 2.0 eq) in NMP (3 mL) was stirred at 90 °C for 48 h. Water (10 mL) was added, and the precipitate was collected. The resulting solid was purified by prep-HPLC to give (lR,3S,4S)-2-(2-(3- acetyl-5-(3-methylureido)-lH-indazol-l-yl)acetyl)-N-(6-chloropyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3- carboxamide (165.8 mg, 44%). LRMS (M+H⁺) m/z calculated 524.2, found 524.1. ¾NMR (DMSO- ₆, 400 MHz) δ 11.24 (s, 0.15H), 10.82 (s, 0.85H), 8.67 (s, IH), 8.24-8.20 (m, IH), 8.11 (d, 0.15), 7.99 (d, 0.85H), 7.89 (t, 0.15H), 7.81 (t, 0.85H), 7.57-7.45 (m, 2H), 7.25 (d, 0.15H), 7.18 (d, 0.85H), 5.95 (brs, IH), 5.70 (d, 0.85H), 5.40 (d, 0.85H), 5.37 (d, 0.15H), 4.88 (d, 0.15H), 4.63 (s, 0.85H), 4.48 (s, 0.15H), 4.38 (s, 0.15H), 4.09 (s, 0.85H), 2.91 (d, 0.15H), 2.68 (s, 0.85H), 2.65 (s, 3H), 2.58 (s, 2.55H), 2.55 (s, 0.45H), 2.08 (d, 0.85H), 1.85-1.27 (m, 5.15H).

Example 165: Preparation of (lR,3S,4S)-2-(2-(3-acetyl-5-(2-methylbenzamido)-lH-indazol-l-yl)acetyl)-N- (6 -chloropyridin-2 -yl) -2 -azabicyclo [2.2.1 ]heptane -3 -carboxamide

[00453] To a mixture of (lR,3S,4S)-2-(2-(3-acetyl-5-amino-lH-indazol-l-yl)acetyl)-N-(6- chloropyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3-carboxamide (100.0 mg, 0.21 mmol, 1.0 eq), HATU (97.6 mg, 0.26 mmol, 1.2 eq) and 2-methylbenzoic acid (32.0 mg, 0.24 mmol, 1.1 eq) in NMP (1 mL) was added DIEA (42.0 mg, 0.32 mmol, 1.5 eq) slowly at 0 °C. The mixture was stirred at rt for 3 h. The resulting mixture was purified by prep-HPLC to afford (lR,3S,4S)-2-(2-(3-acetyl-5-(2-methylbenzamido)-lH-indazol-l- yl)acetyl)-N-(6-chloropyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3-carboxamide (45.1 mg, 36.0%) as a white solid. LRMS (M+H⁺) m/z calculated 585.2, found 584.9. ¾ NMR DMSO-d₆, 400 MHz) δ 11.26 (s, 0.15H), 10.86 (s, 0.85H), 10.44 (s, IH), 8.71 (s, IH), 8.12 (d, 0.15H), 7.99 (d, 0.85H), 7.90 (t, 0.15H), 7.82 (t, 0.85H), 7.76-7.58 (m, 2H), 7.49 (d, IH), 7.39 (t, IH), 7.34-7.21 (m, 2H), 7.25 (d, 0.20H), 7.19 (d, 0.81H), 5.76 (d, 0.85H), 5.50-5.40 (m, IH), 4.95 (d, 0.15H), 4.91 (d, 0.15H), 4.65 (s, 0.85H), 4.49 (s, 0.15H), 4.40 (s, 0.15H), 4.10 (s, 0.85H), 2.91 (s, 0.2H), 2.69 (s, 0.81H), 2.62 (s, 2.7H), 2.58 (s, 0.35H), 2.40 (s, 3H), 2.08 (d, IH), 1.88-1.64 (m, 3H), 1.61-1.41 (m, 2H). Example 166: Preparation of (lR,3S,4S)-2-(2-(3-acetyl-5-(2-fluorobenzamido)-lH-indazol-l-yl)acetyl)-N-(6- chloropyridin-2-yl)-2-azabicyclo [2.2.1 ]heptane-3 -carboxamide

(1 R,3S,4S)-2-(2-(3-acetyl-5-(2-fluorobenzamido)-1 H-indazol-1 -yl)acet l)

-N-(6-chloropyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3-carboxamide

[00454] To a mixture of (lR,3S,4S)-2-(2-(3-acetyl-5-amino-lH-indazol-l-yl)acetyl)-N-(6- chloropyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3-carboxamide (100.0 mg, 0.21 mmol, 1.0 eq), HATU (97.6 mg, 0.26 mmol, 1.2 eq) and 2-fluorobenzoic acid (33.0 mg, 0.24 mmol, 1.1 eq) in NMP (1 mL) was added DIEA (42.0 mg, 0.32 mmol, 1.5 eq) slowly at 0 °C. The result mixture was stirred at rt for 3 h. The reaction mixture was purified by prep-HPLC to afford (lR,3S,4S)-2-(2-(3-acetyl-5-(2-fluorobenzamido)-lH-indazol-l- yl)acetyl)-N-(6-chloropyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3-carboxamide (45.1 mg, 36%) as a white solid. LRMS (M+H⁺) m/z calculated 589.2, found 588.9. ¾ NMR DMSO-d₆, 400 MHz) δ 11.26 (s, 0.15H), 10.86 (s, 0.85H), 10.57 (s, IH), 8.66 (s, IH), 8.12 (d, 0.15H), 7.99 (d, 0.85H), 7.90 (t, 0.15H), 7.82 (t, 0.85H), 7.78-7.65 (m, 3H), 7.63-7.55 (m, IH), 7.35 (dd, 2H), 7.25 (d, 0.15H), 7.19 (d, 0.85H), 5.78 (d, 0.85H), 5.50- 5.40 (m, IH), 4.95 (d, 0.15H), 4.91 (d, 0.15H), 4.65 (s, 0.85H), 4.48 (s, 0.15H), 4.41 (s, 0.15H), 4.10 (s, 0.85H), 2.92 (s, 0.15H), 2.69 (s, 0.88H), 2.62 (s, 2.50H), 2.58 (s, 0.5 IH), 2.08 (d, IH), 1.88-1.66 (m, 3H), 1.61-1.41 (m, 2H).

Example 167: Preparation of (lR,3S,4S)-2-(2-(3-acetyl-5-(2-methylnicotinamido)-lH-indazol-l-yl)acetyl)- N-(6-chloropyridin-2-yl)-2-azabicyclo [2.2.1 ]heptane-3 -carboxamide

(1R,3S,4S)-2-(2-(3-acetyl-5-(2-met ylnicotinamido)-1H-indazol-1-yl)acetyl)

-N-(6-chloropyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3-carboxamide

[00455] A mixture of (lR,3S,4S)-2-(2-(3-acetyl-5-amino-lH-indazol-l-yl)acetyl)-N-(6- chloropyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3-carboxamide (100 mg, 0.21 mmol, 1.0 eq), 2- methylnicotinic acid (34 mg, 0.25 mmol, 1.2 eq), HATU (160 mg, 0.42 mmol, 2.0 eq) and DIEA (81mg, 0.63 mmol, 3.0 eq) in NMP (2 mL) was stirred at rt for 2 h. The reaction mixture was concentrated, and the resulting residue was purified by prep-HPLC to afford (lR,3S,4S)-2-(2-(3-acetyl-5-(2-methylnicotinamido)- lH-indazol-1 -yl)acetyl)-N-(6-chloropyridin-2-yl)-2-azabicyclo[2.2. l]heptane-3-carboxamide (97.6 mg, 79%) as a white solid. LRMS (M+H⁺) m/z calculated 586.2, found 586.1. ¾ NMR (DMSO- ₆, 400 MHz) δ 11.27 (s, 0.15H), 10.87 (s, 0.85H), 10.60 (s, 1H), 8.69 (s, 1H), 8.57-8.56 (m, 1H), 8.01-7.68 (m, 5H), 7.37-7.18 (m, 2H), 5.78 (d, 0.85H), 5.49-5.45 (m, lH), 4.93 (d, 0.15H), 4.66 (s, 0.85H), 4.48 (s, 0.15H), 4.41 (s, 0.15H), 4.10 (s, 0.85H), 2.92 (d, 0.15H), 2.69-2.59 (m, 7H), 2.09 (d, 0.85H), 1.82-1.29 (m, 5H).

Example 168: Preparation of (lR,3S,4S)-2-(2-(3-acetyl-5-(2-methoxynicotinamido)-lH-indazol-l-yl)acetyl)- N-(6-chloropyridin-2-yl)-2-azabicyclo [2.2.1 ]heptane-3 -carboxamide

(1 R,3S,4S)-2-(2-(3-acetyl-5-(2-methoxynicotinamido)-1 H-indazol-1 -yl)

-/V-(6-ohloropyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3-carboxamide

[00456] A mixture of (lR,3S,4S)-2-(2-(3-acetyl-5-amino-lH-indazol-l-yl)acetyl)-N-(6- chloropyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3-carboxamide (100 mg, 0.21 mmol, 1.0 eq), 2- methylnicotinic acid (38 mg, 0.25 mmol, 1.2 eq), HATU (160 mg, 0.42 mmol, 2.0 eq) and DIEA (81mg, 0.63 mmol, 3.0 eq) in NMP (2 mL) was stirred at rt for 2 h. The reaction mixture was concentrated and the resulting residue was purified by prep-HPLC to afford (lR,3S,4S)-2-(2-(3-acetyl-5-(2-methoxynicotinamido)- lH-indazol-1 -yl)acetyl)-N-(6-chloropyridin-2-yl)-2-azabicyclo[2.2. l]heptane-3-carboxamide (71.6 mg, 57%) as a white solid. LRMS (M+H⁺) m/z calculated 602.2, found 602.1. ¾ NMR (DMSO- ₆, 400 MHz) δ 1 1.27 (s, 0.15H), 10.86 (s, 0.85H), 10.36 (s, 1H), 8.69 (s, 1H), 8.34 (d, 1H), 8.14 - 7.60 (m, 5H), 7.27 - 7.14 (m, 2H), 5.78 (d, 0.85H), 5.49 - 5.45 (m, 1H), 4.94 (d, 0.15H), 4.65 (s, 0.85H), 4.49 (s, 0.15H), 4.41 (s, 0.15H), 4.10 (s, 0.85H), 3.99 (s, 3H), 2.92 (d, 0.15H), 2.69 - 2.59 (m, 4H), 2.09 (d, 0.85H), 1.82 - 1.29 (m, 5H).

Example 169: Preparation of (lR,3S,4S)-2-(2-(3-acetyl-5-(2-cyanobenzamido)-lH-indazol-l -yl)acetyl)-N-(6- chloropyridin-2-yl)-2-azabicyclo [2.2.1 ]heptane-3 -carboxamide

[00457] A mixture of (lR,3S,4S)-2-(2-(3-acetyl-5-amino-lH-indazol-l-yl)acetyl)-N-(6- chloropyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3-carboxamide ( 100.0 mg, 0.21 mmol, 1.0 eq), HATU (97.6 mg, 0.26 mmol, 1.2 eq), DIEA (42.0 mg, 0.32 mmol, 1.5 eq) and 2-cyanobenzoic acid (38.0 mg, 0.24 mmol, 1.1 eq) in NMP (1 mL) was stirred at rt for 3 h. The resulting mixture was purified by prep-HPLC to afford (lR,3S,4S)-2-(2-(3-acetyl-5-(2-cyanobenzamido)-lH-indazol-l-yl)acetyl)-N-(6-chloropyridin-2-yl)-2- azabicyclo[2.2.1]heptane-3-carboxamide (58.7 mg, 46.0%) as a white solid. LRMS (M+H⁺) m/z calculated 596.2, found 596.0. ¹HNMR (OMSO-d₆, 400 MHz) δ 1 1.30 (s, 0.15H), 10.85 (s, 0.85H), 10.26 (s, 0.80H), 8.67 (s, 0.15H), 8.32-8.1 1 (m, 2H), 8.01 (t, 1H), 7.95-7.71 (m, 5H), 7.58-7.44 (m, 1H), 7.25 (d, 0.20H), 7.18 (d, 0.81H), 5.93-5.78 (m, 0.80H), 5.60-5.46 (m, 1H), 5.00 (d, 0.15H), 4.68 (s, 0.85H), 4.49 (s, 0.40H), 4.12 (s, 0.81H), 2.95 (s, 0.15H), 2.69 (s, 0.89H), 2.61 (s, 2.50H), 2.59 (s, 0.51H), 2.09 (d, 1H), 1.94-1.64 (m, 3H), 1.64-1.42 (m, 2H).

Example 170: Preparation of (lR,3S,4S)-2-(2-(3-acetyl-5-(2-methoxybenzamido)-lH-indazol-l -yl)acetyl)-N- (6 -chloropyridin-2 -yl) -2 -azabicyclo [2.2.1 ]heptane -3 -carboxamide

[00458] A mixture of ( lR,3S,4S)-2-(2-(3-acetyl-5-amino-lH-indazol-l-yl)acetyl)-N-(6- chloropyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3-carboxamide ( 100.0 mg, 0.21 mmol, 1.0 eq), HATU (97.6 mg, 0.26 mmol, 1.2 eq), DIEA (42.0 mg, 0.32 mmol, 1.5 eq) and 2-methoxybenzoic acid (39.0 mg, 0.24 mmol, 1.1 eq) in NMP (1 mL) was stirred at rt for 3 h. The resulting mixture was purified by prep-HPLC to afford ( lR,3S,4S)-2-(2-(3-acetyl-5-(2-methoxybenzamido)-lH-indazol-l -yl)acetyl)-N-(6-chloropyridin-2-yl)- 2-azabicyclo[2.2.1]heptane-3-carboxamide (73.3 mg, 56.9%) as a white solid. LRMS (M+H⁺) m/z calculated 601.2, found 600.9. ¹HNMR (OMSO-d₆, 400 MHz) δ 1 1.27 (s, 0.15H), 10.86 (s, 0.85H), 10.26 (s, 1H), 8.71 (s, 1H), 8.12 (d, 0.15H), 7.99 (d, 0.85H), 7.90 (t, 0.15H), 7.82 (t, 0.85H), 7.75-7.57 (m, 3H), 7.51 (t, 1H), 7.25 (d, 0.15H), 7.19 (d, 0.85H), 7.07 (t, 1H), 5.76 (d, 0.85H), 5.50-5.41 (m, 1H), 4.93 (d, 0.15H), 4.65 (s, 0.85H), 4.48 (s, 0.15H), 4.41 (s, 0.15H), 4.10 (s, 0.85H), 3.90 (s, 3H), 2.92 (s, 0.15H), 2.69 (s, 0.88H), 2.62 (s, 2.50H), 2.58 (s, 0.51H), 2.08 (d, 1H), 1.88-1.66 (m, 3H), 1.61-1.41 (m, 2H).

Example 171: Preparation of ( lR,3S,4S)-2-(2-(3-acetyl-5-(2-chloro-3-fluorobenzamido)-lH-indazol-l - yl)acetyl)-N-(6-chloropyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3-carboxamide

(1 R,3S,4S)-2-(2-(3-acet l-5-(2-chloro-3-fluorobenzamido)-1 H-indazol-1 -yl)acetyl)

-N-(6-chloropyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3-carboxamide

[00459] A mixture of (lR,3S,4S)-2-(2-(3-acetyl-5-amino-lH-indazol-l-yl)acetyl)-N-(6- chloropyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3-carboxamide (100.0 mg, 0.21 mmol, 1.0 eq), HATU (163.1 mg, 0.42 mmol, 1.2 eq), DIEA (83.2 mg, 0.64 mmol, 1.5 eq) and 2-chloro-3-fluorobenzoic acid (43.4 mg, 0.257 mmol, 1.2 eq) in NMP (2 mL) was stirred at rt for 2 h. The reaction mixture was purified by prep-HPLC to afford (lR,3S,4S)-2-(2-(3-acetyl-5-(2-chloro-3-fluorobenzamido)-lH-indazol-l-yl)acetyl)-N-(6- chloropyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3-carboxamide (80.0 mg, 60%) as a white solid. LRMS (M+H⁺) m/z calculated 623.1, found 622.9. ¾ NMR DMSO-d₆, 400 MHz) δ 11.24 (s, 0.15H), 10.83 (s, 0.85H), 10.68 (s, IH), 8.67 (s, IH), 8.12 (d, 0.15H), 7.99 (d, 0.85H), 7.89 (t, 0.15H), 7.81 (t, 0.85H), 7.76-7.64 (m, 2H), 7.58-7.48 (m, 3H), 7.25 (d, 0.15H), 7.18 (d, 0.85H), 5.76 (d, 0.85H), 5.50-5.41 (m, IH), 4.93 (d, 0.15H), 4.65 (s, 0.85H), 4.49 (s, 0.15H), 4.40 (s, 0.15H), 4.10 (s, 0.85H), 2.92 (s, 0.20H), 2.69 (s, 0.8 IH), 2.62 (s, 2.70H), 2.58 (s, 0.35H), 2.08 (d, IH), 1.90-1.63 (m, 3H), 1.63-1.35 (m, 2H).

Example 172: Preparation of (lR,3S,4S)-2-(2-(3-acetyl-5-(2-chloro-5-fluorobenzamido)-lH-indazol-l- yl)acetyl)-N-(6-chloropyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3-carboxamide

[00460] A mixture of (lR,3S,4S)-2-(2-(3-acetyl-5-amino-lH-indazol-l-yl)acetyl)-N-(6- chloropyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3-carboxamide (100.0 mg, 0.21 mmol, 1.0 eq), HATU (163.1 mg, 0.42 mmol, 1.2 eq), DIEA (83.2 mg, 0.64 mmol, 1.5 eq) and 2-chloro-5-fluorobenzoic acid (43.4 mg, 0.257 mmol, 1.2 eq) in NMP (1.5 mL) was stirred at rt for 2 h. The reaction mixture was purified by prep- HPLC to afford (lR,3S,4S)-2-(2-(3-acetyl-5-(2-chloro-5-fluorobenzamido)-lH-indazol-l-yl)acetyl)-N-(6- chloropyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3-carboxamide (78 mg, 58%) as a white solid. LRMS (M+H⁺) m/z calculated 623.1, found 623.0. ¾ NMR DMSO-d₆, 400 MHz) δ 1 1.24 (s, 0.15H), 10.83 (s, 0.85H), 10.68 (s, 1H), 8.67 (s, 1H), 8.12 (d, 0.15H), 7.99 (d, 0.85H), 7.89 (t, 0.15H), 7.81 (t, 0.85H), 7.76-7.59 (m, 4H), 7.43-7.38 (m, 1H), 7.25 (d, 0.15H), 7.18 (d, 0.85H), 5.76 (d, 0.85H), 5.50-5.41 (m, 1H), 4.93 (d, 0.15H), 4.65 (s, 0.85H), 4.49 (s, 0.15H), 4.40 (s, 0.15H), 4.10 (s, 0.85H), 2.92 (s, 0.20H), 2.69 (s, 0.81H), 2.62 (s, 2.70H), 2.58 (s, 0.35H), 2.08 (d, 1H), 1.90-1.63 (m, 3H), 1.63-1.35 (m, 2H).

Example 173: Preparation of ( li?,3^,4^-2-(2-(3-acetyl-5-(2-methylpyrimidin-5-yl)-lH-indazol-l-yl)acetyl)- N-(3-chloro-2-fluoro

[00461] A mixture of 2-(3-acetyl-5-(2-methylpyrimidin-5-yl)-lH-indazol-l -yl)acetic acid (100 mg, 0.32 mmol, 1.0 eq), ( l i^^^^-N-iS-chloro^-fluorobenzy^^-azabicyclo [2.2.1]heptane-3-carboxamide hydrochloride( 123 mg, 0.39 mmol, 1.2 eq), HATU ( 147 mg, 0.39 mmol, 1.2 eq) and DIEA (125 mg, 0.97 mmol, 3.0 eq) in DMF (7 mL) was stirred at rt overnight. The mixture was concentrated, and the resulting residue was purified by prep-HPLC to afford ( li?,35',45)-2-(2-(3-acetyl-5-(2-methylpyrimidin-5-yl)-lH- indazol-l -yl)acetyl)-N-(3-chloro-2-fluorobenzyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide (36 mg, 20%) as a white solid. LRMS (M+H⁺) m/z calculated 575.2, found 575.0. ¾ NMR DMSO-d₆, 400 MHz) δ 9.05 (s, 1H), 8.54-8.57 (m, 1H), 8.42-8.44 (m, 1H), 7.73-7.91 (m, 2H), 7.39-7.43 (m, M), 7. 17-7.19 (m, 1H), 6.99- 7.03 (m, 1H), 5.81 -5.85 (d, 1H), 5.47-5.51 (d, 1H), 4.58 (s, 1H), 4.34-4.43 (m, 1H), 4.26-4.28 (m, 1H), 3.85 (s, 1H), 2.69 (s, 3H),2.63-2.65 (d, 3H), 2.59 (s, 1H), 2.03-2.05 (d, 1H), 1.78-1.84 (m, 3H), 1.45-1.52 (m, 2H). Example 174: Preparation of (li?,35',45)-2-(2-(3-acetyl-5-(2-methoxypyrimidm-5-y/)-lH-indazol-l - yl)acetyl)-N-(3-chloro-2-fluorobenzyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide

(1R,3S,4S)-2-(2-(3-acetyl-5-(2-methoxypyrimidin-5-yl)-1H-indazol-1-yl)acetyl)-N- (3-chloro-2-fluorobenzyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide

[00462] A mixture of (li?,35',45)-N-(3-chloro-2-fluorobenz^yl)-2-azabicyc_/o[2.2.1]heptane-3- carboxamide (75 mg, 0.236 mmol, 1.0 eq), 2-(3-acetyl-5-(2-methoxypyrimidin-5-yl)-lH-indazol-l-yl)acetic acid (100 mg, 0.306 mmol, 1.3 eq), HATU (135 mg, 0.354 mmol, 1.5 eq) and DIEA (122 mg, 0.944 mmol, 4.0 eq) in DMF (5 mL) was stirred at 35 °C for 1.5 h. The resulting mixture was purified by prep-HPLC to give (li?,35',45)-2-(2-(3-acetyl-5-(2-methoxypyrimidin-5-yl)-lH-indazol-l-yl)acetyl)-N-(3-chloro-2- fluorobenzyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide (22.2 mg, 16%) as a white solid. LRMS (M+H⁺) m/z calculated 591.2, found 591.2. 'H NMR DMSO-d₆, 400 MHz) δ 8.95 (s, 2H), 8.47-8.50 (t, IH), 8.37-8.39 (d, IH), 7.76-7.84 (dd, 2H), 7.40-7.44 (t, IH), 7.18-7.22 (t, IH), 7.01-7.05 (t, IH), 5.75-5.80 (d, IH), 5.46- 5.50 (d, IH), 4.59 (s, IH), 4.28-4.45 (m, 2H), 3.99 (s, 3H), 2.87 (s, IH), 2.61-2.65 (t, 4H), 2.03-2.09 (t, IH), 1.78-1.86 (m, 3H), 1.46-1.52 (m, 2H).

Example 175: Preparation of (li?,35',45)-2-(2-(3-acetyl-5-(pyrimidin-5-yl)-lH-indazol-l-yl)acetyl)-N-(3- chloro -2 -fluorobenzyl) -2 -azabicyclo [2.2.1 ]heptane -3 -carboxamide

(1R,3S^S)-2-(2-(3-acet l-5-(pyrimidin-5-yl)-1H-indazol-1-yl)acetyl)-/\/-(3-chloro-2-fluorobenzyl)

-2-azabicyclo[2.2.1]heptane-3-carboxamide

[00463] A mixture of the TFA salt of 2-(3-carbamoyl-5-(pyrimidin-5-yl)-lH-indazol-l-yl)acetic acid (140 mg, 0.34 mmol, 1.0 eq), (l i^.S'^^-N-iS-chloro^-fluorobenzy ^-azabicycloP^. llheptane-S- carboxamide (108.0 mg, 0.34 mmol, 1.0 eq), HATU (150 mg, 0.40 mmol, 1.2 eq) and DIEA (260 mg, 2.0 mmol, 6.0 eq) in DMF (10 mL) was stirred at 35 °C overnight. The mixture was concentrated in vacuo and the resulting residue was purified by prep-HPLC to give (li?,35',45)-2-(2-(3-acetyl-5-(pyrimidin-5-yl)-lH- indazol-l-yl)acetyl)-N-(3-chloro-2-fluorobenzyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide (38 mg, 20.0%) as a white solid. LRMS (M+H⁺) m/z calculated 561.1, found 561.0. ¾ NMR (DMSO- ₆, 400 MHz) δ 9.22 (s, 1H), 9.18 (s, 1H), 8.45-8.48 (m, 2H), 7.72-7.90 (m, 2H), 8.47 (s, 1H), 7.37-7.48 (m, 1H), 7.16-7.21 (m, 1H), 7.01-7.05 (m, 1H), 5.57-5.81 (m, 1H), 5.32-5.52 (m, 1H), 4.49-4.58 (m, 1H), 4.32-4.45 (m, 2H), 3.85-4.24 (s, 1H), 2.60-2.67 (m, 1H), 2.65 (s, 3H), 1.96-2.05 (m, 1H), 1.67-1.85 (m, 3H), 1.51-1.54 (m, 1H), 1.44-1.53 (m, 1H).

Example 176: Preparation of (li?,35',45)-2-(2-(3-acetyl-5-(2-cyanopyrimidin-5-yl)-lH-indazol-l-yl)acetyl)- N-(3-chloro-2-fluorobenzyl)-2-azabicyclo ide

(1 R,3S,4S)-2-(2-(3-acetyl-5-(2-cyanopyrimidin-5-yl)-1 H-indazol-1 -yl)acetyl)

-A - 3-chloro-2-fluorobenzyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide

[00464] To a stirred solution of 2-(3-acetyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH- indazol-l-yl)acetic acid (170 mg, 0.5 mmol, 1.0 eq) in DMF (5 mL) were added DIEA (258 mg, 2.0 mmol, 4.0 eq) and N-((lR,3S,4S)-2-azabicyclo[2.2.1]heptan-3-ylmethyl)-l-(3-chloro-2-fluorophenyl)methanamine (140 mg,0.5 mmol), HATU(190 mg,0.5 mmol). The reaction mixture was stirred at rt for 12 h. The mixture was extracted with EA and the combined organic layers were washed with brine, dried over Na₂S0₄ and concentrated under reduce pressure. The resulting residue was purified by chromatography on silica gel column (PE/EA = 9/1 to 3/1, v/v) to give (lR,3S,4S)-2-(2-(3-acetyl-5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-lH-indazol-l-yl)acetyl)-N-(3-chloro-2-fluorobenzyl)-2-azabicyclo[2.2.1]heptane-3- carboxamide (0.3 g, 95%) as a light yellow oil. LRMS (M+H⁺) m/z calculated 609.2, found 609.3.

