Indazoles and azaindazoles as LRRK2 inhibitors

FIELD OF THE INVENTION

The present invention is directed to indazole and azaindazole compounds which are inhibitors of LRRK2 and are useful in the treatment of CNS disorders.

BACKGROUND OF THE INVENTION

Parkinson's disease (“PD”) is the most common form of parkinsonism, a movement disorder, and the second most common, age-related neurodegenerative disease estimated to affect 1-2% of the population over age 65. PD is characterized by tremor, rigidity, postural instability, impaired speech, and bradykinesia. It is a chronic, progressive disease with increasing disability and diminished quality of life. In addition to PD, parkinsonism is exhibited in a range of conditions such as progressive supranuclear palsy, corticobasal degeneration, multiple system atrophy, and dementia with Lewy bodies.

Current therapeutic strategies for PD are primarily palliative and focus on reducing the severity of symptoms using supplemental dopaminergic medications. At present, there is no disease-modifying therapy that addresses the underlying neuropathological cause of the disease, thus constituting a significant unmet medical need.

It has long been known that family members of PD patients have an increased risk of developing the disease compared to the general population. Leucine-rich repeat kinase 2 (“LRRK2,” also known as dardarin) is a 286 kDa multi-domain protein that has been linked to PD by genome-wide association studies. LRRK2 expression in the brain is highest in areas impacted by PD (Eur. J. Neurosci. 2006, 23(3):659) and LRRK2 has been found to localize in Lewy Bodies, which are intracellular protein aggregates considered to be a hallmark of the disease. Patients with point mutations in LRRK2 present disease that is nearly indistinguishable from idiopathic patients. While more than 20 LRRK2 mutations have been associated with autosomal-dominantly inherited parkinsonism, the G2019S mutation located within the kinase domain of LRRK2 is by far the most common. This particular mutation is found in >85% of LRRK2-linked PD patients. It has been shown that the G2019S mutation in LRRK2 leads to an enhancement in LRRK2 kinase activity and inhibition of this activity is a therapeutic target for the treatment of PD.

In addition to PD, LRRK2 has been linked to other diseases such as cancer, leprosy, and Crohn's disease (Sci. Signal., 2012, 5(207), pe2). As there are presently limited therapeutic options for treating PD and other disorders associated with aberrant LRRK2 kinase activity, there remains a need for developing LRRK2 inhibitors.

SUMMARY OF THE INVENTION

The present invention is directed to a compound of Formula I:

embedded image

or a pharmaceutically acceptable salt thereof, wherein constituent members are defined herein.

The present invention is further directed to a pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

The present invention is further directed to a method of inhibiting LRRK2 activity, comprising contacting a compound of Formula I, or a pharmaceutically acceptable salt thereof, with LRRK2.

The present invention is further directed to a method of treating a disease or disorder associated with elevated expression or activity of LRRK2, or a functional variant thereof, said method comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof.

The present invention is further directed to a method for treating a neurodegenerative disease in a patient comprising administering to the patient a therapeutically effective amount of the compound of Formula I, or a pharmaceutically acceptable salt thereof.

The present invention is further directed to a compound of Formula I, or a pharmaceutically acceptable salt thereof, for use in therapy.

The present invention is further directed to a use of a compound of Formula I, or a pharmaceutically acceptable salt thereof, for the preparation of a mediciment for use in therapy.

DETAILED DESCRIPTION

The present invention is directed to an inhibitor of LRRK2 which is a compound of Formula I:

embedded image

or a pharmaceutically acceptable salt thereof, wherein:

A is Cy¹, Cy¹-C_1-4alkyl-, Cy¹-C_2-4alkenyl-, Cy¹-C_2-4alkynyl-, halo, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, CN, NO₂, OR^a, SR^a, C(O)R^b, C(O)NR^cR^d, C(O)OR^a, OC(O)R^b, OC(O)NR^cR^d, C(═NR^e)NR^cR^d, NR^cC(═NR^e)NR^cR^d, NR^cR^d, NR^cC(O)R^b, NR^cC(O)OR^a, NR^cC(O)NR^cR^d, NR^cS(O)R^b, NR^cS(O)₂R^b, NR^cS(O)₂NR^cR^d, S(O)R^b, S(O)NR^cR^d, S(O)₂R^b, S(O)₂NR^cR^d, or P(O)R^cR^d; wherein said C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, and C_1-6haloalkyl of A are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, CN, NO₂, OR^a, SR^a, C(O)R^b, C(O)NR^cR^d, C(O)OR^a, OC(O)R^b, OC(O)NR^cR^d, C(═NR^e)NR^cR^d, NR^cC(═NR^e)NR^cR^d, NR^cR^d, NR^cC(O)R^b, NR^cC(O)OR^a, NR^cC(O)NR^cR^d, NR^cS(O)R^b, NR^cS(O)₂R^b, NR^cS(O)₂NR^cR^d, S(O)R^b, S(O)NR^cR^d, S(O)₂R^b, S(O)₂NR^cR^d, and P(O)R^cR^d;

Ring B is phenyl or 5-10 membered heteroaryl, wherein said 5-10 membered heteroaryl comprises 1, 2, or 3 ring-forming heteroatoms independently selected from N, O, and S;

X²is N or CR²;

X³is N or CR³;

X⁴is N or CR⁴; wherein not more than two of X², X³, and X⁴are simultaneously N;

Cy¹is selected from C_6-10aryl, C_3-10cycloalkyl, 5-14 membered heteroaryl, and 4-14 membered heterocycloalkyl, each optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, C_6-10aryl, C_3-10cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C_6-10aryl-C_1-4alkyl, C_3-7cycloalkyl-C_1-4alkyl, 5-10 membered heteroaryl-C_1-4alkyl, 4-10 membered heterocycloalkyl-C_1-4alkyl, CN, NO₂, OR^a, SR^a, C(O)R^b, C(O)NR^cR^d, C(O)OR^a, OC(O)R^b, OC(O)NR^cR^d, NR^cR^d, CC(O)R^b, NR^cC(O)OR^a, N^cC(O)NR^cR^d, C(═NR^e)R^b, C(═NR^e)NR^cR^d, NR^cC(═NR^e)NR^cR^d, NR^cS(O)R^b, NR^cS(O)₂R^b, NR^cS(O)₂NR^cR^d, S(O)R^b, S(O)NR^cR^d, S(O)₂R^b, and S(O)₂NR^cR^d, wherein said substituents C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, C_6-10aryl, C_3-10cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C_6-10aryl-C_1-4alkyl, C_3-7cycloalkyl-C_1-4alkyl, 5-10 membered heteroaryl-C_1-4alkyl, 4-10 membered heterocycloalkyl-C_1-4alkyl are each optionally substituted by 1, 2, or 3 further substituents independently selected from halo, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, CN, NO₂, OR^a, SR^a, C(O)R^b, C(O)NR^cR^d, C(O)OR^a, OC(O)R^b, OC(O)NR^cR^d, N^cR^d, NR^cC(O)R^b, NR^cC(O)OR^a, NR^cC(O)NR^cR^d, C(═NR^e)R^b, C(═NR^e)NR^cR^d, NR^cC(═NR^e)NR^cR^d, NR^cS(O)R^b, NR^cS(O)₂R^b, NR^cS(O)₂NR^cR^d, S(O)R^b, S(O)NR^cR^d, S(O)₂R^b, and S(O)₂NR^cR^d;

each R¹is independently selected from H, halo, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, C_6-10aryl, C_3-7cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C_6-10aryl-C_1-4alkyl, C_3-7cycloalkyl-C_1-4alkyl, 5-10 membered heteroaryl-C_1-4alkyl, 4-10 membered heterocycloalkyl-C_1-4alkyl, CN, NO₂, OR^a1, SR^a1, C(O)R^b1, C(O)NR^c1R^d1, C(O)OR^a1, OC(O)R^b1, OC(O)NR^c1R^d1, N^c1R^d1, NR^c1C(O)R^b1, NR^c1C(O)OR^a1, NR^c1C(O)NR^c1R^d1, C(═NR^e1)R^b1, C(═NR^e1)NR^c1R^d1, NR^c1C(═NR^e)NR^c1R^d1, NR^c1S(O)R^b1, NR^c1S(O)₂R^b1, NR^c1S(O)₂NR^c1R^d1, S(O)R^b1, S(O)NR^c1R^d1, S(O)₂R^b1, and S(O)₂NR^c1R^d1; wherein said C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, C_6-10aryl, C_3-7cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C_6-10aryl-C_1-4alkyl, C_3-7cycloalkyl-C_1-4alkyl, 5-10 membered heteroaryl-C_1-4alkyl, and 4-10 membered heterocycloalkyl-C_1-4alkyl of R¹are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, CN, NO₂, OR^a1, SR^a1, C(O)R^b1, C(O)NR^c1R^d1, C(O)OR^a1, OC(O)R^b1, OC(O)NR^c1R^d1, C(═NR^e1)NR^c1R^d1, NR^c1C(═NR^e1)NR^c1R^d1, NR^c1R^d1, NR^c1C(O)R^b1, NR^c1C(O)OR^a1, NR^c1C(O)NR^c1R^d1, NR^c1S(O)R^b1, NR^c1S(O)₂R^b1, NR^c1S(O)₂NR^c1R^d1, S(O)R^b1, S(O)NR^c1R^d1, S(O)₂R^b1, and S(O)₂NR^c1R^d1;

or two R¹groups together with the atoms to which they are attached form a C_5-7cycloalkyl group which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, CN, NO₂, OR^a1, SR^a1, C(O)R^b1, C(O)NR^c1R^d1, C(O)OR^a1, OC(O)R^b1, OC(O)NR^c1R^d1, C(═NR^e1)NR^c1R^d1, NR^c1C(═NR^e1)NR^c1R^d1, NR^c1R^d1, NR^c1C(O)R^b1, NR^c1C(O)OR^a1, NR^c1C(O)NR^c1R^d1, NR^c1S(O)R^b1, NR^c1S(O)₂R^b1, NR^c1S(O)₂NR^c1R^d1, S(O)R^b1, S(O)NR^c1R^d1, S(O)₂R^b1, and S(O)₂NR^c1R^d1;

R²and R⁴are each independently selected from H, halo, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, C_6-10aryl, C_3-7cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C_6-10aryl-C_1-4alkyl, C_3-7cycloalkyl-C_1-4alkyl, 5-10 membered heteroaryl-C_1-4alkyl, 4-10 membered heterocycloalkyl-C_1-4alkyl, CN, NO₂, OR^a2, SR^a2, C(O)R^b2, C(O)NR^c2R^d2, C(O)OR^a2, OC(O)R^b2, OC(O)NR^c2R^d2, NR^c2R^d2, NR^c2C(O)R^b2, NR^c2C(O)OR^a2, NR^c2C(O)NR^c2R^d2, C(═NR^e2)R^b2, C(═NR^e2)NR^c2R^d2, NR^c2C(═NR^e2)NR^c2R^d2, NR^c2S(O)R^b2, NR^c2S(O)₂R^b2, NR^c2S(O)₂NR^c2R^d2, S(O)R^b2, S(O)NR^c2R^d2, S(O)₂R^b2and S(O)₂NR^c2R^d2, wherein said C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, C_6-10aryl, C_3-7cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C_6-10aryl-C_1-4alkyl, C_3-7cycloalkyl-C_1-4alkyl, 5-10 membered heteroaryl-C_1-4alkyl, and 4-10 membered heterocycloalkyl-C_1-4alkyl of R²and R⁴are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, CN, NO₂, OR^a2, SR^a2, C(O)R^b2, C(O)NR^c2R^d2, C(O)OR^a2, OC(O)R^b2, OC(O)NR^c2R^d2, NR^c2R^d2, NR^c2C(O)R^b2, NR^c2C(O)OR^a2, NR^c2C(O)NR^c2R^d2, C(═NR^e2)R^b2, C(═NR^e2)NR^c2R^d2, NR^c2C(═NR^e2)NR^c2R^d2, NR^c2S(O)R^b2, NR^c2S(O)₂R^b2, NR^c2S(O)₂NR^c2R^d2, S(O)R^b2, S(O)NR^c2R^d2, S(O)₂R^b2, and S(O)₂NR^c2R^d2;

R³is selected from H, halo, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, C_3-4cycloalkyl, CN, NO₂, OR^a3, SR^a3, C(O)R^b3, C(O)NR^c3R^d3, C(O)OR^a3, OC(O)R^b3, OC(O)NR^c3R^d3, NR^c3R^d3, NR^c3C(O)R^b3, NR^c3C(O)OR^a3, NR^c3C(O)NR^c3R^d3, C(═NR^e3)R^b3, C(═NR^c3)NR^c3R^d3, NR^c3C(═NR^e3)NR^c3R^d3, NR^c3S(O)R^b3, NR^c3S(O)₂R^b3, NR^c3S(O)₂NR^c3R^d3, S(O)R^b3, S(O)NR^c3R^d3, S(O)₂R^b3, and S(O)₂NR^c3R^d3, wherein said C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, and C_3-4cycloalkyl of R³are each optionally substituted with 1, 2, or 3 substituents independently selected from halo, C_1-4alkyl, CN, NO₂, OR^a3, SR^a3, C(O)R^b3, C(O)NR^c3R^d3, C(O)OR^a3, OC(O)R^b3, OC(O)NR^c3R^d3, NR^c3R^d3, NR^c3C(O)R^b3, NR^c3C(O)OR^a3, NR^c3C(O)NR^c3R^d3, C(═NR^e3)R^b3, C(═NR^e3)NR^c3R^d3, NR^c3C(═NR^e3)NR^c3R^d3, NR^c3S(O)R^b3, NR^c3S(O)₂R^b3, NR^c3S(O)₂NR^c3R^d3, S(O)R^b3, S(O)NR^c3R^d3, S(O)₂R^b3, and S(O)₂NR^c3R^d3;

each R^a, R^b, R^c, R^d, R^a1, R^b1, R^c1, R^d1, R^a2, R^b2, R^c2, R^d2is independently selected from H, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C_6-10aryl, C_3-7cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C_6-10aryl-C_1-4alkyl, C_3-7cycloalkyl-C_1-4alkyl, 5-10 membered heteroaryl-C_1-4alkyl, and 4-10 membered heterocycloalkyl-C_1-4alkyl, wherein said C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_6-10aryl, C_3-7cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C_6-10aryl-C_1-4alkyl, C_3-7cycloalkyl-C_1-4alkyl, 5-10 membered heteroaryl-C_1-4alkyl, and 4-10 membered heterocycloalkyl-C_1-4alkyl of R^a, R^b, R^c, R^d, R^a1, R^b1, R^c1, R^d1, R^a2, R^b2, R^c2, and R^d2is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C_1-4alkyl, C_1-4haloalkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, CN, OR^a3, SR^a3, C(O)R^b3, C(O)NR^c3R^d3, C(O)OR^a3, OC(O)R^b3, OC(O)NR^c3R^d3, NR^c3R^d3, NR^c3C(O)R^b3, NR^c3C(O)NR^c3R^d3, NR^c3C(O)OR^a3, C(═NR^e3)NR^c3R^d3, NR^c3C(═NR^e3)NR^c3R^d3, S(O)R^b3, S(O)NR^c3R^d3, S(O)₂R^b3, NR^c3S(O)₂R^b3, NR^c3S(O)₂NR^c3R^d3and S(O)₂NR^c3R^d3;

each R^a3, R^b3, R^c3, and R^d3is independently selected from H, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C_6-10aryl, C_3-7cycloalkyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl, wherein said C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C_6-10aryl, C_3-7cycloalkyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl are each optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C_1-6alkyl, C_1-6alkoxy, C_1-6haloalkyl, and C_1-6haloalkoxy;

each R^e, R^e1, R^e2, and R^e3is independently selected from H, C_1-4alkyl, and CN; and

n is 0, 1, 2, or 3;

wherein when X²is CR², X³is CR³; and X⁴is CR⁴, then A is other than —C(═O)OH or —C(═O)OCH₃; and

wherein the compound is other than:

embedded image

The present invention is directed to an inhibitor of LRRK2 which is a compound of Formula I:

embedded image

or a pharmaceutically acceptable salt thereof, wherein:

A is Cy¹, Cy¹-C_1-4alkyl-, halo, C_1-6alkyl, C_2-6alkenyl, C_2-6, alkynyl, C_1-6haloalkyl, CN, NO₂, OR^a, SR^a, C(O)R^b, C(O)NR^cR^d, C(O)OR^a, OC(O)R^b, OC(O)NR^cR^d, C(═NR^e)NR^cR^d, NR^cC(═NR^e)NR^cR^d, NR^cR^d, NR^cC(O)R^b, NR^cC(O)OR^a, NR^cC(O)NR^cR^d, NR^cS(O)R^b, NR^cS(O)₂R^b, NR^cS(O)₂NR^cR^d, S(O)R^b, S(O)NR^cR^d, S(O)₂R^b, and S(O)₂NR^cR^d; wherein said C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, and C_1-6haloalkyl of A are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, C_3-7cycloalkyl, CN, NO₂, OR^a, SR^a, C(O)R^b, C(O)NR^cR^d, C(O)OR^a, OC(O)R^b, OC(O)NR^cR^d, C(═NR^e)NR^cR^d, NR^cC(═NR^e)NR^cR^d, NR^cR^d, NR^cC(O)R^b, NR^cC(O)OR^a, NR^cC(O)NR^cR^d, NR^cS(O)R^b, NR^cS(O)₂R^b, NR^cS(O)₂NR^cR^d, S(O)R^b, S(O)NR^cR^d, S(O)₂R^b, and S(O)₂NR^cR^d;

Ring B is phenyl or 5-10 membered heteroaryl, wherein said 5-10 membered heteroaryl comprises 1, 2, or 3 ring-forming heteroatoms independently selected from N, O, and S;

X²is N or CR²;

X³is N or CR³;

X⁴is N or CR⁴; wherein not more than two of X², X³, and X⁴are simultaneously N;

Cy¹is selected from C_6-10aryl, C_3-10cycloalkyl, 5-14 membered heteroaryl, and 4-14 membered heterocycloalkyl, each optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, C_6-10aryl, C_3-10cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C_6-10aryl-C_1-4alkyl, C_3-7cycloalkyl-C_1-4alkyl, 5-10 membered heteroaryl-C_1-4alkyl, 4-10 membered heterocycloalkyl-C_1-4alkyl, CN, NO₂, OR^a, SR^a, C(O)R^b, C(O)NR^cR^d, C(O)OR^a, OC(O)R^b, OC(O)NR^cR^d, NR^cR^d, NR^cC(O)R^b, NR^cC(O)OR^a, NR^cC(O)NR^cR^d, C(═NR^e)R^b, C(═NR^e)NR^cR^d, NR^cC(═NR^e)NR^cR^d, NR^cS(O)R^b, NR^cS(O)₂R^b, NR^cS(O)₂NR^cR^d, S(O)R^b, S(O)NR^cR^d, S(O)₂R^b, and S(O)₂NR^cR^d, wherein said substituents C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, C_6-10aryl, C_3-10cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C_6-10aryl-C_1-4alkyl, C_3-7cycloalkyl-C_1-4alkyl, 5-10 membered heteroaryl-C_1-4alkyl, 4-10 membered heterocycloalkyl-C_1-4alkyl are each optionally substituted by 1, 2, or 3 further substituents independently selected from halo, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, CN, NO₂, OR^a, SR^a, C(O)R^b, C(O)NR^cR^d, C(O)OR^a, OC(O)R^b, OC(O)NR^cR^d, NR^cR^d, NR^cC(O)R^b, NR^cC(O)OR^a, NR^cC(O)NR^cR^d, C(═NR^e)R^b, C(═NR^e)NR^cR^d, NR^cC(═NR^e)NR^cR^d, NR^cS(O)R^b, NR^cS(O)₂R^b, NR^cS(O)₂NR^cR^d, S(O)R^b, S(O)NR^cR^d, S(O)₂R^b, and S(O)₂NR^cR^d.

each R¹is independently selected from H, halo, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, C_6-10aryl, C_3-7cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C_6-10aryl-C_1-4alkyl, C_3-7cycloalkyl-C_1-4alkyl, 5-10 membered heteroaryl-C_1-4alkyl, 4-10 membered heterocycloalkyl-C_1-4alkyl, CN, NO₂, OR^a1, SR^a1, C(O)R^b1, C(O)NR^c1R^d1, C(O)OR^a1, OC(O)R^b1, OC(O)NR^c1R^d1, NR^c1R^d1, NR^c1C(O)R^b1, NR^c1C(O)OR^a1, NR^c1C(O)NR^c1R^d1, C(═NR^e1)R^b1, C(═NR^e1)NR^c1R^d1, NR^c1C(═NR^e1)NR^c1R^d1, NR^c1S(O)R^b1, NR^c1S(O)₂R^b1, NR^c1S(O)₂NR^c1R^d1, S(O)R^b1, S(O)NR^c1R^d1, S(O)₂R^b1, and S(O)₂NR^c1R^d1; wherein said C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, C_6-10aryl, C_3-7cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C_6-10aryl-C_1-4alkyl, C_3-7cycloalkyl-C_1-4alkyl, 5-10 membered heteroaryl-C_1-4alkyl, and 4-10 membered heterocycloalkyl-C_1-4alkyl of R¹are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, CN, NO₂, OR^a1, SR^a1, C(O)R^b1, C(O)NR^c1R^d1, C(O)OR^a1, OC(O)R^b1, OC(O)NR^c1R^d1, C(═NR^c1)NR^c1R^d1, NR^c1C(═NR^e1)NR^c1R^d1, NR^c1R^d1, NR^c1C(O)R^b1, NR^c1C(O)OR^a1, NR^c1C(O)NR^c1R^d1, NR^c1S(O)R^b1, NR^c1S(O)₂R^b1, NR^c1S(O)₂NR^c1R^d1, S(O)R^b1, S(O)NR^c1R^d1, S(O)₂R^b1, and S(O)₂NR^c1R^d1;

or two R¹groups together with the atoms to which they are attached form a C_5-7cycloalkyl group which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, CN, NO₂, OR^a1, SR^a1, C(O)R^b1, C(O)NR^c1R^d1, C(O)OR^a1, OC(O)R^b1, OC(O)NR^c1R^d1, C(═NR^e1)NR^c1R^d1, NR^c1C(═NR^e1)NR^c1R^d1, NR^c1R^d1, NR^c1C(O)R^b1, NR^c1C(O)OR^a1, NR^c1C(O)NR^c1R^d1, NR^c1S(O)R^b1, NR^c1S(O)₂R^b1, NR^c, S(O)₂NR^c1R^d1, S(O)R^b1, S(O)NR^c1R^dS(O)₂R^b1, and S(O)₂NR^c1R^d1;

R²and R⁴are each independently selected from H, halo, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, C_6-10aryl, C_3-7cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C_6-10aryl-C_1-4alkyl, C_3-7cycloalkyl-C_1-4alkyl, 5-10 membered heteroaryl-C_1-4alkyl, 4-10 membered heterocycloalkyl-C_1-4alkyl, CN, NO₂, OR^a2, SR^a2, C(O)R^b2, C(O)NR^c2R^d2, C(O)OR^a2, OC(O)R^b2, OC(O)NR^c2R^d2, NR^c2R^d2, NR^c2C(O)R^b2, NR^c2C(O)OR^a2, NR^c2C(O)NR^c2R^d2, C(═NR^c2)R^b2, C(═NR^c2)NR^c2R^d2, NR^c2C(═NR^e2)NR^c2R^d2, NR^c2S(O)R^b2, NR^c2S(O)₂R^b2, NR^c2S(O)₂NR^c2R^d2, S(O)R^b2, S(O)NR^c2R^d2, S(O)₂R^b2, and S(O)₂NR^c2R^d2, wherein said C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, C_6-10aryl, C_3-7cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C_6-10aryl-C_1-4alkyl, C_3-7cycloalkyl-C₁₄alkyl, 5-10 membered heteroaryl-C_1-4alkyl, and 4-10 membered heterocycloalkyl-C_1-4alkyl of R²and R⁴are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, CN, NO₂, OR^a2, SR^a2, C(O)R^b2, C(O)NR^c2R^d2, C(O)OR^a2, OC(O)R^b2, OC(O)NR^c2R^d2, NR^c2R^d2, NR^c2C(O)R^b2, NR^c2C(O)OR^a2, NR^c2C(O)NR^c2R^d2, C(═NR^e2)R^b2, C(═NR^e2)NR^c2R^d2, NR^c2C(═NR^e2)NR^c2R^d2, NR^c2S(O)R^b2, NR^c2S(O)₂R^b2, NR^c2S(O)₂NR^c2R^d2, S(O)R^b2, S(O)NR^c2R^d2, S(O)R^b2, and S(O)₂NR^c2R^d2;

R³is selected from H, halo, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, C_3-4cycloalkyl, CN, NO₂, OR^a3, SR^a3C(O)R^b3, C(O)NR^c3R^d3, C(O)OR^a3, OC(O)R^b3, OC(O)NR^c3R^d3, NR^c3R^d3, NR^c3C(O)R^b3, NR^c3C(O)OR^a3, NR^c3C(O)NR^c3R^dC(═NR^e3)R^bC(═NR^c3)NR^c3R^d3, NR^c3C(═NR^e3)NR^c3R^d3, NR^c3S(O)R^b3, NR^c3S(O)₂R^b3, NR^c3S(O)₂NR^c3R^d3, S(O)R^b3, S(O)NR^c3R^d3, S(O)₂R^b3, and S(O)₂NR^c3R^d3, wherein said C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, and C_3-4cycloalkyl of R³are each optionally substituted with 1, 2, or 3 substituents independently selected from halo, C_1-4alkyl, CN, NO₂, OR^a3, SR^a3C(O)R^b3, C(O)NR^c3R^d3, C(O)OR^a3, OC(O)R^b3, OC(O)NR^c3R^d3, NR^c3R^d, NR^c3C(O)R^b3, NR^c3C(O)OR^a3, NR^c3C(O)NR^c3R^d3, C(═NR^e3)R^b3, C(═NR^e3)NR^c3R^d, NR^c3C(═NR^e3)NR^c3R^d3, NR^c3S(O)R^b3, NR^c3S(O)₂R^b3, NR^c3S(O)₂NR^c3R^d3, S(O)R^b3, S(O)NR^c3R^dS(O)₂R^b3and S(O)₂NR^c3R^d3;

each R^a, R^b, R^c, R^d, R^a1, R^b1, R^c1, R^d1, R^a2, R^b2, R^c2, R^d2is independently selected from H, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C_6-10aryl, C_3-7cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C_6-10aryl-C_1-4alkyl, C_3-7cycloalkyl-C_1-4alkyl, 5-10 membered heteroaryl-C_1-4alkyl, and 4-10 membered heterocycloalkyl-C_1-4alkyl, wherein said C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_6-10aryl, C_3-7cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C_6-10aryl-C_1-4alkyl, C_3-7cycloalkyl-C_1-4alkyl, 5-10 membered heteroaryl-C_1-4alkyl, and 4-10 membered heterocycloalkyl-C_1-4alkyl of R^a, R^b, R^c, R^d, R^a1, R^b1, R^c1, R^d1, R^a2, R^b2, R^c2, and R^d2is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C_1-4alkyl, C_1-4haloalkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, CN, OR^a3, SR^a3, C(O)R^b3, C(O)NR^c3R^d3, C(O)OR^a3, OC(O)R^b3, OC(O)NR^c3R^d3, NR^c3R^d3, NR^c3C(O)R^b3, NR^c3C(O)NR^c3R^d3, NR^c3C(O)OR^a3, C(═NR^c3)NR^c3R^d3, NR^c3C(═NR^e3)NR^c3R^d3, S(O)R^b3, S(O)NR^c3R^d3, S(O)₂R^b3, NR^c3S(O)₂R^b3, NR^c3S(O)₂NR^c3R^d3, and S(O)₂NR^c3R^d3;

each R^c, R^c1, R^c2, and R^c3is independently selected from H, C_1-4alkyl, and CN; and

n is 0, 1, 2, or 3;

wherein when X²is CR²; X³is CR; and X⁴is CR⁴, then A is other than —C(═O)OH or —C(═O)OCH₃; and

wherein the compound is other than:

embedded image

The present invention is directed to an inhibitor of LRRK2 which is a compound of Formula I:

embedded image

or a pharmaceutically acceptable salt thereof, wherein:

A is Cy¹, Cy¹-C_1-4alkyl-, halo, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, CN, NO₂, OR^a, SR^a, C(O)R^b, C(O)NR^cR^d, C(O)OR^a, OC(O)R^b, OC(O)NR^cR^d, C(═NR^e)NR^cR^d, NR^cC(═NR^e)NR^cR^d, NR^cR^d, NR^cC(O)R^b, NR^cC(O)OR^a, NR^cC(O)NR^cR^d, NR^cS(O)R^b, NR^cS(O)₂R^b, NR^cS(O)₂NR^cR^d, S(O)R^b, S(O)NR^cR^d, S(O)₂R^b, and S(O)₂NR^cR^d; wherein said C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, and C_1-6haloalkyl of A are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, CN, NO₂, OW, SR^a, C(O)R^b, C(O)NR^cR^d, C(O)OR^a, OC(O)R^b, OC(O)NR^cR^d, C(═NR^e)NR^cR^d, NR^cC(═NR^e)NR^cR^d, NR^cR^d, NR^cC(O)R^b, NR^c1C(O)OR^a, NR^cC(O)NR^cR^d, NR^cS(O)R^b, NR^cS(O)₂R^b, NR^cS(O)₂NR^cR^d, S(O)R^b, S(O)NR^cR^d, S(O)₂R^b, and S(O)₂NR^cR^d;

Ring B is phenyl, 5-membered heteroaryl, or 6-membered heteroaryl, wherein said 5- or 6-membered heteroaryl comprises 1, 2, or 3 ring-forming heteroatoms independently selected from N, O, and S;

X²is N or CR²;

X³is N or CR³;

X⁴is N or CR⁴; wherein not more than two of X², X³, and X⁴are simultaneously N;

Cy¹is selected from C_6-10aryl, C_3-10cycloalkyl, 5-14 membered heteroaryl, and 4-14 membered heterocycloalkyl, each optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, C_6-10aryl, C_3-10cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C_6-10aryl-C_1-4alkyl, C_3-7cycloalkyl-C_1-4alkyl, 5-10 membered heteroaryl-C_1-4alkyl, 4-10 membered heterocycloalkyl-C_1-4alkyl, CN, NO₂, OR^a, SR^a, C(O)R^b, C(O)NR^cR^d, C(O)OR^a, OC(O)R^b, OC(O)NR^cR^d, NR^cR^d, NR^cC(O)R^b, NR^cC(O)OR^a, NR^cC(O)NR^cR^d, C(═NR^e)R^b, C(═NR^e)NR^cR^d, NR^cC(═NR^e)NR^cR^d, NR^cS(O)R^b, NR^cS(O)₂R^b, NR^cS(O)₂NR^cR^d, S(O)R^b, S(O)NR^cR^d, S(O)₂R^b, and S(O)₂NR^cR^d, wherein said substituents C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, C_6-10aryl, C_3-10cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C_6-10aryl-C_1-4alkyl, C_3-7cycloalkyl-C_1-4alkyl, 5-10 membered heteroaryl-C_1-4alkyl, 4-10 membered heterocycloalkyl-C_1-4alkyl are each optionally substituted by 1, 2, or 3 further substituents independently selected from halo, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, CN, NO₂, OR^a, SR^a, C(O)R^b, C(O)NR^cR^d, C(O)OR^a, OC(O)R^b, OC(O)NR^cR^d, NR^cR^d, NR^cC(O)R^b, NR^cC(O)OR^a, NR^cC(O)NR^cR^d, C(═NR^e)R^b, C(═NR^e)NR^cR^d, NR^cC(═NR^e)NR^cR^d, NR^cS(O)R^b, NR^cS(O)₂R^b, NR^cS(O)₂NR^cR^d, S(O)R^b, S(O)NR^cR^d, S(O)₂R^b, and S(O)₂NR^cR^d;

each R¹is independently selected from H, halo, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, C_6-10aryl, C_3-7cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C_6-10aryl-C_1-4alkyl, C_3-7cycloalkyl-C_1-4alkyl, 5-10 membered heteroaryl-C_1-4alkyl, 4-10 membered heterocycloalkyl-C_1-4alkyl, CN, NO₂, OR^a1, SR^a1, C(O)R^b1, C(O)NR^c1R^d1, C(O)OR^a1, OC(O)R^b1, OC(O)NR^c1R^d1, NR^c1R^d1, NR^c1C(O)R^b1, NR^c1C(O)OR^a1, NR^c1C(O)NR^c1R^d1, C(═NR^e1)R^b1, C(═NR^e1)NR^c1R^d1, NR^c1C(═NR^e1)NR^c1R^d1, NR^c1S(O)R^b1, NR^c1S(O)₂R^b1, NR^c1S(O)₂NR^c1R^d1, S(O)R^b1, S(O)NR^c1R^d1, S(O)₂R^b1, and S(O)₂NR^c1R^d1, wherein said C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, C_6-10aryl, C_3-7cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C_6-10aryl-C_1-4alkyl, C_3-7cycloalkyl-C_1-4alkyl, 5-10 membered heteroaryl-C_1-4alkyl, and 4-10 membered heterocycloalkyl-C_1-4alkyl of R¹are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, CN, NO₂, OR^a1, SR^a1, C(O)R^b1, C(O)NR^c1R^d1, C(O)OR^a1, OC(O)R^b1, OC(O)NR^c1R^d1, C(═NR^e1)NR^c1R^d1, NR^c1C(═NR^e1)NR^c1R^d1, NR^c1R^d1, NR^c1C(O)R^b1, NR^c1C(O)OR^a1, NR^c1C(O)NR^c1R^d1, NR^c1S(O)R^b1, NR^c1S(O)₂R^b1, NR^c1S(O)₂NR^c1R^d1, S(O)R^b1, S(O)NR^c1R^d1, S(O)₂R^b1, and S(O)₂NR^c1R^d1;

R²and R⁴are each independently selected from H, halo, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, C_6-10aryl, C_3-7cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C_6-10aryl-C_1-4alkyl, C_3-7cycloalkyl-C_1-4alkyl, 5-10 membered heteroaryl-C_1-4alkyl, 4-10 membered heterocycloalkyl-C_1-4alkyl, CN, NO₂, OR^a2, SR^a2, C(O)R^b2, C(O)NR^c2R^d2, C(O)OR^a2, OC(O)R^b2, OC(O)NR^c2R^d2, NR^c2R^d2, NR^c2C(O)R^b2, NR^c2C(O)OR^a2, NR^c2C(O)NR^c2R^d2, C(═NR^e2)R^b2, C(═NR^e2)NR^c2R^d2, NR^c2C(═NR^e2)NR^c2R^d2, NR^c2S(O)R^b2, NR^c2S(O)₂R^b2, NR^c2S(O)₂NR^c2R^d2, S(O)R^b2, S(O)NR^c2R^d2, S(O)₂R^b2, and S(O)₂NR^c2R^d2, wherein said C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, C_6-10aryl, C_3-7cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C_6-10aryl-C_1-4alkyl, C_3-7cycloalkyl-C_1-4alkyl, 5-10 membered heteroaryl-C_1-4alkyl, and 4-10 membered heterocycloalkyl-C_1-4alkyl of R²and R⁴are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, CN, NO₂, OR^a2, SR^a2, C(O)R^b2, C(O)NR^c2R^d2, C(O)OR^a2, OC(O)R^b2, OC(O)NR^c2R^d2, NR^c2R^d2, NR^c2C(O)R^b2, NR^c2C(O)OR^a2, NR^c2C(O)NR^c2R^d2, C(═NR^e2)R^b2, C(═NR^e2)NR^c2R^d2, NR^c2C(═NR^e2)NR^c2R^d2, NR^c2S(O)R^b2, NR^c2S(O)₂R^b2, NR^c2S(O)₂NR^c2R^d2, S(O)R^b2, S(O)NR^c2R^d2, S(O)₂R^b2, and S(O)₂NR^c2R^d2;

R³is selected from H, halo, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, C_3-4cycloalkyl, CN, NO₂, OR^a3, SR^a3, C(O)R^b3, C(O)NR^c3R^d3, C(O)OR^a3, OC(O)R^b3, OC(O)NR^c3R^d3, NR^c3R^d3, NR^c3C(O)R^b3, NR^c3C(O)OR^a3, NR^c3C(O)NR^c3R^d3, C(═NR^e3)R^b3, C(═NR^e3)NR^c3R^d3, NR^c3C(═NR^e3)NR^c3R^d3, NR^c3S(O)R^b3, NR^c3S(O)₂R^b3, NR^c3S(O)₂NR^c3R^d3, S(O)R^b3, S(O)NR^c3R^d3, S(O)₂R^b3, and S(O)₂NR^c3R^d3wherein said C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, and C_3-4cycloalkyl of R³are each optionally substituted with 1, 2, or 3 substituents independently selected from halo, C_1-4alkyl, CN, NO₂, OR^a3, SR^a3, C(O)R^b3, C(O)NR^c3R^d3, C(O)OR^a3, OC(O)R^b3, OC(O)NR^c3R^d3, NR^c3R^d3, NR^c3C(O)R^b3, NR^c3C(O)OR^a3, NR^c3C(O)NR^c3R^d3, C(═NR^c3)R^b3, C(═NR^c3)NR^c3R^d3, NR^c3C(═NR^e3)NR^c3R^d3, NR^c3S(O)R^b3, NR^c3S(O)₂R^b3, NR^c3S(O)₂NR^c3R^d3, S(O)R^b3S(O)NR^c3R^d3, S(O)₂^b3, and S(O)₂NR^c3R^d3;

each R^a, R^b, R^c, R^d, R^a1, R^b1, R^c1, R^d1, R^a2, R^b2, R^c2, R^d2is independently selected from H, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C_6-10aryl, C_3-7cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C_6-10aryl-C_1-4alkyl, C_3-7cycloalkyl-C_1-4alkyl, 5-10 membered heteroaryl-C_1-4alkyl, and 4-10 membered heterocycloalkyl-C_1-4alkyl, wherein said C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_6-10aryl, C_3-7cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C_6-10aryl-C_1-4alkyl, C_3-7cycloalkyl-C_1-4alkyl, 5-10 membered heteroaryl-C_1-4alkyl, and 4-10 membered heterocycloalkyl-C_1-4alkyl of R^a, R^b, R^c, R^d, R^a1, R^b1, R^c1, R^d1, R^a2, R^b2, R^c2, and R^d2is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C_1-4alkyl, C_1-4haloalkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, CN, OR^a3, SR^a3, C(O)R^b3, C(O)NR^c3R^d3, C(O)OR^a3, OC(O)R^b3, OC(O)NR^c3R^d3, NR^c3R^d3, NR^c3C(O)R^b3, NR^c3C(O)NR^c3R^d3, NR^c3C(O)OR^a3, C(═NR^c3)NR^c3R^dNR^c3C(═NR^e3)NR^c3R^d3, S(O)R^b3, S(O)NR^c3R^d3, S(O)₂R^b3, NR^c3S(O)₂R^b3, NR^c3S(O)₂NR^c3R^d3, and S(O)₂NR^c3R^d3;

each R^e, R^e1, R^e2, and R^e3is independently selected from H, C_1-4alkyl, and CN; and

n is 0, 1, 2, or 3;

wherein when X²is CR²; X³is CR³; and X⁴is CR⁴, then A is other than —C(═O)OH or —C(═O)OCH₃; and

wherein the compound is other than:

embedded image

In some embodiments, X²is CR²; X³is CR³; and X⁴is CR⁴.

In some embodiments, X²is N; X³is CR³; and X⁴is CR⁴.

In some embodiments, X²is CR²; X³is N; and X⁴is CR⁴.

In some embodiments, X²is CR²; X³is CR³; and X⁴is N.

In some embodiments, X²is N; X³is CR³; and X⁴is N.

In some embodiments, X²is N; X³is N; and X⁴is CR⁴.

In some embodiments, X²is CR²; X³is N; and X⁴is N.

In some embodiments, R², R³, and R⁴are each H.

In some embodiments, R²is H or halo. In some embodiments, R²is halo. In some embodiments, R²is H.

In some embodiments, R³is H or halo. In some embodiments, R³is halo. In some embodiments, R³is H or fluoro. In some embodiments, R³is H. In some embodiments, R³is fluoro.

In some embodiments, R⁴is H or halo. In some embodiments, R⁴is halo. In some embodiments, R⁴is H.

In some embodiments, A is Cy¹, Cy¹-C_2-4alkenyl-, halo, CN, C_1-6alkyl, C_2-6alkenyl, C_1-6haloalkyl, OR^a, SR^a, NR^cC(O)R^b, or S(O)₂R^b, wherein said C_1-6alkyl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, CN, NO₂, OR^a, SR^a, C(O)R^b, C(O)NR^cR^d, C(O)OR^a, OC(O)R^b, OC(O)NR^cR^d, C(═NR^e)NR^cR^d, N^cC(═NR^e)NR^cR^d, NR^cR^d, NR^cC(O)R^b, NR^cC(O)OR^a, NR^cC(O)NR^cR^d, NR^cS(O)R^b, NR^cS(O)₂R^b, NR^cS(O)₂NR^cR^d, S(O)R^b, S(O)NR^cR^d, S(O)₂R^b, and S(O)₂NR^cR^d.

In some embodiments, A is Cy¹, halo, C_1-6alkyl, or NR^cC(O)R^b, wherein said C_1-6alkyl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, CN, NO₂, OR, SR^a, C(O)R^b, C(O)NR^cR^d, C(O)OR^a, OC(O)R^b, OC(O)NR^cR^d, C(═NR^e)NR^cR^d, NR^cC(═NR^e)NR^cR^d, NR^cR^d, NR^cC(O)R^b, NR^cC(O)OR^a, NR^cC(O)NR^cR^d, NR^cS(O)R^b, NR^cS(O)₂R^b, NR^cS(O)₂NR^cR^d, S(O)R^b, S(O)NR^cR^d, S(O)₂R^b, and S(O)₂NR^cR^d.

In some embodiments, A is Cy¹, halo, or C_1-6alkyl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, CN, NO₂, OR^a, SR^a, C(O)R^b, C(O)NR^cR^d, C(O)OR^a, OC(O)R^b, OC(O)NR^cR^d, C(═NR^e)NR^cR^d, NR^cC(═NR^e)NR^cR^d, NR^cR^d, NR^cC(O)R^b, NR^c1C(O)OR^a, NR^cC(O)NR^cR^d, NR^cS(O)R^b, NR^cS(O)₂R^b, NR^cS(O)₂NR^cR^d, S(O)R^b, S(O)NR^cR^d, S(O)₂R^b, and S(O)₂NR^cR^d.

In some embodiments, A is methyl.

In some embodiments, A is halo.

A is iodo, bromo, chloro, or fluoro.

In some embodiments, A is iodo or bromo.

In some embodiments, A is iodo. In some embodiments, A is bromo.

In some embodiments, Cy¹-C_2-4alkenyl-.

In some embodiments, A is Cy¹.

In some embodiments, Cy¹is C_6-10aryl or 5-14 membered heteroaryl, each optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, C_6-10aryl, C_3-10cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C_6-10aryl-C_1-4alkyl, C_3-7cycloalkyl-C_1-4alkyl, 5-10 membered heteroaryl-C_1-4alkyl, 4-10 membered heterocycloalkyl-C_1-4alkyl, CN, NO₂, OR^a, SR^a, C(O)R^b, C(O)NR^cR^d, C(O)OR^a, OC(O)R^b, OC(O)NR^cR^d, NR^cR^dNR^cC(O)R^b, NR^cC(O)OR^a, NR^cC(O)NR^cR^d, C(═NR^e)R^b, C(═NR^e)NR^cR^d, NR^cC(═NR^e)NR^cR^d, NR^cS(O)R^b, NR^cS(O)₂R^b, NR^cS(O)₂NR^cR^d, S(O)R^b, S(O)NR^cR^d, S(O)₂R^b, and S(O)₂NR^cR^d, wherein said substituents C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, C_6-10aryl, C_3-10cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C_6-10aryl-C_1-4alkyl, C_3-7cycloalkyl-C_1-4alkyl, 5-10 membered heteroaryl-C_1-4alkyl, 4-10 membered heterocycloalkyl-C_1-4alkyl are each optionally substituted by 1, 2, or 3 further substituents independently selected from halo, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, CN, NO₂, OR^a, SR^a, C(O)R^b, C(O)NR^cR^d, C(O)OR^a, OC(O)R^b, OC(O)NR^cR^dNR^cR^d, NR^cC(O)R^b, NR^cC(O)OR^a, NR^cC(O)NR^cR^d, C(═NR^e)R^b, C(═NR^e)NR^cR^d, NR^cC(═NR^e)NR^cR^d, NR^cS(O)R^b, NR^cS(O)₂R^b, NR^cS(O)₂NR^cR^d, S(O)R^b, S(O)NR^cR^d, S(O)₂R^b, and S(O)₂NR^cR^d.

In some embodiments, Cy¹is phenyl or 5-, 6-, or 8-membered heteroaryl, each optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, C_6-10aryl, C_3-10cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C_6-10aryl-C_1-4alkyl, C_3-7cycloalkyl-C_1-4alkyl, 5-10 membered heteroaryl-C_1-4alkyl, 4-10 membered heterocycloalkyl-C_1-4alkyl, CN, NO₂, OR^a, SR^a, C(O)R^b, C(O)NR^cR^d, C(O)OR^a, OC(O)R^b, OC(O)NR^cR^d, NR^cR^d, NR^cC(O)R^b, NR^cC(O)OR^a, NR^cC(O)NR^cR^d, C(═NR^e)R^b, C(═NR^e)NR^cR^d, NR^cC(═NR^c)NR^cR^d, NR^cS(O)R^b, NR^cS(O)₂R^b, NR^cS(O)₂NR^cR^d, S(O)R^b, S(O)NR^cR^d, S(O)₂R^b, and S(O)₂NR^cR^d, wherein said substituents C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, C_6-10aryl, C_3-10cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C_6-10aryl-C_1-4alkyl, C_3-7cycloalkyl-C_1-4alkyl, 5-10 membered heteroaryl-C_1-4alkyl, 4-10 membered heterocycloalkyl-C_1-4alkyl are each optionally substituted by 1, 2, or 3 further substituents independently selected from halo, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, CN, NO₂, OR^a, SR^a, C(O)R^b, C(O)NR^cR^d, C(O)OR^a, OC(O)R^b, OC(O)NR^cR^d, NR^cR^d, NR^cC(O)R^b, NR^cC(O)OR^a, NR^cC(O)NR^cR^d, C(═NR^e)R^b, C(═NR^e)NR^cR^d, NR^cC(═NR^e)NR^cR^d, NR^cS(O)R^b, NR^cS(O)₂R^b, NR^cS(O)₂NR^cR^d, S(O)R^b, S(O)NR^cR^d, S(O)₂R^b, and S(O)₂NR^cR^d.

In some embodiments, Cy¹is selected from C_3-10cycloalkyl and 4-14 membered heterocycloalkyl, each optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, C_6-10aryl, C_3-10cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C_6-10aryl-C_1-4alkyl, C_3-7cycloalkyl-C_1-4alkyl, 5-10 membered heteroaryl-C_1-4alkyl, 4-10 membered heterocycloalkyl-C_1-4alkyl, CN, NO₂, OR^a, SR^a, C(O)R^b, C(O)NR^cR^d, C(O)OR^a, OC(O)R^b, OC(O)NR^cR^d, NR^cR^d, NR^cC(O)R^b, NR^cC(O)OR^a, NR^cC(O)CR^d, C(═NR^e)R^b, C(═NR^e)NR^cR^d, NR^cC(═NR^c)NR^cR^d, NR^cS(O)R^b, NR^cS(O)₂R^b, NR^cS(O)₂NR^cR^d, S(O)R^b, S(O)NR^cR^d, S(O)₂R^b, and S(O)₂NR^cR^d, wherein said substituents C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, C_6-10aryl, C_3-10cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C_6-10aryl-C_1-4alkyl, C_3-7cycloalkyl-C_1-4alkyl, 5-10 membered heteroaryl-C_1-4alkyl, 4-10 membered heterocycloalkyl-C_1-4alkyl are each optionally substituted by 1, 2, or 3 further substituents independently selected from halo, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, CN, NO₂, OR^a, SR^a, C(O)R^b, C(O)NR^cR^d, C(O)OR^a, OC(O)R^b, OC(O)NR^cR^d, NR^cR^dNR^cC(O)R^b, NR^cC(O)OR^a, NR^cC(O)NR^cR^d, C(═NR^e)R^b, C(═NR^e)NR^cR^d, NR^cC(═NR^e)NR^cR^d, NR^cS(O)R^b, NS(O)₂R^b, NR^cS(O)₂NR^cR^d, S(O)R^b, S(O)NR^cR^d, S(O)₂R^b, and S(O)₂NR^cR^d.

In some embodiments, Cy¹is selected from C_3-7cycloalkyl and 4-6 membered heterocycloalkyl, each optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, C_6-10aryl, C_3-10cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C_6-10aryl-C_1-4alkyl, C_3-7cycloalkyl-C_1-4alkyl, 5-10 membered heteroaryl-C_1-4alkyl, 4-10 membered heterocycloalkyl-C_1-4alkyl, CN, NO₂, OR^a, SR^a, C(O)R^b, C(O)NR^cR^d, C(O)OR^a, OC(O)R^b, OC(O)NR^cR^d, NR^cR^d, NR^cC(O)R^b, NR^cC(O)OR^a, NR^cC(O)NR^cR^d, C(═NR^e)R^b, C(═NR^e)NR^cR^d, NR^cC(═NR^e)NR^cR^d, NR^cS(O)R^b, NR^cS(O)₂R^b, NR^cS(O)₂NR^cR^d, S(O)R^b, S(O)NR^cR^d, S(O)₂R^b, and S(O)₂NR^cR^d, wherein said substituents C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, C_6-10aryl, C_3-10cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C_6-10aryl-C_1-4alkyl, C_3-7cycloalkyl-C_1-4alkyl, 5-10 membered heteroaryl-C_1-4alkyl, 4-10 membered heterocycloalkyl-C_1-4alkyl are each optionally substituted by 1, 2, or 3 further substituents independently selected from halo, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, CN, NO₂, OR^a, SR^a, C(O)R^b, C(O)NR^cR^d, C(O)OR^a, OC(O)R^b, OC(O)NR^cR^d, NR^cR^dNR^cC(O)R^b, NR^cC(O)OR^a, NR^cC(O)NR^cR^d, C(═NR^e)R^b, C(═NR^e)NR^cR^d, NR^cC(═NR^e)NR^cR^d, NR^cS(O)R^b, NR^cS(O)₂R^b, NR^cS(O)₂NR^cR^d, S(O)R^b, S(O)NR^cR^d, S(O)₂R^b, and S(O)₂NR^cR^d.

In some embodiments, Cy¹is phenyl, furanyl, pyridyl, pyrazolyl, isoxazolyl, thienyl, benzoxazolyl, thiazolyl, oxazolyl, imidazolyl, oxodihydropyridinyl, isothiazolyl, pyrrolyl, cyclopropyl, pyrimidinyl, triazolyl, oxooxazolyl, azetidinyl, oxetanyl, piperidinyl, dihydrofuranyl, tetrahydropyranyl, cyclobutyl, thieno[2,3-c]pyridinyl, or pyridazinyl, each optionally substituted by 1, 2, or 3 substituents independently selected from halo, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, C_6-10aryl, C_3-10cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C_6-10aryl-C_1-4alkyl, C_3-7cycloalkyl-C_1-4alkyl, 5-10 membered heteroaryl-C_1-4alkyl, 4-10 membered heterocycloalkyl-C_1-4alkyl, CN, NO₂, OR^a, SR^a, C(O)R^b, C(O)NR^cR^d, C(O)OR^a, OC(O)R^b, OC(O)NR^cR^d, NR^cR^d, NR^cC(O)R^b, NR^cC(O)OR^a, NR^cC(O)NR^cR^d, C(═NR^e)R^b, C(═NR^e)NR^cR^d, NR^cC(═NR^e)NR^cR^d, NR^cS(O)R^b, NR^cS(O)₂R^b, NR^cS(O)₂NR^cR^d, S(O)R^b, S(O)NR^cR^d, S(O)₂R^b, and S(O)₂NR^cR^d, wherein said substituents C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, C_6-10aryl, C_3-10cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C_6-10aryl-C_1-4alkyl, C_3-7cycloalkyl-C_1-4alkyl, 5-10 membered heteroaryl-C_1-4alkyl, 4-10 membered heterocycloalkyl-C_1-4alkyl are each optionally substituted by 1, 2, or 3 further substituents independently selected from halo, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, CN, NO₂, OR^a, SR^a, C(O)R^b, C(O)NR^cR^d, C(O)OR^a, OC(O)R^b, OC(O)NR^cR^d, NR^cR^d, NR^cC(O)R^b, NR^cC(O)OR^a, NR^cC(O)NR^cR^d, C(═NR^e)R^b, C(═NR^e)NR^cR^d, N^cC(═NR^e)NR^cR^d, NR^cS(O)R^b, NR^cS(O)₂R^b, NR^cS(O)₂NR^cR^d, S(O)R^b, S(O)NR^cR^d, S(O)₂R^b, and S(O)₂NR^cR^d.

In some embodiments, Cy¹is phenyl, furanyl, pyridyl, pyrazolyl, isoxazolyl, thienyl, benzoxazolyl, thiazolyl, oxazolyl, imidazolyl, oxodihydropyridinyl, isothiazolyl, pyrrolyl, cyclopropyl, or pyrimidinyl, each optionally substituted by 1, 2, or 3 substituents independently selected from halo, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, C_6-10aryl, C_3-10cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C_6-10aryl-C_1-4alkyl, C_3-7cycloalkyl-C_1-4alkyl, 5-10 membered heteroaryl-C_1-4alkyl, 4-10 membered heterocycloalkyl-C_1-4alkyl, CN, NO₂, OR^a, SR^a, C(O)R^b, C(O)NR^cR^d, C(O)OR^a, OC(O)R^b, OC(O)NR^cR^d, NR^cR^dNR^cC(O)R^b, NR^cC(O)OR^a, NR^cC(O)NR^cR^d, C(═NR^e)R^b, C(═NR^e)NR^cR^d, NR^cC(═NR^e)NR^cR^d, NR^cS(O)R^b, NR^cS(O)₂R^b, NR^cS(O)₂NR^cR^d, S(O)R^b, S(O)NR^cR^d, S(O)₂R^b, and S(O)₂NR^cR^d, wherein said substituents C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, C_6-10aryl, C_3-10cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C_6-10aryl-C_1-4alkyl, C_3-7cycloalkyl-C_1-4alkyl, 5-10 membered heteroaryl-C_1-4alkyl, 4-10 membered heterocycloalkyl-C_1-4alkyl are each optionally substituted by 1, 2, or 3 further substituents independently selected from halo, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, CN, NO₂, OR^a, SR^a, C(O)R^b, C(O)NR^cR^d, C(O)OR^a, OC(O)R^b, OC(O)NR^cR^d, NR^cR^dNR^cC(O)R^b, NR^c1C(O)OR^a, NR^cC(O)NR^cR^d, C(═NR^e)R^b, C(═NR^e)NR^cR^d, NR^cC(═NR^e)NR^cR^d, NR^cS(O)R^b, NR^cS(O)₂R^b, NR^cS(O)₂NR^cR^d, S(O)R^b, S(O)NR^cR^d, S(O)₂R^b, and S(O)₂NR^cR^d.

In some embodiments, Cy¹is phenyl, furanyl, pyridyl, pyrazolyl, isoxazolyl, thienyl, or benzoxazolyl, each optionally substituted by 1, 2, or 3 substituents independently selected from halo, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, C_6-10aryl, C_3-10cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C_6-10aryl-C_1-4alkyl, C_3-7cycloalkyl-C_1-4alkyl, 5-10 membered heteroaryl-C_1-4alkyl, 4-10 membered heterocycloalkyl-C_1-4alkyl, CN, NO₂, OR^a, SR^a, C(O)R^b, C(O)NR^cR^d, C(O)OR^a, OC(O)R^b, OC(O)NR^cR^d, NR^cR^d, NR^cC(O)R^b, NR^cC(O)OR^a, NR^cC(O)NR^cR^d, C(═NR^e)R^b, C(═NR^e)NR^cR^d, NR^cC(═NR^e)NR^cR^d, NR^cS(O)R^b, NR^cS(O)₂R^b, NR^cS(O)₂NR^cR^d, S(O)R^b, S(O)NR^cR^d, S(O)₂R^b, and S(O)₂NR^cR^d, wherein said substituents C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, C_6-10aryl, C_3-10cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C_6-10aryl-C_1-4alkyl, C_3-7cycloalkyl-C_1-4alkyl, 5-10 membered heteroaryl-C_1-4alkyl, 4-10 membered heterocycloalkyl-C_1-4alkyl are each optionally substituted by 1, 2, or 3 further substituents independently selected from halo, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, CN, NO₂, OR^a, SR^a, C(O)R^b, C(O)NR^cR^d, C(O)OR^a, OC(O)R^b, OC(O)NR^cR^d, NR^cR^d, N^cC(O)R^b, NR^cC(O)OR^a, CC(O)NR^cR^d, C(═NR^e)R^b, C(═NR^e)NR^cR^d, NR^cC(═NR^e))R^cR^d, NR^cS(O)R^b, NR^cS(O)₂R^b, NR^cS(O)₂NR^cR^d, S(O)R^b, S(O)NR^cR^d, S(O)₂R^b, and S(O)₂NR^cR^d.

In some embodiments, Cy¹is phenyl, furanyl, pyridyl, or oxazolyl.

In some embodiments, Cy¹is phenyl, furanyl, or pyridyl.

In some embodiments, Cy¹is furanyl.

In some embodiments, Cy¹is oxazolyl.

In some embodiments, Cy¹is cyclopropyl.

In some embodiments, Ring B is 5-membered heteroaryl or 6-membered heteroaryl, wherein said 5- or 6-membered heteroaryl comprises 1, 2, or 3 ring-forming heteroatoms independently selected from N, O, and S.

In some embodiments, Ring B is 6-membered heteroaryl, wherein said 6-membered heteroaryl comprises 1, 2, or 3 ring-forming N atoms.

In some embodiments, Ring B is phenyl, pyridyl, pyrimidinyl, thiazolyl, pyrrolyl, furanyl, pyrazolyl, imidazolyl, isothiazolyl, isoxazolyl, pyrazinyl, pyridazinyl, oxodihydropyridinyl, thienopyridyl, or indazolyl.

In some embodiments, Ring B is phenyl, pyridyl, pyrimidinyl, thiazolyl, pyrrolyl, furanyl, pyrazolyl, imidazolyl, isothiazolyl, or isoxazolyl.

In some embodiments, Ring B is phenyl, pyridyl, pyrimidinyl, thiazolyl, pyrrolyl, or furanyl.

In some embodiments, Ring B is phenyl.

In some embodiments, Ring B is pyridyl.

In some embodiments, Ring B is pyrimidinyl.

In some embodiments, Ring B is thiazolyl.

In some embodiments, Ring B is pyrolyl.

In some embodiments, Ring B is furanyl.

In some embodiments, Ring B is pyrazolyl.

In some embodiments, Ring B is imidazolyl.

In some embodiments, Ring B is isothiazolyl.

In some embodiments, Ring B is isoxazolyl.

In some embodiments, each R¹is independently selected from H, halo, C_1-6alkyl, C_2-6alkenyl, C_1-6haloalkyl, and OR^a1.

In some embodiments, each R¹is independently selected from H, halo, and C_1-6alkyl.

In some embodiments, R¹is independently selected from H, F, Cl, Br, I, CH₃, CH₂CH₃, isopropyl, isopropenyl, —CH═CH₂, C≡CH, CHF₂, CF₃, OH, methoxy, OCF₃, and cyclopropyl.

In some embodiments, each R¹is independently selected from H, F, Cl, Br, I, CH₃, CH₂CH₃, isopropyl, isopropenyl, —CH═CH₂, C≡CH, CHF₂, CF₃, OH, methoxy, and OCF₃.

In some embodiments, each R¹is independently selected from H, F, Cl, Br, I, CH₃, —CH═CH₂, CHF₂, CF₃, OH, and methoxy.

In some embodiments, each R¹is independently selected from H, F, Cl, Br, I, and CH₃.

In some embodiments, two R¹groups together with the atoms to which they are attached form a C_5-7cycloalkyl group which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, CN, NO₂, OR^a1, SR^a1, C(O)R^b1, C(O)NR^c1R^d1, C(O)OR^a1, OC(O)R^b1, OC(O)NR^c1R^d1, C(═NR^e1)NR^c1R^d1, NR^c1C(═NR^e1)NR^c1R^d1, NR^c1R^d1, NR^c1C(O)R^b1, NR^c1C(O)OR^a1, NR^c1C(O)NR^c1R^d1, NR^c1S(O)R^b1, NR^c1S(O)₂R^b1, NR^c1S(O)₂NR^c1R^d1, S(O)R^b1, S(O)NR^c1R^d, S(O)₂R^b1, and S(O)₂NR^c1R^d1.

In some embodiments, two R¹groups together with the atoms to which they are attached form a cyclopentane group.

In some embodiments, n is 0, 1, or 2.

In some embodiments, n is 0 or 1.

In some embodiments, n is 0.

In some embodiments, n is 1.

In some embodiments, n is 2.

In some embodiments, n is 1 or 2.

In some embodiments, the compound is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein:

A is Cy¹;

Ring B is phenyl, pyridyl, pyrimidinyl, thiazolyl, pyrrolyl, furanyl, pyrazolyl, imidazolyl, isothiazolyl, isoxazolyl, pyrazinyl, pyridazinyl, oxodihydropyridinyl, thienopyridyl, indazolyl, dihydro-5H-cyclopenta[c]pyridinyl, or quinolinyl;

X²is N or CR²;

X³is CR³;

X⁴is CR⁴;

Cy¹is phenyl, furanyl, pyridyl, pyrazolyl, isoxazolyl, thienyl, benzoxazolyl, thiazolyl, oxazolyl, imidazolyl, oxodihydropyridinyl, isothiazolyl, pyrrolyl, cyclopropyl, pyrimidinyl, triazolyl, oxooxazolyl, azetidinyl, oxetanyl, piperidinyl, dihydrofuranyl, tetrahydropyranyl, cyclobutyl, thieno[2,3-c]pyridinyl, or pyridazinyl, each optionally substituted by 1, 2, or 3 substituents independently selected from halo, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, C_6-10aryl, C_3-10cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C_6-10aryl-C_1-4alkyl, C_3-7cycloalkyl-C_1-4alkyl, 5-10 membered heteroaryl-C_1-4alkyl, 4-10 membered heterocycloalkyl-C_1-4alkyl, CN, NO₂, OR^a, SR^a, C(O)R^b, C(O)NR^cR^d, C(O)OR^a, OC(O)R^b, OC(O)NR^cR^d, NR^cR^d, NR^cC(O)R^b, NR^cC(O)OR^a, NR^cC(O)NR^cR^d, C(═NR^e)R^b, C(═NR^e)NR^cR^d, NR^cC(═NR^e)NR^cR^d, NR^cS(O)R^b, NR^cS(O)₂R^b, NR^cS(O)₂NR^cR^d, S(O)R^b, S(O)NR^cR^d, S(O)₂R^b, and S(O)₂NR^cR^d, wherein said substituents C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, C_6-10aryl, C_3-10cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C_6-10aryl-C_1-4alkyl, C_3-7cycloalkyl-C_1-4alkyl, 5-10 membered heteroaryl-C_1-4alkyl, 4-10 membered heterocycloalkyl-C_1-4alkyl are each optionally substituted by 1, 2, or 3 further substituents independently selected from halo, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, CN, NO₂, OR^a, SR^a, C(O)R^b, C(O)NR^cR^d, C(O)OR^a, OC(O)R^b, OC(O)NR^cR^d, NR^cR^dNR^cC(O)R^b, NR^cC(O)OR^a, NR^cC(O)NR^cR^d, C(═NR^e)R^b1, C(═NR^e)NR^cR^d, NR^cC(═NR^e)NR^cR^d, NR^cS(O)R^b, NR^cS(O)₂R^b, NR^cS(O)₂NR^cR^d, S(O)R^b, S(O)NR^cR^d, S(O)₂R^b, and S(O)₂NR^cR^d;

each R¹is independently selected from H, F, Cl, Br, I, CH₃, CH₂CH₃, isopropyl, isopropenyl, —CH═CH₂, C≡CH, CHF₂, CF₃, OH, methoxy, OCF₃, and cyclopropyl;

R², R³, and R⁴are each H;

each R^a, R^b, R^c, and R^dis independently selected from H, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C_6-10aryl, C_3-7cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C_6-10aryl-C_1-4alkyl, C_3-7cycloalkyl-C_1-4alkyl, 5-10 membered heteroaryl-C_1-4alkyl, and 4-10 membered heterocycloalkyl-C_1-4alkyl, wherein said C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_6-10aryl, C_3-7cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C_6-10aryl-C_1-4alkyl, C_3-7cycloalkyl-C_1-4alkyl, 5-10 membered heteroaryl-C_1-4alkyl, and 4-10 membered heterocycloalkyl-C_1-4alkyl of R^a, R^b, R^c, R^d, and R^a1is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C_1-4alkyl, C_1-4haloalkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, CN, OR^a3, SR^a3, C(O)R^b3, C(O)NR^c3R^d3, C(O)OR^a3OC(O)R^b3, OC(O)NR^c3R^d3, NR^c3R^d3, NR^c3C(O)R^b3, NR^c3C(O)NR^c3R^d3, NR^c3C(O)OR^a3, C(═NR^e3)NR^c3R^d3, NR^c3C(═NR^e3)NR^c3R^d3, S(O)R^b3S(O)NR^c3R^d3, S(O)₂R^b3, NR^c3S(O)₂R^b3NR^c3S(O)₂NR^c3R^d3, and S(O)₂NR^c3R^d3;

each R^a3, R^b3, R^c3, and R³is independently selected from H, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C_6-10aryl, C_3-7cycloalkyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl, wherein said C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C_6-10aryl, C_3-7cycloalkyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl are each optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C_1-6alkyl, C_1-6alkoxy, C_1-6haloalkyl, and C_1-6haloalkoxy;

each R^cand R^c3is independently selected from H, C_1-4alkyl, and CN; and n is 0, 1, 2, or 3.

In some embodiments, the compound is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein:

A is Cy¹;

Ring B is phenyl, pyridyl, pyrimidinyl, thiazolyl, pyrrolyl, furanyl, pyrazolyl, imidazolyl, isothiazolyl, isoxazolyl, pyrazinyl, pyridazinyl, oxodihydropyridinyl, thienopyridly, or indazolyl;

X²is N or CR²;

X³is CR³;

X⁴is CR⁴;

Cy¹is phenyl, furanyl, pyridyl, pyrazolyl, isoxazolyl, thienyl, benzoxazolyl, thiazolyl, oxazolyl, imidazolyl, oxodihydropyridinyl, isothiazolyl, pyrrolyl, cyclopropyl, or pyrimidinyl, each optionally substituted by 1, 2, or 3 substituents independently selected from halo, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, C_6-10aryl, C_3-10cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C_6-10aryl-C_1-4alkyl, C_3-7cycloalkyl-C_1-4alkyl, 5-10 membered heteroaryl-C_1-4alkyl, 4-10 membered heterocycloalkyl-C_1-4alkyl, CN, NO₂, OR^a, SR^a, C(O)R^b, C(O)NR^cR^d, C(O)OR^a, OC(O)R^b, OC(O)NR^cR^d, NR^cR^dNR^cC(O)R^b, NR^cC(O)OR^a, NR^cC(O)NR^cR^d, C(═NR^e)R^b, C(═NR^e)NR^cR^d, NR^cC(═NR^e)NR^cR^d, NR^cS(O)R^b, NR^cS(O)₂R^b, NR^cS(O)₂NR^cR^d, S(O)R^b, S(O)NR^cR^d, S(O)₂R^b, and S(O)₂NR^cR^d, wherein said substituents C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, C_6-10aryl, C_3-10cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl. C_6-10aryl-C_1-4alkyl, C_3-7cycloalkyl-C_1-4alkyl, 5-10 membered heteroaryl-C_1-4alkyl, 4-10 membered heterocycloalkyl-C_1-4alkyl are each optionally substituted by 1, 2, or 3 further substituents independently selected from halo, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, CN, NO₂, OR^a, SR^a, C(O)R^b, C(O)NR^cR^d, C(O)OR^a, OC(O)R^b, OC(O)NR^cR^d, NR^cR^d, NR^cC(O)R^b, NR^cC(O)OR^a, NR^cC(O)NR^cR^d, C(═NR^e)R^b, C(═NR^e)NR^cR^d, NR^cC(═NR^e)NR^cR^d, NR^cS(O)R^b, NR^cS(O)₂R^b, NR^cS(O)₂NR^cR^d, S(O)R^b, S(O)NR^cR^d, S(O)₂R^b, and S(O)₂NR^cR^d;

each R¹is independently selected from H, halo, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, and OR^a1;

R², R³, and R⁴are each H;

each R^a, R^b, R^c, R^d, and R^a1is independently selected from H, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C_6-10aryl, C_3-7cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C_6-10aryl-C_1-4alkyl, C_3-7cycloalkyl-C_1-4alkyl, 5-10 membered heteroaryl-C_1-4alkyl, and 4-10 membered heterocycloalkyl-C_1-4alkyl, wherein said C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_6-10aryl, C_3-7cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C_6-10aryl-C_1-4alkyl, C_3-7cycloalkyl-C_1-4alkyl, 5-10 membered heteroaryl-C_1-4alkyl, and 4-10 membered heterocycloalkyl-C_1-4alkyl of R^a, R^b, R^c, R^d, and R^a1is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C_1-4alkyl, C_1-4haloalkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, CN, OR^a3, SR^a3, C(O)R^b3, C(O)NR^c3R^d3, C(O)OR^a3, OC(O)R^b3, OC(O)NR^c3R^d3, NR^c3R^d3, NR^c3C(O)R^b3, NR^c3C(O)NR^c3R^d3, NR^c3C(O)OR^a3, C(═NR^e3)NR^c3R^d3, NR^c3C(═NR^e3)NR^c3R^d3, S(O)R^b3, S(O)NR^c3R^d3, S(O)₂R^b3, NR^c3S(O)₂R^b3, NR^c3S(O)₂NR^c3R^d3, and S(O)₂NR^c3R^d3;

each R^cand R^c3is independently selected from H, C_1-4alkyl, and CN; and

n is 0, 1, 2, or 3.

In some embodiments, the compound is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein:

A is Cy¹;

Ring B is phenyl, pyridyl, pyrimidinyl, thiazolyl, pyrrolyl, furanyl, pyrazolyl, imidazolyl, isothiazolyl, or isoxazolyl;

X²is N or CR²;

X³is CR³;

X⁴is CR⁴;

Cy¹is phenyl, furanyl, pyridyl, pyrazolyl, isoxazolyl, thienyl, or benzoxazolyl, each optionally substituted by 1, 2, or 3 substituents independently selected from halo, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, C_6-10aryl, C_3-10cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C_6-10aryl-C_1-4alkyl, C_3-7cycloalkyl-C_1-4alkyl, 5-10 membered heteroaryl-C_1-4alkyl, 4-10 membered heterocycloalkyl-C_1-4alkyl, CN, NO₂, OR^a, SR^a, C(O)R^b, C(O)NR^cR^d, C(O)OR^a, OC(O)R^b, OC(O)NR^cR^d, R^cR^d, NR^cC(O)R^b, NR^cC(O)OR^a, NR^cC(O)NR^cR^d, C(═NR^e)R^b, C(═NR^e)NR^cR^d, NR^cC(═NR^e)NR^cR^d, NR^cS(O)R^b, NR^cS(O)₂R^b, NR^cS(O)₂NR^cR^d, S(O)R^b, S(O)NR^cR^d, S(O)₂R^b, and S(O)₂NR^cR^d, wherein said substituents C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, C_6-10aryl, C_3-10cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C_6-10aryl-C_1-4alkyl, C_3-7cycloalkyl-C_1-4alkyl, 5-10 membered heteroaryl-C_1-4alkyl, 4-10 membered heterocycloalkyl-C_1-4alkyl are each optionally substituted by 1, 2, or 3 further substituents independently selected from halo, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, CN, NO₂, OR^a, SR^a, C(O)R^b, C(O)NR^cR^d, C(O)OR^a, OC(O)R^b, OC(O)NR^cR^dNR^cR^d, NR^cC(O)R^b, NR^cC(O)OR^a, NR^cC(O)NR^cR^d, C(═NR^e)R^b, C(═NR^e)NR^cR^d, NR^cC(═NR^e)NR^cR^d, NR^cS(O)R^b, NR^cS(O)₂R^b, NR^cS(O)₂NR^cR^d, S(O)R^b, S(O)NR^cR^d, S(O)₂R^b, and S(O)₂NR^cR^d;

each R¹is independently selected from H, halo, C_1-6alkyl, C_2-6alkenyl, C_1-6haloalkyl, and OR^a;

R², R³, and R⁴are each H;

each R^cand R^c3is independently selected from H, C_1-4alkyl, and CN; and

n is 0, 1, 2, or 3.

It is further appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, can also be provided in combination in a single embodiment (while the embodiments are intended to be combined as if written in multiply dependent form). Conversely, various features of the invention which are, for brevity, described in the context of a single embodiment, can also be provided separately or in any suitable subcombination. Thus, it is contemplated as features described as embodiments of the compounds of Formula I can be combined in any suitable combination.

At various places in the present specification, certain features of the compounds are disclosed in groups or in ranges. It is specifically intended that such a disclosure include each and every individual subcombination of the members of such groups and ranges. For example, the term “C_1-6alkyl” is specifically intended to individually disclose (without limitation) methyl, ethyl, C₃alkyl, C₄alkyl, C₅alkyl and C₆alkyl.

The term “n-membered,” where n is an integer, typically describes the number of ring-forming atoms in a moiety where the number of ring-forming atoms is n. For example, piperidinyl is an example of a 6-membered heterocycloalkyl ring, pyrazolyl is an example of a 5-membered heteroaryl ring, pyridyl is an example of a 6-membered heteroaryl ring and 1,2,3,4-tetrahydro-naphthalene is an example of a 10-membered cycloalkyl group.

At various places in the present specification, variables defining divalent linking groups may be described. It is specifically intended that each linking substituent include both the forward and backward forms of the linking substituent. For example, —NR(CR′R″)_n— includes both —NR(CR′R″)_n— and —(CR′R″)_nNR— and is intended to disclose each of the forms individually. Where the structure requires a linking group, the Markush variables listed for that group are understood to be linking groups. For example, if the structure requires a linking group and the Markush group definition for that variable lists “alkyl” or “aryl” then it is understood that the “alkyl” or “aryl” represents a linking alkylene group or arylene group, respectively.

The term “substituted” means that an atom or group of atoms formally replaces hydrogen as a “substituent” attached to another group. The term “substituted”, unless otherwise indicated, refers to any level of substitution, e.g., mono-, di-, tri-, tetra- or penta-substitution, where such substitution is permitted. The substituents are independently selected, and substitution may be at any chemically accessible position. It is to be understood that substitution at a given atom is limited by valency. It is to be understood that substitution at a given atom results in a chemically stable molecule. The phrase “optionally substituted” means unsubstituted or substituted. The term “substituted” means that a hydrogen atom is removed and replaced by a substituent. A single divalent substituent, e.g., oxo, can replace two hydrogen atoms.

The term “C_n-m” indicates a range which includes the endpoints, wherein n and m are integers and indicate the number of carbons. Examples include C_1-4, C_1-6and the like.

The term “alkyl” employed alone or in combination with other terms, refers to a saturated hydrocarbon group that may be straight-chained or branched. The term “Cn-m alkyl”, refers to an alkyl group having n to m carbon atoms. An alkyl group formally corresponds to an alkane with one C—H bond replaced by the point of attachment of the alkyl group to the remainder of the compound. In some embodiments, the alkyl group contains from 1 to 6 carbon atoms, from 1 to 4 carbon atoms, from 1 to 3 carbon atoms, or 1 to 2 carbon atoms. Examples of alkyl moieties include, but are not limited to, chemical groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl; higher homologs such as 2-methyl-1-butyl, n-pentyl, 3-pentyl, n-hexyl, 1,2,2-trimethylpropyl and the like.

The term “alkenyl” employed alone or in combination with other terms, refers to a straight-chain or branched hydrocarbon group corresponding to an alkyl group having one or more double carbon-carbon bonds. An alkenyl group formally corresponds to an alkene with one C—H bond replaced by the point of attachment of the alkenyl group to the remainder of the compound. The term “C_n-malkenyl” refers to an alkenyl group having n to m carbons. In some embodiments, the alkenyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms. Example alkenyl groups include, but are not limited to, ethenyl, n-propenyl, isopropenyl, n-butenyl, sec-butenyl and the like.

The term “alkynyl” employed alone or in combination with other terms, refers to a straight-chain or branched hydrocarbon group corresponding to an alkyl group having one or more triple carbon-carbon bonds. An alkynyl group formally corresponds to an alkyne with one C—H bond replaced by the point of attachment of the alkyl group to the remainder of the compound. The term “C_n-malkynyl” refers to an alkynyl group having n to m carbons. Example alkynyl groups include, but are not limited to, ethynyl, propyn-1-yl, propyn-2-yl and the like. In some embodiments, the alkynyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms.

The term “alkylene”, employed alone or in combination with other terms, refers to a divalent alkyl linking group. An alkylene group formally corresponds to an alkane with two C—H bond replaced by points of attachment of the alkylene group to the remainder of the compound. The term “C_n-malkylene” refers to an alkylene group having n to m carbon atoms. Examples of alkylene groups include, but are not limited to, ethan-1,2-diyl, ethan-1,1-diyl, propan-1,3-diyl, propan-1,2-diyl, propan-1,1-diyl, butan-1,4-diyl, butan-1,3-diyl, butan-1,2-diyl, 2-methyl-propan-1,3-diyl and the like.

The term “alkoxy”, employed alone or in combination with other terms, refers to a group of formula —O-alkyl, wherein the alkyl group is as defined above. The term “C_n-malkoxy” refers to an alkoxy group, the alkyl group of which has n to m carbons. Example alkoxy groups include methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), t-butoxy and the like. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. The term “C_n-mdialkoxy” refers to a linking group of formula —O—(C_n-malkyl)-O—, the alkyl group of which has n to m carbons. Example dialkyoxy groups include —OCH₂CH₂O— and OCH₂CH₂CH₂O—. In some embodiments, the two O atoms of a C_n-mdialkoxy group may be attached to the same B atom to form a 5- or 6-membered heterocycloalkyl group.

The term “amino” refers to a group of formula —NH₂.

The term “carbonyl”, employed alone or in combination with other terms, refers to a —C(═O)— group, which also may be written as C(O).

The term “cyano” or “nitrile” refers to a group of formula —C≡N, which also may be written as —CN.

The terms “halo” or “halogen”, used alone or in combination with other terms, refers to fluoro, chloro, bromo and iodo. In some embodiments, “halo” refers to a halogen atom selected from F, Cl, or Br. In some embodiments, halo groups are F.

The term “haloalkyl” as used herein refers to an alkyl group in which one or more of the hydrogen atoms has been replaced by a halogen atom. The term “C_n-mhaloalkyl” refers to a C_n-malkyl group having n to m carbon atoms and from at least one up to {2(n to m)+1} halogen atoms, which may either be the same or different. In some embodiments, the halogen atoms are fluoro atoms. In some embodiments, the haloalkyl group has 1 to 6 or 1 to 4 carbon atoms. Example haloalkyl groups include CF₃, C₂F₅, CHF₂, CH₂F, CCl₃, CHCl₂, C₂Cl₅and the like. In some embodiments, the haloalkyl group is a fluoroalkyl group.

The term “haloalkoxy”, employed alone or in combination with other terms, refers to a group of formula —O-haloalkyl, wherein the haloalkyl group is as defined above. The term “C_n-mhaloalkoxy” refers to a haloalkoxy group, the haloalkyl group of which has n to m carbons. Example haloalkoxy groups include trifluoromethoxy and the like. In some embodiments, the haloalkoxy group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

The term “oxo” refers to an oxygen atom as a divalent substituent, forming a carbonyl group when attached to carbon, or attached to a heteroatom forming a sulfoxide or sulfone group, or an N-oxide group. In some embodiments, heterocyclic groups may be optionally substituted by 1 or 2 oxo (═O) substituents.

The term “sulfido” refers to a sulfur atom as a divalent substituent, forming a thiocarbonyl group (C═S) when attached to carbon.

The term “oxidized” in reference to a ring-forming N atom refers to a ring-forming N-oxide.

The term “oxidized” in reference to a ring-forming S atom refers to a ring-forming sulfonyl or ring-forming sulfinyl.

The term “aromatic” refers to a carbocycle or heterocycle having one or more polyunsaturated rings having aromatic character (i.e., having (4n+2) delocalized π (pi) electrons where n is an integer).

The term “aryl,” employed alone or in combination with other terms, refers to an aromatic hydrocarbon group, which may be monocyclic or polycyclic (e.g., having 2 fused rings). The term “C_n-maryl” refers to an aryl group having from n to m ring carbon atoms. Aryl groups include, e.g., phenyl, naphthyl, and the like. In some embodiments, aryl groups have from 6 to about 10 carbon atoms. In some embodiments aryl groups have 6 carbon atoms. In some embodiments aryl groups have 10 carbon atoms. In some embodiments, the aryl group is phenyl.

The term “heteroaryl” or “heteroaromatic,” employed alone or in combination with other terms, refers to a monocyclic or polycyclic aromatic heterocycle having at least one heteroatom ring member selected from sulfur, oxygen and nitrogen. In some embodiments, the heteroaryl ring has 1, 2, 3 or 4 heteroatom ring members independently selected from nitrogen, sulfur and oxygen. In some embodiments, any ring-forming N in a heteroaryl moiety can be an N-oxide. In some embodiments, the heteroaryl has 5-14 ring atoms including carbon atoms and 1, 2, 3 or 4 heteroatom ring members independently selected from nitrogen, sulfur and oxygen. In some embodiments, the heteroaryl has 5-10 ring atoms including carbon atoms and 1, 2, 3 or 4 heteroatom ring members independently selected from nitrogen, sulfur and oxygen. In some embodiments, the heteroaryl has 5-6 ring atoms and 1 or 2 heteroatom ring members independently selected from nitrogen, sulfur and oxygen. In some embodiments, the heteroaryl is a five-membered or six-membered heteroaryl ring. In other embodiments, the heteroaryl is an eight-membered, nine-membered or ten-membered fused bicyclic heteroaryl ring. Example heteroaryl groups include, but are not limited to, pyridinyl (pyridyl), pyrimidinyl, pyrazinyl, pyridazinyl, and the like.

A five-membered heteroaryl ring is a heteroaryl group having five ring atoms wherein one or more (e.g., 1, 2 or 3) ring atoms are independently selected from N, O and S. Exemplary five-membered ring heteroaryls include thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-triazolyl, 1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-triazolyl, 1,3,4-thiadiazolyl and 1,3,4-oxadiazolyl.

A six-membered heteroaryl ring is a heteroaryl group having six ring atoms wherein one or more (e.g., 1, 2 or 3) ring atoms are independently selected from N, O and S. Exemplary six-membered ring heteroaryls are pyridyl, pyrazinyl, pyrimidinyl, triazinyl, isoindolyl, and pyridazinyl.

The term “cycloalkyl,” employed alone or in combination with other terms, refers to a non-aromatic hydrocarbon ring system (monocyclic, bicyclic or polycyclic), including cyclized alkyl and alkenyl groups. The term “C_n-mcycloalkyl” refers to a cycloalkyl that has n to m ring member carbon atoms. Cycloalkyl groups can include mono- or polycyclic (e.g., having 2, 3 or 4 fused rings) groups and spirocycles. Cycloalkyl groups can have 3, 4, 5, 6 or 7 ring-forming carbons (C_3-7). In some embodiments, the cycloalkyl group has 3 to 6 ring members, 3 to 5 ring members, or 3 to 4 ring members. In some embodiments, the cycloalkyl group is monocyclic. In some embodiments, the cycloalkyl group is monocyclic or bicyclic. In some embodiments, the cycloalkyl group is a C_3-6monocyclic cycloalkyl group. Ring-forming carbon atoms of a cycloalkyl group can be optionally oxidized to form an oxo or sulfido group. Cycloalkyl groups also include cycloalkylidenes. In some embodiments, cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. Also included in the definition of cycloalkyl are moieties that have one or more aromatic rings fused (i.e., having a bond in common with) to the cycloalkyl ring, e.g., benzo or thienyl derivatives of cyclopentane, cyclohexane and the like. A cycloalkyl group containing a fused aromatic ring can be attached through any ring-forming atom including a ring-forming atom of the fused aromatic ring. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcarnyl, bicyclo[1.1.1]pentanyl, bicyclo[2.1.1]hexanyl, and the like. In some embodiments, the cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

The term “heterocycloalkyl,” employed alone or in combination with other terms, refers to a non-aromatic ring or ring system, which may optionally contain one or more alkenylene groups as part of the ring structure, which has at least one heteroatom ring member independently selected from nitrogen, sulfur, oxygen and phosphorus, and which has 4-10 ring members, 4-7 ring members, or 4-6 ring members. Included within the term “heterocycloalkyl” are monocyclic 4-, 5-, 6- and 7-membered heterocycloalkyl groups. Heterocycloalkyl groups can include mono- or bicyclic (e.g., having two fused or bridged rings) or spirocyclic ring systems. In some embodiments, the heterocycloalkyl group is a monocyclic group having 1, 2 or 3 heteroatoms independently selected from nitrogen, sulfur and oxygen. Ring-forming carbon atoms and heteroatoms of a heterocycloalkyl group can be optionally oxidized to form an oxo or sulfido group or other oxidized linkage (e.g., C(O), S(O), C(S) or S(O)₂, N-oxide etc.) or a nitrogen atom can be quaternized. The heterocycloalkyl group can be attached through a ring-forming carbon atom or a ring-forming heteroatom. In some embodiments, the heterocycloalkyl group contains 0 to 3 double bonds. In some embodiments, the heterocycloalkyl group contains 0 to 2 double bonds. Also included in the definition of heterocycloalkyl are moieties that have one or more aromatic rings fused (i.e., having a bond in common with) to the heterocycloalkyl ring, e.g., benzo or thienyl derivatives of piperidine, morpholine, azepine, etc. A heterocycloalkyl group containing a fused aromatic ring can be attached through any ring-forming atom including a ring-forming atom of the fused aromatic ring.

At certain places, the definitions or embodiments refer to specific rings (e.g., an azetidine ring, a pyridine ring, etc.). Unless otherwise indicated, these rings can be attached to any ring member provided that the valency of the atom is not exceeded. For example, an azetidine ring may be attached at any position of the ring, whereas an azetidin-3-yl ring is attached at the 3-position.

The compounds described herein can be asymmetric (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise indicated. Compounds of the present invention that contain asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods on how to prepare optically active forms from optically inactive starting materials are known in the art, such as by resolution of racemic mixtures or by stereoselective synthesis. Many geometric isomers of olefins, C═N double bonds and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms.

Resolution of racemic mixtures of compounds can be carried out by any of numerous methods known in the art. One method includes fractional recrystallization using a chiral resolving acid which is an optically active, salt-forming organic acid. Suitable resolving agents for fractional recrystallization methods are, e.g., optically active acids, such as the D and L forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or the various optically active camphorsulfonic acids such as β-camphorsulfonic acid. Other resolving agents suitable for fractional crystallization methods include stereoisomerically pure forms of α-methylbenzylamine (e.g., S and R forms, or diastereomerically pure forms), 2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane and the like.

Resolution of racemic mixtures can also be carried out by elution on a column packed with an optically active resolving agent (e.g., dinitrobenzoylphenylglycine). Suitable elution solvent composition can be determined by one skilled in the art.

In some embodiments, the compounds of the invention have the (R)-configuration. In other embodiments, the compounds have the (S)-configuration. In compounds with more than one chiral centers, each of the chiral centers in the compound may be independently (R) or (S), unless otherwise indicated.

Compounds of the invention also include tautomeric forms. Tautomeric forms result from the swapping of a single bond with an adjacent double bond together with the concomitant migration of a proton. Tautomeric forms include prototropic tautomers which are isomeric protonation states having the same empirical formula and total charge. Example prototropic tautomers include ketone-enol pairs, amide-imidic acid pairs, lactam-lactim pairs, enamine-imine pairs, and annular forms where a proton can occupy two or more positions of a heterocyclic system, e.g., 1H- and 3H-imidazole, 1H-, 2H- and 4H-1,2,4-triazole, 1H- and 2H-isoindole and 1H- and 2H-pyrazole. Tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution.

Compounds of the invention can also include all isotopes of atoms occurring in the intermediates or final compounds. Isotopes include those atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium. One or more constituent atoms of the compounds of the invention can be replaced or substituted with isotopes of the atoms in natural or non-natural abundance. In some embodiments, the compound includes at least one deuterium atom. For example, one or more hydrogen atoms in a compound of the present disclosure can be replaced or substituted by deuterium. In some embodiments, the compound includes two or more deuterium atoms. In some embodiments, the compound includes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 deuterium atoms. Synthetic methods for including isotopes into organic compounds are known in the art (Deuterium Labeling in Organic Chemistry by Alan F. Thomas (New York, N.Y., Appleton-Century-Crofts, 1971; The Renaissance of H/D Exchange by Jens Atzrodt, Volker Derdau, Thorsten Fey and Jochen Zimmermann, Angew. Chem. Int. Ed. 2007, 7744-7765; The Organic Chemistry of Isotopic Labelling by James R. Hanson, Royal Society of Chemistry, 2011). Isotopically labeled compounds can used in various studies such as NMR spectroscopy, metabolism experiments, and/or assays.

The term, “compound,” as used herein is meant to include all stereoisomers, geometric isomers, tautomers and isotopes of the structures depicted. The term is also meant to refer to compounds of the inventions, regardless of how they are prepared, e.g., synthetically, through biological process (e.g., metabolism or enzyme conversion), or a combination thereof.

All compounds, and pharmaceutically acceptable salts thereof, can be found together with other substances such as water and solvents (e.g., hydrates and solvates) or can be isolated. When in the solid state, the compounds described herein and salts thereof may occur in various forms and may, e.g., take the form of solvates, including hydrates. The compounds may be in any solid state form, such as a polymorph or solvate, so unless clearly indicated otherwise, reference in the specification to compounds and salts thereof should be understood as encompassing any solid state form of the compound.

In some embodiments, the compounds of the invention, or salts thereof, are substantially isolated. By “substantially isolated” is meant that the compound is at least partially or substantially separated from the environment in which it was formed or detected. Partial separation can include, e.g., a composition enriched in the compounds of the invention. Substantial separation can include compositions containing at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, or at least about 99% by weight of the compounds of the invention, or salt thereof.

The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

The expressions, “ambient temperature” and “room temperature,” as used herein, are understood in the art, and refer generally to a temperature, e.g., a reaction temperature, that is about the temperature of the room in which the reaction is carried out, e.g., a temperature from about 20° C. to about 30° C.

The present invention also includes pharmaceutically acceptable salts of the compounds described herein. The term “pharmaceutically acceptable salts” refers to derivatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts of the present invention include the non-toxic salts of the parent compound formed, e.g., from non-toxic inorganic or organic acids. The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, non-aqueous media like ether, ethyl acetate, alcohols (e.g., methanol, ethanol, iso-propanol or butanol) or acetonitrile (MeCN) are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17^thEd., (Mack Publishing Company, Easton, 1985), p. 1418, Berge et al., J. Pharm. Sci., 1977, 66(1), 1-19 and in Stahl et al., Handbook of Pharmaceutical Salts: Properties, Selection, and Use, (Wiley, 2002). In some embodiments, the compounds described herein include the N-oxide forms.

Synthesis

Compounds of the invention, including salts thereof, can be prepared using known organic synthesis techniques and can be synthesized according to any of numerous possible synthetic routes, such as those in the Schemes below.

The reactions for preparing compounds of the invention can be carried out in suitable solvents which can be readily selected by one of skill in the art of organic synthesis. Suitable solvents can be substantially non-reactive with the starting materials (reactants), the intermediates or products at the temperatures at which the reactions are carried out, e.g., temperatures which can range from the solvent's freezing temperature to the solvent's boiling temperature. A given reaction can be carried out in one solvent or a mixture of more than one solvent. Depending on the particular reaction step, suitable solvents for a particular reaction step can be selected by the skilled artisan.

Preparation of compounds of the invention can involve the protection and deprotection of various chemical groups. The need for protection and deprotection, and the selection of appropriate protecting groups, can be readily determined by one skilled in the art. The chemistry of protecting groups is described, e.g., in Kocienski, Protecting Groups, (Thieme, 2007); Robertson, Protecting Group Chemistry, (Oxford University Press, 2000). Smith et al., March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 6^thEd. (Wiley, 2007); Peturssion et al., “Protecting Groups in Carbohydrate Chemistry,” J. Chem. Educ., 1997, 74(11), 1297; and Wuts et al., Protective Groups in Organic Synthesis, 4th Ed., (Wiley, 2006).

Reactions can be monitored according to any suitable method known in the art. For example, product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g., ¹H or ³C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), mass spectrometry or by chromatographic methods such as high performance liquid chromatography (HPLC) or thin layer chromatography (TLC).

The Schemes below provide general guidance in connection with preparing the compounds of the invention. One skilled in the art would understand that the preparations shown in the Schemes can be modified or optimized using general knowledge of organic chemistry to prepare various compounds of the invention.

embedded image

A general synthesis of compounds of the invention comprises a 2-step procedure as shown in General Scheme 1 above. A 5-aminoindazole or aza derivative (1.1) with suitable substitution at C3 (L=leaving group, eg.: Cl, Br, I, OTf) is coupled with a suitable aryl, alkenyl, or alkyl borane (1.2) using a metal-catalyzed cross-coupling reaction employing reagents such as Pd(amphos)Cl₂or PdCl₂(dppf)₂(see: Chem. Rev. 1995, 95, 2457; Chem. Soc. Rev. 2014, 43, 412; J. Organomet. Chem. 1999, 576, 147) to afford intermediate 1.3. Combining intermediate 1.3 and carboxylic acid 1.4 with a suitable activating agent such as T3P or EDCI (see: Chem. Soc. Rev. 2009, 38, 606) to form an amide bond will lead to products of type 1.5 (Formula I). Products of type 1.3 and 1.5 can be purified by silica gel chromatography, preparative reverse-phase HPLC, SFC, as well as other purification methods such as crystallization.

embedded image

Alternatively, products of type 1.5 may be prepared using the 2-step procedure as shown in General Scheme 2. A 5-aminoindazole or aza derivative thereof (1.1) with substitution at C3 (L=leaving group, eg.: Cl, Br, I, OTf) is coupled with a carboxylic acid using a suitable activating agent such as T3P or EDCI (see: Chem. Soc. Rev. 2009, 38, 606) to form an amide of type 1.6. The amide intermediate (1.6) is then coupled with a suitable aryl, alkenyl, or alkyl borane (1.2) using a metal-catalyzed cross-coupling reaction employing reagents such as Pd(amphos)Cl₂or PdCl₂(dppf)₂(see: Chem. Rev. 1995, 95, 2457; Chem. Soc. Rev. 2014, 43, 412; J. Organomet. Chem. 1999, 576, 147) to afford products of type 1.5 (Formula I). Products of type 1.6 and 1.5 can be purified by silica gel chromatography, preparative reverse-phase HPLC, SFC, as well as other purification methods such as crystallization.

Methods of Use

Over-activation of LRRK2 kinase activity, e.g., in kinase mutant G2019S, is a mechanism in alpha-synuclein related neurodegeneration, and is implicated in diseases that are characterized by the formation of Lewy bodies. Compounds as described herein, e.g., compounds of Formula I, exhibit inhibitory activity against LRRK2 kinase, including LRRK2 mutant kinase, such as mutant G2019S. Kinase activity can be determined using a kinase assay, which typically employs a kinase substrate and a phosphate group donor, such as ATP (or a derivative thereof). An exemplary kinase assay is described in Example A.

The present disclosure provides methods of modulating (e.g., inhibiting) LRRK2 activity, by contacting LRRK2 with a compound of the invention, or a pharmaceutically acceptable salt thereof. In some embodiments, the contacting can be administering to a patient, in need thereof, a compound provided herein, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compounds of the present disclosure, or pharmaceutically acceptable salts thereof, are useful for therapeutic administration to treat neurodegenerative disease. For example, a method of treating a disease or disorder associated with inhibition of LRRK2 interaction can include administering to a patient in need thereof a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof. The compounds of the present disclosure can be used alone, in combination with other agents or therapies or as an adjuvant or neoadjuvant for the treatment of diseases or disorders, including neurodegenerative diseases. For the uses described herein, any of the compounds of the disclosure, including any of the embodiments thereof, may be used.

Compounds and compositions as described herein, e.g., compounds of Formula I are useful in the treatment and/or prevention of LRRK2 kinase mediated disorders, including LRRK2 kinase mutant mediated diseases. LRRK2 kinase mutant G2019S mediated diseases include, but are not limited to, neurological diseases such as Parkinson's disease and other Lewy body diseases such as Parkinson disease with dementia, Parkinson's associated risk syndrome, dementia with Lewy bodies (e.g., diffuse Lewy body disease (DLBD), Lewy body dementia, Lewy body disease, cortical Lewy body disease or senile dementia of Lewy type), Lewy body variant of Alzheimer's disease (i.e., diffuse Lewy body type of Alzheimer's disease), combined Parkinson's disease and Alzheimer's disease, as well as diseases associated with glial cortical inclusions, such as syndromes identified as multiple system atrophy, including striatonigral degeneration, olivopontocerebellar atrophy, and Shy-Drager syndrome, or other diseases associated with Parkinsonism, such as Hallervorden-Spatz syndrome (also referred to as Hallervorden-Spatz disease), fronto-temporal dementia, Sandhoff disease, progressive supranuclear palsy, corticobasal degeneration, autonomic dysfunctions (e.g., postural or orthostatic hypotension), cerebellar dysfunctions, ataxia, movement disorders, cognitive deterioration, sleep disorders, hearing disorders, tremors, rigidity (e.g., joint stiffness, increased muscle tone), bradykinesia, akinesia and postural instability (failure of postural reflexes, along other disease related factors such as orthostatic hypotension or cognitive and sensory changes, which lead to impaired balance and falls); cancers, including melanoma, acute myelogenous leukemia, breast carcinoma, lung adenocarincoma, prostate adenocarcinoma, renal cell carcinoma, and papillary thyroid carcinoma; autoimmune diseases such as Inflammatory Bowel Disease (e.g. Crohn's disease and ulcerative colitis); and leprosy.

In some embodiments, a method of treating a disease is provided comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein the disease is selected from the group consisting of Parkinson's disease, Parkinson disease with dementia, Parkinson's associated risk syndrome, dementia with Lewy bodies, Lewy body variant of Alzheimer's disease, combined Parkinson's disease and Alzheimer's disease, multiple system atrophy, striatonigral degeneration, olivopontocerebellar atrophy, Shy-Drager syndrome, Hallervorden-Spatz syndrome, fronto-temporal dementia, Sandhoff disease, progressive supranuclear palsy, corticobasal degeneration, postural hypotension, orthostatic hypotension, cerebellar dysfunctions, ataxia, movement disorders, cognitive deterioration, sleep disorders, hearing disorders, tremors, rigidity, bradykinesia, akinesia, postural instability, melanoma, acute myelogenous leukemia, breast carcinoma, lung adenocarincoma, prostate adenocarcinoma, renal cell carcinoma, papillary thyroid carcinoma, Crohn's disease, ulcerative colitis, and leprosy.

In some embodiments, a method of treating a neurological disease is provided comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein the neurological disease is selected from the group consisting of Parkinson's disease, Parkinson disease with dementia, Parkinson's associated risk syndrome, dementia with Lewy bodies, Lewy body variant of Alzheimer's disease, combined Parkinson's disease and Alzheimer's disease, multiple system atrophy, striatonigral degeneration, olivopontocerebellar atrophy, Shy-Drager syndrome, Hallervorden-Spatz syndrome, fronto-temporal dementia, Sandhoff disease, progressive supranuclear palsy, corticobasal degeneration, postural hypotension, orthostatic hypotension, cerebellar dysfunctions, ataxia, movement disorders, cognitive deterioration, sleep disorders, hearing disorders, tremors, rigidity, bradykinesia, akinesia, and postural instability.

In some embodiments, a method of treating Parkinson's disease is provided comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof.

In some embodiments, a method of treating a cancer is provided comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein the cancer is selected from the group consisting of melanoma, acute myelogenous leukemia, breast carcinoma, lung adenocarincoma, prostate adenocarcinoma, renal cell carcinoma, and papillary thyroid carcinoma.

In some embodiments, a method of treating an autoimmune disease is provided comprising administering to a patient in need thereof a therapeutically effective amount of a compound od Formula I, or a pharmaceutically acceptable salt thereof, wherein the autoimmune disease is selected from the group consisting of Crohn's disease and ulcerative colitis.

In some embodiments, a method of treating leprosy is provided comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, or a composition comprising such compound or salt thereof.

In some embodiments, the compounds as described herein, e.g., compounds of Formula I, are inhibitors of LRRK2 kinase activity. In some embodiments, the compounds as described herein, e.g. compounds of Formula I, are inhibitors of LRRK2 mutant kinase activity. In some embodiments, the compounds as described herein, e.g. compounds of Formula I, are inhibitors of LRRK2 mutant G2019S kinase activity.

Compounds as described herein, e.g., compounds of Formula I, exhibit cellular biological activities, including but not limited to reduction in phosphorylation of ser910 or ser935 in HEK-293 cells transfected with either wild-type LRRK2 or LRRK2 G2019S mutant.

In some embodiments, compounds of Formula I are selective LRRK2 G2019S mutant inhibitors as compared to wild-type LRRK2.

As used herein, the term “contacting” refers to the bringing together of the indicated moieties in an in vitro system or an in vivo system such that they are in sufficient physical proximity to interact.

The terms “individual” or “patient,” used interchangeably, refer to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans.

The phrase “therapeutically effective amount” refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal, individual or human that is being sought by a researcher, veterinarian, medical doctor or other clinician.

As used herein, the term “treating” or “treatment” refers to one or more of (1) inhibiting the disease; e.g., inhibiting a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., arresting further development of the pathology and/or symptomatology); and (2) ameliorating the disease; e.g., ameliorating a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reversing the pathology and/or symptomatology) such as decreasing the severity of disease.

As used herein, the term “selective” or “selectivity” as it relates to kinase activity, means that a compound as described herein, e.g. a compound of Formula I, is a more potent inhibitor of a particular kinase, such as LRRK2 kinase, when compared to another kinase. While LRRK2 has other enzymatic activities, it is understood that when inhibitory activity or selectivity of LRRK2, or any mutation thereof, is mentioned, it is the LRRK2 kinase activity that is being referred to, unless clearly stated otherwise. As such, selectivity of LRRK2 relative to another kinase indicates a comparison of the IC₅₀of a compound on the kinase activity of LRRK2 to the IC₅₀of the compound on the kinase activity of another kinase. For example, a compound that is 10 fold selective for LRRK2 kinase activity relative to another kinase activity will have a ratio of IC₅₀(other kinase)÷IC₅₀(LRRK2)=10 (or a ratio of IC₅₀(LRRK2)÷IC₅₀(other kinase)=0.1).

In some embodiments, a compound as described herein, e.g., a compound of Formula I, is selective for a LRRK2 mutant over wild type LRRK2. Selectivity of LRRK2 mutants relative to wild type LRRK2 indicates a comparison of the IC₅₀of a compound on the kinase activity of the mutant LRRK2 to the IC₅₀of the compound on the kinase activity of wild type LRRK2. For example, a compound that is 10 fold selective for LRRK2 mutant kinase activity relative to wild type LRKK2 kinase activity will have a ratio of IC₅₀(wild type LRRK2)÷IC₅₀(mutant LRRK2)=10. In some embodiments, a compound provided herein is greater than 1 fold selective, greater than 2 fold selective, greater than 5 fold selective, greater than 10 fold selective, greater than 25 fold selective, or greater than 50 fold selective for LRRK2 mutant kinase over wild type LRRK2. In some embodiments, the LRRK2 mutant is LRRK2 G2019S.

The term “LRRK2-mediated condition”, “Leucine-rich repeat kinase 2 mediated disorder” or any other variation thereof, as used herein means any disease or other condition in which LRRK2, including any mutations thereof, is known to play a role, or a disease state that is associated with elevated activity or expression of LRRK2, including any mutations thereof. For example, a “LRRK2-mediated condition” may be relieved by inhibiting LRRK2 kinase activity. Such conditions include certain neurodegenerative diseases, such as Lewy body diseases, including, but not limited to, Parkinson's disease, Lewy body variant of Alzheimer's disease, combined Parkinson's disease and Alzheimer's disease, dementia with Lewy bodies, diffuse Lewy body disease, as well as any syndrome identified as multiple system atrophy; certain cancers, such as melanoma, papillary renal cell carcinoma and papillary thyroid carcinoma; certain autoimmune diseases, such as Inflammatory Bowel Disease (e.g. Crohn's disease and ulcerative colitis); and leprosy.

The term “neurodegenerative diseases” includes any disease or condition characterized by problems with movements, such as ataxia, and conditions affecting cognitive abilities (e.g., memory) as well as conditions generally related to all types of dementia. “Neurodegenerative diseases” may be associated with impairment or loss of cognitive abilities, potential loss of cognitive abilities and/or impairment or loss of brain cells. Exemplary “neurodegenerative diseases” include Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), Down syndrome, dementia, multi-infarct dementia, mild cognitive impairment (MCI), epilepsy, seizures, Huntington's disease, neurodegeneration induced by viral infection (e.g. AIDS, encephalopathies), traumatic brain injuries, as well as ischemia and stroke.

“Neurodegenerative diseases” also includes any undesirable condition associated with the disease. For instance, a method of treating a neurodegenerative disease includes methods of treating or preventing loss of neuronal function characteristic of neurodegenerative disease.

In some embodiments, the compounds of the invention are useful in preventing or reducing the risk of developing any of the diseases referred to herein; e.g., preventing or reducing the risk of developing a disease, condition or disorder in an individual who may be predisposed to the disease, condition or disorder but does not yet experience or display the pathology or symptomatology of the disease.

Combination Therapies

One or more additional pharmaceutical agents or treatment methods can be used in combination with a compound of Formula I for treatment of LRRK2-associated diseases, disorders, or conditions, or diseases or conditions as described herein. The agents can be combined with the present compounds in a single dosage form, or the agents can be administered simultaneously or sequentially as separate dosage forms. In some embodiments, the additional pharmaceutical agent is a dopamine precursor, including, for example, levodopa, melevodopa, and etilevodopa. In some embodiments, the additional pharmaceutical agent is a dopamine agonist, including, for example, pramipexole, ropinorole, apomorphine, rotigotine, bromocriptine, cabergoline, and pergolide. In some embodiments, the additional pharmaceutical agent is a monamine oxidase B (“MAO B”) inhibitor, including, for example, selegiline and rasagiline. In some embodiments, the additional pharmaceutical agent is a catechol O-methyltransferase (“COMT”) inhibitor, including, for example, tolcapone and entacapone. In some embodiments, the additional pharmaceutical agent is an anticholinergic agent including, for example, benztropine, trihexyphenidyl, procyclidine, and biperiden. In some embodiments, the additional pharmaceutical agent is a glutamate (“NMDA”) blocking drug, including, for example, amantadine. In some embodiments, the additional pharmaceutical agent is an adenosine A2A antagonist, including, for example, istradefylline and preladenant. In some embodiments, the additional pharmaceutical agent is a 5-HT1a antagonist, including, for example, piclozotan and pardoprunox. In some embodiments, the additional pharmaceutical agent is an alpha 2 antagonist, including, for example, atipamezole and fipamezole.

Formulations, Dosage Forms, and Administration

When employed as pharmaceuticals, the compounds of the present disclosure can be administered in the form of pharmaceutical compositions. Thus the present disclosure provides a composition comprising a compound of Formula I or any of the formulas as described herein, a compound as recited in any of the claims and described herein, or a pharmaceutically acceptable salt thereof, or any of the embodiments thereof, and at least one pharmaceutically acceptable carrier. These compositions can be prepared in a manner well known in the pharmaceutical arts, and can be administered by a variety of routes, depending upon whether local or systemic treatment is indicated and upon the area to be treated. Administration may be topical (including transdermal, epidermal, ophthalmic and to mucous membranes including intranasal, vaginal and rectal delivery), pulmonary (e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal or intranasal), oral or parenteral. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal intramuscular or injection or infusion; or intracranial, e.g., intrathecal or intraventricular, administration. Parenteral administration can be in the form of a single bolus dose, or may be, e.g., by a continuous perfusion pump. Pharmaceutical compositions and formulations for topical administration may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders. Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like may be necessary or desirable.

This invention also includes pharmaceutical compositions which contain, as the active ingredient, the compound of the present disclosure or a pharmaceutically acceptable salt thereof, in combination with one or more pharmaceutically acceptable carriers. In some embodiments, the composition is suitable for topical administration. In making the compositions of the invention, the active ingredient is typically mixed with an excipient, diluted by an excipient or enclosed within such a carrier in the form of, e.g., a capsule, sachet, paper, or other container. When the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, e.g., up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions and sterile packaged powders.

In some embodiments, the composition is a sustained release composition comprising at least one compound described herein, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier or excipient

The compositions can be formulated in a unit dosage form, each dosage containing from about 5 to about 1,000 mg (1 g). The term “unit dosage forms” refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.

The active compound may be effective over a wide dosage range and is generally administered in a therapeutically effective amount. It will be understood, however, that the amount of the compound actually administered will usually be determined by a physician, according to the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms and the like.

The therapeutic dosage of a compound of the present invention can vary according to, e.g., the particular use for which the treatment is made, the manner of administration of the compound, the health and condition of the patient, and the judgment of the prescribing physician. The proportion or concentration of a compound of the invention in a pharmaceutical composition can vary depending upon a number of factors including dosage, chemical characteristics (e.g., hydrophobicity), and the route of administration. The dosage is likely to depend on such variables as the type and extent of progression of the disease or disorder, the overall health status of the particular patient, the relative biological efficacy of the compound selected, formulation of the excipient, and its route of administration. Effective doses can be extrapolated from dose-response curves derived from in vitro or animal model test systems.

The liquid forms in which the compounds and compositions of the present invention can be incorporated for administration orally or by injection include aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.

Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described supra. In some embodiments, the compositions are administered by the oral or nasal respiratory route for local or systemic effect. Compositions can be nebulized by use of inert gases. Nebulized solutions may be breathed directly from the nebulizing device or the nebulizing device can be attached to a face mask, tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions can be administered orally or nasally from devices which deliver the formulation in an appropriate manner.

Topical formulations can contain one or more conventional carriers. In some embodiments, ointments can contain water and one or more hydrophobic carriers.

EXAMPLES

Experimental procedures for compounds of the invention are provided below. Where the preparation of starting materials is not described, these are commercially available, known in the literature, or readily obtainable by those skilled in the art using standard procedures. Where it is stated that compounds were prepared analogously to earlier examples or intermediates, it will be appreciated by the skilled person that the reaction time, number of equivalents of reagents and temperature can be modified for each specific reaction and that it may be necessary or desirable to employ different work-up or purification techniques. Where reactions are carried out using microwave irradiation, the microwave used is a Biotage Initiator. The actual power supplied varies during the course of the reaction in order to maintain a constant temperature.

All solvents used were commercially available and were used without further purification. Reactions were typically run using anhydrous solvents under an inert atmosphere of nitrogen.

Liquid Chromatography-Mass Spectrometry Method A

Instrument Name: MDAP_Fractionlynx; Method Description: Semi preparative MDAP Method; LC/MS System: Fractionlynx (Waters) with ZQ MS detector; LC/MS Conditions: Column: XSelect CSH Prep. C18 5 μm OBD 30×100 mm @ room T; Injection loop: 1 ml; Solvents: A=H₂O+0.1% HCOOH; B=MeCN.

Gradient:

Time
Flow Rate

(min)
(ml/min)
% A
% B
Curve

initial
40.0
60.0
40.0
—

10.0
40.0
20.0
80.0
6

10.5
40.0
0.0
100.0
6

14.5
40.0
0.0
100.0
6

15.0
40.0
60.0
40.0
6

16.1
3.0
60.0
40.0
6

The curve parameter followed Waters definition (6=linear, 11=step); Acquisition stop time: 15 min; UV Conditions: UV detection range: 210 nm to 350 nm; Acquisition rate: 1.0 spectra/s; MS Conditions: Ionisation mode: Positive Electrospray (ES+); Scan Range: ES+ 100 to 900 AMU; Scan Duration: 0.50 seconds.

Liquid Chromatography-Mass Spectrometry Method B

Gradient:

Time
Flow Rate

(min)
(ml/min)
% A
% B
Curve

initial
40.0
60.0
40.0
—

10.0
40.0
30.0
70.0
6

10.5
40.0
0.0
100.0
6

14.5
40.0
0.0
100.0
6

15.0
40.0
60.0
40.0
6

16.1
3.0
60.0
40.0
6

Liquid Chromatography-Mass Spectrometry Method C

Instrument Name: MDAP_Fractionlynx; Method Description: Semi preparative MDAP Method; LC/MS System: Fractionlynx (Waters) with ZQ MS detector; LC/MS Conditions: Column: XSelect CSH Prep. C18 5 μm OBD 30×100 mm @ room T, Injection loop: 1 mL; Solvents: A=H₂O+0.1% HCOOH; B=MeCN.

Gradient:

Time
Flow Rate

(min)
(ml/min)
% A
% B
Curve

initial
40.0
60.0
40.0
—

6.0
40.0
35.0
65.0
6

7.0
40.0
0.0
100.0
6

10.0
40.0
0.0
100.0
6

10.5
40.0
60.0
40.0
6

11.0
3.0
60.0
40.0
6

The curve parameter followed Waters definition (6=linear, 11=step); Acquisition stop time: 11 min; UV Conditions: UV detection range: 210 nm to 350 nm; Acquisition rate: 1.0 spectra/s; MS Conditions: Ionisation mode: Positive Electrospray (ES+); Scan Range: ES+ 100 to 900 AMU; Scan Duration: 0.50 seconds.

Liquid Chromatography-Mass Spectrometry Method D

Gradient:

Time
Flow Rate

(min)
(ml/min)
% A
% B
Curve

initial
40.0
90.0
10.0
—

10.0
40.0
40.0
60.0
6

10.5
40.0
0.0
100.0
6

14.5
40.0
0.0
100.0
6

15.0
40.0
90.0
10.0
6

16.1
3.0
90.0
10.0
6

Liquid Chromatography Method E

Instrument Name: Gilson GX-281 AutoPurification System

Column: Welch Ultimate AQ-C18, 150×30 mm, 5 um particle size

Solvents: A=H₂O+0.1% TFA; B=MeCN

Gradient: 30-60% B depending on compound polarity

Liquid Chromatography-Mass Spectrometry Method F

Gradient:

Time
Flow Rate

(min)
(ml/min)
% A
% B
Curve

initial
40.0
76.0
24.0
—

10.0
40.0
66.0
34.0
6

10.5
40.0
0.0
100.0
6

14.5
40.0
0.0
100.0
6

15.0
40.0
76.0
24.0
6

15.1
3.0
76.0
24.0
6

Liquid Chromatography-Mass Spectrometry Method G

Instrument Name: MDAP_Fractionlynx; Method Description: Semi preparative MDAP Method; LC/MS System: Fractionlynx (Waters) with ZQ MS detector: LC/MS Conditions: Column: XSelect CSH Prep. C18 5 μm OBD 30×100 mm @ room T; Injection loop: 1 ml; Solvents: A=H₂O+0.1% HCOOH; B=MeCN.

Gradient:

Time
Flow Rate

(min)
(ml/min)
% A
% B
Curve

initial
40.0
33.0
67.0
—

10.0
40.0
25.0
75.0
6

10.5
40.0
0.0
100.0
6

14.5
40.0
0.0
100.0
6

15.0
40.0
33.0
67.0
6

15.1
3.0
33.0
67.0
6

Liquid Chromatography-Mass Spectrometry Method H

Gradient:

Time
Flow Rate

(min)
(ml/min)
% A
% B
Curve

initial
40.0
40.0
60.0
—

10.0
40.0
0.0
100.0
6

10.5
40.0
0.0
100.0
6

14.5
40.0
0.0
100.0
6

15.0
40.0
40.0
60.0
6

16.1
3.0
40.0
60.0
6

Liquid Chromatography-Mass Spectrometry Method I

Gradient:

Time
Flow Rate

(min)
(ml/min)
% A
% B
Curve

initial
40.0
55.0
45.0
—

10.0
40.0
40.0
60.0
6

10.5
40.0
0.1
99.9
6

14.5
40.0
0.1
99.9
6

15.0
40.0
55.0
45.0
6

Liquid Chromatography-Mass Spectrometry Method J

Gradient:

Time
Flow Rate

(min)
(ml/min)
% A
% B
Curve

initial
40.0
50.0
50.0
—

10.0
40.0
30.0
70.0
6

10.5
40.0
0.1
99.9
6

14.5
40.0
0.1
99.9
6

15.0
40.0
50.0
50.0
6

Liquid Chromatography-Mass Spectrometry Method K

Instrument Name: MDAP_Fractionlynx; Method Description: Semi preparative MDAP Method: LC/MS System: Fractionlynx (Waters) with ZQ MS detector; LC/MS Conditions: Column: XSelect CSH Prep. C18 5 μm OBD 30×100 mm @ room T; Injection loop: 1 ml; Solvents: A=H₂O+0.1% HCOOH; B=MeCN.

Gradient:

Time
Flow Rate

(min)
(ml/min)
% A
% B
Curve

initial
40.0
45.0
55.0
—

10.0
40.0
30.0
70.0
6

10.5
40.0
0.0
100.0
6

14.5
40.0
0.0
100.0
6

15.0
40.0
45.0
55.0
6

16.1
3.0
45.0
55.0
6

Liquid Chromatography-Mass Spectrometry Method L

Instrument Name: MDAP_Fractionlynx; Method Description: Semi preparative MDAP Method; LC/MS System: Fractionlynx (Waters) with ZQ MS detector; LC/MS Conditions: Column: Gemini 5 μm C18 110A AXIA (100×30 mm) @ room T; Injection loop: 1 ml; Solvents: A=10 mM ammonium bicarbonate aqueous solution adjusted to pH 10 with ammonia; B=MeCN.

Gradient:

Time
Flow Rate

(min)
(ml/min)
% A
% B
Curve

initial
40.0
60.0
40.0
—

10.0
40.0
20.0
80.0
6

10.5
40.0
0.0
100.0
6

14.5
40.0
0.0
100.0
6

15.0
40.0
60.0
40.0
6

Liquid Chromatography-Mass Spectrometry Method M

Gradient:

Time
Flow Rate

(min)
(ml/min)
% A
% B
Curve

initial
40.0
40.0
60.0
—

10.0
40.0
21.0
79.0
6

10.5
40.0
0.0
100.0
6

14.5
40.0
0.0
100.0
6

15.0
40.0
40.0
60.0
6

15.1
40.0
40.0
60.0
6

Liquid Chromatography-Mass Spectrometry Method N

Gradient:

Time
Flow Rate

(min)
(ml/min)
% A
% B
Curve

initial
40.0
80.0
20.0
—

10.0
40.0
30.0
70.0
6

10.5
40.0
0.0
100.0
6

14.5
40.0
0.0
100.0
6

15.0
40.0
80.0
20.0
6

16.1
3.0
80.0
20.0
6

Gradient:

Time
Flow Rate

(min)
(ml/min)
% A
% B
Curve

initial
40.0
55.0
45.0
—

10.0
40.0
15.0
85.0
6

10.5
40.0
0.0
100.0
6

14.5
40.0
0.0
100.0
6

15.0
40.0
55.0
45.0
6

15.1
40.0
55.0
45.0
6

Liquid Chromatography-Mass Spectrometry Method P

Instrument Name: MDAP_Fractionlynx; Method Description: Semi preparative MDAP Method; LC/MS System: Fractionlynx (Waters) with ZQ MS detector; LC/MS Conditions: Column: XSelect CSH Prep. C18 5 sum OBD 30×100 mm @ room T; Injection loop: 1 ml; Solvents: A=H₂O+0.1°/% HCOOH; B=MeCN.

Gradient:

Time
Flow Rate

(min)
(ml/min)
% A
% B
Curve

initial
40.0
55.0
45.0
—

10.0
40.0
10.0
90.0
6

10.5
40.0
0.0
100.0
6

14.5
40.0
0.0
100.0
6

15.0
40.0
55.0
45.0
6

15.1
40.0
55.0
45.0
6

Liquid Chromatography-Mass Spectrometry Method O

Instrument Name: MDAP_Fractionlynx; Method Description: Semi preparative MDAP Method; LC/MS System: Fractionlynx (Waters) with ZQ MS detector; LC/MS Conditions: Column: XSelect CSH Prep. C18 5 sum OBD 30×100 mm @ room T; Injection loop: 1 ml; Solvents: A=H₂O+0.1°/% HCOOH; B=MeCN.

Gradient:

Time
Flow Rate

(min)
(ml/min)
% A
% B
Curve

initial
40.0
40.0
60.0
—

10.0
40.0
30.0
70.0
6

10.5
40.0
0.0
100.0
6

14.5
40.0
0.0
100.0
6

15.0
40.0
40.0
60.0
6

15.1
40.0
40.0
60.0
6

Liquid Chromatography-Mass Spectrometry Method R

Instrument Name: MDAP_Fractionlynx; Method Description: Semi preparative MDAP Method; LC/MS System: Fractionlynx (Waters) with QDa MS detector; LC/MS Conditions: Column: XSelect CSH Prep. C18 5 sim OBD 30×100 mm @ room T; Injection loop: 1 ml; Solvents: A=H₂O+0.10% HCOOH; B=MeCN.

Gradient:

Time
Flow Rate

(min)
(ml/min)
% A
% B
Curve

initial
40.0
90.0
10.0
—

10.0
40.0
65.0
35.0
6

10.5
40.0
0.0
100.0
6

14.5
40.0
0.0
100.0
6

15.0
40.0
90.0
10.0
6

16.1
3.0
90.0
10.0
6

Liquid Chromatography-Mass Spectrometry Method S

Gradient:

Time
Flow Rate

(min)
(ml/min)
% A
% B
Curve

initial
40.0
70.0
30.0
—

10.0
40.0
52.0
48.0
6

10.5
40.0
0.0
100.0
6

14.5
40.0
0.0
100.0
6

15.0
40.0
70.0
30.0
6

16.1
3.0
70.0
30.0
6

Liquid Chromatography-Mass Spectrometry Method T

Instrument Name: MDAP_Fractionlynx; Method Description: Semi preparative MDAP Method; LC/MS System: Fractionlynx (Waters) with ZQ MS detector: LC/MS Conditions: Column: Gemini 5 μm C18 110A AXIA (100×30 mm) @ room T; Injection loop: 1 ml; Solvents: A=10 mM ammonium bicarbonate aqueous solution adjusted to pH 10 with ammonia; B=MeCN.

Gradient:

Time
Flow Rate

(min)
(ml/min)
% A
% B
Curve

initial
40.0
70.0
30.0
—

10.0
40.0
25.0
75.0
6

10.5
40.0
0.0
100.0
6

14.5
40.0
0.0
100.0
6

15.0
40.0
70.0
30.0
6

Liquid Chromatography Method U

Column: Welch Xbridge BEH C18 100×30 mm×10 um @ room temperature; mobile phase: water (10 mM NH₄HCO₃)-MeCN: 33-53% over 10 minutes.

Liquid Chromatography Method V

Column: Welch Ultimate AQ-C18 150×30 mm×5 um @ room temperature; mobile phase: water (0.1% TFA)-MeCN: 35-65% over 12 minutes.

Liquid Chromatography Method W

Column: Welch Xbridge BEH C18 100×30 mm×10 um @ room temperature; mobile phase: water (10 mM NH₄HCO₃)-MeCN: 15-43% over 10 minutes.

Liquid Chromatography Method X

Column: Welch Xbridge BEH C18 100×30 mm×10 um @ room temperature; mobile phase: water (0.4% NH₃H₂O+10 mM NH₄HCO₃)-MeCN: 28-58% over 10 minutes.

Liquid Chromatography Method Y

Column: Welch Xbridge Prep OBD C18 150×40 mm×5 um @ room temperature; mobile phase: water (0.4% NH₃H₂O+10 mM NH₄HCO₃)-MeCN: 30-60% over 10 minutes.

Liquid Chromatography Method Z

Column: Welch Xbridge Prep OBD C18 150×40 mm×10 um @ room temperature; mobile phase: water (10 mM NH₄HCO₃)-MeCN: 30-55% over 10 minutes.

Liquid Chromatography Method AA

Column: Nano-micro Kromasil C18 100×30 mm×5 um @ room temperature; mobile phase: water (0.1% TFA)-MeCN: 36-46% over 10 minutes.

Liquid Chromatography Method AB

Column: Nano-micro Kromasil C18 80×25 mm×3 um @ room temperature; mobile phase: water (0.1% TFA)-MeCN: 35-55% over 10 minutes.

Liquid Chromatography Method AC

Column: Welch Xbridge BEH C18 100×30 mm×10 um @ room temperature; mobile phase: water (10 mM NH₄HCO₃)-MeCN: 35-55% over 10 minutes.

Liquid Chromatography Method AD

Column: Welch Xbridge BEH C18 100×30 mm×10 um @ room temperature; mobile phase: water (10 mM NH₄HCO₃)-MeCN: 25-55% over 8 minutes.

Liquid Chromatography Method AE

Column: Nano-micro Kromasil C18 80×25 mm×3 um @ room temperature; mobile phase: water (0.1% TFA)-MeCN: 25-55% over 10 minutes.

Liquid Chromatography Method AF

Column: Welch Xbridge Prep OBD C18 150×40 mm×10 um @ room temperature; mobile phase: water (10 mM NH₄HCO₃)-MeCN: 30-60% over 8 minutes.

Liquid Chromatography Method AG

Column: Welch Xbridge Prep OBD C18 150×40 mm×10 um @ room temperature; mobile phase: water (10 mM NH₄HCO₃)-MeCN: 35-65% over 8 minutes.

Liquid Chromatography Method AH

Column: Welch Ultimate AQ-C18 150×30 mm×5 um @ room temperature; mobile phase: water (0.1% TFA)-MeCN: 30-60% over 12 minutes.

Liquid Chromatography Method AI

Prep-HPLC column: Phenomenex Luna C18 (150×30 mm, 5 um); mobile phase: [water (0.1% TFA)-MeCN]; B %: 25%-55%, 10 min

Liquid Chromatography Method AJ

Prep-HPLC column: Waters Xbridge BEH C18 (100×30 mm, 10 um); mobile phase: [water (10 mM NH₄HCO₃)-MeCN]; B %: 30%-60%, 8 min

Liquid Chromatography Method AK

Prep-HPLC column: Phenomenex Luna C18 (150×30 mm, 5 um); mobile phase: [water (0.1% TFA)-MeCN]; B %: 30%-60%, 10 min

Liquid Chromatography Method AL

SFC column: DAICEL CHIRALPAK AD (250×30 mm, 10 um); mobile phase: [0.1% NH₃H₂O IPA]; B %: 30%-30%, min

Liquid Chromatography Method AM

Prep-HPLC column: Waters Xbridge BEH C18 (100×30 mm, 10 um); mobile phase: [water (10 mM NH₄HCO₃)-MeCN]; B %: 27%-57%, 8 min

Liquid Chromatography Method AN

Prep-HPLC column: Phenomenex Synergi C18 (150×25 mm, 10 um); mobile phase: [water (0.1% TFA)-MeCN]; B %: 20%-50%, 10 min

Liquid Chromatography Method AO

Prep-HPLC (column: Phenomenex Luna C18 (100×40 mm, 3 um); mobile phase: [water (0.1% TFA)-MeCN]; B %: 30%-60%, 10 min

Liquid Chromatography Method AP

Prep-HPLC (neutral condition, column: Waters Xbridge BEH C18 (100×25 mm, 5 um); mobile phase: [water (10 mM NH₄HCO₃)-MeCN]; B %: 30%-60%, 10 min

Liquid Chromatography Method AO

Prep-HPLC column: Nano-micro Kromasil C18 (100×40 mm, 10 um); mobile phase: [water (0.1% TFA)-MeCN], B %: 10%-40%, 8 min

Liquid Chromatography Method AR

Prep-HPLC column: Waters Xbridge Prep OBD C18 (150×40 mm, 10 um); mobile phase: [water (10 mM NH₄HCO₃)-MeCN]; B %: 15%-45%, 8 min

Liquid Chromatography Method AS

Prep-HPLC basic condition, column: Phenomenex Gemini-NX C18 (75×30 mm, 3 um); mobile phase: [water (0.05% NH₃H₂O+10 mM NH₄HCO₃)-MeCN]; B %: 25%-55%, 8 min

Liquid Chromatography Method AT

Prep-HPLC neutral condition, column: Waters Xbridge BEH C18 (100×30 mm, 10 um); mobile phase: [water (10 mM NH₄HCO₃)-MeCN]; B %: 15%-45%, 8 min

Liquid Chromatography Method AU

Prep-HPLC column: Phenomenex Luna C18 (150×30 mm, 5 um); mobile phase: [water (0.1% TFA)-MeCN]; B %: 35%-65%, 10 min

Liquid Chromatography Method AV

Prep-HPLC neutral condition, column: Waters Xbridge BEH C18 (100×30 mm, 10 um); mobile phase: [water (10 mM NH₄HCO₃)-MeCN]; B %: 35%-65%, 8 min

Liquid Chromatography Method AW

Prep-HPLC TFA condition, column: Nano-micro Kromasil C18 (100×40 mm, 10 um); mobile phase: [water (0.1% TFA)-MeCN]; B %: 1%-37%, 8 min

Liquid Chromatography Method AX

Prep-HPLC column: Waters Xbridge BEH C18 (100×30 mm, 10 um); mobile phase: [water (0.1% TFA)-MeCN]; B %: 25%-55%, 8 min

Liquid Chromatography Method AY

Prep-HPLC column: Waters Xbridge BEH C18 (100×30 mm, 10 um); mobile phase: [water (0.05% NH₃H₂O-MeCN]; B %: 15%-45%, 12 min

Liquid Chromatography Method AZ

Prep-HPLC column: Waters Xbridge BEH C18 (100×30 mm, 10 um); mobile phase: [water (10 mM NH₄HCO₃)-MeCN]; B %: 32%-62%, 8 min

Liquid Chromatography Method BA

Prep-HPLC TFA condition, column: Phenomenex Synergi C18 (150×25 mm, 10 um); mobile phase: [water (0.1% TFA)-MeCN]; B %: 35%-65%, 8 min

Liquid Chromatography Method BB

Prep-HPLC column: Waters Xbridge BEH C18 (100×30 mm, 10 um); mobile phase: [water (10 mM NH₄HCO₃)-MeCN]; B %: 15%-45%, 8 min

Liquid Chromatography Method BC

Prep-HPLC TFA condition, column: Welch Ultimate AQ-C18 (150×30 mm, 5 um); mobile phase: [water (0.1% TFA)-MeCN]; B %: 27%-57%, 12 min

Liquid Chromatography Method BD

Prep-HPLC TFA condition, column: Welch Ultimate AQ-C18 (150×30 mm, 5 um); mobile phase: [water (0.1% TFA)-MeCN]; B %: 33%-63%, 12 min

Liquid Chromatography Method BE

Prep-HPLC TFA condition, column: Nano-micro Kromasil C18 (80×25 mm, 3 um); mobile phase: [water (0.1% TFA)-MeCN]; B %: 33%-57%, 7 min

Liquid Chromatography Method BF

Prep-HPLC column: Phenomenex Luna C18 (150×30 mm, 5 um); mobile phase: [water (0.04% HCl)-MeCN]; B %: 30%-60%, 10 min

Liquid Chromatography Method BG

Prep-HPLC column: Nano-micro Kromasil C18 (80×25 mm, 3 um), mobile phase: [water (0.1% TFA)-MeCN]; B %: 40%-60%, 7 min

Liquid Chromatography Method BH

Prep-HPLC column: Waters Xbridge BEH C18 (100×30 mm, 10 um); mobile phase: [water (10 mM NH₄HCO₃)-MeCN], B %: 32%-55%, 10 min

Liquid Chromatography Method BI

Prep-HPLC column: Waters Xbridge BEH C18 (100×30 mm, 10 um); mobile phase: [water (10 mM NH₄HCO₃)-MeCN]; B %: 27%-47%, 10 min

Liquid Chromatography Method BJ

Prep-HPLC TFA condition, column: Welch Ultimate AQ-C18 (150×30 mm, 5 um); mobile phase: [water (0.1% TFA)-MeCN]; B %: 25%-55%, 12 min

Liquid Chromatography Method BK

Prep-HPLC TFA condition, column: Welch Ultimate AQ-C18 (150×30 mm, 5 um); mobile phase: [water (0.1% TFA)-MeCN]; B %: 15%-45%, 12 min

Liquid Chromatography Method BL

Prep-HPLC column: Phenomenex Luna C18 (100×30 mm, 5 um); mobile phase: [water (0.1% TFA)-MeCN]; B %: 40%-55%, 12 min

Liquid Chromatography Method BM

Prep-HPLC column: Waters Xbridge Prep OBD C18 (150×40 mm, 10 um); mobile phase: [water (0.04% NH₃H₂O+10 mM NH₄HCO₃)-MeCN]; B %: 15%-45%, 10 min

Liquid Chromatography Method BN

Prep-HPLC TFA condition, column: Nano-micro Kromasil C18 (80×25 mm, 3 um); mobile phase: [water (0.1% TFA)-MeCN]; B %: 39%-56%, 7 min

Liquid Chromatography Method BO

Prep-HPLC column: Nano-micro Kromasil C18 (80×5 mm, 3 um); mobile phase: [water (0.1% TFA)-MeCN]; B %: 35%-55%, 7 min

Liquid Chromatography Method BP

Prep-HPLC column: Nano-micro Kromasil C18 (80×25 mm, 3 um); mobile phase: [water (0.1% TFA)-MeCN]; B %: 30%-52%, 7 min

Liquid Chromatography Method BO

Prep-HPLC Waters Xbridge BEH C18 (100×30 mm, 10 um); mobile phase: [water (10 mM NH₄HCO₃)-MeCN]; B %: 32%-52%, 10 min

Liquid Chromatography Method BR

Prep-HPLC TFA condition, column: Nano-micro Kromasil C18 (80×25 mm, 3 um); mobile phase: [water (0.1% TFA)-MeCN]; B %: 45%-61%, 7 min

Liquid Chromatography Method BS

Prep-HPLC basic condition, column: Waters Xbridge Prep OBD C18 (150×40 mm, 10 um); mobile phase: [water (0.04% NH₃H₂O+10 Mm NH₄HCO₃)-MeCN]; B %: 25%-55%, 8 min

Liquid Chromatography Method BT

Prep-HPLC TFA condition, column: Nano-micro Kromasil C18 (80×25 mm, 3 um); mobile phase: [water (0.1% TFA)-MeCN]; B %: 32%-48%, 7 min

Liquid Chromatography Method BU

Prep-HPLC neutral condition, column: Waters Xbridge Prep OBD C18 (150×40 mm, 10 um); mobile phase: [water (10 mM NH₄HCO₃)-MeCN]; B %: 20%-50%, 8 min

Liquid Chromatography Method BV

Prep-HPLC column: Nano-micro Kromasil C18 (80×25 mm, 3 um); mobile phase: [water (0.1% TFA)-MeCN]; B %: 30%-45%, 7 min

Liquid Chromatography Method BW

Prep-HPLC TFA condition; column: Phenomenex Luna C18 (100×30 mm, 5 um); mobile phase: [water (0.1% TFA)-MeCN]; B %: 35%-60%, 12 min

Liquid Chromatography Method BX

Prep-HPLC TFA condition, column: Nano—micro Kromasil C18 (80×25 mm, 3 um); mobile phase: [water (0.1% TFA)-MeCN]; B %: 37%-63%, 7 min

Liquid Chromatography Method BY

Prep-HPLC column: Waters Xbridge BEH C18 (100×30 mm, 10 um); mobile phase: [water (10 mM NH₄HCO₃)-MeCN]; B %: 30%-55%, 10 min

Liquid Chromatography Method BZ

Prep-HPLC (column: Waters Xbridge BEH C18 (100×30 mm, 10 um); mobile phase: [water (10 mM NH₄HCO₃)-MeCN]; B %: 35%-60%, 10 min)

Liquid Chromatography Method CA

Prep-HPLC column: Waters Xbridge BEH C18 (100×30 mm, 10 um); mobile phase: [water (10 mM NH₄HCO₃)-MeCN]; B %: 5%-25%, 10 min

Liquid Chromatography Method CB

Prep-HPLC (column: Waters Xbridge BEH C18 (100×30 mm, 10 um); mobile phase: [water (10 mM NH₄HCO₃)-MeCN]; B %: 30%-60%, 10 min)

Liquid Chromatography Method CC

Prep-HPLC (TFA condition, column: phenolmenex Luna C18 (100×30 mm, 5 um); mobile phase: [water (0.1% TFA)-MeCN]; B %:25%-55%, 12 min)

Liquid Chromatography Method CD

Prep-HPLC column: Waters Xbridge BEH C18 (100×25 mm, 5 um); mobile phase: [water (10 mM NH₄HCO₃)-MeCN]; B %: 30%-60%, 8 min

Liquid Chromatography Method CE

Prep-HPLC column: Nano-micro Kromasil C18 (80×25 mm, 3 um); mobile phase: [water (0.1% TFA)-MeCN]; B %: 38%-60%, 7 min

Liquid Chromatography Method CF

Prep-HPLC neutral condition, column: Waters Xbridge BEH C18 (100×30 mm, 10 um; mobile phase: [water (10 mM NH₄HCO₃)-MeCN]; B %: 20%-45%, 8 min

Liquid Chromatography Method CG

Prep-HPLC column: Waters Xbridge BEH C18 (100×30 mm, 10 um); mobile phase: [water (10 mM NH₄HCO₃)-MeCN]; B %: 20%-50%, 8 min

Liquid Chromatography Method CH

Prep-HPLC column: Waters Xbridge BEH C18 (100×30 mm, 10 um); mobile phase: [water (10 mM NH₄HCO₃)-MeCN]; B %: 30%-55%, 8 min

Liquid Chromatography Method CI

Prep-HPLC column: Waters Xbridge BEH C18 (100×30 mm, 10 um); mobile phase: [water (10 mM NH₄HCO₃)-MeCN]; B %: 30%-53%, 10 min

Liquid Chromatography Method CJ

Prep-HPLC column: Nano-micro C18 (100×40 mm, 3 um); mobile phase: [water (0.1% TFA)-MeCN]; B %: 25%-55%, 8 min

Liquid Chromatography Method CK

Prep-HPLC column: Waters Xbridge BEH C18 (100×30 mm, 10 um); mobile phase: [water (10 mM NH₄HCO₃)-MeCN]; B %: 1%-30%, 10 min

Liquid Chromatography Method CL

Prep-HPLC column: Nano-micro Kromasil C18 (100×40 mm, 3 um); mobile phase: [water (0.1% TFA)-MeCN]; B %: 30%-60%, 8 min

Liquid Chromatography Method CM

Prep-HPLC column: Nano-micro Kromasil C18 (100×40 mm, 3 um); mobile phase: [water (0.1% TFA)-MeCN]; B %: 13%-43%, 8 min

Liquid Chromatography Method CN

Prep-HPLC TFA condition, column: YMC-Actus Triart C18 (100×30 mm, 5 um); mobile phase: [water (0.1% TFA)-MeCN]; B %: 10%-40%, 10 min

Liquid Chromatography Method CO

Prep-HPLC TFA condition column: Phenomenex Synergi C18 (150×25 mm, 10 um); mobile phase: [water (0.1% TFA)-MeCN]; B %: 10%-35%, 10 min

Liquid Chromatography Method CP

Prep-HPLC TFA condition column: Phenomenex Luna C18 (100×40 mm×3 um); mobile phase: [water (0.1% TFA)-MeCN]; B %: 10%-50%, 10 min

Liquid Chromatography Method CO

Prep-HPLC neutral condition column: Phenomenex Gemini-NX C18 (75×30 mm, 3 um); mobile phase: [water (10 mM NH₄HCO₃)-MeCN]; B %: 20%-40%, 6 min

Liquid Chromatography Method CR

Prep-HPLC neutral condition column: Phenomenex Gemini-NX C18 (75×30 mm, 3 um); mobile phase: [water (10 mM NH₄HCO₃)-MeCN]; B %: 15%-45%, 12 min

Liquid Chromatography Method CS

Prep-HPLC TFA condition column: Phenomenex Luna C18 (100×40 mm, 5 um); mobile phase: [water (0.1% TFA)-MeCN]; B %: 15%-45%, 8 min

Liquid Chromatography Method CT

Prep-HPLC basic condition column: Phenomenex Gemini-NX C18 (75×30 mm, 3 um); mobile phase: [water (0.05% NH₃H₂O+10 mM NH₄HCO₃)-MeCN]; B %: 30%-60%, 8 min

Liquid Chromatography Method CU

Semipreparative HPLC conditions and results: Column Chiralpak AD-H (25×2.0 cm, 5μ) Mobile phase n-Hexane/Ethanol 70/30% v/v Flow rate (mL/min) 18 mL/min DAD detection 220 nm Loop 300 μL Total amount 150 mg Solubilization 150 mg in 3 mL MeOH=50 mg/mL Injection 17 mg/injection

Liquid Chromatography Method CV

Prep. HPLC Method:

Instrument Name: MDAP_Fractionlynx; Method Description: Semi preparative MDAP Method; LC/MS System: Fractionlynx (Waters) with QDa MS detector; LC/MS Conditions: Column: XSelect CSH Prep. C18 5 μm OBD 30×100 mm @ room T; Injection loop: 1 mL; Solvents: A=H₂O+0.1% HCOOH; B=MeCN.

