AU2016329075A1

AU2016329075A1 - Combinations of the BTK inhibitor GS-4059 with inhibitors selected from a JAK, ASK1, BRD and/or MMP9 inhibitor to treat cancer, allergic disorders, autoimmune diseases or inflammatory diseases

Info

Publication number: AU2016329075A1
Application number: AU2016329075A
Authority: AU
Inventors: Jamie BATES; David Breckenridge; Julie Di Paolo; Daniel Tumas
Original assignee: Gilead Sciences Inc
Current assignee: Gilead Sciences Inc
Priority date: 2015-10-02
Filing date: 2016-09-30
Publication date: 2018-04-26
Also published as: CA3000746A1; EP3355871A1; TW201726130A; JP2018534263A; WO2017059252A1; JP2021014466A; HK1258762A1

Abstract

Provided herein are methods that relate to a therapeutic strategy for treatment of cancer, and allergic, autoimmune, and inflammatory disorders including hematological malignancies. In particular, the methods include administration of a BTK inhibitor and with one or more inhibitor. For example, the one or more inhibitor may be a JAK inhibitor, a ASK1 inhibitor, a BRD4 inhitibor or an MMP9 inhibitor.

Description

FIELD OF THE INVENTION [6601] The present disclosure relates generally to therapeutics and compositions for treating cancers and allergic, autoimmune, and inflammatory disorders, and more specifically to the use of Bruton’s Tyrosine Kinase (ΒΪΚ) inhibitors (hereinafter refered to BTK or Btk inhibitors) in combination with one or more agent which modulates Janus Kinase (JAK), Apoptosis signal-regulating kinase 1 (ASKI), bromodomain-containing proteins, or matrix metailopeptidases 9 (MMP9).

BACKGROUND [6002] BTK inhibitors useful in treating cancers such as hematological cancers and inflammatory conditions include those taught in U.S, Pat, No, 8,940,725 (Yamamoto et al.)_s U.S, 2014/0330015 Yamamoto et al.) and U.S. Pat. No.

7,514,444 (Honigberg et ah), [6063] Janus Kinase (JAK) inhibitors are known in the art, including momelotinib, pefictiinib, tofaciiinih, oclacitinib, ruxolitinib, baracitinib, lestaurtinib, paeritinib, fiigotinib, TGI01348, JS-124, and INCB39110, CHZ868, and GSK2586184. There remains a need for beneficial combination therapies. [6064] Mitogen-activated protein kinase (MAFK) signaling cascades couple diverse extracellular and intracellular queues to appropriate cellular stress responses, including cell .growth, differentiation, inflammation, and apoptosis (Kumar, S„ Boehm, J,, and Lee,, J. C. (2003) Nat. Rev, Drug. Dis, 2:717-726; Pimienta, G., and Pascual, J, (2007) Cell Cycle, 6: 2826-2632). MAPKs exist in three groups, M AlBKs, MAP2Ks, and. MAPKs, which are sequentially activated. MAPKSs directly respond to environmental signals and phosphorylate MAP2Ks, which in turn phosphoiylate specific MAPKs. MAPKs then mediated the appropriate cellular response by phosphoryiating cellular substrates, including transcription factors that regulate gene expression.

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Apoptosis signal regulating kinase 1 (ASKI) is a member of the mitogenactivated protein kinase kinase kinase (“MAP3K”) family that activates the c-j'un N-terminal protein kinase (“INK”) andp38 MAP kinase, (l'chijo, H._e et al. (1997) Science, 275. 90-94). ASK) is activated by a variety of stimuli including oxidative stress, reactive oxygen species (ROS), LPS,'TNP-a, Fast, ER stress, and increased intracellular calcium concentrations {Hattori, K., et al. (2009) Cell Comm. Signal. 7:1-10; Takeda, K., et al, (2007) Atmu. Rev, Pharmacal. Toxicol. 48: 1-8.27; Nagai, IL, et al. (2007) J. Biochem. Mol. Biol, 40; 1-6). ASKI 'undergoes activation via autophosphorylation at Thr838 in response io these signals and in turn phosphorylates MAP2Ks, such as MKK3/6 and MKK4/7, which (hen phosphorylate and activate p38 and INK MAPKs, respectively.

ASK2 is a related MAP3K that shares 45% sequence homology with ASKI (Wang, X. S., et al. (1998) Biochem. Biophys. Res. Commun, 253, 53-37, Although ASK2 tissue distribution is restricted, in some cell types ASKI andASK2 have been reported to interact and function together in a protein complex (Takeda. K., et al. (.2007) I. Bioi. Chem, 282: 7522 -7531; Iriyama, T., et ah (2009) Emho J. 28: 843-853) hi non-stressed conditions, A SKI is kept in an inactive state through binding to its repressor Thioredoxin (Trx) (Saitoh, M., et aid 1998) Embo J. 17:2596-2606), and through association with ART (Zhang, L., Chen, J. and Ftp H. (1999) Proe. Nai Acad. Sci. U.S.A 96:8511-8515). Phosphorylation of ASKI protein can lead to apoptosis or 30 other cellular responses depending on the eel! type. ASKI activation and signaling have been reported to play an important role in a broad range of diseases including neurodegenerative, cardiovascular, inflammatory, autoimmunity, and metabolic disorders. In addition, ASKi has been implicate in mediating organ damage following ischemia and reperiusion of the heart, brain, and kidney (Watanabe et ah (2005) BBRC333, 562-567; Zhang et ah, (2003) Life Sci 74-37-43; Terada et al. (2007)BBRC 364: 1043-49). Emerging evidence suggests that ASK2, either alone or in a complex with ASKI, may play important roles in human diseases as well. Therefore, therapeutic agents that function as inhibitors of ASKI and ASR2 signaling complexes have the potential to remedy or improve the lives of patients suffering from such conditions. U.S, Publication No. 2007/0276050 describes

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PCT/US2016/054780 methods for identifying A SKI inhibitors useful for preventing and/or treating cardiovascular disease and methods for preventing and/or treating cardiovascular disease in an animal. The methods comprise administering to the animal an ASK! 30 inhibitor and, optionally, a hypertensive compound, U.S. Publication No, 2007/0167386 reports a drug for at least one of prevention and treatment of cardiac failure containing a compound that inhibits a functional expression of ASK.1 protein in a cardiomyocyie, and a method for screening the drug. W02009027283 discloses triazolopyridine compounds, methods for preparation thereof and methods for treating autoimmune disorders, inflammatory diseases, cardiovascular diseases and neurodegenerahve diseases, U.S, Patent Nos. 8,552,196 and 8,742,126 teach ASK1 inhibiting compounds useful as pharmaceutical agents.

[6006] BET or BRD inhibitors are a class of drugs with anti-cancer, immunosuppressive, and other effects demonstrated in clinical trials arid widely used in research. They reversibly bind the bromodomains of Bromodomain and Extra-Terminal motif (BET) proteins BRD2, BRP3, BR.D4 and BRDT and prevent protein-protein interaction between BET proteins and aeetylated histones and transcription factors. Bromodomain inhibitors include the benzimidazole derivatives taught, in US 2014-0336190, [0007] Abnormal activity of certain MMPs plays a role in tumor growth, metastasis, inflammation, autoimmunity, and vascular disease. See, for example, Hu et al, (2007) Nature Reviews: Drug Discovery 6:480-498, One notable source of MMP9 is tumor-associated macrophages (TAMs), which support metastasis and invasion in a complex co-activation loop via paracrine interaction with the primary tumor cells. This combination of the proteolytic breakdown of physical barriers to ceil invasion plus liberation of factors that activate growth and angiogenesis paves the way for tumor expansion, with the accompanying development of neovascularization to support tumor outgrowth.

[0008] MMP9 is a target of oncogenic signaling pathways such as RAS/RAF, PI3K/AKT/NFkB, and WNT/beta-catenin and functions as an upstream regulator of these pathways via modulation of integrin and receptor tyrosine kinase function. MMP9 is also expressed by subsets of stromal cells (e.g, vasculature,

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fibroblasts) and tumor-associated infiltrating cells, including myeloid-derived suppressor cells, macrophages and neutrophils. MMP9 is elevated in a wide variety of tumor types and MMP9 levels are correlated with poor prognosis in many cancers, including gastric, lung, and colorectal cancer. MP9 is also implicated in chemoresistance and is upregulated upon loss of several tumor suppressors. MMP9 is upregulated in many diverse tumor types and can promote primary growth and distal invasion of cancerous ceils.

{0009] it can be desirable to inhibit the activity of one or more MMPs in certain therapeutic settings. However, the acti vity of certain oilier MMPs, e.g,, MMP2, is often required for normal function and/or is protective against disease. Since most MMP inhibitors are targeted to the conserved catalytic domain and, as a result, inhibit a number of different MMPS, use of available MMP inhibitors has caused side effects due to the inhibition of essential, nompathogenicaily-related MMPs. Useful MMP9 inhibitors include the antibodies and fragments disclosed in U.S. 2015-0140580 (Smith et at) and U.S. Patent Nos, 8,377,443 (McAuley el al.), 8,501,916 (McAuley et ah), and 9,120,863 (McAuley et ah).

10010] There remains a need for additional treatments for cancers.

BRIEF SUMMARY (0011] Provided herein are methods for treating cancers, allergic disorders, autoimmune diseases and inflammatory diseases that involve the administration of a BTK inhibitor in combination with one or more inhibitor selected from the group consisting of a JAK inhibitor, a ASK inhibitor, a BRD inhibitor, and a MMP9 inhibitor, hi some embodiments, the BTK. inhibitor is 6-amino-9-i(3R)-l(2-butynoyl)^3-pytrolidinyl]-7-(4-phenoxyphenyl)”7,9'-dihydro-8H-purin~8~one₅or a pharmaceutically acceptable salt or 'hydrate thereof. In. some variations, the BTK inhibitor is a hydrochloride salt of •6-amino~9-[(3R)-l-(2“butyhoylj3p>'Tro1idinyl]-7-(4”phenoxyphenyl)-7,9-dihydrO“8[l“purin-8-one, ora pharmaceutically acceptable hydrate thereof [0012] in some aspects, provided is a method for treating cancer in a human in need thereof, comprising administering to the human a therapeutically effective

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amount of a BTK inhibitor and a. therapeutically effective amount of a JAK inhibitor.

[0013] In some embodiments, the JAK inhibitor is selected from the group of momelotinih, peficitinib, tofacitinib, ociacitinib, ruxolitmib, baraeitinib, lestaurtinib, pacritinib, filgotinib, 1 -[ 1 -[[3-fluoro-2-(trifluoromethyl)~4pyridinyI]-4-piperidinyl]-3~i4-(7i/pyrrolo[2,3-<^pynnidin-4-yl)»lH»pyrazal»lyl}-3-azetidineacetonitrile, TG101348, JS-124, INCB39110, INCB16562, CHZ868, VX-509, XL019, NVP-BSK.80S, CEP33779, R-348, AC-430, CDPR723, BMS91.1543, GSK2586184, or a pharmaceutically acceptable salt or hydrate thereof. In some aspects, provided is a method for treating cancer in a human in need thereof comprising administering to the human a therapeutically effective amount of a BTK inhibitor and a therapeutically effective amount of a ASK inhibitor. In some embodiments, the ASK inhibitor is selected from the group of Compound CI, Compound C2. or the compound of Formula (I).

In some aspects, provided is a method for treating cancer in a human in need thereof comprising administering to the human a therapeutically effective amount of a BTK inhibitor and a therapeutically effective amount of a BRD inhibitor, in some embodiments, the BRD inhibitor is the compound of Formula (II).In some aspects, provided is a method for treating cancer in a human in need thereof compri sing administering to the human a therapeutically effective amount of a BTK inhibitor and a therapeutically effective amount of an MMP9 inhibitor..in some embodiments., the MMP9 inhibitor is MMP9 binding proteins, e.g., antibodies and antigen-binding fragments thereof that bind to the matrix metalloproteinase-9 (MM.P9) protein (MMP9 is also known as gelatinase-B), wherein the binding proteins comprise an immunoglobulin (Ig) heavy chain (or functional fragment thereof) and an Ig light chain (or functional fragment thereof). In certain embodiments, the MMP9 inhibitor comprises the amino acid sequence sefeued from the group consisting of SEQ ID NOs: 3,4, and 5-12, Provided herein are also articles of manufacture and kits that, comprise the BTK inhibitor and one or more inhibitor selected from a JAK inhibitor, a ASK inhibitor, a BRD inhibitor, and a MMP9 inhibitor. Also provided herein are methods comprising a BTK inhibitor and one or more inhibitor selected from a

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--6 JAK inhibitor, a ASK inhibitor, -a BRI.) inhibitor, and a MMP9 inhibitor for the use in therapy or in the manufacture of a medicament for cancer treatment.

BRIEF DESCRIPTION OF THE DRAWINGS [0014] FIG. 1 provides a chart of Mean & SE Ankle Diameter for a rat collageninduced arthritis model conducted using Compound Al and tofacitinib.

[0015] FIG, 2: depicts a heat map representing the percent of D'LBCL cell growth inhibition for every pairwise combination of Compound Ai and a BET inhibitor 6-aminO“9“[(3R.)-l-(2-butynoyl)-3-pyrro1idinyI]-7-(4-phenoxyphenyi)·· 7.9-dihydro-8Hpurin-8-one (Compound D) from one representative experiment [0016] FIG, 3: depicts a heatmap of the calculated Bliss excess over predicted additivity for every pairwise combination using the percent growth inhibition shown in: FIG. 2, [0017] FIG. 4: depicts the average percent cell growth inhibition relative to a DMSO control (n^:::3) for DLBCL cells treated with a dilution series of Compound D either alone or in the presence of 5.5 nM or 11 nM of Compound Al,

DETAILED DESCRIPT ION [0018] The following description sets forth exemplary methods, parameters and the like, it should be recognized, however, that such description is not intended as a limitation on the scope of the present disclosure but is instead provided as a description of exemplary embodiments. Provided are methods, compositions (including pharmaceutical compositions, formulations, or unit dosages), articles of manufacture-and kits comprising a BTK inhibitor and one or more inhibitor selected from a JAK inhibitor, a .ASK inhibitor, -a B'RD inhibitor, and a MMP9 inhibitor.

[0019] Combinations of pharmaceutically effective amounts of the ΒΪΚ inhibitor and one or more inhibitor selected from a JAK inhibitor, a ASK inhibitor, a BRD inhibitor, and a MMP9 inhibitor as described heroin may be used to treat cancers, allergic disorders, autoimmune diseases and inflammatory diseases in a human, the method comprising administering to the human in need

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PCT/US2016/054780 '7 thereof a pharmaceutically effective amount of the BTK inhibitor, cr a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically effective amount of one or more inhibitor selected from a JAK inhibitor, a ASK inhibitor, a BRD inhibitor, and a. MM.P9 inhibitor. The combinations taught herein may be used for the treatment of allergic disorders, autoimmune diseases and inflammatory diseases such as: systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), multiple vasculitides, idiopathic thrombocytopenic purpura (FTP), myasthenia gravis, allergic rhinitis, chronic obstructive pulmonary disease (COPD), adult respiratory distress syndrome ( ARDs) and asthma. The combinations taught herein may be used for the treatment of cancers such as hematologic malignancy, leukemia, lymphoma chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), non-Hodgkin’s lymphoma, indolent non-Hodgkin’s lymphoma (iNHL), refractory iNHL, mantle cell lymphoma, follicular lymphoma (EL), lymphoplasmacytic lymphoma, and marginal zone lymphoma.

