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Title:
PYRROLIDINYL-BASED COMPOUNDS
Document Type and Number:
WIPO Patent Application WO/2021/067266
Kind Code:
A1
Abstract:
Disclosed herein are pyrrolidinyl-based compounds, together with pharmaceutical compositions and methods of ameliorating and/or treating a cancer described herein with one or more of the compounds described herein.

Inventors:
BUNKER KEVIN (US)
KAHRAMAN MEHMET (US)
HUANG PETER (US)
HEGDE SAYEE (US)
SIT RAKESH (US)
SUMMERS CLAIRE (US)
Application Number:
PCT/US2020/053270
Publication Date:
April 08, 2021
Filing Date:
September 29, 2020
Export Citation:
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Assignee:
RECURIUM IP HOLDINGS LLC (US)
International Classes:
C07D401/14; A61K31/4427; A61K31/496; A61P35/00; C07D417/14
Attorney, Agent or Firm:
MILLER, Kimberly, J. (US)
Download PDF:
Claims:
WHAT IS CLAIMED IS: 1. A compound of Formula (I), or a pharmaceutically acceptable salt thereof: wherein: ring Ar is a phenyl, a pyridinyl or a pyrimidinyl; A1 is an optionally substituted phenyl or an optionally substituted heteroaryl; each R1 is independently selected from the group consisting of –OR4A, a halogen, an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted mono-substituted amino group and an optionally substituted di-substituted amino group, wherein R4A is an optionally substituted alkyl or an optionally substituted cycloalkyl; R2A and R2B are each independently hydrogen or deuterium; R3 is haloalkyl, an optionally substituted alkyl or an optionally substituted cycloalkyl; X1, X2 and X3 are each independently N or CR5, wherein each R5 is independently hydrogen, a halogen or an optionally substituted alkyl; X4 is C, CH or N, provided that when X4 is C, then “ is a double bond, and when X4 is CH or N, then “ ” is a single bond; and m is 1 or 2; wherein at least one of R3 and R4A is an optionally substituted cycloalkyl. 2. The compound of Claim 1, or a pharmaceutically acceptable salt thereof, wherein m is 1.

3. The compound of Claim 1, or a pharmaceutically acceptable salt thereof, wherein m is 2. 4. The compound of any one of Claims 1-3, or a pharmaceutically acceptable salt thereof, wherein ring Ar is phenyl. 5. The compound of any one of Claims 1-3, or a pharmaceutically acceptable salt thereof, wherein ring Ar is pyridinyl. 6. The compound of any one of Claims 1-3, or a pharmaceutically acceptable salt thereof, wherein ring Ar is pyrimidinyl. 7. The compound of any one of Claims 1-6, or a pharmaceutically acceptable salt thereof, wherein A1 is an optionally substituted phenyl. 8. The compound of Claim 7, or a pharmaceutically acceptable salt thereof, wherein A1 is an unsubstituted phenyl. 9. The compound of Claim 7, or a pharmaceutically acceptable salt thereof, wherein A1 is a substituted phenyl. 10. The compound of any one of Claims 1-6, or a pharmaceutically acceptable salt thereof, wherein A1 is an optionally substituted heteroaryl. 11. The compound of Claim 10, or a pharmaceutically acceptable salt thereof, wherein A1 is an unsubstituted heteroaryl. 12. The compound of Claim 10, or a pharmaceutically acceptable salt thereof, wherein A1 is a substituted heteroaryl. 13. The compound of any one of Claims 10-12, wherein A1 is a thienyl, a thiazole, a 1,3,4-thiadiazole or pyridinyl. 14. The compound of any one of Claims 1-13, or a pharmaceutically acceptable salt thereof, wherein R1 is –OR4A. 15. The compound of Claim 14, or a pharmaceutically acceptable salt thereof, wherein R4A is an optionally substituted alkyl. 16. The compound of Claim 14, or a pharmaceutically acceptable salt thereof, wherein R4A is an optionally substituted cycloalkyl. 17. The compound of Claim 16, or a pharmaceutically acceptable salt thereof, wherein R4A is an optionally substituted cyclopropyl, an optionally substituted cyclobutyl, an optionally substituted cyclopentyl, an optionally substituted bicyclo[1.1.1]pentyl or an optionally substituted cyclohexyl. 18. The compound of Claim 14, or a pharmaceutically acceptable salt thereof, wherein R4A is an unsubstituted cycloalkyl. 19. The compound of Claim 18, or a pharmaceutically acceptable salt thereof, wherein R4A is an unsubstituted cyclopropyl, an unsubstituted cyclobutyl, an unsubstituted cyclopentyl, an unsubstituted bicyclo[1.1.1]pentyl or an unsubstituted cyclohexyl. 20. The compound of any one of Claims 1-13, or a pharmaceutically acceptable salt thereof, wherein m is 1. 21. The compound of any one of Claims 1-13, or a pharmaceutically acceptable salt thereof, wherein m is 2. 22. The compound of any one of Claims 20-21, or a pharmaceutically acceptable salt thereof, wherein R1 is a halogen. 23. The compound of any one of Claims 20-21, or a pharmaceutically acceptable salt thereof, wherein R1 is an optionally substituted alkyl. 24. The compound of any one of Claims 20-21, or a pharmaceutically acceptable salt thereof, wherein R1 is an optionally substituted cycloalkyl. 25. The compound of Claim 24, or a pharmaceutically acceptable salt thereof, wherein R1 is a substituted cycloalkyl. 26. The compound of Claim 25, or a pharmaceutically acceptable salt thereof, wherein R1 is an optionally substituted cyclopropyl, an optionally substituted cyclobutyl, an optionally substituted cyclopentyl, an optionally substituted bicyclo[1.1.1]pentyl or an optionally substituted cyclohexyl. 27. The compound of Claim 24, or a pharmaceutically acceptable salt thereof, wherein R1 is an unsubstituted cycloalkyl. 28. The compound of Claim 27, or a pharmaceutically acceptable salt thereof, wherein R1 is an unsubstituted cyclopropyl, an unsubstituted cyclobutyl, an unsubstituted cyclopentyl, an unsubstituted bicyclo[1.1.1]pentyl or an unsubstituted cyclohexyl. 29. The compound of any one of Claims 1-13, or a pharmaceutically acceptable salt thereof, wherein R1 is an optionally substituted mono-substituted amino group.

30. The compound of any one of Claims 1-13, or a pharmaceutically acceptable salt thereof, wherein R1 is an optionally substituted di-substituted amino group. 31. The compound of any one of Claims 20-30, or a pharmaceutically acceptable salt thereof, wherein A1 is selected from the group consisting of: , 32. The compound of any one of Claims 1-31, or a pharmaceutically acceptable salt thereof, wherein at least one of R2A and R2B is deuterium. 33. The compound of any one of Claims 1-31, or a pharmaceutically acceptable salt thereof, wherein each R2A and R2B is hydrogen. 34. The compound of any one of Claims 1-33, or a pharmaceutically acceptable salt thereof, wherein one, two or three of X1, X2 and X3 is CR5. 35. The compound of any one of Claims 1-33, or a pharmaceutically acceptable salt thereof, wherein each of X1, X2 and X3 is CR5. 36. The compound of Claim 34 or 35, or a pharmaceutically acceptable salt thereof, wherein R5 is hydrogen. 37. The compound of Claim 34 or 35, or a pharmaceutically acceptable salt thereof, wherein R5 is an optionally substituted alkyl. 38. The compound of Claim 34 or 35, or a pharmaceutically acceptable salt thereof, wherein R5 is a halogen. 39. The compound of any one of Claims 1-33, or a pharmaceutically acceptable salt thereof, wherein one, two or three of X1, X2 and X3 is N. 40. The compound of any one of Claims 1-33, or a pharmaceutically acceptable salt thereof, X1 is CR5, wherein R5 is halogen; and each of X2 and X3 is CR5, wherein each R5 is hydrogen.

41. The compound of any one of Claims 1-40, or a pharmaceutically acceptable salt thereof, wherein R3 is an optionally substituted alkyl. 42. The compound of Claim 41, or a pharmaceutically acceptable salt thereof, wherein R3 is an unsubstituted C1-6 alkyl. 43. The compound of Claim 42, or a pharmaceutically acceptable salt thereof, wherein R3 is methyl. 44. The compound of any one of Claims 1-40, or a pharmaceutically acceptable salt thereof, wherein R3 is an optionally substituted cycloalkyl. 45. The compound of Claim 44, or a pharmaceutically acceptable salt thereof, wherein R3 is a substituted cycloalkyl. 46. The compound of Claim 45, or a pharmaceutically acceptable salt thereof, wherein R3 is an optionally substituted cyclopropyl, an optionally substituted cyclobutyl, an optionally substituted cyclopentyl, an optionally substituted bicyclo[1.1.1]pentyl or an optionally substituted cyclohexyl. 47. The compound of Claim 44, or a pharmaceutically acceptable salt thereof, wherein R3 is an unsubstituted cycloalkyl. 48. The compound of Claim 47, or a pharmaceutically acceptable salt thereof, wherein R3 is an unsubstituted cyclopropyl, an unsubstituted cyclobutyl, an unsubstituted cyclopentyl, an unsubstituted bicyclo[1.1.1]pentyl or an unsubstituted cyclohexyl. 49. The compound of any one of Claims 1-40, or a pharmaceutically acceptable salt thereof, wherein R3 is haloalkyl.

50. The compound of Claim 1, wherein the compound is also represented by at least one of the following Formulae:

or a pharmaceutically acceptable salt of any of the foregoing. 51. The compound of Claim 1, selected from the group consisting of , , and , or a pharmaceutically acceptable salt of any of the foregoing. 52. The compound of Claim 1, selected from the group consisting of pharmaceutically acceptable salt of any of the foregoing. 53. A pharmaceutical composition comprising an effective amount of a compound of any one of Claims 1-52, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, excipient, or combination thereof. 54. A method for ameliorating or treating a cancer comprising administering to a subject in need thereof an effective amount of a compound of any one of Claims 1-52, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of Claim 53, wherein the cancer is selected from the group consisting of a lung cancer, a pancreatic cancer, a colon cancer, a myeloid leukemia, a thyroid cancer, myelodysplastic syndrome (MDS), a bladder carcinoma, an epidermal carcinoma, a melanoma, a breast cancer, a prostate cancer, a head and neck cancer, an ovarian cancer, a brain cancer, a cancer of mesenchymal origin, a sarcoma, a tetracarcinoma, a neuroblastoma, a kidney carcinoma, a hepatoma, a non-Hodgkin's lymphoma, a multiple myeloma, an anaplastic thyroid carcinoma and neurofibromatosis. 55. A method for inhibiting replication of a malignant growth or a tumor comprising contacting the growth or the tumor with an effective amount of a compound of any one of Claims 1-52, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of Claim 53, wherein the malignant growth or tumor is due to a cancer that is selected from the group consisting of a lung cancer, a pancreatic cancer, a colon cancer, a myeloid leukemia, a thyroid cancer, myelodysplastic syndrome (MDS), a bladder carcinoma, an epidermal carcinoma, a melanoma, a breast cancer, a prostate cancer, a head and neck cancer, an ovarian cancer, a brain cancer, a cancer of mesenchymal origin, a sarcoma, a tetracarcinoma, a neuroblastoma, a kidney carcinoma, a hepatoma, a non-Hodgkin's lymphoma, a multiple myeloma, an anaplastic thyroid carcinoma and neurofibromatosis. 56. A method for ameliorating or treating a cancer comprising contacting a malignant growth or a tumor with an effective amount of a compound of any one of Claims 1-52, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of Claim 53, wherein the malignant growth or tumor is due to a cancer that is selected from the group consisting of a lung cancer, a pancreatic cancer, a colon cancer, a myeloid leukemia, a thyroid cancer, myelodysplastic syndrome (MDS), a bladder carcinoma, an epidermal carcinoma, a melanoma, a breast cancer, a prostate cancer, a head and neck cancer, an ovarian cancer, a brain cancer, a cancer of mesenchymal origin, a sarcoma, a tetracarcinoma, a neuroblastoma, a kidney carcinoma, a hepatoma, a non-Hodgkin's lymphoma, a multiple myeloma, an anaplastic thyroid carcinoma and neurofibromatosis.

57. A method for inhibiting the activity of ERK1 and/or ERK2 comprising providing an effective amount of a compound of any one of Claims 1-52, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of Claim 53 to a sample comprising a cancer cell, wherein the cancer cell is selected from the group consisting of a lung cancer, a pancreatic cancer, a colon cancer, a myeloid leukemia, a thyroid cancer, myelodysplastic syndrome (MDS), a bladder carcinoma, an epidermal carcinoma, a melanoma, a breast cancer, a prostate cancer, a head and neck cancer, an ovarian cancer, a brain cancer, a cancer of mesenchymal origin, a sarcoma, a tetracarcinoma, a neuroblastoma, a kidney carcinoma, a hepatoma, a non-Hodgkin's lymphoma, a multiple myeloma, an anaplastic thyroid carcinoma and neurofibromatosis.

58. Use of an effective amount of a compound of any one of Claims 1-52, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of Claim 53 in the manufacture of a medicament for ameliorating or treating a cancer, wherein the cancer is selected from the group consisting of a lung cancer, a pancreatic cancer, a colon cancer, a myeloid leukemia, a thyroid cancer, myelodysplastic syndrome (MDS), a bladder carcinoma, an epidermal carcinoma, a melanoma, a breast cancer, a prostate cancer, a head and neck cancer, an ovarian cancer, a brain cancer, a cancer of mesenchymal origin, a sarcoma, a tetracarcinoma, a neuroblastoma, a kidney carcinoma, a hepatoma, a non-Hodgkin's lymphoma, a multiple myeloma, an anaplastic thyroid carcinoma and neurofibromatosis.

59. Use of an effective amount of a compound of any one of Claims 1-52, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of Claim 53 in the manufacture of a medicament for inhibiting replication of a malignant growth or a tumor, wherein the malignant growth or tumor is due to a cancer that is selected from the group consisting of a lung cancer, a pancreatic cancer, a colon cancer, a myeloid leukemia, a thyroid cancer, myelodysplastic syndrome (MDS), a bladder carcinoma, an epidermal carcinoma, a melanoma, a breast cancer, a prostate cancer, a head and neck cancer, an ovarian cancer, a brain cancer, a cancer of mesenchymal origin, a sarcoma, a tetracarcinoma, a neuroblastoma, a kidney carcinoma, a hepatoma, a non-Hodgkin's lymphoma, a multiple myeloma, an anaplastic thyroid carcinoma and neurofibromatosis.

60. Use of an effective amount of a compound of any one of Claims 1-52, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of Claim 53 in the manufacture of a medicament for ameliorating or treating a cancer comprising contacting a malignant growth or a tumor with an effective amount of the compound, wherein the malignant growth or a tumor is due to a cancer selected from the group consisting of a lung cancer, a pancreatic cancer, a colon cancer, a myeloid leukemia, a thyroid cancer, myelodysplastic syndrome (MDS), a bladder carcinoma, an epidermal carcinoma, a melanoma, a breast cancer, a prostate cancer, a head and neck cancer, an ovarian cancer, a brain cancer, a cancer of mesenchymal origin, a sarcoma, a tetracarcinoma, a neuroblastoma, a kidney carcinoma, a hepatoma, a non-Hodgkin's lymphoma, a multiple myeloma, an anaplastic thyroid carcinoma and neurofibromatosis.

61. Use of an effective amount of a compound of any one of Claims 1-52, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of Claim 53 in the manufacture of a medicament for inhibiting the activity of ERK1 and/or ERK2 by providing an effective amount of the compound, salt or composition to a sample comprising a cancer cell, wherein the cancer cell is selected from the group consisting of a lung cancer, a pancreatic cancer, a colon cancer, a myeloid leukemia, a thyroid cancer, myelodysplastic syndrome (MDS), a bladder carcinoma, an epidermal carcinoma, a melanoma, a breast cancer, a prostate cancer, a head and neck cancer, an ovarian cancer, a brain cancer, a cancer of mesenchymal origin, a sarcoma, a tetracarcinoma, a neuroblastoma, a kidney carcinoma, a hepatoma, a non-Hodgkin's lymphoma, a multiple myeloma, an anaplastic thyroid carcinoma and neurofibromatosis.

Description:
PYRROLIDINYL-BASED COMPOUNDS

INCORPORATION BY REFERENCE TO ANY PRIORITY APPLICATIONS [0001] Any and all applications for which a foreign or domestic priority claim is identified, for example, in the Application Data Sheet or Request as filed with the present application, are hereby incorporated by reference under 37 CFR 1.57, and Rules 4.18 and 20.6., including U.S. Provisional Application No. 62/908,736, filed October 1, 2019, which is hereby incorporated by reference in its entirety.

BACKGROUND

Field

[0002] The present application relates to the fields of chemistry, biochemistry and medicine. More particularly, disclosed herein are pyrrolidinyl-based compounds, together with pharmaceutical compositions, and methods of synthesizing the same. Also disclosed herein are methods of ameliorating and/or treating a cancer described herein with one or more of the compounds described herein.

Description

[0003] The RAS/MAPK pathway is activated in response to growth factor binding and regulates cellular growth, differentiation and survival in a variety of cell types. Activation of this pathway occurs via a cascade of protein phosphorylation events, which culminates in the phosphorylation and activation of ERK (ERK1 and/or ERK2). ERK lies downstream from the small GTPase RAS and the protein kinases RAF and MEK in the RAS/MAPK pathway. Following its activation by RAS, RAF phosphorylates MEK, which in turn phosphorylates ERK. Activated ERK phosphorylates other substrates that govern the transcriptional output of cells.

SUMMARY

[0004] Some embodiments disclosed herein relate to a compound of Formula (I), or a pharmaceutically acceptable salt thereof. [0005] Some embodiments described herein relate to a pharmaceutical composition, that can include an effective amount a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0006] Some embodiments described herein relate to a method for ameliorating and/or treating a cancer described herein that can include administering an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) to a subject having a cancer described herein.