Gradient:

Time
Flow Rate

(min)
(ml/min)
% A
% B
Curve

initial
40.0
80.0
20.0
—

10.0
40.0
30.0
70.0
6

10.5
40.0
0.0
100.0
6

14.5
40.0
80.0
20.0
6

16.1
3.0
80.0
20.0
6

The curve parameter followed Waters definition (6=linear, 11=step); Acquisition stop time: 15 min; UV Conditions: UV detection range: 210 nm to 350 nm; Acquisition rate: 1.0 spectra/s; MS Conditions: Ionization mode: Positive Electrospray (ES+); Scan Range: ES+ 100 to 900 AMU; Scan Duration: 0.50 seconds.

Liquid Chromatography Mass Spectrometry Method CW

Prep. HPLC Method:

Instrument Name: MDAP_Fractionlynx; Method Description: Semi preparative MDAP Method; LC/MS System: Fractionlynx (Waters) with QDa MS detector; LC/MS Conditions: Column: XSelect CSH Prep. C18 5 μm OBD 30×100 mm @ room T; Injection loop: 1 mL; Solvents: A=H₂O+0.1% HCOOH; B=MeCN.

Gradient:

Time
Flow Rate

(min)
(ml/min)
% A
% B
Curve

initial
40.0
65.0
45.0
—

10.0
40.0
45.0
55.0
6

10.5
40.0
0.1
99.9
6

14.5
40.0
0.1
99.9
6

15.0
40.0
65.0
45.0
6

The curve parameter followed Waters definition (6=linear, 11=step); Acquisition stop time: 15 min; UV Conditions: UV detection range: 210 nm to 350 nm; Acquisition rate: 1.0 spectra/s; MS Conditions: Ionization mode: Positive Electrospray (ES+); Scan Range: ES+ 100 to 900 AMU; Scan Duration: 0.50 seconds.

Liquid Chromatography-Mass Spectrometry Method CX:

Instrument Name: MDAP_Fractionlynx; Method Description: Semi preparative MDAP Method; LC/MS System: Fractionlynx (Waters) with QDa MS detector; LC/MS Conditions: Column: XSelect CSH Prep. C18 5 μm OBD 30×100 mm @ room T: Injection loop: 1 mL; Solvents: A=H₂O+0.1% HCOOH; B=MeCN.

Gradient:

Time
Flow Rate

(min)
(ml/min)
% A
% B
Curve

initial
40.0
70.0
30.0
—

10.0
40.0
50.0
50.0
6

10.5
40.0
0.1
99.9
6

14.5
40.0
0.1
99.9
6

15.0
40.0
50.0
50.0
6

The curve parameter followed Waters definition (6=linear, 11=step); Acquisition stop time: 15 min; UV Conditions: UV detection range: 210 nm to 350 nm; Acquisition rate: 1.0 spectra/s; MS Conditions: Ionization mode: Positive Electrospray (ES+); Scan Range: ES+ 100 to 900 AMU; Scan Duration: 0.50 seconds.

Liquid Chromatography Method CY

Chiral prep. HPLC Method:

Column Chiralpak IC (25×2.0 cm), 5μ

Mobile phase n-Hexane/(Ethanol+0.1% isopropylamine) 60/40% v/v

Flow rate (mL/min) 17 mL/min

DAD detection 220 nm

Loop 1000 μL

Total amount 58 mg

Solubilization 58 mg in 3.0 mL DCM=19.3 mg/mL

Injection 19.3 mg/injection

Liquid Chromatography Method CZ

Instrument Name: MDAP_Fractionlynx; Method Description: Semi preparative MDAP Method; LC/MS System: Fractionlynx (Waters) with QDa MS detector; LC/MS Conditions: Column: XSelect CSH Prep. C18 5 μm OBD 30×100 mm @ room T; Injection loop: 1 mL; Solvents: A=H₂O+0.1% HCOOH; B=MeCN.

Gradient:

Time
Flow Rate

(min)
(ml/min)
% A
% B
Curve

initial
40.0
50.0
50.0
—

10.0
40.0
43.0
57.0
6

10.5
40.0
0.0
100.0
6

14.5
40.0
0.0
100.0
6

15.0
40.0
50.0
50.0
6

15.1
40.0
50.0
50.0
6

The curve parameter followed Waters definition (6=linear, 11=step); Acquisition stop time: 15 min; UV Conditions: UV detection range: 210 nm to 350 nm; Acquisition rate: 1.0 spectra/s; MS Conditions: Ionization mode: Positive Electrospray (ES+); Scan Range: ES+ 100 to 900 AMU; Scan Duration: 0.50 seconds.

Liquid Chromatography Method DA

Prep-HPLC basic condition 30 g C18 column; mobile phase [water (0.1% NH₃)-MeCN]; B % 5%-35%.

Liquid Chromatography Method DB

C-18 chromatography (from 100% water+0.1% formic acid to 90/10 100% water+0.1% formic acid/MeCN+0.1% formic acid in 12CV)

Liquid Chromatography Method DC

Prep HPLC:

Column: XSelect CSH Prep. C18 5 μm OBD 30×100 mm @ room T Injection loop: 1 ml Solvents: A=H₂O+0.1% HCOOH B=MeCN

Gradient:

Time
Flow Rate

(min)
(ml/min)
% A
% B
Curve

initial
40.0
70.0
30.0
—

10.0
40.0
50.0
55.0
6

10.5
40.0
0.1
99.9
6

14.5
40.0
0.1
99.9
6

15.0
40.0
70.0
30.0
6

The curve parameter followed Waters definition (6=linear, 11=step). Acquisition stop time: 15.0 min UV Conditions: UV detection range: 210 nm to 350 nm Acquisition rate: 1.0 spectra/s MS Conditions: Ionization mode: Positive Electrospray (ES+) Scan Range: ES+ 100 to 900 AMU Scan Duration: 0.50 seconds

Liquid Chromatography Method DD

Prep HPLC:

Column: XSelect CSH Prep. C18 5 μm OBD 30×100 mm @ room T Injection loop: 1 mL Solvents: A=H₂O+0.1% HCOOH B=Acetonitrile

Gradient:

Time
Flow Rate

(min)
(ml/min)
% A
% B
Curve

initial
40.0
70.0
30.0
—

10.0
40.0
60.0
40.0
6

10.5
40.0
0.1
99.9
6

15.0
40.0
0.1
99.9
6

15.0
40.0
70.0
30.0
6

Liquid Chromatography Method DE

Prep HPLC:

Column: XSelect CSH Prep. C18 5 μm OBD 30×100 mm @ room T Injection loop: 1 mL Solvents: A=H₂O+0.1% HCOOH B=MeCN

Gradient:

Time
Flow Rate

(min)
(ml/min)
% A
% B
Curve

initial
40.0
55.0
45.0
—

10.0
40.0
53.0
47.0
6

10.5
40.0
0.0
100.0
6

15.0
40.0
0.0
100.0
6

15.1
40.0
55.0
45.0
6

Liquid Chromatography Method DF

Prep HPLC:

Column: XSelect CSH Prep. C18 5 μm OBD 30×100 mm @ room T Injection loop: 1 ml Solvents: A=H₂O+0.1% HCOOH B=MeCN

Gradient:

Time
Flow Rate

(min)
(ml/min)
% A
% B
Curve

initial
40.0
70.0
30.0
—

10.0
40.0
50.0
50.0
6

10.5
40.0
0.1
99.9
6

14.5
40.0
0.1
99.9
6

15.0
40.0
70.0
30.0
6

Liquid Chromatography Method DG

Prep. HPLC Method:

Instrument Name: MDAP_Fractionlynx; Method Description: Semi preparative MDAP Method; LC/MS System: Fractionlynx (Waters) with QDa MS detector; LC/MS Conditions: Column: XSelect CSH Prep. C18 5 μm OBD 30×100 mm @ room T; Injection loop: 1 ml; Solvents: A=H₂O+0.1% HCOOH; B=MeCN.

Gradient:

Time
Flow Rate

(min)
(ml/min)
% A
% B
Curve

initial
40.0
50.0
60.0
—

10.0
40.0
35.0
65.0
6

10.5
40.0
0.1
99.9
6

14.5
40.0
0.1
99.9
6

15.0
40.0
50.0
50.0
6

The curve parameter followed Waters definition (6=linear, 11=step); Acquisition stop time: 15 min; UV Conditions: UV detection range: 210 nm to 350 nm; Acquisition rate: 1.0 spectra/s; MS Conditions: Ionisation mode: Positive Electrospray (ES+): Scan Range: ES+ 100 to 900 AMU; Scan Duration: 0.50 seconds.

Liquid Chromatography Method DH

Prep. HPLC Method:

Instrument Name: MDAP_Fractionlynx; Method Description: Semi preparative MDAP Method; LC/MS System: Fractionlynx (Waters) with QDa MS detector; LC/MS Conditions: Column: XSelect CSH Prep. C18 5 μm OBD 30×100 mm @ room T; Injection loop: 1 ml; Solvents: A=H₂O+0.1% HCOOH; B=MeCN.

Gradient:

Time
Flow Rate

(min)
(ml/min)
% A
% B
Curve

initial
40.0
53.0
37.0
—

10.0
40.0
33.0
67.0
6

10.5
40.0
0.1
99.9
6

14.5
40.0
0.1
99.9
6

15.0
40.0
53.0
17.0
6

Liquid Chromatography Method DI

Prep. HPLC Method:

Instrument Name: MDAP_Fractionlynx; Method Description: Semi preparative MDAP Method; LC/MS System: Fractionlynx (Waters) with QDa MS detector; LC/MS Conditions: Column: XSelect CSH Prep. C18 5 μm OBD 30×100 mm @ room T; Injection loop: 1 ml; Solvents: A=H₂O+0.1% HCOOH; B=MeCN.

Gradient:

Time
Flow Rate

(min)
(ml/min)
% A
% B
Curve

initial
40.0
50.0
50.0
—

10.0
40.0
30.0
70.0
6

10.5
40.0
0.1
99.9
6

14.5
40.0
0.1
99.9
6

15.0
40.0
50.0
50.0
6

Liquid Chromatography Method DJ

Preparative HPLC (neutral condition) column: Waters Xbridge BEH C18 (100×30 mm, 10) um; mobile phase: [water (10 mM NH₄HCO₃)-MeCN]; B %: 10%-40%, 6 min

Other Analytical Methods

¹H Nuclear magnetic resonance (NMR) spectroscopy was carried out using one of the following instruments: a Bruker Avance 400 instrument equipped with probe DUAL 400 MHz S1, a Bruker Avance 400 instrument equipped with probe 6 S1 400 MHz 5 mm ¹H-¹³C ID, a Bruker Avance III 400 instrument with nanobay equipped with probe Broadband BBFO 5 mm direct, a 400 MHz Agilent Direct Drive instrument with ID AUTO-X PFG probe, all operating at 400 MHz, or an Agilent VNMRS500 Direct Drive instrument equipped with a 5 mm Triple Resonance ¹H{¹³C/¹⁵N} cryoprobe operating at 500 MHz. The spectra were acquired in the stated solvent at around room temperature unless otherwise stated. In all cases, NMR data were consistent with the proposed structures. Characteristic chemical shifts (8) are given in parts-per-million using conventional abbreviations for designation of major peaks: e.g. s, singlet; d, doublet; t, triplet; q, quartet; dd, doublet of doublets; dt, doublet of triplets; br, broad.

Where thin layer chromatography (TLC) occurs, it refers to silica gel TLC using silica gel F254 (Merck) plates, Rf is the distance travelled by the compound divided by the distance travelled by the solvent on a TLC plate. Column chromatography was performed using an automatic flash chromatography (Biotage SP1 or Isolera) system over Biotage silica gel cartridges (KP-Sil or KP-NH) or in the case of reverse phase chromatography over Biotage C18 cartridges (KP-C18).

Intermediate A-1: 3-(Furan-3-yl)-1H-indazol-5-amine

embedded image

3-Bromo-1H-indazol-5-amine (2.82 g, 13.3 mmol) was dissolved in THF (40 mL). Then a solution of tripotassium phosphate (8.47 g, 39.9 mmol) and 3-furanylboronic acid (1.79 g, 15.96 mmol) in water (15 mL) was added. The resulting mixture was degassed with N₂for 15 minutes. S-Phos Pd G2 (0.96 g, 1.33 mmol) was added and the mixture was stirred at 80° C. under N₂for 15 h. Water was added and the organic solvent was evaporated. The resulting solid was filtered, washed with water and dried. The residue was purified by column chromatography (SiO₂, 100 g) using a 0-10% gradient of MeOH in DCM for 10 CV followed by 10% MeOH in DCM for 5 CV giving a solid which was triturated with MeCN to afford the title compound (1.65 g, 8.28 mmol, 62.28% yield) as a pale yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 12.60 (s, 1H), 8.14 (t, J=1.2 Hz, 1H), 7.78 (t, J=1.7 Hz, 1H), 7.25 (d, J=8.8 Hz, 1H), 6.98 (d, J=1.9 Hz, 1H), 6.93 (d, J=1.8 Hz, 1H), 6.82 (dd, J=8.8, 2.0 Hz, 1H), 4.79 (s, 2H). MS-ESI (m/z) calc'd for C11H₁₀N₃O [M+H]⁺: 200.1. Found 200.0.

Intermediate A-2: 3-(Pyridin-4-yl)-1H-indazol-5-amine

embedded image

Step 1. 5-Nitro-3-(pyridin-4-yl)-1H-indazole

embedded image

A mixture of 3-bromo-5-nitro-1H-indazole (8 g, 33.05 mmol), 4-pyridylboronic acid (4.88 g, 39.66 mmol), AcOK (9.73 g, 99.16 mmol), and Pd(Amphos)Cl₂(1.17 g, 1.65 mmol) in EtOH (120 mL) and H₂O (30 mL) was degassed and purged with N₂(3×). The mixture was stirred at 100° C. for 16 hrs under N₂atmosphere. The reaction mixture was concentrated to give a residue which was diluted with 2 N HCl (100 mL) and EtOAc (100 mL). A yellow solid formed that was filtered and collected. The solid was dried under vacuum to afford the title compound (5.6 g) as a yellow solid.

Step 2. 3-(Pyridin-4-yl)-1H-indazol-5-amine

embedded image

To a solution of 5-nitro-3-(pyridin-4-yl)-1H-indazole (5.6 g, 23.31 mmol) in EtOH (80 mL) and H₂O (20 mL) was added Zn (7.62 g, 116.56 mmol) and NH₄Cl (6.24 g, 116.56 mmol). The mixture was stirred at 80° C. for 12 hrs. The reaction mixture was filtered and the filtrate was concentrated to afford the title compound (1.37 g) as a yellow solid which was used without further purification.

Intermediate A-3: 3-Phenyl-1H-indazol-5-amine

embedded image

Step 1: 5-Nitro-3-phenyl-1H-indazole

embedded image

To a mixture of 3-bromo-5-nitro-1H-indazole (200 mg, 826 umol), phenylboronic acid (120.91 mg, 991 umol), and AcOK (243.30 mg, 2.48 mmol) in EtOH (5 mL) and H₂O (1.25 mL) was added Pd(AmPhos)Cl₂(29.26 mg, 41.32 μmol). The resulting mixture was degassed and purged with N₂(3×), and then the mixture was stirred at 100° C. for 12 hrs under a N₂atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO; 20 g SepaFlash column, 100 mL/min) using a 0-50% EtOAc/petroleum ether gradient eluent to afford the title compound (180 mg, 91% yield) as a yellow solid.

Step 2: 3-Phenyl-1H-indazol-5-amine

embedded image

To a solution of 5-nitro-3-phenyl-1H-indazole (180 mg, 752 umol) in EtOH (8 mL) was added SnCl₂.2H₂O (848.90 mg, 3.76 mmol). The mixture was stirred at 70° C. for 3 hrs. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was diluted with H₂O (10 mL) and the pH adjusted to 8 by addition of sat. aq. NaHCO₃followed by extraction with EtOAc (20 mL×3). The combined organic layers were dried over Na₂SO₄, filtered and concentrated under reduced pressure to afford the title compound (170 mg) as a brown gum which was used without further purification.

Intermediate A-4: 5-Cyano-1,2-dimethyl-1H-pyrrole-3-carboxylic acid

embedded image

Step 1: 4-Bromo-1,5-dimethyl-1H-pyrrole-2-carbonitrile

embedded image

To a solution of 1,5-dimethyl-1H-pyrrole-2-carbonitrile (400 mg, 3.33 mmol) in HOAc (2 mL) was added Br₂(585.22 mg, 3.66 mmol). The mixture was stirred at 20° C. for 12 hrs and then concentrated under reduced pressure to remove solvent. The reaction mixture was filtered and the solid was washed with 60 mL of H₂O and dried under vacuum to give a residue. The residue was purified by flash silica gel chromatography (ISCO; 12 g SepaFlash column, 50 mL/min) using a 0-10% EtOAc/petroleum ether gradient eluent to afford the title compound (202 mg, 31% yield) as a white solid.

Step 2: 5-(Cyano-1,2-dimethyl-1H-pyrrole-3-carboxylic acid

embedded image

To a solution of 4-bromo-1,5-dimethyl-1H-pyrrole-2-carbonitrile (200 mg, 1.00 mmol) in THF (12 mL) was added n-BuLi (2.5 M, 1.21 mL) at −78° C. and the mixture was stirred for 1 hr under N₂. Dry ice (CO₂solid, >10 eq) was added and the mixture was stirred at −78° C. for 2 hrs. The reaction mixture was acidified with 1N HCl to pH=3. The resulting precipitate was collected by filtration to afford the title compound (95 mg) as a gray solid. ¹H NMR (400 MHz, DMSO-d₆) δ 7.25 (s, 1H), 3.70 (s, 3H), 2.59 (s, 3H).

Intermediate A-5: Methyl 5-cyano-2-methylfuran-3-carboxylate

embedded image

Step 1: Methyl 5-formyl-2-methylfuran-3-carboxylate

embedded image

POCl₃(1.09 g, 7.14 mmol, 663.12 uL) was added to DMF (678.57 mg, 9.28 mmol, 714.29 uL) dropwise at 0° C. After stirring at 0° C. for 15 min, methyl 2-methylfuran-3-carboxylate (1.0 g, 7.14 mmol, 892.86 uL) was added to the mixture at 15° C. The mixture was then stirred at 100° C. for 3 hrs. The mixture was poured onto 20 g of ice and the pH was adjusted to 8 with 10% aq. NaOH at 0-10° C. The mixture was filtered. The filter solid was washed with H₂O (5.0 mL×3) and dried in vacuo to afford the title compound (1.0 g, 83%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 9.56 (s, 1H), 7.47 (s, 1H), 3.87 (s, 3H), 2.69 (s, 3H).

Step 2: Methyl 5-((2, 2-dimethylhydrazineylidene)methyl)-2-methylfuran-3-carboxylate

embedded image

To a stirred solution of methyl 5-formyl-2-methylfuran-3-carboxylate (900 mg, 5.35 mmol) in dry EtOH (10 mL) was added 1,1-dimethylhydrazine hydrochloride (775.24 mg, 8.03 mmol, 978.84 μL) in one portion. Then the mixture was stirred at 80° C. for 12 hrs. TLC (petroleum ether:EtOAc=5/1, R_f(product)=0.32) showed the reaction was complete. The mixture was concentrated in vacuo and purified by silica gel chromatography (petroleum ether:EtOAc=10/1-5/1) to afford the title compound (550 mg, 2.62 mmol, 49% yield) as a yellow oil.

Step 3: Methyl 5-cyano-2-methylfuran-3-carboxylate

embedded image

To a stirred solution of methyl 5-((2,2-dimethylhydrazineylidene)methyl)-2-methylfuran-3-carboxylate (550 mg, 2.62 mmol) in DCM (10 mL) was added m-CPBA (1.41 g, 6.54 mmol, 80% purity) in one portion at 0° C. Then the mixture was stirred at 20° C. for 18 hrs. Then K₂CO₃(1.63 g, 11.77 mmol) was added to the mixture. The mixture was stirred for an additional 2 hrs. TLC (petroleum ether:EtOAc=3/1, Rr (product)=0.39) showed the reaction was complete. The mixture was filtered and the filtrate was concentrated in vacuo to afford the title compound (450 mg) as a yellow solid which was used without further purification.

Intermediate A-6: 5-Chloro-3-iodo-1H-pyrazolo[4,3-b]pyridine

embedded image

To a stirred solution of 5-chloro-1H-pyrazolo[4,3-b]pyridine (4.0 g, 26.05 mmol) in DMF (100 mL) was added I₂(26.44 g, 104.19 mmol, 20.99 mL), followed by adding KOH (7.31 g, 130.23 mmol) in portions at 0° C. Then the mixture was stirred at 25° C. for 12 hrs. The mixture was diluted with EtOAc (300 mL), washed with sat. aq. Na₂SO₃(150 mL×3), dried over Na₂SO₄and concentrated under vacuum to afford the title compound (4.0 g) as a yellow solid which was used without further purification.

Intermediate A-7: 3-(Isoxazol-4-yl)-1H-indazol-5-amine

embedded image

A mixture of 3-bromo-1H-indazol-5-amine (100 mg, 471.59 umol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (101.17 mg, 518.75 umol), Pd(Amphos)Cl₂(33.39 mg, 47.16 umol) and AcOK (138.85 mg, 1.41 mmol) in EtOH (4 mL) and H₂O (0.5 mL) was degassed and purged with N₂(3×), and then the mixture was stirred at 40° C. for 12 hrs under an N₂atmosphere. The process was repeated and the reaction mixtures were combined and concentrated to give a residue. The residue was diluted with 30 mL of H₂O, filtered and the filtrate was extracted with EtOAc (10 mL×3). The combined organic phases were dried over Na₂SO₄, filtered and the filtrate was concentrated. The material was purified by flash silica gel chromatography (ISCO; 4 g SepaFlash column) using a 0-30% EtOAc/petroleum ether gradient eluent to afford the title compound (64 mg, 67%) as a brown oil. MS-ESI (m/z) calcd for C₁₀H₉N₄O [M+H]⁺: 201.1. Found 201.0.

Intermediate A-8: 5-Cyano-3-methylpyrazine-2-carboxylic acid and Intermediate A-8′: 6-Cyano-3-methylpyrazine-2-carboxylic acid

embedded image

Step 1: 3-(Methoxycarbonyl)-2-methylpyrazine 1-oxide

embedded image

To a suspension of methyl 3-methylpyrazine-2-carboxylate (1.52 g, 10 mmol) in CHCl₃(30.3 mL) was added MCPBA (2.71 g, 11 mmol) and the mixture was stirred at 70° C. for 5 hrs. The solvent was evaporated and the residue was taken up in EtOAc and washed with aqueous K₂CO₃(3×). The aqueous layer was extracted with EtOAc (2×) and the combined organic layers were passed through a phase separator and evaporated to give a light orange solid which was purified by silica gel column chromatography using a 0-100% EtOAc/cyclohexane gradient eluent to afford the title compound (500 mg, 30%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.54 (d, J=4.0 Hz, 1H), 8.47 (d, J=4.0 Hz, 1H), 3.92 (s, 3H), 2.47 (s, 3H). MS-ESI (m/z) calc'd for C7H₉N₂O₃[M+H]⁺: 169.1. Found 168.9.

Step 2: Methyl 5-chloro-3-methylpyrazine-2-carboxylate and Methyl 6-chloro-3-methylpyrazine-2-carboxylate

embedded image

A suspension of 3-(methoxycarbonyl)-2-methylpyrazine 1-oxide (310.0 mg, 1.84 mmol) in POCl₃(10.0 mL, 106.96 mmol) was heated at 100° C. for 2 hrs. The excess POCl₃was evaporated and the residue was purified by silica gel column chromatography using a 0-100% EtOAc/cyclohexane gradient eluent to afford a mixture of the title compounds (171 mg, 49%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.89 (s, 1H), 3.91 (s, 4H), 2.71 (s, 3H). ¹H NMR (400 MHz, DMSO-d₆) δ 8.73 (d, J=0.8 Hz, 1H), 3.90 (s, 3H), 2.70 (d, J=0.7 Hz, 3H). MS-ESI (m/z) calc'd for C₇H₈ClN₂O₂[M+H]⁺: 187.0. Found 187.0

Step 3: Methyl 3-methyl-5-vinylpyrazine-2-carboxylate and methyl 3-Methyl-6-vinylpyrazine-2-carboxylate

embedded image

A solution of methyl 5-chloro-3-methylpyrazine-2-carboxylate and methyl 6-chloro-3-methylpyrazine-2-carboxylate (171.0 mg, 0.920 mmol) and tributyl(ethenyl)stannane (0.32 mL, 1.1 mmol) was degassed with N₂for 10 minutes. Bis(triphenylphosphine)palladium(II) dichloride (64.51 mg, 0.090 mmol) was added and the mixture was stirred at 100° C. for 1 hr. The solvent was evaporated and the residue was purified by silica gel column chromatography using a 0-100% EtOAc/cyclohexane gradient eluent to afford a mixture of the title compounds (163.3 mg, 100% yield) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.87 (s, 1H), 6.89 (dd, J=17.6, 11.0 Hz, 1H), 6.36 (dd, J=17.6, 1.3 Hz, 1H), 5.66 (dd, J=11.0, 1.3 Hz, 1H), 3.91 (s, 3H), 2.67 (s, 3H). ¹H NMR (400 MHz, DMSO-d₆) δ 8.70 (s, 1H), 6.92 (dd, J=17.5, 10.9 Hz, 1H), 6.48 (dd, J=17.5, 1.4 Hz, 1H), 5.76 (dd, J=10.9, 1.4 Hz, 1H), 3.89 (s, 2H), 2.70 (d, J=0.7 Hz, 2H). MS-ESI (m/z) calc'd for C₉H₁₁N₂O₂[M+H]⁺: 179.1. Found 179.0 and 179.0.

Step 4: Methyl 5-formyl-3-methylpyrazine-2-carboxylate and Methyl 6-formyl-3-methylpyrazine-2-carboxylate

embedded image

To a solution of methyl 3-methyl-5-vinylpyrazine-2-carboxylate and methyl 3-methyl-6-vinylpyrazine-2-carboxylate (163.3 mg, 0.920 mmol) in 1,4-dioxane (4.582 mL) was added a solution of NaIO₄(392.03 mg, 1.83 mmol) in H₂O (4.58 mL). After 5 minutes, a 4% solution of osmium tetroxide (0.29 mL, 0.050 mmol) was added and the mixture was stirred at 25° C. for 2 hrs. The suspension was diluted with water and then extracted with DCM (3×). The combined organic layers were passed through a phase separator and concentrated to afford a mixture of the title compounds (145 mg, 88%) as a black oil. ¹H NMR (400 MHz, DMSO-d₆) δ 10.06 (s, 1H), 9.15 (s, 1H), 3.96 (s, 3H), 2.82 (s, 3H). ¹H NMR (400 MHz, DMSO-d₆) δ 10.07 (s, 1H), 9.01 (d, J=0.8 Hz, 1H), 3.95 (s, 3H), 2.79 (d, J=0.7 Hz, 3H). MS-ESI (m/z) calc'd for C₈H₉N₂O₃[M+H]⁺: 179.1. Found 181.0 and 181.1.

Step 5: Methyl 5-cyano-3-methylpyrazine-2-carboxylate and Methyl 6-cyano-3-methylpyrazine-2-carboxylate

embedded image

A mixture of methyl 5-formyl-3-methylpyrazine-2-carboxylate and methyl 6-formyl-3-methylpyrazine-2-carboxylate (145.0 mg, 0.800 mmol) and hydroxylamine hydrochloride (55.93 mg, 0.800 mmol) in DMSO (1 mL) was heated at 90° C. for 1 hr. Water was added and the suspension was extracted with EtOAc (3×). The combined organic layers were washed with H₂O (2×) and brine, passed through a phase separator and evaporated to obtain a black solid. POCl₃was added and the solution was heated at 90° C. for 2 hrs. The mixture was poured into a solution of K₂CO₃and extracted with DCM (3×); the combined organic layers were passed through a phase separator and evaporated to afford a mixture of the title compounds (85 mg, 60%) as a dark solid. ¹H NMR (400 MHz, DMSO-d₆) δ 9.27 (s, 1H), 3.94 (s, 3H), 2.81 (s, 3H). ¹H NMR (400 MHz, DMSO-d₆) δ 9.15 (s, 1H), 3.94 (s, 3H), 2.74 (s, 3H). MS-ESI (m/z) calc'd for C₈H₈N₃O₂[M+H]⁺: 178.1. Found 178.0

Step 6: 5-Cyano-3-methylpyrazine-2-carboxylic acid and 6-Cyano-3-methylpyrazine-2-carboxylic acid

embedded image

To a solution of methyl 5-cyano-3-methylpyrazine-2-carboxylate and methyl 6-cyano-3-methylpyrazine-2-carboxylate (85.0 mg, 0.480 mmol) in THF (2.399 mL) was added a solution of NaOH (39.35 mg, 0.960 mmol) in H₂O (2.399 mL) and the mixture was stirred at 25° C. for 3 hrs. The solvent was evaporated and the residue was taken up in POCl₃(2 mL) and heated at 100° C. for 30 minutes. Excess POCl₃was then evaporated and the residue was taken up in H₂O and extracted with EtOAc (3×). The combined organic layers were passed through a phase separator and evaporated to afford a mixture of the title compounds (61 mg, 78%) as a dark oil. ¹H NMR (400 MHz, DMSO-d₆) δ 14.27 (s, 1H), 9.12 (s, 1H), 2.72 (d, J=0.6 Hz, 3H). ¹H NMR (400 MHz, DMSO-d₆) δ 14.27 (s, 1H), 9.04 (s, 1H), 2.74-2.73 (m, 3H). MS-ESI (m/z) calc'd for C₈H₈N₃O₂[M+H]⁺: 162.0. Found 162.0.

Intermediate A-9: 5-Cyano-3,4-dimethylpicolinic acid

embedded image

Step 1: 4,5,6-Trimethyl-2-oxo-1,2-dihydropyridine-3-carbonitrile

embedded image

To a solution of (Z)-4-amino-3-methylpent-3-en-2-one (18.2 g, 160.83 mmol) in THF (120 mL) was added dropwise a solution of malononitrile (10.62 g, 160.83 mmol) in THF (40 mL) and the mixture was stirred at 25° C. for 15 hrs. The solid formed was collected by filtration and washed with EtOAc to afford the title compound (17.89 g, 69%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 12.17 (s, 1H), 2.32 (s, 3H), 2.27-2.24 (m, 3H), 1.93 (s, 3H). MS-ESI (m/z) calc'd for C₉H₁₁N₂O [M+H]⁺: 163.1. Found 163.0.

Step 2: 2-Chloro-4,5,6-trimethylnicotinonitrile

embedded image

A suspension of 4,5,6-trimethyl-2-oxo-1,2-dihydropyridine-3-carbonitrile (17.89 g, 110.3 mmol) in POCl₃(70.0 mL, 748.71 mmol) was heated at 100° C. for 15 hrs. The reaction mixture was concentrated and then poured into water (1 L). The pH was adjusted to 7 by addition of Na₂CO₃. The solid was collected by filtration and dried to afford the title compound (18.59 g, 93%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 2.51 (s, 3H), 2.47 (s, 3H), 2.22 (s, 3H). MS-ESI (m/z) calc'd for C₉H₁₀ClN₂[M+H]⁺: 181.1. Found 181.0.

Step 3: 4,5,6-Trimethylnicotinonitrile

embedded image

To a solution of 2-chloro-4,5,6-trimethylnicotinonitrile (1.81 g, 10 mmol) in MeOH (50 mL) was added 10% Pd/C (1.06 g, 1 mmol). Ammonium formate (630.6 mg, 10 mmol) was then added and the mixture was stirred at 60° C. for 1 hr. The mixture was filtered through Celite and the filtrate was evaporated to dryness to give a residue that was taken up in water and extracted with DCM (3×). The combined organic layers were passed through a phase separator and concentrated to afford the title compound (1.19 g, 81%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.61 (s, 1H), 2.53 (s, 3H), 2.44 (s, 3H), 2.23 (s, 3H). MS-ESI (m/z) calc'd for C₉H₁₁N₂[M+H]⁺: 147.1. Found 146.9.

Step 4: 5-Cyano-2,3,4-trimethylpyridine 1-oxide

embedded image

To a solution of 4,5,6-trimethylnicotinonitrile (1.19 g, 8.14 mmol) in DCM (40.7 mL) was added MCPBA (2.01 g, 8.14 mmol) and the mixture was stirred at 25° C. for 5 hrs. The solution was washed with K₂CO₃solution (3×) and the aqueous layer was extracted with DCM (3×). The combined organic phases were passed through a phase separator and concentrated to afford the title compound (1.19 g, 90%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.73 (s, 1H), 2.44 (s, 3H), 2.39 (s, 3H), 2.28 (s, 3H). MS-ESI (m/z) calc'd for C₉H₁₁N₂O [M+H]⁺: 163.1. Found 163.0.

Step 5: 6-(Hydroxymethyl)-4,5-dimethylnicotinonitrile

embedded image

To a solution of 5-cyano-2,3,4-trimethylpyridine 1-oxide (4.15 g, 25.59 mmol) in DCM (39.15 mL) was added dropwise 2,2,2-trifluoroacetic acid (2,2,2-trifluoro-1-oxoethyl) ester (10.67 mL, 76.76 mmol) in DCM (39.15 mL) at 0° C. and the mixture was stirred at 25° C. for 15 h. The solvent was evaporated to dryness and the red oil obtained was dissolved in MeOH (50 mL). Then K₂CO₃(3 g) was added and the suspension was stirred for 15 min. The solvent was evaporated to give a residue that was taken up in water and extracted with DCM (3×). The combined organic layers were passed through a phase separator and evaporated to afford the title compound (3.65 g, 88%) as a dark orange solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.70 (s, 1H), 5.22 (t, J=5.6 Hz, 1H), 4.64 (d, J=5.6 Hz, 2H), 2.46 (s, 3H), 2.29 (s, 3H). MS-ESI (m/z) calc'd for C₉H₁₁N₂O [M+H]⁺: 163.1. Found 163.0.

Step 6: 5-Cyano-3,4-dimethylpicolinic acid

embedded image

To a solution of 6-(hydroxymethyl)-4,5-dimethylnicotinonitrile (3.65 g, 22.5 mmol) in acetone (62.98 mL) was added dropwise (over 15 min) a solution of KMnO₄(3.91 g, 24.75 mmol) in water (31.49 mL) at 25° C. and the mixture was stirred for 30 minutes. The dark material was filtered and washed with 1 M K₂CO₃solution. The filtrate was concentrated to remove the organic solvent and the pH was adjusted to 4-5 by addition of 6 M HCl and the solution was extracted with EtOAc (3×). Then additional 6 M HCl was added until pH=1 was reached and the aqueous phase was further extracted with EtOAc (3×). The combined organic layers were passed through a phase separator and concentrated to afford the title compound (1.75 g, 44%) as a beige solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.82 (s, 1H), 8.78 (s, 1H), 2.50 (s, 3H), 2.33 (s, 3H). MS-ESI (m/z) calc'd for C₉H₉N₂O₂[M+H]⁺: 177.1. Found 177.1.

Intermediate A-10: 3-(2-Methoxypyridin-4-yl)-1H-indazol-5-amine

embedded image

3-Bromo-1H-indazol-5-amine (1.0 g, 4.72 mmol), 2-methoxypyridine-4-boronic acid (1081.87 mg, 7.07 mmol) and tripotassium phosphate (3003.11 mg, 14.15 mmol) were dissolved in a mixture of THF (12 mL) and H₂O (4 mL). The reaction mixture was degassed with nitrogen for 15 min and then SPhos-Pd-G2 (0.51 g, 0.710 mmol) was added. The mixture was heated to 80° C. and stirred for 20 hrs. Then 0.5 eq of 2-methoxypyridine-4-boronic acid and 0.075 eq of Sphos-Pd-G2 were added and the mixture was stirred at 80° C. for an additional 16 hrs. The reaction was cooled to r.t. and diluted with H₂O and EtOAc. The phases were separated and the aqueous layer was extracted with EtOAc (2×). The combined organic layers were concentrated under reduced pressure to give a residue that was purified by preparative HPLC using Method CM to afford the title compound (385 mg, 34%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.13 (br. s., 1H) 8.19-8.28 (m, 1H) 7.52 (dd, J=5.39, 1.43 Hz, 1H) 7.35 (d, J=8.80 Hz, 1H) 7.24 (d, J=0.66 Hz, 1H) 7.17 (d, J=1.32 Hz, 1H) 6.86 (dd, J=8.80, 1.98 Hz, 1H) 5.02 (s, 2H) 3.92 (s, 3H). MS-ESI (m/z) calc'd for C₁₃H₁₃N₄O₂[M+H]⁺: 241.1. Found 241.2.

Intermediate A-11: 3-(1-(Difluoromethyl)-1H-pyrazol-4-yl)-1H-indazol-5-amine

embedded image

3-Iodo-1H-indazol-5-amine (1.3 g, 5 mmol) was dissolved in THF (28.37 mL) then a solution of tripotassium phosphate (3.18 g, 15 mmol) and 1-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (1.46 g, 6 mmol) in H₂O (10.64 mL) was added and the mixture was degassed with N₂for 15 minutes. SPhos-Pd-G2 (0.36 g, 0.500 mmol) was added and the mixture was stirred at 100° C. under N₂for 1 hr. H₂O was added and the organic solvent was evaporated. The solid that formed was collected by filtration and washed with water and dried. The filtrate was extracted with EtOAc (3×) and the combined organic layers were concentrated and added to the solid to obtain a residue which was triturated with DCM to afford the title compound (880 mg, 71%) as a grey solid. ¹H NMR (400 MHz, DMSO-d₆) δ 12.70 (s, 1H), 8.61 (s, 1H), 8.22 (s, 1H), 7.88 (t, J=59.1 Hz, 1H), 7.28 (d, J=8.8 Hz, 1H), 7.03 (d, J=2.0 Hz, 1H), 6.84 (dd, J=8.8, 2.0 Hz, 1H), 4.82 (s, 2H). MS-ESI (m/z) calc'd for C₁₁H₁₀F₂N₅[M+H]⁺: 250.1. Found 250.3.

Intermediate A-12: 4-Cyano-2-fluoro-6-methylbenzoic acid

embedded image

Step 1: Methyl 4-bromo-2-fluoro-6-methylbenzoate

embedded image

To a solution of 4-bromo-2-fluoro-6-methylbenzoic acid (1.37 g, 5.88 mmol) in DMF (9.798 mL) was added potassium carbonate (2.44 g, 17.64 mmol) and iodomethane (0.73 mL, 11.76 mmol), then the mixture was stirred at 80° C. for 1 hr. The mixture was poured into water (150 mL) and the mixture was extracted with Et₂O (3×). The combined organic layers were washed with H₂O (2×) and brine, then passed through a phase separator and evaporated to give the title compound (1.452 g, 100%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 7.54 (ddd, J=9.5, 1.8, 0.7 Hz, 1H), 7.46 (dt, J=1.8, 0.8 Hz, 1H), 3.87 (s, 3H), 2.33 (d, J=0.7 Hz, 3H). MS-ESI (m/z) calc'd for C₉H₉BrFO₂[M+H]⁺: 247.0/249.0. Found 247.0/249.0.

Step 2: Methyl 2-fluoro-6-methyl-4-vinylbenzoate

embedded image

A solution of methyl 4-bromo-2-fluoro-6-methylbenzoate (1.45 g, 5.88 mmol) and tributyl(ethenyl)stannane (2.06 mL, 7.05 mmol) in 1,4-dioxane (58.79 mL) was sparged with N₂for 10 minutes. Triphenylphosphine palladium(II) dichloride (413.84 mg, 0.590 mmol) was added and the mixture was stirred at 100° C. for 1.5 hrs. The solvent was evaporated and the residue was purified by silica gel column chromatography using a 0-10% EtOAc/cyclochexane gradient eluent to afford the title compound (1.142 g, 100%) as yellow oil. ¹H NMR (400 MHz, DMSO-d₆) δ 7.31 (dd, J=11.2, 1.5 Hz, 1H), 7.28-7.26 (m, 1H), 6.79-6.62 (m, 1H), 6.00 (dd, J=17.7, 0.8 Hz, 1H), 5.42 (d, J=10.9 Hz, 1H), 3.86 (s, 3H), 2.33 (d, J=0.8 Hz, 3H). MS-ESI (m/z) calc'd for C₁₁H₁₂FO₂[M+H]⁺: 195.1. Found 195.0.

Step 3: Methyl 2-fluoro-4-formyl-6-methylbenzoate

embedded image

To a solution of methyl 2-fluoro-6-methyl-4-vinylbenzoate (1.14 g, 5.88 mmol) in 1,4-dioxane (29.39 mL) was added a solution of NaIO₄(2.51 g, 11.76 mmol) in H₂O (29.39 mL) and the mixture was stirred at 25° C. for 5 minutes. Osmium tetroxide (1.87 mL, 0.290 mmol) was added and the reaction was stirred for 2 hrs. The reaction was diluted with H₂O and the mixture was extracted with DCM (3×). The combined organic layers were passed through a phase separator (charged with activated carbon) and concentrated to afford the title compound (1.14 g, 99%) as a dark solid. ¹H NMR (400 MHz, DMSO-d₆) δ 9.99 (d, J=1.7 Hz, 1H), 7.73 (t, J=1.1 Hz, 1H), 7.66 (ddd, J=9.4, 1.4, 0.7 Hz, 1H), 3.92 (s, 3H), 2.41 (t, J=0.7 Hz, 3H). MS-ESI (m/z) calc'd for C₁₀H₁₀FO₃[M+H]⁺: 197.1. Found 197.0.

Step 4: 3-Fluoro-4-(methoxycarbonyl)-5-methylbenzoic acid

embedded image

To a solution of methyl 2-fluoro-4-formyl-6-methylbenzoate (1.14 g, 5.81 mmol) in DMSO (5 mL) was added hydroxylamine hydrochloride (403.81 mg, 5.81 mmol) and the mixture was stirred at 90° C. for 2 hrs. Water was added and the mixture was extracted with EtOAc. The organic layer was washed with H₂O (3×) then passed through a phase separator and concentrated. The residue was purified by silica gel column chromatography using a 0-50% EtOAc/cyclohexane gradient eluent to afford the title compound (457 mg, 37%) as a yellow oil. ¹H NMR (400 MHz, DMSO-d₆) δ 13.49 (s, 1H), 7.72 (s, 1H), 7.58 (dd, J=9.9, 1.5 Hz, 1H), 3.90 (s, 3H), 2.38 (s, 3H). MS-ESI (m/z) calc'd for C₁₀H₁₀FO₄[M+H]⁺: 213.1. Found 213.0.

Step 5: Methyl 4-cyano-2-fluoro-6-methylbenzoate

embedded image

A solution of 3-fluoro-4-(methoxycarbonyl)-5-methylbenzoic acid (457.0 mg, 2.15 mmol) in thionyl chloride (10.0 mL, 137.09 mmol) was heated at 80° C. for 2 hrs. The excess of thionyl chloride was evaporated and the residue was taken up in THF (10 mL). A solution of 0.5 M ammonia (17.23 mL, 8.62 mmol) in dioxane was added and the mixture was stirred at 25° C. for 1 hr. The solvent was evaporated and the residue was taken up in POCl₃(10.0 mL, 106.96 mmol) and the resulting suspension was stirred at 100° C. for 3 hrs. Excess POCl₃was evaporated and the residue was taken up in water and extracted with DCM (3×). The combined organic layers were passed through a phase separator and concentrated to afford the title compound (410 mg, 99%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 7.85 (ddd, J=9.5, 1.4, 0.7 Hz, 1H), 7.74 (dd, J=1.5, 0.7 Hz, 1H), 3.92 (s, 3H), 2.36 (d, J=0.7 Hz, 3H). MS-ESI (m/z) calc'd for C₁₀H₉FNO₂[M+H]⁺: 194.1. Found 194.1.

Step 6: 4-Cyano-2-fluoro-6-methylbenzoic acid

embedded image

To a solution of methyl 4-cyano-2-fluoro-6-methylbenzoate (410.0 mg, 2.12 mmol) in THF (5.31 mL) was added 1 M NaOH (4.24 mL, 4.24 mmol) and the mixture was stirred at 25° C. for 6 hrs. The organic solvent was evaporated and the mixture was acidified by addition of 1 M HCl and extracted with EtOAc (3×). The combined organic layers were passed through a phase separator and concentrated to afford the title compound (380 mg, 99%) as a brown solid. ¹H NMR (400 MHz, DMSO-d₆) δ 14.08 (s, 1H), 7.80 (dd, J=9.3, 1.4 Hz, 1H), 7.72-7.66 (m, 1H), 2.37 (s, 3H). MS-ESI (m/z) calc'd for C₉H₅FNO₂[M−H]⁻: 178.1. Found 178.1.

Intermediate A-13: 6-Chloro-5-cyano-3,4-dimethylpicolinic acid

embedded image

Step 1: 2-Chloro-6-(hydroxymethyl)-4,5-dimethylnicotinonitrile

embedded image

To a solution of 2-chloro-3-cyano-4,5,6-trimethylpyridine 1-oxide (634.0 mg, 3.22 mmol) in DCM (9.86 mL) was added dropwise 2,2,2-trifluoroacetic anhydride (1.34 mL, 9.67 mmol) in DCM (9.86 mL) at 0° C. and the mixture was stirred at 25° C. for 15 hrs. The solvent was evaporated to give a residue that was taken up in water and extracted with DCM (2×). The combined organic layers were passed through a phase separator and concentrated to afford the title compound (650 mg, 100%) as a pale yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 5.42 (t, J=5.8 Hz, 1H), 4.60 (d, J=5.4 Hz, 2H), 2.50 (s, 3H), 2.28 (s, 3H). MS-ESI (m/z) calc'd for C₉H₁₀ClN₂O [M+H]⁺: 197.0. Found 197.0.

Step 2: 6-Chloro-5-cyano-3,4-dimethylpicolinic acid

embedded image

To a solution of 2-chloro-6-(hydroxymethyl)-4,5-dimethylnicotinonitrile (100.0 mg, 0.510 mmol) in acetone (1.5 mL) was added dropwise a solution of KMnO₄(88.41 mg, 0.560 mmol) in H₂O (0.750 mL) at r.t. and the mixture was stirred for 2 hrs. The dark mixture was filtered and the solid was washed with 1 M aqueous K₂CO₃. The filtrate was concentrated to remove acetone and then extracted with EtOAc. The pH was adjusted to pH=2 by addition of 6 M HCl and was extracted with EtOAc (3×). The combined organic layers were passed through a phase separator and concentrated to afford the title compound (78 mg, 73%) as a beige solid. ¹H NMR (400 MHz, DMSO-d₆) δ 2.55 (s, 3H), 2.33 (s, 3H). MS-ESI (m/z) calc'd for C₉H₈ClN₂O₂[M+H]⁺: 211.0. Found 211.0.

Intermediate A-14: 5-Cyano-3,4,6-trimethylpicolinic acid

embedded image

Step 1:6-(Hydroxymethyl)-2,4,5-trimethylnicotinonitrile

embedded image

A solution of 2-chloro-6-(hydroxymethyl)-4,5-dimethylnicotinonitrile (150.0 mg, 0.760 mmol), K₂CO₃(210.87 mg, 1.53 mmol) and trimethylboroxine (0.21 mL, 1.53 mmol) in 1,4-dioxane (2 mL)/H₂O (1 mL) was degassed with N₂for 15 min. Tetrakis(triphenylphosphine)palladium(0) (176.3 mg, 0.150 mmol) was added and the mixture was stirred at 90° C. for 6 hours. The residue was taken up in H₂O and extracted with EtOAc (2×). The combined organic layers were passed through a phase separator and evaporated to obtain a residue which was purified by reversed phase column chromatography using a 2-80% MeCN/H₂O (0.1% formic acid) gradient eluent to afford the title compound (83 mg, 62%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 5.19 (t, J=5.5 Hz, 1H), 4.60 (d, J=5.5 Hz, 2H), 2.62 (s, 3H), 2.44 (s, 3H), 2.25 (s, 3H). MS-ESI (m/z) calc'd for C₁₀H₁₃N₂O [M+H]⁺: 177.1. Found 177.0.

Step 2: 5-Cyano-3,4,6-trimethylpicolinic acid

embedded image

To a solution of 6-(hydroxymethyl)-2,4,5-trimethylnicotinonitrile (83.0 mg, 0.47 mmol) in acetone (1.5 mL) was added dropwise a solution of KMnO₄(81.88 mg, 0.52 mmol) in H₂O (0.75 mL) at r.t. and the mixture was stirred for 2 hrs. The dark mixture was filtered and the solid was washed with 1 M aqueous K₂CO₃. The filtrate was concentrated to remove the organic solvent and extracted with EtOAc. Then the pH was adjusted to pH=2 by addition of 6 M HCl and the solution was extracted with EtOAc (3×). The combined organic layers were passed through a phase separator and evaporated to afford the title compound (90 mg, 100%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.63 (br s, 1H), 2.63 (s, 3H), 2.49 (s, 3H), 2.29 (s, 3H). MS-ESI (m/z) calc'd for C₁₀H₉N₂O₂[M−H]⁻: 189.1. Found 189.2.

Intermediate A-15: 3-(Thiazol-5-yl)-1H-indazol-5-amine

embedded image

A microwave reactor vial was charged with 3-iodo-1H-indazol-5-amine (500.0 mg, 1.93 mmol), Pd(amphos)Cl₂(137.06 mg, 0.190 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazole (448.17 mg, 2.12 mmol), 1,4-dioxane (3.281 mL) and H₂O (0.750 mL). The vial was flushed with N₂for 5 min after which KOAc (340.96 mg, 3.47 mmol) was added and the vial was sealed and irradiated in a microwave reactor at 100° C. for 30 min. The reaction mixture was partitioned between H₂O and EtOAc. The phases were separated and the aqueous layer was extracted with EtOAc (2×). The combined organic phases were washed with brine (1×), dried over Na₂SO₄and concentrated to give a residue that was purified by preparative HPLC using Method CN to afford the title compound (93 mg, 22%). MS-ESI (m/z) calc'd for C₁₀H₉N₄S [M+H]⁺: 217.1. Found 217.1.

Intermediate A-16: 3-Bromo-2-methoxy-6-methyl-N-(3-(oxazol-5-yl)-1H-indazol-5-yl)benzamide

embedded image

To a mixture of 3-bromo-2-methoxy-6-methylbenzoic acid (40.0 mg, 0.160 mmol), 3-(1,3-oxazol-5-yl)-1H-indazol-5-amine (35.94 mg, 0.180 mmol) and Et₃N (45.5 uL, 0.330 mmol) in MeCN (2.5 mL) was added HATU (62.06 mg, 0.160 mmol) and the mixture was stirred at r.t. for 1 hr. The reaction mixture was partitioned between H₂O and EtOAc and the phases were separated. The aqueous layer was extracted with EtOAc (2×) and the combined organic phases were washed with brine (1×), dried over Na₂SO₄, and concentrated to afford the title compound (110 mg) which was used without further purification. ¹H NMR (400 MHz, DMSO-d₆) δ 13.50 (s, 1H) 10.59 (s, 1H) 8.59 (d, J=6.60 Hz, 2H) 7.50-7.79 (m, 4H) 6.97-7.14 (m, 1H) 3.82 (s, 3H) 2.29 (s, 3H). MS-ESI (m/z) calc'd for C₁₉H₁₆BrN₄O₃[M+H]⁺: 427.0/429.0. Found 427.2/429.2.

Intermediate A-17: 4-Cyano-6,7-dihydro-5H-cyclopenta[c]pyridine-1-carboxylic acid

embedded image

Step 1: 1-Methyl-3-oxo-4,5,6,7-tetrahydro-3H-cyclopenta[c]pyridine-4-carbonitrile and 4-Methyl-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridine-3-carbonitrile

embedded image

To a solution of 2-acetyl-1-cyclopentanone (5.05 g, 40 mmol) and 2-cyanoacetamide (3.36 g, 40 mmol) was added piperidine (3.95 mL, 40 mmol) and the mixture was stirred at 75° C. for 22 hrs. After cooling the solid formed was collected by filtration and dried to afford a mixture of the title compounds (3.35 g, 48%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 12.26 (s, 1H), 2.80 (t, J=7.8 Hz, 2H), 2.63 (t, J=7.3 Hz, 2H), 2.27 (s, 3H), 2.07-1.96 (m, 2H). MS-ESI (m/z) calc'd for C₁₀H₁₁N₂O [M+H]⁺: 175.1. Found 175.0.

Step 2: 3-Chloro-1-methyl-6,7-dihydro-5H-cyclopenta[c]pyridine-4-carbonitrile and 2-Chloro-4-methyl-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carbonitrile

embedded image

A suspension of 1-methyl-3-oxo-4,5,6,7-tetrahydro-3H-cyclopenta[c]pyridine-4-carbonitrile and 4-methyl-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridine-3-carbonitrile (3.35 g, 19.23 mmol) in POCl₃(20.0 mL, 213.92 mmol) was heated [upon heating the solid slowly dissolves until complete dissolution] at 100° C. for 17 hrs. The excess of POCl₃was evaporated and the oil that remained was taken up in water and stirred for 30 minutes. The solid that formed was collected by filtration and dried under vacuum to afford a mixture of the title compounds (3.704 g, 19.23 mmol) as an off-white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 3.08 (t, J=7.7 Hz, 2H), 2.94-2.85 (m, 2H), 2.45 (s, 3H), 2.21-2.05 (m, 2H). MS-ESI (m/z) calc'd for C₁₀H₁₀ClN₂[M+H]⁺: 193.1. Found 193.0.

Step 3: 1-Methyl-6,7-dihydro-5H-cyclopenta[c]pyridine-4-carbonitrile and 4-Methyl-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carbonitrile

embedded image

A mixture of 3-chloro-1-methyl-6,7-dihydro-5H-cyclopenta[c]pyridine-4-carbonitrile and 2-chloro-4-methyl-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carbonitrile (0.96 g, 5 mmol), NaOAc.3H₂O (685.45 mg, 5 mmol) and 10% Pd/C (532.1 mg, 0.500 mmol) was hydrogenated for 1 hr. The catalyst was filtered through Celite and the filtrate was evaporated to give a residue. The residue was taken up in H₂O and extracted with DCM (3×). The combined organic layers were passed through a phase separator and evaporated to afford a mixture of the title compounds (380 mg, 2.402 mmol) as a clear oil. ¹H NMR (400 MHz, DMSO-d₆) δ 8.62 (s, 1H), 3.06 (dd, J=8.1, 7.2 Hz, 2H), 2.96-2.87 (m, 2H), 2.47 (s, 3H), 2.15-2.03 (m, 2H). MS-ESI (m/z) calc'd for C₁₀H₁₀N, [M+H]⁺: 159.1. Found 159.0.

Step 4: 4-Cyano-1-methyl-6,7-dihydro-5H-cyclopenta[c]pyridine 2-oxide and 3-Cyano-4-methyl-6,7-dihydro-5H-cyclopenta[b]pyridine 1-oxide

embedded image

To a solution of 1-methyl-6,7-dihydro-5H-cyclopenta[c]pyridine-4-carbonitrile and 4-methyl-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carbonitrile (380.0 mg, 2.4 mmol) in DCM (24.02 mL) was added MCPBA (592.17 mg, 2.4 mmol) and the mixture was stirred at 25° C. for 5 hrs. The solution was washed with a K₂CO₃solution (3×) and the aqueous layers were extracted with DCM (3×). All the organic phases were combined, passed through a phase separator and evaporated to dryness to afford a mixture of the title compounds (355 mg, 85%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.70 (s, 1H), 3.06-2.94 (m, 4H), 2.34 (s, 3H), 2.19-2.06 (m, 2H). MS-ESI (m/z) calc'd for C₁₀H₁₀N₂O [M+H]⁺: 175.1. Found 175.0.

Step 5: 1-(Hydroxymethyl)-6,7-dihydro-5H-cyclopenta[c]pyridine-4-carbonitrile and 7-Hydroxy-4-methyl-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carbonitrile

embedded image

To a solution of 4-cyano-1-methyl-6,7-dihydro-5H-cyclopenta[c]pyridine 2-oxide and 3-cyano-4-methyl-6,7-dihydro-5H-cyclopenta[b]pyridine 1-oxide (355.0 mg, 2.04 mmol) in DCM (6 mL) was added dropwise 2,2,2-trifluoroacetic anhydride (0.85 mL, 6.11 mmol) in DCM (2 mL) at 25° C. and the mixture was stirred at 25° C. for 15 hrs. The solvent was evaporated and the red oil obtained was dissolved in MeOH (10 mL). Then K₂CO₃(0.5 g) was added and the suspension was stirred for 15 min. The solvent was evaporated and the residue was taken up in water and extracted with DCM (3×). The combined organic layers were passed through a phase separator and evaporated to afford a mixture of the title compounds (310 mg, 87%) as a dark oil. ¹H NMR (400 MHz, DMSO-d₆) δ 8.69 (s, 1H), 5.31 (t, J=6.0 Hz, 1H), 4.59 (d, J=5.4 Hz, 2H), 3.11-3.01 (m, 4H), 2.10 (p, J=7.6 Hz, 2H). MS-ESI (m/z) calc'd for C₁₀H₁₀N₂O [M+H]⁺: 175.1. Found 175.0.

Step 6: 4-Cyano-6,7-dihydro-5H-cyclopenta[c]pyridine-1-carboxylic acid

embedded image

To a solution of 1-(hydroxymethyl)-6,7-dihydro-5H-cyclopenta[c]pyridine-4-carbonitrile and 7-hydroxy-4-methyl-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carbonitrile (310.0 mg, 0.710 mmol) in acetone (8.898 mL) and H₂O (8.898 mL) was added KMnO₄(224.98 mg, 1.42 mmol) and the mixture was stirred at 25° C. for 3 hrs. The dark mixture was filtered under vacuum and the solid was washed with acetone and 1 M aqueous K₂CO₃. The filtrate was concentrated to remove the organic solvent and the remaining aqueous layer was extracted with Et₂O (3×). The aqueous layer was adjusted to pH≤1 by addition of conc. HCl and extracted with EtOAc (3×). The combined organic layers were passed through a phase separator and concentrated to afford the title compound (133.9 mg, 99° %) as a dark solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.51 (bs, 1H), 8.86 (s, 1H), 3.25 (t, J=7.6 Hz, 2H), 3.12 (t, J=7.7 Hz, 2H), 2.16-2.06 (m, 2H). MS-ESI (m/z) calc'd for C₁₀H₉N₂O₂[M+H]⁺: 189.1. Found 189.0.

Intermediate A-18: 5-Cyano-4-methoxy-3-methylpicolinic acid

embedded image

Step 1: 4-Methoxy-2,3-dimethylpyridine 1-oxide

embedded image

To a suspension of 2,3-dimethyl-4-nitro-1-oxidopyridin-1-ium (5.04 g, 30 mmol) in MeOH (50 mL) was added K₂CO₃(4.98 g, 36 mmol) portionwise at 0° C. [Caution: without the ice bath, the reaction can be violently exothermic]. The mixture was heated at 65° C. for 4 hrs, then the solvent was evaporated to dryness and the residue was taken up in CH₃CN (100 mL) and stirred at reflux for 30 minutes. The solid was filtered and washed with CH₃CN (10 mL, ×3). The filtered solution rapidly became a suspension and was filtered again to remove the solids and concentrated to afford the title compound (3.8 g, 83%) as an orange solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.10 (d, J=7.5 Hz, 1H), 6.94 (d, J=7.3 Hz, 1H), 3.83 (s, 3H), 2.35 (s, 3H), 2.12 (s, 3H). MS-ESI (m/z) calc'd for C₈H₁₂NO₂[M+H]⁺: 154.1. Found 153.0.

Step 2: 5-Bromo-4-methoxy-2,3-dimethylpyridine 1-oxide

embedded image

To a solution of 4-methoxy-2,3-dimethylpyridine 1-oxide (4.0 g, 26.11 mmol) in trifluoroacetic acid (5.201 mL) and sulfuric acid (6.96 mL, 130.57 mmol) was added N-bromosuccinimide (9.3 g, 52.23 mmol) portionwise and the mixture was stirred at 25° C. for 15 hrs. The mixture was poured onto cracked ice and quenched with an aqueous Na₂S₂O₃solution. The pH was adjusted to 7 by addition of 6 M NaOH and then extracted with DCM (3×). The combined organic layers were passed through a phase separator and concentrated to afford the title compound (4.53 g, 75%) as a dark oil. ¹H NMR (400 MHz, DMSO-d₆) δ 8.51-8.49 (m, 1H), 3.76 (s, 3H), 2.32 (d, J=0.6 Hz, 3H), 2.24 (t, J=0.7 Hz, 3H). MS-ESI (m/z) calc'd for C₈H₁₁BrNO₂[M+H]⁺: 232.0/234.0. Found 232.0/234.0.

Step 3: (5-Bromo-4-methoxy-3-methylpyridin-2-yl)methanol

embedded image

To a solution of 5-bromo-4-methoxy-2,3-dimethylpyridine 1-oxide (4.53 g, 19.52 mmol) in DCM (40 mL) was added dropwise 2,2,2-trifluoroacetic anhydride (8.14 mL, 58.56 mmol) in DCM (20 mL) at 0° C. The mixture was stirred at 0° C. for 5 hrs. The solvent was evaporated and the residue was taken up in MeOH (60 mL). Solid K₂CO₃was added and the suspension was stirred at 25° C. for 30 minutes. The solvent was evaporated to give a residue that was taken up in H₂O and extracted with DCM (3×). The combined organic layers were passed through a phase separator and concentrated to afford the title compound (4.53 g, 100%) as an orange oil. ¹H NMR (400 MHz, DMSO-d₆) δ 8.48 (d, J=0.7 Hz, 1H), 5.12 (t, J=5.6 Hz, 1H), 4.54 (d, J=5.4 Hz, 2H), 3.81 (s, 3H), 2.28 (d, J=0.6 Hz, 3H). MS-ESI (m/z) calc'd for C₈H₁₁BrNO₂[M+H]⁺: 232.0/234.0. Found 232.0/234.0.

Step 4: 5-Bromo-4-methoxy-3-methylpicolinic acid

embedded image

To a solution of (5-bromo-4-methoxy-3-methylpyridin-2-yl)methanol (4.53 g, 19.52 mmol) in acetone (54 mL) was added dropwise a solution of KMnO₄(3.08 g, 19.52 mmol) in H₂O (27 mL) at 25° C. and the mixture was stirred for 2 hrs. The dark mixture was filtered and washed with acetone and H₂O. The filtrate was concentrated and the pH was adjusted to pH=2 by addition of conc. HCl and the solution was extracted with EtOAc (5×). The combined organic layers were passed through a phase separator and concentrated to afford the title compound (1.6 g, 33%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 14.91 (s, 1H), 8.61 (s, 1H), 3.86 (s, 3H), 2.38 (s, 3H). MS-ESI (m/z) calc'd for C₈H₉BrNO₃[M+H]⁺: 246.0/248.0. Found 246.0/248.0.

Step 5: Methyl 5-bromo-4-methoxy-3-methylpicolinate

embedded image

To a solution of 5-bromo-4-methoxy-3-methylpicolinic acid (1.6 g, 6.5 mmol) in DMF (10.84 mL) was added K₂CO₃(2.7 g, 19.51 mmol) and iodomethane (0.81 mL, 13 mmol) and the mixture was stirred at 80° C. for 1 hr. The mixture was then poured into H₂O (150 mL) and the mixture was extracted with Et₂O (3×). The combined organic layers were washed with H₂O (2×) and brine then passed through a phase separator and concentrated to afford the title compound (1 g, 59%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.63 (d, J=0.7 Hz, 1H), 3.87 (s, 3H), 3.86 (s, 3H), 2.37 (d, J=0.6 Hz, 3H). MS-ESI (m/z) calc'd for C₉H₁₁BrNO₃[M+H]⁺: 260.0/262.0. Found 260.0/262.0.

Step 6: Methyl 4-methoxy-3-methyl-5-vinylpicolinate

embedded image

A solution of methyl 5-bromo-4-methoxy-3-methylpicolinate (1.0 g, 3.84 mmol) and tributyl(ethenyl)stannane (1.35 mL, 4.61 mmol) in 1,4-dioxane (38.45 mL) was purged with N₂for 10 minutes. Bis(triphenylphosphine)palladium(II) dichloride (270.65 mg, 0.380 mmol) was added and the mixture was stirred at 100° C. for 15 hrs. The solvent was evaporated and the residue was purified by silica gel column chromatography using a 0-50% EtOAc/cyclohexane gradient eluent to afford the title compound (504 mg, 63%) as a yellow oil. ¹H NMR (400 MHz, DMSO-d₆) δ 8.73-8.56 (m, 1H), 6.89 (ddd, J=17.8, 11.3, 0.6 Hz, 1H), 6.07 (dd, J=17.9, 1.1 Hz, 1H), 5.55 (dd, J=11.3, 1.1 Hz, 1H), 3.86 (s, 3H), 3.76 (s, 3H), 2.32 (d, J=0.6 Hz, 3H). MS-ESI (m/z) calc'd for C₁₁H₁₄NO₃[M+H]⁺: 208.1. Found 208.1.

Step 7: Methyl 5-formyl-4-methoxy-3-methylpicolinate

embedded image

To a solution of methyl 4-methoxy-3-methyl-5-vinylpicolinate (504.0 mg, 2.43 mmol) in 1,4-dioxane (12.16 mL) was added a solution of NaIO₄(1.04 g, 4.86 mmol) in H₂O (12.16 mL) and the mixture was stirred at 25° C. for 1 hr. The mixture was diluted with water and extracted with DCM (3×). The combined organic layers were passed through a phase separator and concentrated to afford the title compound (406 mg, 80%) as a dark solid. ¹H NMR (400 MHz, DMSO-d₆) δ 10.32 (s, 1H), 8.74 (s, 1H), 4.01 (s, 3H), 3.90 (s, 3H), 2.32 (d, J=0.6 Hz, 3H). MS-ESI (m/z) calc'd for C₁₀H₁₂NO₄[M+H]⁺: 210.1. Found 210.1.

Step 8: Methyl 4-chloro-5-cyano-3-methylpicolinate

embedded image

To a solution of methyl 5-formyl-4-methoxy-3-methylpicolinate (406.0 mg, 1.94 mmol) in DMSO (2.4 mL) was added hydroxylamine hydrochloride (134.86 mg, 1.94 mmol) and the mixture was stirred at 90° C. for 1 hr. The mixture was taken up in H₂O and extracted with EtOAc (3×). The combined organic layers were washed with H₂O, passed through a phase separator, and evaporated to give a black solid which was taken up in POCl₃(3 mL) and heated at 100° C. for 1 hr. Excess POCl₃was evaporated and the residue was taken up in H₂O and extracted with EtOAc (3×). The combined organic layers were passed through a phase separator and concentrated to afford the title compound (270 mg, 66%) as a dark solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.99 (q, J=0.6 Hz, 1H), 3.93 (s, 3H), 2.46 (d, J=0.6 Hz, 3H). MS-ESI (m/z) calc'd for C₉H₈ClN₂O₂[M+H]⁺: 211.0. Found 211.0.

Step 9: 5-Cyano-4-methoxy-3-methylpicolinic acid

embedded image

To a solution of methyl 4-chloro-5-cyano-3-methylpicolinate (170.0 mg, 0.810 mmol) in MeOH (8.071 mL) was added 30% NaOMe (0.3 mL, 1.61 mmol) and the mixture was stirred at 25° C. for 15 minutes. The solvent was evaporated and the residue was taken up in H₂O and extracted with EtOAc (3×). The combined organic layers were passed through a phase separator and concentrated to afford the title compound (125 mg, 81%) as a dark yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 14.74 (s, 1H), 8.74 (d, J=0.7 Hz, 1H), 4.24 (s, 3H), 2.24 (d, J=0.5 Hz, 3H).). MS-ESI (m/z) calc'd for C₉H₉N₂O₃[M+H]⁺: 193.1. Found 193.1.

Intermediate A-19: 5-Cyano-3-cyclopropylpicolinic acid

embedded image

Step 1: Methyl 3-chloro-5-cyanopicolinate

embedded image

To a solution of 3-chloro-5-cyanopyridine-2-carboxylic acid (50.0 mg, 0.270 mmol) in DMF (0.456 mL) was added K₂CO₃(113.56 mg, 0.820 mmol) and iodomethane (34.1 uL, 0.550 mmol) and the mixture was stirred at 80° C. for 1 hr. The mixture was then partitioned between EtOAc and H₂O. The organic phase was separated, dried over Na₂SO₄, filtered and concentrated to afford the title compound (58 mg) which was used without further purification. ¹H NMR (400 MHz, DMSO-d₆) δ 9.07 (d, J=1.6 Hz, 1H), 8.82 (d, J=1.7 Hz, 1H), 3.95 (s, 3H). MS-ESI (m/z) calc'd for CH₈ClN₂O₂[M+H]⁺: 197.0. Found 197.0.

Step 2: Methyl 5-cyano-3-cyclopropylpicolinate

embedded image

To a microwave vial was added methyl 3-chloro-5-cyanopyridine-2-carboxylate (58.0 mg, 0.280 mmol), cesium carbonate (273.96 mg, 0.840 mmol), potassium cyclopropyl trifluoroborate (62.21 mg, 0.420 mmol), toluene (1 mL) and water (0.100 mL). The vial was capped and degassed with nitrogen (15 min). [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with DCM (22.95 mg, 0.030 mmol) was added and the vial was sealed and the reaction mixture was stirred and heated to 100° C. under microwave irradiation for 12 hrs. The mixture was filtered through Celite, then H₂O (200 mL) and EtOAc (200 mL) were added. The organic phase was separated, dried over Na₂SO₄, filtered and concentrated. The residue was purified by silica gel column chromatography using a 0-50% EtOAc/cyclohexane gradient eluent to afford the title compound (35 mg, 62%) as a white solid. ¹H NMR (400 MHz, chloroform-d₆) δ 8.73 (d, J=1.9 Hz, 1H), 7.62 (dd, J=1.9, 0.6 Hz, 1H), 4.05 (s, 3H), 2.57 (ddd, J=8.5, 5.3, 3.2 Hz, 1H), 1.24-1.15 (m, 2H), 0.83-0.72 (m, 2H). MS-ESI (m/z) calc'd for C₁₁H₁₁N₂O₂[M+H]⁺: 203.1. Found 203.1.

Step 3: 5-Cyano-3-cyclopropylpicolinic acid

embedded image

A solution of 2 N NaOH (0.17 mL, 0.350 mmol) was added to a solution of methyl 5-cyano-3-cyclopropylpyridine-2-carboxylate (35.0 mg, 0.170 mmol) in EtOH (2 mL) and was stirred at r.t. for 1 hr. 5 N Hydrochloric acid was added to the reaction mixture (until pH=1) at r.t., followed by extraction with EtOAc. The extract was dried over Na₂SO₄, filtered and the solvent was concentrated to afford the title compound (20 mg, 61%) which was used without further purification. MS-ESI (m/z) calc'd for C₁₀H₇N₂O₂[M−H]⁻: 187.1. Found 187.0.

Intermediate A-20: 5-Cyano-3-(prop-1-en-2-yl)picolinic acid

embedded image

Step 1: Ethyl 5-cyano-3-(prop-1-en-2-yl)picolinate

embedded image

To a microwave vial was added cesium carbonate (464.09 mg, 1.42 mmol), ethyl 3-chloro-5-cyanopyridine-2-carboxylate (150.0 mg, 0.710 mmol), 4,4,5,5-tetramethyl-2-(1-methylethenyl)-1,3,2-dioxaborolane (179.51 mg, 1.07 mmol), toluene (1 mL) and H₂O (0.100 mL). The vial was capped and degassed with N₂(15 min). [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (78.38 mg, 0.110 mmol) was added, the vial was sealed and heated in a microwave reactor to 100° C. The reaction was left stirring for 4 hrs at 100° C. The mixture was filtered through Celite, then H₂O (200 mL) and EtOAc (200 mL) were added. The organic phase was separated, dried over Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a 0-50% EtOAc/cyclohexane gradient eluent to afford the title compound (127 mg, 82%) as a colorless oil. ¹H NMR (400 MHz, DMSO-d₆) δ 8.98 (d, J=1.9 Hz, 1H), 8.48 (d, J=1.9 Hz, 1H), 5.29 (t, J=1.5 Hz, 1H), 4.99 (t, J=1.1 Hz, 1H), 4.32 (q, J=7.1 Hz, 2H), 2.07 (dd, J=1.5, 0.9 Hz, 4H), 1.27 (t, J=7.1 Hz, 3H). MS-ESI (m/z) calc'd for C₁₂H₁₃N₂O₂[M+H]⁺: 217.1. Found 217.0.

Step 2: 5-Cyano-3-(prop-1-en-2-yl)picolinic acid

embedded image

To a solution of ethyl 5-cyano-3-(prop-1-en-2-yl)picolinate (60.0 mg, 0.280 mmol) in EtOH (1 mL) was added a solution of LiOH.H₂O (11.64 mg, 0.280 mmol) in H₂O (0.600 mL) and the resulting solution was stirred for 15 min at r.t. EtOAc and water were added and the aqueous phase was separated and acidified with 1 M HCl until pH=1 and extracted with EtOAc (2×). The organic phases were combined and concentrated under reduced pressure to afford the title compound (21 mg, 40%) as a white solid which was used without further purification. ¹H NMR (400 MHz, DMSO-d₆) δ 13.77 (s, 1H), 8.94 (d, J=1.9 Hz, 1H), 8.41 (d, J=1.9 Hz, 1H), 5.28 (t, J=1.5 Hz, 1H), 5.07 (d, J=1.4 Hz, 1H), 2.08 (t, J=1.3 Hz, 3H). MS-ESI (m/z) calc'd for C₁₀H₉N₂O₂[M+H]⁺: 189.1. Found 189.1.

Intermediate A-21: 5-Cyano-6-methoxy-3,4-dimethylpicolinic acid

embedded image

Step 1: 2-Chloro-3-cyano-4,5,6-trimethylpyridine 1-oxide

embedded image

To a solution of 2-chloro-4,5,6-trimethylpyridine-3-carbonitrile (3.0 g, 16.61 mmol) in DCM (83.04 mL) was added MCPBA (8.19 g, 33.22 mmol) and the mixture was stirred at 50° C. for 24 hrs. Another portion of MCPBA (4.09 g, 16.61 mmol) was then added and the reaction was stirred for an additional 15 hrs. The solvent was evaporated and the residue was purified by silica gel column chromatography using a 0-100% EtOAc/cyclohexane gradient eluent to afford the title compound (1.95 g, 60%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 2.51 (s, 3H), 2.45 (s, 3H), 2.29 (s, 3H). MS-ESI (m/z) calc'd for C₉H₁₀ClN₂O [M+H]⁺: 197.0. Found 197.0.

Step 2: 2-Chloro-6-(hydroxymethyl)-4,5-dimethylnicotinonitrile

embedded image

To a solution of 2-chloro-3-cyano-4,5,6-trimethylpyridine 1-oxide (1.95 g, 9.92 mmol) in DCM (49.59 mL) was added dropwise trifluoroacetic acid anhydride (4.14 mL, 29.75 mmol) and the mixture was stirred at 25° C. for 15 hrs. The solvent was evaporate and the residue was taken up in MeOH. Then K₂CO₃(2 g) was added and the suspension was stirred at 25° C. for 1 hr. The solvent was evaporated, the residue was taken up in H₂O and extracted with DCM (3×). The combined organic layers were passed through a phase separator and evaporated to obtain 2-chloro-6-(hydroxymethyl)-4,5-dimethylpyridine-3-carbonitrile (1.29 g, 66%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 5.41 (t, J=5.9 Hz, 1H), 4.59 (d, J=5.8 Hz, 2H), 2.49 (s, 3H), 2.27 (s, 3H). MS-ESI (m/z) calc'd for C₉H₁₀ClN₂O [M+H]⁺: 197.0. Found 197.0.

Step 3: 6-Formyl-2-methoxy-4,5-dimethylnicotinonitrile

embedded image

To a solution of 2-chloro-6-(hydroxymethyl)-4,5-dimethylnicotinonitrile (0.39 g, 2 mmol) in MeOH (10 mL) was added NaOMe (0.74 mL, 4 mmol) and the mixture was stirred at 25° C. for 15 hrs. The solvent was evaporated and the residue was taken up in H₂O and extracted with DCM (3×). The combined organic layers were passed through a phase separator and concentrated to afford the title compound (166 mg, 44%) as a dark oil. ¹H NMR (400 MHz, DMSO-d₆) δ 10.04 (s, 1H), 4.04 (s, 3H), 2.51 (d, J=1.1 Hz, 3H), 2.47 (s, 3H). MS-ESI (m/z) calc'd for C₁₀H₁₁N₂O₂[M+H]⁺: 191.0. Found 191.0.

Step 4: 5-Cyano-6-methoxy-3,4-dimethylpicolinic acid

embedded image

To a solution of 6-formyl-2-methoxy-4,5-dimethylnicotinonitrile (166.0 mg, 0.870 mmol) in acetone (8 mL) was added a solution of KMnO₄(137.92 mg, 0.870 mmol) in H₂O (2 mL) and the mixture was stirred at 25° C. for 2 hrs. The organic solvent was evaporated, 1 M K₂CO₃was added, and the mixture was filtered through Celite. The H₂O layer was washed with EtOAc and then acidified by addition of HCl and extracted with EtOAc (3×). The combined organic layers were passed through a phase separator and concentrated to afford the title compound (82 mg, 46%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.68 (s, 1H), 3.95 (s, 3H), 2.46 (s, 3H), 2.22 (s, 3H). MS-ESI (m/z) calc'd for C₁₀H₁₁N₂O₃[M+H]⁺: 207.1. Found 207.0.

Intermediate A-22: 1-(3-(Piperidin-1-yl)propyl)-1H-indazol-5-amine

embedded image

Step 1: 1-(Prop-2-yn-1-yl)piperidine

embedded image

To a solution of piperidine (4.94 mL, 50 mmol) in DCM (10 mL) was added dropwise 3-bromo-1-propyne (2.38 g, 20 mmol) and the mixture was stirred at 25° C. for 15 hrs. The solvent was evaporated and the residue was taken up in Et₂O and washed with H₂O (3×). The organic layer was passed through a phase separator and evaporated to afford the title compound (2.33 g, 95%) as an orange oil. ¹H NMR (400 MHz, DMSO-d₆) δ 3.20 (d, J=2.4 Hz, 2H), 3.08 (t, J=2.4 Hz, 1H), 2.41-2.33 (m, 4H), 1.61-1.28 (m, 6H).

Step 2: 3-(3-(Piperidin-1-yl)prop-1-yn-1-yl)-1H-indazol-5-amine

embedded image

A mixture of 3-iodo-1H-indazol-5-amine (1.04 g, 4 mmol), 1-(prop-2-yn-1-yl)piperidine (0.74 g, 6 mmol), bis(triphenylphosphine)palladium(II) dichloride (281.56 mg, 0.400 mmol) and copper (I) iodide (38.09 mg, 0.200 mmol) in Et₃N (4 mL) was heated at 90° C. for 2 hrs. The solvent was evaporated and the residue was purified by silica gel column chromatography using a 0-50% MeOH/DCM gradient eluent to afford the title compound (160 mg, 16%) as an orange oil. ¹H NMR (400 MHz, DMSO-d₆) δ 12.83 (s, 1H), 7.26 (dd, J=8.7, 0.8 Hz, 1H), 6.80 (dd, J=8.8, 2.1 Hz, 1H), 6.69 (dd, J=2.1, 0.8 Hz, 1H), 4.97 (d, J=2.7 Hz, 2H), 3.54 (s, 2H), 2.64 (t, J=5.3 Hz, 2H), 1.64-1.29 (m, 8H). MS-ESI (m/z) calc'd for C₁₅H₁₉N₄[M+H]⁺: 255.2. Found 255.4.

Step 3: 3-(3-(Piperidin-1-yl)propyl)-1H-indazol-5-amine

embedded image

To a solution of 3-(3-(piperidin-1-yl)prop-1-yn-1-yl)-1H-indazol-5-amine (160.0 mg, 0.630 mmol) in EtOH (6.291 mL) was added 10% Pd/C (66.95 mg, 0.060 mmol) and the mixture was hydrogenated at 3 bars for 24 hrs. The catalyst was removed by filtration through Celite and the filtrate evaporated to afford the title compound (116 mg, 71%) as an orange solid. ¹H NMR (400 MHz, DMSO-d₆) δ 12.15 (s, 1H), 7.27-7.13 (m, 1H), 6.79-6.75 (m, 1H), 6.75-6.68 (m, 1H), 4.73 (s, 2H), 3.13-2.97 (m, 2H), 2.78 (t, J=7.4 Hz, 2H), 2.73-2.55 (m, 2H), 1.99-1.83 (m, 2H), 1.74-1.31 (m, 8H). MS-ESI (m/z) calc'd for C₁₅H₂₃N₄[M+H]⁺: 259.2. Found 259.5.

Intermediate A-23: 3-Cyclopropyl-1H-indazol-5-amine

embedded image

Step 1: 3-Iodo-5-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole and 3-Iodo-5-nitro-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazole

embedded image

To a solution of NaH (276.79 mg, 6.92 mmol) in THF (6 mL) at 0° C. was added 3-iodo-5-nitro-1H-indazole (1.0 g, 3.46 mmol) in THF (10 mL) dropwise and the mixture was stirred for 20 minutes at r.t. 2-(Chloromethoxy)ethyl-trimethylsilane (0.8 mL, 4.5 mmol) was added slowly to the mixture and stirring was continued for 1 hr at 0° C. The mixture was diluted with H₂O and extracted with EtOAc (2×). The combined organic layers were washed with H₂O (1×), dried over Na₂SO₄, filtered and concentrated to give a residue. The residue was purified by silica gel column chromatography using a 0-20% EtOAc/cyclohexane gradient eluent to afford a 3:1 mixture (determined by NMR) respectively of the title compounds (1.23 g, 85%) as a yellow solid. 3-Iodo-5-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole: ¹H NMR (400 MHz, DMSO-d₆) δ 8.33-8.40 (m, 2H) 8.00-8.05 (m, 1H) 5.85 (s, 2H) 3.51-3.60 (m, 2H) 0.78-0.84 (m, 2H) −0.10 (s, 9H). 3-Iodo-5-nitro-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazole: ¹H NMR (400 MHz, DMSO-d₆) δ 8.47 (dd, J=2.20, 0.66 Hz, 1H) 8.07 (d, J=2.20 Hz, 1H) 7.89 (dd, J=9.46, 0.66 Hz, 1H) 5.86 (s, 2H) 3.63-3.70 (m, 2H) 0.85-0.91 (m, 2H) −0.07 (s, 9H). MS-ESI (m/z) calc'd for C₁₃H₁₉IN₃O₃Si [M+H]⁺: 420.1. Found 420.1.

Step 2: 3-Cyclopropyl-5-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole and 3-Cyclopropyl-5-nitro-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazole

embedded image

A mixture of 3-iodo-5-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole and 3-iodo-5-nitro-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazole (1.0 g, 2.38 mmol), cyclopropylboronic acid (307.31 mg, 3.58 mmol) and tripotassium phosphate (988.89 mg, 7.15 mmol) were dissolved in 1,4-dioxane (15 mL) and degassed with N₂for 5 minutes. [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (174.51 mg, 0.240 mmol) was then added and the mixture was stirred at 100° C. under N₂for 3 hrs. The reaction mixture was partitioned between H₂O and EtOAc. The phases were separated and the aqueous layer was extracted with EtOAc (2×). The combined organic phases were washed with H₂O (1×), dried over Na₂SO₄, and evaporated to dryness. The material was purified by silica gel column chromatography using a 0-20% EtOAc/cyclohexane gradient eluent to afford a 3:1 mixture (determined by NMR) respectively of the title compounds (785 mg, 99%). Methyl 6-chloro-5-cyano-3-methylpicolinate: ¹H NMR (400 MHz, DMSO-d₆) δ 8.58 (s, 1H) 3.92 (s, 3H) 2.48 (d, J=0.66 Hz, 3H). 3-Cyclopropyl-5-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole: ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.86-8.91 (m, 1H) 8.27 (dd, J=9.24, 2.20 Hz, 1H) 7.88 (d, J=9.24 Hz, 1H) 5.72 (s, 2H) 3.48-3.55 (m, 2H) 2.52-2.58 (m, 1H) 1.06-1.12 (m, 2H) 0.96-1.04 (m, 2H) 0.75-0.83 (m, 2H) −0.13-−0.09 (m, 9H). 3-Cyclopropyl-5-nitro-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazole: ¹H NMR (400 MHz, DMSO-d₆) δ 8.66 (d, J=2.20 Hz, 1H) 7.99 (dd, J=9.46, 2.20 Hz, 1H) 7.76 (d, J=9.46 Hz, 1H) 5.87 (s, 2H) 3.64-3.71 (m, 2H) 2.30-2.38 (m, 1H) 1.22-1.30 (m, 2H) 1.13-1.17 (m, 2H) 0.85-0.91 (m, 2H) −0.07-−0.03 (m, 9H). MS-ESI (m/z) calc'd for C₁₆H₂₄N₃O₃Si [M+H]⁺: 334.2. Found 334.3.

Step 3: 3-Cyclopropyl-5-nitro-1H-indazole

embedded image

To a solution of 3-cyclopropyl-5-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole and 3-cyclopropyl-5-nitro-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazole, 2-[(3-cyclopropyl-5-nitroindazol-1-yl)methoxy]ethyl-trimethylsilane and 3-cyclopropyl-5-nitro-2-{[2-(trimethylsilyl)ethoxy]methyl}-2H-indazole (785.0 mg, 2.35 mmol) in DCM (25 mL) was added trifluoroacetic acid (1.0 mL, 13.07 mmol). The mixture was stirred at r.t. for 2 hrs. The mixture was concentrated and redissolved in MeOH (20 mL). Aqueous NH₃(5 mL) was added and the mixture was stirred at r.t. for 2 hrs. The reaction mixture was partitioned between H₂O and EtOAc and the phases were separated. The aqueous layer was extracted with EtOAc (2×) and the combined organic phases were washed with H₂O (1×), dried over Na₂SO₄and evaporated to dryness. The residue was purified by reversed phase chromatography on a 12 g C18 column, using a 5-50% CH₃CN/H₂O (0.1% formic acid) gradient eluent to afford the title compound (65 mg, 14%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.25 (br. s., 1H) 8.84 (d, J=2.20 Hz, 1H) 8.17 (dd, J=9.13, 2.09 Hz, 1H) 7.63 (d, J=9.02 Hz, 1H) 2.44-2.49 (m, 1H) 0.93-1.10 (m, 4H). MS-ESI (m/z) calc'd for C10H₁₀N₃O₂[M+H]⁺: 204.1. Found 204.0.

Step 4: 3-Cyclopropyl-1H-indazol-5-amine

embedded image

A mixture of 3-cyclopropyl-5-nitro-1H-indazole (65.0 mg, 0.320 mmol), NH₄Cl (18.82 mg, 0.350 mmol) and Fe powder (71.46 mg, 1.28 mmol) in EtOH (2 mL) and H₂O (2 mL) was stirred at 80° C. for 1.5 hrs. The solids were removed by filtration through Celite and the solid was washed with EtOH. The filtrate was concentrated and re-dissolved in EtOAc. H₂O was added and the two phases were separated. The aqueous layer was extracted with EtOAc (2×) and the combined organic layers were washed with H₂O (1×), dried over Na₂SO₄, and the solvent was removed to afford the title compound (50 mg, 90%) as a yellow solid which was used without further purification. ¹H NMR (400 MHz, DMSO-d₆) δ 12.02 (br. s., 1H) 7.05-7.23 (m, 1H) 6.65-6.79 (m, 2H) 4.70 (br. s., 2H) 2.01-2.11 (m, 1H) 0.80-0.95 (m, 4H). MS-ESI (m/z) calc'd for C10H₁₂N₃[M+H]⁺: 174.1. Found 174.1.

Example 1: 5-Cyano-3-fluoro-N-(3-(furan-3-yl)-1H-indazol-5-yl)picolinamide

embedded image

To a mixture of 5-cyano-3-fluoropyridine-2-carboxylic acid (33 mg, 0.200 mmol), 3-(furan-3-yl)-1H-indazol-5-amine (Intermediate A-1, 39.84 mg, 0.200 mmol) and triethylamine (27.88 μL, 0.200 mmol) was added HATU (76.05 mg, 0.200 mmol) and the mixture was stirred at 25° C. for 15 h. Water was added and the solid that formed was filtered and purified by reverse phase column chromatography on a Biotage Isolera One apparatus (NH, 11 g) using a gradient of 0-5% MeOH in DCM for 10 CV to afford the title compound (20.6 mg, 0.059 mmol, 30.0% yield) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.12 (s, 1H), 10.82 (s, 1H), 9.06 (dd, J=1.6, 1.0 Hz, 2H), 8.68 (dd, J=10.3, 1.6 Hz, 2H), 8.42 (dd, J=2.0, 0.7 Hz, 2H), 8.25 (dd, J=1.6, 0.8 Hz, 2H), 7.84 (t, J=1.7 Hz, 3H), 7.80 (dd, J=8.9, 1.9 Hz, 1H), 7.57 (dd, J=9.0, 0.7 Hz, 2H), 7.00 (dd, J=1.9, 0.9 Hz, 2H). MS-ESI (m/z) calc'd for C₁₅H₁₁FN₅O₂[M+H]⁺: 348.1. Found 348.0.

Example 2: 2-Bromo-4-cyano-N-(3-(furan-3-yl)-1H-indazol-5-yl)benzamide

embedded image

To a mixture of 2-bromo-4-cyanobenzoic acid (45.21 mg, 0.200 mmol), 3-(furan-3-yl)-1H-indazol-5-amine (Intermediate A-1, 39.84 mg, 0.200 mmol) and triethylamine (27.88 μL, 0.200 mmol) was added HATU (76.05 mg, 0.200 mmol) and the mixture was stirred at 25° C. for 15 h. Water was added and the solid that formed was filtered and purified by reverse phase column chromatography on a Biotage Isolera One apparatus (NH, 11 g) using a gradient of 0-5% MeOH in DCM for 10 CV to afford the title compound (22.3 mg, 0.055 mmol, 27.4% yield) as a beige solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.11 (s, 1H), 10.66 (s, 1H), 8.38-8.33 (m, 2H), 8.18 (dd, J=1.5, 0.8 Hz, 1H), 8.02 (dd, J=7.9, 1.5 Hz, 1H), 7.85 (t, J=1.7 Hz, 1H), 7.80 (d, J=7.8 Hz, 1H), 7.61 (dd, J=8.9, 1.8 Hz, 1H), 7.57 (dd, J=8.9, 0.8 Hz, 1H), 6.98 (dd, J=1.8, 0.8 Hz, 1H). MS-ESI (m/z) calc'd for C₁₉H₁₂BrN₄O₂[M+H]⁺: 407.0, 409.0. Found 406.9, 408.9.

Example 3: 4-Cyano-2-fluoro-N-(3-(furan-3-yl)-1H-indazol-5-yl)benzamide

embedded image

To a mixture of 4-cyano-2-fluorobenzoic acid (33.02 mg, 0.200 mmol), 3-(furan-3-yl)-1H-indazol-5-amine (Intermediate A-1, 39.84 mg, 0.200 mmol) and triethylamine (27.88 μL, 0.200 mmol) was added HATU (76.05 mg, 0.200 mmol) and the mixture was stirred at 25° C. for 15 h. Water was added and the solid that formed was filtered and purified by column chromatography on a Biotage Isolera One apparatus (SiO₂, 10 g) using a gradient of 0-5% MeOH in DCM for 10 CV to afford the title compound (15 mg, 0.043 mmol, 21.7% yield) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.11 (s, 1H), 10.65 (s, 1H), 8.37 (d, J=1.8 Hz, 1H), 8.24-8.18 (m, 1H), 8.07 (dd, J=9.7, 1.4 Hz, 1H), 7.95-7.88 (m, 1H), 7.86 (dd, J=7.9, 1.4 Hz, 1H), 7.84 (t, J=1.7 Hz, 1H), 7.63 (dd, J=8.9, 1.8 Hz, 1H), 7.57 (d, J=8.9 Hz, 1H), 6.98 (dd, J=1.9, 0.8 Hz, 1H). MS-ESI (m/z) calc'd for C₁₉H₁₂FN₄O₂[M+H]⁺: 347.1. Found 347.1.

Example 4: 4-Cyano-N-(3-(furan-3-yl)-1H-indazol-5-yl)-2-iodobenzamide

embedded image

To a mixture of 4-cyano-2-iodobenzoic acid (54.61 mg, 0.200 mmol), 3-(furan-3-yl)-1H-indazol-5-amine (Intermediate A-1, 39.84 mg, 0.200 mmol) and triethylamine (27.88 μL, 0.200 mmol) was added HATU (76.05 mg, 0.200 mmol) and the mixture was stirred at 25° C. for 15 hrs. Water was added and the solid formed was filtered and purified by reverse phase column chromatography on a Biotage Isolera One apparatus (NH, 11 g) using a gradient of 0-5% MeOH in DCM for 10 CV to obtain the title compound (25.5 mg, 0.056 mmol, 28.1% yield) as an off-white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.12 (s, 1H), 10.59 (s, 1H), 8.48 (d, J=1.6 Hz, 1H), 8.35 (dd, J=1.8, 0.8 Hz, 1H), 8.18 (dd, J=1.5, 0.9 Hz, 1H), 8.02 (dd, J=7.9, 1.6 Hz, 1H), 7.86 (t, J=1.7 Hz, 1H), 7.71 (d, J=7.8 Hz, 1H), 7.63 (dd, J=8.9, 1.8 Hz, 1H), 7.58 (dd, J=8.9, 0.8 Hz, 1H), 6.99 (dd, J=1.9, 0.8 Hz, 1H). MS-ESI (m/z) calc'd for C₁₉H₁₂IN₄O₂[M+H]⁺: 455.0. Found 455.0.

Example 5: 2-Chloro-4-cyano-N-(3-(furan-3-yl)-1H-indazol-5-yl)benzamide

embedded image

To a mixture of 2-chloro-4-cyanobenzoic acid (36.32 mg, 0.200 mmol), 3-(furan-3-yl)-1H-indazol-5-amine (Intermediate A-1, 39.84 mg, 0.200 mmol) and triethylamine (27.88 μL, 0.200 mmol) was added HATU (76.05 mg, 0.200 mmol) and the mixture was stirred at 25° C. for 15 h. Water was added and the solid that formed was filtered and purified by reverse phase column chromatography on a Biotage Isolera One apparatus (NH, 11 g) using a gradient of 0-5% MeOH in DCM for 10 CV to obtain the title compound (17.4 mg, 0.048 mmol, 24.0% yield) as a beige solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.12 (s, 1H), 10.69 (s, 1H), 8.36 (dd, J=1.8, 0.8 Hz, 1H), 8.23 (d, J=1.5 Hz, 1H), 8.19 (dd, J=1.5, 0.8 Hz, 1H), 7.99 (dd, J=7.9, 1.5 Hz, 1H), 7.87-7.82 (m, 2H), 7.61 (dd, J=9.0, 1.8 Hz, 1H), 7.57 (dd, J=8.9, 0.8 Hz, 1H), 6.98 (dd, J=1.9, 0.8 Hz, 1H). MS-ESI (m/z) calc'd for C₁₉H₁₂ClN₄O₂[M+H]⁺: 363.1, 365.1. Found 363.0, 365.0.

Example 6: 4-Cyano-N-(3-(furan-3-yl)-1H-indazol-5-yl)-2-(trifluoromethyl)benzamide

embedded image

To a mixture of 4-cyano-2-(trifluoromethyl)benzoic acid (43.03 mg, 0.200 mmol), 3-(furan-3-yl)-1H-indazol-5-amine (Intermediate A-1, 39.84 mg, 0.200 mmol) and triethylamine (27.88 μL, 0.200 mmol) was added HATU (76.05 mg, 0.200 mmol) and the mixture was stirred at 25° C. for 15 h. Water was added and the solid that formed was filtered and purified by reverse phase column chromatography on a Biotage Isolera One apparatus (NH, 11 g) using a gradient of 0-5% MeOH in DCM for 10 CV to obtain the title compound (20.5 mg, 0.052 mmol, 25.9% yield) as a beige solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.13 (s, 1H), 10.74 (s, 1H), 8.50-8.46 (m, 1H), 8.33 (dd, J=7.9, 1.6 Hz, 1H), 8.30 (t, J=1.3 Hz, 1H), 8.21-8.16 (m, 1H), 7.98 (d, J=7.9 Hz, 1H), 7.85 (t, J=1.7 Hz, 1H), 7.62-7.53 (m, 2H), 6.98 (dd, J=1.9, 0.8 Hz, 1H). MS-ESI (m/z) calc'd for C₂₀H₁₂F₃N₄O₂[M+H]⁺: 397.1. Found 397.0.

Example 7: 4-Cyano-2,6-difluoro-N-(3-(furan-3-yl)-1H-indazol-5-yl)benzamide

embedded image

To a mixture of 4-cyano-2,6-difluorobenzoic acid (36.62 mg, 0.200 mmol), 3-(furan-3-yl)-1H-indazol-5-amine (Intermediate A-1, 39.84 mg, 0.200 mmol) and triethylamine (27.88 L, 0.200 mmol) was added HATU (76.05 mg, 0.200 mmol) and the mixture was stirred at 25° C. for 15 h. Water was added and the solid that formed was filtered to obtain the product (55 mg, 0.151 mmol, 75.5% yield) as a beige solid which was further purified by prep HPLC (Method A) to afford the title compound (26.1 mg, 0.072 mmol, 35.8% yield) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.15 (s, 1H), 11.00 (s, 1H), 8.33 (t, J=1.3 Hz, 1H), 8.21 (dd, J=1.5, 0.8 Hz, 1H), 8.06-7.97 (m, 2H), 7.84 (t, J=1.7 Hz, 1H), 7.63-7.53 (m, 2H), 6.98 (dd, J=1.8, 0.8 Hz, 11H). MS-ESI (m/z) calc'd for C₁₉H₁₁F₂N₄O₂[M+H]⁺: 365.1. Found 365.0.

Example 8: 6-Cyano-N-(3-(furan-3-yl)-1H-indazol-5-yl)-2-methylnicotinamide

embedded image

To a mixture of 6-cyano-2-methylpyridine-3-carboxylic acid (32.43 mg, 0.200 mmol), 3-(furan-3-yl)-1H-indazol-5-amine (Intermediate A-1, 39.84 mg, 0.200 mmol) and triethylamine (27.88 μL, 0.200 mmol) was added HATU (76.05 mg, 0.200 mmol) and the mixture was stirred at 25° C. for 15 h. Water was added and the solid that formed was filtered to obtain the product (60 mg, 0.175 mmol, 87.4% yield) as a beige solid which was further purified by prep HPLC (Method A) to afford the title compound (26.22 mg, 0.076 mmol, 38.2% yield) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.12 (s, 1H), 10.65 (s, 1H), 8.37 (dd, J=1.8, 0.7 Hz, 1H), 8.21 (dd, J=1.5, 0.9 Hz, 1H), 8.18 (d, J=7.8 Hz, 1H), 8.06 (dd, J=7.8, 0.6 Hz, 1H), 7.85 (t, J=1.7 Hz, 1H), 7.62 (dd, J=8.9, 1.8 Hz, 1H), 7.57 (dd, J=8.9, 0.8 Hz, 1H), 6.99 (dd, J=1.9, 0.8 Hz, 1H), 2.65 (s, 3H). MS-ESI (m/z) calc'd for C₁₉H₁₄N₅O₂[M+H]⁺: 344.1. Found 344.0.

Example 9: 6-Cyano-N-(3-(furan-3-yl)-1H-indazol-5-yl)nicotinamide

embedded image

To a mixture of 6-cyano-3-pyridinecarboxylic acid (29.62 mg, 0.200 mmol), 3-(furan-3-yl)-1H-indazol-5-amine (Intermediate A-1, 39.84 mg, 0.200 mmol) and triethylamine (27.88 μL, 0.200 mmol) was added HATU (76.05 mg, 0.200 mmol) and the mixture was stirred at 25° C. for 15 h. Water was added and the solid formed was filtered and purified by reverse phase column chromatography on a Biotage Isolera One apparatus (SiO₂, 10 g) using a gradient of 0-5% MeOH in DCM for 10 CV to obtain the product (24 mg, 0.073 mmol, 36.44% yield) as a yellow solid which was further purified by prep HPLC (Method A) to obtain the title compound (12 mg, 0.036 mmol, 18.2% yield) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.14 (s, 1H), 10.73 (s, 1H), 9.28 (dd, J=2.2, 0.9 Hz, 1H), 8.57 (dd, J=8.1, 2.2 Hz, 1H), 8.43-8.36 (m, 1H), 8.26 (dd, J=8.1, 0.9 Hz, 1H), 8.24 (dd, J=1.5, 0.9 Hz, 1H), 7.85 (t, J=1.7 Hz, 1H), 7.71 (dd, J=8.9, 1.9 Hz, 1H), 7.59 (d, J=8.9 Hz, 1H), 7.00 (dd, J=1.9, 0.8 Hz, 1H). MS-ESI (m/z) calc'd for C₁₅H₁₂N₅O₂[M+H]⁺: 330.1. Found 330.3.

Example 10: 4-Cyano-N-(3-(furan-3-yl)-1H-indazol-5-yl)-2,6-dimethylbenzamide

embedded image

To a mixture of 4-cyano-2,6-dimethylbenzoic acid (35.09 mg, 0.200 mmol), 3-(furan-3-yl)-1H-indazol-5-amine (Intermediate A-1, 39.84 mg, 0.200 mmol) and triethylamine (27.88 μL, 0.200 mmol) was added HATU (76.05 mg, 0.200 mmol) and the mixture was stirred at 25° C. for 15 h. Water was added and the solid formed was filtered to obtain the product (66 mg, 0.185 mmol, 92.5% yield) which was further purified by prep HPLC (Method B) to obtain the title compound (2.3 mg, 0.006 mmol, 3.22% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₄) δ 13.11 (br. s, 1H), 10.55 (s, 1H), 8.37 (s, 1H), 8.21 (s, 1H), 7.86 (t, J=1.65 Hz, 1H), 7.52-7.70 (m, 4H), 6.99 (d, J=1.10 Hz, 1H), 2.37 (s, 6H). MS-ESI (m/z) calc'd for C₂₁H₁₇N₄O₂[M+H]⁺: 357.1. Found 357.1.

Example 11: 4-Cyano-N-(3-(furan-3-yl)-1H-indazol-5-yl)benzamide

embedded image

To a mixture of 4-cyanobenzoic acid (29.54 mg, 0.200 mmol), 3-(furan-3-yl)-1H-indazol-5-amine (Intermediate A-1, 39.84 mg, 0.200 mmol) and triethylamine (27.88 μL, 0.200 mmol) was added HATU (76.05 mg, 0.200 mmol) and the mixture was stirred at 25° C. for 15 hrs. Water was added and the solid that formed was filtered to obtain the product (55 mg, 0.168 mmol, 83.4% yield) which was further purified by prep HPLC (Method C) to obtain the title compound (5.5 mg, 0.017 mmol, 8.34% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.12 (br. s., 1H), 10.54 (br. s., 1H), 8.39 (s, 1H), 8.25 (s, 1H), 8.02-8.19 (m, 4H), 7.86 (t, J=1.65 Hz, 1H), 7.73 (dd, J=8.91, 1.43 Hz, 1H), 7.58 (d, J=9.02 Hz, 1H), 7.01 (d, J=1.54 Hz, 1H). MS-ESI (m/z) calc'd for C₁₉H₃N₄O₂[M+H]⁺: 329.1. Found 329.1.

Example 12: 4-Cyano-2-methyl-N-(3-methyl-1H-indazol-5-yl)benzamide

embedded image

To a mixture of 4-cyano-2-methylbenzoic acid (32.23 mg, 0.200 mmol), 3-methyl-1H-indazole (29.44 mg, 0.200 mmol) and triethylamine (27.88 uL, 0.200 mmol) was added HATU (76.05 mg, 0.200 mmol) and the mixture was stirred at 25° C. for 4 hrs. Water was added and the solid that formed was filtered and washed with Et₂O to obtain the title compound (20 mg, 0.069 mmol, 34.4% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 12.59 (s, 1H), 10.44 (s, 1H), 8.20 (d, J=1.8 Hz, 1H), 7.86-7.82 (m, 1H), 7.80 (dd, J=8.1, 1.4 Hz, 1H), 7.66 (d, J=7.9 Hz, 1H), 7.49 (dd, J=8.9, 1.9 Hz, 1H), 7.43 (d, J=8.8 Hz, 1H), 2.47 (s, 3H), 2.43 (s, 3H). MS-ESI (m/z) calc'd for C₁₇H₁₅N₄O [M+H]⁺: 291.1. Found 291.1.

Example 13: 5-Cyano-N-(3-(furan-3-yl)-1H-indazol-5-yl)-6-methylpicolinamide

embedded image

To a mixture of (32.43 mg, 0.200 mmol), 3-(furan-3-yl)-1H-indazol-5-amine (Intermediate A-1, 39.84 mg, 0.200 mmol) and triethylamine (27.88 μL, 0.200 mmol) was added HATU (76.05 mg, 0.200 mmol) and the mixture was stirred at 25° C. for 15 hrs. Water was added and the solid that formed was filtered and purified by column chromatography on a Biotage Isolera One apparatus (SiO₂, 10 g) using a gradient of 0-5% MeOH in DCM for 10 CV to obtain the title compound (60 mg, 0.175 mmol, 87.4% yield) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.11 (s, 1H), 10.65 (s, 1H), 8.51 (d, J=8.1 Hz, 1H), 8.47-8.44 (m, 1H), 8.31 (dd, J=1.4, 0.8 Hz, 1H), 8.13 (d, J=8.0 Hz, 1H), 7.94 (dd, J=8.9, 1.9 Hz, 1H), 7.85 (t, J=1.7 Hz, 1H), 7.58 (d, J=8.9 Hz, 1H), 7.02 (dd, J=1.9, 0.8 Hz, 1H), 2.86 (s, 3H). MS-ESI (m/z) calc'd for C₁₉H₁₄N₅O₂[M+H]⁺: 344.1. Found 344.4.

Example 14: 5-Cyano-N-(3-(furan-3-yl)-1H-indazol-5-yl)-3-methylpicolinamide

embedded image

To a mixture of 5-cyano-3-methylpyridine-2-carboxylic acid (32.43 mg, 0.200 mmol), 3-(furan-3-yl)-1H-indazol-5-amine (Intermediate A-1, 39.84 mg, 0.200 mmol) and triethylamine (27.88 μL, 0.200 mmol) was added HATU (76.05 mg, 0.200 mmol) and the mixture was stirred at 25° C. for 4 h. Water was added and the solid that formed was filtered and purified by reverse phase column chromatography on a Biotage Isolera One apparatus (NH, 11 g) using a gradient of 0-5% MeOH in DCM for 15 CV to obtain the title compound (37 mg, 0.108 mmol, 53.9% yield) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.09 (s, 1H), 10.70 (s, 1H), 9.00 (dd, J=2.0, 0.7 Hz, 1H), 8.45-8.39 (m, 2H), 8.26 (dd, J=1.5, 0.9 Hz, 1H), 7.84 (t, J=1.7 Hz, 1H), 7.82 (dd, J=9.0, 1.9 Hz, 1H), 7.61-7.53 (m, 1H), 7.00 (dd, J=1.8, 0.8 Hz, 1H), 2.61 (t, J=0.7 Hz, 3H). MS-ESI (m/z) calc'd for C₁₉H₁₄N₅O₂[M+H]⁺: 344.1. Found 344.1.

Example 15: 4-Cyano-N-(3-(furan-3-yl)-1H-indazol-5-yl)-2-methoxybenzamide

embedded image

To a mixture of 4-cyano-2-methoxybenzoic acid (35.43 mg, 0.200 mmol), 3-(furan-3-yl)-1H-indazol-5-amine (Intermediate A-1, 39.84 mg, 0.200 mmol) and triethylamine (27.88 μL, 0.200 mmol) was added HATU (76.05 mg, 0.200 mmol) and the mixture was stirred at 25° C. for 3 hrs. Water was added and the resulting solid was filtered and dried under vacuum to obtain the title compound (67 mg, 0.187 mmol, 93.5% yield) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 12.27 (s, 1H), 9.51 (s, 1H), 7.60-7.53 (m, 1H), 7.40 (dd, J=1.5, 0.8 Hz, 1H), 7.03 (t, J=1.7 Hz, 1H), 6.95 (d, J=7.8 Hz, 1H), 6.89 (d, J=1.4 Hz, 1H), 6.83 (dd, J=9.0, 1.9 Hz, 1H), 6.77-6.71 (m, 2H), 6.17 (dd, J=1.9, 0.8 Hz, 11H), 3.14 (s, 3H). MS-ESI (m/z) calc'd for C₂₀H₁₅N₄O₃[M+H]⁺: 359.1. Found 359.1.

Example 16: 5-Cyano-N-(3-(furan-3-yl)-1H-indazol-5-yl)picolinamide

embedded image

To a mixture of 5-cyanopyridine-2-carboxylic acid (29.62 mg, 0.200 mmol), 3-(furan-3-yl)-1H-indazol-5-amine (Intermediate A-1, 39.84 mg, 0.200 mmol) and triethylamine (20.24 mg, 0.200 mmol) was added HATU (76.05 mg, 0.200 mmol) and the mixture was stirred at 25° C. for 3 hrs. Water was added and the resulting solid was filtered and dried under vacuum to obtain the title compound (58 mg, 0.176 mmol, 88.1% yield) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.10 (s, 1H), 10.84 (s, 1H), 9.22 (dd, J=2.0, 0.9 Hz, 1H), 8.60 (dd, J=8.2, 2.1 Hz, 1H), 8.52 (d, J=1.9 Hz, 1H), 8.33 (dd, J=8.2, 0.9 Hz, 1H), 8.30 (t, J=1.1 Hz, 1H), 8.00 (dd, J=9.0, 1.9 Hz, 1H), 7.85 (t, J=1.7 Hz, 1H), 7.57 (d, J=8.9 Hz, 1H), 7.02 (dd, J=1.9, 0.8 Hz, 1H). MS-ESI (m/z) calc'd for C₁₅H₁₂N₅O₂[M+H]⁺: 330.1. Found 330.1.

Example 17: 5-Cyano-N-(3-(furan-3-yl)-1H-indazol-5-yl)-2-methylbenzamide

embedded image

To a mixture of 5-cyano-2-methylbenzoic acid (40.29 mg, 0.250 mmol), 3-(furan-3-yl)-1H-indazol-5-amine (Intermediate A-1, 49.8 mg, 0.250 mmol) and triethylamine (34.85 μL, 0.250 mmol) was added HATU (95.06 mg, 0.250 mmol) and the mixture was stirred at 25° C. for 15 hrs. The solvent was evaporated, the residue was taken up in water and extracted with EtOAc (3×), the combined organic layers were passed through a phase separator and evaporated to obtain a residue which was taken up in DCM and stirred for 15 min. The solid that formed was filtered and purified by column chromatography on a Biotage Isolera One apparatus using a gradient of 0-100% EtOAc in cyclohexane for 10 CV to obtain the title compound (42 mg, 0.123 mmol, 49.1% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.05 (bs, 1H), 10.45 (s, 1H), 8.37 (d, J=1.9 Hz, 1H), 8.20 (q, J=1.0 Hz, 1H), 8.01 (d, J=1.8 Hz, 1H), 7.87 (dd, J=8.0, 1.9 Hz, 1H), 7.85 (t, J=1.7 Hz, 1H), 7.66 (dd, J=8.9, 1.9 Hz, 1H), 7.58-7.53 (m, 2H), 7.01-6.96 (m, 1H), 2.50 (s, 3H). MS-ESI (m/z) calc'd for C₂₀H₁₅N₄O₂[M+H]⁺: 343.1. Found 343.1.

Example 18: 4-Cyano-N-(3-(furan-3-yl)-1H-indazol-5-yl)-2-methylbenzamide

embedded image

To a mixture of 4-cyano-2-methylbenzoic acid (40.29 mg, 0.250 mmol), 3-(furan-3-yl)-1H-indazol-5-amine (Intermediate A-1, 49.8 mg, 0.250 mmol), and triethylamine (0.03 mL, 0.250 mmol) was added HATU (95.06 mg, 0.250 mmol) and the mixture was stirred at 25° C. for 15 hrs. The solvent was evaporated, the residue was taken up in water and extracted with EtOAc (3×), the combined organic layers were passed through a phase separator and evaporated to obtain a residue which was taken up in DCM and stirred for 15 min. The solid that formed was filtered and purified by column chromatography on a Biotage Isolera One apparatus using a gradient of 0-100% EtOAc in cyclohexane for 10 CV to obtain the title compound (42 mg, 0.123 mmol, 49.1% yield) as a light pink solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.09 (s, 1H), 10.49 (s, 1H), 8.38 (d, J=1.9 Hz, 1H), 8.20 (t, J=1.2 Hz, 1H), 7.85 (q, J=1.6 Hz, 2H), 7.81 (dd, J=7.9, 1.6 Hz, 1H), 7.69 (d, J=7.9 Hz, 1H), 7.64 (dd, J=9.0, 1.8 Hz, 1H), 7.55 (d, J=8.9 Hz, 1H), 6.98 (dd, J=1.8, 0.8 Hz, 1H), 2.45 (s, 3H). MS-ESI (m/z) calc'd for C₂₀H₁₅N₄O₂[M+H]⁺: 343.1. Found 343.1.

Example 19: 3-Cyano-N-(3-(furan-3-yl)-1H-indazol-5-yl)-2-methylbenzamide

embedded image

To a mixture of 3-cyano-2-methylbenzoic acid (32.23 mg, 0.200 mmol), 3-(furan-3-yl)-1H-indazol-5-amine (Intermediate A-1, 39.84 mg, 0.200 mmol) and triethylamine (27.88 μL, 0.200 mmol) was added HATU (76.05 mg, 0.200 mmol) and the mixture was stirred at 25° C. for 15 hrs. Water was added and the solid that formed was filtered and purified by reverse phase column chromatography on Biotage Isolera One apparatus (NH, 11 g) using a gradient of 0-5% MeOH in DCM for 10 CV to obtain the title compound (19.1 mg, 0.056 mmol, 27.9% yield) as a grey solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.10 (s, 1H), 10.51 (s, 1H), 8.39 (d, J=1.5 Hz, 2H), 8.21 (dd, J=1.6, 0.8 Hz, 1H), 7.94 (dd, J=7.7, 1.3 Hz, 1H), 7.87-7.82 (m, 2H), 7.65 (dd, J=9.0, 1.9 Hz, 1H), 7.61-7.50 (m, 2H), 6.99 (dd, J=1.9, 0.8 Hz, 1H), 2.60 (s, 3H). MS-ESI (m/z) calc'd for C₂₀H₁₅N₄O₂[M+H]⁺: 343.1. Found 343.1.

Example 20: 2-Cyano-N-(3-(furan-3-yl)-1H-indazol-5-yl)thiazole-5-carboxamide

embedded image

To a mixture of 2-cyano-1,3-thiazole-5-carboxylic acid (30.83 mg, 0.200 mmol), 3-(furan-3-yl)-1H-indazol-5-amine (Intermediate A-1, 39.84 mg, 0.200 mmol) and triethylamine (27.88 μL, 0.200 mmol) was added HATU (76.05 mg, 0.200 mmol) and the mixture was stirred at 25° C. for 15 hrs. Water was added and the solid that formed was filtered to obtain the product (55 mg, 0.164 mmol, 82.01% yield) which was further purified by prep HPLC (Method A) to afford the title compound (28.3 mg, 0.084 mmol, 42.2% yield) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.16 (s, 1H), 10.85 (s, 1H), 8.90 (s, 1H), 8.31 (dd, J=1.8, 0.8 Hz, 1H), 8.26 (dd, J=1.5, 0.9 Hz, 1H), 7.84 (t, J=1.7 Hz, 1H), 7.65 (dd, J=9.0, 1.8 Hz, 1H), 7.60 (dd, J=8.9, 0.8 Hz, 1H), 7.00 (dd, J=1.8, 0.8 Hz, 1H). MS-ESI (m/z) calc'd for C₁₆H₁₀N₅O₂S [M+H]⁺: 336.1. Found 336.0.

Example 21: 3-Cyano-N-(3-(pyridin-4-yl)-1H-indazol-5-yl)benzamide

embedded image

To a solution of 3-cyanobenzoic acid (50 mg, 339.83 μmol) in DCM (4 mL) was added T3P/EtOAc (324.39 mg, 509.75 μmol, 50% purity) and TEA (103.16 mg, 1.02 mmol) followed by 3-(pyridin-4-yl)-1H-indazol-5-amine (Intermediate A-2, 107.17 mg, 509.75 μmol). The mixture was stirred at 15° C. for 12 hrs. The reaction mixture was concentrated and purified by prep-HPLC (Method E) to afford the title compound (18.76 mg, 40.36 umol, 12% yield, 97% purity, TFA salt) as a pale yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.96 (br s, 1H) 10.63 (s, 1H) 8.86 (br d, J=5 Hz, 2H) 8.75 (s, 1H) 8.48 (s, 1H) 8.32 (d, J=8 Hz, 1H) 8.24 (br s, 2H) 8.11 (d, J=8 Hz, 1H) 7.72-7.85 (m, 3H). MS-ESI (m/z) calc'd for C₂₀H₁₄N₅O [M+H]⁺: 340.1. Found 340.1.

Example 22: 2-Cyano-N-(3-(pyridin-4-yl)-1H-indazol-5-yl)isonicotinamide

embedded image

This compound was prepared as described for 3-cyano-N-(3-(pyridin-4-yl)-1H-indazol-5-yl)benzamide (Example 20) using 2-cyanoisonicotinic acid in place of 3-cyanobenzoic acid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.67 (br s, 1H), 10.80 (s, 1H), 9.00 (d, J=5.0 Hz, 1H), 8.75-8.71 (m, 2H), 8.67 (s, 1H), 8.57 (s, 1H), 8.24 (dd, J=1.7, 5.1 Hz, 1H), 7.96-7.92 (m, 2H), 7.83-7.78 (m, 1H), 7.73-7.68 (m, 1H). MS-ESI (m/z) calc'd for C₁₉H₁₃N₆O [M+H]⁺: 341.1. Found 341.1.

Example 23: 4-Cyano-N-(3-(pyridin-4-yl)-1H-indazol-5-yl)picolinamide

embedded image

This compound was prepared as described for 3-cyano-N-(3-(pyridin-4-yl)-1H-indazol-5-yl)benzamide (Example 20) using 4-cyanopicolinic acid in place of 3-cyanobenzoic acid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.93 (br s, 1H), 10.96 (s, 1H), 9.00 (d, J=5.07 Hz, 1H), 8.75-8.89 (m, 3H), 8.50 (s, 1H), 8.25 (br s, 2H), 8.17 (dd, J=4.85, 1.54 Hz, 1H), 8.04 (dd, J=9.04, 1.76 Hz, 1H), 7.71 (d, J=9.04 Hz, 1H). MS-ESI (m/z) calc'd for C₁₉H₁₃N₆O [M+H]⁺: 341.1. Found 341.1.

Example 24: 5-Cyano-N-(3-(pyridin-4-yl)-1H-indazol-5-yl)nicotinamide

embedded image

This compound was prepared as described for 3-cyano-N-(3-(pyridin-4-yl)-1H-indazol-5-yl)benzamide (Example 20) using 5-cyanonicotinic acid in place of 3-cyanobenzoic acid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.99 (br s, 1H), 10.79 (s, 1H), 9.38 (d, J=1.8 Hz, 1H), 9.24 (d, J=1.5 Hz, 1H), 8.86 (br s, 3H), 8.75 (s, 1H), 8.23 (br d, J=4.2 Hz, 2H), 7.83-7.72 (m, 2H). MS-ESI (m/z) calc'd for C₁₉H₁₃N₆O [M+H]⁺: 341.1. Found 341.1.

Example 25: 2-Cyano-N-(3-(pyridin-4-yl)-1H-indazol-5-yl)pyrimidine-5-carboxamide

embedded image

This compound was prepared as described for 3-cyano-N-(3-(pyridin-4-yl)-1H-indazol-5-yl)benzamide (Example 20) using 2-cyanopyrimidine-5-carboxylic acid in place of 3-cyanobenzoic acid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.66 (br s, 1H), 10.91 (br s, 1H), 9.49 (s, 2H), 8.74-8.66 (m, 3H), 7.92 (d, J=4.9 Hz, 2H), 7.79-7.68 (m, 2H). MS-ESI (m/z) calc'd for C₁₉H₁₂N₇O [M+H]⁺: 342.1. Found 342.0.

Example 26: 5-Cyano-1,2-dimethyl-N-(3-phenyl-1H-indazol-5-yl)-1H-pyrrole-3-carboxamide

embedded image

To a solution of 5-cyano-1,2-dimethyl-1H-pyrrole-3-carboxylic acid (Intermediate A-4, 85 mg, 517.78 μmol) and 3-phenyl-1H-indazol-5-amine (Intermediate A-3, 108.34 mg, 517 μmol) in DCM (4 mL) was added T₃P/EtOAc (428.35 mg, 673 umol, 400 μL, 50% purity) and TEA (209.58 mg, 2.07 mmol). The mixture was stirred at 15° C. for 3 hrs. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by Prep-HPLC (column: Waters XBridge 150*25 mm, 5 μm; mobile phase: [water (10 mM NH₄HCO₃)-MeCN]; B %: 30%-50%, 10 min) to afford the title compound (24.73 mg, 69 μmol, 13% yield, 99% purity) as a pale purple solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.19 (br s, 1H), 9.76 (s, 1H), 8.47 (s, 1H), 7.94 (br d, J=7.1 Hz, 2H), 7.72 (br dd, J=1.3, 8.8 Hz, 1H), 7.61 (s, 1H), 7.59-7.51 (m, 3H), 7.44-7.37 (m, 1H), 3.67 (s, 3H), 2.56 (s, 3H). MS-ESI (m/z) calc'd for C₂₁H₁₈N₅O [M+H]⁺: 356.1. Found 356.1.

Example 27: 5-Cyano-2-methyl-N-(3-phenyl-1H-indazol-5-yl)furan-3-carboxamide

embedded image

To a stirred solution of methyl 5-cyano-2-methylfuran-3-carboxylate (Intermediate A-5, 200 mg, 1.21 mmol) in toluene (2 mL) was added 3-phenyl-1H-indazol-5-amine (Intermediate A-3, 253.41 mg, 1.21 mmol), followed by AlMe₃(2 M, 1.21 mL) dropwise at 15° C. The mixture was then stirred at 15° C. for 12 hrs under N₂and the reaction was monitored by TLC (petroleum ether:EtOAc=1/1, Rr (product)=0.06). The mixture was quenched by slow addition of sat. aq. NH₄Cl (5.0 mL) at 0° C. The mixture was filtered and the solid was washed with EtOAc (5.0 mL×3). The combined filtrates were separated and the aqueous layer was extracted with EtOAc (2.0 mL×2). The combined organic layers were dried over Na₂SO₄and concentrated under vacuum. The residue was purified by Prep-HPLC (Method E) to afford the title compound (29.12 mg, 63 umol, 5% yield, 99% purity, TFA salt) as a pale yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.24 (br s, 1H) 10.09 (s, 1H) 8.45 (s, 1H) 8.11 (s, 1H) 7.94 (d, J=7.70 Hz, 2H) 7.67 (s, 1H) 7.50-7.63 (m, 3H) 7.42 (s, 1H) 2.66 (s, 3H). MS-ESI (m/z) calc'd for C₂₀H₁₅N₄O₂[M+H]⁺: 343.1. Found 343.1.

Further compounds of the invention, which were prepared according to the methods described above, are provided in Table 1 below.

TABLE 1

Ex. No.
Structure/Name
Data

28

embedded image

¹H NMR (400 MHz, DMSO-d₆) δ 3.15 (s, 1H), 10.75 (s, 1H), 9.01 (dd, J = 2.0, 0.8 Hz, 1H), 8.62-8.51 (m, 1H), 8.41 (dd, J = 2.0, 0.9 Hz, 1H), 7.82 (dd, J = 8.9, 1.9 Hz, 1H), 7.74 (d, J = 1.5 Hz, 1H), 7.67 (dd, J = 7.7, 1.9 Hz, 1H), 7.58 (d, J = 9.2 Hz, 1H), 7.30 (d, J = 7.8 Hz, 1H), 2.59 (s, 3H), 2.34 (s, 3H), 2.30 (s, 3H). MS-ESI (m/z calc'd for C₂₃H₂₀N₅O [M + H]⁺: 382.2. Found 382.2.

5-cyano-N-(3-(3,4-dimethylphenyl)-1H-

indazol-5-yl)-3-methylpicolinamide

29

embedded image

¹H NMR (400 MHz, DMSO-d₆) δ 13.26 (s, 1H), 10.76 (s, 1H), 9.00 (d, J = 1.9 Hz, 1H), 8.69-8.57 (m, 1H), 8.41 (dd, J = 2.0, 0.9 Hz, 1H), 7.87 (dd, J = 1.8, 0.8 Hz, 1H), 7.76 (dd, J = 9.0, 1.9 Hz, 1H), 7.61-7.52 (m, 1H), 6.90 (dd, J = 3.4, 0.8 Hz, 1H), 6.69 (dd, J = 3.4, 1.8 Hz, 1H), 2.60 (s, 3H). MS-ESI (m/z) calc'd for C₁₉H₁₃N₅O₂[M + H]⁺:

5-cyano-N-(3-(furan-2-yl)-1H-indazol-5-
344.1. Found 344.1.

yl-3-methylpicolinamide

30

embedded image

¹H NMR (400 MHz, DMSO-d₆) δ 13.14 (s, 1H), 10.76 (s, 1H), 9.00 (d, J = 1.9 Hz, 1H), 8.69 (d, J = 1.8 Hz, 1H), 8.41 (dd, J = 2.0, 0.9 Hz, 1H), 7.75 (dd, J = 9.0, 1.9 Hz, 1H), 7.58 (d, J = 8.9 Hz, 1H), 7.35 (t, J = 7.9 Hz, 1H), 7.29 (dd, J = 2.6, 1.4 Hz, 1H), 7.24 (dt, J = 7.6, 1.2 Hz, 1H), 6.80 (ddd, J = 8.4, 2.8, 1.0 Hz, 1H), 3.00 (s, 6H), 2.58 (s, 3H). MS-ESI (m/z) calc'd for C₂₃H₂₁N₆O [M + H]⁺: 397.2. Found 397.2.

5-cyano-N-(3-(3-(dimethylamino)phenyl)-

1H-indazol-5-yl)-3-methylpicolinamide

31

embedded image

¹H NMR (400 MHz, DMSO-d₆) δ 13.62 (s, 1H), 10.82 (s, 1H), 9.02 (d, J = 1.9 Hz, 1H), 8.76-8.69 (m, 3H), 8.43 (dd, J = 2.0, 0.9 Hz, 1H), 8.20 (s, 1H), 7.98-7.93 (m, 2H), 7.88 (dd, J = 9.0, 1.9 Hz, 1H), 7.67 (d, J = 9.0 Hz, 1H), 2.62 (s, 3H). MS-ESI (m/z) calc'd for C₂₀H₁₄N₆O [M + H]⁺: 355.1. Found 355.2.

5-cyano-3-methyl-N-(3-(pyridin-4-yl)-1H-

indazol-5-yl)picolinamide

32

embedded image

¹H NMR (400 MHz, DMSO-d₆) δ 13.20 (s, 1H) 10.73 (s, 1H) 9.01 (d, J = 1.35 Hz, 1H) 8.74 (s, 1H) 8.43 (dd, J = 9.48, 1.28 Hz, 2H) 8.30 (s, 1H) 7.78- 8.09 (m, 2H) 7.58 (d, J = 8.93 Hz, 1 H) 2.61 (s, 3H). MS-ESI (m/z) calc'd for C₁₉H₁₄F₂N₇O [M + H]⁺: 394.1. Found 394.2.

5-Cyano-N-(3-(1-(difluoromethyl)-1H-

pyrazol-4-yl)-1H-indazol-5-yl)-3-

methylpicolinamide

33

embedded image

¹H NMR (400 MHz, DMSO-d₆) δ 12.97 (s, 1H) 10.69 (s, 1H) 9.01 (d, J = 1.47 Hz, 1H) 8.40-8.46 (m, 2H) 8.31 (s, 1H) 7.97 (s, 1H) 7.80-7.84 (m, 1H) 7.54 (d, J = 8.93 Hz, 1H) 4.49- 4.58 (m, 1H) 3.98-4.03 (m, 2H) 3.47-3.54 (m, 2H) 2.61 (s, 3H) 2.02- 2.08 (m, 4H). MS-ESI (m/z) calc'd for C₂₃H₂₂N₇O₂[M + H]⁺: 428.2. Found 428.1.

5-cyano-3-methyl-N-(3-(1-(tetrahydro-2H-

pyran-4-yl)-1H-pyrazol-4-yl)-1H-indazol-

5-yl)picolinamide

34

embedded image

¹H NMR (400 MHz, DMSO-d₆) δ 13.50 (s, 1H), 10.83 (s, 1H), 9.01 (d, J = 1.5 Hz, 1H), 8.60 (s, 1H), 8.46 (s, 1H), 8.41 (d, J = 1.2 Hz, 1H), 8.29 (d, J = 7.8 Hz, 1H), 7.97 (d, J = 8.1 Hz, 1H), 7.89-7.83 (m, 2H), 7.65 (d, J = 9.0 Hz, 1H), 3.31 (s, 3H), 2.59 (s, 3H). MS- ESI (m/z) calc'd for C₂₂H₁₈N₅O₂S [M + H]⁺: 432.1. Found 432.0.

5-Cyano-3-methyl-N-(3-(3-

(methylsulfonyl)phenyl)-1H-indazol-5-

yl)picolinamide

35

embedded image

¹H NMR (400 MHz, DMSO-d₆) δ 13.50 (s, 1H), 10.81 (s, 1H), 9.01 (d, J = 1.6 Hz, 1H), 8.66 (s, 1H), 8.41 (d, J = 1.2 Hz, 1H), 8.18 (d, J = 8.1 Hz, 2H), 7.91 (d, J = 8.4 Hz, 2H), 7.84 (dd, J = 1.7, 9.0 Hz, 1H), 7.64 (d, J = 8.9 Hz, 1H), 2.60 (s, 3H). MS-ESI (m/z) calc'd for C₂₂H₁₅F₃N₅O [M + H]⁺: 422.1. Found 422.0.

5-Cyano-3-methyl-N-(3-(4-

(trifluoromethyl)phenyl)-1H-indazol-5-

yl)picolinamide

36

embedded image

¹H NMR (400 MHz, DMSO-d₆) δ 13.32 (s, 1H) 10.75 (s, 1H) 9.00 (s, 2 H) 8.40 (dd, J = 11, 1 Hz, 2H) 7.85 (dd, J = 9, 2 Hz, 1H) 7.61 (d, J = 9 Hz, 1H) 2.71 (s, 3H) 2.60 (s, 3H). MS-ESI (m/z) calc'd for C₁₉H₁₅N₆O₂[M + H]⁺: 359.1. Found 359.0.