Definitions [0020] A dash at the front or end of a chemical group is a matter of convenience; chemical groups may he depicted with or without one or more dashes without, losing their ordinary meaning, A wavy line drawn through a line in a structure indicates a point of attachment of a group. A dashed line indicates an optional bond. Unless chemically or structurally required, no directionality is indicated or implied by the order in which a chemical group is written. For instance, the group “-SOjCHr” is equivalent to “-ClUSiU” and both may he connected in either direction.. The prefix “CfoA indicates that the following group lias from u to v carbon atoms, one or more of which, in certain groups (e,g, heteroalkyl, heteroaryl, heteroarylalkyl, etc,), may be replaced with one or more heteroatoms or heteroatomic groups. For example, “C alkyl” indicates that the alkyl group has from l ίο 6 carbon atoms, [6021] Also, certain commonly used alternative chemical names may or may not be used. For example, a divalent group such as a divalent “alkyl” group, a divalent “aryl” group, etc., may also be referred to as an “alkylene” group or an “alkylenyl” group, an “arylene” group or an “aryienyl” group, respectively.

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- 8 [0022) “Alkyl” refers io any aliphatic hydrocarbon group, i.e. any linear, branched, cyclic, or spiro nonaromatie hydrocarbon group or an isomer or combination thereof. As used herein, the terra “alkyl” includes terms used in the art to describe saturated and uasaturated aliphatic hydrocarbon groups with one or more points of attachment, including alkenyl (an aliphatic group containing at least one carbon-carbon double bond), alkylene (a divalent aliphatic group), alkynyl (an aliphatic group containing at least one carbon-carbon triple bond), cycloalkyl (a cyclic aliphatic group), alkylcycloalkyl (a linear or branched aliphatic group attached to a cyclic aliphatic group), and the like. Alkyl groups include, but are not limited to, methyl; ethyl; propyls such as propan-l-yl, propan-2-vi (iso-propyl), and cycioptopyls such as cyclopropan-l-yl, etc.; butyls such as botan-l-yl, butan-2-yl (see-butyl), 2-methyl-propan-l-yl (iso-butyl), 2-methyi-propan-2-yl (t-butyi), eyelobutan-l-yi; butenes (e.g. (£)-but-2-ene, (2)-but-2-ene); pentyls; pentenes; hexyls; hexenes; octyls; decyls; cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylcyclohexyl, spiro[2.4]heptyl, and the like, An alkyl group comprises from 1 to about 10 carbon atoms, e.g., from 1 to 6 carbon atoms. In some embodiments, alkyl is a monovalent, linear or branched, satura ted aliphatic hydrocarbon group comprising from I to about 10 carbon atoms, e.g., from 1 to 6 carton atoms.

[0023] “Alkenyl” is a subset of “alkyl” and refers ίο an alipha tic group containing at least one carbon-carbon double bond and having from 2 to about 10 carbon atoms, e.g., from 2 to 6 carbon atoms or 2 to 4 carbon atoms and having at least one site of vinyl unsaturation (>C^::: C<). Alkenyl groups include ethenyl, propenyi, 1,3-butadienyl, and the like,. Alkynyl may have from 2 to about 10 carbon atoms, e,g. from 2 to 6 carbon atoms or 2 to 4 carbon atoms.

[0024] “Alkynyl” is a subset of “alkyl” and refers to an aliphatic group containing at least one carton-carton triple bond. The term “alkynyl” is also meant to include those groups having one tripie bond and one double bond.

[0025] “Alkoxy” refers to the group -O-aikyl, wherein the alkyl group may be optionally substituted. Alkoxy includes, by way of example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy, sec-butoxy, and n-pentoxy.

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.. ί)..

(0026] “Acyl” refers to a group -Ci’^:;:O)R, where R is hydrogen, alkyl, cycloalkyl, cycloheteroalkyi, aryl, arylalkyl, heieroalkyl, heteroaryl or heteroarylalkyl as defined herein, each of which may he optionally substituted, as defined herein. Representative examples include, but are not limited to formyl, acetyl, cylcohexylcarbonyl, cyclohexylmethyf-carbonyl, benzoyl, benzyloxycarbonyl and the like.

(0027] “ Amido” refers to both a “C-amido” group which refers to the group t ! P mean \ it ' <>io mwlu i'l'Ki's o Ik <> oup-NR^yC{M3)R^z, wherein R^y and R.“ are independently sdefred troro the group consisting of hydrogen, alkyl, aryl, heteralkyl, heieroaryl (each of which may be optionally substituted), and where R^y and R’ are optionally joined together with the nitrogen or carbon hound thereto to form an optionally substituted heterocycloaikyl.

[0028] “Amino” refers to the group -NR/R* wherein R^y and R^z are independently selected from the group consisting of hydrogen, alkyl, aryl, heteralkyl, heieroaryl (each of which may be optionally substituted), and where R^y and R^z are optionally joined together with the nitrogen bound thereto to form a heterocycloaikyl or heieroaryl heteroaryl (each of which may be optionally substituted), [0029] “Amidine” refers to the group Al(^:::NR^x)NR^yR^z where R\ R^y, and R’ are independently selected from the- group consisting of hydrogen, alkyl, aryl, heteralkyl, heieroaryl (each of which may be optionally substituted), and where R^y and R are optionally joined together with the nitrogen bound thereto to form a heterocycloaikyl or heieroaryl (each of which may be optionally substituted). [0038] “Aryl” refers to a group with one or more aromatic rings, ft may be a single aromatic ring or multiple aromatic rings which are fused together, linked covalently, or linked via one or more such as a methylene or ethylene moiety.

Aryl groups include, but are not limited io, those groups deri ved from acenaphthylene, anthracene, azulene, benzene, biphenyl, chrysene, cyclopentadienyl anion, diphenyhnethyl, fluoranthene, fluorene, indane, indene, naphthalene, perylene, phe-nalene, phenanthrene, pyrene, triphenylene, and the like. An aryl group comprises from 5 to about 20 carbon atoms, e.g., from 5 to

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- 10 20 carbon atoms, e.g. from 5 to 10 carbon atoms. In some embodiments, ary] is a a single aromatic ring or multiple aromatic rings which are fused together, [0031] “Arylaikyl” (also “aralkyl”) refers io an aryl group attached to an alkyl group. Arylaikyl groups include, but are not limited to, benzyl, tolyl, dimethvlphenyl, 2-phenylethan -1 -yl, 2-naphthylmethyl, 2-naphthyiethan-1 -yl, naphthobenzyl, phenylvinyl, diphenylmethyl, and the like. For example, the “arylaikyl” may be attached to the rest of the compound of formula (I) through die aryl group. Alternatively, the “arylaikyl” may be attached to the rest of the compound of formula (I) through the alkyl group. Where specific alkyl moieties are intended, the nomenclature arylalkanyl, arylalkenyl and/or arylalkynyl may be used. An arylaikyl group comprises from 6 to about 30 carbon atoms, e.g. the alkyl portion of the arylaikyl group can comprise from 1 to about 10 carbon atoms and the aryl portion of the arylaikyl group can. comprise from 5 to about 20 carbon atoms. In some instances an arylaikyl group comprises from 6 to about 20 carbon atoms, e.g. the alkyl portion of the arylaikyl group can comprise from 1 to about 10 carbon atoms and the aryl portion of the arylaikyl group can comprise from 5 to about 10 carbon atoms.

[0032] “Aryloxy” refers to the group -O-aryl, including by way of example, phenoxy and naphthoxy.

[0033] “Azido” refers to the group -N3.

[0034] “Boronic acid” refers to the group -B(OH)>.

[0035] Boronic acid ester” refers to an ester derivative of a boronic acid compound. Suitable boronic acid ester derivatives include those of the formula B(()R)₂ where R is hydrogen, alkyl, aryl, arylaikyl, heteroaikyl, or heteroaryl, each of which may be optionally substituted. For example, boronic acid ester may be pinaeol ester or catechol ester.

[003hJ “Cafbocycle or “carbocyclyl” refers to a saturated, partially unsaturated or aromatic ring having 3 to 7 carbon atoms as a monocycle, 7 to 12 carbon atoms as a bicycle, and up to about 20 carbon atoms as a polycycle, Monocyclic carbocycles have 3 to 6 ring atoms, still more typically 5 or 6 ring atoms.

Bicyciic carbocycles have 7 to 12 ring atoms, e.g., arranged as a bicyclo (4,5), (5,5), (5,6) or (6,6) system, or 9 or 10 ring atoms arranged as a bicyclo (5,6) or

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PCT/US2016/054780 (6,6) system. Carbocycles includes aromatic and non-aromatic mono··, bi-, and poly-cyclic rings, whether fused, bridged, or spiro. Non-limiting examples of monocyclic carbocycles include the cycloalkyls group such as cyclopropyl, cyclobulyl, cyclopentyl, 1-cyclopent-l-enyi, l-cyclopent-2-enyl, l-cyclopent-3enyl, cyclobexyl, 1-cyclohex-l-enyk l-cyclohex-2-enyl, l-cyclohex-3-enyl or aryl groups such as phenyl, and the like. Thus, “carbocycle, as used herein, encompasses but is not limited to “aryl”, “phenyl” and “biphenyl.” [8037] “Carbamoyl” refers to the group ~C(O)NR.ⁱR.^z where R^y and R7 are defined as in “amino” above.

[0038] “Carbonyl” refers to the divalent group -€(())- which is equivalent to -C(^:::O)-, [0()39] “Carboxyl” or “carboxy” refers to -COOH or salts the’ ·οί [(Midi)] “Carboxyl ester” or “carboxy ester” refers, to the groups -C(O)OR, wherein R is. hydrogen, alkyl, aryi, arylalkyk heteroalkyl, or heteroaryl, each of which may be optionally substituted. In one embodiment, R is alkyl, aryl, arylalkyk heteroalkyl, or heteroaryl, each of which may be optionally substituted. [0041] “ Cyano” or “carboriitrile” refen to the group -CN.

[0042] “Cycloalkyl is a subset < >f “alkyl” and refers to a saturated or partially saturated cyclic group of from 3 to about If) carbon atoms and no ring heteroatoms and having a single ring or multiple rings including fused, bridged, and spiro ring systems. For multiple ring systems having aromatic and nonaromatic rings that have no ring heteroatoms, the term “cycloalkyl” applies when the point of attachment is at. a non-aromatic carbon atom (e.g., 5,6,7,8,tetrahydronaphthalene-5-yl). The term “cycloalkyl” includes cycloalkenyl groups. Examples of cycloalkyl groups include, for instance, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyk and cyclohexenyi.

[0043] “Guanidino” refers to the group -NKCfeNHfNffe.

[0044] “Halo” or “halogen” refers to fluoro, chloro, bromo and iodo.

[0045] “Haloalkyl” refers io substitution of alkyl groups with 1 to 5 or, in some embodiments, I to 3 halo groups, e.g,, -CFECl, -CHjF, ~CH2.Br, -CFClBr, C.H2C.H2CI, ~C.H2C.H2F5 CFs, “CH2CF5, -CiCCCfe and the like, and further

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includes those alkyl groups such. as perfiuorpalkyl hi which ail hydrogen atoms are replaced by fluorine atoms, [0Q46] “Haloaryl” refers to aryl groups with one or more halo or halogen substituents, For example, haloaryl groups include phenyl groups in which from 1 to 5 hydrogens are replaced with a halogen, Haloaryl groups include, for example, fluorophenyl, difluorophenyl, triiluorophenyl, chlorophenyl,, dorofitjorophenyl, and the like.

[0047] “Heteroalky 1” refers to an alkyl group in which one or more of the carbon atoms (and any associated hydrogen atoms) are each independently replaced with the same or different heteroatom or heteroatomic group. For example, heteroalkyl may include 1, 2 or 3 heteroatomic groups, e.g. I heteroatomic group. Heteroatoms include, but are not limited to, N, P, O, S, etc,. Heteroatomic groups include, but are not limited to, -NR.-, -O-, -S-, -PH-, -P/Ofr-, -8(0)-, -8(0)2-, and the like,.where R is 11 alkyl, aryl, cycloaikyl, heteroalkyl,.heteroaryi or cycloheteroalkyl. The term “heteroalkyl” includes heterocydoalkyl (a cyclic heteroalkyl group), alkyl-heterocycloalkyl (a linear or branched aliphatic group attached to a cyclic heteroalkyl group), and the like. Heteroalkyl groups include, but are not limited to, -OCI1?, -CH2OCH3, -SCife, CHjSCHj, -NRCH3, CH2NRCH3, and the like, where R is hydrogen, alkyl, aryl, arylalkyl, heteroalkyl, or heteroaryl, each of which may be optionally substituted. A heteroalkyl group comprises from 1 to about 10 carbon and hetero atoms, e.g., from 1 to 6 carbon and hetero atoms.

[0048] ‘Tfeteroaryl” refers to an aryl group in which, one w more of the carbon atoms (and any associated bvdrogen atoms) are each independently replaced with the same or different hi u' >. t< m , as defined above. For example, heteroaryi may include 1,2 or 3 heteroatomic groups, e.g. 1 heteroatomic group. Heteroaryi groups include, but are not limited to, groups derived from acridine, henzoimidazole, benzothiophene, benzofuran, benzoxazole, benzothiazole, carbazole, carboline, cinnoline, furan, imidazole, imidazopyridine, indazole, indole, indoline, indolizine, isobenzofuran, isochromene, isoindole, isoindolme. isoquinoJine, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, perimidine, phenandiridine, phenanthroline, phenazine, phthalazine, pteridine,

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purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolizine, quinazoline, quinoline, quinolizine, quinoxaline, tetrazole·, thiadiazole, thiazole, thiophene, friazole, xanthene, and the like, A heteroaryl group comprises from 5 to about 20 carbon and hetero atoms in the ring or rings, e.g., from 5 to 20 carbon and hetero atoms, e.g. from 5 to 10 carbon and hetero atoms.