[0007] Some embodiments described herein relate to a use of an effective amount of a compound compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for ameliorating or treating a cancer described herein.

[0008] Some embodiments described herein relate to a method for inhibiting replication of a malignant growth or a tumor that can include contacting the growth or the tumor with an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof), wherein the malignant growth or tumor is due to a cancer described herein.

[0009] Some embodiments described herein relate to the use of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for inhibiting replication of a malignant growth or a tumor, wherein the malignant growth or tumor is due to a cancer described herein.

[0010] Some embodiments described herein relate to a method for ameliorating or treating a cancer described herein that can include contacting a malignant growth or a tumor with an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof).

[0011] Some embodiments described herein relate to the use of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for ameliorating or treating a cancer described herein by contacting a malignant growth or a tumor with an effective amount of the compound.

[0012] Some embodiments described herein relate to a method for inhibiting the activity of ERK1 and/or ERK2 that can include providing an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) to a sample that includes a cancer cell from a cancer described herein.

[0013] Some embodiments described herein relate to the manufacture of a medicament for inhibiting the activity of ERK1 and/or ERK2 by providing an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) to a sample comprising a cancer cell of a cancer described herein.

[0014] These and other embodiments are described in greater detail below.

DETAILED DESCRIPTION

[0015] Inhibition of ERK can have therapeutic effects in the treatment of certain types of cancer. It has been shown that the RAS/MAPK/ERK pathway can be aberrantly activated in certain tumors via activating mutations in RAS and BRAF, and this activation has been implicated in the growth and pathologic behavior of certain cancer cells. Constitutive activation of this pathway has been observed in human cancers and has been associated with high rates of cancer cell proliferation. Tumor cells that harbor either BRAF or RAS mutations are generally dependent on the activity of the altered proteins for growth and survival, a phenomenon described as “oncogene addiction.” Activating mutations of RAS have been reported in ~30% of all cancers, with some, such as pancreatic and colon cancer, harboring mutation rates of ~90% and ~50%, respectively. RAS mutations have been identified in ~15% of melanomas and ~30% of NSCLCs (non-small cell lung cancers). BRAF somatic mutations have been identified in 50–70% of malignant melanomas, where all mutations are within the kinase domain and a single substitution (V600E) accounts for 80% of mutations. Activating BRAF mutations have also been documented in a variety of human cancers, including colorectal cancer (~10%), NSCLC (2-3%), and thyroid cancer (~36%). The high frequency of mutations makes targeting this pathway a strategy for cancer therapy. Accordingly, there is a large unmet medical need for improved therapies in these diseases especially in the advanced, refractory setting. [0016] Provided herein are compounds that can inhibit the kinase activity of ERKl and/or the kinase activity of ERK2. The compounds described herein can also inhibit the phosphorylation of ERKl and ERK2, and thus can be ERK inhibitors (for example, ERK1 inhibitors and/or ERK2 inhibitors). The compounds described herein may also effectively inhibit MAPK signaling through a dual mechanism, via inhibiting both the phosphorylation and activation of ERK by MEK, in addition to inhibiting ERK phosphorylation of RSK. As ERK inhibitors, the compounds described herein can be used to ameliorate and/or treat a variety of cancers, such as, melanoma, pancreatic cancer, thyroid cancer, colon/colorectal cancer and lung cancer. Definitions [0017] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art. All patents, applications, published applications and other publications referenced herein are incorporated by reference in their entirety unless stated otherwise. In the event that there are a plurality of definitions for a term herein, those in this section prevail unless stated otherwise. [0018] As used herein, any "R" group(s) such as, without limitation, R 1 , R 2a , R 2b , R 3 , R 4a , R 5 , X 1 , X 2 , X 3 , X 4 , A 1 and Ar, represent substituents that can be attached to the indicated atom. An R group may be substituted or unsubstituted. If two "R" groups are described as being "taken together" the R groups and the atoms they are attached to can form a cycloalkyl, cycloalkenyl, aryl, heteroaryl or heterocycle. For example, without limitation, if R a and R b of an NR a R b group are indicated to be "taken together," it means that they are covalently bonded to one another to form a ring: In addition, if two “R” groups are described as being “taken together” with the atom(s) to which they are attached to form a ring as an alternative, the R groups are not limited to the variables or substituents defined previously. [0019] Whenever a group is described as being “optionally substituted” that group may be unsubstituted or substituted with one or more of the indicated substituents. Likewise, when a group is described as being “unsubstituted or substituted” if substituted, the substituent(s) may be selected from one or more the indicated substituents. If no substituents are indicated, it is meant that the indicated “optionally substituted” or “substituted” group may be substituted with one or more group(s) individually and independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, acylalkyl, hydroxy, alkoxy, alkoxyalkyl, aminoalkyl, amino acid, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl), heterocyclyl(alkyl), hydroxyalkyl, acyl, cyano, halogen, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, azido, nitro, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, an amino, a mono-substituted amino group and a di-substituted amino group. [0020] As used herein, “C a to C b ” in which “a” and “b” are integers refer to the number of carbon atoms in an alkyl, alkenyl or alkynyl group, or the number of carbon atoms in the ring of a cycloalkyl, cycloalkenyl, aryl, heteroaryl or heteroalicyclyl group. That is, the alkyl, alkenyl, alkynyl, ring(s) of the cycloalkyl, ring(s) of the cycloalkenyl, ring(s) of the aryl, ring(s) of the heteroaryl or ring(s) of the heteroalicyclyl can contain from “a” to “b”, inclusive, carbon atoms. Thus, for example, a “C1 to C4 alkyl” group refers to all alkyl groups having from 1 to 4 carbons, that is, CH3-, CH3CH2-, CH3CH2CH2-, (CH3)2CH-, CH 3 CH 2 CH 2 CH 2 -, CH 3 CH 2 CH(CH 3 )- and (CH 3 ) 3 C-. If no “a” and “b” are designated with regard to an alkyl, alkenyl, alkynyl, cycloalkyl cycloalkenyl, aryl, heteroaryl or heteroalicyclyl group, the broadest range described in these definitions is to be assumed. [0021] As used herein, “alkyl” refers to a straight or branched hydrocarbon chain that comprises a fully saturated (no double or triple bonds) hydrocarbon group. The alkyl group may have 1 to 20 carbon atoms (whenever it appears herein, a numerical range such as “1 to 20” refers to each integer in the given range; e.g., “1 to 20 carbon atoms” means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 20 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated). The alkyl group may also be a medium size alkyl having 1 to 10 carbon atoms. The alkyl group could also be a lower alkyl having 1 to 6 carbon atoms. The alkyl group of the compounds may be designated as “C 1 -C 4 alkyl” or similar designations. By way of example only, “C1-C4 alkyl” indicates that there are one to four carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and t-butyl. Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl and hexyl. The alkyl group may be substituted or unsubstituted. [0022] As used herein, “alkenyl” refers to an alkyl group that contains in the straight or branched hydrocarbon chain one or more double bonds. Examples of alkenyl groups include allenyl, vinylmethyl and ethenyl. An alkenyl group may be unsubstituted or substituted. [0023] As used herein, “alkynyl” refers to an alkyl group that contains in the straight or branched hydrocarbon chain one or more triple bonds. Examples of alkynyls include ethynyl and propynyl. An alkynyl group may be unsubstituted or substituted. [0024] As used herein, “cycloalkyl” refers to a completely saturated (no double or triple bonds) mono- or multi- cyclic hydrocarbon ring system. When composed of two or more rings, the rings may be joined together in a fused fashion. Cycloalkyl groups can contain 3 to 10 atoms in the ring(s) or 3 to 8 atoms in the ring(s). A cycloalkyl group may be unsubstituted or substituted. Typical cycloalkyl groups include, but are in no way limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[1.1.1]pentane, bicyclco[2.1.1]heptane, admantanyl and norbornyl. [0025] As used herein, “cycloalkenyl” refers to a mono- or multi- cyclic hydrocarbon ring system that contains one or more double bonds in at least one ring; although, if there is more than one, the double bonds cannot form a fully delocalized pi- electron system throughout all the rings (otherwise the group would be “aryl,” as defined herein). Cycloalkenyl groups can contain 3 to 10 atoms in the ring(s) or 3 to 8 atoms in the ring(s). When composed of two or more rings, the rings may be connected together in a fused fashion. A cycloalkenyl group may be unsubstituted or substituted. [0026] As used herein, “aryl” refers to a carbocyclic (all carbon) monocyclic or multicyclic aromatic ring system (including fused ring systems where two carbocyclic rings share a chemical bond) that has a fully delocalized pi-electron system throughout all the rings. The number of carbon atoms in an aryl group can vary. For example, the aryl group can be a C6-C14 aryl group, a C6-C10 aryl group, or a C6 aryl group. Examples of aryl groups include, but are not limited to, benzene, naphthalene and azulene. An aryl group may be substituted or unsubstituted. [0027] As used herein, “heteroaryl” refers to a monocyclic or multicyclic aromatic ring system (a ring system with fully delocalized pi-electron system) that contain(s) one, two, three or more heteroatoms, that is, an element other than carbon, including but not limited to, nitrogen, oxygen and sulfur. The number of atoms in the ring(s) of a heteroaryl group can vary. For example, the heteroaryl group can contain 4 to 14 atoms in the ring(s), 5 to 10 atoms in the ring(s) or 5 to 6 atoms in the ring(s). Furthermore, the term “heteroaryl” includes fused ring systems where two rings, such as at least one aryl ring and at least one heteroaryl ring, or at least two heteroaryl rings, share at least one chemical bond. Examples of heteroaryl rings include, but are not limited to, those described herein and the following: furan, furazan, thiophene, benzothiophene, phthalazine, pyrrole, oxazole, benzoxazole, 1,2,3- oxadiazole, 1,2,4-oxadiazole, thiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, benzothiazole, imidazole, benzimidazole, indole, indazole, pyrazole, benzopyrazole, isoxazole, benzoisoxazole, isothiazole, triazole, benzotriazole, thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, purine, pteridine, quinoline, isoquinoline, quinazoline, quinoxaline, cinnoline and triazine. A heteroaryl group may be substituted or unsubstituted. [0028] As used herein, “heterocyclyl” or “heteroalicyclyl” refers to three-, four-, five-, six-, seven-, eight-, nine-, ten-, up to 18-membered monocyclic, bicyclic, and tricyclic ring system wherein carbon atoms together with from 1 to 5 heteroatoms constitute said ring system. A heterocycle may optionally contain one or more unsaturated bonds situated in such a way, however, that a fully delocalized pi-electron system does not occur throughout all the rings. The heteroatom(s) is an element other than carbon including, but not limited to, oxygen, sulfur, and nitrogen. A heterocycle may further contain one or more carbonyl or thiocarbonyl functionalities, so as to make the definition include oxo-systems and thio- sy stems such as lactams, lactones, cyclic imides, cyclic thioimides and cyclic carbamates. When composed of two or more rings, the rings may be joined together in a fused fashion. Additionally, any nitrogens in a heterocyclyl may be quatemized. Heterocyclyl or heteroalicyclic groups may be unsubstituted or substituted. Examples of such “heterocyclyl” or “heteroalicyclyl” groups include, but are not limited to, those described herein and the following: 1,3-dioxin, 1,3-dioxane, 1,4-dioxane, 1,2-dioxolane, 1,3-dioxolane, 1,4- dioxolane, 1,3-oxathiane, 1,4-oxathiin, 1,3-oxathiolane, 1,3-dithiole, 1,3-dithiolane, 1,4- oxathiane, tetrahydro-l,4-thiazine, 1,3-thiazinane, 2H-l,2-oxazine, maleimide, succinimide, barbituric acid, thiobarbituric acid, dioxopiperazine, hydantoin, dihydrouracil, trioxane, hexahydro-l,3,5-triazine, imidazoline, imidazolidine, isoxazoline, isoxazolidine, oxazoline, oxazolidine, oxazolidinone, thiazoline, thiazolidine, morpholine, oxirane, piperidine N- Oxide, piperidine, piperazine, pyrrolidine, pyrrolidone, pyrrolidione, 4-piperidone, pyrazoline, pyrazolidine, 2-oxopyrrolidine, tetrahydropyran, 4H-pyran, tetrahydrothiopyran, thiamorpholine, thiamorpholine sulfoxide, thiamorpholine sulfone, and their benzo-fused analogs (e.g., benzimidazolidinone, tetrahydroquinoline, and 3,4-methylenedioxyphenyl).

[0029] As used herein, “aralkyl” and “aryl(alkyl)” refer to an aryl group connected, as a substituent, via a lower alkylene group. The lower alkylene and aryl group of an aralkyl may be substituted or unsubstituted. Examples include but are not limited to benzyl, 2-phenylalkyl, 3-phenylalkyl and naphthylalkyl.

