NZ623274B2 - Heterocyclic compounds and use thereof as modulators of type iii receptor tyrosine kinases - Google Patents

Abstract

Disclosed herein are heterocyclic 1H-benzo[d]imidazol-1-yl-methyl-benzo[d]thiazol derivatives of formula (VIIb), wherein the variables are as defined in the specification. These compounds are suitable for the treatment of a disease mediated or modulated by wild type or mutant CSFIR, FLT3, KIT, and/or PDGFR? kinase, wherein the disease is selected from an inflammatory disease, an inflammatory condition, an autoimmune disease and cancer. r PDGFR? kinase, wherein the disease is selected from an inflammatory disease, an inflammatory condition, an autoimmune disease and cancer.

Description

HETEROCYCLIC COMPOUNDS AND USE THEREOF AS MODULATORS OF TYPE III RECEPTOR NE KINASES also leads to the proliferation and differentiation of osteoclast precursors and therefore mediates the process of bone tion.

Because of its role in osteoclast biology, CSFlR is believed to be an important therapeutic target for osteoporosis and inflammatory arthritis. For example, elevated M-CFS signaling leads to elevated osteoclast activity, which leads to bone loss attending arthritis and other inflammatory bone n. (See Scott et al.

Rheamatology 2000, 39: 122-132, Ritchlin et al. J. Clin. Invest. 2003, 1-831).

Inhibition of CSFlR therefore represents a promising eutic approach for arthritis and other inflammatory bone n which is filrther supported by the efficacy data of known CSFlR inhibitors such as Ki-20227 and GW25 80 in arthritic animal models (See Conwat et al. JPET 2008, -50 and Ohno et al. Eur. J.

Immunol. 2008, 38:283-291). Dysregulation of osteoclast development and disruption in the balance of bone resorption and bone formation that underlie osteoporosis might also be treated with a modulator of CSFlR.

Elevated sion or activation of CSFlR and/or its ligand have been found in patients with acute myeloid leukemia, prostate, breast, ovarian, endometrial, colorectal, pancreatic and a variety of other cancers, and ed levels of M-CSF is associated with poor prognosis in n cancers (See, Muller-Tidow et al. Clin Cancer Res, 2004, 10: 1241-1249, Bauknecht et al. Cancer Detect. Prev., 1994, 18: 231-239; hi G et al. Cancer 1991, -996; Kirma et al Cancer Res. 2007; Sapi et al. Exp. Biol. Merl, 2004, 229: 1-1 1; Kluger et al. Clz'n. Canc. Res. 2004 :173-177; Mroczko et al., Clin. Chem. Lab. Med. 2005 43:146-50 and Mroczko et al., Clin. Chim. Acta 2007, 380:208—212). The data suggests that CSFlR may be a valuable therapeutic target for these solid tumors.

Early studies have associated elevated expression of M-CSF with increased leukocyte infiltration of solid tumors in human breast and ovarian cancers (Scholl et al. J. Natl. Cancer Inst. 1994, 86:120-126, Tang et al. J. Cell. Biochem. 1990, 44:189-198). Further studies have shown that M-CSF is one of several cytokines implicated in the recruitment of tumor-associated hages (TAMs) that contribute to tumor angiogenesis and tumor progression to metastasis, and more recently, that the preclinical inhibitor GW25 80 inhibits tumor metastasis and angiogenesis in mice tumor xenograft experiments (Priceman et al. Blood 2010 1 15(7): 1461-1471). Stimulated osteoclast activity is also believed to underlie the pathophysiology of bone metastases. (Lipton, J. t. Oncol. 2004 2:205-220).

Metastatic bone lesions results in significant zed bone loss and lead to skeletal morbidity, symptoms which include bone pain, bone fractures and hypercalcemia.

Inhibition of CSFlR therefore may therefore provide therapy for solid tumors and metastatic cancer including metastases to the bone.

Another member of the PDGFR family, FLT3 (also called Flk2), plays an important role in the eration and differentiation of hematopoietic stem cells and activating mutation or overexpression of this receptor is found in AML (See, ch Mini-Reviews in nal Chemistry 2004, 4(3):255-27l, Kiyoi et al. IntJ Hematol, 2005 82:85-92). More than a dozen known FLT3 inhibitors are being developed and some have shown promising clinical effects t AML (See Levis et al. IntJHematol. 2005 82:100-107). The FLT3 receptor is also expressed in a large portion of dendritic cell progenitors and stimulation of the receptor causes the proliferation and differentiation of these itors into dendritic cells (DC). Since dendritic cells are the main initiators of the T-cell mediated immune response, including the autoreactive immune response, FLT3 inhibition is a mechanism for downregulating DC-mediated inflammatory and autoimmune responses. One study shows the FLT3 inhibtor l to be effective in reducing myelin loss in experimental autoimmune alomyelitis (EAE), a mouse model for multiple sclerosis (See Whartenby et al. PNAS 2005 102: 16741-16746). A high level of the FLT3 ligand is found in the serum of ts with Langerhans cell histiocytosis and systemic lupus erythematosus, which further implicates FLT3 signaling in the dysregulation of dendritic cell progenitors in those mune diseases (See Rolland et al. J. Immunol. 2005 174:3067-3071).

KIT (or stem cell factor receptor, or SCFR) is another member of the RTK family, and the presence of kit mutations is a key diagnostic marker for gastrointestinal stromal tumors (GIST) (Duensing et al. Cancer Investigation 2004, 22(1): 106-1 16). Gleevec® (imatinib mesylate or STI57l), the first FDA-approved RTK inhibitor originally approved for c-Abl-mediated chronic myeloid leukemia, gained FDA-approval for KIT-mediated GIST in 2002 and has ted the molecular-based ch of Kit inhibition for the treatment of GIST. (Giorgi and Verweij, M01. Cancer Ther. 2005 95-50l). Gain of function mutations of the Kit receptor are also associated with mast cell/myeloid leukemia and seminomas/dysgerminomas (Blume-Jensen Nature 2001 41 1(17): 5. KIT ons have been also identified in certain mas and is recognized as a potential therapeutic target for melanoma (Curtain et al. J Clin. Oncol. 2006 24(26):4340-4346).

There continues to be a need for the identification of small molecules that inhibit RTKs, particularly nds useful for the treatment of CSFlR-, FLT3, PDGFRB- and/or KIT- mediated diseases.

SUMMARY Provided herein are nds of formula (I) or ceutically acceptable salts, solvates, hydrates, clathrates, single stereoisomers, mixture of stereoisomers or racemic mixture of stereoisomers thereof. In certain embodiment, the compounds have activity as CSFlR, FLT3, KIT, and/or PDGFRB kinase modulators. The compounds are useful in medical treatments, pharmaceutical compositions and methods for modulating the activity of CSFlR, FLT3, KIT, and/or PDGFRB kinases, including Wildtype and/or mutated forms of CSFlR, FLT3, KIT, and/or PDGFRB kinases. In certain embodiments, the compounds provided herein have activity as CSFlR, FLT3, KIT, and/or PDGFRB kinase modulators. In one embodiment, the compounds for use in the compositions and methods provided herein have formula (I).

In certain ments, provided herein are compounds of Formula I: R1 R2 [W1 3 R 1 W\ Z \ 4+6 n w / N\Y_R4 W \W N or pharmaceutically acceptable salts, solvates, hydrates, clathrates, single stereoisomers, mixture of stereoisomers or racemic e of isomers thereof, wherein: R1 and R2 are each independently selected from hydrogen, deuterium, halogen, hydroxyl and alkoxy, or R1 and R2 together form =0; R3 is hydrogen or alkyl; R4 is cycloalkyl, lkenyl, aryl, heterocyclyl or heteroaryl, where R4 is optionally substituted with one or more, in one embodiment, one to three, in another ment, one, two or three groups selected from Q1; each Q1 is independently deuterium, halo, cyano, oxo, thioxo, alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, -RuORX, - uORuN(Ry)(RZ), -RuN(Ry)(RZ), - RuSRX, - uC(J)Rx, - uC(J)ORX, - uC(J)N(Ry)(RZ), )tRW, -RuN(RX)C(J)RX, -RuN(RX)C(J)ORX, -RuN(RX)S(O)tRW, =NORd, or —C(=NRy)N(Ry)ORX, where the alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, and cyclyl groups are optionally substituted with one or more Q3 , in one embodiment, one to three Q3 ; each Q3 is independently selected from ium, halo, hydroxyl, alkyl, haloalkyl and hydroxyalkyl; Y is -(CR5R6)q-; R5 and R6 are each ndently hydrogen, deuterium, halo, alkyl, haloalkyl or hydroxyalkyl; Z is O, S or NR7; R7 is hydrogen, deuterium or alkyl; each W is independently CR8 or N; R8 is hydrogen, deuterium, halo, haloalkyl or alkyl; ring A is a bicyclic or tricyclic aryl, heteroaryl or heterocyclyl optionally substituted with one to four substituents selected from Q2; W1 is N or C; w2 is N, NR9a or CR9b; W3 is N, NR10a or CRIOb; w4 is N, NR11a or CRllb; Rga, Rgb,R10a, R101), R1181 and R11b are selected as follows: i) R981, R1081 and R1181 are each independently hydrogen, deuterium or alkyl and Rgb, R10b and R11b are each independently hydrogen or Q2; or ii) R9&1 and R101), R981 and Rloa, R9b and R101), R9b and Rloa, R10b and Rm, R1021 and R1 1b, R1021 and R11b or R10b and R11b together with the atoms to which they are ed form an aryl, heteroaryl or heterocyclyl ring, optionally substituted with one or more, in one embodiment, one to three, in another embodiment, one, two or three groups selected from Q2; and the remainder of R981 or R1181 is hydrogen, deuterium or alkyl; and the remainder of R9b or R11b is hydrogen or Q2; or iii) R9&1 and R101), R981 and Rloa, R9b and R101), R9b and Rloa, R10b and Rlla, R1021 and R1 1b, R1021 and R11b or R10b and R11b together with the atoms to which they are attached form an aryl, heteroaryl or heterocyclyl ring optionally fused to a phenyl ring ally substituted with one or more, in one embodiment, one to three, in another embodiment, one, two or three groups selected from Q2; and the remainder of R981 or R1121 is hydrogen, deuterium or alkyl and the remainder of R9b or R11b is hydrogen or each Q2 is independently halo, deuterium, cyano, oxo, thioxo, alkyl, haloalkyl, haloalkenyl, lkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, lkylalkyl, cycloalkenylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, -RuORX, - uORuORX,-RuORuN(Ry)(RZ), RuN(Ry)(RZ), -RuSRX, - uC(J)Rx, - uC(J)ORX, -RuC(J)N(Ry)(RZ), - uC(J)RuN(Ry)(RZ) , )N(Ry)ORX, -C(=NORX)RX’ uS(O)tRW, -RuN(RX)C(J)RX, -RuN(RX)C(J)ORX, -RuN(RX)S(O)tRW or —C(=NRy)N(Ry)ORX, where the alkyl, kyl, aminoalkyl, alkenyl, l, lkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl groups are optionally substituted with one or more groups Q4; in one embodiment, one to three Q4 groups, each Q4 is independently selected from halo, deuterium, hydroxyl, alkyl, haloalkyl and hydroxyalkyl; each Rd is independently hydrogen or alkyl; each R11 is independently ne, alkenylene or a direct bond; RW is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, cyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; each Rx is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cyanoalkyl, alkenyl, alkynyl, cycloalkyl, lkenyl, cycloalkylalkyl, cycloalkenylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; Ry and RZ are each independently selected from (i) or (ii) below: (i) Ry and RZ are each independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, l, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; or [0011a] In ular the present invention provides a nd having formula VIIb: W5 R1 R2 W2 W Z R3 N (Q1)0-2 W4 W Y W N VIIb or a pharmaceutically acceptable salt, solvate, hydrate, clathrate, a single stereoisomer, a mixture of stereoisomers or a racemic mixture of stereoisomers thereof, wherein: R1 and R2 are each independently selected from hydrogen or halogen; R3 is hydrogen or alkyl; each Q1 is independently deuterium, halo, cyano, oxo, thioxo, alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, lkylalkyl, cycloalkenylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, cyclylalkyl, -RuORx, -RuORuN(Ry)(Rz), -RuN(Ry)(Rz), - RuSRx, -RuC(J)Rx, -RuC(J)ORx, -RuC(J)N(Ry)(Rz), -RuS(O)tRw, -RuN(Rx)C(J)Rx, - RuN(Rx)C(J)ORx, -RuN(Rx)S(O)tRw, =NORd, or –C(=NRy)N(Ry)ORx, where the alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl groups are optionally substituted with one or more Q3 groups, in one embodiment, one to three Q3 groups; each Q3 is independently selected from ium, halo, hydroxyl, alkyl, haloalkyl and hydroxyalkyl; Y is -(CR5R6)q-; R5 and R6 are each independently en, halo, alkyl, haloalkyl or hydroxyalkyl; Z is O, S, or NH; each W is independently CR8 or N; R8 is hydrogen, halo, haloalkyl or alkyl; W1 is N or C; W2 is N or CR9b; R9b is hydrogen or alkyl; W4 is N or CR11b; W5 is N or CR13; R11b and R13 are each ndnetly hydrogen or Q2; Q2 is halo, deuterium, cyano, oxo, thioxo, alkyl, haloalkyl, haloalkenyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, lkylalkyl, lkenylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, cyclylalkyl, -RuORx, -RuORuORx, -RuORuN(Ry)(Rz), - RuN(Ry)(Rz), -RuSRx, -RuC(J)Rx, -RuC(J)ORx, -RuC(J)N(Ry)(Rz), -RuC(J)RuN(Ry)(Rz), -RuC(J)N(Ry)O Rx, -C(=NORx)Rx, -RuS(O)tRw, -RuN(Rx)C(J)Rx, -RuN(Rx)C(J)ORx, -RuN(Rx)S(O)tRw or – C(=NRy)N(Ry)ORx, where the alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl groups are optionally substituted with one or more groups Q4; in one embodiment, one to three Q4 groups, each Q4 is ndently ed from halo, deuterium, hydroxyl, alkyl, kyl and hydroxyalkyl; (followed by 8A) Q5 and Q6 are each independently hydrogen, deuterium, halo, cyano, oxo, thioxo, alkyl, haloalkyl, aminoalkyl, alkenyl, haloalkenyl, alkynyl, cycloalkyl, cycloalkenyl, lkylalkyl, cycloalkenylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, , - RuORuORx, -RuORuN(Ry)(Rz), -RuN(Ry)(Rz), -RuSRx, -RuC(J)Rx, -RuC(J)ORx, -RuC(J)N(Ry)(Rz), -RuC (J)RuN(Ry)(Rz), -RuC(J)N(Ry)ORx, -C(=NORx)Rx, -RuS(O)tRw, -RuN(Rx)C(J)Rx, -RuN(Rx)C(J)ORx, - RuN(Rx)S(O)tRw or –C(=NRy)N(Ry)ORx, where the alkyl, haloalkyl, aminoalkyl, l, l, cycloalkyl, cycloalkenyl, aryl, heteroaryl, and cyclyl groups are optionally substituted with one or more Q8 groups; each Q8 is independently selected from halo, deuterium, hydroxyl, alkyl, haloalkyl and hydroxyalkyl; each Rd is independently hydrogen or alkyl; each Ru is independently alkylene, alkenylene or a direct bond; Rw is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, heterocyclyl, cyclylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; each Rx is independently en, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cyanoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; Ry and Rz are each independently selected from (i) or (ii) below: (i) Ry and Rz are each independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; or (ii) Ry and Rz, together with the nitrogen atom to which they are attached, form a heterocyclyl or heteroaryl, optionally substituted with one or more, in one embodiment, one, two or three Q7 groups; each Q7 is ndently selected from halo, ium, oxo, thioxo, hydroxy, , alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, l, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, lkenylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl; J is O, NRx or S; each t is independently an integer from 0-2; n is 1 or 2; and q is an integer from 0-4. (followed by 8B) ] Thus in certain embodiments the invention provides the use of a compound as bed herein in the manufacture of a medicament for ng a disease selected from an inflammatory disease, an matory condition, an autoimmune disease and cancer. [0013b] In other embodiments the invention provides the use of a compound as described , in the manufacture of a medicament for the treatment of a disease, wherein the treatment comprises administering a therapeutically effective amount of the compound, and wherein the disease is selected from myeloproliferative disorder (MPD), ysplastic syndrome (MDS), polycythemia vera (PCV), essential thrombocythemia (ET), primary myelofibrosis (PMF), chronic eosinophilic leukemia (CEL), c myelomonocytic leukemia (CMML), systemic mastocytosis (SM), idiopathic myelofibrosis (IMF), myeloid leukemia, chronic myeloid leukemia (CML), imatinib-resistant CML, acute myeloid leukemia (AML), acute megakaryoblastic leukemia (AMKL), lymphoma, Hodgkin's lymphoma, lymphoblastic leukemia, myeloma, multiple myeloma, cancer of the head and neck, prostate cancer, breast cancer, ovarian , endometrial cancer, melanoma, lung cancer, brain cancer, thyroid cancer, stomach , gastrointestinal stromal tumor, colorectal cancer, pancreatic cancer, renal , non-small cell lung cancer, bone cancer, tenosynovial giant cell tumors, glioblastoma multiforme, atherosclerosis, restenosis, obliterative bronchiolitis, idiopathic myelofibrosis, obesity, obesity-induced insulin resistance, alcemia of malignancy, lupus nephritis, glomerular nephritis, idiopathic hypereosinophilic syndrome, chronic eosinophilic syndrome, systemic mastocytosis, hans cell histiocytosis, Kaposi's sarcoma, multiple endocrine neoplasia, deficiency, autoimmune diseases, tissue transplant rejection, graft-versus-host disease, wound, kidney disease, multiple sclerosis, thyroiditis, type 1 diabetes, sarcoidosis, psoriasis, allergic rhinitis, inflammatory bowel e including Crohn’s e and ulcerative colitis (UC), systemic lupus erythematosis (SLE), cutaneous lupus erythematosis, arthritis, osteoarthritis, (followed by 8C) rheumatoid arthritis, psoriatic arthritis, osteoporosis, endometriosis, asthma, allergic asthma, ankylosing spondylitis, chronic obstructive pulmonary disease (COPD), Alzheimer’s disease and multiple sclerosis. [0014a] Thus also provided are the uses described above wherein the treatment r comprises administering a second ceutical agent. [0017a] In other embodiments, ed herein is the use of a compound as described herein in the manufacture of a medicament for use modulating a CSF1R, FLT3, KIT, and/or PDGFRβ kinase. (followed by 9) delivery, or for local or l application are administered to an individual exhibiting the symptoms of the disease or disorder to be treated. The amounts are effective to ameliorate or eliminate one or more symptoms of the disease or disorder.

Further provided is a pharmaceutical pack or kit comprising one or more containers filled with one or more of the ingredients of the pharmaceutical compositions. Optionally ated with such container(s) can be a notice in the form ibed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals or biological products, which notice reflects approval by the agency of manufacture, use of sale for human administration. The pack or kit can be labeled with ation regarding mode of administration, sequence of drug administration (e. g., separately, sequentially or concurrently), or the like.

These and other aspects of the subject matter described herein will become evident upon reference to the following detailed description.

BRIEF DESCRIPTION OF THE DRAWING Fig. 1 s the in viva inhibition of CSF-l dependent M-NFS-60 tumor cell proliferation in the peritoneal cavity of athymic nu/nu mice from the administration of one of the compounds provided herein having the Formula I (Compound A).

Fig. 2 depicts the in viva inhibition of CSF-l dependent M-NFS-60 tumor cell proliferation in the peritoneal cavity of athymic nu/nu mice from the administration of one of the compounds ed herein having the Formula I (Compound B).

Fig. 3 s the in viva inhibition of PTHrP-induced hypercalcemia from the administration of Compound A having the Formula I, in BDFl mice challenged twice daily for seven days with 0.5 mg/kg inant PTHrP, as measured by serum TRAPCSB levels, a bone resorption marker.

Fig. 4 depicts the in viva inhibition of PTHrP-induced hypercalcemia from the administration of Compound B having the Formula I, in BDFl mice challenged twice daily for seven days with 0.5 mg/kg recombinant PTHrP, as measured by serum TRAPCSB levels, a bone tion .

Fig. 5 depicts the in viva inhibition of MCP-l induction in Balb/c mice treated with Compound A having the Formula I, prior to M-CSF stimulation.

Fig. 6 depicts the in viva inhibition of MCP-l induction in Balb/c mice treated with nd B having the Formula I, prior to M-CSF stimulation.

DETAILED DESCRIPTION Provided herein are compounds of formula I that have activity as CSFlR, FLT3, KIT, and/or PDGFRB kinase modulators. Further provided are methods of treating, preventing or ameliorating diseases that are modulated by CSFlR, FLT3, KIT, and/or PDGFRB kinases, and pharmaceutical compositions and dosage forms useful for such methods. The methods and compositions are described in detail in the sections below.

A. DEFINITIONS Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art.

All patents, applications, published applications and other publications are incorporated by reference in their entirety. In the event that there are a ity of definitions for a term herein, those in this section prevail unless stated otherwise.

“Alkyl” refers to a straight or branched hydrocarbon chain group consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to ten, one to eight, one to six or one to four carbon atoms, and which is attached to the rest of the molecule by a single bond, 6.g. , , ethyl, n-propyl, l-methylethyl (iso-propyl), n-butyl, n-pentyl, l,l-dimethylethyl (t—butyl), and the like. yl” refers to a straight or branched hydrocarbon chain group consisting solely of carbon and hydrogen atoms, containing at least one double bond, having from two to ten carbon atoms, and which is attached to the rest of the molecule by a single bond or a double bond, e.g., ethenyl, prop-l-enyl, enyl, pent-l-enyl, penta-l,4-dienyl, and the like. yl” refers to a ht or branched hydrocarbon chain group ting solely of carbon and hydrogen atoms, containing at least one triple bond, having from two to ten carbon atoms, and which is attached to the rest of the molecule by a single bond or a triple bond, e.g., l, prop-l-ynyl, but-l-ynyl, pent-l-ynyl, pentynyl and the like.

“Alkylene” and “alkylene chain” refer to a straight or ed divalent hydrocarbon chain consisting solely of carbon and hydrogen, containing no unsaturation and having from one to eight carbon atoms, e.g., methylene, ethylene, propylene, n-butylene and the like. The alkylene chain may be attached to the rest of the molecule through any two carbons within the chain.

“Alkenylene” or “alkenylene chain” refers to a ht or branched chain unsaturated divalent radical consisting solely of carbon and hydrogen atoms, haVing from two to eight carbon atoms, n the unsaturation is present only as double bonds and wherein the double bond can exist between any two carbon atoms in the chain, e.g., ethenylene, prop-l-enylene, butenylene and the like. The lene chain may be attached to the rest of the molecule h any two carbons within the chain.

“Alkynylene” or “alkynylene chain” refers to a straight or ed chain unsaturated divalent radical consisting solely of carbon and en atoms, haVing from two to eight carbon atoms, wherein the unsaturation is present only as triple bonds and wherein the triple bond can exist between any two carbon atoms in the chain, 6.g. , ethynylene, prop-l-ynylene, butynylene, pent-l-ynylene, pentynylene and the like. The alkynylene chain may be attached to the rest of the molecule through any two s within the chain.

“Alkoxy” refers to the group haVing the formula -OR wherein R is alkyl or haloalkyl. An “optionally substituted alkoxy” refers to the group haVing the formula - OR wherein R is an optionally substituted alkyl as defined herein. ” refers to a radical haVing the formula -NR’R’ ’ n R’ and R’’ are each independently hydrogen, alkyl or haloalkyl. An “optionally substituted amino” refers to a radical haVing the formula —NR’R’ ’ n one or both of R’ and R’’ are optionally substituted alkyl as defined herein.

“Aryl” refers to a group of carbocylic ring system, including monocyclic, ic, tricyclic, tetracyclic C6-C18 ring systems, wherein at least one of the rings is aromatic. The aryl may be fully aromatic, examples of which are phenyl, naphthyl, anthracenyl, acenaphthylenyl, azulenyl, fluorenyl, l and pyrenyl. The aryl may also contain an aromatic ring in combination with a non-aromatic ring, examples of which are acenaphene, indene, and fluorene.

“Cycloalkyl” refers to a stable monovalent monocyclic or bicyclic hydrocarbon group consisting solely of carbon and hydrogen atoms, having from three to ten carbon atoms which is saturated, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, decalinyl, ane, norbomene, adamantyl, bicyclo[2.2.2]octane and the like.

“Cycloalkenyl” refers to a stable monovalent monocyclic or bicyclic arbon group consisting solely of carbon and hydrogen atoms, haVing from three to ten carbon atoms, which is partially unsaturated. Examples of lkenyl include cyclopropene, cyclobutylene, cyclopentene and cyclohexene.

“Halo, “halogen” or “halide” refers to F, Cl, Br or I.

“Haloalkyl” refers to an alkyl group, in certain embodiments, C1_6alkyl group in which one or more of the hydrogen atoms are replaced by halogen. Such groups include, but are not limited to, chloromethyl, trifluoromethyl rofluoroethyl, 2,2-difluoroethyl, 2-fluoropropyl, 2-fluoropropanyl, 2,2,2- trifluoroethyl, l,l-difluoroethyl, l,3-difluoromethylpropyl, 2,2- ocyclopropyl, (trifluoromethyl)cyclopropyl, 4,4-difluorocyclohexyl and 2,2,2- trifluoro- l l -dimethyl-ethyl.

“Heterocycle” or “Heterocyclyl” refers to a stable 3- to lS-membered non- aromatic ring l which consists of carbon atoms and from one to five heteroatoms selected from a group consisting of nitrogen, oxygen and sulfur. In one embodiment, the heterocyclic ring system radical may be a monocyclic, bicyclic or tricyclic ring or tetracyclic ring system, which may include fused or bridged ring systems; and the en or sulfur atoms in the heterocyclic ring system radical may be optionally oxidized; the nitrogen atom may be optionally quatemized; and the heterocyclyl radical may be partially or fully saturated. The heterocyclic ring system may be attached to the main structure at any atom or carbon atom which results in the creation of a stable compound. Exemplary heterocylic radicals e, morpholinyl, piperidinyl, piperazinyl, pyranyl, pyrrolidinyl, oxetanyl, azetidinyl, quinuclidinyl, octahydroquinolizinyl, decahydroquinolizinyl, yclo[3.2. l]octanyl, azabicyclo[2.2.2]octanyl, isoindolinyl, indolinyl and others. oaryl” refers to a heterocyclyl group as defined above which is aromatic. The heteroaryl groups include, but are not limited to monocyclyl, bicyclyl and tricyclyl groups, and may be attached to the main ure at any heteroatom or carbon atom which results in the creation of a stable nd. Examples of such heteroaryl groups include, but are not limited to: furanyl, imidazolyl, oxazolyl, isoxazolyl, pyrimidinyl, pyridinyl, pyridazinyl, lyl, thienyl, benzimidazolyl, imidazo[4,5-b]pyridinyl, imidazo[l ,2-a]pyridinyl, imidazo[l ,2-b]pyridazinyl, imidazo[l ,2-a]pyrazinyl and .

“Heterocyclylalkyl” refers to a group of the formula —RaRe wherein Ra is an alkyl group as defined above and Re is a heterocyclyl group as defined herein, where the alkyl group Ra may attach at either the carbon atom or the heteroatom of the heterocyclyl group Re. The alkyl group and the heterocyclyl group may be optionally substituted as defined herein.

“IC50” refers to an amount, concentration or dosage of a particular test compound that achieves a 50% tion of a maximal se, such as cell growth or eration measured via any the in vitro or cell based assay described herein.

“OX0” refers to the group =0 attached to a carbon atom.

Pharmaceutically acceptable salts include, but are not limited to, amine salts, such as but not limited to N,N'-dibenzylethylenediamine, chloroprocaine, choline, ammonia, diethanolamine and other hydroxyalkylamines, ethylenediamine, N—methylglucamine, procaine, N—benzylphenethylamine, l-para-chlorobenzylpyrrolidin-l'-ylmethyl- benzimidazole, diethylamine and other alkylamines, piperazine and tris(hydroxymethyl)aminomethane; alkali metal salts, such as but not limited to lithium, ium and sodium; alkali earth metal salts, such as but not limited to barium, calcium and magnesium; transition metal salts, such as but not d to zinc; and other metal salts, such as but not limited to sodium hydrogen phosphate and disodium phosphate; and also including, but not limited to, salts of mineral acids, such as but not limited to hlorides and sulfates; and salts of organic acids, such as but not d to acetates, lactates, malates, tartrates, es, ascorbates, succinates, butyrates, valerates, fumarates and organic sulfonates.

As used herein and unless otherwise indicated, the term te” means a compound provided herein or a salt thereof, that further includes a stoichiometric or non-stoichiometeric amount of water bound by non-covalent olecular forces.

As used herein and unless otherwise indicated, the term “solvate” means a solvate formed from the association of one or more solvent molecules to a compound provided herein. The term “solvate” includes hydrates (e.g., mono-hydrate, dihydrate, trihydrate, tetrahydrate and the like).

As used , “substantially pure” means sufficiently homogeneous to appear fiee of readily detectable impurities as determined by standard methods of analysis, such as thin layer chromatography (TLC), gel ophoresis, high performance liquid chromatography (HPLC) and mass spectrometry (MS), used by those of skill in the art to assess such purity, or ently pure such that further purification would not ably alter the physical and chemical properties, such as enzymatic and biological activities, of the substance. Methods for purification of the compounds to produce ntially chemically pure nds are known to those of skill in the art. A substantially chemically pure compound may, however, be a mixture of stereoisomers. In such instances, further purification might increase the specific activity of the compound.

Unless stated otherwise specifically described in the specification, it is understood that the substitution can occur on any atom of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl group.

Unless cally stated otherwise, where a compound may assume ative tautomeric, regioisomeric and/or stereoisomeric forms, all alternative isomers are intended to be encompassed within the scope of the d subject matter. For example, where a compound is described as having one of two tautomeric forms, it is intended that the both ers be encompassed herein.

Thus, the compounds provided herein may be enantiomerically pure, or be stereoisomeric or diastereomeric mixtures.

It is to be understood that the compounds provided herein may contain chiral centers. Such chiral centers may be of either the (R) or (S) configuration, or may be a mixture thereof It is to be understood that the chiral centers of the compounds provided herein may undergo epimerization in viva. As such, one of skill in the art will recognize that administration of a compound in its (R) form is equivalent, for compounds that undergo epimerization in vivo, to administration of the compound in its (S) form.

Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)-isomers may be ed using chiral synthons or chiral reagents, or resolved using conventional techniques, such as chromatography on a chiral stationary phase.

As used herein, “isotopic composition” refers to the amount of each isotope present for a given atom, and “natural isotopic composition” refers to the lly occurring isotopic composition or abundance for a given atom. Atoms containing their natural ic composition may also be referred to herein as “non- ed” atoms. Unless otherwise designated, the atoms of the compounds recited herein are meant to represent any stable isotope of that atom. For example, unless otherwise stated, when a position is designated specifically as “H” or “hydrogen”, the position is understood to have en at its natural isotopic composition.

As used herein, pically enriched” refers to an atom having an isotopic composition other than the natural isotopic composition of that atom.

“Isotopically ed” may also refer to a compound containing at least one atom haVing an isotopic composition other than the natural isotopic composition of that atom.

As used herein, “isotopic enrichment” refers to the percentage of incorporation of an amount of a specific isotope at a given atom in a le in the place of that atom’s natural isotopic abundance. For example, deuterium enrichment of 1% at a given position means that 1% of the molecules in a given sample n deuterium at the ed position. Because the naturally occurring distribution of deuterium is about 001.56%, deuterium enrichment at any position in a compound synthesized using non-enriched starting materials is about 0.0156%. The isotopic enrichment of the compounds provided herein can be determined using conventional analytical methods known to one of ry skill in the art, including mass spectrometry and nuclear magnetic resonance spectroscopy.

Where the number of any given substituent 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 ent halogens.

In the description herein, if there is any discrepancy between a chemical name and chemical structure, the structure controls.

“Anti-cancer agents” refers to anti-metabolites (e.g., S-fluoro-uracil, methotrexate, bine), antimicrotubule agents (e.g., vinca alkaloids such as vincristine, vinblastine; s such as paclitaxel, docetaxel), alkylating agents (e.g., cyclophosphamide, lan, carmustine, nitrosoureas such as bischloroethylnitrosurea and hydroxyurea), platinum agents (e.g. cisplatin, latin, oxaliplatin, JM-2l6 or satraplatin, CI-973), anthracyclines (e.g., doxrubicin, daunorubicin), antitumor antibiotics (e.g., mitomycin, idarubicin, adriamycin, daunomycin), topoisomerase inhibitors (e.g., etoposide, camptothecins), anti-angiogenesis agents (e.g. Sutent® and Bevacizumab) or any other cytotoxic agents, mustine phosphate, prednimustine), hormones or hormone agonists, nists, partial agonists or partial antagonists, kinase inhibitors, and radiation treatment.

“Anti-inflammatory agents” refers to matrix metalloproteinase inhibitors, inhibitors of flammatory cytokines (e.g., anti-TNF les, TNF soluble receptors, and ILl) non-steroidal anti-inflammatory drugs (NSAIDs) such as glandin synthase inhibitors (e.g., choline magnesium salicylate, salicylsalicyclic acid), COX-1 or COX-2 inhibitors), or glucocorticoid receptor agonists such as corticosteroids, methylprednisone, prednisone, or cortisone.

As used herein, the abbreviations for any protective , amino acids and other nds, are, unless ted otherwise, in accord with their common usage, recognized abbreviations, or the IUPAC-IUB Commission on Biochemical Nomenclature (see, Biochem. 1972, 11:942-944).

B. COMPOUNDS In certain embodiments, provided herein are compounds of Formula I: 3’ ’A\W’l W4;><:|(W\w2 w wikN/m—\Y or pharmaceutically acceptable salts, solvates, hydrates, clathrates, single stereoisomers, mixture of stereoisomers or racemic mixture of stereoisomers thereof, wherein: R1 and R2 are each independently selected from hydrogen, deuterium, halogen, hydroxyl and alkoxy, or R1 and R2 together form =0; R3 is hydrogen or alkyl; R4 is cycloalkyl, cycloalkenyl, aryl, heterocyclyl or heteroaryl, where R4 is optionally substituted with one or more, in one embodiment, one to three, in another embodiment, one, two or three groups ed from Q1; each Q1 is independently deuterium, halo, cyano, oxo, thioxo, alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, -RuORX, - uORuN(Ry)(RZ), -RuN(Ry)(RZ), - RuSRX, - uC(J)RX, - uC(J)ORX, - uC(J)N(Ry)(RZ), -RuS(O)tRW, -RuN(RX)C(J)RX, -RuN(RX)C(J)ORX, -RuN(RX)S(O)tRW, =NORd, or —C(=NRy)N(Ry)ORX, where the alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl groups are optionally substituted with one or more Q3 groups, in one embodiment, one to three Q3 ; each Q3 is independently selected from deuterium, halo, hydroxyl, alkyl, haloalkyl and hydroxyalkyl; Y is -(CR5R6)q-; R5 and R6 are each independently hydrogen, deuterium, halo, alkyl, haloalkyl or yalkyl; Z is O, S or NR7; R7 is hydrogen, deuterium or alkyl; each W is independently CR8 or N; R8 is en, deuterium, halo or alkyl; ring A is a monocyclic, ic or lic aryl, heteroaryl or heterocyclyl optionally substituted with one to four tuents selected from Q2; W1 is N or C; w2 is N, NR9a or CR9b; W3 is N, NR10a or CRIOb; w4 is N, NR11a or CRllb; Rga, Rgb,R10a, R101), R1181 and R11b are selected as follows: i) R981, R1021 and R1121 are each independently hydrogen or alkyl and R91), R10b and R11b are each independently hydrogen, ium, oxo, hydroxyl, halo or alkyl; or ii) R9a and R101), R9b and R101), R9b and RIOa’ R10b and Rlla’ R10a and Rllb or R10b and R11b together with the atoms to which they are attached form an aryl, heteroaryl or heterocyclyl ring, optionally substituted with one or more, in one embodiment, one to three, in another embodiment, one, two or three groups selected from Q2; and the remainder of Rga, R1021 and R1121 are each independently hydrogen, deuterium or alkyl; and the remainder of R91), R10b and R11b are each ndently hydrogen, deuterium, halo or alkyl; or iii) R9&1 and R101), R9b and R101), R9b and Rloa, R10b and Rlla, R1021 and R11b or R10b and R11b er with the atoms to which they are attached form an aryl, heteroaryl or cyclyl ring optionally fused to a phenyl ring optionally substituted with one or more, in one embodiment, one to three, in another embodiment, one, two or three groups selected from Q2; and the remainder of R9&1 and R9b or the remainder of R1121 and R11b are each independently hydrogen, deuterium or alkyl; each Q2 is independently halo, deuterium, cyano, oxo, thioxo, alkyl, haloalkyl, haloalkenyl, aminoalkyl, l, alkynyl, cycloalkyl, cycloalkenyl, lkylalkyl, cycloalkenylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, -RuORX, - uORuORX,-RuORuN(Ry)(RZ), - )(RZ), -R“SRX, - uC(J)Rx, - uC(J)ORX, -RuC(J)N(Ry)(RZ), - uC(J)RuN(Ry)(RZ) , )N(Ry)ORX, -C(=NORX)RX’ uS(O)tRw, X)C(J)RX, -RuN(RX)C(J)ORX, -RuN(RX)S(O)tRW or —C(=NRy)N(Ry)ORX, where the alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, lkenyl, aryl, heteroaryl, and heterocyclyl groups are optionally substituted with one or more groups Q4; in one embodiment, one to three Q4 groups, each Q4 is independently selected from halo, deuterium, hydroxyl, alkyl, haloalkyl and hydroxyalkyl; Rd is hydrogen or alkyl; each R11 is independently alkylene, alkenylene or a direct bond; RW is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, cyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; each Rx is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cyanoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; Ry and RZ are each independently selected from (i) or (ii) below: W0 2013/056070 (i) Ry and RZ are each independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; or (ii) Ry and RZ, together with the nitrogen atom to which they are ed, form a heterocyclyl or heteroaryl, optionally substituted with one or more, in one embodiment, one, two or three Q7 groups; each Q7 is independently selected from halo, deuterium, oxo, thioxo, hydroxy, alkoxy, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, aralkyl, heteroaryl, aralkyl, heterocyclyl and heterocyclylalkyl; J is O, NRx or S; each t is independently an integer from 0-2; 11 is l or 2; and q is an integer from 0-4, n the compounds are selected such that: i) when W is CH; W1 is C; Z is S; R1 is hydrogen, or hydroxyl and R2 is hydrogen, or R1 and R2 together form =0; then ring A is not pyridine; ii) when W is CH; W1 is N; Z is S; R1 and R2 are hydrogen, then ring A is not pyrrolidine; iii) when W is CH, Z is NH, R1 and R2 er form =0, q is 0, and R4 is pyridinyl, then ring A is not , iV) when W is CH, Z is NH, R1 and R2 together form =0, q is 0, and R4 is phenyl, then ring A is not pyrrolidine, and V) when Z is N, one of R1 and R2 is methyl and the other of R1 and R2 is H, q is 0, and R3 is pyridine, and W1 is N, ring A cannot be piperidine, l,2,3,4- tetrahydroisoquinoline, or isoindoline.

In certain embodiments, ed herein are compounds of Formula I or pharmaceutically acceptable salts, solvates, hydrates, clathrates, single stereoisomers, mixture of stereoisomers or racemic e of stereoisomers f, wherein: R1 and R2 are each independently selected from hydrogen, halogen, hydroxyl and alkoxy, or R1 and R2 together form =0; R3 is en or alkyl; R4 is cycloalkyl, cycloalkenyl, aryl, heterocyclyl or heteroaryl, where R4 is optionally substituted with one or more, in one embodiment, one to three, in another embodiment, one, two or three groups selected from Q1; each Q1 is independently halo, cyano, oxo, thioxo, alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, lkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, cyclylalkyl, , - Ry)(RZ), -RuN(Ry)(RZ), -RuSRX, - uC(J)Rx, - RuC(J)ORX, -RuC(J)N(Ry)(RZ), )tRw, -RuN(RX)C(J)RX, -RuN(RX)C(J)ORX, - RuN(RX)S(O)tRW, =NORd, or —C(=NRy)N(Ry)ORX, where the alkyl, haloalkyl, aminoalkyl, l, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl groups are optionally substituted with one or more Q3 groups, in one embodiment, one to three Q3 groups; each Q3 is independently selected from halo, hydroxyl, alkyl, haloalkyl and hydroxyalkyl; Y is -(CR5R6)q-; R5 and R6 are each independently hydrogen, halo, alkyl, haloalkyl or yalkyl; Z is O, S or NR7; R7 is hydrogen or alkyl; each W is independently CR8 or N; R8 is hydrogen or alkyl; ring A is aryl or heteroaryl, optionally substituted with one to four substituents selected from Q2; W1 is N or C; W2 is N, NR9a or CR9b; W3 is N, NR10a or CRIOb; W4 is N, NR11a or CRllb; Rga, Rgb,R10a, R101), R1181 and R11b are selected as follows: i) R981, R1021 and R1121 are each independently hydrogen or alkyl and R91), R10b and R11b are each independently hydrogen, oxo, hydroxyl, halo or alkyl; or ii) R9a and R101), R9b and R101), R9b and RIOa’ R10b and Rlla’ R10a and Rllb or R10b and R11b together with the atoms to which they are attached form an aryl or heteroaryl ring, optionally substituted with one or more, in one embodiment, one to three, in another embodiment, one, two or three groups selected from Q2; and the remainder of R981, R1021 and R1121 are each independently hydrogen or alkyl; and the der of R91), R10b and R11b are each independently en, halo or alkyl; each Q2 is independently halo, cyano, oxo, thioxo, alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, , - Ry)(RZ), -RuN(Ry)(RZ), -RuSRX, - RuC(J)RX, -RuC(J)ORX, -RuC(J)N(Ry)(RZ), - uC(J)N(Ry)ORX, - uS(O)tRW, - RuN(RX)C(J)RX, -RuN(RX)C(J)ORX, -RuN(RX)S(O)tRW or —C(=NRy)N(Ry)ORX, where the alkyl, haloalkyl, aminoalkyl, l, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl groups are optionally substituted with one or more groups Q4; in one ment, one to three Q4 groups, each Q4 is independently selected from halo, hydroxyl, alkyl, haloalkyl and yalkyl; Rd is hydrogen or alkyl; each R11 is independently alkylene or a direct bond; RW is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, l, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, cyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; each Rx is independently hydrogen, alkyl, haloalkyl, yalkyl, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; Ry and RZ are each independently selected from (i) or (ii) below: (i) Ry and RZ are each independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, lkenyl, cycloalkylalkyl, cycloalkenylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; or (ii) Ry and RZ, together with the nitrogen atom to which they are attached, form a heterocyclyl or heteroaryl, optionally substituted with one or more, in one embodiment, one, two or three Q7 groups; each Q7 is independently selected from halo, deuterium, oxo, thioxo, hydroxy, alkoxy, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, lkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl; J is O, NRx or S; each t is ndently an integer from 0-2; 11 is l or 2; and q is an integer from 0-4, wherein the compounds are selected such that when W is CH; W1 is C; Z is S; R1 is hydrogen, or hydroxyl and R2 is hydrogen, or R1 and R2 together form =0; then ring A is not pyridine.

In certain embodiments, provided herein are nds of Formula I wherein ring A is heteroaryl, n is l and the other variables are as described elsewhere herein. In certain embodiments, provided herein are compounds of Formula I wherein ring A is heteroaryl, W1 is N, n is l or 2 and the other variables are as described elsewhere herein. In certain embodiments, provided herein are compounds of a I wherein ring A is heteroaryl, W1 is C or N, n is l or 2, provided that when W1 is C, n is l and the other les are as described elsewhere herein.

In certain embodiments, provided herein are compounds of Formula I, wherein ring A is bicyclic or tricyclic heteroaryl, and the other variables are as described elsewhere herein.

In certain ments, provided herein are nds of Formula I or pharmaceutically acceptable salts, solvates, hydrates, clathrates, single stereoisomers, mixture of stereoisomers or racemic mixture of stereoisomers thereof, wherein: R1 and R2 are each independently selected from hydrogen, n, hydroxyl and alkoxy; R3 is hydrogen or alkyl; R4 is cycloalkyl, cycloalkenyl, aryl, heterocyclyl or aryl, where R4 is optionally substituted with one or more, in one embodiment, one to three, in another ment, one, two or three groups selected from Q1; each Q1 is independently halo, oxo, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, =NOH, - uORx or -RuC(O)RX; Y is -(CR5R6)q-; R5 and R6 are each ndently hydrogen, halo, alkyl, haloalkyl or hydroxyalkyl; Z is O, S or NR7; R7 is hydrogen or alkyl; each W is independently CR8 or N; R8 is hydrogen, haloalkyl or alkyl; ring A is aryl or heteroaryl, optionally tuted with one to four substituents selected from Q2; W1 is N or C; w2 is N, NR9a or CR9b; w3 is N, NR10a or CRIOb; w4 is N, NR11a or CRllb; Rga, Rgb,R10a, R101), R1181 and R11b are ed as follows: i) R981, R1021 and R1121 are each independently hydrogen or alkyl and R91), R10b and R11b are each ndently en, oxo, hydroxyl, halo or alkyl; or ii) R9&1 and R101), R981 and Rloa, R9b and R101), R9b and Rloa, R1021 and Rm, R10b and Rm, R1021 and R11b or R10b and R11b together with the atoms to which they are attached form an aryl, heteroaryl or heterocyclyl ring, optionally substituted with one or more, in one ment, one to three, in another embodiment, one, two or three groups selected from Q2; and the der of Rga, R1081 and R1181 are each independently hydrogen or alkyl; and the der of R9b R10b and R11b are each independently hydrogen, halo or alkyl; each Q2 is independently halo, cyano, oxo, thioxo, alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, -RuORX, - uORuN(Ry)(RZ), -RuN(Ry)(RZ), -RuSRX, - uC(J)Rx, - RuC(J)ORX, -RuC(J)N(Ry)(RZ), -RuC(J)N(Ry)ORX, - uS(O)tRw, -RuN(RX)C(J)RX, - RuN(RX)C(J)ORX, -RuN(RX)S(O)tRW or —C(=NRy)N(Ry)ORX, where the alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl groups are optionally substituted with one or more Q4 groups; in one embodiment, one to three Q4 groups, each Q4 is independently selected from halo, hydroxyl, alkyl, haloalkyl and yalkyl; each R11 is independently alkylene or a direct bond; RW is alkyl; each Rx is independently hydrogen or alkyl; Ry and RZ are each independently hydrogen or alkyl; J is O, NRx or S; each t is ndently an integer from 0-2; 11 is l or 2; and q is an integer from 0-4, W0 2013/056070 wherein the compounds are ed such that when W is CH; W1 is C; Z is S; R1 is hydrogen, or hydroxyl and R2 is hydrogen, or R1 and R2 together form =0; then ring A is not ne.

In certain embodiments, the compounds of Formula I is selected such that when W is CH; W1 is C; Z is NH; R1 and R2 together form =0; and q is 0, then ring A is not phenyl. In certain ments, the compounds of a I is selected such that when i) W is CH; W1 is C; Z is S; R1 is hydrogen or hydroxyl and R2 is hydrogen, or R1 and R2 together form =0; then ring A is not pyridine and ii) when W is CH; W1 is C; Z is NH; R1 and R2 together form =0; and q is 0, then ring A is not phenyl.

In certain embodiments, the compounds provided herein are selected such that when W is CH; W1 is C; Z is S; R1 is hydrogen, or hydroxyl and R2 is hydrogen, or R1 and R2 together form =0; then ring A is not a 6 membered heteroaryl ring.

In certain embodiments, the compounds provided herein are selected such that when W is CH; W1 is C; Z is S; R1 is hydrogen, or hydroxyl and R2 is hydrogen, or R1 and R2 together form =0; then ring A is a fused bicyclic ring.

In certain ments, the compounds provided herein are ed such that when W is CH; W1 is N; Z is S; R1 and R2 are hydrogen, then ring A is not pyrrolidine.

In certain embodiments, the compounds provided herein are selected such that when W is CH; W1 is N; Z is S; R1 and R2 are hydrogen, then ring A is not -membered cyclyl.

In certain embodiments, the compounds provided herein are selected such that when W is CH, Z is NH, R1 and R2 er form =0, q is 0, and R4 is pyridinyl, then ring A is not phenyl.

In certain embodiments, the compounds provided herein are selected such that when W is CH, Z is NH, R1 and R2 together form =0, q is 0, and R4 is nitrogen containing heteroaryl, then ring A is not phenyl.

In certain embodiments, the compounds provided herein are selected such that when W is CH, Z is NH, R1 and R2 er form =0, q is 0, and R4 is monocyclic heteroaryl, then ring A is not phenyl.

In certain embodiments, the compounds provided herein are ed such that when W is CH, Z is NH, R1 and R2 together form =0, q is 0, and R4 is phenyl, then ring A is not pyrrolidine.

In n embodiments, the compounds provided herein are selected such that when W is CH, Z is NH, R1 and R2 together form =0, q is 0, and R4 is phenyl, then ring A is not en containing heterocyclyl.

In certain embodiments, the compounds provided herein are selected such that when Z is N, one of R1 and R2 is methyl and the other of R1 and R2 is H, q is 0, and R3 is pyridine, and W1 is N, ring A cannot be piperidine, l,2,3,4- tetrahydroisoquinoline, or isoindoline.

In certain embodiments, the compounds provided herein are selected such that when Z is N, one of R1 and R2 is methyl and the other of R1 and R2 is H, q is 0, and R3 is pyridine, and W1 is N, ring A cannot be nitrogen containing heterocyclyl.

In certain embodiments, the compounds provided herein are selected such that when Z is N, one of R1 and R2 is methyl and the other of R1 and R2 is H, q is 0, and R3 is pyridine, and W1 is N, ring A cannot be heterocyclyl.

In certain embodiments, provided herein are compounds of a I, wherein R1 and R2 are each independently ed from hydrogen and halogen. In n embodiments, R1 and R2 are each hydrogen. In certain embodiments, R1 is en and R2 is halogen. In certain embodiments, R1 and R2 are each halogen. In certain embodiments, R1 and R2 are each independently selected from hydrogen and fluorine. In certain embodiments, R1 is alkoxy and R2 is hydrogen. In certain embodiments, R1 is hydroxy and R2 is hydrogen.

In certain ments, R3 is hydrogen or alkyl. In n ments, R3 is hydrogen or . In certain embodiments, R3 is hydrogen.

In certain embodiments, R4 is cycloalkyl, aryl, heterocyclyl or heteroaryl, where R4 is optionally substituted with one or more, in one embodiment, one to three, in another embodiment, one, two or three groups selected from Q1; each Q1 is independently halo, oxo, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, =NOH, -RuORX or -RuC(O)RX, each R11 is independently alkylene or a direct bond; and each Rx is independently hydrogen or alkyl. In certain embodiments, R4 is cycloalkyl or heterocyclyl, where R4 is optionally substituted with one or more Q1.

In certain ments, R4 is cyclohexyl, tetrahydrofuryl, pyridinyl, phenyl, morpholinyl, cyclopentyl, piperidinyl, tetrahydro-2H—pyranyl or 2,3-dihydro- lH-indenyl, where R4 is optionally substituted with one or more, in one embodiment, one to three, in another embodiment, one, two or three groups selected from Q1; each Q1 is ndently halo, oxo, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, =NOH, -RuORX or -RuC(O)RX, each R11 is independently alkylene or a direct bond; and each Rx is independently hydrogen or alkyl.

In certain embodiments, R4 is cycloalkyl, optionally substituted with one, two or three groups selected from Q1; each Q1 is independently halo, oxo, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, =NOH, -RuORX or - uC(O)Rx, each R11 is independently alkylene or a direct bond; and each Rx is independently hydrogen or alkyl.

In certain embodiments, R4 is cyclohexyl, optionally substituted with hydroxyl.

In certain embodiments, Y is direct bond or —(CR5R6)q-; R5 and R6 are each independently hydrogen, halo, alkyl, haloalkyl or hydroxyalkyl. In n embodiments, Y is direct bond or —(CR5R6)q-; R5 and R6 are each independently hydrogen, alkyl or hydroxyalkyl. In certain embodiments, Y is direct bond, -CH2-, -CH(CH3)- OI' -CH(CH20H)-.

In certain embodiments, Z is O, S or NH. In certain embodiments, Z is O or S.

In certain embodiments, each W is independently CR8 or N; and R8 is hydrogen, halo or alkyl. In n embodiments, each W is CR8; and R8 is hydrogen or alkyl. In certain embodiments, each W is CH.

In certain embodiments, ring A is aryl or heteroaryl, optionally substituted with one or two substituents selected from Q2; where Q2 is heteroaryl, -RuC(J)N(Ry)(RZ), or -RuN(RX)C(J)RX, where when Q2 is the heteroaryl, it is ally tuted with one or more alkyl; each R11 is independently alkylene or a direct bond; each Rx is ndently hydrogen or alkyl; Ry and RZ are each independently hydrogen or alkyl; and J is O, NRx or S.

In certain embodiments, ring A is heteroaryl, ally tuted with one or two substituents selected from Q2; where Q2 is heteroaryl, -RuC(J)N(Ry)(RZ), or -RuN(RX)C(J)RX, where when Q2 heteroaryl, it is optionally substituted with one or more alkyl; each R11 is independently alkylene or a direct bond; each Rx is independently hydrogen or alkyl; Ry and RZ are each independently hydrogen or alkyl; and J is O, NRx or S.

In certain embodiments, provided herein are compounds of Formula I: or pharmaceutically acceptable salts, es, hydrates, clathrates, single stereoisomers, mixture of stereoisomers or racemic mixture of stereoisomers thereof, wherein: R1 and R2 are each independently selected from hydrogen, halogen, hydroxyl and alkoxy, or R1 and R2 together form =0; R3 is hydrogen or alkyl; R4 is cycloalkyl, cycloalkenyl, aryl, heterocyclyl or heteroaryl, where R4 is optionally substituted with one or more, in one embodiment, one to three, in r embodiment, one, two or three groups selected from Q1; each Q1 is independently halo, cyano, oxo, thioxo, alkyl, haloalkyl, aminoalkyl, alkenyl, l, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, , - uORuN(Ry)(RZ), -RuN(Ry)(RZ), -RuSRX, - uC(J)Rx, - ORX, )N(Ry)(RZ), -RuS(O)tRw, X)C(J)RX, -RuN(RX)C(J)ORX, - RuN(RX)S(O)tRW, =NORd, or —C(=NRy)N(Ry)ORX, where the alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, and cyclyl groups are optionally substituted with one or more Q3 groups, in one embodiment, one to three Q3 groups; each Q3 is independently selected from halo, hydroxyl, alkyl, haloalkyl and hydroxyalkyl; Y is -(CR5R6)q-; R5 and R6 are each independently hydrogen, halo, alkyl, haloalkyl or hydroxyalkyl; Z is O, S or NR7; R7 is hydrogen or alkyl; each W is independently CR8 or N; R8 is hydrogen, halo, haloalkyl or alkyl; ring A is a bicyclic or tricyclic heteroaryl or heterocyclyl optionally substituted with one to four substituents selected from Q2; W1 is N or C; w2 is N, NR9a or CR9b; w3 is N, NR10a or CRIOb; w4 is N, NR11a or CRllb; Rga, Rgb,R10a, R101), R1181 and R11b are selected as follows: i) R9a and R101), R9a and RIOa’ R9b and R101), R9b and RIOa’ R10a and Rlla’ R10b and Rm, R1021 and R11b or R10b and R11b together with the atoms to which they are attached form an aryl, heteroaryl or heterocyclyl ring, ally substituted with one or more, in one embodiment, one to three, in r embodiment, one, two or three groups selected from Q2; and the remainder of Rga, R1081 and R1181 are each independently hydrogen or alkyl; and the remainder of R91), R10b and R11b are each independently hydrogen, halo or alkyl; or ii) R9&1 and R101), R981 and Rloa, R9b and R101), R9b and Rloa, R1021 and Rm, R10b and Rm, R1021 and R11b or R10b and R11b together with the atoms to which they are attached form an aryl, aryl or heterocyclyl ring optionally fused to a phenyl ring optionally substituted with one or more, in one embodiment, one to three, in another embodiment, one, two or three groups selected from Q2; and the remainder of R981 and R9b or the remainder of R1121 and R11b are each independently en or alkyl; each Q2 is independently halo, cyano, oxo, thioxo, alkyl, haloalkyl, haloalkenyl, aminoalkyl, alkenyl, l, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, aralkyl, heteroaryl, aralkyl, cyclyl, heterocyclylalkyl, -RuORX, - uORuORX,-RuORuN(Ry)(RZ), - RuN(Ry)(RZ), -R“SRX, - uC(J)Rx, - uC(J)ORX, )N(Ry)(RZ), - uC(J)RuN(Ry)(RZ) , )N(Ry)ORX, -C(=NORX)RX’ uS(O)tRw, -RuN(RX)C(J)RX, -RuN(RX)C(J)ORX, -RuN(RX)S(O)tRW or —C(=NRy)N(Ry)ORX, where the alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl groups are optionally substituted with one or more groups Q4; in one ment, one to three Q4 , each Q4 is independently ed from halo, hydroxyl, alkyl, haloalkyl and hydroxyalkyl; Rd is hydrogen or alkyl; each R11 is independently alkylene, alkenylene or a direct bond; RW is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; each Rx is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cyanoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; Ry and RZ are each independently selected from (i) or (ii) below: (i) Ry and RZ are each ndently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; or (ii) Ry and RZ, together with the nitrogen atom to which they are attached, form a heterocyclyl or heteroaryl, optionally substituted with one or more, in one embodiment, one, two or three Q7 groups; each Q7 is independently selected from halo, ium, oxo, thioxo, hydroxy, alkoxy, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, l, lkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, l, aryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl; J is O, NRx or S; each t is independently an integer from 0-2; 11 is l or 2; and q is an integer from 0-4, wherein the compound is selected such that when Z is N, one of R1 and R2 is methyl and the other of R1 and R2 is H, q is 0, and R3 is pyridine, and W1 is N, ring A cannot be l,2,3,4-tetrahydroisoquinoline, or isoindoline In certain embodiments, W1 is N. In certain embodiments, W1 is C.

In n ments, W2 is N or CR9b, where R9b is hydrogen oxo, hydroxyl or alkyl. 10b In n embodiments, W3 is N or CR where R10b is hydrogen or alkyl. In certain embodiments, W4 is N or CR where R11b is hydrogen or alkyl.

In certain embodiments, W2 is CRgb; W3 is CRIOb; W4 is N or CR1“); where R9b and R10b together with the carbon atoms on which they are substituted form an aryl or heteroaryl ring, optionally substituted with one or more, in one embodiment, one to three, in another embodiment, one, two or three groups ed from Q2; R11b is hydrogen or alkyl; each Q2 is independently halo, cyano, oxo, thioxo, alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, lkylalkyl, cycloalkenylalkyl, aryl, l, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, -RuORX, - uORuN(Ry)(RZ), y)(RZ), -RuSRX, - uC(J)Rx, - RuC(J)ORX, -RuC(J)N(Ry)(RZ), -RuC(J)N(Ry)ORX, - uS(O)tRW, X)C(J)RX, - RuN(RX)C(J)ORX, -RuN(RX)S(O)tRW or —C(=NRy)N(Ry)ORX, where the alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl groups are optionally substituted with one or more Q4 groups; each Q4 is independently selected from halo, hydroxyl, alkyl, haloalkyl and hydroxyalkyl; each R11 is independently alkylene or a direct bond; RW is alkyl; each Rx is independently hydrogen or alkyl; Ry and RZ are each independently hydrogen or alkyl; J is O, NRx or S; and each t is independently an integer from 0-2.

In certain embodiments, W2 is CRgb; W3 is CRIOb; W4 is N; where R9b and R10b together with the carbon atoms on which they are substituted form an aryl or heteroaryl ring, optionally substituted with one or two groups selected from Q2, where Q2 is as defined elsewhere herein. In certain embodiments, each Q2 is independently halo, cyano, alkyl, haloalkyl, aminoalkyl, l, alkynyl, cycloalkyl, heteroaryl, heterocyclyl, -RuORX, -RuN(Ry)(RZ), -RuSRX, - uC(J)Rx, - uC(J)ORX, - RuC(J)N(Ry)(RZ), -RuC(J)N(Ry)ORX, - RW, -RuN(RX)C(J)RX, -RuN(RX)C(J)ORX, -RuN(RX)S(O)tRW or —C(=NRy)N(Ry)ORX, where the alkyl, kyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, and heterocyclyl groups are optionally substituted with one or more Q4 ; each Q4 is independently selected from halo, hydroxyl, alkyl, haloalkyl and hydroxyalkyl; each R11 is independently alkylene or a direct bond; RW is alkyl; each Rx is independently hydrogen or alkyl; Ry and RZ are each independently hydrogen or alkyl; J is O, NRx or S; and each t is independently an r from 0-2.

In certain embodiments, n is l or 2. In certain embodiments, n is 1. In certain embodiments, n is 2.

In certain embodiments, q is an integer from 0-4. In certain embodiments, q is 0-3. In n embodiments, q is 0-2. In certain embodiments, q is 0, l or 2. In certain ments, q is 0. In certain embodiments, q is 1. In certain embodiments, qis 2.

In n embodiments, provided herein are compounds of Formula I or pharmaceutically acceptable salts, solvates, hydrates, clathrates, single stereoisomers, mixture of stereoisomers or racemic mixture of stereoisomers thereof, wherein: R1 and R2 are each independently selected from hydrogen, alkoxy and halogen; R3 is hydrogen or alkyl; R4 is cycloalkyl, aryl, cyclyl or heteroaryl, Where R4 is optionally substituted with one or more, in one embodiment, one to three, in r embodiment, one, two or three groups selected from Q1; each Q1 is independently halo, oxo, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, =NOH, - uORx or -RuC(O)RX; Y is direct bond or -(CR5R6)q-; R5 and R6 are each independently hydrogen, halo, alkyl, haloalkyl or hydroxyalkyl; Z is O, S, or NR7; R7 is hydrogen or alkyl; each W is independently CR8 or N; R8 is en, haloalkyl or alkyl; ring A is aryl or heteroaryl; W1 is N or C; w2 is N, NR9a or CR9b; w3 is N, NR10a or CRIOb; w4 is N, NR11a or CRllb; Rga, Rgb,R10a, R101), R1181 and R11b are ed as follows: i) R981, R1021 and R1121 are each independently hydrogen or alkyl; and R91), R10b and R11b are each independently hydrogen, oxo, hydroxyl, halo or alkyl; or ii) R9&1 and R101), R981 and Rloa, R9b and R101), R9b and Rloa, R1021 and Rm, R10b and Rm, R1021 and R11b or R10b and R11b together with the atoms to which they are attached form an aryl or heteroaryl ring, optionally substituted with one or more, in one embodiment, one to three, in another embodiment, one, two or three groups ed from Q2; the remainder of Rga, R1021 and R1121 are each independently en or alkyl; the remainder of R9b R10b and R11b are each independently hydrogen, halo or alkyl; each Q2 is independently halo, cyano, oxo, thioxo, alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, -RuORX, - uORuN(Ry)(RZ), -RuN(Ry)(RZ), -RuSRX, - uC(J)Rx, - RuC(J)ORX, -RuC(J)N(Ry)(RZ), -RuC(J)N(Ry)ORX, - uS(O)tRW, -RuN(RX)C(J)RX, - RuN(RX)C(J)ORX, -RuN(RX)S(O)tRW or —C(=NRy)N(Ry)ORX, where the alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl groups are optionally tuted with one or more Q4 ; each Q4 is independently selected from halo, hydroxyl, alkyl, haloalkyl and hydroxyalkyl; each R11 is ndently alkylene or a direct bond; RW is alkyl; each Rx is independently hydrogen or alkyl; Ry and RZ are each ndently hydrogen or alkyl; J is O, NRx or S; each t is independently an integer from 0-2; 11 is l; and q is an integer from 0-2.

In certain embodiments, provided herein are compounds of Formula II WO 56070 R1 R2 2 3 M “K 2 r WV? WI / N\Y—R4 W \ N w 11 or pharmaceutically acceptable salts, solvates, es, ates, single stereoisomers, mixture of stereoisomers or racemic mixture of stereoisomers thereof, wherein: R1 and R2 are each independently selected from hydrogen, alkoxy and R3 is hydrogen or alkyl; R4 is lkyl, cycloalkenyl, aryl, heterocyclyl or heteroaryl, where R4 is optionally substituted with one or more, in one embodiment, one to three, in another embodiment, one, two or three groups selected from Q1; each Q1 is independently deuterium, halo, cyano, oxo, thioxo, alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, lkenylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, -RuORX, - uORuN(Ry)(RZ), -RuN(Ry)(RZ), - RuSRX, - uC(J)Rx, - uC(J)ORX, - uC(J)N(Ry)(RZ), -RuS(O)tRW, -RuN(RX)C(J)RX, -RuN(RX)C(J)ORX, -RuN(RX)S(O)tRW, =NORd, or —C(=NRy)N(Ry)ORX, where the alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl groups are optionally substituted with one or more Q3 groups, in one embodiment, one to three Q3 groups; each Q3 is independently ed from deuterium, halo, hydroxyl, alkyl, kyl and hydroxyalkyl; Y is —(CR5R6)q-; R5 and R6 are each independently hydrogen, halo, alkyl, haloalkyl or hydroxyalkyl; Z is O, S, or NR7; R7 is hydrogen or alkyl; each W is independently CR8 or N; R8 is hydrogen, haloalkyl or alkyl; ring A is aryl or heteroaryl, optionally tuted with one to four substituents selected from Q2; W1 is N or C; w2 is N, NR9a or CR9b; w3 is N, NR10a or CRIOb; w4 is N, NR11a or CRllb; Rga, Rgb,R10a, R101), R1181 and R11b are selected as follows: i) R981, R1021 and R1121 are each independently hydrogen or alkyl and R91), R10b and R11b are each independently hydrogen or Q2; or ii) R9&1 and R101), R981 and Rloa, R9b and R101), R9b and Rloa, R1021 and Rlla, R10b and Rlla, R1021 and R11b or R10b and R11b together with the atoms to which they are attached form an aryl or heteroaryl ring, optionally substituted with one or more, in one embodiment, one to three, in r embodiment, one, two or three groups selected from Q2; the remainder of R921 or R1121 is hydrogen or alkyl; and the der of R9b or R11b is independently hydrogen or Q2; each Q2 is independently halo, deuterium, cyano, oxo, thioxo, alkyl, haloalkyl, aminoalkyl, alkenyl, haloalkenyl, l, lkyl, lkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, -RuORX, - uORuORX,-RuORuN(Ry)(RZ), - RuN(Ry)(RZ), -RuSRX, - x, - uC(J)ORX, - RuC(J)N(Ry)(RZ), -RuC(J)RuN(Ry)(RZ), - uC(J)N(Ry)ORX, -C(=NORX)RX, - RuS(O)tRw, -RuN(RX)C(J)RX, -RuN(RX)C(J)ORX, -RuN(RX)S(O)tRW or — C(=NRy)N(Ry)ORX, where the alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl groups are optionally tuted with one or more Q4 groups; each Q4 is independently selected from halo, hydroxyl, alkyl, haloalkyl and hydroxyalkyl; each Rd is independently hydrogen or alkyl; each R11 is independently alkylene, alkenylene or a direct bond; RW is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, lkenylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, aryl, or heteroaralkyl; each Rx is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkyl, cyanoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; Ry and RZ are each independently selected from (i) or (ii) below: (i) Ry and RZ are each independently hydrogen, alkyl, haloalkyl, yalkyl, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; or (ii) Ry and RZ, together with the nitrogen atom to which they are attached, form a heterocyclyl or heteroaryl, optionally substituted with one or more, in one embodiment, one, two or three Q7 ; each Q7 is independently selected from halo, deuterium, oxo, thioxo, hydroxy, alkoxy, alkyl, haloalkyl, yalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, lkylalkyl, lkenylalkyl, aryl, l, heteroaryl, heteroaralkyl, cyclyl and heterocyclylalkyl; J is O, NRx or S; each t is independently an integer from 0-2; and q is an integer from 0-2; wherein the compounds are selected such that when i) W is CH; W1 is C; Z is S; R1 is hydrogen, or hydroxyl and R2 is hydrogen, or R1 and R2 together form =0; then ring A is not pyridine and ii) when W is CH; W1 is C; Z is NH; R1 and R2 together form =0; and q is 0, then ring A is not phenyl.

In certain ments, provided herein are compounds of Formula II n each Q1 is independently halo, oxo, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, =NOH, - uORx or -RuC(O)RX; each R11 is independently alkylene or a direct bond; each Rx is independently hydrogen or alkyl; and the other variables are as described elsewhere herein. In certain embodiments, provided herein are compounds of Formula II wherein ring A is heteroaryl optionally substituted with one to four substituents ed from Q2; 11 is l and the other variables are as described elsewhere herein.

In certain embodiments, provided herein are compounds of Formula II or pharmaceutically acceptable salts, solvates, hydrates, clathrates, single stereoisomers, mixture of stereoisomers or racemic mixture of stereoisomers thereof, wherein: R1 and R2 are each independently selected from hydrogen, alkoxy and halogen; R3 is hydrogen or alkyl; R4 is lkyl, cycloalkenyl, aryl, heterocyclyl or heteroaryl, where R4 is optionally substituted with one or more, in one embodiment, one to three, in another ment, one, two or three groups selected from Q1; each Q1 is independently halo, oxo, alkyl, haloalkyl, yalkyl, cycloalkyl, =NOH, - uORx or -RuC(O)RX; Y is —(CR5R6)q-; R5 and R6 are each ndently hydrogen, halo, alkyl, haloalkyl or hydroxyalkyl; Z is O, S, or NR7; R7 is hydrogen or alkyl; each W is independently CR8 or N; R8 is hydrogen, halo, haloalkyl or alkyl; ring A is aryl or heteroaryl, optionally substituted with one to four substituents selected from Q2; W1 is N or C; w2 is N, NR9a or CR9b; W3 is N, NR10a or CRIOb; w4 is N, NR11a or CRllb; Rga, Rgb,R10a, R101), R1181 and R11b are selected as follows: i) R981, R1021 and R1121 are each independently hydrogen or alkyl and R91), R10b and R11b are each ndently hydrogen, oxo, hydroxyl, halo or alkyl; or ii) R9&1 and R101), R981 and Rloa, R9b and R101), R9b and Rloa, R1021 and Rm, R10b and Rm, R1021 and R11b or R10b and R11b er with the atoms to which they are attached form an aryl or heteroaryl ring, optionally substituted with one or more, in one embodiment, one to three, in another embodiment, one, two or three groups selected from Q2; the remainder of Rga, R1021 and R1121 are each independently en or alkyl; the remainder of R9b R10b and R11b are each independently hydrogen, halo or alkyl; each Q2 is independently halo, cyano, oxo, thioxo, alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, WO 56070 heterocyclylalkyl, -RuORX, - uORuN(Ry)(RZ), -RuN(Ry)(RZ), -RuSRX, - x, - RuC(J)ORX, -RuC(J)N(Ry)(RZ), -RuC(J)N(Ry)ORX, - uS(O)tRw, -RuN(RX)C(J)RX, - RuN(RX)C(J)ORX, X)S(O)tRW or —C(=NRy)N(Ry)ORX, where the alkyl, haloalkyl, aminoalkyl, l, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl groups are ally substituted with one or more Q4 groups; each Q4 is ndently selected from halo, hydroxyl, alkyl, haloalkyl and hydroxyalkyl; each R11 is independently alkylene or a direct bond; RW is alkyl; each Rx is independently hydrogen or alkyl; Ry and RZ are each independently hydrogen or alkyl; J is O, NRx or S; each t is independently an integer from 0-2; and q is an integer from 0-2.

In certain embodiments, provided herein are compounds of Formula II wherein ring A is heteroaryl optionally substituted with one to four substituents selected from Q2 and the other variables are as described elsewhere herein.

In certain ments, compound of formula 11 us selected such that: i) when W is CH; W1 is N; Z is S; R1 and R2 are hydrogen, then ring A is not pyrrolidine; ii) when W is CH, Z is NH, R1 and R2 together form =0, q is 0, and R4 is phenyl, then ring A is not pyrrolidine, and iii) when Z is N, one of R1 and R2 is methyl and the other of R1 and R2 is H, q is 0, and R3 is pyridine, and W1 is N, ring A cannot be isoindoline.

In certain embodiments, provided herein are compounds of Formula II, wherein ring A is bicyclic or tricyclic heteroaryl, and the other variables are as bed elsewhere herein.

In certain embodiments, provided herein are compounds of Formula II or pharmaceutically acceptable salts, solvates, hydrates, ates, single stereoisomers, mixture of stereoisomers or c mixture of stereoisomers thereof, wherein: R1 and R2 are each independently selected from hydrogen, alkoxy and halogen; R3 is hydrogen or alkyl; R4 is cycloalkyl, cycloalkenyl, aryl, heterocyclyl or heteroaryl, where R4 is optionally substituted with one or more, in one embodiment, one to three, in another embodiment, one, two or three groups selected from Q1; each Q1 is independently halo, oxo, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, =NOH, - uORx or -RuC(O)RX; Y is —(CR5R6)q—; R5 and R6 are each independently hydrogen, halo, alkyl, haloalkyl or hydroxyalkyl; Z is O, S, or NR7; R7 is hydrogen or alkyl; each W is independently CR8 or N; R8 is hydrogen, halo, haloalkyl or alkyl; ring A is aryl or heterocyclyl, optionally substituted with one to four substituents selected from Q2; W1 is N or C; w2 is N, NR9a or CR9b; W3 is N, NR10a or CRIOb; w4 is N, NR11a or CRllb; Rga, Rgb,R10a, R101), R1181 and R11b are selected as follows: i) R981, R1021 and R1121 are each ndently hydrogen or alkyl and R91), R10b and R11b are each independently hydrogen, oxo, hydroxyl, halo or alkyl; or ii) R9&1 and R101), R981 and Rloa, R9b and R101), R9b and Rloa, R1021 and Rm, R10b and Rm, R1021 and R11b or R10b and R11b together with the atoms to which they are attached form an aryl, heteroaryl or heterocyclyl ring, optionally tuted with one or more, in one embodiment, one to three, in another embodiment, one, two or three groups selected from Q2; the remainder of Rga, R1081 and R1181 are each ndently hydrogen or alkyl; the der of R9b R10b and R11b are each independently hydrogen, halo or alkyl; or iii) R9&1 and R101), R981 and Rloa, R9b and R101), R9b and Rloa, R1021 and Rlla, R10b and Rm, R1021 and R11b or R10b and R11b together with the atoms to which they are attached form an aryl, heteroaryl or heterocyclyl ring optionally fused to a phenyl ring optionally substituted with one or more, in one embodiment, one to three, in another ment, one, two or three groups selected from Q2; and the remainder of R981 and R9b or the der of R1121 and R11b are each independently hydrogen or alkyl; each Q2 is independently halo, cyano, oxo, thioxo, alkyl, haloalkyl, lkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, lkylalkyl, cycloalkenylalkyl, aryl, aralkyl, aryl, heteroaralkyl, heterocyclyl, cyclylalkyl, -RuORX, - uORuORx, - uORuN(Ry)(RZ), -RuN(Ry)(RZ), - RuSRX, - uC(J)RX, - uC(J)ORX, - uC(J)N(Ry)(RZ), -RuC(J)RuN(Ry)(RZ),- RuC(J)N(Ry)ORX, -C(=NORX)RX, - uS(O)tRW, -RuN(RX)C(J)RX, -RuN(RX)C(J)ORX, - RuN(Rx)S(O)tRW or —C(=NRy)N(Ry)ORX, where the alkyl, haloalkyl, lkyl, l, l, cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl groups are optionally substituted with one or more Q4 groups; each Q4 is independently ed from halo, hydroxyl, alkyl, haloalkyl and hydroxyalkyl; each R11 is independently alkylene, alkenylene or a direct bond; RW is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, or aralkyl; each Rx is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cyanoalkyl, l, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; Ry and RZ are each independently selected from (i) or (ii) below: (i) Ry and RZ are each independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, aryl, or heteroaralkyl; or (ii) Ry and RZ, together with the nitrogen atom to which they are attached, form a heterocyclyl or aryl, optionally substituted with one or more, in one embodiment, one, two or three Q7 groups; each Q7 is independently selected from halo, deuterium, oxo, , hydroxy, alkoxy, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl; J is O, NRx or S; each t is independently an integer from 0-2; and q is an integer from 0-2; WO 56070 wherein the compounds are ed such that when W is CH; W1 is N; Z is S; R1 and R2 are hydrogen, then ring A is not pyrrolidine.

In certain embodiments, ed herein are compounds of Formula II or pharmaceutically acceptable salts, solvates, hydrates, clathrates, single stereoisomers, mixture of stereoisomers or racemic mixture of stereoisomers thereof, wherein: R1 and R2 are each independently selected from hydrogen, alkoxy and halogen; R3 is hydrogen or alkyl; R4 is cycloalkyl, cycloalkenyl, aryl, heterocyclyl or heteroaryl, where R4 is optionally substituted with one or more, in one embodiment, one to three, in another embodiment, one, two or three groups selected from Q1; each Q1 is independently halo, oxo, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, =NOH, - uORx or -RuC(O)RX; Y is —(CR5R6)q-; R5 and R6 are each independently hydrogen, halo, alkyl, haloalkyl or yalkyl; Z is O, S, or NR7; R7 is en or alkyl; each W is independently CR8 or N; R8 is en, halo, haloalkyl or alkyl; ring A is bicyclic heteroaryl or heterocyclyl, optionally substituted with one to four substituents selected from Q2; W1 is N or C; w2 is N, NR9a or CR9b; w3 is CRIOb; W4 is N; Rga, Rgb, and R10b are selected as follows: R9&1 and R10b or R9b and R101), together with the atoms to which they are attached, form an aryl, heteroaryl or heterocyclyl ring, optionally substituted with one or more, in one embodiment, one to three, in another embodiment, one, two or three groups selected from Q2; the remainder of R981 and R10b is hydrogen or alkyl; each Q2 is ndently halo, cyano, oxo, thioxo, alkyl, haloalkyl, lkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, 2012/059983 cycloalkenylalkyl, aryl, l, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, -RuORX, - uORuORx, - uORuN(Ry)(RZ), -RuN(Ry)(RZ), - RuSRX, - uC(J)Rx, - uC(J)ORX, - uC(J)N(Ry)(RZ), -RuC(J)RuN(Ry)(RZ),- RuC(J)N(Ry)ORX, -C(=NORX)RX, - Rw, -RuN(RX)C(J)RX, -RuN(RX)C(J)ORX, - RuN(Rx)S(O)tRW or —C(=NRy)N(Ry)ORX, where the alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl groups are optionally substituted with one or more Q4 groups; each Q4 is independently selected from halo, hydroxyl, alkyl, haloalkyl and hydroxyalkyl; each R11 is independently ne, alkenylene or a direct bond; RW is alkyl, haloalkyl, hydroxyalkyl, alkyl, alkenyl, alkynyl, lkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; each Rx is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cyanoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; Ry and RZ are each independently selected from (i) or (ii) below: (i) Ry and RZ are each independently hydrogen, alkyl, kyl, hydroxyalkyl, alkyl, alkenyl, alkynyl, lkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; or (ii) Ry and RZ, together with the nitrogen atom to which they are attached, form a heterocyclyl or heteroaryl, optionally substituted with one or more, in one embodiment, one, two or three Q7 groups; each Q7 is independently selected from halo, deuterium, oxo, thioxo, hydroxy, alkoxy, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, l, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl; J is O, NRx or S; each t is independently an integer from 0-2; and q is an integer from 0-2.

In certain ments, provided herein are compounds of Formula 11 wherein W4 is N; W2 is N, NR9a or CRgb; W3 is CRIOb; and R981 and R10b or R9b and R101), er with the atoms to which they are attached, form an aryl, heteroaryl or heterocyclyl ring, optionally substituted with one or more, in one ment, one to three, in another embodiment, one, two or three groups selected from Q2 and the other variables are as bed elsewhere herein.

In n embodiments, provided herein are compounds of Formula II wherein R4 is cycloalkyl, optionally substituted with one or more, in one embodiment, one to three, in another embodiment, one, two or three groups selected from Q1;each Q1 is independently halo, oxo, alkyl, haloalkyl, hydroxyalkyl, lkyl, =NOH, - RuORx or - x; Y is —(CR5R6)q-; each R11 is independently ne, alkenylene or a direct bond; each Rx is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, lkyl, alkenyl, alkynyl, cycloalkyl, lkenyl, cycloalkylalkyl, cycloalkenylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; and q is 0; and the other variables are as described elsewhere herein.

In certain embodiments, provided herein are compounds of Formula III R1 R2 ’W2\ W\ Z R3 \ 4/9,) / n w / N\Y—R4 W \w N or pharmaceutically acceptable salts, solvates, es, ates, single stereoisomers, e of stereoisomers or racemic mixture of stereoisomers thereof, wherein: R1 and R2 are each independently selected from hydrogen, halogen, alkoxy and hydroxyl; R3 is hydrogen or alkyl; R4 is cycloalkyl, aryl, heterocyclyl or heteroaryl, where R4 is optionally substituted with one or more, in one embodiment, one to three, in another embodiment, one, two or three groups selected from Q1; each Q1 is independently deuterium, halo, cyano, oxo, thioxo, alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, -RuORX, - uORuN(Ry)(RZ), -RuN(Ry)(RZ), - RuSRX, - uC(J)Rx, - uC(J)ORX, - uC(J)N(Ry)(RZ), -RuS(O)tRW, -RuN(RX)C(J)RX, -RuN(RX)C(J)ORX, -RuN(RX)S(O)tRW, =NORd, or —C(=NRy)N(Ry)ORX, where the alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl groups are optionally substituted with one or more Q3 , in one ment, one to three Q3 groups; each Q3 is ndently selected from deuterium, halo, hydroxyl, alkyl, haloalkyl and yalkyl; Y is —(CR5R6)q-; R5 and R6 are each independently hydrogen, halo, alkyl, haloalkyl or hydroxyalkyl; Z is O, S or NH; each W is independently CR8 or N; R8 is hydrogen, halo, haloalkyl or alkyl; ring A is heteroaryl or heterocyclyl, optionally substituted with one to four substituents selected from Q2; W2 is N or CRgb; W3 is N or CRIOb; W4 is N or CR1“); R91),R10b and R11b are selected as follows: i) Rgb, R10b and R11b are each independently en or Q2; or ii) R9b and R10b or R10b and R11b together with the atoms to which they are attached form an aryl or heteroaryl ring, optionally substituted with one or more, in one embodiment, one to three, in another embodiment, one, two or three groups ed from Q2; and the remainder of R91), R10b and R11b is hydrogen or Q2; each Q2 is independently halo, cyano, oxo, thioxo, alkyl, haloalkyl, aminoalkyl, alkenyl, haloalkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cyclyl, heterocyclylalkyl, -RuORX, - uORuORX,-RuORuN(Ry)(RZ), -RuN(Ry)(RZ), -RuSRX, - RuC(J)RX, -RuC(J)ORX, -RuC(J)N(Ry)(RZ), - uC(J)RuN(Ry)(RZ), - RuC(J)N(Ry)ORX, -C(=NORX)RX, - uS(O)tRW, X)C(J)RX, -RuN(RX)C(J)ORX, - RuN(Rx)S(O)tRW or —C(=NRy)N(Ry)ORX, where the alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, and cyclyl groups are optionally substituted with one or more Q4 groups; each Q4 is independently ed from halo, hydroxyl, alkyl, haloalkyl and hydroxyalkyl; Rd is hydrogen or alkyl; each R11 is independently alkylene, alkenylene or a direct bond; RW is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; each Rx is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkyl, cyanoalkyl, alkenyl, alkynyl, lkyl, cycloalkenyl, lkylalkyl, cycloalkenylalkyl, cyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; Ry and RZ are each ndently selected from (i) or (ii) below: (i) Ry and RZ are each independently hydrogen, alkyl, haloalkyl, yalkyl, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; or (ii) Ry and RZ, together with the nitrogen atom to which they are attached, form a heterocyclyl or heteroaryl, optionally substituted with one or more, in one embodiment, one, two or three Q7 groups; each Q7 is independently selected from halo, deuterium, oxo, thioxo, hydroxy, alkoxy, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, l, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, l, heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl; J is O, NRx or S; each t is independently an integer from 0-2; 11 is l or 2; and q is an integer from 0-4.

In certain embodiments, provided herein are compounds of a 111 wherein each Q1 is independently halo, oxo, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, =NOH, - uORx or -RuC(O)RX; each R11 is independently alkylene or a direct bond; each Rx is independently hydrogen or alkyl; and the other variables are as described elsewhere herein.

In certain embodiments, provided herein are compounds of Formula 111 R1 R2 ,Wi W 2 R3 \ ”d \ 4 W4 )n w\ / Y—R w 111 or pharmaceutically able salts, solvates, hydrates, ates, single stereoisomers, mixture of stereoisomers or racemic mixture of stereoisomers thereof, wherein: R1 and R2 are each independently selected from hydrogen, halogen, alkoxy and hydroxyl; R3 is hydrogen or alkyl; R4 is cycloalkyl, aryl, heterocyclyl or heteroaryl, where R4 is optionally substituted with one or more, in one embodiment, one to three, in another embodiment, one, two or three groups selected from Q1; each Q1 is independently halo, oxo, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, =NOH, - uORx or -RuC(O)RX; Y is —(CR5R6)q-; R5 and R6 are each independently hydrogen, halo, alkyl, kyl or hydroxyalkyl; Z is O, S or NH; each W is independently CR8 or N; R8 is hydrogen, halo, haloalkyl or alkyl; ring A is heteroaryl, optionally substituted with one to four substituents selected from Q2; W2 is N or CRgb; W3 is N or CRIOb; W4 is N or CR1“); R91),R10b and R11b are ed as follows: i) R91), R10b and R11b are each independently hydrogen, oxo, hydroxyl, halo or alkyl; or ii) R9b and R10b or R10b and R11b together with the atoms to which they are attached form an aryl or heteroaryl ring, optionally tuted with one or more, in one embodiment, one to three, in another embodiment, one, two or three groups selected from Q2; and the remainder of R91), R10b and R11b is hydrogen, halo or alkyl; each Q2 is independently halo, cyano, oxo, thioxo, alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, lkenyl, cycloalkylalkyl, lkenylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, -RuORX, - uORuN(Ry)(RZ), y)(RZ), -RuSRX, - uC(J)Rx, - ORX, -RuC(J)N(Ry)(RZ), -RuC(J)N(Ry)ORX, - uS(O)tRW, -RuN(RX)C(J)RX, - RuN(RX)C(J)ORX, -RuN(RX)S(O)tRW or —C(=NRy)N(Ry)ORX, where the alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, aryl, and heterocyclyl groups are optionally substituted with one or more Q4 groups; each Q4 is independently selected from halo, hydroxyl, alkyl, haloalkyl and hydroxyalkyl; each R11 is independently alkylene or a direct bond; RW is alkyl; each Rx is independently hydrogen or alkyl; Ry and RZ are each independently hydrogen or alkyl; J is O, NRx or S; each t is independently an integer from 0-2; 11 is l or 2; and q is an integer from 0-4.

] In certain embodiments, compound of a III is selected such that: i) when W is CH; Z is S; R1 and R2 are hydrogen, then ring A is not pyrrolidine; ii) when W is CH, Z is NH, R1 and R2 together form =0, q is 0, and R4 is phenyl, then ring A is not idine; and iii) when Z is NH, one of R1 and R2 is methyl and the other of R1 and R2 is H, q is 0, and R3 is pyridine, and W1 is N, ring A cannot be A cannot be piperidine, l,2,3,4-tetrahydroisoquinoline, or isoindoline.

In certain embodiments, provided herein are compounds of Formula III wherein ring A is aryl and the other variables are as bed elsewhere herein.

In certain embodiments, provided herein are nds of Formula III, wherein ring A is bicyclic or tricyclic aryl, and the other variables are as described elsewhere herein.

In certain embodiments, provided herein are compounds of Formula III or pharmaceutically acceptable salts, solvates, hydrates, clathrates, single stereoisomers, mixture of stereoisomers or racemic mixture of stereoisomers f, wherein R1 and R2 are each independently selected from hydrogen or halogen; R3 is hydrogen or alkyl; R4 is cycloalkyl, optionally substituted with one or more, in one embodiment, one to three, in another embodiment, one, two or three groups selected from Q1; each Q1 is independently halo, oxo, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, =NOH, - uORx or -RuC(O)RX; Y is —(CR5R6)q-; R5 and R6 are each independently hydrogen, halo, alkyl, haloalkyl or yalkyl; Z is O, S, or NH; each W is independently CR8 or N; R8 is hydrogen, halo, haloalkyl or alkyl; ring A is heteroaryl optionally substituted with one to four substituents selected from Q2; W2 is N or CRgb; W3 is N or CRIOb; W4 is N or CR1“); 10b and R11b are selected as follows: i) Rgb, R10b and R11b are each independently hydrogen or Q2; or ii) R9b and R10b or R10b and Rllb, together with the atoms to which they are attached, form an aryl or heteroaryl ring, optionally substituted with one or more, in one embodiment, one to three, in another embodiment, one, two or three groups selected from Q2; and the remainder of R91), R10b and R11b is hydrogen or Q2; each Q2 is independently halo, cyano, oxo, thioxo, alkyl, kyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, lkenylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, -RuORX, - uORuN(Ry)(RZ), -RuN(Ry)(RZ), -RuSRX, - x, - RuC(J)ORX, -RuC(J)N(Ry)(RZ), -RuC(J)N(Ry)ORX, - uS(O)IRW, X)C(J)RX, - RuN(RX)C(J)ORX, -RuN(RX)S(O)tRW or —C(=NRy)N(Ry)ORX, where the alkyl, kyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl groups are ally substituted with one or more Q4 groups; each Q4 is independently selected from halo, hydroxyl, alkyl, haloalkyl and hydroxyalkyl; each R11 is independently alkylene or a direct bond; RW is alkyl; each Rx is independently hydrogen or alkyl; Ry and RZ are each independently hydrogen or alkyl; J is O, NRx or S; each t is independently an integer from 0-2; nis l or 2; and q is an integer from 0-2.

In certain embodiments, provided herein are compounds of Formula 111 or ceutically acceptable salts, solvates, hydrates, clathrates, single stereoisomers, mixture of stereoisomers or c mixture of stereoisomers thereof, wherein R1 and R2 are each independently selected from hydrogen or halogen; R3 is hydrogen or alkyl; R4 is cycloalkyl, optionally substituted with one or more, in one embodiment, one to three, in another embodiment, one, two or three groups selected from Q1; each Q1 is independently halo, oxo, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, =NOH, - uORx or -RuC(O)RX; Y is —(CR5R6)q-; R5 and R6 are each independently hydrogen, halo, alkyl, haloalkyl or hydroxyalkyl; Z is O, S, or NH; each W is independently CR8 or N; R8 is hydrogen, halo, haloalkyl or alkyl; ring A is heteroaryl optionally substituted with one to four substituents ed from Q2; W2 is N or CRgb; W3 is N or CRIOb; W4 is N or CR1“); R91),R10b and R11b are selected as follows: i) R91), R10b and R11b are each independently en, oxo, hydroxyl, halo or alkyl; or ii) R9b and R10b or R10b and Rllb, er with the atoms to which they are attached, form an aryl or heteroaryl ring, optionally tuted with one or more, in one embodiment, one to three, in another embodiment, one, two or three groups ed from Q2; and the remainder of R91), R10b and R11b is hydrogen, halo or alkyl; each Q2 is independently halo, cyano, oxo, thioxo, alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, aralkyl, aryl, heteroaralkyl, heterocyclyl, WO 56070 heterocyclylalkyl, -RuORX, - uORuN(Ry)(RZ), -RuN(Ry)(RZ), -RuSRX, - uC(J)Rx, - RuC(J)ORX, -RuC(J)N(Ry)(RZ), )N(Ry)ORX, - uS(O)tRW, -RuN(RX)C(J)RX, - RuN(RX)C(J)ORX, -RuN(RX)S(O)tRW or —C(=NRy)N(Ry)ORX, where the alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl groups are optionally substituted with one or more Q4 groups; each Q4 is independently selected from halo, hydroxyl, alkyl, haloalkyl and hydroxyalkyl; each R11 is independently alkylene or a direct bond; RW is alkyl; each Rx is independently hydrogen or alkyl; Ry and RZ are each independently hydrogen or alkyl; J is O, NRx or S; each t is independently an integer from 0-2; 11 is l or 2; and q is an integer from 0-2.

In certain embodiments, provided herein are compounds of Formula 111 or pharmaceutically able salts, solvates, hydrates, clathrates, single stereoisomers, mixture of stereoisomers or racemic mixture of stereoisomers f, wherein: R1 and R2 are each ndently ed from hydrogen, n, alkoxy and yl; R3 is hydrogen or alkyl; R4 is cycloalkyl, aryl, heterocyclyl or heteroaryl, where R4 is optionally substituted with one or more, in one embodiment, one to three, in another embodiment, one, two or three groups selected from Q1; each Q1 is independently deuterium, halo, cyano, oxo, thioxo, alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, aralkyl, aryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, -RuORX, - uORuN(Ry)(RZ), -RuN(Ry)(RZ), - RuSRX, - uC(J)RX, - uC(J)ORX, - uC(J)N(Ry)(RZ), -RuS(O)tRW, -RuN(RX)C(J)RX, -RuN(RX)C(J)ORX, -RuN(RX)S(O)tRW, =NORd, or y)N(Ry)ORX, where the alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl groups are optionally substituted with one or more Q3 groups, in one embodiment, one to three Q3 groups; each Q3 is independently selected from deuterium, halo, hydroxyl, alkyl, haloalkyl and hydroxyalkyl; Y is —(CR5R6)q-; R5 and R6 are each independently hydrogen, halo, alkyl, haloalkyl or yalkyl; Z is O, S or NH; each W is independently CR8 or N; R8 is hydrogen, halo, haloalkyl or alkyl; ring A is heteroaryl optionally substituted with one to four substituents selected from Q2; W2 is N or CRgb; W3 is N or CRIOb; W4 is N or CR1“); R91),R10b and R11b are selected as follows: i) Rgb, R10b and R11b are each ndently hydrogen, or Q2; or ii) R9b and R10b or R10b and R11b together with the atoms to which they are ed form an aryl or heteroaryl ring, optionally substituted with one or more, in one embodiment, one to three, in another embodiment, one, two or three groups selected from Q2; and the remainder of R91), R10b and R11b is hydrogen or Q2; each Q2 is independently halo, cyano, oxo, thioxo, alkyl, haloalkyl, aminoalkyl, l, haloalkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, -RuORX, - uORuORX,-RuORuN(Ry)(RZ), -RuN(Ry)(RZ), -RuSRX, - RuC(J)RX, -RuC(J)ORX, -RuC(J)N(Ry)(RZ), - uN(Ry)(RZ), -RuC(J)N(Ry)ORX, - C(=NORX)RX, - uS(O)tRw, -RuN(RX)C(J)RX, -RuN(RX)C(J)ORX, -RuN(RX)S(O)tRW or — C(=NRy)N(Ry)ORX, where the alkyl, kyl, aminoalkyl, alkenyl, alkynyl, lkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl groups are optionally substituted with one or more Q4 groups; each Q4 is independently ed from halo, hydroxyl, alkyl, haloalkyl and hydroxyalkyl; Rd is hydrogen or alkyl; each R11 is independently alkylene, alkenylene or a direct bond; RW is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, lkenyl, cycloalkylalkyl, cycloalkenylalkyl, cyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; each Rx is independently en, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, lkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; Ry and RZ are each independently selected from (i) or (ii) below: (i) Ry and RZ are each independently hydrogen, alkyl, kyl, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, heterocyclyl, heterocyclylalkyl, aryl, l, heteroaryl, or heteroaralkyl; or (ii) Ry and RZ, er with the nitrogen atom to which they are attached, form a heterocyclyl or aryl, optionally substituted with one or more, in one embodiment, one, two or three Q7 groups; each Q7 is independently selected from halo, deuterium, oxo, thioxo, hydroxy, alkoxy, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl; J is O, NRx or S; each t is independently an integer from 0-2; 11 is l; and q is an integer from 0-4.

In n embodiments, provided herein are compounds of Formula 111 or pharmaceutically acceptable salts, solvates, hydrates, clathrates, single isomers, mixture of stereoisomers or racemic mixture of stereoisomers thereof, wherein: R1 and R2 are each independently selected from hydrogen, halogen, alkoxy and yl; R3 is hydrogen or alkyl; R4 is cycloalkyl, aryl, heterocyclyl or heteroaryl, where R4 is optionally substituted with one or more, in one embodiment, one to three, in another embodiment, one, two or three groups ed from Q1; each Q1 is independently halo, oxo, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, =NOH, - uORx or -RuC(O)RX; Y is —(CR5R6)q-; R5 and R6 are each independently hydrogen, halo, alkyl, haloalkyl or yalkyl; Z is O, S or NH; each W is independently CR8 or N; R8 is hydrogen, halo, haloalkyl or alkyl; ring A is heteroaryl or heterocyclyl optionally substituted with one to four substituents selected from Q2; W2 is N or CRgb; W3 is N or CRIOb; W4 is N or CR1“); R91),R10b and R11b are selected as follows: i) R91), R10b and R11b are each ndently hydrogen, oxo, hydroxyl, halo or alkyl; or ii) R9b and R10b or R10b and R11b together with the atoms to which they are attached form an aryl or heteroaryl ring, optionally substituted with one or more, in one embodiment, one to three, in another embodiment, one, two or three groups selected from Q2; and the remainder of R91), R10b and R11b is hydrogen, halo or alkyl; each Q2 is independently halo, cyano, oxo, thioxo, alkyl, kyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, lkylalkyl, cycloalkenylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, -RuORX, - uORuORX,-RuORuN(Ry)(RZ), -RuN(Ry)(RZ), , - RuC(J)RX, -RuC(J)ORX, )N(Ry)(RZ), - uC(J)RuN(Ry)(RZ), -RuC(J)N(Ry)ORX, - C(=NORX)RX, - uS(O)tRw, -RuN(RX)C(J)RX, -RuN(RX)C(J)ORX, -RuN(Rx)S(O)tRW or — C(=NRy)N(Ry)ORX, where the alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl groups are optionally substituted with one or more Q4 ; each Q4 is independently selected from halo, hydroxyl, alkyl, haloalkyl and hydroxyalkyl; each R11 is independently alkylene, alkenylene or a direct bond; RW is alkyl; each Rx is independently hydrogen or alkyl; Ry and RZ are each independently hydrogen or alkyl; J is O, NRx or S; each t is ndently an integer from 0-2; nis l or 2; and WO 56070 q is an integer from 0-4; wherein the compounds are selected such that when i) when W is CH; W1 is C; Z is S; R1 is hydrogen, or hydroxyl and R2 is hydrogen, or R1 and R2 er form =0; then ring A is not pyridine and ii) W is CH; W1 is N; Z is S; R1 and R2 are hydrogen, then ring A is not pyrrolidine.

In certain embodiments, ed herein are compounds of Formula 111 or pharmaceutically acceptable salts, solvates, es, clathrates, single stereoisomers, mixture of stereoisomers or racemic e of stereoisomers thereof, wherein R1 and R2 are each independently selected from hydrogen or halogen; R3 is hydrogen or alkyl; R4 is cycloalkyl, optionally substituted with one or more, in one embodiment, one to three, in another embodiment, one, two or three groups selected from Q1; each Q1 is independently deuterium, halo, cyano, oxo, thioxo, alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, lkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, aralkyl, heteroaryl, aralkyl, heterocyclyl, cyclylalkyl, -RuORX, - uORuN(Ry)(RZ), -RuN(Ry)(RZ), - RuSRX, - uC(J)Rx, - uC(J)ORX, - uC(J)N(Ry)(RZ), -RuS(O)tRW, -RuN(RX)C(J)RX, -RuN(RX)C(J)ORX, X)S(O)tRW, =NORd, or —C(=NRy)N(Ry)ORX, where the alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl groups are optionally substituted with one or more Q3 groups, in one embodiment, one to three Q3 groups; each Q3 is independently selected from deuterium, halo, hydroxyl, alkyl, haloalkyl and hydroxyalkyl; Y is —(CR5R6)q-; R5 and R6 are each independently hydrogen, halo, alkyl, haloalkyl or hydroxyalkyl; Z is O, S, or NH; each W is independently CR8 or N; R8 is hydrogen, halo, haloalkyl or alkyl; ring A is heteroaryl optionally substituted with one to four substituents selected from Q2; W2 is N or CRgb; W3 is N or CRIOb; W4 is N or CR1“); R91),R10b and R11b are selected as s: i) R91), R10b and R11b are each independently hydrogen, oxo, hydroxyl, halo or alkyl; or ii) R9b and R10b or R10b and Rllb, together with the atoms to which they are attached, form an aryl or heteroaryl ring, ally substituted with one or more, in one embodiment, one to three, in another embodiment, one, two or three groups selected from Q2; and the remainder of R91), R10b and R11b is hydrogen, halo or alkyl; each Q2 is independently halo, cyano, oxo, thioxo, alkyl, haloalkyl, aminoalkyl, alkenyl, haloalkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, -RuORX, - uORuORx, - uORuN(Ry)(RZ), y)(RZ), -RuSRX, - RX, -RuC(J)ORX, -RuC(J)N(Ry)(RZ), - uC(J)RuN(Ry)(RZ), - RuC(J)N(Ry)ORX, -C(=NORX)RX, - uS(O)tRW, -RuN(RX)C(J)RX, -RuN(RX)C(J)ORX, - RuN(Rx)S(O)tRW or —C(=NRy)N(Ry)ORX, where the alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, aryl, and heterocyclyl groups are optionally substituted with one or more Q4 groups; each Q4 is independently selected from halo, hydroxyl, alkyl, haloalkyl and hydroxyalkyl; Rd is hydrogen or alkyl; each R11 is independently alkylene, alkenylene or a direct bond; RW is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, heterocyclyl, cyclylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; each Rx is ndently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cyanoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, lkylalkyl, cycloalkenylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; Ry and RZ are each independently selected from (i) or (ii) below: (i) Ry and RZ are each independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, l, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; or (ii) Ry and RZ, together with the nitrogen atom to which they are ed, form a heterocyclyl or heteroaryl, optionally substituted with one or more, in one 2012/059983 embodiment, one, two or three Q7 groups; each Q7 is independently selected from halo, deuterium, oxo, , hydroxy, alkoxy, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, l, heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl; J is O, NRx or S; each t is independently an integer from 0-2; 11 is l or 2; and q is an r from 0-2.

In certain embodiments, provided herein are compounds of Formula III wherein n is l and the other variables are as described elsewhere herein. In certain embodiments, ed herein are compounds of a 111 wherein each Q1 is independently halo, oxo, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, =NOH, -RuORX or -RuC(O)RX; each R11 is independently alkylene or a direct bond; each Rx is independently hydrogen or alkyl; 11 is l and the other les are as described elsewhere .

In certain embodiments, provided herein are compounds of Formula III or pharmaceutically acceptable salts, solvates, hydrates, clathrates, single stereoisomers, mixture of stereoisomers or racemic mixture of stereoisomers thereof, wherein R1 and R2 are each independently selected from hydrogen or halogen; R3 is hydrogen or alkyl; R4 is cycloalkyl, optionally substituted with one or more, in one embodiment, one to three, in another embodiment, one, two or three groups ed from Q1; each Q1 is independently halo, oxo, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, =NOH, - uORx or -RuC(O)RX; Y is —(CR5R6)q-; R5 and R6 are each independently hydrogen, halo, alkyl, kyl or hydroxyalkyl; Z is O, S, or NH; each W is independently CR8 or N; R8 is hydrogen, halo, haloalkyl or alkyl; ring A is heteroaryl optionally substituted with one to four tuents selected from Q2; W2 is N or CRgb; W3 is N or CRIOb; W4 is N or CR1“); R91),R10b and R11b are selected as follows: i) R91), R10b and R11b are each independently hydrogen, oxo, hydroxyl, halo or alkyl; or ii) R9b and R10b or R10b and Rllb, together with the atoms to which they are attached, form an aryl or heteroaryl ring, optionally substituted with one or more, in one embodiment, one to three, in another embodiment, one, two or three groups selected from Q2; and the remainder of R91), R10b and R11b is en, halo or alkyl; each Q2 is independently halo, cyano, oxo, thioxo, alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, l, aryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, -RuORX, - uORuN(Ry)(RZ), -RuN(Ry)(RZ), -RuSRX, - x, - RuC(J)ORX, -RuC(J)N(Ry)(RZ), -RuC(J)N(Ry)ORX, - uS(O)IRW, -RuN(RX)C(J)RX, - RuN(RX)C(J)ORX, -RuN(RX)S(O)tRW or —C(=NRy)N(Ry)ORX, where the alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, and cyclyl groups are optionally substituted with one or more Q4 groups; each Q4 is ndently ed from halo, hydroxyl, alkyl, haloalkyl and hydroxyalkyl; each R11 is independently alkylene or a direct bond; RW is alkyl; each Rx is ndently hydrogen or alkyl; Ry and RZ are each independently hydrogen or alkyl; J is O, NRx or S; each t is independently an integer from 0-2; 11 is l or 2; and q is an integer from 0-2.

In certain embodiments, ed herein are compounds of Formula 111 or pharmaceutically acceptable salts, solvates, hydrates, clathrates, single stereoisomers, mixture of stereoisomers or racemic mixture of stereoisomers thereof, wherein R1 and R2 are each independently selected from hydrogen or halogen; R3 is hydrogen or alkyl; R4 is cycloalkyl, optionally substituted with one or more, in one embodiment, one to three, in r embodiment, one, two or three groups selected from Q1; each Q1 is independently halo, oxo, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, =NOH, - uORx or -RuC(O)RX; Y is —(CR5R6)q-; R5 and R6 are each independently hydrogen, halo, alkyl, haloalkyl or hydroxyalkyl; Z is O, S, or NH; each W is ndently CR8 or N; R8 is en, halo, haloalkyl or alkyl; ring A is heteroaryl, optionally substituted with one to four substituents selected from Q2; W2 is N or CRgb; W3 is N or CRIOb; W4 is N or CR1“); R9b and R101), together with the atoms to which they are attached, form an aryl or heteroaryl ring, ally substituted with one or two groups selected from each Q2 is independently halo, cyano, oxo, thioxo, alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, lkenylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, -RuORX, - uORuN(Ry)(RZ), -RuN(Ry)(RZ), -RuSRX, - uC(J)Rx, - RuC(J)ORX, -RuC(J)N(Ry)(RZ), -RuC(J)N(Ry)ORX, - uS(O)tRW, X)C(J)RX, - RuN(RX)C(J)ORX, -RuN(RX)S(O)tRW or —C(=NRy)N(Ry)ORX, where the alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl groups are optionally tuted with one or more Q4 groups; each Q4 is independently selected from halo, hydroxyl, alkyl, haloalkyl and hydroxyalkyl; each R11 is independently alkylene or a direct bond; RW is alkyl; each Rx is independently hydrogen or alkyl; Ry and RZ are each independently hydrogen or alkyl; J is O, NRx or S; each t is independently an integer from 0-2; R11b is hydrogen; n is l or 2; and q is an integer from 0-2.

In certain embodiments, provided herein are compounds of Formula 111 or pharmaceutically acceptable salts, solvates, hydrates, clathrates, single stereoisomers, mixture of stereoisomers or racemic mixture of isomers thereof, wherein R1 and R2 are each independently selected from en or halogen; R3 is hydrogen or alkyl; R4 is cycloalkyl, optionally substituted with one or more, in one embodiment, one to three, in another embodiment, one, two or three groups selected from Q1; each Q1 is independently halo, oxo, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, =NOH, - uORx or -RuC(O)RX; Y is —(CR5R6)q-; R5 and R6 are each independently hydrogen, halo, alkyl, haloalkyl or yalkyl; Z is O, S, or NH; each W is independently CR8 or N; R8 is hydrogen, halo, haloalkyl or alkyl; ring A is heteroaryl, optionally substituted with one to four substituents ed from Q2; W2 is N or CRgb; W3 is N or CRIOb; W4 is N or CR1“); R9b and R101), together with the atoms to which they are attached, form an aryl or heteroaryl ring, optionally substituted with one or two groups selected from each Q2 is independently halo, cyano, oxo, thioxo, alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, cyclylalkyl, -RuORX, - uORuN(Ry)(RZ), -RuN(Ry)(RZ), -RuSRX, - x, - ORX, )N(Ry)(RZ), -RuC(J)N(Ry)ORX, - uS(O)tRw, -RuN(RX)C(J)RX, - RuN(RX)C(J)ORX, -RuN(RX)S(O)tRW or —C(=NRy)N(Ry)ORX, where the alkyl, kyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl groups are optionally substituted with one or more Q4 groups; each Q4 is independently ed from halo, hydroxyl, alkyl, haloalkyl and hydroxyalkyl; each R11 is independently alkylene or a direct bond; RW is alkyl; each Rx is independently hydrogen or alkyl; Ry and RZ are each independently hydrogen or alkyl; J is O, NRx or S; each t is independently an r from 0-2; R11b is hydrogen; n is l or 2; and q is an integer from 0-2.

In certain embodiments, ed herein are nds of Formula 111 or pharmaceutically acceptable salts, solvates, hydrates, clathrates, single stereoisomers, mixture of stereoisomers or racemic mixture of stereoisomers thereof, n R1 and R2 are each independently ed from hydrogen or halogen; R3 is hydrogen or alkyl; R4 is cycloalkyl, optionally substituted with one or more, in one embodiment, one to three, in another embodiment, one, two or three groups selected from Q1; each Q1 is independently halo, oxo, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, =NOH, - uORx or -RuC(O)RX; Y is —(CR5R6)q-; R5 and R6 are each independently hydrogen, halo, alkyl, haloalkyl or hydroxyalkyl; Z is O, S, or NH; each W is independently CR8 or N; R8 is hydrogen, halo, haloalkyl or alkyl; ring A is heteroaryl, optionally substituted with one to four substituents selected from Q2; W2 is N or CRgb; W3 is N or CRIOb; W4 is N or CR1“); R9b and R101), together with the carbon atoms to which they are attached, form an aryl or heteroaryl ring, optionally substituted with one or two groups Q2, each Q2 is independently halo, cyano, alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, heterocyclyl, -RuORX, y)(RZ), -RuSRX, - uC(J)Rx, - RuC(J)ORX, -RuC(J)N(Ry)(RZ), -RuC(J)N(Ry)ORX, - uS(O)IRW, -RuN(RX)C(J)RX, - RuN(RX)C(J)ORX, -RuN(RX)S(O)tRW or —C(=NRy)N(Ry)ORX, where the cycloalkyl, heteroaryl, heterocyclyl are optionally tuted with one or more alkyl; R11b is hydrogen or Q2; each R11 is independently alkylene or a direct bond; RW is alkyl; each Rx is independently en or alkyl; Ry and RZ are each independently hydrogen or alkyl; J is O, NRx or S; each t is independently an integer from 0-2; and q is an integer from 0-2.

In certain embodiments, provided herein are nds of Formula 111 or pharmaceutically acceptable salts, solvates, hydrates, clathrates, single stereoisomers, mixture of stereoisomers or racemic mixture of isomers thereof, wherein R1 and R2 are each independently selected from hydrogen or halogen; R3 is hydrogen or alkyl; R4 is cycloalkyl, optionally substituted with one or more, in one embodiment, one to three, in r embodiment, one, two or three groups selected from Q1; each Q1 is ndently halo, oxo, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, =NOH, - uORx or -RuC(O)RX; Y is —(CR5R6)q-; R5 and R6 are each independently hydrogen, halo, alkyl, haloalkyl or hydroxyalkyl; Z is O, S, or NH; each W is independently CR8 or N; R8 is hydrogen, halo, haloalkyl or alkyl; ring A is heteroaryl, optionally substituted with one to four substituents selected from Q2; W2 is N or CRgb; W3 is N or CRIOb; W4 is N or CR1“); R9b and R101), together with the carbon atoms to which they are attached, form an aryl or heteroaryl ring, optionally substituted with one or two groups Q2, each Q2 is independently halo, cyano, alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, lkyl, heteroaryl, heterocyclyl, -RuORX, -RuN(Ry)(RZ), -RuSRX, - uC(J)Rx, - RuC(J)ORX, -RuC(J)N(Ry)(RZ), )N(Ry)ORX, - uS(O)IRW, -RuN(RX)C(J)RX, - RuN(RX)C(J)ORX, -RuN(RX)S(O)tRW or —C(=NRy)N(Ry)ORX, where the cycloalkyl, heteroaryl, heterocyclyl are optionally substituted with one or more alkyl; each R11 is independently alkylene or a direct bond; RW is alkyl; each Rx is independently hydrogen or alkyl; Ry and RZ are each independently en or alkyl; J is O, NRx or S; each t is independently an integer from 0-2; and q is an integer from 0-2.

In certain ments, provided herein are compounds of Formula 111 or ceutically acceptable salts, solvates, hydrates, clathrates, single stereoisomers, mixture of isomers or c mixture of stereoisomers thereof wherein: R1 and R2 are each independently selected from hydrogen, halogen, and hydroxyl; R3 is hydrogen or alkyl; R4 is cycloalkyl, where R4 is optionally substituted with one or more, in one embodiment, one to three, in another embodiment, one, two or three groups selected from Q1; each Q1 is independently halo, oxo, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, =NOH, - uORx or -RuC(O)RX; Y is -(CR5R6)q-; R5 and R6 are each independently hydrogen, halo, alkyl, haloalkyl or hydroxyalkyl; Z is O, S, or NH; each W is independently CR8 or N; R8 is hydrogen, halo, haloalkyl or alkyl; ring A is heteroaryl, optionally substituted with one to four substituents selected from Q2; W2 is N or CRgb; W3 is N or CRIOb; W4 is N or CR1“); Rgb, R10b and R11b are selected as follows: i) Rgb, R10b and R11b are each independently hydrogen or Q2; or ii) R9b and R10b or R10b and R1 1b, together with the atoms on which they are substituted form an aryl, heteroaryl ring, optionally substituted with one or two groups selected from Q2; and the remainder of R9b or R11b is hydrogen or Q2; each Q2 is hydrogen, halo, alkoxy, tetrazole or pyrazole, where the tetrazole and le rings are optionally substituted with one or more alkyl; each R11 is independently alkylene or a direct bond; RW is alkyl; each Rx is independently hydrogen or alkyl; Ry and RZ are each independently en or alkyl; J is O, NRx or S; each t is independently an integer from 0-2; 11 is l or 2; and q is an integer from 0-4.

In certain ments, provided herein are compounds of Formula 111 or pharmaceutically acceptable salts, solvates, hydrates, clathrates, single stereoisomers, e of stereoisomers or racemic e of stereoisomers thereof wherein: R1 and R2 are each independently selected from en, halogen, and hydroxyl; R3 is hydrogen or alkyl; R4 is cycloalkyl, where R4 is optionally substituted with one or more, in one embodiment, one to three, in another embodiment, one, two or three groups selected from Q1; each Q1 is ndently halo, oxo, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, =NOH, - uORx or -RuC(O)RX; Y is -(CR5R6)q-; R5 and R6 are each independently hydrogen, halo, alkyl, haloalkyl or hydroxyalkyl; Z is O, S, or NH; each W is independently CR8 or N; R8 is en, halo, haloalkyl or alkyl; ring A is heteroaryl, optionally substituted with one to four substituents selected from Q2; W2 is N or CRgb; W3 is N or CRIOb; W4 is N or CR1“); Rgb, R10b and R11b are selected as follows: i) R91), R10b and R11b are each independently hydrogen, oxo, hydroxyl, halo or alkyl; or ii) R9b and R10b or R10b and R1 1b, together with the atoms on which they are substituted form an aryl, heteroaryl ring, optionally substituted with one or two groups selected from Q2; and the remainder of Rgb, RIObor R11b is hydrogen or alkyl; each Q2 is hydrogen, halo, alkoxy, tetrazole or pyrazole, where the tetrazole and pyrazole rings are ally substituted with one or more alkyl; each R11 is independently alkylene or a direct bond; RW is alkyl; each Rx is independently hydrogen or alkyl; Ry and RZ are each ndently hydrogen or alkyl; J is O, NRx or S; each t is ndently an integer from 0-2; 11 is l or 2; and q is an integer from 0-4.

In certain embodiments, provided herein are compounds of Formula III wherein W4 is N; W2 is CRgb; W3 is CRIOb; R9b and R101), together with the atoms to which they are attached, form an aryl or heteroaryl ring, optionally substituted with one or more, in one embodiment, one to three, in another embodiment, one, two or three groups selected from Q2; and the other variables are as described elsewhere herein.

In certain embodiments, provided herein are nds of Formula IV “<5 R1 R2 06 oz WOW |W\ Z ’R W4J N w\ / \Y—R4 W IV or pharmaceutically acceptable salts, solvates, hydrates, clathrates, single stereoisomers, mixture of stereoisomers or c mixture of stereoisomers thereof, wherein the variables are as bed elsewhere herein.

In certain embodiments, provided herein are compounds of Formula IV, R1 and R2 are each independently selected from hydrogen or n; R3 is hydrogen or alkyl; R4 is lkyl, cycloalkenyl, aryl, heterocyclyl or heteroaryl, where R4 is ally substituted with one or more, in one embodiment, one to three, in another embodiment, one, two or three groups selected from Q1; each Q1 is independently deuterium, halo, cyano, oxo, thioxo, alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, aralkyl, heteroaryl, aralkyl, heterocyclyl, heterocyclylalkyl, -RuORX, - uORuN(Ry)(RZ), -RuN(Ry)(RZ), - RuSRX, - uC(J)RX, - uC(J)ORX, - uC(J)N(Ry)(RZ), )tRW, -RuN(RX)C(J)RX, -RuN(RX)C(J)ORX, -RuN(RX)S(O)tRW, =NORd, or y)N(Ry)ORX, where the alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl groups are optionally substituted with one or more Q3 groups, in one embodiment, one to three Q3 groups; each Q3 is independently selected from deuterium, halo, hydroxyl, alkyl, haloalkyl and hydroxyalkyl; Y is -(CR5R6)q-; R5 and R6 are each independently hydrogen, halo, alkyl, haloalkyl or yalkyl; Z is O, S, or NH; each W is independently CR8 or N; R8 is hydrogen, halo, haloalkyl or alkyl; W1 is N or C; W2 is N or CRgb; R9b is hydrogen or Q2; W4 is N or CR1“); W5 is N or CR”; R11b and R13 are each independently hydrogen or Q2; Q2 is halo, deuterium, cyano, oxo, thioxo, alkyl, haloalkyl, haloalkenyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, aralkyl, heteroaryl, aralkyl, cyclyl, heterocyclylalkyl, , - uORuORX,-RuORuN(Ry)(RZ), - RuN(Ry)(RZ), , - uC(J)RX, - uC(J)ORX, -RuC(J)N(Ry)(RZ), - uC(J)RuN(Ry)(RZ) - uS(O)tRW, -RuN(RX)C(J)RX, -RuN(RX)C(J)ORX, - , -RuC(J)N(Ry)ORX, -C(=NORX)RX, RuN(Rx)S(O)tRW or —C(=NRy)N(Ry)ORX, Where the alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, lkenyl, aryl, heteroaryl, and heterocyclyl groups are optionally substituted with one or more groups Q4; in one embodiment, one to three Q4 groups, each Q4 is independently selected from halo, deuterium, hydroxyl, alkyl, haloalkyl and hydroxyalkyl; Q5 and Q6 are each ndently hydrogen, deuterium, halo, cyano, oxo, thioxo, alkyl, haloalkyl, aminoalkyl, alkenyl, haloalkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, -RuORX, - RuORuORX, N(Ry)(RZ), -RuN(Ry)(RZ), -RuSRX, -RuC(J)RX, -RuC(J)ORX, - uC(J)N(Ry)(RZ), - uC(J)R“N(Ry)(RZ), - RuC(J)N(Ry)ORX, -C(=NORX)RX, - uS(O)tRW, -RuN(RX)C(J)RX, -RuN(RX)C(J)ORX, - RuN(Rx)S(O)tRW or —C(=NRy)N(Ry)ORX, Where the alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl groups are ally substituted with one or more Q8 groups; each Q8 is independently selected from halo, deuterium, hydroxyl, alkyl, kyl and yalkyl; each Rd is independently hydrogen or alkyl; Rd is hydrogen or alkyl; each R11 is independently alkylene, alkenylene or a direct bond; RW is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, l, cycloalkyl, cycloalkenyl, lkylalkyl, cycloalkenylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; each Rx is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cyanoalkyl, alkenyl, l, cycloalkyl, cycloalkenyl, lkylalkyl, cycloalkenylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; Ry and RZ are each independently selected from (i) or (ii) below: (i) Ry and RZ are each independently hydrogen, alkyl, kyl, hydroxyalkyl, alkyl, l, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; or (ii) Ry and RZ, together with the nitrogen atom to which they are attached, form a cyclyl or aryl, optionally substituted with one or more, in one embodiment, one, two or three Q7 groups; each Q7 is independently selected from halo, deuterium, oxo, thioxo, hydroxy, alkoxy, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, lkenylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl; J is O, NRx or S; each t is independently an integer from 0-2; and q is an integer from 0-4.

In certain embodiments, provided herein are compounds of Formula IV n R1 and R2 are both hydrogen. In certain embodiments, provided herein are nds of a IV wherein R9b and R11b are each independently hydrogen, alkyl or haloalkyl and the other variables are as described elsewhere herein. In certain embodiments, provided herein are compounds Formula IV wherein each Q1 is independently halo, oxo, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, =NOH, -RuORX or -RuC(O)RX; each R11 is independently alkylene or a direct bond; each Rx is independently hydrogen or alkyl; and the other variables are as described elsewhere herein. In certain embodiments, provided herein are compounds Formula IV wherein each Q1 is independently halo, oxo, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, =NOH, -RuORX or -RuC(O)RX; each R11 is independently ne or a direct bond; each Rx is independently en or alkyl; R11b and R13 are each ndently hydrogen, halo or alkyl and the other variables are as described elsewhere herein. In certain embodiments, provided herein are compounds of Formula IV wherein R4 is cycloalkyl.

In n embodiments, provided herein are nds of Formula IV wherein R9b and R11b are each independently hydrogen, halo or alkyl and the other variables are as described elsewhere herein. In certain embodiments, provided herein are compounds a IV wherein each Q1 is independently halo, oxo, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, =NOH, -RuORX or - uC(O)Rx; each R11 is independently alkylene or a direct bond; each Rx is independently hydrogen or alkyl; and the other variables are as described elsewhere . In certain embodiments, provided herein are nds Formula IV wherein each Q1 is ndently halo, oxo, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, =NOH, -RuORX or - uC(O)Rx; each R11 is independently alkylene or a direct bond; each Rx is independently hydrogen or alkyl; R11b and R13 are each independently hydrogen, halo or alkyl and the other variables are as described elsewhere herein.

In certain embodiments, provided herein are compounds of Formula IV or pharmaceutically acceptable salts, solvates, hydrates, clathrates, single stereoisomers, mixture of stereoisomers or racemic mixture of stereoisomers thereof, wherein: R1 and R2 are each ndently selected from hydrogen or halogen; R3 is hydrogen or alkyl; R4 is cycloalkyl, lkenyl, aryl, heterocyclyl or heteroaryl, where R4 is optionally tuted with one or more, in one embodiment, one to three, in another embodiment, one, two or three groups selected from Q1; each Q1 is independently halo, oxo, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, =NOH, - uORx or -RuC(O)RX; Y is -(CR5R6)q-; R5 and R6 are each independently hydrogen, halo, alkyl, haloalkyl or hydroxyalkyl; Z is O, S, or NH; each W is independently CR8 or N; R8 is hydrogen, halo, haloalkyl or alkyl; W1 is N or C; W2 is N or CRgb; R9b is en or alkyl; W4 is N or CR1“); R11b is hydrogen, halo or alkyl; W5 is N or CR”; R13 is hydrogen, halo or alkyl; Q5 and Q6 are each ndently hydrogen, deuterium, halo, cyano, oxo, thioxo, alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl,heterocyclylalkyl, -RuORX, - uORuN(Ry)(RZ), -RuN(Ry)(RZ), - uSR", -RuC(J)RX, -RuC(J)ORX, - uC(J)N(Ry)(RZ), - RuC(J)N(Ry)ORX, - uS(O)tRw, -RuN(RX)C(J)RX, -RuN(RX)C(J)ORX, -RuN(RX)S(O)tRW or —C(=NRy)N(Ry)ORX, where the alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl groups are optionally substituted with one or more Q8 groups; each Q8 is independently selected from halo, deuterium, hydroxyl, alkyl, haloalkyl and hydroxyalkyl; each R11 is independently alkylene or a direct bond; RW is alkyl; each Rx is independently hydrogen or alkyl; Ry and RZ are each independently hydrogen or alkyl; J is O, NRx or S; each t is independently an integer from 0-2; and q is an r from 0-4.

In certain embodiments, provided herein are compounds of Formula IV or ceutically acceptable salts, solvates, hydrates, clathrates, single stereoisomers, mixture of stereoisomers or c e of stereoisomers f, wherein: R1 and R2 are each ndently selected from hydrogen or halogen; R3 is hydrogen or alkyl; R4 is cycloalkyl, cycloalkenyl, aryl, heterocyclyl or heteroaryl, where R4 is ally substituted with one or more, in one embodiment, one to three, in another embodiment, one, two or three groups selected from Q1; each Q1 is independently halo, oxo, alkyl, kyl, hydroxyalkyl, cycloalkyl, =NOH, - uORx or -RuC(O)RX; Y is -(CR5R6)q-; R5 and R6 are each independently hydrogen, halo, alkyl, haloalkyl or hydroxyalkyl; Z is O, S, or NH; each W is independently CR8 or N; R8 is hydrogen, halo, haloalkyl or alkyl; W1 is N or C; W2 is N or CRgb; R9b is hydrogen or alkyl; W4 is N or CR1“); R11b is hydrogen or Q2; Q2 is halo, deuterium, cyano, oxo, thioxo, alkyl, haloalkyl, haloalkenyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, -RuORX, - uORuORX,-RuORuN(Ry)(RZ), - RuN(Ry)(RZ), -RuSRX, - uC(J)R", - uC(J)ORX, -RuC(J)N(Ry)(RZ), - uC(J)RuN(Ry)(RZ) , -RuC(J)N(Ry)ORX, -C(=NORX)RX, uS(O)tRW, -RuN(RX)C(J)RX, X)C(J)ORX, - RuN(Rx)S(O)tRW or —C(=NRy)N(Ry)ORX, Where the alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, aryl, and heterocyclyl groups are optionally substituted with one or more groups Q4; in one embodiment, one to three Q4 groups, each Q4 is ndently selected from halo, deuterium, hydroxyl, alkyl, haloalkyl and hydroxyalkyl;; W5 is N or CR”; R13 is hydrogen, halo or alkyl; Q5 and Q6 are each independently hydrogen, ium, halo, cyano, oxo, thioxo, alkyl, haloalkyl, aminoalkyl, l, haloalkenyl, l, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, -RuORX, - uORuORx, - uORuN(Ry)(RZ), -RuN(Ry)(RZ), -RuSRX, -RuC(J)RX, -RuC(J)ORX, - uC(J)N(Ry)(RZ), - uC(J)RuN(Ry)(RZ), -RuC(J)N(Ry)ORX, -C(=NORX) RX, - uS(O)IRW, -RuN(RX)C(J)RX, -RuN(RX)C(J)ORX, -RuN(RX)S(O)tRW or —C(=NRy)N(Ry)ORX, where the alkyl, kyl, aminoalkyl, l, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl groups are optionally substituted with one or more Q8 ; each Q8 is independently selected from halo, deuterium, hydroxyl, alkyl, haloalkyl and hydroxyalkyl; each R11 is independently alkylene, alkenylene or a direct bond; RW is alkyl; each Rx is independently hydrogen or alkyl; Ry and RZ are each independently hydrogen or alkyl; J is O, NRx or S; each t is independently an integer from 0-2; and q is an integer from 0-4.

In certain embodiments, provided herein are nds of Formula IV or pharmaceutically able salts, solvates, hydrates, clathrates, single stereoisomers, mixture of stereoisomers or racemic mixture of stereoisomers thereof, wherein: R1 and R2 are each independently selected from hydrogen or halogen; R3 is hydrogen or alkyl; R4 is cycloalkyl, cycloalkenyl, aryl, heterocyclyl or heteroaryl, where R4 is optionally substituted with one or more, in one embodiment, one to three, in r embodiment, one, two or three groups ed from Q1; each Q1 is independently halo, oxo, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, =NOH, - uORx or )RX; Y is -(CR5R6)q-; R5 and R6 are each independently hydrogen, halo, alkyl, haloalkyl or hydroxyalkyl; Z is O, S, or NH; each W is independently CR8 or N; R8 is hydrogen, halo, haloalkyl or alkyl; W1 is N or C; W2 is N or CRgb; R9b is hydrogen or alkyl; W4 is N or CR1“); R11b is hydrogen, halo or alkyl; W5 is N or CR”; R13 is hydrogen, halo or alkyl; Q5 and Q6 are each independently hydrogen, deuterium, halo, cyano, oxo, thioxo, alkyl, haloalkyl, aminoalkyl, l, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, -RuORX, - uORuORx, - uORuN(Ry)(RZ), -RuN(Ry)(RZ), -RuSRX, -Ru , -RuC(J)ORX, )N(Ry)(RZ), - uC(J) RuN(Ry)(RZ), - uC(J)N(Ry)ORX, -C(=NORX) RX, - uS(O)IRW, -RuN(RX)C(J)RX, -RuN(RX)C(J)ORX, -RuN(RX)S(O)tRW or y)N(Ry)ORX, where the alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl groups are optionally substituted with one or more Q8 groups; each Q8 is independently selected from halo, deuterium, hydroxyl, alkyl, haloalkyl and hydroxyalkyl; each R11 is independently ne, alkenylene or a direct bond; RW is alkyl; each Rx is independently hydrogen or alkyl; Ry and RZ are each ndently hydrogen or alkyl; J is O, NRx or S; each t is independently an integer from 0-2; and q is an integer from 0-4.

In certain ments, provided herein are compounds of Formula IV wherein R1 and R2 are both hydrogen and the other variables are as described elsewhere herein.

In certain embodiments, provided herein are nds of Formula IV wherein R11b and R13 are each ndently hydrogen, halo or alkyl and the other variables are as described elsewhere herein.

In certain embodiments, provided herein are compounds of Formula V \VV5 R1 R2 \ W R3 / Nxf \ Z WrJ N w\ / \Y—R4 W V or pharmaceutically acceptable salts, solvates, hydrates, clathrates, single stereoisomers, mixture of stereoisomers or racemic mixture of stereoisomers thereof, wherein the variables are as described elsewhere herein.

In certain embodiments, provided herein are compounds of Formula V or ceutically acceptable salts, solvates, hydrates, clathrates, single stereoisomers, mixture of stereoisomers or racemic e of stereoisomers thereof, n R1 and R2 are each independently ed from hydrogen or halogen; R3 is hydrogen or alkyl; R4 is cycloalkyl, aryl, heterocyclyl or heteroaryl, where R4 is optionally tuted with one or more, in one embodiment, one to three, in another embodiment, one, two or three groups selected from Q1; each Q1 is independently deuterium, halo, cyano, oxo, thioxo, alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, l, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, -RuORX, - uORuN(Ry)(RZ), -RuN(Ry)(RZ), - RuSRX, - uC(J)RX, - RX, - (Ry)(RZ), -RuS(O)tRW, -RuN(RX)C(J)RX, -RuN(RX)C(J)ORX, -RuN(RX)S(O)tRW, =NORd, or —C(=NRy)N(Ry)ORX, where the alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl groups are optionally substituted with one or more Q3 groups, in one embodiment, one to three Q3 groups; each Q3 is independently selected from deuterium, halo, hydroxyl, alkyl, haloalkyl and hydroxyalkyl; Y is 6)q-; R5 and R6 are each independently hydrogen, halo, alkyl, haloalkyl or yalkyl; Z is O, S, or NH; each W is independently CR8 or N; R8 is en, halo, haloalkyl or alkyl; W4 is N or CR1“); W5 is N or CR”; R11b and R13 are each independently hydrogen or Q2; Q2 is halo, deuterium, cyano, oxo, thioxo, alkyl, haloalkyl, haloalkenyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, l, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, -RuORX, - uORuORX,-RuORuN(Ry)(RZ), - RuN(Ry)(RZ), -RuSRX, - uC(J)Rx, - uC(J)ORX, -RuC(J)N(Ry)(RZ), - uC(J)RuN(Ry)(RZ) - - , -RuC(J)N(Ry)ORX, -C(=NORX)RX, Rw, -RuN(RX)C(J)RX, -RuN(RX)C(J)ORX, RuN(Rx)S(O)tRW or —C(=NRy)N(Ry)ORX, Where the alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, lkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl groups are optionally substituted with one or more groups Q4; in one embodiment, one to three Q4 groups, each Q4 is independently selected from halo, deuterium, hydroxyl, alkyl, haloalkyl and hydroxyalkyl; Q5 and Q6 are each independently hydrogen, deuterium, halo, cyano, oxo, thioxo, alkyl, kyl, aminoalkyl, alkenyl, haloalkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, -RuORX, - uORuORX,- uORuN(Ry)(RZ), -RuN(Ry)(RZ), - uSR", -RuC(J)RX, -RuC(J)ORX, - RuC(J)N(Ry)(RZ), -RuC(J)RuN(Ry)(RZ), - uC(J)N(Ry)ORx, -C(=NORX)RX, - RuS(O)tRw, -RuN(RX)C(J)RX, -RuN(RX)C(J)ORX, -RuN(RX)S(O)tRW or — C(=NRy)N(Ry)ORX, Where the alkyl, kyl, aminoalkyl, alkenyl, alkynyl, lkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl groups are optionally substituted with one or more Q8 groups; each Q8 is independently selected from halo, deuterium, yl, alkyl, haloalkyl and hydroxyalkyl; each Rd is independently hydrogen or alkyl; each R11 is independently alkylene, alkenylene or a direct bond; RW is alkyl, haloalkyl, hydroxyalkyl, alkyl, alkenyl, l, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; each Rx is independently hydrogen, alkyl, kyl, hydroxyalkyl, alkoxyalkyl, cyanoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, lkenylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; Ry and RZ are each independently selected from (i) or (ii) below: (i) Ry and RZ are each independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkyl, alkenyl, l, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; or WO 56070 (ii) Ry and RZ, together with the nitrogen atom to which they are attached, form a heterocyclyl or heteroaryl, optionally substituted with one or more, in one embodiment, one, two or three Q7 groups; each Q7 is independently selected from halo, deuterium, oxo, thioxo, y, alkoxy, alkyl, haloalkyl, hydroxyalkyl, lkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, aralkyl, heteroaryl, aralkyl, heterocyclyl and heterocyclylalkyl; Ry and RZ are each independently hydrogen or alkyl; J is O, NRx or S; each t is ndently an integer from 0-2; and q is an integer from 0-4.

In certain embodiments, provided herein are compounds of Formula V or pharmaceutically acceptable salts, solvates, hydrates, clathrates, single stereoisomers, mixture of stereoisomers or c mixture of stereoisomers thereof, wherein: R1 and R2 are each independently selected from hydrogen or halogen; R3 is hydrogen or alkyl; R4 is cycloalkyl, aryl, heterocyclyl or heteroaryl, where R4 is optionally tuted with one or more, in one embodiment, one to three, in another embodiment, one, two or three groups selected from Q1; each Q1 is independently halo, oxo, alkyl, haloalkyl, hydroxyalkyl, lkyl, =NOH, - uORx or -RuC(O)RX; Y is -(CR5R6)q-; R5 and R6 are each independently hydrogen, halo, alkyl, haloalkyl or hydroxyalkyl; Z is O, S, or NH; each W is independently CR8 or N; R8 is hydrogen, halo, haloalkyl or alkyl; W4 is N or CR1“); R11b is hydrogen, halo or alkyl; W5 is N or CR”; R13 is hydrogen, halo or alkyl; Q5 and Q6 are each independently hydrogen, deuterium, halo, cyano, oxo, thioxo, alkyl, haloalkyl, aminoalkyl, alkenyl, l, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, -RuORX, - uORuN(Ry)(RZ), -RuN(Ry)(RZ), -RuSRX, - RuC(J)RX, -RuC(J)ORX, -RuC(J)N(Ry)(RZ), - uC(J)N(Ry)ORX, - uS(O)IRW, - RuN(RX)C(J)RX, -RuN(RX)C(J)ORX, X)S(O)tRW or —C(=NRy)N(Ry)ORX, where the alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl groups are optionally substituted with one or more Q8 groups; each Q8 is ndently selected from halo, deuterium, hydroxyl, alkyl, haloalkyl and hydroxyalkyl; each R11 is independently alkylene or a direct bond; RW is alkyl; each Rx is independently hydrogen or alkyl; Ry and RZ are each independently hydrogen or alkyl; J is O, NRx or S; each t is independently an integer from 0-2; and q is an integer from 0-4.

In n embodiments, ed herein are compounds of Formula V wherein W4 is N and the other variables are as described elsewhere herein.

] In certain embodiments, ed herein are compounds of Formula V wherein W4 is N; W5 is N; Q5 and Q6 are each independently hydrogen, halo, or alkoxy; R4 is cycloalkyl, optionally substituted with one or two groups selected from Q1; each Q1 is independently halo, oxo, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, =NOH, -R“ORx or -RuC(O)RX; and the other variables are as described ere herein.

In certain embodiments, provided herein are compounds of Formula V wherein W4 is N; W5 is CR1“); R11b is hydrogen; Q5 and Q6 are each independently hydrogen, halo, or alkoxy; R4 is cycloalkyl, ally substituted with one or two groups selected from Q1; each Q1 is ndently halo, oxo, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, =NOH, -RuORX or )RX; and the other variables are as described elsewhere herein.

In certain embodiments, provided herein are compound of Formula V n Q1 is independently halo, oxo, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, =NOH, -RuORX or -RuC(O)RX; each R11 is independently alkylene or a direct bond; each Rx is independently hydrogen or alkyl; and the other variables are as bed elsewhere herein.

] In n embodiments, provided herein are compounds of Formula V wherein W4 is N; W5 is CH or N; Q5 and Q6 are each independently en, halo, or alkoxy; R4 is cyclohexyl, optionally tuted with one or two hydroxy; and the other variables are as described elsewhere herein.

In certain embodiments, provided herein are compounds of Formula V wherein W is C; Z is S; W4 is N; W5 is CH or N; Q5 and Q6 are each independently hydrogen, halo, alkyl, or alkoxy; R3 is hydrogen or alkyl; Y is -(CR5R6)q-; q is 0; and R4 is cycloalkyl, optionally substituted with one or two hydroxy.

In certain embodiments, provided herein are compounds of Formula V wherein W is C; Z is S; W4 is N; W5 is CH or N; Q5 and Q6 are each independently en, halo, alkyl, or alkoxy; R3 is hydrogen or alkyl; Y is -(CR5R6)q-; q is 0; and R4 is cyclohexyl, optionally substituted with one or two hydroxy.

In certain embodiments, provided herein are compounds of Formula V or pharmaceutically acceptable salts, solvates, hydrates, clathrates, single stereoisomers, e of stereoisomers or racemic mixture of isomers thereof, R1 and R2 are each independently selected from hydrogen or halogen; R3 is hydrogen or alkyl; R4 is cycloalkyl, aryl, heterocyclyl or heteroaryl, where R4 is optionally substituted with one or more, in one embodiment, one to three, in another embodiment, one, two or three groups selected from Q1; each Q1 is independently halo, oxo, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, =NOH, - uORx or -RuC(O)RX; Y is -(CR5R6)q-; R5 and R6 are each independently hydrogen, halo, alkyl, haloalkyl or hydroxyalkyl; Z is O, S, or NH; each W is independently CR8 or N; R8 is hydrogen, halo, haloalkyl or alkyl; W4 is N or CR1“); R11b is en, halo or alkyl; W5 is N or CR”; R13 is hydrogen, halo or alkyl; Q5 and Q6 are each independently hydrogen, deuterium, halo, cyano, oxo, , alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, aralkyl, heteroaryl, aralkyl, heterocyclyl, cyclylalkyl, -RuORX, - uORuN(Ry)(RZ), - uORuORX, - RuN(Ry)(RZ), -RuSRX, - uC(J)RX, - uC(J)ORX, -RuC(J)N(Ry)(RZ), - RuC(J)RuN(Ry)(RZ), -RuC(J)N(Ry)ORX, -C(=NORX) RX, - uS(O)tRw, -RuN(RX)C(J)RX, X)C(J)ORX, -RuN(RX)S(O)tRW or y)N(Ry)ORX, Where the alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl groups are optionally substituted with one or more Q8 ; each Q8 is independently selected from halo, deuterium, hydroxyl, alkyl, haloalkyl and hydroxyalkyl; each R11 is independently alkylene, alkenylene or a direct bond; RW is alkyl; each Rx is independently hydrogen or alkyl; Ry and RZ are each independently hydrogen or alkyl; J is O, NRx or S; each t is independently an integer from 0-2; and q is an integer from 0-4.

In certain embodiments, provided herein are compounds of Formula VI or pharmaceutically acceptable salts, solvates, hydrates, clathrates, single stereoisomers, mixture of stereoisomers or racemic mixture of stereoisomers thereof Wherein R3 is hydrogen or alkyl; 2012/059983 R4 is cycloalkyl, aryl, heterocyclyl or heteroaryl, where R4 is optionally substituted with one or more, in one embodiment, one to three, in another embodiment, one, two or three groups selected from Q1; each Q1 is independently deuterium, halo, cyano, oxo, thioxo, alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, aralkyl, aryl, heteroaralkyl, heterocyclyl, cyclylalkyl, -RuORX, - uORuN(Ry)(RZ), -RuN(Ry)(RZ), - RuSRX, - uC(J)Rx, - uC(J)ORX, - uC(J)N(Ry)(RZ), -RuS(O)tRW, X)C(J)RX, -RuN(RX)C(J)ORX, -RuN(RX)S(O)tRW, =NORd, or —C(=NRy)N(Ry)ORX, where the alkyl, kyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl groups are optionally substituted with one or more Q3 groups, in one embodiment, one to three Q3 groups; each Q3 is independently selected from deuterium, halo, hydroxyl, alkyl, haloalkyl and hydroxyalkyl; Y is —(CR5R6)q-; R5 and R6 are each independently hydrogen, halo, alkyl, kyl or hydroxyalkyl; Z is O, S, or NH; W5 is N or CH; W4 is N or CR1“); R11b is hydrogen or Q2; Q2 is halo, deuterium, cyano, oxo, , alkyl, haloalkyl, haloalkenyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, lkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, cyclylalkyl, -RuORX, - uORuORX,-RuORuN(Ry)(RZ), - R“N(Ry)(RZ), -R“SRX, - uC(J)Rx, - uC(J)ORX, -RuC(J)N(Ry)(RZ), - uN(Ry)(RZ) , -RuC(J)N(Ry)ORX, -C(=NORX)RX, uS(O)IRW, -RuN(RX)C(J)RX, -RuN(RX)C(J)ORX, - )S(O)tRW or —C(=NRy)N(Ry)ORX, where the alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl groups are optionally substituted with one or more groups Q4; in one embodiment, one to three Q4 groups, each Q4 is independently selected from halo, deuterium, hydroxyl, alkyl, haloalkyl and hydroxyalkyl; Q5 and Q6 are each independently hydrogen, deuterium, halo, cyano, oxo, thioxo, alkyl, haloalkyl, aminoalkyl, alkenyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, -RuORX, - uORuORX,- uORuN(Ry)(RZ), -RuN(Ry)(RZ), - uSR", -RuC(J)RX, -RuC(J)ORX, - RuC(J)N(Ry)(RZ), -RuC(J)RuN(Ry)(RZ), - uC(J)N(Ry)ORX, -C(=NORX)RX, - RuS(O)tRw, -RuN(RX)C(J)RX, -RuN(RX)C(J)ORX, -RuN(RX)S(O)tRW or — C(=NRy)N(Ry)ORX, where the alkyl, kyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl groups are optionally substituted with one or more Q8 groups; each Q8 is independently selected from halo, ium, hydroxyl, alkyl, haloalkyl and hydroxyalkyl; each Rd is ndently hydrogen or alkyl; each R11 is independently alkylene, alkenylene or a direct bond; RW is alkyl, haloalkyl, hydroxyalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; each Rx is independently hydrogen, alkyl, haloalkyl, yalkyl, alkoxyalkyl, cyanoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; Ry and RZ are each independently selected from (i) or (ii) below: (i) Ry and RZ are each independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; or (ii) Ry and RZ, together with the nitrogen atom to which they are attached, form a heterocyclyl or heteroaryl, optionally substituted with one or more, in one embodiment, one, two or three Q7 groups; each Q7 is independently selected from halo, deuterium, oxo, thioxo, hydroxy, alkoxy, alkyl, haloalkyl, hydroxyalkyl, lkyl, alkenyl, alkynyl, lkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, l, heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl; J is O, NRx or S; each t is independently an integer from 0-2; and q is an integer from 0-4.

In certain embodiments, provided herein are compounds of a VI n W4 is N and the other variables are as bed elsewhere herein. In certain embodiments, provided herein are compound of Formula VI wherein Q1 is independently halo, oxo, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, =NOH, -RuORX or -RuC(O)RX; each R11 is independently alkylene or a direct bond; each Rx is independently hydrogen or alkyl; and the other variables are as described elsewhere herein.

In certain embodiments, provided herein are compounds of Formula VI or pharmaceutically able salts, solvates, hydrates, clathrates, single stereoisomers, mixture of stereoisomers or racemic mixture of stereoisomers thereof wherein R3 is en or alkyl; R4 is cycloalkyl, aryl, heterocyclyl or heteroaryl, where R4 is optionally substituted with one or more, in one embodiment, one to three, in another embodiment, one, two or three groups selected from Q1; each Q1 is independently halo, oxo, alkyl, haloalkyl, hydroxyalkyl, lkyl, =NOH, - uORx or -RuC(O)RX; Y is —(CR5R6)q-; R5 and R6 are each ndently hydrogen, halo, alkyl, kyl or hydroxyalkyl; Z is O, S, or NH; W5 is N or CH; W4 is N or CR1“); R11b is hydrogen, halo or alkyl; Q5 and Q6 are each independently hydrogen, deuterium, halo, cyano, oxo, thioxo, alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, -RuORX, - uORuN(Ry)(RZ), -RuN(Ry)(RZ), -RuSRX, - RuC(J)RX, -RuC(J)ORX, )N(Ry)(RZ), - uC(J)N(Ry)ORX, - uS(O)tRW, - RuN(RX)C(J)RX, -RuN(RX)C(J)ORX, -RuN(RX)S(O)tRW or —C(=NRy)N(Ry)ORX, where the alkyl, haloalkyl, lkyl, alkenyl, l, cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl groups are optionally substituted with one or more Q8 groups; each Q8 is independently selected from halo, deuterium, hydroxyl, alkyl, haloalkyl and yalkyl; each R11 is independently alkylene or a direct bond; RW is alkyl; each Rx is independently hydrogen or alkyl; Ry and RZ are each independently hydrogen or alkyl; J is O, NRx or S; each t is ndently an integer from 0-2; and q is an integer from 0-4.

In certain embodiments, provided herein are compounds of Formula VI or pharmaceutically acceptable salts, solvates, hydrates, clathrates, single stereoisomers, mixture of stereoisomers or racemic mixture of stereoisomers thereof wherein R3 is hydrogen or alkyl; R4 is lkyl, aryl, cyclyl or heteroaryl, Where R4 is optionally substituted with one or more, in one embodiment, one to three, in another embodiment, one, two or three groups selected from Q1; each Q1 is independently halo, oxo, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, =NOH, - uORx or -RuC(O)RX; Y is —(CR5R6)q-; R5 and R6 are each ndently hydrogen, halo, alkyl, haloalkyl or hydroxyalkyl; Z is O, S, or NH; W5 is N or CH; W4 is N or CR1“); R11b is hydrogen, halo or alkyl; Q5 and Q6 are each independently hydrogen, deuterium, halo, cyano, oxo, thioxo, alkyl, haloalkyl, aminoalkyl, l, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, l, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, -RuORX, - uORuN(Ry)(RZ), - uORuORX, -R“N(Ry)(RZ), - uSR", )RX, -RuC(J)ORX, - R“C(J)N(Ry)(RZ), -RuC(J)RuN(Ry)(RZ),-RuC(J)N(Ry)ORX, - RW, - RuN(RX)C(J)RX, X)C(J)ORX, -C(=NORX) RX, -RuN(Rx)S(O)tRW or — C(=NRy)N(Ry)ORX, Where the alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl groups are optionally substituted with one or more Q8 groups; each Q8 is independently selected from halo, deuterium, hydroxyl, alkyl, kyl and hydroxyalkyl; each R11 is independently alkylene, alkenylene or a direct bond; RW is alkyl; each Rx is independently hydrogen or alkyl; Ry and RZ are each independently hydrogen or alkyl; J is O, NRx or S; each t is independently an integer from 0-2; q is an integer from 0-4.