5-Cyano-3-methyl-N-(3-(5-

methylisoxazol-4-yl)-1H-indazol-5-

yl)picolinamide

37

embedded image

¹H NMR (400 MHz, DMSO-d₆) δ 13.39 (br s, 1H), 10.79 (s, 1H), 9.00 (d, J = 1.1 Hz, 1H), 8.66 (s, 1H), 8.61 (d, J = 1.1 Hz, 1H), 8.44-8.35 (m, 2H), 7.84 (dd, J = 1.2, 8.9 Hz, 1H), 7.75 (br s, 1H), 7.62 (d, J = 9.0 Hz, 1H), 3.83- 3.76 (m, 4H), 3.31-3.23 (m, 4H), 2.59 (s, 3H). MS-ESI (m/z) calc'd for C₂₄H₂₂N₇O₂[M + H]⁺: 440.2. Found 440.1.

5-Cyano-3-methyl-N-(3-(5-

morpholinopyridin-3-yl)-1H-indazol-5-

yl)picolinamide

38

embedded image

¹H NMR (400 MHz, DMSO-d₆) δ 13.26 (br s, 1H), 10.77 (s, 1H), 9.00 (d, J = 1.3 Hz, 1H), 8.72 (d, J = 2.4 Hz, 1H), 8.62 (s, 1H), 8.41 (d, J = 1.1 Hz, 1H), 8.20 (dd, J = 2.4, 8.6 Hz, 1H), 7.82 (dd, J = 1.87 9.0 Hz, 1H), 7.59 (d, J = 8.8 Hz, 1H), 6.93 (d, J = 8.6 Hz, 1H), 5.34 (quin, J = 6.2 Hz, 1H), 2.60 (s, 3H), 1.34 (d, J = 6.2 Hz, 6H). MS-ESI (m/z) calc'd for C₂₃H₂₁N₆O₂[M + H]⁺: 413.2. Found 413.0.

5-Cyano-N-(3-(6-isopropoxypyridin-3-yl)-

1H-indazol-5-yl)-3-methylpicolinamide

39

embedded image

¹H NMR (400 MHz, DMSO-d₆) δ 13.09 (s, 1H), 10.61 (s, 1H), 8.48 (s, 1H) 8.43 (s, 1H) 8.30 (s, 1H) 7.90 (br d, J = 8.9 Hz, 1H), 7.84 (t, J = 1.7 Hz, 1H), 7.55 (d, J = 8.9 Hz, 1H), 7.26 (s, 1H), 7.01 (d, J = 1.1 Hz, 1H). MS-ESI (m/z) calc'd for C₁₁H₁₉N₅O₃[M + H]⁺: 345.1. Found 345.5.

5-Cyano-N-(3-(furan-3-yl)-1H-indazol-5-

yl)-4-hydroxypicolinamide

40

embedded image

¹H NMR (400 MHz, DMSO-d₆) δ 10.76 (br s, 1H), 8.99 (d, J = 1.4 Hz, 1H), 8.62 (d, J = 1.3 Hz, 1H), 8.41- 8.38 (m, 1H), 7.99-7.93 (m, 2H), 7.80 (dd, J = 1.8, 8.9 Hz, 1H), 7.63-7.51 (m, 3H), 7.45-7.38 (m, 1H), 2.59 (s, 3H). MS-ESI (m/z) calc'd for C₂₁H₁₆N₅O [M + H]⁺: 354.1. Found 354.1.

5-Cyano-3-methyl-N-(3-phenyl-1H-

indazol-5-yl)picolinamide

41

embedded image

¹H NMR (400 MHz, DMSO-d₆) δ 13.49 (br s, 1H), 10.81 (s, 1H), 9.01 (s, 1H), 8.58 (s, 1H), 8.42 (s, 1H), 8.35- 8.26 (m, 2H), 7.91 (br dd, J = 8.4, 17.3 Hz, 2H), 7.82-7.72 (m, 1H), 7.64 (br d, J = 8.9 Hz, 1H), 2.60 (s, 3H). MS- ESI (m/z) calc'd for C₂₂H₁₅N₆O [M + H]⁺: 379.1. Found 379.1.

5-Cyano-N-(3-(3-cyanophenyl)-1H-

indazol-5-yl)-3-methylpicolinamide

42

embedded image

¹H NMR (400 MHz, DMSO-d₆) δ 13.68 (s, 1H), 10.82 (s, 1H), 9.43 (d, J = 2.0 Hz, 1H), 9.06 (d, J = 1.8 Hz, 1H), 9.01 (d, J = 1.3 Hz, 1H), 8.75 (t, J = 2.0 Hz, 1H), 8.61 (s, 1H), 8.42 (s, 1H), 7.96 (dd, J = 1.5, 9.0 Hz, 1H), 7.67 (d, J = 9.0 Hz, 1H), 2.61 (s, 3H), MS-ESI (m/z) calc'd for C₂₁H₁₄N₇O [M + H]⁺: 380.1. Found 380.1.

5-Cyano-N-(3-(5-cyanopyridin-3-yl)-1H-

indazol-5-yl)-3-methylpicolinamide

43

embedded image

¹H NMR (400 MHz, DMSO-d₆) δ 13.28 (br s, 1H), 10.48 (s, 1H), 8.52 (s, 1H), 7.95-7.92 (m, 2H), 7.66-7.60 (m, 2H), 7.55 (t, J = 7.6 Hz, 2H), 7.44- 7.40 (m, 1H), 3.91 (s, 3H), 2.38 (s, 3H). MS-ESI (m/z) calc'd for C₂₀H₁₇N₆O [M + H]⁺: 357.1. Found 357.1.

2-Cyano-1,4-dimethyl-N-(3-phenyl-1H-

indazol-5-yl)-1H-imidazole-5-carboxamide

44

embedded image

¹H NMR (400 MHz, DMSO-d₆) δ 13.10 (s, 1H), 10.63 (s, 1H), 8.41- 8.37 (m, 1H), 8.31 (s, 1H), 8.26 (dd, J = 1.6, 0.8 Hz, 1H), 7.85 (t, J = 1.7 Hz, 1H), 7.78 (dd, J = 9.0, 1.9 Hz, 1H), 7.56 (d, J = 9.1 Hz, 1H), 7.00 (dd, J = 1.9, 0.8 Hz, 1H), 2.76 (s, 3H), 2.54 (s, 3H), MS-ESI (m/z) calc'd for C₂₀H₁₆N₅O₂[M + H]⁺: 358.1. Found

5-cyano-N-(3-(furan-3-yl)-1H-indazol-5-
358.1

yl)-3,6-dimethylpicolinamide

45

embedded image

¹H NMR (400 MHz, DMSO-d₆) δ 13.02 (s, 1H), 10.73 (s, 1H), 9.00 (d, J = 2.0 Hz, 1H), 8.59 (d, J = 1.9 Hz, 1H), 8.40 (dd, J = 2.0, 0.9 Hz, 1H), 7.80 (d, J = 8.7 Hz, 2H), 7.75 (dd, J = 9.0, 1.9 Hz, 1H), 7.54 (d, J = 8.9 Hz, 1H), 7.10 (d, J = 8.9 Hz, 2H), 3.26-3.19 (m, 4H), 2.59 (s, 3H), 2.49-2.45 (m, 4H), 2.24 (s, 3H). MS-ESI: (m/z) calc'd for C₂₆H₂₆N₇O [M + H]⁺: 452.2. Found 452.2.

5-cyano-3-methyl-N-(3-(4-(4-

methylpiperazin-1-yl)phenyl)-1H-indazol-

5-yl)picolinamide

46

embedded image

¹H NMR (400 MHz, DMSO-d₆) δ 13.39 (br. s., 1H), 10.81 (s, 1H), 9.01 (d, J = 1.54 Hz, 1H), 8.62 (d, J = 1.32 Hz, 1H), 8.38-8.44 (m, 1H), 7.89 (dd, J = 9.02, 1.76 Hz, 1H), 7.63 (d, J = 9.02 Hz, 1H), 7.27-7.39 (m, 2H), 6.90 (dt, J = 11.11, 2.26 Hz, 1H), 3.89 (s, 3H), 2.60 (s, 3H). MS-ESI (m/z) calc'd for C₂₂H₁₇FN₅O₂[M + H]⁺: 402.1. Found 402.2.

5-cyano-N-(3-(3-fluoro-5-methoxyphenyl)-

1H-indazol-5-yl)-3-methylpicolinamide

47

embedded image

¹H NMR (400 MHz, DMSO-d₆) δ 13.10 (s, 1H), 10.74 (s, 1H), 9.00 (dd, J = 2.0, 0.6 Hz, 1H), 8.59 (dd, J = 1.9, 0.7 Hz, 1H), 8.40 (dd, J = 2.0, 0.8 Hz, 1H), 7.88 (d, J = 8.8 Hz, 2H), 7.77 (dd, J = J = 8.9, 1.9 Hz, 1H), 7.56 (d, J = 9.0 Hz, 1H), 7.12 (d, J = 8.8 Hz, 2H), 3.83 (s, 3H), 2.59 (d, J = 0.7 Hz, 3H). MS- ESI (m/z) calc'd for C₂₂H₁₈N₅O₂ [M + H]⁺: 384.1. Found 384.2.

5-cyano-N-(3-(4-methoxyphenyl)-1H-

indazol-5-yl)-3-methylpicolinamide

48

embedded image

¹H NMR (400 MHz, DMSO-d₆) δ 13.58 (br. s., 1H) 10.83 (s, 1H) 9.02 (d, J = 1.54 Hz, 1H) 8.69 (d, J = 1.32 Hz, 1H) 8.42 (d, J = 1.10 Hz, 1H) 8.31 (d, J = 5.28 Hz, 1H) 7.91 (dd, J = 9.13, 1.87 Hz, 1H) 7.66 (d, J = 9.02 Hz, 1H) 7.59 (dd, J = 5.39, 1.43 Hz, 1H) 7.33 (s, 1H) 3.94 (s, 3H) 2.62 (s, 3H). MS-ESI (m/z) calc'd for C₂₁H₁₇N₆O₂[M + H]⁺: 485.1. Found 485.2.

5-cyano-N-(3-(2-methoxypyridin-4-yl)-1H-

indazol-5-yl)-3-methylpicolinamide

49

embedded image

¹H NMR (400 MHz, DMSO-d₆) δ 13.12 (s, 1H), 10.69 (s, 1H), 8.86 (s, 1H), 8.38 (dd, J = 1.7, 0.8 Hz, 1H), 8.21 (t, J = 1.2 Hz, 1H), 8.11 (d, J = 0.9 Hz, 1H), 7.85 (t, J = 1.7 Hz, 1H), 7.63 (dd, J = 8.9, 1.8 Hz, 1H), 7.57 (d, J = 8.9 Hz, 1H), 6.99 (dd, J = 1.8, 0.8 Hz, 1H), 2.51 (s, 3H). MS-ESI (m/z) calc'd for C₁₉H₁₄N₅O₂[M + H]⁺: 344.1. Found 344.1

6-cyano-N-(3-(furan-3-yl)-1H-indazol-5-

yl)-4-methylnicotinamide

50

embedded image

¹H NMR (400 MHz, DMSO-d₆) δ 13.46 (s, 1H), 10.80 (s, 1H), 9.18 (d, J = 2.3, 0.9 Hz, 1H), 9.01 (d, J = 2.0 Hz, 1H), 8.67 (d, J = 1.8 Hz, 1H), 8.63 (dd, J = 4.8, 1.6 Hz, 1H), 8.42 (dd, J = 1.9, 0.9 Hz, 1H), 8.32 (dt, J = 8.0, 1.9 Hz, 1H), 7.86 (dd, J = 9.0, 1.9 Hz, 1H), 7.64 (d, J = 8.9 Hz, 1H), 7.59 (ddd, J = 7.9, 4.7, 0.9 Hz, 1H), 2.61 (s, 3H). MS- ESI (m/z) calc'd for C₂₀H₁₅N₆O

5-cyano-3-methyl-N-(3-(pyridin-3-yl)-1H-
[M + H]⁺: 355.1. Found 355.1.

indazol-5-yl)picolinamide

51

embedded image

¹H NMR (400 MHz, DMSO-d₆) δ 13.23 (s, 1H), 10.75 (s, 1H), 9.02- 8.97 (m, 1H), 8.53 (d, J = 1.8 Hz, 1H), 8.41 (dd, J = 2.0, 0.9 Hz, 1H), 7.84 (td, J = 8.8, 2.1 Hz, 2H), 7.78 (ddd, J = 8.0, 5.1, 2.3 Hz, 1H), 7.59 (d, J = 9.0 Hz, 1H), 7.35-7.28 (m, 1H), 2.59 (s, 3H), 2.35 (d, J = 1.9 Hz, 3H). MS-ESI (m/z) calc'd for C₂₂H₁₇FN₅O [M + H]⁺: 386.1. Found 386.2.

5-cyano-N-(3-(4-fluoro-3-methylphenyl)-

1H-indazol-5-yl)-3-methylpicolinamide

52

embedded image

¹H NMR (400 MHz, DMSO-d₆) δ 13.28 (s, 1H), 10.77 (s, 1H), 9.01 (dd, J = 2.0, 0.8 Hz, 1H), 8.75 (dd, J = 2.4, 0.8 Hz, 1H), 8.64 (dd, J = 2.0, 0.7 Hz, 1H), 8.42 (dd, J = 2.0, 0.8 Hz, 1H), 8.24 (dd, J = 8.6, 2.4 Hz, 1H), 7.81 (dd, J = 9.0, 1.9 Hz, 1H), 7.61 (d, J = 9.0, 0.7 Hz, 1H), 7.02 (dd, J = 8.6, 0.8 Hz, 1H), 3.95 (s, 3H), 2.61 (d, J = 0.8 Hz, 3H). MS-ESI (m/z) calc'd for C₂₁H₁₇N₆O₂ [M + H]⁺: 385.1. Found 385.1.

5-cyano-N-(3-(6-methoxypyridin-3-yl)-1H-

indazol-5-yl)-3-methylpicolinamide

53

embedded image

¹H NMR (400 MHz, DMSO-d₆) δ 13.25 (br. s, 1H), 10.75 (br. s, 1H), 9.01 (d, J = 1.32 Hz, 1H), 8.64 (d, J = 1.32 Hz, 1 H), 8.41 (d, J = 1.10 Hz, 1H), 7.83 (dd, J = 9.02, 1.76 Hz, 1H), 7.60 (d, J = 9.24 Hz, 1H), 7.52-7.57 (m, 1H), 7.44- 7.51 (m, 2H), 6.94-7.03 (m, 1H), 3.87 (s, 3H), 2.60 (s, 3H). MS-ESI (m/z) calc'd for C₂₂H₁₈N₅O₂[M + H]⁺: 384.1. Found 384.2.

5-cyano-N-(3-(3-methoxyphenyl)-1H-

indazol-5-yl)-3-methylpicolinamide

54

embedded image

¹H NMR (400 MHz, DMSO-d₆) δ 13.44 (s, 1H), 10.80 (s, 1H), 9.00 (d, J = 1.9 Hz, 1H), 8.62 (d, J = 1.8 Hz, 1H), 8.41 (dd, J = 2.0, 0.8 Hz, 1H), 8.04- 7.96 (m, 1H), 7.90-7.81 (m, 2H), 7.70 (t, J = 8.0 Hz, 1H), 7.63 (d, J = 9.0 Hz, 1H), 7.41 (ddt, J = 8.2, 2.4, 1.0 Hz, 1H), 2.59 (s, 3H). MS-ESI (m/z) calc'd for C₂₂H₁₅F₃N₅O₂[M + H]⁺: 438.1. Found 438.1.

5-cyano-3-methyl-N-(3-(3-

(trifluoromethoxy)phenyl)-1H-indazol-5-

yl)picolinamide

55

embedded image

¹H NMR (400 MHz, DMSO-d₆) δ 13.38 (s, 1H), 10.78 (s, 1H), 9.03 (d, J = 2.3 Hz, 1H), 9.00 (d, J = 1.9 Hz, 1H), 8.64 (d, J = 1.8 Hz, 1H), 8.41 (dd, J = 2.0, 0.9 Hz, 1H), 8.19 (dd, J = 8.0, 2.3 Hz, 1H), 7.82 (dd, J = 9.0, 1.9 Hz, 1H), 7.62 (d, J = 8.9 Hz, 1H), 7.44 (d, J = 8.1 Hz, 1H), 2.60 (s, 3H), 2.55 (s, 3H). MS-ESI (m/z) calc'd for C₂₁H₁₇N₆O [M + H]⁺: 369.2. Found 369.2.

5-cyano-3-methyl-N-(3-(6-methylpyridin-

3-yl)-1H-indazol-5-yl)picolinamide

56

embedded image

¹H NMR (400 MHz, DMSO-d₆) δ 13.20 (br. s., 1H), 10.76 (s, 1H), 9.01 (d, J = 1.54 Hz, 1H), 8.61 (s, 1H), 8.41 (d, J = 1.10 Hz, 1H), 7.85 (d, J = 8.14 Hz, 2 H), 7.80 (dd, J = 8.91, 1.65 Hz, 1H), 7.59 (d, J = 9.02 Hz, 1H), 7.36 (d, J = 7.92 Hz, 2H), 2.60 (s, 3H), 2.39 (s, 3H). MS- ESI (m/z) calc'd for C₂₂H₁₈N₅O [M + H]⁺: 368.1. Found 368.2.

5-cyano-3-methyl-N-(3-(p-tolyl)-1H-

indazol-5-yl)picolinamide

57

embedded image

¹H NMR (400 MHz, DMSO-d₆) δ 12.95 (s, 1H) 10.70 (s, 1H) 9.01 (d, J = 1.32 Hz, 1H) 8.38-8.47 (m, 2H) 8.22 (s, 1H) 7.93 (s, 1H) 7.80 (dd, J = 9.02, 1.76 Hz, 1H) 7.54 (d, J = 8.80 Hz, 1H) 3.96 (s, 3H) 2.62 (s, 3H). MS-ESI (m/z) calc'd for C₁₉H₁₆N₇O [M + H]⁺: 358.1. Found 358.1.

5-cyano-3-methyl-N-(3-(1-methyl-1H-

pyrazol-4-yl)-1H-indazol-5-

yl)picolinamide

58

embedded image

¹H NMR (400 MHz, DMSO-d₆) δ 13.22 (s, 1H), 10.75 (s, 1H), 9.00 (dd, J = 2.0, 0.7 Hz, 1H), 8.60-8.49 (m, 1H), 8.40 (dd, J = 2.0, 0.8 Hz, 1H), 7.83 (dd, J = 9.0, 1.9 Hz, 1H), 7.77 (s, 1.11), 7.74 (d, J = 7.8 Hz, 1H), 7.59 (d, J = 9.2 Hz, 1H), 7.43 (t, J = 7.6 Hz, 1H), 7.25-7.21 (m, 1H), 2.59 (d, J = 0.7 Hz, 3H), 2.42 (s, 3H). MS-ESI (m/z) calc'd for C₂₂H₁₈N₅O [M + H]⁺: 368.1. Found 368.2.

5-cyano-3-methyl-N-(3-(m-tolyl)-1H-

indazol-5-yl)picolinamide

59

embedded image

¹H NMR (400 MHz, DMSO-d₆) δ 13.47 (s, 1H), 10.81 (s, 1H), 9.00 (dd, J = 1.9, 0.7 Hz, 1H), 8.61 (d, J = 1.9 Hz, 1H), 8.41 (dd, J = 1.9, 0.9 Hz, 1H), 8.27 (d, J = 7.5 Hz, 1H), 8.23 (s, 1H), 7.87 (dd, J = 9.0, 1.9 Hz, 1H), 7.81 (t, J = 7.6 Hz, 1H), 7.78 (d, J = 7.9 Hz, 1H), 7.64 (d, J = 9.2 Hz, 1H), 2.59 (s, 3H). MS-ESI (m/z) calc'd for C₂₂H₁₅F₃N₅O [M + H]⁺: 422.1. Found 422.1.

5-cyano-3-methyl-N-(3-(3-

(trifluoromethyl)phenyl)-1H-indazol-5-

yl)picolinamide

60

embedded image

¹H NMR (400 MHz, DMSO-d₆) δ 13.69 (br. s., 1H) 10.83 (s, 1H) 9.36 (d, J = 1.98 Hz, 1H) 9.02 (d, J = 1.32 Hz, 1H) 8.72 (d, J = 1.32 Hz, 1H) 8.60 (dd, J = 8.25, 1.65 Hz, 1H) 8.39-8.47 (m, 1H) 8.10 (d, J = 8.14 Hz, 1H) 7.88 (dd, J = 8.91, 1.87 Hz, 1H) 7.69 (d, J = 8.58 Hz, 1H) 2.62 (s, 3H). MS-ESI (m/z) calc'd for C₂₁H₁₄F₃N₆O [M + H]⁺: 423.1. Found 423.1.

5-cyano-3-methyl-N-(3-(6-

(trifluoromethyl)pyridin-3-yl)-1H-indazol-

5-yl)picolinamide

61

embedded image

¹H NMR (400 MHz, DMSO-d₆) δ 13.36 (br. s., 1H) 10.79 (s, 1H) 9.01 (d, J = 1.32 Hz, 1H) 8.56 (d, J = 1.32 Hz, 1H) 8.42 (dd, J = 1.87, 0.77 Hz, 1H) 7.91 (dd, J = 9.02, 1.98 Hz, 1H) 7.57- 7.69 (m, 2H) 7.51 (d, J = 10.12 Hz, 1 H) 7.09 (d, J = 9.68 Hz, 1H) 2.60 (s, 3 H) 2.45 (s, 3H). MS-ESI (m/z) calc'd for C₂₂H₁₇FN₅O [M + H]⁺: 386.1. Found 386.2.

5-cyano-N-(3-(3-fluoro-5-methylphenyl)-

1H-indazol-5-yl)-3-methylpicolinamide

62

embedded image

¹H NMR (400 MHz, DMSO-d₆) δ 13.22 (br. s., 1H) 10.77 (s, 1H) 9.01 (d, J = 1.54 Hz, 1H) 8.61 (d, J = 1.32 Hz, 1H) 8.38-8.46 (m, 1H) 7.80 (dd, J = 9.02, 1.76 Hz, 1H) 7.71 (d, J = 7.70 Hz, 1H) 7.64 (s, 1H) 7.60 (d, J = 9.02 Hz, 1H) 7.42 (t, J = 7.70 Hz, 1H) 7.14 (d, J = 7.48 Hz, 1H) 2.59 (s, 3H) 2.00- 2.10 (rn, 1H) 0.99-1.06 (m, 2H) 0.75- 0.82 (m, 2H). MS-ESI (m/z) calc'd

5-cyano-N-(3-(3-cyclopropylphenyl)-1H-
for C₂₄H₂₀N₅O [M + H]⁺: 394.2. Found

indazol-5-yl)-3-methylpicolinamide
394.2.

63

embedded image

¹H NMR (400 MHz, DMSO-d₆) δ 13.32 (br. s., 1H), 10.79 (s, 1H), 9.01 (d, J = 1.32 Hz, 1H), 8.57-8.67 (m, 1 H), 8.42 (dd, J = 1.98, 0.66 Hz, 1H), 7.86 (dd, J = 8.91, 1.87 Hz, 1H), 7.59- 7.75 (m, 3H), 7.47 (t, J = 8.25 Hz, 1H), 2.61 (s, 3H), 2.32 (d, J = 1.32 Hz, 3H). MS-ESI (m/z) calc'd for C₂₂H₁₇FN₅O [M + H]⁺: 386.1. Found 386.2.

5-cyano-N-(3-(3-fluoro-4-methylphenyl)-

1H-indazol-5-yl)-3-methylpicolinamide

64

embedded image

¹H NMR (400 MHz, DMSO-d₆) δ 13.15 (s, 1H) 11.00 (s, 1H) 9.36 (s, 1 H) 8.90 (s, 1H) 8.46 (s, 1H) 8.29 (s, H) 7.68-7.96 (m, 3H) 7.58 (d, J = 9 Hz, 1H) 7.02 (d, J = 1 Hz, 1H). MS- ESI (m/z) calc'd for C₁₉H₁₂F₂N₅O₂ [M + H]⁺: 380.1. Found 380.1.

5-Cyano-3-(difluoromethyl)-N-(3-(furan-3-

yl)-1H-indazol-5-yl)picolinamide

65

embedded image

¹H NMR (400 MHz, DMSO-d₆) δ 13.16 (br s, 1H) 11.11 (s, 1H) 8.95 (s, 1H) 8.46 (d, J = 1.47 Hz, 1H) 8.26 (s, 1H) 7.89 (dd, J = 9.05, 1.83 Hz, 1H) 7.85 (t, J = 1.65 Hz, 1H) 7.58 (d, J = 8.93 Hz, 1H) 6.98-7.03 (m, 1H). MS-ESI (m/z) calc'd for C₁₆H₁₀N₅O₂S [M + H]⁺: 336.0. Found 336.0.

5-Cyano-N-(3-(furan-3-yl)-1H-indazol-5-

yl)thiazole-2-carboxamide

66

embedded image

¹H NMR (400 MHz, DMSO-d₆) δ 13.13 (s, 1H), 10.91 (s, 1H), 9.29 (s, 1H), 8,51 (s, 1H), 8.44 (s, 1H), 8.29 (s, 1H), 7.99 (br d, J = 9.0 Hz, 1H), 7.85 (s, 1H), 7.57 (d, J = 9.0 Hz, 1H), 7.01 (s, 1H). MS-ESI (m/z) calc'd for C₁₈H₁₁ClN₅O₂[M + H]⁺: 364.0. Found 364.0.

4-Chloro-5-cyano-N-(3-(furan-3-yl)-1H-

indazol-5-yl)picolinamide

67

embedded image

¹H NMR (400 MHz, DMSO-d₆) δ 13.10 (s, 1H), 10.67 (s, 1H), 8.89 (s, 1H), 8.40 (d, J = 1.7 Hz, 1H), 8.23 (t, J =1.1 Hz, 1H), 7.84 (t, J = 1.7 Hz, 1H), 7.74 (dd, J = 8.9, 1.9 Hz, 1H), 7.56 (d, J = 9.0 Hz, 1H), 6.99 (dd, J = 1.9, 0.8 Hz, 1H), 2.56 (s, 3H), 2.47 (s, 3H). MS-ESI (m/z) calc'd for C₂₀H₁₆N₅O₂[M + H]⁺: 358.1. Found

5-cyano-N-(3-(furan-3-yl)-1H-indazol-5-
358.1

yl)-3,4-dimethylpicolinamide

68

embedded image

¹H NMR (400 MHz, DMSO-d₆) δ 13.49 (bs, 1H), 10.81 (s, 1H), 9.01 (d, J = 2.0 Hz, 1H), 8.79 (d, J = 1.7 Hz, 1H), 8.67 (d, J = 1.8 Hz, 1H), 8.42 (dd, J = 2.0, 0.9 Hz, 1H), 8.36 (d, J = 2.8 Hz, 1H), 7.88 (dd, J = 9.0, 1.9 Hz, 1H), 7.84 (dd, J = 2.9, 1.7 Hz, 1H), 7.65 (d, J = 9.0 Hz, 1H), 3.96 (s, 3H), 2.61 (s, 3H). MS-ESI (m/z) calc'd for C₂₁H₁₇N₆O₂ [M + H]⁺: 385.1. Found 385.2.

5-cyano-N-(3-(5-methoxypyridin-3-yl)-1H-

indazol-5-yl)-3-methylpicolinamide

69

embedded image

¹H NMR (400 MHz, DMSO-d₆) δ 13.10 (s, 1H), 10.60 (s, 1H), 8.70 (d, J = 1.5 Hz, 1H), 8.39 (d, J = 1.8 Hz, 1H), 8.24 (d, J = 1.6 Hz, 1H), 8.21 (d, J = 1.2 Hz, 1H), 7.85 (t, J = 1.7 Hz, 1H), 7.67 (dd, J = 8.9, 1.9 Hz, 1H), 7.56 (d, J = 8.9 Hz, 1H), 6.99 (d, J = 1.9 Hz, 1H), 3.94 (s, 3H). MS-ESI (m/z) calc'd for C₁₉H₁₄N₅O₃[M + H]⁺: 360.1.

5-cyano-N-(3-(furan-3-yl)-1H-indazol-5-
Found 360.2.

yl)-3-methoxypicolinamide

70

embedded image

¹H NMR (400 MHz, Chloroform-d) δ 10.12 (s, 1H), 8.74 (d, J = 2.0 Hz, 1H), 8.49 (d, J = 2.0 Hz, 1H), 7.96 (d, J = 1.9 Hz, 1H), 7.91 (d, J = 8.7 Hz, 2H), 7.68 (dd, J = 8.9, 1.9 Hz, 1H), 7.51 (d, J = 8.9 Hz, 1H), 7.09-7.05 (m, 2H), 3.93-3.89 (m, 4H), 3.28-3.24 (m, 4H), 2.90 (s, 3H). MS-ESI (m/z) calc'd for C₂₅H₂₃N₆O₂[M + H]⁺: 439.2. Found 439.1.

5-cyano-3-methyl-N-(3-(4-

morpholinophenyl)-1H-indazol-5-

yl)picolinamide

71

embedded image

¹H NMR (400 MHz, DMSO-d₆) δ 13.30 (s, 1H), 10.81 (s, 1H), 9.01 (dd, J = 2.0, 0.8 Hz, 1H), 8.84 (s, 1H), 8.68 (d, 1H), 8.42 (dd, J = 2.0, 0.9 Hz, 1H), 8.30 (d, J = 1.6 Hz, 1H), 8.07 (dd, J = 8.5, 1.7 Hz, 1H), 7.96 (d, J = 8.5 Hz, 1H), 7.87 (dd, J = 9.0, 1.9 Hz, 1H), 7.63 (d, J = 9.0 Hz, 1H), 2.61 (s, 3H). MS-ESI (m/z) calc'd for C₂₂H₁₅N₆O₂ [M + H]⁺: 395.1. Found 395.1.

N-(3-(benzo[d]oxazol-5-yl)-1H-indazol-5-

yl)-5-cyano-3-methylpicolinamide

72

embedded image

¹H NMR (400 MHz, DMSO-d₆) δ 13.10 (br. s., 1H), 10.51 (s, 1H), 8.38 (d, J = 1.1 Hz, 1H), 8.22 (dd, J = 0.8, 1.4 Hz, 1H), 7.96 (dd, J = 1.7, 7.8 Hz, 1H), 7.91 (dd, J = 1.5, 7.7 Hz, 1H), 7.86 (t, J = 1.7 Hz, 1H), 7.70-7.63 (m, 1H), 7.61-7.53 (m, 1H), 7.41 (t, J = 7.7 Hz, 1H), 7.00 (dd, J = 0.8, 1.9 Hz, 1H), 4.03 (s, 3H), MS-ESI (m/z) calc'd for

3-cyano-N-(3-(furan-3-yl)-1H-indazol-5-
C₂₀H₁₅N₄O₃[M + H]⁺: 359.1. Found

yl)-2-methoxybenzamide
359.2.

73

embedded image

¹H NMR (400 MHz, DMSO-d₆) δ 13.13 (bs, 1H), 10.74 (s, 1H), 9.01 (d, J = 2.0 Hz, 1H), 8.60 (d, J = 1.8 Hz, 1H), 8.42 (dd, J = 2.0, 0.9 Hz, 1H), 7.96 (dd, J = 2.9, 1.3 Hz, 1H), 7.81 (dd, J = 9.0, 1.9 Hz, 1H), 7.74 (dd, J = 5.0, 2.8 Hz, 1H), 7.70 (dd, J = 5.0, 1.3 Hz, 1H), 7.58 (d, J = 8.9 Hz, 1H), 2.62 (s, 3H). MS-ESI (m/z) calc'd for

5-cyano-3-methyl-N-(3-(thiophen-3-yl)-
C₁₉H₁₄N₅OS [M + H]⁺: 360.1. Found

1H-indazol-5-yl)picolinamide
360.1.

74

embedded image

¹H NMR (400 MHz, DMSO-d₆) δ 13.57 (bs, 1H), 10.80 (s, 1H), 9.02 (d, J = 1.9 Hz, 1H), 8.64 (d, J = 1.8 Hz, 1H), 8.58 (d, J = 5.1 Hz, 1H), 8.42 (dd, J = 1.8, 0.8 Hz, 1H), 7.91 (dd, J = 9.0, 1.9 Hz, 1H), 7.82 (d, J = 1.7 Hz, 1H), 7.74 (dd, J = 5.3, 1.7 Hz, 1H), 7.66 (d, J = 9.0 Hz, 1H), 2.61 (s, 3H), 2.59 (s, 3H). MS-ESI (m/z) calc'd for C₂₁H₁₆N₆O [M + H]⁺: 369.1. Found 369.2.

5-cyano-3-methyl-N-(3-(2-methylpyridin-

4-yl)-1H-indazol-5-yl)picolinamide

75

embedded image

¹H NMR (400 MHz, DMSO-d₆) δ 13.10 (s, 1H), 10.55 (s, 1H), 8.37 (d, J = 1.1 Hz, 1H), 8.21 (dd, J = 0.8, 1.4 Hz, 1H), 7.95 (dd, J = 1.3, 7.7 Hz, 1H), 7.89- 7.81 (m, 2H), 7.71-7.63 (m, 1H), 7.61-7.52 (m, 2H), 6.99 (dd, J = 0.7, 1.8 Hz, 1H), 2.95 (q, J = 7.4 Hz, 2H), 1.27 (t, J = 7.5 Hz, 3H). MS-ESI (m/z) calc'd for C₂₁H₁₇N₄O₂[M + H]⁺: 357.1. Found 357.1.

3-cyano-2-ethyl-N-(3-(furan-3-yl)-1H-

indazol-5-yl)benzamide

76

embedded image

¹H NMR (400 MHz, DMSO-d₆) δ 13.38 (s, 1H) 10.73 (s, 1H) 9.01 (s, H) 8.69 (s, 1H) 8.42 (br d, J = 6 Hz, 2 H) 8.14 (s, 1H) 7.85 (br d, J = 8 Hz, H) 7.61 (d, J = 9 Hz, 1H) 2.62 (s, 3H). MS-ESI (m/z) calc'd for C₂₀H₁₃N₆O₂ [M + H]⁺: 369.1. Found 369.0.

5-Cyano-N-(3-(5-cyanofuran-3-yl)-1H-

indazol-5-yl)-3-methylpicolinamide

77

embedded image

¹H NMR (400 MHz, DMSO-d₆) δ 13.13 (br. s., 1H), 10.64 (br. s., 1H), 8.37 (d, J = 0.9 Hz, 1H), 8.22 (dd, J = 0.8, 1.4 Hz, 1H), 8.18-8.03 (m, 2H), 7.86 (t, J = 1.7 Hz, 1H), 7.68-7.53 (m, 3H), 7.00 (dd, J = 0.8, 1.9 Hz, 1H). MS-ESI (m/z) calc'd for C₁₉H₁₂FN₄O₂ [M + H]⁺: 347.1. Found 347.1.

3-cyano-2-fluoro-N-(3-(furan-3-yl)-1H-

indazol-5-yl)benzamide

78

embedded image

¹H NMR (400 MHz, DMSO-d₆) δ 13.12 (s, 1H), 10.60 (s, 1H), 8.45 (d, J = 1.5 Hz, 1H), 8.37-8.27 (m, 2H), 8.07 (d, J = 0.9 Hz, 1H), 7.96 (dd, J = 1.9, 8.9 Hz, 1H), 7.86 (t, J = 1.7 Hz, 1H), 7.59 (d, J = 8.8 Hz, 1H), 7.03 (dd, J = 0.9, 1.8 Hz, 1H), 2.74 (s, 3H). MS- EST (m/z) calc'd for C₁₉H₁₄N₅O₂ [M + H]⁺: 344.1. Found 344.2.

4-cyano-N-(3-(furan-3-yl)-1H-indazol-5-

yl)-6-methylpicolinamide

79

embedded image

¹H NMR (400 MHz, DMSO-d₆) δ 13.12 (s, 1H), 10.77 (s, 1H), 8.82 (d, J = 4.8 Hz, 1H), 8.43 (s, 1H), 8.32-8.24 (m, 2H), 7.90-7.80 (m, 2H), 7.58 (d, J = 9.0 Hz, 1H), 7.01 (d, J = 0.9 Hz, 1H). MS-ESI (m/z) calc'd for C₁₈H₁₁FN₅O₂ [M + H]⁺: 348.1. Found 348.1.

4-cyano-3-fluoro-N-(3-(furan-3-yl)-1H-

indazol-5-yl)picolinamide

80

embedded image

¹H NMR (400 MHz, DMSO-d₆) δ 13.17 (s, 1H), 10.61 (s, 1H), 9.04-8.97 (m, 1H), 8.41 (dd, J = 0.8, 1.9 Hz, 1H), 8.30-8.20 (m, 2H), 7.85 (t, J = 1.7 Hz, 1H), 7.64 (s, 1H), 7.01 (dd, J = 0.9, 1.8 Hz, 1H), 2.61 (s, 3H), 2.55 (s, 3H). MS-ESI (m/z) calc'd for C₂₄H₁₆N₅O₂ [M + H]⁺: 358.1. Found 358.2.

5-cyano-N-(3-(furan-3-yl)-7-methyl-1H-

indazol-5-yl)-3-methylpicolinamide

81

embedded image

¹H NMR (400 MHz, DMSO-d₆) δ 13.11 (br s, 1H) 10.18 (s, 1H) 8.31 (s, 1H) 8.22 (s, 1H) 7.85 (t, J = 1.59 Hz, 1 H) 7.56 (s, 2H) 6.99 (d, J = 1.10 Hz, 1 H) 4.01 (s, 3H) 2.42 (s, 3H). MS-ESI (m/z) calc'd for C₁₈H₁₅N₆O₂[M + H]⁺: 347.1. Found 347.1.

5-Cyano-N-(3-(furan-3-yl)-1H-indazol-5-

yl)-1,3-dimethyl-1H-pyrazole-4-

carboxamide

82

embedded image

¹H NMR (400 MHz, DMSO-d₆) δ 13.15 (s, 1H), 11.02 (s, 1H), 8.38 (s, 1H), 8.24 (s, 1H), 8.14 (s, 1H), 7.85 (s, 1H), 7.75 (d, J = 9.0 Hz, 1H), 7.58 (d, J = 8.9 Hz, 1H), 6.99 (s, 1H). MS-ESI (m/z) calc'd for C₁₆H₁₀N₅O₃[M + H]⁺: 320.1. Found 320.0.

5-Cyano-N-(3-(furan-3-yl)-1H-indazol-5-

yl)isoxazole-3-carboxamide

83

embedded image

¹H NMR (400 MHz, DMSO-d₆) δ 13.11 (br s, 1H) 10.71 (s, 1H) 9.00 (d, J = 1.10 Hz, 1H) 8.42 (d, J = 12.59 Hz, 2 H) 8.25 (s, 1H) 7.85 (s, 1H) 7.76- 7.82 (m, 1H) 7.56 (d, J = 8.93 Hz, 1H) 7.00 (s, 1H) 2.97 (q, J = 7.34 Hz, 2H) 1.24 (t, J = 7.46 Hz, 3H). MS-ESI (m/z) calc'd for C₂₀H₁₆N₅O₂[M + H]⁺: 358.1. Found 358.1.

5-Cyano-3-ethyl-N-(3-(furan-3-yl)-1H-

indazol-5-yl)picolinamide

84

embedded image

¹H NMR (400 MHz, DMSO-d₆) δ 13.12 (br s, 1H) 10.79 (s, 1H) 9.06 (s, 1H) 8.82 (s, 1H) 8.43 (s, 1H) 8.26 (s, 1H) 7.73-7.88 (m, 2H) 7.56 (br d, J = 8.80 Hz, 1H) 7.35 (br dd, J = 17.42, 11.07 Hz, 1H) 7.00 (s, 1H) 6.14 (br d, J = 17.48 Hz, 1H) 5.61 (br d, J = 11.13 Hz, 1H). MS-ESI (m/z) calc'd for C₂₀H₁₄N₅O₂[M + H]⁺: 356.1. Found

5-Cyano-N-(3-(furan-3-yl)-1H-indazol-5-
356.0.

yl)-3-vinylpicolinamide

85

embedded image

¹H NMR (400 MHz, DMSO-d₆) δ 13.11 (s, 1H), 10.62 (s, 1H), 8.45 (s, 1H), 8.33 (s, 1H), 8.09 (s, 1H), 7.97 (dd, J = 9.0, 1.9 Hz, 1H), 7.85 (t, J = 1.7 Hz, 1H), 7.59 (d, J = 9.0 Hz, 1H), 7.03 (d, J = 1.9 Hz, 1H), 2.84 (s, 3H), 2.63 (s, 3H). MS-ESI (m/z) calc'd for C₂₀H₁₆N₅O₂[M + H]⁺: 358.1. Found 358.2.

5-cyano-N-(3-(furan-3-yl)-1H-indazol-5-

yl)-4,6-dimethylpicolinamide

86

embedded image

¹H NMR (400 MHz, DMSO-d₆) δ 13.13 (br. s., 1H), 10.69 (br. s., 1H), 8.37 (s, 1H), 8.23-8.18 (m, 1H), 8.13 (dd, J = 1.7, 7.8 Hz. 1H), 8.00 (dd, J = 1.5, 7.7 Hz, 1H), 7.86 (t, J = 1.7 Hz, 1H), 7.71 (t, J = 7.7 Hz, 1H), 7.64-7.55 (m, 2H), 6.99 (dd, J = 0.8, 1.9 Hz, 1H). MS-ESI (m/z) calc'd for C₁₉H₁₂ClN₄O₂[M + H]⁺: 363.1. Found 363.1, 365.3.

2-chloro-3-cyano-N-(3-(furan-3-yl)-1H-

indazol-5-yl)benzamide

87

embedded image

¹H NMR (400 MHz, DMSO-d₆) δ 13.50 (s, 1H), 10.80 (s, 1H), 9.00 (d, J = 1.9 Hz, 1H), 8.41 (d, J = 2.0 Hz, 1H), 8.14 (s, 1H), 7.72 (dd, J = 9.0, 1.9 Hz, 1H), 7.56 (d, J = 8.9 Hz, 1H), 2.59 (s, 3H). MS-ESI (m/z) calc'd for C₁₅H₁₁IN₅O [M + H]⁺: 404.0. Found 404.1.

5-cyano-N-(3-iodo-1H-indazol-5-yl)-3-

methylpicolinamide

88

embedded image

¹H NMR (400 MHz, DMSO-d₆) δ 13.12 (br. s., 1H), 10.65 (br. s., 1H), 8.37 (s, 1H), 8.23-8.16 (m, 1H), 8.08 (dd, J = 1.7, 7.8 Hz, 1H), 7.93 (dd, J = 1.7, 7.6 Hz, 1H), 7.86 (t, J = 1.7 Hz, 1H), 7.74 (t, J = 7 .7 Hz, 1H), 7.67-7.53 (m, 2H), 6.99 (dd, J = 0.8, 1.9 Hz, 1H). MS-ESI (m/z) calc'd for C₁₉H₁₂BrN₄O₂[M + H]⁺: 407.0. Found 407.0.

3-cyano-N-(3-(furan-3-yl)-7-methyl-1H-

indazol-5-yl)-2-methylbenzamide

89

embedded image

¹H NMR (400 MHz, DMSO-d₆) δ 13.16 (s, 1H), 10.42 (s, 1H), 8.19 (d, J = 6.6 Hz, 2H), 7.93 (d, J = 6.8 Hz, 1H), 7.87-7.78 (m, 2H), 7.54 (t, J = 7.7 Hz, 1H), 7.45 (s, 1H), 6.99 (s, 1H), 2.90 (s, 1H), 2.59 (s, 3H), 2.54 (s, 3H). MS- ESI (m/z) calc'd for C₂₁H₁₇N₄O₂ [M + H]⁺: 357.1. Found 357.2.

2-bromo-3-cyano-N-(3-(furan-3-yl)-1H-

indazol-5-yl)benzamide

90

embedded image

¹H NMR (400 MHz, DMSO-d₆) δ 13.10 (br s, 1H) 10.24 (s, 1H) 8.30 (s, 1H) 8.22 (s, 1H) 7.85 (t, J = 1.59 Hz, 1 H) 7.56 (s, 2H) 6.98 (d, J = 1.22 Hz, 1 H) 3.91 (s, 3H) 2.49 (br s, 3H). MS- ESI (m/z) calc'd for C₁₈H₁₅N₆O₂ [M + H]⁺: 347.1. Found 347.1.

3-Cyano-N-(3-(furan-3-yl)-1H-indazol-5-

yl)-1,5-dimethyl-1H-pyrazole-4-

carboxamide

91

embedded image

¹H NMR (400 MHz, DMSO-d₆) δ 8.67 (s, 1H), 8.49-8.39 (m. 1H), 8.25 (s, 1H), 7.93-7.81 (m, 2H), 7.57 (br d, J = 8.9 Hz, 1H), 7.04-6.98 (m, 1H). MS-ESI (m/z) calc'd for C₁₆H₁₀N₅O₂S [M + H]⁺: 336.1. Found 336.1.

5-Cyano-N-(3-(furan-3-yl)-1H-indazol-5-

yl)isothiazole-3-carboxamide

92

embedded image

¹H NMR (400 MHz, DMSO-d₆) δ 13.15 (br s, 1H) 10.57 (br s, 1H) 8.36 (s, 1H) 8.25 (s, 1H) 7.86 (s, 1H) 7.55- 7.68 (m, 2H) 7.00 (s, 1H) 4.06 (s, 3 H) 2.51 (br s, 3H). MS-ESI (m/z) calc'd for C₁₈H₁₅N₆O₂[M + H]⁺: 347.1. Found 347.1.

3-Cyano-N-(3-(furan-3-yl)-1H-indazol-5-

yl)-1,4-dimethyl-1H-pyrazole-5-

carboxamide

93

embedded image

¹H NMR (400 MHz, DMSO-d₆) δ 13.04 (s, 1H) 10.23 (s, 1H) 8.37 (s, 1 H) 8.25 (s, 1H) 7.79-7.89 (m, 2H) 7.52 (d, J = 9.05 Hz, 1H) 7.00 (s, 1H) 4.10 (s, 3H) 2.42 (s, 3H). MS-ESI (m/z) calc'd for C₁₈H₁₅N₆O₂[M + H]⁺: 347.1. Found 347.1.

5-Cyano-N-(3-(furan-3-yl)-1H-indazol-5-

yl)-1,4-dimethyl-1H-pyrazole-3-

carboxamide

94

embedded image

¹H NMR (400 MHz, DMSO-d₆) δ 13.10 (s, 1H), 10.81 (s, 1H), 9.11 (s, 1H), 8.50 (s, 1H), 8.29 (d, J = 9.7 Hz, 2H), 8.01 (br d, J = 8.9 Hz, 1H), 7.85 (s, 1H), 7.57 (d, J = 8.9 Hz, 1H), 7.02 (s, 1H), 2.65 (s, 3H). MS-ESI (m/z) calc'd for C₁₉H₁₄N₅O₂[M + H]⁺: 344.1. Found 344.2.

5-Cyano-N-(3-(furan-3-yl)-1H-indazol-5-

yl)-4-methylpicolinamide

95

embedded image

¹H NMR (400 MHz, DMSO-d₆) δ 13.14 (s, 1H), 10.85 (s, 1H), 9.13 (d, J = 1.7 Hz, 1H), 8.82 (d, J = 1.7 Hz, 1H), 8.37 (dd, J = 1.9, 0.8 Hz, 1H), 8.22 (dd, J = 1.5, 0.8 Hz, 1H), 7.85 (t, J = 1.7 Hz, 1H), 7.67 (dd, J = 9.0, 1.9 Hz, 1H), 7.58 (dd, J = 8.9, 0.8 Hz, 1H), 6.99 (dd, J =1.8, 0.8 Hz, 1H). MS-ESI (m/z) calc'd for C₁₈H₁₁ClN₅O₂[M + H]⁺: 364.1. Found 364.0, 366.0.

3-chloro-5-cyano-N-(3-(furan-3-yl)-1H-

indazol-5-yl)picolinamide

96

embedded image

¹H NMR (400 MHz, DMSO-d₆) δ 13.08 (br s, 1H), 10.65 (br s, 1H), 8.41 (s, 1H), 8.26 (s, 1H), 8.04 (s, 1H), 7.88 (br d, J = 8.9 Hz, 1H), 7.84 (s, 1H), 7.55 (d, J = 9.0 Hz, 1H), 7.01 (s, 1H), 4.12 (s, 3H). MS-ESI (m/z) calc'd for C₁₇H₁₃N₆O₂[M + H]⁺: 333.1. Found 333.0.

5-Cyano-N-(3-(furan-3-yl)-1H-indazol-5-

yl)-1-methyl-1H-imidazole-2-carboxamide

97

embedded image

¹H NMR (400 MHz, DMSO-d₆) δ 13.08 (s, 1H) 10.37 (s, 1H) 8.39 (s, 1 H) 8.25 (s, 1H) 7.80-7.88 (m, 2H) 7.65 (s, 1H) 7.53 (d, J = 9.04 Hz, 1H) 7.00 (s, 1H) 4.15 (s, 3H). MS-ESI (m/z calc'd for C₁₇H₁₃N₆O₂[M + H]⁺: 333.1. Found 333.0.

5-Cyano-N-(3-(furan-3-yl)-1H-indazol-5-

yl)-1-methyl-1H-pyrazole-3-carboxamide

98

embedded image

¹H NMR (400 MHz, DMSO-d₆) δ 13.21 (br s, 1H), 10.72 (s, 1H), 8.97 (d, J = 1.1 Hz, 1H), 8.38 (s, 1H), 8.23 (s, 1H), 7.72 (dd, J = 1.5, 9.0 Hz, 1H), 7.59 (d, J = 9.0 Hz, 1H), 7.53-7.46 (m, 1H), 7.44-7.31 (m, 3H), 2.54 (s, 3H), 2.36 (s, 3H). MS-ESI (m/z) calc'd for C₂₂H₁₈N₅O [M + H]⁺: 368.1. Found 368.1.

5-Cyano-3-methyl-N-(3-(o-tolyl)-1H-

indazol-5-yl)picolinamide

99

embedded image

¹H NMR (400 MHz, DMSO-d₆) δ 13.12 (br s, 1H) 10.65 (s, 1H) 8.97 (d, J = 0.98 Hz, 1H) 8.38 (s, 1H) 8.24 (s, 1H) 7.65 (dd, J = 8.93, 1.22 Hz, 1H) 7.53 (br d, J = 8.19 Hz, 2H) 7.41-7.47 (m, 1H) 7.20 (d, J = 8.31 Hz, 1H) 7.07 (t, J = 7.40 Hz, 1H) 3.82 (s, 3H) 2.54 (s, 3H). MS-ESI (m/z) calc'd for C₂₂H₁₈N₅O₂[M + H]⁺: 384.1. Found 384.1.

5-Cyano-N-(3-(2-methoxyphenyl)-1H-

indazol-5-yl)-3-methylpicolinamide

Detailed methods for the preparation of Examples 28-99 are provided below:

Example 28: 5-Cyano-N-(3-(3,4-dimethylphenyl)-1H-indazol-5-yl)-3-methylpicolinamide

embedded image

5-Cyano-N-(3-iodo-1H-indazol-5-yl)-3-methylpicolinamide (70 mg, 0.170 mmol) was dissolved in 1,4-dioxane (3.53 mL). Then a solution of K₃PO₄(110.56 mg, 0.52 mmol) and (3,4-dimethylphenyl)boronic acid (52.08 mg, 0.350 mmol) in water (0.882 mL) was added and the mixture was degassed with N₂for 15 minutes. SPhos-Pd-G2 (12.51 mg, 0.020 mmol) was added and the mixture was stirred at 80° C., under N₂atmosphere for 2 hrs. Then another portion of (3,4-dimethylphenyl)boronic acid (52.08 mg, 0.350 mmol) and SPhos-Pd-G2 (12.51 mg, 0.020 mmol) were added and stirring was continued at 80° C. for further 18 hrs. The mixture was diluted with water and then extracted with EtOAc. The phases were separated and the organic solvent was evaporated under reduced pressure. The residue (124 mg) was purified by semi-preparative HPLC (Method A) to afford the title compound (22.4 mg, 0.059 mmol, 34% yield) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.15 (s, 1H), 10.75 (s, 1H), 9.01 (dd, J=2.0, 0.8 Hz, 1H), 8.62-8.51 (m, 1H), 8.41 (dd, J=2.0, 0.9 Hz, 1H), 7.82 (dd, J=8.9, 1.9 Hz, 1H), 7.74 (d, J=1.5 Hz, 1H), 7.67 (dd, J=7.7, 1.9 Hz, 1H), 7.58 (d, J=9.2 Hz, 1H), 7.30 (d, J=7.8 Hz, 1H), 2.59 (s, 3H), 2.34 (s, 3H), 2.30 (s, 3H). MS-ESI (m/z) calc'd for C₂₃H₂₀N₃O [M+H]⁺: 382.2. Found 382.2.

Example 29: 5-Cyano-N-(3-(furan-2-yl)-1H-indazol-5-yl)-3-methylpicolinamide

embedded image

5-Cyano-N-(3-iodo-1H-indazol-5-yl)-3-methylpicolinamide (70.0 mg, 0.170 mmol) was dissolved in 1,4-dioxane (3.53 mL). Then a solution of K₃PO₄(110.56 mg, 0.520 mmol) and (furan-2-yl)boronic acid (38.85 mg, 0.350 mmol) in water (0.882 mL) was added and the mixture was degassed with N₂for 15 minutes. SPhos-Pd-G2 (12.51 mg, 0.020 mmol) was added and the mixture was stirred at 80° C. under N₂atmosphere for 3 hrs. Water was added and the mixture was extracted with EtOAc. The phases were separated and the organic solvent was evaporated under reduced pressure. The residue was purified by column chromatography (SiO₂, acetone in DCM [0%, 50%, 6 CV]). The appropriate fractions were collected and concentrated under reduced pressure. The residue was triturated with MeCN (1 mL) and then the solid was taken up in 1 mL of water and then concentrated and dried to obtain the product (37.1 mg, 0.108 mmol, 62.24% yield) as a yellow solid, which was further purified by reverse phase column chromatography (Cis-cartridge, MeCN in H₂O+0.1% HCOOH, [2%, 30%, 7 CV]) to afford the title compound (19.2 mg, 0.056 mmol, 32% yield) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.26 (s, 1H), 10.76 (s, 1H), 9.00 (d, J=1.9 Hz, 1H), 8.69-8.57 (m, 1H), 8.41 (dd, J=2.0, 0.9 Hz, 1H), 7.87 (dd, J=1.8, 0.8 Hz, 1H), 7.76 (dd, J=9.0, 1.9 Hz, 1H), 7.61-7.52 (m, 1H), 6.90 (dd, J=3.4, 0.8 Hz, 1H), 6.69 (dd, J=3.4, 1.8 Hz, 1H), 2.60 (s, 3H). MS-ESI (m/z) calc'd for C₁₉H₁₄N₅O₂[M+H]⁺: 344.1. Found 344.1.

Example 30: 5-Cyano-N-(3-(3-(dimethylamino)phenyl)-1H-indazol-5-yl)-3-methylpicolinamide

embedded image

5-Cyano-N-(3-iodo-1H-indazol-5-yl)-3-methylpicolinamide (70.0 mg, 0.170 mmol) was dissolved in 1,4-dioxane (3.529 mL). Then a solution of K₃PO₄(110.56 mg, 0.520 mmol) and [3-(dimethylamino)phenyl]boronic acid (57.29 mg, 0.350 mmol) in water (0.882 mL) was added and the mixture was degassed with N₂for 15 minutes. SPhos-Pd-G2 (12.51 mg, 0.020 mmol) was added and the mixture was stirred at 80° C., under N₂atmosphere, for 18 hrs. Water was added and the mixture was extracted with EtOAc. The phases were separated and the organic solvent was evaporated under reduced pressure. The residue (130 mg) was purified by semi-preparative HPLC (Method B). The batch obtained (26.1 mg) was further purified by reverse phase column chromatography (C₁₈-cartridge, MeCN in H₂O+0.1% HCOOH, [2%, 100%, 7 CV]) to afford the title compound (14.1 mg, 0.036 mmol, 20% yield) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.14 (s, 1H), 10.76 (s, 1H), 9.00 (d, J=1.9 Hz, 1H), 8.69 (d, J=1.8 Hz, 1H), 8.41 (dd, J=2.0, 0.9 Hz, 1H), 7.75 (dd, J=9.0, 1.9 Hz, 1H), 7.58 (d, J=8.9 Hz, 1H), 7.35 (t, J=7.9 Hz, 1H), 7.29 (dd, J=2.6, 1.4 Hz, 1H), 7.24 (dt, J=7.6, 1.2 Hz, 1H), 6.80 (ddd, J=8.4, 2.8, 1.0 Hz, 1H), 3.00 (s, 6H), 2.58 (s, 3H). MS-ESI (m/z) calc'd for C₂₃H₂₁N₆O [M+H]⁺: 397.2. Found 397.2.

Example 31: 5-Cyano-3-methyl-N-(3-(pyridin-4-yl)-1H-indazol-5-yl)picolinamide

embedded image

5-Cyano-N-(3-iodo-1H-indazol-5-yl)-3-methylpicolinamide (70.0 mg, 0.170 mmol) was dissolved in 1,4-dioxane (3.294 mL). Then a solution of K₃PO₄(110.56 mg, 0.520 mmol) and pyridin-4-ylboronic acid (32.01 mg, 0.260 mmol) in water (0.824 mL) was added and the mixture was degassed with N₂for 15 minutes. SPhos-Pd-G2 (12.51 mg, 0.020 mmol) was added and the mixture was stirred at 80° C., under N₂atmosphere for 2 hrs. Then, additional pyridin-4-ylboronic acid (60 mg) and SPhos-Pd-G2 (12.51 mg, 0.020 mmol) were added and the reaction was left stirring under N₂atmosphere at 80° C. for 18 hrs. Water was added and the mixture was extracted with EtOAc. The organic phase was separated, dried over Na₂SO₄, filtered and concentrated under reduced pressure. The residue (90 mg) was purified by semi-preparative HPLC (Method R) to afford the formic acid salt of the title compound (10.2 mg, 0.025 mmol, 15% yield) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.62 (s, 1H), 10.82 (s, 1H), 9.02 (d, J=1.9 Hz, 1H), 8.76-8.69 (m, 3H), 8.43 (dd, J=2.0, 0.9 Hz, 1H), 8.20 (s, 1H), 7.98-7.93 (m, 2H), 7.88 (dd, J=9.0, 1.9 Hz, 1H), 7.67 (d, J=9.0 Hz, 1H), 2.62 (s, 3H). MS-ESI (m/z) calc'd for C₂₀H₁₅N₆O [M+H]⁺: 355.1. Found 355.2.

Example 32: 5-Cyano-N-(3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-1H-indazol-5-yl)-3-methylpicolinamide

embedded image

Prepared as described for 5-cyano-3-methyl-N-(3-(3-(methylsulfonyl)phenyl)-1H-indazol-5-yl)picolinamide using (1-(difluoromethyl)-1H-pyrazol-4-yl)boronic acid in place of 3-(methylsulfonyl)phenyl)boronic acid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.20 (s, 1H) 10.73 (s, 1H) 9.01 (d, J=1.35 Hz, 1H) 8.74 (s, 1H) 8.43 (dd, J=9.48, 1.28 Hz, 2H) 8.30 (s, 1H) 7.78-8.09 (m, 2H) 7.58 (d, J=8.93 Hz, 1H) 2.61 (s, 3H). MS-ESI (m/z) calc'd for C₁₉H₁₄F₂N₇O [M+H]⁺: 394.1. Found 394.2.

Example 33: 5-cyano-3-methyl-N-(3-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)-1H-indazol-5-yl)picolinamide

embedded image

Prepared as described for 5-cyano-3-methyl-N-(3-(3-(methylsulfonyl)phenyl)-1H-indazol-5-yl)picolinamide using (1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)boronic acid in place of 3-(methylsulfonyl)phenyl)boronic acid. ¹H NMR (400 MHz, DMSO-d₆) δ 12.97 (s, 1H) 10.69 (s, 1H) 9.01 (d, J=1.47 Hz, 1H) 8.40-8.46 (m, 2H) 8.31 (s, 1H) 7.97 (s, 1H) 7.80-7.84 (m, 1H) 7.54 (d, J=8.93 Hz, 1H) 4.49-4.58 (m, 1H) 3.98-4.03 (m, 2H) 3.47-3.54 (m, 2H) 2.61 (s, 3H) 2.02-2.08 (m, 4H). MS-ESI (m/z) calc'd for C₂₃H₂₂N₇O₂[M+H]⁺: 428.2. Found 428.1.

Example 34: 5-Cyano-3-methyl-N-(3-(3-(methylsulfonyl)phenyl)-1H-indazol-5-yl)picolinamide

embedded image

Step 1: N-(3-bromo-1H-indazol-5-yl)-5-cyano-3-methylpicolinamide

embedded image

To a solution of 3-bromo-1H-indazol-5-amine (1.96 g, 9.25 mmol) and 5-cyano-3-methylpicolinic acid (1.5 g, 9.25 mmol) in pyridine (45 mL) was added EDCI (2.66 g, 13.88 mmol). The mixture was stirred at 25° C. for 12 hrs and monitored by TLC (petroleum ether:EtOAc=1:1, Rf=0.43). The reaction mixture was concentrated to give a residue. The residue was diluted with MeOH (300 mL) and filtered. The solid was washed with MeOH (200 mL) and dried to afford the title compound (2.5 g) as a white solid which was used without further purification.

Step 2: 5-Cyano-3-methyl-N-(3-(3-(methylsulfonyl)phenyl)-1H-indazol-5-yl)picolinamide

embedded image

A mixture of N-(3-bromo-1H-indazol-5-yl)-5-cyano-3-methylpicolinamide (70 mg, 197 umol), (3-(methylsulfonyl)phenyl)boronic acid (47 mg, 236 umol), Pd(Amphos)Cl₂(14 mg, 20 umol) and AcOK (58 mg, 590 umol) in EtOH (2 mL) and H₂O (0.5 mL) was degassed and purged with N₂(3×). The mixture was then stirred at 100° C. for 12 hrs under N₂atmosphere. The reaction mixture was concentrated under reduced pressure to remove solvent and the residue was purified by preparative HPLC (Method AH) to afford the title compound (49 mg, 88 umol, 45% yield, TFA salt) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.50 (s, 1H), 10.83 (s, 1H), 9.01 (d, J=1.5 Hz, 1H), 8.60 (s, 1H), 8.46 (s, 1H), 8.41 (d, J=1.2 Hz, 1H), 8.29 (d, J=7.8 Hz, 1H), 7.97 (d, J=8.1 Hz, 1H), 7.89-7.83 (m, 2H), 7.65 (d, J=9.0 Hz, 1H), 3.31 (s, 3H), 2.59 (s, 3H). MS-ESI (m/z) calc'd for C₂₂H₁₅N₅O₂S [M+H]⁺: 432.1. Found 432.0.

Example 35: 5-Cyano-3-methyl-N-(3-(4-(trifluoromethyl)phenyl)-1H-indazol-5-yl)picolinamide

embedded image

Prepared as described for 5-cyano-3-methyl-N-(3-(3-(methylsulfonyl)phenyl)-1H-indazol-5-yl)picolinamide using (4-(trifluoromethyl)phenyl)boronic acid in place of 3-(methylsulfonyl)phenyl)boronic acid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.50 (s, 1H), 10.81 (s, 1H), 9.01 (d, J=1.6 Hz, 1H), 8.66 (s, 1H), 8.41 (d, J=1.2 Hz, 1H), 8.18 (d, J=8.1 Hz, 2H), 7.91 (d, J=8.4 Hz, 2H), 7.84 (dd, J=1.7, 9.0 Hz, 1H), 7.64 (d, J=8.9 Hz, 1H), 2.60 (s, 3H). MS-ESI (m/z) calc'd for C₂₂H₁₅F₃N₅O [M+H]⁺: 422.1. Found 422.0.

Example 36: 5-Cyano-3-methyl-N-(3-(5-methylisoxazol-4-yl)-1H-indazol-5-yl)picolinamide

embedded image

Prepared as described for 5-cyano-3-methyl-N-(3-(3-(methylsulfonyl)phenyl)-1H-indazol-5-yl)picolinamide using (5-methylisoxazol-4-yl)boronic acid in place of 3-(methylsulfonyl)phenyl)boronic acid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.32 (s, 1H) 10.75 (s, 1H) 9.00 (s, 2H) 8.40 (dd, J=11, 1 Hz, 2H) 7.85 (dd, J=9, 2 Hz, 1H) 7.61 (d, J=9 Hz, 1H) 2.71 (s, 3H) 2.60 (s, 3H). MS-ESI (m/z) calc'd for C₁₉H₁₁N₆O₂[M+H]⁺: 359.1. Found 359.0.

Example 37: 5-Cyano-3-methyl-N-(3-(5-morpholinopyridin-3-yl)-1H-indazol-5-yl)picolinamide

embedded image

Prepared as described for 5-cyano-3-methyl-N-(3-(3-(methylsulfonyl)phenyl)-1H-indazol-5-yl)picolinamide using (5-morpholinopyridin-3-yl)boronic acid in place of 3-(methylsulfonyl)phenyl)boronic acid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.39 (br s, 1H), 10.79 (s, 1H), 9.00 (d, J=1.1 Hz, 1H), 8.66 (s, 1H), 8.61 (d, J=1.1 Hz, 1H), 8.44-8.35 (m, 2H), 7.84 (dd, J=1.2, 8.9 Hz, 1H), 7.75 (br s, 1H), 7.62 (d, J=9.0 Hz, 1H), 3.83-3.76 (m, 4H), 3.31-3.23 (m, 4H), 2.59 (s, 3H). MS-ESI (m/z) calc'd for C₂₄H₂₂N₇O₂[M+H]⁺: 440.2. Found 440.1.

Example 38: 5-Cyano-N-(3-(6-isopropoxypyridin-3-yl)-1H-indazol-5-yl)-3-methylpicolinamide

embedded image

Prepared as described for 5-cyano-3-methyl-N-(3-(3-(methylsulfonyl)phenyl)-1H-indazol-5-yl)picolinamide using (6-isopropoxypyridin-3-yl)boronic acid in place of 3-(methylsulfonyl)phenyl)boronic acid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.26 (br s, 1H), 10.77 (s, 1H), 9.00 (d, J=1.3 Hz, 1H), 8.72 (d, J=2.4 Hz, 1H), 8.62 (s, 1H), 8.41 (d, J=1.1 Hz, 1H), 8.20 (dd, J=2.4, 8.6 Hz, 1H), 7.82 (dd, J=1.8, 9.0 Hz, 1H), 7.59 (d, J=8.8 Hz, 1H), 6.93 (d, J=8.6 Hz, 1H), 5.34 (quin, J=6.2 Hz, 1H), 2.60 (s, 3H), 1.34 (d, J=6.2 Hz, 6H). MS-ESI (m/z) calc'd for C₂₃H₂₁N₆O₂[M+H]⁺: 413.2. Found 413.0.

Example 39: 5-Cyano-N-(3-(furan-3-yl)-1H-indazol-5-yl)-4-hydroxypicolinamide

embedded image

Step 1:5-Bromo-4-chloro-N-(3-(furan-3-yl)-1H-indazol-5-yl)picolinamide

embedded image

To a solution of 5-bromo-4-chloropicolinic acid (50 mg, 211.46 umol) and 3-(furan-3-yl)-1H-indazol-5-amine (42.12 mg, 211.46 umol) in pyridine (2 mL) was added EDCI (60.81 mg, 317.19 umol). The reaction mixture was stirred at 25° C. for 12 hrs. The reaction mixture was poured into water (5 mL) and extracted with dichloromethane (5 mL×3). The combined organic phases were washed with brine (5 mL×1), dried over anhydrous Na₂SO₄, filtered and concentrated. The residue was purified by column chromatography (SiO₂, petroleum ether/EtOAc=20/1 to 0/1) to afford the title compound (60 mg, 144 umol, 68% yield) as a green solid.

Step 2: 4-Chloro-5-cyano-N-(3-(furan-3-yl)-1H-indazol-5-yl))picolinamide

embedded image

To a solution of 5-bromo-4-chloro-N-(3-(furan-3-yl)-1H-indazol-5-yl)picolinamide (60 mg, 143.66 umol) and Zn(CN)₂(8.43 mg, 71.83 umol) in DMF (2 mL) was added Pd(PPh₃)₄(16.60 mg, 14.37 umol). The reaction mixture was stirred at 150° C. for 1 hr under N₂. The reaction mixture was filtered and the filtrate was concentrated. The residue was purified by preparative HPLC under neutral conditions (Method U) and further purified by preparative HPLC under TFA conditions (Method V) to afford the title compound (8.37 mg, 17.48 umol, 12% yield, TFA salt) as a yellow solid.

Step 3: 5-Cyano-N-(3-(furan-3-yl)-1H-indazol-5-yl)-4-hydroxypicolinamide

To a solution of 4-chloro-5-cyano-N-(3-(furan-3-yl)-1H-indazol-5-yl)picolinamide (70 mg, 146 umol, TFA salt) in DMSO (3 mL) was added CsF (67 mg, 439 umol, 16 uL). The reaction mixture was stirred at 120° C. for 12 hrs. The reaction mixture was filtered and the filtrate was concentrated. The residue was purified by preparative HPLC (Method W) to afford the title compound (5.98 mg, 17 umol, 12% yield) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.09 (s, 1H), 10.61 (s, 1H), 8.48 (s, 1H), 8.43 (s, 1H), 8.30 (s, 1H), 7.90 (br d, J=8.9 Hz, 1H), 7.84 (t, J=1.7 Hz, 1H), 7.55 (d, J=8.9 Hz, 1H), 7.26 (s, 1H), 7.01 (d, J=1.1 Hz, 1H). MS-ESI (m/z) calc'd for C₁₁H₁₉N₅O₃[M+H]⁺: 345.1. Found 345.5.

Example 40: 5-Cyano-3-methyl-N-(3-phenyl-1H-indazol-5-yl)picolinamide

embedded image

Prepared as described for 5-cyano-3-methyl-N-(3-(3-(methylsulfonyl)phenyl)-1H-indazol-5-yl)picolinamide using phenylboronic acid in place of 3-(methylsulfonyl)phenyl)boronic acid. ¹H NMR (400 MHz, DMSO-d₆) δ 10.76 (br s, 1H), 8.99 (d, J=1.4 Hz, 1H), 8.62 (d, J=1.3 Hz, 1H), 8.41-8.38 (m, 1H), 7.99-7.93 (m, 2H), 7.80 (dd, J=1.8, 8.9 Hz, 1H), 7.63-7.51 (m, 3H), 7.45-7.38 (m, 1H), 2.59 (s, 3H). MS-ESI (m/z) calc'd for C₂₁H₁₆N₅O [M+H]⁺: 354.1. Found 354.1.

Example 41: 5-Cyano-N-(3-(3-cyanophenyl)-1H-indazol-5-yl)-3-methylpicolinamide

embedded image

Prepared as described for 5-cyano-3-methyl-N-(3-(3-(methylsulfonyl)phenyl)-1H-indazol-5-yl)picolinamide using (3-cyanophenyl)boronic acid in place of 3-(methylsulfonyl)phenyl)boronic acid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.49 (br s, 1H), 10.81 (s, 1H), 9.01 (s, 1H), 8.58 (s, 1H), 8.42 (s, 1H), 8.35-8.26 (m, 2H), 7.91 (br dd, J=8.4, 17.3 Hz, 2H), 7.82-7.72 (m, 1H), 7.64 (br d, J=8.9 Hz, 1H), 2.60 (s, 3H). MS-ESI (m/z) calc'd for C₂₂H₁₅N₆O [M+H]⁺: 379.1. Found 379.1.

Example 42: 5-Cyano-N-(3-(5-cyanopyridin-3-yl)-1H-indazol-5-yl)-3-methylpicolinamide

embedded image

Prepared as described for 5-cyano-3-methyl-N-(3-(3-(methylsulfonyl)phenyl)-1H-indazol-5-yl)picolinamide using (5-cyanopyridin-3-yl)boronic acid in place of 3-(methylsulfonyl)phenyl)boronic acid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.68 (s, 1H), 10.82 (s, 1H), 9.43 (d, J=2.0 Hz, 1H), 9.06 (d, J=1.8 Hz, 1H), 9.01 (d, J=1.3 Hz, 1H), 8.75 (t, J=2.0 Hz, 1H), 8.61 (s, 1H), 8.42 (s, 1H), 7.96 (dd, J=1.5, 9.0 Hz, 1H), 7.67 (d, J=9.0 Hz, 1H), 2.61 (s, 3H). MS-ESI (m/z) calc'd for C₂₁H₁₄N₇O [M+H]⁺: 380.1. Found 380.1.

Example 43: 2-Cyano-1,4-dimethyl-N-(3-phenyl-1H-indazol-5-yl)-1H-imidazole-5-carboxamide

embedded image

Step 1: Ethyl 1,4-dimethyl-1H-imidazole-5-carboxylate

embedded image

To a solution of NaH (778.38 mg, 19.46 mmol, 60% purity) in DMF (25 mL) was added ethyl 5-methyl-1H-imidazole-4-carboxylate (2 g, 12.97 mmol) at 0° C. The mixture was stirred at 0° C. for 1 hr; MeI (2.76 g, 19.46 mmol, 1.21 mL) was then added at 0° C. The mixture was stirred at 25° C. for 12 hrs and monitored by TLC (CHCl₂:MeOH=10:1). The reaction mixture was quenched by addition of 10 mL of H₂O at 20° C. The mixture was then concentrated under reduced pressure to remove solvent. Then the mixture diluted with H₂O (30 mL) and extracted with EtOAc (50 mL×8). The combined organic layers were dried over Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO₂, petroleum ether/MeOH=1/0 to 0/1) to afford ethyl 1,5-dimethyl-1H-imidazole-4-carboxylate (1.8 g, 3.83 mmol, 30%/a yield) as an orange solid and the title compound (500 mg, 2.97 mmol, 23% yield) as a yellow oil.

Step 2: Ethyl 2-bromo-1,4-dimethyl-1H-imidazole-5-carboxylate

embedded image

To a solution of ethyl 1,4-dimethyl-1H-imidazole-5-carboxylate (500 mg, 2.97 mmol) in CH₃CN (15 mL) was added NBS (635 mg, 3.57 mmol). The mixture was stirred at 20° C. for 12 hrs and monitored by TLC (petroleum ether:EtOAc=5:1, Rf=0.50). The reaction mixture was concentrated under reduced pressure to remove solvent and purified by column chromatography (SiO₂, petroleum ether/EtOAc=I/O to 10/1) to afford the title compound (160 mg, 647 umol, 22% yield) as a yellow solid.

Step 3: Ethyl 2-cyano-1,4-dimethyl-1H-imidazole-5-carboxylate

embedded image

A mixture of ethyl 2-bromo-1,4-dimethyl-1H-imidazole-5-carboxylate (160 mg, 648 umol), Zn (5 mg, 78 umol), Zn(CN)₂(46 mg, 388 umol), dppf (14.36 mg, 26 umol) and Pd₂(dba)₃(11.86 mg, 13 umol) in DMA (4 mL) was degassed and purged with N₂(3×). The reaction mixture was stirred at 120° C. for 3 hrs under N₂atmosphere and monitored by TLC (petroleum ether:EtOAc=1:1, Rf=0.71). The reaction mixture was diluted with 20 mL H₂O and extracted with EtOAc (20 mL×3). The combined organic phases were dried with Na₂SO₄and concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO₂, petroleum ether:EtOAc=1:1, Rf=0.71) to afford the title compound (55 mg, 219 umol, 34% yield) as a yellow solid.

Step 4: 2-Ethynyl-1,4-dimethyl-1H-imidazole-5-carboxylic acid

embedded image

To solution of ethyl 2-cyano-1,4-dimethyl-1H-imidazole-5-carboxylate (50 mg, 259 umol) in THF (3 mL) was added a solution of LiOH.H₂O (21.72 mg, 518 umol) in H₂O (1 mL) at 0° C. The mixture was stirred at 0° C. for 1 hr and monitored by TLC (petroleum ether:EtOAc=1:1). Water (2 mL) was added and the reaction mixture was extracted with EtOAc (3 mL×4). The organic layer was discarded. The aqueous phase was then acidified with IN HCl to pH=1 and extracted with EtOAc (3 mL×4). This organic layer was dried over anhydrous Na₂SO₄, filtered and the filtrate was concentrated under vacuum to afford the title compound (40 mg) as a white solid which was used without further purification.

Step 5: 2-Cyano-1,4-dimethyl-N-(3-phenyl-1H-indazol-5-v)-1H-imidazole-5-carboxamide

To a solution of 2-ethynyl-1,4-dimethyl-1H-imidazole-5-carboxylic acid (40 mg, 242.21 umol) and 3-phenyl-1H-indazol-5-amine (50.68 mg, 242 umol) in DMF (2 mL) was added DIEA (93.91 mg, 726.62 umol), EDCI (55.72 mg, 290 umol) and HOBt (39.27 mg, 290 umol). The mixture was stirred at 20° C. for 12 hrs. The reaction mixture was concentrated under reduced pressure to remove solvent and purified by preparative HPLC (Method AH) to afford the title compound (23 mg, 49 umol, 20% yield, TFA salt) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.28 (br s, 1H), 10.48 (s, 1H), 8.52 (s, 1H), 7.95-7.92 (m, 2H), 7.66-7.60 (m, 2H), 7.55 (t, J=7.6 Hz, 2H), 7.44-7.40 (m, 1H), 3.91 (s, 3H), 2.38 (s, 3H). MS-ESI (m/z) calc'd for C₂₀H₁₇N₆O [M+H]⁺: 357.1. Found 357.1.

Example 44: 5-Cyano-N-(3-(furan-3-yl)-1H-indazol-5-yl)-3,6-dimethylpicolinamide

embedded image

Step 1: 3-Bromo-2,5-dimethyl-6-vinylpyridine

embedded image

A solution of 2,5-dibromo-3,6-dimethylpyridine (1.32 g, 5 mmol) and tributyl(vinyl)tin (1.46 mL, 5 mmol) in toluene (25 mL) was sparged with N₂for 10 minutes. Tetrakis(triphenylphosphine)palladium(0) (0.29 g, 0.250 mmol) was then added and the mixture was stirred at 100° C. under N₂for 3 hrs. The solvent was evaporated and the residue was purified by column chromatography (SiO₂, 25 g, EtOAc in cyclohexane [0%, 10%, 10 CV]) to afford the title compound (1.06 g, 5 mmol, 100% yield) as a clear oil. ¹H NMR (400 MHz, DMSO-d₆) δ 7.83 (s, 1H), 6.95 (dd, J=16.9, 10.6 Hz, 1H), 6.28 (dd, J=16.9, 2.5 Hz, 1H), 5.49 (dd, J=10.7, 2.5 Hz, 1H), 2.53 (s, 3H), 2.29 (d, J=1.1 Hz, 3H). MS-ESI (m/z) calc'd for C₉H₁₁BrN [M+H]⁺: 212.0, 214.0. Found 211.9, 213.9.

Step 2: 5-Bromo-3,6-dimethylpicolinic acid

embedded image

To a solution of 5-bromo-2-ethenyl-3,6-dimethylpyridine (1.06 g, 5 mmol) in acetone (25 mL) was added a solution of potassium permanganate (1.74 g, 11 mmol) in water (25 mL) and the mixture was stirred at 25° C. for 2 days. Excess permanganate was quenched by addition of formic acid and the solid was filtered and dried. The solid was taken up in water and extracted with EtOAc (3×). The combined organic layers were passed through a phase separator and evaporated to afford the title compound (900 mg, 3.912 mmol, 78% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.22 (s, 1H), 8.01 (s, 1H), 2.55 (s, 3H), 2.39 (s, 3H). MS-ESI (m/z) calc'd for C₈H₉BrNO₂[M+H]⁺: 230.0, 232.0. Found 229.9, 231.9.

Step 3: Methyl 5-bromo-3,6-dimethylpicolinate

embedded image

To a solution of 5-bromo-3,6-dimethylpicolinic acid (900.0 mg, 3.91 mmol) in DMF (6.52 mL) was added potassium carbonate (1.62 g, 11.74 mmol) and iodomethane (0.49 mL, 7.82 mmol). The mixture was stirred at 80° C. for 1 hr and then poured into water (150 mL) and stirred for 10 minutes. The solid formed was filtered and dried under vacuum to afford the title compound (833 mg, 3.413 mmol, 87% yield) as a brown solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.08 (s, 1H), 3.85 (s, 3H), 2.56 (s, 3H), 2.40 (s, 3H). MS-ESI (m/z) calc'd for C₉H₁₁BrNO₂[M+H]⁺: 244.0, 246.0. Found 243.9, 245.9.

Step 4: Methyl 3,6-dimethyl-5-vinylpicolinate

embedded image

A solution of methyl 5-bromo-3,6-dimethylpicolinate (0.83 g, 3.41 mmol) and tributyl(vinyl)tin (1.99 mL, 6.83 mmol) in 1,4-dioxane (34.13 mL) was sparged with N₂for 15 minutes. Bis(triphenylphosphine)palladium chloride (0.24 g, 0.340 mmol) was added and the mixture was stirred at 100° C. under N₂for 2 hrs. The solvent was evaporated and the residue was purified by column chromatography (SiO₂, 50 g, EtOAc in cyclohexane [0%, 0%, 4 CV; 0%, 20%, 10 CV]) to afford the title compound (460 mg, 2.405 mmol, 70% yield) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 7.88 (s, 1H), 6.94 (dd, J=17.5, 11.2 Hz, 1H), 5.92 (dd, J=17.4, 1.2 Hz, 1H), 5.52 (dd, J=11.0, 1.1 Hz, 1H), 3.84 (s, 3H), 2.49 (s, 3H), 2.42 (s, 3H). MS-ESI (m/z) calc'd for C₁₁H₁₄NO₂[M+H]⁺: 192.1. Found 192.0.

Step 5: Methyl 5-formyl-3,6-dimethylpicolinate

embedded image

To a solution of methyl 3,6-dimethyl-5-vinylpicolinate (460.0 mg, 2.41 mmol) in 1,4-dioxane (12.03 mL) was added a solution of sodium periodate (1.03 g, 4.81 mmol) in water (12.03 mL) and the mixture was stirred at 25° C. for 5 minutes. Osmium tetroxide (4 wt % in water) (766.08 uL, 0.120 mmol) was added and the reaction mixture was stirred for 1 hr. The mixture was diluted with water and extracted with DCM (3×). The combined organic layers were passed through a phase separator and evaporated to afford the title compound (464.75 mg, 2.406 mmol, 100% yield) as a dark solid. ¹H NMR (400 MHz, DMSO-d₆) δ 10.27 (s, 1H), 8.15 (s, 1H), 3.89 (s, 3H), 2.76 (s, 3H), 2.44 (t, J=0.7 Hz, 3H). MS-ESI (m/z) calc'd for C₁₀H₁₂NO₃[M+H]⁺: 194.1. Found 193.9.

Step 6: Methyl 5-cyano-3,6-dimethylpicolinate

embedded image

To a solution of methyl 5-formyl-3,6-dimethylpicolinate (464.75 mg, 2.41 mmol) in DMSO (2.406 mL) was added hydroxylamine hydrochloride (183.88 mg, 2.65 mmol) and the mixture was stirred at 90° C. for 4 hrs. Water was added and the mixture was extracted with EtOAc (3×).

The combined organic layers were washed with water (3×), passed through a phase separator and evaporated to afford the title compound (380 mg, 1.998 mmol, 83% yield) as a purple solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.30 (s, 1H), 3.89 (s, 3H), 2.65 (s, 3H), 2.41 (s, 3H). MS-ESI (m/z) calc'd for C₁₀H₁₁N₂O₂[M+H]⁺: 191.1. Found 191.0.

Step 7: 5-Cyano-3,6-dimethylpicolinic acid

embedded image

To a solution of methyl 5-cyano-3,6-dimethylpicolinate (380.0 mg, 2 mmol) in THF (10 mL) was added a solution of sodium hydroxide (81.93 mg, 2 mmol) in water (5 mL) and the mixture was stirred at 25° C. for 2 hrs. The THF was evaporated and the solution was extracted with Et₂O. The aqueous layer was acidified by addition of 1M HCl and extracted with EtOAc (6×). The combined organic layers were passed through a phase separator and evaporated to afford the title compound (260 mg, 1.476 mmol, 74% yield) as a grey-purple solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.68 (s, 1H), 8.25 (s, 1H), 2.65 (s, 3H), 2.39 (s, 3H). MS-ESI (m/z) calc'd for C₉H₉N₂O₂[M+H]⁺: 177.1. Found 177.0.

Step 8: 5-Cyano-N-(3-(furan-3-yl)-1H-indazol-5-yl)-3,6-dimethylpicolinamide

embedded image

To a solution of 5-cyano-3,6-dimethylpicolinic acid (35.23 mg, 0.200 mmol) and triethylamine (27.88 uL, 0.200 mmol) in MeCN (2 mL) was added HATU (76.05 mg, 0.200 mmol) and the mixture was stirred at 25° C. for 15 minutes. This solution was then added to a suspension of 3-(furan-3-yl)-1H-indazol-5-amine (39.84 mg, 0.200 mmol) in MeCN (2 mL) and the mixture was stirred at 25° C. for 30 minutes, then poured into water. The solid formed was filtered under vacuum. The residue was purified by column chromatography (NH, 11 g, MeOH in DCM [0%, 5%, 10 CV]) to afford the title compound (46 mg, 0.129 mmol, 64% yield) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.10 (s, 1H), 10.63 (s, 1H), 8.41-8.37 (m, 1H), 8.31 (s, 1H), 8.26 (dd, J=1.6, 0.8 Hz, 1H), 7.85 (t, J=1.7 Hz, 1H), 7.78 (dd, J=9.0, 1.9 Hz, 1H), 7.56 (d, J=9.1 Hz, 1H), 7.00 (dd, J=1.9, 0.8 Hz, 1H), 2.76 (s, 3H), 2.54 (s, 3H). MS-ESI (m/z) calc'd for C₂₀H₁₆N₅O₂[M+H]⁺: 358.1. Found 358.1.

Example 45: 5-Cyano-3-methyl-N-(3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-indazol-5-yl)picolinamide

embedded image

To a suspension of 5-cyano-N-(3-iodo-1H-indazol-5-yl)-3-methylpicolinamide (75.0 mg, 0.190 mmol) in 1,4-dioxane (3.72 mL) was added a solution of tripotassium phosphate (118.46 mg, 0.560 mmol) and (4-(4-methylpiperazin-1-yl)phenyl)boronic acid (53.22 mg, 0.240 mmol) in water (0.930 mL). The mixture was then degassed with N₂for 15 minutes. SPhos-Pd-G2 (13.41 mg, 0.020 mmol) was added and the mixture was stirred at 80° C. under N₂for 15 hrs. The solvent was evaporated and the residue was taken up in water and extracted with EtOAc (3×). The combined organic layers were passed through a phase separator and evaporated to afford a residue which was passed through a 2 g SCX ion exchange cartridge to obtain a dark yellow solid which was purified by column chromatography (NH, 11 g, acetone in DCM [0%, 10%, 10 CV]) to afford a yellow solid. This solid was further purified by prep HPLC (Method T) to afford the title compound (17 mg, 0.038 mmol, 20% yield) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.02 (s, 1H), 10.73 (s, 1H), 9.00 (d, J=2.0 Hz, 1H), 8.59 (d, J=1.9 Hz, 1H), 8.40 (dd, J=2.0, 0.9 Hz, 1H), 7.80 (d, J=8.7 Hz, 2H), 7.75 (dd, J=9.0, 1.9 Hz, 1H), 7.54 (d, J=8.9 Hz, 1H), 7.10 (d, J=8.9 Hz, 2H), 3.26-3.19 (m, 4H), 2.59 (s, 3H), 2.49-2.45 (m, 4H), 2.24 (s, 3H). MS-ESI (m/z) calc'd for C₂₆H₂₆N₇O [M+H]⁺: 452.2. Found 452.2.

Example 46: 5-Cyano-N-(3-(3-fluoro-5-methoxyphenyl)-1H-indazol-5-yl)-3-methylpicolinamide

embedded image

To a suspension of 5-cyano-N-(3-iodo-1H-indazol-5-yl)-3-methylpicolinamide (70.0 mg, 0.170 mmol) in 1,4-dioxane (3.48 mL) was added a solution of tripotassium phosphate (112.14 mg, 0.520 mmol) and 3-fluoro-5-methoxybenzeneboronic acid (38.36 mg, 0.230 mmol) in water (0.800 mL) and the mixture was degassed with N₂for 15 minutes. SPhos-Pd-G2 (12.51 mg, 0.020 mmol) was added and the mixture was stirred at 80° C. under N₂for 15 hrs. The solvent was evaporated and the residue was taken up in water and extracted with EtOAc (3×). The combined organic layers were passed through a phase separator and evaporated to obtain a residue that was purified by preparative HPLC (Method J) to afford the title compound (9.2 mg, 0.023 mmol, 13% yield) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 13.39 (br. s., 1H), 10.81 (s, 1H), 9.01 (d, J=1.54 Hz, 1H), 8.62 (d, J=1.32 Hz, 1H), 8.38-8.44 (m, 1H), 7.89 (dd, J=9.02, 1.76 Hz, 1H), 7.63 (d, J=9.02 Hz, 1H), 7.27-7.39 (m, 2H), 6.90 (dt, J=11.11, 2.26 Hz, 1H), 3.89 (s, 3H), 2.60 (s, 3H). MS-ESI (m/z) calc'd for C₂₂H₁₇N₅O₂[M+H]⁺: 402.1. Found 402.2.

Example 47: 5-Cyano-N-(3-(4-methoxyphenyl)-1H-indazol-5-yl)-3-methylpicolinamide

embedded image

To a suspension of 5-cyano-N-(3-iodo-1H-indazol-5-yl)-3-methylpicolinamide (70.0 mg, 0.170 mmol) in 1,4-dioxane (3.472 mL) was added a solution of tripotassium phosphate (110.56 mg, 0.520 mmol) and (4-methoxyphenyl)boronic acid (34.3 mg, 0.230 mmol) in water (0.868 mL). The mixture was then degassed with N₂for 15 minutes. SPhos-Pd-G2 (12.51 mg, 0.020 mmol) was added and the mixture was stirred at 80° C. under N₂for 15 hrs. The solvent was evaporated and the residue was taken up in water and extracted with EtOAc (3×). The combined organic layers were passed through a phase separator and evaporated to obtain a residue which was purified by column chromatography (SiO₂, 10 g, acetone in DCM [0%, 10%, 15 CV]) to give a yellow solid which was further purified by prep HPLC (method I) to afford the title compound (17 mg, 0.044 mmol, 26% yield) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.10 (s, 1H), 10.74 (s, 1H), 9.00 (dd, J=2.0, 0.6 Hz, 1H), 8.59 (dd, J=1.9, 0.7 Hz, 1H), 8.40 (dd, J=2.0, 0.8 Hz, 1H), 7.88 (d, J=8.8 Hz, 2H), 7.77 (dd, J=8.9, 1.9 Hz, 1H), 7.56 (d, J=9.0 Hz, 1H), 7.12 (d, J=8.8 Hz, 2H), 3.83 (s, 3H), 2.59 (d, J=0.7 Hz, 3H). MS-ESI (m/z) calc'd for C₂₂H₁₈N₅O₂[M+H]⁺: 384.1. Found 384.2.

Example 48: 5-Cyano-N-(3-(2-methoxypyridin-4-yl)-1H-indazol-5-yl)-3-methylpicolinamide

embedded image

To a suspension of 5-cyano-N-(3-iodo-1H-indazol-5-yl)-3-methylpicolinamide (75.0 mg, 0.190 mmol) and 2-methoxypyridine-4-boronic acid (36.99 mg, 0.240 mmol) in 1,4-dioxane (4 mL) was added a solution of tripotassium phosphate (118.46 mg, 0.560 mmol) in water (1 mL) and the mixture was degassed with N₂for 5 minutes. SPhos-Pd-G2 (13.41 mg, 0.020 mmol) was added and the mixture was stirred at 80° C. under N₂for 16 hrs. Another 37 mg of 2-methoxypyridine-4-boronic acid and 13.41 mg of SPhos-Pd-G2 were added under N₂and the mixture was stirred at 80° C. for an additional 24 hrs. The reaction mixture was partitioned between water and EtOAc, the phases were separated, the aqueous layer was extracted with EtOAc (2×) and the combined organic phases were washed with brine (1×), dried over anhydrous Na₂SO₄and evaporated to dryness. The material was purified by normal phase chromatography on a 25 g silica gel column using a 0-50% EtOAc/cyclohexane gradient eluent. The purest fractions were combined, evaporated to dryness and the residue purified again by reversed phase chromatography on a 12 g C18 cartridge using a 5-55% MeCN/H₂O (0.1% formic acid) gradient eluent to afford the title compound (16.5 mg, 23% yield) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 13.58 (br. s., 1H) 10.83 (s, 1H) 9.02 (d, J=1.54 Hz, 1H) 8.69 (d, J=1.32 Hz, 1H) 8.42 (d, J=1.10 Hz, 1H) 8.31 (d, J=5.28 Hz, 1H) 7.91 (dd, J=9.13, 1.87 Hz, 1H) 7.66 (d, J=9.02 Hz, 1H) 7.59 (dd, J=5.39, 1.43 Hz, 1H) 7.33 (s, 1H) 3.94 (s, 3H) 2.62 (s, 3H). MS-ESI (m/z) calc'd for C₂₁H₁₇N₆O₂[M+H]⁺: 385.1. Found 385.2.

Example 49: 6-Cyano-N-(3-(furan-3-yl)-1H-indazol-5-yl)-4-methylnicotinamide

embedded image

To a mixture of 6-cyano-4-methylpyridine-3-carboxylic acid (32.43 mg, 0.200 mmol), 3-(furan-3-yl)-1H-indazol-5-amine (39.84 mg, 0.200 mmol) and triethylamine (27.88 uL, 0.200 mmol) in MeCN (2 mL) was added HATU (76.05 mg, 0.200 mmol). The mixture was then stirred at 25° C. for 15 h. The reaction mixture was poured into 1M NaOH (10 mL) and extracted with EtOAc (3×). The combined organic layers were passed through a phase separator and evaporated to give a yellow residue which was purified by reversed phase column chromatography using a 0-5% MeOH/DCM gradient eluent over 10 CV to afford the title compound (20 mg, 29% yield) as a pale yellow solid. ¹H NMR (400 MHz, DMSO-d₄) δ 13.12 (s, 1H), 10.69 (s, 1H), 8.86 (s, 1H), 8.38 (dd, J=1.7, 0.8 Hz, 1H), 8.21 (t, J=1.2 Hz, 1H), 8.11 (d, J=0.9 Hz, 1H), 7.85 (t, J=1.7 Hz, 1H), 7.63 (dd, J=8.9, 1.8 Hz, 1H), 7.57 (d, J=8.9 Hz, 1H), 6.99 (dd, J=1.8, 0.8 Hz, 1H), 2.51 (s, 3H). MS-ESI (m/z) calc'd for C₁₉H₁₄N₅O₂[M+H]⁺: 344.1. Found 344.1.

Example 50: 5-Cyano-3-methyl-N-(3-(pyridin-3-yl)-1H-indazol-5-yl)picolinamide

embedded image

5-Cyano-N-(3-iodo-1H-indazol-5-yl)-3-methylpicolinamide (75.0 mg, 0.190 mmol) was dissolved in 1,4-dioxane (3.529 mL). Then a solution of K₃PO₄(118.46 mg, 0.560 mmol) and pyridin-3-ylboronic acid (29.73 mg, 0.240 mmol) in water (0.882 mL) was added and the mixture was degassed with N₂for 15 minutes. SPhos-Pd-G2 (13.41 mg, 0.020 mmol) was added and the mixture was stirred at 80° C. under N₂atmosphere for 2 hrs. Then additional 3-pyridinylboronic acid (60 mg) and SPhos-Pd-G2 (13.41 mg, 0.020 mmol) were added and the reaction was stirred for 18 hrs. Water was added and the mixture was extracted with EtOAc (2×). The organic phases were collected, dried over Na₂SO₄, filtered and evaporated. The residue was purified by silica gel column chromatography using a 0-30% MeOH/DCM gradient eluent over 12 CV to obtain 49 mg of a yellow solid. To remove trace impurities the solid was triturated with 1 mL of MeCN and the solid was taken up in 1 mL of water and concentrated and dried to afford 23 mg of a solid which was further purified by reversed phase column chromatography using 2-100% MeCN/H₂O (0.1% HCOOH) gradient eluent over 7 CV to afford the title compound (15.5 mg, 24% yield) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.46 (s, 1H), 10.80 (s, 1H), 9.18 (d, J=2.3, 0.9 Hz, 1H), 9.01 (d, J=2.0 Hz, 1H), 8.67 (d, J=1.8 Hz, 1H), 8.63 (dd, J=4.8, 1.6 Hz, 1H), 8.42 (dd, J=1.9, 0.9 Hz, 1H), 8.32 (dt, J=8.0, 1.9 Hz, 1H), 7.86 (dd, J=9.0, 1.9 Hz, 1H), 7.64 (d, J=8.9 Hz, 1H), 7.59 (ddd, J=7.9, 4.7, 0.9 Hz, 1H), 2.61 (s, 3H). MS-ESI (m/z) calc'd for C₂₀H₁₅N₆O [M+H]⁺: 355.1. Found 355.2.

Example 51: 5-Cyano-N-(3-(4-fluoro-3-methylphenyl)-1H-indazol-5-yl)-3-methylpicolinamide

embedded image

To a suspension of 5-cyano-N-(3-iodo-1H-indazol-5-yl)-3-methylpicolinamide (70.0 mg, 0.170 mmol) in 1,4-dioxane (3.472 mL) was added a solution of tripotassium phosphate (110.56 mg, 0.520 mmol) and (4-fluoro-3-methylphenyl)boronic acid (34.75 mg, 0.230 mmol) in water (0.868 mL). The mixture was then degassed with N₂for 15 minutes. SPhos-Pd-G2 (12.51 mg, 0.020 mmol) was added and the mixture was stirred at 80° C. under N₂for 15 hrs. The solvent was evaporated, the residue was taken up in water and extracted with EtOAc (3×). The combined organic layers were passed through a phase separator and evaporated to obtain a residue which was purified by silica gel column chromatography using a 0-20% acetone/DCM gradient eluent over 15 CV to give a solid (60 mg) which was further purified by preparative HPLC (method H) to afford the title compound (21 mg, 31% yield) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.23 (s, 1H), 10.75 (s, 1H), 9.02-8.97 (m, 1H), 8.53 (d, J=1.8 Hz, 1H), 8.41 (dd, J=2.0, 0.9 Hz, 1H), 7.84 (td, J=8.8, 2.1 Hz, 2H), 7.78 (ddd, =8.0, 5.1, 2.3 Hz, 1H), 7.59 (d, J=9.0 Hz, 1H), 7.35-7.28 (m, 1H), 2.59 (s, 3H), 2.35 (d, J=1.9 Hz, 3H). MS-ESI (m/z) calc'd for C₂₂H₁₇FN₅O [M+H]⁺: 386.1. Found 386.2.

Example 52: 5-Cyano-N-(3-(6-methoxypyridin-3-yl)-1H-indazol-5-yl)-3-methylpicolinamide

embedded image

5-Cyano-N-(3-iodo-1H-indazol-5-yl)-3-methylpicolinamide (70.0 mg, 0.170 mmol) was dissolved in 1,4-dioxane (3.294 mL). Then a solution of K₃PO₄(110.56 mg, 0.520 mmol) and (6-methoxypyridin-3-yl)boronic acid (39.83 mg, 0.260 mmol) in water (0.824 mL) was added and the mixture was degassed with N₂for 15 minutes. SPhos-Pd-G2 (12.51 mg, 0.020 mmol) was added and the mixture was stirred at 80° C., under N₂atmosphere, for 2 hrs. Then another portion of (6-methoxypyridin-3-yl)boronic acid (39.83 mg, 0.260 mmol) and SPhos-Pd-G2 (12.51 mg, 0.020 mmol) were added and the reaction was stirred for 18 hrs. Water was added and the mixture was extracted with EtOAc. The phases were separated and the organic solvent was evaporated. The residue was purified by silica gel column chromatography using a 0-50% acetone/DCM gradient eluent over 6 CV. Product-containing fractions were collected and concentrated under reduced pressure. The residue was triturated with 1 mL of MeCN and then the solid was taken up in 1 mL of water and concentrated and dried to afford the title compound (26.1 mg, 39% yield) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.28 (s, 1H), 10.77 (s, 1H), 9.01 (dd, J=2.0, 0.8 Hz, 1H), 8.75 (dd, J=2.4, 0.8 Hz, 1H), 8.64 (dd, J=2.0, 0.7 Hz, 1H), 8.42 (dd, J=2.0, 0.8 Hz, 1H), 8.24 (dd, J=8.6, 2.4 Hz, 1H), 7.81 (dd, J=9.0, 1.9 Hz, 1H), 7.61 (d, J=9.0, 0.7 Hz, 1H), 7.02 (dd, J=8.6, 0.8 Hz, 1H), 3.95 (s, 3H), 2.61 (d, J=0.8 Hz, 3H). MS-ESI (m/z) calc'd for C₂₁H₁₇N₆O₂[M+H]⁺: 385.1. Found 385.1.

Example 53: 5-Cyano-N-(3-(3-methoxyphenyl)-1H-indazol-5-yl)-3-methylpicolinamide

embedded image

To a suspension of 5-cyano-N-(3-iodo-1H-indazol-5-yl)-3-methylpicolinamide (70.0 mg, 0.170 mmol) in 1,4-dioxane (3.5 mL) was added a solution of tripotassium phosphate (110.56 mg, 0.520 mmol) and (3-methoxyphenyl)boronic acid (34.3 mg, 0.230 mmol) in water (0.868 mL) and the mixture was degassed with N₂for 15 minutes. SPhos-Pd-G2 (12.51 mg, 0.020 mmol) was added and the mixture was stirred at 80° C. under N₂for 15 hrs. The solvent was evaporated and the residue was taken up in water and extracted with EtOAc (3×). The combined organic layers were passed through a phase separator and evaporated and the material was purified by preparative HPLC (Method L) to afford crude product (14.2 mg, 0.037 mmol, 21% yield) that was re-purified by chiral chromatography to afford the title compound (6.7 mg, 10% yield) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 13.25 (br. s, 1H), 10.75 (br. s, 1H), 9.01 (d, J=1.32 Hz, 1H), 8.64 (d, J=1.32 Hz, 1H), 8.41 (d, J=1.10 Hz, 1H), 7.83 (dd, J=9.02, 1.76 Hz, 1H), 7.60 (d, J=9.24 Hz, 1H), 7.52-7.57 (m, 1H), 7.44-7.51 (m, 2H), 6.94-7.03 (m, 1H), 3.87 (s, 3H), 2.60 (s, 3H). MS-ESI (m/z) calc'd for C₂₂H₁₈N₅O₂[M+H]⁺: 384.1. Found 384.2.

Example 54: 5-Cyano-3-methyl-N-(3-(3-(trifluoromethoxy)phenyl)-1H-indazol-5-yl)picolinamide

embedded image

To a suspension of 5-cyano-N-(3-iodo-1H-indazol-5-yl)-3-methylpicolinamide (70.0 mg, 0.170 mmol) in 1,4-dioxane (3.472 mL) was added a solution of tripotassium phosphate (110.56 mg, 0.520 mmol) and [3-(trifluoromethoxy)phenyl]boronic acid (46.48 mg, 0.230 mmol) in water (0.868 mL). The mixture was then degassed with N₂for 15 minutes. SPhos-Pd-G2 (12.51 mg, 0.020 mmol) was added and the mixture was stirred at 80° C. under N₂for 15 hrs. The solvent was evaporated and the residue was taken up in water and extracted with EtOAc (3×). The combined organic layers were passed through a phase separator and evaporated to obtain a residue which was purified by silica gel column chromatography using a 0-20% acetone/DCM gradient eluent over 15 CV to give a yellow solid (70 mg) which was further purified by preparative HPLC (method H) to obtain the title compound (35.3 mg, 46.49% yield) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₄) δ 13.44 (s, 1H), 10.80 (s, 1H), 9.00 (d, J=1.9 Hz, 1H), 8.62 (d, J=1.8 Hz, 1H), 8.41 (dd, J=2.0, 0.8 Hz, 1H), 8.04-7.96 (m, 1H), 7.90-7.81 (m, 2H), 7.70 (t, J=8.0 Hz, 1H), 7.63 (d, J=9.0 Hz, 1H), 7.41 (ddt, J=8.2, 2.4, 1.0 Hz, 1H), 2.59 (s, 3H). MS-ESI (m/z) calc'd for C₂₂H₁₅F₃N₅O₂[M+H]⁺: 438.1. Found 438.1.

Example 55: 5-Cyano-3-methyl-N-(3-(6-methylpyridin-3-yl)-1H-indazol-5-yl)picolinamide

embedded image

To a suspension of 5-cyano-N-(3-iodo-1H-indazol-5-yl)-3-methylpicolinamide (75.0 mg, 0.190 mmol) in 1,4-dioxane (3.72 mL) was added a solution of tripotassium phosphate (118.46 mg, 0.560 mmol) and (6-methylpyridin-3-yl)boronic acid (33.12 mg, 0.240 mmol) in water (0.930 mL). The mixture was then degassed with N₂for 15 minutes. SPhos-Pd-G2 (13.41 mg, 0.020 mmol) was added and the mixture was stirred at 80° C. under N₂for 15 h. The solvent was evaporated and the residue was taken up in water and extracted with EtOAc (3×). The combined organic layers were passed through a phase separator and evaporated to give crude material which was purified by preparative HPLC (method F) to afford the title compound (15 mg, 22% yield) as an orange solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.38 (s, 1H), 10.78 (s, 1H), 9.03 (d, J=2.3 Hz, 1H), 9.00 (d, J=1.9 Hz, 1H), 8.64 (d, J=1.8 Hz, 1H), 8.41 (dd, J=2.0, 0.9 Hz, 1H), 8.19 (dd, J=8.0, 2.3 Hz, 1H), 7.82 (dd, J=9.0, 1.9 Hz, 1H), 7.62 (d, J=8.9 Hz, 1H), 7.44 (d, J=8.1 Hz, 1H), 2.60 (s, 3H), 2.55 (s, 3H). MS-ESI (m/z) calc'd for C₂₁H₁₇N₆O [M+H]⁺: 369.1. Found 369.2.

Example 56: 5-Cyano-3-methyl-N-(3-(p-tolyl)-1H-indazol-5-yl)picolinamide

embedded image

5-cyano-N-(3-iodo-1H-indazol-5-yl)-3-methylpyridine-2-carboxamide (70.0 mg, 0.170 mmol) was suspended in 1,4-dioxane (3.5 mL). A solution of tripotassium phosphate (110.56 mg, 0.520 mmol) and (4-methylphenyl)boronic acid (30.69 mg, 0.230) in water (0.8 ml) was added and the mixture was degassed with N₂for 15 minutes. S-Phos-Pd-G2 (12.51 mg, 0.020 mmol) was added and the mixture was stirred at 80° C. under N₂for 15 hrs. The solvent was evaporated; the residue was taken up in water and extracted with EtOAc (3×). The combined organic layers were passed through a phase separator and evaporated to obtain crude material that was purified by prep. HPLC (Method K) to afford the title compound (8.8 mg, 14% yield) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 13.20 (br. s., 1H), 10.76 (s, 1H), 9.01 (d, J=1.54 Hz, 1H), 8.61 (s, 1H), 8.41 (d, J=1.10 Hz, 1H), 7.85 (d, J=8.14 Hz, 2H), 7.80 (dd, J=8.91, 1.65 Hz, 1H), 7.59 (d, J=9.02 Hz, 1H), 7.36 (d, J=7.92 Hz, 2H), 2.60 (s, 3H), 2.39 (s, 3H). MS-ESI (m/z) calc'd for C₂₂H₁₅N₅O [M+H]⁺: 368.1. Found 368.2.

Example 57: 5-Cyano-3-methyl-N-(3-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-5-yl)picolinamide

embedded image

To a suspension of 5-cyano-N-(3-iodo-1H-indazol-5-yl)-3-methylpicolinamide (75.0 mg, 0.190 mmol) and 1-methyl-1H-pyrazole-4-boronic acid (30.45 mg, 0.240 mmol) in 1,4-dioxane (4 mL) was added a solution of tripotassium phosphate (118.46 mg, 0.560 mmol) in water (1 mL) and the mixture was degassed with N₂for 5 minutes. SPhos-Pd-G2 (13.41 mg, 0.020 mmol) was added and the mixture was stirred at 80° C. under N₂for 16 hrs. The reaction mixture was partitioned between water and EtOAc, the phases were separated, the aqueous layer was extracted with EtOAc (2×) and the combined organic phases washed with brine (1×), dried over anhydrous Na₂SO₄and evaporated to dryness. The crude material was purified by normal phase chromatography on a 25 g silica gel column using a 0-70% EtOAc/cyclohexane gradient eluent to afford the title compound (12.5 mg, 19% yield) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 12.95 (s, 1H) 10.70 (s, 1H) 9.01 (d, J=1.32 Hz, 1H) 8.38-8.47 (m, 2H) 8.22 (s, 1H) 7.93 (s, 1H) 7.80 (dd, J=9.02, 1.76 Hz, 1H) 7.54 (d, J=8.80 Hz, 1H) 3.96 (s, 3H) 2.62 (s, 3H). MS-ESI (m/z) calc'd for C9H₁₆N₇O [M+H]⁺: 358.1. Found 358.1.

Example 58: 5-Cyano-3-methyl-N-(3-(m-tolyl)-1H-indazol-5-yl)picolinamide

embedded image

To a suspension of 5-cyano-N-(3-iodo-1H-indazol-5-yl)-3-methylpicolinamide (70.0 mg, 0.170 mmol) in 1,4-dioxane (3.472 mL) was added a solution of tripotassium phosphate (110.56 mg, 0.520 mmol) and (3-methylphenyl)boronic acid (30.69 mg, 0.230 mmol) in water (0.868 mL). The mixture was then degassed with N₂for 15 minutes. SPhos-Pd-G2 (12.51 mg, 0.020 mmol) was added and the mixture was stirred at 80° C. under N₂for 15 hrs. The solvent was evaporated and the residue was taken up in water and extracted with EtOAc (3×). The combined organic layers were passed through a phase separator and evaporated to obtain a residue which was purified by silica gel column chromatography using a0-10% acetone/DCM gradient eluent over 15 CV to give a yellow solid (60 mg) which was further purified by prep HPLC (method H) to afford the title compound (12 mg, 19% yield) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.22 (s, 1H), 10.75 (s, 1H), 9.00 (dd, J=2.0, 0.7 Hz, 1H), 8.60-8.49 (m, 1H), 8.40 (dd, J=2.0, 0.8 Hz, 1H), 7.83 (dd, J=9.0, 1.9 Hz, 1H), 7.77 (s, 1H), 7.74 (d, J=7.8 Hz, 1H), 7.59 (d, J=9.2 Hz, 1H), 7.43 (t, J=7.6 Hz, 1H), 7.25-7.21 (m, 1H), 2.59 (d, J=0.7 Hz, 3H), 2.42 (s, 3H). MS-ESI (m/z) calc'd for C₂₂H₁₅N₅O [M+H]⁺: 368.1. Found 368.2.

Example 59: 5-Cyano-3-methyl-N-(3-(3-(trifluoromethyl)phenyl)-1H-indazol-5-yl)picolinamide

embedded image

To a suspension of 5-cyano-N-(3-iodo-1H-indazol-5-yl)-3-methylpicolinamide (70.0 mg, 0.170 mmol) in 1,4-dioxane (3.472 mL) was added a solution of tripotassium phosphate (110.56 mg, 0.520 mmol) and [3-(trifluoromethyl)phenyl]boronic acid (42.87 mg, 0.230 mmol) in water (0.868 mL). The mixture was then degassed with N₂for 15 minutes. SPhos-Pd-G2 (12.51 mg, 0.020 mmol) was added and the mixture was stirred at 80° C. under N₂for 15 hrs. The solvent was evaporated and the residue was taken up in water and extracted with EtOAc (3×). The combined organic layers were passed through a phase separator and evaporated to give crude material which was further purified by prep HPLC (method G) to afford the title compound (24.3 mg, 33% yield) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.47 (s, 1H), 10.81 (s, 1H), 9.00 (dd, J=1.9, 0.7 Hz, 1H), 8.61 (d, J=1.9 Hz, 1H), 8.41 (dd, J=1.9, 0.9 Hz, 1H), 8.27 (d, J=7.5 Hz, 1H), 8.23 (s, 1H), 7.87 (dd, J=9.0, 1.9 Hz, 1H), 7.81 (t, J=7.6 Hz, 1H), 7.78 (d, J=7.9 Hz, 1H), 7.64 (d, J=9.2 Hz, 1H), 2.59 (s, 3H). MS-ESI (m/z) calc'd for C₂₂H₁₅F₃N₅O [M+H]⁺: 422.1. Found 422.1.

Example 60: 5-Cyano-3-methyl-N-(3-(6-(trifluoromethyl)pyridin-3-yl)-1H-indazol-5-yl)picolinamide

embedded image

To a suspension of 5-cyano-N-(3-iodo-1H-indazol-5-yl)-3-methylpicolinamide (75.0 mg, 0.190 mmol) and 2-(trifluoromethyl)pyridine-5-boronic acid (46.17 mg, 0.240 mmol) in 1,4-dioxane (4 mL) was added a solution of tripotassium phosphate (118.46 mg, 0.560 mmol) in water (1 mL) and the mixture was degassed with N₂for 5 minutes. SPhos-Pd-G2 (13.41 mg, 0.020 mmol) was added and the mixture was stirred at 80° C. under N₂for 16 hrs. The reaction mixture was partitioned between water and EtOAc, the phases were separated, the aqueous layer was extracted with EtOAc (2×) and the combined organic phases washed with water (1×), dried over anhydrous Na₂SO₄and evaporated to dryness. The crude material was purified by normal phase chromatography on a 25 g silica gel column using a 0-50% EtOAc/cyclohexane gradient eluent. Pure fractions were combined and evaporated to dryness to afford the title compound (13 mg, 17% yield) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 13.69 (br. s., 1H) 10.83 (s, 1H) 9.36 (d, J-=1.98 Hz, 1H) 9.02 (d, J=1.32 Hz, 1H) 8.72 (d, J-=1.32 Hz, 1H) 8.60 (dd, J-=8.25, 1.65 Hz, 1H) 8.39-8.47 (m, 1H) 8.10 (d, J=8.14 Hz, 1H) 7.88 (dd, J=8.91, 1.87 Hz, 1H) 7.69 (d, J=8.58 Hz, 1H) 2.62 (s, 3H). MS-ESI (m/z) calc'd for C₂H₁₄F₃N₆O [M+H]⁺: 423.1. Found 423.1.

Example 61. 5-Cyano-N-(3-(3-fluoro-5-methylphenyl)-1H-indazol-5-yl)-3-methylpicolinamide

embedded image

To a suspension of 5-cyano-N-(3-iodo-1H-indazol-5-yl)-3-methylpicolinamide (75.0 mg, 0.190 mmol) and (3-fluoro-5-methylphenyl)boronic acid (37.23 mg, 0.240 mmol) in 1,4-dioxane (4 mL) was added a solution of tripotassium phosphate (118.46 mg, 0.560 mmol) in water (1 mL) and the mixture was degassed with N₂for 5 minutes. SPhos-Pd-G2 (13.41 mg, 0.020 mmol) was added and the mixture was stirred at 80° C. under N₂for 16 hrs. The reaction mixture was partitioned between water and EtOAc, the phases were separated, the aqueous layer was extracted with EtOAc (2×) and the combined organic phases washed with brine (1×), dried over anhydrous Na₂SO₄and evaporated to dryness. The crude material was purified by normal phase chromatography on a 25 g silica gel column using a 0-50% EtOAc/cyclohexane gradient eluent. The purest fractions were combined and evaporated to dryness to obtain material of insufficient purity that was further purified by preparative HPLC (method A) to afford the title compound (30 mg, 42% yield) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 13.36 (br. s., 1H) 10.79 (s, 1H) 9.01 (d, J=1.32 Hz, 1H) 8.56 (d, J=1.32 Hz, 1H) 8.42 (dd, J=1.87, 0.77 Hz, 1H) 7.91 (dd, J=9.02, 1.98 Hz, 1H) 7.57-7.69 (m, 2H) 7.51 (d, J=10.12 Hz, 1H) 7.09 (d, J=9.68 Hz, 1H) 2.60 (s, 3H) 2.45 (s, 3H). MS-ESI (m/z) calc'd for C₂₂H₁₇FN₅O [M+H]⁺: 386.1. Found 386.2.

Example 62: 5-cyano-N-(3-(3-cyclopropylphenyl)-1H-indazol-5-yl)-3-methylpicolinamide

embedded image

To a suspension of 5-cyano-N-(3-iodo-1H-indazol-5-yl)-3-methylpicolinamide (75.0 mg, 0.190 mmol) and (3-cyclopropylphenyl)boronic acid (39.17 mg, 0.240 mmol) in 1,4-dioxane (4 mL) was added a solution of tripotassium phosphate (118.46 mg, 0.560 mmol) in water (1 mL) and the mixture was degassed with N₂for 5 minutes. SPhos-Pd-G2 (13.41 mg, 0.020 mmol) was added and the mixture was stirred at 80° C. under N₂for 15 hrs. The reaction mixture was partitioned between water and EtOAc, the phases were separated, the aqueous layer was extracted with EtOAc (2×) and the combined organic phases washed with water (1×), dried over anhydrous Na₂SO₄and evaporated to dryness. The material was purified by normal phase chromatography on a 25 g silica gel column, using a 0-50% EtOAc/cyclohexane gradient eluent. The purest fractions were combined and evaporated to dryness to afford material of insufficient purity that was further purified by preparative HPLC (method M) to afford the title compound (22.7 mg, 31% yield) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 13.22 (br. s., 1H) 10.77 (s, 1H) 9.01 (d, J=1.54 Hz, 1H) 8.61 (d, J=1.32 Hz, 1H) 8.38-8.46 (m, 1H) 7.80 (dd, J=9.02, 1.76 Hz, 1H) 7.71 (d, J=7.70 Hz, 1H) 7.64 (s, 1H) 7.60 (d, J=9.02 Hz, 1H) 7.42 (t, J=7.70 Hz, 1H) 7.14 (d, J=7.48 Hz, 1H) 2.59 (s, 3H) 2.00-2.10 (m, 1H) 0.99-1.06 (m, 2H) 0.75-0.82 (m, 2H). MS-ESI (m/z) calc'd for C₂₄H₂₀N₅O [M+H]⁺: 394.2. Found 394.2.

Example 63: 5-Cyano-N-(3-(3-fluoro-4-methylphenyl)-1H-indazol-5-yl)-3-methylpicolinamide

embedded image

To a suspension of 5-cyano-N-(3-iodo-1H-indazol-5-yl)-3-methylpicolinamide (70.0 mg, 0.170 mmol)) in 1,4-dioxane (3.48 mL) was added a solution of tripotassium phosphate (112.14 mg, 0.520 mmol) and (3-fluoro-4-methylphenyl)boronic acid (34.75 mg, 0.230 mmol) in water (0.870 mL) and the mixture was degassed with N₂for 15 minutes. SPhos-Pd-G2 (12.51 mg, 0.020 mmol)) was added and the mixture was stirred at 80° C. under N₂for 15 hrs. The solvent was evaporated and the residue was taken up in water and extracted with EtOAc (3×). The combined organic layers were passed through a phase separator and evaporated to obtain a residue (90 mg) which was purified by preparative HPLC (method Q) to afford the title compound (13 mg, 19% yield) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 13.32 (br. s., 1H), 10.79 (s, 1H), 9.01 (d, J=1.32 Hz, 1H), 8.57-8.67 (m, 1H), 8.42 (dd, J=1.98, 0.66 Hz, 1H), 7.86 (dd, J=8.91, 1.87 Hz, 1H), 7.59-7.75 (m, 3H), 7.47 (t, J=8.25 Hz, 1H), 2.61 (s, 3H), 2.32 (d, J=1.32 Hz, 3H). MS-ESI (m/z) calc'd for C₂₂H₁₇FN₅O [M+H]⁺: 386.1. Found 386.2.

Example 64: 5-Cyano-3-(difluoromethyl)-N-(3-(furan-3-yl)-1H-indazol-5-yl)picolinamide

embedded image

Step 1: 5-Bromo-3-formylpicolinic acid

embedded image

To a solution of n-BuLi (2.5 M, 15.66 mL) in THF (50 mL) was added 3,5-dibromopicolinic acid (5 g, 17.80 mmol) in THF (75 mL) at −70° C. After 1 hr, DMF (13.01 g, 178.00 mmol) was added to the mixture and stirring was continued at 0° C. for 2 hrs. The reaction mixture was quenched by addition of H₂O (100 mL) at 20° C. and extracted with EtOAc (90 mL×5). The aqueous phase was acidified with 1N HCl to pH=3 and extracted with EtOAc (90 mL×3). The organic layers were dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to afford the title compound (3.37 g) as a yellow oil which was used without further purification.

Step 2: Methyl 5-bromo-3-(dimethoxymethyl)picolinate

embedded image

A solution of 5-bromo-3-formylpicolinic acid (3.37 g, 14.65 mmol) in MeOH (40 mL) and H₂SO₄(0 mL) (98% purity) was stirred at 70° C. for 1 hr. The reaction was concentrated to give a residue, which was diluted with H₂O (40 mL), basified with saturated aqueous NaHCO₃to pH=8, and extracted with EtOAc (30 mL×3). The combined organic layers were dried over Na₂SO₄, filtered and concentrated to give a residue. The residue was purified by silica gel column chromatography using a 0-10% EtOAc/petroleum ether gradient eluent to afford the title compound (1.3 g, 31% yield) as a light yellow solid.

Step 3: Methyl 5-bromo-3-formylpicolinate

embedded image

To a solution of methyl 5-bromo-3-(dimethoxymethyl)picolinate (1.3 g, 4.48 mmol) in dioxane (15 mL) and H₂O (15 mL) was added PTSA (231.49 mg, 1.34 mmol). The mixture was stirred at 50° C. for 16 hrs. The reaction mixture was basified with saturated aqueous NaHCO₃to pH=8 and extracted with EtOAc (5 mL×4). The combined organic layers were dried over Na₂SO₄, filtered and concentrated to afford the title compound (750 mg) as a pale yellow solid which was used without further purification.

Step 4: Methyl 5-bromo-3-(difluoromethyl)picolinate

embedded image

To a solution of methyl 5-bromo-3-formylpicolinate (500 mg, 2.05 mmol) in CH₂Cl₂(15 mL) was added DAST (825.62 mg, 5.12 mmol). The mixture was stirred at 20° C. for 12 hrs. The reaction mixture was concentrated and purified by silica gel column chromatography using a 0-10% EtOAc/petroleum ether gradient eluent to afford the title compound (280 mg, 51% yield) as a white solid.

Step 5: Methyl 5-cyano-3-(difluoromethyl)picolinate

embedded image

A mixture of methyl 5-bromo-3-(difluoromethyl)picolinate (280 mg, 1.05 mmol), Zn(CN)₂(247.17 mg, 2.10 mmol), Pd(PPh₃)₄(121.62 mg, 105.25 umol) in DMF (4 mL) was degassed and purged with N₂(3×). The mixture was then stirred at 120° C. for 12 hrs under an N₂atmosphere. The reaction mixture was concentrated and purified by silica gel column chromatography using a 0-10% EtOAc/petroleum ether gradient eluent to afford the title compound (40 mg, 18% yield) as a white solid.

Step 6: 5-Cyano-3-(difluoromethyl)picolinic acid

embedded image

To a solution of methyl 5-cyano-3-(difluoromethyl)picolinate (40 mg, 189 umol) in THF (2 mL) was added TMSOK (73 mg, 566 umol). The mixture was stirred at 20° C. for 10 min and monitored by TLC (petroleum ether:EtOAc=3:1). The reaction mixture was acidified with IN HCl to pH=3 and then extracted with EtOAc (2 mL×3). The combined organic layers were dried over Na₂SO₄, filtered and concentrated to afford the title compound (25 mg) as a yellow solid which was used without further purification.

Step 7: 5-Cyano-3-(difluoromethyl)-N-(3-(furan-3-yl)-1H-indazol-5-yl)picolinamide

embedded image

To a solution of 5-cyano-3-(difluoromethyl)picolinic acid (20 mg, 101 umol) in CH₂Cl₂(2 mL) was added 3-(furan-3-yl)-1H-indazol-5-amine (40 mg, 202 umol) and T3P (50 wt. % in EtOAc, 96 mg, 151 umol). The mixture was stirred at 20° C. for 2.5 hrs. The reaction mixture was concentrated and purified by preparative HPLC (Method V) to afford the title compound (8.24 mg, 16% yield) as a yellow solid, TFA salt. ¹H NMR (400 MHz, DMSO-d₆) δ 13.15 (s, 1H) 11.00 (s, 1H) 9.36 (s, 1H) 8.90 (s, 1H) 8.46 (s, 1H) 8.29 (s, 1H) 7.68-7.96 (m, 3H) 7.58 (d, J=9 Hz, 1H) 7.02 (d, J=1 Hz, 1H). MS-ESI (m/z) calc'd for C₁₉H₁₂F₂N₅O₂[M+H]⁺: 380.1. Found 380.1.

Example 65: 5-Cyano-N-(3-(furan-3-yl)-1H-indazol-5-yl)thiazole-2-carboxamide

embedded image

Step 1: Methyl 5-bromothiazole-2-carboxylate

embedded image

To a solution of 5-bromothiazole-2-carboxylic acid (400 mg, 1.92 mmol) in DCM (5 mL) was added (COCl)₂(297.74 mg, 2.35 mmol) and DMF (28.11 mg, 384.55 umol). The mixture was stirred at 20° C. for 0.5 hr. MeOH (1 mL) was then added and the mixture was stirred at 20° C. for 1 hr and monitored by TLC (petroleum ether:EtOAc=3:1 Rf=0.63). The reaction mixture was concentrated under reduced pressure to remove solvent and purified by flash silica gel chromatography (ISCO; 4 g SepaFlash column) using a 0-7% EtOAc/petroleum ether gradient eluent to afford the title compound (380 mg, 89%) as a white solid.

Step 2: Methyl 5-cyanothiazole-2-carboxylate

embedded image

A mixture of methyl 5-bromothiazole-2-carboxylate (200 mg, 900.66 umol), Zn(CN)₂(211.52 mg, 1.80 mmol), Pd₂(dba)₃(24.74 mg, 27.02 umol), dppf (29.96 mg, 54.04 umol) and Zn (5.30 mg, 81.06 umol) in DMA (10 mL) was degassed and purged with N₂(3×). The mixture was stirred at 110° C. for 2 hrs under N₂atmosphere in a microwave reactor and monitored by TLC (petroleum ether:EtOAc=2:1, Rf=0.49). The reaction mixture was concentrated under reduced pressure to remove solvent and purified by flash silica gel chromatography (ISCO; 4 g SepaFlash column) using a 0-5% EtOAc/petroleum ether gradient eluent to afford the title compound (100 mg, 61%) as a white solid.

Step 3: 5-Cyano-N-(3-(furan-3-yl)-1H-indazol-5-yl)thiazole-2-carboxamide

embedded image

To a solution of methyl 5-cyanothiazole-2-carboxylate (10 mg, 59.46 umol) and 3-(furan-3-yl)-1H-indazol-5-amine (23.69 mg, 118.93 umol) in toluene (2 mL) was added AlMe₃(2 M, 89.19 uL). The mixture was stirred at 0° C. for 1 hr. The reaction mixture was quenched by addition of MeOH (3 mL) at 0° C. and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (Method AH) to afford the title compound (7 mg, 25% yield) as a yellow solid, TFA salt. ¹H NMR (400 MHz, DMSO-d₆) δ 13.16 (br s, 1H) 11.11 (s, 1H) 8.95 (s, 1H) 8.46 (d, J=1.47 Hz, 1H) 8.26 (s, 1H) 7.89 (dd, J=9.05, 1.83 Hz, 1H) 7.85 (t, J=1.65 Hz, 1H) 7.58 (d, J=8.93 Hz, 1H) 6.98-7.03 (m, 1H). MS-ESI (m/z) calc'd for C₁₆H₁₀N₅O₂S [M+H]⁺: 336.0. Found 336.0.

Example 66: 4-Chloro-5-cyano-N-(3-(furan-3-yl)-1H-indazol-5-yl)picolinamide

embedded image

Step 1: 5-Bromo-4-chloro-N-(3-(furan-3-yl)-1H-indazol-5-yl)picolinamide

embedded image

To a solution of 5-bromo-4-chloropicolinic acid (50 mg, 211.46 umol) and 3-(furan-3-yl)-1H-indazol-5-amine (42.12 mg, 211.46 umol) in pyridine (2 mL) was added EDCI (60.81 mg, 317.19 umol). The reaction mixture was stirred at 25° C. for 12 hrs and then poured into water (5 mL) and extracted with CH₂Cl₂(5 mL×3). The combined organic phases were washed with brine (5 mL×1), dried over anhydrous Na₂SO₄, filtered and concentrated in vacuum. The residue was purified by silica gel column chromatography using a 5-100% EtOAc/petroleum ether gradient eluent to afford the title compound (60 mg, 68% yield) as a green solid.

Step 2: 4-Chloro-5-cyano-N-(3-(furan-3-yl)-1H-indazol-5-yl)picolinamide

embedded image

To a solution of 5-bromo-4-chloro-N-(3-(furan-3-yl)-1H-indazol-5-yl)picolinamide (60 mg, 143.66 umol) and Zn(CN)₂(8.43 mg, 71.83 umol) in DMF (2 mL) was added Pd(PPh₃)₄(16.60 mg, 14.37 umol). The reaction mixture was stirred at 150° C. for 1 hr under N₂. The reaction mixture was filtered and the filtrate was concentrated. The residue was purified by preparative HPLC (Method U) and further purified by preparative HPLC (Method V) to afford the title compound (8.37 mg, 12% yield) as a yellow solid, TFA salt. ¹H NMR (400 MHz, DMSO-d₆) δ 13.13 (s, 1H), 10.91 (s, 1H), 9.29 (s, 1H), 8.51 (s, 1H), 8.44 (s, 1H), 8.29 (s, 1H), 7.99 (br d, J=9.0 Hz, 1H), 7.85 (s, 1H), 7.57 (d, J=9.0 Hz, 1H), 7.01 (s, 1H). MS-ESI (m/z) calc'd for C₁₈H₁₁ClN₅O₂[M+H]⁺: 364.0. Found 364.0.

Example 67: 5-Cyano-N-(3-(furan-3-yl)-1H-indazol-5-yl)-3,4-dimethylpicolinamide

embedded image

Step 1: 5-Cyano-2,3,4-trimethylpyridine 1-oxide

embedded image

To a solution of 4,5,6-trimethylnicotinonitrile (500.0 mg, 3.42 mmol) in DCM (17.1 mL) was added meta-chloroperoxybenzoic acid (843.18 mg, 3.42 mmol) and the mixture was stirred at 25° C. for 5 hrs. The solution was washed with aqueous K₂CO₃solution (3×) and the combined aqueous layers were extracted with DCM (3×). All the organic phases were combined, passed through a phase separator, and evaporated to dryness to afford the title compound (530 mg, 96% yield) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.73 (s, 1H), 2.44 (s, 3H), 2.39 (s, 3H), 2.28 (s, 3H). MS-ESI (m/z) calc'd for C₉H₁₁N₂O [M+H]⁺: 162.1. Found 162.9.

Step 2: 6-(Hydroxymethyl)-4,5-dimethylnicotinonitrile

embedded image

To a solution of 5-cyano-2,3,4-trimethylpyridine 1-oxide (530.0 mg, 3.27 mmol) in DCM (5 mL) was added a solution of 2,2,2-trifluoroacetic acid (2,2,2-trifluoro-1-oxoethyl) ester (1.36 mL, 9.8 mmol) in DCM (5 mL) dropwise and the mixture was stirred at 25° C. for 15 hrs. The solvent was evaporated to dryness to give a red oil which was dissolved in MeOH (20 mL). K₂CO₃(1 g) was added and the suspension was stirred for 1 hr. The solvent was evaporated and the residue was taken up in water and extracted with DCM (3×). The combined organic layers were passed through a phase separator and evaporated to afford the title compound (510 mg, 96% yield) as a beige solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.70 (s, 1H), 5.23 (t, J=5.6 Hz, 1H), 4.64 (d, J=5.6 Hz, 2H), 2.46 (s, 3H), 2.29 (s, 3H). MS-ESI (m/z) calc'd for C₉H₁₁N₂O [M+H]⁺: 162.1. Found 162.9.

Step 3: 5-Cyano-3,4-dimethylpicolinic acid

embedded image

To a solution of 6-(hydroxymethyl)-4,5-dimethylnicotinonitrile (510.0 mg, 3.14 mmol) in acetone (10 mL) was added a solution of potassium permanganate (546.61 mg, 3.46 mmol) in water (5 mL) dropwise at 0° C. and the mixture was stirred for 30 minutes. The dark solid was filtered and washed with 1M aqueous K₂CO₃. The filtrate was concentrated to remove the organic solvent and the pH was adjusted to 4-5 by addition of conc. HCl. The solution was extracted with EtOAc (3×) and the combined organic layers were passed through a phase separator and evaporated to afford the title compound (500 mg, 90% yield) as a beige solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.82 (s, 1H), 8.78 (s, 1H), 2.50 (s, 3H), 2.33 (s, 3H). MS-ESI (m/z) calc'd for C₉H₉N₂O₂[M+H]⁺: 177.1. Found 177.3.

Step 4: 5-Cyano-N-(3-(furan-3-yl)-1H-indazol-5-yl)-3,4-dimethylpicolinamide

embedded image

To a solution of 5-cyano-3,4-dimethylpicolinic acid (35.23 mg, 0.200 mmol), triethylamine (27.88 uL, 0.200 mmol) and 3-(furan-3-yl)-1H-indazol-5-amine (0.05 mL, 0.200 mmol) was added HATU (76.05 mg, 0.200 mmol) and the mixture was stirred at 25° C. for 2 hrs. Water was added and the solid that formed was filtered under vacuum and purified by silica gel column chromatography using a 0-5% MeOH/DCM gradient eluent to afford the title compound (40 mg, 56% yield) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.10 (s, 1H), 10.67 (s, 1H), 8.89 (s, 1H), 8.40 (d, J=1.7 Hz, 1H), 8.23 (t, J=1.1 Hz, 1H), 7.84 (t, J=1.7 Hz, 1H), 7.74 (dd, J=8.9, 1.9 Hz, 1H), 7.56 (d, J=9.0 Hz, 1H), 6.99 (dd, J=1.9, 0.8 Hz, 1H), 2.56 (s, 3H), 2.47 (s, 3H). MS-ESI (m/z) calc'd for C₂₀H₁₆N₅O₂[M+H]⁺: 358.1. Found 358.1.

Example 68: 5-Cyano-N-(3-(5-methoxypyridin-3-yl)-1H-indazol-5-yl)-3-methylpicolinamide

embedded image

5-Cyano-N-(3-iodo-1H-indazol-5-yl)-3-methylpicolinamide (50.0 mg, 0.110 mmol) was dissolved in 1,4-dioxane (2 mL). Then a solution of K₃PO₄(67.13 mg, 0.320 mmol) and (5-methoxypyridin-3-yl)boronic acid (20.96 mg, 0.140 mmol) in water (0.500 mL) was added and the mixture was degassed with N₂for 15 minutes. SPhos-Pd-G2 (7.6 mg, 0.010 mmol) was added and the mixture was stirred at 80° C. under an N₂atmosphere for 2 hrs. Water was added and the mixture was extracted with EtOAc (2×). The organic phases were separated, dried over Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by semi-preparative HPLC (Method S) to afford the title compound (9.9 mg, 24% yield) as an orange solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.49 (bs, 1H), 10.81 (s, 1H), 9.01 (d, J=2.0 Hz, 1H), 8.79 (d, J=1.7 Hz, 1H), 8.67 (d, J=1.8 Hz, 1H), 8.42 (dd, J=2.0, 0.9 Hz, 1H), 8.36 (d, J=2.8 Hz, 1H), 7.88 (dd, J=9.0, 1.9 Hz, 1H), 7.84 (dd, J=2.9, 1.7 Hz, 1H), 7.65 (d, J=9.0 Hz, 1H), 3.96 (s, 3H), 2.61 (s, 3H). MS-ESI (m/z) calc'd for C₂₁H₁₇N₆O₂[M+H]⁺: 385.1. Found 385.2.

