3-(1h-pyrrolo[2,3-b]pyridin-2-yl)-1h-indazoles and therapeutic uses thereof

Description

BACKGROUND
Technical Field

This disclosure relates to inhibitors of one or more proteins in the Wnt pathway, including inhibitors of one or more Wnt proteins, and compositions comprising the same. More particularly, it concerns the use of an indazole compound or salts or analogs thereof, in the treatment of disorders characterized by the activation of Wnt pathway signaling (e.g., cancer, abnormal cellular proliferation, angiogenesis, fibrotic disorders, bone or cartilage diseases, and osteoarthritis), the modulation of cellular events mediated by Wnt pathway signaling, as well as genetic diseases and neurological conditions/disorders/diseases due to mutations or dysregulation of the Wnt pathway and/or of one or more of Wnt signaling components. Also provided are methods for treating Wnt-related disease states.

Background

The Wnt growth factor family includes more than 10 genes identified in the mouse and at least 19 genes identified in the human. Members of the Wnt family of signaling molecules mediate many short- and long-range patterning processes during invertebrate and vertebrate development. The Wnt signaling pathway is known for its role in the inductive interactions that regulate growth and differentiation, and it also plays roles in the homeostatic maintenance of post-embryonic tissue integrity. Wnt stabilizes cytoplasmic 3-catenin, which stimulates the expression of genes including c-myc, c jun, fra-1, and cyclin D1. In addition, misregulation of Wnt signaling can cause developmental defects and is implicated in the genesis of several human cancers. The Wnt pathway has also been implicated in the maintenance of stem or progenitor cells in a growing list of adult tissues including skin, blood, gut, prostate, muscle, and the nervous system.

SUMMARY

The present disclosure provides methods and reagents, involving contacting a cell with an agent, such as an indazole compound, in a sufficient amount to antagonize a Wnt activity, e.g., to reverse or control an aberrant growth state or correct a genetic disorder due to mutations in Wnt signaling components.

Some embodiments disclosed herein include Wnt inhibitors containing an indazole core. Other embodiments disclosed herein include pharmaceutical compositions and methods of treatment using these compounds.

One embodiment disclosed herein includes a compound having the structure of Formula I:

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as well as prodrugs and pharmaceutically acceptable salts thereof.

In some embodiments of Formula (I):

R¹, R², and R⁴are independently selected from the group consisting of H and halide;

R³is selected from the group consisting of -heteroaryl optionally substituted with 1-4 R⁶and -heterocyclyl optionally substituted with 1-10 R⁷;

R⁵is selected from the group consisting of H, -heteroaryl optionally substituted with 1-4 R⁸, -heterocyclyl optionally substituted with 1-10 R⁹, and -aryl optionally substituted with 1-5 R¹⁰;

each R⁶is independently selected from the group consisting of halide, —(C_1-6alkyl), —(C_2-6alkenyl), —(C_2-6alkynyl), —(C_1-4alkylene)_pheterocyclyl optionally substituted with 1-10 R¹¹, —(C_2-4alkenylene)_pheterocyclyl optionally substituted with 1-10 R¹¹, —(C_2-4alkynylene)_pheterocyclyl optionally substituted with 1-10 R¹¹, —(C_1-4alkylene)_pcarbocyclyl optionally substituted with 1-12 R¹², —(C_2-4alkenylene)_pcarbocyclyl optionally substituted with 1-12 R¹², —(C_2-4alkynylene)_pcarbocyclyl optionally substituted with 1-12 R¹², —(C_1-4alkylene)_paryl optionally substituted with 1-5 R¹³, —(C_2-4alkenylene)_paryl optionally substituted with 1-5 R¹³, —(C_2-4alkynylene)_paryl optionally substituted with 1-5 R¹³, —NHC(═O)R¹⁴, —NR¹⁵R¹⁶, —(C_1-6alkylene)NR¹⁷R¹⁸, —(C_2-6alkenylene)NR¹⁷R¹⁸, —(C_2-6alkynylene)NR¹⁷R¹⁸, and —(C_1-4alkylene)_pOR²⁴;

each R⁷is independently selected from the group consisting of —(C_1-4alkyl), —(C_2-4alkenyl), —(C_2-4alkynyl), halide, —CF₃, and —CN;

each R⁸is independently selected from the group consisting of —(C_1-6alkyl), —(C_2-6alkenyl), —(C_2-6alkynyl), halide, —CF₃, —OCH₃, —CN, and —C(═O)R¹⁹;

each R⁹is independently selected from the group consisting of —(C_1-6alkyl), —(C_2-6alkenyl), —(C_2-6alkynyl), halide, —CF₃, —CN, and —OCH₃;

each R¹⁰is independently selected from the group consisting of —(C_1-6alkyl), —(C_2-6alkenyl), —(C_2-6alkynyl), halide, —CF₃, —CN, —(C_1-6alkylene)_pNHSO₂R¹⁹, —(C_2-6alkenylene)_pNHSO₂R¹⁹, —(C_2-6alkynylene)_pNHSO₂R¹⁹, —NR¹⁵(C_1-6alkylene)NR¹⁵R¹⁶, —NR¹⁵(C_2-6alkenylene)NR¹⁵R¹⁶, —NR¹⁵(C_2-6alkynylene)NR¹⁵R¹⁶, —(C_1-6alkylene)_pNR¹⁵R¹⁶, —(C_2-6alkenylene)_pNR¹⁵R¹⁶, —(C_2-6alkynylene)_pNR⁵⁵R¹⁶, and —OR²⁷;

each R¹¹is independently selected from the group consisting of amino, —(C_1-4alkyl), —(C_2-4alkenyl), —(C_2-4alkynyl), halide, —CF₃, and —CN;

each R¹²is independently selected from the group consisting of —(C_1-4alkyl), —(C_2-4alkenyl), —(C_2-4alkynyl), halide, —CF₃, and —CN;

each R¹³is independently selected from the group consisting of —(C_1-4alkyl), —(C_2-4alkenyl), —(C_2-4alkynyl), halide, —CF₃, and —CN;

each R¹⁴is independently selected from the group consisting of —(C_1-9alkyl), —(C_1-4haloalkyl), —(C_2-9alkenyl), —(C_2-9alkynyl), -heteroaryl optionally substituted with 1-4 R²⁰, -aryl optionally substituted with 1-5 R²¹, —CH₂aryl optionally substituted with 1-5 R²¹, -carbocyclyl optionally substituted with 1-12 R²², —CH₂carbocyclyl optionally substituted with 1-12 R²², —(C_1-4alkylene)_pNR²⁵R²⁶, —(C_2-4alkenylene)_pNR²⁵R²⁶, —(C_2-4alkynylene)_pNR²⁵R²⁶, -heterocyclyl optionally substituted with 1-10 R²³, and —CH₂heterocyclyl optionally substituted with 1-10 R²³;

each R¹⁵is independently selected from the group consisting of H, —(C_1-6alkyl), —(C_2-6alkenyl), and —(C_2-6alkynyl);

each R¹⁶is independently selected from the group consisting of H, —(C_1-6alkyl), —(C_2-6alkenyl), —(C_2-6alkynyl), —CH₂aryl optionally substituted with 1-5 R²¹, and —CH₂carbocyclyl optionally substituted with 1-12 R²²;

each R¹⁷is independently selected from the group consisting of H, —(C_1-6alkyl), —(C_2-6alkenyl), and —(C_2-6alkynyl);

each R¹⁸is independently selected from the group consisting of H, —(C_1-6alkyl), —(C_2-6alkenyl), —(C_2-6alkynyl), —CH₂aryl optionally substituted with 1-5 R²¹and —CH₂carbocyclyl optionally substituted with 1-12 R²²;

each R¹⁹is independently selected from the group consisting of —(C_1-6alkyl), —(C_2-6alkenyl), and —(C_2-6alkynyl);

each R²⁰is independently selected from the group consisting of —(C_1-4alkyl), —(C_2-4alkenyl), —(C_2-4alkynyl), halide, —CF₃, and —CN;

each R²¹is independently selected from the group consisting of —(C_1-4alkyl), —(C_2-4alkenyl), —(C_2-4alkynyl), halide, —CF₃, and —CN;

each R²²is independently selected from the group consisting of —(C_1-4alkyl), —(C_2-4alkenyl), —(C_2-4alkynyl), halide, —CF₃, and —CN;

each R²³is independently selected from the group consisting of —(C_1-4alkyl), —(C_2-4alkenyl), —(C_2-4alkynyl), halide, —CF₃, and —CN;

R²⁴is selected from the group consisting of H, —(C_1-6alkyl), —(C_2-6alkenyl), —(C_2-6alkynyl), —(C_1-4alkylene)_pheterocyclyl optionally substituted with 1-10 R²³, —(C_2-4alkenylene)_pheterocyclyl optionally substituted with 1-10 R²³, —(C_2-4alkynylene)_pheterocyclyl optionally substituted with 1-10 R²³, —(C_1-4alkylene)_pcarbocyclyl optionally substituted with 1-12 R²², —(C_2-4alkenylene)_pcarbocyclyl optionally substituted with 1-12 R²², —(C_2-4alkynylene)_pcarbocyclyl optionally substituted with 1-12 R²², —(C_1-4alkylene)_paryl optionally substituted with 1-5 R²¹, —(C_2-4alkenylene)_paryl optionally substituted with 1-5 R²¹, —(C_2-4alkynylene)_paryl optionally substituted with 1-5 R²¹, —(C_1-6alkylene)_pNR²⁵R²⁶, —(C_2-4alkenylene)_pNR²⁵R²⁶, and —(C_2-4alkynylene)_pNR²⁵R²⁶;

each R²⁵is independently selected from the group consisting of H, —(C_1-6alkyl), —(C_2-6alkenyl), and —(C_2-6alkynyl);

each R²⁶is independently selected from the group consisting of H, —(C_1-6alkyl), —(C_2-6alkenyl), and —(C_2-6alkynyl);

R²⁷is selected from the group consisting of H, —(C_1-6alkyl), —(C_2-6alkenyl), —(C_2-6alkynyl), —(C_1-4alkylene)_pheterocyclyl optionally substituted with 1-10 R²³, —(C_2-4alkenylene)_pheterocyclyl optionally substituted with 1-10 R²³, —(C_2-4alkynylene)_pheterocyclyl optionally substituted with 1-10 R²³, —(C_1-6alkylene)_pNR²⁵R²⁶, —(C_2-6alkenylene)_pNR²⁵R²⁶, and —(C_2-6alkynylene)_pNR²⁵R²⁶; and

each p is independently an integer of 0 or 1.

In some embodiments of Formula (I):

R¹, R², and R⁴are independently selected from the group consisting of H and halide;

R³is selected from the group consisting of -heteroaryl optionally substituted with 1-4 R⁶and -heterocyclyl optionally substituted with 1-10 R⁷;

each R⁷is independently selected from the group consisting of —(C_1-4alkyl), —(C_2-4alkenyl), —(C_2-4alkynyl), halide, —CF₃, and —CN;

each R⁸is independently selected from the group consisting of —(C_1-6alkyl), —(C_2-6alkenyl), —(C_2-6alkynyl), halide, —CF₃, —OCH₃, —CN, and —C(═O)R¹⁹;

each R⁹is independently selected from the group consisting of —(C_1-6alkyl), —(C_2-6alkenyl), —(C_2-6alkynyl), halide, —CF₃, —CN, and —OCH₃;

each R¹⁰is independently selected from the group consisting of —(C_1-6alkyl), —(C_2-6alkenyl), —(C_2-6alkynyl), halide, —CF₃, —CN, —(C_1-6alkylene)_pNHSO₂R¹⁹, —(C_2-6alkenylene)_pNHSO₂R¹⁹, —(C_2-6alkynylene)_pNHSO₂R¹⁹, —NR¹⁵(C_1-6alkylene)NR⁵⁵R¹⁶, —NR¹⁵(C_2-6alkenylene)NR¹⁵R¹⁶, —NR¹⁵(C_2-6alkynylene)NR¹⁵R¹⁶, —(C_1-6alkylene)_pNR¹⁵R¹⁶, —(C_2-6alkenylene)_pNR¹⁵R¹⁶, —(C_2-6alkynylene)_pNR¹⁵R¹⁶, and —OR²⁷;

each R¹¹is independently selected from the group consisting of amino, —(C_1-4alkyl), —(C_2-4alkenyl), —(C_2-4alkynyl), halide, —CF₃, and —CN;

each R¹²is independently selected from the group consisting of —(C_1-4alkyl), —(C_2-4alkenyl), —(C_2-4alkynyl), halide, —CF₃, and —CN;

each R¹³is independently selected from the group consisting of —(C_1-4alkyl), —(C_2-4alkenyl), —(C_2-4alkynyl), halide, —CF₃, and —CN;

each R¹⁴is independently selected from the group consisting of —(C_1-9alkyl), —(C_2-9alkenyl), —(C_2-9alkynyl), -heteroaryl optionally substituted with 1-4 R²⁰, -aryl optionally substituted with 1-5 R²¹, —CH₂aryl optionally substituted with 1-5 R²¹, -carbocyclyl optionally substituted with 1-12 R²², —CH₂carbocyclyl optionally substituted with 1-12 R²², —(C_1-4alkylene)_pNR²⁵R²⁶, —(C_2-4alkenylene)_pNR²⁵R²⁶, —(C_2-4alkynylene)_pNR²⁵R²⁶, -heterocyclyl optionally substituted with 1-10 R²³, and —CH₂heterocyclyl optionally substituted with 1-10 R²³;

each R¹⁵is independently selected from the group consisting of H, —(C_1-6alkyl), —(C_2-6alkenyl), and —(C_2-6alkynyl);

each R¹⁷is independently selected from the group consisting of H, —(C_1-6alkyl), —(C_2-6alkenyl), and —(C_2-6alkynyl);

each R¹⁹is independently selected from the group consisting of —(C_1-6alkyl), —(C_2-6alkenyl), and —(C_2-6alkynyl);

each R²⁰is independently selected from the group consisting of —(C_1-4alkyl), —(C_2-4alkenyl), —(C_2-4alkynyl), halide, —CF₃, and —CN;

each R²¹is independently selected from the group consisting of —(C_1-4alkyl), —(C_2-4alkenyl), —(C_2-4alkynyl), halide, —CF₃, and —CN;

each R²²is independently selected from the group consisting of —(C_1-4alkyl), —(C_2-4alkenyl), —(C_2-4alkynyl), halide, —CF₃, and —CN;

each R²³is independently selected from the group consisting of —(C_1-4alkyl), —(C_2-4alkenyl), —(C_2-4alkynyl), halide, —CF₃, and —CN;

R²⁴is selected from the group consisting of H, —(C_1-6alkyl), —(C_2-6alkenyl), —(C_2-6alkynyl), —(C_1-4alkylene)_pheterocyclyl optionally substituted with 1-10 R²³, —(C_2-4alkenylene)_pheterocyclyl optionally substituted with 1-10 R²³, —(C_2-4alkynylene)_pheterocyclyl optionally substituted with 1-R²³, —(C_1-4alkylene)_pcarbocyclyl optionally substituted with 1-12 R²², —(C_2-4alkenylene)_pcarbocyclyl optionally substituted with 1-12 R²², —(C_2-4alkynylene)_pcarbocyclyl optionally substituted with 1-12 R²², —(C_1-4alkylene)_paryl optionally substituted with 1-5 R²¹, —(C_2-4alkenylene)_paryl optionally substituted with 1-5 R²¹, —(C_2-4alkynylene)_paryl optionally substituted with 1-5 R²¹, —(C_1-6alkylene)_pNR²⁵R²⁶, —(C_2-4alkenylene)_pNR²⁵R²⁶, and —(C_2-4alkynylene)_pNR²⁵R²⁶;

each R²⁵is independently selected from the group consisting of H, —(C_1-6alkyl), —(C_2-6alkenyl), and —(C_2-6alkynyl);

each R²⁶is independently selected from the group consisting of H, —(C_1-6alkyl), —(C_2-6alkenyl), and —(C_2-6alkynyl);

each p is independently an integer of 0 or 1.

Some embodiments include stereoisomers and pharmaceutically acceptable salts of a compound of Formula (I).

Some embodiments include pro-drugs of a compound of Formula (I).

Some embodiments of the present disclosure include pharmaceutical compositions comprising a compound of Formula (I) and a pharmaceutically acceptable carrier, diluent, or excipient.

Other embodiments disclosed herein include methods of inhibiting one or more members of the Wnt pathway, including one or more Wnt proteins by administering to a patient affected by a disorder or disease in which aberrant Wnt signaling is implicated, such as cancer and other diseases associated with abnormal angiogenesis, cellular proliferation, cell cycling and mutations in Wnt signaling components, a compound according to Formula (I). Accordingly, the compounds and compositions provided herein can be used to treat cancer, to reduce or inhibit angiogenesis, to reduce or inhibit cellular proliferation and correct a genetic disorder due to mutations in Wnt signaling components.

Non-limiting examples of diseases which can be treated with the compounds and compositions provided herein include a variety of cancers, diabetic retinopathy, pulmonary fibrosis, rheumatoid arthritis, sepsis, ankylosing spondylitis, psoriasis, scleroderma, mycotic and viral infections, osteochondrodysplasia, Alzheimer's disease, lung disease, bone/osteoporotic (wrist, spine, shoulder and hip) fractures, articular cartilage (chondral) defects, degenerative disc disease (or intervertebral disc degeneration), polyposis coli, osteoporosis-pseudoglioma syndrome, familial exudative vitreoretinopathy, retinal angiogenesis, early coronary disease, tetra-amelia syndrome, Müllerian-duct regression and virilization, SERKAL syndrome, diabetes mellitus type 2, Fuhrmann syndrome, Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndrome, odonto-onycho-dermal dysplasia, obesity, split-hand/foot malformation, caudal duplication syndrome, tooth agenesis, Wilms tumor, skeletal dysplasia, focal dermal hypoplasia, autosomal recessive anonychia, neural tube defects, alpha-thalassemia (ATRX) syndrome, fragile X syndrome, ICF syndrome, Angelman syndrome, Prader-Willi syndrome, Beckwith-Wiedemann Syndrome, Norrie disease, and Rett syndrome.

Some embodiments of the present disclosure include methods to prepare compounds of Formula (I).

It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the disclosure, as claimed.

DETAILED DESCRIPTION

Provided herein are compositions and methods for inhibiting one or more members of the Wnt pathway, including one or more Wnt proteins. Other Wnt inhibitors and methods for using the same are disclosed in U.S. application Ser. Nos. 12/852,706; 12/968,505; 13/552,188; 13/800,963; 13/855,874; 13/887,177 13/938,691; 13/938,692; 14/019,103; 14/019,147; 14/019,940; 14/149,948; 14/178,749; 14/331,427; 14/334,005; and 14/664,517 and U.S. Provisional Application Ser. Nos. 61/232,603; 61/288,544; 61/305,459; 61/620,107; 61/642,915; 61/750,221; 61/968,350; 62/047,324; 62/047,371; 62/047,395; 62/047,401; 62/047,406; 62/047,438; 62/047,509; 62/047,575; 62/047,567, all of which are incorporated by reference in their entirety herein.

Some embodiments provided herein relate to a method for treating a disease or disorder including, but not limited to, cancers, diabetic retinopathy, pulmonary fibrosis, rheumatoid arthritis, sepsis, ankylosing spondylitis, psoriasis, scleroderma, mycotic and viral infections, bone and cartilage diseases, Alzheimer's disease, lung disease, osteoarthritis, bone/osteoporotic (wrist, spine, shoulder and hip) fractures, articular cartilage (chondral) defects, degenerative disc disease (or intervertebral disc degeneration), polyposis coli, bone density and vascular defects in the eye (Osteoporosis-pseudoglioma Syndrome, OPPG), familial exudative vitreoretinopathy, retinal angiogenesis, early coronary disease, tetra-amelia, Müllerian-duct regression and virilization, SERKAL syndrome, type II diabetes, Fuhrmann syndrome, Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndrome, odonto-onycho-dermal dysplasia, obesity, split-hand/foot malformation, caudal duplication, tooth agenesis, Wilms tumor, skeletal dysplasia, focal dermal hypoplasia, autosomal recessive anonychia, neural tube defects, alpha-thalassemia (ATRX) syndrome, fragile X syndrome, ICF syndrome, Angelman syndrome, Prader-Willi syndrome, Beckwith-Wiedemann Syndrome, Norrie disease, and Rett syndrome.

In some embodiments, non-limiting examples of bone and cartilage diseases which can be treated with the compounds and compositions provided herein include bone spur (osteophytes), craniosynostosis, fibrodysplasia ossificans progressiva, fibrous dysplasia, giant cell tumor of bone, hip labral tear, meniscal tears, bone/osteoporotic (wrist, spine, shoulder and hip) fractures, articular cartilage (chondral) defects, degenerative disc disease (or intervertebral disc degeneration), osteochondritis dissecans, osteochondroma (bone tumor), osteopetrosis, relapsing polychondritis, and Salter-Harris fractures.

In some embodiments, pharmaceutical compositions are provided that are effective for treatment of a disease of an animal, e.g., a mammal, caused by the pathological activation or mutations of the Wnt pathway. The composition includes a pharmaceutically acceptable carrier and a compound as described herein.

Definitions

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art to which this disclosure belongs. All patents, applications, published applications, and other publications are incorporated by reference in their entirety. In the event that there is a plurality of definitions for a term herein, those in this section prevail unless stated otherwise.

As used herein, “alkyl” means a branched, or straight chain chemical group containing only carbon and hydrogen, such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, iso-pentyl, sec-pentyl and neo-pentyl. Alkyl groups can either be unsubstituted or substituted with one or more substituents. In some embodiments, alkyl groups include 1 to 9 carbon atoms (for example, 1 to 6 carbon atoms, 1 to 4 carbon atoms, or 1 to 2 carbon atoms).

As used herein, “alkenyl” means a straight or branched chain chemical group containing only carbon and hydrogen and containing at least one carbon-carbon double bond, such as ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, and the like. In various embodiments, alkenyl groups can either be unsubstituted or substituted with one or more substituents. Typically, alkenyl groups will comprise 2 to 9 carbon atoms (for example, 2 to 6 carbon atoms, 2 to 4 carbon atoms, or 2 carbon atoms).

“Exocyclic double bond” means a carbon-carbon double bond connected to and hence external to, a ring structure.

As used herein, “alkynyl” means a straight or branched chain chemical group containing only carbon and hydrogen and containing at least one carbon-carbon triple bond, such as ethynyl, 1-propynyl, 1-butynyl, 2-butynyl, and the like. In various embodiments, alkynyl groups can either be unsubstituted or substituted with one or more substituents. Typically, alkynyl groups will comprise 2 to 9 carbon atoms (for example, 2 to 6 carbon atoms, 2 to 4 carbon atoms, or 2 carbon atoms).

As used herein, “alkylene” means a bivalent branched, or straight chain chemical group containing only carbon and hydrogen, such as methylene, ethylene, n-propylene, iso-propylene, n-butylene, iso-butylene, sec-butylene, tert-butylene, n-pentylene, iso-pentylene, sec-pentylene and neo-pentylene. Alkylene groups can either be unsubstituted or substituted with one or more substituents. Alkylene groups can be saturated or unsaturated (e.g., containing —C═C— or —C≡C— subunits), at one or several positions. In some embodiments, alkylene groups include 1 to 9 carbon atoms (for example, 1 to 6 carbon atoms, 1 to 4 carbon atoms, or 1 to 2 carbon atoms).

As used herein, “alkenylene” means a bivalent branched, or straight chain chemical group containing only carbon and hydrogen and containing at least one carbon-carbon double bond, such as ethenylene, 1-propenylene, 2-propenylene, 2-methyl-1-propenylene, 1-butenylene, 2-butenylene, and the like. In various embodiments, alkenylene groups can either be unsubstituted or substituted with one or more substituents. Typically, alkenylene groups will comprise 2 to 9 carbon atoms (for example, 2 to 6 carbon atoms, 2 to 4 carbon atoms, or 2 carbon atoms).

As used herein, “alkynylene” means a bivalent branched, or straight chain chemical group containing only carbon and hydrogen and containing at least one carbon-carbon triple bond, such as ethynylene, 1-propynylene, 1-butynylene, 2-butynylene, and the like. In various embodiments, alkynylene groups can either be unsubstituted or substituted with one or more substituents. Typically, alkynylene groups will comprise 2 to 9 carbon atoms (for example, 2 to 6 carbon atoms, 2 to 4 carbon atoms, or 2 carbon atoms).

As used herein, “carbocyclyl” means a cyclic ring system containing only carbon atoms in the ring system backbone, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclohexenyl. Carbocyclyls may include multiple fused rings. Carbocyclyls may have any degree of saturation provided that at least one ring in the ring system is not aromatic. Carbocyclyl groups can either be unsubstituted or substituted with one or more substituents. In some embodiments, carbocyclyl groups include 3 to 10 carbon atoms, for example, 3 to 6 carbon atoms.

As used herein, “aryl” means a mono-, bi-, tri- or polycyclic group with only carbon atoms present in the ring backbone having 5 to 14 ring atoms, alternatively 5, 6, 9, or 10 ring atoms; and having 6, 10, or 14 pi electrons shared in a cyclic array; wherein at least one ring in the system is aromatic. Aryl groups can either be unsubstituted or substituted with one or more substituents. Examples of aryl include phenyl, naphthyl, tetrahydronaphthyl, 2,3-dihydro-1H-indenyl, and others. In some embodiments, the aryl is phenyl.

As used herein, “arylalkylene” means an aryl-alkylene-group in which the aryl and alkylene moieties are as previously described. In some embodiments, arylalkylene groups contain a C_1-4alkylene moiety. Exemplary arylalkylene groups include benzyl and 2-phenethyl.

As used herein, the term “heteroaryl” means a mono-, bi-, tri- or polycyclic group having 5 to 14 ring atoms, alternatively 5, 6, 9, or 10 ring atoms; and having 6, 10, or 14 pi electrons shared in a cyclic array; wherein at least one ring in the system is aromatic, and at least one ring in the system contains one or more heteroatoms independently selected from the group consisting of N, O, and S. Heteroaryl groups can either be unsubstituted or substituted with one or more substituents. Examples of heteroaryl include thienyl, pyridinyl, furyl, oxazolyl, oxadiazolyl, pyrrolyl, imidazolyl, triazolyl, thiodiazolyl, pyrazolyl, isoxazolyl, thiadiazolyl, pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thiazolyl benzothienyl, benzoxadiazolyl, benzofuranyl, benzimidazolyl, benzotriazolyl, cinnolinyl, indazolyl, indolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, purinyl, thienopyridinyl, pyrido[2,3-d]pyrimidinyl, pyrrolo[2,3-b]pyridinyl, quinazolinyl, quinolinyl, thieno[2,3-c]pyridinyl, pyrazolo[3,4-b]pyridinyl, pyrazolo[3,4-c]pyridinyl, pyrazolo[4,3-c]pyridine, pyrazolo[4,3-b]pyridinyl, tetrazolyl, chromane, 2,3-dihydrobenzo[b][1,4]dioxine, benzo[d][1,3]dioxole, 2,3-dihydrobenzofuran, tetrahydroquinoline, 2,3-dihydrobenzo[b][1,4]oxathiine, and others. In some embodiments, the heteroaryl is selected from thienyl, pyridinyl, furyl, pyrazolyl, imidazolyl, pyranyl, pyrazinyl, and pyrimidinyl.

As used herein, “halo”, “halide” or “halogen” is a chloro, bromo, fluoro, or iodo atom radical. In some embodiments, a halo is a chloro, bromo or fluoro. For example, a halide can be fluoro.

As used herein, “haloalkyl” means a hydrocarbon substituent, which is a linear or branched, alkyl, alkenyl or alkynyl substituted with one or more chloro, bromo, fluoro, and/or iodo atom(s). In some embodiments, a haloalkyl is a fluoroalkyls, wherein one or more of the hydrogen atoms have been substituted by fluoro. In some embodiments, haloalkyls are of 1 to about 3 carbons in length (e.g., 1 to about 2 carbons in length or 1 carbon in length). The term “haloalkylene” means a diradical variant of haloalkyl, and such diradicals may act as spacers between radicals, other atoms, or between a ring and another functional group.

As used herein, “heterocyclyl” means a nonaromatic cyclic ring system comprising at least one heteroatom in the ring system backbone. Heterocyclyls may include multiple fused rings. Heterocyclyls may be substituted or unsubstituted with one or more substituents. In some embodiments, heterocycles have 5-7 members. In six membered monocyclic heterocycles, the heteroatom(s) are selected from one to three of O, N or S, and wherein when the heterocycle is five membered, it can have one or two heteroatoms selected from O, N, or S. Examples of heterocyclyl include azirinyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, 1,4,2-dithiazolyl, dihydropyridinyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-dioxolanyl, morpholinyl, thiomorpholinyl, piperazinyl, pyranyl, pyrrolidinyl, tetrahydrofuryl, tetrahydropyridinyl, oxazinyl, thiazinyl, thiinyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl, piperidinyl, pyrazolidinyl imidazolidinyl, thiomorpholinyl, and others. In some embodiments, the heterocyclyl is selected from azetidinyl, morpholinyl, piperazinyl, pyrrolidinyl, and tetrahydropyridinyl.

As used herein, “monocyclic heterocyclyl” means a single nonaromatic cyclic ring comprising at least one heteroatom in the ring system backbone. Heterocyclyls may be substituted or unsubstituted with one or more substituents. In some embodiments, heterocycles have 5-7 members. In six membered monocyclic heterocycles, the heteroatom(s) are selected from one to three of O, N or S, and wherein when the heterocycle is five membered, it can have one or two heteroatoms selected from O, N, or S. Examples of heterocyclyl include azirinyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, 1,4,2-dithiazolyl, dihydropyridinyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-dioxolanyl, morpholinyl, thiomorpholinyl, piperazinyl, pyranyl, pyrrolidinyl, tetrahydrofuryl, tetrahydropyridinyl, oxazinyl, thiazinyl, thiinyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl, piperidinyl, pyrazolidinyl imidazolidinyl, thiomorpholinyl, and others.

The term “substituted” refers to moieties having substituents replacing a hydrogen on one or more non-hydrogen atoms of the molecule. It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. Substituents can include, for example, —(C_1-9alkyl) optionally substituted with one or more of hydroxyl, —NH₂, —NH(C_1-3alkyl), and —N(C_1-3alkyl)₂; —(C_1-9haloalkyl); a halide; a hydroxyl; a carbonyl [such as —C(O)OR, and —C(O)R]; a thiocarbonyl [such as —C(S)OR, —C(O)SR, and —C(S)R]; —(C_1-9alkoxyl) optionally substituted with one or more of halide, hydroxyl, —NH₂, —NH(C_1-3alkyl), and —N(C_1-3alkyl)₂; —OPO(OH)₂; a phosphonate [such as —PO(OH)₂and —PO(OR′)₂]; —OPO(OR′)R¹¹; —NRR′; —C(O)NRR′; —C(NR)NR′R″; —C(NR′)R″; a cyano; a nitro; an azido; —SH; —S—R; —OSO₂(OR); a sulfonate [such as —SO₂(OH) and —SO₂(OR)]; —SO₂NR′R″; and —SO₂R; in which each occurrence of R, R′ and R″ are independently selected from H; —(C_1-9alkyl); C_6-10aryl optionally substituted with from 1-3R′″; 5-10 membered heteroaryl having from 1-4 heteroatoms independently selected from N, O, and S and optionally substituted with from 1-3 R′″; C_3-7carbocyclyl optionally substituted with from 1-3 R′″; and 3-8 membered heterocyclyl having from 1-4 heteroatoms independently selected from N, O, and S and optionally substituted with from 1-3 R′″; wherein each R′″ is independently selected from —(C_1-6alkyl), —(C_1-6haloalkyl), a halide (e.g., F), a hydroxyl, —C(O)OR, —C(O)R, —(C_1-6alkoxyl), —NRR′, —C(O)NRR′, and a cyano, in which each occurrence of R and R′ is independently selected from H and —(C_1-6alkyl). In some embodiments, the substituent is selected from —(C_1-6alkyl), —(C_1-6haloalkyl), a halide (e.g., F), a hydroxyl, —C(O)OR, —C(O)R, —(C_1-6alkoxyl), —NRR′, —C(O)NRR′, and a cyano, in which each occurrence of R and R′ is independently selected from H and —(C_1-6alkyl).

As used herein, when two groups are indicated to be “linked” or “bonded” to form a “ring”, it is to be understood that a bond is formed between the two groups and may involve replacement of a hydrogen atom on one or both groups with the bond, thereby forming a carbocyclyl, heterocyclyl, aryl, or heteroaryl ring. The skilled artisan will recognize that such rings can and are readily formed by routine chemical reactions. In some embodiments, such rings have from 3-7 members, for example, 5 or 6 members.

The skilled artisan will recognize that some structures described herein may be resonance forms or tautomers of compounds that may be fairly represented by other chemical structures, even when kinetically, the artisan recognizes that such structures are only a very small portion of a sample of such compound(s). Such compounds are clearly contemplated within the scope of this disclosure, though such resonance forms or tautomers are not represented herein.

The compounds provided herein may encompass various stereochemical forms. The compounds also encompass diastereomers as well as optical isomers, e.g., mixtures of enantiomers including racemic mixtures, as well as individual enantiomers and diastereomers, which arise as a consequence of structural asymmetry in certain compounds. Separation of the individual isomers or selective synthesis of the individual isomers is accomplished by application of various methods which are well known to practitioners in the art. Unless otherwise indicated, when a disclosed compound is named or depicted by a structure without specifying the stereochemistry and has one or more chiral centers, it is understood to represent all possible stereoisomers of the compound.

The term “administration” or “administering” refers to a method of providing a dosage of a compound or pharmaceutical composition to a vertebrate or invertebrate, including a mammal, a bird, a fish, or an amphibian, where the method is, e.g., orally, subcutaneously, intravenously, intralymphatic, intranasally, topically, transdermally, intraperitoneally, intramuscularly, intrapulmonarilly, vaginally, rectally, ontologically, neuro-otologically, intraocularly, subconjuctivally, via anterior eye chamber injection, intravitreally, intraperitoneally, intrathecally, intracystically, intrapleurally, via wound irrigation, intrabuccally, intra-abdominally, intra-articularly, intra-aurally, intrabronchially, intracapsularly, intrameningeally, via inhalation, via endotracheal or endobronchial instillation, via direct instillation into pulmonary cavities, intraspinally, intrasynovially, intrathoracically, via thoracostomy irrigation, epidurally, intratympanically, intracisternally, intravascularly, intraventricularly, intraosseously, via irrigation of infected bone, or via application as part of any admixture with a prosthetic device. The method of administration can vary depending on various factors, e.g., the components of the pharmaceutical composition, the site of the disease, the disease involved, and the severity of the disease.

A “diagnostic” as used herein is a compound, method, system, or device that assists in the identification or characterization of a health or disease state. The diagnostic can be used in standard assays as is known in the art.

The term “mammal” is used in its usual biological sense. Thus, it specifically includes humans, cattle, horses, monkeys, dogs, cats, mice, rats, cows, sheep, pigs, goats, and non-human primates, but also includes many other species.

The term “pharmaceutically acceptable carrier”, “pharmaceutically acceptable diluent” or “pharmaceutically acceptable excipient” includes any and all solvents, co-solvents, complexing agents, dispersion media, coatings, isotonic and absorption delaying agents and the like which are not biologically or otherwise undesirable. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions. In addition, various adjuvants such as are commonly used in the art may be included. These and other such compounds are described in the literature, e.g., in the Merck Index, Merck & Company, Rahway, N.J. Considerations for the inclusion of various components in pharmaceutical compositions are described, e.g., in Gilman et al. (Eds.) (2010); Goodman and Gilman's: The Pharmacological Basis of Therapeutics, 12th Ed., The McGraw-Hill Companies.

The term “pharmaceutically acceptable salt” refers to salts that retain the biological effectiveness and properties of the compounds provided herein and, which are not biologically or otherwise undesirable. In many cases, the compounds provided herein are capable of forming acid and/or base salts by virtue of the presence of amino and/or carboxyl groups or groups similar thereto. Many such salts are known in the art, for example, as described in WO 87/05297. Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, for example, acetic 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, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like; particularly preferred are the ammonium, potassium, sodium, calcium, and magnesium salts. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, specifically such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine.

“Solvate” refers to the compound formed by the interaction of a solvent and a compound as provided herein or a salt thereof. Suitable solvates are pharmaceutically acceptable solvates including hydrates.

“Patient” as used herein, means a human or a non-human mammal, e.g., a dog, a cat, a mouse, a rat, a cow, a sheep, a pig, a goat, a non-human primate, or a bird, e.g., a chicken, as well as any other vertebrate or invertebrate. In some embodiments, the patient is a human.

A “therapeutically effective amount” of a compound as provided herein is one which is sufficient to achieve the desired physiological effect and may vary according to the nature and severity of the disease condition, and the potency of the compound. “Therapeutically effective amount” is also intended to include one or more of the compounds of Formula I in combination with one or more other agents that are effective to treat the diseases and/or conditions described herein. The combination of compounds can be a synergistic combination. Synergy, as described, for example, by Chou and Talalay, Advances in Enzyme Regulation (1984), 22, 27-55, occurs when the effect of the compounds when administered in combination is greater than the additive effect of the compounds when administered alone as a single agent. In general, a synergistic effect is most clearly demonstrated at sub-optimal concentrations of the compounds. It will be appreciated that different concentrations may be employed for prophylaxis than for treatment of an active disease. This amount can further depend upon the patient's height, weight, sex, age and medical history.

A therapeutic effect relieves, to some extent, one or more of the symptoms of the disease.

“Treat,” “treatment,” or “treating,” as used herein refers to administering a compound or pharmaceutical composition as provided herein for therapeutic purposes. The term “therapeutic treatment” refers to administering treatment to a patient already suffering from a disease thus causing a therapeutically beneficial effect, such as ameliorating existing symptoms, ameliorating the underlying metabolic causes of symptoms, postponing or preventing the further development of a disorder, and/or reducing the severity of symptoms that will or are expected to develop.

“Drug-eluting” and/or controlled release as used herein refers to any and all mechanisms, e.g., diffusion, migration, permeation, and/or desorption by which the drug(s) incorporated in the drug-eluting material pass therefrom over time into the surrounding body tissue.

“Drug-eluting material” and/or controlled release material as used herein refers to any natural, synthetic or semi-synthetic material capable of acquiring and retaining a desired shape or configuration and into which one or more drugs can be incorporated and from which incorporated drug(s) are capable of eluting over time.

“Elutable drug” as used herein refers to any drug or combination of drugs having the ability to pass over time from the drug-eluting material in which it is incorporated into the surrounding areas of the body.

Compounds

The compounds and compositions described herein can be used as anti-proliferative agents, e.g., anti-cancer and anti-angiogenesis agents, and/or as inhibitors of the Wnt signaling pathway, e.g., for treating diseases or disorders associated with aberrant Wnt signaling. In addition, the compounds can be used as inhibitors of one or more kinases, kinase receptors, or kinase complexes. Such compounds and compositions are also useful for controlling cellular proliferation, differentiation, and/or apoptosis.

Some embodiments of the present disclosure include compounds of Formula I:

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or salts, pharmaceutically acceptable salts, or prodrugs thereof.

In some embodiments, R¹, R², and R⁴are independently selected from the group consisting of H and halide (e.g., F, Cl, Br, I).

In some embodiments, R¹and R²are H, and R⁴is F.

In some embodiments, R¹is H, and R²and R⁴are F.

In some embodiments, R¹and R⁴are H, and R²is F.

In some embodiments, R²is H, and R¹and R⁴are F.

In some embodiments, R¹and R²are F, and R⁴is H.

In some embodiments, R¹, R², and R⁴are all H.

In some embodiments, R¹, R², and R⁴are all F.

In some embodiments, R³is selected from the group consisting of -heteroaryl optionally substituted with 1-4 (e.g., 1-3, 1-2, 1) R⁶and -heterocyclyl optionally substituted with 1-10 (e.g., 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R⁷.

In some embodiments, R³is selected from the group consisting of -heteroaryl optionally substituted with 1-2 (e.g., 1) R⁶and -heterocyclyl optionally substituted with 1-2 (e.g., 1) R⁷.

In some embodiments, the heteroaryl of R³is selected from the group consisting of -pyridinyl, -pyrimidinyl, -pyrazolyl, -imidazolyl, -thiazolyl, and -oxazolyl.

In some embodiments, the heteroaryl of R³is selected from the group consisting of -pyridin-3-yl, -pyrimidin-5-yl, -pyrazol-4-yl, -imidazol-5-yl, -thiazol-2-yl, -thiazol-5-yl, -oxazol-2-yl, and -oxazol-5-yl.

In some embodiments, the -heterocyclyl of R³is selected from the group consisting of -tetrahydropyridinyl and -piperidinyl.

In some embodiments, the -heterocyclyl of R³is selected from the group consisting of -1,2,3,6-tetrahydropyridinyl and -piperidin-4-yl.

In some embodiments, R³is -pyridinyl optionally substituted with 1 R⁶.

In some embodiments, R³is -pyridin-3-yl optionally substituted with 1 R⁶.

In some embodiments, R³is -pyrimidinyl optionally substituted with 1 R⁶.

In some embodiments, R³is -pyrimidin-5-yl optionally substituted with 1 R⁶.

In some embodiments, R³is -pyrazolyl optionally substituted with 1 R⁶.

In some embodiments, R³is -pyrazolyl substituted with 1 R⁶.

In some embodiments, R³is -pyrazolyl substituted with 1 methyl.

In some embodiments, R³is -pyrazolyl optionally substituted with 2 R⁶.

In some embodiments, R³is -pyrazolyl substituted with 2 R⁶.

In some embodiments, R³is -pyrazolyl substituted with 1 methyl and 1 —CH₂OH.

In some embodiments, R³is -pyrazol-4-yl optionally substituted with 1 R⁶.

In some embodiments, R³is -pyrazol-4-yl substituted with 1 R⁶.

In some embodiments, R³is -pyrazol-4-yl substituted with 1 methyl.

In some embodiments, R³is -pyrazol-4-yl optionally substituted with 2 R⁶.

In some embodiments, R³is -pyrazol-4-yl substituted with 2 R⁶.

In some embodiments, R³is -pyrazol-4-yl substituted with 1 methyl and 1 —CH₂OH.

In some embodiments, R³is -imidazolyl optionally substituted with 1-2 R⁶.

In some embodiments, R³is -imidazolyl substituted with 1-2 R⁶.

In some embodiments, R³is -imidazolyl substituted with 1-2 methyls.

In some embodiments, R³is -imidazolyl substituted with 1 methyl.

In some embodiments, R³is -imidazolyl substituted with 2 methyls.

In some embodiments, R³is -imidazol-5-yl optionally substituted with 1-2 R⁶.

In some embodiments, R³is -imidazol-5-yl substituted with 1-2 R⁶.

In some embodiments, R³is -imidazol-5-yl substituted with 1-2 methyls.

In some embodiments, R³is -imidazol-5-yl substituted with 1 methyl.

In some embodiments, R³is -imidazol-5-yl substituted with 2 methyls.

In some embodiments, R³is -thiazolyl optionally substituted with 1 R⁶.

In some embodiments, R³is -thiazol-2-yl optionally substituted with 1 R⁶.

In some embodiments, R³is thiazol-5-yl optionally substituted with 1 R⁶.

In some embodiments, R³is -oxazolyl optionally substituted with 1 R⁶.

In some embodiments, R³is -oxazol-2-yl optionally substituted with 1 R⁶.

In some embodiments, R³is -oxazol-5-yl optionally substituted with 1 R⁶.

In some embodiments, R⁵is selected from the group consisting of H, -heteroaryl optionally substituted with 1-4 (e.g., 1-3, 1-2, 1) R⁸, -heterocyclyl optionally substituted with 1-10 (e.g., 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R⁹, and -aryl optionally substituted with 1-5 (e.g., 1-4, 1-3, 1-2, 1) R¹⁰.

In some embodiments, R⁵is selected from the group consisting of H, -heteroaryl optionally substituted with 1-2 (e.g., 1) R⁸, -heterocyclyl optionally substituted with 1-2 (e.g., 1) R⁹, and -phenyl optionally substituted with 1-2 (e.g., 1) R¹⁰.

In some embodiments, R⁵is H.

In some embodiments, R⁵is -heteroaryl optionally substituted with 1-2 (e.g., 1) R⁸.

In some embodiments, R⁵is -heterocyclyl optionally substituted with 1-2 (e.g., 1) R⁹.

In some embodiments, R⁵is -piperidinyl optionally substituted with 1-2 (e.g., 1) R⁹.

In some embodiments, R⁵is -piperazinyl optionally substituted with 1-2 (e.g., 1) R⁹.

In some embodiments, R⁵is -aryl optionally substituted with 1-2 (e.g., 1) R¹⁰.

In some embodiments, R⁵is -phenyl optionally substituted with 1-2 (e.g., 1) R¹⁰.

In some embodiments, R⁵is -pyridinyl optionally substituted with 1-2 (e.g., 1) R⁸.

In some embodiments, R⁵is -pyridin-3-yl optionally substituted with 1-2 (e.g., 1) R⁸.

In some embodiments, R⁵is -pyridin-4-yl optionally substituted with 1-2 (e.g., 1) R⁸.

In some embodiments, R⁵is -pyridin-5-yl optionally substituted with 1-2 (e.g., 1) R⁸.

In some embodiments, R⁵is -imidazolyl optionally substituted with 1-2 (e.g., 1) R⁸.

In some embodiments, R⁵is -imidazolyl substituted with 1-2 (e.g., 1) R.

In some embodiments, R⁵is -imidazolyl substituted with 1 R.

In some embodiments, R⁵is -imidazolyl substituted with 1 methyl.

In some embodiments, R⁵is -imidazol-1-yl optionally substituted with 1-2 (e.g., 1) R.

In some embodiments, R⁵is -imidazol-1-yl substituted with 1-2 (e.g., 1) R⁸.

In some embodiments, R⁵is -imidazol-1-yl substituted with 1 R⁸.

In some embodiments, R⁵is -imidazol-1-yl substituted with 1 methyl.

In some embodiments, R⁵is -furanyl optionally substituted with 1-2 (e.g., 1) R⁸.

In some embodiments, R⁵is -furan-2-yl optionally substituted with 1-2 (e.g., 1) R⁸.

In some embodiments, R⁵is -furan-3-yl optionally substituted with 1-2 (e.g., 1) R⁸.

In some embodiments, R⁵is -thiophenyl optionally substituted with 1-2 (e.g., 1) R⁸.

In some embodiments, R⁵is -thiophen-2-yl optionally substituted with 1-2 (e.g., 1) R⁸.

In some embodiments, R⁵is -thiophen-2-yl optionally substituted with 1-2 (e.g., 1) R⁸, and each R⁸is independently halide.

In some embodiments, R⁵is -thiophen-2-yl optionally substituted with 1-2 (e.g., 1) F.

In some embodiments, R⁵is -thiophen-2-yl optionally substituted with 1-2 (e.g., 1) Cl.

In some embodiments, R⁵is -thiophen-2-yl optionally substituted with 1-2 (e.g., 1) R⁸, and each R⁸is independently —(C_1-6alkyl).

In some embodiments, R⁵is -thiophen-2-yl optionally substituted with 1-2 (e.g., 1) R⁸, and each R⁸is independently —(C_1-2alkyl).

In some embodiments, R⁵is -thiophen-2-yl optionally substituted with 1-2 (e.g., 1) methyls.

In some embodiments, R⁵is -thiophen-2-yl optionally substituted with 1-2 (e.g., 1) —CF₃.

In some embodiments, R⁵is -thiophen-2-yl optionally substituted with 1-2 (e.g., 1) —CN.

In some embodiments, R⁵is -thiophen-2-yl optionally substituted with 1 —C(═O)R¹⁹.

In some embodiments, R⁵is -thiophen-2-yl optionally substituted with 1 —C(═O)R¹⁹, and R¹⁹is —(C_1-6alkyl).

In some embodiments, R⁵is -thiophen-2-yl optionally substituted with 1 —C(═O)R¹⁹, and R¹⁹is —(C_1-4alkyl).

In some embodiments, R⁵is -thiophen-2-yl optionally substituted with 1 —C(═O)R¹⁹, and R¹⁹is —(C_1-2alkyl).

In some embodiments, R⁵is -thiophen-2-yl optionally substituted with 1 —C(═O)R¹⁹, and R¹⁹is methyl.

In some embodiments, R⁵is -thiophen-3-yl optionally substituted with 1-2 (e.g., 1) R⁸.

In some embodiments, R⁵is -thiophen-3-yl optionally substituted with 1-2 (e.g., 1) R⁸and each R⁸is independently halide.

In some embodiments, R⁵is -thiophen-3-yl optionally substituted with 1-2 (e.g., 1) F.

In some embodiments, R⁵is -thiophen-3-yl optionally substituted with 1-2 (e.g., 1) Cl.

In some embodiments, R⁵is -thiophen-3-yl optionally substituted with 1-2 (e.g., 1) R⁸, and each R⁸is independently —(C_1-6alkyl).

In some embodiments, R⁵is -thiophen-3-yl optionally substituted with 1-2 (e.g., 1) R⁸, and each R⁸is independently —(C_1-2alkyl).

In some embodiments, R⁵is -thiophen-3-yl optionally substituted with 1-2 (e.g., 1) methyls.

In some embodiments, R⁵is -thiophen-3-yl optionally substituted with 1-2 (e.g., 1) —CF₃.

In some embodiments, R⁵is -thiophen-3-yl optionally substituted with 1-2 (e.g., 1) —CN.

In some embodiments, R⁵is -thiophen-3-yl optionally substituted with 1 —C(═O)R¹⁹.

In some embodiments, R⁵is -thiophen-3-yl optionally substituted with 1 —C(═O)R¹⁹, and R¹⁹is —(C_1-6alkyl).

In some embodiments, R⁵is -thiophen-3-yl optionally substituted with 1 —C(═O)R¹⁹, and R¹⁹is —(C_1-4alkyl).

In some embodiments, R⁵is -thiophen-3-yl optionally substituted with 1 —C(═O)R¹⁹, and R¹⁹is —(C_1-2alkyl).

In some embodiments, R⁵is -thiophen-3-yl optionally substituted with 1 —C(═O)R¹⁹, and R¹⁹is methyl.

In some embodiments, R⁵is selected from the group consisting of:

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In some embodiments, R⁵is -phenyl optionally substituted with 1-2 (e.g., 1) R¹⁰, and each R¹⁰is independently halide.

In some embodiments, R⁵is -phenyl optionally substituted with 1-2 (e.g., 1) F.

In some embodiments, R⁵is -phenyl optionally substituted with 2 R¹⁰, one R¹⁰is halide and the other R¹⁰is —(C_1-6alkylene)NHSO₂R¹⁹.

In some embodiments, R⁵is -phenyl optionally substituted with 2 R¹⁰, one R¹⁰is halide and the other R¹⁰is —(C_1-4alkylene)NHSO₂R¹⁹.

In some embodiments, R⁵is -phenyl optionally substituted with 2 R¹⁰, one R¹⁰is halide and the other R¹⁰is —(C_1-2alkylene)NHSO₂R¹⁹.

In some embodiments, R⁵is -phenyl optionally substituted with 2 R¹⁰, one R¹⁰is halide and the other R¹⁰is —CH₂NHSO₂R¹⁹.

In some embodiments, R⁵is -phenyl optionally substituted with 2 R¹⁰, one R¹⁰is halide and the other R¹⁰is —CH₂NHSO₂R¹⁹, R¹⁹is —(C_1-4alkyl).

In some embodiments, R⁵is -phenyl optionally substituted with 2 R¹⁰, one R¹⁰is halide and the other R¹⁰is —CH₂NHSO₂R¹⁹, R¹⁹is —(C_1-2alkyl).

In some embodiments, R⁵is -phenyl optionally substituted with 2 R¹⁰, one R¹⁰is halide and the other R¹⁰is —CH₂NHSO₂R¹⁹, R¹⁹is methyl.

In some embodiments, R⁵is -phenyl optionally substituted with 2 R¹⁰, one R¹⁰is F and the other R¹⁰is —CH₂NHSO₂R¹⁹, R¹⁹is —(C_1-2alkyl).

In some embodiments, R⁵is -phenyl optionally substituted with 2 R¹⁰, one R¹⁰is F and the other R¹⁰is —CH₂NHSO₂R¹⁹, R¹⁹is methyl.

In some embodiments, R⁵is -phenyl optionally substituted with 2 R¹⁰, one R¹⁰is halide and the other R¹⁰is —NR¹⁵(C_1-6alkylene)NR⁵⁵R¹⁶.

In some embodiments, R⁵is -phenyl optionally substituted with 2 R¹⁰, one R¹⁰is halide and the other R¹⁰is —NR¹⁵(C_1-5alkylene)NR⁵⁵R¹⁶.

In some embodiments, R⁵is -phenyl optionally substituted with 2 R¹⁰, one R¹⁰is halide and the other R¹⁰is —NR⁵¹(C_1-4alkylene)NR⁵⁵R¹⁶.

In some embodiments, R⁵is -phenyl optionally substituted with 2 R¹⁰, one R¹⁰is halide and the other R¹⁰is —NR^IS(C_1-3alkylene)NR⁵⁵R¹⁶.

In some embodiments, R⁵is -phenyl optionally substituted with 2 R¹⁰, one R¹⁰is halide and the other R¹⁰is —NR¹⁵CH₂CH₂NR¹⁵R¹⁶.

In some embodiments, R⁵is -phenyl optionally substituted with 2 R¹⁰, one R¹⁰is halide and the other R¹⁰is —NHCH₂CH₂NR¹⁵R¹⁶.

In some embodiments, R⁵is -phenyl optionally substituted with 2 R¹⁰, one R¹⁰is halide and the other R¹⁰is —NHCH₂CH₂NR¹⁵R¹⁶, and R¹⁵and R¹⁶are independently selected from —(C_1-6alkyl).

In some embodiments, R⁵is -phenyl optionally substituted with 2 R¹⁰, one R¹⁰is halide and the other R¹⁰is —NHCH₂CH₂NR⁵⁵R¹⁶, and R¹⁵and R¹⁶are independently selected from —(C_1-2alkyl).

In some embodiments, R⁵is -phenyl optionally substituted with 2 R¹⁰, one R¹⁰is halide and the other R¹⁰is —NHCH₂CH₂NR¹⁵R¹⁶, and both R¹⁵and R¹⁶are methyls.

In some embodiments, R⁵is -phenyl optionally substituted with 2 R¹⁰, one R¹⁰is F and the other R¹⁰is —NHCH₂CH₂NR¹⁵R¹⁶, and R¹⁵and R¹⁶are independently selected from —(C_1-2alkyl).

In some embodiments, R⁵is -phenyl optionally substituted with 2 R¹⁰, one R¹⁰is F and the other R¹⁰is —NHCH₂CH₂NR¹⁵R¹⁶, and both R¹⁵and R¹⁶are methyls.

In some embodiments, R⁵is -phenyl optionally substituted with 2 R¹⁰, one R¹⁰is halide and the other R¹⁰is —OR²⁷.

In some embodiments, R⁵is -phenyl optionally substituted with 2 R¹⁰, one R¹⁰is halide and the other R¹⁰is —OCH₂CH₂NR²⁵R²⁶.

In some embodiments, R⁵is -phenyl optionally substituted with 2 R¹⁰, one R¹⁰is halide and the other R¹⁰is —OCH₂CH₂NR²⁵R²⁶, and R²⁵and R²⁶are independently —(C_1-2alkyl).

In some embodiments, R⁵is -phenyl optionally substituted with 2 R¹⁰, one R¹⁰is halide and the other R¹⁰is —OCH₂CH₂NR²⁵R²⁶, and R²⁵and R²⁶are both methyl.

In some embodiments, R⁵is -phenyl optionally substituted with 2 R¹⁰, one R¹⁰is F and the other R¹⁰is —OCH₂CH₂NR²⁵R²⁶, and R²⁵and R²⁶are both methyl.

In some embodiments, R⁵is -phenyl optionally substituted with 2 R¹⁰, one R¹⁰is halide and the other R¹⁰is —OCH₂CH₂heterocyclyl optionally substituted with 1-2 (e.g., 1) R²³.

In some embodiments, R⁵is -phenyl optionally substituted with 2 R¹⁰, one R¹⁰is F and the other R¹⁰is —OCH₂CH₂heterocyclyl optionally substituted with 1-2 (e.g., 1) R²³.

In some embodiments, R⁵is -phenyl optionally substituted with 2 R¹⁰, one R¹⁰is halide and the other R¹⁰is —OH.

In some embodiments, R⁵is -phenyl optionally substituted with 2 R¹⁰, one R¹⁰is halide and the other R¹⁰is —OMe.

In some embodiments, R⁵is -phenyl optionally substituted with 1 —OMe.

In some embodiments, R⁵is selected from the group consisting of:

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In some embodiments, R⁵is -piperidin-1-yl optionally substituted with 1-2 (e.g., 1) R⁹.

In some embodiments, R⁵is -piperidin-1-yl optionally substituted with 1-2 (e.g., 1) R⁹, and each R⁹is independently halide.

In some embodiments, R⁵is -piperazin-1-yl optionally substituted with 1-2 (e.g., 1) R⁹.

In some embodiments, R⁵is -piperazin-1-yl optionally substituted with 1 C_1-3alkyl.

In some embodiments, R⁵is -piperazin-1-yl optionally substituted with 1 methyl.

In some embodiments, R⁵is -morpholinyl optionally substituted with 1-2 (e.g., 1) R⁹.

In some embodiments, R⁵is -morpholin-1-yl optionally substituted with 1-2 (e.g., 1) R⁹.

In some embodiments, R⁵is selected from the group consisting of:

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In some embodiments, each R⁶is independently selected from the group consisting of halide, —(C_1-6alkyl), —(C_2-6alkenyl), —(C_2-6alkynyl), —(C_1-4alkylene)_pheterocyclyl optionally substituted with 1-10 (e.g., 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R¹¹, —(C_2-4alkenylene)_pheterocyclyl optionally substituted with 1-10 (e.g., 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R¹¹, —(C_2-4alkynylene)_pheterocyclyl optionally substituted with 1-10 (e.g., 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R¹¹, —(C_1-4alkylene)_pcarbocyclyl optionally substituted with 1-12 (e.g., 1-11, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R¹², —(C_2-4alkenylene)_pcarbocyclyl optionally substituted with 1-12 (e.g., 1-11, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R¹², —(C_2-4alkynylene)_pcarbocyclyl optionally substituted with 1-12 (e.g., 1-11, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R¹², —(C_1-4alkylene)_paryl optionally substituted with 1-5 (e.g., 1-4, 1-3, 1-2, 1) R¹³, —(C_2-4alkenylene)_paryl optionally substituted with 1-5 (e.g., 1-4, 1-3, 1-2, 1) R¹³, —(C_2-4alkynylene)_paryl optionally substituted with 1-5 (e.g., 1-4, 1-3, 1-2, 1) R¹³, —NHC(═O)R¹⁴, —NR¹⁵R¹⁶, —(C_1-6alkylene)NR¹⁷R¹⁸, —(C_2-6alkenylene)NR¹⁷R¹⁸, —(C_2-6alkynylene)NR¹⁷R¹⁸, and —OR²⁴.

In some embodiments, each R⁶is independently selected from the group consisting of F, Cl, —(C_1-3alkyl), -heterocyclyl optionally substituted with 1-2 (e.g., 1) R¹¹, —CH₂heterocyclyl optionally substituted with with 1-2 (e.g., 1) R¹¹, -carbocyclyl optionally substituted with 1-2 (e.g., 1) R¹², —CH₂carbocyclyl optionally substituted with 1-2 (e.g., 1) R¹², -aryl optionally substituted with 1-2 (e.g., 1) R¹³, —CH₂aryl optionally substituted with 1-2 (e.g., 1) R¹³, —NHC(═O)R¹⁴, —NR¹⁵R¹⁶, —CH₂NR¹⁷R¹⁸, and —OR²⁴.

In some embodiments, each R⁶is independently selected from the group consisting of F, -Me, -heterocyclyl optionally substituted with 1-2 (e.g., 1) halides, -heterocyclyl optionally substituted with 1-2 (e.g., 1) methyls, —CH₂heterocyclyl optionally substituted with with 1-2 (e.g., 1) halides, —CH₂heterocyclyl optionally substituted with with 1-2 (e.g., 1) methyls, -carbocyclyl optionally substituted with 1-2 (e.g., 1) halides, —CH₂carbocyclyl optionally substituted with 1-2 (e.g., 1) halides, -aryl optionally substituted with 1-2 (e.g., 1) halides, —CH₂aryl optionally substituted with 1-2 (e.g., 1) halides, —NHC(═O)R¹⁴, —NH₂, —NHMe, —NHEt, —NHPr, —NMe₂, —CH₂NMe₂, —CH₂NHMe, —CH₂NHEt, —CH₂NHCH₂phenyl, —CH₂NHCH₂carbocylyl, —CH₂OH, and —OR²⁴.