In certain embodiments, provided herein are nds of Formula VI or ceutically acceptable salts, solvates, hydrates, clathrates, single stereoisomers, mixture of stereoisomers or racemic mixture of stereoisomers f wherein R3 is hydrogen or alkyl; R4 is cycloalkyl, aryl, heterocyclyl or heteroaryl, where R4 is optionally substituted with one or more, in one embodiment, one to three, in another embodiment, one, two or three groups selected from Q1; each Q1 is independently halo, oxo, alkyl, haloalkyl, yalkyl, cycloalkyl, =NOH, - uORx or -RuC(O)RX; Y is —(CR5R6)q-; R5 and R6 are each independently hydrogen, halo, alkyl, haloalkyl or hydroxyalkyl; Z is O, S, or NH; W5 is N or CH; W4 is N or CR1“); R11b is hydrogen, halo or alkyl; Q5 and Q6 are each independently hydrogen, deuterium, halo, cyano, oxo, thioxo, alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, aralkyl, heteroaryl, aralkyl, heterocyclyl, heterocyclylalkyl, , - uORuN(Ry)(RZ), -RuN(Ry)(RZ), -RuSRX, - RuC(J)RX, -RuC(J)ORX, -RuC(J)N(Ry)(RZ), - uC(J)N(Ry)ORX, - uS(O)tRW, - RuN(RX)C(J)RX, -RuN(RX)C(J)ORX, x)S(O)tRW or —C(=NRy)N(Ry)ORX, where the alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, lkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl groups are optionally substituted with one or more Q8 groups; each Q8 is independently selected from halo, deuterium, hydroxyl, alkyl, haloalkyl and hydroxyalkyl; each R11 is independently alkylene or a direct bond; RW is alkyl; each Rx is independently hydrogen or alkyl; Ry and RZ are each independently hydrogen or alkyl; J is O, NRx or S; each t is independently an integer from 0-2; and q is an integer from 0-4.

In certain embodiments, provided herein are compounds of Formula VI or pharmaceutically acceptable salts, solvates, hydrates, clathrates, single stereoisomers, mixture of isomers or racemic mixture of stereoisomers thereof wherein R3 is hydrogen or alkyl; R4 is lkyl, aryl, heterocyclyl or heteroaryl, Where R4 is optionally tuted with one or more, in one embodiment, one to three, in another embodiment, one, two or three groups selected from Q1; each Q1 is independently halo, oxo, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, =NOH, - uORx or -RuC(O)RX; Y is —(CR5R6)q-; R5 and R6 are each independently hydrogen, halo, alkyl, haloalkyl or hydroxyalkyl; Z is O, S, or NH; W5 is N or CH; W4 is N or CR1“); R11b is en, halo or alkyl; Q5 and Q6 are each independently hydrogen, ium, halo, cyano, oxo, thioxo, alkyl, haloalkyl, lkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, -RuORX, - uORuN(Ry)(RZ), - uORuORX, -RuN(Ry)(RZ), - uSR", )RX, -RuC(J)ORX, - RuC(J)N(Ry)(RZ), )RuN(Ry)(RZ),-RuC(J)N(Ry)ORX, - uS(O)tRw, - RuN(RX)C(J)RX, -RuN(RX)C(J)ORX, -C(=NORX) RX, -RuN(Rx)S(O)tRW or — C(=NRy)N(Ry)ORX, Where the alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl groups are optionally substituted with one or more Q8 groups; each Q8 is independently selected from halo, deuterium, hydroxyl, alkyl, haloalkyl and hydroxyalkyl; each R11 is independently alkylene, alkenylene or a direct bond; RW is alkyl; each Rx is independently hydrogen or alkyl; Ry and RZ are each independently hydrogen or alkyl; J is O, NRx or S; each t is independently an r from 0-2; q is an integer from 0-4.

In certain ments, provided herein are compounds of Formulae IV, V or VI wherein W4 is N, W5 is N or CR13 ; R13 is hydrogen, halo or alkyl; and the other variables are as described elsewhere herein. In certain embodiments, provided herein are nds of Fomulae IV, V or VI wherein W4 is N; W5 is N or CH and the other les are as described elsewhere .

In certain embodiments, provided herein are compounds of Formulae IV, V or VI, wherein Q5 and Q6 are each independently hydrogen, deuterium, halo, cyano, alkyl, haloalkyl, lkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, heteroaralkyl, cyclyl, heterocyclylalkyl, -RuORX, -RuN(Ry)(RZ), -RuSRX, - uC(J)Rx, - RuC(J)ORX, -RuC(J)N(Ry)(RZ), -RuC(J)N(Ry)ORX, - uS(O)tRw, -RuN(RX)C(J)RX, - RuN(RX)C(J)ORX, -RuN(RX)S(O)tRW or —C(=NRy)N(Ry)ORX, where the alkyl, haloalkyl, aminoalkyl, alkenyl, l, cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl groups are optionally substituted with one or more Q8 groups; each Q8 is independently selected from halo, deuterium, hydroxyl, alkyl, haloalkyl and yalkyl; each R11 is independently alkylene or a direct bond; RW is alkyl; each Rx is independently hydrogen or alkyl; Ry and RZ are each independently hydrogen or alkyl; J is O, NRx or S; each t is independently an integer from 0-2; 11 is l or 2; and q is an integer from 0-4, and the other variables are as described elsewhere herein.

In certain embodiments, Q5 and Q6 are each independently hydrogen, deuterium, chloro, fluoro, bromo, cyano, alkyl, alkenyl, alkynyl, cycloalkyl, methoxy or alkylcarbonyl, and the other variables are as described elsewhere herein. In certain embodiments, provided herein are compounds of Formula IV, V or VI, wherein Q5 and Q6 are each independently hydrogen, deuterium, halo, cyano, cycloalkyl, alkoxy, tetrazole or pyrazole, where the tetrazole and pyrazole rings are optionally substituted with one or more alkyl, and the other variables are as described ere herein. In certain embodiments, provided herein are compounds of Formula IV, V or VI, wherein Q5 and Q6 are each independently hydrogen, deuterium, halo, alkoxy, tetrazole or pyrazole, where the tetrazole and pyrazole rings are ally substituted with one or more alkyl, and the other variables are as described elsewhere herein. In certain embodiments, Q5 and Q6 are each independently hydrogen, ium, chloro, fluoro, bromo, cyano, alkyl, alkenyl, alkynyl, cycloalkyl, methoxy or arbonyl, and the other variables are as described elsewhere herein. In certain embodiments, Q5 and Q6 are each independently hydrogen, deuterium, chloro, fluoro, bromo, cyano, alkyl, alkenyl, alkynyl, cycloalkyl or methoxy, and the other variables are as described elsewhere . In certain embodiments, Q5 and Q6 are each independently en, deuterium, chloro, fluoro, bromo, cyano, cycloalkyl or methoxy, and the other variables are as described elsewhere herein. In certain embodiments, Q5 and Q6 are each independently hydrogen, deuterium, chloro, fluoro, bromo or y, and the other variables are as described elsewhere herein.

] In certain embodiments, provided herein are compounds of Formula IV, V or VI, wherein R3 is hydrogen; R4 is cyclohexyl, tetrahydrofuryl, nyl, phenyl, linyl, cyclopentyl, piperidinyl, tetrahydro-2H—pyranyl or 2,3-dihydro-lH—indenyl, where R4 is optionally substituted with one or more, in one embodiment, one to three, in another embodiment, one, two or three groups ed from Q1; each Q1 is independently halo, oxo, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, =NOH, -RuORX or -RuC(O)RX; each R11 is independently ne or a direct bond; each Rx is independently hydrogen or alkyl; Q5 and Q6 are each independently en, deuterium, halo, cyano, alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, -RuORX, -RuN(Ry)(RZ), -RuSRX, - uC(J)Rx, - RuC(J)ORX, -RuC(J)N(Ry)(RZ), -RuS(O)tRw, -RuN(RX)C(J)RX, -RuN(RX)C(J)ORX, - RuN(Rx)S(O)tRW or —C(=NRy)N(Ry)ORX, where the alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl groups are optionally substituted with one or more Q8 groups; each Q8 is independently selected from halo, deuterium, hydroxyl, alkyl, kyl and hydroxyalkyl; each R11 is independently alkylene or a direct bond; RW is alkyl; each Rx is independently hydrogen or alkyl; Ry and RZ are each ndently hydrogen or alkyl; J is O, NRx or S; each t is independently an integer from 0-2; 11 is l or 2; and q is an integer from 0-4, and the other variables are as described elsewhere herein.

In certain embodiments, ed herein are compounds of Formula VIIa or pharmaceutically acceptable salts, solvates, hydrates, clathrates, single stereoisomers, mixture of stereoisomers or racemic mixture of stereoisomers thereof, wherein: R1 and R2 are each independently selected from hydrogen or halogen; R3 is hydrogen or alkyl; each Q1 is independently deuterium, halo, cyano, oxo, thioxo, alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, aralkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, -RuORX, - Ry)(RZ), -RuN(Ry)(RZ), - RuSRX, - uC(J)Rx, - uC(J)ORX, - uC(J)N(Ry)(RZ), -RuS(O)tRW, -RuN(RX)C(J)RX, -RuN(RX)C(J)ORX, -RuN(RX)S(O)tRW, =NORd, or —C(=NRy)N(Ry)ORX, where the alkyl, kyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl groups are optionally substituted with one or more Q3 groups, in one embodiment, one to three Q3 groups; each Q3 is independently ed from ium, halo, hydroxyl, alkyl, haloalkyl and hydroxyalkyl; Y is -(CR5R6)q-; R5 and R6 are each independently hydrogen, halo, alkyl, haloalkyl or hydroxyalkyl; Z is O, S, or NH; each W is independently CR8 or N; R8 is hydrogen, halo, haloalkyl or alkyl; ring A is aryl or heteroaryl, optionally substituted with one to four substituents selected from Q2; W1 is N or C; W2 is N, NR9a or CR9b; W3 is N, NR10a or CRIOb; W4 is N, NR11a or CRllb; Rga, Rgb, Rloa, R101), R1181 and R11b are selected as follows: i) R981, R1021 and R1121 are each ndently hydrogen or alkyl and R91), R10b and R11b are each independently hydrogen or Q2; or ii) R9a and R101), R9b and R101), R9b and R10a’R10b and Rlla’ R10a and Rllb or R10b and Rllb, er with the atoms to which they are attached form an aryl, heteroaryl or heterocyclyl ring, wherein the aryl, heteroaryl or heterocyclyl ring is ally tuted with one or more, in one embodiment, one to three, in another embodiment, one, two or three groups selected from Q2; and the remainder of R981 or R1121 is hydrogen or alkyl and the remainder of R9b or R11b is hydrogen or Q2; each Q2 is independently halo, deuterium, cyano, oxo, thioxo, alkyl, kyl, aminoalkyl, alkenyl, haloalkenyl, alkynyl, cycloalkyl, lkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, -RuORX, - uORuORx, - uORuN(Ry)(RZ), - RuN(Ry)(RZ), -RuSRX, - uC(J)RX, - uC(J)ORX, -uC(J)N(Ry)(RZ), - uC(J)RuN(Ry)(RZ), - RuC(J)N(Ry)ORX, -C(=NORX)RX, - uS(O)tRW, -RuN(RX)C(J)RX, -RuN(RX)C(J)ORX, - RuN(Rx)S(O)tRW or y)N(Ry)ORX, where the alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl groups are optionally substituted with one or more Q4 groups; each Q4 is independently selected from halo, hydroxyl, alkyl, haloalkyl and hydroxyalkyl; each Rd is ndently hydrogen or alkyl; each R11 is ndently alkylene or a direct bond; RW is alkyl; each Rx is independently hydrogen or alkyl; Ry and RZ are each independently hydrogen or alkyl; J is O, NRx or S; each t is independently an integer from 0-2; 11 is l or 2; and q is an integer from 0-4.

In certain embodiments, provided herein are compounds of Formula VIIa wherein each Q1 is independently halo, oxo, alkyl, haloalkyl, hydroxyalkyl, lkyl, =NOH, - uORx or -RuC(O)RX; each R11 is independently alkylene or a direct bond; each Rx is independently hydrogen or alkyl; and the other variables are as described elsewhere herein.

] In certain embodiments, provided herein are compounds of Formula VIIa or pharmaceutically acceptable salts, solvates, hydrates, clathrates, single stereoisomers, mixture of stereoisomers or racemic mixture of stereoisomers thereof, wherein: R1 and R2 are each independently selected from en or halogen; R3 is en or alkyl; each Q1 is independently halo, oxo, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, =NOH, - uORx or -RuC(O)RX; Y is -(CR5R6)q-; R5 and R6 are each independently hydrogen, halo, alkyl, haloalkyl or hydroxyalkyl; Z is O, S, or NH; each W is ndently CR8 or N; R8 is en, halo, haloalkyl or alkyl; ring A is aryl or heteroaryl, optionally substituted with one to four substituents selected from Q2; W1 is N or C; w2 is N, NR9a or CR9b; w3 is N, NR10a or CRIOb; w4 is N, NR11a or CRllb; Rga, Rgb, Rloa, R101), R1181 and R11b are selected as follows: i) R981, R1021 and R1121 are each independently hydrogen or alkyl and R91), R10b and R11b are each ndently hydrogen, oxo, hydroxyl, halo or alkyl; or ii) R9a and R101), R9b and R101), R9b and RIOa’ R10b and Rlla’ R10a and Rllb or R10b and Rllb, together with the atoms to which they are attached form an aryl, heteroaryl or heterocyclyl ring, wherein the aryl, heteroaryl or heterocyclyl ring is optionally substituted with one or more, in one embodiment, one to three, in another embodiment, one, two or three groups selected from Q2; and the remainder of Rga, R1021 or R1121 is hydrogen or alkyl and the remainder of R91), R10b or R11b is en, halo or alkyl; each Q2 is independently halo, cyano, oxo, thioxo, alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, lkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, -RuORX, - uORuN(Ry)(RZ), -RuN(Ry)(RZ), -RuSRX, - uC(J)Rx, - RuC(J)ORX, -RuC(J)N(Ry)(RZ), -RuC(J)N(Ry)ORX, - uS(O)tRW, -RuN(RX)C(J)RX, - RuN(RX)C(J)ORX, X)S(O)tRW or y)N(Ry)ORX, where the alkyl, kyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, aryl, and heterocyclyl groups are optionally substituted with one or more Q4 groups; each Q4 is independently selected from halo, hydroxyl, alkyl, haloalkyl and yalkyl; each R11 is independently alkylene or a direct bond; RW is alkyl; each Rx is independently hydrogen or alkyl; Ry and RZ are each independently hydrogen or alkyl; J is O, NRx or S; each t is independently an integer from 0-2; 11 is l or 2; and q is an integer from 0-4.

In n embodiments, provided herein are compounds of Formula VIIa or pharmaceutically acceptable salts, es, hydrates, clathrates, single stereoisomers, mixture of stereoisomers or racemic mixture of stereoisomers thereof, wherein: R1 and R2 are each independently selected from en or halogen; R3 is hydrogen or alkyl; each Q1 is independently halo, oxo, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, =NOH, - uORx or -RuC(O)RX; Y is -(CR5R6)q-; 2012/059983 R5 and R6 are each independently hydrogen, halo, alkyl, haloalkyl or hydroxyalkyl; Z is O, S, or NH; each W is independently CR8 or N; R8 is hydrogen, halo, haloalkyl or alkyl; ring A is aryl, heteroaryl or heterocyclyl, optionally substituted with one to four substituents ed from Q2; W1 is N or C; w2 is N, NR9a or CR9b; w3 is N, NR10a or CRIOb; w4 is N, NR11a or CRllb; Rga, Rgb, Rloa, R101), R1181 and R11b are selected as follows: i) R981, R1021 and R1121 are each independently hydrogen or alkyl and R91), R10b and R11b are each independently hydrogen, oxo, hydroxyl, halo or alkyl; or ii) R9a and R101), R9b and R101), R9b and RIOa’ R10b and Rlla’ R10a and Rllb or R10b and Rllb, together with the atoms to which they are attached form an aryl, heteroaryl or heterocyclyl ring, wherein the aryl, heteroaryl or heterocyclyl ring is optionally substituted with one or more, in one embodiment, one to three, in r embodiment, one, two or three groups selected from Q2; and the remainder of Rga, R1021 or R1121 is hydrogen or alkyl and the remainder of R91), R10b or R11b is hydrogen, halo or alkyl; or iii) R9&1 and R101), R9b and R101), R9b and Rloa, R10b and Rm, R1021 and R11b or R10b and R11b er with the atoms to which they are attached form an aryl, aryl or heterocyclyl ring ally fused to a phenyl ring optionally substituted with one or more, in one embodiment, one to three, in another embodiment, one, two or three groups selected from Q2; and the remainder of R9&1 and R9b or the remainder of R1121 and R11b are each independently hydrogen or alkyl; each Q2 is independently halo, cyano, oxo, thioxo, alkyl, haloalkyl, aminoalkyl, alkenyl, l, cycloalkyl, cycloalkenyl, lkylalkyl, cycloalkenylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, -RuORX, - uORuORX,-RuORuN(Ry)(RZ), -RuN(Ry)(RZ), -RuSRX, - RuC(J)RX, -RuC(J)ORX, -RuC(J)N(Ry)(RZ), - uC(J)RuN(Ry)(RZ), - RuC(J)N(Ry)ORX, -C(=NORX)RX, - uS(O)tRW, -RuN(RX)C(J)RX, -RuN(RX)C(J)ORX, - RuN(Rx)S(O)tRW or —C(=NRy)N(Ry)ORX, where the alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl groups are optionally substituted with one or more Q4 groups; each Q4 is independently selected from halo, hydroxyl, alkyl, haloalkyl and hydroxyalkyl; each R11 is independently alkylene, alkenylene or a direct bond; RW is alkyl; each Rx is independently hydrogen or alkyl; Ry and RZ are each ndently hydrogen or alkyl; J is O, NRx or S; each t is independently an integer from 0-2; 11 is l or 2; and q is an integer from 0-4; wherein the compounds are selected such that: i) when W is CH; W1 is C; Z is S; R1 is hydrogen, or hydroxyl and R2 is hydrogen, or R1 and R2 together form =0; then ring A is not pyridine and ii) when W is CH; W1 is N; Z is S; R1 and R2 are hydrogen, then ring A is not pyrrolidine.

] In n embodiments, provided herein are compounds of a VIIb fiWW5 R1 R2 W\ Z r W€>J | N/ \Y@>—N (Q1)oz W, / W VHb or pharmaceutically acceptable salts, solvates, hydrates, clathrates, single stereoisomers, mixture of stereoisomers or c mixture of isomers thereof, wherein: R1 and R2 are each independently selected from hydrogen or halogen; R3 is hydrogen or alkyl; each Q1 is independently deuterium, halo, cyano, oxo, thioxo, alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, -RuORX, - uORuN(Ry)(RZ), -RuN(Ry)(RZ), - uSR", - uC(J)RX, - uC(J)ORX, -RuC(J)N(Ry)(RZ), - uS(O)tRW, -RuN(RX)C(J)RX, X)C(J)ORX, -RuN(RX)S(O)tRW, =NORd, or —C(=NRy)N(Ry)ORX, where the alkyl, haloalkyl, aminoalkyl, alkenyl, l, cycloalkyl, cycloalkenyl, aryl, aryl, and heterocyclyl groups are optionally substituted with one or more Q3 WO 56070 groups, in one embodiment, one to three Q3 groups; each Q3 is ndently ed from deuterium, halo, hydroxyl, alkyl, kyl and hydroxyalkyl; Y is -(CR5R6)q-; R5 and R6 are each independently hydrogen, halo, alkyl, haloalkyl or hydroxyalkyl; Z is O, S, or NH; each W is independently CR8 or N; R8 is hydrogen, halo, haloalkyl or alkyl; W1 is N or C; W2 is N or CRgb; R9b is hydrogen or alkyl; W4 is N or CR1“); W5 is N or CR”; R11b and R13 are each independnetly hydrogen or Q2; Q2 is halo, deuterium, cyano, oxo, thioxo, alkyl, haloalkyl, haloalkenyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cyclyl, heterocyclylalkyl, -RuORX, - uORuORX,-RuORuN(Ry)(RZ), - R“N(Ry)(RZ), -R“SRX, - uC(J)Rx, - RX, -RuC(J)N(Ry)(RZ), -RuC(J)RuN(Ry)(RZ), - uC(J)N(Ry)ORX, -C(=NORX)RX, - uS(O)tRW, -RuN(RX)C(J)RX, -RuN(RX)C(J)ORX, -RuN(RX)S(O)tRW or —C(=NRy)N(Ry)ORX, Where the alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl groups are ally substituted with one or more groups Q4; in one embodiment, one to three Q4 groups, each Q4 is independently selected from halo, deuterium, hydroxyl, alkyl, haloalkyl and hydroxyalkyl; Q5 and Q6 are each independently hydrogen, ium, halo, cyano, oxo, thioxo, alkyl, haloalkyl, aminoalkyl, l, haloalkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, aralkyl, heteroaryl, aralkyl, heterocyclyl, heterocyclylalkyl, -RuORX, - RuORuORX, N(Ry)(RZ), -R“N(Ry)(RZ), -R“SRX, - uC(J)Rx, -RuC(J)ORX, -RuC(J)N(Ry)(RZ), - uC(J)RuN(Ry)(RZ), - RuC(J)N(Ry)ORX, -C(=NORX)RX, - uS(O)IRW, -RuN(RX)C(J)RX, -RuN(RX)C(J)ORX, -RuN(RX)S(O)tRW or —C(=NRy)N(Ry)ORX, Where the alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, and WO 56070 heterocyclyl groups are optionally substituted with one or more Q8 groups; each Q8 is independently selected from halo, ium, hydroxyl, alkyl, kyl and hydroxyalkyl; each Rd is independently hydrogen or alkyl; each R11 is independently alkylene, alkenylene or a direct bond; RW is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, l, cycloalkyl, cycloalkenyl, cycloalkylalkyl, lkenylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; each Rx is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cyanoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, or aralkyl; Ry and RZ are each independently selected from (i) or (ii) below: (i) Ry and RZ are each independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, lkenylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; or (ii) Ry and RZ, together with the nitrogen atom to which they are attached, form a heterocyclyl or heteroaryl, optionally substituted with one or more, in one embodiment, one, two or three Q7 groups; each Q7 is independently ed from halo, ium, oxo, , hydroxy, alkoxy, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, lkylalkyl, cycloalkenylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl; J is O, NRx or S; each t is independently an integer from 0-2; 11 is l or 2; and q is an integer from 0-4.

In certain embodiment, provided herein are compounds of Formula VIIb wherein each Q1 is independently halo, oxo, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, =NOH, - uORx or -RuC(O)RX; each R11 is independently alkylene or a direct bond; each Rx is independently hydrogen or alkyl; and the other variables are as described elsewhere herein.

In certain embodiments, provided herein are compounds of Formula VIIb wherein R1 and R2 are both hydrogen. In certain embodiments, provided herein are nds of a VIIb wherein Q5 and Q6 are each independently hydrogen, deuterium, halo, cyano, alkyl, l, alkynyl, cycloalkyl, alkoxy or alkylcarbonyl, and the other variables are as described elsewhere herein. In n embodiments, provided herein are compounds of Formula VIIb, wherein Q5 is hydrogen and Q6 is halo, deuterium, cyano, alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy or alkylcarbonyl.

In certain ments, provided herein are compounds of Formula VIIb, wherein Q5 is hydrogen and Q6 is halo, alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy or alkylcarbonyl. In certain embodiments, provided herein are compounds of Formula VIIb, wherein Q5 is en and Q6 is halo, cyano, cycloalkyl, alkoxy or alkylcarbonyl. In certain embodiments, provided herein are compounds of Formula VIIb, wherein Q5 is hydrogen and Q6 is bromo, chloro, fluoro, cyano, cyclopropyl, methoxy or methylcarbonyl.

In certain embodiments, provided herein are compounds of Formula VIII mm W\ 2 W3 A | N\ W \< —|(Q1 be VIII or pharmaceutically acceptable salts, solvates, hydrates, clathrates, single stereoisomers, e of stereoisomers or racemic e of stereoisomers thereof wherein: R1 and R2 are each independently selected from hydrogen or halogen; R3 is hydrogen or alkyl; each Q1 is independently deuterium, halo, cyano, oxo, , alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, -RuORX, - Ry)(RZ), -RuN(Ry)(RZ), - RuSRX, - x, - uC(J)ORX, - uC(J)N(Ry)(RZ), -RuS(O)tRW, -RuN(RX)C(J)RX, X)C(J)ORX, -RuN(RX)S(O)tRW, =NORd, or —C(=NRy)N(Ry)ORX, where the alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, aryl, and heterocyclyl groups are optionally substituted with one or more Q3 groups, in one embodiment, one to three Q3 groups; each Q3 is independently selected from deuterium, halo, hydroxyl, alkyl, haloalkyl and hydroxyalkyl; Y is -(CR5R6)q-; R5 and R6 are each independently hydrogen, halo, alkyl, haloalkyl or hydroxyalkyl; Z is O, S, or NH; each W is independently CR8 or N; R8 is en, halo, haloalkyl or alkyl; ring A is aryl or heteroaryl, optionally substituted with one to four substituents selected from Q2; W1 is N or C; W2 is N, NR9a or CR9b; W3 is N, NR10a or CRIOb; W4 is N, NR11a or CRllb; Rga, Rgb, Rloa,R10b,R11aandR11b are selected as follows: i) R981, R1021 and R1121 are each independently hydrogen or alkyl and R91), R10b and R11b are each independently hydrogen or Q2; or ii) R9a and R101), R9b and R101), R9b and RIOa’ R10b and Rlla’ R10a and Rllb or R10b and Rllb, together with the atoms to which they are attached form an aryl, heteroaryl ring, wherein the aryl, heteroaryl ring is optionally substituted with one or more, in one ment, one to three, in another embodiment, one, two or three groups selected from Q2; and the remainder of R981 or R1181 is en or alkyl and the remainder of R9b or R11b is hydrogen or Q2; each Q2 is independently halo, cyano, oxo, thioxo, alkyl, haloalkyl, aminoalkyl, alkenyl, haloalkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, -RuORX, - uORuORX,-RuORuN(Ry)(RZ), -RuN(Ry)(RZ), -RuSRX, - RuC(J)RX, -RuC(J)ORX, -RuC(J)N(Ry)(RZ), - uC(J)RuN(Ry)(RZ), , -RuC(J)N(Ry)ORX, -C(=NORX)RX uS(O)tRW, -RuN(RX)C(J)RX, -RuN(RX)C(J)ORX, - )S(O)tRW or —C(=NRy)N(Ry)ORX, where the alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, lkyl, lkenyl, aryl, heteroaryl, and cyclyl groups are optionally substituted with one or more Q4 groups; each Q4 is independently selected from halo, yl, alkyl, haloalkyl and hydroxyalkyl; each Rd is independently hydrogen or alkyl; each R11 is independently alkylene, alkenylene or a direct bond; RW is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; each Rx is independently hydrogen, alkyl, haloalkyl, yalkyl, alkoxyalkyl, cyanoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; Ry and RZ are each independently selected from (i) or (ii) below: (i) Ry and RZ are each independently hydrogen, alkyl, kyl, hydroxyalkyl, alkyl, alkenyl, alkynyl, lkyl, cycloalkenyl, lkylalkyl, cycloalkenylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, or aralkyl; or (ii) Ry and RZ, together with the en atom to which they are attached, form a heterocyclyl or heteroaryl, optionally tuted with one or more, in one embodiment, one, two or three Q7 groups; each Q7 is independently selected from halo, deuterium, oxo, thioxo, hydroxy, alkoxy, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, aralkyl, aryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl; J is O, NRx or S; each t is independently an integer from 0-2; 11 is l or 2; and q is an integer from 0-4.

In certain ments, provided herein are compounds of Formula VIIa, VIIb or VIII, wherein: R1 and R2 are each hydrogen; R3 is hydrogen or alkyl; each Q1 is independently halo, oxo, alkyl, hydroxyl, alkoxy, haloalkyl, hydroxyalkyl, cycloalkyl, =NOH, or -RuC(O)RX; Y is —(CR5R6)q-; R5 and R6 are each independently hydrogen, halo, alkyl, haloalkyl or hydroxyalkyl; Z is O, S, or NH; each W is CH; ring A is aryl or aryl, optionally substituted with one to four tuents ed from Q2; W1 is N or C; W2 is N, NR9a or CR9b; W3 is N, NR10a or CRIOb; W4 is N, NR11a or CRllb; Rga, Rgb, Rloa,R10b,R11aandR11b are selected as follows: i) R981, R1021 and R1121 are each independently hydrogen or alkyl and R91), R10b and R11b are each independently hydrogen, oxo, hydroxyl, halo or alkyl; or ii) R9a and R101), R9b and R101), R9b and RIOa’ R10b and Rlla’ R10a and Rllb or R10b and Rllb, together with the atoms to which they are attached form an aryl, heteroaryl or heterocyclyl ring, wherein the aryl, heteroaryl or heterocyclyl ring is optionally substituted with one or more, in one embodiment, one to three, in another embodiment, one, two or three groups selected from Q2; and the remainder of Rga, R1021 or R1121 is hydrogen or alkyl or the remainder of Rgb’ RIObor R11b is en, halo or alkyl; each Q2 is independently halo, cyano, oxo, thioxo, alkyl, haloalkyl, aminoalkyl, l, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, aralkyl, heteroaryl, aralkyl, heterocyclyl, heterocyclylalkyl, -RuORX, - uORuN(Ry)(RZ), -RuN(Ry)(RZ), -RuSRX, - uC(J)Rx, - RuC(J)ORX, -RuC(J)N(Ry)(RZ), -RuS(O)tRw, -RuN(RX)C(J)RX, -RuN(RX)C(J)ORX, - RuN(Rx)S(O)tRW or y)N(Ry)ORX, where the alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl groups are optionally substituted with one or more Q4 groups; each Q4 is independently selected from halo, hydroxyl, alkyl, haloalkyl and yalkyl; each R11 is independently alkylene or a direct bond; RW is alkyl; each Rx is independently hydrogen or alkyl; Ry and RZ are each independently hydrogen or alkyl; J is O, NRx or S; each t is independently an integer from 0-2; nis l or 2; and WO 56070 q is an integer from 0-4.

In certain embodiments, provided herein are compounds of Formula V111 V111 or pharmaceutically acceptable salts, solvates, hydrates, clathrates, single stereoisomers, mixture of stereoisomers or racemic mixture of stereoisomers thereof wherein: R1 and R2 are each independently selected from hydrogen or halogen; R3 is hydrogen or alkyl; each Q1 is ndently halo, oxo, alkyl, haloalkyl, hydroxyalkyl, lkyl, =NOH, - uORx or -RuC(O)RX; Y is -(CR5R6)q-; R5 and R6 are each independently hydrogen, halo, alkyl, haloalkyl or hydroxyalkyl; Z is O, S, or NH; each W is independently CR8 or N; R8 is hydrogen, halo, haloalkyl or alkyl; ring A is aryl or heteroaryl, optionally substituted with one to four substituents ed from Q2; W1 is N or C; w2 is N, NR9a or CR9b; w3 is N, NR10a or CRIOb; w4 is N, NR11a or CRllb; Rga, Rgb, Rloa,R10b,R11aandR11b are selected as follows: i) R981, R1021 and R1121 are each independently hydrogen or alkyl and R91), R10b and R11b are each ndently hydrogen, oxo, hydroxyl, halo or alkyl; or ii) R9a and R101), R9b and R101), R9b and R10a’R10b and Rlla’ R10a and Rllb or R10b and Rllb, together with the atoms to which they are attached form an aryl, heteroaryl ring, wherein the aryl, heteroaryl ring is optionally substituted with one or more, in one embodiment, one to three, in another embodiment, one, two or three groups selected from Q2; and the remainder of Rga, R1081 or R1181 is hydrogen or alkyl or the remainder of R91), R10b or R11b is hydrogen, halo or alkyl; each Q2 is independently halo, cyano, oxo, thioxo, alkyl, haloalkyl, lkyl, alkenyl, alkynyl, lkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, -RuORX, - uORuN(Ry)(RZ), -RuN(Ry)(RZ), -RuSRX, - uC(J)Rx, - RuC(J)ORX, -RuC(J)N(Ry)(RZ), -RuS(O)tRw, -RuN(RX)C(J)RX, -RuN(RX)C(J)ORX, - RuN(Rx)S(O)tRW or —C(=NRy)N(Ry)ORX, where the alkyl, kyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl groups are optionally substituted with one or more Q4 ; each Q4 is independently selected from halo, hydroxyl, alkyl, haloalkyl and hydroxyalkyl; each R11 is independently alkylene or a direct bond; RW is alkyl; each Rx is independently hydrogen or alkyl; Ry and RZ are each independently hydrogen or alkyl; J is O, NRx or S; each t is independently an integer from 0-2; 11 is l or 2; and q is an r from 0-4.

In certain embodiments, provided herein are compounds of Formula VIIa, VIIb or VIII, wherein: R1 and R2 are each hydrogen; R3 is en or alkyl; each Q1 is independently halo, oxo, alkyl, hydroxyl, , haloalkyl, hydroxyalkyl, cycloalkyl, =NOH, or -RuC(O)RX; Y is —(CR5R6)q-; R5 and R6 are each ndently hydrogen, halo, alkyl, haloalkyl or hydroxyalkyl; Z is O, S, or NH; each W is CH; ring A is aryl or heteroaryl, optionally substituted with one to four substituents selected from Q2; W1 isN or C; w2 is N, NR9a or CR9b; w3 is N, NR10a or CRIOb; w4 is N, NR11a or CRllb; Rga, Rgb, Rloa,R10b,R11aandR11b are selected as follows: i) R981, R1021 and R1121 are each independently hydrogen or alkyl and R91), R10b and R11b are each independently hydrogen, oxo, hydroxyl, halo or alkyl; or ii) R9a and R101), R9b and R101), R9b and RIOa’ R10b and Rlla’ R10a and Rllb or R10b and Rllb, together with the atoms to which they are attached form an aryl, heteroaryl or heterocyclyl ring, wherein the aryl, heteroaryl or heterocyclyl ring is optionally substituted with one or more, in one embodiment, one to three, in another embodiment, one, two or three groups ed from Q2; and the remainder of Rga, R1021 or R1121 is hydrogen or alkyl or the remainder of Rgb’ RIObor R11b is hydrogen, halo or alkyl; each Q2 is ndently halo, cyano, oxo, thioxo, alkyl, haloalkyl, lkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, l, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, -RuORX, - uORuN(Ry)(RZ), -RuN(Ry)(RZ), -RuSRX, - uC(J)Rx, - RuC(J)ORX, -RuC(J)N(Ry)(RZ), -RuS(O)tRw, -RuN(RX)C(J)RX, -RuN(RX)C(J)ORX, - RuN(Rx)S(O)tRW or —C(=NRy)N(Ry)ORX, where the alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl groups are optionally substituted with one or more Q4 ; each Q4 is independently ed from halo, hydroxyl, alkyl, haloalkyl and hydroxyalkyl; each R11 is independently alkylene or a direct bond; RW is alkyl; each Rx is independently hydrogen or alkyl; Ry and RZ are each independently hydrogen or alkyl; J is O, NRx or S; each t is ndently an integer from 0-2; 11 is l or 2; and q is an integer from 0-4.

In n embodiments, ed herein are compounds of Formula VIII wherein each Q1 is independently halo, oxo, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, =NOH, - uORx or -RuC(O)RX; each R11 is independently alkylene or a direct bond; each Rx is independently hydrogen or alkyl; and the other variables are as described ere herein.

In certain embodiments, ed herein are compounds of Formula IX QS‘QVVS\\ MAKIN/ng2 R3 / N / (Q1)_M or pharmaceutically acceptable salts, solvates, hydrates, clathrates, single stereoisomers, mixture of stereoisomers or racemic mixture of stereoisomers thereof, wherein: R3 is en or alkyl; each Q1 is independently deuterium, halo, cyano, oxo, thioxo, alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, aralkyl, aryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, -RuORX, - uORuN(Ry)(RZ), -RuN(Ry)(RZ), - RuSRX, - uC(J)Rx, - uC(J)ORX, - uC(J)N(Ry)(RZ), -RuS(O)tRW, -RuN(RX)C(J)RX, -RuN(RX)C(J)ORX, -RuN(RX)S(O)tRW, =NORd, or y)N(Ry)ORX, where the alkyl, haloalkyl, lkyl, alkenyl, alkynyl, cycloalkyl, lkenyl, aryl, heteroaryl, and cyclyl groups are optionally substituted with one or more Q3 groups, in one embodiment, one to three Q3 groups; each Q3 is independently selected from deuterium, halo, hydroxyl, alkyl, haloalkyl and hydroxyalkyl; Y is —(CR5R6)q-; R5 and R6 are each ndently hydrogen, halo, alkyl, haloalkyl or hydroxyalkyl; Z is O, S, or NH; W4 is N or CR1“); W5 is N or CR”; R11b and R13 are each independently hydrogen or Q2; each Q2 is independently halo, deuterium, cyano, oxo, thioxo, alkyl, haloalkyl, haloalkenyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cyclyl, heterocyclylalkyl, -RuORX, - uORuORX,-RuORuN(Ry)(RZ), - RuN(Ry)(RZ), -RuSRX, - uC(J)Rx, - uC(J)ORX, -RuC(J)N(Ry)(RZ), - uC(J)RuN(Ry)(RZ) , )N(Ry)ORX, -C(=NORX)RX’ uS(O)tRw, -RuN(RX)C(J)RX, -RuN(RX)C(J)ORX, -RuN(RX)S(O)tRW or —C(=NRy)N(Ry)ORX, where the alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl groups are optionally substituted with one or more groups Q4; in one embodiment, one to three Q4 groups, each Q4 is independently selected from halo, deuterium, yl, alkyl, haloalkyl and hydroxyalkyl; Q5 and Q6 are each ndently hydrogen, halo, cyano, alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, , -RuN(Ry)(RZ), - uSR", -RuC(J)RX, - uC(J)ORX, - RuC(J)N(Ry)(RZ), -RuS(O)tRW, -RuN(RX)C(J)RX, -RuN(RX)C(J)ORX, -RuN(RX)S(O)tRW or —C(=NRy)N(Ry)ORX, where the alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, lkenyl, aryl, heteroaryl, and cyclyl groups are optionally substituted with one or more Q8 groups; each Q8 is independently selected from halo, deuterium, hydroxyl, alkyl, kyl and hydroxyalkyl; Rd is hydrogen or alkyl; each R11 is independently alkylene, alkenylene or a direct bond; RW is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; each Rx is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cyanoalkyl, alkenyl, l, cycloalkyl, cycloalkenyl, lkylalkyl, cycloalkenylalkyl, heterocyclyl, heterocyclylalkyl, aryl, l, heteroaryl, or heteroaralkyl; Ry and RZ are each independently selected from (i) or (ii) below: (i) Ry and RZ are each independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; or (ii) Ry and RZ, together with the en atom to which they are attached, form a heterocyclyl or heteroaryl, optionally substituted with one or more, in one embodiment, one, two or three Q7 groups; each Q7 is independently selected from halo, deuterium, oxo, , y, alkoxy, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, 1 02 cycloalkenylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl; J is O, NRx or S; each t is ndently an r from 0-2; 11 is l or 2; and q is an integer from 0-4.

In certain embodiments, provided herein are nds of Formula IX or pharmaceutically acceptable salts, solvates, hydrates, clathrates, single stereoisomers, mixture of stereoisomers or racemic mixture of stereoisomers thereof, wherein: R3 is hydrogen or alkyl; each Q1 is independently halo, oxo, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, =NOH, - uORx or -RuC(O)RX; Y is —(CR5R6)q-; R5 and R6 are each independently hydrogen, halo, alkyl, haloalkyl or hydroxyalkyl; Z is O, S, or NH; W4 is N or CR1“); R11b is hydrogen, halo or alkyl; W5 is N or CR”; R13 is hydrogen, halo or alkyl; Q5 and Q6 are each independently hydrogen, halo, cyano, alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, -RuORX, y)(RZ), - uSR", -RuC(J)RX, - RX, - RuC(J)N(Ry)(RZ), -RuS(O)tRW, -RuN(RX)C(J)RX, -RuN(RX)C(J)ORX, -RuN(RX)S(O)tRW or —C(=NRy)N(Ry)ORX, Where the alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl groups are optionally substituted with one or more Q8 groups; each Q8 is ndently selected from halo, deuterium, hydroxyl, alkyl, kyl and hydroxyalkyl; each R11 is independently alkylene or a direct bond; RW is alkyl; each Rx is independently hydrogen or alkyl; Ry and RZ are each independently hydrogen or alkyl; J is O, NRx or S; each t is independently an integer from 0-2; 11 is l or 2; and q is an integer from 0-4.

In certain ments, provided herein are compounds of Formula IX wherein each Q1 is independently halo, oxo, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, =NOH, - uORx or -RuC(O)RX; each R11 is independently alkylene or a direct bond; each Rx is independently hydrogen or alkyl; R11b and R13 are each independently hydrogen, halo or alkyl; and the other variables are as described elsewhere herein. In certain embodiments, provided herein are compounds of Formula IX, wherein Q5 and Q6 are each independently hydrogen, halo, alkoxy, tetrazole or pyrazole, where the tetrazole and pyrazole rings are optionally substituted with one or more alkyl, and the other variables are as described elsewhere herein. In certain embodiments, Q5 and Q6 are each independently hydrogen, chloro, fluoro, bromo or methoxy, and the other les are as described elsewhere herein.

In n embodiments, provided herein are compounds of Formula X \ \ws \/ 2 R3 N / WrJ N/>—N\Y—R4X or pharmaceutically acceptable salts, solvates, es, ates, single isomers, mixture of stereoisomers or racemic mixture of isomers thereof, wherein: R3 is hydrogen or alkyl; R4 is lkyl, aryl, heterocyclyl or heteroaryl, where R4 is ally substituted with one or more, in one embodiment, one to three, in another embodiment, one, two or three groups selected from Q1; each Q1 is independently deuterium, halo, cyano, oxo, thioxo, alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, -RuORX, - uORuN(Ry)(RZ), -RuN(Ry)(RZ), - RuSRX, - uC(J)RX, - uC(J)ORX, - uC(J)N(Ry)(RZ), -RuS(O)tRW, -RuN(RX)C(J)RX, -RuN(RX)C(J)ORX, -RuN(RX)S(O)tRW, =NORd, or —C(=NRy)N(Ry)ORX, where the alkyl, kyl, aminoalkyl, alkenyl, alkynyl, lkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl groups are optionally substituted with one or more Q3 groups, in one embodiment, one to three Q3 groups; each Q3 is independently selected from deuterium, halo, hydroxyl, alkyl, kyl and hydroxyalkyl; each Rd is independently hydrogen or alkyl; each R11 is independently alkylene, alkenylene or a direct bond; RW is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, lkylalkyl, cycloalkenylalkyl, heterocyclyl, heterocyclylalkyl, aryl, l, aryl, or heteroaralkyl; each Rx is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cyanoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; Ry and RZ are each independently selected from (i) or (ii) below: (i) Ry and RZ are each independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; or (ii) Ry and RZ, together with the nitrogen atom to which they are attached, form a heterocyclyl or aryl, ally substituted with one or more, in one embodiment, one, two or three Q7 groups; each Q7 is independently selected from halo, deuterium, oxo, thioxo, hydroxy, alkoxy, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, lkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl; Y is —(CR5R6)q-; R5 and R6 are each independently hydrogen, halo, alkyl, haloalkyl or hydroxyalkyl; Z is O, S, or NH; W4 is N or CR1“); R11b is hydrogen or Q2; Q2 is halo, deuterium, cyano, oxo, thioxo, alkyl, haloalkyl, haloalkenyl, lkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, lkylalkyl, lkenylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, WO 56070 heterocyclylalkyl, -RuORX, - uORuORX,-RuORuN(Ry)(RZ), - RuN(Ry)(RZ), -RuSRX, - uC(J)R", - uC(J)ORX, -RuC(J)N(Ry)(RZ), - uC(J)RuN(Ry)(RZ) , -RuC(J)N(Ry)ORX, -C(=NORX)RX, RW, -RuN(RX)C(J)RX, X)C(J)ORX, - RuN(Rx)S(O)tRW or -C=(NRy)N(Ry)ORX, where the alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl groups are optionally substituted with one or more groups Q4; in one embodiment, one to three Q4 groups, each Q4 is independently selected from halo, deuterium, hydroxyl, alkyl, haloalkyl and hydroxyalkyl; W5 is N or CR”; R13 is en, halo or alkyl; and q is an integer from 0-4.

In certain embodiments, provided herein are compounds of Formula X wherein each Q1 is independently halo, oxo, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, =NOH, - uORx or -RuC(O)RX; each R11 is independently alkylene or a direct bond; each Rx is independently hydrogen or alkyl; and the other variables are as described elsewhere herein.

In certain ments, provided herein are compounds of Formula X or ceutically acceptable salts, solvates, hydrates, clathrates, single stereoisomers, mixture of stereoisomers or c mixture of stereoisomers thereof, wherein: R3 is en or alkyl; R4 is lkyl, aryl, heterocyclyl or heteroaryl, where R4 is optionally substituted with one or more, in one embodiment, one to three, in another embodiment, one, two or three groups selected from Q1; each Q1 is independently halo, oxo, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, =NOH, - uORx or -RuC(O)RX; each R11 is independently ne or a direct bond; each Rx is independently hydrogen or alkyl; Y is —(CR5R6)q-; R5 and R6 are each independently hydrogen, halo, alkyl, haloalkyl or hydroxyalkyl; Z is O, S, or NH; W4 is N or CR1“); R11b is hydrogen, halo or alkyl; W5 is N or CR”; R13 is hydrogen, halo or alkyl; and q is an integer from 0-4.

In n embodiments, provided herein are compounds of Formula XI at;O \ /WrJAEIf v0Z N I 2 N\ / or ceutically acceptable salts, solvates, hydrates, clathrates, single stereoisomers, mixture of stereoisomers or racemic mixture of stereoisomers thereof, wherein: R3 is hydrogen or alkyl; each Q1 is independently halo, oxo, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, =NOH, - uORx or -RuC(O)RX; each R11 is independently alkylene or a direct bond; each Rx is independently hydrogen or alkyl; Y is —(CR5R6)q-; R5 and R6 are each independently hydrogen, halo, alkyl, haloalkyl or yalkyl; Z is O, S, or NH; W4 is N or CR1“); R11b is hydrogen, halo or alkyl; W5 is N or CR”; R13 is hydrogen, halo or alkyl; and q is an integer from 0-4.

In certain embodiments, provided herein are compounds of Formula X1 or pharmaceutically acceptable salts, solvates, hydrates, ates, single stereoisomers, mixture of stereoisomers or racemic e of stereoisomers thereof, wherein: R3 is hydrogen or alkyl; each Q1 is independently halo, oxo, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, =NOH, - uORx or -RuC(O)RX; Y is —(CR5R6)q-; R5 and R6 are each independently hydrogen, halo, alkyl, haloalkyl or yalkyl; Z is O, S, or NH; W4 is N or CR1“); R11b is hydrogen, halo or alkyl; W5 is N or CR”; R13 is hydrogen, halo or alkyl; and q is an integer from 0-4.

In certain embodiments, ed herein are compounds of Formula XII R1 R2 \ F3 R11a_N \Y—R4 / N/: W6\A/ (02)a XII or pharmaceutically acceptable salts, solvates, es, clathrates, single stereoisomers, mixture of stereoisomers or racemic mixture of stereoisomers thereof, wherein: R3 is hydrogen or alkyl; R4 is cycloalkyl, aryl, heterocyclyl or heteroaryl, Where R4 is optionally substituted with one or more, in one embodiment, one to three, in another embodiment, one, two or three groups selected from Q1; each Q1 is independently halo, oxo, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, =NOH, - uORx or -RuC(O)RX; each R11 is ndently ne or a direct bond; each Rx is independently hydrogen or alkyl; Y is —(CR5R6)q-; R5 and R6 are each independently hydrogen, halo, alkyl, haloalkyl or hydroxyalkyl; Z is O, S, or NH; R1121 is hydrogen or alkyl; W6 is N or CR”; R14 is hydrogen or alkyl; a is 0-4; and q is an integer from 0-4.

In certain embodiments, provided herein are compounds of Formula XII or pharmaceutically acceptable salts, solvates, hydrates, clathrates, single stereoisomers, mixture of stereoisomers or racemic mixture of stereoisomers thereof, wherein: R3 is hydrogen or alkyl; R4 is cycloalkyl, Where R4 is ally tuted with hydroxy; Y is —(CR5R6)q-; R5 and R6 are each independently hydrogen, halo, alkyl, haloalkyl or hydroxyalkyl; Z is O, S, or NH; R1121 is hydrogen or alkyl; W6 is N or CR”; R14 is hydrogen or alkyl; a is 0-2; and q is an integer from 0-2.

In one embodiment, the compound provided herein is selected from: 2-((6-((lH—benzo[d]imidazol- l -yl)methyl)benzo [d]thiazol-Z- yl)amino)cyclohexanol, (lR,2R)((6-((5 ,6-dimethoxy- l H-benzo [d]imidazol- l - yl)methyl)benzo [d]thiazolyl)amino)cyclohexanol, 2-((6-((5 ,6-dimethoxy- l H-benzo [d]imidazol- l -yl)methyl)benzo [d]thiazol yl)amino)cyclohexanol, )((6-((3H-imidazo [4,5 -b]pyridinyl)methyl)benzo azol-2— yl)amino)cyclohexanol methanesulfonic acid, )((6-((3H-imidazo [4,5 -b]pyridinyl)methyl)benzo [d]thiazol-2— yl)amino)cyclohexanol 2-((6-((3H-imidazo [4 ,5 idin-3 -yl)methyl)benzo [d]thiazol yl)amino)cyclohexanol ( lR,2R)((6-((6-methoxy- l o [d]imidazol- l - yl)methyl)benzo [d]thiazolyl)amino)cyclohexanol, 2-((6-((6-methoxy- l H-benzo [d]imidazol- l -yl)methyl)benzo [d]thiazol yl)amino)cyclohexanol, ( lR,2R)((6-((5-methoxy- l o [d]imidazol- l - yl)methyl)benzo [d]thiazolyl)amino)cyclohexanol, 2-((6-((5 -rneth0xy- 1 H-benzo [d]imidazol- 1 thy1)benzo [d]thiaz01—2- yl)amino)cyclohexanol, (1R,2R)((6-(( 1 H-irnidazo [4,5 -b]pyridiny1)rnethy1)benzo[d]thiaz01—2- no)cyclohexanol, 2-((6-(( 1 H-irnidazo [4 ,5 -b]pyridiny1)rnethy1)benzo[d]thiaz01—2- yl)amino)cyclohexanol, (1R,2R)((6-((1H-benz0[d]irnidazoly1)rnethyl)benzo[d]thiaz01—2- yl)amino)cyclohexanol, 2-((6-(( 1 dazo [4 ,5 -b]pyridiny1)rnethy1)benzo[d]thiaz01—2- yl)amino)cyclohexanol, (1S,2S)((6-((1H-benzo[d]irnidazoly1)rnethy1)benzo[d]thiaz01—2- yl)amino)cyclohexanol, ((1H-benz0[d]imidazol- 1 ethy1)benzo[d]thiaz01—2- yl)amino)cyclohexanol, (R)((5 ,6-dirnethoxy-1H-benz0[d]imidazoly1)rnethyl)-N- ((tetrahydrofuran-Z-y1)rnethyl)benzo [d]thiaz01—2-arnine, 6-((5 ,6-dirnethoxy-1H-benzo[d]imidazoly1)rnethy1)—N—((tetrahydrofuran-Z- y1)rnethyl)benzo [d]thiaz01—2-arnine, 6-((5 ,6-dirnethoxy-1H-benz0[d]irnidazoly1)rnethy1)—N—(pyridin ylmethyl)benzo[d]thiaz01—2-arnine, (1R,2S)—1-((6-((5 ,6-dirnethoxy-1H-benz0[d]irnidazol y1)rnethyl)benzo [d]thiaz01—2-yl)amino)-2,3 -dihydr0-1H-indenol, 1-((6-((5 ,6-dirnethoxy-1H-benz0[d]irnidazoly1)rnethy1)benzo[d]thiaz01—2- y1)arnino)-2,3 -dihydr0-1H-indenol, (S)—N—(2,3 -dihydr0-1H-indenyl)((5 ,6-dirnethoxy-1H-benz0[d]irnidazoly1)rnethy1)benzo [d]thiaz01—2-arnine, N—(2,3-dihydr0-1H-indenyl)((5 ,6-dirnethoxy-1H-benz0[d]irnidazol y1)rnethyl)benzo [d]thiaz01—2-arnine, (1R,2R)((6-(rnethoxy(1H-pyrr010[2,3-b]pyridin-3 - y1)rnethyl)benzo [d]thiaz01—2-yl)amino)cyclohexanol, 2-((6-(rnethoxy(1H-pyrr010[2 ,3 -b]pyridin-3 ethy1)benz0 [d]thiaz01—2— yl)amino)cyclohexanol, N—benzyl((5 ,6-dirnethoxy-1H-benz0[d]irnidazol y1)rnethyl)benzo [d]thiaz01—2-arnine, 1 1 0 6-((5 ,6-dirncthoxy-1H—bcnz0[d]irnidazoly1)rncthy1)—N—(2- morpholinocthyl)bcnzo[d]thiaz01—2-arninc, 6-((5 ,6-dirncthoxy- z0 [d]irnidaz01— 1 cthy1)—N—(tctrahydro-ZH— pyrany1)bcnz0 [d]thiaz01—2-arninc, N—cyclohcxyl((5 ,6-dirncthoxy-1H-bcnzo[d]irnidazoly1)rncthy1)-N— methylbcnzo[d]thiaz01—2-arninc, ( 1R,2R)((6-((1H-pyrr010 [2,3 -b]pyridin-3 -y1)rncthy1)bcnzo [d]thiaz01—2— y1)arnino)cyclohcxanol, 2-((6-((1H-pyrr010 [2,3 -b]pyridin-3 -y1)rncthy1)bcnzo [d]thiaz01—2— y1)arnino)cyclohcxanol, N—cyclohcxyl((5 ,6-dirncth0xy-1H-bcnz0[d]irnidazol y1)rncthy1)bcnzo[d]thiazolarninc, (1R,2R)((6-((5 ,6-dirncth0xy-1H-bcnz0[d]irnidazol thy1)bcnzo[d]thiaz01y1)arnino)-2,3-dihydr0-1H-indcnol, 1-((6-((5 ,6-dirncthoxy-1H-bcnz0[d]irnidaz01—1-y1)rncthy1)bcnzo[d]thiaz01—2- yl)arnin0)-2,3 -dihydr0-1H-indcnol, (1R,2R)((6-((5 ,6-dirncth0xy-1H-bcnz0[d]irnidazol yl)rncthy1)bcnzo[d]thiaz01y1)arnino)cyclopcntanol, 2-((6-((5 ,6-dirncthoxy-1H-bcnz0[d]irnidaz01—1-y1)rncthy1)bcnzo[d]thiaz01—2- in0)cyclopcntanol, 6-((5 cthoxy-1H-bcnz0[d]irnidazoly1)rncthy1)—N—(pyridin ylmcthyl)bcnz0[d]thiaz01—2-arninc, 6-((5 ,6-dirncthoxy-1H-bcnzo[d]irnidazoly1)rncthy1)—N— bcnzo[d]thiaz01—2-arninc, (1R,2R)((6-((5-rncth0xy-3H-irnidaz0 [4,5 -b]pyridin—3 - yl)rncthy1)bcnzo[d]thiaz01y1)arnin0)cyc10hcxan01, 2-((6-((5 -rncthoxy-3H-irnidazo [4,5 -b]pyridin-3 -y1)rncthy1)bcnzo [d]thiaz01—2— y1)arnino)cyclohcxanol, 1-(4-((6-((5 ,6-dirncth0xy-1H-bcnz0[d]irnidazoly1)rncthy1)bcnzo[d]thiaz01— 2-y1)arnin0)pipcridiny1)cthan0nc acetic acid, 1-(4-((6-((5 ,6-dirncth0xy-1H-bcnz0[d]irnidazoly1)rncthy1)bcnzo[d]thiaz01— 2-y1)arnino)pipcridinyl)cthanonc, (R, S)—6-((5 ,6-dirncthoxy-1H-bcnz0[d]irnidazoly1)rncthy1)—N— (tctrahydrofuran-3 -y1)bcnz0[d]thiaz01—2-arninc acetic acid, 1 1 1 (R, S)—6-((5 ,6-dirnethoxy-1H-benz0[d]irnidazoly1)rnethy1)—N— (tetrahydrofurany1)benz0 [d]thiaz01—2-arnine, 6-((5 ,6-dirnethoxy-1H-benzo[d]imidazol- 1 ethyl)-N-(tetrahydrofuran-3 - yl)benz0 [d]thiaz01—2-arnine, 3 -((2-(((1R,2R)hydr0xycyclohexy1)amino)benzo[d]thiaz01—6-yl)rnethyl)- 3H-irnidaz0 [4,5 -b]pyridinarniniurn acetate, (1R,2R)((6-((2-amino-3H-irnidazo [4,5 idin-3 - yl)methyl)benzo[d]thiazo1—2-y1)arnin0)cyclohexanol, 2-((6-((2-arnino-3H-irnidazo [4,5 idin-3 -y1)rnethyl)benzo [d]thiaz01—2— yl)arnino)cyclohexanol, 6-((5 ,6-dirnethoxy-1H-benz0[d]irnidazoly1)rnethy1)—N—(2- ethoxyphenyl)benzo[d]thiaz01—2-arnine, N—(cyclohexylmethy1)((5,6-dimethoxy-1H—benzo[d]irnidazol y1)rnethy1)benzo[d]thiazolarnine, (1R,2R)((6-((6-brorn0-3H-imidaz0 [4,5 -b]pyridin-3 - yl)methyl)benzo[d]thiazo1—2-y1)arnin0)cyclohexanol, 2-((6-((6-br0rn0-3H-irnidazo [4,5 -b]pyridin—3 -y1)rnethy1)benzo [d]thiaz01—2— yl)arnino)cyclohexanol, 6-((5 nethoxy-1H—benzo[d]imidazoly1)rnethy1)—N—(2- methoxypheny1)benzo[d]thiaz01—2-arnine, 2-((6-((5 ,6-dirnethoxy-1H—benz0[d]irnidazoly1)rnethy1)benzo[d]thiaz01—2- yl)amino)phenol, (1R,2R)((6-((4-(1-methy1—1H—pyrazoly1)-lH-irnidazol yl)methyl)benzo[d]thiazol-Z-yl)arnino)—2,3-dihydr0-1H—indenol, 1 -((6-((4-(1 -rnethy1— 1H-pyraz01—4-yl)- 1H-irnidaz01— 1 - yl)methyl)benzo[d]thiazol-Z-yl)arnino)—2,3-dihydr0-1H—indenol, (1R,2R)((6-((5 -( 1 -methyl- 1H-pyraz01—4-y1)-1H-irnidaz01— 1 - hyl)benzo[d]thiazol-Z-yl)arnino)—2,3-dihydr0-1H—indenol, 1-((6-((5 -(1 -methyl- 1H-pyraz01—4-yl)- 1H-irnidaz01— 1 - hyl)benzo[d]thiazol-Z-yl)arnino)—2,3-dihydr0-1H—indenol, (S)-N—( 1 -cyclohexylethy1)((5 ,6-dirnethoxy-1H—benzo[d]imidazol y1)rnethy1)benzo[d]thiazolarnine, N—( 1 -cyclohexylethy1)—6-((5 ,6-dirnethoxy-1H—benzo[d]irnidazol y1)rnethy1)benzo[d]thiazolarnine, 1 1 2 (1R,2R)((6-((5 ,6-dirnethoxy-1H—benz0[d]irnidazol yl)methyl)benzo[d]oxazol-Z-yl)arnino)cyclohexanol, 2-((6-((5 ,6-dirnethoxy-1H—benzo[d]imidazoly1)rnethyl)benzo[d]0xaz01—2- yl)arnino)cyclohexanol, N—(cyclohexylmethy1)((5,6-dimethoxy-1H—benzo[d]irnidazol yl)methyl)benzo[d]0xaz01—2-arnine, ( 1R,2R)((6-((4-( 1 -methyl- 1H-pyraz01—4-y1)-1H-irnidaz01— 1 - yl)rnethyl)benzo[d]thiaz01—2-y1)arnino)cyclohexanol, 2-((6-((4-(1 -rnethy1— 1H-pyraz01—4-yl)- 1H-irnidaz01— 1 - yl)rnethyl)benzo[d]thiaz01—2-y1)arnino)cyclohexanol, 1 -((2-(((1R,2R)hydroxycyclohexyl)amino)benzo[d]thiazoly1)rnethyl)-N— methyl-1H—imidazolecarboxarnide, 1 (2-hydr0xycyclohexyl)amino)benzo [d]thiaz01y1)rnethy1)—N—rnethy1— 1H-irnidazo16carboxarnide (1R,2R)((6-(irnidazo[1 ,2-a]pyridiny1methyl)benzo [d]thiaz01—2- yl)arnino)cyclohexanol, 2-((6-(irnidaz0[1 ,2-a]pyridiny1methyl)benzo [d]thiaz01—2- yl)arnino)cyclohexanol, (1R, ((6-((6-( 1 -methyl- 1 H-pyraz01y1)-3H-irnidazo[4,5 -b]pyridin-3 - yl)methyl)benzo[d]thiazo1y1)arnin0)cyclohexanol, 2-((6-((6-(1-rnethy1—1H-pyrazoly1)—3H-irnidazo[4,5 idin-3 - yl)methyl)benzo[d]thiazo1y1)arnin0)cyclohexanol, (1R,2R)((6-((6-(pyridin-3 -y1)-3H—irnidazo [4,5 -b]pyridin-3 - yl)rnethyl)benzo[d]thiaz01—2-y1)arnino)cyclohexanol, ((6-(pyridin—3 -y1)-3H—irnidazo [4,5 -b]pyridin-3 - thyl)benzo[d]thiaz01—2-y1)arnino)cyclohexanol, )((6-((5-brorn0rnethoxy-1H—benz0[d]irnidazol yl)rnethyl)benzo[d]thiaz01—2-y1)arnino)cyclohexanol, 2-((6-((5 -brornornethoxy-1H—benzo[d]irnidazol yl)rnethyl)benzo[d]thiaz01—2-y1)arnino)cyclohexanol, (1R,2R)((6-((6-brorn0-3H—imidazo[4,5-b]pyridin-3 - yl)methyl)benzo[d]thiazol-Z-yl)arnino)—2,3-dihydr0-1H—indenol, 1-((6-((6-brorno-3H—imidazo [4,5 -b]pyridin-3 -y1)rnethy1)benzo [d]thiaz01—2— yl)arnin0)-2,3 -dihydr0-1H—indenol, 1 1 3 3 -((2-(((1R,2R)hydr0xycyclohexyl)amino)benzo[d]thiaz01—6-yl)rnethyl)- 3H-irnidaz0 [4,5 -b]pyridinecarbonitrile, 3 -((2-((2-hydr0xycyc10hexy1)arnino)benzo[d]thiaz01—6-yl)methyl)-3H- imidazo [4,5 -b]pyridinecarbonitrile, (1R,2R)((6-((7-rnethoxyirnidazo[1 ,2-a]pyridin-3 -y1)rnethy1)benzo [d]thiaz01— 2-yl)amino)cyclohexanol, 2-((6-((7-methoxyimidazo[1 ,2-a]pyridiny1)rnethyl)benzo [d]thiaz01—2— yl)arnino)cyclohexanol, (1R,2R)((6-((6-cyc10propy1—3H—imidazo [4,5 -b]pyridin—3 - yl)rnethyl)benzo[d]thiaz01—2-y1)arnino)cyclohexanol, 2-((6-((6-cyclopr0py1—3H—imidazo [4,5 -b]pyridin-3 -y1)rnethy1)benzo [d]thiaz01— 2-yl)amino)cyclohexanol, (1R,2R)((6-((3H—irnidazo[4,5 -b]pyridin—3 -y1)rnethy1)benzo [d]thiaz01—2— yl)arnin0)-2,3 -dihydr0-1H—indenol, 1-((6-((3H—imidazo [4,5 idin-3 -y1)rnethy1)benzo azolyl)arnino)— 2,3 -dihydr0-1H—indenol, (1R,2R)((6-((6-br0rn0rnethoxy-1H—benz0[d]irnidazol yl)rnethyl)benzo[d]thiaz01—2-y1)arnino)cyclohexanol, 2-((6-((6-brornornethoxy-1H—benzo[d]irnidazol yl)rnethyl)benzo[d]thiaz01—2-y1)arnino)cyclohexanol, ( 1R,2R)-2—((6-((9H—puriny1)rnethyl)benzo [d]thiaz01—2— ino)cyclohexanol, 2-((6-((9H—puriny1)rnethyl)benzo[d]thiazo1—2-y1)amino)cyclohexanol, (1R,2R)((6-((5-brorn0rnethoxy-1H—benz0[d]irnidazol yl)methyl)benzo[d]thiazol-Z-yl)arnino)—2,3-dihydr0-1H—indenol, 1-((6-((5 -brornornethoxy-1H—benzo[d]irnidazol yl)methyl)benzo[d]thiazol-Z-yl)arnino)—2,3-dihydr0-1H—indenol, 1R,2R)(1S,2S)—2-((6-((5 ,6-dirnethoxy-1H—benzo[d]irnidazol thy1)benzo[d]thiazo1—2-yl)arnin0)cycloheptanol, 2-((6-((5 ,6-dirnethoxy-1H—benz0[d]irnidazoly1)rnethy1)benzo[d]thiaz01—2- in0)cycloheptanol, (1R,2R)((6-((6-rnethoxy-5 -( 1 -methyl- 1H—pyraz01—4-yl)- 1H- benzo[d]irnidazoly1)rnethy1)benzo [d]thiaz01—2-yl)amino)cyclohexanol, ((6-rnethoxy(1-rnethy1—1H—pyraz01—4-y1)—1H—benz0[d]irnidazol yl)rnethyl)benzo[d]thiaz01—2-y1)arnino)cyclohexanol, )((6-((5 -rnethoxy(1-rnethy1—1H—pyraz01—4-yl)- 1H- benzo[d]irnidazoly1)rnethy1)benzo [d]thiaz01—2-yl)amino)cyclohexanol, 2-((6-((5 -rneth0xy(1-rnethy1—1H—pyraz01—4-yl)—1H—benzo[d]imidazol yl)rnethyl)benzo[d]thiaz01—2-y1)arnino)cyclohexanol, 1-((2-((( 1R,2R)hydr0xycyclohexyl)amino)benzo[d]thiaz01—6-yl)methy1)-5 - y- 1H-benz0[d]imidazo16carbonitrile, 1 -((2-((2-hydr0xycyc10hexy1)arnino)benzo[d]thiaz01—6-yl)methy1)rneth0xy- 1H-benz0[d]imidazolecarbonitrile, (R)((6-((3H-irnidaz0 [4,5 -b]pyridin-3 -y1)rnethy1)benzo [d]thiaz01—2— yl)amino)cyclohexanone, 2-((6-((3H-irnidazo [4,5 -b]pyridin-3 -y1)rnethy1)benzo[d]thiaz01—2- yl)amino)cyclohexanone, (1R,2R)((6-((6-ch10r0-3H—imidazo [4,5 -b]pyridin-3 - yl)rnethyl)benzo[d]thiaz01—2-y1)arnino)cyclohexanol, 2-((6-((6-chlor0-3H—irnidazo [4,5 -b]pyridin-3 -y1)rnethyl)benzo [d]thiaz01—2- yl)arnino)cyclohexanol, (1R,2R)((6-((3H—irnidazo [4,5 -b]pyridin—3 -y1)rnethy1)benzo [d]0xaz01—2- yl)arnino)cyclohexanol, 2-((6-((3H—irnidazo [4,5 -b]pyridin-3 -y1)rnethy1)benzo [d]0xaz01—2- yl)arnino)cyclohexanol, (1R,2R)((6-((3H—irnidazo[4,5 -b]pyridin—3 -y1)rnethy1)benzo z01—2- yl)arnin0)-2,3 -dihydr0-1H—indenol, 1-((6-((3H—imidazo [4,5 -b]pyridin-3 -y1)rnethy1)benzo [d]oxaz01—2-y1)arnino)- 2,3 -dihydr0-1H—indenol, (R)((6-((3H-irnidaz0 [4,5 -b]pyridin-3 ethy1)benzo [d]thiaz01—2— yl)amino)cyclohexanone oxirne, 2-((6-((3H-irnidazo [4,5 -b]pyridin-3 thy1)benzo [d]thiaz01—2- yl)amino)cyclohexanone oxirne, (1S,2R)—2-((6-((3H-irnidazo [4,5 -b]pyridiny1)methy1)benzo [d]thiaz01—2- yl)arnin0)rnethy1cyclohexanol, (1R,2R)((6-((3H-irnidazo [4,5 idin-3 -y1)rnethy1)benzo [d]thiaz01—2— yl)arnin0)rnethy1cyclohexanol, 1 1 5 2-((6-((3H-irnidazo [4,5 -b]pyridin-3 -y1)rnethy1)benzo[d]thiaz01—2—yl)amino)— 1 - cyclohexanol, (1R,2R)((6-((6-brorno-3H—imidazo [4,5 -b]pyridin-3 - hyl)benzo[d]oxazol-Z-yl)arnino)cyclohexanol, 2-((6-((6-br0rn0-3H—irnidazo [4,5 idin-3 -y1)rnethy1)benzo [d]0xaz01—2- yl)arnino)cyclohexanol, )((6-((6-brorn0-3H—imidazo[4,5-b]pyridin-3 - y1)rnethy1)benzo[d]0xazolyl)arnino)-2,3-dihydr0-1H—indenol, ((6-brorno-3H—imidazo [4,5 -b]pyridin-3 -y1)rnethy1)benzo [d]0xaz01—2- yl)arnin0)-2,3 -dihydr0-1H—indenol, (S)((6-((3H—irnidazo [4,5 -b]pyridin-3 -y1)rnethy1)benzo[d]thiaz01—2- yl)arnino)cyclohexylethanol, 2-((6-((3H—irnidazo [4,5 -b]pyridin-3 -y1)rnethy1)benzo [d]thiaz01—2-yl)amino) cyclohexylethanol, (R)((6-((3H—irnidazo [4,5 -b]pyridin-3 -y1)rnethy1)benzo [d]thiaz01—2— yl)arnino)cyclohexylethanol, 1-((2-(((1R,2R)hydr0xycyclohexyl)amino)benzo[d]thiazoly1)rnethyl) methoxy- 1H-benz0[d]irnidazole-5 -carb0nitrile, 1 -((2-((2-hydr0xycyc10hexyl)arnino)benzo[d]thiazo1—6-y1)methy1)methoxy- 1H-benz0[d]irnidazole-5 -carb0nitrile, ((1R,2R)((6-((3H—irnidazo[4,5 -b]pyridin-3 -y1)rnethy1)benzo[d]thiaz01—2- yl)amino)cyclohexyl)methanol, 2-((6-((3H—irnidazo [4,5 -b]pyridin-3 -y1)rnethy1)benzo [d]thiaz01—2- yl)amino)cyclohexyl)methanol, (1R,2R)((6-((6-rnethoxy-1H—benzo[d]irnidazol yl)rnethyl)benzo[d]thiaz01—2-y1)arnino)cyclohexanol, 2-((6-((6-rnethoxy-1H—benz0[d]irnidazoly1)rnethyl)benzo[d]thiazol yl)arnino)cyclohexanol, (1R,2R)((6-((5-rnethoxy-1H—benz0[d]irnidazol yl)rnethyl)benzo[d]thiaz01—2-y1)arnino)cyclohexanol, 2-((6-((5 -rneth0xy-1H—benz0[d]imidazoly1)rnethyl)benzo[d]thiazol yl)arnino)cyclohexanol, (1R,2R)((6-((6-fluoro-3H—irnidazo[4,5-b]pyridin-3 - yl)methyl)benzo[d]thiazol-Z-yl)arnino)—2,3-dihydr0-1H—indenol, 1 1 6 1-((6-((6-fluoro-3H—imidazo [4,5 -b]pyridin-3 -y1)rnethy1)benzo [d]thiaz01—2— yl)arnin0)-2,3 -dihydr0-1H—indenol, (1R,2R)((6-((6-flu0r0-3H—imidazo [4,5-b]pyridin-3 - yl)rnethyl)benzo[d]thiaz01—2-y1)arnino)cyclohexanol, 2—((6-((6-fluor0-3H—imidazo [4,5 -b]pyridin-3 -y1)rnethy1)benzo [d]thiaz01—2— yl)arnino)cyclohexanol, )((6-((3H-irnidazo [4,5 -c]pyridin—3 -y1)rnethy1)benzo az01—2- yl)arnino)cyclohexanol, 2-((6-((3H-irnidazo [4,5 -c]pyridin-3 -y1)methy1)benzo [d]thiaz01—2- yl)arnino)cyclohexanol, (1R,2R)((6-((1H-irnidazo[4,5 -c]pyridin— 1 -y1)rnethy1)benzo [d]thiaz01—2- yl)arnino)cyclohexanol, 2-((6-((1H-irnidaz0[4,5 -c]pyridiny1)rnethy1)benz0[d]thiaz01—2- yl)arnino)cyclohexanol, 1-(3 -((2-(((1R,2R)hydr0xycyclohexy1)amino)benzo[d]thiaz01—6-yl)rnethyl)- idaz0 [4,5 -b]pyridinyl)ethanone, 1 -(3 -((2-((2-hydr0xycyclohexyl)arnino)benzo[d]thiaz01—6-y1)methyl)-3H- imidazo [4,5 -b]pyridinyl)ethanone, (1R,2R)((6-((6-(rnethylsulfonyl)-3H—irnidazo [4,5 -b]pyridin-3 - yl)rnethyl)benzo[d]thiaz01—2-y1)arnino)cyclohexanol, 2-((6-((6-(rnethylsulfonyl)-3H—imidazo [4,5 -b]pyridin-3 - yl)rnethyl)benzo[d]thiaz01—2-y1)arnino)cyclohexanol, 1-(((6-((3H—irnidazo [4,5 -b]pyridin-3 -y1)rnethy1)benzo [d]thiaz01—2— yl)amino)rnethyl)cyclohexanol, (1 ((3H—irnidaz0[4,5 -b]pyridin-3 -y1)rnethy1)benzo [d]thiaz01—2— yl)amino)rnethyl)cyclohexyl)methanol, ( 1R,2R)((6-((4-( 1 -methyl- 1H-pyraz01—4-y1)-1H-irnidaz01— 1 - yl)methyl)benzo[d]oxazol-Z-yl)arnino)cyclohexanol, ((4-(1 -rnethy1— az01—4-yl)- 1H-irnidaz01— 1 - yl)methyl)benzo[d]oxazol-Z-yl)arnino)cyclohexanol, )((6-((5-br0rno-3H—irnidazo [4,5 -b]pyridin-3 - yl)rnethyl)benzo[d]thiaz01—2-y1)arnino)cyclohexanol, 2-((6-((5 -br0rn0-3H—irnidazo [4,5 -b]pyridin-3 -y1)rnethy1)benzo [d]thiaz01—2— yl)arnino)cyclohexanol, 1 1 7 methyl 3-((2-(((1R,2R)hydr0xycyclohexy1)amino)benzo [d]thiaz01—6- yl)rnethy1)—3H—irnidazo [4 ,5 -b]pyridinecarboxy1ate, methyl 3-((2-((2-hydr0xycyclohexyl)amino)benzo [d]thiazoly1)rnethy1)—3H— imidazo [4,5 -b]pyridinecarboxy1ate, (1R,2R)((6-((5-br0rno-3H—irnidazo [4,5 -b]pyridin-3 - y1)rnethyl)benzo [d]thiazol-Z-yl)amino)—2,3 -dihydr0-1H—indenol, 1-((6-((5 -br0rn0-3H—irnidazo [4 ,5 -b]pyridin-3 -y1)rnethy1)benzo [d]thiaz01—2— y1)arnino)-2,3 -dihydr0-1H—indenol, 3 -((2-(((1R,2R)hydr0xycyclohexyl)amino)benzo[d]thiaz01—6-yl)rnethyl)- 3H-irnidaz0 [4,5 -b]pyridinecarboxylic acid, 3 -((2-((2-hydr0xycyc10hexy1)arnino)benzo[d]thiaz01—6-yl)methyl)-3H- imidazo [4,5 -b]pyridinecarboxylic acid, (1R,2R)((6-((6-(rnorpho1in0rnethyl)—3H-imidazo [4,5 idin-3 - y1)rnethyl)benzo az01—2-yl)amino)cyclohexanol, 2-((6-((6-(m0rpholinornethyl)-3H-imidazo [4 ,5 -b]pyridin—3 - y1)rnethyl)benzo [d]thiaz01—2-yl)amino)cyclohexanol, (1R,2R)((6-((6-(hydr0xyrnethy1)—3H—irnidazo [4,5 -b]pyridin-3 - thy1)benzo[d]thiaz01—2-y1)amino)cyclohexanol, 2-((6-((6-(hydroxyrnethyl)-3H—irnidazo [4 ,5 -b]pyridin-3 - y1)rnethy1)benzo[d]thiaz01—2-y1)amino)cyclohexanol, (1R,2R)((6-((6-(rnethylthio)-3H-imidazo [4,5 -b]pyridin-3 - y1)rnethyl)benzo [d]thiaz01—2-yl)amino)cyclohexanol, 2-((6-((6-(methylthio)-3H-irnidazo [4 ,5 -b]pyridin-3 -y1)rnethyl)benzo [d]thiaz01— 2-yl)amino)cyclohexanol, )((6-((6-((rnethylthi0)rnethy1)-3H-irnidazo[4,5 -b]pyridin-3 - y1)rnethyl)benzo [d]thiaz01—2-yl)amino)cyclohexanol, 2-((6-((6-((methy1thi0)methyl)—3H-irnidazo [4,5 -b]pyridin-3 - y1)rnethyl)benzo [d]thiaz01—2-yl)amino)cyclohexanol, 3 ((1R,2R)hydr0xycyclohexyl)amino)benzo[d]thiaz01—6-yl)rnethyl)- idaz0 [4,5 -b]pyridine-5 -carb0nitrile, 3 -((2-((2-hydr0xycyc10hexy1)arnino)benzo[d]thiaz01—6-yl)methyl)-3H- imidazo [4,5 -b]pyridine-5 -carb0nitrile, 1-(3 -((2-(((1R,2R)hydr0xycyclohexy1)amino)benzo[d]thiaz01—6-yl)rnethyl)- 3H-irnidaz0 [4 5 -b]pyridin-5 -y1)ethanone, 1 1 8 1 -(3 -((2-((2-hydr0xycyclohexyl)amin0)benzo [d]thiazoly1)rnethy1)—3H— imidazo [4,5 -b]pyridin-5 -y1)ethanone 3 -((2-(((1R,2R)hydroxycyclohexyl)amino)benzo[d]thiazoly1)rnethyl)-N— methyl-3H—imidazo[4,5-b]pyridinecarboxamide, 3 -((2-((2-hydr0xycyc10hexy1)arnino)benzo[d]thiaz01—6-y1)rnethy1)—N—rnethy1— 3H-irnidaz0 [4,5 -b]pyridinecarboxarnide, N—hydroxy((2-(((1R,2R)-2—hydroxycyclohexyl)amino)benzo[d]thiaz01—6- yl)rnethyl)-3H-imidazo [4 ,5 -b]pyridinecarboxirnidarnide, (1R,2R)-2—((6-((6-(aminornethy1)—3H-irnidazo [4,5 idin-3 - y1)rnethyl)benzo [d]thiaz01—2-yl)amino)cyclohexanol acetic acid, (1R,2R)-2—((6-((6-(aminornethy1)—3H-irnidazo [4,5 -b]pyridin-3 - thyl)benzo [d]thiaz01—2-yl)amino)cyclohexanol, 2-((6-((6-(aminornethyl)-3H-irnidazo [4,5 -b]pyridin-3 - y1)rnethyl)benzo [d]thiaz01—2-yl)amino)cyclohexanol, 3 -((2-(((1R,2R)hydr0xycyclohexyl)amino)benzo[d]thiaz01—6-yl)rnethyl)- N,N-dirnethy1—3H—irnidazo [4,5 idinecarboxarnide, 3 -((2-((2-hydr0xycyc10hexy1)arnino)benzo[d]thiazo1—6-y1)rnethy1)—N,N— dimethyl-3H—irnidazo [4,5-b]pyridinecarboxamide , (1R,2R)((6-((6-(2H-tetrazol-5 -y1)-3H-irnidaz0 [4,5 -b]pyridin-3 - y1)rnethyl)benzo az01—2-yl)amino)cyclohexanol, 2-((6-((6-(2H-tetrazol-5 -y1)-3H-irnidaz0 [4,5 -b]pyridin-3 - y1)rnethyl)benzo [d]thiaz01—2-yl)amino)cyclohexanol, )((6-((6-(2-rnethy1—2H-tetrazol-5 -y1)-3H-irnidaz0 [4,5 -b]pyridin-3 - y1)rnethyl)benzo [d]thiaz01—2-yl)amino)cyclohexanol, 2-((6-((6-(2-methy1—2H-tetrazol-5 -y1)-3H-irnidaz0 [4,5 idin-3 - y1)rnethyl)benzo [d]thiaz01—2-yl)amino)cyclohexanol, (1R,2R)((6-((6-(1 -rnethy1— 1H-tetraz01—5 -y1)-3H-irnidaz0 [4,5 -b]pyridin-3 - y1)rnethyl)benzo az01—2-yl)amino)cyclohexanol, 2-((6-((6-(1 -rnethy1— 1H-tetraz01—5 -y1)-3H-irnidaz0 [4,5 -b]pyridin-3 - y1)rnethyl)benzo [d]thiaz01—2-yl)amino)cyclohexanol, (1R,2R)((6-((9H—puriny1)rnethyl)benzo[d]thiaz01—2-y1)arnino)—2 ,3-dihydro-1H— inden-Z-ol, ((9H—puriny1)rnethy1)benzo[d]thiaz01—2-yl)amino)-2,3-dihydr0-1H— inden-Z-ol, (1R,2R)((6-((6-ethyny1—3H-irnidazo [4,5 -b]pyridin-3 - yl)methyl)benzo[d]thiazo1—2-y1)arnin0)cyclohexanol, 2-((6-((6-ethynyl-3H-imidazo [4,5 -b]pyridiny1)methy1)benzo [d]thiaz01—2- yl)arnino)cyclohexanol, (1R,2R)((6-((6-rnorpholino-3H-irnidazo [4,5 -b]pyridin-3 - yl)methyl)benzo[d]thiazo1—2-y1)arnin0)cyclohexanol, 2-((6-((6-rn0rpholino-3H-irnidazo [4,5 -b]pyridin-3 -y1)rnethy1)benzo [d]thiaz01— 2-yl)amino)cyclohexanol, )((6-((6-Vinyl-3H-imidazo [4,5 -b]pyridin-3 - yl)methyl)benzo[d]thiazo1—2-y1)arnin0)cyclohexanol, 2-((6-((6-Viny1-3H-irnidazo [4,5 -b]pyridiny1)rnethy1)benzo[d]thiaz01—2- yl)arnino)cyclohexanol, N—((3 -((2-((( 1 R,2R)hydr0xycyclohexy1)amino)benzo [d]thiaz01—6- yl)methy1)-3H-irnidazo [4,5 -b]pyridinyl)methyl)acetarnide, N—((3-((2-((2-hydr0xycyc10hexy1)arnino)benzo[d]thiazoly1)rnethyl)-3H- imidazo [4,5 -b]pyridiny1)methyl)acetarnide, (1R,2R)((6-((5 -br0rn0- 1H-benz0 [d]imidazoly1)rnethy1)benzo [d]thiaz01— 2-yl)amino)cyclohexanol, 2-((6-((5 -br0rno-1H—benz0[d]imidazoly1)methyl)benzo[d]thiaz01—2- yl)arnino)cyclohexanol, N—( 1 -((2-(((1R,2R)hydr0xycyclohexy1)amino)benzo [d]thiaz01—6-yl)rnethyl)- 1H—imidazo1—4-yl)acetarnide, N—( 1 -((2-((2-hydr0xycyclohexy1)amino)benzo[d]thiaz01—6-yl)rnethyl)- 1H- imidazolyl)acetarnide, )((6-((6-ethy1—3H-irnidazo [4,5 -b]pyridin-3 - hyl)benzo[d]thiazo1—2-y1)arnin0)cyclohexanol, 2-((6-((6-ethyl-3H-imidazo [4,5 -b]pyridin-3 -y1)rnethy1)benzo [d]thiaz01—2— yl)arnino)cyclohexanol, 1 -((2-((( 1R,2R)hydr0xycyclohexy1)amino)benzo[d]thiaz01—6-y1)rnethy1)-3 - (1 -methyl- azo1—4-y1)pyrazin-2(1H)—0ne, and 1 (2-hydr0xycyc10hexy1)arnino)benzo[d]thiazolyl)rnethyl)-3 -(1 - methyl-1H-pyrazoly1)pyrazin-2(1H)-0ne. 1 20 In one embodiment, the compound provided herein is selected from: (1R,2R)((6-((6-(3-hydroxymethy1butyny1)-3H-imidazo[4,5 - b]pyridiny1)methy1)benzo[d]thiazo1y1)amino)cyclohexano1; ((6-(3-hydroxymethy1butyny1)-3H-imidazo[4,5-b]pyridin—3 - y1)methy1)benzo[d]thiazo1y1)amino)cyclohexanol; (1R,2R)((6-((2-(trifluoromethy1)-9H-puriny1)methy1)benzo[d]thiazol no)cyclohexanol; 2-((6-((2-(trifluoromethy1)-9H-puriny1)methy1)benzo [d]thiazol yl)amino)cyclohexanol; (1R,2R)((6-((5-(methylsu1fony1)-3H—imidazo[4,5-b]pyridin-3 - y1)methy1)benzo[d]thiazoly1)amino)cyclohexanolg 2-((6-((5 -(methylsu1fonyl)-3H—imidazo [4,5 -b]pyridin-3 - hy1)benzo[d]thiazoly1)amino)cyclohexanol; (1R,2R)((6-((6-bromo-1H—benzo[d]imidazoly1)methy1)benzo[d]thiazol- 2-y1)amino)cyclohexanol; 2—((6-((6-bromo-1H—benzo[d]imidazoly1)methyl)benzo[d]thiazol yl)amino)cyclohexanol; 1 -((2-(((1R,2R)hydroxycyclohexyl)amino)benzo[d]thiazolyl)methyl)- zo[d]imidazole-5 -carbonitri1e; 1 -((2-((2-hydroxycyclohexy1)amino)benzo[d]thiazolyl)methy1)— 1H- benzo[d]imidazole-5 -carbonitri1e; (1R,2R)((6-((6-(2-hydroxypropany1)-3H—imidazo[4,5-b]pyridin-3 - y1)methy1)benzo[d]thiazoly1)amino)cyclohexanolg 2-((6-((6-(2-hydroxypropany1)—3H—imidazo [4,5 -b]pyridin-3 - y1)methy1)benzo[d]thiazoly1)amino)cyclohexanol; 1-(1-((2-(((1R,2R)hydroxycyclohexy1)amino)benzo[d]thiazolyl)methyl)- 1H-benzo[d]imidazoly1)ethanone; 1-(1-((2-((2-hydroxycyclohexyl)amino)benzo[d]thiazoly1)methyl)—1H- benzo[d]imidazoly1)ethanone; 1 -((2-(((1R,2R)hydroxycyclohexyl)amino)benzo[d]thiazolyl)methyl)- 1H-benzo[d]imidazo1ecarbonitrile; 1 -((2-((2-hydroxycyclohexy1)amino)benzo[d]thiazolyl)methy1)— 1H- benzo[d]imidazolecarbonitrile; )—2-((6-((5-(rnethylsulf0nyl)-1H—benz0[d]imidazol yl)methy1)benzo[d]thiaz01—2-y1)arnino)cyclohexan01; 2-((6-((5 -(rnethylsulf0nyl)-1H—benz0[d]imidazoly1)rnethy1)benzo[d]thiaz01— 2-y1)arnino)cyclohexanol; (1R,2R)((6-((6-(rnethylsulfonyl)-1H—benzo[d]irnidazol yl)methy1)benzo[d]thiaz01—2-y1)arnino)cyclohexan01; 2-((6-((6-(rnethylsulfonyl)-1H—benz0[d]irnidazoly1)rnethy1)benzo[d]thiaz01— 2-y1)arnino)cyclohexanol; (1R,2R)—2-((6-((3H—irnidazo [4,5 -b]pyridin-3 -y1)rnethy1)thiazolo[4,5 - b]pyridiny1)arnino)cyclohexanol; 2-((6-((3H—irnidazo [4,5 -b]pyridin-3 -y1)rnethy1)thiazolo[4,5 -b]pyridin yl)arnino)cyclohexanol; (1R,2R)((6-((6-((R, S)—1-hydr0xyethyl)-3H—imidazo[4,5 -b]pyridin-3 - yl)methy1)benzo[d]thiaz01—2-y1)arnino)cyclohexan01; ((6-(1-hydr0xyethy1)—3H—irnidazo[4,5 -b]pyridin-3 - yl)methy1)benzo[d]thiaz01—2-y1)arnino)cyclohexan01; 2-(dirnethylamino)(3 -((2-(((1R,2R)—2- hydroxycyclohexy1)arnino)benzo[d]thiaz01—6-yl)methy1)-3H—irnidazo [4,5 -b]pyridin yl)ethanone acetate salt; 2-(dirnethylarnino)(3 -((2-((2-hydr0xycyc10hexy1)arnino)benzo[d]thiazol thy1)—3H—irnidazo [4,5 -b]pyridinyl)ethanone; 2-(dirnethylamino)(3 -((2-(((1R,2R)—2- hydroxycyclohexy1)arnino)benzo[d]thiaz01—6-yl)methy1)-3H—irnidazo [4,5 -b]pyridin y1)ethanone; 3 ((1R,2R)-2—hydroxycyclohexyl)amino)benzo[d]thiaz01—6- y1)rnethyl)irnidazo[1 ,2-a]pyridinecarbonitrile; 3 -((2-((2-hydr0xycyc10hexy1)arnino)benzo[d]thiaz01y1)rnethyl)irnidazo[ 1 ,2- a]pyridinecarbonitrile; (1R,2R)((6-((9H-puriny1)rnethy1)benzo[d]oxazol yl)arnino)cyclohexanol; 2-((6-((9H-puriny1)rnethyl)benzo[d]oxaz01—2-y1)arnino)cyclohexanol; (1R,2R)((6-((5 ,6-dimethy1—1H—benz0[d]irnidazol yl)methy1)benzo[d]thiaz01—2-y1)amino)cyclohexanolg 2-((6-((5 ethy1—1H—benzo[d]irnidazolyl)methy1)benzo[d]thiazol yl)arnino)cyclohexanol; (2-(((1R,2R)hydr0xycyclohexy1)amino)benzo[d]thiaz01—6-yl)rnethyl)- 1H—benzo[d]irnidaz01—6-y1)ethanone; 1-(1-((2-((2-hydr0xycyclohexyl)amino)benzo[d]thiazolyl)rnethyl)-1H- benzo[d]imidazolyl)ethanone; (1R,2R)—2-((6-((5-ethyny1—1H—benz0[d]irnidazoly1)methyl)benzo[d]thiazol- 2-y1)amino)cyclohexanol; 2-((6-((5 -ethyny1—1H—benz0[d]irnidazoly1)rnethyl)benzo[d]thiaz01—2- yl)arnino)cyclohexanol; (1R,2R)—2-((6-((6-ethyny1—1H—benz0[d]irnidazolyl)methyl)benzo[d]thiaz01— 2-y1)amino)cyclohexanol; 2-((6-((6-ethyny1—1H—benz0[d]irnidazol-1 -y1)rnethy1)benzo[d]thiaz01—2- yl)arnino)cyclohexanol; )—2-((6-((6-br0rn0rnethoxy-3H-irnidazo [4,5 -b]pyridin-3 - yl)rnethy1)benzo[d]thiazol-Z-yl)arnino)cyclohexanol; 2-((6-((6-brornornethoxy-3H-irnidazo [4,5 -b]pyridin-3 - yl)rnethy1)benzo[d]thiazol-Z-yl)arnino)cyclohexanol; 3 -((2-(((1R,2R)hydr0xycyclohexy1)arnino)benzo[d]oxaz01—6-y1) methyl)- 3H-irnidaz0 [4,5 -b]pyridinecarbonitrile; 3 -((2-((2-hydr0xycyclohexyl)arnino)benzo[d]0xaz01—6-yl) methy1)-3H- imidazo [4,5 -b]pyridinecarbonitrile; (1R,2R)((6-(irnidazo [1 ,2-a]pyrazin-3 -y1rnethyl)benz0 [d]thiaz01—2— yl)arnino)cyclohexanol; 2-((6-(irnidaz0[1 ,2-a]pyrazin-3 thy1)benzo [d]thiaz01—2— yl)arnino)cyclohexanol; 3 -((2-((( 1R,2R)hydr0xycyclohexy1)amino)benzo[d]thiaz01—6-y1)rnethy1)-5 - methoxy-3H-irnidazo [4,5 -b]pyridinecarbonitrile; 3 -((2-((2-hydr0xycyc10hexy1)arnino)benzo[d]thiazolyl)rnethyl)-5 0xy- 3H-irnidaz0 [4,5 -b]pyridinecarbonitrile; (1R,2R)—2-((6-((5 -rnethy1—1H—benz0[d]irnidazoly1)rnethyl)benzo[d]thiazol- 2-y1)amino)cyclohexanol; 2-((6-((5 -rnethy1—1H—benz0[d]irnidazoly1)rnethyl)benzo[d]thiaz01—2- yl)arnino)cyclohexanol; 1 23 (1R,2R)—2-((6-((5 ,6-difluoro-1H—benz0[d]irnidazol yl)methyl)benzo[d]thiaz01—2-y1)amino)cyclohexanolg 2-((6-((5 ,6-diflu0ro- 1H-benz0 [d]irnidazol- 1 ethy1)benzo [d]thiaz01—2— yl)arnino)cyclohexanol; (1R,2R)—2-((6-((5-flu0ro- 1H-benz0 [d]imidazoly1)rnethy1)benzo [d]thiaz01— 2-yl) amino)cyclohexanol; 2-((6-((5 -flu0r0-1H—benz0[d]irnidazoly1)rnethy1)benzo[d]thiaz01—2-y1) amino)cyclohexanol; ( 1R,2R)((6-((5-(triflu0r0rnethy1)- z0 [d]irnidazoly1) methyl)benzo[d]thiaz01y1)amino)cyclohexanol; ((5 -(trifluor0rnethyl)- 1H—benz0[d]irnidazoly1) methyl)benzo[d]thiaz01y1)amino)cyclohexanol; (1R,2R)—2-((6-(irnidazo[ 1 ,2-b]pyridazin-3 -y1rnethyl)benz0 [d]thiaz01—2— yl)arnino)cyclohexanol; 2-((6-(irnidaz0[1 ,2-b]pyridaziny1methyl)benzo [d]thiaz01—2- yl)arnino)cyclohexanol; )((6-((6-flu0r0-3H—imidazo [4,5-b]pyridin-3 - y1)rnethy1)benzo[d]oxazol-Z-yl)arnino)cyclohexanol; 2—((6-((6-fluor0-3H—imidazo [4,5 -b]pyridin-3 -y1)rnethy1)benzo [d]0xaz01—2- yl)arnino)cyclohexanol; R)—2-((6-((6-brorno-3H—imidazo[4,5-b]pyridin-3 - yl)methyl)benzo[d]thiazol-Z-yl)arnino)cyclohexyl)methan01; 2-((6-((6-br0rn0-3H—irnidazo [4,5 -b]pyridin-3 -y1)rnethy1)benzo az01—2— yl)amino)cyclohexy1)rnethanol; (1R,2R)((6-((6-(1 -rnethy1— 1H-tetraz01—5 -y1)-3H-irnidaz0 [4,5 -b]pyridin-3 - yl)rnethy1)benzo[d]thiazol-Z-yl)arnino)cyclohexanol; 2-((6-((6-(1 -rnethy1— 1H-tetraz01—5 -y1)-3H-irnidazo [4,5 -b]pyridin-3 - yl)rnethy1)benzo[d]thiazol-Z-yl)arnino)cyclohexanol; (1R,2R)((6-((7-(2-hydr0xyethoxy)irnidazo[1,2-a]pyridin-3 - yl)methyl)benzo[d]thiazo1y1)arnin0)cyclohexanol; 2-((6-((7-(2-hydr0xyethoxy)imidazo[1 ,2-a]pyridin-3 - hyl)benzo[d]thiazo1y1)arnin0)cyclohexanol; ((1S,2R)((6-((6-brorno-3H—irnidazo[4,5 -b]pyridin-3 - y1)rnethyl)benzo[d]thiazol-Z-y1)amin0)cyclohexyl)methanol; 1 24 2-((6-((6-br0rn0-3H—irnidazo [4 ,5 -b]pyridin-3 -y1)rnethy1)benzo [d]thiaz01—2— y1)arnino)cyc10hexy1)rnethan01; (1R,2R)((6-((5 ,6-dich10r0-3H-imidazo [4,5 -b]pyridin-3 - y1)rnethy1)benzo [d]thiaz01—2-y1)amino)cyc10hexan01; 2-((6-((5 ,6-dich10ro-3H-imidazo [4,5 -b]pyridin-3 -y1)rnethy1)benzo [d]thiaz01—2— yl)amino)cyc10hexan01; (1R,2R)((6-((5-ethoxy-1H-benz0 idaz01y1)rnethy1)benzo [d]thiaz01— 2-y1)arnino)cyclohexan01; 2-((6-((5 -ethoxy-1H—benzo[d]irnidaz01y1)rnethy1)benzo[d]thiaz01—2- yl)amino)cyc10hexan01; 3 -((2-((( 1R,2R)hydr0xycyc10hexy1)amino)benzo [d]thiaz01y1)rnethy1)- 3H-irnidaz0 [4,5 -b]pyridine-5 ,6-dicarbonitrile; 3 -((2-((2-hydr0xycyc10hexy1)arnino)benzo [d]thiaz01y1)rnethy1)-3H- imidazo [4,5 -b]pyridine-5 ,6-dicarbonitrile; 3 -((2-((( (hydr0xyrnethy1)cyclohexy1)arnino)benzo[d]thiaz01—6- y1)rnethy1)—3H—irnidazo [4 ,5 -b]pyridinecarbonitrile; 3 -((2-((2-(hydroxymethy1)cyc10hexy1)arnino)benzo[d]thiaz01—6-y1)rnethy1)— 3H-irnidaz0 [4,5 -b]pyridinecarbonitrile; (1R,2R)—2—((6-((6-(1H-pyrazoly1)-3H-irnidaz0[4,5 -b]pyridin-3 - y1)rnethy1)benzo [d]thiazo1y1)arnino)cyclohexano1; 2-((6-((6-(1H-pyraz01—1-y1)-3H-irnidaz0[4,5 -b]pyridin—3 - thy1)benzo [d]thiaz01—2-y1)amino)cyc10hexan01; (1R,2R)((6-(irnidazo[1,2-b]pyridazin-3 -y1rnethy1)benz0 z01—2- yl)amino)cyc10hexan01; 2-((6-(irnidaz0[1 ,2-b]pyridazin—3 -y1rnethy1)benz0 [d]0xaz01—2- yl)amino)cyc10hexan01; 3 -((2-(((1R,2R)hydr0xycyc10hexy1)amino)benzo[d]thiaz01y1)methy1)-N- methylirnidazo [1 ,2-b]pyridazinecarboxamide; 3 (2-hydr0xycyc10hexy1)arnino)benzo [d]thiaz01y1)rnethy1)-N- methylirnidazo [1 ,2-b]pyridazinecarboxamide; (1R,2R)((6-((6-(hydr0xyrnethy1)imidazo [1 ,2-b]pyridazin-3 - y1)rnethy1)benzo [d]thiazo1y1)arnino)cyclohexano1; 2-((6-((6-(hydr0xyrnethy1)imidazo[1 ,2-b]pyridazin-3 - y1)rnethy1)benzo [d]thiaz01—2-y1)amino)cyc10hexan01; 1 25 (1R,2R)—2-((6-((6-(1H-1,2,4-triaz01—1-y1)-3H-irnidazo[4,5 -b]pyridin-3 - yl)rnethy1)benzo[d]thiazol-Z-yl)arnino)cyclohexanol; 2-((6-((6-(1H-1,2,4-triaz01—1-y1)-3H-irnidazo[4,5 -b]pyridin-3 - yl)rnethy1)benzo[d]thiazol-Z-yl)arnino)cyclohexanol; (1R,2R)((6-((6-i0do-3H-irnidazo [4,5 -b]pyridin-3 - yl)rnethy1)benzo[d]thiazol-Z-yl)arnino)cyclohexanol; 2-((6-((6-i0d0-3H-irnidazo [4,5 -b]pyridiny1)methy1)benzo [d]thiaz01—2- yl)arnino)cyclohexanol; 1 -((2-(((1R,2R)hydr0xycyclohexyl)amino)benzo[d]thiaz01—6-yl)rnethyl)- 1H-benz0[d]irnidazol-5 -01; 1 -((2-((2-hydroxycyclohexyl)arnino)benzo[d]thiaz01—6-yl)rnethyl)- 1H- benzo[d]irnidaz01—5 -01; (1R,2R)—2-((6-((5 ,7-difluoro-1H—benz0[d]irnidazol yl)methyl)benzo[d]thiazol-Z-y1)arnin0)cyclohexanol; 2-((6-((5 ,7-diflu0ro- 1H-benz0 [d]irnidazoly1)rnethy1)benzo [d]thiaz01—2— yl)arnino)cyclohexanol; (1R,2R)—2-((6-((5 -(triflu0r0rnethoxy)— 1H-benz0 [d]irnidazoly1) methyl)benzo[d]thiaz01y1)amino)cyclohexanol; 2-((6-((5 -(trifluorornethoxy)- z0 [d]imidazoly1) methyl)benzo[d]thiaz01—2-yl)arnin0)cyclohexan01; (1R,2R)((6-((6-methoxyirnidazo[1 ,2-b]pyridazin-3 -y1)rnethy1) d]thiazo1yl)arnino)cyclohexanol; ((6-rnethoxyirnidazo[1 yridaziny1)rnethy1) benzo[d]thiazol yl)arnino)cyclohexanol; (1R,2R)—2-((6-((5-rnethoxy-1H-benz0[d]imidazol y1)rnethyl)benzo[d]0Xazo1yl)amin0)cyclohexan01; 2-((6-((5 -rnethoxy-1H-benz0[d]irnidazoly1)methyl)benzo[d]oxaz01—2- yl)arnino)cyclohexanol; (1R,2R)—2-((6-((6-rnethoxy- 1H-benz0[d]irnidazol-1 - y1)rnethyl)benzo[d]0Xazo1y1)arnin0)cyclohexan01; 2-((6-((6-rnethoxy-1H-benzo[d]imidazoly1)rnethyl)benzo[d]oxaz01—2- yl)arnino)cyclohexanol; (1R,2R)((6-((7-(2-rneth0xyethoxy)irnidazo [1 yridin-3 - yl)rnethy1)benzo[d]thiazol-Z-yl)arnino)cyclohexanol; 1 26 2012/059983 2-((6-((7-(2-methoxyethoxy)imidazo[1 ,2-a]pyridin-3 - yl)rnethy1)benzo[d]thiazol-Z-yl)arnino)cyclohexanol; (1R,2R)((6-((3H—irnidazo[4,5-b]pyridin—3-y1)rnethy1) fluorobenzo[d]thiazo1y1)arnino)cyclohexano1; ((3H—irnidazo [4,5 -b]pyridin-3 -y1)rnethy1)flu0r0benz0 [d]thiaz01—2— yl)arnino)cyclohexanol; (1R,2R)—2-((6-((6-rn0rpholinoirnidazo[1,2-b]pyridazin-3 - yl)methyl)benzo[d]thiazo1y1)arnino)cyclohexano1; 2-((6-((6-rnorpholinoirnidazo [1 ,2-b]pyridazin-3 -y1)rnethy1)benzo [d]thiaz01—2— yl)arnino)cyclohexanol; (1R,2R)—2-((4-ch10r0((6-rn0rph01inoirnidazo[1,2-b]pyridazin-3 - yl)methyl)benzo[d]thiazo1y1)arnino)cyclohexano1; 2-((4-ch10r0((6-m0rpholinoirnidazo[1,2-b]pyridazin-3 - hyl)benzo[d]thiazo1y1)arnin0)cyclohexanol; (1R,2R)((6-(irnidazo [2 ,1-b]thiaz01-5 thy1)benzo [dthiazol-Z- yl)amin0)cyc10hexanol; 2-((6-(irnidazo[2,1-b]thiaz01-5 -y1rnethy1)benzo [dthiazol-Z- yl)amin0)cyc10hexanol; (1R,2R)((6-((6-chlor0irnidazo[ 1 ,2-b]pyridazin-3 ethyl) benzo[d]thiaz01—2-y1)arnin0)cyclohexanol; 2-((6-((6-chlor0imidazo[1 ,2-b]pyridaziny1)rnethy1) benzo[d]thiazol yl)arnino)cyclohexanol; (1R,2R)—2-((6-((6-(1H-pyrazoly1)irnidaz0[1,2-a]pyridin yl)methyl)benzo[d]thiazo1y1)arnino)cyclohexano1; 2-((6-((6-(1H-pyraz01—1-yl)irnidaz0[1,2-a]pyridin yl)methyl)benzo[d]thiazo1y1)arnin0)cyclohexanol; (1R,2R)—2-((6-((5-(lH-pyrazoly1)-1H—benzo[d]irnidazol yl)methyl)benzo[d]thiaz01—2-y1)arnino)cyclohexanol; 2-((6-((5-(1H—pyrazoly1)-1H—benz0[d]irnidazol yl)methyl)benzo[d]thiaz01—2-y1)arnino)cyclohexanol; (1R,2R)—2-((6-((5-(1H—1,2,4-triaz01—1-y1)-1H—benzo[d]imidazol yl)methyl)benzo[d]thiaz01—2-y1)amino)cyclohexanolg 2-((6-((5-(1H—1,2,4-triaz01—1-y1)-1H—benz0[d]irnidazol yl)methyl)benzo[d]thiaz01—2-y1)arnino)cyclohexanol; 1 27 (1S,2R)((6-((6-flu0r0-3H—imidazo [4,5 -b]pyridin-3 - yl)methyl)benzo[d]thiaz01—2-y1)amino)cyclohexanolg 2—((6-((6-fluor0-3H—imidazo [4,5 -b]pyridin-3 -y1)rnethy1)benzo [d]thiaz01—2— yl)amin0)cyclohexanol; trans((6-((6-fluoro-3H—irnidazo [4 ,5 idin-3 ethy1)benzo [d]thiaz01— 2-y1)arnino)cyclohexanol; ((6-fluor0-3H—imidazo [4,5 idin-3 -y1)rnethy1)benzo [d]thiaz01—2— yl)amin0)cyclohexanol; (1R,2R)((6-((3H—irnidazo [4,5 -b]pyridin—3 -y1)rnethy1) fluorobenzo[d]thiazo1—2-y1)arnino)cyclohexano1; 2-((6-((3H—irnidazo [4 ,5 -b]pyridin-3 -yl)methy1)fluorobenzo [d]thiaz01—2— yl)amin0)cyclohexanol; (1R,2R)((6-((6-rneth0xyirnidazo[1,2-a]pyridin-3 - y1)rnethyl)benzo [d]thiaz01—2-yl)amino)cyclohexanol; 2-((6-((6-methoxyimidazo[1 yridin-3 -y1)rnethyl)benzo [d]thiaz01—2— yl)amin0)cyclohexanol; (1R,2R)—2-((6-((3H—irnidazo [4,5 -b]pyridin-3 -y1)rnethy1) bromobenzo[d]thiaz01—2-y1)arnin0)cyclohexanol; 2-((6-((3H—irnidazo [4 ,5 -b]pyridin-3 -y1)rnethy1)brornobenzo [d]thiaz01—2— yl)amin0)cyclohexanol; )—2-((6-((7-(1H-pyrazoly1)irnidaz0[1,2-a]pyridin-3 - y1)rnethyl)benzo [d]thiaz01—2-yl)amino)cyclohexanol; 2—((6-((7-(1H-pyraz01—1-y1)irnidazo[1,2-a]pyridin-3 - y1)rnethyl)benzo [d]thiaz01—2-yl)amin0)cyclohexanol; (1R,2R)—2-((6-((3H—irnidazo [4,5 -b]pyridin-3 -y1)rnethy1)-4,7- difluorobenzo[d]thiazol-Z-y1)arnin0)cyclohexanol; 2-((6-((3H—irnidazo [4 ,5 -b]pyridin-3 -y1)rnethy1)-4,7-difluorobenzo az01—2 - yl)amin0)cyclohexanol; (1R,2R)((6-((7-(1H-1,2,4-triazoly1)irnidazo[1,2-a]pyridin-3 - y1)rnethyl)benzo [d]thiaz01—2-yl)amin0)cyclohexanol; 2-((6-((7-(1H-1,2,4-triaz01—1-y1)irnidaz0[1,2-a]pyridin—3 - y1)rnethyl)benzo [d]thiaz01—2-yl)amin0)cyclohexanol; 1-((2-((( 1R,2R)hydr0xycyclohexy1)amino)benzo[d]0xaz01—6-yl) methyl)- 1H-benzo[d]imidazole-5 -carb0nitrile; 1 28 1-((2-((2-hydr0xycyc10hexy1)arnino)benzo[d]0xaz01y1) methy1)-1H- d]irnidazole-5 -carb0nitrile; (1R,2R)((6-((5-(2-rn0rph01inoethoxy)-1H-benz0 [d]irnidaz01 y1)methy1)benzo[d]thiaz01y1)amino)cyclohexanolg 2-((6-((5 -(2-m0rph01inoethoxy)- z0 [d]imidazol y1)methy1)benzo[d]thiaz01y1)arnino)cyclohexan01; (1 R,2R)((6-((5-(2-hydr0xyethoxy)-1H-benz0[d]imidaz01 y1)rnethy1)benzo [d]thiazo1y1)arnino)cyclohexano1; 2-((6-((5 -(2-hydr0xyethoxy)-1H-benz0[d]irnidaz01 y1)rnethy1)benzo [d]thiazo1y1)arnin0)cyclohexanol; 1 -((2-(((1R,2R)hydroxycyc10hexy1)arnino)benzo[d]thiaz01y1)rnethy1)-N- methyl-1H-benz0[d]irnidazolecarb0xarnide; 1 -((2-((2-hydr0xycyc10hexy1)arnino)benzo [d]thiazo1y1)rnethy1)—N—rnethy1- 1H-benz0[d]irnidazolecarb0xarnide; (1R, 2R)((6-((5 -(3 ,6-dihydr0-2H-pyrany1)- 1H-benz0 [d]imidazol y1)methy1)benzo[d]thiaz01y1)amino)cyclohexanolg 2-((6-((5 -(3 ,6-dihydr0-2H-pyrany1)— 1H-benz0 [d]imidazol y1)methy1)benzo[d]thiazo1y1)arnino)cyclohexan01; (1R,2R)—2-((6-((5 -(3 ,3 ,3 -triflu0ropropeny1)-1H-benz0 [d]irnidaz01 hy1)benzo[d]thiaz01y1)amino)cyclohexanolg 2-((6-((5 -(3 ,3 ,3 -triflu0ropropeny1)- z0 [d]irnidaz01 y1)methy1)benzo[d]thiazo1y1)arnino)cyclohexan01; (R)-N—(cycloheXeny1)((6-flu0r0-3H—imidazo [4,5 -b]pyridin—3 - y1)methy1)benzo[d]thiaz01arnine; N—(cycloheX-Z-eny1)((6-fluoro-3H—irnidazo [4,5 -b]pyridin-3 - y1)methy1)benzo[d]thiaz01arnine; (1R,2R)((6-((6-brornoirnidazo [1 ,2-b]pyridazin-3 - y1)rnethy1)benzo [d]thiazo1y1)arnino)cyclohexano1; ((6-bromoirnidazo[1 ,2-b]pyridazin-3 -y1)rnethy1)benzo [d]thiaz01 y1)arnino)cyclohexan01; (1R,2R)((6-((6-(4-rnethy1piperazin- 1 nidazo [1 ,2-b]pyridazin-3 - y1)rnethy1)benzo azo1y1)arnino)cyclohexano1; 2-((6-((6-(4-rnethy1piperaziny1)irnidaz0 [1 ,2-b]pyridazin-3 - y1)rnethy1)benzo [d]thiazo1y1)arnin0)cyclohexanol; 1 29 (trans((6-((6-fluoro-3H—imidazo [4,5 -b]pyridin-3 - y1)rnethyl)benzo[d]thiazol-Z-y1)amin0)cyclohexyl)methanol; (cis((6-((6-fluoro-3H—irnidazo [4,5 -b]pyridin-3 -y1)rnethy1)benzo [d]thiaz01— 2-yl)arnin0)cyclohexyl)methanol; 4-((6-((6-fluor0-3H—imidazo [4,5 -b]pyridin-3 -y1)rnethy1)benzo [d]thiaz01—2— yl)amino)cyclohexy1)rnethanol; 6-((6-flu0r0-3H—imidazo [4,5 idin-3 -y1)rnethy1)-N—((1R,2R)-2— (methylthio)cyclohexy1)benzo[d]thiaz01—2-arnine; 6-((6-flu0r0-3H—imidazo [4,5 -b]pyridin-3 -y1)rnethyl)-N—(2- (methylthio)cyclohexy1)benzo[d]thiaz01—2-arnine; (1R,2R)—2-((6-((5 an-3 -y10xy)— 1H-benz0 [d]irnidaz0 1— 1 - yl)methyl)benzo[d]thiaz01—2-y1)amino)cyclohexanolg 2-((6-((5 -(oxetan-3 -y10xy)—1H—benz0[d]irnidazolyl)methyl)benzo[d]thiaz01— 2-yl)amino)cyclohexanol; (1R,2R)—2-((6-((5 -Viny1-1H—benz0[d]irnidazoly1)rnethyl)benz0[d]thiaz01—2- yl)arnino)cyclohexanol; 2-((6-((5 -Viny1-1H—benz0[d]imidazol-1 -y1)rnethyl)benzo[d]thiaz01—2- yl)arnino)cyclohexanol; (1R,2R)—2-((6-((5-(cyclohexeny1)—1H—benzo[d]imidazolyl) methyl)benzo[d]thiaz01—2-y1)amino)cyclohexanol; 2-((6-((5 -(cyclohexeny1)-1H—benzo[d]imidazol yl)methyl)benzo[d]thiazo1—2-y1)arnino)cyclohexanol; (1R,2R)—2-((6-((5 -(1 -rnethy1—3-(trifluor0rnethyl)- 1H—pyraz01—4-yl)- 1H- benzo[d]imidazol-1 -y1)rnethy1)benzo[d]thiaz01—2-yl)amino)cyclohexanol; 2-((6-((5 -(1-rnethy1—3 -(trifluor0rnethyl)- 1H-pyraz01—4-y1)- 1 H- benzo[d]imidazol-1 -y1)rnethy1)benzo [d]thiaz01—2-yl)arnin0)cyclohexanol; )—2-((6-((5-flu0r0irnidazo[ 1 ,2-a]pyridin-3 -y1)rnethy1)benzo [d]thiaz01— mino)cyclohexanol; 2-((6-((5 -fluor0irnidazo[ 1 yridin-3 -y1)rnethyl)benzo[d]thiaz01—2- ino)cyclohexanol; (1R,2R)((6-((7-rn0rpholinoirnidazo[1,2-a]pyridin-3 - yl)methyl)benzo[d]thiazo1—2-yl)arnino)cyclohexano1; 2-((6-((7-rnorpholinoirnidazo [1 ,2-a]pyridin-3 -y1)rnethyl)benzo [d]thiaz01—2— yl)arnino)cyclohexanol; 1 30 (1R,2R)((6-((7-(4-rnethy1piperaziny1)irnidazo [1 ,2-a]pyridin-3 - yl)methyl)benzo[d]thiazo1y1)arnino)cyclohexano1; 2-((6-((7-(4-rnethy1piperaziny1)irnidazo[1 yridin-3 - yl)methyl)benzo[d]thiazo1y1)arnin0)cyclohexanol; ((1R,2R)—2-((6-((5 ,7-dimethy1—1H—benz0[d]irnidazol yl)methyl)benzo[d]thiaz01—2-y1)amino)cyclohexanolg 2-((6-((5 ,7-dimethy1—1H—benzo[d]irnidazolyl)methy1)benzo[d]thiazol ino)cyclohexanol; (1R,2R)—2-((6-((5-br0rn0rnethyl-1H—benzo[d]imidazol yl)methyl)benzo[d]thiaz01—2-y1)amino)cyclohexanolg 2-((6-((5 -br0rn0rnethy1—1H—benzo[d]irnidazoly1)rnethy1)benzo[d]thiaz01— 2-yl)amino)cyclohexanol; 6-((6-flu0r0-3H—irnidazo [4,5 -b]pyridinyl)rnethy1)-N—phenylbenz0 [d]thiaz01— 2-amine; ((1R,3R)—3-((6-((6-flu0r0-3H—irnidazo [4,5 -b]pyridin-3 - y1)rnethyl)benzo[d]thiazol-Z-y1)amin0)cyclohexyl)methanol; 3 -((6-((6-flu0r0-3H—imidazo [4,5 -b]pyridin-3 -y1)rnethy1)benzo [d]thiaz01—2— yl)amino)cyclohexy1)rnethanol; (1R,2S,3R)((6-((6-flu0r0-3H—irnidazo [4,5 -b]pyridin-3 - yl)methyl)benzo[d]thiaz01—2-yl)amino)cyclohexane- 1 ,2-diol; 3 -((6-((6-flu0r0-3H—imidazo [4,5 -b]pyridin-3 -y1)rnethy1)benzo [d]thiaz01—2— yl)arnin0)cyclohexane-1 ,2-diol; (( 1 S,3R)-3 -((6-((6-fluor0-3H—irnidazo [4,5 idin-3 - thyl)benzo[d]thiazol-Z-y1)amin0)cyclohexyl)methanol; 3 -((6-((6-flu0r0-3H—imidazo [4,5 -b]pyridin-3 -y1)rnethy1)benzo az01—2— yl)amino)cyclohexy1)rnethanol; 6-chlor0((2-(((1R,2R)hydr0xycyclohexy1)amino)benzo[d]0xaz01—6- yl)rnethy1)-1H-benz0[d]irnidazole-5 -carb0nitrile; 6-chlor0((2-((2-hydr0xycyclohexyl)arnino)benzo [d]0xaz01—6-y1)rnethy1)— 1H-benzo[d]imidazole-5 -carb0nitrile; 2-((1-((2-(((1R,2R)hydr0xycyclohexy1)amino)benzo[d]thiazol yl)rnethy1)— 1H-benz0 [d]irnidazol-5 -y1)oxy)acet0nitrile; 2-((1-((2-((2-hydr0xycyclohexyl)amino)benzo[d]thiaz01—6-yl)methyl)-1H- benzo[d]irnidaz01—5 -y1)oxy)acetonitrile; 1 31 6-((6-flu0r0-3H—imidazo [4,5 -b]pyridin-3 -y1)rnethy1)-N—(2- methoxypheny1)benzo[d]thiaz01—2-arnine; N—(( 1 R,2R)ch10rocyc10hexy1)((6-fluoro-3H—irnidazo [4,5 -b]pyridin-3 - y1)methy1)benzo[d]thiaz01arnine; N—(2-ch10rocyc10hexy1)((6-fluoro-3H—irnidazo [4,5 -b]pyridin-3 - y1)methy1)benzo[d]thiaz01arnine; 1-(3 -((2-((( 1R,2R)hydr0xycyc10hexy1)amino)benzo az01—6- thy1)irnidazo[ 1 ,2-a]pyridiny1)piperidin01; 1-(3 -((2-((2-hydr0xycyc10hexy1)arnino)benzo az01—6- y1)rnethy1)irnidazo [1 ,2-a]pyridiny1)piperidin01; 1-(3 (( 1R,2R)hydr0xycyc10hexy1)amino)benzo [d]thiaz01—6- y1)rnethy1)irnidazo [1 ,2-a]pyridiny1)ethanone; 1-(3 -((2-((2-hydr0xycyc10hexy1)arnino)benzo [d]thiaz01—6- y1)rnethy1)irnidazo [1 ,2-a]pyridiny1)ethanone; (1R,2R)—2-((6-((7-(1-hydr0xyethy1)imidazo[1,2-a]pyridin-3 - y1)rnethy1)benzo [d]thiazo1y1)arnino)cyclohexano1; 2-((6-((7-(1-hydr0xyethy1)irnidazo[1 ,2-a]pyridin-3 -y1)rnethy1)benzo [d]thiaz01— 2-y1)arnino)cyclohexan01; 1-(3 -((2-((( 1R,2R)hydr0xycyc10hexy1)amino)benzo [d]thiaz01—6- y1)rnethy1)irnidazo[1 ,2-a]pyridiny1)ethanone oxirne; 1-(3 -((2-((2-hydr0xycyc10hexy1)arnino)benzo [d]thiaz01—6- y1)rnethy1)irnidazo[1 ,2-a]pyridiny1)ethanone oxirne; (1R,2R)—2-((6-((5-br0rn0fluor0- 1H—benz0 [d]irnidaz01 y1)methy1)benzo[d]thiaz01—2-y1)amino)cyclohexanolg ((5 -br0rnoflu0r0- z0 [d]irnidaz01y1)rnethy1)benzo [d]thiaz01— 2-y1)amino)cyclohexan01; 1-(3 -((2-((( 1R,2R)hydr0xycyc10hexy1)amino)benzo [d]thiaz01—6- y1)rnethy1)irnidazo[1,2-a]pyridiny1)ethanone 0-methy1 oxirne; 1-(3 -((2-((2-hydr0xycyc10hexy1)arnino)benzo [d]thiaz01—6- thy1)irnidazo[1,2-a]pyridiny1)ethanone 0-methy1 oxirne; (1R,2R)—2-((6-((9H—benzo [d]irnidazo[ 1 ,2-a]irnidaz01—3 - y1)methy1)benzo[d]thiaz01—2-y1)amino)cyclohexanolg 2-((6-((9H—benz0 [d]irnidazo[ 1 ,2-a]irnidaz01—3 -y1)rnethy1)benzo [d]thiaz01—2— y1)arnino)cyclohexan01; 1 32 2012/059983 7-fluor0((2-(((1R,2R)hydr0xycyclohexy1)amino)benzo [d]thiaz01—6- thy1)—1H—benz0[d]irnidazole-5 -carb0nitrile; 7-fluoro((2-((2-hydr0xycyclohexyl)arnino)benzo [d]thiaz01—6-yl)rnethyl)- z0[d]irnidazole-5 -carb0nitrile; (1R,2R)((6-((7-flu0r0Viny1-1H—benzo[d]irnidazol yl)methyl)benzo[d]thiaz01—2-y1)amino)cyclohexanolg 2-((6-((7-flu0r0Viny1-1H—benzo[d]irnidazoly1)rnethy1)benzo[d]thiaz01—2- yl)arnino)cyclohexanol; (1R,2R)—2-((6-((5 -(3 ,6-dihydr0-2H—pyranyl)fluor0- 1H- benzo[d]imidazol-1 ethy1)benzo[d]thiaz01—2-yl)amino)cyclohexanol; 2-((6-((5 -(3 ,6-dihydr0-2H—pyrany1)fluoro-1H—benz0[d]imidazol yl)methyl)benzo[d]thiazo1y1)arnino)cyclohexanol; )—2-((6-((5 -rnorpholino- 1H—benz0[d]irnidazol- 1- yl)methyl)benzo[d]thiaz01—2-y1)amino)cyclohexanolg 2-((6-((5 -rnorpholino- 1H-benz0 [d]irnidazoly1)rnethy1)benzo [d]thiaz01—2— yl)arnino)cyclohexanol; 1-(1-((2-(((1R,2R)hydr0xycyclohexy1)amino)benzo[d]thiaz01—6-yl)rnethyl)- 1H-benz0[d]irnidaz01—5 -y1)piperidinone; 1-(1-((2-((2-hydr0xycyclohexyl)amino)benzo[d]thiazolyl)rnethyl)-1H- benzo[d]irnidaz01—5-y1)piperidinone; (1R,2R)—2-((6-((5 -(1H-pyraz01—3 -y1)-1H—benz0[d]irnidazol yl)methyl)benzo[d]thiaz01—2-y1)amino)cyclohexanolg 2-((6-((5-(1H-pyraz01—3-y1)-1H—benz0[d]irnidazol yl)methyl)benzo[d]thiaz01—2-y1)arnino)cyclohexanol; (1R,2R)((6-((6-(triflu0rornethy1)-3H-irnidazo [4,5 -b]pyridin-3 - yl)rnethy1)benzo[d]thiazol-Z-yl)arnino)cyclohexanol; 2-((6-((6-(trifluorornethyl)-3H-irnidazo [4,5 -b]pyridin-3 - yl)rnethy1)benzo[d]thiazol-Z-yl)arnino)cyclohexanol; (1S,2S)((6-((6-flu0r0-3H—imidazo [4,5 -b]pyridin-3 - yl)methyl)benzo[d]thiaz01—2-y1)amino)cyclohexanolg 2-((6-((6-flu0r0-3H—imidazo [4,5 -b]pyridin-3 -y1)rnethy1)benzo [d]thiaz01—2— yl)arnino)cyclohexanol; )—2-((6-((7-(1H-imidazol-l-y1)irnidaz0[1,2-a]pyridin-3 - yl)rnethy1)benzo[d]thiazol-Z-yl)arnino)cyclohexanol; 1 33 ((7-(1H-irnidaz01y1)irnidaz0[1,2-a]pyridin-3 - y1)rnethy1)benzo[d]thiaz01y1)arnino)cyclohexan01; (1R,2R)—2-((6-((7-(2H-1,2,3 -triaz01y1)irnidaz0[1,2-a]pyridin-3 - y1)rnethy1)benzo[d]thiaz01y1)arnin0)cyc10hexan01; 2-((6-((7-(2H-1,2,3 01y1)irnidaz0[1,2-a]pyridin—3 - y1)rnethy1)benzo[d]thiaz01y1)arnino)cyclohexan01; (1R,2R)((6-((7-Viny1irnidazo [1 ,2-a]pyridin-3 -y1)rnethy1)benzo [d]thiaz01-2— ino)cyclohexan01; 2-((6-((7-Viny1irnidazo[1 ,2-a]pyridin—3 -y1)rnethy1)benzo az01 y1)arnino)cyclohexan01; (1R,2R)((6-((7-(a11y10xy)irnidazo[1,2-a]pyridin-3 - y1)rnethy1)benzo[d]thiaz01y1)arnin0)cyc10hexan01; 2-((6-((7-(a11y10xy)irnidaz0 [1 ,2-a]pyridin-3 -y1)rnethy1)benz0 [d]thiaz01-2— y1)arnino)cyclohexan01; (1R,2R)—2-((6-((7-(1H-1,2,3 -triaz01y1)irnidaz0[1,2-a]pyridin-3 - y1)rnethy1)benzo[d]thiaz01y1)arnin0)cyc10hexan01; 2-((6-((7-(1H-1,2,3 -triaz01y1)irnidaz0[1,2-a]pyridin—3 - y1)rnethy1)benzo[d]thiaz01y1)arnino)cyclohexan01; N—(( 1 R,2S)—2-ch10rocyc10hexy1)—6-((6-fluor0-3H—imidazo [4,5 idin-3 - y1)rnethy1)benzo [d]thiaz01arnine; N—(2-ch10rocyc10hexy1)((6-fluoro-3H—irnidazo [4,5 -b]pyridin-3 - y1)rnethy1)benzo [d]thiaz01arnine; 3 -arnin0((2-(((1R,2R)—2-hydroxycyc10hexy1)amino)benzo[d]thiaz01 y1)rnethy1)pyrazin-2(1H)-0ne acetate salt; 3 -arnin0((2-(((1R,2R)—2-hydroxycyc10hexy1)amino)benzo[d]thiaz01 y1)rnethy1)pyrazin-2(1H)-0ne; 3-amino((2-((2-hydr0xycyclohexy1)amino)benzo [d]thiaz01 y1)rnethy1)pyrazin-2(1H)-0ne; 3 -((2-((( 1R,2R)hydr0xycyc10hexy1)amino)benzo [d]thiaz01 y1)rnethy1)irnidazo[1 ,2-b]pyridazinecarb0nitrile; 3 (2-hydr0xycyc10hexy1)arnino)benzo [d]thiaz01y1)rnethy1)irnidaz0[ 1 ,2- b]pyridazinecarbonitrile; 1 -((2-(((1R,2R)hydr0xycyc10hexy1)arnino)benzo[d]thiaz01y1)rnethy1)-3 - morpholinopyrazin-2(1H)—0ne; 1 34 1 -((2-((2-hydr0xycyc10hcxy1)arnino)bcnzo[d]thiazolyl)rncthy1)—3 - morpholinopyrazin-2(1H)—0nc; (3 -((2-(((1R,2R)hydroxycyc10hcxy1)arnino)bcnzo[d]thiaz01—6- yl)rncthyl)irnidazo[ 1 ,2-a]pyridiny1)(pyrr0lidiny1)rncthan0nc; (3 -((2-((2-hydr0xycyclohcxy1)amino)bcnzo [d]thiaz01—6- yl)rncthyl)irnidazo[ 1 ,2-a]pyridiny1)(pyrr0lidiny1)rncthan0nc; (1-((2-(((1R,2R)—2-hydroxycyclohcxyl)amino)bcnzo[d]thiaz01—6- yl)mcthy1)—1H—bcnzo[d]irnidazol-5 -y1)acry1ic acid; (1-((2-((2-hydroxycyclohcxyl)amino)bcnzo[d]thiaz01—6-yl)rncthyl)-1H- bcnzo[d]imidaz01—5-y1)acry1ic acid; 3 -(1 -((2-((2-hydr0xycyc10hcxyl)amin0)bcnz0[d]thiaz01—6-yl)rncthyl)- 1H- bcnzo[d]imidaz01—5-y1)acry1ic acid; (1R,2R)((6-((5 -(1,2,3 ,6-tctrahydropyridiny1)-1H-bcnz0 [d]irnidaz01— 1 - yl)mcthyl)bcnzo[d]thiaz01—2-y1)amino)cyclohcxanol; 2-((6-((5 -(1 ,2 ,3 ,6-tctrahydr0pyridiny1)- z0 [d]irnidaz01— 1 - yl)mcthyl)bcnzo[d]thiaz01—2-y1)arnin0)cyc10hcxanol; (1R,2R)—2-((6-((5 -(1H—irnidaz01—1-y1)-1H—bcnz0[d]irnidazol yl)mcthyl)bcnzo[d]thiaz01—2-y1)amino)cyclohcxanol; 2-((6-((5 -(1H—irnidaz01—1-y1)-1H—bcnzo[d]irnidazol yl)mcthyl)bcnzo[d]thiazo1y1)arnin0)cyc10hcxan01; )((6-((5 -(2-mcthy1—2H—tctrazol-5 -y1)- 1H-bcnz0 [d]irnidaz01— 1 - yl)mcthyl)bcnzo[d]thiaz01—2-y1)amino)cyclohcxanol; ((5 -(2-mcthy1—2H—tctrazoly1)-1H—bcnz0[d]irnidazol yl)mcthyl)bcnzo[d]thiazo1y1)arnin0)cyc10hcxan01; ( 1S,2R,3R)—3 -((6-((6-flu0r0-3H—irnidazo [4,5 -b]pyridin-3 - yl)mcthyl)bcnzo[d]thiazo1y1)arnino)cyclohcxanc-1 ,2-di01; 3 -((6-((6-flu0r0-3H—imidazo [4,5 -b]pyridin-3 -y1)rncthy1)bcnzo [d]thiaz01—2— y1)amino)cyclohcxanc-1 ,2-di01; (1R,2S,3R)((6-((7-(1H-pyraz01—1-y1)irnidaz0[1,2-a]pyridin-3 - yl)mcthy1)bcnzo[d]thiaz01y1)arnin0)cyc10hcxanc- 1 ,2-di01; 3 -((6-((7-(1H-pyraz01—1-y1)irnidaz0[1,2-a]pyridin-3 - yl)mcthy1)bcnzo[d]thiaz01y1)arnin0)cyc10hcxanc- 1 ,2-di01; ,3R)—3 -((6-((5 -rncth0xy- lH-bcnzo [d]irnidaz01— 1 - yl)rncthy1)bcnzo[d]thiazoly1)arnino)cyclohcxanc- 1 ,2-di01; 1 35 3 -((6-((5 -methoxy- 1H-benzo [d]imidazolyl)methyl)benzo [d]thiazol yl)amino)cyclohexane-1 ,2-diol; (1R,2S,3R)—3-((6-((7-(2H-1,2,3-triazolyl)imidazo[1,2-a]pyridin yl)methyl)benzo[d]thiazolyl)amino)cyclohexane- 1 ,2-diol; 3-((6-((7-(2H-1,2,3-triazolyl)imidazo[1,2-a]pyridin yl)methyl)benzo[d]thiazolyl)amino)cyclohexane- 1 ,2-diol; (1R,2S,3R)((6-((5 -vinyl- 1H—benzo[d]imidazol yl)methyl)benzo[d]thiazolyl)amino)cyclohexane- 1 ,2-diol; 3-((6-((5 -1H-benzo[d]imidazolyl)methyl)benzo[d]thiazol yl)amino)cyclohexane- 1 ,2-diol; (1R,2S,3R)((6-((5-(oxetanyloxy)-1H-benzo[d]imidazol yl)methyl)benzo[d]thiazolyl)amino)cyclohexane- 1 ,2-diol; 3 -((6-((5 -(oxetan-3 -yloxy)- 1 o [d]imidazolyl)methyl)benzo [d]thiazol- 2-yl)amino)cyclohexane- 1 ,2-diol; ,3R)—3-((6-((6-(1H-1,2,4-triazolyl)-3H-imidazo[4,5-b]pyridin yl)methyl)benzo[d]thiazolyl)amino)cyclohexane- 1 l; ((6-(1H-1,2,4-triazolyl)-3H-imidazo[4,5-b]pyridin yl)methyl)benzo[d]thiazolyl)amino)cyclohexane- 1 ,2-diol; (1R,2S,3R)((6-((5-morpholino- 1H—benzo[d]imidazol yl)methyl)benzo[d]thiazolyl)amino)cyclohexane- 1 ,2-diol; 3 -((6-((5 -morpholino- 1H-benzo [d]imidazolyl)methyl)benzo [d]thiazol-2— yl)amino)cyclohexane- 1 ,2-diol; (1R,2S,3R)((6-((5-(2-methyl-2H—tetrazol-5 -yl)— 1H-benzo dazol yl)methyl)benzo[d]thiazo1yl)amino)cyclohexane-1 ,2-diol; and 3 -((6-((5 -(2-methyl-2H-tetrazolyl)- 1H-benzo dazol yl)methyl)benzo[d]thiazolyl)amino)cyclohexane- 1 ,2-diol.

Also provided herein are isotopically enriched analogs of the compounds provided herein. Isotopic enrichment (for example, deuteration) of pharmaceuticals to improve pharmacokinetics (“PK”), pharmacodynamics (“PD”), and toxicity profiles, has been demonstrated previously with some classes of drugs. See, for example, Lijinsky et. al. Food Cosmet. Toxicol. 20: 393 ; Lijinsky et. al. J. Nat. Cancer , , , Inst, 69: 1127 (1982); d et. al., Mutation Res. 308: 33 (1994); Gordon et. al., Drug Metab. Dispos., 15: 589 (1987); Zello et. al. 43: 487 (1994); , Metabolism, Gately et. al., J. Nucl. Med, 27: 388 ; Wade D, Chem. Biol. Interact. 117: 191 (1999).

] Isotopic enrichment of a drug can be used, for example, to (1) reduce or eliminate unwanted metabolites, (2) increase the half-life of the parent drug, (3) decrease the number of doses needed to achieve a desired effect, (4) decrease the amount of a dose necessary to achieve a d effect, (5) increase the formation of active metabolites, if any are , and/or (6) decrease the production of rious metabolites in specific tissues and/or create a more effective drug and/or a safer drug for combination therapy, whether the combination therapy is intentional or not.

Replacement of an atom for one of its isotopes often will result in a change in the reaction rate of a chemical reaction. This enon is known as the Kinetic Isotope Effect (“KIE”). For example, if a C—H bond is broken during a rate- determining step in a chemical reaction (z'.e. the step with the t transition state energy), substitution of a deuterium for that hydrogen will cause a decrease in the reaction rate and the process will slow down. This phenomenon is known as the Deuterium Kinetic Isotope Effect (“DKIE”). (See, e. g, Foster et al., Adv. Drug Res., vol. 14, pp. 1-36 (1985); Kushner et al., Can. J. Physiol. Pharmacol., vol. 77, pp. 79- 88 (1999)).

Tritium (“T”) is a radioactive isotope of hydrogen, used in research, fusion reactors, neutron generators and radiopharmaceuticals. Tritium is a hydrogen atom that has 2 neutrons in the nucleus and has an atomic weight close to 3. It occurs naturally in the environment in very low concentrations, most ly found as T20. Tritium decays slowly (half-life = 12.3 years) and emits a low energy beta particle that cannot penetrate the outer layer of human skin. Internal exposure is the main hazard associated with this isotope, yet it must be ed in large amounts to pose a significant health risk. As compared with deuterium, a lesser amount of tritium must be ed before it reaches a hazardous level. Substitution of m (“T”) for hydrogen results in yet a stronger bond than deuterium and gives numerically larger isotope effects. Similarly, substitution of isotopes for other ts, including, but not limited to, 13 3 3 C or 14C for carbon, S, 34S, or 36S for sulfur, 15N for nitrogen, and 17O or 18O for oxygen, will provide a similar kinetic isotope effects.

In another embodiment, provided herein are methods of using the disclosed compounds and compositions, or pharmaceutically acceptable salts, solvates, hydrates, clathrates, single stereoisomers, mixture of stereoisomers or racemic e of stereoisomers thereof, for the local or systemic treatment or laxis of human and veterinary diseases, disorders and conditions modulated or ise affected mediated via CSFlR, FLT3, KIT, and/or PDGFRB kinase activity.

C. FORMULATION OF PHARMACEUTICAL COMPOSITIONS The pharmaceutical itions provided herein contain therapeutically effective amounts of one or more of compounds provided herein that are useful in the prevention, treatment, or amelioration of CSFlR, FLT3, KIT, and/or PDGFRB kinase mediated diseases or one or more of the symptoms thereof ] The itions contain one or more compounds ed herein. The compounds can be formulated into suitable pharmaceutical preparations such as solutions, suspensions, s, sible tablets, pills, capsules, powders, sustained e formulations or elixirs, for oral administration or in sterile solutions or suspensions for parenteral administration, as well as transdermal patch preparation and dry powder rs. Typically the compounds bed above are formulated into pharmaceutical compositions using techniques and procedures well known in the art.

In the compositions, effective concentrations of one or more compounds or pharmaceutically acceptable salts, solvates, hydrates, clathrates, single stereoisomers, mixture of stereoisomers or racemic mixture of stereoisomers or prodrug is (are) mixed with a suitable pharmaceutical carrier or vehicle. The concentrations of the compounds in the compositions are effective for delivery of an amount, upon administration, that treats, prevents, or rates one or more of the symptoms of CSFlR, FLT3, KIT, and/or PDGFRB kinase mediated es.

Typically, the compositions are formulated for single dosage administration. To formulate a composition, the weight fraction of compound is dissolved, suspended, dispersed or otherwise mixed in a selected vehicle at an effective concentration such that the treated condition is relieved or ameliorated.

Pharmaceutical carriers or vehicles suitable for administration of the compounds provided herein include any such carriers known to those skilled in the art to be suitable for the ular mode of administration.

In addition, the compounds may be ated as the sole ceutically active ingredient in the composition or may be combined with other active ingredients. Liposomal suspensions, including tissue-targeted liposomes, such as tumor-targeted liposomes, may also be suitable as pharmaceutically acceptable carriers. These may be prepared ing to methods known to those skilled in the art. For example, liposome formulations may be prepared as known in the art.

Briefly, liposomes such as multilamellar vesicles (MLV's) may be formed by drying down egg phosphatidyl e and brain phosphatidyl serine (7:3 molar ratio) on the inside of a flask. A solution of a compound ed herein in phosphate buffered saline lacking divalent cations (PBS) is added and the flask shaken until the lipid film is dispersed. The resulting es are washed to remove unencapsulated compound, pelleted by centrifugation, and then resuspended in PBS.

] The active compound is included in the pharmaceutically acceptable carrier in an amount sufficient to exert a therapeutically useful effect in the absence of undesirable side effects on the patient treated. The therapeutically effective concentration may be determined empirically by testing the compounds in in vitro and in viva systems described herein and then extrapolated therefrom for s for humans.

The concentration of active compound in the pharmaceutical composition will depend on absorption, vation and excretion rates of the active compound, the physicochemical characteristics of the compound, the dosage schedule, and amount administered as well as other factors known to those of skill in the art. For example, the amount that is delivered is sufficient to ameliorate one or more of the symptoms of CSFlR, FLT3, KIT, and/or PDGFRB kinase mediated diseases.

] Typically a therapeutically ive dosage should produce a serum concentration of active ingredient of from about 1 ng/ml to about 50-100 ug/ml. The pharmaceutical compositions typically should provide a dosage of from about 10 mg to about 4000 mg of compound per kilogram of body weight per day. Pharmaceutical dosage unit forms are prepared to provide from about 10 mg to about 1000 mg and in certain embodiments, from about 10 mg to about 500 mg, from about 20 mg to about 250 mg or from about 25 mg to about 100 mg of the essential active ingredient or a combination of ial ingredients per dosage unit form. In certain embodiments, the pharmaceutical dosage unit forms are ed to provide about 10 mg, 20 mg, 25 mg, 50 mg, 100 mg, 250 mg, 500 mg, 1000 mg or 2000 mg ofthe essential active ingredient.

The active ient may be administered at once, or may be divided into a number of smaller doses to be administered at intervals of time. It is understood that the precise dosage and duration of treatment is a function of the disease being treated and may be determined cally using known testing protocols or by extrapolation from in vivo or in vitro test data. It is to be noted that concentrations and dosage values may also vary with the severity of the condition to be alleviated. It is to be further understood that for any particular t, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that the concentration ranges set forth herein are exemplary only and are not ed to limit the scope or practice of the claimed itions.

Pharmaceutically acceptable derivatives include acids, bases, enol ethers and esters, salts, esters, hydrates, solvates and prodrug forms. The derivative is selected such that its pharmacokinetic properties are superior to the corresponding neutral compound.

Thus, effective trations or amounts of one or more of the compounds described herein or pharmaceutically able derivatives thereof are mixed with a suitable pharmaceutical carrier or vehicle for systemic, l or local administration to form pharmaceutical compositions. Compounds are included in an amount ive for ameliorating one or more symptoms of, or for treating or preventing CSFlR, FLT3, KIT, and/or PDGFRB kinase mediated diseases. The concentration of active compound in the composition will depend on absorption, inactivation, excretion rates of the active nd, the dosage schedule, amount administered, particular formulation as well as other factors known to those of skill in the art.

The compositions are intended to be administered by a suitable route, including, but not limited to, orally, parenterally, rectally, topically and locally. For oral administration, es and tablets can be formulated. The compositions are in liquid, semi-liquid or solid form and are formulated in a manner suitable for each route of administration.

Solutions or sions used for parenteral, intradermal, subcutaneous, or topical application can include any of the following components: a sterile t, such as water for injection, saline solution, fixed oil, polyethylene glycol, glycerine, propylene glycol, dimethyl acetamide or other synthetic solvent; antimicrobial agents, such as benzyl alcohol and methyl parabens; idants, such as ascorbic acid and sodium bisulfite; chelating agents, such as nediaminetetraacetic acid (EDTA); buffers, such as acetates, citrates and ates; and agents for the adjustment of tonicity such as sodium chloride or se. Parenteral preparations can be enclosed in ampules, disposable syringes or single or multiple dose Vials made of glass, plastic or other suitable al.

In instances in which the compounds exhibit insufficient solubility, methods for solubilizing compounds may be used. Such methods are known to those of skill in this art, and e, but are not limited to, using cosolvents, such as dimethylsulfoxide (DMSO), using surfactants, such as TWEEN®, or dissolution in aqueous sodium bicarbonate.

Upon mixing or addition of the compound(s), the resulting mixture may be a solution, suspension, emulsion or the like. The form of the resulting mixture depends upon a number of factors, including the intended mode of administration and the solubility of the compound in the selected carrier or vehicle. In one embodiment, the effective concentration is sufficient for ameliorating the symptoms of the disease, disorder or condition treated and may be empirically determined.

The pharmaceutical compositions are provided for administration to humans and s in unit dosage forms, such as tablets, capsules, pills, powders, granules, sterile parenteral solutions or suspensions, and oral solutions or sions, and oil-water emulsions containing suitable quantities of the nds or pharmaceutically acceptable derivatives thereof. The pharmaceutically therapeutically active compounds and derivatives thereof are typically formulated and administered in osage forms or multiple-dosage forms. Unit-dose forms as used herein refer to physically discrete units le for human and animal subjects and packaged individually as is known in the art. Each unit-dose contains a predetermined quantity of the therapeutically active compound sufficient to produce the desired therapeutic effect, in association with the required pharmaceutical carrier, vehicle or diluent. Examples of unit-dose forms include ampules and syringes and individually packaged s or capsules. Unit-dose forms may be stered in fractions or multiples thereof. A multiple-dose form is a plurality of identical unit-dosage forms packaged in a single container to be administered in segregated unit-dose form. Examples of multiple-dose forms include vials, bottles of tablets or capsules or s of pints or gallons. Hence, multiple dose form is a le of unit-doses which are not segregated in ing.

] Sustained-release preparations can also be prepared. Suitable examples of sustained-release preparations include rmeable matrices of solid hydrophobic rs containing the compound provided herein, which matrices are in the form of shaped articles, e.g., films, or microcapsule. Examples of sustained-release es include polyesters, hydrogels (for example, poly(2-hydroxyethyl-methacrylate), or poly(vinylalcohol)), polylactides, copolymers of L-glutamic acid and ethyl-L- glutamate, non-degradable ethylene-vinyl acetate, able lactic lycolic acid copolymers such as the LUPRON DEPOTTM (injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide e), and poly-D-(-) ybutyric acid. While polymers such as ethylene-vinyl acetate and lactic acid- glycolic acid enable release of molecules for over 100 days, certain hydrogels release proteins for shorter time periods. When encapsulated nd remain in the body for a long time, they may denature or aggregate as a result of exposure to moisture at 37 0C, resulting in a loss of biological activity and possible changes in their structure.

Rational strategies can be devised for ization depending on the mechanism of action involved. For example, if the aggregation mechanism is discovered to be intermolecular S--S bond formation through thio-disulfide interchange, stabilization may be achieved by modifying sulfhydryl residues, lyophilizing from acidic solutions, controlling moisture content, using appropriate additives, and developing specific polymer matrix compositions Dosage forms or compositions ning active ingredient in the range of 0.005% to 100% with the balance made up from non-toxic carrier may be prepared.

For oral administration, a ceutically acceptable non-toxic composition is formed by the incorporation of any of the normally employed excipients, such as, for e pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, talcum, cellulose derivatives, sodium crosscarmellose, glucose, sucrose, magnesium carbonate or sodium saccharin. Such compositions include solutions, suspensions, s, capsules, powders and sustained release formulations, such as, but not limited to, ts and microencapsulated delivery systems, and biodegradable, biocompatible polymers, such as collagen, ne vinyl acetate, polyanhydrides, polyglycolic acid, polyorthoesters, polylactic acid and others. Methods for preparation of these compositions are known to those d in the art. The contemplated compositions may contain about 0.001%-100% active ingredient, in certain embodiments, about 01-85%, typically about 75-95%.

] The active compounds or pharmaceutically acceptable derivatives may be prepared with carriers that protect the nd against rapid elimination from the body, such as time release formulations or coatings.

The compositions may include other active compounds to obtain desired combinations of properties. The compounds provided herein, or pharmaceutically acceptable derivatives thereof as bed herein, may also be advantageously administered for therapeutic or prophylactic purposes together with another pharmacological agent known in the general art to be of value in treating one or more of the diseases or medical conditions referred to above, such as CSFlR, FLT3, KIT, and/or PDGFRB kinase mediated diseases. It is to be understood that such combination therapy constitutes a further aspect of the itions and methods of treatment provided herein. 1. Compositions for oral administration Oral pharmaceutical dosage forms are either solid, gel or liquid. The solid dosage forms are tablets, capsules, granules, and bulk powders. Types of oral tablets include compressed, le lozenges and tablets which may be enteric-coated, sugar-coated or film-coated. Capsules may be hard or soft gelatin capsules, while granules and powders may be provided in fervescent or escent form with the ation of other ingredients known to those skilled in the art.

In certain embodiments, the formulations are solid dosage forms, such as es or tablets. The tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder; a diluent; a disintegrating agent; a lubricant; a glidant; a sweetening agent; and a flavoring agent.

Examples of s include microcrystalline cellulose, gum tragacanth, glucose solution, acacia mucilage, n solution, sucrose and starch paste.