[00465] A mixture of (lR,3S,4S)-2-(2-(3-acetyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)- lH-indazol-l -yl)acetyl)-N-(3-chloro-2-fluorobenzyl)-2-azabicyclo[2.2. l]heptane-3-carboxamide ( 120 mg, 0.2 mmol, 1.0 eq) and 5-bromo-pyrimidine-2-carbonitrile (36.8 mg, 0.2 mmol, 1.0 eq), K₂C0₃ (80 mg, 0.6 mmol, 3.0 eq), Pd(PPh₃)₄, (20 mg, 0.02 mmol) in dioxane (5 mL) was stirred at 100 °C for 12 h. After cooling the mixture was poured into a mixture of H₂0 (200 mL) and EA ( 100 mL) with stirring. The organic layer was separated, dried and concentrated. The resulting residue was purified by prep-HPLC to give ( lR,3S,4S)-2-(2- (3-acetyl-5-(2-cyanopyrimidin-5-yl)-lH-indazol-l-yl)acetyl)-N-(3-chloro-2-fluorobenzyl)-2- azabicyclo[2.2.1]heptane-3-carboxamide (30.1 mg, 26%) as a white solid. LRMS (M+H⁺) m/z calculated 586.1, found 586.2. ¾ NMR (OMSO-d₆, 400 MHz) δ 9.42 (s, 2H), 8.43-8.60 (m, 2H), 7.91-7.95 (m, 2H), 7.01 -7.43 (m, 3H), 5.48-5.81 (m, 2H), 4.26-4.58 (m, 4H), 4.10 (s, 2H), 2.59-2.65 (m, 4H), 2.02-2.03 (m, 1H), 1.78-1.80 (m, 3H), 1.44-1.5 1 (m, 2H).

Example 177: Preparation of ( lR,3S,4S)-2-(2-(3-acetyl-5-(nicotinamido)-lH-indazol-l-yl)acetyl)-N-(3- chloro -2 -fluorobenzyl) -2 -azabicyclo [2.2.1 ]heptane -3 -carboxamide

(1 R,3S,4S)-2-(2-(3-acetyl-5-(nicotinamido)-1 H-indazol-1 -yl)aceryl)

-W-(3-chloro-2-fluorobenzyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide

[00466] To a mixture of 2-(3-acetyl-5-((teri-butoxycarbonyl)amino)-lH-indazol-l-yl)acetic acid

(700 mg, 2.1 mmol, 1.0 eq), (lR,3S,4S)-N-(3-chloro-2-fluorobenzyl)-2-azabicyclo[2.2.1]heptane-3- carboxamide (595.0 mg, 2.1 mmol, 1.0 eq) and HATU (1.6 g, 4.2 mmol, 2.0 eq) in DMF (5 mL) was added DIEA (812 mg, 6.3 mmol, 3.0 eq). The reaction mixture was stirred at rt for 2 h. The reaction mixture was purified by prep-HPLC to give fert-butyl (3-acetyl-l-(2-((lR,3S,4S)-3-((3-chloro-2-fluorobenzyl)carbamoyl)- 2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-lH-indazol-5-yl)carbamate (1.1 g, 91%) as a yellow solid. LRMS (M+H⁺) m/z cal

[00467] To a solution of fert-butyl (3-acetyl-l-(2-((lR,3S,4S)-3-((3-chloro-2- fluorobenzyl)carbamoyl) -2 -azabicyclo [2.2.1] heptan-2 -yl) -2 -oxoethyl)- 1 H-indazol-5 -yl)carbamate (1.10 g, 1.83 mmol, 1.0 eq) in DCM (12 mL) was added TFA (6 mL) dropwise at 0 °C. The result solution was stirred at rt for 1 h. The reaction mixture was concentrated, and the resulting residue was purified by prep- HPLC to give (lR,3S,4S)-2-(2-(3-acetyl-5-amino-lH-indazol-l-yl)acetyl)-N-(3-chloro-2-fluorobenzyl)-2- azabicyclo[2.2.1]heptane-3-carboxamide (1.06 g, 87%) as a yellow solid. LRMS (M+H⁺) m/z calculated 498.2, found 498.0.

[00468] To a mixture of (lR,3S,4S)-2-(2-(3-acetyl-5-amino-lH-indazol-l-yl)acetyl)-N-(3-chloro-

2-fluorobenzyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide (200.0 mg, 0.4 mmol, 1.0 eq), nicotinic acid (54.1 mg, 0.44 mmol, 1.1 eq) and HATU(182.4 mg, 0.48 mmol, 1.2 eq) in NMP (1.5 mL) was added DIEA (77.4 mg, 0.6 mmol, 1.5 eq). The mixture was stirred at rt for 0.5 h. The resulting mixture was purified by prep- HPLC to afford (lR,3S,4S)-2-(2-(3-acetyl-5-(nicotinamido)-lH-indazol-l-yl)acetyl)-N-(3-chloro-2- fluorobenzyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide (150 mg, 62%) as a white solid. ¾ NMR (DMSO- d₆, 400 MHz) δ 10.48 (d, 1H),9.15 (m, lH), 8.78-8.77 (m, IH), 8.67 (d, IH), 8.44-8.31 (m, 2H),7.85-7.82 (d, IH), 7.67 (d, 0.73H),7.76-7.57 (m,lH),7.52 (d, 0.27H), 7.47-7.36 (m, 1.26H), 7.21-7.15 (m, 1H),7.05 (t, 0.75H), 5.57 (d, 0.72H), 5.29 (d, 0.92H), 4.82 (s, 0.23H), 4.59 (s, IH), 4.48-4.40 (m, 1.4H), 4.30-4.22 (m, 0.8H),3.85 (s, 0.74H), 2.60 (d, 4H), 2.05 (d, IH) 1.82-1.71 (m, 3H), 1.58-1.45 (m, 2H). LRMS (M+H⁺) m/z calculated 603.2, found 603.1.

Example 178: Preparation of (lR,3S,4S)-2-(2-(3-acetyl-5-(2-chlorobenzamido)-lH-indazol-l-yl)acetyl)-N- (3-chloro-2-fluoroben

[00469] To a mixture of (lR,3S,4S)-2-(2-(3-acetyl-5-amino-lH-indazol-l-yl)acetyl)-N-(3-chloro-

2-fluorobenzyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide (200.0 mg, 0.4 mmol, 1.0 eq), 2-chlorobenzoic acid (69.1 mg, 0.44 mmol, 1.1 eq) and HATU (182.4 mg, 0.48 mmol, 1.2 eq) in NMP (2 mL) was added DIEA (77.4 mg, 0.6 mmol, 1.5 eq). The reaction mixture was stirred at rt for 0.5 h. The resulting mixture was purified by prep-HPLC to afford (lR,3S,4S)-2-(2-(3-acetyl-5-(2-chlorobenzamido)-lH-indazol-l-yl)acetyl)- N-(3-chloro-2-fluorobenzyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide (150 mg, 58%) as a white solid. ^l NMR (DMSO- ₆, 400 MHz) δ 10.48 (d, IH), 8.84 (s, 0.24H), 8.69 (s,lH), 8.47-8.42 (m, 0.75H),7.76-7.41 (m, 7H), 7.37 (d, 0.21H),7.20-7.15 (m, 1H),7.04 (t, 0.79H), 5.70 (d, 0.75H), 5.52-5.40 (s, 1H),4.84 (d, 0.25H), 4.55 (s, IH), 4.45-4.38 (m, 2H), 4.28-4.22 (d, 0.29H), 4.33 (s, IH), 2.60 (d, 4H), 2.01(s, 0.82H), 1.78-1.69 (m, 3H), 1.55-1.42 (m, 2H). LRMS (M+H⁺) m/z calculated 636.2, found 636.1.

Example 179: Preparation of methyl (3-acetyl-l-(2-((lR,3S,4S)-3-((3-chloro-2-fluorobenzyl)carbamoyl)-2- azabicyclo [2.2.1 ]heptan-2-yl)-2-oxoethyl)- lH-indazol-5 -yl)carbamate

[00470] To a mixture of (lR,3S,4S)-2-(2-(3-acetyl-5-amino-lH-indazol-l-yl)acetyl)-N-(3-chloro-

2-fluorobenzyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide (200.0 mg, 0.4 mmol, 1.0 eq) and methyl carbonochloridate (57.0 mg, 0.6 mmol, 1.5 eq) in NMP (1.5 mL) was added DIEA (155.0 mg, 1.2 mmol, 3.0 eq) at 0 °C. The reaction mixture was stirred at rt fori h. The resulting mixture was purified by prep-HPLC to afford methyl (3-acetyl-l-(2-((lR,3S,4S)-3-((3-chloro-2-fluorobenzyl)carbamoyl)-2-azabicyclo[2.2.1]heptan- 2-yl)-2-oxoethyl)-lH-indazol-5-yl)carbamate (150.0 mg, 67.0%) as a white solid. ¾ NMR (DMSO- ₆, 400 MHz) δ 9.74 (d, 1H), 892 (t, 0.24H), 8.41 (t,0.73H), 8.35 (t,lH), 7.57 (d, 0.68H), 7.50-7.37 (s, 2.48H), 7.20- 7.16 (m, 1H), 7.03(m, 0.74H), 5.49 (d, 0.72H), 5.27 (d, 0.99H), 4.76 (d, 0.23H), 4.54 (s,lH), 4.41-4.37 (m, 1H), 4.27-4.22 (m, 1H), 3.83 (s, 1H), 2.58 (d, 4H), 2.01(d, 1H) 1.77 (s, 3H), 1.58-1.43 (m, 2H). LRMS (M+H⁺) m/z calculated 556.2, found 556.1.

Example 180: Preparation of methyl (3-carbamoyl-l-(2-oxo-2-((lR,3S,4S)-3-((6-(trifluoromethyl)pyridin-2- yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2 -yl)carbamate

methyl (3-carbamoyl-1 -(2-oxo-2-((1 R,3S,4S)-3-((6-(trif luoromethyl)pyridin-2-yl)carbamoyl)

-2-azabicyclo[2.2.1]heptan-2-yl)ethyl)-1H-indazol-5-yl)carbamate

[00471] A mixture of fert-butyl 2-(3-acetyl-5-bromo-lH-indazol-l-yl)acetate (32.0 g, 90.6 mmol, 1.0 eq), NH₂Boc (15.9 g, 135.9 mmol, 1.5 eq), tris(dibenzylideneacetone)dipalladium(0) (8.3 g, 9.06 mmol, 0.1 eq), Xantphos (5.2 g, 9.06 mmol, 0.1 eq) and Cs₂C0₃ (59.1 g, 181.2 mmol, 2.0 eq) in dioxane (320 mL) was stirred at 80 °C under N₂ for 24 h. The reaction mixture was diluted with EA (1 L), washed with brine (500 mL x 2), dried over Na₂S0₄, filtered and concentrated. The resulting residue was purified by chromatography on silica gel column (PE/EA = 10/1, v/v) to give fert-butyl 2-(3 -acetyl -5 -((tert- butoxycarbonyl)amino)-lH-indazol-l-yl)acetate (12.4 g, 36%) as a white solid. LRMS (M+H⁺) m/z calculated 390.2, found 390.0.

[00472] To a solution of fert-butyl 2-(3-acetyl-5-((teri-butoxycarbonyl)amino)-lH-indazol-l- yl)acetate (10.0 g, 25.7 mmol, 1.0 eq) in MeOH (150 mL) was added a solution of NaOH (5.1 g, 128.4 mmol, 5.0 eq) in H₂0 (37 mL) at 0 °C. The reaction mixture was stirred at rt for 4 h under N₂. The reaction mixture was adjusted to pH 4 by citric acid and extracted with EA (300 mL x 2). The combined organic phases were washed with brine (300 mL x 2), dried over Na₂S0₄, filtered and concentrated to give 2-(3-acetyl-5-((fert- butoxycarbonyl)amino)-lH-indazol-l-yl)acetic acid (5.8 g, 67%). LRMS (M+H⁺) m/z calculated 334.1, found 334.0.

[00473] To a mixture of (lR,3S,4S)-N-(6-(trifluoromethyl)pyridin-2-yl)-2- azabicyclo[2.2.1]heptane-3-carboxamide(515.0 mg 1.8 mmol, 1.0 eq), 2-(3-acetyl-5-((fert- butoxycarbonyl)amino)-lH-indazol-l-yl)acetic acid (600.0 mg, 1.8 mmol, 1.0 eq), and HATU (822.0 mg, 2.2 mmol, 1.2 eq) in DMF (5 mL) was added DIEA (349.0 mg, 2.7 mmol, 1.5 eq) at 0 °C. The reaction mixture was stirred at rt for 1 h. The reaction mixture was purified by prep-HPLC to afford fert-butyl (3-acetyl-l-(2- oxo-2-((lR,3S,4S)-3-((6-(trifluoromethyl)pyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)ethyl)-lH- indazol-5-yl)carbamate (1.1 g, 99.0%) as a yellow solid. LRMS (M+H⁺) m/z calculated 601.2, found 601.0.

[00474] To a solution of fert-butyl (3-acetyl-l-(2-oxo-2-((lR,3S,4S)-3-((6-

(trifluoromethyl)pyridin-2 -yl)carbamoyl) -2 -azabicyclo [2.2.1] heptan-2 -yl)ethyl) - 1 H-indazol-5 -yl)carbamate (1.1 g,1.9 mmol, 1.0 eq) in DCM (10 mL) was added TFA (5 mL) slowly at 0 °C. The above mixture was stirred at rt for 4 h. The reaction mixture was concentrated and the resulting residue was treated with ammonium hydroxide (2 mL). The mixture was concentrated and the resulting residue was purified by prep- HPLC to afford (lR,3S,4S)-2-(2-(3-acetyl-5-amino-lH-indazol-l-yl)acetyl)-N-(6-(trifluoromethyl)pyridin-2- yl)-2-azabicyclo[2.2.1]heptane-3-carboxamide (790 mg, 88%) as a yellow solid. LRMS (M+H⁺) m/z calculated 501.2, foun

[00475] To a mixture of (lR,3S,4S)-2-(2-(3-acetyl-5-amino-lH-indazol-l-yl)acetyl)-N-(6-

(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3-carboxamide (90.0 mg, 0.18 mmol, 1.0 eq) and methyl carbonochloridate (34.0 mg, 0.36 mmol, 2.0 eq) in NMP (1.5 mL) was added DIEA (46.4 mg, 0.36 mmol, 2.0 eq) slowly at 0 °C. The reaction mixture was stirred at 0 °C for 30 min. The reaction mixture was purified by prep-HPLC to afford methyl (3-acetyl-l-(2-oxo-2-((lR,3S,4S)-3-((6-(trifluoromethyl)pyridin-2- yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)ethyl)-lH-indazol-5-yl)carbamate (61.9 mg, 61.6%) as a white solid. LRMS (M+H⁺) m/z calculated 559.2, found 558.9. ¾ NMR DMSO-d₆, 400 MHz) δ 11.40 (s, 0.15H), 11.03 (s, 0.85H), 9.77 (s, 1H), 8.47-8.23 (m, 2H), 8.15-7.96 (m, 1H), 7.67-7.42 (m, 3H), 5.74 (d, 0.84H), 5.50- 5.35 (m, 1H), 4.92 (d, 0.15H), 4.65 (s, 0.86H), 4.48 (s, 0.18H), 4.41 (s, 0.16H), 4.15 (s, 0.87H), 3.68 (s, 3H), 2.71 (s, 1H), 2.59 (s, 2.51H), 2.55 (s, 0.52H), 2.10 (d, 1H), 1.88-1.67 (m, 3H), 1.59-1.39 (m, 2H).

Example 181: Preparation of (lR,3S,4S)-2-(2-(3-acetyl-5-(nicotinamido)-lH-indazol-l-yl)acetyl)-N-(6- (trifluoromethyl)pyridin-2 -yl) -2 -azabicyclo [2.2.1 ]heptane -3 -carboxamide

(1 R,3S,4S)-2-(2-(3-acetyl-5-(nicotinamido)-1 H-indazol-1 -yl)acetyl)-N

-(6-(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3-carboxamide

[00476] To a solution of (lR,3S,4S)-2-(2-(3-acetyl-5-amino-lH-indazol-l-yl)acetyl)-N-(6-

(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3-carboxamide (200.0 mg, 0.40 mmol, 1.0 eq), nicotinic acid (54.1 mg, 0.44 mmol, 1.1 eq) and HATU (182.4 mg, 0.48 mmol, 1.2 eq) in NMP (1.5 mL) was added DIEA (77.4 mg, 0.60 mmol, 1.5 eq) slowly at 0 °C. The reaction mixture was stirred at rt for 2 h. The resulting mixture was purified by prep-HPLC to afford (lR,3S,4S)-2-(2-(3-acetyl-5-(nicotinamido)-lH- indazol-l-yl)acetyl)-N-(6-(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3-carboxamide(138.7 mg, 57%) as a white solid. LRMS (M+H⁺) m/z calculated 606.2, found 606.0. ¾ NMR DMSO-d₆, 400 MHz) δ 11.40 (s, 0.15H), 11.03 (s, 0.83H), 10.61 (s, IH), 9.15 (d, IH), 8.77 (dd, IH), 8.66 (d, IH), 8.47-8.25 (m, 2H), 8.13 (t, 0.16H), 8.05 (t, 0.83H), 7.87 (dd, IH), 7.71 (d, 0.82H), 7.65 (d, 0.18H), 7.71 (d, 0.82H), 7.63- 7.54 (m, 2H), 5.78 (d, 0.84H), 5.50-5.35 (m, IH), 4.97 (d, 0.15H), 4.67 (s, 0.86H), 4.50 (s, 0.18H), 4.44 (s, 0.16H), 4.17 (s, 0.87H), 2.95 (s, 0.15H), 2.71 (s, 0.86H), 2.62 (s, 2.5 IH), 2.58 (s, 0.52H), 2.10 (d, IH), 1.95- 1.68 (m, 3H), 1.62-1.41 (m, 2H).

Example 182: Preparation of (lR,3S,4S)-2-(2-(3-acetyl-5-(2-chlorobenzamido)-lH-indazol-l-yl)acetyl)-N- (6-(trifluoromethyl)pyridin-2-yl)-2-azabi oxamide

(1 R,3S,4S)-2-(2-(3-acetyl-5-(2-chlorobenzamido)-1 H-indazol-1 -yl)acetyl)

-N-(6-(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3-carboxamide

[00477] To a mixture of (lR,3S,4S)-2-(2-(3-acetyl-5-amino-lH-indazol-l-yl)acetyl)-N-(6-

(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3-carboxamide (200.0 mg, 0.40 mmol, 1.0 eq), 2- chlorobenzoic acid (69.0 mg, 0.44 mmol, 1.1 eq) and HATU (182.4 mg, 0.48 mmol, 1.2 eq) in NMP (1.5 mL) was added DIEA (77.4 mg, 0.60 mmol, 1.5 eq) slowly at 0 °C. The reaction mixture was stirred at rt for 2 h. The resulting mixture was purified by prep-HPLC to afford (lR,3S,4S)-2-(2-(3-acetyl-5-(2-chlorobenzamido)- lH-indazol-l-yl)acetyl)-N-(6-(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3-carboxamide (110.0 mg, 43.1%) as a white solid. LRMS (M+H⁺) m/z calculated 639.2, found 638.9. ¹HNMR DMSO-d₆, 400 MHz) δ 11.37 (s, 0.15H), 11.00 (s, 0.83H), 10.63 (s, 1H), 8.68 (s, lH), 8.43 (d, 0.16H), 8.29 (d, 0.83H), 8.12 (t, 0.17H), 8.04 (t, 0.81H), 7.64 (d, 2H), 7.54 (d, 3H), 7.43 (d, 2H), 5.76 (d, 0.84H), 5.45 (t, 1H), 4.94 (d, 0.15H), 4.67 (s, 0.86H), 4.50 (s, 0.18H), 4.44 (s, 0.16H), 4.17 (s, 0.87H), 2.94 (s, 0.16H), 2.72 (s, 0.86H), 2.62 (s, 2.41H), 2.58 (s, 0.65H), 2.10 (d, 1H), 1.89-1.68 (m, 3H), 1.62-1.41 (m, 2H).

Example 183: Preparation of (lR,3S,4S)-2-(2-(3-acetyl-5-(3-methylureido)-lH-indazol-l-yl)acetyl)-N-(6- (trifluoromethyl)pyridin-2 -yl) -2 -azabicyclo [2.2.1 ]heptane -3 -carboxamide

(1R,3S,4S)-2-(2-(3-acetyl-5-(3-methylureido)-1H-indazol-1-yl)acet l)

-N-(6-(trifluoromethyl)pyridin-2-yl)-2-_--iabicyclo[2.2.1]heptane-3-carboxamide

[00478] To a cooled solution of CDI (3.26 g, 20.0 mmol) in THF (30 mL) was added dropwise a solution of methanamine (2.0 M in THF, 10 mL) at 0 °C. The reaction mixture was stirred at rt for 2 h to give a solution of N-methyl-lH-imidazole-1 -carboxamide in THF (0.5 M). A mixture of (lR,3S,4S)-2-(2-(3-acetyl- 5-amino-lH-indazol-l-yl)acetyl)-N-(6-(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3- carboxamide (327.0 mg, 0.65 mmol, 1.0 eq), N-methyl-lH-imidazole-l-carboxamide (0.5 M in THF, 2.6 mL, 1.3 mmol, 2.0 eq) and DIEA (169.0 mg, 1.31 mmol, 2.0 eq) in NMP (2 mL) was stirred at 90 °C for 36 h under N₂. The reaction mixture was purified by prep-HPLC to afford (lR,3S,4S)-2-(2-(3-acetyl-5-(3- methylureido)-lH-indazol-l-yl)acetyl)-N-(6-(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3- carboxamide (119.9 mg, 33%) as a white solid. LRMS (M+H⁺) m/z calculated 558.2, found 558.0. ¾NMR (DMSO-£¾, 400 MHz) δ 11.39 (s, 0.15H), 11.01 (s, 0.85H), 8.69 (s, 1H), 8.43 (d, 0.16H), 8.29 (d, 0.83H), 8.23 (s, 1H), 8.10 (t, 0.17H), 8.04 (t, 0.84H), 7.64 (d, 0.21H), 7.59-7.48 (m, 2.82H), 7.09 (t, 0.25H), 5.97 (s, 1H), 5.71 (d, 0.82H), 5.39 (t, 1H), 4.90 (d, 0.15H), 4.65 (s, 0.86H), 4.49 (s, 0.18H), 4.42 (s, 0.16H), 4.15 (s, 0.87H), 2.93 (s, 0.12H), 2.70 (s, 0.91H), 2.65 (s, 3H), 2.58 (s, 2.41H), 2.54 (s, 0.65H), 2.10 (d, 1H), 1.89-1.68 (m, 3H), 1.62-1.40 (m, 2H).

Example 184: Preparation of l-(2-((li?,35',45)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo [2.2.1 ]heptan-2-yl)-2-oxoethyl) -6 -(pyrimidin-5 -yl) - lH-indazole -3 -carboxamide

1 -(2-((1 ?,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabiG Glo[2.2.1 ]heptan-2- l -2-oxoeth l -6- rimidin-5- l -1H-indazole-3-

[00479] A mixture of 6-bromo-lH-indazole (31.8 g, 161.4 mmol, 1.0 eq), ΚΟΗ (27.1 g, 484.2 mmol, 3.0 eq) in DMF (200 mL) was added I₂ (82.0 g, 322.8 mmol, 2.0 eq). The mixture was stirred at 30 °C for 1 h. The reaction was poured into aqueous Na₂S0₃ solution and stirred for 15 min. The resulting solid was collected to give 6-bromo-3-iodo-lH-indazole (48.0 g, 92%) as an off-white solid. LRMS (M+H⁺) m/z calculated 322.9, found 322.7 and 324.7.

[00480] To a suspension of 6-bromo-3-iodo-lH-indazole (48.0 g, 149.0 mmol, 1.0 eq) and potassium carbonate (41.0 g, 298.0 mmol, 2.0 eq) in DMF (150 L) was added fert-butyl bromoacetate (35.0 g, 178.8 mmol, 1.2 eq) dropwise at rt. The resulting mixture was stirred at rt for 3 h. The mixture was diluted with EA (4.0 L) and washed with brine (1.0 L x 4), dried over Na₂S0₄, filtered and concentrated. The resulting residue was washed with PE (500 mL) to give fert-butyl 2-(6-bromo-3-iodo-lH-indazol-l-yl)acetate (59.0 g, 91%) as an off-white solid. LRMS (M-56+H⁺) m/z calculated 380.8, found 380.7 and 382.7.

[00481] A mixture of fert-butyl 2-(6-bromo-3-iodo-lH-indazol-l-yl)acetate (11.5 g , 26.31 mmol,

1.0 eq), Zn (1.035 g, 15.92 mmol, 0.6 eq), Zn(CN)₂ (6.2 g, 53.0 mmol, 2.0 eq), Pd(dppf)Cl₂ (3.2 g, 3.92 mmol, 0.15 eq) and Cul (5 g, 26.31 mmol, 1.0 eq) in DMF (100 mL) was stirred at 100 °C for 18 h under N₂ protected. The reaction mixture was concentrated in vacuo, and the resulting residue was purified by chromatography on silica gel column (EA/PE = 1/30, v/v) to give fert-butyl 2-(6-bromo-3-cyano-lH-indazol- l-yl)acetate (5.8 g, 46%) as a white solid. LRMS (M+H⁺) m/z calculated 336.0, found 279.9.

[00482] A mixture of fert-butyl 2-(6-bromo-3-cyano-lH-indazol-l-yl)acetate (2.3 g , 6.84 mmol,

1.0 eq) in DMSO (40 mL) was stirred at 0 °C, then K₂C0₃ (142 mg , 1.03 mmol, 0.15 eq) in H₂0₂ (3.9 g , 34.2 mmol, 5.0 eq) was added. After the addition was completed, the mixture was stirred at rt for 2 h. The mixture was extracted with EA (200 mL* 2), washed with water (200 mL> 2). The combined organic layers were concentrated and the resulting residue was purified by chromatography on silica gel column (EA/PE = 1/1, v/v) to give fert-butyl 2-(6-bromo-3 -carbamoyl- lH-indazol-l-yl)acetate (2.19 g, 90%) as a white solid. LRMS (M+H⁺) m/z calculated 354.0, found 353.9.