In some embodiments, R⁶is selected from the group consisting of —(C_1-3alkyl), —CH₂heterocyclyl optionally substituted with 1-2 R¹¹, —NHC(═O)R¹⁴, —NR¹⁵R¹⁶, —CH₂NR¹⁷R¹⁸, —CH₂OH, and —OR²⁴.

In some embodiments, at least one R⁶is —(C_1-3alkyl).

In some embodiments, at least one R⁶is —(C_1-2alkyl).

In some embodiments, at least one R⁶is -Me.

In some embodiments, at least one R⁶is halide.

In some embodiments, at least one R⁶is F.

In some embodiments, at least one R⁶is —(C_1-4alkylene)heterocyclyl optionally substituted with 1-2 R¹¹.

In some embodiments, at least one R⁶is —(C_1-3alkylene)heterocyclyl optionally substituted with 1-2 R¹¹.

In some embodiments, at least one R⁶is —(C_1-2alkylene)heterocyclyl optionally substituted with 1-2 R¹¹.

In some embodiments, at least one R⁶is —CH₂pyrrolidinyl optionally substituted with 1-2 R¹¹.

In some embodiments, R⁶is —CH₂pyrrolidinyl optionally substituted with 1-2 R¹¹.

In some embodiments, R⁶is —CH₂pyrrolidinyl optionally substituted with 1-2 R¹¹, and each R¹¹is independently halide.

In some embodiments, R⁶is —CH₂pyrrolidinyl optionally substituted with 1-2 F.

In some embodiments, R⁶is —CH₂pyrrolidinyl substituted with 1-2 F.

In some embodiments, R⁶is —CH₂pyrrolidinyl substituted with 2 F.

In some embodiments, at least one R⁶is —CH₂piperidinyl optionally substituted with 1-2 R¹¹.

In some embodiments, R⁶is —CH₂piperidinyl optionally substituted with 1-2 R¹¹.

In some embodiments, R⁶is —CH₂piperidinyl optionally substituted with 1-2 R¹¹, and each R¹¹is independently halide.

In some embodiments, R⁶is —CH₂piperidinyl optionally substituted with 1-2 F.

In some embodiments, R⁶is

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In some embodiments, at least one R⁶is —(C_1-4alkylene)carbocyclyl optionally substituted with 1-2 (e.g., 1) R¹².

In some embodiments, at least one R⁶is —(C_1-3alkylene)carbocyclyl optionally substituted with 1-2 (e.g., 1) R¹².

In some embodiments, at least one R⁶is —(C_1-2alkylene)carbocyclyl optionally substituted with 1-2 (e.g., 1) R¹².

In some embodiments, at least one R⁶is —CH₂carbocyclyl optionally substituted with 1-2 (e.g., 1) R¹².

In some embodiments, R⁶is —CH₂carbocyclyl optionally substituted with 1-2 (e.g., 1) R¹².

In some embodiments, at least one R⁶is —CH₂aryl optionally substituted with 1-2 (e.g., 1) R¹³,

In some embodiments, at least one R⁶is —CH₂phenyl optionally substituted with 1-2 (e.g., 1) R¹³,

In some embodiments, R⁶is —CH₂phenyl optionally substituted with 1-2 (e.g., 1) R¹³,

In some embodiments, at least one R⁶is —NHC(═O)R⁴.

In some embodiments, R⁶is —NHC(═O)R⁴.

In some embodiments, at least one R⁶is —NHC(═O)R¹⁴and R¹⁴is —(C_1-9alkyl).

In some embodiments, at least one R⁶is —NHC(═O)R¹⁴and R¹⁴is —(C_1-8alkyl).

In some embodiments, at least one R⁶is —NHC(═O)R¹⁴and R¹⁴is —(C_1-7alkyl).

In some embodiments, at least one R⁶is —NHC(═O)R¹⁴and R¹⁴is —(C_1-6alkyl).

In some embodiments, at least one R⁶is —NHC(═O)R¹⁴and R¹⁴is —(C_1-5alkyl).

In some embodiments, R⁶is —NHC(═O)R¹⁴and R¹⁴is —(C_1-5alkyl).

In some embodiments, at least one R⁶is —NHC(═O)R¹⁴and R¹⁴is —(C_1-4alkyl).

In some embodiments, R⁶is —NHC(═O)R¹⁴and R¹⁴is —(C_1-4alkyl).

In some embodiments, at least one R⁶is —NHC(═O)R¹⁴and R¹⁴is —(C_1-3alkyl).

In some embodiments, R⁶is —NHC(═O)R⁴and R¹⁴is —(C_1-3alkyl).

In some embodiments, at least one R⁶is —NHC(═O)R¹⁴and R¹⁴is —(C_1-2alkyl).

In some embodiments, R⁶is —NHC(═O)R⁴and R¹⁴is —(C_1-2alkyl).

In some embodiments, R⁶is —NHC(═O)R¹⁴and R¹⁴is —CF₃.

In some embodiments, at least one R⁶is —NHC(═O)R¹⁴and R¹⁴is —(C_2-5alkyl).

In some embodiments, R⁶is —NHC(═O)R⁴and R¹⁴is —(C_2-5alkyl).

In some embodiments, at least one R⁶is —NHC(═O)R¹⁴and R¹⁴is —(C_3-4alkyl).

In some embodiments, at least one R⁶is —NHC(═O)R¹⁴, R¹⁴is -aryl optionally substituted with 1-2 (e.g., 1) R²¹.

In some embodiments, at least one R⁶is —NHC(═O)R¹⁴, R¹⁴is -phenyl optionally substituted with 1-2 (e.g., 1) R²¹.

In some embodiments, at least one R⁶is —NHC(═O)R¹⁴, R¹⁴is —CH₂aryl optionally substituted with 1-2 (e.g., 1) R²¹.

In some embodiments, at least one R⁶is —NHC(═O)R¹⁴, R¹⁴is —CH₂phenyl optionally substituted with 1-2 (e.g., 1) R²¹.

In some embodiments, at least one R⁶is —NHC(═O)R¹⁴, R¹⁴is -heteroaryl optionally substituted with 1-2 (e.g., 1) R²⁰.

In some embodiments, at least one R⁶is —NHC(═O)R¹⁴, R¹⁴is -carbocyclyl optionally substituted with 1-2 (e.g., 1) R²².

In some embodiments, at least one R⁶is —NHC(═O)R¹⁴, R¹⁴is -cyclopropyl optionally substituted with 1-2 (e.g., 1) R²².

In some embodiments, at least one R⁶is —NHC(═O)R¹⁴, R¹⁴is -cyclobutyl optionally substituted with 1-2 (e.g., 1) R²².

In some embodiments, at least one R⁶is —NHC(═O)R¹⁴, R¹⁴is -cyclopentyl optionally substituted with 1-2 (e.g., 1) R²².

In some embodiments, at least one R⁶is —NHC(═O)R¹⁴, R¹⁴is -cyclohexyl optionally substituted with 1-2 (e.g., 1) R²².

In some embodiments, at least one R⁶is —NHC(═O)R¹⁴, R¹⁴is —CH₂carbocyclyl optionally substituted with 1-2 (e.g., 1) R²².

In some embodiments, at least one R⁶is —NHC(═O)R¹⁴, R¹⁴is —CH₂cyclopropyl optionally substituted with 1-2 (e.g., 1) R²².

In some embodiments, at least one R⁶is —NR¹⁵R¹⁶.

In some embodiments, at least one R⁶is —NR¹⁵R¹⁶, and R¹⁵and R¹⁶are independently selected from the group consisting of H and —(C_1-6alkyl).

In some embodiments, at least one R⁶is —NR¹⁵R¹⁶, and R¹⁵and R¹⁶are independently selected from the group consisting of H and —(C_1-5alkyl).

In some embodiments, at least one R⁶is —NR¹⁵R¹⁶, and R¹⁵and R¹⁶are independently selected from the group consisting of H and —(C_1-4alkyl).

In some embodiments, at least one R⁶is —NR¹⁵R¹⁶, and R¹⁵and R¹⁶are independently selected from the group consisting of H and —(C_1-3alkyl).

In some embodiments, at least one R⁶is —NR¹⁵R¹⁶, and R¹⁵and R¹⁶are independently selected from the group consisting of H and —(C_1-2alkyl).

In some embodiments, at least one R⁶is —NR¹⁵R¹⁶, and R¹⁵and R¹⁶are independently selected from the group consisting of H and methyl.

In some embodiments, at least one R⁶is —NH₂.

In some embodiments, R⁶is —NH₂.

In some embodiments, at least one R⁶is —NHR¹⁶and R¹⁶is —(C_1-4alkyl).

In some embodiments, at least one R⁶is —NHR¹⁶and R¹⁶is —(C_1-3alkyl).

In some embodiments, at least one R⁶is —NHR¹⁶and R¹⁶is —(C_1-2alkyl).

In some embodiments, R⁶is —NHR⁶and R¹⁶is —(C_1-2alkyl).

In some embodiments, at least one R⁶is —NHR⁶and R¹⁶is —CH₂aryl optionally substituted with 1-2 (e.g., 1) R²¹.

In some embodiments, at least one R⁶is —NHR⁶and R¹⁶is —CH₂phenyl optionally substituted with 1-2 (e.g., 1) R²¹.

In some embodiments, at least one R⁶is —NHR¹⁶and R¹⁶is —CH₂carbocyclyl optionally substituted with 1-2 (e.g., 1) R²².

In some embodiments, at least one R⁶is —NHR¹⁶and R¹⁶is —CH₂cyclopropyl optionally substituted with 1-2 (e.g., 1) R²².

In some embodiments, at least one R⁶is —NHR¹⁶and R¹⁶is —CH₂cyclobutyl optionally substituted with 1-2 (e.g., 1) R²².

In some embodiments, at least one R⁶is —NHR¹⁶and R¹⁶is —CH₂cyclopentyl optionally substituted with 1-2 (e.g., 1) R²².

In some embodiments, at least one R⁶is —NHR¹⁶and R¹⁶is —CH₂cyclohexyl optionally substituted with 1-2 (e.g., 1) R²².

In some embodiments, at least one R⁶is —(C_1-6alkylene)NR¹⁷R¹⁸.

In some embodiments, at least one R⁶is —(C_1-salkylene)NR¹⁷R¹⁸.

In some embodiments, at least one R⁶is —(C_1-4alkylene)NR¹⁷R¹⁸.

In some embodiments, at least one R⁶is —(C_1-3alkylene)NR¹⁷R¹⁸.

In some embodiments, at least one R⁶is —(C_1-2alkylene)NR¹⁷R¹⁸.

In some embodiments, at least one R⁶is —CH₂NR¹⁷R¹⁸.

In some embodiments, R⁶is —CH₂NR¹⁷R¹⁸.

In some embodiments, at least one R⁶is —CH₂NR¹⁷R¹⁸, and R¹⁷and R¹⁸are independently selected from the group consisting of H and —(C_1-6alkyl).

In some embodiments, at least one R⁶is —CH₂NR¹⁷R¹⁸, and R¹⁷and R¹⁸are independently selected from the group consisting of H and —(C_1-5alkyl).

In some embodiments, at least one R⁶is —CH₂NR¹⁷R¹⁸, and R¹⁷and R¹⁸are independently selected from the group consisting of H and —(C_1-4alkyl).

In some embodiments, at least one R⁶is —CH₂NR¹⁷R¹⁸, and R¹⁷and R¹⁸are independently selected from the group consisting of H and —(C_1-3alkyl).

In some embodiments, at least one R⁶is —CH₂NR¹⁷R¹⁸, and R¹⁷and R¹⁸are independently selected from the group consisting of H and —(C_1-2alkyl).

In some embodiments, at least one R⁶is —CH₂NR¹⁷R¹⁸, and R¹⁷and R¹⁸are independently selected from the group consisting of H and methyl.

In some embodiments, R⁶is —CH₂NR¹⁷R¹⁸, and R¹⁷and R¹⁸are independently selected from the group consisting of H and methyl.

In some embodiments, at least one R⁶is —CH₂NH₂.

In some embodiments, R⁶is —CH₂NH₂.

In some embodiments, at least one R⁶is —CH₂NMe₂.

In some embodiments, R⁶is —CH₂NMe₂.

In some embodiments, at least one R⁶is —CH₂NHR¹⁸and R¹⁸is —(C_1-4alkyl).

In some embodiments, at least one R⁶is —CH₂NHR¹⁸and R¹⁸is —(C_1-3alkyl).

In some embodiments, at least one R⁶is —CH₂NHR¹⁸and R¹⁸is —(C_1-2alkyl).

In some embodiments, R⁶is —CH₂NHR¹⁸and R¹⁸is —(C_1-2alkyl).

In some embodiments, at least one R⁶is —CH₂NHR¹⁸and R¹⁸is —CH₂aryl optionally substituted with 1-2 (e.g., 1) R²¹.

In some embodiments, at least one R⁶is —CH₂NHR¹⁸and R¹⁸is —CH₂phenyl optionally substituted with 1-2 (e.g., 1) R²¹.

In some embodiments, R⁶is —CH₂NHR¹⁸and R¹⁸is —CH₂phenyl optionally substituted with 1-2 (e.g., 1) R²¹.

In some embodiments, at least one R⁶is —CH₂NHR¹⁸and R¹⁸is —CH₂carbocyclyl optionally substituted with 1-2 (e.g., 1) R²².

In some embodiments, at least one R⁶is —CH₂NHR¹⁸and R¹⁸is —CH₂cyclopropyl optionally substituted with 1-2 (e.g., 1) R²².

In some embodiments, R⁶is —CH₂NHR¹⁸and R¹⁸is —CH₂cyclopropyl optionally substituted with 1-2 (e.g., 1) R²².

In some embodiments, at least one R⁶is —CH₂NHR¹⁸and R¹⁸is —CH₂cyclobutyl optionally substituted with 1-2 (e.g., 1) R²².

In some embodiments, R⁶is —CH₂NHR¹⁸and R¹⁸is —CH₂cyclobutyl optionally substituted with 1-2 (e.g., 1) R²².

In some embodiments, at least one R⁶is —CH₂NHR¹⁸and R¹⁸is —CH₂cyclopentyl optionally substituted with 1-2 (e.g., 1) R²².

In some embodiments, R⁶is —CH₂NHR¹⁸and R¹⁸is —CH₂cyclopentyl optionally substituted with 1-2 (e.g., 1) R²².

In some embodiments, at least one R⁶is —CH₂NHR¹⁸and R¹⁸is —CH₂cyclohexyl optionally substituted with 1-2 (e.g., 1) R²².

In some embodiments, R⁶is —CH₂NHR¹⁸and R¹⁸is —CH₂cyclohexyl optionally substituted with 1-2 (e.g., 1) R²².

In some embodiments, at least one R⁶is —OR²⁴.

In some embodiments, at least one R⁶is —OH.

In some embodiments, R⁶is —OH.

In some embodiments, at least one R⁶is —(C_1-4alkylene)OR²⁴.

In some embodiments, R⁶is —(C_1-4alkylene)OR²⁴.

In some embodiments, R⁶is —(C_1-3alkylene)OR²⁴.

In some embodiments, R⁶is —(C_1-2alkylene)OR²⁴.

In some embodiments, R⁶is —CH₂OR²⁴.

In some embodiments, R⁶is —CH₂OH.

In some embodiments, at least one R⁶is —OR²⁴and R²⁴is —(C_1-3alkyl).

In some embodiments, at least one R⁶is —OR²⁴and R²⁴is —(C_1-2alkyl).

In some embodiments, at least one R⁶is —OMe.

In some embodiments, R⁶is —OMe.

In some embodiments, at least one R⁶is —OR²⁴and R²⁴is -heterocyclyl optionally substituted with 1-2 (e.g., 1) R²³.

In some embodiments, R⁶is —OR²⁴and R²⁴is -heterocyclyl optionally substituted with 1-2 (e.g., 1) R²³.

In some embodiments, at least one R⁶is —OR²⁴and R²⁴is -carbocyclyl optionally substituted with 1-2 (e.g., 1) R²².

In some embodiments, R⁶is —OR²⁴and R²⁴is -carbocyclyl optionally substituted with 1-2 (e.g., 1) R²².

In some embodiments, at least one R⁶is —OR²⁴and R²⁴is —(C_1-4alkylene)heterocyclyl optionally substituted with 1-2 (e.g., 1) R²³.

In some embodiments, at least one R⁶is —OR²⁴and R²⁴is —(CH₂CH₂)heterocyclyl optionally substituted with 1-2 (e.g., 1) R²³.

In some embodiments, R⁶is —OR²⁴and R²⁴is —(CH₂CH₂)heterocyclyl optionally substituted with 1-2 (e.g., 1) R²³.

In some embodiments, at least one R⁶is —OR²⁴and R²⁴is —(C_1-4alkylene)NR²⁵R²⁶and R²⁵and R²⁶are independently —(C_1-4alkyl).

In some embodiments, at least one R⁶is —OR²⁴and R²⁴is —(CH₂CH₂)NR²⁵R²⁶and R²⁵and R²⁶are independently —(C_1-2alkyl).

In some embodiments, at least one R⁶is —OR²⁴and R²⁴is —(CH₂CH₂)NMe₂.

In some embodiments, R⁶is —OR²⁴and R²⁴is —(CH₂CH₂)NMe₂.

In some embodiments, at least one R⁶is —OR²⁴and R²⁴is —(C_1-4alkylene)aryl optionally substituted with 1-2 (e.g., 1) R²¹, and each R²¹is independently halide.

In some embodiments, at least one R⁶is —OR²⁴and R²⁴is —(CH₂CH₂)phenyl optionally substituted with 1-2 (e.g., 1) R²¹, and each R²¹is independently halide.

In some embodiments, R⁶is —OR²⁴and R²⁴is —(CH₂CH₂)phenyl optionally substituted with 1-2 (e.g., 1) R²¹, and each R²¹is independently halide.

In some embodiments, at least one R⁶is —OR²⁴and R²⁴is —(CH₂)phenyl optionally substituted with 1-2 (e.g., 1) R²¹, and each R²¹is independently halide.

In some embodiments, R⁶is —OR²⁴and R²⁴is —(CH₂)phenyl optionally substituted with 1-2 (e.g., 1) R²¹, and each R²¹is independently halide.

In some embodiments, each R⁷is independently selected from the group consisting of —(C_1-4alkyl), —(C_2-4alkenyl), —(C_2-4alkynyl), halide, —CF₃, and —CN.

In some embodiments, each R⁷is independently selected from the group consisting of methyl, F, Cl, —CF₃, and —CN.

In some embodiments, at least one R⁷is —(C_1-4alkyl).

In some embodiments, at least one R⁷is —(C_1-3alkyl).

In some embodiments, at least one R⁷is —(C_1-2alkyl).

In some embodiments, at least one R⁷is methyl.

In some embodiments, at least one R⁷is halide.

In some embodiments, at least one R⁷is F.

In some embodiments, each R⁸is independently selected from the group consisting of —(C_1-6alkyl), —(C_2-6alkenyl), —(C_2-6alkynyl), halide, —CF₃, —OCH₃, —CN, and —C(═O)R¹⁹.

In some embodiments, each R⁸is independently selected from the group consisting of methyl, F, Cl, —CF₃, —OCH₃, —CN, and —C(═O)Me.

In some embodiments, at least one R⁸is halide.

In some embodiments, at least one R⁸is F.

In some embodiments, at least one R⁸is —(C_1-4alkyl).

In some embodiments, at least one R⁸is —(C_1-3alkyl).

In some embodiments, at least one R⁸is —(C_1-2alkyl).

In some embodiments, at least one R⁸is methyl.

In some embodiments, R⁸is methyl.

In some embodiments, at least one R⁸is —C(═O)(C_1-3alkyl).

In some embodiments, at least one R⁸is —C(═O)Me.

In some embodiments, R⁸is —C(═O)Me.

In some embodiments, each R⁹is independently selected from the group consisting of —(C_1-6alkyl), —(C_2-6alkenyl), —(C_2-6alkynyl), halide, —CF₃, —CN, and —OCH₃.

In some embodiments, each R⁹is independently selected from the group consisting of methyl, F, Cl, —CF₃, —CN, and —OCH₃.

In some embodiments, each R¹⁰is independently selected from the group consisting of —(C_1-6alkyl), —(C_2-6alkenyl), —(C_2-6alkynyl), halide, —CF₃, —CN, —(C_1-6alkylene)_pNHSO₂R¹⁹, —(C_2-6alkenylene)_pNHSO₂R¹⁹, —(C_2-6alkynylene)_pNHSO₂R¹⁹, —NR⁵(C_1-6alkylene)NR¹⁵R¹⁶, —NR¹⁵(C_2-6alkenylene)NR¹⁵R¹⁶, —NR¹⁵(C_2-6alkynylene)NR¹⁵R¹⁶, —(C_1-6alkylene)_pNR¹⁵R¹⁶, —(C_2-6alkenylene)_pNR¹⁵R¹⁶, —(C_2-6alkynylene)_pNR¹⁵R¹⁶, and —OR²⁷.

In some embodiments, each R¹¹is independently selected from the group consisting of amino, —(C_1-4alkyl), —(C_2-4alkenyl), —(C_2-4alkynyl), halide, —CF₃, and —CN.

In some embodiments, each R¹¹is independently selected from the group consisting of amino, methyl, F, Cl, —CF₃, and —CN.

In some embodiments, each R¹²is independently selected from the group consisting of —(C_1-4alkyl), —(C_2-4alkenyl), —(C_2-4alkynyl), halide, —CF₃, and —CN.

In some embodiments, each R¹²is independently selected from the group consisting of methyl, F, Cl, —CF₃, and —CN.

In some embodiments, each R¹³is independently selected from the group consisting of —(C_1-4alkyl), —(C_2-4alkenyl), —(C_2-4alkynyl), halide, —CF₃, and —CN.

In some embodiments, each R¹³is independently selected from the group consisting of methyl, F, Cl, —CF₃, and —CN.

In some embodiments, each R¹⁴is independently selected from the group consisting of —(C_1-9alkyl), —(C_1-4haloalkyl), —(C_2-9alkenyl), —(C_2-9alkynyl), -heteroaryl optionally substituted with 1-4 (e.g., 1-3, 1-2, 1) R²⁰, -aryl optionally substituted with 1-5 (e.g., 1-4, 1-3, 1-2, 1) R²¹, —CH₂aryl optionally substituted with 1-5 (e.g., 1-4, 1-3, 1-2, 1) R²¹, -carbocyclyl optionally substituted with 1-12 (e.g., 1-11, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R²², —CH₂carbocyclyl optionally substituted with 1-12 (e.g., 1-11, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R²², —(C_1-4alkylene)_pNR²⁵R²⁶, —(C_2-4alkenylene)_pNR²⁵R²⁶, —(C_2-4alkynylene)_pNR²⁵R²⁶, -heterocyclyl optionally substituted with 1-10 (e.g., 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R²³, and —CH₂heterocyclyl optionally substituted with 1-10 (e.g., 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R²³.

In some embodiments, each R¹⁵is independently selected from the group consisting of H, —(C_1-6alkyl), —(C_2-6alkenyl), and —(C_2-6alkynyl).

In some embodiments, each R¹⁶is independently selected from the group consisting of H, —(C_1-6alkyl), —(C_2-6alkenyl), —(C_2-6alkynyl), —CH₂aryl optionally substituted with 1-5 (e.g., 1-4, 1-3, 1-2, 1) R²¹, and —CH₂carbocyclyl optionally substituted with 1-12 (e.g., 1-11, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R²².

In some embodiments, each R¹⁷is independently selected from the group consisting of H, —(C_1-6alkyl), —(C_2-6alkenyl), and —(C_2-6alkynyl).

In some embodiments, each R¹⁸is independently selected from the group consisting of H, —(C_1-6alkyl), —(C_2-6alkenyl), —(C_2-6alkynyl), —CH₂aryl optionally substituted with 1-5 (e.g., 1-4, 1-3, 1-2, 1) R²¹and —CH₂carbocyclyl optionally substituted with 1-12 (e.g., 1-11, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R²².

In some embodiments, each R¹⁹is independently selected from the group consisting of —(C_1-6alkyl), —(C_2-6alkenyl), and —(C_2-6alkynyl).

In some embodiments, each R²⁰is independently selected from the group consisting of —(C_1-4alkyl), —(C_2-4alkenyl), —(C_2-4alkynyl), halide, —CF₃, and —CN.

In some embodiments, each R²⁰is independently selected from the group consisting of methyl, F, Cl, —CF₃, and —CN.

In some embodiments, each R²¹is independently selected from the group consisting of —(C_1-4alkyl), —(C_2-4alkenyl), —(C_2-4alkynyl), halide, —CF₃, and —CN.

In some embodiments, each R²¹is independently selected from the group consisting of methyl, F, Cl, —CF₃, and —CN.

In some embodiments, each R²²is independently selected from the group consisting of —(C_1-4alkyl), —(C_2-4alkenyl), —(C_2-4alkynyl), halide, —CF₃, and —CN.

In some embodiments, each R²²is independently selected from the group consisting of methyl, F, Cl, —CF₃, and —CN.

In some embodiments, each R²³is independently selected from the group consisting of —(C_1-4alkyl), —(C_2-4alkenyl), —(C_2-4alkynyl), halide, —CF₃, and —CN.

In some embodiments, each R²³is independently selected from the group consisting of methyl, F, Cl, —CF₃, and —CN.

In some embodiments, R²⁴is selected from the group consisting of H, —(C_1-6alkyl), —(C_2-6alkenyl), —(C_2-6alkynyl), —(C_1-4alkylene)_pheterocyclyl optionally substituted with 1-10 (e.g., 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R²³, —(C_2-4alkenylene)_pheterocyclyl optionally substituted with 1-10 (e.g., 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R²³, —(C_2-4alkynylene)_pheterocyclyl optionally substituted with 1-10 (e.g., 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R²³, —(C_1-4alkylene)_pcarbocyclyl optionally substituted with 1-12 (e.g., 1-11, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R²², —(C_2-4alkenylene)_pcarbocyclyl optionally substituted with 1-12 (e.g., 1-11, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R²², —(C_2-4alkynylene)_pcarbocyclyl optionally substituted with 1-12 (e.g., 1-11, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R²², —(C_1-4alkylene)_paryl optionally substituted with 1-5 (e.g., 1-4, 1-3, 1-2, 1) R²¹, —(C_2-4alkenylene)_paryl optionally substituted with 1-5 (e.g., 1-4, 1-3, 1-2, 1) R²¹, —(C_2-4alkynylene)_paryl optionally substituted with 1-5 (e.g., 1-4, 1-3, 1-2, 1) R²¹, —(C_1-6alkylene)_pNR²⁵R²⁶, —(C_2-4alkenylene)_pNR²⁵R²⁶, and —(C_2-4alkynylene)_pNR²⁵R²⁶.

In some embodiments, each R²⁵is independently selected from the group consisting of H, —(C_1-6alkyl), —(C_2-6alkenyl), and —(C_2-6alkynyl).

In some embodiments, each R²⁶is independently selected from the group consisting of H, —(C_1-6alkyl), —(C_2-6alkenyl), and —(C_2-6alkynyl).

In some embodiments, R²⁷is selected from the group consisting of H, —(C_1-6alkyl), —(C_2-6alkenyl), —(C_2-6alkynyl), —(C_1-4alkylene)_pheterocyclyl optionally substituted with 1-10 (e.g., 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R²³, —(C_2-4alkenylene)_pheterocyclyl optionally substituted with 1-10 (e.g., 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R²³, —(C_2-4alkynylene)_pheterocyclyl optionally substituted with 1-10 (e.g., 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R²³, —(C_1-6alkylene)_pNR²⁵R²⁶, —(C_2-6alkenylene)_pNR²⁵R²⁶, and —(C_2-6alkynylene)NR²⁵R²⁶.

In some embodiments, each p is independently an integer of 0 or 1.

In some embodiments, p is 0.

In some embodiments, p is 1.

Illustrative compounds of Formula (I) are shown in Table 1.

TABLE 1

100

101

102

103

104

105

106

107

108

109

110

111

112

113

114

115

116

117

118

119

120

121

122

123

124

125

126

127

128

129

130

131

132

133

134

135

136

137

138

139

140

141

142

143

144

145

146

147

148

149

150

151

152

153

154

155

156

157

158

159

160

161

162

163

164

165

166

167

168

169

170

171

172

173

174

175

176

177

178

179

180

181

182

183

184

185

186

187

188

189

190

191

192

193

194

195

196

197

198

199

200

201

202

203

204

205

206

207

208

209

210

211

212

213

214

215

216

217

218

219

220

221

222

223

224

225

226

227

228

229

230

231

232

233

234

235

236

237

238

239

240

241

242

243

244

245

246

247

248

249

250

251

252

253

254

255

256

257

258

259

260

261

262

263

264

265

266

267

268

269

270

271

272

273

274

275

276

277

278

279

280

281

282

283

284

285

286

287

288

289

290

291

292

293

294

295

296

297

298

299

300

301

302

303

304

305

306

307

308

309

310

311

312

313

314

315

316

317

318

319

320

321

322

323

324

325

326

327

328

329

330

331

332

333

334

335

336

337

338

339

340

341

342

343

344

345

346

347

348

349

350

351

352

353

354

355

356

357

358

359

360

361

362

363

364

365

366

367

368

369

370

371

372

373

374

375

376

377

378

379

380

381

382

383

384

385

386

387

388

389

390

391

392

393

394

395

396

397

398

399

400

401

402

403

404

405

406

407

408

409

410

411

412

413

414

415

416

417

418

419

420

421

422

423

424

425

426

427

428

429

430

431

432

433

434

435

436

437

438

439

440

441

442

443

444

445

446

447

448

449

450

451

452

453

454

455

456

457

458

459

460

461

462

463

464

465

466

467

468

469

470

471

472

273

474

475

476

477

478

479

480

481

482

483

484

485

486

487

488

489

490

491

492

493

494

495

496

497

498

499

500

501

502

503

504

505

506

507

508

509

510

511

512

513

514

515

516

517

518

519

520

521

522

523

524

525

526

527

528

529

530

531

532

533

534

535

536

537

538

539

540

541

542

543

544

545

546

547

548

549

550

551

552

553

554

555

556

557

558

559

560

561

562

563

564

565

566

567

568

569

570

571

572

573

574

575

576

577

578

579

580

581

582

583

584

585

586

587

588

589

590

591

592

593

594

595

596

597

598

599

600

601

602

603

604

605

606

607

608

609

610

611

612

613

614

615

616

617

618

619

620

621

622

623

624

625

626

627

628

629

630

631

632

633

634

635

636

637

638

639

640

641

642

643

644

645

646

647

648

649

650

651

652

653

654

655

656

657

658

659

660

661

662

663

664

665

666

667

668

669

670

671

672

673

674

675

676

677

678

679

680

681

682

683

684

685

686

687

688

689

690

691

692

693

694

695

696

697

698

699

700

701

702

703

704

705

706

707

708

709

710

711

712

713

714

715

716

717

718

719

720

721

722

723

724

725

726

727

728

729

730

731

732

733

734

735

736

737

738

739

740

741

742

743

744

745

746

747

748

749

750

751

752

753

754

755

756

757

758

759

760

761

762

763

764

765

766

767

768

769

770

771

772

773

774

775

776

777

778

779

780

781

782

783

784

785

786

787

788

789

790

791

792

793

794

795

796

797

798

799

800

801

802

803

804

805

806

807

808

809

810

811

812

813

814

815

816

817

818

819

820

821

822

823

824

825

826

827

828

829

830

831

832

833

834

835

836

837

838

839

840

841

842

843

844

845

846

847

848

849

850

851

852

853

854

855

856

857

858

859

860

861

862

863

864

865

866

867

868

869

870

871

872

873

874

875

876

877

878

879

880

881

882

883

884

885

886

887

888

889

890

891

892

893

894

895

896

897

898

899

900

901

902

903

904

905

906

907

908

909

910

911

912

913

914

915

916

917

918

919

920

921

922

923

924

925

926

927

928

929

930

931

932

933

934

935

936

937

938

939

940

941

942

943

944

945

946

947

948

949

950

951

952

953

954

955

956

957

958

959

960

961

962

963

964

965

966

967

968

969

970

971

972

973

974

975

976

977

978

979

980

981

982

983

984

985

986

987

988

989

990

991

992

993

994

Administration and Pharmaceutical Compositions

Some embodiments include pharmaceutical compositions comprising: (a) a therapeutically effective amount of a compound provided herein, or its corresponding enantiomer, diastereoisomer or tautomer, or pharmaceutically acceptable salt; and (b) a pharmaceutically acceptable carrier.

The compounds provided herein may also be useful in combination (administered together or sequentially) with other known agents.

Non-limiting examples of diseases which can be treated with a combination of a compound of Formula (I) and other known agents are colorectal cancer, ovarian cancer, retinitis pigmentosa, macular degeneration, diabetic retinopathy, idiopathic pulmonary fibrosis/pulmonary fibrosis, and osteoarthritis.

In some embodiments, colorectal cancer can be treated with a combination of a compound of Formula (I) and one or more of the following drugs: 5-Fluorouracil (5-FU), which can be administered with the vitamin-like drug leucovorin (also called folinic acid); capecitabine (XELODA®), irinotecan (CAMPOSTAR®), oxaliplatin (ELOXATIN®). Examples of combinations of these drugs which could be further combined with a compound of Formula (I) are FOLFOX (5-FU, leucovorin, and oxaliplatin), FOLFIRI (5-FU, leucovorin, and irinotecan), FOLFOXIRI (leucovorin, 5-FU, oxaliplatin, and irinotecan) and CapeOx (Capecitabine and oxaliplatin). For rectal cancer, chemo with 5-FU or capecitabine combined with radiation may be given before surgery (neoadjuvant treatment).

In some embodiments, ovarian cancer can be treated with a combination of a compound of Formula (I) and one or more of the following drugs: Topotecan, Liposomal doxorubicin (DOXIL®), Gemcitabine (GEMZAR®), Cyclophosphamide (CYTOXAN®), Vinorelbine (NAVELBINE®), Ifosfamide (IFEX®), Etoposide (VP-16), Altretamine (HEXALEN®), Capecitabine (XELODA®), Irinotecan (CPT-11, CAMPTOSAR®), Melphalan, Pemetrexed (ALIMTA®) and Albumin bound paclitaxel (nab-paclitaxel, ABRAXANE®). Examples of combinations of these drugs which could be further combined with a compound of Formula (I) are TIP (paclitaxel [Taxol], ifosfamide, and cisplatin), VeIP (vinblastine, ifosfamide, and cisplatin) and VIP (etoposide [VP-16], ifosfamide, and cisplatin).

In some embodiments, a compound of Formula (I) can be used to treat cancer in combination with any of the following methods: (a) Hormone therapy such as aromatase inhibitors, LHRH [luteinizing hormone-releasing hormone] analogs and inhibitors, and others; (b) Ablation or embolization procedures such as radiofrequency ablation (RFA), ethanol (alcohol) ablation, microwave thermotherapy and cryosurgery (cryotherapy); (c) Chemotherapy using alkylating agents such as cisplatin and carboplatin, oxaliplatin, mechlorethamine, cyclophosphamide, chlorambucil and ifosfamide; (d) Chemotherapy using anti-metabolites such as azathioprine and mercaptopurine; (e) Chemotherapy using plant alkaloids and terpenoids such as vinca alkaloids (i.e. Vincristine, Vinblastine, Vinorelbine and Vindesine) and taxanes; (f) Chemotherapy using podophyllotoxin, etoposide, teniposide and docetaxel; (g) Chemotherapy using topoisomerase inhibitors such as irinotecan, topotecan, amsacrine, etoposide, etoposide phosphate, and teniposide; (h) Chemotherapy using cytotoxic antibiotics such as actinomycin, anthracyclines, doxorubicin, daunorubicin, valrubicin, idarubicin, epirubicin, bleomycin, plicamycin and mitomycin; (i) Chemotherapy using tyrosine-kinase inhibitors such as Imatinib mesylate (GLEEVEC®, also known as STI-571), Gefitinib (Iressa, also known as ZD1839), Erlotinib (marketed as TARCEVA®), Bortezomib (VELCADE®), tamoxifen, tofacitinib, crizotinib, Bcl-2 inhibitors (e.g. obatoclax in clinical trials, ABT-263, and Gossypol), PARP inhibitors (e.g. Iniparib, Olaparib in clinical trials), PI3K inhibitors (e.g. perifosine in a phase III trial), VEGF Receptor 2 inhibitors (e.g. Apatinib), AN-152, (AEZS-108), Braf inhibitors (e.g. vemurafenib, dabrafenib and LGX818), MEK inhibitors (e.g. trametinib and MEK162), CDK inhibitors, (e.g. PD-0332991), salinomycin and Sorafenib; (j) Chemotherapy using monoclonal antibodies such as Rituximab (marketed as MABTHERA® or RITUXAN®), Trastuzumab (Herceptin also known as ErbB2), Cetuximab (marketed as ERBITUX®), and Bevacizumab (marketed as AVASTIN®); and (k) radiation therapy.

In some embodiments, diabetic retinopathy can be treated with a combination of a compound of Formula (I) and one or more of the following natural supplements: Bilberry, Butcher's broom, Ginkgo, Grape seed extract, and Pycnogenol (Pine bark).

In some embodiments, idiopathic pulmonary fibrosis/pulmonary fibrosis can be treated with a combination of a compound of Formula (I) and one or more of the following drugs: pirfenidone (pirfenidone was approved for use in 2011 in Europe under the brand name Esbriet®), prednisone, azathioprine, N-acetylcysteine, interferon-γ 1b, bosentan (bosentan is currently being studied in patients with IPF, [The American Journal of Respiratory and Critical Care Medicine (2011), 184(1), 92-9]), Nintedanib (BIBF 1120 and Vargatef), QAX576 [British Journal of Pharmacology (2011), 163(1), 141-172], and anti-inflammatory agents such as corticosteroids.

In some embodiments, a compound of Formula (I) can be used to treat idiopathic pulmonary fibrosis/pulmonary fibrosis in combination with any of the following methods: oxygen therapy, pulmonary rehabilitation and surgery.

In some embodiments, a compound of Formula (I) can be used to treat osteoarthritis in combination with any of the following methods: (a) Nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen, naproxen, aspirin and acetaminophen; (b) physical therapy; (c) injections of corticosteroid medications; (d) injections of hyaluronic acid derivatives (e.g. Hyalgan, Synvisc); (e) narcotics, like codeine; (f) in combination with braces and/or shoe inserts or any device that can immobilize or support your joint to help you keep pressure off it (e.g., splints, braces, shoe inserts or other medical devices); (g) realigning bones (osteotomy); (h) joint replacement (arthroplasty); and (i) in combination with a chronic pain class.

In some embodiments, macular degeneration can be treated with a combination of a compound of Formula (I) and one or more of the following drugs: Bevacizumab (Avastin®), Ranibizumab (Lucentis®), Pegaptanib (Macugen), Aflibercept (Eylea®), verteporfin (Visudyne®) in combination with photodynamic therapy (PDT) or with any of the following methods: (a) in combination with laser to destroy abnormal blood vessels (photocoagulation); and (b) in combination with increased vitamin intake of antioxidant vitamins and zinc.

In some embodiments, retinitis pigmentosa can be treated with a combination of a compound of Formula (I) and one or more of the following drugs: UF-021 (Ocuseva™), vitamin A palmitate and pikachurin or with any of the following methods: (a) with the Argus® II retinal implant; and (b) with stem cell and/or gene therapy.

Administration of the compounds disclosed herein or the pharmaceutically acceptable salts thereof can be via any of the accepted modes of administration, including, but not limited to, orally, subcutaneously, intravenously, intranasally, topically, transdermally, intraperitoneally, intramuscularly, intrapulmonarilly, vaginally, rectally, ontologically, neuro-otologically, intraocularly, subconjuctivally, via anterior eye chamber injection, intravitreally, intraperitoneally, intrathecally, intracystically, intrapleurally, via wound irrigation, intrabuccally, intra-abdominally, intra-articularly, intra-aurally, intrabronchially, intracapsularly, intrameningeally, via inhalation, via endotracheal or endobronchial instillation, via direct instillation into pulmonary cavities, intraspinally, intrasynovially, intrathoracically, via thoracostomy irrigation, epidurally, intratympanically, intracisternally, intravascularly, intraventricularly, intraosseously, via irrigation of infected bone, or via application as part of any admixture with a prosthetic devices. In some embodiments, the administration method includes oral or parenteral administration.

Compounds provided herein intended for pharmaceutical use may be administered as crystalline or amorphous products. Pharmaceutically acceptable compositions may include solid, semi-solid, liquid, solutions, colloidal, liposomes, emulsions, suspensions, complexes, coacervates and aerosols. Dosage forms, such as, e.g., tablets, capsules, powders, liquids, suspensions, suppositories, aerosols, implants, controlled release or the like. They may be obtained, for example, as solid plugs, powders, or films by methods such as precipitation, crystallization, milling, grinding, supercritical fluid processing, coacervation, complex coacervation, encapsulation, emulsification, complexation, freeze drying, spray drying, or evaporative drying. Microwave or radio frequency drying may be used for this purpose. The compounds can also be administered in sustained or controlled release dosage forms, including depot injections, osmotic pumps, pills (tablets and or capsules), transdermal (including electrotransport) patches, implants and the like, for prolonged and/or timed, pulsed administration at a predetermined rate.

The compounds can be administered either alone or in combination with a conventional pharmaceutical carrier, excipient or the like. Pharmaceutically acceptable excipients include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) such as d-α-tocopherol polyethylene glycol 1000 succinate, surfactants used in pharmaceutical dosage forms such as Tweens, poloxamers or other similar polymeric delivery matrices, serum proteins, such as human serum albumin, buffer substances such as phosphates, tris, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium-chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, and wool fat. Cyclodextrins such as α-, β, and γ-cyclodextrin, or chemically modified derivatives such as hydroxyalkylcyclodextrins, including 2- and 3-hydroxypropyl-β-cyclodextrins, or other solubilized derivatives can also be used to enhance delivery of compounds described herein. Dosage forms or compositions containing a compound as described herein in the range of 0.005% to 100% with the balance made up from non-toxic carrier may be prepared. The contemplated compositions may contain 0.001%-100% of a compound provided herein, in one embodiment 0.1-95%, in another embodiment 75-85%, in a further embodiment 20-80%. Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see Remington: The Science and Practice of Pharmacy, 22^ndEdition (Pharmaceutical Press, London, U K. 2012).

In one embodiment, the compositions will take the form of a unit dosage form such as a pill or tablet and thus the composition may contain, along with a compound provided herein, a diluent such as lactose, sucrose, dicalcium phosphate, or the like; a lubricant such as magnesium stearate or the like; and a binder such as starch, gum acacia, polyvinylpyrrolidine, gelatin, cellulose, cellulose derivatives or the like. In another solid dosage form, a powder, marume, solution or suspension (e.g., in propylene carbonate, vegetable oils, PEG's, poloxamer 124 or triglycerides) is encapsulated in a capsule (gelatin or cellulose base capsule). Unit dosage forms in which one or more compounds provided herein or additional active agents are physically separated are also contemplated; e.g., capsules with granules (or tablets in a capsule) of each drug; two-layer tablets; two-compartment gel caps, etc. Enteric coated or delayed release oral dosage forms are also contemplated.

Liquid pharmaceutically administrable compositions can, for example, be prepared by dissolving, dispersing, etc. a compound provided herein and optional pharmaceutical adjuvants in a carrier (e.g., water, saline, aqueous dextrose, glycerol, glycols, ethanol or the like) to form a solution, colloid, liposome, emulsion, complexes, coacervate or suspension. If desired, the pharmaceutical composition can also contain minor amounts of nontoxic auxiliary substances such as wetting agents, emulsifying agents, co-solvents, solubilizing agents, pH buffering agents and the like (e.g., sodium acetate, sodium citrate, cyclodextrin derivatives, sorbitan monolaurate, triethanolamine acetate, triethanolamine oleate, and the like).

In some embodiments, the unit dosage of compounds of Formula (I) is about 0.25 mg/Kg to about 50 mg/Kg in humans.

In some embodiments, the unit dosage of compounds of Formula (I) is about 0.25 mg/Kg to about 20 mg/Kg in humans.

In some embodiments, the unit dosage of compounds of Formula (I) is about 0.50 mg/Kg to about 19 mg/Kg in humans.

In some embodiments, the unit dosage of compounds of Formula (I) is about 0.75 mg/Kg to about 18 mg/Kg in humans.

In some embodiments, the unit dosage of compounds of Formula (I) is about 1.0 mg/Kg to about 17 mg/Kg in humans.

In some embodiments, the unit dosage of compounds of Formula (I) is about 1.25 mg/Kg to about 16 mg/Kg in humans.

In some embodiments, the unit dosage of compounds of Formula (I) is about 1.50 mg/Kg to about 15 mg/Kg in humans.

In some embodiments, the unit dosage of compounds of Formula (I) is about 1.75 mg/Kg to about 14 mg/Kg in humans.

In some embodiments, the unit dosage of compounds of Formula (I) is about 2.0 mg/Kg to about 13 mg/Kg in humans.

In some embodiments, the unit dosage of compounds of Formula (I) is about 3.0 mg/Kg to about 12 mg/Kg in humans.

In some embodiments, the unit dosage of compounds of Formula (I) is about 4.0 mg/Kg to about 11 mg/Kg in humans.

In some embodiments, the unit dosage of compounds of Formula (I) is about 5.0 mg/Kg to about 10 mg/Kg in humans.

In some embodiments, the compositions are provided in unit dosage forms suitable for single administration.

In some embodiments, the compositions are provided in unit dosage forms suitable for twice a day administration.

In some embodiments, the compositions are provided in unit dosage forms suitable for three times a day administration.

Injectables can be prepared in conventional forms, either as liquid solutions, colloid, liposomes, complexes, coacervate or suspensions, as emulsions, or in solid forms suitable for reconstitution in liquid prior to injection. The percentage of a compound provided herein contained in such parenteral compositions is highly dependent on the specific nature thereof, as well as the activity of the compound and the needs of the patient. However, percentages of active ingredient of 0.01% to 10% in solution are employable, and could be higher if the composition is a solid or suspension, which could be subsequently diluted to the above percentages.

In some embodiments, the composition will comprise about 0.1-10% of the active agent in solution.

In some embodiments, the composition will comprise about 0.1-5% of the active agent in solution.

In some embodiments, the composition will comprise about 0.1-4% of the active agent in solution.

In some embodiments, the composition will comprise about 0.15-3% of the active agent in solution.

In some embodiments, the composition will comprise about 0.2-2% of the active agent in solution.

In some embodiments, the compositions are provided in dosage forms suitable for continuous dosage by intravenous infusion over a period of about 1-96 hours.

In some embodiments, the compositions are provided in dosage forms suitable for continuous dosage by intravenous infusion over a period of about 1-72 hours.

In some embodiments, the compositions are provided in dosage forms suitable for continuous dosage by intravenous infusion over a period of about 1-48 hours.

In some embodiments, the compositions are provided in dosage forms suitable for continuous dosage by intravenous infusion over a period of about 1-24 hours.

In some embodiments, the compositions are provided in dosage forms suitable for continuous dosage by intravenous infusion over a period of about 1-12 hours.

In some embodiments, the compositions are provided in dosage forms suitable for continuous dosage by intravenous infusion over a period of about 1-6 hours.

In some embodiments, these compositions can be administered by intravenous infusion to humans at doses of about 5 mg/m²to about 300 mg/m².

In some embodiments, these compositions can be administered by intravenous infusion to humans at doses of about 5 mg/m²to about 200 mg/m².

In some embodiments, these compositions can be administered by intravenous infusion to humans at doses of about 5 mg/m²to about 100 mg/m².

In some embodiments, these compositions can be administered by intravenous infusion to humans at doses of about 10 mg/m²to about 50 mg/m².

In some embodiments, these compositions can be administered by intravenous infusion to humans at doses of about 50 mg/m²to about 200 mg/m².

In some embodiments, these compositions can be administered by intravenous infusion to humans at doses of about 75 mg/m²to about 175 mg/m².

In some embodiments, these compositions can be administered by intravenous infusion to humans at doses of about 100 mg/m²to about 150 mg/m².

It is to be noted that concentrations and dosage values may also vary depending on the specific compound and the severity of the condition to be alleviated. It is to be further understood that for any particular patient, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that the concentration ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed compositions.

In one embodiment, the compositions can be administered to the respiratory tract (including nasal and pulmonary) e.g., through a nebulizer, metered-dose inhalers, atomizer, mister, aerosol, dry powder inhaler, insufflator, liquid instillation or other suitable device or technique.

In some embodiments, aerosols intended for delivery to the nasal mucosa are provided for inhalation through the nose. For optimal delivery to the nasal cavities, inhaled particle sizes of about 5 to about 100 microns are useful, with particle sizes of about 10 to about 60 microns being preferred. For nasal delivery, a larger inhaled particle size may be desired to maximize impaction on the nasal mucosa and to minimize or prevent pulmonary deposition of the administered formulation. In some embodiments, aerosols intended for delivery to the lung are provided for inhalation through the nose or the mouth. For delivery to the lung, inhaled aerodynamic particle sizes of about less than 10 μm are useful (e.g., about 1 to about 10 microns). Inhaled particles may be defined as liquid droplets containing dissolved drug, liquid droplets containing suspended drug particles (in cases where the drug is insoluble in the suspending medium), dry particles of pure drug substance, drug substance incorporated with excipients, liposomes, emulsions, colloidal systems, coacervates, aggregates of drug nanoparticles, or dry particles of a diluent which contain embedded drug nanoparticles.

In some embodiments, compounds of Formula (I) disclosed herein intended for respiratory delivery (either systemic or local) can be administered as aqueous formulations, as non-aqueous solutions or suspensions, as suspensions or solutions in halogenated hydrocarbon propellants with or without alcohol, as a colloidal system, as emulsions, coacervates, or as dry powders. Aqueous formulations may be aerosolized by liquid nebulizers employing either hydraulic or ultrasonic atomization or by modified micropump systems (like the soft mist inhalers, the Aerodose® or the AERx® systems). Propellant-based systems may use suitable pressurized metered-dose inhalers (pMDIs). Dry powders may use dry powder inhaler devices (DPIs), which are capable of dispersing the drug substance effectively. A desired particle size and distribution may be obtained by choosing an appropriate device.

In some embodiments, the compositions of Formula (I) disclosed herein can be administered to the ear by various methods. For example, a round window catheter (e.g., U.S. Pat. Nos. 6,440,102 and 6,648,873) can be used.

Alternatively, formulations can be incorporated into a wick for use between the outer and middle ear (e.g., U.S. Pat. No. 6,120,484) or absorbed to collagen sponge or other solid support (e.g., U.S. Pat. No. 4,164,559).

If desired, formulations of the disclosure can be incorporated into a gel formulation (e.g., U.S. Pat. Nos. 4,474,752 and 6,911,211).

In some embodiments, compounds of Formula (I) disclosed herein intended for delivery to the ear can be administered via an implanted pump and delivery system through a needle directly into the middle or inner ear (cochlea) or through a cochlear implant stylet electrode channel or alternative prepared drug delivery channel such as but not limited to a needle through temporal bone into the cochlea.

Other options include delivery via a pump through a thin film coated onto a multichannel electrode or electrode with a specially imbedded drug delivery channel (pathways) carved into the thin film for this purpose. In other embodiments the acidic or basic solid compound of Formula (I) can be delivered from the reservoir of an external or internal implanted pumping system.

Formulations of the disclosure also can be administered to the ear by intratympanic injection into the middle ear, inner ear, or cochlea (e.g., U.S. Pat. No. 6,377,849 and Ser. No. 11/337,815).

Intratympanic injection of therapeutic agents is the technique of injecting a therapeutic agent behind the tympanic membrane into the middle and/or inner ear. In one embodiment, the formulations described herein are administered directly onto the round window membrane via transtympanic injection. In another embodiment, the ion channel modulating agent auris-acceptable formulations described herein are administered onto the round window membrane via a non-transtympanic approach to the inner ear. In additional embodiments, the formulation described herein is administered onto the round window membrane via a surgical approach to the round window membrane comprising modification of the crista fenestrae cochleae.

In some embodiments, the compounds of Formula (I) are formulated in rectal compositions such as enemas, rectal gels, rectal foams, rectal aerosols, suppositories, jelly suppositories, or retention enemas, containing conventional suppository bases such as cocoa butter or other glycerides, as well as synthetic polymers such as polyvinylpyrrolidone, PEG (like PEG ointments), and the like.

Suppositories for rectal administration of the drug (either as a solution, colloid, suspension or a complex) can be prepared by mixing a compound provided herein with a suitable non-irritating excipient that is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt or erode/dissolve in the rectum and release the compound. Such materials include cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, poloxamers, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol. In suppository forms of the compositions, a low-melting wax such as, but not limited to, a mixture of fatty acid glycerides, optionally in combination with cocoa butter, is first melted.

Solid compositions can be provided in various different types of dosage forms, depending on the physicochemical properties of the compound provided herein, the desired dissolution rate, cost considerations, and other criteria. In one of the embodiments, the solid composition is a single unit. This implies that one unit dose of the compound is comprised in a single, physically shaped solid form or article. In other words, the solid composition is coherent, which is in contrast to a multiple unit dosage form, in which the units are incoherent.

Examples of single units which may be used as dosage forms for the solid composition include tablets, such as compressed tablets, film-like units, foil-like units, wafers, lyophilized matrix units, and the like. In one embodiment, the solid composition is a highly porous lyophilized form. Such lyophilizates, sometimes also called wafers or lyophilized tablets, are particularly useful for their rapid disintegration, which also enables the rapid dissolution of the compound.

On the other hand, for some applications the solid composition may also be formed as a multiple unit dosage form as defined above. Examples of multiple units are powders, granules, microparticles, pellets, mini-tablets, beads, lyophilized powders, and the like. In one embodiment, the solid composition is a lyophilized powder. Such a dispersed lyophilized system comprises a multitude of powder particles, and due to the lyophilization process used in the formation of the powder, each particle has an irregular, porous microstructure through which the powder is capable of absorbing water very rapidly, resulting in quick dissolution. Effervescent compositions are also contemplated to aid the quick dispersion and absorption of the compound.

Another type of multiparticulate system which is also capable of achieving rapid drug dissolution is that of powders, granules, or pellets from water-soluble excipients which are coated with a compound provided herein so that the compound is located at the outer surface of the individual particles. In this type of system, the water-soluble low molecular weight excipient may be useful for preparing the cores of such coated particles, which can be subsequently coated with a coating composition comprising the compound and, for example, one or more additional excipients, such as a binder, a pore former, a saccharide, a sugar alcohol, a film-forming polymer, a plasticizer, or other excipients used in pharmaceutical coating compositions.

Also provided herein are kits. Typically, a kit includes one or more compounds or compositions as described herein. In certain embodiments, a kit can include one or more delivery systems, e.g., for delivering or administering a compound as provided herein, and directions for use of the kit (e.g., instructions for treating a patient). In another embodiment, the kit can include a compound or composition as described herein and a label that indicates that the contents are to be administered to a patient with cancer. In another embodiment, the kit can include a compound or composition as described herein and a label that indicates that the contents are to be administered to a patient with one or more of hepatocellular carcinoma, colon cancer, leukemia, lymphoma, sarcoma, ovarian cancer, diabetic retinopathy, pulmonary fibrosis, rheumatoid arthritis, sepsis, ankylosing spondylitis, psoriasis, scleroderma, mycotic and viral infections, bone and cartilage diseases, Alzheimer's disease, lung disease, bone/osteoporotic (wrist, spine, shoulder and hip) fractures, articular cartilage (chondral) defects, degenerative disc disease (or intervertebral disc degeneration), polyposis coli, bone density and vascular defects in the eye (Osteoporosis-pseudoglioma Syndrome, OPPG), familial exudative vitreoretinopathy, retinal angiogenesis, early coronary disease, tetra-amelia, Müllerian-duct regression and virilization, SERKAL syndrome, type II diabetes, Fuhrmann syndrome, Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndrome, odonto-onycho-dermal dysplasia, obesity, split-hand/foot malformation, caudal duplication, tooth agenesis, Wilms tumor, skeletal dysplasia, focal dermal hypoplasia, autosomal recessive anonychia, neural tube defects, alpha-thalassemia (ATRX) syndrome, fragile X syndrome, ICF syndrome, Angelman syndrome, Prader-Willi syndrome, Beckwith-Wiedemann Syndrome, Norrie disease, and Rett syndrome.

Methods of Treatment

The compounds and compositions provided herein can be used as inhibitors and/or modulators of one or more components of the Wnt pathway, which may include one or more Wnt proteins, and thus can be used to treat a variety of disorders and diseases in which aberrant Wnt signaling is implicated, such as cancer and other diseases associated with abnormal angiogenesis, cellular proliferation, and cell cycling. Accordingly, the compounds and compositions provided herein can be used to treat cancer, to reduce or inhibit angiogenesis, to reduce or inhibit cellular proliferation, to correct a genetic disorder, and/or to treat a neurological condition/disorder/disease due to mutations or dysregulation of the Wnt pathway and/or of one or more of Wnt signaling components. Non-limiting examples of diseases which can be treated with the compounds and compositions provided herein include a variety of cancers, diabetic retinopathy, pulmonary fibrosis, rheumatoid arthritis, scleroderma, mycotic and viral infections, bone and cartilage diseases, neurological conditions/diseases such as Alzheimer's disease, amyotrophic lateral sclerosis (ALS), motor neuron disease, multiple sclerosis or autism, lung disease, bone/osteoporotic (wrist, spine, shoulder and hip) fractures, polyposis coli, bone density and vascular defects in the eye (Osteoporosis-pseudoglioma Syndrome, OPPG), familial exudative vitreoretinopathy, retinal angiogenesis, early coronary disease, tetra-amelia, Müllerian-duct regression and virilization, SERKAL syndrome, type II diabetes, Fuhrmann syndrome, Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndrome, odonto-onycho-dermal dysplasia, obesity, split-hand/foot malformation, caudal duplication, tooth agenesis, Wilms tumor, skeletal dysplasia, focal dermal hypoplasia, autosomal recessive anonychia, neural tube defects, alpha-thalassemia (ATRX) syndrome, fragile X syndrome, ICF syndrome, Angelman syndrome, Prader-Willi syndrome, Beckwith-Wiedemann Syndrome, Norrie disease and Rett syndrome.

The compounds and compositions described herein can be used to treat tendinopathy includes all tendon pathologies (tendinitis, tendinosis and paratenonitis) localized in and around the tendons and is characterized by pain, swelling and impaired performance due to the degeneration of the tendon's collagen in response tendon overuse, often referred to as tendinosis. Tendinopathy may be categorized into two histopathologic entities—tendonitis, which results from acute injury to the tendon accompanied by intratendinous inflammation, and more commonly, tendinosis, which is a degenerative response to repetitive microtrauma resulting from overuse. Tendinosis may be accompanied by paratenonitis, an inflammatory condition of the lining of the tendon.

With respect to cancer, the Wnt pathway is known to be constitutively activated in a variety of cancers including, for example, colon cancer, hepatocellular carcinoma, lung cancer, ovarian cancer, prostate cancer, pancreatic cancer and leukemias such as CML, CLL and T-ALL. Accordingly, the compounds and compositions described herein may be used to treat these cancers in which the Wnt pathway is constitutively activated. In certain embodiments, the cancer is chosen from hepatocellular carcinoma, colon cancer, leukemia, lymphoma, sarcoma and ovarian cancer.

Other cancers can also be treated with the compounds and compositions described herein.

More particularly, cancers that may be treated by the compounds, compositions and methods described herein include, but are not limited to, the following:

1) Breast cancers, including, for example ER⁺ breast cancer, ER⁻ breast cancer, her2⁻ breast cancer, her2⁺ breast cancer, stromal tumors such as fibroadenomas, phyllodes tumors, and sarcomas, and epithelial tumors such as large duct papillomas; carcinomas of the breast including in situ (noninvasive) carcinoma that includes ductal carcinoma in situ (including Paget's disease) and lobular carcinoma in situ, and invasive (infiltrating) carcinoma including, but not limited to, invasive ductal carcinoma, invasive lobular carcinoma, medullary carcinoma, colloid (mucinous) carcinoma, tubular carcinoma, and invasive papillary carcinoma; and miscellaneous malignant neoplasms. Further examples of breast cancers can include luminal A, luminal B, basal A, basal B, and triple negative breast cancer, which is estrogen receptor negative (ER⁻), progesterone receptor negative, and her2 negative (her2⁺). In some embodiments, the breast cancer may have a high risk Oncotype score.

2) Cardiac cancers, including, for example sarcoma, e.g., angiosarcoma, fibrosarcoma, rhabdomyosarcoma, and liposarcoma; myxoma; rhabdomyoma; fibroma; lipoma and teratoma.

3) Lung cancers, including, for example, bronchogenic carcinoma, e.g., squamous cell, undifferentiated small cell, undifferentiated large cell, and adenocarcinoma; alveolar and bronchiolar carcinoma; bronchial adenoma; sarcoma; lymphoma; chondromatous hamartoma; and mesothelioma.