[0030] As used herein, “heteroaralkyl” and “heteroaryl(alkyl)” refer to a heteroaryl group connected, as a substituent, via a lower alkylene group. The lower alkylene and heteroaryl group of heteroaralkyl may be substituted or unsubstituted. Examples include but are not limited to 2-thienylalkyl, 3-thienylalkyl, furylalkyl, thienylalkyl, pyrrolylalkyl, pyridylalkyl, isoxazolylalkyl, imidazolylalkyl and their benzo-fused analogs. [0031] A “heteroalicyclyl(alkyl)” and “heterocyclyl(alkyl)” refer to a heterocyclic or a heteroalicyclylic group connected, as a substituent, via a lower alkylene group. The lower alkylene and heterocyclyl of a heteroalicyclyl(alkyl) may be substituted or unsubstituted. Examples include but are not limited tetrahydro-2H-pyran-4-yl(methyl), piperidin-4-yl(ethyl), piperidin-4-yl(propyl), tetrahydro-2H-thiopyran-4-yl(methyl), and 1,3- thiazinan-4-yl(methyl). [0032] “Lower alkylene groups” are straight-chained -CH 2 - tethering groups, forming bonds to connect molecular fragments via their terminal carbon atoms. Examples include but are not limited to methylene (-CH2-), ethylene (-CH2CH2-), propylene (- CH 2 CH 2 CH 2 -), and butylene (-CH 2 CH 2 CH 2 CH 2 -). A lower alkylene group can be substituted by replacing one or more hydrogen of the lower alkylene group with a substituent(s) listed under the definition of “substituted.” [0033] As used herein, “alkoxy” refers to the formula –OR wherein R is an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl) is defined herein. A non-limiting list of alkoxys are methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, phenoxy and benzoxy. An alkoxy may be substituted or unsubstituted. [0034] As used herein, “acyl” refers to a hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl) connected, as substituents, via a carbonyl group. Examples include formyl, acetyl, propanoyl, benzoyl and acryl. An acyl may be substituted or unsubstituted. [0035] As used herein, “acylalkyl” refers to an acyl connected, as a substituent, via a lower alkylene group. Examples include aryl-C(=O)-(CH2)n- and heteroaryl-C(=O)- (CH2)n-, where n is an integer in the range of 1 to 6. [0036] As used herein, “alkoxyalkyl” refers to an alkoxy group connected, as a substituent, via a lower alkylene group. Examples include C1-4 alkyl-O-(CH2)n- ,wherein n is an integer in the range of 1 to 6. [0037] As used herein, “aminoalkyl” refers to an optionally substituted amino group connected, as a substituent, via a lower alkylene group. Examples include H2N(CH2)n- ,wherein n is an integer in the range of 1 to 6. [0038] As used herein, “hydroxyalkyl” refers to an alkyl group in which one or more of the hydrogen atoms are replaced by a hydroxy group. Exemplary hydroxyalkyl groups include but are not limited to, 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, and 2,2-dihydroxyethyl. A hydroxyalkyl may be substituted or unsubstituted. [0039] As used herein, “haloalkyl” refers to an alkyl group in which one or more of the hydrogen atoms are replaced by a halogen (e.g., mono-haloalkyl, di-haloalkyl and tri- haloalkyl). Such groups include but are not limited to, chloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chloro-fluoroalkyl, chloro-difluoroalkyl and 2- fluoroisobutyl. A haloalkyl may be substituted or unsubstituted. [0040] As used herein, “haloalkoxy” refers to an alkoxy group in which one or more of the hydrogen atoms are replaced by a halogen (e.g., mono-haloalkoxy, di- haloalkoxy and tri- haloalkoxy). Such groups include but are not limited to, chloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloro-fluoroalkyl, chloro- difluoroalkoxy and 2-fluoroisobutoxy. A haloalkoxy may be substituted or unsubstituted. [0041] A “sulfenyl” group refers to an “-SR” group in which R can be hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). A sulfenyl may be substituted or unsubstituted. [0042] A “sulfinyl” group refers to an “-S(=O)-R” group in which R can be the same as defined with respect to sulfenyl. A sulfinyl may be substituted or unsubstituted. [0043] A “sulfonyl” group refers to an “SO 2 R” group in which R can be the same as defined with respect to sulfenyl. A sulfonyl may be substituted or unsubstituted. [0044] An “O-carboxy” group refers to a “RC(=O)O-” group in which R can be hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl), as defined herein. An O-carboxy may be substituted or unsubstituted. [0045] The terms “ester” and “C-carboxy” refer to a “-C(=O)OR” group in which R can be the same as defined with respect to O-carboxy. An ester and C-carboxy may be substituted or unsubstituted. [0046] A “thiocarbonyl” group refers to a “-C(=S)R” group in which R can be the same as defined with respect to O-carboxy. A thiocarbonyl may be substituted or unsubstituted. [0047] A “trihalomethanesulfonyl” group refers to an “X 3 CSO 2 -” group wherein each X is a halogen. [0048] A “trihalomethanesulfonamido” group refers to an “X3CS(O)2N(RA)-” group wherein each X is a halogen, and R A hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). [0049] The term “amino” as used herein refers to a –NH2 group. [0050] As used herein, the term “hydroxy” refers to a –OH group. [0051] A “cyano” group refers to a “-CN” group. [0052] The term “azido” as used herein refers to a –N3 group. [0053] An “isocyanato” group refers to a “-NCO” group. [0054] A “thiocyanato” group refers to a “-CNS” group. [0055] An “isothiocyanato” group refers to an “ -NCS” group. [0056] A “carbonyl” group refers to a C=O group. [0057] An “S-sulfonamido” group refers to a “-SO 2 N(R A R B )” group in which R A and RB can be independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). An S-sulfonamido may be substituted or unsubstituted. [0058] An “N-sulfonamido” group refers to a “RSO2N(RA)-” group in which R and RA can be independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). An N-sulfonamido may be substituted or unsubstituted. [0059] An “O-carbamyl” group refers to a “-OC(=O)N(RARB)” group in which R A and R B can be independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). An O-carbamyl may be substituted or unsubstituted. [0060] An “N-carbamyl” group refers to an “ROC(=O)N(RA)-” group in which R and R A can be independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). An N-carbamyl may be substituted or unsubstituted. [0061] An “O-thiocarbamyl” group refers to a “-OC(=S)-N(R A R B )” group in which RA and RB can be independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). An O-thiocarbamyl may be substituted or unsubstituted. [0062] An “N-thiocarbamyl” group refers to an “ROC(=S)N(RA)-” group in which R and RA can be independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). An N-thiocarbamyl may be substituted or unsubstituted. [0063] A “C-amido” group refers to a “-C(=O)N(R A R B )” group in which R A and RB can be independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). A C-amido may be substituted or unsubstituted. [0064] An “N-amido” group refers to a “RC(=O)N(R A )-” group in which R and RA can be independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). An N-amido may be substituted or unsubstituted. [0065] The term “halogen atom” or “halogen” as used herein, means any one of the radio-stable atoms of column 7 of the Periodic Table of the Elements, such as, fluorine, chlorine, bromine and iodine. [0066] As used herein, indicates a single or double bond, unless stated otherwise. [0067] Where the numbers of substituents is not specified (e.g. haloalkyl), there may be one or more substituents present. For example “haloalkyl” may include one or more of the same or different halogens. As another example, “C 1 -C 3 alkoxyphenyl” may include one or more of the same or different alkoxy groups containing one, two or three atoms. [0068] As used herein, the abbreviations for any protective groups, amino acids and other compounds, are, unless indicated otherwise, in accord with their common usage, recognized abbreviations, or the IUPAC-IUB Commission on Biochemical Nomenclature (See, Biochem. 11:942-944 (1972)). [0069] The terms “protecting group” and “protecting groups” as used herein refer to any atom or group of atoms that is added to a molecule in order to prevent existing groups in the molecule from undergoing unwanted chemical reactions. Examples of protecting group moieties are described in T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 3. Ed. John Wiley & Sons, 1999, and in J.F.W. McOmie, Protective Groups in Organic Chemistry Plenum Press, 1973, both of which are hereby incorporated by reference for the limited purpose of disclosing suitable protecting groups. The protecting group moiety may be chosen in such a way, that they are stable to certain reaction conditions and readily removed at a convenient stage using methodology known from the art. A non-limiting list of protecting groups include benzyl; substituted benzyl; alkylcarbonyls and alkoxycarbonyls (e.g., t-butoxycarbonyl (BOC), acetyl, or isobutyryl); arylalkylcarbonyls and arylalkoxycarbonyls (e.g., benzyloxycarbonyl); substituted methyl ether (e.g. methoxymethyl ether); substituted ethyl ether; a substituted benzyl ether; tetrahydropyranyl ether; silyls (e.g., trimethylsilyl, triethylsilyl, triisopropylsilyl, t-butyldimethylsilyl, tri-iso- propylsilyloxymethyl, [2-(trimethylsilyl)ethoxy]methyl or t-butyldiphenylsilyl); esters (e.g. benzoate ester); carbonates (e.g. methoxymethylcarbonate); sulfonates (e.g. tosylate or mesylate); acyclic ketal (e.g. dimethyl acetal); cyclic ketals (e.g., 1,3-dioxane, 1,3- dioxolanes, and those described herein); acyclic acetal; cyclic acetal (e.g., those described herein); acyclic hemiacetal; cyclic hemiacetal; cyclic dithioketals (e.g., 1,3-dithiane or 1,3- dithiolane); orthoesters (e.g., those described herein) and triarylmethyl groups (e.g., trityl; monomethoxytrityl (MMTr); 4,4'-dimethoxytrityl (DMTr); 4,4',4"-trimethoxytrityl (TMTr); and those described herein). [0070] The term “leaving group” as used herein refers to any atom or moiety that is capable of being displaced by another atom or moiety in a chemical reaction. More specifically, in some embodiments, “leaving group” refers to the atom or moiety that is displaced in a nucleophilic substitution reaction. In some embodiments, “leaving groups” are any atoms or moieties that are conjugate bases of strong acids. Examples of suitable leaving groups include, but are not limited to, tosylates, mesylates, trifluoroacetates and halogens (e.g., I, Br, and Cl). Non-limiting characteristics and examples of leaving groups can be found, for example in Organic Chemistry, 2d ed., Francis Carey (1992), pages 328-331; Introduction to Organic Chemistry, 2d ed., Andrew Streitwieser and Clayton Heathcock (1981), pages 169-171; and Organic Chemistry, 5 th ed., John McMurry (2000), pages 398 and 408; all of which are incorporated herein by reference for the limited purpose of disclosing characteristics and examples of leaving groups. [0071] The term “pharmaceutically acceptable salt” refers to a salt of a compound that does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity and properties of the compound. In some embodiments, the salt is an acid addition salt of the compound. Pharmaceutical salts can be obtained by reacting a compound with inorganic acids such as hydrohalic acid (e.g., hydrochloric acid or hydrobromic acid), sulfuric acid, nitric acid and phosphoric acid. Pharmaceutical salts can also be obtained by reacting a compound with an organic acid such as aliphatic or aromatic carboxylic or sulfonic acids, for example formic, acetic, succinic, lactic, malic, tartaric, citric, ascorbic, nicotinic, methanesulfonic, ethanesulfonic, p-toluensulfonic, salicylic or naphthalenesulfonic acid. Pharmaceutical salts can also be obtained by reacting a compound with a base to form a salt such as an ammonium salt, an alkali metal salt, such as a sodium or a potassium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of organic bases such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, C1-C7 alkylamine, cyclohexylamine, triethanolamine, ethylenediamine, and salts with amino acids such as arginine and lysine. [0072] Terms and phrases used in this application, and variations thereof, especially in the appended claims, unless otherwise expressly stated, should be construed as open ended as opposed to limiting. As examples of the foregoing, the term ‘including’ should be read to mean ‘including, without limitation,’ ‘including but not limited to,’ or the like; the term ‘comprising’ as used herein is synonymous with ‘including,’ ‘containing,’ or ‘characterized by,’ and is inclusive or open-ended and does not exclude additional, unrecited elements or method steps; the term ‘having’ should be interpreted as ‘having at least;’ the term ‘includes’ should be interpreted as ‘includes but is not limited to;’ the term ‘example’ is used to provide exemplary instances of the item in discussion, not an exhaustive or limiting list thereof; and use of terms like ‘preferably,’ ‘preferred,’ ‘desired,’ or ‘desirable,’ and words of similar meaning should not be understood as implying that certain features are critical, essential, or even important to the structure or function, but instead as merely intended to highlight alternative or additional features that may or may not be utilized in a particular embodiment. In addition, the term “comprising” is to be interpreted synonymously with the phrases "having at least" or "including at least". When used in the context of a process, the term "comprising" means that the process includes at least the recited steps, but may include additional steps. When used in the context of a compound, composition or device, the term "comprising" means that the compound, composition or device includes at least the recited features or components, but may also include additional features or components. Likewise, except for the claims, a group of items linked with the conjunction ‘and’ should not be read as requiring that each and every one of those items be present in the grouping, but rather should be read as ‘and/or’ unless expressly stated otherwise. Similarly, except for the claims, a group of items linked with the conjunction ‘or’ should not be read as requiring mutual exclusivity among that group, but rather should be read as ‘and/or’ unless expressly stated otherwise.

[0073] With respect to the use of substantially any plural and/or singular terms herein, those having skill in the art can translate from the plural to the singular and/or from the singular to the plural as is appropriate to the context and/or application. The various singular/plural permutations may be expressly set forth herein for sake of clarity. The indefinite article “a” or “an” does not exclude a plurality. The mere fact that certain measures are recited in mutually different dependent claims does not indicate that a combination of these measures cannot be used to advantage.

[0074] It is understood that, in any compound described herein having one or more chiral centers, if an absolute stereochemistry is not expressly indicated, then each center may independently be of R-configuration or S -configuration or a mixture thereof. Thus, the compounds provided herein may be enantiomerically pure, enantiomeric ally enriched, racemic mixture, diastereomerically pure, diastereomerically enriched, or a stereoisomeric mixture. In addition it is understood that, in any compound described herein having one or more double bond(s) generating geometrical isomers that can be defined as E or Z, each double bond may independently be E or Z a mixture thereof.

[0075] Likewise, it is understood that, in any compound described, all tautomeric forms are also intended to be included.

[0076] It is to be understood that where compounds disclosed herein have unfilled valencies, then the valencies are to be filled with hydrogens or isotopes thereof, e.g., hydrogen- 1 (protium) and hydrogen-2 (deuterium).

[0077] It is understood that the compounds described herein can be labeled isotopically. Substitution with isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, such as, for example, increased in vivo half-life or reduced dosage requirements. Each chemical element as represented in a compound structure may include any isotope of said element. For example, in a compound structure a hydrogen atom may be explicitly disclosed or understood to be present in the compound. At any position of the compound that a hydrogen atom may be present, the hydrogen atom can be any isotope of hydrogen, including but not limited to hydrogen- 1 (protium) and hydrogen-2 (deuterium). Thus, reference herein to a compound encompasses all potential isotopic forms unless the context clearly dictates otherwise.

[0078] It is understood that the methods and combinations described herein include crystalline forms (also known as polymorphs, which include the different crystal packing arrangements of the same elemental composition of a compound), amorphous phases, salts, solvates, and hydrates. In some embodiments, the compounds described herein exist in solvated forms with pharmaceutically acceptable solvents such as water, ethanol, or the like. In other embodiments, the compounds described herein exist in unsolvated form. Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and may be formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol, or the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. In addition, the compounds provided herein can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein. [0079] Where a range of values is provided, it is understood that the upper and lower limit, and each intervening value between the upper and lower limit of the range is encompassed within the embodiments. Compounds Formula (I) [0080] Some embodiments disclosed herein relate to a compound of Formula (I), or a pharmaceutically acceptable salt thereof, having the structure: wherein: ring Ar can be a phenyl, a pyridinyl or a pyrimidinyl; A 1 can be an optionally substituted phenyl or an optionally substituted heteroaryl; each R 1 can be independently selected from –OR 4A , a halogen, an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted mono-substituted amino group and an optionally substituted di-substituted amino group; R 2A and R 2B can be each independently hydrogen or deuterium; R 3 can be haloalkyl, an optionally substituted alkyl or an optionally substituted cycloalkyl; R 4A can be an optionally substituted alkyl or an optionally substituted cycloalkyl; at least one of R 3 and R 4A can be an optionally substituted cycloalkyl; m can be 1 or 2; X 1 , X 2 and X 3 can be each independently N or CR 5 , wherein each R 5 can be independently hydrogen, a halogen or an optionally substituted alkyl; and X 4 is C (carbon), CH or N (nitrogen), provided that when X 4 is C (carbon), then “ 4 is a double bond, and when X is CH or N, then is a single bond. [0081] Examples of compounds of Formula (I), or pharmaceutically acceptable salts thereof, include those having the following general Formulae (Ia), (Ib), (Ic), (Id), (Ie), (If) and (Ig), or pharmaceutically acceptable salts thereof:

[0082] Other examples of compounds of Formula (I), or pharmaceutically acceptable salts thereof, are described in the Examples below. The variables in the general Formulae (Ia), (Ib), (Ic), (Id), (Ie), (If) and (Ig) are defined in the same manner as the corresponding variables for the Formula (I). Reference herein to a feature of a compound of Formula (I), or that of a pharmaceutically acceptable salt thereof, will be understood by those skilled in the art as applying to the corresponding feature of a compound of general Formulae (Ia), (Ib), (Ic), (Id), (Ie), (If) and/or (Ig), or that of a pharmaceutically acceptable salt thereof, and vice versa, unless the context clearly indicates otherwise. [0083] In various embodiments of Formula (I) or a pharmaceutically acceptable salt thereof, the ring Ar can be phenyl. In other embodiments, the ring Ar can be pyridinyl. In other embodiments, the ring Ar can be pyrimidinyl. The ring nitrogen(s) of the pyridinyl and pyrimidinyl rings can be located at various positions, for example as illustrated by Formulae (Ib) and (Ic) as well as by various compounds described in the Examples below. [0084] In various embodiments of Formula (I) or a pharmaceutically acceptable salt thereof, the variable m can be 1 or 2, and thus in some embodiments, the ring Ar can be substituted with one R 1 group, and in others the ring Ar can be substituted with two R 1 groups. The position of each R 1 can vary. Examples of where the R 1 group(s) can be present are shown below: , [0085] In some embodiments, R 1 can be –OR 4A , wherein R 4A can be an optionally substituted alkyl or an optionally substituted cycloalkyl. For example, in an embodiment, R 4A can be an optionally substituted alkyl, such as an unsubsituted alkyl or an alkyl bearing an optional substituent group as described elsewhere herein, such those groups described for “optionally substituted.” In an embodiment, R 4A can be an unsubstituted C 1-6 alkyl. In some embodiments, R 4A can be methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, pentyl (branched and straight-chained) and hexyl (branched and straight-changed). In some embodiments, R 4A can be methyl. [0086] In other embodiments, R 4A can be an optionally substituted cycloalkyl, such as an unsubsituted cycloalkyl or a cycloalkyl bearing an optional substituent group as described elsewhere herein. In various embodiments, R 4A can be an optionally substituted C 3-6 cycloalkyl, such as an optionally substituted C 3-6 cycloalkyl. For example, in various embodiments, R 4A can be an optionally substituted cyclopropyl, an optionally substituted cyclobutyl, an optionally substituted cyclopentyl, an optionally substituted bicyclo[1.1.1]pentyl or an optionally substituted cyclohexyl. In some embodiments, R 4A can be a substituted cycloalkyl, such as as a substituted C3-6 cycloalkyl. For example, in various embodiments, R 4A can be a substituted cyclopropyl, a substituted cyclobutyl, a substituted cyclopentyl, a substituted bicyclo[1.1.1]pentyl or a substituted cyclohexyl. In other embodiments, R 4A is an unsubstituted cycloalkyl, such as an unsubstituted C 3-6 cycloalkyl. For example, in various embodiments, R 4A can be an unsubstituted cyclopropyl, an unsubstituted cyclobutyl, an unsubstituted cyclopentyl, an unsubstituted bicyclo[1.1.1]pentyl or an unsubstituted cyclohexyl. [0087] In an embodiment, R 1 can be a halogen. Examples of suitable halogens include fluorine, chlorine, bromine and iodine. In other embodiments, R 1 can be an optionally substituted alkyl, such as an unsubsituted alkyl or an alkyl bearing an optional substituent group as described elsewhere herein. In an embodiment, R 1 can be an unsubstituted C1-6 alkyl. Examples of C1-6 alkyl include methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, pentyl (branched and straight-chained) and hexyl (branched and straight-changed). [0088] In an embodiment, R 1 can be an optionally substituted cycloalkyl, such as an unsubsituted cycloalkyl or a cycloalkyl bearing an optional substituent group as described elsewhere herein. In various embodiments, R 1 can be an optionally substituted C 3-6 cycloalkyl, such as an optionally substituted C3-6 cycloalkyl. For example, in various embodiments, R 1 can be an optionally substituted cyclopropyl, an optionally substituted cyclobutyl, an optionally substituted cyclopentyl, an optionally substituted bicyclo[1.1.1]pentyl or an optionally substituted cyclohexyl. In some embodiments, R 1 can be a substituted cycloalkyl, such as as a substituted C3-6 cycloalkyl. For example, in various embodiments, R 1 can be a substituted cyclopropyl, a substituted cyclobutyl, a substituted cyclopentyl, a substituted bicyclo[1.1.1]pentyl or a substituted cyclohexyl. In other embodiments, R 1 can be an unsubstituted cycloalkyl, such as an unsubstituted C3-6 cycloalkyl. For example, in various embodiments, R 1 can be an unsubstituted cyclopropyl, an unsubstituted cyclobutyl, an unsubstituted cyclopentyl, an unsubstituted bicyclo[1.1.1]pentyl or an unsubstituted cyclohexyl. [0089] In an embodiment, R 1 can be an optionally substituted mono-substituted amino group, such as an unsubsituted mono-substituted amino group or a mono-substituted amino group bearing an additional optional substituent group as described elsewhere herein. In an embodiment, the mono-substituted amino group can be a –NH(C1-6 alkyl) that is unsubstituted or optionally substituted on the C 1-6 alkyl substituent. In other embodiments, R 1 can be an optionally substituted di-substituted amino group, such as an unsubsituted di-substituted amino group or a di-substituted amino group bearing an additional optional substituent group as described elsewhere herein. In an embodiment, the di-substituted amino group can be a –N(C1-6 alkyl)2 group that is unsubstituted or optionally substituted on either or both of the C 1-6 alkyl substituents. [0090] In some embodiments, when m is 2, at least one R 1 can be –OR 4A . In some embodiments, when m is 2, each R 1 can be –OR 4A . In other embodiments, at least one R 1 can be a halogen or an optionally substituted cycloalkyl. In still other embodiments, at least one R 1 can be an optionally substituted mono-substituted amino group or an optionally substituted di-substituted amino group. [0091] Exemplary ring Ar moieties include, but are not limited to the following: . [0092] The ring Ar can be attached to another ring structure in which certain atoms are represented by the variables X 1 , X 2 and X 3 as shown in Formula (I). In various embodiments, X 1 , X 2 and X 3 can be each independently N or CR 5 , wherein each R 5 can be independently hydrogen, a halogen or an optionally substituted alkyl. In an embodiment, at least one of X 1 , X 2 and X 3 can be CR 5 , and each R 5 can be hydrogen. In various embodiments, any one, two or three of X 1 , X 2 and X 3 can be N. In other embodiments, any one, two or three of X 1 , X 2 and X 3 can be CR 5 . For example, in some embodiments any one of X 1 , X 2 and X 3 can be CR 5 . In other embodiments, any two of X 1 , X 2 and X 3 can be CR 5 . In still further embodiments, all three of X 1 , X 2 and X 3 can be CR 5 . In some embodiments, each of X 1 , X 2 and X 3 can be CR 5 , and each R 5 can be hydrogen. In other embodiments, at least one of X 1 , X 2 and X 3 can be CR 5, and R 5 can be fluorine, chlorine, bromine or iodine. In other embodiments, at least one of X 1 , X 2 and X 3 can be CR 5, and R 5 can be unsubstituted C1-6 alkyl. In some embodiments, X 1 can be CR 5 , wherein R 5 can be halogen (such as fluoro, chloro or iodo), and each of X 2 and X 3 can be CR 5 , wherein each R 5 can be hydrogen. [0093] The Formula (I) includes another ring structure that includes the variable X 4 . In various embodiments, X 4 can be C, CH or N. Those skilled in the art will understand that when X 4 is C, then the bond depicted by is a d 4 ouble bond, and that when X is CH or N, then the bond depicted by is a single bond. The Formula (Id) illustrates a chemical structure in which X 4 is C and the bond depicted by is a double bond. In some embodiments, X 4 can be C, and the bond depicted by “ is a double bond. In other embodiments, X 4 can be CH, and the bond depicted by “ is a single bond. In still other embodiments, X 4 can be N, and the bond depicted by is a single bond. [0094] The X 4 variable in Formula (I) is attached to the variable A 1 , which represents an optionally substituted phenyl or an optionally substituted heteroaryl. In an embodiment, A 1 can be an optionally substituted phenyl, such as an unsubsituted phenyl or a substituted phenyl bearing an optional substituent group as described elsewhere herein, such those groups described for “optionally substituted.” In an embodiment, A 1 can be an unsubstituted phenyl. For example, the Formula (Ie) illustrates a chemical structure in which A 1 is an unsubstituted phenyl. In other embodiments, A 1 can be an a substituted phenyl, such as a fluorophenyl as described in the Examples below. In some embodiments, A 1 can be an optionally substituted heteroaryl, such as an unsubstituted heteroaryl or a substituted heteroaryl bearing an optional substituent group as described elsewhere herein. In some embodiments, A 1 can be an optionally substituted heteroaryl, such as an optionally substituted 5-membered heteroaryl. In other embodiments, A 1 can be an optionally substituted heteroaryl, such as an optionally substituted 6-membered heteroaryl. For example, in various embodiments, A 1 can be an optionally substituted thienyl, an optionally substituted thiazole, an optionally substituted 1,3,4-thiadiazole or an optionally substituted pyridinyl. In some embodiments, A 1 can be a substituted heteroaryl, such as a substituted 5- membered heteroaryl or a substituted 6-membered heteroaryl. For example, in various embodiments, A 1 can be a substituted thienyl, a substituted thiazole, a substituted 1,3,4- thiadiazole or a substituted heteroaryl. In some embodiments, A 1 can be an unsubstituted heteroaryl. For example, Formulae (If) and (Ig) illustrate chemical structures in which A 1 is an unsubstituted 5-membered heteroaryl or an unsubstituted 6-membered heteroaryl. In various embodiments, A 1 can be an unsubstituted thienyl, an unsubstituted thiazole, an unsubstituted 1,3,4-thiadiazole or an unsubstituted pyridinyl. Examples of A 1 moieties include the following: . [0095] As described elsewhere herein, any of the hydrogen atoms of Formula (I) can be any isotope of hydrogen, including deuterium. In some embodiments, R 2A and R 2B can be each independently hydrogen or deuterium. In some embodiment, at least one of R 2A and R 2B can be deuterium. In other embodiments, each R 2A and R 2B can be hydrogen. [0096] The Formula (I) contains a triazole ring structure to which the variable R 3 is attached. In various embodiments, R 3 can be haloalkyl, an optionally substituted alkyl or an optionally substituted cycloalkyl. In an embodiment, R 3 can be haloalkyl. For example, in various embodiments, R 3 can be a C 1-6 haloalkyl. Examples of suitable haloalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl and fluoropropyl. [0097] In various embodiments, R 3 can be an optionally substituted alkyl. For example, in an embodiment, R 3 can be an optionally substituted alkyl, such as an unsubsituted alkyl or an alkyl bearing an optional substituent group as described elsewhere herein. In an embodiment, R 3 can be an unsubstituted C1-6 alkyl, such as methyl, ethyl, n- propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, pentyl (straight or branched) or hexyl (straight or branched). In some embodiments, R 3 can be methyl. In another embodiment, R 3 can be a substituted C 1-6 alkyl. For example, in an embodiment, R 3 can be a hydroxyethyl group. [0098] In other embodiments, R 3 can be an optionally substituted cycloalkyl, such as an unsubsituted cycloalkyl or a cycloalkyl bearing an optional substituent group as described elsewhere herein, such those groups described for “optionally substituted.” In various embodiments, R 3 can be an optionally substituted C3-6 cycloalkyl, such as an optionally substituted C 3-6 cycloalkyl. For example, in various embodiments, R 3 can be an optionally substituted cyclopropyl, an optionally substituted cyclobutyl, an optionally substituted cyclopentyl, an optionally substituted bicyclo[1.1.1]pentyl or an optionally substituted cyclohexyl. In some embodiments, R 3 can be a substituted cycloalkyl, such as as a substituted C 3-6 cycloalkyl. For example, in various embodiments, R 3 can be a substituted cyclopropyl, a substituted cyclobutyl, a substituted cyclopentyl, a substituted bicyclo[1.1.1]pentyl or a substituted cyclohexyl. In other embodiments, R 3 can be an unsubstituted cycloalkyl, such as an unsubstituted C 3-6 cycloalkyl. For example, in various embodiments, R 3 can be an unsubstituted cyclopropyl, an unsubstituted cyclobutyl, an unsubstituted cyclopentyl, an unsubstituted bicyclo[1.1.1]pentyl or an unsubstituted cyclohexyl. [0099] In an embodiment, a compound of compound of Formula (I) includes at least one optionally substituted cycloalkyl group. For example, in an embodiment, R 1 is - OR 4A and R 4A is an optionally substituted cycloalkyl. In another embodiment, R 3 is an optionally substituted cycloalkyl. In an embodiment, at least one of R 3 and R 4A is an optionally substituted cycloalkyl.

[0100] Examples of compounds of Formula (I) include the following:

, or a pharmaceutically acceptable salt of any of the foregoing.

[0101] Additional examples of compounds of Formula (I) include

and or a pharmaceutically acceptable salt of any of the foregoing. [0102] In some embodiments, Ar cannot be an unsubstituted pyridinyl. In other embodiments, Ar cannot be a substituted pyridinyl, for example, a fluoro-substituted pyridinyl, a chloro-substituted pyridinyl, a methoxy-substituted pyridinyl, an ethoxy- substituted pyridinyl, an n-propoxy-substituted pyridinyl, an isopropoxy-substituted pyridinyl. In other still embodiments, Ar cannot be an unsubstituted phenyl. In yet still other embodiments, Ar cannot be a substituted phenyl (such as a fluoro-substituted phenyl, a chloro-substituted phenyl, a methoxy-substituted phenyl, an ethoxy-substituted phenyl, an n- propoxy-substituted phenyl, an isopropoxy-substituted phenyl). In some embodiments, X 4 cannot be C (carbon), and cannot be a double bond. In other embodiments, X 4 cannot be CH, and cannot be a single bond. In some embodiments, 3 R cannot be an unsubstituted alkyl, including an unsubstituted C 1-6 alkyl (such as methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, pentyl (branched or straight-chained) and/or hexyl (branched or straight-chained). In other embodiments, R 3 cannot be a substituted alkyl, such as a substituted C1-6 alkyl. Examples of substituted C1-6 alkyls include hydroxy-substituted C 1-6 alkyls. In still other embodiments, R 3 cannot be an unsubstituted cycloalkyl, such as unsubstituted monocyclic C3-6 cycloalkyls. In yet still other embodiments, R 3 cannot be a substituted cycloalkyl, for example, substituted monocyclic C3- 6 cycloalkyls. In some embodiments, R 3 cannot be a haloalkyl (such as fluoro-substitued haloalkyl). In some embodiments, A 1 cannot be an unsubstituted phenyl. In some embodiments, A 1 cannot be a substituted phenyl, for example, a halo-substituted phenyl. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, cannot be a compound or salt described in one or more of the following: Boga et al., ACS Medicinal Chemistry Letters (2018), 9(7), 761-767; U.S. 2014/0309234, WO 2009/105500, WO 2010/021978, WO 2016/100152, WO 2016/100147 and WO 2017/040362. Synthesis [0103] Compounds of Formula (I), and those described herein may be prepared in various ways. Compounds of Formula (I) can be prepared utilizing known synthetic procedures informed by the detailed guidance provided herein. General synthetic routes to the compounds of Formula (I), and some examples of starting materials used to synthesize the compounds of Formula (I) are shown and described herein. The routes shown and described herein are illustrative only and are not intended, nor are they to be construed, to limit the scope of the claims in any manner whatsoever. Those skilled in the art will be able to recognize modifications of the disclosed syntheses and to devise alternate routes based on the disclosures herein; all such modifications and alternate routes are within the scope of the claims. Scheme 1 [0104] As shown in Scheme 1, compound (A) and compound (B) can be coupled to form a compound of Formula (I), for example, via a nucleophilic substitution reaction. Compound (A) and compound (B) can be formed using methods known to those skilled in the art, and shown herein. In Scheme 1, LG 1 can be a suitable leaving group, such as a halogen (for example, chloro or iodo). In some embodiments, an amine base can be utilized in the reaction of compound (A) and compound (B). Examples of suitable amine bases, include, but are not limited to, alkylamine (including mono-, di- and tri-alkylamines (e.g., triethylamine)), optionally substituted pyridines (e.g. collidine) and optionally substituted imidazoles (e.g., N-methylimidazole). In some embodiments, the triazole ring can be attached to A 1 after the reaction between compound (A) and compound (B). For example, when A 1 is a phenyl group, the triazole bearing the R 3 group can be added via a Suzuki coupling reaction to a coupled compound bearing an -A 1 -LG 2 group, wherein LG 2 is a second leaving group. Pharmaceutical Compositions [0105] Some embodiments described herein relate to a pharmaceutical composition, that can include an effective amount of one or more compounds described herein (e.g., a compound of Formula (I), or a pharmaceutically acceptable salt thereof) and a pharmaceutically acceptable carrier, diluent, excipient or combination thereof. [0106] The term “pharmaceutical composition” refers to a mixture of one or more compounds disclosed herein with other chemical components, such as diluents or carriers. The pharmaceutical composition facilitates administration of the compound to an organism. Pharmaceutical compositions can also be obtained by reacting compounds with inorganic or organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid. Pharmaceutical compositions will generally be tailored to the specific intended route of administration.

[0107] The term “physiologically acceptable” defines a carrier, diluent or excipient that does not abrogate the biological activity and properties of the compound nor cause appreciable damage or injury to an animal to which delivery of the composition is intended.

[0108] As used herein, a “carrier” refers to a compound that facilitates the incorporation of a compound into cells or tissues. For example, without limitation, dimethyl sulfoxide (DMSO) is a commonly utilized carrier that facilitates the uptake of many organic compounds into cells or tissues of a subject.

[0109] As used herein, a “diluent” refers to an ingredient in a pharmaceutical composition that lacks appreciable pharmacological activity but may be pharmaceutically necessary or desirable. For example, a diluent may be used to increase the bulk of a potent drug whose mass is too small for manufacture and/or administration. It may also be a liquid for the dissolution of a drug to be administered by injection, ingestion or inhalation. A common form of diluent in the art is a buffered aqueous solution such as, without limitation, phosphate buffered saline that mimics the pH and isotonicity of human blood.

[0110] As used herein, an “excipient” refers to an essentially inert substance that is added to a pharmaceutical composition to provide, without limitation, bulk, consistency, stability, binding ability, lubrication, disintegrating ability etc., to the composition. A “diluent” is a type of excipient.

[0111] The pharmaceutical compositions described herein can be administered to a human patient per se, or in pharmaceutical compositions where they are mixed with other active ingredients, as in combination therapy, or carriers, diluents, excipients or combinations thereof. Proper formulation is dependent upon the route of administration chosen. Techniques for formulation and administration of the compounds described herein are known to those skilled in the art.

[0112] The pharmaceutical compositions disclosed herein may be manufactured in a manner that is itself known, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or tableting processes. Additionally, the active ingredients are contained in an amount effective to achieve its intended purpose. Many of the compounds used in the pharmaceutical combinations disclosed herein may be provided as salts with pharmaceutically compatible counterions.

[0113] Multiple techniques of administering a compound exist in the art including, but not limited to, oral, rectal, pulmonary, topical, aerosol, injection and parenteral delivery, including intramuscular, subcutaneous, intravenous, intramedullary injections, intrathecal, direct intraventricular, intraperitoneal, intranasal and intraocular injections.

[0114] One may also administer the compound in a local rather than systemic manner, for example, via injection or implantation of the compound directly into the affected area, often in a depot or sustained release formulation. Furthermore, one may administer the compound in a targeted drug delivery system, for example, in a liposome coated with a tissue-specific antibody. The liposomes will be targeted to and taken up selectively by the organ. For example, intranasal or pulmonary delivery to target a respiratory infection may be desirable.

[0115] As described herein, compounds of Formula (I), or a pharmaceutically acceptable salt thereof, can be administered by a variety of methods. In some of the methods described herein, administration can be by injection, infusion and/or intravenous administration over the course of 1 minute, 5 minutes, 10 minutes, 30 minutes, 1 hour, 2 hours, 6 hours, 12 hours, 24 hours or longer, or any intermediate time. Other methods described herein can include oral, intravenous and/or intraperitoneal administration to a subject in need thereof, for example, to a subject to treat a cancer described herein responsive to an ERK inhibitor.

[0116] The compositions may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient. The pack may for example comprise metal or plastic foil, such as a blister pack. The pack or dispenser device may be accompanied by instructions for administration. The pack or dispenser may also be accompanied with a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the drug for human or veterinary administration. Such notice, for example, may be the labeling approved by the U.S. Food and Drug Administration for prescription drugs, or the approved product insert. Compositions that can include a compound described herein formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.

Methods of Use

[0117] Some embodiments described herein relate to a method for ameliorating and/or treating a cancer described herein that can include administering to a subject in need thereof an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) to a subject having a cancer described herein. Other embodiments described herein relate to the use of an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for ameliorating and/or treating a cancer described herein.

[0118] Some embodiments described herein relate to a method for inhibiting replication of a malignant growth or a tumor that can include contacting the growth or the tumor with an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof), wherein the malignant growth or tumor is due to a cancer described herein. Other embodiments described herein relate to the use of an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for inhibiting replication of a malignant growth or a tumor, wherein the malignant growth or tumor is due to a cancer described herein.

[0119] Some embodiments described herein relate to a method for ameliorating or treating a cancer described herein that can include contacting a malignant growth or a tumor with an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) wherein the malignant growth or tumor is due to a cancer described herein. Other embodiments described herein relate to the use of an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for ameliorating or treating a cancer that can include contacting a malignant growth or a tumor with the compound, wherein the malignant growth or tumor is due to a cancer described herein.

[0120] Some embodiments described herein relate to a method for inhibiting the activity of ERK1 and/or ERK2 that can include providing an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) to a sample that includes a cancer cell from a cancer described herein. Other embodiments described herein relate to the use of an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for inhibiting the activity of ERK1 and/or ERK2.

[0121] Some embodiments described herein relate to a method for ameliorating or treating a cancer described herein that can include inhibiting the activity of ERK1 and/or ERK2 using an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof). Other embodiments described herein relate to the use of an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for ameliorating or treating a cancer described herein by inhibiting the activity of ERK1 and/or ERK2.

[0122] Examples of suitable cancers include, but are not limited to: a lung cancer, a pancreatic cancer, a colon cancer, a myeloid leukemia, a thyroid cancer, myelodysplastic syndrome (MDS), a bladder carcinoma, an epidermal carcinoma, a melanoma, a breast cancer, a prostate cancer, a head and neck cancer, an ovarian cancer, a brain cancer, a cancer of mesenchymal origin, a sarcoma, a tetracarcinoma, a neuroblastoma, a kidney carcinoma, a hepatoma, a non-Hodgkin's lymphoma, a multiple myeloma, an anaplastic thyroid carcinoma and neurofibromatosis.

[0123] As used herein, a “subject” refers to an animal that is the object of treatment, observation or experiment. “Animal” includes cold- and warm-blooded vertebrates and invertebrates such as fish, shellfish, reptiles and, in particular, mammals. “Mammal” includes, without limitation, mice, rats, rabbits, guinea pigs, dogs, cats, sheep, goats, cows, horses, primates, such as monkeys, chimpanzees, and apes, and, in particular, humans. In some embodiments, the subject can be human. In some embodiments, the subject can be a child and/or an infant, for example, a child or infant with a fever. In other embodiments, the subject can be an adult.