[00483] A mixture of fert-butyl 2-(6-bromo-3-carbamoyl-lH-indazol-l-yl)acetate (2.0 g , 5.65 mmol, 1.0 eq), bin₂P (2.15 g , 8.47 mmol, 1.5 eq), Pd(dppf).DCM (461mg , 0.565 mmol, 0.1 eq) and KOAc (1.66 g , 16.95 mmol, 3.0 eq) in dioxane (50 mL) was stirred at 100 °C for 16 h under N₂ protected. The reaction mixture was concentrated in vacuo and the resulting residue was purified by chromatography on silica gel column (PE/EA = 1/9, v/v) to give fert-butyl 2-(3-carbamoyl-6-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-lH-indazol-l-yl)acetate (1.1 g, 48%) as a yellow solid. LRMS (M+H⁺) m/z calculated 402.2, found 401.9.

[00484] A mixture fert-butyl 2-(3-carbamoyl-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH- indazol-l-yl)acetate (300 m g , 0.748 mmol, 1.0 eq), 5-bromopyrimidine (143 mg , 0.897 mmol, 1.2 eq), Pd(PPh₃)₄ (43 mg , 0.037 mmol, 0.05 eq) and K₂C0₃ (1.55 mg , 1.12 mmol, 1.5 eq) in dioxane (15 mL) was stirred at 100 °C for 16 h under N₂ protected. The resulting mixture was purified by chromatography on silica gel column (PE/EA = 1/8, v/v) to give fert-butyl 2-(3-carbamoyl-6-(pyrimidin-5-yl)-lH-indazol-l-yl)acetate (300 mg, 100%) as a yello ⁺) m/z calculated 354.1, found 354.0.

[00485] To a solution of fert-butyl 2-(3-carbamoyl-6-(pyrimidin-5-yl)-lH-indazol-l-yl)acetate

(200 mg, 0.566 mmol, 1.0 eq) in DCM (8 mL) was added TFA (2 mL ) at rt. The mixture was stirred at 25 °C for 16 h. Then the solution was concentrated to give crude 2-(3-carbamoyl-6-(pyrimidin-5-yl)-lH-indazol-l- yl)acetic acid (200 mg, 100% ) as a brown solid. LRMS (M+H⁺) m/z calculated 298.1, found 297.8.

[00486] A mixture of (l i^.S'^^-N-ie-chloropyridin^-y ^-azabicycloP^. llheptane-S- carboxamide (59 mg, 0.234 mmol, 1.0 eq), 2-(3-carbamoyl-6-(pyrimidin-5-yl)-lH-indazol-l-yl)acetic acid (90 mg, 0.303 mmol, 1.3 eq), HATU (133 mg, 0.350 mmol, 1.5 eq) and DIEA (120 mg, 0.932 mmol, 4.0 eq) in DMF (5 mL) was stirred at 35 °C for 16 h. The reaction mixture was concentrated in vacuo, and the resulting residue was purified by prep-HPLC to give l-(2-((li?,35',45)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-6-(pyrimidin-5-yl)-lH-indazole-3-carboxamide (20 mg, 16%) as a white solid. LRMS (M+H⁺) m/z calculated 531.2, found 531.0. ¾ NMR (DMSO- ₆, 400 MHz) δ 10.86 (s, 1H), 9.22-9.26 (t, 3H), 8.29-8.31 (d, 1H) > 8.15 (s, 1H), 7.96-7.98 (d, 1H), 7.71-7.80 (m, 3H), 7.45 (s, 1H), 7.16-7.18 (d, 1H), 5.75-5.79 (d, 1H), 5.42-5.46 (d, 1H), 4.66 (s, lH), 4.11 (s, 1H) > 2.70 (s, 1H) > 2.08-2.11 (d, 1H), 1.78-1.86 (m, 3H), 1.44-1.51 (m, 2H).

Example 185: Preparation of l-(2-((li?,35',45)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-6-(2-methylpyrimidin-5-yl)-lH-indazole-3-carboxamide

1 -(2-((1 R,3S,4S)-3-((6-c loropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1 ]heptan-2-yl)- -oxoethyl)-6-(2-methylpyrimidin-5-yl)-1H-indazole-3-carboxamide

[00487] A mixture fert-butyl 2-(3-carbamoyl-6-(4,4,5,5 etramethyl-l,3,2-dioxaborolan-2-yl)-lH- indazol-l-yl)acetate (300 mg, 0.748 mmol, 1.0 eq), 5-bromo-2-methylpyrimidine (155.2 mg , 0.897 mmol, 1.2 eq), Pd(PPh₃)₄ (43 mg , 0.037 mmol, 0.05 eq) and K₂C0₃ (1.55 mg , 1.12 mmol, 1.5 eq) in dioxane (15 mL) was stirred at 100 °C for 16 h under N₂ protected. The resulting mixture was purified by chromatography on silica gel column (PE/EA = 1/8, v/v) to give fert-butyl 2-(3-carbamoyl-6-(2-methylpyrimidin-5-yl)-lH- indazol-l-yl)acetate (200 mg, 73%) as a yellow solid. LRMS (M+H⁺) m/z calculated 368.2, found 367.8.

[00488] To a solution of fert-butyl 2-(3 -carbamoyl -6-(2-methylpyrimidin -5 -yl)-lH-indazol-l - yl)acetate (200 mg, 0.544 mmol, 1.0 eq) in DCM (8 mL) was added TFA (2 mL ) at rt. The mixture was stirred at 25 °C for 16 h. Then the solution was concentrated to give crude 2-(3-carbamoyl-6-(2- methylpyrimidin-5-yl)-lH-indazol-l-yl)acetic acid (200 mg, 90% ) as a brown solid. LRMS (M+H⁺) m/z calculated 312.1, found 312.0.

[00489] A mixture of (li?,35',45)-N-(6-chloropyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3- carboxamide (48 mg, 0.188 mmol, 1.0 eq), 2-(3-carbamoyl-6-(2-methylpyrimidin-5-yl)-lH-indazol-l- yl)acetic acid (100 mg, 0.245 mmol, 1.3 eq), HATU (107.2 mg, 0.282 mmol, 1.5 eq) and DIEA (146 mg, 1.128 mmol, 4.0 eq) in DMF (5 mL) was stirred at 35 °C for 4 h. The resulting mixture was purified by prep- HPLC to give l-(2-((li?,35',45)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2. l]heptan-2-yl)-2- oxoethyl)-6-(2-methylpyrimidin-5-yl)-lH-indazole-3-carboxamide (37.1 mg, 36%) as a white solid. LRMS (M+H⁺) m/z calculated 545.2, found 545.0. ¾ NMR DMSO-d₆, 400 MHz) δ 10.87 (s, 1H), 9.12 (s, 2H), 8.28-8.29 (d, 1H) > 8.09 (s, 1H), 7.96-7.98 (d, 1H), 7.74-7.80 (m, 2H), 7.66-7.68 (d, 2H), 7.45 (s, 1H), 7.15- 7.17 (d, 1H), 5.73-5.78 (d, 1H), 5.40-5.45 (d, 1H), 4.66 (s, 1H), 4.11 (s, 1H) > 2.70 (s, 4H) > 2.08-2.10 (d, 1H), 1.78-1.85 (m, 3H), 1.43-1.50 (m, 2H).

Example 186: Preparation of l-(2-((li?,35',45)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-6-( -5-yl)-lH-indazole-3-carboxamide

1-(2-((1R,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2- l)-2-oxoethyl)-6-(2-cyanopyrimidin-5-yl)-1H-in

[00490] A mixture fert-butyl 2-(3-carbamoyl-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH- indazol-l-yl)acetate (300 mg , 0.748 mmol, 1.0 eq), 5-bromo-2-methylpyrimidine (165 mg , 0.897 mmol, 1.2 eq), Pd(PPh₃)₄ (43 mg , 0.037 mmol, 0.05 eq) and K₂C0₃ (155 mg , 1.12 mmol, 1.5 eq) in dioxane (15 mL) was stirred at 100 °C for 16 h under N₂ protected. The resulting mixture was purified by chromatography on silica gel column (PE/EA = 1/7, v/v) to give fert-butyl 2-(3 -carbamoyl -6-(2-cyanopyrimidin-5-yl)-lH-indazol- l-yl)acetate (190 mg, 67%) as a yellow solid. LRMS (M-56+H⁺) calculated 323.1, found 322.8.

[00491] To a solution of fert-butyl 2-(3 -carbamoyl -6-(2-cyanopyrimidin-5-yl)-lH-indazol-l- yl)acetate (190 mg, 0.502 mmol, 1.0 eq) in DCM (8 mL) was added TFA (2 mL ) at rt. The mixture was stirred at 25 °C for 16 h. Then the solution was concentrated and the resulting mixture was purified by prep- HPLC to give 2-(3-carbamoyl-6-(2-cyanopyrimidin-5-yl)-lH-indazol-l-yl)acetic acid (60 mg, 37% ) as a yellow solid. LRMS (M+H⁺) m/z calculated 323.1, found 322.8.

[00492] A mixture of (li?,35',45)-N-(6-chloropyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3- carboxamide (18 mg, 0.072 mmol, 1.0 eq), 2-(3-carbamoyl-6-(2-cyanopyrimidin-5-yl)-lH-indazol-l-yl)acetic acid (30 mg, 0.093 mmol, 1.3 eq), HATU (41 mg, 0.107 mmol, 1.5 eq) and DIEA (37 mg, 0.286 mmol, 4.0 eq) in DMF (3 mL) was stirred at 35 °C for 16 h. Ther eaction mixture was was concentrated in vacuo and the resulting residue was purified by prep-HPLC to give l-(2-((li?,35',45)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo[2.2. l]heptan-2-yl)-2-oxoethyl)-6-(2-cyanopyrimidin-5-yl)-lH-indazole-3-carboxamide (2 mg, 5%) as a white solid. LRMS (M+H⁺) m/z calculated 556.2, found 556.2. ¾ NMR (DMSO- ₆, 400 MHz) δ 10.87 (s, 1H), 9.48(s, 2H), 8.31-8.33 (d, 1H) > 8.27 (s, 1H), 7.95-7.97 (d, 1H), 7.76-7.81 (m, 3H), 7.48 (s, 1H), 7.16- 7.18 (d, 1H), 5.76-5.80 (d, 1H), 5.42-5.46 (d, 1H), 4.66 (s, 1H), 4.11 (s, 1H) > 2.69 (s, 1H) > 2.08-2.1 l(d, 1H), 1.79-1.87 (m, 3H), 1.44-1.50 (m, 2H).

Example 187: Preparation of 6-(2-carbamoylpyrimidin-5-yl)-l-(2-((li?,35',45)-3-((6-chloropyridin-2- yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-lH-indazole-3-carboxamide

6-(2-carbamoylpyrimidin-5-yl)-1-(2-((1R,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-

[00493] To a solution of fert-butyl 2-(3 -carbamoyl -6-(2-cyanopyrimidin-5-yl)-lH-indazol-l- yl)acetate (150 mg , 0.398 mmol, 1.0 eq) in DMSO (8 mL) was added K₂C0₃ (9 mg , 0.06 mmol, 0.15 eq) in H₂0₂ (226 mg , 1.99 mmol, 5.0 eq) at 0 °C. After the addition was completed, the mixture was stirred at rt for 2 h. The mixture was extracted with EA (100 mL> 2), washed with water (100 mL> 2). The combined organic layers were concentrated to give tert-b tyl 2-(3-carbamoyl-6-(2-carbamoylpyrimidin-5-yl)-lH-indazol-l- yl)acetate (180 mg, crude) as a light yellow solid. LRMS (M+H⁺) m/z calculated 397.2, found 397.1

[00494] To a solution of fert-butyl 2-(3-carbamoyl-6-(2-carbamoylpyrimidin-5-yl)-lH-indazol-l- yl)acetate (180 mg, 0.454 mmol, 1.0 eq) in DCM (6 mL) was added TFA (2 mL ) at rt. The mixture was stirred at 25 °C for 16 h. Then the solution was concentrated to give 2-(3 -carbamoyl -6-(2- carbamoylpyrimidin-5-yl)-lH-indazol-l-yl)acetic acid (130 mg, 65% ) as a brown solid.

[00495] A mixture of (li?,35',45)-N-(6-chloropyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3- carboxamide (29 mg, 0.114 mmol, 1.0 eq), 2-(3-carbamoyl-6-(2-carbamoylpyrimidin-5-yl)-lH-indazol-l- yl)acetic acid (65 mg, 0.149 mmol, 1.3 eq), HATU (65 mg, 0.171 mmol, 1.5 eq) and DIEA (59 mg, 0.456 mmol, 4.0 eq) in DMF (3 mL) was stirred at 35 °C for 4 h. The reaction mxiture was concentrated and the resulting residue was purified by prep-HPLC to give 6-(2-carbamoylpyrimidin-5-yl)-l-(2-((li?,35',45)-3-((6- chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-lH-indazole-3-carboxamide (7 mg, 11%) as a white solid. LRMS (M+H⁺) m/z calculated 556.2, found 556.2. ¾ NMR DMSO-d₆, 400 MHz) δ 10.88 (s, 1H), 9.37(s, 2H), 8.29-8.33 (m, 2H) > 8.27 (s, 1H), 7.96-7.98 (d, 1H), 7.76-7.90 (m, 4H), 7.47 (s, 1H), 7.15-7.17 (d, 1H), 5.76-5.80 (d, 1H), 5.43-5.48 (d, 1H), 4.67 (s, 1H), 4.12 (s, 1H), 2.70 (s, 1H), 2.09- 2.1 l(d, 1H), 1.79-1.87 (m, 3H), 1.44-1.53 (m, 2H).

Example 188: Preparation of 6-benzamido-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo [2.2.1 ]heptan-2-yl)-2-oxoethyl)- lH-indazole-3 -carboxamide

6-benzamido-1-(2-((1R,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2

-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-1H-indazole-3-carboxamide

[00496] To a solution of fert-butyl 2-(64jromo-3-cyano-lH-indazol-l-yl)acetate (5.5 g, 16.4 mmol, 1.0 eq) in dioxane (40 mL) were added Pd₂(dba)₃ (1.5 g, 1.6 mmol, 0.1 eq), Xantphos (949 mg, 1.6 mmol, 0.1 eq) and Cs₂C0₃ (10.7g, 32.7 mmol, 2.0 eq) carefully. The result mixture was stirred at 80 °C for 2 h under N₂ protected. The mixture was concentrated, and the resulting residue was purified by chromatography on silica gel column (EA/PE = 1/5, v/v) to afford fert-butyl 2-(6-((tert-butoxycarbonyl)amino)-3-cyano-lH- indazol-l-yl)acetate (6.4 g, 89%) as a yellow solid. LRMS (M+H⁺) m/z calculated 373.2, found 373.2.

[00497] To a mixture of fert-butyl 2-(6-((teri-butoxycarbonyl)amino)-3-cyano-lH-indazol-l- yl)acetate (1.0 g, 2.69 mmol, 1.0 eq) in DMSO (10 mL) was added a solution of K₂C0₃ (56.0 mg, 0.40 mmol, 0.15 eq) in H₂0₂ (1.5 g, 13.45 mmol, 5.0 eq) at 0 °C. The reaction mixture was stirred at rt for 2 h. The resulting mixture was purified by prep-HPLC to give fert-butyl 2-(6-((fert-butoxycarbonyl)amino)-3- carbamoyl-lH-indazol-l-yl)acetate (950 mg, 90%) as a white solid. LRMS (M+H⁺) m/z calculated 391.2, found 391.0.

[00498] To a mixture of fert-butyl 2-(6-((teri-butoxycarbonyl)amino)-3-carbamoyl-lH-indazol-l yl)acetate (950 mg, 2.44 mmol, 1.0 eq) in THF (8 mL) at 0 °C was added a solution of NaOH (195 mg, 4.88 mmol, 2.0 eq) in H₂0 (2 mL). The mixture was stirred at rt overnight. The resulting mixture was purified by prep-HPLC to give 2-(6-((teri-butoxycarbonyl)amino)-3-carbamoyl-lH-indazol-l-yl)acetic acid (675 mg, 83%) as a white solid. LR ⁺) m/z calculated 335.1, found 335.0.

[00499] To a mixture of 2-(6-((teri-butoxycarbonyl)amino)-3-carbamoyl-lH-indazol-l-yl)acetic acid (100 mg 0.30 mmol, 1.0 eq) and (lR,3S,4S)-N-(6-chloropyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3- carboxamide (110 mg, 0.30 mmol, 1.0 eq) in DMF (2 mL) were added HATU (228 mg, 0.60 mmol, 2.0 eq) and DIEA (116 mg, 0.90 mmol, 3.0 eq) at 0 °C. The mixture was stirred at rt for 2 h. The resulting mixture was purified by prep-HPLC to afford fert-butyl (3-carbamoyl-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2- yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-lH-indazol-6-yl)carbamate (115 mg, 68%) as white solid. LRMS (M+H⁺)

[00500] To a mixture of fert-butyl (3-carbamoyl-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2- yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-lH-indazol-6-yl)carbamate (110 mg, 0.19 mmol) in DCM (2 mL) at 0 °C was added TFA (2 mL) slowly. The resulting mixture was purified by prep-HPLC to afford 6-amino-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- oxoethyl)-lH-indazole-3 -carboxamide (80 mg, 90%) as a white solid. LRMS (M+H⁺) m/z calculated 468.2, found 467.7.

[00501] To a solution of 6-amino-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-lH-indazole-3-carboxamide (75 mg, 0.16 mmol, 1.0 eq) and DIEA (62 mg, 0.30 mmol, 3.0 eq) in DMF (1 mL) was added benzoyl chloride (27 mg, 0.19 mmol, 1.2 eq) slowly at 0 °C. The result mixture was stirred at 0 °C for 1 h. The reaction mixture was purified by prep-HPLC to afford 6-benzamido-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- oxoethyl)-lH-indazole -3 -carboxamide (63.6 mg, 67%) as a white solid. LRMS (M+H⁺) m/z calculated 572.2, found 571.9. ¾ NMR DMSO-d₆, 400 MHz) δ 11.23 (s, 0.15H), 11.86 (s, 0.85H), 10.49 (s, 1H), 8.22 (s, 0.85H), 8.16 (d, 0.3H), 8.11- 8.09 (m, lH), 8.01- 7.97 (m, 2.85H), 7.89 - 7.85 (t, 0.15H), 7.80 - 7.76 (m, 0.85H), 7.66 (s, 1H), 7.62 - 7.52 (m, 4H), 7.37 (s, lH), 7.24 (d, 0.15H), 7.17 (d, 0.85H), 5.58 (d, 0.85H), 5.35 - 5.25 (m, 1H), 4.82 (d, 0.15H), 4.66 (s, 0.85H), 4.50 (s, 0.15H), 4.49 (s, 0.15H), 4.09 (s, 0.85H), 3.67 (s, 3H), 2.93 (d, 0.15H), 2.68 (s, 1H), 2.09 (d, 0.85H), 1.82 - 1.29 (m, 5.15H).

Example 189: Preparation of 6-acetamido-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo [2.2.1 ]heptan-2-yl)-2-oxoethyl)- lH-indazole-3 -carboxamide

[00502] To a solution of 6-amino-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-lH-indazole-3-carboxamide (100 mg, 0.21 mmol, 1.0 eq) and DIEA (81 mg, 0.63 mmol, 3.0 eq) in NMP (1 mL) was added acetyl chloride (25 mg, 0.32 mmol, 1.5 eq) slowly at 0 °C. The result mixture was stirred at 0 °C for 1 h. The reaction mixture was purified by prep-HPLC to afford 6-benzamido-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2- yl)-2-oxoethyl)-lH-indazole-3-carboxamide (66.6 mg, 62%) as a white solid. LRMS (M+H⁺) m/z calculated 510.2, found 509.9. ¾ NMR (DMSO- ₆, 400 MHz) δ 11.23 (s, 0.15H), 11.86 (s, 0.85H), 10.49 (s, 1H), 8.22 (s, 0.85H), 8.16 (d, 0.3H), 8.11- 8.09 (m, 1H), 8.01- 7.97 (m, 2.85H), 7.89 - 7.85 (t, 0.15H), 7.80 - 7.76 (m, 0.85H), 7.66 (s, 1H), 7.62 - 7.52 (m, 4H), 7.37 (s, IH), 7.24 (d, 0.15H), 7.17 (d, 0.85H), 5.58 (d, 0.85H), 5.35 - 5.25 (m, IH), 4.82 (d, 0.15H), 4.66 (s, 0.85H), 4.50 (s, 0.15H), 4.49 (s, 0.15H), 4.09 (s, 0.85H), 3.67 (s, 3H), 2.93 (d, 0.15H), 2.68 (s, 0.95H), 2.33 (s, 0.05H), 2.09 (d, 0.85H), 1.82 - 1.29 (m, 5H).

Example 190: Preparation of methyl (3-carbamoyl-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-lH-indazol-6-yl)carbamate

methyl (3-carbamoyl-1 -(2-((1 R,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azablcyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-1H-lndazol-6-yl)carbamate

[00503] To a mixture of 6-amino-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-lH-indazole-3-carboxamide (100 mg, 0.21 mmol, 1.0 eq) and methyl carbonochloridate (30 mg, 0.32 mmol, 1.5 eq) in NMP (1 mL) was added DIEA (81 mg, 0.63 mmol, 3.0 eq) slowly at 0 °C. The reaction mixture was stirred at 0 °C for 1 h. The resulting mixture was purified by prep-HPLC to afford methyl (3-carbamoyl-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-lH-indazol-6-yl)carbamate (84.5 mg, 77%) as a white solid. LRMS (M+H⁺) m/z calculated 526.2, found 526.1. ¾ NMR (DMSO- ₆, 400 MHz) δ 11.23 (s, 0.15H), 11.86 (s, 0.85H), 10.49 (s, 1H), 8.22 (s, 0.85H), 8.16 (d, 0.3H), 8.11- 8.09 (m, 1H), 8.01- 7.97 (m, 2.85H), 7.89 - 7.85 (t, 0.15H), 7.80 - 7.76 (m, 0.85H), 7.66 (s, 1H), 7.62 - 7.52 (m, 4H), 7.37 (s, lH), 7.24 (d, 0.15H), 7.17 (d, 0.85H), 5.58 (d, 0.85H), 5.35 - 5.25 (m, 1H), 4.82 (d, 0.15H), 4.66 (s, 0.85H), 4.50 (s, 0.15H), 4.49 (s, 0.15H), 4.09 (s, 0.85H), 3.67 (s, 3H), 2.93 (d, 0.15H), 2.68 (s, 0.95H), 2.33 (s, 0.05H), 2.09 (d, 0.85H), 1.82 - 1.29 (m, 5H).

Example 191: Preparation of l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-6 azole-3-carboxamide

1 -(2-((1 R,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1 ]

-2-yl)-2-oxoethyl)-6-(nicotinamido)-1H-indazole-3-carboxamide

[00504] A mixture of 6-amino-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-lH-indazole-3-carboxamide (100 mg, 0.21 mmol, 1.0 eq), nicotinic acid (39 mg, 0.32 mmol, 1.5 eq), HATU (160 mg, 0.42 mmol, 2.0 eq) and DIEA (81 mg, 0.63 mmol, 3.0 eq) in NMP (2 mL) was stirred at rt for 2 h. The reaction mixture was concentrated and the resulting residue was purified by prep-HPLC to afford l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-6-(nicotinamido)-lH-indazole-3-carboxamide (91.1 mg, 76%) as a white solid. LRMS (M+H⁺) m/z calculated 573.2, found 573.2. ¾ NMR (DMSO- ₆, 400 MHz) δ 11.23 (s, 0.15H), 11.86 (s, 0.85H), 10.49 (s, 1H), 8.22 (s, 0.85H), 8.16 (d, 0.3H), 8.11- 8.09 (m, 1H), 8.01- 7.97 (m, 2.85H), 7.89 - 7.85 (t, 0.15H), 7.80 - 7.76 (m, 0.85H), 7.66 (s, 1H), 7.62 - 7.52 (m, 4H), 7.37 (s, 1H), 7.24 (d, 0.15H), 7.17 (d, 0.85H), 5.58 (d, 0.85H), 5.35 - 5.25 (m, 1H), 4.82 (d, 0.15H), 4.66 (s, 0.85H), 4.50 (s, 0.15H), 4.49 (s, 0.15H), 4.09 (s, 0.85H), 3.67 (s, 3H), 2.93 (d, 0.15H), 2.68 (s, 0.95H), 2.33 (s, 0.05H), 2.09 (d, 0.85H), 1.82 - 1.29 (m, 5H).

Example 192: Preparation of l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-6 azole-3-carboxamide

1-(2-((1R,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]

-2-yl)-2-oxoet yl)-6-(picolinamido)-1 -/-indazole-3-carboxamide

[00505] A mixture of 6-amino-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-lH-indazole-3-carboxamide (100 mg, 0.21 mmol, 1.0 eq), picolinic acid (39 mg, 0.32 mmol, 1.5 eq), HATU (160 mg, 0.42 mmol, 2.0 eq) and DIEA (81mg, 0.63 mmol, 3.0 eq) in DMF (2 mL) was stirred at rt for 2 h. The reaction mixture was concentrated, and the resulting residue was purified by prep-HPLC to afford l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-6-(picolinamido)-lH-indazole-3-carboxamide (72.6 mg, 61%) as a white solid. LRMS (M+H⁺) m/z calculated 573.2, found 572.9. ¾ NMR (DMSO- ₆, 400 MHz) δ 11.23 (s, 0.15H), 11.86 (s, 0.85H), 10.49 (s, 1H), 8.22 (s, 0.85H), 8.16 (d, 0.3H), 8.11-8.09 (m, 1H), 8.01-7.97 (m, 2.85H), 7.89-7.85 (t, 0.15H), 7.80 - 7.76 (m, 0.85H), 7.66 (s, 1H), 7.62-7.52 (m, 4H), 7.37 (s, 1H), 7.24 (d, 0.15H), 7.17 (d, 0.85H), 5.58 (d, 0.85H), 5.35-5.25 (m, 1H), 4.82 (d, 0.15H), 4.66 (s, 0.85H), 4.50 (s, 0.15H), 4.49 (s, 0.15H), 4.09 (s, 0.85H), 3.67 (s, 3H), 2.93 (d, 0.15H), 2.68 (s, 0.95H), 2.33 (s, 0.05H), 2.09 (d, 0.85H), 1.82-1.29 (m, 5H).