4) Gastrointestinal cancer, including, for example, cancers of the esophagus, e.g., squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, and lymphoma; cancers of the stomach, e.g., carcinoma, lymphoma, and leiomyosarcoma; cancers of the pancreas, e.g., ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, and vipoma; cancers of the small bowel, e.g., adenocarcinoma, lymphoma, carcinoid tumors, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, and fibroma; cancers of the large bowel, e.g., adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, and leiomyoma.

5) Genitourinary tract cancers, including, for example, cancers of the kidney, e.g., adenocarcinoma, Wilm's tumor (nephroblastoma), lymphoma, and leukemia; cancers of the bladder and urethra, e.g., squamous cell carcinoma, transitional cell carcinoma, and adenocarcinoma; cancers of the prostate, e.g., adenocarcinoma, and sarcoma; cancer of the testis, e.g., seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, and lipoma.

6) Liver cancers, including, for example, hepatoma, e.g., hepatocellular carcinoma; cholangiocarcinoma; hepatoblastoma; angiosarcoma; hepatocellular adenoma; and hemangioma.

7) Bone cancers, including, for example, osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochrondroma (osteocartilaginous exostoses), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumors.

8) Nervous system cancers, including, for example, cancers of the skull, e.g., osteoma, hemangioma, granuloma, xanthoma, and osteitis deformans; cancers of the meninges, e.g., meningioma, meningiosarcoma, and gliomatosis; cancers of the brain, e.g., astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma, and congenital tumors; and cancers of the spinal cord, e.g., neurofibroma, meningioma, glioma, and sarcoma.

9) Gynecological cancers, including, for example, cancers of the uterus, e.g., endometrial carcinoma; cancers of the cervix, e.g., cervical carcinoma, and pre tumor cervical dysplasia; cancers of the ovaries, e.g., ovarian carcinoma, including serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma, granulosa theca cell tumors, Sertoli Leydig cell tumors, dysgerminoma, and malignant teratoma; cancers of the vulva, e.g., squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, and melanoma; cancers of the vagina, e.g., clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma, and embryonal rhabdomyosarcoma; and cancers of the fallopian tubes, e.g., carcinoma.

10) Hematologic cancers, including, for example, cancers of the blood, e.g., acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, and myelodysplastic syndrome, Hodgkin's lymphoma, non-Hodgkin's lymphoma (malignant lymphoma) and Waldenström's macroglobulinemia.

11) Skin cancers and skin disorders, including, for example, malignant melanoma and metastatic melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma, keloids, and scleroderma.

12) Adrenal gland cancers, including, for example, neuroblastoma.

Cancers may be solid tumors that may or may not be metastatic. Cancers may also occur, as in leukemia, as a diffuse tissue. Thus, the term “tumor cell,” as provided herein, includes a cell afflicted by any one of the above identified disorders.

A method of treating cancer using a compound or composition as described herein may be combined with existing methods of treating cancers, for example by chemotherapy, irradiation, or surgery (e.g., oophorectomy). In some embodiments, a compound or composition can be administered before, during, or after another anticancer agent or treatment.

The compounds and compositions described herein can be used as anti-angiogenesis agents and as agents for modulating and/or inhibiting the activity of protein kinases, thus providing treatments for cancer and other diseases associated with cellular proliferation mediated by protein kinases. For example, the compounds described herein can inhibit the activity of one or more kinases. Accordingly, provided herein is a method of treating cancer or preventing or reducing angiogenesis through kinase inhibition.

In addition, and including treatment of cancer, the compounds and compositions described herein can function as cell-cycle control agents for treating proliferative disorders in a patient. Disorders associated with excessive proliferation include, for example, cancers, scleroderma, immunological disorders involving undesired proliferation of leukocytes, and restenosis and other smooth muscle disorders. Furthermore, such compounds may be used to prevent de-differentiation of post-mitotic tissue and/or cells.

Diseases or disorders associated with uncontrolled or abnormal cellular proliferation include, but are not limited to, the following:

- a variety of cancers, including, but not limited to, carcinoma, hematopoietic tumors of lymphoid lineage, hematopoietic tumors of myeloid lineage, tumors of mesenchymal origin, tumors of the central and peripheral nervous system and other tumors including melanoma, seminoma and Kaposi's sarcoma.
- a disease process which features abnormal cellular proliferation, e.g., benign prostatic hyperplasia, familial adenomatosis polyposis, neurofibromatosis, atherosclerosis, arthritis, glomerulonephritis, restenosis following angioplasty or vascular surgery, inflammatory bowel disease, transplantation rejection, endotoxic shock, and fungal infections. Fibrotic disorders such as skin fibrosis; scleroderma; progressive systemic fibrosis; lung fibrosis; muscle fibrosis; kidney fibrosis; glomerulosclerosis; glomerulonephritis; hypertrophic scar formation; uterine fibrosis; renal fibrosis; cirrhosis of the liver, liver fibrosis; fatty liver disease (FLD); adhesions, such as those occurring in the abdomen, pelvis, spine or tendons; chronic obstructive pulmonary disease; fibrosis following myocardial infarction; pulmonary fibrosis; fibrosis and scarring associated with diffuse/interstitial lung disease; central nervous system fibrosis, such as fibrosis following stroke; fibrosis associated with neuro-degenerative disorders such as Alzheimer's Disease or multiple sclerosis; fibrosis associated with proliferative vitreoretinopathy (PVR); restenosis; endometriosis; ischemic disease and radiation fibrosis.
- defective apoptosis-associated conditions, such as cancers (including but not limited to those types mentioned herein), viral infections (including but not limited to herpesvirus, poxvirus, Epstein-Barr virus, Sindbis virus and adenovirus), prevention of AIDS development in H1V-infected individuals, autoimmune diseases (including but not limited to systemic lupus erythematosus, rheumatoid arthritis, sepsis, ankylosing spondylitis, psoriasis, scleroderma, autoimmune mediated glomerulonephritis, inflammatory bowel disease and autoimmune diabetes mellitus), neuro-degenerative disorders (including but not limited to Alzheimer's disease, lung disease, amyotrophic lateral sclerosis, retinitis pigmentosa, Parkinson's disease, AIDS-related dementia, spinal muscular atrophy and cerebellar degeneration), myelodysplastic syndromes, aplastic anemia, ischemic injury associated with myocardial infarctions, stroke and reperfusion injury, arrhythmia, atherosclerosis, toxin-induced or alcohol related liver diseases, hematological diseases (including but not limited to chronic anemia and aplastic anemia), degenerative diseases of the musculoskeletal system (including but not limited to osteoporosis and arthritis), tendinopathies such as tendinitis and tendinosis, aspirin-sensitive rhinosinusitis, cystic fibrosis, multiple sclerosis, kidney diseases and cancer pain.
- genetic diseases due to mutations in Wnt signaling components, such as polyposis coli, bone density and vascular defects in the eye (Osteoporosis-pseudoglioma Syndrome, OPPG), familial exudative vitreoretinopathy, retinal angiogenesis, early coronary disease, tetra-amelia, Müllerian-duct regression and virilization, SERKAL syndrome, type II diabetes, Fuhrmann syndrome, Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndrome, odonto-onycho-dermal dysplasia, obesity, split-hand/foot malformation, caudal duplication, tooth agenesis, Wilms tumor, skeletal dysplasia, focal dermal hypoplasia, autosomal recessive anonychia, neural tube defects, alpha-thalassemia (ATRX) syndrome, fragile X syndrome, ICF syndrome, Angelman syndrome, Prader-Willi syndrome, Beckwith-Wiedemann Syndrome, Norrie disease and Rett syndrome.

The compounds and compositions described herein can be used to treat neurological conditions, disorders and/or diseases caused by dysfunction in the Wnt signaling pathway. Non-limiting examples of neurological conditions/disorders/diseases which can be treated with the compounds and compositions provided herein include Alzheimer's disease, aphasia, apraxia, arachnoiditis, ataxia telangiectasia, attention deficit hyperactivity disorder, auditory processing disorder, autism, alcoholism, Bell's palsy, bipolar disorder, brachial plexus injury, Canavan disease, carpal tunnel syndrome, causalgia, central pain syndrome, central pontine myelinolysis, centronuclear myopathy, cephalic disorder, cerebral aneurysm, cerebral arteriosclerosis, cerebral atrophy, cerebral gigantism, cerebral palsy, cerebral vasculitis, cervical spinal stenosis, Charcot-Marie-Tooth disease, Chiari malformation, chronic fatigue syndrome, chronic inflammatory demyelinating polyneuropathy (CIDP), chronic pain, Coffin-Lowry syndrome, complex regional pain syndrome, compression neuropathy, congenital facial diplegia, corticobasal degeneration, cranial arteritis, craniosynostosis, Creutzfeldt-Jakob disease, cumulative trauma disorder, Cushing's syndrome, cytomegalic inclusion body disease (CIBD), Dandy-Walker syndrome, Dawson disease, de Morsier's syndrome, Dejerine-Klumpke palsy, Dejerine-Sottas disease, delayed sleep phase syndrome, dementia, dermatomyositis, developmental dyspraxia, diabetic neuropathy, diffuse sclerosis, Dravet syndrome, dysautonomia, dyscalculia, dysgraphia, dyslexia, dystonia, empty sella syndrome, encephalitis, encephalocele, encephalotrigeminal angiomatosis, encopresis, epilepsy, Erb's palsy, erythromelalgia, essential tremor, Fabry's disease, Fahr's syndrome, familial spastic paralysis, febrile seizure, Fisher syndrome, Friedreich's ataxia, fibromyalgia, Foville's syndrome, Gaucher's disease, Gerstmann's syndrome, giant cell arteritis, giant cell inclusion disease, globoid cell leukodystrophy, gray matter heterotopia, Guillain-Barre syndrome, HTLV-1 associated myelopathy, Hallervorden-Spatz disease, hemifacial spasm, hereditary spastic paraplegia, heredopathia atactica polyneuritiformis, herpes zoster oticus, herpes zoster, Hirayama syndrome, holoprosencephaly, Huntington's disease, hydranencephaly, hydrocephalus, hypercortisolism, hypoxia, immune-mediated encephalomyelitis, inclusion body myositis, incontinentia pigmenti, infantile phytanic acid storage disease, infantile Refsum disease, infantile spasms, inflammatory myopathy, intracranial cyst, intracranial hypertension, Joubert syndrome, Karak syndrome, Kearns-Sayre syndrome, Kennedy disease, Kinsbourne syndrome, Klippel Feil syndrome, Krabbe disease, Kugelberg-Welander disease, kuru, Lafora disease, Lambert-Eaton myasthenic syndrome, Landau-Kleffner syndrome, lateral medullary (Wallenberg) syndrome, Leigh's disease, Lennox-Gastaut syndrome, Lesch-Nyhan syndrome, leukodystrophy, Lewy body dementia, lissencephaly, locked-in syndrome, Lou Gehrig's disease, lumbar disc disease, lumbar spinal stenosis, Lyme disease, Machado-Joseph disease (Spinocerebellar ataxia type 3), macrencephaly, macropsia, megalencephaly, Melkersson-Rosenthal syndrome, Meniere's disease, meningitis, Menkes disease, metachromatic leukodystrophy, microcephaly, micropsia, Miller Fisher syndrome, misophonia, mitochondrial myopathy, Mobius syndrome, monomelic amyotrophy, motor neuron disease, motor skills disorder, Moyamoya disease, mucopolysaccharidoses, multi-infarct dementia, multifocal motor neuropathy, multiple sclerosis, multiple system atrophy, muscular dystrophy, myalgic encephalomyelitis, myasthenia gravis, myelinoclastic diffuse sclerosis, myoclonic Encephalopathy of infants, myoclonus, myopathy, myotubular myopathy, myotonia congenital, narcolepsy, neurofibromatosis, neuroleptic malignant syndrome, lupus erythematosus, neuromyotonia, neuronal ceroid lipofuscinosis, Niemann-Pick disease, O'Sullivan-McLeod syndrome, occipital Neuralgia, occult Spinal Dysraphism Sequence, Ohtahara syndrome, olivopontocerebellar atrophy, opsoclonus myoclonus syndrome, optic neuritis, orthostatic hypotension, palinopsia, paresthesia, Parkinson's disease, paramyotonia congenita, paraneoplastic diseases, paroxysmal attacks, Parry-Romberg syndrome, Pelizaeus-Merzbacher disease, periodic paralyses, peripheral neuropathy, photic sneeze reflex, phytanic acid storage disease, Pick's disease, polymicrogyria (PMG), polymyositis, porencephaly, post-polio syndrome, postherpetic neuralgia (PHN), postural hypotension, Prader-Willi syndrome, primary lateral sclerosis, prion diseases, progressive hemifacial atrophy, progressive multifocal leukoencephalopathy, progressive supranuclear palsy, pseudotumor cerebri, Ramsay Hunt syndrome type I, Ramsay Hunt syndrome type II, Ramsay Hunt syndrome type III, Rasmussen's encephalitis, reflex neurovascular dystrophy, Refsum disease, restless legs syndrome, retrovirus-associated myelopathy, Rett syndrome, Reye's syndrome, rhythmic movement disorder, Romberg syndrome, Saint Vitus dance, Sandhoff disease, schizophrenia, Schilder's disease, schizencephaly, sensory integration dysfunction, septo-optic dysplasia, Shy-Drager syndrome, Sjögren's syndrome, snatiation, Sotos syndrome, spasticity, spina bifida, spinal cord tumors, spinal muscular atrophy, spinocerebellar ataxia, Steele-Richardson-Olszewski syndrome, Stiff-person syndrome, stroke, Sturge-Weber syndrome, subacute sclerosing panencephalitis, subcortical arteriosclerotic encephalopathy, superficial siderosis, Sydenham's chorea, syncope, synesthesia, syringomyelia, tarsal tunnel syndrome, tardive dyskinesia, tardive dysphrenia, Tarlov cyst, Tay-Sachs disease, temporal arteritis, tetanus, tethered spinal cord syndrome, Thomsen disease, thoracic outlet syndrome, tic douloureux, Todd's paralysis, Tourette syndrome, toxic encephalopathy, transient ischemic attack, transmissible spongiform encephalopathies, transverse myelitis, tremor, trigeminal neuralgia, tropical spastic paraparesis, trypanosomiasis, tuberous sclerosis, ubisiosis, Von Hippel-Lindau disease (VHL), Viliuisk Encephalomyelitis (VE), Wallenberg's syndrome, Werdnig, Hoffman disease, west syndrome, Williams syndrome, Wilson's disease and Zellweger syndrome.

The compounds and compositions may also be useful in the inhibition of the development of invasive cancer, tumor angiogenesis and metastasis.

In some embodiments, the disclosure provides a method for treating a disease or disorder associated with aberrant cellular proliferation by administering to a patient in need of such treatment an effective amount of one or more of the compounds of Formula (I), in combination (simultaneously or sequentially) with at least one other agent.

In some embodiments, the disclosure provides a method of treating or ameliorating in a patient a disorder or disease selected from the group consisting of: cancer, pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), degenerative disc disease, bone/osteoporotic fractures, bone or cartilage disease, and osteoarthritis, the method comprising administering to the patient a therapeutically effective amount of a compound according to claim 1, or a pharmaceutically acceptable salt thereof.

In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

In some embodiments, the method of treats a disorder or disease in which aberrant Wnt signaling is implicated in a patient, the method comprises administering to the patient a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

In some embodiments, the disorder or disease is cancer.

In some embodiments, the disorder or disease is systemic inflammation.

In some embodiments, the disorder or disease is metastatic melanoma.

In some embodiments, the disorder or disease is fatty liver disease.

In some embodiments, the disorder or disease is liver fibrosis.

In some embodiments, the disorder or disease is tendon regeneration.

In some embodiments, the disorder or disease is diabetes.

In some embodiments, the disorder or disease is degenerative disc disease.

In some embodiments, the disorder or disease is osteoarthritis.

In some embodiments, the disorder or disease is diabetic retinopathy.

In some embodiments, the disorder or disease is pulmonary fibrosis.

In some embodiments, the disorder or disease is idiopathic pulmonary fibrosis (IPF).

In some embodiments, the disorder or disease is degenerative disc disease.

In some embodiments, the disorder or disease is rheumatoid arthritis.

In some embodiments, the disorder or disease is scleroderma.

In some embodiments, the disorder or disease is a mycotic or viral infection.

In some embodiments, the disorder or disease is a bone or cartilage disease.

In some embodiments, the disorder or disease is Alzheimer's disease.

In some embodiments, the disorder or disease is osteoarthritis.

In some embodiments, the disorder or disease is lung disease.

In some embodiments, the disorder or disease is tendinitis.

In some embodiments, the disorder or disease is tendinosis.

In some embodiments, the disorder or disease is paratenonitis.

In some embodiments, the disorder or disease is degeneration of the tendon's collagen.

In some embodiments, the disorder or disease is tendinopathy.

In some embodiments, the disorder or disease is a genetic disease caused by mutations in Wnt signaling components, wherein the genetic disease is selected from: polyposis coli, osteoporosis-pseudoglioma syndrome, familial exudative vitreoretinopathy, retinal angiogenesis, early coronary disease, tetra-amelia syndrome, Müllerian-duct regression and virilization, SERKAL syndrome, diabetes mellitus type 2, Fuhrmann syndrome, Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndrome, odonto-onycho-dermal dysplasia, obesity, split-hand/foot malformation, caudal duplication syndrome, tooth agenesis, Wilms tumor, skeletal dysplasia, focal dermal hypoplasia, autosomal recessive anonychia, neural tube defects, alpha-thalassemia (ATRX) syndrome, fragile X syndrome, ICF syndrome, Angelman syndrome, Prader-Willi syndrome, Beckwith-Wiedemann Syndrome, Norrie disease and Rett syndrome.

In some embodiments, the patient is a human.

In some embodiments, the cancer is chosen from: hepatocellular carcinoma, colon cancer, breast cancer, pancreatic cancer, chronic myeloid leukemia (CML), chronic myelomonocytic leukemia, chronic lymphocytic leukemia (CLL), acute myeloid leukemia, acute lymphocytic leukemia, Hodgkin lymphoma, lymphoma, sarcoma and ovarian cancer.

In some embodiments, the cancer is chosen from: lung cancer—non-small cell, lung cancer—small cell, multiple myeloma, nasopharyngeal cancer, neuroblastoma, osteosarcoma, penile cancer, pituitary tumors, prostate cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skin cancer—basal and squamous cell, skin cancer—melanoma, small intestine cancer, stomach (gastric) cancers, testicular cancer, thymus cancer, thyroid cancer, uterine sarcoma, vaginal cancer, vulvar cancer, laryngeal or hypopharyngeal cancer, kidney cancer, Kaposi sarcoma, gestational trophoblastic disease, gastrointestinal stromal tumor, gastrointestinal carcinoid tumor, gallbladder cancer, eye cancer (melanoma and lymphoma), Ewing tumor, esophagus cancer, endometrial cancer, colorectal cancer, cervical cancer, brain or spinal cord tumor, bone metastasis, bone cancer, bladder cancer, bile duct cancer, anal cancer and adrenal cortical cancer.

In some embodiments, the cancer is hepatocellular carcinoma.

In some embodiments, the cancer is colon cancer.

In some embodiments, the cancer is colorectal cancer.

In some embodiments, the cancer is breast cancer.

In some embodiments, the cancer is pancreatic cancer.

In some embodiments, the cancer is chronic myeloid leukemia (CML).

In some embodiments, the cancer is chronic myelomonocytic leukemia.

In some embodiments, the cancer is chronic lymphocytic leukemia (CLL).

In some embodiments, the cancer is acute myeloid leukemia.

In some embodiments, the cancer is acute lymphocytic leukemia.

In some embodiments, the cancer is Hodgkin lymphoma.

In some embodiments, the cancer is lymphoma.

In some embodiments, the cancer is sarcoma.

In some embodiments, the cancer is ovarian cancer.

In some embodiments, the cancer is lung cancer—non-small cell.

In some embodiments, the cancer is lung cancer—small cell.

In some embodiments, the cancer is multiple myeloma.

In some embodiments, the cancer is nasopharyngeal cancer.

In some embodiments, the cancer is neuroblastoma.

In some embodiments, the cancer is osteosarcoma.

In some embodiments, the cancer is penile cancer.

In some embodiments, the cancer is pituitary tumors.

In some embodiments, the cancer is prostate cancer.

In some embodiments, the cancer is retinoblastoma.

In some embodiments, the cancer is rhabdomyosarcoma.

In some embodiments, the cancer is salivary gland cancer.

In some embodiments, the cancer is skin cancer—basal and squamous cell.

In some embodiments, the cancer is skin cancer—melanoma.

In some embodiments, the cancer is small intestine cancer.

In some embodiments, the cancer is stomach (gastric) cancers.

In some embodiments, the cancer is testicular cancer.

In some embodiments, the cancer is thymus cancer.

In some embodiments, the cancer is thyroid cancer.

In some embodiments, the cancer is uterine sarcoma.

In some embodiments, the cancer is vaginal cancer.

In some embodiments, the cancer is vulvar cancer.

In some embodiments, the cancer is Wilms tumor.

In some embodiments, the cancer is laryngeal or hypopharyngeal cancer.

In some embodiments, the cancer is kidney cancer.

In some embodiments, the cancer is Kaposi sarcoma.

In some embodiments, the cancer is gestational trophoblastic disease.

In some embodiments, the cancer is gastrointestinal stromal tumor.

In some embodiments, the cancer is gastrointestinal carcinoid tumor.

In some embodiments, the cancer is gallbladder cancer.

In some embodiments, the cancer is eye cancer (melanoma and lymphoma).

In some embodiments, the cancer is Ewing tumor.

In some embodiments, the cancer is esophagus cancer.

In some embodiments, the cancer is endometrial cancer.

In some embodiments, the cancer is colorectal cancer.

In some embodiments, the cancer is cervical cancer.

In some embodiments, the cancer is brain or spinal cord tumor.

In some embodiments, the cancer is bone metastasis.

In some embodiments, the cancer is bone cancer.

In some embodiments, the cancer is bladder cancer.

In some embodiments, the cancer is bile duct cancer.

In some embodiments, the cancer is anal cancer.

In some embodiments, the cancer is adrenal cortical cancer.

In some embodiments, the disorder or disease is a neurological condition, disorder or disease, wherein the neurological condition/disorder/disease is selected from: Alzheimer's disease, frontotemporal dementias, dementia with lewy bodies, prion diseases, Parkinson's disease, Huntington's disease, progressive supranuclear palsy, corticobasal degeneration, multiple system atrophy, amyotrophic lateral sclerosis (ALS), inclusion body myositis, autism, degenerative myopathies, diabetic neuropathy, other metabolic neuropathies, endocrine neuropathies, orthostatic hypotension, multiple sclerosis and Charcot-Marie-Tooth disease.

In some embodiments, the compound of Formula (I) inhibits one or more proteins in the Wnt pathway.

In some embodiments, the compound of Formula (I) inhibits signaling induced by one or more Wnt proteins.

In some embodiments, the Wnt proteins are chosen from: WNT1, WNT2, WNT2B, WNT3, WNT3A, WNT4. WNT5A, WNT5B, WNT6, WNT7A, WNT7B, WNT8A, WNT8B, WNT9A, WNT9B, WNT10A, WNT10B, WNT11, and WNT16.

In some embodiments, the compound of Formula (I) inhibits a kinase activity.

In some embodiments, the method treats a disease or disorder mediated by the Wnt pathway in a patient, the method comprises administering to the patient a therapeutically effective amount of a compound (or compounds) of Formula (I), or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (I) inhibits one or more Wnt proteins.

In some embodiments, the method treats a disease or disorder mediated by kinase activity in a patient, the method comprises administering to the patient a therapeutically effective amount of a compound (or compounds) of Formula (I), or a pharmaceutically acceptable salt thereof.

In some embodiments, the disease or disorder comprises tumor growth, cell proliferation, or angiogenesis.

In some embodiments, the method inhibits the activity of a protein kinase receptor, the method comprises contacting the receptor with an effective amount of a compound (or compounds) of Formula (I), or a pharmaceutically acceptable salt thereof.

In some embodiments, the method treats a disease or disorder associated with aberrant cellular proliferation in a patient; the method comprises administering to the patient a therapeutically effective amount of a compound (or compounds) of Formula (I), or a pharmaceutically acceptable salt thereof.

In some embodiments, the method prevents or reduces angiogenesis in a patient; the method comprises administering to the patient a therapeutically effective amount of a compound (or compounds) of Formula (I), or a pharmaceutically acceptable salt thereof.

In some embodiments, the method prevents or reduces abnormal cellular proliferation in a patient; the method comprises administering to the patient a therapeutically effective amount of a compound (or compounds) of Formula (I), or a pharmaceutically acceptable salt thereof.

In some embodiments, the method treats a disease or disorder associated with aberrant cellular proliferation in a patient, the method comprises administering to the patient a pharmaceutical composition comprising one or more of the compounds of claim 1 in combination with a pharmaceutically acceptable carrier and one or more other agents.

Moreover, the compounds and compositions, for example, as inhibitors of the cyclin-dependent kinases (CDKs), can modulate the level of cellular RNA and DNA synthesis and therefore are expected to be useful in the treatment of viral infections such as H1V, human papilloma virus, herpes virus, Epstein-Barr virus, adenovirus, Sindbis virus, pox virus and the like.

Compounds and compositions described herein can inhibit the kinase activity of, for example, CDK/cyclin complexes, such as those active in the G₀. or G.₁stage of the cell cycle, e.g., CDK2, CDK4, and/or CDK6 complexes.

Evaluation of Biological Activity

The biological activity of the compounds described herein can be tested using any suitable assay known to those of skill in the art, see, e.g., WO 2001/053268 and WO 2005/009997. For example, the activity of a compound may be tested using one or more of the test methods outlined below.

In one example, tumor cells may be screened for Wnt independent growth. In such a method, tumor cells of interest are contacted with a compound (i.e. inhibitor) of interest, and the proliferation of the cells, e.g. by uptake of tritiated thymidine, is monitored. In some embodiments, tumor cells may be isolated from a candidate patient who has been screened for the presence of a cancer that is associated with a mutation in the Wnt signaling pathway. Candidate cancers include, without limitation, those listed above.

In another example, one may utilize in vitro assays for Wnt biological activity, e.g. stabilization of β-catenin and promoting growth of stem cells. Assays for biological activity of Wnt include stabilization of β-catenin, which can be measured, for example, by serial dilutions of a candidate inhibitor composition. An exemplary assay for Wnt biological activity contacts a candidate inhibitor with cells containing constitutively active Wnt/β-catenin signaling. The cells are cultured for a period of time sufficient to stabilize β-catenin, usually at least about 1 hour, and lysed. The cell lysate is resolved by SDS PAGE, then transferred to nitrocellulose and probed with antibodies specific for β-catenin.

In a further example, the activity of a candidate compound can be measured in a Xenopus secondary axis bioassay (Leyns, L. et al. Cell (1997), 88(6), 747-756).

To further illustrate this disclosure, the following examples are included. The examples should not, of course, be construed as specifically limiting the disclosure. Variations of these examples within the scope of the claims are within the purview of one skilled in the art and are considered to fall within the scope of the disclosure as described, and claimed herein. The reader will recognize that the skilled artisan, armed with the present disclosure, and skill in the art is able to prepare and use the disclosure without exhaustive examples.

EXAMPLES

Compound Preparation

The starting materials used in preparing the compounds of the disclosure are known, made by known methods, or are commercially available. It will be apparent to the skilled artisan that methods for preparing precursors and functionality related to the compounds claimed herein are generally described in the literature. The skilled artisan given the literature and this disclosure is well equipped to prepare any of the compounds.

It is recognized that the skilled artisan in the art of organic chemistry can readily carry out manipulations without further direction, that is, it is well within the scope and practice of the skilled artisan to carry out these manipulations. These include reduction of carbonyl compounds to their corresponding alcohols, oxidations, acylations, aromatic substitutions, both electrophilic and nucleophilic, etherifications, esterification and saponification and the like. These manipulations are discussed in standard texts such as March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure 7^thEd., John Wiley & Sons (2013), Carey and Sundberg, Advanced Organic Chemistry 5^thEd., Springer (2007), Comprehensive Organic Transformations: A Guide to Functional Group Transformations, 2nd Ed., John Wiley & Sons (1999) (incorporated herein by reference in its entirety) and the like.

The skilled artisan will readily appreciate that certain reactions are best carried out when other functionality is masked or protected in the molecule, thus avoiding any undesirable side reactions and/or increasing the yield of the reaction. Often the skilled artisan utilizes protecting groups to accomplish such increased yields or to avoid the undesired reactions. These reactions are found in the literature and are also well within the scope of the skilled artisan. Examples of many of these manipulations can be found for example in T. Greene and P. Wuts Protective Groups in Organic Synthesis, 4th Ed., John Wiley & Sons (2007), incorporated herein by reference in its entirety.

Trademarks used herein are examples only and reflect illustrative materials used at the time of the disclosure. The skilled artisan will recognize that variations in lot, manufacturing processes, and the like, are expected. Hence the examples, and the trademarks used in them are non-limiting, and they are not intended to be limiting, but are merely an illustration of how a skilled artisan may choose to perform one or more of the embodiments of the disclosure.

(¹H) nuclear magnetic resonance spectra (NMR) were measured in the indicated solvents on a Bruker NMR spectrometer (Avance™ DRX300, 300 MHz for ¹H or Avance™ DRX500, 500 MHz for ¹H) or Varian NMR spectrometer (Mercury 400BB, 400 MHz for ¹H). Peak positions are expressed in parts per million (ppm) downfield from tetramethylsilane. The peak multiplicities are denoted as follows, s, singlet; d, doublet; t, triplet; q, quartet; ABq, AB quartet; quin, quintet; sex, sextet; sep, septet; non, nonet; dd, doublet of doublets; ddd, doublet of doublets of doublets; d/ABq, doublet of AB quartet; dt, doublet of triplets; td, triplet of doublets; dq, doublet of quartets; m, multiplet.

The following abbreviations have the indicated meanings:

Ac₂O=acetic anhydride

BH₃-Me₂S=borane dimethyl sulfide complex

B(i-PrO)₃=triisopropyl borate

(Boc)₂O=di-tert-butyl dicarbonate

brine=saturated aqueous sodium chloride

CDCl₃=deuterated chloroform

CD₃OD=deuterated methanol

mCPBA=meta-chloroperoxybenzoic acid

Cy₃P=tricyclohexylphosphine

DCAD=di-(4-chlorobenzyl)azodicarboxylate

DCE=dichloroethane

DCM=dichloromethane

DEAD=diethyl azodicarboxylate

DHP=dihydropyran

DIPEA=diisopropylethylamine

DMAP=4-dimethylaminopyridine

DMF=N,N-dimethylformamide

DMSO-d₆=deuterated dimethylsulfoxide

ESIMS=electron spray mass spectrometry

EtOAc=ethyl acetate

EtOH=ethanol

HCl=hydrochloric acid

HOAc=acetic acid

K₂CO₃=potassium carbonate

KOAc=potassium acetate

LC/MS=liquid chromatography-mass spectrometry

LDA=lithium diisopropylamide

MeOH=methanol

MgSO₄=magnesium sulfate

MPLC=Medium pressure liquid chromatography

MsC1=methanesulfonyl chloride or mesyl chloride

MTBE=methyl tert-butyl ether

MW=microwave

NaBH₄=sodium borohydride

NaBH(OAc)₃=sodium triacetoxyborohydride

NaCNBH₃=sodium cyanoborohydride

NaHCO₃=sodium bicarbonate

NaH₂PO₄=monosodium phosphate

Na₂HPO₄=disodium phosphate

NaIO₄=sodium periodate

NaOH=sodium hydroxide

Na₂SO₄=sodium sulfate

NBS=N-bromo succinimide

NMR=nuclear magnetic resonance

ON=overnight

Pd₂(dba)₃=tris(dibenzylideneacetone)dipalladium(0)

Pd(dppf)Cl₂=1,1′-bis(diphenylphosphino)ferrocene]palladium(II) chloride

Pd(PPh₃)₄=tetrakis(triphenylphosphine)palladium(0)

PE=petroleum ether

PhMe=toluene

Pin₂B₂=bis(pinacolato)diboron

POCl₃=phosphorus oxychloride

PPh₃=triphenylphosphine

prep-HPLC=preparative High-performance liquid chromatography

r.t=room temperature

SEM-Cl=2-(trimethylsilyl)ethoxymethyl chloride

TBAF=tetra-n-butylammonium fluoride

TEA=triethylamine

TFA=trifluoroacetic acid

THF=tetrahydrofuran

THP=tetrahydropyran

TLC=thin layer chromatography

p-TsOH=p-toluenesulfonic acid

XPhos=2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl

The following example schemes are provided for the guidance of the reader, and collectively represent an example method for making the compounds provided herein. Furthermore, other methods for preparing compounds of the disclosure will be readily apparent to the person of ordinary skill in the art in light of the following reaction schemes and examples. The skilled artisan is thoroughly equipped to prepare these compounds by those methods given the literature and this disclosure. The compound numberings used in the synthetic schemes depicted below are meant for those specific schemes only, and should not be construed as or confused with same numberings in other sections of the application. Unless otherwise indicated, all variables are as defined above.

General Procedure

Compounds of Formula (I) of the present disclosure can be prepared as depicted in Scheme 1a.

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Compound I, wherein PG is a protecting group such as THP, undergoes Suzuki coupling with Compound II to provide Compound III. In certain embodiments, Compound I (X=Br) undergoes Suzuki coupling with Compound II (Y=—B(OH)₂or boronate ester) to provide Compound III after removal of the protecting group. In other embodiments, Compound I (X=Br) is first converted to the corresponding boronic acid or boronate ester (not shown), which in turn undergoes Suzuki coupling with Compound II (Y=Br) to provide Compound III after removal of the protecting group. Treatment of Compound III with KOH and 1₂followed by Boc₂O affords the protected iodide IV.

In certain embodiments, when R* is R⁵(e.g., a six-membered ring), Suzuki coupling between iodide (IV) and boronic acid (V) followed by removal of the protecting groups affords the desired bi-heteroaryl product VI (see, for example, conditions A above).

In other embodiments, when R* is Br or Cl, the resultant Suzuki product can further undergo a second Suzuki coupling to install the R⁵substituent. In some cases, this procedure is useful when the R⁵substituent is a five-membered ring. In these embodiments, removal of the protecting groups affords the desired bi-heteroaryl product VI. See, for example, conditions B above.

Compounds of Formula (I) of the present disclosure can be prepared as depicted in Scheme 1.

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Scheme 1 describes a method for preparation of 3-(1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole compounds (X) by converting the N-protected 5-bromo-1H-indazole (I) to the boronate (II) followed by Suzuki coupling with various bromo compounds to produce compound (III) analogs. (III) is then deprotected to form (IV). Iodination with iodine and potassium hydroxide can either be performed directly on (IV) to form (V) followed by Boc protection (Path A) or (IV) can be first protected with Boc to give (VI) followed by iodination (Path B) to produce compound (VII) analogs. The protected 3-iodo-1H-indazole (VII) is then reacted with the Boc/SEM protected (1H-pyrrolo[2,3-b]pyridin-2-yl)boronic acid (VIII) using Suzuki coupling to form the protected 3-(1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole compounds (IX). Final deprotection of the pyrazole nitrogen yields the desired substituted 3-(1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole compounds (X).

Alternatively, compounds of Formula (I) of the present disclosure can be prepared as depicted in Scheme 2.

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Scheme 2 describes an alternative method for preparation of 3-(1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole compounds (XIV) by reacting Boc protected 3-iodo-1H-indazole (VII) with the Boc/SEM protected (4-bromo-1H-pyrrolo[2,3-b]pyridin-2-yl)boronic acid (XI) by Suzuki coupling. A second Suzuki coupling with various boronic acids yields the protected 3-(1H-pyrrolo[2,3-c]pyridin-2-yl)-1H-indazole (XIII). Final deprotection of the pyrazole nitrogen yields the desired substituted 3-(1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole analogs (XIV).

Illustrative Compound Examples

Preparation of intermediate 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (XVII) is depicted below in Scheme 3.

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Step 1

A mixture of 5-bromo-1H-indazole (XV) (500 g, 2.54 mol), DHP (256 g, 3.05 mol), and p-TsOH (48.3 g, 254 mmol) in DCM (4 L) was stirred at 25° C. for 4 h. TLC (PE:EtOAc=2:1, Rf=0.83) showed that the reaction was complete. The mixture was washed with a saturated NaHCO₃solution (1000 mL), brine, dried over Na₂SO₄, and concentrated to give 5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (XVI) (700 g, crude) as a yellow oil. ESIMS found for C₁₂H₁₃BrN₂O m/z 281.1 (M+H).

Step 2

A mixture of 5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (XVI) (200 g, 711 mmol), bis(pinacolato)diboron (217 g, 854 mmol), KOAc (279 g, 2.85 mol) and Pd(dppf)Cl₂(10.4 g, 14.23 mmol) in dioxane (2 L) was stirred at 85° C. for 16 h. TLC (PE:EtOAc=2:1, Rf=0.78) showed that the reaction was complete. The mixture was filtered and the filtrate was concentrated. The residue was purified by column chromatography on silica gel (PE:EtOAc=20:1) to give 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (XVII) (110 g, 335 mmol, 47.1% yield) as a white solid. ¹H NMR (CDCl₃, 400 MHz) δ ppm 1.26 (s, 12H), 1.36 (s, 12H), 1.60-1.84 (m, 3H), 2.06 (dd, J=3.2 Hz, J=13.2 Hz, 1H), 2.15 (br s, 1H), 2.49-2.66 (m, 1H), 3.74 (t, J=8.8 Hz, 1H), 4.03 (d, J=12 Hz, 1H), 5.72 (dd, J=2.8 Hz, J=11.2 Hz, 1H), 7.56 (d, J=8.4 Hz, 1H), 7.80 (d, J=8.4 Hz, 1H), 8.03 (s, 1H), 8.25 (s, 1H); ESIMS found for C₁₈H₂₅BN₂O₃m/z 329.1 (M+H).

Preparation of the 7-fluoro-substituted indazole intermediate (XXIII) is depicted below in Scheme 4.

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Step 1

To a stirred solution of 2,3-difluorobenzaldehyde (XVIII) (75.0 g, 528 mmol, 1.0 eq) in H₂SO₄(565 mL) was added NBS (113 g, 633 mmol, 1.2 eq) in portions at 60° C. The resulting mixture was stirred at 60° C. for 12 hr. LC/MS showed the reaction was completed. The reaction mixture was poured into ice water and petroleum ether (500 mL) and stirred for 10 min, the organic layer was separated and concentrated under vacuum to give crude product. The residue was purified column chromatography silica gel (100% petroleum ether) to give 5-bromo-2,3-difluorobenzaldehyde (XIX) (120 g, 543.0 mmol, quantitative yield). ESIMS found C₇H₃BrF₂O m/z 221.1 (M+1).

Step 2

To a solution of 5-bromo-2,3-difluorobenzaldehyde (XIX) (115 g, 520 mmol, 1.0 eq), MeONH₂.HCl (47.8 g, 572 mmol, 1.1 eq) and K₂CO₃(86.3 g, 624 mmol, 1.20 eq) was in DME (1.30 L) was heated to 40° C. for 15 h. TLC (petroleum ether) showed (XIX) was consumed. The reaction was filtered and the filtrate was concentrated under vacuum to give crude product. The residue was purified by column chromatography on silica gel (100% petroleum ether) to give (E)-5-bromo-2,3-difluorobenzaldehyde O-methyl oxime (XX) (74 g, 56.9% yield). ¹H NMR (CDCl₃, 400 MHz) δ ppm 4.04 (s, 3H), 7.37-7.32 (m, 1H), 7.77 (s, 1H), 8.23 (s, 1H); ESIMS found C₈H₆BrF₂NO m/z 250.2 (M+1).

Step 3

A solution of (E)-5-bromo-2,3-difluorobenzaldehyde O-methyl oxime (XX) (150 g, 600 mmol, 1.0 eq), NH₂NH₂—H₂O (600 mL) in dry THF (600 mL) was heated to 90° C. for 84 h. LC/MS showed the reaction was completed. The solvent was evaporated and the resulting mixture was diluted with EtOAc, washed with water, dried over Na₂SO₄and concentrated under vacuum to give crude product. The residue was purified by column chromatography on silica gel (PE:EtOAc=10:1) to give 5-bromo-7-fluoro-1H-indazole (XXI) as a white solid (78 g, 362.7 mmol, 60.5% yield). ¹H NMR (DMSO-d₆, 400 MHz) δ ppm 7.44 (d, J=9.6 Hz, 1H), 7.87 (d, J=1.6 Hz, 1H), 8.17 (s, 1H), 13.90 (s, 1H); ESIMS found C₇H₄BrFN₂m/z 215 (M+1).

Step 4

Preparation of 5-bromo-7-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (XXII) was performed following the procedure listed in Scheme 3, Step 1. Light yellow solid (98 g, 327.6 mmol, 93.9% yield). ¹H NMR (CDCl₃, 400 MHz) δ ppm 1.78-1.62 (m, 3H), 2.17-2.09 (m, 2H), 2.63-2.58 (m, 1H), 3.76 (t, J=11.6 Hz, 1H), 4.05 (d, J=9.6 Hz, 1H), 5.85 (d, J=9.6 Hz, 1H), 7.22 (d, J=12.0 Hz, 1H), 7.65 (s, 1H), 8.00 (s, 1H); ESIMS found C₁₂H₁₂BrFN₂O m/z 299.2 (M+1).

Step 5

Preparation of 7-fluoro-1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (XXIII) was performed following the procedure listed in Scheme 3, Step 2. White solid (45 g, 130.0 mmol, 86.7% yield). ESIMS found C₁₈H₂₄BFN₂O₃m/z 347.1 (M+1).

Preparation of the 6-fluoro-substituted indazole intermediate (XXX) is depicted below in Scheme 5.

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Step 1

A solution of 5-fluoro-2-methylaniline (XXIV) (100 g, 799 mmol, 1.0 eq) and Ac₂O (89 g, 879 mmol, 1.1 eq) in toluene (4.0 L) was stirred at 110° C. for 4 h. TLC (PE:EtOAc=2:1) showed (XXIV) was consumed. The reaction mixture was cooled to 25° C. The precipitated solid was filtered, washed with petro ether. The solid was dried in vacuo to give N-(5-fluoro-2-methylphenyl)acetamide (XXV) as a white solid (120 g, 717.8 mmol, 89.8% yield), which was used in step 2 without further purification. ESIMS found C₉H₁₀FNO m/z 168.1 (M+1).

Step 2

To a solution of N-(5-fluoro-2-methylphenyl)acetamide (XXV) (120 g, 717 mmol, 1.0 eq) in HOAc (3 L) was added a solution of Br₂(140 g, 876 mmol, 1.2 eq) in HOAc (1 L) dropwise. The mixture was stirred at 25° C. for 3 h. LC/MS showed compound 2 was (XXV) completely consumed. The reaction mixture was quenched with water (8 L). The solid was filtered, washed with water and petroleum ether. The solid was dried in vacuo to give N-(4-bromo-5-fluoro-2-methylphenyl)acetamide (XXVI) as a white solid (155 g, 629.9 mmol, 87.8% yield). ¹H NMR (CDCl₃, 400 MHz) δ ppm 2.20 (s, 6H), 7.07 (brs, 1H), 7.32 (d, J=7.2 Hz, 1H), 7.85 (d, J=10.8 Hz, 1H); ESIMS found C₉H₉BrFNO m/z 247.2 (M+1).

Step 3

A solution of N-(4-bromo-5-fluoro-2-methylphenyl)acetamide (XXVI) (155 g, 629.9 mmol, 1.0 eq), Ac₂O (192 g, 1.8 mol, 3.0 eq), KOAc (123 g, 1.26 mol, 2.0 eq), 18-CROWN-6 (8.3 g, 31 mmol, 0.05 eq) and isoamyl nitrite (147 g, 1.2 mol, 2.0 eq) in CHCl₃(7.0 L) was stirred at 65° C. for 12 h. TLC (PE:EtOAc=5:1, Rf=0.2) showed (XXVI) was consumed completely. The solvent was removed under reduced pressure. The residue was extracted with EtOAc (1.5 L) and water (1.5 L). The organic layer was dried over anhydrous Na₂SO₄, concentrated under reduced pressure to give 1-(5-bromo-6-fluoro-1H-indazol-1-yl)ethan-1-one (XXVII) as a white solid (170 g, crude, quantitative yield), which was used in step 4 without further purification. ESIMS found C₉H6BrFN₂O m/z 258.1 (M+1).

Step 4

A solution of 1-(5-bromo-6-fluoro-1H-indazol-1-yl)ethan-1-one (XXVII) (170 g, 629.9 mmol, 1.0 eq) in 3 N HCl (6.6 mol, 10 eq) and MeOH (900 mL) was stirred at 60° C. for 12 h. TLC (PE:EtOAc=5:1, Rf=0.8) showed (XXVII) was consumed completely. The reaction mixture was cooled to room temperature and basified with 1N aq. NaOH to pH=10. The precipitated solid was filtered and dried in vacuo to afford 5-bromo-6-fluoro-1H-indazole (XXVIII) as a yellow solid (100 g, 465.1 mmol, 73.8% yield). ESIMS found C₇H₄BrFN₂m/z 215.1 (M+1).

Step 5

To solution of a mixture of 5-bromo-6-fluoro-1H-indazole (XXVIII) (90 g, 418 mmol, 1.0 eq) and 3,4-dihydro-2H-pyran (70 g, 837 mmol, 2.0 eq) in DCM (2.0 L) was added p-TsOH (3.6 g, 20 mmol, 0.05 eq) at 25° C. The resulting mixture was stirred at 25° C. for 12 h. TLC (PE:EtOAc=5:1, Rf=0.7) showed (XXVIII) was completely consumed. To the reaction mixture was added saturated aqueous NaHCO₃(4 L). The organic layer was separated, dried over Na₂SO₄, concentrated in vacuo to give a residue, which was further purified by silica gel column (EtOAc:PE=20:1) to give 5-bromo-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (XXIX) as a brown oil (120 g, 401.1 mmol, 96.0% yield), which was used in step 6 without further purification. ESIMS found C₁₂H₁₂BrFN₂O m/z 299.2 (M+1).

Step 6

A solution of 5-bromo-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (XXIX) (30 g, 100 mmol, 1.0 eq), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (25 g, 100 mmol, 1.0 eq), Pd(dppf)Cl₂(3.6 g, 5.0 mmol, 0.05 eq), KOAc (19.6 g, 200 mmol, 2.0 eq) in dioxane (550 mL) was stirred at 100° C. for 12 h under N₂. LC/MS showed (XXIX) was completely consumed. The reaction mixture was concentrated and then extracted with EtOAc (300 mL) and water (100 mL). The mixture was filtered and separated. The organic layer was dried over anhydrous Na₂SO₄, concentrated to give crude product, which was further purified by silica gel column (EtOAc:PE=20/1) to give 6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (XXX) as a green solid (13 g, 37.5 mmol, 37.4% yield). ¹H NMR (CDCl₃, 400 MHz) δ ppm 1.37 (s, 12H), 1.73-1.43 (m, 3H), 2.58-2.50 (m, 1H), 3.79-3.73 (m, 1H), 4.06-4.04 (m, 1H), 5.66-5.63 (m, 1H), 7.28-7.21 (m, 1H), 8.00 (s, 1H), 8.19 (d, J=5.6 Hz, 1H); ESIMS found C₁₈H₂₄BFN₂O₃m/z 347.2 (M+1).

Preparation of the 4-fluoro-substituted indazole intermediate (XXXV) is depicted below in Scheme 6.

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Step 1

To a stirred solution of 3-fluoro-2-methylaniline (XXXI) (50 g, 399 mmol, 1.0 eq) in CH₃CN (1.2 L) was added NBS (78 g, 439 mmol, 1.1 eq) in portions at 10° C., the resulting mixture was stirred at 25° C. for 1 h. LC/MS showed the reaction was completed. Saturated Na₂S₂O₃(1.2 L) was then added slowly to the reaction mixture at 10° C., extracted with EtOAc (2 L) and the organic layer was concentrated under vacuum to give crude product. The residue was washed with PE (1 L), the solid was filtered, washed again with PE (500 mL) and dried under vacuum to give 4-bromo-3-fluoro-2-methylaniline (XXXII) as a white solid (163.0 g, 798.9 mmol, 66.7% yield). ESIMS found C₇H₇BrFN m/z 204.1 (M+1).

Step 2

To a stirred solution of 4-bromo-3-fluoro-2-methylaniline (XXXII) (40 g, 196 mmol, 1.0 eq) in HOAc (1.2 L) was added NaNO₂(16 g, 235 mmol, 1.2 eq) in portions at 10° C., the resulting mixture was stirred at 25° C. for 4 h. LC/MS showed the reaction was completed. Upon completion, aqueous NaOH (50%) was added to the reaction mixture until pH 7-8, then the mixture was extracted with EtOAc (1.6 L), the organic layer was dried over Na₂SO₄, filtered; filtrate was concentrated under vacuum to give crude 5-bromo-4-fluoro-1H-indazole (XXXIII) (40 g, 186.0 mmol, 94.9% yield), which was used in step 3 without further purification. ¹H NMR (CDCl₃, 400 MHz) δ ppm 7.47-7.42 (m, 1H), 7.56-7.53 (m, 1H), 8.23 (s, 1H); ESIMS found C₇H4BrFN₂m/z 215 (M+1).

Step 3

Preparation of 5-bromo-4-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (XXXIV) was performed following the procedure listed in Scheme 4, Step 5. Brown oil (9.9 g, 33.1 mmol, 71.9% yield). ¹H NMR (CDCl₃, 400 MHz) δ ppm 1.75-1.67 (m, 3H), 2.10-1.76 (m, 2H), 2.52-2.14 (m, 1H), 3.76-3.71 (m, 1H), 4.01-3.97 (m, 1H), 5.70-5.69 (m, 1H), 7.30-7.26 (m, 1H), 7.47-7.45 (m, 1H), 8.06 (s, 1H); ESIMS found C₁₂H₁₂BrFN₂O m/z 299 (M+1).

Step 4

Preparation of 4-fluoro-1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (XXXV) was performed following the procedure listed in Scheme 4, Step 6. Red oil (25 g, 72.2 mmol, 72.2% yield). ¹H NMR (CD₃OD, 400 MHz) δ ppm 1.72 (s, 12H), 2.12-1.74 (m, 5H), 2.52-2.16 (m, 1H), 3.85-3.80 (m, 1H), 4.12-4.00 (m, 1H), 5.84-5.81 (m, 1H), 7.48 (d, J=8.0 Hz, 1H), 7.71-7.67 (m, 1H), 8.15 (s, 1H); ESIMS found C₁₈H₂₄BFN₂O₃m/z 347 (M+1).

Preparation of intermediate N-(5-bromopyridin-3-yl)pivalamide (XXXVIII) is depicted below in Scheme 7.

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Step 1

To a solution of 3-amino-5-bromo pyridine (XXXVI) (1.0 g, 5.78 mmol) in dry pyridine (10 mL) was added pivaloyl chloride (XXXVII) (769 mg, 6.38 mmol). The reaction mixture was stirred at room temperature for 3 h. The reaction was poured into an ice water/saturated aqueous NaHCO₃mixture and stirred for 30 min. The precipitate was filtered, washed with cold water and dried at room temperature to yield N-(5-bromopyridin-3-yl)pivalamide (XXXVIII) as an off-white solid (1.082 g, 4.22 mmol, 73.1% yield). ¹H NMR (DMSO-d₆, 500 MHz) δ ppm 1.23 (s, 9H), 8.37 (d, J=2 Hz, 1H), 8.39 (t, J=2 Hz, 1H), 8.80 (d, J=2 Hz, 1H), 9.58 (brs, 1H); ESIMS found C₁₀H₁₃BrN₂O m/z 258.9 (Br⁸¹M+H).

The following intermediates were prepared in accordance with the procedure described in the above Scheme 7.

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N-(5-Bromopyridin-3-yl)isobutyramide (XXXIX): Off-white solid, (71% yield). ¹H NMR (CDCl₃) δ ppm 8.55-8.35 (m, 3H), 7.32 (s, 1H), 2.59-2.48 (m, 1H), 1.28-1.27 (d, 6H); ESIMS found C₉H₁₁BrN₂O m/z 242.9 (Br⁷⁹M+H).

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N-(5-Bromopyridin-3-yl)propionamide (XL): Off white solid (92% yield). ¹H NMR (DMSO-d₆) δ ppm 1.09 (t, J=7.54 Hz, 3H), 2.36 (q, J=7.54 Hz, 2H), 8.36 (m, 2H), 8.65 (d, J=2.07 Hz, 1H), 10.26 (s, 1H); ESIMS found C₈H9BrN₂O m/z 231.1 (Br^s8M+H).

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N-(5-Bromopyridin-3-yl)butyramide (XLI): Yellow solid (2.1 g, 8.64 mmol, 88.8% yield). ¹H NMR (CD₃OD, 400 MHz) δ ppm 1.02 (t, J=7.2 Hz, 3H), 1.74 (sxt, J=7.2 Hz, 2H), 2.40 (t, J=7.2 Hz, 2H), 8.35 (d, J=2 Hz, 1H), 8.46 (t, J=2 Hz, 1H), 8.63 (d, J=2 Hz, 1H); ESIMS found C₉H₁₁BrN₂O m/z 243.1 (Br⁷⁹M+H).

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N-(5-Bromopyridin-3-yl)pentanamide (XLII): Yellow solid (2.0 g, 7.78 mmol, 85.3% yield). ¹H NMR (CD₃OD, 400 MHz) δ ppm 0.98 (t, J=7.4 Hz, 3H), 1.43 (sxt, J=7.4 Hz, 2H), 1.70 (quin, J=7.4 Hz, 2H), 2.43 (t, J=7.6 Hz, 2H), 8.35 (s, 1H), 8.45 (d, J=2 Hz, 1H), 8.64 (d, J=2 Hz, 1H); ESIMS found C₁₀H₁₃BrN₂O m/z 256.9 (Br⁷⁹M+H).

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N-(5-Bromopyridin-3-yl)-3-methylbutanamide (XLIII): Off white solid, (67% yield), ¹H NMR (CDCl₃, 500 MHz) δ ppm 8.55-8.42 (m, 3H), 7.62 (s, 1H), 2.31-2.18 (m, 3H), 1.02-1.01 (d, J=6 Hz, 6H); ESIMS found C₁₀H₁₃BrN₂O m/z 258.9 (Br⁸¹M+H).

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N-(5-Bromopyridin-3-yl)-3,3-dimethylbutanamide (XLIV): Yellow solid (1.7 g, 6.27 mmol, 78.6% yield). ¹H NMR (CD₃OD, 400 MHz) δ ppm 1.10 (s, 9H), 2.29 (s, 2H), 8.36 (d, J=1.6 Hz, 1H), 8.46 (d, J=2.0 Hz, 1H), 8.64 (d, J=2.0 Hz, 1H); ESIMS found C₁₁H₁₅BrN₂O m/z 273.1 ((Br⁸¹M+H).

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N-(5-Bromopyridin-3-yl)-2-phenylacetamide (XLV): White solid (2.5 g, 8.59 mmol, 77.9% yield). ¹H NMR (CDCl₃, 400 MHz) δ ppm 3.76 (s, 2H), 7.26-7.45 (m, 5H), 7.57 (brs, 1H), 8.33 (s, 1H), 8.37 (s, 2H); ESIMS found C₁₃H₁₁BrN₂O m/z 292.8 (Br⁸¹M+H).

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N-(5-Bromopyridin-3-yl)benzamide (XLVI): White solid (2.7 g, 9.74 mmol, 60% yield). ¹H NMR (CDCl₃, 400 MHz) δ ppm 7.40-7.52 (m, 2H), 7.52-7.62 (m, 1H), 7.86 (d, J=7.2 Hz, 2H), 8.39 (d, J=1.6 Hz, 1H), 8.46 (s, 1H), 8.55 (d, J=1.6 Hz, 1H), 8.57 (d, J=2.0 Hz, 1H); ESIMS found C₁₂H₉BrN₂O m/z 278.8 (Br⁸′M+H).

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N-(5-Bromopyridin-3-yl)cyclopropanecarboxamide (XLVII): Off-white solid, (83% yield), ¹H NMR (CDCl₃, 500 MHz) δ ppm 8.46-8.39 (m, 3H), 7.54 (bs, 1H), 1.56-1.50 (m, 1H), 1.13-1.07 (m, 2H), 0.96-0.90 (m, 2H); ESIMS found for C₉H₉BrN₂O m/z 240.9 (Br⁷⁹M+H).

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N-(5-Bromopyridin-3-yl)cyclobutanecarboxamide (XLVIII): Yellow solid (2.1 g, 6.27 mmol, 86.6% yield). ¹H NMR (CD₃OD, 400 MHz) δ ppm 1.80-1.99 (m, 1H), 1.99-2.15 (m, 1H), 2.16-2.30 (m, 2H), 2.30-2.45 (m, 2H), 3.25-3.35 (m, 1H), 8.34 (d, J=2.0 Hz, 1H), 8.47 (s, 1H), 8.64 (d, J=2.0 Hz, 1H); ESIMS found C₁₀H₁₁BrN₂O m/z 257.1 (Br⁸¹M+H).

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N-(5-Bromopyridin-3-yl)cyclopentanecarboxamide (XLIX): Yellow solid (1.9 g, 7.06 mmol, 80.2% yield). ¹H NMR (CD₃OD, 400 MHz) δ ppm 1.57-1.74 (m, 2H), 1.74-1.91 (m, 4H), 1.91-2.07 (m, 2H), 2.77-2.92 (m, 1H), 8.34 (d, J=1.6 Hz, 1H), 8.45 (s, 1H), 8.65 (d, J=2.0 Hz, 1H); ESIMS found C₁₁H₁₃BrN₂O m/z 271.1 (Br⁸¹M+H).

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N-(5-Bromopyridin-3-yl)cyclohexanecarboxamide (L): Yellow solid (2.0 g, 7.06 mmol, 84.3% yield). ¹H NMR (CD₃OD, 400 MHz) δ ppm 1.19-1.46 (m, 3H), 1.46-1.63 (m, 2H), 1.74 (d, J=11.6 Hz, 1H), 1.88 (t, J=14.0 Hz, 4H), 2.40 (tt, J=11.6 Hz, J=3.6 Hz, 1H), 8.34 (d, J=2.0 Hz, 1H), 8.44 (t, J=2.0 Hz, 1H), 8.64 (d, J=2.0 Hz, 1H); ESIMS found C₁₂H15BrN₂O m/z 285.1 (Br⁸¹M+H).

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N-(5-Bromopyridin-3-yl)-2-cyclohexylacetamide (LI): Yellow solid (261 mg, 0.878 mmol, 84.4% yield). ESIMS found C₁₃H17BrN₂O m/z 297.1 (Br⁸¹M+H).

Preparation of intermediate 5-bromo-N,N-dimethylpyridin-3-amine (LIII) is depicted below in Scheme 8.

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Step 1

To a solution of 3,5-dibromopyridine (LII) (2.37 g, 10.0 mmol) in dry DMF (20.0 mL) was added K₂CO₃(4.5 g, 33 mmol) and dimethylamino hydrochloride (1.79 g, 22 mmol). The mixture was heated overnight at 200° C. in a sealed tube. The solution was cooled to room temperature and excess DMF was removed under vacuum. The residue was partitioned between EtOAc and water. The organic phase was separated. The aqueous phase was washed with EtOAc and the combined organic phases were dried over MgSO₄, and concentrated to afford 5-bromo-N,N-dimethylpyridin-3-amine (LIII) as an off-white solid (1.78 g, 8.85 mmol, 88% yield). H NMR (DMSO-d₆, 500 MHz) δ ppm 2.94 (s, 6H), 7.25 (t, J=2 Hz, 1H), 7.91 (d, J=2 Hz, 1H), 8.07 (d, J=2 Hz, 1H); ESIMS found C₇H9BrN₂m/z 201.1 (M+H).

Preparation of intermediate 5-bromo-N-isopropylpyridin-3-amine (LIV) is depicted below in Scheme 9.

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Scheme 9

To a solution of 5-bromopyridin-3-amine (XXXVI) (535 mg, 3.09 mmol) in MeOH (62 mL) was added acetone (296 μL, 4.02 mL). The pH was adjusted to 4 using HOAc and stirred for 30 min. NaCNBH₃(272 mg, 4.33 mmol) was added and stirred at room temperature overnight. The MeOH was removed under vacuum and the residue was partitioned between EtOAc and saturated aqueous NaHCO₃. The organic layer was dried over MgSO₄and evaporated under vacuum. The crude product was purified on a silica gel column (100% hexanes→90:10 hexanes:EtOAc) to produce 5-bromo-N-isopropylpyridin-3-amine (LIV) as an oil which slowly solidified into an off-white solid (309 mg, 1.44 mmol, 47% yield). ¹H NMR (DMSO-d₆, 500 MHz) δ ppm 1.12 (d, J=6.3 Hz, 6H), 3.55-3.59 (m, 1H), 6.03 (d, J=7.9 Hz, 1H), 7.05-7.06 (m, 1H), 7.75 (d, J=2 Hz, 1H), 7.90 (d, J=2 Hz, 1H); ESIMS found C₈H₁₁BrN₂m/z 215.1 (M+H).