Example 69: 5-Cyano-N-(3-(furan-3-yl)-1H-indazol-5-yl)-3-methoxypicolinamide

embedded image

Step 1: 5-Bromo-N-(3-(furan-3-yl)-1H-indazol-5-yl)-3-methoxypicolinamide

embedded image

To a mixture of 5-bromo-3-methoxypyridine-2-carboxylic acid (100.0 mg, 0.430 mmol) in MeCN (3.814 mL) was added triethylamine (0.07 mL, 0.520 mmol) and HATU (163.87 mg, 0.430 mmol). The mixture was then stirred at 25° C. for 15 minutes. This solution was added dropwise to a solution of 3-(furan-3-yl)-1H-indazol-5-amine (85.86 mg, 0.430 mmol) in MeCN (3.814 mL) and the mixture was stirred at 25° C. for 18 hrs. The reaction was filtered and the solid was washed with MeCN. The solid was triturated with MeOH and then dried under vacuum to afford the title compound (160 mg, 90% yield) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.08 (s, 1H), 10.44 (s, 1H), 8.40 (d, J=1.8 Hz, 1H), 8.37 (d, J=1.7 Hz, 1H), 8.21 (s, 1H), 7.98 (d, J=1.8 Hz, 1H), 7.85 (t, 1H), 7.70 (dd, J=9.0, 1.8 Hz, 1H), 7.54 (d, J=8.9 Hz, 1H), 6.99 (d, 1H), 3.92 (s, 3H). MS-ESI (m/z) calc'd for C₂₀H₁₆N₅O₂[M+H]⁺: 413.0, 415.0. Found 413.2, 415.1.

Step 2: 5-Cyano-N-(3-(furan-3-yl)-1H-indazol-5-yl)-3-methoxypicolinamide

embedded image

To a microwave reaction vial (vial A) equipped with a magnetic stir bar was added a 0.1 N solution of potassium hexacyanoferrate (III) (0.69 mL, 0.070 mmol) in water. To a separate microwave reaction vial (vial B) equipped with a magnetic stir bar was added XPhos (9.21 mg, 0.020 mmol) and XPhos-Pd-G3 (16.36 mg, 0.020 mmol). The vials were sealed with a teflon-lined screw cap septum, evacuated and flushed with nitrogen (3×). 1,4-Dioxane (9.66 mL) was added to vial B via syringe and the solution was stirred until all solids dissolved. This solution was degassed with N₂and then added via syringe to vial A. 5-Bromo-N-(3-(furan-3-yl)-1H-indazol-5-yl)-3-methoxypicolinamide (113.8 mg, 0.275 mmol) and a 0.2 M solution of KOAc in degassed water (0.692 mL) (13.51 mg, 0.5 equivalent of KOAc) was then added and the reaction was stirred at 100° C. for 4 hrs. Additional Xphos-Pd-G3 (9.32 mg, 0.010 mmol), XPhos (5.25 mg, 0.010 mmol) and 0.1 N potassium hexacyanoferrate (11) (0.69 mL, 0.070 mmol) were added and the reaction mixture was stirred at 100° C. for 18 hrs. Sat. aq. NaHCO₃was added and the mixture was extracted with EtOAc (2×). The organic phases were combined, dried over Na₂SO₄, filtered and concentrated under reduced pressure. The residue (106 mg) was purified by semi-preparative HPLC (Method S) to afford the title compound (3.4 mg, 3% yield) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.10 (s, 1H), 10.60 (s, 1H), 8.70 (d, J=1.5 Hz, 1H), 8.39 (d, J=1.8 Hz, 1H), 8.24 (d, J=1.6 Hz, 1H), 8.21 (d, J=1.2 Hz, 1H), 7.85 (t, J=1.7 Hz, 1H), 7.67 (dd, J=8.9, 1.9 Hz, 1H), 7.56 (d, J=8.9 Hz, 1H), 6.99 (d, J=1.9 Hz, 1H), 3.94 (s, 3H). MS-ESI (m/z) calc'd for C19H₁₄N₅O₃[M+H]⁺: 360.1. Found 360.2.

Example 70: 5-Cyano-3-methyl-N-(3-(4-morpholinophenyl)-1H-indazol-5-yl)picolinamide

embedded image

To a suspension of 5-cyano-N-(3-iodo-1H-indazol-5-yl)-3-methylpicolinamide (47.43 mg, 0.100 mmol) in 1,4-dioxane (2 mL) was added a solution of tripotassium phosphate (63.68 mg, 0.300 mmol) and (4-morpholinophenyl)boronic acid (26.91 mg, 0.130 mmol) in water (0.500 mL). The mixture was degassed with N₂for 15 minutes. SPhos-Pd-G2 (7.21 mg, 0.010 mmol) was added and the mixture was stirred at 80° C. under N₂for 15 hrs. The solvent was evaporated and the residue was taken up in water and extracted with EtOAc (3×). The combined organic layers were passed through a phase separator and evaporated to obtain a residue which was purified by reversed phase column chromatography using a 0-10% MeOH/DCM gradient eluent to afford a solid (18 mg) which was passed through a 2 g SCX ion exchange cartridge to give a yellow solid which was further purified by reversed phase column chromatography using a 5-100% MeCN/H₂O (0.1% formic acid) gradient eluent to afford the title compound (2.3 mg, 5% yield) as a yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 10.12 (s, 1H), 8.74 (d, J=2.0 Hz, 1H), 8.49 (d, J=2.0 Hz, 1H), 7.96 (d, J=1.9 Hz, 1H), 7.91 (d, J=8.7 Hz, 2H), 7.68 (dd, J=8.9, 1.9 Hz, 1H), 7.51 (d, J=8.9 Hz, 1H), 7.09-7.05 (m, 2H), 3.93-3.89 (m, 4H), 3.28-3.24 (m, 4H), 2.90 (s, 3H). MS-ESI (m/z) calc'd for C₂₅H₂₃N₆O₂[M+H]⁺: 439.2. Found 439.1.

Example 71: N-(3-(Benzo[d]oxazol-5-yl)-1H-indazol-5-yl)-5-cyano-3-methylpicolinamide

embedded image

5-Cyano-N-(3-iodo-1H-indazol-5-yl)-3-methylpicolinamide (75.0 mg, 0.190 mmol) was dissolved in 1,4-dioxane (3.543 mL). Then a solution of K₃PO₄(118.46 mg, 0.560 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-benzoxazole (59.27 mg, 0.240 mmol) in water (0.886 mL) was added and the mixture was degassed with N₂for 15 minutes. SPhos-Pd-G2 (13.41 mg, 0.020 mmol) was added and the mixture was stirred at 80° C., under an N₂atmosphere, for 2 hrs. Additional SPhos-Pd-G2 (13.41 mg, 0.020 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-benzoxazole (59.27 mg, 0.240 mmol) were added and the mixture was stirred for 2 hrs. Water was added and the mixture was extracted with EtOAc (2×). The organic phase was separated, dried over Na₂SO₄, filtered and concentrated under reduced pressure. The residue was then purified by silica gel column chromatography using a 0-100% acetone/DCM gradient eluent to obtain the title compound (31.1 mg, 42% yield) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.30 (s, 1H), 10.81 (s, 1H), 9.01 (dd, J=2.0, 0.8 Hz, 1H), 8.84 (s, 1H), 8.68 (d, 1H), 8.42 (dd, J=2.0, 0.9 Hz, 1H), 8.30 (d, J=1.6 Hz, 1H), 8.07 (dd, J=8.5, 1.7 Hz, 1H), 7.96 (d, J=8.5 Hz, 1H), 7.87 (dd, J=9.0, 1.9 Hz, 1H), 7.63 (d, J=9.0 Hz, 1H), 2.61 (s, 3H). MS-ESI (m/z) calc'd for C₂₂H₁₅N₆O₂[M+H]⁺: 395.1. Found 395.1.

Example 72: 3-Cyano-N-(3-(furan-3-yl)-1H-indazol-5-yl)-2-methoxybenzamide

embedded image

A mixture of 3-(furan-3-yl)-1H-indazol-5-amine (30.0 mg, 0.150 mmol) and methyl 3-cyano-2-methoxybenzoate (28.79 mg, 0.150 mmol) in toluene (1.5 mL) was flushed with nitrogen for 5 min. A 2 M solution of trimethylaluminum in toluene (0.23 mL, 0.450 mmol) was then added and the reaction mixture was stirred for 1 hr at 95° C. The reaction mixture was then cooled to rt, diluted with water and EtOAc, the phases were separated, the aqueous layer was extracted with EtOAc (2×), and the combined organic phases were washed with water (1×), dried over anhydrous Na₂SO₄and evaporated to dryness. The material obtained was purified by normal phase chromatography on a 10 g silica gel column using a 0-70% EtOAc/cyclohexane gradient eluent. Product-containing fractions were combined and evaporated to dryness to afford impure product. This was further purified by reverse phase chromatography on a 12 g C18 column using a 5-55% CH₃CN/H₂O (0.1% formic acid) gradient eluent to afford the title compound (29 mg, 54% yield) as an off-white solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 13.10 (br. s., 1H), 10.51 (s, 1H), 8.38 (d, J=1.1 Hz, 1H), 8.22 (dd, J=0.8, 1.4 Hz, 1H), 7.96 (dd, J=1.7, 7.8 Hz, 1H), 7.91 (dd, J=1.5, 7.7 Hz, 1H), 7.86 (t, J=1.7 Hz, 1H), 7.70-7.63 (m, 1H), 7.61-7.53 (m, 1H), 7.41 (t, J=7.7 Hz, 1H), 7.00 (dd, J=0.8, 1.9 Hz, 1H), 4.03 (s, 3H). MS-ESI (m/z) calc'd for C₂₀H₁₅N₄O₃[M+H]⁺: 359.1. Found 359.2.

Example 73: 5-Cyano-3-methyl-N-(3-(thiophen-3-yl)-1H-indazol-5-yl)picolinamide

embedded image

5-Cyano-N-(3-iodo-1H-indazol-5-yl)-3-methylpicolinamide (75 mg, 0.19 mmol) was dissolved in 1,4-dioxane (3.529 mL). A solution of K₃PO₄(118.46 mg, 0.56 mmol) and 3-thiophenylboronic acid (30.94 mg, 0.24 mmol) in water (0.88 mL) was then added and the mixture was degassed with N₂for 15 minutes. SPhos-Pd-G2 (13.41 mg, 0.02 mmol) was added and the mixture was stirred at 80° C. under N₂atmosphere for 2 hrs. Water was added and the mixture was extracted with EtOAc (2×). The organic phases were separated, dried over Na₂SO₄, filtered and concentrated under reduced pressure. The residue was then purified by silica gel column chromatography using a 0-100% acetone/DCM gradient eluent to afford the title compound (50.4 mg, 75% yield) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.13 (bs, 1H), 10.74 (s, 1H), 9.01 (d, J=2.0 Hz, 1H), 8.60 (d, J=1.8 Hz, 1H), 8.42 (dd, J=2.0, 0.9 Hz, 1H), 7.96 (dd, J=2.9, 1.3 Hz, 1H), 7.81 (dd, J=9.0, 1.9 Hz, 1H), 7.74 (dd, J=5.0, 2.8 Hz, 1H), 7.70 (dd, J=5.0, 1.3 Hz, 1H), 7.58 (d, J=8.9 Hz, 1H), 2.62 (s, 3H). MS-ESI (m/z) calc'd for C₁₉H₁₄N₅OS [M+H]⁺: 360.1. Found 360.2.

Example 74: 5-Cyano-3-methyl-N-(3-(2-methylpyridin-4-yl)-1H-indazol-5-yl)picolinamide

embedded image

5-Cyano-N-(3-iodo-1H-indazol-5-yl)-3-methylpicolinamide (75 mg, 0.190 mmol) was dissolved in 1,4-dioxane (3.543 mL). Then a solution of K₃PO₄(118.46 mg, 0.560 mmol) and (2-methylpyridin-4-yl)boronic acid (33.12 mg, 0.24 mmol) in water (0.886 mL) was added and the mixture was degassed with N₂for 15 minutes. SPhos-Pd-G2 (13.41 mg, 0.02 mmol) was added and the mixture was stirred at 80° C. under N₂atmosphere for 2 hrs. Additional SPhos-Pd-G2 (13.41 mg, 0.020 mmol) and 2-picoline-4-boronic acid (33.12 mg, 0.24 mmol) were then added and the mixture was stirred for 18 hrs. Water was added and the mixture was extracted with EtOAc (2×). The organic phases were separated, dried over Na₂SO₄, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a 0-60% acetone/DCM gradient eluent. The product-containing fractions were collected and concentrated under reduced pressure to afford 40 mg of a yellow solid. The solid was then triturated with 1 mL of MeCN and taken up in 1 mL of water and concentrated to afford the title compound (15 mg, 22% yield) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.57 (bs, 1H), 10.80 (s, 1H), 9.02 (d, J=1.9 Hz, 1H), 8.64 (d, J=1.8 Hz, 1H), 8.58 (d, J=5.1 Hz, 1H), 8.42 (dd, J=1.8, 0.8 Hz, 1H), 7.91 (dd, J=9.0, 1.9 Hz, 1H), 7.82 (d, J=1.7 Hz, 1H), 7.74 (dd, J=5.3, 1.7 Hz, 1H), 7.66 (d, J=9.0 Hz, 1H), 2.61 (s, 3H), 2.59 (s, 3H). MS-ESI (m/z) calc'd for C₂₁H₁₇N₆O [M+H]⁺: 369.1. Found 369.2.

Example 75: 3-Cyano-2-ethyl-N-(3-(furan-3-yl)-1H-indazol-5-yl)benzamide

embedded image

2-Bromo-3-cyano-N-[3-(furan-3-yl)-1H-indazol-5-yl]benzamide (50.0 mg, 0.120 mmol) was dissolved in toluene (5 mL) and water (0.500 mL). The mixture was flushed with N₂for 5 min. A 1M solution of triethylborane (0.12 mL, 0.120 mmol) in hexanes was added followed by tripotassium phosphate (52.13 mg, 0.250 mmol), (1E,4E)-1,5-diphenyl-3-penta-1,4-dienone palladium (22.49 mg, 0.020 mmol) and bis(1-adamantyl)-butylphosphine (4.4 mg, 0.010 mmol). The mixture was then stirred at 110° C. for 2 hrs. Another 60 μL of 1M triethylborane in hexanes and 11 mg of Pd₂(dba)₃were added and the mixture was stirred at 110° C. for an additional 2 hrs. The reaction mixture was partitioned between water and EtOAc, the phases were separated, the aqueous layer was extracted with EtOAc (2×) and the combined organic phases washed with water (1×), dried over anhydrous Na₂SO₄and evaporated to dryness. The material obtained was purified by preparative HPLC (method N) to afford the title compound (2.2 mg, 5% yield) as a white solid. ¹H NMR (400 MHz, DMSO-de) δ ppm 13.10 (s, 1H), 10.55 (s, 1H), 8.37 (d, J=1.1 Hz, 1H), 8.21 (dd, J=0.8, 1.4 Hz, 1H), 7.95 (dd, J=1.3, 7.7 Hz, 1H), 7.89-7.81 (m, 2H), 7.71-7.63 (m, 1H), 7.61-7.52 (m, 2H), 6.99 (dd, J=0.7, 1.8 Hz, 1H), 2.95 (q, J=7.4 Hz, 2H), 1.27 (t, J=7.5 Hz, 3H). MS-ESI (m/z) calc'd for C₂₁H₁₇N₄O₂[M+H]⁺: 357.1. Found 357.1.

Example 76: 5-Cyano-N-(3-(5-cyanofuran-3-yl)-1H-indazol-5-yl)-3-methylpicolinamide

embedded image

Step 1: 4-(5-Nitro-1H-indazol-3-yl)furan-2-carbaldehyde

embedded image

A mixture of 3-bromo-5-nitro-1H-indazole (150 mg, 619.76 umol), (5-formyl-3-furyl)boronic acid (95.38 mg, 681.74 umolq), Pd(Amphos)Cl₂(43.88 mg, 61.98 umol), KOAc (182.47 mg, 1.86 mmol) in EtOH (2 mL) and H₂O (0.5 mL) was degassed and purged with N₂(3×). The mixture was then stirred at 90° C. for 12 hrs under an N₂atmosphere. The reaction mixture was concentrated to give a residue. The residue was diluted with EtOAc (50 mL) and H₂O (30 mL). The mixture was filtered and the solid was collected, washed with H₂O (30 mL×2) and EtOAc (50 mL×3), and dried under vacuum. The procedure was repeated an additional 3× and the products were combined to afford the title compound (500 mg) as a yellow solid which was used without further purification.

Step 2: 4-(5-Nitro-1H-indazol-3-yl)furan-2-carbonitrile

embedded image

To a solution of 4-(5-nitro-1H-indazol-3-yl)furan-2-carbaldehyde (500 mg, 1.94 mmol) in pyridine (50 mL) was added NH₂OH.HCl (500 mg, 7.20 mmol). The mixture was stirred at 100° C. for 30 min and then Ac₂O (10 mL) was added. The mixture was stirred at 100° C. for another 12 hrs and monitored by TLC (petroleum ether:EtOAc=3:1, Rf=0.53). The reaction mixture was concentrated and purified by silica gel column chromatography using a 0-30% EtOAc/petroleum ether gradient eluent to afford the title compound (400 mg, 57% yield) as a yellow solid.

Step 3: 4-(5-Amino-1H-indazol-3-yl)furan-2-carbonitrile

embedded image

To a solution of 4-(5-nitro-1H-indazol-3-yl)furan-2-carbonitrile (380 mg, 1.05 mmol) in EtOH (20 mL) was added SnCl₂2H₂O (1.18 g, 5.23 mmol). The mixture was stirred at 80° C. for 1 hr and monitored by TLC (petroleum ether:EtOAc=1:1, Rf=0.24). The reaction mixture was concentrated to give a residue which was diluted with EtOAc (30 mL) and basified with saturated aqueous NaHCO₃to pH=8. The mixture was filtered and the filtrate was extracted with EtOAc (30 mL×3), dried over Na₂SO₄, filtered and concentrated to afford the title compound (200 mg) as a yellow solid which was used without further purification.

Step 4: 5-Cyano-N-(3-(5-cyanofuran-3-yl)-1H-indazol-5-yl)-3-methylpicolinamide

embedded image

To a solution of 5-cyano-3-methylpicolinic acid (70 mg, 431.71 umol) in pyridine (5 mL) was added EDCI (124.14 mg, 647.57 umol) and 4-(5-amino-1H-indazol-3-yl)furan-2-carbonitrile (96.80 mg, 431.71 umol). The mixture was stirred at 20° C. for 12 hrs. The reaction mixture was concentrated and purified by preparative HPLC twice under basic conditions (Method X and Method Y) to afford the title compound (12 mg, 7% yield) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.38 (s, 1H) 10.73 (s, 1H) 9.01 (s, 1H) 8.69 (s, 1H) 8.42 (br d, J=6 Hz, 2H) 8.14 (s, 1H) 7.85 (br d, J=8 Hz, 1H) 7.61 (d, J=9 Hz, 1H) 2.62 (s, 3H). MS-ESI (m/z) calc'd for C₂₀H₁₃N₆O₂[M+H]⁺: 369.1. Found 369.0.

Example 77: 3-Cyano-2-fluoro-N-(3-(furan-3-yl)-1H-indazol-5-yl)benzamide

embedded image

To a mixture of 3-cyano-2-fluorobenzoic acid (24.87 mg, 0.150 mmol), 3-(furan-3-yl)-1H-indazol-5-amine (30.0 mg, 0.150 mmol) and triethylamine (20.99 uL, 0.150 mmol) was added HATU (57.26 mg, 0.150 mmol) and the mixture was stirred at room temperature over the weekend. The reaction mixture was partitioned between water and EtOAc, the phases were separated, the aqueous layer was extracted with EtOAc (2×) and the combined organic phases washed with brine (1×), dried over anhydrous Na₂SO₄and evaporated to dryness. Crude material was purified by normal phase chromatography on a 25 g silica gel column using as a 0-100% EtOAc/cyclohexane gradient eluent. The purest fractions were combined and evaporated to dryness to afford the title compound (32 mg, 61% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 13.13 (br. s., 1H), 10.64 (br. s., 1H), 8.37 (d, J=0.9 Hz, 1H), 8.22 (dd, J=0.8, 1.4 Hz, 1H), 8.18-8.03 (m, 2H), 7.86 (t, J=1.7 Hz, 1H), 7.68-7.53 (m, 3H), 7.00 (dd, J=0.8, 1.9 Hz, 1H). MS-ESI (m/z) calc'd for C₁₈H₁₂FN₄O₂[M+H]⁺: 347.1. Found 347.1.

Example 78: 4-Cyano-N-(3-(furan-3-yl)-1H-indazol-5-yl)-6-methylpicolinamide

embedded image

To a mixture of 4-cyano-6-methylpyridine-2-carboxylic acid (24.42 mg, 0.150 mmol), 3-(furan-3-yl)-1H-indazol-5-amine (30.0 mg, 0.150 mmol) and triethylamine (20.99 uL, 0.150 mmol) was added HATU (57.26 mg, 0.150 mmol) and the mixture was stirred at room temperature over the weekend. The reaction mixture was partitioned between water and EtOAc, the phases were separated, the aqueous layer was extracted with EtOAc (2×) and the combined organic phases washed with brine (1×), dried over anhydrous Na₂SO₄and evaporated to dryness. The material obtained was purified by normal phase chromatography on a 25 g silica gel column using a 0-100% EtOAc/cyclohexane gradient eluent. Clean fractions were combined and evaporated to dryness to afford crude product which was further purified by preparative HPLC (method 0) to afford the title compound (20.7 mg, 40% yield) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 13.12 (s, 1H), 10.60 (s, 1H), 8.45 (d, J=1.5 Hz, 1H), 8.37-8.27 (m, 2H), 8.07 (d, J=0.9 Hz, 1H), 7.96 (dd, J=1.9, 8.9 Hz, 1H), 7.86 (t, J=1.7 Hz, 1H), 7.59 (d, J=8.8 Hz, 1H), 7.03 (dd, J=0.9, 1.8 Hz, 1H), 2.74 (s, 3H). MS-ESI (m/z) calc'd for C₁₉H₄N₅O₂[M+H]⁺: 344.1. Found 344.2.

Example 79: 4-Cyano-3-fluoro-N-(3-(furan-3-yl)-1H-indazol-5-yl)picolinamide

embedded image

To a mixture of 4-cyano-3-fluoropyridine-2-carboxylic acid (25.02 mg, 0.150 mmol), 3-(furan-3-yl)-1H-indazol-5-amine (30.0 mg, 0.150 mmol) and triethylamine (20.99 uL, 0.150 mmol) was added HATU (57.26 mg, 0.150 mmol) and the mixture was stirred at room temperature over the weekend. The reaction mixture was partitioned between water and EtOAc, the phases were separated, the aqueous layer was extracted with EtOAc (2×) and the combined organic phases washed with brine (1×), dried over anhydrous Na₂SO₄and evaporated to dryness. The material was purified by reversed phase chromatography using a 5-55% CH₃CN/H₂O (0.1% formic acid) gradient eluent on a 12 g C18 column. Pure fractions were combined and evaporated to dryness to afford the title compound (24 mg, 46% yield) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 13.12 (s, 1H), 10.77 (s, 1H), 8.82 (d, J=4.8 Hz, 1H), 8.43 (s, 1H), 8.32-8.24 (m, 2H), 7.90-7.80 (m, 2H), 7.58 (d, J=9.0 Hz, 1H), 7.01 (d, J=0.9 Hz, 1H). MS-ESI (m/z) calc'd for C₁₅H₁₁FN₅O₂[M+H]⁺: 348.1. Found 348.1.

Example 80: 5-Cyano-N-(3-(furan-3-yl)-7-methyl-1H-indazol-5-yl)-3-methylpicolinamide

embedded image

Step 1: 3-Iodo-7-methyl-5-nitro-1H-indazole

embedded image

7-Methyl-5-nitro-1H-indazole (500.0 mg, 2.82 mmol) was dissolved in DCM (7 mL). The solution was cooled to 0° C. and 1-iodopyrrolidine-2,5-dione (698.46 mg, 3.1 mmol) was added in portions. The mixture was stirred at room temperature overnight. Then 1 additional equivalent of NIS was added and the mixture was stirred at 50° C. for 24 hrs. The mixture was quenched with water and extracted with DCM (2×). The combined organic layers were washed with water (1×), passed through a phase separator and evaporated to dryness. The residue was purified by column chromatography on a 100 g silica gel column using a 0-20% EtOAc/cyclohexane gradient eluent to afford the title compound (0.560 g, 65% yield) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 14.25 (br. s., 1H), 8.21-8.15 (m, 1H), 8.10 (dd, J=1.1, 2.0 Hz, 1H), 2.61 (s, 3H). MS-ESI (m/z) calc'd for C₈H₇IN₃O₂[M+H]⁺: 304.0. Found 304.0.

Step 2: 3-Iodo-7-methyl-1H-indol-5-amine

embedded image

A mixture of 3-iodo-7-methyl-5-nitro-1H-indazole (560.0 mg, 1.79 mmol), ammonium chloride (0.11 g, 1.97 mmol) and iron powder (400.42 mg, 7.17 mmol) in ethanol (10 mL) and water (10 mL) was stirred at 80° C. for 2 hrs. The solids were removed by filtration through Celite and the solid was washed with EtOH. Volatiles were removed from the filtrate under vacuum and re-dissolved in EtOAc. Water was added and the two phases were separated, the aqueous layer was extracted with EtOAc (2×) and the combined organic layers were washed with water (1×), dried over anhydrous Na₂SO₄and the solvent was removed under reduced pressure to afford the title compound (430 mg, 88% yield) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 13.24-12.97 (m, 1H), 6.64 (dd, J=1.0, 1.9 Hz, 1H), 6.26 (s, 1H), 4.88 (br. s., 2H), 2.38 (s, 3H). MS-ESI (m/z) calc'd for C₈H₉IN₃[M+H]⁺: 274.0. Found 274.0.

Step 3: 3-(Furan-3-yl)-7-methyl-1H-indazol-5-amine

embedded image

3-Furanylboronic acid (264.29 mg, 2.36 mmol), 3-iodo-7-methyl-1H-indazol-5-amine (430.0 mg, 1.57 mmol) and tripotassium phosphate (1002.78 mg, 4.72 mmol) were dissolved in a mixture of THF (9 mL) and water (3 mL). The reaction mixture was degassed with nitrogen for 15 min and then SPhos-Pd-G2 (170.21 mg, 0.240 mmol) was added. The mixture was heated to 80° C. and stirred for 16 hrs. The reaction was cooled to rt and then diluted with water and EtOAc. The phases were separated, the aqueous layer was extracted with EtOAc (2×) and the combined organic layers washed with water (1×), dried over anhydrous Na₂SO₄and then concentrated under reduced pressure. The material was purified by reversed phase column chromatography on a 30 g C₁₈column using a 3-15% CH₃CN/H₂O (0.1% formic acid) gradient eluent to afford the title compound (60 mg, 18% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 12.67 (br. s., 1H), 8.13 (dd, J=0.8, 1.4 Hz, 1H), 7.78 (t, J=1.7 Hz, 1H), 6.94 (dd, J=0.9, 1.8 Hz, 1H), 6.80 (d, J=1.3 Hz, 1H), 6.61 (dd, J=0.9, 1.8 Hz, 1H), 2.41 (s, 3H). MS-ESI (m/z) calc'd for C₁₂H₁₂N₃O [M+H]⁺: 214.1. Found 214.1.

Step 4: 5-Cyano-N-(3-(furan-3-yl)-7-methyl-1H-indazol-5-yl)-3-methylpicolinamide

embedded image

To a mixture of 5-cyano-3-methylpyridine-2-carboxylic acid (22.81 mg, 0.140 mmol), 3-(furan-3-yl)-7-methyl-1H-indazol-5-amine (30.0 mg, 0.140 mmol) and triethylamine (39.22 uL, 0.280 mmol) was added HATU (53.49 mg, 0.140 mmol) and the mixture was stirred at room temperature for 1 hr. The reaction mixture was partitioned between water and EtOAc, the phases were separated. The aqueous layer was extracted with EtOAc (2×) and the combined organic phases were washed with brine (1×), dried over anhydrous Na₂SO₄and evaporated to dryness. The material was purified by silica gel chromatography on a 25 g column using a 0-100% EtOAc/cyclohexane gradient eluent. Product-containing fractions were combined, evaporated to dryness to afford impure material which was further purified by preparative HPLC (method P) to afford the title compound (16.5 mg, 33% yield) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 13.17 (s, 1H), 10.61 (s, 1H), 9.04-8.97 (m, 1H), 8.41 (dd, J=0.8, 1.9 Hz, 1H), 8.30-8.20 (m, 2H), 7.85 (t, J=1.7 Hz, 1H), 7.64 (s, 1H), 7.01 (dd, J=0.9, 1.8 Hz, 1H), 2.61 (s, 3H), 2.55 (s, 3H). MS-ESI (m/z) calc'd for C₂₀H₁₆N₅O₂[M+H]⁺: 358.1. Found 358.2.

Example 81: 5-Cyano-N-(3-(furan-3-yl)-1H-indazol-5-yl)-1,3-dimethyl-1H-pyrazole-4-carboxamide

embedded image

Prepared as described for 5-cyano-N-(3-(furan-3-yl)-1H-indazol-5-yl)-1,4-dimethyl-1H-pyrazole-3-carboxamide using ethyl 5-ethynyl-3-methyl-1H-pyrazole-4-carboxylate in place of ethyl 5-ethynyl-4-methyl-1H-pyrazole-3-carboxylate in step 2. ¹H NMR (400 MHz, DMSO-d₆) δ 13.11 (br s, 1H) 10.18 (s, 1H) 8.31 (s, 1H) 8.22 (s, 1H) 7.85 (t, J=1.59 Hz, 1H) 7.56 (s, 2H) 6.99 (d, J=1.10 Hz, 1H) 4.01 (s, 3H) 2.42 (s, 3H). MS-ESI (m/z) calc'd for C₁₈H₁₅N₆O₂[M+H]⁺: 347.1. Found 347.1.

Example 82: 5-Cyano-N-(3-(furan-3-yl)-1H-indazol-5-yl)isoxazole-3-carboxamide

embedded image

To a solution of 5-ethynylisoxazole-3-carboxylic acid (40 mg, 289.69 umol) and 3-(furan-3-yl)-1H-indazol-5-amine (69.25 mg, 347.62 umol) in pyridine (2 mL) was added EDCI (111.07 mg, 579.37 umol). The mixture was stirred at 20° C. for 12 hrs. The reaction was combined with another 10 mg batch and the combined reaction mixtures were concentrated under reduced pressure to remove solvent. The residue was purified by preparative HPLC under neutral condition (Method Z) and then further purified by preparative HPLC under TFA conditions (Method AA) to afford the title compound (10.14 mg, TFA salt) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.15 (s, 1H), 11.02 (s, 1H), 8.38 (s, 1H), 8.24 (s, 1H), 8.14 (s, 1H), 7.85 (s, 1H), 7.75 (d, J=9.0 Hz, 1H), 7.58 (d, J=8.9 Hz, 1H), 6.99 (s, 1H). MS-ESI (m/z) calc'd for C₁₆H₁₀N₅O₃[M+H]⁺: 320.1. Found 320.0.

Example 83: 5-Cyano-3-ethyl-N-(3-(furan-3-yl)-1H-indazol-5-yl)picolinamide

embedded image

Step 1: 2-Chloro-5-ethynyl-3-vinylpyridine

embedded image

A mixture of 3-bromo-2-chloro-5-ethynylpyridine (2 g, 9.20 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (1.42 g, 9.20 mmol, 1.56 mL), Pd(dppf)Cl₂.CH₂Cl₂(751.10 mg, 919.75 umol), Na₂CO₃(2 M, 13.80 mL) in dioxane (50 mL) was degassed and purged with N₂(3×). The mixture was then stirred at 90° C. for 1.5 hrs under N₂atmosphere and monitored by TLC (petroleum ether:EtOAc=10:1, Rf=0.48). The reaction mixture was concentrated under reduced pressure to remove solvent, diluted with H₂O (30 mL) and extracted with EtOAc (50 mL×4). The combined organic layers were dried over Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO; 20 g SepaFlash column) using a 0-7% EtOAc/petroleum ether gradient eluent to afford the title compound (920 mg, 30% yield) as a yellow solid.

Step 2: Methyl 5-ethynyl-3-vinylpicolinate

embedded image

A mixture of 2-chloro-5-ethynyl-3-vinylpyridine (900 mg, 5.47 mmol), Pd(dppf)Cl₂(400.10 mg, 547.00 umol), Et₃N (2.77 g, 27.35 mmol) in MeOH (10 mL) was degassed and purged with CO (3×), and then the mixture was stirred at 30° C. for 2 hrs under CO atmosphere (50 psi). The reaction mixture was concentrated under reduced pressure to remove solvent and purified by flash silica gel chromatography (ISCO; 20 g SepaFlash column) using a 0-8% EtOAc/petroleum ether gradient eluent to afford the title compound (240 mg, 23% yield) as a white solid.

Step 3: Methyl 3-ethyl-5-ethynylpicolinate

embedded image

A mixture of methyl 5-ethynyl-3-vinylpicolinate (230 mg, 1.22 mmol) and 10% Pd/C (200 mg) in EtOH (10 mL) was degassed and purged with H₂(3×). The mixture was then stirred at 20° C. for 2 hrs under H₂atmosphere (15 psi). The mixture was filtered and the filtrate was concentrated under reduced pressure to afford the title compound (170 mg) as a yellow solid which was used without further purification.

Step 4: 3-Ethyl-5-ethynylpicolinic acid

embedded image

To a solution methyl 3-ethyl-5-ethynylpicolinate of (170 mg, 893.80 umol) in THF (5 mL) was added NaOH (71.50 mg, 1.79 mmol). The mixture was stirred at 20° C. for 2 hrs and monitored by TLC (petroleum ether:EtOAc=3:1, Rf=0.00). The reaction mixture was diluted with H₂O (10 mL) and the mixture was adjusted to pH 3 with IN HCl. Then it was extracted with EtOAc (20 mL×6). The combined organic layers were dried over Na₂SO₄, filtered and concentrated under reduced pressure to afford the title compound (110 mg) as a pale yellow solid that was used without further purification.

Step 4: 5-Cyano-3-ethyl-N-(3-(furan-3-yl)-1H-indazol-5-yl)picolinamide

embedded image

To a solution of 3-ethyl-5-ethynylpicolinic acid (110 mg, 624.39 umol) in pyridine (3 mL) was added EDCI (239.39 mg, 1.25 mmol) and 3-(furan-3-yl)-1H-indazol-5-amine (136.82 mg, 686.83 umol). The mixture was stirred at 20° C. for 12 hrs. The reaction mixture was concentrated and purified by preparative HPLC (Method AB) to afford the title compound (65.03 mg, 21% yield) as a yellow solid, TFA salt. ¹H NMR (400 MHz, DMSO-d₆) δ 13.11 (br s, 1H) 10.71 (s, 1H) 9.00 (d, J=1.10 Hz, 1H) 8.42 (d, J=12.59 Hz, 2H) 8.25 (s, 1H) 7.85 (s, 1H) 7.76-7.82 (m, 1H) 7.56 (d, J=8.93 Hz, 1H) 7.00 (s, 1H) 2.97 (q, J=7.34 Hz, 2H) 1.24 (t, J=7.46 Hz, 3H). MS-ESI (m/z) calc'd for C₂₀H₁₆N₅O₂[M+H]⁺: 358.1. Found 358.1.

Example 84: 5-Cyano-N-(3-(furan-3-yl)-1H-indazol-5-yl)-3-vinylpicolinamide

embedded image

Prepared as described for 5-cyano-3-ethyl-N-(3-(furan-3-yl)-1H-indazol-5-yl)picolinamide using methyl 5-ethynyl-3-vinylpicolinate in place of methyl 3-ethyl-5-ethynylpicolinate in step 4. ¹H NMR (400 MHz, DMSO-d₆) δ 13.12 (br s, 1H) 10.79 (s, 1H) 9.06 (s, 1H) 8.82 (s, 1H) 8.43 (s, 1H) 8.26 (s, 1H) 7.73-7.88 (m, 2H) 7.56 (br d, J=8.80 Hz, 1H) 7.35 (br dd, J=17.42, 11.07 Hz, 1H) 7.00 (s, 1H) 6.14 (br d, J=17.48 Hz, 1H) 5.61 (br d, J=11.13 Hz, 1H). MS-ESI (m/z) calc'd for C₂₀H₁₄N₅O₂[M+H]⁺: 358.1. Found 356.0.

Example 85: 5-Cyano-N-(3-(furan-3-yl)-1H-indazol-5-yl)-4,6-dimethylpicolinamide

embedded image

Step 1: 2,4-Dimethyl-6-vinylnicotinonitrile

embedded image

A mixture of 6-chloro-2,4-dimethylnicotinonitrile (70.0 mg, 0.420 mmol), tributyl(vinyl)tin (0.15 mL, 0.500 mmol) and tetrakis(triphenylphosphine)palladium(0) (24.28 mg, 0.020 mmol) in toluene (3.6 mL) was heated in a sealed tube at 100° C. for 1.5 hrs. After cooling to r.t., volatiles were evaporated at reduced pressure and the residue was partitioned between EtOAc and water. The organic phase was concentrated under reduced pressure and purified by reversed phase column chromatography using a 0-30% EtOAc/cyclohexane gradient eluent (C-18 Biotage) to afford the title compound (90 mg) as a pale yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 7.09 (s, 1H), 6.75 (dd, J=17.4, 10.7 Hz, 1H), 6.33 (dd, J=17.4, 1.2 Hz, 1H), 5.62 (dd, J=10.7, 1.2 Hz, 1H), 2.74 (s, 3H), 2.52 (s, 3H). MS-ESI (m/z) calc'd for C₁₀H₁₁N₂[M+H]⁺: 159.1. Found 159.0.

Step 2: 5-Cyano-4,6-dimethylpicolinic acid

embedded image

To a solution of 2,4-dimethyl-6-vinylnicotinonitrile (90.0 mg, 0.570 mmol) in acetone (3.3 mL) and water (3.3 mL) was added potassium permanganate (89.9 mg, 0.570 mmol). The mixture was stirred at r.t. for 1 hr. The solution was then diluted with water and extracted with EtOAc. The organic phase was concentrated under reduced pressure to afford the title compound (60 mg, 60% yield) which was used directly without further purification. MS-ESI (m/z) calc'd for C₉H₉N₂O₂[M+H]⁺: 177.1. Found 177.0.

Step 3: 5-(Cyano-N-(3-(furan-3-yl)-1H-indazol-5-yl)-4,6-dimethylpicolinamide

embedded image

5-Cyano-4,6-dimethylpicolinic acid (60.0 mg, 0.340 mmol) and 3-(furan-3-yl)-1H-indazol-5-amine (0.12 mL, 0.440 mmol) were dissolved in DMF (3.014 mL). Triethylamine (0.06 mL, 0.410 mmol) and HATU (129.5 mg, 0.340 mmol) were sequentially added and the mixture was stirred at r.t. for 18 hrs. Water was added and the mixture was extracted with EtOAc. The organic phase was dried over Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by reverse phase column chromatography (Cis-cartridge, MeCN in H₂O+0.1% HCOOH, [2%, 100%, 7 CV] and then with 100% MeOH). The product-containing fractions were collected and concentrated under reduced pressure. The residue was triturated with MeCN and then the solid phase was filtered. To remove traces of solvent, the product was taken up in 1 mL of water and then concentrated and dried to afford the title compound (13.6 mg, 11% yield) as a beige solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.11 (s, 1H), 10.62 (s, 1H), 8.45 (s, 1H), 8.33 (s, 1H), 8.09 (s, 1H), 7.97 (dd, J=9.0, 1.9 Hz, 1H), 7.85 (t, J=1.7 Hz, 1H), 7.59 (d, J=9.0 Hz, 1H), 7.03 (d, J=1.9 Hz, 1H), 2.84 (s, 3H), 2.63 (s, 3H). MS-ESI (m/z) calc'd for C₂₀H₁₆N₅O₂[M+H]⁺: 358.1. Found 358.2.

Example 86: 2-Chloro-3-cyano-N-(3-(furan-3-yl)-1H-indazol-5-yl)benzamide

embedded image

To a mixture of 2-chloro-3-cyanobenzoic acid (45.58 mg, 0.250 mmol), 3-(furan-3-yl)-1H-indazol-5-amine (50.0 mg, 0.250 mmol) and triethylamine (34.98 uL, 0.250 mmol) was added HATU (95.43 mg, 0.250 mmol) and the mixture was stirred at room temperature for 56 hrs. The reaction mixture was partitioned between water and EtOAc, the phases were separated, the aqueous layer was extracted with EtOAc (2×) and the combined organic phases were washed with water (1×), dried over anhydrous Na₂SO₄and evaporated to dryness. The material was purified by silica gel chromatography on a 25 g column using a 0-80% EtOAc/cyclohexane gradient eluent to afford the title compound (73 mg, 80% yield) as an off-white solid. ¹H NMR (400 MHz, DMSO-d₄) δ ppm 13.13 (br. s., 1H), 10.69 (br. s., 1H), 8.37 (s, 1H), 8.23-8.18 (m, 1H), 8.13 (dd, J=1.7, 7.8 Hz, 1H), 8.00 (dd, J=1.5, 7.7 Hz, 1H), 7.86 (t, J=1.7 Hz, 1H), 7.71 (t, J=7.7 Hz, 1H), 7.64-7.55 (m, 2H), 6.99 (dd, J=0.8, 1.9 Hz, 1H). MS-ESI (m/z) calc'd for C₁₉H₁₂ClN₄O₂[M+H]⁺: 363.1. Found 363.1, 365.0.

Example 87: 5-Cyano-N-(3-iodo-1H-indazol-5-yl)-3-methylpicolinamide

embedded image

To a mixture of 3-iodo-1H-indazol-5-amine (2.3 g, 8.88 mmol) and 5-cyano-3-methylpyridine-2-carboxylic acid (1.06 g, 6.51 mmol) in MeCN (57.58 mL) was added triethylamine (906.85 uL, 6.51 mmol) and HATU (2.47 g, 6.51 mmol). The mixture was stirred at r.t. for 45 minutes. The suspension was filtered and the residue was washed with MeCN and water. The solid was dried under reduced pressure at 50° C. for 18 hrs. To remove traces of impurities, the solid was triturated with MeOH and water and then filtered. The solid was washed with MeOH and then dried under reduced pressure to afford the title compound (2.49 g, 95% yield) as a beige solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.50 (s, 1H), 10.80 (s, 1H), 9.00 (d, J=1.9 Hz, 1H), 8.41 (d, J=2.0 Hz, 1H), 8.14 (s, 1H), 7.72 (dd, J=9.0, 1.9 Hz, 1H), 7.56 (d, J=8.9 Hz, 1H), 2.59 (s, 3H). MS-ESI (m/z) calc'd for C₁₅H₁₀IN₅O [M+H]⁺: 404.1. Found 404.1.

Example 88: 3-Cyano-N-(3-(furan-3-yl)-7-methyl-1H-indazol-5-yl)-2-methylbenzamide

embedded image

To a mixture of 3-cyano-2-methylbenzoic acid (22.67 mg, 0.140 mmol), 3-(furan-3-yl)-7-methyl-1H-indazol-5-amine (30.0 mg, 0.140 mmol) and triethylamine (39.22 uL, 0.280 mmol) was added HATU (53.49 mg, 0.140 mmol) and the mixture was stirred at room temperature overnight. The reaction mixture was partitioned between water and EtOAc and the phases were separated. The aqueous layer was extracted with EtOAc (2×) and the combined organic phases washed with brine (1×), dried over anhydrous Na₂SO₄and evaporated to dryness. The material was dissolved in DMF and purified by silica gel chromatography on a 25 g column using a 0-80% EtOAc/cyclohexane gradient eluent to afford the title compound (18 mg, 36% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 13.16 (s, 1H), 10.42 (s, 1H), 8.19 (d, J=6.6 Hz, 2H), 7.93 (d, J=6.8 Hz, 1H), 7.87-7.78 (m, 2H), 7.54 (t, J=7.7 Hz, 1H), 7.45 (s, 1H), 6.99 (s, 1H), 2.90 (s, 1H), 2.59 (s, 3H), 2.54 (s, 3H). MS-ESI (m/z) calc'd for C₂₁H₁₇N₄O₂[M+H]⁺: 357.1. Found 357.2.

Example 89: 2-Bromo-3-cyano-N-(3-(furan-3-yl)-1H-indazol-5-yl)benzamide

embedded image

To a mixture of 2-bromo-3-cyanobenzoic acid (113.46 mg, 0.500 mmol), 3-(furan-3-yl)-1H-indazol-5-amine (100.0 mg, 0.500 mmol) and triethylamine (50.8 mg, 0.500 mmol) was added HATU (190.87 mg, 0.500 mmol) and the mixture was stirred at room temperature over the weekend. The reaction mixture was partitioned between water and EtOAc, the phases were separated, the aqueous layer was extracted with EtOAc (2×) and the combined organic phases washed with brine (1×), dried over anhydrous Na₂SO₄and evaporated to dryness. The material was purified by silica gel chromatography on a 25 g column using a 0-100% EtOAc/cyclohexane gradient eluent. Pure fractions were combined and evaporated to dryness to afford the title compound (29 mg, 0.071 mmol) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 13.12 (br. s., 1H), 10.65 (br. s., 1H), 8.37 (s, 1H), 8.23-8.16 (m, 1H), 8.08 (dd, J=1.7, 7.8 Hz, 1H), 7.93 (dd, J=1.7, 7.6 Hz, 1H), 7.86 (t, J=1.7 Hz, 1H), 7.74 (t, J=7.7 Hz, 1H), 7.67-7.53 (m, 2H), 6.99 (dd, J=0.8, 1.9 Hz, 1H). MS-ESI (m/z) calc'd for C₁₉H₁₂BrN₄O₂[M+H]⁺: 407.0. Found 407.1, 409.1.

Example 90: 3-Cyano-N-(3-(furan-3-yl)-1H-indazol-5-yl)-1,5-dimethyl-1H-pyrazole-4-carboxamide

embedded image

Prepared as described for 5-cyano-N-(3-(furan-3-yl)-1H-indazol-5-yl)-1,4-dimethyl-1H-pyrazole-3-carboxamide using 3-cyano-1,5-dimethyl-1H-pyrazole-4-carboxylic acid in place of 5-cyano-1,4-dimethyl-1H-pyrazole-3-carboxylic acid in step 4. ¹H NMR (400 MHz, DMSO-d₆) δ 13.10 (br s, 1H) 10.24 (s, 1H) 8.30 (s, 1H) 8.22 (s, 1H) 7.85 (t, J=1.59 Hz, 1H) 7.56 (s, 2H) 6.98 (d, J=1.22 Hz, 1H) 3.91 (s, 3H) 2.49 (br s, 3H). MS-ESI (m/z) calc'd for C₁₈H₁₅N₆O₂[M+H]⁺: 347.1. Found 347.1.

Example 91: 5-Cyano-N-(3-(furan-3-yl)-1H-indazol-5-yl)isothiazole-3-carboxamide

embedded image

Step 1: 3-Azidothiophene-2-carbaldehyde

embedded image

To a stirred solution of 3-bromothiophene-2-carbaldehyde (2 g, 10.47 mmol) in DMSO (15 mL) was added NaN₃(2.72 g, 41.87 mmol). The reaction mixture was stirred at 80° C. for 4 hrs under N₂and monitored by TLC (petroleum ether:EtOAc=5:1, R_f=0.40). After cooling to 20° C., the reaction mixture was poured into water (100 mL) and extracted with EtOAc (100 mL×2). The combined organic phases were dried over anhydrous Na₂SO₄, filtered and concentrated. The residue was purified by silica gel column chromatography using a 0-20% EtOAc/petroleum ether gradient eluent to afford the title compound (1 g, 62% yield) as a light yellow solid.

Step 2: Ethyl (Z)-2-azido-3-(3-azidothiophen-2-yl)acrylate

embedded image

To a stirred solution of EtONa (3.17 g, 9.30 mmol, 20% purity) in EtOH (20 mL) at −15° C. was added a mixture of 3-azidothiophene-2-carbaldehyde (950 mg, 6.20 mmol) and ethyl 2-azidoacetate (800.86 mg, 6.20 mmol, 870.50 uL) in EtOH (10 mL) dropwise while keeping the temperature below −10° C. The reaction mixture was stirred at −15° C. for 2.5 hrs and monitored by TLC (petroleum ether:EtOAc=5:1, Rf=0.50). After warming to 0° C., the reaction mixture was poured into water (30 mL) and extracted with EtOAc (30 mL×3). The combined organic phases were dried over anhydrous Na₂SO₄, filtered and concentrated. The residue was purified by silica gel column chromatography using a 0-20% EtOAc/petroleum ether gradient eluent to afford the title compound (210 mg, 13% yield) as a light yellow solid.

Step 4: Ethyl 5-cyanoisothiazole-3-carboxylate

embedded image

Ethyl (Z)-2-azido-3-(3-azidothiophen-2-yl)acrylate (210 mg, 794.66 umol) was dissolved in toluene (5 mL) and the reaction mixture was stirred at 110° C. for 0.5 hr under N₂and monitored by TLC (petroleum ether:EtOAc=4:1, Rf=0.50). After cooling to 20° C., the reaction mixture was concentrated and the residue was purified by silica gel column chromatography using a 0-20% EtOAc/petroleum ether gradient eluent to afford the title compound (30 mg, 21% yield) as a yellow oil.

Step 5: 5-Cyano-N-(3-(furan-3-yl)-1H-indazol-5-yl)isothiazole-3-carboxamide

embedded image

To a stirred solution of ethyl 5-cyanoisothiazole-3-carboxylate (20 mg, 109.77 umol) and 3-(furan-3-yl)-1H-indazol-5-amine (21.87 mg, 109.77 umol) in toluene (1 mL) was added AlMe₃(2 M, 109.77 uL) and the reaction mixture was stirred at 20° C. for 12 hrs. The reaction mixture was poured into ice-water (3 mL) and extracted with EtOAc (3 mL×3). The combined organic phases were concentrated. The residue was purified by preparative HPLC (Method AC) to afford the title compound (6.31 mg, 17% yield) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.67 (s, 1H), 8.49-8.39 (m, 1H), 8.25 (s, 1H), 7.93-7.81 (m, 2H), 7.57 (br d, J=8.9 Hz, 1H), 7.04-6.98 (m, 1H). MS-ESI (m/z) calc'd for C₁₆H₁₀N₅O₂S [M+H]⁺: 336.1. Found 336.1.

Example 92: 3-Cyano-N-(3-(furan-3-yl)-1H-indazol-5-yl)-1,4-dimethyl-1H-pyrazole-5-carboxamide

embedded image

Prepared as described for 5-cyano-N-(3-(furan-3-yl)-1H-indazol-5-yl)-1,4-dimethyl-1H-pyrazole-3-carboxamide using ethyl 3-ethynyl-1,4-dimethyl-1H-pyrazole-5-carboxylate in place of ethyl 5-cyano-1,4-dimethyl-1H-pyrazole-3-carboxylate in step 2. ¹H NMR (400 MHz, DMSO-d₆) δ 13.15 (br s, 1H) 10.57 (br s, 1H) 8.36 (s, 1H) 8.25 (s, 1H) 7.86 (s, 1H) 7.55-7.68 (m, 2H) 7.00 (s, 1H) 4.06 (s, 3H) 2.51 (br s, 3H). MS-ESI (m/z) calc'd for C₁₅H₅N₆O₂[M+H]⁺: 347.1. Found 347.1.

Example 93: 5-Cyano-N-(3-(furan-3-yl)-1H-indazol-5-yl)-1,4-dimethyl-1H-pyrazole-3-carboxamide

embedded image

Step 1: Ethyl 5-cyano-4-methyl-1H-pyrazole-3-carboxylate

embedded image

To a solution of ethyl but-2-ynoate (5 g, 44.59 mmol, 5.20 mL) and 2-aminoacetonitrile (7.43 g, 80.27 mmol, HCl) in CHCl₃(120 mL) and H₂O (4 mL) was added NaNO₂(9.23 g, 133.78 mmol). The mixture was stirred at 20° C. for 12 hrs and monitored by TLC (petroleum ether/EtOAc=5:1). The reaction mixture was diluted with H₂O (100 mL) and extracted with CHCl₃(30 mL×3). The combined organic layers were washed with brine (50 mL×1), dried over Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography using a 0-25% EtOAc/petroleum ether gradient eluent to afford the title compound (200 mg, 870.65 umol) as a yellow oil and ethyl 5-cyano-3-methyl-1H-pyrazole-4-carboxylate (140 mg, 687.59 umol) as a yellow solid.

Step 2: Ethyl 5-cyano-1,4-dimethyl-1H-pyrazole-3-carboxylate

embedded image

To a solution of ethyl 5-cyano-4-methyl-1H-pyrazole-3-carboxylate (150 mg, 837.17 umol) in DMF (2 mL) was added K₂CO₃(347.11 mg, 2.51 mmol) and the mixture was stirred at 20° C. for 0.5 hr, then MeI (142.59 mg, 1.00 mmol) was added and the resulting mixture was stirred at 20° C. for 12 hrs and monitored by TLC (SiO₂, petroleum ether/EtOAc=3/1). The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by preparative TLC (SiO₂, petroleum ether/EtOAc=3:1) to afford the title compound (40 mg, 25%) as a light yellow solid and ethyl 3-cyano-1,4-dimethyl-1H-pyrazole-5-carboxylate (100 mg, 517.59 umol) as a white solid.

Step 3: 5-Cyano-1,4-dimethyl-1H-pyrazole-3-carboxylic acid

embedded image

To a solution of ethyl 5-cyano-1,4-dimethyl-1H-pyrazole-3-carboxylate (15 mg, 77.64 umol) in THF (1 mL) and H₂O (0.5 mL) was added NaOH (6.21 mg, 155.28 umol) and the mixture was stirred at 20° C. for 1 hr. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was diluted with H₂O (10 mL) and adjusted pH to 3 with 1 N HCl. Then the aqueous phase was extracted with EtOAc (3 mL×3). The combined organic layers were dried over Na₂SO₄, filtered and concentrated under reduced pressure to afford the title compound (15 mg) as a white solid which was used without further purification.

Step 4: 5-Cyano-N-(3-(furan-3-yl)-1H-indazol-5-yl)-1,3-dimethyl-1H-pyrazole-4-carboxamide

embedded image

To a solution of 5-cyano-1,4-dimethyl-1H-pyrazole-3-carboxylic acid (15 mg, 90.83 umol) and 3-(furan-3-yl)-1H-indazol-5-amine (18.09 mg, 90.83 umol) in pyridine (1 mL) was added EDCI (34.82 mg, 181.65 umol) and the mixture was stirred at 20° C. for 12 hrs. The reaction was filtered and the filtrate was collected and purified by preparative HPLC (Method AD) to afford the title compound (13.37 mg, 42%) as a pale yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.04 (s, 1H) 10.23 (s, 1H) 8.37 (s, 1H) 8.25 (s, 1H) 7.79-7.89 (m, 2H) 7.52 (d, J=9.05 Hz, 1H) 7.00 (s, 1H) 4.10 (s, 3H) 2.42 (s, 3H). MS-ESI (m/z) calc'd for C15H₁₅N₆O₂[M+H]⁺: 347.1. Found 347.1.

Example 94: 5-Cyano-N-(3-(furan-3-yl)-1H-indazol-5-yl)₄-methylpicolinamide

embedded image

Step 1: Methyl 5-cyano-4-methylpicolinate

embedded image

A mixture of 6-bromo-4-methylnicotinonitrile (350 mg, 1.78 mmol), TEA (359.50 mg, 3.55 mmol) and Pd(dppf)Cl₂(259.95 mg, 355.27 umol) in MeOH (5 mL) and DMF (5 mL) was degassed and purged with CO (3×). The mixture was then stirred at 60° C. under a CO atmosphere (50 Psi) and monitored by TLC (petroleum ether:EtOAc=1:1, Rf=0.17). After 12 hrs, the temperature was raised to 70° C. and stirring under a CO atmosphere (50 Psi) was continued for 5 hrs. The reaction mixture was concentrated under reduced pressure to remove solvent and purified by silica gel column chromatography using a 0-30% EtOAc/petroleum ether gradient eluent to afford the title compound (360 mg, 81% yield) as a white solid.

Step 2: 5-Cyano-4-methylpicolinic acid

embedded image

To a solution of methyl 5-cyano-4-methylpicolinate (200 mg, 1.14 mmol) in H₂O (3 mL) and THF (9 mL) was added LiOH.H₂O (95.28 mg, 2.27 mmol). The mixture was stirred at 20° C. for 4 hrs. The reaction mixture was added to H₂O (10 mL) and acidified with IN HCl to pH=2, extracted with EtOAc (10 mL×4), the combined organic layers were dried over anhydrous Na₂SO₄, filtered and the filtrate was concentrated under vacuum to afford the title compound (150 mg) as a white solid which was used without further purification.

Step 3: 5-Cyano-N-(3-(furan-3-yl)-1H-indazol-5-yl)-4-methylpicolinamide

embedded image

To a solution of 5-cyano-4-methylpicolinic acid (100 mg, 616.73 umol) and 3-(furan-3-yl)-1H-indazol-5-amine (245.72 mg, 1.23 mmol) in pyridine (4 mL) was added EDCI (236.46 mg, 1.23 mmol) and the mixture was stirred at 20° C. for 12 hrs. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was diluted with DMF (1 mL) and acidified with TFA to pH=1. The mixture was purified by preparative HPLC (Method AE) to afford the title compound (117.52 mg, 42% yield) as a gray solid, TFA salt. ¹H NMR (400 MHz, DMSO-d₆) δ 13.10 (s, 1H), 10.81 (s, 1H), 9.11 (s, 1H), 8.50 (s, 1H), 8.29 (d, J=9.7 Hz, 2H), 8.01 (br d, J=8.9 Hz, 11H), 7.85 (s, 11H), 7.57 (d, J=8.9 Hz, 1H), 7.02 (s, 1H), 2.65 (s, 3H). MS-ESI (m/z) calc'd for C19H₁₄N₅O₂[M+H]⁺: 344.1. Found 344.2.

Example 95: 3-Chloro-5-cyano-N-(3-(furan-3-yl)-1H-indazol-5-yl)picolinamide

embedded image

To a mixture of 3-chloro-5-cyanopicolinic acid (36.51 mg, 0.200 mmol) and triethylamine (27.88 uL, 0.200 mmol) in MeCN (2 mL) was added HATU (76.05 mg, 0.200 mmol). The mixture was stirred at 25° C. for 5 minutes and then 3-(furan-3-yl)-1H-indazol-5-amine (39.84 mg, 0.200 mmol) was added and the mixture was stirred at 25° C. for 15 minutes. The solvent was evaporated and the residue was taken up in water and extracted with EtAOc (3×). The combined organic layers were passed through a phase separator and evaporated to obtain a residue which was purified by silica gel column chromatography using a 0-5% MeOH/DCM gradient eluent to afford the title compound (31 mg, 43% yield) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.14 (s, 1H), 10.85 (s, 1H), 9.13 (d, J=1.7 Hz, 1H), 8.82 (d, J=1.7 Hz, 1H), 8.37 (dd, J=1.9, 0.8 Hz, 1H), 8.22 (dd, J=1.5, 0.8 Hz, 11H), 7.85 (t, J=1.7 Hz, 11H), 7.67 (dd, J=9.0, 1.9 Hz, 1H), 7.58 (dd, J=8.9, 0.8 Hz, 1H), 6.99 (dd, J=1.8, 0.8 Hz, 1H). MS-ESI (m/z) calc'd for C₁₅H₁₁ClN₅O₂[M+H]⁺: 364.1, 366.1. Found 364.0, 366.0.

Example 96: 5-Cyano-N-(3-(furan-3-yl)-1H-indazol-5-yl)-1-methyl-1H-imidazole-2-carboxamide

embedded image

Step 1: 5-Cyano-1-methyl-1H-imidazole-2-carboxylic acid

embedded image

To a solution of 1-methyl-1H-imidazole-5-carbonitrile (100 mg, 933.59 umol) in THF (6 mL) was added LDA (2 M, 560.16 uL) at −78° C. and the reaction mixture was stirred at −78° C. for 0.5 hr. Then dry ice (410.87 mg, 9.34 mmol) was added and the reaction mixture was stirred at −78° C. for 1.5 hrs under N₂(15 Psi). The reaction mixture was quenched with water (10 mL), basified to pH=9 with saturated aqueous Na₂CO₃, and extracted with EtOAc (15 mL×2). The aqueous phase was then acidified to pH=3 with IN HCl solution and the mixture was filtered and dried to afford the title compound (60 mg, 43% yield) as a white solid, which was used without further purification.

Step 2: 5-Cyano-N-(3-(furan-3-yl)-1H-indazol-5-yl)-1-methyl-1H-imidazole-2-carboxamide

embedded image

To a solution of 5-cyano-1-methyl-1H-imidazole-2-carboxylic acid (40 mg, 264.69 umol) in pyridine (1 mL) was added EDCI (101.48 mg, 529.37 umol) and 3-(furan-3-yl)-1H-indazol-5-amine (52.73 mg, 264.69 umol) and the reaction mixture was stirred at 20° C. for 12 hrs. The reaction mixture was concentrated and purified by preparative HPLC (Method AF) to afford the title compound (38.95 mg, 44% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.08 (br s, 1H), 10.65 (br s, 1H), 8.41 (s, 1H), 8.26 (s, 1H), 8.04 (s, 1H), 7.88 (br d, J=8.9 Hz, 1H), 7.84 (s, 1H), 7.55 (d, J=9.0 Hz, 1H), 7.01 (s, 1H), 4.12 (s, 3H). MS-ESI (m/z) calc'd for C₁₇H₁₃N₆O₂[M+H]⁺: 333.1. Found 333.0.

Example 97: 5-Cyano-N-(3-(furan-3-yl)-1H-indazol-5-yl)-1-methyl-1H-pyrazole-3-carboxamide

embedded image

Step 1: Methyl 5-cyano-1-methyl-1H-pyrazole-3-carboxylate

embedded image

To a solution of methyl 5-bromo-1-methyl-1H-pyrazole-3-carboxylate (200 mg, 913.09 umol) in DMF (5 mL) was added CuCN (327.12 mg, 3.65 mmol). The mixture was stirred at 140° C. for 12 hrs in a sealed tube. The reaction mixture was concentrated and purified by silica gel column chromatography using a 0-30% EtOAc/petroleum ether gradient eluent to afford the title compound (60 mg, 40% yield) as a white solid and methyl 5-carbamoyl-1-methyl-1H-pyrazole-3-carboxylate (28 mg, 152.87 umol) as a pale yellow solid.

Step 2: 5-Cyano-N-(3-(furan-3-yl)-1H-indazol-5-yl)-1-methyl-1H-pyrazole-3-carboxamide

embedded image

To a solution of methyl 5-cyano-1-methyl-1H-pyrazole-3-carboxylate (50 mg, 302.76 umol) and methyl 5-carbamoyl-1-methyl-1H-pyrazole-3-carboxylate (90.47 mg, 454.14 umol) in toluene (2 mL) was added AlMe₃(2 M, 454.14 uL). The mixture was stirred at 80° C. for 12 hrs. The reaction mixture was concentrated under reduced pressure and purified by preparative HPLC (Method AH) to afford the title compound (45.23 mg, 33% yield) as a brown solid, TFA salt. ¹H NMR (400 MHz, DMSO-d₄) δ 13.08 (s, 1H) 10.37 (s, 1H) 8.39 (s, 1H) 8.25 (s, 1H) 7.80-7.88 (m, 2H) 7.65 (s, 1H) 7.53 (d, J=9.04 Hz, 1H) 7.00 (s, 1H) 4.15 (s, 3H). MS-ESI (m/z) calc'd for C₁₇H₁₃N₆O₂[M+H]⁺: 333.1. Found 333.0.

Example 98: 5-Cyano-3-methyl-N-(3-(o-tolyl)-1H-indazol-5-yl)picolinamide

embedded image

Prepared as described for 5-cyano-N-(3-(2-methoxyphenyl)-1H-indazol-5-yl)-3-methylpicolinamide using o-tolylboronic acid in place of (2-methoxyphenyl)boronic acid in step 2. ¹H NMR (400 MHz, DMSO-d₆) δ 13.21 (br s, 1H), 10.72 (s, 1H), 8.97 (d, J=1.1 Hz, 11H), 8.38 (s, 1H), 8.23 (s, 1H), 7.72 (dd, J=1.5, 9.0 Hz, 1H), 7.59 (d, J=9.0 Hz, 1H), 7.53-7.46 (m, 1H), 7.44-7.31 (m, 3H), 2.54 (s, 3H), 2.36 (s, 3H). MS-ESI (m/z) calc'd for C₂₂H₁₈N₅O [M+H]⁺: 368.1. Found 368.1.

Example 99: 5-Cyano-N-(3-(2-methoxyphenyl)-1H-indazol-5-yl)-3-methylpicolinamide

embedded image

Step 1: 3-Bromo-1H-indazol-5-amine

embedded image

To a solution of 3-bromo-5-nitro-1H-indazole (1.42 g, 5.87 mmol) in EtOH (30 mL) was added SnCl₂.2H₂O (6.62 g, 29.34 mmol). The mixture was stirred at 90° C. for 12 hrs and monitored by TLC (petroleum ether:EtOAc=1:1, Rf=0.40). The reaction mixture was concentrated under reduced pressure to remove solvent and then diluted with 1 M NaOH (70 mL) and extracted with EtOAc (80 mL×4). The combined organic layers were dried over Na₂SO₄, filtered and concentrated under reduced pressure to afford the title compound (1.1 g) as a blue solid which was used without further purification.

Step 2: 3-(2-Methoxyphenyl)-1H-indazol-5-amine

embedded image

To a solution of 3-bromo-1H-indazol-5-amine (600 mg, 2.83 mmol) in dioxane (8 mL) and H₂O (8 mL) was added (2-methoxyphenyl)boronic acid (644.95 mg, 4.24 mmol), Pd(dppf)Cl₂(207.04 mg, 282.96 umol) and Na₂CO₃(1.50 g, 14.15 mmol). The mixture was stirred at 120° C. for 3 hrs under N₂atmosphere and monitored by TLC (petroleum ether:EtOAc=1:1, Rf=0.25). The reaction mixture was concentrated under reduced pressure to remove solvent and purified by flash silica gel chromatography (ISCO; 20 g SepaFlash column) using a 0-34% EtOAc/petroleum ether gradient to afford the title compound (400 mg, 59% yield) as a brown solid.

Step 3: 5-Cyano-N-(3-(2-methoxyphenyl)-1H-indazol-5-yl)-3-methylpicolinamide

embedded image

To a solution of 5-cyano-N-(3-(2-methoxyphenyl)-1H-indazol-5-yl)-3-methylpicolinamide (130 mg, 543.31 umol) in pyridine (3 mL) was added 5-cyano-3-methyl-pyridine-2-carboxylic acid (129.49 mg, 651.98 umol, HCl) and EDCI (208.31 mg, 1.09 mmol). The mixture was stirred at 20° C. for 12 hrs. The reaction mixture was concentrated and purified by preparative HPLC (Method AG) to afford the title compound (35.88 mg, 17% yield) as a pale yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.12 (br s, 1H) 10.65 (s, 1H) 8.97 (d, J=0.98 Hz, 1H) 8.38 (s, 1H) 8.24 (s, 1H) 7.65 (dd, J=8.93, 1.22 Hz, 1H) 7.53 (br d, J=8.19 Hz, 2H) 7.41-7.47 (m, 1H) 7.20 (d, J=8.31 Hz, 1H) 7.07 (t, J=7.40 Hz, 1H) 3.82 (s, 3H) 2.54 (s, 3H). MS-ESI (m/z) calc'd for C₂₂H₁₈N₅O₂[M+H]⁺: 384.1. Found 384.1.

Example 100: 5-Cyano-N-(3-(furan-3-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-methylpicolinamide

embedded image

Step 1: Methyl 5-cyano-3-methylpicolinate

embedded image

A mixture of methyl 5-bromo-3-methylpicolinate (1 g, 4.35 mmol), Zn(CN)₂(612.49 mg, 5.22 mmoL), Pd(PPh₃)₄(251.14 mg, 217.34 umol) in DMF (10 mL) was degassed and purged with N₂for 3 times, and then the mixture was stirred at 120° C. for 2 hrs under N₂atmosphere. The reaction mixture was concentrated to give a residue. The residue was purified by flash silica gel chromatography (ISCO; 4 g SepaFlash column) using a 0-10% EtOAc/petroleum ether gradient eluent to afford the title compound (640 mg, 84% yield) as a white solid.

Step 2: 5-Cyano-3-methylpicolinamide

embedded image

A stirred mixture of methyl 5-cyano-3-methylpicolinate (200 mg, 1.14 mmol) in NH₃.H₂O (18.20 g, 129.83 mmol, 20.00 mL, 25% purity) was stirred at 25° C. for 10 min. The mixture was extracted with EtOAc (6.0 mL×3). The combined organic layers were dried over Na₂SO₄and concentrated under vacuum to afford the title compound (180 mg) as a white solid which was used without further purification.

Step 3: 5-Chloro-3-(furan-3-yl)-1H-pyrazolo[4,3-b]pyridine

embedded image

To a stirred solution of 5-chloro-3-iodo-1H-pyrazolo[4,3-b]pyridine (Intermediate A-6, 5.0 g, 17.89 mmol) in dioxane (100 mL) was added furan-3-ylboronic acid (2.40 g, 21.47 mmol), followed by adding Pd(dppf)Cl₂(1.31 g, 1.79 mmol) and K₂CO₃(4.95 g, 35.78 mmol) in one portion. Then the mixture was stirred at 90° C. for 24 hrs under N₂. The mixture was cooled to room temperature and filtered. The filtrate was concentrated under vacuum and purified by silica gel column chromatography using a 5:1, then 2:1, then 1:1 petroleum ether/EtOAc step gradient to afford the title compound (700 mg) as a brown solid.

Step 4: 5-(Chloro-3-(furan-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-b]pyridine

embedded image

To a stirred solution of 5-chloro-3-(furan-3-yl)-1H-pyrazolo[4,3-b]pyridine (650 mg, 2.96 mmol) in DCM (20 mL) was added 3,4-dihydro-2H-pyran (373.42 mg, 4.44 mmol, 405.89 μL), followed by adding TsOH (50.96 mg, 295.96 μmol) in one portion. The mixture was then stirred at 25° C. for 12 hrs. The mixture was washed with 20% aq. sodium bicarbonate (5.0 mL 3), dried over Na₂SO₄and concentrated under vacuum to afford the title compound (1.2 g) as a brown oil which was used without further purification.

Step 5: 5-Cyano-N-(3-(furan-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-methylpicolinamide

embedded image

To a stirred solution of 5-chloro-3-(furan-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-b]pyridine (200 mg, 658.45 μmol) in toluene (10 mL) was added 5-cyano-3-methylpicolinamide (116.73 mg, 724.30 μmol), followed by adding Pd₂(dba)₃(30.15 mg, 32.92 μmol), XPhos (31.39 mg, 65.85 μmol) and Cs₂CO₃(536.34 mg, 1.65 mmol). Then the mixture was degassed under vacuum and purged with N₂(3×). Then the mixture was stirred at 110° C. for 12 hrs. The mixture was filtered. The filtrate was concentrated under vacuum and purified by Prep-TLC (petroleum ether:EtOAc=1/1, Rf=0.62) to afford the title compound (100 mg, 35% yield) as a yellow solid.

Step 6: 5-Cyano-N-(3-(furan-3-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-methylpicolinamide

embedded image

To a stirred solution of 5-cyano-N-(3-(furan-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-methylpicolinamide (90 mg, 210.06 umol) in DCM (3.0 mL) was added TFA (1.54 g, 13.51 mmol, 1 mL) dropwise at 0° C. Then the mixture was stirred at 25° C. for 1 hr. The mixture was concentrated under vacuum and purified by Prep-HPLC (Method E) to afford the TFA salt of the title compound (12.4 mg, 12% yield) as a pale yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.26-13.38 (m, 1H) 10.85-10.98 (m, 1H) 8.96-9.09 (m, 1H) 8.50-8.61 (m, 1H) 8.40-8.46 (m, 1H) 8.28-8.40 (m, 1H) 8.06-8.19 (m, 1H) 7.77-7.88 (m, 1H) 7.01-7.18 (m, 1H) 2.62 (br s, 3H). MS-ESI (m/z) calc'd for C₁₈H₁₃N₆O₂[M+H]⁺: 345.1. Found 345.1.

Further compounds of the invention, which were prepared according to the methods described above, are provided in Table 2 below.

TABLE 2

Ex.

No
Structure
Name
m/z

101

embedded image

5-cyano-N-(3-(isoxazol-5- yl)-1H-indazol-5-yl)-3- methylpicolinamide
345.23

102

embedded image

5-cyano-3-methyl-N-(3-(5- (morpholinomethyl)thiophen- 2-yl)-1H-indazol-5- yl)picolinamide
459.16

103

embedded image

N-(3-(2-bromopyridin-4-yl)- 1H-indazol-5-yl)-5-cyano-3- methylpicolinamide
433.15, 435.19

104

embedded image

2-cyano-1,5-dimethyl-N-(3- phenyl-1H-indazol-5-yl)-1H- imidazole-4-carboxamide
357.0

105

embedded image

5-cyano-N-(3-(furan-3-yl)- 1H-pyrazolo[4,3-b]pyridin-5- yl)-3-methylpicolinamide
345.1

106

embedded image

N-(3-bromo-1H-indazol-5- yl)-5-cyano-3- methylpicolinamide
355.9/ 357.9

107

embedded image

4-cyano-N-(3-(furan-3-yl)- 1H-indazol-5-yl)-2- hydroxybenzamide
345.0

108

embedded image

5-cyano-3-methyl-N-(3-(4- (morpholine-4- carbonyl)phenyl)-1H- indazol-5-yl)picolinamide
467.1

109

embedded image

5-cyano-N-(3-(5- isopropoxypyridin-3-yl)-1H- indazol-5-yl)-3- methylpicolinamide
413.1

110

embedded image

5-cyano-3-methyl-N-(3- (thiazol-5-yl)-1H-indazol-5- yl)picolinamide
361.1

111

embedded image

5-cyano-3-methyl-N-(3- (oxazol-5-yl)-1H-indazol-5- yl)picolinamide
345.2

112

embedded image

5-cyano-3-methyl-N-(3-(6- methylpyridin-2-yl)-1H- indazol-5-yl)picolinamide
369.0

113

embedded image

5-cyano-N-(3-(2- cyanopyridin-4-yl)-1H- indazol-5-yl)-3- methylpicolinamide
380.0

114

embedded image

5-cyano-3-methyl-N-(3- (pyridin-2-yl)-1H-indazol-5- yl)picolinamide
355.0

115

embedded image

5-cyano-N-(3-(2-((2S,6S)- 2,6- dimethylmorpholino)pyridin- 4-yl)-1H-indazol-5-yl)-3- methylpicolinamide
468.39

116

embedded image

4-cyano-N-(3-(furan-3-yl)- 1H-indazol-5-yl)thieno[2,3- c]pyridine-7-carboxamide
386.2

117

embedded image

5-cyano-N-(3-(2-(3R,5S)- 3,5-dimethylpiperidin-1- yl)pyridin-4-yl)-1H-indazol- 5-yl)-3-methylpicolinamide
466.42

118

embedded image

5-cyano-N-(3-(2-((2S,6R)- 2,6- dimethylmorpholino)pyridin- 4-yl)-1H-indazol-5-yl)-3- methylpicolinamide
468.41

119

embedded image

5-cyano-N-(3-(3-((2S,6R)- 2,6- dimethylmorpholino)phenyl)- 1H-indazol-5-yl)-3- methylpicolinamide
467.39

120

embedded image

3-cyano-2,6-difluoro-N-(3- (furan-3-yl)-1H-indazol-5- yl)benzamide
365.21

121

embedded image

N-(3-(5-chloropyridin-3-yl)- 1H-indazol-5-yl)-5-cyano-3- methylpicolinamide
389.1

122

embedded image

5-cyano-2-fluoro-N-(3- (furan-3-yl)-1H-indazol-5- yl)benzamide
347.1

123

embedded image

5-cyano-N-(3-(1,5-dimethyl- 1H-pyrazol-4-yl)-1H-indazol- 5-yl)-3-methylpicolinamide
372.1

124

embedded image

4-cyano-N-(3-(furan-3-yl)- 1H-indazol-5-yl)-1-methyl- 1H-imidazole-2-carboxamide
333.0

125

embedded image

5-cyano-N-(3-(furan-3-yl)- 1H-indazol-5-yl)-2- hydroxybenzamide
345.0

126

embedded image

N-(3-(1H-imidazol-1-yl)-1H- indazol-5-yl)-5-cyano-3- methylpicolinamide
344.2

127

embedded image

6-cyano-N-(3-(furan-3-yl)- 1H-indazol-5-yl)picolinamide
330.1

128

embedded image

3-cyano-2-fluoro-N-(3- (furan-3-yl)-1H-indazol-5- yl)-6-methylbenzamide
361.0

129

embedded image

5-cyano-3-methyl-N-(3-(2- methyloxazol-5-yl)-1H- indazol-5-yl)picolinamide
359.2

130

embedded image

5-cyano-N-(3-(4- cyanothiophen-2-yl)-1H- indazol-5-yl)-3- methylpicolinamide
385.0

131

embedded image

5-cyano-N-(3-(5- cyanothiophen-2-yl)-1H- indazol-5-yl)-3- methylpicolinamide
384.9

132

embedded image

4-cyano-N-(3-(furan-3-yl)- 1H-indazol-5-yl)pyrimidine- 2-carboxamide
331.19

133

embedded image

5-cyano-N-(3-(furan-3-yl)- 1H-indazol-5-yl)-4-methyl- 1H-pyrazole-3-carboxamide
333.0

134

embedded image

3-cyano-6-fluoro-N-(3- (furan-3-yl)-1H-indazol-5- yl)-2-methylbenzamide
361.1

135

embedded image

N-(3-benzamido-1H-indazol- 5-yl)-5-cyano-3- methylpicolinamide
397.2

136

embedded image

N-(3-(1H-pyrazol-1-yl)-1H- indazol-5-yl)-5-cyano-3- methylpicolinamide
344.0

137

embedded image

5-cyano-N-(3-(furan-3-yl)- 1H-indazol-5-yl)-3-methyl- 1H-pyrazole-4-carboxamide
333

138

embedded image

3-bromo-5-cyano-N-(3- (furan-3-yl)-1H-indazol-5- yl)picolinamide
407.9/ 409.9

139

embedded image

N-(3-(5-chlorothiophen-2- yl)-1H-indazol-5-yl)-5- cyano-3-methylpicolinamide
393.9/ 395.9

140

embedded image

5-cyano-3-methyl-N-(3-(2- methylthiazol-5-yl)-1H- indazol-5-yl)picolinamide
375.1

141

embedded image

5-cyano-3-methyl-N-(3-(5- methylfuran-2-yl)-1H- indazol-5-yl)picolinamide
358.2

142

embedded image

5-cyano-N-(3-(furan-3-yl)- 1H-indazol-5-yl)quinoline-8- carboxamide
380.13

143

embedded image

5-cyano-N-(7-fluoro-3- (furan-3-yl)-1H-indazol-5- yl)-3-methylpicolinamide
362.07

144

embedded image

3-chloro-4-cyano-N-(3- (furan-3-yl)-1H-indazol-5- yl)picolinamide
364.17

145

embedded image

5-cyano-N-(3-(furan-3-yl)- 1H-indazol-5-yl)-3- methylpyrazine-2- carboxamide
345.16

146

embedded image

5-cyano-N-(3-(isoxazol-4- yl)-1H-indazol-5-yl)-3- methylpicolinamide
345.73

147

embedded image

6-cyano-N-(3-(furan-3-yl)- 1H-indazol-5-yl)-3- methylpyrazine-2- carboxamide
345.16

148

embedded image

6-cyano-N-(3-(furan-3-yl)- 1H-indazol-5-yl)-3- methylpicolinamide
344.19

149

embedded image

4-cyano-3-ethyl-N-(3-(furan- 3-yl)-1H-indazol-5- yl)picolinamide
358.14

150

embedded image

5-cyano-3-ethynyl-N-(3- (furan-3-yl)-1H-indazol-5- yl)picolinamide
354.0

151

embedded image

5-cyano-3-methyl-N-(3-(1- methyl-6-oxo-1,6- dihydropyridin-3-yl)-1H- indazol-5-yl)picolinamide
385.0

152

embedded image

5-cyano-3-methyl-N-(3-(1- methyl-2-oxo-1,2- dihydropyridin-4-yl)-1H- indazol-5-yl)picolinamide
385.0

153

embedded image

5-cyano-3-methyl-N-(3-(1- methyl-1H-pyrazol-3-yl)-1H- indazol-5-yl)picolinamide
358.0

154

embedded image

5-cyano-N-(3-(furan-3-yl)- 1H-indazol-5-yl)-3- hydroxypicolinamide
346.0

155

embedded image

5-cyano-N-(3-(furan-3-yl)- 1H-pyrazolo[3,4-c]pyridin-5- yl)-3-methylpicolinamide
345.0

156

embedded image

5-cyano-3-methyl-N-(3- (thiazol-4-yl)-1H-indazol-5- yl)picolinamide
361.1

157

embedded image

5-cyano-N-(3-(1- (difluoromethyl)-1H-pyrazol- 4-yl)-1H-indazol-5-yl)-3,4- dimethylpicolinamide
408.18

158

embedded image

5-cyano-3,4-dimethyl-N-(3- (oxazol-5-yl)-1H-indazol-5- yl)picolinamide
359.21

159

embedded image

5-cyano-N-(3-(2- methoxypyridin-4-yl)-1H- indazol-5-yl)-3,4- dimethylpicolinamide
399.21

160

embedded image

5-cyano-N-(3-(isothiazol-4- yl)-1H-indazol-5-yl)-3- methylpicolinamide
361.0

161

embedded image

5-cyano-N-(3-(furan-3-yl)- 1H-pyrazolo[4,3- d]pyrimidin-5-yl)-3- methylpicolinamide
346.0

162

embedded image

6-cyano-N-(3-(furan-3-yl)- 1H-indazol-5-yl)-4- methylpyridazine-3- carboxamide
345.1

163

embedded image

3-cyano-N-(3-(1- (difluoromethyl)-1H-pyrazol- 4-yl)-1H-indazol-5-yl)-2,6- difluorobenzamide
415.21

164

embedded image

3-cyano-N-(3-(1- (difluoromethyl)-1H-pyrazol- 4-yl)-1H-indazol-5-yl)-2- methoxybenzamide
409.23

165

embedded image

4-cyano-N-(3-(1- (difluoromethyl)-1H-pyrazol- 4-yl)-1H-indazol-5-yl)-2- fluoro-6-methylbenzamide
411.31

166

embedded image

2-chloro-3-cyano-N-(3-(1- (difluoromethyl)-1H-pyrazol- 4-yl)-1H-indazol-5- yl)benzamide
413.2- 415.2

167

embedded image

3-cyano-N-(3-(1- (difluoromethyl)-1H-pyrazol- 4-yl)-1H-indazol-5-yl)-2- fluorobenzamide
397.24

168

embedded image

5-cyano-N-(3-(isoxazol-4- yl)-1H-indazol-5-yl)-3,4- dimethylpicolinamide
359.24

169

embedded image

5-cyano-3,4-dimethyl-N-(3- (1-(trifluoromethyl)-1H- pyrazol-4-yl)-1H-indazol-5- yl)picolinamide
426.31

170

embedded image

2-cyano-3-fluoro-N-(3-(2- methoxypyridin-4-yl)-1H- indazol-5-yl)isonicotinamide
389.26

171

embedded image

N-(3-(5-chloropyridin-3-yl)- 1H-indazol-5-yl)-5-cyano- 3,4-dimethylpicolinamide
403.27, 405.22

172

embedded image

5-cyano-N-(3-(1- (fluoromethyl)-1H-pyrazol-4- yl)-1H-indazol-5-yl)-3,4- dimethylpicolinamide
390.31

173

embedded image

3-cyano-N-(3-(furan-3-yl)- 1H-indazol-5-yl)-2- (trifluoromethyl)benzamide
397.23

174

embedded image

5-cyano-3,4-dimethyl-N-(3- (2-methyloxazol-5-yl)-1H- indazol-5-yl)picolinamide
373.29

175

embedded image

6-chloro-5-cyano-N-(3-(1- (difluoromethyl)-1H-pyrazol- 4-yl)-1H-indazol-5-yl)-3,4- dimethylpicolinamide
442.22; 444.23

176

embedded image

3-cyano-2-methoxy-N-(3- (oxazol-5-yl)-1H-indazol-5- yl)benzamide
360.2

177

embedded image

3-cyano-N-(3-(1- (difluoromethyl)-1H-pyrazol- 4-yl)-1H-indazol-5-yl)-2- fluoro-6-methylbenzamide
411.0

178

embedded image

5-cyano-N-3-(2- methoxypyrimidin-4-yl)-1H- indazol-5-yl)-3- (trifluoromethyl)picolinamide
439.2

179

embedded image

5-cyano-N-(3-(furan-3-yl)- 1H-indazol-5-yl)-4- methylisoxazole-3- carboxamide
334.0

180

embedded image

3-cyano-N-(3-(furan-3-yl)- 1H-indazol-5-yl)-4- methylisoxazole-5- carboxamide
334.0

181

embedded image

5-cyano-N-(3-(2- isopropyloxazol-5-yl)-1H- indazol-5-yl)-3,4- dimethylpicolinamide
401.0

182

embedded image

5-cyano-3,4-dimethyl-N-(3- (6-methylpyridin-2-yl)-1H- indazol-5-yl)picolinamide
383.2

183

embedded image

N-(3-(1H-pyrazol-4-yl)-1H- indazol-5-yl)-5-cyano-3,4- dimethylpicolinamide
358.28

184

embedded image

6-chloro-5-cyano-3,4- dimethyl-N-(3-(oxazol-5-yl)- 1H-indazol-5-yl)picolinamide
393.14; 395.13

185

embedded image

5-cyano-N-(3-(1- (difluoromethyl)-1H-pyrazol- 4-yl)-1H-indazol-5-yl)-3,4,6- trimethylpicolinamide
422.21

186

embedded image

5-cyano-3,4-dimethyl-N-(3- (1-methyl-1H-pyrrol-3-yl)- 1H-indazol-5-yl)picolinamide
371.22

187

embedded image

5-cyano-3,4-dimethyl-N-(3- (1-methyl-1H-pyrazol-4-yl)- 1H-indazol-5-yl)picolinamide
372.31

188

embedded image

3-cyano-2,6-difluoro-N-(3- (oxazol-5-yl)-1H-indazol-5- yl)benzamide
366.11

189

embedded image

4-cyano-N-(3-(1- (difluoromethyl)-1H-pyrazol- 4-yl)-1H-indazol-5-yl)-2- methoxybenzamide
409.26

190

embedded image

4-cyano-2-fluoro-6-methyl- N-(3-(oxazol-5-yl)-1H- indazol-5-yl)benzamide
362.2

191

embedded image

5-cyano-N-(3-(2,6- dimethylpyridin-4-yl)-1H- indazol-5-yl)-3,4- dimethylpicolinamide
397.3

192

embedded image

3-cyano-N-(3-(1- (difluoromethyl)-1H-pyrazol- 4-yl)-1H-indazol-5-yl)-2- (trifluoromethyl)benzamide
447.1

193

embedded image

3-cyano-N-(3-(1- (difluoromethyl)-1H-pyrazol- 4-yl)-1H-indazol-5-yl)-2,6- dimethylbenzamide
407.2

194

embedded image

3-cyano-N-(3-(2- methoxypyridin-4-yl)-1H- indazol-5-yl)-1,4-dimethyl- 1H-pyrazole-5-carboxamide
388.2

195

embedded image

3-cyano-N-(3-(1- (difluoromethyl)-1H-pyrazol- 4-yl)-1H-indazol-5-yl)-1,4- dimethyl-1H-pyrazole-5- carboxamide
397.2

196

embedded image

3-cyano-N-(3-(isoxazol-4- yl)-1H-indazol-5-yl)-1,4- dimethyl-1H-pyrazole-5- carboxamide
348.0

197

embedded image

5-cyano-3,4-dimethyl-N-(3- (4-methyloxazol-2-yl)-1H- indazol-5-yl)picolinamide
373.29

198

embedded image

5-cyano-3,4-dimethyl-N-(3- (oxazol-2-yl)-1H-indazol-5- yl)picolinamide
359.23

199

embedded image

3-cyano-2-fluoro-N-(3- (oxazol-5-yl)-1H-indazol-5- yl)benzamide
348.15

200

embedded image

4-cyano-2-methoxy-N-(3- (oxazol-5-yl)-1H-indazol-5- yl)benzamide
360.26

201

embedded image

4-cyano-N-(3-(1- (difluoromethyl)-1H-pyrazol- 4-yl)-1H-indazol-5-yl)-2- methoxy-6-methylbenzamide
423.3

202

embedded image

5-cyano-3,4,6-trimethyl-N- (3-(oxazol-5-yl)-1H-indazol- 5-yl)picolinamide
373.3

203

embedded image

3-cyano-2-fluoro-6-methyl- N-(3-(oxazol-5-yl)-1H- indazol-5-yl)benzamide
362.0

204

embedded image

5-cyano-N-(3-(1- (difluoromethyl)-1H-pyrazol- 3-yl)-1H-indazol-5-yl)-3,4- dimethylpicolinamide
408.0

205

embedded image

5-cyano-N-(3-(2- ethoxypyridin-4-yl)-1H- indazol-5-yl)-3,4- dimethylpicolinamide
413.0

206

embedded image

4-cyano-N-(3-(oxazol-5-yl)- 1H-indazol-5-yl)-6,7- dihydro-5H- cyclopenta[c]pyridine-1- carboxamide
371.19

207

embedded image

5-cyano-3,4-dimethyl-N-(3- (5-methyloxazol-2-yl)-1H- indazol-5-yl)picolinamide
373.26

208

embedded image

4-cyano-2-methoxy-6- methyl-N-(3-(oxazol-5-yl)- 1H-indazol-5-yl)benzamide
374.25

209

embedded image

2-chloro-3-cyano-N-(3- (oxazol-5-yl)-1H-indazol-5- yl)benzamide
364.16- 366.15

210

embedded image

5-cyano-N-(3-(isoxazol-4- yl)-1H-indazol-5-yl)-3,4,6- trimethylpicolinamide
373.26

211

embedded image

5-cyano-4-methoxy-3- methyl-N-(3-(oxazol-5-yl)- 1H-indazol-5-yl)picolinamide
375.2

212

embedded image

3-cyano-N-(3-(oxazol-5-yl)- 1H-indazol-5-yl)-2- (trifluoromethoxy)benzamide
413.9

213

embedded image

5-cyano-1,2-dimethyl-N-(3- (oxazol-5-yl)-1H-indazol-5- yl)-6-oxo-1,6- dihydropyridine-3- carboxamide
375.1

214

embedded image

3-cyano-N-(3-(oxazol-5-yl)- 1H-indazol-5-yl)-2-(prop-1- en-2-yl)benzamide
370.2

215

embedded image

5-cyano-3,4-dimethyl-N-(3- (1-(1-methylpiperidin-4-yl)- 1H-pyrazol-4-yl)-1H-indazol- 5-yl)picolinamide
455.42

216

embedded image

6-chloro-5-cyano-N-(3- (isoxazol-4-yl)-1H-indazol-5- yl)-3,4-dimethylpicolinamide
393.16

217

embedded image

5-cyano-N-(3-(1-isopropyl- 1H-pyrazol-4-yl)-1H-indazol- 5-yl)-3,4- dimethylpicolinamide
400.32

218

embedded image

4-cyano-N-(3-(isoxazol-4- yl)-1H-indazol-5-yl)-6,7- dihydro-5H- cyclopenta[c]pyridine-1- carboxamide
371.22

219

embedded image

5-cyano-N-(3-(2-methoxy-6- methylpyridin-4-yl)-1H- indazol-5-yl)-3,4- dimethylpicolinamide
413.32

220

embedded image

2-chloro-3-cyano-N-(3- (isoxazol-4-yl)-1H-indazol-5- yl)benzamide
364.14, 366.16

221

embedded image

5-cyano-3,4-dimethyl-N-(3- (1-(oxetan-3-yl)-1H-pyrazol- 4-yl)-1H-indazol-5- yl)picolinamide
414.25

222

embedded image

5-cyano-3,4,6-trimethyl-N- (3-(thiazol-5-yl)-1H-indazol- 5-yl)picolinamide
389.23

223

embedded image

5-cyano-N-(3-cyclopropyl- 1H-indazol-5-yl)-3,4- dimethylpicolinamide
332.1

224

embedded image

5-cyano-1-methyl-N-(3- (oxazol-5-yl)-1H-indazol-5- yl)-6-oxo-1,6- dihydropyridine-3- carboxamide
361.1

225

embedded image

3-cyano-2-isopropyl-N-(3- (oxazol-5-yl)-1H-indazol-5- yl)benzamide
372.2

226

embedded image

5-cyano-N-(3-(isoxazol-4- yl)-1H-indazol-5-yl)-4- methoxy-3- methylpicolinamide

227

embedded image

5-cyano-3,4-dimethyl-N-(3- (thiazol-5-yl)-1H-indazol-5- yl)picolinamide
375.2

228

embedded image

4-cyano-N-(3-(isoxazol-4- yl)-1H-indazol-5-yl)-3- methoxypicolinamide
361.19

229

embedded image

5-cyano-3,4-dimethyl-N-(3- (3-methylisoxazol-5-yl)-1H- indazol-5-yl)picolinamide
373.18

230

embedded image

5-cyano-3,4-dimethyl-N-(3- (pyrimidin-4-yl)-1H-indazol- 5-yl)picolinamide
370.2

231

embedded image

3-cyano-2-ethyl-6-fluoro-N- (3-(oxazol-5-yl)-1H-indazol- 5-yl)benzamide
376.1

232

embedded image

2-cyano-3-ethyl-N-(3- (oxazol-5-yl)-1H-indazol-5- yl)isonicotinamide
359.1

233

embedded image

(E)-5-cyano-N-(3-(2- cyclopropylvinyl)-1H- indazol-5-yl)-3,4- dimethylpicolinamide
358.1

234

embedded image

3-cyano-2-methoxy-6- methyl-N-(3-(oxazol-5-yl)- 1H-indazol-5-yl)benzamide
374.27

235

embedded image

5-cyano-3-methyl-N-(3-(3- methylisoxazol-5-yl)-1H- indazol-5-yl)picolinamide
359.19

236

embedded image

3-cyano-2-fluoro-N-(3- (isoxazol-4-yl)-1H-indazol-5- yl)-6-methylbenzamide
362.22

237

embedded image

5-cyano-3,4-dimethyl-N-(3- (2-methylpyrimidin-4-yl)- 1H-indazol-5-yl)picolinamide
384.3

238

embedded image

5-cyano-3,4-dimethyl-N-(3- (oxazol-5-yl)-1H- pyrazolo[3,4-c]pyridin-5- yl)picolinamide
360.1

239

embedded image

3-cyano-1,4-dimethyl-N-(3- (oxazol-5-yl)-1H-indazol-5- yl)-1H-pyrazole-5- carboxamide
348.1

Detailed methods for the preparation of Examples 101-239 are provided below:

Example 101: 5-Cyano-N-(3-(isoxazol-5-yl)-1H-indazol-5-yl)-3-methylpicolinamide

embedded image

Prepared as described for 5-cyano-N-(7-fluoro-3-(furan-3-yl)-1H-indazol-5-yl)-3-methylpicolinamide using 5-cyano-3-methylpicolinic acid in place of 5-cyano-3-methylpicolinic acid and using 3-(isoxazol-5-yl)-1H-indazol-5-amine in place of 7-fluoro-3-(furan-3-yl)-1H-indazol-5-amine to afford the title compound (1.7 mg, 4%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.79 (br. s., 1H) 10.85 (s, 1H) 9.01 (d, J=1.54 Hz, 1H) 8.75 (d, J=1.76 Hz, 2H) 8.42 (s, 1H) 7.79-7.89 (m, 1H) 7.68 (d, J=9.02 Hz, 1H) 6.95 (d, J=1.98 Hz, 1H) 2.61 (s, 3H). MS-ESI (m/z) calc'd for C₁₅H₁₃N₆O₂[M+H]⁺: 345.1. Found 345.2.

Example 102: 5-Cyano-3-methyl-N-(3-(5-(morpholinomethyl)thiophen-2-yl)-1H-indazol-5-yl)picolinamide

embedded image

Prepared as described for 5-cyano-N-(3-(isoxazol-4-yl)-1H-indazol-5-yl)-3-methylpicolinamide using (5-(morpholinomethyl)thiophen-2-yl)boronic acid in place of isoxazole-4-boronic acid to afford the title compound (60.7 mg, 65%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.18 (s, 1H), 10.78 (s, 1H), 9.00 (d, J=1.9 Hz, 1H), 8.63 (d, J=1.8 Hz, 1H), 8.41 (d, J=2.3 Hz, 1H), 8.18 (s, 1H), 7.81 (dd, J=9.0, 1.9 Hz, 1H), 7.57 (d, J=9.0 Hz, 1H), 7.46 (d, J=3.6 Hz, 1H), 7.07 (d, J=3.6 Hz, 1H), 3.72 (s, 2H), 3.60 (t, J=4.6 Hz, 4H), 2.60 (s, 3H), 2.46 (d, J=4.6 Hz, 4H). MS-ESI (m/z) calc'd for C₂₄H₂₃N₆O₂S [M+H]⁺: 459.2. Found 459.2.

Example 103: N-(3-(2-Bromopyridin-4-yl)-1H-indazol-5-yl)-5-cyano-3-methylpicolinamide

embedded image

Prepared as described for 5-cyano-N-(3-(isoxazol-4-yl)-1H-indazol-5-yl)-3-methylpicolinamide using (2-bromopyridin-4-yl)boronic acid in place of isoxazole-4-boronic acid to afford the title compound (6 mg, 7%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.73 (br. s., 1H) 10.86 (s, 1H) 9.02 (d, J=1.76 Hz, 1H) 8.64 (s, 1H) 8.54 (d, J=5.06 Hz, 1H) 8.43 (d, J=1.32 Hz, 1H) 8.11 (s, 1H) 8.01 (dd, J=5.17, 1.43 Hz, 1H) 7.95 (dd, J=9.13, 1.65 Hz, 1H) 7.69 (d, J=9.02 Hz, 1H) 2.62 (s, 3H). MS-ESI (m/z) calc'd for C₂₀H₁₄BrN₆O [M+H]⁺: 433.0/435.0. Found 433.2/435.2.

Example 104: 2-Cyano-1,5-dimethyl-N-(3-phenyl-1H-indazol-5-yl)-1H-imidazole-4-carboxamide

embedded image

Step 1: Ethyl 1,5-dimethyl-1H-imidazole-4-carboxylate

embedded image

To a solution of NaH (155.66 mg, 3.89 mmol, 60% purity) in DMF (10 mL) was added ethyl 5-methyl-1H-imidazole-4-carboxylate (500 mg, 3.24 mmol) at 0° C. and the mixture was stirred for 15 min. Then MeI (552.41 mg, 3.89 mmol) was added and the mixture was stirred at 25° C. for 12 hrs. The reaction mixture was quenched by addition of H₂O (10 mL) at 20° C., concentrated, and then diluted with H₂O (20 mL) and extracted with EtOAc (50 mL×4). The combined organic layers were dried over Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO: 20 g SepaFlash column) using a 0-54% EtOAc/petroleum ether gradient eluent to afford the title compound (140 mg, 26%) as a yellow solid. MS-ESI (m/z) calcd for C₈H₁₃N₂O₂[M+H]⁺: 169.1. Found 169.1.

Step 2: Ethyl 2-bromo-1,5-dimethyl-1H-imidazole-4-carboxylate

embedded image

To a solution of ethyl 1,5-dimethyl-1H-imidazole-4-carboxylate (760 mg, 4.52 mmol) in MeCN (23 mL) was added NBS (965.09 mg, 5.42 mmol) and the mixture was stirred at 20° C. for 12 hrs. The reaction mixture was concentrated and then diluted with H₂O (25 mL) and extracted with EtOAc (50 mL×3). The combined organic layers were dried over Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO; 20 g SepaFlash column) using a 0-60% EtOAc/petroleum ether gradient eluent to afford the tite compound (880 mg, 79%) as a yellow oil. MS-ESI (m/z) calcd for C₈H₁₂BrN₂O₂[M+H]⁺: 247.0/249.0. Found 247.0/249.0.

Step 3: 2-Bromo-1,5-dimethyl-1H-imidazole-4-carboxylic acid

embedded image

To a solution of ethyl 2-bromo-1,5-dimethyl-1H-imidazole-4-carboxylate (90 mg, 364.24 umol) in H₂O (1 mL) and THF (3 mL) was added NaOH (43.71 mg, 1.09 mmol). The mixture was stirred at 20° C. for 5 hrs and then acidified with 1 N HCl to pH=3. The mixture was extracted with EtOAc (15 mL×5) and the combined organic layers were dried over Na₂SO₄, filtered and concentrated to afford the title compound (60 mg) as an orange solid which was used without further purification. MS-ESI (m/z) calcd for C₆H₈BrN₂O₂[M+H]⁺: 219.0/221.0. Found 218.9/220.9.

Step 4: 2-Bromo-1,5-dimethyl-N-(3-phenyl-1H-indazol-5-yl)-1H-imidazole-4-carboxamide

embedded image

To a solution of 2-bromo-1,5-dimethyl-1H-imidazole-4-carboxylic acid (110 mg, 502.20 umol) in pyridine (3 mL) was added 3-phenyl-1H-indazol-5-amine (126.10 mg, 602.64 umol) and EDCI (192.55 mg, 1.00 mmol). The mixture was stirred at 20° C. for 12 hrs and then concentrated. The material was purified by flash silica gel chromatography (ISCO; 12 g SepaFlash column) using a 0-30% (EtOAc/MeOH=20/1)/petroleum ether gradient eluent to afford the title compound (50 mg, 12%) as a yellow solid. MS-ESI (m/z) calcd for C₁₉H₁₇BrN₅O [M+H]⁺: 410.1/412.1. Found 410.0/412.0.

Step 5: 2-Cyano-1,5-dimethyl-N-(3-phenyl-1H-indazol-5-yl)-1H-imidazole-4-carboxamide

embedded image

To a solution of 2-bromo-1,5-dimethyl-N-(3-phenyl-1H-indazol-5-yl)-1H-imidazole-4-carboxamide (50 mg, 121.87 umol) in DMA (2 mL) was added Zn (956.30 ug, 14.62 umol), Zn(CN)₂(14.31 mg, 121.87 umol), Pd₂(dba)₃(2.23 mg, 2.44 umol), and DPPF (2.70 mg, 4.87 umol). The mixture was stirred at 120° C. for 3 hrs under an N₂atmosphere and then concentrated under reduced pressure to remove solvent to afford a residue. The residue was diluted with H₂O (2 mL) and extracted with EtOAc (8 mL×4). The combined organic layers were dried over Na₂SO₄, filtered and concentrated under reduced pressure. The material was purified by preparative HPLC using Method BE to afford the title compound (9.58 mg, 17%) as an off-white solid TFA salt. ¹H NMR (400 MHz, DMSO-d₆) δ 10.18 (s, 1H) 8.62 (d, J=1.22 Hz, 1H) 7.93-7.99 (m, 2H) 7.89 (dd, J=8.99, 1.77 Hz, 1H) 7.51-7.57 (m, 3H) 7.38-7.44 (m, 1H) 3.76 (s, 3H) 2.61 (s, 3H). MS-ESI (m/z) calc'd for C₂₀H₁₇N₆O [M+H]⁺: 357.1 Found 357.0.

Example 105: 5-Cyano-N-(3-(furan-3-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-methylpicolinamide

embedded image

Step 1: 5-Chloro-3-iodo-1H-pyrazolo[4,3-b]pyridine

embedded image

To a stirred solution of 5-chloro-1H-pyrazolo[4,3-b]pyridine (4.0 g, 26.05 mmol) in DMF (100 mL) was added I₂(26.44 g, 104.19 mmol) followed by addition of KOH (7.31 g, 130.23 mmol) in portions at 0° C. and the mixture was stirred at 25° C. for 12 hrs. The mixture was diluted with EtOAc (300 mL), washed with saturated aqueous Na₂SO₃(150 mL×3), dried over Na₂SO₄and concentrated to afford the title compound (4.0 g) as a yellow solid, which was used without further purification. MS-ESI (m/z) calcd for C₆H₄ClIN₃[M+H]⁺: 279.9/281.9. Found 279.9/281.9.

Step 2: 5-Chloro-3-(furan-3-yl)-1H-pyrazolo[4,3-b]pyridine

embedded image

To a stirred solution of 5-chloro-3-iodo-1H-pyrazolo[4,3-b]pyridine (5.0 g, 17.89 mmol) in dioxane (100 mL) was added furan-3-ylboronic acid (2.40 g, 21.47 mmol) followed by addition of Pd(dppf)Cl₂(1.31 g, 1.79 mmol) and K₂CO₃(4.95 g, 35.78 mmol) in one portion. The mixture was then stirred at 90° C. for 24 hrs under N₂. The mixture was cooled to room temperature, filtered and the filtrate was concentrated to afford a residue. The residue was purified by silica gel column chromatography using a 20-50% EtOAc/petroleum ether gradient eluent to afford the title compound (700 mg, 18%) as a brown solid. MS-ESI (m/z) calcd for C₁₀H₇ClN₃O [M+H]⁺: 220.0/222.0. Found 220.0/222.0.

Step 3: 5-Chloro-3-(furan-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-b]pyridine

embedded image

To a stirred solution of 5-chloro-3-(furan-3-yl)-1H-pyrazolo[4,3-b]pyridine (650 mg, 2.96 mmol) in DCM (20 mL) was added 3,4-dihydro-2H-pyran (373.42 mg, 4.44 mmol, 405.89 uL), followed by addition of TsOH (50.96 mg, 295.96 umol) in one portion and the mixture was then stirred at 25° C. for 12 hrs. The mixture was washed with 20% aqueous NaHCO₃(5.0 mL×3), dried over Na₂SO₄and concentrated to afford the title compound (1.2 g) as a brown oil which was used without further purification. MS-ESI (m/z) calcd for C₁₅H₁₅ClN₃O₂[M+H]⁺: 304.1/306.1. Found 304.0/306.0.

Step 4: 5-Cyano-N-(3-(furan-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)-3-methylpicolinamide

embedded image

To a stirred solution of 5-chloro-3-(furan-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-b]pyridine (200 mg, 658.45 umol) in toluene (10 mL) was added 5-cyano-3-methylpicolinamide (116.73 mg, 724.30 umol) followed by addition of Pd₂(dba)₃(30.15 mg, 32.92 umol), XPhos (31.39 mg, 65.85 umol) and Cs₂CO₃(536.34 mg, 1.65 mmol). Then the mixture was degassed under vacuum and purged with N₂(3×) after which it was stirred at 110° C. for 12 hrs. The mixture was then filtered and the filtrate was concentrated and purified by preparative TLC (SiO₂, 1:1 petroleum ether/EtOAc, R_f=0.62) to afford the title compound (100 mg, 35%) as a yellow solid. MS-ESI (m/z) calcd for C₂₃H₂₁N₆O₃[M+H]⁺: 429.2. Found 429.1.

Step 5: 5-Cyano-N-(3-(furan-3-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-methylpicolinamide

embedded image

To a stirred solution of 5-cyano-N-(3-(furan-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)-3-methylpicolinamide (90 mg, 210.06 umol) in DCM (3.0 mL) was added TFA (1.54 g, 13.51 mmol, 1 mL) dropwise at 0° C. and the mixture was stirred at 25° C. for 1 hr. The mixture was then concentrated to afford a residue which was purified by preparative HPLC using Method BG to afford the title compound (12.40 mg, 12%) as a pale yellow solid, TFA salt. ¹H NMR (400 MHz, DMSO-de) δ 13.30 (s, 1H), 10.93 (s, 1H), 9.03 (s, 1H), 8.54 (s, 1H), 8.45 (s, 1H), 8.28-8.40 (m, 1H), 8.12-8.14 (m, 1H), 7.82 (s, 1H), 7.12 (s, 1H), 2.62 (br s, 3H). MS-ESI (m/z) calc'd for C₁₈H₁₃N₆O₂[M+H]⁺: 345.1 Found 345.0.

Example 106: N-(3-Bromo-1H-indazol-5-yl)-5-cyano-3-methylpicolinamide

embedded image

Step 1: Methyl 5-ethynyl-3-methylpicolinate

embedded image

A mixture of methyl 5-bromo-3-methylpicolinate (1 g, 4.35 mmol), Zn(CN)₂(612.49 mg, 5.22 mmol) and Pd(PPh₃)₄(251.14 mg, 217.34 umol) in DMF (10 mL) was degassed and purged with N₂(3×) and the mixture was stirred at 120° C. for 2 hrs under an N₂atmosphere. The reaction mixture was concentrated and the residue obtained was purified by flash silica gel chromatography (ISCO; 4 g SepaFlash column) using a 0-10% EtOAc/petroleum ether gradient eluent to afford the title compound (640 mg, 84%) as a white solid.

Step 2: 5-Ethynyl-3-methylpicolinic acid

embedded image

To a solution of methyl 5-ethynyl-3-methylpicolinate (640 mg, 3.63 mmol) in THF (15 mL) was added NaOH (290.60 mg, 7.27 mmol) and the mixture was stirred at 20° C. for 5 hrs. To the reaction mixture was then added H₂O (20 mL) and the aqueous phase was acidified with 1 N HCl to pH=3. The reaction was filtered, the solid was washed with H₂O (10 mL) and concentrated to give a residue. The phase that was recovered after separating the solid was extracted with EtOAc (30 mL×4), the organic layer was dried over anhydrous Na₂SO₄, filtered and the filtrate was concentrated to give a residue. This residue was combined with the separated solid to afford the title compound (580 mg) as a white solid, which was used without further purification. MS-ESI (m/z) calcd for C₈H₇N₂O₂[M+H]⁺: 163.0. Found 163.0.

Step 3: N-(3-Bromo-1H-indazol-5-yl)-5-cyano-3-methylpicolinamide

embedded image

To a solution of 3-bromo-1H-indazol-5-amine (1.96 g, 9.25 mmol) and 5-ethynyl-3-methylpicolinic acid (1.5 g, 9.25 mmol) in pyridine (45 mL) was added EDCI (2.66 g, 13.88 mmol) and the mixture was stirred at 25° C. for 12 hrs. The reaction mixture was then concentrated to give a residue. The residue was diluted with MeOH (300 mL) and filtered. The solid was washed with MeOH (200 mL), filtered and dried to afford a residue (2.4 g) as a white solid. 100 mg of this material was purified by preparative HPLC using Method V to afford the title compound (6.2 mg, 5%) as a white solid TFA salt. ¹H NMR (400 MHz, DMSO-d₆) δ 13.42 (br s, 1H), 10.83 (s, 1H), 8.99 (s, 1H), 8.41 (s, 1H), 8.26 (s, 1H), 7.72 (br d, J=9.2 Hz, 1H), 7.58 (d, J=9.0 Hz, 11H), 2.58 (s, 3H). MS-ESI (m/z) calc'd for C₁₅H₁₁BrN₅O [M+H]⁺: 356.0/358.0. Found 355.9/357.9.

Example 107: 4-Cyano-N-(3-(furan-3-yl)-1H-indazol-5-yl)-2-hydroxybenzamide

embedded image

Step 1: Methyl 4-cyano-2-hydroxybenzoate

embedded image

Methyl 2-hydroxy-4-iodobenzoate (1 g, 3.60 mmol) was dissolved in DMF (9 mL) and CuCN (773.33 mg, 8.63 mmol, 1.89 mL) was added. The reaction was heated to reflux at 140° C. for 2 hrs. The reaction was cooled to r.t. and dissolved in neat H₂O (50 mL). The resulting mixture was diluted with EtOAc (80 mL) and saturated aqueous NaHCO₃(20 mL). The organic phase was separated, washed with H₂O (30 mL), dried over Na₂SO₄, filtered and concentrated under reduced pressure to afford the title compound (420 mg) as a yellow solid which was used without further purification. ¹H NMR (400 MHz, DMSO-d₆) δ 10.75 (s, 1H), 7.84 (d, J=8 Hz, 1H), 7.41 (s, 1H), 7.33 (d, J=8 Hz, 1H), 3.88 (s, 3H).

Step 2: 4-Cyano-N-(3-(furan-3-yl)-1H-indazol-5-yl)-2-hydroxybenzamide

embedded image

To a solution of methyl 4-cyano-2-hydroxybenzoate (70 mg, 395.13 umol) and 3-(furan-3-yl)-1H-indazol-5-amine (78.71 mg, 395.13 umol) in toluene (3 mL) was added AlMe₃(2 M, 592.69 uL) and the mixture was stirred at 80° C. for 2 hrs. The reaction mixture was quenched by addition H₂O (10 mL) at 0° C., and concentrated under reduced pressure to remove solvent and give a residue. The residue was purified by preparative HPLC using Method BM to afford the title compound (12.25 mg, 9%) as a pale yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.11 (s, 1H), 11.21 (br s, 1H), 8.36 (s, 1H), 8.27 (s, 1H), 8.03 (d, J=7.9 Hz, 1H), 7.84 (s, 1H), 7.67-7.60 (m, 1H), 7.58-7.53 (m, 1H), 7.35-7.26 (m, 2H), 7.00 (s, 1H). MS-ESI (m/z) calc'd for C₁₉H₁₃N₄O₃[M+H]⁺: 345.1. Found 345.0.

Example 108: 5-Cyano-3-methyl-N-(3-(4-(morpholine-4-carbonyl)phenyl)-1H-indazol-5-yl)picolinamide

embedded image

Prepared as described for 5-cyano-N-(3-(1,5-dimethyl-1H-pyrazol-4-yl)-1H-indazol-5-yl)-3-methylpicolinamide using (4-(morpholine-4-carbonyl)phenyl)boronic acid in place of (1,5-dimethyl-1H-pyrazol-4-yl)boronic acid to afford the title compound (10.94 mg, 17%) as a pale yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 10.79 (br s, 1H) 9.01 (s, 1H) 8.64 (s, 1H) 8.42 (s, 1H) 8.03 (d, J=8.19 Hz, 2H) 7.77-7.85 (m, 1H) 7.57-7.66 (m, 3H) 3.63 (br s, 8H) 2.60 (s, 3H). MS-ESI (m/z) calc'd for C₂₆H₂₃N₆O₃[M+H]⁺: 467.2. Found 467.1.

Example 109: 5-Cyano-N-(3-(5-isopropoxypyridin-3-yl)-1H-indazol-5-yl)-3-methylpicolinamide

embedded image

Prepared as described for 5-cyano-N-(3-(1,5-dimethyl-1H-pyrazol-4-yl)-1H-indazol-5-yl)-3-methylpicolinamide using (5-isopropoxypyridin-3-yl)boronic acid in place of (1,5-dimethyl-1H-pyrazol-4-yl)boronic acid to afford the title compound (10.29 mg, 17%) as a pale yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.53 (br s, 1H) 10.83 (s, 1H) 9.00 (d, J=1.59 Hz, 1H) 8.78 (d, J=1.22 Hz, 1H) 8.67 (d, J=1.10 Hz, 1H) 8.40 (dd, J=9.72, 1.90 Hz, 2H) 7.93 (s, 1H) 7.85 (dd, J=9.05, 1.59 Hz, 1H) 7.65 (d, J=8.93 Hz, 1H) 4.87 (spt, J=5.89 Hz, 1H) 2.59 (s, 3H) 1.37 (d, J=5.99 Hz, 6H). MS-ESI (m/z) calc'd for C₂₃H₂₁N₆O₂[M+H]⁺: 413.2. Found 413.1.

Example 110: 5-Cyano-3-methyl-N-(3-(thiazol-5-yl)-1H-indazol-5-yl)picolinamide

embedded image

A mixture of N-(3-bromo-1H-indazol-5-yl)-5-cyano-3-methylpicolinamide (50 mg, 140.38 umol), 5-(tributylstannyl)thiazole (52.53 mg, 140.38 umol), and Pd(PPh₃)₂Cl₂(9.85 mg, 14.04 umol) in dioxane (3 mL) was degassed and purged with N₂(3×), and then the mixture was stirred at 110° C. for 12 hrs under an N₂atmosphere. The reaction mixture was then filtered and the filtrate was concentrated to give a residue which was purified by preparative HPLC using Method BI to afford the title compound (13.67 mg, 26%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.39 (br s, 1H), 10.80 (br s, 1H), 9.15 (s, 1H), 9.01 (br s, 1H), 8.64 (br s, 1H), 8.42 (br s, 2H), 7.87 (br d, J=8.9 Hz, 1H), 7.62 (br d, J=9.0 Hz, 1H), 2.61 (s, 3H). MS-ESI (m/z) calc'd for C₁₈H₁₃N₆O S [M+H]⁺: 361.1 Found 361.1.

Example 111: 5-Cyano-3-methyl-N-(3-(oxazol-5-yl)-1H-indazol-5-yl)picolinamide

embedded image

Prepared as described for 5-cyano-N-(3-(1,5-dimethyl-1H-pyrazol-4-yl)-1H-indazol-5-yl)-3-methylpicolinamide using oxazol-5-ylboronic acid in place of (1,5-dimethyl-1H-pyrazol-4-yl)boronic acid to afford the title compound (3.69 mg, 4%) as a pale yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 10.79 (br s, 1H), 9.00 (d, J=1.4 Hz, 1H), 8.61 (d, J=1.3 Hz, 1H), 8.58 (s, 1H), 8.41 (d, J=1.1 Hz, 1H), 7.80 (dd, J=1.9, 9.0 Hz, 1H), 7.65 (s, 11H), 7.62 (d, J=9.0 Hz, 1H), 2.60 (s, 3H). MS-ESI (m/z) calc'd for C₁₈H₁₃N₆O₂[M+H]⁺: 345.1. Found 345.2.

Example 112: 5-Cyano-3-methyl-N-(3-(6-methylpyridin-2-yl)-1H-indazol-5-yl)picolinamide

embedded image

A mixture of N-(3-bromo-1H-indazol-5-yl)-5-cyano-3-methylpicolinamide (70 mg, 196.53 umol), 2-methyl-6-(tributylstannyl)pyridine (90.13 mg, 235.84 umol) and Pd(PPh₃)₂Cl₂(13.79 mg, 19.65 umol) in dioxane (2.5 mL) was degassed and purged with N₂(3×). The mixture was then stirred at 150° C. for 3 hrs under N₂atmosphere in a microwave reactor. The reaction mixture was concentrated and purified by preparative HPLC using Method BK to afford the title compound (18.61 mg, 20%) as a pale yellow solid, TFA salt. ¹H NMR (400 MHz, DMSO-d₆) δ 13.48 (br s, 1H) 10.76 (s, 1H) 8.94-9.14 (m, 2H) 8.41 (d, J=1.10 Hz, 1H) 8.01 (br d, J=7.70 Hz, 1H) 7.91 (br s, 1H) 7.81 (dd, J=9.05, 1.83 Hz, 1H) 7.61 (d, J=8.93 Hz, 1H) 7.33 (br d, J=7.09 Hz, 1H) 2.65 (s, 3H) 2.57 (s, 3H). MS-ESI (m/z) calc'd for C₂₁H₁₇N₆O [M+H]⁺: 369.1. Found 369.0.

Example 113: 5-Cyano-N-(3-(2-cyanopyridin-4-yl)-1H-indazol-5-yl)-3-methylpicolinamide

embedded image

Prepared as described for 5-cyano-N-(3-(1,5-dimethyl-1H-pyrazol-4-yl)-1H-indazol-5-yl)-3-methylpicolinamide using (2-cyanopyridin-4-yl)boronic acid in place of (1,5-dimethyl-1H-pyrazol-4-yl)boronic acid to afford the title compound (5.23 mg, 8%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.87 (s, 1H) 10.85 (s, 1H) 9.02 (d, J=1.47 Hz, 1H) 8.88 (d, J=5.14 Hz, 1H) 8.66 (s, 1H) 8.49 (s, 1H) 8.43 (d, J=0.98 Hz, 1H) 8.26 (dd, J=5.20, 1.65 Hz, 1H) 7.98 (dd, J=8.99, 1.53 Hz, 1H) 7.70 (d, J=9.05 Hz, 1H) 2.62 (s, 3H). MS-ESI (m/z) calc'd for C₂₁H₁₄N₇O [M+H]⁺: 380.1. Found 380.0.

Example 114: 5-Cyano-3-methyl-N-(3-(pyridin-2-yl)-1H-indazol-5-yl)picolinamide

embedded image

Prepared as described for 5-cyano-N-(3-(1,5-dimethyl-1H-pyrazol-4-yl)-1H-indazol-5-yl)-3-methylpicolinamide using pyridin-2-ylboronic acid in place of (1,5-dimethyl-1H-pyrazol-4-yl)boronic acid to afford the title compound (6.76 mg, 10%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.46 (br s, 1H), 10.75 (s, 1H), 8.99 (s, 2H), 8.73 (br d, J=4.5 Hz, 1H), 8.40 (s, 1H), 8.19 (d, J=7.9 Hz, 1H), 7.96 (br t, J=7.0 Hz, 1H), 7.79 (dd, J=1.7, 8.9 Hz, 1H), 7.61 (d, J=8.9 Hz, 1H), 7.40 (br t, J=5.7 Hz, 1H), 2.58 (s, 3H). MS-ESI (m/z) calc'd for C₂₀H₁₅N₆O [M+H]⁺: 355.1. Found 355.0.

Example 115: 5-Cyano-N-(3-(2-((2S,6S)-2,6-dimethylmorpholino)pyridin-4-yl)-1H-indazol-5-yl)-3-methylpicolinamide

embedded image

Prepared as described for 5-cyano-N-(7-fluoro-3-(furan-3-yl)-1H-indazol-5-yl)-3-methylpicolinamide using 5-cyano-3-methylpicolinic acid in place of 5-cyano-3-methylpicolinic acid and using 3-(2-((2S,6S)-2,6-dimethylmorpholino)pyridin-4-yl)-1H-indazol-5-amine in place of 7-fluoro-3-(furan-3-yl)-1H-indazol-5-amine to afford the title compound (69.8 mg, 40%) as a white solid. ¹H NMR (400 MHz, acetone-d₆) δ 12.58 (s, 1H), 10.49 (s, 1H), 9.04 (q, J=1.7 Hz, 1H), 8.97-8.86 (m, 1H), 8.31 (dd, J=2.0, 0.9 Hz, 1H), 8.28 (dd, J=5.2, 0.7 Hz, 1H), 7.83 (dd, J=8.8, 1.9 Hz, 1H), 7.70 (d, J=8.9 Hz, 1H), 7.42 (t, J=1.1 Hz, 1H), 7.32 (dd, J=5.2, 1.3 Hz, 1H), 4.15 (qd, J=6.4, 3.4 Hz, 2H), 3.79 (dd, J=12.7, 3.4 Hz, 2H), 3.41 (dd, J=12.6, 6.3 Hz, 2H), 2.85 (s, 3H), 1.30 (d, J=6.4 Hz, 6H). MS-ESI (m/z) calc'd for C₂₆H₂₆N₇O₂[M+H]⁺: 468.2. Found 468.4.

Example 116: 4-Cyano-N-(3-(furan-3-yl)-1H-indazol-5-yl)thieno[2,3-c]pyridine-7-carboxamide

embedded image

Prepared as described for 5-cyano-N-(7-fluoro-3-(furan-3-yl)-1H-indazol-5-yl)-3-methylpicolinamide using 4-cyanothieno[2,3-c]pyridine-7-carboxylic acid in place of 5-cyano-3-methylpicolinic acid and using 3-(furan-3-yl)-1H-indazol-5-amine in place of 7-fluoro-3-(furan-3-yl)-1H-indazol-5-amine to afford the title compound (4.3 mg, 15%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.13 (br. s., 1H) 11.14 (s, 1H) 9.19 (s, 1H) 8.64 (d, J=5.50 Hz, 1H) 8.55 (d, J=1.32 Hz, 1H) 8.34 (dd, J=1.54, 0.88 Hz, 1H) 8.08 (dd, J=9.02, 1.98 Hz, 1H) 7.87 (t, J=1.65 Hz, 1H) 7.80 (d, J=5.50 Hz, 1H) 7.60 (d, J=8.80 Hz, 1H) 7.04 (dd, J=1.76, 0.88 Hz, 1H). MS-ESI (m/z) calc'd for C₂₀H₂N₅O₂S [M+H]⁺: 386.1. Found 386.2.

Example 117: 5-Cyano-N-(3-(2-((3R,5S)-3,5-dimethylpiperidin-1-yl)pyridin-4-yl)-1H-indazol-5-yl)-3-methylpicolinamide

embedded image

Prepared as described for 5-cyano-N-(7-fluoro-3-(furan-3-yl)-1H-indazol-5-yl)-3-methylpicolinamide using 5-cyano-3-methylpicolinic acid in place of 5-cyano-3-methylpicolinic acid and using 3-(2-((3R,5S)-3,5-dimethylpiperidin-1-yl)pyridin-4-yl)-1H-indazol-5-amine in place of 7-fluoro-3-(furan-3-yl)-1H-indazol-5-amine to afford the title compound (47.4 mg, 61%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.45 (s, 1H), 10.80 (s, 1H), 9.01 (d, J=2.0 Hz, 1H), 8.82 (d, J=1.8 Hz, 1H), 8.41 (dd, J=2.0, 0.9 Hz, 1H), 8.23 (d, J=5.2 Hz, 1H), 7.74 (dd, J=9.0, 1.8 Hz, 1H), 7.63 (d, J=9.0 Hz, 1H), 7.30 (s, 1H), 7.15 (dd, J=5.2, 1.2 Hz, 1H), 4.39 (d, J=12.7 Hz, 2H), 2.60 (s, 3H), 2.37 (t, J=12.9, 11.3 Hz, 2H), 1.86-1.76 (m, 1H), 1.72-1.58 (m, 2H), 0.95 (d, J=6.5 Hz, 6H), 0.83 (q, J=12.1 Hz, 1H). MS-ESI (m/z) calc'd for C₂₇H₂₈N₇O [M+H]⁺: 466.2. Found 466.4.

Example 118: 5-Cyano-N-(3-(2-((2S,6R)-2,6-dimethylmorpholino)pyridin-4-yl)-1H-indazol-5-yl)-3-methylpicolinamide

embedded image

Prepared as described for 5-cyano-N-(7-fluoro-3-(furan-3-yl)-1H-indazol-5-yl)-3-methylpicolinamide using 5-cyano-3-methylpicolinic acid in place of 5-cyano-3-methylpicolinic acid and using 3-(2-((2S,6R)-2,6-dimethylmorpholino)pyridin-4-yl)-1H-indazol-5-amine in place of 7-fluoro-3-(furan-3-yl)-1H-indazol-5-amine to afford the title compound (91.1 mg, 53%) as a yellow solid. ¹H NMR (400 MHz, acetone-d₆) δ 12.58 (s, 1H), 10.49 (s, 1H), 9.02 (d, J=2.1 Hz, 1H), 8.91 (d, J=2.0 Hz, 1H), 8.36-8.24 (m, 2H), 7.84 (dd, J=9.0, 1.9 Hz, 1H), 7.71 (d, J=8.9 Hz, 1H), 7.44 (s, 1H), 7.35 (dd, J=5.1, 1.3 Hz, 1H), 4.41-4.28 (m, 2H), 3.75 (ddd, J=10.5, 6.3, 2.5 Hz, 2H), 2.85 (s, 3H), 2.55 (dd, J=12.7, 10.5 Hz, 2H), 1.27 (d, J=6.2 Hz, 6H). MS-ESI (m/z) calc'd for C₂₆H₂₆N₇O₂[M+H]⁺: 468.2. Found 468.4.

Example 119: 5-Cyano-N-(3-(3-((2S,6R)-2,6-dimethylmorpholino)phenyl)-1H-indazol-5-yl)-3-methylpicolinamide

embedded image

Prepared as described for 5-cyano-N-(7-fluoro-3-(furan-3-yl)-1H-indazol-5-yl)-3-methylpicolinamide using 5-cyano-3-methylpicolinic acid in place of 5-cyano-3-methylpicolinic acid and using 3-(3-((2S,6R)-2,6-dimethylmorpholino)phenyl)-1H-indazol-5-amine in place of 7-fluoro-3-(furan-3-yl)-1H-indazol-5-amine to afford the title compound (135.9 mg, 78%) as a yellow solid. ¹H NMR (400 MHz, acetone-d₆) δ 12.31 (s, 1H), 10.44 (s, 1H), 8.98-8.94 (m, 1H), 8.92-8.88 (m, 1H), 8.30 (dd, J=1.9, 0.8 Hz, 1H), 7.79 (dd, J=8.9, 1.9 Hz, 1H), 7.70-7.62 (m, 2H), 7.53 (dt, J=7.7, 1.2 Hz, 1H), 7.41 (t, J=7.9 Hz, 1H), 7.09-7.01 (m, 1H), 3.82 (dtt, J=12.5, 6.2, 3.1 Hz, 2H), 3.75 (dt, J=10.8, 2.0 Hz, 2H), 2.84 (d, J=0.7 Hz, 3H), 2.46 (dd, J=11.9, 10.3 Hz, 2H), 1.26 (d, J=6.3 Hz, 6H). MS-ESI (m/z) calc'd for C₂₇H₂₇N₆O₂[M+H]⁺: 467.2. Found 467.4.

Example 120: 3-Cyano-2,6-difluoro-N-(3-(furan-3-yl)-1H-indazol-5-yl)benzamide

embedded image

Prepared as described for 5-cyano-N-(7-fluoro-3-(furan-3-yl)-1H-indazol-5-yl)-3-methylpicolinamide using 3-cyano-2,6-difluorobenzoic acid in place of 5-cyano-3-methylpicolinic acid and using 3-(furan-3-yl)-1H-indazol-5-amine in place of 7-fluoro-3-(furan-3-yl)-1H-indazol-5-amine to afford the title compound (29.4 mg, 40%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.16 (br. s., 1H) 10.97 (s, 1H) 8.34 (s, 1H) 8.18-8.28 (m, 2H) 7.85 (t, J=1.65 Hz, 1H) 7.53-7.64 (m, 3H) 6.99 (dd, J=1.87, 0.77 Hz, 1H). MS-ESI (m/z) calc'd for C₁₉H₁₁F₂N₄O₂[M+H]⁺: 365.1. Found 365.2.

Example 121: N-(3-(5-Chloropyridin-3-yl)-1H-indazol-5-yl)-5-cyano-3-methylpicolinamide

embedded image

Prepared as described for 5-cyano-N-(3-(isoxazol-4-yl)-1H-indazol-5-yl)-3-methylpicolinamide using (5-chloropyridin-3-yl)boronic acid in place of isoxazole-4-boronic acid to afford the title compound (2 mg, 3%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.64 (br. s., 1H) 10.83 (s, 1H) 9.14 (s, 1H) 9.02 (s, 1H) 8.59-8.75 (m, 2H) 8.40 (d, J=18.27 Hz, 2H) 7.94 (d, J=8.80 Hz, 1H) 7.67 (d, J=9.02 Hz, 1H) 2.61 (s, 3H). MS-ESI (m/z) calc'd for C₂₀H₁₄ClN₆O [M+H]⁺: 389.1/391.1. Found 389.1/391.1.

Example 122: 5-Cyano-2-fluoro-N-(3-(furan-3-yl)-1H-indazol-5-yl)benzamide

embedded image

To a solution of 5-cyano-2-fluorobenzoic acid (100 mg, 605.62 umol) and 3-(furan-3-yl)-1H-indazol-5-amine (120.64 mg, 605.62 umol) in pyridine (3 mL) was added EDCI (197.37 mg, 1.03 mmol) and the reaction mixture was stirred at 40° C. for 2 hrs. The reaction mixture was concentrated to give a residue which was purified by preparative HPLC using Method BQ to afford the title compound (38.70 mg, 18%) as an off-white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.13 (s, 1H), 10.62 (s, 1H), 8.37 (s, 1H), 8.28 (dd, J=2.2, 6.4 Hz, 1H), 8.21 (s, 1H), 8.12 (ddd, J=2.1, 4.7, 8.6 Hz, 1H), 7.85 (t, J=1.7 Hz, 1H), 7.67-7.63 (m, 1H), 7.63-7.61 (m, 1H), 7.59-7.55 (m, 1H), 6.99-6.95 (m, 1H). MS-ESI (m/z) calc'd for C₁₉H₁₂FN₄O₂[M+H]⁺: 347.1. Found 347.1.

Example 123: 5-Cyano-N-(3-(1,5-dimethyl-1H-pyrazol-4-yl)-1H-indazol-5-yl)-3-methylpicolinamide

embedded image

A mixture of N-(3-bromo-1H-indazol-5-yl)-5-cyano-3-methylpicolinamide (70 mg, 196.53 umol), (1,5-dimethyl-1H-pyrazol-4-yl)boronic acid (33.01 mg, 235.84 umol), Pd(Amphos)Cl₂(13.92 mg, 19.65 umol) and AcOK (57.86 mg, 589.60 umol) in EtOH (2 mL) and H₂O (0.5 mL) was degassed and purged with N₂(3×). The mixture was then stirred at 100° C. for 12 hrs under an N₂atmosphere. The reaction mixture was then concentrated and purified by preparative HPLC using Method BJ to afford the title compound (18.45 mg, 18%) as a yellow solid, TFA salt. ¹H NMR (400 MHz, DMSO-d₆) δ 12.96 (br s, 1H), 10.70 (s, 1H), 8.99 (d, J=1.5 Hz, 1H), 8.41 (dd, J=1.2, 6.9 Hz, 2H), 7.80 (s, 1H), 7.77 (dd, J=1.9, 8.9 Hz, 1H), 7.53 (d, J=9.0 Hz, 1H), 3.84 (s, 3H), 2.59 (s, 3H), 2.53 (s, 3H). MS-ESI (m/z) calc'd for C₂₀H₁₈N₇O [M+H]⁺: 372.2. Found 372.1.

Example 124: 4-Cyano-N-(3-(furan-3-yl)-1H-indazol-5-yl)-1-methyl-1H-imidazole-2-carboxamide

embedded image

Step 1: Methyl 4-cyano-1-methyl-1H-imidazole-2-carboxylate

embedded image

A mixture of methyl 4-bromo-1-methyl-1H-imidazole-2-carboxylate (300 mg, 1.37 mmol), Zn(CN)₂(160.83 mg, 1.37 mmol), Zn (10.75 mg, 164.36 umol), DPPF (30.37 mg, 54.79 umol) and Pd₂(dba)₃(250.84 mg, 273.93 umol) in DMA (5 mL) was degassed and purged with N₂(3×), and then the mixture was stirred at 120° C. for 4 hrs under an N₂atmosphere. The reaction mixture was concentrated and purified by flash silica gel chromatography using a 0-30% EtOAc/petroleum ether gradient eluent to afford the title compound (78 mg, 34%) as a yellow oil.

Step 2: 4-Cyano-N-(3-(furan-3-yl)-1H-indazol-5-yl)-1-methyl-1H-imidazole-2-carboxamide

embedded image

To a solution of methyl 4-cyano-1-methyl-1H-imidazole-2-carboxylate (40 mg, 242.21 umol) and 3-(furan-3-yl)-1H-indazol-5-amine (48.25 mg, 242.21 umol) in toluene (2 mL) was added Al(CH₃)₃(2 M in toluene, 363.31 uL) and the mixture was stirred at 90° C. for 24 hrs. The reaction mixture was concentrated and purified by preparative HPLC using Method CB to afford the title compound (10.45 mg, 100%) as a brown solid, TFA salt. ¹H NMR (400 MHz, DMSO-dt) δ 13.50-12.76 (m, 1H), 10.64 (s, 1H), 8.40 (br d, J=15.0 Hz, 2H), 8.25 (s, 1H), 7.90-7.82 (m, 2H), 7.54 (d, J=8.9 Hz, 1H), 7.00 (s, 1H), 4.05 (s, 3H). MS-ESI (m/z) calc'd for C₁₇H₁₃N₆O₂[M+H]⁺: 333.1. Found 333.0.