Example 193: Preparation of l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-6-(isonicotinamido)-lH-indazole-3-carboxamide

1 -(2-((1 R,3S,4S)-3-((6-chloropyridin-2-yl)car amoyl)-2-azabicyclo[2.2.1 ]

heptan-2-yl)-2-oxoethyl)-6-(isonicotinamido)-1H-indazole-3-carboxamicle

[00506] A mixture of 6-amino-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-lH-indazole-3-carboxamide (100 mg, 0.21 mmol, 1.0 eq), picolinic acid (39 mg, 0.32 mmol, 1.5 eq), HATU (160 mg, 0.42 mmol, 2.0 eq) and DIEA (81 mg, 0.63 mmol, 3.0 eq) in DMF (2 mL) was stirred at rt for 2 h. The reaction mixture was concentrated, and the resulting residue was purified by prep-HPLC to afford l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-6-(picolinamido)-lH-indazole-3-carboxamide (87.1 mg, 73%) as a white solid. LRMS (M+H⁺) m/z calculated 573.2, found 572.9. ¾ NMR (DMSO- ₆, 400 MHz) δ 11.23 (s, 0.15H), 11.86 (s, 0.85H), 10.49 (s, 1H), 8.22 (s, 0.85H), 8.16 (d, 0.3H), 8.11- 8.09 (m, 1H), 8.01- 7.97 (m, 2.85H), 7.89 - 7.85 (t, 0.15H), 7.80 - 7.76 (m, 0.85H), 7.66 (s, 1H), 7.62 - 7.52 (m, 4H), 7.37 (s, 1H), 7.24 (d, 0.15H), 7.17 (d, 0.85H), 5.58 (d, 0.85H), 5.35 - 5.25 (m, 1H), 4.82 (d, 0.15H), 4.66 (s, 0.85H), 4.50 (s, 0.15H), 4.49 (s, 0.15H), 4.09 (s, 0.85H), 3.67 (s, 3H), 2.93 (d, 0.15H), 2.68 (s, 0.95H), 2.33 (s, 0.05H), 2.09 (d, 0.85H), 1.82 - 1.29 (m, 5H).

Example 194: Preparation of l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-6-(3-methylureido)-lH-indazole-3-carboxamide

1 -(2-((1 R,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1 ]

heptan-2-yl)-2-oxoethyl)-6-(3-methylureido)-1H-indazole-3-carboxamide

[00507] To a cooled solution of CDI (3.26 g, 20.0 mmol) in THF (30 mL) was added dropwise a solution of methanamine (2.0 M in THF, 10 mL) at 0 °C. The result mixture was stirred at rt for 2 h to give a solution of N-methyl-lH-imidazole-l-carboxamide in THF (0.5 M). Then a mixture of 6-amino-l-(2- ((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-lH-indazole-3- carboxamide (100 mg, 0.21 mmol, 1.0 eq), DIEA (81 mg, 0.63 mmol, 3.0 eq) and N-methyl-lH-imidazole-1- carboxamide (1.26 mL, 0.64 mmol, 3.0 eq, 0.5 M in THF) in DMF (1 mL) was stirred at 90 °C overnight. The resulting mixture was purified by prep-HPLC to afford l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)- 2-azabicyclo[2.2. l]heptan-2-yl)-2-oxoethyl)-6-(3-methylureido)-lH-indazole-3-carboxamide (42.1 mg, 38%) as a white solid. LRMS (M+H⁺) m/z calculated 525.2, found 525.1. ¾ NMR (DMSO- ₆, 400 MHz) δ 11.23 (s, 0.15H), 11.86 (s, 0.85H), 10.49 (s, 1H), 8.22 (s, 0.85H), 8.16 (d, 0.3H), 8.11- 8.09 (m, 1H), 8.01- 7.97 (m, 2.85H), 7.89 - 7.85 (t, 0.15H), 7.80 - 7.76 (m, 0.85H), 7.66 (s, 1H), 7.62 - 7.52 (m, 4H), 7.37 (s, 1H), 7.24 (d, 0.15H), 7.17 (d, 0.85H), 5.58 (d, 0.85H), 5.35 - 5.25 (m, 1H), 4.82 (d, 0.15H), 4.66 (s, 0.85H), 4.50 (s, 0.15H), 4.49 (s, 0.15H), 4.09 (s, 0.85H), 3.67 (s, 3H), 2.93 (d, 0.15H), 2.68 (s, 0.95H), 2.33 (s, 0.05H), 2.09 (d, 0.85H), 1.82 - 1.29 (m, 5H).

Example 195: Preparation of 6-benzamido-l-(2-((lR,3S,4S)-3-((3-chloro-2-fluorobenzyl)carbamoyl)-2- azabicyclo [2.2.1 ]heptan-2-yl)-2-oxoethyl)- lH-indazole-3 -carboxamide

6-benzamido-1-(2-((1R,3S,4S)-3-((3-chloro-2-fluorobenzyl)carbamoyl)-2

-azabic clo[2.2.1]heptan-2-yl)-2-oxoet yl)-1H-indaz

[00508] To a solution of fert-butyl 2-(6-bromo-3-cyano-lH-indazol-l-yl)acetate (5.5 g, 16.4 mmol, 1.0 eq) in dioxane (40 mL) was added Pd₂(dba)₃ (1.5 g, 1.6 mmol, 0.1 eq), Xantphos (949 mg, 1.6 mmol, 0.1 eq) and Cs₂C0₃ (10.7g, 32.7 mmol ,2.0 eq) carefully. The reaction mixture was stirred at 80 °C for 2 h under N₂ protected. The reaction mixture was concentrated, and the resulting residue was purified by chromatography on silica gel column (EA/PE = 1/5, v/v) to afford tert-b tyl 2-(6-((tert- butoxycarbonyl)amino)-3-cyano-lH-indazol-l-yl)acetate (6.4 g, 89%) as a yellow solid. LRMS (M+H⁺) m/z calculated 373.2, found 373.2.

[00509] To a mixture of tert-butyl 2-(6-((fer^butoxycarbonyl)amino)-3-cyano-lH-indazol-l- yl)acetate (1.0 g, 2.69 mmol, 1.0 eq) in DMSO (10 mL) was added a solution of K₂C0₃ (56.0 mg, 0.40 mmol, 0.15 eq) in H₂0₂ (1.5 g, 13.45 mmol, 5.0 eq) at 0 °C. The reaction mixture was stirred at rt for 2 h. The reaction mixture was purified by prep-HPLC to give tert-butyl 2-(6-((fert-butoxycarbonyl)amino)-3- carbamoyl-lH-indazol-l-yl)acetate (950 mg, 90%) as a white solid. LRMS (M+H⁺) m/z calculated 391.2, found 391.0.

[00510] To a solution of tert-butyl 2-(6-((teri-butoxycarbonyl)amino)-3-carbamoyl-lH-indazol-l- yl)acetate (950 mg, 2.44 mmol, 1.0 eq) in THF (8 mL) at 0 °C was added a solution of NaOH (195 mg, 4.88 mmol, 2.0 eq) in water (2 mL). The reaction mixture was stirred at rt overnight. The reaction mixture was adjusted to pH 4 by IN HC1 and extracted with EA. The combined organic layers were dried over anhydrous Na₂S0₄ and concentrated. The resulting residue was purified by prep-HPLC to give 2-(6-((tert- butoxycarbonyl)amino)-3-carbamoyl-lH-indazol-l-yl)acetic acid (675 mg, 83%) as a white solid. LRMS (M+H⁺) m/z calculated 335

[00511] To a mixture of 2-(6-((tert-butoxycarbonyl)amino)-3-carbamoyl-lH-indazol-l-yl)acetic acid (1.0 g, 3.0 mmol, 1.0 eq) and (lR,3S,4S)-N-(3-chloro-2-fluorobenzyl)-2-azabicyclo[2.2.1]heptane-3- carboxamide trifluoroacetate salt (1.4 g, 3.6 mmol, 1.2 eq) in DMF (10 mL) were added HATU (2.3 g, 6.0 mmol, 2.0 eq) and DIEA (2 g, 15.0 mmol, 5.0 eq) at rt. The mixture was stirred at rt for 0.5 h. The reaction mixture was concentrated and the resulting residue was purified by prep-HPLC to give tert-butyl (3- carbamoyl-l-(2-((lR,3S,4S)-3-((3-chloro-2-fluorobenzyl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- oxoethyl)-lH-indazol-6-yl)carbamate (1.5 g, 83 %) as a pale yellow solid. LRMS (M+H ) m/z calculated 599.2, found 599.5

[00512] To a solution of fert-butyl (3-carbamoyl-l-(2-((lR,3S,4S)-3-((3-chloro-2- fluorobenzyl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-lH-indazol-6-yl)carbamate (1.5 g, 2.9 mmol) in anhydrous DCM (5 mL) was added TFA (3 mL) slowly at 0 °C. After stirred at room temperature for 2 h under nitrogen atmosphere, the mixture was concentrated. The resulting residue was purified by prep- HPLC to give 6-amino-l-(2-((lR,3S,4S)-3-((3-chloro-2-fluorobenzyl)carbamoyl)-2-azabicyclo[2.2. l]heptan- 2-yl)-2-oxoethyl)-lH-indazole-3-carboxamide (850 mg, 68 %) as a pale yellow solid. LRMS (M+H⁺) m/z calculated 499.2, found

[00513] To a mixture of 6-amino-l-(2-((lR,3S,4S)-3-((3-chloro-2-fluorobenzyl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-lH-indazole-3-carboxamide (30.0 mg, 0.06 mmol, 1.0 eq), benzoyl chloride (10.1 mg, 0.072 mmol, 1.2 eq) in NMP (1.5 mL) was added DIEA (15.5 mg, 0.12 mmol, 2.0 eq) at 0 °C. The reaction mixture was stirred at rt for 1 h. The reaction mixture was purified by prep-HPLC to afford 6- benzamido-l-(2-((lR,3S,4S)-3-((3-chloro-2-fluorobenzyl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- oxoethyl)-lH-indazole-3-carboxamide (7 mg, 19.5%) as a white solid. ^l NMR (DMSO- ₆, 400 MHz) δ 10.48 (d, 1H),8.84 (s, 0.19H), 8.44 (s,0.73H), 8.27 (d, 0.75H), 8.14-8.09 (m, IH), 8.00-7.88 (m, 2H),7.62-7.43 (m, 5H), 7.36-7.32 (m, 2H), 7.00 (t, IH), 5.57 (d, 0.72H), 5.29 (d, 0.92H), 4.82 (s, 0.23H), 4.52 (d, IH), 4.41- 4.24(m, 2H), 3.82 (s, IH), 2.58 (s, IH), 2.03 (d, IH) 1.90-1.66 (m, 3H), 1.59-1.43 (m, 2H). LRMS (M+H⁺) m/z calculated 603.2, found 603.1.

Example 196: Preparation of 6-acetamido-l-(2-((lR,3S,4S)-3-((3-chloro-2-fluorobenzyl)carbamoyl)-2- azabicyclo [2.2.1 ]heptan-2-yl)-2-oxoethyl)- lH-indazole-3 -carboxamide

6-acetamido-1-(2-((1R,3S,4S)-3-((3-chloro-2-fluorobenzyl)carbamoyl)

-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-1H-indazole-3-carboxamide

[00514] To a mixture of 6-amino-l-(2-((lR,3S,4S)-3-((3-chloro-2-fluorobenzyl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-lH-indazole-3-carboxamide (60.0 mg,0.12 mmol, 1.0 eq), acetyl chloride (11.0 mg, 0.144 mmol, 1.2 eq) in NMP (1.5 mL) was added DIEA (30.9 mg, 0.24 mmol, 2.0 eq) at 0 °C. The reaction mixture was stirred at rt for 1 h. The reaction mixture was purified by prep-HPLC to afford 6- acetamido-l-(2-((lR,3S,4S)-3-((3-chloro-2-fluorobenzyl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- oxoethyl)-lH-indazole-3-carboxamide (27mg, 42.0%) as a white solid. LRMS (M+H⁺) m/z calculated 541.2, found 541.1. ¾ NMR (DMSO- ₆, 400 MHz) δ 10.15 (d, 1H), 8.84-8.81 (m, 0.19H), 8.44-8.41 (s,0.81H), 8.07-8.02 (m, 1.75H), 7.94 (s, 0.25H), 7.59 (s, 1Η),7.50-7.34 (m, 2H), 7.25-7.17 (m, 2H), 7.04 (s, 1H), 5.49 (d, 0.72H), 5.27 (d, lH), 4.76 (d, 0.23H), 4.45-4.24 (m, 2H), 3.83 (s, 1H), 2.79-2.58 (m, 1H), 2.08-2.00 (m, 4H) 1.79-1.70 (m, 3H), 1.57-1.42 (m, 2H).

Example 197: Preparation of methyl (3-carbamoyl-l-(2-((lR,3S,4S)-3-((3-chloro-2-fluorobenzyl)carbamoyl)- 2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-l -indazol-6-yl)carbamate

methyl (3-carbamoyl-1-(2-((1R,3S,4S)-3-((3-chlora-2-fluorobenzyl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-1H-indazol-6-yl)carbamate

[00515] To a mixture of 6-amino-l-(2-((lR,3S,4S)-3-((3-chloro-2-fluorobenzyl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-lH-indazole-3-carboxamide (80 mg, 0.16 mmol, 1.0 eq) and methyl carbonochloridate (30 mg, 0.32 mmol, 2.0 eq) in NMP (2 mL) was added DIEA (42 mg, 0.32 mmol, 2.0 eq) at 0 °C under N₂.The mixture was stirred at 0 °C for 0.5 h. The resulting mixture was purified by prep- HPLC to give methyl (3-carbamoyl-l-(2-((lR,3S,4S)-3-((3-chloro-2-fluorobenzyl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-lH-indazol-6-yl)carbamate (73 mg, 82%) as a white solid. LRMS (M+H⁺) m/z calculated 556.2, found 556.9. ¾ NMR (400 MHz, DMSO- ₆) δ 9.90 (s, 0.1H), 9.87 (s, 0.9H), 8.85 (t, 0.2H), 8.45 (t, 0.8H), 8.02 (d, lH), 7.82 (s, 0.8H), 7.72 (s, 0.2H), 7.58 (s, 0.7H), 7.50 - 7.34 (m, 2.3H), 7.20 - 7.16 (m, 2.1H), 7.04 - 7.00 (m, 0.9H), 5.51 (d, 1H), 5.24 (d, 0.8H), 4.76 (d, 0.2H), 4.56 - 4.25 (m, 3.2H), 3.84 (s, 0.8H), 3.70 (s, 0.5H), 3.66 (s, 2.5H), 2.79 (s, 0.2H), 2.58 (s, 0.8H), 2.03 (d, 0.9H), 1.80 - 1.43 (m, 5.2H).

Example 198: Preparation of l-(2-((lR,3S,4S)-3-((3-chloro-2-fluorobenzyl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-6-( ndazole-3-carboxamide

1-(2-((1R,3S,4S)-3-((3-chloro-2-fluorobenzyl)carbamoyl)-2

[00516] To a mixture of 6-amino-l-(2-((lR,3S,4S)-3-((3-chloro-2-fluorobenzyl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-lH-indazole-3-carboxamide (100.0 mg, 0.2 mmol, 1.0 eq), picolinic acid (37.1 mg, 0.3 mmol, 1.5 eq), HATU (153.0 mg, 0.6 mmol, 3.0 eq) in NMP (2.0 mL) was added DIEA (78.3 mg, 0.4 mmol, 2.0 eq) at 0 °C. The reaction mixture was stirred at 0 °C for 2 h. The resulting mixture was purified by prep-HPLC to afford l-(2-((lR,3S,4S)-3-((3-chloro-2-fluorobenzyl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-6-(picolinamido)-lH-indazole-3-carboxamide (40 mg, 33%) as a white solid. LRMS (M+H⁺) m/z calculated 604.2, found 604.0. ¾ NMR (DMSO- 6, 400 MHz) δ 10.48 (d, IH), 8.84 (s, 0.19H), 8..87-8.82 (m, IH), 8.47-8.44 (m, 0.75H), 8.31 (s, 0.25H), 8.26 (s, 0.81H), 8.18 (d, 0.37H), 8.12 (s, 0.63H), 8.10-8.05 (m, 2H), 7.74-7.65 (m, 2H), 7.63 (s, 0.77H), 7.56 (s, 0.19H), 7.37 (s, IH), 7.24-7.11 (m, 2H), 6.89 (t, IH), 5.57 (d, 0.72H), 5.29 (d, 0.92H), 4.82 (s, 0.23H), 4.59 (s, IH), 4.48-4.40 (m, 1.4H), 4.30-4.22 (m, 0.8H), 2.80 (s, 0.16H), 2.60 (s, 0.88H), 2.05 (d, IH) 1.82-1.71 (m, 3H), 1.58-1.45 (m, 2H).

Example 199: Preparation of l-(2-((lR,3S,4S)-3-((3-chloro-2-fluorobenzyl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-6-( -indazole-3-carboxamide

1-(2-((1R,3S,4S)-3-((3-chlora-2-fluorobenzyl)oarbamoyl)-2-azabicyclo[2.2.1]heptan-2

-yl)-2-oxoethyl)-6-(isonicotinamido)-1H-indazole-3-carboxamide

[00517] To a mixture of 6-amino-l-(2-((lR,3S,4S)-3-((3-chloro-2-fluorobenzyl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-lH-indazole-3-carboxamide (100.0 mg,0.2mmol, 1.0 eq), isonicotinic acid (37.1 mg, 0.3 mmol, 1.5 eq), HATU (153.0 mg, 0.6 mmol, 3.0 eq) in NMP (2 mL) was added DIEA (78.3 mg, 0.4 mmol, 2.0 eq) at 0 °C. The reaction mixture was stirred at 0 °C for 2 h. The reaction mixture was purified by prep-HPLC to afford l-(2-((lR,3S,4S)-3-((3-chloro-2-fluorobenzyl)carbamoyl)-2- azabicyclo[2.2. l]heptan-2-yl)-2-oxoethyl)-6-(isonicotinamido)-lH-indazole-3-carboxamide (59 mg, 49%). LRMS (M+H⁺) m/z calculated 604.2, found 604.2. ¾ NMR (DMSO- ₆, 400 MHz) δ 10.48 (d, IH), 8.84 (s, 0.19H), 8..87-8.82 (m, IH), 8.47-8.44 (m, 0.75H), 8.31 (s, 0.25H), 8.26 (s, 0.81H), 8.18 (d, 0.37H), 8.12 (s, 0.63H), 8.10-8.05 (m, 2H),7.74-7.65 (m, 2H), 7.63 (s, 0.77H), 7.56 (s, 0.19H), 7.37 (s, IH), 7.24-7.11 (m, 2H), 6.89 (t, IH), 5.57 (d, 0.72H), 5.29 (d, 0.92H), 4.82 (s, 0.23H), 4.59 (s, IH), 4.48-4.40 (m, 1.4H), 4.30- 4.22 (m, 0.8H), 2.80 (s, 0.16H), 2.60 (s, 0.88H), 2.05 (d, IH) 1.82-1.71 (m, 3H), 1.58-1.45 (m, 2H).

Example 200: Preparation of l-(2-((lR,3S,4S)-3-((3-chloro-2-fluorobenzyl)carbamoyl)-2- azabicyclo [2.2.1 ]heptan-2-yl)-2-oxoethyl)-5 -(nicotinamido)- lH-indazole-3 -carboxamide

1-(2-((1 ,3S,4S)-3-((3-chloro-2-fluorobenzyl)carbamoyl)-2-azabicyclo[2.2.1]

-2-yl)-2-oxoethyl)-5-(nicotinamido)-1H-indazole-3-carboxamide

[00518] A mixture of 5-amino-l-(2-((lR,3S,4S)-3-((3-chloro-2-fluorobenzyl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-lH-indazole-3-carboxamide (150 mg, 0.30 mmol, 1.0 eq), nicotinic acid (45 mg, 0.36 mmol, 1.2 eq), HATU (240 mg, 0.60 mmol, 2.0 eq) and DIEA (115 mg, 0.90 mmol, 3.0 eq) in NMP (2 mL) was stirred at rt for 2 h. The reaction mixture was concentrated and the resulting residue was purified by prep-HPLC to afford l-(2-((lR,3S,4S)-3-((3-chloro-2-fluorobenzyl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(nicotinamido)-lH-indazole-3-carboxamide (166.6 mg, 92%) as a white solid. LRMS (M+H⁺) m/z calculated 604.2, found 604.0. ¾ NMR (DMSO- ₆, 400 MHz) δ 10.57 (s, IH), 9.17 (s, IH), 8.94 - 8.35 (m, 4H), 7.83-7.80 (m, IH), 7.64-7.05 (m, 6H), 5.62 (d, 0.85H), 5.35-5.30 (m, IH), 4.80 (d, 0.15H), 4.55-4.27 (s, 3.15H), 3.85 (s, 0.85H), 2.79 (d, 0.15H), 2.59 (s, IH), 2.03 (d, 0.85H), 1.79-1.29 (m, 5H).

Example 201: Preparation of l-(2-((lR,3S,4S)-3-((3-chloro-2-fluorobenzyl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-6- -methylureido)-lH-indazole-3-carboxamide

1-(2-((1R,3 S)-3-((3-chloro-2-fluorobenzyl)ca*amo

[00519] To a cooled solution of CDI (3.26 g, 20.0 mmol) in THF (30 mL) was added dropwise a solution of methanamine (2.0 M in THF, 10 mL) at 0 °C. The reaction mixture was stirred at rt for 2 h to give a solution of N-methyl-lH-imidazole-l-carboxamide in THF (0.5 M). Then a mixture of 6-amino-l-(2- ((lR,3S,4S)-3-((3-chloro-2-fluorobenzyl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-lH- indazole-3-carboxamide (100 mg, 0.2 mmol, 1.0 eq), N-methyl-lH-imidazole-l-carboxamide (0.5 M in THF, 2.0 mL, 1 mmol, 5.0 eq) and DIEA (52 mg, 0.4 mmol, 2.0 eq) in DMF (1.0 mL) was stirred at 90 °C for 16 h. The reaction mixture was concentrated and the resulting residue was purified by chromatography on silica gel column (DCM/MeOH = 15/1, v/v) to give the crude product, which was further purified by prep-HPLC to give l-(2-((lR,3S,4S)-3-((3-chloro-2-fluorobenzyl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)- 6-(3-methylureido)-lH-indazole-3-carboxamide (45.0 mg, 40%) as a white solid. LRMS (M+H⁺) m/z calculated 556.2, found 556.1. ¾NMR (DMSO- ₆, 400 MHz) δ 8.83 (t, 0.20H), 8.76 (s, 0.2H), 8.74 (s, 0.8H), 8.43 (m, 0.8H), 7.97 (d, 0.8H), 7.96 (d, 0.2H), 7.85 (d, 0.8H), 7.70 (m, 0.2H), 7.57-7.98 (m, 6 H), 6.10- 6.03 (m, 1H), 5.45 (d, 0.8H), 5.25-5.16 (m, 1H), 4.73 (d, 0.2H), 4.59-4.22 (m, 3.2H), 3.83 (s, 0.8H), 2.77 (d, 0.2H), 2.66 (d, 0.6H), 2.64 (d, 2.4H), 2.58 (d, 0.8H), 2.02 (d, 0.8H), 1.82-1.25 (m,5.2H).

Example 202: Preparation of (li?,35',45)-2-(2-(3-acetyl-6-(pyrimidin-5-yl)-lH-indazol-l-yl)acetyl)-N-(6- chloropyridin-2-yl)-2-azabicyclo [2.2.1 ]heptane-3 -carboxamide

[00520] To a solution of fert-butyl 2-(6-bromo-3-iodo-lH-indazol-l-yl)acetate (4.5 g, 10.30 mol,

1.0 eq) in DMF (60 mL) was added Pd(PPh₃)₄ (178 mg, 0.154 mmol, 0.015 eq) under N₂ stirred at rt for 15 min. Then tributyl(l-ethoxyvinyl)stannane (4.09 g, 11.33 mmol, 1.1 eq) was added to this mixture. The resulting mixture was stirred at 100 °C for 4 h. After cooled to rt, the reaction mixture was quenched with water (100 mL), extracted with EA (50 mL x 3). The combined organic layers were dried and concentrated to give fert-butyl 2-(6-bromo-3-(l-ethoxyvinyl)-lH-indazol-l-yl)acetate as a oil.

To this oil in THF (40 mL) was added 4 N HC1 (5 mL) slowly. The reaction mixture was stirred at rt for 0.5 h. The mixture was diluted with water (20 mL), extracted with EA (50 mL x 2). The combined organic layers were concentrated and the resulting residue was purified by chromatography on silica gel column (PE/EA = 10/1, v/v) to give fert-butyl 2-(3 -acetyl -6-bromo-lH-indazol-l-yl)acetate (2.8 g, 78%) as a white solid. LCMS (M+H⁺) m/z calculated 353.0, found 352.8.

[00521] A mixture of fert-butyl 2-(3-acetyl-6-bromo-lH-indazol-l-yl)acetate (2 g, 5.66 mmol, 1.0 eq), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (2.16 g, 8.50 mmol, 1.5 eq) KOAc (1.67 g, 16.98 mmol, 3.0 eq) and Pd(dppf)Cl₂ (462 mg, 0.57 mmol, 0.1 eq) in dioxane (20 mL) was stirred at 120 °C for 4 h.The mixture was concentrated and the resulting residue was purified by chromatography on silica gel column (PE/EA = 10/1, v/v) to give fert-butyl 2-(3-acetyl-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH- indazol-l-yl)acetate (2.2 g, 97%) as a yellow solid. LCMS (M+H⁺) m/z calculated 401.2, found 401.1.

[00522] To a solution of fert-butyl 2-(3-acetyl-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan -2-yl)- lH-indazol-l-yl)acetate (500 mg, 1.25 mmol, 1.0 eq) and 5-bromopyrimidine (238 mg, 1.5 mmol, 1.2 eq) in dioxane (5 mL) were added K₂C0₃ (259 mg, 1.88 mmol, 1.5 eq) in H₂0 (1.9 mL) and Pd(PPh₃)₄ (72 mg, 0.063 mmol, 0.05 eq). The mixture was stirred at 100 °C overnight. Water (10 mL) was added, and the mixture was extracted with EA (20 mL x 2). The combined organic layers were dried over Na₂S0₄, filtered and concentrated. The resulting residue was purified by chromatography on silica gel column (PE/EA = 10/1, v/v) to give the target compound (260 mg, 60%) as a yellow solid. LCMS (M+H⁺) m/z calculated 353.2, found 353.1.

[00523] To a solution of fert-butyl 2-(3-acetyl-6-(pyrimidin-5-yl)-lH-indazol-l-yl)acetate (260 mg, 0.74 mmol, 1.0 eq) in DCM (6 mL) was added TFA (2 mL ) at rt. The mixture was stirred at rt overnight. Then the resulting mixture was concentrated to give 2-(3-acetyl-6-(pyrimidin-5-yl)-lH-indazol-l-yl)acetic acid trifluoroacetate (250 mg, 83%) as a yellow oil. LCMS (M+H⁺) m/z calculated 297.1, found 297.2.