Preparation of intermediate 1-(5-bromopyridin-3-yl)-N,N-dimethylmethanamine (LVI) is depicted below in Scheme 10.

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Steps 1

Preparation of 1-(5-bromopyridin-3-yl)-N,N-dimethylmethanamine (LVI) was performed following the procedure listed in Scheme 9, Step 1. Brown oil (1.20 g, 5.59 mmol, 45% yield). ¹H NMR (DMSO-d₆, 500 MHz) δ ppm 2.15 (s, 6H), 3.43 (s, 2H), 7.94 (s, 1H), 8.47 (d, J=1.1 Hz, 1H), 8.59 (d, J=2.2 Hz, 1H); ESIMS found C₈H₁₁BrN₂m/z 215 (M^Br79+H) and 217 (M^Br81+H).

Preparation of intermediate 3-bromo-5-((3,3-difluoropyrrolidin-1-yl)methyl)pyridine (LVII) is depicted below in Scheme 11.

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Steps 1

To a mixture of 5-bromopyridine-3-carbaldehyde (LV) (6.00 g, 32.26 mmol, 1.0 eq), 3,3-difluoropyrrolidine (5.56 g, 38.71 mmol, 1.20 eq) and TEA (5.39 mL, 38.71 mmol, 1.2 eq) in DCE (200 mL) was stirred at room temperature for 30 min, then added sodium triacetoxyborohydride (10.25 g, 48.38 mmol, 1.50 eq) in one portion at room temperature under N₂. The mixture was stirred at room temperature for 6 h. TLC showed the reaction was complete. The reaction was quenched with 1N NaOH (100 mL), extracted with DCE (100 mL×2). The combined organic layers were washed with brine (100 mL), dried and concentrated. The residue was purified by silica gel chromatography (column height: 50 mm, diameter: 50 mm, 300-400 mesh silica gel, DCM/MeOH=30/1→20/1) to give 3-bromo-5-((3,3-difluoropyrrolidin-1-yl)methyl)pyridine (LVII): Yellow oil (8.00 g, 28.9 mmol, 89.5% yield). ¹H NMR (CDCl₃, 400 MHz) δ ppm 2.30 (spt, J=7.2 Hz. 2H), 2.75 (t, J=6.8 Hz, 2H), 2.91 (t, J=13.2 Hz, 2H), 7.85 (s, 1H), 8.45 (s, 1H), 8.59 (d, J=2 Hz, 1H); ESIMS found for C₁₀H₁₁BrF₂N₂m/z 277.0 (M+H).

The following intermediates were prepared in accordance with the procedure described in the above Schemes 9-11.

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3-Bromo-5-(pyrrolidin-1-ylmethyl)pyridine (LVIII): Golden liquid (1.35 g, 97% yield). ¹H NMR (DMSO-d₆) δ ppm 1.68-1.71 (m, 4H), 2.42-2.44 (m, 4H), 3.60 (s, 2H), 7.96 (s, 1H), 8.48 (d, J=2 Hz, 1H), 8.58 (d, J=3 Hz, 1H); ESIMS found for C₁₀H₁₃BrN₂m/z 242.2 (M+H).

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3-Bromo-5-(piperidin-1-ylmethyl)pyridine (LIX): Brown liquid (13.1 g, 94% yield). ¹H NMR (DMSO-d₆) δ ppm 1.36-1.39 (m, 2H), 1.46-1.51 (m, 4H), 2.31-2.32 (m, 4H), 3.46 (s, 2H), 7.94 (s, 1H), 8.47 (d, J=2 Hz, 1H), 8.58 (d, J=3 Hz, 1H); ESIMS found for C₁₁H₁₅BrN₂m/z 257.0 (M+H).

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N-((5-Bromopyridin-3-yl)methyl)ethanamine (LX): Golden liquid (1.29 g, 6.00 mmol, 60% yield). ¹H NMR (CDCl₃, 400 MHz) δ ppm 1.14 (t, J=7.2 Hz, 3H), 2.67 (q, J=7.2 Hz, 2H), 3.79 (s, 2H), 7.85 (t, J=2 Hz, 1H), 8.46 (d, J=1.6 Hz, 1H), 8.56 (d, J=2.4 Hz, 1H); ESIMS found for C₈H₁₁BrN₂m/z 215.1 (M+H).

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N-Benzyl-1-(5-bromopyridin-3-yl)methanamine (LXI): Yellow oil (8.0 g, 28.9 mmol, 89.5% yield). ¹H NMR (DMSO-d₆, 400 MHz) δ ppm 3.71 (s, 2H), 3.74 (s, 2H), 7.18-7.28 (m, 1H), 7.28-7.40 (m, 4H), 8.04 (s, 1H), 8.52 (s, 1H), 8.58 (s, 1H); ESIMS found for C₁₃H₁₃BrN₂m/z 277.1 (M+H).

Preparation of intermediate tert-butyl (5-bromopyridin-3-yl)methyl (cyclopentylmethyl)carbamate (LXVI) is depicted below in Scheme 12.

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Step 1

To a solution of 5-bromonicotinaldehyde (LV) (2.0 g, 10.8 mmol, 1 eq) in MeOH (20 mL) was added NaBH₄(2.4 g, 64.9 mmol, 6 eq) and the reaction mixture was stirred at room temperature for 3 h. The mixture was concentrated in vacuo and the residue was diluted in water (15 mL), the aqueous phase was extracted with DCM (10 mL×3). The combined organic layers were dried over MgSO₄, filtered and concentrated in vacuo to afford (5-bromopyridin-3-yl)methanol (LXII) (1.8 g, 9.57 mmol, 90.0% yield) as a colorless oil. ¹H NMR (CDCl₃, 500 MHz) δ ppm 4.73 (s, 2H), 7.90 (s, 1H), 8.47 (s, 1H), 8.57 (s, 1H). ESIMS found for C₆H₆BrNO m/z 188.0 (M+H).

Step 2

To a stirred solution of (5-bromopyridin-3-yl)methanol (LXII) (1.60 g, 8.5 mmol, 1 eq), phthalimide (1.24 g, 8.5 mmol, 1 eq) and PPh₃(3.33 g, 12.75 mmol, 1.5 eq) in anhydrous THF (15 mL) was added DEAD (2.21 g, 12.75 mmol, 1.5 eq) dropwise at 0° C. under N₂. Then the reaction mixture was stirred at room temperature for 6 h. The mixture was washed with saturated NaHCO₃solution (15 mL), water (15 mL) and brine (15 mL) subsequently. The organic layers were dried over MgSO₄, concentrated under reduced pressure, the resultant residue was purified by flash chromatography on silica gel (PE:EtOAc=4:1) to give 2-((5-bromopyridin-3-yl)methyl)isoindoline-1,3-dione (LXIII) (2.5 g, 7.88 mmol, 82.3% yield) as a white solid. ESIMS found for C₁₄H9BrN₂O₂m/z 317.1 (M+H).

Step 3

A solution of 2-((5-bromopyridin-3-yl)methyl)isoindoline-1,3-dione (LXIII) (1.9 g, 6.0 mmol, 1 eq) and hydrazine hydrate (2.0 g, 40 mmol, 6 eq) in EtOH (20 mL) was heated at 70° C. for 3 h. The mixture was filtered through a Celite® pad and the filtrate was concentrated in vacuo, the crude product was dissolved in 1N HCl solution (15 mL) and concentrated to dryness, then it was washed with acetone (10 mL×3), the precipitate was collected by filtration, dried in vacuo to give (5-bromopyridin-3-yl)methanamine (LXIV) (1.3 g, 6.95 mmol, 97.7% yield) as a white solid. ¹H NMR (D₂O, 500 MHz) δ ppm 4.34 (s, 2H), 8.56 (s, 1H), 8.75 (d, J=1.2 Hz, 1H), 8.91 (d, J=1.6 Hz, 1H). ESIMS found for C₆H7BrN₂m/z 187.0 (M+H).

Step 4

A solution of (5-bromopyridin-3-yl)methanamine (LXIV) (1.30 g, 5.8 mmol, 1.0 eq), cyclopentanecarbaldehyde (0.57 g, 5.8 mmol, 1.0 eq) and TEA (0.60 g, 5.8 mmol, 1.0 eq) in MeOH (15 mL) was stirred at room temperature for 2 h. Then NaBH₃CN (1.98 g, 34.6 mmol, 6.0 eq) was added and the mixture was stirred at the same temperature for another 3 h. The solvent was removed under reduced pressure and the residue was diluted in water (20 mL) and extracted with DCM (10 mL×3), combined organic layers were dried over MgSO₄and concentrated in vacuo to give 1-(5-bromopyridin-3-yl)-N-(cyclopentylmethyl)methanamine (LXV) (1.23 g, 4.57 mmol, 79.3% yield) as a yellow oil. ¹H NMR (CDCl₃, 400 MHz) δ ppm 1.07-1.23 (m, 2H), 1.47-1.67 (m, 4H), 1.70-1.84 (m, 2H), 2.02 (spt, J=7.6 Hz. 1H), 2.53 (d, J=7.2 Hz, 2H), 3.80 (s, 2H), 7.86 (s, 1H), 8.47 (s, 1H), 8.56 (d, J=2.0 Hz, 1H); ESIMS found for C₁₂H17BrN₂m/z 269.1 (M+H).

Step 5

To a solution of 1-(5-bromopyridin-3-yl)-N-(cyclopentylmethyl)methanamine (LXV) (1.00 g, 3.7 mmol, 1 eq) and TEA (0.93 g, 9.2 mmol, 2.5 eq) in DCM (20 mL) was added portion wise Boc₂O (0.85 g, 4.0 mmol, 1.1 eq) at 0° C., the reaction mixture was stirred at room temperature for 1 h. The mixture was washed with water (10 mL), brine (10 mL), the organic layer was separated, dried over MgSO₄and concentrated in vacuo to give tert-butyl (5-bromopyridin-3-yl)methyl(cyclopentylmethyl) carbamate (LXVI) (1.25 g, 3.38 mmol, 91.9% yield) as a white solid. ESIMS found for C₁₇H₂₅BrN₂O₂m/z 369.1 (M+H).

Preparation of intermediate 3-bromo-5-(cyclohexyloxy)pyridine (LXIX) is depicted below in Scheme 13.

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Step 1

To a solution of 5-bromopyridin-3-ol (LXVII) (523 mg, 3.01 mmol) in THF (30 mL) cooled to 0° C. were added triphenylphosphine (867 mg, 3.31 mmol) and cyclohexanol (LXVIII) (331 mg, 3.31 mmol) followed by (E)-bis(4-chlorobenzyl) diazene-1,2-dicarboxylate (1.21 g, 3.31 mmol), added portion wise. The reaction mixture was then stirred at 25° C. overnight. The reaction was worked-up with an EtOAc—NaHCO₃extraction and the solid filtered off. The solvent was removed and the residue was purified by ISCO (20% EtOAc-hexanes) to give 3-bromo-5-(cyclohexyloxy)pyridine (LXIX) (209 mg, 0.82 mmol, 27.2% yield) as a yellow oil. ¹H NMR (DMSO-d₆, 500 MHz) δ ppm 1.21-1.31 (m, 1H) 1.34-1.48 (m, 4H) 1.49-1.57 (m, 1H) 1.70 (br dd, J=9.74, 4.25 Hz, 2H) 1.88-1.96 (m, 2H) 2.50 (dt, J=3.70, 1.72 Hz, 5H) 4.46-4.54 (m, 1H) 7.72 (t, J=2.20 Hz, 1H) 8.24 (d, J=1.92 Hz, 1H) 8.27 (d, J=2.47 Hz, 1H).

The following intermediate was prepared in accordance with the procedure described in the above Scheme 13.

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tert-Butyl 4-((5-bromopyridin-3-yl)oxy)piperidine-1-carboxylate (LXX): Yellow oil (244 mg, 0.683 mmol, 23.2% yield). ESIMS found for C₁₅H₂₁BrN₂O₃m/z 358.3 (M+H).

Preparation of intermediate 3-(benzyloxy)-5-bromopyridine (LXXII) is depicted below in Scheme 14.

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Step 1

To a solution of 5-bromopyridin-3-ol (LXVII) (174 mg, 1.0 mmol) in DMF (3 mL) was added potassium carbonate (415 mg, 3.0 mmol). The slurry was heated at 90° C. for 1 h and then cooled to 25° C. The (bromomethyl)benzene (LXXI) (171 mg, 1.0 mmol) was added and the mixture was stirred at 25° C. overnight. The reaction was worked-up using a saturated sodium bicarbonate and EtOAc extraction. The product was purified by ISCO column (40-100% EtOAc-hexanes). The 3-(benzyloxy)-5-bromopyridine (LXXII) (105 mg, 0.398 mmol, 39.8% yield) was obtained as yellow oil. ESIMS found for C₁₂H₁₀BrNO m/z 266.1 (M+H).

The following intermediates were prepared in accordance with the procedure described in the above Scheme 14.

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3-Bromo-5-(2-(pyrrolidin-1-yl)ethoxy)pyridine (LXXIII): Yellow oil (97 mg, 0.358 mmol, 15.56% yield). ESIMS found for C₁₁H₁₅BrN₂O m/z 272.2 (M+H).

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2-((5-Bromopyridin-3-yl)oxy)-N,N-dimethylethan-1-amine (LXXIV): Yellow oil (97 mg, 0.396 mmol, 28.9% yield). ESIMS found for C₉H₁₃BrN₂O m/z 245.1 (M+H).

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1-(2-(3-Bromo-5-fluorophenoxy)ethyl)pyrrolidine (LXXV): Yellow oil (370 mg, 1.284 mmol, 85.8% yield). ESIMS found for C₁₂H1₅BrFNO m/z 289.0 (M+H).

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2-(3-Bromo-5-fluorophenoxy)-N,N-dimethylethan-1-amine (LXXVI): Yellow oil (364 mg, 1.389 mmol, 50.2% yield). ESIMS found for C₁₀H₁₃BrFNO m/z 263.9 (M+H).

Preparation of intermediate tert-butyl 4-(2-((5-bromopyridin-3-yl)amino)-2-oxoethyl)piperidine-1-carboxylate (LXXVIII) is depicted below in Scheme 15.

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Step 1

To a solution of 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)acetic acid (LXXVII) (3.4 g, 13.97 mmol) in DCM (10 mL) was added DMF (1 mL). The solution was cooled in ice-water to 0° C. Oxalyl chloride (1.835 mL, 20.96 mmol) was then added dropwise. The mixture was stirred for 1 h at 25° C. The organic volatile was then removed under vacuum. The residue was dissolved in DCM (10 mL). DMAP (0.171 g, 1.397 mmol) and 5-bromopyridin-3-amine (XXXVI) (2.418 g, 13.97 mmol) were added to the solution and cooled to 0° C. DIPEA (4.88 ml, 27.9 mmol) was then added dropwise and the mixture was stirred for 2 h at 25° C. The reaction was worked-up with DCM and saturated NaHCO₃. The product was purified by ISCO (0-100% EtOAc-hexanes). The tert-butyl 4-(2-((5-bromopyridin-3-yl)amino)-2-oxoethyl)piperidine-1-carboxylate (LXXVIII) (2.82 g, 7.08 mmol, 50.7% yield) was obtained as a yellow oil. ESIMS found for C₁₇H₂₄BrN₃O₃m/z 343.1 (M-56).

The following intermediate was prepared in accordance with the procedure described in the above Scheme 15.

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N-(5-Bromopyridin-3-yl)-2-(dimethylamino)acetamide (LXXIX): Yellow oil (528 mg, 2.05 mmol, 19.0% yield). ESIMS found for C₉H1₂BrN₃O m/z 259.3 (M+H).

Preparation of intermediate tert-butyl (1-(6-chloropyrazin-2-yl)azetidin-3-yl)carbamate (LXXXII) is depicted below in Scheme 16.

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Step 1

To a solution of tert-butyl azetidin-3-ylcarbamate hydrochloride (LXXX) (2 g, 9.58 mmol) in dry DMF (19.2 mL) was added DIPEA (8.37 ml, 47.9 mmol). To this mixture was added 2,6-dichloropyrazine (LXXXI) (1.428 g, 9.58 mmol) and the reaction was stirred at 95° C. for 3 h. The reaction was quenched with water (20 mL) and extracted with EtOAc. The organic layer was dried over anhydrous Na₂SO₄, filtered and concentrated. The residue was purified by silica gel column chromatography (40 g) (100% hexanes-hexanes:EtOAc 1:1) to yield tert-butyl (1-(6-chloropyrazin-2-yl)azetidin-3-yl)carbamate (LXXXII) (2.2882 g, 8.04 mmol, 84% yield) as a white solid. ESIMS found for C₁₂H₁₇ClN₄O₂m/z 285.1 (M+H).

Preparation of intermediate N-(3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl) methanesulfonamide (LXXXVI) is depicted below in Scheme 17.

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Step 1

A solution of 3-bromo-5-fluorobenzonitrile (LXXXIII) (44.0 g, 220.0 mmol, 1.0 eq) was dissolved in THF (30 mL). BH₃-Me₂S (33.43 g, 440.0 mmol, 2.0 eq) was added to the solution at 20° C. Then it was stirred at 80° C. for 2 h, HCl (6 N, 100 mL) was added to the mixture slowly at 20° C. The mixture was stirred at 80° C. for 1 h, then it was washed with EtOAc (300 mL). The water phase was basified with 50% aqueous NaOH and it was extracted with EtOAc (300 mL×3). The combined organic layers were dried over anhydrous Na₂SO₄and concentrated in vacuo to produce (3-bromo-5-fluoro-phenyl)methanamine (LXXXIV) (24.0 g, 117.62 mmol, 53.5% yield). ¹H NMR (CDCl₃, 300 MHz) ppm 3.86 (s, 2H), 7.01 (d, J=8 Hz, 1H), 7.12 (d, J=8 Hz, 1H), 7.28 (s, 1H); ESIMS found C₇H₇BrFN m/z 203.9 (Br⁷⁹M+H).

Step 2

A solution of (3-bromo-5-fluoro-phenyl)methanamine (LXXXIV) (23.0 g, 112.7 mmol, 1.0 eq) was dissolved in DCM (15 mL), TEA (34.22 g, 338.2 mmol, 3.0 eq) was added to the mixture. Then MsC1 (13.44 g, 117.3 mmol, 1.04 eq) was added slowly to the solution at 0° C. It was stirred at 0-30° C. for 2 h. The reaction was washed with water and extracted with EtOAc. The combined organic layers were dried over anhydrous Na₂SO₄and concentrated to give N-(3-bromo-5-fluorobenzyl)methanesulfonamide (LXXXV) (34.0 g, 102.44 mmol, 90.9% yield, 85% purity) as an oil. ¹H NMR (CDCl₃, 300 MHz) ppm 2.88 (s, 3H), 4.24 (d, J=4.5 Hz, 2H), 6.99 (d, J=9 Hz, 1H), 7.13 (dt, J=8.1 Hz, J=2 Hz, 1H), 7.25 (s, 1H); ESIMS found C₈H₉BrFNO₂S m/z 282.0 (Br⁷⁹M+H).

Step 3

A solution of N-(3-bromo-5-fluorobenzyl)methanesulfonamide (LXXXV) (34.0 g, 102.4 mmol, 1.0 eq) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (52.02 g, 204.9 mmol, 2.0 eq), KOAc (20.11 g, 204.9 mmol, 2.0 eq) was dissolved in dioxane (20 mL). Then Pd(dppf)Cl₂(7.60 g, 10.2 mmol, 0.1 eq) was added to the mixture. It was stirred at 90° C. for 2 h. Then the solvent was removed to get the residue which was purified by silica gel column (PE:EtOAc=10:1-100% EtOAc) to get N-(3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)methanesulfonamide (LXXXVI) (30.0 g, crude). ¹H NMR (CDCl₃, 400 MHz) δ ppm 1.37 (s, 12H), 2.92 (s, 3H), 4.34 (d, J=6.3 Hz, 2H), 7.19 (dt, J=9.3 Hz, J=2.1 Hz, 1H), 7.44 (dd, J=8.7 Hz, J=2.4 Hz, 1H), 7.54 (s, 1H); ESIMS found C₁₄H₂₁BFNO₄S m/z 330.1 (M+H).

Preparation of intermediate N-(3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl) methanesulfonamide (XC) is depicted below in Scheme 18.

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Step 1

To mixture of 1,3-dibromo-5-fluorobenzene (LXXXVII) (100 g, 393 mmol) and N′,N′-dimethylethane-1,2-diamine (173 g, 1.97 mol, 214 mL) was added t-BuOK (88 g, 787 mmol) in one portion at 25° C. under N₂. The mixture was stirred at 25° C. for 30 min, then heated to 110° C. and stirred for 11.5 h. The mixture was cooled to 25° C. and concentrated in reduced pressure at 45° C. The residue was purified by silica gel chromatography (column height: 250 mm, diameter: 100 mm, 100-200 mesh silica gel, PE/EtOAc=2:1, Rf=0.6) to give N¹-(3-bromo-5-fluorophenyl)-N²,N²-dimethylethane-1,2-diamine (LXXXVIII) (30 g, 114.9 mmol, 29.2% yield) as a yellow oil. ESIMS found for C₁₀H₁₄BrFN₂m/z 261.1 (M+H).

Step 2

To a mixture of N¹-(3-bromo-5-fluorophenyl)-N²,N²-dimethylethane-1,2-diamine (LXXXVIII) (30 g, 114 mmol) in DCM (200 mL) was added (Boc)₂O (37.6 g, 172 mmol), TEA (34.8 g, 344 mmol) and DMAP (7 g, 57.4 mmol) in one portion at 25° C. under N₂. The mixture was stirred at 25° C. for 12 h. The mixture was concentrated in reduced pressure at 45° C. The residue was purified by silica gel chromatography (column height: 250 mm, diameter: 100 mm, 100-200 mesh silica gel, PE/EtOAc=2:1, R_f=0.43) to give tert-butyl (3-bromo-5-fluorophenyl)(2-(dimethylamino)ethyl)carbamate (LXXXIX) (20 g, 55.4 mmol, 48.2% yield) as yellow oil. ¹H NMR (CDCl₃, 400 MHz) δ ppm 1.43 (s, 9H), 2.21 (s, 6H), 2.41 (t, J=7 Hz, 2H), 3.67 (t, J=7.2 Hz, 2H), 6.96 (d, J=9.6 Hz, 1H), 7.06 (d, J=6 Hz, 1H), 7.22 (s, 1H); ESIMS found for C₁₅H₂₂BrFN₂O₂m/z 361.0 (M+H).

Step 3

To a mixture of tert-butyl (3-bromo-5-fluorophenyl)(2-(dimethylamino)ethyl) carbamate (LXXXIX) (19 g, 52.6 mmol) and bis(pinacolato)diboron (20 g, 78.9 mmol) in dioxane (60 mL) was added Pd(dppf)Cl₂(3.8 g, 5.26 mmol) and KOAc (30.9 g, 315.6 mmol) in one portion at 25° C. under N₂. The mixture was stirred at 25° C. for 30 min, then heated to 110° C. and stirred for 11.5 h. The mixture was cooled to 25° C. and concentrated in reduced pressure at 45° C. The residue was purified by silica gel chromatography (column height: 250 mm, diameter: 100 mm, 100-200 mesh silica gel, /EtOAc=1:1, Rf=0.24) to give tert-butyl (2-(dimethylamino)ethyl)(3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamate (XC) (15 g, 36.7 mmol, 69.8% yield) as yellow oil. ESIMS found for C₂₁H₃₄BFN₂O₄m/z 327.2 (M+H as the boronic acid).

Preparation of intermediate (1-(tert-butoxycarbonyl)-4-(3-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)boronic acid (XCV) is depicted below in Scheme 19.

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Step 1

To a solution of 4-bromo-1H-pyrrolo[2,3-b]pyridine (XCI) (5 g, 25.4 mmol, 1 eq.), DMAP (311 mg, 2.55 mmol, 0.1 eq.) and TEA (5.3 mL, 38 mmol, 3 eq.) in DCM (100 mL) was added Boc₂O (7.2 mL, 31 mmol, 1.2 eq.) at 0° C. The reaction was warmed to room temperature and stirred for 2 h. Water (100 mL) was added and extracted with DCM (×2). Removal solvents gave tert-butyl 4-bromo-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (XCII) as a colorless oil (6.95 g, 23.4 mmol, 92.1% yield). ¹H NMR (CDCl₃, 400 MHz) δ ppm 1.60 (s, 9H), 6.50 (d, J=4 Hz, 1H), 7.31 (d, J=5.2 Hz, 1H), 7.63 (d, J=4 Hz, 1H), 8.23 (d, J=5.2 Hz, 1H); ESIMS found for C₁₂H₁₃BrN₂O₂m/z 297.1 (M+H).

Step 2

To a solution of tert-butyl 4-bromo-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (XCII) (1.5 g, 5.1 mmol, 1.0 eq) and (3-fluorophenyl)boronic acid (XCIII) (1.07 g, 7.65 mmol, 1.1 eq) in a mixture solvent of dioxane (18 mL) and water (6 mL) was added K₃PO₄(2.11 g, 15.3 mmol, 2.5 eq). The suspension was purged with nitrogen (×3) followed by addition of Pd(dppf)Cl₂(373 mg, 0.51 mmol, 0.1 eq). The reaction was stirred at 60° C. for 5 h. The suspension was poured into water (10 mL) and extracted with EtOAc (10 mL×3). The combined organic layer was washed with brine (5 mL), dried over Na₂SO₄and concentrated under reduced pressure. Then the crude product was purified by column chromatography on silica gel to afford tert-butyl 4-(3-fluorophenyl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (XCIV) as a white solid (1.37 g, 4.39 mmol, 86.0% yield). ¹H NMR (CDCl₃, 400 MHz) δ ppm 1.69 (s, 9H), 6.68 (d, J=4 Hz, 1H), 7.17 (dt, J=2 Hz, J=8.4 Hz, 1H), 7.25 (d, J=4.8 Hz, 1H), 7.35 (d, J=12 Hz, 1H), 7.41-7.53 (m, 2H), 7.70 (d, J=4 Hz, 1H), 8.57 (d, J=4.8 Hz, 1H); ESIMS found for C₁₈H₁₇FN₂O₂m/z 313.1 (M+H).

Step 3

To a solution of tert-butyl 4-(3-fluorophenyl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (XCIV) (1.37 g, 4.4 mmol, 1.0 eq) and triisopropyl borate (2.06 g, 10.9 mmol, 2.5 eq) in THF (10 mL), was added dropwise LDA (2 M, 5.45 mL, 10.9 mmol, 2.5 eq) at −78° C. under N₂. The reaction was stirred at this temperature for 5 h. The reaction was acidified with 1N HCl at −45° C. until pH<2. The aqueous phase was extracted with EtOAc (20 mL×3). The combined organic phase was washed with cooled 1N NaOH (50 ml×2). The aqueous was added ice and acidified with 1N HCl. The cloud solution was extracted with EtOAc (×2). The organic phase was separated and dried with Na₂SO₄. The solvent was removed under reduced pressure to give crude (1-(tert-butoxycarbonyl)-4-(3-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)boronic acid (XCV) as a brown solid (0.98 g, 2.75 mmol, 62.5% yield). ESIMS found for C₁₈H₁₈BFN₂O₄m/z 357.0 (M+H).

The following intermediate was prepared in accordance with the procedure described in the above Scheme 19.

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(1-(tert-Butoxycarbonyl)-4-(4-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)boronic acid (XCVI): White solid (580 mg, 1.63 mmol, 37.0% yield). ¹H NMR (DMSO-d6, 400 MHz) δ ppm 1.60 (s, 9H), 7.36 (d, J=4.8 Hz, 1H), 7.41 (t, J=8.8 Hz, 2H), 7.78 (dd, J=5.6 Hz, J=9.2 Hz, 2H), 8.36 (s, 2H), 8.42 (d, J=5.2 Hz, 2H); ESIMS found for C₁₈H₁₈BFN₂O₄m/z 357.0 (M+H).

Preparation of intermediate (1-(tert-butoxycarbonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)boronic acid (XCIX) is depicted below in Scheme 20.

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Step 1

To a solution of 1H-pyrrolo[2,3-b]pyridine (XCVII) (2.0 g, 16.9 mmol, 1 eq.), DMAP (103 mg, 0.84 mmol, 0.05 eq.) and TEA (12.7 mL, 50.7 mmol, 3 eq.) in DCM (30 mL) was added Boc₂O (4.7 mL, 18.6 mmol, 1.1 eq.) at 0° C. The reaction was warmed to room temperature and stirred for 2 h. Water (50 mL) was added and extracted with DCM (×2). Removal solvents gave tert-butyl 1H-pyrrolo[2,3-b]pyridine-1-carboxylate (XCVIII) as a yellow oil (3.4 g, 15.6 mmol, 92.2% yield). ESIMS found for C₁₂H₁₄N₂O₂m/z 219.1 (M+H).

Step 2

To a solution of tert-butyl 1H-pyrrolo[2,3-b]pyridine-1-carboxylate (XCVIII) (1.1 g, 5.0 mmol, 1.0 eq) and triisopropyl borate (2.0 g, 11.0 mmol, 2.2 eq) in THF (20 mL), was added dropwise LDA (2 M, 5.0 mL, 10.0 mmol, 2.0 eq) at −78° C. under N₂. The reaction was stirred at this temperature for 5 h. The reaction was acidified with 1N HCl at −45° C. until pH<2. The aqueous phase was extracted with EtOAc (20 mL×3). The combined organic phase was washed with cooled 1N NaOH (50 mL×2). The aqueous was added ice and acidified with 1N HCl. The cloud solution was extracted with EtOAc (×2). The organic phase was separated and dried with Na₂SO₄. The solvent was removed under reduced pressure to give crude (1-(tert-butoxycarbonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)boronic acid (XCIX) as a white solid (0.89 g, 3.39 mmol, 67.9% yield). ESIMS found for C₁₂H₁₅BN₂O₄m/z 263.1 (M+H).

Preparation of intermediate (1-(tert-butoxycarbonyl)-4-(pyridin-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)boronic acid (CIII) is depicted below in Scheme 21.

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Step 1

A solution of tert-butyl 4-bromo-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (XCII) (2 g, 6.8 mmol, 1.0 eq), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (2.07 g, 8.16 mmol, 1.02 eq), KOAc (1.99 g, 20.4 mmol, 3 eq) in dioxane (25 mL) was degassed (×3) with a water pump. Pd(dppf)Cl₂(246 mg, 0.34 mmol, 0.05 eq) was then added quickly in one portion under nitrogen. The reaction was stirred at 90° C. for 6 h. Water (100 mL) was added and extracted with EtOAc (×3). Flash chromatography (PE:EtOAc 20:1) gave tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (C) as a green oil (2.0 g, 5.82 mmol, 86.4%). ¹H NMR (CDCl₃, 400 MHz) δ ppm 1.39 (s, 12H), 1.67 (s, 9H), 6.93 (d, J=4 Hz, 1H), 7.54 (d, J=4.8 Hz, 1H), 7.65 (d, J=4 Hz, 1H), 8.51 (d, J=4.4 Hz, 1H); ESIMS found for C₁₈H₂₅BN₂O₄m/z 345.1 (M+H).

Step 2

The solution of tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (C) (890 mg, 2.59 mmol, 1.0 eq), 2-bromopyridine (CI) (410 mg, 2.59 mmol, 1.0 eq), K₂CO₃(1.07 g, 7.77 mmol, 3 eq) in dioxane/water (11 mL 10:1) was degassed (×3) with a water pump. Pd(dppf)Cl₂(95 mg, 0.13 mmol, 0.05 eq) was added quickly in one portion under nitrogen. The reaction was stirred at 90° C. for 5 h. Water (10 mL) was added and extracted with EtOAc (×3). Flash chromatography gave tert-butyl 4-(pyridin-2-yl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (CII) as a yellow solid (420 mg, 1.42 mmol, 54.9%). ¹H NMR (CDCl₃, 400 MHz) δ ppm 1.69 (s, 9H), 7.10 (d, J=4 Hz, 1H), 7.36 (t, J=6 Hz, 1H), 7.58 (d, J=5.2 Hz, 1H), 7.72 (d, J=4 Hz, 1H), 7.80-7.86 (m, 2H), 8.62 (d, J=4.8 Hz, 1H), 8.82 (d, J=4.4 Hz, 1H); ESIMS found for C₁₇H₁₇N₃O₂m/z 318.2 (M+Na).

Step 3

To a solution of tert-butyl 4-(pyridin-2-yl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (CII) (1.91 g, 6.5 mmol, 1.0 eq) and triisopropyl borate (3.05 g, 16.2 mmol, 2.5 eq) in THF (30 mL), was added dropwise LDA (2 M, 8.1 mL, 16.2 mmol, 2.5 eq) at −78° C. under N₂. The reaction was stirred at this temperature for 5 h. The reaction was acidified with 1N HCl at −45° C. until pH<2. The aqueous phase was extracted with EtOAc (20 mL×3). The combined organic phase was washed with cooled 1N NaOH (50 ml×2). The aqueous was added ice and acidified with 1N HCl. The cloud solution was extracted with EtOAc (×2). The organic phase was separated and dried with Na₂SO₄. The solvent was removed under reduced pressure to give crude (1-(tert-butoxycarbonyl)-4-(pyridin-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)boronic acid (CIII) as a white solid (1.31 g, 3.86 mmol, 59.4% yield). ESIMS found for C₁₇H₁₈BN₃O₄m/z 362.1 (M+Na).

Preparation of intermediate (1-(tert-butoxycarbonyl)-4-(4-methylpiperazin-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)boronic acid (CVIII) is depicted below in Scheme 22.

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Step 1

A solution of 4-bromo-1H-pyrrolo[2,3-b]pyridine (XCI) (10 g, 50.8 mmol, 1.0 eq) in anhydrous THF (150 mL) was degassed (×3) with a water pump, then cooled to 0° C. under Ar. NaH (60% in mineral oil) (2.436 g, 60.9 mmol, 1.2 eq) was added portion wise slowly under Ar. The reaction was stirred at 0° C. for 30 min. (2-(chloromethoxy)ethyl)trimethylsilane (10.15 g, 60.9 mmol, 1.2 eq) was added dropwise slowly. The reaction was stirred at room temperature for 2.5 h. The reaction mixture was added water (2 mL) then was concentrated in vacuo and water (50 mL) was added and extracted with EtOAc (×3). The organic layer was washed with brine and dried over Na₂SO₄. Flash chromatography (PE:ETOAc=10:1) gave 4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine (CIV) as a yellow oil (14.38 g, 43.9 mmol, 86.6% yield). ESIMS found for C₁₃H₁₉BrN₂OSi m/z 327.0 (M+H).

Step 2

A solution of 4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine (CIV) (3.27 g, 10 mmol, 1.0 eq), 1-methylpiperazine (2 g, 20 mmol, 2.0 eq), tBuOK (2.24 g, 20 mmol, 2.0 eq), Pd₂(dba)₃(915 mg, 1.0 mmol, 0.1 eq), XPhos (953 mg, 2 mmol, 0.2 eq), and toluene (50 mL) was degassed (×3) with a water pump. The reaction was stirred at 110° C. for overnight. The reaction mixture was concentrated in vacuo and water (50 mL) was added and extracted with DCM (×3). The organic layer was washed with brine and dried over Na₂SO₄. Flash chromatography (DCM:MeOH=40:1) gave 4-(4-methylpiperazin-1-yl)-1-((2-(trimethylsilyl) ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine (CV) as a yellow oil (2.81 g, 8.1 mmol, 81.1% yield). ESIMS found for C₁₈H₃₀N₄OSi m/z 347.3 (M+H).

Step 3

A solution of 4-(4-methylpiperazin-1-yl)-1-((2-(trimethylsilyl)ethoxy) methyl)-1H-pyrrolo[2,3-b]pyridine (CV) (2.4 g, 6.92 mmol, 1.0 eq), ethane-1,2-diamine (1.25 g, 20.76 mmol, 3.0 eq), TBAF (5.43 g, 20.76 mmol, 3.0 eq) and anhydrous THF (50 mL) was degassed (×3) with a water pump. Then the reaction was stirred at 80° C. for overnight. The reaction mixture was concentrated in vacuo and DCM (200 mL) was added. The organic layer was washed with brine and dried over Na₂SO₄. Flash chromatography (DCM:MeOH=30:1) gave 4-(4-methylpiperazin-1-yl)-1H-pyrrolo[2,3-b]pyridine (CVI) as a yellow solid (1.2 g, 5.55 mmol, 80.2% yield). ESIMS found for C₁₂H₁₆N₄m/z 217.1 (M+H).

Step 4

To a solution of 4-(4-methylpiperazin-1-yl)-1H-pyrrolo[2,3-b]pyridine (CVI) (1.2 g, 5.55 mmol, 1 eq.), DMAP (68 mg, 0.56 mmol, 0.1 eq.) and DIPEA (1.9 mL, 11.1 mmol, 2 eq.) in DCM (50 mL) was added Boc₂O (2.42 g, 11.1 mmol, 2.0 eq.) at 0° C. The reaction was warmed to room temperature and stirred overnight. The reaction mixture was concentrated in vacuo. Flash chromatography with (DCM:MeOH=30:1) gave tert-butyl 4-(4-methylpiperazin-1-yl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (CVII) as a yellow oil (980 mg, 3.10 mmol, 55.8% yield). ¹H NMR (CDCl₃, 400 MHz) δ ppm 1.65 (s, 9H), 2.37 (s, 3H), 2.61 (t, J=4.8 Hz, 4H), 3.42 (t, J=4.8 Hz, 4H), 6.47 (d, J=4 Hz, 1H), 6.55 (d, J=5.2 Hz, 1H), 7.47 (d, J=4 Hz, 1H), 8.28 (d, J=5.6 Hz, 1H); ESIMS found for C₁₇H₂₄N₄O₂m/z 317.2 (M+H).

Step 5

To a solution of tert-butyl 4-(4-methylpiperazin-1-yl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (CVII) (1.05 g, 3.3 mmol, 1.0 eq) and triisopropyl borate (1.57 g, 8.4 mmol, 2.5 eq) in THF (30 mL), was added dropwise LDA (2 M, 4.2 mL, 8.4 mmol, 2.5 eq) at -78° C. under N₂. The reaction was stirred at this temperature for 5 h. The reaction was acidified with 1N HCl at −45° C. until pH<2. The aqueous phase was extracted with EtOAc (50 mL×3). The combined organic phase was washed with cooled 1N NaOH (50 mL×2). The aqueous was added ice and acidified with 1N HCl. The cloud solution was extracted with EtOAc (×2). The organic phase was separated and dried with Na₂SO₄. The solvent was removed under reduced pressure to give crude (1-(tert-butoxycarbonyl)-4-(4-methylpiperazin-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)boronic acid (CVIII) as a white solid (732 mg, 2.03 mmol, 61.6% yield). ESIMS found for C₁₇H₂₅BN₄O₄m/z 361.1 (M+H).

The following intermediate was prepared in accordance with the procedure described in the above Scheme 22.

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(1-(tert-Butoxycarbonyl)-4-(piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)boronic acid (CIX): White solid (580 mg, 1.68 mmol, 56.0% yield). ESIMS found C₁₇H₂₄BN₃O₄m/z 346.1 (M+H).

Preparation of intermediate (4-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy) methyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)boronic acid (CXII) is depicted below in Scheme 23.

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Step 1

To a solution of 4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine (CIV) (5.0 g, 15.3 mmol, 1.0 eq) and pyridin-3-ylboronic acid (CX) (2.44 g, 19.9 mmol, 1.3 eq) in a mixture solvent of dioxane (60 mL) and water (20 mL) was added K₃PO₄(8.1 g, 38.2 mmol, 2.5 eq). The suspension was purged with nitrogen (×3) followed by addition of Pd(dppf)Cl₂(894 mg, 1.22 mmol, 0.08 eq). The reaction was stirred at 60° C. for 5 h. The suspension was cooled and poured into water (100 mL) and extracted with EtOAc (150 mL×3). The combined organic layer was washed with brine (100 mL), dried over Na₂SO₄and concentrated under reduced pressure. Then the residue was purified by silica gel chromatography (column height: 25 cm, diameter: 10 cm, 100-200 mesh silica gel) to afford 4-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine (CXI) as a yellow oil (4.97 g, 15.3 mmol, 99.9% yield). ESIMS found for C₁₈H₂₃N₃OSi m/z 326.0 (M+H).

Step 2

To a solution of 4-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine (CXI) (3.8 g, 11.7 mmol, 1.0 eq) and triisopropyl borate (7.68 g, 40.6 mmol, 3.5 eq) in THF (65 mL), was added dropwise LDA (2 M, 23.3 mL, 46.7 mmol, 4.0 eq) at -78° C. under N₂. The reaction was stirred at this temperature for 30 min. The reaction was quench with buffer pH=7, then warmed to 25° C. and extracted with EtOAc (100 mL×3), washed with brine (50 mL), and dried with Na₂SO₄. The solvent was removed under reduced pressure to give crude (4-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-2-yl) boronic acid (CXII) as a yellow solid (3.7 g, 10.0 mmol, 85.8% yield). ¹H NMR (DMSO-d6, 400 MHz) δ ppm -0.12 (s, 9H), 0.79 (t, J=8 Hz, 2H), 3.49 (dt, J=4.8 Hz, J=8 Hz, 2H), 5.97 (s, 2H), 7.36 (dd, J=3.2 Hz, J=8 Hz, 2H), 7.75 (dd, J=4.8 Hz, J=8 Hz, 1H), 8.36 (d, J=8 Hz, 1H), 8.44 (d, J=4.8 Hz, 1H), 8.77 (dd, J=1.6 Hz, J=4.8 Hz, 1H), 9.08 (d, J=1.6 Hz, 1H); ESIMS found for C₁₈H₂₄BN₃O₃Si m/z 370.1 (M+H).

The following intermediates were prepared in accordance with the procedure described in the above Scheme 23.

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(4-(2-Fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)boronic acid (CXIII): Yellow solid (5.3 g, 13.7 mmol, 95.9% yield). ¹H NMR (acetone-d6, 400 MHz) δ ppm 0.00 (s, 9H), 1.00 (dt, J=2.8 Hz, J=8.4 Hz, 2H), 3.71 (t, J=8.4 Hz, 2H), 6.11 (s, 2H), 7.16 (d, J=1.6 Hz, 1H), 7.29 (dd, J=1.6 Hz, J=5.2 Hz, 1H), 7.38-7.50 (m, 2H), 7.57-7.65 (m, 1H), 7.69-7.77 (m, 1H), 8.50 (d, J=4.8 Hz, 1H); ESIMS found C₁₉H₂₄BFN₂O₃Si m/z 387.1 (M+H).

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(4-(Pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)boronic acid (CXIV): Yellow solid (8.0 g, 21.7 mmol, 70.5% yield). ¹H NMR (acetone-d6, 400 MHz) δ ppm 0.06 (s, 9H), 1.06 (dt, J=2.8 Hz, J=8.4 Hz, 2H), 3.76 (dt, J=2.8 Hz, J=8.4 Hz, 2H), 6.21 (s, 2H), 7.53 (s, 1H), 7.58 (d, J=5.2 Hz, 1H), 8.25 (d, J=6.4 Hz, 2H), 8.33 (brs, 2H), 8.65 (d, J=5.2 Hz, 1H), 9.10 (d, J=6 Hz, 1H); ESIMS found C₁₈H₂₄BN₃O₃Si m/z 370.2 (M+H).

Preparation of intermediate (1-(tert-butoxycarbonyl)-4-(3-((tert-butoxycarbonyl)(2-(dimethylamino)ethyl)amino)-5-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)boronic acid (CXVIII) is depicted below in Scheme 24.

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Step 1

To a solution of tert-butyl (2-(dimethylamino)ethyl)(3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamate (XC) (5.0 g, 12.2 mmol, 1.0 eq), 4-chloro-1H-pyrrolo[2,3-b]pyridine (CXV) (2.06 g, 13.5 mmol, 1.1 eq) and K₂CO₃(3.4 g, 24.5 mmol, 2.0 eq), Pd(dppf)Cl₂(896 mg, 1.22 mmol, 0.1 eq) in dioxane (100 mL) was de-gassed and then heated to 80° C. for 12 h under N₂. The suspension was poured into water (150 mL) and extracted with EtOAc (200 mL×2). The combined organic layers was washed with brine (100 mL), dried over Na₂SO₄and concentrated under reduced pressure to give the crude product which was purified by silica gel (PE:EtOAc=30:1) to give tert-butyl (2-(dimethylamino)ethyl)(3-fluoro-5-(1H-pyrrolo[2,3-b]pyridin-4-yl)phenyl)carbamate (CXVI) (3.6 g, 9.06 mmol, 74.0% yield) as yellow oil. ESIMS found for C₂₂H₂₇FN₄O₂m/z 399.1 (M+H).

Step 2

To a solution of tert-butyl (2-(dimethylamino)ethyl)(3-fluoro-5-(1H-pyrrolo[2,3-b]pyridin-4-yl)phenyl)carbamate (CXVI) (4.0 g, 10.0 mmol, 1.0 eq) and Boc₂O (6.5 g, 30.0 mmol, 3.0 eq) in DCM (20 mL) was added Et₃N (5.6 mL, 40.0 mmol, 4.0 eq) in one portion at 20° C. under N₂. The mixture was stirred at 20° C. for 12 h. The aqueous phase was extracted with DCM (50 mL×4). The combined organic phase was washed with brine (10 mL×2), dried with anhydrous Na₂SO₄, filtered and concentrated in vacuum to give tert-butyl 4-(3-((tert-butoxycarbonyl)(2-(dimethylamino)ethyl)amino)-5-fluorophenyl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (CXVII) as a yellow solid (2.0 g, 4.0 mmol, 40.0% yield). ¹H NMR (CDCl₃, 400 MHz) δ ppm 1.49 (s, 9H), 1.70 (s, 9H), 2.27 (s, 6H), 2.52 (brs, 2H), 3.80 (t, J=6.4 Hz, 2H), 6.71 (d, J=4 Hz, 1H), 7.13 (d, J=10 Hz, 1H), 7.20 (d, J=8.8 Hz, 1H), 7.24 (d, J=5.2 Hz, 1H), 7.38 (s, 1H), 7.71 (d, J=4.4 Hz, 1H), 8.58 (d, J=4.8 Hz, 1H); ESIMS found for C₂₇H₃₅FN₄O₄m/z 499.1 (M+H).

Step 3

To a solution of tert-butyl 4-(3-((tert-butoxycarbonyl)(2-(dimethylamino) ethyl)amino)-5-fluorophenyl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (CXVII) (1.5 g, 3.01 mmol, 1.0 eq) in THF (20 mL) was added triisopropyl borate (1.98 g, 10.5 mmol, 3.5 eq) at −30° C., then the solution was cooled to −78° C. LDA (2 M, 6 mL, 12.0 mmol, 4 eq) was added dropwise under N₂. The reaction was stirred at this temperature for 30 min. The reaction was quench with buffer solution (pH=7), then warmed to 25° C. and extracted with EtOAc (40 mL×3), washed with brine (10 mL), dried with Na₂SO₄, filtered and concentrated to afford the crude product (1-(tert-butoxycarbonyl)-4-(3-((tert-butoxycarbonyl)(2-(dimethylamino)ethyl)amino)-5-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)boronic acid (CXVIII) as a yellow solid (1.5 g, 2.77 mmol, 91.9% yield). ¹H NMR (CDCl₃, 400 MHz) δ ppm 1.49 (s, 9H), 2.28 (s, 6H), 2.54 (t, J=6.4 Hz, 2H), 3.82 (t, J=6.4 Hz, 2H), 6.72 (s, 1H), 7.11 (d, J=9.6 Hz, 1H), 7.17 (d, J=3.6 Hz, 1H), 7.32 (d, J=8.8 Hz, 1H), 7.43 (s, 1H), 7.46 (s, 1H), 8.39 (d, J=3.2 Hz, 1H); ESIMS found for C₂₇H₃₆BFN₄O₆m/z 543.2 (M+H).

The following intermediates were prepared in accordance with the procedure described in the above Scheme 24.

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(1-(tert-Butoxycarbonyl)-4-(furan-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)boronic acid (CXIX): Yellow solid (2.0 g, 6.10 mmol, 57.5% yield). ESIMS found C₁₆H₁₇BN₂O₅m/z 229.0 (M+H-Boc).

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(1-(tert-Butoxycarbonyl)-4-(thiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)boronic acid (CXX): Yellow solid (2.0 g, 5.81 mmol, 58.2% yield). ESIMS found C₁₆H₁₇BN₂O₄S m/z 345.1 (M+H).

Example 1

Preparation of 5-(5-(benzyloxy)pyridin-3-yl)-3-(4-(4-methylpiperazin-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole (646) is depicted below in Scheme 25.

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Steps 1-2

To a stirred solution of 5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (XVI) (1.52 g, 5.42 mmol, 1.0 eq), bis(pinacolato)diboron (1.65 g, 6.50 mmol, 1.2 eq), and KOAc (1.60 g, 16.3 mmol, 3 eq) in dioxane (27 mL)(degassed with nitrogen) was added Pd(dppf)Cl₂(265.5 mg, 0.325 mmol, 0.06 eq). The reaction was heated to 90° C. for 3 h to form 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (XVII). The reaction was cooled to room temperature before adding 3-(benzyloxy)-5-bromopyridine (LXXII) (1.43 g, 5.42 mmol, 1.0 eq), K₃PO₄(1.73 g, 9.13 mmol, 1.5 eq), and water (3 mL). The solution was degassed with nitrogen before adding Pd(PPh₃)₄(313.1 mg, 0.271 mmol, 0.05 eq). The reaction was heated to 90° C. overnight. The solvent was evaporated and the residue partitioned between CHCl₃and water. The organic phase was separated, washed with water and brine, dried, and concentrated to give 3.06 g of crude. The product was chromatographed with an 40 g column (0-3% 7N NH₃(MeOH)/CHCl₃) to give 5-(5-(benzyloxy)pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (CXXI) (1.30 g, 3.36 mmol, 62.0% yield) as a brown oil. ESIMS found for C₂₄H₂₃N₃O₂m/z 386.0 (M+H).

Step 3

To a solution of 5-(5-(benzyloxy)pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (CXXI) (1.30 g, 3.36 mmol, 1.0 eq) in DCM (10 mL) was added TFA (10 mL). The reaction was stirred at 25° C. for 2 h. The reaction was evaporated under high vacuum and the residue was purified by column chromatography (0-20% 7N NH₃(MeOH)/CHCl₃) to obtain 5-(5-(benzyloxy)pyridin-3-yl)-1H-indazole (CXXII) (990 mg, 3.29 mmol, 97.8% yield) as a white solid. ESIMS found for C₁₉H₁₅N₃O m/z 301.9 (M+H).

Steps 4

To a solution of 5-(5-(benzyloxy)pyridin-3-yl)-1H-indazole (CXXII) (990 mg, 3.29 mmol, 1.0 eq) in DMF (10 mL) was added iodine (1.0 g, 3.94 mmol, 1.2 eq) and KOH (921.7 mg, 14.65 mmol, 5.0 eq). The suspension was stirred at 25° C. overnight. The reaction suspension was poured into water (200 mL) and extracted with EtOAc (300 mL×3). The combined organic layer was washed with saturated Na₂SO₃solution (100 mL), brine (100 mL), dried over sodium sulfate, concentrated and purified on column chromatography to obtain 5-(5-(benzyloxy)pyridin-3-yl)-3-iodo-1H-indazole (CXXIII) (674 mg, 1.58 mmol, 48.0% yield) as a brown solid. ESIMS found for C₁₉H₁₄IN₃O m/z 427.8 (M+H).

Steps 5

To a solution of 5-(5-(benzyloxy)pyridin-3-yl)-3-iodo-1H-indazole (CXXIII) (674 mg, 1.58 mmol, 1.0 eq) in DCM (100 mL) was added di-tert-butyl dicarbonate (516.5 mg, 2.37 mmol, 1.5 eq), DMAP (19.3 mg, 0.158 mmol, 0.1 eq) and TEA (0.66 mL, 4.73 mmol, 3.0 eq). The reaction was stirred at 25° C. for 4 h. The reaction was washed with sat. NaHCO₃-EtOAc, brine, dried over sodium sulfate and concentrated. The residue was purified by column chromatography (0-100% EtOAc-hexanes) to give tert-butyl 5-(5-(benzyloxy)pyridin-3-yl)-3-iodo-1H-indazole-1-carboxylate (CXXIV) (210 mg, 0.398 mmol, 25.2% yield) as a brown solid. ESIMS found for C₂₄H₂₂IN₃O₃m/z 527.8 (M+H).

Steps 6

A mixture of tert-butyl 5-(5-(benzyloxy)pyridin-3-yl)-3-iodo-1H-indazole-1-carboxylate (CXXIV) (100 mg, 0.190 mmol, 1.0 eq), (1-(tert-butoxycarbonyl)-4-(4-methylpiperazin-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)boronic acid (CVIII) (75.1 mg, 0.209 mmol, 1.1 eq), K₂CO₃(78.6 mg, 0.569 mmol, 3.0 eq) and Pd(dppf)Cl₂(7.7 mg, 0.0095 mmol, 0.05 eq) in EtOH (1 mL) and toluene (2 mL) was purged with nitrogen. The mixture was heated at 110° C. using microwave energy for 0.5 h. The reaction was cooled to room temperature and concentrated. The crude product was purified by flash column chromatography (0-100% EtOAc-hexanes) to produce tert-butyl 5-(5-(benzyloxy)pyridin-3-yl)-3-(1-(tert-butoxycarbonyl)-4-(4-methylpiperazin-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole-1-carboxylate (CXV) (75 mg, 0.105 mmol, 55.3% yield) was obtained as a white solid. ESIMS found for C₄₁H₄₅N₇O₅m/z 616.0 (M+H-Boc).

Step 7

To a solution of tert-butyl 5-(5-(benzyloxy)pyridin-3-yl)-3-(1-(tert-butoxycarbonyl)-4-(4-methylpiperazin-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole-1-carboxylate (CXV) (75 mg, 0.105 mmol, 1.0 eq) in DCM (2 mL) was added 4 N HCl in dioxane (0.26 mL, 1.05 mmol). The reaction was stirred at 60° C. for 1 h. The precipitated solids were filtered, washed with MeOH and dried under high vacuum to obtain 5-(5-(benzyloxy)pyridin-3-yl)-3-(4-(4-methylpiperazin-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole (646) (30 mg, 0.054 mmol, 51.9% yield) as a yellow solid. ¹H NMR (499 MHz, DMSO-d₆) δ ppm 2.76 (s, 3H), 3.24-3.34 (m, 2H), 3.57 (br d, J=11.80 Hz, 2H), 3.85-3.93 (m, 2H), 4.66 (br d, J=14.00 Hz, 2H), 5.43 (s, 2H), 6.97 (d, J=7.14 Hz, 1H), 7.37-7.42 (m, 1H), 7.45 (t, J=7.41 Hz, 2H), 7.56 (d, J=7.14 Hz, 2H), 7.64 (d, J=1.65 Hz, 1H), 7.81 (d, J=8.51 Hz, 1H), 7.95 (dd, J=8.78, 1.37 Hz, 1H), 8.11 (d, J=7.13 Hz, 1H), 8.35 (br s, 1H), 8.55 (d, J=2.20 Hz, 1H), 8.68 (s, 1H), 8.90 (s, 1H), 13.38 (s, 1H), 13.90 (br s, 1H); ESIMS found for C₃₁H₂₉N₇O m/z 516.0 (M+1).

The following compounds were prepared in accordance with the procedures described herein. See, for example, Schemes 1a and 1-25.

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N-(5-(3-(4-(3-Fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)propionamide 1

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.12 (t, J=7.50 Hz, 3H), 2.40 (q, J=7.79 Hz, 3H), 7.27 (s, 1H), 7.28 (d, J=5.07 Hz, 1H), 7.30-7.38 (m, 1H), 7.62-7.70 (m, 2H), 7.72-7.80 (m, 3H), 8.34 (d, J=5.07 Hz, 1H), 8.39-8.43 (m, 2H), 8.72 (d, J=1.98 Hz, 2H), 10.20 (s, 1H), 12.48 (s, 1H), 13.63 (s, 1H); ESIMS found for C₂₈H₂₁FN₆O m/z 477.0 (M+1).

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N-((5-(3-(4-(3-Fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)methyl)ethanamine 6

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.26 (t, J=7.17 Hz, 3H), 2.99-3.07 (m, 2H), 4.27-4.33 (m, 2H), 7.27-7.40 (m, 3H), 7.61-7.69 (m, 1H), 7.71 (dt, J=10.14, 2.21 Hz, 1H), 7.78-7.85 (m, 2H), 7.85-7.92 (m, 1H), 8.36 (d, J=5.07 Hz, 1H), 8.55 (s, 1H), 8.61 (br s, 1H), 8.76 (s, 1H), 9.16-9.22 (m, 1H), 12.58 (s, 1H), 13.75 (br s, 1H); ESIMS found for C₂₈H₂₃FN₆m/z 463.1 (M+1).

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1-(5-(3-(4-(3-Fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)-N,N-dimethylmethanamine 13.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.20 (s, 6H), 3.53 (br s, 2H), 7.25-7.30 (m, 2H), 7.31-7.39 (m, 1H), 7.59-7.67 (m, 1H), 7.67-7.72 (m, 1H), 7.72-7.78 (m, 2H), 7.78-7.85 (m, 1H), 8.09 (s, 1H), 8.34 (d, J=5.04 Hz, 1H), 8.45 (br s, 1H), 8.48 (br s, 1H), 8.93 (d, J=1.32 Hz, 1H), 12.49 (s, 1H), 13.62 (s, 1H); ESIMS found for C₂₈H₂₃FN₆m/z 463.0 (M+1).

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3-(4-(3-Fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(pyridin-4-yl)-1H-indazole 18.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.29 (d, J=5.09 Hz, 1H), 7.30 (d, J=1.96 Hz, 1H), 7.32-7.39 (m, 1H), 7.61-7.73 (m, 2H), 7.76 (d, J=8.61 Hz, 2H), 7.85-7.90 (m, 3H), 8.35 (d, J=5.09 Hz, 1H), 8.56 (s, 1H), 8.66 (d, J=6.26 Hz, 2H), 12.49 (s, 1H), 13.65 (s, 1H); ESIMS found for C₂₅H₁₆FN₅m/z 406.1 (M+1).

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N-(5-(3-(4-(3-Fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)cyclopropanecarboxamide 20

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.86 (br d, J=5.51 Hz, 4H), 1.84 (dt, J=12.13, 6.28 Hz, 1H), 7.26 (s, 1H), 7.28 (br d, J=5.07 Hz, 1H), 7.29-7.38 (m, 1H), 7.61-7.70 (m, 2H), 7.71-7.80 (m, 3H), 8.34 (br d, J=4.85 Hz, 1H), 8.41 (br d, J=3.31 Hz, 2H), 8.72 (s, 2H), 10.52 (s, 1H), 12.47 (br s, 1H), 13.61 (s, 1H); ESIMS found for C₂₉H₂₁FN₆O m/z 489.1 (M+1).

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5-(5-((3,3-Difluoropyrrolidin-1-yl)methyl)pyridin-3-yl)-3-(4-(3-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole 26

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.57-2.66 (m, 2H), 3.61 (br s, 2H), 3.94 (br dd, J=15.21, 3.09 Hz, 2H), 4.66 (br d, J=18.30 Hz, 2H), 7.33-7.55 (m, 3H), 7.63-7.77 (m, 2H), 7.85 (br d, J=6.84 Hz, 2H), 7.95-8.04 (m, 1H), 8.42 (br s, 1H), 8.70 (br d, J=12.35 Hz, 1H), 8.99 (br s, 1H), 9.02-9.15 (m, 1H), 9.39 (br d, J=15.88 Hz, 1H), 12.88 (br s, 1H), 13.90 (br s, 1H); ESIMS found for C₃₀H₂₃F₃N₆m/z 525.2 (M+1).

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3-(4-(3-Fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(pyridin-2-yl)-1H-indazole 28

¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.21-7.31 (m, 2H), 7.34 (ddd, J=10.53, 7.11, 5.29 Hz, 2H), 7.62-7.79 (m, 4H), 7.88-7.95 (m, 1H), 8.10-8.16 (m, 1H), 8.22 (br dd, J=5.29, 3.75 Hz, 1H), 8.35 (br s, 1H), 8.68 (br d, J=2.65 Hz, 1H), 8.79 (br s, 1H), 12.47 (br s, 1H), 13.59 (br s, 1H); ESIMS found for C₂₅H₁₆FN₅m/z 406.1 (M+1).