[00491 “Heteroarylalkyl” refers to an arylalkyl group in which one or snore carbon atoms (and any associated hydrogen atoms) are independently replaced with the same or different heteroatoms, as defined above. For example, heleroarylalkyl may include 1,2 or 3 heteroatomic groups,Heteroarylalkyl groups include, but are no limited to, groups derived from heteroaryl groups with alkyl substituents (e.g. methylpyridine·, dirocthylisoxaxoM etc.), hydrogenated heteroaryl groups (dihydroquinelines, e.g. 3,4-dshydroquinoline, dihydroisoquinolines, e.g, 1,2-dihydroisoquinoline, dihydroimidazole, tetrahydroimidazole, etc.), isoindoline, isoindolones (e.g. isoindolin-l-one), dihydrophthalazine, quinolinone, spiro[cyclopropane-l,lMsomdolin]-3'-one, di(pyridm~2-yl)methyl, di(pyridin-:Uyl)methyl, di(pyridin-4-yl)methyl, and the like. A heteroarylalkyl group comprises from 6 to about 30 carbon and hetero atoms, for example from 6 to about 20 carbon and hetero atoms,

10050] “Beterocycloalkyl” is a subset of “heteroalkyl” and refers to a saturated or unsaturated eydoalkyi group in which one or more carbon atoms (and any associated hydrogen atoms) are independently replaced with the same or different heteroatom. Heteroatoms include, but are not limited to, N, P, O, S, etc, A heterocycloalkyl group may also contain a charged heteroatom or group, e.g., a quatemized ammonium group such as -Ν·ΗΚ)2- wherein R is alkyl, e.g.. methyl, ethyl, etc, Heterocycloalkyl groups include, hut are not limited to, groups derived from epoxide, imidazolithne, morpholine, piperazine, piperidine, pyrazolidine, piperidine, pyrrolidine, pyrrolidinone. tetrahydrofuran, tetrahydrothiophene, dihydropyridine, teteahydn >py ndine, quinuclidine, Nbromopyrrohdine,N-bromopiperidme, N-chloropyrrolidine, N-chloropiperidine, an Ν,Ν-dialkylpyrroHdinium, such, as hyNwliniethyipyrrolidinium, a N,Ndialkylpiperidinium such as Ν,Ν-dimethylpvperidium, and the like. The

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PCT/US2016/054780 heterocyeioalkyi -group comprises from 3 to about 10 carbon and hetero atoms in the ring or rings. In some embodiments, heterocyeioalkyi includes 1,2 or 3 heteroatomic groups, [0051] “.Heterocycle” or “heterocyclyl” as used herein, includes by way of example and not limitation those heterocycles described in Paquette. Leo A,;

Benjamin, New York,

1968), particularly Chapters 1, 3,4,6, 7, and 9; The.Chennrini.<Hsterocy^ Compounds, A Series of Monographs” (John Wiley & Sons, New York, 1950 to present), in particular Volumes 13,14,16,19, and 28; and J, Am. Chem. Soc. (1960) 82:5566. In one specific embodiment of the invention “heterocycle” includes a “carbocycle” as defined herein, wherein one or more (e.g. 1,2, 3, or 4) carbon atoms have been replaced with a heteroatom (e.g. Q, N, P or S), The terms “heterocycie” or “heterocyclyl” includes saturated rings, partially unsaturated rings, and aromatic rings (i,c., heteroaromatic: rings), Heterocycles includes aromatic and non-aromatic mono-, bi-, and poly-cyclic rings, whether fused, bridged, or spiro. As used herein, the term “heterocycie” encompasses, but is not limited to “heteroaryl.Substituted heterocyelyis include, for example, heterocyclic rings substituted with any of the substituents disclosed herein including carbonyl groups. Examples of heterocycles include by way of example and not limitation pyridyl, dihydroypyridyl. tetrahydropyridyl (piperidyl), thiazolyi, tetrahydrothiophenyl, sulfur oxidized tetrahydrothiophenyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzoftiranyi, thianaphthalenyi, indoiyl, indolenyl, quinolinyl, isoquinolinyl, henzimidazolyl, pipsridinyl, 4~piperidonyl, pyrrolidinyl, azetidinyl, 2pyrrolidonyl, pyrrolinyl, teirahydrofuranyl, tetrahydroquinolmyl, tetrahydroisoquinolinyl, decahydroquinolinyl, octahydroisoquinolinyl, azoeinyl, triazinyl, 6HH,2,5-thiadiazinyi, 2H,6H-l,5,2-dithiazmyl, thienyl, thianthrenyl, pyranyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxathinyl, IH-pyrrolyi, isothiazolyl, isoxazolyi, pyrazinyl, pyridazinyl. indolizinyl, isoindolyl, 3Hindoiyl, IH-indazoly, purinyl, 4H-quinolizinyl, phthaiazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, 4aH-cafbazolyl, carbazolyl, βcarbolinyl, phenantbridinyl, aeridinyl, pyrimidinyl, phenanthrolinyl, phenazinyl,

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PCT/US2016/054780 · 15phenothiazinyl, fttrazanyl, phenoxazinyl, isoehrananyl, chtomanyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperazinyl, indolinyl, isoindolinyl, quinuclidinyl, marpholinyl, oxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, isatinoyl, and bis-tetrahydrofuranyi. [0052) By way of example and not limitation, carbon bonded heterocycles are bonded at position 2, 3, 4, 5, or 6 of a pyridine, position 3,4, 5, or 6 of a pyridazine, position 2,4, 5,, or 6 of a pyrimidine, position 2, 3, 5, or 6 of a pyrazine, position 2,3,4, or 5 of a furan, tetrahydroftran, thiofuran, thiophene, pyrrole or tetrahydropyrrole, position 2,4, or 5 of an oxazole, imidazole or thiazole, position 3,4, or 5 of an isoxazole, pyrazole, or isothiazole, position 2 or 3 of an aziridine, position 2,3, or 4 of an azetidine, position 2, 3,4, 5,6, 7, or 8 of a quinoline or position 1,3, 4, 5,6, 7, or 8 of an isoquinoline; Still more typically, carbon bonded heterocyeles include 2~pyridyl, 3-pyridyl, 4-pyridyl, 5pyridyl, 6-pyridyl, 3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl, 6-pyridazinyl, 2» pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyi, 2-pyrazinyl, 3pyrazinvf, 5-pyrazinyi, 6-pyrazinyl, 2-thiazolyl, 4-thiazolyl, or 5-thiazolyl. By way of example and not limitation, nitrogen bonded heterocyeles are bonded at position 1 of m 4,iodine, mumme. pjrrHe p)n.»iidiue. 2 λOne, e-nwiobne imidazole, imidazolidine, 2-imidazoline, 3-imidazolme, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline, IH-indazole, position 2 of a isoindole, or isoindoline, position 4 of a morpholine, and position 9 of a carbazole, or β-carboline. Still more typically, nitrogen bonded heterocyeles include 1-aziridyl, '1-azetedyl, 1-pyrrolyl, 1-imidazoiyl, l-pyrazolyl, and 1-ptperidinyl.

[0053] “Hydrasano” refers to the group -N'HNH;;.

[0054] “’Hydroxy” or “hydroxyl” refers to the group -OH, [0055] “Imino” refers to the group -C(=^;NR)- wherein R is hydrogen, alkyl, aryl, arylalkyl, heteroalkyl, or heteroatyl, each of which may foe optionally substituted. [0056] ‘ ‘Nitro” refers to the group -NO?.

[0057] The terms “optional” or “optionally” mean that the subsequently described event or circumstance may but need not occur, and that the description

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- 16 · includes instances where the event or circumstance occurs and instances in which it does not.

[0058] “Oxide” refers to products resulting from the oxidation of one or more heteroatoms. Examples include N-oxides, sulfoxides, and sulfones,

10059] “Oxo” refers to a double-bonded oxygen (=0), In compounds where an oxo group is hound to an sp‘ nitrogen atom, an N-oxide is indicated.

[0060] “Racemates” refers to a mixture of enantiomers.

[0061 ] “Stereoisomer” or “stereoisomers” refer to compounds that differ in the chirality of one or more stemocenters Stereoisomers include enantiomers and diastereomers. The compounds may exist in stereoisomeric form if they possess one or more asymmetric centers or a double bond with asymmetric substitution and, therefore, can be produced as individual stereoisomers or as mixtures.

Unless otherwise indicated, the description is intended to include individual stereoisomers as well as mixtures. The methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art (see, e.g·, Chapter 4 of Advanced Organic Chemistry. 4th ed,. J. March, John Wiley and Sons, New York, 1992).

[0062] “Substituted” (as in, e.g., “substituted alkyl”) refers io a group wherein one or more hydrogens have been independently replaced with one or more substituents including, but not limited to, alkyl, alkenyl, alkynyl, alkoxy, acyl, amino, amido, amidino, aryl, azido, carbamoyl, carboxyl, carboxyl ester, cyano, guanidine, halo, haloalkyl, heteroalkyl, heteroaryl, heterocycloalkyl, hydroxy, hydraz.ino, hydroxyl, imino, oxo, nitro, sulfinyl, sulfonic acid, sulfonyl, thiocyanate, thiol, thione, or combinations thereof, Polymers or similar indefinite structures arrived at by defining substituents with further substituents appended ad infinitum (e.g., a substituted aryl having a substituted alkyl which is itself substituted with a substituted aryl group, which is further substituted by a substituted heteroalkyl group, etc.) are not intended for inclusion herein. Unless otherwise noted, the maximum number of serial substitutions in compounds described herein is three. For example, serial substitutions of substituted aryl groups with two other substituted aryl groups are limited to -substituted aryi“(substiluted aryl)-substituted aryl. For example, in some embodiments,

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PCT/US2016/054780 ·· Π when a group described above as being “optionally substituted” is substituted, that substituent is itself unsubstituted. Similarly, it is understood that the above definitions are not intended to include impermissible substitution patterns'(e.g., methyl substituted with 5 fluoro groups or heteroaryl groups having two adjacent oxygen ring atoms). Such impermissible substitution patterns are well known to the skilled artisan. When used to modify a chemical group, the term “substituted” may describe other chemical groups defined herein. For example, the term “substituted aryl” includes, but is not limited to, “arylalkylGenerally, substituted groups will have 1 to 5 substituents, 1. to 3 substituents, 1 or 2 substituents or 1 substituent. Alternatively, the optionally substituted groups of tht iwtjttoi m.n !» mbvhsu med.

[()063) “Sulfonyl” refers to the divalent group -SfO);-, [6064) “Tautomer”' refers to alternate forms of a compound tha t differ in the position of a proton, such as enol-keto and imine-enamine tautomers, or the tautomeric forms of heteroaryl groups containing a ring atom attached to both a ring -NH- moiety and a ring moiety such as pyrazoles, imidazoles, benzimidazoles, triazoles, and tetrazoles.

[0065) “Thiocyanate” refers to the group -SCN.

[0066] “Thiol” refers to the group -SH.

[0067) Thione” refers to a thioketone US) group.

[0068) “Pharmaceutically acceptable’' refers to compounds, salts, compositions, dosage forms and other materials which are useful in preparing a pharmaceutical composition that is suitable for veterinary or human pharmaceutical use.

(0069) “Pharmaceutically acceptable salt” refers to a salt of a compound that is pharmaceutically acceptable and that possesses (or can be converted to a form that possesses) the desired pharmacological activity of the parent compound.

Such salts include acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric add, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic add, citric acid, ethanesulfonic acid, fhmarie acid, glucoheptonic acid, gluconic acid, lactic acid, maleic acid, malonic acid, mandelic acid, methane-sulfonic acid, 2-napththalenesulfonic acid, oleic acid,

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PCT/US2016/054780 ·· : S · palmitic acid, propionic acid, stearic acid, succinic add, tartaric acid, ptoluenesuifonic acid, trimetbylacetic acid, and the like, and salts formed when an acidic proton present in the parent compound is replaced by either a metal ion, e.g,, an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with, an organic base such as diethanolamine, triethanolamine, Nmethylglucamine and the like. Also included in ibis definition are ammonium and substituted or quatemized ammonium salts. Representative non-limiting lists of phaimaoeutically acceptable salts can be found in S.M. Berge et ah, J, Pharma Sci., <>6{ I), 1.-1911977), and Remington: The Science and Practice of Pharmacy, R. Hendrickson, ed., 21st edition, Lippincott, Williams & Wilkins, Philadelphia, PA, (2005), at p. 732, Table 38-5., both of which are hereby incorporated byreference herein, [0970j The following abbreviations may also be:used: AcGl-ί: acetic acid; riBuLt: u-buiyllithium; CC: column diromatography; CsjCOy cesium carbonate; CII2CI2 or DCM: dichloromethane; CHjMgl: methyl magnesium iodide; CuCl?.: copper chloride; DAST: (diethylamino)sulfur trifluoride·; DEAD: diethyl azodicarboxylate; DIBAL: diisobutylaluminum hydride; DIPEA;

diisopropylethylamine; DMF: dimethylforrnamide; DMSO: dimethyl sulfoxide; EriN: tri ethylamine; EtOAc; ethyl acetate; EtOH: ethanol; g: gram(s); h: hour;

Hy hydrogen; HBr; hydrogen bromide; HC1: hydrogen chloride; H2O: water; H2O2: hydrogen peroxide; HPLC: high performance liquid chromatography; KCN: potassium cyanide; LHMDS: lithium hexamethyldisilazide; LiAlHj: lithium aluminum hydride; LiOH: lithium hydroxide; M: molar; MeCN: acetonitrile; Mei: methyl iodide; MeOH: methanol; MgSO₄: magnesium sulfate; MgCCfy magnesium carbonate; mg: millilgram; MsCF mesyl chloride; mmol: millimoles mL: milliliter; sodium hydrogen sulfite; mCPBA: metacbloroperoxybenzoic acid; N: normality; Ny nitrogen; NujCOj: sodium carbonate; NaHCOy sodium bicarbonate; NaNOy sodium nitrite; NaOH: sodium hydroxide; Na_::>S_:?Oy sodium bisulfate; NgjSOy sodium sulfate; NBS: Nbromosuccinimide; NH4CI: ammonium chloride; NI-LOAc: ammonium acetate; NMR: nuclear magnetic resonance; Pd/C: palladium on carbon; PPky triphenyl

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PCT/US2016/054780 ~ τυ phosphine; iPrO'H; isopropyl alcohol; RT; room temperature; SOCT: thionyl chloride; THF: tetrahydroforan; 11..(/ thin layer chromatography; al.·: microliter, [0(171] It is understood that combinations of chemical groups may be used and will be recognized by persons of ordinary skill in the art. For instance, the group “hydroxyalkyl” would refer to a hydroxyl group attached to an alkyl group. A great number of such combinations may be readily envisaged.

[00721 Compounds of a given formula described herein encompasses the compound disclosed and all pharmaceutically acceptable salts, esters, stereoisomers, tautomers, prodrugs, solvates, and deuterated forms thereof, unless otherwise specified.

[0073] “Effective amount” or “therapeutically effective amount” means the amount of a compound or molecule described herein that may be effective to elicit the desired biological or medical response. These terms include the amount of a compound that, when administered to a subject for treating a disease, is sufficient to effect such treatment for the disease. The effective amount will vary depending on the compound, the disease and its severity and the age, weight, etc., of the subject to be treated.

[0074| In another aspect, provided herein is a method for treating a human who is “refractory” to a cancer treatment or who is in “relapse” after treatment for cancer (e,g., a hematologic malignancy). A subject “refractory” to an anti-cancer therapy means they do not respond to the particular treatment, also referred to as resistant. The cancer may he resistant to treatment from the beginning of treatment, or may become resistant during the comse of treatment, for example after the treatment has shown some effect on the c.uu e«, but not enough to be considered a remission or partial remission. A subject in “relapse” means that the cancer has returned :or the signs and symptoms of cancer have retunred after a period of improvement, e.g, after a treatment has shown effective reduction in the cancer, such as after a subject is in remission or partial remission, [0075] In some variations, the human is (i) refractory io at least one anti-cancer therapy, or (ii) in relapse after treatment with at least one anti-cancer therapy, or both (i) and (ii). In some of embodiments, the human is refractory to at least two,

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PCT/US2016/054780 •20at least three, or at least four anti-cancer therapies (including, for example, standard or experimental chemotherapies).