[00524] A mixture of 2-(3-acetyl-6-(pyrimidin-5-yl)-lH-indazol-l-yl)acetic acid trifluoroacetate

(1 16 mg, 0.28 mmol, 1.0 eq), (li?,35',45)-N-(6-chloropyridin-2-yl)-2- azabicyclo[2.2.1]heptane-3-carboxamide trifluoroacetate ( 150 mg, 0.42 mmol, 1.5 eq), HATU (129 mg, 0.34 mmol, 1.2 eq) and DIEA (1 10 mg, 0.85 mmol, 3.0 eq) in DMF (10 mL) was stirred at rt overnight. The reaction mixture was concentrated, and the resulting residue was purified by prep-HPLC to afford ( li?,35',45)-2-(2-(3-acetyl-6-(pyrimidin-5-yl)-lH- indazol-l -yl)acetyl)-N-(6-chloropyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3-carboxamide (52 mg, 17%) as a white solid. LCMS (M+H⁺) m/z calculated 530.2, found 529.9. ¾ NMR (DMSO- ₆, 400 MHz) δ 10.87 (s, 1H), 9.26 (s, 3H), 8.26-8.30 (m, 1H), 8.12-8.18 (m, 1H), 7.96-7.98 (d, 1H), 7.76-7.8(5 (m, 2H), 7.15-7.17 (d, 1H), 5.85-5.89 (d, 1H), 5.52-5.56 (d, 1H), 4.69 (s, 1H), 4.12 (s, 1H), 2.70 (s, lH), 2.65 (s, 3H), 2.08-2.12 (m, 1H), 1.81-1.91 (m, 3H), 1.44-1.54 (m, 2H).

Example 203: Preparation of ( li?,35',45)-2-(2-(3-acetyl-6-(2-methylpyrimidin-5-yl)-lH-indazol-l-yl)acetyl)- N-(6 -chloropyridin-2-yl) -2 -azabicyclo [2.2.1] heptane -3 -carboxamide

(1 R,3S,4S)-2-(2-(3-acetyl-6-(2-methylpyrimidin-5-yl)-1 H-indazol-1 -yl)acetyl)- ]heptane-3-carboxamlde

[00525] To a mixture of fert-butyl 2-(3-acetyl-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan -2-yl)-

^-indazol-l-y^acetate (500 mg, 1.25 mmol, 1.0 eq) and 5-bromo-2-methylpyrimidine (260 mg, 1.5 mmol, 1.2 eq) in dioxane (5 mL) was added K₂C0₃ (259 mg, 1.88 mmol, 1.5 eq) in 1.9 mL and Pd(PPh₃)₄ (72 mg, 0.063 mmol, 0.05 eq). The mixture was stirred at 100 °C overnight. After that, water (10 mL) was added and the mixture was extracted with EA (20 mL x 2). The combined organic layers were dried over Na₂S0₄, filtered and concentrated. The resulting residue was purified by chromatography on silica gel column (PE/EA = 10/1, v/v) to give fert-butyl 2-(3-acetyl-6-(2-methylpyrimidin-5-yl)-lH-indazol-l-yl)acetate (200 mg, 44%) as a yellow solid. LCMS (M+H⁺

[00526] To a solution of fert-butyl 2-(3-acetyl-6-(2-methylpyrimidin-5-yl)-lH-indazol -1 - yl)acetate (200 mg, 0.55 mmol, 1.0 eq) in DCM (6 mL) was added TFA (2 mL ) at rt. The mixture was stirred at rt overnight. Then the mixture was concentrated to give 2-(3-acetyl-6-(2-methylpyrimidin-5-yl)-lH- indazol-l-yl)acetic acid trifluoroacetate (190 mg, 82%) as a yellow oil. LRMS (M+H⁺) m/z calculated 311.1, found 311.0.

[00527] A mixture of 2-(3-acetyl-6-(2-methylpyrimidin-5-yl)-lH-indazol-l-yl)acetic acid trifluoroacetate (115 mg, 0.27 mmol, 1.0 eq), (l ^S^^-N-^-chloropyridin^-yl)^- azabicyclo[2.2.1]heptane-3-carboxamide trifluoroacetate (149 mg, 0.41 mmol, 1.5 eq), HATU (124 mg, 0.33 mmol, 1.2 eq) and DIEA (106 mg, 0.82 mmol, 3.0 eq) in DMF (10 mL) was stirred at rt overnight. The reaction mixture was concentrated, and the resulting residue was purified by prep-HPLC to afford (\R,3S,4S)- 2-(2-(3-acetyl-6-(2-methylpyrimidin-5 -yl)- lH-indazol- 1 -yl)acetyl)-N-(6-chloropyridin-2-yl)-2- azabicyclo[2.2.1]heptane-3-carboxamide (25 mg, 17%) as a white solid. LRMS (M+H⁺) m/z calculated 544.2, found 544.2. ¾ NMR DMSO-d₆, 400 MHz) δ 10.87 (s, IH), 9.13 (s, 2H), 8.26-8.28 (d, IH), 8.12 (s, IH), 7.96-7.98 (d, IH), 7.74-7.80 (m, 2H), 7.16-7.18 (d, IH), 5.84-5.88 (d, IH), 5.52-5.56 (d, IH), 4.69 (s, IH), 4.12 (s, IH), 2.71 (s,4H), 2.65 (s,3H), 2.08-2.12 (m, IH), 1.79-1.88 (m, 3H), 1.44-1.52 (m, 2H).

Example 204: Preparation of (li?,35',45)-2-(2-(3-acetyl-6-(2-cyanopyrimidin-5-yl)-lH-indazol-l-yl)acetyl)- N-(6 -chloropyridin-2-yl) -2 -azabicyclo [2.2.1] heptane -3 -carboxamide

(1R,3S,4S)-2-(2-(3-acetyl-6-(2-c anopyrimidin-5-yl)-1H-indazol-1-yl)acetyl)

-N-(6-ohloropyridin-2-yl)-2-azabioyclo[2.2.1]heptane-3-carboxamide

[00528] To a solution of fert-butyl 2-(3-acetyl-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan -2-yl)- lH-indazol-l-yl)acetate (500 mg, 1.25 mmol, 1.0 eq) and 5-bromopyrimidine-2 -carbonitrile (276 mg, 1.5 mmol, 1.2 eq) in dioxane (5 mL) were added K₂C0₃ (259 mg, 1.88 mmol, 1.5 eq), H₂0 (1.9 mL) and

Pd(PPh₃)₄ (72 mg, 0.063 mmol, 0.05 eq). The mixture was stirred at 100 °C overnight. After that, water (10 mL) was added and the mixture was extracted with EA (20 mL x 2). The combined organic layers were dried over Na₂S0₄, filtered and concentrated. The resulting residue was purified by chromatography on silica gel column (PE/EA = 30/1, v/v) to give fert-butyl 2-(3-acetyl-6-(2-cyanopyrimidin-5-yl)-lH-indazol-l-yl)acetate (150 mg, 31%) as a yellow solid. ⁺) m/z calculated 378.1, found 378.2.

[00529] To a solution of fert-butyl 2-(3-acetyl-6-(2-cyanopyrimidin-5-yl)-lH-indazol-l-yl) acetate

(150 mg, 0.40 mmol, 1.0 eq) in DCM (6 mL) was added TFA (2 mL ) at rt. The mixture was stirred at rt overnight. Then the resulting solution was concentrated to give 2-(3-acetyl-6-(2-cyanopyrimidin-5-yl)-lH- indazol-l-yl)acetic acid trifluoroacetate (200 mg, 100%) as a yellow oil. LRMS (M+H⁺) m/z calculated 322.1, found 321.3.

[00530] A mixture of 2-(3-acetyl-6-(2-cyanopyrimidin-5-yl)-lH-indazol-l-yl)acetic acid trifluoroacetate (130 mg crude, 0.30 mmol, 1.0 eq), (l ^S^^-N-^-chloropyridin^-yl)^- azabicyclo[2.2.1]heptane-3-carboxamide trifluoroacetate (160 mg, 0.45 mmol, 1.5 eq), HATU (137 mg, 0.36 mmol, 1.2 eq) and DIEA (116 mg, 0.90 mmol, 3.0 eq) in DMF (10 mL) was stirred at rt overnight. The mixture was concentrated, and the resulting residue was purified by prep-HPLC to afford (li?,35^*,45)-2-(2-(3- acetyl-6-(2-cyanopyrimidin-5-yl)-lH-indazol-l-yl)acetyl)-N-(6-chloropyridin-2-yl)-2- azabicyclo[2.2.1]heptane-3-carboxamide (54 mg, 32%) as a white solid. LRMS (M+H⁺) m/z calculated 555.2, found 554.9. ¾NMR DMSO-d₆, 400 MHz) δ 10.87 (s, 1H), 9.49 (s, 2H), 8.29-8.33 (m, 2H), 7.95-7.97 (d, 1H), 7.86-7.87 (d, 1H), 7.76-7.80 (m, IH), 7.76-7.15 (d, 1H), 5.86-5.90 (d, 1H), 5.53-5.57 (d, 1H), 4.69 (s, 1H), 4.12 (s, IH), 2.71 (s, lH), 2.66 (s, 3H), 2.09-2.12 (m, IH), 1.80-1.91 (m, 3H), 1.45-1.52 (m, 2H).

Example 205: Preparation of (li?,35',45)-2-(2-(3-acetyl-6-(2-carbamoylpyrimidin-5-yl)-7H-indazol-l- yl)acetyl)-N-(6-chloropyridin-2-yl)-2-azabicyclo[2.2.1]heptone-3-carboxamide

[00531] To a solution of (\R,3S,4S)-2-(2-(3 -acetyl -6-(2-cyanopyrimidin-5 -yl)-lH-indazol-l - yl)acet^yl)-N-(6-chloropyridin-2-yl)-2-azabicy^clo[2.2.1]hepi_ane-3-carboxamide (18 mg, 0.03 mmol, 1.0 eq) in DMSO (3 mL) was added H₂0₂ (3.7 mg, 0.3 mmol, 10 eq) and K₂C0₃ (1.4 mg, 0.01 mmol, 0.3 eq). The mixture was stirred at 30 °C for 4 h. Then the mixture was treated with brine (3 mL) and extracted with EA (20 mL x 3). The combined organic layers were dried over Na₂S0₄, filtered and concentrated. The resulting residue was purified by prep-HPLC to afford (li?,35',45)-2-(2-(3-acetyl-6-(2-carbamoylpyrimidin-5-yl)-lH- indazol-l-yl)acetyl)-N-(6-chloropyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3-carboxamide (11.2 mg, 65%) as a yellow oil. LRMS (M+H⁺) m/z calculated 572.2, found 572.9. ¾ NMR DMSO-d₆, 400 MHz) δ 11.27 (s,

0.1.), 10.88 (s, 0.8H), 9.34-9.38 (m, 2H), 8.27-8.32 (m, 2H), 8.21-8.23 (m, 1H), 7.96 (d, 1H), 7.84-7.90 (m, 2H), 7.79 (t, 1H), 7.15-7.23 (m, lH), 5.88 (d, 1H), 5.56 (d, 1H), 4.70 (s, 1H), 4.12 (s, 1H), 2.71 (s, 1H), 2.63- 2.66 (m, 3H), 2.10 (d, 1H), 1.88-1.92 (m, 1H), 1.76-1.84 (m, 2H), 1.50-1.54 (m, 1H), 1.45 (d, 1H).

II. Biological Evaluation

Example 1: In vitro enzyme inhibition

[00532] The ability of the compounds disclosed herein to inhibit human complement factor D inhibitory activity was quantified according to the 12-step protocol provided below.

1. Prepare assay buffer: 50mM Tris/HCl, pH 7.5, 1 M NaCl.

2. Dilute 10 mM Complement Factor D inhibitor Nafamostat Mesilate (Selleckchem, Catalog# S 1386) solution from 10000μΜ to 9.77μΜ in 100% DMSO, 8 concentrations. Then dilute the serial concentrations of Nafamostat Mesilate 20-fold in assay buffer.

3. Add 10 μΐ diluted Nafamostat Mesilate duplicated into each of the inhibitor control well of a 96-well plate (Corning, Catalog# 3599). Final concentrations were 50μΜ, 25μΜ, 12.5μΜ, 6.25μΜ, 3.125μΜ, 0.781μΜ, 0.195μΜ and 0.049μΜ. 0.5%DMSO was in each well finally.

4. Dilute 20 mM test compounds from 10000μΜ to 35.72μΜ in 100%DMSO, 6-fold dilution, 8 concentrations. Then dilute the serial concentrations of test compounds 20-fold in assay buffer. 5. Add 10 μΐ diluted test compounds duplicated into the 96-well plate. Final concentrations were 50μΜ, 8.33μΜ, 1.39μΜ, 0.23μΜ, 0.0386μΜ, 0.0064μΜ, 0.001 ΙμΜ and 0.0002μΜ. 0.5%DMSO was in each well finally.

6. Dilute 20 mM substrate Z-Lys-SBzl (Bachem, Cat# M-1300) to 200μΜ in assay buffer with 200μΜ DTNB(Sigma, Catalog# D8130).

7. Dilute 738ng/μL Complement Factor D (R&D Systems, Catalog# 1824-SE) to 6.25ng/μL in assay buffer. Add 40μ1 diluted Complement Factor D in the 96-well plate.

8. Positive control well contains Complement Factor D without test compound. Negative control well contains neither Complement Factor D nor test compound. Using assay buffer, bring the total volume of all controls to 50μ1.

9. Pre-incubate the plate for 5 min at room temperature.

10. Add 50μ1 of diluted substrate/DTNB mixture into each well. Mix the reagents completely by shaking the plate gently for 30 sec.

11. For kinetic reading: Immediately start measuring absorbance (A₄₀5nm) continuously and record data every 30sec for 60 min.

12. Data analysis

Inhibition activity of compound was evaluated by IC₅₀. IC₅₀ was calculated according the dose-response curve of compound fitted using GraphPadPrism with "log(inhibitor)-response (variable slope)" equation.

%inhibition was calculated by using following equation:

Sample value-Mean(NC)

Inhibition%=100 X 100

Mean(PC)-Mean(NC)

Mean(NC): The average value of the negative control wells' A₄o_5mn values.

Mean(PC): The average value of the positive control wells' A₄o_5mn values.

[00533] The ability of the compounds in Table 2 to inhibit human complement factor D inhibitory activity was determined.

TABLE 2

Ex. Chemical Name CFD IC₅₀

7-(aminomethyl)-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-

5 yl)carbamoyl) -2 -azabicyclo [2.2.1] heptan-2 -yl) -2 -oxoethyl) - 1 H- B indazole -3 -carboxamide

methyl 3 -carbamoyl- 1 -(2-(( 1 R,3 S,4S)-3 -((6-chloropyridin-2-

6 yl)carbamoyl) -2 -azabicyclo [2.2.1] heptan-2 -yl) -2 -oxoethyl) - 1 H- B indazole-7-carboxylate

methyl 7-chloro-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-

7 yl)carbamoyl) -2 -azabicyclo [2.2.1] heptan-2 -yl) -2 -oxoethyl) - 1 H- C indazole-3 -carboxylate

l-(2-((lR,3S,4S)-3-((7-chloro-l,6-naphthyridin-5-yl)carbamoyl)-2-

8 azabicyclo [2.2.1] heptan-2 -yl) -2 -oxoethyl)- 1 H-indazole -3 - B carboxamide

l-(2-((lR,3S,4S)-3-((6-chloro-3H-imidazo[4,5-c]pyridin-4-

9 yl)carbamoyl) -2 -azabicyclo [2.2.1] heptan-2 -yl) -2 -oxoethyl) - 1 H- B indazole -3 -carboxamide

1 -(2-(( 1R,3 S,4S)-3 -((6-chloro-5 -cyanopyridin-2-yl)carbamoyl)-2-

10 azabicyclo [2.2.1] heptan-2 -yl) -2 -oxoethyl)- 1 H-indazole -3 - C carboxamide

1 -(2-(( 1R,3 S,4S)-3 -((6-chloro-5 -(trifluoromethyl)pyridin-2-

11 yl)carbamoyl) -2 -azabicyclo [2.2.1] heptan-2 -yl) -2 -oxoethyl) - 1 H- C indazole -3 -carboxamide

l-(2-((lS,3S,4S)-3-((6-chloro-5-fluoropyridin-2-yl)carbamoyl)-2-

12 azabicyclo [2.2.1 ]heptan-2 -yl) -2 -oxoethyl)- 1 H-indazole -3 - C carboxamide

l-(2-((lR,3S,4S)-3-((3-chloroisoquinolin-l-yl)carbamoyl)-2-

13 azabicyclo [2.2.1] heptan-2 -yl) -2 -oxoethyl)- 1 H-indazole -3 - B carboxamide

l-(2-((lS,3S,4S)-3-((6-chloro-5-fluoropyridin-2-yl)carbamoyl)-2-

14 azabicyclo [2.2.1] heptan-2 -yl) -2 -oxoethyl)- 1 H-indazole -3 - A carboxamide

l-(2-((lR,3S,4S)-3-((7-chloropyrido[3,4-b]pyrazin-5-yl)carbamoyl)-

15 2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-lH-indazole-3- C carboxamide

l-(2-((lR,3S,4S)-3-((5-chloro-lH-pyrazolo[3,4-c]pyridin-7-

16 yl)carbamoyl) -2 -azabicyclo [2.2.1] heptan-2 -yl) -2 -oxoethyl) - 1 H- B indazole -3 -carboxamide

1 -(2-(( 1R,3 S,4S)-3 -((3 -chloronaphthalen- 1 -yl)carbamoyl)-2-

17 azabicyclo [2.2.1] heptan-2 -yl) -2 -oxoethyl)- 1 H-indazole -3 - C carboxamide

1 -(2-(( 1R,3 S,4S)-3 -((5 -chloro-lH-indazol-7-yl)carbamoyl)-2-

18 azabicyclo [2.2.1] heptan-2 -yl) -2 -oxoethyl)- 1 H-indazole -3 - C carboxamide

5-acetamido-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-

19 2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-lH-indazole-3- B carboxamide

5 -benzamido - 1 -(2-(( 1 R, 3 S,4 S) -3 -((6 -chloropyridin-2 -

20 yl)carbamoyl) -2 -azabicyclo [2.2.1] heptan-2 -yl) -2 -oxoethyl) - 1 H- A indazole -3 -carboxamide

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-

21 azabicyclo [2.2.1 ]heptan-2-yl)-2 -oxoethyl) -5 -(nicotinamide) - 1 H- A indazole -3 -carboxamide Ex. Chemical Name CFD IC₅₀ l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-

22 azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(2-phenylacetamido)- A

lH-indazole-3-carboxamide

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-

23 azabicyclo [2.2.1] heptan-2 -yl) -2 -oxoethyl)-7-( 1 -hydroxyethyl) - 1 H- B indazole -3 -carboxamide

(lR,3S,4S)-N-(6-chloropyridin-2-yl)-2-(2-(3-methoxy-lH-indazol-

24 C

1 -yl)acetyl) -2 -azabicyclo [2.2.1] heptane -3 -carboxamide

7-acetyl-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-

25 B azabicyclo [2.2.1] heptan-2 -yl)acetyl) - 1 H-indazole-3 -carboxamide

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-

26 azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-7-(2-hydroxypropan-2- C

yl)-l H-indazole -3 -carboxamide

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-

27 azabicyclo [2.2.1 ]heptan-2-yl)-2-oxoethyl) - 1 H-indole -3 - C

carboxamide

l-(2-((lR,3S,4S)-3-((3-chloro-2-fluorophenyl)carbamoyl)-2-

28 azabicyclo [2.2.1 ]heptan-2-yl)-2-oxoethyl) - 1 H-indole -3 - C

carboxamide

methyl (3-carbamoyl-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-

29 yl)carbamoyl) -2 -azabicyclo [2.2.1] heptan-2 -yl) -2 -oxoethyl) - 1 H- A

indazol-5 -yl)carbamate

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-

30 azabicyclo [2.2.1 ]heptan-2-yl)-2-oxoethyl)-5 -(2- A

(dimethylamino)acetamido)-lH-indazole-3-carboxamide

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-

31 azabicyclo [2.2.1 ]heptan-2-yl)-2-oxoethyl)-5 -(2- A

morpholinoacetamido) - 1 H-indazole -3 -carboxamide

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-

32 azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(2-(4-methylpiperazin- B

1 -yl)acetamido)- lH-indazole-3 -carboxamide

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-

33 azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(phenylsulfonamido)- B lH-indazole-3-carboxamide

(lR,3S,4S)-N-(6-chloropyridin-2-yl)-2-(2-(l-methoxyisoquinolin-3-

34 D yl) -2 -oxoethyl) -2 -azabicyclo [2.2.1 ]heptane-3 -carboxamide

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-

35 azabicyclo [2.2.1] heptan-2 -yl) -2 -oxoethyl)isoquinoline-3 - C

carboxamide

isopropyl (3-carbamoyl-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-

36 yl)carbamoyl) -2 -azabicyclo [2.2.1] heptan-2 -yl) -2 -oxoethyl) - 1 H- A

indazol-5 -yl)carbamate

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-

37 azabicyclo [2.2.1 ] heptan-2 -yl) -2 -oxoethyl)-5 -(tetrahydrofuran-3 - A

carboxamido)-lH-indazole-3-carboxamide

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-

38 azabicyclo [2.2.1] heptan-2 -yl) -2 -oxoethyl)-5 - A

(cyclopentanecarboxamido)-lH-indazole-3-carboxamide

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-

39 azabicyclo [2.2.1] heptan-2 -yl) -2 -oxoethyl)-5 -(methylsulfonamido) - B lH-indazole-3-carboxamide Ex. Chemical Name CFD IC₅₀ l-(2-((l ,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-

40 azabicyclo [2.2.1 ]heptan-2-yl)-2-oxoethyl)-5 -(2-(2- A fluorophenyl)acetamido) - 1 H-indazole -3 -carboxamide

l-(2-((l ,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-

41 azabicyclo [2.2.1 ]heptan-2-yl)-2-oxoethyl)-5 -(2-(3 - A fluorophenyl)acetamido) - 1 H-indazole -3 -carboxamide

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-

42 azabicyclo [2.2.1 ]heptan-2-yl)-2-oxoethyl)-5 -(2-(4- A fluorophenyl)acetamido) - 1 H-indazole -3 -carboxamide

5-(2-(4-chlorophenyl)acetamido)-l-(2-((lR,3S,4S)-3-((6-

43 chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- B oxoethyl) - 1 H-indazole-3 -carboxamide

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-

44 azabicyclo [2.2.1 ]heptan-2-yl)-2-oxoethyl)-5 -(2-(4- A cyanophenyl)acetamido)-lH-indazole-3-carboxamide

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-

45 azabicyclo [2.2.1 ]heptan-2-yl)-2-oxoethyl)-5 -(2-(m- B tolyl)acetamido) - 1 H-indazole-3 -carboxamide

5-(4-chlorobenzamido)-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-

46 yl)carbamoyl) -2 -azabicyclo [2.2.1] heptan-2 -yl) -2 -oxoethyl) - 1 H- A indazole -3 -carboxamide

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-

47 azabicyclo [2.2.1] heptan-2 -yl) -2 -oxoethyl)-5 -(4 -cyanobenzamido) - B lH-indazole-3-carboxamide

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-

48 azabicyclo [2.2.1] heptan-2 -yl) -2 -oxoethyl)-5 - A

(cyclopropanecarboxamido) - 1 H-indazole -3 -carboxamide

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-

49 azabicyclo [2.2.1 ]heptan-2-yl)-2-oxoethyl)-5 -(piperazine-2- A carboxamido)-lH-indazole-3-carboxamide

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-

50 azabicyclo [2.2.1 ]heptan-2-yl)-2 -oxoethyl) -5 -(picolinamido) - 1 H- A indazole -3 -carboxamide

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-

51 azabicyclo [2.2.1 ]heptan-2-yl)-2-oxoethyl)-5 -(pyrimidine-4- A carboxamido)-lH-indazole-3-carboxamide

N-(3 -carbamoyl- 1 -(2-(( 1 R,3 S,4S)-3 -((6-chloropyridin-2-

52 yl)carbamoyl) -2 -azabicyclo [2.2.1] heptan-2 -yl) -2 -oxoethyl) - 1 H- A indazol-5-yl)morpholine-2 -carboxamide

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-

53 azabicyclo [2.2.1] heptan-2 -yl) -2 -oxoethyl)-5 -(1 H-pyrazole -4 - A carboxamido)-lH-indazole-3-carboxamide

5-((S)-2-amino-3-methylbutanamido)-l-(2-((lR,3S,4S)-3-((6-

54 chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- A oxoethyl) - 1 H-indazole-3 -carboxamide

5-(2-(2-chlorophenyl)acetamido)-l-(2-((lR,3S,4S)-3-((6-

55 chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- A oxoethyl) - 1 H-indazole-3 -carboxamide

5-(2-(3 -chlorophenyl)acetamido)- 1 -(2-(( 1R,3 S,4S)-3-((6-

56 chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- A oxoethyl) - 1 H-indazole-3 -carboxamide Ex. Chemical Name CFD IC₅₀ l-(2-((l ,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-

57 azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(2-(o-tolyl)acetamido)- A lH-indazole-3-carboxamide

N-(3 -carbamoyl- 1 -(2-(( 1 R,3 S,4S)-3 -((6-chloropyridin-2-

58 yl)carbamoyl) -2 -azabicyclo [2.2.1] heptan-2 -yl) -2 -oxoethyl) - 1 H- A indazol-5-yl)moφholine-3-carboxamide

5 -(3 -aminopropanamido) - 1 -(2-(( 1 R, 3 S,4 S) -3 -((6 -chloropyridin-2 -

59 yl)carbamoyl) -2 -azabicyclo [2.2.1] heptan-2 -yl) -2 -oxoethyl) - 1 H- A indazole -3 -carboxamide

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-

60 azabicyclo [2.2.1] heptan-2 -yl) -2 -oxoethyl)-5 -(1 H-imidazole -4 - A carboxamido)-lH-indazole-3-carboxamide

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-

61 azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(isonicotinamido)-lH- A indazole -3 -carboxamide

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-

62 azabicyclo [2.2.1] heptan-2 -yl) -2 -oxoethyl)-5 -(1 H-pyrrole -3 - A carboxamido)-lH-indazole-3-carboxamide

5-((S)-2-amino-4-methylpentanamido)-l-(2-((lR,3S,4S)-3-((6-

63 chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- A oxoethyl) - 1 H-indazole-3 -carboxamide

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-

64 azabicyclo [2.2.1] heptan-2 -yl) -2 -oxoethyl)-5 -(3 -cyanobenzamido) - A lH-indazole-3-carboxamide