[0124] As used herein, the terms “treat,” “treating,” “treatment,” “therapeutic,” and “therapy” do not necessarily mean total cure or abolition of the disease or condition. Any alleviation of any undesired signs or symptoms of a disease or condition, to any extent can be considered treatment and/or therapy. Furthermore, treatment may include acts that may worsen the subject’s overall feeling of well-being or appearance, and may positively affect one or more symptoms or aspects of the disease while having effects on other aspects of the disease or on unrelated systems that may be considered undesireable.

[0125] The terms “therapeutically effective amount” and “effective amount” are used to indicate an amount of an active compound, or pharmaceutical agent, that elicits the biological or medicinal response indicated. For example, a therapeutically effective amount of compound can be the amount needed to treat, alleviate or ameliorate one or more symptoms or conditions of disease or prolong the survival of the subject being treated This response may occur in a tissue, system, animal or human and includes alleviation of the signs or symptoms of the disease being treated. Determination of an effective amount is well within the capability of those skilled in the art, in view of the disclosure provided herein.

[0126] For example, an effective amount of a compound, or radiation, is the amount that results in: (a) the reduction, alleviation or disappearance of one or more symptoms caused by the cancer, (b) the reduction of tumor size, (c) the elimination of the tumor, and/or (d) long-term disease stabilization (growth arrest) of the tumor. In the treatment of lung cancer (such as non- small cell lung cancer) a therapeutically effective amount is that amount that alleviates or eliminates cough, shortness of breath and/or pain. As another example, an effective amount, or a therapeutically effective amount of an ERK inhibitor is the amount which results in the reduction in ERK (ERKI and/or ERK2) activity and/or phosphorylation. The reduction in ERK activity are known to those skilled in the art and can be determined by the analysis of pharmacodynamic markers such as phosphorylated RSKI,2 and phosphorylated ERKI, 2 and/or or gene expression profile (mRNA).

[0127] The therapeutically effective amount of the compounds disclosed herein required as a dose will depend on the route of administration, the type of animal, including human, being treated, and the physical characteristics of the specific animal under consideration. The dose can be tailored to achieve a desired effect, but will depend on such factors as weight, diet, concurrent medication and other factors which those skilled in the medical arts will recognize.

[0128] Various indicators for determining the effectiveness of a method for treating a cancer, are known to those skilled in the art. Example of suitable indicators include, but are not limited to, the reduction, alleviation or disappearance of one or more symptoms caused by the cancer, the reduction of tumor size, the elimination of the tumor, and/or long-term disease stabilization (growth arrest) of the tumor.

[0129] As will be readily apparent to one skilled in the art, the useful in vivo dosage to be administered and the particular mode of administration will vary depending upon the age, weight, the severity of the affliction, and mammalian species treated, the particular compounds employed, and the specific use for which these compounds are employed. The determination of effective dosage levels, that is the dosage levels necessary to achieve the desired result, can be accomplished by one skilled in the art using routine methods, for example, human clinical trials and in vitro studies.

[0130] The dosage may range broadly, depending upon the desired effects and the therapeutic indication. Alternatively dosages may be based and calculated upon the surface area of the patient, as understood by those of skill in the art. Although the exact dosage will be determined on a drug-by-drug basis, in most cases, some generalizations regarding the dosage can be made. The daily dosage regimen for an adult human patient may be, for example, an oral dose of between 0.01 mg and 3000 mg of each active ingredient, preferably between 1 mg and 700 mg, e.g. 5 to 200 mg. The dosage may be a single one or a series of two or more given in the course of one or more days, as is needed by the subject. In some embodiments, the compounds will be administered for a period of continuous therapy, for example for a week or more, or for months or years.

[0131] In instances where human dosages for compounds have been established for at least some condition, those same dosages may be used, or dosages that are between about 0.1% and 500%, more preferably between about 25% and 250% of the established human dosage. Where no human dosage is established, as will be the case for newly- discovered pharmaceutical compositions, a suitable human dosage can be inferred from ED50 or ID50 values, or other appropriate values derived from in vitro or in vivo studies, as qualified by toxicity studies and efficacy studies in animals.

[0132] In cases of administration of a pharmaceutically acceptable salt, dosages may be calculated as the free base. As will be understood by those of skill in the art, in certain situations it may be necessary to administer the compounds disclosed herein in amounts that exceed, or even far exceed, the above-stated, preferred dosage range in order to effectively and aggressively treat particularly aggressive diseases or infections. [0133] Dosage amount and interval may be adjusted individually to provide plasma levels of the active moiety which are sufficient to maintain the modulating effects, or minimal effective concentration (MEC). The MEC will vary for each compound but can be estimated from in vitro data. Dosages necessary to achieve the MEC will depend on individual characteristics and route of administration. However, HPLC assays or bioassays can be used to determine plasma concentrations. Dosage intervals can also be determined using MEC value. Compositions should be administered using a regimen which maintains plasma levels above the MEC for 10-90% of the time, preferably between 30-90% and most preferably between 50-90%. In cases of local administration or selective uptake, the effective local concentration of the drug may not be related to plasma concentration.

[0134] It should be noted that the attending physician would know how to and when to terminate, interrupt, or adjust administration due to toxicity or organ dysfunctions. Conversely, the attending physician would also know to adjust treatment to higher levels if the clinical response were not adequate (precluding toxicity). The magnitude of an administrated dose in the management of the disorder of interest will vary with the severity of the condition to be treated and to the route of administration. The severity of the condition may, for example, be evaluated, in part, by standard prognostic evaluation methods. Further, the dose and perhaps dose frequency, will also vary according to the age, body weight, and response of the individual patient. A program comparable to that discussed above may be used in veterinary medicine.

[0135] Compounds disclosed herein can be evaluated for efficacy and toxicity using known methods. For example, the toxicology of a particular compound, or of a subset of the compounds, sharing certain chemical moieties, may be established by determining in vitro toxicity towards a cell line, such as a mammalian, and preferably human, cell line. The results of such studies are often predictive of toxicity in animals, such as mammals, or more specifically, humans. Alternatively, the toxicity of particular compounds in an animal model, such as mice, rats, rabbits, or monkeys, may be determined using known methods. The efficacy of a particular compound may be established using several recognized methods, such as in vitro methods, animal models, or human clinical trials. When selecting a model to determine efficacy, the skilled artisan can be guided by the state of the art to choose an appropriate model, dose, route of administration and/or regime. EXAMPLES [0136] These examples are provided for illustrative purposes only and not to limit the scope of the claims provided herein. Intermediate 1 tert-Butyl (S)-3-((3-iodo-1-trityl-1H-indazol-5-yl)carbamoyl)-3-(methyl thio)pyrrolidine- 1-carboxylate [0137] Step 1: 1H-indazol-5-amine: To a stirred solution of 5-nitro-1H-indazole (500 g, 4.05 mmol) in methanol (20 mL) was added 10% Pd/C (200 mg) and stirred at room temperature (rt) under hydrogen atmosphere for 2 h. The reaction mixture was filtered through Celite pad and the organic fractions were concentrated to afford the title compound (350 mg, 65% yield) as a brown colored solid. 1 H NMR (300 MHz, DMSO-d6) δ 12.56 (br s, 1H), 7.72 (s, 1H), 7.24 (d, J=8.4 Hz, 1H), 6.83-6.67 (m, 2H), 4.88 (br s, 2H); MS (ESI) m/z 134.06 [M+1] + . [0138] Step 2: (S)-tert-butyl 3-(1H-indazol-5-ylcarbamoyl)-3- (methylthio)pyrrolidine-1-carboxylate: To a stirred solution of (S)-1-(tert- butoxycarbonyl)-3-(methylthio)pyrrolidine-3-carboxylic acid (5 g, 19.15 mmol) (See ACS Med Chem Lett 2018, 761 for synthesis) in DMF (50 mL), was added 1H-indazol-5-amine (2.55 g , 19.1 mmol), HATU (10.9 g, 28.72 mmol) and N-ethyldiisopropyl amine (10.29 mL, 57.45 mmol) stirred at rt for 16 h. Water (100 mL) was added to the reaction mixture which was extracted with ethyl acetate (3 x 150 mL). The combined organic layers were washed with water (3 x 100 mL), brine (100 mL), dried over sodium sulphate and concentrated. The resultant residue was purified by column chromatography (100-200 silica) using 50% ethyl acetate in hexane as eluent to afford the title compound (5 g, 69% yield) as brown solid. 1 H NMR (400 MHz, DMSO-d6) δ 12.98 (br s, 1H), 9.70 (br d, J=5.9 Hz, 1H), 8.09-7.98 (m, 2H), 7.54-7.45 (m, 2H), 3.83-3.71 (m, 1H), 3.70-3.56 (m, 1H), 3.50-3.35 (m, 2H), 2.55-2.40 (m, 1H), 2.26 (br s, 1H), 2.08 (s, 3H), 1.22 (s, 9H); MS (ESI) m/z 377.17 [M+1] + . [0139] Step 3: (S)-tert-butyl 3-(3-iodo-1H-indazol-5-ylcarbamoyl)-3- (methylthio)pyrrolidine-1-carboxylate: To a stirred solution of (S)-tert-butyl 3-(1H- indazol-5-ylcarbamoyl)-3-(methylthio)pyrrolidine-1-carboxyla te (5 g, 13.26 mmol) in DMF (50 mL) at 0-5 °C, was added potassium hydroxide (7.31, 53.04 mmol) followed by iodine (3.69 g, 14.58 mmol). The mixture was stirred for 3 h at 0-5 °C. 10% NaHSO 4 in water (150 mL) was added to the reaction mixture which was extracted with ethyl acetate (3 x 150 mL). The combined organic layers were washed with water (150 mL), brine (100 mL), dried over sodium sulphate and concentrated. The resultant residue was purified by column chromatography using 20% ethyl acetate in hexane as eluent to afford the title compound (4.7 g, 70% yield) a solid. 1 H NMR (300 MHz, DMSO-d6) δ = 13.45 (br s, 1H), 9.82 (br d, J=4.0 Hz, 1H), 7.85 (br s, 1H), 7.65 (br d, J=8.8 Hz, 1H), 7.51 (d, J=9.2 Hz, 1H), 3.84-3.58 (m, 3H), 3.52-3.27 (m, 3H), 2.90 (s, 1H), 2.73 (s, 1H), 2.38 - 2.19 (br d, J=8.8 Hz, 2H), 2.08 (s, 3H), 1.47-1.37 (m, 9H). MS (ESI) m/z 503.09 [M+1] + . [0140] Step 4: (S)-tert-butyl 3-(3-iodo-1-trityl-1H-indazol-5-ylcarbamoyl)-3- (methylthio)pyrrolidine-1-carboxylate: To a stirred solution of (S)-tert-butyl 3-(3-iodo- 1H-indazol-5-ylcarbamoyl)-3-(methylthio)pyrrolidine-1-carbox ylate (4.7 g, 9.36 mmol) in acetonitrile (50 mL), at 0 -5 °C, was added potassium carbonate (6.45 g, 46.8 mmol) followed by trityl chloride (2.87 g, 10.29 mmol). The mixture was stirred for 3 h at rt. The solvent was concentrated followed by addition of water (150 mL). The mixture was extracted with EtOAc (3 x 150 mL). The combined organic layers were washed with brine (150 mL), dried over sodium sulfate and concentrated. The resultant residue was purified by column chromatography (100-200 silica) using 15% ethyl acetate: hexane as eluent to afford the title compound (4.5 g, 65% yield) as brown solid. 1 H NMR (400 MHz, DMSO-d6) δ = 9.79 (br d, J=9.3 Hz, 1H), 7.86 (s, 1H), 7.41-7.10 (m, 16H), 6.33 (d, J=9.3 Hz, 1H), 3.74 (br t, J=13.0 Hz, 1H), 3.59 (br dd, J=12.0, 17.4 Hz, 1H), 3.38 (br dd, J=7.1, 13.9 Hz, 2H), 2.56-2.37 (m, 1H), 2.21 (br s, 1H), 2.04 (s, 3H), 1.40 (s, 9H). Intermediate 2 tert-butyl (3S)-3-((3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl )carbamoyl)-3- (methylthio)pyrrolidine-1-carboxylate [0141] Step 1: (S)-tert-butyl 3-(3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H- indazol-5-ylcarbamoyl)-3-(methylthio)pyrrolidine-1-carboxyla te: To a stirred solution of (S)-tert-butyl 3-(3-iodo-1H-indazol-5-ylcarbamoyl)-3-(methylthio)pyrrolidin e-1-carboxylate (18.5 g, 36.8 mmol) in dichloromethane (200 mL) at 0 -5 °C, was added DHP (15.4 g, 183 mmole) followed by PTSA (0.699 g, 3.68 mmol). The mixture was stirred for 3 h at rt. The solvent was concentrated followed by addition of water (300 mL). The mixture was extracted with EtOAC (3 x 300 mL). The combined organic layers were washed with brine (150 mL), dried over sodium sulfate and concentrated. The resultant residue was purified by column chromatography using 15% ethyl acetate:hexane as eluent to afford the title compound (15.5 g, 72% yield). MS (ESI) m/z 587.35 [M+H] + . Intermediate 3 2-Chloro-1-(4-(4-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-3,6 -dihydropyridin-1(2H)- yl)ethan-1-one-2,2-d2 [0142] To a solution of chloroacetic acid-d2 (250 mg, 2.57 mmol) in toluene (5 mL) was added a drop of DMF followed by addition of oxalyl chloride (0.4 mL, 3.86 mmol) at 0 °C and stirred at rt for 1 h. The resulting clear solution was added to the dichloromethane (15 mL) solution of 4-(4-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-1,2,3,6-tetrahy dropyridine hydrochloride (500 mg, 1.80 mmol) and N,N-diisopropylethylamine (0.4 mL, 2.57 mmol) at 0 °C drop-wise and the reaction was stirred at rt for 1 h. The reaction mixture was quenched with sodium bicarbonate (10 mL) and extracted with ethyl acetate (2 x 20 mL). The combined organic layers were washed with water (10 mL), brine (10 mL), dried over sodium sulphate and concentrated. The resulting crude compound was purified by column chromatography by using 5% of methanol in dichloromethane as eluent to afford the title compound (200 mg, 20% yield) as an off-white solid. 1 H NMR (300 MHz, DMSO-d6) δ 8.51 (s, 1H), 7.96 (d, J = 8.4 Hz, 2H), 7.56-7.52 (m, 2H), 6.28 (s, 1H), 4.20-4.14 (m, 2H), 3.91 (s, 3H), 3.72-3.66 (m, 2H), 2.73-2.61 (m, 2H). MS (ESI) m/z 319.0 [M+1] + . Intermediate 4 (S)-N-(3-(6-Cyclopropoxypyridin-3-yl)-1H-indazol-5-yl)-3-(me thylthio)pyrrolidine-3- carboxamide [0143] Step 1: 5-Bromo-2-cyclopropoxypyridine: To a stirred solution of 5- bromo-2-fluoropyridine (12.0 g, 68.6 mmol) in NMP (120 mL) was added cyclopropanol (5.97 g, 102.9 mmol), Potassium t-butoxide solution in THF (1M, 103 mL, 102.9 mmol) at 0 °C and stirred at rt for 2 h. The reaction mixture was quenched with cold water (0-5 °C) and extracted with 50% EtOAc in pet-ether (2 x 500 mL). The combined organic layer was washed with water and dried over sodium sulfate and concentrated under reduced pressure to afford 5-bromo-2-cyclocycloxypyridine (11.2 g, 76% yield) which was used directly in the next step. MS (ESI) m/z 213.8 [M+H] + . [0144] Step 2: 2-Cyclopropoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)pyridine: To a stirred solution of 5-bromo-2-cyclopropoxypyridine (11.2 g, 52.7 mmol) in 1,4-dioxane (200 mL), were added bis(pinacalato)diboron (26.1 g, 103.3 mmol) and KOAc (15.2 g, 154.944 mmol). The reaction mixture was degassed with nitrogen for 10 min and then added PdCl 2 (dppf)-dichloromethane complex (4.22 g, 5.16 mmol) and continued the degassing for further 10 min. The mixture was stirred at 80 °C for 16 h and cooled for use in the next step without purification. [0145] Step 3: (3S)-tert-butyl 3-(3-(6-cyclopropoxypyridin-3-yl)-1-(tetrahydro- 2H-pyran-2-yl)-1H-indazol-5-ylcarbamoyl)-3-(methylthio)pyrro lidine-1-carboxylate: To a stirred solution of (3S)-tert-butyl 3-(3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5- ylcarbamoyl)-3-(methylthio)pyrrolidine-1-carboxylate (14.0 g, 23.9 mmol) and 2- cyclopropoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridine (11.2 g, 43.0 mmol) in dioxane: water (1:1 200 mL total) was added potassium carbonate (16.5 g, 119.4 mmol) followed by tetrakis(triphenylphosphine)palladium (0) (1.38 g, 1.19 mmol), degassed for 10 min followed by heating at 80 °C for 16 h. The reaction mixture was cooled to rt, cold water was added and extracted with ethyl acetate (3 x 500 mL). The combined organic layers were washed with water (200 mL), brine (200 mL), dried over sodium sulphate and concentrated. The crude compound was purified by column chromatography using 40 - 50% ethyl acetate in hexane as eluent to afford (3S)-tert-butyl 3-(3-(6-cyclopropoxypyridin-3-yl)-1-(tetrahydro- 2H-pyran-2-yl)-1H-indazol-5-ylcarbamoyl)-3-(methylthio)pyrro lidine-1-carboxylate (13.6 g, 41% yield) as colorless thick liquid. MS (ESI) m/z 594.19 [M+H] + . [0146] Step 4: (S)-N-(3-(6-Cyclopropoxypyridin-3-yl)-1H-indazol-5-yl)- 3(methylthio)pyrrolidine-3-carboxamide: To a stirred solution of (3S)-tert-butyl 3-(3-(6- cyclopropoxypyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-in dazol-5-ylcarbamoyl)-3- (methylthio)pyrrolidine-1-carboxylate (13.6 g, 22.9 mmol) was added TFA (130 mL) and the mixture was stirred at rt for 16 h. The reaction mixture was concentrated under reduced pressure. The crude compound was purified by column chromatography using 10 - 20% dichloromethane in methanol to afford (S)-N-(3-(6-cyclopropoxypyridin-3-yl)-1H-indazol-5- yl)-3(methylthio)pyrrolidine-3-carboxamide (4.0 g, 42% yield) which was used to next step without any further purification. MS (ESI) m/z 410.11 [M+H] + .