[00761 “Subject” and “subjects” refer to human in need thereof may he an individual who has or is suspected of having a cancer, in some of variations, the human is at risk, of developing a cancer (e.g., a human who is genetically or otherwise predisposed to developing a cancer) and who has or has not been diagnosed with the cancer. As used herein, an “at risk” subject is a subject who is at risk of developing cancer (e.g., a hematologic malignancy). The subject may, or may not have detectable disease, and may or may not have displayed detectable disease prior to the treatment methods described herein. An at risk subject may have one or more so-called risk factors, which are measurable parameters that correlate with development of cancer, such as described herein, A subject having one or more of these risk factors has: a higher probability of developing cancer than an individual without, these risk: factor(s). These risk factors may include, for example, age, sex, race, diet, history of previous disease, presence of precursor disease, genetic (e.g., hereditary) considerations, and environmental exposure. In some embodiments, a human at risk tor cancer includes, for example, a human whose relatives have experienced this disease, and those whose risk is determined by analysis of genetic or biochemical markers. Prior history of having cancer may also be a risk factor for instances of cancer recurrence [0077] As used herein, “treatment” or “treating” is an approach for obtaining beneficial or desired results including clinical results. Beneficial or desired clinical results may include one or more .of the following:

(j) inhibiting the disease or condition (kg., decreasing one or more symptoms resulting from the disease or condition, and/or diminishing the extent of the disease or condition);

(ii) slowing or arresting the development of one or more- clinical symptoms associated with the disease or condition (e.g., stabilizing the disease or condition, preventing or delaying the worsening or progression of the disease or condition, and/or preventing or delaying the spread (e.g., metastasis) of the disease or condition): and/or

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PCT/US2016/054780 (iii) relieving the disease, that is, causing the regression of clinical symptoms (e.g., ameliorating the disease state, providing partial or iota) remission of the disease or condition, enhancing effect of another m· On anon, delaying the progression of the disease, increasing the quality or life, and/or prolonging survival).

[0078) In some variations, “delaying” the development of a disease or condition, means to defer, hinder, slow, retard, stabilize, anchor postpone development of the disease or condition. This delay can be of varying length s of time, depending on the history of the disease or condition, and/or subject being treated. For example, a method that “delays” development of a disease or condition is a method that reduces probability of disease or condition development in a given time frame and/or reduces the extent of the disease or condition in a given time frame, when compared to not using the method. Such comparisons are typically based on clinical studies, using a statistically significant number of subjects. •Disease or condition development can be detectable using standard methods, such as routine physical exams, mammography, imaging, or biopsy. Development may also refer to disease or condition progression that may be initially undetectable and includes occurrence, recurrence, and onset.

[0079] [0080] Reference to “about” a value or parameter herein includes (and. describes) embodiments that are directed to that value or parameter per se. In certain embodiments, the term “about” includes the indicated amount ± 10%. In other embodiments, the term “about⁵ includes the indicated amount + 5%. In certain other embodiments, the term ‘‘about” includes the indicated amount v }%, Also, to the term “about X” includes description of “Τ’, Also, the singular forms a and the include plural references unless the context clearly dictates otherwise. Thus, e.g., reference to the compound includes a plurality of such compounds and reference to the assay includes reference to one or more assays and equivalents thereof known to those skilled in the art.

Antibodies

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PCT/US2016/054780 . 22 [0081] As used -herein, the term antibody means an isolated or recombinant polypeptide binding agent that, comprises peptide sequences (c.g., variable region sequences) that specifically bind an antigenic epitope. The term is used in its broadest sense and specifically covers monoclonal antibodies (including fulllength monoclonal antibodies), polyclonal antibodies, human antibodies, humanized antibodies, chimeric antibodies, nanobodies, diabodies, multispecific antibodies (e.g., bispecific antibodies), and antibody fragments including but not limited to Fv, scFv, Fab, Fab' F(ab')₂ and Fab?., so long as they exhibit the desired biological activity. The term “human antibody” refers to antibodies containing sequences of human origin, except for possible non-human CDR regions, and does not imply that the full structure of an immunoglobulin molecule be present, only that the antibody has minimal immunogenic effect, in. a human (/. e., does not induce the production of antibodies, to itself).

[0082] An “antibody fragment” comprises a portion of a full-length antibody, for example, the antigen binding or variable region of a full-length antibody, Such antibody fragments may also be referred to herein as “functional fragments: or “antigen-binding fragments”. Examples of antibody fragments include Fab, Fab’, F(ab'>2, and Fv fragments: diabodies; linear antibodies (Zapata etoi. (1995) Protein Etig. 8(30): 1057-3062); single-chain antibody molecules; and multispecific antibodies formed from antibody fragments. Papain digestion of antibodies produces two identical antigen-binding fragments, called Fab” fragments, each with a single antigen-binding site, and a residual Fc fragment, a designation reflecting the ability to crystallize readily. Pepsin treatment yields an ,F(ab'>₂ fragment that has two antigen combining sites and is still capable of cross-linking antigen.

[00831 ”Fv is the minimum antibody fragment which contains a complete antigen-recognition and -binding site. This region consists of a dimer of one heavy- and one light-chain variable domain in tight, non-covalent association. It is in this configuration that the three coroplementarity-deiermining regions (CDRs) of each variable domain interact to define an antigen-binding site on the surface of the Vn-Vi, dimer. Collectively, the six CDRs confer antigen-binding specificity to the antibody. However, even a single variable domain (or an

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- 23 isolated V» or V), region comprising only three of the six CDRs specific for an antigen) has the ability to recognize and hind antigen, although generally at a lower affinity than does the entire F), fragment, (0084] The ^UF₈)>” fragment also contains, in addition to heavy and light chain variable regions, the constant domain of the light chain and the first constant domain (CH)) of the heavy chain. Fab fragments were originally observed following papain digestion of an antibody. Fab¹ fragments differ from Fab hugmefos in that F(ab') fragments contain several additional residues at the carboxy ternuuus of the heavy chain CH j domain, including one or mors cysteines from the antibody hinge region. F(ab')2 fragments contain two Fab fragments joined, near the binge region, by disulfide bonds, and were originally observed following pepsin digestion of an antibody. Fab-SH is the designation herein for Fab' fragments in which the cysteine residue(s) of the constant domains bear a free thiol group. Other chemical couplings of antibody- fragments are also known.

(0085( The light chains” of antibodies (immunoglobulins) from any vertebrate species can he assigned to one of two dearly distinct types, called kappa and lambda, based on the amino acid sequences of their constant domains.

Depending on the amino acid sequence of the constant domain of their heavy chains, immunoglobulins can be assigned to five major classes: IgA, IgD, IgE, IgG, and IgM, and several of these may be further divided into subclasses (isotypes), e.g., IgGl, IgG2, lgG3, IgG4, IgAl, and IgA2.

[0086( Single-chain Fv or sFv or “scFv antibody fragments comprise the Y); and Vi. domains of antibody, wherein these domains are present in a single polypeptide chain. In some embodiments, the Fv polypeptide further comprises a polypeptide linker between the Vn and V), domains, which enables the sFv to fbnn the desired structure for antigen binding. For a review of sFv, see Pluckthun, in /’fo Ph»nmxofoyvnt l fouw/«ufo frmfra/ii.x vol. 113 (Rosenborg and Moore eds.) Springer-Verlag, New York, pp. 269-315 (1994).

[0087( The term diabodies refers to small antibody fragments with two antigen-binding sites, which fragments comprise a beavy-chain variable domain (V'h) connected ίο a light-chain variable domain (Vf.) in the same polypeptide

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-24chain (Vfi-Vij. By using a linker that js too short to allow pairing between the two domains on the same chain, the domains are forced to pair with the complementary domains of another chain, thereby creating two antigen- binding sites. Diabodies ate additionally described, tor example, in EP 404,097; WO 93/1 1 163 and Hollinger t?/ al. (.1993) Proc. Natl. Acad. Sci. USA 90:6444-6448. [0088] An isolated” antibody is one that, has been identified and separated and/or recovered from a component of its natural environment. Components of its natural environment may include enzymes, hormones, and other proteinaceous or nonproteinaceous solutes. In some embodiments, an isolated antibody is purified (1) to greater than 95% by weight of antibody as determined by the Lowry method, for example, more than 99% by weight. (2) to a degree sufficient to obtain at least 15 residues of N-terminal or internal amino acid, sequence, e.g, by use of a spinning cup sequenator, or (3) to homogeneity by gel electrophoresis (e.g., SDS-PAGE) under reducing or nonreducing'conditions, with detection by Coomassie blue or silver stain. The term isolated antibody” includes an antibody in situ within recombinant cells, since at least one component of the antibody's natural environment will not be present. In certain embodiments, isolated antibody is prepared by at least one purification step.

[0089] As used herein, “immunoreactive” refers io antibodies or fragments thereof that are specific to a sequence of amino acid residues (“binding site” or “epitope”), yet if are cross-reactive to other peptides/proteins, are not toxic at the levels at which they are formulated for administration to human use. Epitope” refers to that portion of an antigen capable of forming a binding .interaction with an antibody or antigen binding fragment thereof. An epitope can be a linear peptide sequence (i.e., “continuous”) or can be composed of noncontiguous amino acid sequences (i.e., “conformational” or “discontinuous”). The term preferentially binds” means that the binding agent binds to the binding site with greater affinity than it hinds unrelated amino acid sequences.

[0090] As used herein, the term CDR or complementarity determining region is intended to mean the non-contiguous antigen combining sites found within the variable region of both heavy and light chain polypeptides. These particular regions have been described by Rabat et ah, I Biol, Chem. 252:6609SUBSTITUTE SHEET (RULE 26)

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6616 (1977); Rabat etal., ILS. Dept, of Health and Human Services, Sequences of proteins of immunological interest” (1991); by Chothia et ai., J, Mol. Biol. 196:901-917 (1987); and MacCailum et ai, J. Md. Bio). 262:732-745 (1996), where the definitions include overlapping or subsets of amino acid residues when compared against each other. Nevertheless, application of either definition to refer to a CDR of an antibody or grafted antibodies or variants thereof is intended to he within the scope of the term as defined and used herein. The amino acid residues which encompass the CDRs as defined by each of the above cited references are set forth below in Table 1 as a comparison.

Table 1: CDR Definitions

	Rabat*'	Gwthiih	MacClatiu»»⁵
V-fo’DRl	.31-35	26-32	30-35
V_aCDR2	50-65	53-53	47-58
V:, CDR3	95-102	96-301	93-101
V, CDR1	24-34	26-32	30-36
Vj CDR2	50-56	50-52	46-53
V_t CDR 3	89-97	91-96	89-96

Residue numbering follow the nomenclature of Rabat et ai., supra '’Residue numbering follows the nonieuclatwe of Chothia et si., supra 'Residue ftianbering follow the nemeiiclstare ofet al,. supra [0092-1 As used herein, the tenn framework when used in reference to an antibody variable region is intended to mean all amino acid residues outside the CDR regions within the variable region of an antibody. A variable region framework is generally a discontinuous amino acid sequence between about 100120 amino acids in length but is intended to reference only those amino acids outside of the CDRs. As used herein, the term framework region is intended to mean each domain of the framework that is separated by the CDRs, )0093 ) “Homology” or “identity” or “similarity” as used herein in the context of nucleic acids and polypeptides refers to the relationship between two polypeptides or two nucleic acid molecules based on an alignment of the amino acid sequences or nucleic add sequences, respectively. Homology and identity can each be determined by comparing a position in each sequence which may be aligned for purposes of comparison. When an equivalent position in the compared sequences is occupied by the same base or amino acid, then the molecules are identical at that position; when the equivalent site occupied by the

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26same or a similar amino acid residue (e.g,, similar in steric and/or electronic nature), then the molecules can be referred to as homologous (similar) at that position. Expression as a percentage of homology,''similarity or identity refers to a function of the number of identical or similar amino acids at positions shared by the compared sequences, In comparing two sequences, the absence of residues (amino acids or nucleic acids) or presence of extra residues also decreases the identity and homoiogy/similarity.

)0094) As used herein, “ideniity” means the percentage of identical nucleotide or amino acid residues at corresponding positions in two or more sequences when the sequences are aligned to maximize sequence matching, i.e., taking into account gaps and insertions. Sequences are generally aligned for maximum correspondence over a designated region, e.g., a region at least about 20, 25, 30, 35,40,45, 50,55,60,65 or more amino acids or nucleotides in length, and can be up to the full-length of the reference amino acid or nucleotide. For sequence comparison, typically one sequence acts as a reference sequence, to which test sequences are compared. When using a sequence comparison algorithm, test and reference sequences are input into a computer program, subsequence coordinates are designated, if necessary, and sequence algorithm program parameters are designated. The sequence comparison algorithm then calculates the percent sequence identity for the test sequence^) relative to the reference sequence, based on the designated program parameters.

[0095) Examples of algorithms that are suitable for determining percent sequence identity are tire BLAST and BLAST 2,0 algorithms, which are described in Altschul et al. (1990) J, Mol. Biol. 21.5.: 403-410 and Altschul et al. (1977) Khxfeic Acids Res. 2.5: 3389-3402, respectively. Software for performing BLAST -analyses is publicly available through the National Center for Biotechnology information (wwwmefri.nim.nih.gov). Further exemplary algorithms include ClustalW (Higgins 1)., et al, (1994) Nucleic Acids Res 22:

4673-4680), avail able a t www.ebi. ac ,uk/Tool s/clus tai w7 index ,html, )0096) Residue positions which are not identical can differ by conservative amino acid substitutions. Conservative amino acid substitutions refer to the interchangeability of residues ha ving similar side chains. For example, a group of

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-27amino acids having aliphatic side chains is glycine, alanine, valine, leucine, and isoieucine; a group of amino acids having aliphatic-hydroxyl side chains is serine and threonine; a group of amino acids having amide-containing side chains is asparagine and glutamine; a group of amino acids having aromatic side chains is phenylalanine, tyrosine, and tryptophan; a group of amino acids having basic side chains is lysine, arginine, and histidine; and a group of amino acids having sulfurcontaining side chains is cysteine and methionine.

Compounds (0697] The compound names provided herein are named using ChemBioDraw Ultra. One skilled in the art understands that the compound may be named or identified using various commonl) κιοριι cd nomen» Unne Άstems mid symbols-. -By way of example, the compound may be named of identified with common names, systematic or non-system-atie names. The nomenclature systems and symbols that are commonly recognized in the art of chemistry include, for example, Chemical Abstract Service (CAS), ChemBioDraw Ultra, and international Union of Pure and Applied Chemistry (IUPAC).

[0098] Also provided herein are isotopically labeled forms of compounds detailed herein. Isotopically labeled compounds have structures depicted b> me formulas gn» n hucm except that one or more atoms are replaced by an atom having a }· elected atomic mass or mass number. Examples of isotopes that can be incorporated into compounds of the disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as, but not limited to ²K (deuterium, D), 'Ή (tritium), ^!>C, ^bC, ‘’C, ^bN, ^:'F, ^5lP, ^VP, ^iJS, ^WC1 and ^k'⁵.l. Various isotopically labeled compounds of the present disclosure, for example those into which radioactive isotopes such as 'Ή, ^!:’C and ^l4C are uicorporated, arc provided. Such isotopically labeled compounds may be useful in metabolic studies, reaction kinetic studies, detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPBCT) including drug or substrate tissue distribution assays or in radioactive treatment of subjects (e.g. humans). Also provided for isotopically labeled compounds described herein are any pharmaceutically acceptable salts, or hydrates, as the case may be.

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-28[0899] in some variations, the compounds disclosed herein may be varied such that from I to n hydrogens attached to a carbon atom is/are replaced by deuterium, in which n is the number of hydrogens in the molecule. Such compounds may exhibit increased resistance to metabolism and are thus useful for increasing the half life of the compound when administered to a mammal. See, for example, Foster, “Deuterium Isotope Effects in Studies of Drug Metabolism”, Trends Pharmacol. Sci. 5(12):524-527 (1984). Such compounds are synthesized by means well known in the art, for example by employing starting materials in which one or more hydrogens have been replaced by deuterium.