5 -(3 -chlorobenzamido) - 1 -(2-(( 1 R, 3 S,4 S) -3 -((6 -chloropyridin-2 -

65 yl)carbamoyl) -2 -azabicyclo [2.2.1] heptan-2 -yl) -2 -oxoethyl) - 1 H- A indazole -3 -carboxamide

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-

66 azabicyclo [2.2.1] heptan-2 -yl) -2 -oxoethyl)-5 -(2 -cyanobenzamido) - A lH-indazole-3-carboxamide

5-(2-aminoacetamido)-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-

67 yl)carbamoyl) -2 -azabicyclo [2.2.1] heptan-2 -yl) -2 -oxoethyl) - 1 H- B indazole -3 -carboxamide

5-((S)-2-aminopropanamido)-l-(2-((lR,3S,4S)-3-((6-chloropyridin-

68 2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-lH- A indazole -3 -carboxamide

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-

69 azabicyclo [2.2.1] heptan-2 -yl) -2 -oxoethyl)-5 -(piperidine -3 - A carboxamido)-lH-indazole-3-carboxamide

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-

70 azabicyclo [2.2.1] heptan-2 -yl) -2 -oxoethyl)-5 -(piperidine -2 - A carboxamido)-lH-indazole-3-carboxamide

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-

71 azabicyclo [2.2.1 ]heptan-2-yl)-2-oxoethyl)-5 -(2-hydroxyacetamido)- A lH-indazole-3-carboxamide

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-

72 azabicyclo [2.2.1] heptan-2 -yl) -2 -oxoethyl)-5 -(piperidine -4 - A carboxamido)-lH-indazole-3-carboxamide

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-

73 azabicyclo [2.2.1 ]heptan-2-yl)-2-oxoethyl)-5 -(3 -fluorobenzamido)- A lH-indazole-3-carboxamide Ex. Chemical Name CFD IC₅₀ l-(2-((l ,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-

74 azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(thiophene-2- A carboxamido)-lH-indazole-3-carboxamide

l-(2-((l ,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-

75 azabicyclo [2.2.1 ]heptan-2-yl)-2-oxoethyl)-5 -(2-(2- A cyanophenyl)acetamido)-lH-indazole-3-carboxamide

5 -(2 -chlorobenzamido) - 1 -(2-(( 1 R, 3 S,4 S) -3 -((6 -chloropyridin-2 -

76 yl)carbamoyl) -2 -azabicyclo [2.2.1] heptan-2 -yl) -2 -oxoethyl) - 1 H- A indazole -3 -carboxamide

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-

77 azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(2-fluorobenzamido)- A lH-indazole-3-carboxamide

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-

78 azabicyclo [2.2.1 ]heptan-2-yl)-2-oxoethyl)-5 -(2-(3 - A cyanophenyl)acetamido)-lH-indazole-3-carboxamide

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-

79 azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(2-(p-tolyl)acetamido)- A lH-indazole-3-carboxamide

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-

80 azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(4-fluorobenzamido)- A lH-indazole-3-carboxamide

N-(3 -carbamoyl- 1 -(2-(( 1 R,3 S,4S)-3 -((6-chloropyridin-2-

81 yl)carbamoyl) -2 -azabicyclo [2.2.1] heptan-2 -yl) -2 -oxoethyl) - 1 H- A indazol-5 -yl)oxazole-5 -carboxamide

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-

82 azabicyclo [2.2.1] heptan-2 -yl) -2 -oxoethyl)-5 -(2 -methoxyacetamido)- A lH-indazole-3-carboxamide

5-((S)-2-aminobutanamido)-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-

83 yl)carbamoyl) -2 -azabicyclo [2.2.1] heptan-2 -yl) -2 -oxoethyl) - 1 H- A indazole -3 -carboxamide

5-((S)-2-amino-3 -hydroxypropanamido)- 1 -(2-(( 1R,3 S,4S)-3-((6-

84 chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- A oxoethyl) - 1 H-indazole-3 -carboxamide

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-

85 azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-ureido-lH-indazole-3- A carboxamide

N-(3 -carbamoyl- 1 -(2-(( 1 R,3 S,4S)-3 -((6-chloropyridin-2-

86 yl)carbamoyl) -2 -azabicyclo [2.2.1] heptan-2 -yl) -2 -oxoethyl) - 1 H- A indazol-5-yl)morpholine-4-carboxamide

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-

87 azabicyclo [2.2.1 ]heptan-2-yl)-2-oxoethyl)-5 -(4-methylpiperazine- 1 - A carboxamido)-lH-indazole-3-carboxamide

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-

88 azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(3-isopropylureido)- A lH-indazole-3-carboxamide

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-

89 azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(3-cyclopentylureido)- B lH-indazole-3-carboxamide

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-

90 azabicyclo [2.2.1 ]heptan-2-yl)-2-oxoethyl)-5 -(3 -(2- B fluorophenyl)ureido)- lH-indazole-3 -carboxamide Ex. Chemical Name CFD IC₅₀ l-(2-((l ,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-

91 azabicyclo [2.2.1] heptan-2 -yl) -2 -oxoethyl)-5 -(3 -cyclopropylureido)- A lH-indazole-3-carboxamide

5-(3-(2-aminoethyl)ureido)-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-

92 yl)carbamoyl) -2 -azabicyclo [2.2.1] heptan-2 -yl) -2 -oxoethyl) - 1 H- A indazole -3 -carboxamide

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-

93 azabicyclo [2.2.1 ]heptan-2-yl)-2-oxoethyl)-5 -(3 -(tetrahydrofuran-3 - A yl)ureido)-lH-indazole-3-carboxamide

5-(3-(4-chlorophenyl)ureido)-l-(2-((lR,3S,4S)-3-((6-chloropyridin-

94 2-yl)carbamoyl) -2 -azabicyclo [2.2.1] heptan-2 -yl) -2 -oxoethyl)- 1 H- B indazole -3 -carboxamide

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-

95 azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(3-(m-tolyl)ureido)- B lH-indazole-3-carboxamide

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-

96 azabicyclo [2.2.1 ]heptan-2-yl)-2-oxoethyl)-5 -(piperazine- 1 - B carboxamido)-lH-indazole-3-carboxamide

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-

97 azabicyclo [2.2.1 ]heptan-2-yl)-2-oxoethyl)-5 -(3 -(2- A hydroxyethyl)ureido)-lH-indazole-3-carboxamide

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-

98 azabicyclo [2.2.1 ]heptan-2-yl)-2-oxoethyl)-5 -(3 -(2- A methoxyethyl)ureido)-lH-indazole -3 -carboxamide

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-

99 azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(3-(p-tolyl)ureido)-lH- B indazole -3 -carboxamide

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-

100 azabicyclo [2.2.1 ]heptan-2-yl)-2-oxoethyl)-5 -(3 -(4- B fluorophenyl)ureido)- lH-indazole-3 -carboxamide

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-

101 azabicyclo [2.2.1] heptan-2 -yl) -2 -oxoethyl)-5 -(3 -(pyridin-3 - A yl)ureido)-lH-indazole-3-carboxamide

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-

102 azabicyclo [2.2.1 ]heptan-2-yl)-2-oxoethyl)-5 -(3 -(4- C

cyanophenyl)ureido) - 1 H-indazole -3 -carboxamide

5-(3-(3-chlorophenyl)ureido)-l-(2-((lR,3S,4S)-3-((6-chloropyridin-

103 2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-lH- B indazole -3 -carboxamide

5-(4-acetylpiperazine- 1 -carboxamido)- 1 -(2-(( 1R,3 S,4S)-3 -((6-

104 chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- A oxoethyl) - 1 H-indazole-3 -carboxamide

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-

105 azabicyclo [2.2.1 ]heptan-2-yl)-2-oxoethyl)-5 -(3 -(3 - A cyanophenyl)ureido) - 1 H-indazole -3 -carboxamide

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-

106 azabicyclo [2.2.1] heptan-2 -yl) -2 -oxoethyl)-5 -(3 -(pyridin-2- A yl)ureido)-lH-indazole-3-carboxamide

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-

107 azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(3-methylureido)-lH- A indazole -3 -carboxamide Ex. Chemical Name CFD IC₅₀

l-(2-((l ,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-

108 azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(3-(thiazol-2- A

yl)ureido)-lH-indazole-3-carboxamide

l-(2-((l ,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-

109 azabicyclo [2.2.1 ]heptan-2-yl)-2-oxoethyl)-5 -(3 -(3 - B

fluorophenyl)ureido)- lH-indazole-3 -carboxamide

l-(2-((l ,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-

110 azabicyclo [2.2.1 ]heptan-2-yl)-2-oxoethyl)-5 -(3 -phenylureido)- 1H- A

indazole -3 -carboxamide

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-

111 azabicyclo [2.2.1 ]heptan-2-yl)-2-oxoethyl)-5 -(3 -(2- A

(dimethylamino)ethyl)ureido) - 1 H-indazole -3 -carboxamide

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-

112 azabicyclo [2.2.1] heptan-2 -yl) -2 -oxoethyl)-5 -(3 -(pyridin-4- A

yl)ureido)-lH-indazole-3-carboxamide

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-

113 azabicyclo [2.2.1 ]heptan-2-yl)-2-oxoethyl)-5 -(3 -(2- A

(methylamino)ethyl)ureido)-lH-indazole-3-carboxamide

5-(3-(lH-imidazol-2-yl)ureido)-l-(2-((lR,3S,4S)-3-((6-

114 chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- A

oxoethyl) - 1 H-indazole-3 -carboxamide

5-(3-(lH-imidazol-5-yl)ureido)-l-(2-((lR,3S,4S)-3-((6-

115 chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- A

oxoethyl) - 1 H-indazole-3 -carboxamide

Note: Biochemical assay IC₅₀ data in Table 2 are designated within the following ranges:

Α: < 0.10 μΜ C: > 1.0 μΜ to < 10 μΜ

B: > 0.10 μΜ ΐο < 1.0 μΜ D: > 10 μΜ

Example 2: In vitro enzyme inhibition: Fluorescent Method

[00534] Recombinant human complement factor D at 6 nM concentration was incubated with a complement factor D inhibitory compound described in Table 1 at various concentrations (starting from 10 mM, 4 fold dilution) for 5 min at 25°C in 0.1 M Hepes buffer, pH 7.5, containing 1 mM MgCl₂, 1 M NaCl and 0.05% CHAPS. Synthetic substrate Z-Lys-thiobenzyl and 2,4-dinitrobenzenesulfonyl-flurescenine were added with final concentration of 150 μΜ and 5 μΜ, respectively. The increase in fluorescence intensity was monitored at excitation of 485 nm and emission at 535 nm using a microplate spectrofluorimeter. IC₅₀ values were calculated from percentage of inhibition of activity of complement factor D as a function of concentration of the complement factor D inhibitory compound.

[00535] The ability of the compounds in Table 3 to inhibit human complement factor D inhibitory activity was determined. TABLE 3

Ex. Chemical Name CFD ICso l-(2-((lR,3S,4S)-3-((6-bromopyridin-2-yl)carbamoyl)-2-

121 azabicyclo [2.2.1 ]heptan-2-yl)-2-oxoethyl) -5 -(nicotinamide)) - 1 H- A indazole -3 -carboxamide

l-(2-((lR,3S,4S)-3-((6-bromopyridin-2-yl)carbamoyl)-2-

122 azabicyclo [2.2.1] heptan-2 -yl) -2 -oxoethyl)-5 -(2 -chlorobenzamido)- A lH-indazole-3-carboxamide

l-(2-((lR,3S,4S)-3-((6-bromopyridin-2-yl)carbamoyl)-2-

123 azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(3-methylureido)-lH- A indazole -3 -carboxamide

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-

124 azabicyclo [2.2.1 ]heptan-2-yl)-2-oxoethyl)-5 -(2-methylpyrimidin-5 - B yl)- 1 H-indazole -3 -carboxamide

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-

125 azabicyclo [2.2.1 ]heptan-2-yl)-2-oxoethyl)-5 -(2-cyanopyrimidin-5 - B yl)- 1 H-indazole -3 -carboxamide

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-

126 azabicyclo [2.2.1] heptan-2 -yl) -2 -oxoethyl)-5 -(2 -methoxypyrimidin- B

5 -yl) - 1 H-indazole-3 -carboxamide

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-

127 azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(pyrimidin-5-yl)-lH- B indazole -3 -carboxamide

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-

128 azabicyclo [2.2.1] heptan-2 -yl) -2 -oxoethyl)-5 -(piperidin- 1 -yl) - 1 H- C

indazole -3 -carboxamide

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-

129 azabicyclo [2.2.1] heptan-2 -yl) -2 -oxoethyl)-5 -mo holino- 1 H- C

indazole -3 -carboxamide

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-

130 azabicyclo [2.2.1 ]heptan-2-yl)-2-oxoethyl) -6 -(pyrrolidin- 1 -yl) - 1 H- B indazole -3 -carboxamide

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-

131 azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(lH-pyrazol-l-yl)-lH- C

indazole -3 -carboxamide

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-

132 azabicyclo [2.2.1] heptan-2 -yl) -2 -oxoethyl)-5 -(1 H-imidazol- 1 -yl) - B lH-indazole-3-carboxamide

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-

133 azabicyclo [2.2.1] heptan-2 -yl) -2 -oxoethyl)-5 -(oxazol-2 -yl) - 1 H- B indazole -3 -carboxamide

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-

134 azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(lH-imidazol-2-yl)- B lH-indazole-3-carboxamide

l-(2-((lR,3S,4S)-3-((3-chloro-2-fluorobenzyl)carbamoyl)-2-

135 azabicyclo [2.2.1] heptan-2 -yl) -2 -oxoethyl)-5 -(2 -methoxypyrimidin- B

5 -yl) - 1 H-indazole-3 -carboxamide

l-(2-((lR,3S,4S)-3-((3-chloro-2-fluorobenzyl)carbamoyl)-2-

136 azabicyclo [2.2.1 ]heptan-2-yl)-2-oxoethyl)-5 -(2-cyanopyrimidin-5 - B yl)- 1 H-indazole -3 -carboxamide

l-(2-((lR,3S,4S)-3-((3-chloro-2-fluorobenzyl)carbamoyl)-2-

137 azabicyclo [2.2.1 ]heptan-2-yl)-2-oxoethyl)-5 -(2-methylpyrimidin-5 - B yl)- 1 H-indazole -3 -carboxamide Ex. Chemical Name CFD ICso l-(2-((lR,3S,4S)-3-((3-chloro-2-fluorobenzyl)carbamoyl)-2-

138 azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(pyrimidin-5-yl)-lH- B indazole -3 -carboxamide

l-(2-((lR,3S,4S)-3-((3-chloro-2-fluorobenzyl)carbamoyl)-2-

139 azabicyclo [2.2.1 ]heptan-2-yl)-2-oxoethyl) -5 -(nicotinamide)) - 1 H- A

indazole -3 -carboxamide

l-(2-((lR,3S,4S)-3-((3-chloro-2-fluorobenzyl)carbamoyl)-2-

140 azabicyclo [2.2.1] heptan-2 -yl) -2 -oxoethyl)-5 -(2 -chlorobenzamido)- A

lH-indazole-3-carboxamide

methyl (3-carbamoyl-l-(2-((lR,3S,4S)-3-((3-chloro-2-

141 fluorobenzyl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- A

oxoethyl) - 1 H-indazol-5 -yl)carbamate

l-(2-((lR,3S,4S)-3-((3-chloro-2-fluorobenzyl)carbamoyl)-2-

142 azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(lH-pyrazol-l-yl)-lH- C

indazole -3 -carboxamide

l-(2-((lR,3S,4S)-3-((3-chloro-2-fluorobenzyl)carbamoyl)-2-

143 azabicyclo [2.2.1] heptan-2 -yl) -2 -oxoethyl)-5 -(1 H-imidazol- 1 -yl) - C

lH-indazole-3-carboxamide

l-(2-((lR,3S,4S)-3-((3-chloro-2-fluorobenzyl)carbamoyl)-2-

144 azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(thiazol-2-yl)-lH- C

indazole -3 -carboxamide

methyl (3-carbamoyl-l-(2-oxo-2-((lR,3S,4S)-3-((6-

145 (trifluoromethyl)pyridin-2-yl)carbamoyl)-2- A

azabicyclo[2.2.1]heptan-2-yl)ethyl)-lH-indazol-5-yl)carbamate

5-(2-chlorobenzamido)-l-(2-oxo-2-((lR,3S,4S)-3-((6-

146 (trifluoromethyl)pyridin-2-yl)carbamoyl)-2- A

azabicyclo [2.2.1] heptan-2 -yl)ethyl)- 1 H-indazole -3 -carboxamide

5-(nicotinamido)-l-(2-oxo-2-((lR,3S,4S)-3-((6-

147 (trifluoromethyl)pyridin-2-yl)carbamoyl)-2- A

azabicyclo [2.2.1] heptan-2 -yl)ethyl)- 1 H-indazole -3 -carboxamide

5-(3-methylureido)-l-(2 -oxo-2 -((lR,3S,4S)-3-((6-

148 (trifluoromethyl)pyridin-2-yl)carbamoyl)-2- B azabicyclo [2.2.1] heptan-2 -yl)ethyl)- 1 H-indazole -3 -carboxamide

(lR,3S,4S)-2-(2-(3-acetyl-5-(2-methylpyrimidin-5-yl)-lH-indazol-

149 l-yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3- A

carboxamide

(lR,3S,4S)-2-(2-(3-acetyl-5-(pyrimidin-5-yl)-lH-indazol-l-

150 yl)acetyl) -N-(6 -bromopyridin-2-yl) -2 -azabicyclo [2.2.1 ]heptane -3 - A

carboxamide

(lR,3S,4S)-2-(2-(3-acetyl-6-(2-methoxypyrimidin-5-yl)-lH-

151 indazol-l-yl)acetyl)-N-(6-bromopyridin-2-yl)-2- A

azabicyclo [2.2.1 ]heptane -3 -carboxamide

(lR,3S,4S)-2-(2-(3-acetyl-5-(2-cyanopyrimidin-5-yl)-lH-indazol-l-

152 yl)acetyl) -N-(6 -bromopyridin-2-yl) -2 -azabicyclo [2.2.1 ]heptane -3 - A

carboxamide

methyl (3-acetyl-l-(2-((lR,3S,4S)-3-((6-bromopyridin-2-

153 yl)carbamoyl) -2 -azabicyclo [2.2.1] heptan-2 -yl) -2 -oxoethyl) - 1 H- A

indazol-5 -yl)carbamate

(lR,3S,4S)-2-(2-(3-acetyl-5-(2-chlorobenzamido)-lH-indazol-l-

154 yl)acetyl)-N-(6 -bromopyridin-2-yl) -2 -azabicyclo [2.2.1 ]heptane -3 - A

carboxamide Ex. Chemical Name CFD ICso

( 1 R,3 S,4S)-2-(2-(3 -acetyl -5 -(nicotinamide))- lH-indazol- 1 -

155 yl)acetyl) -N-(6 -bromopyridin-2-yl) -2 -azabicyclo [2.2.1 ]heptane -3 - A carboxamide

(lR,3S,4S)-2-(2-(3-acetyl-5-(3-methylureido)-lH-indazol-l-

156 yl)acetyl) -N-(6 -bromopyridin-2-yl) -2 -azabicyclo [2.2.1 ]heptane -3 - A carboxamide

(lR,3S,4S)-2-(2-(3-acetyl-5-(2-methylpyrimidin-5-yl)-lH-indazol-

157 1 -yl)acetyl) -N-(6 -chloropyridin-2 -yl) -2 -azabicyclo [2.2.1 ]heptane -3 - A carboxamide

(lR,3S,4S)-2-(2-(3-acetyl-5-(2-methoxypyrimidin-5-yl)-lH-

158 indazol-l-yl)acetyl)-N-(6-chloropyridin-2-yl)-2- A azabicyclo [2.2.1 ]heptane -3 -carboxamide

(lR,3S,4S)-2-(2-(3-acetyl-5-(pyrimidin-5-yl)-lH-indazol-l-

159 yl)acetyl)-N-(6-chloropyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3- A carboxamide

(lR,3S,4S)-2-(2-(3-acetyl-5-(2-cyanopyrimidin-5-yl)-lH-indazol-l-

160 yl)acetyl)-N-(6-chloropyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3- A carboxamide

methyl (3 -acetyl- 1 -(2-(( 1 R,3 S,4S)-3 -((6-chloropyridin-2-

161 yl)carbamoyl) -2 -azabicyclo [2.2.1] heptan-2 -yl) -2 -oxoethyl) - 1 H- A indazol-5 -yl)carbamate

( 1 R,3 S,4S)-2-(2-(3 -acetyl -5 -(nicotinamido)- lH-indazol- 1 -

162 yl)acetyl)-N-(6-chloropyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3- A carboxamide

(lR,3S,4S)-2-(2-(3-acetyl-5-(2-chlorobenzamido)-lH-indazol-l-

163 yl)acetyl)-N-(6-chloropyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3- A carboxamide

(lR,3S,4S)-2-(2-(3-acetyl-5-(3-methylureido)-lH-indazol-l-

164 yl)acetyl)-N-(6-chloropyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3- A carboxamide

(lR,3S,4S)-2-(2-(3-acetyl-5-(2-methylbenzamido)-lH-indazol-l-

165 yl)acetyl)-N-(6-chloropyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3- A carboxamide

( 1R,3 S,4S)-2-(2-(3 -acetyl -5-(2-fluorobenzamido)-lH-indazol- 1 -

166 yl)acetyl)-N-(6-chloropyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3- A carboxamide

(lR,4S)-2-(2-(3-acetyl-5-(2-methylnicotinamido)-lH-indazol-l-

167 yl)acetyl)-N-(6-chloropyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3- A carboxamide

(lR,3S,4S)-2-(2-(3-acetyl-5-(2-cyanobenzamido)-lH-indazol-l-

168 yl)acetyl)-N-(6-chloropyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3- A carboxamide

(lR,3S,4S)-2-(2-(3-acetyl-5-(2-chloro-3-fluorobenzamido)-lH-

169 indazol-l-yl)acetyl)-N-(6-chloropyridin-2-yl)-2- A azabicyclo [2.2.1 ]heptane -3 -carboxamide

(lR,4S)-2-(2-(3-acetyl-5-(2-methoxynicotinamido)-lH-indazol-l-

170 yl)acetyl)-N-(6-chloropyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3- A carboxamide

( 1R,3 S,4S)-2-(2-(3 -acetyl -5-(2-methoxybenzamido)-lH-indazol- 1 -

171 yl)acetyl)-N-(6-chloropyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3- A carboxamide Ex. Chemical Name CFD ICso

(lR,3S,4S)-2-(2-(3-acetyl-5-(2-chloro-5-fluorobenzamido)-lH-

172 indazol-l-yl)acetyl)-N-(6-chloropyridin-2-yl)-2- A azabicyclo [2.2.1 ]heptane -3 -carboxamide

(lR,3S,4S)-2-(2-(3-acetyl-5-(2-methylpyrimidin-5-yl)-lH-indazol-

173 l-yl)acetyl)-N-(3-chloro-2-fluorobenzyl)-2- B azabicyclo [2.2.1 ]heptane -3 -carboxamide

(lR,3S,4S)-2-(2-(3-acetyl-5-(pyrimidin-5-yl)-lH-indazol-l-

174 yl)acetyl)-N-(3 -chloro-2-fluorobenzyl)-2-azabicyclo [2.2.1 ]heptane- B

3 -carboxamide

( 1 R,3 S,4S)-2-(2-(3 -acetyl -5 -(nicotinamido)- lH-indazol- 1 -

175 yl)acetyl)-N-(3-chloro-2-fluorobenzyl)-2-azabicyclo[2.2.1]heptane- B

3 -carboxamide

(lR,3S,4S)-2-(2-(3-acetyl-5-(2-methoxypyrimidin-5-yl)-lH-

176 indazol-l-yl)acetyl)-N-(3-chloro-2-fluorobenzyl)-2- B azabicyclo [2.2.1 ]heptane -3 -carboxamide

(lR,3S,4S)-2-(2-(3-acetyl-5-(2-cyanopyrimidin-5-yl)-lH-indazol-l-

177 yl)acetyl)-N-(3 -chloro-2-fluorobenzyl)-2-azabicyclo [2.2.1 ]heptane- A

3 -carboxamide

(lR,3S,4S)-2-(2-(3-acetyl-5-(2-chlorobenzamido)-lH-indazol-l-

178 yl)acetyl)-N-(3 -chloro-2-fluorobenzyl)-2-azabicyclo [2.2.1 ]heptane- A

3 -carboxamide

methyl (3-acetyl-l-(2-((lR,3S,4S)-3-((3-chloro-2-

179 fluorobenzyl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- A oxoethyl) - 1 H-indazol-5 -yl)carbamate

methyl (3-acetyl-l-(2-oxo-2-((lR,3S,4S)-3-((6-

180 (trifluoromethyl)pyridin-2-yl)carbamoyl)-2- A azabicyclo[2.2.1]heptan-2-yl)ethyl)-lH-indazol-5-yl)carbamate

( 1 R,3 S,4S)-2-(2-(3 -acetyl -5 -(nicotinamido)- lH-indazol- 1 -

181 yl)acetyl)-N-(6-(trifluoromethyl)pyridin-2-yl)-2- A azabicyclo [2.2.1 ]heptane -3 -carboxamide

(lR,3S,4S)-2-(2-(3-acetyl-5-(2-chlorobenzamido)-lH-indazol-l-

182 yl)acetyl)-N-(6-(trifluoromethyl)pyridin-2-yl)-2- A azabicyclo [2.2.1 ]heptane -3 -carboxamide

(lR,3S,4S)-2-(2-(3-acetyl-5-(3-methylureido)-lH-indazol-l-

183 yl)acetyl)-N-(6-(trifluoromethyl)pyridin-2-yl)-2- B azabicyclo [2.2.1 ]heptane -3 -carboxamide

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-

184 azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-6-(pyrimidin-5-yl)-lH- B indazole -3 -carboxamide

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-

185 azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-6-(2-methylpyrimidin-5- B yl)-l H-indazole -3 -carboxamide

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-

186 azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-6-(2-cyanopyrimidin-5- B yl)-l H-indazole -3 -carboxamide

6-(2-carbamoylpyrimidin-5-yl)-l-(2-((lR,3S,4S)-3-((6-

187 chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- B oxoethyl) - 1 H-indazole-3 -carboxamide

6-benzamido-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-

188 yl)carbamoyl) -2 -azabicyclo [2.2.1] heptan-2 -yl) -2 -oxoethyl) - 1 H- B indazole -3 -carboxamide Ex. Chemical Name CFD ICso

6-acetamido-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-

189 2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-lH-indazole-3- B carboxamide

methyl (3-carbamoyl-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-

190 yl)carbamoyl) -2 -azabicyclo [2.2.1] heptan-2 -yl) -2 -oxoethyl) - 1 H- B indazol-6-yl)carbamate