Lubricants e talc, starch, magnesium or calcium stearate, lycopodium and stearic acid. Diluents include, for example, lactose, e, starch, kaolin, salt, mannitol and dicalcium phosphate. Glidants include, but are not limited to, colloidal silicon dioxide. Disintegrating agents include armellose sodium, sodium starch glycolate, alginic acid, corn , potato starch, bentonite, methylcellulose, agar and carboxymethylcellulose. Coloring agents include, for example, any of the approved ed water soluble FD and C dyes, mixtures thereof; and water insoluble FD and C dyes suspended on alumina hydrate. ning agents include sucrose, lactose, mannitol and artificial sweetening agents such as saccharin, and any number of spray dried flavors. ing agents include natural flavors extracted from plants such as fruits and synthetic blends of compounds which produce a pleasant sensation, such as, but not limited to peppermint and methyl salicylate. Wetting agents include propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate and polyoxyethylene laural ether. Emetic-coatings include fatty acids, fats, waxes, shellac, ated shellac and cellulose acetate ates. Film coatings include hydroxyethylcellulose, sodium carboxymethylcellulose, polyethylene glycol 4000 and cellulose acetate phthalate.

If oral administration is desired, the compound could be provided in a composition that protects it from the acidic environment of the stomach. For example, the composition can be formulated in an enteric g that maintains its integrity in the stomach and releases the active compound in the ine. The composition may also be formulated in combination with an antacid or other such ingredient.

When the dosage unit form is a capsule, it can contain, in addition to material of the above type, a liquid carrier such as a fatty oil. In addition, dosage unit forms can contain various other materials which modify the physical form of the dosage unit, for example, coatings of sugar and other enteric agents. The nds can also be administered as a ent of an elixir, suspension, syrup, wafer, sprinkle, chewing gum or the like. A syrup may contain, in addition to the active compounds, sucrose as a sweetening agent and certain preservatives, dyes and colorings and flavors.

The active materials can also be mixed with other active materials which do not impair the desired action, or with materials that supplement the desired action, such as antacids, H2 blockers, and diuretics. The active ingredient is a compound or pharmaceutically acceptable derivative thereof as described herein. Higher concentrations, up to about 98% by weight ofthe active ingredient may be included.

Pharmaceutically acceptable carriers included in tablets are binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring , and wetting agents. Enteric-coated tablets, because of the enteric-coating, resist the action of stomach acid and dissolve or disintegrate in the l or alkaline intestines.

Sugar-coated tablets are compressed tablets to which different layers of pharmaceutically acceptable substances are d. Film-coated tablets are ssed tablets which have been coated with a polymer or other suitable coating.

Multiple compressed tablets are compressed tablets made by more than one compression cycle utilizing the pharmaceutically acceptable substances previously mentioned. Coloring agents may also be used in the above dosage forms. Flavoring and sweetening agents are used in compressed tablets, sugar-coated, multiple compressed and chewable tablets. Flavoring and sweetening agents are especially useful in the formation of chewable tablets and lozenges.

Liquid oral dosage forms include aqueous solutions, emulsions, suspensions, solutions and/or suspensions reconstituted from non-effervescent granules and effervescent ations reconstituted from effervescent granules.

Aqueous solutions include, for example, elixirs and syrups. Emulsions are either oil-in-water or water-in-oil.

Elixirs are clear, sweetened, hydroalcoholic preparations.

Pharmaceutically able carriers used in s include solvents. Syrups are concentrated s solutions of a sugar, for example, sucrose, and may contain a preservative. An emulsion is a two-phase system in which one liquid is sed in the form of small es throughout r liquid. Pharmaceutically able carriers used in emulsions are non-aqueous liquids, emulsifying agents and preservatives. Suspensions use pharmaceutically able suspending agents and vatives. Pharmaceutically acceptable substances used in non-effervescent es, to be reconstituted into a liquid oral dosage form, include diluents, sweeteners and wetting agents. Pharmaceutically acceptable substances used in effervescent granules, to be tituted into a liquid oral dosage form, include organic acids and a source of carbon dioxide. Coloring and flavoring agents are used in all of the above dosage forms.

Solvents include glycerin, sorbitol, ethyl alcohol and syrup. Examples of preservatives include glycerin, methyl and propylparaben, benzoic add, sodium benzoate and alcohol. Examples of non-aqueous liquids utilized in emulsions include mineral oil and cottonseed oil. Examples of emulsifying agents include gelatin, acacia, tragacanth, bentonite, and surfactants such as polyoxyethylene sorbitan monooleate. Suspending agents e sodium carboxymethylcellulose, pectin, tragacanth, Veegum and . Diluents include lactose and sucrose. Sweetening agents include sucrose, syrups, glycerin and artificial sweetening agents such as saccharin. Wetting agents include propylene glycol monostearate, an monooleate, diethylene glycol monolaurate and polyoxyethylene lauryl ether.

Organic adds e citric and tartaric acid. Sources of carbon dioxide include sodium bicarbonate and sodium carbonate. Coloring agents e any of the approved certified water soluble ED and C dyes, and es thereof. ing agents include natural flavors extracted from plants such fruits, and synthetic blends of compounds which produce a pleasant taste sensation.

For a solid dosage form, the solution or suspension, in for example propylene carbonate, vegetable oils or triglycerides, is encapsulated in a gelatin capsule. For a liquid dosage form, the on, e.g, for example, in a polyethylene , may be diluted with a sufficient quantity of a pharmaceutically acceptable liquid carrier, 6.g. , water, to be easily measured for administration.

Alternatively, liquid or olid oral formulations may be prepared by dissolving or dispersing the active nd or salt in vegetable oils, glycols, triglycerides, propylene glycol esters (e.g., propylene carbonate) and other such carriers, and encapsulating these solutions or suspensions in hard or soft gelatin capsule . Other useful formulations include, but are not limited to, those containing a compound provided herein, a dialkylated mono- or poly-alkylene , including, but not d to, l,2-dimethoxymethane, diglyme, triglyme, tetraglyme, 1 46 polyethylene glycoldimethyl ether, polyethylene glycoldimethyl ether, polyethylene glycoldimethyl ether wherein 350, 550 and 750 refer to the approximate average molecular weight of the polyethylene glycol, and one or more antioxidants, such as ted hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone, hydroxycoumarins, ethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoric acid, thiodipropionic acid and its esters, and dithiocarbamates.

Other formulations include, but are not limited to, aqueous lic solutions including a pharmaceutically acceptable . Alcohols used in these formulations are any pharmaceutically acceptable water-miscible ts haVing one or more hydroxyl groups, including, but not limited to, propylene glycol and ethanol.

Acetals include, but are not limited to, er alkyl) acetals of lower alkyl aldehydes such as acetaldehyde diethyl acetal.

In all embodiments, tablets and capsules formulations may be coated as known by those of skill in the art in order to modify or sustain dissolution of the active ingredient. Thus, for example, they may be coated with a conventional enterically digestible coating, such as salicylate, waxes and cellulose acetate phthalate. 2. Inj ectables, solutions and emulsions Parenteral administration, generally terized by injection, either subcutaneously, intramuscularly or enously is also contemplated herein.

Inj ectables can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solution or suspension in liquid prior to injection, or as emulsions. le excipients are, for example, water, saline, dextrose, glycerol or ethanol. In addition, if desired, the pharmaceutical compositions to be administered may also contain minor amounts of non-toxic auxiliary substances such as wetting or emulsifying agents, pH buffering , stabilizers, solubility enhancers, and other such agents, such as for example, sodium acetate, sorbitan urate, anolamine oleate and cyclodextrins. In one embodiment, the composition is administered as an aqueous on with hydroxypropyl-betacyclodextrin ) as an excipient. In one embodiment, the aqueous solution contains about 1% to about 50% HPBCD. In one embodiment, the aqueous solution contains about 1%, 3%, 5%, 10% or about 20% HPBCD.

Implantation of a slow-release or sustained-release system, such that a constant level of dosage is maintained is also contemplated herein. Briefly, a compound provided herein is dispersed in a solid inner matrix, e.g., polymethylmethacrylate, polybutylmethacrylate, plasticized or unplasticized polyvinylchloride, plasticized nylon, plasticized polyethyleneterephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ne- vinylacetate copolymers, silicone rubbers, polydimethylsiloxanes, silicone carbonate copolymers, hydrophilic polymers such as hydrogels of esters of acrylic and methacrylic acid, collagen, cross-linked polyvinylalcohol and cross-linked lly hydrolyzed polyvinyl acetate, that is surrounded by an outer polymeric membrane, e. g., polyethylene, polypropylene, ethylene/propylene copolymers, ethylene/ethyl te copolymers, ethylene/vinylacetate copolymers, silicone rubbers, polydimethyl siloxanes, neoprene rubber, chlorinated hylene, polyvinylchloride, vinylchloride copolymers with vinyl acetate, vinylidene chloride, ethylene and propylene, ionomer polyethylene terephthalate, butyl rubber epichlorohydrin s, ethylene/vinyl alcohol mer, ethylene/vinyl acetate/vinyl alcohol terpolymer, and ethylene/vinyloxyethanol copolymer, that is insoluble in body fluids. The compound dlffilSGS through the outer polymeric membrane in a e rate controlling step. The tage of active compound ned in such parenteral compositions is highly dependent on the specific nature thereof, as well as the activity of the compound and the needs of the subject.

Parenteral administration of the compositions includes enous, subcutaneous and intramuscular administrations. Preparations for eral administration include sterile ons ready for injection, e dry soluble products, such as lyophilized powders, ready to be combined with a solvent just prior to use, including hypodermic tablets, sterile suspensions ready for injection, e dry insoluble products ready to be combined with a vehicle just prior to use and sterile emulsions. The solutions may be either aqueous or nonaqueous.

] If administered intravenously, suitable carriers include physiological saline or phosphate buffered saline (PBS), and ons containing thickening and solubilizing agents, such as glucose, polyethylene glycol, and polypropylene glycol and mixtures thereof.

Pharmaceutically acceptable carriers used in parenteral preparations include aqueous vehicles, nonaqueous vehicles, antimicrobial agents, isotonic , buffers, antioxidants, local anesthetics, suspending and dispersing agents, emulsifying , tering or chelating agents and other pharmaceutically acceptable substances.

] Examples of aqueous vehicles e Sodium Chloride Injection, s Injection, Isotonic se Injection, Sterile Water Injection, se and Lactated Ringers Injection. eous eral es include fixed oils of vegetable origin, cottonseed oil, corn oil, sesame oil and peanut oil. Antimicrobial agents in bacteriostatic or fungistatic concentrations must be added to parenteral preparations packaged in multiple-dose containers which include phenols or cresols, mercurials, benzyl alcohol, chlorobutanol, methyl and propyl p-hydroxybenzoic acid esters, thimerosal, benzalkonium chloride and benzethonium chloride. Isotonic agents include sodium chloride and dextrose. Buffers include ate and e.

Antioxidants include sodium bisulfate. Local anesthetics include procaine hydrochloride. Suspending and dispersing agents include sodium carboxymethylcelluose, hydroxypropyl methylcellulose and polyvinylpyrrolidone. fying agents include Polysorbate 80 (TWEEN® 80). A sequestering or chelating agent of metal ions include EDTA. Pharmaceutical carriers also include ethyl alcohol, hylene glycol and propylene glycol for water miscible vehicles and sodium hydroxide, hydrochloric acid, citric acid or lactic acid for pH adjustment.

The concentration of the pharmaceutically active compound is adjusted so that an ion provides an effective amount to produce the desired pharmacological effect. The exact dose depends on the age, weight and condition of the patient or animal as is known in the art.

The unit-dose parenteral preparations are packaged in an ampule, a vial or a syringe with a needle. All preparations for parenteral administration must be sterile, as is known and practiced in the art.

Illustratively, intravenous or intraarterial infusion of a sterile aqueous solution containing an active compound is an effective mode of administration.

Another embodiment is a sterile aqueous or oily solution or suspension containing an active material injected as necessary to produce the desired pharmacological effect.

WO 56070 ables are designed for local and systemic administration. Typically a therapeutically effective dosage is formulated to contain a concentration of at least about 0.1% w/w up to about 90% w/w or more, such as more than 1% w/w of the active compound to the treated tissue(s). The active ingredient may be administered at once, or may be d into a number of smaller doses to be administered at intervals of time. It is tood that the precise dosage and duration of ent is a fianction of the tissue being treated and may be determined empirically using known testing protocols or by extrapolation from in vivo or in vitro test data. It is to be noted that concentrations and dosage values may also vary with the age of the individual treated. It is to be fiarther understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the sional judgment of the person stering or supervising the administration of the formulations, and that the concentration ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed ations.

The compound may be suspended in micronized or other suitable form or may be tized to produce a more soluble active product or to produce a g.

The form of the resulting mixture depends upon a number of factors, including the intended mode of administration and the solubility of the compound in the selected carrier or vehicle. The effective concentration is ient for ameliorating the symptoms of the condition and may be empirically determined. 3. Lyophilized powders Of interest herein are also lyophilized powders, which can be tituted for administration as solutions, emulsions and other mixtures. They may also be reconstituted and formulated as solids or gels.

The e, lyophilized powder is prepared by dissolving a compound provided herein, or a pharmaceutically acceptable derivative thereof, in a suitable solvent. The solvent may contain an excipient which improves the stability or other pharmacological ent of the powder or reconstituted solution, prepared from the powder. Excipients that may be used include, but are not limited to, dextrose, sorbital, fructose, corn syrup, xylitol, glycerin, glucose, sucrose, hydroxypropyl-beta- cyclodextrin (HPBCD) or other suitable agent. The solvent may also n a buffer, such as citrate, sodium or potassium phosphate or other such buffer known to those of skill in the art at, typically, about neutral pH. Subsequent sterile filtration of the 1 50 WO 56070 solution followed by lyophilization under standard conditions known to those of skill in the art provides the desired formulation. lly, the resulting solution will be apportioned into vials for lyophilization. Each vial will contain a single dosage (10- 1000 mg, 100-500 mg, 10-500 mg, 50-250 mg or 25-100 mg) or multiple dosages of the compound. The lyophilized powder can be stored under appropriate conditions, such as at about 4°C to room temperature.

Reconstitution of this lyophilized powder with water for injection es a formulation for use in parenteral administration. For reconstitution, about l-50 mg, about 5-35 mg, or about 9-30 mg of lyophilized powder, is added per mL of e water or other suitable carrier. The precise amount depends upon the selected compound. Such amount can be empirically determined. 4. Topical administration Topical mixtures are prepared as bed for the local and ic administration. The resulting mixture may be a solution, sion, emulsions or the like and are formulated as creams, gels, ointments, emulsions, solutions, elixirs, lotions, suspensions, tinctures, pastes, foams, aerosols, irrigations, sprays, suppositories, bandages, dermal patches or any other formulations le for topical administration.

The compounds or pharmaceutically acceptable derivatives thereofmay be formulated as aerosols for topical application, such as by inhalation. These formulations for administration to the respiratory tract can be in the form of an aerosol or solution for a nebulizer, or as a microf1ne powder for insufflation, alone or in combination with an inert carrier such as lactose. In such a case, the particles of the formulation will lly have diameters of less than 50 s or less than 10 microns.

The compounds may be formulated for local or topical application, such as for topical application to the skin and mucous membranes, such as in the eye, in the form of gels, , and lotions and for application to the eye or for intracistemal or pinal application. Topical administration is contemplated for transdermal delivery and also for administration to the eyes or mucosa, or for inhalation therapies.

Nasal solutions of the active compound alone or in combination with other pharmaceutically acceptable excipients can also be administered.

WO 56070 These solutions, particularly those intended for ophthalmic use, may be ated as 0.01% - 10% isotonic solutions, pH about 5-7, with riate salts.

. Compositions for other routes of administration Other routes of administration, such as l application, transdermal patches, and rectal administration are also contemplated .

For example, pharmaceutical dosage forms for rectal administration are rectal itories, capsules and tablets for systemic effect. Rectal suppositories are used herein mean solid bodies for insertion into the rectum which melt or soften at body temperature releasing one or more pharmacologically or therapeutically active ients. Pharmaceutically acceptable substances utilized in rectal suppositories are bases or vehicles and agents to raise the melting point. Examples of bases include cocoa butter (theobroma oil), glycerin-gelatin, carbowax (polyoxyethylene glycol) and appropriate mixtures of mono-, di- and triglycerides of fatty acids. Combinations of the various bases may be used. Agents to raise the melting point of suppositories include spermaceti and wax. Rectal suppositories may be prepared either by the compressed method or by molding. The typical weight of a rectal suppository is about 2 to 3 gm.

Tablets and capsules for rectal administration are manufactured using the same pharmaceutically acceptable substance and by the same methods as for formulations for oral administration. 6. Sustained e Compositions Active ingredients provided herein can be administered by controlled release means or by ry devices that are well known to those of ordinary skill in the art. Examples include, but are not limited to, those described in US. Patent Nos.: 3,845,770; 3,916,899; 3,536,809; 3,598,123; and 4,008,719, 5,674,533, 5,059,595, ,591,767, 548, 5,073,543, 5,639,476, 5,354,556, 5,639,480, 5,733,566, ,739,108, 474, 5,922,356, 5,972,891, 5,980,945, 5,993,855, 6,045,830, 324, 6,113,943, 6,197,350, 6,248,363, 6,264,970, 6,267,981, 6,376,461,6,419,961, 6,589,548, 6,613,358, 6,699,500 and 6,740,634, each ofwhich is incorporated herein by reference. Such dosage forms can be used to provide slow or controlled-release of one or more active ingredients using, for e, hydropropylmethyl cellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, pheres, or a combination thereof to provide the desired release profile in varying proportions.

Suitable controlled-release formulations known to those of ordinary skill in the art, including those described herein, can be readily selected for use with the active ingredients provided herein.

All controlled-release pharmaceutical products have a common goal of improving drug therapy over that achieved by their non-controlled counterparts.

Ideally, the use of an optimally designed controlled-release preparation in l treatment is characterized by a minimum of drug substance being employed to cure or control the condition in a minimum amount of time. Advantages of controlled-release formulations include extended activity of the drug, reduced dosage frequency, and increased patient compliance. In addition, controlled-release formulations can be used to affect the time of onset of action or other characteristics, such as blood levels of the drug, and can thus affect the occurrence of side (e.g., adverse) s.

Most controlled-release formulations are designed to initially release an amount of drug (active ingredient) that promptly produces the d therapeutic , and gradually and continually release of other s of drug to maintain this level of therapeutic or prophylactic effect over an extended period of time. In order to maintain this constant level of drug in the body, the drug must be ed from the dosage form at a rate that will replace the amount of drug being metabolized and excreted from the body. Controlled-release of an active ingredient can be stimulated by various conditions including, but not limited to, pH, ature, enzymes, water, or other physiological conditions or compounds.

In certain ments, the agent may be administered using intravenous infusion, an implantable c pump, a ermal patch, liposomes, or other modes of administration. In one embodiment, a pump may be used. In another embodiment, polymeric materials can be used. In yet another embodiment, a controlled release system can be placed in proximity of the eutic target, z'.e., thus requiring only a fraction of the systemic dose. In some embodiments, a controlled release device is introduced into a subject in proximity of the site of inappropriate immune activation or a tumor. The active ingredient can be sed in a solid inner matrix, e. g., polymethylmethacrylate, tylmethacrylate, plasticized or unplasticized polyvinylchloride, plasticized nylon, plasticized polyethyleneterephthalate, natural rubber, polyisoprene, polyisobutylene, tadiene, polyethylene, ethylene-vinylacetate copolymers, silicone rubbers, polydimethylsiloxanes, silicone carbonate copolymers, hydrophilic polymers such as hydrogels of esters of acrylic and methacrylic acid, collagen, cross-linked polyvinylalcohol and cross-linked partially hydrolyzed polyvinyl acetate, that is nded by an outer polymeric membrane, e.g., polyethylene, polypropylene, ethylene/propylene copolymers, ethylene/ethyl acrylate copolymers, ethylene/vinylacetate mers, silicone rubbers, polydimethyl siloxanes, neoprene rubber, chlorinated polyethylene, polyvinylchloride, vinylchloride copolymers with vinyl acetate, vinylidene chloride, ethylene and propylene, ionomer polyethylene terephthalate, butyl rubber epichlorohydrin rubbers, ethylene/vinyl l copolymer, ethylene/vinyl acetate/vinyl alcohol ymer, and ethylene/vinyloxyethanol copolymer, that is ble in body fluids. The active ingredient then diffuses through the outer polymeric membrane in a release rate controlling step. The percentage of active ingredient contained in such parenteral compositions is highly dependent on the specific nature thereof, as well as the needs of the t. 7. ed Formulations The compounds provided herein, or pharmaceutically acceptable derivatives thereof, may also be formulated to be targeted to a particular tissue, receptor, or other area of the body of the subject to be treated. Many such ing methods are well known to those of skill in the art. All such targeting methods are contemplated herein for use in the instant compositions. For non-limiting examples oftargeting methods, see, e.g., US. Patent Nos. 6,316,652, 6,274,552, 6,271,359, 6,253,872, 6,139,865, 6,131,570, 6,120,751, 6,071,495, 6,060,082, 6,048,736, 6,039,975, 6,004,534, 5,985,307, 5,972,366, 5,900,252, 5,840,674, 542 and 874.

In one ment, liposomal suspensions, including tissue-targeted liposomes, such as tumor-targeted liposomes, may also be suitable as pharmaceutically acceptable carriers. These may be prepared according to methods known to those skilled in the art. Briefly, liposomes such as multilamellar vesicles (MLV's) may be formed by drying down egg phosphatidyl e and brain phosphatidyl serine (7:3 molar ratio) on the inside of a flask. A solution of a compound provided herein in phosphate buffered saline lacking divalent cations (PBS) is added and the flask shaken until the lipid film is dispersed. The resulting vesicles are washed to remove unencapsulated compound, pelleted by centrifiagation, and then resuspended in PBS.

D. EVALUATION OF THE ACTIVITY OF THE NDS Standard physiological, pharmacological and biochemical procedures are available for testing the compounds to identify those that possess biological activities that modulate the activity of CSFlR, FLT3, KIT, and/or PDGFRB kinase.

] Such assays include, for example, biochemical assays such as binding , radioactivity incorporation assays, as well as a y of cell based assays.

In certain embodiments, the compounds disclosed herein are tested in an M-NFS-60 cell proliferation assay to determine their cellular potency against CSFlR.

M-NFS-60s are mouse monocytic cells that depend on the binding of the ligand M- CSF to its or, CSFlR, to erate. Inhibition of CSFlR kinase activity will cause reduced growth and/or cell death. This assay assesses the potency of compounds as CSFlR inhibitors by measuring the reduction of Alamar Blue reagent by viable cells. An ary assay is described in the Examples section.

In certain embodiments, competition binding assays were performed as bed in Fabian et al., Nature Biotechnology 2005, 23,329-336.

In one embodiment, the compounds provided herein were found to have de of about or less than about 150 nM against FLT3 kinase. In one embodiment, the nds provided herein have de of about 1 nM or less, 3 nM or less, 5 nM or less, 0.1-2 nM, 2-5 nM, 5-lOnM, M, 25-50 nM, or 50-150 nM, against FLT3 kinase. In one embodiment, the compounds provided herein have de of less than about 50, 25, 10, 5, 4, 3, 2, or 1 nM against FLT3 kinase. In r embodiment, the compounds ed herein have de of about or less than about 5 nM, 3 nM or 1 nM against FLT3 kinase.

In one embodiment, the compounds provided herein were found to have de of about or less than about 50 nM against KIT kinase. In one embodiment, the compounds provided herein have de of about 1 nM or less, 3 nM or less, 0.1-2 nM, 2-5 nM, 5-lOnM, or 10-25 M, against KIT kinase. In one embodiment, the compounds provided herein have de of less than about 10, 5, 4, 3, 2 or 1 nM against KIT kinase. In another embodiment, the compounds ed herein have de of about or less than about 5 nM, 3 nM or 1 nM against KIT kinase.

In one ment, the compounds provided herein were found to have de of about or less than about 100 nM or 50 nM against PDGFRB kinase. In one embodiment, the compounds provided herein have de of about about 1 nM or less, 3 nM or less, 0.1-2 nM, 2-5 nM, 5-10nM, or 10-25 M, against PDGFRB kinase. In one embodiment, the compounds provided herein have de of less than about 10, 5, 4, 3, 2 or 1 nM against PDGFRB kinase. In another embodiment, the compounds ed herein have de of about or less than about 5 nM, 3 nM or 1 nM against PDGFRB kinase.

In one embodiment, the compounds provided herein were found to have de of about or less than about 1 uM against CSFlR kinase. In one embodiment, the compounds provided herein were found to have de of less than about 1, 0.5, 0.1 or 0.01 uM against CSF1R kinase. In one embodiment, the compounds provided herein were found to have de ofless than about 300, 200, 100, 50, 10, 5, 4, 3, 2, or 1 nM against CSF1R kinase. In another embodiment, the compounds provided herein were found to have de of about or less than about 5 nM, 3 nM or 1 nM against CSF1R kinase.

E. S OF USE OF THE COMPOUNDS AND ITIONS Also ed herein are methods of using the disclosed compounds and compositions, or ceutically acceptable salts, solvates, hydrates, clathrates, single stereoisomers, mixture of stereoisomers, racemic mixture of stereoisomers or prodrugs thereof, for the treatment, tion, or amelioration of a disease or disorder that is mediated or otherwise affected via protein kinase activiy or one or more symptoms of diseases or disorders that are mediated or otherwise ed via protein kinase activity (see, Krause and Van Etten, N Engl JMed (2005) 353(2): 172- 187, Blume-Jensen and Hunter, Nature (2001) 411(17): 355-365 and Plowman et al., DN&P, 7:334-339 ).

In certain embodiments, provided herein are methods of treating the following diseases or disorders: 1) carcinomas include Kit-mediated and/or CSFlR—mediated carcinomas, adenocarcinoma, squamous cell carcinoma, adenosquamous carcinoma, carcinoma, head and neck , brain cancer, ranial carcinoma, glioblastoma including PDGFR-mediated glioblastoma, glioblastoma multiforme including PDGFR-mediated astoma multiforme, neuroblastoma, cancer of the larynx, multiple endocrine neoplasias 2A and 2B (MENS 2A and MENS 2B) including RET-mediated MENS, thyroid cancer, including sporadic and familial medullary thyroid carcinoma, papillary thyroid carcinoma, parathyroid carcinoma including any RET-mediated thyroid carcinoma, follicular thyroid cancer, anaplastic d cancer, bronchial carcinoid, oat cell carcinoma, lung cancer, small-cell lung cancer ing flt-3 and/or Kit-mediated small cell lung cancer, h/ gastric cancer, gastrointestinal cancer, gastrointestinal stromal tumors (GIST) including Kit- mediated GIST and PDGFRu —mediated GIST, colon cancer, colorectal cancer, pancreatic cancer, islet cell oma, hepatic/liver , metastases to the liver, bladder cancer, renal cell cancer including PDGFR-mediated renal cell cancer, cancers of the genitourinary tract, ovarian cancer ing Kit-mediated and/or mediated and/or mediated ovarian cancer, endometrial cancer including CSFlR-mediated endometrial cancer, cervical cancer, breast cancer including Fltmediated and/or PDGFR-mediated and/or CSFlR—mediated breast cancer, prostate cancer including Kit-mediated prostate cancer, germ cell tumors including Kit-mediated germ cell tumors, seminomas including Kit-mediated seminomas, dysgerminomas, including Kit-mediated minomas, melanoma including PDGFR-mediated melanoma, metastases to the bone including CSFlR- mediated bone metastases, metastatic tumors including VEGFR—mediated and/or CSFlR metastatic tumors, stromal tumors, neuroendocrine tumors, tumor angiogenesis including mediated and/or CSFlR—mediated tumor angiogenesis, mixed mesodermal tumors; 2) sarcomas including PDGFR-mediated as, osteosarcoma, osteogenic sarcoma, bone cancer, glioma including PDGFR-mediated and/or CSFlR- mediated glioma, astrocytoma, vascular tumors including mediated vascular tumors, Kaposi’s sarcoma, carcinosarcoma, iosarcomas including VEGFR3- mediated hemangiosarcomas, lymphangiosarcoma including VEGFR3-mediated lymphangiosarcoma; WO 56070 3) liquid tumors, myeloma, multiple myeloma, leukemia, myeloproliferative diseases (MPD), acute myeloid leukemia (AML) including flt-3 ed and/or KIT-mediated and/or CSFlR—mediated acute myeloid leukemia, chronic myeloid leukemias (CML) including Fltmediated and/or PDGFR-mediated chronic myeloid leukemia, myelodysplastic leukemias including Fltmediated myelodysplastic ia, acute megakaryoblastic leukemia CSFlR-mediated acute megakaryoblastic leukemia, myelodysplastic syndrome, including Flt-3 mediated and/or diated myelodysplastic syndrome (MDS), idiopathic osinophilic syndrome (HES) including PDGFR-mediated HES, chronic eosinophilic leukemia (CEL) including PDGFR-mediated CEL, c myelomonocytic leukemia (CMML), mast cell leukemia including Kit-mediated mast cell ia, or systemic mastocytosis ing Kit-mediated systemic mastocytosis; and 4) lymphoma, Hodgkin’s lymphoma, proliferative diseases, acute lymphoblastic leukemia (ALL), B- cell acute lymphoblastic leukemias, T-cell acute lymphoblastic leukemias, natural killer (NK) cell leukemia, B-cell lymphoma, T-cell lymphoma, and natural killer (NK) cell lymphoma, any of which may be Flt-3 ed and/or PDGFR-mediated, Langerhans cell histiocytosis including CSFlR- mediated and fltmediated Langerhans cell histiocytosis, mast cell tumors and mastocytosis; 2) Nonmalignant proliferation diseases; atherosclerosis including CSFlR- mediated atherosclerosis or PDGFR-mediated atherosclerosis, restenosis following vascular angioplasty including PDGFR-mediated restenosis, and flbroproliferative disorders such as rative bronchiolitis and idiopathic myelofibrosis, both of which may be mediated, pulmonary fibrosis and also obesity and obesity- induced insulin resistance, either of which may be CSFlR mediated; 5) Inflammatory diseases or immune disorders ing autoimmune diseases, which include, but is not limited to, tissue transplant rejection, graft-versus- host disease, wound healing, kidney disease, multiple sclerosis, thyroiditis, type 1 diabetes, sarcoidosis, allergic rhinitis, nephritis, mer’s e, inflammatory bowel e including Crohn’s disease and ulcerative colitis (UC), systemic lupus erythematosis (SLE), cutaneous lupus erythematosis (SLE), lupus nephritis, glomerular nephritis, arthritis, osteoarthritis, toid arthritis, psoriatic arthritis, inflammatory arthritis, osteoporosis, asthma and chronic obstructive pulmonary disease (COPD), allergic asthma, ankylosing spondylitis, including any of the aforementioned diseases which are fltmediated and/or CSFlR—mediated and/or diated; 6) Bone diseases including disorders relating to the mineralization, formation and resorption of the bone, including but not limited to osteoporosis, glucocorticoid-induced osteoporosis, periodontitis, bone loss due to cancer y, osthetic osteolysis, Paget’s disease, hypercalcemia, hypercalcemia of malignancy, osteomyelitis, and bone pain; and 7) Infectious es mediated either via viral or bacterial pathogens and sepsis, including KIT-mediated and/or mediated sepsis.

] Also provided are methods of modulating the activity, or subcellular distribution, of kinases in a cell, tissue or whole organism, using the nds and compositions provided , or pharmaceutically acceptable derivatives thereof In one embodiment, provided herein are methods of ting the activity of FLT3 ty in a cell, tissue or whole organism using the compounds and compositions provided herein, or pharmaceutically acceptable derivatives thereof In one embodiment, ed herein are methods of modulating the ty of CSFlR activity in a cell, tissue or whole organism using the compounds and compositions provided herein, or pharmaceutically acceptable derivatives thereof In one embodiment, provided herein are methods of modulating the activity of KIT activity in a cell, tissue or whole organism using the compounds and compositions provided herein, or pharmaceutically acceptable derivatives thereof In one embodiment, the methods provided herein are for treating tumor- associated osteolysis, osteoporosis including ovariectomy-induced bone loss, orthopedic implant failure, renal inflammation and glomerulonephritis, transplant rejection including renal and bone marrow allografts and skin xenograft, obesity, Alzheimer's Disease and Langerhans cell histiocytosis. In one embodiment, the methods provided herein are for ng chronic skin disorders including psoriasis.

In another embodiment, a method for treating periodontitis, hans cell histiocytosis, osteoporosis, Paget's disease of bone (PDB), bone loss due to cancer therapy, periprosthetic ysis, glucocorticoid-induced osteoporosis, rheumatoid arthritis, psoriatic arthritis, osteoarthritis, and/or inflammatory arthritis is provided herein.

] In one embodiment, the methods provided herein are for treating bone diseases including disorders relating to the mineralization, formation and resorption of the bone, including but not limited to osteoporosis, Paget’s disease, hypercalcemia, hypercalcemia of malignancy, osteolysis, osteomyelitis, and bone pain.

In one embodiment, the methods provided herein are for treating cancers, including, but not limited to liquid tumors, head and neck cancer, (originating in lip, oral cavity, oropharynx, hypopharynx, larynx, nasopharynx, nasal cavity and sal sinuses or salivary ); lung cancer, including small cell lung cancer, non-small cell lung cancer; gastrointestinal tract s, including esophageal , gastric cancer, colorectal cancer, anal cancer, pancreatic cancer, liver cancer, gallbladder cancer, extrahepatic bile duct cancer, cancer of the ampulla of vater; breast cancer; gynecologic cancers, including, cancer of uterine cervix, cancer of the uterine body, vaginal cancer, vulvar cancer, ovarian , gestational trophoblastic cancer neoplasia; testicular ; urinary tract cancers, including, renal , urinary bladder cancer, prostate cancer, penile cancer, urethral cancer; neurologic tumors; tenosynovial giant cell tumors, endocrine neoplasms, including carcinoid and islet cell tumors, pheochromocytoma, l cortical carcinoma, parathyroid carcinoma and metastases to endocrine glands. In r embodiment, the methods provided herein are for treating carcinoma, breast cancer, ovarian cancer, bone ases, osteoporosis, Paget’s disease, hypercalcemia, hypercalcemia of malignancy, osteolysis, yelitis, bone pain, inflammatory bowel disease (IBD), Crohn’s disease, ulcerative colitis (UC), systemic lupus erythematosis (SLE), lupus nephritis, glomerular nephritis, arthritis, osteoarthritis, rheumatoid arthritis, osteoporosis, asthma, allergic asthma, chronic obstructive pulmonary disease (COPD), psoriasis, ankylosing spondylitis, and multiple sclerosis. In r embodiment, provided herein are s for ng inflammatory diseases of the eye including conjunctivitis, uveitis, iritis, scleritis, blepheritis, meibomitis and optical neuritis. In yet another embodiment, provided herein are methods for treating glaucoma, diabetic retinopathy and macular ration. r examples of cancers are basal cell carcinoma; us cell carcinoma; chondrosarcoma (a cancer arising in cartilage cells); mesenchymal- 2012/059983 chondrosarcoma; soft tissue sarcomas, including, malignant tumours that may arise in any of the mesodermal tissues (muscles, tendons, s that carry blood or lymph, joints and fat); soft tissue sarcomas include; alveolar soft-part sarcoma, angiosarcoma, f1brosarcoma, leiomyosarcoma, liposarcoma, ant fibrous histiocytoma, hemangiopericytoma, mesenchymoma, schwannoma, peripheral neuroectodermal s, rhabdomyosarcoma, synovial sarcoma; gestational trophoblastic tumour(malignancy in which the tissues formed in the uterus following conception become cancerous); Hodgkin's lymphoma and laryngeal cancer.

In one embodiment, the cancer is a leukemia. In one ment, the leukemia is chronic lymphocytic leukemia, chronic myelocytic leukemia, acute lymphoblastic leukemia, acute myeloid leukemia, and acute myeloblastic leukemia.

In another embodiment, the leukemia is acute leukemia. In one embodiment, the acute leukemia is acute myeloid leukemia (AML). In one embodiment, acute d leukemia is undifferentiated AML (M0), myeloblastic leukemia (Ml), myeloblastic leukemia (M2), locytic leukemia (M3 or M3 t [M3V]), myelomonocytic leukemia (M4 or M4 variant with philia [M4E]), monocytic leukemia (M5), erythroleukemia (M6), or megakaryoblastic leukemia (M7). In another ment, the acute myeloid leukemia is undifferentiated AML (M0). In yet another embodiment, the acute myeloid leukemia is myeloblastic leukemia (Ml). In yet r embodiment, the acute myeloid leukemia is myeloblastic leukemia (M2). In yet another embodiment, the acute myeloid leukemia is promyelocytic leukemia (M3 or M3 t [M3V]). In yet another embodiment, the acute myeloid leukemia is myelomonocytic leukemia (M4 or M4 variant with philia [M4E]). In yet another embodiment, the acute myeloid leukemia is monocytic leukemia (M5). In yet another embodiment, the acute myeloid leukemia is erythroleukemia (M6). In yet another embodiment, the acute myeloid ia is megakaryoblastic leukemia (M7). In yet another embodiment, the acute myeloid ia is promyelocytic leukemia In another embodiment, the acute leukemia is acute lymphocytic leukemia (ALL). In one embodiment, the acute lymphocytic ia is leukemia that ates in the blast cells of the bone marrow (B-cells), thymus (T-cells), or lymph nodes. The acute lymphocytic leukemia is categorized according to the French- American-British (FAB) Morphological Classification Scheme as Ll - Mature- 1 61 appearing lymphoblasts (T-cells or pre-B-cells), L2 - Immature and pleomorphic (variously shaped) lymphoblasts (T-cells or cells), and L3 - blasts (B- cells; t's cells). In another embodiment, the acute lymphocytic leukemia originates in the blast cells of the bone marrow (B-cells). In yet another embodiment, the acute lymphocytic leukemia originates in the thymus (T-cells). In yet another embodiment, the acute lymphocytic leukemia originates in the lymph nodes. In yet another ment, the acute lymphocytic leukemia is Ll type characterized by mature-appearing lymphoblasts (T-cells or cells). In yet another embodiment, the acute lymphocytic leukemia is L2 type characterized by immature and rphic (variously shaped) lymphoblasts (T-cells or cells). In yet another ment, the acute lymphocytic leukemia is L3 type characterized by lymphoblasts (B-cells; Burkitt's cells).

In yet another ment, the leukemia is T-cell leukemia. In one embodiment, the T-cell ia is peripheral T-cell leukemia, T-cell lymphoblastic leukemia, cutaneous T-cell leukemia, and adult T-cell leukemia. In another embodiment, the T-cell leukemia is peripheral T-cell leukemia. In yet another embodiment, the T-cell leukemia is T-cell lymphoblastic leukemia. In yet another embodiment, the T-cell ia is cutaneous T-cell leukemia. In still another embodiment, the T-cell leukemia is adult T-cell leukemia.

In yet another embodiment, the leukemia is Philadelphia positive. In one ment, the Philadelphia positive leukemia is Philadelphia positive AML, including, but not limited to, undifferentiated AML (M0), myeloblastic leukemia (Ml), myeloblastic ia (M2), promyelocytic leukemia (M3 or M3 variant [M3V]), myelomonocytic leukemia (M4 or M4 variant with eosinophilia [M4E]), monocytic leukemia (M5), erythroleukemia (M6), or megakaryoblastic ia (M7). In another embodiment, the Philadelphia positive leukemia is Philadelphia positive ALL.

In still another embodiment, the leukemia is drug resistant. In still another embodiment, the gastrointestinal l tumor (GIST) is drug resistant. In still another embodiment, the melanoma is drug resistant. In one embodiment, the subject has developed drug resistance to the anticancer therapy.

] The cancers to be treated herein may be primary or atic. In one embodiment, the cancer is a solid or blood born metastatic tumor. In another embodiment, the cancer is metastatic cancer of bone.

Also provided are methods of modulating the activity, or subcellular distribution, of CSFlR kinase in a cell, tissue or whole organism, using the compounds and compositions provided herein, or pharmaceutically acceptable salts, solvates, hydrates, clathrates, single stereoisomers, mixture of stereoisomers or racemic e of stereoisomers thereof.

The active ingredient(s) in one ment are stered in an amount sufficient to deliver to a patient a eutically effective amount of the active compound in order to e.g., treat the diseases described herein, without causing serious toxic effects in a treated subject.

A typical dose of the compound may be in the range of from about 1 to about 50 mg/kg, from about 1 to about 20 mg/kg, from about 0.1 to about 10 mg/kg, from about 0.5 mg/kg to about 10 mg/kg, of body weight per day, more generally from about 0.1 to about 100 mg/kg body weight of the recipient per day.

Alternatively, a typical dose of the nd may be in the range of from about 50 mg to about 500 mg. Lower dosages may be used, for example, doses of about 0.5- 100 mg, 05-10 mg, or 0.5-5 mg per kilogram body weight per day. Even lower doses may be , and thus ranges can include from about 0.1-0.5 mg/kg body weight of the ent per day. The effective dosage range of the pharmaceutically acceptable derivatives is calculated based on the weight of the parent compound to be delivered.

If the derivative compound itself exhibits activity, then the effective dosage can be estimated as above using the weight of the derivative, or by other means known to those of skill in the art.

The compounds are conveniently administered in units of any suitable dosage form, including but not limited to one containing from about 1 to 2000 mg, from about 10 to 1000 mg, or from about 25 to 700 mg of active ient per unit dosage form. In one embodiment, the unit dose is selected from 12, 18, 25, 27, 40, 50, 60, 90, 100, 135, 200, 250, 300, 400, 450, 500, 600, 675, 700, 800, 900 and 1000 mgs. For example, an oral dosage of from about 25 to 1000 mg is usually convenient, including in one or multiple dosage forms of 10, 12, 18, 25, 27, 40, 50, 60, 90, 100, 135, 200, 250, 300, 400, 450, 500, 600, 675, 700, 800, 900 or 1000 mgs. In certain embodiments, lower dosages may be used, for example, from about 10-100 or l-50 mgs. Also contemplated are doses of 01-50 mg, 01-20 mg, or 01-10 mg. rmore, lower doses may be utilized in the case of administration by a non-oral route, as for example, by injection or inhalation.

The active ingredient may be administered at once, or may be divided into a number of smaller doses to be administered at intervals of time. It is tood that the precise dosage and duration of treatment is a fianction of the disease being treated and may be determined cally using known testing protocols or by extrapolation from in vivo or in vitro test data. It is to be noted that concentrations and dosage values may also vary with the ty of the condition to be alleviated. It is to be further understood that for any particular subject, c dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that the concentration ranges set forth herein are exemplary only and are not intended to limit the scope or ce of the compositions provided herein.

In n ments, the compound or composition ed herein can be administered as a single once-a-day dose (QD) or as divided doses throughout a day. In particular ments, the compound or composition is administered four times per day (QID). In particular embodiments, the compound or composition is administered three times per day (TID). In particular embodiments, the compound or composition is administered two times per day (BID). In particular embodiments, the compound or composition is administered once per day (QD).

The administration can also be continuous (i.e., daily for consecutive days or every day) or ittent . The term “intermittent” or “intermittently” as used herein is intended to mean stopping and starting at either regular or irregular intervals.

For example, intermittent administration of the compound of Formula I may be administration for one to six days per week or administration on alternate days.

In one embodiment, the compound or composition provided herein is stered intermittently. In yet another embodiment, the compound or composition provided herein is administered intermittently once weekly, twice weekly or three times weekly. In yet another embodiment, the compound or composition provided herein is administered once weekly. In yet another embodiment, the compound or composition provided herein is administered twice weekly. In yet another embodiment, the compound or composition provided herein is administered three times . In one embodiment, the compound or ition ed herein is administered QD intermittently once weekly, twice weekly or three times . In yet another embodiment, the compound or composition ed herein is administered QD once weekly. In another embodiment, the compound or ition provided herein is administered QD twice weekly. In another embodiment, the compound or composition provided herein is administered QD three times weekly.

In one embodiment, the active ingredient is administered to achieve peak plasma concentrations of the active compound of from about 0.02 to 20 uM, from about 0.2 to about 5 uM or from about 0.5 to 10 uM. For example, this can be achieved by intravenous injection of a 0.1 to 5% solution of active ingredient, optionally in saline, or administered as a bolus of active ingredient. It is to be understood that for any particular subject, specific dosage ns should be adjusted over time to meet individual needs, and will vary depending upon absorption, inactivation and excretion rates of the drug. The concentrations set forth here are exemplary only and are not intended to limit the scope or practice of the d ition. The active ingredient may be administered all at once, or may be d into a number of smaller doses to be administered at varying intervals of time.

The subject matter has been described in an illustrative manner, and it is to be understood that the terminology used is intended to be in the nature of description rather than of limitation. Thus, it will be iated by those of skill in the art that conditions such as choice of solvent, temperature of reaction, volumes, reaction time may vary while still producing the desired compounds. In on, one of skill in the art will also iate that many of the reagents provided in the examples may be substituted with other suitable reagents. See, e. g., Smith & March, Advanced Organic Chemistry, 5‘11 ed. (2001).

F. COMBINATION THERAPY Furthermore, it will be understood by those skilled in the art that the compounds, isomers, and pharmaceutically acceptable salts, hydrates, solvates provided herein, ing pharmaceutical compositions and formulations containing these compounds, can be used in a wide variety of combination therapies to treat the conditions and diseases described above. Thus, also contemplated herein is the use of compounds, and pharmaceutically acceptable salts provided herein in combination with other active pharmaceutical agents for the treatment of the disease/conditions described herein.

In one embodiment, such additional pharmaceutical agents include without limitation anti-cancer agents (including chemotherapeutic agents and anti- proliferative agents), anti-inflammatory agents, immunomodulatory agents or immunosuppressive agents.

In certain embodiments, the anti-cancer agents include anti-metabolites (e.g., S-fluoro-uracil, cytarabine, clofarabine, methotrexate, fludarabine and ), antimicrotubule agents (e.g., vinca alkaloids such as vincristine, vinblastine; taxanes such as paclitaxel and docetaxel), alkylating agents (e.g., hosphamide, melphalan, carmustine, nitrosoureas such as bischloroethylnitrosurea and hydroxyurea), platinum agents (6.g. cisplatin, carboplatin, oxaliplatin, satraplatin and CI-973), anthracyclines (e.g., doxrubicin and daunorubicin), antitumor antibiotics (e.g., mitomycin, idarubicin, adriamycin and daunomycin), topoisomerase inhibitors (e. g., etoposide and camptothecins), ngiogenesis agents (e.g. Sutent®, sorafenib and Bevacizumab) or any other xic agents, (6.g. estramustine phosphate, mustine), hormones or hormone agonists, antagonists, partial agonists or partial antagonists, kinase inhibitors (such as imatinib), and radiation treatment.

In certain embodiments, the anti-inflammatory agents include matrix metalloproteinase tors, inhibitors of pro-inflammatory cytokines (e.g., anti-TNF molecules, TNF soluble receptors, and IL1) non-steroidal anti-inflammatory drugs s) such as prostaglandin synthase inhibitors (e.g., choline magnesium salicylate and lsalicyclic acid), COX-l or COX-2 inhibitors, glucocorticoid receptor agonists (e.g., corticosteroids, prednisone, prednisone, and cortisone) or antifolates such as methotrexate.

The nd or ition provided herein, or pharmaceutically acceptable salt of the compound, may be administered aneously with, prior to, or after administration of one or more of the above agents.

WO 56070 ] Pharmaceutical compositions containing a compound provided herein or pharmaceutically acceptable salt thereof, and one or more of the above agents are also provided.

Also provided, in one ment, is a combination y that treats or prevents the onset of the ms, or ated complications of cancer and related diseases and disorders, said therapy comprising the administration to a subject in need thereof, one of the compounds or compositions disclosed herein, or pharmaceutically acceptable salts thereof, with one or more anti-cancer agents. Also provided, in another embodiment, is a combination therapy that treats or prevents the onset of the symptom of osteoporosis and related diseases and disorders, said therapy comprising the administration to a subject in need f, one of the compounds or compositions disclosed herein, or ceutically acceptable salts thereof, with one or more anti- inflammatory or immunomodulatory . Also provided, in yet another embodiment, is a combination therapy that treats or prevents the onset of the symptom of rheumatoid arthritis and related es and disorders, said therapy comprising the stration to a subject in need thereof, one of the nds or compositions disclosed herein, or pharmaceutically acceptable salts thereof, with one or more anti- inflammatory or immunomodulatory agents.

G. PREPARATION OF COMPOUNDS Starting materials in the synthesis examples provided herein are either available from commercial sources or via literature procedures (e.g., March Advanced Organic Chemistry: ons, Mechanisms, and Structure, (1992) 4th Ed.; Wiley Interscience, New York). All commercially available compounds were used without further purification unless otherwise indicated. 300 MHz Proton (1H) nuclear magnetic resonance (NMR) spectra were recorded on a Bruker Avance 300 NMR spectrometer. Significant peaks are tabulated and typically include: number of protons, and multiplicity (s, singlet; d, double; t, triplet; q, quartet; m, let; br s, broad singlet). Chemical shifts are reported as parts per million (8) relative to tetramethylsilane. Low resolution mass spectra (MS) were obtained as electrospray tion (ESI) mass spectra, which were recorded on a Shimadzu HPLC/MS instrument using reverse-phase conditions (acetonitrile/water, 0.05% acetic acid). ative reverse phase HPLC was typically performed using a Varian HPLC system equipped with a Phenomenex phenylhexyl, a Phenomenex Luna C18, or a Varian Pursuit diphenyl reverse phase column; typical elution conditions utilized a gradient containing an increasing composition of organic cosolvent (0.05% HOAc/CHgCN or 0.05% HOAc/MeOH) to aqueous cosolvent (0.05% aq HOAc).

Silica gel chromatography was either performed manually, typically following the published procedure for flash tography (Still et al. (1978) J. Org. Chem. 43 , or on an automated system (for example, Biotage SP instrument) using pre- packed silica gel s.

It is understood that in the following description, combinations of substituents and/or variables of the depicted formulae are permissible only if such contributions result in stable compounds under standard conditions.

It will also be appreciated by those skilled in the art that in the process described below, the functional groups of intermediate compounds may need to be ted by suitable protecting groups. Such fianctional groups include hydroxy, amino, mercapto and carboxylic acid. le protecting groups for hydroxy include trialkylsilyl or diarylalkylsilyl (e.g, t-butyldimethylsilyl, t-butyldiphenylsilyl or hylsilyl), tetrahydropyranyl, benzyl, and the like. Suitable protecting groups for amino, amidino and guanidino include t-butoxycarbonyl, benzyloxycarbonyl, and the like. Suitable protecting groups for mercapto e -C(O)—R (where R is alkyl, aryl or aralkyl), p-methoxybenzyl, trityl and the like. Suitable protecting groups for ylic acid include alkyl, aryl or aralkyl esters.

Protecting groups may be added or removed in ance with standard techniques, which are well-known to those skilled in the art and as described herein.

The use of protecting groups is described in detail in Green, T.W. and P.G.M. Wutz, Protective Groups in Organic Synthesis (1991), 2nd Ed., Wiley-Interscience.

One of ordinary skill in the art could easily ascertain which choices for each substituent are possible for the reaction conditions of each Scheme. Moreover, the tuents are selected from components as indicated in the specification heretofore, and may be attached to starting als, ediates, and/or final products according to s known to those of ordinary skill in the art.

Also it will be nt that the compounds provided herein could exist as one or more isomers, that is, E/Z isomers, enantiomers and/or diastereomers.

Compounds of formula (I) may be generally ed as depicted in the following schemes, unless otherwise noted, the various substituents are as defined elsewhere herein.

Standard abbreviations and acronyms as defined in J. Org. Chem. 2007 72(1): 23A-24A are used herein. Other abbreViations and acronyms used herein are as follows: EDCI N—(3-Dimethylaminopropyl)-N’- ethylcarbodiimide hydrochloride HATU O-(7-azabenzotriazol- lyl)-N,N,N’ ,N’ - ethyluronium orophosphate LCMS liquid chromatography mass Scheme 1: General synthesis of compounds of formula (I).

O 0 W KSCN, Br2 RO / l . ROJKr/W S CuBr2, MeCN RO /W 8 WW NH2 W.~WIN’>_NH2 nitrite N’>_Br 1 R=alkyl 2 reduction W S R'SOZCI, R'\ // —.Ho/\W(/ I />_Br :W N base, solvent OIIS\O/\r/W]:S>—B/ r W N R' = alkyl or aryl, etc. 3 4 WE R3 WSVQ£H5n w2 W 7 \ s H'il‘Y-R4 2 3 N \ We W R —» mm 1H 3m \Im base, solvent W )n ‘W N base, t, heating W4(J)n W‘W/ N/ ‘Y-R“ In an illustrative method, certain compounds of formula (I) may be routinely prepared according to the synthetic route outlined in Scheme 1. The readily available 2-amino-substituted azole compounds 1 are either commercially available or can be prepared from ponding oarylcarboxylates or 4- aminoheteroarylcarboxylates using procedures analogous to those described by Molinos-Gomez, et al. Tetrahedron 61, 9075 (2005). Amines 1 can be converted to bromides 2 under Sandmeyer conditions with a bromine source such as, but not limited to, cupric bromide, using an organic nitrite such as, but not limited to, tert- butyl nitrite or iso-amyl e. The reaction can be conducted in a solvent such as, but not limited to, MeCN. The carboxylates of 2 can be reduced to give alcohols 3 using a reducing agent such as, but not limited to, DIBAL-H or LiBH4, in a solvent such as, but not limited to, DCM or THF. The alcohols 3 can be converted to sulfonates 4 using a sulfonating agent such as, but not limited to, methanesulfonyl chloride or enesulfonyl chloride. The reaction can be conducted in a solvent such as, but not limited to, DCM or THF and promoted with a base such as, but not limited to, TEA or ne. Alkylation of heteroaryls/heterocyclyls 5 with sulfonate 4 to give compounds 6 can be effected in the presence of a base, such as, but not limited to, NaH or t—BuOK. The alkylation can be ted in a solvent such as, but not d to, DMF or THF, at elevated temperature if necessary. The regiochemistry of the alkylation can be discerned by carefill examination of the 2-dimensional nuclear Overhauser effect (NOE) in the NMR of products. The bromides 6 can be treated with amine 7 under philic tution conditions at elevated temperature in a solvent such as, but not limited to, DMA or DMF, and promoted with a base such as, but not limited to, DIEA or TEA to afford compounds 8.

Scheme 2: General synthesis of compounds of formula (I). i O O O NBS, solvent /\0 SK ,W s W W Br R0 I SH RO / l —> R0 / I W: NI) W . W: W.W NH2 W NH2 11 9 Mel, base, solvent 0 O reductlon. W NaSMe THF S W Y W HO / / | , Br | ,)—s w w “w N ‘w N ‘w N 2 (2 =3) 12 13 NH 2 W w s. / s W” ‘18» / catalyst, solvent W N base, solvent W HN~ . . WE s 4 _ 7 W3A\N/Y \w2 W OXIdatlon W3AN/\f j: />—S/ Y R S R3 W44)“ W~ ’ W N ‘b W4(J)n W~ , ’>_N‘Y—R4 base, solvent, heating W N 16 3(2 :3) ] In an illustrative method, certain compounds of formula (I) may be routinely prepared according to the synthetic route outlined in Scheme 2. The y available aminoaryl/heteroaryl compounds 9 can be converted to bromides 10 with a bromination agent such as, but not limited to, N-bromosuccimide or e. The reaction can be ted in a solvent such as, but not limited to, MeCN or DCM.

Condensation of bromides 10 with potassium O-ethyl carbonodithioate in a solvent such as, but not limited to, DMF under refluxing conditions can afford mercaptan compounds 11, which can be alkylated with iodomethane to give sulfides 12.

The reaction can be run in a solvent such as, but not limited to, DMF or DMA and promoted with a base such as, but not limited to, K2C03 or C82C03 at elevated temperature if ary. Alternatively, methylsulfides 12 can be prepared starting from bromides 2 by treating with sodium thiomethoxide in a solvent, such as, but not limited to, THF or MeCN. The carboxylate group of 12 can be reduced to give ls 13 using a reducing agent such as, but not limited to, DIBAL-H or LiBH4, in a solvent such as, but not limited to, DCM or THF. The alcohols 13 can be converted to chlorides 14 using an agent such as, but not limited to, l chloride or oxalyl de, in a solvent such as, but not limited to, DCM. The reaction can be catalyzed by the addition of a small amount of DMF. Alkylation of heteroaryls/heterocyclyls 5 with chlorides 14 to give compounds 15 can be effected using a base such as, but not d to, NaH or t—BuOK. The alkylation can be conducted in a t such as, but not limited to, DMF or THF, at elevated temperature if necessary. The sulfide moiety of 15 can be oxidized to the corresponding sulfoxide using an oxidizing agent such as, but not limited to, m-CPBA or peracetic acid. The oxidation can be conducted in a solvent such as, but not limited to, DCM or AcOH. The sulfinyl group of 16 can be displaced with an amine 7 under nucleophilic tution conditions at elevated ature to afford nds 8. The reaction can be run in a solvent such as, but not limited to, DMA or DMF, and promoted with a base such as, but not limited to, DIEA or TEA.

Scheme 3: General synthesis of compounds of formula (I).

Hlil w 1%3W s ‘Y—R4 7 PIC/\mlr j:’>_N‘Y—R4W 3 R3 oxidation HO / I ‘W N base, solvent, heating ~W N 3 17 O base, solvent OR 3 3 . ”m .—» / ~ 4 I ~ 4 _ [Wm/ _ . 19 W ’ 18 WW W'W 20 R=Hora|kyl silane, acid yv: W\ S $3 —> HN | I />—N‘ solvent / W*W Y_R W~-W’W In r illustrative method, nds of formula (I) may also be routinely prepared according to the synthetic route outlined in Scheme 3. Heteroaryl bromides 3 can react with amines 7 as previously described to give products 17, which can be oxidized to the corresponding aldehydes 18 with an oxidizing agent such as, but not limited to, Dess-Martin periodinane or M1102, in a solvent such as, but not limited to, DCM or MeCN. Condensation of aldehydes 18 and heteroaryls 19 can provide carbinol compounds 20 (R = H). The condensation can be promoted with a base such as, but not limited to, KOH or NaOH, in a solvent such as, but not limited to, MeOH or EtOH. When the on is conducted in an alcohol solvent, products 20 (R = alkyl) can also be isolated. Reduction of compounds 20 with a silane such as, but not limited to, , promoted with the addition of an acid such as, but not limited to, trifluoroacetic acid or methanesulfonic acid will provide compounds 21. The reduction reaction can be conducted in a solvent such as, but not limited to, DCM or MeCN.

Scheme 4: General synthesis of compounds of formula (I).

AJL N\ /\0 \ W enation /W| X SK S halo , W N NH2 NH2 23 24 X = Cl or Br Mel base W solvent N\rwl: reduction HzN/Y IS}! W N’ 26 fl, solvent, Y heating “\kw WZ W.yv NHZ ion trialkyl orthoformate IN,)—)—s/ —> WWWIN/YWWI:/>_S/ cat. HCOOH 28 29 /\ w //\N W s HN, N/ N/Y S>_ / N oxidation /\'// l >—S/ Y_R4 7 F( | W: N/ S )4 W:W N/ W \b V\/_. n W.- II base, solvent, heating w—W W’W 31 w s F3 MW 1M W:W N Y’R4 W_. ll In another illustrative method, certain compounds of formula (I) may be routinely prepared according to the synthetic route outlined in Scheme 4. The readily ble aminoaryl/heteroaryl nitriles 22 can be treated with a halogenating agent such as, but not limited to, N—chlorosuccimide or N—bromosuccimide to afford halogenated products 23. The reaction can be conducted in a solvent such as, but not d to, MeCN or DCM. Condensation of compounds 23 with potassium l carbonodithioate in a solvent such as, but not limited to, DMF, under refluxing ions can afford mercaptan nds 24, which can be ted with iodomethane to give methylsulf1des 25. The methylation reaction can be conducted in a solvent such as, but not limited to, DMF or DMA and promoted with a base such as, but not limited to, K2C03 or CSZC03, at elevated temperatures if necessary. The nitrile group of 25 can be reduced to aminomethyl compounds 26 using a reducing agent such as, but not d to, LiAlH4 or nickel , in a solvent such as, but not limited to, THF or diethyl ether. Aryl/heteroaryl compounds 27 appropriately substituted with halo and nitro groups can react with amines 26 to afford corresponding amino and nitro substituted aryl/heteroaryl compounds 28, promoted with a base such as, but not d to, K2C03 or DIEA, in a solvent such as, but not limited to, DMF or DMA. The reaction can be be further promoted by elevated temperatures if necessary. The nitro group of 28 can be reduced to an amino group using a reducing agent such as, but not limited to, Zn or Fe, in the presence of an acid such as, but not limited to, AcOH or HCl, in a solvent such as, but not limited to, DCM or EtOH. The diamino heteroaryls 29 can react with a trialkyl orthoformate such as, but not limited to, trimethyl orthoformate or triethyl orthoformate to form bicyclic heteroaryl compounds 30.. The cyclization reaction can be promoted with an acid catalyst such as, but not limited to, HCOOH or AcOH at ed temperature.

The sulfides 30 can be converted to sulfoxides 31, then to final compounds 32 as described for Scheme 2. 2012/059983 Scheme 5: General sis of nds of formula (1).

W3 aminolysis WNH with HNR'R" W S w X w4(J)n 33 mm IH _.XVEN \ / (X=COZR) W3 W S my 13,»; / o w Amt :1H W:W l . base, solvent 34 14 X = Cl, Br, I or 002R \oxidation oxidation HES 4 3 \7 Y R I W3 w WWW“2 HN\ o 3 N x I S / 7 WAw4(J)n l F53 />—8 WEN W\ 8 w3 I W(1) w' 1H- n w N Y-R4 x w. , / W N ‘b /AW;(J)n W N,Y_R4 base, solvent, heating X ‘w N NR'R" 4o 36 X=C|,Br,| X=C|,Br,| orCOzR orCOzR Suzuki coupling Ullmann coupling with HNR'R" W\2 W S R3 Cu|,base W ‘1 x>—NI)n W‘W/ N Y—R4 In another illustrative method, compounds of formula (I) may also be routinely prepared according to the synthetic route outlined in Scheme 5. tion of heteroaryls/heterocyclyls 33 with chlorides 14 to give nds 34 can be effected using a base such as, but not limited to, NaH or . The alkylation can be conducted in a solvent such as, but not limited to, DMF or THF, at elevated temperatures if necessary. Following a two step sequence of oxidation and nucleophilic substitution as described in Scheme 2, the s 34 can be converted first to sulfoxides 35 and then to compounds 36. Suzuki coupling of 36 with aryl or heteroaryl boronic acids or boronate esters catalyzed by a palladium st such as, but not limited to, Pd(dppf)Clz or PdClz(PPh3)2, in a solvent such as, but not limited to, MeCN or 1,4-dioxane, can provide the aryl-heteroaryl/biheteroaryl compounds 37.

The Suzuki reaction can be promoted with a base such as, but not limited to, N32C03 or KOAc, at elevated temperatures as needed. Compounds 36 can also undergo Ullmann-type coupling with a NH-containing nucleophile such as, but not limited to, an amine or carboxamide, to yield compounds 38. The on can be catalyzed with a catalyst such as, but not limited to, copper (I) iodide or copper, promoted with a base such as, but not limited to, K2C03 or C82C03, and conducted in a solvent such as, but not limited to, DMF or NMP, at elevated temperature. Alternatively, compounds 34 (X = COZR) can undergo aminolysis with any of various amines to give carboxamides 39. The reaction can be promoted with a reagent such as, but not limited to, trimethylaluminum or triethylaluminum, and conducted in a solvent such as, but not d to, DCE or DCM. Following a two step sequence of ion and nucleophilic tution as described in Scheme 2, compounds 39 can be converted to final compounds 40.

Scheme 6: General synthesis of compounds of formula8(1).

W'W\ NH2 ////TMS |:VVH:I:2 i0“ I \(W\ X W Y PolC|2(PPh3)2 Cul MF Wjj:2,>—SH X: B“ Y:4F CI Y = F, CI Mel, base V\{ —> j:N\>—S/I W solvent // 44 (HCHO)n, CuCI W’</M I \>—S + —> W N W S JN\HZ Cu(OTf)2, toluene, 120 °C W VM \i}i W.W—.W ~ N 7 W'W\ 1R3 oxidation Y—R4 ,</M I \>—N‘ —> V\\,//V N W/ S Y-R4 base, solvent, heating - W=V\II In another illustrative method, compounds of formula (I) may also be routinely prepared according to the synthetic route outlined in Scheme 6. Starting from appropriate aminoaryl/heteroaryl des 41, Sonogashira coupling with ethynyltrimethylsilane catalyzed by a catalyst such as PdClz(PPh3)2 or PdClz(dppf) can afford the acetylenes 42. The coupling reaction can be promoted with a base such as, but not limited to, DIEA or TEA, and ted in a solvent such as, but not d to, DMF or MeCN, at ed temperatures if ary. Condensation of 42 with potassium O-ethyl carbonodithioate in a solvent such as, but not limited to, DMF, with heating can afford mercaptan compounds 43, which can be alkylated with iodomethane to give methylsulfides 44. The on can be conducted in a solvent such as, but not limited to, DMF or DMA and promoted with bases such as, but not limited to, K2C03 or CSZC03, at elevated temperatures if necessary. Three component cyclization using acetylenes 44, aminoaryl/heteroaryl compounds 45,and paraformaldehyde in a solvent such as, but not limited to, toluene at elevated temperature provides compounds 46. The cyclization can be promoted with a catalyst such as, but not d to, copper (I) chloride and copper (II) triflate. Following a two step sequence of oxidation and nucleophilic substitution as described in Scheme 2, compounds 46 can be converted to final compounds 47.

Scheme 7: General sis of compounds of formula (I).

X W\ S \ / R3 Cl/Y I />—SW S base, solvent W / [IV/\mllr I />—3 . . Hl\l\ W N OXIdatIon Y—R4 7 ‘W ‘W W:W N W I X = CI,Br,I W base, 1“ (”or X 49 222:2; “(Vi/[5% :ESfNIR2 W 3 W . . WE S R3 Suzuklcoupllng \ qu/TAl/r I />—N’‘ Y-R4 W 4 W N W N Y R— ‘W W~W X=CI,Br,or| ‘W W I W I .W_ w X Q2 51 50 X = CI.BF.OF I Q2: Ar, alkyl, alkenyl, cycloalkyl, cycloalkenyl Ullmann Sonogashlra- COUP Ing|_ coupling with X=CLBFJOFI with HNRVRZ — QZ' Cul, base WE 3 Rs 2 3 w mr IH W 3 ‘W W N Y—R WWQW’W TQM/R W WW/ N ‘Y_R4 W. , ’ W w 52 W‘ ' NRVRZ W 53 In r illustrative , compounds of formula (I) may also be routinely prepared ing to the synthetic route outlined in Scheme 7. Alkylation of heteroaryls 48 (wherein X is connected to W = carbon) with chlorides 14 from Scheme 2 using conditions described in Scheme 2 can provide compounds 49.

Following a two step sequence of oxidation and nucleophilic substitution as described in Scheme 2, compounds 49 can be converted to common intermediates 50. As described in Scheme 5, Suzuki coupling of 50 with coupling partners such as, but not limited to, boronic acids, boronate esters, or Molander trifluoroborates can yield compounds 51. Ullmann coupling of 50 with NH-containing nucleophiles such as, but not limited to, amines or carboxamides, under ions described for Scheme 5 can lead to compounds 52. Sonogashira coupling of 50 with enes under conditions described for Scheme 6 can yield compounds 53.

Scheme 8: General synthesis of nds of a (1). reduction (X = COZR) N \ I X=|BrorCl wZ W s R3 WQW ’ ’ \ I I | j: />—N N W. / ‘ 4 Stille coupling H30+ W 1% j: />— N.

W W N Y_R / w w W~ —>vl W N Y—R4 W , R6‘ JL W X ‘o 55 SnBu3 Zn(CN)2, X = r Cl Pd catalyst, hydrolysis base, solvent (X = 002R) WE W 5 R3 W WW :1:ka w w. ‘w W l warm rM 5.

I W‘ ’ ‘w 56 \ w N Y-R4 O , W HO \\ W I HNRVRZ, amide N W coupling reagent, RHSS’OO base WE W s R3 W [ll/\W j: ,)—N’ W. / ‘ 4 N Y-R l ‘W W Ra and Rb are alkyl, aryl, etc. W I RVRZN In another illustrative method, compounds of a (I) may also be routinely prepared according to the synthetic route outlined in Scheme 8. Starting from the common intermediates 50 described in Scheme 7, reduction of the carboxylates of 50 (X: COZR) using a reducing agent such as, but not limited to, DIBAL-H or LiBH4, in a solvent such as, but not limited to, DCM or THF, can afford alcohols 54. Stille coupling of 50 (X = 1, Br, or Cl) with an appropriate tributyl alkoxyvinyl stannane followed by acidic hydrolysis can yield the acetyl compounds 55. The reaction is typically catalyzed by a catalyst such as Pd(PPh3)4 and conducted in a t such as, but not limited to, DMF or DMA. Similarly, palladium-mediated cyanation of 50 (X = 1, Br, or Cl) with a reagent such as, but not d to, Zn(CN)2, can provide the cyano compounds 56. The reaction is catalyzed by catalysts such as PdClz(PPh3)2 or PdClz(dppf), promoted with bases such as, but not limited to, DIEA or TEA, and conducted in solvents such as, but not limited to, DMF or MeCN, at elevated temperature. Analogously, palladium-mediated sulfonylation of 50 (X = 1, Br, or Cl) with a reagent such as, but not limited to, sodium methanesulf1nate, can generate sulfonyl compounds 57. The reaction is catalyzed by a st such as, but not limited to, copper (I) trifluoromethane-sulfonate benzene complex, promoted with an amine such as, but not limited to, unsymmetrical N,N—dimethylethylene e, and ted in a solvent such as, but not limited to, DMF or DMSO, at elevated temperature. The carboxylate of common intermediates 50 (X = COZR) can be yzed using a base such as, but not limited to, NaOH or KOH, in a solvent such as, but not limited to, MeOH or THF, to give carboxylic acids 58. Coupling of acids 58 with any of various amines using peptide coupling agents such as, but not limited to, EDCI or HATU, can afford the carboxamides 59. The reaction can be promoted with a base such as, but not limited to, DIEA or TEA and conducted in a solvent such as, but not limited to, DMF or THF.

Scheme 9: l synthesis of compounds of formula (I). 02N\8/\Vl\lN / rN/H base, solvent 14 W N02 W" I w w H2N ‘w S N / / w “Ar I/FS w OzN / \ W s N WW 60 W- I/>—S 28 ‘w N 61 acid, reducing agent, solvent T ¢ oxidation ll W W Si R3 S I HOAvg 1%3/ / /\ / N N’ N/\( In), ‘Y’R4 ‘W N %W ~W 13 W. ll ‘w—W 32 In r illustrative , compounds of formula (I) may also be routinely prepared according to the tic route outlined in Scheme 9. Alkylation of amino nitro aryls/heteroaryls 60 with chlorides 14 can be effected using a base such as, but not limited to, NaH or t—BuOK to give compounds 28. The alkylation can be conducted in a t such as, but not limited to, DMF or THF. Alternatively, alcohols 13 can be oxidized to aldehydes 61 using an oxidizing agent such as, but not limited to, Dess-Martin periodinane or MnOz, in a solvent such as, but not limited to, DCM or MeCN. Reductive alkylation of amino nitro aryls/heteroaryls 60 with aldehydes 61 can be effected using a reducing agent such as, but not limited to, NaCNBH3 or Na(OAc)3BH, usually in the presence of an acid such as, but not limited to, TFA or AcOH, to give compounds 28. The reductive alkylation on can be conducted in a solvent such as, but not limited to, DCM or DCE. nds 28 can be converted to the final compounds 32 as described in Scheme 4.

Scheme 10: General synthesis of compounds of a (I).

H N2 U N\\\rVV:WIN/>—S/W N\\ W S OXIdatIOn WT I />—NH \\OH ‘W N ‘ base, solvent, heating. 62 Z:> N Rb Rb Rb Rb Rb \\ W Rb \é 3:st O 9 reduction HZN/YWWIN/>—N —> - . W‘W acnd, solvent 53 64 Rb Rb /W S 9 /W S /\ N acid OH —> N/ N/Y 1’)“ T —> N/FN/Y IfNH —> W:W N w:W N / solvent W / W. ” w_ II W‘W ‘W‘W 65 66 w s 0 N5" ion N//\N/\(’ IfNH NHZORd' /N/\(1/>’NH / —> rt t —»’rtW / W W W W.- II base solvent W 1/ 21> WW 67 Wm 68 alkyl-metal solvent NQZY‘W‘W188,/ NH OH alkyl Wm 69 In r illustrative method, compounds of formula (I) may also be routinely prepared according to the tic route outlined in Scheme 10. Starting 2012/059983 with nitriles 25 from Scheme 4, oxidation of the sulfide moiety and nucleophilic tution with amino alcohols such as, but not limited to, a single stereoisomer of 2-aminocyclohexanol, can provide the compounds 62. Simultaneous protection of the NH and OH groups of 62 by treatment with a ketal such as, but not limited to, 2,2- dimethoxypropane in the ce of an acid catalyst such as, but not limited to, p- toluenesulfonic acid or camphorsulfonic acid, in a solvent such as, but not limited to, toluene or 1,4-dioxane, with heating as ed can afford compounds 63. Reduction of the nitrile group of 63 can be realized using a metal hydride such as, but not d to, LiAlH4 or nickel boride, in a solvent such as THF or diethyl ether to give amines 64. Using procedures analogous to those described in Scheme 4 for conversion of compounds 26 to nds 30, a three step sequence can convert compounds 64 to compounds 65, after which the protecting group can be removed using an acid such as, but not limited to, TFA in DCM or HCl in oxane, to give compounds of the invention 66. Compounds 66 can furthermore be oxidized to ketones 67 using an ing agent such as, but not limited to, Dess-Martin periodinane or 2- iodoxybenzoic acid, in a solvent such as, but not limited to, DCM or MeCN.

Treatment of ketones 67 with hydroxylamine or an alkoxylamine at elevated temperature in a solvent such as, but not limited to, EtOH or MeOH can generate oximes 68. The reaction can be promoted with a base such as, but not limited to, pyridine. On the other hand, s 67 can react with organometallic agents such as, but not limited to, Grignard reagents or organolithium agents, in a solvent such as, but not limited to, THF or diethyl ether, to give compounds 69, which may be formed as a mixture of diastereoisomers.

Scheme 11: General synthesis of compounds of formula (I).

WZW W\ S ,R3 W‘ W l S W \ R3 WW WY I/>-N NHRYORX, base, W I fil/ I />-N \IN WW W~W N \Y_R4 Y"_R4 —> W WW W~W N W I solvent W‘ ' W 56 W 70 \\ NRYORX NaN3 reduction NH4CI solvent W2 1 W\ 3 R3 W VIV \f j: ,)—N' W W~ / W N \Y_R4 2 w 3 I w W~ 1 S R WQ‘I/(IV W I | j: />-N w 74 yv W~W’ N ‘v-R4 W I H2N W 71 RXCOCI base, solvent ' Q -X, base4 ’ H Q4 = alkyl, haloalkyl In another illustrative method, compounds of formula (I) may also be routinely prepared according to the synthetic route outlined in Scheme 11. Reaction of es 56 from Scheme 8 with hydroxylamine derivatives at ed temperature in a solvent such as, but not limited to, EtOH or MeOH can generate hydroxyl or alkoxyl amidines 70. The reaction can be promoted with a base such as, but not d to, pyridine. Reaction of nitriles 56 with azide, for example with NaNg and NH4Cl, in a solvent such as, but not d to, DMF or DMA, can provide tetrazole compounds 71. Alkylation of the tetrazoles with alkyl or haloalkyl s using bases such as, but not limited to, K2C03 or C82C03, in solvents such as, but not d to, DMF or DMA, at elevated temperature can yield tetrazole derivatives 72 and 73. ion of the nitrile group of 56 can be realized using metal hydrides such as, but not limited to, LiAlH4 or nickel boride, in a solvent such as THF or diethyl ether to give amino compounds 74. Acylation of the amino group of 74 with an acylating group in the presence of a base such as, but not limited to, pyridine or DIEA, in a solvent such as DCM or DCE, can afford amides 75; corresponding carbamates or ureas can be prepared similarly, by using a chloroformate or an nate, respectively, as the acylating agent.

Scheme 12: General synthesisSof oxazole compounds WIOH fib—SH—>Mel cho3 pyridine : DMF 76 77 \okr \W 0 reduction HOW \ HW chlorination ,H/ O / CI“r I/>—sW\ O / W / W I W. / N N W N ‘w ‘w 78 79 80 1. Ester ysis 2. Primary amide formation \33ehydration NC W YWIN,>—s/ In an illustrative method, the oxazole derivatives used herein may be routinely prepared according to the synthetic route outlined in Scheme 12. Heating of aminophenols 76 with potassium O-ethyl carbonodithioate in solvent such as, but not limited to, pyridine can yield compounds 77. As described in Scheme 2, a three step sequence of alkylation, reduction, and chlorination can generate chloride derivatives 80. Intermediate 78 from the above sequence can alternatively be converted to nitrile 783 by a standard three-step sequence consisting of ester hydrolysis, y amide formation, and dehydration. Final oxazole compounds of the invention can be prepared by substituting oxazoles 79 in place of thiazoles 13 in Scheme 9 and conducting the remainder of the synthetic ce using procedures analogous to those in Scheme 9; additional final oxazole compounds of the invention can be prepared by substituting oxazoles 80 in place of thiazoles 14 in Schemes 2, 5, 7, and 9 and conducting the der of the respective tic sequences using procedures analogous to those in Scheme 2, 5, 7, or 9; and additional final oxazole compounds of the invention can also be prepared by substituting oxazoles 783 in place of thiazoles in Schemes 4 and 10 and ting the remainder of the respective synthetic sequences using procedures analogous to those in Scheme 4 or 10.

Scheme 13: General synthesis of bicyclic imidazole derivatives (examples of heteroaryls 48) Né‘NH WWail“ HN03 WWIN: reduction W'W orthoformate )4W , 1; H2 H2304 acid W’W 81 84 In an illustrative method, bicyclic imidazole derivatives used herein may be routinely prepared according to the synthetic route outlined in Scheme 13.

Nitration of amino aryl/heteroaryl compounds 81 can be realized using reagents such as, but not limited to, a mixture of concentrated ic acid and nitric acid, to give amino nitro compounds 82. Reduction of compounds 82 using a reducing agent such as, but not limited to, Zn or Fe in the presence of an acid such as, but not limited to, AcOH or HCl, in a solvent such as, but not limited to, DCM or EtOH can give diamino nds 83. Compounds 83 can be converted to bicyclic imidazole derivatives 84 by on with an orthoformate such as, but not d to, hyl orthoformate or triethyl orthoformate. The reaction can be promoted with an acid catalyst such as, but not limited to, HCOOH or AcOH at elevated temperature.

Scheme 14: General sis of amino alcohol tives (examplesNof aminesOH7) . . N3 OH OXIdatIOH _ azide .\\ reduction 1 \\ 1—’ —> n 701 :Q1—> \Q1 86 87 n=1,2,3 n=1,2,3 n=1,2,3 n=1,82,3 (Q1 optional) In an illustrative method, amino l derivatives used herein may be ely prepared according to the synthetic route outlined in Scheme 14.

Cycloalkenes 85 can be oxidized using reagents such as, but not limited to, mCPBA or NaOCl to give epoxides 86, which can react with an azide such as, but not limited to, TMSN3 or n-Bu4NN3, in a solvent such as, but not limited to, THF or DCM, to give azido alcohols 87. The azido group of 87 can be reduced to an amino group using hydrogenation or Staudinger reduction conditions to afford amino alcohols 88.

Scheme 15: General synthesis of amino alcohol derivatives (examples of amines 7) l:ln Q reductlon \ 1 —> \Q1 89 90 n — 1, 2, 3 n = 1, 2, 3 HN\O\-OH N2§—>reduction H2N {OH Q Q n— 1,1,2 3 n = 1, 2, 3 OH HZN OH reduction ~‘\ \ 1—>nQ \Q1 n=1?2,3 94 n=1,2,3 (Q1 optional) In another illustrative method, amino l derivatives used herein may also be routinely prepared according to the synthetic route ed in Scheme 15.

Amino acids 89 and 91 can be reduced to amino alcohols 90 and 92, respectively, using a reagent such as, but not limited to, LiAlH4 or ne, in a solvent such as THF or diethyl ether. Similarly, cyanohydrins 93 can be d to amino alcohols 94 using a metal hydride such as, but not limited to, LiAlH4 or nickel boride, in a solvent such as THF or diethyl ether.

Scheme 16: General synthesis of 5-membered heteroaryl derivatives (examples of heterocyclyl compounds 5) W‘N/\O aCId, solvent.

I W‘NH WW\W\ I, —. W\W Ar 97 98 Ar T Suzuki coupling W‘NH TMS\/\O/\CI W‘NAO Ullmann coupllng. w’ \ W \ \W\W ‘W\W X ase, so ven| t X NRYRZ 95 96 X=C|,Br,| X=C|,Br,| acid, solvent ’IW‘NAON W‘NH \ - I, W W 99 100 NRyRZ NRyRZ In an illustrative method, certain 5-membered heteroaryl derivatives used herein may be routinely prepared according to the synthetic route ed in Scheme 16. Heteroaryls 95 containing an appropriate halo substituent can be ted with a protecting group such as, but not limited to, hylsilylethoxymethylene group, to give compounds 96. The protection can be effected using a base such as, but not d to, NaH or t—BuOK, and ted in a solvent such as, but not d to, DMF or THF, at elevated temperature if necessary. Haloheteroaryl compounds 96 can undergo Suzuki coupling as described in Scheme 5 with coupling partners such as, but not limited to, boronic acids, boronate , or Molander trifluoroborates to yield compounds 97. Subsequent removal of the protecting group using a reagent such as, but not limited to, TFA in DCM or HCl in l,4-dioxane can provide heteroaryl derivatives 98. Similarly, Ullmann-type coupling of 96 with NH-containing nucleophiles such as, but not limited to, amine or carboxamides, can lead to compounds 99, from which the protecting group can be d as above to afford heteroaryl derivatives 100.

Scheme 17: General synthesis of 6-membered heteroaryl/heterocyclyl derivatives (examples of heteroaryl/heterocyclyl compounds 5) W"W‘ wjxx Suzukicoupling W" NH —> I \ W\(kX—>solventbase, H20 W\ W\\(KO 1 o2 103 X=Cl, Br,| Ullmann coupling NRYRZ VIV'W‘N base, H20 l —> VIV‘W‘NH W\ W\ X solvent 0 NRYRZ NRYRZ 104 105 In an illustrative method, certain 6-membered heteroaryl/heterocyclyl derivatives used herein may be routinely prepared according to the synthetic route outlined in Scheme 17. nated heteroaryl/heterocyclyl compounds 101 can undergo Suzuki coupling as described in Scheme 5 with coupling partners such as, but not limited to, boronic acids, boronate esters, or er trifluoroborates to yield compounds 102. Subsequent ne hydrolysis with, for example, KOH or NaOH, in a solvent such as, but not d to, DMSO or THF can provide heterocyclyl derivatives 103. Similarly, Ullmann-type coupling of s 101 with a NH- containing nucleophile such as, but not limited to, an amine or carboxamide, can lead to nds 104, from which subsequent hydrolysis can lead to heteroaryl/heterocyclyl derivatives 105.

Scheme 18: General synthesis of compounds of a (I).

YWWIOH AOJLSK W.W/ NH2 2:0 106aY= lorBr YYWIN»_SHDYYWIZ’)_S//\/Mel base Pd catalyst ligand HMWI:FS base sol entV YYW F(Cl)2/\o/=sv 107 Y: lorBr 1os,Y= lorBr WINH DMF 106 Y: lor Br .W NH2 W‘W1 it I Z NCS, catalyst HWW1w}:,)—3/ \ \ / mCPBA DCM 111 NWIN/fs solvent base solvent ~ AN W-W 112 Z / N\W“I II)‘S\ H NW W~W’ R3‘ (7) N ‘0 ‘Y—R“ W‘ II WIN/>—NEY—R4 W‘W base, solvent, heating WW 113 114 In an illustrative method, compounds of formula (I) may also be routinely prepared according to the synthetic route outlined in Scheme 18. The y available ryl/heteroaryl derivatives 106 and 10621 can react with potassium O-ethyl carbonodithioate in solvent such as, but not limited to, DMF or pyridine with heating to give fused mercaptan derivatives 107. Methylation of compounds 107 can be ed using Mel promoted with a base such as, but not limited to, K2C03 or C82C03 in a solvent such as, but not limited to, DMF or DMA, to give compounds 108. Heck coupling of halides 108 with allyl alcohol catalyzed with a palladium- based catalyst such as, but not d to, Pd(OAc)2 or Pd(dba)2 es the propanals 109. The reaction can be promoted with a palladium ligand such as, but not limited to, P(o-tolyl)3 or As(PPh3)3 and accelerated with a base such as, but not limited to, NaHC03 or KHCOg. The reaction can be conducted in a solvent such as, but not limited to, MeCN or DMF. nation of propanals 109 can be effected using a chlorinating agent such as, but not limited to, N—chlorosuccinimide and catalyzed with an amine such as, but not limited to, L-proline or piperidine to give chlorides 110. sation of compounds 110 with six-membered 2-amino heteroaryl tives 111 at elevated temperature promoted with a base such as, but not limited to, NaHCOg or triethylamine in a solvent such as, but not limited to, n- BuOH or DMF yields bicyclic heteroaryls 112. The sulfides of 112 can be oxidized to sulfoxides using an oxidizing agent such as, but not limited to, m-CPBA or peracetic acid. The oxidation can be conducted in solvent such as, but not limited to, DCM or AcOH. Sulfoxides 113 may react with amines 7 under nucleophilic substitution conditions at elevated temperature to afford compounds 114. The reaction can be conducted in a t such as, but not limited to, DMA or NMP and promoted with a base such as, but not limited to, DIEA or TEA.

Scheme 19: General sis of compounds of formula (I). 0 II /)—NH HM\Z 2 W we CPBA NWI/>_S\xZ W N M>/ m \ \ / C|V\|I//S 115 YN‘W-WNO \W N base, solvent WW 110 117 x=o,s, NR R3'N‘Y—R4 (7) W\ R3 base, solvent, heating YW ‘w N ‘Y—R4 In an illustrative method, compounds of formula (I) may also be routinely prepared according to the tic route outlined in Scheme 19. Condensation of compounds 110 from Scheme 18 with five-membered aminoheteroaryl derivatives 115 at elevated temperature promoted with a base such as, but not limited to, NaHCOg or triethylamine in a solvent such as, but not limited to, n-BuOH or DMF yields bicyclic heteroaryls 116. Using procedures analogous to those described in Scheme 18, oxidation of compounds 116 to give sulfoxides 117, followed by reaction with amines 7 provides compounds 118.

Scheme 20: General synthesis of compounds of formula (I).

Y vv 2 Y vv 2 y“, 4 (7) Y\T’ \W Z 33 WOH WT I />—s fl, WI/ lif—s‘,/ / R Y‘R N W. WWI /)—N.N Y_R4 .

W W o Pd st, ligand base, solvent, heating base, solvent 108,Y=|orBr 119,Y=lorBr O W NH HMW\ o 2 W z \ B3 w' \ Z B3 n Y />_N NCS, catalyst Z R3 NW j:/>_N I H \ , 111 W~ ’ w~ , ‘ | W~W=N />—N )IN.w W ‘Y—R4 W N Y_R4 —> CI W~ / ‘ N Y—R4 . I solvent W base, solvent ‘W-W 122 114 base, W" X t VIV I />—NH2 ‘W N In an illustrative method, compounds of formula (I) may also be ely prepared according to the synthetic route outlined in Scheme 20. Sulfides 108 from Scheme 18 can be oxidized to sulfoxides 119 using an oxidizing agent such as, but not limited to, m-CPBA or peracetic acid, as described in Scheme 18. Reaction of ides 119 with amines 7 provides compounds 120, using a procedure analogous to that bed in Scheme 18. Heck coupling of halides 120 with allyl alcohol yields propanals 121, using a procedure analogous to that described in Scheme 18.

Chlorination of 121 using NCS affords compounds 122. sation of compounds 122 with mbered aminoheteroaryl derivatives 111 gives compounds 114, using ures analogous to those described in Scheme 18. Alternatively, condensation of chloroaldehydes 122 with bicyclic amino aryls 123 es tricyclic nds 124.

Scheme 21: General synthesis of compounds of formula (I).

W: .W NO W—W N02 W N 2 ,yV N02 VIV' VIV I AC2O I VIV I 14or80 : W:W :Z _> / W: | W NH2 W NH g base, solvent A W2 / o H w N/>—S 82 O H é\N/Y 19—8/W z N//\N/\r/w z R3 reduction/cyclization N >§L W: l />—N’ —> w_ \ W w N / N Y—R W. —> ‘w Acid, solvent I; W [\IN W—w ,. 127 32 In an illustrative method, compounds of formula (I) may also be routinely prepared according to the synthetic route outlined in Scheme 21. Amino nitro aryls/heteroaryls 82 from Scheme 13 can be converted to formamides 125 when heated in acetic formic mixed anhydride. Alkylation of formamides 125 with chlorides 14 or 80 yields compounds 126. The alkylation reaction is promoted with a base such as, but not limited to, NaH or t-BuOK in a solvent such as, but not d to, DMF or THF. Reduction of the nitro group to an amino group, accompanied by cyclization to compounds 127 may be effected utilizing a reducing agent such as, but not limited to, iron or zinc, in the presence of an acid such as, but not limited to, AcOH or trifluoroacetic acid. The reaction is conducted in a solvent such as, but not limited to, EtOH or MeOH and may be promoted by heating at elevated temperature.

Compound 127 can be converted to the requisite compounds 32 using procedures analogous to those described in Scheme 18 for conversion of 112 to 114.

Scheme 22: General synthesis of compounds of formula (I).

:W N 2,2-dimethoxypropane W 2:; BBr3, DCM W:W N W\ \K/ —>W\ \K/ acid,solvent ] In an illustrative method, compounds of formula (I) may also be routinely prepared ing to the synthetic route outlined in Scheme 22. The benzyl groups of compounds 128, which are prepared by methods bed above, are removed using a reagent such as, but not limited to, BBrg or TMSI in a solvent such as, but not limited to, DCM or CH3CN, to give hydroxyl compounds 129. The vicinal amino alcohol fianctionality of 129 is ted, for example as an acetonide, by reacting with a t such as, but not limited to, 2,2-dimethoxypropane to give compounds 130. The reaction is zed by acid such as, but not limited to, p-toluenesulfonic acid or camphor sulfonic acid in a solvent such as, but not limited to, l,4-dioxane or toluene. Alkylation of the hydroxyl group of 130 with alkyl halides is promoted with a base such as, but not limited to, C82C03 or NaH in a solvent such as, but not limited to, NMP or THF to afford ethers 131. Deprotection of 131 with acid such as, but not limited to, HCl or trifluoroacetic acid in a solvent such as, but not limited to, DCM or CH3CN provides compounds 132.

Scheme 23: General synthesis of compounds of formula (I).

W Z O\\ ’10 W /\ Z /\ / N / N/ N/Y I/VWH CI’S‘CI N AVE 19"“ 0' >¢L OH W ¥ N / ‘W N w —’ w. I‘I’V W. _I/ base, t ‘W—W 133 134 W Z O\\ 00 W /\ Z /\ / N / N/ N/Y I)—NH I N /\Wr 19"“ >4L OH 30' W: / ~W N W N W —> w- ”V base so IVent ‘ w-W — ' WW l W z DAST //\N / solvent N)/k />_NH W~ I §H / ‘W N W Z W I] '“lOH //\N / .W 138 O N W )éL I ,)—NH 0504, NMO W‘W N + W VII/1V solvent w w— /\ Z N’ ”A? 1%NH OH 137 PL W~*W N W.. ,‘,’V OH 1 39 In an illustrative method, nds of formula (I) may also be routinely prepared according to the synthetic route outlined in Scheme 23. Compounds 133, prepared as described above, can be converted to chlorides 134 by the treatment with sulfuryl chloride in a solvent such as, but not limited to, DCM or CH3CN.

Analogously, compounds 135 can be converted to chlorides 136 under the similar conditions. Furthermore, treatment of compounds 135 with an agent such as, but not limited to, diethylaminosulfur trifluoride (DAST) or fluor in a solvent such as, but not limited to, DCM, can afford cyclohexenes 137. Dihydroxylation at the isolated double bond of 137 with OsO4 and N-methylmorpholine oxide (NMO) in a solvent such as, but not limited to, HzO/acetone/t-BuOH provides diol nds 138 and 139.

Scheme 24: General synthesis of compounds of formula (I).

WO 56070 OR' OR' HN ml 1’)—N‘Y—R / SW N 'W'W 141 R‘OH,acid solvent, heating OR 0 3 3 W\ W\ Z R W Z V\|I IkN‘Y-R“ oxndatlon. . W\ B HN HN /yv ~W N —> V\|/ 1%N‘Y-R / ~W N W I xv .- R=H .W W-' .W W 20 W 140 nation fluorination F F 3 3 w J:’>_N‘Y—R4 HN W I’>—N‘Y-R / W N xv / xv W N W'W W_ 142a ‘W'W 142 In an illustrative method, compounds of formula (I) may also be routinely prepared according to the synthetic route outlined in Scheme 24. Compounds 20 (R = H) from Scheme 3 can be ed to ketones 140 with a reagent, such as, but not limited to, Dess-Martin periodinane or Jones reagent in a solvent such as, but not limited to, CH3CN or acetone. Ketals 141 can be ed by heating ketones 140 with an alcohol or diol in a solvent such as, but not limited to, toluene or benzene. The reaction can be catalyzed with an acid such as, but not limited to, p-toluene sulfonic acid or camphorsulfonic acid. Ketones 140 can also be bis-fluorinated to give compounds 142 using a fluorinating t such as, but not limited to, diethylaminosulfur trifluoride (DAST) or Deoxo-Fluor. ls 20 can also be converted to fluorides 142a using a fluorinating reagent, such as, but not limited to, diethylaminosulfur trifluoride (DAST) or Deoxo-Fluor.

Scheme 25: l synthesis of compounds of formula (I).

HO/Y I ,>—s/W 3 oxidation HJkrwI S / Mb VMVVI N N 13 143 OH W 8 Br l Wj: / N/\I \ N | S bromination N\ \ N_ W. / NI)— N.W , NW W —> W 1W w. W W.- n-BuLi,THF ‘w—W 146 W‘ W.w W=CH orN 144 145 . .

W31:’>_Nl:3_ OXIdatIon NWVKWIN NFF3 ketalformation N 4—» />— />_NIRS W‘ ‘Y——R4 NW Y-R4 W“ ll W.W‘W W‘W 1 48 1 49 1 47 fluorination fluorination In an illustrative method, the compounds of formula (I) may also be routinely prepared according to the synthetic route outlined in Scheme 25. nds 13 from Scheme 2 can be oxidized to aldehydes 143 with a reagent such as, but not limited to, Dess-Martin inane, in a solvent such as, but not limited to, CH3CN or DCM. Meanwhile, readily ble compounds 144 can be brominated with a reagent such as, but not limited to, bromine or N—bromosuccimide to give compounds 145. Trans-metallation of 145 with a reagent such as, but not limited to, n-butyl lithium followed by treatment with aldehydes 143 can yield alcohols 146, which can be converted to compounds 147 using procedures analogous to those described in Scheme 4 for conversion of 30 to 32. The alcohols 147 can further be converted to ketones 148, fluorides 1503, ketals 149, and difluoro compounds 150 using procedures analogous to those described in Scheme 24.

The subject matter has been described in an illustrative manner, and it is to be understood that the terminology used is intended to be in the nature of description rather than of tion. Thus, it will be appreciated by those of skill in the art that conditions such as choice of t, temperature of reaction, volumes, reaction time may vary while still producing the desired compounds. In addition, one of skill in the art will also appreciate that many of the reagents provided in the following es may be substituted with other suitable reagents. See, e.g., Smith & March, Advanced Organic Chemistry, 5th ed. (2001). Such changes and modifications, including without limitation those ng to the chemical structures, substituents, derivatives, intermediates, syntheses, formulations and/or s of use provided herein, may be made without departing from the spirit and scope thereof. US. patents and publications referenced herein are orated by reference.

EXAMPLES Example 1 Preparation of 2-((6-((1H-benz0[d]imidazol—1-yl)methyl)benzo[d]thiazol-Z- yl)amin0)cyclohexanol NREE“ o” SHE” Step 1: -Benzo[d]imidazolyl)methyl)bromobenzo[d]thiazole (150 mg, 44%) was ed as a white solid using a procedure analogous to that described in Step 5 of Example 2, substituting 1H-benzo[d]imidazole for 5,6- dimethoxy-1H-benzo[d]imidazole used in Example 2. 1H NMR (300 MHz, DMSO- d6) 5 8.45 (s, 1H), 8.06 (s, 1H), 7.97 (d, J: 8.5 Hz, 1H), 7.62 - 7.72 (m, 1H), 7.45 - 7.58 (m, 2H), 7.13 - 7.28 (m, 2H), 5.65 (s, 2H). LCMS (ESI) m/z 344, 346 (M+H)+.

Step 2: 2-((6-((1H-Benzo[d]imidazolyl)methyl)benzo[d]thiazol yl)amino)cyclohexanol was obtained as a white solid (12 mg, 22%) using a ure analogous to that described in Step 4 of Example 2, substituting 6-((1H- benzo[d]imidazolyl)methyl)bromobenzo[d]thiazole from Step 1 of this Example for 2-bromo((5 ,6-dimethoxy-1H-benzo[d]imidazolyl)methyl)benzo[d]thiazole, and racemic transaminocyclohexanol for (1R,2R)aminocyclohexanol used in Example 2.1H NMR (300 MHz, 6) 5 8.40 (s, 1H), 7.98 (d, .1: 7.5 Hz, 1H), 7.61 - 7.69 (m, 2H), 7.49 - 7.59 (m, 1H), 7.25 - 7.34 (m, 1H), 7.13 - 7.24 (m, 3H), .46 (s, 2H), 4.75 (br s, 1H), 3.47 - 3.59 (m, 2H), 2.02 (d, J: 10.9 Hz, 1H), 1.87 (d, J = 9.2 Hz, 1H), 1.61 (br s, 2H), 1.04 - 1.36 (m, 4H). LCMS (ESI) m/z 379 (M+H)+.

Example 2 2012/059983 Preparation of (1R,2R)((6-((5,6-dimethoxy-1H-benzo[d]imidazol yl)methyl)benzo [d] thiazol—2-yl)amino)cyclohexanol N N Cr“\j H” O” \ 8 O C5 Step 1: To a solution of tert—butyl nitrite (4.5 mL, 37.5 mmol) and copper(II) bromide (6.0 g, 27 mmol) in CH3CN (100 mL) at rt was added a mixture of ethyl 0benz0[d]thiazolecarb0xylate (5.0 g, 22.5 mmol) in CH3CN (50 mL).

The reaction suspension was stirred at rt for l h. The resulting reaction mixture was quenched with 300 mL of l N HCl aqueous on and extracted with CHZCIZ (3x200 mL). The combined organic layers were dried over MgSO4, and concentrated under reduced pressure. The crude product was purified on a silica gel column using a mixture of CHzClg-hexanes (4:l, V/V) as eluent to give ethyl 2- bromobenzo[d]thiazolecarboxylate as a white solid (6.2 g, 96%). 1H NMR (300 MHZ,CDC13)8 8.54 (d, J: 1.1 Hz, 1H), 8.16 (dd, J: 1.5, 8.7 Hz, 1H), 8.02 (d, J: 8.7 Hz, 1H), 4.43 (q, J: 7.2 Hz, 2H), 1.43 (t, J: 7.2 Hz, 3H). LCMS (ESI) m/z 288, 286 (M+H)+.

Step 2: To a solution of ethyl 2-bromobenzo[d]thiazolecrboxylate (5.0 g, 17.5 mmol) from Step 1 of this Example in anhydrous CHzClz was added DIBAL- H (1.0 M in CHzClz, 36.7 mL, 36.7 mmol) slowly at -78 0C. The solution was stirred at -78 0C for 2 h. The resulting mixture was quenched with 10 mL of saturated aq sodium potassium tartrate at -78 0C. After slowly warming to 0 0C, the mixture was further treated with 50 mL of saturated aq sodium potassium tartrate and stirred at rt for 2 h. The aqueous layer was separated and extracted with CHZClz (3 x 100 mL).

The combined organic layers were washed with brine, dried over MgSO4, and concentrated under reduced pressure. The crude product was purified on a silica gel column using a mixture of EtOAc-hexanes (2:3, V/V) as eluent to give (2- bromobenzo[d]thiazolyl)methanol as a white solid (3.4 g, 80%). 1H NMR (300 MHz, CDClg) 8 7.96 (d, J: 8.3 Hz, 1H), 7.85 (s, 1H), 7.45 (dd, J: 1.4, 8.4 Hz, 1H), 4.83 (s, 2H), 1.86 (br s, 1H). LCMS (ESI) m/z 244, 246 (M+H)+.

Step 3: To a on of mobenzo[d]thiazolyl)methanol (205 mg, 0.83 mmol) from Step 2 of this e and DIEA (1 18 mg, 0.92 mmol) in CHzClz (20 mL) cooled in an ethylene glycol-water (4: l, V/V) dry ice bath was added WO 56070 methanesulfonyl chloride (105 mg, 0.92 mmol) slowly. The reaction solution was warmed to rt and stirred at rt for 1 h. The resulting mixture was quenched with 20 mL of water. The separated aqueous layer was extracted with CHzClz (3 x 20 mL). The combined organic layers were washed with brine, dried over MgSO4, and concentrated under reduced pressure to give (2-bromobenzo[d]thiazolyl)methyl methanesulfonate as a light yellow solid (267 mg, 100%). LCMS (ESI) m/Z 322, 324 (M+H)+.

Step 4: To a solution of (2-bromobenzo[d]thiazolyl)methyl methanesulfonate (460 mg, 1.4 mmol) from Step 3 of this Example in DMF (5 mL) was added 5,6-dimethoxy-1H-benzo[d]imidazole (560 mg, 3.14 mmol) portion wise at rt. The mixture was stirred at rt overnight. The resulting solution was diluted with 40 mL of EtOAc and washed with water, brine. The separated c layer was dried over MgSO4, and concentrated under reduced pressure The crude product was purified on a silica gel column using a mixture of MeOH-CHzClz (1 :20, v/v) as eluent to give 2-bromo((5,6-dimethoxy-1H-benzo[d]imidazol hyl)benzo[d]thiazole as a light yellow solid (427 mg, 75%). LCMS (ESI) m/Z 404, 406 (M+H)+.

Step 5: To a suspension of 2-bromo((5,6-dimethoxy-1H- benzo[d]imidazolyl)methyl)benzo[d]thiazole (202 mg, 0.5 mmol) from Step 4 of this Example in DMA (4 mL) were added DIEA (129 mg, 1.0 mmol) and (1R,2R) aminocyclohexanol (69 mg, 0.6 mmol) at rt. The mixture was stirred in a sealed tube at 120 0C ght. After cooling to rt, the mixture was trated under reduced pressure. The crude product was purified by HPLC using a mixture of water (5% CH3CN, 0.05% AcOH) and CH3CN (0.05% AcOH) as the mobile phase and Varian Pursuit XRs Diphenyl column as the stationary phase to afford (1R,2R)((6-((5,6- dimethoxy- 1 o [d]imidazolyl)methyl)benzo [d]thiazol yl)amino)cyclohexanol as a white solid (127 mg, 58%). 1H NMR (300 MHZ, DMSO- d6) 5 8.14 (s, 1H), 7.99 (d, J: 7.5 Hz, 1H), 7.62 (s, 1H), 7.04 - 7.34 (m, 4H), 5.40 (s, 2H), 4.77 (br s, 1H), 3.76 (s, 6H), 3.51 (br s, 1H), 1.77 - 2.14 (m, 3H), 1.61 (br, 2H), 1.04 — 1.38 (m, 4H). LCMS (ESI) m/Z 439 (M+H)+.

Example 3 Preparation of (1R,2R)((6-((3H-imidazo[4,5-b]pyridin yl)methyl)benz0[d]thiazol—Z-yl)amin0)cyclohexanol methanesulfonic acid Step 1: To a solution of ethyl 2-bromobenzo[d]thiazolecarboxylate (4.8 g, 16.8 mmol) from Step 1 of e 2 in THE (100 mL) was added sodium thiomethoxide (1.74 g, 25.2 mmol) slowly at 0 0C. The reaction mixture was d at rt overnight. The mixture was d with EtzO (200 mL) and washed with saturated aq NaHC03 and brine. The organic layer was dried over MgSO4 and trated under reduced pressure to give ethyl 2-(methylthio)benzo[d]thiazolecarboxylate as a white solid (4.18 g, 98%). 1H NMR (300 MHz, CDC13)8 8.48 (d, J: 1.5 Hz, 1H), 8.11 (dd, J: 1.6, 8.6 Hz, 1H), 7.87 (d, J: 8.5 Hz, 1H), 4.41 (q, J: 7.1 Hz, 2H), 2.82 (s, 3H), 1.42 (t, J: 7.1 Hz, 3H) LCMS (ESI) m/z 254 (M+H)+.

Step 2: (2-(Methylthio)benzo[d]thiazolyl)methanol (4.1 g, 88%) was obtained as a white solid using a procedure analogous to that described in Step 2 of Example 2, tuting ethyl 2-(methylthio)benzo[d]thiazolecarboxylate from Step 1 of this Example for ethyl 2-bromobenzo[d]thiazolecarboxylate used in Example 2. LCMS (ESI) m/Z 212 (M+H)+.

Step 3: To a solution of (2-(methylthio)benzo[d]thiazolyl)methanol (4.1 g, 19.4 mmol) from Step 2 of this Example and DIEA (3.26 g, 25.3 mmol) in CHzClz (200 mL) was added methanesulfonyl chloride (2.88 g, 25.3 mmol) slowly at 0 0C. The mixture was then treated with 2 drops ofDMF and stirred at rt overnight.

The mixture was quenched with 300 mL of saturated aq NaHCOg. The separated aqueous layer was extracted with CHZCIZ (2 x 250 mL). The combined organic layers were washed with brine, dried over MgSO4, and trated under reduced pressure to give 6-(chloromethyl)(methylthio)benzo[d]thiazole as a light brown solid (4.4 g, 99%). 1H NMR (300 MHz, DMSO-d6) 8 8.10 (d, J: 1.5 Hz, 1H), 7.84 (d, J: 8.5 Hz, 1H), 7.53 (dd, J: 1.6, 8.4 Hz, 1H), 4.89 (s, 2H), 2.80 (s, 3H). LCMS (ESI) m/z 231 (M+H)+.

Step 4: To a solution of 3H-imidazo[4,5-b]pyridine (2.99 g, 25 mmol) in DMF (100 mL) was added sodium hydride (60% in mineral oil, 1.0 g, 25 mmol) slowly at 0 0C. After the reaction mixture was stirred at rt for 20 min, it was treated with a solution of oromethyl)(methylthio)benzo[d]thiazole from Step 3 of this Example (4.8 g, 21 mmol) in DMF (20 mL) at 0 0C. The reaction mixture was then stirred at rt ght. The mixture was quenched with 3 mL of saturated aq NH4C1 and concentrated under reduced pressure. The residue was diluted with 600 mL of EtOAc and washed with water and brine. The organic layer was dried over MgSO4 and concentrated under reduced pressure The crude product was purified on a silica gel column using a mixture of HzClz (1 :30, v/v) as eluent to give 6- ((3H-imidazo[4,5-b]pyridinyl)methyl)(methylthio)benzo[d]thiazole as a tan solid (2.5 g, 38%). The regiochemistry of the alkylation was determined by a 2- dimensional nuclear Overhauser effect (NOE) experiment. 1H NMR (300 MHz, DMSO-d6) 5 8.65 (s, 1H), 8.38 (dd, J: 1.2, 4.8 Hz, 1H), 8.11 (dd, J: 1.3, 8.1 Hz, 1H), 8.00 (d, J: 1.1 Hz, 1H), 7.81 (d, J: 8.3 Hz, 1H), 7.46 (dd, J: 1.6, 8.4 Hz,1H), 7.30 (dd, J: 4.8, 8.0 Hz, 1H), 5.62 (s, 2H), 2.77 (s, 3H). LCMS (ESI) m/z 313 (M+H)+.

Step 5: To a solution of 6-((3H-imidazo[4,5-b]pyridinyl)methyl) (methylthio)benzo[d]thiazole (2.5 g, 8 mmol) in CHzClz (150 mL) was added mCPBA (70%, 2.36 g, 9.6 mmol) slowly at 0 0C. The mixture was stirred at rt overnight. The resulting solution was diluted with 150 mL CHzClz and washed tially with saturated aq NazSzOg, saturated aq NaHCOg and brine. The organic layer was dried over MgSO4, and concentrated under reduced pressure to give 6-((3H- imidazo[4,5-b]pyridinyl)methyl)(methylsulf1nyl)benzo[d]thiazole as a white solid (2.6 g, 99%). 1H NMR (300 MHz, DMSO-d6) 8 8.68 (s, 1H), 8.37 (dd, J: 1.3, 4.7 Hz, 1H), 8.23 (d, J: 0.9 Hz, 1H), 7.99 - 8.18 (m, 2H), 7.63 (dd, J: 1.7, 8.5 Hz, 1H), 7.30 (dd, J: 4.7, 8.1 Hz, 1H), 5.70 (s, 2H), 3.06 (s, 3H). LCMS (ESI) m/Z 339 (M+H)+.

Step 6: To a suspension of 6-((3H-imidazo[4,5-b]pyridinyl)methyl) (methylsulf1nyl)benzo[d]thiazole (1.3 g, 3.96 mmol) from Step 5 of this Example in DMA (6 mL) were added DIEA (511 mg, 3.96 mmol) and (1R,2R) aminocyclohexanol (1.36 g, 11.9 mmol) at rt. The reaction mixture was stirred in a sealed tube at 120 0C for 6 h. After cooling to rt, the mixture was diluted with 120 mL of EtOAc and washed with 120 mL of water. The organic layer was dried over MgSO4 and concentrated under d pressure. The crude product was purified on a silica gel column using a e of acetone-EtOAc (1 :12, v/v) as eluent to give (1R,2R)((6-((3H-imidazo[4,5-b]pyridinyl)methyl)benzo[d]thiazol yl)amino)cyclohexanol as an off white solid (864 mg, 58%). 1H NMR (300 MHZ, DMSO-d6) 5 8.60 (s, 1H), 8.38 (dd, J: 1.3, 4.7 Hz, 1H), 8.09 (dd, J: 1.2, 8.0 Hz, 1H), 7.95 (d, J: 7.5 Hz, 1H), 7.67 (s, 1H), 7.17 - 7.35 (m, 3H), 5.49 (s, 2H), 4.73 (d, J: 5.3 Hz, 1H), 3.52 (d, J: 8.5 Hz, 1H), 3.32 (br s, 1H), 1.76 - 2.12 (m, 2H), 1.61 (br s, 2H), 1.07 - 1.38 (m, 4H). LCMS (ESI) m/z 380 (M+H)+.

] Step 7: To a suspension of (1R,2R)((6-((3H-imidazo[4,5-b]pyridin yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol (1.84 g, 4.88 mmol) in EtOH (100 mL) was added methanesulfonic acid (478 mg, 4.98 mmol) at rt. The reaction mixture was stirred at 55 0C for 2 h. After cooling to rt, the mixture was concentrated under d pressure. The residue was diluted with 15 mL of water and freeze dried overnight to give (1R,2R)((6-((3H-imidazo[4,5-b]pyridin yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol methanesulfonate as a tan solid (2.32 g, 100%).1H NMR (300 MHz, MeOH-d4) 8 8.80 (s, 1H), 8.50 (dd, J: 1.1, 4.7 Hz, 1H), 8.15 (dd, J: 1.1, 8.1 Hz, 1H), 7.82 (s, 1H), 7.36 - 7.59 (m, 3H), 5.68 (s, 2H), 3.40 - 3.65 (m, 2H), 2.71 (s, 3H), 2.06 (d, J: 12.2 Hz, 2H), 1.79 (d, J: 6.6 Hz, 2H), 1.24 — 1.55 (m, 4H). LCMS (ESI) m/Z 380 (M+H)+.

Preparation of a mixture of (1R,2R)((6-((6—meth0xy—1H-benz0[d]imidazol yl)methyl)benzo[d]thiazol-Z-yl)amin0)cyclohexanol and (1R,2R)((6—((5- methoxy-lH-benzo[d]imidazol—1-yl)methyl)benzo[d]thiazol n0)cyclohexanol Step 1: A mixture of 2-bromo((6-methoxy-1H-benzo[d]imidazol yl)methyl)benzo[d]thiazole and 2-bromo((5-methoxy-1H-benzo[d]imidazol yl)methyl)benzo[d]thiazole (846 mg, 81%) was obtained as white solid using a procedure analogous to that described in Step 4 of e 2, substituting 6- methoxy-1H-benzo[d]imidazole for 5 ,6-dimethoxy-1H-benzo[d]imidazole used in Example 2. LCMS (ESI) m/Z 374, 376 (M+H)+.

Step 2: A mixture of (1R,2R)((6-((6-methoxy-lH-benzo[d]imidazol yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol and (1R,2R)((6-((5-methoxy- 1H-benzo [d]imidazolyl)methyl)benzo[d]thiazolyl)amino)cyclohexanol (1 19 mg, 51%) was obtained as a white solid using a procedure analogous to that described in Step 5 of e 2, substituting the mixture of 2-bromo((6-methoxy-1H- benzo[d]imidazolyl)methyl)benzo[d]thiazole and 2-bromo((5-methoxy-1H- benzo[d]imidazolyl)methyl)benzo[d]thiazole from Step 1 of this Example for 2- bromo((5 ,6-dimethoxy-1H-benzo[d]imidazolyl)methyl)benzo[d]thiazole used in Example 2. 1H NMR (300 MHz, DMSO-d6) 5 8.31 (s, 1H), 8.24 (s, 1H), 7.98 (d, J: 7.3 Hz, 2H), 7.58 - 7.69 (m, 2H), 7.52 (d, J: 8.7 Hz, 1H), 7.35 - 7.46 (m, 1H), 7.25 - 7.34 (m, 2H), 7.06 - 7.24 (m, 4H), 6.82 (ddd, J: 2.3, 6.8, 8.8 Hz, 2H), 5.42 (s, 4H), 4.78 (br s, 2H), 3.76 (d, J: 2.3 Hz, 6H), 3.51 (br s, 3H), 3.27 - 3.40 (m, 2H), 1.77 - 2.18 (m, 4H), 1.62 (d, J: 5.1 Hz, 4H), 1.04 - 1.42 (m, 7H). LCMS (ESI) m/Z 409 (M+H)+.

Example 5 Preparation of (1R,2R)((6-((1H-imidaz0[4,5-b]pyridin yl)methyl)benz0[d]thiazol—2-yl)amin0)cyclohexanol wflsfG?NN‘ \ NH OH Step 1: To a solution of (2-bromobenzo[d]thiazolyl)methyl methanesulfonate (900 mg, 2.79 mmol) from Step 3 of e 2 and 1H- o[4,5-b]pyridine (365 mg, 3.07 mmol) in DMF (8 mL) was added potassium carbonate (560 mg, 3.14 mmol) at rt. The reaction mixture was stirred at rt overnight.

It was then diluted with 80 mL of EtOAc and the resulting mixture was washedwith water and brine. The organic layer was ted and dried over MgSO4, and trated under reduced pressure. The crude product was purified on a silica gel column using a mixture of MeOH-CH2C12 (1:20, V/V) as eluent to give three s: Isomer l: 6-((3H-Imidazo[4,5-b]pyridinyl)methyl) bromobenzo[d]thiazole N:\d c N\>_Br 1H NMR (300 MHz, DMSO-d6) 8 8.67 (s, 1H), 8.37 (dd, .1: 1.3, 4.7 Hz, 1H), 8.12 (dd, .1: 1.2, 8.0 Hz, 1H), 8.06 (d, .1: 0.9 Hz, 1H), 7.93 — 8.00 (m, 1H), 7.55 (dd, .1: 1.5, 8.5 Hz, 1H), 7.31 (dd, .1: 4.8, 8.0 Hz, 1H), 5.67 (s, 2H). NOESY: a-b, a- c, a-d. LCMS (ESI) m/Z 345, 347 (M+H)+.

Isomer 2: -Imidazo[4,5-b]pyridinyl)methyl) bromobenzo[d]thiazole N\ d C N N \\'\\l\/©:S\>—Br // b 1H NMR (300 MHz, DMSO-d6) 8 8.72 (s, 1H), 8.42 (dd, J: 1.5, 4.7 Hz, 1H), 8.08 (d, J: 0.9 Hz, 1H), 7.99 (td, J: 1.7, 8.1 Hz, 2H), 7.50 - 7.60 (m, 1H), 7.25 (dd, J: 4.7, 8.1 Hz, 1H), 5.70 (s, 2H). NOESY: a-b, a-c, a-d, a-e. LCMS (ESI) m/z 345, 347 (M+H)+.

Isomer 3: 6-((4H-Imidazo[4,5-b]pyridinyl)methyl) bromobenzo[d]thiazole e@331Hf C N NLI) a b 1H NMR (300 MHz, DMSO-d6) 8 8.42 - 8.51 (m, 1H), 8.28 - 8.40 (m, 2H), 8.20 (d, J: 0.9 Hz, 1H), 7.99 (d, J: 8.5 Hz, 1H), 7.68 (dd, J: 1.6, 8.4 Hz, 1H), 7.21 - 7.35 (m, 1H), 6.04 (s, 2H). NOESY: a-b, a-c, a-f. LCMS (ESI) m/z 345, 347 (M+H)+.

Step 2: (lR,2R)((6-((1H-Imidazo[4,5-b]pyridin yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol (41 mg, 42%) was obtained as a White solid using a procedure ous to that described in Step 5 of Example 2, tuting the 6-((1H-imidazo[4,5 -b]pyridinyl)methyl)bromobenzo [d]thiazole (Isomer 2) from Step 1 of this Example for 2-bromo((5,6-dimethoxy-1H- benzo[d]imidazol-l-yl)methyl)benzo[d]thiazole used in Example 2. 1H NMR (300 MHz, DMSO-d6) 8 8.66 (s, 1H), 8.35 - 8.44 (m, 1H), 8.00 (d, J: 7.0 Hz, 2H), 7.69 (s, 1H), 7.12 - 7.36 (m, 3H), 5.50 (s, 2H), 4.77 (br s, 1H), 3.24 - 3.40 (m, 2H), 2.02 (d, J = 10.2 Hz, 1H), 1.87 (d, J: 9.4 Hz, 1H), 1.62 (d, J: 4.9 Hz, 2H), 1.22 (d, J: 6.0 Hz, 4H). LCMS (ESI) m/Z 380 (M+H)+.

Example 6 Preparation of (1R,2R)((6-((1H-benzo[d]imidazol-l-yl)methyl)benzo[d]thiazol- 2-yl)amino)cyclohexanol Cf”U31W PH S D To a suspension of 6-((1H-benzo[d]imidazolyl)methyl) bromobenz0[d]thiazole from Step 1 of Example 1 (34.4 mg, 0.1 mmol) in DMA (3 mL) were added DIEA (15 mg, 0.12 mmol) and (1R,2R)amin0cyclohexanol (13.8 mg, 0.12 mmol) at rt. The reaction e was stirred in a sealed tube at 120 0C overnight. After g to rt, the mixture was concentrated under d pressure.

The crude product was purified by ative HPLC using a mixture of water (containing 5% CH3CN, 0.05% HCOOH) and CH3CN (containing 0.05% HCOOH) as the mobile phase and Varian Pursuit XRs C-18 column as the stationary phase to afford (1R,2R)((6-(( 1 H-benzo [d]imidazolyl)methyl)benzo [d]thiazol yl)amin0)cyclohexanol (22 mg, 58%) as a white solid. 1H NMR (300 MHZ, DMSO- d6) 5 8.40 (s, 1H), 7.99 (d, J: 7.3 Hz, 1H), 7.60 - 7.72 (m, 2H), 7.55 (dd, J: 2.6, 6.0 Hz, 1H), 7.26 - 7.34 (m, 1H), 7.12 - 7.25 (m, 3H), 5.47 (s, 2H), 4.76 (br s, 1H), 3.26 - 3.39 (m, 2H), 2.03 (d, J: 10.0 Hz, 1H), 1.87 (d, J: 9.4 Hz, 1H), 1.62 (d, J: 4.7 Hz, 2H), 1.03 — 1.39 (m, 4H). LCMS (ESI) m/Z 379 (M+H)+.

Preparation of (1S,21S')((6-((1H-benzo[d]imidazolyl)methyl)benzo[d]thiazol- 2-yl)amino)cyclohexanol Cr“ailW OH 8 G (1S,2S)((6-((1H-Benz0[d]imidazolyl)methyl)benz0[d]thiazol yl)amino)cyclohexanol (27 mg, 71%) was obtained as a white solid using a procedure analogous to that described in Example 6, substituting (1S,2S)—2-amin0cyclohexanol for (1R,2R)amin0cyclohexanol used in Example 6. 1H NMR (300 MHZ, DMSO-d6) 8 8.40 (s, 1H), 8.03 (d, J: 7.3 Hz, 1H), 7.60 - 7.72 (m, 2H), 7.55 (dd, J: 2.6, 6.0 Hz, 1H), 7.25 - 7.34 (m, 1H), 7.11 - 7.24 (m, 3H), 5.46 (s, 2H), 4.82 (br s, 1H), 3.50 (br s, 2H), 1.82 — 2.15 (m, 2H), 1.61 (br s, 2H), 1.02 - 1.41 (m, 4H). LCMS (ESI) m/z 379 (M+H)+.

Example 8 ation of (R)((5,6-dimethoxy-1H-benzo[d]imidazol—l-yl)methyl)—N- ((tetrahydrofuranyl)methyl)benzo[d]thiazolamine (R)((5 ,6-Dimethoxy- l H-benzo [d]imidazol-l -yl)methyl)-N— ((tetrahydrofuranyl)methyl)benzo[d]thiazol-2—amine (33 mg, 65%) was obtained as a White solid using a ure analogous to that described in Step 5 of Example 2, substituting (R)-(tetrahydrofuranyl)methanamine for (lR,2R)aminocyclohexanol used in e 2. 1H NMR (300 MHZ, DMSO-d6) 8 8.05 - 8.22 (m, 2H), 7.64 (d, J: 1.1 Hz, 1H), 7.27 - 7.37 (m, 1H), 7.11 - 7.25 (m, 3H), 5.41 (s, 2H), 3.95 - 4.07 (m, 1H), 3.70 - 3.83 (m, 7H), 3.57 - 3.68 (m, 2H), 3.43 - 3.52 (m, 1H), 1.72 - 2.00 (m, 3H), 1.48 - 1.64 (m, 1H). LCMS (ESI) m/z 425 (M+H)+.

Example 9 ation of 6-((5,6-dimethoxy-1H-benzo[d]imidazolyl)methyl)-N-(pyridin- 2—ylmethyl)benzo[d]thiazolamine N=\\/©:\>—NH \OQN N_ 3 W) 6-((5 ,6-Dimethoxy- l H-benzo [d]imidazol- l -yl)methyl)-N—(pyridin-2— ylmethyl)benzo[d]thiazol-2—amine (31 mg, 60%) was ed as a White solid using a procedure analogous to that described in Step 5 of Example 2, substituting pyridin ylmethanamine for (lR,2R)aminocyclohexanol used in Example 2. 1H NMR (300 MHz, DMSO-d6) 8 8.67 (t, J: 5.5 Hz, 1H), 8.52 (d, J: 4.3 Hz, 1H), 8.15 (s, 1H), 7.56 - 7.85 (m, 2H), 7.05 - 7.46 (m, 6H), 5.42 (s, 2H), 4.67 (d, J: 5.3 Hz, 2H), 3.76 (s, 6H). LCMS (ESI) m/Z 432 (M+H)+.

Example 10 Preparation of (1R,2S)((6-((5,6-dimethoxy-1H-benzo[d]imidazol yl)methyl)benzo[d]thiazolyl)amino)-2,3-dihydro-1H-indenol =\ \/©: \>-NH OH N s (1R,2S)((6-((5,6-Dimethoxy-1H-benzo[d]imidazol yl)methyl)benzo[d]thiazolyl)amino)-2,3-dihydro-1H-indenol (27 mg, 39%) was obtained as a white solid using a procedure analogous to that bed in Step 5 of Example 2, substituting (1R,2S)amino-2,3-dihydro-1H-indenol for ) aminocyclohexanol used in Example 2. 1H NMR (300 MHZ, DMSO-d6) 8 8.33 (d, J = 8.5 Hz, 1H), 8.16 (s, 1H), 7.69 (s, 1H), 7.31 - 7.39 (m, 1H), 7.10 - 7.29 (m, 7H), 5.35 - .50 (m, 3H), 4.53 - 4.63 (m, 1H), 3.77 (d, J: 3.2 Hz, 6H), 3.08 (dd, J: 4.8, 16.1 Hz, 2H), 2.83 (d, J: 16.0 Hz, 1H). LCMS (ESI) m/z 473 (M+H)+.

Example 11 Preparation of (S)-N-(2,3-dihydr0-1H-indenyl)—6-((5,6-dimeth0xy-1H- benzo[d]imidazol-l-yl)methyl)benz0[d]thiazol-Z-amine =\fl \>——NH N s a (9 (S)-N—(2,3-dihydro-1H-indenyl)—6-((5 ,6-dimethoxy-1H- benzo[d]imidazolyl)methyl)benzo[d]thiazolamine (22 mg, 33%) was obtained as a white solid using a procedure ous to that described in Step 5 of Example 2, substituting 3-dihydro-1H-indenamine for (1R,2R)—2-aminocyclohexanol used in Example 2. 1H NMR (300 MHZ, DMSO-d6) 8 8.43 (d, J: 7.9 Hz, 1H), 8.17 (s, 1H), 7.68 (d, J: 0.9 Hz, 1H), 7.05 - 7.46 (m, 7H), 5.35 - 5.53 (m, 3H), 3.77 (d, J: 2.6 Hz, 2H), 3.36 (s, 6H), 2.74 - 3.08 (m, 2H), 1.79 - 2.02 (m, 1H). LCMS (ESI) m/z 457 (M+H)+.

Example 12 Preparation of (1R,2R)((6-(meth0xy(1H-pyrrolo[2,3-b]pyridin yl)methyl)benzo[d]thiazol—Z-yl)amin0)cyclohexanol WM)H”OH Step 1: To a suspension of (2-bromobenzo[d]thiazolyl)methanol (400 mg, 1.6 mmol) from Step 2 of Example 2 in DMA (6 mL) were added DIEA (258 mg, 2.0 mmol) and (1R,2R)aminocyclohexanol (226 mg, 2.0 mmol) at rt. The reaction mixture was stirred in a sealed tube at 120 0C overnight. After cooling to rt, the e was concentrated under reduced pressure to give crude (1R,2R)—2-((6- (hydroxymethyl)benzo[d]thiazolyl)amino)cyclohexanol as a brown oil (445 mg, 100%), which was used for the next step without any further purification. LCMS (ESI) m/Z 279 (M+H)+.

Step 2: To a solution of (1R,2R)((6-(hydroxymethyl)benzo[d]thiazol no)cyclohexanol from Step 1 of this Example (445 mg, 1.6 mmol) in CHZClz (40 mL) was added manganese(IV) oxide (696 mg, 8.0 mmol) at rt. The reaction suspension was heated under reflux overnight. After cooling to rt, the reaction mixture was filtered through a Celite pad. The filtrate was concentrated under reduced pressure to give crude 2-(((1R,2R)hydroxycyclohexyl)amino)benzo[d]thiazole dehyde as a brown oil (440 mg, 99%), which was used to next step without further purification. LCMS (ESI) m/Z 277 (M+H)+.

Step 3: To a solution of 1H-pyrrolo[2,3-b]pyridine (205 mg, 1.74 mmol) in MeOH (20 mL) were added potassium hydroxide (162 mg, 2.9 mmol) and 2- 2R)hydroxycyclohexyl)amino)benzo[d]thiazolecarbaldehyde from Step 2 of this Example (400 mg, 1.45 mmol) sequentially at rt. The on mixture was stirred at rt for 14 d. The resulting mixture was diluted with EtOAc (80 mL) and washed with water, brine. The c layer was dried over MgSO4, and concentrated under reduced pressure. The crude product was purified by HPLC using a mixture of water (5% CH3CN, 0.05% HCOOH) and CH3CN (0.05% HCOOH) as the mobile phase and Varian Pursuit XRs C-18 column as the stationary phase to afford (1R,2R)- 2-((6-(methoxy(1H-pyrrolo[2,3-b]pyridinyl)methyl)benzo[d]thiazol yl)amino)cyclohexanol as a white solid (32 mg, 5.4%). 1H NMR (300 MHZ, CDClg) 8 9.70 (br s, 1H), 8.26 (dd, J: 1.4, 4.8 Hz, 1H), 7.85 (dd, J: 1.3, 7.7 Hz, 1H), 7.64 (d, J: 1.3 Hz, 1H), 7.44 - 7.54 (m, 1H), 7.34 (d, J: 8.3 Hz, 1H), 6.97 - 7.11 (m, 2H), .64 (br s, 1H), 5.56 (s, 1H), 3.44 - 3.67 (m, 3H), 3.42 (s, 3H), 2.06 - 2.27 (m, 2H), 1.65 - 1.87 (m, 2H), 1.14 - 1.53 (m, 4H). LCMS (ESI) m/z 409 (M+H)+.

Example 13 Preparation of yl—6-((5,6-dimeth0xy-1H-benz0[d]imidazol yl)methyl)benz0[d]thiazolamine :\ \ N—Benzyl((5 ethoxy-1H-benzo[d]imidazol yl)methyl)benzo[d]thiazolamine (21 mg, 33%) was obtained as a white solid using a procedure analogous to that described in Step 5 of Example 2, substituting phenylmethanamine for (1R,2R)aminocyclohexanol used in Example 2. 1H NMR (300 MHz, DMSO-d6) 8 8.54 (t, J: 5.7 Hz, 1H), 8.15 (s, 1H), 7.66 (d, J: 1.3 Hz, 1H), 7.07 - 7.47 (m, 9H), 5.41 (s, 2H), 4.57 (d, J: 5.7 Hz, 2H), 3.76 (s, 6H). LCMS (ESI) m/Z 431 .

Example 14 Preparation of 6-((5,6-dimeth0xy-1H-benzo[d]imidazol—1-yl)methyl)—N-(2- morpholinoethyl)benz0 [d] thiazol-Z-amine N\ N\ \ QPNQESHL x0N3 6-((5 ,6-Dimethoxy- 1 H-benzo [d]imidazolyl)methyl)-N-(2- morpholinoethyl) benzo[d]thiazolamine (14 mg, 21%) was obtained as a white solid using a procedure analogous to that described in Step 5 of Example 2, tuting 2-morpholinoethanamine for (1R,2R)aminocyclohexanol used in Example 2. 1H NMR (300 MHz, DMSO-d6) 8 8.15 (s, 1H), 7.99 (t, J: 5.0 Hz, 1H), 7.64 (s, 1H), 7.27 - 7.36 (m, 1H), 7.11 - 7.26 (m, 3H), 5.41 (s, 2H), 3.76 (s, 6H), 3.52 - 3.66 (m, 4H), 3.38 - 3.51 (m, 4H), 2.33 - 2.45 (m, 4H). LCMS (ESI) m/z 454 (M+H)+.

Example 15 Preparation of 6-((5,6-dimeth0xy-1H-benzo[d]imidazol—l-yl)methyl)—N- (tetrahydro-ZH-pyranyl)benz0[d]thiazolamine QLEIWS {3O 6-((5 ethoxy- 1 H-benzo [d]imidazolyl)methyl)-N-(tetrahydro-2H- 4-yl)benzo[d]thiazolamine (34 mg, 54%) was obtained as a white solid using a procedure analogous to that described in Step 5 of Example 2, substituting tetrahydro-2H-pyranamine for (1R,2R)aminocyclohexanol used in Example 2. 1H NMR (300 MHz, DMSO-d6) 8 8.15 (s, 1H), 8.09 (d, J: 7.2 Hz, 1H), 7.65 (d, J: 1.1Hz, 1H), 7.30 - 7.37 (m, 1H), 7.13 - 7.25 (m, 3H), 5.41 (s, 2H), 3.81 - 4.00 (m, 2H), 3.76 (s, 6H), 3.37 - 3.51 (m, 3H), 1.93 (d, J: 10.5 Hz, 2H), 1.37 - 1.56 (m, 2H).

LCMS (ESI) m/Z 425 (M+H)+.

Example 16 ation of ohexyl((5,6-dimeth0xy-1H-benz0[d]imidazol yl)methyl)—N-methylbenz0[d]thiazolamine WowN s \Q C) N—Cyclohexyl((5 ,6-dimethoxy-1H-benzo[d]imidazolyl)methyl)-N- methylbenzo[d]thiazolamine (47 mg, 73%) was obtained as a white solid using a ure analogous to that described in Step 5 of Example 2, substituting N- methylcyclohexanamine for (1R,2R)aminocyclohexanol used in Example 2. 1H NMR (300 MHz, DMSO-d6) 8 8.16 (s, 1H), 7.75 (d, J: 1.1Hz, 1H), 7.37 (d, J: 8.3 Hz, 1H), 7.24 (dd, J: 1.5, 8.3 Hz, 1H), 7.18 (d, J: 3.0 Hz, 2H), 5.43 (s, 2H), 3.88 (br s, 1H), 3.76 (s, 6H), 2.98 (s, 3H), 1.47 - 1.90 (m, 7H), 1.35 (q, .1: 12.5 Hz, 2H), 1.03 — 1.22 (m, 1H). LCMS (ESI) m/Z 437 (M+H)+. e 17 Preparation of (1R,2R)((6-((1H-pyrrolo[2,3-b]pyridin hyl)benz0[d]thiazol—Z-yl)amin0)cyclohexanol WENOH To a solution of (1R,2R)((6-(methoxy(1H-pyrrolo[2,3-b]pyridin yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol (20 mg, 0.049 mmol) from Step 3 of Example 12 in CH3CN (10 mL) were added triethylsilane (11.4 mg, 0.092 mmol) and TFA (10.4 mg, 0.092 mmol) at rt. The mixture was stirred at 60 0C overnight.

After cooling to rt, the reaction mixture was concentrated under reduced pressure. The crude product was purified by HPLC using a mixture of water (5% CH3CN, 0.05% AcOH) and CH3CN (0.05% AcOH) as the mobile phase and Varian Pursuit XRs Diphenyl column as the stationary phase to afford (1R,2R)((6-((1H-pyrrolo[2,3- b]pyridinyl)methyl)benzo[d]thiazolyl)amino)cyclohexanol (5.7 mg, 31%) as a brown solid. 1H NMR (300 MHz, DMSO-d6) 8 11.71 (br s, 1H), 9.56 (br s, 1H), 8.23 (d, J: 4.1 Hz, 1H), 7.93 (d, J: 7.0 Hz, 1H), 7.70 (s, 1H), 7.26 - 7.42 (m, 3H), 7.07 (dd, J: 4.9, 7.9 Hz, 1H), 4.11 (s, 2H), 3.53 (br s, 1H), 3.27 - 3.43 (m, 2H), 1.83 - 2.12 (m, 2H), 1.66 (br s, 2H), 1.27 (br s, 4H). LCMS (ESI) m/z 379 (M+H)+.

Example 18 ation of N-cyclohexyl((5,6-dimeth0xy-1H-benzo[d]imidazol yl)methyl)benz0[d]thiazolamine =\ \/Q: \>—NH N s \Q {3 N—Cyclohexyl((5 ,6-dimethoxy-1H-benzo[d]imidazol yl)methyl)benzo[d]thiazolamine (41 mg, 66%) was obtained as a white solid using a procedure analogous to that described in Step 5 of Example 2, substituting exanamine for (1R,2R)aminocyclohexanol used in Example 2. 1H NMR (300 MHz, DMSO-d6) 8 8.15 (s, 1H), 7.97 (d, J: 7.5 Hz, 1H), 7.63 (s, 1H), 7.27 - 7.36 (m, 1H), 7.08 - 7.25 (m, 3H), 5.40 (s, 2H), 3.76 (s, 6H), 3.60 - 3.71 (m, 1H), 1.95 (d, J: .4 Hz, 2H), 1.49 - 1.80 (m, 3H), 1.06 - 1.46 (m, 5H). LCMS (ESI) m/z 423 (M+H)+.

Example 19 Preparation of (1R,2R)((6-((5,6-dimeth0xy-1H-benzo[d]imidazol—1- hyl)benz0[d]thiazol-Z-yl)amin0)—2,3-dihydr0-1H-indenol =\ \>—NH OH N 8 §’ (1R,2R)—1-((6-((5 ,6-Dimethoxy-1H-benzo[d]imidazol yl)methyl)benzo[d]thiazolyl)amino)-2,3-dihydro-1H-indenol (41 mg, 66%) was obtained as a white solid using a procedure analogous to that described in Step 5 of Example 2, substituting (1R,2R)amino-2,3-dihydro-1H-indenol for (1R,2R) aminocyclohexanol used in Example 2. 1H NMR (300 MHZ, DMSO-d6) 8 8.49 (d, J = 7.9 Hz, 1H), 8.17 (s, 1H), 7.69 (s, 1H), 7.32 - 7.43 (m, 1H), 7.05 - 7.31 (m, 7H), 5.44 (s, 2H), 5.18 (t, J: 6.9 Hz, 1H), 4.30 (q, .1: 6.9 Hz, 1H), 3.77 (d, J: 3.0 Hz, 6H), 3.38 (br s, 1H), 3.16 (dd, .1: 7.0, 15.4 Hz, 1H), 2.75 (dd, .1: 7.2, 15.4 Hz, 1H).

LCMS (ESI) m/Z 473 (M+H)+.

Example 20 Preparation of (1R,2R)((6-((5,6-dimethoxy-1H-benzo[d]imidazol—1- yl)methyl)benzo[d]thiazolyl)amino)cyclopentanol =\ \)——NH OH ” S U )—2-((6-((5 ,6-Dimeth0xy-1H-benzo[d]imidazol yl)methyl)benz0[d]thiazolyl)amino)cyclopentanol (31 mg, 49%) was ed as a White solid using a procedure analogous to that described in Step 5 of Example 2, substituting (1R,2R)amin0cyclopentanol for (1R,2R)amin0cyclohexanol used in Example 2. 1H NMR (300MHz, DMSO-d6) 5 8.15 (s, 1 H), 8.05 (d, J=6.6 Hz, 1 H), 7.64 (d, J=1.1 Hz, 1 H), 7.28 - 7.37 (m, 1 H), 7.11 - 7.26 (m, 3 H), 5.41 (s, 2 H), 4.95 (br. s., 1 H), 3.91 - 4.03 (m, 1 H), 3.81 - 3.91 (m, 1 H), 3.76 (s, 6 H), 1.75 - 1.94 (m, 2 H), 1.56 - 1.74 (m, 2 H), 1.39 - 1.55 (m, 2 H). LCMS (ESI) m/z 425 (M+H)+.

Example 21 Preparation of 6-((5,6-dimethoxy-1H-benzo[d]imidazolyl)methyl)-N-(pyridin- thyl)benzo[d]thiazol-Z-amine \o/Q/NUQWH - S LCM 6-((5 ,6-Dimeth0xy- 1 H-benzo [d]imidazolyl)methyl)-N—(pyridin ylmethyl)benzo[d] thiazolamine (29 mg, 45%) was obtained as a White solid using a procedure analogous to that bed in Step 5 of Example 2, substituting pyridin- 4-ylmethanamine for (1R,2R)amin0cyclohexanol used in Example 2. 1H NMR (300 MHz, DMSO-d6) 8 8.67 (t, J: 5.8 Hz, 1H), 8.50 (d, J: 5.7 Hz, 2H), 8.15 (s, 1H), 7.68 (d, J: 0.9 Hz, 1H), 7.06 - 7.42 (m, 6H), 5.42 (s, 2H), 4.62 (d, J: 5.5 Hz, 2H), 3.76 (s, 6H). LCMS (ESI) m/Z 432 (M+H)+. e 22 Preparation of 6-((5,6-dimethoxy-1H-benzo[d]imidazol—l-yl)methyl)—N- phenylbenzo [d]thiazol-Z-amine 2012/059983 =\fl \)——NH N s \0Q Q To a suspension of 2-bromo((5,6-dimethoxy-1H-benzo[d]imidazol yl)methyl) benzo[d]thiazole (60 mg, 0.148 mmol) from Step 4 of Example 2 in aniline (0.6 mL) was added DIEA (23 mg, 0.178 mol) at rt. The reaction mixture was stirred in a sealed tube at 120 0C for 48 h. After cooling to rt, the reaction mixture was trated under reduced pressure. The crude t was purified by HPLC using a mixture of water (5% CH3CN, 0.05% HCOOH) and CH3CN (0.05% HCOOH) as the mobile phase and Varian Pursuit XRs C18 column as the stationary phase to afford 6-((5 ,6-dimethoxy-1H-benzo[d]imidazolyl)methyl)-N- phenylbenzo[d]thiazolamine (31 mg, 50%) as a white solid. 1H NMR (300 MHZ, DMSO-d6) 5 10.53 (br s, 1H), 8.18 (s, 1H), 7.71 - 7.82 (m, 3H), 7.56 (d, J: 8.3 Hz, 1H), 7.26 - 7.42 (m, 3H), 7.19 (d, J: 3.2 Hz, 2H), 7.01 (t, J: 7.3 Hz, 1H), 5.48 (s, 2H), 3.77 (s, 6H). LCMS (ESI) m/Z 417 (M+H)+.

Example 23 Preparation of (1R,2R)((6-((5-meth0xy-3H-imidaz0[4,5-b]pyridin yl)methyl)benz0[d]thiazol—Z-yl)amin0)cyclohexanol CW):N\ N Step 1: To a stirred solution of 4-aminobenzonitrile (10.0 g, 84.7 mmol) in MeCN (100 mL) at 90 0C was slowly added N—chlorosuccinimide (12.4 g, 93 mmol).

After the addition ofN—chlorosuccinimide, the reaction e was stirred at 90 0C for 2 h. The reaction mixture was then cooled to rt and concentrated under d pressure. The residue was dissolved in 500 mL of CHzClz and washed with 5% aq NaOH. The organic layer was dried over MgSO4 and trated under reduced pressure to give 4-aminochlorobenzonitrile as a tan solid (12.2 g, 95%). 1H NMR (300 MHz,CDC13)8 7.54 (d, J: 1.7 Hz, 1H), 7.35 (dd, J: 1.8, 8.4 Hz, 1H), 6.77 (d, J: 8.5 Hz, 1H), 4.63 (br s, 2H).

Step 2: To a solution of 4-aminochlorobenzonitrile (12.2 g, 80.2 mmol) from Step 1 of this Example in DMF (60 mL) was added potassium O-ethyl carbonodithioate (28.9 g, 180.7 mmol) at rt. The mixture was refluxed for 4 h. After cooling to rt, the reaction mixture was poured into ice water and acidified with 2N aq HCl . The tan solids were collected and dried in vacuum oven overnight. Then the solids were refluxed with 500 mL of CHC13 for 10 min. After cooling to rt, the mixture was treated with 200 mL of hexanes and sonicated for 20 min. The pale brown solid was collected by filtration to give 2-mercaptobenzo[d]thiazole carbonitrile (12.9 g, 84%). 1H NMR (300 MHz, DMSO-d6) 8 14.16 (br s, 1H), 8.23 (d, J: 0.9 Hz, 1H), 7.83 (dd, J: 1.3, 8.5 Hz, 1H), 7.31 - 7.51 (m, 1H).

Step 3: Sodium e (60% in mineral oil, 1.92 g, 48 mmol) was suspended in DMF (60 mL) at 0 0C and 2-mercaptobenzo[d]thiazole carbonitrile (5.76 g, 30 mmol) from Step 2 of this e was added slowly. After gas evolution ceased, iodomethane (8.4 mL, 135 mmol) was added and the reaction mixture was stirred at rt overnight. To the reaction mixture was added 300 mL of water and the precipitate was collected by filtration to give 2-(methylthio)benzo[d]thiazole carbonitrile as a light yellow solid (5.47 g, 89%). 1H NMR (300 MHZ, CDClg) 8 8.08 (d, J: 1.1 Hz, 1H), 7.91 (d, J: 8.3 Hz, 1H), 7.67 (dd, J: 1.5, 8.5 Hz, 1H), 2.83 (s, 3H).

] Step 4: To a solution of 2-(methylthio)benzo[d]thiazolecarbonitrile (10.0 g, 48.5 mmol) from Step 3 of this Example in THE (150 mL) was added lithium um hydride solution (2.0 M in THF, 50.9 mL, 101.9 mmol) slowly at -78 0C.

The reaction mixture was slowly warmed to 0 0C and stirred at 0 0C for 3 h treated with 4 mL of water, 4 mL of 10% aq NaOH and 12 mL of water. The resulting reaction mixture was d at rt for 1 h before it was filtered through a Celite pad and the itates were washed with 100 ofmL EtOAc. The combined filtrates were concentrated under reduced pressure. The crude product was purified on a silica gel column using a mixture of MeOH-CHzClz (1 :2, v/v) as eluent to give (2- (methylthio)benzo[d]thiazolyl)methanamine as an yellow oil (3.5 g, 34%). 1H NMR (300 MHz, CDC13)8 7.82 (d, J: 8.3 Hz, 1H), 7.73 (s, 1H), 7.35 (dd, J: 1.4, 8.4 Hz, 1H), 3.97 (s, 2H), 2.79 (s, 3H), 1.55 (s, 2H). LCMS (ESI) m/z 211 (M+H)+.

Step 5: To a on of romethoxynitropyridine (430 mg, 2.3 mmol) in DMF (6 mL) was added (2-(methylthio)benzo[d]thiazolyl)methanamine (437 mg, 2.1 mmol) from Step 4 of this Example slowly at 0 0C. The reaction mixture was stirred at rt overnight. The resulting reaction mixture was diluted with 60 mL of EtOAc and washed with saturated aq NaHCOg and brine. The organic layer was dried over MgSO4, and concentrated under reduced pressure. The crude product was purified on a silica gel column using CHzClz as eluent to give 6-methoxy-N-((2- (methylthio)benzo[d]thiazolyl)methyl)nitropyridinamine as a yellow solid (431 mg, 57%). LCMS (ESI) m/Z 363 (M+H)+.

Step 6: To a mixture of 6-methoxy-N-((2-(methylthio)benzo[d]thiazol yl)methyl)nitropyridinamine (431 mg, 1.19 mmol) from Step 5 of this Example in acetic acid (6 mL) was added zinc powder (235 mg, 3.57 mmol) slowly at 0 0C.

The on mixture was stirred at 0 0C for 20 min and then stirred at rt for 4 h. The resulting reaction mixture was d with 30 mL of EtOAc and filtered through a Celite pad. The e was neutralized with saturated aq NaHCOg. The organic layer was separated, dried over MgSO4, and trated under reduced pressure. The crude product was purified on a silica gel column using a mixture of EtOAc-CHzClz (1 :3, v/v) as eluent to give 6-methoxy-N2-((2-(methylthio)benzo[d]thiazol hyl)pyridine-2,3-diamine as a brown oil (389 mg, 98%). LCMS (ESI) m/Z 333 (M+H)+.

Step 7: To a solution of triethoxymethane (5 mL) was added 6-methoxy- NZ-((2-(methylthio)benzo[d]thiazolyl)methyl)pyridine-2,3-diamine (332 mg, 1.0 mmol) from Step 6 of this e at rt. The reaction mixture was heated under reflux overnight. After g to rt, the e was concentrated under reduced pressure. The crude product was purified on a silica gel column using a mixture of EtOAc-CHzClz (0 to 100%, v/v) as eluent to give 6-((5-methoxy-3H-imidazo[4,5- b]pyridinyl)methyl)(methylthio)benzo[d]thiazole as a brown solid (180 mg, 53%). 1H NMR (300 MHz,CDC13)8 7.95 (d, J: 8.7 Hz, 1H), 7.87 (s, 1H), 7.82 (d, J = 8.5 Hz, 1H), 7.70 (d, J: 1.1 Hz, 1H), 7.41 (dd,.]= 1.7, 8.3 Hz, 1H), 6.71 (d, J: 8.7 Hz, 1H), 5.47 (s, 2H), 3.99 (s, 3H), 2.78 (s, 3H). LCMS (ESI) m/z 343 (M+H)+.

Step 8: (6-((5-Methoxy-3H-imidazo[4,5-b]pyridinyl)methyl) (methylsulfinyl) benzo[d]thiazole (180 mg, 100%) was obtained as an off white solid using a procedure analogous to that described in Step 5 of Example 3, substituting 6- ((5 -methoxy-3H-imidazo[4,5-b]pyridinyl)methyl)(methylthio)benzo[d]thiazole from Step 7 of this Example for 6-((3H-imidazo[4,5-b]pyridinyl)methyl) (methylthio)benzo[d]thiazole used in Example 3. LCMS (ESI) m/Z 359 (M+H)+.