[OOlOOf Deuterium labeled or substituted therapeutic compounds of the disclosure may have improved DMPK (drug metabolism and pharmacokinetics) properties, relating to absorption, distribution, metabolism and excretion (ADME). Substitution with heavier isotopes such as'deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life, reduced dosage requirements and/or an improvement in therapeutic index. An ^iftF labeled compound may be useful for PET or SPECT studies, isotopieally labeled compounds of this disclosure can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopieally labeled reagent tor a non-isotopicaliy labeled reagent. It is understood that deuterium in this context is regarded as a substituent in the compounds provided herein, [00101[ The concentration of such a heavier isotope, specifically deuterium, maybe defined by an isotopic enrichment factor. In the compounds of this disclosure any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom. Unless otherwise stated, when a position is designated specifically as “H” or “hydrogen”, the position is understood to have hydrogen at its natural abundance isotopic composition. Accordingly, in the compounds of this disclosure any atom specifically designated as a deuterium (D) is meant to represent deuterium.

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-29 ·

BI K Inhibitor [00.102] in some variations, the BTK inhibitor is Compound Al, or a pharmaceutically acceptable salt or hydrate thereof. Compound Al has the structure:

[00103] in some variations, the BTK inhibitor is a hydrochloride salt of Compound Al, or a hydrate thereof. Compound. Al may be synthesized according to the methods described in C.S. Patent No. 8,557,803 (Yamamoto et ah) and US 2014/0330015. Compound Al may he referred to as fR)-6-araino-9(l-(hut-2-ynoyl)pynulidm-3y1)-7-(4-pheno.xyphenyl)-7H-purin-8(9H)-one or 6amino-9-[(3R)-l“(2“butynoyl)-3-pyffolidinyl]7”(4-p.henoxyphenyl)-7,9-dihydro8H -purio-8-one. Additional BTK inhibitors include, but are not limited to, (S)6-aminO“9“(l-('but»2«ynoyl)pyrrolidm-3-yl)-7-(4~phenoxyphenyl)”7H“purin8(9H)-one ibratinib (l-[(3R)-3-[4-Amino-3”(4-phenoxyphenyl)-lHpyrazoio[3.4“d]pyrimidin~l-yl]piperidin-l-yl]prop-2-en-l-one), acalabrutinib, HM71224, CNX-774, RN486, ONO-4059, and CC-292 (speburtinib).

IAK Inhibitor [001041 In some variations, the JAK inhibitor is Compound B1, Compound B2, Compound B3, or Compound B4, or a pharmaceutically-acceptable salt thereof.Compound B i, which may be referred to as momelotinib, CYTI .137., CYT387. or N-(cyanomethyl)-4-[2»[[4“(4-moipholinyI)phenyl]amino]-4pyrimidinyl]-benzaniide or N-(cyanomethyI)-4“(2-((4“morpholinophenyi) amino)pyrimidin“4yi)benzamide, has the structure:

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(Bi) [00105] Compound B2, which may be referred to as fi'Jgotinib, GLPG0634,

G146034, N”( 5 -(4-((1., 1 -dioxidothi omorpholino )methyl )phenyl){'l,2,4]iriazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide, N-{5-[4-[(l,l·· dioxo-l,4~tbiazinan-4-yl)methyl]pbenyl]-i.i,2.,4]triazoIo[l,5-a]pyridin-2yljcyci opropanecarboxamide, or N ~ 15 - ( 4-( (1,1 -dioxido-4- ihi omorphol iny 1) Tneihyl]phenyl][l,2,4'jtriazi5lo[l,5-a]pyridin-2-yl]-cyc.lopropanecarboxamide and has the structure:

iB2) i<M)iObi Compound BC obn.η di; Chemical Akimcmispistfy numk-r 1334298-90-6, may be referred to as l-[l-[[3-fluoro-2-(trifluoromethyf)-4pyridinyi]carbonyl]4»piperidiny]3-3-[4-(7if~pyrrolo[23-if{pyrinudin-4-yl)-1.//pyrazoi-l-yl}- 3-azetidineacetonitrile and has the structure:

(B3)

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-31 (00107J Compound B4, which may he referred to as tofacitinib, (3R,4R)-1- 4~methyl-3-(methyl-7fI-pyirolo[2.,3-d]pyrimidin-4-ylamjno)-[Toxopiperidinepropanenitrile or 3-((3R,4R)-4-methyi-3-(methyl(7B-pynOlo[2,3d ]pyrin·! idirt-4-yl)amino ipiperidin-1 -yl)-3 -ox opropaneni trile has the structore:

A

P._:P ,fe.

(B4) (001081 Compound B5, which, may be referred to as ociacitinib or N-methyH((lr,4r)-4-(methy{(7H-pyrrolo[2,3“dJpyrimidin-4yl)affiino)cyclobcxy])methanesulfonamide, has the structure:

ί (B5) [00109} Compound B6. which may he referred to as ruxoiotinib (INC424, 1NCB18424, 3ΑΚΑΗΆ JAKAVI®, available from Incyte Pharmaceuticals and Novartis) or (3R.)-3-Cyciopentyl-3-[4-(7H-pyrrolo[2,3~d]pyrimidin~4-yr)-lHpyrazol-l-yijpropaneriitrile has the structure:

(001.J0] Compound B7, which may he referred to as barachinib {LY3009104, i. \CB ^,vbrt} ^; p Kthvfeulfo'iyl-l j 1 ί <11 p<.uUo[' ' di mi indin I U»j>yrev»>l l-yl]azetidtn-3“yl3acetomtrile or 2-(3-(4-(7H-pyrroio[2,3-d}pyritnidin4-yl)-lHpyrazol~ 1 -yl)-1 -(ethyl sul fonyl)azetidin-3 -yl)acetonitrile, has the structure:

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[00111] Compound B8, winch may be referred to as iestaurtinih (CEP-703, KT5555, and A 154475.0) · 2,3,9,10,1 l,i2-hexah.ydro-10~hydroxy-10(hydroxymediylH-niethyl-, (9S,1OS,32R)- 9,12-Epoxy-l H-diindolo[l,2,.3-fg:3'. 2‘,l'-kl]pyrrolo[3_J4”i][l,63beiuodiazocin»l-ORe_J has the structure:

(B8) [001.12] Compound B9, which may be referred to as pacritinib (SB 1518) or (16E)-11 -[2-( 1-Pyrroli.dinyl)ethoxy]-14,19-dioxa-5,7,26triazatetracyclo} 19.3.1,12,6.18,12]heptacosa1 (2.5),2(26),3,5,8,10,12(27),16,21,23-decaene, has the structure:

[00113] Compound B10, which may be referred to as TG101348, SAR.302503, /V“terl»Butyl“3-{5-methyi~2-[4-(2-pyrfolidin-byl-etlioxy>phenylainiiK>]pyrimidin-d-ylaminoj-benzenesulfbaaraide, or N-(te.rt~butyl)-3“((5-methyl“2“C(4(2~(pyrrolidin-l-yl)ethoxy)phenyl)amino)pyrimidin-4yl)amino)benzenesulfonamide, has the structure:

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[00114] Compound BI 1, which may be referred to as JSI-124, Cucurbitracin, ElatericmB,NSC-521777,(8S,9S,10R,13R,14'R,i6R,r7R)-17-((R,E)-2,6~ dihydroxy-6~methyl'3'Oxohept''4'eri--2--y3)--2,16-dihydr()xy--4,4_i8,9,13.14·· hexamethyl-?,8,9,10,12,13,14,15,16,17-decahydro-3.Hcyclopenta[ajphenanthrene~3,l U'4H f-dione or 2,16a,20,25-tetrahydroxy-9~ methyl-19··Νοί-9β, 1 Οα-ianosta-1,5,23-triene-3,11,22-trione, has the structure:

NC\, (1311) [001151 zldditional 1AK inhibitor compounds that may be used in the combinations, methods, kits, and articles of manufacture herein include GSK2586184, VX-509, INCB16562, XL019, NYP-BSK803, CEP33779, R-348,

AC-430, CDP-R723 or BMS 911543, NVP-BSK8G5, CEP33779, as well as those disclosed in U.S. Pat. No. 7,879,844, and the JAR inhibitor cyclodextrin-based polymer conjugates described in U.S, 2014-0357557,

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PCT/US2016/054780 iNCSiSSSi —£·· • •Ά., A-.

,..A, ^n:

;I Z

XiQts

Ϊ i

N X.N w

-'.V

BSSSSl 1343 i' A

NVP-BSXSGS

AZD14SQ

SP3377S / fo..../ \ /' \

A j!

..¼¼ X'

V ,-¼ X*’ W ,:,::,.⁷ \......../ and

In some embodiments, Compound Bl, or a pharmaceutically acceptable salt thereof, is used in combination with Compound Al, or a pharmaceutically acceptable salt or hydrate thereof. In other embodiments, Compound B2, or a

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PCT/US2016/054780 ·· 35 · pharmaceutically acceptable salt (hereof, is used in combination with Compound Al, or a pharmaceutically acceptable salt or hydrate thereof. In yet other embodiments, Compound B3, or a pharmaceutically acceptable salt thereof, is used in combination with Compound AI, or a pharmaceutically acceptable salt oxhydrate thereof. In yet other embodiments·, Compound B4, or a pharmaceutically acceptable salt thereof, is used in combination with Compound Al, or a pharmaceutically acceptable salt or hydrate thereof, in. yet other embodiments, Compound B5, or a pharmaceutically acceptable salt thereof, is used in combination with Compound Ai, or a pharmaceutically acceptable salt or hydrate thereof In still another embodiment, Compound B6, or a pharmaceutically acceptable salt thereof, is used in combination with Compound Al, or a pharmaceutically acceptable salt or hydrate thereof In another embodiment, Compound 137, or a pharmaceutically acceptable salt thereof, is used in combination with Compound Al, or a pharmaceutically acceptable salt or hydrate thereof in yet other embodiments. Compound B8, or a pharmaceutically acceptable salt thereof, is used in combination with Compound Al, or a pharmaceutically acceptable salt or hydrate thereof In further embodiments, Compound 139, or a pharmaceutically acceptable salt thereof, is used in combination with Compound Al, or a pharmaceutically acceptable salt or hydrate thereof in yet other embodiments, Compound BI O, or a pharmaceutically acceptable salt thereof, is used in combination with Compound Al. or a pharmaceutically acceptable salt or hydrate thereof In other embodiments, Compound 1311, or a pharmaceutically acceptable salt thereof, is used in combination with Compound Al, or a pharmaceutically acceptable salt or hydrate thereof [00117] Reference herein to “Compounds BI -RI 1”, “BI to B.l. I”, or “BI through BI U is understood to include the fell group of BI, 132 B3,134,135, B6, B7, B8, B9, B10, and B11. Coropouinds B1 - B11 are commercially available or their methods of synthesis are generally known in the art. For instance, tofecitinib may he prepared as described in U.S. .Patent No. 6,956,041, rilgotinib may be prepared by the· methods seen in U.S. Patent No. 8,853,240 and US 201' O' sh<· ,\· NxhtlMl¹ A< 1' '<‘U G) be pup nod b, -he methods

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- 36 seen in US 2011/11.2662 and US 2015/1246046, peiicithub may be prepared as described in U.S. Patent Nos, 7,879,844 and 8,779,140, and momeiotinib may be prepared as described in U.S. Patent No. 8,486,94.1, [00118] In one embodiment, the JAK inhibitor is selected from the group of momeiotinib (CYT0387), ruxolitinib, fedratinib, baricitinib, lestarirtinib, pacntmsb, XL019, AZD1480, LY2784544, BMS911543, and NS018, or a pharmaceutically acceptable salt thereof'. In one embodiment, the JAK inhibitor is selected from the group of 144101348, JS-124, and INCB39110, CUZ868, and GSK?asm 84, or a pharmaceutically acceptable salt thereof. In another variation, the JAR inhibitor is momeiotinib, or a pharmaceutically acceptable hydrochloride salt thereof. In another variation, the JAK. inhibitor is filgoiinib, or a phannaceutically acceptable salt thereof.

ASK! Inhibitors

In some variations, the ASK.1 inhibiting compound is a compound of

Formula I:

Wherein:

R¹ is selected from alkyl of 1 -10 carbon atoms, alkenyl of 2-10 carbon atoms, alkynyl of 2-1.0 carbon atoms, cycioalkyl of 3-8 carbon atoms, aryl, heteroaryl, or heterocyclyl, all of which are optionally substituted with 1,2, or 3 substituents selected from halo, oxo, alkyl, cycioalkyl, heterocyclyl, aryl, aryloxy, N03, R⁶, -C(O)R⁶, -OCIOfrR⁶, -OC(Q>O-R⁶, -C(O)-N(R⁶)(R⁷)s -S<\ <-0)·Μ -S(-())_rR⁶, -8ύΟ)2.·Ν(Κ^ή)(Κ·), -SUO)r()-R⁶, -N(R⁶)(R⁷), ,N(R⁶)-C(O)-R⁷, N(R.⁶)-C(O)-Q-R⁷, »N(R^f!)-C(O)N(R⁶)(R⁷). -N(R⁶)-S{O)2-R*, CN, and -OR⁶;

wherein alkyl, cycioalkyl., heterocyclyl, phenyl, and phenoxy arc optionally substituted by .1,2, or 3 substituents selected from alkyl, cycioalkyl, alkoxy, hydroxyl, and halo;

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PCT/US2016/054780 wherein R° and R are independently selected from the group consisting of hydrogen, Cj-Cu alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, all of which are optionally substituted with 1-3 substituents selected from halo, alkyl, mono- or dialkyiamino, alkyl or aryl or heteroaryl amide, -CN, lower alkoxy, -CF3, aryl, and heteroaryl; or

R-’ and R^z when taken, together with the nitrogen to which they are attached form a heterocycle;

R^z is hydrogen, halo, cyano, alkoxy, or alkyl optionally substituted by halo;

R ' is aryl, heteroaryl, or heterocyclyl, all of which are optionally substituted with one or more substituents selected from alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, cycloalkyl of 3-8 carbon atoms, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylaikyl, heterocyclyl, heterocyclylalkyl, halo, oxo, NO₂, haloalkyl, haloalkoxy, -CN, -O-R⁶, -OC(O)~R\ -OC(0>0-R⁶, -C(O)~ N(R^fi)(R⁷), -S-R⁶, -N(R⁶)(R^?),.~SUO>R^<', -S(=O)2-R*, ~Si<))2-N(R⁶Xin, -SCO)·· O-R⁶, -N(R⁶)-C(O)-R⁷, -N(R⁶)-C(^:O)N(R⁶)(R⁷), -N(R⁶)-C(0)-O-R⁷, -N(R⁶)CUO)N(R⁶)(R⁷), -C(O)R⁶, -C(O)-O-R⁶, -C(O)-NC.R⁶)(R⁷), and -N(R^f>SUO)2-R^?, wherein the alkyl, alkoxy, cycloalkyl, aryl·, heteroaryl, or heterocyclyl is further optionally substituted with one or more substituents selected from halo, oxo, -NO2, alkyl, haloalkyl, haloalkoxy, -N(R⁶)(R⁷), -C(())R⁶, -OC(O)-R⁶, -C(O)-N(R⁶)(R⁷}, CN, -O-R, cycloalkyl, aryl, heteroaryl, and heterocyclyl:

with the proviso that the heteroaryl or heterocyclyl moiety includes at leastone ring nitrogen atom; X’, X², X\ X'\ X'¹, X°, X', and X^s are independently C(R⁴) or N in which each R’ is independently hydrogen, hydroxyl, halo, alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, or cycloalkyl of 3-8 carbon atoms, aryl, heteroaryl, heterocyclyl, halo, -NO?, haloalkyl, haloalkoxy, -CN, -O-R'’, -SR⁶, .N(R⁶XR⁷), -SUO)-R⁶, ·8{······Ο)2-Κ⁶, -S(-O)2-N(R^e)(R⁷), -S:UQ)~CUR⁶, -N(R⁶)C(O)-R⁶. -N(R>C(Oj-O-R⁷, -N(R⁶)-C(-O)N(R⁶)(R⁷), -C(O)-R⁶, -C(O)-O-R⁶, C(O)-NfR-)(R⁷), -N(R‘')S(^:::O)2-R·;, wherein the alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl is farther optionally substituted with one or more substituents selected from halo, 0x0, -NO2, -CF₃, -O-CIh, -NfU'iiR⁷), ~C(O)~R⁶, -C(O)-O-R⁷, C(O)-N(R⁶)(R⁷), -CN, -CO-R⁶: or

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- 38 X⁵ and X” or X” and X' are joined to provide optionally substituted fused aryl or optionally substituted fused heteroaryl; and with the proviso that at least one of X², X’, and X⁴ is C(l<⁴); at least two of X‘\ X°, X', and X⁸ are is C(R*); and at least one of Xg X\ X”, XL X'¹, Xy and X⁸ is N; or a pharmaceutically acceptable salt or hydrate thereof.