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-

191 azabicyclo [2.2.1 ]heptan-2-yl)-2 -oxoethyl) -6 -(nicotinamide) - 1 H- B indazole -3 -carboxamide

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-

192 azabicyclo [2.2.1 ]heptan-2-yl)-2 -oxoethyl) -6 -(picolinamido) - 1 H- B indazole -3 -carboxamide

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-

193 azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-6-(isonicotinamido)-lH- B indazole -3 -carboxamide

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-

194 azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-6-(3-methylureido)-lH- B indazole -3 -carboxamide

6-benzamido- 1 -(2-(( 1R,3 S lS -^-chloro^-

195 fluorobenzy^carbamoyl^-azabicycloP^. ^heptan^-yl)^- C oxoethyl) - 1 H-indazole-3 -carboxamide

6-acetamido- 1 -(2-(( 1 R,3 S,4S)-3 -((3 -chloro-2-

196 fluorobenzyl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- B oxoethyl) - 1 H-indazole-3 -carboxamide

methyl (3-carbamoyl-l-(2-((lR,3S,4S)-3-((3-chloro-2-

197 fluorobenzyl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- B oxoethyl)-lH-indazol-6-yl)carbamate

l-(2-((lR,3S,4S)-3-((3-chloro-2-fluorobenzyl)carbamoyl)-2-

198 azabicyclo [2.2.1 ]heptan-2-yl)-2 -oxoethyl) -6 -(picolinamido) - 1 H- C indazole -3 -carboxamide

l-(2-((lR,3S,4S)-3-((3-chloro-2-fluorobenzyl)carbamoyl)-2-

199 azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-6-(isonicotinamido)-lH- C indazole -3 -carboxamide

l-(2-((lR,3S,4S)-3-((3-chloro-2-fluorobenzyl)carbamoyl)-2-

200 azabicyclo [2.2.1 ]heptan-2-yl)-2 -oxoethyl) -6 -(nicotinamide) - 1 H- C indazole -3 -carboxamide

l-(2-((lR,3S,4S)-3-((3-chloro-2-fluorobenzyl)carbamoyl)-2-

201 azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-6-(3-methylureido)-lH- B indazole -3 -carboxamide

(lR,3S,4S)-2-(2-(3-acetyl-6-(pyrimidin-5-yl)-lH-indazol-l-

202 yl)acetyl)-N-(6-chloropyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3- B carboxamide

(lR,3S,4S)-2-(2-(3-acetyl-6-(2-methylpyrimidin-5-yl)-lH-indazol-

203 1 -yl)acetyl) -N-(6 -chloropyridin-2 -yl) -2 -azabicyclo [2.2.1 ]heptane -3 - B carboxamide

(lR,3S,4S)-2-(2-(3-acetyl-6-(2-cyanopyrimidin-5-yl)-lH-indazol-l-

204 yl)acetyl)-N-(6-chloropyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3- B carboxamide

(lR,3S,4S)-2-(2-(3-acetyl-6-(2-carbamoylpyrimidin-5-yl)-lH-

205 indazol-l-yl)acetyl)-N-(6-chloropyridin-2-yl)-2- B azabicyclo [2.2.1 ]heptane -3 -carboxamide

Note: Biochemical assay IC₅₀ data in Table 3 are designated within the following ranges: A: < 0.10 μΜ C: > 1.0 μΜ ΐο < ΙΟ μΜ

B: > 0.10 μΜ ΐο < 1.0 μΜ D: > 10 μΜ

Example 3: Alternative Pathway (AP) Hemolysis Assay

[00536] In this assay red blood cells (RBC), chicken or rabbit erythrocytes (SbjBio), were washed three time using assay buffer containing 0.1% gelatin, 5mM Veronal, 145 mM NaCl, 0.025% NaN₃, 10 mM Mg-EGTA pH 7.3. In 100 μΐ_^ reaction system, 1300 to 1500 ng/μΐ_^ final concentration of Normal Human Serum (CompTech) was incubated with compound for 15 min at 37 °C. Then 2xl0⁶ cells/well of chicken or rabbit erythrocytes in assay buffer were added and incubated for an additional 60 min at 37 °C. Positive control (100% lysis) consisted of serum and RBC, and negative control (0% lysis) consisted of assay buffer and RBC only. Samples were centrifuged at 2000 g for 5 min, and supernatants collected. Optical density of the supernatant was monitored at 414 nm using Synergy 2 (BioTek). Percentage lysis in each sample was calculated relative to positive control (100% lysis). The results are shown in Table 4.

TABLE 4

Note: Assay IC₅₀ data in Table 4 are designated within the following ranges:

Α: < 0.10 μΜ C: > 1.0 μΜ to < 10 μΜ

B: > 0.10 μΜ ΐο < 1.0 μΜ D: > 10 μΜ

III. Preparation of Pharmaceutical Dosage Forms

Example 1: Oral Capsule

[00537] The active ingredient is a compound of any one of Formula (I)-(VI), or a

pharmaceutically acceptable salt thereof. A capsule for oral administration is prepared by mixing 1 -1000 of active ingredient with starch or other suitable powder blend. The mixture is incorporated into an oral dosage unit such as a hard gelatin capsule, which is suitable for oral administration.

Claims

CLAIMS We Claim:

1. A compound, or a pharmaceutically acceptable salt thereof, having the structure of Formula

(I):

wherein,

W, X, and Z are each independently selected from N or C-R¹;

20 20 20

R² is optionally substituted aryl, or optionally substituted heteroaryl;

n is 0, 1, or 2; and m is 0, 1, 2, or 3.

2. A compound, or a pharmaceutically acceptable salt thereof, having the structure of Formula (II):

wherein,

U is NH and V is CH, or U is CH₂ and V is N;

W, X, and Z are each independently selected from N or C-R¹;

20 20 20

R² is optionally substituted aryl, or optionally substituted heteroaryl;

n is 0, 1, or 2; and m is 0, 1, 2, or 3.

3. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein U is NH and V is CH.

4. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein U is CH₂ and V is N.

5. A compound, or a pharmaceutically acceptable salt thereof, having the structure of Formula (III):

wherein,

V is N, T is N, and U is C; or V is C, T is CH, and U is N;

W, X, and Z are each independently selected from N or C-R¹;

20 20 20

R² is optionally substituted aryl, or optionally substituted heteroaryl;

n is 0, 1, or 2; and m is 0, 1, 2, or 3.

6. The compound of claim 5, or a pharmaceutically acceptable salt thereof, wherein V is N, T is N, and U is C.

7. The compound of claim 5, or a pharmaceutically acceptable salt thereof, wherein V is C, T is CH, and U is N.

8. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt thereof, wherein W, X, and Z are C-R¹ and each R¹ is independently selected from hydrogen, halogen, optionally substituted alkyl, optionally substituted carbocyclyl, or optionally substituted alkoxy.

9. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt thereof, wherein W, X, and Z are C-R¹ and each R¹ is hydrogen.

10. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt thereof, wherein X is N; W and Z are C-R¹; and each R¹ is independently selected from hydrogen, halogen, optionally substituted alkyl, optionally substituted carbocyclyl, or optionally substituted alkoxy.

11. The compound of any one of claims 1 -7, or a pharmaceutically acceptable salt thereof, wherein X is N; W and Z are C-H.

12. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt thereof, wherein W is N; X and Z are C-R¹; and each R¹ is independently selected from hydrogen, halogen, optionally substituted alkyl, optionally substituted carbocyclyl, or optionally substituted alkoxy.

13. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt thereof, wherein W is N; X and Z are C-H.

14. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt thereof, wherein both X and W are N; Z is C-H.

15. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt thereof, wherein both Z and W are N; W is C-H.

16. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt thereof, wherein Z is N or C-H.

17. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt thereof, wherein Z is C-H.

18. The compound of any one of claims 1-17, or a pharmaceutically acceptable salt thereof, wherein R² is optionally substituted aryl.

19. The compound of any one of claims 1-17, or a pharmaceutically acceptable salt thereof, wherein R² is optionally substituted heteroaryl.

20. The compound of claim 19, or a pharmaceutically acceptable salt thereof, wherein the optionally substituted heteroaryl is an optionally substituted pyridine.

21. The compound of any one of claims 1 -20, or a pharmaceutically acceptable salt thereof, wherein R³ is NH₂.

22. The compound of any one of claims 1-20, or a pharmaceutically acceptable salt thereof, wherein R³ is optionally substituted alkyl.

23. The compound of any one of claims 1 -22, or a pharmaceutically acceptable salt thereof, wherein m is 0.

24. The compound of any one of claims 1-22, or a pharmaceutically acceptable salt thereof, wherein m is 1.

25. The compound of any one of claims 1 -24, or a pharmaceutically acceptable salt thereof, wherein R⁴ is hydrogen.

26. The compound of any one of claims 1-25, or a pharmaceutically acceptable salt thereof, wherein each R⁶ is hydrogen.

27. The compound of any one of claims 1-26, or a pharmaceutically acceptable salt thereof, wherein R⁵ is -NRⁿCO-R¹⁰.

28. The compound of any one of claims 1-26, or a pharmaceutically acceptable salt thereof, wherein R⁵ is -NRⁿC0₂-R¹⁰.

29. The compound of any one of claims 1-26, or a pharmaceutically acceptable salt thereof, wherein R⁵ is -NR¹ CO-N(R¹²)₂.

30. The compound of any one of claims 1-26, or a pharmaceutically acceptable salt thereof, wherein R⁵ is -NR¹ S0₂-N(R¹²)₂.

31. The compound of any one of claims 1 -26, or a pharmaceutically acceptable salt thereof, wherein R⁵ is -O-CO-R¹⁰.

32. The compound of any one of claims 1-26, or a pharmaceutically acceptable salt thereof, wherein R⁵ is -O-CO-R²⁰.

33. The compound of any one of claims 1-26, or a pharmaceutically acceptable salt thereof, wherein R⁵ is -0-C0₂-R¹⁰.

34. The compound of any one of claims 1-26, or a pharmaceutically acceptable salt thereof, wherein R⁵ is -0-C0₂-R²⁰.

35. The compound of any one of claims 1-26, or a pharmaceutically acceptable salt thereof, wherein R⁵ is optionally substituted aralkoxy.

36. The compound of any one of claims 1-26, or a pharmaceutically acceptable salt thereof, wherein R⁵ is optionally substituted heteroarylalkoxy.

37. The compound of any one of claims 1-26, or a pharmaceutically acceptable salt thereof, wherein R⁵ is optionally substituted (carbocyclyl)-O-.

38. The compound of any one of claims 1-26, or a pharmaceutically acceptable salt thereof, wherein R⁵ is optionally substituted heterocyclylalkoxy.

39. The compound of any one of claims 27-28, or a pharmaceutically acceptable salt thereof, wherein R¹¹ is hydrogen.

40. The compound of any one of claims 29-30, or a pharmaceutically acceptable salt thereof, wherein R¹³ is hydrogen.

41. A compound, or a pharmaceuticall acceptable salt thereof, having the structure of Formula (VII):

wherein,

Ring A is an optionally substituted bicyclic heteroaryl;

U is C(R⁷⁰)(R⁷¹), or NH;

R² is optionally substituted aryl, or optionally substituted heteroaryl;

n is 0, 1, or 2; and m is 0, 1, 2, or 3.

42. The compound of claim 41, or a pharmaceutically acceptable salt thereof, wherein Ring A is an optionally substituted 10-membered bicyclic heteroaryl.

43. The compound of claim 41, or a pharmaceutically acceptable salt thereof, wherein Ring A is an optionally substituted 9-membered bicyclic heteroaryl.

44. The compound of claim 41, or a pharmaceutically acceptable salt thereof, wherein Ring A is an optionally substituted bicyclic heteroaryl ring selected from optionally substituted quinolyl, optionally substituted indolyl, optionally substituted indazolyl, optionally substituted benzimidazolyl, optionally substituted isoquinolyl, optionally substituted cinnolinyl, optionally substituted phthalazinyl, optionally substituted quinazolinyl, optionally substituted naphthyridinyl, or optionally substituted benzoisoxazolyl.

45. The compound of claim 41, or a pharmaceutically acceptable salt thereof, wherein Ring A is optionally substituted isoquinolyl.

46. The compound of claim 41, or a pharmaceutically acceptable salt thereof, wherein Ring A is an optionally substituted bicyclic heteroaryl ring selected from optionally substituted benzofuranyl, optionally substituted benzooxazolyl, optionally substituted benzonaphthoiuranyl, optionally substituted benzopyranyl, optionally substituted benzopyranonyl, optionally substituted benzofuranyl, optionally substituted benzofuranonyl, optionally substituted benzotriazolyl, optionally substituted

benzo[4,6]imidazo[l,2-a]pyridinyl, optionally substituted furo[3,2-c]pyridinyl, optionally substituted pyrazolo[3,4-d]pyrimidinyl, optionally substituted pyrido[3,2-d]pyrimidinyl, or optionally substituted pyrido [3 ,4 -d] pyrimidinyl .

47. The compound of claim 41, or a pharmaceutically acceptable salt thereof, wherein Ring A is an optionally substituted bicyclic heteroaryl ring selected from optionally substituted benzo[d]thiazolyl, optionally substituted benzothienyl, optionally substituted benzothieno[3,2-d]pyrimidinyl, optionally substituted 6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl, optionally substituted

thieno[2,3-d]pyrimidinyl, optionally substituted thieno[3,2-d]pyrimidinyl, or optionally substituted thieno [2,3 -c]pridinyl .

48. The compound of claim 41, or a pharmaceutically acceptable salt thereof, wherein U is C(R⁷⁰)(R⁷¹), and Ring A has the structure of Formula (Vila):

wherein,

20 20 20

21 20 20 aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, -N(R ), -CO-R , -C0₂-R , - CO(NR²¹)₂, -NR²¹CO-R²⁰, -NR²¹C0₂-R²⁰, -S0₂(NR²¹)₂, -C(=NR²²)-(NR²¹)₂, -NR²¹CO-R²⁰, -NR²¹C0₂-R²⁰, - NR²¹CO-N(R²⁰)₂, -NR²¹SO₂-N(R²⁰)₂; each R²⁰ is independently optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;

49. The compound of claim 41, or a pharmaceutically acceptable salt thereof, wherein Ring A has the structure of Formula (Vllb):

R^ (Vllb)

wherein,

U is NH and V is CH; or U is C(R ^U)(R ¹) and V is N;

20 20 20

C0₂H, -S(0)-R , -S-R , -S(0)₂-R , optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted (heterocyclyl) -0-, optionally substituted alkyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted alkenyl, optionally substituted 21 20 20 aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, -N(R ), -CO-R , -C0₂-R , - CO(NR²¹)₂, -NR²¹CO-R²⁰, -NR²¹C0₂-R²°, -S0₂(NR²¹)₂, -C(=NR²²)-(NR²¹)₂, -NR²¹CO-R²⁰, -NR²¹C0₂-R²⁰, - NR²¹CO-N(R²⁰)₂, -NR²¹SO₂-N(R²⁰)₂;

50. The compoundof claim 49, or a pharmaceutically acceptable salt thereof, wherein U is NH and V is CH.

51. The compound of claim 49, or a pharmaceutically acceptable salt thereof, wherein U is C(R⁷⁰)(R⁷¹) and V is N.

52. The compound of claim 41, or a pharmaceutically acceptable salt thereof, wherein U is C(R⁷⁰)(R⁷¹), and Ring A has the structure of Formula (VIIc):

* 3

^C0R (VIIc)

wherein,

V is N, T is N, and Q is C; or V is C, T is CH, and Q is N; W, X, Y and Z are each independently selected from N, C-R¹, or C-R⁵, provided that at least one of W, X, Y, and Z is C-R⁵;

20 20 20

R³ is selected from NH₂, optionally substituted alkylamino, optionally substituted

dialkylamino, optionally substituted alkyl, optionally substituted carbocyclyl, or optionally substituted heterocyclyl;

53. The compound of claim 52, or a pharmaceutically acceptable salt thereof, wherein V is N, T is N, and Q is C.

54. The compound of claim 52, or a pharmaceutically acceptable salt thereof, wherein V is C, T is CH, and Q is N.

55. The compound of claim 41, or a pharmaceutically acceptable salt thereof, wherein only one of W, X, Y and Z is C-R⁵.

56. The compound of claim 41, or a pharmaceutically acceptable salt thereof, wherein only X is C-R⁵.

57. The compound of claim 41, or a pharmaceutically acceptable salt thereof, wherein X is C-R⁵, and W, Y, and Z are C-R¹.

58. The compound of claim 41, or a pharmaceutically acceptable salt thereof, wherein R² is optionally substituted aryl.

59. The compound of claim 41, or a pharmaceutically acceptable salt thereof, wherein R² is optionally substituted heteroaryl.

60. The compound of claim 59, or a pharmaceutically acceptable salt thereof, wherein the optionally substituted heteroaryl is an optionally substituted pyridine.

61. The compound of claim 41 , or a pharmaceutically acceptable salt thereof, wherein Ring A has the structure of Formula (Vila), (Vllb), or (VIIc), wherein R³ is NH₂.

62. The compound of claim 41, or a pharmaceutically acceptable salt thereof, wherein Ring A has the structure of Formula (Vila), (Vllb), or (VIIc), or a pharmaceutically acceptable salt thereof, wherein R³ is optionally substituted alkyl.

63. The compound of claim 41, or a pharmaceutically acceptable salt thereof, wherein m is 0.

64. The compound of claim 41 , or a pharmaceutically acceptable salt thereof, wherein m is 1.

65. The compound of claim 41, or a pharmaceutically acceptable salt thereof, wherein R⁴ is hydrogen.

66. The compound of claim 41, or a pharmaceutically acceptable salt thereof, wherein Ring A has the structure of Formula (Vila), (Vllb), or (VIIc), wherein R⁵ is -NRⁿCO-R¹⁰.

67. The compound of claim 41, or a pharmaceutically acceptable salt thereof, wherein Ring A has the structure of Formula (Vila), (Vllb), or (VIIc), wherein R⁵ is -NRⁿC0₂-R¹⁰.

68. The compound of claim 41, or a pharmaceutically acceptable salt thereof, wherein Ring A has the structure of Formula (Vila), (Vllb), or (VIIc), wherein R¹¹ is hydrogen.

69. The compound of claim 41, or a pharmaceutically acceptable salt thereof, wherein Ring A has the structure of Formula (Vila), (Vllb), or (VIIc), wherein R⁵ is -NR¹ CO-N(R¹²)₂.

70. The compound of claim 41, or a pharmaceutically acceptable salt thereof, wherein Ring A has the structure of Formula (Vila), (Vllb), or (VIIc), wherein R⁵ is -NR¹ S0₂-N(R¹²)₂.

71. The compound of claim 41 , or a pharmaceutically acceptable salt thereof, wherein Ring A has the structure of Formula (Vila), (Vllb), or (VIIc), wherein R¹³ is hydrogen.

72. The compound of claim 41, or a pharmaceutically acceptable salt thereof, wherein Ring A has the structure of Formula (Vila), (Vllb), or (VIIc), wherein R⁵ is -O-CO-R¹⁰.

73. The compound of claim 41, or a pharmaceutically acceptable salt thereof,, wherein Ring A has the structure of Formula (Vila), (Vllb), or (VIIc), wherein R⁵ is -O-CO-R²⁰.

74. The compound of claim 41, or a pharmaceutically acceptable salt thereof, wherein Ring A has the structure of Formula (Vila), (Vllb), or (VIIc), wherein R⁵ is -0-C0₂-R¹⁰.

75. The compound of claim 41, or a pharmaceutically acceptable salt thereof, wherein Ring A has the structure of Formula (Vila), (Vllb), or (VIIc), wherein R⁵ is -0-C0₂-R²°.

76. The compound of claim 41, or a pharmaceutically acceptable salt thereof, wherein Ring A has the structure of Formula (Vila), (Vllb), or (VIIc), wherein R⁵ is optionally substituted aralkoxy.

77. The compound of claim 41, or a pharmaceutically acceptable salt thereof, wherein Ring A has the structure of Formula (Vila), (Vllb), or (VIIc), wherein R⁵ is optionally substituted heteroarylalkoxy.

78. The compound of claim 41, or a pharmaceutically acceptable salt thereof, wherein Ring A has the structure of Formula (Vila), (Vllb), or (VIIc), wherein R⁵ is optionally substituted (carbocyclyl)-O-.

79. The compound of claim 41, or a pharmaceutically acceptable salt thereof, wherein Ring A has the structure of Formula (Vila), (Vllb), or (VIIc), wherein R⁵ is optionally substituted heterocyclylalkoxy.

80. A compound, or a pharmaceutically acceptable salt thereof, selected from:

7-chloro-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)- 1 H-indazole-3 -carboxamide ,

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-7-methyl- lH-indazole-3-carboxamide,

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-7-fluoro- 1 H-indazole-3 -carboxamide ,

1- (2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-7-cyano- 1 H-indazole-3 -carboxamide ,

7-(aminomethyl)-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- oxoethyl) - 1 H-indazole -3 -carboxamide ,

methyl 3-carbamoyl-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-

2- oxoethyl)-lH-indazole-7-carboxylate,

methyl 7-chloro-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- oxoethyl) - 1 H-indazole -3 -carboxylate ,

l-(2 -((lR,3S,4S)-3-((7-chloro-l,6-naphthyridin-5-yl)carbamoyl)-2-azabicyclo[2.2. l]heptan-2-yl)-2 -oxoethyl)- 1 H-indazole-3 -carboxamide ,

l-(2-((lR,3S,4S)-3-((6-chloro-3H-imidazo[4,5-c]pyridin-4-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- oxoethyl) - 1 H-indazole -3 -carboxamide ,

l-(2-((lR,3S,4S)-3-((6-chloro-5-cyanopyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2 -oxoethyl)- 1 H-indazole-3 -carboxamide ,

l-(2-((lS,3S,4S)-3-((6-chloro-5-fluoropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2 -oxoethyl)- 1 H-indazole-3 -carboxamide ,

l-(2-((lR,3S,4S)-3-((6-chloro-5-(trifluoromethyl)pyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- oxoethyl) - 1 H-indazole -3 -carboxamide ,

l-(2-((lR,3S,4S)-3-((3-chloroisoquinolin-l-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-lH- indazole-3-carboxamide,

l-(2-((lR,3S,4S)-3-((7-chloropyrido[3,4-b]pyrazin-5-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- oxoethyl) - 1 H-indazole -3 -carboxamide ,

l-(2-((lR,3S,4S)-3-((5-chloro-lH-pyrazolo[3,4-c]pyridin-7-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- oxoethyl) - 1 H-indazole -3 -carboxamide , l-(2-((lR,3S,4S)-3-((3-chloronaphthalen-l-yl)carbamoyl)-2-azabicyclo[2.2 ]heptan-2-yl)-2-oxoethyl)-lH- indazole-3-carboxamide,

l-(2-((lR,3S,4S)-3-((5-chloro-lH-indazol-7-yl)carb^

indazole-3-carboxamide,

5-acetamido-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2 ]heptan-2-yl)-2- oxoethyl) - 1 H-indazole -3 -carboxamide ,

5-benzamido-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- oxoethyl) - 1 H-indazole -3 -carboxamide ,

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5- (nicotinamido)- 1 H-indazole -3 -carboxamide,

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(2- phenylacetamido)- 1 H-indazole -3 -carboxamide,

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-7-(l- hydroxyethyl) - 1 H-indazole -3 -carboxamide ,

(lR,3S,4S)-N-(6-chloropyridin-2-yl)-2-(2-(3-methoxy-lH-indazol-l-yl)acetyl)-2-azabicyclo[2.2.1]heptane-3- carboxamide,

7-acetyl-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)acetyl)-lH- indazole-3-carboxamide,

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-7-(2- hydroxypropan-2 -yl) - 1 H-indazole -3 -carboxamide,

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-lH- indole -3 -carboxamide ,

1- (2-((lR,3S,4S)-3-((3-chloro-2-fluorophenyl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-lH- indole -3 -carboxamide ,

methyl (3-carbamoyl-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-

2 - oxoethyl)- lH-indazol-5 -yl)carbamate,

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(2- (dimethylamino)acetamido) - 1 H-indazole -3 -carboxamide,

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(2- morpholinoacetamido) - 1 H-indazole -3 -carboxamide,

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(2-(4- methylpiperazin- 1 -yl)acetamido) - lH-indazole-3 -carboxamide,

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5- (phenylsulfonamido)- lH-indazole-3 -carboxamide,

(lR,3S,4S)-N-(6-chloropyridin-2-yl)-2-(2-(l-methoxyisoquinolin-3-yl)-2-oxoethyl)-2- azabicyclo [2.2.1 ]heptane -3 -carboxamide ,

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- oxoethyl)isoquinoline -3 -carboxamide ,

isopropyl (3-carbamoyl-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2- yl) -2 -oxoethyl) - 1 H-indazol-5 -yl)carbamate ,

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5- (tetrahydrofuran-3 -carboxamido) - 1 H-indazole -3 -carboxamide ,

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5- (cyclopentanecarboxamido) - 1 H-indazole -3 -carboxamide ,

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5- (methylsulfonamido) - 1 H-indazole -3 -carboxamide,

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(2-(2- fluorophenyl)acetamido) - 1 H-indazole -3 -carboxamide, l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2 ]heptan-2-yl)-2-oxoethyl)-5-(2-(3- fluorophenyl)acetamido) - 1 H-indazole -3 -carboxamide,

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoy ^^^

fluorophenyl)acetamido) - 1 H-indazole -3 -carboxamide,

5-(2-(4-chlorophenyl)acetamido)-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo [2.2.1 ]heptan-2-yl)-2-oxoethyl)- lH-indazole-3 -carboxamide,

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(2^ cyanophenyl)acetamido)-lH-indazole-3-carboxamide,

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(2-(m- tolyl)acetamido) - 1 H-indazole -3 -carboxamide,

5-(4-chlorobenzamido)-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2- yl) -2-oxoethyl) - 1 H-indazole -3 -carboxamide ,

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(4- cyanobenzamido) - 1 H-indazole -3 -carboxamide,

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5- (cyclopropanecarboxamido) - 1 H-indazole -3 -carboxamide,

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5- (piperazine -2 -carboxamido) - 1 H-indazole -3 -carboxamide ,

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5- (picolinamido) - 1 H-indazole -3 -carboxamide ,

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5- (pyrimidine -4-carboxamido) - 1 H-indazole -3 -carboxamide ,

N-(3-carbamoyl-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- oxoethyl)- lH-indazol-5 -yl)morpholine-2 -carboxamide,

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(lH- pyrazole -4-carboxamido) - 1 H-indazole -3 -carboxamide,