Intermediate 5 (S)-N-(3-(6-Cyclobutoxypyridin-3-yl)-1H-indazol-5-yl)-3-(met hylthio)pyrrolidine-3- carboxamide [0147] The title compound was prepared following procedures described for Intermediate 4 using (S)-tert-butyl 3-(3-iodo-1-trityl-1H-indazol-5-ylcarbamoyl)-3- (methylthio)pyrrolidine-1-carboxylate and 2-cyclobutoxy-5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)pyridine. MS (ESI) m/z 666.41 [M+H] + . Intermediate 6 (S)-N-(3-(5-Cyclopropoxy-6-methoxypyridin-2-yl)-1H-indazol-5 -yl)-3- (methylthio)pyrrolidine-3-carboxamide [0148] The title compound was prepared following procedures described for Intermediate 4 using t-butyl (3S)-3-((3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5- yl)carbamoyl)-3-(methylthio)pyrrolidine-1-carboxylate and 3-cyclopropoxy-2-methoxy-6- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine. MS (ESI) m/z 440.45 [M+H] + . Intermediate 7 (S)-N-(3-(5-Cyclopropoxy-6-ethoxypyridin-2-yl)-1H-indazol-5- yl)-3- (methylthio)pyrrolidine-3-carboxamide [0149] Step 1: 2-Chloro-6-iodo-3-(4-methoxybenzyloxy)pyridine: To a stirred solution of 2-chloro-6-iodopyridin-3-ol (6 g, 19.60 mmol) in DMF (30 mL) was added 4- methoxybenzyl bromide (3.6 mL, 25.5 mmol), potassium carbonate (3.7 g, 29.40 mmol) and the reaction mixture heated to 70 °C for 5 h. The reaction mixture was diluted with water and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with water (2 x 50 mL), brine (1 x 60 mL), dried over sodium sulphate and concentrated. The resultant residue was purified by column chromatography using 10% ethyl acetate in hexane as eluent to afford 2-chloro-6-iodo-3-(4-methoxybenzyloxy)pyridine (7 g, 80% yield) as a solid. MS (ESI) m/z 376.17 [M+H] + . [0150] Step 2: 2-Ethoxy-6-iodo-3-(4-methoxybenzyloxy)pyridine: To the stirred solution of 2-chloro-6-iodo-3-(4-methoxybenzyloxy)pyridine (6.5 g, 17.3 mmol) in EtOH (65 mL) was added potassium t-butoxide (1.94 g, 17.44 mmol) at rt and the reaction was stirred at 80 °C for 24 h in a sealed vessel. Solvent was removed in-vacuo and the residue was diluted with water and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with water (2 x 40 mL), brine (1 x 60 mL), dried over sodium sulfate and concentrated. The resultant residue was purified by column chromatography using 15% ethyl acetate in hexane to afford 2-ethoxy-6-iodo-3-(4- methoxybenzyloxy)pyridine (3.4 g, 51% yield) as a liquid. MS (ESI) m/z 385.92 [M+H] + . [0151] Step 3: 2-Ethoxy-6-iodopyridin-3-ol: To the stirred solution of compound 2-ethoxy-6-iodo-3-(4-methoxybenzyloxy)pyridine (3 g, 7.79 mmol) in dichloromethane (15 mL) was added TFA (5 mL) at 0 °C and the reaction was heated to the reflux temperature for 30 min. The reaction mixture was quenched with aq. NaHCO 3 and extracted with ethyl acetate (3 x 40 mL). The combined organic layers were washed with water (2 x 30 mL), brine (1 x 50 mL), dried over sodium sulphate and concentrated. The resultant residue was purified by column chromatography using 25% ethyl acetate in hexane as eluent to afford 2-ethoxy-6-iodopyridin-3-ol (1.5 g, 75% yield) as a liquid. MS (ESI) m/z 266.04 [M+H] + . [0152] Step 4: 3-Cyclopropoxy-2-ethoxy-6-iodopyridine: To the stirred solution of 2-ethoxy-6-iodopyridin-3-ol (1.5 g, 5.66 mmol) in DMF (30 mL) was added bromocyclopropane (4.5 mL, 56.6 mmol), cesium carbonate (5.51 g, 17.0 mmol) and sodium iodide (0.84 g, 5.66 mmol) at rt. The mixture was stirred at 150 °C for 12 h in sealed vessel. The reaction mixture was quenched with ice-cold water and extracted with ethyl acetate (2 x 40 mL). The combined organic layer was washed with water (30 mL) and brine solution (30 mL), dried over sodium sulphate, concentrated under reduced pressure. The resultant crude was purified by column chromatography using 5% ethyl acetate in petroleum ether to afford 3-cyclopropoxy-2-ethoxy-6-iodopyridine (550 mg, 34% yield) as a liquid. MS (ESI) m/z 306.18 [M+H] + . [0153] Step 5: 3-Cyclopropoxy-2-ethoxy-6-(trimethylstannyl)pyridine: To a stirred and degassed solution of 3-cyclopropoxy-2-ethoxy-6-iodopyridine (350 mg, 1.14 mmol) in dioxane (15 mL) was added hexamethylditin (0.3 mL, 1.37 mmol) followed by tetrakis(triphenylphosphine)palladium (0) (65 mg, 0.05 mmol) at rt. The reaction was stirred at 80° C for 5 h in sealed vessel. The reaction was used directly in the next step. [0154] Step 6: (3S)-tert-butyl 3-(3-(5-Cyclopropoxy-6-ethoxypyridin-2-yl)-1- (tetrahydro-2H-pyran-2-yl)-1H-indazol-5-ylcarbamoyl)-3-(meth ylthio)pyrrolidine-1- carboxylate: To a stirred and degassed solution of the above reaction mixture was added 3- cyclopropoxy-2-ethoxy-6-(trimethylstannyl)pyridine (450 mg, 0.71 mmol) in dioxane (15 mL), (3S)-tert-butyl 3-(3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-ylcarbam oyl)-3- (methylthio)pyrrolidine-1-carboxylate (0.25 g, 0.49 mmol), cesium fluoride (0.35 mg, 2.28 mmol), cupper iodide (21 mg, 0.11 mmol) followed by tetrakis(triphenylphosphine)palladium(0) (65 mg, 0.05 mmol) at rt, and the mixture was stirred at 90 °C for 16 h in sealed tube. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulphate and concentrated under reduced pressure. The resultant residue was purified by column chromatography using 35% ethyl acetate in hexane as eluent to afford (3S)-tert-butyl 3-(3-(5-cyclopropoxy-6-ethoxypyridin-2-yl)-1-(tetrahydro- 2H-pyran-2-yl)-1H-indazol-5-ylcarbamoyl)-3-(methylthio)pyrro lidine-1-carboxylate (200 mg, 29% yield overall for 2 steps) as an off-white solid. MS (ESI) m/z 638.22 [M+H] + . [0155] Step 7: (S)-N-(3-(5-Cyclopropoxy-6-ethoxypyridin-2-yl)-1H-indazol-5- yl)-3-(methylthio)pyrrolidine-3-carboxamide: To (3S)-tert-butyl 3-(3-(5-cyclopropoxy-6- ethoxypyridin-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol- 5-ylcarbamoyl)-3- (methylthio)pyrrolidine-1-carboxylate (190 mg, 0.29 mmol) was added TFA (5 mL) at 0 °C and with stirring at rt for 16 h. The reaction was concentrated in-vacuo and the crude mixture was triturated with diethyl ether to afford (S)-N-(3-(5-cyclopropoxy-6-ethoxypyridin-2-yl)- 1H-indazol-5-yl)-3-(methylthio) pyrrolidine-3-carboxamide (80 mg, 61% yield) as an off- white solid. MS (ESI) m/z 454.10 [M+H] + . Intermediate 8 (S)-N-(3-(5-Cyclopropoxy-6-(methoxy-d3)pyridin-2-yl)-1H-inda zol-5-yl)-3- (methylthio)pyrrolidine-3-carboxamide [0156] The title compound was prepared following procedures described for Intermediate 7 using 2-chloro-6-iodo-3-(4-methoxybenzyloxy)pyridine, sodium methoxide- d 3 , and 3-(3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-ylcarbam oyl)-3- (methylthio)pyrrolidine-1-carboxylate. MS (ESI) m/z 443.20 [M+H] + . Intermediate 9 (S)-N-(3-(5-Cyclopropoxy-6-methylpyridin-2-yl)-1H-indazol-5- yl)-3- (methylthio)pyrrolidine-3-carboxamide [0157] The title compound was prepared following procedures described for Intermediate 7 using 6-bromo-2-methylpyridin-3-ol, bromocyclopropane, and 3-(3-iodo-1- (tetrahydro-2H-pyran-2-yl)-1H-indazol-5-ylcarbamoyl)-3-(meth ylthio)pyrrolidine-1- carboxylate. MS (ESI) m/z 423.17 [M+H] + . Intermediate 10 (S)-N-(3-(5-cyclopropoxy-6-(dimethylamino)pyridin-2-yl)-1H-i ndazol-5-yl)-3- (methylthio)pyrrolidine-3-carboxamide [0158] The title compound was prepared following procedures described for Intermediate 7 using 3-cyclopropoxy-N,N-dimethyl-6-(trimethylstannyl)pyridin-2-am ine and 3-(3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-ylcarbam oyl)-3- (methylthio)pyrrolidine-1-carboxylate. MS (ESI) m/z 453.15 [M+H] + . Intermediate 11 2-Chloro-1-(4-(3-fluoro-4-(1-methyl-1H-1,2,4-triazol-3-yl)ph enyl)-3,6-dihydropyridin- 1(2H)-yl)ethan-1-one-2,2-d2 [0159] The title compound was prepared following procedures described for Intermediate 3 using 4-(3-fluoro-4-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-1,2,3, 6- tetrahydropyridine hydrochloride and chloroacetic acid-d 3 . MS (ESI) m/z 337.02 [M+H] + . Intermediate 12 (S)-N-(3-(6-Cyclopropoxy-5-fluoropyridin-2-yl)-1H-indazol-5- yl)-3- (methylthio)pyrrolidine-3-carboxamide [0160] The title compound was prepared following procedures described for Intermediate 4 using 3-(3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-ylcarbam oyl)-3- (methylthio)pyrrolidine-1-carboxylate and (6-cyclopropoxy-5-fluoropyridin-2-yl)boronic acid. MS (ESI) m/z 428.10 [M+H] + . Intermediate 13 3-(6-Cyclopropoxypyridin-3-yl)-7-fluoro-1-(tetrahydro-2H-pyr an-2-yl)-1H-indazol-5- amine [0161] Step 1: 3-bromo-7-fluoro-5-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H- indazole: To a stirred mixture of 3-bromo-7-fluoro-5-nitro-1H-indazole (3.5 g, 13.46 mmol) and p-toluenesulfonic acid monohydrate (0.256 g, 1.35 mmol) in dichloromethane (67 mL) was added 3,4-dihydro-2H-pyran (2.83 g, 33.7 mmol). The mixture was stirred for 2 h at rt, and then washed with water (100 mL) and aqueous sodium bicarbonate solution (100 mL). The organic phase was concentrated in-vacuo to provide a brown solid, and then triturated with a diethyl ether/hexane mixture followed by filtration to afford 3-bromo-7-fluoro-5-nitro- 1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (3.1 g, 67% yield) as a white solid. MS (ESI) m/z 345.1 [M+H] + . [0162] Step 2: 3-(6-Cyclopropoxypyridin-3-yl)-7-fluoro-5-nitro-1- (tetrahydro-2H-pyran-2-yl)-1H-indazole: To a mixture of 3-bromo-7-fluoro-5-nitro-1- (tetrahydro-2H-pyran-2-yl)-1H-indazole (2.0 g, 5.8 mmol) in DME:H2O (8:2, 20 mL) was added 2-cyclopropoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-y l)pyridine) (3.0 g, 11.6 mmol) and Cs 2 CO 3 (3.7 g, 11.66 mmol). The mixture was degassed for 15 min. Pd(dppf)Cl 2 (426 mg, 0.58 mmol) was added, and the mixture was degassed for an additional 10 min. The mixture was heated at 80 °C for 4 h. The mixture was cooled to rt, filtered through a celite pad which was washed with ethyl acetate (500 mL). The filtrate was diluted with water (200 mL) and extracted with ethyl acetate (3 x 300 mL). The combined organic layers were washed with water (3 x 300 mL) and brine (250 mL), dried over sodium sulfate and concentrated. The crude compound was purified by column chromatography using 40-50% ethyl acetate in hexane as the eluent to afford 3-(6-cyclopropoxypyridin-3-yl)-7-fluoro-5- nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (1.5 g, 3.7 mmol, 65% yield) as an off-white solid. MS (ESI) m/z 399.08 [M+H] + . [0163] Step 3: 3-(6-cyclopropoxypyridin-3-yl)-7-fluoro-1-(tetrahydro-2H- pyran-2-yl)-1H-indazol-5-amine: To a solution of 3-(6-cyclopropoxypyridin-3-yl)-7- fluoro-5-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (1.5 g, 3.7 mmol) in toluene:MeOH (1:1 v/v, 40 mL total) was added 10% Pd/C (500 mg). The reaction was stirred under H 2 (60 psi) for 6 h. The mixture was filtered through a celite bed, and the filtrate was concentrated under reduced pressure to afford 3-(6-cyclopropoxypyridin-3-yl)-7-fluoro-1-(tetrahydro-2H- pyran-2-yl)-1H-indazol-5-amine (1.3 g, 3.33 mmol, 94% yield) as a brown solid, which was used directly in the next step. MS (ESI) m/z 369.54 [M+H] + . General Procedure A: Amide coupling [0164] To a stirred solution of corresponding amine (A) (1 equiv, PG 1 = Trt or THP) in DMF (0.1-0.5 M, initial concentration of the amine in DMF varied from 0.1 M to 0.5 M based on solubility) was added corresponding the carboxylic acid (B) (1.0-1.1 equiv, PG 2 = Cbz or Boc), HATU (1.0-1.2 equiv) and DIPEA (2-4 equiv) and the mixture was stirred at rt for 4-16 h. Water was added and the mixture was extracted with ethyl acetate. The combined organic layers were washed with water, brine, dried over sodium sulfate and concentrated. The residue was purified by column chromatography using ethyl acetate in hexane to afford the desired corresponding compound. General Procedure B: De-protection of amine/indazole [0165] A solution of C (1 equiv, PG 1 = Trt or THP; PG 2 = Cbz or Boc) in DCM/TFA/water (0.05 or 0.5 M, 3:1:0.5 ratio, conditions varied based on solubility of staring material; a mixed DCM/TFA solvent was used in some preparations; see also Note #1) was stirred at 25 °C overnight. Upon completion as determined by LCMS, the reaction was quenched with saturated aqueous sodium bicarbonate and extracted with dichloromethane (or extracted with ethyl acetate or ethyl acetate/tetrahydrofuran mixtures). The combined organic layers were dried over sodium sulfate, filtered and concentrated to afford the crude product D. Crude product D was then either, 1) purified on a silica gel column eluting with 0-100% dichloromethane/ (0-10% 7 M NH 3 in methanol)/dichloromethane, or 2) purified on a rp-C18 HPLC column eluting with 0-100% acetonitrile:water in the presence of 0.1% formic acid to afford the pure compound D. When crude material was purified on rp-C18 HPLC column or C18 cartridges, compounds were free-based using aqueous saturated aqueous sodium bicarbonate and extracted with either dichloromethane, ethyl acetate or ethyl acetate/THF mixtures. [0166] Note #1: In some cases, a solution of HCl in alcoholic solvents was used to de-protect both PG 1 and PG 2 . General Procedure C: Alkylation of secondary amine (a representative example) [0167] To a solution of corresponding secondary amine D (1 equiv.) in N,N- dimethylformamide (0.1-0.5 M, initial concentration of secondary amine in DMF varied from 0.1 M to 0.5 M based on solubility) at 25 °C, were added neat N-ethyl-N-isopropylpropan-2- amine (3-6 equiv., excess N-ethyl-N-isopropylpropan-2-amine was used, or N-ethyl-N- isopropylpropan-2-amine was replaced with trimethylamine) and the corresponding alkylating agent E (1.0-1.1 equiv., preferably 1.0 equiv. of alkylating agent was used in order to minimize over-alkylation) in one portion. The mixture was stirred at rt for 6-24 h; if needed, the mixture was heated at 50 °C. Upon completion as determined by LCMS or TLC, the mixture was either 1) concentrated directly on a rotary evaporator to give the crude mixture that was purified on a silica gel column eluting with methanol in dichloromethane or 2) purified on a rp-C18 HPLC column eluting with acetonitrile in water in the presence of 0.1% formic acid to afford the desired corresponding compound F. General Procedure D: Preparation of hydrochloride salt [0168] Compound F was dissolved in a suitable solvent (0.1-0.5 M, dichloromethane, methanol or i-propyl alcohol). Hydrochloric acid (1-3 equiv., 2.0 M in diethyl ether) was added at 0 °C. The precipitate was stirred for 5-10 mins at 0 °C. Excess solvent(s) and hydrochloric acid were removed using a rotary evaporator at 0 °C. The product was dried to afford the corresponding compound G as a hydrochloric acid salt (equiv. of hydrochloride salt was determined by 1 H NMR analysis). Example 1 (S)-1-(2-(4-(4-(1-Cyclopropyl-1H-1,2,4-triazol-3-yl)phenyl)- 3,6-dihydropyridin-1(2H)- yl)-2-oxoethyl)-N-(3-(6-isopropoxypyridin-3-yl)-1H-indazol-5 -yl)-3- (methylthio)pyrrolidine-3-carboxamide [0169] The title compound was prepared following General Procedures A, B and C using 3-(6-isopropoxypyridin-3-yl)-1-trityl-1H-indazol-5-amine (See WO 2016/161160), (S)-1-(tert-butoxycarbonyl)-3-(methylthio)pyrrolidine-3-carb oxylic acid (See ACS Med Chem Lett 2018, 761 for synthesis) and 2-chloro-1-(4-(4-(1-cyclopropyl-1H-1,2,4- triazol-3-yl)phenyl)-5,6-dihydropyridin-1(2H)-yl)ethanone (See WO 2016/161160). 1 H NMR (400 MHz, DMSO-d6) δ 13.19 (s, 1H), 9.98 (d, J = 11.4 Hz, 1H), 8.70 (s, 1H), 8.61 (s, 1H), 8.41 (s, 1H), 8.18 (d, J = 8.80 Hz, 1H), 7.92 (d, J = 8.80 Hz, 1H), 7.86 (d, J = 12.0 Hz, 1H), 7.77 (d, J = 8.80,1.60 Hz, 1H), 7.53-7.47 (m, 2H), 7.40 (d, J = 8.80 Hz, 1H), 6.92-6.88 (m, 1H), 6.25-6.20 (m, 1H), 5.33-5.28 (m, 1H), 4.26-4.12 (m, 3H), 3.84-3.60 (m, 4H), 3.55-3.44 (m, 3H), 2.88-2.70 (m, 4H), 2.05 (s, 3H), 2.00-1.95 (m, 1H), 1.33 (s, 3H), 1.31 (s, 3H), 1.15- 1.02 (m, 4H). MS (ESI) m/z 718.42 [M+H] + . Example 2 (S)-N-(3-(6-Cyclopropoxypyridin-3-yl)-1H-indazol-5-yl)-1-(2- (4-(4-(1-methyl-1H-1,2,4- triazol-3-yl)phenyl)-3,6-dihydropyridin-1(2H)-yl)-2-oxoethyl )-3- (methylthio)pyrrolidine-3-carboxamide [0170] The title compound was prepared following General Procedures B and C using (3S)-tert-butyl 3-(3-(6-cyclopropoxypyridin-3-yl)-1-(tetrahydro-2H-pyran-2-y l)-1H- indazol-5-ylcarbamoyl)-3-(methylthio)pyrrolidine-1-carboxyla te acid and 2-chloro-1-(4-(4- (1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-5,6-dihydropyridin-1 (2H)-yl)ethanone (See WO 2016/161160). mp: 156–158 °C: 1 H NMR (400 MHz, DMSO-d6) δ 13.25 (s, 1H), 9.99 (s, 1H), 8.75 (s, 1H), 8.50 (s, 1H), 8.42 (s, 1H), 8.21 (d, J = 8.7 Hz, 1H), 7.95-7.84 (m, 2H), 7.76 (d, J = 9.3 Hz, 1H), 7.55-7.84 (m, 2H), 7.41 (d, J = 8.4 Hz, 1H), 7.06-6.99 (m, 1H), 6.27-6.19 (m, 1H), 4.27-4.20 (m, 2H), 4.16-4.14 (m, 1H), 3.91 (s, 3H), 3.72-3.66 (m, 3H), 3.50-3.46 (m, 3H), 2.79-2.64 (m, 5H), 2.05 (s, 3H), 1.99-1.97 (m, 1H), 0.83-0.71 (m, 4H); MS (ESI) m/z 690.14 [M+H] + .