Step 9: (lR,2R)—2-((6-((5-Methoxy-3H-imidazo[4,5-b]pyridin hyl)benzo [d]thiazolyl)amino)cyclohexanol (36 mg, 35%) was obtained as a white solid using a ure analogous to that described in Step 5 of Example 2, substituting 6-((5 -methoxy-3H-imidazo[4,5-b]pyridinyl)methyl) (methylsulf1nyl)benzo[d]thiazole from Step 8 of this e for 2-bromo((5,6- dimethoxy-lH-benzo[d]imidazol-l-yl)methyl)benzo[d]thiazole used in Example 2. 1H NMR (300 MHz, 6) 8 8.34 (s, 1H), 7.90 - 8.08 (m, 2H), 7.73 (s, 1H), 7.29 (s, 2H), 6.69 (d, J: 8.5 Hz, 1H), 5.39 (s, 2H), 4.76 (br s, 1H), 3.94 (s, 3H), 3.51 (br s, 2H), 1.76 - 2.17 (m, 2H), 1.61 (br s, 2H), 1.04 - 1.42 (m, 4H). LCMS (ESI) m/z 410 (M+H)+.

Example 24 Preparation of 1-(4-((6-((5,6-dimeth0xy-lH-benzo[d]imidazol yl)methyl)benz0[d] thiazol-Z-yl)amin0)piperidinyl)ethan0ne acetic acid ] A stirred mixture of 2-bromo((5,6-dimethoxy-lH—benzo[d]imidazol-l- yl)methyl)benzo[d]thiazole (80 mg, 0. 198 mmol) from Example 2, l-(4- aminopiperidin-l-yl)ethanone (56 mg, 0.396 mmol) and DIEA (77 mg, 0.594 mmol) in anhydrous DMA (1 mL) was heated at 120 CC for 15 h. After cooling to rt, the mixture was purified directly by reverse-phase HPLC using a mixture of water (5% CH3CN, 0.05% HCOOH) and CH3CN (0.05% HCOOH) as the mobile phase and Varian Pursuit XRs C-l 8 column as the stationary phase to afford l-(4-((6-((5,6- dimethoxy- lH—benzo [d]imidazol- l -yl)methyl)benzo [d]thiazolyl)amino)piperidin- l-yl)ethanone acetate (7 mg, 7%) as a white solid. 1H NMR (300 MHZ, DMSO-d6) 8 8.15 (s, 1H), 8.08 (d, J: 7.2 Hz, 1H), 7.65 (s, 1H), 7.30 - 7.37 (m, 1H), 7.14 - 7.25 (m, 3H), 5.41 (s, 2H), 4.18 (m, 1H), 3.94 (m, 1H), 3.75 — 3.77 (m, 7H), 3.11 - 3.24 (m, 2H), 2.78 — 2.85 (m, 1H), 1.95 — 2.05 (m, 4H), 1.89 (s, 3H), 1.19 - 1.48 (m, 2H).

LCMS (ESI) m/Z 466 (M+H)+.

Example 25 Preparation of (R,S)((5,6-dimeth0xy-lH-benzo[d]imidazol-l-yl)methyl)—N— (tetrahydrofuranyl)benz0[d]thiazolamine acetic acid 21 4 /\ S N/ N/\©:N/>—ij )LOH ; 7\ O A stirred mixture of 2-bromo((5,6-dimethoxy-1H—benzo[d]imidazol yl)methyl)benzo[d]thiazole (80 mg, 0.198 mmol) from Example 2, (R,S)- tetrahydrofiaranamine (34 mg, 0.396 mmol) and DIEA (77 mg, 0.594 mmol) in anhydrous DMA (1 mL) was heated at 120 CC for 3 h. After cooling to rt, the mixture was purified directly by reverse-phase HPLC using a mixture of water (5% CH3CN, 0.05% HCOOH) and CH3CN (0.05% HCOOH) as the mobile phase and Varian Pursuit XRs C-18 column as the stationary phase to afford (R,S)((5,6-dimethoxy- zo[d]imidazolyl)methyl)-N—(tetrahydrofi.1ran-3 -yl)benzo [d]thiazolamine acetate (15 mg, 16%) as a white solid. 1H NMR (300 MHZ, DMSO-d6) 8 8.28 (d, J = 6.0 Hz, 1H), 8.15 (s, 1H), 7.66 (d, J: 1.1 Hz, 1H), 7.36 (d, J: 8.1 Hz, 1H), 7.14 - 7.26 (m, 3H), 5.42 (s, 2H), 4.39 (br s, 1H), 3.59 - 3.88 (m, 11H), 2.12 - 2.26 (m, 1H), 1.88 (s, 3H). LCMS (ESI) m/Z 411 .

Example 26 Preparation of 3-((2-(((1R,2R)hydr0xycyclohexyl)amin0)benzo[d]thiazol yl)methyl)-3H-imidaz0[4,5-b]pyridinaminium acetic acid + AU (9&1stN N ,N C Step 1: 3-((2-Bromobenzo[d]thiazolyl)methyl)-3H-imidazo[4,5- dinamine (34 mg, 20%) was obtained as a white solid using a procedure analogous to that bed in Step 4 of Example 2, substituting 3H-imidazo[4,5- b]pyridinamine for 5,6-dimethoxy-1H-benzo[d]imidazole used in Example 2. 1H NMR (300MHz, : 5 7.97 (d, J=8.5 Hz, 1 H), 7.51 (d, J=5.5 Hz, 2 H), 7.35 (dd, J=8.3, 1.5 Hz, 1 H), 7.14 - 7.23 (m, 1 H), 7.05 - 7.14 (m, 3 H), 5.28 (s, 2 H).

Step 2: (1R,2R)((6-((2-Amino-3H-imidazo[4,5-b]pyridin yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol (14 mg, 36%) was obtained as a white solid using a procedure analogous to that described in Step 5 of Example 2, substituting 3-((2-bromobenzo[d]thiazolyl)methyl)-3H-imidazo[4,5-b]pyridin amine from Step 1 of this Example for 2-brom0((5,6-dimeth0xy-1H- benzo[d]imidazolyl)methyl)benz0[d]thiazole used in Example 2. 1H NMR (300 MHz, DMSO-d6) 5 7.95 (d, J=7.5 Hz, 1 H), 7.48 (d, J=1.1 Hz, 1 H), 7.27 (d, J=8.3 Hz, 1 H), 7.02 - 7.19 (m, 3 H), 6.91 (t, J=7.1 Hz, 1 H), 6.76 - 6.85 (m, 1 H), 6.54 (s, 2 H), 5.22 (s, 2 H), 4.77 (br. s., 1 H), 3.11 (br. s., 2 H), 1.95 - 2.16 (m, 2 H), 1.87 (s, 3 H), 1.62 (d, J=4.5 Hz, 2 H), 1.01 - 1.41 (m, 4 H). LCMS (ESI) m/z 395 (M+H)+. e 27 Preparation of 6-((5,6-dimethoxy-lH-benzo[d]imidazol—1-yl)methyl)—N—(2- ethoxyphenyl)benzo[d] thiazol-Z-amine NpN/Uskw <0 Q “ d o\ ,0 ] To a suspension of 2-bromo((5,6-dimethoxy-1H—benzo[d]imidazol hyl)benzo[d]thiazole (60 mg, 0.15 mmol) from Example 2 and 2-eth0xyaniline (61 mg, 0.46 mmol) in anhydrous DMA (600 uL) at rt was added DIEA (155 uL, 0.90 mmol). The mixture was heated in a sealed tube at 110 0C for 72 h. After g to rt, the resulting reaction solution was purified by reverse-phase preparative HPLC using a mixture of water (5% CH3CN, 0.05% HCOOH) and CH3CN (0.05% HCOOH) as the mobile phase and Varian Pursuit XRs C18 column as the stationary phase to afford 6-((5 ,6-dimeth0xy-1H-benz0[d]imidazolyl)methyl)-N-(2- ethoxyphenyl)benz0[d]thiazolamine (15.2 mg, 22%) as a white solid. 1H NMR (300 MHz, DMSO-d6) 8 9.69 (s, 1H), 8.31 - 8.44 (m, 1H), 8.18 (s, 1H), 7.76 (d, J: 1.1 Hz, 1H), 7.51 (d, J: 8.1 Hz, 1H), 7.29 (dd, J: 1.5, 8.3 Hz, 1H), 7.19 (d, J: 2.4 Hz, 2H), 6.91 - 7.07 (m, 3H), 5.47 (s, 2H), 4.12 (q, .1: 6.8 Hz, 2H), 3.76 (s, 6H), 1.37 (t, .1: 7.0 Hz, 3H). LCMS (ESI) m/z 461 (M+H)+.

Example 28 Preparation of N-(cyclohexylmethyl)—6-((5,6-dimethoxy-lH-benzo[d]imidazol yl)methyl)benzo[d]thiazolamine s A) A stirred mixture of o((5,6-dimethoxy-1H—benzo[d]imidazol yl)methyl)benzo[d]thiazole (70 mg, 0.173 mmol) from Example 2, cyclohexanemethylamine (39 mg, 0.346 mmol) and DIEA (67 mg, 0.519 mmol) in anhydrous DMA (1.5 mL) was heated at 100 CC for 2.5 h. After cooling to rt, the mixture was purified directly by reverse-phase HPLC using a mixture of water (5% CH3CN, 0.05% HCOOH) and CH3CN (0.05% HCOOH) as the mobile phase and Varian Pursuit XRs C-18 column as the stationary phase to afford N- (cyclohexylmethyl)((5 ,6-dimethoxy- zo [d]imidazol yl)methyl)benzo[d]thiazolamine (25 mg, 33%) as a white solid. 1H NMR (300 MHz, DMSO-d6) 5 8.15 (br s, 1H), 8.04 (t, J: 5.4 Hz, 1H), 7.63 (s, 1H), 7.31 (m, 1H), 7.12 - 7.24 (m, 3H), 5.40 (s, 2H), 3.76 (s, 6H), 3.17 (t, J: 6.1 Hz, 2H), 1.49 - 1.78 (m, 6H), 1.07 - 1.27 (m, 3H), 0.84 - 1.02 (m, 2H). LCMS (ESI) m/z 437 (M+H)+.

Example 29 Preparation of (1R,2R)((6-((6-br0m0-3H-imidaz0[4,5-b]pyridin yl)methyl)benz0[d]thiazol—Z-yl)amin0)cyclohexanol .wfirb“N\ N Step 1: 5-Bromo-N—((2-(methylthio)benzo[d]thiazolyl)methyl) nitropyridinamine (605 mg, 44%) was obtained as a yellow solid using a procedure analogous to that bed in Step 5 of Example 23, substituting 5-bromochloro nitropyridine for 2-chloromethoxynitropyridine used in Example 23. LCMS (ESI) m/Z 409, 411 (M+H)+.

Step 2: o-N2-((2-(methylthio)benzo[d]thiazol yl)methyl)pyridine-2,3-diamine (170 mg, 30%) was obtained as an yellow oil using a ure analogous to that described in Step 6 of Example 23, substituting 5-bromo- N—((2-(methylthio)benzo[d]thiazolyl)methyl)nitropyridinamine from Step 1 of this e for 6-methoxy-N-((2-(methylthio)benzo[d]thiazolyl)methyl) nitropyridinamine used in Example 23. LCMS (ESI) m/Z 381, 383 (M+H)+.

Step 3: 6-((6-Bromo-3H-imidazo[4,5-b]pyridinyl)methyl) lthio)benzo [d]thiazole (71 mg, 40%) was obtained as an off white solid using a procedure analogous to that described in Step 7 of Example 23, substituting 5- bromo-NZ-((2-(methylthio)benzo[d]thiazolyl)methyl)pyridine-2,3-diamine from 2012/059983 Step 2 of this e for 6-methoxy-N2-((2-(methylthio)benzo[d]thiazol yl)methyl)pyridine-2,3-diamine used in Example 23. LCMS (ESI) m/Z 391, 393 (M+H)+.

] Step 4: 6-((6-Bromo-3H-imidazo[4,5-b]pyridinyl)methyl) (methylsulfinyl) benzo[d]thiazole (73 mg, 100%) was obtained as an off white solid using a procedure analogous to that described in Step 8 of Example 23, substituting 6- ((6-bromo-3H-imidazo[4,5-b]pyridinyl)methyl)(methylthio)benzo[d]thiazole from Step 3 of this Example for 6-((5-methoxy-3H-imidazo[4,5-b]pyridin yl)methyl)(methylthio)benzo[d]thiazole used in e 23. LCMS (ESI) m/Z 407, 409 (M+H)+.

Step 5: (1R,2R)((6-((6-Bromo-3H-imidazo[4,5-b]pyridin yl)methyl)benzo [d]thiazolyl)amino)cyclohexanol (22 mg, 27%) was obtained as a white solid using a procedure analogous to that described in Step 5 of Example 2, substituting 6-((6-bromo-3H-imidazo[4,5-b]pyridinyl)methyl) (methylsulfinyl)benzo[d]thiazole from Step 4 of this Example for 2-bromo((5,6- dimethoxy-1H-benzo[d]imidazolyl)methyl)benzo[d]thiazole used in Example 2. 1H NMR (300 MHz, DMSO-d6) 5 8.66 (s, 1H), 8.48 (d, J: 2.1 Hz, 1H), 8.40 (d, J: 2.1 Hz, 1H), 8.00 (d, J: 7.5 Hz, 1H), 7.65 (s, 1H), 7.15 - 7.36 (m, 2H), 5.48 (s, 2H), 4.78 (br s, 1H), 3.51 (br s,1H),1.96 - 2.13 (m, 1H), 1.87 (d, J: 9.6 Hz,1H),1.61(br s, 2H), 1.01 - 1.40 (m, 4H). LCMS (ESI) m/z 458, 460 . e 30 Preparation of 6-((5,6-dimeth0xy-lH-benzo[d]imidazol—1-yl)methyl)—N—(2- methoxyphenyl)benzo[d] thiazol-Z-amine To a suspension of 2-bromo((5,6-dimethoxy-1H-benzo[d]imidazol yl)methyl)benzo[d]thiazole (26 mg, 0.063 mmol) from Example 2 and 2- methoxyaniline (15.5 mg, 0.13 mmol) in anhydrous 1,4-dioxane (0.30 mL) at rt was added C82C03 (41 mg, 0.13 mmol). Argon was bubbled into the mixture for 5 min followed by the addition of 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (3.0 mg, 0.005 mmol) and tris(dibenzylideneacetone)dipalladium (0) (2.3 mg, 0.003 mmol). Argon was bubbled into the mixture for an additional 5 min and then the mixture was heated in a sealed tube at 100 0C for 4 h. After cooling to rt, the reaction mixture was d through a Celite plug and the filtrate was purified by reverse- phase preparative HPLC using a mixture of water (5% CH3CN, 0.05% HCOOH) and CH3CN (0.05% HCOOH) as the mobile phase and Varian Pursuit XRs C18 column as the stationary phase to afford 6-((5,6-dimethoxy-1H—benzo[d]imidazolyl)methyl)- ethoxyphenyl)benzo[d]thiazolamine (9.4 mg, 33%) as a white solid. 1H NMR (300 MHz, DMSO-d6) 8 9.85 (s, 1H), 8.42 (d, J: 7.3 Hz, 1H), 8.18 (s, 1H), 7.76 (d, J: 1.1 Hz, 1H), 7.51 (d, J: 8.1 Hz, 1H), 7.28 (dd, J: 1.5, 8.3 Hz, 1H), 7.19 (d, J: 2.1 Hz, 2H), 6.92 - 7.09 (m, 3H), 5.46 (s, 2H), 3.86 (s, 3H), 3.76 (d, J: 0.8 Hz, 6H). LCMS (ESI) m/Z 447 .

Example 31 Preparation of 2-((6-((5,6-dimeth0xy-lH-benzo[d]imidazol yl)methyl)benz0[d]thiazol-Z-yl)amin0)phenol NQUZG/>—NH OH To a suspension of 2-bromo((5,6-dimethoxy-1H—benzo[d]imidazol yl)methyl)benzo[d]thiazole (70 mg, 0.17 mmol) from Example 2 and 2-aminophenol (95 mg, 0.87 mmol) in anhydrous DMA (300 uL) at rt was added DIEA (90 uL, 0.52 mmol). The mixture was stirred and heated in a sealed tube at 110 0C for 96 h. After cooling to rt, the e was purified by reverse-phase preparative HPLC using a mixture of water (5% CH3CN, 0.05% HCOOH) and CH3CN (0.05% HCOOH) as the mobile phase and Varian Pursuit XRs C18 column as the stationary phase to afford 2- ((6-((5 ,6-dimethoxy- 1H-benzo[d]imidazolyl)methyl)benzo [d]thiazol yl)amino)phenol (12 mg, 16%) as a white solid. 1H NMR (300 MHZ, DMSO-d6) 8 9.77 (br s, 1H), 8.14 - 8.26 (m, 2H), 7.75 (s, 1H), 7.49 (d, J: 8.3 Hz, 1H), 7.24 - 7.29 (m, 1H), 7.16 — 7.22 (m, 2H), 6.79 - 6.92 (m, 3H), 5.46 (s, 2H), 3.76 (s, 6H). LCMS (ESI) m/Z 461 (M+H)+.

Example 32 Preparation of (1R,2R)((6-((4-(l-methyl-lH-pyrazolyl)-lH-imidazol hyl)benzo[d]thiazol-Z-yl)amino)—2,3-dihydr0-1H-indenol 0r (1R,2R) ((6-((5-(1-methyl-lH-pyrazolyl)-lH-imidazolyl)methyl)benz0[d]thiazol yl)amin0)—2:\©:3-dihydr0-1H-indenol (alternative of Example 83)/\©::/>—NH N’ N/\N ::/>_NHOH \ ”é?“ “5 N d? ] Step 1: To a stirred mixture ofDMF (15 mL) and NaH (60% dispersion in mineral oil, 539 mg, 21 mmol) at 0 0C under argon was added 4-bromo-1H-imidazole (3 g, 20 mmol) in one portion. The mixture was stirred for 5 min at 0 0C. A on of 2-(trimethylsilyl)ethoxymethyl chloride (4.3 mL, 24 mmol) in DMF (3 mL) was added se. After stirring at 0 0C for 1 h, the mixture was warmed slowly to rt and stirred for 6 h. The mixture was then partitioned n EtOAc (100 mL) and water (50 mL). The EtOAc layer was separated and washed with brine, dried over NaZSO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified Via silica gel flash chromatography ng with a gradient of 100% hexanes to 100% EtOAc) to afford a regioisomeric mixture of 4-bromo((2- (trimethylsilyl)ethoxy)methyl)- dazole and 5-bromo((2- (trimethylsilyl)ethoxy)methyl)-1H—imidazole as an oil (2.9 g, 53%). LCMS (ESI) m/Z 277 and 279 (M+H)+.

Step 2: To a mixture of 4-bromo((2-(trimethylsilyl)ethoxy)methyl)—1H- imidazole and 5-bromo((2-(trimethylsilyl)ethoxy)methyl)-1H—imidazole (345 mg, 1.3 mmol) from Step 1 of this Example, and 1-methylpyrazoleboronic acid pinacol ester (390 mg, 1.9 mmol) in DME (3 mL) was added K2C03 (691, 5 mmol). Argon was bubbled into the mixture for 5 min followed by the addition of Pd(PPh3)2Clz (44 mg, 0.06 mmol). Argon was bubbled into the mixture for an additional 5 min. Then the reaction vessel was sealed and the mixture was heated at 100 0C for 15 h. The mixture was cooled to rt, then partitioned between EtOAc (100 mL) and water (50 mL). The EtOAc layer was ted and washed with brine, dried over NaZSO4, filtered, and concentrated under reduced pressure. The residue was purified Via silica gel flash chromatography eluting with a gradient of 100% CHzClz to 10% MeOH in CHzClz to afford a regioisomeric mixture of yl(1-((2- (trimethylsilyl)ethoxy)methyl)- 1H-imidazolyl)-1H-pyrazole and 1 -methyl(1 -((2- (trimethylsilyl)ethoxy)methyl)-1H—imidazol-5 -yl)-1H-pyrazole as an oil (280 mg, 82%). LCMS (ESI) m/Z 280 (M+H)+.

Step 3: A mixture of 1-methyl(1-((2-(trimethylsilyl)ethoxy)methyl)- 1H-imidazolyl)- azole and 1 -methyl(1-((2-(trimethylsilyl)ethoxy)methyl)- dazol-5 -yl)-1H-pyrazole (170 mg, 0.7 mmol) from Step 2 of this Example were stirred in a 1:1 mixture of TFA and CHZClz (5 mL) for 15 h. The mixture was then concentrated under reduced re to afford 4-(1H—imidazolyl)—1-methyl- azole (248 mg) as an oil and was used in the next step without further purification. LCMS (ESI) m/Z 149 (M+H)+.

Step 4: To a stirred mixture of 6-(chloromethyl) lthio)benzo[d]thiazole (209 mg, 0.9 mmol) from Step 4 of Example 36 and 4- (1H—imidazolyl)methyl-1H-pyrazole (248 mg, 1.0 mmol) from Step 3 of this Example, in anhydrous DMF (3.0 mL) was added K2C03 (700 mg, 5 mmol). After stirring for 3 h at 80 0C, the reaction mixture was cooled to rt and partitioned between EtOAc (150 mL) and water (50 mL). The EtOAc layer was separated, washed with brine (50 ml), dried over Na2S04, filtered, and concentrated under reduced pressure.

The residue was purified Via silica gel flash chromatography (eluting isocratically with 1% MeOH in CHzClz) to afford separately 6-((5-(1-methyl-1H-pyrazolyl)—1H- imidazolyl)methyl)(methylthio)benzo [d]thiazole and 6-((4-(1 -methyl- 1 H- lyl)- 1 H-imidazolyl)methyl)(methylthio)benzo [d]thiazole as white solids. The first eluting somer is referred to as regioisomer 1 (55 mg, 16%) and the second g regioisomer is referred to as regioisomer 2 (142 mg, 42%). The regiochemistry of the alkylation was examined by 2-dimensional nuclear Overhauser effect (NOE) ment but was inconclusive. Regioisomer 1: 1H NMR (300 MHz, CDC13)8 7.81 (d, J: 8.3 Hz, 1H), 7.60 (s, 1H), 7.37 (s, 1H), 7.31 (s, 1H), 7.19 (s, 1H), 7.08 - 7.14 (m, 2H), 5.23 (s, 2H), 3.85 (s, 3H), 2.78 (s, 3H). LCMS (ESI) m/Z 342 (M+H)+. Regioisomer 2: 1H NMR (300 MHZ, CDClg) 8 7.81 (d, J: 8.3 Hz, 1H), .71 (m, 2H), 7.47 - 7.56 (m, 2H), 7.22 (dd, J: 1.6, 8.4 Hz, 1H), 6.94 (s, 1H), .15 (s, 2H), 3.87 (s, 3H), 2.76 (s, 3H). LCMS (ESI) m/z 342 (M+H)+.

Step 5: To a stirred mixture of regioisomer 1 from Step 4 of this Example (55 mg, 0.2 mmol) in CHzClz (15 mL) at 0 0C was added 70 — 75% 3- chloroperoxybenzoic acid (40 mg, 0.2 mmol). After the mixture was stirred at 0 0C for 2 h, saturated aq NaHCOg (10 mL) was added. The mixture was stirred for 10 min and the CHZCIZ layer was separated, dried over Na2S04, filtered, and concentrated under reduced pressure to afford either 6-((5-(1-methyl-1H—pyrazolyl)-1H—imidazol 22 1 yl)methyl)(methylsulfinyl)benzo[d]thiazole or 6-((4-(1 -methyl- 1H-pyrazolyl)- dazolyl)methyl)(methylsulfinyl)benzo[d]thiazole (55 mg) as a white foam. The material was used in the next step without filrther purification. LCMS (ESI) m/Z 356 (M+H)+.

Step 6: To a mixture of either (1-methyl-1H—pyrazolyl)-1H- imidazolyl)methyl)(methylsulfinyl)benzo[d]thiazole or 6-((4-( 1 -methyl- 1H- pyrazolyl)- 1H-imidazolyl)methyl)(methylsulfinyl)benzo azole (5 5 mg, 0.2 mmol) from Step 5 of this Example and (1R,2R)amino-2,3-dihydro-1H—inden- 2-01 (48 mg, 0.4 mmol) NMP (1.5 mL) was added DIEA (112 uL, 0.8 mmol). The reaction vessel was sealed and heated at 150 0C in the Biotage microwave reactor for 2 h. The mixture was ly purified by reverse-phase preparative HPLC using a mixture of water (5% CH3CN, 0.05% HCOOH) and CH3CN (0.05% HCOOH) as the mobile phase and Varian Pursuit XRs C18 column as the stationary phase to afford a single compound identified as either )((6-((4-(1-methyl-1H—pyrazolyl)- 1H-imidazolyl)methyl)benzo [d]thiazolyl)amino)-2,3 -dihydro-1H-indenol or (1R,2R)((6-((5-(1-methyl-1H—pyrazolyl)-1H—imidazol yl)methyl)benzo[d]thiazolyl)amino)—2,3-dihydro-1H—indenol (alternative to Example 83) (6 mg, 7%) as a white powder. 1H NMR (300 MHZ, DMSO-d6) 8 8.47 (d, J: 7.9 Hz, 1H), 7.72 - 7.86 (m, 2H), 7.49 (s, 1H), 7.28 - 7.39 (m, 2H), 7.12 - 7.26 (m, 4H), 7.01 (s, 1H), 6.92 (dd, J: 1.7, 8.3 Hz, 1H), 5.52 (m, 1H), 5.28 (s, 2H), 5.17 (t, J: 7.1 Hz, 1H), 4.30 (m, 1H), 3.82 (s, 3H), 3.16 (m, 1H), 2.74 (m, 1H). LCMS (ESI) m/Z 443 (M+H)+.

Example 33 Preparation of (S)-N-(1-cyclohexylethyl)—6-((5,6-dimeth0xy-1H- benzo[d]imidazolyl)methyl)benz0[d] thiazol-Z-amine » s m A stirred mixture of 2-bromo((5,6-dimethoxy-1H—benzo[d]imidazol yl)methyl)benzo[d]thiazole from Example 2 (80 mg, 0.198 mmol), (S)-(+) cyclohexylethylamine (50 mg, 0.396 mmol) and DIEA (77 mg, 0.594 mmol) in anhydrous DMA (2 mL) was heated at 100 CC for 72 h. After cooling to rt, the mixture was purified directly by reverse-phase HPLC using a mixture of water (5% CH3CN, 0.05% HOAc) and CH3CN (0.05% HOAc) as the mobile phase and Varian Pursuit XRs diphenyl column as the nary phase to afford (S)-N-(1- cyclohexylethyl)((5 ,6-dimethoxy-1H-benzo[d]imidazol yl)methyl)benzo[d]thiazolamine (48 mg, 54%) as a white solid. 1H NMR (300 MHz, DMSO-d6) 5 8.14 (s, 1H), 7.89 (d, J: 8.3 Hz, 1H), 7.62 (s, 1H), 7.29 (m, 1H), 7.12 - 7.23 (m, 3H), 5.40 (s, 2H), 3.76 (2 x s, 6H), 1.55 - 1.79 (m, 6H), 1.32 (m, 1H), 0.93 — 1.22 (m, 8H). LCMS (ESI) m/Z 451 (M+H)+.

Example 34 ation of (1R,2R)((6-((5,6-dimeth0xy-lH-benzo[d]imidazol yl)methyl)benz0[d] 0xazolyl)amin0)cyclohexanol 1111c Step 1: To a stirred solution of (2-(methylthio)benzo[d]oxazol yl)methanol (1.2 g, 6.15 mmol) from Example 56 and DIEA (1.19 g, 9.23 mmol) in anhydrous DCM (40 mL) at 0 0C was added se methanesulfonyl chloride (771 mg, 6.77 mmol). The mixture was allowed to warm to rt and was stirred for a filrther 2 h. The mixture was partitioned between saturated aq NaHCOg and DCM. The organic layer was ted and washed with 2 M aq HCl. The organic layer was separated, dried over MgSO4, filtered, and concentrated under reduced pressure to afford a 9:1 mixture of (2-(methylthio)benzo[d]oxazolyl)methyl methanesulfonate and oromethyl)(methylthio)benzo[d]oxazole (1.45 g) as a light pink solid which was not purified filrther. (2-(Methylthio)benzo[d]oxazolyl)methyl methanesulfonate: 1H NMR (300 MHZ, DMSO-d6) 8 7.78 (m, 1H), 7.68 (d, J: 8.1 Hz, 1H), 7.45 (m, 1H), 5.36 (s, 2H), 3.25 (s, 3H), 2.78 (s, 3H); 6-(chloromethyl)—2- (methylthio)benzo[d]oxazole: 1H NMR (300 MHz, DMSO-d6) 8 7.75 (d, J = 1.3 Hz, 1H), 7.63 (d, J: 8.1 Hz, 1H), 7.43 (dd, J: 1.3, 8.1 Hz, 1H), 4.89 (s, 2H), 2.77 (s, 3H).

] Step 2: To a stirred solution of a 9:1 mixture of (2- (methylthio)benzo[d]oxazolyl)methyl methanesulfonate and 6-(chloromethyl) (methylthio)benzo[d]oxazole (1.45 g) from Step 1 of this Example and 5,6- 2012/059983 dimethoxybenzimidazole (945 mg, 5.31 mmol) in anhydrous DMF (10 mL) at rt was added solid K2C03 (1.47 g, 10.62 mmol). The mixture was stirred at rt for 3 h. The mixture was partitioned between water and DCM. The organic layer was separated and washed with water. The organic layer was separated, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash tography eluting with 100% DCM to 10% MeOH in DCM to afford 6-((5,6- dimethoxy- 1H-benzo [d]imidazolyl)methyl)(methylthio)benzo[d]oxazole (430 mg) as a solid. 1H NMR (300 MHZ, DMSO-d6) 8 8.20 (s, 1H), 7.66 (m, 1H), 7.60 (d, J: 9.0 Hz, 1H), 7.32 (dd, J: 9.0, 3.0 Hz, 1H), 7.19 (s, 2H), 5.53 (s, 2H), 3.76 (s, 6H), 2.73 (s, 3H). LCMS (ESI) m/Z 356 .

Step 3: To a stirred solution of 6-((5,6-dimethoxy-1H—benzo[d]imidazol yl)methyl)(methylthio)benzo[d]oxazole (160 mg, 0.451 mmol) from Step 2 of this Example in DCM (2 mL) at 0 0C was added 70% meta-chloroperbenzoic acid (114 mg, 0.496 mmol) and the mixture was allowed to warm to rt and stirred for a filrther 2.5 h. To the e was added ted aq NaHCOg and the organic layer was ted. The aqueous layer was extracted with DCM and the combined organic layers were washed with saturated aq . The organic layer was separated, dried over MgSO4, filtered, and concentrated under reduced pressure to afford a solid (121 mg). The solid was dissolved in anhydrous DMA (2 mL) and then (1R,2R)-(-) aminocyclohexanol (38 mg, 0.324 mmol) and DIEA (63 mg, 0.486 mmol)were added.

The reaction vessel was sealed and the mixture was heated at 90 0C for 15 h. After cooling to rt, the reaction mixture was purified directly by reverse-phase HPLC using a mixture of water (5% CH3CN, 0.05% HCOOH), CH3CN (0.05% HCOOH) as the mobile phase and Varian Pursuit XRs C-18 column as the stationary phase to afford (1R,2R)((6-((5 ,6-dimethoxy-1H-benzo[d]imidazolyl)methyl)benzo[d]oxazol yl)amino)cyclohexanol (35 mg) as a white solid. 1H NMR (300 MHZ, DMSO-d6) 8 8.16 (s, 1H), 7.81 (m, 1H), 7.35 (s, 1H), 7.11 - 7.21 (m, 4H), 5.41 (s, 2H), 4.70 (br s, 1H), 3.76 (s, 6H), 1.80 — 2.00 (m, 2H), 1.55 — 1.67 (m, 2H), 1.15 — 1.30 (m, 4H).

LCMS (ESI) m/Z 423 (M+H)+.

Example 35 ation of N-(cyclohexylmethyl)—6-((5,6-dimethoxy-1H-benzo[d]imidazol yl)methyl)benzo[d]oxazol-Z-amine A o 4) NZ/ 1UWN O\ / Step 1: To a stirred solution of 6-((5,6-dimethoxy-1H—benzo[d]imidazol yl)methyl)(methylthio)benzo[d]oxazole (270 mg, 0.761 mmol) from Step 2 of Example 34 in DCM (5 mL) at 0 0C was added 70% meta-chloroperbenzoic acid (262 mg, 1.14 mmol), and the mixture was d to warm to rt and stirred for a filrther 4.5 h. To the mixture was added saturated aq NaHCOg and the organic layer was separated. The aqueous layer was extracted with DCM and the combined organic layers were washed with saturated aq NaHCOg. The organic layer was separated, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified Via silica gel flash chromatography eluting with 100% DCM to 10% MeOH in DCM to afford 6-((5,6-dimethoxy-1H—benzo[d]imidazolyl)methyl) lsulfmyl)benzo[d]oxazole (127 mg, 45%) as a solid. 1H NMR (300 MHZ, DMSO-d6) 8 8.24 (s, 1H), 7.85 - 7.92 (m, 2H), 7.48 (d, J: 8.3 Hz, 1H), 7.21 (s, 1H), 7.20 (s, 1H), 5.62 (s, 2H), 3.76 (s, 6H), 3.18 (s, 3H). LCMS (ESI) m/z 372 (M+H)+.

Step 2: A stirred mixture of 6-((5,6-dimethoxy-1H—benzo[d]imidazol yl)methyl)(methylsulfmyl)benzo[d]oxazole (60 mg, 0.162 mmol), cyclohexylmethylamine (36 mg, 0.323 mmol), and DIEA (63 mg, 0.485 mmol) in anhydrous DMA (2 mL) was heated at 90 CC for 15 h. After cooling to rt, the on e was purified directly by e-phase HPLC using a mixture of water (5% CH3CN, 0.05% HOAc), CH3CN (0.05% HOAc) as the mobile phase and Varian Pursuit XRs diphenyl column as the stationary phase to afford N—(cyclohexylmethyl)- 6-((5 ,6-dimethoxy- 1H-benzo [d]imidazolyl)methyl)benzo[d]oxazolamine (20 mg) as a white solid. 1H NMR (300 MHZ, DMSO-d6) 8 8.17 (s, 1H), 7.99 (t, J: 5.7 Hz, 1H), 7.37 (s, 1H), 7.11 - 7.24 (m, 4H), 5.42 (s, 2H), 3.77 (s, 3H), 3.76 (s, 3H), 3.11 (t, J: 6.2 Hz, 2H), 1.50 - 1.79 (m, 7H), 1.07 - 1.26 (m, 2H), 0.81 - 1.00 (m, 2H).

LCMS (ESI) m/Z 421 (M+H)+.

Example 36 Preparation of )((6-((4-(l-methyl-1H-pyrazolyl)—lH-imidazol yl)methyl)benzo[d]thiazol—2-yl)amino)cyclohexanol Kgfiib/>—NH OH I \ Step 1: To a stirred mixture of CuBrz (6.5 g, 0.03 mol) and t—butylnitrite (3.9 g, 0.04 mol) in CH3CN (100 mL) at 0 0C under argon was added ethyl 2- aminobenzo[d]thiazolecarb0xylate (5.0 g, 0.02 mol) portionwise. After stirring at 0 0C for 15 min, the mixture was allowed to warm to rt and d under argon for 2 h. 2 N HCl (300 ml) was added and the resulting solution was extracted with EtOAc (2 X 200 mL). The combined EtOAc layers were washed with brine (100 mL), dried over MgSO4, d, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with a gradient of 100% hexanes to 50% EtOAc in hexanes to afford ethyl 0benz0[d]thiazolecarb0xylate (3.94 g, 61%) as a yellow solid. 1H NMR (300 MHz, DMSO-d6) 8 8.81 (s, 1H), 8.05 - 8.12 (m, 2H), 4.37 (q, J: 7.2 Hz, 2H), 1.36 (t, J: 7.1 Hz, 3H). LCMS (ESI) m/Z 286 and 288 .

Step 2: To a stirred e of 2-br0m0benz0[d]thiazolecarb0xylate (2.3 g, 7.9 mmol) from Step 1 of this Example in THF (15 mL) at 0 0C was added sodium thiomethoxide (607 mg, 8.7 mmol) in one portion. The mixture was d to warm to rt and stirred for 20 h. The mixture was partitioned between EtOAc (150 mL) and water (100 mL). The EtOAc layer was separated and washed with water (100 mL) and brine (100 mL), dried over MgSO4, filtered, and concentrated under reduced pressure to afford ethyl 2-(methylthio)benzo[d]thiazolecarboxylate (1.7 g, 83%) as a yellow solid which did not require further purification. 1H NMR (300 MHz, DMSO-d6) 8 8.69 (d, J: 1.3 Hz, 1H), 8.02 (m, 1H), 7.92 (m, 1H), 4.35 (q, .1: 7.0 Hz, 2H), 2.83 (s, 3H), 1.35 (t, J: 7.1 Hz, 3H). LCMS (ESI) m/z 254 (M+H)+.

Step 3: To a stirred mixture of ethyl 2-(methylthi0)benz0[d]thiazole carboxylate (1.7 g, 6.6 mmol) from Step 2 of this Example in CHZClz (50 mL) at -78 0C under argon was added 1 M diisobutyl aluminum hydride in CHzClz (13.8 mL, 13.8 mmol) dropwise. After the mixture was stirred at -78 0C under argon for 3 h it was allowed to warm slowly to 0 0C. To the stirring mixture was added a saturated aq potassium sodium tartrate (50 mL) and the mixture was allowed to slowly warm to rt.

After the mixture was stirred for 12 h, the c layer was separated, dried over NaZSO4, filtered, and concentrated under reduced pressure. The e was d by silica gel flash chromatography eluting with a gradient of 100% hexanes to 100% EtOAc to afford (2-(methylthio)benzo[d]thiazolyl)methanol (1.05 g, 76%) as a white solid. 1H NMR (300 MHz, DMSO-d6) 8 7.93 (m, 1H), 7.79 (d, J: 8.3 Hz, 1H), 7.40 (dd, J: 1.3, 8.3 Hz, 1H), 5.32 (t, J: 5.7 Hz, 1H), 4.60 (d, J: 5.8 Hz, 2H), 2.78 (s, 3H). LCMS (ESI) m/Z 212 (M+H)+.

] Step 4: To a stirred mixture of (2-(methylthio)benzo[d]thiazol yl)methanol (1.05 g, 5 mmol) from Step 3 of this Example and DIEA ( 1.3 mL, 7.5 mmol) in anhydrous CHzClz (20 mL) under argon at -10 0C was added dropwise a solution of methanesulfonyl chloride (0.6 g, 5.5 mmol) in CHzClz (10 mL). The mixture was allowed to warm to rt and stirred for 3 h. Additional methanesulfonyl chloride (190 mg, 1.7 mmol) was added, and the mixture was stirred for a further 2 h.

Water (50 mL) was added, and the mixture was stirred for 10 min. The resulting mixture was then ted with CHzClz (200 mL). The CHzClz layer was separated, dried over NaZSO4, filtered, and concentrated under reduced pressure to afford 6- (chloromethyl)(methylthio)benzo[d]thiazole (1.0 g, 88%) as a light red solid. The material was used in the next step without filrther purification. LCMS (ESI) m/Z 230 (M+H)+.

Step 5: To a d mixture of 6-(chloromethyl) (methylthio)benzo[d]thiazole (0.2 g, 0.9 mmol) from Step 4 of this Example and 4- 1H-imidazole (0.2 g, 1.3 mmol) in anhydrous DMF (3.0 mL) was added K2C03 (0.37 g, 2.7 mmol). After stirred for 3 h at rt, the reaction mixture was ioned between EtOAc (100 mL) and water (50 mL). The EtOAc layer was separated, washed with brine (50 ml), dried over NaZSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with a gradient of 30% EtOAc in hexanes to 100% EtOAc to afford 6-((4- bromo-1H—imidazolyl)methyl)(methylthio)benzo[d]thiazole (160 mg, 54%) as a yellow oil. The regiochemistry of the tion was determined by 2-dimensional nuclear Overhauser effect (NOE) experiment. 1H NMR (300 MHz, CDClg) 8 7.85 (d, J: 8.3 Hz, 1H), 7.54 (d, J: 1.1 Hz, 1H), 7.45 (d, J: 1.3 Hz, 1H), 7.24 (dd, J: 1.7, 8.5 Hz, 1H), 6.88 (d, .1: 1.5 Hz, 1H), 5.17 (s, 2H), 2.80 (s, 3H). LCMS (ESI) m/Z 340 and 342 (M+H)+.

Step 6: To a d mixture of 6-((4-bromo-1H—imidazolyl)methyl) (methylthio)benzo[d]thiazole (105 mg, 0.3 mmol) from Step 5 of this Example in CHzClz (15 mL) at 0 0C was added 70 — 75% 3-chloroperoxybenzoic acid (91 mg, 0.4 mmol). After the mixture was stirred at 0 0C for 2 h, saturated aq NaHCOg (10 mL) was added. The mixture was d for 10 min and the CHzClz layer was ted, dried over Na2S04, d, and concentrated under reduced re to afford 6-((4- bromo-1H—imidazolyl)methyl)(methylsulf1nyl)benzo[d]thiazole (130 mg) as a white foam. The material was used in the next step without r purification.

LCMS (ESI) m/Z 356 and 358 (M+H)+.

Step 7: To a suspension of 6-((4-bromo-1H—imidazolyl)methyl) (methylsulf1nyl)benzo[d]thiazole (130 mg, 0.37 mmol) from Step 6 of this Example and )aminocyclohexanol (126 mg, 1 mmol) in anhydrous DMA (1.0 mL) was added DIEA (320 uL, 1.8 mmol). The mixture was heated in a sealed tube at 110 0C for 7 h. The mixture was cooled to rt and water was slowly added while stirring to give a precipitate. The mixture stirred for 10 min and the solid was collected by filtration to afford (1R,2R)—2-((6-((4-bromo- 1H—imidazol yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol (100 mg, 68%) as a tan solid.

The material was used in the next step without further purification. LCMS (ESI) m/z 407 and 409 (M+H)+.

Step 8: To a suspension of (1R,2R)((6-((4-bromo-1H—imidazol yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol (50 mg, 0.12 mmol) from Step 7 of this Example and 1-methylpyrazoleboronic acid pinacol ester (51 mg, 0.25mmol) in a mixture of DME (0.7 mL) and H20 (0.3 mL) was added K2C03 (68 mg, 0.5 mmol). Argon was bubbled into the mixture for 5 min. To the mixture was added tetrakis(triphenylphosphine)palladium (0) (14 mg, 0.01 mmol). Argon was bubbled into the mixture for 5 min. The reaction vessel was sealed and the mixture was heated at 100 0C for 16 h. Additional portions of 1-methylpyrazoleboronic acid l ester (51 mg, 0.25mmol) and tetrakis(triphenylphosphine)palladium (0) (14 mg, 0.01 mmol) were added to the mixture and argon was bubbled into the mixture for 5 min. The reaction vessel was sealed and the mixture was heated at 110 0C for 4 h. The mixture was cooled to rt and partitioned between EtOAc (100 mL) and aq 1 N WO 56070 K2C03 (50 mL). The EtOAc layer was separated and washed with water (50 mL) and brine (50 mL), dried over Na2S04, filtered, and trated under reduced pressure.

The residue was purified by preparative reverse-phase HPLC using a mixture of water (5% CH3CN, 0.05% HCOOH) and CH3CN (0.05% HCOOH) as the mobile phase and Varian Pursuit XRs C18 column as the stationary phase to afford (1R,2R)((6-((4- ( 1 -methyl- 1H-pyrazolyl)- 1H-imidazolyl)methyl)benzo [d]thiazol yl)amino)cyclohexanol (10.3 mg, 20%) as a white solid. 1H NMR (300 MHZ, DMSO- d6) 5 7.97 (d, J: 7.5 Hz, 1H), 7.80 (s, 1H), 7.71 (s, 1H), 7.54 - 7.62 (m, 2H), 7.32 (d, J: 8.3 Hz, 1H), 7.24 (s, 1H), 7.16 (dd, J: 1.3, 8.3 Hz, 1H), 5.13 (s, 2H), 4.75 (brm, 1H), 3.80 (s, 3H), 3.52 (br s, 1H), 3.34 (br s, 1H), 2.04 (d, J: 10.2 Hz, 1H), 1.88 (d, J = 9.4 Hz, 1H), 1.55 — 1.66 (m, 2H), 1.10 - 1.33 (m, 4H). LCMS (ESI) m/z 409 (M+H)+.

Example 37 Preparation of 1-((2-(((1R,2R)hydr0xycyclohexyl)amin0)benz0[d]thiazol hyl)-N—methyl-lH-imidazolecarboxamide HNfiUZkNHOH Step 1: To a stirred mixture of 6-(chloromethyl) (methylthio)benzo[d]thiazole (500 mg, 2.2 mmol) from Example 36 and methyl 4- imidazole carboxylate (400 mg, 3.3 mmol) in DMF (15 mL) was added K2C03 (0.9 g, 6.5 mmol). After the e was stirred for 3 h at rt, it was partitioned between EtOAc (100 mL) and water (50 mL). The EtOAc layer was separated and washed with water (50 mL) and brine (50 mL), then dried over Na2S04, filtered, and concentrated under reduced pressure. The e was purified by silica gel fiash chromatography eluting with 2% MeOH in CHzClz to afford methyl 1-((2- (methylthio)benzo[d]thiazolyl)methyl)-1H—imidazolecarboxylate (130 mg, 19%) as a white solid. The regiochemistry of the alkylation was determined by 2- ional nuclear Overhauser effect (NOE) experiment. 1H NMR (300 MHz, DMSO-d6) 8 8.01 (d, J: 0.9 Hz, 1H), 7.98 (d, J: 1.1 Hz, 1H), 7.93 (d, J: 0.9 Hz, 1H), 7.84 (d, J: 8.3 Hz, 1H), 7.43 (dd, J: 1.7, 8.3 Hz, 1H), 5.35 (s, 2H), 3.72 (s, 3H), 2.78 (s, 3H). LCMS (ESI) m/Z 322 (M+H)+.

Step 2: To a stirred on of methylamine (623 uL of a 2 M solution in THE, 1.3 mmol) at 0 0C was added trimethylaluminum (623 uL of a 2 M on in toluene, 1.2 mmol). The mixture was stirred for 2 min and then a solution of 1-((2- (methylthio)benzo[d]thiazolyl)methyl)-1H—imidazolecarboxylate (80 mg, 0.25 mmol) from Step 1 of this Example in DCE (1 mL) was added dropwise. The on vessel was sealed and the mixture was heated at 70 0C for 20 h. The mixture was then concentrated under reduced pressure and the residue was purified by silica gel flash chromatography eluting with 5% MeOH in EtOAc to afford N—methyl-l -((2- (methylthio)benzo[d]thiazolyl)methyl)-1H—imidazolecarboxamide (46 mg, 58%) as a white solid. 1H NMR (300 MHZ, DMSO-d6) 8 7.98 (d, J: 1.3 Hz, 1H), 7.81 - 7.94 (m, 3H), 7.71 (d, J: 1.1 Hz, 1H), 7.42 (dd, J: 1.6, 8.4 Hz, 1H), 5.33 (s, 2H), 2.78 (s, 3H), 2.70 (d, J: 4.9 Hz, 3H). LCMS (ESI) m/z 319 .

Step 3: N—Methyl-l-((2-(methylsulf1nyl)benzo[d]thiazolyl)methyl)-1H- imidazolecarboxamide was synthesized as a white foam (76 mg, 100%) using a procedure analogous to that described in Step 6 of Example 36, substituting N- methyl((2-(methylthio)benzo [d]thiazolyl)methyl)— 1H-imidazolecarboxamide from Step 2 of this Example for 6-((4-bromo-1H-imidazolyl)methyl) (methylthio)benzo[d]thiazole used in Example 36. LCMS (ESI) m/Z 335 (M+H)+.

] Step 4: 1-((2-(((1R,2R)Hydroxycyclohexyl)amino)benzo[d]thiazol yl)methyl)-N-methyl-1H—imidazolecarboxamide was synthesized as a white powder (26 mg, 46%) using a procedure analogous to that described in Step 7 of Example 36, substituting N-methyl((2-(methylsulfinyl)benzo[d]thiazol yl)methyl)-1H—imidazolecarboxamide from Step 3 of this Example for 6-((4- bromo- 1H-imidazolyl)methyl)(methylsulf1nyl)benzo [d]thiazole used in Example 36 and subjecting the crude residue to purification by reverse-phase preparative HPLC using a mixture of water (5% CH3CN, 0.05% HCOOH) and CH3CN (0.05% HCOOH) as the mobile phase and Varian t XRs C18 column as the nary phase. 1H NMR (300 MHz, DMSO-d6) 8 8.01 (d, J: 7.5 Hz, 1H), 7.84 — 7.92 (m, 1H), 7.80 (d, J: 1.1 Hz, 1H), 7.62 — 7.67 (m, 2H), 7.31 (d, 1H), 7.18 (dd, J = 1.7, 8.3 Hz, 1H), 5.18 (s, 2H), 4.77 (br m, 1H), 3.55 (br m, 1H), 3.35 (br m, 1H), 2.69 (br m, 3H), 2.04 (br m 1H), 1.86 (br m, 1H), 1.61 (br m, 2H), 1.10 — 1.35 (br m, 4H). LCMS (ESI) m/Z 386 (M+H)+.

Example 38 Preparation of (1R,2R)((6-(imidazo[1,2-a]pyridinylmethyl)benzo[d]thiazol- 2-yl)amino)cyclohexanol N N / N S 33 Step 1: A stirred mixture of 2-fiuor0i0doaniline (5.0g, 21.1 mmol), CuI (90 mg, 0.42 mmol), and PdC12(PPh3)2 (300 mg, 0.42 mmol) in a pressure tube was flushed with argon. Ethynyltrimethylsilane (2.28 g, 23.2 mmol) in TEA (20 mL) was added and the resulting mixture was stirred at rt over night. The on mixture was then diluted with EtzO and filtered through a Celite pad. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography eluting with 5% EtOAc in hexanes to afford 2-fluor0 ((trimethylsilyl)ethynyl)aniline (4.4 g, 100%) as a brown solid. LCMS (ESI) m/Z 208 (M+H)+.

Step 2: To a solution of 2-fluoro((trimethylsilyl)ethynyl)aniline (4.4 g, 21.2 mmol) from Step 1 of this Example in 20 mL ofDMF was added potassium O- ethyl odithioate (7.48 g, 46.8 mmol). The resulting mixture was heated under reflux for 4h. After cooling to rt, the on mixture was treated with water (30 mL) and 1N HCl (100 mL). The mixture was stirred at rt for 2h before the precipitates were collected byfiltration and washed with water to give the crude 6- ethynylbenzo[d]thiazolethiol (4.0 g, 99%) as a dark brown solid. LCMS (ESI) m/Z 192 .

Step 3: To a stirred solution of 6-ethynylbenz0[d]thiazolethiol (4.0 g, 21 mmol) from Step 2 of this Example in 20 mL ofDMF at 0 0C were added K2C03 (7.25 g, 5.25 mmol), and Mel (5 mL). The mixture was stirred at rt for 2 h before it was partitioned between EtOAc and water, the organic layer was washed with brine, dried over Na2S04, and concentrated under reduced pressure. The residue was purified by silica gel chromatography g with 3 :1 DCM/hexanes to afford 6- ethynyl(methylthi0)benz0[d]thiazole (1.5g, 35%) as an off-white solid. LCMS (ESI) m/Z 206 (M+H)+.

] Step 4: A d mixture of 2-amin0pyridine (100 mg, 1.1 mmol), rmaldehyde (34 mg, 1.1 mmol), CuCl (5 mg, 0.06 mmol), and Cu(OTf)2 (19 mg, 0.06 mmol) in 3 mL of toluene in a re tube was flushed with argon. 6- l(methylthio)benzo[d]thiazole (327 mg, 1.6 mmol) from Step 3 of this Example was added. The reaction vessel was sealed and the e was heated in an oil bath at 120 0C for 6 h. LCMS analysis showed that the reaction was mostly complete. The reaction mixture was partitioned between EtOAc and saturated aq NaHC03. The organic layer was washed with brine, dried over Na2S04, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0-100% EtOAc in hexanes to afford 6-(imidazo[1,2- dinylmethyl)(methylthio)benzo[d]thiazole (127 mg, 38%) as a brown oil.

LCMS (ESI) m/Z 312 .

Step 5: (1R,2R)((6-(Imidazo[1,2-a]pyridinylmethyl)benzo[d]thiazol- 2-yl)amino)cyclohexanol (28 mg, 18%) was obtained as a yellow powder using procedures analogous to those described in Step 5 of Example 3 and Step 5 of Example 2, sequentially, substituting 6-(imidazo[1,2-a]pyridinylmethyl) (methylthio)benzo[d]thiazole from Step 4 of this e for 6-((3H-imidazo[4,5- b]pyridinyl)methyl)(methylthio)benzo[d]thiazole used in Example 3. 1H NMR (300 MHz, DMSO-d6) 8 8.20 (d, J: 6.4 Hz, 1H), 7.89 (d, J: 7.5 Hz, 1H), 7.48 - 7.62 (m, 2H), 7.43 (br s, 1H), 7.27 (d, J: 8.1 Hz, 1H), 7.14 - 7.23 (m, 1H), 7.09 (dd, J: 1.2, 8.2 Hz, 1H), 6.86 (t, J: 6.7 Hz, 1H), 4.75 (br s, 1H), 4.29 (s, 2H), 3.47 - 3.59 (m, 1H), 2.03 (d, J: 10.4 Hz, 1H), 1.88 (br s, 2H), 1.61 (br s, 2H), 1.23 (d, J: 5.5 Hz, 4H). LCMS (ESI) m/Z 379 (M+H)+.

Example 39 Preparation of (IR, 2R)—2-((6-((6-(l-methyl-1H-pyrazolyl)—3H-imidazo[4,5- b]pyridinyl)methyl)benz0[d]thiazol—Z-yl)amin0)cyclohexanol //\N S N U />—NH §OH \ , O A stirred mixture of (1R,2R)((6-((6-bromo-3H—imidazo[4,5-b]pyridin yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol from Example 29(80 mg, 0.175 mmol), 1-methylpyrazoleboronic acid pinacol ester (73 mg, 0.351 mmol), 2M aq Na2C03 (400 uL, 0.40 mmol), and ous DME (1.5 mL) was degassed under argon for 15 min. Bis(triphenylphosphine)palladium (II) dichloride (12 mg, 0.0171 mmol) was added and the reaction vessel was sealed and the mixture was heated at 100 0C for 15 h. After cooling to rt, the mixture was d directly by reverse-phase HPLC using a mixture of water (5% CH3CN, 0.05% HOAc) and CH3CN (0.05% HOAc) as the mobile phase and Varian Pursuit XRs diphenyl column as the stationary phase to afford (1R, 2R)((6-((6-(1-methyl-1H—pyrazolyl)-3H—imidazo[4,5- b]pyridinyl)methyl)benzo[d]thiazolyl)amino)cyclohexanol (33 mg, 41%) as a white solid. 1H NMR (300 MHz, DMSO-d6) 8 8.64 (d, J: 1.9 Hz, 1H), 8.56 (s, 1H), 8.26 (d, J: 1.9 Hz, 1H), 8.23 (s, 1H), 7.95 - 8.01 (m, 2H), 7.67 (d, J: 1.1 Hz, 1H), 7.20 - 7.32 (m, 2H), 5.47 (s, 2H), 4.76 (br s, 1H), 3.88 (s, 3H), 3.51 (m, 1H), 3.35 (m, 1H), 2.03 (m, 1H), 1.90 (m, 1H), 1.62 (d, J: 4.7 Hz, 2H), 1.10 - 1.33 (m, 4H). LCMS (ESI) m/Z 460 (M+H)+. e 40 Preparation of (1R,2R)((6-((6-(pyridinyl)—3H-imidazo[4,5-b]pyridin yl)methyl)benz0[d]thiazol—Z-yl)amin0)cyclohexanol A stirred mixture of (1R,2R)((6-((6-bromo-3H—imidazo[4,5-b]pyridin yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol (80 mg, 0.175 mmol) from Example 29, neylboronic acid (43 mg, 0.350 mmol), 2M aq N32C03 (400 uL, 0.40 mmol), and anhydrous DME (1.5 mL) was degassed under argon for 15 min.

Bis(triphenylphosphine)palladium (II) dichloride (12 mg, 0.0171 mmol) was added and the reaction vessel was sealed and the mixture was heated at 100 CC for 15 h.

After cooling to rt, the mixture was purified directly by reverse-phase HPLC using a mixture of water (5% CH3CN, 0.05% HOAc) and CH3CN (0.05% HOAc) as the mobile phase and Varian t XRs diphenyl column as the stationary phase to afford (1R,2R)((6-((6-(pyridinyl)-3H-imidazo[4,5-b]pyridin yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol (25 mg, 31%) as a white solid. 1H NMR (300 MHz, DMSO-d6) 8 8.99 (br s, 1H), 8.66 - 8.77 (m, 2H), 8.60 (br s, 1H), 8.46 (s, 1H), 8.19 (d, .1: 7.9 Hz, 1H), 8.00 (d, .1: 7.3 Hz, 1H), 7.69 (s, 1H), 7.52 (dd, .1: 4.7, 7.7 Hz, 1H), 7.21 — 7.34 (m, 2H), 5.53 (s, 2H), 4.77 (br s, 1H), 3.51 (m, 1H), 3.35 (m, 1H), 2.03 (m, 1H), 1.87 (m, 1H), 1.56 — 1.66 (m, 2H), 1.11 _ 1.34 (m, 4H).

LCMS (ESI) m/Z 457 (M+H)+.

Example 41 Preparation of (1R,2R)((6-((5-bromomethoxy-lH-benzo[d]imidazol—1- yl)methyl)benzo[d]thiazol—2-yl)amino)cyclohexanol NQFZO/>—NH OH Step 1: To a stirred mixture of DMF (15 mL) and NaH (60% in mineral oil,75 mg,, 1.9 mmol) at -10 0C under argon was added 4-br0m0methoxy niline (490 mg, 2.2 mmol) in one portion. The mixture was stirred for 5 min at - 0C. A solution of 6-(chloromethyl)(methylthi0)benz0[d]thiazole from Example 36 (500 mg, 2.2 mmol) in DMF (5 mL) was added dropwise. After stirring at -10 0C for l h, the mixture was allowed to warm slowly to rt. The mixture was stirred at rt for 58 h and then ioned n EtOAc (150 mL) and l M aq N32C03 (50 mL). The EtOAc layer was separated and washed with water (50 mL) and brine, dried over Na2S04, d, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with a gradient of 100% hexanes to 100% EtOAc to afford 4-bromomethoxy-N—((2- (methylthi0)benzo[d]thiazolyl)methyl)nitr0aniline (239 mg, 25%) as an orange solid. 1H NMR (300 MHz, DMSO-d6) 5 9.02 (t, J: 5.8 Hz, 1H), 8.23 (s, 1H), 8.06 (s, 1H), 7.83 (d, J: 8.5 Hz, 1H), 7.53 (d, J: 8.3 Hz, 1H), 6.40 (s, 1H), 4.80 (d, J: 5.8 Hz, 2H), 3.77 (s, 3H), 2.78 (s, 3H). LCMS (ESI) m/Z 440 and 442 (M+H)+.

Step 2: To a stirred suspension of 4-bromomethoxy-N—((2- (methylthi0)benzo[d]thiazolyl)methyl)nitr0aniline (212 mg, 0.5 mmol) from Step 1 of this Example in EtOH (4 mL) and HOAc (2 mL) at 0 0C under argon was added zinc powder (160 mg, 2.4 mmol) in one portion. After 1.5 h at 0 0C, MeOH (5 mL), additional HOAc (2 mL), and zinc powder (160 mg, 2.4 mmol) were added. The mixture was allowed to warm to rt and stirred for 18 h. The mixture was filtered and the filtrate was cooled to 0 0C. The pH of the filtrate was ed to pH~9 by addition of solid N32C03. The mixture was then partitioned between EtOAc (150 mL) and water (100 mL). The EtOAc layer was separated, dried over Na2S04, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography g with a gradient of 100% hexanes to 100% EtOAc to afford 4- bromomethoxy-N1 -((2-(methylthio)benzo[d]thiazolyl)methyl)benzene- 1 ,2- diamine (120 mg, 61%). LCMS (ESI) m/Z 410 and 412 (M+H)+.

Step 3: To a stirred mixture of 4-bromomethoxy-N1-((2- (methylthio)benzo[d]thiazolyl)methyl)benzene-1,2-diamine (120 mg, 0.3 mmol) from Step 2 of this Example and triethylorthoformate (20 mL) was added formic acid (1 mL). The mixture was heated under reflux for 2 h, then concentrated under reduced pressure. The residue was d by silica gel flash tography eluting with100% EtOAc to afford 6-((5-bromomethoxy-1H—benzo[d]imidazol yl)methyl)(methylthio)benzo[d]thiazole (50 mg, 40%) as an oil. 1H NMR (300 MHz, CDClg) 8 8.01 (s, 1H), 7.78 - 7.91 (m, 2H), 7.46 (s, 1H), 7.25 (m, 1H), 6.69 (s, 1H), 5.42 (s, 2H), 3.81 (s, 3H), 2.78 (s, 3H). LCMS (ESI) m/z 420 and 422 (M+H)+.

Step 4: 6-((5-Bromomethoxy-1H—benzo[d]imidazolyl)methyl) (methylsulfinyl)benzo[d]thiazole was synthesized as a white foam (75 mg) using a procedure analogous to that described in Step 6 of e 36, substituting 6-((5- bromomethoxy- zo [d]imidazolyl)methyl)(methylthio)benzo [d]thiazole from Step 3 of this Example for 6-((4-bromo-1H-imidazolyl)methyl) (methylthio)benzo[d]thiazole used in Example 36. LCMS (ESI) m/Z 436 and 438 (M+H)+.

Step 5: (1R,2R)((6-((5-Bromomethoxy-1H—benzo[d]imidazol yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol was synthesized as a white powder (15 mg, 26%) using a procedure ous to that described in Step 4 of Example 37, substituting 6-((5-bromomethoxy-1H—benzo[d]imidazolyl)methyl)- 2-(methylsulfinyl)benzo[d]thiazole from Step 4 of this Example for yl-l-((2- (methylsulfinyl)benzo[d]thiazolyl)methyl)-1H—imidazolecarboxamide used in Example 37. 1H NMR (300 MHZ, DMSO-d6) 8 8.29 (s, 1H), 7.98 (d, J: 7.5 Hz, 1H), 7.85 (s, 1H), 7.66 (d, J: 1.1 Hz, 1H), 7.37 (s, 1H), 7.27 - 7.33 (m, 1H), 7.22 (dd, J: 9, 1.5 Hz, 1H), 5.46 (s, 2H), 4.75 (d, J: 4.9 Hz, 1H), 3.85 (s, 3H), 3.52 (br m, 1H), 3.33 (br m, 1H), 2.02 (br m, 1H), 1.85 (br m, 1H), 1.55 — 1.68 (br m, 2H), 1.10 — 1.34 (br m, 4H). LCMS (ESI) m/Z 487 and 489 (M+H)+.

Example 42 Preparation of (1R,2R)((6-((6-bromo-3H-imidazo[4,5-b]pyridin hyl)benzo[d] thiazol—2-yl)amino)—2,3-dihydro-1H—indenol :grfijsNgw A stirred mixture of 6-((6-brom0-3H—imidazo[4,5-b]pyridinyl)methyl)- 2-(methylsulfmyl)benz0[d]thiazole from Example 29 (210 mg, 0.3 mmol), (1R,2R)- 1-amin0-2,3-dihydr0-1H—indenol (92 mg, 0.6 mmol), and DIEA (267 uL, 1.5 mmol) in DMA (3 mL) was heated at 130 0C for 120 h in a sealed tube. The e was cooled to rt and subjected to purification by reverse-phase preparative HPLC using a mixture of water (5% CH3CN, 0.05% HCOOH) and CH3CN (0.05% HCOOH) as the mobile phase and Varian Pursuit XRs C18 column as the nary phase to afford )((6-((6-br0m0-3H—imidazo[4,5-b]pyridin yl)methyl)benz0[d]thiazolyl)amin0)-2,3-dihydr0-1H—indenol (5.4 mg, 4%) as a white powder. 1H NMR (300 MHz, DMSO-d6) 8 8.68 (s, 1H), 8.36 - 8.54 (m, 3H), 7.71 (s, 1H), 7.35 (m, 1H), 7.11 - 7.30 (m, 5H), 5.51 (s, 2H), 5.18 (t, J: 7.0 Hz, 1H), 4.30 (m, 1H), 3.16 (dd, J: 7.2, 15.8 Hz, 1H), 2.74 (dd, J: 7.3, 15.4 Hz, 1H). LCMS (ESI) m/Z 492 and 494 (M+H)+.

Example 43 Preparation of 3-((2-(((1R,2R)hydroxycyclohexyl)amino)benzo[d] thiazol yl)methyl)-3H—imidazo[4,5-b]pyridinecarbonitrile //\ S N ”U />—NH SOH \ / C A stirred e of (1R,2R)((6-((6-br0m0-3H—imidazo[4,5-b]pyridin yl)methyl)benzo[d]thiazolyl)amin0)cyclohexanol from Example 29 (170 mg, 0.372 mmol), zinc cyanide (131 mg, 1.12 mmol), 1,1’-bis(diphenylph0sphino)ferr0cene (31 mg, 0.0558 mmol) and anhydrous DMF (2 mL) was degassed under argon for 15 min.

Tris(dibenzylideneacetone) dipalladium (0) (34 mg, 0.0372 mmol) was added. The reaction vessel was sealed and the mixture was heated at 100 0C for 6 h. After cooling to rt, the mixture was purified directly by reverse-phase HPLC using a mixture of water (5% CH3CN, 0.05% HCOOH) and CH3CN (0.05% HCOOH) as the mobile phase and Varian t XRs C-l 8 column as the stationary phase to afford ((2- (((lR,2R)hydroxycyclohexyl)amino)benzo[d]thiazolyl)methyl)-3H-imidazo[4,5- b]pyridinecarbonitrile (51 mg, 34%) as a white solid. 1H NMR (300 MHz, DMSO- d6) 5 8.80 - 8.91 (m, 2H), 8.72 (d, J: 1.5 Hz, 1H), 7.99 (d, J: 7.3 Hz, 1H), 7.68 (s, 1H), 7.20 - 7.34 (m, 2H), 5.53 (s, 2H), 4.74 (br s, 1H), 3.29 - 3.38 (m, 2H), 2.04 (m, 1H), 1.88 (m, 1H), 1.55 — 1.70 (m, 2H), 1.10 — 1.35 (m, 4H). LCMS (ESI) m/Z 405 (M+H)+.

Example 44 Preparation of (1R,2R)((6-((7-meth0xyimidaz0[1,2-a]pyridin yl)methyl)benz0[d]thiazol—Z-yl)amin0)cyclohexanol Q C ] (lR,2R)((6-((7-Methoxyimidazo[l,2-a]pyridin yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol (25 mg) was obtained as a yellow powder using procedures analogous to those described in Steps 4-5 of Example 38, substituting 4-methoxypyridinamine for 2-aminopyridine used in Example 38. 1H NMR (300 MHZ, DMSO-d6) 8 8.03 (d, J: 7.3 Hz, 1H), 7.87 (d, J: 7.5 Hz, 1H), 7.49 (s, 1H), 7.17 - 7.33 (m, 2H), 7.07 (dd, J: 1.2, 8.2 Hz, 1H), 6.92 (d, J: 2.3 Hz, 1H), 6.59 (dd, J: 2.4, 7.4 Hz, 1H), 4.73 (br s, 1H), 4.22 (s, 2H), 3.80 (s, 3H), 3.41 - 3.63 (m, 2H), 2.03 (d, J: 10.2 Hz, 1H), 1.88 (d, J: 9.6 Hz, 1H), 1.61 (br s, 2H), 1.23 (d, .1: 5.3 Hz, 4H). LCMS (ESI) m/Z 409 (M+H)+.

Example 45 Preparation of (1R,2R)((6-((6-cyclopr0pyl—3H—imidazo[4,5-b]pyridin yl)methyl)benz0[d]thiazol—Z-yl)amin0)cyclohexanol A stirred mixture of (1R,2R)((6-((6-bromo-3H—imidazo[4,5-b]pyridin yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol from Example 29 (30 mg, 0.0656 mmol), cyclopropylboronic acid (11 mg, 0.131 mmol), K2C03 (36 mg, 0.262 mmol), 2-dicyclohexylphosphino-2’,4’,6’-triisopropylbiphenyl (16 mg, 0.0328 mmol) and anhydrous toluene (1 mL) was degassed under argon for 15 min.

Tris(dibenzylideneacetone) dipalladium (0) (6 mg, 0.0066 mmol) was added. The reaction vessel was sealed and the mixture was heated at 100 0C for 15 h. After cooling to rt, the mixture was d directly by reverse-phase HPLC using a mixture of water (5% CH3CN, 0.05% HOAc) and CH3CN (0.05% HOAc) as the mobile phase and Phenomenex Luna C-18 column as the stationary phase to afford (1R,2R)((6-((6-cyclopropyl-3H-imidazo[4,5-b]pyridin—3- hyl)benzo[d]thiazolyl)amino)cyclohexanol (1 mg, 4%) as a white solid. 1H NMR (300 MHz, DMSO-d6) 8 8.51 (s, 1H), 8.24 (d, J: 1.5 Hz, 1H), 8.03 (d, J: 7.3 Hz, 1H), 7.70 (d, J: 1.5 Hz, 1H), 7.63 (s, 1H), 7.28 (m, 1H), 7.19 (m, 1H), 5.44 (s, 2H), 4.82 (br s, 1H), 1.97 - 2.13 (m, 2H), 1.85 (m, 1H), 1.54 - 1.74 (m, 3H), 1.09 - 1.34 (m, 4H), 0.92 - 1.02 (m, 2H), 0.70 - 0.80 (m, 2H). LCMS (ESI) m/z 420 (M+H)+. e 46 Preparation of (1R,2R)((6-((3H-imidazo[4,5-b]pyridin yl)methyl)benz0[d] l—Z-yl)amin0)—2,3-dihydr0-1H—indenol Nara:,>—NH OH (1R,2R)((6-((3H-Imidazo[4,5-b]pyridinyl)methyl)benzo[d]thiazol no)-2,3-dihydro-1H—indenol was synthesized as a white powder (8 mg, 6%) using a procedure analogous to that described in Example 42, substituting 6-((3H- imidazo[4,5-b]pyridinyl)methyl)(methylsulf1nyl)benzo[d]thiazole from Example 3 for 6-((6-bromo-3H-imidazo[4,5-b]pyridinyl)methyl) (methylsulfinyl)benzo[d]thiazole used in Example 42. 1H NMR (300 MHz, DMSO- d6) 5 8.62 (s, 1H), 8.46 (d, J: 8.1 Hz, 1H), 8.39 (dd, J: 1.3, 4.7 Hz, 1H), 8.10 (dd, J = 1.3, 8.1 Hz, 1H), 7.73 (d,.]= 1.1 Hz, 1H), 7.10 - 7.40 (m, 7H), 5.51 (s, 2H), 5.17 (t, J: 7.2 Hz, 1H), 4.29 (m, 1H), 3.16 (dd, J: 7.0, 15.6 Hz, 1H), 2.74 (m, 1H). LCMS (ESI) m/Z 414 (M+H)+.

Example 47 ation of (1R,2R)((6-((6-bromomethoxy-lH-benzo[d]imidazol—1- yl)methyl)benzo [d]thiazol—Z-yl)amino)cyclohexanol “IQ/EEC/>—NH OH Step 1: To a stirred mixture of 4-bromomethoxynitroaniline (5 g, 20 mmol) in MeOH (50 mL) and HOAc (20 mL) at 0 0C under argon was added zinc powder (5.3 g, 80 mmol) portionwise. The mixture was stirred for 2 h, then filtered, and the e was cooled to 0 0C. The pH of the filtrate was ed to pH~9 by addition of solid N32C03. The e was then partitioned n EtOAc (250 mL) and water (200 mL). The EtOAc layer was separated, dried over NaZSO4, filtered, and concentrated under reduced pressure to afford 4-bromomethoxybenzene-l ,2- diamine (3.8 g, 88%) as a dark purple solid. The material was used in the next step without further purification. 1H NMR (300 MHZ, DMSO-d6) 8 6.66 (s, 1H), 6.34 (s, 1H), 4.08 - 4.83 (m, 4H), 3.63 (s, 3H). LCMS (ESI) m/z 217 and 219 (M+H)+.

] Step 2: To a stirred mixture of 4-br0momethoxybenzene-l,2-diamine (3.8 g, 18 mmol) from Step 1 of this Example and triethyl orthoformate (50 mL) was added formic acid (1 mL). The mixture was heated at reflux for 3 h, then concentrated under reduced pressure. The residue was partitioned between EtOAc (200 mL) and a l N aq N32C03 (100 mL). The EtOAc layer was separated, washed with brine (100 mL), dried over NaZSO4, filtered, and concentrated under reduced pressure to afford -br0m0meth0xy-lH—benz0[d]imidazole (4.0 g) as a brown oil. The material was used in the next step without further purification. LCMS (ESI) m/z 228 and 230 (M+H)+.

Step 3: To a stirred mixture ofDMF (3 mL) and NaH (60% in mineral oil, 67 mg, 1.6 mmol) at 0 0C under argon was added 5-bromomethoxy-lH— benz0[d]imidazole (346 mg, 1.5 mmol) from Step 2 of this Example in one portion.

The mixture was stirred for 5 min at 0 0C. A on of 6-(chlor0methyl) (methylthio)benz0[d]thiazole (500 mg, 2.2 mmol) from Step 4 of Example 36 in DMF (3 mL) was added se. The mixture was d at 0 0C for l h, then allowed to warm slowly to rt and stirred for 6 h. The mixture was then partitioned between EtOAc (100 mL) and water (50 mL). The EtOAc layer was separated and washed with brine, dried over NaZSO4, filtered, and concentrated under reduced pressure. The e was purified by silica gel flash chromatography elutingwith 100% EtOAc to afford the two regioisomers: Regioisomer 1; 6-((5-bromomethoxy-1H- benzo[d]imidazolyl)methyl)(methylthio)benzo[d]thiazole (127 mg, 20%). The structure was confirmed by comparison with NMR from the regiospecific synthesis of the same compound described in Step 3 of Example 41. 1H NMR (300 MHz, CDClg) 8 8.02 (s, 1H), 7.78 - 7.91 (m, 2H), 7.47 (s, 1H), 7.25 (m, 1H), 6.70 (s, 1H), 5.43 (s, 2H), 3.82 (s, 3H), 2.79 (s, 3H). LCMS (ESI) m/z 420 and 422 . Regioisomer 2; 6-((6-bromomethoxy- 1H-benzo [d]imidazolyl)methyl) (methylthio)benzo[d]thiazole (81 mg, 13%). 1H NMR (300 MHZ, CDClg) 8 7.92 (s, 1H), 7.84 (d, J: 8.5 Hz, 1H), 7.48 (m, 2H), 7.34 (s, 1H), 7.25 (m, 1H), 5.40 (s, 2H), 3.94 (s, 3H), 2.79 (s, 3H). LCMS (ESI) m/z 420 and 422 (M+H)+.

Step 4: 6-((6-Bromomethoxy-1H—benzo[d]imidazolyl)methyl) (methylsulfmyl)benzo[d]thiazole was synthesized as a white foam (115 mg) using a procedure analogous to that described in Step 6 of Example 36, substituting 6-((6- bromomethoxy- 1H-benzo [d]imidazolyl)methyl)(methylthio)benzo [d]thiazole (regioisomer 2 from Step 3 of this Example) for 6-((4-bromo-1H-imidazol yl)methyl)(methylthio)benzo[d]thiazole used in e 36. LCMS (ESI) m/Z 436 and 438 (M+H)+.

Step 5: (1R,2R)((6-((6-Bromomethoxy-1H—benzo[d]imidazol yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol was synthesized as a white powder (15 mg, 19%) using a procedure analogous to that described in Step 4 of e 37, substituting 6-((5-bromomethoxy-1H—benzo[d]imidazolyl)methyl)- 2-(methylsulf1nyl)benzo[d]thiazole from Step 4 of this Example for yl-l-((2- (methylsulfmyl)benzo[d]thiazolyl)methyl)-1H—imidazolecarboxamide used in e 37. 1H NMR (300 MHZ, DMSO-d6) 8 8.37 (s, 1H), 7.98 (d, J: 7.5 Hz, 1H), 7.79 - 7.91 (m, 2H), 7.63 (s, 1H), 7.35 (s, 1H), 7.17 (dd, J: 1.6, 8.2 Hz, 1H), 5.43 (s, 2H), 4.75 (br s, 1H), 3.84 (s, 3H), 3.51 (m, 1H), 3.33 (m, 1H), 2.03 (m, 1H), 1.87 (m, 1H), 1.13 — 1.35 (br m, 2H), 1.09 - 1.35 (m, 4H). LCMS (ESI) m/Z 487 and 489 (M+H)+.

Example 48 Preparation of (1R,2R)((6-((9H-purinyl)methyl)benz0[d]thiazol yl)amin0)cyclohexanol 2012/059983 N223] :)—NH OH Step 1: 2-(Methylsulfinyl)benzo[d]thiazolecarbonitrile was synthesized as a tan solid (6.0 g) using a procedure analogous to that described in Step 5 of Example 3, substituting 2-(methylthio)benzo[d]thiazolecarbonitrile from Step 3 of Example 23 for 6-((3H—imidazo[4,5-b]pyridinyl)methyl) (methylthio)benzo[d]thiazole used in Example 3. LCMS (ESI) m/z 223 (M+H)+.

Step 2: 2-(((lR,2R)Hydroxycyclohexyl)amino)benzo[d]thiazole carbonitrile was synthesized as a white solid (1 .8 g, 69%) using a ure analogous to that described in Step 6 of Example 3, substituting 2- (methylsulfinyl)benzo[d]thiazolecarbonitrile from Step 1 of this e for 6- ((3H—imidazo[4,5-b]pyridinyl)methyl)(methylsulfinyl)benzo[d]thiazole used in e 3. LCMS (ESI) m/Z 274 (M+H)+.

Step 3: To a stirred mixture of 2-(((lR,2R) hydroxycyclohexyl)amino)benzo[d]thiazolecarbonitrile (l .2 g, 4.5 mmol) from Step 2 of this Example and 2,2-dimethoxypropane (4.7 g, 45 mmol) in l,4-dioxane (30 mL) were added para-toluenesulfonic acid (89 mg, 0.5 mmol) and lar sieves (4A) and the mixture was heated at reflux for 15 h. The mixture was cooled to rt, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified Via silica gel flash chromatography to afford 2-((3aR,7aR)—2,2- dimethylhexahydrobenzo[d]oxazol-3(2H)-yl)benzo[d]thiazolecarbonitrile (700 mg, 50%) as a white solid. LCMS (ESI) m/Z 314 (M+H)+.

Step 4: To a stirred mixture of 2-((3aR,7aR)-2,2- dimethylhexahydrobenzo[d]oxazol-3(2H)-yl)benzo[d]thiazolecarbonitrile (260 mg, 0.8 mmol) from Step 3 of this Example in THF (10 mL) at 0 0C was added LAH (3.3 mL of a 1M solution in THE, 3.3 mmol). The e was allowed to warm slowly to rt and stirred for 15 h. The mixture was again cooled to 0 0C and Na2S04.lOH20 was added slowly. The mixture was stirred for 2 h, d, and the filtrate was concentrated under reduced pressure to afford (2-((3aR,7aR)-2,2- dimethylhexahydrobenzo[d]oxazol-3(2H)-yl)benzo[d]thiazolyl)methanamine (237 mg). The material was used in the next step without filrther ation. LCMS (ESI) m/Z 318 (M+H)+.

Step 5: To a stirred mixture of (2-((3aR,7aR)-2,2- dimethylhexahydrobenzo[d]oxazol-3(2H)-yl)benzo[d]thiazolyl)methanamine (236 mg, 0.7 mmol) from Step 4 of this Example and DIEA (388 uL, 2.2 mmol) at 0 0C under argon was added 4,6-dichloronitropyrimidine (159 mg, 0.8 mmol) in one portion. The mixture was stirred for 4 h and then concentrated under reduced pressure. The e was purified by silica gel flash chromatography (eluting with a nt of 100% hexanes to 50% EtOAc in hexanes) to afford 6-chloro-N-((2- 7aR)-2,2-dimethylhexahydrobenzo[d]oxazol-3(2H)-yl)benzo[d]thiazol yl)methyl)nitropyrimidinamine (153 mg, 43%) as an oil. 1H NMR (300 MHz, CDC13)5 8.45 (s, 1H), 7.81 (br s, 1H), 7.57 — 7.63 (m, 2H), 7.22 - 7.31 (m, 1H), 4.85 (d, J: 5.7 Hz, 2H), 3.11 (m, 1H), 2.82 (m, 1H), 2.11 — 2.16 (m, 1H), 1.90 (m, 1H), 1.80 (s, 3H), 1.51 - 1.69 (m, 5H), 1.19 - 1.49 (m, 4H). LCMS (ESI) m/z 475 (M+H)+.

Step 6: To a stirred mixture of 6-chloro-N—((2-((3aR,7aR)-2,2- dimethylhexahydrobenzo[d]oxazol-3(2H)-yl)benzo[d]thiazolyl)methyl)—5- nitropyrimidinamine (153 mg, 0.3 mmol) from Step 5 of this Example in MeOH (5 mL) and EtOAc (5 mL) was added Pd 10% wt. on carbon (20 mg, 0.02 mmol).

Hydrogen gas was bubbled through the stirred mixture for 2 min, then stirring was continued for 15 h under 1 atm of H2. The mixture was d and the filtrate was concentrated under reduced pressure to afford N4-((2-((3aR,7aR)-2,2- dimethylhexahydrobenzo[d]oxazol-3(2H)-yl)benzo[d]thiazolyl)methyl)pyrimidine- 4,5-diamine as an oil (155 mg). The al was used in the next step without further purification. LCMS (ESI) m/Z 411 (M+H)+.

] Step 7: (3aR,7aR)—3-(6-((9H—Purinyl)methyl)benzo[d]thiazolyl)-2,2- dimethyloctahydrobenzo[d]oxazole was synthesized as an oil (220 mg) using a procedure analogous to that described in Step 3 of e 41, tuting N4-((2- ((3aR,7aR)-2,2-dimethylhexahydrobenzo[d]oxazol-3(2H)-yl)benzo[d]thiazol yl)methyl)pyrimidine-4,5-diamine from Step 6 of this Example for 4-bromo methoxy-N1-((2-(methylthio)benzo[d]thiazolyl)methyl)benzene- 1 ,2-diamine used in Example 41. LCMS (ESI) m/Z 421 (M+H)+.

Step 8: A solution of (3aR,7aR)(6-((9H-purin yl)methyl)benzo[d]thiazolyl)-2,2-dimethyloctahydrobenzo[d]oxazole (220 mg, 0.5 mmol) from Step 7 of this Example in TFA (5 mL) and CHZClz (5 mL) was stirred for 2 h at rt. The mixture was concentrated under reduced pressure and the residue was d by reverse-phase preparative HPLC using a mixture of water (5% CH3CN, 0.05% HCOOH) and CH3CN (0.05% HCOOH) as the mobile phase and Varian Pursuit XRs C18 column as the stationary phase to afford (1R,2R)((6-((9H-purin yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol (7 mg, 4%) as a white powder. 1H NMR (300 MHz, DMSO-d6) 5 9.17 (s, 1H), 8.96 (s, 1H), 8.74 (s, 1H), 8.01 (d, J: 7.5 Hz, 1H), 7.68 (d, J: 1.1Hz, 1H), 7.17 - 7.36 (m, 2H), 5.50 (s, 2H), 4.78 (d, J: 4.5 Hz, 1H), 3.52 (m, 1H), 3.33 (m, 1H), 2.03 (m, 1H), 1.87 (m, 1H), 1.57 — 1.67 (m, 2H), 1.11 - 1.34 (m, 4H). LCMS (ESI) m/z 381 (M+H)+.

Example 49 Preparation of (1R,2R)((6-((5-br0m0meth0xy-lH-benzo[d]imidazol yl)methyl)benz0[d] thiazol—Z-yl)amin0)—2,3-dihydr0-1H—indenol 3:22”mm0H83 Step 1: 6-((5-Bromomethoxy-1H—benzo[d]imidazolyl)methyl) (methylsulfinyl)benzo[d]thiazole was synthesized as a white foam (200 mg) using a procedure analogous to that described in Step 6 of Example 36, tuting 6-((5- bromomethoxy- 1H-benzo [d]imidazolyl)methyl)(methylthio)benzo [d]thiazole regioisomer 1 from Step 3 of e 47 for 6-((4-bromo-1H—imidazolyl)methyl)- 2-(methylthio)benzo[d]thiazole used in e 36. LCMS (ESI) m/Z 436 and 438 (M+H)+.

Step 2: To a suspension of 6-((5-bromomethoxy-1H—benzo[d]imidazol— 1-yl)methyl)(methylsulf1nyl)benzo[d]thiazole (279 mg, 0.07 mmol) and (1R,2R) amino-2,3-dihydro-1H—indenol (30 mg, 0.2 mmol) was added DIEA (60 uL, 0.3 mmol). The mixture was heated in a Biotage microwave synthesizer at 160 0C in a sealed tube for 30 min. The mixture was then subjected to purification by reverse- phase ative HPLC using a mixture of water (5% CH3CN, 0.05% HCOOH) and CH3CN (0.05% HCOOH) as the mobile phase and Varian Pursuit XRs C18 column as the stationary phase to afford (1R,2R)((6-((5-bromomethoxy-1H- d]imidazolyl)methyl)benzo[d]thiazolyl)amino)-2 ,3-dihydro- 1H-inden ol (7 mg, 20%) as a white powder. 1H NMR (300 MHZ, DMSO-d6) 8 8.48 (d, J: 7.9 Hz, 1H), 8.31 (s, 1H), 7.86 (s, 1H), 7.72 (s, 1H), 7.33 - 7.41 (m, 2H), 7.28 (m, 1H), 7.12 _ 7.24 (m, 4H), 5.49 (s, 2H), 5.17 (t, .1: 7.1 Hz, 1H), 4.29 (br s, 1H), 3.87 (s, 3H), 3.16 (dd, .1: 7.0, 15.6 Hz, 1H), 2.74 (dd, .1: 7.3, 15.5 Hz, 1H). LCMS (ESI) m/Z 522 and 524 (M+H)+.

Example 50 Preparation of (i) ((6-((5,6-dimethoxy-lH-benzo[d]imidazol—1- yl)methyl)benzo[d]thiazol-Z-yl)amino)cycloheptanol pN S //\ S N UHH9N N HH 0N N N O O \ / O\ / ] Step 1: To a stirred mixture of (::)azidocycloheptanol (190 mg, 1.2 mmol) in THF (1 mL) and H20 (100 uL) was added PPh3 (321 mg, 1.2 mmol). The mixture was stirred at rt for 15 h, then concentrated under reduced pressure. The residue was purified Via silica gel flash chromatography g with 100: 15:1, CH2C12:MeOH:TEA to afford (::)aminocycloheptanol (103 mg, 50%) as a white solid. LCMS(ELSD) (ESI) m/Z 130 .

Step 2: (::)((6-((5,6-Dimeth0xy-lH—benz0[d]imidazol- l - yl)methyl)benzo[d]thiazolyl)amin0)cycloheptanol was synthesized as a white powder (39 mg, 16%) using a procedure analogous to that described in Example 27, substituting -aminocycloheptanol from Step 1 of this Example for 2- ethoxyaniline used in Example 27. 1H NMR (300 MHZ, DMSO-d6) 8 8.15 (s, 1H), 8.05 (d, J: 7.3 Hz, 1H), 7.63 (d, J: 1.1 Hz, 1H), 7.30 (m, 1H), 7.13 - 7.24 (m, 3H), .41 (s, 2H), 4.80 (d, J: 4.1 Hz, 1H), 3.64 - 3.81 (m, 8H), 3.58 (br s, 1H), 1.23 - 1.99 (m, 9H). LCMS (ESI) m/Z 453 (M+H)+.

Example 51 Preparation of (1R,2R)((6-((6-methoxy(1-methyl-1H-pyrazolyl)-1H— benzo[d]imidazol—1-yl)methyl)benzo[d]thiazol-Z-yl)amino)cyclohexanol N/ N/U>_NH/\ “ CS \ / Step 1: To a suspension of 6-((5-bromomethoxy-1H—benzo[d]imidazol— l-yl)methyl)(methylsulfinyl)benz0[d]thiazole (502 mg, 1 mmol) from Step 1 of Example 49 and (1R,2R)aminocyclohexanol in DMA (4 mL) was added DIEA (1 mL, 6 mmol). The mixture was heated in a sealed tube at 110 0C for 16 h. The mixture was cooled to rt and added dropwise with stirring to H20 (200 mL). After the mixture was stirred for 30 min, the solid was ted by filtration to afford )((6- ((5 -bromomethoxy- 1H-benzo [d]imidazolyl)methyl)benzo [d]thiazol yl)amino)cyclohexanol (443 mg, 80%) as a tan solid. 1H NMR (300 MHZ, DMSO-d6) 8 8.30 (s, 1H), 7.99 (d, J: 7.5 Hz, 1H), 7.86 (s, 1H), 7.66 (d, J: 1.1 Hz, 1H), 7.37 (s, 1H), 7.30 (m, 1H), 7.22 (m, 1H), 5.46 (s, 2H), 4.76 (d, J: 5.1 Hz, 1H), 3.86 (s, 3H), 3.53 (m, 1H), 3.33 (m, 1H), 2.03 (m, 1H), 1.88 (m 1H), 1.55 - 1.69 (m 2H), 1.11 - 1.33 (m, 4H). LCMS (ESI) m/Z 486 and 488 (M+H)+.

Step 2: A suspension of )((6-((5-bromomethoxy-1H- benzo[d]imidazolyl)methyl)benzo[d]thiazolyl)amino)cyclohexanol (30 mg, 0.06 mmol) from Step 1 of this Example and 1-methylpyrazoleboronic acid pinacol ester (26 mg, 0.1 mmol) in DME (300 uL) was added aq 2M K2C03 (150 uL, 0.2 mmol). Argon was bubbled into the mixture for 5 min followed by the addition of dichlorobis(triphenylphosphine)palladium II (4 mg, 0.006 mmol). Argon was bubbled into the mixture for an additional 5 min and then the mixture was heated in a sealed tube for 15 h. The mixture was cooled to rt and then partitioned between EtOAc (100 mL) and water (50 mL). The EtOAc layer was separated and concentrated under reduced re. The residue was purified by reverse-phase ative HPLC, using a mixture of water (5% CH3CN, 0.05% HCOOH) and CH3CN (0.05% HCOOH) as the mobile phase and Varian t XRs C18 column as the stationary phase to afford (1R,2R)((6-((6-methoxy-5 -( 1 -methyl- 1H-pyrazolyl)-1H- benzo[d]imidazolyl)methyl)benzo[d]thiazolyl)amino)cyclohexanol (16 mg, 53%) as a white powder. 1H NMR (300 MHz, DMSO-d6) 8 8.21 (s, 1H), 7.97 - 8.06 (m, 2H), 7.87 (s, 1H), 7.80 (s, 1H), 7.66 (d, J: 1.1 Hz, 1H), 7.27 - 7.33 (m, 1H), 7.19 - 7.25 (m, 2H), 5.44 (s, 2H), 4.78 (d, J: 4.3 Hz, 1H), 3.85 (s, 6H), 3.51 (m, 1H), 3.33 (m, 1H), 2.03 (m, 1H), 1.87 (m, 1H), 1.56 — 1.66 (m, 2H), 1.12 - 1.32 (m, 4H). LCMS (ESI) m/Z 489 (M+H)+.

Example 52 Preparation of (1R,2R)((6-((5-meth0xy(l-methyl-1H-pyrazolyl)—1H— benzo[d]imidazolyl)methyl)benzo[d]thiazol—Z-yl)amin0)cyclohexanol (lR,2R)((6-((5-Methoxy(l -methyl- lH—pyrazolyl)- lH— benzo[d]imidazol- l -yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol (19 mg, 55%) was synthesized as a white powder using a procedure analogous to that described in Step 2 of Example 51, substituting (lR,2R)((6-((6-bromomethoxy- lH—benzo[d]imidazol- l -yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol from Step 5 of Example 47 for (lR,2R)((6-((5-bromomethoxy-lH—benzo[d]imidazol- l-yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol used in e 5 l. 1H NMR (300 MHz, DMSO-d6) 5 8.27 (s, 1H), 8.06 (s, 1H), 7.99 (d, J: 7.3 Hz, 1H), 7.88 (s, 1H), 7.77 (s, 1H), 7.68 (d, J: 1.1 Hz, 1H), 7.18 - 7.33 (m, 3H), 5.44 (s, 2H), 4.77 (d, J: 4.5 Hz, 1H), 3.86 (s, 6H), 3.50 (m, 1H), 3.33 (m, 1H), 2.02 (m, 1H), 1.86 (m, 1H), 1.55 — 1.65 (m, 2H), 1.10 - 1.31 (m, 4H). LCMS (ESI) m/z 489 (M+H)+.

Example 53 Preparation of (((1R,2R)hydr0xycyclohexyl)amin0)benz0[d]thiazol hyl)—5-meth0xy-lH-benzo[d]imidazole—6-carb0nitrile % S N NU />—NH $OH N C} O\ \N To a suspension of (lR,2R)((6-((6-bromomethoxy-lH- benzo[d]imidazol-l-yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol (50 mg, 0.1 mmol) from Step 5 of Example 47 in DMF (l .5 mL) was added zinc cyanide (24 mg, 0.2 mmol). Argon was bubbled into the mixture for 5 min followed by the addition of l,l'-bis(diphenylphosphino)ferrocene (9 mg, 0.02 mmol) and tris(dibenzylideneacetone)dipalladium (9 mg, 0.01 mmol). Argon was bubbled into the mixture for an onal 5 min. The reaction vessel was sealed and the mixture was heated at 110 0C for 15 h. The mixture was cooled to rt and argon was again bubbled into the mixture for 5 min. Additional zinc cyanide (24 mg, 0.2 mmol), l,l'- Bis(diphenylphosphino)ferrocene (9 mg, 0.02 mmol) and tris(dibenzylideneacetone)dipalladium (9 mg, 0.01 mmol) were added to the mixture, and the on vessel was ed and heated for 5 h. The mixture was cooled to rt, filtered, and the filtrate was purified by reverse-phase preparative HPLC using a mixture of water (5% CH3CN, 0.05% HCOOH) and CH3CN (0.05% HCOOH) as the mobile phase and Varian Pursuit XRs C18 column as the stationary phase to afford 1- ((2-(((1R,2R)hydroxycyclohexyl)amino)benzo[d]thiazolyl)methyl)methoxy- lH—benzo[d]imidazolecarbonitrile (18 mg, 41%) as a white powder. 1H NMR (300 MHz, DMSO-d6) 5 8.60 (s, 1H), 8.12 (s, 1H), 8.01 (d, J: 7.3 Hz, 1H), 7.70 (d, J: 0.9 Hz, 1H), 7.43 (s, 1H), 7.20 - 7.34 (m, 2H), 5.46 (s, 2H), 4.76 (d, J: 4.9 Hz, 1H), 3.90 (s, 3H), 3.51 (m, 1H), 3.33 (m, 1H), 2.03 (m, 1H), 1.87 (m, 1H), 1.57 — 1.67 (m, 2H), 1.15 — 1.34 (m, 4H). LCMS (ESI) m/z 434 (M+H)+ Example 54 Preparation of (R)((6-((3H-imidaz0[4,5-b]pyridin yl)methyl)benzo[d]thiazol—Z-yl)amin0)cyclohexan0ne 888% (1R,2R)((6-((3H-Imidazo [4,5 idinyl)methyl)benzo [d]thiazol yl)amino)cyclohexanol from Example 3 (188 mg, 0.50 mmol) was stirred in a mixture ofDCM/MeCN/DMA (4:4:2, v/v/v) at rt. Dess-Martin periodinane (254 mg, 0.60 mmol) was added and the mixture was stirred at rt for 30 min before another batch of periodinane (254 mg, 0.60 mmol) was added. The resulting mixture was heated at 55 0C for 4 h, then another batch of periodinane (254 mg, 0.60 mmol) was added and the reaction mixture was heated at 60 0C for 6 h. LCMS showed that the reaction was mostly complete. The mixture was then cooled to rt and partitioned between DCM and 3% aq NaOH, and then the c layer was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel chromatography g with 0-100% EtOAc in hexanes to give (R)((6-((3H- imidazo [4,5 -b]pyridin-3 -yl)methyl)benzo[d]thiazolyl)amino)cyclohexanone (150 mg, 80%) as a white solid. 1H NMR (300 MHZ, DMSO-d6) 8 8.60 (s, 1H), 8.38 (dd, J = 1.2, 4.8 Hz, 1H), 8.22 (d, J: 7.3 Hz, 1H), 8.09 (dd, J: 1.3, 8.1 Hz, 1H), 7.70 (d, J = 1.1 Hz, 1H), 7.26 - 7.35 (m, 2H), 7.19 - 7.26 (m, 1H), 5.49 (s, 2H), 4.68 (td, J: 6.5, 12.8 Hz, 1H), 2.53 - 2.67 (m, 1H), 2.42 (ddd, J: 2.7, 5.9, 12.3 Hz, 1H), 2.30 (d, J: 13.4 Hz, 1H), 1.94 — 2.12 (m, 1H), 1.82 (br s, 2H), 1.38 — 1.66 (m, 2H). LCMS (ESI) m/Z 378 (M+H)+.

Example 55 Preparation of (1R,2R)((6-((6-chloro-3H-imidazo[4,5-b]pyridin yl)methyl)benzo[d]thiazol—2-yl)amino)cyclohexanol EUR“:\/ Step 1: 5-Chloro-N—((2-(methylthio)benz0[d]thiazolyl)methyl) nitropyridinamine was synthesized as a yellow foam (126 mg, 29%) using a procedure analogous to that described in Step 1 of e 41, substituting 5-chloro- 3-nitr0pyridinamine for 4-brom0methoxynitr0aniline used in Example 41.

LCMS (ESI) m/Z 367 (M+H)+.

Step 2: Crude 5-chloro-N2-((2-(methylthi0)benzo[d]thiazol yl)methyl)pyridine-2,3-diamine was synthesized as a yellow solid using a procedure ous to that describe in Step 2 of Example 41, substituting 5-chlor0-N—((2- (methylthi0)benz0[d]thiazolyl)methyl)nitropyridinamine from Step 1 of this Example for 4-brom0meth0xy-N—((2-(methylthio)benz0[d]thiazolyl)methyl) nitroaniline used in e 41. The residue was purified by silica gel flash chromatography eluting with a gradient of 100% hexanes to 100% EtOAc to afford 5- chloro-N2-((2-(methylthi0)benz0[d]thiazolyl)methyl)pyridine-2,3-diamine (75 mg, 65%). LCMS (ESI) m/Z 337 (M+H)+.

Step 3: 6-((6-Chlor0-3H—imidaz0[4,5-b]pyridinyl)methyl) lthio)benz0[d]thiazole was synthesized as a white foam (62 mg, 80%) using a procedure analogous to that described in Step 3 of Example 41, substituting 5-chloro- NZ-((2-(methylthi0)benz0[d]thiazolyl)methyl)pyridine-2,3-diamine from Step 2 of this Example for 4-br0m0methoxy-N1-((2-(methylthi0)benzo[d]thiazol yl)methyl)benzene-l,2-diamine used in Example 41. LCMS (ESI) m/z 347 (M+H)+.

Step 4: 6-((6-Chloro-3H—imidazo[4,5-b]pyridinyl)methyl) lsulfmyl)benz0[d]thiazole was sized as a white foam (1 ll mg) using a procedure analogous to that bed in Step 6 of Example 36, substituting 6-((6- chloro-3H—imidaz0[4,5-b]pyridinyl)methyl)(methylthi0)benz0[d]thiazole from Step 3 of this Example for 6-((4-bromo-1H—imidazolyl)methyl) (methylthio)benzo[d]thiazole used in Example 36. LCMS (ESI) m/Z 363 (M+H)+.

Step 5: (1R,2R)((6-((6-Chloro-3H—imidazo[4,5-b]pyridin yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol was synthesized as a white powder (35 mg, 47%) using a procedure analogous to that described in Step 7 of Example 36, substituting 6-((6-chloro-3H-imidazo[4,5-b]pyridinyl)methyl) (methylsulfinyl)benzo[d]thiazole from Sep 4 of this e for 6-((4-bromo-1H- imidazolyl)methyl)(methylsulfinyl)benzo[d]thiazole used in Example 36. 1H NMR (300 MHz, DMSO-d6) 8 8.69 (s, 1H), 8.42 (d, J: 2.1 Hz, 1H), 8.28 (d, J: 2.3 Hz, 1H), 7.97 (d, J: 7.5 Hz, 1H), 7.66 (d, J: 1.3 Hz, 1H), 7.29 (m, 1H), 7.21 (m, 1H), 5.48 (s, 2H), 4.74 (d, J: 5.1 Hz, 1H), 3.51 (m, 1H), 3.33 (m, 1H), 2.02 (m, 1H), 1.87 (m, 1H), 1.55 — 1.65 (m, 2H), 1.12 - 1.31 (m, 4H). LCMS (ESI) m/z 414 (M+H)+.

Example 56 Preparation of (1R,2R)((6-((3H—imidaz0[4,5-b]pyridin yl)methyl)benz0[d] oxazolyl)amin0)cyclohexanol ] Step 1: To a stirred mixture of methyl 2-mercaptobenzo[d]oxazole carboxylate (5 g, 23.92 mmol) and solid K2C03 (9.9 g, 71.76 mmol) in anhydrous DMF (50 mL) at rt was added methyl iodide (10.2 g, 71.76 mmol). The mixture was stirred at rt for 15 h. The on mixture was diluted with water then extracted with DCM (X 3). The combined organic layers were washed with water and 2 M aq HCl.

The organic layer was separated and dried over MgSO4, filtered, and concentrated under reduced re to afford methyl hylthio)benzo[d]oxazolecarboxylate (4.24 g, 80%) as a light pink solid that did not require r purification. 1H NMR (300 MHz,CDC13)8 8.12 (d, J: 1.1 Hz, 1H), 8.04 (dd, J: 1.1, 8.3 Hz, 1H), 7.61 (d, J: 8.3 Hz, 1H), 3.95 (s, 3H), 2.79 (s, 3H). LCMS (ESI) m/z 224 (M + H)+.

Step 2: To a stirred solution of methyl 2-(methylthio)benzo[d]oxazole carboxylate (4.24 g, 19 mmol) from Step 1 of this Example in anhydrous DCM (100 mL) under an argon atmosphere at — 78 0C was added dropwise diisobutylaluminum hydride (1.0 M solution in DCM, 40 mL, 40 mmol). The mixture was allowed to warm to — 30 0C over 2 h. The reaction was quenched by addition of saturated aq sodium potassium tartrate and the resulting mixture stirred at rt for an additional 15 h.

The organic layer was separated and the aqueous layer extracted with additional DCM (X 2). The combined organic layers were washed with water dried over MgSO4, filtered, and concentrated under reduced pressure to afford (2- (methylthio)benzo[d]oxazolyl)methanol (2 g, 54%) as a tan solid that did not require further purification. 1H NMR (300 MHz, DMSO-d6) 8 7.51 - 7.61 (m, 2H), 7.28 (d, J: 8.3 Hz, 1H), 5.34 (t, J: 5.7 Hz, 1H), 4.59 (d, J: 5.7 Hz, 2H), 2.76 (s, 3H). LCMS (ESI) m/Z 196 (M + H)+.

Step 3: To a stirred solution of (2-(methylthio)benzo[d]oxazol yl)methanol (2 g, 10.26 mmol) from Step 2 of this Example in a mixture of anhydrous DMF (0.5 mL) and anhydrous DCM (100 mL) at 0 0C was added dropwise thionyl chloride (4 mL, 55 mmol). The mixture was d to warm to rt and stirred for a further 40 min. The mixture was concentrated under reduced pressure and the residue was partitioned between saturated aq NaHCOg and a 10:1 mixture of DCM:MeOH.

The organic layer was ted and dried over MgSO4, filtered, and concentrated under reduced pressure to afford 6-(chloromethyl)(methylthio)benzo[d]oxazole (2g, 92%) as a light pink solid which did not require further ation. 1H NMR (300 MHz, DMSO-d6) 8 ppm 7.75 (d, J: 1.3 Hz, 1H), 7.63 (d, J: 8.1 Hz, 1H), 7.43 (dd, J: 1.3, 8.1 Hz, 1H), 4.89 (s, 2H), 2.77 (s, 3H). LCMS (ESI) m/z 214 (M + H)+.

Step 4: To a stirred solution of 4-azabenzimidazole (304 mg, 2.55 mmol) in anhydrous DMF (10 mL) at 0 0C was added in one portion sodium e (60% dispersion in mineral oil, 107 mg, 2.68 mmol) and the e was stirred at 0 CC for min. The mixture was allowed to warm to rt and stirred for a filrther 20 min. To the on mixture was added a solution of 6-(chloromethyl) (methylthio)benzo[d]oxazole (600 mg, 2.81 mmol) from Step 3 of this Example in DMF (5 mL). The mixture was d at rt for 15 h. To the reaction mixture was added water and the mixture was extracted with DCM. The combined organic layers were washed with brine. The organic layer was separated, dried over MgSO4, filtered, and the filtrate was concentrated under reduced pressure. The crude al was purified by silica gel flash chromatography eluting with 100% DCM followed by 1% MeOH in DCM to afford —imidazo[4,5-b]pyridinyl)methyl) (methylthio)benzo[d]oxazole (290 mg, 38%) as a white solid. The regiochemistry of the alkylation was determined by 2-dimensional nuclear Overhauser effect (NOE) experiment. 1H NMR (300 MHZ, DMSO-d6) 8 8.64 (s, 1H), 8.38 (dd, J: 1.2, 4.6 HZ, 1H), 8.10 (dd, J: 1.2, 8.0 HZ, 1H), 7.69 (s, 1H), 7.58 (d, J: 8.1 HZ, 1H), 7.25 - 7.41 (m, 2H), 5.61 (s, 2H), 2.73 (s, 3H). LCMS (ESI) m/z 297 (M+H)+.

Step 5: To a d solution of 6-((3H-imidazo[4,5-b]pyridin yl)methyl)(methylthio)benZ0[d]oxazole (290 mg, 0.979 mmol) from Step 4 of this e in DCM (25 mL) at 0 0C was added 70% hloroperbenzoic acid (582 mg, 2.36 mmol), and the mixture was stirred at 0 CC for 2.5 h. To the mixture was added saturated aq NaHCOg and the organic layer was separated. The aqueous layer was extracted with DCM and the combined organic layers were washed with saturated aq NaHC03. The organic layer was separated, dried over MgSO4, filtered, and concentrated under reduced pressure to afford 6-((3H-imidazo[4,5-b]pyridin yl)methyl)(methylsulf1nyl)benZ0[d]oxazole (305 mg, 100%) as a solid which did not require r purification. 1H NMR (300 MHZ, DMSO-d6) 8 8.67 (s, 1H), 8.38 (d, J: 4.5 HZ, 1H), 8.11 (d, J: 7.2 HZ, 1H), 7.84 - 7.94 (m, 2H), 7.52 (d, J: 8.3 HZ, 1H), 7.30 (dd, J: 4.8, 8.0 HZ, 1H), 5.69 (s, 2H), 3.18 (s, 3H). LCMS (ESI) m/z 313 (M+H)+.

] Step 6: A d mixture of 6-((3H—imidazo[4,5-b]pyridinyl)methyl) (methylthio)benZ0[d]oxazole (165 mg, 0.53 mmol) from Step 5 of this Example, (1R,2R)-(-)aminocyclohexanol (122 mg, 1.06 mmol), and DIEA (137 mg, 1.06 mmol) in anhydrous DMA (3 mL) was sealed and heated at 100 °C for 15 h. The reaction mixture was cooled to rt and purified directly by reverse-phase HPLC using a mixture of water (5% CH3CN, 0.05% HOAc), CH3CN (0.05% HOAc) as the mobile phase and Varian Pursuit XRs diphenyl column as the stationary phase to afford (1R,2R)((6-((3H—imidaZ0[4,5-b]pyridinyl)methyl)benZ0[d]ova01 yl)amino)cyclohexanol (44 mg, 23%) as a white solid. 1H NMR (300 MHZ, DMSO- d6) 5 8.60 (s, 1H), 8.39 (dd, J: 1.1, 4.7 HZ, 1H), 8.08 (dd, J: 1.2, 8.0 HZ, 1H), 7.81 (d, J: 7.5 HZ, 1H), 7.40 (s, 1H), 7.29 (dd, J: 4.7, 8.1 HZ, 1H), 7.10 - 7.19 (m, 2H), .50 (s, 2H), 4.70 (br s, 1H), 3.25 — 3.45 (m, 2H), 1.83 — 1.97 (m, 2H), 1.57 — 1.67 (m, 2H), 1.14 - 1.32 (m, 4H). LCMS (ESI) m/z 364 (M+H)+.

Example 57 Preparation of (1R,2R)((6-((3H-imidazo[4,5-b]pyridin hyl)benzo[d] oxazolyl)amino)—2,3-dihydro-1H—indenol Ng/UN/>—NH OH \ / A d mixture of 6-((3H-imidazo[4,5-b]pyridin-3 -yl)methyl) (methylthi0)benz0[d]0xazole (108 mg, 0.346 mmol) from Step 5 of Example 56, (1R,2R)-(-)-transamin0indanol (104 mg, 0.698 mmol), and DIEA (90 mg, 0.698 mmol) in anhydrous DMA (1.5 mL) was sealed and heated in a Biotage microwave synthesizer at 120 CC for 30 min. The reaction mixture was cooled to rt and purified directly by reverse-phase HPLC using a mixture of water (5% CH3CN, 0.05% HCOOH) and CH3CN (0.05% HCOOH) as the mobile phase and Varian Pursuit XRs C-18 column as the stationary phase to afford (1R,2R)((6-((3H-imidaz0[4,5- b]pyridinyl)methyl)benz0[d]0xazolyl)amino)-2,3-dihydr0-1H—indenol (35 mg, 26%) as a white solid. 1H NMR (300 MHZ, DMSO-d6) 8 8.62 (s, 1H), 8.36 - 8.45 (m, 2H), 8.09 (dd, J: 1.3, 8.1 Hz, 1H), 7.47 (s, 1H), 7.29 (dd, J: 4.7, 8.1 Hz, 1H), 7.12 - 7.25 (m, 6H), 5.52 (s, 2H), 5.47 (d, J: 5.1 Hz, 1H), 5.02 (m, 1H), 4.34 (m, 1H), 3.15 (dd, J: 7.2, 15.6 Hz, 1H), 2.73 (dd, J: 7.6, 15.4 Hz, 1H). LCMS (ESI) m/z 398 (M+H)+. e 58 Preparation of (R)((6-((3H-imidazo[4,5-b]pyridin yl)methyl)benzo[d]thiazolyl)amino)cyclohexanone oxime 8x1:H5 (R)((6-((3H-Imidaz0[4,5-b]pyridinyl)methyl)benzo[d]thiazol yl)amin0)cyclohexanone from Example 54 (70 mg, 0.19 mmol) was stirred in EtOH.

Pyridine (100 uL, excess) and NHzOH’HCl (100 mg, excess) were added and the resulting mixture was heated at 88 0C for 1h. LCMS showed that the on was complete. The e was then cooled to rt and purified by HPLC using a mixture of water (5% CH3CN, 0.05% HCOOH) and CH3CN (0.05% HCOOH) as the mobile phase and Varian Pursuit XRs C-18 column as the stationary phase to afford (R) ((6-((3H-imidazo[4,5-b]pyridinyl)methyl)benzo[d]thiazol yl)amino)cyclohexanone oxime (53 mg, 73%) as a white powder. 1H NMR (300 MHz, DMSO-d6) 8 10.57 (s, 1H), 8.60 (s, 1H), 8.38 (d, J: 4.0 Hz, 1H), 8.13 - 8.27 (m, 1H), 8.09 (dd, J: 0.8, 7.9 Hz, 1H), 7.58 - 7.76 (m, 1H), 7.10 - 7.39 (m, 3H), 5.49 (s, 2H), 4.33 - 4.77 (m, 1H), 2.69 - 2.95 (m, 1H), 1.92 - 2.38 (m, 2H), 1.26 - 1.86 (m, 5H). LCMS (ESI) m/Z 393 (M+H)+.

Example 59 Preparation of either (1S,2R)((6-((3H-imidazo[4,5-b]pyridin yl)methyl)benz0[d]thiazolyl)amin0)—l-methylcyclohexanol or (1R,2R)((6- ((3H—imidazo[4,5-b]pyridinyl)methyl)benzo[d]thiazolyl)amin0)—1- methylcyclohexanol eflher é‘ S N NU ,>—NH OH / N ”I” \ / 2 ; //\ S N NU />—NH §H / N (R)((6-((3H-Imidazo[4,5-b]pyridinyl)methyl)benzo[d]thiazol yl)amino)cyclohexanone from Example 54 (60 mg, 0.16 mmol) was stirred in 5 mL of THF at 0 0C under argon. Methyl lithium in THF (1.6 M, 99 uL, 0.16 mmol) was dropped in . The resulting mixture was stirred at rt for 30 min before more methyl lithium in THF (495 uL, 0.80 mmol) was added. After 90 min, the on was quenched with sat. NH4C1 (20 mL) and the resulting mixture was ted with DCM (2 x 50 mL). The combined organic layers were washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel preparative TLC, eluting with 5:95 2N NHg/MeOH: EtOAc, followed by HPLC using a mixture of water (5% CH3CN, 0.05% HCOOH) and CH3CN (0.05% HCOOH) as the mobile phase and Varian Pursuit XRs C-18 column as the stationary phase to afford two te diastereoisomers: The first eluting isomer on e-phase HPLC is one of (1S,2R)((6- ((3H-imidazo [4,5 -b]pyridin-3 -y1)methy1)benzo[d]thiazoly1)amino) methylcyclohexanol or (1R,2R)((6-((3H-imidazo[4,5-b]pyridin y1)methy1)benzo[d]thiazoly1)amino)- 1 1cyclohexanol (5 mg, 8%) as a white powder. 1H NMR (300 MHz, MeOH-d4) 8 8.40 - 8.51 (m, 2H), 8.10 (dd, J: 0.9, 8.1 Hz, 1H), 7.64 (s, 1H), 7.23 - 7.43 (m, 3H), 5.57 (s, 2H), 3.78 - 3.92 (m, 1H), 1.56 - 1.84 (m, 4H), 1.31 - 1.55 (m, 4H), 1.22 (s, 3H).

LCMS (ESI) m/Z 394 (M+H)+.

Example 60 Preparation of either (1R,2R)((6-((3H-imidaz0[4,5-b]pyridin yl)methyl)benz0[d]thiazolyl)amin0)—l-methylcyclohexanol or (1S,2R)((6- ((3H—imidaz0[4,5-b]pyridinyl)methyl)benz0[d]thiazolyl)amin0)—1- methylcyclohexanol eflher For the two diastereoisomers obtained in Example 59, the second e1uting isomer on e-phase HPLC is one of (1R,2R)((6-((3H-imidazo[4,5-b]pyridin y1)methy1)benzo[d]thiazoly1)amino)methy1cyclohexanol or (1S,2R)((6-((3H- imidazo [4,5 -b]pyridin-3 -y1)methy1)benzo[d]thiazoly1)amino) methylcyclohexanol and is the alternative to Example 59; obtained as a white powder (4 mg, 6%). 1H NMR (300 MHz, MeOH-d4) 8 8.28 - 8.40 (m, 2H), 7.99 (dd, J: 1.1, 8.1 Hz, 1H), 7.52 (d, J: 0.9 Hz, 1H), 7.13 - 7.35 (m, 3H), 5.45 (s, 2H), 3.58 (dd, J: 3.9, 11.2 Hz, 1H), 1.17 - 1.74 (m, 8H), 1.12 (s, 3H). LCMS (ESI) m/z 394 (M+H)+.

Example 61 Preparation of (1R,2R)((6-((6-bromo-3H—imidazo[4,5-b]pyridin yl)methyl)benzo[d] oxazolyl)amino)cyclohexanol :i {IE/HM6 Step 1: A stirred mixture of opyridine-2,3-diamine (5 g, 26.6 mmol), formic acid (2.5 mL), and triethylorthoformate (70 mL) was heated at 100 °C for 2.5 h. The reaction mixture was cooled to rt and the solid itate was collected by filtration, washed with EtzO and dried to afford 0-3H—imidaz0[4,5- b]pyridine as a solid (3.22 g, 61%) which did not require further purification. 1H NMR (300 MHz, DMSO-d6) 8 13.14 (br s, 1H), 8.50 (s, 1H), 8.44 (d, J: 2.1 Hz, 1H), 8.31 (d, J: 1.9 Hz, 1H). LCMS (ESI) m/z 198 and 200 (M+H)+.

Step 2: To a stirred solution of 6-bromo-3H—imidazo[4,5-b]pyridine (506 mg, 2.55 mmol) from Step 1 of this Example in anhydrous DMF (10 mL) at 0 CC was added in one portion sodium hydride (60% dispersion in mineral oil, 107 mg, 2.68 mmol), and the mixture was stirred at 0 CC for 30 min. To the reaction mixture was added a solution of 6-(chlor0methyl)—2-(methylthi0)benz0[d]oxazole (600 mg, 2.81 mmol) from Step 3 of e 56 in DMF (2 mL). The mixture was allowed to warm to rt, then stirred for a fithher 15 h. To the reaction mixture was added water and the mixture was extracted with EtOAc. The organic layer was separated and the aq layer extracted with additional EtOAc. The combined organic layers were washed with water then brine. The organic layer was separated, dried over MgSO4, filtered, and trated under d pressure. The residue was purified by silica gel flash chromatography eluting with 100% DCM, followed by 1% MeOH in DCM to afford br0m0-3H—imidaz0[4,5-b]pyridinyl)methyl)(methylthio)benzo[d]0xazole (460 mg, 48%) as a white solid. The regiochemistry of the alkylation was determined by 2-dimensional nuclear Overhauser effect (NOE) experiment. 1H NMR (300 MHz, DMSO-d6) 5 8.70 (s, 1H), 8.48 (d, J: 1.9 Hz, 1H), 8.40 (d, J: 1.9 Hz, 1H), 7.68 (s, 1H), 7.58 (d, J: 8.1 Hz, 1H), 7.34 (d, J: 8.1Hz, 1H), 5.59 (s, 2H), 2.73 (s, 3H).

LCMS (ESI) m/Z 375 and 377 (M+H)+.

] Step 3: To a stirred solution of 6-((6-bromo-3H-imidazo[4,5-b]pyridin yl)methyl)(methylthio)benzo[d]oxazole (460 mg, 1.23 mmol) from Step 2 of this Example in DCM (25 mL) at 0 0C was added 70% meta-chloroperbenzoic acid (333 mg, 1.35 mmol), and the mixture was allowed to warm to rt and stirred for a fiarther min. To the mixture was added saturated aq NaHCOg and the organic layer was separated. The s layer was re-extracted with DCM and the combined organic layers were washed with saturated aq NaHCOg. The c layer was separated, dried over MgSO4, filtered, and concentrated under d pressure to afford 6-((6- bromo-3H-imidazo[4,5-b]pyridinyl)methyl)(methylsulf1nyl)benzo[d]oxazole (481 mg, 100%) as a cream solid which did not require fiarther purification. 1H NMR (300 MHz, DMSO-d6) 8 8.73 (s, 1H), 8.40 — 8.50 (m, 2H), 7.84 - 7.95 (m, 2H), 7.50 (d, J: 8.3 Hz, 1H), 5.68 (s, 2H), 3.18 (s, 3H). LCMS (ESI) m/z 391 and 393 (M+H)+.

Step 4: A stirred mixture of 6-((6-bromo-3H-imidazo[4,5-b]pyridin yl)methyl)(methylsulf1nyl)benzo[d]oxazole (150 mg, 0.384 mmol) from Step 3 of this Example, (1R,2R)-(-)aminocyclohexanol (88 mg, 0.768 mmol), and DIEA (99 mg, 0.768 mmol) in anhydrous DMA (3 mL) in a sealed Vial was heated in a Biotage microwave synthesizer at 120 CC for 30 min. After the reaction mixture was cooled to rt, it was purified directly by reverse-phase HPLC using a mixture of water (5% CH3CN, 0.05% HCOOH) and CH3CN (0.05% HCOOH) as the mobile phase and Varian Pursuit XRs C-18 column as the stationary phase to afford (1R,2R)((6-((6- bromo-3H-imidazo[4,5-b]pyridinyl)methyl)benzo[d]oxazol yl)amino)cyclohexanol (64 mg, 38%) as a white solid. 1H NMR (500 MHZ, DMSO- d6) 5 8.66 (s, 1H), 8.49 (d, J: 2.0 Hz, 1H), 8.38 (d, J: 1.7 Hz, 1H), 7.81 (d, J: 7.6 Hz, 1H), 7.39 (s, 1H), 7.10 - 7.16 (m, 2H), 5.48 (s, 2H), 4.69 (d, J: 4.2 Hz, 1H), 3.30 — 3.40 (m, 2H), 1.83 - 1.97 (m, 2H), 1.57 — 1.67 (m, 2H), 1.15 — 1.30 (m, 4H). LCMS (ESI) m/Z 442 and 444 (M+H)+. e 62 Preparation of (1R,2R)((6-((6-br0m0-3H—imidaz0[4,5-b]pyridin hyl)benz0[d] oxazolyl)amin0)-2,3-dihydr0-1H—indenol “18/ng/>—NH OH A d mixture of 6-((6-bromo-3H—imidazo[4,5-b]pyridinyl)methyl)- 2-(methylsulf1nyl)benzo[d]oxazole (150 mg, 0.384 mmol) from Step 3 of Example 61, (1R,2R)-(-)-transaminoindanol (114 mg, 0.768 mmol), and DIEA (99 mg, 0.768 mmol) in ous DMA (3 mL) in a sealed Vial was heated in a Biotage microwave synthesizer at 120 CC for 30 min. After the reaction mixture was cooled to rt, it was purified directly by reverse-phase HPLC using a mixture of water (5% CH3CN, 0.05% HCOOH) and CH3CN (0.05% HCOOH) as the mobile phase and Varian Pursuit XRs C-18 column as the stationary phase to afford (1R,2R)((6-((6- bromo-3H-imidazo[4,5-b]pyridinyl)methyl)benzo[d]oxazolyl)amino)-2,3- dihydro-1H-indenol (40 mg, 22%) as a white solid. 1H NMR (499 MHz, DMSO- d6) 5 8.68 (s, 1H), 8.49 (d, J: 2.0 Hz, 1H), 8.36 - 8.44 (m, 2H), 7.45 (s, 1H), 7.12 - 7.24 (m, 6H), 5.51 (s, 2H), 5.47 (d, J: 5.2 Hz, 1H), 5.01 (t, J: 7.6 Hz, 1H), 4.34 (m, 1H), 3.15 (dd, J: 7.1, 15.5 Hz, 1H), 2.73 (dd, J: 7.6, 15.5 Hz, 1H). LCMS (ESI) m/z 476 and 478 (M+H)+.

Example 63 ation of (S)((6-((3H—imidazo[4,5-b]pyridinyl)methyl)benz0[d] thiazol- 2—yl)amin0)cyclohexylethanol Step 1: To a stirred solution of 4-azabenzimidazole (613 mg, 5.15 mmol) in anhydrous DMF (20 mL) at 0 0C was added in one n sodium hydride (60% dispersion in mineral oil, 216 mg 5.41 mmol) and the mixture was stirred at 0 CC for min. The mixture was allowed to warm to rt and stirred for a filrther 20 min. To the reaction mixture was added a solution of 6-(chloromethyl) (methylthio)benzo[d]thiazole (1.3 g, 5.66 mmol) from Step 4 of Example 36 in DMF (5 mL). The mixture was stirred at rt for 15 h. To the reaction mixture was added water (300 mL) and the mixture was extracted with DCM (3 X 50 mL). The combined c layers were washed with brine. The organic layer was ted, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography ng with 100% DCM followed by 1% MeOH in DCM) to afford 6-((3H-imidazo[4,5-b]pyridinyl)methyl) lthio)benzo[d]thiazole (670 mg, 41%) as a white solid. The regiochemistry of the alkylation was determined by 2-dimensional nuclear Overhauser effect (NOE) experiment. 1H NMR (300 MHz, DMSO-d6) 8 8.65 (s, 1H), 8.38 (dd, J: 1.3, 4.7 Hz, 1H), 8.11 (dd, J: 1.2, 8.0 Hz, 1H), 8.00 (d,.]= 1.1 Hz, 1H), 7.81 (d,.]= 8.5 Hz,1H), 7.46 (dd, J: 1.6, 8.4 Hz, 1H), 7.30 (dd, J: 4.7, 8.1 Hz, 1H), 5.62 (s, 2H), 2.77 (s, 3H). LCMS (ESI) m/Z 313 (M+H)+.

Step 2: To a stirred solution of 6-((3H-imidazo[4,5-b]pyridin yl)methyl)(methylthio)benzo[d]thiazole (670 mg, 2.15 mmol) in DCM (25 mL) at 0 0C was added 70% meta-chloroperbenzoic acid (582 mg, 2.36 mmol) and the mixture was stirred at 0 0C for 1 h. To the mixture was added saturated aqueous NaHCOg and the organic layer was separated. The aqueous layer was extracted with DCM and the combined c layers were washed with saturated aq NaHCOg. The organic layer was separated, dried over MgSO4, filtered, and under reduced pressure to afford 670 mg of a 4:1 mixture of 6-((3H—imidazo[4,5-b]pyridinyl)methyl) (methylsulfinyl)benzo[d]thiazole and 6-((3H—imidazo[4,5-b]pyridinyl)methyl) (methylsulfonyl)benzo[d]thiazole as a solid that was not purified r. LCMS (ESI) m/Z 329 (M+H)+ (consistent with 6-((3H—imidazo[4,5-b]pyridinyl)methyl) (methylsulfinyl)benzo[d]thiazole) and m/z 345 (M+H)+ (consistent with 6-((3H- imidazo[4,5-b]pyridinyl)methyl)(methylsulfonyl)benzo[d]thiazole).

] Step 3: To a stirred mixture of LiAlH4 (724 mg, 19.08 mmol) in anhydrous THF (20 mL) at rt was added portionwise L-(+)cyclohexylglycine (1 g, 6.36 mmol). The mixture was heated at 80 0C for 4 h. The mixture was cooled to 0 oC and then water (1 mL), 1M aq NaOH (1 mL), and water (3 mL) were added sequentially. The mixture was d and the filtrate was ioned between a mixture of DCM, 1M aq NaOH, and saturated aq sodium potassium te. The organic layer was separated and r washed with 1M aq NaOH. The organic layer was separated, dried over MgSO4, filtered, and concentrated under reduced pressure to afford (S)aminocyclohexylethanol (500 mg) which was not purified further.

LCMS (ESI) m/Z 144 .

Step 4: A 4:1 mixture of 6-((3H-imidazo[4,5-b]pyridinyl)methyl) (methylsulfinyl)benzo[d]thiazole and 6-((3H—imidazo[4,5-b]pyridinyl)methyl) (methylsulfonyl)benzo[d]thiazole (60 mg) fiom Step 2 of this Example was dissolved in anhydrous DMA (1.5 mL) and to this solution were added (S)amino cyclohexylethanol (52 mg, 0.366 mmol) from Step 3 of this Example and DIEA (94 mg, 0.732 mmol). The reaction vessel was sealed and the mixture was heated in a Biotage microwave synthesizer at 150 CC for 30 min. LCMS analysis ted that the on was not complete. To the on mixture was added onal (S) aminocyclohexylethanol (52 mg, 0.366 mmol). The reaction vessel was sealed and the miexture was heated in a Biotage microwave synthesizer at 150 CC for 40 min.

After cooling to rt, the mixture was purified directly by reverse-phase HPLC using a mixture of water (5% CH3CN, 0.05% HCOOH) and CH3CN (0.05% HCOOH) as the mobile phase and Varian Pursuit XRs C-l8 column as the stationary phase to afford (S)((6-((3H-imidazo[4,5-b]pyridinyl)methyl)benzo[d]thiazolyl)amino) cyclohexylethanol (4 mg) as a white solid. 1H NMR (500 MHZ, DMSO-d6) 8 8.58 (s, 1H), 8.37 (m, 1H), 8.08 (m, 1H), 7.84 (d, J: 8.9 Hz, 1H), 7.66 (s, 1H), 7.18 - 7.31 (m, 3H), 5.48 (s, 2H), 3.71 (m, 1H), 3.50 (m, 1H), 1.54 - 1.77 (m, 7H), 0.95 - 1.24 (m, 6H). LCMS (ESI) m/Z 408 (M+H)+.

Example 64 Preparation of (R)((6-((3H—imidaz0[4,5-b]pyridinyl)methyl)benz0[d]thiazol- min0)cyclohexylethanol “/NUHHA S W d“ N ] Step 1: To a stirred mixture of LiAlH4 (724 mg, 1908 mmol) in anhydrous THF (20 mL) at rt was added portionwise 2-cyclohexyl-D-glycine (l g, 6.36 mmol). The mixture was heated at 80 0C for 4 h. The e was cooled to 0 oC and then water (1 mL), 1M aq NaOH (1 mL), and water (3 mL) were added sequentially. The mixture was filtered and the filtrate was partitioned between a mixture of DCM, lM aq NaOH, and saturated aq sodium potassium tartrate. The organic layer was separated and further washed with 1M aq NaOH. The organic was separated, dried over MgSO4, filtered, and concentrated under reduced pressure to afford (R)aminocyclohexylethanol (400 mg) which was not purified filrther.

LCMS (ESI) m/Z 144 (M+H)+.

Step 2: A 4:1 mixture of 6-((3H-imidazo[4,5-b]pyridinyl)methyl) (methylsulf1nyl)benzo[d]thiazole and 6-((3H—imidazo[4,5-b]pyridinyl)methyl) lsulfonyl)benzo[d]thiazole (120 mg) from Step 2 of Example 63 was dissolved in anhydrous DMA (2 mL), and then (R)aminocyclohexylethanol (209 mg, 1.46 mmol) from Step 1 of this Example and DIEA (188 mg, 1.46 mmol) were added. The reaction vessel was sealed and the e was heated with ng at 120 0C for 15 h.

After cooling to rt, the mixture was purified directly by reverse-phase HPLC using a mixture of water (5% CH3CN, 0.05% HCOOH) and CH3CN (0.05% HCOOH) as the mobile phase and Varian Pursuit XRs C-18 column as the stationary phase to afford (R)((6-((3H-imidazo[4,5-b]pyridinyl)methyl)benzo[d]thiazolyl)amino) cyclohexylethanol (18 mg) as a white solid. 1H NMR (300 MHZ, DMSO-d6) 8 8.59 (s, 1H), 8.38 (m, 1H), 8.09 (dd, J: 1.0, 8.0 Hz, 1H), 7.85 (d, J: 8.9 Hz, 1H), 7.66 (s, 1H), 7.18 - 7.32 (m, 3H), 5.48 (s, 2H), 4.70 (br s, 1H), 3.72 (m, 1H), 3.50 (m, 2H), 1.54 - 1.77 (m, 6H), 0.94 - 1.23 (m, 5H). LCMS (ESI) m/z 408 (M+H)+.

Example 65 Pre aration of 1- 2— 1R 2R h drox c clohex lamino benzo thiazol lmeth lmeth0x -1H-benzo imidazole—S-carbonitrile /\©EZ%NHOH 1 -((2-(((1R,2R)Hydroxycyclohexyl)amino)benzo[d]thiazol yl)methyl)methoxy-1H—benzo[d]imidazolecarbonitrile was synthesized as a white powder (20 mg, 45%) using a procedure analogous to that bed in Example 53 1 - , substituting (1R,2R)((6-((5-bromomethoxy- 1H—benzo[d]imidazol- yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol for (1R,2R)((6-((6-bromo methoxy- 1H-benzo[d]imidazolyl)methyl)benzo[d]thiazolyl)amino)cyclohexanol used in example 53. 1H NMR (300 MHz, DMSO-d6) 8 8.60 (s, 1H), 8.12 (s, 1H), 8.01 (d, J: 7.3 Hz, 1H), 7.70 (d, J: 0.9 Hz, 1H), 7.43 (s, 1H), 7.20 - 7.34 (m, 2H), 5.46 (s, 2H), 4.76 (d, J: 4.9 Hz, 1H), 3.90 (s, 3H), 3.51 (m, 1H), 3.33 (m, 1H), 2.03 (m, 1H), 1.87 (m, 1H), 1.57 — 1.67 (m, 2H), 1.15 — 1.34 (m, 4H). LCMS (ESI) m/z 434 (M+H)+.

Example 66 Preparation of ((1R,2R)((6-((3H-imidazo[4,5-b]pyridin yl)methyl)benzo[d]thiazol—Z-yl)amino)cyclohexyl)methanol Step 1: To a stirred mixture of LiAlH4 (796 mg, 20.97 mmol) in anhydrous THF (20 mL) at rt was added portion-wise (lR,2R)—2- aminocyclohexanecarboxylic acid (1 g, 6.99 mmol). The mixture was heated at 80 0C for 4 h before it was cooled to 0 CC. Water (1 mL), 1M aq NaOH (1 mL), and water (3 mL) were added sequentially. The mixture was filtered and the e partitioned between a mixture of DCM, 1M aq NaOH, and saturated aq sodium potassium tartrate. The organic layer was separated and washed with 1M aq NaOH. The organic layer was separated, dried over MgSO4, filtered, and under reduced re to afford ((lR,2R)aminocyclohexyl)methanol (180 mg) which was not purified r.

LCMS (ESI) m/Z 130 (M+H)+.

Step 2: A 4:1 e of 6-((3H—imidazo[4,5-b]pyridin—3-yl)methyl) (methylsulfinyl)benz0[d]thiazole and 6-((3H—imidaz0[4,5-b]pyridinyl)methyl) (methylsulfonyl)benzo[d]thiazole (120 mg) from Step 2 of Example 63 was ved in anhydrous DMA (2 mL), and then ((lR,2R)aminocyclohexyl)methanol (180 mg, 1.40 mmol) from Step 1 of this Example and DIEA (188 mg, 1.46 mmol) were added.

The reaction vessel was sealed and the mixture was heated with stirring at 120 0C for 4.5 h. After cooling to rt, the e was purified directly by reverse-phase HPLC using a mixture of water (5% CH3CN, 0.05% HCOOH) and CH3CN (0.05% HCOOH) as the mobile phase and Varian Pursuit XRs C-18 column as the stationary phase to afford ((lR,2R)—2-((6-((3H—imidaz0[4,5-b]pyridin yl)methyl)benz0[d]thiazolyl)amin0)cyclohexyl)methanol. (41 mg) as a white solid. 1H NMR (300 MHz, DMSO-d6) 8 8.59 (s, 1H), 8.38 (dd, .1: 1.1, 4.7 Hz, 1H), 8.09 (dd, .1: 1.2, 8.0 Hz, 1H), 8.00 (d, .1: 8.3 Hz, 1H), 7.67 (s, 1H), 7.20 - 7.32 (m, 3H), 5.49 (s, 2H), 4.48 (br s, 1H), 3.55 (m, 2H), 1.99 (m, 1H), 1.82 (m, 1H), 1.60 — 1.75 (m, 2H), 1.10 — 1.43 (m, 6H). LCMS (ESI) m/Z 394 (M+H)+.

Example 67 Preparation of (1R,2R)((6-((6-methoxy-lH-benzo[d]imidazol yl)methyl)benzo[d]thiazol—2-yl)amino)cyclohexanol N©:©EZ/O,>—NH OH To a mixture of (1R,2R)((6-((5-bromomethoxy-1H— benzo[d]imidazolyl)methyl)benzo[d]thiazolyl)amino)cyclohexanol (100 mg, 0.2 mmol) from Step 1 of Example 51 in 1,4-dioxane (1.4 mL) and aq 1 N NaOH (300 uL) was added zinc powder (134 mg, 2 mmol). The mixture was heated at 80 CC for 55 h. The mixture was cooled to rt, filtered, and the filtrate was purified by reverse- phase preparative HPLC using a mixture of water (5% CH3CN, 0.05% HCOOH) and CH3CN (0.05% HCOOH) as the mobile phase and Varian Pursuit XRs C18 column as the stationary phase to afford (1R,2R)((6-((6-methoxy-1H—benzo[d]imidazol yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol (45 mg, 56%) as a white powder. 1H NMR (500 MHz, DMSO-d6) 8 8.23 (s, 1H), 7.98 (d, J: 7.6 Hz, 1H), 7.64 (d, J: 1.0 Hz, 1H), 7.51 (d, J: 8.6 Hz, 1H), 7.29 (d, J: 8.4 Hz, 1H), 7.20 (dd, J: 1.4, 8.2 Hz, 1H), 7.12 (d, J: 2.2 Hz, 1H), 6.80 (dd, J: 2.3, 8.7 Hz, 1H), 5.41 (s, 2H), 4.76 (m, 1H), 3.76 (s, 3H), 3.51 (m, 1H), 3.33 (m, 1H), 2.03 (m, 1H), 1.87 (m, 1H), 1.56 - 1.66 (m, 2H), 1.14 - 1.29 (m, 4H). LCMS (ESI) m/z 410 (M+H)+.

Example 68 ation of (1R,2R)((6-((5-methoxy-lH-benzo[d]imidazol yl)methyl)benzo[d]thiazol—2-yl)amino)cyclohexanol NQW/>—NH§OH )((6-((5-Methoxy-1H—benzo[d]imidazol yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol was sized as a white powder (39 mg, 53%) using a procedure ous to that described in Example 67, substituting (1R,2R)((6-((6-bromomethoxy- 1H-benzo [d]imidazol yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol from Step 5 of Example 47 for (1R,2R)((6-((5-bromomethoxy- zo[d]imidazol yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol used in Example 67. 1H NMR (500 MHz, DMSO-d6) 8 8.31 (s, 1H), 7.99 (d, .1: 7.6 Hz, 1H), 7.62 (s, 1H), 7.40 (d, J = 8.9 Hz, 1H), 7.28 (d, .1: 8.4 Hz, 1H), 7.13 - 7.19 (m, 2H), 6.82 (dd, .1: 2.2, 8.9 Hz, 1H), 5.41 (s, 2H), 4.78 (m, 1H), 3.75 (s, 3H), 3.50 (m, 1H), 3.33 (m, 1H), 2.03 (m, 1H), 1.87 (m, 1H), 1.56 — 1.66 (m, 2H), 1.13 — 1.29 (m, 4H). LCMS (ESI) m/Z 410 (M+H)+. e 69 Preparation of (lR,2R)((6-((6-fluoro-3H-imidazo[4,5-b]pyridin yl)methyl)benzo[d] thiazol—2-yl)amino)—2,3-dihydro-1H-indenol Ngrg:/>—NH OH \ / A stirred mixture of 6-((6-fluor0-3H—imidaz0[4,5-b]pyridinyl)methyl)— 2-(methylsulfmyl)benz0[d]thiazole (120 mg, 0.346 mmol) from Step 4 of Example 70, (1R,2R)-(—)-transaminoindanol (103 mg, 0.692 mmol), and DIEA (89 mg, 0.692 mmol) in anhydrous DMA (2.5 mL) was heated in a Biotage microwave synthesizer at 150 CC for 30 min. LCMS analysis indicated that the reaction was incomplete. Additional (1R,2R)—(-)-transamin0indanol (103 mg, 0.692 mmol) and DIEA (89 mg, 0.692 mmol) were added and the mixture was further heated in a Biotage microwave synthesizer at 150 CC for 2 h. After the on mixture was cooled to rt, it was purified directly by reverse-phase HPLC using a e of water (5% CH3CN, 0.05% HCOOH) and CH3CN (0.05% HCOOH) as the mobile phase and Varian Pursuit XRs C-18 column as the stationary phase to afford (1R,2R)((6-((6- flu0r0-3H-imidaz0[4,5-b]pyridinyl)methyl)benz0[d]thiazolyl)amino)—2,3- dihydro-lH—indenol (24 mg, 16%) as a white solid. 1H NMR (300 MHz, DMSO- d6) 5 8.70 (s, 1H), 8.40 - 8.50 (m, 2H), 8.09 (dd, J: 2.6, 9.4 Hz, 1H), 7.73 (d, J: 1.1 Hz, 1H), 7.32 - 7.39 (m, 1H), 7.10 - 7.31 (m, 5H), 5.47 — 6.00 (m, 3H), 5.18 (t, J: 7.1 Hz, 1H), 4.30 (d, J: 3.6 Hz, 1H), 3.16 (dd, J: 7.0, 15.6 Hz, 1H), 2.74 (dd, J: 7.1, .5 Hz, 1H). LCMS (ESI) m/Z 432 (M+H)+. e 70 Preparation of (1R,2R)((6-((6-fluoro-3H-imidazo[4,5-b]pyridin yl)methyl)benzo[d]thiazol—2-yl)amino)cyclohexanol W0 2013/056070 2012/059983 4\N S N U />—NH 9H Step 1: To a d mixture of ofluoronitropyridine (2.46 g, .66 mmol) in a mixture of glacial HOAc (10 mL) and MeOH (20 mL) at 0 CC was added zinc dust (5.09 g, 78.3 mmol) portion-wise, and the mixture was allowed to warm slowly to rt. After stirring at rt for 15 h, the mixture was filtered through Celite and the e was concentrated under reduced pressure. The residue was partitioned between EtOAc and saturated aq NaHCOg. The organic layer was ted and the aqueous layer was extracted with additional EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure to afford 5- fluoropyridine-2,3-diamine (1.13 g) as a solid which was not purified further. LCMS (ESI) m/Z 128 (M+H)+.

Step 2: A stirred mixture of 5-fluoropyridine-2,3-diamine (1.13 g) from Step 1 of this Example, formic acid (0.5 mL), and triethylorthoformate (15 mL) was heated at 100 CC for 1 h. The reaction mixture was cooled to rt, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified Via silica gel flash chromatography eluting with 100% DCM to 10% MeOH in DCM to afford 6-fluoro-3H—imidazo[4,5-b]pyridine (760 mg, 36% over two steps) as a yellow solid. 1H NMR (500 MHz, DMSO-d6) 8 13.09 (br s, 1H), 8.49 (s, 1H), 8.37 (s, 1H), 7.97 (d, .1: 7.9 Hz, 1H). LCMS (ESI) m/Z 138 (M+H)+.

Step 3: To a stirred solution of 6-fluoro-3H—imidazo[4,5-b]pyridine (325 mg, 2.37 mmol) from Step 2 of this Example in anhydrous DMF (10 mL) at 0 CC was added in one portion sodium hydride (60% dispersion in l oil, 100 mg, 2.49 mmol), and the mixture was stirred at 0 CC for 30 min. To the reaction mixture was added a solution of 6-(chloromethyl)(methylthio)benzo[d]thiazole (600 mg, 2.61 mmol) from Step 4 of Example 36 in DMF (2 mL). The mixture was allowed to warm to rt then stirred for a further 15 h. To the reaction mixture was added water (250 mL) and the mixture was extracted with DCM (3 X 100 mL). The ed organic layers were washed with water and brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was d by silica gel flash chromatography eluting with 100% DCM followed by 1% MeOH in DCM to afford 6-((6-fluoro-3H— imidazo[4,5-b]pyridinyl)methyl)(methylthio)benzo[d]thiazole (356 mg, 45%) as a white solid. The regiochemistry of the alkylation was determined by 2-dimensional nuclear Overhauser effect (NOE) experiment. 1H NMR (300 MHz, DMSO-d6) 8 8.73 (s, 1H), 8.41 (t, J: 2.0 Hz, 1H), 8.10 (dd, J: 2.6, 9.4 Hz, 1H), 7.99 (s, 1H), 7.81 (d, J = 8.3 Hz, 1H), 7.46 (dd, J: 1.3, 8.3 Hz, 1H), 5.62 (s, 2H), 2.77 (s, 3H). LCMS (ESI) m/Z 331 (M+H)+.

Step 4: To a stirred solution of 6-((6-fiuoro-3H-imidazo[4,5-b]pyridin yl)methyl)(methylthio)benzo[d]thiazole (350 mg, 1.06 mmol) from Step 3 of this Example in DCM (15 mL) at 0 0C was added 70% meta-chloroperbenzoic acid (287 mg, 1.17 mmol), and the mixture was allowed to warm to rt and d for a filrther 2 h. To the mixture was added saturated aq NaHCOg and the organic layer was separated. The aqueous layer was extracted with DCM and the combined organic layers were washed with saturated aq NaHCOg. The organic layer was separated, dried over MgSO4, filtered, and concentrated under reduced pressure to afford a solid.

The solid was triturated with EtzO, filtered, then dried to afford 6-((6-fiuoro-3H— imidazo[4,5-b]pyridinyl)methyl)(methylsulfinyl)benzo[d]thiazole (336 mg, 92%) as a white solid. 1H NMR (300 MHz, 6) 8 8.76 (s, 1H), 8.41 (br s, 1H), 8.22 (s, 1H), 8.04 - 8.15 (m, 2H), 7.63 (d, J: 8.3 Hz, 1H), 5.70 (s, 2H), 3.06 (s, 3H).

LCMS (ESI) m/Z 347 (M+H)+.

Step 5: A d mixture of 6-((6-fiuoro-3H-imidazo[4,5-b]pyridin yl)methyl)(methylsulfinyl)benzo[d]thiazole (90 mg, 0.260 mmol) from Step 4 of this Example, (1R,2R)-(-)aminocyclohexanol (120 mg, 1.03 mmol), and DIEA (133 mg, 1.03 mmol) in anhydrous DMA (3 mL) was heated at 125 CC for 15 h. After the reaction mixture had cooled to rt, the mixture was d directly by reverse- phase HPLC using a mixture of water (5% CH3CN, 0.05% HCOOH) and CH3CN (0.05% HCOOH) as the mobile phase and Varian Pursuit XRs C-18 column as the stationary phase to afford (1R,2R)((6-((6-fiuoro-3H—imidazo[4,5-b]pyridin hyl)benzo[d]thiazolyl)amino)cyclohexanol (41 mg) as a white solid. 1H NMR (300 MHz, 6) 8 8.68 (s, 1H), 8.42 (s, 1H), 8.08 (dd, J: 2.4, 9.4 Hz, 1H), 7.98 (d, J: 7.5 Hz, 1H), 7.66 (s, 1H), 7.17 - 7.33 (m, 2H), 5.48 (s, 2H), 4.76 (br s, 1H), 3.45 — 3.55 (m, 2H), 2.03 (m, 1H), 1.87 (m, 1H), 1.55 — 1.67 (m, 2H), 1.10 - 1.33 (m, 4H). LCMS (ESI) m/Z 398 (M+H)+.

Example 71 Preparation of (1R,2R)((6-((3H-imidazo[4,5-c]pyridin yl)methyl)benzo[d]thiazol-Z-yl)amino)cyclohexanol Step 1: 6-((3H-Imidazo[4,5-c]pyridinyl)methyl) (methylthio)benz0[d]thiazole (162 mg, 21%) was obtained as a white solid using a procedure analogous to that bed in Step 4 of Example 3, substituting 1H- imidaz0[4,5-c]pyridine for 3H-imidaz0[4,5-b]pyridine used in Example 3. The regiochemistry of the alkylation was determined by 2-dimensional nuclear Overhauser effect (NOE) experiment. 1H NMR (300 MHz, MeOH-d4) 8 8.82 (d, J = 0.8 Hz, 1H), 8.62 (s, 1H), 8.37 (d, J: 5.8 Hz, 1H), 7.92 (d, J: 1.1 Hz, 1H), 7.81 (d, J = 8.3 Hz, 1H), 7.75 (dd, J: 0.8, 5.7 Hz, 1H), 7.46 (dd, J: 1.7, 8.3 Hz, 1H), 5.74 (s, 2H), 2.79 (s, 3H). LCMS (ESI) m/Z 313 (M+H)+.

Step 2: (1R,2R)((6-((3H-Imidazo[4,5-c]pyridin yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol (30 mg, 15% over two steps) was obtained as a yellow powder using ures ous to those described in Step 5 of Example 3 followed by procedures analogous to those described in Step 5 of Example 2, substituting 6-((3H-imidaz0[4,5-c]pyridinyl)methyl) (methylthio)benz0[d]thiazole from Step 1 of this Example for 6-((3H-imidaz0[4,5- b]pyridinyl)methyl)(methylthi0)benzo[d]thiazole used in Example 3 and substituting the product of that reaction for the 2-br0m0((5,6-dimeth0xy-1H- benzo[d]imidazolyl)methyl)benz0[d]thiazole used in Example 2. 1H NMR (300 MHz, 6) 8 8.94 (s, 1H), 8.63 (s, 1H), 8.30 (d, J: 5.7 Hz, 1H), 8.01 (d, J: 7.3 Hz, 1H), 7.74 (s, 1H), 7.65 (d, J: 5.1 Hz, 1H), 7.18 - 7.36 (m, 2H), 5.56 (s, 2H), 4.76 (br s, 1H), 3.53 (d, J: 14.5 Hz, 2H), 2.02 (d, J: 10.2 Hz, 1H), 1.86 (s, 1H), 1.61 (br s, 2H), 1.03 — 1.37 (m, 4H). LCMS (ESI) m/Z 380 (M+H)+. e 72 Preparation of (1R,2R)((6-((1H-imidazo[4,5-c]pyridin yl)methyl)benzo[d]thiazol-Z-yl)amino)cyclohexanol Nphi/Us Step 1: 6-((1H-Imidazo[4,5-c]pyridinyl)methyl) lthio)benzo[d]thiazole (206 mg, 26%) was obtained as a white solid using a procedure analogous to that bed in Step 4 of Example 3, substituting 1H- imidazo[4,5-c]pyridine for 3H-imidazo[4,5-b]pyridine used in Example 3. The regiochemistry of the alkylation was determined by nsional nuclear user effect (NOE) experiment. 1H NMR (300 MHz, MeOH-d4) 8 8.95 (s, 1H), 8.53 (s, 1H), 8.31 (d, J: 5.8 Hz, 1H), 7.84 (s, 1H), 7.77 (d, J: 8.3 Hz, 1H), 7.59 (d, J = 5.3 Hz, 1H), 7.41 (dd, J: 1.4, 8.4 Hz, 1H), 5.65 (s, 2H), 2.76 (s, 3H). LCMS (ESI) m/Z 313 (M+H)+.