[00120} An embodiment within each of the methods herein in which a compound of Formula I is used comprises use of a compound of Formula 1, as described above, or a pharmaceutically acceptable salt or hydrate thereof, wherein R’ is selected from the group of:

wherein:

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- 39 R^s! is selected from hydrogen, alkyl of 1-6 carton atoms, or cycloalkyl of

3-8 carbon atoms, wherein alkyl and eycloalkyl arc optionally substituted by hydroxyl or halo;

R/^; j§ selected from hydrogen, alkyl of 1-6 carbon atoms, or eycloalkyl of

3-8 carbon atoms, -S(~O)-R^ft or, -SUOfr-R*¹, wherein the alkyl and eycloalkyl are optionally substituted by hydroxyl or halo.

[00121] Another embodiment comprises use in the methods herein of a compound of Formula I, as described above, or a pharmaceutically acceptable salt or hydrate thereof in which X¹, X², and X^s are all N, and X\ X, X^!\, Xk and X* are C(R⁴). This embodiment includes compounds in which R' is optionally substituted alkyl of from I to 6 carbon atoms, optionally substituted eycloalkyl of from 3 to 8 carbon atoms, or an optionally substituted heterocyclyl, particularly when the optional substituents are 1,2, or 3 substituents chosen from hydroxyl, halo,, or eycloalkyl of from 3 to S carbon atoms. Within the embodiment another embodiment includes compounds in which 1U is optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocyclyl, wherein the heteroaryl or heterocyclyl moieties contain, 1,2, or 3 ring nitrogen atoms, and the aryl, heteroaryl, and heterocyclyl moieties are optionally substituted by alkyl of from 1 to 6 carbon atoms, eycloalkyl of from 3 to 8 carbon atoms, halo, cyano, or -OP?, in which alklyl and eycloalkyl are optionally substituted by hydroxyl or halo. A preferred group of R* moieties includes those non-limiting examples described above.

(00.122) Another embodiment includes use in the methods herein of a compound of Formula I in which X^! and X'’ are N, and X? X³, X⁴, X^J, X°, X', and X^s are C(R4). This group includes compounds in which R¹ is optionally substituted alkyl of from 1 to 6 carbon atoms, .optionally substituted eycloalkyl of from 3 to 8 carton-atoms, or optionally substituted heterocyclyl, particularly where the optional substituents are 1,2, or 3 substituents chosen from hydroxyl, halo, or eycloalkyl of from 3 to 8 carbon atoms. Within this group, a subgroup includes compounds in which R* is optionally substituted aryl, optionally substituted heferoarvl, or optionally substituted heterocyclyl, wherein the heteroaryl or heterocyclyl moieties contain 1,2, or 3 ring nitrogen atoms, and the aryl,

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--1()heteroaryh and heterocyclyl moieties contain 1, 2, or 3 ring nitrogen atoms, and the aryl, heteroaryl, and heterocyclyl moieties are optionally substituted by alkyl of from 1 io 6 carbon atoms, cycloalkyl of from 3 to 8 carbon atoms, halo, cyano, or-OR⁴, in which alkyl and cycloalkyl are optionally substituted by hydroxyl or halo.

[00123] Another embodiment provides use in the methods herein of a compound of Formula I in which X‘ and X² are N and X\ X', X \ X°, X', and X^fc are C(R4), This group includes compounds in which RI is optionally substituted alkyl of from 1 to 6 carbon atoms, optionally substituted cycloalkyl of from 3 to 8 carbon atoms, or optionally substituted heterocyclyl, particularly where the optional substituents are 1.2, or 3 substituentschosen from hydroxyl, halo, or cycloalkyl. Within this group, a subgroup: includes: compounds in which R3 is optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, wherein the heteroaryl or heterocyclyl moieties contain 1, 2, or 3 ring nitrogen atoms, and the aryl, heteroaryl. and heterocyclyl moieties are optionally substituted by alkyl of from 1 to 6 carbon atoms, cycloalkyl of from 3 to 8 carbon atoms, halo, cyano, or -OR⁰, in which the alkyl and cycloalkyl are optionally substituted by hydroxyl or halo.

[00124] Another embodiment includes use in the methods herein of a compound of Formula I in which X¹ is CtU i This group includes compounds in which R¹is optionally substituted alkyl of from 1 to 6 carbon atoms, optionally substituted cycloalkyl of from 3 to 8 carbon atoms, or optionally substituted heterocyclyl, particularly where the optional substituents are chosen from hydroxyl, halo, or cycloalkyl of from 3 to 8 carbon atoms. Within this group, a subgroup includes compounds in which R’ is optionally substituted heteroaryl or optionally substituted heterocyclyl, wherein the heteroaryl or heterocyclyl moieties contain 1,2, or 3 ring nitrogen atoms, and the aryl, heteroaryl, and heterocyclyl moieties are optionally substituted by alkyl of from 1 to 6 carbon atoms, cycloalkyl of from 3 to 8 carbon atoms, halo, cyano, or --OR⁶, in which, the alkyl and cycloalkyl groups are optionally substituted by hydroxyl or halo, (001.25] The ASK1 inhibiting compounds for use in the methods herein include, but are not limited to, those compounds named below, which may be prepared by

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PCT/US2016/054780 the methods described in U.S. Patent Nos. 8,552, i 96 and 8,742,126, which are incorporated herein by reference:

5“(2,5-difluorophenyl)-N~(3-{4-m6thyl-4'H-l₅2,4“triazol“3” y 1 )pheny 1) 5ii co t i 5ϊ am i de;

4-(imidazo[ 1 ,2-a ]pyridin-3-yi)-N-(3-(4-methyl-4H-l ₅2,4-triazo1-3yl )phen yl )-pi col inam ide;

4-('2-aminopyrimidin-5-yl)-N-(3“(4”Cydopropyl-4H~l,2,4-tliiazol-3y])phenvl)picoUnamide;

N-(3-(4-methyl“4H-l₎2_s4-iria2o{-3-yl)phenyl)“5-phenyinicotinamide;

N-(3~(4-cyclopropyi-4H-l,2,4-triazol-3-y1)phenyl)-4-phenylpicoiinaroide;

N-(3'-(4-(tetrahydro-2H--pyian-4-yl)-4H'-l_i2,4-triazoi-3-yl)phenyl)-3,4’bipyridine 2’-carboXamide;

2-hydroxy-N-(3-(4-meihyb4Hri,2,4'4riazol-3-yl)pbettyl)-6phenylpyrimidine-4 -carboxamide;

N-(3-(4~cyclapropyMH-i,2,4-triazok3~y1)phenyf)3,4’“hipyridine“ carboxamide;

N-(3-(4-cyciopropyi“4H-l_>2_<4-triazol3-yl)phenyl)-4-(lH~imidazol-ly1)picolinamide;

N-(3-(4-methyl4H“l,2,4-tri.azol-3-yl)phenyl)“4“phenylpicolinamide;

N-<3-(4-(3“amiftO“3OXOpropyl)”4H“l,2_s4“triazol“3yl)phenyl)-3,4’bipyridine-carboxamide;

N“(3“(4-cyclopropyl-4H-l₅2,4triazol3-y1)phenyi)-4-(lH“l,2,4”triazoM' yOpicolinamide;

N-iS-id-methyi^H-l^^-triazobS’yljphenyD-^-pbenyipicolinamide;

N-(3--(4-(2--acotara:idoethyl)--4H-l,2,4-4riazol-3-yl)phenyI)-3₅4⁵~bipyridinecarboxamide;

N-(3-(4--methyl-411- ] jl^-triazol-S^yOphenylH^-raethylpiperazin-1 -yOpicolinamide;

N-(3-(4~methyl-4R-l ,2,4-triazol-3-yi)phenyr)-2,31 -bipyridine-6carboxaraide;

N-(3-(4-methyl-4H«l,2_s4-triazol-3-yi)phenyi)4-morpholinopicolinamide;

SUBSTITUTE SHEET (RULE 26)

WO 2017/059252

PCT/US2016/054780

-42'N~(3-(4-methyl-4'H- 1 ,2,4-46 axel -3-)4)phenyl)“6-(qiiinolin-6“ yppieolinamide;

(R) -N-(3-(4-(l-hydroxypropan-2 -yi)-4H-i,2,4-triazol-3-yl.)phenyi)-3,4’bipyridine-S’-carboxamide;

N-(3-(4-cyclopropyl-4H-I,2,4-triazol-3-yJ.)p.henyl)-6-hydroxy-3,4’bipyridine-2’-carboxamide;

N -(3 -(4 -methyl -4H 1,2,4-iriazol--3 -yl)phenyl )-3,3 ’ -bipyri dine-5carboxamide;

(S) -N-(3-(4-(l“hydroxypropan-2’yl)“4Hl,2,4-triazol3-yl)phenyl)“3,4’bipyri dine-2’ -carboxamide;

N“(3-(4-methyl-4H-l,2,4~lriazoi-3~yl)ph.enyf.)-4'-(3-oxopiperazin“iyOpicolinandde;

N“i'3-(4-methyi-4I-i-l_i2,4iriazo{3--yl)pheuyl)-3_s4^s-bipyndine-2ⁱcarboxamide;

N~(3 -(4-cycl opropyi-4 H.-1,2,4-tri azol~3 -yi)ph enyl)-6-methoxy-3,4 ’ bipyridine-2’-carboxamide;

4- ·(3-έίηύηορνπ·ο1ί4ίιι-1-γ1)~Ν-(3~(4~!ηβ11η4~4Η-Τ2.,4-ίϊί<ϊ2θ1-3yl)phenyl)pico3inamide;

N-(3-(4-methyl-4H-1.2,4-triazoj-3-yI)phenyl)-2-phenylisonicotinamide; 6-amino-N-(3-(4-eyvh !propyl-4H-i_!2,4-triazoi-3-yl)pheuyr)-3,4’bipyridine -2 ’-carboxamide;

(R)-N-(3 ~(4“(2-hydroxypropyl)-4H-1,2,4-triazol ·3 ~yl)pheny1)~3,4 ’ bi pyridine-2 ’ -carboxamide;

5- ra.ethoxy-N-(3-(4-methyl-4H-l,2,4~triazol-3-yi)phenyi)-3₄4’-bipyridine’2⁵-carboxamide;

methyl 2’-'(3-(4--cycIoptOpyl-4H“l₎2,4-iriazoi-3-yi)pheoylcarbamoyi)-3,4’ bipyridin-b-ylcaibamate;

5-ίηεί1ιοχ>'-Ν·'(3··ί'4'ίηεΑν]4Η·Ί,2_;44Γί3ζο1-3·}4)ρΗεηγ1)··3₅4’-ΒίργΓί(·1ίηε

2’-carboxaniide;

methyl 2 ’ -(3 -(d-eyelopropyMH-· 1,2.,4-triazoJ.-3 -yl)phenylcarbamoyl)-3,4 ’ bipyridin-6-yl carbamate;

SUBSTITUTE SHEET (RULE 26)

WO 2017/059252

PCT/US2016/054780 (3)--Ν--(3--(4-·(12-1ινάΓθΧ7ρΓορνί)-4Η-1,2,4-1ι-ί«ζο1-3-νΓ)ρ1ιεηγ1)-3,4’·bipyridine-2 ’ -carboxamide;

4-(I-aiethyl4H-imidazol-5-yl)-N-f3-(4-meihyl~4H-l,2,4-triazol-3y])phen yl)pi eolmarnide;

N-Q-OUcyciopropyl^H-V^-triazoi-S-y^phenylj^-Q-meihyl-lH im idazol --5 -yl )pi coii n amide;

ΐ'ί4Εΐ\'η.·ο|ύ|ηοιύ.ιζυ1 1 eyUopiopyl 411 1,2 4 ΐπ3?οί·Τ yl)phenyi)pieolmamid.e;

N-(3-(4-cyclopropyi-4H-l,2,4-tnazo{-3-yl)pheny1)-4-(2,4dimethoxypyrimidiN-5-yl)picolinamide;

M44d b\dto\u\iUpnuqbnmdrriHli U-bw/ol ' vliplieny!)