Example 3 (S)-N-(3-(6-Cyclopropoxypyridin-3-yl)-1H-indazol-5-yl)-1-(2- (4-(4-(1-methyl-1H-1,2,4- triazol-3-yl)phenyl)-3,6-dihydropyridin-1(2H)-yl)-2-oxoethyl -1,1-d2)-3- (methylthio)pyrrolidine-3-carboxamide [0171] The title compound was prepared following General Procedures B and C using (3S) tert-butyl 3-(3-(6-cyclopropoxypyridin-3-yl)-1-(tetrahydro-2H-pyran-2-y l)-1H- indazol-5-ylcarbamoyl)-3-(methylthio)pyrrolidine-1-carboxyla te acid and 2-chloro-1-(4-(4- (1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-3,6-dihydropyridin-1 (2H)-yl)ethan-1-one-2,2-d 2 . mp: 156–158 °C; 1 H NMR (300 MHz, DMSO-d6) δ 13.25 (s, 1H), 9.99 (s, 1H), 8.75 (s, 1H), 8.50 (s, 1H), 8.42 (s, 1H), 8.21 (d, J = 8.7 Hz, 1H), 7.95-7.84 (m, 2H), 7.76 (d, J = 9.3 Hz, 1H), 7.55-7.84 (m, 2H), 7.41 (d, J = 8.4 Hz, 1H), 7.06-6.99 (m, 1H), 6.27– 6.19 (m, 1H), 4.27-4.14 (m, 3H), 3.91 (s, 3H), 3.72-3.66 (m, 2H), 3.50-3.46 (m, 1H), 2.80-2.64 (m, 6H), 2.05 (s, 3H), 1.99-1.97 (m, 1H), 0.83-0.71 (m, 4H); MS (ESI) m/z: 692.15 [M+H] + . Example 4 (S)-N-(3-(6-Cyclobutoxypyridin-3-yl)-1H-indazol-5-yl)-1-(2-( 4-(4-(1-methyl-1H-1,2,4- triazol-3-yl)phenyl)-3,6-dihydropyridin-1(2H)-yl)-2-oxoethyl -1,1-d2)-3- (methylthio)pyrrolidine-3-carboxamide [0172] The title compound was prepared following General Procedure C using (S)-N-(3-(6-cyclobutoxypyridin-3-yl)-1H-indazol-5-yl)-3-(met hylthio)pyrrolidine-3- carboxamide and 2-chloro-1-(4-(4-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-3,6 - dihydropyridin-1(2H)-yl)ethan-1-one-2,2-d2. 1 H NMR (DMSO–d6, 400 MHz) δ 13.21 (s, 1H), 9.95-9.93 (m, 1H), 8.68 (s, 1H), 8.49 (s, 1H), 8.39 (s, 1H), 8.18 (dd, J = 8.8, 2.8 Hz, 1H), 7.96-7.85 (m, 2H), 7.76 (d, J = 8.8 Hz, 1H), 7.55-7.47 (m, 2H), 7.41 (d, J = 8.4 Hz, 1H), 6.97-6.91 (m, 1H), 6.27-6.18 (m, 1H), 5.19 (qt, J = 7.6 Hz, 1H), 4.27-4.07 (m, 2H), 3.91 (s, 3H), 3.77-3.63 (m, 2H), 3.50-3.46 (m, 1H), 2.86-2.57 (m, 5H), 2.44-2.38 (m, 3H), 2.15-1.96 (m, 6H), 1.83-1.76 (m, 1H), 1.69-1.60 (m, 1H). MS (ESI) m/z 706.60 [M+H] + . Example 5 (S)-N-(3-(5-Cyclopropoxy-6-methoxypyridin-2-yl)-1H-indazol-5 -yl)-1-(2-(4-(4-(1- methyl-1H-1,2,4-triazol-3-yl)phenyl)-3,6-dihydropyridin-1(2H )-yl)-2-oxoethyl)-3- (methylthio)pyrrolidine-3-carboxamide [0173] The title compound was prepared following General Procedure C using (S)-N-(3-(5-cyclopropoxy-6-methoxypyridin-2-yl)-1H-indazol-5 -yl)-3- (methylthio)pyrrolidine-3-carboxamide and 2-chloro-1-(4-(4-(1-methyl-1H-1,2,4-triazol-3- yl)phenyl)-5,6-dihydropyridin-1(2H)-yl)ethanone. mp: 144–146 °C; 1 H NMR (400 MHz, DMSO-d 6, VT NMR, 90 °C) δ 13.02 (s, 1H), 9.62 (s, 1H), 8.98 (s, 1H), 8.41 (s, 1H), 7.90 (d, J = 8.0 Hz, 2H), 7.68 (d, J = 8.0 Hz, 1H), 7.60 (d, J = 8.4 Hz, 1H), 7.46-7.40 (m, 4H), 6.23- 6.17 (m, 1H), 4.22-4.10 (m, 2H), 4.09 (s, 3H), 3.96-3.87 (m, 4H), 3.73-3.69 (m, 2H), 3.51- 3.43 (m, 3H), 2.86-2.75 (m, 3H), 2.67-2.60 (m, 1H), 2.54-2.52 (m, 2H), 2.07 (s, 3H), 2.05- 1.98 (m, 1H), 0.81-0.68 (m, 4H). MS (ESI) m/z 720.58 [M+H] + . Example 6 (S)-N-(3-(5-Cyclopropoxy-6-ethoxypyridin-2-yl)-1H-indazol-5- yl)-1-(2-(4-(4-(1-methyl- 1H-1,2,4-triazol-3-yl)phenyl)-3,6-dihydropyridin-1(2H)-yl)-2 -oxoethyl)-3- (methylthio)pyrrolidine-3-carboxamide [0174] The title compound was prepared following General Procedure C using (S)-N-(3-(5-cyclopropoxy-6-ethoxypyridin-2-yl)-1H-indazol-5- yl)-3-(methylthio) pyrrolidine-3-carboxamide and 2-chloro-1-(4-(4-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)- 5,6-dihydropyridin-1(2H)-yl)ethanone. NMR (400 MHz, DMSO-d6) δ 13.05 (s, 1H), 9.83-9.81 (m, 1H), 9.09-9.05 (m, 1H), 8.49 (s, 1H), 7.92 (d, J = 8 Hz, 1H), 7.86 (d, J = 8.4 Hz, 1H), 7.72-7.69 (m, 1H), 7.65-7.60 (m, 1H), 7.50-7.47 (m, 2H), 7.42-7.38 (m, 2H), 6.27- 6.18 (m, 1H), 4.63-4.57 (m, 2H), 4.28-4.08 (m, 3H), 3.91 (s, 3H), 3.90-3.87 (m, 1H) 3.74- 3.65 (m, 2H), 3.49–3.41 (m, 4H), 2.79-2.65 (m, 4H), 2.06 (s, 3H), 2.02-1.99 (m, 1H), 1.40 (t, J = 6.8 Hz, 3H), 0.82-0.72 (m, 4H). MS (ESI) m/z 734.59 [M+H] + . Example 7 (S)-N-(3-(6-Cyclopropoxypyridin-3-yl)-1H-indazol-5-yl)-1-(2- (4-(5-(1-methyl-1H-1,2,4- triazol-3-yl)thiazol-2-yl)-3,6-dihydropyridin-1(2H)-yl)-2-ox oethyl)-3- (methylthio)pyrrolidine-3-carboxamide [0175] The title compound was prepared following General Procedure C using (S)-N-(3-(6-cyclopropoxypyridin-3-yl)-1H-indazol-5-yl)-3(met hylthio)pyrrolidine-3- carboxamide and 2-chloro-1-(4-(5-(1-methyl-1H-1,2,4-triazol-3-yl)thiazol-2-y l)-5,6- dihydropyridin-1(2H)-yl)ethanone (See WO 2018/067512). mp: 138–140 °C; NMR (400 MHz, DMSO-d6) δ 13.21 (s, 1H), 9.97-9.90 (m, 1H), 8.74 (s, 1H), 8.55 (s, 1H), 8.39 (s, 1H), 8.25-8.17 (m, 1H), 8.15-8.09 (m, 1H), 7.74 (d, J = 8.8 Hz, 1H), 7.50 (d, J = 9.2 Hz, 1H), 7.02 (d, J = 8.8 Hz, 1H), 6.70-6.60 (m, 1H), 4.40-4.20 (m, 2H), 4.22-4.15 (m, 1H), 3.90 (s, 3H), 3.72-3.66 (m, 2H), 3.53-3.29 (m, 3H), 2.83-2.70 (m, 3H), 2.70-2.60 (m, 3H), 2.03 (s, 3H), 2.02-1.93(m, 1H), 0.83-0.70 (m, 4H); MS (ESI) m/z 697.52 [M+H] + . Example 8 (S)-N-(3-(6-Cyclopropoxypyridin-3-yl)-1H-indazol-5-yl)-1-(2- (4-(5-(1-methyl-1H-1,2,4- triazol-3-yl)-1,3,4-thiadiazol-2-yl)-3,6-dihydropyridin-1(2H )-yl)-2-oxoethyl)-3- (methylthio)pyrrolidine-3-carboxamide [0176] The title compound was prepared following General Procedure C using (S)-N-(3-(6-cyclopropoxypyridin-3-yl)-1H-indazol-5-yl)-3-(me thylthio)pyrrolidine-3- carboxamide and 2-chloro-1-(4-(5-(1-methyl-1H-1,2,4-triazol-3-yl)-1,3,4-thia diazol-2-yl)- 5,6-dihydropyridin-1(2H)-yl)ethanone (See WO 2018/067512). mp: 95-97 °C; 1 H NMR (400 MHz, DMSO-d 6 ) δ 13.17 (s, 1H), 9.91 (s, 1H), 8.72 (d, J = 13.6 Hz, 2H), 8.38 (d, J = 8.4 Hz, 1H), 8.21 (dd, J = 8.4, 2 Hz, 1H), 7.75-7.72 (m, 1H), 7.50 (d, J = 8.8 Hz, 1H), 7.02 (d, J = 8.4 Hz, 1H), 6.78-6.71 (m, 1H), 4.36-4.23 (m, 3H), 3.98 (s, 3H), 3.75-3.71 (m, 2H), 3.54-3.34 (m, 3H), 2.82-2.61 (m, 6H), 2.04 (s, 3H), 2.01-1.98 (m, 1H), 0.82-0.70 (m, 4H). MS (ESI) m/z 698.18 [M+H] + . Example 9 (S)-N-(3-(5-Cyclopropoxy-6-methoxypyridin-2-yl)-1H-indazol-5 -yl)-1-(2-(4-(4-(1- methyl-1H-1,2,4-triazol-3-yl)phenyl)-3,6-dihydropyridin-1(2H )-yl)-2-oxoethyl-1,1-d2)-3- (methylthio)pyrrolidine-3-carboxamide [0177] The title compound was prepared following General Procedure C using (S)-N-(3-(5-cyclopropoxy-6-methoxypyridin-2-yl)-1H-indazol-5 -yl)-3- (methylthio)pyrrolidine-3-carboxamide and 2-chloro-1-(4-(4-(1-methyl-1H-1,2,4-triazol-3- yl)phenyl)-3,6-dihydropyridin-1(2H)-yl)ethan-1-one-2,2-d2. mp: 145–147 °C: 1 H NMR (400 MHz, DMSO-d 6 ) δ 13.20 (s, 1H), 9.98 (m, 1H), 8.92 (s, 1H), 8.55 (s, 1H), 7.9 (d, J = 8.4 Hz, 1H), 7.86 (d, J = 8.4 Hz, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.68-7.60 (m, 1H), 7.50-7.40 (m, 4H), 6.30-6.20 (m, 1H), 4.40-4.10 (m, 3H), 4.08 (s, 3H), 3.91 (s, 4H), 3.74-3.70 (m, 1H), 3.68- 3.64 (m, 1H), 3.50-3.43 (m, 1H), 2.80-2.70 (m, 3H), 2.70-2.60 (m, 2H), 2.05 (s, 3H), 2.02- 1.93(m, 1H), 0.83-0.70 (m, 4H). MS (ESI) m/z 722.60 [M+H] + . Example 10 (S)-N-(3-(5-Cyclopropoxy-6-methoxypyridin-2-yl)-1H-indazol-5 -yl)-1-(2-(4-(3-fluoro-4- (1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-3,6-dihydropyridin-1 (2H)-yl)-2-oxoethyl)-3- (methylthio)pyrrolidine-3-carboxamide [0178] The title compound was prepared following General Procedure C using (S)-N-(3-(5-cyclopropoxy-6-methoxypyridin-2-yl)-1H-indazol-5 -yl)-3- (methylthio)pyrrolidine-3-carboxamide and 2-chloro-1-(4-(3-fluoro-4-(1-methyl-1H-1,2,4- triazol-3-yl)phenyl)-5,6-dihydropyridin-1(2H)-yl)ethanone (See WO 2016/161160). mp:146 –148 °C; NMR (400 MHz, DMSO-d6) δ 13.02 (s, 1H), 9.89 (s, 1H), 9.07 (s, 1H), 8.54 (s, 1H), 7.98-7.82 (m, 1H), 7.73-7.59 (m, 2H), 7.47-7.41 (m, 2H), 7.37 –7.23 (m, 2H), 6.38-6.28 (m, 1H), 4.32-4.06 (m, 2H), 4.08 (s, 3H), 3.93 (s, 3H), 3.74-3.62 (m, 2H), 3.48-3.41 (m, 3H), 2.81-2.71 (m, 3H), 2.68-2.61 (m, 3H), 2.04 (s, 3H), 2.02-1.94 (m, 1H), 0.83-0.68 (m, 4H). MS (ESI) m/z 738.56 [M+H] + . Example 11 (S)-N-(3-(6-Cyclopropoxypyridin-3-yl)-1H-indazol-5-yl)-1-(2- (4-(3-fluoro-4-(1-methyl- 1H-1,2,4-triazol-3-yl)phenyl)-3,6-dihydropyridin-1(2H)-yl)-2 -oxoethyl)-3- (methylthio)pyrrolidine-3-carboxamide [0179] The title compound was prepared following General Procedure C using (S)-N-(3-(6-cyclopropoxypyridin-3-yl)-1H-indazol-5-yl)-3(met hylthio)pyrrolidine-3- carboxamide and 2-chloro-1-(4-(3-fluoro-4-(1-methyl-1H-1,2,4-triazol-3-yl)ph enyl)-5,6- dihydropyridin-1(2H)-yl)ethanone. mp: 133–135 °C; 1 H NMR (400 MHz, DMSO-d6) δ 13.25 (s, 1H), 9.97-9.93 (m, 1H), 8.74 (s, 1H), 8.54 (s, 1H), 8.40 (s, 1H), 8.25-8.15 (m, 1H), 8.00-7.85 (m, 1H), 7.76 (d, J = 9.2 Hz, 1H), 7.52 (d, J = 8.8 Hz, 1H), 7.40-7.20 (m, 2H), 7.10-6.99 (m, 1H), 6.40-6.25 (m, 1H), 4.27-4.10 (m, 3H), 3.93 (s, 3H), 3.72-3.66 (m, 2H), 3.50-3.46 (m, 3H), 2.85-2.45 (m, 6H), 2.05 (s, 3H), 2.02-1.93(m, 1H), 0.83-0.70 (m, 4H). MS (ESI) m/z 708.55 [M+H] + . Example 12 (S)-N-(3-(6-Cyclopropoxypyridin-3-yl)-1H-indazol-5-yl)-1-(2- (4-(3-fluoro-4-(1-methyl- 1H-1,2,4-triazol-3-yl)phenyl)-3,6-dihydropyridin-1(2H)-yl)-2 -oxoethyl-1,1-d2)-3- (methylthio)pyrrolidine-3-carboxamide [0180] The title compound was prepared following General Procedure C using (S)-N-(3-(6-cyclopropoxypyridin-3-yl)-1H-indazol-5-yl)-3-(me thylthio)pyrrolidine-3- carboxamide and 2-chloro-1-(4-(3-fluoro-4-(1-methyl-1H-1,2,4-triazol-3-yl)ph enyl)-3,6- dihydropyridin-1(2H)-yl)ethan-1-one-2,2-d2. 