Example 125: 5-Cyano-N-(3-(furan-3-yl)-1H-indazol-5-yl)-2-hydroxybenzamide

embedded image

Step 1: 5-Cyano-2-hydroxybenzoic acid

embedded image

To a solution of methyl 5-cyano-2-hydroxybenzoate (200 mg, 861.95 umol) in THF (1 mL) and MeOH (1 mL) and H₂O (0.5 mL) was added LiOH.H₂O (142.12 mg, 3.39 mmol) and the mixture was stirred at 20° C. for 20 hrs. The reaction was adjusted to pH=4 with 1 N HCl. The mixture was filtered and the filtrate was concentrated to afford the title compound (140 mg) as a white solid which was used without further purification. MS-ESI (m/z) calcd for C₈H₄NO₃[M−H]⁻: 162.0. Found 161.9.

Step 2: 5-Cyano-N-(3-(furan-3-v)-1H-indazol-5-yl)-2-hydroxybenzamide

embedded image

To a solution of 5-cyano-2-hydroxybenzoic acid (70 mg, 429.11 umol) in DMF (2 mL) was added 3-(furan-3-yl)-1H-indazol-5-amine (85.48 mg, 429.11 umol), EDCI (98.71 mg, 514.93 umol), HOBt (69.58 mg, 514.93 umol), and DIEA (83.19 mg, 643.66 umol). The mixture was stirred at 20° C. for 12 hrs and concentrated. The residue was purified by preparative HPLC using Method BN to afford the title compound (19.78 mg, 13%) as an off-white solid, TFA salt. ¹H NMR (400 MHz, DMSO-d₆) δ 13.14 (s, 1H) 12.72 (br s, 1H) 10.56 (s, 1H) 8.42 (d, J=2.08 Hz, 1H) 8.30 (d, J=9.29 Hz, 2H) 7.83-7.91 (m, 2H) 7.64-7.67 (m, 1H) 7.56-7.60 (d, 1H) 7.15 (d, J=8.56 Hz, 1H) 7.01 (d, J=1.10 Hz, 1H). MS-ESI (m/z) calc'd for C₁₉H₁₃N₄O₃[M+H]⁺: 345.1. Found 345.0.

Example 126: N-(3-(1H-Imidazol-1-yl)-1H-indazol-5-yl)-5-cyano-3-methylpicolinamide

embedded image

Step 1: 2,5-Dinitro-2H-indazole

embedded image

To a solution of 5-nitro-1H-indazole (1 g, 6.13 mmol) in AcOH (9 mL) was added HNO₃(2.42 g, 37.58 mmol, 98% purity) and Ac₂O (4.38 g, 42.91 mmol) at −5° C. for 2 min. The mixture was then poured onto ice and stirred at 0° C. for 30 min. The mixture was filtered and the solid was dried under vacuum to afford the title compound (1.28 g) as an orange solid which was used without further purification.

Step 2: 3-(1H-Imidazol-1-yl)-5-nitro-1H-indazole

embedded image

To a solution of 2,5-dinitro-2H-indazole (1.2 g, 4.80 mmol) in THF (27 mL) and H₂O (36 mL) was added 1H-imidazole (654.18 mg, 9.61 mmol). The mixture was stirred at 20° C. for 12 hrs. The reaction mixture was extracted with EtOAc (30 mL 10). The combined organic layers were dried over Na₂SO₄, filtered and concentrated under reduced pressure to afford the title compound (1 g) as a yellow solid which was used without further purification. MS-(ESI) (m/z) calcd for C₁₀H₈N₅O₂(M+H)⁺: 230.1. Found 230.0.

Step 3: 3-(1H-Imidazol-1-yl)-1H-indazol-5-amine

embedded image

To a solution of 3-(1H-imidazol-1-yl)-5-nitro-1H-indazole (300 mg, 1.31 mmol) in EtOH (5 mL) and H₂O (5 mL) was added Fe (365.49 mg, 6.54 mmol) and NH₄Cl (350.08 mg, 6.54 mmol) and the mixture was stirred at 80° C. for 1 hr. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. Then the reaction mixture was diluted with H₂O (15 mL) and extracted with EtOAc (30 mL×4). The combined organic layers were washed with saturated aqueous NaHCO₃(30 mL×3), dried over Na₂SO₄, filtered and concentrated under reduced pressure to afford the title compound (120 mg, 46%) as a yellow solid which was used without further purification. MS-(ESI) (m/z) calcd for C₁₀H₁₀N₅(M+H)⁺: 200.1. Found 200.1.

Step 4: N-(3-(1H-Imidazol-1-yl)-1H-indazol-5-yl)-5-cyano-3-methylpicolinamide

embedded image

To a solution of 3-(1H-imidazol-1-yl)-1H-indazol-5-amine (100 mg, 501.98 umol) in pyridine (3 mL) was added EDCI (192.46 mg, 1.00 mmol) and 5-cyano-3-methylpicolinic acid (122.09 mg, 752.97 umol) and the mixture was stirred at 20° C. for 3 hrs. The reaction mixture was then concentrated and purified by preparative HPLC using Method BS to afford the title compound (45.59 mg, 26%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.15 (br s, 1H) 10.82 (s, 1H) 9.00 (d, J=1.34 Hz, 1H) 8.39-8.44 (m, 2H) 8.25 (s, 1H) 7.84 (dd, J=9.05, 1.83 Hz, 1H) 7.76 (t, J=1.16 Hz, 1H) 7.62 (d, J=8.93 Hz, 1H) 7.22 (s, 1H) 2.58 (s, 3H). MS-ESI (m/z) calc'd for C₁₈H₁₄N₇O [M+H]⁺: 344.1. Found 344.2.

Example 127: 6-Cyano-N-(3-(furan-3-yl)-1H-indazol-5-yl)picolinamide

embedded image

Step 1: 6-Bromo-N-(3-(furan-3-yl)-1H-indazol-5-yl)picolinamide

embedded image

To a solution of 6-bromopicolinic acid (500 mg, 2.48 mmol) and 3-(furan-3-yl)-1H-indazol-5-amine (493.08 mg, 2.48 mmol) in pyridine (2 mL) was added EDCI (711.75 mg, 3.71 mmol) and the reaction mixture was stirred at 25° C. for 12 hrs. The reaction mixture was concentrated and the residue obtained was purified by silica gel column chromatography using a 5-100% EtOAc/petroleum ether gradient eluent to afford the title compound (800 mg, 84%) as a yellow solid. MS-(ESI) (m/z) calcd for C₁₇H₁₂BrN₄O₂(M+H)⁺: 383.0/385.0. Found 383.0/385.0.

Step 2: 6-Cyano-N-(3-(furan-3-yl)-1H-indazol-5-yl)picolinamide

embedded image

A mixture of 6-bromo-N-(3-(furan-3-yl)-1H-indazol-5-yl)picolinamide (300 mg, 782.88 umol), Zn(CN)₂(45.97 mg, 391.44 umol) and Pd(PPh₃)₄(90.47 mg, 78.29 umol) was placed in a microwave reactor tube in DMF (5 mL) under N₂. The sealed tube was heated at 150° C. for 1 hr in a microwave reactor. The reaction mixture was concentrated to give a residue which was poured into water (15 mL). The aqueous phase was extracted with EtOAc (15 mL×3). The combined organic phases were washed with brine (15 mL×1), dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC using Method BP to afford the title compound (109.5 mg, 31%) as a pale yellow solid, TFA salt. ¹H NMR (400 MHz, DMSO-d₆) δ 13.11 (br s, 1H), 10.68 (s, 1H), 8.47-8.42 (m, 2H), 8.37-8.32 (m, 1H), 8.31 (dd, J=1.7, 2.4 Hz, 2H), 7.95 (dd, J=1.8, 9.0 Hz, 1H), 7.85 (t, J=1.6 Hz, 1H), 7.57 (d, J=8.9 Hz, 1H), 7.02 (d, J=1.2 Hz, 1H). MS-ESI (m/z) calc'd for C₁₈H₁₂N₅O₂[M+H]⁺: 330.1. Found 330.1.

Example 128: 3-Cyano-2-fluoro-N-(3-(furan-3-yl)-1H-indazol-5-yl)-6-methylbenzamide

embedded image

Step 1: 3-Bromo-2-fluoro-6-methylbenzoic acid

embedded image

To a solution of 1-bromo-2-fluoro-4-methylbenzene (5 g, 26.45 mmol) in THF (50 mL) was added LDA (2 M, 15.87 mL) dropwise at −70° C. The mixture was stirred at −70° C. for 1 hr, and then dry ice (CO₂solid, more than 10 eq) was added to the mixture. Stirring was continued at −70° C. for 1 hr. The mixture was diluted with H₂O (10 mL) and extracted with EtOAc (10 mL×2). The organic phase was discarded. The reaction was acidified with 1N HCl to adjust to pH=1. The reaction was filtered, the filtrate was collected and dried to afford the title compound (2.3 g, 37%) as a white solid.

Step 2: 3-Bromo-2-fluoro-N-(3-(furan-3-yl)-1H-indazol-5-yl)-6-methylbenzamide

embedded image

To a solution of 3-bromo-2-fluoro-6-methylbenzoic acid (200 mg, 858.24 umol) in pyridine (2 mL) was added EDCI (246.79 mg, 1.29 mmol) and 3-(furan-3-yl)-1H-indazol-5-amine (170.97 mg, 858.24 umol) and the mixture was stirred at 30° C. for 12 hrs. The reaction mixture was then concentrated under reduced pressure to remove solvent. The residue obtained was diluted with H₂O (20 mL), filtered and the solid was collected and dried to afford the title compound (300 mg) as a black solid which was used without further purification. MS-ESI (m/z) calcd for C₁₉H₁₄BrFN₃O₂[M+H]⁺: 414.0/416.0. Found 414.0/416.0.

Step 3: 3-(Cyano-2-fluoro-N-(3-(furan-3-yl)-1H-indazol-5-yl)-6-methylbenzamide

embedded image

A mixture of 3-bromo-2-fluoro-N-(3-(furan-3-yl)-1H-indazol-5-yl)-6-methylbenzamide (100 mg, 241.41 umol), Zn(CN)₂(56.70 mg, 482.83 umol), Zn (1.42 mg, 21.73 umol), dppf (4.02 mg, 7.24 umol), Pd₂(dba)₃(13.26 mg, 14.48 umol) in DMF (1 mL) was degassed and purged with N₂(3×). The mixture was stirred at 120° C. for 5 hrs under a N₂atmosphere in a microwave reactor. The reaction mixture was concentrated and purified by preparative HPLC using Method BO to afford the title compound (7.15 mg, 6%) as a white solid, TFA salt. ¹H NMR (400 MHz, DMSO-d₆) δ 13.12 (s, 1H) 10.54 (s, 1H) 8.35 (s, 1H) 8.22 (s, 1H) 7.96 (t, J=7.76 Hz, 1H) 7.85 (s, 1H) 7.54-7.66 (m, 2H) 7.47 (d, J=8.07 Hz, 1H) 6.99 (s, 1H) 2.59 (s, 3H). MS-ESI (m/z) calc'd for C₂₀H₁₄FN₄O₂[M+H]⁺: 361.1. Found 361.0.

Example 129: 5-Cyano-3-methyl-N-(3-(2-methyloxazol-5-yl)-1H-indazol-5-yl)picolinamide

embedded image

Prepared as described for 5-cyano-N-(3-(isoxazol-4-yl)-1H-indazol-5-yl)-3-methylpicolinamide using (2-methyloxazol-5-yl)boronic acid in place of isoxazole-4-boronic acid to afford the title compound (10.3 mg, 12%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.47 (s, 1H), 10.78 (s, 1H), 9.01 (d, J=1.9 Hz, 1H), 8.48 (d, J=1.9 Hz, 1H), 8.42 (d, J=2.0 Hz, 1H), 7.86 (dd, J=9.0, 1.9 Hz, 1H), 7.61 (d, J=9.0 Hz, 1H), 7.49 (s, 1H), 2.60 (s, 3H), 2.56 (s, 3H). MS-ESI (m/z) calc'd for C₁₉H₅N₆O₂[M+H]⁺: 359.1. Found 359.2.

Example 130: 5-Cyano-N-(3-(4-cyanothiophen-2-yl)-1H-indazol-5-yl)-3-methylpicolinamide

embedded image

Prepared as described for 5-cyano-N-(3-(5-cyanothiophen-2-yl)-1H-indazol-5-yl)-3-methylpicolinamide using (4-cyanothiophen-2-yl)boronic acid in place of (5-cyanothiophen-2-yl)boronic acid to afford the title compound (6.13 mg, 9%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.48 (s, 1H) 10.81 (s, 1H) 9.02 (s, 1H) 8.61 (s, 2H) 8.44 (s, 1H) 7.91-7.98 (m, 2H) 7.64 (d, J=9 Hz, 1H) 2.63 (s, 3H). MS-ESI (m/z) calc'd for C₁₉H₁₃N₆OS [M+H]⁺: 385.1. Found 385.0.

Example 131: 5-Cyano-N-(3-(5-cyanothiophen-2-yl)-1H-indazol-5-yl)-3-methylpicolinamide

embedded image

To a solution of N-(3-bromo-1H-indazol-5-yl)-5-cyano-3-methylpicolinamide (50 mg, 140.38 umol) and (5-cyanothiophen-2-yl)boronic acid (25.77 mg, 168.46 umol) in THF (3 mL) was added XPhos-Pd-G2 (11.05 mg, 14.04 umol) and an aqueous solution of K₃PO₄(0.4 M, 701.90 uL) and the mixture was stirred at 80° C. for 15 hrs under an N₂atmosphere. The reaction mixture was concentrated and purified by preparative HPLC using Method V twice to afford the title compound (3.38 mg, 5%) as a yellow solid, TFA salt. ¹H NMR (400 MHz, DMSO-d₆) δ 13.64 (s, 1H) 10.86 (s, 1H) 9.02 (s, 1H) 8.70 (s, 1H) 8.44 (s, 1H) 8.11 (d, J=4 Hz, 1H) 7.88 (br d, J=9 Hz, 1H) 7.74 (d, J=4 Hz, 1H) 7.67 (d, J=9 Hz, 1H) 2.62 (s, 3H). MS-ESI (m/z) calc'd for C₂₀H₁₃N₆O S [M+H]⁺: 385.1.1 Found 384.9.

Example 132: 4-Cyano-N-(3-(furan-3-yl)-1H-indazol-5-yl)pyrimidine-2-carboxamide

embedded image

Step 1: 2-Vinylpyrimidine-4-carbonitrile

embedded image

A mixture of 2-chloro-4-pyridinecarbonitrile (183.0 mg, 1.31 mmol), tributyl(ethenyl)stannane (0.42 mL, 1.44 mmol), and tetrakis(triphenylphosphine)palladium(0) (106.08 mg, 0.090 mmol) in toluene (6.6 mL) was refluxed under an atmosphere of N₂for 2 hrs and then cooled to r.t. The organic phase was separated, dried over Na₂SO₄, filtered and concentrated to give a residue. The residue was purified by NH-silica gel column chromatography using a 0-30% EtOAc/cyclohexane gradient eluent to afford the title compound (247 mg, 100%). MS-ESI (m/z) calc'd for C₇H₆N₃[M+H]⁺: 132.1. Found 132.1.

Step 2: 4-Cyanopyrimidine-2-carboxylic acid

embedded image

To a solution of 2-ethenylpyrimidine-4-carbonitrile (247.0 mg, 1.47 mmol) in acetone (8.606 mL) and H₂O (8.606 mL) was added KMnO₄(348.27 mg, 2.2 mmol). The mixture was stirred at r.t. for 1 hr. and another portion of KMnO₄(348.27 mg, 2.2 mmol) was added and stirring was continued for 6 hrs. A saturated aqueous solution of NaHCO₃was added and then the solution was extracted with EtOAc. The aqueous phase was acidified with 2 M HCl to lower the pH to 3 and extracted with EtOAc (2×). The organic phases were collected and concentrated under reduced pressure to afford the title compound (40 mg, 18%) as a white solid. NMR (400 MHz, MeOH-d₄) δ 9.00 (d, J=4.9 Hz, 1H), 7.72 (d, J=4.9 Hz, 1H), 6.90 (dd, J=17.3, 10.5 Hz, 1H), 6.79-6.66 (m, 1H), 5.89 (dd, J=10.5, 1.7 Hz, 1H). MS-ESI (m/z) calc'd for C₆H₂N₃O₂[M−H]⁺: 148.0. Found 148.0.

Step 3: 4-Cyano-N-(3-(furan-3-yl)-1H-indazol-5-yl)pyrimidine-2-carboxamide

embedded image

Prepared as described for 5-cyano-N-(7-fluoro-3-(furan-3-yl)-1H-indazol-5-yl)-3-methylpicolinamide using 4-cyanopyrimidine-2-carboxylic acid in place of 5-cyano-3-methylpicolinic acid and using 3-(furan-3-yl)-1H-indazol-5-amine in place of 7-fluoro-3-(furan-3-yl)-1H-indazol-5-amine to afford the title compound (1.4 mg, 2%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.13 (s, 1H), 10.89 (s, 1H), 9.38 (d, J=4.9 Hz, 1H), 8.46 (d, J=1.9 Hz, 1H), 8.38 (d, J=4.9 Hz, 1H), 8.32-8.25 (m, 1H), 7.93 (dd, J=8.9, 1.9 Hz, 1H), 7.85 (t, J=1.7 Hz, 1H), 7.58 (d, J=9.0 Hz, 1H), 7.02 (d, J=1.8 Hz, 1H). MS-ESI (m/z) calc'd for C₇H₁₁N₆O₂[M+H]⁺: 331.1. Found 331.2.

Example 133: 5-Cyano-N-(3-(furan-3-yl)-1H-indazol-5-yl)-4-methyl-1H-pyrazole-3-carboxamide

embedded image

Step 1: Ethyl 5-cyano-4-methyl-1H-pyrazole-3-carboxylate

embedded image

To a solution of ethyl but-2-ynoate (5 g, 44.59 mmol) and 2-aminoacetonitrile (7.43 g, 80.27 mmol, HCl salt) in CHCl₃(120 mL) and H₂O (4 mL) was added NaNO₂(9.23 g, 133.78 mmol) and the mixture was stirred at 60° C. for 12 hrs. The reaction mixture was then diluted with H₂O (100 mL) and extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine (30 mL×2), dried over Na₂SO₄, filtered and concentrated to give a residue. The residue was purified by silica gel column chromatography using a 0-10% EtOAc/petroleum ether gradient eluent to afford the title compound (0.2 g, 3%) as a yellow oil. MS-(ESI) (m/z) calcd for C₈H₁₀N₃O₂(M+H)⁺: 180.1. Found 180.0.

Step 2: 5-Cyano-N-(3-(fura-3-yl)-1H-indazol-5-yl)-4-methyl-1H-pyrazole-3-carboxamide

embedded image

To a solution of ethyl 5-cyano-4-methyl-1H-pyrazole-3-carboxylate (80 mg, 446.49 umol) and 3-(furan-3-yl)-1H-indazol-5-amine (106.73 mg, 535.79 umol) in toluene (3 mL) was added AlMe₃(2 M in toluene, 892.98 uL) and the mixture was stirred at 90° C. for 12 hrs. The reaction mixture was then quenched with MeOH (10 mL). A solid formed and the mixture was filtered. The filtrate was concentrated and purified by preparative HPLC using Method BT to afford the title compound (20.71 mg, 10%) as a gray solid, TFA salt. ¹H NMR (400 MHz, DMSO-d₆) δ 14.27 (br s, 1H) 12.89 (br s, 1H) 9.99 (s, 1H) 8.30 (br s, 1H) 8.19 (s, 1H) 7.80 (t, J=2 Hz, 1H) 7.69 (br s, 1H) 7.56 (br d, J=8 Hz, 1H) 7.00 (d, J=1 Hz, 1H) 2.42 (s, 3H). MS-ESI (m/z) calc'd for C₁₇H₁₃N₆O₂[M+H]⁺: 333.1. Found 333.0.

Example 134: 3-Cyano-6-fluoro-N-(3-(furan-3-yl)-1H-indazol-5-yl)-2-methylbenzamide

embedded image

Step 1: 3-Bromo-6-fluoro-2-methylbenzoic acid

embedded image

To a solution of 2-fluoro-6-methylbenzoic acid (700 mg, 4.54 mmol) in H₂SO₄(20 mL) (purity: 98%) was added NBS (848.71 mg, 4.77 mmol) at 0° C. and the mixture was stirred at 0° C. for 3 hrs. The reaction mixture was then poured into ice water (100 mL), and extracted with EtOAc (2×100 mL). The organic layers were combined, dried over Na₂SO₄, and concentrated under vacuum to afford the title compound (1.2 g) as a gray solid which was used without further purification. ¹H NMR (400 MHz, CDCl₃) δ 10.89 (s, 1H), 7.63-7.60 (m, 1H), 6.90 (t, J=8.8 Hz, 1H), 2.51 (s, 3H).

Step 2: 3-Bromo-6-fluoro-N-(3-(furan-3-yl)-1H-indazol-5-yl)-2-methylbenzamide

embedded image

To a solution of 3-bromo-6-fluoro-2-methylbenzoic acid (300 mg, 1.29 mmol) and 3-(furan-3-yl)-1H-indazol-5-amine (256.45 mg, 1.29 mmol) in pyridine (8 mL) was added EDCI (493.58 mg, 2.57 mmol) and the mixture was stirred at 25° C. for 12 hrs. The reaction mixture was concentrated and purified by flash silica gel chromatography (ISCO; 20 g SepaFlash column) using a 0-30% EtOAc/petroleum ether gradient eluent to afford the title compound (90 mg, 17%) as a redish brown solid. MS-(ESI) (m/z) calcd for C₁₉H₁₄BrFN₃O₂(M+H)˜: 414.0/416.0. Found 414.0/416.0.

Step 3: 3-(Cyano-6-fluoro-N-(3-(furan-3-yl)-1H-indazol-5-yl)-2-methylbenzamide

embedded image

A mixture of 3-bromo-6-fluoro-N-(3-(furan-3-yl)-1H-indazol-5-yl)-2-methylbenzamide (90 mg, 217.27 umol), Zn(CN)₂(51.03 mg, 434.54 umol), Zn (1.28 mg, 19.55 umol), Pd₂(dba)₃(11.94 mg, 13.04 umol) and DPPF (3.61 mg, 6.52 umol) in DMF (1 mL) in a sealed microwave tube was heated at 120° C. for 5 hrs under microwave irradiation. The reaction mixture was concentrated and purified by preparative HPLC using Method V to afford the title compound (33.02 mg, 32%) as a white solid, TFA salt. ¹H NMR (400 MHz, DMSO-d₆) δ 13.14 (br s, 1H), 10.79 (s, 1H), 8.37 (s, 1H), 8.22 (d, J=0.9 Hz, 1H), 8.03 (dd, J=5.5, 8.8 Hz, 1H), 7.85 (t, J=1.5 Hz, 1H), 7.62-7.54 (m, 2H), 7.47 (t, J=8.7 Hz, 1H), 7.01-6.96 (m, 1H), 2.54 (s, 3H). MS-ESI (m/z) calc'd for C₂₀H₁₄FN₄O₂[M+H]⁺: 361.1. Found 361.1.

Example 135: N-(3-Benzamido-1H-indazol-5-yl)-5-cyano-3-methylpicolinamide

embedded image

Step 1: N-(5-Nitro-1H-indazol-3-yl)benzamide

embedded image

To a solution of 5-nitro-1H-indazol-3-amine (500 mg, 2.81 mmol) in pyridine (7.5 mL) was added a solution of benzoyl chloride (414.25 mg, 2.95 mmol) in MeCN (2.5 mL) at 0° C. The mixture was stirred at 0° C. for 2 hrs and then concentrated under reduced pressure to remove solvent. The residue obtained was washed with MeOH (10 mL), filtered, and the solid was dried under vacuum to afford the title compound (620 mg, 78%) as a yellow solid which was used without further purification. MS (ESI+) calcd for C₁₄H₁₁N₄O₃(M+H)⁺: 283.1. Found 283.0.

Step 2: N-(5-amino-1H-indazol-3-yl)benzamide

embedded image

To a solution of N-(5-nitro-1H-indazol-3-yl)benzamide (620 mg, 2.20 mmol) in EtOH (12 mL) and H₂O (3 mL) was added Fe (613.35 mg, 10.98 mmol) and NH₄Cl (587.50 mg, 10.98 mmol). The mixture was stirred at 80° C. for 2 hrs and then filtered. The filtrate was concentrated under reduced pressure, diluted with H₂O (15 mL) and extracted with EtOAc (30 mL×4). The combined organic layers were dried over Na₂SO₄, filtered and concentrated under reduced pressure to afford the title compound (350 mg, 63%) as a brown gum which was used without further purification. MS (ESI+) calcd for C₁₄H₁₃N₄O (M+H)⁺: 253.1. Found 253.1

Step 3: N-(3-Benzamido-1H-indazol-5-yl)-5-cyano-3-methylpicolinamide

embedded image

To a solution of N-(5-amino-1H-indazol-3-yl)benzamide (100 mg, 396.40 umol) in DCM (4 mL) was added 5-cyano-3-methylpicolinic acid (38.56 mg, 237.84 umol), T3P (50 wt. % in EtOAc, 756.76 mg, 1.19 mmol), and Et₃N (160.45 mg, 1.59 mmol). The mixture was stirred at 25° C. for 12 hrs and then concentrated. The material was purified by preparative HPLC using Method BU to afford the title compound (43.85 mg, 28%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 12.82 (s, 1H) 10.76 (s, 1H) 10.68 (s, 1H) 8.97 (d, J=1.34 Hz, 1H) 8.36-8.39 (m, 1H) 8.21 (s, 1H) 8.08 (d, J=7.34 Hz, 2H) 7.70 (dd, J=9.05, 1.83 Hz, 1H) 7.60-7.65 (m, 1H) 7.53-7.59 (m, 2H) 7.50 (d, J=9.05 Hz, 1H) 2.54 (s, 3H). MS-ESI (m/z) calc'd for C₂₂H₁₇N₆O₂[M+H]⁺: 397.1. Found 397.2.

Example 136: N-(3-(1H-Pyrazol-1-yl)-1H-indazol-5-yl)-5-cyano-3-methylpicolinamide

embedded image

Step 1: 5-Nitro-3-(1H-pyrazol-1-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole

embedded image

To a solution of 3-iodo-5-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (1 g, 2.68 mmol) and 1H-pyrazole (182.44 mg, 2.68 mmol) in DMF (12 mL) was added CuI (102.08 mg, 535.98 umol) and Cs₂CO₃(1.31 g, 4.02 mmol) under N₂and the mixture was stirred at 20° C. for 0.5 hr followed by stirring at 120° C. for 24 hrs under N₂. The reaction mixture was concentrated and purified by flash silica gel chromatography (ISCO; 20 g SepaFlash column) using a 0-24% EtOAc/petroleum ether gradient eluent to afford the title compound (190 mg, 23%) as a yellow solid. MS-(ESI) (m/z) calcd for C₁₅H₁₆N₅O₃(M+H)⁺: 314.1. Found 314.1.

Step 2: 3-(1H-Pyrazol-1-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-amine

embedded image

To a solution of 5-nitro-3-(1H-pyrazol-1-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (190 mg, 606.43 umol) in EtOH (2.5 mL) and H₂O (2.5 mL) was added Fe (169.33 mg, 3.03 mmol) and NH₄Cl (162.19 mg, 3.03 mmol) and the mixture was stirred at 80° C. for 1 hr. The reaction mixture was then filtered and the filtrate was concentrated under reduced pressure to give a residue which was taken up in H₂O (10 mL) and extracted with EtOAc (30 mL×4). The combined organic layers were dried over Na₂SO₄, filtered and concentrated under reduced pressure to afford the title compound (170 mg) as a brown gum which was used without further purification.

Step 3: N-(3-(1H-Pyrazol-1-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-5-cyano-3-methylpicolinamide

embedded image

To a solution of 3-(1H-pyrazol-1-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-amine (160 mg, 564.72 umol) in pyridine (5 mL) was added EDCI (216.51 mg, 1.13 mmol) and 5-cyano-3-methylpicolinic acid (91.57 mg, 564.72 umol) and the mixture was stirred at 20° C. for 12 hrs. The reaction mixture was then concentrated under reduced pressure to remove solvent, diluted with H₂O (5 mL) and extracted with EtOAc (15 mL×6). The combined organic layers were dried over Na₂SO₄, filtered and concentrated under reduced pressure to afford the title compound (240 mg) as a brown solid which was used without further purification. MS-(ESI) (m/z) calcd for C₂H₂₂N₇O₂(M+H)⁺: 428.2. Found 428.2.

Step 4: N-(3-(1H-Pyrazol-1-yl)-1H-indazol-5-yl)-5-cyano-3-methylpicolinamide

embedded image

To a solution of N-(3-(1H-pyrazol-1-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-5-cyano-3-methylpicolinamide (240 mg, 561.46 umol) in DCM (4 mL) was added TFA (6.16 g, 54.02 mmol) and the mixture was stirred at 20° C. for 12 hrs. The reaction mixture was then concentrated and purified by preparative HPLC using Method BO to afford the title compound (48.62 mg, 19%) as a yellow solid TFA salt. ¹H NMR (400 MHz, DMSO-d₆) δ 13.06 (s, 1H) 10.77 (s, 1H) 8.99 (d, J=1.34 Hz, 1H) 8.79 (d, J=1.83 Hz, 1H) 8.38-8.43 (m, 2H) 7.89 (d, J=1.34 Hz, 1H) 7.75 (dd, J=9.05, 1.96 Hz, 1H) 7.56 (d, J=8.93 Hz, 1H) 6.57-6.61 (m, 1H) 2.58 (s, 3H). MS-ESI (m/z) calc'd for C₁₈H₁₄N₇O [M+H]⁺: 344.1. Found 344.0.

Example 137: 5-Cyano-N-(3-(furan-3-yl)-1H-indazol-5-yl)-3-methyl-1H-pyrazole-4-carboxamide

embedded image

Step 1: Ethyl 5-cyano-3-methyl-1H-pyrazole-4-carboxylate

embedded image

To a solution of ethyl but-2-ynoate (2.5 g, 22.30 mmol) in CHCl₃(60 mL) and H₂O (2 mL) was added 2-aminoacetonitrile (3.71 g, 40.13 mmol, HCl salt) and NaNO₂(4.61 g, 66.89 mmol). The mixture was stirred at 30° C. for 12 hrs and then warmed to 60° C. and stirred for an additional 12 hrs. The reaction mixture was quenched by addition of H₂O (20 mL) at 25° C. to give a biphasic mixture. The organic layer was separated and washed with H₂O (20 mL×1), dried over Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO; 20 g SepaFlash column) using a 0-30% EtOAc/petroleum ether gradient eluent to afford the title compound (100 mg, 3%) as a pale yellow solid.

Step 2: 5-Cyano-N-(3-(furan-3-yl)-1H-indazol-5-yl)-3-methyl-1H-pyrazole-4-carboxamide

embedded image

To a solution of ethyl 5-cyano-3-methyl-1H-pyrazole-4-carboxylate (50 mg, 279.06 umol), 3-(furan-3-yl)-1H-indazol-5-amine (66.71 mg, 334.87 umol) in toluene (2 mL) was added AlMe₃(2 M in toluene, 558.11 uL) and the mixture was stirred at 90° C. for 12 hrs. The reaction mixture was quenched by addition of MeOH (2 mL) at 30° C. The reaction mixture was concentrated and purified by preparative HPLC using Method BO to afford the title compound (10.9 mg, 8%) as a white solid, TFA salt. ¹H NMR (400 MHz, DMSO-d₆) δ 14.03 (br s, 1H) 13.10 (s, 1H) 10.11 (s, 1H) 8.18-8.35 (m, 2H) 7.85 (t, J=1.65 Hz, 1H) 7.50-7.61 (m, 2H) 6.99 (dd, J=1.76, 0.66 Hz, 1H). MS-ESI (m/z) calc'd for C₁₇H₁₃N₆O₂[M+H]⁺: 333.1. Found 333.0.

Example 138: 3-Bromo-5-cyano-N-(3-(furan-3-yl)-1H-indazol-5-yl)picolinamide

embedded image

Step 1: 3-Bromo-5-cyanopicolinic acid

embedded image

To a solution of methyl 3-bromo-5-cyanopicolinate (160 mg, 663.79 umol) in THF (3 mL) was added NaOH (53.10 mg, 1.33 mmol) and the mixture was stirred at 30° C. for 1 hr. The reaction mixture was quenched by addition of H₂O (2 mL) at 30° C., and then diluted with 1 N HCl to pH=2 and extracted with EtOAc (8 mL×2). The combined organic layers were dried over Na₂SO₄, filtered and concentrated under reduced pressure to afford the title compound (150 mg) as a pale yellow solid which was used without further purification. MS-ESI (m/z) calcd for C₇H₂BrN₂O₂[M−H]⁻: 224.9/226.9. Found 224.8/226.8.

Step 2: 3-Bromo-5-cyano-N-(3-(furan-3-yl)-1H-indazol-5-yl)picolinamide

embedded image

To a solution of 3-bromo-5-cyanopicolinic acid (150 mg, 660.75 umol) in pyridine (3 mL) was added EDCI (190.00 mg, 991.12 umol) and 3-(furan-3-yl)-1H-indazol-5-amine (157.95 mg, 792.90 umol) and the mixture was stirred at 30° C. for 12 hrs. The reaction mixture was concentrated to afford a residue. The residue was washed with H₂O (20 mL) and dried to afford 250 mg crude product, 100 mg was further purified by preparative HPLC using Method BD to afford the title compound (32.98 mg, 26%) as a yellow solid TFA salt. ¹H NMR (400 MHz, DMSO-d₆) δ 13.14 (s, 1H) 10.84 (s, 1H) 9.15 (s, 1H) 8.93 (s, 1H) 8.36 (s, 1H) 8.22 (s, 1H) 7.85 (s, 1H) 7.62-7.69 (m, 1H) 7.53-7.61 (m, 1H) 6.99 (s, 1H). MS-ESI (m/z) calc'd for C₁₈H₁₁BrN₅O₂[M+H]⁺: 408.0/410.0. Found 407.9/409.9.

Example 139: N-(3-(5-Chlorothiophen-2-yl)-1H-indazol-5-yl)-5-cyano-3-methylpicolinamide

embedded image

Prepared as described for 5-cyano-N-(3-(5-cyanothiophen-2-yl)-1H-indazol-5-yl)-3-methylpicolinamide using (5-chlorothiophen-2-yl)boronic acid in place of (5-cyanothiophen-2-yl)boronic acid to afford the title compound (9.74 mg, 14%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.33 (s, 1H) 10.81 (s, 1H) 9.01 (s, 1H) 8.64 (s, 1H) 8.43 (s, 1H) 7.83 (br d, J=9 Hz, 1H) 7.61 (br d, J=9 Hz, 1H) 7.48 (br d, J=4 Hz, 1H) 7.27 (d, J=4 Hz, 1H) 2.61 (s, 3H). MS-ESI (m/z) calc'd for C₁₉H₁₃ClN₅OS [M+H]⁺: 394.1. Found 393.9.

Example 140: 5-Cyano-3-methyl-N-(3-(2-methylthiazol-5-yl)-1H-indazol-5-yl)picolinamide

embedded image

Prepared as described for 5-cyano-N-(3-(5-cyanothiophen-2-yl)-1H-indazol-5-yl)-3-methylpicolinamide using (2-methylthiazol-5-yl)boronic acid in place of (5-cyanothiophen-2-yl)boronic acid to afford the title compound (1.98 mg, 2%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.34 (s, 1H), 10.80 (s, 1H), 9.01 (d, J=1.1 Hz, 1H), 8.59 (s, 1H), 8.42 (s, 1H), 8.13 (s, 1H), 7.86 (dd, J=1.7, 8.9 Hz, 1H), 7.60 (d, J=8.8 Hz, 1H), 2.72 (s, 3H), 2.61 (s, 3H). MS-ESI (m/z) calc'd for C₁₉H₁₈N₆OS [M+H]⁺: 375.1. Found 375.1.

Example 141: 5-Cyano-3-methyl-N-(3-(5-methylfuran-2-yl)-1H-indazol-5-yl)picolinamide

embedded image

Prepared as described for 5-cyano-N-(3-(1,5-dimethyl-1H-pyrazol-4-yl)-1H-indazol-5-yl)-3-methylpicolinamide using (5-methylfuran-2-yl)boronic acid in place of (1,5-dimethyl-1H-pyrazol-4-yl)boronic acid to afford the title compound (36.81 mg, 52%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.17 (s, 1H), 10.75 (s, 1H), 9.00 (d, J=1.5 Hz, 1H), 8.54 (d, J=1.3 Hz, 1H), 8.40 (d, J=1.1 Hz, 1H), 7.80 (dd, J=1.7, 8.9 Hz, 1H), 7.55 (d, J=9.0 Hz, 1H), 6.78 (d, J=3.1 Hz, 1H), 6.32-6.25 (m, 1H), 2.59 (s, 3H), 2.41 (s, 3H). MS-ESI (m/z) calc'd for C₂₀H₁₆N₅O₂[M+H]⁺: 358.1. Found 358.2.

Example 142: 5-Cyano-N-(3-(furan-3-yl)-1H-indazol-5-yl)quinoline-8-carboxamide

embedded image

Step 1: Methyl 5-vinylquinoline-8-carboxylate

embedded image

To a solution of methyl 5-bromoquinoline-8-carboxylate (1.33 g, 5 mmol) in 1,4-dioxane (50 mL) was added tributyl(ethenyl)stannane (1.75 mL, 6 mmol) and the mixture was degassed with N₂for 10 minutes. Bis(triphenylphosphine)palladium(II) dichloride (175.98 mg, 0.250 mmol) was added and the reaction was stirred at 100° C. for 8 hrs. The solvent was evaporated and the residue was purified by silica gel column chromatography using 0-100% EtOAc/cyclohexane gradient eluent to afford the title compound (678 mg, 64%) as an orange oil. ¹H NMR (400 MHz, DMSO-d₆) δ 8.98 (dd, J=4.2, 1.7 Hz, 1H), 8.72 (dd, J=8.7, 1.7 Hz, 1H), 7.92 (d, J=7.5 Hz, 1H), 7.86 (d, J=7.5 Hz, 1H), 7.67-7.55 (m, 2H), 6.02 (dd, J=17.3, 1.3 Hz, 1H), 5.63 (dd, J=11.0, 1.3 Hz, 1H), 3.91 (s, 3H). MS-ESI (m/z) calc'd for C₁₃H₁₂NO₂[M+H]⁺: 214.1. Found 214.1.

Step 2: Methyl 5-formylquinoline-8-carboxylate

embedded image

To a solution of methyl 5-ethenylquinoline-8-carboxylate (678.0 mg, 3.18 mmol) in 1,4-dioxane (15.9 mL) was added a solution of NaIO₄(1.36 g, 6.36 mmol) in H₂O (15.9 mL) and the mixture was stirred at 25° C. for 1 hr. The mixture was diluted with H₂O and extracted with DCM (3×). The combined organic layers were passed through a phase separator and evaporated to afford the title compound (684 mg, 99%) as a dark green oil. ¹H NMR (400 MHz, DMSO-d₆) δ 10.46 (s, 1H), 9.49 (dd, J=8.7, 1.8 Hz, 1H), 9.06 (dd, J=4.2, 1.7 Hz, 1H), 8.34 (d, J=7.3 Hz, 1H), 8.13 (d, J=7.3 Hz, 1H), 7.81 (dd, J=8.7, 4.2 Hz, 1H), 3.57 (s, 3H). MS-ESI (m/z) calc'd for C₁₂H₁₀NO₃[M+H]⁺: 216.1. Found 216.0.

Step 3: Methyl 5-cyanoquinoline-8-carboxylate

embedded image

To a solution of methyl 5-formylquinoline-8-carboxylate (684.0 mg, 3.18 mmol) in DMSO (4 mL) was added hydroxylamine hydrochloride (220.87 mg, 3.18 mmol) and the mixture was stirred at 90° C. for 1 hr. Water was added and a solid formed and the mixture was filtered. The filtrate was extracted with EtOAc (3×) and the combined organic layers were washed with H₂O, passed through a phase separator and evaporated to afford the title compound (327 mg, 48%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 9.24 (dd, J=4.4, 1.6 Hz, 1H), 8.74 (dd, J=8.5, 1.6 Hz, 1H), 8.44 (d, J=1.0 Hz, 2H), 8.00 (dd, J=8.5, 4.4 Hz, 1H), 3.96 (s, 3H). MS-ESI (m/z) calc'd for C₁₂H₈N₂O₂[M+H]⁺: 213.1. Found 213.0.

Step 4: 5-Cyanoquinoline-8-carboxylic acid

embedded image

To a solution of methyl 5-cyanoquinoline-8-carboxylate (327.0 mg, 1.54 mmol) in THF (7.705 mL) was added a solution of NaOH (126.39 mg, 3.08 mmol) in H₂O (7.705 mL) and the mixture was stirred at 25° C. for 1 hr. The solvent was evaporated to dryness and the residue was taken up in POCl₃(10 mL) and stirred at 100° C. for 1 hr. Excess POCl₃was removed under vacuum and the solid that remained was extracted with H₂O and EtOAc (3×). The combined organic layers were passed through a phase separator and evaporated to afford the title compound (279 mg, 91%) as a beige solid. ¹H NMR (400 MHz, DMSO-d₆) δ 15.26 (s, 1H), 9.24 (dd, J=4.4, 1.6 Hz, 1H), 8.74 (dd, J=8.5, 1.6 Hz, 1H), 8.49-8.37 (m, 2H), 8.00 (dd, J=8.5, 4.4 Hz, 1H). MS-ESI (m/z) calc'd for C₁₁H₅N₂O₂[M−H]⁻: 197.0. Found 197.1.

Step 5: 5-Cyano-N-(3-(furan-3-yl)-1H-indazol-5-yl)quinoline-8-carboxamide

embedded image

Prepared as described for 5-cyano-N-(7-fluoro-3-(furan-3-yl)-1H-indazol-5-yl)-3-methylpicolinamide using 5-cyanoquinoline-8-carboxylic acid in place of 5-cyano-3-methylpicolinic acid and using 3-(furan-3-yl)-1H-indazol-5-amine in place of 7-fluoro-3-(furan-3-yl)-1H-indazol-5-amine to afford the title compound (8 mg, 11%) as a orange solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.13 (s, 1H), 12.41 (s, 1H), 9.33 (dd, J=4.3, 1.7 Hz, 1H), 8.72 (dd, J=8.5, 1.7 Hz, 1H), 8.56 (d, J=7.6 Hz, 1H), 8.52-8.51 (m, 1H), 8.46 (d, J=7.6 Hz, 1H), 8.30 (dd, J=1.5, 0.8 Hz, 1H), 7.98 (dd, J=8.5, 4.3 Hz, 1H), 7.85 (t, J=1.7 Hz, 1H), 7.80 (dd, J=9.0, 1.9 Hz, 1H), 7.60 (d, J=8.8 Hz, 1H), 7.02 (dd, J=1.8, 0.8 Hz, 1H). MS-ESI (m/z) calc'd for C₂₂H₁₄N₅O₂[M+H]⁺: 380.1. Found 380.1.

Example 143: 5-Cyano-N-(7-fluoro-3-(furan-3-yl)-1H-indazol-5-yl)-3-methylpicolinamide

embedded image

Step 1: 7-Fluoro-3-iodo-5-nitro-1H-indazole

embedded image

To a solution of 7-fluoro-5-nitro-1H-indazole (1.0 g, 5.52 mmol) in DMF (20 mL) was added KOH (1.17 g, 20.43 mmol)) and I₂(2.8 g, 11.04 mmol) and the mixture was stirred for 1 hr. The mixture was then poured into saturated aqueous sodium metabisulfite (200 mL) and the solid formed was collected by filtration, washed with H₂O and dried to give the title compound (1.3 g, 77%) as a light brown solid which was used without further purification. MS-ESI (m/z) calc'd for C₇H₄FIN₃O₂[M+H]⁺: 308.0. Found 307.8.

Step 2: 7-Fluoro-3-iodo-1H-indazol-5-amine

embedded image

A mixture of 7-fluoro-3-iodo-5-nitro-1H-indazole (1.3 g, 4.23 mmol), NH₄Cl (249.14 mg, 4.66 mmol) and iron powder (945.93 mg, 16.94 mmol) in EtOH (13.43 mL) and water (13.43 mL) was stirred 80° C. for 1 hr. The solids were removed by filtration through Celite and the solid was washed with EtOH. The filtrate was evaporated, the residue was taken up in water and extracted with EtOAc (3×), the combined organic layers were passed through a phase separator and evaporated to afford the title compound (228 mg, 19%) as a yellow solid. MS-ESI (m/z) calc'd for C₇H₆FIN₃[M+H]⁺: 278.0. Found 278.1.

Step 3: 7-Fluoro-3-(furan-3-yl)-1H-indazol-5-amine

embedded image

A microwave vial was charged with 7-fluoro-3-iodo-1H-indazol-5-amine (55.0 mg, 0.200 mmol), 3-furanylboronic acid (44.43 mg, 0.400 mmol), KOAc (35.43 mg, 0.360 mmol) and Pd(amphos)Cl₂(14.1 mg, 0.020 mmol). The vial was flushed with Ar, then 1,4-dioxane (0.375 ml) and H₂O (0.125 ml) were added in sequence. The vial was sealed and stirred at 100° C. in a microwave reactor for 30 minutes. The reaction was diluted with EtOAc and washed with H₂O. The aqueous layer was extracted with EtOAc and the combined organic layers were washed with brine, dried with Na₂SO₄, filtered and concentrated. The material was purified by silica gel column chromatography (Redi-Sep Gold (Teledyne Isco)) using a 0-100% EtOAc/cyclohexane gradient eluent to afford the title compound (20 mg, 46%). MS-ESI (m/z) calc'd for C₁₁H₉FN₃O [M+H]⁺: 218.1. Found 218.0.

Step 4: 5-Cyano-N-(7-fluoro-3-(furan-3-yl)-1H-indazol-5-yl)-3-methylpicolinamide

embedded image

To a solution of 5-cyano-3-methylpicolinic acid (15.0 mg, 0.090 mmol), triethylamine (0.01 mL, 0.090 mmol) and 7-fluoro-3-(furan-3-yl)-1H-indazol-5-amine (20.09 mg, 0.090 mmol) was added HATU (35.17 mg, 0.090 mmol) and the mixture was stirred at r.t. for 1 hr. Water and EtOAc were added and the organic phase was separated and washed with brine to afford a residue that was purified by preparative HPLC using Method CV to afford the title compound (2.2 mg, 7%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 2.57-2.70 (m, 3H) 7.02 (dd, J=1.87, 0.77 Hz, 1H) 7.81-7.97 (m, 2H) 8.22-8.34 (m, 2H) 8.38-8.57 (m, 1H) 9.02 (dd, J=1.98, 0.66 Hz, 1H) 10.85 (s, 1H) 13.68 (br. s., 1H). MS-ESI (m/z) calc'd for C₁₉H₁₃FN₅O₂[M+H]⁺: 362.1. Found 362.1.

Example 144: 3-Chloro-4-cyano-N-(3-(furan-3-yl)-1H-indazol-5-yl)picolinamide

embedded image

Prepared as described for 5-cyano-N-(7-fluoro-3-(furan-3-yl)-1H-indazol-5-yl)-3-methylpicolinamide using 3-chloro-4-cyanopicolinic acid in place of 5-cyano-3-methylpicolinic acid and using 3-(furan-3-yl)-1H-indazol-5-amine in place of 7-fluoro-3-(furan-3-yl)-1H-indazol-5-amine to afford the title compound (10.4 mg, 15%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.14 (br. s., 1H) 10.82 (s, 1H) 8.90 (d, J=4.84 Hz, 1H) 8.38 (d, J=1.10 Hz, 1H) 8.17-8.28 (m, 2H) 7.86 (t, J=1.65 Hz, 1H) 7.70 (dd, J=8.91, 1.87 Hz, 1H) 7.59 (d, J=9.46 Hz, 1H) 7.00 (dd, J=1.76, 0.88 Hz, 1H). MS-ESI (m/z) calc'd for C₁₈H₁₁ClN₅O₂[M+H]⁺: 364.1/366.1. Found 364.2/366.0.

Example 145: 5-Cyano-N-(3-(furan-3-yl)-1H-indazol-5-yl)-3-methylpyrazine-2-carboxamide

embedded image

Prepared as described for 5-cyano-N-(7-fluoro-3-(furan-3-yl)-1H-indazol-5-yl)-3-methylpicolinamide using 5-cyano-3-methylpyrazine-2-carboxylic acid in place of 5-cyano-3-methylpicolinic acid and using 3-(furan-3-yl)-1H-indazol-5-amine in place of 7-fluoro-3-(furan-3-yl)-1H-indazol-5-amine to afford the title compound (16.1 mg, 13%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.14 (s, 1H), 10.78 (s, 1H), 9.30 (s, 1H), 8.44-8.37 (m, 1H), 8.27 (dd, J=1.5, 0.9 Hz, 1H), 7.86 (t, J=1.7 Hz, 1H), 7.79 (dd, J=9.0, 1.9 Hz, 1H), 7.59 (dd, J=9.0, 0.8 Hz, 1H), 7.01 (dd, J=1.8, 0.8 Hz, 1H), 2.88 (s, 3H). MS-ESI (m/z) calc'd for C₁₈H₁₃N₆O₂[M+H]⁺: 345.1. Found 345.2.

Example 146: 5-Cyano-N-(3-(isoxazol-4-yl)-1H-indazol-5-yl)-3-methylpicolinamide

embedded image

A microwave vial was charged with 5-cyano-N-(3-iodo-1H-indazol-5-yl)-3-methylpyridine-2-carboxamide (50.0 mg, 0.120 mmol), isoxazole-4-boronic acid (28.0 mg, 0.250 mmol), KOAc (22.13 mg, 0.220 mmol) and Pd(amphos)Cl₂(8.81 mg, 0.010 mmol). The vial was flushed with N₂, then 1,4-dioxane (0.800 mL) and H₂O (0.125 mL) were added in sequence. The vial was sealed and irradiated in a microwave reactor at 100° C. for 30 minutes. The reaction was diluted with EtOAc and washed with water. The aqueous layer was extracted with EtOAc and the combined organic layers were washed with brine, dried with Na₂SO₄, filtered and concentrated. The residue was purified by preparative HPLC using Method CW to afford the title compound (23.5 mg, 55%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.35 (br. s., 1H) 10.71 (s, 1H) 9.57 (s, 1H) 9.15 (s, 1H) 9.01 (d, J=1.32 Hz, 1H) 8.51-8.35 (m, 2H) 7.85 (dd, J=9.02, 1.76 Hz, 1H) 7.61 (d, J=8.36 Hz, 1H) 3.33-3.33 (m, 1H) 2.67 (s, 1H) 2.72-2.56 (m, 3H). MS-ESI (m/z) calc'd for C₁₉H₁₃N₆O₂[M+H]⁺: 345.1. Found 345.2.

Example 147: 6-Cyano-N-(3-(furan-3-yl)-1H-indazol-5-yl)-3-methylpyrazine-2-carboxamide

embedded image

Prepared as described for 5-cyano-N-(7-fluoro-3-(furan-3-yl)-1H-indazol-5-yl)-3-methylpicolinamide using 6-cyano-3-methylpyrazine-2-carboxylic acid in place of 5-cyano-3-methylpicolinic acid and using 3-(furan-3-yl)-1H-indazol-5-amine in place of 7-fluoro-3-(furan-3-yl)-1H-indazol-5-amine to afford the title compound (12.5 mg, 10%) as an orange solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.13 (s, 1H), 10.85 (s, 1H), 9.22 (q, J=0.7 Hz, 1H), 8.42 (dd, J=1.9, 0.8 Hz, 1H), 8.26 (dd, J=1.5, 0.9 Hz, 1H), 7.85 (t, J=1.7 Hz, 1H), 7.81 (dd, J=9.0, 1.9 Hz, 1H), 7.58 (dd, J=9.0, 0.7 Hz, 1H), 7.00 (dd, J=1.9, 0.8 Hz, 1H), 2.84 (d, J=0.7 Hz, 3H). MS-ESI (m/z) calc'd for C₁₅H₁₃N₆O₂[M+H]⁺: 345.1. Found 345.2.

Example 148: 6-Cyano-N-(3-(furan-3-yl)-1H-indazol-5-yl)-3-methylpicolinamide

embedded image

A mixture of 3-(furan-3-yl)-1H-indazol-5-amine (40.0 mg, 0.200 mmol) and methyl 6-cyano-3-methylpyridine-2-carboxylate (35.37 mg, 0.200 mmol) in toluene (2 mL) was flushed with N₂for 5 min. Then a 2 M solution of trimethylaluminum in toluene (0.3 mL, 0.600 mmol) was added and the reaction mixture was stirred for 1 hr at 95° C. The reaction mixture was then cooled to r.t., diluted with H₂O and EtOAc, the phases were separated, the aqueous layer was extracted with EtOAc (2×) and the combined organic phases were washed with H₂O (1×), dried over Na₂SO₄and evaporated to dryness. The material was purified by preparative HPLC using Method CZ to afford the title compound (9.2 mg, 13%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.12 (s, 1H) 10.63 (s, 1H) 8.40 (d, J=1.54 Hz, 1H) 8.26 (d, J=0.88 Hz, 1H) 8.13-8.19 (m, 1H) 8.07-8.12 (m, 1H) 7.85 (t, J=1.65 Hz, 1H) 7.79 (dd, J=9.02, 1.76 Hz, 1H) 7.57 (d, J=8.80 Hz, 1H) 6.98-7.05 (m, 1H) 2.63 (s, 3H). MS-ESI (m/z) calc'd for C₁₉H₁₄N₅O₂[M+H]⁺: 344.1. Found 344.2.

Example 149: 4-Cyano-3-ethyl-N-(3-(furan-3-yl)-1H-indazol-5-yl)picolinamide

embedded image

Step 1: Ethyl 4-cyano-3-vinylpicolinate

embedded image

Ethyl 3-chloro-4-cyanopyridine-2-carboxylate (80.0 mg, 0.380 mmol) and 2-ethenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.1 mL, 0.570 mmol) were suspended in 1,4-dioxane (4 mL) and a solution of potassium carbonate (157.49 mg, 1.14 mmol) in H₂O (1 mL) was added. The mixture was degassed with N₂for 5 minutes and tetrakis(triphenylphosphine)palladium(0) (43.89 mg, 0.040 mmol) was added and the mixture was stirred at 110° C. under N₂for 2 hrs. The reaction mixture was partitioned between H₂O and EtOAc, the phases were separated, the aqueous layer was extracted with EtOAc (2×) and the combined organic phases were washed with water (1×), dried over anhydrous Na₂SO₄and evaporated to dryness. The material was purified by silica gel column chromatography using a 0-50% EtOAc/cyclohexane gradient eluent to afford the title compound (60 mg, 78%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.79 (d, J=5.28 Hz, 1H) 8.11 (d, J=5.06 Hz, 1H) 7.02 (dd, J=17.72, 11.55 Hz, 1H) 5.78-5.93 (m, 2H) 4.36 (q, J=7.04 Hz, 2H) 1.31 (t, J=7.15 Hz, 3H). MS-ESI (m/z) calc'd for C₁₁H₁N₂O₂[M+H]⁺: 203.1. Found 203.1.

Step 2: Ethyl 4-cyano-3-ethylpicolinate

embedded image

Ethyl 4-cyano-3-ethenylpyridine-2-carboxylate (60.0 mg, 0.140 mmol) was dissolved in EtOH (5 mL) and 10% Pd/C (15.16 mg) was added. The mixture was stirred at r.t. under H₂atmosphere for 1 hr. The Pd/C was filtered off, washing with EtOH. The filtrate was collected and evaporated to dryness under reduced pressure to afford the title compound (40 mg) as a white solid which was used without further purification. ¹H NMR (400 MHz, MeOH-d₄) δ 8.68 (d, J=4.84 Hz, 1H) 7.87 (d, J=5.06 Hz, 1H) 4.47 (q, J=7.26 Hz, 2H) 3.09 (q, J=7.56 Hz, 2H) 1.43 (t, J=7.15 Hz, 3H) 1.34 (t, J=7.59 Hz, 3H). MS-ESI (m/z) calc'd for C₁₁H₁₃N₂O₂[M+H]⁺: 205.1. Found 205.1.

Step 3: 4-Cyano-3-ethylpicolinic acid

embedded image

To a solution of ethyl 4-cyano-3-ethylpyridine-2-carboxylate (40.0 mg, 0.080 mmol) in THF (1.5 mL) was added a solution of NaOH (3.13 mg, 0.080 mmol) in H₂O (0.750 mL) and the mixture was stirred at r.t. for 2 hrs. The reaction was concentrated to afford the title compound (45 mg) as a white solid which was used without further purification. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.37 (d, J=5.06 Hz, 1H) 7.47 (d, J=4.84 Hz, 1H) 2.80 (q, J=7.48 Hz, 2H) 1.19 (t, J=7.48 Hz, 3H). MS-ESI (m/z) calc'd for C₉H₇N₂O₂[M−H]⁻: 175.1. Found 175.0.

Step 4: 4-Cyano-3-ethyl-N-(3-(furan-3-yl)-1H-indazol-5-yl)picolinamide

embedded image

Prepared as described for 5-cyano-N-(7-fluoro-3-(furan-3-yl)-1H-indazol-5-yl)-3-methylpicolinamide using 4-cyano-3-ethylpicolinic acid in place of 5-cyano-3-methylpicolinic acid and using 3-(furan-3-yl)-1H-indazol-5-amine in place of 7-fluoro-3-(furan-3-yl)-1H-indazol-5-amine to afford the title compound (9.1 mg, 34%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.10 (s, 1H) 10.71 (s, 1H) 8.80 (d, J=5.06 Hz, 1H) 8.40 (d, J=1.54 Hz, 1H) 8.26 (dd, J=1.54, 0.88 Hz, 1H) 8.07 (d, J=4.84 Hz, 1H) 7.85 (t, J=1.65 Hz, 1H) 7.81 (dd, J=9.02, 1.98 Hz, 1H) 7.57 (d, J=8.80 Hz, 1H) 7.01 (dd, J=1.87, 0.77 Hz, 1H) 3.14 (q, J=7.41 Hz, 2H) 1.31 (t, J=7.48 Hz, 3H). MS-ESI (m/z) calc'd for C₂₀H₁₆N₅O₂[M+H]⁺: 358.1. Found 358.1.

Example 150: 5-Cyano-N-(3-(1-methoxyethyl)-1H-indazol-5-yl)-3,4-dimethylpicolinamide

embedded image

Step 1: 5-Bromo-6-iodonicotinonitrile

embedded image

To a solution of 5-bromo-6-chloronicotinonitrile (2.26 g, 10.39 mmol) in MeCN (40 mL) was added NaI (4.52 g, 30.14 mmol) and TMSI (2.29 g, 11.43 mmol). The mixture was stirred at 25° C. for 1 hr. The mixture was quenched by addition of saturated aqueous NaHCO₃(20 mL) and extracted with EtOAc (40 mL×2). The combined organic layers were dried over Na₂SO₄and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO; 20 g SepaFlash column) using a 0-3% EtOAc/petroleum ether gradient eluent to afford the title compound (3.1 g, 97%) as a yellow solid. MS-ESI (m/z) calcd for C₆H₃BrIN₂[M+H]⁺: 308.8/310.8. Found 308.8/310.8.

Step 2: Methyl 3-bromo-5-cyanopicolinate

embedded image

To a solution of 5-bromo-6-iodonicotinonitrile (1 g, 3.24 mmol) in MeCN (20 mL) and MeOH (6 mL) was added Pd(PPh₃)₂Cl₂(113.61 mg, 161.86 umol) and Et₃N (982.74 mg, 9.71 mmol) under an N₂atmosphere. The suspension was degassed and purged with CO (3×). The mixture was then stirred under CO (3 Mpa) at 50° C. for 7 hrs. The reaction mixture was concentrated and purified by flash silica gel chromatography (ISCO; 12 g SepaFlash column) using a 0-11% EtOAc/petroleum ether gradient eluent to afford the title compound (700 mg, 90%) as a pale yellow solid. MS-ESI (m/z) calcd for C₈H₆BrN₂O₂[M+H]⁺: 241.0/243.0. Found 241.1/243.1.

Step 3: 5-Cyano-3-((trimethylsilyl)ethynyl)picolinic acid

embedded image

A mixture of methyl 3-bromo-5-cyanopicolinate (400 mg, 1.66 mmol), ethynyl(trimethyl)silane (488.97 mg, 4.98 mmol, 689.66 uL), CuI (15.80 mg, 82.97 umol), Pd(PPh₃)₄(191.76 mg, 165.95 umol) and Et₃N (671.69 mg, 6.64 mmol, 923.91 uL) in THF (3.5 mL) was degassed and purged with N₂(3×), and then the mixture was stirred at 80° C. for 12 hrs under an N₂atmosphere. The reaction mixture was concentrated to afford a residue. The residue was purified by flash silica gel chromatography (ISCO; 12 g SepaFlash column) using a 0-8% EtOAc/petroleum ether gradient eluent to afford the title compound (210 mg, 39%) as a pale yellow solid. MS-ESI (m/z) calcd for C₁₃H₁₅N₂O₂Si [M+H]⁺: 259.1. Found 259.0.

Step 4: 5-Cyano-3-ethynylpicolinic acid

embedded image

To a solution of 5-cyano-3-((trimethylsilyl)ethynyl)picolinic acid (110 mg, 425.78 umol) in THF (1.5 mL) was added NaOH (34.06 mg, 851.57 umol) and the mixture was stirred at 30° C. for 2 hrs. The mixture was diluted with H₂O (3 mL and extracted with EtOAc (5 mL×2). The EtOAc layer was discarded. The aqueous layer was then adjusted to pH=1 by addition of 1 N HCl, and the mixture was extracted with EtOAc (5 mL 2). The combined organic layers were dried over Na₂SO₄, filtered and concentrated under reduced pressure to afford the title compound (68 mg) as a pale yellow solid which was used without further purification. MS-ESI (m/z) calcd for C₉H₅N₂O₂[M+H]⁺: 173.0. Found 173.0.

Step 5: 5-Cyano-N-(3-(1-methoxyethyl)-1H-indazol-5-yl)-3,4-dimethylpicolinamide

embedded image

To a solution of 5-cyano-3-vinylpicolinic acid (20 mg, 116.18 umol) in DMF (1 mL) was added HOBt (23.55 mg, 174.28 umol), Et₃N (35.27 mg, 348.55 umol, 48.51 uL), EDCI (33.41 mg, 174.28 umol) and 3-(furan-3-yl)-1H-indazol-5-amine (23.14 mg, 116.18 umol). The reaction mixture was stirred at 30° C. for 12 hrs and then concentrated to afford a residue. The residue was purified by preparative HPLC using Method BC to afford the title compound (1.4 mg, 3%) as a yellow solid TFA salt. ¹H NMR (400 MHz, DMSO-d₆) δ 13.38 (s, 1H), 9.32 (d, J=1.76 Hz, 1H), 9.24 (d, J=1.76 Hz, 1H), 8.46 (s, 1H), 8.17 (s, 1H), 7.82 (t, J=1.65 Hz, 1H), 7.75 (d, J=8.60 Hz, 1H), 7.42 (dd, J=1.87, 8.71 Hz, 1H), 7.05 (d, J=1.10 Hz, 1H), 5.77 (d, J=2.43 Hz, 1H), 4.95 (d, J=2.43 Hz, 1H). MS-ESI (m/z) calc'd for C₂₀H₁₂N₅O₂[M+H]⁺: 354.1. Found 354.0.

Example 151: 5-Cyano-3-methyl-N-(3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-1H-indazol-5-yl)picolinamide

embedded image

Prepared as described for 5-cyano-N-(3-(1,5-dimethyl-1H-pyrazol-4-yl)-1H-indazol-5-yl)-3-methylpicolinamide using (1-methyl-6-oxo-1,6-dihydropyridin-3-yl)boronic acid in place of (1,5-dimethyl-1H-pyrazol-4-yl)boronic acid to afford the title compound (22.18 mg, 27%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.18 (s, 1H), 10.71 (s, 1H), 9.00 (s, 1H), 8.40 (br d, J=13.8 Hz, 2H), 8.24 (d, J=2.1 Hz, 1H), 7.99 (dd, J=2.3, 9.3 Hz, 1H), 7.86 (br d, J=8.1 Hz, 1H), 7.57 (d, J=9.0 Hz, 1H), 6.58 (d, J=9.4 Hz, 1H), 3.57 (s, 3H), 2.60 (s, 3H). MS-ESI (m/z) calc'd for C₂₁H₁₇N₆O₂[M+H]⁺: 385.1. Found 385.0.

Example 152: 5-cyano-3-methyl-N-(3-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)-1H-indazol-5-yl)picolinamide

embedded image

Prepared as described for 5-cyano-N-(3-(1,5-dimethyl-1H-pyrazol-4-yl)-1H-indazol-5-yl)-3-methylpicolinamide using (1-methyl-2-oxo-1,2-dihydropyridin-4-yl)boronic acid in place of (1,5-dimethyl-1H-pyrazol-4-yl)boronic acid to afford the title compound (7.75 mg, 8%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.62 (s, 1H), 10.87 (s, 1H), 9.01 (d, J=1.3 Hz, 1H), 8.68 (s, 1H), 8.42 (d, J=1.1 Hz, 1H), 7.92 (dd, J=9.2, 1.7 Hz, 1H), 7.80 (d, J=7.3 Hz, 1H), 7.65 (d, J=9.0 Hz, 1H), 6.95 (d, J=1.8 Hz, 1H), 6.87 (dd, J=7.1, 1.8 Hz, 1H), 6.85-6.90 (m, 1H), 6.85-6.90 (m, 1H), 3.48 (s, 3H), 2.61 ppm (s, 3H). MS-ESI (m/z) calc'd for C₂₁H₁₇N₆O₂[M+H]⁺: 385.1. Found 385.0.

Example 153: 5-Cyano-3-methyl-N-(3-(1-methyl-1H-pyrazol-3-yl)-1H-indazol-5-yl)picolinamide

embedded image

Prepared as described for 5-cyano-N-(3-(1,5-dimethyl-1H-pyrazol-4-yl)-1H-indazol-5-yl)-3-methylpicolinamide using (1-methyl-1H-pyrazol-3-yl)boronic acid in place of (1,5-dimethyl-1H-pyrazol-4-yl)boronic acid to afford the title compound (30.42 mg, 32%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.03 (br s, 1H), 10.71 (s, 1H), 8.99 (d, J=1.5 Hz, 1H), 8.67 (d, J=1.3 Hz, 1H), 8.40 (d, J=1.0 Hz, 1H), 7.79 (d, J=2.1 Hz, 1H), 7.74 (dd, J=2.0, 8.9 Hz, 1H), 7.53 (d, J=8.9 Hz, 1H), 6.69 (d, J=2.2 Hz, 1H), 3.96 (s, 3H), 2.57 (s, 3H). MS-ESI (m/z) calc'd for C₁₉H₁₆N₇O [M+H]⁺: 358.1. Found 358.0.

Example 154: 5-Cyano-N-(3-(furan-3-yl)-1H-indazol-5-yl)-3-hydroxypicolinamide

embedded image

Step 1: 5-Bromo-3-hydroxypicolinic acid

embedded image

To a solution of methyl 5-bromo-3-hydroxypicolinate (200 mg, 861.95 umol) in MeOH (4 mL) was added 6 M aqueous NaOH (0.8 mL) and the mixture was stirred at 20° C. for 3 hrs. The reaction mixture was then concentrated under reduced pressure and diluted with H₂O (3 mL). The mixture was adjusted to pH=4 with 1 N HCl, and then extracted with EtOAc (10 mL×5). The combined organic layers were dried over Na₂SO₄, filtered and concentrated under reduced pressure to afford the title compound (170 mg) as a white solid which was used without further purification. MS-ESI (m/z) calcd for C₆H₅BrNO₃[M+H]⁺: 217.9/219.9. Found 217.9/219.9.

Step 2: 5-Bromo-N-(3-(furan-3-yl)-1H-indazol-5-yl)-3-hydroxypicolinamide

embedded image

To a solution of 5-bromo-3-hydroxypicolinic acid (150 mg, 688.06 umol) in pyridine (5 mL) was added EDCI (263.80 mg, 1.38 mmol) and 3-(furan-3-yl)-1H-indazol-5-amine (150.77 mg, 756.86 umol) and the mixture was stirred at 20° C. for 3 hrs. The reaction mixture was concentrated under reduced pressure, then diluted with H₂O (8 mL) and MeOH (8 mL). The reaction mixture was concentrated under reduced pressure. The reaction was diluted with H₂O (20 mL) and filtered, the solid was dried under vacuum to afford the title compound (210 mg, 77%) as a brown solid which was used without further purification. MS-ESI (m/z) calcd for C₁₇H₁₂BrN₄O₃[M+H]⁺: 399.0/401.0. Found 399.0/401.0.

Step 3: 5-Cyano-N-(3-(furan-3-yl)-1H-indazol-5-yl)-3-hydroxypicolinamide

embedded image

To a solution of 5-bromo-N-(3-(furan-3-yl)-1H-indazol-5-yl)-3-hydroxypicolinamide (210 mg, 526.06 umol) in DMF (5 mL) was added Zn(CN)₂(74.13 mg, 631.27 umol) and Pd(PPh₃)₄(60.79 mg, 52.61 umol) and the mixture was stirred at 100° C. for 5 hrs. The reaction mixture was then concentrated under reduced pressure and then diluted with H₂O (5 mL) and extracted with EtOAc (15 mL×6). The combined organic layers were dried over Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC using Method BX to afford the title compound (12.42 mg, 5%) as a yellow solid, TFA salt. ¹H NMR (400 MHz, DMSO-d₆) δ 13.16 (s, 1H) 12.53 (s, 1H) 11.11 (s, 1H) 8.67 (d, J=1.59 Hz, 1H) 8.43 (s, 1H) 8.32 (s, 1H) 8.13 (d, J=1.59 Hz, 1H) 7.83-7.91 (m, 2H) 7.59 (d, J=9.05 Hz, 1H) 7.02 (d, J=1.34 Hz, 1H). MS-ESI (m/z) calc'd for C₁₉H₁₂N₅O₃[M+H]⁺: 346.1. Found 346.0.

Example 155: 5-Cyano-N-(3-(1-methoxyethyl)-1H-indazol-5-yl)-3,4-dimethylpicolinamide

embedded image

Step 1: 5-Chloro-3-iodo-1H-pyrazolo[3,4-c]pyridine

embedded image

To a solution of 5-chloro-1H-pyrazolo[3,4-c]pyridine (1 g, 6.51 mmol) in DMF (15 mL) was added KOH (548.02 mg, 9.77 mmol) and I₂(2.48 g, 9.77 mmol) and the reaction mixture was stirred at 25° C. for 2 hrs. The reaction mixture was poured into saturated aqueous NaHCO₃solution (30 mL). The aqueous phase was extracted with EtOAc (30 mL×3). The combined organic phases were washed with brine (30 mL×1), dried over Na₂SO₄, filtered and concentrated to afford the title compound (2.1 g) as an orange gum, which was used without further purification. MS-ESI (m/z) calcd for C₆H₄ClIN₃[M+H]⁺: 279.9/281.9. Found 279.9/281.9.

Step 2: 5-Chloro-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine

embedded image

To a solution of 5-chloro-3-iodo-1H-pyrazolo[3,4-c]pyridine (1.3 g, 4.65 mmol) in DCM (15 mL) was added 3,4-dihydro-2H-pyran (586.93 mg, 6.98 mmol, 637.97 uL) and TsOH (160.21 mg, 930.35 umol) and the reaction mixture was stirred at 40° C. for 5 hr. The reaction mixture was poured into saturated aqueous NaHCO₃solution (30 mL) and extracted with dichloromethane (30 mL×3). The combined organic phases were washed with brine (30 mL×1), dried over Na₂SO₄, filtered and concentrated to afford a residue. The residue was purified by flash silica gel chromatography using a 0-5% EtOAc/petroleum ether gradient eluent to afford the title compound (1.6 g, 95%) as a white solid. MS-ESI (m/z) calcd for C₁₁H₁₂ClIN₃O [M+H]⁺: 364.0/366.0. Found 363.9/365.9.

Step 3: 5-Chloro-3-(furan-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine

embedded image

To a solution of 5-chloro-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine (0.7 g, 1.93 mmol) and furan-3-ylboronic acid (129.25 mg, 1.16 mmol) in dioxane (12 mL) and H₂O (4 mL) was added Pd(dppf)Cl₂(140.87 mg, 192.53 umol) and K₂CO₃(798.26 mg, 5.78 mmol) under N₂. Then the reaction mixture was then stirred at 90° C. for 3 hrs under N₂. The reaction mixture was concentrated under reduced pressure at 40° C. and then poured into H₂O (20 mL). The aqueous phase was extracted with EtOAc (20 mL×3) and the combined organic phases were washed with brine (20 mL×1), dried over anhydrous Na₂SO₄, filtered and concentrated to afford a residue. The residue was purified by flash silica gel chromatography using a 0-5% EtOAc/petroleum ether gradient eluent to afford the title compound (400 mg, 68%) as a red solid. MS-ESI (m/z) calcd for C₁₅H₁₅ClN₃O₂[M+H]⁺: 304.1/306.1. Found 304.1/306.1.

Step 4: N-(3-(Furan-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)-1,1-diphenylmethanimine

embedded image

A mixture of 5-chloro-3-(furan-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine (250 mg, 823.06 umol), diphenylmethanimine (179.00 mg, 987.68 umol, 165.74 uL), Pd₂(dba)₃(75.37 mg, 82.31 umol), BINAP (51.25 mg, 82.31 umol) and t-BuONa (102.83 mg, 1.07 mmol) in toluene (3 mL) was degassed and purged with N₂(3×). The mixture was stirred at 110° C. for 12 hrs under an N₂atmosphere. The reaction mixture was filtered and the filtrate was concentrated. The residue was purified by flash silica gel chromatography using a 0-13% EtOAc/petroleum ether gradient eluent to afford the title compound (190 mg, 51%) as a yellow oil. MS-ESI (m/z) calcd for C₂₈H₂₅N₄O₂[M+H]⁺: 449.2. Found 449.2.

Step 5: 3-(Furan-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-5-amine

embedded image

To a solution of N-(3-(furan-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)-1,1-diphenylmethanimine (160 mg, 356.73 umol) in THF (2 mL) was added HCl (4 M, 500.00 uL). Then the reaction mixture was stirred at 25° C. for 0.1 hr and then poured into H₂O (10 mL) and washed with EtOAc (10 mL×1). Then the aqueous phase was adjusted to pH 8 with saturated aqueous NaHCO₃solution and extracted with EtOAc (10 mL×3). The combined organic phases were washed with brine (10 mL×1), dried over Na₂SO₄, filtered and concentrated to afford the title compound (101 mg) as a yellow oil, which was used without further purification. MS-ESI (m/z) calcd for C₁₅H₁₇N₄O₂[M+H]⁺: 285.1. Found 285.1.

Step 6: 5-Cyano-N-(3-(furan-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)-3-methylpicolinamide

embedded image

To a solution of 3-(furan-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-5-amine (85 mg, 298.97 umol) and 5-cyano-3-methylpicolinic acid (48.48 mg, 298.97 umol) in pyridine (2 mL) was added EDCI (171.94 mg, 896.90 umol) and the reaction mixture was stirred at 25° C. for 2 hrs. The mixture was then concentrated under reduced pressure at 40° C. The residue was poured into H₂O (2 mL) and extracted with EtOAc (2 mL×3). The combined organic phases were washed with brine (2 mL×1), dried over Na₂SO₄, filtered and concentrated to afford the title compound (140 mg) as a yellow oil, which was used without further purification. MS-ESI (m/z) calcd for C₂₃H₂₁N₆O₃[M+H]⁺: 429.2. Found 429.1.

Step 7: 5-Cyano-N-(3-(1-methoxyethyl)-1H-indazol-5-yl)-3,4-dimethylpicolinamide

embedded image

To a solution of 5-cyano-N-(3-(furan-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)-3-methylpicolinamide (70 mg, 163.38 umol) in DCM (1 mL) was added TFA (770.00 mg, 6.75 mmol, 0.5 mL) and the reaction mixture was stirred at 25° C. for 12 hrs. The mixture was then directly purified by preparative HPLC using Method BF to afford the title compound (4.01 mg, 6%) as a yellow solid, HCl salt. ¹H NMR (400 MHz, DMSO-d₆) δ 10.83 (s, 1H), 9.00 (s, 1H), 8.92 (s, 1H), 8.65 (s, 1H), 8.43 (s, 1H), 8.31 (s, 1H), 7.90 (t, J=1.6 Hz, 1H), 7.03 (d, J=1.0 Hz, 1H), 2.66 (s, 3H). MS-ESI (m/z) calc'd for C₁₈H₃N₆O₂[M+H]⁺: 345.1 Found 345.0.

Example 156: 5-Cyano-3-methyl-N-(3-(thiazol-4-yl)-1H-indazol-5-yl)picolinamide

embedded image

A mixture of N-(3-bromo-1H-indazol-5-yl)-5-cyano-3-methylpicolinamide (40 mg, 112.30 umol), 4-(tributylstannyl)thiazole (42.02 mg, 112.30 umol) and Pd(t-Bu₃P)₂(5.74 mg, 11.23 umol) were taken up into a microwave tube in DMF (2 mL) under N₂. The sealed tube was heated at 150° C. for 1 hr under microwave irradiation. The reaction mixture was filtered and the filtrate was concentrated to give a residue. The residue was purified by preparative HPLC using Method BY to afford the title compound (11.93 mg, 29%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.28 (br s, 1H), 10.74 (br s, 1H), 9.33 (d, J=2.0 Hz, 1H), 9.00 (d, J=1.3 Hz, 1H), 8.87 (s, 1H), 8.41 (d, J=1.1 Hz, 1H), 8.12 (d, J=2.0 Hz, 1H), 7.72 (dd, J=1.9, 8.9 Hz, 1H), 7.58 (d, J=9.0 Hz, 1H), 2.58 (s, 3H). MS-ESI (m/z) calc'd for C18H₁₃N₆OS [M+H]⁺: 361.1. Found 361.1.

Example 157: 5-Cyano-N-(3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-1H-indazol-5-yl)-3,4-dimethylpicolinamide

embedded image

Prepared as described for 5-cyano-N-(7-fluoro-3-(furan-3-yl)-1H-indazol-5-yl)-3-methylpicolinamide using 5-cyano-3,4-dimethylpicolinic acid in place of 5-cyano-3-methylpicolinic acid and using 3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-1H-indazol-5-amine in place of 7-fluoro-3-(furan-3-yl)-1H-indazol-5-amine to afford the title compound (77 mg, 95%) as a pale yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.20 (s, 1H), 10.68 (s, 1H), 8.90 (s, 1H), 8.72 (s, 1H), 8.46-8.38 (m, 1H), 8.29 (s, 1H), 7.93 (t, J=59.0 Hz, 1H), 7.77 (dd, J=9.0, 1.9 Hz, 1H), 7.62-7.54 (m, 1H), 2.56 (s, 3H), 2.48 (s, 3H). MS-ESI (m/z) calc'd for C₂₀H₁₆F₂N₇O [M+H]⁺: 408.1. Found 408.2.

Example 158: 5-Cyano-3,4-dimethyl-N-(3-(oxazol-5-yl)-1H-indazol-5-yl)picolinamide

embedded image

Step 1: (Z)-4-Amino-3-methylpent-3-en-2-one

embedded image

3-Methylpentane-2,4-dione (27.78 mL, 219.03 mmol) and NH₄OH (75.0 mL, 1925.8 mmol) were combined and stirred at 25° C. for 2 hrs. A white solid formed and the mixture was extracted with Et₂O. The combined organic layers were evaporated to give a yellow residue that was triturated with cyclohexane and then filtered and concentrated to afford the title compound (18.2 g, 73%) as a pale yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 10.20 (bs, 1H), 7.15 (bs, 1H), 1.99 (s, 3H), 1.89 (s, 3H), 1.74 (s, 3H). MS-ESI (m/z) calc'd for C₆H₁₂NO [M+H]⁺: 114.1. Found 114.0.

Step 2: 4,5,6-Trimethyl-2-oxo-1,2-dihydropyridine-3-carbonitrile

embedded image

To a solution of (Z)-4-amino-3-methylpent-3-en-2-one (18.2 g, 160.83 mmol) in THF (120 mL) was added dropwise a solution of malononitrile (10.62 g, 160.83 mmol) in THF (40 mL) and the mixture was stirred at 25° C. for 15 hrs. The solid that formed was collected by filtration and washed with EtOAc to afford the title compound (17.89 g, 69%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 12.17 (s, 1H), 2.32 (s, 3H), 2.25 (s, 3H), 1.93 (s, 3H). MS-ESI (m/z) calc'd for C₉H₁₁N₂O [M+H]⁺: 163.1. Found 163.0.

Step 3: 2-Chloro-4,5,6-trimethylnicotinonitrile

embedded image

A suspension of 4,5,6-trimethyl-2-oxo-1,2-dihydropyridine-3-carbonitrile (17.89 g, 110.3 mmol) in POCl₃(70.0 mL, 748.71 mmol) was heated at 100° C. for 15 hrs. The solution was concentrated and then poured into H₂O (1 L) and the pH was adjusted to 7 by addition of Na₂CO₃. The solid that formed was collected by filtration and concentrated to afford the title compound (18.59 g, 93%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 2.51 (s, 3H), 2.47 (s, 3H), 2.22 (s, 3H). MS-ESI (m/z) calc'd for C₉H₁₀ClN₂[M+H]⁺: 163.1. Found 181.0.

Step 4: 4,5,6-Trimethylnicotinonitrile

embedded image

To a solution of 2-chloro-4,5,6-trimethylnicotinonitrile (1.81 g, 10 mmol) in MeOH (50 mL) was added 10% Pd/C (1.06 g, 1 mmol) followed by ammonium formate (630.6 mg, 10 mmol) and the mixture was stirred at 60° C. for 1 hr. The reaction mixture was filtered through Celite and the filtrate was evaporated to dryness. The residue was taken up in water and extracted with DCM (3×). The combined organic layers were passed through a phase separator and concentrated to afford the title compound (1.19 g, 81%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.61 (s, 1H), 2.53 (s, 3H), 2.44 (s, 3H), 2.23 (s, 3H). MS-ESI (m/z) calc'd for C₉H₁₀N₂[M+H]⁺: 147.1. Found 146.9.

Step 5: 5-Cyano-2,3,4-trimethylpyridine 1-oxide

embedded image

To a solution of 4,5,6-trimethylnicotinonitrile (1.19 g, 8.14 mmol) in DCM (40.7 mL) was added MCPBA (2.01 g, 8.14 mmol) and the mixture was stirred at 25° C. for 5 hrs. The solution was washed with K₂CO₃solution (3×) and the aqueous layer was extracted with DCM (3×). The organic phases were combined, passed through a phase separator and concentrated to afford the title compound (1.19 g, 90%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.73 (s, 1H), 2.44 (s, 3H), 2.39 (s, 3H), 2.28 (s, 3H). MS-ESI (m/z) calc'd for C₉H₁₁N₂O [M+H]⁺: 163.1. Found 163.0.

Step 6: 6-(Hydroxymethyl)-4,5-dimethylnicotinonitrile

embedded image

To a solution of 5-cyano-2,3,4-trimethylpyridine 1-oxide (4.15 g, 25.59 mmol) in DCM (39.15 mL) was added dropwise 2,2,2-trifluoroacetic anhydride (10.67 mL, 76.76 mmol) in DCM (39.15 mL) at 0° C. and the mixture was stirred at 25° C. for 15 hrs. The solvent was evaporated to give a red oil that was dissolved in MeOH (50 mL). K₂CO₃(3 g) was added and the suspension was stirred for 15 min. The solvent was evaporated, the residue was taken up in H₂O and extracted with DCM (3×). The combined organic layers were passed through a phase separator and concentrated to afford the title compound (3.65 g, 88%) as a dark orange solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.70 (s, 1H), 5.22 (t, J=5.6 Hz, 1H), 4.63 (d, J=5.4 Hz, 2H), 2.45 (s, 3H), 2.29 (s, 3H). MS-ESI (m/z) calc'd for C₉H₁₁N₂O [M+H]⁺: 163.1. Found 163.0.

Step 7: 5-Cyano-3,4-dimethylpicolinic acid

embedded image

To a solution of 6-(hydroxymethyl)-4,5-dimethylnicotinonitrile (3.65 g, 22.5 mmol) in acetone (62.98 mL) was added dropwise (over 15 min) a solution of KMnO₄(3.91 g, 24.75 mmol) in H₂O (31.49 mL) at 25° C. and the mixture was stirred for 30 minutes. The dark mixture was filtered and the solid was washed with 1 M aqueous K₂CO₃. The filtrate was concentrated to remove the organic solvent. The pH was adjusted to 4-5 by addition of 6 M HCl and the solution was extracted with EtOAc (3×). Then another portion of 6 M HCl was added until pH 1 and the aqueous phase was further extracted with EtOAc (3×). The combined organic layers were passed through a phase separator and concentrated to afford the title compound (1.75 g, 44%) as a beige solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.81 (s, 1H), 8.78 (s, 1H), 2.50 (s, 3H), 2.33 (s, 3H). MS-ESI (m/z) calc'd for C₉H₉N₂O₂[M+H]⁺: 177.1. Found 177.1.

Step 8: 5-(5-Nitro-1H-indazol-3-yl)oxazole

embedded image

To a suspension of 5-nitro-1H-indazole-3-carbaldehyde (1.91 g, 10 mmol) and 1-(isocyanomethylsulfonyl)-4-methylbenzene (2.15 g, 11 mmol) in MeOH (50 mL) was added K₂CO₃(2.76 g, 20 mmol) and the mixture was stirred at 65° C. for 15 minutes. The mixture was poured into water and the solid that formed was collected by vacuum filtration and dried. The material was purified by silica gel column chromatography using a 0-100% EtOAc/cyclohexane gradient eluent to afford the title compound (653 mg, 28%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 14.13 (s, 1H), 8.96 (dd, J=2.1, 0.7 Hz, 1H), 8.64 (s, 1H), 8.28 (dd, J=9.2, 2.1 Hz, 1H), 7.96 (s, 1H), 7.82 (dd, J=9.2, 0.7 Hz, 1H). MS-ESI (m/z) calc'd for C₁₀H₇N₄O₃[M+H]⁺: 231.0. Found 231.1.

Step 9: 3-(Oxazol-5-yl)-1H-indazol-5-amine

embedded image

A mixture of 5-(5-nitro-1H-indazol-3-yl)oxazole (653.0 mg, 2.84 mmol) in MeOH (56.74 mL) was hydrogenated in the presence of 10% Pd/C (0.3 g, 0.280 mmol) at 25° C. for 2 hrs. The catalyst was removed by filtration through Celite and the solvent was concentrated to afford the title compound (516 mg, 91%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 12.99 (s, 1H), 8.48 (s, 1H), 7.51 (s, 1H), 7.31 (dd, J=8.8, 0.7 Hz, 1H), 7.03 (dd, J=2.0, 0.8 Hz, 1H), 6.86 (dd, J=8.8, 2.0 Hz, 1H), 4.98 (s, 2H). MS-ESI (m/z) calc'd for C₁₀H₉N₄O [M+H]⁺: 201.1. Found 201.1.

Step 10: 5-Cyano-3,4-dimethyl-N-(3-(oxazol-5-yl)-1H-indazol-5-yl)picolinamide

embedded image

To a mixture of 5-cyano-3,4-dimethylpicolinic acid (330.0 mg, 1.84 mmol), 3-(oxazol-5-yl)-1H-indazol-5-amine (404.26 mg, 2.02 mmol) and Et₃N (255.86 uL, 1.84 mmol) in MeCN (18.36 mL) was added HATU (698.0 mg, 1.84 mmol) and the reaction was stirred at 25° C. for 2 hrs. Water was added and a solid precipitated which was collected by vacuum filtration, washed with H₂O and dried to afford the title compound (626 mg, 95%) as a yellow solid. ¹H NMR (600 MHz, DMSO-d₆) δ 13.51 (s, 1H), 10.76 (s, 1H), 8.89 (s, 1H), 8.59 (s, 2H), 7.74 (dd, J=8.9, 1.5 Hz, 1H), 7.64 (s, 1H), 7.63 (d, J=8.9 Hz, 1H), 2.55 (s, 3H), 2.46 (s, 3H). MS-ESI (m/z) calc'd for C₁₉H₁₅N₆O₂[M+H]⁺: 359.1. Found 359.2.

Example 159: 5-Cyano-N-(3-(2-methoxypyridin-4-yl)-1H-indazol-5-yl)-3,4-dimethylpicolinamide

embedded image

Prepared as described for 5-cyano-N-(7-fluoro-3-(furan-3-yl)-1H-indazol-5-yl)-3-methylpicolinamide using 5-cyano-3,4-dimethylpicolinic acid in place of 5-cyano-3-methylpicolinic acid and using 3-(2-methoxypyridin-4-yl)-1H-indazol-5-amine in place of 7-fluoro-3-(furan-3-yl)-1H-indazol-5-amine to afford the title compound (70 mg, 88%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.58 (s, 1H), 10.78 (s, 1H), 8.90 (s, 1H), 8.65 (d, J=1.8 Hz, 1H), 8.30 (d, J=5.5 Hz, 1H), 7.83 (dd, J=8.9, 1.5 Hz, 1H), 7.65 (d, J=9.0 Hz, 1H), 7.57 (dd, J=5.4, 1.4 Hz, 18H), 7.30 (t, J=1.0 Hz, 1H), 3.93 (s, 3H), 2.56 (s, 3H), 2.47 (s, 3H). MS-ESI (m/z) calc'd for C₂₂H₁₉N₆O₂[M+H]⁺: 399.2. Found 399.2.

Example 160: 5-Cyano-N-(3-(isothiazol-4-yl)-1H-indazol-5-yl)-3-methylpicolinamide

embedded image

Prepared as described for 5-cyano-N-(3-(1,5-dimethyl-1H-pyrazol-4-yl)-1H-indazol-5-yl)-3-methylpicolinamide using isothiazol-4-ylboronic acid in place of (1,5-dimethyl-1H-pyrazol-4-yl)boronic acid to afford the title compound (27.23 mg, 34%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.32 (br s, 1H), 10.75 (s, 1H), 9.41 (s, 1H), 9.11 (s, 1H), 8.98 (d, J=1.54 Hz, 1H), 8.56 (d, J=1.10 Hz, 1H), 8.39 (d, J=10 Hz, 1H), 7.80 (dd, J=9.04, 1.54 Hz, 1H), 7.60 (d, J=9.04 Hz, 1H), 2.59 (s, 3H). MS-ESI (m/z) calc'd for C₁₈H₁₃N₆OS [M+H]⁺: 361.1. Found 361.0.

Example 161: 5-Cyano-N-(3-(furan-3-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-3-methylpicolinamide

embedded image

Step 1: 5-Chloro-3-iodo-1H-pyrazolo[4,3-d]pyrimidine

embedded image

To a solution of 5-chloro-1H-pyrazolo[4,3-d]pyrimidine (400 mg, 2.59 mmol) in DMF (5 mL) was added N-iodosuccinimide (698.72 mg, 3.11 mmol) and the mixture was stirred at 30° C. for 12 hrs. The reaction mixture was then concentrated under reduced pressure to give a residue. The residue was diluted with H₂O (10 mL) and a pale yellow solid precipitated. The solid was collected by filtration, washed with H₂O (20 mL), and dried to afford the title compound (470 mg, 65%) as a pale yellow solid which was used without further purification. MS-(ESI) (m/z) calcd for C₅H₃ClIN₄(M+H)⁺: 280.9/282.9. Found 280.8/282.8.

Step 2: 5-Chloro-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-d]pyrimidine

embedded image

To a solution of 5-chloro-3-iodo-1H-pyrazolo[4,3-d]pyrimidine (470 mg, 1.51 mmol) in CHCl₃(8 mL) was added MsOH (14.50 mg, 150.83 umol) and 3,4-dihydro-2H-pyran (380.61 mg, 4.52 mmol) and the mixture was stirred at 70° C. for 3 hrs. The reaction mixture was concentrated and purified by flash silica gel chromatography (ISCO; 4 g SepaFlash column) using a 0-9% EtOAc/petroleum ether gradient eluent to afford the title compound (470 mg, 50%) as a pale yellow solid. MS-(ESI) (m/z) calcd for C₁₀H₁₁ClIN₄O (M+H)⁺: 365.0/367.0. Found 364.9/366.9.

Step 3: 5-Chloro-3-(furan-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-d]pyrimidine

embedded image

A mixture of 5-chloro-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-d]pyrimidine (470 mg, 1.29 mmol), furan-3-ylboronic acid (158.67 mg, 1.42 mmol), Pd(Amphos)Cl₂(91.28 mg, 128.92 umol), AcOK (379.57 mg, 3.87 mmol) in EtOH (4 mL) and H₂O (1 mL) was degassed and purged with N₂(3×). The mixture was stirred at 90° C. for 3 hrs under an N₂atmosphere. The reaction mixture was then concentrated and purified by flash silica gel chromatography (ISCO; 20 g SepaFlash column) using a 0-10% EtOAc/petroleum ether gradient eluent to afford the title compound (250 mg, 64%) as a purple solid. MS-(ESI) (m/z) calcd for C₁₄H₁₄ClN₄O₂(M+H)⁺: 305.1/307.1. Found 305.0/307.0.

Step 4: 5-Cyano-N-(3-(furan-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-3-methylpicolinamide

embedded image

A mixture of 5-chloro-3-(furan-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-d]pyrimidine (250 mg, 820.40 umol), 5-cyano-3-methylpicolinamide (158.66 mg, 984.47 umol), Pd₂(dba)₃(75.13 mg, 82.04 umol), Xantphos (47.47 mg, 82.04 umol) and Cs₂CO₃(374.22 mg, 1.15 mmol) in dioxane (3 mL) was degassed and purged with N₂(3×), and then the mixture was stirred at 100° C. for 12 hrs under an N₂atmosphere. The reaction mixture was concentrated and purified by flash silica gel chromatography (ISCO; 20 g SepaFlash column) using a 0-30% EtOAc/petroleum ether gradient eluent to afford the title compound (240 mg, 68%) as a yellow solid. MS-(ESI) (m/z) calcd for C₂₂H₂₀N₇O₃(M+H)⁺: 430.2. Found 430.1.

Step 5: 5-Cyano-N-(3-(furan-3-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-3-methylpicolinamide

embedded image

To a solution of 5-cyano-N-(3-(furan-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-3-methylpicolinamide (100 mg, 232.87 umol) in MeOH (2 mL) and H₂O (0.4 mL) was added 4-toluenesulfonic acid (120.30 mg, 698.60 umol) and the mixture was stirred at 70° C. for 2 hrs. The reaction mixture was concentrated and purified by preparative HPLC using Method BV to afford the title compound (6.66 mg, 6%) as a white solid, TFA salt. ¹H NMR (400 MHz, DMSO-d₆) δ 12.94 (br s, 1H), 10.46 (br s, 1H), 8.36 (br s, 1H), 8.01 (br s, 1H), 7.56 (s, 1H), 7.05-7.49 (m, 1H), 6.98-7.01 (m, 1H), 6.09-6.20 ppm (m, 1H). MS-ESI (m/z) calc'd for C₁₇H₁₂N₇O₂[M+H]⁺: 346.1. Found 346.0.

Example 162: 6-Cyano-N-(3-(furan-3-yl)-1H-indazol-5-yl)-4-methylpyridazine-3-carboxamide

embedded image

Step 1: 6-Hydroxy-5-methylpyridazine-3-carbonitrile

embedded image

A stirred mixture of 6-chloro-4-methylpyridazin-3-ol (2.5 g, 17.29 mmol), Zn(CN)₂(2.64 g, 22.48 mmol, 1.43 mL), Pd₂(dba)₃(791.82 mg, 864.70 umol) and DPPF (766.99 mg, 1.38 mmol) in DMF (18 mL) was degassed and then heated to 120° C. for 3 hrs under N₂. After cooling to 25° C., the reaction mixture was concentrated to afford a residue which was diluted with dichloromethane (50 mL) and saturated aqueous NaHCO₃(50 mL). The aqueous layer was separated and extracted with dichloromethane (50 mL×3) and DCM/i-PrOH (4/1) (50 mL×3). The combined organic layers were dried over Na₂SO₄, filtered and concentrated to give a residue. The residue was triturated with a mixture of petroleum ether/EtOAc (3:1) (40 mL) and filtered. The solid obtained was washed with petroleum ether (30 mL) and dried to afford the title compound (2 g) as a brown solid, which was used without further purification. MS-ESI (m/z) calcd for C₆H₆N₃O [M+H]⁺: 136.0. Found 136.1.

Step 2: 6-Chloro-5-methylpyridazine-3-carbonitrile

embedded image

To a stirred solution of 6-hydroxy-5-methylpyridazine-3-carbonitrile (2 g, 14.80 mmol) in MeCN (15 mL) was added POCl₃(6.81 g, 44.40 mmol, 4.13 mL) and the reaction mixture was stirred at 80° C. for 3 hrs. After cooling to 20° C., the mixture was concentrated to give a residue which was diluted with EtOAc (20 mL) and poured into ice-water (w/w=1/1) (50 mL). The aqueous phase was extracted with EtOAc (20 mL×3). The combined organic phases were washed with brine (20 mL×1), dried over Na₂SO₄, filtered and concentrated. The residue obtained was purified by silica gel column chromatography using 0-20% EtOAc/petroleum ether gradient eluent to afford the title compound (1.5 g, 66%) as a pale brown solid. MS-ESI (m/z) calcd for C₆H₅ClN₃[M+H]⁺: 154.0/156.0. Found 153.9/155.9.

Step 3: 6-(1-Ethoxyvinyl)-5-methylpyridazine-3-carbonitrile

embedded image

A stirred mixture of 6-chloro-5-methylpyridazine-3-carbonitrile (800 mg, 5.21 mmol), tributyl(1-ethoxyvinyl)stannane (3.76 g, 10.42 mmol, 3.52 mL) and Pd(PPh₃)₂Cl₂(182.82 mg, 260.47 umol) in dioxane (20 mL) was degassed and then heated to 80° C. for 12 hrs under N₂. After cooling to 25° C., the reaction mixture was concentrated to give a residue. The residue was purified by silica gel column chromatography using 0-20% EtOAc/petroleum ether gradient eluent to afford the title compound (800 mg, 81%) as a light yellow oil. MS-ESI (m/z) calcd for C₁₀H₁₂N₃O [M+H]⁺: 190.1. Found 190.1.

Step 4: Ethyl 6-cyano-4-methylpyridazine-3-carboxylate

embedded image

To a stirred solution of 6-(1-ethoxyvinyl)-5-methylpyridazine-3-carbonitrile (800 mg, 4.23 mmol) in dioxane (30 mL) was added a solution of NaIO₄(1.81 g, 8.46 mmol, 468.57 uL) in H₂O (15 mL), followed by KMnO₄(133.63 mg, 845.61 umol) and the reaction mixture was stirred at 25° C. for 12 hrs. The reaction mixture was then filtered and washed with EtOAc (20 mL). The filtrate was diluted with H₂O (20 mL) and extracted with EtOAc (20 mL×3). The combined organic phases were concentrated and purified by silica gel column chromatography using a 0-20% EtOAc/petroleum ether gradient eluent to afford the title compound (410 mg, 51%) as a light yellow oil. MS-ESI (m/z) calcd for C₉H₁₀N₃O₂[M+H]⁺: 192.1 Found 192.1.

Step 5: 6-Cyano-4-methylpyridazine-3-carboxylic acid

embedded image

To a stirred solution of ethyl 6-cyano-4-methylpyridazine-3-carboxylate (30 mg, 156.92 umol) in THF (2 mL) was added NaOH (8.16 mg, 203.99 umol) at 0° C. and the reaction mixture was warmed to 25° C. and stirred for 12 hrs. The reaction mixture was adjusted to pH=3 with 1 N aqueous citric acid and extracted with EtOAc (5 mL×3). The combined organic phases were washed with brine (5 mL×1), dried over Na₂SO₄, filtered and concentrated to afford the title compound (60 mg) as a brown solid, which was used without further purification. MS-ESI (m/z) calcd for C₇H₆N₃O₂[M+H]⁺: 164.0 Found 164.0.

Step 6: 6-Cyano-N-(3-(furan-3-yl)-1H-indazol-5-yl)-4-methylpyridazine-3-carboxamide

embedded image

To a stirred solution of 6-cyano-4-methylpyridazine-3-carboxylic acid (60 mg, 367.80 umol) and 3-(furan-3-yl)-1H-indazol-5-amine (36.63 mg, 183.90 umol) in pyridine (2 mL) was added EDCI (105.76 mg, 551.70 umol) and the reaction mixture was stirred at 25° C. for 3 hrs.

The reaction mixture was then concentrated to give a residue which was purified by preparative HPLC using Method BH to afford the title compound (14.99 mg, 11%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.14 (br s, 1H), 11.05 (s, 1H), 8.49 (s, 1H), 8.46 (s, 1H), 8.26 (s, 1H), 7.85 (d, J=1.4 Hz, 1H), 7.83-7.80 (m, 1H), 7.59 (d, J=8.9 Hz, 1H), 7.02-7.00 (m, 1H), 2.62 (s, 3H). MS-ESI (m/z) calc'd for C₁₈H₁₃N₆O₂[M+H]⁺: 345.1 Found 345.0.

Example 163: 3-Cyano-N-(3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-1H-indazol-5-yl)-2,6-difluorobenzamide

embedded image

Prepared as described for 5-cyano-N-(7-fluoro-3-(furan-3-yl)-1H-indazol-5-yl)-3-methylpicolinamide using 3-cyano-2,6-difluorobenzoic acid in place of 5-cyano-3-methylpicolinic acid and using 3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-1H-indazol-5-amine in place of 7-fluoro-3-(furan-3-yl)-1H-indazol-5-amine to afford the title compound (37.4 mg, 41%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.25 (br. s., 1H) 10.98 (s, 1H) 8.73 (d, J=0.66 Hz, 1H) 8.36 (d, J=1.54 Hz, 1H) 8.29 (s, 1H) 8.23 (ddd, J=8.86, 7.65, 5.94 Hz, 1H) 7.77-8.12 (m, 1H) 7.53-7.67 (m, 3H). MS-ESI (m/z) calc'd for C₁₉H₁₁F₄N₆O [M+H]⁺: 415.1. Found 415.2.

Example 164: 3-Cyano-N-(3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-1H-indazol-5-yl)-2-methoxybenzamide

embedded image

Prepared as described for 5-cyano-N-(7-fluoro-3-(furan-3-yl)-1H-indazol-5-yl)-3-methylpicolinamide using 3-cyano-2-methoxybenzoic acid in place of 5-cyano-3-methylpicolinic acid and using 3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-1H-indazol-5-amine in place of 5-cyano-3-methylpicolinic acid to afford the title compound (34.7 mg, 32%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.21 (s, 1H), 10.53 (s, 1H), 8.70 (d, J=0.7 Hz, 1H), 8.40 (dd, J=1.9, 0.8 Hz, 1H), 8.29 (d, J=0.7 Hz, 1H), 8.13-7.77 (m, 3H), 7.68 (dd, J=9.0, 1.9 Hz, 1H), 7.59 (dd, J=8.9, 0.7 Hz, 1H), 7.42 (t, J=7.7 Hz, 1H), 4.03 (s, 3H). MS-ESI (m/z) calc'd for C₂₀H₁₅F₂N₆O₂[M+H]⁺: 409.1. Found 409.2.

Example 165: 4-Cyano-N-(3-(1-(difluoromethyl)-1H-pyrazol-3-yl)-1H-indazol-5-yl)-2-fluoro-6-methylbenzamide

embedded image

Prepared as described for 5-cyano-N-(7-fluoro-3-(furan-3-yl)-1H-indazol-5-yl)-3-methylpicolinamide using 4-cyano-2-fluoro-6-methylbenzoic acid in place of 5-cyano-3-methylpicolinic acid and using 3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-1H-indazol-5-amine in place of 7-fluoro-3-(furan-3-yl)-1H-indazol-5-amine to afford the title compound (30 mg, 26%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.21 (s, 1H), 10.79 (s, 1H), 8.70 (s, 1H), 8.38 (t, J=1.3 Hz, 1H), 8.27 (s, 1H), 8.11-7.77 (m, 2H), 7.75 (s, 1H), 7.65-7.55 (m, 2H), 2.41 (s, 3H). MS-ESI (m/z) calc'd for C₂₀H₁₄F₃N₆O [M+H]⁺: 411.1. Found 411.3.

Example 166: 2-Chloro-3-cyano-N-(3-(1-(difluoromethyl)-1H-pyrazol-3-yl)-1H-indazol-5-yl)benzamide

embedded image

Prepared as described for 5-cyano-N-(7-fluoro-3-(furan-3-yl)-1H-indazol-5-yl)-3-methylpicolinamide using 2-chloro-3-cyanobenzoic acid in place of 5-cyano-3-methylpyridine-2-carboxylic acid and using 3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-1H-indazol-5-amine in place of 7-fluoro-3-(furan-3-yl)-1H-indazol-5-amine to afford the title compound (10 mg, 9%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.22 (s, 1H), 10.70 (s, 1H), 8.69 (d, J=0.7 Hz, 1H), 8.39 (dd, J=1.8, 0.9 Hz, 1H), 8.27 (d, J=0.7 Hz, 1H), 8.19-7.89 (m, 3H), 7.83-7.67 (m, 1H), 7.65-7.56 (m, 2H). MS-ESI (m/z) calc'd for C₁₉H₁₂ClF₂N₆O [M+H]⁺: 413.1. Found 413.2.

Example 167: 3-Cyano-N-(3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-1H-indazol-5-yl)-2-fluorobenzamide

embedded image

Prepared as described for 5-cyano-N-(7-fluoro-3-(furan-3-yl)-1H-indazol-5-yl)-3-methylpicolinamide using 3-cyano-2-fluorobenzoic acid in place of 5-cyano-3-methylpicolinic acid acid and using 3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-1H-indazol-5-amine in place of 7-fluoro-3-(furan-3-yl)-1H-indazol-5-amine to afford the title compound (41.5 mg, 49%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.23 (s, 1H), 10.66 (s, 1H), 8.72 (d, J=0.7 Hz, 1H), 8.39 (dd, J=1.9, 0.8 Hz, 1H), 8.29 (d, J=0.6 Hz, 1H), 8.18-7.74 (m, 3H), 7.69-7.53 (m, 3H). MS-ESI (m/z) calc'd for C₁₉H₁₂F₃N₆O [M+H]⁺: 397.1. Found 397.2.

Example 168: 5-Cyano-N-(3-(isoxazol-4-yl)-1H-indazol-5-yl)-3,4-dimethylpicolinamide

embedded image

Prepared as described for 5-cyano-N-(7-fluoro-3-(furan-3-yl)-1H-indazol-5-yl)-3-methylpicolinamide using 5-cyano-3,4-dimethylpicolinic acid in place of 5-cyano-3-methylpicolinic and using 3-(isoxazol-4-yl)-1H-indazol-5-amine in place of 7-fluoro-3-(furan-3-yl)-1H-indazol-5-amine to afford the title compound (207.9 mg, 64%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.35 (s, 1H), 10.69 (s, 1H), 9.56 (s, 1H), 9.15 (s, 1H), 8.90 (s, 1H), 8.39 (d, J=1.8 Hz, 1H), 7.76 (dd, J=8.9, 1.9 Hz, 1H), 7.61 (d, J=9.0 Hz, 1H), 2.57 (s, 3H), 2.49 (s, 3H). MS-ESI (m/z) calc'd for C₁₉H₅N₆O₂[M+H]⁺: 359.1. Found 359.2.

Example 169: 5-Cyano-3,4-dimethyl-N-(3-(1-(trifluoromethyl)-1H-pyrazol-4-yl)-1H-indazol-5-yl)picolinamide

embedded image

Prepared as described for 5-cyano-N-(3-(isoxazol-4-yl)-1H-indazol-5-yl)-3-methylpicolinamide using (1-(trifluoromethyl)-1H-pyrazol-4-yl)boronic acid in place of isoxazole-4-boronic acid and 5-cyano-N-(3-iodo-1H-indazol-5-yl)-3,4-dimethylpicolinamide in place of 5-cyano-N-(3-iodo-1H-indazol-5-yl)-3-methylpyridine-2-carboxamide to afford the title compound (13.2 mg, 33%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.31 (br. s, 1H) 10.67 (s, 1H) 8.97 (s, 1H) 8.90 (s, 1H) 8.46 (s, 1H) 8.40 (d, J=1.32 Hz, 1H) 7.83 (dd, J=9.02, 1.76 Hz, 1H) 7.61 (d, J=9.02 Hz, 1H) 2.57 (s, 3H) 2.49 (s, 3H). MS-ESI (m/z) calc'd for C₂₀H₁₅F₃N₇O [M+H]⁺: 426.1. Found 426.3.

Example 170: 2-Cyano-3-fluoro-N-(3-(2-methoxypyridin-4-yl)-1H-indazol-5-yl)isonicotinamide

embedded image

Prepared as described for 4-cyano-N-(3-(isoxazol-4-yl)-1H-indazol-5-yl)-3-methoxypicolinamide using 2-chloro-3-fluoro-N-(3-(2-methoxypyridin-4-yl)-1H-indazol-5-yl)isonicotinamide in place of 4-chloro-3-methoxy-N-[3-(1,2-oxazol-4-yl)-1H-indazol-5-yl]pyridine-2-carboxamide to afford the title compound (21.5 mg, 22%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.64 (s, 1H), 10.94 (s, 1H), 8.81 (dd, J=4.7, 0.8 Hz, 1H), 8.58 (t, J=1.3 Hz, 1H), 8.31 (dd, J=5.4, 0.7 Hz, 1H), 8.17 (dd, J=5.6, 4.7 Hz, 1H), 7.74-7.68 (m, 2H), 7.56 (dd, J=5.3, 1.4 Hz, 1H), 7.29 (dd, J=1.4, 0.7 Hz, 1H), 3.94 (s, 3H). MS-ESI (m/z) calc'd for C₂₀H₁₄FN₆O₂[M+H]⁺: 389.1. Found 389.3.

Example 171: N-(3-(5-Chloropyridin-3-yl)-1H-indazol-5-yl)-5-cyano-3,4-dimethylpicolinamide

embedded image

Prepared as described for 5-cyano-N-(3-(isoxazol-4-yl)-1H-indazol-5-yl)-3-methylpicolinamide using (5-chloropyridin-3-yl)boronic acid in place of isoxazole-4-boronic acid and 5-cyano-N-(3-iodo-1H-indazol-5-yl)-3,4-dimethylpicolinamide in place of 5-cyano-N-(3-iodo-1H-indazol-5-yl)-3-methylpyridine-2-carboxamide to afford the title compound (2.6 mg, 9%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.62 (br. s., 1H) 10.78 (s, 1H) 9.13 (d, J=1.98 Hz, 1H) 8.91 (s, 1H) 8.68 (d, J=2.42 Hz, 1H) 8.60 (d, J=1.32 Hz, 1H) 8.32-8.40 (m, 1H) 7.86 (dd, J=9.02, 1.76 Hz, 1H) 7.67 (d, J=9.02 Hz, 1H) 2.57 (s, 3H) 2.47 (s, 3H). MS-ESI (m/z) calc'd for C₁₂H₁₆ClN₆O [M+H]⁺: 403.1/405.1. Found 403.3/405.2.

Example 172: 5-Cyano-N-(3-(1-(fluoromethyl)-1H-pyrazol-4-yl)-1H-indazol-5-yl)-3,4-dimethylpicolinamide

embedded image

Prepared as described for 5-cyano-N-(3-(isoxazol-4-yl)-1H-indazol-5-yl)-3-methylpicolinamide using (1-(fluoromethyl)-1H-pyrazol-4-yl)boronic acid in place of isoxazole-4-boronic acid and 5-cyano-N-(3-iodo-1H-indazol-5-yl)-3,4-dimethylpicolinamide in place of 5-cyano-N-(3-iodo-1H-indazol-5-yl)-3-methylpyridine-2-carboxamide to afford the title compound (24.8 mg, 66%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.12 (br. s., 1H) 10.48-10.81 (m, 1H) 8.90 (s, 1H) 8.61 (s, 1H) 8.44 (d, J=1.10 Hz, 1H) 8.17 (s, 1H) 7.72 (dd, J=9.02, 1.76 Hz, 1H) 7.57 (d, J=8.80 Hz, 1H) 6.15-6.40 (m, 2H) 2.57 (s, 3H) 2.48 (s, 3H). MS-ESI (m/z) calc'd for C₂₀H₁₇FN₇O [M+H]⁺: 390.1. Found 390.3.

Example 173: 3-Cyano-N-(3-(furan-3-yl)-1H-indazol-5-yl)-2-(trifluoromethyl)benzamide

embedded image

Prepared as described for 4-cyano-N-(3-(isoxazol-4-yl)-1H-indazol-5-yl)-3-methoxypicolinamide using 3-chloro-N-(3-(furan-3-yl)-1H-indazol-5-yl)-2-(trifluoromethyl)benzamide in place of 4-chloro-3-methoxy-N-[3-(1,2-oxazol-4-yl)-1H-indazol-5-yl]pyridine-2-carboxamide to afford the title compound (5.7 mg, 26%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.16 (br. s., 1H) 10.77 (s, 1H) 8.26-8.37 (m, 2H) 8.19 (dd, J=1.54, 0.88 Hz, 1H) 8.00-8.12 (m, 2H) 7.86 (t, J=1.65 Hz, 1H) 7.58 (s, 2H) 6.98 (dd, J=1.76, 0.88 Hz, 1H). MS-ESI (m/z) calc'd for C₂₀H₁₂F₃N₄O₂[M+H]⁺: 397.1. Found 397.2.

Example 174: 5-Cyano-3,4-dimethyl-N-(3-(2-methyloxazol-5-yl)-1H-indazol-5-yl)picolinamide

embedded image

Prepared as described for 5-cyano-N-(3-(isoxazol-4-yl)-1H-indazol-5-yl)-3-methylpicolinamide using (2-methyloxazol-5-yl)boronic acid in place of isoxazole-4-boronic acid and 5-cyano-N-(3-iodo-1H-indazol-5-yl)-3,4-dimethylpicolinamide in place of 5-cyano-N-(3-iodo-1H-indazol-5-yl)-3-methylpyridine-2-carboxamide to afford the title compound (19.8 mg, 57%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.45 (br. s., 1H) 10.75 (s, 1H) 8.90 (s, 1H) 8.45-8.50 (m, 1H) 7.80 (dd, J=9.02, 1.98 Hz, 1H) 7.58-7.65 (m, 1H) 7.48 (s, 1H) 2.56 (s, 3H) 2.55 (s, 3H) 2.47 (s, 3H). MS-ESI (m/z) calc'd for C₂₀H₁₇N₆O₂[M+H]⁺: 373.1. Found 373.3.

Example 175: 6-Chloro-5-cyano-N-(3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-1H-indazol-5-yl)-3,4-dimethylpicolinamide

embedded image

Prepared as described for 5-cyano-N-(7-fluoro-3-(furan-3-yl)-1H-indazol-5-yl)-3-methylpicolinamide using 6-chloro-5-cyano-3,4-dimethylpicolinic acid in place of 5-cyano-3-methylpicolinic acid and using 3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-1H-indazol-5-amine in place of 7-fluoro-3-(furan-3-yl)-1H-indazol-5-amine to afford the title compound (54.2 mg, 70%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.24 (s, 1H), 10.75 (s, 1H), 8.74 (s, 1H), 8.38 (d, J=1.7 Hz, 1H), 8.30 (s, 1H), 7.94 (t, J=59.0 Hz, 1H), 7.71 (dd, J=9.0, 1.8 Hz, 1H), 7.60 (d, J=9.1 Hz, 1H), 2.61 (s, 3H), 2.42 (s, 3H). MS-ESI (m/z) calc'd for C₂₀H₁₅ClF₂N₇O [M+H]⁺: 442.1/444.1. Found 442.2/444.2.

Example 176: 3-Cyano-2-methoxy-N-(3-(oxazol-5-yl)-1H-indazol-5-yl)benzamide

embedded image

Prepared as described for 5-cyano-N-(7-fluoro-3-(furan-3-yl)-1H-indazol-5-yl)-3-methylpicolinamide using 3-cyano-2-methoxybenzoic acid in place of 5-cyano-3-methylpicolinic acid and using 3-(oxazol-5-yl)-1H-indazol-5-amine in place of 7-fluoro-3-(furan-3-yl)-1H-indazol-5-amine to afford the title compound (17 mg, 17%) as an off-white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.52 (s, 1H), 10.60 (s, 1H), 8.64-8.38 (m, 2H), 7.93 (ddd, J=21.0, 7.7, 1.7 Hz, 2H), 7.73-7.56 (m, 3H), 7.40 (t, J=7.7 Hz, 1H), 4.01 (s, 3H). MS-ESI (m/z) calc'd for C₁₉H₁₄N₅O₃[M+H]⁺: 360.1. Found 360.2.

Example 177: 3-Cyano-N-(3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-1H-indazol-5-yl)-2-fluoro-6-methylbenzamide

embedded image

Step 1: 3-(1-(Difluoromethyl)-1H-pyrazol-4-yl)-5-nitro-1H-indazole

embedded image

A mixture of 3-bromo-5-nitro-1H-indazole (400 mg, 1.65 mmol), 1-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (321.09 mg, 1.98 mmol), Pd(Amphos)Cl₂(117.02 mg, 165.27 umol), KOAc (486.60 mg, 4.96 mmol) in EtOH (4 mL) and H₂O (0.8 mL) was degassed and purged with N₂(3×), and then the mixture was stirred at 90° C. for 4 hrs under an N₂atmosphere. The reaction mixture was concentrated and purified by flash silica gel chromatography (ISCO; 12 g SepaFlash column) using a 0-14% EtOAc/petroleum ether gradient eluent to afford the title compound (220 mg, 48%) as a yellow solid. MS-ESI (m/z) calcd for C₁₁H₈F₂N₅O₂[M+H]⁺: 280.1/282.1. Found 280.0/282.1.

Step 2: 3-(1-(Difluoromethyl)-1H-pyrazol-4-yl)-1H-indazol-5-amine

embedded image

To a solution of 3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-5-nitro-1H-indazole (100 mg, 358.16 umol) in EtOH (3 mL) was added SnCl₂.2H₂O (242.46 mg, 1.07 mmol) and the mixture was stirred at 90° C. for 3 hrs. The reaction mixture was then concentrated under reduced pressure to give a residue. The residue was diluted with 1 M NaOH (5 mL) and EtOAc (5 mL). The suspension was filtered through a pad of Celite and the pad was washed with EtOAc (30 mL). The aqueous layers were extracted with EtOAc (10 mL×3). The combined organic layers were dried over Na₂SO₄, filtered and concentrated under reduced pressure to afford the title compound (60 mg, 67%) as a blue oil which was used without further purification. MS-ESI (m/z) calcd for C₁₁H₁₀F₂N₅[M+H]⁺: 250.1. Found 250.0.

Step 3: 3-Bromo-N-(3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-1H-indazol-5-yl)-2-fluoro-6-methylbenzamide

embedded image

To a solution of 3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-1H-indazol-5-amine (120 mg, 481.50 umol), 3-bromo-2-fluoro-6-methylbenzoic acid (134.65 mg, 577.80 umol) in pyridine (3 mL) was added EDCI (138.46 mg, 722.26 umol) and the mixture was stirred at 30° C. for 12 hrs. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was diluted with H₂O (15 mL) and extracted with EtOAc (5 mL×3). The combined organic layers were dried over Na₂SO₄, filtered and concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography (ISCO; 4 g SepaFlash column) using a 0-15% EtOAc/petroleum ether gradient eluent to afford the title compound (100 mg, 45%) as a brown solid. MS-ESI (m/z) calcd for C₁₉H₁₄BrF₃N₅O [M+H]⁺: 464.0/466.0. Found 464.0/466.0.

Step 4: 3-Cyano-N-(3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-1H-indazol-5-yl)-2-fluoro-6-methylbenzamide

embedded image

A mixture of 3-bromo-N-(3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-1H-indazol-5-yl)-2-fluoro-6-methylbenzamide (100 mg, 215.41 umol), Zn(CN)₂(50.59 mg, 430.81 umol), Zn (2.82 mg, 43.08 umol), Pd₂(dba)₃(19.73 mg, 21.54 umol) and dppf (11.94 mg, 21.54 umol) in DMA (2 mL) was degassed and purged with N₂(3×), and then the mixture was stirred at 120° C. for 5 hrs under an N₂atmosphere in a microwave reactor. The reaction mixture was concentrated and purified by preparative HPLC using Method CE to afford the title compound (11.31 mg, 10%) as a white solid, TFA salt. ¹H NMR (400 MHz, DMSO-d₆) δ 13.21 (s, 1H), 10.56 (s, 1H), 8.72 (s, 1H), 8.39 (s, 1H), 8.29 (s, 1H), 7.78-8.10 (m, 2H), 7.63-7.67 (m, 1H), 7.57-7.61 (m, 1H), 7.48 (d, J=8.1 Hz, 1H), 2.59 ppm (s, 3H). MS-ESI (m/z) calc'd for C₂₀H₁₄F₃N₆O [M+H]⁺: 411.1. Found 411.0.

Example 178: 5-Cyano-N-(3-(2-methoxypyridin-4-yl)-1H-indazol-5-yl)-3-(trifluoromethyl)picolinamide

embedded image

Step 1: (2-Methoxypyridin-4-yl)boronic acid

embedded image

A mixture of 3-bromo-1H-indazol-5-amine (300 mg, 1.41 mmol), 3-(2-methoxypyridin-4-yl)-1H-indazol-5-amine (259.66 mg, 1.70 mmol), Pd(Amphos)Cl₂(100.18 mg, 141.48 umol, 100.18 uL) and AcOK (416.54 mg, 4.24 mmol) in EtOH (6 mL) and H₂O (1.5 mL) was degassed and purged with N₂(3×), and then the mixture was stirred at 100° C. for 12 hrs under an N₂atmosphere. The reaction mixture was concentrated to give a residue which was diluted with 30 mL of H₂O and extracted with EtOAc (10 mL×3). The combined organic phases were dried over Na₂SO₄and concentrated under reduced pressure to afford the title compound (333 mg) as a brown oil which was used without purification. MS-ESI (m/z) calcd for C₃H₁₃N₄O [M+H]⁺: 241.1. Found 241.1.

Step 2: 5-Bromo-3-(trifluoromethyl)picolinic acid

embedded image

To a solution of methyl 5-bromo-3-(trifluoromethyl)picolinate (200 mg, 699.19 umol) in THF (8 mL) and H₂O (4 mL) was added NaOH (55.94 mg, 1.40 mmol) and the mixture was stirred at 25° C. for 2 hrs. The reaction mixture was diluted with 1M HCl to pH=4. The aqueous layers were extracted with EtOAc (15 mL×3). The combined organic layers were dried over Na₂SO₄, filtered and concentrated under reduced pressure to afford the title compound (187 mg) as a white solid which was used without purification. MS-ESI (m/z) calcd for C₇H₄BrF₃NO₂[M+H]⁺: 269.9/271.9. Found 269.9/271.9.

Step 3: 5-Bromo-N-(3-(2-methoxypyridin-4-yl)-1H-indazol-5-yl)-3-(trifluoromethyl)picolinamide

embedded image

To a solution of 5-bromo-3-(trifluoromethyl)picolinic acid (260 mg, 962.95 umol) in pyridine (10 mL) was added EDCI (276.90 mg, 1.44 mmol) and (2-methoxypyridin-4-yl)boronic acid (347.04 mg, 1.44 mmol) and the mixture was stirred at 25° C. for 12 hrs. The mixture was concentrated and purified by flash silica gel chromatography (ISCO; 4 g SepaFlash column) using a 0-20% EtOAc/petroleum ether gradient eluent to afford the title compound (270 mg, 57%) as a yellow solid which was used without further purification. MS-ESI (m/z) calcd for C₂₀H₁₄BrF₃N₅O₂[M+H]⁺: 492.0/494.0. Found 492.0/494.0.

Step 4: 5-Cyano-N-(3-(2-methoxypyridin-4-yl)-1H-indazol-5-yl)-3-(trifluoromethyl)picolinamide

embedded image

A mixture of 5-bromo-N-(3-(2-methoxypyridin-4-yl)-1H-indazol-5-yl)-3-(trifluoromethyl)picolinamide (100 mg, 203.15 umol), Zn(CN)₂(23.85 mg, 203.15 umol), Pd₂(dba)₃(18.60 mg, 20.31 umol), Zn (2.66 mg, 40.63 umol) and DPPF (33.79 mg, 60.94 umol) in DMA (10 mL) was degassed and purged with N₂(3×), and then the mixture was stirred at 120° C. for 2 hrs under an N₂atmosphere. The reaction was filtered and the filtrate was purified by preparative HPLC using Method CD to afford the title compound (22.14 mg, 25%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.00 (br s, 1H), 9.43 (d, J=1.54 Hz, 1H), 9.06 (d, J=1.32 Hz, 1H), 8.53 (s, 1H), 8.28 (d, J=5.29 Hz, 1H), 7.71-7.76 (m, 1H), 7.64-7.68 (m, 1H), 7.53 (dd, J=5.29, 1.32 Hz, 1H), 7.26 (s, 1H), 3.90 (s, 3H). MS-ESI (m/z) calc'd for C₂₁H₁₄F₃N₆O₂[M+H]⁺: 439.1. Found 439.2.

Example 179: 5-Cyano-N-(3-(furan-3-yl)-1H-indazol-5-yl)-4-methylisoxazole-3-carboxamide

embedded image

Step 1: Ethyl 4-methyl-5-oxo-2,5-dihydroisoxazole-3-carboxylate

embedded image

To a solution of diethyl 2-methylmalonate (10 g, 49.46 mmol, 9.17 mL) in EtOH (100 mL) was added NH₂OH.HCl (6.12 g, 88.03 mmol) and the mixture was stirred at 78° C. for 12 hrs. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was diluted with H₂O (20 mL) and extracted with EtOAc (25 mL×2). The combined organic layers were dried over Na₂SO₄, filtered and concentrated under reduced pressure to afford the title compound (6.6 g, 52%) as a white solid which was used without further purification. MS-(ESI) (m/z) calcd for C₇H₁₀NO₄(M+H)⁺:172.1. Found 172.1.

Step 2: Ethyl 5-bromo-4-methylisoxazole-3-carboxylate

embedded image

To a solution of ethyl 4-methyl-5-oxo-2,5-dihydroisoxazole-3-carboxylate (3.5 g, 20.45 mmol) in POBr₃(23.45 g, 81.80 mmol) was added Et₃N (2.07 g, 20.45 mmol) and the mixture was stirred at 80° C. for 2 hrs. The reaction mixture was quenched by addition of ice water (20 mL), and then the mixture was extracted with EtOAc (20 mL×2). The combined organic layers were dried over Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO; 12 g SepaFlash column), using petroleum ether as eluent to afford the title compound (3.5 g, 73%) as a colorless oil. MS-(ESI) (m/z) calcd for C₇H₉BrNO₃(M+H)⁺: 234.0/236.0. Found 233.9/235.9.

Step 3: Ethyl 4-methyl-5-vinylisoxazole-3-carboxylate

embedded image

A mixture of ethyl 5-bromo-4-methylisoxazole-3-carboxylate (3.5 g, 14.95 mmol), tributyl(vinyl)stannane (5.69 g, 17.95 mmol), and Pd(PPh₃)₄(1.73 g, 1.50 mmol) in dioxane (24 mL) was degassed and purged with N₂(3×), and then the mixture was stirred at 100° C. for 3 hrs under an N₂atmosphere. The reaction mixture was concentrated and purified by flash silica gel chromatography (ISCO; 12 g SepaFlash column) using a 0-5% EtOAc/petroleum ether gradient eluent to afford the title compound (1.7 g, 63%) as a pale yellow liquid. MS-(ESI) (m/z) calcd for C₉H₁₂NO₃(M+H)⁺: 182.1. Found 182.0.

Step 4: Ethyl 5-formyl-4-methylisoxazole-3-carboxylate

embedded image

To a solution of ethyl 4-methyl-5-vinylisoxazole-3-carboxylate (1.7 g, 9.38 mmol) in THF (30 mL) and H₂O (15 mL) was added NaIO₄(6.02 g, 28.15 mmol) and OsO₄(477.06 mg, 1.88 mmol) and the mixture was stirred at 30° C. for 12 hrs. The mixture was then filtered through Celite washing with EtOAc. The filtrate was diluted with H₂O (15 mL) and extracted with EtOAc (15 mL×3). The combined organic layers were dried over Na₂SO₄, filtered and concentrated under reduced pressure to afford the title compound (1 g, 58%) as a pale yellow oil which was used without further purification. ¹H NMR (400 MHz, DMSO-d₆) δ 4.49 (q, 2H, J=7.1 Hz), 2.43 (s, 3H), 1.45 (t, 3H, J=7.1 Hz). MS-(ESI) (m/z) calcd for C₈H₁₀NO₄(M+H)˜: 184.1. Found 184.

Step 5: Ethyl 5-cyano-4-methylisoxazole-3-carboxylate

embedded image

To a solution of ethyl 5-formyl-4-methylisoxazole-3-carboxylate (900 mg, 4.91 mmol) in pyridine (8 mL) was added NH₂OH.HCl (341.46 mg, 4.91 mmol) and the mixture was stirred at 90° C. for 0.5 hr. Ac₂O (5 mL) was then added and stirring was continued at 90° C. for another 1 hr. The reaction mixture was concentrated and purified by flash silica gel chromatography (ISCO; 4 g SepaFlash column) using a 0-3% EtOAc/petroleum ether gradient eluent to afford the title compound (600 mg, 68%) as a pale yellow oil.

Step 6: 5-Cyano-4-methylisoxazole-3-carboxylic acid

embedded image

To a solution of ethyl 5-cyano-4-methylisoxazole-3-carboxylate (60 mg, 333.04 umol) in THF (3 mL) and H₂O (3 mL) was added LiOH.H₂O (27.95 mg, 666.07 umol) and the mixture was stirred at 0° C. for 0.25 hr. The mixture was acidified to pH=2 by addition of IN HCl, and then the mixture was diluted with H₂O (3 mL) and extracted with EtOAc (5 mL×3). The combined organic layers were dried over Na₂SO₄, filtered and concentrated under reduced pressure to afford the title compound (40 mg, 79%) as a white solid which was used without further purification.

Step 7: 5-Cyano-N-(3-(furan-3-yl)-1H-indazol-5-yl)-4-methylisoxazole-3-carboxamide

embedded image

To a solution of 5-cyano-4-methylisoxazole-3-carboxylic acid (40 mg, 262.97 umol) and 3-(furan-3-yl)-1H-indazol-5-amine (62.86 mg, 315.57 umol) in pyridine (2 mL) was added EDCI (75.62 mg, 394.46 umol) and the mixture was stirred at 30° C. for 3 hrs. The reaction mixture was concentrated and purified by preparative HPLC using Method BW to afford the title compound (8.87 mg, 8%) as a white solid, TFA salt. ¹H NMR (400 MHz, DMSO-d₆) δ 13.14 (s, 1H), 10.99 (s, 1H), 8.39 (s, 1H), 8.24 (s, 1H), 7.85 (s, 1H), 7.75 (dd, J=1.54, 9.04 Hz, 1H), 7.57 (d, J=9.04 Hz, 1H), 6.99 (s, 1H), 2.38 (s, 3H). MS-ESI (m/z) calc'd for C₁₇H₁₂N₅O₃[M+H]⁺: 334.1. Found 334.0.

Example 180: 3-Cyano-N-(3-(furan-3-yl)-1H-indazol-5-yl)-4-methylisoxazole-5-carboxamide

embedded image

Step 1: 5-(1-Ethoxyvinyl)-4-methylisoxazole-3-carboxamide

embedded image

A mixture of 5-bromo-4-methylisoxazole-3-carboxamide (840 mg, 4.10 mmol), tributyl(1-ethoxyvinyl)stannane (1.78 g, 4.92 mmol), Pd(PPh₃)₂Cl₂(143.80 mg, 204.87 umol) in dioxane (20 mL) was degassed and purged with N₂(3×), and then the mixture was stirred at 90° C. for 3 hrs under an N₂atmosphere. The reaction mixture was concentrated and purified by flash silica gel chromatography (ISCO; 20 g SepaFlash column) using a 0-20% EtOAc/petroleum ether gradient eluent to afford the title compound (690 mg, 86% yield) as a light yellow solid. MS-ESI (m/z) calcd for C₉H₁₃N₂O₃[M+H]⁺: 197.1. Found 197.0.

Step 2: Ethyl 3-carbamoyl-4-methylisoxazole-5-carboxylate

embedded image

To a solution of 5-(1-ethoxyvinyl)-4-methylisoxazole-3-carboxamide (690 mg, 3.52 mmol) in dioxane (20 mL) was added NaIO₄(1.50 g, 7.03 mmol) in H₂O (10 mL), followed by KMnO₄(111.15 mg, 703.35 umol). The mixture was then stirred at 25° C. for 12 hrs. The reaction mixture was filtered and the filtrate was concentrated to give a residue which was diluted with H₂O (30 mL) and extracted with EtOAc (15 mL×3). The combined organic layers were dried over Na₂SO₄, filtered and concentrated to give a residue. The residue was purified by flash silica gel chromatography (ISCO; 20 g SepaFlash column) using a 0-19% EtOAc/petroleum ether gradient eluent to afford the title compound (360 mg, 52%) as a white solid. MS-ESI (m/z) calcd for C₈H₁₁N₂O₄[M+H]⁺: 199.1. Found 199.0.

Step 3: 3-Carbamoyl-4-methylisoxazole-5-carboxylic acid

embedded image

To a solution of ethyl 3-carbamoyl-4-methylisoxazole-5-carboxylate (100 mg, 504.60 umol) in THF (4 mL) and H₂O (2 mL) was added NaOH (40.37 mg, 1.01 mmol). The mixture was stirred at 25° C. for 1 hr. The reaction mixture was acidified with 1 N HCl to pH=3 and extracted with EtOAc (4 mL×4). The combined organic layers were dried over Na₂SO₄, filtered and concentrated to afford the title compound (65 mg, 38%) as a white solid which was used without further purification. MS-ESI (m/z) calcd for C₆H₇N₂O₄[M+H]⁺: 171.0. Found 171.0.

Step 4: N-(3-(Furan-3-yl)-1H-indazol-5-yl)-4-methylisoxazole-3,5-dicarboxamide

embedded image

To a solution of 3-carbamoyl-4-methylisoxazole-5-carboxylic acid (65 mg, 382.08 umol) in pyridine (4 mL) was added EDCI (87.89 mg, 458.49 umol) and 3-(furan-3-yl)-1H-indazol-5-amine (76.11 mg, 382.08 umol) and the mixture was stirred at 25° C. for 2 hrs. The reaction mixture was then concentrated and purified by preparative TLC (SiO₂, 1:3 petroleum ether/EtOAc, R_f=0.34) to afford the title compound (80 mg, 60%) as a yellow solid. MS-ESI (m/z) calcd for C₇H₁₄N₅O₄[M+H]⁺: 352.1. Found 352.2.

Step 5: 3-Cyano-N-(3-(furan-3-yl)-1H-indazol-5-yl)-4-methylisoxazole-5-carboxamide

embedded image

To a solution of N⁵-(3-(furan-3-yl)-1H-indazol-5-yl)-4-methylisoxazole-3,5-dicarboxamide (80 mg, 227.72 umol) in THF (2 mL) was added TFAA (239.14 mg, 1.14 mmol) and Et₃N (46.08 mg, 455.43 umol) at 0° C. and the mixture was stirred at 20° C. for 10 hrs. The reaction mixture was then concentrated to give a residue. The process was repeated to give another 30 mgs of residue which was combined and purified by preparative HPLC using Method BL twice to afford the title compound (9.96 mg, 13%) as a yellow solid, TFA salt. ¹H NMR (400 MHz, DMSO-d₆) δ 13.16 (s, 1H) 11.00 (s, 1H) 8.37 (s, 1H) 8.25 (s, 1H) 7.86 (d, J=1 Hz, 1H) 7.76 (br d, J=9 Hz, 1H) 7.58 (d, J=9 Hz, 1H) 7.00 (s, 1H) 2.42 (s, 3H). MS-ESI (m/z) calc'd for C₁₇H₁₂N₅O₃[M+H]⁺: 334.1. Found 334.0.