Step 2: (1R,2R)((6-((1H-Imidazo[4,5-c]pyridin yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol (85 mg, 42% over two steps) was obtained as a yellow powder using procedures analogous to those described in Step 5 of Example 3 followed by procedures analogous to those described in Step 5 of Example 2, substituting 6-((1H-imidazo[4,5-c]pyridinyl)methyl) lthio)benzo[d]thiazole from Step 1 of this Example for 6-((3H-imidazo[4,5- b]pyridinyl)methyl)(methylthio)benzo[d]thiazole used in Example 3 and substituting the product of that reaction for the 2-bromo((5,6-dimethoxy-1H- benzo[d]imidazolyl)methyl)benzo[d]thiazole used in Example 2. 1H NMR (300 MHz, DMSO-d6) 8 8.95 (br s, 1H), 8.56 (s, 1H), 8.31 (d, J: 4.9 Hz, 1H), 8.00 (d, J: 7.2 Hz, 1H), 7.69 (d, J: 1.1Hz, 1H), 7.64 (d, J: 5.5 Hz, 1H), 7.26 - 7.37 (m, 1H), 7.11 - 7.26 (m, 1H), 5.51 (s, 2H), 4.74 (br s, 1H), 3.34 (d, J: 4.1 Hz, 2H), 2.02 (d, J: .2 Hz, 1H), 1.86 (br s, 1H), 1.60 (d, J: 4.0 Hz, 2H), 0.90 - 1.37 (m, 4H). LCMS (ESI) m/Z 380 (M+H)+.

Example 73 Preparation of 1-(3-((2-(((1R,2R)hydr0xycyclohexyl)amin0)benz0[d]thiazol yl)methyl)-3H—imidaz0[4,5-b]pyridinyl)ethan0ne A stirred mixture of (1R,2R)((6-((6-bromo-3H—imidazo[4,5-b]pyridin yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol (50 mg, 0.109 mmol) from e 29, tributyl(1-ethoxyVinyl)tin (79 mg, 0.218 mmol) and TEA (22 mg, 0.218 mmol) in anhydrous DMF (1 mL) at rt was flushed with a stream of argon for 15 min.

To the ing mixture was added tetrakis(triphenylphosphine)palladium (0) (19 mg, 0.0165 mmol). The reaction vessel was sealed and the mixture was heated with stirring at 110 CC for 1.5 h. After cooling to rt, aq 2 M HCl (500 uL) was added and the mixture was stirred for 1 h. The reaction mixture was purified directly by reverse- phase HPLC using a mixture of water (5% CH3CN, 0.05% HCOOH) and CH3CN (0.05% HCOOH) as the mobile phase and Varian Pursuit XRs C18 column as the nary phase to afford 1-(3-((2-(((1R,2R)—2- hydroxycyclohexyl)amino)benzo[d]thiazolyl)methyl)—3H—imidazo[4,5-b]pyridin anone (8 mg, 17%) as a white solid. 1H NMR (300 MHZ, DMSO-d6) 8 9.00 (d, J = 1.5 Hz, 1H), 8.76 (s, 1H), 8.64 (s, 1H), 7.99 (d, J: 7.5 Hz, 1H), 7.68 (s, 1H), 7.20 7.32 (m, 2H), 5.53 (s, 2H), 4.76 (br s, 1H), 3.50 (m, 1H), 3.30 (m, 1H), 2.68 (s, 3H), 2.04 (m, 1H), 1.87 (m, 1H), 1.55 — 1.65 (m, 2H), 1.10 — 1.30 (m, 4H). LCMS (ESI) m/Z 422 (M+H)+.

Example 74 Preparation of (1R,2R)((6-((6-(methylsulfonyl)-3H-imidaz0[4,5-b]pyridin yl)methyl)benz0[d]thiazol—2-yl)amin0)cyclohexanol Q/\N/\©:N/>_NH OH :8:0 A stirred mixture of (1R,2R)((6-((6-bromo-3H—imidazo[4,5-b]pyridin yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol (100 mg, 0.218 mmol) from Example 29, sodium methanesulfinate (90 mg, 0.436 mmol) and unsymmetrical N,N- ylethylene diamine (6 mg, 0.066 mmol) in anhydrous DMSO (1 mL) at rt was flushed with a stream of argon for 15 min. To the resulting mixture was added copper (I) trifluoromethane-sulfonate e complex (20 mg, 0.0328 mmol). The reaction vessel was sealed and the mixture was heated with stirring at 125 0C for 5 h. After cooling to rt, the reaction e was purified directly by reverse-phase HPLC using a mixture of water (5% CH3CN, 0.05% HOAc) and CH3CN (0.05% HOAc) as the mobile phase and Varian t XRs diphenyl column as the stationary phase to afford (1R,2R)((6-((6-(methylsulfonyl)-3H—imidazo[4,5-b]pyridin yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol (12 mg, 12%) as a white solid. 1H NMR (300 MHz, DMSO-d6) 8 8.85 — 8.95 (br m, 2H), 8.61 (s, 1H), 8.02 (d, J: 7.3 Hz, 1H), 7.69 (s, 1H), 7.18 - 7.35 (m, 2H), 5.56 (s, 2H), 4.79 (br s, 1H), 3.25 — 3.60 (m, 5H), 2.03 (m, 1H), 1.87 (m, 1H), 1.55 — 1.70 (m, 2H), 1.08 - 1.36 (m, 4H).

LCMS (ESI) m/Z 458 (M+H)+.

Example 75 ation of 1-(((6-((3H-imidazo[4,5-b]pyridinyl)methyl)benzo[d]thiazol yl)amin0)methyl)cyclohexanol NfiN/US)—NH C Step 1: To a stirred solution of cyclohexanone cyanohydrin (2 g, 15.98 mmol) in anhydrous THF (40 mL) at rt was added portion-wise LiAlH4 (1.82 g, 47.94 mmol). The reaction vessel was sealed and the mixture was heated at 80 0C for 5 h.

The mixture was cooled to 0 CC and water (1 mL), 1M aq NaOH (1 mL), and water (3 mL) were added sequentially. To the resulting mixture was added DCM and saturated aq sodium ium tartrate and the mixture stirred for 3 h. The organic layer was separated and further washed with brine. The organic layer was separated, dried over MgSO4, filtered, and concentrated under reduced pressure to afford 1- (aminomethyl)cyclohexanol (1.3 g) which was not purif1ed further. LCMS (ESI) m/Z 130 (M+H)+.

Step 2: A 4:1 mixture of 6-((3H-imidazo[4,5-b]pyridinyl)methyl) lsulfmyl)benzo[d]thiazole and 6-((3H—imidazo[4,5-b]pyridinyl)methyl) (methylsulfonyl)benzo[d]thiazole (50 mg) from Step 2 of Example 63 was dissolved in anhydrous DMA (1.5 mL), and then 1-(aminomethyl)cyclohexanol (79 mg, 0.608 mmol) from Step 1 of this Example and DIEA (98 mg, 0.760 mmol)were added. The 2012/059983 reaction vessel was sealed and the e was heated with stirring at 125 0C for 15 h. LCMS analysis indicated that the reaction was not complete. Further amounts of 1- (aminomethyl)cyclohexanol (79 mg, 0.608 mmol) from Step 1 of this Example and DIEA (98 mg, 0.760 mmol) were added and the mixture stirred at 125 CC for further 5 h. After cooling to rt, the mixture was purified directly by reverse-phase HPLC using a mixture of water (5% CH3CN, 0.05% HOAc) and CH3CN (0.05% HOAc) as the mobile phase and Varian Pursuit XRs Diphenyl column as the stationary phase to afford 1-(((6-((3H-imidazo[4,5-b]pyridinyl)methyl)benzo[d]thiazol yl)amino)methyl)cyclohexanol (10 mg) as a white solid. 1H NMR (300 MHZ, DMSO- d6) 5 8.60 (s, 1H), 8.38 (dd, J: 1.1, 4.7 Hz, 1H), 8.09 (dd, J: 1.2, 8.0 Hz, 1H), 7.96 (t, J: 5.6 Hz, 1H), 7.67 (s, 1H), 7.19 - 7.33 (m, 3H), 5.48 (s, 2H), 4.42 (br s, 1H), 1.12 - 1.62 (m, 12H). LCMS (ESI) m/z 394 (M+H)+.

Example 76 Preparation of (1-(((6-((3H-imidaz0[4,5-b]pyridinyl)methyl)benz0[d]thiazol yl)amin0)methyl)cyclohexyl)methanol “NU/mA 8 AG d“ N ] Step 1: To a stirred solution of methyl 1-cyanocyclohexanecarboxylate (2 g, 11.96 mmol) in anhydrous THF (40 mL) at rt was added portionwise LiAlH4 (1.36 g, 35.88 mmol). The reaction vessel was sealed and the e was heated at 80 0C for 5 h. The mixture was cooled to 0 CC and water (1 mL), 1M aq NaOH (1 mL), and water (3 mL) were added sequentially. To the resulting e were added DCM and saturated aq sodium potassium te, and the mixture was stirred for 3 h. The organic layer was separated and further washed with brine. The organic layer was separated, dried over MgSO4, filtered, and concentrated under reduced pressure to afford (1-(aminomethyl)cyclohexyl)methanol (1 g) which was not ed further.

LCMS (ESI) m/Z 144 (M+H)+.

Step 2: A 4:1 mixture of 6-((3H-imidazo[4,5-b]pyridinyl)methyl) (methylsulfinyl)benzo[d]thiazole and 6-((3H—imidazo[4,5-b]pyridinyl)methyl) (methylsulfonyl)benzo[d]thiazole (80 mg) from Step 2 of Example 63 was dissolved in anhydrous DMA (2 mL), and (1-(aminomethyl)cyclohexyl)methanol (175 mg, 1.22 mmol) from Step 1 of this Example and DIEA (157 mg, 1.22 ere added. The reaction vessel was sealed and the mixture was heated with stirring at 125 0C for 15 h.

After cooling to rt, the mixture was purified ly by reverse-phase HPLC using a mixture of water (5% CH3CN, 0.05% HOAc) and CH3CN (0.05% HOAc) as the mobile phase and Varian Pursuit XRs yl column as the stationary phase to afford 1-(((6-((3H-imidazo[4,5-b]pyridinyl)methyl)benzo[d]thiazol yl)amino)methyl)cyclohexanol (22 mg) as a white solid. 1H NMR (300 MHZ, DMSO- d6) 5 8.60 (s, 1H), 8.38 (dd, J: 1.1, 4.7 Hz, 1H), 8.09 (dd, J: 1.3, 7.9 Hz, 1H), 7.99 (t, J: 5.7 Hz, 1H), 7.68 (s, 1H), 7.20 - 7.33 (m, 3H), 5.49 (s, 2H), 3.33 (d, J: 5.8 Hz, 2H), 3.21 (s, 1H), 1.21 - 1.49 (m, 12H). LCMS (ESI) m/z 408 (M+H)+.

Example 77 Preparation of (1R,2R)((6-((4-(l-methyl-lH-pyrazolyl)-lH-imidazol yl)methyl)benz0[d]0xaz01—2-yl)amin0)cyclohexanol rt “CNU />—NHO 9H N Cs Step 1: 6-((4-Bromo-1H—imidazolyl)methyl) (methylthio)benzo[d]oxazole was synthesized as an oil (241 mg, 79%) using a procedure analogous to that described in Step 5 of Example 36, substituting the 9:1 mixture of (2-(methylthio)benzo[d]oxazolyl)methyl methanesulfonate and 6- (chloromethyl)(methylthio)benzo[d]oxazole from Step 1 of Example 34 for 6- (chloromethyl)(methylthio)benzo[d]thiazole used in Example 36. The regiochemistry of the alkylation was ined by nsional nuclear Overhauser effect (NOE) experiment. 1H NMR (300 MHz, DMSO-d6) 8 7.81 (d, J = 1.3 Hz, 1H), 7.65 (m, 2H), 7.41 (d, J: 1.3 Hz, 1H), 7.32 (dd, J: 1.3, 8.1 Hz, 1H), .27 (s, 2H), 2.76 (s, 3H). LCMS (ESI) m/z 324 and 326 (M+H)+.

Step 2: 6-((4-Bromo-1H—imidazolyl)methyl) (methylsulf1nyl)benzo[d]oxazole was sized as a white foam (443 mg) using a procedure analogous to that described in Step 6 of Example 36, substituting 6-((4- bromo-1H—imidazolyl)methyl)(methylthio)benzo[d]oxazole from Step 1 of this Example for 6-((4-bromo-1H-imidazolyl)methyl)(methylthio)benzo [d]thiazole used in Example 36. LCMS (ESI) m/Z 340 and 342 (M+H)+.

Step 3: (lR,2R)((6-((4-Bromo- lH—imidazol- l - yl)methyl)benzo[d]oxazolyl)amino)cyclohexanol was synthesized as an orange solid (280 mg, 96%) using a procedure ous to that described in Step 7 of e 36, substituting 6-((4-bromo- lH—imidazol- l -yl)methyl) (methylsulfinyl)benzo[d]oxazole from Step 2 of this Example for 6-((4-bromo-lH- imidazol-l-yl)methyl)(methylsulfinyl)benzo[d]thiazole used in Example 36.

LCMS (ESI) m/Z 392 and 394 (M+H)+.

Step 4: (lR,2R)((6-((4-(l-Methyl-lH—pyrazolyl)—lH—imidazol-l- yl)methyl)benzo[d]oxazolyl)amino)cyclohexanol was synthesized as a white powder (27 mg, 10%) using a procedure analogous to that described in Step 8 of Example 36, substituting (lR,2R)((6-((4-bromo-lH—imidazol-l- yl)methyl)benzo[d]oxazolyl)amino)cyclohexanol from Step 3 of this Example for )((6-((4-bromo- dazol- l -yl)methyl)benzo [d]thiazol yl)amino)cyclohexanol used in Example 36. 1H NMR (300 MHZ, DMSO-d6) 8 7.78 - 7.86 (m, 2H), 7.75 (s, 1H), 7.57 (s, 1H), 7.32 (s, 1H), 7.26 (s, 1H), 7.17 (m, 1H), 7.09 (m, 1H), 5.15 (s, 2H), 4.71 (d, J: 4.3 Hz, 1H), 3.80 (s, 3H), 3.27 — 3.42 (m, 2H), 1.81 - 2.03 (m, 2H), 1.55 — 1.70 (m, 2H), 1.10 — 1.34 (m, 4H). LCMS (ESI) m/Z 393 (M+H)+. e 78 Preparation of (1R,2R)((6-((5-br0m0-3H—imidaz0[4,5-b]pyridin yl)methyl)benz0[d]thiazol—Z-yl)amin0)cyclohexanol Step 1: To a stirred mixture of 6-bromonitropyridinamine (2.5 g, 11.47 mmol) in a mixture of l HOAc (10 mL), MeOH (10 mL) and EtOH (10 mL) at 0 0C was added portionwise zinc dust (3.73 g, 57.35 mmol). The mixture was stirred at rt for 15 h. The mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was partitioned between saturated aq NaHC03 and EtOAc. The organic layer was separated and the aqueous layer was extracted with additional EtOAc. The combined organic layers were washed with brine, separated and dried over MgSO4, filtered, and concentrated under reduced WO 56070 pressure to afford 6-bromopyridine-2,3-diamine (1.30 g, 60%) as a solid that did not require further purification. 1H NMR (300 MHZ, DMSO-d6) 8 6.61 (d, J = 7.7 Hz, 1H), 6.47 (d, J: 7.7 Hz, 1H), 5.82 (s, 2H), 4.79 (s, 2H). LCMS (ESI) m/z 188 and 190 (M+H)+.

Step 2: A stirred mixture of 6-bromopyridine-2,3-diamine (1.30 g, 6.91 mmol) from Step 1 of this Example, formic acid (0.7 mL), and triethylorthoformate (28 mL) was heated at 100 CC for 1.5 h. After the reaction mixture was cooled to rt, the mixture was concentrated under reduced pressure. The residue was triturated with a mixture of 5% MeOH in DCM. The solid was collected by filtration and dried to afford 5-bromo-3H-imidazo[4,5-b]pyridine (245 mg, 18%) as a tan solid which did not require fiarther ation. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel flash tography (eluting with 100% DCM to 10% MeOH in DCM) to afford additional o-3H-imidazo[4,5- dine (756 mg, 55%) as a tan solid. 1H NMR (300 MHz, DMSO-d6) 8 13.08 (br s, 1H), 8.50 (s, 1H), 8.00 (d, J: 8.3 Hz, 1H), 7.43 (d, J: 8.3 Hz, 1H). LCMS (ESI) m/z 198 and 200 (M+H)+.

] Step 3: To a stirred solution of 5-bromo-3H-imidazo[4,5-b]pyridine (1 g, .05 mmol) from Step 2 of this Example in anhydrous DMF (25 mL) at 0 CC was added in one portion sodium hydride (60% dispersion in mineral oil, 222 mg 5.56 mmol), and the mixture was stirred at 0 CC for 30 min. To the reaction mixture was added a solution of 6-(chloromethyl)(methylthio)benzo[d]thiazole (1.39 g, 6.06 mmol) from Step 4 of Example 36 in DMF (5 mL). The mixture was allowed to warm to rt and d for a further 15 h. To the reaction mixture was added water (300 mL) and the mixture was extracted with EtOAc (3 X 50 mL). The combined organic layers were washed with water and then brine. The organic layer was separated, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with 100% DCM, followed by 1% MeOH in DCM to afford bromo-3H—imidazo[4,5-b]pyridinyl)methyl) (methylthio)benzo[d]thiazole (1.02 g, 52%) as a white solid. The regiochemistry of the alkylation was determined by 2-dimensional nuclear Overhauser effect (NOE) experiment. 1H NMR (300 MHZ, DMSO-d6) 8 8.65 (s, 1H), 8.09 (d, J: 8.3 Hz, 1H), 7.96 (d, J: 0.9 Hz, 1H), 7.83 (d, J: 8.3 Hz, 1H), 7.49 (d, J: 8.3 Hz, 1H), 7.43 (dd, J = 1.5, 8.3 Hz, 1H), 5.60 (s, 2H), 2.77 (s, 3H). LCMS (ESI) m/z 391 and 393 (M+H)+.

Step 4: To a stirred on of 6-((5-bromo-3H-imidazo[4,5-b]pyridin yl)methyl)(methylthio)benzo[d]thiazole (1.02 g, 2.61 mmol) from Step 3 of this Example in DCM (50 mL) at 0 0C was added 70% meta-chloroperbenzoic acid (707 mg, 2.87 mmol) and the mixture was d to warm to rt and d for a further 45 min. To the mixture was added saturated aq NaHCOg and the organic layer was ted. The aqueous layer was ted with DCM and the combined organic layers were washed with saturated aq NaHCOg. The organic layer was separated, dried over MgSO4, filtered, and the filtrate was concentrated under reduced pressure to afford 6-((5 -bromo-3H-imidazo[4,5-b]pyridinyl)methyl) (methylsulfinyl)benzo[d]thiazole (1.06 g, 100%) as a cream solid which did not require further purification. 1H NMR (300 MHZ, DMSO-d6) 8 8.68 (s, 1H), 8.18 (s, 1H), 8.08 — 8.12 (m, 2H), 7.61 (m, 1H), 7.50 (d, J: 9 Hz, 1H), 5.68 (s, 2H), 3.07 (s, 3H); LCMS (ESI) m/Z 407 and 409 (M+H)+.

Step 5: A stirred mixture of 6-((5-bromo-3H-imidazo[4,5-b]pyridin yl)methyl)(methylsulfinyl)benzo[d]thiazole (50 mg, 0.123 mmol) from Step 4 of this Example, (1R,2R)-(-)aminocyclohexanol (42 mg, 0.369 mmol), and DIEA (46 mg, 0.369 mmol) in anhydrous DMA (1 mL) was heated in a sealed vessel at 100 0C for 15 h. The reaction was allowed to cool to rt and then was purified directly by reverse-phase HPLC using a mixture of water (5% CH3CN, 0.05% HOAc) and CH3CN (0.05% HOAc) as the mobile phase and Varian Pursuit XRs diphenyl column as the stationary phase to afford (1R,2R)((6-((5-bromo-3H-imidazo[4,5-b]pyridin- 3-yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol (12 mg, 21%) as a white solid. 1H NMR (300 MHz, DMSO-d6) 8 8.60 (s, 1H), 7.98 - 8.10 (m, 2H), 7.64 (d, J: 1.1 Hz, 1H), 7.48 (d, J: 8.5 Hz, 1H), 7.31 (m, 1H), 7.18 (dd, J: 1.6, 8.2 Hz, 1H), 5.46 (s, 2H), 4.79 (br s, 1H), 3.50 (m, 1H), 3.30 (m, 1H), 2.04 (m, 1H), 1.87 (m, 1H), 1.65 — 1.67 (m, 2H), 1.12 — 1.34 (m, 4H). LCMS (ESI) m/z 458 and 460 (M+H)+.

Example 79 Preparation of methyl (((1R,2R)—2- hydroxycyclohexyl)amin0)benz0[d]thiazol—6-yl)methyl)—3H—imidaz0[4,5- b]pyridinecarb0xylate Step 1: To a stirred mixture of methyl 6-aminonitronicotinate (2 g, .15 mmol) in a mixture of THF (30 mL) and MeOH (10 mL) at rt was added palladium (10 wt% on activated carbon, 100 mg), and the mixture stirred under hydrogen gas (1 here) for 15 h. The mixture was filtered through Celite, and the e was concentrated under reduced pressure to afford methyl 5,6- diaminonicotinate (1.69 g, 100%) as a yellow solid which did not require r purification. 1H NMR (300 MHz, DMSO-d6) 8 7.94 (d, J: 2.1 Hz, 1H), 7.16 (d, J: 2.1 Hz, 1H), 6.27 (br s, 2H), 4.92 (br s, 2H), 3.74 (s, 3H). LCMS (ESI) m/z 168 (M+H)+.

Step 2: A stirred mixture of methyl 5,6-diaminonicotinate (1.69 g, 10.12 mmol) from Step 1 of this Example, formic acid (0.5 mL), and triethylorthoformate (25 mL) was heated at 90 CC for 2.5 h. The reaction mixture was cooled to rt and then the precipitated solid was ted by ion and dried to afford methyl 3H- imidazo[4,5-b]pyridinecarboxylate (588 mg, 33%) as a cream solid which did not require further purification. The filtrate was concentrated under reduced pressure, and the residue purified by silica gel flash chromatography eluting with 100% DCM to % MeOH in DCM to afford additional methyl 3H—imidazo[4,5-b]pyridine carboxylate (550 mg, 31%) as a cream solid. 1H NMR (300 MHz, DMSO-d6) 5 13.33 (br s, 1H), 8.95 (d, J: 1.5 Hz, 1H), 8.64 (s, 1H), 8.50 (d, J: 1.5 Hz, 1H), 3.91 (s, 3H). LCMS (ESI) m/Z 178 (M+H)+.

Step 3: To a stirred solution of methyl 3H—imidazo[4,5-b]pyridine carboxylate (1.34 g, 7.56 mmol) from Step 2 of this Example in anhydrous DMF (25 mL) at 0 0C was added in one n sodium hydride (60% sion in mineral oil, 333 mg, 8.32 mmol) and the mixture was stirred at 0 CC for 30 min. To the reaction e was added a solution of 6-(chloromethyl)(methylthio)benzo[d]thiazole (1.3 g, 5.66 mmol) from Step 4 of Example 36 in DMF (5 mL). The mixture was allowed to warm to rt then stirred for a further 15 h. To the reaction mixture was added water (300 mL) and the mixture was extracted with EtOAc (3 X 50 mL). The combined WO 56070 organic layers were washed with water and then brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with 100% DCM ed by 1% MeOH in DCM to afford methyl 3-((2-(methylthio)benzo[d]thiazolyl)methyl)—3H—imidazo[4,5-b]pyridine carboxylate (1.3 g, 46%) as a white solid. The hemistry of the alkylation was determined by 2-dimensional nuclear Overhauser effect (NOE) experiment. 1H NMR (300 MHz, DMSO-d6) 8 8.95 (d, J: 1.9 Hz, 1H), 8.81 (s, 1H), 8.56 (d, J: 1.7 Hz, 1H), 8.00 (d, J: 1.1 Hz, 1H), 7.80 (d, J: 8.5 Hz, 1H), 7.47 (dd, J: 1.6, 8.4 Hz,1H), .66 (s, 2H), 3.90 (s, 3H), 2.76 (s, 3H). LCMS (ESI) m/z 371 (M+H)+.

Step 4: To a stirred solution of methyl 3-((2-(methylthio)benzo[d]thiazol- ethyl)-3H-imidazo[4,5-b]pyridinecarboxylate (300 mg, 0.811 mmol) from Step 3 of this Example in DCM (10 mL) at 0 0C was added 70% meta- chloroperbenzoic acid (154 mg, 0.892 mmol) and the mixture was allowed to warm to rt and d for a further 4 h. To the mixture was added saturated aq NaHCOg and the organic layer was separated. The aqueous layer was extracted with DCM and the combined organic layers were washed with saturated aq NaHC03. The organic layer was separated, dried over MgSO4, filtered, and trated under reduced pressure to afford 370 mg of a 2:1 mixture of methyl 3-((2-(methylsulfinyl)benzo[d]thiazol yl)methyl)-3H-imidazo[4,5-b]pyridinecarboxylate and methyl 3-((2- lsulfonyl)benzo[d]thiazolyl)methyl)-3H—imidazo[4,5-b]pyridine carboxylate as an oil that was not purified filrther. LCMS (ESI) m/Z 387 (M+H)+ (consistent with methyl (methylsulfinyl)benzo[d]thiazolyl)methyl)-3H— imidazo[4,5-b]pyridinecarboxylate) and m/z 403 (M+H)+ (consistent with methyl 3-((2-(methylsulfonyl)benzo[d]thiazolyl)methyl)-3H—imidazo[4,5-b]pyridine carboxylate).

Step 5: A 2:1 mixture of methyl 3-((2-(methylsulfinyl)benzo[d]thiazol yl)methyl)-3H-imidazo[4,5-b]pyridinecarboxylate and methyl 3-((2- (methylsulfonyl)benzo[d]thiazolyl)methyl)-3H—imidazo[4,5-b]pyridine carboxylate (360 mg) from Step 4 of this Example was dissolved in anhydrous DMA (10 mL), and (1R,2R)-(-)aminocyclohexanol (322 mg, 2.79 mmol) and DIEA (360 mg, 2.79 mmol) were added. The reaction vessel was sealed and the mixture was heated with stirring at 100 CC for 19 h. LCMS indicated the reaction was not complete. To the reaction mixture was added additional (1R,2R)-(-) yclohexanol (100 mg, 0.870 mmol) and the reaction vessel was sealed and the mixture was heated at 100 CC for a further 15 h. After the reaction mixture was cooled to rt, one half of the reaction mixture was purified directly by reverse-phase HPLC using a mixture of water (5% CH3CN, 0.05% HOAc) and CH3CN (0.05% HOAc) as the mobile phase and Varian Pursuit XRs diphenyl column as the stationary phase to afford methyl 3-((2-(((lR,2R)hydroxycyclohexyl)amino)benzo[d]thiazol yl)methyl)-3H-imidazo[4,5-b]pyridinecarboxylate (19 mg) as a white solid. 1H NMR (300 MHz, DMSO-d6) 5 8.96 (d, J: 7.3 Hz, 1H), 8.76 (m, 1H), 8.54 (m, 1H), 7.99 (br s, 1H), 7.66 (d, J: 7.2 Hz, 1H), 7.16 - 7.33 (m, 2H), 5.51 (br s, 2H), 4.76 (br s, 1H), 3.89 (s, 3H), 3.30 — 3.50 (m, 2H), 2.02 (m, 1H), 1.86 (m, 1H), 1.50 — 1.70 (m, 2H), 1.10 — 1.30 (m, 4H). LCMS (ESI) m/z 438 (M+H)+.

Example 80 Preparation of (1R,2R)((6-((5-br0m0-3H—imidaz0[4,5-b]pyridin yl)methyl)benz0[d] thiaz01yl)amin0)-2,3-dihydr0-lH-inden-Z-ol A stirred mixture of 6-((5-bromo-3H-imidazo[4,5-b]pyridinyl)methyl)- hylsulf1nyl)benzo[d]thiazole (130 mg, 0.332 mmol) from Step 4 of Example 78, (lR,2R)-(-)-trans-l-aminoindanol (198 mg, 1.33 mmol), and DIEA (214 mg, 1.66 mmol) in anhydrous DMA (2 mL) in a sealed reaction vessel was heated in a Biotage microwave synthesizer at 140 CC for 1.5 h. LCMS indicated that the reaction was incomplete. Additional )-(-)-trans-l-aminoindanol (50 mg, 0.335 mmol) was added, and the mixture was heated in a Biotage microwave synthesizer at 140 CC for a further 45 min. The reaction mixture was cooled to rt and purified directly by e-phase HPLC using a mixture of water (5% CH3CN, 0.05% HOAc) and CH3CN (0.05% HOAc) as the mobile phase and Varian Pursuit XRs diphenyl column as the stationary phase to afford (lR,2R)-l-((6-((5-bromo-3H-imidazo[4,5- dinyl)methyl)benzo[d]thiazolyl)amino)-2,3-dihydro- lH—indenol (24 mg, 15%) as a white solid. 1H NMR (300 MHZ, DMSO-d6) 8 8.62 (s, 1H), 8.47 (d, J: 7.9 Hz, 1H), 8.08 (d, J: 8.3 Hz, 1H), 7.69 (s, 1H), 7.49 (d, J: 8.3 Hz, 1H), 7.37 (d, J = 8.3 Hz, 1H), 7.11 - 7.28 (m, 5H), 5.45 - 5.54 (m, 3H), 5.18 (t, J: 7.1 Hz, 1H), 4.24 — 4.35 (m, 1H), 3.16 (dd, .1: 6.9, 15.5 Hz, 1H), 2.74 (dd, .1: 7.1, 15.5 Hz, 1H). LCMS (ESI) m/Z 492 and 494 (M+H)+.

Example 81 Preparation of 3-((2-(((1R,2R)hydroxycyclohexyl)amino)benzo[d] thiazol hyl)-3H-imidazo [4,5-b]pyridinecarboxylic acid é\N S N UkNH 9H A mixture of methyl 3-((2-(((1R,2R) hydroxycyclohexyl)amin0)benzo[d]thiazolyl)methyl)—3H—imidazo[4,5-b]pyridine- 6-carboxylate (210 mg, 0.48 mmol) from Example 79 in THF (5 mL) and 1 M aq LiOH (5 mL) was stirred at rt for 3 h. The reaction mixture was acidified to pH~l .0 with 2 M aq HCl, and the mixture was purified directly by e-phase HPLC using a mixture of water (5% CH3CN, 0.05% HOAc) and CH3CN (0.05% HOAc) as the mobile phase and Varian Pursuit XRs diphenyl column as the stationary phase to afford 3-((2-(((1R,2R)hydr0xycyclohexyl)amin0)benz0[d]thiazolyl)methyl)—3H— imidazo[4,5-b]pyridinecarboxylic acid (37 mg, 18%) as a white solid. 1H NMR (300 MHz, DMSO-d6) 5 13.15 (br s, 1H), 8.96 (d, J: 1.7 Hz, 1H), 8.74 (s, 1H), 8.52 (d, J: 1.9 Hz, 1H), 7.98 (d, J: 7.3 Hz, 1H), 7.67 (d, J: 1.1 Hz, 1H), 7.19 - 7.33 (m, 2H), 5.53 (s, 2H), 4.75 (br s, 1H), 3.51 (m, 1H), 3.33 (m, 1H), 2.03 (m, 1H), 1.87 (m, 1H), 1.55 — 1.68 (m, 2H), 1.09 - 1.35 (m, 4H). LCMS (ESI) m/z 424 (M+H)+. e 82 Preparation of (1R,2R)((6-((6-(morpholinomethyl)-3H-imidazo[4,5-b]pyridin- 3-yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol rN S CFACEHC A stirred e of (1R,2R)((6-((6-br0m0-3H-imidazo[4,5-b]pyridin yl)methyl)benz0[d]thiazolyl)amino)cyclohexanol (100 mg, 0.22 mmol) from Example 29, potassium (morpholinyl)methyltriflu0r0b0rate (59 mg, 0.28 mmol) , 2012/059983 Pd(OAc)2 (1.5 mg, 0.007 mmol), 2-dicyclohexylphosphino-2’,4’,6’- triisopropylbiphenyl (6.2 mg, 0.013 mmol) and CS2C03 (213 mg, 0.66 mmol) in THF/HZO (1.5 mL, 4:1, v/v) was purged with argon for 10 min. The mixture was then heated at 85 0C in a sealed reaction vessel overnight. LCMS showed the reaction complete. After cooling to rt, the reaction mixture was filtered through a Celite plug and the filtrate was purified by reverse-phase preparative HPLC using a mixture of water (5% CH3CN, 0.05% HCOOH) and CH3CN (0.05% HCOOH) as the mobile phase and Varian Pursuit XRs C18 column as the stationary phase to afford (1R,2R)- 2-((6-((6-(morpholinomethyl)-3H-imidazo[4,5-b]pyridin yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol as a white powder (36 mg, 35%). 1H NMR (300 MHz, DMSO-d6) 8 8.57 (s, 1H), 8.31 (d, J: 1.5 Hz, 1H), 7.88 - 8.04 (m, 2H), 7.67 (d, J: 0.9 Hz, 1H), 7.26 - 7.33 (m, 1H), 7.17 - 7.26 (m, 1H), 5.46 (s, 2H), 4.75 (br s, 1H), 3.60 (s, 2H), 3.45 - 3.58 (m, 5H), 2.36 (br s, 4H), 2.03 (d, J: .4 Hz, 1H), 1.79 - 1.89 (m, 1H), 1.62 (d,.]= 5.1 Hz, 2H), 1.05 - 1.37 (m, 4H).

LCMS (ESI) m/Z 479 (M+H)+. e 83 Preparation of either (1R,2R)((6-((4-(1-methyl-1H-pyrazol—4-yl)—lH-imidazol- 1-yl)methyl)benz0[d]thiazol—Z-yl)amin0)—2,3-dihydr0-lH-inden-Z-ol 0r (1R,2R) ((6-((5-(1-methyl-1H-pyrazolyl)—lH-imidazolyl)methyl)benz0[d]thiazol—Z- yl)amin0)—2,3-dihydr0-lH-inden-Z-ol (alternative to product of Example 32) N/ UN/>—NH §OH N/ ”U />—NH \ or N I ,N N I \ Step 1: 6-((5-(1-Methyl-1H—pyrazolyl)-1H—imidazolyl)methyl) (methylsulfinyl)benzo[d]thiazole or 6-((4-( 1 -methyl- 1H-pyrazolyl)-1H-imidazol hyl)(methylsulfinyl)benzo[d]thiazole was synthesized as a white foam (140 mg) using a procedure analogous to that described in Step 5 of Example 32, substituting somer 2 from Step 4 of e 32, ( either 6-((5-(1-methyl-1H- pyrazolyl)-1H-imidazolyl)methyl)(methylthio)benzo[d]thiazole or 6-((4-(1- methyl- 1 H-pyrazolyl)- 1H-imidazol-1 -yl)methyl)(methylthio)benzo [d]thiazole) for somer 1, used in Example 32. LCMS (ESI) m/Z 356 (M+H)+.

Step 2: (1R,2R)((6-((4-(1-Methyl-1H—pyrazolyl)—1H—imidazol yl)methyl)benzo[d]thiazolyl)amino)-2,3-dihydro-1H-indenol or (1R,2R)((6- ((5 -( 1 -methyl- 1H-pyrazolyl)-1H-imidazolyl)methyl)benzo [d]thiazol yl)amino)-2,3-dihydro-1H—indenol (alternative of starting material in Step 6 of Example 32) was sized as a white powder (10 mg, 8%) using a ure ous to that described in Step 6 of Example 32, subsituting the product from Step 1 of this Example for 6-((5-(1-methyl-1H—pyrazolyl)-1H—imidazol yl)methyl)(methylsulfinyl)benzo[d]thiazole or 6-((4-(1 -methyl- 1H-pyrazolyl)- 1H—imidazolyl)methyl)(methylsulfinyl)benzo[d]thiazole used in e 32. 1H NMR (300 MHz, DMSO-d6) 5 8.50 (d, J: 7.9 Hz, 1H), 7.81 (s, 1H), 7.73 (d, J: 0.9 Hz, 1H), 7.66 (s, 1H), 7.58 (s, 1H), 7.38 (d, J: 8.3 Hz, 1H), 7.11 - 7.30 (m, 6H), 5.54 (m, 1H), 5.11 - 5.25 (m, 3H), 4.31 (m, 1H), 3.81 (s, 3H), 3.17 (m, 1H), 2.75 (m, 1H).

LCMS (ESI) m/Z 443 (M+H)+.

Example 84 Preparation of (1R,2R)((6-((6-(hydroxymethyl)-3H-imidaz0[4,5-b]pyridin yl)methyl)benz0[d]thiazol—2-yl)amin0)cyclohexanol % S N NU />—NH 9H \ , O To a stirred mixture of methyl 3-((2-(((1R,2R) hydroxycyclohexyl)amino)benzo[d]thiazolyl)methyl)—3H—imidazo[4,5-b]pyridine- 6-carboxylate (76 mg, 0.174 mmol) from Example 79 in anhydrous DCM (1 mL) at — 50 0C under argon was added dropwise diisobutylaluminum hydride (1 M solution in DCM, 0. 696 uL, 696 mmol). The e was allowed to warm to — 20 OC and stirred for 10 min. The reaction mixture was acidified to pH~1.0 with 2 M aq HCl, and the mixture was purified directly by reverse-phase HPLC using a mixture of water (5% CH3CN, 0.05% HOAc) and CH3CN (0.05% HOAc) as the mobile phase and Varian Pursuit XRs yl column as the stationary phase to afford (1R,2R) ((6-((6-(hydroxymethyl)-3H—imidazo[4,5-b]pyridinyl)methyl)benzo[d]thiazol yl)amino)cyclohexanol (20 mg, 28%) as a white solid. 1H NMR (300 MHz, DMSO- d6) 5 8.56 (s, 1H), 8.35 (d, J: 1.3 Hz, 1H), 7.93 - 8.01 (m, 2H), 7.65 (s, 1H), 7.28 (m, 1H), 7.20 (m, 1H), 5.47 (s, 2H), 5.29 (br s, 1H), 4.75 (d, J: 4.0 Hz, 1H), 4.62 (br s, 2H), 3.50 (m, 1H), 3.30 (m, 1H), 2.03 (m, 1H), 1.87 (m, 1H), 1.55 — 1.65 (m, 2H), 1.10 — 1.35 (m, 4H). LCMS (ESI) m/z 410 (M+H)+.

Example 85 Preparation of (1R,2R)((6-((6-(methylthio)—3H-imidazo[4,5-b]pyridin yl)methyl)benzo[d]thiazol—2-yl)amino)cyclohexanol //‘N S N NH / §H N N/>‘ )((6-((6-(Methylthi0)—3H-imidazo[4,5-b]pyridin yl)methy1)benz0[d]thiazolyl)amino)cyclohexanol (25 mg, 18%) was obtained as a tan powder using a procedure analogous to that described in Example 82, tuting potassium (thiomethy1)methy1trifluoroborate for potassium (morpholin yl)methyltrifluor0b0rate, substituting dioxane/HZO for THF/HZO used in Example 82, and running the reaction at 100 0C instead of 85 0C. 1H NMR (300 MHZ, MeOH-d4) 8 8.37 - 8.50 (m, 2H), 8.07 (d, J: 1.7 Hz, 1H), 7.64 (s, 1H), 7.34 - 7.40 (m, 1H), 7.25 - 7.34 (m, 1H), 5.53 (s, 2H), 3.58 (dd, J: 3.4, 9.8 Hz, 1H), 3.39 - 3.51 (m, 1H), 2.56 (s, 3H), 2.10 - 2.24 (m, 1H), 2.03 (d,.]= 10.9 Hz, 1H), 1.64 - 1.85 (m, 2H), 1.13 - 1.51 (m, 4H). LCMS (ESI) m/Z 426 (M+H)+.

Example 86 Preparation of )((6-((6-((methylthio)methyl)—3H-imidazo[4,5-b]pyridin- 3-yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol N//\N/\©:s/>—NH OH [\J N 6 (1R,2R)((6-((6-((methylthio)methyl)-3H-imidazo[4,5-b]pyridin yl)methy1)benz0[d]thiazolyl)amino)cyclohexanol (5 mg, 4%) was obtained as a tan powder using a procedure analogous to that described in Example 82, tuting potassium (thiomethy1)methy1trifluoroborate for potassium (morpholin yl)methyltriflu0r0b0rate used in Example 82, substituting dioxane/HZO for THF/HZO used in Example 82, and running the reaction at 100 0C instead of 85 0C. 1H NMR (300 MHz, MeOH-d4) 5 8.29 (s, 2H), 7.95 (br s, 1H), 7.52 (s, 1H), 7.22 - 7.30 (m, 1H), 7.13 — 7.22 (m, 1H), 5.43 (s, 2H), 3.76 (s, 2H), 3.47 (dd, J: 3.4, 9.8 Hz, 1H), 3.27 — 3.40 (m, 1H), 2.04 (d, J: 11.7 Hz, 1H), 1.93 (br s, 1H), 1.90 (s, 3H), 1.52 — 1.74 (m, 2H), 1.01 _ 1.40 (m, 4H). LCMS (ESI) m/Z 440 .

Example 87 Preparation of 3-((2-(((1R,2R)hydroxycyclohexyl)amino)benzo[d] thiazol yl)methyl)-3H-imidazo[4,5-b]pyridine-S-carbonitrile //\N S N />—NH SOH A stirred mixture of (1R,2R)((6-((5-br0mo-3H—imidaz0[4,5-b]pyridin yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol (100 mg, 0.218 mmol) from Example 78, zinc cyanide (77 mg, 0.654 mmol), and 1,1’- phenylphosphino)ferrocene (18 mg, 0.0327 mmol) in anhydrous DMF (2 mL) at rt was purged for 15 min with a stream of argon. To the resulting mixture was added tris(dibenzy1ideneacetone) dipa11adium (18 mg, 0.0218 mmol). The reaction vessel was sealed and the mixture was stirred at 100 CC for 2 h. After cooling to rt, the on mixture was purified directly by reverse-phase HPLC using a mixture of water (5% CH3CN, 0.05% HOAc) and CH3CN (0.05% HOAc) as the mobile phase and Varian Pursuit XRs diphenyl column as the stationary phase to afford 3-((2- (((1R,2R)hydr0xycyclohexyl)amin0)benz0[d]thiazolyl)methyl)-3H—imidazo[4,5- b]pyridinecarb0nitrile (34 mg, 39%) as a white solid. 1H NMR (300 MHz, DMSO- d6) 8 8.91 (s, 1H), 8.34 (d, J: 8.3 Hz, 1H), 8.01 (d, J: 7.3 Hz, 1H), 7.92 (d, J: 8.1 Hz, 1H), 7.67 (d, J: 1.1 Hz, 1H), 7.32 (m, 1H), 7.22 (m, 1H), 5.53 (s, 2H), 4.77 (br s, 1H), 3.51 (m, 1H), 3.30 (m, 1H), 2.03 (m, 1H), 1.85 (m, 1H), 1.65 — 1.67 (m, 2H), 1.08 — 1.37 (m, 4H). LCMS (ESI) m/Z 405 (M+H)+. e 88 Preparation of 1-(3-((2-(((1R,2R)hydroxycyclohexyl)amino)benzo[d]thiazol yl)methyl)-3H-imidazo[4,5-b]pyridin-S-yl)ethanone é\N S N U)—NH §OH A stirred e of (1R,2R)((6-((5-bromo-3H-imidazo[4,5-b]pyridin yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol (100 mg, 0.218 mmol) from Example 78, tributyl(1-ethoxyVinyl)tin (157 mg, 0.436 mmol) in anhydrous DMF (2 mL) at rt was purged for 15 min with a stream of argon. To the resulting mixture was added tetrakis(triphenylphosphine) palladium (0) (38 mg, 0.0327 mmol). The reaction vessel was sealed and the mixture was stirred at 110 0C for 2 h. After cooling to rt, 2 M aq HCl (0.5 mL) was added, and the mixture was stirred at rt for 1.5 h. The mixture was purified directly by reverse-phase HPLC using a mixture of water (5% CH3CN, 0.05% HOAc) and CH3CN (0.05% HOAc) as the mobile phase and Varian Pursuit XRs diphenyl column as the nary phase to afford crude 1-(3 ((1R,2R) hydroxycyclohexyl)amino)benzo[d]thiazolyl)methyl)—3H—imidazo[4,5-b]pyridin yl)ethanone. The crude product was triturated with EtzO and the solid was collected by filtration and dried to afford 1-(3-((2-(((1R,2R) ycyclohexyl)amino)benzo[d]thiazolyl)methyl)—3H—imidazo[4,5-b]pyridin yl)ethanone (19 mg, 21%) as a white solid. 1H NMR (300 MHZ, DMSO-d6) 8 8.84 (s, 1H), 8.22 (d, J: 8.5 Hz, 1H), 8.00 (d, J: 7.5 Hz, 1H), 7.92 (d, J: 8.3 Hz, 1H), 7.80 (s, 1H), 7.26 - 7.39 (m, 2H), 5.55 (s, 2H), 4.77 (d, J: 4.9 Hz, 1H), 3.50 (m, 1H), 3.30 (m, 1H), 2.74 (s, 3H), 2.02 (m, 1H), 1.87 (m, 1H), 1.55 — 1.67 (m, 2H), 1.12 - 1.32 (m, 4H). LCMS (ESI) m/Z 422 (M+H)+.

Example 89 Preparation of 3-((2-(((1R,2R)hydr0xycyclohexyl)amin0)benz0[d] thiazol yl)methyl)-N-methyl-3H—imidaz0[4,5-b]pyridinecarb0xamide //\N S N _NH §OH To a stirred mixture of 3-((2-(((1R,2R) ycyclohexyl)amino)benzo[d]thiazolyl)methyl)—3H—imidazo[4,5-b]pyridine- 6-carboxylic acid (70 mg, 0.165 mmol) from Example 81 and TEA (67 mg, 0.660 mmol) in anhydrous THE (2.5 mL) at rt was added methylamine (2 M solution in THE, 413 uL, 0.825 mmol) followed by benzotriazol-l- yloxytris(dimethylamino)phosphonium hexafluorophosphate (109 mg, 0.248 mmol).

The mixture was stirred at rt for 4.5 h. The mixture was purified by reverse-phase HPLC using a mixture of water (5% CH3CN, 0.05% HOAc) and CH3CN (0.05% HOAc) as the mobile phase and Varian Pursuit XRs diphenyl column as the stationary phase to afford 3-((2-(((1R,2R)hydroxycyclohexyl)amino)benzo[d]thiazol yl)methyl)-N-methyl-3H—imidazo[4,5-b]pyridinecarboxamide (26 mg, 36%) as a white solid. 1H NMR (300 MHz, DMSO-d6) 8 8.86 (d, .1: 1.88 Hz, 1H), 8.69 (s, 1H), 8.59 (d, .1: 4.52 Hz, 1H), 8.49 (d, .1: 1.88 Hz, 1H), 7.97 (d, .1: 7.54 Hz, 1H), 7.67 (d, .1: 1.13 Hz, 1H), 7.19 - 7.32 (m, 2H), 5.51 (s, 2H), 4.73 (br. s., 1H), 3.51 (m, 1H), 3.30 (m, 1H), 2.82 (d, .1: 4.33 Hz, 3H), 2.02 (m, 1H), 1.88 (m, 1H), 1.55 — 1.65 (m 2H), 1.10 — 1.30 (m, 4H). LCMS (ESI) m/z 437 .

Example 90 Preparation of N-hydroxy((2-(((1R,2R) hydroxycyclohexyl)amin0)benzo[d]thiazolyl)methyl)-3H-imidazo[4,5- b] pyridinecarb0ximidamide /\N S [\l N § \ <3 A stirred mixture of 3-((2-(((1R,2R) hydroxycyclohexyl)amino)benzo[d]thiazolyl)methyl)-3H-imidazo[4,5-b]pyridine- 6-carbonitrile from Example 43 (55 mg, 0.14 mmol) and excess 50% NHZOH in H20 (300 uL) in EtOH (3 mL) was heated at 80 0C for 1h. LCMS analysis showed that the on was complete. The crude product was purified by preparative HPLC using a e of water (5% CH3CN, 0.05% AcOH) and CH3CN (0.05% AcOH) as the mobile phase and Varian Pursuit XRs Diphenyl column as the stationary phase to afford N-hydroxy((2-(((1R,2R)hydroxycyclohexyl)amino)benzo[d]thiazol yl)methyl)-3H-imidazo[4,5-b]pyridinecarboximidamide (8 mg, 13%) as a tan powder. 1H NMR (300 MHz, MeOH-d4) 8 8.73 (d, J: 1.7 Hz, 1H), 8.50 (s, 1H), 8.29 (d, J: 1.7 Hz, 1H), 7.63 (s, 1H), 7.32 - 7.39 (m, 1H), 7.25 - 7.32 (m, 1H), 5.55 (s, 2H), 3.50 - 3.65 (m, 1H), 3.37 - 3.49 (m, 1H), 2.13 (d, J: 12.1 Hz, 1H), 2.02 (d, J: .4 Hz, 1H), 1.62 - 1.82 (m, 2H), 1.15 - 1.49 (m, 4H). LCMS (ESI) m/z 438 .

Example 91 Preparation of (1R,2R)((6-((6-(aminomethyl)—3H-imidazo[4,5-b]pyridin yl)methyl)benzo[d]thiazol-Z-yl)amino)cyclohexanol acetate /\N s N/ U)—NH //\I N 23§\~ \ o H2N AOH To a stirred mixture of 3-((2-(((1R,2R) hydroxycyclohexyl)amin0)benz0[d]thiazolyl)methyl)-3H-imidazo[4,5-b]pyridine- 6-carb0nitrile from Example 43 (85 mg, 0.21 mmol) in THF (3 mL) at 0 0C was added dropwise LAH in diethyl ether (2.0 M, 0.4 mL, 0.4 mmol). The resulting mixture was stirred at rt for 1h, before another 0.4 mL of 2.0 M LAH in diethyl ether was added.

After stirring at rt overnight, the reaction mixture was treated with sequential on 0f61 uL of H20, 61 uL of 10% NaOH, and 183 uL of H20. The resulting mixture was filtered through a Celite plug and concentrated under d pressure. The residue was purified by preparative HPLC using a mixture of water (5% CH3CN, 0.05% ACOH) and CH3CN (0.05% ACOH) as the mobile phase and Varian t XRs Diphenyl column as the stationary phase to afford (1R,2R)((6-((6- (aminomethyl)-3H-imidaz0[4,5-b]pyridinyl)methyl)benz0[d]thiazol yl)amin0)cyclohexanol acetate (4 mg, 5%) as a tan powder. 1H NMR (300 MHz, MeOH-d4) 5 8.54 (d, J: 9.2 Hz, 2H), 8.19 (s, 1H), 7.63 (s, 1H), 7.19 - 7.42 (m, 2H), .56 (s, 2H), 4.27 (s, 2H), 3.57 (d, J: 9.6 Hz, 1H), 3.37 - 3.50 (m, 1H), 2.13 (d, J: 11.3 Hz, 1H), 2.01 (br s, 1H), 1.92 (s, 3H), 1.62 - 1.81 (m, 2H), 1.17 - 1.49 (m, 4H).

LCMS (ESI) m/Z 409 (M+H)+.

Example 92 ation of 3-((2-(((1R,2R)hydroxycyclohexyl)amino)benzo[d] thiazol yl)methyl)—N,N—dimethyl-3H-imidazo[4,5-b]pyridinecarboxamide To a stirred mixture of 3-((2-(((1R,2R) hydroxycyclohexyl)amin0)benzo[d]thiazolyl)methyl)—3H—imidazo[4,5-b]pyridine- 2012/059983 6-carboxylic acid (65 mg, 0.153 mmol) from Example 81 and TEA (77 mg, 0.767 mmol) in a mixture of anhydrous THE (1.5 mL) and anhydrous DMF (0.5 mL) at rt was added dimethylamine (2 M solution in MeOH, 383 uL, 0.767 mmol) followed by benzotriazolyloxytris(dimethylamino)phosphonium hexafluorophosphate (102 mg, 0.230 mmol). The resulting mixture was stirred at rt for 2 h. The mixture was purified directly by e-phase HPLC using a mixture of water (5% CH3CN, 0.05% HOAc) and CH3CN (0.05% HOAc) as the mobile phase and Varian Pursuit XRs diphenyl column as the nary phase to afford 3-((2-(((1R,2R) hydroxycyclohexyl)amino)benzo[d]thiazolyl)methyl)-N,N—dimethyl-3H- imidazo[4,5-b]pyridinecarboxamide (33 mg, 48%) as a white solid. 1H NMR (300 MHz, DMSO-d6) 8 8.70 (s, 1H), 8.45 (s, 1H), 8.16 (s, 1H), 7.96 (d, J: 7.54 Hz, 1H), 7.68 (s, 1H), 7.20 - 7.33 (m, 2H), 5.50 (s, 2H), 4.73 (d, J: 4.90 Hz, 1H), 3.51 (m, 1H), 3.30 (m, 1H), 2.99 (br. s., 6H), 2.02 (m, 1H), 1.87 (m, 1H), 1.55 — 1.65 (m, 2H), 1.10 — 1.30 (m, 4H). LCMS (ESI) m/z 451 (M+H)+.

Example 93 Preparation of (1R,2R)((6-((6-(2H-tetrazolyl)-3H-imidazo[4,5-b]pyridin hyl)benz0[d]thiazol—Z-yl)amin0)cyclohexanol //\N S N /mlf—NH $314 \ 33 A stirred mixture of 3-((2-(((1R,2R) hydroxycyclohexyl)amino)benzo[d]thiazolyl)methyl)-3H-imidazo[4,5-b]pyridine- 6-carbonitrile from Example 43 (120 mg, 0.30 mmol), NaNg (29 mg, 0.45 mmol) and NH4Cl (24 mg, 0.45 mmol) in DMF (1.5 mL) was heated at 100 0C overnight. LCMS showed the reaction mostly completed. A portion of the reaction mixture (~ 1/3) was cooled to rt and purified by preparative HPLC using a mixture of water (5% CH3CN, 0.05% AcOH) and CH3CN (0.05% AcOH) as the mobile phase and Varian Pursuit XRs Diphenyl column as the stationary phase to afford (1R,2R)((6-((6-(2H- tetrazolyl)-3H-imidazo[4,5-b]pyridinyl)methyl)benzo[d]thiazol yl)amino)cyclohexanol (4 mg, 9%) as a white powder. 1H NMR (300 MHZ, MeOH- d4) 5 9.13 (s, 1H), 8.67 (s, 1H), 8.60 (s, 1H), 7.76 (dd, J: 7.5, 10.9 Hz, 2H), 7.69 (s, 1H), 5.60 (s, 2H), 3.56 (d, .1: 9.6 Hz, 1H), 3.37 — 3.50 (m, 1H), 1.92 — 2.21 (m, 2H), 1.72 (d, .1: 8.9 Hz, 2H), 1.17 — 1.49 (m, 4H). LCMS (ESI) m/Z 448 (M+H)+.

Example 94 Preparation of (1R,2R)((6-((6-(2-methyl-2H-tetrazol—5-yl)-3H- imidazo[4,5-b]pyridinyl)methyl)benzo[d]thiazol-Z-yl)amino)cyclohexanol /\N S \ C To the remaining portion of the reaction mixture from Example 93 were added excess CS2C03 (300 mg) and excess Mel (200 uL). The resulting mixture was heated at 90 0C for 4h. LCMS showed that the reaction was mostly completed. After cooling to rt, the e was purified by preparative HPLC using a mixture of water (5% CH3CN, 0.05% AcOH) and CH3CN (0.05% AcOH) as the mobile phase and Varian Pursuit XRs Diphenyl column as the stationary phase to afford (1R,2R)((6- ((6-(2-methyl-2H-tetrazolyl)—3H-imidaz0[4,5-b]pyridin yl)methyl)benz0[d]thiazolyl)amino)cyclohexanol (8 mg) as a white powder. The hemistry assignment of the compound was consistent with the result from a NMR Nuclear Overhauser Effect (NOE) experiment. 1H NMR (300 MHz, MeOH-d4) 9.17 (s, 1H), 8.69 (s, 1H), 8.55 (s, 1H), 7.67 (s, 1H), 7.25 - 7.41 (m, 2H), 5.58 (s, 2H), 4.36 - 4.51 (m, 3H), 3.57 (d, J: 9.6 Hz, 1H), 3.36 - 3.49 (m, 1H), 2.13 (d, J: 11.3 Hz, 1H), 2.01 (br s, 1H), 1.71 (d, J: 10.0 Hz, 2H), 1.12 - 1.48 (m, 4H). LCMS (ESI) m/Z 462 .

Example 95 Preparation of (lR,2R)((6-((9H-purinyl)methyl)benzo[d]thiazol no)—2,3-dihydro-1H-indenol 6UH“67‘ Step 1: 6-((9H—Purinyl)methyl)(methylthio)benzo[d]thiazole was synthesized as a white solid (690 mg, 30%) using a procedure ous to that described in Step 3 of Example 47, substituting 9H—purine for omethoxy- lH—benzo[d]—imidazole used in Example 47. The regiochemistry of the alkylation was determined by 2-dimensional nuclear Overhauser effect (NOE) experiment. 1H NMR (300 MHz, 6) 8 9.19 (s, 1H), 8.96 (s, 1H), 8.80 (s, 1H), 8.01 (d, J: 0.9 Hz, 1H), 7.82 (d, J: 8.3 Hz, 1H), 7.49 (dd, J: 1.5, 8.5 Hz, 1H), 5.64 (s, 2H), 2.77 (s, 3H). LCMS (ESI) m/Z 314 (M+H)+.

Step 2: 6-((9H-Purinyl)methyl)(methylsulf1nyl)benzo[d]thiazole was synthesized as a white foam (473 mg) using a procedure analogous to that described in Step 6 of Example 36, substituting 6-((9H-purinyl)methyl) (methylthio)benzo[d]thiazole from Step 1 of this Example for 6-((4-bromo-lH- imidazol-l-yl)methyl)(methylthio)benzo[d]thiazole used in Example 36. LCMS (ESI) m/Z 330 (M+H)+.

] Step 3: To a mixture of 6-((9H—purinyl)methyl) (methylsulf1nyl)benzo[d]thiazole (270 mg, 0.8 mmol) from Step 2 of the this Example and (lR,2R)-l-amino-2,3-dihydro-lH—indenol (246 mg, 1.6 mmol) in NMP (l .5 mL) was added DIEA (570 uL, 3.3 mmol). The reaction vessel was sealed and the mixture was heated at 150 CC in the Biotage microwave reactor for 1.5 h. The mixture was purified by reverse-phase ative HPLC using a mixture of water (5% CH3CN, 0.05% HCOOH) and CH3CN (0.05% HCOOH) as the mobile phase and Varian Pursuit XRs C l 8 column as the stationary phase to afford (lR,2R)-l-((6-((9H— purinyl)methyl)benzo[d]thiazolyl)amino)-2,3-dihydro- lH—indenol (71 mg, 21%) as a white powder. 1H NMR (300 MHZ, DMSO-d6) 8 9.18 (s, 1H), 8.97 (s, 1H), 8.77 (s, 1H), 8.47 (d, J: 8.1 Hz, 1H), 7.74 (d, J: 1.3 Hz, 1H), 7.37 (m, 1H), 7.30 (m, 1H), 7.11 - 7.25 (m, 4H), 5.45 - 5.57 (m, 3H), 5.18 (t, J: 7.1 Hz, 1H), 4.28 (m, 1H), 3.16 (dd, J: 6.9, 15.5 Hz, 1H), 2.74 (m, 1H). LCMS (ESI) m/z 415 (M+H)+.

Example 96 Preparation of (1R,2R)((6-((6-ethynyl-3H-imidazo[4,5-b]pyridin yl)methyl)benz0[d]thiazol—Z-yl)amin0)cyclohexanol Step 1: 6-Iodo-3H-imidazo[4,5-b]pyridine (3.78 g) was obtained using a ure analogous to that described in Step 7 of Example 23, substituting 5- iodopyridine-2,3-diamine for 6-methoxy-N2-((2-(methylthio)benzo[d]thiazol yl)methyl)pyridine-2,3-diamine used in Example 23. LCMS (ESI) m/z 246 (M+H)+.

Step 2: (lR,2R)((6-((6-Iodo-3H-imidazo[4,5-b]pyridin yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol was obtained as an off-white solid using ures analogous to those described in Steps 4-5 of Example 3 and Step 5 of Example 2, tially, substituting 6-iodo-3H-imidazo[4,5-b]pyridine from Step 1 of this Example for 3H-imidazo[4,5-b]pyridine used in Step 4 of Example 3, and then making the analogous substitutions for the starting materials used in Step 5 of Example 3 and Step 5 of Example 2. LCMS (ESI) m/Z 506 (M+H)+.

Step 3: To a stirred suspension of (lR,2R)((6-((6-iodo-3H-imidazo[4,5- b]pyridinyl)methyl)benzo[d]thiazolyl)amino)cyclohexanol (152 mg, 0.30 mmol) from Step 2 of this Example in DMF (3 mL) were added CuI (6 mg, 0.032 mmol) and PdC12(PPh3)2 (11 mg, 0.015 mmol). The e was purged with argon while ethynyltrimethylsilane (85 uL, 0.60 mmol) and TEA (127 uL, 0.90 mmol) were added sequentially. The ing mixture was stirred at rt for lh. LCMS analysis showed that the reaction was complete. Water (30 mL) was added and the resulting dark brown solid was collected by filtration and dried to give crude (1R,2R)((6-((6- ethylsilyl)ethynyl)-3H-imidazo[4,5-b]pyridinyl)methyl)benzo[d]thiazol yl)amino)cyclohexanol (100 mg, 70%). LCMS (ESI) m/Z 476 (M+H)+.

Step 4: To a stirred solution of (lR,2R)((6-((6-((trimethylsilyl)ethynyl)- 3H-imidazo[4,5-b]pyridinyl)methyl)benzo[d]thiazolyl)amino)cyclohexanol (100 mg, 0.21 mmol) from Step 3 of this Example in MeOH (5 mL) was added excess K2C03 (150 mg). The resulting mixture was stirred at rt for 30 min. LCMS analysis showed that the reaction was complete. The on e was filtered through a Celite plug and the filtrate was purified by preparative HPLC using a mixture of water (5% CH3CN, 0.05% AcOH) and CH3CN (0.05% AcOH) as the mobile phase and Varian Pursuit XRs Diphenyl column as the stationary phase to afford (1R,2R)((6- ((6-ethynyl-3H-imidazo[4,5-b]pyridinyl)methyl)benzo[d]thiazol yl)amino)cyclohexanol as a tan powder (40 mg, 47%). 1H NMR (300 MHZ, DMSO- d6) 5 8.69 (s, 1H), 8.50 (d, J: 1.5 Hz, 1H), 8.23 (d, J: 1.7 Hz, 1H), 8.02 (d, J: 6.6 Hz, 1H), 7.66 (s, 1H), 7.26 - 7.34 (m, 1H), 7.15 - 7.26 (m, 1H), 5.49 (s, 2H), 4.29 (s, 1H), 3.26 - 3.38 (m, 2H), 2.03 (d, J: 10.4 Hz, 1H), 1.85 (br s, 1H), 1.62 (d, J: 4.7 Hz, 2H), 1.00 - 1.38 (m, 4H). LCMS (ESI) m/z 404 (M+H)+.

Example 97 Preparation of (1R,2R)((6-((6-morpholin0-3H-imidaz0[4,5-b]pyridin yl)methyl)benz0[d]thiazol—Z-yl)amin0)cyclohexanol To a stirred solution of (1R,2R)((6-((6-iodo-3H-imidazo[4,5-b]pyridin- 3-yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol from Step 2 of e 96 (150 mg, 0.30 mmol) in DMSO (3 mL) were added morpholine (156 uL, 1.78 mmol), CuI (23 mg, 0.12 mmol), L-proline (14 mg, 0.12 mmol), and K2C03 (123 mg, 0.89 mmol). The resulting mixture was flushed with argon, the reaction vessel was sealed and the mixture was heated at 100 0C for 2 h, then at 110 0C for 2 h. LCMS analysis showed that the reaction complete. The reaction mixture was cooled to rt, filtered through a Celite plug, and the filtrate was d by preparative HPLC using a mixture of water (5% CH3CN, 0.05% AcOH) and CH3CN (0.05% AcOH) as the mobile phase and Varian t XRs Diphenyl column as the stationary phase to afford (1R,2R)((6-((6-morpholino-3H-imidazo[4,5-b]pyridin hyl)benzo[d]thiazolyl)amino)cyclohexanol (15 mg, 11%) as a tan powder. 1H NMR (300 MHz, DMSO-d6) 5 8.46 (s, 1H), 8.22 (d, J: 2.3 Hz, 1H), 8.03 (d, J: 7.2 Hz, 1H), 7.63 (br s, 2H), 7.24 - 7.34 (m, 1H), 7.14 - 7.22 (m, 1H), 5.42 (s, 2H), 3.70 - 3.83 (m, 4H), 3.48 - 3.55 (m, 2H), 3.07 - 3.15 (m, 4H), 2.03 (d, J: 10.2 Hz, 1H), 1.87 (d, J: 9.6 Hz, 1H), 1.61 (br s, 2H), 1.22 (d, J: 7.3 Hz, 4H). LCMS (ESI) m/Z 465 (M+H)+.

Example 98 Preparation of (1R,2R)((6-((6-vinyl-3H-imidazo[4,5-b]pyridin yl)methyl)benzo[d]thiazol-Z-yl)amino)cyclohexanol N/N/\©:/\/NN73>—NH OH To a stirred mixture of (1R,2R)((6-((6-brom0-3H-imidaz0[4,5- b]pyridiny1)methyl)benz0[d]thiaz01—2-yl)amino)cyclohexanol (200 mg, 0.44 mmol) from e 29 in n-PrOH were added potassium vinyltrifluoroborate (117 mg, 0.88 mmol), PdC12(dppf)‘DCM (18 mg, 0.022 mmol), and TEA (122 uL, 0.88 mmol). The resulting e was purged with argon for 5 min, the reaction vessel was sealed and the mixture was heated at 100 0C overnight. LCMS analysis showed that the reaction was complete. The reaction e was cooled to rt and purified by reverse-phase preparative HPLC using a e of water (5% CH3CN, 0.05% HCOOH) and CH3CN (0.05% HCOOH) as the mobile phase and Varian Pursuit XRs C18 column as the stationary phase to afford (1R,2R)((6-((6-viny1-3H-imidazo[4,5-b]pyridin yl)methyl)benz0[d]thiazolyl)amino)cyclohexanol as a tan powder (40 mg, 23%). 1H NMR (300 MHz, MeOH-d4) 8 8.50 (d, J: 1.7 Hz, 1H), 8.43 (s, 1H), 8.15 (d, J: 1.7 Hz, 1H), 7.63 (s, 1H), 7.32 - 7.41 (m, 1H), 7.25 - 7.32 (m, 1H), 6.91 (dd, J: 10.9, 17.7 Hz, 1H), 5.91 (d,.]= 17.5 Hz, 1H), 5.53 (s, 2H), 5.35 (d, J: 11.1 Hz, 1H), 3.50 - 3.66 (m, 1H), 3.37 - 3.49 (m, 1H), 2.14 (d, J: 12.1 Hz, 1H), 2.01 (br s, 1H), 1.63 - 1.82 (m, 2H), 1.13 - 1.50 (m, 4H). LCMS (ESI) m/z 406 (M+H)+.

Example 99 Preparation of N-((3-((2-(((1R,2R)hydroxycyclohexyl)amino)benzo[d]thiazol- 6-yl)methyl)—3H-imidazo[4,5-b]pyridinyl)methyl)acetamide To a stirred solution of (1R,2R)((6-((6-(aminomethyl)-3H-imidazo[4,5- b]pyridinyl)methyl)benzo[d]thiazolyl)amino)cyclohexanol (50 mg, 0.12 mmol) from Example 91 in DCM (2 mL) were added pyridine (40 uL, 0.48 mmol) and AcCl (27 uL, 0.36 mmol). The ing mixture was stirred at rt for 3h before it was concentrated under reduced pressure. The residue was purified by reverse-phase preparative HPLC using a mixture of water (5% CH3CN, 0.05% HCOOH) and CH3CN (0.05% HCOOH) as the mobile phase and Varian Pursuit XRs C18 column as the nary phase to afford N—((3-((2-(((1R,2R) hydroxycyclohexyl)amino)benzo[d]thiazolyl)methyl)-3H-imidazo[4,5-b]pyridin yl)methyl)acetamide (45 mg, 82 %) as a white . 1H NMR (300 MHZ, DMSO- d6) 5 8.58 (s, 1H), 8.40 (br s, 1H), 8.31 (s, 1H), 7.84 - 8.10 (m, 2H), 7.65 (s, 1H), 7.24 - 7.41 (m, 1H), 7.10 - 7.24 (m, 1H), 5.47 (s, 2H), 4.37 (d, J: 5.5 Hz, 2H), 3.34 (d, J: 8.7 Hz, 2H), 1.97 - 2.16 (m, 1H), 1.89 (br s, 1H), 1.86 (s, 3H), 1.61 (br s, 2H), 0.99 - 1.39 (m, 4H). LCMS (ESI) m/Z 451 (M+H)+.

Example 100 Preparation of (1R,2R)((6-((5-br0m0-lH-benzo[d]imidazol yl)methyl)benz0[d]thiazol—Z-yl)amin0)cyclohexanol //\ S N NU />—NH: OH N Z 3 Step 1: To a stirred mixture of thylthio)benzo[d]thiazol yl)methanol (958 mg, 4.5 mmol) from Step 3 of Example 36 in CHzClz (20 mL) at 0 0C under argon was added Dess-Martin periodinane (2.0 g, 5.0 mmol) nwise.

The mixture was stirred for 1 h and then diluted with CHZClz (100 mL). To this mixture was added a 50/50 mixture of saturated aq sodium sulfite and saturated aq sodium bicarbonate (40 mL). This mixture was stirred for 10 min and then the CHzClz layer was separated, washed with a saturated aq sodium bicarbonate (50 mL), dried over NaZSO4, d, and concentrated under reduced pressure to afford 2- (methylthio)benzo[d]thiazolecarbaldehyde (937 mg, 99%) as a white solid. LCMS (ESI) m/Z 210 (M+H)+.

Step 2: To a stirred mixture of 4-bromonitroaniline (694 mg, 3.2 mmol) in TFA (5 mL) at -15 0C under argon was added NaBH(OAc)3 (1.1g, 5.3 mmol) nwise. The mixture was stirred for 10 min. To the stirred mixture was added dropwise 2-(methylthio)benzo[d]thiazolecarbaldehyde (735 mg, 3.5 mmol) from Step 1 of this Example in CHzClz (3 mL). The mixture was stirred for 1 h and then concentrated under reduced pressure. The residue was d by silica gel flash chromatography eluting with a gradient of 100% hexanes to 100% EtOAc to afford 4- bromo-N—((2-(methylthio)benzo[d]thiazolyl)methyl)nitroaniline (1.0 g, 77%) as a yellow solid. 1H NMR (300 MHz, DMSO-d6) 8 8.84 (t, J: 6.0 Hz, 1H), 8.19 (d, J: 2.4 Hz, 1H), 7.98 (s, 1H), 7.81 (d, J: 8.3 Hz, 1H), 7.56 (dd, J: 2.4, 9.3 Hz, 1H), 7.46 (d, J: 8.3 Hz, 1H), 6.88 (d, J: 9.2 Hz, 1H), 4.75 (d, J: 6.0 Hz, 2H), 2.77 (s, 3H). LCMS (ESI) m/Z 410 and 412 (M+H)+.

Step 3: 4-Bromo-N1-((2-(methylthio)benzo[d]thiazol yl)methyl)benzene-l ,2-diamine was synthesized as an oil (1 g) using a procedure analogous to that described in Step 2 of Example 41, substituting 4-bromo-N-((2- (methylthio)benzo[d]thiazolyl)methyl)nitroaniline from Step 2 of this Example for 4-bromomethoxy-N-((2-(methylthio)benzo[d]thiazolyl)methyl) nitroaniline used in Example 41. LCMS (ESI) m/Z 379 and 381 (M+H)+.

Step 4: 6-((5-Bromo-1H—benzo[d]imidazolyl)methyl) (methylthio)benzo[d]thiazole was synthesized as a white solid (630 mg, 57%) using a procedure ous to that described in Step 3 of Example 41, tuting o- N1-((2-(methylthio)benzo[d]thiazolyl)methyl)benzene-1,2-diamine from Step 3 of this Example for 4-bromomethoxy -N2-((2-(methylthio)benzo[d]thiazol yl)methyl)benzene-1,2-diamine used in Example 41. 1H NMR (300 MHz, DMSO-d6) 8 8.51 (s, 1H), 8.00 (s, 1H), 7.75 - 7.91 (m, 2H), 7.54 (d, J: 8.5 Hz, 1H), 7.33 — 7.45 (m, 2H), 5.62 (s, 2H), 2.77 (s, 3H). LCMS (ESI) m/Z 389 and 391 (M+H)+.

] Step 5: 6-((5-Bromo-1H—benzo[d]imidazolyl)methyl) (methylsulf1nyl)benzo[d]thiazole was sized as a white foam (1.0 g) using a procedure analogous to that described in Step 6 of Example 36, substituting 6-((5- bromo-1H—benzo[d]imidazolyl)methyl)(methylthio)benzo[d]thiazole from Step 4 of this Example for the 6-((4-bromo-1H—imidazolyl)methyl) (methylthio)benzo[d]thiazole used in Example 36. LCMS (ESI) m/Z 405 and 407 (M+H)+.

Step 6: (lR,2R)((6-((5-Bromo-lH-benzo[d]imidazol-l- yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol was sized as a white powder (36 mg, 36%) using a procedure analogous to that described in Step 7 of Example 36, subsituting 6-((5-bromo-lH-benzo[d]imidazol-l-yl)methyl) (methylsulf1nyl)benzo[d]thiazole from Step 5 of this Example for 6-((4-bromo-lH- imidazol-l-yl)methyl)(methylsulf1nyl)benzo[d]thiazole used in e 36. 1H NMR (300 MHz, DMSO-d6) 8 8.46 (s, 1H), 8.00 (d, J: 7.5 Hz, 1H), 7.85 (d, J: 1.7 Hz, 1H), 7.64 (d, J: 1.3 Hz, 1H), 7.54 (d, J: 8.7 Hz, 1H), 7.25 - 7.39 (m, 2H), 7.18 (dd, J: 1.5, 8.3 Hz, 1H), 5.47 (s, 2H), 4.76 (m, 1H), 3.50 (m, 1H), 3.33 (m, 1H), 2.02 (m, 1H), 1.87 (m, 1H), 1.55 — 1.65 (m, 2H), 1.12 - 1.32 (m, 4H). LCMS (ESI) m/z 456 and 458 (M+H)+.

Example 101 Preparation of N—(1-((2-(((1R,2R)hydr0xycyclohexyl)amin0)benz0[d]thiazol yl)methyl)-1H-imidazolyl)acetamide /,\ s oleUN>_&OH Step 1: To a mixture of the regioisomers 4-bromo-l-((2- (trimethylsilyl)ethoxy)methyl)- lH-imidazole and o- l -((2- (trimethylsilyl)ethoxy)methyl)-lH-imidazole (643 mg, 2.3 mmol) from Step 1 of Example 32, acetamide (275 mg, 5.0 mmol), and C82C03 (1.5 g, 5 mmol) in 1,4- dioxane (7 mL) was added N,N'-dimethylethylenediamine (500 uL, 5 mmol). Argon was bubbled into the mixture for 5 min followed by the on of CuI (221 mg, 1.1 mmol). Argon was bubbled into the mixture for an onal 5 min. Then the reaction vessel was sealed and the mixture was heated at 100 0C for 15 h. The mixture was cooled to rt, then partitioned between EtOAc (100 mL) and water (50 mL). The EtOAc layer was separated, washed with brine, dried over Na2S04, d, and trated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with a gradient of 100% hexanes to 100% EtOAc to afford a mixture of regioisomers N—(l -((2-(trimethylsilyl)ethoxy)methyl)- lH-imidazol yl)acetamide and N—(l-((2-(trimethylsilyl)ethoxy)methyl)-lH-imidazol yl)acetamide (170 mg, 29%) as an oil. LCMS (ESI) m/Z 256 (M+H)+.

Step 2: The mixture of regioisomers N—(l-((2- (trimethylsilyl)ethoxy)methyl)- lH—imidazolyl)acetamide and N-( l -((2- thylsilyl)ethoxy)methyl)-1H—imidazolyl)acetamide (170 mg, 0.7 mmol) from Step 1 of this Example was d in 70% TFA in CHzClz (10 mL) at rt for 4 h. The mixture was concentrated under reduced pressure to afford N—(1H—imidazol yl)acetamide (147 mg) as a yellow film which was used in the next step without further purification. LCMS (ESI) m/z 126 (M+H)+.

] Step 3: N—(l-((2-(Methylthio)benzo[d]thiazolyl)methyl)-1H—imidazol- 4-yl)acetamide was synthesized as a white solid (58 mg, 15%) using a procedure analogous to that described in Step 5 of Example 36, substituting N—(1H—imidazol yl)acetamide from Step 2 of this Example for 4-bromo-1H-imidazole used in Example 36. The hemistry of the alkylation was determined by 2-dimensional nuclear Overhauser effect (NOE) experiment. 1H NMR (300 MHz, DMSO-d6) 8 10.27 (s, 1H), 7.94 (s, 1H), 7.83 (d, J: 8.5 Hz, 1H), 7.60 (s, 1H), 7.38 (d, J: 8.5 Hz, 1H), 7.20 (s, 1H), 5.24 (s, 2H), 2.78 (s, 3H), 1.94 (s, 3H). LCMS (ESI) m/z 319 (M+H)+.

Step 4: N—(l-((2-(Methylsulfinyl)benzo[d]thiazolyl)methyl)— 1H- olyl)acetamide was synthesized as a white foam (106 mg) using a procedure analogous to that described in Step 6 of Example 36, substituting (2- (methylthio)benzo[d]thiazolyl)methyl)-1H—imidazolyl)acetamide from Step 3 of this Example for 6-((4-bromo-1H-imidazolyl)methyl) (methylthio)benzo[d]thiazole used in Example 36. LCMS (ESI) m/z 351 (M+H)+ Step 5: N—(l-((2-(((1R,2R)Hydroxycyclohexyl)amino)benzo[d]thiazol- 6-yl)methyl)-1H—imidazolyl)acetamide was synthesized as a white powder (4 mg) using a procedure analogous to that described in Step 7 of Example 36, subsituting N- (1 -((2-(methylsulfinyl)benzo [d]thiazolyl)methyl)-1H-imidazolyl)acetamide from Step 4 of this Example for 6-((4-bromo-1H-imidazolyl)methyl) (methylsulf1nyl)benzo[d]thiazole used in Example 36. The powder was fiarther purified by preparative TLC eluting with 10% MeOH in CHZClz to afford N—(l-((2- 2R)hydroxycyclohexyl)amino)benzo[d]thiazolyl)methyl)- 1H-imidazol yl)acetamide (2 mg, 2%) as a white solid. 1H NMR (300 MHz, MeOH-d4) 8 7.50 (s, 2H), 7.35 (d, J: 8.1 Hz, 1H), 7.12 - 7.25 (m, 2H), 5.13 (s, 2H), 3.60 (m, 1H), 3.43 (m, 1H), 1.96 - 2.20 (m, 5H), 1.67 — 1.80 (m, 2H), 1.20 - 1.47 (m, 4H). LCMS (ESI) m/Z 386 (M+H)+.

Example 102 ation of (1R,2R)((6-((6-ethyl-3H-imidazo[4,5-b]pyridin yl)methyl)benzo [d]thiazolyl)amino)cyclohexanol /\N S NI /\©: />_NH OH \ 53 To a stirred solution of (1R,2R)((6-((6-vinyl-3H-imidazo[4,5-b]pyridin- 3-yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol (20 mg, 0.049 mmol) from Example 98 in 1:1 MeOH/THF (2 mL) was added Raney Ni (10 mg). The resulting mixture was d under a H2 balloon at rt for 4h. LCMS is showed that the reaction was complete. The reaction mixture was filtered through a Celite plug and the filtrate was purified with preparative TLC to give (1R,2R)((6-((6-ethyl-3H- imidazo[4,5-b]pyridinyl)methyl)benzo[d]thiazolyl)amino)cyclohexanol (6 mg, %). 1H NMR (300 MHz, 6) 8 8.53 (br s, 1H), 8.26 (br s, 1H), 7.95 (d, J: 12.4 Hz, 2H), 7.66 (br s, 1H), 7.25 - 7.42 (m, 1H), 7.06 - 7.25 (m, 1H), 5.45 (br s, 2H), 4.74 (d, J: 4.5 Hz, 1H), 3.51 (br s, 1H), 2.73 (d, J: 7.2 Hz, 2H), 2.04 (br s, 1H), 1.86 (br s, 1H), 1.62 (br s, 2H), 1.23 (t, J: 6.8 Hz, 7H). LCMS (ESI) m/z 408 (M+H)+.

Example 103 Pre aration of 1- 2- 1R 2R h drox c clohex 1 amino benzo d thiazol- 6- lmeth l l-meth l-1H- razol—4- l razin-2 1H -one O ” O Step 1: To 2,3-dichlor0pyrazine (1.12 g, 7.52 mmol), 1-methyl (4,4,5,5-tetramethyl-1,3,2-di0xaborolanyl)-1H-pyrazole (1.56 g, 7.52 mmol), bis(triphenylph0sphine)palladium(II) dichloride (270 mg, 0.38 mmol), and N32C03 (2.4 g, 22.56 mmol) in a pressure tube were added 1,2-dimethoxyethane (15 mL) and water (2 mL). The flask was evacuated and flushed with argon (3x) and then sealed and heated at 90 0C overnight. The mixture was concentrated under reduced pressure and purified by silica gel chromatography eluting with % EtOAc/hexanes to afford 2-chloro(1-methyl-1H-pyrazolyl)pyrazine (780 mg, 53%). LCMS (ESI) m/Z 195 (M + H)+.

Step 2: To 2-chloro(1-methyl-1H-pyrazolyl)pyrazine (200 mg, 1.03 mmol) from Step 1 of this Example in DMSO (1.5 mL) and water (1.5 mL) was added KOH (890 mg, 15.4 mmol) and the mixture was heated at 80 0C for 3 h. The mixture was cooled and ioned between EtOAc and 4 N HCl. The aqueous layer was concentrated under reduced pressure and then a mixture ofMeOH and EtOH was added and the sion was filtered through Celite. The filtrate was concentrated under reduced pressure and then EtzO was added and the mixture again concentrated under reduced pressure. The residue was triturated with DCM and filtered to afford crude 3-(1-methyl-1H-pyrazolyl)pyrazin-2(1H)-one (300 mg, quantitative) as a yellow solid. 1H NMR (300 MHz, DMSO-d6) 8 8.60 (s, l H), 8.18 (s, l H), 7.24 - 7.39 (m, 2 H), 3.91 (s, 3 H).

Step 3: To ethyl-1H-pyrazolyl)pyrazin-2(1H)-one (139 mg, 0.78 mmol) from Step 2 of this Example in DMF (3 mL) was added NaH (60% in mineral oil, 32 mg, 0.78 mmol) and the e was stirred at rt for 10 min. 6- (Chloromethyl)(methylthio)benzo[d]thiazole (180 mg, 0.78 mmol) from Step 4 of e 36 was then added. The mixture was stirred at rt overnight and then concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0-15% MeOH/DCM to afford impure 3-(1-methyl-1H- pyrazolyl)((2-(methylthio)benzo[d]thiazolyl)methyl)pyrazin-2(1H)-one (80 mg, 27%) which was used without further purification. LCMS (ESI) m/z 370 (M + H)+.

Step 4: To 3-(1-Methyl-1H-pyrazolyl)((2- (methylthio)benzo[d]thiazolyl)methyl)pyrazin-2(1H)-one (80 mg, 0.21 mmol) from Step 3 of this Example in DCM (5 mL) at 0 0C was added 3-chloroperbenzoic acid (70%, 75 mg, 0.3 mmol) and the e was stirred for 20 min. The mixture was diluted with DCM and then washed with aq sodium thiosulfate and saturate aq sodium bicarbonate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. To the residue was added N,N- ylacetamide (4 mL), DIEA (0.075 mL, 0.43 mmol) and (1R,2R) aminocyclohexanol (50 mg, 0.43 mmol). The mixture was heated at 100 0C for 3 d 2012/059983 and then purified by reverse-phase preparative HPLC using a mixture of water (5% CH3CN, 0.05% HCOOH) and CH3CN (0.05% HCOOH) as the mobile phase and Varian Pursuit XRs C18 column as the stationary phase to afford 1-((2-(((1R,2R) hydroxycyclohexyl)amino)benzo[d]thiazolyl)methyl)-3 -( 1 -methyl- 1 H-pyrazol azin-2(1H)-one (7 mg, 8%). 1H NMR (300 MHZ, DMSO-d6) 8 8.55 (s, 1 H), 8.09 (s, 1 H), 8.00 (d, J=7.54 Hz, 1 H), 7.66 - 7.71 (m, 2 H), 7.35 (d, J=4.33 Hz, 1 H), 7.29 - 7.33 (m, 1 H), 7.22 - 7.27 (m, 1 H), 5.14 (s, 2 H), 4.77 (br. s., 1 H), 3.89 (s, 3 H) 3.52 (br. s., 1 H), 2.04 (d, J=10.36 Hz, 1 H), 1.89 (br. s., 1 H), 1.63 (br. s., 2 H), 1.23 (d, J=5.84 Hz, 4 H). LCMS (ESI) m/Z 437 (M + H)+.

Example 104 Pre aration of IR 2R 6- 6- 3-h drox meth lbut-l- n-l- l-3H- imidazo 4 5-b ridin l meth l benzo d thiazol-Z- 1 amino c clohexanol (1R,2R)—2-((6-((6-(3-Hydroxymethylbutynyl)-3H-imidazo[4,5 - b]pyridinyl)methyl)benzo[d]thiazolyl)amino)cyclohexanol (125 mg, 91%) was obtained as a White powder using a procedure analogous to that described in Step 3 of Example 96, substituting 2-methylbutynol for ethynyltrimethylsilane used in Example 96. 1H NMR (300 MHz, DMSO-d6) 8 8.67 (br s, 1H), 8.41 (s, 1H), 8.10 (br s, 1H), 7.99 (d, J: 7.3 Hz, 1H), 7.66 (s, 1H), 7.26 - 7.36 (m, 1H), 7.17 - 7.26 (m, 1H), .48 (s, 2H), 4.77 (br s, 1H), 3.48 - 3.61 (m, 2H), 2.03 (d, J: 10.2 Hz, 1H), 1.88 (d, J = 10.0 Hz, 1H), 1.62 (d, J: 4.5 Hz, 2H), 1.49 (s, 6H), 1.22 (d, J: 5.8 Hz, 4H).

LCMS (ESI) m/Z 462 .

Example 105 Pre aration of IR 2R 6- 2— rometh l-9H- urin 1] )methyl )benz0| d|thiazolyl )amino )cyclohexanol WO 56070 //\N S N U/>_NH \OH / N \ ii F F Step 1: 2-(Trifluoromethyl)-9H-purine (940 mg, 94%) was obtained as a white solid using a procedure analogous to that described in Step 7 of Example 23, substituting 2-(trifluoromethyl)pyrimidine-4,5-diamine for 6-methoxy-N2-((2- (methylthio)benzo[d]thiazolyl)methyl)pyridine-2,3-diamine used in Example 23.

LCMS (ESI) m/Z 189 (M+H)+.

Step 2: 2-(Methylthio)—6-((2-(trifluoromethyl)—9H-purin yl)methyl)benzo[d]thiazole (480 mg, 47%) was obtained as an oil using a procedure analogous to that described in Step 1 of Example 63, substituting 2-(trifluoromethyl)— 9H-purine from Step 1 of this Example for 4-azabenzimidazole used in Example 63.

LCMS (ESI) m/Z 382 (M+H)+.

Step 3: (lR,2R)((6-((2-(Trifluoromethyl)-9H-purin hyl)benzo[d]thiazolyl)amino)cyclohexanol was obtained as a light brown solid using ures analogous to those described in Step 5 of Example 3 ed by procedures analogous to those used in Step 5 of Example 2, substituting 2- (methylthio)((2-(trifluoromethyl)-9H-purinyl)methyl)benzo[d]thiazole from Step 2 of this Example for 6-((3H-imidazo[4,5-b]pyridinyl)methyl) (methylthio)benzo[d]thiazole used in Example 3, and substituting the product of that on for the 2-bromo((5,6-dimethoxy-lH-benzo[d]imidazol-l- yl)methyl)benzo[d]thiazole used in Example 2. 1H NMR (300 MHZ, DMSO-d6) 8 9.39 (s, 1H), 8.97 (s, 1H), 8.05 (d, J: 7.5 Hz, 1H), 7.69 (s, 1H), 7.29 - 7.39 (m, 1H), 7.14 - 7.28 (m, 1H), 5.56 (s, 2H), 4.81 (br s, 1H), 3.50 (d, J: 7.7 Hz, 2H), 1.96 - 2.17 (m, 1H), 1.88 (d, J: 9.6 Hz, 1H), 1.62 (br s, 2H), 0.93 - 1.41 (m, 4H). LCMS (ESI) m/Z 449 (M+H)+.

Example 106 Pre aration of IR 2R 6- 5- meth lsulfon l idazo 4 5- b ridin lmeth lbenzo thiazol-Z- lamino c clohexanol A stirred mixture of (1R,2R)((6-((5-bromo-3H-imidazo[4,5-b]pyridin yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol (89 mg, 0.194 mmol) from e 78, sodium methane te (80 mg, 0.777 mmol), and N,N— dimethylethylenediamine (7 mg, 0.078 mmol) in anhydrous DMSO (2 mL) at rt was purged for 15 min with a stream of argon. To the resulting mixture was added copper (I) trifluoromethane-sulfonate e complex (20 mg, 0.038 mmol). The reaction vessel was sealed and the mixture was stirred at 125 0C for 5 h. After cooling to rt, the reaction mixture was purified directly by reverse-phase HPLC using a mixture of water (5% CH3CN, 0.05% HOAc) and CH3CN (0.05% HOAc) as the mobile phase and Varian Pursuit XRs diphenyl column as the stationary phase to afford (1R,2R) ((6-((5-(methylsulfonyl)-3H—imidazo[4,5-b]pyridinyl)methyl)benzo[d]thiazol yl)amino)cyclohexanol (33 mg, 37%) as a white solid. 1H NMR (300 MHZ, DMSO- d6) 5 8.91 (s, 1H), 8.39 (d, J: 8.3 Hz, 1H), 7.90 - 8.02 (m, 2H), 7.78 (s, 1H), 7.25 - 7.36 (m, 2H), 5.54 (s, 2H), 4.74 (br s, 1H), 3.50 (br s, 1H), 3.33 — 3.34 (m, 4H), 2.02 (m 1.87 (m, 1H), 1.55 — 1.65 (m, 2H), 1.15 — 1.30 (m, 4H); LCMS (ESI) m/Z , 1H), 458 (M+H)+.

Example 107 Pre aration of IR 2R 6- 6-br0m0-1H—benz0 imidazol—l- l meth lbenzo thiazol-Z- 1 amino c clohexanol //\N S Q N {3 Step 1: To a d mixture of thylthio)benzo[d]thiazol yl)methanol (958 mg, 4.5 mmol) from Step 3 of Example 36 in CHZClz (20 mL) at 0 0C under argon was added Dess—Martin periodinane (2.1 g, 5.0 mmol) in small portions. After the mixture was stirred for 1 hr at 0 CC, it was diluted with CHzClz (100 mL) followed by the addition of a 1:1 mixture of saturated aq Na2S03 and saturated aq NaHCOg (40 mL). The mixture was stirred for 10 min. The layers were separated and the CHzClz layer was tially washed with saturated aq NaHCOg (50 mL) and brine (50 mL). The organic layer was separated and dried over NazSO4, filtered, and concentrated under reduced pressure to yield 2- lthio)benzo[d]thiazolecarbaldehyde (937 mg, 99%) as an off white solid which did not require r purification. 1H NMR (300 MHZ, DMSO-d6) 8 10.06 (s, 1H), 8.62 (s, 1H), 7.99 (s, 2H), 2.84 (s, 3H); LCMS (ESI) m/z 210 (M+H)+.

Step 2: To a stirred mixture of 5-bromonitroaniline (714 mg, 4.0 mmol) in TFA (7 mL) at -15 CC under argon, was added NaBH(OAc)3 (1.2 g, 5.4 mmol) in small portions. The mixture was stirred for 15 min, then a solution of 2- (methylthio)benzo[d]thiazolecarbaldehyde in CHzClz (2 mL) was added dropwise.

The mixture was stirred for 30 min then trated under reduced pressure to give a red oil. The oil was partitioned between EtOAc (200 mL) and saturated aq NaHCOg (100 mL). The organic layer was separated and washed with brine (100 mL). The organic layer was separated, dried over , filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with a gradient of 100% hexanes to 50% hexanes in EtOAc to afford 5-bromo-N—((2- (methylthio)benzo[d]thiazolyl)methyl)nitroaniline (1.1 g, 73%) as a yellow solid. LCMS (ESI) m/Z 409, 411 (M+H)+.

Step 3: o-N1-((2-(methylthio)benzo[d]thiazolyl)methyl)benzene- 1,2-diamine was sized as a brown solid (920 mg) using a procedure analogous to that described in Step 2 of Example 41, tuting 5-bromo-N—((2- (methylthio)benzo[d]thiazolyl)methyl)nitroaniline from the preVious step for 4- bromo-S-methoxy-N-((2-(methylthio)benzo[d]thiazolyl)methyl)nitroaniline used in Example 41. LCMS (ESI) m/Z 379, 381 (M+H)+.

Step 4: 6-((6-Bromo-1H—benzo[d]imidazolyl)methyl) (methylthio)benzo[d]thiazole was synthesized as a yellow solid (701 mg, 70%) using a procedure analogous to that described in Step 3 of Example 41, substituting 5- bromo-N1-((2-(methylthio)benzo[d]thiazolyl)methyl)benzene- 1 ,2-diamine from the preVious step for 4-bromomethoxy-N1-((2-(methylthio)benzo[d]thiazol yl)methyl)benzene-l,2-diamine used in Example 41. LCMS (ESI) m/Z 389, 391 (M+H)+.

Step 5: 6-((6-Bromo-1H—benzo[d]imidazolyl)methyl) (methylsulfinyl)benzo[d]thiazole was synthesized as a yellow foam (811 mg) using a procedure analogous to that described in Step 6 of Example 36, substituting 6-((6- bromo- 1H-benzo [d]imidazolyl)methyl)(methylthio)benzo [d]thiazole from the preVious step for 6-((4-bromo-1H-imidazolyl)methyl) (methylthio)benzo[d]thiazole used in Example 36. LCMS (ESI) m/Z 405, 407 (M+H)+.

] Step 6: (1R,2R)((6-((6-Bromo-1H—benzo[d]imidazol yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol was synthesized using a procedure analogous to that described in Step 7 of e 36, substituting 6-((6- bromo- 1H-benzo [d]imidazolyl)methyl)(methylsulfinyl)benzo [d]thiazole from the preVious step for 6-((4-bromo-lH-imidazol-l-yl)methyl) (methylsulfinyl)benzo[d]thiazole used in Example 36. A n of crude product was purified by ative HPLC using a e of water (5% CH3CN, 0.05% HCOOH) and CH3CN (0.05% HCOOH) as the mobile phase and a Varian Diphenyl column as the stationary phase to yield (1R,2R)((6-((6-bromo-1H- benzo[d]imidazolyl)methyl)benzo[d]thiazolyl)amino)cyclohexanol as a white powder (33 mg) 1H NMR (300 MHz, DMSO-d6) 8 8.44 (s, 1H), 8.00 (d, J: 7.5 Hz, 1H), 7.85 (d, J: 1.5 Hz, 1H), 7.56 - 7.68 (m, 2H), 7.26 - 7.36 (m, 2H), 7.15 - 7.24 (m, 1H), 5.47 (s, 2H), 4.76 (d, J: 4.5 Hz, 1H), 3.52 (m, 1H), 3.32 (m, 1H), 1.99 (m, 1H), 1.88 (m, 1H), 1.55 — 1.67 (m, 2H), 1.12 — 1.30 (m, 4H); LCMS (ESI) m/z 456, 458 (M+H)+.

Example 108 Pre aration of 1- 2— 1R 2R h drox c clohex lamino benzo thiazol l meth l -1H-benzo d imidazole-S-carbonitrile /\ S N/ N/U />—NH ¢ 9H N g Step 1: 4-Bromo-N—((2-(methylthio)benzo[d]thiazolyl)methyl) nitroaniline was synthesized as a yellow solid (1.08 g, 77%) using a procedure analogous to that described in Step 2 of Example 107, substituting 4-bromo nitroaniline for 5-bromonitroaniline used in Example 107. 1H NMR (300 MHz, DMSO-d6) 5 8.84 (t, J: 6.0 Hz, 1H), 8.19 (d, J: 2.4 Hz, 1H), 7.98 (s, 1H), 7.81 (d, J = 8.3 Hz, 1H), 7.56 (dd, J: 2.4, 9.3 Hz, 1H), 7.46 (d, J: 8.3 Hz, 1H), 6.88 (d, J: 9.2 Hz, 1H), 4.75 (d, J: 6.0 Hz, 2H), 2.77 (s, 3H); LCMS (ESI) m/z 410, 412 (M+H)+.

Step 2: 4-Bromo-N1-((2-(methylthio)benzo[d]thiazolyl)methyl)benzene- 1,2-diamine was sized as a red oil using a ure analogous to that described in Step 2 of Example 41, substituting 4-bromo-N-((2- (methylthio)benzo[d]thiazolyl)methyl)nitroaniline from the preVious step for 4- bromomethoxy-N-((2-(methylthio)benzo[d]thiazolyl)methyl)nitroaniline used in Example 41. LCMS (ESI) m/Z 380, 382 (M+H)+.

Step 3: 6-((5-Bromo-1H—benzo[d]imidazolyl)methyl) (methylthio)benzo[d]thiazole was synthesized as a white solid (630 mg, 62% over two steps) using a procedure analogous to that described in Step 3 of Example 41, substituting 4-bromo-N1-((2-(methylthio)benzo[d]thiazolyl)methyl)benzene- 1 ,2- diamine from the preVious step for omethoxy-N1-((2- (methylthio)benzo[d]thiazolyl)methyl)benzene-1,2-diamine used in Example 41. 1H NMR (300 MHz, DMSO-d6) 8 8.51 (s, 1H), 8.00 (s, 1H), 7.87 (d, J: 1.7 Hz, 1H), 7.81 (d, J: 8.5 Hz, 1H), 7.54 (d, J: 8.5 Hz, 1H), 7.33 — 7.45 (m, 2H), 5.62 (s, 2H), 2.77 (s, 3H); LCMS (ESI) m/Z 390, 392 (M+H)+.

Step 4: 6-((5-Bromo-1H—benzo[d]imidazolyl)methyl) (methylsulfinyl)benzo[d]thiazole was synthesized as a white foam (830 mg) using a procedure analogous to that described in Step 6 of Example 36, substituting 6-((5- bromo- 1H-benzo [d]imidazolyl)methyl)(methylthio)benzo [d]thiazole from the previous step for 6-((4-bromo-1H-imidazolyl)methyl) (methylthio)benzo[d]thiazole used in e 36. LCMS (ESI) m/Z 405, 407 (M+H)+.

Step 5: To a sion of 6-((5-bromo-1H—benzo[d]imidazol hyl)(methylsulfinyl)benzo[d]thiazole (655 mg, 1.6 mmol) and (1R,2R) aminocyclohexanol (558 mg, 4.8 mmol) in anhydrous DMA (3.0 mL) was added DIEA (842 uL, 4.8 mmol). The mixture was heated in a sealed tube at 110 °C for 18 h. The mixture was cooled to rt and added dropwise to a stirred solution of water causing a itate to form. After stirring for 10 min, the solid was collected by 2012/059983 filtration to afford (1R,2R)((6-((5-bromo-1H—benzo[d]imidazol yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol (837 mg) as a tan solid. The material was used in the next step without further purification. 1H NMR (300 MHz, DMSO-d6) 5 8.46 (s, 1H), 7.97 (d, J: 7.5 Hz, 1H), 7.85 (d, J: 1.7 Hz, 1H), 7.65 (s, 1H), 7.54 (d, J: 8.5 Hz, 1H), 7.26 - 7.39 (m, 2H), 7.19 (m, 1H), 5.47 (s, 2H), 4.74 (d, J: 5.1 Hz, 1H), 3.51 (m, 1H), 3.32 (m, 1H), 2.01 (m, 1H), 1.87 (m, 1H), 1.55 —1.67 (m, 2H), 1.13 — 1.32 (m, 4H); LCMS (ESI) m/z 457, 459 (M+H)+.

Step 6: 1-((2-(((1R,2R)Hydroxycyclohexyl)amino)benzo[d]thiazol yl)methyl)-1H—benzo[d]imidazolecarbonitrile was synthesized as a white powder (32 mg, 6%) using a procedure analogous to that described in Step 1 of Example 53, substituting )((6-((5-bromo-1H—benzo[d]imidazol yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol from the preVious step for )((6-((6-bromomethoxy- 1H-benzo[d]imidazol yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol used in Example 53. The product was further purified by silica gel flash chromatography eluting with 5% MeOH in CHzClz. 1H NMR (300 MHz, DMSO-d6) 8 8.66 (s, 1H), 8.22 (s, 1H), 7.98 (d, J: 7.5 Hz, 1H), 7.79 (d, J: 8.5 Hz, 1H), 7.68 (s, 1H), 7.62 (m, 1H), 7.29 (m, 1H), 7.21 (m, 1H), 5.54 (s, 2H), 4.73 (d, J: 5.3 Hz, 1H), 3.51 (m, 1H), 3.33 (m, 1H), 2.03 (m, 1H), 1.88 (m, 1H), 1.56 — 1.67 (m, 2H), 1.10 — 1.35 (m, 4H); LCMS (ESI) m/z 404 (M+H)+.

Example 109 Pre aration of IR 2R 6- 6- 2-h drox r0 an l-3H-imidaz0 4 5- b ridin lmeth lbenzo thiazol-Z- lamino c anol é‘NU>_NHS N s0H Step 1: To a stirred solution of methyl 3-((2-(methylthio)benzo[d]thiazol- 6-yl)methyl)-3H-imidazo[4,5-b]pyridinecarboxylate (253 mg, 0.684 mmol) from Step 3 of Example 79 in a mixture of ous DCM (2.5 mL) and anhydrous THE (6.4 mL) at 0 CC under an inert atmosphere was added dropwise methyl magnesium bromide (3M solution in diethyl ether, 0.49 mL, 1.47 mmol). The mixture was allowed to slowly warm to rt and stir for 1.5 h. Additional methyl magnesium bromide (3M solution in diethyl ether, 0.49 mL, 1.47 mmol) was added and the mixture was stirred at rt for an onal 48 h. onal methyl magnesium bromide (3M solution in diethyl ether, 0.25 mL, 0.74 mmol) was added and the mixture was stirred at rt for an additional 4 h. The reaction mixture was partitioned between EtOAc and a 1:1 mixture of saturated aq NH4Cl and ted aq NaHCOg.

The organic layer was separated, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with 100% DCM to 15% MeOH in DCM to afford 2-(3-((2- (methylthio)benzo[d]thiazolyl)methyl)-3H—imidazo[4,5-b]pyridinyl)propanol (191 mg, 75%) as a solid. 1H NMR (300 MHz, DMSO-d6) 8 8.59 (s, 1H), 8.52 (d, J: 3.0 Hz, 1H), 8.12 (d, J: 3.0 Hz, 1H), 8.00 (m, 1H), 7.81 (d, J: 9.0 Hz, 1H), 7.45 (dd, J: 9.0, 3.0 Hz, 1H), 5.59 (s, 2H), 5.20 (s, 1H), 2.77 (s, 3H), 1.51 (s, 6H); LCMS (ESI) m/Z 371 (M+H)+.

] Step 2: 2-(3-((2-(Methylsulfinyl)benzo[d]thiazolyl)methyl)-3H- imidazo[4,5-b]pyridinyl)propanol (140 mg, 70%) was obtained as a yellow solid using a procedure analogous to that described in Step 5 of Example 3, substituting 2- (3 -((2-(methylthio)benzo[d]thiazolyl)methyl)-3H—imidazo[4,5-b]pyridin yl)propanol from Step 1 of this Example for 6-((3H-imidazo[4,5-b]pyridin yl)methyl)(methylthio)benzo[d]thiazole used in Example 3. LCMS (ESI) m/Z 387 Step 3: )((6-((6-(2-Hydroxypropanyl)-3H—imidazo[4,5- b]pyridinyl)methyl)benzo[d]thiazolyl)amino)cyclohexanol (17 mg, 11%) was obtained as a solid using a procedure analogous to that described in Step 5 of Example 70, substituting 2-(3-((2-(methylsulfinyl)benzo[d]thiazolyl)methyl)-3H— imidazo[4,5-b]pyridinyl)propanol from Step 2 of this Example for 6-((6-fluoro- 3H—imidazo[4,5-b]pyridinyl)methyl)(methylsulfinyl)benzo[d]thiazole used in e 70. 1H NMR (300 MHZ, DMSO-d6) 8 8.54 (s, 1H), 8.53 (d, J: 3.0 Hz, 1H), 8.10 (d, J: 3.0 Hz, 1H), 7.97 (d, J: 6.0 Hz, 1H), 7.66 (m, 1H), 7.19 — 7.30 (m, 2H), .46 (s, 2H), 5.22 (br s, 1H), 4.76 (br d, J: 3.0 Hz, 1H), 3.50 (m, 1H), 3.30 (m, 1H), 2.03 (m, 1H), 1.86 (m, 1H), 1.60 — 1.70 (m, 2H), 1.51 (s, 6H), 1.15 — 1.30 (m, 4H); LCMS (ESI) m/Z 438 (M+H)+.

Example 110 Pre aration of 1- 1- 2— 1R 2R h drox c clohex lamino benzo thiazol l meth l -1H-benzo imidazol—S- l ethanone A stirred suspension of (1R,2R)((6-((5-bromo-1H—benzo[d]imidazol yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol (150 mg, 0.33 mmol) from Step of e 108 and tributyl(1-ethoxyVinyl)tin (177 mg, 0.5 mmol) in DMA (1.5 mL) was purged with a stream of argon for 5 min. To the mixture was added tetrakis(triphenylphosphine)palladium (0) (57 mg, 0.05 mmol) and argon was bubbled into the mixture for an additional 5 min. The reaction vessel was sealed and the mixture was heated at 110 0C for 3 h. The mixture was cooled to rt. To the mixture was added 0.5 M aq HCl (500 uL) ed by stirreing at rt for 12 h. The mixture was filtered, and the filtrate was d directly by reverse-phase preparative HPLC using a mixture of water (5% CH3CN, 0.05% HCOOH) and CH3CN (0.05% HCOOH) as the mobile phase and a Varian t XRs C18 column as the stationary phase. The product was fithher purified by silica gel flash chromatography eluting with 5% MeOH in CHzClz to afford 1-(1-((2-(((1R,2R) hydroxycyclohexyl)amino)benzo[d]thiazolyl)methyl)— zo[d]imidazol-5 - yl)ethanone (11 mg, 8%) as a white powder. 1H NMR (300 MHZ, DMSO-d6) 8 8.57 (s, 1H), 8.32 (s, 1H), 7.97 (d, J: 7.5 Hz, 1H), 7.85 (d, J: 8.5 Hz, 1H), 7..64 — 7.72 (m, 2H), 7.30 (m, 1H), 7.20 (m, 1H), 5.52 (s, 2H), 4.73 (d, J: 5.1 Hz, 1H), 3.52 (m, 1H), 3.34 (m, 1H), 2.62 (s, 3H), 2.02 (m, 1H), 1.90 (m, 1H), 1.55 — 1.69 (m, 2H), 1.10 — 1.35 (m, 4H); LCMS (ESI) m/Z 421 (M+H)+.

Example 111 Pre aration of 1- 2— 1R 2R h drox c clohex lamino benzo thiazol l meth l -1H-benz0 d imidazolecarb0nitrile N&:l©::©/>—NH OH 1 -((2-(((1R,2R)Hydroxycyclohexyl)amino)benzo[d]thiazol yl)methyl)-1H—benzo[d]imidazolecarbonitrile was synthesized as a white powder (23 mg, 13%) using a procedure analogous to that bed in Step 6 of Example 108, substituting (1R,2R)((6-((6-bromo-1H—benzo[d]imidazol yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol from Step 6 of Example 107 for (1R,2R)((6-((5-bromo-1H—benzo[d]imidazolyl)methyl)benzo[d]thiazol yl)amino)cyclohexanol used in Example 108. 1H NMR (300 MHZ, DMSO-d6) 8 8.70 (s, 1H), 8.27 (s, 1H), 8.01 (d, J: 7.3 Hz, 1H), 7.83 (d, J: 8.3 Hz, 1H), 7.73 (s, 1H), 7.58 (d, J: 8.5 Hz, 1H), 7.23 — 7.35 (m, 2H), 5.53 (s, 2H), 4.76 (d, J: 4.5 Hz, 1H), 3.51 (m, 1H), 2.50 (m, 1H), 2.03 (m, 1H), 1.87 (m, 1H), 1.55 — 1.67 (m, 2H), 1.13 — 1.31 (m, 4H); LCMS (ESI) m/Z 404 .

Example 112 Pre aration of IR 2R 6- 5— meth lsulfon l -1H-benzo d imidazol-l- l meth lbenzo thiazol-Z- 1 amino c clohexanol W S N2:! />—NH §OH N , .

O:S~ A d suspension of (1R,2R)((6-((5-bromo-1H—benzo[d]imidazol yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol (100 mg, 0.22 mmol) (prepared as described in Example 108, steps 1 through 6), sodium methane sulfinate (89 mg, 0.9 mmol) and methylethylenediamine (9.6 uL, 0.9 mmol) was degassed under a stream of argon for 5 min. Copper (1) trifluoromethane-sulfonate benzene complex (22 mg, 0.04 mmol) was added and the mixture was sealed and heated at 125 CC for 7 h. The mixture was cooled to rt, d, and the filtrate subjected to purification by reverse-phase preparative HPLC eluting with a mixture of water (5% CH3CN, 0.05% HOAc) and CH3CN (0.05% HOAc) as the mobile phase and a Varian diphenyl column as the stationary phase, to afford (1R,2R)((6-((5-(methylsulfonyl)-1H- benzo [d]imidazolyl)methyl)benzo[d]thiazolyl)amino)cyclohexanol (30 mg, %) as a white powder. 1H NMR (300 MHz, DMSO-d6) 8 8.69 (s, 1H), 8.20 (s, 1H), 8.06 (d, J: 7.5 Hz, 1H), 7.84 (m, 1H), 7.76 (m, 1H), 7.69 (s, 1H), 7.30 (m, 1H), 7.21 (m, 1H), 5.56 (s, 2H), 4.82 (m, 1H), 3.50 (m, 1H), 3.36 (m, 1H), 3.19 (s, 3H), 2.01 (m, WO 56070 1H), 1.87 (m, 1H), 1.56 — 1.67 (m, 2H), 1.11 — 1.31 (m, 4H); LCMS (ESI) m/Z 457 (M+H)+.

Example 113 Pre aration of IR 2R 6- 6- meth lsulfon l -1H-benzo d imidazol-l- l meth lbenzo thiazol-Z- 1 amino c clohexanol “IQ/F20/>—NH OH 08”\ (1R,2R)((6-((6-(Methyolsulfonyl)- 1H—benzo[d]imidazol yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol was synthesized as a white powder (22 mg, 26%) using a procedure ous to that bed in Example 112, substituting )((6-((6-bromo-1H—benzo[d]imidazol yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol (as prepared in Example 107, steps 1 through 6) for (1R,2R)((6-((5-bromo-1H—benzo[d]imidazol yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol used in Example 112. 1H NMR (300 MHz, DMSO-d6) 5 8.69 (s, 1H), 8.21 (s, 1H), 8.01 (d, J: 7.3 Hz, 1H), 7.89 (d, J = 8.5 Hz, 1H), 7.75 (m, 1H), 7.67 (d, J: 1.1 Hz, 1H), 7.32 (m, 1H), 7.20 (m, 1H), .60 (s, 2H), 4.76 (d, J: 4.3 Hz, 1H), 3.51 (m, 1H), 3.35 (m, 1H), 3.21 (s, 3H), 2.02 (m, 1H), 1.88 (m, 1H), 1.55 — 1.67 (m, 2H), 1.13 — 1.34 (m, 4H); LCMS (ESI) m/z 457 (M+H)+.

Example 114 Pre aration of IR 2R 6- 3H-imidaz0 4 5-b ridin l meth l thiazolo 4 5-b ridin-Z- 1 amino c clohexanol Step 1: A mixture of ethyl 6-aminobromon1cotinate (1.0 g, 4 mmol) and O-ethylxanthic acid potassium salt (785 mg, 4.2 mmol) in DMF (15 mL) was heated at reflux for 6 h. The mixture was cooled to rt and was partitioned between EtOAc (200 mL) and 1 M aq Na2C03 (150 mL). A solid formed between the two layers and was ted by filtration. The layers were separated and the organic layer was concentrated under reduced pressure until a slurry began to form. The mixture was cooled to 0 oC and the resulting solid was collected by filtration. The two solid batches were combined to afford ethyl 2-mercaptothiazolo[4,5-b]pyridine carboxylate potassium salt (871 mg, 89%), which did not require further purification. 1H NMR (300 MHz, DMSO-d6) 8 8.69 (d, J: 2.1 Hz, 1H), 8.19 (d, J: 2.1 Hz, 1H), 4.29 (q, J: 7.0 Hz, 2H), 1.31 (t, J: 7.1 Hz, 3H); LCMS (ESI) m/z 241 (M+H)+.

Step 2: To a stirred mixture of ethyl 2-mercaptothiazolo[4,5-b]pyridine carboxylate ium salt (1.7 g, 6.6 mmol) from the previous step in DMF (10 mL) at 0 0C was added iodomethane (226 uL, 3.6 mmol). After the mixture was stirred at 0 0C for 2 h, it was allowed to warm slowly to rt. The mixture was partitioned between EtOAc (100 mL) and 0.5 M aq N32C03 (50 mL). The organic layer was separated and washed with brine (50 mL), dried over MgZSO4, filtered, and concentrated under reduced pressure to afford ethyl 2-(methylthio)thiazolo[4,5-b]pyridinecarboxylate (724 mg, 82%) as a yellow solid. The al was used in the next step without further cation. 1H NMR (300 MHz, DMSO-d6) 8 9.07 (s, 2H), 4.38 (q, J = 7.0 Hz, 2H), 2.86 (s, 3H), 1.36 (t, J: 7.1 Hz, 3H); LCMS (ESI) m/z 255 (M+H)+.

Step 3: (2-(Methylthio)thiazolo[4,5-b]pyridinyl)methanol was synthesized as a white solid (404 mg, 67%) using a procedure analogous to that described in Step 3 of Example 36, substituting ethyl 2-(methylthio)thiazolo[4,5- b]pyridinecarboxylate from the us step for ethyl 2- (methylthio)benzo[d]thiazolecarboxylate used in e 36. 1H NMR (300 MHZ, DMSO-d6) 5 8.51 (d, J: 1.9 Hz, 1H), 8.42 (d, J: 1.9 Hz, 1H), 5.44 (t, J: 5.7 Hz, 1H), 4.63 (d, J: 5.7 Hz, 2H), 2.82 (s, 3H); LCMS (ESI) m/z 213 (M+H)+.

Step 4: To a stirred mixture of (2-(methylthio)thiazolo[4,5-b]pyridin yl)methanol (404 mg, 2 mmol) in anhydrous CHzClz (20 mL) at rt was added SOClz (166 uL, 2.4 mmol). After 3 h, the mixture was concentrated under reduced re to afford 6-(chloromethyl)(methylthio)thiazolo[4,5-b]pyridine (497 mg) as a white solid. The material was used in the next step t further purification. 1H NMR (300 MHz, DMSO-d6) 8 8.65 (d, J: 1.9 Hz, 1H), 8.60 (d, J: 1.9 Hz, 1H), 4.95 (s, 2H), 2.83 (s, 3H); LCMS (ESI) m/Z 231 (M+H)+.

Step 5: To a stirred mixture ofDMF (5 mL) and sodium hydride (60% in mineral oil, 64 mg, 1.6 mmol) at 0 CC under argon, was added 4-azabenzimidazole (204 mg, 1.1 mmol) in one portion. The mixture was stirred for 5 min at 0 CC followed by dropwise addition of a solution of 6-(chloromethyl) (methylthio)thiazolo[4,5-b]pyridine (497 mg, 2.2 mmol) in DMF (2 mL). The mixture was warmed slowly to rt then heated at 70 0C for 18 h. The mixture was cooled to rt, then partitioned between EtOAc (150 mL) and 0.5 M aq N32C03 (50 mL). The organic layer was separated and washed with water (50 mL), then brine, dried over NazSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with a gradient of 100% CHzClz to 5% MeOH in DCM to afford -imidazo[4,5-b]pyridinyl)methyl) (methylthio)thiazolo[4,5-b]pyridine (126 mg, 35%) as a yellow solid. The regiochemistry of the alkylation was determined by nsional nuclear Overhauser effect (NOE) experiment. 1H NMR (300 MHz, DMSO-d6) 8 8.64 - 8.74 (m, 2H), 8.46 (d, J: 2.1 Hz, 1H), 8.38 (dd, J: 1.1, 4.7 Hz, 1H), 8.12 (dd, J: 1.3, 8.1 Hz, 1H), 7.31 (dd, J: 4.7, 8.1 Hz, 1H), 5.67 (s, 2H), 2.80 (s, 3H); LCMS (ESI) m/z 314 (M+H)+.

Step 6: —Imidazo[4,5-b]pyridinyl)methyl) (methylsulf1nyl)thiazolo[4,5-b]pyridine was synthesized as a white foam (135 mg) using a procedure ous to that described in Step 6 of Example 36, substituting 6- ((3H—imidazo[4,5-b]pyridinyl)methyl)(methylthio)thiazolo[4,5-b]pyridine from the preVious step for bromo-1H—imidazolyl)methyl) (methylthio)benzo[d]thiazole used in Example 36. LCMS (ESI) m/Z 330 (M+H)+.

Step 7: (1R,2R)—2-((6-((3H—Imidazo[4,5-b]pyridin yl)methyl)thiazolo[4,5-b]pyridinyl)amino)cyclohexanol was synthesized as a white powder (80 mg, 53%) using a procedure analogous to that described in Step 7 of Example 36, substituting 6-((3H—imidazo[4,5-b]pyridinyl)methyl) (methylsulf1nyl)thiazolo[4,5-b]pyridine from the us step for 6-((4-bromo-1H— imidazolyl)methyl)(methylsulf1nyl)benzo[d]thiazole used in Example 36. 1H NMR (300 MHz, DMSO-d6) 8 8.62 (s, 1H), 8.46 (d, J: 7.5 Hz, 1H), 8.39 (dd, J: 1.2, 4.8 Hz, 1H), 8.33 (d, J: 2.1 Hz, 1H), 8.09 (dd, J: 1.3, 8.1 Hz, 1H), 8.05 (d, J: 2.1Hz, 1H), 7.30 (m, 1H), 5.50 (s, 2H), 4.82 (d, J: 5.3 Hz, 1H), 3.61 (m, 1H), 3.35 (m, 1H), 2.03 (m, 1H), 1.88 (m, 1H), 1.55 — 1.70 (m, 2H), 1.15 — 1.33 (m, 4H); LCMS (ESI) m/Z 381 (M+H)+.

Example 115 Pre aration of IR 2R 6- 6— R S h drox eth l -3H-imidaz0 4 5- b ridin lmeth lbenzo thiazol-Z- lamino c clohexanol //\NU)—NHS N §OH To a stirred solution of 1-(3-((2-(((1R,2R) hydroxycyclohexyl)amino)benzo[d]thiazolyl)methyl)—3H—imidazo[4,5-b]pyridin yl)ethanone (92 mg, 0.22 mmol) from Example 73, MeOH (5 mL) and DMF (3 mL) at rt was added sodium borohydride (17 mg, 0.44 mmol). The mixture was stirred at rt for 15 min. The reaction mixture was purified directly by reverse-phase HPLC using a mixture of water (5% CH3CN, 0.05% HOAc) and CH3CN (0.05% HOAc) as the mobile phase and Varian Pursuit XRs diphenyl column as the stationary phase to afford (1R,2R)((6-((6-((R,S)hydroxyethyl)-3H—imidazo[4,5 idin-3 - hyl)benzo[d]thiazolyl)amino)cyclohexanol (38 mg, 41%) as a white solid. 1H NMR (300 MHz, DMSO-d6) 8 8.55 (s, 1H), 8.37 (d, J: 1.5 Hz, 1H), 7.97 — 8.00 (m, 2H), 7.66 (m, 1H), 7.28 (d, J: 6.0 Hz, 1H), 7.20 (dd, J: 6.0, 3.0 Hz, 1H), 5.46 (s, 2H), 5.30 (br m, 1H), 4.90 (m, 1H), 4.76 (br m, 1H), 3.50 (m, 1H), 3.30 (m, 1H), 2.03 (m, 1H), 1.87 (m, 1H), 1.55 — 1.65 (m, 2H), 1.40 (d, J: 6.0 Hz, 3H), 1.10 — 1.30 (m, 4H). LCMS (ESI) m/Z 424 (M+H)+.

Example 116 Pre aration of 2- dimeth lamino 3- 2— 1R 2R h drox c clohex lamino benzo thiazol—6- lmeth midaz0 4 5- b ridin l ethanone acetate salt é\N S N UkNH s0H Step 1: A stirred mixture of (1R,2R)((6-((6-bromo-3H—imidazo[4,5- dinyl)methyl)benzo[d]thiazolyl)amino)cyclohexanol (693 mg, 1.51 mmol) from Example 29, tributyl (1-ethoxyVinyl)tin (1.10 g, 3.03 mmol) and DMF (10 mL) was purged with argon. To the mixture was added tetrakis(triphenylphosphine)palladium (0) (262 mg, 0.23 mmol). The reaction vessel was sealed and the mixture was heated at 110 CC for 2 h. The mixture was allowed to cool to rt. The mixture was partitioned between water and DCM and the organic layer was separated. The aqueous layer was extracted with additional DCM. The combined organic layers were washed with water then brine, dried over magnesium sulfate, filtered, and concentrated under reduced re. The residue was purified by silica gel flash chromatography g with 100% DCM to 15% MeOH in DCM to afford (1R,2R)((6-((6-(1-ethoxyVinyl)-3H-imidazo[4,5-b]pyridin—3- yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol (320 mg, 47%) as a solid. LCMS (ESI) m/Z 450 (M+H)+.

] Step 2: To a stirred solution of )((6-((6-(1-ethoxyVinyl)-3H- imidazo[4,5-b]pyridinyl)methyl)benzo[d]thiazolyl)amino)cyclohexanol (90 mg, 0.20 mmol) from the preVious step in DMF (2 mL) at 0 °C was added N- bromosuccinimide (36 mg, 0.20 mmol), and the mixture was stirred for 15 min. To the mixture was added dimethylamine (2M in THF, 0.90 mL, 1.80 mmol) and stirring was continued at 0 CC for 5 min. The reaction mixture was purified directly by reverse-phase HPLC using a mixture of water (5% CH3CN, 0.05% HOAc) and CH3CN (0.05% HOAc) as the mobile phase and Varian t XRs diphenyl column as the stationary phase to afford 2-(dimethylamino)(3-((2-(((1R,2R) hydroxycyclohexyl)amino)benzo[d]thiazolyl)methyl)—3H—imidazo[4,5-b]pyridin yl)ethanone acetate salt (5 mg, 5%) as a white solid. 1H NMR (300 MHZ, 6) 8 9.01 (d, J: 1.7 Hz, 1H), 8.75 (s, 1H), 8.67 (d, J: 1.7 Hz, 1H), 8.03 (d, J: 7.5 Hz, 1H), 7.68 (s, 1H), 7.20 - 7.32 (m, 2H), 5.52 (s, 2H), 4.80 (br s, 1H), 3.78 (s, 2H), 3.51 (br m, 1H), 3.30 (br m, 1H), 2.25 (s, 6H), 2.04 (br m, 1H), 1.82 — 1.86 (m, 4H), 1.59 — 1.65 (br m, 2H), 1.10 — 1.60 (m, 4H); LCMS (ESI) m/z 465 (M+H)+.

Example 117 Pre aration of 3- 2- 1R 2R h drox c clohex lamino benzo thiazol yllmethyllimidazo|1,2-a|pyridine—7—carb0nitrile N\ N N/>—NH §OH \ / O Step 1: A mixture of 2-fluoroiodoaniline (2.4 g, 10 mmol) and sodium O-ethyl carbonodithioate (3.2 g, 20 mmol) in DMF (8 mL) was stirred at 95 0C for 5 h. The reaction mixture was cooled to rt then diluted with water (25 mL) and 1 N aqueous HCl (20 mL). The mixture was stirred at room temperature for 1 h. The resulting precipitate was collected by ion and washed with water. The solid was dried to afford 6-iodobenzo[d]thiazolethiol as a light yellow solid (3.3 g, 100%). 1H NMR (300 MHz, CDgOD) 8 7.89 (d, J: 1.2 Hz, 1H), 7.67 (dd, J: 1.8, 8.7 Hz, 1H), 7.05 (d, J: 8.4 Hz, 1H). LCMS (ESI) m/z 294 (M+H)+.

] Step 2: To a stirred mixture of 6-iodobenzo[d]thiazolethiol (0.5 g, 1.7 mmmol) and potassium carbonate (0.23 g, 1.7 mmol) in THF (10 mL) was added methyl iodide (0.12 mL, 1.1 mmol). After stirring at rt ght, the mixture was concentrated under d pressure to give a solid. The solid was partitioned between saturated aq sodium carbonate and DCM. The organic layer was dried over Na2S04 and ed, and concentrated under reduced pressure to give 6-iodo (methylthio)benzo[d]thiazole as a off-white solid (0.4 g, 76%). 1H NMR (300 MHZ, CDC13)5 8.07 (d, J: 1.2 Hz, 1H), 7.69 (dd, J: 1.8, 8.4 Hz, 1H), 7.58 (d, J: 8.4 Hz, 1H), 2.78 (s, 3H). LCMS (ESI) m/Z 308 (M+H)+.

Step 3: A e of 6-iodo(methylthio)benzo[d]thiazole (5.0 g, 16.3 mmol), allyl alcohol (2.2 mL, 32.6 mmol), Pd(OAc)2 (0.36 g, 1.63 mmol), tris(o-tolyl) phosphine (1.0 g, 3.3 mmol) and NaHCOg (2.8 g, 32.6 mmol) in DMF (75 mL) was stirred at 100 0C under nitrogen atmosphere for 4 h. Then the mixture was cooled to rt and water (300 mL) was added. The mixture was extracted with EtOAc (200 mL>< 3). The combined organic layers were washed with brine, dried over Na2S04, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography g with : 1 to 5: 1 petroleum ether/EtOAc to afford 3-(2- (methylthio)benzo[d]thiazolyl)propanal as a dark yellow oil (2.0 g, 52%). 1H NMR (300 MHz, CDC13)5 9.83 (t, J: 1.2 Hz, 1H), 7.78 (d, J=8.4 Hz, 1H), 7.58 (d, J = 1.2 Hz, 1H), 7.23 (dd, .1: 1.8, 8.4 Hz, 1H), 3.05 (t, .1: 7.5 Hz, 2H), 2.85 (t, .1: 7.5 Hz, 2H), 2.78 (s, 3H). LCMS (ESI) m/Z 238 (M+H)+.

Step 4: L-proline (0.22 g, 1.9 mmol) was added to a solution of 3-(2- lthio)benzo[d]thiazolyl)propanal (2.3 g, 9.7 mmol) in DCM (40 mL) at 0 0C followed by addition ofN—chlorosuccinimide (1.4 g, 10 mmol). The reaction mixture was slowly warmed to ambient temperature and stirred overnight. The reaction mixture was concentrated under reduced pressure and purified by silica gel chromatography, eluting with 10: 1 to 2: 1 petroleum EtOAc to afford ro(2-(methylthio)benzo[d]thiazolyl)propanal as a yellow oil (2.1 g, 79%). 1H NMR (300 MHz, CDClg) 8 9.56 (dd, J: 1.2, 2.1 Hz, 1H), 7.81 (d, J: 8.4 Hz, 1H), 7.63 (d, J: 0.6 Hz, 1H), 7.28 (d, J: 1.5 Hz, 1H), 4.44-4.39 (m, 1H), 3.51- 3.44 (m, 1H), 3.20-3.13 (m, 1H), 2.78 (s, 3H). LCMS (ESI) m/z 290 (M+18+H)+.

Step 5: A mixture of 4-bromopyridinamine (4.9 g, 28.5 mmol), Zn(CN)2 (5.0 g, 42.5 mmol), Pd2(dba)3 (1.3 g, 1.4 mmol) and dppf(1.6 g, 2.8 mmol) in DMF (150 mL) was stirred at 100 0C under nitrogen here for 1.5 h. The mixture was cooled to rt and water (500 mL) was added. The mixture was extracted with EtOAc (300 mL>< 3). The combined organic layers were washed with brine, dried over , filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 10: 1 to 2: 1 petroleum ether/EtOAc to afford 2-aminoisonicotinonitrile as a light yellow solid (2.7 g, 80%). 1H NMR (300 MHz, CDC13)8 8.19 (d, J: 5.1 Hz, 1H), 6.82 (d, J: 4.8 Hz, 1H), 6.69 (d, J: 0.9 Hz, 1H), 4.72 (br s, 2H). LCMS (ESI) m/z 120 (M+H)+.

Step 6: A mixture of 2-chloro(2-(methylthio)benzo[d]thiazol yl)propanal (0.35 g, 1.3 mmol) and 2-aminoisonicotinonitrile (0.30 g, 2.6 mmol) in 1- butanol (15 mL) was heated at reflux overnight. After g to rt, the formed solid was collected and washed with water, then dried to afford 3-((2-(methylthio)benzo[d] thiazolyl)methyl)imidazo[1,2-a]pyridinecarbonitrile as a white solid (0.27 g, 62%). 1H NMR (300 MHz, CDClg) 8 8.45 (d, J: 7.2 Hz, 1H), 8.34 (s, 1H), 7.90 (s, 1H), 7.78 (d, J: 8.7 Hz, 1H), 7.75 (s, 1H), 7.37 (dd, J: 1.2, 7.8 Hz, 1H), 7.20 (dd, J = 1.8, 7.2 Hz, 1H), 4.49 (s, 2H), 2.77 (s, 3H). LCMS (ESI) m/z 337 (M+H)+.

Step 7: To a solution of 3-((2-(methylthio)benzo[d]thiazol yl)methyl)imidazo[1,2-a]pyridinecarbonitrile (0.27 g, 0.8 mmol) in DCM (15 mL) was added m-CPBA (0.17 g, 0.9 mmol) at 0 0C. The reaction mixture was stirred for 2 h at 0 0C, then aq Na2S03 (15 mL) was added and the mixture was stirred for 0.5 h.

The organic layer was separated, dried over Na2S04, filtered and concentrated under d re to afford 3-((2-(methylsulfinyl)benzo[d] thiazol yl)methyl)imidazo[1,2-a]pyridinecarbonitrile as a yellow solid (0.28 g, 99%). 1H NMR (300 MHz,CDC13)5 8.46 (d, J: 7.2 Hz, 1H), 8.36 (s, 1H), 8.15 (d, J = 1.2 Hz, 1H), 8.04 (d, J: 8.7 Hz, 1H), 7.78 (s, 1H), 7.55 (dd, J: 1.5, 8.4 Hz, 1H), 7.21 (dd, J: 1.8, 7.2 Hz, 1H), 4.57 (s, 2H), 3.06 (s, 3H). LCMS (ESI) m/z 353 (M+H)+.

Step 8: A mixture of 3-((2-(methylsulfinyl)benzo[d]thiazol yl)methyl) imidazo[1,2-a]pyridinecarbonitrile (0.20 g, 0.56 mmol), (1R,2R) amino cyclohexanol (97 mg, 0.84 mmol) and DIEA (0.18 g, 1.4 mmol) in DMA (10 mL) was stirred for 2 d at 140 0C. The mixture was cooled to rt and water (50 mL) was added. The mixture was extracted with EtOAc (30 mL>< 3). The combined organic layers were washed with brine, dried over Na2S04, filtered and concentrated under d pressure. The residue was purified by silica gel chromatography eluting with 50: 1 to 10: 1 DCM/MeOH to afford a solid, which was recrystallized in 10:1 DCM/ MeOH (10 mL) to afford 3-((2- (((1R,2R)hydroxycyclohexyl)amino)benzo[d]thiazol hyl)imidazo[1,2-a]pyridinecarbonitrile as a white solid (75 mg, 33%). 1H NMR (300 MHz, DMSO-d6) 5 8.40 (d, J: 6.9 Hz, 1H), 8.32 (s, 1H), 7.88 (d, J: 6.9 Hz, 1H), 7.72 (s, 1H), 7.53 (s, 1H), 7.27 (d, J: 8.1 Hz, 1H), 7.19 (d, J: 6.9 Hz, 1H), 7.09 (d, J: 7.5 Hz, 1H), 4.73 (d, J: 4.2 Hz, 1H), 4.36 (s, 2H), .50 (m, 1H), 3.37-3.34 (m, 1H), .01 (m, 1H), 1.90-1.86 (m, 1H), 1.65-1.59 (m, 2H), 1.30-1.16 (m, 4H). LCMS (ESI) m/Z 404 (M+H)+.

Example 118 Pre aration of IR 2R 6- 9H- urin lmeth lbenzo d oxazol-Z- 1 aminocclohexanol 2K1”55’ Step 1: A solution of pyrimidine-4,5-diamine (718 mg, 6.53 mmol) and HCOOH (0.36 mL) in triethoxymethane (19 mL) was stirred at 90 0C for 3.5 h. The reaction mixture was concentrated under d pressure. The e was purified by silica gel tography eluting with 40:1 DCM/MeOH to give 9H-purine as a brown solid (784 mg, 100%). 1H NMR (300 MHz, DMSO-d6) 8 13.40 (br s, 1H), 9.12 (s, 1H), 8.92 (s, 1H), 8.60 (s, 1H). LCMS (ESI) m/z 121 (M+H)+.

Step 2: To a stirred solution of 9H-purine (784 mg, 6.53 mmol) in DMF ( 16 mL) was added NaH (60% dispersion in mineral oil, 373 mg, 9.33 mmol,) portionwise at 0 0C. After stirring for 30 min, 6-(chloromethyl) (methylthio)benzo[d]oxazole (1.3 g, 6.22 mmol) was added to the mixture. The reaction mixture was allowed to warm to rt and stir for 3 h. The reaction mixture was poured into water (150 mL) and extracted with ethyl acetate (150 mL><4). The combined organic layers were washed with water and brine, dried over NazSO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography g with 40:1 DCM/MeOH to give 6-((9H-purin yl)methyl)(methylthio)benzo[d] oxazole as a light yellow solid (569 mg, 32.7%). 1H NMR (300 MHz, 6) 8 9.14 (s, 1H), 8.92 (s, 1H), 8.77 (s, 1H), 7.69 (s, 1H), 7.56 (d, J: 7.8 Hz, 1H), 7.35 (d, J: 9.0 Hz,1H), 5.59 (s, 2H), 2.70 (s, 3H).

LCMS (ESI) m/Z 298 (M+H)+.

] Step 3: A mixture of 6-((9H-purinyl)methyl) (methylthio)benzo[d]oxazole (400 mg, 1.35 mmol) and m-CPBA (289 mg, 1.69 mmol) in DCM (25 mL) was stirred at 0 0C for 6 h. The reaction mixture was washed with aq Na2S203 and brine, dried over NazSO4, filtered and concentrated under reduced pressure. The residue was d by silica gel chromatography eluting with 1:5 petroleum ether/ethyl acetate to give 6-((9H-purinyl)methyl) (methylsulfinyl)benzo[d]oxazole as a light yellow solid (143 mg, 33.89%). 1H NMR (300 MHz,CDC13)8 9.18 (s, 1H), 9.03 (s, 1H), 8.13 (s, 1H), 7.82 (d, J: 8.4 Hz, 1H), 7.66 (s, 1H), 7.44 (d, J: 9.9 Hz, 1H), 5.62 (s, 2H), 3.18 (s, 3H). LCMS (ESI) m/z 314 Step 4: A mixture of 6-((9H-purinyl)methyl) (methylsulfinyl)benzo[d]oxazole (106 mg, 0.34 mmol), (1R,2R)aminocyclohexanol (77 mg, 0.51 mg) and DIEA (132 mg, 1.02 mmol) in DMA (3 mL) was stirred at 135 0C for 2 h. The reaction mixture was cooled to rt, poured into water (30 mL) and ted with ethyl acetate (20 mL><2). The combined organic layers were washed with brine, dried over Na2S04, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 1:6 petroleum ether/ethyl acetate to give crude product, which was washed with 10:1 petroleum ether/ethyl acetate to afford (1R,2R)((6-((9H-purinyl)methyl)benzo[d]oxazol yl)amino)cyclohexanol as a light yellow solid (68 mg, 48.57%). 1H NMR (300 MHz, DMSO-d6) 5 9.16 (s, 1H), 8.96 (s, 1H), 8.73 (s, 1H), 7.79 (d, J: 7.8 Hz, 1H), 7.42 (s, 1H), 7.16 (d, J: 1.2 Hz, 1H), 7.14 (d, J: 8.1 Hz, 1H) 5.51 (s, 2H), 4.66 (d, J: 4.2 Hz, 1H), 3.34 (br s, 2H), 1.90 (br s, 2H), 1.60 (br s, 2H), 1.22 (br s, 4H). LCMS (ESI) m/Z 365 (M+H)+.

Example 119 Pre aration of IR 2R 6- 56-dimeth l-lH-benzo imidazol-l- l meth lbenzo thiazol-Z- 1 amino c clohexanol Ngfi:©/>—NH OH Step 1: To a stirred mixture of anhydrous DMF (15 mL) and sodium hydride (60% dispersion in l oil, 105 mg, 2.63 mmol) at 0 CC under nitrogen, was added portionwise 5,6-dimethyl-1H—benzo[d]imidazole (215 mg, 1.4 mmol). The on mixture was stirred for 5 min. A solution of 6-(chloromethyl) (methylthio)benzo[d]thiazole (320 mg, 1.4 mmol) from Step 4 of e 36 in ous DMF (2 mL) was added dropwise.. The reaction mixture was allowed to warm to rt and stir for 1 h. The reaction solution was poured into ice-water and extracted with EtOAc (50 mL X 3). The ed organic layers were further washed with water (20 mL), then brine (20 mL). The organic layer was separated, dried over Na2S04, d, and concentrated under reduced pressure to afford 6-((5,6-dimethyl- 1H—benzo[d]imidazolyl)methyl)(methylthio)benzo[d]thiazole (450 mg, 96%) as a yellow solid which was not purified further. 1H NMR (300 MHz, CDClg) 8 7.86 (s, 1H), 7.81 (d, J: 8.4 Hz, 1H), 7.59 (s, 1H), 7.46 (s, 1H), 7.24-7.26 (m, 1H), 7.03 (s, 1H), 5.40 (s, 2H), 2.77 (s, 3H), 2.37 (s, 3H), 2.32 (s, 3H); LCMS (ESI) m/z 340 (M + H)+.

Step 2: To a stirred solution of 6-((5,6-dimethyl-1H—benzo[d]imidazol hyl) (methylthio)benzo[d]thiazole (450 mg, 1.32 mmol) from the preVious step in DCM (20 mL) at 0 0C was added a solution of meta-chloroperbenzoic acid (270 mg, 1.32 mmol) in DCM (3 mL). After stirring for 2 h at 0 CC, the reaction solution was diluted with EtOAc (100 mL) and washed sequentially with saturated aq Na2S203, saturated aq NaHC03, and brine. The organic layer was dried over Na2S04, filtered, and concentrated under reduced pressure to afford 6-((5,6-dimethyl-1H- benzo[d]imidazolyl)methyl)(methylsulf1nyl)benzo[d]thiazole (460 mg, 98%) as a colorless solid which was not purified r. 1H NMR (300 MHz, CDClg) 8 8.01 (d, J: 8.4 Hz, 1H), 7.90 (s, 1H), 7.72 (s, 1H), 7.60 (s, 1H), 7.37 (m, 1H), 7.02 (s, 1H), .48 (s, 2H), 3.06 (s, 3H), 2.37 (s, 3H), 2.32 (s, 3H); LCMS (ESI) m/z 356 (M + H)+.

Step 3: A stirred e of 6-((5,6-dimethyl-1H—benzo[d]imidazol yl)methyl) (methylsulf1nyl)benzo[d]thiazole (150 mg, 0.42 mmol) from the previous step, (1R,2R)- 2-aminocyclohexanol (140 mg, 1.2 mmol), DIEA (540 mg, 4.2 mmol) and NMP (2 mL) was heated at 130 CC for 12 h. The reaction mixture was cooled to rt, diluted with EtOAc (30 mL) and washed with water (10 mL x 2). The c layer was separated, dried over Na2S04, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash tography eluting with 3% MeOH in DCM to afford )((6-((5,6-dimethyl-1H- benzo[d]imidazolyl)methyl)benzo[d]thiazolyl)amino)cyclohexanol (80 mg, 47%) as a white solid. 1H NMR (300 MHz, DMSO-d6) 8 8.22 (s, 1H), 7.92 (d, J: 6.0 Hz, 1H), 7.58 (m, 1H), 7.41 (s, 1H), 7.26 — 7.31 (m, 2H), 7.14 (m, 1H), 5.40 (s, 2H), 4.71 (d,J= 3.0 Hz, 1H), 3.50 (m, 1H), 3.35 (m, 1H), 2.30 (s, 6H), 2.02 (m, 1H), 1.88 (m, 1H), 1.86 — 1.90 (m, 2H), 1.12 — 1.27 (m, 4H); LCMS (ESI) m/z 407 (M + H)+.

Example 120 Pre aration of 1- 1- 2— 1R 2R h drox c clohex lamino benzo thiazol l meth l -1H-benzo imidazol—6- l ethanone 1-(1-((2-(((1R,2R)Hydroxycyclohexyl)amino)benzo[d]thiazol yl)methyl)-1H—benzo[d]imidazolyl)ethanone was synthesized as a white powder (8 mg, 6%) using a procedure analogous to that described in Example 110, substituting (1R,2R)((6-((6-bromo- zo [d]imidazolyl)methyl)benzo [d]thiazol 31 8 yl)amin0)cyclohexanol from Steo 6 of Example 107 for (1R,2R)((6-((5-br0m0-1H- d]imidazolyl)methyl)benzo[d]thiazolyl)amino)cyclohexanol used in Example 110. 1H NMR (300 MHz, DMSO-d6) 8 8.60 (s, 1H), 8.24 (s, 1H), 7.99 (d, J = 7.5 Hz, 1H), 7.82 (m, 1H), 7.74 (m, 1H), 7.68 (s, 1H), 7.31 (m, 1H), 7.21 (m, 1H), .58 (s, 2H), 4.75 (d, J: 5.1 Hz, 1H), 3.51 (m, 1H), 3.35 (m, 1H), 2.61 (s, 3H), 2.02 (m, 1H), 1.87 (m, 1H), 1.55 — 1.67 (m, 2H), 1.10 — 1.34 (m, 4H); LCMS (ESI) m/z 421 (M+H)+.

Example 121 Preparation of (1R,2R)((6-((5-ethynyl—lH-benzo[d]imidazol-l- yl)methyl)benzo[d]thiazol—Z-yl)amino)cyclohexanol mfNHOH Step 1: A stirred mixture of (1R,2R)((6-((5b-romo-lH— benzo[d]imidazolyl)methyl)benzo[d]thiazolyl)amino)cyclohexanol (109 mg, 0.24 mmol) from Step 6 of Example 108, (trimethylsilyl)acetylene (68 uL, 0.48 mmol), and DIEA (62 uL, 0.36 mmol) in CH3CN (2 mL), was purged with a stream of argon for 5 min. To the mixture was added tetrakis(triphenylphosphine)palladium (0) (57 mg, 0.05 mmol) and argon was bubbled into the mixture for an onal 5 min. The reaction vessel was sealed and the mixture was heated at 80 °C for 5 h. The mixture was cooled to rt and was ioned between EtOAc (100 mL) and 1 M aq NaHC03 (50 mL). The organic layer was washed with brine (50 mL), dried over MgZSO4, filtered, and concentrated under d pressure. The residue was purified by silica gel flash chromatography eluting with 5% MeOH in DCM to afford (1R,2R)- 2-((6-((5 -((trimethylsilyl)ethynyl)- 1H-benz0 [d]imidazolyl)methyl)benzo [d]thiazol- 2-yl)amino)cyclohexanol (61 mg, 54%) as an amber oil. LCMS (ESI) m/Z 476 (M+H)+.

Step 2: A e of (1R,2R)((6-((5-((trimethylsilyl)ethynyl)-1H- benzo[d]imidazolyl)methyl)benzo[d]thiazolyl)amino)cyclohexanol ( 61 mg, 0.13 mmole) and N32C03 (177 mg, 1.3 mmole) in MeOH (2 mL) was stirred at rt for 2 h. The mixture was d and the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase preparative HPLC using a mixture of water (5% CH3CN, 0.05% HCOOH) and CH3CN (0.05% HCOOH) as the mobile phase and a Varian Pursuit XRs C18 column as the stationary phase to afford (1R,2R)((6-((5 -ethynyl- 1H-benzo [d]imidazol- 1 thyl)benzo [d]thiazol yl)amino)cyclohexanol (8 mg, 17%) as a white powder. 1H NMR (300 MHZ, DMSO- d6) 5 8.49 (s, 1H), 8.01 (d, J: 7.3 Hz, 1H), 7.76 (s, 1H), 7.65 (s, 1H), 7.57 (d, J: 8.3 Hz, 1H), 7.27 — 7.33 (m, 2H), 7.19 (m, 1H), 5.48 (s, 2H), 4.78 (d, J: 4.9 Hz, 1H), 4.03 (s, 1H), 3.51 (m, 1H), 3.35 (m, 1H), 2.03 (m, 1H), 1.87 (m, 1H), 1.56 — 1.69 (m, 2H), 1.11 - 1.31 (m, 4H); LCMS (ESI) m/z 405 (M+H)+.

Example 122 Preparation of (1R,2R)((6-((6-ethynyl—lH-benzo[d]imidazol-l- yl)methyl)benz0[d]thiazol—Z-yl)amin0)cyclohexanol Step 1: )((6-((6-((Trimethylsilyl)ethynyl)-1H—benzo[d]imidazol- 1-yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol was synthesized as an oil (46 mg, 41%) using a procedure analogous to that described in Step 1 of Example 121, substituting (1R,2R)((6-((6-bromo-1H—benzo[d]imidazol hyl)benzo[d]thiazolyl)amino)cyclohexanol from Step 6 of Example 107 for (1R,2R)((6-((5-bromo- 1H-benzo [d]imidazolyl)methyl)benzo [d]thiazol yl)amino)cyclohexanol used in Example 121. LCMS (ESI) m/z 476 (M+H)+.

Step 2: (1R,2R)((6-((6-Ethynyl-1H—benzo[d]imidazol hyl)benzo[d]thiazolyl)amino)cyclohexanol was synthesized as a powder (7 mg, 18%) using a procedure analogous to that described in Step 2 of Example 121, substituting (1R,2R)((6-((6-((trimethylsilyl)ethynyl)- 1H-benzo [d]imidazol yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol from the preVious step for ( ((6-((5-((trimethylsilyl)ethynyl)-1H-benzo [d]imidazol yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol used in Example 121. 1H NMR (300 MHz, DMSO-d6) 8 8.50 (s, 1H), 8.03 (d, J: 7.2 Hz, 1H), 7.74 (s, 1H), 7.60 - 7.68 (m, 2H), 7.16 - 7.34 (m, 3H), 5.48 (s, 2H), 4.80 (d, J: 4.0 Hz, 1H), 4.10 (s, 1H), 3.51 (m, 1H), 3.35 (m, 1H), 2.02 (m, 1H), 1.87 (m, 1H), 1.56 — 1.67 (m, 2H), 1.11— 1.34 (m, 4H); LCMS (ESI) m/Z 405 (M+H)+.