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N-(5-(3-(4-(4-Fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)-3-methylbutanamide 30

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.98 (br d, J=6.62 Hz, 6H), 2.16 (td, J=13.23, 6.17 Hz, 1H), 2.28 (br d, J=7.06 Hz, 2H), 7.21-7.28 (m, 2H), 7.43 (br t, J=8.71 Hz, 2H), 7.76 (s, 2H), 7.91-7.99 (m, 2H), 8.33 (br d, J=4.63 Hz, 1H), 8.39 (s, 1H), 8.47 (br s, 1H), 8.71 (br s, 2H), 10.20 (s, 1H), 12.43 (br s, 1H), 13.60 (br s, 1H); ESIMS found for C₃₀H₂₅FN₆O m/z 505.1 (M+1).

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N-(5-(3-(4-(4-Fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)pivalamide 36

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.29 (s, 9H), 7.24 (br d, J=4.85 Hz, 1H), 7.26 (s, 1H), 7.43 (br t, J=8.71 Hz, 2H), 7.73-7.81 (m, 2H), 7.95 (br dd, J=8.05, 5.84 Hz, 2H), 8.33 (br d, J=4.85 Hz, 1H), 8.41 (s, 1H), 8.46 (br s, 1H), 8.72 (s, 1H), 8.85 (s, 1H), 9.52 (s, 1H), 12.44 (br s, 1H), 13.60 (s, 1H); ESIMS found for C₃₀H₂₅FN₆O m/z 505.1 (M+1).

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N-(5-(3-(4-(4-Fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)benzamide 39

¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.24 (br d, J=3.31 Hz, 1H), 7.27 (br s, 1H), 7.42 (br t, J=7.83 Hz, 2H), 7.59 (br d, J=6.84 Hz, 2H), 7.64 (br d, J=6.62 Hz, 1H), 7.80 (br s, 2H), 7.95 (br s, 2H), 8.04 (br d, J=6.62 Hz, 2H), 8.33 (br d, J=3.09 Hz, 1H), 8.45 (br s, 1H), 8.63 (br s, 1H), 8.80 (br s, 1H), 8.96 (br s, 1H), 10.60 (br s, 1H), 12.45 (br s, 1H), 13.65 (br s, 1H); ESIMS found for C₃₂H₂₁FN₆O m/z 525.1 (M+1).

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3-(4-(4-Fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(5-(pyrrolidin-1-ylmethyl)pyridin-3-yl)-1H-indazole 42

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.71 (br s, 4H), 3.32 (s, 4H), 3.71 (br s, 2H), 7.23 (br d, J=4.85 Hz, 1H), 7.27 (s, 1H), 7.41 (br t, J=8.71 Hz, 2H), 7.71-7.77 (m, 1H), 7.77-7.84 (m, 1H), 7.95 (br dd, J=8.38, 5.73 Hz, 2H), 8.09 (br s, 1H), 8.33 (br d, J=5.07 Hz, 1H), 8.43 (s, 1H), 8.50 (s, 1H), 8.92 (br s, 1H), 12.42 (br s, 1H), 13.57 (br s, 1H); ESIMS found for C₃₀H₂₅FN₆m/z 489.1 (M+1).

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N-(5-(3-(4-(4-Fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)butyramide 45

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.96 (t, J=7.39 Hz, 2H), 1.68 (dq, J=14.55, 7.28 Hz, 2H), 2.38 (br t, J=7.28 Hz, 2H), 7.22-7.27 (m, 2H), 7.44 (br t, J=8.71 Hz, 2H), 7.76 (s, 2H), 7.95 (br dd, J=8.27, 5.40 Hz, 2H), 8.33 (d, J=5.07 Hz, 1H), 8.39 (s, 1H), 8.47 (br s, 1H), 8.67-8.74 (m, 2H), 10.21 (s, 1H), 12.42 (br s, 1H), 13.60 (br s, 1H); ESIMS found for C₂₉H₂₃FN₆O m/z 491.1 (M+1).

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N-(5-(3-(4-(4-Fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)cyclobutanecarboxamide 49

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.85 (br s, 1H), 1.92-2.05 (m, 1H), 2.11-2.22 (m, 2H), 2.24-2.36 (m, 2H), 7.20-7.28 (m, 2H), 7.45 (br t, J=8.49 Hz, 2H), 7.76 (s, 2H), 7.91-7.99 (m, 2H), 8.33 (br d, J=4.85 Hz, 1H), 8.40 (s, 1H), 8.50 (br s, 1H), 8.71 (br d, J=4.63 Hz, 2H), 10.12 (br s, 1H), 12.43 (br s, 1H), 13.59 (br s, 1H); ESIMS found for C₃₀H₂₃FN₆O m/z 503.1 (M+1).

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3-(4-(4-Fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(pyrimidin-5-yl)-1H-indazole 55

¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.23 (br d, J=5.29 Hz, 1H), 7.33 (s, 1H), 7.42 (br t, J=8.60 Hz, 2H), 7.78 (br d, J=8.60 Hz, 1H), 7.87 (br d, J=7.94 Hz, 1H), 7.95 (br dd, J=8.38, 5.51 Hz, 2H), 8.33 (br d, J=4.85 Hz, 1H), 8.59 (s, 1H), 9.20 (s, 1H), 9.29 (s, 2H), 12.38 (br s, 1H), 13.63 (br s, 1H); ESIMS found for C₂₄H₁₅FN₆m/z 407.0 (M+1).

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5-(3-(4-(2-Fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl) pyridin-3-amine 59.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 5.41 (s, 2H), 6.96 (s, 1H), 7.18 (br d, J=3.97 Hz, 1H), 7.21 (s, 1H), 7.39-7.48 (m, 2H), 7.53-7.60 (m, 1H), 7.63-7.68 (m, 1H), 7.69-7.78 (m, 2H), 7.93 (d, J=2.21 Hz, 1H), 8.14 (s, 1H), 8.24 (s, 1H), 8.34 (d, J=4.85 Hz, 1H), 12.42 (s, 1H), 13.56 (s, 1H); ESIMS found for C₂₅H₁₇FN₆m/z 421.1 (M+1).

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3-(4-(2-Fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(4-methylpyridin-3-yl)-1H-indazole 61

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.29 (s, 3H), 6.94 (br s, 1H), 7.16 (br d, J=4.60 Hz, 1H), 7.33-7.43 (m, 3H), 7.47 (br d, J=9.21 Hz, 1H), 7.49-7.56 (m, 1H), 7.68-7.75 (m, 2H), 8.08 (s, 1H), 8.32 (br d, J=4.82 Hz, 1H), 8.42-8.46 (m, 1H), 8.48 (s, 1H), 12.38 (br s, 1H), 13.61 (br d, J=0.88 Hz, 1H); ESIMS found for C₂₆H₁₈FN₅m/z 420.0 (M+1).

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N-(5-(3-(4-(2-Fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)isobutyramide 65

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.16 (d, J=6.58 Hz, 7H), 2.53-2.56 (m, 1H), 6.97-7.03 (m, 1H), 7.19 (d, J=3.73 Hz, 1H), 7.40-7.48 (m, 2H), 7.51-7.60 (m, 1H), 7.73-7.81 (m, 3H), 8.32-8.38 (m, 2H), 8.43 (d, J=0.88 Hz, 1H), 8.69 (d, J=1.53 Hz, 1H), 8.73 (d, J=1.75 Hz, 1H), 10.17 (s, 1H), 12.42-12.46 (m, 1H), 13.61 (s, 1H); ESIMS found for C₂₉H₂₃FN₆O m/z 491.0 (M+1).

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5-(3-(4-(2-Fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)-N-isopropylpyridin-3-amine 68

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.17 (d, J=6.36 Hz, 6H), 3.63-3.72 (m, 1H), 5.81 (br d, J=7.89 Hz, 1H), 6.99 (s, 1H), 7.15 (br s, 1H), 7.18 (br d, J=3.73 Hz, 1H), 7.37-7.46 (m, 2H), 7.52-7.60 (m, 1H), 7.71 (s, 2H), 7.76 (br t, J=7.34 Hz, 1H), 7.94 (br d, J=1.97 Hz, 1H), 8.10 (s, 1H), 8.25 (s, 1H), 8.34 (d, J=4.82 Hz, 1H), 12.43 (s, 1H), 13.57 (s, 1H); ESIMS found for C₂₈H₂₃FN₆m/z 463.1 (M+1).

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N-(5-(3-(4-(2-Fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)-3,3-dimethylbutanamide 72

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.06 (s, 9H), 2.26 (s, 2H), 6.99 (br s, 1H), 7.19 (br d, J=4.63 Hz, 1H), 7.38-7.47 (m, 2H), 7.51-7.58 (m, 1H), 7.67-7.80 (m, 3H), 8.28-8.36 (m, 2H), 8.38 (br s, 1H), 8.68 (br s, 1H), 8.72 (br d, J=1.54 Hz, 1H), 10.12 (br s, 1H), 12.40 (br s, 1H), 13.59 (br s, 1H); ESIMS found for C₃₁H₂₇FN₆O m/z 519.1 (M+1).

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N-(5-(3-(4-(2-Fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)pentanamide 75

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.92 (br t, J=7.39 Hz, 3H), 1.36 (dq, J=14.83, 7.33 Hz, 2H), 1.62 (dt, J=14.88, 7.55 Hz, 2H), 2.39 (brt, J=7.39 Hz, 2H), 6.99 (s, 1H), 7.19 (br d, J=4.63 Hz, 1H), 7.40-7.48 (m, 2H), 7.51-7.59 (m, 1H), 7.68-7.81 (m, 3H), 8.34 (br s, 2H), 8.40 (br s, 1H), 8.68 (br s, 1H), 8.71 (br s, 1H), 10.21 (br s, 1H), 12.42 (br s, 2H), 13.61 (br s, 1H); ESIMS found for C₃₀H₂₅FN₆O m/z 505.1 (M+1).

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N-(5-(3-(4-(2-Fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)cyclopentanecarboxamide 78

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.54-1.64 (m, 2H), 1.67-1.82 (m, 4H), 1.85-1.95 (m, 2H), 2.81-2.88 (m, 1H), 7.00 (s, 1H), 7.17-7.22 (m, 1H), 7.39-7.49 (m, 2H), 7.53 (ddd, J=9.37, 2.90, 1.75 Hz, 1H), 7.70-7.81 (m, 3H), 8.30-8.37 (m, 2H), 8.43 (s, 1H), 8.68 (d, J=0.88 Hz, 1H), 8.71 (s, 1H), 10.22 (s, 1H), 12.45 (br d, J=1.10 Hz, 1H), 13.62 (s, 1H); ESIMS found for C₃₁H₂₅FN₆O m/z 517.1 (M+1).

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3-Methyl-N-(5-(3-(4-(pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)butanamide 86

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.97 (d, J=6.84 Hz, 6H), 2.09-2.17 (m, 1H), 2.26 (br d, J=7.28 Hz, 2H), 7.29 (br d, J=1.54 Hz, 1H), 7.32 (br d, J=5.07 Hz, 1H), 7.59-7.67 (m, 1H), 7.70-7.79 (m, 2H), 8.28-8.34 (m, 1H), 8.37 (br d, J=4.63 Hz, 1H), 8.38-8.41 (m, 1H), 8.43 (br d, J=1.32 Hz, 1H), 8.69 (br d, J=3.31 Hz, 1H), 8.71-8.76 (m, 2H), 9.07 (s, 1H), 10.21 (s, 1H), 12.50 (br s, 1H), 13.63 (br s, 1H); ESIMS found for C₂₉H25N₇O m/z 488.1 (M+1).

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5-(Pyridin-3-yl)-3-(4-(pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole 88

¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.34 (d, J=5.07 Hz, 1H), 7.38 (d, J=1.76 Hz, 1H), 7.65-7.75 (m, 2H), 7.75-7.81 (m, 1H), 7.81-7.87 (m, 1H), 8.38 (d, J=4.85 Hz, 1H), 8.39-8.43 (m, 1H), 8.46 (br d, J=8.16 Hz, 1H), 8.55 (s, 1H), 8.68 (d, J=5.07 Hz, 1H), 8.75 (br d, J=3.75 Hz, 1H), 9.14 (br d, J=1.32 Hz, 1H), 9.17 (d, J=1.76 Hz, 1H), 12.53 (s, 1H), 13.68 (br d, J=0.66 Hz, 1H); ESIMS found for C₂₄H₁₆N₆m/z 389.0 (M+1).

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N-((5-(3-(4-(Pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl) pyridin-3-yl)methyl)ethanamine 90

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.07-1.17 (m, 3H), 2.96-3.07 (m, 2H), 4.01 (br s, 2H), 7.25-7.35 (m, 2H), 7.57-7.65 (m, 2H), 7.75-7.85 (m, 2H), 8.18-8.28 (m, 2H), 8.30-8.36 (m, 1H), 8.36-8.41 (m, 1H), 8.44-8.51 (m, 1H), 8.66-8.72 (m, 1H), 9.09 (br d, J=1.98 Hz, 1H), 12.47 (br s, 1H), 13.64 (br s, 1H); ESIMS found for C₂₇H₂₃N₇m/z 446.1 (M+1).

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N-Isopropyl-5-(3-(4-(pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-amine 96

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.18 (d, J=6.17 Hz, 6H), 3.66-3.77 (m, 1H), 5.78 (br d, J=8.38 Hz, 1H), 7.19 (br s, 1H), 7.29 (br d, J=1.76 Hz, 1H), 7.31 (d, J=4.85 Hz, 1H), 7.60 (br dd, J=7.83, 4.96 Hz, 1H), 7.72 (s, 2H), 7.95 (br d, J=2.21 Hz, 1H), 8.14 (s, 1H), 8.28-8.35 (m, 2H), 8.36 (d, J=4.85 Hz, 1H), 8.67-8.72 (m, 1H), 9.08 (br d, J=1.76 Hz, 1H), 12.47 (s, 1H), 13.57 (s, 1H); ESIMS found for C₂₇H₂₃N₇m/z 446.1 (M+1).

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5-(5-(Piperidin-1-ylmethyl)pyridin-3-yl)-3-(4-(pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole 99

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.39 (br dd, J=5.04, 1.75 Hz, 2H), 1.48 (br d, J=4.82 Hz, 4H), 2.31-2.43 (m, 4H), 3.56 (br s, 2H), 7.29-7.34 (m, 2H), 7.58-7.66 (m, 1H), 7.71-7.83 (m, 2H), 8.04 (br s, 1H), 8.30-8.34 (m, 1H), 8.37 (d, J=4.82 Hz, 1H), 8.45 (br s, 1H), 8.48 (br s, 1H), 8.68-8.73 (m, 1H), 8.92 (s, 1H), 9.09 (d, J=0.88 Hz, 1H), 12.50 (br d, J=0.88 Hz, 1H), 13.62 (s, 1H); ESIMS found for C₃₀H₂₇N₇m/z 486.1 (M+1).

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N-(5-(3-(4-(Pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl) pyridin-3-yl)cyclohexanecarboxamide 107

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.20-1.36 (m, 3H), 1.42-1.54 (m, 2H), 1.64-1.71 (m, 1H), 1.73-1.82 (m, 2H), 1.82-1.93 (m, 2H), 7.29 (d, J=1.98 Hz, 1H), 7.32 (d, J=5.07 Hz, 1H), 7.63 (br dd, J=7.72, 4.63 Hz, 1H), 7.69-7.79 (m, 2H), 8.28-8.34 (m, 1H), 8.37 (d, J=4.85 Hz, 1H), 8.42 (br dd, J=1.98, 1.10 Hz, 2H), 8.69 (dd, J=5.07, 1.54 Hz, 1H), 8.71 (d, J=1.98 Hz, 1H), 8.74 (d, J=2.43 Hz, 1H), 9.08 (br d, J=1.54 Hz, 1H), 10.14 (s, 1H), 12.48-12.52 (m, 1H), 13.62 (s, 1H); ESIMS found for C₃₁H₂₇N₇O m/z 514.1 (M+1).

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5-(5-((3,3-Difluoropyrrolidin-1-yl)methyl)pyridin-3-yl)-3-(4-(pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole 110

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.19-2.31 (m, 2H), 2.71-2.79 (m, 2H), 2.94 (br t, J=13.23 Hz, 2H), 3.76 (br s, 2H), 7.32 (br s, 2H), 7.58-7.66 (m, 1H), 7.72-7.84 (m, 2H), 8.09 (br s, 1H), 8.32 (br d, J=7.28 Hz, 1H), 8.34-8.41 (m, 1H), 8.47 (br s, 1H), 8.51 (br s, 1H), 8.69 (br dd, J=2.32, 1.21 Hz, 1H), 8.96 (br s, 1H), 9.09 (br s, 1H), 12.49 (br s, 1H), 13.61 (br s, 1H); ESIMS found for C₂₉H₂₃F₂N₇m/z 508.1 (M+1).

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5-(4-Methylpyridin-3-yl)-3-(4-(pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole 117

¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.03-3.15 (m, 3H), 7.35 (s, 1H), 7.42 (br d, J=4.85 Hz, 1H), 7.56 (br d, J=8.60 Hz, 1H), 7.79 (br d, J=8.82 Hz, 1H), 7.91-7.98 (m, 1H), 8.15-8.22 (m, 2H), 8.33 (s, 1H), 8.42 (br d, J=5.07 Hz, 1H), 8.75 (br d, J=5.95 Hz, 1H), 8.84 (s, 1H), 8.87 (br d, J=5.29 Hz, 2H), 12.63 (br s, 1H), 13.78 (br s, 1H); ESIMS found for C₂₅H₁₈N₆m/z 403.1 (M+1).

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N-(5-(3-(4-(Pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl) pyridin-3-yl)pivalamide 120

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.29 (s, 9H), 7.33-7.38 (m, 2H), 7.77 (s, 2H), 7.90 (br d, J=4.85 Hz, 2H), 8.39 (br d, J=4.85 Hz, 1H), 8.45 (br d, J=5.07 Hz, 2H), 8.73 (br s, 1H), 8.78 (br d, J=5.51 Hz, 2H), 8.85 (br s, 1H), 9.51 (br s, 1H), 12.54 (br s, 1H), 13.63 (br s, 1H); ESIMS found for C₂₉H₂₅NO₇O m/z 488.1 (M+1).

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2-Phenyl-N-(5-(3-(4-(pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)acetamide 122

¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.73 (s, 2H), 7.23-7.29 (m, 1H), 7.31-7.44 (m, 6H), 7.71-7.79 (m, 2H), 7.89 (br d, J=4.85 Hz, 2H), 8.39 (br d, J=4.63 Hz, 1H), 8.44 (br s, 2H), 8.74 (br s, 2H), 8.78 (br d, J=4.41 Hz, 2H), 10.51 (br s, 1H), 12.53 (br s, 1H), 13.63 (br s, 1H); ESIMS found for C₃₂H₂₃N₇O m/z 522.1 (M+1).

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N-(5-(3-(4-(Pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl) pyridin-3-yl)benzamide 123

¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.36 (br s, 2H), 7.55-7.62 (m, 2H), 7.64 (br d, J=6.39 Hz, 1H), 7.80 (br s, 2H), 7.91 (br d, J=3.97 Hz, 2H), 8.04 (br d, J=7.06 Hz, 2H), 8.39 (br d, J=4.63 Hz, 1H), 8.49 (br s, 1H), 8.61 (br s, 1H), 8.78 (br d, J=3.75 Hz, 2H), 8.81 (br s, 1H), 8.97 (br s, 1H), 10.55 (br s, 1H), 12.55 (br s, 1H), 13.65 (br s, 1H); ESIMS found for C₃₁H₂₁N₇O m/z 508.1 (M+1).

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N,N-Dimethyl-1-(5-(3-(4-(pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)methanamine 125

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.20 (br s, 6H), 3.53 (br s, 2H), 7.36 (br s, 2H), 7.71-7.84 (m, 2H), 7.86-7.96 (m, 2H), 8.10 (br s, 1H), 8.35-8.43 (m, 1H), 8.48 (br s, 2H), 8.71-8.80 (m, 2H), 8.94 (br d, J=1.10 Hz, 1H), 12.56 (br s, 1H), 13.64 (br s, 1H); ESIMS found for C₂₇H₂₃N₇m/z 446.1 (M+1).

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N-(5-(3-(4-(Pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl) pyridin-3-yl)pentanamide 131

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.93 (br t, J=7.28 Hz, 3H), 1.31-1.43 (m, 2H), 1.59-1.70 (m, 2H), 2.40 (br t, J=7.28 Hz, 2H), 7.33 (s, 1H), 7.35 (br d, J=4.85 Hz, 1H), 7.71-7.81 (m, 2H), 7.90 (br d, J=4.85 Hz, 2H), 8.38 (br d, J=4.63 Hz, 1H), 8.43 (br s, 1H), 8.46 (br s, 1H), 8.72 (br s, 2H), 8.78 (br d, J=5.07 Hz, 2H), 10.25 (br s, 1H), 12.56 (br s, 1H), 13.71 (br s, 1H); ESIMS found for C₂₉H₂₅N₇O m/z 488.1 (M+1).

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N-(5-(3-(4-(Pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl) pyridin-3-yl)cyclobutanecarboxamide 133

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.83-1.91 (m, 1H), 1.93-2.05 (m, 1H), 2.12-2.22 (m, 2H), 2.24-2.39 (m, 3H), 7.31-7.38 (m, 2H), 7.72-7.81 (m, 2H), 7.90 (br d, J=5.07 Hz, 2H), 8.39 (br d, J=4.85 Hz, 1H), 8.44 (br s, 1H), 8.48 (br s, 1H), 8.72 (br s, 2H), 8.79 (br d, J=5.29 Hz, 2H), 10.05 (br s, 1H), 12.53 (br s, 1H), 13.65 (br s, 1H); ESIMS found for C₂₉H₂₃N₇O m/z 486.1 (M+1).

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3-(4-(Pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(pyrimidin-5-yl)-1H-indazole 139

¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.46-7.54 (m, 2H), 7.81 (d, J=8.82 Hz, 1H), 7.90 (br dd, J=8.82, 1.32 Hz, 1H), 8.40 (br d, J=5.73 Hz, 2H), 8.47 (br d, J=5.07 Hz, 1H), 8.63 (s, 1H), 8.99 (br d, J=4.85 Hz, 2H), 9.21 (s, 1H), 9.30 (s, 2H), 12.72 (br s, 1H), 13.79 (br s, 1H); ESIMS found for C₂₃H₁₅N₇m/z 390.1 (M+1).

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N-(5-(3-(4-(Pyridin-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)propionamide 141

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.15 (t, J=7.53 Hz, 3H), 2.39-2.46 (m, 2H), 7.46 (dd, J=7.15, 5.14 Hz, 1H), 7.61-7.67 (m, 2H), 7.68-7.73 (m, 1H), 7.74-7.79 (m, 1H), 7.98-8.06 (m, 1H), 8.20 (d, J=7.78 Hz, 1H), 8.34 (d, J=5.02 Hz, 1H), 8.40 (s, 1H), 8.52 (s, 1H), 8.71 (d, J=1.51 Hz, 2H), 8.90 (br d, J=4.02 Hz, 1H), 10.28 (br s, 1H); ESIMS found for C₂₇H₂₁N₇O m/z 460.2 (M+1).

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5-(3-(4-(Pyridin-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl) pyridin-3-amine 143

¹H NMR (400 MHz, DMSO-d₆) δ ppm 5.43 (br s, 2H), 7.26 (br s, 1H), 7.46-7.52 (m, 1H), 7.60-7.67 (m, 2H), 7.71 (q, J=8.62 Hz, 2H), 7.95 (br d, J=1.25 Hz, 1H), 8.01 (br t, J=7.40 Hz, 1H), 8.15-8.22 (m, 2H), 8.29-8.40 (m, 1H), 8.35-8.35 (m, 1H), 8.85 (br d, J=4.02 Hz, 1H), 12.41 (br s, 1H), 13.57 (s, 1H); ESIMS found for C₂₄H₁₇N₇m/z 404.2 (M+1).

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N,N-Dimethyl-5-(3-(4-(pyridin-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-amine 147

¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.05 (s, 6H), 7.42 (br s, 1H), 7.46-7.52 (m, 1H), 7.65 (d, J=5.02 Hz, 1H), 7.67 (s, 1H), 7.72-7.77 (m, 1H), 7.77-7.83 (m, 1H), 7.99 (br t, J=7.78 Hz, 1H), 8.13 (d, J=2.26 Hz, 1H), 8.22 (d, J=8.03 Hz, 1H), 8.31 (s, 1H), 8.37 (d, J=4.89 Hz, 1H), 8.41 (s, 1H), 8.82 (br d, J=4.27 Hz, 1H), 12.41 (br s, 1H), 13.57 (br s, 1H); ESIMS found for C₂₆H₂₁N₇m/z 432.3 (M+1).

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N-(5-(3-(4-(Pyridin-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl) pyridin-3-yl)cyclohexanecarboxamide 163

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.21-1.39 (m, 3H), 1.41-1.55 (m, 2H), 1.69 (br d, J=11.54 Hz, 1H), 1.80 (br d, J=12.05 Hz, 2H), 1.89 (br d, J=11.54 Hz, 2H), 2.38-2.47 (m, 1H), 7.48 (dd, J=7.40, 5.02 Hz, 1H), 7.68 (d, J=5.02 Hz, 1H), 7.73 (s, 1H), 7.80 (s, 2H), 8.04 (br t, J=7.84 Hz, 1H), 8.22 (d, J=7.91 Hz, 1H), 8.39 (d, J=5.02 Hz, 1H), 8.45 (s, 1H), 8.64 (s, 1H), 8.82 (br s, 2H), 8.92 (br d, J=4.52 Hz, 1H), 10.35 (s, 1H), 12.50 (s, 1H), 13.69 (br s, 1H); ESIMS found for C₃₁H₂₇N₇O m/z 514.3 (M+1).

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N-(5-(3-(4-(Piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl) pyridin-3-yl)propionamide 169

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.12 (br t, J=7.50 Hz, 3H), 1.64 (br s, 3H), 1.73 (br s, 3H), 2.36-2.45 (m, 2H), 3.47 (br s, 4H), 6.46 (br d, J=5.51 Hz, 1H), 7.02 (s, 1H), 7.74 (s, 2H), 7.98 (br d, J=5.29 Hz, 1H), 8.38 (s, 1H), 8.51 (br s, 1H), 8.69 (br s, 1H), 8.72 (br s, 1H), 10.28 (br s, 1H), 11.98 (br s, 1H), 13.55 (br s, 1H); ESIMS found for C₂₇H₂₇N₇O m/z 466.1 (M+1).

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5-(3-(4-(Piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl) pyridin-3-amine 171

¹H NMR (400 MHz, METHANOL-d₄) δ ppm 1.86 (br s, 6H), 3.97 (br s, 4H), 6.77 (br d, J=7.06 Hz, 1H), 7.33 (s, 1H), 7.63 (br s, 1H), 7.72 (s, 1H), 7.85 (br d, J=6.84 Hz, 1H), 7.98 (s, 1H), 8.13 (s, 1H), 8.23 (s, 1H), 8.28 (s, 1H); ESIMS found for C₂₄H₂₃N₇m/z 410.1 (M+1).

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3-(4-(Piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(pyridin-3-yl)-1H-indazole 172

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.66 (br d, J=3.97 Hz, 2H), 1.72 (br d, J=4.63 Hz, 4H), 3.46 (br d, J=5.29 Hz, 4H), 6.46 (br d, J=5.51 Hz, 1H), 7.05 (s, 1H), 7.52 (br dd, J=7.72, 4.63 Hz, 1H), 7.69-7.76 (m, 1H), 7.76-7.84 (m, 1H), 7.97 (br d, J=5.51 Hz, 1H), 8.22 (br d, J=8.16 Hz, 1H), 8.44 (s, 1H), 8.58 (br dd, J=4.63, 1.32 Hz, 1H), 9.05 (br d, J=1.76 Hz, 1H), 11.93 (br s, 1H), 13.42 (br s, 1H); ESIMS found for C₂₄H₂₂N₆m/z 395.1 (M+1).

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N,N-Dimethyl-5-(3-(4-(piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-amine 175

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.75 (br s, 6H), 3.18 (s, 6H), 3.96 (br s, 4H), 6.84 (d, J=7.40 Hz, 1H), 7.58 (s, 1H), 7.82 (d, J=8.78 Hz, 1H), 7.91-8.01 (m, 2H), 8.17 (s, 1H), 8.22 (d, J=1.88 Hz, 1H), 8.60 (br d, J=3.14 Hz, 2H), 13.25 (br s, 1H); ESIMS found for C₂₆H₂₇N₇m/z 438.3 (M+1).

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2-Phenyl-N-(5-(3-(4-(piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)acetamide 178

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.74 (br s, 6H), 3.81 (s, 2H), 3.94 (br s, 4H), 6.83 (br d, J=7.28 Hz, 1H), 7.23-7.30 (m, 1H), 7.35 (br t, J=7.50 Hz, 2H), 7.38-7.50 (m, 3H), 7.83 (s, 2H), 7.93 (br d, J=7.28 Hz, 1H), 8.49 (s, 1H), 8.88 (br s, 1H), 9.01 (br s, 2H), 11.47 (br s, 1H), 13.16 (br s, 1H), 13.86 (br s, 1H); ESIMS found for C₃₂H₂₉N₇O m/z 528.2 (M+1).

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N,N-Dimethyl-1-(5-(3-(4-(piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)methanamine 181

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.66 (br d, J=3.75 Hz, 2H), 1.72 (br d, J=3.75 Hz, 4H), 3.46 (br d, J=5.29 Hz, 4H), 3.54 (br s, 2H), 6.46 (br d, J=5.51 Hz, 1H), 7.05 (br s, 1H), 7.72 (br d, J=8.82 Hz, 1H), 7.80 (br d, J=8.38 Hz, 1H), 7.97 (br d, J=5.29 Hz, 1H), 8.11 (br s, 1H), 8.41 (br s, 1H), 8.48 (br s, 1H), 8.94 (br d, J=1.10 Hz, 1H), 11.95 (br s, 1H), 13.42 (br s, 1H); ESIMS found for C₂₇H₂₉N₇m/z 452.2 (M+1).

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3-(4-(Piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(5-(pyrrolidin-1-ylmethyl)pyridin-3-yl)-1H-indazole 182

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.53-1.85 (m, 10H), 3.17-3.41 (m, 4H), 3.47 (br s, 4H), 3.71 (br s, 2H), 6.45 (br d, J=1.76 Hz, 1H), 7.05 (br s, 1H), 7.67-7.75 (m, 1H), 7.78 (br d, J=5.28 Hz, 1H), 7.98 (br s, 1H), 8.10 (br s, 1H), 8.41 (br s, 1H), 8.49 (br s, 1H), 8.92 (br s, 1H), 11.97 (br s, 1H), 13.41 (br s, 1H); ESIMS found for C₂₉H₃₁N₇m/z 478.3 (M+1).

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3,3-Dimethyl-N-(5-(3-(4-(piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)butanamide 184

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.06 (s, 9H), 1.59-1.68 (m, 2H), 1.68-1.77 (m, 4H), 3.44-3.49 (m, 4H), 6.45 (br d, J=5.51 Hz, 1H), 7.02 (s, 1H), 7.74 (s, 2H), 7.97 (d, J=5.29 Hz, 1H), 8.36 (s, 1H), 8.49 (t, J=1.98 Hz, 1H), 8.69 (br d, J=2.20 Hz, 1H), 8.72 (d, J=2.20 Hz, 1H), 10.17 (s, 1H), 11.97 (br s, 1H), 13.49 (br s, 1H); ESIMS found for C₃₀H₃₃N₇O m/z 508.2 (M+1).

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N-(5-(3-(4-(Piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl) pyridin-3-yl)cyclopropanecarboxamide 188

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.81-0.92 (m, 4H), 1.61-1.69 (m, 2H), 1.69-1.76 (m, 4H), 1.82-1.90 (m, 1H), 3.44-3.49 (m, 4H), 6.46 (br d, J=5.73 Hz, 1H), 7.01 (s, 1H), 7.71-7.79 (m, 2H), 7.97 (br d, J=5.51 Hz, 1H), 8.37 (s, 1H), 8.53 (br d, J=1.98 Hz, 1H), 8.68 (br d, J=2.43 Hz, 1H), 8.72 (br d, J=1.98 Hz, 1H), 10.62 (s, 1H), 11.98 (br s, 1H), 13.52 (br s, 1H); ESIMS found for C₂₈H₂₇N₇O m/z 478.1 (M+1).

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1-Cyclopentyl-N-((5-(3-(4-(piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)methyl)methanamine 193

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.25 (br d, J=4.64 Hz, 2H), 1.47-1.64 (m, 4H), 1.69-1.84 (m, 8H), 2.18 (dt, J=14.49, 7.06 Hz, 1H), 3.03 (br s, 2H), 3.95 (br s, 4H), 4.45 (br s, 2H), 6.83 (br d, J=6.78 Hz, 1H), 7.51 (br s, 1H), 7.84-7.91 (m, 1H), 7.91-8.01 (m, 2H), 8.62 (br s, 1H), 8.94 (br s, 1H), 8.99 (br s, 1H), 9.46 (br s, 1H), 13.30 (br s, 1H); ESIMS found for C₃₁H₃₅N₇m/z 506.4 (M+1).

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5-(5-((3,3-Difluoropyrrolidin-1-yl)methyl)pyridin-3-yl)-3-(4-(piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole 194

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.61-1.69 (m, 2H), 1.69-1.77 (m, 4H), 2.19-2.30 (m, 2H), 2.73-2.80 (m, 2H), 2.94 (ddd, J=13.37, 12.50, 0.88 Hz, 2H), 3.44-3.49 (m, 4H), 3.76 (s, 2H), 6.41-6.49 (m, 1H), 7.06 (s, 1H), 7.69-7.76 (m, 1H), 7.76-7.84 (m, 1H), 7.97 (br d, J=6.14 Hz, 1H), 8.13 (br d, J=1.97 Hz, 1H), 8.42 (br d, J=1.32 Hz, 1H), 8.51 (s, 1H), 8.96 (s, 1H), 11.97 (br d, J=2.41 Hz, 1H), 13.44 (s, 1H); ESIMS found for C₂₉H₂₉F₂N₇m/z 514.2 (M+1).

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5-(3-(4-(4-Methylpiperazin-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-amine 227

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.26 (br s, 3H), 2.54 (br s, 4H), 3.45 (br s, 4H), 5.40 (br s, 2H), 6.47 (br s, 1H), 7.00 (br s, 1H), 7.26 (br s, 1H), 7.61 (br d, J=7.28 Hz, 1H), 7.69 (br d, J=6.53 Hz, 1H), 7.93 (br s, 1H), 7.99 (br s, 1H), 8.18 (br s, 1H), 8.28 (br s, 1H); ESIMS found for C₂₄H₂₄N₈m/z 425.3 (M+1).

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3-(4-(4-Methylpiperazin-1l-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(5-(pyrrolidin-1-ylmethyl)pyridin-3-yl)-1H-indazole 238

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.92 (br s, 2H), 2.09 (br s, 2H), 2.92 (s, 3H), 3.25 (br s, 2H), 3.34 (br s, 2H), 3.55 (br s, 2H), 3.60-3.69 (m, 2H), 3.69-3.81 (m, 2H), 4.70 (br s, 2H), 4.66 (br s, 2H), 6.99 (br d, J=7.40 Hz, 1H), 7.62 (s, 1H), 7.84-7.92 (m, 1H), 7.92-8.00 (m, 1H), 8.13 (br d, J=7.15 Hz, 1H), 8.71 (s, 1H), 9.02 (s, 1H), 9.08 (br d, J=1.26 Hz, 1H), 9.52 (s, 1H); ESIMS found for C₂₉H₃₂N₈m/z 493.3 (M+1).

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N-Benzyl-1-(5-(3-(4-(4-methylpiperazin-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)methanamine 248

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.37 (br s, 3H), 2.72 (br s, 4H), 3.52 (br s, 4H), 3.98 (br s, 2H), 4.04 (br s, 2H), 6.50 (d, J=5.40 Hz, 1H), 7.13 (s, 1H), 7.27-7.34 (m, 1H), 7.38 (br t, J=7.28 Hz, 2H), 7.42-7.47 (m, 2H), 7.69-7.77 (m, 1H), 7.77-7.84 (m, 1H), 8.02 (d, J=5.40 Hz, 1H), 8.25 (br s, 1H), 8.46 (s, 1H), 8.58 (s, 1H), 9.02 (s, 1H), 12.05 (br s, 1H), 13.49 (br s, 1H); ESIMS found for C₃₂H₃₂N₈m/z 529.2 (M+1).

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5-(3-(1H-Pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-amine 255

¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.38 (dd, J=7.72, 5.29 Hz, 1H), 7.61 (s, 1H), 7.78-7.87 (m, 2H), 8.03-8.10 (m, 2H), 8.35-8.42 (m, 2H), 8.58 (d, J=2.87 Hz, 2H), 13.11 (br d, J=1.10 Hz, 1H), 14.02 (br s, 1H); ESIMS found for C₁₉H₁₄N₆m/z 327.1 (M+1).

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N-(5-(3-(1H-Pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl) isobutyramide 261

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.18 (d, J=6.84 Hz, 6H), 2.79 (dt, J=13.56, 6.89 Hz, 1H), 7.35 (dd, J=7.61, 5.40 Hz, 1H), 7.61 (s, 1H), 7.86 (s, 2H), 8.31-8.40 (m, 2H), 8.66 (s, 1H), 9.01 (s, 1H), 9.17 (d, J=1.54 Hz, 1H), 9.25 (d, J=1.76 Hz, 1H), 11.34 (s, 1H), 13.04 (br s, 1H), 13.99 (br s, 1H); ESIMS found for C₂₃H₂₀N₆O m/z 397.1 (M+1).

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5-(5-(Piperidin-1-ylmethyl)pyridin-3-yl)-3-(1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole 267

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.35-1.47 (m, 1H), 1.70-1.85 (m, 3H), 1.88-2.01 (m, 2H), 2.93-3.05 (m, 2H), 3.43 (br d, J=11.25 Hz, 2H), 4.59 (br d, J=4.85 Hz, 2H), 7.44 (dd, J=7.72, 5.51 Hz, 1H), 7.85 (d, J=8.82 Hz, 1H), 7.96 (s, 1H), 8.08 (dd, J=8.82, 1.54 Hz, 1H), 8.37-8.42 (m, 1H), 8.45 (d, J=7.06 Hz, 1H), 8.86 (s, 1H), 8.99 (s, 1H), 9.40 (s, 1H), 9.47 (d, J=1.76 Hz, 1H), 13.30 (br s, 1H), 14.09 (br s, 1H); ESIMS found for C₂₅H₂₄N₆m/z 409.1 (M+1).

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5-(Pyridin-4-yl)-3-(1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole 270

¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.12 (dd, J=7.72, 4.63 Hz, 1H), 7.38 (s, 1H), 7.81 (d, J=8.82 Hz, 1H), 8.02 (br dd, J=12.68, 8.49 Hz, 2H), 8.27 (br t, J=5.07 Hz, 3H), 8.72 (s, 1H), 8.82 (br d, J=5.73 Hz, 2H), 12.26 (br s, 1H), 13.79 (br s, 1H); ESIMS found for C₁₉H₁₃N₅m/z 312.0 (M+1).

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N-(5-(3-(1H-Pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl) pentanamide 271

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.92 (t, J=7.28 Hz, 3H), 1.36 (dq, J=14.86, 7.40 Hz, 2H), 1.64 (dt, J=14.88, 7.33 Hz, 2H), 2.45-2.49 (m, 2H), 7.33 (dd, J=7.72, 5.29 Hz, 1H), 7.57 (s, 1H), 7.82-7.92 (m, 2H), 8.32 (br d, J=7.72 Hz, 1H), 8.34-8.38 (m, 1H), 8.64 (s, 1H), 8.89 (s, 1H), 9.14 (br d, J=1.54 Hz, 1H), 9.20 (d, J=1.76 Hz, 1H), 11.27 (s, 1H), 12.95 (br s, 1H), 13.95 (br s, 1H); ESIMS found for C₂₄H₂₂N₆O m/z 411.1 (M+1).

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N-(5-(3-(1H-Pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl) cyclopentanecarboxamide 274

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.51-1.63 (m, 2H), 1.63-1.73 (m, 2H), 1.78 (br s, 2H), 1.93 (br s, 2H), 2.92-3.01 (m, 2H), 7.29-7.37 (m, 1H), 7.53-7.61 (m, 1H), 7.78-7.89 (m, 2H), 8.27-8.38 (m, 2H), 8.64 (br s, 1H), 8.88-8.97 (m, 1H), 9.08-9.15 (m, 1H), 9.22 (br d, J=1.76 Hz, 1H), 11.27 (br s, 1H), 12.94 (br s, 1H), 13.92 (br s, 1H); ESIMS found for C₂₅H₂₂N₆O m/z 423.1 (M+1).

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5-(Pyrimidin-5-yl)-3-(1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole 279

¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.48 (dd, J=7.61, 5.62 Hz, 1H), 7.75 (s, 1H), 7.83 (d, J=8.82 Hz, 1H), 7.93 (dd, J=8.71, 1.21 Hz, 1H), 8.41 (d, J=5.29 Hz, 1H), 8.51 (d, J=7.72 Hz, 1H), 8.64 (s, 1H), 9.22 (s, 1H), 9.34 (s, 2H), 13.44 (br s, 1H), 14.07 (br s, 1H); ESIMS found for C₁₈H₁₂N₆m/z 313.0 (M+1).

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3-Methyl-N-(5-(3-(4-(thiophen-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)butanamide 282

¹H NMR (499 MHz, DMSO-d₆) δ ppm 0.96 (d, J=6.59 Hz, 6H), 2.07-2.14 (m, 1H), 2.23 (d, J=7.14 Hz, 2H), 6.54-6.58 (m, 1H), 6.85 (dd, J=4.94, 1.10 Hz, 1H), 7.26 (s, 1H), 7.35 (dd, J=4.94, 3.02 Hz, 1H), 7.55-7.62 (m, 3H), 7.66 (dd, J=2.74, 0.82 Hz, 1H), 8.18 (s, 1H), 8.37 (d, J=1.92 Hz, 1H), 8.42 (s, 1H), 8.62 (d, J=2.20 Hz, 1H), 10.08 (s, 1H), 11.90 (br s, 1H), 13.25 (br s, 1H); ESIMS found for C₂₈H₂₄N₆OS m/z 493.2 (M+1).

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5-(Pyridin-3-yl)-3-(4-(thiophen-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole 284

¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.34 (br d, J=4.89 Hz, 1H), 7.38 (s, 1H), 7.52 (br dd, J=7.59, 4.58 Hz, 1H), 7.70-7.83 (m, 4H), 8.22 (br d, J=7.91 Hz, 1H), 8.26 (br d, J=4.77 Hz, 1H), 8.31 (br s, 1H), 8.48 (s, 1H), 8.57 (br d, J=3.39 Hz, 1H), 9.06 (s, 1H); ESIMS found for C₂₃H₁₅N₅S m/z 394.2 (M+1).

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5-(5-(Piperidin-1-ylmethyl)pyridin-3-yl)-3-(4-(thiophen-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole 295

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.39 (br d, J=3.51 Hz, 2H), 1.50 (br d, J=4.77 Hz, 4H), 2.39 (br s, 4H), 3.56 (br s, 2H), 7.28 (s, 1H), 7.30 (br d, J=5.02 Hz, 1H), 7.58 (br d, J=8.41 Hz, 1H), 7.71 (br d, J=8.66 Hz, 1H), 7.73-7.81 (m, 2H), 8.04 (br s, 1H), 8.20 (br d, J=4.89 Hz, 1H), 8.28 (br s, 1H), 8.39 (br s, 1H), 8.44 (br s, 1H), 8.91 (s, 1H); ESIMS found for C₂₉H₂₆N₆S m/z 491.2 (M+1).

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5-(Pyrimidin-5-yl)-3-(4-(thiophen-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole 307

¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.34 (br d, J=4.64 Hz, 1H), 7.42 (s, 1H), 7.74-7.89 (m, 4H), 8.27 (br d, J=4.77 Hz, 1H), 8.33 (br s, 1H), 8.60 (s, 1H), 9.19 (s, 1H), 9.30 (s, 2H); ESIMS found for C₂₂H₁₄N₆S m/z 395.3 (M+1).

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3-(4-(Furan-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(4-methylpyridin-3-yl)-1H-indazole 313

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.34 (s, 3H), 7.20 (br s, 1H), 7.25 (s, 1H), 7.28 (br d, J=4.89 Hz, 1H), 7.35-7.44 (m, 2H), 7.71 (br d, J=8.53 Hz, 1H), 7.85 (br s, 1H), 8.22 (br d, J=4.39 Hz, 1H), 8.29 (s, 1H), 8.46 (br d, J=4.77 Hz, 1H), 8.54 (s, 1H), 8.65 (s, 1H); ESIMS found for C₂₄H₁₇N₅O m/z 392.2 (M+1).

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1-(5-(3-(4-(Furan-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl) pyridin-3-yl)-N,N-dimethylmethanamine 321

¹H NMR (500 MHz, DMSO-d₆) δ ppm 2.23 (s, 6H), 3.56 (s, 2H), 7.23 (dd, J=1.92, 0.82 Hz, 1H), 7.32 (d, J=4.94 Hz, 1H), 7.40 (d, J=1.65 Hz, 1H), 7.72-7.77 (m, 1H), 7.77-7.83 (m, 1H), 7.88 (t, J=1.65 Hz, 1H), 8.11 (t, J=2.06 Hz, 1H), 8.26 (d, J=4.94 Hz, 1H), 8.49 (d, J=1.92 Hz, 1H), 8.55 (s, 1H), 8.70 (s, 1H), 8.98 (d, J=2.20 Hz, 1H), 12.30 (s, 1H), 13.57 (br s, 1H); ESIMS found for C₂₆H₂₂N₆O m/z 434.9 (M+1).

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N-(5-(3-(4-(Furan-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl) pyridin-3-yl)-3,3-dimethylbutanamide 324

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.05 (s, 9H), 2.26 (s, 2H), 7.24 (s, 1H), 7.32 (d, J=5.02 Hz, 1H), 7.38 (s, 1H), 7.70-7.80 (m, 2H), 7.88 (s, 1H), 8.26 (d, J=5.02 Hz, 1H), 8.40 (s, 1H), 8.52 (s, 1H), 8.70 (s, 1H), 8.73-8.81 (m, 2H), 10.15 (s, 1H), 12.31 (br s, 1H), 13.58 (br s, 1H); ESIMS found for C₂₉H₂₆N₆O₂m/z 491.4 (M+1).

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3-(4-(Furan-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(pyridin-2-yl)-1H-indazole 336

¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.23 (s, 1H), 7.32 (d, J=5.02 Hz, 1H), 7.33-7.36 (m, 1H), 7.37 (s, 1H), 7.72 (d, J=8.78 Hz, 1H), 7.89-7.97 (m, 2H), 8.20 (d, J=7.91 Hz, 1H), 8.22-8.30 (m, 2H), 8.66-8.73 (m, 2H), 8.83 (s, 1H), 12.34 (br s, 1H), 13.59 (br s, 1H); ESIMS found for C₂₃H₁₅N₅O m/z 378.2 (M+1).

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3-Methyl-N-(5-(3-(4-(thiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)butanamide 338

¹H NMR (499 MHz, DMSO-d₆) δ ppm 0.97 (d, J=6.59 Hz, 6H), 2.13 (dquin, J=13.64, 6.88, 6.88, 6.88, 6.88 Hz, 1H), 2.27 (d, J=7.14 Hz, 2H), 6.92 (dd, J=3.43, 1.78 Hz, 1H), 7.44 (d, J=4.94 Hz, 1H), 7.58-7.64 (m, 1H), 7.71-7.79 (m, 2H), 7.90 (d, J=3.84 Hz, 1H), 8.03 (d, J=3.84 Hz, 1H), 8.27 (d, J=4.94 Hz, 1H), 8.36-8.41 (m, 2H), 8.72 (d, J=1.92 Hz, 1H), 8.79 (d, J=2.20 Hz, 1H), 10.17 (s, 1H), 11.86 (br s, 1H), 13.47 (s, 1H); ESIMS found for C₂₈H₂₄N₆OS m/z 492.9 (M+1).

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N-(5-(3-(4-(Thiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)pivalamide 344

¹H NMR (499 MHz, DMSO-d₆) δ ppm 1.28 (s, 9H), 6.92 (dd, J=3.57, 1.65 Hz, 1H), 7.44 (d, J=4.94 Hz, 1H), 7.59-7.65 (m, 1H), 7.72-7.79 (m, 2H), 7.90 (d, J=3.84 Hz, 1H), 8.03 (d, J=3.84 Hz, 1H), 8.27 (d, J=4.94 Hz, 1H), 8.37-8.44 (m, 2H), 8.73 (d, J=1.92 Hz, 1H), 8.90 (d, J=2.20 Hz, 1H), 9.50 (s, 1H), 11.86 (br s, 1H), 13.47 (br s, 1H); ESIMS found for C₂₈H₂₄N₆OS m/z 492.9 (M+1).

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N,N-Dimethyl-1-(5-(3-(4-(thiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)methanamine 349

¹H NMR (499 MHz, DMSO-d₆) δ ppm 2.22 (s, 6H), 3.54 (s, 2H), 6.92 (dd, J=3.57, 1.92 Hz, 1H), 7.44 (d, J=4.94 Hz, 1H), 7.59-7.63 (m, 1H), 7.72-7.77 (m, 1H), 7.77-7.83 (m, 1H), 7.90 (d, J=3.84 Hz, 1H), 8.05-8.11 (m, 2H), 8.27 (d, J=4.94 Hz, 1H), 8.43 (s, 1H), 8.50 (d, J=1.65 Hz, 1H), 8.94 (d, J=2.20 Hz, 1H), 11.86 (br s, 1H), 13.45 (br s, 1H); ESIMS found for C₂₆H₂₂N₆S m/z 450.9 (M+1).

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3,3-Dimethyl-N-(5-(3-(4-(thiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)butanamide 352.

¹H NMR (499 MHz, DMSO-d₆) δ ppm 1.06 (s, 9H), 2.27 (s, 2H), 6.92 (dd, J=3.57, 1.92 Hz, 1H), 7.44 (d, J=4.94 Hz, 1H), 7.58-7.65 (m, 1H), 7.70-7.80 (m, 2H), 7.90 (d, J=3.84 Hz, 1H), 8.03 (d, J=4.12 Hz, 1H), 8.27 (d, J=4.94 Hz, 1H), 8.36-8.42 (m, 2H), 8.73 (d, J=1.92 Hz, 1H), 8.79 (d, J=2.20 Hz, 1H), 10.12 (s, 1H), 11.87 (br s, 1H), 13.48 (s, 1H); ESIMS found for C₂₉H₂₆N₆OS m/z 506.9 (M+1).

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N-(5-(3-(4-(Thiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl) pyridin-3-yl)butyramide 353

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.95 (br t, J=7.22 Hz, 3H), 1.61-1.73 (m, 2H), 2.38 (br t, J=7.15 Hz, 2H), 7.28-7.33 (m, 1H), 7.39 (br d, J=4.89 Hz, 1H), 7.46 (s, 1H), 7.77 (br s, 3H), 7.95 (br d, J=2.89 Hz, 1H), 8.28 (br d, J=4.64 Hz, 1H), 8.44 (br s, 1H), 8.47 (br s, 1H), 8.73 (br s, 2H), 10.22 (br s, 1H), 12.47 (br s, 1H), 13.63 (br s, 1H); ESIMS found for C₂₇H₂₂N₆OS m/z 479.3 (M+1).

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5-(Pyridin-2-yl)-3-(4-(thiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole 364

¹H NMR (499 MHz, DMSO-d₆) δ ppm 6.92 (br s, 1H), 7.32-7.38 (m, 1H), 7.43 (br d, J=4.94 Hz, 1H), 7.62 (br s, 1H), 7.72 (br d, J=8.78 Hz, 1H), 7.88-7.95 (m, 2H), 8.00 (br d, J=3.57 Hz, 1H), 8.17 (br d, J=7.96 Hz, 1H), 8.25 (br d, J=8.78 Hz, 1H), 8.28 (br d, J=4.67 Hz, 1H), 8.71 (br d, J=3.57 Hz, 1H), 8.80 (s, 1H), 11.85 (br s, 1H), 13.44 (s, 1H); ESIMS found for C₂₃H₁₅N₅S m/z 393.9 (M+1).

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3-(4-(3-Fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(piperidin-4-yl)-1H-indazole 505

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.78-1.91 (m, 2H), 1.93-2.02 (m, 2H), 2.98 (br t, J=11.23 Hz, 3H), 3.35 (br d, J=10.79 Hz, 2H), 7.12 (s, 1H), 7.26 (d, J=4.89 Hz, 1H), 7.31-7.40 (m, 2H), 7.61 (br d, J=8.66 Hz, 1H), 7.63-7.70 (m, 2H), 7.71-7.77 (m, 1H), 7.90 (s, 1H), 8.33 (d, J=4.89 Hz, 1H), 12.41 (br s, 1H), 13.45 (br s, 1H); ESIMS found for C₂₅H₂₂FN₅m/z 412.3 (M+1).

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3-(4-(4-Fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indazole 522

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.84 (br s, 2H), 3.38 (br s, 2H), 3.81 (br s, 2H), 6.30 (br s, 1H), 7.44-7.53 (m, 3H), 7.60 (d, J=5.90 Hz, 1H), 7.63-7.71 (m, 2H), 8.05 (dd, J=8.72, 5.46 Hz, 2H), 8.13 (s, 1H), 8.49 (d, J=5.90 Hz, 1H), 13.61 (br s, 1H); ESIMS found for C₂₅H₂₀FN₅m/z 410.2 (M+1).

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2-((5-(3-(4-(4-Fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)oxy)-N,N-dimethylethan-1-amine 531

¹H NMR (499 MHz, DMSO-d₆) δ ppm 2.25 (s, 6H), 2.70 (br t, J=5.35 Hz, 2H), 4.21-4.31 (m, 2H), 7.23 (br d, J=4.39 Hz, 1H), 7.31 (br s, 1H), 7.40 (br t, J=8.37 Hz, 2H), 7.73 (br d, J=9.06 Hz, 1H), 7.82 (br s, 2H), 7.93-8.00 (m, 2H), 8.29 (br s, 1H), 8.33 (br d, J=4.39 Hz, 1H), 8.47 (br s, 1H), 8.61 (br s, 1H), 12.34 (br s, 1H), 13.56 (br s, 1H); ESIMS found for C₂₉H₂₅FN₆O m/z 493.0 (M+1).

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5-(1-Methyl-1H-pyrazol-4-yl)-3-(4-(pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole 556

¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.89 (s, 3H), 7.20 (s, 1H), 7.28 (br d, J=4.64 Hz, 1H), 7.54-7.60 (m, 1H), 7.65 (br d, J=7.65 Hz, 2H), 7.95 (s, 1H), 8.18 (br s, 1H), 8.22 (br s, 1H), 8.29-8.38 (m, 2H), 8.71 (br d, J=3.89 Hz, 1H), 9.09 (br s, 1H); ESIMS found for C₂₃H₁₇N₇m/z 392.3 (M+1).

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5-(1H-Pyrazol-4-yl)-3-(4-(pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole 571

¹H NMR (499 MHz, DMSO-d₆) δ ppm 7.32 (br d, J=2.20 Hz, 1H), 7.35 (d, J=4.94 Hz, 1H), 7.61 (d, J=8.51 Hz, 1H), 7.72 (br dd, J=8.64, 1.51 Hz, 1H), 7.89-7.93 (m, 2H), 8.04 (br s, 1H), 8.28 (br s, 1H), 8.31 (s, 1H), 8.38 (d, J=4.94 Hz, 1H), 8.78-8.81 (m, 2H), 12.38 (br s, 1H), 12.88 (br s, 1H), 13.41 (s, 1H); ESIMS found for C₂₂H15N₇m/z 377.9 (M+1).

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5-(1,2-Dimethyl-1H-imidazol-5-yl)-3-(4-(pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole 573

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.39 (s, 3H), 3.58 (s, 3H), 6.94 (s, 1H), 7.28 (s, 1H), 7.34 (d, J=4.89 Hz, 1H), 7.50 (br d, J=8.78 Hz, 1H), 7.70 (d, J=8.78 Hz, 1H), 7.90 (br d, J=4.77 Hz, 2H), 8.18 (s, 1H), 8.37 (d, J=4.89 Hz, 1H), 8.78 (br d, J=4.77 Hz, 2H), 12.47 (br s, 1H), 13.61 (br s, 1H); ESIMS found for C₂₄H₁₉N₇m/z 406.28 (M+1).

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3-(4-(Piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(1H-pyrazol-4-yl)-1H-indazole 603

¹H NMR (499 MHz, DMSO-d₆) δ ppm 1.64-1.70 (m, 2H), 1.72-1.82 (m, 4H), 3.41-3.52 (m, 4H), 6.45 (d, J=5.49 Hz, 1H), 7.02 (s, 1H), 7.58 (d, J=8.51 Hz, 1H), 7.69 (br dd, J=8.78, 1.37 Hz, 1H), 7.97 (d, J=5.49 Hz, 1H), 8.02 (br s, 1H), 8.26 (br d, J=1.37 Hz, 1H), 8.27 (s, 1H), 11.76 (br s, 1H), 12.88 (br s, 1H), 13.20 (s, 1H); ESIMS found for C₂₂H₂₁N₇m/z 384.0 (M+1).

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1-(6-(3-(4-(Piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl) pyrazin-2-yl)azetidin-3-amine 606

¹H NMR (499 MHz, DMSO-d₆) δ ppm 1.65-1.71 (m, 2H), 1.71-1.78 (m, 4H), 3.46-3.52 (m, 4H), 3.75 (dd, J=8.10, 5.90 Hz, 2H), 3.89-3.96 (m, 1H), 4.31 (t, J=7.82 Hz, 2H), 6.46 (d, J=5.49 Hz, 1H), 7.02 (s, 1H), 7.69 (d, J=8.78 Hz, 1H), 7.82 (s, 1H), 7.98 (d, J=5.49 Hz, 1H), 8.14 (dd, J=8.78, 1.65 Hz, 1H), 8.38 (s, 1H), 8.59 (s, 1H), 8.79 (s, 1H), 11.91 (br s, 1H), 13.43 (br d, J=1.65 Hz, 1H); ESIMS found for C₂₆H₂₇N₉m/z 466.0 (M+1).

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5-(5-(Cyclohexyloxy)pyridin-3-yl)-3-(4-(piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole 607

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.26-1.36 (m, 1H), 1.36-1.61 (m, 5H), 1.75 (br s, 8H), 1.94-2.04 (m, 2H), 3.95 (br s, 4H), 4.59-4.69 (m, 1H), 6.82 (d, J=7.28 Hz, 1H), 7.51 (s, 1H), 7.73-7.79 (m, 1H), 7.82-7.88 (m, 2H), 7.94 (d, J=7.28 Hz, 1H), 8.30 (br d, J=1.88 Hz, 1H), 8.42 (s, 1H), 8.60 (s, 1H), 13.19 (br s, 1H), 13.70 (br s, 1H); ESIMS found for C₃₀H₃₂N₆O m/z 493.3 (M+1).

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N-(5-(3-(4-(4-Methylpiperazin-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)-2-(piperidin-4-yl)acetamide 641

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.06-1.19 (m, 3H), 1.63 (br d, J=11.67 Hz, 2H), 1.85-1.95 (m, 1H), 2.22-2.32 (m, 6H), 2.55 (br d, J=4.14 Hz, 4H), 2.93 (br d, J=11.92 Hz, 2H), 3.44-3.52 (m, 4H), 6.48 (d, J=5.52 Hz, 1H), 7.06 (s, 1H), 7.74 (s, 2H), 8.00 (d, J=5.52 Hz, 1H), 8.38 (s, 1H), 8.47 (s, 1H), 8.69 (d, J=1.88 Hz, 1H), 8.73 (d, J=1.63 Hz, 1H), 10.24 (s, 1H), 12.00 (br s, 1H), 13.47 (br s, 1H); ESIMS found for C₃₁H₃₅N₉O m/z 550.3 (M+1).

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5-(5-(Benzyloxy)pyridin-3-yl)-3-(4-(4-methylpiperazin-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole 646

¹H NMR (499 MHz, DMSO-d₆) δ ppm 2.76 (s, 3H), 3.24-3.34 (m, 2H), 3.57 (br d, J=11.80 Hz, 2H), 3.85-3.93 (m, 2H), 4.66 (br d, J=14.00 Hz, 2H), 5.43 (s, 2H), 6.97 (d, J=7.14 Hz, 1H), 7.37-7.42 (m, 1H), 7.45 (t, J=7.41 Hz, 2H), 7.56 (d, J=7.14 Hz, 2H), 7.64 (d, J=1.65 Hz, 1H), 7.81 (d, J=8.51 Hz, 1H), 7.95 (dd, J=8.78, 1.37 Hz, 1H), 8.11 (d, J=7.13 Hz, 1H), 8.35 (br s, 1H), 8.55 (d, J=2.20 Hz, 1H), 8.68 (s, 1H), 8.90 (s, 1H), 13.38 (s, 1H), 13.90 (br s, 1H); ESIMS found for C₃₁H₂₉N₇O m/z 516.0 (M+1).