Example 181: 5-Cyano-N-(3-(2-isopropyloxazol-5-yl)-1H-indazol-5-yl)-3,4-dimethylpicolinamide

embedded image

Step 1: 2-Isopropyl-5-(5-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)oxazole

embedded image

A mixture of 5-nitro-3-(prop-1-en-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole (500 mg, 1.49 mmol), valine (523.86 mg, 4.47 mmol), oxone (2.75 g, 4.47 mmol), and I₂(75.67 mg, 298.13 umol) in DMSO (10 mL) was degassed and purged with N₂(3×), and then the mixture was stirred at 100° C. for 12 hrs under an N₂atmosphere. The reaction mixture was quenched with saturated aqueous NaHCO₃(20 mL) and extracted with EtOAc (15 mL×3). The combined organic layers were dried over Na₂SO₄, filtered and concentrated to give a residue. The residue was purified by flash silica gel chromatography (ISCO; 12 g SepaFlash column) using a 0-7% EtOAc/petroleum ether gradient eluent to afford the title compound (120 mg, 20%) as a yellow solid. MS-(ESI) (m/z) calcd for C₁₉H₂₇N₄O₄Si (M+H)⁺: 403.2. Found 403.1.

Step 2: 2-Isopropyl-5-(5-nitro-1H-indazol-3-yl)oxazole

embedded image

To a solution of 2-isopropyl-5-(5-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)oxazole (110 mg, 273.28 umol) in THF (6 mL) was added TBAF (1 M, 2.73 mL) and ethane-1,2-diamine (164.24 mg, 2.73 mmol) and the mixture was stirred at 70° C. for 12 hrs. The reaction mixture was then concentrated, diluted with EtOAc (10 mL) and washed with H₂O (5 mL×2). The organic layer was dried over Na₂SO₄, filtered and concentrated to afford the title compound (74 mg) as a yellow solid which was used without further purification. MS-(ESI) (m/z) calcd for C₁₃H₁₃N₄O₃(M+H)⁺: 273.1. Found 273.0.

Step 3: 3-(2-Isopropyloxazol-5-yl)-1H-indazol-5-amine

embedded image

To a solution of 2-isopropyl-5-(5-nitro-1H-indazol-3-yl)oxazole (100 mg, 367.30 umol) in EtOH (2 mL) was added SnCl₂.2H₂O (414.40 mg, 1.84 mmol) and the mixture was stirred at 80° C. for 1 hr. The reaction mixture was then concentrated under reduced pressure, diluted with EtOAc (10 mL), and basified with saturated aqueous Na₂CO₃to pH=8. The organic layer was separated and the aqueous phase was extracted with EtOAc (5 mL×3). The combined organic layers were dried over Na₂SO₄, filtered and concentrated to give a residue. The residue was purified by preparative TLC (SiO₂, 0:1 petroleum ether/EtOAc, R_f=0.28) to afford the title compound (39 mg, 44%) as a brown solid. MS-(ESI) (m/z) calcd for C₁₃H₁₅N₄O (M+H)⁺: 243.1. Found 243.1.

Step 4: 5-Cyano-N-(3-(2-isopropyloxazol-5-yl)-1H-indazol-5-yl)-3,4-dimethylpicolinamide

embedded image

To a solution of 5-cyano-3,4-dimethylpicolinic acid (25 mg, 141.91 umol) in pyridine (2 mL) was added EDCI (40.81 mg, 212.86 umol) and 3-(2-isopropyloxazol-5-yl)-1H-indazol-5-amine (34.38 mg, 141.91 umol) and the mixture was stirred at 20° C. for 12 hrs. The reaction mixture was concentrated and purified by preparative HPLC using Method CC to afford the title compound (4.44 mg, 6%) as a pale yellow solid, TFA salt. ¹H NMR (400 MHz, DMSO-d₆) δ 13.44 (s, 1H) 10.78 (s, 1H) 8.90 (s, 1H) 8.56 (s, 1H) 7.77 (dd, J=9, 2 Hz, 1H) 7.61 (d, J=9 Hz, 1H) 7.48 (s, 1H) 3.17-3.26 (m, 1H) 2.56 (s, 3H) 2.45 (s, 3H) 1.39 (d, J=7 Hz, 6H). MS-ESI (m/z) calc'd for C₂₂H₂₁N₆O₂[M+H]⁺: 401.2. Found 401.0.

Example 182: 5-Cyano-3,4-dimethyl-N-(3-(6-methylpyridin-2-yl)-1H-indazol-5-yl)picolinamide

embedded image

A mixture of N-(3-bromo-1H-indazol-5-yl)-5-cyano-3,4-dimethylpicolinamide (80 mg, 216.10 umol), 2-methyl-6-(tributylstannyl)pyridine (99.10 mg, 259.32 umol), Pd(PPh₃)₂Cl₂(15.17 mg, 21.61 umol) in dioxane (3 mL) was degassed and purged with N₂(3×), and then the mixture was stirred at 150° C. for 3 hrs under an N₂atmosphere in a microwave reactor. The reaction mixture was concentrated and purified by preparative HPLC using Method BZ to afford the title compound (3.29 mg, 4%) as a pale yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.30 (s, 1H), 10.70 (s, 1H), 9.04 (s, 1H), 8.89 (s, 1H), 7.94 (d, J=7.72 Hz, 1H), 7.70-7.82 (m, 2H), 7.57 (d, J=9.04 Hz, 1H), 7.21 (d, J=7.50 Hz, 1H), 2.61 (s, 3H), 2.55 (s, 3H), 2.44 (s, 3H). MS-ESI (m/z) calc'd for C₂₂H₁₉N₆O [M+H]⁺: 383.2. Found 383.2.

Example 183: N-(3-(1H-Pyrazol-4-yl)-1H-indazol-5-yl)-5-cyano-3,4-dimethylpicolinamide

embedded image

Prepared as described for 5-cyano-N-(3-(isoxazol-4-yl)-1H-indazol-5-yl)-3-methylpicolinamide using (1H-pyrazol-4-yl)boronic acid in place of isoxazole-4-boronic acid and 5-cyano-N-(3-iodo-1H-indazol-5-yl)-3,4-dimethylpicolinamide in place of 5-cyano-N-(3-iodo-1H-indazol-5-yl)-3-methylpyridine-2-carboxamide to afford the title compound (9.4 mg, 27%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.12 (br. s., 1H) 12.94 (s, 1H) 10.66 (s, 1H) 8.90 (s, 1H) 8.45 (d, J=1.32 Hz, 1H) 8.22 (br. s., 1H) 7.99 (br. s., 1H) 7.64-7.80 (m, 1H) 7.54 (d, J=8.80 Hz, 1H) 2.56 (s, 3H) 2.48 (s, 3H). MS-ESI (m/z) calc'd for C₁₉H₁₆N₇O [M+H]⁺: 358.1. Found 358.3.

Example 184: 6-Chloro-5-cyano-3,4-dimethyl-N-(3-(oxazol-5-yl)-1H-indazol-5-yl)picolinamide

embedded image

Prepared as described for 5-cyano-N-(7-fluoro-3-(furan-3-yl)-1H-indazol-5-yl)-3-methylpicolinamide using 6-chloro-5-cyano-3,4-dimethylpicolinic acid in place of 5-cyano-3-methylpicolinic acid and using 3-(oxazol-5-yl)-1H-indazol-5-amine in place of 7-fluoro-3-(furan-3-yl)-1H-indazol-5-amine to afford the title compound (6.5 mg, 9%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.59 (s, 1H), 10.84 (s, 1H), 8.59 (s, 1H), 8.54 (d, J=2.1 Hz, 1H), 7.72 (dd, J=9.0, 1.9 Hz, 1H), 7.67-7.62 (m, 2H), 2.61 (s, 3H), 2.41 (s, 3H). MS-ESI (m/z) calc'd for C₁₉H₁₄ClN₆O₂[M+H]⁺: 393.1/395.1. Found 393.1/395.1.

Example 185: 5-Cyano-N-(3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-1H-indazol-5-yl)-3,4,6-trimethylpicolinamide

embedded image

Prepared as described for 5-cyano-N-(7-fluoro-3-(furan-3-yl)-1H-indazol-5-yl)-3-methylpicolinamide using 5-cyano-3,4,6-trimethylpicolinic acid in place of 5-cyano-3-methylpicolinic acid and using 3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-1H-indazol-5-amine in place of 7-fluoro-3-(furan-3-yl)-1H-indazol-5-amine to afford the title compound (40.2 mg, 44%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₄) δ 13.20 (s, 1H), 10.63 (s, 1H), 8.73 (s, 1H), 8.41 (d, J=1.8 Hz, 1H), 8.30 (s, 1H), 7.94 (t, J=59.0 Hz, 1H), 7.74 (dd, J=8.9, 1.9 Hz, 1H), 7.59 (d, J=9.0 Hz, 1H), 2.72 (s, 3H), 2.55 (s, 3H), 2.42 (s, 3H). MS-ESI (m/z) calc'd for C₂₁H₁₈F₂N₇O [M+H]⁺: 422.2. Found 422.2.

Example 187: 5-Cyano-3,4-dimethyl-N-(3-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-5-yl)picolinamide

embedded image

Prepared as described for 5-cyano-N-(3-(isoxazol-4-yl)-1H-indazol-5-yl)-3-methylpicolinamide using (1-methyl-1H-pyrazol-4-yl)boronic acid in place of isoxazole-4-boronic acid and 5-cyano-N-(3-iodo-1H-indazol-5-yl)-3,4-dimethylpicolinamide in place of 5-cyano-N-(3-iodo-1H-indazol-5-yl)-3-methylpyridine-2-carboxamide to afford the title compound (16.7 mg, 47%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 12.96 (s, 1H) 10.66 (s, 1H) 8.90 (s, 1H) 8.41 (d, J=1.54 Hz, 1H) 8.21 (s, 1H) 7.91 (d, J=0.66 Hz, 1H) 7.72 (dd, J=8.80, 1.76 Hz, 1H) 7.54 (d, J=9.02 Hz, 1H) 3.96 (s, 3H) 2.57 (s, 3H) 2.48 (s, 3H). MS-ESI (m/z) calc'd for C₂₀H₁₈N₇O [M+H]⁺: 372.2. Found 372.3.

Example 188: 3-Cyano-2,6-difluoro-N-(3-(oxazol-5-yl)-1H-indazol-5-yl)benzamide

embedded image

Prepared as described for 5-cyano-N-(7-fluoro-3-(furan-3-yl)-1H-indazol-5-yl)-3-methylpicolinamide using 3-cyano-2,6-difluorobenzoic acid in place of 5-cyano-3-methylpicolinic acid and using 3-(oxazol-5-yl)-1H-indazol-5-amine in place of 7-fluoro-3-(furan-3-yl)-1H-indazol-5-amine to afford the title compound (2.1 mg, 4%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.57 (s, 1H), 11.06 (s, 1H), 8.59 (s, 1H), 8.50 (dd, J=1.9, 0.8 Hz, 1H), 8.23 (ddd, J=8.8, 7.5, 5.9 Hz, 1H), 7.67 (dd, J=8.9, 0.8 Hz, 1H), 7.65 (s, 1H), 7.64-7.60 (m, 1H), 7.57 (dd, J=8.8, 1.1 Hz, 1H). MS-ESI (m/z) calc'd for C₁₅H₁₀F₂N₅O₂[M+H]⁺: 366.1. Found 366.1.

Example 189: 4-Cyano-N-(3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-1H-indazol-5-yl)-2-methoxybenzamide

embedded image

Prepared as described for 5-cyano-N-(7-fluoro-3-(furan-3-yl)-1H-indazol-5-yl)-3-methylpicolinamide using 4-cyano-2-methoxybenzoic acid in place of 5-cyano-3-methylpicolinic acid and using 3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-1H-indazol-5-amine in place of 7-fluoro-3-(furan-3-yl)-1H-indazol-5-amine to afford the title compound (9.9 mg, 29%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.18 (br. s., 1H) 10.34 (s, 1H) 8.70 (s, 1H) 8.42 (d, J=1.32 Hz, 1H) 8.28 (s, 1H) 7.79-8.10 (m, 1H) 7.77 (d, J=7.70 Hz, 1H) 7.72 (d, J=1.32 Hz, 1H) 7.63-7.68 (m, 1H) 7.54-7.59 (m, 2H) 3.96 (s, 3H). MS-ESI (m/z) calc'd for C₂₀H₁₅F₂N₆O₂[M+H]⁺: 409.1. Found 409.3.

Example 190: 4-Cyano-2-fluoro-6-methyl-N-(3-(oxazol-5-yl)-1H-indazol-5-yl)benzamide

embedded image

Prepared as described for 5-cyano-N-(7-fluoro-3-(furan-3-yl)-1H-indazol-5-yl)-3-methylpicolinamide using 4-cyano-2-fluoro-6-methylbenzoic acid in place of 5-cyano-3-methylpicolinic acid and using 3-(oxazol-5-yl)-1H-indazol-5-amine in place of 7-fluoro-3-(furan-3-yl)-1H-indazol-5-amine to afford the title compound (2.7 mg, 5%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 10.91 (s, 1H), 8.59 (s, 1H), 8.54 (dd, J=2.7, 1.1 Hz, 1H), 7.88 (dd, J=8.9, 1.4 Hz, 1H), 7.76 (d, J=1.3 Hz, 1H), 7.65-7.62 (m, 3H), 2.42 (s, 3H). MS-ESI (m/z) calc'd for C₁₉H₁₃FN₅O₂[M+H]⁺: 362.1. Found 362.2.

Example 191: 5-Cyano-N-(3-(2,6-dimethylpyridin-4-yl)-1H-indazol-5-yl)-3,4-dimethylpicolinamide

embedded image

Step 1: 3-(2,6-Dimethylpyridin-4-yl)-1H-indazol-5-amine

embedded image

A mixture of 3-bromo-1H-indazol-5-amine (300 mg, 1.41 mmol), (2,6-dimethylpyridin-4-yl)boronic acid (256.31 mg, 1.70 mmol), K₂CO₃(586.60 mg, 4.24 mmol) and Pd(dppf)Cl₂(103.52 mg, 141.48 umol) in dioxane (5 mL) and H₂O (0.5 mL) was degassed and purged with N₂(3×), and then the mixture was stirred at 100° C. for 12 hrs under an N₂atmosphere The reaction mixture was poured into water (20 mL) and extracted with EtOAc (20 mL×3). The combined organic phases were washed with brine (20 mL×1), dried over Na₂SO₄, filtered and concentrated to give a residue. The residue was purified by preparative HPLC using Method CA to afford the title compound (80 mg, 24%) as a yellow solid. MS-(ESI) (m/z) calcd for C₁₄H₁₅N₄(M+H)⁺: 239.1. Found 239.2.

Step 2: 5-Cyano-N-(3-(2,6-dimethylpyridin-4-yl)-1H-indazol-5-vi)-3,4-dimethylpicolinamide

embedded image

To a solution of 5-cyano-3,4-dimethylpicolinic acid (50 mg, 283.81 umol) in pyridine (2 mL) was added EDCI (81.61 mg, 425.72 umol) and 3-(2,6-dimethylpyridin-4-yl)-1H-indazol-5-amine (67.63 mg, 283.81 umol) and the mixture was stirred at 25° C. for 12 hrs. The reaction mixture was then concentrated to give a residue. The residue was purified by preparative HPLC using Method CB to afford the title compound (32.94 mg, 29%) as a pale yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.53 (br s, 1H), 10.76 (s, 1H), 8.91 (s, 1H), 8.55 (s, 1H), 7.88 (dd, J=1.6, 9.0 Hz, 1H), 7.65 (d, J=8.9 Hz, 1H), 7.60 (s, 2H), 2.56 (s, 3H), 2.53 (s, 6H), 2.47 (s, 3H). MS-ESI (m/z) calc'd for C₂₃H₂₁N₆O [M+H]⁺: 397.2. Found 397.3.

Example 192: 3-Cyano-N-(3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-1H-indazol-5-yl)-2-(trifluoromethyl)benzamide

embedded image

Step 1: N-(3-(1-(Difluoromethyl)-1H-pyrazol-4-yl)-1H-indazol-5-yl)-3-fluoro-2-(trifluoromethyl)benzamide

embedded image

To a stirred solution of 3-fluoro-2-(trifluoromethyl)benzoic acid (100 mg, 480.52 umol) and 3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-1H-indazol-5-amine (119.75 mg, 480.52 umol) in pyridine (3 mL) was added EDCI (119.75 mg, 624.67 umol) and the reaction mixture was stirred at 25° C. for 12 hrs. The reaction mixture was concentrated to give a residue which was poured into water (5 mL) and extracted with EtOAc (5 mL×3). The combined organic phases were washed with brine (5 mL×1), dried over Na₂SO₄, filtered and concentrated. The material was purified by silica gel column chromatography using a 0-50% EtOAc/petroleum ether gradient eluent to afford the title compound (120 mg, 57%) as an off-white solid which was used without further purification. MS-ESI (m/z) calcd for C₁₉H₁₂F₆N₅O [M+H]⁺: 440.1. Found 440.1

Step 2: 3-Cyano-N-(3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-1H-indazol-5-yl)-2-(trifluoromethyl)benzamide

embedded image

N-(3-(1-(Difluoromethyl)-1H-pyrazol-4-yl)-1H-indazol-5-yl)-3-fluoro-2-(trifluoromethyl)benzamide (50 mg, 113.81 umol) and KCN (22.23 mg, 341.44 umol) were taken up in a microwave tube in DMF (2 mL). The sealed tube was heated at 150° C. for 2 hrs under microwave irradiation. After cooling to 25° C., the reaction mixture was adjusted to pH=8 with saturated aqueous NaHCO₃and extracted with EtOAc (5 mL 3). The combined organic phases were washed with brine (5 mL×1), dried over Na₂SO₄, filtered and concentrated to give a residue. The residue was purified by preparative HPLC using Method CI to afford the title compound (17.96 mg, 17%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.23 (br s, 1H), 10.76 (s, 1H), 8.68 (s, 1H), 8.38-8.23 (m, 3H), 8.09-8.00 (m, 2H), 7.97-7.77 (m, 1H), 7.59 (s, 2H).) MS-ESI (m/z) calc'd for C₂₀H₁₂F₅N₆O [M+H]⁺: 447.1. Found 447.1.

Example 193: 3-Cyano-N-(3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-1H-indazol-5-yl)-2,6-dimethylbenzamide

embedded image

Step 1: 3-(1-(Difluoromethyl)-1H-pyrazol-4-yl)-1H-indazol-5-amine

embedded image

A mixture of 3-bromo-1H-indazol-5-amine (500 mg, 2.36 mmol), (1-(difluoromethyl)-1H-pyrazol-4-yl)boronic acid (572.64 mg, 3.54 mmol), Pd(Amphos)Cl₂(166.96 mg, 235.80 umol) and AcOK (694.23 mg, 7.07 mmol) in EtOH (10 mL) and H₂O (2 mL) was degassed and purged with N₂(3×), and then the mixture was stirred at 80° C. for 12 hrs under an N₂atmosphere. After cooling to 25° C., the reaction mixture was filtered and the filtrate was concentrated. The residue was poured into water (10 mL) and extracted with EtOAc (10 mL×3). The combined organic phases were washed with brine (10 mL×1), dried over Na₂SO₄, filtered and concentrated to give a residue. The residue was purified by silica gel column chromatography using a 0-50% EtOAc/petroleum ether gradient eluent to afford the title compound (300 mg, 51%) as a brown solid. MS-ESI (m/z) calc'd for C₁₁H₁₀F₂N₅[M+H]⁺: 250.1. Found 250.1.

Step 2: 3-Bromo-2,6-dimethylbenzoic acid

embedded image

To a solution of methyl 3-bromo-2,6-dimethylbenzoate (300 mg, 1.23 mmol) in H₂O (3 mL) and MeOH (3 mL) was added NaOH (493.59 mg, 12.34 mmol) and the reaction mixture was stirred at 80° C. for 12 hrs. The reaction mixture was then concentrated and adjusted to pH=3 with 1 N aqueous HCl. The reaction mixture was filtered and the solid was dried to afford the title compound (250 mg, 88%) as a white solid, which was used without further purification. MS-ESI (m/z) calcd for C₉H₁₀BrO₂[M−H]⁻: 227.0/229.0. Found 226.9/228.9

Step 3: 3-Bromo-2,6-dimethylbenzoyl chloride

embedded image

3-Bromo-2,6-dimethylbenzoic acid (160 mg, 698.48 umol) was dissolved into SOCl₂(5 mL) and the reaction mixture was stirred at 80° C. for 12 hrs. The reaction mixture was then concentrated to afford the title compound (100 mg, 58%) as a yellow oil, which was used without further purification.

Step 4: 3-Bromo-N-(3-(f-(difluoromethyl)-1H-pyrazol-4-yl)-1H-indazol-5-yl)-2,6-dimethylbenzamide

embedded image

To a solution of 3-bromo-2,6-dimethylbenzoyl chloride (100 mg, 404.01 umol) in dioxane (5 mL) was added 3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-1H-indazol-5-amine (70.48 mg, 282.81 umol) and Et₃N (122.65 mg, 1.21 mmol, 168.70 uL) and the mixture was stirred at 25° C. for 12 hrs. The reaction mixture was then concentrated to give a residue. The residue was purified by silica gel column chromatography using a 0-50% EtOAc/petroleum ether gradient eluent to afford the title compound (101 mg, 54%) as a yellow solid. MS-ESI (m/z) calcd for C₂₀H₁₇BrF₂N₅O [M+H]⁺: 460.1/462.1. Found 460.1/462.0.

Step 5: 3-Cyano-N-(3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-1H-indazol-5-yl)-2,6-dimethylbenzamide

embedded image

3-Bromo-N-(3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-1H-indazol-5-yl)-2,6-dimethylbenzamide (80 mg, 173.81 umol), Zn(CN)₂(20.41 mg, 173.81 umol, 11.03 uL), dppf (9.64 mg, 17.38 umol), Zn (1.14 mg, 17.38 umol) and Pd₂(dba)₃(15.92 mg, 17.38 umol) were taken up in a microwave tube in DMA (2 mL) under N₂. The sealed tube was heated at 150° C. for 1 hr under microwave irradiation. The reaction mixture was poured into saturated aqueous NaHCO₃(15 mL) and extracted with EtOAc (15 mL×3). The combined organic phases were washed with brine (15 mL×1), dried over Na₂SO₄, filtered and concentrated to give a residue. The residue was purified by preparative HPLC using Method BJ to afford the title compound (19.52 mg, 28%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.19 (br s, 1H), 10.57 (s, 1H), 8.69 (s, 1H), 8.41 (s, 1H), 8.28 (s, 1H), 8.14-7.90 (m, 1H), 7.78 (d, J=8.1 Hz, 1H), 7.70-7.52 (m, 2H), 7.38 (d, J=8.0 Hz, 1H), 2.49 (m, 3H), 2.40 (s, 3H). MS-ESI (m/z) calc'd for C₂₁H₁₇F₂N₆O [M+H]⁺: 407.1. Found 407.2.

Example 194: 3-Cyano-N-(3-(2-methoxypyridin-4-yl)-1H-indazol-5-yl)-1,4-dimethyl-1H-pyrazole-5-carboxamide

embedded image

Prepared as described for 3-cyano-N-(3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-1H-indazol-5-yl)-1,4-dimethyl-1H-pyrazole-5-carboxamide using 3-(2-methoxypyridin-4-yl)-1H-indazol-5-amine in place of 3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-1H-indazol-5-amine to afford the title compound (24.46 mg, 28%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.59 (s, 1H), 8.30 (d, J=5.51 Hz, 1H), 7.61-7.73 (m, 2H), 7.55 (d, J=5.29 Hz, 1H), 7.29 (s, 1H), 4.03-4.07 (s, 3H), 3.93 (s, 3H), 2.31 (s, 3H). MS-ESI (m/z) calc'd for C₂₀H₁₈N₇O₂[M+H]⁺: 388.1. Found 388.2.

Example 195: 3-Cyano-N-(3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-1H-indazol-5-yl)-1,4-dimethyl-1H-pyrazole-5-carboxamide

embedded image

Step 1: Ethyl 3-cyano-4-methyl-1H-pyrazole-5-carboxylate

embedded image

To a solution of ethyl but-2-ynoate (2.5 g, 22.30 mmol) in CHCl₃(60 mL) and H₂O (2 mL) was added 2-aminoacetonitrile (3.71 g, 40.13 mmol, HCl salt) and NaNO₂(4.61 g, 66.89 mmol). The mixture was stirred at 30° C. for 12 hrs, then warmed to 60° C. for another 12 hrs. The reaction mixture was quenched by addition of H₂O (20 mL) at 25° C. and the layers were separated. The organic layers were washed with H₂O (20 mL×1), dried over Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO; 20 g SepaFlash column) using a 0-30% EtOAc/petroleum ether gradient eluent to afford the title compound (170 mg, 4%) as a yellow oil. MS-ESI (m/z) calcd for C₈H₁₀N₃O₂[M+H]⁺: 180.1 Found 180.0.

Step 2: Ethyl 3-cyano-1,4-dimethyl-1H-pyrazole-5-carboxylate

embedded image

To a solution of ethyl 3-cyano-4-methyl-1H-pyrazole-5-carboxylate (100 mg, 558.11 umol) in DMF (1 mL) was added K₂CO₃(231.40 mg, 1.67 mmol). The mixture was stirred at 25° C. for 0.5 hr. Then MeI (95.06 mg, 669.73 umol) was added and the mixture was stirred at 25° C. for 11.5 hrs. The reaction mixture was concentrated under reduced pressure to give a residue which was diluted with H₂O (10 mL) and extracted with EtOAc (5 mL×3). The combined organic layers were dried over Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO₂, 5:1 petroleum ether/EtOAc, R_f=0.40) to afford the title compound (60 mg, 56%) as a white solid. MS-ESI (m/z) calcd for C₉H₁₂N₃O₂[M+H]⁺: 194.1. Found 194.1.

Step 3: 3-Cyano-1,4-dimethyl-1H-pyrazole-5-carboxylic acid

embedded image

To a solution of ethyl 3-cyano-1,4-dimethyl-1H-pyrazole-5-carboxylate (60 mg, 310.56 umol) in THF (1 mL) and H₂O (1 mL) was added NaOH (24.84 mg, 621.11 umol) and the mixture was stirred at 30° C. for 2 hrs. To the reaction mixture was added 1 N HCl to adjust to pH=2. The mixture was then diluted with H₂O (2 mL) and extracted with EtOAc (5 mL×3). The combined organic layers were dried over Na₂SO₄, filtered and concentrated under reduced pressure to afford the title compound (40 mg, 78%) as a white solid, which was used without further purification.

Step 4: 3-Cyano-N-(3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-1H-indazol-5-yl)-1,4-dimethyl-1H-pyrazole-5-carboxamide

embedded image

To a solution of 3-cyano-1,4-dimethyl-1H-pyrazole-5-carboxylic acid (35 mg, 211.93 umol), 3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-1H-indazol-5-amine (63.38 mg, 254.32 umol) in pyridine (1 mL) was added EDCI (60.94 mg, 317.89 umol) and the mixture was stirred at 30° C. for 2 hrs. The reaction mixture was concentrated and purified by preparative HPLC using Method BU to afford the title compound (14.73 mg, 18%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.24 (br s, 1H), 10.58 (s, 1H), 8.72 (s, 1H), 8.37 (s, 1H), 8.29 (s, 1H), 7.75-8.12 (m, 1H), 7.61 (s, 2H), 4.04 (s, 3H), 2.32 (s, 3H). MS-ESI (m/z) calc'd for C₁₈H₁₅F₂N₅O [M+H]⁺: 397.1. Found 397.2.

Example 196: 3-Cyano-N-(3-(isoxazol-4-yl)-1H-indazol-5-yl)-1,4-dimethyl-1H-pyrazole-5-carboxamide

embedded image

Prepared as described for 3-cyano-N-(3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-1H-indazol-5-yl)-1,4-dimethyl-1H-pyrazole-5-carboxamide using 3-(isoxazol-4-yl)-1H-indazol-5-amine in place of 3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-1H-indazol-5-amine to afford the title compound (100 mg, 29%) as a pale pink solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.36 (s, 1H), 10.57 (s, 1H), 9.54 (s, 1H), 9.13 (s, 1H), 8.31 (s, 1H), 7.61 (s, 2H), 4.04 (s, 3H), 2.31 (s, 3H). MS-ESI (m/z) calc'd for C₁₇H₁₄N₇O₂[M+H]⁺: 348.1. Found 348.1.

Example 197: 5-Cyano-3,4-dimethyl-N-(3-(4-methyloxazol-2-yl)-1H-indazol-5-yl)picolinamide

embedded image

Prepared as described for 5-cyano-3,4-dimethyl-N-(3-(2-methylpyrimidin-4-yl)-1H-indazol-5-yl)picolinamide using 4-methyl-2-(trimethylstannyl)oxazole in place of trimethyl-(2-methylpyrimidin-4-yl)stannane to afford the title compound (4 mg, 23%) as a pale yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.64 (s, 1H), 10.80 (s, 1H), 8.90 (s, 1H), 8.77-8.70 (m, 1H), 7.95 (q, J=1.1 Hz, 1H), 7.78 (dd, J=9.0, 2.0 Hz, 1H), 7.65 (dd, J=9.0, 0.8 Hz, 1H), 2.56 (s, 3H), 2.45 (s, 3H), 2.24 (d, J=1.3 Hz, 3H). MS-ESI (m/z) calc'd for C₂₀H₁₇N₆O₂[M+H]⁺: 373.1. Found 373.3.

Example 198: 5-Cyano-3,4-dimethyl-N-(3-(oxazol-2-yl)-1H-indazol-5-yl)picolinamide

embedded image

Prepared as described for 5-cyano-3,4-dimethyl-N-(3-(2-methylpyrimidin-4-yl)-1H-indazol-5-yl)picolinamide using 2-(trimethylstannyl)oxazole in place of trimethyl-(2-methylpyrimidin-4-yl)stannane to afford the title compound (12.2 mg, 9%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.67 (s, 1H), 10.79 (s, 1H), 8.90 (s, 1H), 8.89-8.86 (m, 1H), 8.27 (d, J=0.8 Hz, 1H), 7.72 (dd, J=9.0, 1.9 Hz, 1H), 7.65 (dd, J=9.0, 0.8 Hz, 1H), 7.50 (d, J=0.8 Hz, 1H), 2.56 (s, 3H), 2.46 (s, 3H). MS-ESI (m/z) calc'd for C₁₉H₁₅N₆O₂[M+H]⁺: 359.1. Found 359.2.

Example 199: 3-Cyano-2-fluoro-N-(3-(oxazol-5-yl)-1H-indazol-5-yl)benzamide

embedded image

Prepared as described for 5-cyano-N-(7-fluoro-3-(furan-3-yl)-1H-indazol-5-yl)-3-methylpicolinamide using 3-cyano-2-fluorobenzoic acid in place of 5-cyano-3-methylpicolinic acid and using 3-(oxazol-5-yl)-1H-indazol-5-amine in place of 7-fluoro-3-(furan-3-yl)-1H-indazol-5-amine to afford the title compound (1.75 mg, 3%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 10.11 (dd, J=1.9, 0.8 Hz, 1H), 9.95 (s, 1H), 9.64 (ddd, J=8.4, 7.0, 1.8 Hz, 1H), 9.52 (ddd, J=7.8, 6.1, 1.8 Hz, 1H), 9.30-8.99 (m, 4H). MS-ESI (m/z) calc'd for C₁₈H₁₁FN₅O₂[M+H]⁺: 348.1. Found 348.1.

Example 200: 4-Cyano-2-methoxy-N-(3-(oxazol-5-yl)-1H-indazol-5-yl)benzamide

embedded image

Prepared as described for 5-cyano-N-(7-fluoro-3-(furan-3-yl)-1H-indazol-5-yl)-3-methylpicolinamide using 4-cyano-2-methoxybenzoic acid in place of 5-cyano-3-methylpicolinic acid and using 3-(oxazol-5-yl)-1H-indazol-5-amine in place of 7-fluoro-3-(furan-3-yl)-1H-indazol-5-amine to afford the title compound (18.4 mg, 45%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.49 (br. s., 1H) 10.41 (s, 1H) 8.57-8.59 (m, 1H) 8.55 (d, J=0.88 Hz, 1H) 7.76 (d, J=7.70 Hz, 1H) 7.71 (d, J=1.32 Hz, 1H) 7.59-7.67 (m, 3H) 7.56 (dd, J=7.70, 1.32 Hz, 1H) 3.95 (s, 3H). MS-ESI (m/z) calc'd for C₁₉H₁₄N₅O₃[M+H]⁺: 360.1. Found 360.3.

Example 201: 4-Cyano-N-(3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-1H-indazol-5-yl)-2-methoxy-6-methylbenzamide

embedded image

Prepared as described for 4-cyano-N-(3-(isoxazol-4-yl)-1H-indazol-5-yl)-3-methoxypicolinamide using 4-chloro-2-methoxy-6-methyl-N-(3-(oxazol-5-yl)-1H-indazol-5-yl)benzamide in place of 4-chloro-3-methoxy-N-[3-(1,2-oxazol-4-yl)-1H-indazol-5-yl]pyridine-2-carboxamide to afford the title compound (29.4 mg, 47%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.18 (br. s., 1H) 10.49 (s, 1H) 8.67 (s, 1H) 8.43 (d, J=1.10 Hz, 1H) 8.27 (s, 1H) 7.77-8.12 (m, 1H) 7.61-7.66 (m, 1H) 7.54-7.59 (m, 1H) 7.49 (s, 1H) 7.44 (s, 1H) 3.85 (s, 3H) 2.33 (s, 3H). MS-ESI (m/z) calc'd for C₂₁H₁₇F₂N₆O₂[M+H]⁺: 423.1. Found 432.3.

Example 202: 5-Cyano-3,4,6-trimethyl-N-(3-(oxazol-5-yl)-1H-indazol-5-yl)picolinamide

embedded image

Prepared as described for 5-cyano-N-(7-fluoro-3-(furan-3-yl)-1H-indazol-5-yl)-3-methylpicolinamide using 5-cyano-3,4,6-trimethylpicolinic acid in place of 5-cyano-3-methylpicolinic acid and using 3-(oxazol-5-yl)-1H-indazol-5-amine in place of 7-fluoro-3-(furan-3-yl)-1H-indazol-5-amine to afford the title compound (20.5 mg, 35%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.54 (s, 1H), 10.72 (s, 1H), 8.59 (s, 1H), 8.57 (d, J=1.6 Hz, 1H), 7.73 (dd, J=9.0, 1.9 Hz, 1H), 7.63 (m, 2H), 2.72 (s, 3H), 2.54 (s, 3H), 2.41 (s, 3H). MS-ESI (m/z) calc'd for C₂₀H₁₇N₆O₂[M+H]⁺: 373.3. Found 373.3.

Example 203: 3-Cyano-2-fluoro-6-methyl-N-(3-(oxazol-5-yl)-1H-indazol-5-yl)benzamide

embedded image

Step 1: 3-Bromo-2-fluoro-6-methyl-N-(3-(oxazol-5-yl)-1H-indazol-5-yl)benzamide

embedded image

To a solution of 3-(oxazol-5-yl)-1H-indazol-5-amine (100 mg, 499.51 umol) and 3-bromo-2-fluoro-6-methylbenzoic acid (139.68 mg, 599.41 umol) in pyridine (2 mL) was added EDCI (143.64 mg, 749.27 umol) and the mixture was stirred at 25° C. for 12 hrs. The reaction mixture was concentrated under reduced pressure to remove solvent and then diluted with H₂O (5 mL) and filtered. The solid was washed with H₂O (10 mL) and dried in vacuum to afford the title compound (142 mg) as a red solid which was used without further purification. MS-ESI (m/z) calcd for C₁₅H₁₃BrFN₄O₂[M+H]⁺: 415.0/417.0. Found 415.0/417.0.

Step 2: 3-Cyano-2-fluoro-6-methyl-N-(3-(oxazol-5-yl)-1H-indazol-5-yl)benzamide

embedded image

A mixture of 3-bromo-2-fluoro-6-methyl-N-(3-(oxazol-5-yl)-1H-indazol-5-yl)benzamide (70 mg, 168.59 umol), Zn(CN)₂(39.59 mg, 337.17 umol), Zn (992.15 ug, 15.17 umol), dppf (2.80 mg, 5.06 umol) and Pd₂(dba)₃(9.26 mg, 10.12 umol) in DMA (1 mL) was degassed and purged with N₂(3×), and then the mixture was stirred at 120° C. for 5 hrs under an N₂atmosphere in a microwave reactor. The reaction mixture was concentrated and purified by preparative HPLC using Method CJ to afford the title compound (8.54 mg, 11%) as a white solid, TFA salt. ¹H NMR (400 MHz, DMSO-d₆) δ 13.54 (s, 1H), 10.65 (s, 1H), 8.59 (s, 1H), 8.52 (s, 1H), 7.97 (t, J=7.72 Hz, 11H), 7.60-7.71 (m, 3H), 7.47 (d, J=8.16 Hz, 11H), 2.58 (s, 3H). MS-ESI (m/z) calc'd for C₁₉H₁₃FN₅O₂[M+H]⁺: 362.1. Found 362.0.

Example 204: 5-Cyano-N-(3-(1-(difluoromethyl)-1H-pyrazol-3-yl)-1H-indazol-5-yl)-3,4-dimethylpicolinamide

embedded image

Prepared as described for 5-cyano-3,4-dimethyl-N-(3-(2-methylprop-1-en-1-yl)-1H-indazol-5-yl)picolinamide using 1-(difluoromethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole in place of 4,4,5,5-tetramethyl-2-(2-methylprop-1-en-1-yl)-1,3,2-dioxaborolane to afford the title compound (4.47 mg, 6%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.33 (br s, 1H) 10.74 (s, 1H) 8.88 (s, 1H) 8.63 (s, 1H) 8.34 (d, J=2.57 Hz, 1H) 7.74-8.06 (m, 2H) 7.59 (d, J=8.80 Hz, 1H) 6.98 (d, J=2.57 Hz, 1H) 2.55 (s, 3H) 2.44 (s, 3H). MS-ESI (m/z) calc'd for C₂₀H₁₆F₂N₇O [M+H]⁺: 408.1 Found 408.0.

Example 205: 5-Cyano-N-(3-(2-ethoxypyridin-4-yl)-1H-indazol-5-yl)-3,4-dimethylpicolinamide

embedded image

Prepared as described for 5-cyano-3,4-dimethyl-N-(3-(2-methylprop-1-en-1-yl)-1H-indazol-5-yl)picolinamide using 2-ethoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine in place of 4,4,5,5-tetramethyl-2-(2-methylprop-1-en-1-yl)-1,3,2-dioxaborolane to afford the title compound (45.33 mg, 15%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.59 (s, 1H) 10.81 (s, 1H) 8.90 (s, 1H) 8.62 (s, 1H) 8.28 (d, J=5.26 Hz, 1H) 7.86 (dd, J=8.99, 1.41 Hz, 1H) 7.65 (d, J=9.05 Hz, 1H) 7.55 (d, J=5.38 Hz, 1H) 7.27 (s, 1H) 4.38 (q, J=7.05 Hz, 2H) 2.56 (s, 3H) 2.46 (s, 3H) 1.36 (t, J=7.03 Hz, 3H). MS-ESI (m/z) calc'd for C₂₃H₂₁N₆O₂[M+H]⁺: 413.2 Found 413.0.

Example 206: 4-Cyano-N-(3-(oxazol-5-yl)-1H-indazol-5-yl)-6,7-dihydro-5H-cyclopenta[c]pyridine-1-carboxamide

embedded image

Prepared as described for 5-cyano-N-(7-fluoro-3-(furan-3-yl)-1H-indazol-5-yl)-3-methylpicolinamide using 4-cyano-6,7-dihydro-5H-cyclopenta[c]pyridine-1-carboxylic acid in place of 5-cyano-3-methylpicolinic acid and using 3-(oxazol-5-yl)-1H-indazol-5-amine in place of 7-fluoro-3-(furan-3-yl)-1H-indazol-5-amine to afford the title compound (6 mg, 8.1%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.51 (s, 1H), 10.82 (s, 1H), 8.95 (s, 1H), 8.65 (d, J=1.9 Hz, 1H), 8.59 (s, 1H), 7.93 (dd, J=9.1, 1.9 Hz, 1H), 7.67 (s, 1H), 7.61 (d, J=9.0 Hz, 1H), 3.43 (t, J=7.6 Hz, 2H), 3.16 (t, J=7.7 Hz, 2H), 2.16 (p, J=7.7 Hz, 2H). MS-ESI (m/z) calc'd for C₂₀H₁₅N₆O₂[M+H]⁺: 371.1. Found 371.2.

Example 207: 5-Cyano-3,4-dimethyl-N-(3-(5-methyloxazol-2-yl)-1H-indazol-5-yl)picolinamide

embedded image

Prepared as described for 5-cyano-3,4-dimethyl-N-(3-(2-methylpyrimidin-4-yl)-1H-indazol-5-yl)picolinamide using 5-methyl-2-(trimethylstannyl)oxazole in place of trimethyl-(2-methylpyrimidin-4-yl)stannane to afford the title compound (9.5 mg, 26%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.63 (s, 1H), 10.75 (s, 1H), 8.88 (s, 1H), 8.80 (d, J=1.9 Hz, 1H), 7.69 (dd, J=9.0, 2.0 Hz, 1H), 7.62 (d, J=8.9 Hz, 1H), 7.08 (d, J=1.3 Hz, 1H), 2.55 (s, 3H), 2.44 (s, 3H), 2.43 (d, J=1.2 Hz, 3H). MS-ESI (m/z) calc'd for C₂₀Hi-N₆O₂[M+H]⁺: 373.1. Found 373.3.

Example 208: 4-Cyano-2-methoxy-6-methyl-N-(3-(oxazol-5-yl)-1H-indazol-5-yl)benzamide

embedded image

Prepared as described for 4-cyano-N-(3-(isoxazol-4-yl)-1H-indazol-5-yl)-3-methoxypicolinamide using 4-chloro-2-methoxy-6-methyl-N-(3-(oxazol-5-yl)-1H-indazol-5-yl)benzamide in place of 4-chloro-3-methoxy-N-[3-(1,2-oxazol-4-yl)-1H-indazol-5-yl]pyridine-2-carboxamide to afford the title compound (9.6 mg, 18%) as an off-white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.52 (br. s., 1H) 10.56 (s, 1H) 8.53-8.62 (m, 2H) 7.58-7.65 (m, 3H) 7.49 (s, 1H) 7.44 (s, 1H) 3.86 (s, 3H) 2.32 (s, 3H). MS-ESI (m/z) calc'd for C₂₀H₁₆N₅O₃[M+H]⁺: 374.1. Found 374.3.

Example 210: 5-Cyano-N-(3-(isoxazol-4-yl)-1H-indazol-5-yl)-3,4,6-trimethylpicolinamide

embedded image

Prepared as described for 5-cyano-N-(7-fluoro-3-(furan-3-yl)-1H-indazol-5-yl)-3-methylpicolinamide using 5-cyano-3,4,6-trimethylpicolinic acid in place of 5-cyano-3-methylpicolinic acid and using 3-(isoxazol-4-yl)-1H-indazol-5-amine in place of 7-fluoro-3-(furan-3-yl)-1H-indazol-5-amine to afford the title compound (7.1 mg, 12%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.37 (s, 1H), 10.65 (s, 1H), 9.56 (s, 1H), 9.15 (s, 1H), 8.37 (dd, J=1.9, 0.8 Hz, 1H), 7.74 (dd, J=9.0, 1.9 Hz, 1H), 7.61 (dd, J=9.0, 0.8 Hz, 1H), 2.72 (s, 3H), 2.55 (s, 3H), 2.42 (s, 3H). MS-ESI (m/z) calc'd for C₂₀H₁₇N₆O₂[M+H]⁺: 373.3. Found 373.3.

Example 211: 5-Cyano-4-methoxy-3-methyl-N-(3-(oxazol-5-yl)-1H-indazol-5-yl)picolinamide

embedded image

Prepared as described for 5-cyano-N-(7-fluoro-3-(furan-3-yl)-1H-indazol-5-yl)-3-methylpicolinamide using 5-cyano-4-methoxy-3-methylpicolinic acid in place of 5-cyano-3-methylpicolinic acid and using 3-(oxazol-5-yl)-1H-indazol-5-amine in place of 7-fluoro-3-(furan-3-yl)-1H-indazol-5-amine to afford the title compound (12.7 mg, 17%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.53 (s, 1H), 10.75 (s, 1H), 8.85 (d, J=0.7 Hz, 1H), 8.58 (s, 2H), 7.76 (dd, J=9.0, 1.9 Hz, 1H), 7.64 (s, 1H), 7.62 (dd, J=9.0, 0.8 Hz, 1H), 4.27 (s, 3H), 2.39 (s, 3H). MS-ESI (m/z) calc'd for C₁₉H₁₅N₆O₃[M+H]⁺: 375.1. Found 375.2.

Example 212: 3-Cyano-N-(3-(oxazol-5-yl)-1H-indazol-5-yl)-2-(trifluoromethoxy)benzamide

embedded image

Step 1: 3-Bromo-2-(trifluoromethoxy)benzoic acid

embedded image

To a solution of 1-bromo-2-(trifluoromethoxy)benzene (500 mg, 2.07 mmol) in THF (3 mL) was added LDA (2 M in THF, 1.14 mL, 2.28 mmol). The mixture was stirred at −65° C. for 2 hrs and then dry ice (CO₂solid, more than 10 eq) was added and the mixture was stirred at 25° C. for 10 hrs. The reaction mixture was diluted with 2 M NaOH to pH=12 and extracted with EtOAc (15 mL 3). The organic layers were discarded. To the aqueous layer was added 6 M HCl to pH=4 and the aqueous layers were extracted with EtOAc (15 mL×3). The combined organic layers were dried over Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC using Method CK to afford the title compound (75 mg, 13%) as a colorless oil. MS-ESI (m/z) calcd for C₈H₅BrF₃O₃[M−H]⁻: 282.9/284.9. Found 282.8/284.8.

Step 2: 3-Bromo-N-(3-(oxazol-5-yl)-1H-indazol-5-yl)-2-(trifluoromethoxy)benzamide

embedded image

To a solution of 3-bromo-2-(trifluoromethoxy)benzoic acid (65 mg, 228.06 umol) in pyridine (5 mL) was added EDCI (87.44 mg, 456.12 umol) and 3-(oxazol-5-yl)-1H-indazol-5-amine (54.79 mg, 273.67 umol) and the mixture was stirred at 25° C. for 2 hrs. The mixture was then concentrated to give a residue which was diluted with water (5 mL). A red solid formed that was collected by filtration, washed with H₂O (3 mL×3), and dried under vacuum to afford the title compound (111 mg) as a red solid which was used without further purification. MS-ESI (m/z) calcd for C₁₅H₁₁BrF₃N₄O₃[M−H]⁺: 467.0/469.0. Found 467.1/469.1.

Step 3: 3-Cyano-N-(3-(oxazol-5-yl)-1H-indazol-5-yl)-2-(trifluoromethoxy)benzamide

embedded image

A mixture of 3-bromo-N-(3-(oxazol-5-yl)-1H-indazol-5-yl)-2-(trifluoromethoxy)benzamide (100 mg, 214.04 umol), Zn(CN)₂(25.13 mg, 214.04 umol) and Pd(PPh₃)₄(24.73 mg, 21.40 umol) in DMF (5 mL) was degassed and purged with N₂(3×), and then the mixture was stirred at 100° C. for 2 hrs under an N₂atmosphere. The reaction was filtered and the filtrate was concentrated to give a residue. The residue was purified by preparative HPLC using Method CL to afford the title compound (6.32 mg, 5%) as a pale yellow solid, TFA salt. ¹H NMR (400 MHz, DMSO-d₆) δ 13.48 (br s, 1H), 10.74 (s, 1H), 8.52 (s, 1H), 8.40 (s, 1H), 8.03-8.21 (m, 2H), 7.74 (t, J=7.83 Hz, 1H), 7.46-7.59 (m, 3H). MS-ESI (m/z) calc'd for C₁₉H₁₁F₃N₅O₃[M+H]⁺: 414.1. Found 413.9.

Example 213: 5-Cyano-1,2-dimethyl-N-(3-(oxazol-5-yl)-1H-indazol-5-yl)-6-oxo-1,6-dihydropyridine-3-carboxamide

embedded image

Step 1: Ethyl 2-((dimethylamino)methylene)-3-oxobutanoate

embedded image

To a solution of ethyl 3-oxobutanoate (10 g, 76.84 mmol) in EtOH (50 mL) was added DMF-DMA (9.61 g, 80.68 mmol) and the mixture was stirred at 60° C. for 2 hrs. The reaction mixture was concentrated to afford the title compound (13.14 g, 100%) as a red oil which was used without further purification.

Step 2: Ethyl 5-cyano-2-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate

embedded image

A solution of NaOEt was prepared by adding Na (902.35 mg, 39.25 mmol) to EtOH (15 mL) at 25° C. and stirring for 0.5 hr. This was then added to another solution of 2-cyanoacetamide (3 g, 35.68 mmol) in EtOH (30 mL) slowly at 25° C. After addition, a solution of ethyl 2-((dimethylamino)methylene)-3-oxobutanoate (7.27 g, 39.25 mmol) in EtOH (10 mL) was added to the mixture and stirring was continued at 20° C. for 12 hrs. The mixture was acidified by addition of AcOH (5 g) to pH=5 and concentrated under vacuum at 45° C. 1 N HCl (50 mL) was added and the precipitated product was filtered, washed with H₂O (20 mL×2) and dried under vacuum to afford the title compound (4 g, 58%) as a pink solid which was used without further purification. MS-(ESI) (m/z) calcd for C₁₀H₁₁N₂O₃(M+H)⁺: 207.1. Found 207.0

Step 3: Ethyl 5-cyano-1,2-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylate

embedded image

To a solution of ethyl 5-cyano-2-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate (500 mg, 2.42 mmol) in DMF (12 mL) was added K₂CO₃(402.16 mg, 2.91 mmol) and MeI (344.18 mg, 2.42 mmol) and the mixture was stirred at 20° C. for 2 hrs. The reaction mixture was then diluted with H₂O (30 mL) and extracted with EtOAc (15 mL×5). The combined organic layers were dried over Na₂SO₄, filtered and concentrated to give a residue which was purified by flash silica gel chromatography (ISCO; 12 g SepaFlash column) using a 0-30% EtOAc/petroleum ether gradient eluent to afford the title compound (370 mg, 69%) as a yellow solid. MS-(ESI) (m/z) calcd for C₁₁H₁₃N₂O₃(M+H)⁺: 221.1. Found 221.0.

Step 4: 5-Cyano-1,2-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid

embedded image

To a solution of ethyl 5-cyano-1,2-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylate (150 mg, 681.12 umol) in THF (4 mL) and MeOH (1 mL) was added a 1 M aqueous LiOH solution (2.04 mL, 0.002 mol) and the mixture was stirred at 20° C. for 1 hr. The reaction mixture was acidified with 1 N HCl to pH=2 and extracted with EtOAc (10 mL×3). The combined organic layers were dried over Na₂SO₄, filtered and concentrated to afford the title compound (100 mg, 76%) as a light yellow solid which was used without further purification. MS-(ESI) (m/z) calcd for C₉H₉N₂O₃(M+H)⁺: 193.1. Found 193.0.

Step 5: 5-Cyano-1,2-dimethyl-N-(3-(oxazol-5-yl)-1H-indazol-5-yl)-6-oxo-1,6-dihydropyridine-3-carboxamide

embedded image

To a solution of 5-cyano-1,2-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid (50 mg, 260.18 umol) in pyridine (2 mL) was added EDCI (74.82 mg, 390.28 umol) and 3-(oxazol-5-yl)-1H-indazol-5-amine (52.09 mg, 260.18 umol) and the mixture was stirred at 25° C. for 2 hrs. The reaction mixture was concentrated to give a residue which was diluted with MeOH (2 mL). A solid formed that was collected by filtration and washed with MeOH (2 mL×3). The solid was dried under vacuum and purified by preparative HPLC using Method CN to afford the title compound (35.56 mg, 28%) as a yellow solid, TFA salt. ¹H NMR (400 MHz, DMSO-d₆) δ 13.51 (s, 1H) 10.47 (s, 1H) 8.59 (s, 1H) 8.48 (s, 1H) 8.40 (s, 1H) 7.60-7.69 (m, 3H) 3.60 (s, 3H) 2.65 (s, 3H). MS-ESI (m/z) calc'd for C₁₉H₁₅N₆O₃[M+H]⁺: 375.1. Found 375.1.

Example 214: 3-Cyano-N-(3-(oxazol-5-yl)-1H-indazol-5-yl)-2-(prop-1-en-2-yl)benzamide

embedded image

Step 1: Ethyl 3-cyano-2-iodobenzoate

embedded image

To a solution of ethyl 3-cyanobenzoate (500 mg, 2.85 mmol) in THF (6 mL) was added TMPMgCl.LiCl (1 M in THF/toluene, 4.28 mL, 4.28 mmol) and the mixture was stirred at 25° C. for 1 hr. Then a solution of I₂(869.29 mg, 3.42 mmol, 689.91 uL) in THF (5 mL) was added and the reaction mixture was stirred at 25° C. for an additional 1 hr. The reaction mixture was poured into water (10 mL) and extracted with EtOAc (10 mL 3). The combined organic phases were washed with brine (10 mL×1), dried over Na₂SO₄, filtered and concentrated to give a residue. The residue was purified by silica gel column chromatography using a 0-20% EtOAc/petroleum ether gradient eluent to afford the title compound (450 mg, 52%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 7.86 (d, J=8.0 Hz, 1H), 7.68 (d, J=7.6 Hz, 1H), 7.53 (t, J=8.0 Hz, 1H), 4.43 (q, J=7.2 Hz, 2H), 1.43 (t, J=7.2 Hz, 3H).

Step 2: Ethyl 3-cyano-2-vinylbenzoate

embedded image

A mixture of ethyl 3-cyano-2-iodobenzoate (210 mg, 697.49 umol), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (175.81 mg, 1.05 mmol), Pd(Amphos)Cl₂(49.39 mg, 69.75 umol) and KOAc (205.35 mg, 2.09 mmol) in EtOH (2 mL) and H₂O (0.2 mL) was degassed and purged with N₂(3×), and then the mixture was stirred at 50° C. for 12 hrs under an N₂atmosphere. The reaction mixture was concentrated to give a residue. The residue was purified by silica gel column chromatography using a 0-20% EtOAc/petroleum ether gradient eluent to afford the title compound (120 mg, 80%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.03 (d, J=8.0 Hz, 1H), 7.79 (d, J=6 Hz, 1H), 7.45 (t, J=8.0 Hz, 1H), 5.36 (s, 1H) 4.95 (s, 1H), 4.35 (q, J=7.2 Hz, 2H), 2.20 (s, 3H), 1.37 (t, J=7.2 Hz, 3H).

Step 3: 3-Cyano-2-vinylbenzoic acid

embedded image

To a solution of ethyl 3-cyano-2-vinylbenzoate (210 mg, 975.62 umol) in THF (2 mL) and H₂O (2 mL) was added LiOH.H₂O (81.87 mg, 1.95 mmol) and the mixture was stirred at 25° C. for 12 hrs. The reaction mixture was adjusted to pH=7 with 1 N HCl. The aqueous phase was extracted with dichloromethane (15 mL×3) and the combined organic phases were washed with brine (15 mL×1), dried over Na₂SO₄, filtered and concentrated to afford the title compound (158 mg, 93%) as a brown solid which was used without further purification. MS-ESI (m/z) calcd for C₁₁H₁₀NO₂[M−H]⁻: 186.1. Found 186.0

Step 4: 3-Cyano-N-(3-(oxazol-5-yl)-1H-indazol-5-yl)-2-(prop-1-en-2-yl)benzamide

embedded image

To a solution of 3-cyano-2-vinylbenzoic acid (50 mg, 267.10 umol) in DMF (2 mL) was added HOBt (43.31 mg, 320.52 umol), EDCI (61.44 mg, 320.52 umol) and Et₃N (81.08 mg, 801.31 umol, 111.53 uL) and the mixture was stirred at 25° C. for 0.5 hr. Then 3-(oxazol-5-yl)-1H-indazol-5-amine (53.47 mg, 267.10 umol) was added and the reaction mixture was stirred at 25° C. for 12 hrs. The reaction mixture was poured into water (5 mL) and extracted with EtOAc (5 mL×3). The combined organic phases were washed with brine (5 mL×1), dried over Na₂SO₄, filtered and concentrated to give a residue. The residue was purified by preparative HPLC using Method CG to afford the title compound (60 mg, 60%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.49 (br s, 1H), 10.51 (s, 1H), 8.58 (s, 1H), 8.48 (s, 1H), 7.99 (dd, J=1.1, 7.7 Hz, 1H), 7.89 (dd, J=1.2, 7.7 Hz, 1H), 7.67-7.62 (m, 1H), 7.60 (d, J=2.7 Hz, 3H), 5.36 (s, 1H), 5.05 (s, 1H), 2.13 (s, 3H). MS-ESI (m/z) calc'd for C₂₁H₁₆NO₂[M+H]⁺: 370.1. Found 370.2.

Example 215: 5-Cyano-3,4-dimethyl-N-(3-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-1H-indazol-5-yl)picolinamide

embedded image

Prepared as described for 5-cyano-N-(3-(isoxazol-4-yl)-1H-indazol-5-yl)-3-methylpicolinamide using (1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)boronic acid in place of isoxazole-4-boronic acid and 5-cyano-N-(3-iodo-1H-indazol-5-yl)-3,4-dimethylpicolinamide in place of 5-cyano-N-(3-iodo-1H-indazol-5-yl)-3-methylpyridine-2-carboxamide to afford the title compound (22 mg, 46%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 12.95 (br. s., 1H) 10.64 (s, 1H) 8.90 (s, 1H) 8.39 (d, J=1.32 Hz, 1H) 8.26 (s, 1H) 8.18 (s, 1H) 7.94 (s, 1H) 7.75 (dd, J=9.02, 1.76 Hz, 1H) 7.53 (d, J=8.80 Hz, 1H) 4.20-4.32 (m, 1H) 2.85-2.95 (m, 2H) 2.56 (s, 3H) 2.48 (s, 3H) 2.24 (s, 3H) 2.01-2.15 (m, 6H). MS-ESI (m/z) calc'd for C₂₅H₂₇N₅O [M+H]⁺: 455.2. Found 455.2.

Example 216: 6-Chloro-5-cyano-N-(3-(isoxazol-4-yl)-1H-indazol-5-yl)-3,4-dimethylpicolinamide

embedded image

Prepared as described for 5-cyano-N-(7-fluoro-3-(furan-3-yl)-1H-indazol-5-yl)-3-methylpicolinamide using 6-chloro-5-cyano-3,4-dimethylpicolinic acid in place of 5-cyano-3-methylpicolinic acid and using 3-(isoxazol-4-yl)-1H-indazol-5-amine in place of 7-fluoro-3-(furan-3-yl)-1H-indazol-5-amine to afford the title compound (7.3 mg, 16%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.37 (br. s., 1H) 10.74 (br. s., 1H) 9.57 (s, 1H) 9.15 (s, 1H) 8.34 (d, J=1.10 Hz, 1H) 7.67-7.73 (m, 1H) 7.58-7.66 (m, 1H) 2.61 (s, 3H) 2.42 (s, 3H). MS-ESI (m/z) calc'd for C₁₉H₁₄ClN₆O₂[M+H]⁺: 393.1/395.1. Found 393.2/395.3.

Example 217: 5-Cyano-N-(3-(1-isopropyl-1H-pyrazol-4-yl)-1H-indazol-5-yl)-3,4-dimethylpicolinamide

embedded image

Prepared as described for 5-cyano-N-(3-(isoxazol-4-yl)-1H-indazol-5-yl)-3-methylpicolinamide using (1-isopropyl-1H-pyrazol-4-yl)boronic acid in place of isoxazole-4-boronic acid and 5-cyano-N-(3-iodo-1H-indazol-5-yl)-3,4-dimethylpicolinamide in place of 5-cyano-N-(3-iodo-1H-indazol-5-yl)-3-methylpyridine-2-carboxamide to afford the title compound (15.5 mg, 40%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 12.95 (s, 1H) 10.65 (s, 1H) 8.90 (s, 1H) 8.38 (d, J=1.32 Hz, 1H) 8.24 (s, 1H) 7.93 (s, 1H) 7.75 (dd, J=9.13, 1.65 Hz, 1H) 7.53 (d, J=9.02 Hz, 1H) 4.56-4.69 (m, 1H) 2.56 (s, 3H) 2.47 (s, 3H) 1.50 (d, J=6.60 Hz, 6H). MS-ESI (m/z) calc'd for C₂₂H₂₂N₇O [M+H]⁺: 400.2. Found 400.3.

Example 219: 5-Cyano-N-(3-(2-methoxy-6-methylpyridin-4-yl)-1H-indazol-5-yl)-3,4-dimethylpicolinamide

embedded image

Prepared as described for 5-cyano-N-(3-(isoxazol-4-yl)-1H-indazol-5-yl)-3-methylpicolinamide using (2-methoxy-6-methylpyridin-4-yl)boronic acid in place of isoxazole-4-boronic acid and 3-cyano-2-fluoro-N-(3-iodo-1H-indazol-5-yl)benzamide in place of 5-cyano-N-(3-iodo-1H-indazol-5-yl)-3-methylpyridine-2-carboxamide to afford the title compound (2.1 mg, 4%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.54 (s, 1H), 10.77 (s, 1H), 8.90 (s, 1H), 8.59 (d, J=1.8 Hz, 1H), 7.86 (dd, J=9.0, 1.9 Hz, 1H), 7.64 (d, J=9.0 Hz, 1H), 7.43 (d, J=1.2 Hz, 11H), 7.10 (s, 1H), 3.91 (s, 3H), 3.28 (s, 3H), 2.56 (s, 3H), 2.46 (s, 3H). MS-ESI (m/z) calc'd for C₂₃H₂N₆O₂[M+H]⁺: 413.2. Found 413.3.

Example 220: 2-Chloro-3-cyano-N-(3-(isoxazol-4-yl)-1H-indazol-5-yl)benzamide

embedded image

Prepared as described for 5-cyano-N-(7-fluoro-3-(furan-3-yl)-1H-indazol-5-yl)-3-methylpicolinamide using 2-chloro-3-cyanobenzoic acid in place of 5-cyano-3-methylpicolinic acid acid and using 3-(isoxazol-4-yl)-1H-indazol-5-amine in place of 7-fluoro-3-(furan-3-yl)-1H-indazol-5-amine to afford the title compound (9 mg, 13%) as a light brown solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.36 (s, 1H) 10.72 (s, 1H) 9.52 (s, 1H) 9.13 (s, 1H) 8.35 (s, 1H) 8.13 (dd, J=7.92, 1.54 Hz, 1H) 7.98 (dd, J=7.70, 1.76 Hz, 1H) 7.71 (t, J=7.70 Hz, 1H) 7.63 (s, 2H). MS-ESI (m/z) calc'd for C₁₅H₁₁ClN₅O₂[M+H]⁺: 364.1/366.1. Found 364.1/366.2.

Example 221: 5-Cyano-3,4-dimethyl-N-(3-(1-(oxetan-3-yl)-1H-pyrazol-4-yl)-1H-indazol-5-yl)picolinamide

embedded image

Prepared as described for 5-cyano-N-(3-(isoxazol-4-yl)-1H-indazol-5-yl)-3-methylpicolinamide using (1-(oxetan-3-yl)-1H-pyrazol-4-yl)boronic acid in place of isoxazole-4-boronic acid and 5-cyano-N-(3-iodo-1H-indazol-5-yl)-3,4-dimethylpicolinamide in place of 5-cyano-N-(3-iodo-1H-indazol-5-yl)-3-methylpyridine-2-carboxamide to afford the title compound (22.1 mg, 56%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.01 (s, 1H) 10.66 (s, 1H) 8.90 (s, 1H) 8.35-8.47 (m, 2H) 8.09 (s, 1H) 7.73 (dd, J=9.02, 1.54 Hz, 1H) 7.55 (d, J=8.80 Hz, 1H) 5.67-5.78 (m, 1H) 4.91-5.03 (m, 4H) 2.57 (s, 3H) 2.48 (s, 3H). MS-ESI (m/z) calc'd for C₂₂H₂₀N₇O₂[M+H]⁺: 414.2. Found 414.3.

Example 222: 5-Cyano-3,4,6-trimethyl-N-(3-(thiazol-5-yl)-1H-indazol-5-yl)picolinamide

embedded image

Prepared as described for 5-cyano-N-(7-fluoro-3-(furan-3-yl)-1H-indazol-5-yl)-3-methylpicolinamide using 5-cyano-3,4,6-trimethylpicolinic acid in place of 5-cyano-3-methylpicolinic acid and using 3-(thiazol-5-yl)-1H-indazol-5-amine in place of 7-fluoro-3-(furan-3-yl)-1H-indazol-5-amine to afford the title compound (12.3 mg, 17%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.42 (s, 1H), 10.71 (s, 1H), 9.15 (s, 1H), 8.59 (d, J=1.8 Hz, 1H), 8.40 (s, 1H), 7.77 (dd, J=9.0, 1.9 Hz, 1H), 7.63 (d, J=9.0 Hz, 1H), 2.41 (s, 3H), 2.72 (s, 3H), 2.54 (s, 3H). MS-ESI (m/z) calc'd for C₂₀H₁₇N₆OS [M+H]⁺: 389.1. Found 389.2.

Example 223: 5-Cyano-N-(3-cyclopropyl-1H-indazol-5-yl)-3,4-dimethylpicolinamide

embedded image

Step 1: 3-Cyclopropyl-5-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole

embedded image

To a solution of 3-iodo-5-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (300 mg, 803.98 umol) and cyclopropylboronic acid (103.59 mg, 1.21 mmol) in toluene (6 mL) and H₂O (0.4 mL) was added K₃PO₄(682.63 mg, 3.22 mmol) and Pd(PPh₃)₄(92.90 mg, 80.40 umol) and the mixture was stirred at 90° C. for 12 hrs under N₂. The reaction was concentrated and purified by flash silica gel chromatography (ISCO; 4 g SepaFlash column) using a 0-15% EtOAc/petroleum ether gradient eluent to afford the title compound (183 mg, 70%) as a yellow liquid. MS-ESI (m/z) calcd for C₁₅H₁₈N₃O₃[M+H]⁺: 288.1. Found 288.1.

Step 2: 3-Cyclopropyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-amine

embedded image

To a solution of 3-cyclopropyl-5-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (183 mg, 636.94 umol) in EtOH (4 mL) and H₂O (1 mL) was added Fe (177.85 mg, 3.18 mmol) and NH₄Cl (170.35 mg, 3.18 mmol) and the mixture was stirred at 80° C. for 2 hrs. The reaction was then filtered and the filtrate was concentrated to give residue. The residue was extracted with EtOAc (5 mL×3) and saturated aqueous NaHCO₃(5 mL). The organic layers were dried over anhydrous Na₂SO₄, filtered and the filtrate was concentrated under vacuum to afford the title compound (153 mg, 93%) as a brown liquid which was used without further purification. MS-ESI (m/z) calcd for C₁₅H₂₀N₃O [M+H]⁺: 258.2. Found 258.1.

Step 3: 5-Cyano-N-(3-cyclopropyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-3,4-dimethylpicolinamide

embedded image

To a solution of 5-cyano-3,4-dimethylpicolinic acid (91.05 mg, 516.85 umol) in DMF (3 mL) was added HATU (294.78 mg, 775.27 umol), Et₃N (156.90 mg, 1.55 mmol) and 3-cyclopropyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-amine (133 mg, 516.85 umol) and the mixture was stirred at 25° C. for 12 hrs. The reaction was concentrated to give a residue which was purified by preparative TLC (SiO₂, 3:1 petroleum ether/EtOAc, R_f=0.23) to afford the title compound (57 mg, 27%) as a yellow solid. MS-ESI (m/z) calcd for C₂₄H₂₆N₅O₂[M+H]⁺: 416.2. Found 416.1.

Step 4: 5-Cyano-N-(3-cyclopropyl-1H-indazol-5-yl)-3,4-dimethylpicolinamide

embedded image

To a solution of 5-cyano-N-(3-cyclopropyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-3,4-dimethylpicolinamide (57 mg, 137.19 umol) in MeOH (2 mL) and H₂O (0.4 mL) was added PTSA (118.12 mg, 685.94 umol) and the mixture was stirred at 70° C. for 1.5 hrs. The reaction was filtered and the solid obtained was dried under vacuum to afford the title compound (12.86 mg, 28%) as a pale yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 12.53 (br s, 1H) 10.61 (s, 1H) 8.88 (s, 1H) 8.29 (s, 1H) 7.55 (br d, J=8.82 Hz, 1H) 7.43 (d, J=9.04 Hz, 1H) 2.55 (s, 3H) 2.44 (s, 3H) 2.18-2.23 (m, 1H) 0.96-1.02 (m, 2H) 0.90-0.95 (m, 2H). MS-ESI (m/z) calc'd for C₁₉H₁₈N₅O₂[M+H]⁺: 332.1. Found 332.1.

Example 224: 5-cyano-1-methyl-N-(3-(oxazol-5-yl)-1H-indazol-5-yl)-6-oxo-1,6-dihydropyridine-3-carboxamide

embedded image

Step 1: 5-Bromo-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid

embedded image

To a solution of methyl 5-bromo-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate (200 mg, 812.82 umol) in H₂O (1 mL) and THF (1 mL) was added NaOH (65.02 mg, 1.63 mmol) and the mixture was stirred at 25° C. for 2 hrs. The reaction mixture was then concentrated under reduced pressure to remove solvent and then diluted with H₂O (10 ml) and acidified with 1 N HCl (aqueous) to pH=2. The mixture was filtered and the solid obtained was washed with 20 mL of H₂O and dried to afford the title compound (166 mg, 88%) as a white solid which was used without further purification. MS-ESI (m/z) calcd for C₇H₁₇BrNO₃[M+H]⁺: 232.0/244.0. Found 231.9/233.9.

Step 2: 5-Bromo-1-methyl-N-(3-(oxazol-5-yl)-1H-indazol-5-yl)-6-oxo-1,6-dihydropyridine-3-carboxamide

embedded image

To a solution of 5-bromo-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid (130 mg, 560.27 umol) and 3-(oxazol-5-yl)-1H-indazol-5-amine (112.16 mg, 560.27 umol) in pyridine (3 mL) was added EDCI (161.11 mg, 840.40 umol) and the mixture was stirred at 25° C. for 3 hrs. The reaction mixture was concentrated under reduced pressure to give a residue which was diluted with H₂O (10 mL) and filtered. The solid obtained was washed with 20 mL of H₂O and dried in vacuum to afford the title compound (160 mg, 69%) as a red solid which was used without further purification. MS-ESI (m/z) calcd for C₁₇H₁₃BrN₅O₃[M+H]⁺: 414.0/416.0. Found 413.9/415.9.

Step 3: 5-Cyano-1-methyl-N-(3-(oxazol-5-yl)-1H-indazol-5-yl)-6-oxo-1,6-dihydropyridine-3-carboxamide

embedded image

A mixture of 5-bromo-1-methyl-N-(3-(oxazol-5-yl)-1H-indazol-5-yl)-6-oxo-1,6-dihydropyridine-3-carboxamide (100 mg, 241.42 umol), Zn(CN)₂(56.70 mg, 482.84 umol), Zn (1.42 mg, 21.73 umol), dppf (4.02 mg, 7.24 umol), and Pd₂(dba)₃(13.26 mg, 14.49 umol) in DMA (2 mL) was degassed and purged with N₂(3×), and then the mixture was stirred at 120° C. for 2 hrs under an N₂atmosphere in a microwave reactor. The reaction mixture was concentrated and purified by preparative HPLC using Method BV to afford the title compound (12.71 mg, 10%) as a yellow solid, TFA salt. ¹H NMR (400 MHz, DMSO-d₆) δ 13.51 (s, 1H), 10.23 (s, 1H), 8.88 (d, J=2.43 Hz, 1H), 8.76 (d, J=2.65 Hz, 1H), 8.58 (s, 1H), 8.44 (s, 1H), 7.70-7.75 (m, 1H), 7.59-7.66 (m, 2H), 3.62 (s, 3H). MS-ESI (m/z) calc'd for C₁₈H₁₃N₆O₃[M+H]⁺: 361.1. Found 361.1.

Example 225: 3-Cyano-2-isopropyl-N-(3-(oxazol-5-yl)-1H-indazol-5-yl)benzamide

embedded image

To a solution of 3-cyano-N-(3-(oxazol-5-yl)-1H-indazol-5-yl)-2-(prop-1-en-2-yl)benzamide (40 mg, 108.29 umol) in THF (6 mL) and MeOH (3 mL) was added 10% Pd/C (10 mg) under N₂. The suspension was degassed under vacuum and purged with H₂several times. The mixture was then stirred under Hz (15 psi) at 25° C. for 1 hr. The reaction mixture was filtered and the filtrate was concentrated to give a residue. The residue was purified by preparative HPLC using Method CH to afford the title compound (5.82 mg, 14%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.51 (br s, 1H), 10.67 (s, 1H), 8.58 (d, J=7.7 Hz, 2H), 7.93 (d, J=6.8 Hz, 1H), 7.77 (d, J=7.7 Hz, 1H), 7.71-7.57 (m, 3H), 7.57-7.50 (m, 1H), 3.44-3.36 (m, 1H), 1.44 (d, J=7.1 Hz, 6H). MS-ESI (m/z) calc'd for C₂₁H₁₈N₅O₂[M+H]⁺: 372.1. Found 372.2.

Example 226: 5-Cyano-N-(3-(isoxazol-4-yl)-1H-indazol-5-yl)-4-methoxy-3-methylpicolinamide

embedded image

Prepared as described for 5-cyano-N-(7-fluoro-3-(furan-3-yl)-1H-indazol-5-yl)-3-methylpicolinamide using 5-cyano-4-methoxy-3-methylpicolinic acid in place of 5-cyano-3-methylpicolinic acid and using 3-(isoxazol-4-yl)-1H-indazol-5-amine in place of 7-fluoro-3-(furan-3-yl)-1H-indazol-5-amine to afford the title compound (22.2 mg, 30%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.33 (s, 1H), 10.67 (s, 1H), 9.55 (s, 1H), 9.14 (s, 1H), 8.86 (d, J=0.7 Hz, 1H), 8.38 (dd, J=1.9, 0.8 Hz, 1H), 7.78 (dd, J=9.0, 1.9 Hz, 1H), 7.60 (dd, J=9.0, 0.7 Hz, 1H), 4.27 (s, 3H), 2.41 (d, J=0.6 Hz, 3H). MS-ESI (m/z) calc'd for C₁₉H₁₅N₆O₃[M+H]⁺: 375.1. Found 375.2.

Example 227: 5-Cyano-3,4-dimethyl-N-(3-(thiazol-5-yl)-1H-indazol-5-yl)picolinamide

embedded image

Prepared as described for 5-cyano-N-(7-fluoro-3-(furan-3-yl)-1H-indazol-5-yl)-3-methylpicolinamide using 5-cyano-3,4-dimethylpicolinic acid in place of 5-cyano-3-methylpicolinic acid and using 3-(thiazol-5-yl)-1H-indazol-5-amine in place of 7-fluoro-3-(furan-3-yl)-1H-indazol-5-amine to afford the title compound (22.1 mg, 30%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.41 (s, 1H), 10.77 (s, 1H), 9.15 (s, 1H), 8.90 (s, 1H), 8.61 (d, J=1.8 Hz, 1H), 8.40 (s, 1H), 7.79 (dd, J=9.0, 1.9 Hz, 1H), 7.63 (d, J=9.0 Hz, 1H), 2.56 (s, 3H), 2.47 (s, 3H). MS-ESI (m/z) calc'd for C₁₉H₁₅N₆OS [M+H]⁺: 375.1. Found 375.3.

Example 228: 4-Cyano-N-(3-(isoxazol-4-yl)-1H-indazol-5-yl)-3-methoxypicolinamide

embedded image

A solution of 0.1 N potassium hexacyanoferrate(II) (0.87 mL, 0.090 mmol), 4-chloro-3-methoxy-N-[3-(1,2-oxazol-4-yl)-1H-indazol-5-yl]pyridine-2-carboxamide (32.0 mg, 0.090 mmol) and KOAc (4.25 mg, 0.040 mmol) were dissolved in a mixture of 1,4-dioxane (1.8 mL) and H₂O (0.260 mL) in a sealed microwave reactor vial. The mixture was degassed with N₂for 15 minutes. Then XPhos (1.65 mg, 0,003 mmol) and XPhos-Pd-G3 (2.93 mg, 0,003 mmol) were added and the mixture was left stirring at 100° C. for 8 hrs. Water was added and the mixture was extracted with EtOAc. The organic phase was separated, dried over Na₂SO₄, filtered and concentrated to give a residue. The residue was then purified by semi-preparative HPLC using Method CX to afford the title compound (3 mg, 10%), as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.35 (s, 1H), 10.72 (s, 1H), 9.55 (s, 1H), 9.14 (s, 1H), 8.61 (d, J=4.8 Hz, 1H), 8.36 (d, J=1.8 Hz, 1H), 8.06 (d, J=4.8 Hz, 1H), 7.75 (dd, J=9.0, 1.9 Hz, 1H), 7.62 (d, J=9.0 Hz, 1H), 4.10 (s, 3H). MS-ESI (m/z) calc'd for C₁₅H₁₃N₆O₃[M+H]⁺: 361.1. Found 361.2.

Example 229: 5-Cyano-3,4-dimethyl-N-(3-(3-methylisoxazol-5-yl)-1H-indazol-5-yl)picolinamide

embedded image

Prepared as described for 5-cyano-N-(3-(isoxazol-4-yl)-1H-indazol-5-yl)-3-methylpicolinamide using (3-methylisoxazol-5-yl)boronic acid in place of isoxazole-4-boronic acid and 5-cyano-N-(3-iodo-1H-indazol-5-yl)-3,4-dimethylpicolinamide in place of 5-cyano-N-(3-iodo-1H-indazol-5-yl)-3-methylpyridine-2-carboxamide to afford the title compound (8.6 mg, 24%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.73 (br. s., 1H) 10.81 (s, 1H) 8.90 (s, 1H) 8.67 (d, J=1.10 Hz, 1H) 7.73-7.81 (m, 1H) 7.63-7.70 (m, 1H) 6.81 (s, 1H) 2.57 (s, 3H) 2.47 (s, 3H) 2.36 (s, 3H). MS-ESI (m/z) calc'd for C₂₀H₁₇N₆O₂[M+H]⁺: 373.1. Found 373.2.

Example 230: 5-Cyano-3,4-dimethyl-N-(3-(pyrimidin-4-yl)-1H-indazol-5-yl)picolinamide

embedded image

Step 1: 3-Iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-amine

embedded image

To a solution of 3-iodo-5-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (100 mg, 267.99 umol) in EtOH (2 mL) and H₂O (2 mL) was added Fe (74.83 mg, 1.34 mmol) and NH₄Cl (71.68 mg, 1.34 mmol) and the mixture was stirred at 80° C. for 2 hrs. The reaction mixture was then filtered and the filtrate was concentrated under reduced pressure to remove solvent. Then the mixture was diluted with H₂O (5 mL) and extracted with EtOAc (15 mL×3). The combined organic layers were dried over Na₂SO₄, filtered and concentrated under reduced pressure to afford the title compound (90 mg) as a brown gum which was used without further purification. MS-ESI (m/z) calcd for C₁₂H₁₃IN₃O [M+H]⁺: 344.0. Found 344.1.

Step 2: 5-Cyano-N-(3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-3,4-dimethylpicolinamide

embedded image

To a solution of 3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-amine (90 mg, 262.27 umol) in pyridine (2 mL) was added EDCI (100.55 mg, 524.53 umol) and 5-cyano-3,4-dimethylpicolinic acid (46.20 mg, 262.27 umol) and the mixture was stirred at 20° C. for 12 hrs. The reaction mixture was concentrated under reduced pressure to remove solvent. Then the mixture was diluted with H₂O (5 mL) and filtered. The solid obtained was dried under vacuum to afford the title compound (75 mg) as a brown solid which was used without further purification. MS-ESI (m/z) calcd for C₂₁H₂₁IN₅O₂[M+H]⁺: 502.1. Found 502.2

Step 3: 5-Cyano-3,4-dimethyl-N-(3-(pyrimidin-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)picolinamide

embedded image

To a solution of 5-cyano-N-(3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-3,4-dimethylpicolinamide (68 mg, 135.64 umol) in dioxane (2 mL) was added Pd(PPh₃)₂Cl₂(9.52 mg, 13.56 umol) and 4-(tributylstannyl)pyrimidine (50.07 mg, 135.64 umol) and the mixture was stirred at 120° C. for 24 hrs under an N₂atmosphere. The reaction mixture was concentrated to afford the title compound (50 mg) as a yellow solid which was used without further purification. MS-ESI (m/z) calcd for C₂₅H₂₄N₇O₂[M+H]⁺: 454.2. Found 454.1

Step 4: 5-Cyano-3,4-dimethyl-N-(3-(pyrimidin-4-yl)-1H-indazol-5-yl)picolinamide

embedded image

To a solution of 5-cyano-3,4-dimethyl-N-(3-(pyrimidin-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)picolinamide (50 mg, 110.25 umol) in DCM (2 mL) was added TFA (1.54 g, 13.51 mmol) and the mixture was stirred at 20° C. for 3 hrs. The reaction mixture was then concentrated and purified by preparative HPLC using Method CF to afford the title compound (5.46 mg, 13%) as a pale yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.81 (s, 1H) 10.80 (s, 1H) 9.30 (d, J=1.10 Hz, 1H) 9.04 (d, J=0.66 Hz, 1H) 8.90 (s, 1H) 8.84 (d, J=5.29 Hz, 1H) 8.17 (dd, J=5.40, 1.21 Hz, 1H) 7.80 (dd, J=8.93, 1.87 Hz, 1H) 7.67 (d, J=9.04 Hz, 1H) 2.56 (s, 3H) 2.45 (s, 3H). MS-ESI (m/z) calc'd for C₂₀H₁₆N₇O [M+H]⁺: 370.1. Found 370.2.

Example 231: 3-Cyano-2-ethyl-6-fluoro-N-(3-(oxazol-5-yl)-1H-indazol-5-yl)benzamide

embedded image

Step 1: Methyl 2-bromo-6-fluorobenzoate

embedded image

To a solution of 2-bromo-6-fluorobenzoic acid (1 g, 4.57 mmol) in MeOH (6 mL) was added H₂SO₄(6.5 mL, 98% purity) and the mixture was stirred at 80° C. for 12 hrs. The reaction mixture was then basified with saturated aqueous Na₂CO₃to pH=8 (40 mL) and extracted with EtOAc (15 mL 3). The combined organic layers were dried over Na₂SO₄, filtered and concentrated to afford the title compound (750 mg) as a yellow oil which was used without further purification. ¹H NMR (400 MHz, CDCl₃) δ 7.40 (d, J=8 Hz, 1H), 7.29-7.26 (m, 1H), 7.08 (t, J=8.4 Hz, 1H), 3.97 (s, 3H).

Step 2: Methyl 2-fluoro-6-vinylbenzoate

embedded image

A mixture of methyl 2-bromo-6-fluorobenzoate (750 mg, 3.22 mmol), potassium trifluoro(vinyl)borate (474.22 mg, 3.54 mmol), Pd(dppf)Cl₂(70.65 mg, 96.55 umol), Na₂CO₃(1.02 g, 9.66 mmol) in dioxane (18 mL) and H₂O (6 mL) was degassed and purged with N₂(3×), and then the mixture was stirred at 100° C. for 12 hrs under an N₂atmosphere. The reaction mixture was concentrated and purified by flash silica gel chromatography (ISCO; 12 g SepaFlash column) using a 0-30% EtOAc/petroleum ether gradient eluent to afford the title compound (350 mg, 60%) as a light yellow oil. MS-ESI (m/z) calcd for C₁₀H₁₀FO₂[M+H]⁺: 181.1. Found 181.0.

Step 3: Methyl 2-ethyl-6-fluorobenzoate

embedded image

To a solution of methyl 2-fluoro-6-vinylbenzoate (350 mg, 1.94 mmol) in EtOH (15 mL) was added 10% Pd/C (1 g, 1.94 mmol). The mixture was degassed and purged with H₂(3×), then it was stirred at 25° C. for 1 hr under an H₂atmosphere (15 psi). The reaction mixture was filtered and the filtrate was concentrated to afford the title compound (250 mg, 71%) as a light yellow gum which was used without further purification. ¹H NMR (400 MHz, CDCl₃) δ 7.27-7.22 (m, 1H), 6.97 (d, J=7.6 Hz, 1H), 6.87 (t, J=8.8 Hz, 1H), 3.86 (s, 3H), 2.66-2.60 (q, J=7.6 Hz, 2H), 1.14 (t, J=7.6 Hz, 3H).

Step 4: Methyl 3-bromo-2-ethyl-6-fluorobenzoate

embedded image

To a solution of methyl 2-ethyl-6-fluorobenzoate (250 mg, 1.37 mmol) in H₂SO₄(4 mL, 98% purity) was added NBS (256.44 mg, 1.44 mmol) at 0° C. The mixture was stirred at 0° C. for 2 hrs and then poured into ice water (10 mL), then diluted with saturated aqueous Na₂CO₃(20 mL) and extracted with EtOAc (8 mL×3). The combined organic phases were dried over Na₂SO₄and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO: 4 g SepaFlash column) using 100% petroleum ether eluent to afford the title compound (100 mg, 28%) as a yellow oil. MS-ESI (m/z) calcd for C₁₀H₁₁BrFO₂[M+H]⁺: 261.0/263.0. Found 261.0/263.0.

Step 5: 3-Bromo-2-ethyl-6-fluorobenzoic acid

embedded image

To a solution of methyl 3-bromo-2-ethyl-6-fluorobenzoate (340 mg, 1.30 mmol) in MeOH (6 mL) and H₂O (3 mL) was added LiOH.H₂O (273.23 mg, 6.51 mmol) and the mixture was stirred at 60° C. for 12 hrs. The reaction mixture was then diluted with 1M HCl to pH=4 and extracted with EtOAc (15 mL×3). The combined organic layers were dried over Na₂SO₄, filtered and concentrated under reduced pressure to afford the title compound (300 mg, 93%) as a yellow oil which was used without further purification. MS-ESI (m/z) calcd for C₉H₉BrFO₂[M−H]⁻: 245.0/247.0. Found 244.9/246.9.

Step 6: 3-Bromo-2-ethyl-6-fluoro-N-(3-(oxazol-5-yl)-1H-indazol-5-yl)benzamide

embedded image

To a solution of 3-bromo-2-ethyl-6-fluorobenzoic acid (150 mg, 607.14 umol) in pyridine (5 mL) was added EDCI (174.58 mg, 910.71 umol) and 3-(oxazol-5-yl)-1H-indazol-5-amine (121.55 mg, 607.14 umol) and the mixture was stirred at 25° C. for 12 hrs. The mixture was then concentrated and purified by flash silica gel chromatography (ISCO; 4 g SepaFlash column) using a 0-30% EtOAc/petroleum ether gradient eluent to afford the title compound (138 mg, 53%) as a yellow oil. MS-ESI (m/z) calcd for C₁₉H₁₅BrFN₄O₂[M+H]⁺: 429.0/431.0. Found 429.0/431.0.

Step 7: 3-Cyano-2-ethyl-6-fluoro-N-(3-(oxazol-5-yl)-1H-indazol-5-yl)benzamide

embedded image

A mixture of 3-bromo-2-ethyl-6-fluoro-N-(3-(oxazol-5-yl)-1H-indazol-5-yl)benzamide (150 mg, 349.45 umol), Zn(CN)₂(82.07 mg, 698.91 umol), Zn (2.06 mg, 31.45 umol), dppf (5.81 mg, 10.48 umol) and Pd₂(dba)₃(19.20 mg, 20.97 umol) in DMA (3 mL) was degassed and purged with N₂(3×), and then the mixture was stirred at 120° C. for 5 hrs under an N₂atmosphere. The reaction was filtered and the filtrate was concentrated to give a residue. The residue was purified by preparative HPLC using Method AK to afford the title compound (5.53 mg, 3%) as a yellow solid TFA salt. ¹H NMR (400 MHz, DMSO-d₆) δ 13.54 (s, 1H), 10.90 (s, 1H), 8.59 (s, 1H), 8.53 (s, 1H), 8.05 (dd, J=9.15, 5.40 Hz, 1H), 7.59-7.67 (m, 3H), 7.49 (t, J=8.71 Hz, 1H), 2.81-2.92 (m, 2H), 1.26 (t, J=7.61 Hz, 3H). MS-ESI (m/z) calc'd for C₂₀H₁₅FNO₂[M+H]⁺: 376.1. Found 376.1.

Example 232: 2-Cyano-3-ethyl-N-(3-(oxazol-5-yl)-1H-indazol-5-yl)isonicotinamide

embedded image

Step 1: Methyl 3-bromo-2-chloroisonicotinate

embedded image

To a solution of 3-bromo-2-chloroisonicotinic acid (400 mg, 1.69 mmol) in MeOH (10 mL) was added SOCl₂(1.31 g, 11.00 mmol) dropwise at 0° C.; then the mixture was stirred at 80° C. for 12 hrs. The reaction was concentrated to give a residue which was extracted with EtOAc (10 mL×3) and saturated aqueous Na₂CO₃(10 mL). The organic layer was dried over Na₂SO₄, filtered and the filtrate was concentrated to afford the title compound (390 mg, 92%) as a brown liquid, which was used without further purification. MS-ESI (m/z) calcd for C₇H₆BrClNO₂[M+H]⁺: 249.9/251.9. Found 249.8/251.9.

Step 2: Methyl 2-chloro-3-vinylisonicotinate

embedded image

To a solution of methyl 3-bromo-2-chloroisonicotinate (340 mg, 1.36 mmol) in dioxane (5 mL) was added tributyl(vinyl)tin (473.47 mg, 1.49 mmol, 434.38 uL) and Pd(PPh₃)₄(78.43 mg, 67.87 umol) and the mixture was stirred at 100° C. for 12 hrs under N₂. The procedure was repeated using 50 mg of methyl 3-bromo-2-chloroisonicotinate and the reaction mixtures were combined and concentrated. The material was purified by flash silica gel chromatography (ISCO; 4 g SepaFlash column) using a 0-9% EtOAc/petroleum ether gradient eluent to afford the title compound (227 mg, 85%) as a light yellow liquid, which was used without further purification. MS-ESI (m/z) calcd for C₉H₉ClNO₂[M+H]⁺: 198.0/200.0. Found 198.0/200.0.

Step 3: Methyl 2-chloro-3-ethylisonicotinate

embedded image

To a mixture of 10% Pd/C (200 mg) in MeOH (15 mL) was added methyl 2-chloro-3-vinylisonicotinate (200 mg, 1.01 mmol) and the mixture was stirred at 25° C. under H₂at 15 psi for 30 min. The residue was purified by preparative TLC (SiO₂, 5:1 petroleum ether/EtOAc, R_f=0.51) to afford the title compound (31 mg, 15%) as a light yellow liquid. MS-ESI (m/z) calcd for C₉H₁₁ClNO₂[M+H]⁺: 200.0/202.0. Found 200.0/202.0.

Step 4: 2-Chloro-3-ethylisonicotinic acid

embedded image

To a solution of methyl 2-chloro-3-ethylisonicotinate (31 mg, 155.28 umol) in THF (1 mL) and H₂O (1 mL) was added LiOH.H₂O (26.07 mg, 621.14 umol) and the mixture was stirred at 25° C. for 1 hr. The reaction was repeated with 8 mgs of methyl 2-chloro-3-ethylisonicotinate and the reaction mixtures were combined. The THF was removed under vacuum and the aqueous layer was acidified with 1N HCl to pH=5. The mixture was filtered and the solid was dried under vacuum to afford the title compound (16 mg) as a white solid which was used without further purification. MS-ESI (m/z) calcd for C₈H₉ClNO₂[M+H]⁺: 186.0/188.0. Found 186.0/188.0.

Step 5: 2-Chloro-3-ethyl-N-(3-(oxazol-5-yl)-1H-indazol-5-yl)isonicotinamide

embedded image

To a solution of 2-chloro-3-ethylisonicotinic acid (16 mg, 86.20 umol) and EDCI (24.79 mg, 129.31 umol) in pyridine (1 mL) was added 3-(oxazol-5-yl)-1H-indazol-5-amine (17.26 mg, 86.20 umol) and then the mixture was stirred at 25° C. for 12 hrs. The reaction was then concentrated to give a residue which was extracted with EtOAc (3 mL×3) and water (3 mL). The organic layer was dried over Na₂SO₄, filtered and the filtrate was concentrated under vacuum to afford the title compound (25 mg) as a brown liquid, which was used without further purification. MS-ESI (m/z) calcd for C₁₅H₁₅ClN₅O₂[M+H]⁺: 368.1/370.1. Found 368.0/370.0.

Step 6: 2-Cyano-3-ethyl-1-N-(3-(oxazol-5-yl)-1H-indazol-5-yl)isonicotinamide

embedded image

To a solution of 2-chloro-3-ethyl-N-(3-(oxazol-5-yl)-1H-indazol-5-yl)isonicotinamide (15 mg, 40.78 umol) and Zn(CN)₂(4.79 mg, 40.78 umol) in DMF (1 mL) was added Zn (320.03 ug, 4.89 umol), Pd₂(dba)₃(746.94 ug, 0.816 umol) and dppf (904.40 ug, 1.63 umol) and the mixture was stirred at 120° C. under N₂for 2 hrs in a microwave reactor. The mixture was filtered and the filtrate was purified by preparative HPLC using Method AI to afford the title compound (2.67 mg, 13%) as a pale yellow solid, TFA salt. ¹H NMR (400 MHz, DMSO-d₆) δ 13.54 (s, 1H) 10.83 (s, 1H) 8.77 (d, J=4.85 Hz, 1H) 8.59 (s, 1H) 8.51 (s, 1H) 7.89 (d, J=4.85 Hz, 1H) 7.63 (d, J=6.84 Hz, 3H) 2.95 (q, J=7.42 Hz, 2H) 1.27 (t, J=7.50 Hz, 3H). MS-ESI (m/z) calc'd for C₁₉H₁₅N₆O₂[M+H]⁺: 359.1. Found 359.1.

Example 233: (E)-5-Cyano-N-(3-(2-cyclopropylvinyl)-1H-indazol-5-yl)-3,4-dimethylpicolinamide

embedded image

Prepared as described for 5-cyano-3,4-dimethyl-N-(3-(2-methylprop-1-en-1-yl)-1H-indazol-5-yl)picolinamide using (E)-2-(2-cyclopropylvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane in place of 4,4,5,5-tetramethyl-2-(2-methylprop-1-en-1-yl)-1,3,2-dioxaborolane to afford the title compound (15.77 mg, 12%) as a pale yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 12.86 (br s, 1H), 10.62 (s, 1H), 8.87 (s, 1H), 8.31 (s, 1H), 7.69 (br d, J=8.82 Hz, 1H), 7.47 (d, J=8.82 Hz, 1H), 6.74 (d, J=16.10 Hz, 1H), 6.03 (dd, J=16.21, 8.93 Hz, 1H), 2.54 (s, 3H), 2.43 (s, 3H), 1.63-1.73 (m, 1H), 0.84 (q, J=5.66 Hz, 2H), 0.52-0.58 (m, 2H). MS-ESI (m/z) calc'd for C₂₁H₂₀N₅O [M+H]⁺: 358.2 Found 358.1.

Example 234: 3-Cyano-2-methoxy-6-methyl-N-(3-(oxazol-5-yl)-1H-indazol-5-yl)benzamide

embedded image

Prepared as described for 4-cyano-N-(3-(isoxazol-4-yl)-1H-indazol-5-yl)-3-methoxypicolinamide using 3-chloro-2-methoxy-6-methyl-N-(3-(oxazol-5-yl)-1H-indazol-5-yl)benzamide in place of 4-chloro-3-methoxy-N-[3-(1,2-oxazol-4-yl)-1H-indazol-5-yl]pyridine-2-carboxamide to afford the title compound (9.6 mg, 16%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.53 (br. s., 1H) 10.67 (s, 1H) 8.60 (s, 1H) 8.56 (s, 1H) 7.80 (d, J=7.92 Hz, 1H) 7.58-7.66 (m, 3H) 7.28 (d, J=7.92 Hz, 1H) 3.99 (s, 3H) 2.39 (s, 3H). MS-ESI (m/z) calc'd for C₂₀H₁₆N₅O; [M+H]⁺: 374.1. Found 374.3.

Example 235: 5-Cyano-3-methyl-N-(3-(3-methylisoxazol-5-yl)-1H-indazol-5-yl)picolinamide

embedded image

Prepared as described for 5-cyano-N-(3-(isoxazol-4-yl)-1H-indazol-5-yl)-3-methylpicolinamide using (3-methylisoxazol-5-yl)boronic acid in place of isoxazole-4-boronic acid and 5-cyano-N-(3-iodo-1H-indazol-5-yl)-3-methylpicolinamide in place of 5-cyano-N-(3-iodo-1H-indazol-5-yl)-3-methylpyridine-2-carboxamide to afford the title compound (3.4 mg, 15%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.73 (br. s., 1H) 10.84 (s, 1H) 9.01 (d, J=1.32 Hz, 1H) 8.70 (d, J=1.32 Hz, 1H) 8.42 (dd, J=1.98, 0.66 Hz, 1H) 7.83 (dd, J=9.02, 1.98 Hz, 1H) 7.67 (d, J=9.24 Hz, 1H) 6.82 (s, 1H) 2.61 (s, 3H) 2.36 (s, 3H). MS-ESI (m/z) calc'd for C₁₉H₁₅N₆O₂[M+H]⁺: 359.1. Found 359.2.

Example 236: 3-Cyano-2-fluoro-N-(3-(isoxazol-4-yl)-1H-indazol-5-yl)-6-methylbenzamide

embedded image

Step 1: 3-Bromo-2-fluoro-N-(3-(isoxazol-4-yl)-1H-indazol-5-yl)-6-methylbenzamide

embedded image

To a mixture of 3-bromo-2-fluoro-6-methylbenzoic acid (45.0 mg, 0.190 mmol), 3-(1,2-oxazol-4-yl)-1H-indazol-5-amine (42.96 mg, 0.210 mmol) and Et₃N (53.83 uL, 0.390 mmol) in MeCN (2.5 mL), was added HATU (73.43 mg, 0.190 mmol) and the mixture was stirred at r.t. for 1 hr. The reaction mixture was partitioned between H₂O and EtOAc, the phases were separated, the aqueous layer was extracted with EtOAc (2×) and the combined organic phases were washed with brine (1×), dried over Na₂SO₄and concentrated to afford the title compound (115 mg) which was used without further purification. ¹H NMR (400 MHz, DMSO-d₆) δ 13.34 (s, 1H) 10.72 (s, 1H) 9.53 (s, 1H) 9.13 (s, 1H) 8.35 (s, 1H) 7.68-7.77 (m, 1H) 7.59-7.64 (m, 2H) 7.17 (d, J=8.36 Hz, 1H) 2.35 (s, 3H). MS-ESI (m/z) calc'd for C₁₅H₁₃BrFN₄O₂[M+H]⁺: 415.0/417.0. Found 415.2/417.2.

Step 2: 3-Cyano-2-fluoro-N-(3-(isoxazol-4-yl)-1H-indazol-5-yl)-6-methylbenzamide

embedded image

Prepared as described for 4-cyano-N-(3-(isoxazol-4-yl)-1H-indazol-5-yl)-3-methoxypicolinamide using 3-bromo-2-fluoro-N-(3-(isoxazol-4-yl)-1H-indazol-5-yl)-6-methylbenzamide in place of 4-chloro-3-methoxy-N-[3-(1,2-oxazol-4-yl)-1H-indazol-5-yl]pyridine-2-carboxamide to afford the title compound (1.9 mg, 3%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.37 (br. s., 1H) 10.80 (br. s., 1H) 9.54 (s, 1H) 9.14 (s, 1H) 8.34 (s, 1H) 7.92-8.00 (m, 1H) 7.62 (s, 2H) 7.43 (d, J=8.14 Hz, 1H) 2.47 (s, 3H). MS-ESI (m/z) calc'd for C₁₉H₁₃FN₅O₂[M+H]⁺: 362.1. Found 362.2.

Example 237: 5-Cyano-3,4-dimethyl-N-(3-(2-methylpyrimidin-4-yl)-1H-indazol-5-yl)picolinamide

embedded image

Step 1: tert-Butyl 5-[(5-cyano-3,4-dimethylpyridine-2-carbonyl)amino]-3-(2-methylpyrimidin-4-yl)indazole-1-carboxylate

embedded image

A solution of tert-butyl 5-(5-cyano-3,4-dimethylpicolinamido)-3-iodo-1H-indazole-1-carboxylate (50.0 mg, 0.100 mmol) and trimethyl-(2-methylpyrimidin-4-yl)stannane (500.0 mg, 0.510 mmol) in toluene (2 mL) was degassed with N₂for 15 min in a microwave reactor vial. Tetrakis(triphenylphosphine)palladium(0) (11.17 mg, 0.010 mmol) was added, the vial was sealed, and the resulting mixture was heated at reflux with vigorous stirring under N₂for 24 hrs. Then the mixture was filtered through Celite. A solution of KF in H₂O was added to the filtrate and the mixture was extracted with EtOAc (2×). The combined organic layers were dried over Na₂SO₄, filtered and concentrated under reduced pressure to afford the title compound (149 mg) which was used without further purification.

Step 2: 5-Cyano-3,4-dimethyl-N-(3-(2-methylpyrimidin-4-yl)-1H-indazol-5-yl)picolinamide

embedded image

tert-Butyl 5-[(5-cyano-3,4-dimethylpyridine-2-carbonyl)amino]-3-(2-methylpyrimidin-4-yl)indazole-1-carboxylate was dissolved in DCM (1 mL) and cooled to 0° C. followed by the addition of trifluoroacetic acid (148.9 mg, 1.31 mmol). The reaction mixture stirred at r.t. for 2 hrs. A saturated aqueous solution of NaHCO₃was added followed by DCM. The organic phase was filtered through a phase separator and concentrated. The residue was purified by silica gel column chromatography using a 20-100% EtOAc/cyclohexane gradient eluent. The isolated material was further purified by semi-preparative chiral HPLC using Method CY to afford the title compound (3.1 mg, 8% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.69 (bs, 1H), 10.76 (s, 1H), 9.05 (d, J=1.9 Hz, 1H), 8.90 (s, 1H), 8.71 (d, J=5.3 Hz, 1H), 7.94 (d, J=5.3 Hz, 1H), 7.83 (dd, J=9.0, 2.0 Hz, 1H), 7.65 (d, J=8.9 Hz, 1H), 2.74 (s, 3H), 2.57 (s, 3H), 2.45 (s, 3H). MS-ESI (m/z) calc'd for C₂₁H₁₈N₇O [M+H]⁺: 384.2. Found 384.3.

Example 238: 5-Cyano-3,4-dimethyl-N-(3-(oxazol-5-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)picolinamide

embedded image

Step 1: 5-chloro-1H-pyrazolo[3,4-c]pyridine-3-carbaldehyde

embedded image

To a stirred solution of NaNO₂(14.47 g, 209.72 mmol) in H₂O (40 mL) was slowly added HCl (2 M, 91.75 mL) dropwise at 0° C. and the reaction mixture was stirred at 0° C. for 10 min before adding DMF (60 mL). Then a solution of 5-chloro-1H-pyrazolo[3,4-c]pyridine (4 g, 26.22 mmol) in DMF (60 mL) was added at 0° C. and the reaction mixture was heated to 80° C. and stirred for 12 hrs. After cooling to 25° C., the reaction mixture was concentrated to give a residue. Saturated aqueous NaHCO₃was added to the residue to adjust to pH=8 and the mixture was extracted with EtOAc (200 mL×3). The combined organic phases were washed with brine (200 mL×1), dried over Na₂SO₄, filtered and concentrated. The material was purified by silica gel column chromatography using a 0-33% EtOAc/petroleum ether gradient eluent to afford the title compound (800 mg, 17%) as a light yellow solid. MS-ESI (m/z) calcd for C₇H₅ClN₃O [M+H]⁺: 182.0. Found 182.0.

Step 2: 5-(5-Chloro-1H-pyrazolo[3,4-c]pyridin-3-yl)oxazole

embedded image

To a solution of 5-chloro-1H-pyrazolo[3,4-c]pyridine-3-carbaldehyde (700 mg, 3.86 mmol) in MeOH (21 mL) was added Tos-MIC (827.92 mg, 4.24 mmol) and K₂CO₃(1.07 g, 7.71 mmol). The mixture was then stirred at 80° C. for 30 min under an N₂atmosphere. After cooling to 25° C., the reaction mixture was concentrated and poured into H₂O (10 mL) and extracted with EtOAc (10 mL×3). The combined organic phases were concentrated to give a residue which was purified by silica gel column chromatography using a 0-33% EtOAc/petroleum ether gradient eluent to afford the title compound (120 mg, 14%) as a yellow solid. MS-ESI (m/z) calcd for C₉H₆ClN₄O [M+H]⁺: 221.0. Found 220.9.

Step 3: 5-(5-Chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)oxazole

embedded image

To a solution of 5-(5-chloro-1H-pyrazolo[3,4-c]pyridin-3-yl)oxazole (120 mg, 543.93 umol) in DCM (10 mL) was added 3,4-dihydro-2H-pyran (91.51 mg, 1.09 mmol, 99.46 uL) and TsOH (93.67 mg, 543.93 umol) and the reaction mixture was stirred at 50° C. for 12 hrs. After cooling to 25° C., the reaction mixture was poured into water (10 mL) and extracted with EtOAc (10 mL×3). The combined organic phases were concentrated to give a residue which was purified by silica gel column chromatography using a 0-33% EtOAc/petroleum ether gradient eluent to afford the title compound (65 mg, 39%) as a yellow oil. MS-ESI (m/z) calcd for C₁₄H₁₄ClN₄O₂[M+H]⁺: 305.1/307.1. Found 305.1/307.1.

Step 4: N-(3-(Oxazol-5-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)-1,1-diphenylmethanimine

embedded image

A mixture of 5-(5-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)oxazole (50 mg, 164.08 umol), diphenylmethanimine (35.68 mg, 196.89 umol, 33.04 uL), BINAP (10.22 mg, 16.41 umol), tBuONa (20.50 mg, 213.30 umol) and Pd₂(dba)₃(15.03 mg, 16.41 umol) in tolulene (4 mL) was degassed and purged with N₂(3×), and then the mixture was stirred at 110° C. for 12 hrs under an N₂atmosphere. After cooling to 25° C., the reaction mixture was poured into water (5 mL) and extracted with EtOAc (5 mL×3). The combined organic phases were concentrated to give a residue which was purified by preparative TLC (SiO₂, 1:1 petroleum ether/EtOAc, R_f=0.70) to afford the title compound (15 mg, 20%) as a yellow oil. MS-ESI (m/z) calcd for C₂₇H₂₄N₅O₂[M+H]⁺: 450.2. Found 450.2.

Step 5: 3-(Oxazol-5-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-5-amine

embedded image

To a solution of N-(3-(oxazol-5-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)-1,1-diphenylmethanimine (12 mg, 26.70 umol) in THF (1 mL) was added HCl (4 M, 6.67 uL) and the mixture was stirred at 25° C. for 30 min. After cooling to 25° C., the reaction mixture was poured into water (5 mL) and extracted with EtOAc (5 mL×3). The combined organic phases were concentrated in vacuum to afford the title compound (10 mg) as a yellow oil which was used without further purification. MS-ESI (m/z) calcd for C₁₄H₁₆N₅O₂[M+H]⁺: 286.1. Found 286.1.

Step 6: 5-Cyano-3,4-dimethyl-N-(3-(oxazol-5-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)picolinamide

embedded image

To a solution of 3-(oxazol-5-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-5-amine (10 mg, 35.05 umol) and 5-cyano-3,4-dimethylpicolinic acid (6.17 mg, 35.05 umol) in pyridine (2 mL) was added EDCI (20.16 mg, 105.15 umol) and the mixture was stirred at 25° C. for 2 hrs. After cooling to 25° C., the reaction mixture was poured into water (5 mL) and extracted with EtOAc (5 mL×3). The combined organic phases were concentrated in vacuum and purified by preparative TLC (SiO₂, 1:1 petroleum ether/EtOAc, R_f=0.60) to afford the title compound (10 mg, 640%) as a yellow solid. MS-ESI (m/z) calcd for C₂₃H₂₂N₇O₃[M+H]⁺: 444.2. Found 444.1.

Step 7: 5-Cyano-3,4-dimethyl-N-(3-(oxazol-5-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)picolinamide

embedded image

To a solution of 5-cyano-3,4-dimethyl-N-(3-(oxazol-5-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)picolinamide (10 mg, 22.55 umol) in DCM (1 mL) was added TFA (0.5 mL) and the mixture was stirred at 25° C. for 12 hrs. The reaction mixture was concentrated to give a residue which was purified by preparative HPLC using Method CB to afford the title compound (1.95 mg, 18%) as a pale yellow solid, TFA salt. ¹H NMR (400 MHz, DMSO-d₆) δ 14.08 (br s, 1H), 10.96 (s, 1H), 8.96 (s, 1H), 8.88 (s, 1H), 8.79 (s, 1H), 8.66 (s, 1H), 7.72 (s, 1H), 2.56 (s, 3H), 2.52 (br s, 3H). MS-ESI (m/z) calc'd for C₁₈H₁₄N₇O₂[M+H]⁺: 360.1. Found 360.1.

Example 239: 3-Cyano-1,4-dimethyl-N-(3-(oxazol-5-yl)-1H-indazol-5-yl)-1H-pyrazole-5-carboxamide

embedded image

Prepared as described for 3-cyano-N-(3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-1H-indazol-5-yl)-1,4-dimethyl-1H-pyrazole-5-carboxamide using 3-(oxazol-5-yl)-1H-indazol-5-amine in place of 3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-1H-indazol-5-amine to afford the title compound (13.51 mg, 9%) as a pink solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.55 (s, 1H), 10.65 (s, 1H), 8.59 (s, 1H), 8.52 (s, 1H), 7.65 (s, 3H), 4.05 (s, 3H), 2.31 (s, 3H). MS-ESI (m/z) calc'd for C₁₇H₁₄N₇O₂[M+H]⁺: 348.1. Found 348.1.

Example 240: 5-Cyano-3,4-dimethyl-N-(3-(1-methyl-1H-1,2,3-triazol-4-yl)-1H-indazol-5-yl)picolinamide

embedded image

Step 1: 3-Bromo-5-nitro-1H-indazole

embedded image

To a solution of 5-nitro-1H-indazole (2 g, 12.26 mmol) in AcOH (20 mL) was added Br₂(5.88 g, 36.78 mmol). The mixture was stirred at 80° C. for 2 hrs. After cooling to r.t., the reaction mixture was poured into ice water (200 mL) and filtered. The solid was washed with 200 mL of H₂O and dried under vacuum to afford the title compound (2.9 g) as a yellow solid which was used without further purification.

Step 2: 5-Nitro-3-((trimethylsilyl)ethynyl)-1H-indazole

embedded image

A mixture of 3-bromo-5-nitro-1H-indazole (2.7 g, 11.16 mmol), ethynyl(trimethyl)silane (3.29 g, 33.47 mmol), Et₃N (4.52 g, 44.62 mmol), Pd(PPh₃)₄(1.29 g, 1.12 mmol) and CuI (106.23 mg, 557.78 umol) in THF (50 mL) was degassed and purged with N₂(3×), and then the mixture was stirred at 80° C. for 3 hrs under an N₂atmosphere. The reaction mixture was concentrated and purified by flash silica gel chromatography (ISCO; 40 g SepaFlash column) using a 0-12% EtOAc/petroleum ether gradient eluent to afford the title compound (1.25 g) as a yellow solid which was used without further purification. MS-ESI (m/z) calcd for C₁₂H₁₄N₃O₂Si [M+H]⁺: 260.1. Found 260.0.

Step 3: 3-Ethynyl-5-nitro-1H-indazole

embedded image

To a solution of 5-nitro-3-((trimethylsilyl)ethynyl)-1H-indazole (1.25 g, 4.82 mmol) in MeOH (12 mL) was added K₂CO₃(2.00 g, 14.46 mmol). The reaction mixture was stirred at 25° C. for 2 hrs and concentrated. The residue was diluted with H₂O (20 mL) and extracted with EtOAc (10 mL×3). The combined organic layers were dried over Na₂SO₄, filtered and concentrated under reduced pressure to afford the title compound (813 mg) as a yellow solid which was used without further purification. MS-ESI (m/z) calcd for C₉H₆N₃O₂[M+H]⁺: 188.0. Found 188.0.

Step 4: 5-Nitro-3-(1-((trimethylsilyl)methyl)-1H-1,2,3-triazol-4-yl)-1H-indazole

embedded image

To a solution of 3-ethynyl-5-nitro-1H-indazole (400 mg, 2.14 mmol) and (azidomethyl)trimethylsilane (276.21 mg, 2.14 mmol) in DMF (15 mL) was added CuI (81.41 mg, 427.45 umol) and DIEA (276.23 mg, 2.14 mmol). The mixture was stirred at 25° C. for 12 hrs under an N₂atmosphere. The reaction mixture was concentrated and purified by flash silica gel chromatography (ISCO; 20 g SepaFlash column) using a 0-30% EtOAc/petroleum ether gradient eluent to afford the title compound (232 mg, 34%) as a red solid. MS-ESI (m/z) calcd for C₁₃H₁₇N₆O₂Si [M+H]⁺: 317.1. Found 317.1.

Step 5: 3-(1-Methyl-1H-1,2,3-triazol-4-yl)-5-nitro-1H-indazole

embedded image

To a solution of 5-nitro-3-(1-((trimethylsilyl)methyl)-1H-1,2,3-triazol-4-yl)-1H-indazole (232 mg, 733.27 umol) in MeCN (3 mL) and EtOH (1.5 mL) was added CsF (222.77 mg, 1.47 mmol). The mixture was stirred at 80° C. for 2 hrs and concentrated. The residue was then diluted with H₂O (5 mL) and filtered. The solid was dried under vacuum to afford the title compound (97 mg) as a red solid which was used without further purification. MS-ESI (m/z) calcd for C₁₀H₉N₆O₂[M+H]⁺: 245.1. Found 245.0.

Step 6: 3-(1-Methyl-1H-1,2,3-triazol-4-yl)-1H-indazol-5-amine

embedded image

To a solution of 3-(1-methyl-1H-1,2,3-triazol-4-yl)-5-nitro-1H-indazole (97 mg, 397.20 umol) in EtOH (3 mL) was added SnCl₂.2H₂O (268.88 mg, 1.19 mmol). The mixture was then stirred at 80° C. for 2 hrs, then diluted with Na₂CO₃(5 mL) and extracted with EtOAc (10 mL×3). The combined organic layers were dried over Na₂SO₄, filtered and concentrated under reduced pressure to afford the title compound (53 mg) as a yellow solid which was used without further purification. MS-ESI (m/z) calcd for C₁₀H₁₁N₆[M+H]⁺: 215.1. Found 215.0.

Step 7: 5-Cyano-3,4-dimethyl-N-(3-(1-methyl-1H-1,2,3-triazol-4-yl)-1H-indazol-5-yl)picolinamide

embedded image

To a solution of 3-(1-methyl-1H-1,2,3-triazol-4-yl)-1H-indazol-5-amine (50 mg, 233.40 umol), 5-cyano-3,4-dimethylpicolinic acid (41.12 mg, 233.40 umol) in pyridine (2 mL) was added EDCI (67.11 mg, 350.10 umol). The mixture was stirred at 20° C. for 3 hrs, then concentrated and purified by preparative HPLC using Method AI to afford the title compound (11.31 mg, 10%) as a pale yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.20 (s, 1H), 10.72 (s, 1H), 8.88 (s, 1H), 8.81 (s, 1H), 8.50 (s, 1H), 7.71 (dd, J=1.76, 9.04 Hz, 1H), 7.57 (d, J=8.82 Hz, 1H), 4.15 (s, 3H), 2.55 (s, 3H), 2.45 (s, 3H). MS-ESI (m/z) calc'd for C₁₉H₁₇N₈O [M+H]⁺: 373.1. Found 373.1.

Example 241: 5-Cyano-3-methyl-N-(3-(1-methyl-1H-1,2,3-triazol-4-yl)-1H-indazol-5-yl)picolinamide

embedded image

Prepared as described for 5-cyano-3,4-dimethyl-N-(3-(1-methyl-1H-1,2,3-triazol-4-yl)-1H-indazol-5-yl)picolinamide using 5-cyano-3-methylpicolinic acid in place of 5-cyano-3,4-dimethylpicolinic acid to afford the title compound (20.01 mg, 18% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.18 (br s, 1H), 10.73 (s, 1H), 8.98 (d, J=1.47 Hz, 1H), 8.84 (d, J=1.34 Hz, 1H), 8.50 (s, 1H), 8.39 (d, J=0.98 Hz, 1H), 7.74 (dd, J=1.83, 9.05 Hz, 1H), 7.56 (d, J=8.80 Hz, 1H), 4.15 (s, 3H), 2.59 (s, 3H). MS-ESI (m/z) calc'd for C₁₈H₁₅N₅O [M+H]⁺: 359.1. Found 359.1.

Example 242: 5-Cyano-3-methyl-N-(3-(2-oxooxazol-3(2H)-yl)-1H-indazol-5-yl)picolinamide

embedded image

Step 1: 5-Nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-amine

embedded image

To a solution of 5-nitro-1H-indazol-3-amine (1.1 g, 6.17 mmol) in CHCl₃(20 mL) was added MsOH (29.67 mg, 308.73 umol, 21.98 uL) and 3,4-dihydro-2H-pyran (1.56 g, 18.52 mmol, 1.69 mL). The mixture was stirred at 70° C. for 12 hrs. The reaction mixture was concentrated and purified by flash silica gel chromatography (ISCO; 20 g SepaFlash column) using a 0-21% EtOAc/petroleum ether gradient eluent to afford the title compound (280 mg, 17%) as an orange solid. MS-(ESI) (m/z) calcd for C₁₂H₁₅N₄O₃(M+H)⁺: 263.1. Found 263.0.

Step 2: 2-Hydroxy-N-(5-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)acetamide

embedded image

To a solution of 5-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-amine (170 mg, 648.20 umol) in DCM (3 mL) was added Et₃N (72.15 mg, 713.02 umol) and 2-chloro-2-oxoethyl acetate (88.50 mg, 648.20 umol). The mixture was stirred at 20° C. for 1 hr and then concentrated. THF (3 mL), H₂O (1 mL) and LiOH.H₂O (54.40 mg, 1.30 mmol) was then added and the mixture was stirred at 20° C. for 12 hrs. The reaction mixture was concentrated and purified by preparative TLC (SiO₂, 1:1 petroleum ether/EtOAc, R_f=0.15) to afford the title compound (50 mg, 24%) as a yellow solid. MS-(ESI) (m/z) calcd for C₁₄H₁₇N₄O (M+H)⁺: 321.1. Found 321.1.

Step 3: 3-(5-Nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)oxazolidine-2,4-dione

embedded image

To a solution of 2-hydroxy-N-(5-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)acetamide (50 mg, 156.10 umol) in DMF (2 mL) was added 1,1′-carbonyldiimidazole (75.94 mg, 468.31 umol). The mixture was stirred at 20° C. for 12 hrs, then diluted with H₂O (3 mL) and extracted with EtOAc (10 mL×3). The combined organic layers were dried over Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO₂, 2:1 petroleum ether/EtOAc, R_f=0.25) to afford the title compound (50 mg, 92%) as a yellow oil. MS-(ESI) (m/z) calcd for C₁₈H₁₅N₄O₆(M+H): 347.1. Found 347.0.

Step 4: 4-Hydroxy-3-(5-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)oxazolidin-2-one

embedded image

Toa solution of 3-(5-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)oxazolidine-2,4-dione (90 mg, 259.89 umol) in MeOH (2 mL) was added NaBH₄(9.83 mg, 259.89 umol) at 0° C. The mixture was stirred at 0° C. for 1 hr, then quenched by addition of H₂O (3 mL) at 0° C. The mixture was concentrated and extracted with EtOAc (10 mL×3). The combined organic layers were dried over Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO₂, 1:1 petroleum ether/EtOAc, R_f=0.2) to afford the title compound (28 mg, 30%) as a yellow gum. MS-(ESI) (m/z) calcd for C₁₅H₁₇N₄O₆(M+H)⁺: 349.1. Found 349.0.

Step 5: 3-(5-Nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)oxazol-2(3H)-one

embedded image

To a solution of 4-hydroxy-3-(5-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)oxazolidin-2-one (50 mg, 143.55 umol), Et₃N (29.05 mg, 287.10 umol) and DMAP (1.75 mg, 14.36 umol) in DCE (2 mL) was added MsCl (246.66 mg, 2.15 mmol) at 0° C. The mixture was stirred at 65° C. for 16 hrs, quenched by addition of saturated aqueous Na₂CO₃(1 mL) at 20° C., and then diluted with saturated NH₄Cl (3 mL) and extracted with EtOAc (10 mL×3). The combined organic layers were dried over Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO₂, 1:1 petroleum ether/EtOAc, R_f=0.53) to afford the title compound (30 mg, 63%) as a yellow solid. MS-(ESI) (m/z) calcd for C₁₅H₁₅N₄O₅(M+H)⁺: 331.1. Found 331.1.

Step 6: 3-(5-Amino-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)oxazol-2(3H)-one

embedded image

To a solution of 3-(5-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)oxazol-2(3H)-one (30 mg, 90.83 umol) in EtOH (1 mL) and H₂O (0.5 mL) was added Fe (25.36 mg, 454.14 umol) and NH₄Cl (24.29 mg, 454.14 umol) and the mixture was stirred at 20° C. for 2 hrs. The reaction mixture was then filtered. The filtrate was concentrated under reduced pressure to afford the title compound (25 mg) as a brown solid which was used without further purification. MS-(ESI) (m/z) calcd for C₁₅H₁₇N₄O₃(M+H)⁺: 301.1. Found 301.1.

Step 7: 5-Cyano-3-methyl-N-(3-(2-oxooxazol-3(2H)-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)picolinamide

embedded image

To a solution of 5-cyano-3-methylpicolinic acid (13.50 mg, 83.25 umol) and 3-(5-amino-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)oxazol-2(3H)-one (25 mg, 83.25 umol) in pyridine (2 mL) was added EDCI (23.94 mg, 124.88 umol) and the mixture was stirred at 20° C. for 12 hrs. The reaction mixture was then concentrated to afford the title compound (35 mg) as a brown gum which was used without further purification. MS-(ESI) (m/z) calcd for C₂₃H₂₁N₆O₄(M+H)⁺: 445.15. Found 445.15.

Step 8: 5-Cyano-3-methyl-N-(3-(2-oxooxazol-3(2H)-yl)-1H-indazol-5-yl)picolinamide

embedded image

To a solution of 5-cyano-3-methyl-N-(3-(2-oxooxazol-3(2H)-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)picolinamide (35 mg, 78.75 umol) in DCM (1 mL) was added TFA (8.98 mg, 78.75 umol) and the mixture was stirred at 20° C. for 2 hrs. The reaction mixture was concentrated and purified by preparative HPLC using Method AI to afford the title compound (1.9 mg, 5%) as a pale yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.28 (s, 1H) 10.77 (s, 1H) 8.98 (d, J=1.32 Hz, 1H) 8.40 (br d, J=5.07 Hz, 2H) 7.77 (dd, J=8.93, 1.43 Hz, 1H) 7.58 (d, J=9.04 Hz, 1H) 7.55 (d, J=1.98 Hz, 1H) 7.50 (d, J=1.98 Hz, 1H) 2.56 (s, 3H). MS-ESI (m/z) calc'd for C₁₅H₁₃N₆O₃[M+H]⁺: 361.1. Found 361.1.

Example 243: 5-Cyano-3,4-dimethyl-N-(3-(2-methylprop-1-en-1-yl)-1H-indazol-5-yl)picolinamide

embedded image

Step 1: N-(3-Bromo-1H-indazol-5-yl)-5-cyano-3,4-dimethylpicolinamide

embedded image

To a solution of 3-bromo-1H-indazol-5-amine (500 mg, 2.36 mmol) and 5-cyano-3,4-dimethylpicolinic acid (415.41 mg, 2.36 mmol) in DCM (15 mL) was added T3P (50 wt. % in EtOAc, 1.95 g, 3.07 mmol, 1.82 mL) at 20° C. and the reaction mixture was stirred at 30° C. for 0.5 hr. Et₃N (477.20 mg, 4.72 mmol, 656.40 uL) was then added and the reaction mixture was stirred at 30° C. for 1 hr. The reaction mixture was poured into H₂O (15 mL) and stirred at 25° C. for 0.5 hr. Then the mixture was filtered and the solid was dried to afford the title compound as a brown solid (417 mg), which was used without further purification. MS-ESI (m/z) calcd for C₁₆H₁₃BrN₅O [M+H]⁺: 370.0/372.0. Found 370.0/372.0.

Step 2: 5-Cyano-3,4-dimethyl-N-(3-(2-methylprop-1-en-1-yl)-1H-indazol-5-yl)picolinamide

embedded image

To a solution of N-(3-bromo-1H-indazol-5-yl)-5-cyano-3,4-dimethylpicolinamide (50 mg, 135.06 umol) in EtOH (1 mL) and H₂O (0.25 mL) was added 4,4,5,5-tetramethyl-2-(2-methylprop-1-en-1-yl)-1,3,2-dioxaborolane (73.77 mg, 405.18 umol), KOAc (66.28 mg, 675.31 umol) and Pd(Amphos)Cl₂(9.56 mg, 13.51 umol) at 20° C. Then the reaction mixture was stirred at 90° C. for 12 hrs under N₂. The reaction mixture was filtered and concentrated and purified by preparative HPLC using Method AJ to afford the title compound (12.29 mg, 91%) as a white solid. ¹H NMR (400 MHz, DMSO-d₄) δ 12.92 (s, 1H), 10.65 (s, 1H), 8.88 (s, 1H), 8.30 (s, 1H), 7.57-7.52 (m, 1H), 7.50-7.46 (m, 1H), 6.44 (s, 1H), 2.55 (s, 3H), 2.44 (s, 3H), 2.13 (s, 3H), 1.99 (s, 3H). MS-ESI (m/z) calc'd for C₂₀H₂₀N₅₀[M+H]⁺: 346.2. Found 346.2.

Example 244: (E)-5-Cyano-3,4-dimethyl-N-(3-styryl-1H-indazol-5-yl)picolinamide

embedded image

Prepared as described for 5-cyano-3,4-dimethyl-N-(3-(2-methylprop-1-en-1-yl)-1H-indazol-5-yl)picolinamide using (E)-4,4,5,5-tetramethyl-2-styryl-1,3,2-dioxaborolane in place of 4,4,5,5-tetramethyl-2-(2-methylprop-1-en-1-yl)-1,3,2-dioxaborolane to afford the title compound (45.33 mg, 15%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.19 (s, 1H), 10.71 (s, 1H), 8.90 (s, 1H), 8.57 (s, 1H), 7.74 (d, J=9.0 Hz, 1H), 7.68 (d, J=7.5 Hz, 2H), 7.58-7.51 (m, 2H), 7.45-7.37 (m, 3H), 7.33-7.27 (m, 1H), 2.56 (s, 3H), 2.47 (s, 3H). MS-ESI (m/z) calc'd for C₂₄H₂₀N₅O [M+H]⁺: 394.2 Found 394.1.

Example 245: (E)-5-cyano-3,4-dimethyl-N-(3-(prop-1-en-1-yl)-1H-indazol-5-yl)picolinamide

embedded image

Prepared as described for 5-cyano-3,4-dimethyl-N-(3-(2-methylprop-1-en-1-yl)-1H-indazol-5-yl)picolinamide using (E)-4,4,5,5-tetramethyl-2-(prop-1-en-1-yl)-1,3,2-dioxaborolane in place of 4,4,5,5-tetramethyl-2-(2-methylprop-1-en-1-yl)-1,3,2-dioxaborolane to afford the title compound (127.86 mg, 55% yield) as a gray solid. ¹H NMR (400 MHz, DMSO-d₆) δ 12.92 (s, 1H), 10.67 (s, 1H), 8.89 (s, 1H), 8.47 (s, 1H), 7.68-7.61 (m, 1H), 7.50 (d, J=8.9 Hz, 1H), 6.72 (dd, J=1.6, 16.1 Hz, 1H), 6.56-6.45 (m, 1H), 2.56 (s, 3H), 2.45 (s, 3H), 1.96 (dd, J=1.4, 6.5 Hz, 3H). MS-ESI (m/z) calc'd for C₁₉H₁₅N₅O [M+H]⁺: 332.1 Found 332.2.

Example 246: 4-Cyano-N-(3-(isoxazol-4-yl)-1H-indazol-5-yl)-1,3-dimethyl-1H-pyrrole-2-carboxamide and Example 247: 4-Cyano-N-(3-(isoxazol-4-yl)-1H-indazol-5-yl)-1-methyl-1H-pyrrole-2-carboxamide

embedded image

Step 1: 2-((Methylamino)methylene)malononitrile

embedded image

To a solution of 2-(ethoxymethylene)malononitrile (1.1 g, 9.01 mmol) in EtOH (4 mL) was added methylamine (1.03 g, 9.91 mmol, 300% in EtOH). The mixture was stirred at 25° C. for 0.5 hr. The reaction mixture was filtered and the solid was dried under vacuum to afford the title compound (760 mg) as a yellow solid which was used without further purification.

Step 2: Ethyl 3-amino-4-cyano-1-methyl-1H-pyrrole-2-carboxylate

embedded image

To a solution of 2-((methylamino)methylene)malononitrile (630 mg, 5.88 mmol) in DMF (4 mL) was added ethyl 2-bromoacetate (982.24 mg, 5.88 mmol) and K₂CO₃(812.88 mg, 5.88 mmol). The mixture was stirred at 80° C. for 30 min. NaOEt (600.37 mg, 8.82 mmol) was then added and the mixture was stirred at 90° C. for 4.5 hrs. The reaction was filtered and the filtrate was diluted with H₂O (20 mL) and extracted with EtOAc (10 mL 3). The combined organic phases were dried over Na₂SO₄, filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO; 4 g SepaFlash column) using a 0-20% EtOAc/petroleum ether gradient eluent to afford the title compound (364 mg, 32%) as a yellow solid. MS-ESI (m/z) calcd for C₉H₁₂N₃O₂[M+H]⁺: 194.1. Found 194.3.

Step 3: Ethyl 4-cyano-3-iodo-1-methyl-1H-pyrrole-2-carboxylate

embedded image

To a solution of ethyl 3-amino-4-cyano-1-methyl-1H-pyrrole-2-carboxylate (360 mg, 1.86 mmol) in MeCN (6 mL) at 25° C. was added diiodomethane (1.80 g, 6.71 mmol). The mixture was then heated to 35° C. and isopentyl nitrite (545.71 mg, 4.66 mmol) was added. The reaction mixture was then stirred at 65° C. for an additional 10 min. The reaction mixture was diluted with H₂O (30 mL) and extracted with EtOAc (15 mL×3). The combined organic phases were dried over Na₂SO₄and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO; 4 g SepaFlash column) using a 0-8% EtOAc/petroleum ether gradient eluent to afford the title compound (266 mg, 47%) as a yellow solid. MS-ESI (m/z) calcd for C₉H₁₀IN₂O₂[M+H]⁺: 305.0. Found 304.9.

Step 4: Ethyl 4-Cyano-1,3-dimethyl-1H-pyrrole-2-carboxylate

embedded image

A mixture of ethyl 4-cyano-3-iodo-1-methyl-1H-pyrrole-2-carboxylate (300 mg, 986.57 umol), K₂CO₃(409.06 mg, 2.96 mmol), Pd(dppf)Cl₂(36.09 mg, 49.33 umol) and trimethylboroxine (247.70 mg, 1.97 mmol) in dioxane (5 mL) was degassed and purged with N₂(3×), and then the mixture was stirred at 100° C. for 12 hrs under an N₂atmosphere. The reaction was filtered and the filtrate was concentrated. The mixture was diluted with H₂O (5 mL) and extracted with EtOAc (2 mL×3). The combined organic phases were dried over Na₂SO₄and concentrated under reduced pressure to afford the title compound (200 mg) as a brown solid which was used without further purification. MS-ESI (m/z) calcd for C₁₀H₁₃N₂O₂[M+H]⁺: 193.1. Found 193.1.

Step 5: 4-Cyano-1,3-dimethyl-1H-pyrrole-2-carboxylic acid

embedded image

To a solution of ethyl 4-cyano-1,3-dimethyl-1H-pyrrole-2-carboxylate (80 mg, 416.20 umol) in EtOH (5 mL) was added NaOH (49.94 mg, 1.25 mmol). The reaction mixture was stirred at 25° C. for 12 hrs, then diluted with 1 M HCl to pH=4, and extracted with EtOAc (20 mL×3). The combined organic layers were dried over Na₂SO₄, filtered and concentrated under reduced pressure to afford the title compound (73 mg) as a brown solid which was used without further purification. MS-ESI (m/z) calcd for C₈H₉N₂O₂[M+H]⁺: 165.1. Found 165.0.

Step 6: 4-Cyano-N-(3-(isoxazol-4-yl)-1H-indazol-5-yl)-1,3-dimethyl-1H-pyrrole-2-carboxamide and 4-Cyano-N-(3-(isoxazol-4-yl)-1H-indazol-5-yl)-1-methyl-1H-pyrrole-2-carboxamide

embedded image

To a solution of 4-cyano-1,3-dimethyl-1H-pyrrole-2-carboxylic acid (100 mg, 609.16 umol) in pyridine (20 mL) was added EDCI (233.55 mg, 1.22 mmol) and 3-(isoxazol-4-yl)-1H-indazol-5-amine (121.95 mg, 609.16 umol). The mixture was stirred at 25° C. for 12 hrs and then concentrated. The material was purified by preparative HPLC using Method AK to afford a mixture of products. The mixture was further separated by SFC using Method AL to give two compounds. 4-cyano-N-(3-(isoxazol-4-yl)-1H-indazol-5-yl)-1,3-dimethyl-1H-pyrrole-2-carboxamide (5.69 mg, 3%) was isolated as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.32 (s, 1H), 10.14 (s, 1H), 9.52 (s, 1H), 9.13 (s, 1H), 8.31 (s, 1H), 7.72 (s, 1H), 7.55-7.63 (m, 2H), 3.76 (s, 3H), 2.31 (s, 3H). MS-ESI (m/z) calc'd for C₁₈H₁₅N₆O₂[M+H]⁺: 347.1 Found 347.1. A second fraction was isolated to afford 4-cyano-N-(3-(isoxazol-4-yl)-1H-indazol-5-yl)-1-methyl-1H-pyrrole-2-carboxamide (2.04 mg, 1%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) 13.35 (br s, 1H), 10.16 (s, 1H), 9.55-9.61 (m, 1H), 9.15 (s, 1H), 8.27 (s, 1H), 7.87 (d, J=1.38 Hz, 1H), 7.65-7.68 (m, 1H), 7.59-7.61 (m, 1H), 7.44 (d, J=1.50 Hz, 1H), 3.95 (s, 3H).). MS-ESI (m/z) calc'd for C₁₇H₁₃N₆O₂[M+H]⁺: 333.1 Found 333.1.

Example 248: (E)-5-Cyano-3,4-dimethyl-N-(3-(2-(pyridin-2-yl)vinyl)-1H-indazol-5-yl)picolinamide

embedded image

Step 1: 3-Iodo-5-nitro-1H-indazole

embedded image

To a solution of 5-nitro-1H-indazole (5 g, 30.65 mmol) in DMF (75 mL) was added KOH (6.02 g, 107.27 mmol) and I₂(23.34 g, 91.95 mmol). The mixture was stirred at 65° C. for 1 hr. The reaction mixture was quenched by addition of an aqueous solution of Na₂S₂O₃(700 mL) at 20° C., and then extracted with EtOAc (150 mL×3). The combined organic layers were dried over Na₂SO₄, filtered and concentrated under reduced pressure to afford the title compound (8.86 g) as a yellow solid which was used without further purification.