Example 123 Preparation of )((6-((6-bromomethoxy-3H-imidazo[4,5-b]pyridin yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol N::O©:SZ:>/>—NH OH Step 1: To a stirred solution of 6-methoxynitropyridinamine (l .56 g, 9.2 mmol) in 15 mL of DMF at rt was added N-bromosuccimide (l .81 g, 10.1 mmol) in ns. The resulting mixture was stirred at rt for lh. TLC showed the reaction was complete. The reaction e was quenched with water and the reddish brown solid was collected by filtration, washed with water, and dried in a vacuum oven to give 5-brom0meth0xynitr0pyridinamine (2.1 g, 92%). LCMS (ESI) m/z 248, 250 (M+H)+.

Step 2: A mixture of acetic anhydride (15.9 mL, 1687 mmol) and formic acid (6.4 mL, 168.7 mmol) was heated at 60 0C for 3 h. After cooling to rt, o- 6-meth0xynitr0pyridinamine (2.1 g, 8.4 mmol) from Step 1 of this Example was added in portions. The resulting mixture was heated at 60 0C for l h, then at 70 0C for lh. LCMS analysis showed that the reaction was complete. The volume was condensed under reduced pressure, and the precipitated solid was collected by filtration to give N—(5-br0momethoxynitr0pyridinyl)formamide as a light yellow solid (2.2 g, 94%). LCMS (ESI) m/Z 276, 278 (M+H)+.

Step 3: Crude N—(5-bromomethoxynitropyridinyl)-N-((2- (methylthi0)benz0[d]thiazolyl)methyl)f0rmamide (950 mg) was obtained as a light yellow solid using a procedure analogous to that bed in Step 4 of Example 3, substituting r0mometh0xynitr0pyridinyl)formamide from Step 2 of this Example for 3H-imidaz0[4,5-b]pyridine used in e 3. LCMS (ESI) m/Z 469,471 (M+H)+.

Step 4: To a stirred solution of crude N—(5-bromomethoxy nitropyridinyl)-N-((2-(methylthi0)benz0 [d]thiazolyl)methyl)f0rmamide (950 mg, 2.0 mmol) in EtOH (8 mL) were added AcOH (2 mL) and iron (169 mg, 3.0 mmol). The resulting mixture was heated at reflux for l h. Another portion of iron (169 mg, 3.0 mmol) was added and heating was continued for l h at 105 0C. LCMS analysis showed that the on was complete. The e was allowed to cool to rt, and then water was added. Crude 6-((6-bromomethoxy-3H-imidazo[4,5- b]pyridinyl)methyl)(methylthio)benzo[d]thiazole was collected by filtration as a sh green solid (1.01 g). LCMS (ESI) m/z 421, 423 (M+H)+.

Step 5: (lR,2R)((6-((6-Bromomethoxy-3H-imidazo[4,5-b]pyridin yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol (115 mg, 23%) was obtained as a light yellow solid using procedures analogous to those described in Step 5 of Example 3 followed by Step 5 of Example 2, substituting bromomethoxy-3H- imidazo[4,5-b]pyridinyl)methyl)(methylthio)benzo[d]thiazole from Step 4 of this Example for 6-((3H-imidazo[4,5-b]pyridinyl)methyl) (methylthio)benzo[d]thiazole used in Example 3, and substituting the product of that reaction for 2-bromo((5 ,6-dimethoxy-1H-benzo[d]imidazol yl)methyl)benzo[d]thiazole used in Example 2. 1H NMR (300 MHz, DMSO-d6) 8 8.41 (s, 1H), 8.35 (s, 1H), 7.97 (d, J: 7.5 Hz, 1H), 7.73 (s, 1H), 7.29 (s, 2H), 5.39 (s, 2H), 4.75 (br s, 1H), 4.01 (s, 3H), 3.50 (br s, 2H), 2.04 (br s, 1H), 1.80 - 1.88 (m, 1H), 1.60 (br s, 2H), 1.22 (d, J: 5.8 Hz, 4H). LCMS (ESI) m/z 488, 490 (M+H)+.

Example 124 Preparation of 3-((2-(((1R,2R)hydroxycyclohexyl)amin0)benz0[d]oxazolyl) methyl)-3H-imidaz0[4,5-b]pyridinecarb0nitrile Step 1: A solution of 5-bromo-pyridine-2,3-diamine (3.0 g, 15.96 mmol) and HCOOH (1.1 mL) in triethoxymethane (48 mL) was stirred at 90 0C for 3 h. The reaction mixture was concentrated under reduced re. The residue was purified by silica gel chromatography eluting with 40:1 DCM/MeOH to give 6-bromo- 3H- imidazo[4,5-b]pyridine as a light brown solid (2.74 g, 86.7%). 1H NMR (300 MHz, DMSO-d6) 5 8.49 (s, 1H), 8.44 (s, 1H), 8.30 (br s, 1H). LCMS (ESI) m/z 198 (M + H)+.

Step 2: To a stirred on of 6-bromo-3H-imidazo[4,5-b]pyridine (200 mg, 1.01 mmol) in DMF (16 mL) was added NaH (60% sion in mineral oil, 581 mg, 1.44 mmol) portionwise at 0 0C. After the mixture was stirred for 30 min, 6- (chloromethyl) lthio)benzo[d]oxazole (203 mg, 0.96 mmol) was added. The reaction mixture was allowed to warm to rt and stir for 2 h. The reaction mixture was poured into water (40 mL) and extracted with ethyl acetate (60 mL>< 4). The ed organic layers were washed with water and brine, dried over , filtered and concentrated under reduced pressure. The residue was purified by preparative TLC eluting with 15:1 DCM/MeOH to give 6-((6-bromo- 3H- imidazo[4,5-b]pyridinyl) methyl)(methylthio)benzo[d]oxazole (156 mg, 43.2%) as a light yellow solid. 1H NMR (300 MHz, DMSO-d6) 5 8.47 (s, 1H), 8.22 (s, 1H), 8.04 (s, 1H), 7.56 (d, J: 8.4 Hz, 1H), 7.40 (s, 1H), 7.26 (d, J: 6.6Hz, 1H), 5.53 (s, 2H), 2.74 (s, 3H). LCMS (ESI) m/Z 374 (M+H)+.

Step 3: A mixture of 6-((6-bromo-3H-imidazo[4,5-b]pyridinyl)methyl)- 2- (methylthio)benzo[d]oxazole (522 mg, 1.39 mmol) and m-CPBA (282 mg, 1.39 mmol) in DCM (20 mL) was stirred at 0 0C for 5 h. The reaction mixture was washed with aq Na2S203 and brine, dried over Na2S04, filtered and concentrated under reduced re. The residue was purified by silica gel chromatography eluting with 1:1 to 1:5 eum ether/ethyl acetate to give 6-((6-bromo-3H-imidazo[4,5- b]pyridinyl) methyl)(methylsulfinyl)benzo[d]oxaz-ole as a light yellow solid (400 mg, 73.7%). 1H NMR (300 MHz, DMSO-d6) 8 8.69 (s, 1H), 8.48 (s, 1H), 8.40 (s, 1H), 7.68 (s, 1H), 7.58 (d, J: 8.1 Hz, 1H), 7.34 (d, J: 9.3 Hz, 1H), 5.60 (s, 2H), 2.73 (s, 3H). LCMS (ESI) m/Z 390 (M+H)+.

Step 4: A mixture of 6-((6-bromo-3H-imidazo[4,5-b]pyridinyl)methyl)- 2-(methyl sulfinyl)benzo[d]oxazole (330 mg, 0.84 mmol), (1R,2R)- 2- aminocyclohexanol (192 mg, 1.27 mg) and DIEA (327 mg, 2.54 mmol) in DMA (15 mL) was stirred at 135 0C for 1 h. The reaction mixture was cooled to rt, poured into water (100 mL) and extracted with ethyl acetate (50 mL>< 3). The ed organic layers were washed with water and brine, dried over Na2S04, d and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 1:6 petroleum ether/ethyl acetate to give )((6- ((6-bromo-3H-imidazo[4,5-b]pyridinyl)methyl)benzo[d]oxazol yl)amino)cyclohexanol as a light yellow solid (373 mg, 100%). 1H NMR (300 MHZ, DMSO-d6) 5 8.65 (s, 1H), 8.48 (s, 1H), 8.38 (s, 1H), 7.79 (d, J: 7.5 Hz, 1H), 7.38 (s, 1H), 7.13 (s, 1H), 5.48 (s, 2H), 4.68 (s, 3H), 3.37 (br s, 2H), 1.92 (br s, 2H), 1.62 (br s, 2H), 1.23 (br s, 4H). LCMS (ESI) m/z 441 (M+H)+.

Step 5: A mixture of (1R,2R)((6-((6-bromo-3H-imidazo[4,5-b]pyridin- 3-yl)methyl) benzo[d]oxazolyl)amino)cyclohexanol (276 mg, 0.62 mmol), Zn(CN)2 (110 mg, 0.94 mmol), a)3 (57 mg, 0.062 mmol) and dppf (68.8 mg, 0.124 mmol) in DMF (6 mL) was stirred at 100 0C for 2 h. The reaction e was cooled to rt, poured into water (100 mL) and extracted with ethyl acetate (100 mL>< 2). The combined organic layers were washed with water and brine, dried over NaZSO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 15:1 DCM/MeOH to give 3-((2- (((lR,2R)- 2-hydroxycyclohexyl)amino) benzo[d]oxazolyl)methyl)-3H-imidazo[4,5- b]pyridinecarbonitrile as a light yellow solid (62 mg, 25.8%). 1H NMR (300 MHZ, DMSO-d6) 5 8.85 (s, 1H), 8.83 (d, J: 1.5 Hz, 1H), 8.70 (s, 1H), 7.81 (d, J: 7.8 Hz, 1H),7.41(s, 1H), 7.14 (m, 2H), 5.54 (s, 2H), 4.68 (d, J: 4.8 Hz, 1H), 3.34 (br s, 2H), 1.91 (br s, 2H), 1.62 (br s, 2H), 1.22 (br, 4H). LCMS (ESI) m/z 389 (M+H)+.

Example 125 Pre n of IR 2R 6- imidazo 1 2-a 3- lmeth lbenzo l - 2- 1 amino c clohexanol N {3 Step 1: A stirred mixture of 2-chloro-3 -(2-(methylthio)benzo[d]thiazol yl)propanal from Step 4 of Example 117 (300 mg, 1.1 mmol) and pyrazinamine (210 mg, 2.2 mmol) in 1-butanol (10 mL) was heated at reflux overnight. The mixture was cooled to rt and water (20 mL) was added. The mixture was extracted with EtOAc (10 mL><3). The combined organic layers were washed with brine, dried over NaZSO4, filtered and concentrated under d pressure. The residue was purified by silica gel chromatography eluting with 50: 1 to 20: 1 DCM/MeOH to afford 6-(imidazo[1,2-a]pyrazinylmethyl)(methylthio)benzo [d]thiazole as a yellow solid (120 mg, 35%). 1H NMR (300 MHZ, CDClg) 5 9.10 (d, J = 1.2 Hz, 1H), 7.83-7.80 (m, 2H), 7.72-7.68 (m, 2H), 7.50 (d, J: 9.0 Hz, 1H), 7.23 (d, J: 1.8 Hz, 1H), 4.38 (s, 2H), 2.78 (s, 3H). LCMS (ESI) m/z 313 (M+H)+.

Step 2: To a solution of 6-(imidazo[1,2-a]pyrazinylmethyl) (methylthio)benzo azole (230 mg, 0.74 mmol) from the preVious step in DCM (14 mL) was added m-CPBA (160 mg, 0.93 mmol) at 0 0C. The reaction mixture was stirred for 2 h at 0 0C, then aq 3 (15 mL) was added and the mixture was stirred for 0.5 h. The organic layer was separated, dried over Na2S04, ed and trated under reduced pressure. The residue was purified by silica gel chromatography, eluting with 50: 1 to 20: 1 DCM/MeOH, to afford 6- (imidazo[1,2-a]pyrazinylmethyl) (methylsulfinyl)benzo[d]thiazole as a yellow solid (200 mg, 83%). 1H NMR (300 MHz, CDClg) 8 9.13 (d, J: 1.5 Hz, 1H), 8.02 (d, J: 8.7 Hz, 1H), 7.85-7.79 (m, 2H), 7.74-7.70 (m, 2H), 7.40 (dd, J: 1.5, 8.4 Hz, 1H), 4.46 (s, 2H), 3.07 (s, 3H). LCMS (ESI) m/z 329 (M+H)+.

Step 3: A mixture of dazo[1 ,2-a]pyrazinylmethyl) lsulfinyl) benzo[d]thiazole (350 mg, 1.07 mmol), (1R,2R) aminocyclohexanol (324 mg, 2.14 mmol) and DIEA (414 mg, 3.21 mmol) in NMP (14 mL) was stirred for 2 d at 140 0C. The mixture was cooled to rt and water (50 mL) was added. The mixture was extracted with EtOAc (30 mL>< 3). The combined organic layers were washed with brine, dried over Na2S04, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 50: 1 to 10: 1 DCM/MeOH to afford 100 mg of solid. The solid was recrystallized with 10:1 DCM/MeOH to afford (1R,2R) ((6-(imidazo [1 ,2-a]pyrazin-3 -ylmethyl)benzo [d]thiazol yl)amino)cyclohexanol as a white solid (70 mg, 17%). 1H NMR (300 MHZ, DMSO-d6) 5 9.03 (d, J: 1.2 Hz, 1H), 8.33 (dd, J: 1.8, 4.5 Hz, 1H), .85 (m, 2H), 7.68 (s, 1H), 7.54 (s, 1H), 7.27 (d, J: 7.8 Hz, 1H), 7.11 (dd, J: 1.5, 7.8 Hz, 1H), 4.71 (d, J: 4.8 Hz, 1H), 4.35 (s, 2H), 3.52-3.49 (m, 1H), 3.39-3.36 (m, 1H), 2.05-2.01 (m, 1H), 1.90-1.86 (m, 1H), 1.65-1.59 (m, 2H), 1.30-1.16 (m, 4H). LCMS (ESI) m/Z 380 .

Example 126 Pre aration of 3- 2- 1R 2R h drox c clohex 1 amino benzo d thiazol l meth l meth0x -3H-imidaz0 4 5-b ridine—6-carb0nitrile WO 56070 3-((2-(((1R,2R)Hydroxycyclohexyl)amino)benzo[d]thiazol hyl)methoxy-3H-imidazo[4,5-b]pyridinecarbonitrile (55 mg, 69%) was ed as a light yellow solid using a procedures analogous to that described in Example 43, substituting (1R,2R)((6-((6-bromomethoxy-3H-imidazo[4,5- b]pyridinyl)methyl)benzo[d]thiazolyl)amino)cyclohexanol from Example 123 for (1R,2R)((6-((6-bromo-3H—imidazo[4,5-b]pyridinyl)methyl)benzo[d]thiazol- 2-yl)amino)cyclohexanol used in Example 43. 1H NMR (300 MHz, 6) 8 8.60 (d, J: 6.6 Hz, 2H), 7.99 (d, J: 7.3 Hz, 1H), 7.74 (s, 1H), 7.30 (s, 2H), 5.42 (s, 2H), 4.76 (br s, 1H), 4.07 (s, 3H), 3.51 - 3.70 (m, 2H), 1.97 - 2.14 (m, 1H), 1.86 (br s, 1H), 1.62 (d, J: 4.5 Hz, 2H), 1.22 (d, J: 5.5 Hz, 4H). LCMS (ESI) m/z 435 (M+H)+.

Example 127 Pre aration of IR 2R 6- 5-meth l-lH-benzo imidazol-l- l meth lbenzo thiazol-Z- 1 amino c clohexanol /\ S N2/ N1/\©: />—NH 9H N 3 s Step 1: To a stirred mixture of 4-methylnitroaniline (1 g, 6.5mmol) in TFA (15 mL) at 0 to 5 0C was added portionwise sodium triacetoxyborohydride (2.78 g, 13.2 mmol) and the mixture was stirred for 10 min. To the reaction mixture was added nwise 2-(methylthio)benzo[d]thiazolecarbaldehyde (1.44 g, 6.9 mmol) from Step 1 of Example 100. After stirring at rt for 4 h, the mixture was poured into ice-water and extracted with EtOAc (100 mL X 3). The combined organic layers were washed with saturated aq NaHCOg (100 mL X 2) and brine (100 mL). The organic layer was separated, dried over Na2S04, filtered, and concentrated under reduced pressure. The e was purified by silica gel flash chromatography eluting with 3% EtOAc in petroleum ether to afford 4-methyl-N-((2-(methylthio)benzo[d]thiazol yl)methyl)-2 -nitroaniline (0.93 g, 41%) as a yellow solid. 1H NMR (300 MHz, CDC13)8 8.37 (br s, 1H), 8.01 (s, 1H), 7.83 (d, J: 8.4 Hz, 1H), 7.71 (s, 1H), 7.38 (dd, J: 8.4, 2.4 Hz, 1H), 7.19 (dd, J: 8.7, 2.1 Hz, 1H), 8.71 (d, J: 8.7 Hz, 1H), 4.83 (d, J: 6.0 Hz, 2H), 2.83 (s, 3H), 2.25 (s, 3H); LCMS (ESI) m/z 346 (M + H)+.

Step 2: A mixture of 4-methyl-N-((2-(methylthio)benzo[d]thiazol yl)methyl l)nitroaniline (0.93 g, 2.7 mmol) from the previous step, MeOH (50 mL) and palladium on activated charcoal (100 mg) was stirred under hydrogen at 1 atm pressure at rt for 12 h. The mixture was filtered and the filtrate was concentrated under d pressure to afford 4-methyl-N1-((2-(methylthio)benzo[d]thiazol yl)methyl)benzene-l,2-diamine (0.70 g, 85%) as a brown solid which was not purified further. LCMS (ESI) m/Z 316 (M + H)+.

Step 3: A stirred mixture of crude 4-methyl-N1-((2- lthio)benzo[d]thiazol yl)methyl)benzene-l,2-diamine (0.7 g, 2.3 mmol), formic acid (0.5 mL) and triethyl ormate (5 mL) was heated at 100 CC for l h.

The reaction e was cooled to rt and concentrated under reduced pressure. The e was purified by silica gel flash chromatography eluting with 3% MeOH in DCM to afford 6-((5-methyl-lH—benzo[d]imidazol-l-yl)methyl) (methylthio)benzo[d]thiazole (0.61 g, 85%) as a yellow solid. 1H NMR (300 MHZ, CDCls) 8 7.94 (s, 1H), 7.82 (d, J: 8.4 Hz, 1H), 7.62 (s, 1H), 7.49 (s, 1H), 7.26 (m, 1H), 7.14 (d, J: 8.1 Hz, 1H), 7.07 (d, J: 8.1 Hz, 1H), 5.43 (s, 2H), 2.77 (s, 3H), 2.47 (s, 3H); LCMS (ESI) m/Z 326 (M + H)+.

Step 4: To a stirred solution of 6-((5-methyl-lH—benzo[d]imidazol-l- yl)methyl) (methylthio)benzo[d]thiazole (0.61 g, 1.8 mmol) from the previous step in DCM (20 mL) at 0 0C was added a solution of meta-chloroperbenzoic acid (0.40 g, 1.57 mmol) in DCM (3 mL). After stirring for 2 h at 0 CC, the solution was diluted with EtOAc (100 mL) and washed sequentially with saturated aq NazSzOg, saturated aq NaHC03, and brine. The organic layer was separated, dried over Na2S04, filtered, and trated under d pressure to afford 6-((5-methyl-1H- benzo[d]imidazol-l-yl)methyl)(methylsulfinyl)benzo[d]thiazole (0.57 g, 89%) as a yellow solid which was not purified further.

Step 5: A stirred mixture of 6-((5-methyl-lH—benzo[d]imidazol-l- yl)methyl) (methylsulfinyl)benzo[d]thiazole (0.26 g, 0.76 mmol) from the previous step, (lR,2R)aminocyclohexanol (0.26 g, 2.2 mmol), DIEA (0.98 g, 7.6 mmol) and NMP (2 mL) was heated at 130 CC for 12 h. The reaction e was cooled to rt, diluted with EtOAc (30 mL), and washed with water (10 mL X 2). The c layer was dried over Na2S04, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with 3% MeOH in DCM to afford (1R,2R)((6-((5-methyl-1H—benzo[d] imidazol yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol (79 mg, 89%) as a white solid. 1H NMR (300 MHz, DMSO-d6) 5 8.30 (s, 1H), 7.91 (d, J: 7.5 Hz, 1H), 7.61 (d, J: 2.0 Hz, 1H), 7.39 — 7.42 (m, 2H), 7.28 (d, J: 8.1 Hz, 1H), 7.16 (dd, J: 8.4, 1.8 Hz, 1H), 7.02 (d, J: 7.2 Hz, 1H), 5.42 (s, 2H), 4.69 (d, J: 5.1 Hz, 1H), 3.39 (m, 1H), 3.33 (m, 1H), 2.38 (s, 3H), 2.03 (m, 1H), 1.86 (m, 1H), 1.59 — 1.63 (m, 2H), 1.21 — 1.23 (m, 4H); LCMS (ESI) m/Z 393 (M + H)+.

Example 128 Pre aration of IR 2R 6- 56-diflu0r0-1H—benz0 imidazol—l- l meth lbenzo thiazol-Z- 1 amino c clohexanol /\ S N/ Nfi />—NH pH Fl N 3 9 Step 1: A e of 4,5-difluoronitroaniline (1.73 g, 10 mmol), palladium on activated al (200 mg), and MeOH (50 mL) was stirred under hydrogen (1 atm) at rt for 12 h. The mixture was filtered to remove the catalyst and the filtrate was concentrated under d pressure to afford 4,5-difluorobenzene- 1,2-diamine (1.42 g, 97%) as a brown solid, which was not purified further. 1H NMR (300 MHz, CDClg) 5 6.50 (m, 2H), 2.75 — 3.48 (br s, 4H).

] Step 2: A stirred mixture of 4,5-difluorobenzene-1,2-diamine (1.40 g, 9.7 mmol) from the preVious step, formic acid (2.0 mL), and triethyl orthoformate (20 mL) was heated at 100 CC for 1 h. The reaction mixture was cooled to rt and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with 5% MeOH in DCM to afford 5,6-difiuoro-1H— benzo[d]imidazole as (1.12 g, 75%) as a white solid. 1H NMR (300 MHZ, CDClg) 8 8.07 (s, 1H), 7.44 (m, 2H); LCMS (ESI) m/Z 155 (M + H)+.

Step 3: To a d mixture of sodium hydride (60% sion in mineral oil, 0.144 g, 3.0 mmol) in anhydrous DMF (10 mL) at 0 CC under a nitrogen atmosphere was added portionwise 6-difluoro-1H—benzo[d]imidazole (0.475 g, 2.0 2012/059983 mmol) from the previous step. The e was d at 0 CC for 5 min. To the mixture was added dropwise a solution of 6-(chloromethyl) (methylthio)benzo[d]thiazole (0.32 g, 2.0 mmol) from Step 4 of Example 36 in anhydrous DMF (2 mL). The reaction mixture was allowed to warm to rt and stir for l h. The mixture was poured into ice-water and extracted with EtOAc (100 mL X 2).

The ed organic layers were filrther washed with water (20 mL) then brine (20 mL). The organic layer was separated and dried over Na2S04, filtered, and concentrated under reduced pressure to afford 6-((5,6-difiuoro- zo[d]imidazol- l-yl)methyl)(methylthio)benzo[d]thiazole (0.55 g, 76%) as a yellow solid, which was not d filrther. 1H NMR (300 MHZ, CDClg) 8 7.97 (s, 1H), 7.84 (d, J: 8.4 Hz, 1H), 7.59 (m, 1H), 7.50 (s, 1H), 7.24 (m, 1H), 7.02 (m, 1H), 5.40 (s, 2H), 2.78 (s, 3H); LCMS (ESI) m/Z 348 (M + H)+.

Step 4: To a stirred solution of 6-((5,6-difiuoro-lH—benzo[d]imidazol-l- yl)methyl) (methylthio)benzo[d]thiazole (0.55 g, 1.58 mmol) from the previous step in DCM (20 mL) at 0 0C was added a solution of meta-chloroperbenzoic acid (0.32 g, 1.58 mmol) in DCM (3 mL). After stirring for 2 h at 0 CC, the mixture was diluted with EtOAc (100 mL) and washed sequentially with saturated aq NazSzOg, saturated aq NaHC03, and brine. The organic layer was separated, dried over , filtered, and concentrated under reduced pressure to afford 6-((5,6-difiuoro-lH— benzo[d]imidazol-l-yl)methyl)(methylsulfinyl)benzo[d]thiazole (0.50 g, 88%) as a white solid, which was not purified further. 1H NMR (300 MHZ, CDClg) 8 8.02 — 8.06 (m, 2H), 7.77 (s, 1H), 7.61 (m, 1H), 7.37 (dd,.]= 8.4, 1.5 Hz, 1H), 7.01 (m, 1H), 5.48 (s, 2H), 3.07 (s, 3H); LCMS (ESI) m/Z 364 (M + H)+.

Step 5: A stirred mixture of 6-((5,6-difiuoro-lH—benzo[d]imidazol-l- yl)methyl) (methylsulfinyl)benzo[d]thiazole (0.20 g, 0.55 mmol), ) aminocyclohexanol (0.19 g, 1.6 mmol), DIEA (0.71 g, 5.5 mmol) and NMP (2 mL) was heated at 130 0C for 12 h. The reaction mixture was cooled to rt, diluted with EtOAc (30 mL) and washed with water (10 mL X 2). The organic layer was separated, dried over Na2S04, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with 3% MeOH in DCM to afford (lR,2R)((6-((5 ,6-difiuoro- lH—benzo[d]imidazol- l - yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol (65 mg, 30%) as a white solid. 1H NMR (300 MHz, DMSO-d6) 5 8.48 (s, 1H), 7.97 (d, J: 7.5 Hz, 1H), 7.69 — 7.78 (m, 3H), 7.30 (d, .1: 8.1 Hz, 1H), 7.22 (d, .1: 8.1 Hz, 1H), 5.44 (s, 2H), 4.74 (d, .1: 4.8 Hz, 1H), 3.51 (m, 1H), 3.42 (m, 1H), 2.00 (m, 1H), 1.87 (m, 1H), 1.58 — 1.60 (m, 2H), 1.15 — 1.25 (m, 4H); LCMS (ESI) m/Z 415 (M + H)+. e 129 IR 2R 6- S-fluoro-lH-benzo imidazol-l- lmeth lbenzo l l amino [cyclohexanol //\ S N N/U/2: N: NH pH 3 9 Step 1: 4-Fluoro-N—((2-(methylthio)benzo[d]thiazolyl)methyl)—2- nitroaniline (0.88 g, 66%) was obtained as a yellow solid using a procedure analogous to that described in Step 1 of Example 127, substituting 4-fluoronitroaniline for 4- methylnitroaniline used in Example 127. 1H NMR (300 MHZ, CDClg) 8 8.37 (br s, 1H), 8.01 (s, 1H), 7.92 (dd, J: 9.0, 3.0 Hz, 1H), 7.85 (d, J: 9.0 Hz, 1H), 7.37 (dd, J = 8.4, 1.5 Hz, 1H), 7.17 (m, 1H), 6.75 (dd, J: 9.6, 4.8 Hz, 1H), 4.64 (d, J: 5.7 Hz, 2H), 3.78 (s, 3H); LCMS (ESI) m/Z 350 (M + H)+.

Step 2: To a stirred e of 4-fluoro-N-((2- (methylthio)benzo[d]thiazolyl)methyl) nitroaniline (1.18 g, 3.3 mmol) from the preVious step, acetic acid (3 mL), MeOH (3 mL) and DCM (20 mL) at -10 0C was added portionwise zinc dust (1.7 g, 26 mmol). The reaction mixture was stirred at —10 0C for 0.5 h. The mixture was poured into ter and extracted with EtOAc (100 mL X 3). The combined organic layers were washed sequentially with water, saturated aq NaHCOg (100 mL X 2), and brine (100 mL). The c layer was separated, dried over Na2S04, filtered, and concentrated under reduced pressure to afford 4-fluoro-N1- ((2-(methylthio)benzo[d]thiazolyl)methyl)benzene-1,2-diamine (0.93 g, yield 87%) as a yellow solid, which was not purified fithher. 1H NMR (300 MHz, CDClg) 8 7.82 (d, J: 8.4 Hz, 1H), 7.76 (s, 1H), 7.42 (dd, J: 8.4, 1.8 Hz, 1H), 6.42 — 6.56 (m, 3H), 4.35 (s, 2H), 3.60 (br s, 2H), 2.79 (s, 3H); LCMS (ESI) m/z 320 (M + H)+.

Step 3: A stirred mixture of 4-fluoro-N1-((2-(methylthio)benzo[d]thiazol- 6-yl)methyl) benzene-1,2-diamine (0.93 g, 2.93 mmol) from the preVious step, formic acid (0.5 mL) and triethyl ormate (5 mL) was heated at 100 CC for l h. The reaction mixture was cooled to rt and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with 3% MeOH in DCM to afford 6-((5-fluoro-lH—benzo[d]imidazol-l-yl)methyl) (methylthio)benzo[d]thiazole (0.64 g, 67%) as a yellow solid. 1H NMR (300 MHZ, CDC13)5 7.99 (s, 1H), 7.83 (d, J: 8.1 Hz, 1H), 7.47 — 7.51 (m, 2H), 7.26 (m, 1H), 7.17 (m, 1H), 7.00 (dt, .1: 9.3, 2.4 Hz, 1H), 5.44 (s, 2H), 2.77 (s, 3H); LCMS (ESI) m/Z 330 (M + H)+.

Step 4: To a stirred solution of 6-((5-fluoro-lH-benzo [d]imidazol—l- yl)methyl)(methylthio)benzo[d]thiazole (0.64 g, 1.9 mmol) from the us step in DCM (20 mL) at 0 0C was added a solution of meta-chloroperbenzoic acid (0.472 g, 2.3 mmol) in DCM (3 mL). The e was stirred at 0 CC for 2 h. The solution was diluted with EtOAc (100 mL) and washed tially with saturated aq NaZSZOg, saturated aq NaHCOg, and brine. The organic layer was separated, dried over Na2S04, filtered, and concentrated under reduced pressure to afford 6-((5-fluoro- lH—benzo[d]imidazol-l-yl)methyl)(methylsulfinyl)benzo[d]thiazole (0.63 g, 94%) as a yellow solid, which was not purified filrther. 1H NMR (300 MHZ, CDClg) 8 8.02 — 8.05 (m, 2H), 7.78 (s, 1H), 7.51 (dd, J: 9.6, 2.4 Hz, 1H), 7.38 (dd, J: 8.4, 1.8 Hz, 1H), 7.20 (m, 1H), 7.00 (dt, J: 9.0, 2.4 Hz, 1H), 5.52 (s, 2H), 3.07 (s, 3H); LCMS (ESI) m/Z 346 (M + H)+.

Step 5: A stirred e of 6-((5-fluoro-lH—benzo[d]imidazol-l- hyl) (methylsulfinyl)benzo[d]thiazole (0.20 g, 0.57 mmol) from the preVious step, (lR,2R)aminocyclohexanol (0.20 g, 1.7 mmol), DIEA (0.73 g, 5.7 mmol) and NMP (2 mL), was heated at 130 CC for 12 h. The reaction mixture was cooled to rt, d with EtOAc (30 mL), and washed with water (10 mL X 2). The organic layer was separated, dried over Na2S04, filtered, and concentrated under reduced pressure.

The residue was purified by silica gel flash chromatography eluting with 3% MeOH in DCM to afford (lR,2R)((6-((5-fluoro-lH—benzo[d]imidazol-l- yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol (75 mg, 33%) as a white solid. 1H NMR (300 MHz, DMSO-d6) 8 8.45 (s, 1H), 7.93 (d, J: 7.2 Hz, 1H), 7.65 (d, J: 1.5 Hz, 1H), 7.56 (m, 1H), 7.43 (dd, J: 9.6, 2.4 Hz, 1H), 7.28 (m, 1H), 7.19 (dd, J: 8.4, 1.8 Hz, 1H), 7.08 (dt, .1: 9.6, 3.0 Hz, 1H), 5.46 (s, 2H), 4.69 (d, J: 5.4 Hz, 1H), 2012/059983 3.51 (m, 1H), 3.37 (m, 1H), 2.01 (m, 1H), 1.87 (m, 1H), 1.59 — 1.63 (m, 2H), 1.15 — 1.23 (m, 4H); LCMS (ESI) m/Z 397 (M + H)+.

Example 130 Pre aration of IR 2R 6- 5- trifluorometh l-lH-benzo imidazol—l- l meth lbenzo thiazol-Z- lamino c clohexanol //\ S N NAG: />—NH:f pH N 3 9 Step 1: N—((2-(Methylthio)benzo[d]thiazolyl)methyl)nitro (trifiuoromethyl)aniline (0.38 g, 49%) was obtained as a yellow solid using a procedure analogous to that described in Step 1 of Example 127, tuting 2-nitro- 4-(trifiuoromethyl)aniline for 4-methylnitroaniline used in Example 127. 1H NMR (300 MHz, CDClg) 8 8.64 (br s, 1H), 8.50 (s, 1H), 7.87 (d, J: 8.4 Hz, 1H), 7.71 (s, 1H), 7.56 (dd, J: 9.0, 2.1 Hz, 1H), 7.38 (dd, J: 8.4, 1.8 Hz, 1H), 6.90 (d, J: 9.0 Hz, 1H), 4.69 (d, J: 5.7 Hz, 2H), 2.79 (s, 3H); LCMS (ESI) m/z 400 (M + H)+.

Step 2: A mixture ofN—((2-(methylthio)benzo[d]thiazolyl)methyl) nitro trifluoromethyl)aniline (0.38 g, 2.0 mmol) from the us step, MeOH (30 mL) and palladium on activated charcoal (50 mg) was stirred under hydrogen (1 atm) at rt for 12 h. The mixture was filtered to remove the catalyst and the filtrate was concentrated under reduced pressure to afford N1-((2-(methylthio)benzo[d]thiazol yl)methyl)(trifluoromethyl) benzene-1,2-diamine (0.32 g, 91%) as a brown solid, which was not purified further. LCMS (ESI) m/Z 370 (M + H)+.

Step 3: A d mixture of N1-((2-(methylthio)benzo[d]thiazol yl)methyl) oromethyl)benzene-l,2-diamine (0.32 g, 0.86 mmol) from the preVious step, formic acid (0.5 mL) and triethyl orthoformate (5 mL) was heated at 100 0C for 1 h. The reaction mixture was cooled to rt and concentrated under reduced pressure. The residue was purified by silica gel flash tography eluting with 3% MeOH in DCM to afford 2-(methylthio)((5-(trifiuoromethyl)-lH- benzo[d]imidazol-l-yl)methyl)benzo[d]thiazole (0.22 g, 69%) as a yellow solid. 1H NMR (300 MHz, CDC13)8 8.12 (s, 1H), 8.08 (s, 1H), 7.84 (d, J: 8.4 Hz, 1H), 7.48 — 7.54 (m, 2H), 7.36 (d, .1: 8.4 Hz, 1H), 7.26 (m, 1H), 5.49 (s, 2H), 2.78 (s, 3H); LCMS (ESI) m/Z 380 (M + H)+.

] Step 4: To a stirred solution of 2-(methylthio)((5-(trifluoromethyl)-1H- benzo[d]imidazol yl)methyl)benzo[d]thiazole (0.22 g, 0.58 mmol) from the previous step in DCM (20 mL) at 0 0C was added a solution of meta-chloroperbenzoic acid (0.30 g, 1.5 mmol) in DCM (3 mL). The mixture was stirred at 0 0C for 2 h. The mixture was diluted with EtOAc (100 mL) and washed sequentially with saturated aq NaZSZOg, saturated aq NaHCOg, and brine. The organic layer was separated, dried over Na2S04, filtered, and concentrated under reduced pressure to afford 2- (methylsulfinyl)((5-(trifluoromethyl)- 1H-benzo [d]imidazol yl)methyl)benzo[d]thiazole (0.22 g, 96%) as a yellow solid, which was not purified further. 1H NMR (300 MHz, 8 8.12 — 8.14 (m, 2H), 8.05 (d, J: 8.4 Hz, 1H), 7.79 (s, 1H), 7.50 (dd, J: 8.7, 1.2 Hz, 1H), 7.37 (t, J = 8.4 Hz, 2H), 5.57 (s, 2H), 3.06 (s, 3H); LCMS (ESI) m/Z 396 (M + H)+.

Step 5: A stirred mixture of 2-(methylsulfinyl)((5-(trifluoromethyl)- 1H- d] imidazolyl)methyl)benzo[d]thiazole (0.20 g, 0.50 mmol) from the preVious step, (1R,2R)aminocyclohexanol (0.17 g, 1.5 mmol), DIEA (0.59 g, 4.6 mmol) and NMP (2 mL) was heated at 130 CC for 12 h. The reaction mixture was cooled to rt, diluted with EtOAc (30 mL), and washed with water (10 mL x 2). The organic layer was separated, dried over Na2S04, filtered, and concentrated under reduced pressure. The residue was d by silica gel flash tography eluting with 3% MeOH in DCM to afford (1R,2R)((6-((5-(trifluoromethyl)—1H - benzo[d]imidazolyl)methyl)benzo[d]thiazolyl)amino)cyclohexanol (54 mg, 23%) as a white solid. 1H NMR (300 MHz, DMSO-d6) 8 8.62 (s, 1H), 8.02 (s, 1H), 7.95 (d, J: 7.8 Hz, 1H), 7.79 (d, J: 8.7 Hz, 1H), 7.67 (d, J: 1.2 Hz, 1H), 7.54 (d, J = 8.7 Hz, 1H), 7.29 (d, J: 8.4 Hz, 1H), 7.20 (d, J: 8.4 Hz, 1H), 5.54 (s, 2H), 4.71 (d, J: 5.1 Hz, 1H), 3.51 (m, 1H), 3.39 (m, 1H), 2.01 (m, 1H), 1.80 (m, 1H), 1.59 — 1.62 (m, 2H), 1.17 — 1.23 (m, 4H); LCMS (ESI) m/z 447 (M + H)+. e 131 Pre aration of IR 2R 6- imidazo 1 2-b ridazin lmeth lbenzo thiazol-Z- lamino c clohexanol N\ />—NH N §OH \ N \ / C ] Step 1: A stirred mixture of 2-chloro-3 -(2-(methylthio)benzo[d]thiazol yl)propanal (500 mg, 1.8 mmol) from Step 4 of Example 117 and pyridazinamine (350 mg, 3.6 mmol) in 1-butanol (20 mL) was heated at reflux for 15 h. The mixture was cooled to rt and water (40 mL) was added. The mixture was extracted with EtOAc (20 mL X 3) and the combined organic layers were washed with brine.

The organic layer was separated, dried over Na2S04, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash tography eluting with 2 to 5% MeOH in DCM to afford 6-(imidazo[1,2- b]pyridazinylmethyl)(methylthio)benzo[d]thiazole (460 mg, 80%) as a light brown solid. 1H NMR (300 MHz, CDClg) 8 8.32 (dd, J: 4.5, 1.5 Hz, 1H), 7.94 (dd, J = 9.3, 1.5 Hz, 1H), 7.79 (d, J: 8.7 Hz, 1H), 7.66 (s, 1H), 7.58 (s, 1H), 7.36 (dd, J: 8.4, 1.8 Hz, 1H), 7.02 (m, 1H), 4.45 (s, 2H), 2.77 (s, 3H); LCMS (ESI) m/z 313 (M+H)+.

Step 2: To a stirred solution of 6-(imidazo[1,2-b]pyridazinylmethyl) (methylthio)benzo[d]thiazole (350 mg, 1.1 mmol) from the preVious step in DCM (30 mL) at 0 0C was added meta-chloroperbenzoic acid (194 mg, 1.1 mmol). The reaction e was stirred at 0 0C for 2 h. To the mixture was added saturated aq Na2S203 (15 mL) and the mixture was stirred for a further 0.5 h. The organic layer was separated, dried over Na2S04, ed, and concentrated under reduced pressure.

The residue was purified by silica gel flash chromatography eluting with 2 to % MeOH in DCM to afford 6-(imidazo[1,2-b]pyridazinylmethyl) (methylsulfinyl)benzo[d]thiazole (320 mg, 87%) as a yellow solid. 1H NMR (300 MHz,CDC13)8 8.33 (dd, J: 4.5, 1.5 Hz, 1H), 7.91 — 8.00 (m, 3H), 7.62 (s, 1H), 7.54 (dd, J: 8.4, 1.8 Hz, 1H), 7.03 (m, 1H), 4.52 (s, 2H), 3.05 (s, 3H); LCMS (ESI) m/Z 329 (M+H)+.

Step 3: A stirred mixture of 6-(imidazo[1,2-b]pyridazinylmethyl) (methylsulfinyl)benzo[d]thiazole (260 mg, 0.79 mmol) from the us step, (1R,2R)aminocyclohexanol hloride (360 mg, 2.38 mmol), DIEA (408 mg, 3.16 mmol) and NMP (10 mL), was heated at 140 CC for 48 h. The mixture was cooled to rt and water (50 mL) was added. The mixture was extracted with EtOAc (30 mL X 3) and the combined organic layers were washed with brine. The organic layer was separated, dried over Na2S04, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography g with 2 to 10% MeOH in DCM to afford a solid. The solid was further purified by recrystallization from a 10:1 mixture of DCM: MeOH to afford (1R,2R)((6-(imidazo [1 ,2-b]pyridazinylmethyl)benzo [d]thiazol yl)amino)cyclohexanol (80 mg, 27%) as a white solid. 1H NMR (300 MHZ, DMSO-d6) 5 8.53 (dd, J: 4.5, 1.5 Hz, 1H), 8.10 (dd, J: 9.3, 1.5 Hz, 1H), 7.83 (d, J = 7.8 Hz, 1H), 7.60 (s, 1H), 7.53 (s, 1H), 7.25 (d, J = 8.7 Hz, 1H), 7.19 (m, 1H), 7.12 (dd, J: 8.4, 1.8 Hz, 1H), 4.71 (d, J: 4.8 Hz, 1H), 4.32 (s, 2H), 3.51 (m, 1H), 3.38 (m, 1H), 2.04 (m, 1H), 1.88 (m, 1H), 1.59 — 1.65 (m, 2H), 1.16 — 1.30 (m, 4H); LCMS (ESI) m/Z 380 (M+H)+.

Example 132 Pre aration of IR 2R 6- 6-flu0r0-3H—imidazo 4 5-b 3- l meth lbenzo oxazol-Z- 1 amino c clohexanol é\ N N />—NH pH v O Step 1: To a stirred solution of 6-fluoro-3H—imidazo[4,5-b]pyridine (502 mg, 3.66 mmol) from Step 2 of Example 70 in ous DMF (10 mL) at 0 CC was added in one portion sodium hydride (60% dispersion in mineral oil, 220 mg, 5.49 mmol), and the e was stirred at 0 CC for 30 min. To the reaction e was added a solution of 6-(chloromethyl)(methylthio)benzo[d]oxazole (858 mg, 4.03 mmol) from Step 3 of Example 56 in DMF (2 mL). The mixture was allowed to warm to rt and stir for a further 3 h. To the reaction mixture was added water and the mixture was extracted with ethyl acetate (3 X 100 mL). The combined organic layers were washed tially with water and brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash tography eluting with 30 to 50% ethyl acetate in petroleum ether to afford 6- ((6-fluoro-3H—imidazo[4,5-b]pyridinyl)methyl)(methylthio)benzo[d]oxazole (698 mg, 61%) as a white solid. The regiochemistry of the alkylation was determined by 2-dimensional nuclear Overhauser effect (NOE) experiment. 1H NMR (300 MHz, 6): 5 8.71 (s, 1H), 8.41 (s, 1H), 8.07 (d, J: 6. 9 Hz, 1H), 7.68 (s, 1H), 7.58 (d, J: 7.8 Hz, 1H), 7.35 (d, J: 6.3 Hz, 1H), 5.59 (s, 2H), 2.73 (s, 3H); LCMS (ESI) m/Z 315 (M+H)+.

Step 2: To a d solution of 6-((6-fiuoro-3H-imidazo[4,5-b]pyridin yl)methyl)(methylthio)benzo[d]oxazole (595 mg, 1.89 mmol) from the previous step in DCM (10 mL) at 0 0C was added 70% meta-chloroperbenzoic acid (425 mg, 2.46 mmol). The reaction mixture was stirred at 0 CC for 2 h. The reaction mixture was washed sequentially with aq sodium sulfite and brine. The organic layer was separated, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash tography eluting with 50% ethyl acetate in petroleum ether to afford 6-((6-fiuoro-3H—imidazo[4,5-b]pyridin- 3-yl)methyl)(methylsulfinyl)benzo[d]oxazole (509 mg, 82%). 1H NMR (300 MHZ, DMSO-d6): 5 8.73 (s, 1H), 8.40 (s, 2H), 7.53 (d, J: 7.2 Hz, 1H), 7.37 (s, 1H), 7.15 (d, J: 4.5 Hz, 1H), 5.69 (s, 2H), 3.18 (s, 3H); LCMS (ESI) m/z 331 (M+H)+.

Step 3: A stirred mixture of 6-((6-fiuoro-3H-imidazo[4,5-b]pyridin yl)methyl)(methylsulfinyl)benzo[d]oxazole (220 mg, 0.67 mmol) from the preVious step, )amino-cyclohexanol (152 mg, 1 mmol), and DIEA (259 mg, 2.01 mmol) in DMA (5 mL) was heated at 135 CC for 2 h. The reaction mixture was cooled to rt, poured into water (30 mL), and extracted with ethyl acetate (50 mL X 3).

The combined organic layers were washed sequentially with water and brine. The organic layer was separated, dried over sodium e, filtered, and concentrated under reduced pressure. The residue was d directly by preparative e- phase HPLC to afford (1R,2R)((6-((6-fiuoro-3H—imidazo[4,5-b]pyridin yl)methyl)benzo[d]oxazolyl)amino)cyclohexanol (68 mg, 27%) as a yellow solid. 1H NMR (300 MHz, DMSO-d6): 5 8.67 (s, 1H), 8.41 (m, 1H), 8.06 (m, 1H), 7.79 (m, 1H), 7.39 (s, 1H), 7.13 — 7.15 (m, 2H), 5.48 (s, 2H), 4.67 (d, J: 3.9 Hz, 1H), 3.30 — 3.35 (m, 2H), 1.86 — 1.95 (m, 2H), 1.60 — 1.65 (m, 2H), 1.15 — 1.35 (m, 4H); LCMS (ESI) m/Z 382 (M+H)+.

Example 133 Pre aration of IR 2R 6- 6-br0m0-3H—imidazo 4 5-b ridin l meth lbenzo thiazol-Z- 1 amino c clohex l methanol WO 56070 PCT/U82012/059983 //\N S N U />—NH g—OH Step 1: To a stirred solution of (1R,2R)aminocyclohexanecarboxylic acid (500 mg, 3.49 mmol) in anhydrous THF (3 mL) at 0 0C was added se a solution of LAH (2M on in THF, 7 mL, 13.99 mmol). The on vessel was sealed and the mixture was stirred at 85 0C for 24 h. The mixture was cooled to 0 oC and diluted with THE (6 mL). To the reaction mixture was added sequentially water (0.5 mL), 1M aq NaOH (0.5 mL), and water (1.5 mL). To the mixture was added MgSO4 and the mixture was stirred at rt for 10 min. The mixture was then diluted with THF (10 mL) and filtered, and the filtrate was concentrated under reduced pressure to afford ((1R,2R)aminocyclohexyl)methanol (326 mg, 70%) as an oil. 1H NMR (300 MHz, DMSO-d6) 8 3.27 - 3.52 (m, 3H), 2.29 (dt, J: 10.1, 4.0Hz, 1H), 1.53 - 1.78 (m, 4H), 0.98 - 1.21 (m, 4H), 0.87 (m, 1H).

Step 2: ((lR,2R)((6-((6-Bromo-3H—imidazo[4,5-b]pyridin yl)methyl)benzo[d]thiazolyl)amino)cyclohexyl)methanol (18 mg, 18%) was obtained as a solid using a procedure ous to that described in Step 5 of Example 70, substituting 6-((6-bromo-3H-imidazo[4,5-b]pyridinyl)methyl) (methylsulfinyl)benzo[d]thiazole from Step 4 of Example 29 for 6-((6-fluoro-3H— imidazo[4,5-b]pyridinyl)methyl)(methylsulfinyl)benzo[d]thiazole used in Example 70, and substituting ((1R,2R)aminocyclohexyl)methanol from Step 1 of this Example for (1R,2R)aminocyclohexanol used in Example 70. 1H NMR (500 MHz, DMSO-d6) 8 8.65 (s, 1H), 8.48 (d, J: 2.0 Hz, 1H), 8.39 (d, J: 2.0 Hz, 1H), 8.00 (d, J: 8.4 Hz, 1H), 7.65 (d, J: 1.0 Hz, 1H), 7.28 (m, 1H), 7.22 (m, 1H), 5.47 (s, 2H), 4.46 (t, J: 5.4 Hz, 1H), 3.55 (br m, 1H), 3.41 (m, 1H), 3.30 (m, 1H), 1.98 (d, J: 8.9 Hz, 1H), 1.83 (d,.]= 10.8 Hz, 1H), 1.62 - 1.73 (m, 2H), 1.37 (m, 1H), 1.12 - 1.29 (m, 4H) LCMS (ESI) m/Z 472, 474 (M+H)+.

Example 134 Pre aration of IR 2R 6- 6- l-meth l-lH-tetrazol-S- l-3H-imidaz0 4 5- b ridin l meth l benzo d thiazol-Z- 1 amino c clohexanol NrN/US NH / 3‘2 §H (1R,2R)((6-((6-(1-Methyl-1H-tetrazolyl)-3H-imidazo[4,5-b]pyridin- ethyl)benzo[d]thiazolyl)amino)cyclohexanol (30 mg, 10%) was obtained as a minor product from the reaction described in e 94. The regiochemical assignment was consistent with the result from a NMR nuclear Overhauser effect (NOE) experiment. 1H NMR (500 MHz, DMSO-d6) 8 8.76 - 8.84 (m, 2H), 8.60 (d, J = 2.0 Hz, 1H), 8.00 (d, J: 7.4 Hz, 1H), 7.71 (s, 1H), 7.67 (d, J: 19.7 Hz, 1H), 7.28 7.35 (m, 2H), 7.20 - 7.28 (m, 2H), 5.56 (s, 3H), 4.77 (br s, 1H), 3.50 (br s, 2H), 2.03 (d, J: 11.8 Hz, 1H), 1.87 (d, J: 11.3 Hz, 1H), 1.52 - 1.69 (m, 2H), 1.08 - 1.34 (m, 4H). LCMS (ESI) m/Z 462 (M+H)+.

Example 135 To a d solution of (1R,2R)((6-((7-(2-methoxyethoxy)imidazo[1,2- a]pyridinyl)methyl)benzo[d]thiazolyl)amino)cyclohexanol (45 mg, 0.099 mmol) from Example 153 in 2 mL ofDCM at -10 0C was added BBr3 in DCM (1.0 M, 110 uL, 0.11 mmol). The resulting mixture was stirred at rt for 30 min before it was cooled to -10 0C and additional BBr3 in DCM (1.0 M, 100 uL, 0.10 mmol) was added.

After stirring at rt ght, BBr3 in DCM (1.0 M, 100 uL, 0.10 mmol) was added and stirring was continued for 1 d. The resulting mixture was quenched with MeOH and the mixture was purified by reverse-phase preparative HPLC using a mixture of water (5% CH3CN, 0.05% HCOOH) and CH3CN (0.05% HCOOH) as the mobile phase and Varian Pursuit XRs C18 column as the stationary phase to afford(1R,2R)— 2-((6-((7-(2-hydroxyethoxy)imidazo[ 1 ,2-a]pyridinyl)methyl)benzo [d]thiazol 2012/059983 y1)amin0)cyc10hexan01 (16 mg, 37%). 1H NMR (500 MHZ, DMSO-d6) 8 8.00 (d, J = 7.9 Hz, 1H), 7.91 (d, J: 7.4 Hz, 1H), 7.49 (s, 1H), 7.26 (d, J: 8.4 Hz, 1H), 7.22 (s, 1H), 7.06 (d, J: 8.4 Hz, 1H), 6.90 (d, J: 2.0 Hz, 1H), 6.57 (dd, J: 2.5, 7.4 Hz, 1H), 4.79 (br s, 1H), 4.22 (s, 2H), 4.02 (t, J: 4.7 Hz, 2H), 3.72 (t, J: 4.7 Hz, 2H), 3.50 (br s, 2H), 2.04 (d, J: 12.8 Hz, 1H), 1.87 (d, J: 11.3 Hz, 1H), 1.54 - 1.68 (m, 2H), 1.10 — 1.37 (m, 4H). LCMS (ESI) m/Z 439 (M+H)+.

Example 136 Pre aration of 1S 2R 6- 6-bromo-3H—imidazo 4 5-b ridin l meth lbenzo thiazol 1 amino c clohex l methanol Sifii Step 1: ((1S,2R)—2-Amin0cyc10hexy1)methan01 (460 mg, 64%) was obtained as a solid using a procedure analogous to that described in Step 1 of Example 133, substituting (1S,2R)amin0cyc10hexanecarboxy1ic acid hydrochloride for (1R,2R)aminocyclohexanecarboxylic acid used in Example 133. 1H NMR (500 MHz, DMSO-d6) 8 3.40 (m, 1H), 3.28 (dd, J: 10.6, 6.2 Hz, 1H), 3.04 (q, .1: 3.4 Hz, 1H), 1.44 - 1.58 (m, 5H), 1.23 - 1.43 (m, 6H), 1.17 (m, 1H).

Step 2: ((1S,2R)—2-((6-((6-Brom0-3H—imidazo[4,5-b]pyridin y1)methy1)benz0[d]thiaz01y1)amino)cyc10hexy1)methan01 (7 mg, 19%) was obtained as a solid using a procedure analogous to that described in Step 5 of Example 70, substituting br0mo-3H—imidazo[4,5-b]pyridiny1)methy1) (methylsulfiny1)benz0[d]thiaz01e from Step 4 of Example 29 for 6-((6-flu0r0-3H— imidazo[4,5-b]pyridiny1)methy1)(methy1su1finy1)benz0[d]thiaz01e used in Example 70, and substituting ((1S,2R)aminocyclohexy1)methan01 from Step 1 of this Example for (1R,2R)amin0cyc10hexan01 used in Example 70. 1H NMR (500 MHz, DMSO-d6) 5 8.66 (s, 1H), 8.48 (d, J: 2.0 Hz, 1H), 8.39 (d, J: 2.0 Hz, 1H), 7.92 (d, J: 8.4 Hz, 1H), 7.65 (d, J: 1.0 Hz, 1H), 7.28 (m, 1H), 7.23 (m, 1H), 5.48 (s, 2H), 4.61 (br s, 1H), 4.23 (br s, 1H), 3.27 (m, 1H), 3.21 (m, 1H), 1.81 (m, 1H), 1.74 (m, 1H), 1.63 (m, 1H), 1.39 - 1.52 (m, 4H), 1.21 - 1.37 (m, 2H); LCMS (ESI) m/z 472, 474 (M+H)+.

Example 137 Pre aration of IR 2R 6- 5 6-dichlor0-3H-imidazo 4 5-b ridin Step 1: 5,6-Dichloro-N-((2-(methylthio)benzo[d]thiazolyl)methyl) yridinamine (105 mg) was obtained as an yellow solid using a procedure analogous to that described in Step 5 of Example 23, substituting 2,3,6-trichloro nitropyridine for 2-chloromethoxynitropyridine used in Example 23. LCMS (ESI) m/Z 401, 403, 405 (M+H)+.

Step 2: (lR,2R)((6-((5,6-Dichloro-3H-imidazo[4,5-b]pyridin hyl)benzo[d]thiazolyl)amino)cyclohexanol (35 mg, 31%) was obtained using procedures analogous to those bed in Step 6-9 of Example 23, substituting ,6-dichloro-N-((2-(methylthio)benzo[d]thiazolyl)methyl)nitropyridinamine from Step 1 of this Example for 6-methoxy-N2-((2-(methylthio)benzo[d]thiazol yl)methyl)pyridine-2,3-diamine used in Step 6 of e 23, and making the analogous substitutions in the subsequent steps. 1H NMR (500 MHz, DMSO-d6) 8 8.69 (s, 1H), 8.52 (s, 1H), 7.98 (d, J: 7.9 Hz, 1H), 7.63 (s, 1H), 7.30 (d, J: 8.4 Hz, 1H), 7.19 (d, J: 7.9 Hz, 1H), 5.45 (s, 2H), 4.74 (br s, 1H), 3.51 (br s, 1H), 2.03 (d, J = 11.8 Hz, 1H), 1.86 (br s, 1H), 1.52 - 1.69 (m, 2H), 1.06 - 1.34 (m, 4H). LCMS (ESI) m/Z 448, 450, 452 (M+H)+.

Example 138 Pre aration of IR 2R 6- 5-eth0x -1H-benzo imidazol—l- l meth lbenzo thiazol-Z- 1 amino c clohexanol N/ NU />—NH/\ ?: QH N 3 : ] A mixture of 1-((2-(((1R,2R) hydroxycyclohexyl)amino)benzo[d]thiazolyl)methyl)— 1H-benzo[d]imidazol-5 -01 (80 mg, 0.20 mmol) from Example 147, iodoethane (47 mg, 0.30 mmol) and C82C03 (196 mg, 0.6 mmol) in NMP (3.5 mL) was d at rt for 5 h. The mixture was added to water and extracted with DCM. The organic layer was separated, washed sequentially with water and brine, dried over Na2S04, filtered, and concentrated under d pressure. The residue was purified by reverse-phase preparative HPLC to afford (1R,2R)((6-((5 -ethoxy- 1H-benzo [d]imidazolyl)methyl)benzo azol yl)amino)cyclohexanol (35 mg, 42%) as a white solid. 1H NMR (300 MHz, DMSO- d6) 5 8.30 (s, 1H), 7.96 (d, J: 7.5 Hz, 1H), 7.62 (s, 1H), 7.39 (d, J: 9.0 Hz, 1H), 7.29 (d, J: 8.4 Hz, 1H), 7.14 — 7.19 (m, 2H), 6.82 (d, J: 9.0 Hz, 1H), 5.41 (s, 2H), 4.72 (d, J: 4.8 Hz, 1H), 3.97 — 4.04 (m, 2H), 3.43 — 3.54 (m, 2H), 2.03 (m, 1H), 1.87 (m, 1H), 1.60 — 1.65 (br m, 2H), 1.32 (t, J: 13.8 Hz, 3H), 1.15 — 1.24 (m, 4H). LCMS (ESI) m/Z 423 (M+H)+.

Example 139 Pre aration of 3- 2- 1R 2R h drox c clohex 1 amino benzo d thiazol l meth l -3H-imidaz0 4 5-b ridine—S 6-dicarb0nitrile 3-((2-(((1R,2R)Hydroxycyclohexyl)amino)benzo[d]thiazol hyl)-3H-imidazo[4,5-b]pyridine-5,6-dicarbonitrile was obtained as a white powder (7 mg, 21%) using a procedures analogous to those described in Example 43, substituting (1R,2R)((6-((5,6-dichloro-3H-imidazo[4,5-b]pyridin yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol from Example 137 for (1R,2R)- 2-((6-((6-bromo-3H—imidazo[4,5-b]pyridinyl)methyl)benzo[d]thiazol yl)amino)cyclohexanol used in Example 43. 1H NMR (500 MHZ, DMSO-d6) 8 9.10 (s, 1H), 9.03 (s, 1H), 8.08 (d, J: 7.4 Hz, 1H), 7.66 (s, 1H), 7.27 - 7.36 (m, 1H), 7.24 (d, J: 8.4 Hz, 1H), 5.56 (s, 2H), 4.84 (br s, 1H), 3.46 - 3.64 (m, 2H), 2.03 (d, J: 11.8 Hz, 1H), 1.87 (d,.]= 10.8 Hz, 1H), 1.51 - 1.70 (m, 2H), 1.08 - 1.39 (m, 4H). LCMS (ESI) m/Z 430 (M+H)+.

Example 140 Pre aration of 3- 2- 1R 2R h drox meth lc clohex lamino benzo thiazol lmeth l-3H-imidaz0 4 5- b |pyridine—6-carbonitrile //\N S N U />—NH s—OH \ / O 3-((2-(((1R,2R)(Hydroxymethyl)cyclohexyl)amino)benzo[d]thiazol yl)methyl)-3H—imidazo[4,5-b]pyridinecarbonitrile was obtained as a solid (18 mg, 19%) using a procedure analogous to that described in Example 43, substituting R)((6-((6-bromo-3H—imidazo[4,5-b]pyridinyl)methyl)benzo[d]thiazol no)cyclohexyl)methanol from e 133 for (1R,2R)((6-((6-bromo-3H- o[4,5-b]pyridinyl)methyl)benzo[d]thiazolyl)amino)cyclohexanol used in Example 43. 1H NMR (500 MHz, DMSO-d6) 5 8.84 (s, 1H), 8.82 (d, J: 1.5 Hz, 1H), 8.72 (d, J: 1.5 Hz, 1H), 8.01 (d, J: 8.4 Hz, 1H), 7.67 (s, 1H), 7.28 (m, 1H), 7.24 (m, 1H), 5.53 (s, 2H), 4.46 (br m, 1H), 3.55 (br m, 1H), 3.41 (d, J: 9.8 Hz, 1H), 3.30 (m, 1H), 1.98 (m, 1H), 1.83 (d,.]= 10.8 Hz, 1H), 1.62 - 1.73 (m,2H), 1.37 (m, 1H), 1.17 - 1.27 (m, 4H); LCMS (ESI) m/Z 419 (M+H)+.

Example 141 Pre aration of IR 2R 6- 6- 1H- razol—l- l-3H-imidaz0 4 5-b ridin To a stirred solution of CuI (14 mg, 0.0053 mmol), K2C03 (102 mg, 0.74 mmol), and pyrazole (30 mg, 0.44 mmol) in 2 mL ofDMF under argon was added (1R,2R)((6-((6-iodo-3H-imidazo[4,5-b]pyridinyl)methyl)benzo[d]thiazol yl)amino)cyclohexanol from Step 2 of Example 96 (150 mg, 0.30 mmol) and trans- Nl,NZ-dimethylcyclohexane-1,2-diamine (21 mg, 0.15 mmol). The reaction mixture was then heated at 110 0C overnight. The mixture was cooled to rt, diluted with MeOH, and purified by preparative HPLC using a mixture of water (5% CH3CN, 0.05% AcOH) and CH3CN (0.05% AcOH) as the mobile phase and Varian Pursuit XRs Diphenyl column as the stationary phase to afford (1R,2R)((6-((6-(1H- pyrazolyl)-3H-imidazo [4,5 -b]pyridin-3 -yl)methyl)benzo [d]thiazol yl)amino)cyclohexanol (85 mg, 64%) as a white solid. 1H NMR (500 MHZ, DMSO- d6) 8 8.92 (d, J: 2.0 Hz, 1H), 8.69 (s, 1H), 8.57 (d, J: 2.5 Hz, 1H), 8.50 (d, J: 2.5 Hz, 1H), 7.96 (d, J: 7.4 Hz, 1H), 7.79 (s, 1H), 7.68 (s, 1H), 7.29 (s, 1H), 7.20 - 7.27 (m, 1H), 6.58 (s, 1H), 5.52 (s, 2H), 4.74 (br s, 1H), 3.51 (br s, 1H), 2.03 (d, J: 12.3 Hz, 1H), 1.80 - 1.95 (m, 1H), 1.52 - 1.72 (m, 2H), 1.08 - 1.33 (m, 4H). LCMS (ESI) m/Z 446 (M+H)+.

Example 142 Pre aration of IR 2R 6- imidazo 1 2-b ridazin lmeth l benzo d oxazol-Z- 1 amino c anol \ O Nmg? NH 43H Step 1: A mixture of 6-iodobenzo[d]oxazol-2(3H)-one (3.2 g, 12.3 mmmol) in 30 mL of toluene was heated with Lawesson’s t (2.7 g, 6.7 mmol) at 100 0C for 4 h. Solvent was then removed under reduced pressure and the residue was cooled to rt and dissolved in 20 mL of DMF. To the mixture was added K2C03 (8.4 g, 61.2 mmol) and iodomethane (2.27 mL, 36.7 mmol). The resulting mixture was d at rt overnight and heated at 55 0C for 1h. After cooling to rt, the reaction mixture was ioned between EtOAc and water, and the organic layer was washed with brine, dried over Na2S04, filtered, and evaporated under reduced pressure. The residue was purified on by silica gel column chromatography g with 0-25% EtOAc in hexanes to give 6-iodo(methylthio)benzo[d]oxazole as a white solid (1.5 g, 42%). LCMS (ESI) m/Z 292 .

Step 2: Crude 2-chloro(2-(methylthio)benzo[d]oxazolyl)propanal (120 mg) was ed using procedures analogous to those described in Steps 3-4 of Example 117, substituting 6-iodo(methylthio)benzo[d]oxazole from Step 1 of this Example for 6-iodo(methylthio)benzo[d]thiazole used in Step 3 of Example 117, and making the analogous substitution in Step 4 of Example 117. LCMS (ESI) m/Z 256, 258 (M+H)+.

Step 3: (1R,2R)((6-(Imidazo[1,2-b]pyridazin ylmethyl)benzo[d]oxazolyl)amino)cyclohexanol (20 mg) was obtained as a tan solid using ures analogous to those described in Steps 1-3 of Example 131, substituting 2-chloro(2-(methylthio)benzo[d]oxazolyl)propanal from Step 2 of this Example for 2-chloro(2-(methylthio)benzo[d]thiazolyl)propanal used in Step 1 of Example 131, and making the analogous substitutions in Steps 2 and 3 of Example 131. 1H NMR (500 MHZ, 6) 8 8.53 (d, J: 3.0 Hz, 1H), 8.09 (d, J: 9.4 Hz, 1H), 7.74 (d, J: 7.4 Hz, 1H), 7.58 (s, 1H), 7.25 (s, 1H), 7.19 (dd, J: 4.4, 8.9 Hz, 1H), 7.06 - 7.13 (m, 1H), 7.03 (d, J: 7.9 Hz, 1H), 4.74 (br s, 1H), 4.33 (s, 2H), 1.96 (d, J: 9.4 Hz, 1H), 1.88 (d, J: 10.3 Hz, 1H), 1.63 (br s, 2H), 1.23 (d, J: 6.4 Hz, 4H). LCMS (ESI) m/Z 364 (M+H)+. e 143 Pre aration of 3- 2- 1R 2R h drox c clohex 1 amino benzo d thiazol l meth l -N-meth limidazo 1 2-b ridazine—6-carb0xamide \ s Nm)—NH \N N ~ n C Step 1: Ethyl 3-((2-(methylthio)benzo[d]thiazolyl)methyl)imidazo[1,2- b]pyridazinecarboxylate (272 mg, 54%) was obtained as a white solid using a ure analogous to that described in Step 6 of Example 117, substituting ethyl 6- aminopyridazinecarboxylate for 2-aminoisonicotinonitrile used in Example 117.

LCMS (ESI) m/Z 385 (M+H)+.

Step 2: Ethyl 3-((2-(methylthio)benzo[d]thiazolyl)methyl)imidazo[1,2- b]pyridazinecarboxylate (115 mg, 0.3 mmol) was heated with 2 mL of 2.0 M NH2M€ in THF at 85 0C in a sealed tube for 1h, at 100 0C for 1 h, then at 110 0C overnight. LCMS analysis showed that the on was complete. Solvent was evaporated under reduced pressure, and the residue was dried in a vacuum oven to give N-methyl((2-(methylthio)benzo[d]thiazolyl)methyl)imidazo[ 1 ,2- b]pyridazinecarboxamide, which was used directly for the next step. LCMS (ESI) m/Z 370 (M+H)+.

Step 3: 3-((2-(((1R,2R)Hydroxycyclohexyl)amino)benzo[d]thiazolyl)methyl)- N—methylimidazo[1,2-b]pyridazinecarboxamide (55 mg, 42%) was obtained as a tan solid using procedures analogous to those described in Step 5 of Example 3 followed by Step 5 of Example 2, tuting N-methyl((2- (methylthio)benzo[d]thiazolyl)methyl)imidazo[ 1 yridazinecarboxamide from Step 2 of this Example for 6-((3H-imidazo[4,5-b]pyridinyl)methyl) (methylthio)benzo[d]thiazole used in Example 3, and making the analogous substitution in Step 5 of Example 2. 1H NMR (500 MHZ, DMSO-d6) 8 8.83 (d, J = 4.9 Hz, 1H), 8.20 (d, J: 9.4 Hz, 2H), 7.88 (d, J: 7.9 Hz, 1H), 7.60 - 7.71 (m, 3H), 7.24 - 7.32 (m, 1H), 7.15 - 7.24 (m, 1H), 4.76 (br s, 1H), 4.44 (s, 2H), 3.51 (br s, 1H), 2.89 (d, J: 4.4 Hz, 3H), 2.04 (d, J: 11.8 Hz, 1H), 1.87 (d, J: 11.3 Hz, 1H), 1.53 - 1.72 (m, 2H), 1.09 - 1.40 (m, 4H). LCMS (ESI) m/z 437 (M+H)+.

Example 144 Pre aration of IR 2R 6- 6- h drox meth l imidazo 1 2-b ridazin l meth l benzo d thiazol-Z- 1 amino c clohexanol Step 1: -(Methylthio)benzo[d]thiazolyl)methyl)imidazo[1,2- b]pyridazinyl)methanol (48 mg, 34%) was obtained as a white solid using a procedure analogous to that described in Step 2 of Example 2, substituting ethyl 3-((2- (methylthio)benzo[d]thiazolyl)methyl)imidazo[ 1 yridazinecarboxylate from Step 1 of Example 143 for ethyl 2-bromobenzo[d]thiazolecarboxylate used in Example 2. LCMS (ESI) m/Z 343 (M+H)+.

Step 2: (lR,2R)((6-((6-(Hydroxymethyl)imidazo[1,2-b]pyridazin yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol (15 mg, 26%) was ed as a yellow powder using procedures analogous to those described in Step 5 of Example 3 followed by Step 5 of Example 2, tuting (3-((2-(methylthio)benzo[d]thiazol yl)methyl)imidazo[1,2-b]pyridazinyl)methanol from Step 1 of this Example for 6- ((3H-imidazo[4,5-b]pyridinyl)methyl)(methylthio)benzo[d]thiazole used in Example 3, and making the analogous substitution in Step 5 of Example 2. 1H NMR (500 MHz, DMSO-d6) 8 8.07 (d, J: 9.4 Hz, 1H), 7.91 (d, J: 7.4 Hz, 1H), 7.55 (s, 1H), 7.50 (s, 1H), 7.21 - 7.30 (m, 2H), 7.13 (d, J: 8.4 Hz, 1H), 4.79 (br s, 1H), 4.60 (s, 2H), 4.28 (s, 2H), 3.50 (br s, 2H), 2.04 (d, J: 11.8 Hz, 1H), 1.87 (d, J: 10.8 Hz, 1H), 1.52 - 1.70 (m, 2H), 1.06 - 1.36 (m, 4H). LCMS (ESI) m/z 410 (M+H)+.

WO 56070 Example 145 Pre n of IR 2R 6- 6- 1H-1 2 4-triazol l -3H-imidaz0 4 5- (1R,2R)((6-((6-(1H-1,2,4-Triazolyl)-3H-imidazo[4,5-b]pyridin yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol (48 mg, 45%) was obtained as a yellow powder using a ure analogous to that described in Example 141, substituting 1,2,4-triazole for pyrazole used in Example 141. 1H NMR (500 MHz, DMSO-d6) 8 9.30 (s, 1H), 8.89 (d, J: 2.0 Hz, 1H), 8.76 (s, 1H), 8.56 (d, J: 2.0 Hz, 1H), 8.29 (s, 1H), 7.99 (d, J: 7.4 Hz, 1H), 7.69 (s, 1H), 7.28 - 7.34 (m, 1H), 7.17 - 7.26 (m, 1H), 5.54 (s, 2H), 4.76 (br s, 1H), 3.47 - 3.60 (m, 2H), 2.03 (d, J: 11.8 Hz, 1H), 1.86 (m, 1H), 1.52 - 1.70 (m, 2H), 1.10 - 1.34 (m, 4H). LCMS (ESI) m/z 447 (M+H)+.

Example 146 Pre aration of IR 2R 6- 6-i0d0-3H-imidaz0 4 5-b ridin /\ S N/ N/\©: />—NH §H (1R,2R)((6-((6-Iodo-3H-imidazo[4,5-b]pyridin yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol was obtained as an off-white solid using procedures analogous to those bed in Steps 4-5 of Example 3 follwed by Step 5 of Example 2, substituting 6-iodo-3H-imidazo[4,5-b]pyridine from Step 1 of Example 96 for 3H-imidazo[4,5-b]pyridine used in Step 4 of Example 3, and making the analogous substitutions in Step 5 of Example 3 and Step 5 of Example 2. 1H NMR (500 MHz, DMSO-d6) 8 8.59 (s, 1H), 8.56 (s, 1H), 8.49 (s, 1H), 8.06 (d, J = 7.4 Hz, 1H), 7.64 (s, 1H), 7.23 - 7.32 (m, 1H), 7.19 (d, J: 8.4 Hz, 1H), 5.46 (s, 2H), 4.84 (br s, 1H), 3.50 (br s, 2H), 2.03 (d, J: 11.8 Hz, 1H), 1.86 (d, J: 10.8 Hz, 1H), 1.53 - 1.67 (m, 2H), 1.09 - 1.36 (m, 4H). LCMS (ESI) m/z 506 (M+H)+.

Example 147 Pre aration of 1- 2- 1R 2R h drox c clohex lamino benzo thi azol lmeth l-lH-benzo imidazol—S-ol % S N N/U />—NH2: 9H N 3 s Step 1: To a stirred mixture of 4-(benzyloxy)nitroaniline (2.0 g, 8.2 mmol) in TFA (14 mL) at —15 0C was added sodium triacetoxyborohydride (2.84 g, 12 mmol). Then a solution of 2-(methylthio)benzo[d]thiazolecarbaldehyde (l .9 g, 9.0 mmol) fiom Step 1 of Example 100 in DCM (10 mL) was added dropwise. The reaction mixture was allowed to warm to 0 CC and stir for 2 h. The mixture was ioned n DCM and water. The organic layer was separated and washed sequentially with saturated aq NaHCOg and brine. The organic layer was separated, dried over Na2S04, d, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with a gradient of 10% EtOAc in petroleum ether to 100% EtOAc to afford 4-(benzyloxy)-N—((2- (methylthio)benzo[d]thiazolyl)methyl)nitroaniline (2.3 g, 64%) as a red-brown solid. 1H NMR (300 MHz, CDC13)8 8.34 (s, 1H), 7.84 (d, J: 8.4 Hz, 1H), 7.72 — 7.77 (m, 2H), 7.33 — 7.43 (m, 6H), 7.14 (m, 1H), 6.76 (d, J: 9.6 Hz, 1H), 5.02 (s, 2H), 4.64 (d, J: 5.7 Hz, 2H), 2.79 (s, 3H); LCMS (ESI) m/z 438 (M+H)+.

] Step 2: To a mixture of 4-(benzyloxy)-N-((2-(methylthio)benzo[d]thiazol- 6-yl)methyl)nitroaniline (2.8 g, 6.42 mmol) from the previous step, HOAc (7.5 mL), MeOH (7.5 mL) and DCM (50 mL) at 0 0C was added portionwise zinc dust (4.25 g, 65.4 mmol). The reaction mixture was stirred at 5 CC for l h. The mixture was filtered and the filtrate was d with DCM and washed tially with water and saturated aq NaHC03. The organic layer was separated, dried over Na2S04, filtered, and trated under reduced pressure to afford 4-(benzyloxy)-N1-((2- (methylthio)benzo[d]thiazolyl)methyl)benzene-l,2-diamine (2.49 g, 95%) as a light orange solid which was not purified further. 1H NMR (300 MHZ, CDClg) 8 7.83 (d, J: 8.4 Hz, 1H), 7.77 (s, 1H), 7.26 — 7.44 (m, 7H), 6.59 (d, J: 8.4 Hz, 1H), 6.46 (s, 1H), 6.38 (m, 1H), 4.97 (s, 2H), 4.34 (s, 2H), 3.54 (br s, 2H), 2.80 (s, 3H). LCMS (ESI) m/Z 408 (M+H)+.

] Step 3: A mixture of zyloxy)-N1-((2-(methylthio)benzo[d]thiazol yl)methyl)benzene-1,2-diamine (2.49 g, 6.1 mmol) from the previous step, triethylorthoformate (60 mL), and formic acid (1.22 g) was d at 90 CC for 2 h.

The reaction e was cooled to rt, and then concentrated under reduced pressure.

The residue was purified by silica gel flash chromatography eluting with a gradient of 50% EtOAc in petroleum ether to 100% EtOAc to afford 6-((5-(benzyloxy)-1H— benzo[d]imidazolyl)methyl)(methylthio)benzo[d]thiazole (1.6 g, 62%) as a light yellow solid. 1H NMR (300 MHz, CDClg) 8 7.93 (s, 1H), 7.82 (d, J: 8.4 Hz, 1H), 7.50 (s, 1H), 7.44 — 7.49 (m, 2H), 7.30 — 7.40 (m, 4H), 7.26 (m, 1H), 7.13 (d, J: 9.0 Hz, 1H), 6.98 (m, 1H), 5.41 (s, 2H), 5.10 (s, 2H), 2.77 (s, 3H); LCMS (ESI) m/z 418 (M+H)+.

Step 4: A mixture of 6-((5-(benzyloxy)—1H—benzo[d]imidazol yl)methyl)(methylthio) benzo[d]thiazole (1.6 g, 3.8 mmol) from the us step and meta-chloroperbenzoic acid (0.82 g, 4.75 mmol) in DCM (38 mL) was stirred at 0 CC for 2 h. The mixture was diluted with DCM and washed sequentially with aq NaZSZOg, saturated aq , and water. The organic layer was separated, dried over Na2S04, filtered, and concentrated under reduced pressure to afford 6-((5- (benzyloxy)-1H-benzo[d]imidazol- 1 thyl)(methylsulf1nyl)benzo [d]thiazole (1.58 g, 96%) as a yellow solid. 1H NMR (300 MHz, CDClg) 8 8.02 (d, J: 8.4 Hz, 1H), 7.96 (s, 1H), 7.76 (s, 1H), 7.44 — 7.47 (m, 2H), 7.31 — 7.40 (m, 5H), 7.12 (d, J: 8.7 Hz, 1H), 6.97 (m, 1H), 5.49 (s, 2H), 5.11 (s, 2H), 3.08 (s, 3H); LCMS (ESI) m/z 434 (M+H)+.

Step 5: A stirred mixture of 6-((5-(benzyloxy)-1H—benzo[d]imidazol yl)methyl)(methylsulf1nyl) benzo[d]thiazole (1.48 g, 3.4 mmol) from the preVious step, (1R,2R)aminocyclohexanol hydrochloride (1.29 g, 8.5 mmol), and DIEA (2.19 g, 17 mmol) in DMA (44 mL) was heated at 138 CC for 15 h. The reaction mixture was cooled to rt and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with 2 to 6% MeOH in DCM to afford (1R,2R)((6-((5-(benzyloxy)- 1H—benzo[d]imidazol yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol (0.98 g, 59%) as a yellow solid. 1H NMR (300 MHz, CDC13)8 7.88 (s, 1H), 7.43 — 7.46 (m, 3H), 7.29 —7.39 (m, 4H), 7.25 (s, 1H), 7.13 — 7.16 (m, 2H), 6.96 (m, 1H), 5.75 (br s, 1H), 5.31 (s, 2H), 5.09 (s, 2H), 3.46 — 3.56 (m, 2H), 2.07 — 2.18 (m, 2H), 1.71 — 1.77 (m, 2H), 1.26 —1.40 (m, 4H); LCMS (ESI) m/Z 485 (M+H)+.

Step 6: To a stirred mixture of (1R,2R)((6-((5-(benzyloxy)-1H- benzo[d]imidazolyl)methyl)benzo[d]thiazolyl)amino)cyclohexanol (3 .4 g, 7.02 mmol) in DCM (40 mL) at -30 0C was added boron tribromide (3.4 mL, 35.4 mmol).

The reaction mixture was d at -30 CC for 2 h. To the mixture was added water and the pH was adjusted to 8 with aq NH4OH. The itate was collected by filtration to give a light yellow solid (2.45 g). A portion of this solid (150 mg) was purified directly by reverse-phase preparative HPLC to afford 1-((2-(((1R,2R) hydroxycyclohexyl)amino)benzo[d]thiazolyl)methyl)—1H-benzo[d]imidazol-5 -01 as a white solid (54 mg). 1H NMR (300 MHz, 6) 8 8.98 (s, 1H), 8.22 (s, 1H), 7.93 (d, J: 7.5 Hz, 1H), 7.61 (s, 1H), 7.30 (s, 1H), 7.27 (s, 1H), 7.17 (m, 1H), 6.94 (s, 1H), 6.69 (m, 1H), 5.37 (s, 2H), 4.71 (d, J: 5.4 Hz, 1H), 3.53 (m, 1H), 3.36 (m, 1H), 2.03 (m, 1H), 1.88 (m, 1H), 1.60 — 1.63 (m, 2H), 1.15 — 1.29 (m, 4H). LCMS (ESI) m/Z 395 (M+H)+.

Example 148 Pre n of IR 2R 6- 57-diflu0r0-1H—benz0 imidazol—l- l meth lbenzo thiazol-Z- 1 amino c clohexanol “1&2?!“,pH Step 1: 2,4-Difluoro-N—((2-(methylthio)benzo[d]thiazolyl)methyl) nitroaniline (0.8 g, 73%) was ed as a yellow solid using a procedure analogous to that described in Step 1 of Example 127, substituting 2,4-difluoronitroaniline for 4-methylnitroaniline used in Example 127. 1H NMR (300 MHZ, CDClg) 8 7.84 (d, J: 8.1 Hz, 1H), 7.70 — 7.74 (m, 2H), 7.36 (dd, J: 8.4, 1.8 Hz, 1H), 7.05 (m, 1H), 4.78 (d, J: 3.6 Hz, 2H), 2.79 (s, 3H); LCMS (ESI) m/z 368 (M + H)+.

Step 2: 4,6-Difluoro-N1-((2-(methylthio)benzo[d]thiazol yl)methyl)benzene-l,2-diamine (0.29 g, 91%) was obtained as a yellow solid using a procedure analogous to that described in Step 2 of Example 130, substituting 2,4- difluoro-N—((2-(methylthio)benzo[d]thiazolyl)methyl)nitroaniline from Step 1 of this Example for N—((2-(methylthio)benzo[d]thiazolyl)methyl)nitro trifluoromethyl)aniline used in Example 130. 1H NMR (300 MHZ, CDClg) 8 7.79 (d, J = 8.4 Hz, 1H), 7.70 (s, 1H), 7.35 (dd, J = 8.7, 1.8 Hz, 1H), 6.18 — 6.24 (m, 2H), 4.20 (br s, 2H), 4.13 (s, 2H), 2.79 (s, 3H); LCMS (ESI) m/z 338 (M + H)+.

Step 3: 6-((5,7-Difluoro-1H—benzo[d]imidazolyl)methyl) (methylthio)benzo[d]thiazole (0.18 g, 59%) was obtained as a yellow solid using a procedure analogous to that described in Step 3 of Example 130, substituting 4,6- difluoro-N1-((2-(methylthio)benzo[d]thiazolyl) methyl)benzene-l,2-diamine from Step 2 of this Example for N1-((2-(methylthio)benzo[d]thiazolyl)methyl) (trifluoromethyl)benzene-1,2-diamine used in Example 130. LCMS (ESI) m/Z 348 (M+H)+.

Step 4: 6-((5,7-Difluoro-1H—benzo[d]imidazolyl)methyl) (methylsulfinyl)benzo[d]thiazole (0.17 g, 90%) was obtained as a yellow solid using a procedure analogous to that described in Step 4 of Example 130, substituting 6-((5,7- difluoro- 1H-benzo[d]imidazolyl)methyl)(methylthio)benzo [d]thiazole from Step 3 of this Example for 2-(methylthio)((5-(trifluoromethyl)-1H- benzo[d]imidazolyl)methyl)benzo[d]thiazole used in Example 130. 1H NMR (300 C13)8 8.01 — 8.05 (m, 2H), 7.81 (s, 1H), 7.41 (dd, J: 8.7, 1.8 Hz, 1H), 7.32 (dd, J = 9.0, 2.1 Hz, 1H), 6.80 (t, J: 9.6 Hz, 1H), 5.64 (s, 2H), 3.06 (s, 3H); LCMS (ESI) m/Z 364 (M+H)+.

Step 5: ((1R,2R)((6-((5,7-Difluoro-1H—benzo[d]imidazolyl) methyl)benzo[d]thiazo1yl)amino)cyclohexanol (65 mg, 34.5%) was obtained as a yellow solid using a procedure analogous to that described in Step 5 of Example 130, substituting 6-((5 ,7-difluoro- 1H-benzo [d]imidazolyl)methyl) (methylsulfinyl)benzo[d]thiazole from Step 4 of this Example for hylsulfinyl)- 6-((5 -(trifluoromethyl)- zo dazolyl)methyl)benzo azole used in Example 130. 1H NMR (300 MHz, DMSO-d6) 8 8.51 (s, 1H), 7.95 (d, J = 7.8 Hz, 1H), 7.54 (s, 1H), 7.36 (dd, J = 9.3, 1.5 Hz, 1H), 7.30 (d, J: 8.1 Hz, 1H), 7.06 — 7.15 (m, 2H), 5.51 (s, 2H), 4.71 (d,.]= 5.1 Hz, 1H), 3.53 (m, 1H), 3.33 (m, 1H), 2.03 (m, 1H), 1.87 (m, 1H), 1.59 — 1.63 (m, 2H), 1.14 — 1.29 (m, 4H); LCMS (ESI) m/z 415 (M+H)+. e 149 Pre aration of IR 2R 6- 5- trifluoromethox -1H-benzo imidazol—l- l meth lbenzo thiazol-Z- lamino c clohexanol //\ s N NU />—NH: pH N :: F3CO Step 1: N—((2-(Methylthio)benzo[d]thiazolyl)methyl)nitro (trifluoromethoxy)aniline (0.85 g, 5 l%) was obtained as a yellow solid using a procedure analogous to that described in Step 1 of Example 127, substituting 2-nitro- 4-(trifluoromethoxy)aniline for 4-methylnitroaniline used in Example 127. 1H NMR (300 MHz, CDC13)5 8.49 (br s, 1H), 8.28 (d, J: 0.6 Hz, 1H), 7.94 (d, J: 3.0 Hz, 1H), 7.84 (s, 1H), 7.38 (dd, J: 8.4, 1.5 Hz, 1H), 7.29 (m, 1H), 6.83 (d, J: 9.0 Hz, 1H), 4.66 (d, J: 5.7 Hz, 2H), 2.79 (s, 3H); LCMS (ESI) m/z 416 (M + H)+.

Step 2: N1-((2-(Methylthio)benzo[d]thiazolyl)methyl) (trifluoromethoxy)benzene-l ,2-diamine (0.69 g, 88%) was obtained as a yellow solid using a procedure analogous to that described in Step 2 of e 130, substituting N—((2-(methylthio)benzo[d]thiazolyl)methyl)nitro(trifluoromethoxy)aniline from Step 1 of this Example for N—((2-(methylthio)benzo[d]thiazolyl)methyl) nitrotrifluoromethyl)aniline used in Example 130. 1H NMR (300 MHZ, CDClg) 5 7.83 (d, J: 8.4 Hz, 1H), 7.75 (s, 1H), 7.41 (dd, J: 8.4, 1.5 Hz, 1H), 6.54 — 6.65 (m, 4H), 4.35 (s, 2H), 3.48 (br s, 2H), 2.77 (s, 3H); LCMS (ESI) m/z 386 (M + H)+.

Step 3: 2-(Methylthio)((5-(trifluoromethoxy)- lH—benzo[d]imidazol-l- yl) methyl)benzo[d]thiazole (0.55 g, 79%) was ed as a yellow solid using a procedure analogous to that described in Step 3 of Example 130, substituting Nl-((2- (methylthio)benzo[d]thiazolyl)methyl)(trifluoromethoxy)benzene- l ,2-diamine from Step 2 of this Example for -(methylthio)benzo[d]thiazolyl)methyl) (trifluoromethyl)benzene-l ,2-diamine used in Example 130. 1H NMR (300 MHz, 8.03 (s, 1H), 7.83 (d, J: 8.4 Hz, 1H), 7.70 (s, 1H), 7.52 (s, 1H), 7.22 — 7.28 (m, 2H), 7.13 (m, 1H), 5.45 (s, 2H), 2.78 (s, 3H); LCMS (ESI) m/z 396 (M + H)+.

Step 4: 2-(Methylsulfinyl)((5-(trifluoromethoxy)-lH—benzo[d]imidazol- l-yl)methyl)benzo[d]thiazole (0.55 g, 96%) was ed as a yellow solid using a procedure analogous to that described in Step 4 of Example 130, substituting 2- (methylthio)((5-(trifluoromethoxy)- 1H-benzo [d]imidazolyl) methyl)benzo[d]thiazole from Step 3 of this Example for 2-(methylthio)((5- (trifluoromethyl)- 1H-benzo [d]imidazolyl)methyl)benzo [d]thiazole used in Example 130. 1H NMR (300 MHz, CDClg) 5 8.08 (s, 1H), 7.04 (d, J: 8.4 Hz, 1H), 7.79 (s, 1H), 7.71 (s, 1H), 7.38 (dd, J: 8.4, 1.8 Hz, 1H), 7.24 (m, 1H), 7.13 (m, 1H), .52 (s, 2H), 3.06 (s, 3H); LCMS (ESI) m/z 412 (M + H)+.

Step 5: (1R,2R)((6-((5-(Trifluoromethoxy)-1H—benzo[d]imidazolyl) methyl)benzo[d]thiazolyl)amino)cyclohexanol (65 mg, 35%) was obtained as a white solid using a procedure analogous to that described in Step 5 of Example 130, tuting 2-(methylsulfinyl)((5-(trifluoromethoxy)-1H-benzo[d]imidazol yl)methyl)benzo[d] le from Step 4 of this Example for 2-(methylsulf1nyl)((5- (trifluoromethyl)- 1H-benzo [d]imidazolyl)methyl)benzo [d]thiazole used in e 130. 1H NMR (300 MHZ, DMSO-d6) 5 8.54 (s, 1H), 7.93 (d, J: 6.6 Hz, 1H), 7.65 — 7.75 (m, 3H), 7.30 (d, J: 8.1 Hz, 1H), 7.21 — 7.26 (m, 2H), 5.50 (s, 2H), 4.69 (d,J= 5.1 Hz, 1H), 3.51 (m, 1H), 3.40 (m, 1H), 2.01 (m, 1H), 1.85 (m, 1H), 1.57 — 1.60 (m, 2H), 1.20 — 1.23 (m, 4H); LCMS (ESI) m/z 463 (M + H)+.

Example 150 Pre aration of IR 2R 6- 6-meth0x imidazo 1 2-b ridazin lmeth l benzo thiazol-Z- lamino c anol \ s N\ />—NH pH N F \/ O Step 1: A stirred mixture of 2-chloro-3 -(2-(methylthio)benzo[d]thiazol panal from Step 4 of Example 117 (600 mg, 2.2 mmol) and 6- methoxypyridazinamine (550 mg, 4.4 mmol) in 1-butanol (20 mL) was heated at reflux overnight. The mixture was cooled to rt and water (40 mL) was added. The mixture was extracted with EtOAc (20 mL>< 3). The combined organic layers were washed with brine, dried over Na2S04, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 50: 1 to 20: 1 DCM/MeOH to afford methoxyimidazo[1,2-b]pyridazin yl)methyl)(methylthio)benzo[d]thiazole as a light brown solid (500 mg, 66%). 1H NMR (300 MHz, CDClg) 5 .73 (m, 2H), 7.67 (d, .1: 1.2 Hz, 1H), 7.43 (s, 1H), 7.38 (dd, .1: 1.5, 8.4 Hz, 1H), 6.64 (d, .1: 9.6 Hz, 1H), 4.33 (s, 2H), 3.94 (s, 3H), 2.78 (s, 3H). LCMS (ESI) m/Z 343 (M+H)+.

Step 2: To a on of 6-((6-methoxyimidazo[1,2-b]pyridazin yl)methyl) (methylthio)benzo[d]thiazole (500 mg, 1.46 mmol) in DCM (30 mL) was added m-CPBA (314 mg, 1.82 mmol) at 0 0C. The reaction mixture was stirred for 2 h at 0 0C, then aq Na2S03 (15 mL) was added and the mixture was stirred for 0.5 h. The organic layer was separated, dried over Na2S04, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 50: 1 to 20: 1 DCM/MeOH to afford 6-((6-methoxyimidazo[1,2- b]pyridazinyl)methyl) (methylsulfinyl)benzo[d]thiazole as a yellow solid (500 mg, 95%). 1H NMR (300 MHz, CDClg) 8 7.99-7.93 (m, 2H), 7.76 (d, J: 9.6 Hz, 1H), 7.53 (dd, J: 1.5, 8.4 Hz, 1H), 7.46 (s, 1H), 6.65 (d, J: 9.3 Hz, 1H), 4.42 (s, 2H), 3.94 (s, 3H), 3.06 (s, 3H). LCMS (ESI) m/z 359 (M+H)+.

Step 3: A mixture of 6-((6-methoxyimidazo[1 ,2-b]pyridazin yl)methyl) (methylsulfinyl)benzo[d]thiazole (320 mg, 0.89 mmol), (1R,2R) amino cyclohexanol (308 mg, 2.68 mmol) and DIEA (231 mg, 1.79 mmol) in NMP (11 mL) was stirred for 1 d at 140 0C. The mixture was cooled to rt and water (50 mL) was added. The mixture was extracted with EtOAc (30 mL>< 3). The ed organic layers were washed with brine, dried over Na2S04, filtered and concentrated under reduced pressure. The e was purified by silica gel chromatography eluting with 50: 1 to 10: 1 DCM/MeOH, then further purified by ative HPLC to afford (1R,2R)((6-((6-methoxyimidazo[1,2- b]pyridazinyl)methyl)benzo[d]thiazolyl)amino)cyclohexanol as a brown solid (120 mg, 33%). 1H NMR (300 MHz, DMSO-d6) 5 7.97 (d, J: 9.6 Hz, 1H), 7.83 (d, J: 7.5 Hz, 1H), 7.61 (s, 1H), 7.44 (s, 1H), 7.26 (d, J: 8.4 Hz, 1H), 7.18 (d, J = 9.9 Hz, 1H), 6.82 (d, J: 9.6 Hz, 1H), 4.72 (d, J: 5.4 Hz, 1H), 4.23 (s, 2H), 3.95 (s, 3H), 3.52-3.49 (m, 1H), 3.39-3.36 (m, 1H), 2.05-2.01 (m, 1H), .86 (m, 1H), 1.65-1.59 (m, 2H), 1.28-1.14 (m, 4H). LCMS (ESI) m/z 410 (M+H)+.

Example 151 Pre aration of IR 2R 6- 5-meth0x nz0 d imidazol-l- l meth 1 ben z0| d| oxazol-Z-ylzamino {cyclohexanol //\ O N N/Ukmi pH N 2 s Step 1: To a solution of 4-methoxynitroaniline (500 mg, 2.99 mmol) and TFA (3.07 mL) in DCM (15 mL) at 5 0C was added NaBH(OAc)3 (1.9 g, 8.97 mmol). To the resulting mixture at 0 0C was added a solution of 2- (methylthio)benzo[d]oxazolecarbaldehyde (630 mg, 3.29 mmol) in DCM (10 mL), and. the mixture was stirred at 0 0C for 2 h. The reaction mixture was d with DCM and washed sequentially with H20, aq NaHCOg and brine. The organic layer was dried over Na2S04 and concentrated under reduced pressure to give 4-methoxy- N—((2-(methylthio)benzo[d]oxazolyl)methyl)nitroaniline as a light brown solid (1.08g, quantitative). 1H NMR (300 MHz, DMSO-d6) 5 8.62 (t, 1H), 7.64 (s, 1H), 7.58 (d, J: 8.4 Hz, 1H), 7.52 (s, 1H), 7.37 (d, J: 9.3 Hz, 1H), 7.18 (d, J: 6.0 Hz, 1H), 6.93 (d, J: 9.3 Hz, 1H), 4.71 (d, J: 5.7 Hz, 1H), 3.72 (s, 3H), 2.75 (s, 3H).

LCMS (ESI) m/Z 346 (M+H)+.

Step 2: To a stirred on of 4-methoxy-N-((2- (methylthio)benzo[d]oxazolyl) methyl)nitroaniline (1.07 g, 3.11 mmol), HOAc (3.7 mL) and MeOH (3.7 mL) in DCM (40 mL) at 0 0C was added zinc dust (2.02 g, 31.1 mmol) portionwise. After stirring for 2 h, the e was filtered. The filtrate was washed with aq NaHCOg and brine, dried over Na2S04 and concentrated under reduced pressure to give oxy-N1-((2-(methylthio)benzo[d]oxazol yl)methyl)benzene-l,2-diamine (775 mg, 79.1%). 1H NMR (300 MHZ, DMSO-d6) 5 7.60 (s, 1H), 7.55 (d, J: 8.4 Hz, 1H), 7.35 (d, J: 9.6 Hz, 1H), 6.26 (d, J: 8.1Hz, 1H), 6.21 (s, 1H), 5.97 (d, J: 9.0 Hz, 2H), 4.74 (t, 1H), 4.68 (s, 1H), 4.31 (d, J: 5.7 Hz, 1H), 3.55 (s, 3H), 2.74 (s, 3H). LCMS (ESI) m/z 316 (M+H)+.

] Step 3: A solution of 4-methoxy-N1-((2-(methylthio)benzo[d]oxazol yl)methyl) benzene-1,2-diamine (755 mg, 2.40 mmol) in triethoxymethane (8 mL) and HCOOH (0.2 mL) was stirred at 90 0C for 40 min. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 1:2 petroleum ether/ethyl acetate to give 6-((5-methoxy- lH-benzo[d]imidazol hyl)(methylthio)benzo[d]oxazole as a light brown solid (683 mg, 87.6%). 1H NMR (300 MHz, DMSO-d6) 8 8.36 (s, 1H), 7.66 (s, 1H), 7.58 (d, .1: 7.8 Hz, 1H), 7.43 (d, .1: 9.0 Hz, 1H), 7.30 (d, .1: 6.6 Hz, 1H), 7.16 (s, 1H), 6.82 (d, .1: 6.6 Hz, 1H), 5.54 (s, 2H), 3.75 (s, 3H), 2.73 (s, 3H). LCMS (ESI) m/Z 326 (M+H)+.

Step 4: A solution of 6-((5-methoxy-1H-benzo[d]imidazolyl)methyl) (methyl enzo[d]oxazole (683 mg, 2.1 mmol) and m-CPBA (471 mg, 2.7 mmol) in DCM (10 mL) was stirred at 0 0C for 3.5 h. The reaction e was washed with aq Na2S203 and brine. The organic layer was dried over Na2S04, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 1:1 petroleum ether/ethyl acetate to give 6-((5-methoxy- 1H-benzo [d]imidazolyl)methyl)(methylsulfinyl)benzo[d]oxazole (45 5 mg, 63.6%) as a yellow solid. 1H NMR (300 MHz, DMSO-d6) 8 8.40 (s, 1H), 7.88 (m, 2H), 7.4 4 (m, 2H), 7.18 (s, 1H), 6.83 (s, 1H), 5.63 (s, 2H), 3.75 (s, 3H), 3.18 (s, 3H).

LCMS (ESI) m/Z 342 (M+H)+.

Step 5: A mixture of 6-((5-methoxy-1H-benzo[d]imidazolyl)methyl) (methylsulfinyl)benzo[d]oxazole (450 mg, 1.32 mmol), (1R,2R)aminocyclohexanol (228 mg, 1.98 mmol) and DIEA (341 mg, 2.64 mmol) in DMA (10 mL) was stirred at 120 0C for 1.5 h. The on mixture was cooled to rt and poured into water (30 mL) and the resulting mixture was extracted with ethyl acetate (30 mL>< 3). The combined organic layers were washed with water and brine, dried over Na2S04, filtered and concentrated under reduced pressure. The residue was purified by ative HPLC to give (1R,2R)((6-((5-methoxy-1H-benzo[d]imidazol yl)methyl)benzo[d]oxazolyl)amino)cyclohexanol as a white solid (155 mg, 29.9%). 1HNMR (300 MHz, DMSO-d6) 5 8.32 (s, 1H), 7.80 (d, J: 7.8 Hz, 1H), 7.41 (d, J: 8.7 Hz, 1H), 7.33 (s, 1H), 7.16-7.08 (m, 3H), 6.82 (dd, J: 2.4, 8.7 Hz, 1H), 5.42 (s, 2H), 4.68 (d, J: 4.5 Hz, 1H), 3.75 (s, 3H), 3.35 (br s, 2H), 1.90 (m, 2H), 1.62 (br s, 2H), 1.22 (br s, 4H). LCMS (ESI) m/Z 393 .

Example 152 Pre aration of IR 2R 6- 6-meth0x -1H-benz0 d imidazol-l- lmeth l benzo d oxazol-Z- 1 amino c clohexanol //\ O N N/\©:/>—NH 9H Step 1: To a on of 5-methoxynitroaniline (500 mg, 2.99 mmol) and TFA (3.07 mL) in DCM (15 mL) at 5 0C was added NaBH(OAc)3 (1.9 g, 8.97 mmol). To the resulting mixture at 0 0C was added dropwise a on of 2- (methylthio)benzo[d]oxazolecarbaldehyde (630 mg, 3.29 mmol) in DCM (10 mL) and . the mixture was stirred at 0 0C for 2 h. The reaction mixture was diluted with DCM and washed with H20, aq NaHC03 and brine. The organic layer was dried over Na2S04 and concentrated under reduced pressure to give 5-methoxy-N-((2- (methylthio)benzo[d]oxazolyl)methyl)nitro aniline as a light brown solid (1.06 g, 100%). 1H NMR (300 MHz, DMSO-d6) 8 8.90 (t, 1H), 8.04 (d, J: 8.7 Hz, 1H), 7.68 (s, 1H), 7.60 (d, J: 8.4 Hz, 1H), 7.41 (d, J: 7.5 Hz, 1H), 6.28-6.32 (m, 2H), 4.73 (d, J: 6 Hz, 2H), 3.72 (s,3H), 2.74 (s, 3H). LCMS (ESI) m/z 345 (M+H)+.

Step 2: To a stirred solution of 5-methoxy-N-((2- lthio)benzo[d]oxazolyl) methyl)nitroaniline (1.05 g, 3.05 mmol), HOAc (3.6 mL) and methnol (3.6 mL) in DCM (40 mL) at 0 0C was added zinc dust (1.98 g, .5 mmol) portionwise. After stirring for 2 h, the mixture was filtered. The filtrate was washed with aq NaHC03 and brine, dried over Na2S04 and concentrated under reduced pressure to give 5-methoxy-N1-((2-(methylthio)benzo[d]oxazol yl)methyl)benzene-l,2-diamine as a light yellow solid (920 mg, 95.7%). 1H NMR (300 MHz, DMSO-d6) 5 .60 (m, 2H), 7.35 (d, J: 7.8 Hz, 1H), 6.47 (d, J: 8.1 Hz, 1H), 5.93-5.99 (m, 2H), 5.32 (t, 1H), 4.38 (d, J: 5.7 Hz, 2H), 4.13 (s, 2H), 3.50 (s, 3H), 2.74 (s, 3H). LCMS (ESI) m/Z 316 (M+H)+.

Step 3: A mixture of 5-methoxy-N1-((2-(methylthio)benzo[d]oxazol yl)methyl) benzene-1,2-diamine (920 mg, 2.92 mmol), triethoxymethane (8.8 mL) and HCOOH (0.2 mL) was stirred at 90 0C for 40 min. The reaction e was concentrated under d pressure. The residue was d by silica gel chromatography eluting with 1:2 petroleum ether/ethyl acetate to give 6-((6-methoxy- lH-benzo[d]imidazol-l-yl)methyl)(methylthio)benzo[d]oxazole as a light brown solid (799mg, 84.1%). 1H NMR (300 MHz, DMSO-d6) 8 8.28 (s, 1H), 7.68 (s, 1H), 7.59 (d, J: 8.1 Hz, 1H), 7.52 (d, J: 9.0 Hz, 1H), 7.33 (d, J: 6.6 Hz, 1H), 7.15 (s, 1H), 6.80 (d, J: 6.6 Hz, 1H), 5.54 (s, 2H), 3.75 (s, 3H), 2.73 (s, 3H). LCMS (ESI) m/Z 326 (M+H)+.

Step 4: A solution of 6-((6-methoxy-1H-benzo[d]imidazolyl)methyl) (methyl lthio)benzo[d]oxazole (799 mg, 2.46 mmol) and m-CPBA (551 mg, 3.20 mmol) in DCM (18 mL) was stirred at 0 0C for 3.5 h. The reaction mixture was washed with s Na2S203 and brine. The organic layer was dried over Na2S04 and concentrated under reduced re. The residue was purified by silica gel chromatography eluting with 1:1 petroleum ether/ethyl acetate to give methoxy- 1H-benzo dazolyl)methyl)(methylsulfinyl)benzo[d]oxazole as a light yellow solid (697 mg, 74.9%). 1H NMR (300 MHz, DMSO-d6) 8 8.34 (s, 1H), 7.87- 7.92 (m, 2H), 7.47-7.55 (m, 2H), 7.16 (s, 1H), 6.82 (d, J: 5.4 Hz, 1H), 5.63 (s, 2H), 3.75 (s, 3H), 3.18 (s, 3H). LCMS (ESI) m/z 342 (M+H)+.

Step 5: A mixture of 6-((6-methoxy-1H-benzo[d]imidazolyl)methyl) (methyl sulfinyl)benzo[d]oxazole (595 mg, 1.74 mmol), ) aminocyclohexanol (301 mg, 2.6 mmol) and DIEA (449 mg, 3.48 mmol) in DMA (12 mL) was stirred at 120 0C for 1.5 h. The reaction mixture was cooled to rt, poured into water (30 mL) and extracted with ethyl acetate (30 mL><3). The combined organic layers were washed with brine, dried over Na2S04 and trated under reduced pressure. The residue was purified by preparative HPLC to give (1R,2R)—2-((6-((6- methoxy- 1 H-benzo [d]imidazolyl)methyl)benzo[d]oxazolyl)amino)cyclohexanol as a white solid (198 mg, 29.0%). 1H NMR (300 MHz, DMSO-d6) 5 8.24 (s, 1H), 7.80 (d, J: 6.9 Hz, 1H), 7.50 (d, J: 8.7 Hz, 1H), 7.36 (s, 1H), 7.14 (s, 3H), 6.80 (dd, J: 2.4, 9.0 Hz, 1H), 5.42 (s, 2H), 4.68 (d, J: 3.3 Hz, 1H), 3.76 (s, 3H), 3.33 (br s, 2H), 1.89 (br s, 2H), 1.62 (br s, 2H), 1.22 (br s, 4H). LCMS (ESI) m/z 393 (M+H)+.

Example 153 Step 1: (lR,2R)((6-Iodobenzo[d]thiazolyl)amino)cyclohexanol (1.9 g, 81%) was obtained as a yellow solid using procedures analogous to those described in Step 5 of Example 3 followed by Step 5 of Example 2, substituting 6-iodo (methylthio)benzo[d]thiazole (Ref: {182009/163464 Al for 6-((3H- , 2009‘) imidazo[4,5-b]pyridinyl)methyl)(methylthio)benzo[d]thiazole used in Example 3, and then making the analogous substitution in Step 5 of e 2. LCMS (ESI) m/Z 375 (M+H)+.

Step 2: Crude 2-chloro(2-(((lR,2R) hydroxycyclohexyl)amino)benzo[d]thiazolyl)propanal (l 80 mg) was obtained as a yellow oil using procedures analogous to those described in Steps 3-4 of Example 117, substituting (lR,2R)((6-iodobenzo[d]thiazolyl)amino)cyclohexanol from Step 1 of this Example for 6-iodo(methylthio)benzo[d]thiazole used in Step 3 of e 117, and making the analogous substitution in Step 4 of Example 117.

LCMS (ESI) m/Z 339, 341 (M+H)+. In the same reaction, 2-chloro(4-chloro (((lR,2R)hydroxycyclohexyl)amino)benzo[d]thiazolyl)propanal was also present as a minor product.

Step 3: )((6-((7-(2-Methoxyethoxy)imidazo[l,2-a]pyridin yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol (28 mg, 18%) was ed as a yellow powder using a procedure analogous to that described in Step 6 of Example 117, substituting 4-(2-methoxyethoxy)pyridinamine (Ref: WOZOG8/lfll687 A2, 2008) for 2-aminoisonicotinonitrile, and ro(2-(((lR,2R) hydroxycyclohexyl)amino)benzo[d]thiazolyl)propanal from Step 2 of this Example for ro(2-(methylthio)benzo[d]thiazolyl)propanal used in Example 117. 1H NMR (500 MHz, DMSO-d6) 5 8.00 (d, J: 7.4 Hz, 1H), 7.89 (d, J: 7.4 Hz, 1H), 7.49 (s, 1H), 7.25 (d, J: 8.4 Hz, 1H), 7.23 (s, 1H), 7.06 (d, J: 7.9 Hz, 1H), 6.92 (d, J: 2.5 Hz, 1H), 6.58 (dd, J: 2.5, 7.4 Hz, 1H), 4.77 (d, J: 5.9 Hz, 1H), 4.22 (s, 2H), 4.07 - 4.16 (m, 2H), 3.60 - 3.72 (m, 2H), 3.50 (br s, 2H), 3.30 (s, 3H), 2.04 (d, J: 12.3 Hz, 1H), 1.87 (d,.]= 11.8 Hz, 1H), 1.53 - 1.71 (m, 2H), 1.06 - 1.36 (m, 4H).

LCMS (ESI) m/Z 453 (M+H)+. e 154 Pre aration of IR 2R 6- 3H-imidaz0 4 5-b ridin l meth l fluorobenzo thiazol lamino c clohexanol PCT/U82012/059983 //\N S N v />_NH §OH Step 1: A mixture of 4-amino-2,5-difluorobenzonitrile (1.0 g, 6.5 mmol) and O-ethylxanthic acid potassium salt (1.2 g, 7.8 mmol) in DMF (15 mL) was heated at reflux for 6 h. The e was cooled to rt and partitioned between EtOAc (200 mL) and 1 M aq Na2C03 (100 mL). The c layer was separated and the aqueous layer was extracted with additional EtOAc (2 X 200 mL). The combined organic layers were washed with brine (100 mL), dried over MgZSO4, filtered, and trated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with 2% MeOH in DCM to afford o fluorobenzo[d]thiazolethiolate potassium salt (1.94 g) as an orange solid. LCMS (ESI) m/Z 211 (M+H)+.

Step 2: 5-Fluoro(methylthio)benzo[d]thiazolecarbonitrile was synthesized as an orange solid (1.2 g, 86%) using a procedure analogous to that described in Step 2 of Example 114, substituting 6-cyanofluorobenzo[d]thiazole thiolate potassium salt from the preVious step for ethyl 2-mercaptothiazolo[4,5- b]pyridinecarboxylate potassium salt used in Example 114. 1H NMR (300 MHz, DMSO-d6) 5 8.67 (d, J: 6.4 Hz, 1H), 8.01 (d, J: 10.5 Hz, 1H), 2.84 (s, 3H); LCMS (ESI) m/Z 225 .

Step 3: To a stirred mixture of 5-fluoro(methylthio)benzo[d]thiazole carbonitrile in anhydrous THF (20 mL) at —20 0C under argon was added dropwise lithium aluminum hydride (2 M solution in THF, 11.7 mL, 5.9 mmol). After 1 h, water (500 uL) and 1 M aq NaOH (500 uL) were added slowly to the reaction mixture. After 5 minutes, additional water (2 mL) was added and the e was stirred at rt for 30 minutes. The mixture was filtered and the filtrate was trated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with 5% MeOH in CHzClz to afford ro(methylthio)benzo[d]thiazol- 6-yl)methanamine (128 mg, 29%) as a colorless oil. 1H NMR (500 MHz, DMSO-d6) 8 8.07 (d, J: 7.1 Hz, 1H), 7.64 (d, J: 11.1 Hz, 1H), 3.83 (s, 2H), 2.78 (s, 3H), 1.80 - 2.06 (m, 2H); LCMS (ESI) m/Z 229 (M+H)+.

Step 4: To a stirred mixture of (5-fluoro(methylthio)benzo[d]thiazol yl)methanamine (128 mg, 0.6 mmol) and DIEA (195 uL, 1.2 mmol) at 0 CC under argon was added 2-chloronitropyridine (98 mg, 0.7 mmol) in one portion. The e was stirred at rt for 18 h and then concentrated under reduced pressure. The e was purified by silica gel flash chromatography eluting with a gradient of 100% hexanes to 50% EtOAc in hexanes to afford N—((5-fluoro (methylthio)benzo[d]thiazolyl)methyl)—3-nitropyridinamine (165 mg, 84%) as a yellow oil. LCMS (ESI) m/Z 351 (M+H)+.

Step 5: NZ-((5-Fluoro(methylthio)benzo[d]thiazol yl)methyl)pyridine-2,3-diamine was synthesized as a yellow solid (200 mg) using a procedure analogous to that described in Step 2 of Example 41, substituting N—((5- fluoro(methylthio)benzo[d]thiazolyl)methyl)nitropyridinamine from the previous step for omethoxy-N-((2-(methylthio)benzo[d]thiazol yl)methyl)nitroaniline used in Example 41. LCMS (ESI) m/z 321 (M+H)+.

Step 6: 6-((3H-Imidazo[4,5-b]pyridinyl)methyl)fluoro (methylthio)benzo[d]thiazole was synthesized as a tan solid (180 mg) using a procedure analogous to that described in Step 3 of Example 41, substituting NZ-((5- fluoro(methylthio)benzo[d]thiazolyl)methyl)pyridine-2,3-diamine from the us step for 4-bromomethoxy-N1-((2-(methylthio)benzo[d]thiazol yl)methyl)benzene-1,2-diamine used in Example 41. LCMS (ESI) m/z 331 (M+H)+.

Step 7: 6-((3H—Imidazo[4,5-b]pyridinyl)methyl)fluoro lsulf1nyl)benzo[d]thiazole was synthesized as a white foam (314 mg) using a procedure analogous to that bed in Step 6 of Example 36, substituting 6-((3H- imidazo[4,5-b]pyridinyl)methyl)fluoro(methylthio)benzo[d]thiazole from the us step for the 6-((4-bromo-lH-imidazol-l-yl)methyl) (methylthio)benzo[d]thiazole used in Example 36. LCMS (ESI) m/Z 347 (M+H)+.

Step 8: )((6-((3H—Imidazo[4,5-b]pyridinyl)methyl) fluorobenzo[d]thiazolyl)amino)cyclohexanol was synthesized as a white powder (42 mg, 19%) using a procedure analogous to that described in Step 7 of Example 36, substituting 6-((3H-imidazo[4,5-b]pyridinyl)methyl)fluoro (methylsulf1nyl)benzo[d]thiazole from the previous step for 6-((4-bromo-1H— imidazolyl)methyl)(methylsulf1nyl)benzo[d]thiazole used in Example 36. 1H NMR (500 MHz, DMSO-d6) 8 8.50 (s, 1H), 8.36 (dd, .1: 1.2, 4.7 Hz, 1H), 8.15 (d, .1 = 7.6 Hz, 1H), 8.09 (dd, .1: 1.1, 8.0 Hz, 1H), 7.60 (d, .1: 7.4 Hz, 1H), 7.29 (m, 1H), 7.18 (d, .1: 11.6 Hz, 1H), 5.52 (s, 2H), 4.75 (d, .1: 5.2 Hz, 1H), 3.51 (m, 1H), 3.32 (m, 1H), 2.01 (m, 1H), 1.89 (m, 1H), 1.56 _ 1.65 (m, 2H), 1.12 _ 1.31 (m, 4H); LCMS (ESI) m/Z 398 (M+H)+.

Example 155 Pre aration of IR 2R 6- 6-m0r holinoimidazo 1 2-b ridazin l meth l benzo d thiazol 1 amino c clohexanol N\ N N,>—NH §H \I 23 (1R,2R)((6-((6-Morpholinoimidazo[1,2-b]pyridazin yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol (55 mg, 13%) was obtained as a yellow powder using a procedure analogous to that described in Step 6 of Example 117, substituting 6-morpholinopyridazinamine (Ref: US4104385 A1, 1978) and 2- chloro(2-(((1R,2R)hydroxycyclohexyl)amino)benzo[d]thiazolyl)propanal from Step 2 of Example 153, tively, for 2-aminoisonicotinonitrile and 2-chloro- 3-(2-(methylthio)benzo[d]thiazolyl)propanal used in Example 117. 1H NMR (500 MHz, DMSO-d6) 8 7.87 (d, J: 7.8 Hz, 1H), 7.81 (d, J: 9.9 Hz, 1H), 7.58 (s, 1H), 7.35 (s, 1H), 7.24 (d, J: 8.3 Hz, 1H), 7.13 (d, J: 8.3 Hz, 1H), 7.09 (d, J: 9.9 Hz, 1H), 4.78 (br s, 1H), 4.17 (s, 2H), 3.72 (d, J: 4.7 Hz, 4H), 3.50 (br s, 2H), 3.42 - 3.49 (m, 4H), 2.04 (d,.]= 11.9 Hz, 1H), 1.87 (d,.]= 10.4 Hz, 1H), 1.53 - 1.71 (m, 2H), 1.10 — 1.37 (m, 4H). LCMS (ESI) m/Z 465 (M+H)+. e 156 Pre aration of IR 2R r0 6-m0r holinoimidazo 12-b ridazin yllmeth111benzo|d|thiazolyl)amin0)cyclohexanol (1R,2R)((4-Chloro((6-morpholinoimidazo[1,2-b]pyridazin yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol (25 mg, 6%) was obtained as a yellow powder using a procedure analogous to that described in Step 6 of Example 117, substituting holinopyridazinamine (Ref: US4104385 A1, 1978) and 2- chloro(4-chloro(((1R,2R)—2-hydroxycyclohexyl)amino)benzo[d]thiazol yl)propanal (minor product from Step 2 of Example 153), respectively, for 2- aminoisonicotinonitrile and 2-chloro(2-(methylthio)benzo[d]thiazolyl)propanal used in e 117. 1H NMR (500 MHZ, DMSO-d6) 8 8.20 (d, J: 7.3 Hz, 1H), 7.82 (d, J: 9.9 Hz, 1H), 7.56 (s, 1H), 7.40 (s, 1H), 7.27 (s, 1H), 7.10 (d, J: 9.9 Hz, 1H), 4.83 (br s, 1H), 4.17 (s, 2H), 3.66 - 3.80 (m, 4H), 3.44 (d, J: 4.7 Hz, 4H), 2.02 (d, J: 7.8 Hz, 1H), 1.88 (d, J: 11.4 Hz, 1H), 1.63 (br s, 2H), 1.10 - 1.37 (m, 4H). LCMS (ESI) m/Z 499, 501 (M+H)+.

Example 157 Pre n of IR 2R 6- imidazo 2 l-b thiazol-S- lmeth l benzo dthiazol-Z- 1 amino c clohexanol Nmikw §OH .5 {3 Step 1: A stirred mixture of 2-chloro-3 -(2-(methylthio)benzo[d]thiazol yl)propanal from Step 4 of Example 117 (500 mg, 1.84 mmol) and thiazolamine (370 mg, 3.68 mmol) in nol (22 mL) was heated at reflux overnight. The mixture was cooled to rt and water (120 mL) was added. The mixture was extracted with EtOAc (60 mL><3). The combined organic layers were washed with brine, dried over Na2S04, filtered and trated under reduced pressure. The residue was purified by silica gel chromatography eluting with 50: 1 to 20: 1 DCM/MeOH to afford 6-(imidazo[2,1-b]thiazolylmethyl)(methylthio)benzo[d] thiazole as a yellow solid (350 mg, 60%). 1H NMR (300 MHZ, CDClg) 5 7.80 (d, J: 8.4 Hz, 1H), 7.55 (d, J: 1.2 Hz, 1H), 7.29 (d, J: 1.8 Hz, 1H), 7.16 (d, J: 0.9 Hz, 1H), 6.99 (d, .1: 4.5 Hz, 1H), 6.71 (dd, .1: 0.9 Hz, .1: 4.5 Hz, 1H), 4.24 (s, 2H), 2.78 (s, 3H). LCMS (ESI) m/Z 318 (M+H)+.

Step 2: To a solution of 6-(imidazo[2,1-b]thiazolylmethyl) (methylthio)benzo[d] thiazole (350 mg, 1.1 mmol) in DCM (20 mL) was added m- CPBA (240 mg, 1.4 mmol) at 0 0C. The reaction mixture was stirred for 2 hat 0 0C, then aq Na2S203 (20 mL) was added and the mixture was stirred for 0.5 h. The organic layer was separated and dried over Na2S04, filtered and concentrated under reduced re. The residue was purified by silica gel chromatography eluting with 50: 1 to 20: 1 DCM/MeOH to afford dazo[2,1-b]thiazol ylmethyl)(methylsulfinyl)benzo[d]thiazole as a yellow solid (310 mg, 85%). 1H NMR (300 MHz,CDC13)8 8.00 (d, J: 8.4 Hz, 1H), 7.82 (d, J: 0.9 Hz, 1H), 7.43 (dd, J: 1.5, 8.4 Hz, 1H), 7.18 (s, 1H), 7.03 (d, J: 4.5 Hz, 1H), 6.75 (dd, J: 0.9, 4.5 Hz, 1H), 4.32 (s, 2H), 3.07 (s, 3H). LCMS (ESI) m/z 334 .

Step 3: A mixture of 6-(imidazo[2,1-b]thiazolylmethyl) (methylsulfinyl) benzo[d]thiazole (310 mg, 0.93 mmol), (1R,2R) yclohexanol (321 mg, 2.79 mmol) and DIEA (240 mg, 1.86 mmol) in NMP (10 mL) was stirred for 1 d at 130 0C. The mixture was cooled to rt and water (50 mL) was added. The e was extracted with EtOAc (100 mL>< 3). The combined organic layers were washed with brine, dried over Na2S04, filtered and concentrated under d pressure. The residue was purified by silica gel chromatography eluting with 50: 1 to 10: 1 DCM/MeOH, and the product was further purified by preparative HPLC to afford )((6-(imidazo[2,1- b]thiazolylmethyl)benzo[d]thiazolyl)amino)cyclohexanol as a brown solid (100 mg, 28%). 1H NMR (300 MHz, DMSO-d6) 8 7.84 (d, J: 7.2 Hz, 1H), 7.68 (d, J: 4.5 Hz, 1H), 7.54 (d, J: 1.8 Hz, 1H), 7.27 (d, J: 8.1 Hz, 1H), 7.20 (dd, J = 0.9, 4.2 Hz, 1H), 7.10 (dd, J: 1.8, 8.4 Hz, 1H), 7.02 (s, 1H), 4.71 (d, J: 4.8 Hz, 1H), 4.15 (s, 2H), 3.52-3.49 (m, 1H), 3.39-3.36 (m, 1H), 2.05-2.01 (m, 1H), 1.90-1.86 (m, 1H), 1.65-1.59 (m, 2H), 1.30-1.16 (m, 4H). LCMS (ESI) m/z 385 (M+H)+.

Example 158 Pre aration of IR 2R 6- 6-chlor0imidaz0 1 2-b ridazin lmeth l benzo thiazol lamino c clohexanol N\ S/>—NH N §OH \ N \ /N {3 Step 1: A mixture of 2-chloro(2-(methylthio)benzo[d]thiazol yl)propanal from Step 4 of Example 117 (1.5 g, 5.5 mmol) and 6-chloropyridazin amine (1.4 g, 11 mmol) in 1-butanol (60 mL) was heated at reflux overnight. Then the mixture was cooled to rt and water (120 mL) was added. The e was extracted with EtOAc (60 mL>< 3). The combined organic layers were washed with brine, dried over Na2S04, filtered and trated under reduced pressure. The e was purified by silica gel chromatography eluting with 50: 1 to 20: 1 DCM/MeOH to afford 6-((6-chloroimidazo[1,2-b]pyridazinyl)methyl) (methylthio)benzo[d]thiazole as a yellow solid (1.6 g, 84%). 1H NMR (300 MHZ, CDC13)5 7.89 (d, J: 9.6 Hz, 1H), 7.81 (d, J: 8.4 Hz, 1H), 7.68 (dd, J: 0.6 1.2 Hz, 1H), 7.53 (s, 1H), 7.37 (dd, J: 1.8, 8.4 Hz, 1H), 7.03 (d, J: 9.3 Hz, 1H), 4.40 (s, 2H), 2.78 (s, 3H). LCMS (ESI) m/Z 347 (M+H)+.

Step 2: To a solution of 6-((6-chloroimidazo[1,2-b]pyridazin yl)methyl) (methylthio)benzo[d]thiazole (1.6 g, 4.6 mmol) in DCM (90 mL) was added m-CPBA (1.0 g, 5.8 mmol) at 0 0C. The reaction e was stirred for 2 h at 0 0C, then aq Na2S203 (45 mL) was added and the mixture was stirred for 0.5 h. The organic layer was separated, dried over Na2S04, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 50: 1 to 20: 1 DCM/MeOH to afford 6-((6-chloroimidazo[1,2- b]pyridazinyl)methyl)(methylsulfinyl)benzo[d]thiazole as a yellow solid (1.68 g, 100%). 1H NMR (300 MHz, CDC13)5 8.00 (d, J: 8.4 Hz, 1H), 7.92 (d, J: 3.6 Hz, 1H), 7.89 (s, 1H), 7.58 (s, 1H), 7.53 (dd, J: 2.1, 8.7 Hz, 1H), 7.05 (d, J: 9.3 Hz, 1H), 4.48 (s, 2H), 3.07 (s, 3H). LCMS (ESI) m/z 363 (M+H)+.

Step 3: A mixture of 6-((6-chloroimidazo[1 ,2-b]pyridazin hyl) (methylsulfinyl)benzo[d]thiazole (1.0 g, 2.7 mmol), (1R,2R) aminocyclohexanol (0.93 g, 8.1 mmol) and DIEA (697 mg, 5.4 mmol) in NMP (40 mL) was stirred for 2 d at 140 0C. The mixture was cooled to rt and water (150 mL) was added. The e was ted with EtOAc (100 mL>< 3). The combined organic layers were washed with brine, dried over Na2S04, filtered and concentrated under reduced pressure. The e was purified by silica gel chromatography eluting with 50: 1 to 10: 1 DCM/MeOH to afford (1R,2R) ((6-((6-chloroimidazo [1 ,2-b]pyridazinyl)methyl)benzo[d]thiazol yl)amino)cyclohexanol as a brown solid (530 mg, 46%). 1H NMR (300 MHZ, DMSO- d6) 5 8.20 (d, J: 9.6 Hz, 1H), 7.86 (d, J: 7.2 Hz, 1H), 7.63 (s, 1H), 7.54 (d, J: 1.8 Hz, 1H), 7.32 (d, J: 9.9 Hz, 1H), 7.27 (d, J: 1.8 Hz, 1H), 7.12 (dd, J: 1.5, 8.4 Hz, 1H), 4.73 (d, J: 5.1 Hz, 1H), 4.29 (s, 2H), 3.52-3.49 (m, 1H), 3.39-3.36 (m, 1H), 2.05-2.01 (m, 1H), 1.90-1.86 (m, 1H), .59 (m, 2H), 1.30-1.16 (m, 4H).

LCMS (ESI) m/Z 414 (M+H)+.

Example 159 Pre aration of IR 2R 6- 6- 1H- razol-l- limidazo 1 2-a ridin l meth l benzo d thiazol-Z- 1 amino c clohexanol wow3\ Q 23 Step 1: )((6-((6-Iodoimidazo[1,2-a]pyridin yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol (50 mg, 13%) was obtained as a light brown solid using a procedure analogous to that described in Step 6 of Example 117, substituting 5-iodopyridinamine and 2-chloro(2-(((1R,2R) ycyclohexyl)amino)benzo[d]thiazolyl)propanal from Step 2 of e 153, respectively, for 2-aminoisonicotinonitrile and 2-chloro(2- (methylthio)benzo[d]thiazolyl)propanal used in Example 117. LCMS (ESI) m/z 505 (M+H)+.

Step 2: (1R,2R)((6-((6-(1H-Pyrazolyl)imidazo[1,2-a]pyridin yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol (7 mg, 16%) was ed as a light tan solid using a procedure analogous to that described in Example 141, substituting(1R,2R)((6-((6-iodoimidazo[1 ,2-a]pyridinyl)methyl)benzo [d]thiazol- 2-yl)amino)cyclohexanol from Step 1 of this Example for (1R,2R)((6-((6-iodo-3H- imidazo[4,5-b]pyridinyl)methyl)benzo[d]thiazolyl)amino)cyclohexanol used in Example 141. 1H NMR (500 MHz, DMSO-d6) 5 8.70 (br s, 1H), 8.48 (d, .1: 2.1 Hz, 1H), 7.92 (d, J: 7.3 Hz, 1H), 7.76 (br s, 2H), 7.73 (br s, 1H), 7.54 (s, 1H), 7.28 (d, J = 8.3 Hz, 1H), 7.12 (d, .1: 8.3 Hz, 1H), 6.57 (s, 1H), 4.79 (br s, 1H), 4.36 (s, 2H), 3.49 (d, .1: 6.7 Hz, 2H), 2.04 (d, .1: 11.4 Hz, 1H), 1.87 (d, .1: 10.4 Hz, 1H), 1.53 _ 1.71 (m, 2H), 1.08 _ 1.36 (m, 4H). LCMS (ESI) m/Z 445 .

Example 160 Pre aration of IR 2R 6- 5— 1H- razol—l- l-lH-benzo ol—l- l meth lbenzo l 1 amino c clohexanol «WI/U />—NHS© 9H N $ (IR,2R)—2-((6-((5-(1H—pyrazolyl)-1H-benzo[d]imidazol yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol (18 mg, 20%) was obtained as a solid using a procedure analogous to that described in e 141, substituting (1R,2R)((6-((5 -iodo- 1H-benzo [d]imidazolyl)methyl)benzo [d]thiazol yl)amino)cyclohexanol from Step 5 of Example 183 for (1R,2R)((6-((6-iodo-3H— imidazo[4,5-b]pyridinyl)methyl)benzo[d]thiazolyl)amino)cyclohexanol used in Example 141. 1H NMR (500 MHz, DMSO-d6) 8 8.43 - 8.53 (m, 2H), 8.06 (d, J: 1.6 Hz, 1H), 7.99 (d, J: 7.8 Hz, 1H), 7.69 - 7.75 (m, 2H), 7.64 - 7.68 (m, 2H), 7.30 (d, J = 8.3 Hz, 1H), 7.22 (d, J: 8.3 Hz, 1H), 6.51 (d, J: 2.1 Hz, 1H), 5.50 (s, 2H), 4.76 (br m, 1H), 3.48-3.56 (br m, 2H), 2.02 (m, 1H), 1.87 (m, 1H), 1.52 - 1.68 (m, 2H), 1.09 - 1.35 (m, 4H); LCMS (ESI) m/Z 445 (M+H)+.

Example 161 Pre aration of IR 2R 6- 5- 1H-1 2 4-triazol l -1H-benz0 imidazol-l- l meth lbenzo thiazol 1 amino c clohexanol /\ S N/ NU />—NH é 9H N S L /> ] (1R,2R)((6-((5-(lH—1 ,2,4-Triazolyl)-1H-benzo[d]imidazol yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol (10 mg, 8%) was obtained as a solid using a procedure analogous to that described in Example 141, substituting (lR,2R)((6-((5 -iodo- 1H—benzo dazolyl)methyl)benzo azol no)cyclohexanol from Step 5 of Example 183 and lH-1,2,4-triazole, respectively, for (1R,2R)((6-((6-iodo-3H—imidazo[4,5-b]pyridin yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol and lH-pyrazole used in e 141. 1H NMR (500 MHz, DMSO-d6) 5 9.23 (s, 1H), 8.54 (s, 1H), 8.20 (s, 1H), 8.12 (s, 1H), 7.97 (d, J: 7.3 Hz, 1H), 7.71-7.74 (m, 2H), 7.68 (s, 1H), 7.30 (d, J = 8.3 Hz, 1H), 7.22 (d, J: 8.3 Hz, 1H), 5.52 (s, 2H), 4.74 (br s, 1H), 3.48-3.56 (br m, 2H), 2.02 (m, 1H), 1.87 (br s, 1H), 1.52 - 1.72 (m, 2H), 1.10 - 1.33 (m, 4H); LCMS (ESI) m/Z 446 (M+H)+.

Example 162 Pre aration of 1S 2R 6- 6-flu0r0-3H-imidazo 4 5-b ridin l meth lbenzo thiazol-Z- 1 amino c clohexanol Step 1: A mixture of acetic anhydride (49 mL, 0.5 mol) and formic acid (19 mL, 0.5 mol) was heated at 60 0C for 3 h. 5-Fluoronitropyridinamine was added and the mixture was stirred at 60 CC for 1 h. The mixture was concentrated under reduced pressure and the residue was stirred vigorously in diethyl ether (200 mL) for 30 minutes. The solid was collected by filtration to afford N—(5-fluoro nitropyridinyl)formamide (4.5 g, 96%) as an orange solid which did not require further purification. LCMS (ESI) m/Z 186 (M+H)+.

Step 2: N—(5-Fluoronitropyridinyl)-N-((2- lthio)benzo[d]thiazolyl)methyl)formamide was synthesized as an yellow solid (4 g, 82%) using a procedure analogous to that described in Step 3 of Example 47, substituting uoro-3 -nitropyridinyl)formamide from the preVious step for -bromomethoxy-1H—benzo[d]imidazole used in Example 47. LCMS (ESI) m/z 379 (M+H)+.

Step 3: A stirred mixture ofN—(5-fluoro-3 -nitropyridinyl)-N-((2- lthio)benzo[d]thiazolyl)methyl)formamide and iron powder (6 g, 108 mmol) in EtOH (70 mL) and HOAc (30 mL) was heated at reflux for 2 h. The mixture was cooled to rt, filtered, and the e was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluting with a nt of 100% hexanes to 100% EtOAc, to afford 6-((6-fluoro-3H—imidazo[4,5-b]pyridin yl)methyl)(methylthio)benzo[d]thiazole (l g, 28%) as a white foam. 1H NMR (500 MHz, DMSO-d6) 8 8.72 (s, 1H), 8.40 (t, J: 2.0 Hz, 1H), 8.09 (dd, J: 2.6, 9.5 Hz, 1H), 7.99 (s, 1H), 7.80 (d, J: 8.4 Hz, 1H), 7.45 (dd, J: 1.5, 8.4 Hz, 1H), 5.61 (s, 2H), 2.76 (s, 3H); LCMS (ESI) m/Z 331 (M+H)+.

Step 4: 6-((6-Fluoro-3H—imidazo[4,5-b]pyridinyl)methyl) (methylsulfinyl)benzo[d]thiazole was synthesized as a white foam (1 .8 g) using a procedure analogous to that described in Step 6 of Example 36, substituting 6-((6- fluoro-3H-imidazo[4,5-b]pyridinyl)methyl)(methylthio)benzo[d]thiazole from the previous step for 6-((4-bromo-lH-imidazol-l-yl)methyl) (methylthio)benzo[d]thiazole used in Example 36. LCMS (ESI) m/Z 347 (M+H)+.

Step 5: To a suspension of 6-((6-fluoro-3H—imidazo[4,5-b]pyridin yl)methyl)(methylsulfinyl)benzo[d]thiazole (l .0 g, 3.0 mmol) and (lS,2R) aminocyclohexanol hydrochloride (916 mg, 6 mmol) in anhydrous DMA (12 mL) was added DIEA (l .6 mL, 9.0 mmol). The mixture was heated in a sealed tube at 110 CC for 12 h. The mixture was cooled to rt and additional (lS,2R)aminocyclohexanol hydrochloride (458 mg, 3 mmol) and DIEA (530 uL, 3 mmol) were added. The mixture was further heated in a sealed tube at 120 CC for 12 h. The e was cooled to rt and partitioned between EtOAc (200 mL) and 0.5 M aq K2C03 (100 mL).

The organic layer was separated, washed with brine (100 mL), dried over , filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluting with 5% MeOH in CHzClz, then by e-phase preparative HPLC using a mixture of water (5% CH3CN, 0.05% HCOOH) and CH3CN (0.05% HCOOH) as the mobile phase and Varian Pursuit XRs C18 column as the stationary phase to afford (lS,2R)((6-((6-fluoro-3H—imidazo[4,5-b]pyridin yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol (89 mg, 7%) as a white . 1H NMR (500 MHz, DMSO-d6) 8 8.67 (s, 1H), 8.41 (s, 1H), 8.06 (dd, J: 2.5, 9.5 Hz, 1H), 7.85 (d, J: 7.5 Hz, 1H), 7.66 (s, 1H), 7.29 (d, J: 8.0 Hz, 1H), 7.21 (dd, J: 1.3, 8.3 Hz, 1H), 5.47 (s, 2H), 4.67 (m, 1H), 3.90 (m, 1H), 3.84 (m, 1H), 1.64 — 1.74 (m, 2H), 1.43 — 1.63 (m, 4H), 1.25 — 1.34 (m, 2H); LCMS (ESI) m/Z 398 (M+H)+.

Example 163 Pre aration of trans-4— 6- 6-flu0r0-3H-imidaz0 4 5-b 3- l meth lbenzo thiazol-Z- 1 amino c clohexanol //\N N />—NH F fill/OH To a stirred suspension of 6-((6-fluoro-3H—imidazo[4,5-b]pyridin yl)methyl)(methylsulfinyl)benzo[d]thiazole (119 g, 0.3 mmol) from Step 4 of e 162 and transaminocyclohexanol (119 mg, 1.0 mmol) in anhydrous DMA (1 mL) was added DIEA (180 uL, 1.0 mmol). The mixture was heated in a sealed tube at 110 0C for 15 h. The mixture was cooled to rt and was purified by reverse-phase preparative HPLC using a mixture of water (5% CH3CN, 0.05% HCOOH) and CH3CN (0.05% HCOOH) as the mobile phase and Varian Pursuit XRs C18 column as the stationary phase to afford trans((6-((6-fluoro-3H—imidazo[4,5-b]pyridin yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol (50 mg, 37%) as a white powder. 1H NMR (500 MHz, DMSO-d6) 8 8.67 (s, 1H), 8.41 (s, 1H), 8.06 (dd, J: 2.6, 9.3 Hz, 1H), 7.92 (d, J: 7.3 Hz, 1H), 7.66 (s, 1H), 7.32 (d, J: 8.3 Hz, 1H), 7.23 (d, J: 8.0 Hz, 1H), 5.48 (s, 2H), 4.55 (m, 1H), 3.60 (m, 1H), 3.40 (m, 1H), 1.93 — 2.03 (m, 2H), 1.78 — 1.87 (m, 2H), 1.19 — 1.30 (m, 4H); LCMS (ESI) m/z 398 (M+H)+.

Example 164 Pre aration of IR 2R 6- 3H-imidaz0 4 5-b ridin l meth l fluorobenzo thiazol-Z- lamino c clohexanol /,\ S N Nfi />—NH §OH \ , C ] Step 1: 6-(Methoxycarbonyl)fluorobenzo[d]thiazolethiolate potassium salt was synthesized as a brown oil (1.2 g) using a procedure analogous to that bed in Step 1 of Example 114, substituting methyl 4-amino-2,3- difluorobenzoate for ethyl 6-aminobromonicotinate used in Example 114. The material was used in the next step without fiarther purification. LCMS (ESI) m/z 243 (M+H)+.

Step 2: Methyl 7-fluoro(methylthio)benzo[d]thiazolecarboxylate was synthesized as a clear oil (400 mg, 29%) using a procedure analogous to that described in Step 2 of Example 114, substituting 6-(methoxycarbonyl) fluorobenzo[d]thiazolethiolate potassium salt from the preVious step for ethyl 2- mercaptothiazolo[4,5-b]pyridinecarboxylate potassium salt used in e 114. 1H NMR (500 MHz, DMSO-d6) 8 7.96 (m, 1H), 7.77 (d, J: 8.6 Hz, 1H), 3.89 (s, 3H), 2.85 (s, 3H): LCMS (ESI) m/Z 258 (M+H)+.

Step 3: (7-Fluoro(methylthio)benzo[d]thiazolyl)methanol was synthesized as a white solid (249 mg, 69%) using a procedure analogous to that described in Step 3 of Example 36, substituting methyl 7-fluoro (methylthio)benzo[d]thiazolecarboxylate from the preVious step for ethyl 2- (methylthio)benzo[d]thiazolecarboxylate used in Example 36. 1H NMR (500 MHz, DMSO-d6) 5 7.70 (d, J: 8.4 Hz, 1H), 7.56 (t, J: 7.8 Hz, 1H), 5.39 (t, J: 5.8 Hz, 1H), 4.64 (d, J: 5.7 Hz, 2H), 2.81 (s, 3H); LCMS (ESI) m/z 230 .

Step 4: 6-(Chloromethyl)fluoro(methylthio)benzo[d]thiazole was synthesized as a white solid (258 mg) using a procedure ous to that described in Step 4 of Example 114, substituting methyl (7-fluoro(methylthio)benzo[d]thiazol- ethanol from the preVious step for thylthio)thiazolo[4,5-b]pyridin yl)methanol used in Example 114. LCMS (ESI) m/z 248 (M+H)+.

Step 5: 6-((3H—Imidazo[4,5-b]pyridinyl)methyl)fluoro (methylthio)benzo[d]thiazole was synthesized as a yellow solid (200 mg, 61%) using a ure analogous to that described in Step 5 of Example 114, substituting 6- (chloromethyl)fluoro(methylthio)benzo[d]thiazole from the preVious step for 6- (chloromethyl)(methylthio)thiazolo[4,5-b]pyridine used in Example 114. The regiochemistry of the alkylation was determined by 2-dimensional nuclear Overhauser effect (NOE) ment. 1H NMR (500 MHz, DMSO-d6) 8 8.60 (s, 1H), 8.36 (dd, J: 1.0, 4.7 Hz, 1H), 8.10 (dd, J: 1.1, 8.0 Hz, 1H), 7.67 (d, J: 8.4 Hz, 1H), 7.42 (t, J: 8.0 Hz, 1H), 7.29 (dd, J: 4.8, 8.0 Hz, 1H), 5.68 (s, 2H), 2.80 (s, 3H); LCMS (ESI) m/Z 331 (M+H)+. 2012/059983 Step 6: 6-((3H—Imidazo[4,5-b]pyridinyl)methyl)fluoro (methylsulfinyl)benzo[d]thiazole was synthesized as a yellow solid (350 mg) using a procedure analogous to that described in Step 6 of Example 36, tuting 6-((3H- imidazo[4,5-b]pyridinyl)methyl)fluoro(methylthio)benzo[d]thiazole from the preVious step for 6-((4-bromo-1H-imidazolyl)methyl) (methylthio)benzo[d]thiazole used in Example 36. LCMS (ESI) m/Z 347 (M+H)+.

Step 7: (1R,2R)((6-((3H—Imidazo[4,5-b]pyridinyl)methyl) fluorobenzo[d]thiazolyl)amino)cyclohexanol was synthesized as a white powder (75 mg, 31%) using a procedure analogous to that described in Step 7 of Example 36, substituting 6-((3H-imidazo[4,5-b]pyridinyl)methyl)fluoro lsulfinyl)benzo[d]thiazole from the preVious step for 6-((4-bromo-1H— olyl)methyl)(methylsulfinyl)benzo[d]thiazole used in Example 36. 1H NMR (500 MHz, DMSO-d6) 8 8.53 (s, 1H), 8.37 (dd, J: 1.2, 4.7 Hz, 1H), 8.26 (d, J = 7.6 Hz, 1H), 8.09 (dd, J: 1.2, 8.1 Hz, 1H), 7.29 (dd, J: 4.8, 8.0 Hz, 1H), 7.11 7.23 (m, 2H), 5.56 (s, 2H), 4.77 (d, J: 4.9 Hz, 1H), 3.50 (m, 1H), 3.32 (m, 1H), 2.03 (m, 1H), 1.88 (m, 1H), 1.56 - 1.68 (m, 2H), 1.12 - 1.32 (m, 4H); LCMS (ESI) m/z 398 (M+H)+.

Example 165 Pre aration of IR 2R 6- 6-meth0x o 1 2-a ridin l meth l benzo d thiazol-Z- 1 amino c clohexanol N />—NH QH w 23 (1R,2R)((6-((6-Methoxyimidazo[1,2-a]pyridin-3 - yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol (58 mg, 6%) was obtained as a light tan solid using a procedure analogous to that described in Step 6 of Example 117, substituting 5-methoxypyridinamine and 2-chloro(2-(((1R,2R) hydroxycyclohexyl)amino)benzo[d]thiazolyl)propanal from Step 2 of Example 153, respectively, for 2-aminoisonicotinonitrile and 2-chloro(2- (methylthio)benzo[d]thiazolyl)propanal used in e 117. 1H NMR (500 MHz, DMSO-d6) 5 7.88 (d, J: 7.4 Hz, 1H), 7.78 (s, 1H), 7.55 (s, 1H), 7.47 (d, J: 9.8 Hz, 2012/059983 1H), 7.30 (s, 1H), 7.28 (d, .1: 8.4 Hz, 1H), 7.13 (d, .1: 8.4 Hz, 1H), 7.00 (dd, .1: 2.0, 9.8 Hz, 1H), 4.76 (br s, 1H), 4.26 (s, 2H), 3.74 (s, 3H), 3.51 (br s, 2H), 2.04 (d, .1: 12.8 Hz, 1H), 1.87 _ 1.92 (m, 1H), 1.55 _ 1.71 (m, 2H), 1.11 _ 1.35 (m, 4H). LCMS (ESI) m/Z 409 (M+H)+.

Example 166 Pre aration of IR 2R 6- 3H-imidaz0 4 5-b ridin l meth l bromobenzo thiazol-Z- lamino c clohexanol 4\N S N />—NH $OH N ‘ \ / Br Step 1: To a stirred mixture of 4-aminofluorobenzonitrile (5 g, 37 mmol) in ous CHzClz (40 mL) under Ar at rt was added dropwise N- uccinimide (6.5 g, 37 mrnol). After 15 h, the mixture was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with a gradient of 100% hexanes to 50% EtOAc in hexanes to afford 4-amino bromofluorobenzonitrile (6.4 g, 81%) as a tan solid. 1H NMR (500 MHz, DMSO- d6) 5 7.76 (s, 1H), 7.62 (dd, J: 1.5, 11.1 Hz, 1H), 6.44 (s, 2H); LCMS (ESI) m/z 214, 216 (M+H)+.

Step 2: 4-Bromo-6—cyanobenzo[d]thiazolethiolate potassium salt was synthesized as a brown oil (9.3 g) using a procedure ous to that described in Step 1 of Example 154, substituting 4-aminobromofluorobenzonitrile from the us step for 4-amino-2,5-difluorobenzonitrile used in Example 154 and omitting the tography used in Step 1 of Example 154.. LCMS (ESI) m/Z 269, 271 (M+H)+.

Step 3: 4-Bromo(methylthio)benzo[d]thiazolecarbonitrile was synthesized as a yellow solid (1.0 g, 12%) using a procedure analogous to that described in Step 2 of Example 114, substituting 4-bromocyanobenzo[d]thiazole thiolate potassium salt from the preVious step for ethyl 2-mercaptothiazolo[4,5- b]pyridinecarboxylate potassium salt used in Example 114. LCMS (ESI) m/z 284, 286 (M+H)+.

WO 56070 Step 4: (4-Bromo(methylthio)benzo[d]thiazolyl)methanamine was synthesized as a clear oil (794 mg, 79%) using a procedure analogous to that described in Step 3 of e 154, substituting 4-bromo (methylthio)benzo[d]thiazolecarbonitrile from the previous step for 5-fluoro (methylthio)benzo[d]thiazolecarbonitrile used in Example 154. LCMS (ESI) m/z 288, 290 (M+H)+.

Step 5: N—((4-Bromo(methylthio)benzo[d]thiazolyl)methyl) nitropyridinamine was synthesized as a yellow solid (115 mg, 39%) using a procedure analogous to that described in Step 4 of e 154, substituting (4- bromo(methylthio)benzo[d]thiazolyl)methanamine from the previous step for (5 -fluoro(methylthio)benzo[d]thiazolyl)methanamine used in Example 154.

LCMS (ESI) m/Z 410, 412(M+H)+.

Step 6: N2-((4-Bromo(methylthio)benzo[d]thiazol yl)methyl)pyridine-2,3-diamine was synthesized as a red solid (120 mg) using a procedure analogous to that described in Step 2 of Example 41, substituting N—((4- bromo(methylthio)benzo[d]thiazolyl)methyl)nitropyridinamine from the previous step for omethoxy-N-((2-(methylthio)benzo[d]thiazol hyl)nitroaniline used in Example 41. LCMS (ESI) m/Z 380, 382 (M+H)+.