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5-(5-(2-(Pyrrolidin-1-yl)ethoxy)pyridin-3-yl)-3-(1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole 658

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.69 (dt, J=6.46, 3.17 Hz, 4H), 2.55 (br s, 4H), 2.85 (t, J=5.77 Hz, 2H), 4.29 (t, J=5.83 Hz, 2H), 7.09 (dd, J=7.84, 4.71 Hz, 1H), 7.32 (s, 1H), 7.73 (d, J=8.66 Hz, 1H), 7.79-7.86 (m, 2H), 8.00 (dd, J=7.78, 1.51 Hz, 1H), 8.24 (dd, J=4.64, 1.51 Hz, 1H), 8.30 (d, J=2.64 Hz, 1H), 8.48 (s, 1H), 8.64 (d, J=1.63 Hz, 1H), 12.17 (br s, 1H), 13.54 (br s, 1H); ESIMS found for C₂₅H₂₄N₆O m/z 425.4 (M+1).

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5-(5-Methoxypyridin-3-yl)-3-(4-(thiophen-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole 676

¹H NMR (499 MHz, DMSO-d₆) δ ppm 3.97 (s, 3H), 7.35 (d, J=4.94 Hz, 1H), 7.46 (d, J=1.92 Hz, 1H), 7.72-7.77 (m, 2H), 7.80 (dd, J=4.94, 1.37 Hz, 1H), 7.81-7.86 (m, 2H), 8.28 (d, J=4.94 Hz, 1H), 8.31 (d, J=2.74 Hz, 1H), 8.35 (dd, J=2.74, 1.10 Hz, 1H), 8.54 (s, 1H), 8.66 (d, J=1.65 Hz, 1H), 12.32 (s, 1H), 13.56 (br s, 1H); ESIMS found for C₂₄H₁₇N₅OS m/z 424.1 (M+1).

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3-(4-(Furan-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(5-methoxypyridin-3-yl)-1H-indazole 692

¹H NMR (499 MHz, DMSO-d₆) δ ppm 3.97 (s, 3H), 7.23-7.26 (m, 1H), 7.32 (d, J=4.94 Hz, 1H), 7.43 (s, 1H), 7.74 (d, J=8.51 Hz, 1H), 7.81-7.86 (m, 2H), 7.89 (t, J=1.65 Hz, 1H), 8.25 (d, J=4.94 Hz, 1H), 8.31 (d, J=2.74 Hz, 1H), 8.57 (s, 1H), 8.67 (d, J=1.65 Hz, 1H), 8.73 (s, 1H), 12.27 (br s, 1H), 13.56 (br s, 1H); ESIMS found for C₂₄H₁₇N₅O₂m/z 408.2 (M+1).

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3-(4-(Furan-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(pyrazin-2-yl)-1H-indazole 696

¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.25 (s, 1H), 7.32 (d, J=4.89 Hz, 1H), 7.39 (s, 1H), 7.77 (d, J=8.78 Hz, 1H), 7.91 (s, 1H), 8.21 (br d, J=8.91 Hz, 1H), 8.25 (d, J=4.77 Hz, 1H), 8.60 (d, J=2.13 Hz, 1H), 8.71 (br s, 1H), 8.74 (br s, 1H), 8.94 (s, 1H), 9.52 (s, 1H), 12.31 (br s, 1H), 13.68 (br s, 1H); ESIMS found for C₂₂H₁₄N₆O m/z 379.2 (M+1).

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5-(Pyrazin-2-yl)-3-(4-(thiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole 712

¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.29-7.34 (m, 1H), 7.39 (d, J=4.89 Hz, 1H), 7.48 (s, 1H), 7.79 (d, J=8.78 Hz, 1H), 7.82 (br d, J=5.14 Hz, 1H), 7.96 (br d, J=3.26 Hz, 1H), 8.25 (br d, J=9.29 Hz, 1H), 8.28 (d, J=5.02 Hz, 1H), 8.62 (d, J=2.13 Hz, 1H), 8.75 (s, 1H), 8.94 (s, 1H), 9.48 (s, 1H), 12.53 (br s, 1H), 13.70 (br s, 1H); ESIMS found for C₂₂H₁₄N₆S m/z 395.2 (M+1).

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3-(4-(Furan-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(5-methoxypyridin-3-yl)-1H-indazole 991

¹H NMR (499 MHz, DMSO-d₆) δ ppm 3.97 (s, 3H), 6.76 (dd, J=3.43, 1.78 Hz, 1H), 7.43 (d, J=5.21 Hz, 1H), 7.50 (d, J=3.29 Hz, 1H), 7.52 (s, 1H), 7.75 (d, J=8.51 Hz, 1H), 7.80-7.86 (m, 2H), 7.96 (d, J=1.37 Hz, 1H), 8.28 (d, J=4.94 Hz, 1H), 8.31 (d, J=2.74 Hz, 1H), 8.54 (s, 1H), 8.67 (d, J=1.65 Hz, 1H), 12.35 (br s, 1H), 13.61 (br s, 1H); ESIMS found for C₂₄H₁₇N₅O₂m/z 408.1 (M+1).

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1-(5-(7-Fluoro-3-(4-(3-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)-N,N-dimethylmethanamine 992

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.81 (br d, J=2.21 Hz, 6H), 4.57 (br s, 2H), 7.40 (td, J=8.60, 2.21 Hz, 1H), 7.48 (d, J=5.51 Hz, 1H), 7.53 (s, 1H), 7.65-7.71 (m, 1H), 7.73-7.78 (m, 1H), 7.87 (br d, J=7.94 Hz, 1H), 7.98 (d, J=12.35 Hz, 1H), 8.44 (d, J=5.29 Hz, 1H), 8.57 (s, 1H), 8.99 (s, 1H), 9.22 (s, 1H), 9.47 (d, J=1.54 Hz, 1H), 11.88 (br s, 1H), 13.15 (br s, 1H); ESIMS found for C₂₈H₂₂F₂N₆m/z 481.1 (M+1).

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1-(5-(6-Fluoro-3-(4-(3-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)-N,N-dimethylmethanamine 993

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.80 (br s, 6H), 4.56 (br s, 2H), 7.40 (td, J=8.60, 1.98 Hz, 1H), 7.49-7.54 (m, 2H), 7.63-7.72 (m, 2H), 7.74 (dt, J=9.76, 2.07 Hz, 1H), 7.86 (d, J=8.16 Hz, 1H), 8.44 (d, J=5.73 Hz, 1H), 8.60 (d, J=7.28 Hz, 1H), 8.94 (s, 1H), 9.05 (s, 1H), 9.21 (br s, 1H), 11.77 (br s, 1H), 13.23 (br s, 1H); ESIMS found for C₂₈H₂₂F₂N₆m/z 481.1 (M+1).

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1-(5-(4-Fluoro-3-(4-(3-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)-N,N-dimethylmethanamine 994

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.78 (br d, J=3.53 Hz, 6H), 4.54 (br d, J=3.31 Hz, 2H), 7.33 (s, 1H), 7.36-7.44 (m, 1H), 7.49 (d, J=5.51 Hz, 1H), 7.62-7.70 (m, 3H), 7.70-7.75 (m, 1H), 7.81 (dd, J=8.60, 6.84 Hz, 1H), 8.45 (d, J=5.51 Hz, 1H), 8.84 (s, 1H), 9.00 (s, 1H), 9.16 (s, 1H), 11.73 (br s, 1H), 13.12 (br s, 1H); ESIMS found for C₂₈H₂₂F₂N₆m/z 481.2 (M+1).

Example 2

The screening assay for Wnt activity is described as follows. Reporter cell lines can be generated by stably transducing cancer cell lines (e.g., colon cancer) or primary cells (e.g., IEC-6 intestinal cells) with a lentiviral construct that includes a Wnt-responsive promoter driving expression of the firefly luciferase gene.

SW480 colon carcinoma cells were transduced with a lentiviral vector expressing luciferase with a human Sp5 promoter consisting of a sequence of eight TCF/LEF binding sites. SW480 cells stably expressing the Sp5-Luc reporter gene and a hygromycin resistance gene were selected by treatment with 150 μg/mL of hygromycin for 7 days. These stably transduced SW480 cells were expanded in cell culture and used for all further screening activities. Each compound was dissolved in DMSO as a 10 mM stock and used to prepare compound source plates. Serial dilution (1:3, 10-point dose-response curves starting from 10 μM) and compound transfer was performed using the ECHO 550 (Labcyte, Sunnyvale, Calif.) into 384-well white solid bottom assay plates (Greiner Bio-One) with appropriate DMSO backfill for a final DMSO concentration of 0.1%. For Sp5-Luc reporter gene assays, the cells were plated at 4,000 cells/well in 384-well plates with medium containing 1% fetal bovine serum and incubated overnight at 37° C. and 5% CO₂. Following incubation, 20 μl of BrightGlo luminescence reagent (Promega) was added to each well of the 384-well assay plates. The plates were placed on an orbital shaker for 2 min and then luminescence was quantified using the Envision (Perkin Elmer) plate reader. Readings were normalized to DMSO only treated cells, and normalized activities were utilized for EC₅₀calculations using the dose-response log (inhibitor) vs. response -variable slope (four parameters) nonlinear regression feature available in GraphPad Prism 5.0 (or Dotmatics). For EC₅₀of >10 μM, the percent inhibition at 10 μM is provided.

Table 2 shows the measured activity for representative compounds of Formula I as described herein.

TABLE 2

Compound
EC₅₀(μM)

1
0.013

6
1.677

13
1.179

18
>10
(18.0%)

20
0.035

26
>10
(49.0%)

28
>10
(8.5%)

30
>10
(13.6%)

36
>10
(11.7%)

39
>10
(0%)

42
>10
(14.8%)

45
>10
(11.0%)

49
>10
(10.6%)

55
>10
(11.7%)

59
0.131

61
>10
(3.5%)

65
>10
(30.5%)

68
>10
(18.7%)

72
>10
(9.3%)

75
>10
(13.0%)

78
>10
(1.9%)

86
0.184

88
>10
(48.8%)

90
>10
(28.6%)

96
>10
(38.9%)

99
>10
(18.6%)

107
>10
(10.6%)

110
0.523

117
>10
(31.8%)

120
>10
(36.6%)

122
>10
(28.3%)

123
>10
(17.3%)

125
>10
(29.7%)

131
>10
(16.7%)

133
>10
(2.8%)

139
>10
(7.5%)

141
0.238

143
0.022

147
>10
(13.7%)

163
>10
(38.8%)

169
1.222

171
0.604

172
>10
(48.2%)

175
>10
(10.7%)

178
>10
(13.8%)

181
>10
(26.2%)

182
>10
(36.0%)

184
>10
(11.9%)

188
>10
(27.6%)

193
>10
(8.0%)

194
>10
(26.2%)

227
1.172

238
3.475

248
3.370

255
0.102

261
0.178

267
1.671

270
>10
(45.7%)

271
0.324

274
0.271

279
>10
(16.6%)

282
2.103

284
>10
(38.0%)

295
>10
(37.1%)

307
>10
(6.0%)

313
4.285

321
>10
(3.7%)

324
0.890

336
>10
(11.0%)

338
0.332

344
0.215

349
3.848

352
0.432

353
0.040

364
3.383

505
0.563

522
3.250

531
>10
(2.3%)

556
>10
(20.0%)

571
>10
(37.0%)

573
>10
(8.0%)

603
0.181

606
>10
(20.2%)

607
>10
(28.4%)

641
>10
(10.8%)

646
4.876

658
3.295

676
>10
(21.0%)

692
>10
(20.0%)

696
4.152

712
>10
(5.6%)

991
>10
(7.9%)

992
>10
(17.0%)

993
>10

994
>10
(20.8%)

Example 3

Representative compounds were screened using the following assay procedure to assess the effect on cell viability as described below.

Each compound was dissolved in DMSO as a 10 mM stock and used to prepare compound source plates. Serial dilution (1:3, 8-point dose-response curves from 10 μM to 0.0045 M) and compound transfer was performed using the ECHO 550 (Labcyte, Sunnyvale, Calif.) into 96-well clear bottom, black-walled plates (Corning-Costar).

Approximately 2×103 SW480 colon cancer cells were seeded into each well and allowed to incubate in the presence or absence of compound for four days at 37° C./5% CO₂. Eight replicates of DMSO-treated cells served as controls and cells treated with compound were performed in duplicate.

After incubation, 20 μL of CellTiter-Blue (Promega) was added to each well allowed to incubate for approximately 3 hours. This reagent was a buffered solution which contains resazurin, metabolically active cells were able to reduce rezarurin (blue) into resorufin (pink) which was highly fluorescent. This measured fluorescence was used as a readout for cell viability.

After incubation, the plates were read at Ex 560 nm Em 590 nm (Cytation 3, BioTek). Dose-response curves were generated and EC₅₀concentration values were calculated using non-linear regression curve fit in the GraphPad Prism (San Diego, Calif.) or Dotmatics' Studies Software (Bishops Stortford, UK). For EC₅₀of >10 μM, the percent inhibition at 10 μM is provided.

Table 3 shows the activity of representative compounds of Formula I as provided herein.

TABLE 3

Compound
EC₅₀(μM)

1
1.028

6
0.561

13
2.922

18
>10
(16.2%)

20
1.060

26
>10
(40.6%)

28
>10
(12.9%)

30
>10
(14.9%)

36
>10
(33.1%)

39
>10
(24.2%)

42
1.512

45
>10
(30.7%)

49
>10
(11.8%)

55
>10
(17.3%)

59
0.399

61
>10
(14.9%)

65
>10
(10.8%)

68
>10
(10.9%)

72
>10
(12.6%)

75
>10
(16.8%)

78
>10
(14.4%)

86
>10
(44.6%)

88
>10
(11.2%)

90
>10
(31.3%)

96
>10
(28.2%)

99
>10
(50.6%)

107
>10
(12.0%)

110
>10
(51.8%)

117
>10
(4.6%)

120
>10
(10.7%)

122
1.945

123
>10
(7.2%)

125
>10
(7.4%)

131
>10
(10.6%)

133
>10
(6.4%)

139
>10
(5.3%)

141
6.074

143
0.089

147
>10
(15.4%)

163
>10
(11.1%)

169
>10
(38.1%)

171
1.227

172
>10
(8.9%)

175
>10
(13.1%)

178
>10
(18.7%)

181
>10
(17.6%)

182
4.077

184
>10
(1.6%)

188
>10
(12.9%)

193
>10
(12.5%)

194
>10
(18.5%)

227
>10
(42.3%)

238
4.339

248
2.168

255
0.632

261
0.405

267
0.675

270
>10
(15.2%)

271
1.065

274
0.656

279
>10
(17.9%)

282
6.940

284
0.352

295
>10
(2.1%)

307
>10
(0%)

313
>10
(0%)

321
>10
(7.9%)

324
9.200

336
>10
(0%)

338
0.747

344
0.606

349
4.640

352
0.872

353
1.300

364
1.141

505
0.465

522
>10
(19.2%)

531
>10
(4.1%)

556
>10
(0%)

571
>10
(23.8%)

573
1.150

603
0.296

606
>10
(10.2%)

607
8.583

641
>10
(16.2%)

646
4.822

658
3.940

676
>10
(0%)

692
>10
(0%)

696
3.990

712
>10
(13.9%)

991
>10
(0%)

992
>10
(3.6%)

993
2.399

994
>10
(34.7%)

Example 4

Representative compounds were screened using primary human fibroblasts (derived from IPF patients) treated with TGF-β1 to determine their ability to inhibit the fibrotic process.

Human Fibroblast Cell Culture:

Primary human fibroblasts derived from IPF patients (LL29 cells) [¹Xiaoqiu Liu, et. al., “Fibrotic Lung Fibroblasts Show Blunted Inhibition by cAMP Due to Deficient cAMP Response Element-Binding Protein Phosphorylation”, Journal of Pharmacology and Experimental Therapeutics (2005), 315(2), 678-687; ²Watts, K. L., et. al., “RhoA signaling modulates cyclin D1 expression in human lung fibroblasts; implications for idiopathic pulmonary fibrosis”, Respiratory Research (2006), 7(1), 88] were obtained from American Type Culture Collection (ATCC) and expanded in F12 medium supplemented with 15% Fetal Bovine Serum and Penicillin/Streptomycin.

Compound Screening:

Each compound was dissolved in DMSO as a 10 mM stock and used to prepare compound source plates. Serial dilution (1:2, 11-point dose-response curves from 10 μM to 1.87 nM) and compound transfer was performed using the ECHO 550 (Labcyte, Sunnyvale, Calif.) into 384-well clear bottom assay plates (Greiner Bio-One) with appropriate DMSO backfill for a final DMSO concentration of 0.1%. LL29 cells are plated at 1,500 cells/well in 80 μL/well F12 medium supplemented with 1% Fetal Bovine Serum. One hour after addition of the cells, TGF-β1 (Peprotech; 20 ng/mL) was added to the plates to induce fibrosis (ref. 1 and 2 above). Wells treated with TGF-β1 and containing DMSO were used as controls. Cells were incubated at 37° C. and 5% CO₂for 4 days. Following incubation for 4 days, SYTOX green nucleic acid stain (Life Technologies [Thermo Fisher Scientific]) was added to the wells at a final concentration of 1 μM and incubated at room temperature for 30 min. Cells were then fixed using 4% formaldehyde (Electron Microscopy Sciences), washed 3 times with PBS followed by blocking and permeabilization using 3% Bovine Serum Albumin (BSA; Sigma) and 0.3% Triton X-100 (Sigma) in PBS. Cells were then stained with antibody specific to α-smooth muscle actin (αSMA; Abcam) (ref. 1 and 2 above) in 3% Bovine Serum Albumin (BSA; Sigma) and 0.3% Triton X-100 (Sigma) in PBS, and incubated overnight at 4° C. Cells were then washed 3 times with PBS, followed by incubation with Alexa Flor-647 conjugated secondary antibody (Life Technologies [Thermo Fisher Scientific]) and DAPI at room temperature for 1 hour. Cells were then washed 3 times with PBS and plates were sealed for imaging. αSMA staining was imaged by excitation at 630 nm and emission at 665 nm and quantified using the Compartmental Analysis program on the CellInsight CX5 (Thermo Scientific). Dead or apoptotic cells were excluded from analysis based on positive SYTOX green staining. % of total cells positive for αSMA were counted in each well and normalized to the average of 11 wells treated with TGF-β1 on the same plate using Dotmatics' Studies Software. The normalized averages (fold change over untreated) of 3 replicate wells for each compound concentration were used to create dose-responses curves and EC₅₀values were calculated using non-linear regression curve fit in the Dotmatics' Studies Software. For EC₅₀of >10 μM, the percent inhibition at 10 μM is provided.

Table 4 shows the activity of representative compounds of Formula I as provided herein.

TABLE 4

Compound
EC₅₀(μM)

1
0.141

6
1.201

13
1.190

18
>10
(33.6%)

20
7.728

26
1.963

28
>10
(12.0%)

30
>10
(20.2%)

36
>10
(0%)

39
4.885

42
2.934

45
5.239

49
>10
(3.2%)

55
>10
(7.3%)

59
0.592

61
0.450

65
>10
(11.7%)

68
>10
(0%)

72
>10
(5.4%)

75
>10
(29.1%)

78
>10
(39.0%)

86
>10
(25.9%)

88
>10
(0%)

90
>10
(0%)

96
>10
(10.0%)

99
>10
(4.0%)

107
>10
(41.7%)

110
0.095

117
>10
(44.2%)

120
>10
(12.8%)

122
6.176

123
>10
(49.2%)

125
>10
(0%)

131
>10
(6.3%)

133
>10
(0%)

139
>10
(14.5%)

141
1.659

143
0.045

147
>10
(34.0%)

163
>10
(0%)

169
>10
(11.6%)

171
1.722

172
>10
(25.1%)

175
>10
(11.3%)

178
>10
(0%)

181
>10
(9.1%)

182
7.763

184
>10
(20 8%)

188
>10
(17.4%)

193
>10
(24.9%)

194
5.896

227
>10
(51.2%)

238
1.921

248
2.260

255
0.138

261
0.102

267
0.458

270
6.523

271
0.712

274
0.427

279
9.835

284
2.204

295
>10
(16.8%)

307
>10
(0%)

313
>10
(36.3%)

321
1.371

324
>10
(0%)

336
>10
(0%)

338
0.580

344
>10
(0%)

349
0.874

352
0.355

353
5.082

364
2.197

505
0.335

522
3.859

531
>10
(15.6%)

556
0.191

571
>10
(28.3%)

573
>10
(113%)

603
0.304

606
3.623

607
7.104

641
>10
(23.5%)

646
0.316

658
1.195

676
7.778

692
>10
(0%)

696
2.481

712
1.397

992
>10
(5.2%)

993
1.626

994
4.902

Example 5

Representative compounds were screened using primary human mesenchymal stem cells (hMSCs) to determine their ability to induce chondrogenesis (process by which cartilage is developed).

Human Mesenchymal Stem Cell Culture:

Primary human mesenchymal stem cells (hMSCs) were purchased from Lonza (Walkersville, Md.) and expanded in Mesenchymal Stem Cell Growth Media (Lonza). Cells between passage 3 and 6 were used for the experiments.

Compound Screening:

Each compound was dissolved in DMSO as a 10 mM stock and used to prepare compound source plates. For the 96 well assay, serial dilution (1:3, 6-point dose-response curves from 2700 nM to 10 nM) and compound transfer was performed using the ECHO 550 (Labcyte, Sunnyvale, Calif.) into 96-well clear bottom assay plates (Greiner Bio-One) with appropriate DMSO backfill for a final DMSO concentration of 0.03%. hMSCs were plated at 20,000 cells/well in 250 μL/well Incomplete Chondrogenic Induction Medium (Lonza; DMEM, dexamethasone, ascorbate, insulin-transferrin-selenium [ITS supplement], gentamycin-amphotericin [GA-1000], sodium pyruvate, proline and L-glutamine). TGF-β3 (10 ng/mL) was used as a positive control for differentiation while negative control wells were treated with 75 nL DMSO for normalization and calculating EC₅₀values. For the 384 well assay, serial dilution (1:3, 8-point dose-response curves from 5000 nM to 2.2 nM) and compound transfer was performed using the ECHO 550 (Labcyte, Sunnyvale, Calif.) into 384-well clear bottom assay plates (Greiner Bio-One) with appropriate DMSO backfill for a final DMSO concentration of 0.03%. hMSCs were plated at 8,000 cells/well in 80 μL/well Incomplete Chondrogenic Induction Medium (Lonza; DMEM, dexamethasone, ascorbate, insulin-transferrin-selenium [ITS supplement], gentamycin-amphotericin [GA-1000], sodium pyruvate, proline and L-glutamine). TGF-β3 (10 ng/mL) was used as a positive control for differentiation while negative control wells were treated with 25 nL DMSO for normalization and calculating EC₅₀values. Cells were incubated at 37° C. and 5% CO₂for 6 days. To image chondrogenic nodules, the cells were fixed using 4% formaldehyde (Electron Microscopy Sciences), and stained with 2 μg/mL Rhodamine B (Sigma-Aldrich) and 20 μM Nile Red (Sigma-Aldrich) [Johnson K., et. al, A Stem Cell-Based Approach to Cartilage Repair, Science, (2012), 336(6082), 717-721]. The nodules imaged (25 images per well for 96 well plates and 9 images per well for 384 well plates at 10× magnification) by excitation at 531 nm and emission at 625 nm and quantified using the CellInsight CX5 (Thermo Scientific). Area of nodules in each well was normalized to the average of 3 DMSO treated wells on the same plate using Excel (Microsoft Inc.). The normalized averages (fold change over DMSO) of 2 or 3 replicate wells for each compound concentration were calculated. Due to solubility limitations of some of the compounds, curve fitting was incomplete leading to inaccurate EC₅₀determinations.

Using TGF-β3 as a positive control, the concentration of representative compounds required to induce 50% levels of chondrogenesis is reported. In addition, the maximum activity of each compound and the respective dose that each compound reached maximum chondrogenesis activity is reported. Table 5 shows the activity of representative compounds as provided herein.

TABLE 5

Max. Activity
Conc (nM)

Conc (nM)
as %
of 50%

of Max.
TGF-β3
TGF-β3

Compound
activity
activity
activity

1
100
167
100

6
900
59
30

13
2700
48
NA

42
900
22
NA

55
2700
82
2700

59
300
24
NA

61
100
54
30

86
900
104
900

88
10
17
NA

90
30
29
NA

96
300
45
NA

99
900
62
30

107
2700
39
NA

110
300
20
NA

117
30
44
NA

120
100
44
NA

123
2700
19
NA

125
900
37
NA

131
2700
18
NA

133
900
73
900

139
100
17
NA

143
100
46
NA

147
10
77
10

171
30
130
30

172
2700
162
2700

182
900
21
NA

227
100
50
100

238
2700
22
NA

248
2700
17
NA

255
30
36
NA

261
2700
131
900

267
10
51
10

271
10
34
NA

274
30
30
NA

279
2700
84
10

284
10
39
NA

295
300
73
30

313
100
67
100

324
100
21
NA

505
2700
103
900

556
900
28
NA

641
900
17
NA

658
100
43
NA

692
30
26
NA

992
300
35
NA

993
900
28
NA

994
100
21
NA

Example 6

Representative compounds were screened using the following assay procedure to determine their ability to inhibit IL-6 and therefore demonstrate their anti-inflammatory properties.

Human Monocyte Cell Culture:

Human monocyte cell line (THP-1 cells; Catalog # TIB-202, ATCC, Manassas, Va.) were cultured in Roswell Park Memorial Institute (RPMI) 1640 Medium (Catalog #21870-100, Buffalo, N.Y.) with 1% L-glutamine, 1% HEPES, 1% Sodium Pyruvate, 2% Sodium Bicarbonate supplemented with 100 units/mL penicillin, 50 μg/mL streptomycin, 2-mercaptoethanol (0.05 mM) [basal medium] and 10% fetal bovine serum (Catalog #16140089, Life Technologies, Carlsbad, Calif.) at 37° C. and 5% CO₂.

Compound Screening:

THP-1 cells were cultured in basal media with 1% FBS for 24 hours before the start of the assay. Each compound was dissolved in DMSO as a 10 mM stock and used to prepare compound source plates. Serial dilution (1:3, 10-point dose-response curves starting from 10 M) and compound transfer was performed using the ECHO 550 (Labcyte, Sunnyvale, Calif.) into 384-well white low volume assay plates (Greiner Bio-One) with appropriate DMSO backfill for a final DMSO concentration of 0.1%. THP-1 cells were plated at 5000 cells/well in the 384-well plates and incubated at 37° C. for 2 h. 500 ng/mL of LPS was added after 2 hours and cells were incubated for another 22 hours at 37° C. Plates were spun in a centrifuge for 1 minute at 10,000 rpm and a mixture of anti-IL6 XL665, and anti-IL6 Cryptate diluted in reconstitution buffer (Cisbio Inc.) was added to each well. Following incubation for 3 hrs at room temperature, Homogeneous Time-Resolved Fluorescence (HTRF) was measured using the Envision (Perkin Elmer) at 665 nm and 620 nM. The ratio of fluorescence at 665 nm to 620 nm was used as a readout for IL6 quantification. All samples were processed in duplicate. Readings were normalized to DMSO treated cells and normalized activities were utilized for EC₅₀calculations using the dose-response log (inhibitor) vs. response -variable slope (four parameters) nonlinear regression feature available in GraphPad Prism 5.0 (or Dotmatics). For EC₅₀of >10 μM, the percent inhibition at 10 M is provided.

Table 6 shows the activity of representative compounds of Formula I as provided herein.

TABLE 6

Compound
EC₅₀(μM)

1
6.144

6
3.971

13
>10
(55.3%)

18
0.995

20
>10
(34.5%)

26
0.285

28
>10
(21.0%)

30
>10
(25.3%)

36
>10
(19.3%)

39
>10
(28.4%)

42
>10
(40.2%)

45
>10
(25.8%)

49
>10
(29.6%)

55
>10
(25.6%)

59
>10
(31.6%)

61
>10
(22.7%)

65
>10
(34.9%)

68
0.384

72
>10
(10.5%)

75
>10
(38.2%)

78
>10
(39.9%)

86
0.550

88
0.648

90
0.561

96
0.409

99
>10
(0%)

107
>10
(34.4%)

110
3.343

117
>10
(31.5%)

120
>10
(35.6%)

122
>10
(47.3%)

123
>10
(20.6%)

125
>10
(49.7%)

131
>10
(31.5%)

133
>10
(33.3%)

139
>10
(43.1%)

141
>10
(30.3%)

143
0.083

147
>10
(30.5%)

163
1.535

169
>10
(33.0%)

171
0.622

172
>10
(31.8%)

175
>10
(15.2%)

178
>10
(36.5%)

181
>10
(29.0%)

182
0.315

184
3.990

188
>10
(4.1%)

193
>10
(18.0%)

194
>10
(33.0%)

227
7.339

238
>10
(29.4%)

248
7.729

255
0.015

261
0.009

267
0.177

270
>10
(48.3%)

271
0.023

274
0.018

279
0.140

282
0.971

284
0.347

295
>10
(34.9%)

307
>10
(45.5%)

313
1.010

321
>10
(19.0%)

324
0.694

336
>10
(45.1%)

338
0.047

344
0.053

349
0.091

352
0.073

353
>10
(37.5%)

364
1.567

505
0.166

522
>10
(48.7%)

531
>10
(0%)

556
0.586

571
>10
(37.0%)

573
>10
(26.4%)

603
0.663

606
>10
(39.1%)

607
>10
(20.0%)

641
>10
(26.0%)

646
>10
(37.9%)

658
0.205

676
>10
(38.4%)

692
>10
(43.9%)

696
>10
(43.3%)

712
>10
(36.3%)

991
0.012

992
>10
(34.2%)

993
0.852

994
>10
(36.6%)