5-((S)-2-amino-3-methylbutanamido)-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-lH-indazole-3-carboxamide,

5-(2-(2-chlorophenyl)acetamido)-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo [2.2.1 ]heptan-2-yl)-2 -oxoethyl)- lH-indazole-3 -carboxamide,

5-(2-(3-chlorophenyl)acetamido)-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo [2.2.1 ]heptan-2-yl)-2 -oxoethyl)- lH-indazole-3 -carboxamide,

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(2-(o- tolyl)acetamido) - 1 H-indazole -3 -carboxamide,

N-(3-carbamoyl-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- oxoethyl)- lH-indazol -5 -yl)mo holine-3 -carboxamide,

5-(3-aminopropanamido)-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2- yl) -2-oxoethyl) - 1 H-indazole -3 -carboxamide ,

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(lH- imidazole -4-carboxamido) - 1 H-indazole -3 -carboxamide,

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5- (isonicotinamido) - 1 H-indazole -3 -carboxamide,

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(lH- pyrrole -3 -carboxamido) - 1 H-indazole -3 -carboxamide ,

5-((S)-2-amino-4-methylpentanamido)-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo [2.2.1 ]heptan-2-yl)-2 -oxoethyl)- lH-indazole-3 -carboxamide,

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(3- cyanobenzamido)-lH-indazole-3-carboxamide, 5-(3 -chlorobenzamido)-l -(2-(( 1R,3 S,4S)-3 -((6-cU

yl) -2-oxoethyl) - 1 H-indazole -3 -carboxamide ,

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(2- cyanobenzamido) - 1 H-indazole -3 -carboxamide,

5-(2-aminoacetamido)-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2 ]heptan-2- yl) -2-oxoethyl) - 1 H-indazole -3 -carboxamide ,

5-((S)-2-aminopropanamido)-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo [2.2.1 ]heptan-2-yl)-2-oxoethyl)- lH-indazole-3 -carboxamide,

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5- (piperidine-3-carboxamido)-lH-indazole-3-carboxamide,

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5- (piperidine-2-carboxamido)-lH-indazole-3-carboxamide,

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(2- hydroxyacetamido) - 1 H-indazole -3 -carboxamide ,

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5- (piperidine-4-carboxamido)-lH-indazole-3-carboxamide,

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(3- fluorobenzamido) - 1 H-indazole -3 -carboxamide ,

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5- (thiophene-2-carboxamido)-lH-indazole-3-carboxamide,

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(2-(2- cyanophenyl)acetamido)-lH-indazole-3-carboxamide,

5-(2-chlorobenzamido)-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2- yl) -2-oxoethyl) - 1 H-indazole -3 -carboxamide ,

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(2- fluorobenzamido) - 1 H-indazole -3 -carboxamide ,

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(2-(3- cyanophenyl)acetamido)-lH-indazole-3-carboxamide,

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(2-(p- tolyl)acetamido) - 1 H-indazole -3 -carboxamide,

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(4- fluorobenzamido) - 1 H-indazole -3 -carboxamide ,

N-(3-carbamoyl-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- oxoethyl) - 1 H-indazol -5 -yl)oxazole -5 -carboxamide ,

1- (2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(2- methoxyacetamido) - 1 H-indazole -3 -carboxamide,

5-((S)-2-aminobutanamido)-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-

2- yl) -2 -oxoethyl) - 1 H-indazole -3 -carboxamide ,

5-((S)-2-amino-3-hydroxypropanamido)-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo [2.2.1 ]heptan-2-yl)-2 -oxoethyl)- lH-indazole-3 -carboxamide,

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-ureido- 1 H-indazole-3 -carboxamide ,

N-(3 -carbamoyl- 1 -(2-(( 1 R,3 S,4S)-3 -((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo [2.2.1 ]heptan-2-yl)-2- oxoethyl)- 1 H-indazol -5 -yl)mo holine-4 -carboxamide,

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(4- methylpiperazine - 1 -carboxamido) - 1 H-indazole -3 -carboxamide

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(3- isopropylureido)-lH-indazole-3-carboxamide, l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(3- cyclopentylureido) - 1 H-indazole -3 -carboxamide,

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2 ]heptan-2-yl)-2-oxoethyl)-5-(3-(2- fluorophenyl)ureido)- lH-indazole-3 -carboxamide,

1- (2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2 ]heptan-2-yl)-2-oxoethyl)-5-(3- cyclopropylureido) - 1 H-indazole -3 -carboxamide ,

5-(3-(2-aminoethyl)ureido)-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-

2- yl) -2 -oxoethyl) - 1 H-indazole -3 -carboxamide ,

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(3- (tetrahydrofuran-3 -yl)ureido) - 1 H-indazole -3 -carboxamide,

5-(3-(4-chlorophenyl)ureido)-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-lH-indazole-3-carboxamide,

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(3-(m- tolyl)ureido) - 1 H-indazole -3 -carboxamide ,

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5- (piperazine - 1 -carboxamido) - 1 H-indazole -3 -carboxamide ,

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(3-(2- hydroxyethyl)ureido) - 1 H-indazole -3 -carboxamide ,

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(3-(2- methoxyethyl)ureido) - 1 H-indazole -3 -carboxamide,

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(3-(p- tolyl)ureido) - 1 H-indazole -3 -carboxamide ,

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2 .₁]heptan-2-yl)-2-oxoethyl)-5-(3-(4- fluorophenyl)ureido)- lH-indazole-3 -carboxamide,

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(3- (pyridin-3 -yl)ureido) - 1 H-indazole -3 -carboxamide ,

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2 .₁]heptan-2-yl)-2-oxoethyl)-5-(3-(4- cyanophenyl)ureido) - 1 H-indazole -3 -carboxamide,

5-(3-(3-chlorophenyl)ureido)-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo [2.2.1 ]heptan-2-yl)-2 -oxoethyl)- lH-indazole-3 -carboxamide,

5-(4-acetylpiperazine-l-carboxamido)-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo [2.2.1 ]heptan-2-yl)-2 -oxoethyl)- lH-indazole-3 -carboxamide,

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(3-(3- cyanophenyl)ureido) - 1 H-indazole -3 -carboxamide,

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(3- (pyridin-2-yl)ureido) - 1 H-indazole -3 -carboxamide ,

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(3- methylureido)- lH-indazole-3 -carboxamide,

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(3- (thiazol -2 -yl)ureido) - 1 H-indazole -3 -carboxamide,

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(3-(3- fluorophenyl)ureido)- lH-indazole-3 -carboxamide,

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(3- phenylureido) - 1 H-indazole -3 -carboxamide ,

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(3-(2- (dimethylamino)ethyl)ureido) - 1 H-indazole -3 -carboxamide,

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(3- (pyridin-4-yl)ureido) - 1 H-indazole -3 -carboxamide , l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2 ]heptan-2-yl)-2-oxoethyl)-5-(3-(2- (methylamino)ethyl)ureido) - 1 H-indazole -3 -carboxamide ,

5-(3 -( lH-imidazol-2-yl)ureido)- 1 -(2-(( 1R,3 S,4S)-3 -((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo [2.2.1 ]heptan-2-yl)-2-oxoethyl)- lH-indazole-3 -carboxamide,

5-(3 -( lH-imidazol-5-yl)ureido)- 1 -(2-(( 1R,3 S,4S)-3 -((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo [2.2.1 ]heptan-2-yl)-2-oxoethyl)- lH-indazole-3 -carboxamide,

l-(2-((lR,3S,4S)-3-((6-bromopyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5- (pyrimidin-5 -yl) - 1 H-indazole -3 -carboxamide ,

l-(2-((lR,3S,4S)-3-((6-bromopyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(2- methylpyrimidin-5 -yl) - 1 H-indazole -3 -carboxamide ,

l-(2-((lR,3S,4S)-3-((6-bromopyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(2- methoxypyrimidin-5 -yl)- 1 H-indazole -3 -carboxamide,

l-(2-((lR,3S,4S)-3-((6-bromopyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(2- cyanopyrimidin-5 -yl) - 1 H-indazole -3 -carboxamide,

methyl (l-(2-((lR,3S,4S)-3-((6-bromopyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)- 3 -carbamoyl - 1 H-indazol -5 -yl)carbamate ,

l-(2-((lR,3S,4S)-3-((6-bromopyridin-2-yl)carbamoyl) -2 -azabicyclo[2.2 l]heptan -2-yl)-2 -oxoethyl -5- (nicotinamido) - 1 H-indazole -3 -carboxamide ,

l-(2-((lR,3S,4S)-3-((6-bromopyridin-2-yl)carbamoyl) -2 -azabicyclo[2.2 l]heptan -2-yl)-2 -oxoethyl -5-(2- chlorobenzamido) - 1 H-indazole -3 -carboxamide ,

l-(2-((lR,3S,4S)-3-((6-bromopyridin-2-yl)carbamoyl) -2 -azabicyclo[2.2 l]heptan -2-yl)-2 -oxoethyl -5-(3- methylureido)- lH-indazole-3 -carboxamide,

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl) -2 ■azabicyclo[2.2 l]heptan -2-yl)-2- ■oxoethyF -5-(2- methylpyrimidin-5 -yl) - 1 H-indazole -3 -carboxamide ,

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl) -2 ■azabicyclo[2.2 l]heptan -2-yl)-2- ■oxoethyF -5-(2- cyanopyrimidin-5 -yl) - 1 H-indazole -3 -carboxamide,

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl) -2 ■azabicyclo[2.2 l]heptan -2-yl)-2- ■oxoethyF -5-(2- methoxypyrimidin-5 -yl)- 1 H-indazole -3 -carboxamide,

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl) -2 ■azabicyclo[2.2 l]heptan -2-yl)-2- ■oxoethyF -5- (pyrimidin-5 -yl) - 1 H-indazole -3 -carboxamide ,

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl) -2 ■azabicyclo[2.2 l]heptan -2-yl)-2- ■oxoethyF -5- (piperidin- 1 -yl) - 1 H-indazole -3 -carboxamide,

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl) -2 ■azabicyclo[2.2 l]heptan -2-yl)-2- ■oxoethyF -5- morpholino - 1 H-indazole -3 -carboxamide ,

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl) -2 ■azabicyclo[2.2 l]heptan -2-yl)-2- ■oxoethyF -6- (pyrrolidin- 1 -yl)- lH-indazole-3-carboxamide,

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl) -2 ■azabicyclo[2.2 l]heptan -2-yl)-2- ■oxoethyF -5-(lH- pyrazol - 1 -yl) - 1 H-indazole -3 -carboxamide ,

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl) -2 ■azabicyclo[2.2 l]heptan -2-yl)-2- ■oxoethyF -5-(lH- imidazol - 1 -yl) - 1 H-indazole -3 -carboxamide ,

1- (2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl) -2 ■azabicyclo[2.2 l]heptan -2-yl)-2- ■oxoethyF -5-(oxazol-

2- yl) - 1 H-indazole-3 -carboxamide ,

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl) -2 ■azabicyclo[2.2 l]heptan -2-yl)-2- ■oxoethyF -5-(lH- imidazol -2 -yl) - 1 H-indazole -3 -carboxamide ,

l-(2-((lR,3S,4S)-3-((3-chloro-2-fluorobenzyl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(2- methoxypyrimidin-5 -yl)- 1 H-indazole -3 -carboxamide,

l-(2-((lR,3S,4S)-3-((3-chloro-2-fluorobenzyl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(2- cyanopyrimidin-5 -yl) - 1 H-indazole -3 -carboxamide, l-(2-((lR,3S,4S)-3-((3-chloro-2-fluorobenzyl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(2- methylpyrimidin-5 -yl) - 1 H-indazole -3 -carboxamide ,

l-(2-((lR,3S,4S)-3-((3-chloro-2-fluorobenzyl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5- (pyrimidin-5 -yl) - 1 H-indazole -3 -carboxamide ,

l-(2-((lR,3S,4S)-3-((3-chloro-2-fluorobenzyl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5- (nicotinamido) - 1 H-indazole -3 -carboxamide ,

l-(2-((lR,3S,4S)-3-((3-chloro-2-fluorobenzyl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(2- chlorobenzamido) - 1 H-indazole -3 -carboxamide ,

methyl (3-carbamoyl-l-(2-((lR,3S,4S)-3-((3-chloro-2-fluorobenzyl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2- yl) -2-oxoethyl) - 1 H-indazol-5 -yl)carbamate ,

l-(2-((lR,3S,4S)-3-((3-chloro-2-fluorobenzyl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(lH- pyrazol - 1 -yl) - 1 H-indazole -3 -carboxamide,

l-(2-((lR,3S,4S)-3-((3-chloro-2-fluorobenzyl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5-(lH- imidazol - 1 -yl) - 1 H-indazole -3 -carboxamide,

l-(2-((lR,3S,4S)-3-((3-chloro-2-fluorobenzyl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-5- (thiazol -2 -yl) - 1 H-indazole -3 -carboxamide ,

methyl (3-carbamoyl-l-(2-oxo-2-((lR,3S,4S)-3-((6-(trifluoromethyl)pyridin-2-yl)carbamoyl)-2- azabicyclo[2.2.1]heptan-2-yl)ethyl)-lH-indazol-5-yl)carbamate,

5-(2-chlorobenzamido)-l-(2-oxo-2-((lR,3S,4S)-3-((6-(trifluoromethyl)pyridin-2-yl)carbamoyl)-2- azabicyclo [2.2.1 ]heptan-2-yl)ethyl)- lH-indazole-3 -carboxamide,

5 -(nicotinamido) -1 -(2 -oxo-2 -((lR,3S,4S)-3-((6-(trifluoromethyl)pyridin-2-yl)carbamoyl)-2- azabicyclo [2.2.1 ]heptan-2-yl)ethyl)- lH-indazole-3 -carboxamide,

5-(3 -methylureido)- 1 -(2-oxo-2-(( 1R,3 S,4S)-3 -((6-(trifluoromethyl)pyridin-2-yl)carbamoyl)-2- azabicyclo [2.2.1 ]heptan-2-yl)ethyl)- lH-indazole-3 -carboxamide,

(lR,3S,4S)-2-(2-(3-acetyl-5-(2-methylpyrimidin-5-yl)-lH-indazol-l-yl)acetyl)-N-(6-bromopyridin-2-yl)-2- azabicyclo [2.2.1 ]heptane -3 -carboxamide,

(lR,3S,4S)-2-(2-(3-acetyl-5-(pyrimidin-5-yl)-lH-indazol-l-yl)acetyl)-N-(6-bromopyridin-2-yl)-2- azabicyclo [2.2.1] heptane -3 -carboxamide,

(lR,3S,4S)-2-(2-(3-acetyl-6-(2-methoxypyrimidin-5-yl)-lH-indazol-l-yl)acetyl)-N-(6-bromopyridin-2-yl)-2- azabicyclo [2.2.1 ]heptane -3 -carboxamide,

(lR,3S,4S)-2-(2-(3-acetyl-5-(2-cyanopyrimidin-5-yl)-lH-indazol-l-yl)acetyl)-N-(6-bromopyridin-2-yl)-2- azabicyclo [2.2.1 ]heptane -3 -carboxamide,

methyl (3-acetyl-l-(2-((lR,3S,4S)-3-((6-bromopyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- oxoethyl)- 1 H-indazol-5 -yl)carbamate,

(lR,3S,4S)-2-(2-(3-acetyl-5-(2-chlorobenzamido)-lH-indazol-l-yl)acetyl)-N-(6-bromopyridin-2-yl)-2- azabicyclo [2.2.1 ]heptane -3 -carboxamide,

(lR,3S,4S)-2-(2-(3-acetyl-5-(nicotinamido)-lH-indazol-l-yl)acetyl)-N-(6-bromopyridin-2-yl)-2- azabicyclo [2.2.1 ]heptane -3 -carboxamide,

(lR,3S,4S)-2-(2-(3-acetyl-5-(3-methylureido)-lH-indazol-l-yl)acetyl)-N-(6-bromopyridin-2-yl)-2- azabicyclo [2.2.1 ]heptane -3 -carboxamide,

(lR,3S,4S)-2-(2-(3-acetyl-5-(2-methylpyrimidin-5-yl)-lH-indazol-l-yl)acetyl)-N-(6-chloropyridin-2-yl)-2 azabicyclo [2.2.1] heptane-3 -carboxamide,

(lR,3S,4S)-2-(2-(3-acetyl-5-(2-methoxypyrimidin-5-yl)-lH-indazol-l-yl)acetyl)-N-(6-chloropyridin-2-yl)-2- azabicyclo [2.2.1 ]heptane -3 -carboxamide,

(lR,3S,4S)-2-(2-(3-acetyl-5-(pyrimidin-5-yl)-lH-indazol-l-yl)acetyl)-N-(6-chloropyridin-2-yl)-2- azabicyclo [2.2.1 ]heptane -3 -carboxamide,

(lR,3S,4S)-2-(2-(3-acetyl-5-(2-cyanopyrimidin-5-yl)-lH-indazol-l-yl)acetyl)-N-(6-chloropyridin-2-yl)-2- azabicyclo [2.2.1 ]heptane -3 -carboxamide, methyl (3-acetyl-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- oxoethyl)- lH-indazol-5 -yl)carbamate,

(lR,3S,4S)-2-(2-(3-acetyl-5-(nicotinamido)-lH-indazol-l-yl)acetyl)-N-(6-chloropyridin-2-yl)-2- azabicyclo [2.2.1 ]heptane -3 -carboxamide,

(lR,3S,4S)-2-(2-(3-acetyl-5-(2-chlorobenzamido)-lH-indazol-l-yl)acetyl)-N-(6-chloropyridin-2-yl)-2- azabicyclo [2.2.1 ]heptane -3 -carboxamide,

(lR,3S,4S)-2-(2-(3-acetyl-5-(3-methylureido)-lH-indazol-l-yl)acetyl)-N-(6-chloropyridin-2-yl)-2- azabicyclo [2.2.1 ]heptane -3 -carboxamide,

(lR,3S,4S)-2-(2-(3-acetyl-5-(2-methylbenzamido)-lH-indazol-l-yl)acetyl)-N-(6-chloropyridin-2-yl)-2- azabicyclo [2.2.1 ]heptane -3 -carboxamide,

(lR,3S,4S)-2-(2-(3-acetyl-5-(2-fluorobenzamido)-lH-indazol-l-yl)acetyl)-N-(6-chloropyridin-2-yl)-2- azabicyclo [2.2.1 ]heptane-3 -carboxamide,

(lR,4S)-2-(2-(3-acetyl-5-(2-methylnicotinamido)-lH-indazol-l-yl)acetyl)-N-(6-chloropyridin-2-yl)-2- azabicyclo [2.2.1 ]heptane -3 -carboxamide,

(lR,3S,4S)-2-(2-(3-acetyl-5-(2-cyanobenzamido)-lH-indazol-l-yl)acetyl)-N-(6-chloropyridin-2-yl)-2- azabicyclo [2.2.1 ]heptane -3 -carboxamide,

(lR,3S,4S)-2-(2-(3-acetyl-5-(2-chloro-3-fluorobenzamido)-lH-indazol-l-yl)acetyl)-N-(6-chloropyridin-2-yl)- 2-azabicyclo [2.2.1 ]heptane-3 -carboxamide,

(lR,4S)-2-(2-(3-acetyl-5-(2-methoxynicotinamido)-lH-indazol-l-yl)acetyl)-N-(6-chloropyridin-2-yl)-2- azabicyclo [2.2.1 ]heptane -3 -carboxamide,

(lR,3S,4S)-2-(2-(3-acetyl-5-(2-methoxybenzamido)-lH-indazol-l-yl)acetyl)-N-(6-chloropyridin-2-yl)-2- azabicyclo [2.2.1 ]heptane -3 -carboxamide,

(lR,3S,4S)-2-(2-(3-acetyl-5-(2-chloro-5-fluorobenzamido)-lH-indazol-l-yl)acetyl)-N-(6-chloropyridin-2-yl)- 2-azabicyclo [2.2.1 ]heptane-3 -carboxamide,

(lR,3S,4S)-2-(2-(3-acetyl-5-(2-methylpyrimidin-5-yl)-lH-indazol-l-yl)acetyl)-N-(3-chloro-2-fluorobenzyl)- 2-azabicyclo [2.2.1 ]heptane-3 -carboxamide,

(lR,3S,4S)-2-(2-(3-acetyl-5-(pyrimidin-5-yl)-lH-indazol-l-yl)acetyl)-N-(3-chloro-2-fluorobenzyl)-2- azabicyclo [2.2.1 ]heptane -3 -carboxamide,

(lR,3S,4S)-2-(2-(3-acetyl-5-(nicotinamido)-lH-indazol-l-yl)acetyl)-N-(3-chloro-2-fluorobenzyl)-2- azabicyclo [2.2.1 ]heptane-3 -carboxamide,

(lR,3S,4S)-2-(2-(3-acetyl-5-(2-methoxypyrimidin-5-yl)-lH-indazol-l-yl)acetyl)-N-(3-chloro-2-fluorobenzyl)- 2-azabicyclo [2.2.1 ]heptane-3 -carboxamide,

(lR,3S,4S)-2-(2-(3-acetyl-5-(2-cyanopyrimidin-5-yl)-lH-indazol-l-yl)acetyl)-N-(3-chloro-2-fluorobenzyl)-2- azabicyclo [2.2.1 ]heptane -3 -carboxamide,

(lR,3S,4S)-2-(2-(3-acetyl-5-(2-chlorobenzamido)-lH-indazol-l-yl)acetyl)-N-(3-chloro-2-fluorobenzyl)-2- azabicyclo [2.2.1 ]heptane -3 -carboxamide,

methyl (3-acetyl-l-(2-((lR,3S,4S)-3-((3-chloro-2-fluorobenzyl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- oxoethyl)- lH-indazol-5 -yl)carbamate,

methyl (3-acetyl-l-(2-oxo-2-((lR,3S,4S)-3-((6-(trifluoromethyl)pyridin-2-yl)carbamoyl)-2- azabicyclo [2.2.1 ]heptan-2-yl)ethyl) - 1 H-indazol-5 -yl)carbamate ,

(lR,3S,4S)-2-(2-(3-acetyl-5-(nicotinamido)-lH-indazol-l-yl)acetyl)-N-(6-(trifluoromethyl)pyridin-2-yl)-2- azabicyclo [2.2.1 ]heptane -3 -carboxamide,

(lR,3S,4S)-2-(2-(3-acetyl-5-(2-chlorobenzamido)-lH-indazol-l-yl)acetyl)-N-(6-(trifluoromethyl)pyridin-2- yl) -2-azabicyclo [2.2.1] heptane -3 -carboxamide ,

(lR,3S,4S)-2-(2-(3-acetyl-5-(3-methylureido)-lH-indazol-l-yl)acetyl)-N-(6-(trifluoromethyl)pyridin-2-yl)-2- azabicyclo [2.2.1 ]heptane -3 -carboxamide,

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-6- (pyrimidin-5 -yl) - 1 H-indazole -3 -carboxamide , l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-6-(2- methylpyrimidin-5 -yl) - 1 H-indazole -3 -carboxamide ,

1- (2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-6-(2- cyanopyrimidin-5 -yl) - 1 H-indazole -3 -carboxamide,

6-(2-carbamoylpyrimidin-5-yl)-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo [2.2.1 ]heptan-2-yl)-2-oxoethyl)- lH-indazole-3 -carboxamide,

6-benzamido-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- oxoethyl)- 1 H-indazole -3 -carboxamide,

6-acetamido-l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- oxoethyl)- 1 H-indazole -3 -carboxamide,

2- oxoethyl) - 1 H-indazol -6 -yl)carbamate,

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-6- (nicotinamido) - 1 H-indazole -3 -carboxamide ,

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-6- (picolinamido) - 1 H-indazole -3 -carboxamide ,

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-6- (isonicotinamido) - 1 H-indazole -3 -carboxamide,

l-(2-((lR,3S,4S)-3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-6-(3- methylureido)- lH-indazole-3 -carboxamide,

6-benzamido-l-(2-((lR,3S,4S)-3-((3-chloro-2-fluorobenzyl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- oxoethyl)- 1 H-indazole -3 -carboxamide,

6-acetamido-l-(2-((lR,3S,4S)-3-((3-chloro-2-fluorobenzyl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2- oxoethyl)- 1 H-indazole -3 -carboxamide,

methyl (3-carbamoyl-l-(2-((lR,3S,4S)-3-((3-chloro-2-fluorobenzyl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2- yl) -2-oxoethyl) - 1 H-indazol-6 -yl)carbamate ,

l-(2-((lR,3S,4S)-3-((3-chloro-2-fluorobenzyl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-6- (picolinamido) - 1 H-indazole -3 -carboxamide ,

l-(2-((lR,3S,4S)-3-((3-chloro-2-fluorobenzyl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-6- (isonicotinamido) - 1 H-indazole -3 -carboxamide,

l-(2-((lR,3S,4S)-3-((3-chloro-2-fluorobenzyl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-6- (nicotinamido) - 1 H-indazole -3 -carboxamide ,

1- (2-((lR,3S,4S)-3-((3-chloro-2-fluorobenzyl)carbamoyl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl)-6-(3- methylureido)- lH-indazole-3 -carboxamide,

(lR,3S,4S)-2-(2-(3-acetyl-6-(pyrimidin-5-yl)-lH-indazol-l-yl)acetyl)-N-(6-chloropyridin-2-yl)-2- azabicyclo [2.2.1 ]heptane -3 -carboxamide,

(lR,3S,4S)-2-(2-(3-acetyl-6-(2-methylpyrimidin-5-yl)-lH-indazol-l-yl)acetyl)-N-(6-chloropyridin-2-yl)-2- azabicyclo [2.2.1 ]heptane -3 -carboxamide,

(lR,3S,4S)-2-(2-(3-acetyl-6-(2-cyanopyrimidin-5-yl)-lH-indazol-l-yl)acetyl)-N-(6-chloropyridin-2-yl)-2- azabicyclo[2.2. l]heptane-3-carboxamide, or

(lR,3S,4S)-2-(2-(3-acetyl-6-(2-carbamoylpyrimidin-5-yl)-lH-indazol-l-yl)acetyl)-N-(6-chloropyridin-2-yl)-

2- azabicyclo [2.2.1 ]heptane-3 -carboxamide .

81. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of any one of claims 1-80, or a pharmaceutically acceptable salt thereof.

82. A method of treating an autoimmune, inflammatory, or neurodegenerative disease in a patient in need thereof comprising administering to the patient a pharmaceutical composition comprising a compound of any one of claims 1-80, or a pharmaceutically acceptable salt thereof.

83. The method of claim 82, wherein the autoimmune, inflammatory, or neurodegenerative disease is paraoxvsmal nocturnal hemoglobinuria.

84. The method of claim 82, wherein the autoimmune, inflammatory, or neurodegenerative disease is C3 glomerulopathy.