3,4 ’ - bipyridine- 2 ’ - ear box am i do;

N-(3-(4~eycloprojni4li4.' -1 i>u-ci l-yOphejiyB—i-i-i-pbcnyl- i Himidazol-1 -yl)pieolinamide;

6-cyciopropyl-N-(3-(4-cyciopropyi“4H“l,2.,4txiazoi“3yi)phenyl)-3,4’bi pyridine-2 carboxamid e;

(S)-N-(3-i4-(2-hydroxypropyi)-4H-l,2,4-triazol-3-yl)pbenyl)-3,4’bipyridine--2 '-carboxamide;

N-(3-(4-cyclobuty.l-4H-] ,2,4-triazol-3-yl)phenyl)~3_s4^>--foipyi idme-2’carboxamide;

N2’-(3-(4-cyclopropyl-4H-1,2,4-teiazol-3-yl)phenyl)-3,4’bipyridiiie-2^>,6di carboxamide;

(S)'-N-(3-(4--(I,l/i-irif]tRWpropair-2--yi)--4H--l_>2.4triazoi-’3y!)phenyi)--3,4’bipyr i dine -2' -carboxamide;

'N-(3-(4-cyclopen{yl-4H-l,2,4-triazo.l-3-yl)phenyl)-3,4’“bipyridine-2’carboxamide;

N“(3-(4-cyclopropyl-4'H-l₅2,4-iriazoi-3-yl)pbenyi)-6-(trifluoromedtyl)3,4’-bipyridine-2 ’-carboxamide;

^'-(S-^-cyciopropyMH-iAd-triazol-S-yOphenylHM’-bipyridine^’jSdicarboxamide;

N-(3-(4«.cyc!opropyl-4H-l,2,4-triazol-3-yI)phenyl)-4-(2-methyj-l.H -imidazol-l-yl)picolinamide;

SUBSTITUTE SHEET (RULE 26)

WO 2017/059252

PCT/US2016/054780

,. 44 ,

N-(3-(4“eycfopfopyl“4H“l_J2.j4-b'ia:zol-3~yi)phen,yl)'-6-m:eihyl-3,4’bipyridme-2’ -Carboxamide;

5-cyano-N-(3-(4~eyclopropyl“4H-l^,4triazol”3-yl)phenyl)-3,4’bipyridine-2 ’ -carboxamide;

N-(3-(4-cyclopropyi-4H“ i ,2,4-triazoi-3 -yi/phenyl )--4-(4 -methyl -1H imidazol-1 -yOpicohnamide;

N(6-(4-cyclopropyl-4H-l,2₅4-triazol-3-yl)pyridin'2-yj)-3,4’-bipyridine-2^!carboxannde;

2-amino-N-(3-{4-cyclopropyl-4H-l,2,4Triazol-3-yl)pbenyl)-3,4’bipyrs dine -2⁵ -carboxam ide;

N-(3-(4-cyciopropyl-4.H-L2_>4-triazol-3-yi)pbenyl)-4-(4,5-dimethyl-lM -ini idazol -1 -yl/picolinamide:

^-(3-(4-((1 S,2S)-2-meihylcyciopropyl)-4H-i,2,4-ttiazoi3-yi)phenyi)-3₎4)bipyri dine/Z’-earhox amide;

N~(3-(4Cyciopropyi4M-i,2_s4“tri azol-3-yl)pheny1)-2-meAoxy-3,4’bipyridine-2’-carboxamide;

N-(3-i4-cyclopropyl-4H-l,2,4-triazol“3yl)phenyl)-4-(4-(trifluoromethyl)1H -imidazol-l -yl)picolinamide;

.N-(3-(4~cyclopiOpyi-4H-l ,2,4-lriazol-3-yi/phenyl )-6-(2,2,2-trifluoroethoxy )-3,4⁵ -bipyridine-2 ’ -earboxami de;

N-(3-(4-cyc1opropyl-4H-l^,4-triazol-3-yl)phenyl)-4-(i-methyl-lH pyrazoi -4~yl)picol inamide;

N-(3-(4--cyeiapropyl--4H-l,.2,4tri:Koi-3-yl)pheiiyl)4(2-meihoxypyrimidin~

5-yl)pieolinamide;

N-(3-(4-cyelopropylr4R-l,2,4-triaxol-;3-yl)phenyi)-4-methyf-3,4’bipyridine-2'’-Carboxamide;

N-(3~(4-cye.lopropyl'4H-l_s2,4-t.nazol-3--yl)pher!yl)«4--(imidazo[i,2„

a]pyridin-3-yl)picolinamide;

eihyi-N-(3-(4-mei:iiyl-41-l-i_!2_!4~triazol'3'yi)phenyi)-3_!4’-bipyridine-2’carboxamide;

N-(3~(4-(2,2,2-trifluoroetliyl)-4H-i,2,4-triazol-3-yi^>hei}yl)-3,4’bipyridine-2 ’ -carboxamide;

SUBSTITUTE SHEET (RULE 26)

WO 2017/059252

PCT/US2016/054780

6-chlfiro-p,2\5· 4 ]terpyridine-2%carix>xylie acid[3-(4 .-cyclopropyl411-{ 1,2_?4iiriazol-3-yl)phenyl] amide

N-(3-(4-eyclopropyl~4H-l_!2,4-iriazol-3'yl)pbenyi)-6-(pynOlidin-l-yl)-3,4’bipyridine-2 ’ -Carboxamide:

N-(3-(4“Cyclopropyl-4H-l,2,4-tiiazol“3“yl)phenyl)’5’(triflnoromethyl)-3₅4’ dhpyridme-??-carboxamide;

N-f3-(.i.-cydopropyi-lH -imidazol-5-yl)phenyI)-3,4’-bipyridine-2’carboxamide;

N-(3-(4-cyclopropyl~4.n~'l ,2,4~iriaz.oi~3-yl)phenyl)4-il,2-dimethyl--lH-imidazoi-5-y{)picoiinamide;

4-Π.Η -benzx>[ d] [1 ^3]triazol-yl)-N<3<4-cyclopropyl“411d,2,4-triazol-3yl)phenyl) picoiinarnide;

N-(3~(4-cydopropyE4R-l_}.2,4-iTia55oI-3-yl)phenyi)4-(4-sui'faraoy lpheny I )pieolinamide;

N-(3-(4 -cyclopropyl -411-1,2,4-friazol-3 -yi)phenyl)-5-medioxy-3,4 ’bipyridine-2 ’ -earboxam ide;

N-(3-i4-cydopiopyi-4H-!,2_s4-iriazoi“3 )phenyl)-6-fluoro-5-metliyl-3,4’bi pvt i di ne-2 ’ -carboxamide;

N-(3-(4-cyclopropyl-4I-l-l,2,4-iriazol-3-yl)phenyl)-5fluoro-3,4^:!bipyri dine -2⁵ -earboxam ide;

N-'(3“(4-cyclopropyl-4Hd ,2,4-triazol-3-yI)phenyl)-2-methyl-3,4’bipyridine-2 ’-Carboxamide;

N-i'3 -(4 -cyelopropyl-4H-1,2,4-triazol-3 -yl)phenyl )-4-(4,5,6,7-telrahydro1H -benzo [ d]iinidazoi-l-yl)picolinamide;

N-(3~(4-eyciopropyl-4H-l ,2,4-iriazoI-3-yi)phenyl)-4-(4(Nmethyj so 1 famoyl)phenyl) picoiinarnide;

N5-te.rt-buiyi-N2'’-(3(4-cyclopropyl-4'H-l,2,4-triazol-3-yl)phenyl)-3,4’bipyridine-2 \ 3-dioarbi ixa onde;

N-(3-(4-eyciopropyl-4H-l,2,4-triazol-3-yl)phenyi)-4-(pyrazin-2yljpicoiinamide;

N-(3-(4-cydopropyl'4il· l₅2,4-triazol-3-y1)phenyl)-4-(4~ (Nisopropylsulfarnoyl) phenyl ,)picoiinamide;

SUBSTITUTE SHEET (RULE 26)

WO 2017/059252

PCT/US2016/054780 · 46 ^k)ro-N“(3(4ejto{:opiOpyi-4H-l,2,4-tria:zol~3“>'l)pbeny'0‘3,4^!-bipyridine* 2' ’Carboxamide;

4-(lH~benzo[ d]imidazol~l“yl)-N-(3-(l“CyclopropyH H-imidaz.ol-3yl)phenyl)picolinamide;

6<γο1ορΓορ„ν1“Ν-(6-(4-ο>τ1οριορν1-4Η· l,2,4-triazol-3“yl)pyridim-2.-yl)3,4’ -bipyridine-2 ’ -carbox am ide;

N-(3-(4-cyek)propyl-4H-l,2,4-triazol-3-yl)phenyl)-4~(3 (methylsuifonyl)phenyi)picoli.namide;

N-(3'-(4-eyc{opropyl4Hl_J2.4“iriazol-3»yl)pheny!)-4-(isoquinol in-4yDpicoiinannde;

N..(6-i4--eyciopiOpyj-4H-.l,2,4-triiizol-3-yi)pyridin-2-yl)-4-(4~ (methyls«lfonyl)pbcnyl)pieolinamide;

N-(3“(4-cye4opiOpyl-4H~l,2,4-triazoi-3-yl)piienyl .)--4--(2(inethylsultbnyljphenyljpicolinamide:

Ν~(3-(4-ογβ1ορ·κ)ρ7ΐ·-4Ι·1-·Ι,2,4-ίηηζο1-3-)4)ρ1ΐί?ηγ1)-4·-(1₅5-ί1.π'ηοΛ541Η pyrazoM-yOpicolinaroide;

6-eyclobutyl-N-(3-(4-cyclop.ropyl-4H~l,2,44riazol-3-yl)phenyl)-3_}4’bipyridins--2’-carboxainide;

N-(3-(4“CyclopiOpyl-4ti-l,2,4-triazol-3-yl)phenyf)-6-isopropyi-3,4’ bipyri dine -2 ’ -carboxamide;

N»(3-(4-cyclopropyl-5H-l ,2_s4-tria2ol-3-yl)phenyl)-4-(4(Tnethylsulfony1)phenyl)picolinamide;

N-(3-(4-cyelopropyl-4H-1 ,2,4-1παζοί-3-γ1)ρϊΐ6ην1)-6-(<1ίηϊ6ύιγ1ατη.ΐηο)-3,4’bipyridine-2’ -carboxamide;

N-(3-(4-eyclopropyi-4H-1,2,4-tri azoD3.-yl)pbenyl)-4-(pyridin-3 vl)quinoline-2-carboxamide;

N-('3-(4-cyclopropyl-4H-l_?2_?4-triazol-3-yl)phenyi)“4-('lHpyrroIo[2,3b]pyridin-5-yl)picolinamide;

6-cydopropoxy-N-(3-(4-eycloprop)4-’4H--l,2,4-iriazol-3-yl)phenyl)~3₅4^?bipyridine-2' -carboxamide;

Ν-·ί3--(4-ογε1ορΓοργ1-4Η-1_!2,4·-ίπΗζο{·-3--ν1)ρΗ&ον1)-4-(1Η·-ΐη'ϊί4<ιζο[ 4,5-bjpyridm-i~yi)picoi.mamide;

SUBSTITUTE SHEET (RULE 26)

WO 2017/059252

PCT/US2016/054780

.. 47 .

N-(3-ί4royclopϊΌpyb4H-l,2_J4-biazoί-3-ylipheπyl!-6-flttoro-3,4^, bipyridine-2’-carboxamide;

N-(3-(4-cydopiOpyi4H-l_;2,4“triazol-3-yl)phenyi)-4-(4-(2oxoimidazoJidin-l-yOphenyljpicoIinamide;

N-(3-(4-cyclopropyi-4H-i,2,4-triazol-3-yl)phetiyl)-4-(3Himid«^<izo[4₅ 5-1 )jpyridin-3-yl)picolinamide;

N-(3-(4-cyclopropyl-4H-i_>2,4-triazol-3-yl)phenyl)-6-isopropoxy-3,4’bipy ri dine-2 ’ -carboxaro ide;

N -(3 -(4-cyel opropyl-4H-1,2,4-triazol-3 -yl)phenyl) - 6-etb yl-3,4 ’ - bipy ridi ne 2’--carboxamide;

N-(3-(4-cyclopropyl-4H” 1,2,4“ώ3Ζοί··3·χ1.)ρ1ΐ6ηγ1)“4“(1Η~ίπιίύ&2θ[4_>5c] pyridin- 1 -yl)picolinamide·

6“Cyclobatoxy“N-(3“(4”Cyctepropyl»4H’l_?2_>4-triaz-ol-3-yi)pbeny1)-3,4ⁱbipyridine-2’-earboxamide;

6-cyclopropyl-N-(3 -(1 -cyclopropyl-lH -imidazol-5 -yl)pbenyl)-3,4⁵ bipyridi.ne-2’-carbo.xamide;

N-(3-(4-cyclopropyl-4H-l,2_s4-triazol-3-yl)phenyl.)-4-( qiiinolin-3yl)pieolinatnidc;

Ν·-(3-(4--ονς1ορΓορ>4-·4]:ί·-1,2,4·-ΐϊ·ικζοΙ·-3··ν1)ρΗβην0-4-(4(Ncyclopropylsulfamoyl) phenyl)pieolinamide;

N-(3-(4 -cycIopropyl-Ul-imidazol-5-yl)pbenyl)-4-iquinol!n-3yhpicoi inamidc;

6-cyclopentyl-N~(3-(4-eyelopropyl 4B-lX4-Mazol~3-yl)phenyl>3,4’'bipyridine-2 ’ -carboxamide;

N-(3-(4-cyclopropy]-4.H-.E2,4-triazol“3-yl)phenyl)-4-(imidazQ[2,1-b] [1 ,3,4]tbiadiazol-5^yl.)picolinaajide;

N~(3-(4-cyciopropyl-4H-l,2,4-triazol-3-yl.)pbenyl)-4-(5cyclopropylpyrazin-2-yl)picolinamide;

N-(3-i4-eyclopropyl“4li“l,2,4-triazoi“3-yl)phenyl)-6-(i-methyl-2oxopyrrolidin~3-yi)-3,4’-bipyridine-2’-Carboxainide;

SUBSTITUTE SHEET (RULE 26)

WO 2017/059252

PCT/US2016/054780

- 48 4-(4-ehIoro-lH •imidgzoM“yi)~N-(3-(4-cyeUpropyi~4M~l_s2,4-tn&zoi3yl)phenyl)pico3mamide;

6~cyclopropyl-N~(3(4-cyclopropyi-4H“l,2,4-triazol-3“y1)phenyl)-5-fluoro3,4^! -bipyridine-2 ’ -carboxamide;

(S)-4”(4-eyclopropyMH-imidazol-lyi)~N-(3-(4“(3-mediylbutan-2-yl)-4H1,2,4-tria zoi-3 -yl jphenyi) picoiinamide;

6-cyeloprQpy3N~(3(4“CyclopropyMH-l,2,4-tria2ol<3-yl)phenyi)~2_>31bipyridme-6-earboxam ide;

6-cyciopropy.bN-(3-i4-cyclopropyl-4H-l,2,4-triazoi-3-yl)phenyl)-2,3tbipyridine-4-caxboxaniide;

N-i6-(4-eyclopropyi-4H~l_>2_!4triazol-3”yl)pyridin2“yl)-5»(6“ cyclopropy{pyridjn-3-yl)-2,4-diiTtK)robenzamide;

6»eyclopiOpyl-N“(6-(4-cyciopropyl-4H-l,3,4“triazol-3-yI)pyridin-2-y 1)2.31 -bipyridine-4-carboxatnide;

6-cyelopropyl-N-(6-(4-cyclopropyl“4H-3^,4-triazol-3-yl)pyridin-2-yl)3.31 -bipyridine--5-earboxaniide;

6-cyelopropyl-N-(6(4-cye1 opropyi-4H·· 1,2,4 - tr iazol-3 -y Qpyridin -2-y 1 )2,31-hipyridine-6~carboxamide;

N-(3“(4-cy'elopiOpyl-4H-l₅2,4-iriazol-3-yi)phenyi)-4-(5-methyI-4·· (trifluoromethyl)-4,5,6,7 -tetehydro-i.H ~imidazo[4,5-c Jpyridin-1yl)picolinamide;

Ν’(6~(4-εγο1ορΓορχ1-4Η-1,2,4-Ιπ3Ζθ1-3-νΓ)ργή(ϋη-2-γ1)-4-(5-ηιεΰιγ1-4·· (triflyoromethyl)-4₅5,6_} 7 -telrahydro-ΓΗ -imidazo[4,5-c jpyridin-1yj)picplmarnide;

4-( 5-cydoprQpyi-4-meihyi-4H-l ,2,4-biaxol-3-yl)~N-f3-(4~cyclopropy 1 -4 H -1,2,4-triazo!-3-yl)phenyl)picolmamide;

4-(3-cyclopropyi-l ,2,4-oxadiazoi-0-yl)-N“(3-i4-cyclopropyt-4H-1,2,4iri azol -3 -yi)phenyi)pieoliiiami de;

N-(3-(4”Cyclopropyl-4H-l,2,4-triazol~3-yl)phenyl)-4-(3mediyl“l ,2,4oxadiazol-5-yl)picolinamide;

6-cyc.lopropylN-(3(4-(3-hydroxybutan-2»yl)-4H-1.,2.4-toiazol“3yljphenyl )-3,4 ’ - bipyridme-2. ’ -earboxami de;

SUBSTITUTE SHEET (RULE 26)

WO 2017/059252

PCT/US2016/054780

- 49 4»e3iloiO-N»(6-(4-fc:yclopropyI~4H-L2_i4~iriazoI-3--ynpyridm-2--y 1 )-5 -(6cyclopropy Ipyridin-3-y l)-2-11u oro benzamide:

ό-cyclopropy 1-44-(6-(4--( (2S,3 R )-3-hydroxybutan-2-y 1)-414-1,2,4-triazol-3 yl)pyridin-2 y 1)-3,4 ’ -bipyridine-2 ’ «carboxamide;

6-cyclopropy 1-N~(6-(4-( (2S,3 S)-3-hydroxybutan-2-y 1)-4 H-1,2,4triazol -3 -yl)pyri din-2 -y 1 )-3,4’-bipyridine-2’ -carboxamide;

6-βγο1ορΓορν4--Ν-(6-(4-(1-(ρνηΌΗάίίΐ-1-}4)ρίορ;ιη-2-γΓ.)-4Η-1,2,4~ί.ϊ’ϊΗζο1-3yl)pyridin-2-yl)-3,4’-bipyridine-2’-carboxamide;

N-(3-(4-cyclopropyl-4H-i_>2_>4-triazol-3-y1)phenyl)-4-(l -(2,2,2trifluoroethyi)-iH-pytTOlo(3,2-b ]pyridin-6-yi)picoli.namide;

N-(3«(4Cyclopropyi-4H-l ,2,4-lriazo1-3-yl )phenyi)-4-{isopropyl“l pyrroio[3,2-b ]pyridin-6-yl.)picoiinamide;.