1 H NMR (400 MHz, DMSO-d6) δ 13.18 (s, 1H), 9.97-9.93 (m, 1H), 8.74 (s, 1H), 8.54 (s, 1H), 8.40 (s, 1H), 8.24-8.18 (m, 1H), 7.92-7.85 (m, 1H), 7.76 (d, J = 8.4 Hz, 1H), 7.52 (d, J = 8.8 Hz, 1H), 7.36-7.24 (m, 2H), 7.04-7.00 (m, 1H), 6.35-6.30 (m, 1H), 4.28-4.14 (m, 3H), 3.93 (s, 3H), 3.76-3.68 (m, 3H), 3.47-3.45 (m, 2H), 2.81-2.73 (m, 4H), 2.05 (s, 3H), 2.00-1.98 (m, 1H), 0.79-0.71 (m, 4H); MS (ESI) m/z 710.23 [M+H] + . Example 13 (S)-N-(3-(5-Cyclopropoxy-6-(methoxy-d3)pyridin-2-yl)-1H-inda zol-5-yl)-1-(2-(4-(4-(1- methyl-1H-1,2,4-triazol-3-yl)phenyl)-3,6-dihydropyridin-1(2H )-yl)-2-oxoethyl)-3- (methylthio)pyrrolidine-3-carboxamide [0181] The title compound was prepared following General Procedure C using (S)-N-(3-(5-cyclopropoxy-6-methoxy-d3-pyridin-2-yl)-1H-indaz ol-5-yl)-3- (methylthio)pyrrolidine-3-carboxamide and 2-chloro-1-(4-(4-(1-methyl-1H-1,2,4-triazol-3- yl)phenyl)-5,6-dihydropyridin-1(2H)-yl)ethanone. 1 H NMR (400 MHz, DMSO-d6) δ 13.08 (s, 1H), 9.63 (s, 1H), 9.98 (s, 1H), 8.41 (s, 1H), 7.90 (d, J = 11.2 Hz, 2H), 7.68 (d, J = 10.8 Hz, 1H), 7.60 (d, J = 10.8 Hz, 1H), 7.45– 7.41 (m, 4H), 6.19 (s, 1H), 4.25-4.13 (m, 2H), 3.95-3.90 (m, 4H), 3.74-3.68 (m, 2H), 3.50-3.45 (m, 3H), 2.84-2.77 (m, 3H), 2.68-2.61 (m, 3H), 2.07 (s, 3H), 2.05-1.97 (m, 1H), 0.79-0.73 (m, 4H); MS (ESI) m/z 723.39 [M+H] + . Example 14 (S)-N-(3-(5-Cyclopropoxy-6-methylpyridin-2-yl)-1H-indazol-5- yl)-1-(2-(4-(4-(1-methyl- 1H-1,2,4-triazol-3-yl)phenyl)-3,6-dihydropyridin-1(2H)-yl)-2 -oxoethyl)-3- (methylthio)pyrrolidine-3-carboxamide [0182] The title compound was prepared following General Procedure C using (S)-N-(3-(5-cyclopropoxy-6-methylpyridin-2-yl)-1H-indazol-5- yl)-3-(methylthio) pyrrolidine-3-carboxamide and 2-chloro-1-(4-(4-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)- 5,6-dihydro pyridin-1(2H)-yl)ethanone. mp: 141– 143 °C; 1 H NMR (DMSO–d6, 400 MHz) δ 13.10 (s, 1H), 9.92 (s, 1H), 8.83 (s, 1H), 8.49 (s, 1H), 8.00-7.80 (m, 3H), 7.72-7.65 (m, 1H), 7.62-7.56 (m, 1H), 7.50-7.39 (m, 3H), 6.31-6.20 (m, 1H), 4.35-4.00 (m, 2H), 3.95-3.93 (m, 1H), 3.91 (s, 3H), 3.80-3.60 (m, 2H), 3.50-3.30 (m, 3H), 2.83-2.60 (m, 3H), 2.59-2.52 (m, 3H), 2.46-2.40 (m, 3H), 2.07 (m, 3H), 2.06-1.95 (m, 1H), 0.86-0.80 (m, 2H), 0.73-0.68 (m, 2H). MS (ESI) m/z: 704.51 [M+H] + . Example 15 (S)-N-(3-(5-Cyclopropoxy-6-(dimethylamino)pyridin-2-yl)-1H-i ndazol-5-yl)-1-(2-(4-(4- (1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-3,6-dihydropyridin-1 (2H)-yl)-2-oxoethyl)-3- (methylthio)pyrrolidine-3-carboxamide [0183] The title compound was prepared following General Procedure C using (S)-N-(3-(5-Cyclopropoxy-6-(dimethylamino)pyridin-2-yl)-1H-i ndazol-5-yl)-3- (methylthio)pyrrolidine-3-carboxamide and 2-chloro-1-(4-(4-(1-methyl-1H-1,2,4-triazol-3- yl)phenyl)-5,6-dihydropyridin-1(2H)-yl)ethanone. mp: 146-148 °C; 1 H NMR (400 MHz, DMSO-d6) δ 13.05 (s, 1H), 9.90-9.75 (m, 1H), 9.01-8.90 (m, 1H), 8.49 (s, 1H), 8.01-7.80 (m, 2H), 7.60-7.49 (m, 2H), 7.40-7.30 (m, 4H), 6.30-6.10 (m, 1H), 4.30-4.00 (m, 3H), 3.91 (s, 3H), 3.90-3.87 (m, s1H), 3.74-3.60 (m, 2H), 3.51-3.20 (m, 4H), 3.00 (s, 6H), 2.80-2.70 (m, 3H), 2.68-2.60 (m, 1H), 2.06 (s, 3H), 2.00-1.90 (m, 1H), 0.85-0.72 (m, 4H). MS (ESI) m/z 733.7 [M+H] + . Example 16 (S)-N-(3-(6-cyclopropoxypyridin-3-yl)-1H-indazol-5-yl)-1-(2- (4-(4-(1-ethyl-1H-1,2,4- triazol-3-yl)phenyl)-3,6-dihydropyridin-1(2H)-yl)-2-oxoethyl )-3- (methylthio)pyrrolidine-3-carboxamide [0184] The title compound was prepared following General Procedure C using (S)-N-(3-(6-cyclopropoxypyridin-3-yl)-1H-indazol-5-yl)-3-(me thylthio)pyrrolidine-3- carboxamide and 2-chloro-1-(4-(4-(1-ethyl-1H-1,2,4-triazol-3-yl)phenyl)-5,6- dihydropyridin-1(2H)-yl)ethanone (See WO 2016/161160). 1 H NMR (400 MHz, DMSO-d6) δ 13.19 (s, 1H), 9.97-9.93 (m, 1H), 8.75 (s, 1H), 8.54 (s, 1H), 8.42 (s, 1H), 8.21 (d, J = 8.0 Hz, 1H), 7.93 (d, J = 8.4 Hz, 1H), 7.87 (d, J = 8.4 Hz, 1H), 7.76 (d, J = 9.2 Hz, 1H), 7.54- 7.47 (m, 2H), 7.41 (d, J = 8 Hz, 1H), 7.03-7.00 (m, 1H), 6.26-6.19 (m, 1H), 4.26-4.12 (m, 5H), 3.72-3.67 (m, 2H), 3.48-3.46 (m, 3H), 2.81-2.73 (m, 3H), 2.66-2.59 (m, 3H), 2.05 (s, 3H), 2.03-1.98 (m, 1H), 1.44 (t, J = 7.2 Hz, 3H), 0.79-0.71 (m, 4H). MS (ESI) m/z 704.55 [M+H] + . Example 17 (S)-N-(3-(6-cyclopropoxy-5-fluoropyridin-2-yl)-1H-indazol-5- yl)-1-(2-(4-(4-(1-methyl- 1H-1,2,4-triazol-3-yl)phenyl)-3,6-dihydropyridin-1(2H)-yl)-2 -oxoethyl)-3- (methylthio)pyrrolidine-3-carboxamide [0185] The title compound was prepared following General Procedures C and D using (S)-N-(3-(6-cyclopropoxy-5-fluoropyridin-2-yl)-1H-indazol-5- yl)-3- (methylthio)pyrrolidine-3-carboxamide and 2-chloro-1-(4-(4-(1-methyl-1H-1,2,4-triazol-3- yl)phenyl)-5,6-dihydropyridin-1(2H)-yl)ethanone. HCl salt: 1 H NMR (400 MHz, DMSO-d6) δ 13.39 (s, 1H), 10.45 (d, 1H), 10.06 (d, 1H), 9.18 (s, 1H), 8.52 (s, 1H), 8.00-7.97 (m, 2H), 7.81-7.73 (m, 2H), 7.58-7.53 (m, 3H), 7.46-7.44 (dd, 1H), 7.18 (t, 1H), 6.32 (br, 1H), 4.77- 4.75 (m, 1H), 3.92 (s, 3H), 3.87-3.78 (m, 3H), 3.63-3.57 (m, 2H), 2.68-2.66 (m, 2H), 2.56- 2.55 (m, 1H), 2.46-2.45 (m, 1H), 2.39-2.33 (br, 1H), 2.13-2.12 (m, 3H), 1.30-1.24 (m, 1H), 1.00-0.99 (m, 2H), 0.83 (br, 2H); MS (ESI) m/z 708.30 [M+H] + . Example 18 (S)-N-(3-(5-Cyclopropoxy-6-methoxypyridin-2-yl)-1H-indazol-5 -yl)-1-(2-(4-(5-(1- methyl-1H-1,2,4-triazol-3-yl)thiazol-2-yl)-3,6-dihydropyridi n-1(2H)-yl)-2-oxoethyl)-3- (methylthio)pyrrolidine-3-carboxamide [0186] The title compound was prepared following General Procedures C and D using (S)-N-(3-(5-cyclopropoxy-6-methoxypyridin-2-yl)-1H-indazol-5 -yl)-3- (methylthio)pyrrolidine-3-carboxamide and 2-chloro-1-(4-(5-(1-methyl-1H-1,2,4-triazol-3- yl)thiazol-2-yl)-5,6-dihydropyridin-1(2H)-yl)ethanone. HCl salt: 1 H NMR (400 MHz, DMSO-d6) δ 13.22 (s, 1H), 10.50 (br, 1H), 10.02 (d, 1H), 9.12 (br, 2H), 8.59-8.57 (m, 1H), 8.22-8.15 (m, 1H), 7.74-7.65 (m, 2H), 7.55-7.44 (m, 2H), 6.74 (br, 1H), 4.64-4.53 (m, 3H), 4.26 (br, 1H), 4.16-4.10 (m, 3H), 3.95-3.91 (m, 5H), 3.77 (t, 1H), 3.59-3.47 (m, 3H), 2.76- 2.73 (m, 2H), 2.67-2.66 (m, 1H), 2.43-2.31 (m, 1H), 2.16 (m, 3H), 0.83-0.81 (m, 2H), 0.72 (m, 2H); MS (ESI) m/z 727.30 [M+H] + . Example 19 (S)-N-(3-(6-cyclopropoxypyridin-3-yl)-7-fluoro-1H-indazol-5- yl)-1-(2-(4-(4-(1-methyl- 1H-1,2,4-triazol-3-yl)phenyl)-3,6-dihydropyridin-1(2H)-yl)-2 -oxoethyl)-3- (methylthio)pyrrolidine-3-carboxamide: [0187] The title compound was prepared following General Procedures A, B and C using 3-(6-cyclopropoxypyridin-3-yl)-7-fluoro-1-(tetrahydro-2H-pyr an-2-yl)-1H-indazol- 5-amine, (S)-1-(tert-butoxycarbonyl)-3-(methylthio)pyrrolidine-3-carb oxylic acid (See Boga et al., ACS Med Chem Lett (2018) 9(7): 761-767) and 2-chloro-1-(4-(4-(1-methyl-1H-1,2,4- triazol-3-yl)phenyl)-5,6-dihydropyridin-1(2H)-yl)ethanone. 1 H NMR (400 MHz, DMSO-d6), δ 10.20-10.10 (m, 1H), 8.73 (s, 1H), 8.40 (s, 1H), 8.21-8.17 (m, 2H), 7.95-7.85 (m, 2H), 7.74 (d, J = 13.2 Hz, 1H), 7.43 (d, J = 8.0 Hz, 2H), 7.00 (d, J = 8.8 Hz, 1H), 6.20 (brs, 1H), 4.31- 4.25 (m, 2H), 4.19 (brs, 2H), 3.91 (s, 3H), 3.75-3.70 (m, 2H), 3.55-3.45 (m, 3H), 2.90-2.82 (m, 1H), 2.82-2.75 (m, 2H), 2.70-2.60 (m, 1H), 2.60-2.45 (m, 2H, merged with solvent peak), 2.10-1.95 (m, 4H), 0.82-0.70 (m, 4H); MS (ESI) m/z 708.20 [M+H] + . Example A Active ERK1 and ERK2 Kinase Assay [0188] Activated ERK1 and ERK2 activity was determined in a Mobility Shift Assay (MSA) format as follows: Compound and kinase solution were prepared with assay buffer (20 mM HEPES, 0.01% Triton X-100, 2 mM DTT, pH7.5) and mixed and incubated in for 30 mins at rt . ERK1 & ERK2 were then activated by the addition of Fl-Substrate, ATP and metal solution and incubated for 1 h at rt . After 1 h, the reaction was terminated by the addition of 70 mL of Termination Buffer (QuickScout Screening Assist MSA; Carna Biosciences) to the well. The reaction mixture was applied to LabChip ™ system (PerkinElmer), and the product and substrate peptide peaks were separated, analyzed and quantitated. The kinase reaction is evaluated by the product ratio calculated from peak heights of product (P) and substrate(S) peptides (P/(P+S)). Example B Proliferation Assay [0189] A375 (melanoma), Colo-205 (colon cancer), Miapaca (pancreatic), HPAFII (pancreatic), sNF02.0 (neurofibromatosis type 1), sNF96.2 (neurofibromatosis type 1) and 8505 (Thyroid) cells were grown and maintained in RPMI-1640 medium containing 100 U/mL penicillin−streptomycin and 10% fetal bovine serum. Cells were in growth medium in 96-well opaque-walled clear bottom plates and incubated in the CO 2 incubator overnight before treatment. Cells were treated with compounds diluted in DMSO and a 10 point 3-fold serial dilutions were done. Plates were placed in 37°C, 5% CO 2 to incubate for 3 days. Before they were developed by adding 100 μL of CellTiter-Glo reagent (Promega) to the assay plate, plates were shaken briefly for 2 mins and allowed to incubate at room temperature for 10 mins. The bottom of the plates was pasted with white back seal and luminescence was recorded with Flexstation3 with setting of luminescence, integration time 500 ms. [0190] Compounds of Formulae (I) are active in this assay as indicated in Table 1, where for ERK2 enzymatic IC50: A = a single IC50 ≤50 nM; B = a single IC50 ≥50 nM and ≤ 250 nM; C = a single IC50 ≥250 nM; For A375 IC50: A = a single IC50 ≤100 nM; B = a single IC 50 ≥100 nM and ≤ 1.0 µM; C = a single IC 50 ≥1.0 µM. Table 1 [0191] Furthermore, although the foregoing has been described in some detail by way of illustrations and examples for purposes of clarity and understanding, it will be understood by those of skill in the art that numerous and various modifications can be made without departing from the spirit of the present disclosure. Therefore, it should be clearly understood that the forms disclosed herein are illustrative only and are not intended to limit the scope of the present disclosure, but rather to also cover all modification and alternatives coming with the true scope and spirit of the invention.