Step 2: 3-Iodo-5-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole

embedded image

To a solution of 3-iodo-5-nitro-1H-indazole (8 g, 27.68 mmol) and 3,4-dihydro-2H-pyran (6.98 g, 83.04 mmol, 7.59 mL) in CHCl₃(100 mL) was added MsOH (2.66 g, 27.68 mmol). The mixture was stirred at 70° C. for 12 hrs and then concentrated. The material was purified by flash silica gel chromatography (ISCO; 40 g SepaFlash column) using a 0-10% EtOAc/petroleum ether gradient eluent to afford the title compound (5.01 g, 37%) as a yellow solid. MS-ESI (m/z) calcd for C₁₂H₁₃IN₃O₃[M+H]⁺: 374.0. Found 373.9.

Step 3: 3-Iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-amine

embedded image

To a solution of 3-iodo-5-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (1 g, 2.68 mmol) in EtOH (24 mL) and H₂O (6 mL) was added Fe (748.30 mg, 13.40 mmol) and NH₄Cl (716.76 mg, 13.40 mmol). The mixture was stirred at 25° C. for 2 hrs and then filtered. The filtrate was concentrated under reduced pressure to remove solvent and then diluted with H₂O (100 mL) and extracted with EtOAc (100 mL×3). The organic phase was dried over Na₂SO₄, filtered and concentrated under reduced pressure to afford the title compound (755 mg) as a brown oil which was used without further purification. MS-ESI (m/z) calcd for C₁₂H₁₅IN₃O [M+H]⁺: 344.0. Found 344.0.

Step 4: 5-Cyano-N-(3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-3,4-dimethylpicolinamide

embedded image

To a solution of 3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-amine (200 mg, 582.81 umol), 5-cyano-3,4-dimethylpicolinic acid (102.68 mg, 582.81 umol) in pyridine (4 mL) was added EDCI (167.59 mg, 874.22 umol). The mixture was stirred at 25° C. for 12 hrs and then concentrated under reduced pressure to remove solvent. The residue was diluted with H₂O (5 mL) and extracted with EtOAc (5 mL×3). The combined organic layers were dried over Na₂SO₄, filtered and concentrated under reduced pressure to afford the title compound (264 mg) as a yellow solid which was used without further purification. MS-ESI (m/z) calcd for C₂₁H₂₁IN₅O₂[M+H]⁺: 502.1. Found 502.0

Step 5: (E)-5-Cyano-3,4-dimethyl-N-(3-(2-(pyridin-2-yl)vinyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)picolinamide

embedded image

A mixture of 5-cyano-N-(3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-3,4-dimethylpicolinamide (60 mg, 119.68 umol), 2-vinylpyridine (15.10 mg, 143.62 umol, 15.50 uL), Pd(OAc)₂(2.69 mg, 11.97 umol), Et₃N (12.11 mg, 119.68 umol) and tris-o-tolylphosphane (3.64 mg, 11.97 umol) in DMF (2 mL) was degassed and purged with N₂(3×). The mixture was then stirred at 120° C. for 4 hrs under an N₂atmosphere in a microwave. The residue was diluted with H₂O (5 mL) and extracted with EtOAc (5 mL×3). The organic phase was dried over Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO₂, petroleum ether/EtOAc=1/1, R_f=0.37) to afford the title compound (37 mg, 65%) as a yellow solid. MS-ESI (m/z) calcd for C₂₈H₂₇N₆O₂[M+H]⁺: 479.2. Found 479.2.

Step 6: (E)-5-Cyano-3,4-dimethyl-N-(3-(2-(pyridin-2-yl)vinyl)-1H-indazol-5-yl)picolinamide

embedded image

To a solution of (E)-5-cyano-3,4-dimethyl-N-(3-(2-(pyridin-2-yl)vinyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)picolinamide (37.00 mg, 77.32 umol) in DCM (2 mL) was added TFA (0.5 mL). The mixture was stirred at 25° C. for 1 hr. The reaction mixture was concentrated and purified by preparative HPLC using Method AI to afford the title compound (10.86 mg, 33%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.49 (br s, 1H), 10.78 (s, 1H), 8.91 (s, 1H), 8.69 (br s, 1H), 8.67 (br s, 1H), 8.05-8.13 (m, 2H), 8.00 (br s, 1H), 7.69-7.72 (m, 1H), 7.61-7.64 (m, 1H), 7.53 (br d, J=16.51 Hz, 1H), 7.45-7.50 (m, 1H), 2.57 (s, 3H), 2.48 (s, 3H). MS-ESI (m/z) calc'd for C₂₃H₁₉N₆O [M+H]⁺: 395.2 Found 395.1.

Example 249: 5-Cyano-4-methoxy-N-(3-(oxazol-5-yl)-1H-indazol-5-yl)picolinamide

embedded image

Step 1: 6-(1-Ethoxyvinyl)-4-methoxynicotinonitrile

embedded image

To a solution of 6-chloro-4-methoxynicotinonitrile (500 mg, 2.97 mmol) in dioxane (5 m L) was added tributyl(1-ethoxyvinyl)stannane (1.29 g, 3.56 mmol) and Pd(PPh₃)₂Cl₂(208.18 mg, 296.59 umol). The mixture was stirred at 100° C. for 12 hrs under an N₂atmosphere. The reaction mixture was concentrated and purified by flash silica gel chromatography (ISCO; 4 g SepaFlash column) using a 0-15% EtOAc/petroleum ether gradient eluent to afford the title compound (500 mg, 83%) as a light yellow solid. MS-ESI (m/z) calcd for C₁₁H₁₃N₂O₂[M+H]⁺: 205.1. Found 205.3.

Step 2: Ethyl 5-cyano-4-methoxypicolinate

embedded image

To a solution of 6-(1-ethoxyvinyl)-4-methoxynicotinonitrile (285 mg, 1.40 mmol) in dioxane (4 mL) was added NaIO₄(596.98 mg, 2.79 mmol) in H₂O (2 mL) and KMnO₄(33.08 mg, 209.33 umol). The mixture was stirred at 25° C. for 1 hr. The process was repeated using 200 mg of 6-(1-ethoxyvinyl)-4-methoxynicotinonitrile and the reaction mixtures were combined and filtered. The filtrate was diluted with saturated aqueous NaHCO₃(10 mL) and extracted with EtOAc (5 mL×3). The combined organic layers were dried over Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO; 10 g SepaFlash column) using a 0-30% EtOAc/petroleum ether gradient eluent to afford the title compound (150 mg, 52%) as a white solid. MS-ESI (m/z) calcd for C₁₀H₁₁N₂O₃[M+H]⁺: 207.1. Found 207.0.

Step 3: 5-Cyano-4-methoxypicolinic acid

embedded image

To a solution of ethyl 5-cyano-4-methoxypicolinate (100 mg, 484.97 umol) in THF (1 mL) and H₂O (1 mL) was added NaOH (23.28 mg, 581.97 umol) and the mixture was stirred at 20° C. for 0.5 hr. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue obtained was diluted with H₂O (10 mL) and treated with 1 M HCl to adjust the pH to about 3. The formed solid was filtered and the solid was dried under reduced pressure to afford the title compound (70 mg) as a light yellow solid which was used without further purification. MS-ESI (m/z) calcd for C₈H₇N₂O₃[M−H]⁻: 177.0. Found 177.0.

Step 4: 5-Cyano-4-methoxy-N-(3-(oxazol-5-yl)picolinamide

embedded image

To a solution of 5-cyano-4-methoxypicolinic acid (70 mg, 392.94 umol) and 3-(oxazol-5-yl)-1H-indazol-5-amine (78.67 mg, 392.94 umol) in pyridine (1 mL) was added EDCI (150.65 mg, 785.88 umol) and the mixture was stirred at 20° C. for 12 hrs. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue obtained was triturated in 5 mL of EtOAc and 1 mL of MeOH for 2 hrs and then the mixture was filtered and the solid was washed with EtOAc (3 mL×3). The solid was dried under reduced pressure to afford the title compound (49.92 mg, 32%) as a pale yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.51 (s, 1H) 10.90 (s, 1H) 9.00 (s, 1H) 8.71 (s, 1H) 8.57 (s, 1H) 7.89-8.02 (m, 2H) 7.55-7.70 (m, 2H) 4.15 (s, 3H). MS-ESI (m/z) calc'd for C₁₈H₁₃N₆O₃[M+H]⁺: 361.1 Found 361.1.

Example 250: 5-Cyano-N-(3-(oxazol-5-yl)-1H-indazol-5-yl)-3-(prop-1-en-2-yl)picolinamide

embedded image

Step 1: 6-Chloro-5-(prop-1-ent-2-yl)nicotinonitrile

embedded image

To a solution of 5-bromo-6-chloronicotinonitrile (1 g, 4.60 mmol) in EtOH (12 mL) and H₂O (3 mL) was added 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (850.05 mg, 5.06 mmol), Pd(Amphos)Cl₂(325.63 mg, 459.87 umol) and KOAc (1.35 g, 13.80 mmol) at 20° C. The mixture was stirred at 100° C. for 1.5 hrs under an N₂atmosphere. The reaction mixture was concentrated and purified by flash silica gel chromatography (ISCO; 20 g SepaFlash column) using a 0-6% EtOAc/petroleum ether gradient eluent to afford the title compound (700 mg, 85%) as a pale yellow oil. MS-ESI (m/z) calcd for C₉H₈ClN₂[M+H]⁺: 179.0/181.0. Found 179.0/181.0.

Step 2: Methyl 5-cyano-3-(prop-1-en-2-yl)picolinate

embedded image

A mixture of 6-chloro-5-(prop-1-en-2-yl)nicotinonitrile (800 mg, 4.48 mmol), Pd(dppf)Cl₂(327.72 mg, 447.88 umol), Et₃N (2.27 g, 22.39 mmol) in MeOH (10 mL) was degassed and purged with CO (3×) at 20° C., and then the mixture was stirred at 50° C. for 24 hrs under a CO atmosphere (30 psi). The reaction mixture was concentrated and purified by flash silica gel chromatography (ISCO; 20 g SepaFlash column) using a 0-9% EtOAc/petroleum ether gradient eluent to afford the title compound (430 mg, 47%) as a white oil. MS-ESI (m/z) calcd for C₁₁H₁₀N₂O₂[M+H]⁺: 203.1. Found 203.1.

Step 3: 5-Cyano-3-(prop-1-en-2-yl)picolinic acid

embedded image

To a solution of methyl 5-cyano-3-(prop-1-en-2-yl)picolinate (30 mg, 148.36 umol) in THF (1 mL) and H₂O (0.5 mL) was added LiOH.H₂O (12.45 mg, 296.72 umol) and the mixture was stirred at 20° C. for 15 min. The reaction mixture was then adjusted to pH=3 with 2 N HCl and extracted with EtOAc (10 mL×3). The combined organic layers were dried over Na₂SO₄, filtered and concentrated under reduced pressure to afford the title compound (25 mg) as a white solid which was used without further purification. MS-ESI (m/z) calcd for C₁₀H₉N₂O₂[M+H]⁺: 189.1. Found 189.0.

Step 4: 5-Cyano-N-(3-(oxazol-5-yl)-1H-indazol-5-yl)-3-(prop-1-en-2-yl)picolinamide

embedded image

To a solution of 5-cyano-3-(prop-1-en-2-yl)picolinic acid (25 mg, 132.85 umol) in pyridine (1 mL) was added EDCI (25.47 mg, 132.85 umol) and 3-(oxazol-5-yl)-1H-indazol-5-amine (26.60 mg, 132.85 umol) and the mixture was stirred at 20° C. for 12 hrs. The reaction mixture was concentrated and purified by preparative HPLC using Method AN to afford the title compound (5.45 mg, 8%) as a yellow solid TFA salt. ¹H NMR (400 MHz, DMSO-d₆) δ 13.52 (s, 1H) 10.81 (s, 1H) 9.06 (d, J=1.47 Hz, 1H) 8.59 (s, 1H) 8.51 (s, 1H) 8.45 (d, J=1.47 Hz, 1H) 7.67-7.71 (m, 1H) 7.59-7.65 (m, 2H) 5.26 (s, 1H) 5.13 (s, 1H) 2.11 (s, 3H). MS-ESI (m/z) calc'd for C₂₀H₁₅N₆O₂[M+H]⁺: 371.1 Found 371.1.

Example 251: 5-Cyano-3-isopropyl-N-(3-(oxazol-5-yl)-1H-indazol-5-yl)picolinamide

embedded image

A mixture of 5-cyano-N-(3-(oxazol-5-yl)-1H-indazol-5-yl)-3-(prop-1-en-2-yl)picolinamide (100 mg, 270.00 umol), 10% Pd/C (100 mg) in EtOH (5 mL) was degassed and purged with H₂(3×), and the mixture was stirred at 15° C. for 12 hrs under an H₂atmosphere (15 psi). The reaction mixture was filtered and the filtrate was concentrated and purified by preparative HPLC using Method AO to afford the title compound (6.89 mg, 5%) as a white solid TFA salt. ¹H NMR (400 MHz, DMSO-de) δ 13.53 (br s, 1H) 10.81 (s, 1H) 8.98 (s, 1H) 8.58 (br d, J=11.86 Hz, 3H) 7.72 (br d, J=8.68 Hz, 1H) 7.59-7.69 (m, 2H) 3.47-3.54 (m, 1H) 1.27 (br d, J=6.72 Hz, 6H). MS-ESI (m/z) calc'd for C₂₀H₁₇N₆O₂[M+H]⁺: 373.1 Found 373.1.

Example 252: 5-Cyano-3,4-dimethyl-N-(3-((1R)-2-phenylcyclopropyl)-1H-indazol-5-yl)picolinamide

embedded image

Step 1: 5-Nitro-3-((1R)-2-phenylcyclopropyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole

embedded image

To a solution of 3-iodo-5-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (100 mg, 267.99 umol) in dioxane (2 mL) and H₂O (0.2 mL) was added 4,4,5,5-tetramethyl-2-((1R,2R)-2-phenylcyclopropyl)-1,3,2-dioxaborolane (65.43 mg, 267.99 umol), K₂CO₃(111.11 mg, 803.98 umol) and Pd(dppf)Cl₂(19.61 mg, 26.80 umol) at 20° C. The mixture was then stirred at 90° C. for 12 hrs under an N₂atmosphere. The process was repeated using 100 mg of 3-iodo-5-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole and the reaction mixtures were combined and concentrated. The material was purified by flash silica gel chromatography (ISCO; 25 g SepaFlash column) using a 0-8% EtOAc/petroleum ether gradient eluent to afford the title compound (60 mg, 80%) as a yellow solid. MS-ESI (m/z) calcd for C₂₁H₂₂N₃O₃[M+H]⁺: 364.2. Found 364.2.

Step 2: 3-((JR)-2-Phenylcyclopropyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-amine

embedded image

To a solution of 5-nitro-3-((1R)-2-phenylcyclopropyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (60 mg, 165.10 umol) in EtOH (1 mL) and H₂O (0.5 mL) was added Fe (46.10 mg, 825.52 umol) and NH₄Cl (44.16 mg, 825.52 umol) at 20° C. and the mixture was stirred at 80° C. for 1 hr. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was diluted with saturated aqueous NaHCO₃(10 mL) and extracted with EtOAc (2 mL 3). The combined organic layers were washed with brine (10 mL×1), dried over Na₂SO₄, filtered and concentrated under reduced pressure to afford the title compound (60 mg) as a brown oil which was used without further purification. MS-ESI (m/z) calcd for C₂₁H₂₄N₃O [M+H]⁺: 334.2. Found 334.3.

Step 3: 5-Cyano-3,4-dimethyl-N-(3-((1R)-2-phenylcyclopropyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)picolinamide

embedded image

To a solution of 3-((1R)-2-phenylcyclopropyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-amine (60 mg, 179.95 umol) in pyridine (1 mL) was added 5-cyano-3,4-dimethylpicolinic acid (31.70 mg, 179.95 umol) and EDCI (68.99 mg, 359.90 umol) at 20° C. and the mixture was stirred at 20° C. for 12 hrs. The reaction mixture was then concentrated under reduced pressure to remove solvent. The residue was diluted with H₂O (10 mL) and extracted with EtOAc (2 mL×3). The combined organic layers were washed with brine (5 mL), dried over Na₂SO₄, filtered and concentrated under reduced pressure to afford the title compound (100 mg) as a brown oil which was used without further purification. MS-ESI (m/z) calcd for C₃₀H₃ON₅O₂[M+H]⁺: 492.2. Found 492.2.

Step 4: 5-Cyano-3,4-dimethyl-N-(3-((1R)-2-phenylcyclopropyl)-1H-indazol-5-yl)picolinamide

embedded image

To a solution of 5-cyano-3,4-dimethyl-N-(3-((1R)-2-phenylcyclopropyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)picolinamide (100 mg, 203.42 umol) in MeOH (2 mL) and H₂O (0.4 mL) was added PTSA (175.15 mg, 1.02 mmol) and the mixture was stirred at 70° C. for 3 hrs. The process was repeated using 30 mg of 5-cyano-3,4-dimethyl-N-(3-((1R)-2-phenylcyclopropyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)picolinamide and the reaction mixtures were combined and concentrated under reduced pressure to remove solvent. The residue was purified by preparative HPLC using Method AP to afford the title compound (7 mg, 8%) as a light yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 10.06 (s, 1H) 9.69 (br s, 1H) 8.65 (s, 1H) 8.29 (s, 1H) 7.60 (dd, J=8.82, 1.67 Hz, 1H) 7.45 (d, J=8.82 Hz, 1H) 7.30-7.36 (m, 2H) 7.19-7.25 (m, 3H) 2.84 (s, 3H) 2.64 (s, 3H) 2.60 (dd, J=8.58, 5.48 Hz, 1H) 2.51-2.57 (m, 1H) 1.82 (dt, J=8.64, 5.33 Hz, 1H) 1.54 (br s, 1H). MS-ESI (m/z) calc'd for C₂₅H₂₂N₆O [M+H]⁺: 408.2. Found 408.2.

Example 253: N-(3-(Azetidin-1-yl)-1H-indazol-5-yl)-5-cyano-3-methylpicolinamide

embedded image

Step 1: 3-(Azetidin-1-yl)-5-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole

embedded image

To a mixture of azetidine hydrochloride (752.16 mg, 8.04 mmol) in toluene (66 mL) was added Cs₂CO₃(2.62 g, 8.04 mmol) and the mixture was stirred at 15° C. for 10 min. 3-Iodo-5-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (1 g, 2.68 mmol) was then added followed by BINAP (166.87 mg, 267.99 umol) and Pd₂(dba)₃(245.40 mg, 267.99 umol). The mixture was degassed and purged with N₂(3×), and stirred at 100° C. for 12 hrs under an N₂atmosphere. The reaction was filtered and the filtrate was concentrated to give a residue. The residue was purified by flash silica gel chromatography (ISCO; 40 g SepaFlash column) using a 0-9% EtOAc/petroleum ether gradient eluent to afford the title compound (240 mg, 29%) as a yellow solid. MS-ESI (m/z) calcd for C₁₅H₁₈N₄O₃[M+H]⁺: 303.1. Found 303.1.

Step 2: 3-(Azetidin-1-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-amine

embedded image

To a solution of 3-(azetidin-1-yl)-5-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (240 mg, 793.84 umol) in THF (15 mL) and H₂O (3 mL) was added Zn (519.09 mg, 7.94 mmol) and NH₄Cl (764.33 mg, 14.29 mmol) at 25° C. The mixture was stirred at 25° C. for 0.5 hr and then filtered. The filtrate was diluted with H₂O (40 mL) and extracted with EtOAc (30 mL×3). The combined organic phases were dried over Na₂SO₄and concentrated to afford the title compound (190 mg) as a yellow oil which was used without further purification. MS-ESI (m/z) calcd for C₁₅H₂₁N₄O [M+H]⁺: 273.2. Found 273.2.

Step 3: N-(3-(Azetidin-1-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-5-cyano-3-methylpicolinamide

embedded image

To a solution of 5-cyano-3-methylpicolinic acid (41.68 mg, 257.03 umol) in pyridine (3 mL) was added EDCI (73.91 mg, 385.54 umol) and 3-(azetidin-1-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-amine (70 mg, 257.03 umol) at 20° C. The mixture was stirred at 20° C. for 12 hrs and then concentrated. The mixture was diluted with H₂O (10 mL) and extracted with EtOAc (5 mL×4). The combined organic phases were dried over Na₂SO₄, filtered, and the filtrate was concentrated under vacuum to afford the title compound (95 mg) as a brown solid which was used without further purification. MS-ESI (m/z) calcd for C₂₃H₂₅N₆O₂[M+H]⁺: 417.2. Found 417.2.

Step 4: N-(3-(Azetidin-1-yl)-1H-indazol-5-yl)-5-cyano-3-methylpicolinamide

embedded image

A solution of N-(3-(azetidin-1-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-5-cyano-3-methylpicolinamide (95 mg, 228.11 umol) in TFA (0.8 mL) and DCM (3 mL) was stirred at 20° C. for 6 hrs. The reaction was filtered and the filtrate was concentrated. The material was purified by preparative HPLC using Method AQ to give material of insufficient purity. The material was then further purified by preparative HPLC using Method AR to afford the title compound (6.47 mg, 6%, TFA salt) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.79 (s, 1H), 10.59 (s, 1H), 8.97 (s, 1H), 8.39 (s, 1H), 8.07 (s, 1H), 7.63 (dd, J=8.93, 1.87 Hz, 1H), 7.29 (d, J=9.04 Hz, 1H), 4.03 (t, J=7.28 Hz, 4H), 2.57 (s, 3H), 2.38 (quin, J=7.22 Hz, 2H). MS-ESI (m/z) calc'd for C₁₈H₁₇N₆O [M+H]⁺: 333.1. Found 333.2.

Example 254: 5-Cyano-N-(3-(3,3-difluoroazetidin-1-yl)-1H-indazol-5-yl)-3-methylpicolinamide

embedded image

Step 1: 3-(3,3-Difluoroazetidin-1-yl)-5-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole

embedded image

A mixture of 3-iodo-5-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (260 mg, 696.78 umol), 3,3-difluoroazetidine hydrochloride (270.77 mg, 2.09 mmol), t-BuONa (334.80 mg, 3.48 mmol), t-BuXPhos-Pd-G3 (44.21 mg, 48.77 umol) in toluene (20 mL) was degassed and purged with N₂(3×), and then the mixture was stirred at 110° C. for 12 hrs under an N₂atmosphere. The process was repeated with an additional 50 mg of 3-iodo-5-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole and the reaction mixtures were combined and concentrated. The material was purified by flash silica gel chromatography (ISCO; 12 g SepaFlash column) using a 0-9% EtOAc/petroleum ether gradient eluent to afford the title compound (145 mg, 62%) as a yellow solid. MS-ESI (m/z) calcd for C₁₅H₁₇F₂N₄O₃[M+H]⁺: 339.1. Found 339.0.

Step 2: 5-Cyano-N-(3-(3,3-difluoroazetidin-1-yl)-1H-indazol-5-yl)-3-methylpicolinamide

embedded image

Prepared as described for N-(3-(azetidin-1-yl)-1H-indazol-5-yl)-5-cyano-3-methylpicolinamide using 3-(3,3-difluoroazetidin-1-yl)-5-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole in place of 3-(azetidin-1-yl)-5-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole. ¹H NMR (400 MHz, DMSO-d₆) δ 12.13 (s, 1H), 10.65 (s, 1H), 8.99 (d, J=1.43 Hz, 1H), 8.40 (d, J=1.07 Hz, 1H), 8.06 (s, 1H), 7.69 (dd, J=1.79, 9.06 Hz, 1H), 7.37 (d, J=8.94 Hz, 1H), 4.49 (t, J=12.58 Hz, 4H), 2.58 (s, 3H). MS-ESI (m/z) calc'd for C₁₈H₁₅F₂N₆O [M+H]⁺: 369.1 Found 369.2.

Example 255: N-(3-(Benzyloxy)-1H-indazol-5-yl)-5-cyano-3-methylpicolinamide

embedded image

Step 1: 5-Nitro-1H-indazol-3-ol

embedded image

To a solution of methyl 2-bromo-5-nitrobenzoate (1 g, 3.85 mmol) in EtOH (1.5 mL) was added NH₂NH₂.H₂O (1.96 g, 38.46 mmol) at 25° C., and the mixture was stirred at 90° C. for 2 hrs. HCl (1 M, 20 mL) was added dropwise until a solid formed, then the mixture was filtered and the solid was dried under vacuum to afford the title compound (533 mg, 77%) as a brown solid, which was used without further purification. MS-ESI (m/z) calcd for C₇H₆N₃O₃[M+H]⁺: 180.0. Found 180.3.

Step 2: Ethyl 3-hydroxy-5-nitro-1H-indazole-1-carboxylate

embedded image

To a solution of 5-nitro-1H-indazol-3-ol (500 mg, 2.79 mmol) in pyridine (3 mL) was added ethyl chloroformate (348.35 mg, 3.21 mmol) at 25° C. The mixture was stirred at 70° C. for 5 hrs. Additional ethyl chloroformate (181.75 mg, 1.67 mmol) was added and stirring was continued at 70° C. for 2.5 hrs. The reaction was poured into H₂O (10 mL) and extracted with EtOAc (10 mL×3). The organic layer was dried over Na₂SO₄, filtered and the filtrate was concentrated to give a residue. The residue was washed with EtOAc (8 mL) and filtered and the solid was dried under vacuum to afford the title compound (336 mg, 46%) as a light yellow solid, which was used without further purification. MS-ESI (m/z) calcd for C₁₀H₁₀N₃O₅[M+H]⁺: 252.1. Found 252.0.

Step 3: 3-(Benzyloxy)-5-nitro-1H-indazole

embedded image

To a solution of ethyl 3-hydroxy-5-nitro-1H-indazole-1-carboxylate (50 mg, 199.05 umol) and K₂CO₃(68.77 mg, 497.62 umol) in acetone (2 mL) was added (bromomethyl)benzene (37.45 mg, 218.95 umol) at 20° C. The mixture was stirred at 70° C. for 12 hrs and then concentrated to give a residue. The residue was washed with MeOH (2 mL), and filtered. The filtrate was purified by preparative TLC (silica gel, petroleum ether/EtOAc=3/1, Rt=0.35) to afford the title compound (19 mg, 35%) as a yellow solid. MS-ESI (m/z) calcd for C₁₄H₁₁N₃O₃[M+H]⁺: 270.1. Found 270.3.

Step 4: 3-(Benzyloxy)-1H-indazol-5-amine

embedded image

To a solution of 3-(benzyloxy)-5-nitro-1H-indazole (19 mg, 70.57 umol) in EtOH (2 mL) and H₂O (0.5 mL) was added Fe (19.70 mg, 352.83 umol) and NH₄Cl (18.87 mg, 352.83 umol), then the mixture was stirred at 80° C. for 1 hr. The reaction was filtered and the filtrate was concentrated under vacuum to afford the title compound (30 mg) as a brown liquid, which was used without further purification. MS-ESI (m/z) calcd for C₁₄H₁₄N₃O [M+H]⁺: 240.1. Found 240.4.

Step 5: N-(3-(Benzyloxy)-1H-indazol-5-yl)-5-cyano-3-methylpicolinamide

embedded image

To a solution of 3-(benzyloxy)-1H-indazol-5-amine (30 mg, 125.38 umol) and 5-cyano-3-methylpicolinic acid (24.40 mg, 150.46 umol) in pyridine (1 mL) was added EDCI (36.05 mg, 188.07 umol) at 20° C. and the mixture was stirred at 20° C. for 2 hrs. The reaction mixture was then concentrated to give a residue. The residue was purified by preparative HPLC using Method AS to afford the title compound (3.83 mg, 8%) as a pale yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.95 (s, 1H) 10.68 (s, 1H) 8.98 (s, 1H) 8.39 (s, 1H) 8.24 (s, 1H) 7.61 (dd, J=9.04, 1.98 Hz, 1H) 7.53 (d, J=7.28 Hz, 2H) 7.32-7.44 (m, 4H) 5.40 (s, 2H) 2.56 (s, 3H). MS-ESI (m/z) calc'd for C₂₂H₁₈N₅O₂[M+H]⁺: 384.1 Found 384.2.

Example 256: 5-Cyano-3-methyl-N-(3-(oxetan-3-yl)-1H-indazol-5-yl)picolinamide

embedded image

Step 1: 3-Iodo-5-nitro-1H-indazole

embedded image

To a solution of 5-nitro-1H-indazole (2 g, 12.26 mmol) in DMF (20 mL) was added KOH (2.61 g, 46.59 mmol) and I₂(6.22 g, 24.52 mmol) at 25° C. The mixture was stirred at 65° C. for 2 hrs and then poured into saturated aqueous Na₂SO₃(200 mL). A yellow solid formed that was filtered, washed with H₂O (100 mL×2), and dried under vacuum to afford the title compound (3.86 g) as a brown solid which was used without further purification.

Step 2: 3-Iodo-5-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole

embedded image

To a solution of 3-iodo-5-nitro-1H-indazole (3.8 g, 13.15 mmol) in CHCl₃(40 mL) was added MsOH (126.35 mg, 1.31 mmol) and 3,4-dihydro-2H-pyran (1.69 g, 20.03 mmol) at 25° C. The mixture was stirred at 80° C. for 12 hrs and then concentrated to afford a residue. The residue was purified by flash silica gel chromatography (ISCO; 25 g SepaFlash column) using a 0-10% EtOAc/petroleum ether gradient eluent to afford the title compound (2.7 g, 55%) as a yellow solid.

Step 3: 5-Nitro-3-(oxetan-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole

embedded image

A mixture of 3-iodo-5-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (400 mg, 1.07 mmol), 3-iodooxetane (394.43 mg, 2.14 mmol), Na₂CO₃(227.23 mg, 2.14 mmol), [Ir(dF(Me)ppy)₂(dtbbpy)]PF₆(10.87 mg, 10.72 umol) and NiCl₂glyme (1.18 mg, 5.36 umol), 4,4′-di-tert-butyl-2,2′-dipyridyl (1.44 mg, 5.36 umol) tris(trimethylsilyl)silane (266.56 mg, 1.07 mmol) in DME (8 mL) was degassed and purged with N₂(3×), and then the mixture was stirred at 25° C. for 12 hrs under an Ar atmosphere while shining a 34 Watt, KessilWide Angle blue LED Grow Light. For similar conditions, see: Zhang, P., Le, C., MacMillian D. W. C. Silyl Radical Activation of Alkyl Halides in Metallaphotoredox Cataylis: A Unique Pathway for Cross-Electrophile Coupling. J Am. Chem. Soc., 2016, 138, 8084-8087. The reaction mixture was concentrated and purified by flash silica gel chromatography (ISCO; 40 g SepaFlash column) using a 0-20% EtOAc/petroleum ether gradient eluent to afford the title compound (220 mg, 7%) as an orange solid. MS-ESI (m/z) calcd for C₁₉H₁₈N₃O₄[M+H]⁺: 304.1. Found 304.2

Step 4: 3-(Oxetan-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-amine

embedded image

To a solution of 5-nitro-3-(oxetan-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (80 mg, 263.75 umol) in H₂O (1 mL) and THF (5 mL) was added NH₄Cl (253.95 mg, 4.75 mmol) and Zn (172.47 mg, 2.64 mmol) at 20° C. and the mixture was stirred for 0.5 hr. The reaction mixture was then filtered and the filtrate was diluted with H₂O (10 mL) and extracted with EtOAc (5 mL×4). The combined organic layers were dried over Na₂SO₄, filtered and concentrated to afford the title compound (87 mg) as a brown gum which was used without further purification. MS-ESI (m/z) calcd for C₁₉H₂₀N₃O₂[M+H]⁺: 274.2. Found 274.1

Step 5: 5-Cyano-3-methyl-N-(3-(oxetan-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)picolinamide

embedded image

To a solution of 5-cyano-3-methylpicolinic acid (40 mg, 246.69 umol) in pyridine (3 mL) was added EDCI (70.94 mg, 370.04 umol) and 3-(oxetan-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-amine (67.43 mg, 246.69 umol). The mixture was stirred at 20° C. for 12 hrs and then concentrated to give a residue. The residue was diluted with H₂O (6 mL) and extracted with EtOAc (4 mL×3). The combined organic layers were dried over Na₂SO₄, filtered and concentrated to afford the title compound (100 mg) as a brown gum which was used without further purification. MS-ESI (m/z) calcd for C₂₃H₂₄N₅O; [M+H]⁺: 418.2. Found 418.1

Step 6: 5-Cyano-3-methyl-N-(3-(oxetan-3-yl)-1H-indazol-5-yl)picolinamide

embedded image

To a solution of 5-cyano-3-methyl-N-(3-(oxetan-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)picolinamide (50 mg, 119.77 umol) in DCM (3 mL) was added TFA (0.5 mL). The mixture was stirred at 15° C. for 12 hrs and then concentrated to give a residue. The residue was purified by preparative HPLC using Method AT to afford the title compound (6.22 mg, 15%) as a pale yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 12.88 (br s, 1H) 10.69 (s, 1H) 8.97 (s, 1H) 8.36 (d, J=17 Hz, 2H) 7.67 (d, J=9 Hz, 1H) 7.49 (d, J=9 Hz, 1H) 5.02 (dd, J=8, 6 Hz, 2H) 4.90 (t, J=6 Hz, 2H) 4.56-4.65 (m, 1H) 2.56 (s, 3H). MS-ESI (m/z) calc'd for C₁₈H₁₆N₅O₂[M+H]⁺: 334.1 Found 334.2.

Example 257: 5-Cyano-N-(3-(2,2-dimethylcyclopropyl)-1H-indazol-5-yl)-3,4-dimethylpicolinamide

embedded image

Step 1: 3-(2,2-Dimethylcyclopropyl)-5-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole

embedded image

To a solution of 3-iodo-5-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (50 mg, 134.00 umol) in H₂O (0.5 mL) and tert-amyl alcohol (1.5 mL) was added 2-(2,2-dimethylcyclopropyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (26.28 mg, 134.00 umol), Cs₂CO₃(87.32 mg, 267.99 umol) and cataCXium A-Pd-G2 (8.96 mg, 13.40 umol) at 20° C. and then the mixture was stirred at 70° C. for 12 hrs under an N₂atmosphere. The reaction mixture was concentrated and purified by preparative TLC (SiO₂, petroleum ether/EtOAc=5/1, R_f=0.61) to afford the title compound (30 mg, 71%) as a yellow solid. MS-ESI (m/z) calcd for C₁₇H₂₂N₃O₃[M+H]⁺: 316.2. Found 316.2.

Step 2: 3-(2,2-Dimethylyclopropyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-amine

embedded image

To a solution of 3-(2,2-dimethylcyclopropyl)-5-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (10 mg, 31.71 umol) in EtOH (1 mL) and H₂O (0.5 mL) was added Fe (17.71 mg, 317.09 umol) and NH₄Cl (16.96 mg, 317.09 umol) at 20° C. Then the mixture was stirred at 80° C. for 1 hr and concentrated to afford a residue. The residue was diluted with saturated aqueous NaHCO₃(5 mL) and extracted with EtOAc (2 mL×3). The combined organic layers were washed with brine (5 mL), dried over Na₂SO₄, filtered and concentrated under reduced pressure to afford the title compound (20 mg) as a brown solid which was used without further purification. MS-ESI (m/z) calcd for C₁₇H₂₄N₃O [M+H]⁺: 286.2. Found 286.3.

Step 3: 5-Cyano-N-(3-(2,2-dimethylcyclopropyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-3,4-dimethylpicolinamide

embedded image

To a solution of 3-(2,2-dimethylcyclopropyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-amine (20 mg, 70.08 umol) in pyridine (1 mL) was added 5-cyano-3,4-dimethylpicolinic acid (12.35 mg, 70.08 umol) and EDCI (26.87 mg, 140.16 umol) at 20° C. Then the mixture was stirred at 20° C. for 12 hrs and then concentrated. The residue was diluted with H₂O (10 mL) and extracted with EtOAc (2 mL×3). The combined organic layers were washed with brine (10 mL), dried over Na₂SO₄, filtered and concentrated under reduced pressure to afford the title compound (40 mg) as a brown solid which was used without further purification. MS-ESI (m/z) calcd for C₂₆H₃₀N₅O₂[M+H]⁺: 444.2. Found 444.3.

Step 4: 5-Cyano-N-(3-(2,2-dimethylcyclopropyl)-1H-indazol-5-yl)-3,4-dimethylpicolinamide

embedded image

To a solution of 5-cyano-N-(3-(2,2-dimethylcyclopropyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-3,4-dimethylpicolinamide (40 mg, 90.18 umol) in MeOH (1 mL) and H₂O (0.2 mL) was added PTSA (77.65 mg, 450.92 umol) at 20° C. The mixture was stirred at 70° C. for 3 hrs and concentrated. The residue was purified by preparative HPLC using Method AP to afford the title compound (10.41 mg, 21%) as a pale yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 10.05 (br s, 1H), 8.66 (s, 1H), 8.23 (s, 1H), 7.60 (dd, J=1.6, 8.8 Hz, 1H), 7.43 (d, J=8.8 Hz, 1H), 2.86 (s, 3H), 2.64 (s, 3H), 2.07 (dd, J=5.7, 8.5 Hz, 1H), 1.35 (s, 3H), 1.28 (t, J=5.0 Hz, 1H), 0.99 (dd, J=4.3, 8.5 Hz, 1H), 0.92 (s, 3H). MS-ESI (m/z) calc'd for C₂₁H₂₂N₅O [M+H]⁺: 360.2 Found 360.2.

Example 258: 5-Cyano-4-methoxy-6-methyl-N-(3-(oxazol-5-yl)-1H-indazol-5-yl)picolinamide

embedded image

Step 1: 4-Hydroxy-2-methyl-6-oxo-1,6-dihydropyridine-3-carbonitrile

embedded image

To a solution of bis(2,4,6-trichlorophenyl) malonate (3 g, 6.48 mmol) in chlorobenzene (30 mL) was added 3-aminobut-2-enenitrile (532.08 mg, 6.48 mmol) and the mixture was stirred at 130° C. for 3 hrs. The reaction mixture was then filtered and the solid was washed with toluene (5 mL) and petroleum ether (5 mL). The solid was dried to afford the title compound (540 mg) as a brown solid, which was used without further purification. MS-ESI (m/z) calcd for C₇H₇N₂O₂[M+H]⁺: 151.0. Found 151.1.

Step 2: 4,6-Dichloro-2-methylnicotinonitrile

embedded image

A mixture of 4-hydroxy-2-methyl-6-oxo-1,6-dihydropyridine-3-carbonitrile (540 mg, 3.60 mmol), benzyltriethylammonium chloride (1.64 g, 7.19 mmol) and POCl₃(1.10 g, 7.19 mmol, 668.48 uL) in MeCN (7 mL) was degassed and purged with N₂(3×) at 25° C., and then stirred at 80° C. for 12 hrs under an N₂atmosphere. The reaction mixture was concentrated and quenched by the addition of 10 g of ice water. The mixture was further diluted with H₂O (8 mL) and adjusted to pH=7 with saturated aqueous NaHCO₃and extracted with EtOAc (8 mL×3). The combined organic phases were washed with brine (8 mL×1), dried over Na₂SO₄, filtered and concentrated to afford the title compound (738 mg) as a brown solid, which was used without further purification.

Step 3: 6-Chloro-4-methoxy-2-methyl-1,6-dihydropyridine-3-carbonitrile

embedded image

To a solution of 4,6-dichloro-2-methylnicotinonitrile (638 mg, 3.13 mmol) in MeOH (8 mL) was added MeONa (169.36 mg, 3.13 mmol). The mixture was stirred at 20° C. for 16 hrs and then concentrated to give a residue. The residue was diluted with water (8 mL) and extracted with dichloromethane (8 mL×3). The combined organic phases were washed with brine (8 mL×1), dried over Na₂SO₄, filtered and concentrated. The material was purified by silica gel column chromatography using a 0-20% EtOAc/petroleum ether gradient eluent to afford the title compound (190 mg, 33%) as a white solid. MS-ESI (m/z) calcd for C₈H₈ClN₂O [M+H]⁺: 183.0/185.0 Found 183.1/185.1.

Step 4: Methyl 5-cyano-4-methoxy-6-methyl-1,2-dihydropyridine-2-carboxylate

embedded image

To a solution of 6-chloro-4-methoxy-2-methyl-1,6-dihydropyridine-3-carbonitrile (190 mg, 1.04 mmol) in MeOH (5 mL) was added Pd(dppf)Cl₂(76.13 mg, 104.05 umol) and Et3N (315.86 mg, 3.12 mmol, 434.47 uL) under an N₂atmosphere. The resulting suspension was degassed and purged with CO (3×). The mixture was then stirred under CO (50 psi) at 80° C. for 12 hrs. The mixture was then filtered and the filtrate was concentrated to afford a residue. The residue was purified by preparative TLC (SiO₂, petroleum ether/EtOAc=1/1, R_f=0.40) to afford the title compound (151 mg, 70%) as a white solid. MS-ESI (m/z) calcd for C₁₀H₁₁N₂O₃[M+H]⁺: 207.1 Found 207.2.

Step 5: 5-Cyano-4-methoxy-6-methyl-1,2-dihydropyridine-2-carboxylic acid

embedded image

To a solution of methyl 5-cyano-4-methoxy-6-methyl-1,2-dihydropyridine-2-carboxylate (170 mg, 824.45 umol) in THF (2 mL) and H₂O (2 mL) was added LiOH.H₂O (69.19 mg, 1.65 mmol) and the mixture was stirred at 40° C. for 2 hrs. The reaction mixture was then concentrated and adjusted to pH=3 with 1 N HCl and extracted with EtOAc (4 mL×3). The combined organic phases were washed with brine (4 mL×1), dried over Na₂SO₄, filtered and concentrated to afford the title compound (98 mg) as a white solid, which was used without further purification. MS-ESI (m/z) calcd for C₉H₉N₂O₃[M+H]⁺: 193.1. Found 193.1.

Step 6: 5-Cyano-4-methoxy-6-methyl-N-(3-(oxazol-5-yl)-1H-indazol-5-yl)picolinamide

embedded image

To a solution of 5-cyano-4-methoxy-6-methyl-1,2-dihydropyridine-2-carboxylic acid (50 mg, 260.18 umol) in pyridine (3 mL) was added EDCI (99.76 mg, 520.37 umol) and 3-(oxazol-5-yl)-1H-indazol-5-amine (52.09 mg, 260.18 umol). The mixture was stirred at 20° C. for 2 hrs and then concentrated to afford a residue. The residue was purified by preparative HPLC using Method AU to afford the title compound (7.79 mg, 6%) as a pale yellow solid TFA salt. ¹H NMR (400 MHz, DMSO-d₆) δ 13.54 (s, 1H), 10.72 (s, 1H), 8.65 (s, 1H), 8.58 (s, 1H), 7.93 (d, J=7.7 Hz, 1H), 7.80 (s, 1H), 7.69 (s, 1H), 7.65 (d, J=9.0 Hz, 1H), 4.12 (s, 3H), 2.77 (s, 3H). MS-ESI (m/z) calc'd for C₁₉H₁₅N₆O₃[M+H]⁺: 375.1 Found 375.1.

Example 259: tert-butyl 4-((5-(5-Cyano-3,4-dimethylpicolinamido)-1H-indazol-3-yl)methylene)piperidine-1-carboxylate

embedded image

Step 1: 3-Iodo-1H-indazol-5-amine

embedded image

To a solution of 3-iodo-5-nitro-1H-indazole (1 g, 3.46 mmol) in H₂O (8 mL) and EtOH (24 mL) was added Fe (966.08 mg, 17.30 mmol) and NH₄Cl (925.36 mg, 17.30 mmol) and the mixture was stirred at 80° C. for 0.5 hr. The reaction was then filtered and the filtrate was concentrated to afford a residue. The residue was diluted with H₂O (30 mL) and extracted with EtOAc (20 mL×3). The combined organic phases were dried with Na₂SO₄, filtered, and the filtrate was concentrated to afford the title compound (850 mg) as a yellow solid which was used without further purification. MS-ESI (m/z) calcd for C₇H₇IN₃[M+H]⁺: 259.9. Found 259.9.

Step 2: 5-Cyano-N-(3-iodo-1H-indazol-5-yl)-3,4-dimethylpicolinamide

embedded image

To a solution of 3-iodo-1H-indazol-5-amine (850 mg, 3.28 mmol) and 5-cyano-3,4-dimethylpicolinic acid (578.07 mg, 3.28 mmol) in pyridine (25 mL) was added EDCI (943.54 mg, 4.92 mmol). The mixture was stirred at 25° C. for 12 hrs and then concentrated to afford a residue. The residue was diluted with H₂O (10 mL) and filtered. The solid was dried under vacuum to afford the title compound (1.2 g) as a yellow solid which was used without further purification. MS-ESI (m/z) calcd for C₁₆H₁₃IN₅O [M+H]⁺: 418.0. Found 418.0.

Step 3: tert-butyl 4-((5-(5-Cyano-3,4-dimethylpicolinamido)-1H-indazol-3-yl)methylene)piperidine-1-carboxylate

embedded image

To a solution of 5-cyano-N-(3-iodo-1H-indazol-5-yl)-3,4-dimethylpicolinamide (64.54 mg, 154.69 umol) in EtOH (4 mL) and H₂O (1 mL) was added KOAc (75.90 mg, 773.43 umol), Pd(Amphos)Cl₂(10.95 mg, 15.47 umol) and tert-butyl 4-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene)piperidine-1-carboxylate (50 mg, 154.69 umol) at 20° C. Then the reaction mixture was stirred at 90° C. for 12 hrs under N₂. The reaction mixture was concentrated and purified by preparative HPLC using Method AV to afford the title compound (28.8 mg, 38%) as a pale yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 12.99 (s, 1H), 10.66 (s, 1H), 8.88 (s, 1H), 8.31 (s, 1H), 7.59-7.47 (m, 2H), 6.52 (s, 1H), 3.49-3.38 (m, 4H), 2.83 (br s, 2H), 2.55 (s, 3H), 2.44 (s, 3H), 2.42-2.38 (m, 2H), 1.43 (s, 9H). MS-ESI (m/z) calc'd for C₂₇H₃₁N₆O₃[M+H]⁺: 487.2 Found 487.3.

Example 260: 5-Cyano-3,4-dimethyl-N-(3-(piperidin-4-ylidenemethyl)-1H-indazol-5-yl)picolinamide

embedded image

To a solution of tert-butyl 4-((5-(5-cyano-3,4-dimethylpicolinamido)-1H-indazol-3-yl)methylene)piperidine-1-carboxylate (85 mg, 174.69 umol) in DCM (4 mL) was added TFA (1 mL). The mixture was stirred at 20° C. for 1 hr. The reaction mixture was then concentrated and purified by preparative HPLC using Method AW to afford the title compound (28.77 mg, 31%, TFA salt) as a pale yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.12 (br s, 1H), 10.71 (s, 1H), 8.89 (s, 1H), 8.74 (br s, 2H), 8.40 (s, 1H), 7.53 (s, 2H), 6.64 (s, 1H), 3.24 (br s, 2H), 3.15 (br d, J=7.7 Hz, 4H), 2.65 (br t, J=5.6 Hz, 2H), 2.55 (s, 3H), 2.43 (s, 3H). MS-ESI (m/z) calc'd for C₂₂H₂₃N₆O [M+H]⁺: 387.2 Found 387.3.

Example 261: (Z)-5-Cyano-N-(3-((dihydrofuran-3(2H)-ylidene)methyl)-1H-indazol-5-yl)-3,4-dimethylpicolinamide

embedded image

Step 1: (Z)-2-((Dihydrofuran-3(2H)-ylidene)methyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

embedded image

To a solution of 2,2,6,6-tetramethylpiperidine (318.18 mg, 2.25 mmol, 382.43 uL) in THF (5 mL) was added n-BuLi (2.5 M, 896.97 uL) dropwise at −30° C. over 0.5 hr under N₂. The mixture was stirred at −30° C. for 0.5 hr. Then a solution of bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methane (500 mg, 1.87 mmol) in THF (5 mL) was added dropwise at −78° C. The mixture was stirred at −78° C. for 0.5 hr. Then a solution of dihydrofuran-3(2H)-one (579.89 mg, 6.74 mmol) in THF (8 mL) was added dropwise at −78° C. and the resulting mixture was stirred at 20° C. for 12 hrs under N₂. After cooling to 0° C., the reaction mixture was poured into saturated aqueous NH₄Cl (8 mL) and the mixture was stirred at 0° C. for 1 hr. The mixture was filtered and the filtrate was poured into water (10 mL) and extracted with EtOAc (10 mL×3). The combined organic phases were washed with brine (10 mL×1), dried over Na₂SO₄, filtered and concentrated in vacuum to afford the title compound (600 mg) as a brown oil, which was used without further purification.

Step 2: (Z)-5-Cyano-N-(3-((dihydrofuran-3(2H)-ylidene)methyl)-1H-indazol-5-yl)-3,4-dimethylpicolinamide

embedded image

A mixture of N-(3-bromo-1H-indazol-5-yl)-5-cyano-3,4-dimethylpicolinamide (90 mg, 243.11 umol), (Z)-2-((dihydrofuran-3(2H)-ylidene)methyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (321.24 mg, 1.53 mmol), Pd(Amphos)Cl₂(17.21 mg, 24.31 umol) and AcOK (71.58 mg, 729.33 umol) in EtOH (3 mL) and H₂O (0.75 mL) was degassed and purged with N₂(3×), and then the mixture was stirred at 90° C. for 12 hrs under an N₂atmosphere. The reaction mixture was concentrated, then the mixture was poured into water (6 mL) and extracted with dichloromethane (6 mL×3). The combined organic phases were washed with brine (6 mL×1), dried over Na₂SO₄, filtered and concentrated. The residue was purified by preparative HPLC using Method AI to afford the title compound (49.96 mg, 40%) as a white solid TFA salt. ¹H NMR (400 MHz, DMSO-d₆) δ 13.06 (s, 1H), 10.67 (s, 1H), 8.88 (s, 1H), 8.39 (s, 1H), 7.59-7.53 (m, 1H), 7.52-7.47 (m, 1H), 6.88-6.71 (m, 1H), 4.61 (br s, 2H), 3.84 (t, J=6.8 Hz, 2H), 2.81 (br t, J=6.1 Hz, 2H), 2.55 (s, 3H), 2.45 (s, 3H). MS-ESI (m/z) calc'd for C₂₁H₂₀N₅O₂[M+H]⁺: 374.2 Found 374.2.

Example 262: 5-Cyano-3,4-dimethyl-N-(3-((tetrahydro-4H-pyran-4-ylidene)methyl)-1H-indazol-5-yl)picolinamide

embedded image

Prepared as described for (Z)-5-cyano-N-(3-((dihydrofuran-3(2H)-ylidene)methyl)-1H-indazol-5-yl)-3,4-dimethylpicolinamide using 4,4,5,5-tetramethyl-2-((tetrahydro-4H-pyran-4-ylidene)methyl)-1,3,2-dioxaborolane in place of (Z)-2-((dihydrofuran-3(2H)-ylidene)methyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane to afford the title compound (8.3 mg, 5%) as a pale yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 12.97 (br s, 1H) 10.66 (s, 1H) 8.88 (s, 1H) 8.32 (s, 1H) 7.53-7.58 (m, 1H) 7.47-7.52 (m, 1H) 6.48 (s, 1H) 3.72 (t, J=5.38 Hz, 2H) 3.65 (t, J=5.44 Hz, 2H) 2.90 (br t, J=4.95 Hz, 2H) 2.55 (s, 3H) 2.42-2.47 (m, 5H). MS-ESI (m/z) calc'd for C₂₂H₂₂N₅O₂[M+H]⁺: 388.2. Found 388.1.

Example 263: 5-Cyano-3,4-dimethyl-N-(3-(oxetan-3-ylidenemethyl)-1H-indazol-5-yl)picolinamide

embedded image

A mixture of 4,4,5,5-tetramethyl-2-(oxetan-3-ylidenemethyl)-1,3,2-dioxaborolane (150 mg, 765.11 umol), N-(3-bromo-1H-indazol-5-yl)-5-cyano-3,4-dimethylpicolinamide (45.03 mg, 121.64 umol), Pd(dppf)Cl₂(4.45 mg, 6.08 umol), and K₂CO₃(50.43 mg, 364.92 umol) in dioxane (4 mL) and H₂O (1 mL) was degassed and purged with N₂(3×), and then the mixture was stirred at 90° C. for 12 hrs under an N₂atmosphere. After cooling to 20° C., the reaction mixture was filtered and the filtrate was concentrated to afford a residue. The residue was purified by preparative HPLC using Method AX to afford the title compound (9 mg, 21%) as a pale yellow solid. ¹H NMR (400 MHz, MeOD) δ 8.75 (s, 1H), 8.30 (d, J=1.3 Hz, 1H), 7.62-7.56 (m, 1H), 7.54-7.49 (m, 1H), 6.58 (quin, J=2.4 Hz, 1H), 5.65 (q, J=2.9 Hz, 2H), 5.50-5.43 (m, 2H), 2.64 (s, 3H), 2.62 (s, 3H). MS-ESI (m/z) calc'd for C₂₂H₂₂N₅O₂[M+H]⁺: 360.1. Found 360.2.

Example 264: 5-Cyano-N-(3-(methoxymethyl)-1H-indazol-5-yl)-3,4-dimethylpicolinamide

embedded image

Step 1: 5-Nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-3-carbaldehyde

embedded image

To a solution of 5-nitro-1H-indazole-3-carbaldehyde (2 g, 10.46 mmol) in THF (70 mL) was added N-cyclohexyl-N-methylcyclohexanamine (2.04 g, 10.46 mmol) and SEM-CI (2.62 g, 15.70 mmol). The mixture was stirred at 20° C. for 12 hrs and then concentrated to afford a residue. The residue was purified by flash silica gel chromatography (ISCO; 20 g SepaFlash column) using a 0-15% EtOAc/petroleum ether gradient eluent to afford the title compound (1.34 g, 40%) as a yellow solid. MS-ESI (m/z) calcd for C₁₄H₂₀N₃O₄Si [M+H]⁺: 322.1. Found 322.1.

Step 2: (5-Nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)methanol

embedded image

To a solution of 5-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-3-carbaldehyde (1 g, 3.11 mmol) in MeOH (25 mL) was added NaBH₄(117.71 mg, 3.11 mmol) at 0° C. and the mixture was stirred at 0° C. for 0.5 hr. The reaction was quenched by addition of H₂O (15 mL), then the mixture was extracted with EtOAc (30 mL×3). The combined organic layers were dried over Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO; 20 g SepaFlash column) using a 0-39% EtOAc/petroleum ether gradient eluent to afford the title compound (500 mg, 50%) as a yellow oil. MS-ESI (m/z) calcd for C₁₄H₂₂N₃O₄Si [M+H]⁺: 324.1. Found 324.1.

Step 3: 3-(Methoxymethyl)-5-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole

embedded image

To a solution of NaH (74.20 mg, 1.86 mmol, 60% purity) in DMF (15 mL) was added a solution of (5-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)methanol (500 mg, 1.55 mmol) in DMF (10 mL) at 0° C. and the mixture was stirred at 0° C. for 1 hr. Then MeI (263.32 mg, 1.86 mmol) was added and the reaction mixture was allowed to warm to 20° C. and stirred for 1.5 hrs. The reaction was quenched by addition of H₂O (20 mL), then the mixture was extracted with EtOAc (40 mL×3). The combined organic layers were dried over Na₂SO₄, filtered and concentrated under reduced pressure to afford the title compound (500 mg) as a yellow oil which was used without further purification. MS-ESI (m/z) calcd for C₁₅H₂₄N₃O₄Si [M+H]⁺: 338.2. Found 338.1.

Step 4: 3-(Methoxymethyl)-1-((2-(trimethylsilyl)ethoxy)methy)-1H-indazol-5-amine

embedded image

To a solution of 3-(methoxymethyl)-5-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole (500 mg, 1.48 mmol) in EtOH (4 mL) and H₂O (0.5 mL) was added Fe (413.73 mg, 7.41 mmol) and NH₄Cl (396.30 mg, 7.41 mmol). The mixture was stirred at 80° C. for 1 hr and then filtered. The filtrate was diluted with H₂O (5 mL) and extracted with EtOAc (10 mL×3). The combined organic layers were dried over Na₂SO₄, filtered and concentrated under reduced pressure to afford the title compound (500 mg) as a brown oil which was used without further purification. MS-ESI (m/z) calcd for C₁₅H₂₅N₃O₂Si [M+H]⁺: 308.2. Found 308.1.

Step 5: 5-Cyano-N-(3-(methoxymethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-5-yl)-3,4-dimethylpicolinamide

embedded image

To a solution of 3-(methoxymethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-5-amine (300 mg, 975.73 umol) in pyridine (5 mL) was added EDCI (374.10 mg, 1.95 mmol) and 5-cyano-3,4-dimethylpicolinic acid (171.90 mg, 975.73 umol). The mixture was stirred at 20° C. for 1 hr and then concentrated under reduced pressure to afford the title compound (450 mg) as a red oil which was used without further purification. MS-ESI (m/z) calcd for C₂₄H₃₁N₅O₃Si [M+H]⁺: 466.2. Found 466.2.

Step 6: 5-Cyano-N-(3-(methoxymethyl)-1H-indazol-5-yl)-3,4-dimethylpicolinamide

embedded image

A solution of 5-cyano-N-(3-(methoxymethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-5-yl)-3,4-dimethylpicolinamide (230 mg, 493.97 umol) in TFA (1.5 mL) was stirred at 20° C. for 12 hrs. The reaction mixture was then concentrated under reduced pressure to remove solvent. The residue was purified by preparative HPLC using Method AY to afford the title compound (18.24 mg, 10%) as a pale yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 12.97 (s, 1H) 10.67 (s, 1H) 8.88 (s, 1H) 8.33 (s, 1H) 7.58-7.62 (m, 1H) 7.49-7.53 (m, 1H) 4.72 (s, 2H) 3.29 (s, 3H) 2.54 (s, 3H) 2.43 (s, 3H). MS-ESI (m/z) calc'd for C₁₅H₁₈N₅O₂[M+H]⁺: 336.1. Found 336.2.

Example 265: 5-Cyano-3,4-dimethyl-N-(3-(2-(trifluoromethyl)cyclopropyl)-1H-indazol-5-yl)picolinamide and Example 266: (E)-5-Cyano-3,4-dimethyl-N-(3-(3,3,3-trifluoroprop-1-en-1-yl)-1H-indazol-5-yl)picolinamide

embedded image

Step 1: 2-Diazo-1,1,1-trifluoroethane

embedded image

To a solution of 2,2,2-trifluoroethan-1-amine hydrochloride (25 g, 184.48 mmol, 19.84 mL) in H₂O (77 mL) and Et₂O (150 mL) was added a solution of NaNO₂(14.00 g, 202.93 mmol) in H₂O (30 mL) at 0° C. The reaction mixture was then, warmed to 20° C. and stirred for 3 hrs. The reaction solution turned from colorless to light yellow. The phases were separated and the Et₂O layer was dried over Na₂SO₄, and filtered to afford the title compound (25 g) in Et₂O as a light yellow liquid, which was used without further purification.

Step 2: 5-Nitro-1-(tetrahydro-2H-pyran-2-yl)-3-vinyl-1H-indazole

embedded image

To a solution of 3-iodo-5-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (2.2 g, 5.90 mmol) and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (1.09 g, 7.07 mmol, 1.20 mL) in dioxane (18 mL) and H₂O (3.6 mL) was added K₃PO₄(2.50 g, 11.79 mmol) and Pd(PPh₃)₄(510.97 mg, 442.19 umol) at 20° C. under an N₂atmosphere and the mixture was stirred at 90° C. for 12 hrs. The reaction mixture was concentrated to afford a residue. The residue was purified by flash silica gel chromatography (ISCO; 12 g SepaFlash column) using a 0-6% EtOAc/petroleum ether gradient eluent to afford the title compound (2.5 g, 78%) as a pale yellow solid. MS-ESI (m/z) calcd for C₁₄H₁₆N₃O₃[M+H]⁺: 274.1. Found 274.1.

Step 3: 5-Nitro-1-(tetrahydro-2H-pyran-2-yl)-3-(2-(trifluoromethyl)cyclopropyl)-1H-indazole

embedded image

To a solution of 5-nitro-1-(tetrahydro-2H-pyran-2-yl)-3-vinyl-1H-indazole (2 g, 7.32 mmol) and Pd(OAc)₂(246.45 mg, 1.10 mmol) in THF (25 mL) was added a solution of 2-diazo-1,1,1-trifluoroethane (24.16 g, 219.55 mmol) in Et₂O (150 mL) dropwised at 0° C. Then the reaction mixture was stirred at 20° C. for 24 hrs under N₂. The reaction mixture was dissolved in H₂O (20 mL) and the aqueous phase was extracted with EtOAc (20 mL×3). The combined organic phases were dried over Na₂SO₄, filtered and concentrated to give a residue. The residue was purified by flash silica gel chromatography (ISCO; 40 g SepaFlash column) using a 0-2% EtOAc/petroleum ether gradient eluent to afford the title compound (143 mg, 6%) as a yellow oil. MS-ESI (m/z) calcd for C₁₆H₁₆F₃N₃O₃[M+H]⁺: 356.1. Found 356.0.

Step 4:1-(Tetrahydro-2H-pyran-2-yl)-3-(2-(trifluoromethyl)cyclopropyl)-1H-indazol-5-amine

embedded image

To a solution of 5-nitro-1-(tetrahydro-2H-pyran-2-yl)-3-(2-(trifluoromethyl)cyclopropyl)-1H-indazole (130 mg, 365.88 umol) in THF (12 mL) and H₂O (3 mL) was added NH₄Cl (117.43 mg, 2.20 mmol) and Zn (191.40 mg, 2.93 mmol) and the reaction mixture was stirred at 20° C. for 2 hrs. The reaction mixture was filtered and the filtrate was concentrated. The residue was dissolved into H₂O (10 mL) and the aqueous phase was extracted with EtOAc (10 mL×3). The combined organic phases were dried over Na₂SO₄, filtered and concentrated in vacuum to afford the title compound (130 mg) as a yellow oil, which was used without further purification. MS-ESI (m/z) calcd for C₁₆H₁₉F₃N₃O [M+H]⁺: 326.1. Found 326.4.

Step 5: 5-Cyano-3,4-dimethyl-N-(1-(tetrahydro-2H-pyran-2-yl)-3-(2-(trifluoromethyl)cyclopropyl)-1H-indazol-5-yl picolinamide

embedded image

To a solution of 1-(tetrahydro-2H-pyran-2-yl)-3-(2-(trifluoromethyl)cyclopropyl)-1H-indazol-5-amine (130 mg, 399.60 umol) and 5-cyano-3,4-dimethylpicolinic acid (77.44 mg, 439.56 umol) in DCM (6 mL) was added T3P (50 wt. % in EtOAc, 381.43 mg, 599.40 umol, 356.48 uL) at 20° C. and the reaction mixture was stirred at 35° C. for 0.5 hr. Then Et₃N (121.31 mg, 1.20 mmol, 166.86 uL) was added and the reaction mixture was stirred at 35° C. for 2 hrs. The reaction mixture was diluted with H₂O (10 mL) and extracted with dichloromethane (10 mL×3). The combined organic phases were dried over Na₂SO₄, filtered and the filtrate was concentrated. The residue was purified by preparative TLC (SiO₂, petroleum ether/EtOAc=3/1, R_f=0.3) to afford the title compound (60 mg, 31%) as a yellow oil. MS-ESI (m/z) calcd for C₂₅H₂₅F₃N₅O₂[M+H]⁺: 484.2. Found 484.3.

Step 6: 5-Cyano-3,4-dimethyl-N-(3-(2-(trifluoromethyl)cyclopropyl)-1H-indazol-5-yl)picolinamide and (E)-5-Cyano-3,4-dimethyl-N-(3-(3,3,3-trifluoroprop-1-en-1-yl)-1H-indazol-5-yl)picolinamide

embedded image

To a solution of 5-cyano-3,4-dimethyl-N-(1-(tetrahydro-2H-pyran-2-yl)-3-(2-(trifluoromethyl)cyclopropyl)-1H-indazol-5-yl)picolinamide (50 mg, 103.42 umol) in DCM (2 mL) was added TFA (770.00 mg, 6.75 mmol, 500.00 uL) and the reaction mixture was stirred at 20° C. for 12 hrs. The reaction mixture was then adjusted to pH=8 by addition of ice cold saturated aqueous NaHCO₃and extracted with dichloromethane (10 mL×3). The combined organic phases were dried over Na₂SO₄, filtered and concentrated. The residue was purified by preparative HPLC using Method AZ to afford 5-cyano-N-(3-(methoxymethyl)-1H-indazol-5-yl)-3,4-dimethylpicolinamide (23.52 mg, 57%) as a pale yellow solid. ¹H NMR (400 MHz, MeOD) δ 8.71 (s, 1H), 8.31-8.24 (m, 1H), 7.59 (dd, J=1.8, 8.9 Hz, 1H), 7.47 (d, J=8.9 Hz, 1H), 2.72-2.65 (m, 1H), 2.59 (d, J=3.4 Hz, 6H), 2.33-2.21 (m, 1H), 1.54-1.42 (m, 2H). MS-ESI (m/z) calc'd for C₂₀H₁₇F₃N₅O [M+H]⁺: 400.1. Found 400.1. (E)-5-Cyano-3,4-dimethyl-N-(3-(3,3,3-trifluoroprop-1-en-1-yl)-1H-indazol-5-yl)picolinamide (15.59 mg, 39° %) as a pale pink solid was also isolated. ¹H NMR (400 MHz, MeOD) δ 8.72 (s, 1H), 8.47 (d, J=1.1 Hz, 1H), 7.69 (dd, J=1.7, 8.9 Hz, 1H), 7.61-7.56 (m, 1H), 7.51 (dd, J=2.2, 16.4 Hz, 1H), 6.69 (qd, J=6.7, 16.3 Hz, 1H), 2.61 (d, J=2.8 Hz, 6H). MS-ESI (m/z) calc'd for C₁₉H₁₅F₃N₅O [M+H]⁺: 386.1. Found 386.1.

Example 267: 5-Cyano-3,4-dimethyl-N-(3-(prop-1-en-2-yl)-1H-indazol-5-yl)picolinamide

embedded image

Step 1: 5-Nitro-3-(prop-1-en-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole

embedded image

A mixture of 3-iodo-5-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (1 g, 2.68 mmol), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (495.37 mg, 2.95 mmol), Pd(dppf)Cl₂(196.09 mg, 267.99 umol), K₃PO₄(1.71 g, 8.04 mmol) in dioxane (24 mL) and H₂O (6 mL) at 20° C. was degassed and purged with N₂(3×). The mixture was stirred at 90° C. for 4 hrs under an N₂atmosphere and then concentrated to remove solvent. The residue was diluted with H₂O (20 mL) and extracted with EtOAc (20 mL×3). The combined organic phases were dried over Na₂SO₄, filtered and concentrated. The material was purified by flash silica gel chromatography (ISCO; 12 g SepaFlash column) using a 0-7% EtOAc/petroleum ether gradient eluent to afford the title compound (570 mg, 74%) as a yellow solid. MS-ESI (m/z) calcd for C₁₅H₁₈N₃O₃[M+H]⁺: 288.1. Found 288.0.

Step 2: 3-(Prop-1-en-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-anine

embedded image

To a solution of 5-nitro-3-(prop-1-en-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (200 mg, 696.10 umol) in EtOH (2 mL) and H₂O (2 mL) was added Fe (194.37 mg, 3.48 mmol) and NH₄Cl (186.18 mg, 3.48 mmol) at 20° C. The mixture was stirred at 80° C. for 1 hr and then filtered. The filtrate was diluted with H₂O (20 mL) and extracted with EtOAc (20 mL×3). The organic phase was dried over Na₂SO₄, filtered and concentrated under reduced pressure to afford the title compound (140 mg) as a red oil which was used without further purification. MS-ESI (m/z) calcd for C₁₅H₂₀N₃O [M+H]⁺: 258.2. Found 258.1.

Step 3: 5-Cyano-3,4-dimethyl-N-(3-(prop-1-en-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)picolinamide

embedded image

To a solution of 3-(prop-1-en-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-amine (140 mg, 544.05 umol), 5-cyano-3,4-dimethylpicolinamide (95.85 mg, 544.05 umol) in pyridine (5 mL) was added EDCI (156.44 mg, 816.07 umol). The mixture was stirred at 20° C. for 12 hrs and then concentrated to remove solvent. The reaction mixture was diluted with water (10 mL) and filtered. The solid was washed with H₂O (10 mL) and dried in vacuum to afford the title compound (210 mg) as a red solid which was used without further purification. MS-ESI (m/z) calcd for C₂₄H₂₆N₅O₂[M+H]⁺: 416.2. Found 416.1.

Step 4: 5-Cyano-3,4-dimethyl-N-(3-(prop-1-en-2-yl)-1H-indazol-5-yl)picolinamide

embedded image

A mixture of 5-cyano-3,4-dimethyl-N-(3-(prop-1-en-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)picolinamide (70 mg, 168.48 umol) in DCM (2 mL) and TFA (0.5 mL) was stirred at 20° C. for 1 hr. Saturated aqueous NaHCO₃(20 mL) was then added to the reaction mixture at 0° C. and the mixture was extracted with DCM (10 m L×3). The organic phase was dried over Na₂SO₄, filtered and concentrated to give a residue. The residue was purified by preparative HPLC using Method AZ to afford the title compound (7.81 mg, 14%) as a pale yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 10.69 (br s, 1H), 8.89 (s, 1H), 8.53 (s, 1H), 7.70 (br d, J=8.80 Hz, 1H), 7.54 (d, J=8.93 Hz, 1H), 5.70 (s, 1H), 5.36 (s, 1H), 2.55 (s, 3H), 2.44 (s, 3H), 2.25 (s, 3H). MS-ESI (m/z) calc'd for C₉H₁₈N₅O [M+H]⁺: 332.1. Found 332.1.

Example 268: 5-Cyano-3,4-dimethyl-N-(3-(1-methylcyclopropyl)-1H-indazol-5-yl)picolinamide

embedded image

Step 1: N-Methoxy-N,1-dimethylcyclopropane-1-carboxamide

embedded image

To a solution of 1-methylcyclopropane-1-carboxylic acid (3 g, 29.97 mmol) in DCM (60 mL) was added CDI (5.83 g, 35.96 mmol), the mixture was stirred at 20° C. for 2 hrs, then N-methoxymethanamine hydrochloride (3.51 g, 35.96 mmol) was added. The mixture was stirred at 20° C. for another 10 hrs and then diluted with MeOH (10 mL). The mixture was purified by flash silica gel chromatography (ISCO; 40 g SepaFlash column) using a 0-10% EtOAc/petroleum ether gradient eluent to afford the title compound (2.7 g, 63%) as a colorless oil. MS-ESI (m/z) calcd for C₇H₁₄NO₂[M+H]⁺: 144.1. Found 144.0.

Step 2: (5-Bromo-2-fluorophenyl)(1-methylcyclopropyl)methanone

embedded image

To a solution of 4-bromo-1-fluoro-2-iodobenzene (3.28 g, 10.90 mmol) in THF (50 mL) was added i-PrMgCl (2M, 7.15 mL) at 0° C. The mixture was stirred at 0° C. for 0.5 hr, then N-methoxy-N,1-dimethylcyclopropane-1-carboxamide (1.3 g, 9.08 mmol) in THF (30 mL) was added. The mixture was stirred at 20° C. for 12 hrs. The process was repeated using 500 mg of N-methoxy-N,1-dimethylcyclopropane-1-carboxamide and the combined reaction mixtures were quenched with saturated aqueous NH₄Cl (100 mL) and extracted with EtOAc (60 mL×3). The combined organic layers were dried over Na₂SO₄, filtered and concentrated to give a residue. The residue was purified by flash silica gel chromatography (ISCO; 40 g SepaFlash column) using 2% EtOAc/Petroleum ether as eluent to afford the title compound (1.2 g, 37%) as a colorless oil. MS-ESI (m/z) calcd for C₁₁H₁₁BrFO [M+H]⁺: 257.0/259.0. Found 256.9/259.0.

Step 3: 5-Bromo-3-(I-methylcyclopropyl)-1H-indazole

embedded image

A solution of (5-bromo-2-fluorophenyl)(1-methylcyclopropyl)methanone (500 mg, 1.94 mmol) in NH₂NH₂H₂O (10 mL) was stirred at 100° C. for 3 hrs. The reaction mixture was diluted with H₂O (30 ml) and extracted with EtOAc (20 mL×5). The combined organic layers were dried over Na₂SO₄, filtered and concentrated to give a residue. The residue was purified by flash silica gel chromatography (ISCO; 4 g SepaFlash column) using a 0-9% EtOAc/petroleum ether gradient eluent to afford the title compound (300 mg, 61%) as a light yellow solid. MS-ESI (m/z) calcd for C₁₁H₁₂BrN₂[M+H]⁺: 251.0/253.0. Found 251.0/253.0.

Step 4: 5-Bromo-3-(I-methylcyclopropyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole

embedded image

To a solution of 5-bromo-3-(1-methylcyclopropyl)-1H-indazole (230 mg, 915.89 umol) in DCM (6 mL) was added 3,4-dihydro-2H-pyran (115.56 mg, 1.37 mmol) and PTSA (15.77 mg, 91.59 umol) at 20° C. and the mixture was stirred at 45° C. for 12 hrs. The reaction mixture was concentrated and purified by flash silica gel chromatography (ISCO; 4 g SepaFlash column) using a 0-5% EtOAc/petroleum ether gradient eluent to afford the title compound (150 mg, 49%) as a light yellow gum. MS-ESI (m/z) calcd for C₁₆H₂₀BrN₂O [M+H]⁺: 335.1/337.1. Found 335.0/337.0.

Step 5: N-(3-(1-Methylcyclopropyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-1,1-diphenylmethanimine

embedded image

A mixture of 5-bromo-3-(1-methylcyclopropyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (150 mg, 447.44 umol), diphenylmethanimine (97.31 mg, 536.93 umol), Pd₂(dba)₃(20.49 mg, 22.37 umol), t-Bu Xphos (19.00 mg, 44.74 umol) and t-BuONa (86.00 mg, 894.89 umol) in toluene (4 mL) was degassed and purged with N₂(3×) at 20° C. The mixture was then stirred at 100° C. for 12 hrs under an N₂atmosphere and concentrated. The material was purified by flash silica gel chromatography (ISCO; 4 g SepaFlash column) using a 0-5% EtOAc/petroleum ether gradient eluent to afford the title compound (180 mg, 92%) as a yellow gum. MS-ESI (m/z) calcd for C₂₉H₃₀N₃O [M+H]⁺: 436.2. Found 436.2.

Step 6: 3-(1-Methylcyclopropyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-amine

embedded image

To a solution of N-(3-(1-methylcyclopropyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-1,1-diphenylmethanimine (180 mg, 413.26 umol) in THF (4 mL) was added 1 M HCl (1.24 mL) and the mixture was stirred at 20° C. for 10 min. The reaction mixture was then basified with saturated aqueous NaHCO₃to pH=7, diluted with H₂O (10 mL), and extracted with EtOAc (5 mL 3). The combined organic layers were dried over Na₂SO₄, filtered and concentrated to give a residue. The residue was purified by preparative TLC (SiO₂, petroleum ether/EtOAc=1/1, R_f=0.24) to afford the title compound (86 mg, 60%) as a yellow gum. MS-ESI (m/z) calcd for C₁₆H₂₂N₃O [M+H]⁺: 272.2. Found 272.4.

Step 7: 5-Cyano-3,4-dimethyl-N-(3-(1-methylcyclopropyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)picolinamide

embedded image

To a solution of 5-cyano-3,4-dimethylpicolinic acid (55.83 mg, 316.93 umol) in pyridine (3 mL) was added EDCI (91.13 mg, 475.39 umol) and 3-(1-methylcyclopropyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-amine (86 mg, 316.93 umol) and the mixture was stirred at 20° C. for 2 hrs. The reaction mixture was then concentrated to give a residue. The residue was diluted with H₂O (10 mL) and extracted with EtOAc (5 mL×4). The combined organic layers were dried over Na₂SO₄, filtered and concentrated to afford the title compound (117 mg) as a brown solid which was used without further purification. MS-ESI (m/z) calcd for C₂₅H₂₁N₅O₂[M+H]⁺: 430.2. Found 430.4.

Step 8: 5-Cyano-3,4-dimethyl-N-(3-(1-methylcyclopropyl)-1H-indazol-5-yl)picolinamide

embedded image

To a solution of 5-cyano-3,4-dimethyl-N-(3-(1-methylcyclopropyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)picolinamide (60 mg, 139.69 umol) in DCM (2 mL) was added TFA (0.5 mL). The mixture was stirred at 20° C. for 12 hrs and then concentrated. The material was purified by preparative HPLC using Method BA to afford the title compound (21.01 mg, 33%) as a pale yellow solid TFA salt. ¹H NMR (400 MHz, DMSO-d₆) δ 12.57 (br s, 1H) 10.63 (s, 1H) 8.89 (s, 1H) 8.31 (d, J=1 Hz, 1H) 7.61 (dd, J=9, 2 Hz, 1H) 7.45 (d, J=9 Hz, 1H) 2.56 (s, 3H) 2.45 (s, 3H) 1.55 (s, 3H) 1.10-1.14 (m, 2H) 0.79-0.83 (m, 2H). MS-ESI (m/z) calc'd for C₂₀H₂₀N₅O [M+H]⁺: 346.2. Found 346.2.

Example 269: 5-Cyano-N-(3-(1-methoxyethyl)-1H-indazol-5-yl)-3,4-dimethylpicolinamide

embedded image

Step 1: 3-Iodo-5-nitro-1H-indazole

embedded image

To a solution of 5-nitro-1H-indazole (10 g, 61.30 mmol) in DMF (100 mL) was added KOH (10.32 g, 183.90 mmol) and the mixture was stirred at 20° C. for 5 min. Then 12 (31.12 g, 122.60 mmol) was added and the reaction mixture was stirred at 20° C. for 3 hrs. The reaction mixture was quenched with saturated aqueous Na₂SO₃(100 mL), then filtered and the solid was washed with petroleum ether (100 mL) and dried to afford the title compound (15 g, 85%) as an orange solid, which was used without further purification. MS-ESI (m/z) calcd for C₇H₅IN₃O₂[M+H]⁺: 289.9. Found 289.9.

Step 2: 3-Iodo-5-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole

embedded image

To a solution of 3-iodo-5-nitro-1H-indazole (15 g, 51.90 mmol) in THF (100 mL) was added NaH (4.15 g, 103.80 mmol, 60% purity) and the reaction mixture was stirred at 0° C. for 0.5 hr. Then SEM-Cl (12.98 g, 77.85 mmol, 13.78 mL) was added and the mixture was stirred at 20° C. for 12 hrs. The reaction mixture was poured into water (100 mL) and extracted with EtOAc (100 mL×3). The combined organic phases were washed with brine (100 mL×1), dried over anhydrous Na₂SO₄, filtered and concentrated. The residue was purified by silica gel column chromatography using a 0-20% EtOAc/petroleum ether gradient eluent to afford the title compound (10 g, 46%) as a yellow solid. MS-ESI (m/z) calcd for C₁₃H₁₉IN₃O₃Si [M+H]⁺: 420.0. Found 420.0.

Step 3: 3-(1-Ethoxyvinyl)-5-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole

embedded image

A mixture of 3-iodo-5-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole (2 g, 4.77 mmol), butyl(1-ethoxyvinyl)-X²-stannane-octane (1/1) (3.45 g, 9.54 mmol, 3.22 mL) and Pd(PPh₃)₂Cl₂(334.80 mg, 477.00 umol) in dioxane (20 mL) was degassed and purged with N₂(3×), and then the mixture was stirred at 100° C. for 4 hrs under N₂atmosphere. The reaction mixture was concentrated and purified by silica gel column chromatography using a 0-20% EtOAc/petroleum ethergradient eluent to afford the title compound (1.7 g, 95%) as a yellow oil. MS-ESI (m/z) calcd for C₁₇H₂₆N₃O₄Si [M+H]⁺: 364.2. Found 364.1.

Step 4: 1-(5-Nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)ethan-1-one

embedded image

To a solution of 3-(1-ethoxyvinyl)-5-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole (1.7 g, 4.68 mmol) in THF (10 mL) was added HCl (1 M, 46.77 mL). The mixture was stirred at 20° C. for 0.5 hr. The reaction mixture was poured into water (10 mL). The aqueous phase was extracted with EtOAc (15 mL×3). The combined organic phases were washed with brine (15 mL×1), dried over anhydrous Na₂SO₄, filtered and concentrated in vacuum. The residue was purified by silica gel column chromatography using a 0-20% EtOAc/petroleum ether gradient eluent to afford the title compound (1 g, 64%) as a pink solid. MS-ESI (m/z) calcd for C₁₅H₂₂N₃O₄Si [M+H]⁺: 336.1. Found 336.1.

Step 5: 1-(5-Nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)ethan-1-ol

embedded image

To a solution of 1-(5-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)ethan-1-one (1 g, 2.98 mmol) in MeOH (10 mL) was added NaBH₄(338.36 mg, 8.94 mmol). The mixture was stirred at 20° C. for 0.5 hr. The reaction mixture was poured into water (10 mL) and extracted with EtOAc (10 mL×3). The combined organic phases were washed with brine (10 mL×1), dried over anhydrous Na₂SO₄, filtered and concentrated in vacuum to afford the title compound (700 mg, 70%) as a brown oil, which was used without further purification. MS-ESI (m/z) calcd for C₁₅H₂₄N₃O₄Si [M+H]⁺: 338.2. Found 338.2.

Step 6: 3-(1-Methoxyethyl)-5-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole

embedded image

To a solution of 1-(5-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)ethan-1-ol (700 mg, 2.07 mmol) in THF (5 mL) was added a 60% NaH dispersion in mineral oil (165.94 mg, 4.15 mmol) at 0° C. and the reaction mixture was stirred at 0° C. for 0.5 hr. Then MeI (588.88 mg, 4.15 mmol, 258.28 uL) was added and the mixture was stirred at 20° C. for 12 hrs. The reaction mixture was poured into water (10 mL) and extracted with EtOAc (10 mL×3). The combined organic phases were washed with brine (10 mL×1), dried over anhydrous Na₂SO₄, filtered and concentrated. The residue was purified by silica gel column chromatography using a 0-30% EtOAc/petroleum ether gradient eluent to afford the title compound (670 mg, 92%) as a colorless oil. MS-ESI (m/z) calcd for C₁₆H₂₆N₃O₄Si [M+H]⁺: 352.2. Found 352.0.

Step 7: 3-(1-Methoxyethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-5-amine

embedded image

To a solution of 3-(1-methoxyethyl)-5-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole (670 mg, 1.91 mmol) in EtOH (10 mL) and H₂O (2.5 mL) was added Fe (532.28 mg, 9.53 mmol) and NH₄Cl (509.84 mg, 9.53 mmol) at 20° C. The reaction mixture was then stirred at 80° C. for 2 hrs. The mixture was filtered and the filtrate was poured into water (5 mL) and extracted with EtOAc (5 mL×3). The combined organic phases were washed with brine (5 mL×1), dried over anhydrous Na₂SO₄, filtered and concentrated in vacuum to afford the title compound (660 mg) as a yellow oil, which was used without further purification. MS-ESI (m/z) calcd for C₁₆H₂₈N₃O₂Si [M+H]⁺: 322.2. Found 322.2.

Step 8: 5-Cyano-N-(3-(I-methoxyethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-5-yl)-3,4-dimethylpicolinamide

embedded image

To a solution of 3-(1-methoxyethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-5-amine (660 mg, 2.05 mmol) and 5-cyano-3,4-dimethylpicolinic acid (361.67 mg, 2.05 mmol) in pyridine (3 mL) was added EDCI (787.11 mg, 4.11 mmol) and the mixture was stirred at 20° C. for 2 hrs. The reaction mixture was concentrated and the residue was diluted with water (10 mL) and extracted with EtOAc (10 mL×3). The combined organic phases were washed with brine (10 mL×1), dried over anhydrous Na₂SO₄, filtered and concentrated. The residue was purified by silic a gel column chromatography using a 0-30% EtOAc/petroleum ether gradient eluent to afford the title compound (740 mg, 75%) as a yellow solid. MS-ESI (m/z) calcd for C₂₅H₃₄N₅O₃Si [M+H]⁺: 480.2. Found 480.3.

Step 9: 5-Cyano-N-(3-(1-methoxyethyl)-1H-indazol-5-yl)-3,4-dimethylpicolinamide

embedded image

To a solution of 5-cyano-N-(3-(1-methoxyethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-5-yl)-3,4-dimethylpicolinamide (300 mg, 625.46 umol) in MeOH (5 mL) was added 12 M HCl (521.22 uL) at 20° C. and the mixture was stirred at 60° C. for 12 hrs. The reaction mixture was diluted with H₂O (10 mL) and adjusted to pH=8 with saturated aqueous NaHCO₃. The mixture was then extracted with EtOAc (10 mL×3). The combined organic phases were washed with brine (10 mL×1), dried over anhydrous Na₂SO₄, filtered and concentrated. The residue was purified by silica gel column chromatography using a 0-50% EtOAc/petroleum ether gradient eluent to afford material of insufficient purity. The material was then further purified by preparative HPLC using Method BB to afford the title compound (74.99 mg, 34%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 12.86 (s, 1H), 10.63 (s, 1H), 8.87 (s, 1H), 8.35 (s, 1H), 7.64 (dd, J=1.9, 8.9 Hz, 1H), 7.50 (d, J=8.8 Hz, 1H), 4.73 (q, J=6.5 Hz, 1H), 3.16 (s, 3H), 2.55 (s, 3H), 2.44 (s, 3H), 1.57 (d, J=6.6 Hz, 3H). MS-ESI (m/z) calc'd for C₁₉H₂₀N₅O₂[M+H]⁺: 350.2. Found 350.2.

Example 270: 6-Chloro-5-cyano-N-(3-isopropyl-1H-indazol-5-yl)-3,4-dimethylpicolinamide

embedded image

Step 1: 3-Bromo-1-(4-methoxybenzyl)-5-nitro-1H-indazole

embedded image

To a solution of 3-bromo-5-nitro-1H-indazole (2.42 g, 10 mmol) in DMF (10 mL) was added K₂CO₃(4.15 g, 30 mmol) and 1-(chloromethyl)-4-methoxybenzene (2.92 mL, 20 mmol) and the mixture was stirred at 25° C. for 2 hrs. H₂O was added and the solid formed was filtered and washed with water and dried. The solid was triturated with Et₂O and dried to obtain 3-bromo-1-[(4-methoxyphenyl)methyl]-5-nitroindazole (3.57 g, 99%) as an off white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.48 (d, J=2.1 Hz, 1H), 8.32 (dd, J=9.3, 2.2 Hz, 1H), 8.08 (d, J=9.3 Hz, 1H), 7.27 (d, J=8.7 Hz, 2H), 6.89 (d, J=8.7 Hz, 2H), 5.67 (s, 2H), 3.71 (s, 3H). MS-ESI (m/z) calc'd for C₁₅H₁₃BrN₃O₃[M+H]⁺: 362.0/364.0. Found 362.0/364.0.

Step 2: 1-(4-Methoxybenzyl)-5-nitro-3-(prop-1-en-2-yl)-1H-indazole

embedded image

To a solution of 3-bromo-1-(4-methoxybenzyl)-5-nitro-1H-indazole (1.09 g, 3 mmol) and 4,4,5,5-tetramethyl-2-(1-methylethenyl)-1,3,2-dioxaborolane (0.5 g, 3 mmol) in THF (12.5 mL) and H₂O (2.5 mL) was added K₂CO₃(1.24 g, 9 mmol) and the mixture was purged with N₂for 5 minutes. Pd(dppf)Cl₂(0.11 g, 0.150 mmol) was added and the reaction was stirred under N₂at 90° C. for 24 hrs. H₂O was added and the mixture was extracted with EtOAc (3×). The combined organic layers were passed through a phase separator and evaporated to obtain a brown residue which was purified by silica gel column chromatography using a 0-30% MeOH/EtOAc gradient eluent to afford the title compound (969.9 mg, 99%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.81 (dd, J=2.1, 0.6 Hz, 1H), 8.25 (dd, J=9.3, 2.1 Hz, 1H), 7.96 (dd, J=9.2, 0.6 Hz, 1H), 7.25 (d, J=8.7 Hz, 2H), 6.88 (d, J=8.7 Hz, 2H), 5.89-5.82 (m, 1H), 5.67 (s, 2H), 5.50 (p, J=1.3 Hz, 1H), 3.70 (s, 3H), 2.28-2.24 (m, 3H). MS-ESI (m/z) calc'd for C₁₈H₁₈N₃O₃[M+H]⁺: 324.1. Found 324.2.

Step 3: 3-Isopropyl-1-(4-methoxybenzyl)-1H-indazol-5-amine

embedded image

To a suspension of 1-(4-methoxybenzyl)-5-nitro-3-(prop-1-en-2-yl)-1H-indazole (969.9 mg, 3 mmol) in EtOH (30 mL) was added 10% Pd/C (319.21 mg, 0.300 mmol) and the mixture was hydrogenated at 6 bar for 4 hrs. The mixture was purified by strong cation exchange (SCX) using MeOH to wash the cartride and NH₃/MeOH to wash out the desired product. The MeOH was evaporated under reduced pressure to afford the title compound (68 mg, 78%) as a dark solid. ¹H NMR (400 MHz, DMSO-d₆) δ 7.25 (dd, J=8.8, 0.8 Hz, 1H), 7.12 (d, J=8.7 Hz, 2H), 6.83 (d, J=8.7 Hz, 2H), 6.78 (dd, J=2.1, 0.8 Hz, 1H), 6.73 (dd, J=8.8, 2.0 Hz, 1H), 5.34 (s, 2H), 4.73 (s, 2H), 3.69 (s, 3H), 3.19 (hept, J=7.0 Hz, 1H), 1.32 (d, J=6.9 Hz, 6H). MS-ESI (m/z) calc'd for C₁₈H₂₂N₃O [M+H]⁺: 296.2. Found 296.2.

Step 4: 3-Isopropyl-1H-indazol-5-amine

embedded image

A solution of 3-isopropyl-1-(4-methoxybenzyl)-1H-indazol-5-amine (690.0 mg, 2.34 mmol) in trifluoroacetic acid (20 mL) was heated at 75° C. for 15 hrs. Analysis indicated incomplete reaction. The volume was then concentrated to ˜10 mL and the solution was irradiated in a microwave reactor (I hr, 90° C., very high absorption, 3 rounds). The solvent was evaporated and the residue was taken up in MeOH. K₂CO₃was added and the mixture was stirred at 50° C. for 24 hrs. The solvent was evaporated, the residue was taken up in H₂O, and the precipitate that formed was filtered and dried. The residue was purified by silica gel column chromatography using a 50-100% EtOAc/cyclohexane to afford the title compound (300 mg, 73%) as a beige solid. ¹H NMR (400 MHz, DMSO-d₆) δ 12.04 (s, 1H), 7.15 (dd, J=8.7, 0.8 Hz, 1H), 6.77 (d, J=1.9 Hz, 1H), 6.73 (dd, J=8.7, 2.0 Hz, 1H), 4.68 (s, 2H), 3.19 (hept, J=6.9 Hz, 1H), 1.32 (d, J=6.9 Hz, 6H). MS-ESI (m/z) calc'd for C₁₀H₁₃N₃O [M+H]⁺: 176.1. Found 176.0.

Step 5: 6-Chloro-5-cyano-N-(3-isopropyl-1H-indazol-5-yl)-3,4-dimethylpicolinamide

embedded image

Prepared as described for 3-chloro-5-cyano-N-(3-cyclopropyl-1H-indazol-5-yl)-4,6-dimethylpicolinamide (Example 283) using 6-chloro-5-cyano-3,4-dimethylpicolinic acid in place of 3-chloro-5-cyano-4,6-dimethylpicolinic acid and using 3-isopropyl-1H-indazol-5-amine in place of 3-cyclopropyl-1H-indazol-5-amine to afford the title compound (43 mg, 58%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 12.59 (s, 1H), 10.66 (s, 1H), 8.24 (d, J=1.9 Hz, 1H), 7.56 (dd, J=8.9, 1.9 Hz, 1H), 7.46 (d, J=8.9 Hz, 1H), 3.34 (h, J=7.0 Hz, 1H), 2.59 (s, 3H), 2.39 (s, 3H), 1.38 (d, J=6.9 Hz, 6H. MS-ESI (m/z) calc'd for C₁₉H₁₉ClN₅O [M+H]⁺: 368.1/370.1. Found 368.1/370.1.

Example 271: 6-Chloro-5-cyano-N-(3-ethyl-1H-indazol-5-yl)-3,4-dimethylpicolinamide

embedded image

Step 1: 3-Bromo-1-(4-methoxybenzyl)-5-nitro-1H-indazole

embedded image

To a solution of 3-bromo-5-nitro-1H-indazole (2.42 g, 10 mmol) in DMF (10 mL) was added K₂CO₃(4.15 g, 30 mmol) and 1-(chloromethyl)-4-methoxybenzene (2.92 mL, 20 mmol). The mixture was stirred at 25° C. for 2 hrs. H₂O was added and the solid that formed was filtered, washed with H₂O, and dried. The solid was triturated with Et₂O and dried to afford the title compound (3.57 g, 99%) as an off white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.48 (d, J=2.1 Hz, 1H), 8.32 (dd, J=9.3, 2.2 Hz, 1H), 8.08 (d, J=9.3 Hz, 1H), 7.27 (d, J=8.7 Hz, 2H), 6.89 (d, J=8.7 Hz, 2H), 5.67 (s, 2H), 3.71 (s, 3H). MS-ESI (m/z) calc'd for C₁₅H₁₃BrN₃O₃[M+H]⁺: 362.0/364.0. Found 362.0/364.0.

Step 2: 1-(4-Methoxybenzyl)-5-nitro-3-vinyl-1H-indazole

embedded image

To a solution of 3-bromo-1-(4-methoxybenzyl)-5-nitro-1H-indazole (1.09 g, 3 mmol) and 2-ethenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.51 mL, 3 mmol) in THF (12.5 mL)/H₂O (2.5 mL) was added K₂CO₃(1.24 g, 9 mmol) and the mixture was purged with N₂for 5 minutes. Pd(dppf)Cl₂(0.11 g, 0.150 mmol) was added and the reaction was stirred under N₂at 90° C. for 24 hours. H₂O was added and the mixture was extracted with EtOAc (3×). The combined organic layers were passed through a phase separator and concentrated. The residue was purified by silica gel column chromatography using a 0-30% MeOH/EtOAc gradient eluent to afford the title compound (794 mg, 86%) as an orange solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.94 (dd, J=2.2, 0.6 Hz, 1H), 8.25 (dd, J=9.3, 2.1 Hz, 1H), 7.96 (dd, J=9.3, 0.6 Hz, 1H), 7.25 (d, J=8.7 Hz, 2H), 7.13 (dd, J=17.9, 11.4 Hz, 1H), 6.88 (d, J=8.7 Hz, 2H), 6.20 (dd, J=17.9, 1.1 Hz, 1H), 5.65 (s, 2H), 5.60 (dd, J=11.4, 1.1 Hz, 1H), 3.70 (s, 3H). MS-ESI (m/z) calc'd for C₁₇H₁₆N₃O₃[M+H]⁺: 310.1. Found 310.1.

Step 3: 3-Ethyl-1-(4-methoxybenzyl)-1H-indazol-5-amine

embedded image

To a suspension of 1-(4-methoxybenzyl)-5-nitro-3-vinyl-1H-indazole (794.0 mg, 2.57 mmol) in MeOH (25.67 mL) was added 10% Pd/C (273.17 mg, 0.260 mmol) and the mixture was hydrogenated at 6 bar for 1 hr. The catalyst was removed by filtration through Celite and the filtrate was purified by strong cation exchange (SCX) using MeOH to wash the cartride and NH₃/MeOH to wash out the desired product. The MeOH was evaporated under reduced pressure to afford the title compound (658 mg, 91%) as a red oil. ¹H NMR (400 MHz, DMSO-d₆) δ 7.27 (dd, J=8.8, 0.8 Hz, 1H), 7.13 (d, J=8.6 Hz, 2H), 6.83 (d, J=8.8 Hz, 2H), 6.74 (dd, J=8.8, 2.0 Hz, 1H), 6.71 (dd, J=2.0, 0.8 Hz, 1H), 5.34 (s, 2H), 4.74 (s, 2H), 3.69 (s, 3H), 2.78 (q, J=7.6 Hz, 2H), 1.26 (t, J=7.6 Hz, 3H). MS-ESI (m/z) calc'd for C₁₇H₂₀N₃O [M+H]⁺: 282.2. Found 282.2.

Step 4: 3-Ethyl-1H-indazol-5-amine

embedded image

A solution of 3-ethyl-1-(4-methoxybenzyl)-1H-indazol-5-amine (658.0 mg, 2.34 mmol) in trifluoroacetic acid (10 mL) was irradiated in a microwave reactor (1 hr, 90° C.), then the mixture was diluted with MeOH. K₂CO₃was added and the suspension was heated at 65° C. for 15 hrs. The solvent was evaporated and the residue was taken up in H₂O and extracted with EtOAc (2×). The combined organic layers were passed through a phase separator and concentrated to obtain a solid. MeOH was added, a suspension formed and the solid was filtered away. The MeOH layer was concentrated and the residue was purified by strong cation exchange (SCX) using MeOH to wash the cartride and NH₃/MeOH to wash out the desired product. The MeOH was evaporated under reduced pressure to afford the title compound (337 mg, 89%) as a red solid. ¹H NMR (400 MHz, DMSO-d₆) δ 12.07 (s, 1H), 7.15 (dd, J=8.7, 0.9 Hz, 1H), 6.74 (dd, J=8.7, 2.0 Hz, 1H), 6.72-6.70 (m, 1H), 4.68 (s, 2H), 2.78 (q, J=7.6 Hz, 2H), 1.26 (t, J=7.6 Hz, 3H). MS-ESI (m/z) calc'd for C₉H₁₂N₃[M+H]⁺: 162.1. Found 161.9.

Step 5: 6-Chloro-5-cyano-N-(3-ethyl-1H-indazol-5-yl)-3,4-dimethylpicolinamide

embedded image

Prepared as described for 3-chloro-5-cyano-N-(3-cyclopropyl-1H-indazol-5-yl)-4,6-dimethylpicolinamide (Example 283) using 6-chloro-5-cyano-3,4-dimethylpicolinic acid in place of 3-chloro-5-cyano-4,6-dimethylpicolinic acid and using 3-ethyl-1H-indazol-5-amine in place of 3-cyclopropyl-1H-indazol-5-amine to afford the title compound (31.4 mg, 44%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 12.62 (s, 1H), 10.67 (s, 1H), 8.20 (d, J=1.8 Hz, 1H), 7.53 (dd, J=8.9, 1.9 Hz, 1H), 7.46 (dd, J=8.8, 0.8 Hz, 1H), 2.91 (q, J=7.6 Hz, 2H), 2.59 (s, 3H), 2.39 (s, 3H), 1.32 (t, J=7.6 Hz, 3H). MS-ESI (m/z) calc'd for C₁₈H₁₇ClN₅O [M+H]⁺: 354.1/356.1. Found 354.1/356.1.

Example 272: 5-Cyano-3-methyl-N-(3-(pyridazin-4-yl)-1H-indazol-5-yl)picolinamide

embedded image

Prepared as described for 5-cyano-N-(3-(isoxazol-4-yl)-1H-indazol-5-yl)-3-methylpicolinamide using pyridazin-4-ylboronic acid in place of isoxazole-4-boronic acid and 5-cyano-N-(3-iodo-1H-indazol-5-yl)-3-methylpicolinamide in place of 5-cyano-N-(3-iodo-1H-indazol-5-yl)-3-methylpyridine-2-carboxamide to afford the title compound (6.1 mg, 12%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.78 (s, 1H), 10.83 (s, 1H), 9.82 (dd, J=2.4, 1.3 Hz, 1H), 9.34 (dd, J=5.4, 1.3 Hz, 1H), 9.01 (d, J=1.9 Hz, 1H), 8.74 (d, J=1.7 Hz, 1H), 8.42 (dd, J=2.0, 0.9 Hz, 1H), 8.14 (dd, J=5.4, 2.4 Hz, 1H), 7.91 (dd, J=9.0, 1.9 Hz, 1H), 7.70 (d, J=9.0 Hz, 1H), 2.62 (s, 3H). MS-ESI (m/z) calc'd for C₁₉H₁₄N₇O [M+H]⁺: 356.1. Found 356.3.

Example 273: 5-Cyano-3-methyl-N-(3-(6-methylpyridazin-4-yl)-1H-indazol-5-yl)picolinamide

embedded image

Prepared as described for 5-cyano-N-(3-(isoxazol-4-yl)-1H-indazol-5-yl)-3-methylpicolinamide using (6-methylpyridazin-4-yl)boronic acid in place of isoxazole-4-boronic acid and 5-cyano-N-(3-iodo-1H-indazol-5-yl)-3-methylpicolinamide in place of 5-cyano-N-(3-iodo-1H-indazol-5-yl)-3-methylpyridine-2-carboxamide to afford the title compound (26 mg, 47%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.82 (s, 1H), 10.82 (s, 1H), 9.65 (d, J=2.1 Hz, 1H), 9.02 (d, J=1.9 Hz, 1H), 8.67 (d, J=1.8 Hz, 1H), 8.42 (d, J=1.9 Hz, 1H), 8.03 (d, J=2.1 Hz, 1H), 7.97 (dd, J=9.0, 1.8 Hz, 1H), 7.70 (d, J=9.0 Hz, 1H), 2.74 (s, 3H), 2.62 (s, 3H). MS-ESI (m/z) calc'd for C₂₀H₁₆N₇O [M+H]⁺: 370.1. Found 370.3.

Example 274: 3-Cyano-N-(3-methyl-1H-indazol-5-yl)-2-(prop-1-en-2-yl)benzamide

embedded image

2-bromo-3-cyano-N-(3-methyl-1H-indazol-5-yl)benzamide (40.0 mg, 0.080 mmol) and 4,4,5,5-tetramethyl-2-(1-methylethenyl)-1,3,2-dioxaborolane (20.72 mg, 0.120 mmol) were dissolved in 1,4-dioxane (1 mL). Then K₂CO₃(34.09 mg, 0.250 mmol) was added and the mixture was degassed with N₂for 5 minutes. Tetrakis(triphenylphosphine)palladium(0) (9.5 mg, 0.010 mmol) was added and the mixture was stirred at 100° C. under N₂for 6 hrs. 4,4,5,5-Tetramethyl-2-(1-methylethenyl)-1,3,2-dioxaborolane (20.72 mg, 0.120 mmol), KOAc (16.14 mg, 0.160 mmol) and water (0.250 mL) were then added and the mixture was stirred under N₂for 5 min. Then Pd(amphos)Cl₂(5.84 mg, 0.010 mmol) was added and the mixture was stirred under microwave irradiation at 100° C. for 30 min. The reaction mixture was partitioned between water and EtOAc. The phases were separated and the aqueous layer was extracted with EtOAc (2×). The combined organic phases were washed with brine (1×), dried over Na₂SO₄, and evaporated to dryness. The material was purified by silica gel column chromatography using a 0-80% EtOAc/cyclohexane gradient eluent. The residue was further purified by preparative HPLC using Method DC to afford the title compound (3 mg, 12%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 12.59 (s, 1H) 10.36 (s, 1H) 8.12 (s, 1H) 7.98 (dd, J=7.70, 1.32 Hz, 1H) 7.86 (dd, J=7.70, 1.10 Hz, 1H) 7.62 (t, J=7.81 Hz, 1H) 7.43 (d, J=1.10 Hz, 2H) 5.36 (t, J=1.54 Hz, 1H) 5.05 (s, 1H) 2.47 (s, 3H) 2.13 (s, 3H). MS-ESI (m/z) calc'd for C₁₉H₁₇N₄O [M+H]⁺: 317.1. Found 317.3.

Example 275: 3-Chloro-5-cyano-4,6-dimethyl-N-(3-methyl-1H-indazol-5-yl)picolinamide

embedded image

Step 1: 2,5-Dichloro-3-cyano-4,6-dimethylpyridine 1-oxide

embedded image

To a solution of 2,5-dichloro-4,6-dimethylpyridine-3-carbonitrile (2.01 g, 10 mmol) in trifluoroacetic acid (50 mL) was added hydrogen peroxide (3.06 mL, 30 mmol) and the mixture was stirred at 75° C. for 1 hr. The reaction was concentrated to afford the title compound (2.17 g, 99%) as a yellow oil which was used without further purification. MS-ESI (m/z) calc'd for C₈H₇Cl₂N₂O [M+H]⁺: 219.0. Found 219.0.

Step 2: 2,5-Dichloro-6-(hydroxymethyl)-4-methylnicotinonitrile

embedded image

To a solution of 2,5-dichloro-3-cyano-4,6-dimethylpyridine 1-oxide (2.17 g, 10 mmol) in DCM (50 mL) was added trifluoroacetic anhydride (4.17 mL, 30 mmol) dropwise and the mixture was stirred at 25° C. for 15 hrs. The solvent was evaporated and the residue was taken up in MeOH. K₂CO₃(3 g) was added and the suspension was stirred at 25° C. for 1 hr. The solvent was evaporated, the residue was taken up in H₂O and extracted with DCM (3×), the combined organic layers were passed through a phase separator and concentrated to afford (1.9 g, 88%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 5.60 (t, J=6.3 Hz, 1H), 4.66 (d, J=6.3 Hz, 2H), 2.58 (s, 3H). MS-ESI (m/z) calc'd for C₈H₇Cl₂N₂O [M+H]⁺: 217.0/219.0. Found 219.0.

Step 3: 5-Chloro-6-(hydroxymethyl)-2,4-dimethylnicotinonitrile

embedded image

To a mixture of 2,5-dichloro-6-(hydroxymethyl)-4-methylnicotinonitrile (868.2 mg, 4 mmol), trimethylboroxine (0.56 mL, 4 mmol) and K₂CO₃(552.84 mg, 4 mmol) in 1,4-dioxane (27 mL)/H₂O (13 mL) was added tetrakis(triphenylphosphine)palladium(0) (462.22 mg, 0.400 mmol) and the mixture was stirred at 90° C. under N₂for 15 hours. The mixture was diluted with H₂O and extracted with DCM (3×). The combined organic layers were passed through a phase separator and concentrated. The residue was purified by silica gel column chromatography using a 12-100% EtOAc/cyclohexane gradient eluent to afford the title compound (120 mg, 15%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 5.35 (t, J=5.9 Hz, 1H), 4.65 (d, J=5.7 Hz, 2H), 2.66 (s, 3H), 2.54 (s, 3H). MS-ESI (m/z) calc'd for C₉H₁₀ClN₂O [M+H]⁺: 197.0/199.0. Found 199.0.

Step 4: 3-Chloro-5-cyano-4,6-dimethylpicolinic acid

embedded image

To a solution of 5-chloro-6-(hydroxymethyl)-2,4-dimethylnicotinonitrile (120.0 mg, 0.610 mmol) in acetone (5 mL) was added a solution of KMnO₄(144.66 mg, 0.920 mmol) in water (1 mL) and the mixture was stirred at 25° C. for 4 hours. The solid formed was filtered and washed with acetone and water. The filtrate was concentrated to remove the acetone and the resulting aqueous layer was washed with EtOAc. The water was acidified by addition of conc. HCl and then extracted with EtOAc (3×). The combined organic layers were passed through a phase separator and concentrated to afford the title compound (98 mg, 76%) as an off white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.62 (s, 1H), 2.66 (s, 3H), 2.57 (s, 3H). MS-ESI (m/z) calc'd for C₉H₈ClN₂O₂[M+H]⁺: 211.0/213.0. Found 212.9.

Step 5: 3-Chloro-5-cyano-4,6-dimethyl-N-(3-methyl-1H-indazol-5-yl)picolinamide

embedded image

Prepared as described for 3-chloro-5-cyano-N-(3-cyclopropyl-1H-indazol-5-yl)-4,6-dimethylpicolinamide (Example 283) using 3-chloro-5-cyano-4,6-dimethylpicolinic acid in place of 3-chloro-5-cyano-4,6-dimethylpicolinic acid and using 3-methyl-1H-indazol-5-amine in place of 3-cyclopropyl-1H-indazol-5-amine to afford the title compound (53 mg, 78%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 12.63 (s, 1H), 10.74 (s, 1H), 8.17 (s, 1H), 7.46 (s, 2H), 2.73 (s, 3H), 2.63 (s, 3H), 2.48 (s, 3H). MS-ESI (m/z) calc'd for C₁₇H₁₅ClN₅O [M+H]⁺: 340.1/342.1. Found 340.1/342.1.

Example 276: 5-Cyano-N-(3-(cyclobutylidenemethyl)-1H-indazol-5-yl)-3,4-dimethylpicolinamide

embedded image

Step 1: 2-(Cyclobutylidenemethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

embedded image

To a solution of 2,2,6,6-tetramethylpiperidine (1.21 g, 8.56 mmol, 1.45 mL) in 15 mL of dry THF was added n-BuLi (2.5 M, 3.42 mL) dropwise under an N₂atmosphere at −30° C. and the mixture was stirred at −30° C. for 0.5 hr. The reaction was then cooled to −78° C. and a solution of bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methane (1.91 g, 7.13 mmol) in 15 mL of dry THF was added dropwise. The reaction mixture was stirred at −78° C. for 0.5 hr and a solution of cyclobutanone (500 mg, 7.13 mmol, 533.05 uL) in 14 mL of dry THF was added dropwise. The reaction mixture was then warmed to 20° C. and stirred for an additional 12 hrs. The reaction mixture was slowly poured into 20 mL of saturated aqueous NH₄Cl at 0° C. and after stirring for 1 hr, the solution was diluted with H₂O (10 mL) and extracted with EtOAc (20 mL×3). The organic phase was dried over Na₂SO₄, filtered and concentrated under reduced pressure to afford the title compound (1.2 g) as a yellow oil which was used without further purification.

Step 2: 5-Cyano-N-(3-(cyclobutylidenemethyl)-1H-indazol-5-yl)-3,4-dimethylpicolinamide

embedded image

A mixture of N-(3-bromo-1H-indazol-5-yl)-5-cyano-3,4-dimethylpicolinamide (100 mg, 270.12 umol), 2-(cyclobutylidenemethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (314.55 mg, 1.62 mmol), AcOK (79.53 mg, 810.37 umol), and Pd(Amphos)Cl₂(19.13 mg, 27.01 umol) in 4 mL of EtOH and 0.8 mL of H₂O was degassed and purged with N₂(3×) at 20° C. The mixture was then stirred at 90° C. for 12 hrs under an N₂atmosphere. The reaction mixture was concentrated and diluted with 5 mL of H₂O and extracted with EtOAc (5 mL×4). The organic phase was dried over Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was diluted with 1 mL of MeCN and 1 mL of DMF. Then the mixture was filtered and the solid was dried in vacuum to afford the title compound (16.14 mg, 16%) as a gray solid. ¹H NMR (400 MHz, DMSO-d₆) δ 12.89 (s, 1H), 10.64 (s, 1H), 8.88 (s, 1H), 8.30 (s, 1H), 7.54-7.59 (m, 1H), 7.45-7.50 (m, 1H), 6.39 (t, J=2.32 Hz, 1H), 3.07 (br t, J=7.89 Hz, 2H), 2.88-2.93 (m, 2H), 2.55 (s, 3H), 2.44 (s, 3H), 2.06 (quin, J=7.82 Hz, 2H). MS-ESI (m/z) calcd for C₂₁H₂₀N₅O [M+H]⁺: 358.2. Found 358.1.

Example 277: 5-Cyano-3,4-dimethyl-N-(3-(2-morpholinopyridin-4-yl)-1H-indazol-5-yl)picolinamide

embedded image

A mixture of N-(3-bromo-1H-indazol-5-yl)-5-cyano-3,4-dimethylpicolinamide (100 mg, 270.12 umol), (2-morpholino-4-pyridyl) boronic acid (84.29 mg, 405.18 umol), Pd(Amphos)Cl₂(19.13 mg, 27.01 umol) and AcOK (79.53 mg, 810.37 umol) in 2 mL of EtOH and 0.4 mL of H₂O was degassed and purged with N₂(3×) at 20° C. The mixture was stirred at 90° C. for 1 hr under an N₂atmosphere. The reaction mixture was concentrated under reduced pressure and purified by preparative-HPLC using Method CO to afford the title compound (13.41 mg, 9%) as a white solid, TFA salt. ¹H NMR (400 MHz, DMSO-d₆) δ 13.73 (br s, 1H), 10.82 (s, 1H), 8.91 (s, 1H), 8.72 (s, 1H), 8.25 (d, 1H, J=5.7 Hz), 7.78 (dd, 1H, J=1.7, 9.0 Hz), 7.68 (d, 1H, J=9.0 Hz), 7.49 (br s, 1H), 7.38 (br d, 1H, J=5.3 Hz), 3.7-3.8 (m, 4H), 3.63 (br s, 4H), 2.56 (s, 3H), 2.45 (s, 3H). MS-ESI (m/z) calcd for C₂₅H₂₄N₇O₂(M+H)⁺: 454.2. Found 454.2.

Example 278: 6-Chloro-5-cyano-3,4-dimethyl-N-(3-(2-morpholinopyridin-4-yl)-1H-indazol-5-yl)picolinamide

embedded image

Step 1: 4-(4-Bromopyridin-2-yl)morpholine

embedded image

To a solution of 4-bromo-2-fluoropyridine (2 g, 11.36 mmol) in 10 mL of DMF was added morpholine (1.19 g, 13.64 mmol) and Cs₂CO₃(7.41 g, 22.73 mmol) at 20° C. and the mixture was stirred at 100° C. for 12 hrs. The reaction mixture was diluted with 40 mL of H₂O and extracted with EtOAc (20 mL×3). The combined organic layers were dried over Na₂SO₄and filtered. The filtrate was concentrated and purified by flash silica gel chromatography (ISCO; 12 g SepaFlash column) using a 0-8% EtOAc/petroleum ether gradient eluent to afford the title compound (2.13 g, 75%) as a white solid. MS-ESI (m/z) calcd for C₉H₁₂BrN₂O [M+H]⁺: 243.0/245.0. Found 243.0/245.0.

Step 2: (2-Morpholinopyridin-4-yl)boronic acid

embedded image

A mixture of 4-(4-bromopyridin-2-yl)morpholine (1 g, 4.11 mmol), bis(pinacolato)diboron (1.25 g, 4.94 mmol), AcOK (1.01 g, 10.28 mmol), Pd(dppf)Cl₂(300.99 mg, 411.35 umol) in 15 mL of dioxane was degassed and purged with N₂(3×) at 20° C., and then the mixture was stirred at 80° C. for 12 hrs under an N₂atmosphere. The mixture was filtered, the filtrate was concentrated under reduced pressure to afford the title compound (0.85 g) as black oil, which was used without further purification. MS-ESI (m/z) calcd for C₉H₁₄BN₂O₃[M+H]⁺: 209.1. Found 209.2.

Step 3: 3-(2-Morpholinopyridin-4-yl)-1H-indazol-5-amine

embedded image

A mixture of (2-morpholinopyridin-4-yl)boronic acid (235.45 mg, 1.13 mmol), 3-bromo-1H-indazol-5-amine (200 mg, 943.19 umol), Pd(Amphos)Cl₂(66.78 mg, 94.32 umol), AcOK (277.69 mg, 2.83 mmol) in 2 mL of EtOH and 0.5 mL of H₂O was degassed and purged with N₂(3×) at 20° C., and then the mixture was stirred at 100° C. for 12 hrs under a N₂atmosphere. The reaction mixture was diluted with 30 mL of H₂O and extracted with EtOAc (40 mL×5), the combined organic layers were dried over solid Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by preparative-TLC (SiO₂, petroleum ether/EtOAc=1/3, P1 Rf=0.15) to afford the title compound (58 mg, 21%) as a yellow solid. MS-ESI (m/z) calcd for C₁₆H₁₈N₅O [M+H]⁺: 296.1. Found 296.1.

Step 4: 6-Chloro-5-cyano-3,4-dimethyl-N-(3-(2-morpholinopyridin-4-yl)-1H-indazol-5-yl)picolinamide

embedded image

To a solution of 3-(2-morpholinopyridin-4-yl)-1H-indazol-5-amine (53 mg, 179.46 umol) in 3 mL of DCM was added 6-chloro-5-cyano-3,4-dimethylpicolinic acid (31.50 mg, 149.55 umol), Et₃N (45.40 mg, 448.64 umol) and T3P (50 wt % in EtOAc, 123.71 mg, 194.41 umol, 115.62 uL). The mixture was stirred at 15° C. for 12 hrs. The reaction mixture was concentrated under reduced pressure and purified by preparative-HPLC using Method AP to afford the title compound (16.48 mg, 22%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.50 (s, 1H) 10.82 (s, 1H) 8.62 (s, 1H) 8.29 (d, J=5 Hz, 1H) 7.70-7.77 (m, 1H) 7.62-7.68 (m, 1H) 7.30 (s, 1H) 7.25 (d, J=5 Hz, 1H) 3.69-3.79 (m, 4H) 3.49-3.59 (m, 4H) 2.60 (s, 3H) 2.40 (s, 3H). MS-(ESI) (m/z) calcd for C₂₅H₂₃ClN₇O₂(M+H)⁺: 488.2/490.2. Found 488.2/490.2.

Example 279: 5-Cyano-N-(3-(2-ethylpyridin-4-yl)-1H-indazol-5-yl)-3,4-dimethylpicolinamide

embedded image

Step 1: (2-Ethylpyridin-4-yl)boronic acid

embedded image

To a solution of 4-bromo-2-ethyl-pyridine (70 mg, 376.25 umol) in 1 mL of dioxane was added bis(pinacolato)diboron (114.65 mg, 451.49 umol), AcOK (111.15 mg, 1.13 mmol) and Pd(dppf)Cl₂(12.39 mg, 16.93 umol) at 20° C. The mixture was degassed and purged with N₂(3×), and then stirred at 80° C. for 12 hrs under an N₂atmosphere. The reaction mixture was concentrated under reduced pressure to afford the title compound (50 mg) as a black solid which was used without further purification. MS-ESI (m/z) calcd for C₇H₁₁BNO₂[M+H]⁺: 152.1. Found 152.1.

Step 2: 5-Cyano-N-(3-(2-ethylpyridin-4-yl)-1H-indazol-5-yl)-3,4-dimethylpicolinamide

embedded image

A mixture of (2-ethyl-4-pyridyl) boronic acid (50 mg, 331.19 umol), N-(3-bromo-1H-indazol-5-yl)-5-cyano-3,4-dimethylpicolinamide (122.61 mg, 331.19 umol), AcOK (97.51 mg, 993.57 umol) and Pd(Amphos)Cl₂(23.45 mg, 33.12 umol, 23.45 uL) in 2 mL of EtOH and 0.5 mL of H₂O was degassed and purged with N₂(3×), and then the mixture was stirred at 100° C. for 2 hrs under an N₂atmosphere. The reaction mixture was concentrated under reduced pressure to remove solvent and diluted with 20 mL of EtOAc. The mixture was filtered, the filtrate was concentrated and purified by preparative HPLC using Method CP to afford the title compound (25.14 mg, 15%) as a white solid TFA salt. ¹H NMR (400 MHz, DMSO-d₆) δ 14.06 (br s, 1H), 10.87 (s, 1H), 8.91 (s, 1H), 8.81 (d, J=6.0 Hz, 1H), 8.77 (s, 1H), 8.24 (s, 1H), 8.17 (br d, J=5.5 Hz, 1H), 7.86-7.81 (m, 1H), 7.77-7.72 (m, 1H), 3.03 (q, J=7.5 Hz, 2H), 2.56 (s, 3H), 2.47 (s, 3H), 1.38 (t, J=7.6 Hz, 3H), MS-ESI (m/z) calcd for C₂₃H₂₁N₆O [M+H]⁺: 397.2. Found 397.2.

Example 280: 5-Cyano-3,4-dimethyl-N-(3-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-1H-indazol-5-yl)picolinamide

embedded image

Step 1: (1-Methyl-2-oxo-1,2-dihydropyridin-3-yl)boronic acid

embedded image

A mixture of 3-bromo-1-methyl-pyridin-2-one (70 mg, 372.30 umol), KOAc (109.61 mg, 1.12 mmol), bis(pinacolato)diboron (141.81 mg, 558.45 umol) and Pd(dppf)Cl₂.CH₂Cl₂(15.20 mg, 18.61 umol) in 2 mL of dioxane was degassed and purged with N₂(3×) at 20° C., and then the mixture was stirred at 100° C. for 3 hrs under an N₂atmosphere. The reaction mixture was concentrated under reduced pressure to afford the title compound (60 mg) as a black solid, which was used without further purification. MS-ESI (m/z) calcd for C₆H₉BNO₃[M+H]⁺: 154.1. Found 154.1.

Step 2: 5-Cyano-3,4-dimethyl-N-(3-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-1H-indazol-5-yl)picolinamide

embedded image

A mixture of (1-methyl-2-oxo-1,2-dihydropyridin-3-yl)boronic acid (60 mg, 392.30 umol), 5-cyano-N-(3-iodo-1H-indazol-5-yl)-3,4-dimethylpicolinamide (181.86 mg, 435.89 umol), Pd(Amphos)C₁₂(30.86 mg, 43.59 umol, 30.86 uL) and AcOK (128.34 mg, 1.31 mmol) in 2 mL of EtOH and 0.5 mL of H₂O was degassed and purged with N₂(3×) at 20° C., and then the mixture was stirred at 100° C. for 12 hrs under an N₂atmosphere. The reaction mixture was concentrated under reduced pressure to remove solvent and purified by preparative HPLC using Method CQ. The material was further purified by preparative HPLC using Method CR to afford the title compound (6.38 mg, 4%) as a pale yellow solid. ¹H NMR (400 MHz, MeOD) δ 8.72 (s, 1H), 8.25 (s, 1H), 7.90 (br d, J=6.8 Hz, 1H), 7.77 (br d, J=5.7 Hz, 1H), 7.71 (br d, J=8.3 Hz, 1H), 7.55 (br d, J=8.9 Hz, 1H), 6.51 (br t, J=6.8 Hz, 1H), 3.69 (s, 3H), 2.61 (s, 3H), 2.58 (s, 3H). MS-ESI (m/z) calcd for C₂₂H₁₉N₆O₂[M+H]⁺: 399.2. Found 399.1.

Example 281: (E)-5-Cyano-3,4-dimethyl-N-(3-(2-(pyridin-4-yl)vinyl)-1H-indazol-5-yl)picolinamide

embedded image

Step 1: (E)-(2-(Pyridin-4-yl)vinyl)boronic acid

embedded image

A mixture of 4-bromopyridine (0.5 g, 3.16 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (536.14 mg, 3.48 mmol, 590.46 uL), tri-tert-butylphosphonium tetrafluoroborate (91.82 mg, 316.46 umol), DIPEA (818.02 mg, 6.33 mmol, 1.10 mL) and Pd₂(dba)₃(144.90 mg, 158.23 umol) in 4 mL of toluene was degassed and purged with N₂(3×) at 20° C., then the mixture was stirred at 100° C. for 3 hrs under an N₂atmosphere. The mixture was filtered and the filtrate was concentrated under vacuum to afford the title compound (1 g) as a yellow oil, which was used without further purification. MS-ESI (m/z) calcd for C₇H₉BNO₂[M+H]⁺: 150.1. Found 150.1.

Step 2: (E)-5-Cyano-3,4-dimethyl-N-(3-(2-(pyridin-4-yl)vinyl)-1H-indazol-5-yl)picolinamide

embedded image

A mixture of 5-cyano-N-(3-iodo-1H-indazol-5-yl)-3,4-dimethylpicolinamide (100 mg, 239.69 umol), (E)-(2-(pyridin-4-yl)vinyl)boronic acid (107.11 mg, 719.07 umol), Pd(Amphos)Cl₂(16.97 mg, 23.97 umol, 16.97 uL) and AcOK (70.57 mg, 719.07 umol) in 2 mL of EtOH and 0.5 mL of H₂O was degassed and purged with N₂(3×) at 20° C., and then the mixture was stirred at 100° C. for 12 hrs under an N₂atmosphere. The reaction mixture was concentrated under reduced pressure to remove solvent and then purified by preparative-HPLC using Method CS to afford the title compound (55.35 mg, 45%) as an orange solid, TFA salt. ¹H NMR (400 MHz, DMSO-d₆) δ 13.67 (br s, 1H), 10.75 (s, 1H), 8.91 (s, 1H), 8.78 (br d, J=6.1 Hz, 2H), 8.67 (s, 1H), 8.26-8.21 (m, 3H), 7.72-7.67 (m, 1H), 7.66-7.61 (m, 1H), 7.58 (d, J=16.4 Hz, 1H), 2.57 (s, 3H), 2.48 (s, 3H). MS-ESI (m/z) calcd for C₂₃H₁₉N₆O [M+H]⁺: 395.2. Found 395.0.

Example 282: (E)-6-chloro-5-cyano-3,4-dimethyl-N-(3-(prop-1-en-1-yl)-1H-indazol-5-yl)picolinamide

embedded image

Step 1: (E)-3-(prop-1-en-1-yl)-1H-indazol-5-amine

embedded image

To a solution of 3-bromo-1H-indazol-5-amine (150 mg, 707.39 umol) and 4,4,5,5-tetramethyl-2-[(E)-prop-1-enyl]-1,3,2-dioxaborolane (136.70 mg, 813.50 umol) in 6 mL of EtOH and 1.5 mL of H₂O was added AcOK (208.27 mg, 2.12 mmol) and Pd(Amphos)Cl₂(50.09 mg, 70.74 umol) at 15° C. under an N₂atmosphere. Then the reaction mixture was stirred at 80° C. for 12 hrs under an N₂atmosphere. The reaction mixture was concentrated and the residue was diluted with 20 mL of H₂O and extracted with EtOAc (15 mL×3). The combined organic phases were dried over Na₂SO₄, filtered, and the filtrate was concentrated to give a residue. The residue was purified by preparative-TLC (SiO₂, petroleum ether/EtOAc=0:1, R_f=0.43) to afford the title compound (75 mg, 13%) as a red solid. MS-(ESI) (m/z) calcd for C₁₀H₁₂N₃[M+H]⁺: 174.1. Found 174.1.

Step 2: (E)-6-Chloro-5-cyano-3,4-dimethyl-N-(3-(prop-1-en-1-yl)-1H-indazol-5-yl)picolinamide

embedded image

To a solution of 6-chloro-5-cyano-3,4-dimethyl-pyridine-2-carboxylic acid (55 mg, 261.14 umol) and (E)-3-(prop-1-en-1-yl)-1H-indazol-5-amine (49.76 mg, 287.25 umol) in 10 mL of dry CH₂C₁₂was added Et₃N (79.27 mg, 783.41 umol) and the reaction mixture was stirred at 20° C. for 0.5 hr. Then T3P (50 wt % in EtOAc, 249.27 mg, 391.71 umol, 232.96 uL) was added and the reaction mixture was stirred at 20° C. for 12 hrs. The reaction mixture was then concentrated and purified by preparative-HPLC using Method CT to afford the title compound (24.38 mg, 13%) as a pale yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 12.94 (br s, 1H), 10.71 (br s, 1H), 8.42 (s, 1H), 7.68-7.56 (m, 1H), 7.51 (br d, J=8.8 Hz, 1H), 6.72 (br d, J=16.0 Hz, 1H), 6.50 (br dd, J=6.5, 15.9 Hz, 1H), 2.59 (s, 3H), 2.39 (s, 3H), 1.95 (br d, J=6.1 Hz, 3H). MS-(ESI) (m/z) calcd for C₁₉H₁₇ClN₅O (M+H)⁺: 366.1. Found 366.0.

Example 283: 3-Chloro-5-cyano-N-(3-cyclopropyl-1H-indazol-5-yl)-4,6-dimethylpicolinamide

embedded image

Step 1: 2,5-Dichloro-3-cyano-4,6-dimethylpyridine 1-oxide

embedded image

To a solution of 2,5-dichloro-4,6-dimethylpyridine-3-carbonitrile (2.01 g, 10 mmol) in trifluoroacetic acid (50 mL) was added hydrogen peroxide (3.06 mL, 30 mmol) and the mixture was stirred at 75° C. for 1 hr. The solvent was evaporated to afford the title compound (2.17 g, 99%) as a yellow oil. ¹H NMR (400 MHz, DMSO-d₆) δ 2.62 (s, 3H), 2.53 (s, 3H). MS-(ESI) (m/z) calcd for C₈H₇Cl₂N₂O (M+H)⁺: 217.0/219.0. Found 217.0/219.0

Step 2: 2,5-Dichloro-6-(hydroxymethyl)-4-methylnicotinonitrile

embedded image

To a solution of 2,5-dichloro-3-cyano-4,6-dimethylpyridine 1-oxide (2.17 g, 10 mmol) in DCM (50 mL) was added trifluoroacetic anhydride (4.17 mL, 30 mmol) dropwise and the mixture was stirred at 25° C. for 15 hrs. The solvent was then evaporate and the residue was taken up in MeOH. K₂CO₃(3 g) was added and the suspension was stirred at 25° C. for 1 hr. The solvent was evaporated to give a residue that was taken up in water and extracted with DCM (3×). The combined organic layers were passed through a phase separator and evaporated to afford the title compound (1.9 g, 88%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 5.60 (t, J=6.3 Hz, 1H), 4.66 (d, J=6.3 Hz, 2H), 2.58 (s, 3H). MS-(ESI) (m/z) calcd for C₈H₇Cl₂N₂O (M+H)⁺: 217.0/219.0. Found 217.0/219.0.

Step 3: 5-Chloro-6-(hydroxymethyl)-2,4-dimethylnicotinonitrile

embedded image

To a mixture of 2,5-dichloro-6-(hydroxymethyl)-4-methylnicotinonitrile (868.2 mg, 4 mmol), 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (0.56 mL, 4 mmol) and potassium carbonate (552.84 mg, 4 mmol) in 1,4-dioxane (27 mL) and H₂O (13 mL) was added tetrakis(triphenylphosphine)palladium(0) (462.22 mg, 0.400 mmol) and the mixture was stirred at 90° C. under N₂for 15 hrs. The mixture was diluted with water and extracted with DCM (3×), the combined organic layers were passed through a phase separator and evaporated to obtain a dark residue which was purified by silica gel column chromatography using a 50-100% EtOAc/cyclohexane gradient eluent to afford the title compound (120 mg, 15%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 5.35 (t, J=5.9 Hz, 1H), 4.65 (d, J=5.7 Hz, 2H), 2.66 (s, 3H), 2.54 (s, 3H). MS-(ESI) (m/z) calcd for C₉H₁₀ClN₂O (M+H)⁺: 197.0/199.0. Found 197.0/199.0.

Step 4: 3-Chloro-5-cyano-4,6-dimethylpicolinic acid

embedded image

To a solution of 5-chloro-6-(hydroxymethyl)-2,4-dimethylpyridine-3-carbonitrile (120.0 mg, 0.610 mmol) in acetone (5 mL) was added a solution of potassium permanganate (144.66 mg, 0.920 mmol) in H₂O (1 mL) and the mixture was stirred at 25° C. for 4 hrs. A solid formed that was removed by filtration and washed with acetone and H₂O. The filtrate was concentrated and the resulting aqueous mixture was washed with EtOAc and then acidified by addition of conc. HCl and then extracted with EtOAc (3×). The combined organic layers were passed through a phase separator and evaporated to afford the title compound (98 mg, 76%) as an off-white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.62 (s, 1H), 2.66 (s, 3H), 2.57 (s, 3H). MS-(ESI) (m/z) calcd for C₉H₈ClN₂O₂(M+H)⁺: 211.0/213.0. Found 210.9/212.9.

Step 5: 3-Chloro-5-cyano-N-(3-cyclopropyl-1H-indazol-5-yl)-4,6-dimethylpicolinamide

embedded image

To a mixture of 3-chloro-5-cyano-4,6-dimethylpicolinic acid (43.0 mg, 0.200 mmol), 3-cyclopropyl-1H-indazol-5-amine (35.36 mg, 0.200 mmol) and Et₃N (28.46 uL, 0.200 mmol) in MeCN (2.389 mL) was added HATU (77.63 mg, 0.200 mmol) and the reaction was stirred at 25° C. for 24 hours. Water was added and a solid formed that was collected by filtration and dried to give the title compound (60 mg, 80%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 12.56 (s, 1H), 10.73 (s, 1H), 8.24 (s, 1H), 7.48 (dd, J=9.0, 1.8 Hz, 1H), 7.44 (d, J=8.9 Hz, 1H), 2.73 (s, 3H), 2.63 (s, 3H), 2.21 (td, J=8.5, 4.3 Hz, 1H), 1.06-0.86 (m, 4H). MS-(ESI) (m/z) calcd for C₁₉H₁₇ClN₅O (M+H)⁺: 366.0/368.1. Found 366.1/368.2.

Example 284: 5-Cyano-N-(3-ethyl-1H-indazol-5-yl)-3-methyl-4-(trifluoromethyl)picolinamide

embedded image

Step 1: 6-Hydroxy-5-methyl-2-oxo-4-(trifluoroethyl)-1,2-dihydropyridine-3-carbonitrile

embedded image

To a mixture of methyl 4,4,4-trifluoro-2-methyl-3-oxobutanoate (3.96 g, 20 mmol) and 2-cyanoacetamide (1.68 g, 20 mmol) in 1,4-dioxane (20 mL) was added Et₃N (3.07 mL, 22 mmol) and the reaction was stirred at 100° C. for 16 hrs. The solvent was evaporated and the residue was taken up in Et₂O, then decanted. The oil obtained was concentrated to afford the title compound (3.2 g, 73%) as a brown solid. ¹H NMR (400 MHz, DMSO-d₆) δ 10.30 (s, 1H), 8.94 (bs, 1H), 1.87 (q, J=3.1 Hz, 3H); ¹⁹F NMR (377 MHz, DMSO-d₆) δ −57.47 (t, J=3.4 Hz). MS-(ESI) (m/z) calcd for C₈H₆F₃N₂O₂(M+H)⁺: 219.0. Found 219.0.

Step 2: 2,6-Dichloro-5-methyl-4-(trifluoromethyl)nicotinonitrile

embedded image

To a solution of 6-hydroxy-5-methyl-2-oxo-4-(trifluoromethyl)-1H-pyridine-3-carbonitrile (3.2 g, 14.67 mmol) in POCl₃(20.0 mL, 213.92 mmol) was added tetraethylammonium chloride (2.43 g, 14.67 mmol) and the mixture was stirred at 100° C. for 48 hrs. The solvent was evaporated to give a residue that was taken up in water and extracted with DCM (3×). The combined organic layers were passed through a phase separator and evaporated to a black oil which was purified by silica gel column chromatography using a 0-50% DCM/cyclohexane gradient eluent to afford the title compound (1.15 g, 31%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 2.51 (s, 3H); ¹⁹F NMR (377 MHz, DMSO-d₆) δ −58.07 (q, J=2.2 Hz). MS-(ESI) (m/z) calcd for C₈H₄Cl₂F₃N₂(M+H)⁺: 255.0/257.0. Found 255.0/257.0.

Step 3: 2-Chloro-6-(furan-2-yl)-5-methyl-4-(trifluoromethyl)nicotinonitrile

embedded image

A mixture of 2,6-dichloro-5-methyl-4-(trifluoromethyl)nicotinonitrile (1.15 g, 4.51 mmol), 2-furanylboronic acid (504.56 mg, 4.51 mmol), K₂CO₃(1.56 g, 11.27 mmol) and tetrakis(triphenylphosphine)palladium(0) (260.55 mg, 0.230 mmol) in 1,4-dioxane (7.516 mL) and H₂O (7.516 mL) was heated at 100° C. for 3 hrs. The organic solvent was evaporated and the resulting mixture was diluted with H₂O and extracted with EtOAc (3×). The combined organic layers were passed through a phase separator and evaporated to give a purple residue which was purified by silica gel column chromatography using a 0-15% EtOAc/cyclohexane gradient eluent to afford the title compound (432 mg, 33%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.11 (dd, J=1.7, 0.7 Hz, 1H), 7.45 (dd, J=3.6, 0.8 Hz, 1H), 6.83 (dd, J=3.6, 1.7 Hz, 1H), 2.64 (q, J=2.1 Hz, 3H); ¹⁹F NMR (377 MHz, DMSO-d₆) δ-57.34 (q, J=2.0 Hz). MS-(ESI) (m/z) calcd for C₁₂H₇ClF₃N₂O (M+H)⁺: 287.0/289.0. Found 287.0/289.0.