Step 7: 6-((3H-Imidazo[4,5-b]pyridinyl)methyl)bromo (methylthio)benzo[d]thiazole was synthesized as an orange solid (180 mg) using a ure analogous to that described in Step 3 of Example 41, substituting NZ-((4- bromo(methylthio)benzo[d]thiazolyl)methyl)pyridine-2,3-diamine from the previous step for 4-bromomethoxy-N1-((2-(methylthio)benzo[d]thiazol hyl)benzene-l,2-diamine used in Example 41. LCMS (ESI) m/Z 390, 392 (M+H)+.

Step 8: 6-((3H-Imidazo[4,5-b]pyridinyl)methyl)bromo (methylsulfinyl)benzo[d]thiazole was synthesized as a yellow foam (211 mg) using a procedure analogous to that described in Step 6 of Exmple 36, substituting 6-((3H- imidazo[4,5-b]pyridinyl)methyl)bromo(methylthio)benzo[d]thiazole from the previous step for 6-((4-bromo-1H-imidazolyl)methyl) (methylthio)benzo[d]thiazole used in Example 36. LCMS (ESI) m/Z 406, 408 (M+H)+. 2012/059983 ] Step 9: (lR,2R)—2-((6-((3H—imidazo[4,5-b]pyridinyl)methyl) bromobenzo[d]thiazolyl)amino)cyclohexanol was synthesized as a white powder (9 mg, 7%) using a procedure analogous to that described in Step 7 of Example 36, substituting 6-((3H-imidazo[4,5-b]pyridinyl)methyl)bromo (methylsulfinyl)benzo[d]thiazole from the preVious step for 6-((4-bromo-1H— imidazolyl)methyl)(methylsulfinyl)benzo[d]thiazole used in Example 36. 1H NMR (500 MHz, DMSO-d6) 8 8.61 (s, 1H), 8.29 — 8.41 (m, 2H), 8.09 (dd, J: 1.2, 8.1 Hz, 1H), 7.68 (s, 1H), 7.49 (d, J: 1.2 Hz, 1H), 7.30 (m, 1H), 5.47 (s, 2H), 4.85 (m, 1H), 3.35 (m, 1H), 1.99 (m, 1H), 1.88 (m, 1H), 1.60 — 1.66 (m, 2H), 1.13 — 1.33 (m, 5H); LCMS (ESI) m/Z 457, 459 (M+H)+.

Example 167 N\ N N/>—NH §H Step 1: (1R,2R)((6-((7-Iodoimidazo[1,2-a]pyridin yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol (50 mg, 13%) was obtained as a light brown solid using a procedure analogous to that described in Step 6 of Example 117, tuting 4-iodopyridinamine and 2-chloro(2-(((1R,2R) hydroxycyclohexyl)amino)benzo[d]thiazolyl)propanal from Step 2 of Example 153, respectively, for oisonicotinonitrile and 2-chloro(2- (methylthio)benzo[d]thiazolyl)propanal used in Example 117. LCMS (ESI) m/z 505 (M+H)+.

Step 2: (1R,2R)((6-((7-(1H-Pyrazolyl)imidazo[1,2-a]pyridin yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol (7 mg, 16%) was obtained as a light tan solid using a procedure analogous to that bed in Example 141, substituting (1R,2R)((6-((7-iodoimidazo [1 ,2-a]pyridin-3 - yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol from Step 1 of this Example for (1R,2R)((6-((6-iodo-3H-imidazo[4,5-b]pyridinyl)methyl)benzo[d]thiazol yl)amino)cyclohexanol used in Example 141. 1H NMR (500 MHz, DMSO-d6) 8 8.64 (d, J: 2.6 Hz, 1H), 8.32 (d, J: 6.7 Hz, 1H), 7.98 (br s, 1H), 7.87 (d, J: 7.3 Hz, 1H), 7.79 (s, 1H), 7.54 (s, 2H), 7.44 (br s, 1H), 7.28 (d, J: 8.3 Hz, 1H), 7.12 (d, J: 7.3 Hz, 1H), 6.59 (s, 1H), 4.74 (br s, 1H), 4.31 (s, 2H), 3.48 - 3.57 (m, 2H), 2.03 (d, J: .9 Hz, 1H), 1.87 (d,.]= 10.4 Hz, 1H), 1.54 - 1.71 (m, 2H), 1.09 - 1.38 (m, 4H).

LCMS (ESI) m/Z 445 (M+H)+.

Example 168 Pre aration of IR 2R 6- 3H-imidazo 4 5-b ridin l meth l -4 7- difluorobenzo thiazol-Z- lamino c clohexanol 4\ S N />—NH 30H \ / F Step 1: obromo-2,5-difluorobenzonitrile was synthesized as a yellow solid (2.4 g, 73%) using a procedure analogous to that described in Step 1 of e 166, substituting 4-amino-2,5-difluorobenzonitrile for 4-amino fluorobenzonitrile used in e 166. 1H NMR (500 MHz, DMSO-d6) 8 7.71 (dd, J = 5.9, 11.1 Hz, 1H), 6.89 (br s, 2H); LCMS (ESI) m/z 232, 234 (M+H)+.

Step 2: 6-Cyano-4,7-difluorobenzo[d]thiazolethiolate potassium salt was synthesized as a brown oil (3.93 g) using a ure analogous to that described in Step 1 of Example 154, substituting 4-aminobromo-2,5-difluorobenzonitrile from the preVious step for 4-amino-2,5-difluorobenzonitrile used in Example 154.

LCMS (ESI) m/Z 228 .

] Step 3: 4,7-Difluoro(methylthio)benzo[d]thiazolecarbonitrile was synthesized as a yellow solid (1.0 g, 37%) using a procedure analogous to that described in Step 2 of Example 114, substituting 6-cyano-4,7- difluorobenzo[d]thiazolethiolate potassium salt from the preVious step for ethyl 2- mercaptothiazolo[4,5-b]pyridinecarboxylate potassium salt used in Example 114. 1H NMR (500 MHz, DMSO-d6) 8 8.04 (m, 1H), 2.88 (s, 3H); LCMS (ESI) m/Z 243 (M+H)+.

Step 4: (4,7-Difluoro(methylthio)benzo[d]thiazolyl)methanamine was synthesized as a clear oil (646 mg, 64%) using a procedure analogous to that described in Step 3 of Example 154, substituting 4,7-difluoro lthio)benzo[d]thiazolecarbonitrile from the previous step for 5-fluoro (methylthio)benzo[d]thiazolecarbonitrile used in Example 154. LCMS (ESI) m/z 247 .

Step 5: N—((4,7-Difluoro(methylthio)benzo[d]thiazolyl)methyl)—3- yridinamine was synthesized as a yellow oil (187 mg, 39%) using a procedure analogous to that described in Step 4 of Example 154, substituting (4,7- o(methylthio)benzo[d]thiazolyl)methanamine from the preVious step for (5 -fluoro(methylthio)benzo[d]thiazolyl)methanamine used in Example 154. 1H NMR (500 MHz, CDC13)8 8.99 (t, J: 6.0 Hz, 1H), 8.40 - 8.48 (m, 2H), 7.36 (dd, J: .5, 11.0 Hz, 1H), 6.80 (dd, J: 4.4, 8.4 Hz, 1H), 4.91 (d, J: 6.2 Hz, 2H), 2.82 (s, 3H); LCMS (ESI) m/Z 369 (M+H)+.

Step 6: NZ-((4,7-Difluoro(methylthio)benzo[d]thiazol yl)methyl)pyridine-2,3-diamine was synthesized as a yellow solid (190 mg) using a procedure analogous to that described in Step 2 of Example 41, substituting N—((4,7- difluoro(methylthio)benzo[d]thiazolyl)methyl)nitropyridinamine from the preVious step for 4-bromomethoxy-N-((2-(methylthio)benzo[d]thiazol yl)methyl)nitroaniline used in Example 41. LCMS (ESI) m/Z 339 (M+H)+.

Step 7: 6-((3H—Imidazo[4,5-b]pyridinyl)methyl)-4,7-difluoro (methylthio)benzo[d]thiazole was synthesized as a orange solid (220 mg) using a procedure ous to that described in Step 3 of Example 41, substituting NZ-((4,7- difluoro(methylthio)benzo[d]thiazolyl)methyl)pyridine-2,3-diamine from the preVious step for omethoxy-N1-((2-(methylthio)benzo[d]thiazol yl)methyl)benzene-l,2-diamine used in Example 41. LCMS (ESI) m/z 349 .

Step 8: 6-((3H—Imidazo[4,5-b]pyridinyl)methyl)-4,7-difluoro (methylsulfinyl)benzo[d]thiazole was synthesized as a yellow foam (200 mg) using a procedure analogous to that described in Step 6 of Example 36, substituting 6-((3H- imidazo[4,5-b]pyridinyl)methyl)-4,7-difluoro(methylthio)benzo[djthiazole from the preVious step for 6-((4-bromo-1H-imidazolyl)methyl) (methylthio)benzo[d]thiazole used in Example 36. LCMS (ESI) m/Z 364 (M+H)+.

Step 9: (1R,2R)—2-((6-((3H-Imidazo[4,5-b]pyridinyl)methyl)-4,7- difluorobenzo[d]thiazolyl)amino)cyclohexanol was synthesized as a white powder (58 mg, 25%) using a procedure analogous to that described in Step 7 of Example 36, substituting 6-((3H—imidazo[4,5-b]pyridinyl)methyl)-4,7-difluoro (methylsulfinyl)benzo[d]thiazole from the preVious step for 6-((4-bromo-1H— imidazolyl)methyl)(methylsulfinyl)benzo[d]thiazole used in Example 36. 1H NMR (500 MHz, DMSO-d6) 8 8.45 - 8.58 (m, 2H), 8.38 (d, J: 4.7 Hz, 1H), 8.09 (d, J: 8.0 Hz, 1H), 7.29 (dd, J: 4.7, 8.0 Hz, 1H), 7.16 (dd, J: 5.8, 10.8 Hz, 1H), 5.54 (s, 2H), 4.80 (d, J: 5.2 Hz, 1H), 3.51 (m, 1H), 3.35 (m, 1H), 2.02 (m, 1H), 1.88 (m, 1H), 1.57 — 1.67 (m, 2H), 1.17 — 1.32 (m, 4H). LCMS (ESI) m/z 416 (M+H)+.

Example 169 Pre aration of IR 2R 6- 7- 1H-1 2 4-triazol l imidazo 1 2-a ridin l meth l benzo d thiazol-Z- 1 amino c clohexanol Q7N N/>—NH §H (1R,2R)((6-((7-(1H-1,2,4-triazolyl)imidazo[1,2-a]pyridin yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol (50 mg, 57%) was obtained as a light yellow powder using a procedure analogous to that described in Example 141, tuting )((6-((7-iodoimidazo [1 ,2-a]pyridin-3 - hyl)benzo[d]thiazolyl)amino)cyclohexanol from Step 1 of e 167 and 1H-1,2,4-triazole, respectively, for (1R,2R)((6-((6-iodo-3H-imidazo[4,5-b]pyridin- 3-yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol and pyrazole used in Example 141.1H NMR (500 MHz, DMSO-d6) 5 9.41 (s, 1H), 8.40 (d, J: 7.3 Hz, 1H), 8.28 (s, 1H), 8.08 (s, 1H), 7.90 (d, J: 7.3 Hz, 1H), 7.54 (s, 1H), 7.50 (s, 1H), 7.48 (d, J: 5.7 Hz, 1H), 7.28 (d, J: 8.3 Hz, 1H), 7.11 (d, J: 8.3 Hz, 1H), 4.76 (br s, 1H), 4.34 (s, 2H), 3.48 - 3.56 (m, 2H), 2.04 (d, J: 11.4 Hz, 1H), 1.88 - 1.93 (m, 1H), 1.53 - 1.70 (m, 2H), 1.08 - 1.36 (m, 4H). LCMS (ESI) m/z 446 (M+H)+.

Example 170 Pre aration of 1- 2— 1R 2R h drox c clohex 1 amino benzo d 0xazol—6- l methyl)—1H-benz0|d|imidazole—S-carbonitrile //\ O N N/U />—NHZ: pH N 3 s Step 1: To a solution of 4-bromonitroaniline (400 mg, 1.84 mmol) and TFA (1.89 mL) in DCM (8 mL) at -5 0C was added NaBH(OAc)3 (1.17 g, 5.52 mmol). Then to the mixture at 0 0C was added a solution of 2- (methylthio)benzo[d]oxazolecarbaldehyde (391 mg, 2.03 mmol) in DCM (7 mL), and the mixture was stirred at 0 0C for 2 h. The mixture was diluted with DCM and washed with H20, aq NaHC03 and brine. The organic layer was dried over Na2S04, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 20:1 to 10:1 petroleum ether/ethyl acetate to give 4- bromo-N-((2-(methylthio)benzo[d]oxazolyl) )nitroaniline as a yellow solid (704 mg, 97.4%). 1H NMR (300 MHz, DMSO-d6) 5 8.80 (t, 1H), 8.15 (s, 1H), 7.64 (s, 1H), 7.50-7.60 (m, 2H), 7.35 (d, J: 8.4 Hz, 1H), 6.90 (d, J: 9.3 Hz, 1H), 4.72 (d, J: 6.6 Hz, 1H), 2.73 (s,3H). LCMS (ESI) m/z 394 (M+H)+.

Step 2: To a stirred solution of 4-bromo-N-((2- (methylthio)benzo[d]oxazolyl) methyl)nitroaniline (704 mg, 1.79 mmol), HOAc (2.1 mL) and methnol (2.1 mL) in DCM (18 mL) at 0 0C was added zinc dust (1.16 g, 17.9 mmol) portionwise. After stirring for 2 h, the mixture was filtered. The filtrate was washed with aq NaHC03 and brine. The organic layer was dried over NaSO4, filtered and trated under d re to give 4-bromo-N1-((2- (methylthio)benzo[d]oxazolyl) methyl)benzene-1,2-diamine (469 mg, 71.9%) as a yellow solid. 1H NMR (300 MHz, DMSO-d6) 8 7.72-7.60 (m, 2H), 7.53 (d, J: 5.4 Hz, 1H), 6.68 (s, 1H), 6.49 (d, J: 1.8 Hz, 1H), 6.23 (d,.]= 8.1 Hz, 1H), 5.36 (t, 1H), 4.90 (s, 2H), 4.38 (d, J: 6.0 Hz, 2H), 2.74 (s, 3H). LCMS (ESI) m/z 365 (M+H)+.

Step 3: A e of 4-bromo-N1-((2-(methylthio)benzo[d]oxazol yl)methyl) benzene-1,2-diamine (465 mg, 2.40 mmol), yl orthoformate (3.8 mL), and HCOOH (0.06 mL) was stirred at 90 0C for 40 min. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 1:1 petroleum ether/ethyl acetate to give 6-((5-bromo- zo[d]imidazolyl)methyl) (methylthio)benzo[d]oxazole as a light brown solid (327mg, 68.3%). 1H NMR (300 MHz, DMSO-d6) 5 8.50 (s, 1H), 7.85 (s, 1H), 7.68 (s, 1H), 7.55-7.60 (m, 2H), 7.30—7.37 (m, 2H), 5.60 (s, 2H), 2.73 (s, 3H). LCMS (ESI) m/Z 375 (M+H)+.

Step 4: A solution of 6-((5-bromo-1H-benzo[d]imidazolyl)methyl) (methylthio) benzo[d]oxazole (327 mg, 0.87 mmol) and m-CPBA (226 mg, 1.31 mmol) in DCM (6 mL) was d at 0 0C for 3.5 h. The mixture was washed with aq Na2S203 and brine. The organic layer was dried over Na2S04, filtered and concentrated under reduced pressure. The e was purified by silica gel chromatography eluting with 1:5 petroleum ether/ethyl acetate to give 6-((5-bromo- 1H-benzo [d]imidazolyl)methyl)(methylsulfinyl)benzo[d]oxazole (256 mg, 75.52%) as a yellow solid. 1H NMR (300 MHz, DMSO-d6) 8 8.54 (s, 1H), 7.97 (s, 1H), 7.87-7.89 (m, 2H), 7.57 (d, J: 9.0 Hz, 1H), 7.46 (d, J: 9.6 Hz, 1H), 7.36 (d, J: 6.6 Hz, 1H), 5.68 (s, 2H), 3.18 (s, 3H). LCMS (ESI) m/z 391 (M+H)+.

Step 5: A e of 6-((5-bromo-1H-benzo[d]imidazolyl)methyl) l sulfinyl)benzo[d]oxazole (206 mg, 0.53 mmol), (1R,2R)—2- aminocyclohexanol (91 mg, 0.79 mmol) and DIEA (136 mg, 1.06 mmol) in DMA (4 mL) was stirred at 120 0C for 2 h. The reaction mixture was cooled to rt, poured into water (30 mL) and extracted with ethyl acetate (30 mL><3). The combined organic layers were washed with brine, dried over Na2S04, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC to give (1R,2R) ((6-((5-bromo- 1 H-benzo [d]imidazolyl)methyl)benzo [d]oxazol yl)amino)cyclohexanol as a light yellow solid (175 mg, 74.8%). 1H NMR (300 MHZ, DMSO-d6) 5 8.46 (s, 1H), 7.81-7.84 (m, 2H), 7.56 (d, J: 8.7 Hz, 1H), 7.33-7.36 (s, 1H), 7.12 (s, 2H), 5.48 (s, 1H), 4.68 (d, J: 4.2 Hz, 1H) 3.35 (br s, 2H), 1.90 (br s, 2H), 1.62 (br s, 2H), 1.22 (br s, 4H). LCMS (ESI) m/z 442 (M+H)+.

] Step 6: A mixture of (1R,2R)((6-((5-bromo-1H-benzo[d]imidazol yl)methyl) benzo[d]oxazolyl)amino)cyclohexanol (126 mg, 0.29 mmol), Zn(CN)2 (134 mg, 1.14 mmol), Pd2(dba)3 (53 mg, 0.06 mmol) and dppf (63 mg, 0.12 mmol) in DMF (4 mL) was stirred at 130 0C for 6 h. The reaction mixture was cooled to rt, poured into water (20 mL) and ted with ethyl acetate (20 mL>< 2). The combined organic layers were washed with water and brine, dried over Na2S04, filtered and concentrated under reduced pressure. The residue was d by preparative HPLC to give (((1R,2R)—2- ycyclohexyl)amino)benzo[d]oxazolyl)methyl)- 1 H-benzo [d]imidazole-5 - carbonitrile as a white solid (40 mg, 35.7%). 1H NMR (300 MHZ, DMSO-d6) 5 8.67 (s, 1H), 8.20 (s, 1H), 7.83-7.78 (m, 2H), 7.61 (d, J: 6.9 Hz, 1H), 7.41 (s, 1H), 7.14 (s, 1H), 5.54 (s, 2H), 4.68 (d, 1H), 3.32 (br s, 2H), 1.91 (br s, 2H), 1.62 (br s, 2H), 1.22 (br s, 4H). LCMS (ESI) m/Z 388 (M+H)+.

Example 171 Pre aration of IR 2R 6- 5- 2-m0r holinoethox -1H-benz0 ol-l- l meth lbenzo thiazol-Z- 1 amino c anol Step 1: To a e of 1-((2-(((1R,2R) hydroxycyclohexyl)amino)benzo[d]thiazolyl)methyl)— zo[d]imidazol-5 -01 (2.4 g, 6.07 mmol) from Example 147 and 2,2-dimethoxypropane (8 g, 76.81 mmol) in oxane (200 mL) was added para-toluenesulfonic acid (0.15 g, 0.8 mmol).

The reaction mixture was heated at 100 CC for 15 h. The mixture was partitioned between ted aq NaHC03 and DCM. The organic layer was separated, dried over Na2S04, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with 2 to 10% MeOH in DCM to afford 1- ((2-((3aR,7aR)-2,2-dimethylhexahydrobenzo[d]oxazol-3(2H)-yl)benzo[d]thiazol yl)methyl)-1H—benzo[d]imidazolol (0.9 g, 34%) as a yellow solid. 1H NMR (300 MHz, DMSO-d6) 8 8.99 (s, 1H), 8.24 (s, 1H), 7.79 (s, 1H), 7.50 (d, J: 8.4 Hz, 1H), 7.24 — 7.30 (m, 2H), 6.94 (s, 1H), 6.68 (m, 1H), 5.43 (s, 2H), 3.68 (m, 1H), 3.05 (m, 1H), 2.67 (m, 1H), 2.04 (m, 1H), 1.76 — 1.78 (m, 2H), 1.70 (s, 3H), 1.53 (s, 3H), 1.26 — 1.39 (m, 4H); LCMS (ESI) m/Z 435 (M+H)+.

Step 2: A stirred mixture of 4-(2-chloroethyl)morpholine (1 g, 5.4 mmol) and K1 (4.5 g 26.8mmol) in acetone (15 mL) was heated at 75 CC for 24 h. The mixture was diluted with saturated aq NaHCOg and extracted with DCM. The organic layer was separated, dried over Na2S04, filtered, and concentrated under reduced pressure to afford 4-(2-iodoethyl)morpholine (0.8 g, 62%) as a pale yellow oil which was not purified fiarther. 1H NMR (300 MHz, CDClg) 8 3.71 (t, J = 9.0 Hz, 4H), 3.20 (t, .1: 7.8 Hz, 2H), 2.72 (t, .1: 7.8 Hz, 2H), 2.49 (t, .1: 9.3 Hz, 4H). LCMS (ESI) m/Z 242 (M+H)+.

Step 3: A mixture of 1-((2-((3aR,7aR)—2,2- dimethylhexahydrobenzo[d]oxazol-3(2H)-yl)benzo[d]thiazolyl)methyl)-1H- benzo[d]imidazolol (100 mg, 0.23 mmol) from Step 1 of this Example, 4-(2- iodoethyl)morpholine (111 mg, 0.46 mmol) from Step 2 of this Example, CS2C03 (250 mg, 0.69mm01), and NMP (2 mL) was stirred at rt for 3 h. The mixture was diluted with EtOAc and washed with brine. The organic layer was ted, dried over Na2S04, filtered, and trated under d pressure. The e was purified by silica gel flash tography, eluting with a gradient of 33% DCM in THF to 100% THF, to afford (3aR,7aR)—2,2-dimethyl(6-((5-(2- morpholinoethoxy)- 1H-benzo[d]imidazolyl)methyl)benzo [d]thiazol yl)octahydrobenzo[d]oxazole (84 mg, 67%) as a yellow solid. 1H NMR (300 MHz, CDC13)6 7.90 (s, 1H), 7.58 (d, J: 8.1 Hz, 1H), 7.40 (s, 1H), 7.29 (s, 1H), 7.14 — 7.19 (m, 2H), 6.90 (m, 1H), 5.35 (s, 2H), 4.11 — 4.17 (m, 2H), 3.70 — 3.75 (m, 4H), 3.65 (m, 1H), 3.08 (m, 1H), 2.76 — 2.84 (m, 3H), 2.57 — 2.60 (m, 4H), 2.17 (m, 1H), 1.82 — 1.92 (m, 2H), 1.78 (s, 3H), 1.46 (s, 3H), 1.33 — 1.39 (m, 4H); LCMS (ESI) m/Z 548 (M+H)+.

Step 4: To a stirred mixture of (3aR,7aR)—2,2-dimethyl(6-((5-(2- morpholinoethoxy)- 1H-benzo[d]imidazolyl)methyl)benzo [d]thiazol yl)octahydrobenzo[d]oxazole (85 mg, 0.15 mmol) from the preVious step in DCM (10 mL) at 0 CC was added methanolic HCl (3 drops). The reaction mixture was stirred at 0 °C for 10 min. The mixture was adjusted to pH ~ 7 by addition of triethylamine and then concentrated under reduced pressure. The residue was d directly by reverse-phase preparative HPLC to afford (1R,2R)((6-((5-(2-morpholinoethoxy)- 1H-benzo[d]imidazolyl)methyl)benzo[d]thiazolyl)amino)cyclohexanol (20 mg, %) as a light yellow solid. 1H NMR (300 MHZ, DMSO-d6) 8 8.30 (s, 1H), 7.97 (m, 1H), 7.62 (s, 1H), 7.39 (d, J: 8.4 Hz, 1H), 7.29 (d, J: 8.1 Hz, 1H), 7.17 (d, J: 6.9 Hz, 2H), 6.83 (m, 1H), 5.41 (s, 2H), 4.73 (d, J: 5.4 Hz, 1H), 4.08 (t, J: 11.7 Hz, 2H), 3.57 (t, J: 9.1 Hz, 4H), 3.47 — 3.52 (m, 2H), 2.68 (t, J: 11.7 Hz, 2H), 2.46 (t, J = 9.3 Hz, 4H), 2.02 (m, 1H), 1.87 (m, 1H), 1.59 — 1.63 (br s, 2H), 1.16 — 1.28 (m, 4H). LCMS (ESI) m/Z 508 (M+H)+.

Example 172 Pre aration of IR 2R 6- 5- 2-h drox ethox -1H-benzo d imidazol—l- l meth l benzo d thiazol-Z- 1 amino c clohexanol /\ S N/ Nfi />—NH N 3 .~ Step 1: A d mixture of 1-((2-((3aR,7aR)—2,2- dimethylhexahydrobenzo[d]oxazol-3(2H)-yl)benzo[d]thiazolyl)methyl)-1H- benzo[d]imidazolol (60 mg, 0.14 mmol) from Step 1 of Example 171, 2- iodoethanol (60 mg, 0.35 mmol), CS2C03 (137 mg, 0.42 mmol), and NMP (2 mL) was heated at 100 CC for 24 h. The mixture was diluted with EtOAc and washed with brine. The organic layer was separated, dried over , filtered, and trated under reduced pressure. The residue was purified by preparative TLC to afford 2-((1- ((2-((3aR,7aR)-2,2-dimethylhexahydrobenzo[d]oxazol-3(2H)-yl)benzo[d]thiazol yl)methyl)-1H—benzo[d]imidazolyl)oxy)ethanol (26 mg, 39%) as a light yellow solid. 1H NMR (300 MHz, CDC13)8 7.93 (s, 1H), 7.58 (d, J: 8.1 Hz, 1H), 7.40 (s, 1H), 7.32 (s, 1H), 7.16 — 7.19 (m, 2H), 6.91 (m, 1H), 5.36 (s, 2H), 4.13 (t, J: 9.0 Hz, 2H), 3.98 (t, J: 9.0 Hz, 2H), 3.65 (m, 1H), 3.08 (m, 1H), 2.80 (m, 1H), 2.14 (m, 1H), 1.84 — 1.92 (m, 2H), 1.78 (s, 3H), 1.63 (s, 3H), 1.28 — 1.40 (m, 4H); LCMS (ESI) m/z 479 (M+H)+.

Step 2: To a stirred mixture of ((2-((3aR,7aR)—2,2- dimethylhexahydrobenzo[d]oxazol-3(2H)-yl)benzo[d]thiazolyl)methyl)-1H- benzo[d]imidazolyl)oxy)ethanol (70 mg, 0.15 mmol) from the us step in DCM (5 mL) at 0 °C was added methanolic HCl (3 drops).. The reaction mixture was stirred at 0 CC for 10 min. The mixture was adjusted to pH ~ 7 by the addition of triethylamine and concentrated under reduced pressure. The residue was purified directly by reverse-phase preparative HPLC to afford ((1R,2R)((6-((5 -(2- hydroxyethoxy)-1H-benzo[d]imidazolyl)methyl)benzo [d]thiazol yl)amino)cyclohexanol (30 mg, 47%) as a light yellow solid. 1H NMR (300 MHz, DMSO-d6) 5 8.30 (s, 1H), 7.95 (d, J: 7.2 Hz, 1H), 7.62 (s, 1H), 7.40 (d, J: 9.0 Hz, 1H), 7.29 (d, J: 8.1 Hz, 1H), 7.16 — 7.18 (m, 2H), 6.84 (m, 1H), 5.41 (s, 2H), 4.83 (br s, 1H), 4.72 (d, J: 4.5 Hz, 1H), 3.98 (t, J: 9.6 Hz, 2H), 3.71 (d, J: 4.5 Hz, 2H), 3.52 (m, 1H), 3.33 (br s, 1H), 2.03 (m, 1H), 1.87 (m, 1H), 1.61 — 1.63 (m, 2H), 1.22 — 1.28 (m, 4H); LCMS (ESI) m/Z 439 (M+H)+.

Example 173 1- 2— 1R 2R h drox c clohex lamino benzo thiazol lmeth l-N— meth enzo imidazole—S-carboxamide /\ S N’ Nfi />—NH 9H N 3 .~ / 0 Step 1: Methyl 4-(((2-(methylthio)benzo[d]thiazolyl)methyl)amino) nitrobenzoate (1.80 g, 91%) was obtained as a yellow solid using a procedure analogous to that bed in Step 1 of Example 127, substituting methyl 4-amino nitrobenzoate for 4-methylnitroaniline used in Example 127. 1H NMR (300 MHz, CDC13)5 9.15 (br s, 1H), 8.63 (s, 1H), 7.98 (s, 1H), 7.88 (dd, J: 9.0, 2.4 Hz, 1H), 7.82 (d, J: 8.4 Hz, 1H), 7.47 (dd, J: 8.7, 1.8 Hz, 1H), 7.02 (d, J: 9.0 Hz, 1H), 4.81 (d, J: 5.7 Hz, 2H), 3.80 (s, 3H), 2.77 (s, 3H); LCMS (ESI) m/z 391 (M + H)+.

Step 2: Methyl 3-amino(((2-(methylthio) benzo[d]thiazol yl)methyl)amino)benzoate (1.01 g, 62%) was obtained as a yellow solid using a procedure ous to that described in Step 2 of Example 129, tuting 4-(((2- (methylthio)benzo[d]thiazolyl)methyl)amino)nitrobenzoate from Step 1 of this e for 4-fluoro-N—((2-(methylthio)benzo[d]thiazolyl)methyl)nitroaniline used in Example 129. LCMS (ESI) m/Z 360 (M + H)+.

Step 3: Methyl 1-((2-(methylthio)benzo[d]thiazolyl)methyl)—1H benzo[d]imidazolecarboxylate (0.42 g, 42%) was obtained as a yellow solid using a procedure analogous to that described in Step 3 of Example 130, substituting methyl 3-amino(((2-(methylthio)benzo[d]thiazolyl)methyl)amino)benzoate from Step 2 of this Example for N1-((2-(methylthio)benzo[d]thiazolyl)methyl) (trifluoromethyl)benzene-1,2-diamine used in Example 130. 1H NMR (300 MHz, CDC13)5 8.55 (s, 1H), 8.05 (s, 1H), 7.98 (dd, J: 8.7, 1.5 Hz, 1H), 7.83 (d, J: 8.4 Hz, 1H), 7.51 (s, 1H), 7.26 — 7.32 (m, 2H), 5.48 (s, 2H), 3.94 (s, 3H), 2.77 (s, 3H); LCMS (ESI) m/Z 370 (M + H)+.

Step 4: Methyl 1-((2-(methylsulfinyl)benzo[d]thiazolyl)methyl)—1H- benzo[d]imidazolecarboxylate (0.40 g, 93%) was obtained as a yellow solid using a procedure analogous to that described in Step 4 of Example 130, substituting methyl 1-((2-(methylthio)benzo [d]thiazolyl)methyl)- 1H benzo[d]imidazolecarboxylate from Step 3 of this Example for 2-(methylthio)((5-(trifluoromethyl)-1H- benzo[d]imidazol yl)methyl)benzo[d]thiazole used in Example 130. 1H NMR (300 C13)8 8.56 (s, 1H), 8.09 (s, 1H), 7.91 — 8.05 (m, 2H), 7.79 (s, 1H), 7.39 (dd, J: 8.7, 1.6 Hz, 1H), 7.29 (d, J: 8.7 Hz, 1H), 5.56 (s, 2H), 3.94 (s, 3H), 3.06 (s, 3H); LCMS (ESI) m/Z 386 (M + H)+.

Step 5: Methyl 1-((2-(((1R,2R)hydroxycyclohexyl)amino) benzo[d]thiazolyl)ethyl)—1H—benzo[d]imidazolecarboxylate (0.27 g, 60%) was obtained as a white solid using a ure analogous to that described in Step 5 of Example 130, substituting methyl 1-((2-(methylsulfinyl)benzo[d]thiazol yl)methyl)-1H—benzo[d]imidazolecarboxylate from Step 4 of this Example for 2- lsulfinyl)((5-(trifluoromethyl)- 1H-benzo [d]imidazol yl)methyl)benzo[d]thiazole used in e 130. 1H NMR (300 MHZ, CDClg) 8 8.51 (s, 1H), 8.01 (s, 1H), 9.76 (dd, J: 8.4, 1.5 Hz, 1H), 7.46 (d, J: 8.1 Hz, 1H), 7.30 (d, J: 8.4 Hz, 1H), 7.13 (dd, J: 8.1, 1.2 Hz, 1H), 7.27 (s, 1H), 5.35 (s, 2H), 3.92 (s, 3H), 3.48 — 3.51 (m, 2H), 2.01 — 2.03 (m, 2H), 1.70 (br m, 2H), 1.25 — 1.32 (m, 4H); LCMS (ESI) m/Z 438 (M + H)+.

Step 6: A mixture of methyl 1-((2-(((1R,2R) hydroxycyclohexyl)amino)benzo[d] thiazolyl)ethyl)-1H—benzo[d]imidazole carboxylate (0.27 g, 0.61 mmol) from the preVious step, lithium hydroxide (84 mg, 3.05 mmol), THF (20 mL) and water (4 mL) was stirred at rt for 3 h. The mixture was concentrated under reduced pressure and the pH was adjusted to 4 -5. The mixture was extracted with EtOAc (30 mL X 3) and the combined organic layers were washed with water (10 mL X 2), dried over Na2S04, filtered, and concentrated under d pressure to afford (((1R,2R)hydroxycyclohexyl)amino)benzo[d]thiazol yl)methyl)-1H-benzo[d] imidazolecarboxylic acid (0. 15 g, 58%) as a white solid which was not purified filrther. 1H NMR (300 MHZ, CDClg) 8 8.25 (s, 1H), 7.94 (s, 1H), 7.81 (d, J: 8.4 Hz, 1H), 7.27 (m, 1H), 7.18 — 7.21 (m, 2H), 7.06 (m, 1H), 5.25 (s, 2H), 3.30 — 3.39 (m, 2H), 1.98 (m, 1H), 1.86 (m, 1H), 1.53 — 1.56 (m, 2H), 1.06 — 1.16 (m, 4H); LCMS (ESI) m/Z 424 (M + H)+. 2012/059983 Step 7: A mixture of (((1R,2R) hydroxycyclohexyl)amino)benzo[d]thiazolyl) methyl)- 1H-benzo[d]imidazole carboxylic acid (100 mg, 0.24 mmol) from the previous step, methylamine (1 mL, 22.5 mmol), DIEA (91 mg, 0.35 mmol) and DMF (5 mL) was stirred at rt for 15 min.

HATU (180 mg, 0.23 mmol) was added and the mixture was stirred at rt for 15 h. The reaction mixture was diluted with EtOAc (50 mL) and washed sequentially with water (10 mL) and brine (10 mL). The organic layer was separated, dried over Na2S04, filtered, and concentrated under reduced pressure. The residue was d directly by reverse-phase preparative HPLC to afford 1-((2-(((1R,2R) hydroxycyclohexyl)amino)benzo[d]thiazolyl)methyl)-N-methyl- 1H- benzo[d]imidazolecarboxamide (26 mg, 25%) as a white solid. 1H NMR (300 MHz, DMSO-d6) 8 8.49 (s, 1H), 8.37 (br s, 1H), 8.16 (s, 1H), 7.95 (d, J: 7.5 Hz, 1H), 7.58 — 7.75 (m, 3H), 7.29 (m, 1H), 7.20 (m, 1H), 5.49 (s, 2H), 4.72 (d, J: 5.1 Hz, 1H), 3.50 (m, 1H), 3.35 (m, 1H), 2.50 (s, 3H), 2.04 (m, 1H), 1.88 (m, 1H), 1.60 — 1.62 (m, 2H), 1.18 — 1.21 (m, 4H). LCMS (ESI) m/z 436 (M + H)+.

Example 174 Pre aration of IR 2R 6- 5- 3 6-dih dro-ZH— ran l-lH-benzo imida zol-l- lmeth lbenzo thiazol-Z- lamino c clohexanol /x\ S N N/\©: /> _NH pH N 3 s ] A stirred mixture of )((6-((5-iodo-1H—benzo[d]imidazol yl)methyl)benzo[d] thiazolyl)amino)cyclohexanol (300 mg, 0.59 mmol) from Step of Example 183, 2-(3,6-dihydro-2H-pyranyl)-4,4,5,5-tetramethyl-1,3,2- dioxaborolane (188 mg, 0.89 mmol), Na2C03 (126 mg, 1.19 mmol), 1,4-dioxane (3 mL) and water (0.5 mL) was purged with a stream of nitrogen for 10 min. [1 , 1 ’- Bis(diphenylphosphino)ferrocene]dichloropalladium (II) (44 mg, 0.5 9mmol) was added and the mixture was heated at 100 CC for 2 h. The reaction mixture was cooled to rt and partitioned n EtOAc and water. The organic layer was separated, dried over Na2S04, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with 30:1 DCM: MeOH and then by e-phase preparative HPLC to afford (1R, 2R)((6-((5-(3, 6-dihydro- 2H-pyranyl)- 1H-benzo[d]imidazolyl)methyl)benzo [d]thia zol yl)amino)cyclohexanol (54 mg, 20%) as a white solid. 1H NMR (300 MHZ, DMSO- d6) 5 8.38 (s, 1H), 7.94 (d, J: 7.8 Hz, 1H), 7.67 (d, J: 1.5 Hz, 1H), 7.63 (d, J: 1.8 Hz, 1H), 7.50 (d, J: 8.4 Hz, 1H), 7.35 (m, 1H), 7.29 (d, J: 8.1 Hz, 1H), 7.18 (m, 1H), 6.19 (s, 1H), 5.46 (s, 2H), 4.71 (d, J: 5.1 Hz, 1H), 4.22 (d, J: 2.7 Hz, 2H), 3.81 — 3.84 (m, 2H), 3.51 (m, 1H), 3.38 (m, 1H), 2.02 (m, 1H), 2.00 (m, 1H), 1.61 (br s, 2H), 1.14 — 1.29 (m, 4H); LCMS (ESI) m/z 460 (M+H)+.

Example 175 Pre n of IR 2R 6- 5- 3 3 3-triflu0r0 r0 en l-lH-benzo imi dazol—l- lmeth lbenzo thiazol-Z- lamino c clohexanol //\ S N N/\©E />—NH 9H N 3 s (1R,2R)((6-((5-(3 ,3 ,3-Trifluoropropenyl)-1H—benzo[d]imidazol yl)methyl) d]thiazolyl)amino)cyclohexanol (71 mg, 25%) was ed as a white solid using a procedure analogous to that described in Example 174, substituting 4,4,5 ,5 -tetramethyl(3 ,3 ,3 -trifluoropropenyl)- 1 ,3 ,2-dioxaborolane for 2-(3,6-dihydro-2H—pyranyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane used in Example 174. 1H NMR (300 MHZ, DMSO-d6) 5 8.49 (s, 1H), 7.95 (d, J: 7.8 Hz, 1H), 7.75 (s, 1H), 7.67 (d, J: 1.2 Hz, 1H), 7.63 (d, J: 8.4 Hz, 1H), 7.35 (d, J: 8.4 Hz, 1H), 7.30 (d, J: 8.4 Hz, 1H), 7.20 (m, 1H), 6.04 (t, J: 1.8 Hz, 2H), 5.49 (s, 2H), 4.17 (d,.]= 5.1Hz, 1H), 3.51 (m, 1H), 3.35 (m, 1H), 2.03 (m, 1H), 1.88 (m, 1H), 1.60 — 1.64 (m, 2H), 1.18 — 1.25 (m, 4H); LCMS (ESI) m/z 473 (M+H)+.

Example 176 Pre aration of R -N— c clohex-Z-en-l- l 6-flu0r0-3H—imidazo 4 5-b ridin- 3- lmeth lbenzo thiazol-Z-amine NpN/U89—NHC “ <3 To a stirred mixture of (1R,2R)((6-((6-fluoro-3H—imidazo[4,5- b]pyridinyl)methyl)benzo[d]thiazolyl)amino)cyclohexanol (156 mg, 0.4 mmol) from Example 162 in CHZCIZ (10 mL) at —78 0C under argon was added diethylaminosulfur trifluoride (63 uL, 0.5 mmol). After stirring the mixture for 3 h, additional diethylaminosulfur trifluoride (63 uL, 0.5 mmol) was added. After the mixture was stirred for a further 3 h, it was poured over ice. Additional CHzClz (50 mL) was added and the mixture was stirred until the ice was melted. The layers were ted and the organic layer was washed with brine (50 mL), dried over MgSO4, filtered, and trated under reduced pressure. The residue was purified by reverse-phase preparative HPLC using a e of water (5% CH3CN, 0.05% HCOOH) and CH3CN (0.05% HCOOH) as the mobile phase and Varian Pursuit XRs C18 column as the stationary phase to afford (R)-N-(cyclohexenyl)((6-fluoro- 3H—imidazo[4,5-b]pyridinyl)methyl)benzo[d]thiazolamine (5 mg, 3%) as a white . 1H NMR (500 MHz, DMSO-d6) 8 8.67 (s, 1H), 8.41 (s, 1H), 8.03 - 8.13 (m, 2H), 7.68 (s, 1H), 7.32 (d, J: 8.3 Hz, 1H), 7.24 (dd, J: 1.3, 8.3 Hz, 1H), .83 (m, 1H), 5.72 (m, 1H), 5.48 (s, 2H), 4.40 (br s, 1H), 1.95 — 2.03 (m, 2H), 1.90 (m, 1H), 1.70 (m, 1H), 1.54 — 1.62 (m, 2H); LCMS (ESI) m/z 380 (M+H)+. e 177 Pre aration of IR 2R 6- 6-br0m0imidaz0 1 2-b ridazin l meth l benzo d thiazol-Z- 1 amino c clohexanol (1R,2R)((6-((6-Bromoimidazo[1,2-b]pyridazin yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol (25 mg, 28%) was obtained as a light tan solid using a procedure analogous to that described in Step 6 of Example 117, substituting 6-bromopyridazinamine and 2-chloro-3 (1R,2R) hydroxycyclohexyl)amino)benzo[d]thiazolyl)propanal from Step 2 of Example 153, respectively, for 2-aminoisonicotinonitrile and 2-chloro(2- (methylthio)benzo[d]thiazolyl)propanal used in Example 117. 1H NMR (500 MHz, WO 56070 DMSO-d6) 5 8.09 (d, .1: 9.8 Hz, 1H), 7.89 (d, .1: 7.4 Hz, 1H), 7.59 (s, 1H), 7.54 (s, 1H), 7.39 (d, .1: 9.4 Hz, 1H), 7.27 (d, .1: 7.9 Hz, 1H), 7.12 (d, .1: 8.4 Hz, 1H), 4.76 (br s, 1H), 4.29 (s, 2H), 3.47 — 3.59 (m, 2H), 2.04 (d, .1: 11.8 Hz, 1H), 1.86 — 1.92 (m, 1H), 1.55 — 1.69 (m, 2H), 1.11 — 1.34 (m, 4H). LCMS (ESI) m/Z 458, 460 (M+H)+.

Example 178 Pre aration of IR 2R 6- 6- 4-meth l i erazin-l- limidazo 1 2- b ridazin l meth l benzo d thiazol 1 amino c clohexanol N N/>—NH §H (1R,2R)((6-((6-(4-Methylpiperazinyl)imidazo[1,2-b]pyridazin yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol (40 mg, 28%) was obtained as a yellow powder using a procedure analogous to that described in Step 6 of Example 117, substituting 6-(1-methylpiperidinyl)pyridazinamine (Ref: {1841043 85 A1, 1978) and 2-chloro(2-(((1R,2R)—2-hydroxycyclohexyl)amino)benzo[d]thiazol panal from Step 2 of Example 153, respectively, for 2-aminoisonicotinonitrile and 2-chloro(2-(methylthio)benzo[d]thiazolyl)propanal used in Example 117. 1H NMR (500 MHz, DMSO-d6) 5 7.88 (d, J: 7.4 Hz, 1H), 7.78 (d, J: 9.8 Hz, 1H), 7.58 (s, 1H), 7.33 (br s, 1H), 7.24 (d, J: 7.9 Hz, 1H), 7.13 (d, J: 8.4 Hz, 1H), 7.10 (d, J: 9.8 Hz, 1H), 4.77 (br s, 1H), 4.16 (s, 2H), 3.44 - 3.51 (m, 4H), 3.34 (td, J: 4.6, 9.0 Hz, 2H), 2.37 - 2.46 (m, 4H), 2.21 (s, 3H), 1.98 - 2.08 (m, 1H), 1.87 - 1.94 (m, 1H), 1.53 - 1.70 (m, 2H), 1.09 - 1.35 (m, 4H). LCMS (ESI) m/z 478 .

Example 179 Pre aration of trans 6- 6-flu0r0-3H—imidaz0 45-b ridin l meth lbenzo thiazol 1 amino c clohex l methanol NEUZOO/>—NH\ / 7 Step 1: To a stirred sion of transaminocyclohexanecarboxylic acid hydrochloride (0.5 g, 2.8 mmol) in anhydrous THF (10 mL) at 0 CC under argon was added se lithium um e (2 M solution in THE, 5.6 mL, 11 mmol). The mixture was stirred for l h at 0 CC, then allowed to warm to rt and stir for an additional 1 h. The mixture was then heated in a sealed tube at 85 CC for 12 h. The mixture was cooled to 0 oC and H20 (600 uL) was slowly added, followed by a l M aq NaOH (1 .2 mL) and H20 (1 .8 mL). The mixture was diluted with CHzClz (50 mL) and stirred for 30 min at rt. The mixture was filtered, and the e was concentrated under reduced pressure to afford (transaminocyclohexyl)methanol (323 mg, 90%) as a white solid that did not require filrther purification.

Step 2: (trans((6-((6-Fluoro-3H—imidazo[4,5-b]pyridin yl)methyl)benzo[d]thiazolyl)amino)cyclohexyl)methanol was synthesized as a white powder (43 mg, 36%) using a procedure analogous to that described in Step 5 of Example 162, substituting (transaminocyclohexyl)methanol for (lS,2R) aminocyclohexanol hydrochloride used in Example 162. 1H NMR (500 MHz, DMSO- d6) 5 8.68 (s, 1H), 8.41 (t, J: 2.0 Hz, 1H), 8.07 (dd, J: 2.6, 9.5 Hz, 1H), 7.95 (d, J: 7.4 Hz, 1H), 7.66 (d, J: 1.2 Hz, 1H), 7.31 (m, 1H), 7.22 (dd, J: 1.6, 8.2 Hz, 1H), .47 (s, 2H), 4.40 (t, J: 5.2 Hz, 1H), 3.58 (m, 1H), 3.22 (m, 2H), 2.00 — 2.07 (m, 2H), 1.73 — 1.80 (m, 2H), 1.32 (m, 1H), 1.13 - 1.25 (m, 2H), 0.92 - 1.03 (m, 2H); LCMS (ESI) m/Z 412 (M+H)+.

Example 180 Pre aration of cis 6- 6-flu0r0-3H-imidazo 45-b ridin l meth lbenzo thiazol-Z- 1 amino c clohex l methanol //\ S N />—NH Step 1: (cisAminocyclohexyl)methanol was synthesized as a white powder (301 mg, 86%) using a procedure analogous to that described in Step 1 of Example 179, substituting cisaminocyclohexanecarboxylic acid for trans yclohexanecarboxylic acid hydrochloride used in Example 179.

] Step 2: (cis((6-((6-Fluoro-3H—imidazo[4,5-b]pyridin yl)methyl)benzo[d]thiazolyl)amino)cyclohexyl)methanol was synthesized as a white powder (26 mg, 21%) using a procedure analogous to that described in Step 5 of Example 162, substituting (cisaminocyclohexyl)methanol from the us step for (1S,2R)aminocyclohexanol hydrochloride used in Example 162. 1H NMR (500 MHz, DMSO-d6) 8 8.67 (s, 1H), 8.41 (t, J: 2.0 Hz, 1H), 8.07 (dd, J: 2.5, 9.4 Hz, 1H), 7.98 (d, J: 7.1 Hz, 1H), 7.66 (d, J: 1.0 Hz, 1H), 7.30 (m, 1H), 7.23 (dd, J: 1.4, 8.2 Hz, 1H), 5.48 (s, 2H), 4.41 (t, J: 4.9 Hz, 1H), 3.96 (m, 1H), 3.26 (t, J: 5.4 Hz, 2H), 1.70 — 1.78 (m, 2H), 1.4 — 1.60 (m, 5H), 1.28 — 1.38 (m, 2H); LCMS (ESI) m/Z 412 (M+H)+.

Example 181 Pre aration of 6- 0-3H—imidazo 4 5-b ridin l meth l -N— 1R 2R meth lthio c clohex lbenzo thiazol-Z-amine /\ S N/ NU ,>—NH :8 Step 1: To a stirred mixture of )((6-((6-fluoro-3H—imidazo[4,5- b]pyridinyl)methyl)benzo[d]thiazolyl)amino)cyclohexanol (517 mg, 1.3 mmol) from Example 162, TEA (194 uL, 1.4 mmol), and CHzClz (15 mL) at rt under argon was added methanesulfonyl chloride (152 uL, 2.0 mmol). After stirring the mixture for 15 h, additional TEA (194 uL, 1.4 mmol) and methanesulfonyl chloride (152 uL, 2.0 mmol) were added. After stirring for an additional 18 h, the mixture was diluted with CHzClz and d with saturated aq NaHCOg (50 mL) for 30 min. The layers were separated and the organic layer was washed with brine (50 mL), dried over MgSO4, filtered, and concentrated under reduced re. The residue was purified by silica gel flash chromatography, eluting with a gradient of 100% hexanes to 100% EtOAc, to afford (1S,2R)((6-((6-fluoro-3H—imidazo[4,5-b]pyridin yl)methyl)benzo[d]thiazolyl)amino)cyclohexyl methanesulfonate (274 mg, 44%) as a clear oil. 1H NMR (500 MHZ, DMSO-d6) 8 8.66 (s, 1H), 8.39 (t, J: 1.8 Hz, 1H), 8.16 (d, J: 7.4 Hz, 1H), 8.04 (dd, J: 2.6, 9.5 Hz, 1H), 7.66 (d, J: 1.0 Hz, 1H), 7.33 (d, J: 8.1 Hz, 1H), 7.22 (dd, J: 1.4, 8.2 Hz, 1H), 5.46 (s, 2H), 4.98 (m, 1H), 4.06 (m, 1H), 2.99 (s, 3H), 2.01 (m, 1H), 1.54 — 1.72 (m, 4H), 1.34 — 1.50 (m, 3H); LCMS (ESI) m/Z 476 (M+H)+. 2012/059983 Step 2: A mixture of (1S,2R)((6-((6-fluoro-3H—imidazo[4,5-b]pyridin- 3-yl)methyl)benzo[d]thiazolyl)amino)cyclohexyl methanesulfonate (100 mg, 0.2 mmol) and sodium thiomethoxide (74 mg, 1.0 mmol) in DMF (1.0 mL) was stirred at rt for 2h. The mixture was purified directly by reverse-phase preparative HPLC using a mixture of water (5% CH3CN, 0.05% HCOOH) and CH3CN (0.05% HCOOH) as the mobile phase and Varian Pursuit XRs C18 column as the stationary phase to afford 6-((6-fluoro-3H—imidazo[4,5-b]pyridinyl)methyl)-N-((1R,2R) (methylthio)cyclohexyl)benzo[d]thiazolamine (5 mg, 4%) as a white powder. 1H NMR (500 MHz, 6) 8 8.68 (s, 1H), 8.41 (t, J: 1.8 Hz, 1H), 8.04 - 8.11 (m, 2H), 7.67 (s, 1H), 7.30 (m, 1H), 7.23 (m, 1H), 5.48 (s, 2H), 3.72 (m, 1H), 2.56 (m, 1H), 1.99 —2.08 (m,5H), 1.63 — 1.71 (m, 2H), 1.41 — 1.51 (m, 1H), 1.21 — 1.36 (m, 3H); LCMS (ESI) m/Z 428 (M+H)+. e 182 Pre aration of IR 2R 6- 5- 0xetan 10x -1H-benz0 imidazol-l- l meth lbenzo thiazol-Z- 1 amino c clohexanol /\ 3 NZ/ “ll/U />—NH 9H N 3 :‘ 09/O Step 1: To a stirred mixture of ol (0.85 g, 11.5 mmol) in DCM (38 mL) were added TEA (3.3 mL, 23 mmol) and 4-methylbenzenesulfonyl chloride (2.7 g, 13.8 mmol). The reaction e was stirred at rt for 15 h. The mixture was partitioned between water and DCM. The organic layer was separated, dried over Na2S04, filtered, and concentrated under reduced pressure. The e was purified by silica gel flash chromatography eluting with a gradient of 30% DCM in petroleum ether to 100% DCM to afford oxetanyl 4-methylbenzenesulfonate (1.3 g, 50%) as a white solid. 1H NMR (300 MHz, CDClg) 8 7.77 (d, J: 8.4 Hz, 2H), 7.35 (d, J: 8.7 Hz, 2H), 5.30 (m, 1H), 4.66 — 4.74 (m, 4H), 2.46 (s, 3H); LCMS (ESI) m/Z 229 (M+H)+.

Step 2: A stirred mixture of 1-((2-((3aR,7aR)—2,2- dimethylhexahydrobenzo[d]oxazol-3(2H)-yl)benzo[d]thiazolyl)methyl)-1H- benzo[d]imidazolol (100 mg, 0.23 mmol) from Step 1 of Example 171, oxetanyl 4-methylbenzenesulfonate (420 mg, 1.84 mmol) from the previous step, C82C03 (225 mg, 0.69 mmol), sodium iodide (276 mg, 0.69 mmol) and NMP (4 mL) was heated at 145 CC for 15 h. The mixture was diluted with EtOAc and washed with brine. The organic layer was dried over NazSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with 40:1 DCM/MeOH to afford (3aR,7aR)—2,2-dimethyl(6-((5-(oxetanyloxy)-1H- d]imidazolyl)methyl)benzo[d]thiazolyl)octahydrobenzo [d]oxazole (35 mg, 31%) as a yellow solid. 1H NMR (300 MHZ, CDClg) 8 7.90 (s, 1H), 7.58 (d, J: 8.4 Hz, 1H), 7.40 (s, 1H), 7.17 — 7.20 (m, 2H), 6.94 (s, 1H), 6.84 (m, 1H), 5.35 (s, 2H), 5.24 (m, 1H), 5.00 (m, 2H), 4.79 (m, 2H), 3.66 (m, 1H), 3.08 (m, 1H), 2.81 (m, 1H), 2.15 (m, 1H), 1.84 — 1.92 (m, 2H), 1.78 (s, 3H), 1.63 (s, 3H), 1.30 — 1.45 (m, 4H); LCMS (ESI) m/Z 491 (M+H)+.

Step 3: )—2-((6-((5-(Oxetanyloxy)-1H—benzo[d]imidazol yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol (20 mg, 50%) was obtained as a yellow solid using a procedure analogous to that described in Step 2 of Example 172, substituting (3aR,7aR)-2,2-dimethyl(6-((5-(oxetanyloxy)-1H-benzo[d]imidazol- 1-yl)methyl)benzo[d]thiazolyl)octahydrobenzo [d]oxazole from Step 2 of this Example for 2-((1-((2-((3aR,7aR)-2,2-dimethylhexahydrobenzo[d]oxazol-3(2H)- yl)benzo[d]thiazolyl)methyl)-1H—benzo[d]imidazolyl)oxy)ethanol used in Example 172. 1H NMR (300 MHz, DMSO-d6) 5 8.21 (s, 1H), 7.49 (s, 1H), 7.34 — 7.37 (m, 2H), 7.19 (m, 1H), 6.82 — 6.89 (m, 2H), 5.44 (s, 2H), 5.28 (t, J: 8.4 Hz, 1H), .00 — 5.04 (m, 2H), 4.67 — 4.71 (m, 2H), 3.57 (m, 1H), 3.44 (m, 1H), 2.08 (m, 1H), 2.00 (m, 1H), 1.70 — 1.77 (m, 2H), 1.29 — 1.41 (m, 4H); LCMS (ESI) m/z 451 (M+H)+.

Example 183 Pre n of IR 2R 6- 5-Vin l-lH-benzo imidazol—l- lmeth lbenzo thiazol-Z- 1 amino c clohexanol Step 1: 4-Iodo-N—((2-(methylthio)benzo[d]thiazolyl)methyl) nitroaniline (5.7 g, 66%) was obtained as a yellow solid using a procedure ous to that described in Step 1 of Example 127, substituting 4-iodonitroaniline for 4- methylnitroaniline used in Example 127. 1H NMR (300 MHZ, CDClg) 8 8.50 (d, J = 2.1 Hz, 1H), 8.46 (br s, 1H), 7.85 (d, J: 8.7 Hz, 1H), 7.70 (s, 1H), 7.57 (d, J: 9.0 Hz, 1H), 7.36 (d, J: 8.4 Hz, 1H), 6.58 (d, J: 9.0 Hz, 1H), 4.63 (d, J: 5.7 Hz, 2H), 2.79 (s, 3H); LCMS (ESI) m/Z 458 (M+H)2+.

Step 2: 4-Iodo-N1-((2-(methylthio)benzo[d]thiazolyl)methyl)benzene- 1,2-diamine (4.89 g, 92%) was obtained as a yellow solid using a procedure analogous to that described in Step 2 of Example 129, substituting 4-iodo-N-((2- lthio)benzo[d]thiazolyl)methyl)nitroaniline from Step 1 of this Example for 4-fluoro-N—((2-(methylthio)benzo[d]thiazolyl)methyl)nitroaniline used in Example 129. LCMS (ESI) m/Z 428 (M+H)+.

Step 3: 6-((5-Iodo-lH—benzo[d]imidazol-l-yl)methyl) (methylthio)benzo[d]thiazole (3 g, 60%) was obtained as a orange solid using a procedure analogous to that described in Step 3 of Example 130, substituting 4-iodo- N1-((2-(methylthio)benzo[d]thiazolyl)methyl)benzene-l,2-diamine from Step 2 of this Example for N1-((2-(methylthio)benzo[d]thiazolyl)methyl) (trifluoromethyl)benzene-l,2-diamine used in Example 130. 1H NMR (300 MHz, 8 8.18 (s, 1H), 7.91 (s, 1H), 7.82 (d, J: 8.4 Hz, 1H), 7.48 — 7.53 (m, 2H), 7.24 (d, J: 9.0 Hz, 1H), 7.04 (d, J: 8.4 Hz, 1H), 5.43 (s, 2H), 2.78 (s, 3H); LCMS (ESI) m/Z 438 .

Step 4: Iodo-lH—benzo[d]imidazol-l-yl)methyl) (methylsulfinyl)benzo[d]thiazole (2.79 g, 90%) was obtained as a tan solid using a procedure analogous to that described in Step 4 of Example 130, substituting 6-((5- iodo-lH—benzo[d]imidazol-l-yl)methyl)(methylthio)benzo[d]thiazole from Step 3 of this Example for 2-(methylthio)((5-(trifluoromethyl)- lH—benzo[d]imidazol -l- yl)methyl)benzo[d]thiazole used in e 130. 1H NMR (300 MHZ, CDClg) 8 8.20 (s, 1H), 8.03 (d, J: 8.4 Hz, 1H), 7.96 (s, 1H), 7.76 (s, 1H), 7.52 (d, J: 8.4 Hz, 1H), 7.36 (d, J: 8.4 Hz, 1H), 7.03 (d, J: 8.4 Hz, 1H), 5.51 (s, 2H), 3.07 (s, 3H); LCMS (ESI) m/Z 454 (M+H)+.

Step 5: )((6-((5-Iodo-1H—benzo[d]imidazol yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol (1.78 g, 57%) was obtained as a brown solid using a procedure analogous to that described in Step 5 of Example 130, substituting 6-((5 1H-benzo [d]imidazolyl)methyl) (methylsulfinyl)benzo[d]thiazole from Step 4 of this Example for 2-(methylsulfinyl)- 6-((5 uoromethyl)— 1H-benzo [d]imidazolyl)methyl)benzo [d]thiazole used in Example 130. 1H NMR (300 MHz,CDC13)8 8.13 (s, 1H), 7.87 (s, 1H), 7.46 (d, J: 8.45 Hz, 1H), 7.44 (d, J: 9.9 Hz, 1H), 7.19 (s, 1H), 7.08 (d, J: 8.4 Hz, 1H), 7.03 (d, J: 8.4Hz, 1H), 5.28 (s, 2H), 3.52 (m, 1H), 3.44 (m, 1H), 2.04 — 2.16 (m, 2H), 1.68 — 2.73 (m, 2H), 1.18 — 1.42 (m, 4H); LCMS (ESI) m/z 505 (M+H)+.

Step 6: (1R,2R)((6-((5-Vinyl-1H—benzo[d]imidazol yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol (64 mg, 20%) was obtained as a white solid using a procedure analogous to that described in Example 174, substituting 4,4,5,5-tetramethylVinyl-1,3,2-dioxaborolane for 2-(3,6-dihydro-2H- pyranyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane used in Example 174. 1H NMR (300 MHz, DMSO-d6) 5 8.39 (s, 1H), 7.95 (d, J: 7.5 Hz, 1H), 7.72 (s, 1H), 7.64 (s, 1H), 7.51 (d, J: 8.4 Hz, 1H), 7.38 (d, J: 8.4 Hz, 1H), 7.28 (d, J: 8.4 Hz, 1H), 7.19 (d, J: 8.4 Hz, 1H), 6.81 (m, 1H), 5.77 (d, J: 18.0 Hz, 1H), 5.45 (s, 2H), 5.16 (d, J: 11.1Hz, 1H), 4.73 (d,.]= 8.4 Hz, 1H), 3.53 (m, 1H), 3.27 (m, 1H), 2.02 (m, 1H), 1.87 (m, 1H), 1.60 — 1.62 (m, 2H), 1.20 — 1.24 (m, 4H); LCMS (ESI) m/z 405 .

Example 184 Pre aration of IR 2R 6- 5- c clohex-l-en-l- l-lH-benzo imidazol-l- l meth lbenzo thiazol-Z- lamino c clohexanol NfiN/UstH §OH O N O )—2-((6-((5-(Cyclohexenyl)—1H—benzo[d]imidazol yl)methyl)benzo[d]thiazol amino)cyclohexanol (80 mg, 30%) was obtained as a white solid using a procedure analogous to that described in Example 174, substituting 2-(cyclohexenyl)-4, 4, 5, 5-tetramethyl-1,3,2-dioxaborolane for 2- (3,6-dihydro-2H—pyranyl)—4,4,5,5-tetramethyl-1,3,2-dioxaborolane used in Example 174.1H NMR (300 MHz, DMSO-d6) 5 8.35 (s, 1H), 7.94 (d, .1: 8.1 Hz, 1H), 7.60 (d, J: 8.7 Hz, 2H), 7.45 (d, J: 8.4 Hz, 1H), 7.29 (d, J: 8.1 Hz, 2H), 7.18 (m, 1H), 6.08 (d, J: 4.5 Hz, 1H), 5.44 (s, 2H), 4.72 (d, J: 5.4 Hz, 1H), 3.51 (m, 1H), 3.37 (m, 1H), 2.39 — 2.45 (m, 2H), 2.13 — 2.20 (m, 2H), 2.04 (m, 1H), 1.89 (m, 1H), 1.80 — 1.83 (m, 2H), 1.56 — 1.66 (m, 4H), 1.11 — 1.36 (m, 4H); LCMS (ESI) m/z 459 (M+H)+.

Example 185 Pre aration of IR 2R 6- 5- l-meth l trifluorometh l-lH- razol—4- l- 1H-benz0 imidazol—l- lmeth lbenzo thiazol-Z- lamino c clohexanol //\ S N N/\©: />—NH pH N 3 s (1R,2R)((6-((5-(1-Methyl(trifluoromethyl)-1H—pyrazolyl)-1H— benzo[d]imidazolyl)methyl)benzo[d]thiazolyl)amino)cyclohexanol (71 mg, %) was obtained as a White solid using a procedure analogous to that described in Example 174, substituting hyl(trifluoromethyl)—1H—pyrazolyl)boronic acid for 2-(3,6-dihydro-2H—pyranyl)—4,4,5,5-tetramethyl-1,3,2-dioxaborolane used in Example 174. 1H NMR (300 MHz, DMSO-d6) 5 8.44 (s, 1H), 8.10 (s, 1H), 7.95 (m, 1H), 7.69 (s, 1H), 7.63 (s, 1H), 7.60 (d, J: 8.7 Hz, 1H), 7.30 (d, J: 8.4 Hz, 1H), 7.23 — 7.75 (m, 2 H), 5.48 (s, 2H), 4.70 (m, 1H), 3.96 (s, 3H), 3.51 (m, 1H), 3.32 (m, 1H), 2.03 (m, 1H), 1.84 (m, 1H), 1.59 — 1.62 (m, 2H), 1.15 — 1.29 (m, 4H); LCMS (ESI) m/Z 527 .

Example 186 Pre aration of IR 2R 6- S-fluoroimidazo 1 2-a ridin l meth l benzo d l-Z- 1 amino c clohexanol N\ N />—NH §oH F N \ / C (lR,2R)((6-((5-Fluoroimidazo[1,2-a]pyridin yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol (5 mg, 10%) was obtained as a yellow powder using a procedure analogous to that described in Step 6 of Example 117, substituting 6-fluoropyridinamine and 2-chloro(2-(((lR,2R) hydroxycyclohexyl)amino)benzo[d]thiazolyl)propanal from Step 2 of Example 153, respectively, for 2-aminoisonicotinonitrile and 2-chloro(2- (methylthio)benzo[d]thiazolyl)propanal used in Example 117. 1H NMR (500 MHz, DMSO-d6) 5 7.92 (d, J: 7.4 Hz, 1H), 7.42 (d, J: 3.9 Hz, 1H), 7.35 - 7.40 (m, 1H), 7.26 (d, J: 8.4 Hz, 1H), 7.22 (dd, J: 7.1, 15.5 Hz, 1H), 6.99 (d, J: 7.9 Hz, 1H), 6.66 (t, J: 7.1 Hz, 1H), 4.80 (br s, 1H), 4.39 (br s, 2H), 3.50 (br s, 2H), 2.04 (d, J: 11.8 Hz, 1H), 1.87 (d, J: 10.8 Hz, 1H), 1.54 - 1.70 (m, 2H), 1.10 - 1.37 (m, 4H).

LCMS (ESI) m/Z 397 (M+H)+.

Example 187 Pre aration of IR 2R 6- 7-m0r holinoimidazo 12-a 3- l meth l benzo d thiazol-Z- 1 amino c anol N\\NWM OS/>—NH §H Step 1: A mixture of ropyridinamine (400 mg, 3.1 mmol) and morpholine (2 mL) in 2 mL ofDMA was heated at 200 0C for 5 min in a microwave reactor. LCMS is indicated completion of the reaction. The mixture was ioned between EtOAc and brine, and the organic layer was dried over Na2S04 and concentrated under reduced pressure to give crude 4-morpholinopyridinamine as a yellow solid (350 mg). LCMS (ESI) m/z 180 (M+H)+.

Step 2: (lR,2R)((6-((7-Morpholinoimidazo[l,2-a]pyridin yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol (50 mg, 31%) was obtained as a yellow powder using a ure analogous to that described in Step 6 of Example 117, substituting 4-morpholinopyridinamine from Step 1 of this Example and 2- chloro(2-(((lR,2R)hydroxycyclohexyl)amino)benzo[d]thiazolyl)propanal from Step 2 of Example 153, respectively, for 2-aminoisonicotinonitrile and 2-chloro- 3-(2-(methylthio)benzo[d]thiazolyl)propanal used in Example 117. 1H NMR (500 MHz, DMSO-d6) 5 7.94 (d, J: 7.9 Hz, 1H), 7.88 (d, J: 7.4 Hz, 1H), 7.48 (s, 1H), 7.25 (d, J: 7.9 Hz, 1H), 7.18 (s, 1H), 7.06 (d, J: 8.4 Hz, 1H), 6.79 (dd, J: 2.2, 7.6 Hz, 1H), 6.67 (d, J: 2.0 Hz, 1H), 4.75 (br s, 1H), 4.20 (s, 2H), 3.67 - 3.79 (m, 4H), 3.50 (br s, 2H), 3.09 - 3.16 (m, 4H), 2.03 (d, J: 11.8 Hz, 1H), 1.86 (br s, 1H), 1.55 - 1.71 (m, 2H), 1.12 - 1.38 (m, 4H). LCMS (ESI) m/z 464 (M+H)+.

Example 188 Pre aration of IR 2R 6- 7- 4-meth l i erazin-l- zo 1 2- a ridin l meth l benzo d thiazol-Z- 1 amino c anol Step 1: A mixture of 4-chloropyridinamine (400 mg, 3.1 mmol) and N- piperizine (2 mL) in DMA (2 mL) was heated at 200 0C for 5 min in a microwave reactor. LCMS analysis indicated completion of the reaction. The reaction mixture was partitioned between EtOAc and brine, and the c layer was dried over Na2S04 and concentrated under reduced pressure to give crude 4-(4- methylpiperazinyl)pyridinamine as a brown solid (350 mg). LCMS (ESI) m/Z 193 (M+H)+.

Step 2: (1R,2R)((6-((7-(4-Methylpiperazinyl)imidazo[1,2-a]pyridin- 3-yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol (17 mg, 9%) was obtained as a yellow solid using a procedure analogous to that bed in Step 6 of Example 117, substituting 4-(4-methylpiperazinyl)pyridinamine from Step 1 of this Example, and 2-chloro(2-(((1R,2R)hydroxycyclohexyl)amino)benzo[d]thiazol yl)propanal from Step 2 of Example 153, respectively, for 2-aminoisonicotinonitrile and 2-chloro(2-(methylthio)benzo[d]thiazolyl)propanal used in Example 117. 1H NMR (500 MHz, DMSO-d6) 5 7.90 (d, J: 7.4 Hz, 1H), 7.87 (d, J: 7.4 Hz, 1H), 7.47 (s, 1H), 7.25 (d, J: 8.4 Hz, 1H), 7.17 (s, 1H), 7.06 (d, J: 6.9 Hz, 1H), 6.72 - 6.81 2012/059983 (m, 2H), 6.64 (s, 1H), 4.19 (s, 2H), 3.51 (br s, 1H), 3.31 — 3.37 (m, 2H), 3.16 (d, J: 4.4 Hz, 4H), 2.42 (d, .1: 4.4 Hz, 4H), 2.21 (s, 3H), 2.03 (d, .1: 11.8 Hz, 1H), 1.83 — 1.87 (m, 1H), 1.55 — 1.70 (m, 2H), 1.10 — 1.35 (m, 4H). LCMS (ESI) m/Z 477 (M+H)+.

Example 189 Pre aration of IR 2R 6- eth l-lH-benzo imidazol-l- l meth lbenzo thiazol-Z- 1 amino c clohexanol //\ S N N/\©: />—NH 9H N 3 3 ] Step 1: N—(2,4-Dimethylnitrophenyl)formamide (746 mg, 64%) was obtained as a solid using a procedure analogous to that described in Step 1 of e 203, substituting 4,6-dimethylnitroaniline for 4-bromofluoro nitroaniline used in Example 203. LCMS (ESI) m/Z 195 (M+H)+.

Step 2: N—(2,4-Dimethylnitrophenyl)-N-((2- (methylthio)benzo[d]thiazolyl)methyl)formamide (1.29 g, 87%) was obtained as a yellow solid using a procedure analogous to that described in Step 2 of Example 203, substituting N-(2,4-dimethylnitrophenyl)formamide from the preVious step for N- (4-bromofluoronitrophenyl)formamide used in Example 203. LCMS (ESI) m/Z 388 (M+H)+.

Step 3: 7-Dimethyl-lH-benzo[d]imidazol-l-yl)methyl) (methylthio)benzo[d]thiazole (696 mg, 62%) was obtained as a solid using a procedure analogous to that described in Step 3 of Example 203, substituting N—(2,4- dimethylnitrophenyl)-N-((2-(methylthio)benzo[d]thiazolyl)methyl)formamide from the preVious step for N-(4-bromofluoronitrophenyl)-N-((2- (methylthio)benzo[d]thiazolyl)methyl)formamide used in Example 203. 1H NMR (500 MHz, DMSO-d6) 8 8.25 (s, 1H), 7.80 (d, J: 8.4 Hz, 1H), 7.60 (d, J: 0.8 Hz, 1H), 7.29 (s, 1H), 7.08 (dd, J: 8.4, 1.6 Hz, 1H), 6.74 (s, 1H), 5.75 (s, 2H), 2.75 (s, 3H), 2.33 (s, 3H), 2.33 (s, 3H); LCMS (ESI) m/z 340 (M+H)+.

Step 4: 6-((5,7-Dimethyl-lH-benzo[d]imidazol-l-yl)methyl) (methylsulfinyl)benzo[d]thiazole (600 mg, 83%) was obtained as a solid using a procedure analogous to that described in Step 4 of Example 203, substituting 6-((5,7- dimethyl- 1H-benzo [d]imidazolyl)methyl)(methylthio)benzo [d]thiazole from the previous step for 6-((5-bromofluoro-1H—benzo[d]imidazolyl)methyl) (methylsulfinyl)benzo[d]thiazole used in Example 203. 1H NMR (500 MHz, DMSO- d6) 5 8.28 (s, 1H), 8.07 (d, J: 8.5 Hz, 1H), 7.83 (m, 1H), 7.31 (m, 1H), 7.28 (dd, J: 8.6, 1.6 Hz, 1H), 6.74 (m, 1H), 5.83 (s, 2H), 3.05 (s, 3H), 2.33 (s, 3H), 2.33 (s, 3H); LCMS (ESI) m/z 356 (M+H)+.

Step 5: ((1R,2R)((6-((5,7-Dimethyl-1H—benzo[d]imidazol hyl)benzo[d]thiazolyl)amino)cyclohexanol (50 mg, 29%) was obtained as a solid using a procedure analogous to that described in Step 5 of Example 203, substituting 6-((5 ,7-dimethyl- zo [d]imidazolyl)methyl) (methylsulfinyl)benzo[d]thiazole from the preVious step for bromofluoro-1H— benzo[d]imidazolyl)methyl)(methylsulfinyl)benzo[d]thiazole used in Example 203. 1H NMR (500 MHz, DMSO-d6) 8 8.21 (s, 1H), 7.96 (d, J: 7.6 Hz, 1H), 7.22 - 7.30 (m, 3H), 6.81 (dd, J: 1.2, 8.4 Hz, 1H), 6.73 (s, 1H), 5.62 (s, 2H), 4.75 (br m, 1H), 3.51 (br m, 1H), 3.30 (br m, 1H), 2.38 (s, 3H), 2.33 (s, 3H), 2.02 (m, 1H), 1.85 (m, 1H), 1.56 - 1.66 (m, 2H), 1.13 - 1.30 (m, 4H); LCMS (ESI) m/z 407 (M+H)+.

Example 190 Pre aration of IR 2R 6- 5-br0m0-7—meth l-lH-benzo imidazol—l- l meth lbenzo thiazol 1 amino c clohexanol % S N N/\©: />—NH 9H N 3 9 ] Step 1: N—(4-bromomethylnitrophenyl)formamide (227 mg, 33%) was obtained as a solid using a procedure analogous to that described in Step 1 of Example 203, substituting 4-bromomethylnitroaniline for ofluoro nitroaniline used in Example 203. LCMS (ESI) m/Z 259 and 260 .

Step 2: N—(4-Bromomethylnitrophenyl)-N-((2- (methylthio)benzo[d]thiazolyl)methyl)formamide (377 mg, 95%) was obtained as an oil using a procedure analogous to that described in Step 2 of Example 203, substituting N—(4-bromomethylnitrophenyl)formamide from the preVious step for N—(4-bromofluoronitrophenyl)formamide used in Example 203. LCMS (ESI) m/Z 452 and 454 (M+H)+.

Step 3: 6-((5-Bromomethyl-1H—benzo[d]imidazolyl)methyl) (methylthio)benzo[d]thiazole (100 mg, 30%) was obtained as a solid using a procedure analogous to that described in Step 3 of Example 203, substituting N—(4- bromomethylnitrophenyl)-N-((2-(methylthio)benzo[d]thiazol yl)methyl)formamide from the preVious step for N-(4-bromofluoronitrophenyl)- N—((2-(methylthio)benzo[d]thiazolyl)methyl)formamide used in Example 203. 1H NMR (500 MHz, DMSO-d6) 8 8.38 (s, 1H), 7.81 (d, J: 8.4 Hz, 1H), 7.72 (m, 1H), 7.62 (m, 1H), 7.10 — 7.11 (m, 2H), 5.79 (s, 2H), 2.76 (s, 3H), 2.37 (s, 3H); LCMS (ESI) m/Z 404 and 406 (M+H)+.

] Step 4: 6-((5-Bromomethyl-1H—benzo[d]imidazolyl)methyl) (methylsulfinyl)benzo[d]thiazole (60 mg, 58%) was obtained as a solid using a procedure analogous to that described in Step 4 of Example 203, substituting 6-((5- bromomethyl- 1H-benzo [d]imidazolyl)methyl)(methylthio)benzo [d]thiazole from the preVious step for 6-((5-bromofluoro-1H—benzo[d]imidazolyl)methyl)- 2-(methylsulfinyl)benzo[d]thiazole used in e 203. 1H NMR (500 MHz, DMSO-d6) 8 8.42 (s, 1H), 8.09 (d, J: 8.5 Hz, 1H), 7.85 (m, 1H), 7.73 (m, 1H), 7.31 (dd, J: 8.6, 1.6 Hz, 1H), 7.12 (m, 1H), 5.87 (s, 2H), 3.05 (s, 3H), 2.37 (s, 3H); LCMS (ESI) m/z 420 and 422 .

Step 5: (1R,2R)((6-((5-Bromomethyl-1H—benzo[d]imidazol yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol (9 mg, 13%) was obtained as a solid using a procedure ous to that described in Step 5 of Example 203, substituting 6-((5-bromomethyl- 1H-benzo[d]imidazolyl)methyl) (methylsulfinyl)benzo[d]thiazole from the us step for 6-((5-bromofluoro-1H— benzo[d]imidazolyl)methyl)(methylsulfinyl)benzo[d]thiazole used in Example 203. 1H NMR (500 MHz, DMSO-d6) 8 8.34 (s, 1H), 7.98 (d, J: 7.6 Hz, 1H), 7.70 (d, J: 1.0 Hz, 1H), 7.25 - 7.31 (m, 2H), 7.10 (s, 1H), 6.83 (dd,.]= 1.2, 8.1 Hz, 1H), 5.66 (s, 2H), 4.76 (br m, 1H), 3.51 (br m, 1H), 3.30 (br m, 1H), 2.42 (s, 3H), 2.03 (m, 1H), 1.87 (m, 1H), 1.56 - 1.66 (m, 2H), 1.13 - 1.32 (m, 4H); LCMS (ESI) m/z 471 and 473 (M+H)+.

Example 191 Pre aration of 6- 6-fluoro-3H—imidazo 4 5-b 3- l meth l -N— hen lbenzo thiazol-Z-amine 6-((6-Fluoro-3H—imidazo[4,5-b]pyridinyl)methyl)-N- phenylbenzo[d]thiazolamine was synthesized as a white powder (38 mg, 23%) using a procedure analogous to that described in Step 5 of Example 162, substituting aniline for (1S,2R)aminocyclohexanol hydrochloride used in e 162 and increasing the reaction temperature to 130 CC. 1H NMR (500 MHZ, DMSO-d6) 8 .50 (br s, 1H), 8.71 (s, 1H), 8.42 (m, 1H), 8.09 (dd, J: 2.5, 9.4 Hz, 1H), 7.80 (s, 1H), 7.73 — 7.77 (m, 2H), 7.55 (d, J: 8.4 Hz, 1H), 7.32 - 7.37 (m, 3H), 7.01 (t, J: 7.4 Hz, 1H), 5.55 (s, 2H); LCMS (ESI) m/Z 376 (M+H)+.

Example 192 Pre aration of IR 3R 6- 6-flu0r0-3H—imidazo 4 5-b ridin l meth l benzo thiazol 1 amino c clohex l methanol Step 1: A mixture of (1R,3R)((tert— butoxycarbonyl)amino)cyclohexanecarboxylic acid in a 1:1 solution of TFA: CHzClz (6 mL) was stirred at rt for 3 h. The mixture was concentrated under reduced pressure.

The residue was triturated in ethyl ether (50 mL) and the resulting solid was collected by filtration to afford )aminocyclohexanecarboxylic acid trifluoroacetate (253 mg, 86%) as a white solid that did not require further purification.

Step 2: ((lR,3R)Aminocyclohexyl)methanol was synthesized as a white powder (213 mg, 75%) using a procedure ous to that described in Step 1 of Example 179, tuting )aminocyclohexanecarboxylic acid trifluoroacetate from the preVious step for transaminocyclohexanecarboxylic acid hydrochloride used in Example 179.

Step 3: ((1R,3R)—3-((6-((6-Fluoro-3H—imidazo[4,5-b]pyridin yl)methyl)benzo[d]thiazolyl)amino)cyclohexyl)methanol was synthesized as a white powder (17 mg, 10%) using a procedure analogous to that described in Step 5 of Example 162, substituting ((1R,3R)aminocyclohexyl)methanol from the preVious step for (1S,2R)aminocyclohexanol hydrochloride used in Example 162. 1H NMR (500 MHz, DMSO-d6) 8 8.68 (s, 1H), 8.41 (t, J: 1.8 Hz, 1H), 8.07 (dd, J: 2.5, 9.4 Hz, 1H), 7.96 (d, J: 7.6 Hz, 1H), 7.66 (s, 1H), 7.31 (m, 1H), 7.23 (dd, J: 1.5, 8.4 Hz, 1H), 5.48 (s, 2H), 4.43 (m 1H), 3.65 (m, 1H), 3.17 — 3.28 (m, 2H), 1.95 — 2.10 (m, 2H), 1.61 — 1.79 (m, 2H), 1.49 (m, 1H), 1.31 (m, 1H), 1.08 (m, 1H), 0.75 — 0.90 (m, 2H); LCMS (ESI) m/Z 412 (M+H)+. e 193 Pre aration of IR 2S 3R 6- 6-flu0r0-3H-imidaz0 4 5-b ridin l meth l benzo thiazol 1 amino c clohexane-l 2-diol é\N S N />—NH §OH \ / "'"OH (1R,2S,3R)—3-((6-((6-Fluoro-3H—imidazo[4,5-b]pyridin yl)methyl)benzo[d]thiazolyl)amino)cyclohexane-1,2-diol was sized as a white powder (15mg, 14%) using a procedure analogous to that described in Step 5 of Example 232, substituting 6-((6-fluoro-3H—imidazo[4,5-b]pyridin—3-yl)methyl) (methylsulfinyl)benzo[d]thiazole from Step 4 of Example 70 for 6-((5-iodo-1H- benzo[d]imidazolyl)methyl)(methylsulfinyl)benzo[d]thiazole used in Example 232. 1H NMR (500 MHz, 6) 8 8.68 (s, 1H), 8.41 (t, J: 2.0 Hz, 1H), 8.07 (dd, J: 2.5, 9.4 Hz, 1H), 7.94 (d, J: 7.9 Hz, 1H), 7.66 (d, J: 1.0 Hz, 1H), 7.29 (m, 1H), 7.22 (dd, J: 1.4, 8.2 Hz, 1H), 5.48 (s, 2H), 4.54 (br s, 1H), 4.44 (br s, 1H), 3.93 (m, 1H), 3.79 (m, 1H), 3.39 (m, 1H), 1.91 (m, 1H), 1.52 — 1.69 (m, 2H), 1.33 — 1.43 (m, 2H), 1.19 (m, 1H); LCMS (ESI) m/Z 414 (M+H)+.

Example 194 Pre aration of 1S 3R 6- 6—flu0r0-3H-imidaz0 4 5-b ridin l meth lbenzo l 1 amino c clohex l methanol p S /N/\©: />—NHN OV/OH Step 1: (1S,3R)—3-Aminocyclohexanecarboxylic acid roacetate was synthesized as a white powder (275 mg, 94%) using a ure analogous to that described in Step 1 of Example 192, substituting (1S,3R)((tert— butoxycarbonyl)amino)cyclohexanecarboxylic acid for )((tert— butoxycarbonyl)amino)cyclohexanecarboxylic acid used in Example 192.

Step 2: ((lS,3R)Aminocyclohexyl)methanol was synthesized as a white powder (157 mg, 59%) using a procedure analogous to that described in Step 1 of Example 179, substituting (1S,3R)aminocyclohexanecarboxylic acid trifluoroacetate from the preVious step for transaminocyclohexanecarboxylic acid hydrochloride used in Example 179.

Step 3: ((1S,3R)—3-((6-((6-Fluoro-3H—imidazo[4,5-b]pyridin hyl)benzo[d]thiazolyl)amino)cyclohexyl)methanol was sized as a white powder (15 mg, 8%) using a procedure analogous to that described in Step 5 of Example 162, substituting ((1S,3R)aminocyclohexyl)methanol from the preVious step for (1S,2R)aminocyclohexanol hydrochloride used in Example 162. 1H NMR (500 MHz, DMSO-d6) 8 8.68 (s, 1H), 8.41 (t, J: 1.8 Hz, 1H), 8.07 (dd, J: 2.5, 9.4 Hz, 1H), 7.96 (d, J: 7.6 Hz, 1H), 7.66 (s, 1H), 7.31 (m, 1H), 7.23 (dd, J: 1.5, 8.4 Hz, 1H), 5.48 (s, 2H), 4.43 (m 1H), 3.65 (m, 1H), 3.17 — 3.28 (m, 2H), 1.95 — 2.10 (m, 2H), 1.61 — 1.79 (m, 2H), 1.49 (m, 1H), 1.31 (m, 1H), 1.08 (m, 1H), 0.75 — 0.90 (m, 2H); LCMS (ESI) m/Z 412 (M+H)+.

Example 195 Pre aration of 6-chlor0 2- 1R 2R h drox c clohex 1 amino benzo d oxazol l meth l -1H-benz0 d imidazole—S- mnitrile % O N Nfi />—NH pH N 3 s Step 1: A mixture of 5-chloronitroaniline (6.0 g, 34.88 mmol) and NBS (6.06 g, 34.0 mmol) in HOAc (240 mL) was stirred at 130 0C for l h. The reaction mixture was poured into water. The precipitate was collected by filtration and washed with petroleum ether to give 4-bromochloronitroaniline as a light brown solid (8.25 g, 96.5%). 1H NMR (300 MHz, 6) 5 8.24 (s, 1H), 7.62 (br s, 2H), 7.29 (s, 1H). LCMS (ESI) m/Z 251 (M+H)+.

Step 2: To a solution of 4-bromochloronitroaniline (550 mg, 2.19 mmol) from the previous step and TFA (2.26 mL) in DCM (10 mL) at -15 0C was added NaBH(OAc)3 (1.39 g, 5.37 mmol). Then a solution of 2- (methylthio)benzo[d]oxazolecarbaldehyde (465 mg, 2.41 mmol) in DCM (6 mL) was added to the mixture. After complete addition, the mixture was d at -10 0C to 0 0C for 2 h. The reaction mixture was diluted with DCM and washed sequentially with H20, aq NaHC03 and brine. The organic layer was dried over , filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 5:1 to 2:1 petroleum ether/DCM to give 4-bromo chloro-N-((2- lthio)benzo[d]oxazolyl)methyl)nitroaniline as a yellow solid (451 mg, 48.2%). 1H NMR (300 MHz, DMSO-d6) 5 8.81 (t, 1H), 8.34 (s, 1H), 7.66 (s, 1H), 7.60 (d, J: 8.1 Hz, 1H), 7.37 (d, J: 6.9 Hz, 1H), 7.19 (s, 1H), 4.76 (d, J = 6.3 Hz, 2H), 2.74 (s, 3H). LCMS (ESI) m/z 428 (M+H)+.

Step 3: To a stirred solution of 4-bromochloro-N—((2- (methylthio)benzo[d]oxazolyl)methyl)nitroaniline (451 mg, 1.06 mmol) in methanol (80 mL) and DCM (80 mL) was added palladium on activated charcoal (100 mg). The mixture was stirred under hydrogen for 2 h, filtered and concentrated under reduced pressure to give 4-bromochloro-N1-((2-(methylthio)benzo[d]oxazol yl)methyl)benzene-l,2-diamine as a light yellow solid (415 mg, 98.6%). 1H NMR (300 MHz, 6) 5 .60 (m, 2H), 7.35 (d, J: 8.1 Hz, 1H), 6.81 (s, 1H), 6.41 (s, 1H), 5.64 (t, 1H), 5.03 (s, 2H), 4.40 (d, J: 6.0 Hz, 2H), 2.74 (s, 3H). LCMS (ESI) m/Z 399 (M+H)+.

Step 4: A mixture of 4-bromochloro-N1-((2- (methylthio)benzo[d]oxazolyl) )benzene-l,2-diamine (622 mg, 2.40 mmol), oxymethane (5 mL) and HCOOH (0.08 mL) was stirred at 90 0C for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was d by silica gel chromatography, eluting with 1:1 petroleum ether/ethyl acetate to give 6- ((5 -bromochloro-1H-benzo[d]imidazolyl)methyl) (methylthio)benzo[d]oxazole as a light brown solid (607 mg, 84.5%). 1H NMR (300 MHz, DMSO-d6) 5 8.56 (s, 1H), 8.07 (s, 1H), 8.02 (s, 1H), 7.72 (s, 1H), 7.60 (d, J: 8.4 Hz, 1H), 7.34 (d, J: 6.6 Hz, 1H), 5.60 (s, 2H), 2.73 (s, 3H). LCMS (ESI) m/z 408 (M+H)+.

Step 5: A solution of 6-((5-bromochloro-1H-benzo[d]imidazol yl)methyl)(methylthio)benzo[d]oxazole (554 mg, 1.80 mmol) and m-CPBA (403 mg, 2.34 mmol) in DCM (18 mL) was d at 0 0C for 3 h. The reaction mixture was washed with aqueous Na2S203 and brine. The organic layer was dried over Na2S04, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 1:5 petroleum ether/ethyl e to give 6-((5- bromochloro- 1 H-benzo [d]imidazol- 1 thyl) (methylsulfinyl)benzo[d]oxazole (510 mg, 87.5%) as a yellow solid. 1H NMR (300 MHz, DMSO-d6) 5 8.59 (s, 1H), 8.08 (s, 1H), 8.04 (s, 1H), 7.97 (s, 1H), 7.90 (d, J: 8.7 Hz, 1H), 7.50 (d, J: 9.3 Hz, 1H), 5.69 (s, 2H), 3.18 (s, 3H). LCMS (ESI) m/z 424 (M+H)+.

] Step 6: A mixture of 6-((5-bromochloro-1H-benzo[d]imidazol yl)methyl) (methylsulfinyl)benzo[d]oxazole (460 mg, 1.08 mmol), (1R,2R) aminocyclohexanol (245 mg, 2.13 mmol) and DIEA (366 mg, 2.84 mmol) in DMA (10 mL) was stirred at 120 0C for 1 h. The reaction mixture was cooled to rt, poured into water (30 mL) and extracted with ethyl acetate (100 mL><3). The combined organic layers were washed with brine, dried over Na2S04, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 1:5 petroleum ethyl acetate to give (1R,2R)((6-((5-bromochloro-1H- benzo [d]imidazol- 1 thyl)benzo[d]oxazolyl)amino)cyclohexanol as a light yellow solid (470 mg, 82.3%). 1H NMR (300 MHz, CDClg) 8 8.52 (s, 1H), 8.06 (s, 1H), 8.00 (s, 1H), 7.82(d, J: 7.8 Hz, 1H),7.41(s, 1H), 7.14 (s, 1H), 5.48 (s, 2H), 4.68 (d, J: 4.2 Hz, 1H), 3.33 (br s, 2H), 1.91 (br s, 2H), 1.63 (br s, 2H), 1.25 (br s, 4H).

LCMS (ESI) m/Z 477 (M+H)+.

Step 7: A mixture of (1R,2R)((6-((5-bromochloro-1H- benzo[d]imidazolyl)methyl)benzo[d]oxazolyl)amino)cyclohexanol (215 mg, 0.45 mmol), Zn(CN)2 (327 mg, 2.71 mmol), Pd2(dba)3 (82 mg, 0.09 mmol) and dppf (100 mg, 0.18 mmol) in DMA (10 mL) was stirred at 100 0C for 16 h. The reaction mixture was cooled to room ature, poured into water (20 mL) and extracted with ethyl acetate (50 mL>< 2). The combined organic layers were washed with water and brine, dried over NaZSO4, filtered and concentrated under d pressure. The residue was purified by preparative HPLC to give 6-chloro((2-(((1R,2R) hydroxycyclohexyl)amino)benzo[d]oxazolyl)methyl)- 1 H-benzo dazole-5 - carbonitrile as a white solid (25 mg, 13.5%). 1H NMR (300 MHZ, DMSO-d6): 5 8.69 (s, 1H), 8.36 (s, 1H), 8.13 (s, 1H), 7.82 (d, J: 7.8 Hz, 1H), 7.45 (s, 1H), 7.16 (s, 1H), .53 (s, 2H), 4.68 (d, J: 4.5 Hz, 1H), 3.38-3.31 (m, 2H), 1.92-1.86 (m, 2H), 1.65- 1.60 (m, 2H), 1.27-1.19 (m, 4H). LCMS (ESI) m/z 422 (M+H)+.

Example 196 Pre aration of 2- 1- 2- 1R 2R h drox c clohex lamino benzo thiazol lmeth l-lH-benzo imidazol-S- 10x acetonitrile N/ N/\©: />_NH/\ 2: pH N 3 s ] Step 1: 2-((1-((2-((3aR,7aR)—2,2-Dimethylhexahydrobenzo[d]oxazol- 3 (2H)-yl)benzo [d]thiazolyl)methyl)- 1H-benzo [d]imidazol-5 -yl)oxy)acetonitrile (42 mg, 25%) was obtained as a yellow solid using a procedure analogous to that described in Step 3 of Example 171, substituting iodoacetonitrile for 4-(2- iodoethyl)morpholine used in Example 171. 1H NMR (300 MHZ, CDClg) 8 7.99 (s, 1H), 7.58 (d, J: 8.1 Hz, 1H), 7.30 — 7.40 (m, 2H), 7.16 — 7.26 (m, 2H), 6.95 (m, 1H), .38 (s, 2H), 4.79 (s, 2H), 3.65 (m, 1H), 3.08 (m, 1H), 2.80 (m, 1H), 2.17 (m, 1H), 1.82 — 1.92 (m, 2H), 1.78 (s, 3H), 1.64 (s, 3H), 1.33 — 1.39 (m, 4H).

Step 2: 2-((1-((2-(((1R,2R)Hydroxycyclohexyl)amino)benzo[d]thiazol- ethyl)-1H—benzo[d]imidazolyl)oxy)acetonitrile (31 mg, 68%) was obtained as a white solid using a procedure analogous to that described in Step 4 of Example , substituting 2-((1-((2-((3aR,7aR)-2,2-dimethylhexahydrobenzo[d]oxazol-3(2H)- yl)benzo[d]thiazolyl)methyl)-1H—benzo[d]imidazol-5 -yl)oxy)acetonitrile for (3aR,7aR)-2,2-dimethyl-3 5-(2-morpholinoethoxy)-1H-benzo[d]imidazol yl)methyl)benzo[d]thiazolyl)octahydrobenzo[d]oxazole used in Example 171. 1H NMR (300 MHz, CDC13)6 7.95 (s, 1H), 7.48 (d, .1: 8.4 Hz, 1H), 7.40 (d, .1: 2.1 Hz, 1H), 7.29 (m, 1H), 7.20 (d, .1: 8.1 Hz, 1H), 7.16 (dd, .1: 8.1, 1.5 Hz, 1H), 6.96 (dd, .1 = 8.7, 2.4 Hz, 1H), 5.36 (s, 2H), 5.21 (m, 1H), 4.80 (s, 2H), 3.83 (br m, 1H), 3.61 (br m, 1H), 3.47 (m, 1H), 2.08 — 2.18 (m, 2H), 1.75 — 1.79 (m, 2H), 1.24 — 1.44 (m, 4H).

LCMS (ESI) m/Z 434 (M+H)+.

Example 197 Pre aration of 6- 6—flu0r0-3H-imidaz0 4 5-b ridin l meth l -N— 2- methox hen lbenzo thiazolamine NgUZ/d)—NH 6-((6-Fluoro-3H—imidazo[4,5-b]pyridinyl)methyl)-N—(2- methoxyphenyl)benzo[d]thiazolamine was sized as a white powder (45 mg, %) using a procedure analogous to that bed in Example 191, substituting 2- methoxyaniline for aniline used in Example 191. 1H NMR (500 MHZ, CDClg) 8 9.84 (s, 1H), 8.71 (s, 1H), 8.35 — 8.46 (m, 2H), 8.08 (dd, J: 2.6, 9.5 Hz, 1H), 7.78 (s, 1H), 7.50 (d, J: 8.4 Hz, 1H), 7.31 (dd, J: 1.5, 8.4 Hz, 1H), 6.91 — 7.10 (m, 3H), 5.53 (s, 2H), 3.85 (s, 3H); LCMS (ESI) m/Z 407 (M+H)+.

Example 198 Pre aration ofN— 1R 2R chlor0c clohex l 6-flu0r0-3H-imidaz0 4 5- b ridin lmeth lbenzo thiazolamine Nggfijo/>—NH CI \ / ] To a d mixture of (1S,2R)—2-((6-((6-fluoro-3H—imidazo[4,5-b]pyridin— 3-yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol (282 mg, 0.7 mmol) from Example 162, DIEA (247 uL, 1.4 mmol), and CHzClz (15 mL) at 0 CC under argon was added sulfidryl chloride (142 mg, 2.0 mmol). The mixture was warmed to rt and stirred for 15 h, and then stirred at 60 0C for 15 h. The mixture was cooled to rt and purified directly by reverse-phase preparative HPLC using a mixture of water (5% CH3CN, 0.05% HCOOH) and CH3CN (0.05% HCOOH) as the mobile phase and Varian Pursuit XRs C18 column as the stationary phase. The product was further purified by ating in CHzClz (5 mL) to afford N—((1R,2R)chlorocyclohexyl) uoro-3H—imidazo[4,5-b]pyridinyl)methyl)benzo[d]thiazolamine (29 mg, %) as a white solid. 1H NMR (500 MHz, CDClg) 8 8.68 (s, 1H), 8.41 (s, 1H), 8.24 (d, J: 8.4 Hz, 1H), 8.07 (dd, J: 2.6, 9.5 Hz, 1H), 7.68 (s, 1H), 7.33 (d, J: 8.4 Hz, 1H), 7.24 (dd, J: 1.4, 8.2 Hz, 1H), 5.48 (s, 2H), 4.02 (m, 1H), 3.87 (m, 1H), 2.20 (m, 1H), 2.07 (m, 1H), 1.63 — 1.75 (m, 3H), 1.29 — 1.41 (m, 3H); LCMS (ESI) m/z 416 (M+H)+.

Example 199 Pre aration of 1- 3- 2- 1R 2R h drox c clohex 1 amino benzo d thiazol lmeth limidazo 1 2-a ridin-7— l i eridinol 1-(3 -((2-(((1R,2R)Hydroxycyclohexyl)amino)benzo[d]thiazol yl)methyl)imidazo[1,2-a]pyridinyl)piperidinol (30 mg, 22%) was obtained as a yellow solid using a procedure analogous to that described in Step 6 of Example 117, substituting 4-(2-aminopyridinyl)cyclohexanol and ro(2-(((1R,2R) hydroxycyclohexyl)amino)benzo[d]thiazolyl)propanal from Step 2 of Example 153, respectively, for 2-aminoisonicotinonitrile and 2-chloro(2- (methylthio)benzo[d]thiazolyl)propanal used in Example 117. 1H NMR (500 MHz, DMSO-d6) 5 7.88 (d, J: 7.4 Hz, 2H), 7.47 (s, 1H), 7.25 (d, J: 8.4 Hz, 1H), 7.15 (s, 1H), 7.06 (d, J: 8.4 Hz, 1H), 6.76 (dd, J: 2.2, 7.6 Hz, 1H), 6.63 (s, 1H), 4.74 (br s, 1H), 4.18 (s, 2H), 3.63 (dd, J: 4.2, 8.6 Hz, 1H), 3.54 (d, J: 12.8 Hz, 2H), 3.31 - 3.37 (m, 4H), 2.80 - 2.93 (m, 2H), 2.04 (d, J: 11.8 Hz, 1H), 1.88 - 1.92 (m, 1H), 1.74 - 1.83 (m, 2H), 1.56 - 1.70 (m, 2H), 1.38 - 1.50 (m, 2H), 1.10 - 1.37 (m, 4H). LCMS (ESI) m/Z 478 (M+H)+.

Example 200 Pre aration of 1- 3- 2- 1R 2R h drox c clohex 1 amino benzo d thiazol l meth l imidazo 1 2-a ridin-7— l ethanone NmNflHS\ §H Step 1: 1-(2-Aminopyridinyl)ethanone was obtained as a yellow solid (398 mg, 64%) using a procedure analogous to that described in Example 73, substituting 4-iodopyridinamine for (1R,2R)((6-((6-bromo-3H—imidazo[4,5- b]pyridinyl)methyl)benzo[d]thiazolyl)amino)cyclohexanol used in Example 73.

LCMS (ESI) m/Z 137 (M+H)+.

Step 2: 1-(3-((2-(((1R,2R)Hydroxycyclohexyl)amino)benzo[d]thiazol- 6-yl)methyl)imidazo[1,2-a]pyridinyl)ethanone (80 mg, 35%) was obtained as a yellow powder using a procedure analogous to that described in Step 6 of Example 117, tuting 1-(2-aminopyridinyl)ethanone from Step 1 of this Example and 2- chloro(2-(((1R,2R)hydroxycyclohexyl)amino)benzo[d]thiazolyl)propanal from Step 2 of e 153, respectively, for 2-aminoisonicotinonitrile and 2-chloro- 3-(2-(methylthio)benzo[d]thiazolyl)propanal used in Example 117. 1H NMR (500 MHz, DMSO-d6) 8 8.32 (s, 1H), 8.29 (d, J: 6.9 Hz, 1H), 7.87 (d, J: 7.4 Hz, 1H), 7.67 (s, 1H), 7.53 (s, 1H), 7.28 (br s, 1H), 7.27 (d, J: 7.9 Hz, 1H), 7.09 (d, J: 8.4 Hz, 1H), 4.72 (d, J: 4.9 Hz, 1H), 4.35 (s, 2H), 3.51 (br s, 1H), 2.62 (s, 3H), 2.03 (d, J = 11.3 Hz, 1H), 1.87 (d, J: 10.8 Hz, 1H), 1.55 - 1.70 (m, 2H), 1.09 - 1.35 (m, 4H).

LCMS (ESI) m/Z 421 (M+H)+.

Example 201 Pre n of IR 2R 6- 7- 1-h drox eth limidazo 1 2-a ridin l meth l benzo d thiazol 1 amino c clohexanol N<\',\I/\©:N/>_NHS\ §H To a d solution of 1-(3-((2-(((1R,2R)—2- hydroxycyclohexyl)amino)benzo[d]thiazolyl)methyl)imidazo[ 1 ,2-a]pyridin yl)ethanone (40 mg, 0.095 mmol) from Example 200 in MeOH at rt was added NaBH4. After 30 min, 3N HCl was added and the mixture was purified by reverse- phase HPLC using a mixture of water (5% CH3CN, 0.05% HCOOH) and CH3CN (0.05% HCOOH) as the mobile phase and Varian Pursuit XRs C18 column as the nary phase to afford (1R,2R)((6-((7-(1-hydroxyethyl)imidazo[1,2-a]pyridin hyl)benzo[d]thiazolyl)amino)cyclohexanol (23 mg, 58%) as white powder. 1H NMR (500 MHz, DMSO-d6) 8 8.11 (d, J: 7.4 Hz, 1H), 7.87 (d, J: 7.9 Hz, 1H), 7.50 (s, 1H), 7.41 (s, 1H), 7.37 (s, 1H), 7.26 (d, J: 8.4 Hz, 1H), 7.07 (d, J: 7.9 Hz, 1H), 6.84 (d, J: 7.4 Hz, 1H), 5.30 (br s, 1H), 4.72 (q, J: 6.4 Hz, 2H), 4.26 (s, 2H), 3.50 (br s, 1H), 2.03 (d, J: 11.8 Hz, 1H), 1.82 - 1.87 (m, 1H), 1.55 - 1.69 (m, 2H), 1.32 (d, J: 6.9 Hz, 3H), 1.10 - 1.30 (m, 4H). LCMS (ESI) m/z 423 (M+H)+.

Example 202 Pre aration of 1- 3- 2- 1R 2R h drox c clohex 1 amino benzo d l l meth l imidazo 1 2-a ridin-7— l ethanone oxime N\ N N/>—NH §H To a stirred solution of 1-(3-((2-(((1R,2R) ycyclohexyl)amino)benzo[d]thiazolyl)methyl)imidazo[ 1 ,2-a]pyridin yl)ethanone (40 mg, 0.095 mmol) from Example 200 in EtOH (2 mL) at rt were added hydroxylamine hydrochloride (120 mg, excess) and pyridine (200 uL, excess). The mixture was heated at 90 0C for 1 h, and then cooled to rt. Purification by reverse- phase HPLC using a mixture of water (5% CH3CN, 0.05% HCOOH), CH3CN (0.05% HCOOH) as the mobile phase and Varian Pursuit XRs C18 column as the stationary phase afforded 1-(3-((2-(((1R,2R)hydroxycyclohexyl)amino)benzo[d]thiazol yl)methyl)imidazo[l,2-a]pyridinyl)ethanone oxime (23 mg, 61%) as yellow powder. 1H NMR (500 MHz, DMSO-d6) 8 11.46 (br s, 1H), 8.13 (d, J: 7.4 Hz, 1H), 7.90 (d, J: 7.4 Hz, 1H), 7.72 (s, 1H), 7.51 (s, 1H), 7.45 (s, 1H), 7.08 (d, J: 8.4 Hz, 1H), 6.44 - 6.58 (m, 1H), 5.89 (s, 1H), 4.78 (d, J: 2.5 Hz, 1H), 4.29 (s, 2H), 3.50 (br s, 1H), 2.18 (s, 3H), 2.04 (d, J: 12.3 Hz, 1H), 1.87 (d, J: 10.8 Hz, 1H), 1.56 - 1.67 (m, 2H), 1.15 - 1.32 (m, 4H). LCMS (ESI) m/z 436 (M+H)+.

Example 203 Pre aration of IR 2R 6- 5-br0m0-7—flu0r0-1H-benz0 d ol—l- l meth lbenzo thiazol-Z- 1 amino c clohexanol &\ S NQFN/\©:/>—NH 9H Step 1: A stirred mixture of acetic anhydride (20 mL, 213 mmol) and formic acid (8 mL, 213 mmol) was heated at 60 0C for 3 h. The mixture was cooled to rt, fluoronitroaniline (2.5 g, 10.64 mmol) was added. The mixture was heated at 60 0C for 15 h, cooled to rt and concentrated under reduced pressure. The residue was partitioned between saturated aq NaHC03 and DCM. The organic layer was separated, dried over MgSO4, filtered, and concentrated under d pressure to afford N—(4-bromofluoronitrophenyl)formamide (2.79 g, 100%) as a brown solid that was not purif1ed filrther. LCMS (ESI) m/z 285 and 287 (M+H + Na)+.

Step 2: To a stirred on ofN—(4-bromofluoro nitrophenyl)formamide (2.79 g, 10.61 mmol) from the previous step in anhydrous DMF (40 mL) at 0 CC was added sodium hydride (60% dispersion in mineral oil, 485 mg, 12.13 mmol). The mixture was stirred at 0 CC for 15 min, then allowed to warm to rt. To the on mixture was added a solution of oromethyl) (methylthio)benzo[d]thiazole (3.04 g, 13.24 mmol) from Step 3 of Example 3 in DMF (10 mL), and the e was stirred at rt for 15 h. The mixture was partitioned between water and DCM and the organic layer was separated and washed sequentially with water and brine. The organic layer was separated, dried over MgSO4, filtered, and concentrated under reduced pressure to afford N—(4-bromofluoro nitrophenyl)-N-((2-(methylthio)benzo[d]thiazolyl)methyl)formamide (4.8 g, 98%) as an oil, which was not purified further. LCMS (ESI) m/Z 456 and 458 (M+H)+.

Step 3: To a stirred mixture ofN—(4-bromofluoronitrophenyl)-N-((2- lthio)benzo[d]thiazolyl)methyl)formamide (4.8 g, 10.55 mmol) from the previous step, HOAc (15 mL) and EtOH (50 mL) at rt was added portionwise iron powder (1.77 g, 31.65 mmol). The mixture was heated at 80 0C for 2.5 h. After cooling to rt, the mixture was partitioned between saturated aq NaHCOg and a 10:1 e of EtOAc and MeOH. The biphasic mixture was filtered through Celite, and the layers of the filtrate were separated. The aqueous layer was extracted with a 10:1 mixture of EtOAc and MeOH. The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The residual solid was d by trituration with diethyl ether to afford bromofiuoro-1H—benzo[d]imidazol yl)methyl)(methylthio)benzo[d]thiazole (1.39 mg, 39%) as a white solid. 1H NMR (500 MHz, 6) 8 8.56 (s, 1H), 7.87 (m, 1H), 7.80 (d, J: 8.4 Hz, 1H), 7.75 (m, 1H), 7.30 — 7.34 (m, 2H), 5.66 (s, 2H), 2.76 (s, 3H); LCMS (ESI) m/Z 408 and 410 (M+H)+.

Step 4: 6-((5-Bromofiuoro-1H—benzo[d]imidazolyl)methyl) (methylsulfinyl)benzo[d]thiazole (1.33 g, 92%) was obtained as a white solid using a procedure analogous to that described in Step 4 of Example 130, tuting 6-((5- bromofiuoro- 1H-benzo[d]imidazolyl)methyl)(methylthio)benzo [d]thiazole from Step 3 of this Example for 2-(methylthio)((5-(trifiuoromethyl)-1H- benzo[d]imidazol yl)methyl)benzo[d]thiazole used in Example 130. 1H NMR (500 MHz, DMSO-d6) 5 8.58 (s, 1H), 8.10 (m, 1H), 8.07 (d, J: 10.6 Hz, 1H), 7.76 (m, 1H), 7.48 (dd, J: 8.5, 1.7 Hz, 1H), 7.32 (dd, J: 10.6, 1.7 Hz, 1H), 5.75 (s, 2H), 3.05 (s, 3H); LCMS (ESI) m/z 424 and 426 (M+H)+.

Step 5: A stirred mixture of 6-((5-bromofiuoro-1H—benzo[d]imidazol yl)methyl)(methylsulfinyl)benzo[d]thiazole (1.33 g, 3.14 mmol), (1R,2R) aminocyclohexanol (1.09 g, 9.43 mmol), DIEA (1.62 g, 12.58 mmol) and DMA (40 mL) was heated in a sealed Vial at 110 CC for 15 h. The e was cooled to rt and then partitioned between water and EtOAc. The organic layer was separated and washed sequentially with water and brine. The organic layer was separated, dried over MgSO4, filtered, and concentrated under reduced pressure. The al solid was purified by ation with a 6:1 mixture of diethyl ether and DCM to afford (1R,2R)- ((5-bromofiuoro- 1H-benzo [d]imidazolyl)methyl)benzo [d]thiazol yl)amino)cyclohexanol (952 mg, 64%) as a tan solid. A 90 mg portion was filrther purified by reverse-phase preparative HPLC using a mixture of water (5% CH3CN, 0.05% HOAc) and CH3CN (0.05% HOAc) as the mobile phase and Varian Pursuit XRs diphenyl column as the stationary phase to afford (1R,2R)((6-((5-bromo fiuoro- 1H-benzo [d]imidazolyl)methyl)benzo[d]thiazolyl)amino)cyclohexanol (15 mg) as a white solid. 1H NMR (500 MHZ, DMSO-d6) 8 8.52 (s, 1H), 7.98 (d, J: .0 Hz, 1H), 7.74 (d, .1: 5.0 Hz, 1H), 7.54 (m, 1H), 7.33 (m, 1H), 7.29 (d, .1: 10.0 Hz, 1H), 7.08 (m, 1H), 5.52 (s, 2H), 4.75 (d, .1: 5.0 Hz, 1H), 3.51 (m, 1H), 3.33 (m, 1H), 2.02 (m, 1H), 1.87 (m, 1H), 1.59 — 1.64 (m, 2H), 1.16 — 1.30 (m, 4H); LCMS (ESI) m/Z 475 and 477 (M+H)+.

Example 204 Pre aration of 1- 3- 2- 1R 2R h drox c clohex 1 amino benzo d l l meth l imidazo 1 2-a ridin l ethanone 0—meth loxime \ N N/>—NH §H 1-(3 -((2-(((1R,2R)Hydroxycyclohexyl)amino)benzo[d]thiazol yl)methyl)imidazo[1,2-a]pyridinyl)ethanone O-methyl oxime was obtained as yellow powder (23 mg, 59%) using a ure analogous to that described in Example 202, substituting O-methylhydroxylamine hydrochloride for ylamine hydrochloride used in Example 202. 1H NMR (500 MHZ, DMSO-d6) 8 8.17 (d, J = 7.4 Hz, 1H), 7.92 (d, J: 7.4 Hz, 1H), 7.79 (s, 1H), 7.51 (s, 1H), 7.46 (s, 1H), 7.27 (d, J: 8.4 Hz, 2H), 7.08 (d, J: 7.9 Hz, 1H), 4.78 (br s, 1H), 4.30 (s, 2H), 3.94 (s, 3H), 3.50 (br s, 1H), 2.21 (s, 3H), 2.04 (d,.]= 11.8 Hz, 1H), 1.85 - 1.93 (m, 1H), 1.54 - 1.69 (m, 2H), 1.09 - 1.35 (m, 4H). LCMS (ESI) m/z 450 (M+H)+.

Example 205 Pre aration of IR 2R 6- 9H-benz0 imidazo 1 2-a imidazol l meth lbenzo thiazol 1 amino c clohexanol \ s NYN N/>—NH §OH HN\© < > (1R,2R)—2-((6-((9H—Benzo[d]imidazo[1,2-a]imidazol yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol (17 mg, 7%) was obtained as a solid using a procedure ous to that described in Step 3 Example 153, using 2- chloro(2-(((1R,2R)hydroxycyclohexyl)amino)benzo[d]thiazolyl)propanal from Step 2 of Example 153 and substituting 1H—benzo[d]imidazolamine for 4-(2- methoxyethoxy)pyridinamine used in Step 3 of Example 153. 1H NMR (500 MHz, 6) 5 11.66 (br s, 1H), 7.87 (d, J: 7.4 Hz, 1H), 7.54 (s, 1H), 7.35 (dd, J: 3.4, 7.9 Hz, 2H), 7.28 (d, J: 8.4 Hz, 1H), 7.08 - 7.17 (m, 2H), 6.84 - 6.95 (m, 2H), 4.74 (br s, 1H), 4.32 (s, 2H), 3.50 (br s, 1H), 3.33 (m, 1H), 2.02 (m, 1H), 1.87 (m, 1H), 1.54 - 1.67 (m, 2H), 1.12 - 1.33 (m, 4H); LCMS (ESI) m/z 418 (M+H)+.

Example 206 Pre aration of 7-flu0r0 2- 1R 2R h drox c clohex lamino benzo thiazol—6- lmeth l-lH-benzo imidazole—S- A stirred mixture of (1R,2R)((6-((5-bromofluoro-1H- benzo[d]imidazolyl)methyl)benzo[d]thiazolyl)amino)cyclohexanol (150 mg, 0.316 mmol) from Example 203, zinc cyanide (111 mg, 0.948 mmol), 1,1’- bis(diphenylphosphino)ferrocene (35 mg, 0.0632 mmol) and anhydrous DMF (2 mL) was purged with a stream of argon. To the mixture was added palladium(trisdibenzylideneacetone) (0) (29 mg, 0.0316 mmol) and the mixture was heated in a sealed tube 100 0C for 6 h. The mixture was cooled and additional zinc cyanide (111 mg, 0.948 mmol), 1,1’-bis(diphenylphosphino)ferrocene (35 mg, 0.0632 mmol), and palladium(trisdibenzylideneacetone) (0) (29 mg, 0.0316 mmol) were added, and g in a sealed tube was continued at 100 CC for 15 h. The e was cooled to rt and purified directly by reverse-phase preparative HPLC using a mixture of water (5% CH3CN, 0.05% HOAc) and CH3CN (0.05% HOAc) as the mobile phase and Varian Pursuit XRs diphenyl column as the stationary phase to afford (7-fluoro((2-(((1R,2R)hydroxycyclohexyl)amino)benzo[d]thiazol yl)methyl)-1H—benzo[d]imidazolecarbonitrile (2.6 mg, 2%) as a white solid. 1H NMR (500 MHz, DMSO-d6) 8 8.70 (s, 1H), 8.13 (s, 1H), 8.02 (d, J: 7.6 Hz, 1H), 7.63 (d, J: 11.1 Hz, 1H), 7.57 (s, 1H), 7.29 (d, J: 8.1 Hz, 1H), 7.10 (d, J: 8.1Hz, 1H), 5.58 (s, 2H), 4.77 (br s, 1H), 3.50 (br m, 1H), 3.30 (br m, 1H), 2.02 (m, 1H), 1.87 (m, 1H), 1.55 — 1.67 (m, 2H), 1.12 — 1.32 (m, 4H); LCMS (ESI) m/z 422 (M+H)+.

Example 207 Pre aration of IR 2R 6- 7-flu0r0Vin l-lH-benzo imidazol-l- l meth lbenzo thiazol 1 amino c clohexanol A stirred mixture of (1R,2R)((6-((5-bromofluoro-1H- benzo[d]imidazoly1)methy1)benzo[d]thiazolyl)amino)cyclohexanol (150 mg, 0.316 mmol) from Example 203, Vinyl boronic acid pinacol ester (97 mg, 0.632 mmol), sodium carbonate (67 mg, 0.0632 mmol), 1,4-dioxane (2 mL), and water (0.5 mL) was purged with a stream of argon. To the mixture was added dichloro[1,1’- pheny1phosphino)ferrocene] palladium (II) DCM adduct (35 mg, 0.0474 mmol) and the mixture was heated in a sealed reaction vessel at 100 °C for 2.5 h. The mixture was cooled to rt and purified directly by reverse-phase preparative HPLC using a e of water (5% CH3CN, 0.05% HOAc) and CH3CN (0.05% HOAc) as the mobile phase and Varian Pursuit XRs diphenyl column as the stationary phase to afford (1R,2R)—2-((6-((7-fluoroViny1-1H—benzo[d]imidazol yl)methy1)benzo[d]thiazolyl)amino)cyclohexanol (23 mg, 17%) as a white solid. 1H NMR (500 MHz, DMSO-d6) 5 8.44 (s, 1H), 7.98 (d, J: 7.6 Hz, 1H), 7.55 (d, J: 6.9 Hz, 2H), 7.23 - 7.31 (m, 2H), 7.09 (m, 1H), 6.79 (dd, J: 11.0, 17.6 Hz, 1H), 5.83 (d, J: 17.5 Hz, 1H), 5.51 (s, 2H), 5.22 (d, J: 11.1 Hz, 1H), 4.74 (d, J: 4.4 Hz, 1H), 3.51 (br m, 1H), 3.30 (br m, 1H), 2.03 (m, 1H), 1.87 (m, 1H), 1.55 - 1.67 (m, 2H), 1.14 - 1.32 (m, 4H); LCMS (ESI) m/z 423 .

Example 208 Pre n of IR 2R 6- 5- 3 6-dih dr0-2H- ran lflu0r0-1H- benzo imidazol-l- lmeth lbenzo thiazol lamino c clohexanol A stirred mixture of (1R,2R)((6-((5-bromofluoro-1H- benzo[d]imidazolyl)methyl)benzo[d]thiazolyl)amino)cyclohexanol (150 mg, 0.316 mmol) from Example 203, 3,6-dihydro-2H—pyranboronic acid pinacol ester (133 mg, 0.632 mmol), sodium carbonate (67 mg, 0.0632 mmol), 1,4-dioxane (2 mL), and water (0.5 mL) was purged with a stream of argon. To the mixture was added dichloro[1,1’-bis(diphenylphosphino)ferrocene] ium (II) DCM adduct (35 mg, 0.0474 mmol) and the mixture was heated in a sealed vessel at 100 0C for 3 h. The mixture was cooled to rt and purified ly by reverse-phase preparative HPLC using a mixture of water (5% CH3CN, 0.05% HOAc) and CH3CN (0.05% HOAc) as the mobile phase and Varian Pursuit XRs diphenyl column as the stationary phase to afford (1R,2R)((6-((5 -(3 ,6-dihydro-2H-pyranyl)fluoro- 1H-benzo [d]imidazol- 1-yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol (55 mg, 36%) as a white solid. 1H NMR (500 MHz, DMSO-d6) 8 8.43 (s, 1H), 7.95 (d, J: 7.6 Hz, 1H), 7.49 - 7.56 (m, 2H), 7.29 (d, J: 8.1 Hz, 1H), 7.21 (d, J: 13.0 Hz, 1H), 7.09 (m, 1H), 6.27 (br m, 1H), 5.51 (s, 2H), 4.72 (d, J: 5.2 Hz, 1H), 4.21 (d, J: 2.5 Hz, 2H), 4.06 (m, 1H), 3.81 (t, J: 5.4 Hz, 2H), 3.61 (m, 1H), 3.51 (br m, 1H), 3.30 (br m, 1H), 2.00 (m, 1H), 1.88 (m, 1H), 1.55 - 1.67 (m, 2H), 1.11 - 1.32 (m, 4H); LCMS (ESI) m/z 479 (M+H)+.

Example 209 Pre aration of IR 2R 6- 5-m0r holino-lH-benzo imidazol—l- l meth lbenzo thiazol-Z- 1 amino c clohexanol />—l\§l:>OH ] (1R,2R)—2-((6-((5-Morpholino-1H—benzo[d]imidazol yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol (10 mg, 7%) was obtained as a solid using a procedure analogous to that described in Example 97, substituting (1R,2R)((6-((5 -iodo- 1H-benzo [d]imidazolyl)methyl)benzo [d]thiazol yl)amino)cyclohexanol from Step 5 of Example 183 for (1R,2R)((6-((6-iodo-3H— imidazo[4,5-b]pyridinyl)methyl)benzo[d]thiazolyl)amino)cyclohexanol from Example 97. 1H NMR (500 MHz, DMSO-d6) 5 8.42 (br s, 1H), 7.62 (br s, 1H), 7.57 (s, 1H), 7.47 (br s, 1H), 7.29 (d, J: 8.4 Hz, 1H), 7.15 (d, J: 7.9 Hz, 2H), 6.94 (d, J: 8.9 Hz, 1H), 5.40 (s, 2H), 4.42 (br s, 1H), 3.70 - 3.81 (m, 4H), 3.52 (m, 1H), 3.41 (br s, 1H), 3.06 - 3.11 (m, 4H), 2.07 (m, 1H), 1.90 (m, 1H), 1.60 - 1.70 (m, 2H), 1.20 - 1.36 (m, 4H); LCMS (ESI) m/Z 464 (M+H)+.

Example 210 Pre aration of 1- 1- 2— 1R 2R h drox c clohex lamino benzo thiazol l meth l Hbenzo imidazoll i eridin-0ne 111% To a d mixture of copper iodide (23 mg, 0.12 mmol) and tripotassium phosphate (190 mg, 0.90 mmol) in DMSO (3 mL) were added (1R,2R)—2-((6-((5-iodo- 1H-benzo[d]imidazol- 1 thyl)benzo[d]thiazolyl)amino)cyclohexanol (150 mg, 0.30 mmol) from Step 5 of Example 183 and piperidinone (200 mg, 2.02 mmol).

The mixture was flushed with argon and heated in a sealed reaction vessel at 125 °C for 15 h. The reaction mixture was cooled to rt and d, and the filtrate was purified directly by reverse-phase preparative HPLC using a mixture of water (5% CH3CN, 0.05% HOAc) and CH3CN (0.05% HOAc) as the mobile phase and Varian Pursuit XRs diphenyl column as the nary phase to afford 1-(1-((2-(((1R,2R) Hydroxycyclohexyl)amino)benzo[d]thiazolyl)methyl)— 1H-benzo[d]imidazol-5 - yl)piperidinone (3 mg, 7%) as a solid. 1H NMR (500 MHZ, DMSO-d6) 8 8.31 (br s, 1H), 7.69 (br s, 1H), 7.62 (s, 1H), 7.44 - 7.53 (m, 2H), 7.30 (d, J: 8.4 Hz, 1H), 7.18 (d, J: 8.4 Hz, 1H), 7.08 (d, J: 8.9 Hz, 1H), 5.45 (s, 2H), 3.62 (t, J: 5.4 Hz, 2H), 3.51 (br s, 1H), 3.37 - 3.46 (m, 2H), 2.36 - 2.43 (m, 2H), 2.06 (m, 1H), 1.82 - 1.93 (m, 5H), 1.61 - 1.70 (m, 2H), 1.20 - 1.36 (m, 4H); LCMS (ESI) m/z 476 (M+H)+.

Example 21 1 WO 56070 2012/059983 Pre aration of IR 2R 6- 5— 1H- 3- l-lH-benzo imidazol—l- l meth lbenzo thiazol-Z- 1 amino c clohexanol //\N S N U />_NH 9H N 3 S To a stirred solution of (1R,2R)((6-((5-iodo-1H—benzo[d]imidazol yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol (100 mg, 0.20 mmol) from Step of Example 183 in DMF (2 mL) were added (1H—pyrazolyl)boronic acid (90 mg, 0.80 mmol), NaHCOg (100mg 1.2 mmol), bis(tripheny1phosphine) palladium(II) dichloride (28 mg, 0.04 mmol), and water (0.4 mL). The mixture was flushed with argon and heated in a sealed vessel at 90 CC for 15 h. The reaction mixture was cooled to rt and partitioned between DCM and water. The s layer was extracted twice with DCM and the combined organic phases were washed three times with a 1:1 mixture of water and brine. The organic phases were then dried over MgSO4, filtered, and concentrated under reduced pressure. The e was purified by silica gel flash chromatography eluting with 100% DCM to 10% MeOH/DCM to afford (1R,2R)((6-((5-(1H—pyrazolyl)— 1H—benzo[d]imidazol yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol (4 mg, 5%) as a solid. 1H NMR (500 MHz, DMSO-d6) 8 12.92 (br s, 1H), 12.53 (br s, 1H), 8.29 (br s, 1H), 8.03 (m, 1H), 7.58 - 7.74 (m, 3H), 7.53 (d, J: 7.9 Hz, 1H), 7.31 (d, J: 7.9 Hz, 1H), 7.20 (d, J = 8.4 Hz, 1H), 6.63 (br s, 1H), 5.47 (s, 2H), 4.42 (d, J: 4.4 Hz, 1H), 3.51 (br s, 1H), 3.41 (tt, .1: 4.5, 8.8 Hz, 1H), 2.06 (m, 1H), 1.90 (d, J: 11.8 Hz, 1H), 1.57 - 1.71 (m, 2H), 1.19 - 1.36 (m, 4H); LCMS (ESI) m/z 445 (M+H)+.

Example 212 Pre aration of IR 2R 6- 6- trifluorometh l -3H-imidaz0 4 5-b ridin y] )methyl lbenz0| d|thiazolyl )amino )cyclohexanol “JPN/U />—NHSQ pH / N N 5 > Step 1: A mixture of 2-chloronitro(trifiuoromethyl)pyridine (500 mg, 2.21 mmol), (2-(methylthio)benzo[d]thiazolyl)methanamine from Step 4 of Example 23 (583 mg, 2.76 mmol), and triethylamine (837 mg, 8.29 mmol) in DMF (10 mL) was stirred at rt overnight. The reaction e was diluted with EtOAc and washed with water. The organic layer was dried over Na2S04, filtered and concentrated under d pressure. The residue was purified by silica gel chromatography g with 1:0 to 10:1 petroleum ether/EtOAc to give N—((2- (methylthio)benzo[d]thiazolyl)methyl)nitro(trifiuoromethyl)pyridinamine as a yellow solid (150 mg, 84.7%). 1H NMR (300 MHz, DMSO-d6) 8 9.46 (t, J: 1.8 Hz,1H), 8.78 (d, J: 2.1 Hz, 1H), 8.66 (d, J: 2.4 Hz, 1H), 7.97 (s, 1H), 7.78 (d, J: 8.4 Hz, 1H), 7.49-7.45 (m, 1H), 4.95 (d, J: 6.6 Hz, 2H), 2.77 (s, 3H); LCMS (ESI) m/Z 401 (M+H)+.

Step 2: To a mixture ofN—((2-(methylthio)benzo[d]thiazolyl)methyl) nitro(trifiuoromethyl)pyridinamine (0.97 g, 2.42 mmol), HOAc (4 mL), and MeOH (4 mL) in DCM (30 mL) cooled in ice-water bath was slowly added zinc dust (1.6 g, 24.2 mmol). The reaction mixture was stirred at 0 0C for 2 h. The mixture was d and the filtrate was diluted with DCM and then washed with water and aq NaHC03. The organic layer was dried over , filtered and trated under reduced pressure to afford NZ-((2-(methylthio)benzo[d]thiazol—6-yl)methyl) (trifiuoromethyl)pyridine-2,3-diamine (0.89 g, 100%). 1H NMR (300 MHZ, DMSO- d6) 5 8.05 (s, 1H), 7.82 (d, J: 8.4 Hz, 1H), 7.77 (s, 1H), 7.44-7.41 (m, 1H), 7.03 (d, J = 1.8 Hz, 1H), 4.84 (br s, 1H), 4.78 (d, J: 5.1 Hz, 2H), 3.29 (br s, 2H), 2.79 (s, 3H).

LCMS (ESI) m/Z 371 (M+H)+.

Step 3: A mixture ofNZ-((2-(methylthio)benzo[d]thiazolyl)methyl) (trifiuoromethyl)pyridine-2,3-diamine (0.89 g, 2.39 mmol), triethoxymethane (30 mL) and HCOOH (0.6g) was d at 90 0C for 2 h. The mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 2:1 to 0:1 petroleum ether/EtOAc to afford 2-(methylthio)((6-(trifiuoromethyl)-3H- imidazo[4,5-b]pyridinyl)methyl)benzo[d]thiazole as a light yellow solid (0.77 g, 79.3%). 1H NMR (300 MHz, DMSO-d6) 8 8.88 (s, 1H), 8.77 (d, .1: 1.2 Hz, 1H), 8.57 (d, .1: 1.8 Hz, 1H), 8.00 (d, .1: 1.2 Hz, 1H), 7.81 (d, .1: 8.4 Hz, 1H), 7.49-7.46 (m, 1H), 5.68 (s, 2H), 2.77 (s, 3H). LCMS (ESI) m/Z 381 (M+H)+.

Step 4: A e of 2-(methylthio)((6-(trifiuoromethyl)-3H- imidazo[4,5-b]pyridinyl)methyl)benzo[d]thiazole (200 mg, 0.53 mmol) and m- CPBA (114 mg, 0.66 mmol) in DCM (5 mL) was stirred in an ice-water bath for 2 h.

The mixture was diluted with DCM and washed with aq NaZSZOg, aq NaHCOg and water. The organic layer was dried over Na2S04, filtered and trated under reduced pressure to afford 2-(methylsulfinyl)((6-(trifiuoromethyl)-3H-imidazo[4,5- b]pyridinyl)methyl)benzo[d]thiazole as a yellow solid (180 mg, 87.8%). 1H NMR (300 MHz, DMSO-d6) 8 8.91 (s, 1H), 8.77 (s, 1H), 8.59 (s, 1H), 8.23 (s, 1H), 8.08 (d, J: 8.1 Hz, 1H), 7.66-7.62 (m, 1H), 5.77 (s, 2H), 3.06 (s, 3H). LCMS (ESI) m/Z 397 (M+H)+.

Step 5: A mixture of 2-(methylsulfinyl)((6-(trifiuoromethyl)-3H- imidazo[4,5-b]pyridinyl)methyl)benzo[d]thiazole (180 mg, 0.45 mmol), (1R,2R) aminocyclohexanol (112 mg, 0.97 mmol) and DIEA (261 mg, 2 mmol) in DMA (2 mL) was stirred at 130 0C overnight. The reaction e was diluted with EtOAc and washed with brine. The organic layer was dried over NaSO4, filtered and concentrated under reduced pressure. The residue was d by preparative HPLC to afford (1R,2R)((6-((6-(trifluoromethyl)-3H-imidazo[4,5-b]pyridin yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol as a yellow solid (64 mg, 31.8%). 1H NMR (300 MHz, DMSO-d6) 8 8.84 (s, 1H), 8.78 (d, J: 1.2 Hz, 1H), 8.55 (d, J: 1.5 Hz, 1H), 7.95 (d, J: 7.8 Hz, 1H), 7.68 (d, J: 1.5 Hz, 1H), 7.29 (d, J: 7.8 Hz, 1H), 7.25-7.22 (m, 1H), 5.55 (s, 2H), 4.71 (d, J: 5.1 Hz, 1H), 3.52-3.50 (m, 1H), 3.37-3.33 (m, 1H), 2.08-2.01 (m, 1H), 1.87-1.85 (m, 1H), 1.64-1.60 (m, 2H), 1.29- 1.19 (m, 4H). LCMS (ESI) m/Z 448 (M+H)+.

Example 213 Pre aration of 1S2 6- 0-3H-imidazo 45-b ridin l meth lbenzo thiazol-Z- 1 amino c clohexanol NgrgZG/>—NH OH \ / (1S,2S)((6-((6-Fluoro-3H—imidazo[4,5-b]pyridin yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol was synthesized as a white powder (48 mg, 42%) using a procedure analogous to that described in Step 5 of Example 162, substituting (1S,2S)aminocyclohexanol for (1S,2R) aminocyclohexanol hydrochloride used in Example 162. 1H NMR (500 MHz, DMSO- d6) 5 8.67 (s, 1H), 8.41 (t, J: 2.0 Hz, 1H), 8.07 (dd, J: 2.6, 9.5 Hz, 1H), 7.95 (d, J: 7.6 Hz, 1H), 7.66 (d, J: 1.2 Hz, 1H), 7.28 (m, 1H), 7.22 (dd, J: 1.5, 8.4 Hz, 1H), .48 (s, 2H), 4.72 (d, J: 5.2 Hz, 1H), 3.51 (m, 1H), 3.33 (m, 1H), 2.02 (m, 1H), 1.87 (m, 1H), 1.57 — 1.65 (m, 2H), 1.15 — 1.29 (m, 4H); LCMS (ESI) m/z 399 (M+H)+. e 214 Pre n of IR 2R 6- 7- 1H-imidazol—1- l imidazo 1 2-a 3- l meth l benzo d thiazol-Z- 1 amino c clohexanol NmeNHS\ Q §H (1R,2R)((6-((7-(1H-Imidazolyl)imidazo[1,2-a]pyridin hyl)benzo[d]thiazolyl)amino)cyclohexanol (27 mg, 47%) was obtained as a light tan solid using a procedure analogous to that described in Example 141, substituting(1R,2R)((6-((7-iodoimidazo[1 ,2-a]pyridinyl)methyl)benzo [d]thiazol- 2-yl)amino)cyclohexanol from Step 1 of Example 167 and imidazole, respectively, for (1R,2R)((6-((6-iodo-3H-imidazo[4,5-b]pyridinyl)methyl)benzo[d]thiazol yl)amino)cyclohexanol and pyrazole used in Example 141. 1H NMR (500 MHz, DMSO-d6) 5 8.42 (br s, 1H), 8.34 (d, J: 6.9 Hz, 1H), 7.93 (br s, 1H), 7.90 (d, J: 7.4 Hz, 2H), 7.54 (s, 1H), 7.49 (br s, 1H), 7.33 (d, J: 7.4 Hz, 1H), 7.27 (d, J: 8.4 Hz, 1H), 7.01 - 7.19 (m, 2H), 4.77 (br s, 1H), 4.33 (s, 2H), 3.51 (br s, 1H), 3.31 - 3.34 (m, 2H), 2.04 (d, J: 11.8 Hz, 1H), 1.87 (d, J: 10.8 Hz, 1H), 1.53 - 1.70 (m, 2H), 1.06 - 1.36 (m, 4H). LCMS (ESI) m/Z 445 (M+H)+.

Example 215 Pre n of IR 2R 6- 7- 2H-1 2 3-triazol l imidazo 1 2-a ridin y] {methyl )benzol d|thiazol—2-yl )amino )cyclohexanol W0 2013/056070 Attorney DOCkePCT/U52012/059983 N\ N N/>—NH §H \ / C N \ |L//N (1R,2R)((6-((7-(2H-1,2,3-Triazolyl)imidazo[1,2-a]pyridin yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol (13 mg, 23%) was obtained as a light tan solid using a procedure analogous to that described in Example 141, substituting (1R,2R)((6-((7-iodoimidazo [1 ,2-a]pyridin-3 - yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol from Step 1 of Example 167 and 1,2,3-triazole, tively, for (1R,2R)((6-((6-iodo-3H-imidazo[4,5-b]pyridin yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol and pyrazole used in Example 141. 1H NMR (500 MHz, DMSO-d6) 5 8.40 (d, J: 7.4 Hz, 1H), 8.18 (s, 2H), 8.04 (s, 1H), 7.90 (d, J: 7.9 Hz, 1H), 7.63 (dd, J: 2.0, 7.4 Hz, 1H), 7.54 (s, 1H), 7.51 (s, 1H), 7.28 (d, J: 8.4 Hz, 1H), 7.11 (d, J: 6.9 Hz, 1H), 4.77 (br s, 1H), 4.34 (s, 2H), 3.51 (br s, 3H), 2.04 (d, J: 11.8 Hz, 1H), 1.87 (d, J: 11.3 Hz, 1H), 1.55 - 1.69 (m, 2H), 1.10 - 1.36 (m, 4H). LCMS (ESI) m/z 446 (M+H)+. e 216 Pre n of IR 2R 6- 7-Vin limidazo 1 2-a ridin l meth l benzo d thiazol-Z- 1 amino c clohexanol Nm'f—NHS\ g9H \/ C ] Step 1: Crude 4-Vinylpyridinamine (200 mg) was obtained as a light tan solid using a procedure analogous to that described in Example 98, substituting 4- iodopyridinamine for (1R,2R)((6-((6-bromo-3H-imidazo[4,5-b]pyridin yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol used in Example 98. LCMS (ESI) m/Z 121 (M+H)+.

Step 2: (1R,2R)((6-((7-Vinylimidazo[1,2-a]pyridin yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol (13 mg, 8%) was obtained as a light tan solid using a procedure ous to that described in Step 6 of Example 117, substituting 4-Vinylpyridinamine from Step 1 of this Example and 2-chloro LAI—3 177908V1 WO 56070 (2-(((1R,2R)hydroxycyclohexyl)amino)benzo[d]thiazolyl)propanal from Step 2 of Example 153, respectively, for 2-aminoisonicotinonitrile and 2-chloro(2- (methylthio)benzo[d]thiazolyl)propanal used in Example 117. 1H NMR (500 MHz, DMSO-d6) 5 8.14 (d, J: 6.9 Hz, 1H), 7.86 (d, J: 7.4 Hz, 1H), 7.52 (d, J: 3.4 Hz, 2H), 7.40 (s, 1H), 7.26 (d, J: 7.9 Hz, 1H), 7.13 (d, J: 5.9 Hz, 1H), 7.09 (d, J: 6.9 Hz, 1H), 6.77 (dd, J: 10.8, 17.7 Hz, 1H), 5.91 (d, J: 17.7 Hz, 1H), 5.34 (d, J: 11.3 Hz, 1H), 4.72 (d, J: 3.4 Hz, 1H), 4.28 (s, 2H), 3.52 (d, J: 8.4 Hz, 2H), 2.03 (d, J: .8 Hz, 1H), 1.87 (d, J: 11.3 Hz, 1H), 1.54 - 1.70 (m, 2H), 1.11 - 1.36 (m, 4H).

LCMS (ESI) m/Z 405 (M+H)+.

Example 217 Pre aration of IR 2R 6- 7- all 10x imidazo 1 2-a ridin l meth l benzo d thiazol-Z- 1 amino c clohexanol Q7N N/>—NH §H < > ] Step 1: To a stirred solution of 2-aminopyridinol (500 mg, 4.5 mmol) in DMF (5 mL) at rt was added K2C03 (940 mg, 6.8 mmol). The resulting mixture was stirred at rt for 20 min before allyl bromide (393 11L, 4.5 mmol) was added. The mixture was then stirred at rt overnight and heated at 60 0C for 2 h. After cooling to rt, the mixture was partitioned between EtOAc and water, and the organic layer was washed with brine, dried over , and evaporated under reduced re. The e was purified by silica gel chromatography eluting with EtOAc in hexanes to give 4-(allyloxy)pyridinamine (110 mg, 16%) as a white solid. LCMS (ESI) m/Z 151 (M+H)+.

Step 2: (1R,2R)((6-((7-(Allyloxy)imidazo[1,2-a]pyridin yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol (56 mg, 34%) was obtained as a light tan solid using a procedure analogous to that described in Step 6 of Example 117, substituting yloxy)pyridinamine from Step 1 of this Example and 2- chloro(2-(((1R,2R)hydroxycyclohexyl)amino)benzo[d]thiazolyl)propanal from Step 2 of Example 153, respectively, for 2-aminoisonicotinonitrile and 2-chloro- 3-(2-(methylthio)benzo[d]thiazolyl)propanal used in Example 117. 1H NMR (500 MHz, DMSO-d6) 8 8.02 (d, J: 7.4 Hz, 1H), 7.88 (d, J: 7.9 Hz, 1H), 7.49 (s, 1H), 7.26 (d, J: 7.9 Hz, 1H), 7.23 (s, 1H), 7.07 (d, J: 8.4 Hz, 1H), 6.92 (d, J: 2.5 Hz, 1H), 6.60 (dd, J: 2.5, 7.4 Hz, 1H), 5.96 - 6.10 (m, 1H), 5.42 (d, J: 17.2 Hz, 1H), .28 (d, J: 10.3 Hz, 1H), 4.75 (br s, 1H), 4.61 (d, J: 5.4 Hz, 2H), 4.22 (s, 2H), 3.51 (br s, 2H), 2.04 (d,.]= 11.8 Hz, 1H), 1.87 - 1.94 (m, 1H), 1.55 - 1.69 (m, 2H), 1.11 - 1.36 (m, 4H). LCMS (ESI) m/Z 435 . e 218 Pre aration of IR 2R 6- 7- 1H-1 2 3-triazol l imidazo 1 2-a ridin l meth l benzo d thiazol-Z- 1 amino c clohexanol NmeNHS\ Q §OH / < > (1R,2R)((6-((7-(1H-1,2,3-triazolyl)imidazo[1,2-a]pyridin hyl)benzo[d]thiazolyl)amino)cyclohexanol (6 mg, 11%) was obtained as a light tan solid using a procedure analogous to that described in Example 141, substituting(1R,2R)((6-((7-iodoimidazo[1 ,2-a]pyridinyl)methyl)benzo [d]thiazol- mino)cyclohexanol from Step 1 of Example 167 and 1,2,3-triazole, respectively, for (1R,2R)((6-((6-iodo-3H-imidazo[4,5-b]pyridinyl)methyl)benzo[d]thiazol yl)amino)cyclohexanol and pyrazole used in Example 141. 1H NMR (500 MHz, DMSO-d6) 5 8.98 (s, 1H), 8.44 (d, J: 7.4 Hz, 1H), 8.17 (s, 1H), 8.01 (s, 1H), 7.96 (d, J: 7.4 Hz, 1H), 7.58 (d, J: 7.4 Hz, 1H), 7.55 (br s, 2H), 7.28 (d, J: 8.4 Hz, 1H), 7.11 (d, J: 8.4 Hz, 1H), 4.83 (br s, 1H), 4.35 (s, 2H), 3.50 (br s, 3H), 2.04 (d, J: 11.8 Hz, 1H), 1.87 (d,.]= 10.8 Hz, 1H), 1.54 - 1.67 (m, 2H), 1.08 - 1.33 (m, 4H).

LCMS (ESI) m/Z 446 (M+H)+.

Example 219 Pre aration ofN— 1R 2 chlor0c clohex 1 6-flu0r0-3H—imidaz0 4 5- b ridin lmeth lbenzo thiazol-Z-amine WO 56070 2012/059983 NpNACES)—NHb CI \ / C5 ] N—((1R,2S)Chlorocyclohexyl)((6-fluoro-3H—imidazo[4,5-b]pyridin yl)methyl)benzo[d]thiazolamine was synthesized as a white powder (6 mg, 2%) using a procedure analogous to that described in Example 198, substituting (1R,2R) ((6-((6-fluoro-3H—imidazo[4,5-b]pyridinyl)methyl)benzo[d]thiazol yl)amino)cyclohexanol for (1S,2R)((6-((6-fluoro-3H—imidazo[4,5-b]pyridin hyl)benzo[d]thiazolyl)amino)cyclohexanol used in e 198. 1H NMR (500 MHz, CDClg) 8 8.68 (s, 1H), 8.41 (s, 1H), 8.24 (d, J: 8.4 Hz, 1H), 8.07 (dd, J: 2.6, 9.5 Hz, 1H), 7.68 (s, 1H), 7.33 (d, J: 8.4 Hz, 1H), 7.24 (dd, J: 1.4, 8.2 Hz, 1H), .48 (s, 2H), 4.02 (m, 1H), 3.87 (m, 1H), 2.20 (m, 1H), 2.07 (m, 1H), 1.63 — 1.75 (m, 3H), 1.29 — 1.41 (m, 3H); LCMS (ESI) m/z 416 (M+H)+.

Example 220 Pre aration of 3-amin0 2- 1R 2R h drox c clohex lamino benzo thiazol lmeth l razin-Z 1 -0ne acetate salt O N C Step 1: To a stirred mixture of sodium iodide (4.89 g, 32.67 mmol) and 2- iodomethoxypyrazine (2.57 g, 10.89 mmol) in acetonitrile (30 mL) at rt was added trimethylsilyl chloride (3.55 g, 32.67 mmol). The mixture was heated at 70 0C for 1.5 h. The mixture was cooled to rt and partitioned between a mixture of DCM, MeOH, and aq 2 M HCl. The organic layer was separated and the aqueous layer was extracted with additional DCM/MeOH e. The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure to afford 3-iodopyrazin- 2(lH)—one (1.21 g, 50%) as a brown solid that did not require fiarther purification. 1H NMR (500 MHz, DMSO-d6) 8 12.54 (br s, 1H), 7.42 (d, J: 3.7 Hz, 1H), 7.17 (d, J: 3.7 Hz, 1H); LCMS (ESI) m/Z 223 (M+H)+.

Step 2: 3-Iodo-l-((2-(methylthio)benzo[d]thiazolyl)methyl)pyrazin- 2(lH)-one (1 g) was obtained as a brown solid using a procedure analogous to that described in Step 2 of Example 203, substituting 3-iodopyrazin-2(1I-I)—one from Step 1 of this Example for N—(4-bromofluoronitrophenyl)formamide used in e 203. 1H NMR (500 MHz, DMSO-d6) 5 7.98 (s, 1H), 7.81 — 7.85 (m, 2H), 7.45 (m, 1H), 7.23 (m, 1H), 5.19 (s, 2H), 2.77 (s, 3H); LCMS (ESI) m/z 416 (M+H)+.

Step 3: A stirred mixture of 3-iodo((2-(methylthio)benzo[d]thiazol yl)methyl)pyrazin-2(1[-I)-one (750 mg, 1.81 mmol), ammonia (7 M on in MeOH, 2 mL, 14 mmol), and DMSO (1.5 mL), was heated in a e Microwave Synthesizer at 150 0C for 15 min. The mixture was cooled to and partitioned between EtOAc and a 1:1 mixture of water and brine. The organic layer was separated, dried over MgSO4, filtered, and trated under reduced pressure. The e was purified by silica gel flash chromatography eluting with a gradient of 100% DCM to 2% MeOH in DCM to afford 3-amino((2-(methylthio)benzo[d]thiazol yl)methyl)pyrazin-2(1[-I)-one (149 mg) as a yellow solid. 1H NMR (500 MHZ, DMSO-d6) 5 7.96 (s, 1H), 7.82 (d, J: 8.4 Hz, 1H), 7.43 (dd, J: 1.5, 8.4 Hz, 1H), 6.92 (d, J: 4.7 Hz, 1H), 6.65 — 6.67 (br m, 3H), 5.11 (s, 2H), 2.78 (s, 3H); LCMS (ESI) m/Z 305 (M+H)+.