Claims

1. A compound, or a pharmaceutically acceptable salt thereof, of Formula I:
2. The compound of claim 1, wherein R1, R2, and R4 are H.
3. The compound of claim 2, wherein R3 is -pyridin-3-yl optionally substituted with 1 R6.
4. The compound of claim 2, wherein R3 is -pyrimidin-5-yl optionally substituted with 1 R6.
5. The compound of claim 2, wherein R3 is -pyrazolyl optionally substituted with 1 R6.
6. The compound of claim 5, wherein R3 is -imidazolyl substituted with 1-2 R6.
7. The compound of claim 3, wherein R6 is selected from the group consisting of —(C1-3 alkyl), —CH2heterocyclyl optionally substituted with 1-2 R11, —NHC(═O)R14, NR15R16, —CH2NR17R18, and —OR24.
8. The compound of claim 5, wherein R6 is —(C1-3 alkyl).
9. The compound of claim 6, wherein R6 is —(C1-3 alkyl).
10. The compound of claim 7, wherein R14 is selected from the group consisting of —(C1-5 alkyl), -phenyl optionally substituted with 1-2 R21, —CH2phenyl optionally substituted with 1-2 R21, and -carbocyclyl optionally substituted with 1-2 R22.
11. The compound of claim 7, wherein R15 and R16 are independently selected from H and —(C1-3 alkyl).
12. The compound of claim 7, wherein R17 and R18 are independently selected from H and —(C1-3 alkyl).
13. The compound of claim 12, wherein R24 is selected from the group consisting of H, —(C1-3 alkyl), -heterocyclyl optionally substituted with 1-2 R23, —(CH2)heterocyclyl optionally substituted with 1-2 R23, —(CH2CH2)heterocyclyl optionally substituted with 1-2 R23-carbocyclyl optionally substituted with 1-2 R22, —(CH2)aryl optionally substituted with 1-2 R21, and —(CH2CH2)N(C1-2 alkyl)2.
14. The compound of claim 2, wherein R5 is -phenyl optionally substituted with 1-2 R10.
15. The compound of claim 14, wherein R5 is substituted with 1 R10, and wherein R10 is halide.
16. The compound of claim 14, wherein R5 is substituted with 2 R10, and wherein one R10 is halide and one R10 is —CH2NHSO2R19.
17. The compound of claim 14, wherein R5 is substituted with 2 R10, and wherein one R10 is halide and one R10 is —NHCH2CH2NR15R16.
18. The compound of claim 2, wherein R5 is selected from the group consisting of -pyridinyl optionally substituted with 1-2 R8, -imidazolyl optionally substituted with 1-2 R8, -furanyl optionally substituted with 1-2 R8, and -thiophenyl optionally substituted with 1-2 R8.
19. The compound of claim 18, wherein R8 is selected from the group consisting of halide, —(C1-3 alkyl), and —C(═O)R19, and R19 is —(C1-2 alkyl).
20. The compound of claim 2, wherein R5 is selected from the group consisting of -piperidinyl optionally substituted with 1-2 R9 and -piperazinyl optionally substituted with 1-2 R9.
21. The compound of claim 1, wherein the compound of Formula I is selected from the group consisting of: N-(5-(3-(4-(3-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)propionamide [1];N-(5-(3-(4-(3-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)-3-methylbutanamide [2];5-(3-(4-(3-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-amine [3];3-(4-(3-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(pyridin-3-yl)-1H-indazole [4];3-(4-(3-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(4-methylpyridin-3-yl)-1H-indazole [5];N-((5-(3-(4-(3-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)methyl)ethanamine [6];5-(3-(4-(3-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)-N,N-dimethylpyridin-3-amine [7];N-(5-(3-(4-(3-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)pivalamide [8];N-(5-(3-(4-(3-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)isobutyramide [9];N-(5-(3-(4-(3-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)-2-phenylacetamide [10];N-(5-(3-(4-(3-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)benzamide [11];5-(3-(4-(3-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)-N-isopropylpyridin-3-amine [12];1-(5-(3-(4-(3-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)-N,N-dimethylmethanamine [13];3-(4-(3-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(5-(pyrrolidin-1-ylmethyl)pyridin-3-yl)-1H-indazole [14];3-(4-(3-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(5-(piperidin-1-ylmethyl)pyridin-3-yl)-1H-indazole [15];N-(5-(3-(4-(3-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)-3,3-dimethylbutanamide [16];N-(5-(3-(4-(3-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)butyramide [17];3-(4-(3-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(pyridin-4-yl)-1H-indazole [18];N-(5-(3-(4-(3-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)pentanamide [19];N-(5-(3-(4-(3-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)cyclopropanecarboxamide [20];N-(5-(3-(4-(3-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)cyclobutanecarboxamide [21];N-(5-(3-(4-(3-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)cyclopentanecarboxamide [22];N-(5-(3-(4-(3-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)cyclohexanecarboxamide [23];N-benzyl-1-(5-(3-(4-(3-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)methanamine [24];1-cyclopentyl-N-((5-(3-(4-(3-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)methyl)methanamine [25];5-(5-((3,3-difluoropyrrolidin-1-yl)methyl)pyridin-3-yl)-3-(4-(3-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole [26];3-(4-(3-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(pyrimidin-5-yl)-1H-indazole [27];3-(4-(3-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(pyridin-2-yl)-1H-indazole [28];N-(5-(3-(4-(4-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)propionamide [29];N-(5-(3-(4-(4-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)-3-methylbutanamide [30];5-(3-(4-(4-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-amine [31];3-(4-(4-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(pyridin-3-yl)-1H-indazole [32];3-(4-(4-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(4-methylpyridin-3-yl)-1H-indazole [33];N-((5-(3-(4-(4-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)methyl)ethanamine [34];5-(3-(4-(4-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)-N,N-dimethylpyridin-3-amine [35];N-(5-(3-(4-(4-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)pivalamide [36];N-(5-(3-(4-(4-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)isobutyramide [37];N-(5-(3-(4-(4-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)-2-phenylacetamide [38];N-(5-(3-(4-(4-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)benzamide [39];5-(3-(4-(4-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)-N-isopropylpyridin-3-amine [40];1-(5-(3-(4-(4-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)-N,N-dimethylmethanamine [41];3-(4-(4-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(5-(pyrrolidin-1-ylmethyl)pyridin-3-yl)-1H-indazole [42];3-(4-(4-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(5-(piperidin-1-ylmethyl)pyridin-3-yl)-1H-indazole [43];N-(5-(3-(4-(4-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)-3,3-dimethylbutanamide [44];N-(5-(3-(4-(4-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)butyramide [45];3-(4-(4-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(pyridin-4-yl)-1H-indazole [46];N-(5-(3-(4-(4-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)pentanamide [47];N-(5-(3-(4-(4-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)cyclopropanecarboxamide [48];N-(5-(3-(4-(4-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)cyclobutanecarboxamide [49];N-(5-(3-(4-(4-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)cyclopentanecarboxamide [50];N-(5-(3-(4-(4-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)cyclohexanecarboxamide [51];N-benzyl-1-(5-(3-(4-(4-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)methanamine [52];1-cyclopentyl-N-((5-(3-(4-(4-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)methyl)methanamine [53];5-(5-((3,3-difluoropyrrolidin-1-yl)methyl)pyridin-3-yl)-3-(4-(4-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole [54];3-(4-(4-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(pyrimidin-5-yl)-1H-indazole [55];3-(4-(4-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(pyridin-2-yl)-1H-indazole [56];N-(5-(3-(4-(2-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)propionamide [57];N-(5-(3-(4-(2-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)-3-methylbutanamide [58];5-(3-(4-(2-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-amine [59];3-(4-(2-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(pyridin-3-yl)-1H-indazole [60];3-(4-(2-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(4-methylpyridin-3-yl)-1H-indazole [61];N-((5-(3-(4-(2-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)methyl)ethanamine [62];5-(3-(4-(2-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)-N,N-dimethylpyridin-3-amine [63];N-(5-(3-(4-(2-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)pivalamide [64];N-(5-(3-(4-(2-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)isobutyramide [65];N-(5-(3-(4-(2-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)-2-phenylacetamide [66];N-(5-(3-(4-(2-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)benzamide [67];5-(3-(4-(2-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)-N-isopropylpyridin-3-amine [68];1-(5-(3-(4-(2-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)-N,N-dimethylmethanamine [69];3-(4-(2-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(5-(pyrrolidin-1-ylmethyl)pyridin-3-yl)-1H-indazole [70];3-(4-(2-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(5-(piperidin-1-ylmethyl)pyridin-3-yl)-1H-indazole [71];N-(5-(3-(4-(2-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)-3,3-dimethylbutanamide [72];N-(5-(3-(4-(2-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)butyramide [73];3-(4-(2-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(pyridin-4-yl)-1H-indazole [74];N-(5-(3-(4-(2-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)pentanamide [75];N-(5-(3-(4-(2-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)cyclopropanecarboxamide [76];N-(5-(3-(4-(2-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)cyclobutanecarboxamide [77];N-(5-(3-(4-(2-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)cyclopentanecarboxamide [78];N-(5-(3-(4-(2-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)cyclohexanecarboxamide [79];N-benzyl-1-(5-(3-(4-(2-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)methanamine [80];1-cyclopentyl-N-((5-(3-(4-(2-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)methyl)methanamine [81];5-(5-((3,3-difluoropyrrolidin-1-yl)methyl)pyridin-3-yl)-3-(4-(2-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole [82];3-(4-(2-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(pyrimidin-5-yl)-1H-indazole [83];3-(4-(2-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(pyridin-2-yl)-1H-indazole [84];N-(5-(3-(4-(pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)propionamide [85];3-methyl-N-(5-(3-(4-(pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)butanamide [86];5-(3-(4-(pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-amine [87];5-(pyridin-3-yl)-3-(4-(pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole [88];5-(4-methylpyridin-3-yl)-3-(4-(pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole [89];N-((5-(3-(4-(pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)methyl)ethanamine [90];N,N-dimethyl-5-(3-(4-(pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-amine [91];N-(5-(3-(4-(pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)pivalamide [92];N-(5-(3-(4-(pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)isobutyramide [93];2-phenyl-N-(5-(3-(4-(pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)acetamide [94];N-(5-(3-(4-(pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)benzamide [95];N-isopropyl-5-(3-(4-(pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-amine [96];N,N-dimethyl-1-(5-(3-(4-(pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)methanamine [97];3-(4-(pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(5-(pyrrolidin-1-ylmethyl)pyridin-3-yl)-1H-indazole [98];5-(5-(piperidin-1-ylmethyl)pyridin-3-yl)-3-(4-(pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole [99];3,3-dimethyl-N-(5-(3-(4-(pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)butanamide [100];N-(5-(3-(4-(pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)butyramide [101];3-(4-(pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(pyridin-4-yl)-1H-indazole [102];N-(5-(3-(4-(pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)pentanamide [103];N-(5-(3-(4-(pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)cyclopropanecarboxamide [104];N-(5-(3-(4-(pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)cyclobutanecarboxamide [105];N-(5-(3-(4-(pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)cyclopentanecarboxamide [106];N-(5-(3-(4-(pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)cyclohexanecarboxamide [107];N-benzyl-1-(5-(3-(4-(pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)methanamine [108];1-cyclopentyl-N-((5-(3-(4-(pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)methyl)methanamine [109];5-(5-((3,3-difluoropyrrolidin-1-yl)methyl)pyridin-3-yl)-3-(4-(pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole [110];3-(4-(pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(pyrimidin-5-yl)-1H-indazole [111];5-(pyridin-2-yl)-3-(4-(pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole [112];N-(5-(3-(4-(pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)propionamide [113];3-methyl-N-(5-(3-(4-(pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)butanamide [114];5-(3-(4-(pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-amine [115];5-(pyridin-3-yl)-3-(4-(pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole [116];5-(4-methylpyridin-3-yl)-3-(4-(pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole [117];N-((5-(3-(4-(pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)methyl)ethanamine [118];N,N-dimethyl-5-(3-(4-(pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-amine [119];N-(5-(3-(4-(pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)pivalamide [120];N-(5-(3-(4-(pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)isobutyramide [121];2-phenyl-N-(5-(3-(4-(pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)acetamide [122];N-(5-(3-(4-(pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)benzamide [123];N-isopropyl-5-(3-(4-(pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-amine [124];N,N-dimethyl-1-(5-(3-(4-(pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)methanamine [125];3-(4-(pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(5-(pyrrolidin-1-ylmethyl)pyridin-3-yl)-1H-indazole [126];5-(5-(piperidin-1-ylmethyl)pyridin-3-yl)-3-(4-(pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole [127];3,3-dimethyl-N-(5-(3-(4-(pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)butanamide [128];N-(5-(3-(4-(pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)butyramide [129];5-(pyridin-4-yl)-3-(4-(pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole [130];N-(5-(3-(4-(pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)pentanamide [131];N-(5-(3-(4-(pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)cyclopropanecarboxamide [132];N-(5-(3-(4-(pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)cyclobutanecarboxamide [133];N-(5-(3-(4-(pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)cyclopentanecarboxamide [134];N-(5-(3-(4-(pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)cyclohexanecarboxamide [135];N-benzyl-1-(5-(3-(4-(pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)methanamine [136];1-cyclopentyl-N-((5-(3-(4-(pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)methyl)methanamine [137];5-(5-((3,3-difluoropyrrolidin-1-yl)methyl)pyridin-3-yl)-3-(4-(pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole [138];3-(4-(pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(pyrimidin-5-yl)-1H-indazole [139];5-(pyridin-2-yl)-3-(4-(pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole [140];N-(5-(3-(4-(pyridin-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)propionamide [141];3-methyl-N-(5-(3-(4-(pyridin-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)butanamide [142];5-(3-(4-(pyridin-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-amine [143];3-(4-(pyridin-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(pyridin-3-yl)-1H-indazole [144];5-(4-methylpyridin-3-yl)-3-(4-(pyridin-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole [145];N-((5-(3-(4-(pyridin-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)methyl)ethanamine [146];N,N-dimethyl-5-(3-(4-(pyridin-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-amine [147];N-(5-(3-(4-(pyridin-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)pivalamide [148];N-(5-(3-(4-(pyridin-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)isobutyramide [149];2-phenyl-N-(5-(3-(4-(pyridin-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)acetamide [150];N-(5-(3-(4-(pyridin-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)benzamide [151];N-isopropyl-5-(3-(4-(pyridin-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-amine [152];N,N-dimethyl-1-(5-(3-(4-(pyridin-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)methanamine [153];3-(4-(pyridin-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(5-(pyrrolidin-1-ylmethyl)pyridin-3-yl)-1H-indazole [154];5-(5-(piperidin-1l-ylmethyl)pyridin-3-yl)-3-(4-(pyridin-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole [155];3,3-dimethyl-N-(5-(3-(4-(pyridin-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)butanamide [156];N-(5-(3-(4-(pyridin-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)butyramide [157];3-(4-(pyridin-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(pyridin-4-yl)-1H-indazole [158];N-(5-(3-(4-(pyridin-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)pentanamide [159];N-(5-(3-(4-(pyridin-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)cyclopropanecarboxamide [160];N-(5-(3-(4-(pyridin-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)cyclobutanecarboxamide [161];N-(5-(3-(4-(pyridin-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)cyclopentanecarboxamide [162];N-(5-(3-(4-(pyridin-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)cyclohexanecarboxamide [163];N-benzyl-1-(5-(3-(4-(pyridin-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)methanamine [164];1-cyclopentyl-N-((5-(3-(4-(pyridin-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)methyl)methanamine [165];5-(5-((3,3-difluoropyrrolidin-1-yl)methyl)pyridin-3-yl)-3-(4-(pyridin-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole [166];3-(4-(pyridin-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(pyrimidin-5-yl)-1H-indazole [167];5-(pyridin-2-yl)-3-(4-(pyridin-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole [168];N-(5-(3-(4-(piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)propionamide [169];3-methyl-N-(5-(3-(4-(piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)butanamide [170];5-(3-(4-(piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-amine [171];3-(4-(piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(pyridin-3-yl)-1H-indazole [172];5-(4-methylpyridin-3-yl)-3-(4-(piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole [173];N-((5-(3-(4-(piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)methyl)ethanamine [174];N,N-dimethyl-5-(3-(4-(piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-amine [175];N-(5-(3-(4-(piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)pivalamide [176];N-(5-(3-(4-(piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)isobutyramide [177];2-phenyl-N-(5-(3-(4-(piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)acetamide [178];N-(5-(3-(4-(piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)benzamide [179];N-isopropyl-5-(3-(4-(piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-amine [180];N,N-dimethyl-1-(5-(3-(4-(piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)methanamine [181];3-(4-(piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(5-(pyrrolidin-1-ylmethyl)pyridin-3-yl)-1H-indazole [182];3-(4-(piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(5-(piperidin-1-ylmethyl)pyridin-3-yl)-1H-indazole [183];3,3-dimethyl-N-(5-(3-(4-(piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)butanamide [184];N-(5-(3-(4-(piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)butyramide [185];3-(4-(piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(pyridin-4-yl)-1H-indazole [186];N-(5-(3-(4-(piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)pentanamide [187];N-(5-(3-(4-(piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)cyclopropanecarboxamide [188];N-(5-(3-(4-(piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)cyclobutanecarboxamide [189];N-(5-(3-(4-(piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)cyclopentanecarboxamide [190];N-(5-(3-(4-(piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)cyclohexanecarboxamide [191];N-benzyl-1-(5-(3-(4-(piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)methanamine [192];1-cyclopentyl-N-((5-(3-(4-(piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)methyl)methanamine [193];5-(5-((3,3-difluoropyrrolidin-1-yl)methyl)pyridin-3-yl)-3-(4-(piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole [194];3-(4-(piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(pyrimidin-5-yl)-1H-indazole [195];3-(4-(piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(pyridin-2-yl)-1H-indazole [196];N-(5-(3-(4-(4-methyl-1H-imidazol-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)propionamide [197];3-methyl-N-(5-(3-(4-(4-methyl-1H-imidazol-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)butanamide [198];5-(3-(4-(4-methyl-1H-imidazol-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-amine [199];3-(4-(4-methyl-1H-imidazol-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(pyridin-3-yl)-1H-indazole [200];3-(4-(4-methyl-1H-imidazol-1-yl)-H-pyrrolo[2,3-b]pyridin-2-yl)-5-(4-methylpyridin-3-yl)-H-indazole [201];N-((5-(3-(4-(4-methyl-1H-imidazol-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)methyl)ethanamine [202];N,N-dimethyl-5-(3-(4-(4-methyl-1H-imidazol-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-amine [203];N-(5-(3-(4-(4-methyl-1H-imidazol-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)pivalamide [204];N-(5-(3-(4-(4-methyl-1H-imidazol-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)isobutyramide [205];N-(5-(3-(4-(4-methyl-1H-imidazol-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)-2-phenylacetamide [206];N-(5-(3-(4-(4-methyl-1H-imidazol-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)benzamide [207];N-isopropyl-5-(3-(4-(4-methyl-1H-imidazol-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-amine [208];N,N-dimethyl-1-(5-(3-(4-(4-methyl-1H-imidazol-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)methanamine [209];3-(4-(4-methyl-1H-imidazol-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(5-(pyrrolidin-1-ylmethyl)pyridin-3-yl)-1H-indazole [210];3-(4-(4-methyl-1H-imidazol-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(5-(piperidin-1-ylmethyl)pyridin-3-yl)-1H-indazole [211];3,3-dimethyl-N-(5-(3-(4-(4-methyl-1H-imidazol-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)butanamide [212];N-(5-(3-(4-(4-methyl-1H-imidazol-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)butyramide [213];3-(4-(4-methyl-1H-imidazol-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(pyridin-4-yl)-1H-indazole [214];N-(5-(3-(4-(4-methyl-1H-imidazol-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)pentanamide [215];N-(5-(3-(4-(4-methyl-1H-imidazol-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)cyclopropanecarboxamide [216];N-(5-(3-(4-(4-methyl-1H-imidazol-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)cyclobutanecarboxamide [217];N-(5-(3-(4-(4-methyl-1H-imidazol-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)cyclopentanecarboxamide [218];N-(5-(3-(4-(4-methyl-1H-imidazol-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)cyclohexanecarboxamide [219];N-benzyl-1-(5-(3-(4-(4-methyl-1H-imidazol-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)methanamine [220];1-cyclopentyl-N-((5-(3-(4-(4-methyl-1H-imidazol-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)methyl)methanamine [221];5-(5-((3, 3-difluoropyrrolidin-1-yl)methyl)pyridin-3-yl)-3-(4-(4-methyl-1H-imidazol-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole [222];3-(4-(4-methyl-1H-imidazol-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(pyrimidin-5-yl)-1H-indazole [223];3-(4-(4-methyl-1H-imidazol-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(pyridin-2-yl)-1H-indazole [224];N-(5-(3-(4-(4-methylpiperazin-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)propionamide [225];3-methyl-N-(5-(3-(4-(4-methylpiperazin-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)butanamide [226];5-(3-(4-(4-methylpiperazin-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-amine [227];3-(4-(4-methylpiperazin-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(pyridin-3-yl)-1H-indazole [228];3-(4-(4-methylpiperazin-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(4-methylpyridin-3-yl)-1H-indazole [229];N-((5-(3-(4-(4-methylpiperazin-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)methyl)ethanamine [230];N,N-dimethyl-5-(3-(4-(4-methylpiperazin-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-amine [231];N-(5-(3-(4-(4-methylpiperazin-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)pivalamide [232];N-(5-(3-(4-(4-methylpiperazin-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)isobutyramide [233];N-(5-(3-(4-(4-methylpiperazin-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)-2-phenylacetamide [234];N-(5-(3-(4-(4-methylpiperazin-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)benzamide [235];N-isopropyl-5-(3-(4-(4-methylpiperazin-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-amine [236];N,N-dimethyl-1-(5-(3-(4-(4-methylpiperazin-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)methanamine [237];3-(4-(4-methylpiperazin-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(5-(pyrrolidin-1-ylmethyl)pyridin-3-yl)-1H-indazole [238];3-(4-(4-methylpiperazin-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(5-(piperidin-1-ylmethyl)pyridin-3-yl)-1H-indazole [239];3,3-dimethyl-N-(5-(3-(4-(4-methylpiperazin-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)butanamide [240];N-(5-(3-(4-(4-methylpiperazin-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)butyramide [241];3-(4-(4-methylpiperazin-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(pyridin-4-yl)-1H-indazole [242];N-(5-(3-(4-(4-methylpiperazin-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)pentanamide [243];N-(5-(3-(4-(4-methylpiperazin-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)cyclopropanecarboxamide [244];N-(5-(3-(4-(4-methylpiperazin-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)cyclobutanecarboxamide [245];N-(5-(3-(4-(4-methylpiperazin-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)cyclopentanecarboxamide [246];N-(5-(3-(4-(4-methylpiperazin-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)cyclohexanecarboxamide [247];N-benzyl-1-(5-(3-(4-(4-methylpiperazin-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)methanamine [248];1-cyclopentyl-N-((5-(3-(4-(4-methylpiperazin-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)methyl)methanamine [249];5-(5-((3,3-difluoropyrrolidin-1-yl)methyl)pyridin-3-yl)-3-(4-(4methylpiperazin-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole [250];3-(4-(4-methylpiperazin-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(pyrimidin-5-yl)-1H-indazole [251];3-(4-(4-methylpiperazin-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(pyridin-2-yl)-1H-indazole [252];N-(5-(3-(1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)propionamide [253];N-(5-(3-(1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)-3-methylbutanamide [254];5-(3-(1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-amine [255];5-(pyridin-3-yl)-3-(1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole [256];5-(4-methylpyridin-3-yl)-3-(1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole [257];N-((5-(3-(1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)methyl)ethanamine [258];5-(3-(1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)-N,N-dimethylpyridin-3-amine [259];N-(5-(3-(1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)pivalamide [260];N-(5-(3-(1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)isobutyramide [261];N-(5-(3-(1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)-2-phenylacetamide [262];N-(5-(3-(1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)benzamide [263];5-(3-(1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)-N-isopropylpyridin-3-amine [264];1-(5-(3-(1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)-N,N-dimethylmethanamine [265];5-(5-(pyrrolidin-1-ylmethyl)pyridin-3-yl)-3-(1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole [266];5-(5-(piperidin-1-ylmethyl)pyridin-3-yl)-3-(1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole [267];N-(5-(3-(1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)-3,3-dimethylbutanamide [268];N-(5-(3-(1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)butyramide [269];5-(pyridin-4-yl)-3-(1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole [270];N-(5-(3-(1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)pentanamide [271];N-(5-(3-(1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)cyclopropanecarboxamide [272];N-(5-(3-(1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)cyclobutanecarboxamide [273];N-(5-(3-(1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)cyclopentanecarboxamide [274];N-(5-(3-(1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)cyclohexanecarboxamide [275];1-(5-(3-(1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)-N-benzylmethanamine [276];1-(5-(3-(1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)-N-(cyclopentylmethyl)methanamine [277];5-(5-((3,3-difluoropyrrolidin-1-yl)methyl)pyridin-3-yl)-3-(1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole [278];5-(pyrimidin-5-yl)-3-(1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole [279];5-(pyridin-2-yl)-3-(1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole [280];N-(5-(3-(4-(thiophen-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)propionamide [281];3-methyl-N-(5-(3-(4-(thiophen-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)butanamide [282];5-(3-(4-(thiophen-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-amine [283];5-(pyridin-3-yl)-3-(4-(thiophen-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole [284];5-(4-methylpyridin-3-yl)-3-(4-(thiophen-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole [285];N-((5-(3-(4-(thiophen-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)methyl)ethanamine [286];N,N-dimethyl-5-(3-(4-(thiophen-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-amine [287];N-(5-(3-(4-(thiophen-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)pivalamide [288];N-(5-(3-(4-(thiophen-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)isobutyramide [289];2-phenyl-N-(5-(3-(4-(thiophen-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)acetamide [290];N-(5-(3-(4-(thiophen-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)benzamide [291];N-isopropyl-5-(3-(4-(thiophen-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-amine [292];N,N-dimethyl-1-(5-(3-(4-(thiophen-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)methanamine [293];5-(5-(pyrrolidin-1-ylmethyl)pyridin-3-yl)-3-(4-(thiophen-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole [294];5-(5-(piperidin-1l-ylmethyl)pyridin-3-yl)-3-(4-(thiophen-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole [295];3,3-dimethyl-N-(5-(3-(4-(thiophen-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)butanamide [296];N-(5-(3-(4-(thiophen-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)butyramide [297];5-(pyridin-4-yl)-3-(4-(thiophen-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole [298];N-(5-(3-(4-(thiophen-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)pentanamide [299];N-(5-(3-(4-(thiophen-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)cyclopropanecarboxamide [300];N-(5-(3-(4-(thiophen-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)cyclobutanecarboxamide [301];N-(5-(3-(4-(thiophen-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)cyclopentanecarboxamide [302];N-(5-(3-(4-(thiophen-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)cyclohexanecarboxamide [303];N-benzyl-1-(5-(3-(4-(thiophen-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)methanamine [304];1-cyclopentyl-N-((5-(3-(4-(thiophen-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)methyl)methanamine [305];5-(5-((3,3-difluoropyrrolidin-1-yl)methyl)pyridin-3-yl)-3-(4-(thiophen-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole [306];5-(pyrimidin-5-yl)-3-(4-(thiophen-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole [307];5-(pyridin-2-yl)-3-(4-(thiophen-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole [308];N-(5-(3-(4-(furan-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)propionamide [309];N-(5-(3-(4-(furan-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)-3-methylbutanamide [310];5-(3-(4-(furan-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-amine [311];3-(4-(furan-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(pyridin-3-yl)-1H-indazole [312];3-(4-(furan-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(4-methylpyridin-3-yl)-1H-indazole [313];N-((5-(3-(4-(furan-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)methyl)ethanamine [314];5-(3-(4-(furan-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)-N,N-dimethylpyridin-3-amine [315];N-(5-(3-(4-(furan-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)pivalamide [316];N-(5-(3-(4-(furan-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)isobutyramide [317];N-(5-(3-(4-(furan-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)-2-phenylacetamide [318];N-(5-(3-(4-(furan-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)benzamide [319];5-(3-(4-(furan-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)-N-isopropylpyridin-3-amine [320];1-(5-(3-(4-(furan-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)-N,N-dimethylmethanamine [321];3-(4-(furan-3-yl)-1H-pyrr(py[2,3-b]pyridin-2-yrrolidin-1-ylmethyl)pyridin-3-yl)-H-inddazole [322];3-(4-(furan-3-yl)-H-pyrrolo[2,3-b]pyridin-2-yl)-5-(5-(piperidin-1-ylmethyl)pyridin-3-yl)-1H-indazole [323];N-(5-(3-(4-(furan-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)-3,3-dimethylbutanamide [324];N-(5-(3-(4-(furan-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)butyramide [325];3-(4-(furan-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(pyridin-4-yl)-1H-indazole [326];N-(5-(3-(4-(furan-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)pentanamide [327];N-(5-(3-(4-(furan-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)cyclopropanecarboxamide [328];N-(5-(3-(4-(furan-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)cyclobutanecarboxamide [329];N-(5-(3-(4-(furan-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)cyclopentanecarboxamide [330];N-(5-(3-(4-(furan-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)cyclohexanecarboxamide [331];N-benzyl-1-(5-(3-(4-(furan-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)methanamine [332];1 cyclopentyl-N-((5-(3-(4-(furan-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)methyl)methanamine [333];5-(5-((3,3-difluoropyrrolidin-1-yl)methyl)pyridin-3-yl)-3-(4-(furan-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole [334];3-(4-(furan-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(pyrimidin-5-yl)-1H-indazole [335];3-(4-(furan-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(pyridin-2-yl)-1H-indazole [336];N-(5-(3-(4-(thiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)propionamide [337];3-methyl-N-(5-(3-(4-(thiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)butanamide [338];5-(3-(4-(thiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-amine [339];5-(pyridin-3-yl)-3-(4-(thiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole [340];5-(4-methylpyridin-3-yl)-3-(4-(thiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole [341];N-((5-(3-(4-(thiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)methyl)ethanamine [342];N,N-dimethyl-5-(3-(4-(thiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-amine [343];N-(5-(3-(4-(thiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)pivalamide [344];N-(5-(3-(4-(thiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)isobutyramide [345];2-phenyl-N-(5-(3-(4-(thiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)acetamide [346];N-(5-(3-(4-(thiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)benzamide [347];N-isopropyl-5-(3-(4-(thiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-amine [348];N,N-dimethyl-1-(5-(3-(4-(thiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)methanamine [349];5-(5-(pyrrolidin-1-ylmethyl)pyridin-3-yl)-3-(4-(thiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole [350];5-(5-(piperidin-1l-ylmethyl)pyridin-3-yl)-3-(4-(thiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole [351];3,3-dimethyl-N-(5-(3-(4-(thiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)butanamide [352];N-(5-(3-(4-(thiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)butyramide [353];5-(pyridin-4-yl)-3-(4-(thiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole [354];N-(5-(3-(4-(thiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)pentanamide [355];N-(5-(3-(4-(thiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)cyclopropanecarboxamide [356];N-(5-(3-(4-(thiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)cyclobutanecarboxamide [357];N-(5-(3-(4-(thiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)cyclopentanecarboxamide [358];N-(5-(3-(4-(thiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)cyclohexanecarboxamide [359];N-benzyl-1-(5-(3-(4-(thiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)methanamine [360];1-cyclopentyl-N-((5-(3-(4-(thiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)methyl)methanamine [361];5-(5-((3,3-difluoropyrrolidin-1-yl)methyl)pyridin-3-yl)-3-(4-(thiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole [362];5-(pyrimidin-5-yl)-3-(4-(thiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole [363];5-(pyridin-2-yl)-3-(4-(thiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole [364];N-(5-(3-(4-(5-fluorothiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)propionamide [365];N-(5-(3-(4-(5-fluorothiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)-3-methylbutanamide [366];5-(3-(4-(5-fluorothiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-amine [367];3-(4-(5-fluorothiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(pyridin-3-yl)-1H-indazole [368];3-(4-(5-fluorothiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(4-methylpyridin-3-yl)-1H-indazole [369];N-((5-(3-(4-(5-fluorothiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)methyl)ethanamine [370];5-(3-(4-(5-fluorothiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)-N,N-dimethylpyridin-3-amine [371];N-(5-(3-(4-(5-fluorothiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)pivalamide [372];N-(5-(3-(4-(5-fluorothiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)isobutyramide [373];N-(5-(3-(4-(5-fluorothiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)-2-phenylacetamide [374];N-(5-(3-(4-(5-fluorothiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)benzamide [375];5-(3-(4-(5-fluorothiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)-N-isopropylpyridin-3-amine [376];1-(5-(3-(4-(5-fluorothiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)-N,N-dimethylmethanamine [377];3-(4-(5-fluorothiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(5-(pyrrolidin-1-ylmethyl)pyridin-3-yl)-1H-indazole [378];3-(4-(5-fluorothiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(5-(piperidin-1-ylmethyl)pyridin-3-yl)-1H-indazole [379];N-(5-(3-(4-(5-fluorothiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)-3,3-dimethylbutanamide [380];N-(5-(3-(4-(5-fluorothiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)butyramide [381];3-(4-(5-fluorothiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(pyridin-4-yl)-1H-indazole [382];N-(5-(3-(4-(5-fluorothiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)pentanamide [383];N-(5-(3-(4-(5-fluorothiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)cyclopropanecarboxamide [384];N-(5-(3-(4-(5-fluorothiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)cyclobutanecarboxamide [385];N-(5-(3-(4-(5-fluorothiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)cyclopentanecarboxamide [386];N-(5-(3-(4-(5-fluorothiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)cyclohexanecarboxamide [387];N-benzyl-1-(5-(3-(4-(5-fluorothiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)methanamine [388];1-cyclopentyl-N-((5-(3-(4-(5-fluorothiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)methyl)methanamine [389];5-(5-((3,3-difluoropyrrolidin-1-yl)methyl)pyridin-3-yl)-13-(4-(5-fluorothiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole [390];3-(4-(5-fluorothiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(pyrimidin-5-yl)-1H-indazole [391];3-(4-(5-fluorothiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(pyridin-2-yl)-1H-indazole [392];N-(5-(3-(4-(5-methylthiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)propionamide [393];3-methyl-N-(5-(3-(4-(5-methylthiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)butanamide [394];5-(3-(4-(5-methylthiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-amine [395];3-(4-(5-methylthiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(pyridin-3-yl)-1H-indazole [396];5-(4-methylpyridin-3-yl)-3-(4-(5-methylthiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole [397];N-((5-(3-(4-(5-methylthiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)methyl)ethanamine [398];N,N-dimethyl-5-(3-(4-(5-methylthiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-amine [399];N-(5-(3-(4-(5-methylthiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)pivalamide [400];N-(5-(3-(4-(5-methylthiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)isobutyramide [401];N-(5-(3-(4-(5-methylthiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)-2-phenylacetamide [402];N-(5-(3-(4-(5-methylthiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)benzamide [403];N-isopropyl-5-(3-(4-(5-methylthiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-amine [404];N,N-dimethyl-1-(5-(3-(4-(5-methylthiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)methanamine [405];3-(4-(5-methylthiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(5-(pyrrolidin-1-ylmethyl)pyridin-3-yl)-1H-indazole [406];3-(4-(5-methylthiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(5-(piperidin-1l-ylmethyl)pyridin-3-yl)-1H-indazole [407];3,3-dimethyl-N-(5-(3-(4-(5-methylthiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)butanamide [408];N-(5-(3-(4-(5-methylthiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)butyramide [409];3-(4-(5-methylthiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(pyridin-4-yl)-1H-indazole [410];N-(5-(3-(4-(5-methylthiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)pentanamide [411];N-(5-(3-(4-(5-methylthiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)cyclopropanecarboxamide [412];N-(5-(3-(4-(5-methylthiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)cyclobutanecarboxamide [413];N-(5-(3-(4-(5-methylthiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)cyclopentanecarboxamide [414];N-(5-(3-(4-(5-methylthiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)cyclohexanecarboxamide [415];N-benzyl-1-(5-(3-(4-(5-methylthiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)methanamine [416];1-cyclopentyl-N-((5-(3-(4-(5-methylthiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)methyl)methanamine [417];5-(5-((3, 3-difluoropyrrolidin-1-yl)methyl)pyridin-3-yl)-3-(4-(5-methylthiophen-2-yl)-1H-pyrrolo[2, 3-b]pyridin-2-yl)-1H-indazole [418];3-(4-(5-methylthiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(pyrimidin-5-yl)-1H-indazole [419];3-(4-(5-methylthiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(pyridin-2-yl)-1H-indazole [420];N-(5-(3-(4-(5-acetylthiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)propionamide [421];N-(5-(3-(4-(5-acetylthiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)-3-methylbutanamide [422];1-(5-(2-(5-(5-aminopyridin-3-yl)-1H-indazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)thiophen-2-yl)ethan-1-one [423];1-(5-(2-(5-(pyridin-3-yl)-1H-indazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)thiophen-2-yl)ethan-1-one [424];1-(5-(2-(5-(4-methylpyridin-3-yl)-1H-indazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)thiophen-2-yl)ethan-1-one [425];1-(5-(2-(5-(5-((ethylamino)methyl)pyridin-3-yl)-1H-indazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)thiophen-2-yl)ethan-1-one [426];1-(5-(2-(5-(5-(dimethylamino)pyridin-3-yl)-1H-indazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)thiophen-2-yl)ethan-1-one [427];N-(5-(3-(4-(5-acetylthiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)pivalamide [428];N-(5-(3-(4-(5-acetylthiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)isobutyramide [429];N-(5-(3-(4-(5-acetylthiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)-2-phenylacetamide [430];N-(5-(3-(4-(5-acetylthiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)benzamide [431];1-(5-(2-(5-(5-(isopropylamino)pyridin-3-yl)-1H-indazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)thiophen-2-yl)ethan-1-one [432];1-(5-(2-(5-(5-((dimethylamino)methyl)pyridin-3-yl)-1H-indazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)thiophen-2-yl)ethan-1-one [433];1-(5-(2-(5-(5-(pyrrolidin-1-ylmethyl)pyridin-3-yl)-1H-indazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)thiophen-2-yl)ethan-1-one [434];1-(5-(2-(5-(5-(piperidin-1-ylmethyl)pyridin-3-yl)-1H-indazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)thiophen-2-yl)ethan-1-one [435];N-(5-(3-(4-(5-acetylthiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)-3,3-dimethylbutanamide [436];N-(5-(3-(4-(5-acetylthiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)butyramide [437];1-(5-(2-(5-(pyridin-4-yl)-1H-indazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)thiophen-2-yl)ethan-1-one [438];N-(5-(3-(4-(5-acetylthiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)pentanamide [439];N-(5-(3-(4-(5-acetylthiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)cyclopropanecarboxamide [440];N-(5-(3-(4-(5-acetylthiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)cyclobutanecarboxamide [441];N-(5-(3-(4-(5-acetylthiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)cyclopentanecarboxamide [442];N-(5-(3-(4-(5-acetylthiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)cyclohexanecarboxamide [443];1-(5-(2-(5-(5-((benzylamino)methyl)pyridin-3-yl)-1H-indazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)thiophen-2-yl)ethan-1-one [444];1-(5-(2-(5-(5-(((cyclopentylmethyl)amino)methyl)pyridin-3-yl)-1H-indazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)thiophen-2-yl)ethan-1-one [445];1-(5-(2-(5-(5-((3,3-difluoropyrrolidin-1-yl)methyl)pyridin-3-yl)-1H-indazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)thiophen-2-yl)ethan-1-one [446];1-(5-(2-(5-(pyrimidin-5-yl)-1H-indazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)thiophen-2-yl)ethan-1-one [447];1-(5-(2-(5-(pyridin-2-yl)-1H-indazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)thiophen-2-yl)ethan-1-one [448];N-(5-(3-(4-(3-((2-(dimethylamino)ethyl)amino)-5-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)propionamide [449];N-(5-(3-(4-(3-((2-(dimethylamino)ethyl)amino)-5-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)-3-methylbutanamide [450];N1-(3-(2-(5-(5-aminopyridin-3-yl)-1H-indazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-5-fluorophenyl)-N2,N2-dimethylethane-1,2-diamine [451];N1-(3-fluoro-5-(2-(5-(pyridin-3-yl)-1H-indazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)phenyl)-N2,N2-dimethylethane-1,2-diamine [452];N1-(3-fluoro-5-(2-(5-(4-methylpyridin-3-yl)-1H-indazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)phenyl)-N2,N2-dimethylethane-1,2-diamine [453];N1-(3-(2-(5-(5-((ethylamino)methyl)pyridin-3-yl)-1H-indazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-5-fluorophenyl)-N2,N2-dimethylethane-1,2-diamine [454];N1-(3-(2-(5-(5-(dimethylamino)pyridin-3-yl)-1H-indazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-5-fluorophenyl)-N2,N2-dimethylethane-1,2-diamine [455];N-(5-(3-(4-(3-((2-(dimethylamino)ethyl)amino)-5-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)pivalamide [456];N-(5-(3-(4-(3-((2-(dimethylamino)ethyl)amino)-5-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)isobutyramide [457];N-(5-(3-(4-(3-((2-(dimethylamino)ethyl)amino)-5-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)-2-phenylacetamide [458];N-(5-(3-(4-(3-((2-(dimethylamino)ethyl)amino)-5-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)benzamide [459];N1-(3-fluoro-5-(2-(5-(5-(isopropylamino)pyridin-3-yl)-1H-indazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)phenyl)-N2,N2-dimethylethane-1,2-diamine [460];N1-(3-(2-(5-(5-((dimethylamino)methyl)pyridin-3-yl)-1H-indazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-5-fluorophenyl)-N2,N2-dimethylethane-1,2-diamine [461];N1-(3-fluoro-5-(2-(5-(5-(pyrrolidin-1-ylmethyl)pyridin-3-yl)-1H-indazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)phenyl)-N2,N2-dimethylethane-1,2-diamine [462];N1-(3-fluoro-5-(2-(5-(5-(piperidin-1-ylmethyl)pyridin-3-yl)-1H-indazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)phenyl)-N2,N2-dimethylethane-1,2-diamine [463];N-(5-(3-(4-(3-((2-(dimethylamino)ethyl)amino)-5-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)-3,3-dimethylbutanamide [464];N-(5-(3-(4-(3-((2-(dimethylamino)ethyl)amino)-5-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)butyramide [465];N1-(3-fluoro-5-(2-(5-(pyridin-4-yl)-1H-indazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)phenyl)-N2,N2-dimethylethane-1,2-diamine [466];N-(5-(3-(4-(3-((2-(dimethylamino)ethyl)amino)-5-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)pentanamide [467];N-(5-(3-(4-(3-((2-(dimethylamino)ethyl)amino)-5-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)cyclopropanecarboxamide [468];N-(5-(3-(4-(3-((2-(dimethylamino)ethyl)amino)-5-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)cyclobutanecarboxamide [469];N-(5-(3-(4-(3-((2-(dimethylamino)ethyl)amino)-5-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)cyclopentanecarboxamide [470];N-(5-(3-(4-(3-((2-(dimethylamino)ethyl)amino)-5-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)cyclohexanecarboxamide [471];N1-(3-(2-(5-(5-((benzylamino)methyl)pyridin-3-yl)-1H-indazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-5-fluorophenyl)-N2,N2-dimethylethane-1,2-diamine [472];N1-(3-(2-(5-(5-(((cyclopentylmethyl)amino)methyl)pyridin-3-yl)-1H-indazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-5-fluorophenyl)-N2,N2-dimethylethane-1,2-diamine [473];N1-(3-(2-(5-(5-((3,3-difluoropyrrolidin-1-yl)methyl)pyridin-3-yl)-1H-indazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-5-fluorophenyl)-N2,N2-dimethylethane-1,2-diamine [474];N1-(3-fluoro-5-(2-(5-(pyrimidin-5-yl)-1H-indazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)phenyl)-N2,N2-dimethylethane-1,2-diamine [475];N1-(3-fluoro-5-(2-(5-(pyridin-2-yl)-1H-indazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)phenyl)-N2,N2-dimethylethane-1,2-diamine [476];N-(5-(3-(4-(3-fluoro-5-(methylsulfonamidomethyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)propionamide [477];N-(5-(3-(4-(3-fluoro-5-(methylsulfonamidomethyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)-3-methylbutanamide [478];N-(3-(2-(5-(5-aminopyridin-3-yl)-1H-indazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-5-fluorobenzyl)methanesulfonamide [479];N-(3-fluoro-5-(2-(5-(pyridin-3-yl)-1H-indazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)benzyl)methanesulfonamide [480];N-(3-fluoro-5-(2-(5-(4-methylpyridin-3-yl)-1H-indazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)benzyl)methanesulfonamide [481];N-(3-(2-(5-(5-((ethylamino)methyl)pyridin-3-yl)-1H-indazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-5-fluorobenzyl)methanesulfonamide [482];N-(3-(2-(5-(5-(dimethylamino)pyridin-3-yl)-1H-indazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-5-fluorobenzyl)methanesulfonamide [483];N-(5-(3-(4-(3-fluoro-5-(methylsulfonamidomethyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)pivalamide [484];N-(5-(3-(4-(3-fluoro-5-(methylsulfonamidomethyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)isobutyramide [485];N-(5-(3-(4-(3-fluoro-5-(methylsulfonamidomethyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)-2-phenylacetamide [486];N-(5-(3-(4-(3-fluoro-5-(methylsulfonamidomethyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)benzamide [487];N-(3-fluoro-5-(2-(5-(5-(isopropylamino)pyridin-3-yl)-1H-indazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)benzyl)methanesulfonamide [488];N-(3-(2-(5-(5-((dimethylamino)methyl)pyridin-3-yl)-1H-indazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-5-fluorobenzyl)methanesulfonamide [489];N-(3-fluoro-5-(2-(5-(5-(pyrrolidin-1-ylmethyl)pyridin-3-yl)-1H-indazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)benzyl)methanesulfonamide [490];N-(3-fluoro-5-(2-(5-(5-(piperidin-1-ylmethyl)pyridin-3-yl)-1H-indazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)benzyl)methanesulfonamide [491];N-(5-(3-(4-(3-fluoro-5-(methylsulfonamidomethyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)-3,3-dimethylbutanamide [492];N-(5-(3-(4-(3-fluoro-5-(methylsulfonamidomethyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)butyramide [493];N-(3-fluoro-5-(2-(5-(pyridin-4-yl)-1H-indazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)benzyl)methanesulfonamide [494];N-(5-(3-(4-(3-fluoro-5-(methylsulfonamidomethyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)pentanamide [495];N-(5-(3-(4-(3-fluoro-5-(methylsulfonamidomethyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)cyclopropanecarboxamide [496];N-(5-(3-(4-(3-fluoro-5-(methylsulfonamidomethyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)cyclobutanecarboxamide [497];N-(5-(3-(4-(3-fluoro-5-(methylsulfonamidomethyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)cyclopentanecarboxamide [498];N-(5-(3-(4-(3-fluoro-5-(methylsulfonamidomethyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)cyclohexanecarboxamide [499];N-(3-(2-(5-(5-((benzylamino)methyl)pyridin-3-yl)-1H-indazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-5-fluorobenzyl)methanesulfonamide [500];N-(3-(2-(5-(5-(((cyclopentylmethyl)amino)methyl)pyridin-3-yl)-1H-indazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-5-fluorobenzyl)methanesulfonamide [501];N-(3-(2-(5-(5-((3,3-difluoropyrrolidin-1-yl)methyl)pyridin-3-yl)-1H-indazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-5-fluorobenzyl)methanesulfonamide [502];N-(3-fluoro-5-(2-(5-(pyrimidin-5-yl)-1H-indazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)benzyl)methanesulfonamide [503];N-(3-fluoro-5-(2-(5-(pyridin-2-yl)-1H-indazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)benzyl)methanesulfonamide [504];3-(4-(3-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(piperidin-4-yl)-1H-indazole [505];3-(4-(3-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indazole [506];3-(4-(3-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(1H-pyrazol-4-yl)-1H-indazole [507];3-(4-(3-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)-1H-indazole [508];5-(1,2-dimethyl-1H-imidazol-5-yl)-3-(4-(3-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole [509];1-(6-(3-(4-(3-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyrazin-2-yl)azetidin-3-amine [510];5-(5-(cyclohexyloxy)pyridin-3-yl)-3-(4-(3-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole [511];3-(4-(3-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(5-(piperidin-4-yloxy)pyridin-3-yl)-1H-indazole [512];N-(5-(3-(4-(3-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)-2-(piperidin-4-yl)acetamide [513];3-(4-(3-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(5-(2-(pyrrolidin-1-yl)ethoxy)pyridin-3-yl)-1H-indazole [514];2-((5-(3-(4-(3-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)oxy)-N,N-dimethylethan-1-amine [515];3-(4-(3-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(5-methoxypyridin-3-yl)-1H-indazole [516];5-(3-(4-(3-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-ol [517];5-(5-(benzyloxy)pyridin-3-yl)-3-(4-(3-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole [518];2-cyclohexyl-N-(5-(3-(4-(3-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)acetamide [519];3-(4-(3-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(pyrazin-2-yl)-1H-indazole [520];3-(4-(4-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(piperidin-4-yl)-1H-indazole [521];3-(4-(4-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indazole [522];3-(4-(4-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(1H-pyrazol-4-yl)-1H-indazole [523];3-(4-(4-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)-1H-indazole [524];5-(1,2-dimethyl-1H-imidazol-5-yl)-3-(4-(4-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole [525];1-(6-(3-(4-(4-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyrazin-2-yl)azetidin-3-amine [526];5-(5-(cyclohexyloxy)pyridin-3-yl)-3-(4-(4-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole [527];3-(4-(4-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(5-(piperidin-4-yloxy)pyridin-3-yl)-1H-indazole [528];N-(5-(3-(4-(4-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)-2-(piperidin-4-yl)acetamide [529];3-(4-(4-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(5-(2-(pyrrolidin-1-yl)ethoxy)pyridin-3-yl)-1H-indazole [530];2-((5-(3-(4-(4-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)oxy)-N,N-dimethylethan-1-amine [531];3-(4-(4-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(5-methoxypyridin-3-yl)-1H-indazole [532];5-(3-(4-(4-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-ol [533];5-(5-(benzyloxy)pyridin-3-yl)-3-(4-(4-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole [534];2-cyclohexyl-N-(5-(3-(4-(4-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)acetamide [535];3-(4-(4-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(pyrazin-2-yl)-1H-indazole [536];3-(4-(2-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(piperidin-4-yl)-1H-indazole [537];3-(4-(2-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indazole [538];3-(4-(2-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(1H-pyrazol-4-yl)-1H-indazole [539];3-(4-(2-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)-1H-indazole [540];5-(1,2-dimethyl-1H-imidazol-5-yl)-3-(4-(2-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole [541];1-(6-(3-(4-(2-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyrazin-2-yl)azetidin-3-amine [542];5-(5-(cyclohexyloxy)pyridin-3-yl)-3-(4-(2-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole [543];3-(4-(2-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(5-(piperidin-4-yloxy)pyridin-3-yl)-1H-indazole [544];N-(5-(3-(4-(2-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)-2-(piperidin-4-yl)acetamide [545];3-(4-(2-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(5-(2-(pyrrolidin-1-yl)ethoxy)pyridin-3-yl)-1H-indazole [546];2-((5-(3-(4-(2-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)oxy)-N,N-dimethylethan-1-amine [547];3-(4-(2-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(5-methoxypyridin-3-yl)-1H-indazole [548];5-(3-(4-(2-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-ol [549];5-(5-(benzyloxy)pyridin-3-yl)-3-(4-(2-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole [550];2-cyclohexyl-N-(5-(3-(4-(2-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)acetamide [551];3-(4-(2-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(pyrazin-2-yl)-1H-indazole [552];5-(piperidin-4-yl)-3-(4-(pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole [553];3-(4-(pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indazole [554];5-(1H-pyrazol-4-yl)-3-(4-(pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole [555];5-(1-methyl-1H-pyrazol-4-yl)-3-(4-(pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole [556];5-(1,2-dimethyl-1H-imidazol-5-yl)-3-(4-(pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole [557];1-(6-(3-(4-(pyridin-3-yl)-H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyrazin-2-yl)azetidin-3-amine [558];5-(5-(cyclohexyloxy)pyridin-3-yl)-3-(4-(pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole [559];5-(5-(piperidin-4-yloxy)pyridin-3-yl)-3-(4-(pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole [560];2-(piperidin-4-yl)-N-(5-(3-(4-(pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)acetamide [561];3-(4-(pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(5-(2-(pyrrolidin-1-yl)ethoxy)pyridin-3-yl)-1H-indazole [562];N,N-dimethyl-2-((5-(3-(4-(pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)oxy)ethan-1-amine [563];5-(5-methoxypyridin-3-yl)-3-(4-(pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole [564];5-(3-(4-(pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-ol [565];5-(pyrazin-2-yl)-3-(4-(pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole [566];2-cyclohexyl-N-(5-(3-(4-(pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)acetamide [567];5-(pyrazin-2-yl)-3-(4-(pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole [568];5-(piperidin-4-yl)-3-(4-(pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole [569];3-(4-(pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indazole [570];5-(1H-pyrazol-4-yl)-3-(4-(pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole [571];5-(1-methyl-1H-pyrazol-4-yl)-3-(4-(pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole [572];5-(1,2-dimethyl-1H-imidazol-5-yl)-3-(4-(pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole [573];1-(6-(3-(4-(pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyrazin-2-yl)azetidin-3-amine [574];5-(5-(cyclohexyloxy)pyridin-3-yl)-3-(4-(pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole [575];5-(5-(piperidin-4-yloxy)pyridin-3-yl)-3-(4-(pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole [576];2-(piperidin-4-yl)-N-(5-(3-(4-(pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)acetamide [577];3-(4-(pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(5-(2-(pyrrolidin-1-yl)ethoxy)pyridin-3-yl)-1H-indazole [578];N,N-dimethyl-2-((5-(3-(4-(pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)oxy)ethan-1-amine [579];5-(5-methoxypyridin-3-yl)-3-(4-(pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole [580];5-(3-(4-(pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-ol [581];5-(5-(benzyloxy)pyridin-3-yl)-3-(4-(pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole [582];2-cyclohexyl-N-(5-(3-(4-(pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)acetamide [583];5-(pyrazin-2-yl)-3-(4-(pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole [584];5-(piperidin-4-yl)-3-(4-(pyridin-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole [585];3-(4-(pyridin-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indazole [586];5-(1H-pyrazol-4-yl)-3-(4-(pyridin-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole [587];5-(1-methyl-1H-pyrazol-4-yl)-3-(4-(pyridin-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole [588];5-(1,2-dimethyl-1H-imidazol-5-yl)-3-(4-(pyridin-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole [589];1-(6-(3-(4-(pyridin-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyrazin-2-yl)azetidin-3-amine [590];5-(5-(cyclohexyloxy)pyridin-3-yl)-3-(4-(pyridin-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole [591];5-(5-(piperidin-4-yloxy)pyridin-3-yl)-3-(4-(pyridin-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole [592];2-(piperidin-4-yl)-N-(5-(3-(4-(pyridin-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)acetamide [593];3-(4-(pyridin-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(5-(2-(pyrrolidin-1-yl)ethoxy)pyridin-3-yl)-1H-indazole [594];N,N-dimethyl-2-((5-(3-(4-(pyridin-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)oxy)ethan-1-amine [595];5-(5-methoxypyridin-3-yl)-3-(4-(pyridin-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole [596];5-(3-(4-(pyridin-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-ol [597];5-(5-(benzyloxy)pyridin-3-yl)-3-(4-(pyridin-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole [598];2-cyclohexyl-N-(5-(3-(4-(pyridin-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)acetamide [599];5-(pyrazin-2-yl)-3-(4-(pyridin-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole [600];3-(4-(piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(piperidin-4-yl)-1H-indazole [601];3-(4-(piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indazole [602];3-(4-(piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(1H-pyrazol-4-yl)-1H-indazole [603];5-(1-methyl-1H-pyrazol-4-yl)-3-(4-(piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole [604];5-(1,2-dimethyl-1H-imidazol-5-yl)-3-(4-(piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole [605];1-(6-(3-(4-(piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyrazin-2-yl)azetidin-3-amine [606];5-(5-(cyclohexyloxy)pyridin-3-yl)-3-(4-(piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole [607];3-(4-(piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(5-(piperidin-4-yloxy)pyridin-3-yl)-1H-indazole [608];N-(5-(3-(4-(piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)-2-(piperidin-4-yl)acetamide [609];3-(4-(piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(5-(2-(pyrrolidin-1-yl)ethoxy)pyridin-3-yl)-1H-indazole [610];N,N-dimethyl-2-((5-(3-(4-(piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)oxy)ethan-1-amine [611];5-(5-methoxypyridin-3-yl)-3-(4-(piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole [612];5-(3-(4-(piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-ol [613];5-(5-(benzyloxy)pyridin-3-yl)-3-(4-(piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole [614];2-cyclohexyl-N-(5-(3-(4-(piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)acetamide [615];3-(4-(piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(pyrazin-2-yl)-1H-indazole [616];3-(4-(4-methyl-1H-imidazol-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(piperidin-4-yl)-1H-indazole [617];3-(4-(4-methyl-1H-imidazol-1-yl)-H-pyrrolo[2,3-b]pyridin-2-yl)-5-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indazole [618];3-(4-(4-methyl-1H-imidazol-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(1H-pyrazol-4-yl)-1H-indazole [619];3-(4-(4-methyl-1H-imidazol-1-yl)-H-pyrrolo[2,3-b]pyridin-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)-1H-indazole [620];5-(1,2-dimethyl-1H-imidazol-5-yl)-3-(4-(4-methyl-1H-imidazol-1-yl)-H-pyrrin-[2,3-b]pyridin-2-yl)-1H-indazole [621];1-(6-(3-(4-(4-methyl-1H-imidazol-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyrazin-2-yl)azetidin-3-amine [622];5-(5-(cyclohexyloxy)pyridin-3-yl)-3-(4-(4-methyl-1H-imidazol-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole [623];3-(4-(4-methyl-1H-imidazol-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(5-(piperidin-4-yloxy)pyridin-3-yl)-1H-indazole [624];N-(5-(3-(4-(4-methyl-1H-imidazol-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)-2-(piperidin-4-yl)acetamide [625];3-(4-(4-methyl-1H-imidazol-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(5-(2-(pyrrolidin-1-yl)ethoxy)pyridin-3-yl)-1H-indazole [626];N,N-dimethyl-2-((5-(3-(4-(4-methyl-1H-imidazol-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)oxy)ethan-1-amine [627];5-(5-methoxypyridin-3-yl)-3-(4-(4-methyl-1H-imidazol-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole [628];5-(3-(4-(4-methyl-1H-imidazol-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-ol [629];5-(5-(benzyloxy)pyridin-3-yl)-3-(4-(4-methyl-1H-imidazol-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole [630];2-cyclohexyl-N-(5-(3-(4-(4-methyl-1H-imidazol-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)acetamide [631];3-(4-(4-methyl-1H-imidazol-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(pyrazin-2-yl)-1H-indazole [632];3-(4-(4-methylpiperazin-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(piperidin-4-yl)-1H-indazole [633];3-(4-(4-methylpiperazin-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indazole [634];3-(4-(4-methylpiperazin-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(1H-pyrazol-4-yl)-1H-indazole [635];5-(1-methyl-1H-pyrazol-4-yl)-3-(4-(4-methylpiperazin-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole [636];5-(1,2-dimethyl-1H-imidazol-5-yl)-3-(4-(4-methylpiperazin-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole [637];1-(6-(3-(4-(4-methylpiperazin-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyrazin-2-yl)azetidin-3-amine [638];5-(5-(cyclohexyloxy)pyridin-3-yl)-3-(4-(4-methylpiperazin-1-yl)-H-pyrrolo 2,3-bpyidin-2-yl)-1H-indazole [639];3-(4-(4-methylpiperazin-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(5-(piperidin-4-yloxy)pyridin-3-yl)-1H-indazole [640];N-(5-(3-(4-(4-methylpiperazin-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)-2-(piperidin-4-yl)acetamide [641];3-(4-(4-methylpiperazin-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(5-(2-(pyrrolidin-1-yl)ethoxy)pyridin-3-yl)-1H-indazole [642];N,N-dimethyl-2-((5-(3-(4-(4-methylpiperazin-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)oxy)ethan-1-amine [643];5-(5-methoxypyridin-3-yl)-3-(4-(4-methylpiperazin-1-yl)-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole [644];5-(3-(4-(4-methylpiperazin-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-ol [645];5-(5-(benzyloxy)pyridin-3-yl)-3-(4-(4-methylpiperazin-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole [646];2-cyclohexyl-N-(5-(3-(4-(4-methylpiperazin-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)acetamide [647];3-(4-(4-methylpiperazin-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(pyrazin-2-yl)-1H-indazole [648];5-(piperidin-4-yl)-3-(1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole [649];3-(1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indazole [650];5-(1H-pyrazol-4-yl)-3-(1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole [651];5-(1-methyl-1H-pyrazol-4-yl)-3-(1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole [652];5-(1,2-dimethyl-1H-imidazol-5-yl)-3-(1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole [653];1-(6-(3-(1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyrazin-2-yl)azetidin-3-amine [654];5-(5-(cyclohexyloxy)pyridin-3-yl)-3-(1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole [655];5-(5-(piperidin-4-yloxy)pyridin-3-yl)-3-(1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole [656];N-(5-(3-(1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)-2-(piperidin-4-yl)acetamide [657];5-(5-(2-(pyrrolidin-1-yl)ethoxy)pyridin-3-yl)-3-(1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole [658];2-((5-(3-(1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)oxy)-N,N-dimethylethan-1-amine [659];5-(5-methoxypyridin-3-yl)-3-(1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole [660];5-(3-(1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-ol [661];5-(5-(benzyloxy)pyridin-3-yl)-3-(1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole [662];N-(5-(3-(1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)-2-cyclohexylacetamide [663];5-(pyrazin-2-yl)-3-(1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole [664];5-(piperidin-4-yl)-3-(4-(thiophen-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole [665];5-(1,2,3,6-tetrahydropyridin-4-yl)-3-(4-(thiophen-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole [666];5-(1H-pyrazol-4-yl)-3-(4-(thiophen-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole [667];5-(1-methyl-1H-pyrazol-4-yl)-3-(4-(thiophen-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole [668];5-(1,2-dimethyl-1H-imidazol-5-yl)-3-(4-(thiophen-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole [669];1-(6-(3-(4-(thiophen-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyrazin-2-yl)azetidin-3-amine [670];5-(5-(cyclohexyloxy)pyridin-3-yl)-3-(4-(thiophen-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole [671];5-(5-(piperidin-4-yloxy)pyridin-3-yl)-3-(4-(thiophen-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole [672];2-(piperidin-4-yl)-N-(5-(3-(4-(thiophen-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)acetamide [673];5-(5-(2-(pyrrolidin-1-yl)ethoxy)pyridin-3-yl)-3-(4-(thiophen-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole [674];N,N-dimethyl-2-((5-(3-(4-(thiophen-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)oxy)ethan-1-amine [675];5-(5-methoxypyridin-3-yl)-3-(4-(thiophen-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole [676];5-(3-(4-(thiophen-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-ol [677];5-(5-(benzyloxy)pyridin-3-yl)-3-(4-(thiophen-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole [678];2-cyclohexyl-N-(5-(3-(4-(thiophen-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)acetamide [679];5-(pyrazin-2-yl)-3-(4-(thiophen-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole [680];3-(4-(furan-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(piperidin-4-yl)-1H-indazole [681];3-(4-(furan-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indazole [682];3-(4-(furan-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(1H-pyrazol-4-yl)-1H-indazole [683];3-(4-(furan-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)-1H-indazole [684];5-(1,2-dimethyl-1H-imidazol-5-yl)-3-(4-(furan-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole [685];1-(6-(3-(4-(furan-3-yl)-H-pyrrolo[2,3-b]pyridin-2-yl)-H-indazol-5-yl)pyrazin-2-yl)azetidin-3-amine [686];5-(5-(cyclohexyloxy)pyridin-3-yl)-3-(4-(furan-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole [687];3-(4-(furan-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(5-(piperidin-4-yloxy)pyridin-3-yl)-1H-indazole [688];N-(5-(3-(4-(furan-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)-2-(piperidin-4-yl)acetamide [689];3-(4-(furan-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(5-(2-(pyrrolidin-1-yl)ethoxy)pyridin-3-yl)-1H-indazole [690];2-((5-(3-(4-(furan-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)oxy)-N,N-dimethylethan-1-amine [691];3-(4-(furan-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(5-methoxypyridin-3-yl)-1H-indazole [692];5-(3-(4-(furan-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-ol [693];5-(5-(benzyloxy)pyridin-3-yl)-3-(4-(furan-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole [694];2-cyclohexyl-N-(5-(3-(4-(furan-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)acetamide [695];3-(4-(furan-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(pyrazin-2-yl)-1H-indazole [696];5-(piperidin-4-yl)-3-(4-(thiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole [697];5-(1,2,3,6-tetrahydropyridin-4-yl)-3-(4-(thiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole [698];5-(1H-pyrazol-4-yl)-3-(4-(thiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole [699];5-(1-methyl-1H-pyrazol-4-yl)-3-(4-(thiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole [700];5-(1,2-dimethyl-1H-imidazol-5-yl)-3-(4-(thiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole [701];1-(6-(3-(4-(thiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyrazin-2-yl)azetidin-3-amine [702];5-(5-(cyclohexyloxy)pyridin-3-yl)-3-(4-(thiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole [703];5-(5-(piperidin-4-yloxy)pyridin-3-yl)-3-(4-(thiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole [704];2-(piperidin-4-yl)-N-(5-(3-(4-(thiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)acetamide [705];5-(5-(2-(pyrrolidin-1-yl)ethoxy)pyridin-3-yl)-3-(4-(thiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole [706];N,N-dimethyl-2-((5-(3-(4-(thiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)oxy)ethan-1-amine [707];5-(5-methoxypyridin-3-yl)-3-(4-(thiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole [708];5-(3-(4-(thiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-ol [709];5-(5-(benzyloxy)pyridin-3-yl)-3-(4-(thiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole [710];2-cyclohexyl-N-(5-(3-(4-(thiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)acetamide [711];5-(pyrazin-2-yl)-3-(4-(thiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole [712];3-(4-(5-fluorothiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(piperidin-4-yl)-1H-indazole [713];3-(4-(5-fluorothiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(1,2,36-tetrahydropyridin-4-yl)-1H-indazole [714];3-(4-(5-fluorothiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(1H-pyrazol-4-yl)-1H-indazole [715];3-(4-(5-fluorothiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)-H-indazdaole [716];5-(1,2-dimethyl-1H-imidazol-5-yl)-3-(4-(5-fluorothiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole [717];1-(6-(3-(4-(5-fluorothiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyrazin-2-yl)azetidin-3-amine [718];5-(5-(cyclohexyloxy)pyridin-3-yl)-3-(4-(5-fluorothiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole [719];3-(4-(5-fluorothiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(5-(piperidin-4-yloxy)pyridin-3-yl)-1H-indazole [720];N-(5-(3-(4-(5-fluorothiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)-2-(piperidin-4-yl)acetamide [721];3-(4-(5-fluorothiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(5-(2-(pyrrolidin-1-yl)ethoxy)pyridin-3-yl)-1H-indazole [722];2-((5-(3-(4-(5-fluorothiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)oxy)-N,N-dimethylethan-1-amine [723];3-(4-(5-fluorothiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(5-methoxypyridin-3-yl)-1H-indazole [724];5-(3-(4-(5-fluorothiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-ol [725];5-(5-(benzyloxy)pyridin-3-yl)-3-(4-(5-fluorothiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole [726];2-cyclohexyl-N-(5-(3-(4-(5-fluorothiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)acetamide [727];3-(4-(5-fluorothiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(pyrazin-2-yl)-1H-indazole [728];3-(4-(5-methylthiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(piperidin-4-yl)-1H-indazole [729];3-(4-(5-methylthiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indazole [730];3-(4-(5-methylthiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(1H-pyrazol-4-yl)-1H-indazole [731];5-(1-methyl-1H-pyrazol-4-yl)-3-(4-(5-methylthiophen-2-yl)-H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole [732];5-(1,2-dimethyl-1H-imidazol-5-yl)-3-(4-(5-methylthiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole [733];1-(6-(3-(4-(5-methylthiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyrazin-2-yl)azetidin-3-amine [734];5-(5-(cyclohexyloxy)pyridin-3-yl)-3-(4-(5-methylthiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole [735];3-(4-(5-methylthiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(5-(piperidin-4-yloxy)pyridin-3-yl)-1H-indazole [736];N-(5-(3-(4-(5-methylthiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)-2-(piperidin-4-yl)acetamide [737];3-(4-(5-methylthiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(5-(2-(pyrrolidin-1-yl)ethoxy)pyridin-3-yl)-1H-indazole [738];N,N-dimethyl-2-((5-(3-(4-(5-methylthiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)oxy)ethan-1-amine [739];5-(5-methoxypyridin-3-yl)-3-(4-(5-methylthiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole [740];5-(3-(4-(5-methylthiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-ol [741];5-(5-(benzyloxy)pyridin-3-yl)-3-(4-(5-methylthiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole [742];2-cyclohexyl-N-(5-(3-(4-(5-methylthiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)acetamide [743];3-(4-(5-methylthiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(pyrazin-2-yl)-1H-indazole [744];1-(5-(2-(5-(piperidin-4-yl)-1H-indazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)thiophen-2-yl)ethan-1-one [745];1-(5-(2-(5-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)thiophen-2-yl)ethan-1-one [746];1-(5-(2-(5-(1H-pyrazol-4-yl)-1H-indazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)thiophen-2-yl)ethan-1-one [747];1-(5-(2-(5-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)thiophen-2-yl)ethan-1-one [748];1-(5-(2-(5-(1,2-dimethyl-1H-imidazol-5-yl)-1H-indazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)thiophen-2-yl)ethan-1-one [749];1-(5-(2-(5-(6-(3-aminoazetidin-1-yl)pyrazin-2-yl)-1H-indazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)thiophen-2-yl)ethan-1-one [750];1-(5-(2-(5-(5-(cyclohexyloxy)pyridin-3-yl)-1H-indazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)thiophen-2-yl)ethan-1-one [751];1-(5-(2-(5-(5-(piperidin-4-yloxy)pyridin-3-yl)-1H-indazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)thiophen-2-yl)ethan-1-one [752];N-(5-(3-(4-(5-acetylthiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)-2-(piperidin-4-yl)acetamide [753];1-(5-(2-(5-(5-(2-(pyrrolidin-1-yl)ethoxy)pyridin-3-yl)-1H-indazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)thiophen-2-yl)ethan-1-one [754];1-(5-(2-(5-(5-(2-(dimethylamino)ethoxy)pyridin-3-yl)-1H-indazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)thiophen-2-yl)ethan-1-one [755];1-(5-(2-(5-(5-methoxypyridin-3-yl)-1H-indazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)thiophen-2-yl)ethan-1-one [756];1-(5-(2-(5-(5-hydroxypyridin-3-yl)-1H-indazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)thiophen-2-yl)ethan-1-one [757];1-(5-(2-(5-(5-(benzyloxy)pyridin-3-yl)-1H-indazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)thiophen-2-yl)ethan-1-one [758];N-(5-(3-(4-(5-acetylthiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)-2-cyclohexylacetamide [759];1-(5-(2-(5-(pyrazin-2-yl)-1H-indazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)thiophen-2-yl)ethan-1-one [760];N-(3-fluoro-5-(2-(5-(piperidin-4-yl)-1H-indazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)benzyl)methanesulfonamide [761];N-(3-fluoro-5-(2-(5-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)benzyl)methanesulfonamide [762];N-(3-(2-(5-(1H-pyrazol-4-yl)-1H-indazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-5-fluorobenzyl)methanesulfonamide [763];N-(3-fluoro-5-(2-(5-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)benzyl)methanesulfonamide [764];N-(3-(2-(5-(1,2-dimethyl-1H-imidazol-5-yl)-1H-indazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-5-fluorobenzyl)methanesulfonamide [765];N-(3-(2-(5-(6-(3-aminoazetidin-1-yl)pyrazin-2-yl)-1H-indazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-5-fluorobenzyl)methanesulfonamide [766];N-(3-(2-(5-(5-(cyclohexyloxy)pyridin-3-yl)-1H-indazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-5-fluorobenzyl)methanesulfonamide [767];N-(3-fluoro-5-(2-(5-(5-(piperidin-4-yloxy)pyridin-3-yl)-1H-indazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)benzyl)methanesulfonamide [768];N-(5-(3-(4-(3-fluoro-5-(methylsulfonamidomethyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)-2-(piperidin-4-yl)acetamide [769];N-(3-fluoro-5-(2-(5-(5-(2-(pyrrolidin-1-yl)ethoxy)pyridin-3-yl)-1H-indazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)benzyl)methanesulfonamide [770];N-(3-(2-(5-(5-(2-(dimethylamino)ethoxy)pyridin-3-yl)-1H-indazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-5-fluorobenzyl)methanesulfonamide [771];N-(3-fluoro-5-(2-(5-(5-methoxypyridin-3-yl)-1H-indazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)benzyl)methanesulfonamide [772];N-(3-fluoro-5-(2-(5-(5-hydroxypyridin-3-yl)-1H-indazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)benzyl)methanesulfonamide [773];N-(3-(2-(5-(5-(benzyloxy)pyridin-3-yl)-1H-indazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-5-fluorobenzyl)methanesulfonamide [774];2-cyclohexyl-N-(5-(3-(4-(3-fluoro-5-(methylsulfonamidomethyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)acetamide [775];N-(3-fluoro-5-(2-(5-(pyrazin-2-yl)-1H-indazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)benzyl)methanesulfonamide [776];N1-(3-fluoro-5-(2-(5-(piperidin-4-yl)-1H-indazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)phenyl)-N2,N2-dimethylethane-1,2-diamine [777];N-(3-fluoro-5-(2-(5-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)phenyl)-N2,N2-dimethylethane-1,2-diamine [778];N1-(3-(2-(5-(1H-pyrazol-4-yl)-1H-indazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-5-fluorophenyl)-N2,N2-dimethylethane-1,2-diamine [779];N1-(3-fluoro-5-(2-(5-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)phenyl)-N2,N2-dimethylethane-1,2-diamine [780];N1-(3-(2-(5-(1,2-dimethyl-1H-imidazol-5-yl)-1H-indazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-5-fluorophenyl)-N2,N2-dimethylethane-1,2-diamine [781];N1-(3-(2-(5-(6-(3-aminoazetidin-1-yl)pyrazin-2-yl)-1H-indazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-5-fluorophenyl)-N2,N2-dimethylethane-1,2-diamine [782];N1-(3-(2-(5-(5-(cyclohexyloxy)pyridin-3-yl)-1H-indazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-5-fluorophenyl)-N2,N2-dimethylethane-1,2-diamine [783];N1-(3-fluoro-5-(2-(5-(5-(piperidin-4-yloxy)pyridin-3-yl)-1H-indazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)phenyl)-N2,N2-dimethylethane-1,2-diamine [784];N-(5-(3-(4-(3-((2-(dimethylamino)ethyl)amino)-5-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)-2-(piperidin-4-yl)acetamide [785];N-(3-fluoro-5-(2-(5-(5-(2-(pyrrolidin-1-yl)ethoxy)pyridin-3-yl)-1H-indazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)phenyl)-N2,N2-dimethylethane-1,2-diamine [786];N1-(3-(2-(5-(5-(2-(dimethylamino)ethoxy)pyridin-3-yl)-1H-indazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-5-fluorophenyl)-N2,N2-dimethylethane-1,2-diamine [787];N1-(3-fluoro-5-(2-(5-(5-methoxypyridin-3-yl)-1H-indazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)phenyl)-N2,N2-dimethylethane-1,2-diamine [788];5-(3-(4-(3-((2-(dimethylamino)ethyl)amino)-5-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-ol [789];N1-(3-(2-(5-(5-(benzyloxy)pyridin-3-yl)-1H-indazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-5-fluorophenyl)-N2,N2-dimethylethane-1,2-diamine [790];2-cyclohexyl-N-(5-(3-(4-(3-((2-(dimethylamino)ethyl)amino)-5-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)acetamide [791];N1-(3-fluoro-5-(2-(5-(pyrazin-2-yl)-1H-indazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)phenyl)-N2,N2-dimethylethane-1,2-diamine [792];N-(5-(3-(4-(3-(2-(dimethylamino)ethoxy)-5-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)propionamide [793];N-(5-(3-(4-(3-(2-(dimethylamino)ethoxy)-5-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)-3-methylbutanamide [794];5-(3-(4-(3-(2-(dimethylamino)ethoxy)-5-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-amine [795];2-(3-fluoro-5-(2-(5-(pyridin-3-yl)-1H-indazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)phenoxy)-N,N-dimethylethan-1-amine [796];2-(3-fluoro-5-(2-(5-(4-methylpyridin-3-yl)-1H-indazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)phenoxy)-N,N-dimethylethan-1-amine [797];2-(3-(2-(5-(5-((ethylamino)methyl)pyridin-3-yl)-1H-indazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-5-fluorophenoxy)-N,N-dimethylethan-1-amine [798];5-(3-(4-(3-(2-(dimethylamino)ethoxy)-5-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)-N,N-dimethylpyridin-3-amine [799];N-(5-(3-(4-(3-(2-(dimethylamino)ethoxy)-5-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)pivalamide [800];N-(5-(3-(4-(3-(2-(dimethylamino)ethoxy)-5-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)isobutyramide [801];N-(5-(3-(4-(3-(2-(dimethylamino)ethoxy)-5-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)-2-phenylacetamide [802];N-(5-(3-(4-(3-(2-(dimethylamino)ethoxy)-5-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)benzamide [803];5-(3-(4-(3-(2-(dimethylamino)ethoxy)-5-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)-N-isopropylpyridin-3-amine [804];2-(3-(2-(5-(5-((dimethylamino)methyl)pyridin-3-yl)-1H-indazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-5-fluorophenoxy)-N,N-dimethylethan-1-amine [805];2-(3-fluoro-5-(2-(5-(5-(pyrrolidin-1-ylmethyl)pyridin-3-yl)-1H-indazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)phenoxy)-N,N-dimethylethan-1-amine [806];2-(3-fluoro-5-(2-(5-(5-(piperidin-1-ylmethyl)pyridin-3-yl)-1H-indazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)phenoxy)-N,N-dimethylethan-1-amine [807];N-(5-(3-(4-(3-(2-(dimethylamino)ethoxy)-5-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)-3,3-dimethylbutanamide [808];N-(5-(3-(4-(3-(2-(dimethylamino)ethoxy)-5-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)butyramide [809];N-(5-(3-(4-(3-(2-(dimethylamino)ethoxy)-5-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)pentanamide [810];N-(5-(3-(4-(3-(2-(dimethylamino)ethoxy)-5-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)cyclopropanecarboxamide [811];N-(5-(3-(4-(3-(2-(dimethylamino)ethoxy)-5-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)cyclobutanecarboxamide [812];N-(5-(3-(4-(3-(2-(dimethylamino)ethoxy)-5-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)cyclopentanecarboxamide [813];N-(5-(3-(4-(3-(2-(dimethylamino)ethoxy)-5-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)cyclohexanecarboxamide [814];2-(3-(2-(5-(5-((benzylamino)methyl)pyridin-3-yl)-1H-indazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-5-fluorophenoxy)-N,N-dimethylethan-1-amine [815];2-(3-(2-(5-(5-(((cyclopentylmethyl)amino)methyl)pyridin-3-yl)-1H-indazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-5-fluorophenoxy)-N,N-dimethylethan-1-amine [816];2-(3-(2-(5-(5-((3,3-difluoropyrrolidin-1-yl)methyl)pyridin-3-yl)-1H-indazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-5-fluorophenoxy)-N,N-dimethylethan-1-amine [817];2-(3-fluoro-5-(2-(5-(pyrimidin-5-yl)-1H-indazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)phenoxy)-N,N-dimethylethan-1-amine [818];2-(3-fluoro-5-(2-(5-(pyridin-2-yl)-1H-indazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)phenoxy)-N,N-dimethylethan-1-amine [819];2-(3-fluoro-5-(2-(5-(piperidin-4-yl)-1H-indazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)phenoxy)-N,N-dimethylethan-1-amine [820];2-(3-fluoro-5-(2-(5-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)phenoxy)-N,N-dimethylethan-1-amine [821];2-(3-(2-(5-(1H-pyrazol-4-yl)-1H-indazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-5-fluorophenoxy)-N,N-dimethylethan-1-amine [822];2-(3-fluoro-5-(2-(5-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)phenoxy)-N,N-dimethylethan-1-amine [823];2-(3-(2-(5-(1,2-dimethyl-1H-imidazol-5-yl)-1H-indazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-5-fluorophenoxy)-N,N-dimethylethan-1-amine [824];1-(6-(3-(4-(3-(2-(dimethylamino)ethoxy)-5-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyrazin-2-yl)azetidin-3-amine [825];2-(3-(2-(5-(5-(cyclohexyloxy)pyridin-3-yl)-1H-indazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-5-fluorophenoxy)-N,N-dimethylethan-1-amine [826];2-(3-fluoro-5-(2-(5-(5-(piperidin-4-yloxy)pyridin-3-yl)-1H-indazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)phenoxy)-N,N-dimethylethan-1-amine [827];N-(5-(3-(4-(3-(2-(dimethylamino)ethoxy)-5-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)-2-(piperidin-4-yl)acetamide [828];2-(3-fluoro-5-(2-(5-(5-(2-(pyrrolidin-1-yl)ethoxy)pyridin-3-yl)-1H-indazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)phenoxy)-N,N-dimethylethan-1-amine [829];2-((5-(3-(4-(3-(2-(dimethylamino)ethoxy)-5-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)oxy)-N,N-dimethylethan-1-amine [830];2-(3-fluoro-5-(2-(5-(5-methoxypyridin-3-yl)-1H-indazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)phenoxy)-N,N-dimethylethan-1-amine [831];5-(3-(4-(3-(2-(dimethylamino)ethoxy)-5-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-ol [832];2-(3-(2-(5-(5-(benzyloxy)pyridin-3-yl)-1H-indazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-5-fluorophenoxy)-N,N-dimethylethan-1-amine [833];2-cyclohexyl-N-(5-(3-(4-(3-(2-(dimethylamino)ethoxy)-5-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)acetamide [834];2-(3-fluoro-5-(2-(5-(pyridin-4-yl)-1H-indazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)phenoxy)-N,N-dimethylethan-1-amine [835];2-(3-fluoro-5-(2-(5-(pyrazin-2-yl)-1H-indazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)phenoxy)-N,N-dimethylethan-1-amine [836];N-(5-(3-(4-(3-fluoro-5-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)propionamide [837];N-(5-(3-(4-(3-fluoro-5-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)-3-methylbutanamide [838];5-(3-(4-(3-fluoro-5-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-amine [839];3-(4-(3-fluoro-5-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(pyridin-3-yl)-1H-indazole [840];3-(4-(3-fluoro-5-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(4-methylpyridin-3-yl)-1H-indazole [841];N-((5-(3-(4-(3-fluoro-5-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)methyl)ethanamine [842];5-(3-(4-(3-fluoro-5-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)-N,N-dimethylpyridin-3-amine [843];N-(5-(3-(4-(3-fluoro-5-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)pivalamide [844];N-(5-(3-(4-(3-fluoro-5-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)isobutyramide [845];N-(5-(3-(4-(3-fluoro-5-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)-2-phenylacetamide [846];N-(5-(3-(4-(3-fluoro-5-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)benzamide [847];5-(3-(4-(3-fluoro-5-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)-N-isopropylpyridin-3-amine [848];1-(5-(3-(4-(3-fluoro-5-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)-N,N-dimethylmethanamine [849];3-(4-(3-fluoro-5-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(5-(pyrrolidin-1-ylmethyl)pyridin-3-yl)-1H-indazole [850];3-(4-(3-fluoro-5-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(5-(piperidin-1-ylmethyl)pyridin-3-yl)-1H-indazole [851];N-(5-(3-(4-(3-fluoro-5-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)-3,3-dimethylbutanamide [852];N-(5-(3-(4-(3-fluoro-5-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)butyramide [853];N-(5-(3-(4-(3-fluoro-5-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)pentanamide [854];N-(5-(3-(4-(3-fluoro-5-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)cyclopropanecarboxamide [855];N-(5-(3-(4-(3-fluoro-5-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)cyclobutanecarboxamide [856];N-(5-(3-(4-(3-fluoro-5-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)cyclopentanecarboxamide [857];N-(5-(3-(4-(3-fluoro-5-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)cyclohexanecarboxamide [858];N-benzyl-1-(5-(3-(4-(3-fluoro-5-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)methanamine [859];1-cyclopentyl-N-((5-(3-(4-(3-fluoro-5-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)methyl)methanamine [860];5-(5-((3,3-difluoropyrrolidin-1-yl)methyl)pyridin-3-yl)-3-(4-(3-fluoro-5-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole [861];3-(4-(3-fluoro-5-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(pyrimidin-5-yl)-1H-indazole [862];3-(4-(3-fluoro-5-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(pyridin-2-yl)-1H-indazole [863];3-(4-(3-fluoro-5-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(piperidin-4-yl)-1H-indazole [864];3-(4-(3-fluoro-5-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indazole [865];3-(4-(3-fluoro-5-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(1H-pyrazol-4-yl)-1H-indazole [866];3-(4-(3-fluoro-5-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)-1H-indazole [867];5-(1,2-dimethyl-1H-imidazol-5-yl)-3-(4-(3-fluoro-5-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole [868];1-(6-(3-(4-(3-fluoro-5-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyrazin-2-yl)azetidin-3-amine [869];5-(5-(cyclohexyloxy)pyridin-3-yl)-3-(4-(3-fluoro-5-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole [870];3-(4-(3-fluoro-5-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(5-(piperidin-4-yloxy)pyridin-3-yl)-1H-indazole [871];N-(5-(3-(4-(3-fluoro-5-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)-2-(piperidin-4-yl)acetamide [872];3-(4-(3-fluoro-5-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(5-(2-(pyrrolidin-1-yl)ethoxy)pyridin-3-yl)-1H-indazole [873];2-((5-(3-(4-(3-fluoro-5-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)oxy)-N,N-dimethylethan-1-amine [874];3-(4-(3-fluoro-5-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(5-methoxypyridin-3-yl)-1H-indazole [875];5-(3-(4-(3-fluoro-5-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-ol [876];5-(5-(benzyloxy)pyridin-3-yl)-3-(4-(3-fluoro-5-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole [877];2-cyclohexyl-N-(5-(3-(4-(3-fluoro-5-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)acetamide [878];3-(4-(3-fluoro-5-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(pyridin-4-yl)-1H-indazole [879];3-(4-(3-fluoro-5-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(pyrazin-2-yl)-1H-indazole [880];N-(5-(3-(4-(3-fluoro-5-hydroxyphenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)propionamide [881];N-(5-(3-(4-(3-fluoro-5-hydroxyphenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)-3-methylbutanamide [882];3-(2-(5-(5-aminopyridin-3-yl)-1H-indazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-5-fluorophenol [883];3-fluoro-5-(2-(5-(pyridin-3-yl)-1H-indazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)phenol [884];3-fluoro-5-(2-(5-(4-methylpyridin-3-yl)-1H-indazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)phenol [885];3-(2-(5-(5-((ethylamino)methyl)pyridin-3-yl)-1H-indazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-5-fluorophenol [886];3-(2-(5-(5-(dimethylamino)pyridin-3-yl)-1H-indazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-5-fluorophenol [887];N-(5-(3-(4-(3-fluoro-5-hydroxyphenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)pivalamide [888];N-(5-(3-(4-(3-fluoro-5-hydroxyphenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)isobutyramide [889];N-(5-(3-(4-(3-fluoro-5-hydroxyphenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)-2-phenylacetamide [890];N-(5-(3-(4-(3-fluoro-5-hydroxyphenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)benzamide [891];3-fluoro-5-(2-(5-(5-(isopropylamino)pyridin-3-yl)-1H-indazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)phenol [892];3-(2-(5-(5-((dimethylamino)methyl)pyridin-3-yl)-1H-indazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-5-fluorophenol [893];3-fluoro-5-(2-(5-(5-(pyrrolidin-1-ylmethyl)pyridin-3-yl)-1H-indazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)phenol [894];3-fluoro-5-(2-(5-(5-(piperidin-1-ylmethyl)pyridin-3-yl)-1H-indazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)phenol [895];N-(5-(3-(4-(3-fluoro-5-hydroxyphenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)-3,3-dimethylbutanamide [896];N-(5-(3-(4-(3-fluoro-5-hydroxyphenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)butyramide [897];N-(5-(3-(4-(3-fluoro-5-hydroxyphenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)pentanamide [898];N-(5-(3-(4-(3-fluoro-5-hydroxyphenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)cyclopropanecarboxamide [899];N-(5-(3-(4-(3-fluoro-5-hydroxyphenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)cyclobutanecarboxamide [900];N-(5-(3-(4-(3-fluoro-5-hydroxyphenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)cyclopentanecarboxamide [901];N-(5-(3-(4-(3-fluoro-5-hydroxyphenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)cyclohexanecarboxamide [902];3-(2-(5-(5-((benzylamino)methyl)pyridin-3-yl)-1H-indazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-5-fluorophenol [903];3-(2-(5-(5-(((cyclopentylmethyl)amino)methyl)pyridin-3-yl)-1H-indazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-5-fluorophenol [904];3-(2-(5-(5-((3,3-difluoropyrrolidin-1-yl)methyl)pyridin-3-yl)-1H-indazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-5-fluorophenol [905];3-fluoro-5-(2-(5-(pyrimidin-5-yl)-1H-indazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)phenol [906];3-fluoro-5-(2-(5-(pyridin-2-yl)-1H-indazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)phenol [907];3-fluoro-5-(2-(5-(piperidin-4-yl)-1H-indazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)phenol [908];3-fluoro-5-(2-(5-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)phenol [909];3-(2-(5-(1H-pyrazol-4-yl)-1H-indazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-5-fluorophenol [910];3-fluoro-5-(2-(5-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)phenol [911];3-(2-(5-(1,2-dimethyl-1H-imidazol-5-yl)-1H-indazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-5-fluorophenol [912];3-(2-(5-(6-(3-aminoazetidin-1-yl)pyrazin-2-yl)-1H-indazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-5-fluorophenol [913];3-(2-(5-(5-(cyclohexyloxy)pyridin-3-yl)-1H-indazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-5-fluorophenol [914];3-fluoro-5-(2-(5-(5-(piperidin-4-yloxy)pyridin-3-yl)-1H-indazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)phenol [915];N-(5-(3-(4-(3-fluoro-5-hydroxyphenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)-2-(piperidin-4-yl)acetamide [916];3-fluoro-5-(2-(5-(5-(2-(pyrrolidin-1-yl)ethoxy)pyridin-3-yl)-1H-indazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)phenol [917];3-(2-(5-(5-(2-(dimethylamino)ethoxy)pyridin-3-yl)-1H-indazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-5-fluorophenol [918];3-fluoro-5-(2-(5-(5-methoxypyridin-3-yl)-1H-indazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)phenol [919];5-(3-(4-(3-fluoro-5-hydroxyphenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-ol [920];3-(2-(5-(5-(benzyloxy)pyridin-3-yl)-1H-indazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-5-fluorophenol [921];2-cyclohexyl-N-(5-(3-(4-(3-fluoro-5-hydroxyphenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)acetamide [922];3-fluoro-5-(2-(5-(pyridin-4-yl)-1H-indazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)phenol [923];3-fluoro-5-(2-(5-(pyrazin-2-yl)-1H-indazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)phenol [924];N-(5-(3-(4-(3-fluoro-5-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)propionamide [925];N-(5-(3-(4-(3-fluoro-5-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)-3-methylbutanamide [926];5-(3-(4-(3-fluoro-5-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-amine [927];3-(4-(3-fluoro-5-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(pyridin-3-yl)-1H-indazole [928];3-(4-(3-fluoro-5-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(4-methylpyridin-3-yl)-1H-indazole [929];N-((5-(3-(4-(3-fluoro-5-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)methyl)ethanamine [930];5-(3-(4-(3-fluoro-5-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)-N,N-dimethylpyridin-3-amine [931];N-(5-(3-(4-(3-fluoro-5-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)pivalamide [932];N-(5-(3-(4-(3-fluoro-5-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)isobutyramide [933];N-(5-(3-(4-(3-fluoro-5-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)-2-phenylacetamide [934];N-(5-(3-(4-(3-fluoro-5-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)benzamide [935];5-(3-(4-(3-fluoro-5-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)-N-isopropylpyridin-3-amine [936];1-(5-(3-(4-(3-fluoro-5-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)-N,N-dimethylmethanamine [937];3-(4-(3-fluoro-5-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(5-(pyrrolidin-1-ylmethyl)pyridin-3-yl)-1H-indazole [938];3-(4-(3-fluoro-5-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(5-(piperidin-1-ylmethyl)pyridin-3-yl)-1H-indazole [939];N-(5-(3-(4-(3-fluoro-5-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)-3,3-dimethylbutanamide [940];N-(5-(3-(4-(3-fluoro-5-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)butyramide [941];N-(5-(3-(4-(3-fluoro-5-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)pentanamide [942];N-(5-(3-(4-(3-fluoro-5-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)cyclopropanecarboxamide [943];N-(5-(3-(4-(3-fluoro-5-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)cyclobutanecarboxamide [944];N-(5-(3-(4-(3-fluoro-5-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)cyclopentanecarboxamide [945];N-(5-(3-(4-(3-fluoro-5-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)cyclohexanecarboxamide [946];N-benzyl-1-(5-(3-(4-(3-fluoro-5-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)methanamine [947];1-cyclopentyl-N-((5-(3-(4-(3-fluoro-5-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)methyl)methanamine [948];5-(5-((3,3-difluoropyrrolidin-1-yl)methyl)pyridin-3-yl)-3-(4-(3-fluoro-5-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole [949];3-(4-(3-fluoro-5-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(pyrimidin-5-yl)-1H-indazole [950];3-(4-(3-fluoro-5-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(pyridin-2-yl)-1H-indazole [951];3-(4-(3-fluoro-5-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(piperidin-4-yl)-1H-indazole [952];3-(4-(3-fluoro-5-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indazole [953];3-(4-(3-fluoro-5-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(1H-pyrazol-4-yl)-1H-indazole [954];3-(4-(3-fluoro-5-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)-1H-indazole [955];5-(1,2-dimethyl-1H-imidazol-5-yl)-3-(4-(3-fluoro-5-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole [956];1-(6-(3-(4-(3-fluoro-5-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyrazin-2-yl)azetidin-3-amine [957];5-(5-(cyclohexyloxy)pyridin-3-yl)-3-(4-(3-fluoro-5-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole [958];3-(4-(3-fluoro-5-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(5-(piperidin-4-yloxy)pyridin-3-yl)-1H-indazole [959];N-(5-(3-(4-(3-fluoro-5-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)-2-(piperidin-4-yl)acetamide [960];3-(4-(3-fluoro-5-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(5-(2-(pyrrolidin-1-yl)ethoxy)pyridin-3-yl)-1H-indazole [961];2-((5-(3-(4-(3-fluoro-5-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)oxy)-N,N-dimethylethan-1-amine [962];3-(4-(3-fluoro-5-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(5-methoxypyridin-3-yl)-1H-indazole [963];5-(3-(4-(3-fluoro-5-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-ol [964];5-(5-(benzyloxy)pyridin-3-yl)-3-(4-(3-fluoro-5-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazole [965];2-cyclohexyl-N-(5-(3-(4-(3-fluoro-5-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)acetamide [966];3-(4-(3-fluoro-5-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(pyridin-4-yl)-1H-indazole [967];3-(4-(3-fluoro-5-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(pyrazin-2-yl)-1H-indazole [968];2-(dimethylamino)-N-(5-(3-(4-(3-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)acetamide [969];2-(dimethylamino)-N-(5-(3-(4-(4-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)acetamide [970];2-(dimethylamino)-N-(5-(3-(4-(2-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)acetamide [971];2-(dimethylamino)-N-(5-(3-(4-(pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)acetamide [972];2-(dimethylamino)-N-(5-(3-(4-(pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)acetamide [973];2-(dimethylamino)-N-(5-(3-(4-(pyridin-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)acetamide [974];2-(dimethylamino)-N-(5-(3-(4-(piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)acetamide [975];2-(dimethylamino)-N-(5-(3-(4-(4-methyl-1H-imidazol-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)acetamide [976];2-(dimethylamino)-N-(5-(3-(4-(4-methylpiperazin-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)acetamide [977];N-(5-(3-(1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)-2-(dimethylamino)acetamide [978];2-(dimethylamino)-N-(5-(3-(4-(thiophen-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)acetamide [979];2-(dimethylamino)-N-(5-(3-(4-(furan-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)acetamide [980];2-(dimethylamino)-N-(5-(3-(4-(thiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)acetamide [981];2-(dimethylamino)-N-(5-(3-(4-(5-fluorothiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)acetamide [982];2-(dimethylamino)-N-(5-(3-(4-(5-methylthiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)acetamide [983];N-(5-(3-(4-(5-acetylthiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)-2-(dimethylamino)acetamide [984];2-(dimethylamino)-N-(5-(3-(4-(3-fluoro-5-(methylsulfonamidomethyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)acetamide [985];2-(dimethylamino)-N-(5-(3-(4-(3-((2-(dimethylamino)ethyl)amino)-5-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)acetamide [986];2-(dimethylamino)-N-(5-(3-(4-(3-(2-(dimethylamino)ethoxy)-5-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)acetamide [987];2-(dimethylamino)-N-(5-(3-(4-(3-fluoro-5-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)acetamide [988];2-(dimethylamino)-N-(5-(3-(4-(3-fluoro-5-hydroxyphenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)acetamide [989];2-(dimethylamino)-N-(5-(3-(4-(3-fluoro-5-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)acetamide [990];3-(4-(furan-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(5-methoxypyridin-3-yl)-1H-indazole [991];1-(5-(7-fluoro-3-(4-(3-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)-N,N-dimethylmethanamine [992];1-(5-(6-fluoro-3-(4-(3-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)-N,N-dimethylmethanamine [993]; and1-(5-(4-fluoro-3-(4-(3-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)-N,N-dimethylmethanamine [994]; or a pharmaceutically acceptable salt thereof.
22. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
23. A method of treating or ameliorating in a patient a disorder or disease selected from the group consisting of: colon cancer, colorectal cancer, pulmonary fibrosis, degenerative disc disease, and osteoarthritis, the method comprising administering to the patient a therapeutically effective amount of a compound according to claim 1, or a pharmaceutically acceptable salt thereof.
24. A method of claim 23, wherein the disorder or disease is colon cancer.
25. A method of claim 23, wherein the disorder or disease is colorectal cancer.
26. A method of claim 23, wherein the disorder or disease is pulmonary fibrosis.
27. A method of claim 26, wherein the pulmonary fibrosis is idiopathic pulmonary fibrosis (IPF).
28. A method of claim 23, wherein the disorder or disease is degenerative disc disease.
29. A method of claim 23, wherein the disorder or disease is osteoarthritis.
30. The method of claim 23, wherein the patient is a human.