Step 4: 6-(Furan-2-yl)-5-methyl-4-(trifluoromethyl)-1,4-dihydropyridine-3-carbonitrile

embedded image

To a mixture of 2-chloro-6-(furan-2-yl)-5-methyl-4-(trifluoromethyl)pyridine-3-carbonitrile (432.0 mg, 1.51 mmol) in acetic acid (0.200 mL) and H₂O (1.8 mL) was added zinc (197.07 mg, 3.01 mmol) and the suspension was stirred at 95° C. for 3 hrs. The mixture was extracted with DCM (3×) and the combined organic layers were passed through a phase separator. The residue was concentrated and purified by silica gel column chromatography using a 2-20% EtOAc/cyclohexane gradient eluent to afford the title compound (132 mg, 30% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 10.49 (s, 1H), 7.82 (d, J=1.8 Hz, 1H), 6.76 (d, J=3.4 Hz, 1H), 6.63 (dd, J=3.5, 1.8 Hz, 1H), 4.32 (q, J=8.1 Hz, 1H), 1.94 (s, 3H). ¹⁹F NMR (377 MHz, DMSO-d₆) δ −72.54 (d, J=7.9 Hz). MS-(ESI) (m/z) calcd for C₁₂H₁₀F₃N₂O (M+H)⁺:255.1 Found 255.1.

Step 5: 5-Cyano-3-methyl-4-(trifluoromethyl)picolinic acid

embedded image

To a solution of 6-(furan-2-yl)-5-methyl-4-(trifluoromethyl)-1,4-dihydropyridine-3-carbonitrile (120.0 mg, 0.470 mmol) in acetone (3.54 mL)/H₂O (1.18 mL) was added K₂CO₃(130.48 mg, 0.940 mmol) and KMnO₄(447.59 mg, 2.83 mmol) and the mixture was stirred at 50° C. for 2 hrs. The reaction was quenched by addition of formic acid and a solid formed that was removed by filtration. The filtrate was concentrated under reduced pressure to remove volatile organics and the remaining aqueous solution was acidified by addition of conc. HCl and then extracted with EtOAc (3×). The combined organic layers were dried over Na₂SO₄, passed through a phase separator and evaporated to afford the title compound (98 mg, 81%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 14.44 (s, 1H), 9.15 (s, 1H), 2.50 (s, 3H), ¹⁹F NMR (377 MHz, DMSO-d₆) δ −58.10. MS-(ESI) (m/z) calcd for C₉H₆F₃N₂O₂(M+H)⁺:231.0 Found 231.0.

Step 6: 5-Cyano-N-(3-ethyl-1H-indazol-5-yl)-3-methyl-4-(trifluoromethyl)picolinamide

embedded image

Prepared as described for 3-chloro-5-cyano-N-(3-cyclopropyl-1H-indazol-5-yl)-4,6-dimethylpicolinamide (Example 283) using 5-cyano-3-methyl-4-(trifluoromethyl)picolinic acid in place of 3-chloro-5-cyano-4,6-dimethylpicolinic acid and using 3-ethyl-1H-indazol-5-amine in place of 3-cyclopropyl-1H-indazol-5-amine to afford the title compound (24.3 mg, 42%) as a beige solid. ¹H NMR (400 MHz, DMSO-d₆) δ 12.64 (s, 1H), 10.78 (s, 1H), 9.40-9.11 (m, 1H), 8.24-8.21 (m, 1H), 7.52 (dd, J=8.9, 1.8 Hz, 1H), 7.47 (d, J=8.7 Hz, 1H), 2.91 (q, J=7.6 Hz, 2H), 2.65-2.56 (m, 3H), 1.32 (t, J=7.6 Hz, 3H). ¹⁹F NMR (377 MHz, DMSO-d₆) δ −57.97 (q, J=2.3 Hz). MS-ESI (m/z) calc'd for C₁₈H₁₅F₃N₅O [M+H]⁺: 374.1. Found 374.2

Example 285: 5-Cyano-N-(3-methoxy-1H-indazol-5-yl)-3-methyl-4-(trifluoromethyl)picolinamide

embedded image

Prepared as described for 3-chloro-5-cyano-N-(3-cyclopropyl-1H-indazol-5-yl)-4,6-dimethylpicolinamide (Example 283) using 5-cyano-3-methyl-4-(trifluoromethyl)picolinic acid in place of 3-chloro-5-cyano-4,6-dimethylpicolinic acid and using 3-methoxy-1H-indazol-5-amine in place of 3-cyclopropyl-1H-indazol-5-amine to afford the title compound (16.2 mg, 28%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.93 (s, 1H), 10.80 (s, 1H), 9.43-9.09 (m, 1H), 8.13 (d, J=1.8 Hz, 1H), 7.53 (dd, J=8.9, 2.0 Hz, 1H), 7.38 (dd, J=8.9, 0.8 Hz, 1H), 4.00 (s, 3H), 2.58 (q, J=1.8 Hz, 5H). ¹⁹F NMR (377 MHz, DMSO-d₆) δ −57.98 (q, J=2.2 Hz). MS-ESI (m/z) calc'd for C₁₇H₁₃F₃N₅O₂[M+H]⁺: 376.1. Found 376.1.

Example 286: 5-Cyano-N-(3-cyclopropyl-1H-indazol-5-yl)-3-methyl-4-(trifluoromethyl)picolinamide

embedded image

Prepared as described for 3-chloro-5-cyano-N-(3-cyclopropyl-1H-indazol-5-yl)-4,6-dimethylpicolinamide (Example 283) using 5-cyano-3-methyl-4-(trifluoromethyl)picolinic acid in place of 3-chloro-5-cyano-4,6-dimethylpicolinic acid to afford the title compound (50 mg, 83%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 12.57 (s, 1H), 10.79 (s, 1H), 9.26 (s, 1H), 8.27 (d, J=1.9 Hz, 1H), 7.52 (dd, J=8.9, 1.8 Hz, 1H), 7.46 (d, J=8.9 Hz, 1H), 2.59 (q, J=2.3 Hz, 3H), 2.22 (tt, J=8.2, 5.0 Hz, 1H), 1.01-0.90 (m, 4H). ¹⁹F NMR (377 MHz, DMSO-d₆) δ −57.97 (q, J=2.3 Hz). MS-ESI (m/z) calc'd for C₁₉H₁₅F₃N₅O [M+H]⁺: 386.1. Found 386.2.

Example 287: 5-Cyano-N-(3-methoxy-1H-indazol-5-yl)-3,4,6-trimethylpicolinamide

embedded image

Prepared as described for 3-chloro-5-cyano-N-(3-cyclopropyl-1H-indazol-5-yl)-4,6-dimethylpicolinamide (Example 283) using 5-cyano-3,4,6-trimethylpicolinic acid in place of 3-chloro-5-cyano-4,6-dimethylpicolinic acid and using 3-methoxy-1H-indazol-5-amine in place of 3-cyclopropyl-1H-indazol-5-amine to afford the title compound (67.8 mg, 93%) as a pale yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.88 (s, 1H), 10.57 (s, 1H), 8.14 (d, J=1.9 Hz, 1H), 7.56 (dd, J=9.0, 2.0 Hz, 1H), 7.35 (dd, J=9.0, 0.8 Hz, 1H), 4.00 (s, 3H), 2.70 (s, 3H), 2.52 (s, 3H), 2.36 (s, 3H). MS-ESI (m/z) calc'd for C₁₈H₁₈N₅O₂[M+H]⁺: 336.1. Found 336.1.

Example 288: 5-Cyano-3-methyl-N-(3-(oxazol-5-yl)-1H-indazol-5-yl)-6-(trifluoromethyl)picolinamide

embedded image

Step 1: Methyl 5-cyano-3-methyl-6-(trifluoromethyl)picolinate

embedded image

A solution of methyl 5-cyano-3-methylpyridine-2-carboxylate (500.0 mg, 2.84 mmol) and zinc trifluoromethanesulfinate (1881.82 mg, 5.68 mmol) in DMSO (8 mL) was cooled in ice water. The mixture was stirred vigorously while adding a 70% solution of tert-butyl hydroperoxide in H₂O (1.18 mL, 8.51 mmol). The solution was allowed to reach r.t. and then warmed at 50° C. for 2 hrs and then at r.t. overnight. To the mixture was added an additional 2 eq. of zinc trifluoromethanesulfinate and 3 eq of tert-butyl hydroperoxide and the reaction was stirred at 50° C. for an additional 2 hrs. The reaction mixture was partitioned between H₂O and EtOAc and the phases were separated. The aqueous layer was extracted with EtOAc (2×), the combined organic phases were washed with saturated aqueous NaHCO₃(1×) and H₂O (1×), dried over Na₂SO₄and evaporated to dryness to give a residue. The residue was purified by silica gel chromatography using a 0-30% EtOAc/cyclohexane gradient eluent to afford a mixture of 2 regioisomers: methyl 5-cyano-3-methyl-4-(trifluoromethyl)pyridine-2-carboxylate and methyl 5-cyano-3-methyl-6-(trifluoromethyl)pyridine-2-carboxylate (150 mg, 22%) in a 1:1 ratio. The isomers were separated using Method CU to afford the title compound (43.6 mg, 6%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.77 (s, 1H) 3.95 (s, 3H) 2.59 (s, 3H). MS-ESI (m/z) calc'd for C₁₀H₈F₃N₂O₂[M+H]⁺: 245.1. Found 245.0.

Step 2: 5-Cyano-3-methyl-6-(trifluoromethyl)picolinic acid

embedded image

To a solution of methyl 5-cyano-3-methyl-6-(trifluoromethyl)pyridine-2-carboxylate (35.0 mg, 0.140 mmol) in MeOH (3.5 mL) was added an aqueous solution of 1 N sodium hydroxide (0.14 mL, 0.140 mmol) and the mixture was stirred at r.t. for 2 hrs. The reaction mixture was concentration to afford the title compound (41 mg) which was used without further purification. ¹H NMR (400 MHz, DMSO-d₆) δ 8.27 (s, 1H) 2.32 (s, 3H). MS-ESI (m/z) calc'd for C₉H₆F₃N₂O₂[M+H]⁺: 231.0. Found 231.0.

Step 3: 5-Cyano-3-methyl-N-(3-(oxazol-5-yl)-1H-indazol-5-yl)-6-(trifluoromethyl)picolinamide

embedded image

Prepared as described for 3-chloro-5-cyano-N-(3-cyclopropyl-1H-indazol-5-yl)-4,6-dimethylpicolinamide (Example 283) using 5-cyano-3-methyl-6-(trifluoromethyl)picolinic acid in place of 3-chloro-5-cyano-4,6-dimethylpicolinic acid and using 3-(oxazol-5-yl)-1H-indazol-5-amine in place of 3-cyclopropyl-1H-indazol-5-amine to afford the title compound (24.9 mg, 37%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.57 (br. s., 1H) 10.82 (s, 1H) 8.78 (s, 1H) 8.59 (s, 1H) 8.54 (d, J=1.10 Hz, 1H) 7.72 (d, J=1.98 Hz, 1H) 7.64-7.68 (m, 2H) 2.62 (s, 3H). MS-ESI (m/z) calc'd for C₁₉H₁₂F₃N₆O₂[M+H]⁺: 413.1. Found 413.1.

Example 289: 5-Cyano-3-methyl-N-(3-(oxazol-5-yl)-1H-indazol-5-yl)-4-(trifluoromethyl)picolinamide

embedded image

Prepared as described for 3-chloro-5-cyano-N-(3-cyclopropyl-1H-indazol-5-yl)-4,6-dimethylpicolinamide (Example 283) using 5-cyano-3-methyl-4-(trifluoromethyl)picolinic acid in place of 3-chloro-5-cyano-4,6-dimethylpicolinic acid and using 3-(oxazol-5-yl)-1H-indazol-5-amine in place of 3-cyclopropyl-1H-indazol-5-amine to afford the title compound (7.9 mg, 18%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.64 (br. s., 1H) 10.99 (br. s., 1H) 9.28 (s, 1H) 8.59-8.61 (m, 1H) 8.56 (d, J=1.10 Hz, 1H) 8.54 (s, 1H) 7.69-7.75 (m, 1H) 7.63-7.68 (m, 2H) 2.59-2.64 (m, 3H). MS-ESI (m/z) calc'd for C₁₉H₁₂F₃N₆O₂[M+H]⁺: 413.1. Found 413.1.

Example 290: 6-Chloro-5-cyano-N-(3-cyano-1H-indazol-5-yl)-3,4-dimethylpicolinamide

embedded image

Prepared as described for 3-chloro-5-cyano-N-(3-cyclopropyl-1H-indazol-5-yl)-4,6-dimethylpicolinamide (Example 283) using 6-chloro-5-cyano-3,4-dimethylpicolinic acid in place of 3-chloro-5-cyano-4,6-dimethylpicolinic acid and using 5-amino-1H-indazole-3-carbonitrile in place of 3-cyclopropyl-1H-indazol-5-amine to afford the title compound (37 mg, 56%) as a light yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 14.37 (bs, 1H) 10.97 (s, 1H) 8.44 (d, J=1.32 Hz, 1H) 7.76-7.82 (m, 1H) 7.70 (dd, J=9.02, 1.76 Hz, 1H) 2.61 (s, 3H) 2.40 (s, 3H). MS-ESI (m/z) calc'd for C₁₇H₁₂ClN₆O [M+H]⁺: 351.1. Found 351.0.

Example 291: 6-Chloro-5-cyano-N-(3-(difluoromethyl)-1H-indazol-5-yl)-3,4-dimethylpicolinamide

embedded image

Step 1: 3-(Difluoromethyl)-1H-indazole

embedded image

DAST (2.71 mL, 20.53 mmol) was added to a solution of 1H-indazole-3-carboxaldehyde (1.5 g, 10.26 mmol) in DCM (6 mL) at 0° C., and the mixture was stirred for 5 hrs at r.t. The reaction was cooled to 0° C. and then carefully quenched with saturated aqueous NaHCO₃. The mixture was extracted with EtOAc (3×100 mL) and the combined organic layers were washed with brine (100 mL), dried over Na₂SO₄and concentrated to give a residue. The residue was purified by silica gel column chromatography using a 0-50% EtOAc/cyclohexane gradient eluent to afford the title compound (710 mg, 41%) as a beige solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.57 (s, 1H), 7.84 (d, J=8.2 Hz, 1H), 7.64 (d, J=8.5 Hz, 1H), 7.51-7.14 (m, 3H). MS-ESI (m/z) calc'd for C₈H₇F₂N₂[M+H]⁺: 169.1. Found 168.9.

Step 2: 3-(Difluoromethyl)-5-nitro-1H-indazole

embedded image

To a stirred solution of 3-(difluoromethyl)-1H-indazole (709.0 mg, 4.22 mmol) in sulfuric acid (3.0 mL, 56.28 mmol) at 0° C. was added nitric acid (1.0 mL, 22.38 mmol) and the mixture was stirred for 30 min at 0° C. The mixture was diluted with water and extracted with EtOAc (2×). The combined organic layers were washed with brine, dried over Na₂SO₄, filtered and concentrated to give a residue. The residue was purified by silica gel column chromatography using a 0-30% EtOAc/cyclohexane gradient eluent to afford the title compound (517 mg, 58%) as a beige solid. ¹H NMR (400 MHz, DMSO-d₆) δ 14.26 (s, 1H), 8.76 (d, J=2.1 Hz, 1H), 8.29 (dd, J=9.2, 2.2 Hz, 1H), 7.86 (d, J=9.2 Hz, 1H), 7.52 (t, J=53.6 Hz, 1H). MS-ESI (m/z) calc'd for C₈H₆F₂N₃O₂[M+H]⁺: 214.0. Found 214.0.

Step 3: 3-(Difluoromethyl)-5-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole

embedded image

To a solution of 3-(difluoromethyl)-5-nitro-1H-indazole (300.0 mg, 1.41 mmol) and 3,4-dihydro-2H-pyran (0.18 mL, 2.11 mmol) in toluene (4 mL) was added p-toluenesulfonic acid (53.55 mg, 0.280 mmol). The reaction mixture was stirred at r.t. for 2 hrs and then at 60° C. for 30 minutes. The reaction mixture was partitioned between water (100 mL) and EtOAc (100 mL), the phases were separated, the aqueous layer was extracted with EtOAc (2×100 mL) and the combined organic phases were washed with brine (1×100 mL), dried over Na₂SO₄and evaporated to dryness. The residue was purified by silica gel column chromatography using a 0-30% EtOAc/cyclohexane gradient eluent to afford the title compound (380 mg, 91%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.77 (d, J=2.1 Hz, 1H), 8.37 (dd, J=9.3, 2.2 Hz, 1H), 8.11 (d, J=9.3 Hz, 1H), 7.55 (t, J=53.5 Hz, 1H), 6.08 (dd, J=9.6, 2.4 Hz, 1H), 3.94-3.86 (m, 1H), 3.85-3.76 (m, 1H), 2.43-2.28 (m, 1H), 2.11-1.99 (m, 2H), 1.84-1.70 (m, 1H), 1.66-1.55 (m, 2H). MS-ESI (m/z) calc'd for C₁₃H₁₄F₂N₃O₃[M+H]⁺: 298.1. Found 298.1.

Step 4: 3-(Difluoromethyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-amine

embedded image

A mixture of 3-(difluoromethyl)-5-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (190.0 mg, 0.640 mmol), ammonium chloride (37.61 mg, 0.700 mmol), and iron (142.79 mg, 2.56 mmol) in 4 mL of EtOH and 4 mL of H₂O was heated to reflux for 1.5 hrs. The mixture was cooled and filtered through Celite. The filtrate was evaporated, and the resulting residue was taken up into EtOAc and saturated aqueous NaHCO₃. The phases were separated and the organic phase was dried over Na₂SO₄, filtered and concentrated under reduced pressure to afford the title compound (140 mg, 82%). MS-ESI (m/z) calc'd for C₁₃H₁₆F₂N₃O [M+H]⁺: 268.1. Found 268.1.

Step 5: 6-Chloro-5-cyano-N-(3-(difluoromethyl)-1-(tetrahydro-2?H-pyran-2-yl)-1H-indazol-5-yl)-3,4-dimethylpicolinamide

embedded image

To a solution of 3-(difluoromethyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-amine (67.0 mg, 0.250 mmol) and 6-chloro-5-cyano-3,4-dimethylpyridine-2-carboxylic acid (50.0 mg, 0.210 mmol) in MeCN (3 mL), Et₃N (0.04 mL, 0.310 mmol) and HATU (79.43 mg, 0.210 mmol) were added, and the resulting solution was stirred at r.t. for 2 hrs. The reaction mixture was then concentrated under reduced pressure and extracted with EtOAc (100 mL) and H₂O (100 mL). The organic phases were concentrated and the residue was triturated with cooled MeCN/H₂O and then filtered to afford the title compound (86 mg, 90%) as a pale yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 10.88 (s, 1H), 8.43 (d, J=1.9 Hz, 1H), 7.87 (d, J=9.1 Hz, 1H), 7.74 (dd, J=9.1, 1.9 Hz, 1H), 7.37 (t, J=53.8 Hz, 1H), 5.99-5.85 (m, 1H), 3.95-3.85 (m, 1H), 3.82-3.72 (m, 1H), 2.59 (s, 3H), 2.39 (s, 3H), 2.38-2.31 (m, 1H), 2.11-1.96 (m, 2H), 1.85-1.69 (m, 1H), 1.67-1.50 (m, 2H). MS-ESI (m/z) calc'd for C₂₂H₂₁ClF₂N₅O₂[M+H]⁺: 460.1. Found 460.1.

Step 6: 6-Chloro-5-Cyano-N-(3-(difluoromethyl)-1H-indazol-5-yl)-3,4-dimethylpicolinamide

embedded image

To a solution of 6-chloro-5-cyano-N-(3-(difluoromethyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-3,4-dimethylpicolinamide (86.0 mg, 0.190 mmol) in DCM (3 mL) was added trifluoroacetic acid (1 mL) at 0° C. and the resulting mixture was stirred at r.t. for 3 hrs. Then the reaction mixture was concentrated under reduced pressure and the residue was taken-up in DCM and washed with saturated aqueous NaHCO₃and brine. The layers were separated and the organic phase was dried over Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was triturated with cooled MeCN (1 mL) and H₂O (3 mL), filtered and the solid dried under reduced pressure at 50° C. to afford the title compound (25.9 mg, 37%) as a pale yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.62 (s, 1H), 10.83 (s, 1H), 8.42 (s, 1H), 7.72-7.60 (m, 1H), 7.34 (t, J=54.0 Hz, 1H), 2.60 (s, 3H), 2.39 (s, 3H). MS-ESI (m/z) calc'd for C₁₇H₁₃ClF₂N₅O [M+H]⁺: 376.1. Found 376.1.

Example 292: 5-Cyano-N-(3-(difluoromethyl)-1H-indazol-5-yl)-3,4-dimethylpicolinamide

embedded image

Step 1: 5-Cyano-N-(3-(d fluoromethyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-3,4-dimethylpicolinamide

embedded image

To a solution of 3-(difluoromethyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-amine (120.0 mg, 0.450 mmol) and 5-cyano-3,4-dimethylpicolinic acid (65.0 mg, 0.360 mmol) in MeCN (3 mL) was added Et₃N (0.08 mL, 0.540 mmol) and HATU (137.48 mg, 0.360 mmol) and the resulting mixture was stirred for 3 hrs at r.t. The reaction mixture was then concentrated under reduced pressure to give a residue that was triturated with cooled MeOH (2 mL) and then filtered. The solid was dried to afford the title compound (133 mg, 86%). ¹H NMR (400 MHz, DMSO-d₆) δ 10.82 (s, 1H), 8.89 (s, 1H), 8.49 (d, 2H), 7.85 (d, J=9.1 Hz, 1H), 7.76 (dd, J=9.2, 1.9 Hz, 1H), 7.36 (t, J=53.7 Hz, 1H), 5.92 (dd, J=9.8, 2.4 Hz, 1H), 3.96-3.84 (m, 1H), 3.82-3.69 (m, 1H), 2.55 (s, 3H), 2.45 (s, 3H), 2.44-2.30 (m, 1H), 2.09-1.96 (m, 2H), 1.66-1.54 (m, 2H). MS-ESI (m/z) calc'd for C₂₂H₂₂F₂N₅O₂[M+H]⁺: 426.2. Found 426.1.

Step 2: 5-Cyano-N-(3-(difluoromethyl)-1H-indazol-5-yl)-3,4-dimethylpicolinamide

embedded image

Prepared as described for 6-chloro-5-cyano-N-(3-(difluoromethyl)-1H-indazol-5-yl)-3,4-dimethylpicolinamide using 6-chloro-5-cyano-N-(3-(difluoromethyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-3,4-dimethylpicolinamide in place of 6-chloro-5-cyano-N-(3-(difluoromethyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-3,4-dimethylpicolinamide to afford the title compound (32.5 mg, 30%) as a pale yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.59 (s, 1H), 10.77 (s, 1H), 8.88 (s, 1H), 8.50-8.44 (m, 1H), 7.69 (dd, J=9.0, 1.9 Hz, 1H), 7.64 (dd, J=9.0, 0.8 Hz, 1H), 7.33 (t, J=54.0 Hz, 1H), 2.55 (s, 3H), 2.44 (s, 3H). MS-ESI (m/z) calc'd for C₁₇H₁₄F₂N₅O [M+H]⁺: 342.1. Found 342.1.

Example 293: 6-Chloro-5-cyano-3,4-dimethyl-N-(3-(trifluoromethyl)-1H-indazol-5-yl)picolinamide

embedded image

Step 1: 5-Bromo-1-(tetrahydro-2H-pyran-2-yl)-3-(trifluoromethyl)-1H-indazole

embedded image

To a solution of 5-bromo-3-(trifluoromethyl)-1H-indazole (500.0 mg, 1.89 mmol) and 3,4-dihydro-2H-pyran (0.34 mL, 3.77 mmol) in toluene (4 mL) was added p-toluenesulfonic acid monohydrate (71.77 mg, 0.380 mmol) and the mixture was stirred at r.t. for 2 hrs and then at 60° C. for 30 minutes. The reaction mixture was partitioned between water and EtOAc and the phases were separated. The aqueous layer was extracted with EtOAc (2×) and the combined organic phases were washed with water (1×), dried over Na₂SO₄and evaporated to dryness. The crude material was purified by silica gel column chromatography using a 0-20% EtOAc/cyclohexane gradient eluent to afford the title compound (570 mg, 87%) as a colourless oil. ¹H NMR (400 MHz, DMSO-d₆) δ 8.03 (s, 1H) 7.95 (d, J=9.02 Hz, 1H) 7.75 (dd, J=9.02, 1.76 Hz, 1H) 6.05 (dd, J=9.46, 2.20 Hz, 1H) 3.85-3.96 (m, 1H) 3.72-3.84 (m, 1H) 2.26-2.41 (m, 1H) 1.97-2.09 (m, 2H) 1.69-1.84 (m, 1H) 1.61 (dt, J=8.25, 4.24 Hz, 2H). MS-ESI (m/z) calc'd for C₁₃H₁₃BrF₂N₂O [M+H]⁺: 349.0/351.0. Found 349.0/350.9.

Step 2: 1,1-Diphenyl-N-(1-(tetrahydro-2H-pyran-2-yl)-3-(trifluoromethyl)-1H-indazol-5-yl)methanimine

embedded image

To a solution of diphenylmethanimine (0.05 mL, 0.300 mmol) in toluene (2.5 mL) was added 5-bromo-1-(tetrahydro-2H-pyran-2-yl)-3-(trifluoromethyl)-1H-indazole (70.0 mg, 0.200 mmol) and sodium tert-butoxide (38.53 mg, 0.400 mmol) and the mixture was degassed and purged with N₂(3×). Then racemic BINAP (37.45 mg, 0.060 mmol) and Pd(dba)₂(18.36 mg, 0.020 mmol) were added and the mixture was degassed again with N₂for 5 min. The reaction mixture was stirred at 80° C. overnight. The reaction mixture was partitioned between water and EtOAc. The phases were separated and the aqueous layer was extracted with EtOAc (2×) and the combined organic phases were washed with brine (1×), dried over Na₂SO₄and concentrated to afford the title compound (190 mg) as a red oil. ¹H NMR (400 MHz, DMSO-d₆) δ 7.59 (d, J=9.02 Hz, 1H) 6.96 (dd, J=9.02, 1.98 Hz, 1H) 6.76 (s, 1H) 5.83 (dd, J=9.68, 2.20 Hz, 1H) 5.24 (s, 2H) 3.88 (d, J=11.22 Hz, 1H) 3.67-3.80 (m, 1H) 2.23-2.40 (m, 1H) 1.91-2.10 (m, 2H) 1.68-1.82 (m, 1H) 1.53-1.63 (m, 2H). MS-ESI (m/z) calc'd for C₂₆H₂₃F₃N₃O [M+H]⁺: 450.2. Found 450.2.

Step 3: 1-(Tetrahydro-2H-pyran-2-yl)-3-(trifluoromethyl)-1H-indazol-5-amine

embedded image

1,1-Diphenyl-N-(1-(tetrahydro-2H-pyran-2-yl)-3-(trifluoromethyl)-1H-indazol-5-yl)methanimine (89.89 mg, 0.200 mmol) was dissolved in THF (2 mL) and then 1 M HCl (2.0 mL, 2 mmol) was added and the mixture was stirred at r.t. for 1 hr. The reaction mixture was partitioned between H₂O and EtOAc, the phases were separated, the aqueous layer was extracted with EtOAc (2×) and the combined organic phases were washed with H₂O (1×), dried over Na₂SO₄and evaporated to dryness. The material was purified by silica gel column chromatography using a 0-30% EtOAc gradient eluent to afford the title compound (43 mg, 75%) as a colorless oil. ¹H NMR (400 MHz, DMSO-d₆) δ 7.59 (d, J=9.02 Hz, 1H) 6.96 (dd, J=9.02, 1.98 Hz, 1H) 6.76 (s, 1H) 5.83 (dd, J=9.68, 2.20 Hz, 1H) 5.24 (s, 2H) 3.88 (d, J=11.22 Hz, 1H) 3.67-3.80 (m, 1H) 2.23-2.40 (m, 1H) 1.91-2.10 (m, 2H) 1.68-1.82 (m, 1H) 1.53-1.63 (m, 2H). MS-ESI (m/z) calc'd for C₁₃H₁₅F₃N₃O [M+H]⁺: 268.1. Found 268.1.

Step 4: 6-Chloro-5-cyano-3,4-dimethyl-N-(1-(tetrahydro-2H-pyran-2-yl)-3-(trifluoromethyl)-1H-indazol-5-yl)picolinamide

embedded image

To a mixture of 6-chloro-5-cyano-3,4-dimethylpicolinic acid (25.0 mg, 0.120 mmol), 1-(tetrahydro-2H-pyran-2-yl)-3-(trifluoromethyl)-1H-indazol-5-amine (40.63 mg, 0.140 mmol) and Et₃N (33.09 uL, 0.240 mmol) in MeCN (2.5 mL) was added HATU (45.13 mg, 0.120 mmol) and the mixture was stirred at r.t. for 1 hr. The reaction mixture was partitioned between water and EtOAc and the phases were separated. The aqueous layer was extracted with EtOAc (2×) and the combined organic phases were washed with H₂O (1×), dried over Na₂SO₄and concentrated to afford the title compound (81 mg) as a yellow oil which was used without further purification. ¹H NMR (400 MHz, DMSO-d₆) δ 10.96 (s, 1H) 8.41 (s, 1H) 7.96 (d, J=9.02 Hz, 1H) 7.80 (dd, J=9.24, 1.76 Hz, 1H) 6.00 (d, J=7.70 Hz, 1H) 3.84-3.97 (m, 1H) 3.68-3.82 (m, 1H) 2.59 (s, 3H) 2.39 (s, 3H) 2.30-2.38 (m, 1H) 2.00-2.11 (m, 2H) 1.76 (br. s., 1H) 1.61 (d, J=3.96 Hz, 2H). MS-ESI (m/z) calc'd for C₂₂H₂₀ClF₃N₅O₂[M+H]⁺: 478.1. Found 478.1.

Step 5: 6-Chloro-5-cyano-3,4-dimethyl-N-(3-(trifluoromethyl)-1H-indazol-5-yl)picolinamide

embedded image

Prepared as described for 6-chloro-5-cyano-N-(3-(difluoromethyl)-1H-indazol-5-yl)-3,4-dimethylpicolinamide using 6-chloro-5-cyano-3,4-dimethyl-N-(1-(tetrahydro-2H-pyran-2-yl)-3-(trifluoromethyl)-1H-indazol-5-yl)picolinamide in place of 6-chloro-5-cyano-N-(3-(difluoromethyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-3,4-dimethylpicolinamide to afford the title compound (26 mg, 56%) as a light yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 14.02 (br. s., 1H) 10.90 (s, 1H) 8.40 (s, 1H) 7.74 (s, 2H) 2.60 (s, 3H) 2.40 (s, 3H). MS-ESI (m/z) calc'd for C₁₇H₁₂ClF₃N₅O [M+H]⁺: 394.0/396.1. Found 394.0/396.0.

Example 294: 5-Cyano-3-isopropyl-N-(3-methyl-1H-indazol-5-yl)picolinamide

embedded image

To a solution of 5-cyano-N-(3-methyl-1H-indazol-5-yl)-3-(prop-1-en-2-yl)picolinamide (17.0 mg, 0.05 mmol) in a mixture of MeOH (2 mL) and EtOH (8 mL) was added 10% Pd/C (1.7 mg, 0.03 mmol) and the mixture was hydrogenated at r.t. for 3 hrs. The mixture was then filtered through Celite and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a 0-80% EtOAc/cyclohexane gradient eluent to afford the title compound (3.4 mg, 20%) as a pale yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 12.62 (s, 1H), 10.66 (s, 1H), 8.97 (d, J=1.9 Hz, 1H), 8.55 (d, J=1.9 Hz, 1H), 8.24 (dd, J=1.8, 0.8 Hz, 1H), 7.52 (dd, J=8.9, 1.9 Hz, 1H), 7.45 (dd, J=8.8, 0.8 Hz, 1H), 3.47 (h, J=6.9 Hz, 1H), 2.48 (s, 3H), 1.27 (d, J=6.9 Hz, 6H). MS-ESI (m/z) calc'd for C₁₈H₁₈N₅O [M+H]⁺: 320.1. Found 320.2.

Example 295: 3-Cyano-2-isopropyl-N-(3-methyl-1H-indazol-5-yl)benzamide

embedded image

Prepared as described for 5-cyano-3-isopropyl-N-(3-methyl-1H-indazol-5-yl)picolinamide 3-cyano-N-(3-methyl-1H-indazol-5-yl)-2-(prop-1-en-2-yl)benzamide in place of 5-cyano-N-(3-methyl-1H-indazol-5-yl)-3-(prop-1-en-2-yl) to afford the title compound (3.8 mg, 25%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 12.61 (br. s., 1H) 10.53 (s, 1H) 8.19 (s, 1H) 7.91 (dd, J=7.70, 1.32 Hz, 1H) 7.72 (dd, J=7.59, 1.43 Hz, 1H) 7.42-7.55 (m, 3H) 3.46 (signal under H2O, 1H) 2.47 (s, 3H) 1.43 (d, J=7.26 Hz, 6H). MS-ESI (m/z) calc'd for C₁₉H₁₉N₄O [M+H]⁺: 319.2. Found 319.3.

Example 296: 6-Chloro-5-cyano-3,4-dimethyl-N-(3-(methylsulfonyl)-1H-indazol-5-yl)picolinamide

embedded image

To a solution of 6-chloro-5-cyano-3,4-dimethyl-N-(3-(methylthio)-1H-indazol-5-yl)picolinamide (35.54 mg, 0.100 mmol) in DMF (12 mL) was added oxone (117.53 mg, 0.190 mmol). The reaction was stirred at r.t. overnight. The reaction was quenched with saturated aqueous NaHSO₃, followed by saturated aqueous NaHCO₃to neutralization, and the mixture was extracted with EtOAc (100 mL×3). The combined organic layers were dried, filtered and concentrated. The residue was purified by reversed phase column chromatography using a 2-100% MeCN/H₂O (0.1% HCOOH) gradient eluent to afford the title compound (5.3 mg, 14%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 10.90 (s, 1H), 8.53-8.50 (m, 1H), 7.77 (dd, J=9.1, 1.8 Hz, 1H), 7.73 (d, J=9.0 Hz, 1H), 3.33 (s, 3H), 2.59 (s, 3H), 2.39 (s, 3H). MS-ESI (m/z) calc'd for C₁₇H₁₅ClN₅O₃S [M+H]⁺: 404.1. Found 404 1.

Example 297: 5-Cyano-3,4-dimethyl-N-(3-methyl-1H-indazol-5-yl)picolinamide

embedded image

Prepared as described for 3-chloro-5-cyano-N-(3-cyclopropyl-1H-indazol-5-yl)-4,6-dimethylpicolinamide (Example 283) using 5-cyano-3,4-dimethylpicolinic acid in place of 3-chloro-5-cyano-4,6-dimethylpicolinic acid and using 3-methyl-1H-indazol-5-amine in place of 3-cyclopropyl-1H-indazol-5-amine to afford the title compound (39.7 mg, 57%) as a light yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 12.61 (s, 1H) 10.62 (s, 1H) 8.88 (s, 1H) 8.24 (d, J=1.32 Hz, 1H) 7.51-7.58 (m, 1H) 7.42-7.48 (m, 1H) 2.56 (s, 3H) 2.48 (s, 3H) 2.45 (s, 3H). MS-ESI (m/z) calc'd for C₁₇H₁₆N₅O [M+H]⁺: 306.1. Found 306.3.

Example 298: 6-Chloro-5-cyano-3,4-dimethyl-N-(3-methyl-1H-indazol-5-yl)picolinamide

embedded image

Prepared as described for 3-chloro-5-cyano-N-(3-cyclopropyl-1H-indazol-5-yl)-4,6-dimethylpicolinamide (Example 283) using 6-chloro-5-cyano-3,4-dimethylpicolinic acid in place of 3-chloro-5-cyano-4,6-dimethylpicolinic acid and using 3-methyl-1H-indazol-5-amine in place of 3-cyclopropyl-1H-indazol-5-amine to afford the title compound (18 mg, 45%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 12.63 (s, 1H) 10.68 (s, 1H) 8.20 (s, 1H) 7.50-7.56 (m, 1H) 7.41-7.48 (m, 1H) 2.60 (s, 3H) 2.48 (s, 3H) 2.39 (s, 3H). MS-ESI (m/z) calc'd for C₁₇H₁₀ClN₅O [M+H]⁺: 340.1. Found 340.2.

Example 299: 3-Cyano-2-methoxy-6-methyl-N-(3-methyl-1H-indazol-5-yl)benzamide

embedded image

Prepared as described for 3-chloro-5-cyano-N-(3-cyclopropyl-1H-indazol-5-yl)-4,6-dimethylpicolinamide (Example 283) using 3-cyano-2-methoxy-6-methylbenzoic acid in place of 3-chloro-5-cyano-4,6-dimethylpicolinic acid and using 3-methyl-1H-indazol-5-amine in place of 3-cyclopropyl-1H-indazol-5-amine to afford the title compound (22.3 mg, 28%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 12.60 (s, 1H) 10.52 (s, 1H) 8.20 (s, 1H) 7.79 (d, J=7.92 Hz, 1H) 7.44 (d, J=1.10 Hz, 2H) 7.23-7.30 (m, 1H) 3.98 (s, 3H) 2.48 (s, 3H) 2.38 (s, 3H). MS-ESI (m/z) calc'd for C₁₈H₁₇N₄O₂[M+H]⁺: 321.1. Found 321.3.

Example 300: N-(3-Bromo-1H-indazol-5-yl)-5-cyano-3,4-dimethylpicolinamide

embedded image

Prepared as described for 3-chloro-5-cyano-N-(3-cyclopropyl-1H-indazol-5-yl)-4,6-dimethylpicolinamide (Example 283) using 5-cyano-3,4-dimethylpicolinic acid in place of 3-chloro-5-cyano-4,6-dimethylpicolinic acid and using 3-bromo-1H-indazol-5-amine in place of 3-cyclopropyl-1H-indazol-5-amine to afford the title compound (16.5 mg, 20%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.43 (br. s., 1H) 10.80 (s, 1H) 8.89 (s, 1H) 8.24 (d, J=1.32 Hz, 1H) 7.64-7.71 (m, 1H) 7.54-7.63 (m, 1H) 2.56 (s, 3H) 2.45 (s, 3H). MS-ESI (m/z) calc'd for C₁₆H₁₃BrN₅O [M+H]⁺: 370.0/372.0. Found 370.3/372.3.

Example 301: N-(3-Chloro-1H-indazol-5-yl)-5-cyano-3,4-dimethylpicolinamide

embedded image

Prepared as described for 3-chloro-5-cyano-N-(3-cyclopropyl-1H-indazol-5-yl)-4,6-dimethylpicolinamide (Example 283) using 6-bromo-5-cyano-3,4-dimethylpicolinic acid in place of 3-chloro-5-cyano-4,6-dimethylpicolinic acid and using 3-chloro-1H-indazol-5-amine in place of 3-cyclopropyl-1H-indazol-5-amine to afford the title compound (29.2 mg, 39%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₄) δ 13.29 (br. s., 1H) 10.80 (br. s., 1H) 8.89 (s, 1H) 8.26-8.34 (m, 1H) 7.63-7.70 (m, 1H) 7.53-7.61 (m, 1H) 2.56 (s, 3H) 2.45 (s, 3H). MS-ESI (m/z) calc'd for C₁₆H₁₃ClN₅O [M+H]⁺: 326.1. Found 326.2.

Example 302: 6-Bromo-5-cyano-3,4-dimethyl-N-(3-methyl-1H-indazol-5-yl)picolinamide

embedded image

Step 1: 6-Bromo-5-cyano-3,4-dimethylpicolinic acid

embedded image

6-Chloro-5-cyano-3,4-dimethylpicolinic acid (20.0 mg, 0.090 mmol) was dissolved in 1 mL of 33% w/w HBr in acetic acid. The reaction was stirred at 100° C. for 10 minutes and concentrated to afford the title compound (22 mg, 98%) as a beige solid which was used without further purification. ¹H NMR (400 MHz, DMSO-d₆) δ 14.17 (br. s., 1H) 2.55 (s, 3H) 2.31 (s, 3H). MS-ESI (m/z) calc'd for C₉H₈BrN₂O₂[M+H]⁺: 255.0/257.0. Found 255.0/257.0.

Step 2: 6-Bromo-5-cyano-3,4-dimethyl-N-(3-methyl-1H-indazol-5-yl)picolinamide

embedded image

Prepared as described for 3-chloro-5-cyano-N-(3-cyclopropyl-1H-indazol-5-yl)-4,6-dimethylpicolinamide (Example 283) using 6-bromo-5-cyano-3,4-dimethylpicolinic acid in place of 3-chloro-5-cyano-4,6-dimethylpicolinic acid and using 3-methyl-1H-indazol-5-amine in place of 3-cyclopropyl-1H-indazol-5-amine to afford the title compound (23 mg, 76%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 12.63 (s, 1H) 10.67 (s, 1H) 8.19 (s, 1H) 7.50-7.56 (m, 1H) 7.44-7.49 (m, 1H) 2.60 (s, 3H) 2.48 (s, 3H) 2.36 (s, 3H). MS-ESI (m/z) calc'd for C₁₇H₁₅BrN₅O [M+H]⁺: 384.0/386.0. Found 384.1/386.2.

Example 303: 6-Chloro-5-cyano-N-(3-cyclopropyl-1H-indazol-5-yl)-3,4-dimethylpicolinamide

embedded image

Prepared as described for 3-chloro-5-cyano-N-(3-cyclopropyl-1H-indazol-5-yl)-4,6-dimethylpicolinamide (Example 283) using 6-chloro-5-cyano-3,4-dimethylpicolinic acid in place of 3-chloro-5-cyano-4,6-dimethylpicolinic acid to afford the title compound (16.1 mg, 53%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 12.57 (s, 1H) 10.68 (s, 1H) 8.26 (d, J=1.32 Hz, 1H) 7.49-7.59 (m, 1H) 7.40-7.49 (m, 1H) 2.60 (s, 3H) 2.40 (s, 3H) 2.17-2.27 (m, 1H) 0.97-1.03 (m, 2H) 0.91-0.96 (m, 2H). MS-ESI (m/z) calc'd for C₁₉H₁₇ClN₅O [M+H]⁺: 366.1/368.0. Found 368.2.

Example 304: 5-Cyano-N-(3-cyclopropyl-1H-indazol-5-yl)-6-methoxy-3,4-dimethylpicolinamide

embedded image

Prepared as described for 3-chloro-5-cyano-N-(3-cyclopropyl-1H-indazol-5-yl)-4,6-dimethylpicolinamide (Example 283) using 5-cyano-6-methoxy-3,4-dimethylpicolinic acid in place of 3-chloro-5-cyano-4,6-dimethylpicolinic acid to afford the title compound (11.8 mg, 40%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 12.55 (s, 1H) 10.48 (s, 1H) 8.28 (d, J=1.32 Hz, 1H) 7.55 (dd, J=9.02, 1.76 Hz, 1H) 7.44 (d, J=8.58 Hz, 1H) 4.06 (s, 3H) 2.52 (peak under DMSO signal, 3H) 2.34 (s, 3H) 2.17-2.26 (m, 1H) 0.89-1.04 (m, 4H). MS-ESI (m/z) calc'd for C₂₀H₂₀N₅O₂[M+H]⁺: 362.2. Found 362.2.

Example 305: 5-Cyano-N-(3-cyclopropyl-1H-indazol-5-yl)-3,4,6-trimethylpicolinamide

embedded image

Prepared as described for 3-chloro-5-cyano-N-(3-cyclopropyl-1H-indazol-5-yl)-4,6-dimethylpicolinamide (Example 283) using 5-cyano-3,4,6-trimethylpicolinic acid in place of 3-chloro-5-cyano-4,6-dimethylpicolinic acid to afford the title compound (10.1 mg, 36%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 12.54 (s, 1H) 10.57 (s, 1H) 8.28 (s, 1H) 7.55 (dd, J=8.91, 1.87 Hz, 1H) 7.44 (d, J=8.80 Hz, 1H) 2.71 (s, 3H) 2.54 (s, 3H) 2.39 (s, 3H) 2.12-2.28 (m, 1H) 0.89-1.10 (m, 4H). MS-ESI (m/z) calc'd for C₂₀H₂₀N₅O [M+H]⁺: 346.2. Found 346.3.

Example 306: 4-Chloro-5-cyano-3-methyl-N-(3-methyl-1H-indazol-5-yl)picolinamide and Example 307: 6-Chloro-5-cyano-3-methyl-N-(3-methyl-1H-indazol-5-yl)picolinamide

embedded image

Step 1: Methyl 5-bromo-3-methylpicolinate

embedded image

To a solution of 5-bromo-2-carboxy-3-methylpyridine (6.48 g, 30 mmol) in DMF (50 mL) was added K₂CO₃(12.44 g, 90 mmol) and iodomethane (3.74 mL, 60 mmol) and the mixture was stirred at 80° C. for 1 hr. The mixture was poured into H₂O (150 mL) and stirred for 10 minutes. A solid formed that was collected by filtration and dried to afford the title compound (4.8 g, 70%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.67-8.57 (m, 1H), 8.15 (dd, J=2.2, 0.9 Hz, 1H), 3.86 (s, 3H), 2.46 (d, J=0.7 Hz, 3H). MS-ESI (m/z) calc'd for C₈H₉BrNO₂[M+H]⁺: 230.0/232.0. Found 229.9/231.9.

Step 2: Methyl 3-methyl-5-vinylpicolinate

embedded image

A solution of methyl 5-bromo-3-methylpyridine-2-carboxylate (4.8 g, 20.86 mmol) and tributyl(ethenyl)stannane (7.32 mL, 25.04 mmol) in 1,4-dioxane (104.32 mL) was purged with N₂for 10 minutes. Bis(triphenylphosphine)palladium(I₁) dichloride (1.47 g, 2.09 mmol) was added and the mixture was stirred at 100° C. for 1.5 hrs. The solvent was evaporated and the residue was purified by silica gel column chromatography using a 0-50% EtOAc/cyclohexane gradient eluent to afford the title compound (3.496 g, 95%) as a yellow oil. ¹H NMR (400 MHz, DMSO-d₆) δ 8.56 (d, J=2.1 Hz, 1H), 7.92 (dt, J=2.1, 0.7 Hz, 1H), 6.80 (dd, J=17.7, 11.0 Hz, 1H), 6.10 (dd, J=17.7, 0.8 Hz, 1H), 5.51 (dd, J=11.0, 0.8 Hz, 1H), 3.85 (s, 3H), 2.46 (d, J=0.6 Hz, 3H). MS-ESI (m/z) calc'd for C₁₀H₁₂NO₂[M+H]⁺: 178.1. Found 178.0.

Step 3: Methyl 5-formyl-3-methylpicolinate

embedded image

To a solution of methyl 3-methyl-5-vinylpicolinate (3.5 g, 19.73 mmol) in 1,4-dioxane (98.65 mL) was added a solution of NaIO₄(8.48 g, 39.46 mmol) in H₂O (98.65 mL) and the mixture was stirred at 25° C. for 10 minutes. A 4% solution of osmium tetroxide in water (6.28 mL, 0.990 mmol) was added and the solution was stirred at 25° C. for 1 hr. The mixture was diluted with H₂O and extracted with DCM (3×). The combined organic layers were passed through a phase separator and concentrated to afford the title compound (3.535 g, 100%) as a black solid. ¹H NMR (400 MHz, DMSO-d₆) δ 10.14 (s, 1H), 8.95 (d, J=1.9 Hz, 1H), 8.24 (dd, J=2.0, 0.9 Hz, 1H), 3.91 (s, 3H), 2.51 (s, 3H). MS-ESI (m/z) calc'd for C₉H₁₀NO₃[M+H]⁺: 180.1. Found 180.0.

Step 4: Methyl 5-cyano-3-methylpicolinate

embedded image

To a solution of methyl 5-formyl-3-methylpicolinate (3.54 g, 19.73 mmol) in DMSO (15 mL) was added hydroxylamine hydrochloride (1.51 g, 21.7 mmol) and the mixture was stirred at 90° C. for 1 hr. After cooling down, H₂O was added and the solid formed was filtered under vacuum, washed with H₂O and dried to afford the title compound (1.7 g, 49%) as a purple solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.92 (dd, 1=1.9, 0.7 Hz, 1H), 8.39 (dd, 1=1.9, 0.8 Hz, 1H), 3.90 (s, 3H), 2.47 (d, J=0.7 Hz, 3H). MS-ESI (m/z) calc'd for C₉H₉N₂O₂[M+H]⁺: 177.1. Found 176.9.

Step 5: 5-Cyano-2-(methoxycarbonyl)-3-methylpyridine 1-oxide

embedded image

To a solution of methyl 5-cyano-3-methylpicolinate (400.0 mg, 2.27 mmol) in DCM (10 mL) was added MCPBA (783.65 mg, 4.54 mmol) and the mixture was stirred at 50° C. overnight After that another equivalent of MCPBA was added and the mixture was stirred at 50° C. for an additional 24 hrs. The solution was washed with 2M aqueous K₂CO₃(1×) and the aqueous layer was extracted with DCM (3×). All the organic phases were combined, washed with H₂O (1×), passed through a phase separator and evaporated to dryness to obtain material that was further purified by silica gel column chromatography using a 0-100% EtOAc gradient eluent to afford the title compound (220 mg, 50%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.88 (s, 1H) 7.85-7.93 (m, 1H) 3.94 (s, 3H) 2.25 (s, 3H).1H) 7.85-7.93 (m, 1H) 3.94 (s, 3H) 2.25 (s, 3H). MS-ESI (m/z) calc'd for C₉H₉N₂O₃[M+H]⁺: 193.1. Found 193.0.

Step 6: Methyl 6-chloro-5-cyano-3-methylpicolinate and Methyl 4-chloro-5-cyano-3-methylpicolinate

embedded image

5-Cyano-2-(methoxycarbonyl)-3-methylpyridine 1-oxide (30.0 mg, 0.160 mmol) was suspended in POCl₃(0.5 mL, 5.35 mmol) and the mixture was stirred at reflux for 1 hr. Excess POCl₃was evaporated and the reaction mixture was partitioned between saturated aqueous NaHCO₃and DCM. The phases were separated; the aqueous layer was extracted with DCM (2×) and the combined organic phases were washed with H₂O (1×), dried over Na₂SO₄and evaporated to dryness to afford a 4:1 mixture (determined by NMR) respectively of the title compounds (27 mg, 82%) as a white solid. Methyl 6-chloro-5-cyano-3-methylpicolinate: ¹H NMR (400 MHz, DMSO-d₆) δ 8.58 (s, 1H) 3.92 (s, 3H) 2.48 (d, J=0.66 Hz, 3H). Methyl 4-chloro-5-cyano-3-methylpicolinate: ¹H NMR (400 MHz, DMSO-d₆) δ 9.00 (d, J=0.66 Hz, 1H) 3.94 (s, 3H) 2.47 (s, 3H). MS-ESI (m/z) calc'd for C₉H₈ClN₂O₂[M+H]⁺: 213.0. Found 213.0.

Step 7: 6-Chloro-5-cyano-3-methylpicolinic acid and 4-Chloro-5-cyano-3-methylpicolinic acid

embedded image

To a solution of methyl 6-chloro-5-cyano-3-methylpicolinate and methyl 4-chloro-5-cyano-3-methylpicolinate (27.0 mg, 0.130 mmol) in EtOH (1 mL) was added a solution of LiOH.H₂O (5.38 mg, 0.130 mmol) in H₂O (0.600 mL) and the resulting mixture was stirred at r.t. for 1 hr. 1 M HCl was added dropwise until pH=1 and the mixture was extracted with EtOAc (2×). The combined organic phases were washed with water (1×), dried over Na₂SO₄and evaporated to afford a 4:1 mixture, respectively, of the title compounds (19 mg, 75%) as a white solid which was used without further purification. 6-Chloro-5-cyano-3-methylpicolinic acid: ¹H NMR (400 MHz, DMSO-d₆) δ 14.09 (br. s., 1H) 8.52 (d, J=0.66 Hz, 1H) 2.45 (s, 3H). 4-Chloro-5-cyano-3-methylpicolinic acid: ¹H NMR (400 MHz, DMSO-d₆) δ 14.09 (br. s., 1H) 8.96 (s, 1H) 2.47 (s, 3H). MS-ESI (m/z) calc'd for C₈H₆ClN₂O₂[M+H]⁺: 197.0/199.0. Found 196.9/198.7.

Step 8: 4-Chloro-5-cyano-3-methyl-N-(3-methyl-1H-indazol-5-yl)picolinamide and 6-Chloro-5-cyano-3-methyl-N-(3-methyl-1H-indazol-5-yl)picolinamide

embedded image

To a mixture of 6-chloro-5-cyano-3-methylpicolinic acid and 4-chloro-5-cyano-3-methylpicolinic acid (18.0 mg, 0.090 mmol), 3-methyl-1H-indazol-5-amine (16.17 mg, 0.110 mmol) and triethylamine (25.52 μL, 0.180 mmol) was added HATU (34.81 mg, 0.090 mmol) and the mixture was stirred at r.t. for 2 hrs. The reaction mixture was evaporated to dryness. The residue was purified via HPLC using Method DE to afford the title compounds. 4-Chloro-5-cyano-3-methyl-N-(3-methyl-1H-indazol-5-yl)picolinamide (2.9 mg, 10%) as a yellow solid: ¹H NMR (400 MHz, DMSO-d₆) δ 12.66 (s, 1H) 10.76 (s, 1H) 9.07 (d, J=0.66 Hz, 1H) 8.23 (d, J=1.32 Hz, 1H) 7.51-7.58 (m, 1H) 7.43-7.50 (m, 1H) 2.57 (s, 3H) 2.48 (s, 3H). MS-ESI (m/z) calc'd for C₁₆H₁₃ClN₅O [M+H]⁺: 326.1. Found 326.1. 6-Chloro-5-cyano-3-methyl-N-(3-methyl-1H-indazol-5-yl)picolinamide (8.1 mg, 27%) as a yellow solid: ¹H NMR (400 MHz, DMSO-d₆) δ 12.65 (br. s., 1H) 10.66 (s, 1H) 8.57 (s, 1H) 8.21 (d, J=1.32 Hz, 1H) 7.53-7.61 (m, 1H) 7.46 (d, J=8.80 Hz, 1H) 2.52 (peak under DMSO signal, s, 3H) 2.48 (s, 3H). MS-ESI (m/z) calc'd for C₁₆H₁₃ClN₅O [M+H]⁺: 326.1. Found 326.1.

Example 308: 6-Chloro-5-cyano-N-(3-methoxy-1H-indazol-5-yl)-3,4-dimethylpicolinamide

embedded image

Prepared as described for 3-chloro-5-cyano-N-(3-cyclopropyl-1H-indazol-5-yl)-4,6-dimethylpicolinamide (Example 283) using 6-chloro-5-cyano-3,4-dimethylpicolinic acid in place of 3-chloro-5-cyano-4,6-dimethylpicolinic acid and using 3-methoxy-1H-indazol-5-amine in place of 3-cyclopropyl-1H-indazol-5-amine to afford the title compound (44 mg, 65%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.93 (s, 1H) 10.70 (s, 1H) 8.13 (d, J=1.98 Hz, 1H) 7.54 (dd, J=9.02, 1.98 Hz, 1H) 7.32-7.41 (m, 1H) 4.01 (s, 3H) 2.59 (s, 3H) 2.38 (s, 3H). MS-ESI (m/z) calc'd for C₁₇H₁₅ClN₅O₂[M+H]⁺: 356.1. Found 356.0.

Example 309: 3-Chloro-5-cyano-N-(3-(isoxazol-4-yl)-1H-indazol-5-yl)picolinamide

embedded image

Prepared as described for 3-chloro-5-cyano-N-(3-cyclopropyl-1H-indazol-5-yl)-4,6-dimethylpicolinamide (Example 283) using 3-chloro-5-cyanopicolinic acid in place of 3-chloro-5-cyano-4,6-dimethylpicolinic acid and using 3-(isoxazol-4-yl)-1H-indazol-5-amine in place of 3-cyclopropyl-1H-indazol-5-amine to afford the title compound (9 mg, 3%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.38 (s, 1H), 10.88 (s, 1H), 9.55 (s, 1H), 9.19-9.09 (m, 2H), 8.83 (d, J=1.7 Hz, 1H), 8.35 (d, J=1.8 Hz, 1H), 7.70 (dd, J=8.9, 1.9 Hz, 1H), 7.63 (d, J=8.9 Hz, 1H). MS-ESI (m/z) calc'd for C₁₇H₁₀ClN₆O₂[M+H]⁺: 365.1/367.1. Found 365.2/367.3.

Example 310: 5-Cyano-3-cyclopropyl-N-(3-(isoxazol-4-yl)-1H-indazol-5-yl)picolinamide

embedded image

Prepared as described for 3-chloro-5-cyano-N-(3-cyclopropyl-1H-indazol-5-yl)-4,6-dimethylpicolinamide (Example 283) using 5-cyano-3-cyclopropylpicolinic acid in place of 3-chloro-5-cyano-4,6-dimethylpicolinic acid and using 3-(isoxazol-4-yl)-1H-indazol-5-amine in place of 3-cyclopropyl-1H-indazol-5-amine to afford the title compound (1.6 mg, 4%) as a pale yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 9.37 (s, 1H), 9.01 (s, 1H), 8.80 (d, J=1.9 Hz, 1H), 8.48 (dd, J=1.9, 0.8 Hz, 1H), 7.94 (d, J=1.9 Hz, 1H), 7.72 (dd, J=9.0, 1.9 Hz, 1H), 7.62 (dd, J=9.0, 0.8 Hz, 1H), 2.88 (td, J=8.5, 4.3 Hz, 1H), 1.21-1.17 (m, 2H), 0.91 (dd, J=5.2, 1.7 Hz, 2H). MS-ESI (m/z) calc'd for C₂₀H₁₅N₆O₂[M+H]⁺: 371.1. Found 371.3.

Example 311: 5-Cyano-3-cyclopropyl-N-(3-(3-methoxyphenyl)-1H-indazol-5-yl)picolinamide

embedded image

Prepared as described for 3-chloro-5-cyano-N-(3-cyclopropyl-1H-indazol-5-yl)-4,6-dimethylpicolinamide (Example 283) using 5-cyano-3-cyclopropylpicolinic acid in place of 3-chloro-5-cyano-4,6-dimethylpicolinic acid and using 3-(3-methoxyphenyl)-1H-indazol-5-amine in place of 3-cyclopropyl-1H-indazol-5-amine to afford the title compound (30.9 mg, 36%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.25 (s, 1H), 10.79 (s, 1H), 8.90 (d, J=1.8 Hz, 11H), 8.63 (d, J=1.8 Hz, 1H), 8.02 (d, J=1.9 Hz, 11H), 7.77 (dd, J=9.0, 1.9 Hz, 1H), 7.60 (d, J=9.0 Hz, 1H), 7.53 (dt, J=7.7, 1.3 Hz, 1H), 7.50-7.43 (m, 2H), 6.99 (ddd, J=8.1, 2.7, 1.1 Hz, 1H), 3.85 (s, 3H), 2.56-2.52 (m, 1H), 1.11-1.02 (m, 2H), 0.95-0.86 (m, 2H). MS-ESI (m/z) calc'd for C₂₄H₂₀N₅O₂[M+H]⁺: 410.2. Found 410.3.

Example 312: 5-Cyano-3-cyclopropyl-N-(3-(oxazol-5-yl)-1H-indazol-5-yl)picolinamide

embedded image

Prepared as described for 3-chloro-5-cyano-N-(3-cyclopropyl-1H-indazol-5-yl)-4,6-dimethylpicolinamide (Example 283) using 5-cyano-3-cyclopropylpicolinic acid in place of 3-chloro-5-cyano-4,6-dimethylpicolinic acid and using 3-(oxazol-5-yl)-1H-indazol-5-amine in place of 3-cyclopropyl-1H-indazol-5-amine to afford the title compound (13.2 mg, 15%). ¹H NMR (400 MHz, DMSO-d₆) δ 13.55 (s, 1H), 10.82 (s, 1H), 8.90 (d, J=1.8 Hz, 1H), 8.61 (d, J=1.8 Hz, 1H), 8.58 (s, 1H), 8.03 (d, J=1.9 Hz, 1H), 7.75 (dd, J=9.0, 1.9 Hz, 1H), 7.63 (d, J=8.6 Hz, 2H), 2.58-2.52 (m, 1H), 1.13-1.03 (m, 2H), 0.96-0.86 (m, 2H). MS-ESI (m/z) calc'd for C₂₀H₁₅N₆O₂[M+H]⁺: 371.1. Found 371.3.

Example 313: 5-Cyano-N-(3-methyl-1H-indazol-5-yl)-3-(prop-1-en-2-yl)picolinamide

embedded image

Prepared as described for 3-chloro-5-cyano-N-(3-cyclopropyl-1H-indazol-5-yl)-4,6-dimethylpicolinamide (Example 283) using 5-cyano-3-(prop-1-en-2-yl)picolinic acid in place of 3-chloro-5-cyano-4,6-dimethylpicolinic acid and using 3-methyl-1H-indazol-5-amine in place of 3-cyclopropyl-1H-indazol-5-amine to afford the title compound (20.1 mg, 60%) as a pale yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 12.61 (s, 1H), 10.66 (s, 1H), 9.04 (d, J=1.9 Hz, 1H), 8.43 (d, J=1.9 Hz, 1H), 8.16 (dd, J=1.9, 0.8 Hz, 1H), 7.48 (dd, J=8.9, 1.9 Hz, 1H), 7.43 (dd, J=8.8, 0.8 Hz, 1H), 5.25 (t, J=1.5 Hz, 1H), 5.16-5.08 (m, 1H), 2.46 (s, 3H), 2.10 (t, J=1.2 Hz, 3H). MS-ESI (m/z) calc'd for C₁₈H₁₆N₅O [M+H]⁺: 318.1. Found 318.2.

Example 314: 5-Cyano-N-(7-fluoro-1H-indazol-5-yl)-3,4-dimethylpicolinamide and Example 315: 5-Cyano-N-(3-fluoro-1H-indazol-5-yl)-3,4-dimethylpicolinamide

embedded image

Step 1: 7-Fluoro-5-nitro-1H-indazole and 3-Fluoro-5-nitro-1H-indazole

embedded image

To a solution of 5-nitro-1H-indazole (300.0 mg, 1.84 mmol) in MeCN (1.24 mL) was added Selectfluor (651.49 mg, 1.84 mmol) and AcOH (1.24 mL) and the reaction mixture was heated in a microwave reactor at 150° C. for 30 min. The reaction was quenched with water and extracted with EtOAc (2×). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated to give a residue. The residue was purified by silica gel chromatography using a 0-80% EtOAc/cyclohexane gradient eluent to afford a mixture of the title compounds (53 mg) as a white solid. Major isomer: 3-fluoro-1H-indazol-5-amine (83.3% mol/mol by NMR): ¹H NMR (400 MHz, DMSO-d₆) δ 13.41 (s, 1H), 8.76 (d, J=2.2 Hz, 1H), 8.25 (dd, J=9.3, 2.2 Hz, 1H), 7.70 (dd, J=9.3, 2.2 Hz, 1H); Minor isomer: 7-fluoro-5-nitro-1H-indazole, 16.67% mol/mol by NMR. ¹H NMR (400 MHz, DMSO-d₆) δ 8.74 (d, J=1.8 Hz, 1H), 8.54 (d, J=3.1 Hz, 1H), 8.07 (dd, J=10.9, 1.9 Hz, 1H). MS-ESI (m/z) calc'd for C₇H₃FN₃O₂[M−H]⁻: 180.0. Found 179.9.

Step 2: 7-Fluoro-1H-indazol-5-amine and 3-Fluoro-1H-indazol-5-amine

embedded image

To a solution of a mixture of 3-fluoro-5-nitro-1H-indazole and 7-fluoro-5-nitro-1H-indazole (53.0 mg, 0.19 mmol) in EtOH (10 mL) was added 10% Pd/C (31.13 mg, 0.030 mmol) and the mixture was hydrogenated at r.t. for 2 hrs. The reaction was filtered through Celite, washing with MeOH, and the resulting solution was concentrated to afford a mixture of the title compounds (23 mg) which was used without further purification. Major isomer: 3-fluoro-1H-indazol-5-amine, 81.6% mol/mol by NMR. ¹H NMR (400 MHz, DMSO-d₆) δ 11.96 (s, 1H), 7.17 (dd, J=9.0, 2.6 Hz, 1H), 6.85 (dd, J=8.9, 2.1 Hz, 1H), 6.59 (d, J=2.1 Hz, 1H), 4.93 (s, 2H); Minor isomer: 7-fluoro-1H-indazol-5-amine, 18.4% mol/mol by NMR. MS-ESI (m/z) calc'd for C₇H₇FN₃[M+H]⁺: 152.1. Found 152.0.

Step 3: 5-Cyano-N-(7-fluoro-1H-indazol-5-yl)-3,4-dimethylpicolinamide and 5-Cyano-N-(3-fluoro-1H-indazol-5-yl)-3,4-dimethylpicolinamide

embedded image

To a solution of a mixture of intermediate 1 and 2, 5-cyano-3,4-dimethylpyridine-2-carboxylic acid (20.0 mg, 0.110 mmol) and 3-fluoro-1H-indazol-5-amine; 7-fluoro-1H-indazol-5-amine (23.0 mg, 0.150 mmol) and triethylamine (0.02 mL, 0.140 mmol) in MeCN (2 mL), HATU (42.3 mg, 0.110 mmol) was added and the mixture was stirred at 25° C. for 1 hr. EtOAC and H₂O were added, the organic phase was separated, dried over Na₂SO₄, filtered and concentrate. The material obtained (54 mg) was purified by semi-preparative HPLC using Method DF to afford the title compounds. The first eluted compound, 5-cyano-N-(7-fluoro-1H-indazol-5-yl)-3,4-dimethylpicolinamide (2.2 mg, 6%) as a white solid: ¹H NMR (400 MHz, DMSO-d₆) δ 13.61 (s, 1H), 10.78 (s, 1H), 8.89 (s, 1H), 8.19 (s, 1H), 8.11 (d, J=1.5 Hz, 1H), 7.58 (d, J=12.8 Hz, 1H), 2.55 (s, 3H), 2.44 (s, 3H). MS-ESI (m/z) calc'd for C₁₆H₁₃FN₅O [M+H]⁺: 310.1. Found 310.2. The second eluted compound 5-cyano-N-(3-fluoro-1H-indazol-5-yl)-3,4-dimethylpicolinamide (18 mg, 52%) as a white solid: ¹H NMR (400 MHz, DMSO-d₆) δ 12.54 (s, 1H), 10.77 (s, 1H), 8.88 (s, 1H), 8.32-8.18 (m, 1H), 7.66 (dd, J=9.1, 1.9 Hz, 1H), 7.50 (dd, J=9.0, 2.3 Hz, 1H), 2.55 (s, 3H), 2.43 (s, 3H). MS-ESI (m/z) calc'd for C₁₆H₁₃FN₅O [M+H]⁺: 310.1. Found 310.2.

Example 316: 3-Cyano-6-fluoro-2-methyl-N-(3-methyl-1H-indazol-5-yl)benzamide

embedded image

Step 1: 3-Bromo-6-fluoro-2-methyl-N-(3-methyl-1H-indazol-5-yl)benzamide

embedded image

To a solution of 3-methyl-1H-indazol-5-amine (75.79 mg, 0.510 mmol), 3-bromo-6-fluoro-2-methylbenzoic acid (100.0 mg, 0.430 mmol) and Et₃N (0.06 mL, 0.430 mmol) in MeCN (3 mL), was added HATU (163.17 mg, 0.430 mmol) and the reaction mixture was left stirring at r.t. for 2 hrs. Water (100 mL) and EtOAc (100 mL) were added and the organic phase was separated, dried over Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography using a 0-20% MeOH/DCM gradient eluent to afford the title compound (110 mg, 71%). ¹H NMR (400 MHz, DMSO-d₆) δ 12.61 (s, 1H), 10.65 (s, 1H), 8.20 (t, J=1.4 Hz, 1H), 7.75 (dd, J=8.9, 5.4 Hz, 1H), 7.43 (d, J=1.0 Hz, 2H), 7.20 (t, J=8.7 Hz, 1H), 2.47 (s, 3H), 2.37 (s, 3H). MS-ESI (m/z) calc'd for C₁₆H₁₄BrFN₃O [M+H]⁺: 362.0/364.0. Found 362.1/364.1.

Step 2: 3-Cyano-6-fluoro-2-methyl-N-(3-methyl-1H-indazol-5-yl)benzamide

embedded image

A 0.1 N aqueous solution of potassium hexacyanoferrate(II) (1.66 mL, 0.170 mmol), 3-bromo-6-fluoro-2-methyl-N-(3-methyl-1H-indazol-5-yl)benzamide (60.0 mg, 0.170 mmol) and K₂CO₃(8.13 mg, 0.080 mmol) were dissolved in a mixture of 1,4-dioxane (2.918 mL) and H₂O (0.403 mL) in a sealed microwave reactor vial. The mixture was degassed with N₂for 15 minutes. Then XPhos (3.16 mg, 0.010 mmol) and Xphos-Pd-G3 (5.61 mg, 0.010 mmol) were added and the mixture was stirred at 100° C. for 6 hrs. Water was added and the mixture was extracted with EtOAc. The organic phase was separated, dried over Na₂SO₄, filtered and concentrated. The solid was purified by semi-preparative HPLC using Method DD to afford the title compound (14.1 mg, 28%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 12.63 (s, 1H), 10.71 (s, 1H), 8.18 (t, J=1.3 Hz, 1H), 8.01 (dd, J=8.7, 5.5 Hz, 1H), 7.50-7.39 (m, 3H), 2.53 (s, 3H), 2.48 (s, 3H). MS-ESI (m/z) calc'd for C₁₇H₁₄FN₄O [M+H]⁺: 309.1. Found 309.2.

Example 317: 6-Chloro-5-cyano-3,4-dimethyl-N-(3-(methylthio)-1H-indazol-5-yl)picolinamide

embedded image

Step 1: 3-(Methylthio)-5-nitro-1H-indazole

embedded image

3-Iodo-5-nitro-1H-indazole (1.0 g, 3.46 mmol), sodium thiomethoxide (1.21 g, 17.3 mmol) and copper(I) iodide (65.89 mg, 0.350 mmol) were dissolved in dry DMSO (30 mL) and H₂O (6 mL) and the mixture was heated at 120° C. for 30 min. under microwave irradiation. The reaction mixture was diluted with saturated aqueous NaHCO₃and extracted with DCM. The organic phase was dried over Na₂SO₄, filtered and evaporated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (10 g Biotage silica cartridge) using a 0-50% EtOAc/cyclohexane gradient eluent to afford the title compound (430 mg, 59%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.72 (s, 1H), 8.56 (dd, J=2.2, 0.6 Hz, 1H), 8.21 (dd, J=9.2, 2.2 Hz, 1H), 7.70 (dd, J=9.2, 0.7 Hz, 1H), 2.65 (s, 3H). MS-ESI (m/z) calc'd for C₈H₈N₃O₂S [M+H]⁺: 210.1. Found 210.0.

Step 2: 3-(Methylthio)-1H-indazol-5-anine

embedded image

A mixture of 3-methylsulfanyl-5-nitro-1H-indazole (150.0 mg, 0.670 mmol), NH₄Cl (38.16 mg, 0.710 mmol), and Fe (161.24 mg, 2.89 mmol) in EtOH/H₂O (3 mL/3 mL) was heated to reflux for 1.5 hrs. The mixture was cooled and filtered through Celite. The filtrate was evaporated, and the resulting residue was purified by strong cation exchange (SCX) using MeOH to wash the cartride and NH₃/MeOH to wash out the desired product. The MeOH was evaporated under reduced pressure to afford the title compound (110 mg, 92%) as a red solid. ¹H NMR (400 MHz, DMSO-d₆) δ 12.62 (s, 1H), 7.21 (d, J=8.7 Hz, 1H), 6.79 (dd, J=8.8, 2.1 Hz, 1H), 6.66 (d, J=2.0 Hz, 1H), 4.86 (s, 2H), 2.47 (s, 3H). MS-ESI (m/z) calc'd for C₈H₁₀N₃S [M+H]⁺: 180.1. Found 180.0.

Step 3: 6-Chloro-5-cyano-3,4-dimethyl-N-(3-(methylthio)-1H-indazol-5-yl)picolinamide

embedded image

Prepared as described for 3-chloro-5-cyano-N-(3-cyclopropyl-1H-indazol-5-yl)-4,6-dimethylpicolinamide (Example 283) using 6-chloro-5-cyano-3,4-dimethylpicolinic acid in place of 3-chloro-5-cyano-4,6-dimethylpicolinic acid and using 3-(methylthio)-1H-indazol-5-amine in place of 3-cyclopropyl-1H-indazol-5-amine to afford the title compound (41.4 mg, 42%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.11 (s, 1H), 10.76 (s, 1H), 8.20 (s, 1H), 7.63-7.56 (m, 1H), 7.53 (d, J=8.9 Hz, 1H), 2.59 (s, 3H), 2.57 (s, 3H), 2.39 (s, 3H). MS-ESI (m/z) calc'd for C₇H₁₅ClN₅OS [M+H]⁺: 372.1. Found 372.0.

Example 318: 3-Chloro-5-cyano-N-(3-(oxazol-5-yl)-1H-indazol-5-yl)picolinamide

embedded image

Prepared as described for 3-chloro-5-cyano-N-(3-cyclopropyl-1H-indazol-5-yl)-4,6-dimethylpicolinamide (Example 283) using 3-chloro-5-cyanopicolinic acid in place of 3-chloro-5-cyano-4,6-dimethylpicolinic acid and using 3-(oxazol-5-yl)-1H-indazol-5-amine in place of 3-cyclopropyl-1H-indazol-5-amine to afford the title compound (51 mg, 70%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.54 (s, 1H), 10.95 (s, 1H), 9.13 (d, J=1.7 Hz, 1H), 8.82 (d, J=1.8 Hz, 1H), 8.59 (s, 1H), 8.55 (dd, J=1.9, 0.9 Hz, 1H), 7.69 (dd, J=9.0, 1.8 Hz, 1H), 7.67-7.63 (m, 2H). MS-ESI (m/z) calc'd for C₁₇H₁₀ClN₆O₂[M+H]⁺: 365.1/367.0. Found 365.1/367.1.

Example 319: 5-Cyano-N-(3-(3-(dimethylphosphoryl)phenyl)-1H-indazol-5-yl)-3-methylpicolinamide

embedded image

Step 1: (3-Bromophenyl)dimethylphosphine oxide

embedded image

Dimethylphosphine oxide (834.0 mg, 10.69 mmol) and 1-bromo-3-iodobenzene (1.36 mL, 10.69 mmol) were dissolved in 1,4-dioxane (36 mL) and the flask was purged with N₂(3×). In a separate vial, Pd(dba)₂(48.92 mg, 0.050 mmol), Xantphos (61.83 mg, 0.110 mmol) and Et₃N (1.74 mL, 12.5 mmol) were stirred in 1,4-dioxane (4 mL) for 10 minutes to prepare a solution. This catalyst solution was added to the previous solution and left stirring at 25° C. for 24 hrs. The solvent was evaporated and the residue obtained was taken up in water and extracted with DCM, the organic layer was passed through a phase separator and evaporated to give an oil which was purified by silica gel column chromatography using a 0-10% MeOH/DCM gradient eluent to afford the title compound (1.67 g, 67%) as a clear oil. ¹H NMR (400 MHz, DMSO-d₆) δ 7.93 (dt, J=11.2, 1.7 Hz, 1H), 7.83-7.72 (m, 2H), 7.49 (td, J=7.7, 3.0 Hz, 1H), 1.67 (d, J=13.5 Hz, 6H). MS-ESI (m/z) calc'd for C₈H₁BrOP [M+H]⁺: 233.0/235.0. Found 233.0/235.0.

Step 2: Dimethyl(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)phosphine oxide

embedded image

(3-Bromophenyl)dimethylphosphine oxide (0.47 g, 2 mmol), bis(pinacolato)diborane (0.68 mL, 2.6 mmol), KOAc (588.84 mg, 6 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (43.9 mg, 0.060 mmol) were placed in a flask that was sealed with a rubber septum. The atmosphere in the flask was purged with N₂and 1,4-dioxane (20 mL) was added. The mixture was stirred at 60° C. for 24 hrs. The solvent was evaporated and the black residue obtained was purified by silica gel column chromatography using a 0-15% MeOH/DCM gradient eluent to afford the title compound (650 mg) as a yellow oil. ¹H NMR (400 MHz, DMSO-d₆) δ 8.09-8.01 (m, 1H), 7.92-7.81 (m, 2H), 7.54 (td, J=7.5, 2.5 Hz, 1H), 1.64 (d, J=13.4 Hz, 6H), 1.06 (s, 12H). MS-ESI (m/z) calc'd for C₁₄H₂₃BO₃P [M+H]⁺: 281.1. Found 281.2.

Step 3: (3-(5-Amino-1H-indazol-3-yl)phenyl)dimethylphosphine oxide

embedded image

3-Iodo-1H-indazol-5-amine (280.6 mg, 1.08 mmol) was dissolved in THF (10 mL) then a solution of tripotassium phosphate (449.12 mg, 3.25 mmol) and dimethyl(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)phosphine oxide (650.17 mg, 1.3 mmol) in H₂O (3 mL) was added and the mixture was degassed with N₂for 15 minutes. SPhos-Pd-G2 (78.06 mg, 0.110 mmol) was added and the mixture was stirred at 80° C. under N₂for 6 hrs. The organic solvent was evaporated and the mixture was diluted with H₂O and extracted with EtOAc (3×). The combined organic layers were passed through a phase separator and evaporated to obtain a residue which was purified by silica gel column chromatography using a 0-100% MeOH/DCM gradient eluent to afford the title compound (61 mg, 20%) as a beige solid. ¹H NMR (400 MHz, DMSO-d₆) δ 12.90 (s, 1H), 8.31-8.20 (m, 1H), 8.05 (dd, J=7.7, 1.6 Hz, 1H), 7.77-7.67 (m, 1H), 7.63 (td, J=7.7, 3.1 Hz, 1H), 7.32 (d, J=8.8 Hz, 1H), 7.16-7.03 (m, 1H), 6.84 (dd, J=8.8, 2.0 Hz, 1H), 4.95 (s, 2H), 1.72 (d, J=13.3 Hz, 6H). MS-ESI (m/z) calc'd for C₁₅H₁₇N₃O P [M+H]⁺: 286.1. Found 286.1.

Step 4: 5-Cyano-N-(3-(3-(dimethylphosphoryl)phenyl)-1H-indazol-5-yl)-3-methylpicolinamide

embedded image

Prepared as described for 3-chloro-5-cyano-N-(3-cyclopropyl-1H-indazol-5-yl)-4,6-dimethylpicolinamide (Example 283) using 5-cyano-3-methylpicolinic acid in place of 3-chloro-5-cyano-4,6-dimethylpicolinic acid and using (3-(5-amino-1H-indazol-3-yl)phenyl)dimethylphosphine oxide in place of 3-cyclopropyl-1H-indazol-5-amine to afford the title compound (54 mg, 63%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.37 (s, 1H), 10.81 (s, 1H), 9.00 (d, J=2.0 Hz, 1H), 8.64-8.59 (m, 1H), 8.41 (dd, J=2.0, 0.8 Hz, 1H), 8.31 (dt, J=12.0, 1.6 Hz, 1H), 8.14-8.06 (m, 1H), 7.86-7.77 (m, 2H), 7.70 (td, J=7.6, 2.9 Hz, 1H), 7.62 (d, J=8.9 Hz, 1H), 2.58 (s, 3H), 1.74 (d, J=13.3 Hz, 6H). MS-ESI (m/z) calc'd for C₂₃H₂₁N₅O₂P [M+H]⁺: 430.1. Found 430.2.

Example 320: 6-Chloro-N-(3-chloro-1H-indazol-5-yl)-5-cyano-3,4-dimethylpicolinamide

embedded image

Prepared as described for 3-chloro-5-cyano-N-(3-cyclopropyl-1H-indazol-5-yl)-4,6-dimethylpicolinamide (Example 283) using 6-chloro-5-cyano-3,4-dimethylpicolinic acid in place of 3-chloro-5-cyano-4,6-dimethylpicolinic acid and using 3-chloro-1H-indazol-5-amine in place of 3-cyclopropyl-1H-indazol-5-amine to afford the title compound (14 mg, 19%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.30 (s, 1H), 10.85 (s, 1H), 8.25 (dd, J=1.9, 0.8 Hz, 1H), 7.63 (dd, J=9.0, 1.8 Hz, 1H), 7.59 (dd, J=9.0, 0.8 Hz, 1H), 2.59 (s, 3H), 2.39 (s, 3H). MS-ESI (m/z) calc'd for C₁₆H₁₂Cl₂N₅O [M+H]⁺: 360.0/362.0. Found 360.0/362.0.

Example 321: N-(3-Chloro-1H-indazol-5-yl)-5-cyano-6-methoxy-3,4-dimethylpicolinamide

embedded image

Prepared as described for 3-chloro-5-cyano-N-(3-cyclopropyl-1H-indazol-5-yl)-4,6-dimethylpicolinamide (Example 283) using 5-cyano-6-methoxy-3,4-dimethylpicolinic acid in place of 3-chloro-5-cyano-4,6-dimethylpicolinic acid and using 3-chloro-1H-indazol-5-amine in place of 3-cyclopropyl-1H-indazol-5-amine to afford the title compound (34 mg, 48%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.30 (s, 1H), 10.65 (s, 1H), 8.27 (s, 1H), 7.66 (dd, J=9.1, 1.9 Hz, 1H), 7.59 (d, J=8.9 Hz, 1H), 4.06 (s, 3H), 2.52 (s, 3H), 2.34 (s, 3H). MS-ESI (m/z) calc'd for C₁₇H₁₅ClN₅O₂[M+H]⁺: 356.1/358.1. Found 356.1/358.1.

Example 322: 5-Cyano-6-methoxy-3,4-dimethyl-N-(3-methyl-1H-indazol-5-yl)picolinamide

embedded image

Prepared as described for 3-chloro-5-cyano-N-(3-cyclopropyl-1H-indazol-5-yl)-4,6-dimethylpicolinamide (Example 283) using 5-cyano-6-methoxy-3,4-dimethylpicolinic acid in place of 3-chloro-5-cyano-4,6-dimethylpicolinic acid and using 3-methyl-1H-indazol-5-amine in place of 3-cyclopropyl-1H-indazol-5-amine to afford the title compound (22.5 mg, 34%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 12.61 (s, 1H), 10.48 (s, 1H), 8.20 (dd, J=1.9, 0.8 Hz, 1H), 7.53 (dd, J=8.9, 1.9 Hz, 1H), 7.45 (dd, J=8.8, 0.8 Hz, 1H), 4.05 (s, 3H), 2.51 (s, 3H), 2.48 (s, 3H), 2.33 (s, 3H). MS-ESI (m/z) calc'd for C₁₈H₁₈N₅O₂[M+H]⁺: 336.1. Found 336.2.

Example 323: 5-cyano-3-methyl-N-(3-(3-(piperidin-1-yl)propyl)-1H-indazol-5-yl)picolinamide

embedded image

Step 1: 1-(Prop-2-yn-1-yl)piperidine

embedded image

To a solution of piperidine (4.94 mL, 50 mmol) in DCM (10 mL) was added 3-bromo-1-propyne (2.38 g, 20 mmol) dropwise and the mixture was stirred at 25° C. for 15 hrs. The solvent was evaporated to give a residue that was taken up in Et₂O and washed with H₂O (3×). The organic layer was passed through a phase separator and evaporated to afford the title compound (2.33 g, 95%) as an orange oil. ¹H NMR (400 MHz, DMSO-d₆) δ 3.20 (d, J=2.4 Hz, 2H), 3.08 (t, J=2.4 Hz, 1H), 2.41-2.33 (m, 4H), 1.61-1.28 (m, 6H).

Step 2: 3-(3-(Piperidin-1-yl)prop-1-yn-1-yl)-1H-indazol-5-amine

embedded image

A mixture of 3-iodo-1H-indazol-5-amine (1.04 g, 4 mmol), 1-prop-2-ynylpiperidine (0.74 g, 6 mmol), bis(triphenylphosphine)palladium(II) dichloride (281.56 mg, 0.400 mmol) and copper (I) iodide (38.09 mg, 0.200 mmol) in Et₃N (4 mL) was heated at 90° C. for 2 hrs. The solvent was evaporated and the residue was purified by silica gel column chromatography using a 0-50% MeOH/DCM gradient eluent to afford the title compound (160 mg, 16%) as an orange oil. ¹H NMR (400 MHz, DMSO-d₆) δ 12.83 (s, 1H), 7.26 (dd, J=8.7, 0.8 Hz, 1H), 6.80 (dd, J=8.8, 2.1 Hz, 1H), 6.69 (dd, J=2.1, 0.8 Hz, 1H), 4.97 (d, J=2.7 Hz, 2H), 3.54 (s, 2H), 2.64 (t, J=5.3 Hz, 2H), 1.64-1.29 (m, 8H). MS-ESI (m/z) calc'd for C₁₅H₁₉N₄[M+H]⁺: 255.2. Found 255.4.

Step 3: 1-(3-(Piperidin-1-yl)propyl)-1H-indazol-5-amine

embedded image

Step 4: 5-cyano-3-methyl-N-(3-(3-(piperidin-1-yl)propyl)-1H-indazol-5-yl)picolinamide

embedded image

Prepared as described for 3-chloro-5-cyano-N-(3-cyclopropyl-1H-indazol-5-yl)-4,6-dimethylpicolinamide (Example 283) using 5-cyano-3-methylpicolinic acid in place of 3-chloro-5-cyano-4,6-dimethylpicolinic acid and using 1-(3-(piperidin-1-yl)propyl)-1H-indazol-5-amine in place of 3-cyclopropyl-1H-indazol-5-amine to afford the title compound (23.6 mg, 12%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 12.66 (s, 1H), 10.65 (s, 1H), 8.99 (d, J=2.1 Hz, 1H), 8.40 (dd, J=2.0, 0.9 Hz, 1H), 8.30 (dd, J=1.9, 0.7 Hz, 1H), 8.18 (s, 1H), 7.61 (dd, J=8.9, 1.9 Hz, 1H), 7.46 (dd, J=8.9, 0.7 Hz, 1H), 2.92 (t, J=7.5 Hz, 2H), 2.61-2.52 (m, 9H), 1.97 (p, J=7.7 Hz, 2H), 1.62-1.49 (m, 4H), 1.41 (p, J=5.9 Hz, 2H). MS-ESI (m/z) calc'd for C₂₃H₂₈N₆O⁺ [M+H]⁺: 404.2. Found 403.2.

Example 324: N-(3-Bromo-1H-indazol-5-yl)-6-chloro-5-cyano-3,4-dimethylpicolinamide

embedded image

Prepared as described for 3-chloro-5-cyano-N-(3-cyclopropyl-1H-indazol-5-yl)-4,6-dimethylpicolinamide (Example 283) using 6-chloro-5-cyano-3,4-dimethylpicolinic acid in place of 3-chloro-5-cyano-4,6-dimethylpicolinic acid and using 3-bromo-1H-indazol-5-amine in place of 3-cyclopropyl-1H-indazol-5-amine to afford the title compound (55 mg, 68%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.44 (s, 1H), 10.85 (s, 1H), 8.20-8.17 (m, 1H), 7.64 (dd, J=9.0, 1.9 Hz, 1H), 7.59 (d, J=9.0 Hz, 1H), 2.59 (s, 3H), 2.39 (s, 3H). MS-ESI (m/z) calc'd for C₁₆H₁₂BrClN₅O [M+H]⁺: 404.0/406.0. Found 404.0/406.0.

Example 325: 5-Cyano-3,4,6-trimethyl-N-(3-methyl-1H-indazol-5-yl)picolinamide

embedded image

Prepared as described for 3-chloro-5-cyano-N-(3-cyclopropyl-1H-indazol-5-yl)-4,6-dimethylpicolinamide (Example 283) using 5-cyano-3,4,6-trimethylpicolinic acid in place of 3-chloro-5-cyano-4,6-dimethylpicolinic acid and using 3-methyl-1H-indazol-5-amine in place of 3-cyclopropyl-1H-indazol-5-amine to afford the title compound (57 mg, 89%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 12.60 (s, 1H), 10.56 (s, 1H), 8.21 (s, 1H), 7.56-7.51 (m, 1H), 7.44 (d, J=8.8 Hz, 1H), 2.70 (s, 3H), 2.53 (s, 3H), 2.47 (s, 3H), 2.38 (s, 3H). MS-ESI (m/z) calc'd for C₁₈H₁₈N₅O [M+H]⁺: 320.1. Found 320.2.

Example 326: 3-Chloro-5-cyano-4-methyl-N-(3-methyl-1H-indazol-5-yl)picolinamide

embedded image

Step 1: 5-Chloro-4,6-dimethylnicotinonitrile

embedded image

To a mixture of 2,5-dichloro-4,6-dimethylpyridine-3-carbonitrile (2.01 g, 10 mmol) in acetic acid (1 mL) and H₂O (9 mL) was added zinc (1.31 g, 20 mmol) and the suspension was stirred at 95° C. for 3 hrs. The mixture was extracted with DCM (3×) and the combined organic layers were passed through a phase separator and evaporated to obtain a yellow solid which was purified by silica gel column chromatography using a 2-20% EtOAc/cyclohexane gradient eluent to afford the title compound (930 mg, 56%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.78 (s, 1H), 2.64 (s, 3H), 2.54 (s, 3H). MS-ESI (m/z) calc'd for C₈H₈ClN₂[M+H]⁺: 167.0. Found 166.9.

Step 2: 3-Chloro-5-cyano-2,4-dimethylpyridine 1-oxide

embedded image

To a solution of 5-chloro-4,6-dimethylnicotinonitrile (930.0 mg, 5.58 mmol) in DCM (55.82 mL) was added MCPBA (1.38 g, 5.58 mmol) and the mixture was stirred at 25° C. for 5 hrs. The solution was washed with saturated aqueous K₂CO₃(3×) and the aqueous layers were extracted with DCM (2×). The organic phases were combined, passed through a phase separator and concentrated to afford the title compound (970 mg, 95%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.94 (s, 1H), 2.55 (s, 3H), 2.48 (s, 3H). MS-ESI (m/z) calc'd for C₈H₈ClN₂[M+H]⁺: 183.0. Found 183.0.

Step 3: 5-Chloro-6-(hydroxymethyl)-4-methylnicotinonitrile

embedded image

To a solution of 3-chloro-5-cyano-2,4-dimethylpyridine 1-oxide (970.0 mg, 5.31 mmol) in DCM (26.56 mL) was added trifluoroacetic anhydride (2.22 mL, 15.94 mmol) dropwise and the mixture was stirred at 25° C. for 15 hours. The solvent was evaporate and the residue was taken up in MeOH. K₂CO₃(3 g) was added and the suspension was stirred at 25° C. for 1 hr. The solvent was evaporated and the residue was taken up in water and extracted with DCM (3×). The combined organic layers were passed through a phase separator and concentrated to afford the title compound (305 mg, 31%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.90 (s, 1H), 5.41 (t, J=6.1 Hz, 1H), 4.70 (d, J=6.0 Hz, 2H), 2.56 (s, 3H). MS-ESI (m/z) calc'd for C₈H₈ClN₂[M+H]⁺: 183.0. Found 182.9.

Step 4: 3-Chloro-5-Cyano-4-methylpicolinic acid

embedded image

To a solution of 5-chloro-6-(hydroxymethyl)-4-methylpyridine-3-carbonitrile (305.0 mg, 1.67 mmol) in acetone (10 mL) was added a solution of KMnO₄(395.92 mg, 2.51 mmol) in H₂O (5 mL) and the mixture was stirred at 25° C. for 2 hrs. The dark mixture was filtered and washed with water. The filtrate was acidified by addition of conc. HCl and then extracted with EtOAc (3×). The combined organic layers were passed through a phase separator and concentrated to afford the title compound (325 mg, 99%) as a beige solid. ¹H NMR (400 MHz, DMSO-d₆) δ 14.41 (bs, 1H), 8.93 (s, 1H), 2.59 (s, 3H). MS-ESI (m/z) calc'd for C₈H₈ClN₂O₂[M+H]⁺: 197.0. Found 197.0.

Step 5: 3-Chloro-5-cyano-4-methyl-N-(3-methyl-1H-indazol-5-yl)picolinamide

embedded image

Prepared as described for 3-chloro-5-cyano-N-(3-cyclopropyl-1H-indazol-5-yl)-4,6-dimethylpicolinamide (Example 283) using 3-chloro-5-cyano-4-methylpicolinic acid in place of 3-chloro-5-cyano-4,6-dimethylpicolinic acid and using 3-methyl-1H-indazol-5-amine in place of 3-cyclopropyl-1H-indazol-5-amine to afford the title compound (57 mg, 89%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 12.63 (s, 1H), 10.77 (s, 1H), 9.02 (s, 1H), 8.19 (d, J=1.4 Hz, 1H), 7.46 (d, J=1.0 Hz, 2H), 2.65 (s, 3H), 2.48 (s, 3H). MS-ESI (m/z) calc'd for C₁₆H₁₃ClN₅O [M+H]⁺: 326.1/328.1. Found 326.1/328.1.

Example 327: 5-Cyano-N-(3-cyclopropyl-1H-indazol-5-yl)-6-(difluoromethyl)-3,4-dimethylpicolinamide

embedded image

Step 1: Methyl 6-chloro-5-cyano-3,4-dimethylpicolinate

embedded image

To a solution of 6-chloro-5-cyano-3,4-dimethylpyridine-2-carboxylic acid (500.0 mg, 2.09 mmol) in DMF (4.017 mL) was added potassium carbonate (866.19 mg, 6.27 mmol) and iodomethane (260.11 uL, 4.18 mmol) and then the mixture was stirred at 80° C. for 4 hrs. The reaction mixture was extracted with water (150 mL) and EtOAc (150 mL). The organic phase was separated, washed with saturated aqueous NaHCO₃, dried over Na₂SO₄, filtered and concentrated. The residue was purified by silica gel column chromatography using a 0-40% EtOAc/cyclehexane gradient eluent to afford the title compound (465 mg, 99%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 3.92 (s, 3H), 2.55 (s, 3H), 2.33 (s, 3H). MS-ESI (m/z) calc'd for C₁₀H₁₀ClN₂O₂[M+H]⁺: 225.0. Found 225.0.

Step 2: Methyl 5-cyano-3,4-dimethyl-6-vinylpicolinate

embedded image

A microwave vial was charged with methyl 6-chloro-5-cyano-3,4-dimethylpicolinate (115.0 mg, 0.510 mmol), triphenylphosphine (4.03 mg, 0.020 mmol), tributyl(ethenyl)stannane (0.18 mL, 0.610 mmol) and toluene (3.171 mL) under N₂. The reaction mixture was degassed with N₂for 10 min, then palladium tetrakis triphenylphosphine (5.92 mg, 0.010 mmol) was added and the mixture was heated to reflux for 3 hrs. Water (150 mL) and EtOAc (150 mL) were added, the organic phase was separated, washed with brine, dried over Na₂SO₄, filtered and concentrated under vacuum. The residue was purified by silica gel column chromatography using a 0-50% EtOAc/cyclohexane gradient eluent to afford the title compound (76 mg, 69%) as a white solid. ¹H NMR (400 MHz, chloroform-d₆) δ 7.15 (dd, J=16.9, 10.7 Hz, 1H), 6.63 (dd, J=16.9, 1.5 Hz, 1H), 5.72 (dd, J=10.7, 1.5 Hz, 1H), 3.99 (s, 3H), 2.55 (s, 3H), 2.38 (s, 3H). MS-ESI (m/z) calc'd for C₁₂H₁₃N₂O₂[M+H]⁺: 217.1. Found 217.0.

Step 3: Methyl 5-cyano-6-formyl-3,4-dimethylpicolinate

embedded image

To a solution of methyl 5-cyano-3,4-dimethyl-6-vinylpicolinate (124.0 mg, 0.570 mmol) (118 mg) in 1,4-dioxane (1.751 mL) was added a solution of sodium:periodate (485.7 mg, 2.27 mmol) in H₂O (1.751 mL), then 4% tetraoxoosmium (0.18 mL, 0.030 mmol) was added and the mixture was stirred at 25° C. for 2 hrs. The suspension was diluted with H₂O and extracted with EtOAc (2×), the combined organic layers were dried over Na₂SO₄, filtered and evaporated to afford the title compound (123.8 mg, 99%) as a beige solid which was used without further purification. MS-ESI (m/z) calc'd for C₁₁H₁₁N₂O₃[M+H]⁺: 219.1. Found 219.0.

Step 4: Methyl 5-cyano-6-(difluoromethyl)-3,4-dimethylpicolinate

embedded image

To a solution of methyl 5-cyano-6-formyl-3,4-dimethylpicolinate (123.8 mg, 0.570 mmol) in DCM (2.5 mL) was added DAST (0.11 mL, 0.850 mmol) dropwise at 0° C. The resulting mixture was allowed to warm to r.t., then stirred for 18 hrs. The reaction solution was quenched with saturated aqueous NaHCO₃at 0° C. and diluted with H₂O (100 ml) and EtOAc (100 mL). The layers were separated and the organic layer was washed with brine, dried over Na₂SO₄and concentrated to give a crude product which was purified by silica gel column chromatography using a 0-50% EtOAc/cyclohexane gradient to afford the title compound (73 mg, 54%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 7.14 (t, J=53.1 Hz, 1H), 3.94 (s, 3H), 2.60 (s, 3H), 2.40 (s, 3H). MS-ESI (m/z) calc'd for C₁₁H₁₁F₂N₂O₂[M+H]⁺: 241.1. Found 241.0.

Step 5: 5-Cyano-6-(difluoromethyl)-3,4-dimethylpicolinic acid

embedded image

To a solution of methyl 5-cyano-6-(difluoromethyl)-3,4-dimethylpicolinate (73.0 mg, 0.300 mmol) in EtOH (2.5 mL) was added a solution of LiOH.H₂O (12.75 mg, 0.300 mmol) in water (1.5 mL) and the resulting mixture was stirred at r.t. for 1 hr. 1 M HCl was added dropwise until pH 1, followed by EtOAc. The reaction mixture was partitioned between H₂O and EtOAc, the phases were separated, the aqueous layer was extracted with EtOAc (2×) and the combined organic phases dried over anhydrous Na₂SO₄, filtered and evaporated to dryness to afford the title compound (66.5 mg, 97%) as a white solid which was used without further purification. ¹H NMR (400 MHz, DMSO-d₆) δ 14.15 (s, 1H), 7.12 (t, J=53.2 Hz, 1H), 2.58 (s, 3H), 2.39 (s, 3H). MS-ESI (m/z) calc'd for C₁₀H₉F₂N₂O₂[M+H]⁺: 227.1. Found 227.1.

Step 6: 5-Cyano-N-(3-cyclopropyl-1H-indazol-5-yl)-6-(difluoromethyl)-3,4-dimethylpicolinamide

embedded image

To a solution of 5-cyano-6-(difluoromethyl)-3,4-dimethylpicolinic acid (36.5 mg, 0.160 mmol) and 3-cyclopropyl-1H-indazol-5-amine (30.75 mg, 0.180 mmol) and Et₃N (0.03 mL, 0.210 mmol) in MeCN (4.138 mL) was added HATU (61.36 mg, 0.160 mmol) in portions and the mixture was stirred at 25° C. for 1 hr. The reaction mixture was filtered and the solid was washed with MeCN (2×5 mL) and H₂O (2×5 mL), then dried under reduced pressure to afford the title compound (43.9 mg, 71%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 12.56 (s, 1H), 10.69 (s, 1H), 8.26 (d, J=1.8 Hz, 1H), 7.53 (dd, J=8.9, 1.9 Hz, 1H), 7.45 (d, J=8.9 Hz, 1H), 7.19 (t, J=53.2 Hz, 1H), 2.63 (s, 3H), 2.48 (s, 3H), 2.21 (ddd, J=13.2, 8.3, 5.1 Hz, 1H), 0.98 (dt, J=8.5, 2.8 Hz, 2H), 0.93 (dt, J=5.0, 2.6 Hz, 2H). MS-ESI (m/z) calc'd for C₂₀H₁₅F₂N₅O [M+H]⁺: 382.1. Found 382.2.

Example 328: 5-Cyano-N-(3-cyclopropyl-1H-indazol-5-yl)-3,4-dimethyl-6-(trifluoromethyl)picolinamide

embedded image

Step 1: Methyl 5-cyano-3,4-dimethyl-6-(trifluoromethyl)picolinate

embedded image

A solution of methyl 5-cyano-3-methylpyridine-2-carboxylate (500.0 mg, 2.84 mmol) and zinc trifluoromethanesulfinate (1881.82 mg, 5.68 mmol) in DMSO (8 mL) was cooled in an ice water bath. The mixture was stirred vigorously while adding a 70% aqueous solution of tert-butyl hydroperoxide (1.18 mL, 8.51 mmol). The solution was allowed to reach r.t. and then warmed at 50° C. for 2 h. An additional 2 eq. of trifluoromethanesulfinate and 3 eq. of t-BuOOH were added and stirring was continued at 50° C. for 2 hrs. The reaction mixture was partitioned between H₂O and EtOAc and the phases were separated. The aqueous layer was extracted with EtOAc (2×) and the combined organic phases were washed with saturated aqueous NaHCO₃(1×) and H₂O (1×), dried over Na₂SO₄and evaporated to dryness. The residue was purified by silica gel column chromatography using a 0-40% EtOAc/cyclohexane gradient eluent to afford the title compound (100 mg, 20%) as a colorless oil. ¹H NMR (400 MHz, DMSO-d₆) δ 3.96 (s, 3H) 2.64 (s, 3H) 2.45 (s, 3H). MS-ESI (m/z) calc'd for C₁₉H₁₀F₃N₂O₂[M+H]⁺: 259.1. Found 259.1.

Step 2: 5-Cyano-3,4-dimethyl-6-(trifluoromethyl)picolinic acid

embedded image

To a solution of methyl 5-cyano-3,4-dimethyl-6-(trifluoromethyl)picolinate (100.0 mg, 0.390 mmol) in MeOH (5 mL) was added a 1 N aqueous solution of NaOH (0.39 mL, 0.390 mmol) and the mixture was stirred at r.t. for 2 hrs. Volatiles were removed under reduced pressure to afford the title compound (105 mg) as a white solid which was used without further purification. ¹H NMR (400 MHz, DMSO-d₆) δ 2.50 (s, 3H) 2.26 (s, 3H). MS-ESI (m/z) calc'd for C₁₀H₈F₃N₂O₂[M+H]⁺: 245.1. Found 244.9.

Step 3: 5-Cyano-N-(3-cyclopropyl-1H-indazol-5-yl)-3,4-dimethyl-6 (trifluoromethyl)picolinamide

embedded image

To a mixture of 5-cyano-3,4-dimethyl-6-(trifluoromethyl)picolinic acid (47.12 mg, 0.190 mmol), 3-cyclopropyl-1H-indazol-5-amine (40.12 mg, 0.230 mmol) and Et₃N (53.8 uL, 0.390 mmol) in MeCN (2.5 mL) was added HATU (73.38 mg, 0.190 mmol) and the mixture was stirred at r.t. for 1 hr. Then 0.5 mL of 1 N aqueous NaOH were added and the mixture was stirred at r.t. for 30 min. The reaction mixture was partitioned between H₂O and EtOAc and the phases were separated. The aqueous layer was extracted with EtOAc (2×) and the combined organic phases were washed with H₂O (1×), dried over Na₂SO₄and evaporated to dryness. The residue was purified by preparative HPLC using Method DG to afford the title compound (38.2 mg, 50%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 12.58 (s, 1H) 10.72 (s, 1H) 8.23-8.32 (m, 1H) 7.50-7.56 (m, 1H) 7.43-7.49 (m, 1H) 2.68 (s, 3H) 2.49 (s, 3H) 2.18-2.28 (m, 1H) 0.91-1.05 (m, 4H). MS-ESI (m/z) calc'd for C₂₀H₁₇F₃N₅O [M+H]⁺: 400.1. Found 400.2.

Example 329: 6-Bromo-5-cyano-N-(3-methoxy-1H-indazol-5-yl)-3,4-dimethylpicolinamide

embedded image

Step 1: 6-Bromo-5-cyano-3,4-dimethylpicolinic acid

embedded image

6-Chloro-5-cyano-3,4-dimethylpyridine-2-carboxylic acid (50.0 mg, 0.240 mmol) was dissolved in 1 mL of HBr (33% w/w in AcOH) and the reaction was stirred at 100° C. for 10 minutes. The reaction mixture was concentrated under reduced pressure and residual acetic acid was removed by co-evaporation with MeCN to afford the title compound (70 mg) as a beige solid which was used without further purification. ¹H NMR (400 MHz, DMSO-d₆) δ 2.55 (s, 3H) 2.31 (s, 3H). MS-ESI (m/z) calc'd for C₉H₈BrN₂O₂[M+H]⁺: 255.0/257.0. Found 255.0/257.0.

Step 2: 6-Bromo-5-cyano-N-(3-methoxy-1H-indazol-5-yl)-3,4-dimethylpicolinamide

embedded image

To a mixture of 6-bromo-5-cyano-3,4-dimethylpicolinic acid (30.0 mg, 0.120 mmol), 3-methoxy-1H-indazol-5-amine (23.03 mg, 0.140 mmol) and Et₃N (32.79 uL, 0.240 mmol) in MeCN (2.5 mL) was added HATU (44.72 mg, 0.120 mmol) and the mixture was stirred at r.t. for 1 hr. The reaction mixture was partitioned between H₂O and EtOAc and the phases were separated. The aqueous layer was extracted with EtOAc (2×) and the combined organic phases were washed with H₂O (1×), dried over Na₂SO₄and evaporated to dryness. The residue was purified by preparative HPLC using Method DH to afford the title compound (29.2 mg, 62%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.92 (s, 1H) 10.69 (s, 1H) 8.12 (d, J=1.98 Hz, 1H) 7.54 (dd, J=9.02, 1.98 Hz, 1H) 7.37 (d, J=8.80 Hz, 1H) 4.01 (s, 3H) 2.59 (s, 3H) 2.35 (s, 3H). MS-ESI (m/z) calc'd for C₁₇H₁₅BrN₅O₂[M+H]⁺: 400.0/402.0. Found 400.2/402.1.

Example 330: 6-Bromo-5-cyano-N-(3-cyclopropyl-1H-indazol-5-yl)-3,4-dimethylpicolinamide

embedded image

To a mixture of 6-bromo-5-cyano-3,4-dimethylpicolinic acid (30.1 mg, 0.120 mmol), 3-cyclopropyl-1H-indazol-5-amine (24.53 mg, 0.140 mmol) and triethylamine (32.89 uL, 0.240 mmol) in MeCN (2.5 mL) was added HATU (44.87 mg, 0.120 mmol) and the mixture was stirred at r.t. for 1 hr. The reaction mixture was partitioned between H₂O and EtOAc and the phases were separated. The aqueous layer was extracted with EtOAc (2×) and the combined organic phases were washed with water (1×), dried over Na₂SO₄and evaporated to dryness. The residue was purified by preparative HPLC using Method DI to afford the title compound (35.1 mg, 73%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 12.57 (s, 1H) 10.67 (s, 1H) 8.25 (d, J=1.54 Hz, 1H) 7.50-7.56 (m, 1H) 7.43-7.48 (m, 1H) 2.60 (s, 3H) 2.37 (s, 3H) 2.18-2.27 (m, 1H) 0.90-1.04 (m, 4H). MS-ESI (m/z) calc'd for C₁₉H₁₇BrN₅O [M+H]⁺: 410.1/412.1. Found 410.2/412.2.

Example 331: 3,6-Dichloro-5-cyano-N-(3-cyclopropyl-1H-indazol-5-yl)-4-methylpicolinamide

embedded image

Step 1: 2,5-Dichloro-3-cyano-4,6-dimethylpyridine 1-oxide

embedded image

To a solution of 2,5-dichloro-4,6-dimethylpyridine-3-carbonitrile (2.01 g, 10 mmol) in trifluoroacetic acid (50 mL) was added hydrogen peroxide (3.06 mL, 30 mmol) and the mixture was stirred at 75° C. for 1 hr. The solvent was evaporated to afford the title compound (2.17 g, 99%) as a yellow oil which was used without further purification. ¹H NMR (400 MHz, DMSO-d₆) δ 2.62 (s, 3H), 2.53 (s, 3H). MS-ESI (m/z) calc'd for C₈H₇Cl₂N₂O [M+H]⁺: 217.0/219.0. Found 217.0/219.0.

Step 2: 2,5-Dichloro-6-(hydroxymethyl)-4-methylnicotinonitrile

embedded image

To a solution of 2,5-dichloro-3-cyano-4,6-dimethylpyridine 1-oxide (2.17 g, 10 mmol) in DCM (50 mL) was added trifluoroacetic anhydride (4.17 mL, 30 mmol) dropwise and the mixture was stirred at 25° C. for 15 hrs. The solvent was evaporated and the residue was taken up in MeOH. K₂CO₃(3 g) was added and the suspension was stirred at 25° C. for 1 hr. The solvent was evaporated and the residue was taken up in water and extracted with DCM (3×). The combined organic layers were passed through a phase separator and evaporated to afford the title compound (1.9 g, 88%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 5.60 (t, J=6.3 Hz, 1H), 4.66 (d, J=6.3 Hz, 2H), 2.58 (s, 3H). MS-ESI (m/z) calc'd for C₈H₇Cl₂N₂O [M+H]⁺: 217.0/219.0. Found 217.0/219.0.

Step 3: 3,6-Dichloro-5-cyano-4-methylpicolinic acid

embedded image

To a solution of 2,5-dichloro-6-(hydroxymethyl)-4-methylpyridine-3-carbonitrile (1.0 g, 4.61 mmol) in acetone (23.91 mL) was added a solution of KMnO₄(0.97 g, 6.13 mmol) in H₂O (23.91 mL) and the mixture was stirred at 25° C. for 1 hr. The solid was filtered and the filtrate was evaporated to remove the organic solvent. The pH was adjusted to 1 by addition of conc. HCl and the suspension was extracted with EtOAc (3×). The combined organic layers were dried over Na₂SO₄, then passed through a phase separator and evaporated to afford the title compound (800 mg, 75%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 14.83 (s, 1H), 2.62 (s, 3H). MS-ESI (m/z) calc'd for C₈H₅Cl₂N₂O₂[M+H]⁺: 231.0/233.0. Found 231.0/232.9.

Step 4: 3,6-Dichloro-5-cyano-N-(3-cyclopropyl-1H-indazol-5-yl)-4-methylpicolinamide

embedded image

To a mixture of 3,6-dichloro-5-cyano-4-methylpicolinic acid (46.21 mg, 0.200 mmol), 3-cyclopropyl-1H-indazol-5-amine (37.25 mg, 0.200 mmol) and Et₃N (27.88 uL, 0.200 mmol) in MeCN (2 mL) was added HATU (76.05 mg, 0.200 mmol) and the reaction was stirred at 25° C. for 2 hrs. Water was added and a solid formed that was collected by filtration and purified by silica gel column chromatography using a 0-50% EtOAc/cyclohexane gradient eluent to afford the title compound (44.5 mg, 58% yield) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 12.59 (s, 1H), 10.85 (s, 1H), 8.22 (s, 1H), 7.57-7.39 (m, 2H), 2.68 (s, 3H), 2.22 (ddd, J=13.4, 8.3, 5.1 Hz, 1H), 0.98 (dt, J=8.3, 2.7 Hz, 2H), 0.93 (dt, J=5.1, 2.7 Hz, 2H). MS-ESI (m/z) calc'd for C₁₈H₁₄Cl₂N₅O [M+H]⁺: 386.1/388.1. Found 386.1/388.2.

Example 332: 5-Cyano-N-(3-cyclopropyl-1H-indazol-5-yl)-3,4-dimethyl-6-vinylpicolinamide

embedded image

Step 1: 5-Cyano-3,4-dimethyl-6-vinylpicolinic acid

embedded image

To a solution of methyl 5-cyano-6-ethenyl-3,4-dimethylpyridine-2-carboxylate (130.0 mg, 0.600 mmol) in EtOH (4.682 mL) was added a solution of LiOH.H₂O (25.23 mg, 0.600 mmol) in water (2.809 mL) and the resulting mixture was stirred at r.t. for 1 hr. 1M aqueous HCl was added dropwise until pH=1 and the mixture was extracted with EtOAc. The phases were separated and the combined organic phases were washed with H₂O (1×), dried over Na₂SO₄and evaporated to dryness to afford the title compound (19 mg, 75%) as a white solid which was used without further purification. MS-ESI (m/z) calc'd for C₁₁H₁₁N₂O₂[M+H]⁺: 203.1. Found 203.3

Step 2: 5-Cyano-N-(3-cyclopropyl-1H-indazol-5-yl)-3,4-dimethyl-6-vinylpicolinamide

embedded image

To a solution of 5-cyano-3,4-dimethyl-6-vinylpicolinic acid (70.0 mg, 0.350 mmol), 3-cyclopropyl-1H-indazol-5-amine (70.92 mg, 0.380 mmol) and Et₃N (0.06 mL, 0.450 mmol) in MeCN (9.07 mL) was added HATU (131.63 mg, 0.350 mmol) in portions and the mixture was stirred at 25° C. for 1 hr. The reaction mixture was filtered and the solid was washed with MeCN (2×5 mL) and H₂O (2×5 mL), then dried under reduced pressure to afford the title compound (107 mg, 86%) as a pale yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 12.54 (s, 1H), 10.61 (s, 1H), 8.29 (d, J=1.8 Hz, 1H), 7.55 (dd, J=8.9, 1.9 Hz, 1H), 7.44 (d, J=8.9 Hz, 1H), 7.13 (dd, J=16.8, 10.6 Hz, 1H), 6.64 (dd, J=16.8, 1.8 Hz, 1H), 5.81 (dd, J=10.7, 1.9 Hz, 1H), 2.55 (s, 3H), 2.41 (s, 3H), 2.27-2.15 (m, 1H), 1.02-0.96 (m, 2H), 0.96-0.90 (m, 2H). MS-ESI (m/z) calc'd for C₂₁H₂₀N₅O [M+H]⁺: 358.2. Found 358.2.

Example 333: 5-Cyano-N-(3-cyclopropyl-1H-indazol-5-yl)-6-ethyl-3,4-dimethylpicolinamide

embedded image

To a suspension of 5-cyano-N-(3-cyclopropyl-1H-indazol-5-yl)-3,4-dimethyl-6-vinylpicolinamide (70.0 mg, 0.200 mmol) in EtOH (2 mL) was added 10% Pd/C (7.0 mg, 0.070 mmol) and the mixture was hydrogenated at r.t. and 1 atm for 4 hrs. The mixture was filtered through Celite and the filtrate was concentrated under reduced pressure to afford the title compound (55.6 mg, 79%) as a pale yellow solid which was used without further purification. ¹H NMR (400 MHz, DMSO-d₆) δ 12.54 (s, 1H), 10.52 (s, 1H), 8.28 (d, 1H), 7.54 (dd, J=8.9, 1.9 Hz, 1H), 7.43 (d, J=8.9 Hz, 1H), 3.00 (q, J=7.5 Hz, 2H), 2.54 (s, 3H), 2.39 (s, 3H), 2.27-2.16 (m, 1H), 1.32 (t, J=7.6 Hz, 3H), 1.06-0.86 (m, 4H). MS-ESI (m/z) calc'd for C₂₁H₂₂N₅O [M+H]⁺: 360.2. Found 360.3.

Example 334: 5-Cyano-6-cyclopropyl-N-(3-cyclopropyl-1H-indazol-5-yl)-3,4-dimethylpicolinamide

embedded image

Step 1: Methyl 5-cyano-6-cyclopropyl-3,4-dimethylpicolinate

embedded image

A mixture of methyl 6-chloro-5-cyano-3,4-dimethylpyridine-2-carboxylate (150.0 mg, 0.670 mmol), cyclopropylboronic acid (172.08 mg, 2 mmol), K₂CO₃(138.43 mg, 1 mmol) and tetrakis(triphenylphosphine)palladium(0) (77.16 mg, 0.070 mmol) in 1,4-dioxane (2.7 mL) was degassed with N₂and then stirred in a closed microwave vial at 110° C. overnight. The mixture was allowed to cool to r.t., diluted with water, and extracted with EtOAc. The organic layer was washed with brine, dried over Na₂SO₄, filtered, and the concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography using a 0-30% EtOAc/cyclohexane gradient eluent to afford the title compound (142 mg, 92%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 3.88 (s, 3H), 2.49 (s, 3H), 2.38 (tt, J=8.0, 4.6 Hz, 1H), 2.23 (s, 3H), 1.11 (dt, J=8.0, 3.2 Hz, 2H), 0.99 (dt, J=4.6, 3.1 Hz, 2H). MS-ESI (m/z) calc'd for C₁₃H₁₅N₂O₂[M+H]⁺: 231.1. Found 231.1.

Step 2: 5-Cyano-6-cyclopropyl-3,4-dimethylpicolinic acid

embedded image

To a solution of methyl 5-cyano-6-cyclopropyl-3,4-dimethylpicolinate (142.0 mg, 0.620 mmol) in EtOH (4.818 mL) was added a solution of LiOH.H₂O (25.88 mg, 0.620 mmol) in H₂O (2.891 mL) and the resulting mixture was stirred at r.t. for 1 hr. 1M aqueous HCl was added dropwise until pH=1. The reaction mixture was partitioned between H₂O and EtOAc, the phases were separated, the aqueous layer was extracted with EtOAc (2×). The combined organic phases were washed with H₂O (1×), dried over Na₂SO₄and evaporated to dryness to afford the title compound (19 mg, 75%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.69 (s, 1H), 2.47 (s, 3H), 2.41-2.32 (m, 1H), 2.24 (s, 3H), 1.14-1.07 (m, 2H), 1.04-0.97 (m, 2H). MS-ESI (m/z) calc'd for C₁₂H₁₃N₂O₂[M+H]⁺: 217.1. Found 217.1.

Step 3: 5-Cyano-6-cyclopropyl-N-(3-cyclopropyl-1H-indazol-5-yl)-3,4-dimethylpicolinamide

embedded image

To a solution of 5-cyano-6-cyclopropyl-3,4-dimethylpicolinic acid (40.0 mg, 0.180 mmol) and 3-cyclopropyl-1H-indazol-5-amine (37.9 mg, 0.200 mmol) and Et₃N (0.03 mL, 0.240 mmol) in MeCN (4.535 mL) was added HATU (70.33 mg, 0.180 mmol) in portions and the mixture was stirred at 25° C. for 1 hr. The reaction mixture was filtered and the solid was washed with MeCN (2×5 mL) and H₂O (2×5 mL), then dried under reduced pressure to afford the title compound (42.2 mg, 61%) as a pale yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 12.53 (s, 1H), 10.37 (s, 1H), 8.26 (s, 1H), 7.51 (d, J=8.8 Hz, 1H), 7.43 (d, J=8.9 Hz, 1H), 2.53 (s, 3H), 2.45-2.37 (m, 1H), 2.34 (s, 3H), 2.26-2.16 (m, 1H), 1.22-1.07 (m, 4H), 1.04-0.86 (m, 4H). MS-ESI (m/z) calc'd for C₂₂H₂₂N₅O [M+H]⁺: 372.2. Found 372.2.

Example 335: 5-Cyano-N-(3-(1-cyclopropyl-1H-pyrazol-4-yl)-1H-indazol-5-yl)-3,4-dimethylpicolinamide

embedded image

A mixture of 1-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (100 mg, 427.16 umol), 5-cyano-N-(3-iodo-1H-indazol-5-yl)-3,4-dimethylpicolinamide (137.09 mg, 328.59 umol), Pd(Amphos)Cl₂(23.27 mg, 32.86 umol, 23.27 uL) and AcOK (96.75 mg, 985.76 umol) in 10 mL of EtOH and 2.5 mL of H₂O was degassed and purged with N₂(3×) at 20° C., and then the mixture was stirred at 100° C. for 12 hrs under an N₂atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC using Method DJ to afford the title compound (22.19 mg, 17%) as a light yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 12.96 (br s, 1H), 10.66 (s, 1H), 8.90 (s, 1H), 8.38 (s, 1H), 8.25 (s, 1H), 7.90 (s, 1H), 7.75 (d, J=8.11 Hz, 1H), 7.53 (d, J=8.82 Hz, 1H), 3.84 (tt, J=3.78, 7.36 Hz, 1H), 2.56 (s, 3H), 2.47 (s, 3H), 1.12-1.16 (m, 2H), 0.98-1.04 (m, 2H). MS-(ESI) (m/z) calcd for C₂₂H₂₀N₇O (M+H)⁺: 398.2. Found 398.2.

Example A. LRRK2 Kinase Activity

LRRK2 kinase activity was measured using a LanthaScreen™ Kinase Activity Assay from ThermoFisher Scientific. Recombinant wild type or G2019S-LRRK2 protein (Life Technologies, PR8604B or PV4881, respectively), was incubated with a fluorescein-labeled peptide substrate called LRRKtide that is based upon ezrin/radixin/moesin (ERM) (Life Technologies, PV4901) in the presence of ATP and serially diluted compound. After an incubation period of 1 hr, the phosphotransferase activity was stopped and a terbium-labelled anti-pERM antibody (Life Technologies, PV4899) was added to detect the phosphorylation of LRRKtide by measuring the time resolved-Forster resonant energy transfer (TR-FRET) signal from the terbium label on the antibody to the fluorescein tag on LRRKtide, expressed as the 520 nm/495 nm emission ratio. Compound-dependent inhibition of the TR-FRET signal was used to generate a concentration-response curve for IC₅₀determination.

The assay was carried out under the following protocol conditions: 1 mM compound in DMSO was serially diluted 1:3, 11 points in DMSO with a Biomek FX and 0.1 μL of the diluted compound was subsequently stamped into the assay plate (384-well format Lumitrac 200, Greiner, 781075) with an Echo Labcyte such that the final compound concentration in the assay was 10 μM to 169 μM. Subsequently, 5 μL of 2× kinase solution (2.9 nM final concentration) was added to the assay plate in assay buffer composed of 50 mM Tris pH 8.5 (Sigma, T6791), 5 mM MgCl₂(Fluka, 63020), 1 mM EGTA (Sigma, E3889), 0.01% BRIJ-35 (Sigma, P1254) and 2 mM DTT. The reaction was started by addition of 2×ATP/LRRKtide solution in assay buffer such that the final concentration was 400 nM LRRKtide and 25 μM ATP. After 60 min incubation at room temperature, the reaction was stopped by addition of 10 μL of 2× stop solution containing a final concentration of 2 nM anti-pERM antibody and 10 mM EDTA. After a 30 min incubation at RT, the TR-FRET signal was measured on a Wallac 2104 EnVision multilabel reader at an excitation wavelength of 340 nm and reading emission at 520 nm and 495 nm. The ratio of the 520 nm and 495 nm emission was used to analyze the data.

The Results of the LRRK2 kinase activity assay are shown in Table A-1 and Table A-2. Data is displayed as follows: + is IC₅₀≤100 nM; ++ is 100 nM<IC₅₀≤1,000 nM; and +++ is 1,000 nM<IC₅₀≤10,000 nM.

TABLE A-I

LRRK2 Kinase Activity Assay

Example
LRRK2 WT IC₅₀
LRRK2 G2019S

No.
(nM)
IC₅₀(nM)

1
+
+

2
+
+

3
+
+

4
+
+

5
+
+

6
+
+

7
+
+

8
++
+

9
++
+

10
+
+

11
++
+

12
++
+

13
++
+

14
++
+

15
++
+

16
++
+

17
+
+

18
+
+

19
+
+

20
++
+

21
+
+

22
+
+

23
++
+

24
++
++

25
++
++

26
++
+

27
++
+

28
++
+

29
++
+

30
++
+

31
++
+

32
++
+

33
+
+

34
+
+

35
>10,000
++

36
>10,000
+

37
++
+

38
++
+

39
+++
+++

40
++
+

41
++
+

42
++
+

43
++
+

44
+
+

45
+
+

46
++
+

47
++
+

48
++
+

49
++
+

50
++
+

51
++
+

52
++
+

53
++
+

54
+++
++

55
++
+

56
++
+

57
+
+

58
++
+

59
++
+

60
+++
++

61
++
+

62
++
+

63
++
+

64
++
+

65
+
+

66
++
++

67
+
+

68
++
+

69
++
+

70
++
+

71
++
+

72
+
+

73
++
+

74
+
+

75
+
+

76
+
+

77
+
+

78
++
+

79
++
++

80
+++
++

81
+
+

82
+
+

83
++
+

84
++
+

85
+++
+

86
+
+

87
++
+

88
+++
++

89
+
+

90
+
+

91
+
+

92
++
+

93
++
++

94
++
+

95
+
+

96
++
++

97
++
+

98
>10,000
+++

99
+++
++

100
+
+

TABLE A-2

Example
LRRK2 WT
LRRK2 G2019S

No.
IC50 (nM)
IC50 (nM)

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
>10,000
>10,000

260
>10,000
+++

261
+++
+

262
+++
+++

263
+++
++

264
+++
++

265
+++
++

266
++
+

267
++
+

268
+++
++

269
>10,000
+++

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
>10,000
>10,000

324
+
+

325
+++
+

326
++
+

327
+
+

328
+
+

329
+
+

330
+
+

331
+
+

332
++
+

333
++
+

334
++
+

335
+
+

Various modifications of the invention, in addition to those described herein, will be apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. Each reference, including all patent, patent applications, and publications, cited in the present application is incorporated herein by reference in its entirety.

Number	Name	Date	Kind
6258822	Geyer	Jul 2001	B1
7872039	Dorsch et al.	Jan 2011	B2
10005720	Sexton et al.	Jun 2018	B2
20030134836	Elbaum et al.	Jul 2003	A1
20030203922	Patel et al.	Oct 2003	A1
20060270686	Kelly et al.	Nov 2006	A1
20080280891	Kelly et al.	Nov 2008	A1
20090054397	Ohi et al.	Feb 2009	A1
20090270394	Galemmo et al.	Oct 2009	A1
20110263612	Whitten et al.	Oct 2011	A1
20130109661	Hermann et al.	May 2013	A1
20140154805	Shi et al.	Jun 2014	A1
20140200227	Xue et al.	Jul 2014	A1
20160024071	Garofalo et al.	Jan 2016	A1
20160113931	Lee et al.	Apr 2016	A1
20210261553	Garofalo et al.	Aug 2021	A1
20210386721	Zhu et al.	Dec 2021	A1

Number	Date	Country
107176932	Jun 2020	CN
102004051277	Apr 2006	DE
102005014089	Sep 2006	DE
3889150	Oct 2021	EP
2889526	Feb 2012	FR
WO 9730119	Aug 1997	WO
WO 9809961	Mar 1998	WO
WO 2000006173	Feb 2000	WO
WO 2002055501	Jul 2002	WO
WO 2002066470	Aug 2002	WO
WO 2002068406	Sep 2002	WO
WO 2004078723	Sep 2004	WO
WO 2004078746	Sep 2004	WO
WO 2004098518	Nov 2004	WO
WO 2004108133	Dec 2004	WO
WO 2005074642	Aug 2005	WO
WO 2005123688	Dec 2005	WO
WO 2006032851	Mar 2006	WO
WO 2006053109	May 2006	WO
WO 2006053227	May 2006	WO
WO 2006081230	Aug 2006	WO
WO 2006099379	Sep 2006	WO
WO 2006100100	Sep 2006	WO
WO 2006132914	Dec 2006	WO
WO 2007017577	Feb 2007	WO
WO 2007048070	Apr 2007	WO
WO 2007058626	May 2007	WO
WO 2007087443	Aug 2007	WO
WO 2007093402	Aug 2007	WO
WO 2007095124	Aug 2007	WO
WO 2007109362	Sep 2007	WO
WO 2007112093	Oct 2007	WO
WO 2008048991	Apr 2008	WO
WO 2008137027	Nov 2008	WO
WO 2009024341	Feb 2009	WO
WO 2009035951	Mar 2009	WO
WO 2009038775	Mar 2009	WO
WO 2009038784	Mar 2009	WO
WO 2009046842	Apr 2009	WO
WO 2009062.258	May 2009	WO
WO 2009061730	May 2009	WO
WO 2009073788	Jun 2009	WO
WO 2009112445	Sep 2009	WO
WO 2009158571	Dec 2009	WO
WO 2010010190	Jan 2010	WO
WO 2010029300	Mar 2010	WO
WO 2010112124	Oct 2010	WO
WO 2011035324	Mar 2011	WO
WO 2011039735	Apr 2011	WO
WO 2011123937	Oct 2011	WO
WO 2011133750	Oct 2011	WO
WO 2011133882	Oct 2011	WO
WO 2011133920	Oct 2011	WO
WO 2011137219	Nov 2011	WO
WO 2012025638	Mar 2012	WO
WO 2012036573	Mar 2012	WO
WO 2012135631	Oct 2012	WO
WO 2012135799	Oct 2012	WO
WO 2012162254	Nov 2012	WO
WO 2013102145	Jul 2013	WO
WO 2013106432	Jul 2013	WO
WO 2013151938	Oct 2013	WO
WO 2014134774	Sep 2014	WO
WO 2014150981	Sep 2014	WO
WO 2014165816	Oct 2014	WO
WO 2014194127	Dec 2014	WO
WO 2014195400	Dec 2014	WO
WO 2014202741	Dec 2014	WO
WO 2015026683	Feb 2015	WO
WO 2015015378	Feb 2015	WO
WO 2015095701	Jun 2015	WO
WO 2016036586	Mar 2016	WO
WO 2016081599	May 2016	WO
WO 2016083433	Jun 2016	WO
WO 2016133935	Aug 2016	WO
WO 2016144702	Sep 2016	WO
WO 2017012576	Jan 2017	WO
WO 2017027400	Feb 2017	WO
WO 2017049172	Mar 2017	WO
WO 2017049409	Mar 2017	WO
WO 2017157885	Sep 2017	WO
WO 2017163078	Sep 2017	WO
WO 2018115383	Jun 2018	WO
WO 2018137573	Aug 2018	WO
WO 2018137607	Aug 2018	WO
WO 2018137619	Aug 2018	WO
WO 2018140513	Aug 2018	WO
WO 2018208985	Dec 2018	WO
WO 2019002624	Jan 2019	WO
WO 2019036534	Feb 2019	WO
WO 2019074810	Apr 2019	WO
WO 2019074809	Apr 2019	WO
WO 2019087129	May 2019	WO
WO 2019222173	Nov 2019	WO
WO 2020092136	May 2020	WO
WO 2020135513	Jul 2020	WO
WO 2020191261	Sep 2020	WO
WO 202.0228649	Nov 2020	WO
WO 2020247298	Dec 2020	WO
WO 2021050688	Mar 2021	WO
WO 2021088859	May 2021	WO
WO 2021222789	Nov 2021	WO

	Number	Date	Country
	62937979	Nov 2019	US
	62872891	Jul 2019	US

Indazoles and azaindazoles as LRRK2 inhibitors

Information

Patent Number

Date Filed

Date Issued

Inventors

Original Assignees

Examiners

Agents

CPC

Field of Search

CPC

International Classifications

Abstract

Description

Claims

US Referenced Citations (17)

Foreign Referenced Citations (102)

Non-Patent Literature Citations (36)

Provisional Applications (2)

Entry
Atzrodt et al., “The renaissance of H/D exchange,” Angew. Chem. Int. Ed., 2007, 46(41):7744-7765.
Berge et al., “Pharmaceutical Salts,” J Pham Sci., 1977, 66(1):1-19.
CAS Accession No. 1808785-20-7, dated Sep. 29, 2015, 10 pages.
Fell et al., “Mli-2, a potent, selective, and centrally active compound for exploring the therapeutic potential and safety of LRRK2 kinase inhibition,” J Pharma Exp Ther., 2015, 355(3):397-409.
Herdemann et al., “Optimization of ITK inhibitors through successive iterative design cycles,” Bioorganic & Medicinal Chemistry letters, 2011, 21(6):1852-1856.
Kaela et al., “The G2019S mutation in LRRK2 imparts resiliency to kinase inhibition,” Experimental Neurology, 2018, 309:1-13.
Kerekes et al., “Aurora kinase inhibitors based on the imidazo[1,2-a]pyrazine core: fluorine and deuterium incorporation improve oral absorption and exposure,” J Med Chem., 2011, 54(1):201-210.
Lennox et al., “Selection of boron reagents for Suzuki-Miyaura coupling,” Chem. Soc. Rev. 2014, 43:412-43.
Lewis et al., “LRRK2 and human disease: a complicated question or a question of complexes?,” Sci. Signal., 2012, 5(207): pe2.
PCT International Preliminary Report on Patentability in International Appln. No. PCT/US2019/032163, dated Nov. 17, 2020, 7 pages.
PCT International Search Report and Written Opinion in International Appln. No. PCT/US2019/032163, dated Aug. 2, 2019, 11 pages.
PCT International Search Report and Written Opinion in International Appln. No. PCT/US2020/023763, dated May 12, 2020, 10 pages.
PCT International Search Report and Written Opinion in International Appln. No. PCT/US2020/041506, dated Sep. 24, 2020, 15 pages.
Peturssion et al., “Protecting Groups in Carbohydrate Chemistry,” J Chem. Educ., 1997, 74(11):1297.
Simon-Sanchez et al., “LRRK2 is expressed in areas affected by Parkinson's disease in the adult mouse brain,” Eur. J Neurosci. 2006, 23(3):659.
STN Accession No. 2129527-41-7, dated Sep. 22, 2017, 1 page.
STN Accession No. 2129840-05-5, dated Sep. 22, 2017, 1 page.
STN Accession No. 2129896-08-6, dated Sep. 22, 2017, 1 page.
STN Accession No. 2190570-67-1, dated Mar. 13, 2018, 4 pages.
STN Accession No. 2191450-42-5, dated Mar. 14, 2018, 10 pages.
STN Accession No. 2191450-42-5, dated Mar. 14, 2018, 4 pages.
STN Accession No. 2221963-04-6, dated Apr. 30, 2018, 8 pages.
STN Accession No. 2253752-25-7, dated Dec. 18, 2018, 23 pages.
STN Accession No. 2253752-25-7, dated Dec. 18, 2018, 27 pages.
STN Accession No. 2253892-33-8, dated Dec. 19, 2018, 13 pages.
STN Accession No. 2253892-33-8, dated Dec. 19, 2018, 6 pages.
STN Accession No. 2379707-93-2, dated Nov. 14, 2019, 17 pages.
STN Accession No. 45703-61-614, dated Jul. 19, 2013, 1 page.
STN International Transcript, dated May 16, 2019, 21 pages.
STN International Transcript, dated Nov. 14, 2018, 21 pages.
Suzuki, “Recent advances in the cross-coupling reactions of organoboron derivatives with organic electrophiles, 1995-1998,” J. Organomet. Chem, 1999, 57:147-168.
Valeur et al., “Amide bond formation: beyond the myth of coupling reagents,” Chem. Soc. Rev., 2009, 38(2):606-631.
Xu et al., “Design, synthesis and biological evaluation of deuterated nintedanib for improving pharmacokinetic properties,” J Label Compd Radiopharm., 2015, 58(7):308-312.
International Preliminary Report on Patentability in International Appln. No. PCT/US2020/023763, dated Sep. 16, 2021, 8 pages.
International Search Report and Written Opinion in International Appln. No. PCT/US2021/021054, dated Apr. 16, 2021, 12 pages.
International Preliminary Report on Patentability in International Appln. No. PCT/US2020/041506, dated Jan. 20, 2022, 7 pages.