Step 4: 3-Amino((2-(methylsulfinyl)benzo[d]thiazol yl)methyl)pyrazin-2(1[-I)-one (84 mg, 54%) was obtained as a yellow solid using a procedure analogous to that described in Step 4 of Example 130, substituting 3- amino((2-(methylthio)benzo[d]thiazolyl)methyl)pyrazin-2(1H)-one from Step 3 of this Example for 2-(methylthio)((5-(trifluoromethyl)-1H—benzo[d]imidazol yl)methyl)benzo[d]thiazole used in Example 130. 1H NMR (500 MHZ, DMSO-d6) 8 8.20 (s, 1H), 8.08 (d, J: 8.6 Hz, 1H), 7.59 (dd, J: 1.5, 8.4 Hz, 1H), 6.94 (d, J: 4.7 Hz, 1H), 6.69 (d, J: 4.4 Hz, 3H), 5.19 (s, 2H), 3.07 (s, 3H); LCMS (ESI) m/z 321 (M+H)+.

Step 5: 3-Amino((2-(((1R,2R) hydroxycyclohexyl)amino)benzo[d]thiazolyl)methyl)pyrazin-2(1H)-one acetate salt (19 mg, 17%) was obtained as a solid using a procedure analogous to that bed in Step 5 of Example 203, substituting 3-amino((2- (methylsulfinyl)benzo[d]thiazolyl)methyl)pyrazin-2(1H)-one from Step 4 of this Example for 6-((5-bromofluoro-1H—benzo[d]imidazolyl)methyl) (methylsulfinyl)benzo[d]thiazole used in Example 130. 1H NMR (500 MHz, DMSO- d6) 5 7.99 (d, J: 7.4 Hz, 1H), 7.62 (s, 1H), 7.30 (d, J: 8.1 Hz, 1H), 7.19 (dd, J: 1.5, 8.1 Hz, 1H), 6.87 (d, .1: 4.7 Hz, 1H), 6.60 — 6.80 (m, 3H), 4.99 (s, 2H), 3.20 — 3.60 (m, 4H), 2.04 (m, 1H), 1.88 (s, 3H), 1.57 _ 1.67 (m, 2H), 1.12 _ 1.33 (m, 4H); LCMS (ESI) m/z 372 (M+H)+.

Example 221 Pre aration of 3- 2- 1R 2R h drox c clohex lamino benzo thiazol l meth l imidazo 1 2-b ridazinecarb0nitrile N\\N S/>—NH §OH \ N \ l“ C) Step 1: A stirred mixture of ro-3 -(2-(methylthio)benzo[d]thiazol yl)propanal from Step 4 of Example 117 (l .3 g, 4.8 mmol) and 6-aminopyridazine carbonitrile (0.8 g, 7.2 mmol) in nol (48 mL) was heated at reflux overnight.

The mixture was cooled to rt and water (100 mL) was added. The mixture was extracted with EtOAc (3 ><60 mL, and the combined organic layers were washed with brine, dried over Na2S04, filtered and concentrated under reduced pressure. The residue was purified by silica gel tography eluting with 50: l to 20: l DCM/MeOH to afford 3-((2-(methylthio)benzo[d]thiazol yl)methyl)imidazo[l,2-b]pyridazinecarbonitrile as a yellow solid (0.7 g, 44%). 1H NMR (300 MHz, CDC13)5 8.09 (d, J: 9.0 Hz, 1H), 7.83-7.78 (m, 2H), 7.69 (s, 1H), 7.36 (d, J: 8.4 Hz, 1H), 7.29 (d, J: 9.3 Hz, 1H), 4.46 (s, 2H), 2.78 (s, 3H). LCMS (ESI) m/Z 338 (M+H)+.

Step 2: To a solution of 3-((2-(methylthio)benzo[d]thiazol yl)methyl)imidazo[l,2-b] pyridazinecarbonitrile (0.7 g, 2.1 mmol) in DCM (30 mL) at 0 0C was slowly added m-CPBA (0.4 g, 2.1 mmol). The reaction mixture was stirred at 0 0C for 2 h, then aq N32803 (25 mL) was added and the e was stirred for 0.5 h. The organic layer was separated and dried over , filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 50: l to 20: l DCM/MeOH to afford 3-((2- (methylsulfinyl)benzo[d]thiazolyl)methyl)imidazo[l ,2-b]pyridazine carbonitrile as a yellow solid (0.7 g, 96%). 1H NMR (300 MHZ, CDClg) 5 8.11 (d, J: 9.3 Hz, 1H), 8.02 (d, J: 8.4 Hz, 1H), 7.92 (s, 1H), 7.82 (s, 1H), 7.51 (d, J: 8.4 Hz, 1H), 7.31 (d, J: 9.3 Hz, 1H), 4.54 (s, 2H), 3.07 (s, 3H). LCMS (ESI) m/Z 354 (M+H)+.

Step 3: A mixture of 3-((2-(methylsulfinyl)benzo[d]thiazol hyl)imidazo [1,2-b]pyridazinecarbonitrile (300 mg, 0.9 mmol), (1R,2R) aminocyclohexanol (293 mg, 2.5 mmol) and DIEA (219 mg, 1.7 mmol) in NMP (16 mL) was stirred at 135 0C overnight. The mixture was cooled to rt and water (40 mL) was added. The mixture was extracted with EtOAc (3>< 30 mL). The combined organic layers were washed with brine, dried over Na2S04, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 50: l to 20: 1 DCM/MeOH to afford 3-((2-(((1R,2R) hydroxycyclohexyl)amino)benzo[d]thiazolyl)methyl)imidazo[ 1 ,2-b]pyridazine carbonitrile as a brown solid (100 mg, 30%). 1H NMR (300 MHZ, DMSO-d6) 5 8.40 (d, J: 9.3 Hz, 1H), 7.87-7.84 (m, 2H), 7.70 (d, J: 9.3 Hz, 1H), 7.55 (d, J: 1.5 Hz, 1H), 7.28 (d, J: 8.1 Hz, 1H), 7.13 (dd,.]= 1.5, 8.1 Hz, 1H), 4.72 (d, J: 5.1 Hz, 1H), 4.36 (s, 2H), 3.54-3.51 (m, 1H), 3.39-3.36 (m, 1H), 2.06-2.02 (m, 1H), 1.90-1.86 (m, 1H), 1.65-1.59 (m, 2H), 1.31-1.17 (m, 4H). LCMS (ESI) m/z 405 (M+H)+.

Example 222 Pre aration of 1- 2- 1R 2R h drox c clohex 1 amino benzo d thiazol l meth l m0r holino razin-Z 1H -0ne NIX/crab] 6/ N S/>_NH SH Step 1: A e of 2,3-dichloropyrazine (894 mg, 6 mmol), morpholine (523 mg, 6 mmol) and DIEA (1.55 g, 12 mmol) in DMSO (8 mL) was stirred at 70 0C for 2 h. The reaction mixture was poured into water (30 mL) and ted with ethyl e (3 ><20 mL). The ed organic layers were washed with 2N aq HCl (30 mL), water (2X30 mL) and brine, dried over Na2S04, filtered and concentrated under reduced pressure to give 4-(3-chloropyrazinyl)morpholine as a light yellow solid (1.01 g, 92.8%). 1H NMR (300 MHz, DMSO-d6) 5 8.11 (d, J=2.4 Hz, 1H), 7.90 (d, J = 2.7 Hz, 1H), 3.86 (t, J: 9.3 Hz, 4H), 3.45 (t, J: 9.6 Hz, 4H). LCMS (ESI) m/z 200 (M+H)+.

WO 56070 Step 2: A mixture of hloropyrazinyl)morpholine (894 mg, 6 mmol) and aq NaOH (13 mL, 52 mmol) in DMSO (18 mL) was stirred at 80 0C for 2 h. The reaction mixture was poured into water (30 mL) and extracted with ethyl acetate (3 ><20 mL). The combined organic layers were washed with brine, dried over NaZSO4, filtered and concentrated under reduced pressure to give 3- morpholinopyrazin-2(1H)-one as a light yellow solid (807 mg, 92.9%). 1H NMR (300 MHz,CDC13)8 11.80 (br s, 1H), 7.05 (d, J: 4.2 Hz, 1H), 6.73 (d, J: 4.2 Hz, 1H), 3.84 (s, 8H). LCMS (ESI) m/Z 182 (M+H)+.

Step 3: To a d solution of 3-morpholinopyrazin-2(1H)-one (317 mg, 1.75 mmol) in DMF (8 mL) at 0 0C was added NaH (60% in mineral oil, 105 mg, 2.63 mmol). After stirring for 20 min, a solution of 6-(chloromethyl) (methylthio)benzo[d]thiazole (400 mg, 1.75 mmol) in DMF (2 mL) was added dropwise, and the mixture was stirred at rt for 2 h. The mixture was poured into water and extracted with ethyl acetate (3X 20 mL). The ed organic layers were washed with brine, dried over Na2S04, filtered and concentrated under reduced pressure to give 1-((2-(methylthio)benzo[d]thiazolyl)methyl)morpho linopyrazin-2(1H)-one as a light yellow solid (625 mg, . 1H NMR (300 MHZ, CDC13)5 7.82 (d, J: 8.4 Hz,1H), 7.71 (s, 1H), 7.36 (d, J: 6.6 Hz, 1H), 6.92 (d, J: 4.2 Hz, 1H), 6.71 (d, J: 4.2 Hz, 1H), 5.10 (s, 2H), 3.81 (s, 8H), 2.80 (s, 3H). LCMS (ESI) m/Z 375 (M+H)+.

Step 4: A solution of 1-((2-(methylthio)benzo[d]thiazolyl)methyl) linopyrazin -2(1H)-one (752 mg, 2.0 mmol) and m-CPBA (449 mg, 2.6 mmol) in DCM (20 mL) was stirred at 0 0C for 4 h. The reaction mixture was washed with aqueous NazSzOg and brine. The organic layer was dried over , filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 1:3 petroleum ether/ethyl acetate to give 1-((2- (methylsulfinyl)benzo[d]thiazolyl) methyl)morpholinopyrazin-2(1H)-one as a light yellow solid (430 mg, 55.1%). 1H NMR (300 MHz, DMSO-d6) 5 8.20 (s, 1H), 8.08 (d, J: 8.4 Hz, 1H), 7.59 (d, J: 6.9 Hz, 1H), 7.29 (d, J: 4.5 Hz, 1H), 6.96 (d, J = 4.2 Hz, 1H), 5.20 (s, 2H), 3.65 (s, 8H), 3.07 (s, 3H). LCMS (ESI) m/z 391 (M+H)+.

Step 5: A mixture of (methylsulfinyl)benzo[d]thiazolyl)methyl)- 3-morpholino pyrazin-2(1H)-one (250 mg, 0.64 mmol), (1R,2R) aminocyclohexanol (221 mg, 1.92 mmol) and DIEA (248 mg, 1.92 mmol) in DMA (6.6 mL) was stirred at 130 0C for 16 h. The reaction mixture was cooled to rt and poured into water (30 mL). The e extracted with ethyl acetate (3>< 100 mL) and the combined organic layers were washed with brine, dried over , d and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 1:5 eum ether/ethyl acetate to give 1-((2- (((1R,2R)hydroxycyclohexyl)amino)benzo[d]thiazolyl)methyl) morpholinopyrazin-2(1H)-one as a light yellow solid (120 mg, 26.5%). 1H NMR (300 MHz, DMSO-d6) 5 7.96 (d, J: 7.2 Hz, 1H), 7.63 (s, 1H), 7.30 (d, J: 8.4 Hz,lH), 7.18-7.22 (m, 2H), 6.90 (d, J: 4.8 Hz,lH), 5.01 (s, 2H), 4.72 (d, J: 5.1 Hz, 1H), 3.65 (s, 8H), 3.55-3.52 (m, 1H), 3.36-3.31 (m, 1H), 2.07-2.02 (m, 1H), 1.90-1.86 (m, 1H), 1.63-1.62 (m, 2H), .22 (m, 4H). LCMS (ESI) m/z 442 (M+H)+.

Example 223 Pre aration of 3- 2- 1R 2R h drox c clohex lamino benzo d thiazol l meth l imidazo 1 2-a ridin-7— l rrolidin-l- l methanone (3-((2-(((1R,2R)Hydroxycyclohexyl)amino)benzo[d]thiazol yl)methyl)imidazo[1,2-a]pyridinyl)(pyrrolidinyl)methanone (65 mg, 46%) was obtained as a light tan solid using a procedure analogous to that described in Step 6 of Example 117, substituting (2-aminopyridinyl)(pyrrolidinyl)methanone and 2- chloro(2-(((1R,2R)hydroxycyclohexyl)amino)benzo[d]thiazolyl)propanal from Step 2 of Example 153, respectively, for 2-aminoisonicotinonitrile and ro- 3-(2-(methylthio)benzo[d]thiazolyl)propanal used in Example 117. 1H NMR (500 MHz, DMSO-d6) 5 8.24 (d, J: 6.9 Hz, 1H), 8.01 (d, J: 7.4 Hz, 1H), 7.72 (s, 1H), 7.53 (s, 2H), 7.31 (br s, 1H), 7.27 (d, J: 7.9 Hz, 1H), 7.10 (d, J: 8.4 Hz, 1H), 6.99 (d, J: 6.9 Hz, 1H), 6.78 (br s, 1H), 4.88 (br s, 1H), 4.31 (s, 2H), 3.43 - 3.58 (m, 6H), 2.04 (d, J: 12.3 Hz, 1H), 1.76 - 1.94 (m, 5H), 1.57 - 1.68 (m, 2H), 1.10 - 1.27 (m, 4H). LCMS (ESI) m/Z 476 (M+H)+.

Example 224 Pre aration of 1- 2- 1R 2R h dro c clohex 1 amino benzo l meth l-1H-benz0 d imidazol-S- yllacrylic acid é\N S N AG: />_NH 9H N 3 t‘ Step 1: To a stirred solution of (1R,2R)((6-((5-iodo-1H- benzo[d]imidazolyl)methyl)benzo[d]thiazolyl)amino)cyclohexanol (150 mg, 0.30 mmol) from Step 5 of Example 183 in DMF (2 mL) were added ethyl acrylate (0.036 mL, 0.33 mmol), palladium (II) acetate (7 mg 0.03 mmol), and triethylamine (0.088 mL, 0.63 mmol). The mixture was flushed with argon and heated in a sealed vessel at 120 0C for 3 h. The e was cooled to rt and ioned between EtOAc and water. The separated aqueous layer was extracted twice with EtOAc and the ed organic phases were washed three times with a 1:1 mixture of water and brine, dried over MgSO4, filtered, and concentrated under d pressure to afford (E)-ethyl 3 -(1-((2-(((1R,2R)hydroxycyclohexyl)amino)benzo[d]thiazol yl)methyl)-1H—benzo[d]imidazolyl)acrylate (187 mg) as a solid. The product was used directly in the next step. LCMS (ESI) m/z 477 (M+H)+.

Step 2: To a stirred solution of (E)-ethyl 3-(1-((2-(((1R,2R) hydroxycyclohexyl)amino)benzo[d]thiazolyl)methyl)— 1H-benzo[d]imidazol-5 - yl)acrylate from the preVious step in THF (2 mL) was added 1M aq LiOH (2 mL) and the mixture was stirred at rt for 48 h. The e was then acidified and concentrated under reduced pressure. The residue was purified directly by reverse-phase preparative HPLC using a mixture of water (5% CH3CN, 0.05% HOAC) and CH3CN (0.05% HOAC) as the mobile phase and Varian Pursuit XRs diphenyl column as the stationary phase to afford (E)(1-((2-(((1R,2R) hydroxycyclohexyl)amino)benzo[d]thiazolyl)methyl)— 1H-benzo [d]imidazol-5 - yl)acrylic acid as a solid (22 mg, 16%).1H NMR (500 MHZ, DMSO-d6) 8 8.46 (s, 1H), 7.90 - 8.01 (m, 2H), 7.68 (d, J: 15.8 Hz, 1H), 7.66 (d, J: 1.0 Hz, 1H), 7.58 (s, 2H), 7.29 (d, J: 10 Hz, 1H), 7.20 (dd, J: 1.2, 8.1 Hz, 1H), 6.48 (d, J: 15.8 Hz, 1H), .48 (s, 2H), 4.73 (br s, 1H), 3.47—3.57 (br m, 2H), 2.02 (m, 1H), 1.86 (m, 1H), 1.55 — 1.67 (m, 2H), 1.12 — 1.32 (m, 4H). LCMS (ESI) m/Z 449 (M+H)+.

Example 225 Pre aration of IR 2R 6- 5- 1 2 3 6-tetrah dro ridin 1 -1H- benzo imidazol-l- lmeth lbenzo thiazol lamino c clohexanol //\ S N ”U />—NH pH N 3 .~‘ Step 1: To a stirred solution of (1R,2R)((6-((5-iodo-1H- benzo[d]imidazolyl)methyl)benzo[d]thiazolyl)amino)cyclohexanol (100 mg, 0.20 mmol) from Step 5 of Example 183 in DMF (2 mL) were added N—Boc-1,2,5,6- tetrahydropyridineboronic acid pinacol ester (93 mg, 0.30 mmol), potassium ate (55 mg 0.40 mmol), bis-triphenylphosphine palladium (II) chloride (6.3 mg, 0.009 mmol), and 1,1 ’-bis(diphenylphosphino)ferrocene (5 mg, 0.009 mmol). The mixture was flushed with argon and heated in a sealed vessel at 80 °C for 15 h. The reaction e was purified directly by reverse-phase preparative HPLC using a mixture of water (5% CH3CN, 0.05% HOAc) and CH3CN (0.05% HOAc) as the mobile phase and Varian Pursuit XRs diphenyl column as the stationary phase to afford tert—butyl 4-(1-((2-(((1R,2R)hydroxycyclohexyl)amino)benzo[d]thiazol yl)methyl)- 1H-benzo[d]imidazol-5 -yl)-5 ,6-dihydropyridine-1(2H)-carboxylate as a solid (35 mg, 31%). 1H NMR (500 MHz, DMSO-d6) 8 8.38 (s, 1H), 7.97 (d, J: 7.9 Hz, 1H), 7.66 (s, 1H), 7.63 (s, 1H), 7.49 (d, J: 8.4 Hz, 1H), 7.33 (m, 1H), 7.28 (d, J: 8.4 Hz, 1H), 7.18 (dd, J: 1.2, 8.1 Hz, 1H), 6.09 (br s, 1H), 5.45 (s, 2H), 4.75 (d, J: 3.9 Hz, 1H), 3.98 (br s, 2H), 3.46 - 3.59 (m, 4H), 3.36-3.42 (m, 2H), 2.02 (m, 1H), 1.87 (m, 1H), 1.56 - 1.67 (m, 2H), 1.38 - 1.48 (m, 9H), 1.13 - 1.32 (m, 4H); LCMS (ESI) m/Z 560 (M+H)+.

Step 2: To a stirred solution of utyl 4-(1-((2-(((1R,2R) hydroxycyclohexyl)amino)benzo[d]thiazolyl)methyl)— zo[d]imidazol-5 -yl)— hydropyridine-1(2H)—carboxylate (30 mg, 0.05 mmol) from the preVious step in DCM (3 mL) at 0 CC was added 4M HCl in 1,4-dioxane (0.3 mL), and the mixture was d at 0 0C for 5 min. The mixture trated under reduced pressure and the residue was purified by reverse-phase preparative HPLC using a mixture of water (5% CH3CN, 0.05% HOAc) and CH3CN (0.05% HOAc) as the mobile phase and Phenomenex Luna C-18 column as the stationary phase to afford )((6-((5- (1 ,2,3 ,6-tetrahydropyridinyl)- 1H-benzo [d]imidazolyl)methyl)benzo [d]thiazol yl)amino)cyclohexanol as a solid (1.38 mg, 5%).1H NMR (500 MHZ, DMSO-d6) 8 8.36 (s, 1H), 8.00 (d, J: 7.4 Hz, 1H), 7.62 (d, J: 5.9 Hz, 2H), 7.47 (d, J: 8.9 Hz, 1H), 7.31 (d, J: 8.4 Hz, 1H), 7.28 (d, J: 8.4 Hz, 1H), 7.18 (dd, J: 1.2, 8.1 Hz, 1H), 6.14 (br s, 1H), 5.44 (s, 2H), 3.47-3.57 (br m, 2H), 2.94 (t, J: 5.4 Hz, 2H), 2.40 (br s, 2H), 2.02 (d, J: 11.8 Hz, 1H), 1.85-1.87 (m, 6H), 1.57 - 1.66 (m, 2H), 1.12 - 1.30 (m, 4H); LCMS (ESI) m/Z 460 (M+H)+. e 226 Pre aration of IR 2R 6- 5- lH-imidazol-l- l-lH-benzo imidazol-l- l meth lbenzo thiazol-Z- 1 amino c clohexanol A stirred mixture of (1R,2R)((6-((5-iodo-1H—benzo[d]imidazol yl)methyl)benzo[d] thiazolyl)amino)cyclohexanol (250 mg, 0.50 mmol) from Step of Example 183, imidazole (80 mg, 1.18 mmol), potassium carbonate (82 mg, 0.59 mmol), trans-N,N—dimethylcyclohexane-1,2-diamine (9 mg, 0.063 mmol), copper (I) iodide (30 mg, 0.158 mmol) and DMF (2 mL) was heated at 120 CC for 3 h. The reaction mixture was cooled to rt and partitioned between EtOAc and water. The organic layer was separated, dried over Na2S04, d, and concentrated under d pressure. The residue was purified by silica gel flash chromatography, eluting with 20:1 DCM: MeOH, to afford (1R,2R)((6-((5-(1H—imidazolyl)-1H- benzo[d]imidazolyl)methyl)benzo[d]thiazolyl)amino)cyclohexanol (78 mg, %) as a white solid. 1H NMR (300 MHz, DMSO-d6) 8 8.52 (s, 1H), 8.18 (s, 1H), 7.91 — 7.96 (m, 2H), 7.72 — 7.86 (m, 3H), 7.47 (dd, J: 8.4, 1.8 Hz, 1H), 7.30 (d, J: 8.1 Hz, 1H), 7.21 (dd,.]= 8.1, 1.5 Hz, 1H), 7.07 (d,.]= 1.2 Hz, 1H), 5.52 (s, 2H), 4.71 (d,.]= 5.1Hz, 1H),3.51(m, 1H), 3.38 (m, 1H), 2.02 (m, 1H), 1.88 (m, 1H), 1.60 — 1.80 (m, 2H), 1.15 — 1.28 (m, 4H); LCMS (ESI) m/Z 445 (M+H)+.

Example 227 Pre aration of IR 2R 6- 5- 2-meth l-2H-tetrazol l-1H- benzo imidazol-l- lmeth lbenzo thiazol lamino c clohexanol //\ S N N/U />—NH 9H N 3 3 )((6-((5-(2-Methyl-2H—tetrazolyl)— 1H—benzo[d]imidazol hyl)benzo[d]thiazolyl)amino)cyclohexanol (18 mg, 18%) was obtained as a solid using a procedure analogous to that described in Step 5 of Example 203, tuting 6-((5-(2-methyl-2H-tetrazolyl)-1H-benzo[d]imidazolyl)methyl) (methylsulfinyl)benzo[d]thiazole from Step 6 of Example 236 for bromo fluoro- 1H-benzo[d]imidazolyl)methyl)(methylsulfinyl)benzo [d]thiazole used in Example 203. 1H NMR (300 MHz, 6) 8 8.53 (s, 1H), 8.29 (s, 1H), 7.91 — 7.97 (m, 2H), 7.68 — 7.76 (m, 2H), 7.21 — 7.32 (m, 2H), 5.52 (s, 2H), 4.72 (d, J: 5.1 Hz, 1H), 4.42 (s, 3H), 3.51 (m, 1H), 3.38 (m, 1H), 2.02 (m, 1H), 1.88 (m, 1H), 1.60 — 1.80 (m, 2H), 1.15 — 1.28 (m, 4H); LCMS (ESI) m/z 461 (M+H)+.

Example 228 Pre aration of 1S 2R 3R 6- 6-flu0r0-3H-imidaz0 4 5-b ridin l meth l benzo thiazol 1 amino c clohexane—l 2-diol To a stirred mixture ofNMO in tert—butanol (5 mL), THF (1.5 mL), H20 (0.5 mL), and a 4% wt solution of OsO4 in H20 (10 uL, 0.3 mmol) at rt was added portionwise (R)-N—(cyclohexenyl)((6-fluoro-3H—imidazo[4,5-b]pyridin-3 - yl)methyl)benzo[d]thiazolamine (142 mg, 0.4 mmol) from Example 176. After the mixture was stirred at rt for 18 h, it was partitioned between EtOAc (200 mL) and 0.5 M aq K2C03 (100 mL). The organic layer was separated, washed with brine (100 mL), dried over MgSO4, filtered, and concentrated under reduced pressure. The e was purified twice by reverse-phase preparative HPLC eluting with a mixture of water (5% CH3CN, 0.05% HCOOH) and CH3CN (0.05% HCOOH) as the mobile phase and Varian Pursuit XRs C l 8 column as the stationary phase to afford (lS,2R,3R)—3-((6-((6-fluoro-3H—imidazo[4,5-b]pyridinyl)methyl)benzo[d]thiazol yl)amino)cyclohexane-l,2-diol (7 mg, 2%) as a white powder. 1H NMR (500 MHZ, DMSO-d6) 5 8.67 (s, 1H), 8.40 (m, 1H), 8.07 (dd, J: 2.6, 9.5 Hz, 1H), 7.95 (d, J: 7.9 Hz, 1H), 7.66 (d, J: 1.2 Hz, 1H), 7.29 (d, J: 8.4 Hz, 1H), 7.21 (dd, J: 1.6, 8.2 Hz, 1H), 5.47 (s, 2H), 4.45 — 4.70 (m, 2H), 3.88 (br s, 1H), 3.76 (m, 1H), 3.43 (m, 1H), 1.40 — 1.62 (m, 5H), 1.25 (m, 1H); LCMS (ESI) m/z 414 (M+H)+.

Example 229 Pre aration of IR 2S 3R 6- 7- 1H- l- limidazo 1 2-a ridin l meth l benzo d thiazol 1 amino c clohexane-l 2-diol \ N N/>—NH §H \ / IIIIOH | ,N Step 1: A 20 mL reaction vessel was charged with 4-iodopyridinamine (1.5 g, 6.8 mmol) and lH-pyrazole (4.0 g, 58.9 mmol). Concentrated hydrochloric acid ( 1.5 ml) and l,4-dioxane (l .5 mL) were added, and the reaction vessel was sealed. The mixture was ated in a microwave oven at 120 0C for 45 min and then at 130 0C for 60 min. The mixture was cooled to rt and then diethyl ether (6 ml) and ethanol (3 ml) were added. The e was sonicated for 10 min, and the solid was collected by filtration and washed with diethyl ether and n-hexane to give 4-(lH- pyrazol-l-yl)pyridinamine hydrochloride (1 .2 g, 90%) as a white solid. LCMS (ESI) m/Z 161 (M+H)+.

Step 2: 6-((7-(lH-pyrazol-l-yl)imidazo[l,2-a]pyridinyl)methyl) lthio)benzo[d]thiazole (176 mg, 63%) was obtained as a yellow solid using a procedure ous to that described in Step 6 of Example 117, substituting 4-(lH- pyrazol-l-yl)pyridinamine hydrochloride from Step 1 of this Example for 2- aminoisonicotinonitrile used in e 117, and adding NaHCOg to the reachion mixture. LCMS (ESI) m/Z 378 (M+H)+.

Step 3: (1R,2S,3R)—3-((6-((7-(1H-Pyrazolyl)imidazo[1,2-a]pyridin yl)methyl)benzo[d]thiazolyl)amino)cyclohexane-1,2-diol (25 mg, 12%) was obtained as a light tan solid using procedures analogous to those described in Steps 7- 8 of Example 117, substituting 6-((7-(1H-pyrazolyl)imidazo[1,2-a]pyridin yl)methyl)(methylthio)benzo[d]thiazole for 3-((2-(methylthio)benzo[d]thiazol yl)methyl)imidazo [1,2-a]pyridinecarbonitrile used in Step 7 of Example 117, and substituting the product of that reaction and (1R,2S,3R)aminocyclohexane-1,2-diol hydrochloride, respectively, for 3-((2-(methylsulfinyl)benzo[d]thiazol yl)methyl) imidazo[1,2-a]pyridinecarbonitrile and (1R,2R)amino cyclohexanol used in Step 8 of e 117. 1H NMR (500 MHZ, DMSO-d6) 8 8.66 (d, J: 2.5 Hz, 1H), 8.32 (d, J: 7.4 Hz, 1H), 7.99 (s, 1H), 7.85 (d, J: 7.9 Hz, 1H), 7.79 (s, 1H), 7.54 (s, 1H), 7.53 (d, J: 2.0 Hz, 1H), 7.43 (s, 1H), 7.28 (d, J: 7.9 Hz, 1H), 7.12 (d, J: 8.4 Hz, 1H), 6.59 (s, 1H), 4.53 (d, J: 5.9 Hz, 1H), 4.43 (d, J: 3.9 Hz, 1H), 4.31 (s, 2H), 3.93 (d, J: 3.9 Hz, 1H), 3.80 (br s, 1H), 3.37 - 3.45 (m, 1H), 1.92 (dd,.]= 34,118 Hz, 1H), 1.65 = 52,165 Hz, 1H), 1.51 - 1.61 (m, 1H), 1.32 - 1.48 (m, 2H), 1.14 - 1.29 (m, 1H). LCMS (ESI) m/z 461 (M+H)+.

Example 230 Pre aration of IR 2S 3R 6- 5-meth0x nz0 imidazol-l- l meth l benzo thiazol-Z- 1 amino c clohexane—l 2-diol /\ S N/ N/\©: />—NH 9H N .~ IIIIIOH Step 1: 4-Methoxy-N—((2-(methylthio)benzo[d]thiazolyl)methyl) nitroaniline (5.2 g, 92%) was obtained as a red solid using a ure analogous to that described in Step 1 of Example 127, substituting 4-methoxynitroaniline for 4- methylnitroaniline used in e 127. 1H NMR (500 MHZ, DMSO-d6) 8 8.64 (t, J: 6.1 Hz, 1H), 7.98 (m, 1H), 7.80 (d, J: 8.4 Hz, 1H), 7.52 (d, J: 3.1 Hz, 1H), 7.45 (dd, J: 8.4, 1.5 Hz, 1H), 7.18 (dd, J: 9.4, 3.1 Hz, 1H), 6.91 (d, J: 9.5 Hz, 1H), 4.72 (d, J: 6.1 Hz, 2H), 3.72 (s, 3H), 2.77 (s, 3H); LCMS (ESI) m/z 362 (M+H)+.

WO 56070 2012/059983 ] Step 2: 4-Methoxy-N1-((2-(methylthio)benzo[d]thiazol yl)methyl)benzene-1,2-diamine (4 g, 84%) was obtained as an oil using a procedure analogous to that described in Step 2 of Example 129, substituting 4-methoxy-N-((2- (methylthio)benzo[d]thiazolyl)methyl)nitroaniline from the preVious step for 4- fluoro-N—((2-(methylthio)benzo[d]thiazolyl)methyl)nitroaniline used in Example 129. LCMS (ESI) m/Z 332 (M+H)+.

Step 3: 6-((5-Methoxy-1H—benzo[d]imidazolyl)methyl) (methylthio)benzo[d]thiazole (1.12 g, 27%) was obtained as a solid using a procedure analogous to that described in Step 3 of Example 129, substituting 4-methoxy-N1-((2- (methylthio)benzo[d]thiazolyl)methyl)benzene-1,2-diamine from the us step for 4-fluoro-N1-((2-(methylthio)benzo[d]thiazolyl)methyl) benzene-1,2-diamine used in Example 129. 1H NMR (500 MHZ, DMSO-d6) 8 8.35 (s, 1H), 7.97 (d, J: 1.2 Hz, 1H), 7.79 (d, J: 8.4 Hz, 1H), 7.38 — 7.41 (m, 2H), 7.18 (d, J: 2.3 Hz, 1H), 6.82 (dd, J: 8.8, 2.3 Hz, 1H), 5.55 (s, 2H), 3.75 (s, 3H), 2.76 (s, 3H); LCMS (ESI) m/Z 342 (M+H)+.

Step 4: 6-((5-Methoxy-1H—benzo[d]imidazolyl)methyl) (methylsulfinyl)benzo[d]thiazole (986 mg, 84%) was obtained as a solid using a procedure analogous to that described in Step 4 of Example 129, substituting 6-((5- methoxy- 1H-benzo[d]imidazolyl)methyl)(methylthio)benzo [d]thiazole from the preVious step for fluoro-1H-benzo [d]imidazolyl)methyl) lthio)benzo[d]thiazole used in Example 129. 1H NMR (500 MHZ, DMSO-d6) 8 8.38 (s, 1H), 8.21 (d, J: 1.2 Hz, 1H), 8.06 (d, J: 8.4 Hz, 1H), 7.55 (dd, J: 8.5,1.6 Hz, 1H), 7.38 (d, J: 8.8 Hz, 1H), 7.19 (d, J: 2.3 Hz, 1H), 6.83 (dd, J: 8.8, 2.3 Hz, 1H), 5.64 (s, 2H), 3.75 (s, 3H), 3.05 (s, 3H); LCMS (ESI) m/z 358 (M+H)+.

Step 5: ,3R)((6-((5-Methoxy-1H—benzo[d]imidazol yl)methyl)benzo[d]thiazolyl)amino)cyclohexane-1,2-diol (53 mg, 15%) was obtained as a solid using a procedure analogous to that described in Step 5 of Example 232, substituting 6-((5-methoxy-1H—benzo[d]imidazolyl)methyl) (methylsulfinyl)benzo[d]thiazole, prepared as described in the preVious step for 6-((5- iodo- 1H-benzo [d]imidazolyl)methyl)(methylsulfinyl)benzo [d]thiazole from Example 232. 1H NMR (500 MHz, DMSO-d6) 5 8.31 (s, 1H), 7.92 (d, .1: 7.9 Hz, 1H), 7.62 (s, 1H), 7.40 (d, J: 8.9 Hz, 1H), 7.29 (d, J: 8.1 Hz, 1H), 7.13 - 7.20 (m, 2H), 6.82 (dd, .1: 2.1, 8.7 Hz, 1H), 5.41 (s, 2H), 4.52 (d, .1: 5.9 Hz, 1H), 4.43 (d, .1: 3.7 Hz, 1H), 3.93 (d, .1: 4.4 Hz, 1H), 3.79 (m, 1H), 3.75 (s, 3H), 3.40 (m, 1H), 1.91 (dd,.]= 3.8, 12.4 Hz, 1H), 1.51 _ 1.70 (m, 2H), 1.32 _ 1.45 (m, 2H), 1.20 (m, 1H); LCMS (ESI) m/Z 425 (M+H)+.

Example 231 Pre aration of IR 2S 3R 6- 7- 2H-1 2 3-triazol l imidazo 1 2-a ridin- Step 1: 4-(2H-1,2,3-triazolyl)pyridinamine (370 mg, 39%) was obtained as a white solid using a procedure ous to that described in Example 141, substituting 4-iodopyridinamine and 1,2,3-triazole, repectively, for (1R,2R) ((6-((6-iodo-3H-imidazo[4,5-b]pyridinyl)methyl)benzo[d]thiazol no)cyclohexanol and le used in Example 141. LCMS (ESI) m/z 162 (M+H)+.

Step 2: 6-((7-(2H-1,2,3-Triazolyl)imidazo[1,2-a]pyridinyl)methyl)- 2-(methylthio)benzo[d]thiazole (87 mg, 31%) was obtained as a yellow solid using a procedure analogous to that described in Step 6 of Example 117, substituting 4-(2H- 1,2,3-triazolyl)pyridinamine from Step 1 of this Example for 2- aminoisonicotinonitrile used in Example 117, and adding NaHCOg to the reaction mixture. LCMS (ESI) m/Z 379 .

Step 3: (1R,2S,3R)—3-((6-((7-(2H-1,2,3-Triazolyl)imidazo[1,2- a]pyridinyl)methyl)benzo[d]thiazolyl)amino)cyclohexane-1,2-diol (35 mg, 33%) was obtained as a light tan solid using procedures analogous to those described in Steps 7-8 of Example 117, substituting 6-((7-(2H-1,2,3-triazolyl)imidazo[1,2- a]pyridin-3 -yl)methyl)(methylthio)benzo[d]thiazole from Step 2 of this Example for (methylthio)benzo[d]thiazolyl)methyl)imidazo [1,2-a]pyridine carbonitrile used in Step 7 of Example 117, and substituting the product of that on and (1R,2S,3R)aminocyclohexane-1,2-diol hydrochloride, respectively, for 3-((2-(methylsulfinyl)benzo[d]thiazolyl)methyl) imidazo[1,2-a]pyridine carbonitrile and (1R,2R)amino cyclohexanol used in Step 8 of Example 117. 1H NMR (500 MHz, DMSO-d6) 5 8.40 (d, J: 7.4 Hz, 1H), 8.19 (s, 2H), 8.04 (s, 1H), 7.85 (d, J: 7.9 Hz, 1H), 7.63 (dd, J: 2.0, 7.4 Hz, 1H), 7.54 (s, 1H), 7.51 (s, 1H), 7.29 (d, J: 8.4 Hz, 1H), 7.12 (d, J: 8.4 Hz, 1H), 4.49 - 4.69 (m, 1H), 4.43 (br s, 1H), 4.34 (s, 2H), 3.93 (d, J: 3.9 Hz, 1H), 3.80 (br s, 1H), 3.40 (d, J: 8.4 Hz, 2H), 1.92 (dd,.]= 3.9, 12.3 Hz, 1H), 1.66 (dd,.]= 54,108 Hz, 1H), 1.51 - 1.61 (m, 1H), 1.31 - 1.48 (m, 2H), 1.12 - 1.29 (m, 1H). LCMS (ESI) m/z 461 (M+H)+.

Example 232 Pre aration of IR 2S 3R 6- 5-Vin l-lH-benzo imidazol-l- l meth l benzo thiazol-Z- 1 amino c clohexane—l 2-diol mkwOH""OH Step 1: odonitrophenyl)formamide was synthesized as a black solid (7.4 g, 71%) using a ure analogous to that described in Step 1 of e 162, substituting 4-iodonitroaniline for 5-fluoro-3 -nitropyridinamine used in Example 162. LCMS (ESI) m/Z 293 (M+H)+.

Step 2: N—(4-Iodonitrophenyl)-N—((2-(methylthio)benzo[d]thiazol yl)methyl)formamide was synthesized as an brown solid (9.7 g, 82%) using a procedure analogous to that described in Step 3 of e 47, substituting N-(4- Iodonitrophenyl)formamide from the preVious step for 5-bromomethoxy-1H- benzo[d]imidazole used in Example 47. LCMS (ESI) m/z 486 (M+H)+.

Step 3: A stirred mixture ofN-(4-iodonitrophenyl)-N-((2- (methylthio)benzo[d]thiazolyl)methyl)formamide and iron powder (16.7 g, 20 mmol) in EtOH (140 mL) and HOAc (60 mL) was heated at reflux for 1 h. The mixture was cooled to rt and filtered, and the filtrate was concentrated under reduced pressure. The residue was partitioned between EtOAc (200 mL) and 0.5 M aq N32C03 (100 mL). The organic layer was separated and filrther washed with brine (100 mL), dried over MgSO4, filtered, and concentrated under reduced pressure to afford 6-((5- iodo-1H—benzo[d]imidazolyl)methyl)(methylthio)benzo[d]thiazole (5 .9 g, 68%) as a yellow solid that did not require r purification. 1H NMR (500 MHz, 2012/059983 DMSO-d6) 8 8.44 (s, 1H), 8.03 (d, .1: 1.0 Hz, 1H), 7.97 (s, 1H), 7.80 (d, .1: 8.4 Hz, 1H), 7.49 (dd, .1: 1.4, 8.5 Hz, 1H), 7.37 — 7.43 (m, 2H), 5.60 (s, 2H), 2.76 (s, 3H); LCMS (ESI) m/Z 438 (M+H)+.

Step 4: 6-((5-Iodo-lH—benzo[d]imidazol-l-yl)methyl) (methylsulflnyl)benzo[d]thiazole was synthesized as a white foam (2.9 g, 94%) using a procedure analogous to that described in Step 6 of Example 36, substituting 6-((5- iodo- lH-benzo [d]imidazol- l -yl)methyl)(methylthio)benzo [d]thiazole from the previous step for the 6-((4-bromo-lH-imidazol-l-yl)methyl) (methylthio)benzo[d]thiazole used in Example 36. 1H NMR (500 MHZ, DMSO-d6) 8 8.47 (s, 1H), 8.21 (s, 1H), 8.02 — 8.10 (m, 2H), 7.56 (dd, J: 1.4, 8.5 Hz, 1H), 7.50 (dd, J: 1.2, 8.4 Hz, 1H), 7.40 (d, J: 8.6 Hz, 1H), 5.69 (s, 2H), 3.05 (s, 3H); LCMS (ESI) m/Z 454 .

] Step 5: To a suspension of 6-((5-iodo-lH-benzo[d]imidazol-l-yl)methyl)- 2-(methylsulf1nyl)benzo[d]thiazole (350 mg, 0.8 mmol) and (lR,2S,3R) aminocyclohexane-l,2-diol hloride (258 mg, 1.6 mmol), prepared as described in Gauthier Errasti, et a], Org. Lett. 2009, 13, 915, in anhydrous DMA (l .5 mL) was added DIEA (402 uL, 2.4 mmol). The mixture was heated in a sealed tube at 120 0C for 15 h. The mixture was cooled to rt and partitioned between EtOAc (150 mL) and 0.5 M aq K2C03 (100 mL). The organic layer was separated and washed with brine (100 mL), dried over Na2S04, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with 5% MeOH in DCM to afford (lR,2S,3R)—3-((6-((5-iodo-lH-benzo[d]imidazol-l- yl)methyl)benzo[d]thiazolyl)amino)cyclohexane-l,2-diol (127 mg, 32%) as a yellow solid. LCMS (ESI) m/Z 521 (M+H)+.

Step 6: A sion of (lR,2S,3R)—3-((6-((5-iodo-lH-benzo[d]imidazol- l-yl)methyl)benzo[d]thiazolyl)amino)cyclohexane-l,2-diol (120 mg, 0.2 mmol), Vinylboronic acid pinacol ester (71 mg, 0.5 mmol), and K2C03 (64 mg, 0.5 mmol) in 6:1 e:water (3.5 mL) was purged with argon for 5 min. [l,l'- Bis(diphenylphosphino)ferrocene] dichloropalladium (II) (19 mg, 0.02 mmol) was added to the mixture, the mixture was purged with argon for an additional 5 min and then heated in a sealed tube at 100 0C for 6 h. The mixture was cooled to rt and partitioned between EtOAc (150 mL) and 0.5 M aq K2C03 (100 mL). The organic layer was separated and washed with brine (100 mL), dried over Na2S04, filtered, and concentrated under reduced pressure. The residue was purified by e-phase preparative HPLC using a mixture of water (5% CH3CN, 0.05% HCOOH) and CH3CN (0.05% HCOOH) as the mobile phase and Varian t XRs C18 column as the stationary phase to afford the nearly pure compound. This was r purified by silica gel flash chromatography, g isocraticlly with 5% MeOH in CHzClz, to afford ,3R)-3 -((6-((5 - 1H-benzo [d]imidazolyl)methyl)benzo [d]thiazol- 2-yl)amino)cyclohexane-1,2-diol (5 mg, 5%) as a white powder. 1H NMR (500 MHZ, MeOH-d4) 8 8.28 (br s, 1H), 7.69 (s, 1H), 7.54 (m, 1H), 7.41 — 7.43 (m, 2H), 7.37 (d, J: 8.1 Hz, 1H), 7.22 (m, 1H), 6.81 — 6.86 (m, 2H), 5.76 (d, J: 17.7 Hz, 1H), 5.49 (s, 2H), 5.19 (d, J: 11.1 Hz, 1H), 3.99 — 4.02 (m, 2H), 3.50 (m, 1H), 2.08 (m, 1H), 1.72 — 1.85 (m, 2H), 1.48 — 1.55 (m, 2H), 1.28 — 1.39 (m, 2H); LCMS (ESI) m/z 421 (M+H)+.

Example 233 Pre aration of IR 2S 3R 6- 5- 0xetan 10x -1H-benzo d imidazol—l- l meth l benzo d thiazol-Z- 1 amino c clohexane-l 2-diol Step 1: To a stirred solution of 4-aminonitrophenol (1.37 g, 8.91 mmol) in DMF (15 mL) at rt was added cesium carbonate (5.79 g, 17.82 mmol) and the mixture was stirred for 30 min. Oxetanylmethylbenzenesulfonate (3.05 g, 13.36 mmol) was added and the mixture was heated at 80 CC for 6 h. The mixture was cooled to rt and partitioned between EtOAc and water. The organic layer was separated, and the aqueous layer was ted with additional EtOAc. The combined organic layers were washed with brine. The organic layer was separated, dried over MgSO4, filtered, and concentrated under reduced pressure. The solid residue was purified by trituration with diethyl ether to afford 2-nitro(oxetanyloxy)aniline (1.33 g, 71%) as a brown solid. 1H NMR (500 MHz, DMSO-d6) 8 7.29 (br s, 2H), 7.15 (dd, J: 9.2, 3.0 Hz, 1H), 7.10 (d, J: 3.0 Hz, 1H), 7.02 (d, J: 9.2 Hz, 1H), 5.24 (pentet, J: 4.9 Hz, 1H), 4.87 — 4.93 (m, 2H), 4.51 — 4.53 (m, 2H); LCMS (ESI) m/z 211 (M+H)+.

Step 2: A stirred mixture of acetic anhydride (15 mL, 161 mmol) and formic acid (6 mL, 161 mmol) was heated at 60 0C for 5 h. The mixture was cooled to rt, then 2-nitro(oxetanyloxy)aniline (1.69 g, 8.02 mmol) was added and the mixture was heated at 70 0C for 15 h. The mixture was cooled to rt and concentrated under reduced pressure. The residue was partitioned between EtOAc and saturated aq NaHC03. The organic layer was separated, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with a gradient of 20% EtOAc in hexanes to 100% EtOAc to afford N—(2-nitro(oxetanyloxy)phenyl)formamide (967 mg, 51%) as a yellow solid. 1H NMR (500 MHz, DMSO-d6) 8 10.36 (br s, 1H), 8.29 (m, 1H), 7.85 (d, J: 8.9 Hz, 1H), 7.36 (d, J: 1.8 Hz, 1H), 7.24 (dd, J: 9.0, 3.0 Hz, 1H), 5.38 (pentet, J: 4.9 Hz, 1H), 4.92 — 4.94 (m, 2H), 4.53 — 4.56 (m, 2H).

Step 3: N—((2-(Methylthio)benzo[d]thiazolyl)methyl)-N-(2-nitro (oxetanyloxy)phenyl)formamide (1.71 g) was obtained as an oil using a procedure analogous to that described in Step 2 of Example 203, substituting N—(2-nitro (oxetanyloxy)phenyl)formamide from Step 2 of this e for N—(4-bromo fluoronitrophenyl)formamide used in Example 203. LCMS (ESI) m/z 432 (M+H)+.

Step 4: 2-(Methylthio)((5-(oxetanyloxy)- lH—benzo[d]imidazol yl)methyl)benzo[d]thiazole (640 mg, 41% from N—(2-nitro(oxetan yloxy)phenyl)formamide) was obtained as a solid using a procedure ous to that described in Step 3 of Example 203, substituting N—((2-(methylthio)benzo[d]thiazol- 6-yl)methyl)-N—(2-nitro(oxetanyloxy)phenyl)formamide from the previous step for N—(4-bromofluoronitrophenyl)-N—((2-(methylthio)benzo[d]thiazol yl)methyl)formamide used in e 203. 1H NMR (500 MHZ, DMSO-d6) 8 8.38 (s, 1H), 7.98 (d, J: 1.4 Hz, 1H), 7.79 (d, J: 8.4 Hz, 1H), 7.43 (d, J: 8.8 Hz, 1H), 7.40 (dd, J: 8.4, 1.8 Hz, 1H), 6.93 (d, J: 2.3 Hz, 1H), 6.79 (dd, J: 8.8, 2.3 Hz, 1H), .55 (s, 2H), 5.27 (pentet, J: 5.6 Hz, 1H), 4.91 — 4.94 (m, 2H), 4.53 — 4.55 (m, 2H), 2.76 (s, 3H); LCMS (ESI) m/Z 384 (M+H)+.

Step 5: hylsulf1nyl)((5-(oxetanyloxy)-lH—benzo[d]imidazol- ethyl)benzo[d]thiazole (496 mg, 74%) was obtained as a white solid using a procedure analogous to that bed in Step 4 of Example 130, substituting 2- (methylthio)((5 -(oxetan-3 -yloxy)- zo [d]imidazol- l - yl)methyl)benzo[d]thiazole from the us step for 2-(methylthio)((5- (trifluoromethyl)- 1H-benzo [d]imidazolyl)methyl)benzo [d]thiazole used in Example 130. 1H NMR (500 MHz, DMSO-d6) 5 8.41 (s, 1H), 8.22 (m, 1H), 8.07 (d, J = 10.0 Hz, 1H), 7.56 (m, 1H), 7.42 (d, J: 10.0 Hz, 1H), 6.95 (d, J: 5.0 Hz, 1H), 6.80 (m, 1H), 5.64 (s, 2H), 5.27 (pentet, J: 5.0 Hz, 1H), 4.92 — 4.95 (m, 2H), 4.52 — 4.55 (m, 2H), 3.05 (s, 3H); LCMS (ESI) m/z 400 (M+H)+.

] Step 6: (1R,2S,3R)—3-((6-((5-(Oxetanyloxy)-1H-benzo[d]imidazol yl)methyl)benzo[d]thiazolyl)amino)cyclohexane-1,2-diol (68 mg, 12%) was obtained as a solid using a procedure analogous to that described in Step 5 of Example 232, substituting 2-(methylsulfinyl)((5-(oxetanyloxy)-1H- d]imidazolyl)methyl)benzo[d]thiazole from the preVious step for 6-((5 -iodo- zo[d]imidazolyl)methyl)(methylsulfinyl)benzo [d]thiazole used in Example 232. 1H NMR (500 MHz, DMSO-d6) 5 8.34 (s, 1H), 7.92 (d, .1: 7.9 Hz, 1H), 7.63 (d, J: 1.5 Hz, 1H), 7.43 (d, J: 8.8 Hz, 1H), 7.28 (d, J: 8.2 Hz, 1H), 7.18 (dd, J: 8.2, 1.6 Hz, 1H), 6.91 (d, J: 2.3 Hz, 1H), 6.79 (dd, J: 8.8, 2.4 Hz, 1H), 5.41 (s, 2H), 5.27 (pentet, J: 5.2 Hz, 1H), 4.91 — 4.94 (m, 2H), 4.51 — 4.54 (m, 2H), 4.43 (d, J: 3.8 Hz, 1H), 3.92 (br m, 1H), 3.79 (m, 1H), 3.38 (m, 1H), 3.31 (m, 1H), 1.91 (m, 1H), 1.54 - 1.67 (m, 2H), 1.34 - 1.42 (m, 2H), 1.21 (m, 1H); LCMS (ESI) m/z 467 (M+H)+.

Example 234 Pre aration of IR 2S 3R 6- 6- 1H-1 2 4-triazol l -3H-imidaz0 4 5- b ridin l meth l benzo d thiazol-Z- 1 amino c clohexane—l 2-diol N|/\//N Step 1: (1H-1,2,4-Triazolyl)-3H-imidazo[4,5-b]pyridin yl)methyl)(methylthio)benzo[d]thiazole (108 mg, 19%) was obtained as a yellow solid using a procedure analogous to that described in Example 141, substituting 6- ((6-iodo-3H-imidazo[4,5-b]pyridinyl)methyl)(methylthio)benzo[d]thiazole, prepared as an intermeidate product in Step 2 of Example 96, and 1,2,4-triazole, tively, for (1R,2R)((6-((6-iodo-3H-imidazo[4,5-b]pyridin hyl)benzo[d]thiazolyl)amino)cyclohexanol and pyrazole used in Example 141. LCMS (ESI) m/Z 380 (M+H)+.

Step 2: (1R,2S,3R)—3-((6-((6-(1H-1,2,4-Triazolyl)-3H-imidazo[4,5- b]pyridinyl)methyl)benzo[d]thiazolyl)amino)cyclohexane-1,2-diol (53 mg, 41%) was obtained as a yellow solid using procedures analogous to those described in Steps 7-8 of Example 117, substituting 6-((6-(1H-1,2,4-triazolyl)-3H-imidazo[4,5- b]pyridinyl)methyl)(methylthio)benzo[d]thiazole from Step 1 of this Example for 3-((2-(methylthio)benzo[d]thiazolyl)methyl)imidazo [1,2-a]pyridine carbonitrile used in Step 7 of Example 117 and substituting the product of that reaction and (1R,2S,3R)aminocyclohexane-1,2-diol hydrochloride, respectively, for 3-((2-(methylsulfinyl)benzo[d]thiazolyl)methyl) imidazo[1,2-a]pyridine itrile and (1R,2R)amino exanol used in Step 8 of Example 117. 1H NMR (500 MHz, DMSO-d6) 5 9.30 (s, 1H), 8.89 (d, J: 2.0 Hz, 1H), 8.76 (s, 1H), 8.56 (d, J: 2.0 Hz, 1H), 8.29 (s, 1H), 8.21 (s, 1H), 7.93 (d, J: 7.9 Hz, 1H), 7.69 (s, 1H), 7.27 - 7.32 (m, 1H), 7.20 - 7.27 (m, 1H), 5.54 (s, 2H), 4.44 (d, J: 4.9 Hz, 2H), 3.93 (d, J: 4.4 Hz, 1H), 3.79 (br s, 1H), 3.39 (d, J: 8.4 Hz, 2H), 1.92 (dd, J: 3.4, 12.8 Hz, 1H), 1.61 - 1.71 (m, 1H), 1.50 - 1.61 (m, 1H), 1.30 - 1.47 (m, 2H), 1.12 - 1.29 (m, 1H). LCMS (ESI) m/Z 463 (M+H)+.

Example 235 Pre n of IR 2S 3R 6- 5-m0r holino-lH-benzo imidazol—l- l meth l benzo thiazol 1 amino c clohexane—l 2-diol N//\N/\©: />—NHsQ spH N Om.

(N0) A sion of (1R,2S,3R)—3-((6-((5-iodo-1H—benzo[d]imidazol yl)methyl)benzo[d]thiazolyl)amino)cyclohexane-1,2-diol (262 mg, 0.5 mmol) from Step 5 of Example 232, morpholine (264 uL, 3.0 mmol), L-proline (23 mg, 0.2 mmol), and K2C03 (209 mg, 1.5 mmol) in DMSO (2.0 mL) was purged with argon for 5 min. Copper (1) iodide (19 mg, 0.02 mmol) was added, and the mixture was purged for an additional 5 min, then heated in a sealed tube at 110 CC for 2 h. The mixture was cooled to rt and filtered through Celite, and the filtrate was purified by reverse-phase preparative HPLC using a mixture of water (5% CH3CN, 0.05% HCOOH) and CH3CN (0.05% HCOOH) as the mobile phase and Varian Pursuit XRs C18 column as the nary phase, followed by silica gel flash chromatography eluting with 5% MeOH in CHZClz to afford (1R,2S,3R)((6-((5-morpholino-1H- benzo[d]imidazolyl)methyl)benzo[d]thiazolyl)amino)cyclohexane-1 ,2-diol (2 mg, 1%) as a white powder. 1H NMR (500 MHz, MeOH-d4) 8 8.19 (s, 1H), 7.50 (s, 1H), 7.31 — 7.39 (m, 2H), 7.16 — 7.23 (m, 2H), 7.05 (dd, J: 2.0, 8.9 Hz, 1H), 5.44 (s, 2H), 3.95 — 4.06 (m, 2H), 3.80 — 3.88 (m, 4H), 3.50 (dd, J: 2.6, 9.2 Hz, 1H), 3.06 — 3.14 (m, 4H), 2.09 (m, 1H), 1.77 — 1.86 (m, 2H), 1.48 — 1.53 (m, 2H), 1.33 (m, 1H); LCMS (ESI) m/Z 480 .

Example 236 Pre aration of IR 2S 3R 6- 5- 2-meth etrazol—51H- benzo imidazol-l- lmeth lbenzo thiazol lamino c clohexane-l 2-diol i\N 3 N U»—NH pH N’EN N F .uIIOH /N‘N ] Step 1: N—(4-Cyanonitrophenyl)formamide was sized as a white solid (4.8 g, 100%) using a procedure analogous to that described in Step 1 of Example 162, substituting 4-cyanonitroaniline for 5-fluoronitropyridinamine used in Example 162. LCMS (ESI) m/Z 192 (M+H)+.

Step 2: N—(4-Cyanonitrophenyl)-N—((2-(methylthio)benzo[d]thiazol yl)methyl)formamide was synthesized as an yellow foam (920 mg, 92%) using a procedure analogous to that described in Step 3 of Example 47, substituting N-(4- cyanonitrophenyl)formamide from the preVious step for 5-bromomethoxy-1H— d]imidazole used in Example 47. LCMS (ESI) m/Z 385 (M+H)+.

Step 3: l-((2-(Methylthio)benzo[d]thiazolyl)methyl)—1H- benzo[d]imidazolecarbonitrile was synthesized as a white solid (694 mg, 86%) using a procedure analogous to that described in Step 3 of Example 232, substituting N—(4-cyanonitrophenyl)-N-((2-(methylthio)benzo[d]thiazolyl)methyl)formamide from the preVious step for N—(4-iodonitrophenyl)-N-((2- (methylthio)benzo[d]thiazolyl)methyl)formamide used in Example 232. LCMS (ESI) m/Z 337 (M+H)+.

Step 4: A suspension of 1-((2-(methylthio)benzo[d]thiazolyl)methyl)- 1H—benzo[d]imidazolecarbonitrile (694 mg, 2.1 mmol), sodium azide (403 mg, 6.3 mmol), and ammonium de (331 mg, 6.3 mmol) in DMF (3 mL) was heated in a sealed tube at 125 CC for 15 h. The mixture was cooled to rt and a precipitate formed.

The solid was collected by filtration to afford (2H-tetrazolyl)-1H- benzo[d]imidazolyl)methyl)(methylthio)benzo[d]thiazole (796 mg, 100%) as a yellow solid that did not require filrther purification. 1H NMR (500 MHz, DMSO-d6) 8 8.41 (s, 1H), 8.19 (s, 1H), 8.02 (s, 1H), 7.88 (dd, J: 1.0, 8.4 Hz, 1H), 7.81 (d, J: 8.6 Hz, 1H), 7.52 (d, J: 8.4 Hz, 1H), 7.45 (dd, J: 1.4, 8.5 Hz, 1H), 7.15 — 7.30 (br s, 2H), 5.60 (s, 2H), 2.76 (s, 3H); LCMS (ESI) m/z 380 (M+H)+.

Step 5: To a stirred mixture of 6-((5-(2H-tetrazolyl)-1H- benzo[d]imidazolyl)methyl)(methylthio)benzo[d]thiazole (796 mg, 2.1 mmol), C82C03 (673 mg, 2.1 mmol), and DMF (10 mL) was added iodomethane (129 uL, 2.1 mmol). The mixture was heated at 60 0C for 6 h. Additional iodomethane (30 uL, 0.5 mmol) was added and the mixture was stirred at 60 CC for an additional 4 h. The mixture was cooled to rt and partitioned between EtOAc (200 mL) and 0.5 M aq N32C03 (100 mL). The c layer was separated and washed with brine (100 mL), dried over MgSO4, filtered and concentrated under d pressure. The e was purified by silica gel flash chromatography, eluting with 2% MeOH in CH2Clz, to afford 6-((5-(2-methyl-2H-tetrazol-5 -yl)- 1H-benzo [d]imidazolyl)methyl) (methylthio)benzo[d]thiazole (318 mg, 39%) as a white solid. The regiochemistry of the alkylation was determined by 2-dimensional nuclear Overhauser effect (NOE) experiment. 1H NMR (500 MHZ, DMSO-d6) 8 8.58 (s, 1H), 8.31 (s, 1H), 8.03 (s, 1H), 7.93 (dd, J: 1.0, 8.4 Hz, 1H), 7.82 (d, J: 8.4 Hz, 1H), 7.73 (d, J: 8.6 Hz, 1H), 7.46 (dd, J: 1.2, 8.4 Hz, 1H), 5.66 (s, 2H), 4.41 (s, 3H), 2.76 (s, 3H); LCMS (ESI) m/z 394 (M+H)+.

] Step 6: 6-((5-(2-Methyl-2H—tetrazolyl)-1H—benzo [d]imidazol hyl)(methylsulfinyl)benzo[d]thiazole was synthesized as a white foam (390 mg) using a procedure analogous to that described in Step 6 of e 36, substituting 6-((5 -(2-methyl-2H-tetrazol-5 -yl)- 1H-benzo [d]imidazolyl)methyl) (methylthio)benzo[d]thiazole from the preVious step for 6-((4-bromo-1H—imidazol WO 56070 yl)methyl)(methylthio)benzo[d]thiazole used in Example 36. LCMS (ESI) m/Z 410 (M+H)+.

Step 7: To a suspension of (2-methyl-2H-tetrazolyl)-1H- benzo[d]imidazolyl)methyl)(methylsulf1nyl)benzo[d]thiazole (330 mg, 0.8 mmol) and (1R,2S,3R)aminocyclohexane-1,2-diol hydrochloride (391 mg, 2.4 mmol), prepared as bed in Gauthier Errasti, et al, Org. Lett. 2009, I3, 2912- 2915, in anhydrous NMP (3.0 mL) was added DIEA (703 uL, 4.0 mmol). The mixture was heated in a sealed tube at 120 CC for 15 h. Additional (1R,2S,3R)—3- aminocyclohexane-1,2-diol hydrochloride (258 mg, 1.6 mmol) and DIEA (703 uL, 4.0 mmol) were added, and the mixture was heated at 140 CC for a fiarther 15 h. The mixture was cooled to rt and was purified by reverse-phase preparative HPLC using a mixture of water (5% CH3CN, 0.05% HCOOH) and CH3CN (0.05% HCOOH) as the mobile phase and Varian Pursuit XRs C18 column as the stationary phase to afford (1R,2S,3R)—3 -((6-((5-(2-methyl-2H-tetrazolyl)- 1H-benzo [d]imidazol yl)methyl)benzo[d]thiazolyl)amino)cyclohexane-1,2-diol (37 mg, 10%) as a white powder. 1H NMR (500 MHz, DMSO-d6) 8 8.53 (s, 1H), 8.29 (s, 1H), 7.90 — 7.98 (m, 2H), 7.74 (d, J: 8.4 Hz, 1H), 7.69 (s, 1H), 7.31 (m, 1H), 7.23 (dd, J: 1.5, 8.4 Hz, 1H), 5.52 (s, 2H), 4.41 (s, 3H), 3.93 (m, 1H), 3.79 (m, 1H), 3.25 (m, 1H), 1.91 (m, 1H), 1.52 — 1.69 (m, 3H), 1.32 — 1.44 (m, 2H), 1.15 — 1.25 (m, 2H); LCMS (ESI) m/z 477 (M+H)+. e 237 60 Cell proliferation assay The compounds disclosed herein were tested in an M-NFS-60 cell proliferation assay to determine their cellular potency against CSFlR. M-NFS-60s are mouse monocytic cells that depend on the binding of the ligand M-CSF to its receptor, CSFlR, to proliferate. Inhibition of CSFlR kinase activity will cause reduced growth and/or cell death. This assay assesses the potency of compounds as CSFlR inhibitors by ing the reduction of Alamar Blue reagent by viable cells.

On day one of the experiment, M-NFS-60 cells were maintained in RPMI complete medium (Omega Scientific) plus 10% FBS supplemented with 20 ng/mL of M-CSF (R&D Systems). 96-well TC- treated, flat bottom plates were seeded at ,000 cell/well at a volume of 100 uL per well. The cells were ed overnight at 37°C under 5% C02.

On day two, compounds were added to the cells at 9 different concentrations, with og intervals alongside a control reference compound serving as a ve l. Final DMSO concentration was kept at 0.5% for a final volume of 200 uL. The compounds were allowed to incubate with the cells for 72 hours at 37°C under 5% C02.

On day five of the experiment, 40 ul of Alamar Blue reagent was added to each well and allowed to incubate for 3 hours. Alamar Blue fluorescence was read using SoftMax Pro software at 560nm (excitation) and 590nm (emission). IC50s were generated as an average of duplicates and represents the concentration of test compound that achieves 50% inhibition of cellular proliferation compared to control.

In one embodiment, the compounds provided herein were found to have IC50 of about or less than about 5, 4, 3, 2, 1, 0.5, 0.1, 0.05 or 0.01 uM. In another embodiment, the compounds provided herein were found to have activity IC50 of about or less than about 2000, 1000, 500, 300, 100, 50, 40, 30 or 20 nM. In another embodiment, the compounds provided herein were found to have activity IC50 of less than about 200 or 100 nM. e 238 HEK293 CSFlR Phosphorylation MSD assay The compounds disclosed herein were tested in a CSFlR phosphorylation assay to determine their cellular potency against CSFlR. A HEK293 cell line expressing CSFlR fused to FK506 binding protein (FKBP) as a molecular tag was generated. Inhibition of CSFlR kinase ty will t ligand-stimulated osphorylation of the CSFlR-FKBP in intact cells. Subsequent cell lysates are assayed in a sandwich ELISA employing the ochemiluminescent Meso Scale Discovery (MSD) technology for the presence of the phosphorylated (p)CSFlR- FKBP. This assay ines the potency of compounds as CSFlR inhibitors by measuring the reduction in the amount ofpCSFlR with increasing doses of compounds added to the cells prior to M-CSF stimulation.

On day one of the experiment, -CSF1R-FKPB cells, maintained in DMEM, with L-glutamine (Mediatech), 10% FBS, and 100 units/mL Penicillin/Streptomycin, were seeded at 50,000 cell/well in a volume of 100 uL per well in 96-well Cell Bind plates (Costar). The cells were cultured overnight at 37 0C W0 2013/056070 under 5% C02. To prepare the plates used in the MSD assay, a 330 nM biotin-FK506 (in TBS pH 7.2) solution was added at 30 uL per well to streptavidin-coated 96-well plates (MSD), and incubated overnight at room temperature, shaking at 500 rpm on an orbital shaker.

On day two, compounds diluted in DMSO were added to the cells in duplicate plates at 9 different concentrations with half-log intervals, plus DMSO only control, alongside a reference compound serving as a positive control. Final DMSO concentration was 0.5% in a volume of 200 uL per well. The compounds were allowed to incubate with the cells for 2 h at 37 0C under 5% C02. At the end of the incubation, human M-CSF (R&D Systems) was added for 5 min to a final concentration of 50 ng/mL to stimulate CSFlR phosphorylation. Cells were lysed for min, and the lysates were applied to the washed, FK506-coated MSD , and ted overnight at 4 CC shaking at 500 rpm.

] On day three, the MSD plates were washed, and the captured CSFlR- FKBP was assayed sequentially for phosphorylation using mouse anti- otyrosine antibody (Millipore) and TAG goat anti-mouse IgG antibody (MSD), and ed on a Sector Imager 6000 instrument (MSD).

A single IC50 value for each compound was determined by averaging the IC50s of the duplicates calculated using Igor Pro 6 software, and represents the compound concentration that achieves a 50% inhibition of ligand-induced CSFlR phosphorylation compared to DMSO control.

Example 239 Competition g assay to ine selectivity scores and binding constants (Kd) of the nds against a panel of s Competition binding assays used herein were developed, ted and performed as described in Fabian et al., Nature Biotechnology 2005, 23,329- 336. Kinases were produced as fusions to T7 phage (See, Fabian et al. or W004/015 142) or alternatively, the kinases were expressed in HEK-293 cells and subsequently tagged with DNA for PCR detection (See, W008/005310). For the binding assays, streptavidin-coated magnetic beads were treated with biotinylated affinity ligands for 30 min at room temperature to generate aff1nity resins. The liganded beads were blocked with excess biotin and washed with blocking buffer ock (Pierce), 1 % BSA, 0.05 % Tween 20, 1 mM DTT) to remove unbound ligand and to reduce non-specific binding. Binding reactions were assembled by combining kinase, ed affinity beads, and test compounds in 1 x binding buffer (20 % SeaBlock, 0.17X PBS, 0.05 % Tween 20, 6 mM DTT). Test compounds were prepared as 100 x stocks in DMSO and diluted into the aqueous environment. de were determined using an eleven point threefold serial ons. DMSO or control compounds were was added to control assays lacking a test compound. Primary screen assays were performed in polypropylene 384-well plates in a final volume of -40 uL, while Kd determinations were performed in yrene 96-well plates in a final volume of 135 uL. The assay plates were incubated at room temperature with shaking for 1 hour to allow the binding reactions to reach equilibrium, and the affinity beads were washed extensively with wash buffer (1X PBS, 0.05 % Tween 20) to remove unbound protein. The beads were then resuspended in elution buffer (1x PBS, 0.05 % Tween 20, 0.5 uM non-biotinylated affinity ligand) and incubated at room temperature with shaking for 30 min. The kinase concentration in the eluates was measured by quantitative PCR.

A selectivity score (S10) is a quantitative measure of selectivity of a compound t a panel of kinases. An S10 was ated for a compound by dividing the number of kinases found to have a percent of control (DMSO) less than by the total number of distinct kinases tested (excluding mutant variants). Percent of control (POC) is calculated by subtracting the signal of the control compound (POC = 0) from the signal of the test compound and dividing the outcome by the signal ofDMSO (POC = 100) minus the signal of the control compound. For the compounds disclosed , S10 scores were obtained by testing the compounds at uM concentration in a kinase panel containing either 386 or 392 distinct s.

In one embodiment, the compounds ed herein were found to have S10 score of about or less than about 0.1, 0.08, 0.06, 0.04, 0.03, or 0.02.

The compounds provided herein were found to have the following activity shown in Table 1: Table 1 Ex. # CSF1R FLT3 KIT PDGFRB CSF1R HEK293 Kinase Kd (nM) Kd Kd Kd (nM) M-NFS-60 pCSF1R icity (nM) (nM) CTB:IC50 M-CSF 8(10) (nM) MSD:IC50 (nM) 2012/059983 Ex. # CSF1R FLT3 KIT PDGFRB CSF1R HEK293 Kinase Kd (nM) Kd Kd Kd (nM) M-NFS-60 pCSF1R specificity (nM) (nM) CTB:IC50 M-CSF 8(10) (nM) MSD:IC50 (nM) 2012/059983 Ex. # CSF1R FLT3 KIT PDGFRB CSF1R HEK293 Kinase Kd (nM) Kd Kd Kd (nM) M-NFS-60 pCSF1R specificity (nM) (nM) CTB:IC50 M-CSF 8(10) (nM) MSD:IC50 (nM) Ex. # CSF1R FLT3 KIT PDGFRB CSF1R HEK293 Kinase Kd (nM) Kd Kd Kd (nM) M-NFS-60 pCSF1R specificity (nM) (nM) 50 M-CSF 8(10) (nM) MSD:IC50 (nM) In Table l, CSFlR Kd (nM): A 55, 5<BS20, 20<CSSO, D>50; and ND: no data; FLT3 Kd (nM): A 5200, 200<BSlOOO, 1000<CSSOOO, D>5000; and ND: no data; KIT Kd (nM): A 5100, SOO, 500<C52000, D>2000; and ND: no data; PDGFRB Kd (nM): A 550, OO, 500<CS2000, D>2000; and ND: no data; CSFlR Cell Proliferation Assay (M-NSF-60) IC50 (nM): A 550, 50<BS400, 400<CSlSOO, D>1500; and ND: no data; HEK293 pCSFlR Assay (M-CSF MSD) ICso (11M): A 550, 50<B5200, 200<CSSOO, D>500; and ND: no data; and S score: A 50.01, 0.01<BS0.02, C > 0.02; and ND: no data.

Additional compounds provided herein were found to have the following activity shown in Table 2: Table 2 Ex. # CSF1R FLT3 KIT PDGFRB CSF1R HEK293 Kinase Kd (nM) Kd Kd Kd (nM) M-NFS-60 pCSF1R specificity (nM) (nM) CTB:IC50 M-CSF 8(10) (nM) MSD:IC50 (nM) Ex. # CSF1R FLT3 KIT PDGFRB CSF1R HEK293 Kinase Kd (nM) Kd Kd Kd (nM) 60 pCSF1R specificity (nM) (nM) CTB:IC50 M-CSF 8(10) (nM) MSD:IC50 (nM) Ex. # CSF1R FLT3 KIT PDGFRB CSF1R HEK293 Kinase Kd (nM) Kd Kd Kd (nM) M-NFS-60 pCSF1R specificity (nM) (nM) 50 M-CSF 8(10) (nM) MSD:IC50 (nM) Ex. # CSF1R FLT3 KIT PDGFRB CSF1R HEK293 Kinase Kd (nM) Kd Kd Kd (nM) M-NFS-60 pCSF1R icity (nM) (nM) CTB:IC50 M-CSF 8(10) (nM) MSD:IC50 (nM) Ex. # CSF1R FLT3 KIT PDGFRB CSF1R HEK293 Kinase Kd (nM) Kd Kd Kd (nM) M-NFS-60 pCSF1R specificity (nM) (nM) CTB:IC50 M-CSF 8(10) (nM) MSD:IC50 (nM) In Table 2, CSFlR Kd (nM): A 55, , 20<CSSO, D>50; and ND: no data; FLT3 Kd (nM): A 5200, 200<BSIOOO, 1000<CSSOOO, D>5000; and ND: no data; KIT Kd (nM): A 5100, 100<BSSOO, 500<CS2000, D>2000; and ND: no data; PDGFRB Kd (nM): A 550, 50<BSSOO, 500<CS2000, D>2000; and ND: no data; CSFlR Cell Proliferation Assay (M-NSF-60) 1C50 (11M): A 550, 50<BS400, 400<C51500, ; and ND: no data; HEK293 pCSFlR Assay (M-CSF MSD) ICso (11M): A 550, 50<B5200, 200<C5500, D>500; and ND: no data; and S score: A 50.01, 0.01<B50.02, C > 0.02; and ND: no data.

Example 24%} in viva} inhibition of the Gmwth and Survivai of NEW % Tumor {Selig in Mice lxlO7 M-NFS-60 cells suspended in PBS were injected into the neal cavity of athymic nu/nu mice (Harlan Research Labs) in all study groups except the naive group, on Day 0. On Days 1-3, Compound A having the Formula I suspended in 0.5% hydroxypropylmethylcellulose (HPMC) was dosed orally at 100, 30, and 10 and 3 mg/kg once a day (QD) in the treatment group and compound Ki20227 suspended in Pharmatek#6 was dosed orally at 30 mg/kg once a day (QD) to the positive control group. The vehicle control group received Pharmatek#6 once a day (QD) and the naive group was untreated. On Day 4, the peritoneal cavity was flushed with 5mL sterile PBS containing s/mL sodium heparin and the peritoneal cells were counted via the Vi-cell cell counter. Figure 1 shows the se in the number of tumor cells in the groups that were administered Compound A.

The same study was conducted using Compound B of having the Formula I, which was administered in the same formulation at the same dose and schedule.

Figure 2 shows the decrease in the number of tumor cells in the groups that were administered nd B.

Example 241 In 3?in inhibii‘inn {if PTHrPéndnced Hypermicemia ] alcemia of malignancy is a significant complication of ed breast and lung cancer, and multiple myeloma. Production of humoral factors by the primary tumor is the mechanism responsible for 80% of cases. The vast majority of HHM is caused by tumor-produced parathyroid hormone-related protein, which acts through PTH/PTHrP receptors in the bone and kidney to stimulate osteoclastic bone resorption and calcium resorption. Transforming growth factor—33 (”E‘Gilfi}, which is 2012/059983 stored in bone matrix and released by osteoclastic bone resorption brings about 111'13‘1111’1131311 "? '111‘011.11cti1.11:1 11111111101 cells 11111111111. fi1creased produefion of PTHrP accelerates further bone resorption and provides more space for tumor cell profife 11111111. 53111111112513.1111 11f 11511111lasfvmedmtcd11111e 11111011 ‘11cm1111cl effective t b11111: metastasis. M47853? has been shown to i11d11ee1‘1a’1e11elast generation and bone resorption and therefore CSFlR inhibition may be an effective mechanism against bone 11'1etastasis. in this l hypercalcemia of malignancy model, 32udayuold EDP} mice (Charles River 1.1113111110111111 in all groups except naive were challenged twice daily ng and evening, by subcutaneous injection) with 0.5mg/kg recombinant PTHrP (Bachem, Torrance,CA) for seven days. The treatment group was administered Compound A of Formula I suspended in 0.5% ypropylmethylcellulose (HPMC) at 1013, 31),“ and H) and 3 mg/kg orally once a day (QB) for seven days On dayl , rPTHrP was injected immediately prior to dosing of Compound A or Vehicle Control. The positive control group was administered compound K1202? suspended, 1.11 Pl‘1a11‘11a1ek116 and was (11.151311111711113; 111,31} /E1g once a day {13D} whi E1: the vehicle control group received 1% hydroxypropylmethylcellulose orally once daily for seven days. The study groups are summarized in Table 3 below. Mandibular blood was drawn exactly 3hr after last dose to monitor changes in blood ionized calcium and TRAPCSb levels (a bone resorption marker). Blood ionized calcium levels were determined using a Chrom Calcium Assay Kit (DICA-SOO) for Quantitative Colorimetric Calcium Determination at 612nm. TRAPCSb levels were determined using mouse TRAP assay (Immunodiagnosticsystems Inc. # SB-TRlO3). Mice were sacrificed on Day8 and the tibiae were harvested for bone TRAPSb and H&E staining.

Table 3.

Grou . l Naive —— 2 PTHrP 0.5 mgg/k PTHrP SC BID vehicle:control 4 0.5 mg/kg PTHrP -- SC BID and PO QD 1% HPMC oositive4 control Ki20227 30mgg/k ex 0 erimental 100 mgg/k ComooundA PO QD 6 0.5 mg/kg PTHrP -- SC BID and mental 30 m_/k; Comoound A PO QD 7 5 0.5 mg/kg PTHrP -- SC BID and ex.erimental 10 m_/k; Comoound A PO QD 8 0.5 mg/kg PTHrP - SC BID and ex 0 tal 3 m/k: Comoound A PO QD The results show that CSFlR inhibitors can be effective in this HHM model. Figure 3 shows Compound A reduced serum TRAP5b levels in a dose related manner and at the highest dose, d TRAP5b levels below that of naive animals.

The same study was conducted using nd B having the Formula I, which was administered in the same formulation at the same dose and schedule.

Figure 4 shows Compound B reduced serum TRAP5b levels in a dose related manner and at the highest dose, reduced TRAP5b levels below that of naive animals.

Example 242 in viva Inhibiting: of MCEH induction MCP-l (monocyte chemo-attractant n 1) is a chemokine that regulates migration and infiltration ofmonocytes/macrophages and is implicated in the development of tumor metastasis. It was demonstrated in prior experiments that M-CSF stimulation of human monocytes, peripheral blood mononuclear cells (PBMC) or whole blood, induced levels of MCP-l. This experiment was conducted to see whether the same observations may be made in viva.

In this study, 55-day old Balb/c mice (Harlan Laboratories) were grouped according to Table 4. One hour prior to M-CSF stimulation, animals were dosed orally with either Compound A, GW-25 80 or vehicle. One hour post dose, animals were administered 0.8 ug each M-CSF resuspended in 200 uL sterile saline I.V.. Two hours after administration of M-CSF, blood was collected Via the maxillary vein and processed for MCP-l ELISA (R&D s # MJE00) according to the manufacturer’s instructions.

Table 4: MCSF mThera Dose Vehicle + sterile saline Saline IV—1%HPMC Vehicle+0.8 /mer-CSF-CF 200 LIV 1%HPMC 0.8 /ms rM-CSF-CF in saline 200 LIV Cm.dA1m”/k 0.8 /ms rM-CSF-CF in saline 200 LIV Cm.dA 3m__/k 0.8 /ms rM-CSF-CF in saline 200 LIVmCm.dA10m__/k n-0.8 /ms rM-CSF-CF in saline 200 LIVmCm.dA30 Inn/k 0.8 /mer-CSF-CFinsaline 200 LIVmCm.dA100m,_/k 4 0.8 ug/ms rM-CSF-CF in saline 200 uL IV GW-2580 (160 mH/k “- Naive for base line none Figure 5 shows that IV injection of M-CSF in mice induces the level of MCP-l approximately three-fold. The most potent MCP-l reduction was observed at 60% at 100 mg/kg, and activity was reduced but comparable at the 30 and 10 mg/kg (46 and 53%, respectively) by atment with Compound A. The same study was conducted using Compound B having the Formula I, which was administered in the same formulation at the same dose and schedule. Figure 6 also shows IV injection of M-CSF inducing a three-fold increase in MCP-l levels. A dose response was less eVident, but maximal actiVity was again observed at 100 mg/kg, and the % reduction (59%) was nearly identical to that measured for Compound A.

The embodiments described above are intended to be merely exemplary, and those d in the art will recognize, or will be able to ascertain using no more than routine experimentation, numerous equivalents of specific nds, materials, and procedures. All such equivalents are considered to be within the scope of the d subject matter and are encompassed by the appended .

Since ations will be apparent to those of skill in the art, it is intended that the d subject matter be limited only by the scope of the appended claims.

Claims (26)

What we claim is:

1. A compound having formula VIIb: W5 R1 R2 W2 W Z R3 N (Q1)0-2 W4 W Y W N VIIb or a pharmaceutically acceptable salt, solvate, hydrate, ate, a single stereoisomer, a mixture of stereoisomers or a racemic mixture of stereoisomers thereof, wherein: R1 and R2 are each independently selected from hydrogen or halogen; R3 is hydrogen or alkyl; each Q1 is independently deuterium, halo, cyano, oxo, thioxo, alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, aralkyl, heteroaryl, aralkyl, heterocyclyl, heterocyclylalkyl, -RuORx, - RuORuN(Ry)(Rz), -RuN(Ry)(Rz), -RuSRx, )Rx, -RuC(J)ORx, -RuC(J)N(Ry)(Rz), - RuS(O)tRw, -RuN(Rx)C(J)Rx, -RuN(Rx)C(J)ORx, -RuN(Rx)S(O)tRw, =NORd, or – C(=NRy)N(Ry)ORx, where the alkyl, haloalkyl, aminoalkyl, alkenyl, l, lkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl groups are optionally substituted with one or more Q3 groups, in one embodiment, one to three Q3 groups; each Q3 is independently selected from deuterium, halo, hydroxyl, alkyl, kyl and hydroxyalkyl; Y is -(CR5R6)q-; R5 and R6 are each independently hydrogen, halo, alkyl, haloalkyl or hydroxyalkyl; Z is O, S, or NH; each W is independently CR8 or N; R8 is hydrogen, halo, haloalkyl or alkyl; W1 is N or C; W2 is N or CR9b; R9b is hydrogen or alkyl; W4 is N or CR11b; W5 is N or CR13; R11b and R13 are each ndnetly hydrogen or Q2; Q2 is halo, deuterium, cyano, oxo, thioxo, alkyl, haloalkyl, kenyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, lkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, -RuORx, -RuORuORx, -RuORuN(Ry)(Rz), - RuN(Ry)(Rz), -RuSRx, -RuC(J)Rx, -RuC(J)ORx, -RuC(J)N(Ry)(Rz), -RuC(J)RuN(Ry)(Rz), -RuC( )ORx, -C(=NORx)Rx, )tRw, -RuN(Rx)C(J)Rx, -RuN(Rx)C(J)ORx, -RuN(Rx)S(O)t Rw or –C(=NRy)N(Ry)ORx, where the alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl groups are optionally substituted with one or more groups Q4; in one embodiment, one to three Q4 , each Q4 is independently selected from halo, deuterium, hydroxyl, alkyl, haloalkyl and hydroxyalkyl; Q5 and Q6 are each independently hydrogen, deuterium, halo, cyano, oxo, thioxo, alkyl, haloalkyl, aminoalkyl, alkenyl, haloalkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, lkenylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cyclyl, heterocyclylalkyl, -RuORx, - RuORuORx, -RuORuN(Ry)(Rz), -RuN(Ry)(Rz), -RuSRx, -RuC(J)Rx, -RuC(J)ORx, -RuC(J)N(Ry)( Rz), -RuC(J)RuN(Ry)(Rz), - RuC(J)N(Ry)ORx, -C(=NORx)Rx, )tRw, -RuN(Rx)C(J)Rx, -RuN(Rx)C(J)ORx, - RuN(Rx)S(O)tRw or –C(=NRy)N(Ry)ORx, where the alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, lkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl groups are ally substituted with one or more Q8 ; each Q8 is independently selected from halo, deuterium, hydroxyl, alkyl, haloalkyl and hydroxyalkyl; each Rd is independently hydrogen or alkyl; each Ru is independently alkylene, alkenylene or a direct bond; Rw is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; each Rx is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, lkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, heterocyclyl, cyclylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; Ry and Rz are each independently selected from (i) or (ii) below: (i) Ry and Rz are each independently en, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; or (ii) Ry and Rz, together with the nitrogen atom to which they are attached, form a heterocyclyl or heteroaryl, ally tuted with one or more, in one ment, one, two or three Q7 groups; each Q7 is independently selected from halo, deuterium, oxo, thioxo, hydroxy, alkoxy, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl; J is O, NRx or S; each t is ndently an integer from 0-2; n is 1 or 2; and q is an integer from 0-4.

2. The compound of claim 1, where R1 and R2 are each hydrogen.

3. The compound of claims 1 or 2, where Y is direct bond, -CH2-, -CH(CH3)- or 2OH)-.

4. The nd of any of claims 1-3, where Z is O or S.

5. The compound of claim 1, where each Q1 is independently halo, oxo, alkyl, haloalkyl, yalkyl, cycloalkyl, =NOH, -RuORx or -RuC(O)Rx; each Ru is independently alkylene or a direct bond; and each Rx is independently hydrogen or alkyl.

6. The compound of claim 1, where Q5 and Q6 are each independently hydrogen, halo, cyano, alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, lkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, -RuORx, -RuN(Ry)(Rz), -RuSRx, -RuC(J)Rx, - ORx, -RuC(J)N(Ry)(Rz), -RuC(J)N(Ry)ORx, -RuS(O)tRw, -RuN(Rx)C(J)Rx, - RuN(Rx)C(J)ORx, -RuN(Rx)S(O)tRw or –C(=NRy)N(Ry)ORx, where the alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl groups are optionally substituted with one to three Q8 groups; each Q8 is independently ed from halo, deuterium, hydroxyl, alkyl, haloalkyl and hydroxyalkyl; each Ru is independently alkylene or a direct bond; Rw is alkyl; each Rx is independently hydrogen or alkyl; Ry and Rz are each independently hydrogen or alkyl; J is O, NRx or S; each t is independently an integer from 0-2; and q is an integer from 0-4.

7. The compound of claim 1, wherein the compound has Formula IX Z R3 N (Q1)0-2 W4 Y or a pharmaceutically acceptable salt, solvate, hydrate, single stereoiomer, mixture of stereoisomers or racemic mixture of stereoisomers thereof, wherein: R3 is hydrogen or alkyl; each Q1 is independently deuterium, halo, cyano, oxo, thioxo, alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, -RuORx, - RuORuN(Ry)(Rz), -RuN(Ry)(Rz), -RuSRx, )Rx, -RuC(J)ORx, -RuC(J)N(Ry)(Rz), - RuS(O)tRw, -RuN(Rx)C(J)Rx, -RuN(Rx)C(J)ORx, -RuN(Rx)S(O)tRw, =NORd, or – C(=NRy)N(Ry)ORx, where the alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl groups are optionally tuted with one to three Q3 groups; each Q3 is independently selected from deuterium, halo, hydroxyl, alkyl, haloalkyl and hydroxyalkyl; Y is –(CR5R6)q-; R5 and R6 are each independently hydrogen, halo, alkyl, haloalkyl or hydroxyalkyl; Z is O, S, or NH; W4 is N or CR11b; W5 is N or CR13; R11b and R13 are each independently hydrogen or Q2; each Q2 is independently halo, deuterium, cyano, oxo, thioxo, alkyl, kyl, haloalkenyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, - RuORx, -RuORuORx,-RuORuN(Ry)(Rz), - )(Rz), -RuSRx, )Rx, -RuC(J)ORx, -RuC(J)N(Ry)(Rz), )RuN(Ry)(Rz), -RuC( J)N(Ry)ORx, -C(=NORx)Rx, )tRw, -RuN(Rx)C(J)Rx, -RuN(Rx)C(J)ORx, -RuN(Rx)S(O)t Rw or y)N(Ry)ORx, where the alkyl, haloalkyl, lkyl, alkenyl, l, cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl groups are optionally substituted with one to three Q4 , each Q4 is independently selected from halo, deuterium, hydroxyl, alkyl, haloalkyl and hydroxyalkyl; Q5 and Q6 are each independently hydrogen, halo, cyano, alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, aralkyl, heterocyclyl, heterocyclylalkyl, -RuORx, -RuN(Ry)(Rz), -RuSRx, )Rx, -RuC(J)ORx, -RuC(J)N(Ry)(Rz), -RuS(O)tRw, -RuN(Rx)C(J)Rx, -RuN(Rx)C(J)ORx, -RuN(Rx)S(O)tRw or –C(=NRy)N(Ry)ORx, where the alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, and cyclyl groups are optionally substituted with one or more Q8 ; each Q8 is independently selected from halo, deuterium, hydroxyl, alkyl, haloalkyl and hydroxyalkyl; Rd is hydrogen or alkyl; each Ru is independently alkylene, alkenylene or a direct bond; Rw is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, heterocyclyl, heterocyclylalkyl, aryl, l, heteroaryl, or heteroaralkyl; each Rx is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cyanoalkyl, alkenyl, l, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, cyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; Ry and Rz are each independently selected from (i) or (ii) below: (i) Ry and Rz are each independently en, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, heterocyclyl, heterocyclylalkyl, aryl, l, heteroaryl, or heteroaralkyl; or (ii) Ry and Rz, together with the nitrogen atom to which they are attached, form a heterocyclyl or heteroaryl, optionally substituted with one, two or three Q7 groups; each Q7 is independently ed from halo, deuterium, oxo, thioxo, hydroxy, alkoxy, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, l, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cyclyl and heterocyclylalkyl; J is O, NRx or S; each t is independently an integer from 0-2; n is 1 or 2; and q is an integer from 0-4.

8. The compound of claim 7, n Q5 and Q6 are each independently hydrogen, halo, alkoxy, tetrazole or pyrazole, where the tetrazole and pyrazole rings are optionally substituted with one or two alkyl groups.

9. The compound of claim 7 or 8, wherein, Q5 and Q6 are each independently hydrogen, chloro, fluoro, bromo or methoxy.

10. The nd of claim 1 having Formula XI Z R3 N (Q1)0-2 W4 Y or a pharmaceutically able salt, solvate, hydrate, single stereoiomer, mixture of stereoisomers or racemic mixture of stereoisomers thereof, wherein: R3 is hydrogen or alkyl; each Q1 is independently halo, oxo, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, =NOH, -RuORx or -RuC(O)Rx; each Ru is independently alkylene or a direct bond; each Rx is independently hydrogen or alkyl; Y is –(CR5R6)q-; R5 and R6 are each ndently hydrogen, halo, alkyl, haloalkyl or hydroxyalkyl; Z is O, S, or NH; W4 is N or CR11b; R11b is hydrogen, halo or alkyl; W5 is N or CR13; R13 is hydrogen, halo or alkyl; and q is an integer from 0-4.

11. The compound of claim 1 having Formula XII: R1 R2 Z R3 R11a N N Y R4 (Q2)a XII or a pharmaceutically acceptable salt, solvate, hydrate, single stereoiomer, mixture of stereoisomers or racemic mixture of stereoisomers thereof, wherein, R3 is hydrogen or alkyl; R4 is cycloalkyl, aryl, heterocyclyl or heteroaryl, where R4 is ally substituted with one to three groups selected from Q1; each Q1 is independently halo, oxo, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, =NOH, -RuORx or -RuC(O)Rx; each Ru is independently alkylene or a direct bond; each Rx is independently hydrogen or alkyl; Y is 6)q-; R5 and R6 are each ndently hydrogen, halo, alkyl, haloalkyl or hydroxyalkyl; Z is O, S, or NH; R11a is hydrogen or alkyl; W6 is N or CR14; R14 is en or alkyl; a is 0-4; and q is an integer from 0-4.

12. The compound of claim 1, wherein the compound is selected from: 2-((6-((1H-benzo[d]imidazolyl)methyl)benzo[d]thiazolyl)amino)cyclohexanol, (1R,2R)((6-((5,6-dimethoxy-1H-benzo[d]imidazolyl)methyl)benzo[d]thiazol yl)amino)cyclohexanol, 2-((6-((5,6-dimethoxy-1H-benzo[d]imidazolyl)methyl)benzo[d]thiazol yl)amino)cyclohexanol, (1R,2R)((6-((3H-imidazo[4,5-b]pyridinyl)methyl)benzo[d]thiazol no)cyclohexanol methanesulfonic acid, (1R,2R)((6-((3H-imidazo[4,5-b]pyridinyl)methyl)benzo[d]thiazol yl)amino)cyclohexanol 2-((6-((3H-imidazo[4,5-b]pyridinyl)methyl)benzo[d]thiazol yl)amino)cyclohexanol (1R,2R)((6-((6-methoxy-1H-benzo[d]imidazolyl)methyl)benzo[d]thiazol yl)amino)cyclohexanol, 2-((6-((6-methoxy-1H-benzo[d]imidazolyl)methyl)benzo[d]thiazol yl)amino)cyclohexanol, (1R,2R)((6-((5-methoxy-1H-benzo[d]imidazolyl)methyl)benzo[d]thiazol no)cyclohexanol, 2-((6-((5-methoxy-1H-benzo[d]imidazolyl)methyl)benzo[d]thiazol yl)amino)cyclohexanol, )((6-((1H-benzo[d]imidazolyl)methyl)benzo[d]thiazol yl)amino)cyclohexanol, (1S,2S)((6-((1H-benzo[d]imidazolyl)methyl)benzo[d]thiazol yl)amino)cyclohexanol, 2-((6-((1H-benzo[d]imidazolyl)methyl)benzo[d]thiazolyl)amino)cyclohexanol, N-benzyl((5,6-dimethoxy-1H-benzo[d]imidazolyl)methyl)benzo[d]thiazol amine, N-cyclohexyl((5,6-dimethoxy-1H-benzo[d]imidazolyl)methyl)-N- methylbenzo[d]thiazolamine, N-cyclohexyl((5,6-dimethoxy-1H-benzo[d]imidazolyl)methyl)benzo[d]thiazol- 2-amine, (1R,2R)((6-((5-methoxy-3H-imidazo[4,5-b]pyridinyl)methyl)benzo[d]thiazol yl)amino)cyclohexanol, 2-((6-((5-methoxy-3H-imidazo[4,5-b]pyridinyl)methyl)benzo[d]thiazol yl)amino)cyclohexanol, 6-((5,6-dimethoxy-1H-benzo[d]imidazolyl)methyl)-N-(2- ethoxyphenyl)benzo[d]thiazolamine, N-(cyclohexylmethyl)((5,6-dimethoxy-1H-benzo[d]imidazol yl)methyl)benzo[d]thiazolamine, (1R,2R)((6-((6-bromo-3H-imidazo[4,5-b]pyridinyl)methyl)benzo[d]thiazol yl)amino)cyclohexanol, 2-((6-((6-bromo-3H-imidazo[4,5-b]pyridinyl)methyl)benzo[d]thiazol yl)amino)cyclohexanol, 6-((5,6-dimethoxy-1H-benzo[d]imidazolyl)methyl)-N-(2- methoxyphenyl)benzo[d]thiazolamine, 2-((6-((5,6-dimethoxy-1H-benzo[d]imidazolyl)methyl)benzo[d]thiazol yl)amino)phenol, (S)-N-(1-cyclohexylethyl)((5,6-dimethoxy-1H-benzo[d]imidazol hyl)benzo[d]thiazolamine, yclohexylethyl)((5,6-dimethoxy-1H-benzo[d]imidazol yl)methyl)benzo[d]thiazolamine, (1R,2R)((6-((5,6-dimethoxy-1H-benzo[d]imidazolyl)methyl)benzo[d]oxazol yl)amino)cyclohexanol, 2-((6-((5,6-dimethoxy-1H-benzo[d]imidazolyl)methyl)benzo[d]oxazol no)cyclohexanol, N-(cyclohexylmethyl)((5,6-dimethoxy-1H-benzo[d]imidazol yl)methyl)benzo[d]oxazolamine, (1R,2R)((6-(imidazo[1,2-a]pyridinylmethyl)benzo[d]thiazol yl)amino)cyclohexanol, 2-((6-(imidazo[1,2-a]pyridinylmethyl)benzo[d]thiazolyl)amino)cyclohexanol, (1R, 2R)((6-((6-(1-methyl-1H-pyrazolyl)-3H-imidazo[4,5-b]pyridin yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol, 2-((6-((6-(1-methyl-1H-pyrazolyl)-3H-imidazo[4,5-b]pyridin yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol, (1R,2R)((6-((6-(pyridinyl)-3H-imidazo[4,5-b]pyridin yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol, 2-((6-((6-(pyridinyl)-3H-imidazo[4,5-b]pyridinyl)methyl)benzo[d]thiazol yl)amino)cyclohexanol, (1R,2R)((6-((5-bromomethoxy-1H-benzo[d]imidazol yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol, 2-((6-((5-bromomethoxy-1H-benzo[d]imidazolyl)methyl)benzo[d]thiazol yl)amino)cyclohexanol, 3-((2-(((1R,2R)hydroxycyclohexyl)amino)benzo[d]thiazolyl)methyl)-3H- imidazo[4,5-b]pyridinecarbonitrile, 3-((2-((2-hydroxycyclohexyl)amino)benzo[d]thiazolyl)methyl)-3H-imidazo[4,5- b]pyridinecarbonitrile, (1R,2R)((6-((7-methoxyimidazo[1,2-a]pyridinyl)methyl)benzo[d]thiazol yl)amino)cyclohexanol, 2-((6-((7-methoxyimidazo[1,2-a]pyridinyl)methyl)benzo[d]thiazol yl)amino)cyclohexanol, (1R,2R)((6-((6-cyclopropyl-3H-imidazo[4,5-b]pyridin yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol, 2-((6-((6-cyclopropyl-3H-imidazo[4,5-b]pyridinyl)methyl)benzo[d]thiazol yl)amino)cyclohexanol, (1R,2R)((6-((6-bromomethoxy-1H-benzo[d]imidazol yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol, 2-((6-((6-bromomethoxy-1H-benzo[d]imidazolyl)methyl)benzo[d]thiazol yl)amino)cyclohexanol, (1R,2R)((6-((6-methoxy(1-methyl-1H-pyrazolyl)-1H-benzo[d]imidazol yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol, 2-((6-((6-methoxy(1-methyl-1H-pyrazolyl)-1H-benzo[d]imidazol yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol, (1R,2R)((6-((5-methoxy(1-methyl-1H-pyrazolyl)-1H-benzo[d]imidazol yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol, 2-((6-((5-methoxy(1-methyl-1H-pyrazolyl)-1H-benzo[d]imidazol yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol, 1-((2-(((1R,2R)hydroxycyclohexyl)amino)benzo[d]thiazolyl)methyl) methoxy-1H-benzo[d]imidazolecarbonitrile, 1-((2-((2-hydroxycyclohexyl)amino)benzo[d]thiazolyl)methyl)methoxy-1H- d]imidazolecarbonitrile, (R)((6-((3H-imidazo[4,5-b]pyridinyl)methyl)benzo[d]thiazol yl)amino)cyclohexanone, 2-((6-((3H-imidazo[4,5-b]pyridinyl)methyl)benzo[d]thiazol no)cyclohexanone, (1R,2R)((6-((6-chloro-3H-imidazo[4,5-b]pyridinyl)methyl)benzo[d]thiazol yl)amino)cyclohexanol, ((6-chloro-3H-imidazo[4,5-b]pyridinyl)methyl)benzo[d]thiazol yl)amino)cyclohexanol, (1R,2R)((6-((3H-imidazo[4,5-b]pyridinyl)methyl)benzo[d]oxazol yl)amino)cyclohexanol, 2-((6-((3H-imidazo[4,5-b]pyridinyl)methyl)benzo[d]oxazol yl)amino)cyclohexanol, (R)((6-((3H-imidazo[4,5-b]pyridinyl)methyl)benzo[d]thiazol yl)amino)cyclohexanone oxime, 2-((6-((3H-imidazo[4,5-b]pyridinyl)methyl)benzo[d]thiazol yl)amino)cyclohexanone oxime, (1S,2R)((6-((3H-imidazo[4,5-b]pyridinyl)methyl)benzo[d]thiazolyl)amino)- 1-methylcyclohexanol, (1R,2R)((6-((3H-imidazo[4,5-b]pyridinyl)methyl)benzo[d]thiazolyl)amino)- 1-methylcyclohexanol, 2-((6-((3H-imidazo[4,5-b]pyridinyl)methyl)benzo[d]thiazolyl)amino) methylcyclohexanol, (1R,2R)((6-((6-bromo-3H-imidazo[4,5-b]pyridinyl)methyl)benzo[d]oxazol yl)amino)cyclohexanol, ((6-bromo-3H-imidazo[4,5-b]pyridinyl)methyl)benzo[d]oxazol yl)amino)cyclohexanol, (S)((6-((3H-imidazo[4,5-b]pyridinyl)methyl)benzo[d]thiazolyl)amino) cyclohexylethanol, 2-((6-((3H-imidazo[4,5-b]pyridinyl)methyl)benzo[d]thiazolyl)amino) cyclohexylethanol, (R)((6-((3H-imidazo[4,5-b]pyridinyl)methyl)benzo[d]thiazolyl)amino) exylethanol, 1-((2-(((1R,2R)hydroxycyclohexyl)amino)benzo[d]thiazolyl)methyl) methoxy-1H-benzo[d]imidazolecarbonitrile, 1-((2-((2-hydroxycyclohexyl)amino)benzo[d]thiazolyl)methyl)methoxy-1H- benzo[d]imidazolecarbonitrile, ((1R,2R)((6-((3H-imidazo[4,5-b]pyridinyl)methyl)benzo[d]thiazol yl)amino)cyclohexyl)methanol, 2-((6-((3H-imidazo[4,5-b]pyridinyl)methyl)benzo[d]thiazol yl)amino)cyclohexyl)methanol, (1R,2R)((6-((6-methoxy-1H-benzo[d]imidazolyl)methyl)benzo[d]thiazol yl)amino)cyclohexanol, 2-((6-((6-methoxy-1H-benzo[d]imidazolyl)methyl)benzo[d]thiazol yl)amino)cyclohexanol, (1R,2R)((6-((5-methoxy-1H-benzo[d]imidazolyl)methyl)benzo[d]thiazol no)cyclohexanol, 2-((6-((5-methoxy-1H-benzo[d]imidazolyl)methyl)benzo[d]thiazol yl)amino)cyclohexanol, (1R,2R)((6-((6-fluoro-3H-imidazo[4,5-b]pyridinyl)methyl)benzo[d]thiazol yl)amino)cyclohexanol, 2-((6-((6-fluoro-3H-imidazo[4,5-b]pyridinyl)methyl)benzo[d]thiazol yl)amino)cyclohexanol, 1-(3-((2-(((1R,2R)hydroxycyclohexyl)amino)benzo[d]thiazolyl)methyl)-3H- imidazo[4,5-b]pyridinyl)ethanone, 1-(3-((2-((2-hydroxycyclohexyl)amino)benzo[d]thiazolyl)methyl)-3H-imidazo[4,5- b]pyridinyl)ethanone, (1R,2R)((6-((6-(methylsulfonyl)-3H-imidazo[4,5-b]pyridin hyl)benzo[d]thiazolyl)amino)cyclohexanol, ((6-(methylsulfonyl)-3H-imidazo[4,5-b]pyridinyl)methyl)benzo[d]thiazol yl)amino)cyclohexanol, 1-(((6-((3H-imidazo[4,5-b]pyridinyl)methyl)benzo[d]thiazol yl)amino)methyl)cyclohexanol, (1-(((6-((3H-imidazo[4,5-b]pyridinyl)methyl)benzo[d]thiazol yl)amino)methyl)cyclohexyl)methanol, (1R,2R)((6-((5-bromo-3H-imidazo[4,5-b]pyridinyl)methyl)benzo[d]thiazol yl)amino)cyclohexanol, 2-((6-((5-bromo-3H-imidazo[4,5-b]pyridinyl)methyl)benzo[d]thiazol yl)amino)cyclohexanol, methyl 3-((2-(((1R,2R)hydroxycyclohexyl)amino)benzo[d]thiazolyl)methyl)- 3H-imidazo[4,5-b]pyridinecarboxylate, methyl 3-((2-((2-hydroxycyclohexyl)amino)benzo[d]thiazolyl)methyl)-3H- imidazo[4,5-b]pyridinecarboxylate, 3-((2-(((1R,2R)hydroxycyclohexyl)amino)benzo[d]thiazolyl)methyl)-3H- imidazo[4,5-b]pyridinecarboxylic acid, 3-((2-((2-hydroxycyclohexyl)amino)benzo[d]thiazolyl)methyl)-3H-imidazo[4,5- b]pyridinecarboxylic acid, (1R,2R)((6-((6-(morpholinomethyl)-3H-imidazo[4,5-b]pyridin yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol, ((6-(morpholinomethyl)-3H-imidazo[4,5-b]pyridin yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol, (1R,2R)((6-((6-(hydroxymethyl)-3H-imidazo[4,5-b]pyridin yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol, 2-((6-((6-(hydroxymethyl)-3H-imidazo[4,5-b]pyridinyl)methyl)benzo[d]thiazol yl)amino)cyclohexanol, (1R,2R)((6-((6-(methylthio)-3H-imidazo[4,5-b]pyridin yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol, 2-((6-((6-(methylthio)-3H-imidazo[4,5-b]pyridinyl)methyl)benzo[d]thiazol yl)amino)cyclohexanol, (1R,2R)((6-((6-((methylthio)methyl)-3H-imidazo[4,5-b]pyridin yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol, ((6-((methylthio)methyl)-3H-imidazo[4,5-b]pyridin yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol, 3-((2-(((1R,2R)hydroxycyclohexyl)amino)benzo[d]thiazolyl)methyl)-3H- imidazo[4,5-b]pyridinecarbonitrile, 3-((2-((2-hydroxycyclohexyl)amino)benzo[d]thiazolyl)methyl)-3H-imidazo[4,5- b]pyridinecarbonitrile, 1-(3-((2-(((1R,2R)hydroxycyclohexyl)amino)benzo[d]thiazolyl)methyl)-3H- imidazo[4,5-b]pyridinyl)ethanone, 1-(3-((2-((2-hydroxycyclohexyl)amino)benzo[d]thiazolyl)methyl)-3H-imidazo[4,5- b]pyridinyl)ethanone, (((1R,2R)hydroxycyclohexyl)amino)benzo[d]thiazolyl)methyl)-N-methyl- 3H-imidazo[4,5-b]pyridinecarboxamide, 3-((2-((2-hydroxycyclohexyl)amino)benzo[d]thiazolyl)methyl)-N-methyl-3H- imidazo[4,5-b]pyridinecarboxamide, N-hydroxy((2-(((1R,2R)hydroxycyclohexyl)amino)benzo[d]thiazol yl)methyl)-3H-imidazo[4,5-b]pyridinecarboximidamide, (1R,2R)((6-((6-(aminomethyl)-3H-imidazo[4,5-b]pyridin yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol acetic acid, (1R,2R)((6-((6-(aminomethyl)-3H-imidazo[4,5-b]pyridin yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol, 2-((6-((6-(aminomethyl)-3H-imidazo[4,5-b]pyridinyl)methyl)benzo[d]thiazol yl)amino)cyclohexanol, 3-((2-(((1R,2R)hydroxycyclohexyl)amino)benzo[d]thiazolyl)methyl)-N,N- dimethyl-3H-imidazo[4,5-b]pyridinecarboxamide, 3-((2-((2-hydroxycyclohexyl)amino)benzo[d]thiazolyl)methyl)-N,N-dimethyl-3H- imidazo[4,5-b]pyridinecarboxamide, (1R,2R)((6-((6-(2H-tetrazolyl)-3H-imidazo[4,5-b]pyridin yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol, 2-((6-((6-(2H-tetrazolyl)-3H-imidazo[4,5-b]pyridinyl)methyl)benzo[d]thiazol yl)amino)cyclohexanol, (1R,2R)((6-((6-(2-methyl-2H-tetrazolyl)-3H-imidazo[4,5-b]pyridin yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol, 2-((6-((6-(2-methyl-2H-tetrazolyl)-3H-imidazo[4,5-b]pyridin yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol, (1R,2R)((6-((6-(1-methyl-1H-tetrazolyl)-3H-imidazo[4,5-b]pyridin yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol, ((6-(1-methyl-1H-tetrazolyl)-3H-imidazo[4,5-b]pyridin yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol, (1R,2R)((6-((6-ethynyl-3H-imidazo[4,5-b]pyridinyl)methyl)benzo[d]thiazol yl)amino)cyclohexanol, 2-((6-((6-ethynyl-3H-imidazo[4,5-b]pyridinyl)methyl)benzo[d]thiazol yl)amino)cyclohexanol, (1R,2R)((6-((6-morpholino-3H-imidazo[4,5-b]pyridin yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol, 2-((6-((6-morpholino-3H-imidazo[4,5-b]pyridinyl)methyl)benzo[d]thiazol yl)amino)cyclohexanol, (1R,2R)((6-((6-vinyl-3H-imidazo[4,5-b]pyridinyl)methyl)benzo[d]thiazol yl)amino)cyclohexanol, 2-((6-((6-vinyl-3H-imidazo[4,5-b]pyridinyl)methyl)benzo[d]thiazol yl)amino)cyclohexanol, N-((3-((2-(((1R,2R)hydroxycyclohexyl)amino)benzo[d]thiazolyl)methyl)-3H- imidazo[4,5-b]pyridinyl)methyl)acetamide, N-((3-((2-((2-hydroxycyclohexyl)amino)benzo[d]thiazolyl)methyl)-3H- imidazo[4,5-b]pyridinyl)methyl)acetamide, )((6-((5-bromo-1H-benzo[d]imidazolyl)methyl)benzo[d]thiazol no)cyclohexanol, 2-((6-((5-bromo-1H-benzo[d]imidazolyl)methyl)benzo[d]thiazol yl)amino)cyclohexanol, (1R,2R)((6-((6-ethyl-3H-imidazo[4,5-b]pyridinyl)methyl)benzo[d]thiazol yl)amino)cyclohexanol, 2-((6-((6-ethyl-3H-imidazo[4,5-b]pyridinyl)methyl)benzo[d]thiazol no)cyclohexanol, (1R,2R)((6-((6-(3-hydroxymethylbutynyl)-3H-imidazo[4,5-b]pyridin yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol; 2-((6-((6-(3-hydroxymethylbutynyl)-3H-imidazo[4,5-b]pyridin yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol; (1R,2R)((6-((5-(methylsulfonyl)-3H-imidazo[4,5-b]pyridin yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol; ((5-(methylsulfonyl)-3H-imidazo[4,5-b]pyridinyl)methyl)benzo[d]thiazol yl)amino)cyclohexanol; (1R,2R)((6-((6-bromo-1H-benzo[d]imidazolyl)methyl)benzo[d]thiazol yl)amino)cyclohexanol; 2-((6-((6-bromo-1H-benzo[d]imidazolyl)methyl)benzo[d]thiazol yl)amino)cyclohexanol; 1-((2-(((1R,2R)hydroxycyclohexyl)amino)benzo[d]thiazolyl)methyl)-1H- d]imidazolecarbonitrile; 1-((2-((2-hydroxycyclohexyl)amino)benzo[d]thiazolyl)methyl)-1H- benzo[d]imidazolecarbonitrile; (1R,2R)((6-((6-(2-hydroxypropanyl)-3H-imidazo[4,5-b]pyridin yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol; 2-((6-((6-(2-hydroxypropanyl)-3H-imidazo[4,5-b]pyridin yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol; 1-(1-((2-(((1R,2R)hydroxycyclohexyl)amino)benzo[d]thiazolyl)methyl)-1H- benzo[d]imidazolyl)ethanone; 1-(1-((2-((2-hydroxycyclohexyl)amino)benzo[d]thiazolyl)methyl)-1H- benzo[d]imidazolyl)ethanone; 1-((2-(((1R,2R)hydroxycyclohexyl)amino)benzo[d]thiazolyl)methyl)-1H- benzo[d]imidazolecarbonitrile; 1-((2-((2-hydroxycyclohexyl)amino)benzo[d]thiazolyl)methyl)-1H- benzo[d]imidazolecarbonitrile; (1R,2R)((6-((5-(methylsulfonyl)-1H-benzo[d]imidazol yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol; 2-((6-((5-(methylsulfonyl)-1H-benzo[d]imidazolyl)methyl)benzo[d]thiazol yl)amino)cyclohexanol; (1R,2R)((6-((6-(methylsulfonyl)-1H-benzo[d]imidazol yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol; 2-((6-((6-(methylsulfonyl)-1H-benzo[d]imidazolyl)methyl)benzo[d]thiazol yl)amino)cyclohexanol; (1R,2R)((6-((6-((R,S)hydroxyethyl)-3H-imidazo[4,5-b]pyridin yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol; 2-((6-((6-(1-hydroxyethyl)-3H-imidazo[4,5-b]pyridinyl)methyl)benzo[d]thiazol yl)amino)cyclohexanol; 2-(dimethylamino)(3-((2-(((1R,2R)hydroxycyclohexyl)amino)benzo[d]thiazol- ethyl)-3H-imidazo[4,5-b]pyridinyl)ethanone acetate salt; 2-(dimethylamino)(3-((2-((2-hydroxycyclohexyl)amino)benzo[d]thiazol yl)methyl)-3H-imidazo[4,5-b]pyridinyl)ethanone; 2-(dimethylamino)(3-((2-(((1R,2R)hydroxycyclohexyl)amino)benzo[d]thiazol- 6-yl)methyl)-3H-imidazo[4,5-b]pyridinyl)ethanone; (((1R,2R)hydroxycyclohexyl)amino)benzo[d]thiazol yl)methyl)imidazo[1,2-a]pyridinecarbonitrile; 3-((2-((2-hydroxycyclohexyl)amino)benzo[d]thiazolyl)methyl)imidazo[1,2- a]pyridinecarbonitrile; (1R,2R)((6-((5,6-dimethyl-1H-benzo[d]imidazolyl)methyl)benzo[d]thiazol yl)amino)cyclohexanol; 2-((6-((5,6-dimethyl-1H-benzo[d]imidazolyl)methyl)benzo[d]thiazol yl)amino)cyclohexanol; 1-(1-((2-(((1R,2R)hydroxycyclohexyl)amino)benzo[d]thiazolyl)methyl)-1H- d]imidazolyl)ethanone; 1-(1-((2-((2-hydroxycyclohexyl)amino)benzo[d]thiazolyl)methyl)-1H- benzo[d]imidazolyl)ethanone; (1R,2R)((6-((5-ethynyl-1H-benzo[d]imidazolyl)methyl)benzo[d]thiazol yl)amino)cyclohexanol; 2-((6-((5-ethynyl-1H-benzo[d]imidazolyl)methyl)benzo[d]thiazol yl)amino)cyclohexanol; (1R,2R)((6-((6-ethynyl-1H-benzo[d]imidazolyl)methyl)benzo[d]thiazol yl)amino)cyclohexanol; 2-((6-((6-ethynyl-1H-benzo[d]imidazolyl)methyl)benzo[d]thiazol yl)amino)cyclohexanol; (1R,2R)((6-((6-bromomethoxy-3H-imidazo[4,5-b]pyridin yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol; ((6-bromomethoxy-3H-imidazo[4,5-b]pyridinyl)methyl)benzo[d]thiazol- 2-yl)amino)cyclohexanol; 3-((2-(((1R,2R)hydroxycyclohexyl)amino)benzo[d]oxazolyl) methyl)-3H- imidazo[4,5-b]pyridinecarbonitrile; ((2-hydroxycyclohexyl)amino)benzo[d]oxazolyl) methyl)-3H-imidazo[4,5- b]pyridinecarbonitrile; 3-((2-(((1R,2R)hydroxycyclohexyl)amino)benzo[d]thiazolyl)methyl) methoxy-3H-imidazo[4,5-b]pyridinecarbonitrile; 3-((2-((2-hydroxycyclohexyl)amino)benzo[d]thiazolyl)methyl)methoxy-3H- imidazo[4,5-b]pyridinecarbonitrile; (1R,2R)((6-((5-methyl-1H-benzo[d]imidazolyl)methyl)benzo[d]thiazol yl)amino)cyclohexanol; 2-((6-((5-methyl-1H-benzo[d]imidazolyl)methyl)benzo[d]thiazol yl)amino)cyclohexanol; (1R,2R)((6-((5,6-difluoro-1H-benzo[d]imidazolyl)methyl)benzo[d]thiazol yl)amino)cyclohexanol; 2-((6-((5,6-difluoro-1H-benzo[d]imidazolyl)methyl)benzo[d]thiazol yl)amino)cyclohexanol; (1R,2R)((6-((5-fluoro-1H-benzo[d]imidazolyl)methyl)benzo[d]thiazolyl) amino)cyclohexanol; 2-((6-((5-fluoro-1H-benzo[d]imidazolyl)methyl)benzo[d]thiazolyl) amino)cyclohexanol; (1R,2R)((6-((5-(trifluoromethyl)-1H-benzo[d]imidazolyl) methyl)benzo[d]thiazolyl)amino)cyclohexanol; 2-((6-((5-(trifluoromethyl)-1H-benzo[d]imidazolyl) methyl)benzo[d]thiazol yl)amino)cyclohexanol; )((6-(imidazo[1,2-b]pyridazinylmethyl)benzo[d]thiazol yl)amino)cyclohexanol; 2-((6-(imidazo[1,2-b]pyridazinylmethyl)benzo[d]thiazolyl)amino)cyclohexanol; (1R,2R)((6-((6-fluoro-3H-imidazo[4,5-b]pyridinyl)methyl)benzo[d]oxazol yl)amino)cyclohexanol; 2-((6-((6-fluoro-3H-imidazo[4,5-b]pyridinyl)methyl)benzo[d]oxazol yl)amino)cyclohexanol; ((1R,2R)((6-((6-bromo-3H-imidazo[4,5-b]pyridinyl)methyl)benzo[d]thiazol yl)amino)cyclohexyl)methanol; 2-((6-((6-bromo-3H-imidazo[4,5-b]pyridinyl)methyl)benzo[d]thiazol yl)amino)cyclohexyl)methanol; (1R,2R)((6-((6-(1-methyl-1H-tetrazolyl)-3H-imidazo[4,5-b]pyridin yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol; 2-((6-((6-(1-methyl-1H-tetrazolyl)-3H-imidazo[4,5-b]pyridin yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol; (1R,2R)((6-((7-(2-hydroxyethoxy)imidazo[1,2-a]pyridin yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol; 2-((6-((7-(2-hydroxyethoxy)imidazo[1,2-a]pyridinyl)methyl)benzo[d]thiazol no)cyclohexanol; ((1S,2R)((6-((6-bromo-3H-imidazo[4,5-b]pyridinyl)methyl)benzo[d]thiazol yl)amino)cyclohexyl)methanol; ((6-bromo-3H-imidazo[4,5-b]pyridinyl)methyl)benzo[d]thiazol yl)amino)cyclohexyl)methanol; (1R,2R)((6-((5,6-dichloro-3H-imidazo[4,5-b]pyridinyl)methyl)benzo[d]thiazol- 2-yl)amino)cyclohexanol; 2-((6-((5,6-dichloro-3H-imidazo[4,5-b]pyridinyl)methyl)benzo[d]thiazol yl)amino)cyclohexanol; (1R,2R)((6-((5-ethoxy-1H-benzo[d]imidazolyl)methyl)benzo[d]thiazol yl)amino)cyclohexanol; 2-((6-((5-ethoxy-1H-benzo[d]imidazolyl)methyl)benzo[d]thiazol yl)amino)cyclohexanol; 3-((2-(((1R,2R)hydroxycyclohexyl)amino)benzo[d]thiazolyl)methyl)-3H- imidazo[4,5-b]pyridine-5,6-dicarbonitrile; 3-((2-((2-hydroxycyclohexyl)amino)benzo[d]thiazolyl)methyl)-3H-imidazo[4,5- b]pyridine-5,6-dicarbonitrile; 3-((2-(((1R,2R)(hydroxymethyl)cyclohexyl)amino)benzo[d]thiazolyl)methyl)- dazo[4,5-b]pyridinecarbonitrile; 3-((2-((2-(hydroxymethyl)cyclohexyl)amino)benzo[d]thiazolyl)methyl)-3H- imidazo[4,5-b]pyridinecarbonitrile; (1R,2R)((6-((6-(1H-pyrazolyl)-3H-imidazo[4,5-b]pyridin yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol; 2-((6-((6-(1H-pyrazolyl)-3H-imidazo[4,5-b]pyridinyl)methyl)benzo[d]thiazol no)cyclohexanol; (1R,2R)((6-(imidazo[1,2-b]pyridazinylmethyl)benzo[d]oxazol yl)amino)cyclohexanol; 2-((6-(imidazo[1,2-b]pyridazinylmethyl)benzo[d]oxazolyl)amino)cyclohexanol; 3-((2-(((1R,2R)hydroxycyclohexyl)amino)benzo[d]thiazolyl)methyl)-N- methylimidazo[1,2-b]pyridazinecarboxamide; 3-((2-((2-hydroxycyclohexyl)amino)benzo[d]thiazolyl)methyl)-N- methylimidazo[1,2-b]pyridazinecarboxamide; (1R,2R)((6-((6-(hydroxymethyl)imidazo[1,2-b]pyridazin yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol; 2-((6-((6-(hydroxymethyl)imidazo[1,2-b]pyridazinyl)methyl)benzo[d]thiazol yl)amino)cyclohexanol; (1R,2R)((6-((6-(1H-1,2,4-triazolyl)-3H-imidazo[4,5-b]pyridin yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol; 2-((6-((6-(1H-1,2,4-triazolyl)-3H-imidazo[4,5-b]pyridin yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol; (1R,2R)((6-((6-iodo-3H-imidazo[4,5-b]pyridinyl)methyl)benzo[d]thiazol yl)amino)cyclohexanol; 2-((6-((6-iodo-3H-imidazo[4,5-b]pyridinyl)methyl)benzo[d]thiazol no)cyclohexanol; 1-((2-(((1R,2R)hydroxycyclohexyl)amino)benzo[d]thiazolyl)methyl)-1H- d]imidazolol; 1-((2-((2-hydroxycyclohexyl)amino)benzo[d]thiazolyl)methyl)-1H- benzo[d]imidazolol; (1R,2R)((6-((5,7-difluoro-1H-benzo[d]imidazolyl)methyl)benzo[d]thiazol yl)amino)cyclohexanol; 2-((6-((5,7-difluoro-1H-benzo[d]imidazolyl)methyl)benzo[d]thiazol yl)amino)cyclohexanol; (1R,2R)((6-((5-(trifluoromethoxy)-1H-benzo[d]imidazolyl) methyl)benzo[d]thiazolyl)amino)cyclohexanol; 2-((6-((5-(trifluoromethoxy)-1H-benzo[d]imidazolyl) methyl)benzo[d]thiazol yl)amino)cyclohexanol; (1R,2R)((6-((6-methoxyimidazo[1,2-b]pyridazinyl)methyl) benzo[d]thiazol yl)amino)cyclohexanol; 2-((6-((6-methoxyimidazo[1,2-b]pyridazinyl)methyl) benzo[d]thiazol yl)amino)cyclohexanol; (1R,2R)((6-((5-methoxy-1H-benzo[d]imidazolyl)methyl)benzo[d]oxazol no)cyclohexanol; 2-((6-((5-methoxy-1H-benzo[d]imidazolyl)methyl)benzo[d]oxazol yl)amino)cyclohexanol; )((6-((6-methoxy-1H-benzo[d]imidazolyl)methyl)benzo[d]oxazol yl)amino)cyclohexanol; 2-((6-((6-methoxy-1H-benzo[d]imidazolyl)methyl)benzo[d]oxazol no)cyclohexanol; (1R,2R)((6-((7-(2-methoxyethoxy)imidazo[1,2-a]pyridin yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol; 2-((6-((7-(2-methoxyethoxy)imidazo[1,2-a]pyridinyl)methyl)benzo[d]thiazol yl)amino)cyclohexanol; 2-((6-((3H-imidazo[4,5-b]pyridinyl)methyl)fluorobenzo[d]thiazol yl)amino)cyclohexanol; (1R,2R)((6-((6-morpholinoimidazo[1,2-b]pyridazinyl)methyl)benzo[d]thiazol- 2-yl)amino)cyclohexanol; 2-((6-((6-morpholinoimidazo[1,2-b]pyridazinyl)methyl)benzo[d]thiazol yl)amino)cyclohexanol; (1R,2R)((4-chloro((6-morpholinoimidazo[1,2-b]pyridazin yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol; 2-((4-chloro((6-morpholinoimidazo[1,2-b]pyridazinyl)methyl)benzo[d]thiazol- 2-yl)amino)cyclohexanol; (1R,2R)((6-((6-chloroimidazo[1,2-b]pyridazinyl)methyl) benzo[d]thiazol yl)amino)cyclohexanol; 2-((6-((6-chloroimidazo[1,2-b]pyridazinyl)methyl) benzo[d]thiazol yl)amino)cyclohexanol; (1R,2R)((6-((6-(1H-pyrazolyl)imidazo[1,2-a]pyridin yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol; ((6-(1H-pyrazolyl)imidazo[1,2-a]pyridinyl)methyl)benzo[d]thiazol yl)amino)cyclohexanol; (1R,2R)((6-((5-(1H-pyrazolyl)-1H-benzo[d]imidazol yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol; 2-((6-((5-(1H-pyrazolyl)-1H-benzo[d]imidazolyl)methyl)benzo[d]thiazol yl)amino)cyclohexanol; (1R,2R)((6-((5-(1H-1,2,4-triazolyl)-1H-benzo[d]imidazol yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol; 2-((6-((5-(1H-1,2,4-triazolyl)-1H-benzo[d]imidazolyl)methyl)benzo[d]thiazol- 2-yl)amino)cyclohexanol; (1S,2R)((6-((6-fluoro-3H-imidazo[4,5-b]pyridinyl)methyl)benzo[d]thiazol yl)amino)cyclohexanol; 2-((6-((6-fluoro-3H-imidazo[4,5-b]pyridinyl)methyl)benzo[d]thiazol yl)amino)cyclohexanol; trans((6-((6-fluoro-3H-imidazo[4,5-b]pyridinyl)methyl)benzo[d]thiazol yl)amino)cyclohexanol; 4-((6-((6-fluoro-3H-imidazo[4,5-b]pyridinyl)methyl)benzo[d]thiazol yl)amino)cyclohexanol; 2-((6-((3H-imidazo[4,5-b]pyridinyl)methyl)fluorobenzo[d]thiazol yl)amino)cyclohexanol; (1R,2R)((6-((6-methoxyimidazo[1,2-a]pyridinyl)methyl)benzo[d]thiazol yl)amino)cyclohexanol; 2-((6-((6-methoxyimidazo[1,2-a]pyridinyl)methyl)benzo[d]thiazol yl)amino)cyclohexanol; 2-((6-((3H-imidazo[4,5-b]pyridinyl)methyl)bromobenzo[d]thiazol yl)amino)cyclohexanol; (1R,2R)((6-((7-(1H-pyrazolyl)imidazo[1,2-a]pyridin hyl)benzo[d]thiazolyl)amino)cyclohexanol; 2-((6-((7-(1H-pyrazolyl)imidazo[1,2-a]pyridinyl)methyl)benzo[d]thiazol yl)amino)cyclohexanol; 1-((2-(((1R,2R)hydroxycyclohexyl)amino)benzo[d]oxazolyl) methyl)-1H- benzo[d]imidazolecarbonitrile; ((2-hydroxycyclohexyl)amino)benzo[d]oxazolyl) methyl)-1H- benzo[d]imidazolecarbonitrile; (1R,2R)((6-((5-(2-morpholinoethoxy)-1H-benzo[d]imidazol yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol; 2-((6-((5-(2-morpholinoethoxy)-1H-benzo[d]imidazolyl)methyl)benzo[d]thiazol yl)amino)cyclohexanol; (1R,2R)((6-((5-(2-hydroxyethoxy)-1H-benzo[d]imidazol yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol; 2-((6-((5-(2-hydroxyethoxy)-1H-benzo[d]imidazolyl)methyl)benzo[d]thiazol yl)amino)cyclohexanol; 1-((2-(((1R,2R)hydroxycyclohexyl)amino)benzo[d]thiazolyl)methyl)-N-methyl- 1H-benzo[d]imidazolecarboxamide; 1-((2-((2-hydroxycyclohexyl)amino)benzo[d]thiazolyl)methyl)-N-methyl-1H- benzo[d]imidazolecarboxamide; (1R, 2R)((6-((5-(3,6-dihydro-2H-pyranyl)-1H-benzo[d]imidazol yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol; 2-((6-((5-(3,6-dihydro-2H-pyranyl)-1H-benzo[d]imidazol yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol; (1R,2R)((6-((5-(3,3,3-trifluoropropenyl)-1H-benzo[d]imidazol yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol; 2-((6-((5-(3,3,3-trifluoropropenyl)-1H-benzo[d]imidazol yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol; (1R,2R)((6-((6-bromoimidazo[1,2-b]pyridazinyl)methyl)benzo[d]thiazol yl)amino)cyclohexanol; 2-((6-((6-bromoimidazo[1,2-b]pyridazinyl)methyl)benzo[d]thiazol yl)amino)cyclohexanol; (1R,2R)((6-((6-(4-methylpiperazinyl)imidazo[1,2-b]pyridazin yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol; 2-((6-((6-(4-methylpiperazinyl)imidazo[1,2-b]pyridazin hyl)benzo[d]thiazolyl)amino)cyclohexanol; (trans((6-((6-fluoro-3H-imidazo[4,5-b]pyridinyl)methyl)benzo[d]thiazol yl)amino)cyclohexyl)methanol; -((6-((6-fluoro-3H-imidazo[4,5-b]pyridinyl)methyl)benzo[d]thiazol no)cyclohexyl)methanol; 4-((6-((6-fluoro-3H-imidazo[4,5-b]pyridinyl)methyl)benzo[d]thiazol yl)amino)cyclohexyl)methanol; 6-((6-fluoro-3H-imidazo[4,5-b]pyridinyl)methyl)-N-((1R,2R) (methylthio)cyclohexyl)benzo[d]thiazolamine; 6-((6-fluoro-3H-imidazo[4,5-b]pyridinyl)methyl)-N-(2- (methylthio)cyclohexyl)benzo[d]thiazolamine; (1R,2R)((6-((5-(oxetanyloxy)-1H-benzo[d]imidazol yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol; ((5-(oxetanyloxy)-1H-benzo[d]imidazolyl)methyl)benzo[d]thiazol yl)amino)cyclohexanol; (1R,2R)((6-((5-vinyl-1H-benzo[d]imidazolyl)methyl)benzo[d]thiazol yl)amino)cyclohexanol; 2-((6-((5-vinyl-1H-benzo[d]imidazolyl)methyl)benzo[d]thiazol yl)amino)cyclohexanol; (1R,2R)((6-((5-(cyclohexenyl)-1H-benzo[d]imidazolyl) methyl)benzo[d]thiazolyl)amino)cyclohexanol; 2-((6-((5-(cyclohexenyl)-1H-benzo[d]imidazolyl)methyl)benzo[d]thiazol yl)amino)cyclohexanol; (1R,2R)((6-((5-(1-methyl(trifluoromethyl)-1H-pyrazolyl)-1H- d]imidazolyl)methyl)benzo[d]thiazolyl)amino)cyclohexanol; 2-((6-((5-(1-methyl(trifluoromethyl)-1H-pyrazolyl)-1H-benzo[d]imidazol yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol; (1R,2R)((6-((5-fluoroimidazo[1,2-a]pyridinyl)methyl)benzo[d]thiazol yl)amino)cyclohexanol; 2-((6-((5-fluoroimidazo[1,2-a]pyridinyl)methyl)benzo[d]thiazol no)cyclohexanol; (1R,2R)((6-((7-morpholinoimidazo[1,2-a]pyridinyl)methyl)benzo[d]thiazol yl)amino)cyclohexanol; 2-((6-((7-morpholinoimidazo[1,2-a]pyridinyl)methyl)benzo[d]thiazol yl)amino)cyclohexanol; ((1R,2R)((6-((5,7-dimethyl-1H-benzo[d]imidazolyl)methyl)benzo[d]thiazol yl)amino)cyclohexanol; 2-((6-((5,7-dimethyl-1H-benzo[d]imidazolyl)methyl)benzo[d]thiazol yl)amino)cyclohexanol; (1R,2R)((6-((5-bromomethyl-1H-benzo[d]imidazol yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol; 2-((6-((5-bromomethyl-1H-benzo[d]imidazolyl)methyl)benzo[d]thiazol yl)amino)cyclohexanol; ((1R,3R)((6-((6-fluoro-3H-imidazo[4,5-b]pyridinyl)methyl)benzo[d]thiazol yl)amino)cyclohexyl)methanol; ((6-fluoro-3H-imidazo[4,5-b]pyridinyl)methyl)benzo[d]thiazol yl)amino)cyclohexyl)methanol; (1R,2S,3R)((6-((6-fluoro-3H-imidazo[4,5-b]pyridinyl)methyl)benzo[d]thiazol- 2-yl)amino)cyclohexane-1,2-diol; 3-((6-((6-fluoro-3H-imidazo[4,5-b]pyridinyl)methyl)benzo[d]thiazol yl)amino)cyclohexane-1,2-diol; ((1S,3R)((6-((6-fluoro-3H-imidazo[4,5-b]pyridinyl)methyl)benzo[d]thiazol yl)amino)cyclohexyl)methanol; 3-((6-((6-fluoro-3H-imidazo[4,5-b]pyridinyl)methyl)benzo[d]thiazol yl)amino)cyclohexyl)methanol; ro((2-(((1R,2R)hydroxycyclohexyl)amino)benzo[d]oxazolyl)methyl)- 1H-benzo[d]imidazolecarbonitrile; 6-chloro((2-((2-hydroxycyclohexyl)amino)benzo[d]oxazolyl)methyl)-1H- benzo[d]imidazolecarbonitrile; ((2-(((1R,2R)hydroxycyclohexyl)amino)benzo[d]thiazolyl)methyl)-1H- benzo[d]imidazolyl)oxy)acetonitrile; 2-((1-((2-((2-hydroxycyclohexyl)amino)benzo[d]thiazolyl)methyl)-1H- benzo[d]imidazolyl)oxy)acetonitrile; N-((1R,2R)chlorocyclohexyl)((6-fluoro-3H-imidazo[4,5-b]pyridin yl)methyl)benzo[d]thiazolamine; N-(2-chlorocyclohexyl)((6-fluoro-3H-imidazo[4,5-b]pyridin yl)methyl)benzo[d]thiazolamine; 1-(3-((2-(((1R,2R)hydroxycyclohexyl)amino)benzo[d]thiazol yl)methyl)imidazo[1,2-a]pyridinyl)piperidinol; 1-(3-((2-((2-hydroxycyclohexyl)amino)benzo[d]thiazolyl)methyl)imidazo[1,2- a]pyridinyl)piperidinol; 1-(3-((2-(((1R,2R)hydroxycyclohexyl)amino)benzo[d]thiazol yl)methyl)imidazo[1,2-a]pyridinyl)ethanone; 1-(3-((2-((2-hydroxycyclohexyl)amino)benzo[d]thiazolyl)methyl)imidazo[1,2- a]pyridinyl)ethanone; (1R,2R)((6-((7-(1-hydroxyethyl)imidazo[1,2-a]pyridin yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol; 2-((6-((7-(1-hydroxyethyl)imidazo[1,2-a]pyridinyl)methyl)benzo[d]thiazol no)cyclohexanol; 1-(3-((2-(((1R,2R)hydroxycyclohexyl)amino)benzo[d]thiazol yl)methyl)imidazo[1,2-a]pyridinyl)ethanone oxime; 1-(3-((2-((2-hydroxycyclohexyl)amino)benzo[d]thiazolyl)methyl)imidazo[1,2- a]pyridinyl)ethanone oxime; (1R,2R)((6-((5-bromofluoro-1H-benzo[d]imidazol yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol; 2-((6-((5-bromofluoro-1H-benzo[d]imidazolyl)methyl)benzo[d]thiazol yl)amino)cyclohexanol; 1-(3-((2-(((1R,2R)hydroxycyclohexyl)amino)benzo[d]thiazol hyl)imidazo[1,2-a]pyridinyl)ethanone O-methyl oxime; 1-(3-((2-((2-hydroxycyclohexyl)amino)benzo[d]thiazolyl)methyl)imidazo[1,2- a]pyridinyl)ethanone O-methyl oxime; 7-fluoro((2-(((1R,2R)hydroxycyclohexyl)amino)benzo[d]thiazolyl)methyl)- 1H-benzo[d]imidazolecarbonitrile; ro((2-((2-hydroxycyclohexyl)amino)benzo[d]thiazolyl)methyl)-1H- benzo[d]imidazolecarbonitrile; (1R,2R)((6-((7-fluorovinyl-1H-benzo[d]imidazolyl)methyl)benzo[d]thiazol- 2-yl)amino)cyclohexanol; 2-((6-((7-fluorovinyl-1H-benzo[d]imidazolyl)methyl)benzo[d]thiazol yl)amino)cyclohexanol; (1R,2R)((6-((5-(3,6-dihydro-2H-pyranyl)fluoro-1H-benzo[d]imidazol yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol; 2-((6-((5-(3,6-dihydro-2H-pyranyl)fluoro-1H-benzo[d]imidazol yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol; (1R,2R)((6-((5-morpholino-1H-benzo[d]imidazolyl)methyl)benzo[d]thiazol yl)amino)cyclohexanol; 2-((6-((5-morpholino-1H-benzo[d]imidazolyl)methyl)benzo[d]thiazol yl)amino)cyclohexanol; 1-(1-((2-(((1R,2R)hydroxycyclohexyl)amino)benzo[d]thiazolyl)methyl)-1H- benzo[d]imidazolyl)piperidinone; 1-(1-((2-((2-hydroxycyclohexyl)amino)benzo[d]thiazolyl)methyl)-1H- benzo[d]imidazolyl)piperidinone; (1R,2R)((6-((5-(1H-pyrazolyl)-1H-benzo[d]imidazol yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol; ((5-(1H-pyrazolyl)-1H-benzo[d]imidazolyl)methyl)benzo[d]thiazol yl)amino)cyclohexanol; (1R,2R)((6-((6-(trifluoromethyl)-3H-imidazo[4,5-b]pyridin yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol; 2-((6-((6-(trifluoromethyl)-3H-imidazo[4,5-b]pyridinyl)methyl)benzo[d]thiazol yl)amino)cyclohexanol; (1S,2S)((6-((6-fluoro-3H-imidazo[4,5-b]pyridinyl)methyl)benzo[d]thiazol yl)amino)cyclohexanol; 2-((6-((6-fluoro-3H-imidazo[4,5-b]pyridinyl)methyl)benzo[d]thiazol yl)amino)cyclohexanol; (1R,2R)((6-((7-(1H-imidazolyl)imidazo[1,2-a]pyridin yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol; 2-((6-((7-(1H-imidazolyl)imidazo[1,2-a]pyridinyl)methyl)benzo[d]thiazol yl)amino)cyclohexanol; (1R,2R)((6-((7-(2H-1,2,3-triazolyl)imidazo[1,2-a]pyridin yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol; 2-((6-((7-(2H-1,2,3-triazolyl)imidazo[1,2-a]pyridinyl)methyl)benzo[d]thiazol yl)amino)cyclohexanol; (1R,2R)((6-((7-vinylimidazo[1,2-a]pyridinyl)methyl)benzo[d]thiazol no)cyclohexanol; 2-((6-((7-vinylimidazo[1,2-a]pyridinyl)methyl)benzo[d]thiazol yl)amino)cyclohexanol; (1R,2R)((6-((7-(allyloxy)imidazo[1,2-a]pyridinyl)methyl)benzo[d]thiazol yl)amino)cyclohexanol; 2-((6-((7-(allyloxy)imidazo[1,2-a]pyridinyl)methyl)benzo[d]thiazol yl)amino)cyclohexanol; (1R,2R)((6-((7-(1H-1,2,3-triazolyl)imidazo[1,2-a]pyridin hyl)benzo[d]thiazolyl)amino)cyclohexanol; 2-((6-((7-(1H-1,2,3-triazolyl)imidazo[1,2-a]pyridinyl)methyl)benzo[d]thiazol yl)amino)cyclohexanol; N-((1R,2S)chlorocyclohexyl)((6-fluoro-3H-imidazo[4,5-b]pyridin yl)methyl)benzo[d]thiazolamine; N-(2-chlorocyclohexyl)((6-fluoro-3H-imidazo[4,5-b]pyridin yl)methyl)benzo[d]thiazolamine; (((1R,2R)hydroxycyclohexyl)amino)benzo[d]thiazol yl)methyl)imidazo[1,2-b]pyridazinecarbonitrile; 3-((2-((2-hydroxycyclohexyl)amino)benzo[d]thiazolyl)methyl)imidazo[1,2- b]pyridazinecarbonitrile; (E)(1-((2-(((1R,2R)hydroxycyclohexyl)amino)benzo[d]thiazolyl)methyl)-1H- benzo[d]imidazolyl)acrylic acid; (E)(1-((2-((2-hydroxycyclohexyl)amino)benzo[d]thiazolyl)methyl)-1H- d]imidazolyl)acrylic acid; 3-(1-((2-((2-hydroxycyclohexyl)amino)benzo[d]thiazolyl)methyl)-1H- benzo[d]imidazolyl)acrylic acid; (1R,2R)((6-((5-(1,2,3,6-tetrahydropyridinyl)-1H-benzo[d]imidazol yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol; 2-((6-((5-(1,2,3,6-tetrahydropyridinyl)-1H-benzo[d]imidazol yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol; (1R,2R)((6-((5-(1H-imidazolyl)-1H-benzo[d]imidazol yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol; 2-((6-((5-(1H-imidazolyl)-1H-benzo[d]imidazolyl)methyl)benzo[d]thiazol yl)amino)cyclohexanol; (1R,2R)((6-((5-(2-methyl-2H-tetrazolyl)-1H-benzo[d]imidazol hyl)benzo[d]thiazolyl)amino)cyclohexanol; 2-((6-((5-(2-methyl-2H-tetrazolyl)-1H-benzo[d]imidazol yl)methyl)benzo[d]thiazolyl)amino)cyclohexanol; (1S,2R,3R)((6-((6-fluoro-3H-imidazo[4,5-b]pyridinyl)methyl)benzo[d]thiazol yl)amino)cyclohexane-1,2-diol; 3-((6-((6-fluoro-3H-imidazo[4,5-b]pyridinyl)methyl)benzo[d]thiazol yl)amino)cyclohexane-1,2-diol; (1R,2S,3R)((6-((7-(1H-pyrazolyl)imidazo[1,2-a]pyridin yl)methyl)benzo[d]thiazolyl)amino)cyclohexane-1,2-diol; 3-((6-((7-(1H-pyrazolyl)imidazo[1,2-a]pyridinyl)methyl)benzo[d]thiazol yl)amino)cyclohexane-1,2-diol; (1R,2S,3R)((6-((5-methoxy-1H-benzo[d]imidazolyl)methyl)benzo[d]thiazol yl)amino)cyclohexane-1,2-diol; 3-((6-((5-methoxy-1H-benzo[d]imidazolyl)methyl)benzo[d]thiazol yl)amino)cyclohexane-1,2-diol; ,3R)((6-((7-(2H-1,2,3-triazolyl)imidazo[1,2-a]pyridin yl)methyl)benzo[d]thiazolyl)amino)cyclohexane-1,2-diol; 3-((6-((7-(2H-1,2,3-triazolyl)imidazo[1,2-a]pyridinyl)methyl)benzo[d]thiazol yl)amino)cyclohexane-1,2-diol; (1R,2S,3R)((6-((5-vinyl-1H-benzo[d]imidazolyl)methyl)benzo[d]thiazol yl)amino)cyclohexane-1,2-diol; 3-((6-((5-vinyl-1H-benzo[d]imidazolyl)methyl)benzo[d]thiazol no)cyclohexane-1,2-diol; (1R,2S,3R)((6-((5-(oxetanyloxy)-1H-benzo[d]imidazol yl)methyl)benzo[d]thiazolyl)amino)cyclohexane-1,2-diol; 3-((6-((5-(oxetanyloxy)-1H-benzo[d]imidazolyl)methyl)benzo[d]thiazol yl)amino)cyclohexane-1,2-diol; (1R,2S,3R)((6-((6-(1H-1,2,4-triazolyl)-3H-imidazo[4,5-b]pyridin yl)methyl)benzo[d]thiazolyl)amino)cyclohexane-1,2-diol; 3-((6-((6-(1H-1,2,4-triazolyl)-3H-imidazo[4,5-b]pyridin yl)methyl)benzo[d]thiazolyl)amino)cyclohexane-1,2-diol; (1R,2S,3R)((6-((5-morpholino-1H-benzo[d]imidazolyl)methyl)benzo[d]thiazol- mino)cyclohexane-1,2-diol; 3-((6-((5-morpholino-1H-benzo[d]imidazolyl)methyl)benzo[d]thiazol yl)amino)cyclohexane-1,2-diol; (1R,2S,3R)((6-((5-(2-methyl-2H-tetrazolyl)-1H-benzo[d]imidazol yl)methyl)benzo[d]thiazolyl)amino)cyclohexane-1,2-diol; and 3-((6-((5-(2-methyl-2H-tetrazolyl)-1H-benzo[d]imidazol yl)methyl)benzo[d]thiazolyl)amino)cyclohexane-1,2-diol.

13. A pharmaceutical composition comprising a nd of any of claims 1-12 and a pharmaceutically acceptable carrier.

14. The use of a compound of any one of claims 1-12 in the manufacture of a medicament for treatment of a disease selected from an inflammatory disease, an inflammatory condition, an autoimmune disease and , wherein the treatment comprises administering a therapeutically effective amount of the compound.

15. The use of claim 14, wherein the disease is modulated by CSF1R, FLT3, KIT, and/or PDGFRβ kinase.

16. The use of claim 14, wherein the disease is modulated by wild type or mutant CSF1R, FLT3, KIT, and/or PDGFRβ kinase.

17. The use of a compound of any one of claims 1-12 in the manufacture of a medicament for the treatment of a disease, wherein the treatment comprises administering a therapeutically effective amount of the compound, and wherein the disease is selected from myeloproliferative disorder (MPD), myelodysplastic syndrome (MDS), themia vera (PCV), essential thrombocythemia (ET), primary myelofibrosis (PMF), chronic eosinophilic leukemia (CEL), chronic myelomonocytic leukemia (CMML), systemic ytosis (SM), idiopathic myelofibrosis (IMF), myeloid ia, chronic myeloid leukemia (CML), imatinib-resistant CML, acute myeloid leukemia (AML), acute megakaryoblastic ia (AMKL), lymphoma, Hodgkin's lymphoma, lymphoblastic leukemia, myeloma, multiple myeloma, cancer of the head and neck, te cancer, breast cancer, ovarian cancer, endometrial cancer, melanoma, lung cancer, brain cancer, d cancer, stomach , gastrointestinal stromal tumor, colorectal cancer, pancreatic cancer, renal cancer, non-small cell lung cancer, bone cancer, tenosynovial giant cell tumors, glioblastoma multiforme, atherosclerosis, restenosis, obliterative bronchiolitis, idiopathic myelofibrosis, obesity, obesity-induced n resistance, hypercalcemia of malignancy, lupus nephritis, glomerular nephritis, idiopathic hypereosinophilic syndrome, chronic eosinophilic syndrome, systemic ytosis, hans cell histiocytosis, 's sarcoma, multiple endocrine neoplasia, immunodeficiency, autoimmune diseases, tissue transplant rejection, graft-versus-host disease, wound, kidney disease, multiple sclerosis, thyroiditis, type 1 diabetes, sarcoidosis, psoriasis, ic rhinitis, inflammatory bowel disease including Crohn’s e and ulcerative colitis (UC), ic lupus erythematosis (SLE), cutaneous lupus erythematosis, arthritis, osteoarthritis, rheumatoid arthritis, psoriatic tis, osteoporosis, endometriosis, asthma, allergic asthma, ankylosing litis, chronic obstructive pulmonary disease (COPD), Alzheimer’s disease and multiple sclerosis.

18. The use of any one of claims 14-17, n the treatment further comprises administering a second pharmaceutical agent selected from anti-proliferative agent, antiinflammatory agent, immunomodulatory agent and immunosuppressive agent.

19. The use of a compound of any one of claims 1-12 in the manufacture of a medicament for use in ting a CSF1R, FLT3, KIT, and/or PDGFRβ .

20. The use of a compound of any of claims 1-12 in the manufacture of a medicament for treating a disease selected from an inflammatory disease, an inflammatory condition, an autoimmune disease and cancer.

21. A compound according to claim 1, substantially as herein described or exemplified.

22. A ceutical composition according to claim 13, substantially as herein described or exemplified.

23. A use according to claim 14, substantially as herein described or exemplified.

24. A use according to claim 17, substantially as herein described or exemplified.

25. A use ing to claim 19, substantially as herein described or exemplified.

26. A use according to claim 20, substantially as herein described or exemplified.