RELATED APPLICATIONS

This application is a National Stage application under 35 U.S.C. § 371 of International Application No. PCT/US2016/045326, having an International Filing Date of Aug. 3, 2016, which claims the benefit of U.S. Provisional Application No. 62/200,187, filed Aug. 3, 2015, all of which are incorporated herein by reference in their entirety.

PCT Information

Filing Document	Filing Date	Country	Kind
PCT/US2016/045326	8/3/2016	WO	00

Publishing Document	Publishing Date	Country	Kind
WO2017/024021	2/9/2017	WO	A

US Referenced Citations (187)

Number	Name	Date	Kind
4164559	Miyata et al.	Aug 1979	A
4474752	Haslam et al.	Oct 1984	A
4603139	King	Jul 1986	A
5037844	Hamminga et al.	Aug 1991	A
5922733	Forbes et al.	Jul 1999	A
6120484	Silverstein	Sep 2000	A
6358978	Ritzeler et al.	Mar 2002	B1
6377849	Lenarz et al.	Apr 2002	B1
6440102	Arenberg et al.	Aug 2002	B1
6555539	Reich et al.	Apr 2003	B2
6648873	Arenberg et al.	Nov 2003	B2
6831175	Li et al.	Dec 2004	B2
6884890	Kania et al.	Apr 2005	B2
6897208	Edwards et al.	May 2005	B2
6911211	Eini et al.	Jun 2005	B2
6919461	Reich et al.	Jul 2005	B2
7008953	Kephart et al.	Mar 2006	B2
7064215	Renhowe et al.	Jun 2006	B2
7232912	Reich et al.	Jun 2007	B2
7285565	Zhu et al.	Oct 2007	B2
7390815	Davies et al.	Jun 2008	B2
7429609	Ohi et al.	Sep 2008	B2
7452993	Arnold et al.	Nov 2008	B2
7468376	Rosales et al.	Dec 2008	B2
7482342	D'Orchymont et al.	Jan 2009	B2
7488737	Xie et al.	Feb 2009	B2
7491710	Cherrier et al.	Feb 2009	B2
7541367	Chiu et al.	Jun 2009	B2
7626021	Arnold et al.	Dec 2009	B2
7642278	Jansen et al.	Jan 2010	B2
7666867	Makriyannis et al.	Feb 2010	B2
7812043	Lau et al.	Oct 2010	B2
7829558	Arnold et al.	Nov 2010	B2
7842711	D'Orchymont et al.	Nov 2010	B2
7902217	Xie et al.	Mar 2011	B2
7943616	Cox et al.	May 2011	B2
8008481	Ericsson et al.	Aug 2011	B2
8088772	Garcia et al.	Jan 2012	B2
8129519	Cholody et al.	Mar 2012	B2
8158647	Blaney et al.	Apr 2012	B2
8252812	Hood et al.	Aug 2012	B2
8288425	Edwards et al.	Oct 2012	B2
8304408	Wrasidlo et al.	Nov 2012	B2
8450340	Hood et al.	May 2013	B2
8604052	Hood et al.	Dec 2013	B2
8618128	Hood et al.	Dec 2013	B1
8637508	Badiger et al.	Jan 2014	B2
8664241	Hood et al.	Mar 2014	B2
8673936	Hood et al.	Mar 2014	B2
8697887	Hood et al.	Apr 2014	B2
8703794	Hood et al.	Apr 2014	B2
8815897	Hood et al.	Aug 2014	B2
8822478	Hood et al.	Sep 2014	B2
8846714	Hood et al.	Sep 2014	B2
8883822	Hood et al.	Nov 2014	B2
8901150	Hood et al.	Dec 2014	B2
8987298	Hood et al.	Mar 2015	B2
9012472	Hood et al.	Apr 2015	B2
9056874	Adams et al.	Jun 2015	B2
9067939	Hood et al.	Jun 2015	B2
9090613	Hood et al.	Jul 2015	B2
9174967	Körber et al.	Nov 2015	B2
9199991	Hood et al.	Dec 2015	B2
9221793	Hood et al.	Dec 2015	B2
9233104	Hood et al.	Jan 2016	B2
9381192	Hood et al.	Jul 2016	B2
9538272	Auclair et al.	Jan 2017	B2
9540398	KC et al.	Jan 2017	B2
9586977	Hood et al.	Mar 2017	B2
9745271	Hood et al.	Aug 2017	B2
9763927	Hood et al.	Sep 2017	B2
9763951	KC et al.	Sep 2017	B2
9802916	Hood et al.	Oct 2017	B2
9815854	KC et al.	Nov 2017	B2
9828372	KC et al.	Nov 2017	B2
9844536	KC et al.	Dec 2017	B2
9855272	Hood et al.	Jan 2018	B2
9889140	KC et al.	Feb 2018	B2
9908867	KC et al.	Mar 2018	B2
20020103229	Bhagwat et al.	Aug 2002	A1
20020161022	Reich et al.	Oct 2002	A1
20030199516	Moser et al.	Oct 2003	A1
20040048868	Edwards et al.	Mar 2004	A1
20040077681	Rawlings et al.	Apr 2004	A1
20040176325	Munson et al.	Sep 2004	A1
20040236101	Makriyannis et al.	Nov 2004	A1
20050009894	Babin et al.	Jan 2005	A1
20050026960	Kephart et al.	Feb 2005	A1
20050070546	Arrington et al.	Mar 2005	A1
20050090529	McAlpine et al.	Apr 2005	A1
20050192262	Hagstrom et al.	Sep 2005	A1
20050208582	Ohi et al.	Sep 2005	A1
20050261339	Ohi et al.	Nov 2005	A1
20060004000	D'Orchymont et al.	Jan 2006	A1
20060014756	Edwards et al.	Jan 2006	A1
20060079564	Jansen et al.	Apr 2006	A1
20060094706	Paruch et al.	May 2006	A1
20060111322	Reich et al.	May 2006	A1
20060116519	Ma et al.	Jun 2006	A1
20060135589	Berdino et al.	Jun 2006	A1
20060142345	Kephart et al.	Jun 2006	A1
20060167056	Rynberg et al.	Jul 2006	A1
20060264897	Lobl	Nov 2006	A1
20070027140	Lau et al.	Feb 2007	A1
20070049598	Billedeau et al.	Mar 2007	A1
20070060616	Bennett et al.	Mar 2007	A1
20070078147	Schumacher et al.	Apr 2007	A1
20070185187	D'Orchymont et al.	Aug 2007	A1
20070219257	Beachy et al.	Sep 2007	A1
20070282101	Ericsson et al.	Dec 2007	A1
20080004270	Gill et al.	Jan 2008	A1
20080132495	Berdini et al.	Jun 2008	A1
20080255085	Arvidsson et al.	Oct 2008	A1
20080262205	Haar et al.	Oct 2008	A1
20080287452	Bursavich et al.	Nov 2008	A1
20090005356	Blaney et al.	Jan 2009	A1
20090005377	Almansa Rosales et al.	Jan 2009	A1
20090048249	Chiu et al.	Feb 2009	A1
20090054397	Ohi et al.	Feb 2009	A1
20090099062	Lee et al.	Apr 2009	A1
20090203690	Akritopoulou-Zanze et al.	Aug 2009	A1
20090247504	Churcher et al.	Oct 2009	A1
20090264446	Rosales et al.	Oct 2009	A9
20090286983	Almansa Rosales et al.	Nov 2009	A1
20100280063	Price et al.	Nov 2010	A1
20100298377	Aletru et al.	Nov 2010	A1
20110009353	Chen-Kiang et al.	Jan 2011	A1
20110021467	D'Orchymont et al.	Jan 2011	A1
20110034441	Hood et al.	Feb 2011	A1
20110082144	Lau et al.	Apr 2011	A1
20110178075	Xie et al.	Jul 2011	A1
20110190290	Hood et al.	Aug 2011	A1
20110034497	Hood et al.	Oct 2011	A1
20120053345	Ericson et al.	Mar 2012	A1
20120059047	Prins et al.	Mar 2012	A1
20120129837	Cholody et al.	May 2012	A1
20120277229	Bearss et al.	Nov 2012	A1
20130039906	Do et al.	Feb 2013	A1
20130267548	Follmann et al.	Oct 2013	A1
20140194441	K.C. et al.	Jul 2014	A1
20140364451	John et al.	Dec 2014	A1
20150087687	Brown	Mar 2015	A1
20150111872	Desroy et al.	Apr 2015	A1
20160068529	K.C. et al.	Mar 2016	A1
20160068547	K.C. et al.	Mar 2016	A1
20160068548	K.C. et al.	Mar 2016	A1
20160068549	K.C. et al.	Mar 2016	A1
20160068550	K.C. et al.	Mar 2016	A1
20160068551	K.C. et al.	Mar 2016	A1
20160075701	KC	Mar 2016	A1
20160090380	KC	Mar 2016	A1
20160101092	Hood et al.	Apr 2016	A1
20160297812	Hood et al.	Oct 2016	A1
20170333409	Hood et al.	Nov 2017	A1
20170349584	KC et al.	Dec 2017	A1
20180086754	KC et al.	Mar 2018	A1
20180133199	Dellamary	May 2018	A1
20180141963	KC et al.	May 2018	A1
20180148444	KC et al.	May 2018	A1
20180153873	Hood et al.	Jun 2018	A1
20180162840	KC et al.	Jun 2018	A1
20180177787	KC et al.	Jun 2018	A1
20180185343	Deshmukh et al.	Jul 2018	A1
20180201624	KC et al.	Jul 2018	A1
20180207141	KC et al.	Jul 2018	A1
20180214427	KC et al.	Aug 2018	A1
20180214428	KC et al.	Aug 2018	A1
20180214429	KC et al.	Aug 2018	A1
20180215753	KC et al.	Aug 2018	A1
20180221341	KC et al.	Aug 2018	A1
20180221350	KC et al.	Aug 2018	A1
20180221351	KC et al.	Aug 2018	A1
20180221352	KC et al.	Aug 2018	A1
20180221353	KC et al.	Aug 2018	A1
20180221354	KC et al.	Aug 2018	A1
20180222891	KC et al.	Aug 2018	A1
20180222923	KC et al.	Aug 2018	A1
20180228780	KC et al.	Aug 2018	A1
20180228781	KC et al.	Aug 2018	A1
20180228782	KC et al.	Aug 2018	A1
20180228783	KC et al.	Aug 2018	A1
20180228784	KC et al.	Aug 2018	A1
20180228785	KC et al.	Aug 2018	A1
20180230142	KC et al.	Aug 2018	A1
20180237416	Hood et al.	Aug 2018	A1
20180250269	KC et al.	Sep 2018	A1
20180256588	Hood et al.	Sep 2018	A1

Foreign Referenced Citations (77)

Number	Date	Country
1394205	Jan 2003	CN
1671710	Sep 2005	CN
1829713	Sep 2006	CN
101440092	May 2009	CN
20122	Jan 2010	KZ
2331640	Aug 2008	RU
2416610	Apr 2011	RU
WO1987005297	Sep 1987	WO
WO1996002537	Feb 1996	WO
WO2001002369	Jan 2001	WO
WO2001053268	Jul 2001	WO
WO2003004488	Jan 2003	WO
WO2003035005	May 2003	WO
WO2003035065	May 2003	WO
WO2003035644	May 2003	WO
WO2003051366	Jun 2003	WO
WO2003070236	Aug 2003	WO
WO2003070706	Aug 2003	WO
WO2003097610	Nov 2003	WO
WO2003101968	Dec 2003	WO
WO2003101993	Dec 2003	WO
WO2004014864	Feb 2004	WO
WO2004031158	Apr 2004	WO
WO2004076450	Sep 2004	WO
WO2005009997	Feb 2005	WO
WO2005012301	Feb 2005	WO
WO2005014554	Feb 2005	WO
WO2005047266	May 2005	WO
WO2005049019	Jun 2005	WO
WO2005092890	Oct 2005	WO
WO2005099703	Oct 2005	WO
WO2005110410	Nov 2005	WO
WO2006001894	Jan 2006	WO
WO2006015124	Feb 2006	WO
WO2006024945	Mar 2006	WO
WO2006054143	May 2006	WO
WO2006054151	May 2006	WO
WO2006063302	Jun 2006	WO
WO2006063841	Jun 2006	WO
WO2006130673	Dec 2006	WO
WO2007061360	May 2007	WO
WO2007107346	Sep 2007	WO
WO2007117465	Oct 2007	WO
WO2007147874	Dec 2007	WO
WO2008061109	May 2008	WO
WO2008071397	Jun 2008	WO
WO2008071398	Jun 2008	WO
WO2008071451	Jun 2008	WO
WO2008124848	Oct 2008	WO
WO2008137408	Nov 2008	WO
WO2008140792	Nov 2008	WO
WO2008147713	Dec 2008	WO
WO2008150914	Dec 2008	WO
WO2008154241	Dec 2008	WO
WO2008156757	Dec 2008	WO
WO2009011850	Jan 2009	WO
WO2009016072	Feb 2009	WO
WO2009029609	Mar 2009	WO
WO2009061345	May 2009	WO
WO2010064875	Jun 2010	WO
WO2010107765	Sep 2010	WO
WO2010111060	Sep 2010	WO
WO2010132725	Nov 2010	WO
WO2011011722	Jan 2011	WO
WO2011019648	Feb 2011	WO
WO2011019651	Feb 2011	WO
WO2011050245	Apr 2011	WO
WO2011079076	Jun 2011	WO
WO2011084486	Jul 2011	WO
WO2011123890	Oct 2011	WO
WO2012068589	May 2012	WO
WO2012104388	Aug 2012	WO
WO2012129562	Sep 2012	WO
WO2013024011	Feb 2013	WO
WO2013030138	Mar 2013	WO
WO2013113722	Aug 2013	WO
WO2017079765	May 2017	WO

Non-Patent Literature Citations (245)

Entry
Yamada et al. Cancer Sci 108 (2017) 818-823.
Cecil Textbook of Medicine, edited by Bennet, J.C., and Plum F., 20th edition,vol. 1, 1004-1010, 1996.
Freshney et al.,Culture of Animal Cells, A Manual of Basic Technique, Alan R. Liss, Inc., 1983, New York, p. 4.
Dermeret al., Bio/Technology, 1994, 12:320.
Golub et al., Science, 286, 531-537, 1999.
“Application of Hamish Christopher Swan Wood, Norman Whittaker, Irene Stirling and Kyuji Ohta.,” 582 F.2d 638 (Fed. Cir. 1978), 2 pages.
Adaimy et al., “Mutation in WNT10A Is Associated with an Autosomal Recessive Ectodermal Dysplasia: The Odonto-onycho-dermal Dysplasia,” Am. J. Hum. Genet., (Oct. 2007), 81(4), 821-828.
Anastas and Moon, “WNT signalling pathways as therapeutic targets in cancer,” Nat Rev Cancer, 13(1):11-26, Jan. 2013.
Andres, “Molecular genetics and animal models in autistic disorder,” Brain Research Bulletin, (2002), 57(1), 109-119.
Barker and Clevers, “Mining the Wnt pathway for cancer therapeutics,” Nat Rev Drug Discov,. 5(12):997-1014, Dec. 2006.
Beyer et al., “Extended report: β-catenin is a central mediator of pro-fibrotic Wnt signaling in systemic sclerosis,” Ann Rheum Dis, 71:761-767, online Feb. 2012.
Biason-Lauber et al., “A WNT4 Mutation Associated with Mullerian-Duct Regression and Virilization in a 46,XX Woman,” N. Engl. J. Med., (Aug. 2004), 351(8), 792-798.
Blaydon et al., “The gene encoding R-spondin 4 (RSPO4), a secreted protein implicated in Wnt signaling, is mutated in inherited anonychia,” Nat. Genet., (Nov. 2006), 38(11), 1245-1247.
Blom et al., “Involvement of the Wnt signaling pathway in experimental and human osteoarthritis: prominent role of Wnt-induced signaling protein 1,” Arthritis Rheum., 60(2):501-512, Feb. 2009.
Boyden et al., “High Bone Density Due to a Mutation in LDL-Receptor—Related Protein 5,” N. Engl. J. Med., (May 2002), 346(20):1513-1521.
Brack et al., “Increased Wnt signaling during aging alters muscle stem cell fate and increases fibrosis” , Science., 317(5839):807-810, Aug. 2007.
Brown et al., “Toxicity and toxicokinetics of the cyclin-dependent kinase inhibitor AG-024322 in cynomolgus monkeys following intravenous infusion,” Cancer Chemother Pharmacol., 62(6):1091-1101, Epub May 2008.
Chilosi et al., “The pathogenesis of COPD and IPF: Distinct horns of the same devil?,” Respiratory Research, 13:3, 2012.
Chockalingam et al., “Elevated aggrecanase activity in a rat model of joint injury is attenuated by an aggrecanase specific inhibitor,” Osteoarthritis Cartilage, Mar. 2011, 19(3): 315-323.
Chou and Talalay, “Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors,” Advances in Enzyme Regulation (1984), 22, 27-55.
Chou, “Drug combination studies and their synergy quantification using the Chou-Talalay method,” Cancer Res., 70(2):440-446, Jan. 2010.
Chou, “Graphic rule for drug metabolism systems,” Current Drug Metabolism, (May 2010) 11(4): 369-378.
Christodoulides et al., “WNT10B mutations in human obesity,” Diabetologia, (2006) 49(4):678-684.
Clevers and Nusse, “Wnt/β-catenin signaling and disease,” Cell, (Jun. 2012), 149(6):1192-1205.
Clevers, “Wnt/beta-catenin signaling in development and disease,” Cell, (Nov. 2006), 127(3), 469-480.
Corr, “Wnt-beta-catenin signaling in the pathogenesis of osteoarthritis,” Nat Clin Pract Rheumatol., 4(10):550-556, Oct. 2008.
D'Alessio et al., “Benzodipyrazoles: a new class of potent CDK2 inhibitors,” Bioorganic & Medicinal Chemistry Letters (2005), 15(5), 1315-1319.
Dann et al., “Insights into Wnt binding and signaling from the structures of two Frizzled cysteine-rich domains,” Nature, (Jul. 2001), 412, pp. 86-90.
Datta et al., “Novel therapeutic approaches for pulmonary fibrosis,” Br J Pharmacol., 163(1):141-172, May 2011.
Davidson et al., “Emerging links between CDK cell cycle regulators and Wnt signaling,” Trends Cell Biol., Aug. 2010, 20(8):453-460.
De Ferrari and Inestrosa, “Wnt signaling function in Alzheimer's disease,” Brain Research Reviews, (2000), 33(1): 1-12.
De Ferrari and Moon, “The ups and downs of Wnt signaling in prevalent neurological disorders,” Oncogene, (2006) 25(57): 7545-7553.
De Ferrari et al., “Common genetic variation within the Low-Density Lipoprotein Receptor-Related Protein 6 and late-onset Alzheimer's disease,” Proc. Natl. Acad. Sci. USA, (May 2007), 104(22):9434-9439.
Dermer, “Another Anniversary for the War on Cancer,” Nature Biotechnology, 12:320 (1994).
Dessalew et al., “3D-QSAR CoMFA and CoMSIA study on benzodipyrazoles as cyclin dependent kinase 2 inhibitors,” Medicinal Chemistry, (2008), 4(4), 313-321.
Dong et al., “QSAR study of Akt/protein kinase B (PKB) inhibitors using support vector machine,” European Journal of Medicinal Chemistry, (Oct. 2009), pp. 44(10): 4090-4097.
du Bois, “Strategies for treating idiopathic pulmonary fibrosis,” Nature Reviews Drug Discovery, 9(2): 129-140 (Feb. 2010).
Edamoto et al., “Alterations of RB1, p53 and Wnt pathways in hepatocellular carcinomas associated with hepatitis C, hepatitis B and alcoholic liver cirrhosis,” Int J Cancer., 106(3):334-341, Sep. 1, 2003.
Egloff et al., “Gastrin-releasing peptide receptor expression in non-cancerous bronchial epithelia is associated with lung cancer: a case-control study,” Respiratory Research, 13:9, Feb. 2012.
Espada et al., “Wnt signalling and cancer stem cells,” Clin. Transl. Oncol., (2009), 11(7), 411-27.
Ewan et al., “A useful approach to identify novel small-molecule inhibitors of Wnt-dependent transcription,” Cancer Res. (2010), 70(14), 5963-5973.
Florez et al., “TCF7L2 Polymorphisms and Progression to Diabetes in the Diabetes Prevention Program,” N. Engl. J. Med., (Jul. 2006), 355(3):241-250.
Freese et al., “Wnt signaling in development and disease,” Neurobiology of Disease, (2010) 38(2):148-153.
Fujii et al., “An antagonist of dishevelled protein-protein interaction suppresses beta-catenin-dependent tumor cell growth,” Cancer Res., 67(2):573-579, Jan. 2007.
Fukuzawa et al., “Beckwith-Wiedemann Syndrome-associated Hepatoblastoma: Wnt Signal Activation Occurs Later in Tumorigenesis in Patients with 11p15.5 Uniparental Disomy,” Pediatric and Developmental Pathology (2003), 6(4): 299-306.
Giles et al., “Caught up in a Wnt storm: Wnt signaling in cancer,” Biochim Biophys Acta., 1653(1):1-24, Jun. 2003.
Handeli and Simon, “A small-molecule inhibitor of Tcf/beta-catenin signaling down-regulates PPARgamma and PPARdelta activities,” Mol Cancer Ther., 7(3):521-529, Mar. 2008.
Henderson Jr. et al., “Inhibition of Wnt/beta-catenin/CREB binding protein (CBP) signaling reverses pulmonary fibrosis,” Proc Natl Acad Sci U S A., 107(32):14309-14314, Epub Jul. 2010.
Hu et al., “Discovery of indazoles as inhibitors of Tp12 kinase,” Bioorganic & Medicinal Chemistry Letters, (Aug. 2011) 21(16): 4758-4761.
Huang et al., “Tankyrase inhibition stabilizes axin and antagonizes Wnt signaling,” Nature, (Oct. 2009), 461(7264): 614-620.
Huang et al., “Synthesis of 3-(1H-benzimidazol-2-yl)-5-isoquinolin-4-ylpyrazolo[1,2-b]pyridine, a potent cyclin dependent kinase 1 (CDK1) inhibitor,” Bioorganic & Medicinal Chemistry Letters, (2007) 17(5): 1243-1245.
Hübner et al., “Standardized quantification of pulmonary fibrosis in histological samples,”Biotechniques, 44(4):507-511, 514-517, Apr. 2008.
Im et al., “Wnt inhibitors enhance chondrogenesis of human mesenchymal stem cells in a long-term pellet culture,” Biotechnol Lett., 33(5):1061-1068, Epub Jan. 2011.
Inestrosa and Toledo, “The role of Wnt signaling in neuronal dysfunction in Alzheimer's Disease,” Mol Neurodegener, 3:9, doi:10.1186/1750-1326-3-9, 13 pages, Jul. 2008.
International Preliminary Report on Patentability for International Application No. PCT/US2016/45326, dated Feb. 15, 2018, 6 pages.
International Search Report and Written Opinion for International Application No. PCT/US2016/45326, dated Nov. 16, 2016, 13 pages.
Janssens et al., “The Wnt-dependent signaling pathways as target in oncology drug discovery,” Invest New Drugs., 24(4):263-280, Jul. 2006.
Jenkins et al., “Germline mutations in WTX cause a sclerosing skeletal dysplasia but do not predispose to tumorigenesis,” Nat. Genet. (Jan. 2009), 41(1), 95-100.
Jessen et al., “Peripheral white blood cell toxicity induced by broad spectrum cyclin-dependent kinase inhibitors,” Journal of Applied Toxicology (Jan. 2007), 27(2), 133-142.
Johnson et al., “A stem cell-based approach to cartilage repair,” Science., 336(6082):717-721, Epub Apr. 5, 2012.
Kanazawa et al., “Association of the Gene Encoding Wingless-Type Mammary Tumor Virus Integration-Site Family Member 5B (WNT5B) with Type 2 Diabetes,” Am. J. Hum. Genet. (2004), 75(5), 832-843.
Karlberg et al., “Structural basis for the interaction between tankyrase-2 and a potent Wnt-signaling inhibitor,” J. Med. Chem. (2010), 53(14), 5352-5.
Kibar et al., “Mutations in VANGL1 Associated with Neural-Tube Defects,” N. Engl. J. Med., (Apr. 2007), 356(14):1432-1437.
King et al., “BUILD-3: a randomized, controlled trial of bosentan in idiopathic pulmonary fibrosis,” Am J Respir Crit Care Med., 184(1):92-99, Epub Apr. 2011.
Kishimoto et al: “Wnt/Beta-Catenin Signaling Suppresses Expressions of Ses, Mkx and Tnmd in Tendon-Derived Cells,” Plos One, Jul. 27, 2017, 12(7), E0182051, pp. 1-17.
Kuwajima et al., “Necdin Promotes GABAergic Neuron Differentiation in Cooperation with Dlx Homeodomain Proteins,” Journal of Neuroscience (May 2006), 26(20), 5383-5392.
Lacy et al., “Generation and characterization of ABT-981, a dual variable domain immunoglobulin (DVD-Ig(TM)) molecule that specifically and potently neutralizes both IL-1α and IL-1β,” Mabs, May 2015, 7(3): 605-619.
Lammi et al., “Mutations in AXIN2 Cause Familial Tooth Agenesis and Predispose to Colorectal Cancer,” Am. J. Hum. Genet. (2004), 74(5), 1043-1050.
Leyns et al., “Frzb-1 Is a Secreted Antagonist of Wnt Signaling Expressed in the Spemann Organizer,” Cell (Mar. 1997), 88(6), 747-756.
Li et al., “Artesunate attenuates the growth of human colorectal carcinoma and inhibits hyperactive Wnt/beta-catenin pathway,” Int J Cancer., 121(6):1360-1365, Sep. 2007.
Lin et al., “Synthesis and evaluation of pyrazolo[3,4-b]pyridine CDK1 inhibitors as anti-tumor agents,” Bioorganic & Medicinal Chemistry Letters, (Aug. 2007), 17(15): 4297-4302.
Liu, et.al., “Fibrotic lung fibroblasts show blunted inhibition by cAMP due to deficient cAMP response element-binding protein phosphorylation,” J Pharmacol Exp Ther., 315(2):678-687, Epub Aug. 3, 2005.
Lories et al., “To Wnt or not to Wnt: the bone and joint health dilemma,” Nat Rev Rheumatol., 9(6):328-339, Epub Mar. 2013.
Low et al., “Phenotypic fingerprinting of small molecule cell cycle kinase inhibitors for drug discovery,” Curr Chem Genomics., 3:13-21, Mar. 2009.
Lu et al., “Structure-activity relationship studies of small-molecule inhibitors of Wnt response,” Bioorganic & Medicinal Chemistry Letters, (Jul. 2009), 19(14):3825-3827.
Lui: “Histopathological Changes in Tendinopathypotential Roles of BMPs?” Rheumatology, May 2013, 52:2116-2126.
Luo et al., “Fragile X Mental Retardation Protein Regulates Proliferation and Differentiation of Adult Neural Stem/Progenitor Cells,” PLoS Genetics, (Apr. 2010), 6(4):e1000898, 15 pages.
Luu et al., “Wnt/beta-catenin signaling pathway as a novel cancer drug target,” Curr Cancer Drug Targets., 4(8):653-671, Dec. 2004.
Luyten et al., “Wnt signaling and osteoarthritis,” Bone, 44(4):522-527, Epub Dec. 14, 2008.
MacDonald et al., “Wnt/beta-catenin signaling: components, mechanisms, and diseases,” Dev. Cell (Jul. 2009), 17(1), 9-26.
Mandel et al., “SERKAL Syndrome: An Autosomal-Recessive Disorder Caused by a Loss-of-Function Mutation in WNT4,” Am. J. Hum. Genet., (Jan. 2008), 82(1), 39-47.
Mani, et al., “LRP6 Mutation in a Family with Early Coronary Disease and Metabolic Risk Factors,” Science, (Mar. 2007), 315(5816), 1278-1282.
McBride, et al. “Design and structure-activity relationship of 3-benzimidazol-2-yl-1H-indazoles as inhibitors of receptor tyrosine kinases,” Bioorganic & Medicinal Chemistry Letters (2006), 16(13), 3595-3599.
Misra et al., “1H-Pyrazolo[3,4-b]pyridine inhibitors of cyclin-dependent kinases highly potent 2,6-Difluorophenacyl analogues,” Bioorganic & Medicinal Chemistry Letters, (2003), 13:2405-2408.
Morrisey, “Wnt signaling and pulmonary fibrosis,” Am J Pathol., 162(5):1393-1397, May 2003.
Muddassar et al., “Elucidation of binding mode and three dimensional quantitative structure-activity relationship studies of a novel series of protein kinase B/Akt inhibitors ,” Journal of Molecular Modeling, (2009), 15(2): 183-192.
Niemann et al., “Homozygous WNT3 Mutation Causes Tetra-Amelia in a Large Consanguineous Family,” Am. J. Hum. Genet. (2004), 74(3), 558-563.
Nishisho et al., “Mutations of chromosome 5q21 genes in FAP and colorectal cancer patients,” Science, (Aug. 1991), 253(5020):665-669.
Nusse, “Wnt signaling in disease and in development,” Cell Res., 15(1):28-32, Jan. 2005.
Oates et al., “Increased DNA Methylation at the AXIN1 Gene in a Monozygotic Twin from a Pair Discordant for a Caudal Duplication Anomaly,” Am. J. Hum. Genet. (2006 ), 79(1), 155-162.
Oduor et al., “Trypanosoma bracer glycogen synthase kinase-3, a target for anti-trypanosomal drug development: a public-private partnership to identify novel leads,” PLoS Negl Trop Dis., 5(4):e1017, Apr. 2011.
Okerlund and Cheyette, “Synaptic Wnt signaling-a contributor to major psychiatric disorders?” J Neurodev Disord., (2011) 3(2):162-174.
Parsons et al., “Benzo[d]imidazole Transient Receptor Potential Vanilloid 1 Antagonists for the Treatment of Pain: Discovery of trans-2-(2-{2-[2-(4-Trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phenyl)-propan-2-ol (Mavatrep),” J Med Chem, May 2015, 58(9): 3859-3874.
Piersanti et al., “Synthesis of benzo[1,2-d;3,4-d']diimidazole and 1 H-pyrazolo[4,3-b]pyridine as putative A2A receptor antagonists,” Organic and Biomolecular Chemistry, Aug. 2007, 5(16):2567-2571.
Polakis, “Wnt signaling and cancer,” Genes Dev., 14: 1837-1851, 2000.
Pubchem. Substance Record for SID 164345938. Deposit Date: Nov. 4, 2013. [retrieved on Nov. 16, 2015]. Retrieved from the Internet. <URL: https://pubchem.ncbi.nlm.nih.gov/substance/164345938#section=Top>, 5 pages.
Qin et al. “Complexity of the genotype-phenotype correlation in familial exudative vitreoretinopathy with mutations in the LRP5 and/or FZD4 genes,” Hum. Mutat. (2005), 26(2), 104-112.
Reya and Clevers, “Wnt signalling in stem cells and cancer,” Nature 434: 843-850, Apr. 2005.
Richards et al., “Peripheral blood proteins predict mortality in idiopathic pulmonary fibrosis,” Am J.Respir Crit Care Med., 185(1):67-76, Jan. 2012.
Rivera et al., “An X Chromosome Gene, WTX, Is Commonly Inactivated in Wilms Tumor,” Science, (Feb. 2007), 315(5812):642-645, published online Jan. 4 2007.
Robitaille et al., “Mutant frizzled-4 disrupts retinal angiogenesis in familial exudative vitreoretinopathy,” Nat. Genet., (Sep. 2002), 32(2):326-330.
Rother et al., “Efficacy and safety of epicutaneous ketoprofen in Transfersome (IDEA-033) versus oral celecoxib and placebo in osteoarthritis of the knee: multicentre randomised controlled trial,” Annals of the Rheumatic Diseases, Sep. 2007, 66(9): 1178-1183.
Ryu et al., “Natural derivatives of curcumin attenuate the Wnt/beta-catenin pathway through down-regulation of the transcriptional coactivator p300,” Biochem Biophys Res Commun., 377(4):1304-1308, print Dec. 2008, Epub Nov. 2008.
Salinas, “Wnt signaling in the vertebrate central nervous system: from axon guidance to synaptic function,” Cold Spring Harb Perspect Biol., (2012) 4(2). pii: a008003, 15 pages.
Sato, “Upregulation of the Wnt/beta-catenin pathway induced by transforming growth factor-beta in hypertrophic scars and keloids,” Acta Derm Venereol., 86(4):300-307, 2006.
Seah et al., “Neuronal Death Resulting from Targeted Disruption of the Snf2 Protein ATRX Is Mediated by p53,” Journal of Neuroscience (Nov. 2008), 28(47), 12570-12580.
Shih et al., “Pharmacophore modeling and virtual screening to identify potential RET kinase inhibitors,” Bioorg Med Chem Lett., 21(15):4490-4497, Epub Jun. 2011.
Shruster et al., “Wnt signaling enhances neurogenesis and improves neurological function after focal ischemic injury,” PLoS One, (Jul. 2012), 7(7):e40843, 11 pages.
Silva et al, “Advances in Prodrug Design,” Mini-Revs. In Med. Chem. (2005), 5: 893-914.
Solowiej et al., “Characterizing the Effects of the Juxtamembrane Domain on Vascular Endothelial Growth Factor Receptor-2 Enzymatic Activity, Autophosphorylation, and Inhibition by Axitinib,” Biochemistry, (2009), 48(29), 7019-7031.
Staines et al., “Cartilage development and degeneration: a Wnt situation,” Cell Biochem Funct., 30(8):633-642, Epub Jun. 2012.
Sutherland et al., “A robust high-content imaging approach for probing the mechanism of action and phenotypic outcomes of cell-cycle modulators,” Molecular Cancer Therapeutics, (Feb. 2011), 10(2): 242-254.
Swaney et al., “A novel, orally active LPA(1) receptor antagonist inhibits lung fibrosis in the mouse bleomycin model,” Br J Pharmacol., 160(7):1699-1713, Aug. 2010.
Takahashi-Yanaga et al., “Celecoxib-induced degradation of T-cell factors-1 and -4 in human colon cancer cells,” Biochem Biophys Res Commun., 377(4):1185-1190, print Dec. 2008, Epub Nov. 2008.
Tamamura et al., “Developmental regulation of Wnt/beta-catenin signals is required for growth plate assembly, cartilage integrity, and endochondral ossification,” J Biol Chem., 280(19):19185-95. Epub Mar. 2005.
Thompson et al., “WNT/beta-catenin signaling in liver health and disease,” Hepatology., 45(5):1298-1305, May 2007.
Trujillo et al., “2-(6-Phenyl-1H-indazol-3-yl)-1H-benzo[d]imidazoles: design and synthesis of a potent and isoform selective PKC-zeta inhibitor,” Bioorg Med Chem Lett., 19(3):908-911, Epub Dec. 6, 2008.
Ugur et al., “Homozygous WNT10b mutation and complex inheritance in Split-Hand/Foot Malformation,” Hum. Mol. Genet. (2008), 17(17), 2644-2653.
Vulpetti et al., “Structure-Based Approaches to Improve Selectivity: CDK2-GSK3fβ Binding Site Analysis,” Journal of Chemical Information and Modeling (2005), 45(5), 1282-1290.
Wagner et al., “The therapeutic potential of the Wnt signaling pathway in bone disorders,” Curr Mol Pharmacol., 4(1):14-25, Jan. 2011.
Walters and Kleeberger, “Mouse models of bleomycin-induced pulmonary fibrosis,” Current Protocols in Pharmacology, (2008) Chapter 5: Unit 5.46, 1-17.
Wang, et al., “Mutations in X-linked PORCN, a putative regulator of Wnt signaling, cause focal dermal hypoplasia,” Nat. Genet. (Jul. 2007), 39(7), 836-838.
Wantanabe and Dai, “Winning WNT: race to Wnt signaling inhibitors,” Proc Natl Acad Sci U S A.108(15):5929-5930, Epub Mar. 2011.
Watts et.al., “RhoA signaling modulates cyclin D1 expression in human lung fibroblasts; implications for idiopathic pulmonary fibrosis,” Respir Res., 7:88, Jun. 15, 2006.
Weng et al., “Control of Dkk-1 ameliorates chondrocyte apoptosis, cartilage destruction, and subchondral bone deterioration in osteoarthritic knees,” Arthritis Rheum., 62(5):1393-1402, May 2010.
Witherington et al., “5-Aryl-pyrazolo[3,4-b]pyridazines: potent inhibitors of glycogen synthase kinase-3 (GSK-3),” Bioorganic & Medicinal Chemistry Letters, (May 2003), 13(9):1581-1584.
Woods, S. et al., “Mutations in WNT7A Cause a Range of Limb Malformations, Including Fuhrmann Syndrome and Al-Awadi/Raas-Rothschild/Schinzel Phocomelia Syndrome,” Am. J. Hum. Genet. (Aug. 2006), 79(2), 402-408.
Yardy and Brewster, “Wnt signalling and prostate cancer,” Prostate Cancer Prostatic Dis, 8(2):119-126, 2005.
Zhang et al., “Small-molecule synergist of the Wnt/beta-catenin signaling pathway,” Proc Natl Acad.Sci U S A., 104(18):7444-7448, Epub Apr. 2007 and correction 104(30):12581, Jul. 2007.
Zhong et al., “Characterization of in vitro and in vivo metabolism of AG-024322, a novel cyclin-dependent kinase (CDK) inhibitor,” Health (2009), 1(4): 249-262.
Zhu et al. “Design and synthesis of pyridine-pyrazolopyridine-based inhibitors of protein kinase B/Akt,” Bioorganic & Medicinal Chemistry, Mar. 2007, 15(6):2441-2452.
U.S. Appl. No. 12/852,681, filed Aug. 9, 2010, Hood et al.
U.S. Appl. No. 12/968,505, filed Dec. 15, 2010, Hood et al.
U.S. Appl. No. 13/855,874, filed Apr. 3, 2013, Hood et al.
U.S. Appl. No. 13/938,692, filed Jul. 10, 2013, Hood et al.
U.S. Appl. No. 14/331,427, filed Jul. 15, 2014, Hood et al.
U.S. Appl. No. 14/465,056, filed Aug. 21, 2014, Hood et al.
U.S. Appl. No. 14/718,354, filed May 21, 2015, Hood et al.
U.S. Appl. No. 15/244,687, filed Aug. 23, 2016, Hood et al.
U.S. Appl. No. 15/812,629, filed Nov. 14, 2017, Hood et al.
U.S. Appl. No. 12/852,706, filed Aug. 9, 2010, Hood et al.
U.S. Appl. No. 13/552,188, filed Jul. 18, 2012, Hood et al.
U.S. Appl. No. 13/938,691, filed Jul. 10, 2013, Hood et al.
U.S. Appl. No. 14/019,103, filed Sep. 5, 2013, Hood et al.
U.S. Appl. No. 14/334,005, filed Jul. 17, 2014, Hood et al.
U.S. Appl. No. 14/741,645, filed Jun. 17, 2016, Hood et al.
U.S. Appl. No. 15/184,553, filed Jun. 16, 2016, Hood et al.
U.S. Appl. No. 15/681,035, filed Aug. 18, 2017, Hood et al.
U.S. Appl. No. 13/614,296, filed Sep. 13, 2012, Hood et al.
U.S. Appl. No. 14/019,229, filed Sep. 5, 2013, Hood et al.
U.S. Appl. No. 14/940,958, filed Nov. 13, 2015, Hood et al.
U.S. Appl. No. 15/709,057, filed Sep. 19, 2017, Hood et al.
U.S. Appl. No. 13/800,963, filed Mar. 13, 2013, Hood et al.
U.S. Appl. No. 14/019,940, filed Sep. 6, 2013, Hood et al.
U.S. Appl. No. 14/178,749, filed Feb. 12, 2014, Hood et al.
U.S. Appl. No. 14/621,195, filed Feb. 12, 2015, Hood et al.
U.S. Appl. No. 14/939,434, filed Nov. 12, 2015, Hood et al.
U.S. Appl. No. 13/887,177, filed May 3, 2013, Hood et al.
U.S. Appl. No. 14/019,147, filed Sep. 5, 2013, Hood et al.
U.S. Appl. No. 14/454,279, filed Aug. 7, 2014, Hood et al.
U.S. Appl. No. 14/621,222, filed Feb. 12, 2015, Hood et al.
U.S. Appl. No. 14/962,681, filed Dec. 8, 2015, Hood et al.
U.S. Appl. No. 15/420,398, filed Jan. 31, 2017, Hood et al.
U.S. Appl. No. 14/149,948, filed Jan. 8, 2014, Kumar KC et al.
U.S. Appl. No. 15/889,403, filed Feb. 6, 2018, Kumar KC et al.
U.S. Appl. No. 14/847,259, filed Sep. 8, 2015, Kumar KC et al.
U.S. Appl. No. 15/298,346, filed Oct. 20, 2016, Kumar KC et al.
U.S. Appl. No. 15/716,803, filed Sep. 27, 2017, Kumar KC et al.
U.S. Appl. No. 14/847,336, filed Sep. 8, 2015, Kumar KC et al.
U.S. Appl. No. 15/661,231, filed Jul. 27, 2017, Kumar KC et al.
U.S. Appl. No. 14/847,299, filed Sep. 8, 2015, Kumar KC et al.
U.S. Appl. No. 15/591,566, filed May 10, 2017, Kumar KC et al.
U.S. Appl. No. 14/847,287, filed Sep. 8, 2015, Kumar KC et al.
U.S. Appl. No. 15/363,086, filed Nov. 29, 2016, Kumar KC et al.
U.S. Appl. No. 15/808,602, filed Nov. 9, 2017, Kumar KC et al.
U.S. Appl. No. 14/847,344, filed Sep. 8, 2015, Kumar KC et al.
U.S. Appl. No. 15/257,398, filed Sep. 6, 2016, Kumar KC et al.
U.S. Appl. No. 15/673,834, filed Aug. 10, 2017, Kumar KC et al.
U.S. Appl. No. 14/847,394, filed Sep. 8, 2015, Kumar KC et al.
U.S. Appl. No. 15/357,494, filed Nov. 21, 2016, Kumar KC et al.
U.S. Appl. No. 15/716,894, filed Sep. 27, 2017, Kumar KC et al.
U.S. Appl. No. 14/847,371, filed Sep. 8, 2015, Kumar KC et al.
U.S. Appl. No. 15/267,939, filed Sep. 16, 2016, Kumar KC et al.
U.S. Appl. No. 15/843,818, filed Dec. 15, 2017, Kumar KC et al.
U.S. Appl. No. 14/847,379, filed Sep. 8, 2015, Kumar KC et al.
U.S. Appl. No. 15/668,992, filed Aug. 4, 2017, Kumar KC et al.
U.S. Appl. No. 15/749,587, filed Feb. 1, 2018, Kumar KC et al.
U.S. Appl. No. 15,749,586, filed Feb. 1, 2018, Kumar KC et al.
U.S. Appl. No. 15/749,592, filed Feb. 1, 2018, Kumar KC et al.
U.S. Appl. No. 15/749,608, filed Feb. 1, 2018, Kumar KC et al.
U.S. Appl. No. 15/749,701, filed Feb. 1, 2018, Kumar KC et al.
U.S. Appl. No. 15/749,706, filed Feb. 1, 2018, Kumar KC et al.
U.S. Appl. No. 15/749,713, filed Feb. 1, 2018, Kumar KC et al.
U.S. Appl. No. 15/749,718, filed Feb. 1, 2018, Kumar KC et al.
U.S. Appl. No. 15/749,721, filed Feb. 1, 2018, Kumar KC et al.
U.S. Appl. No. 15/749,741, filed Feb. 1, 2018, Kumar KC et al.
U.S. Appl. No. 15/749,727, filed Feb. 1, 2018, Kumar KC et al.
U.S. Appl. No. 15/749,739, filed Feb. 1, 2018, Kumar KC et al.
U.S. Appl. No. 15/749,737, filed Feb. 1, 2018, Kumar KC et al.
U.S. Appl. No. 15/749,742, filed Feb. 2, 2018, Kumar KC et al.
U.S. Appl. No. 15/749,868, filed Feb. 2, 2018, Kumar KC et al.
U.S. Appl. No. 15/749,929, filed Feb. 2, 2018, Kumar KC et al.
U.S. Appl. No. 15/749,910, filed Feb. 2, 2018, Kumar KC et al.
U.S. Appl. No. 15/749,923, filed Feb. 2, 2018, Kumar KC et al.
U.S. Appl. No. 15/749,922, filed Feb. 2, 2018, Kumar KC et al.
U.S. Appl. No. 15/611,150, filed Jun. 1, 2017, Kumar KC.
U.S. Appl. No. 15/806,321, filed Nov. 7, 2017, Dellamary.
U.S. Appl. No. 15/790,544, filed Oct. 23, 2017, Deshmukh.
Ai et al., “Optimal Method to Stimulate Cytokine Producti on and Its Use in Immunotoxicity Assessment,” Int J Environ Res Public Health, Sep. 2013, 10(9):3834-3842.
Chanput et.al., “Transcription profiles of LPS-stimulated THP-1 monocytes and macrophages: a tool to study inflammation modulating effects of food-derived compounds,” Food Funct, Dec. 2010, 1(3):254-61.
clinicaltrials.gov' [online]. ClinicalTrials.gov Identifier: NCT02095548, “Phase 1, Dose Escalation Study Evaluating the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of SM04690 in Moderate to Severe Knee Osteoarthritis (OA),” Mar. 26, 2014, [retreived on Aug. 1, 2018]. Retreived from the Internet: URL<https://clinicaltrials.gov/ct2/show/NCT02095548?term=NCT02095548&rank=1>, 7 pages.
clinicaltrials.gov' [online]. ClinicalTrials.gov Identifier: NCT02536833, “A Study Evaluating the Safety, Tolerability, and Efficacy of SM04690 Injected in the Target Knee Joint of Moderately to Severely Symptomatic Osteoarthritis Subjects,” Sep. 1, 2015, [retrieved on Aug. 1, 2018]. Retrieved from the Internet: URL<https://clinicaltrials.gov/ct2/show/NCT02536833?term=NCT02536833&rank=1>, X pages.
Gitter et al., “Characteristics of human synovial fibroblast activation by IL-1 beta and TNF alpha,”Immunology, Feb. 1989, 66(2):196-200.
Gunther et al., “Prevalence of generalised osteoarthritis in patients with advanced hip and knee osteoarthritis: the Ulm Osteoarthritis Study,” Ann. Rheum. Dis., Dec. 1998, 57(12):717-723.
Ikejima et al., “Interleukin-1 induces tumor necrosis factor (TNF) in human peripheral blood mononuclear cells in vitro and a circulating TNF-like activity in rabbits,” J Infect Dis, Jul. 1990, 162(1):215-23.
Monner et al., “Induction of lymphokine synthesis in peripheral blood mononuclear cells with phorbol ester and calcium ionophore allows precise measurement of individual variations in capacity to produce IL 2,” Lymphokine Res. 1986;5 Suppl 1:S67-73.
Ngkelo et. al., “LPS induced inflammatory responses in human peripheral blood mononuclear cells is mediated through NOX4 and Gia dependent PI-3 kinase signaling,” Journal of Inflammation, Dec. 2012, 9(1):1, 7 pages.
Park et. al., “Optimized THP-1 differentiation is required for the detection of responses to weak stimuli,” Inflamm Res, Jan. 2007, 56(1):45-50.
Pritzker et al., “Osteoarthritis cartilage histopathology: grading and staging,” Osteoarthr. Cartil., Jan. 2006, 14(1):13-29.
Sperber et al., “Cytokine secretion induced by superantigens in peripheral blood mononuclear cells, lamina propria lymphocytes, and intraepithelial lymphocytes,” Clin Diagn Lab Immunol, Jul. 1995, 2(4):473-477.
Adult Brain Tumors Treatment, National Cancer Institute, pp. 1-21 (Jan. 24, 2013), 21 pages.
Barroga et al., “Discovery of an Intra-Articular Injection Small Molecule Inhibitor of the Wnt Pathway (SM04690) As a Potential Disease Modifying Treatment for Knee Osteoarthritis,” 2015 ACR/ARHP Annual Meeting, Abst. No. 2007, Sep. 29, 2015, retrieved on Sep. 27, 2018, URL <https://acrabstracts.org/abstract/discovery-of-an-intra-articular-injection-small-molecule-inhibitor-of-the-wnt-pathway-sm04690-as-a-potential-disease-modifying-treatment-for-knee-osteoarthritis/>, 3 pages.
Bass, “Why the difference between tendinitis and tendinosis matters,” International Journal of Therapeutic Massage and Bodywork, vol. 5, No. 1, Mar. 2012.
Bone fractures—https://my.clevelandclinic.org/health/diseases/15241-bone-fractures—Jun. 2018, 5 pages.
Cancer definition in MedicineNet.com—2005, 1 page.
Cancer Drug Design and Discovery Neidle, Stephen, ed. (Elsevier/Academic Press, 2008), 5 pages.
Deshmukh et al., “A small-molecule inhibitor of the Wnt pathway (SM04690) as a potential disease modifying agent for the treatment of osteoarthritis of the knee,” Osteoarthritis and Cartilage, Jan. 2018, 26(1):18-27.
Enzo et al., “The Wnt/β-catenin pathway in human fibrotic-like diseases and its eligibility as a therapeutic target,” Molecular and Cellular Therapies, 2015, 3(1), 13 pages.
Forestier et al., “Prevalence of generalized osteoarthritis in a population with knee osteoarthritis,” Joint Bone Spine, May 2011, 78(3):275-278.
GastricMALTLynnphonna-LynnphonnaAssociation—2011, 10 pages.
Hayami et al., “Characterization of articular cartilage and subchondral bone changes in the rat anterior cruciate ligament transection and meniscectomized models of osteoarthritis,” Bone, Feb. 2006, 38(2):234-243.
Lala and Orucevic, “Role of nitric oxide in tumor progression: lessons from experimental tumors,” Cancer and Metastasi Review, vol. 17, Mar. 1998, pp. 91-106.
MedlinePlus, [online] “Cancer,” [retrieved on Jul. 6, 2007]. Retrieved from the internet, URL http://www.nInn.nih.govinnedlineplus/cancer.html>.
Osteoarthritis, https://www.rnayoclinic.org/diseases-conditions/osteoarthritis/diagnosis-treatment/drc-20351930—Sep. 2018, 8 pages.
Exhibit A: Otsuka Pharmaceutical Co., Ltd., v. Sandoz, Inc., Sun Pharmaceutical Industries, Ltd., Synton BV, Synthon Holding BV, Synthon Laboratories, Inc., and Synton Pharmaceuticals, Inc., and Apo l'Ex Inc. and Apotex Corp., and Teva Pharmaceuticals Usa, Inc., Barr Laboratories, Inc., and Barr Pharmaceuticals, Inc., Decision on Appeal, 2011-1126, -1127, May 7, 2012, 33 pages.
Patani and Lavoie, “Bioisosterism: A Rational Approach in Drug Design,” Chem. Rev, Jul. 25, 1996, vol. 96, p. 3147-3176.
stomach cancer—Mayoclinic.com—Apr. 9, 2011, 8 pages.
Types of Brain Cancer at http://www.cancercenter.corn/brain-cancer/types-of-brain-cancer.cfrn (Mar. 12, 2013), 3 pages.
Types of Breast Cancer, published in breastcancer.org (Sep. 30, 2012), 1 page.
Yazici et al., “Abstract #: 312: Safety, Efficacy and Biomarker Outcomes of a Novel, Intra-Articular, Injectable, Wnt Inhibitor (SM04690) in the Treatment of Osteoarthritis of the Knee: Interim, Exploratory Analysis of Results from a Randomized, Double-Blind, Placebo-Controlled Phase 1 Study,” Poster, Presented at 2015 ACR/American College of Rheumatology Annual Meeting, San Francisco CA, Nov. 6-11, 2015; Arthritis Rheumatol. 2015; 67 (suppl 10): 1 page.
Yazici et al., “Abstract #: 313: Magnetic Resonance Imaging Outcomes Using an Intra-Articular Injection (SM04690) in the Treatment of Osteoarthritis of the Knee: Interim, Exploratory Analysis of Results from a Randomized, Double-Blind, Placebo-Controlled, Phase 1 Study,” Poster, Presented at 2015 ACR/American College of Rheumatology Annual Meeting, San Francisco CA, Nov. 6-11, 2015; Arthritis Rheumatol. 2015; 67 (suppl 10): 1 page.
U.S. Appl. No. 15/968,555, filed May 1, 2018, Hood et al.
U.S. Appl. No. 16/015,996, filed Jun. 22, 2018, Kumar KC et al.
U.S. Appl. No. 15/773,951, filed May 4, 2018, Hood et al.
U.S. Appl. No. 15/773,737, filed May 4, 2018, Hood et al.

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3-(1h-pyrrolo[2,3-b]pyridin-2-yl)-1h-indazoles and therapeutic uses thereof

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