S)-6-eyclopropyl-N-(3 -(4-(3,3-diinethylbutari2-yi)-4H«{,2,4-triazoi-3yi)phenyi)-3,4’ -bipyridine-2 ’ -carboxamide;

6-cyclopropyl-N-(6-(4-(l-inethyipiperidin-4-yi)-4H-l_!2₅4-triazol-3yOpyndm-? vri-M bipvndmo ?' unboxtrnnk, 'N''(3(4Sec--butyi-4H-l,2,4-triazol-3-yl)phenyl)-()-cyclopropyl-3_s4’ bipyridine-2’-carboxamide;

(S)-6-cyc1opropyl-N-(3-(4-(l-cyciopropylethyl)-4H-l,2,4-tfiazoi-3·· yl)phenyl)«3,4’~bipyridine-2’-carboxamide;

6«eyclopropyl-ri7.(3../4..(pent3;_fi-3-yi)--4H--’_>2,4--iri3Zoi-3-yl)pfeeiiyl)~3,4’bipyridine-2’-carboxamide;

(S)-6-cyclopropyl-N-(3 -(4-(1 .-methoxypropan -2-yi)-4H- 1,2,4-triazol-3 yl )pheny 1 )-3,4 ’ -bi pyridine -2 ’ -carbox amide;

:6-cyclopropyi.-N-(6-(4-cyc]opropyl-4H-l₅2,44riazo}-3-yl)pyridin-2-yi')6’methyi“3,4’-bipyridine-2⁵-carboxamide:

(S)-6~eye.lopropyi-N--(6-(4-(I-n-iethoxypropa5i-2-yl)-4H-l,2,4--tr.iaxol3·· yi)pyridin-2-yl)-dme-2’-carboxamide;

iS)N-(3-(4--seobaiyl-4H--L2;4-tnazol-3-yl)phenyl)-6-cyciopropyi-3,,9’bipyridine-2’-Carboxamide;

N-(6-(4«cyclopropyj-4FI-l,2_s4-txiazol-3-yl)pyridin-2-yi)-3-(4«(2,2,2{ri.fhjoro-l~methoxyetbyl)-lH -imidazol-l-yl)benzamide;

SUBSTITUTE SHEET (RULE 26)

WO 2017/059252

PCT/US2016/054780

N~(6-(4-Gydopropyl-'411-l,2,4-in_:azol-3“yl)pyridiii-2-yl)-4-(6cyclopropylpyridin-3-yl)-7 ,8-dimethyl quinoline-2~carboxa,tnide;

IS )-6-cyciopropyi-N-(3-(4-(3-inetliyibutan2yl)-4Il· 1,2,4-triazol-3yl)phenyl)-3,4’ -bipyridine-2 ’ -carboxamide;

(R) -6Cyclopropyl-N-(3-(4-(l-(2,6-dimethylphenoxy )propan-2-yl)-4Ml^^-triazol-d-yOphenyO-S/I’-bipyridine^’-carboxamide;

N-(3-(4-cyclopropyl-4H-l,2,4-triazol~3-yl)phenyi .)-4-(6cyciopropyip5Tidin-3-yl)-7.8-dimethyiqumoline-2-carboxamide;

3-(4-cyelopropyi-lH -imidazoi-l-yl)“N(6“(4-cyclopropyl-4H-l,2,4-triazol3-yi)pyridin-2-yl)-4~methoxybenzajnide;

4Chloro-3-(4-cye.lopn)pyl-i H-imidazol-i-yl)-N-(6-(4-cyclopropyl-4Hl,2,4-triazoi-3-yl')pyridin-2-yl)bemmi.de;

4~(4-cyclopiOpyMH -inndazoM-yl)-N-(6-(4-cydopropyl-4B-l,2,4-triazoI3-yl)pyridin-2-yl)quinoline-2^carboxamide;

Ν-(6-(4-ογο1ορΓοργ?-4Η-1,2,4-ΐΓί8ζο1-3-γ1)ργή4ίη-2-γ1)~4-(6“ cyclopropylpyridin-3-yl)quinoline-2-carboxamide;

N-(6-(4-cyclopropyl-4H-1,2,4-Maz0i-3-yl)pyridin2--yl)“5-i6cyclopropylpyridin-3-yl)-2-tluorobenzamide;

(S) -6-cyclopropyl-N-(3-(4-( 1,1,1 -trifluoropropan~2-yl)-4I I- i ,2,4-triazol-3yl )phenyl)-3,4 ’ -hipyri dine-2 ’ -carbox ami de;

(S )-leri -butyl 2-(3-(3-(6-cyclopropyl-3,4’-bipyridine-2’caiboxamido)phenyl)-4H-l,2,4-tria2ol-4-yl)propanoate;

N-(3-(4“Cyclobutyi-4H-l,2,4-triazol-3-yl)phenyl)-6-eyclop«)pyl“3_}4^>bipyridine-2’ -carboxamide;

(S)-6-cyc1opmpyl-N-(3-(4-(lphenylethyl)4H-l,2,4-triaxol“3-yl)phenyl)’ 3,4’ -bipyridinedT -carboxamide;

6-cyclopropy3“N-(3-(4-isopropyl-4H-l,2,4-iriazol-3-yl)pheuyl5-3,4’bipyridine-2’-earboxamide;

3-(4-cyelopropyl-.lH-imidazol-l-yl)-N-(6-(4-isopropyi-4Hl,2,4-tria2ol~3yl)pyridin-2-yl)benzamide;

N-(6-(4-eycIopropyl-4H-l,2,4-iriazol-3-yl)pyridin-2.-yi)-4-(4-(2,2,2trifl uoro-1 -hy droxyethyl)-1H -imidazol-1 -yl)pi colinam ide;

SUBSTITUTE SHEET (RULE 26)

WO 2017/059252

PCT/US2016/054780 • SI (S)-3-(4-cydopropyi-iH-imidazoH-yl)’N^(644-(Upbenyl .tothyl)-4H-1,2,4-triazol-3-yl)pyridin-2-yl)benzamide;

N-(3-(4~eyclopropyi-4H-l,2_i44riazol-3-yi)phenyl)-4-(4-(2,2_>2-lrifluoro-lhydroxyethyl)-lH“iinidazoM-y})picoi!namtde;

N-(6-( 1-cyel opropyl-1H -imidazol-5-yl)pyridin2-yl)-4-(4,5-dimethyl-iHimidazol-1 -yl )picolinamide;

'N-(6-(4-cyclopropyf-4H-l,2,44riazoi-3-yl)pyridin-2-yl)-3-(4-(2,2₃2trifluoro-1 -hydroxyethyl)-1H -imidazol-1 -yl)benzamide;

N-(6-(l-cyclopropyl-lH -imidazol-5-yi,!pyr!din-2-yi)-6-(2- benzamide; hydroxypropan-2-yl)- 3,4 ’ -bipyr i dine-2 ’ -carboxamide;

3- (4-cyclopropyl-IH. -imidazol-l-y1)-N-(6-(4-cyclopropyl-4H-l,2₅4-iriazol3~y{ipyridin-2-yl )-5 -methy Ibenzamide;

N-(6-(4~eyetopropyb4B-l,2,4-tnazol3-yl)pyridin-2-yl)-3-(4_i5dimethyb 1 H-irmdazoi-1 -yl)benzamide;

N-(3-(4-(cyclopropylmethyl)-4H-l,2,4-triazol-3~yl)phenyl>3,4’-bipyridin carboxamide;

4~(4-eyclopropyi-2.-methyi-lH-imidazol-1. -yl)-N-(3-(4-cyciopropyl-4H1.2.4- triazoi-3 -yl )phenyl)picolinamide;

4- (4-cyclopropyl-2-raethyl-lH-imidazol-l-yl)-N-(6-i4-cyclopropyl-4B1.2.4- triazol-3-yl)pyridin-2-yl)picolinamide;

4-(4-cyciopropyl“lH“imidazollyl)-N-(3'(4-isopropyl-4H-I,2,4-triazol-3yl)phenyl)pieolinamide;

4-(4-eyelQpr0pyl-lB-imidazoM-yl)-N-(3-(4“( cyclopropylmethyl)-4Hl,2,4“triazol-3-vl)phenyi)picolinamide;

4-(4-cycf opropyl-1 -imidazol-1 -yl)~N~(3~(4-( 1 -phenyleihyl)-41I-1,2,4taazol-3-yl)phenyl)picoiinamide;

N-(6-t4-cyelopropyI-4H-1_i2,4-triazol-3-yi)pyridin-2-yl)-4-(4,5,6,7tetfa hydro- i H- benzo [ d jimidazol -1 -yl )pi cob n amide;

N~(6~(4~cyclopropyl-4H-l₅2_s4-triazol-3-yi)pyridin-2~yl)-4-i4(trifluoromethyl)-lH -imidazol-l-yl)picolinamide;

Ν-(6“(4--ονο1ορΓ0ργ1-4Η-1,2,44π3Ζ0ΐ3“γ1)ργη41η·-2-γ1)-3~(4..5,6,7' tetra hydro-1 -benzo [ d j i mi dazol -1 -yl jbenzarnide;

SUBSTITUTE SHEET (RULE 26)

WO 2017/059252

PCT/US2016/054780 ·· S2 l-(3-(6-(4’Cyclopropyl-4H-3.,2,4triazol-3-yl)pyndin-2yicarbamoyl)ph8nyi)-5-raeihyl-lH-imidazole-4~carboxylieacid;

(S)“3“(4-cyclopropyMH-imidazoi-l-yl)-N-(6-(4-(l-phenylethyl)-4H-.1,2,4” triazol-3-yl)pyridin-2-yl)benzamide;

6-cyclopropyl-N-(6-(4-cyc1opropyMH-l,2,4»triazol-3-yl)p'yridin~2-yl)-5’methyl-3,4 ’ -bipyridine-2’-carboxamide;

(8)-3-( 4,5-dimetbyl-lH-imidazol-l -yl)-N-(6~(4-( 1 ,1,1 -trifluoropropan-2yl)-4H-I,2_>4-triazol-3-yl)pyridin-2-yl)benzamide;

N-i3-(4-cyciopropyl-4H-l,2_!4-iriazol-3-yl)pheny!)”4-(2-ethylpynmidin-5yl)picoliiiamide;

(R)-4-i4-cyclopropyl-jH“imidazol-l-yl)-N-('3-(4-(1,1, l-ni-fluoropropan-2yl>4H-i,2,4-fcriaz.ol-3-'yl)pbenyl)pieQlinaroide

N-(3-(4-cycIopropyE4H-l ,2,4-ίπ8ζοΚ3-γ{)ρΗ6ην1)-5-«±γί-3,4’-bipyridine2’-carboxamide;

6-cydopropyl-N-(3-(4-cyclopropyl-4H-1,2,4-triazol-3-yl)“

4-{luorophenyl)-3,4’-bipyridine-2’-Carboxamide;

N-(3-(4-cyclopropyl-4H-l,2,4-tnazol-3-yl)phenyl)-4-(l,5-naphthyridin-3yl)picolinamide;

N-(6“(4-cyclopropyl-4H-i ,2,4-iriaz0l-3-yl)pyridm~2-yi )-3-(1,5naphthyridin-3 ·yl)benzami de;

3»{4-cyclopropyWH-iroidazol-l-yl)~N-(6-{4-cyclopropy1-4H-i,2,4-iriazol~ 3 - y i >py ri din -2 ~yl)henzamide;

N-(3-(4-cyclopropyl-4H-l,2,4-triazoi-3-yl)-4-f3«orophcnyl)“6-eiby 1-3,4’bipyri din carboxamide;

6-tert-butybN-(3-(4-eyclopropyi-4H-1,2,4-triaxoU3vyi)pbenyl)43,4’bipyridme-27-earboxainide,’

N--(6-(4-cyciopropyl-4H-t2,4”iriazoi-3-yl)pyridin--2’yh-3-(quinoHn-3-yl)benzamide;

N-(6-(4-cycfopropyl-4H-l,2₅4-triazol-3~yl)pyridin~2-yl)«3-(4isopropyl-lH -im id azol-1 -yl )benzami de;

N.-(6-(4-cyciopropyl-4H4,2.4-tria2oi-3-yi)pyridin-2-yl)-3-(6cyclopropylpyridin-S-yljbenzamide;

SUBSTITUTE SHEET (RULE 26)

WO 2017/059252

PCT/US2016/054780

6-cyelopropyENX2<4-cyclopfopyl-4H-l ,2,4-iriazol-3-yl)

3-(4 -cycfopropyl-lH-imid«-izo{l-yl)-N-(6-(4 -cyclopropyl- pyridin-4-yl)3,4’ -bipyridine-2 ’ -carboxamide;

R-l,2,4-triazol-3-yl)pyridin-2-yl )-2 -methylbenzanride; N-(6-(4-eyclopropyl-4H-1,2,4-triazoi-3-yl)pyridin-2-yi)-4-i4(trifluorome'thyl)-4,5,6,7-tetrahydro-lH-iinidazo[4,5-c]pyridm-l-yi)pic0linamide; N-(3 -(4-cyelopropyl-4H-1,2,4-triazol-3-yi)phenyl)4-(4(iri.fluorornethyl)-4,5,6,7 -teixahydro-lH -imidazo[4,5-c]pyridin-lyljpicoiittamide;

5-i4-cydopropyl-iH~iinida2oJ-i-yl)-N-(6-(4-cyelopropyi-4 H -1 ,2,4triazol-3-yl)pyridin-2-y l)-2-metbylbenzamide;

N-(3-(4-cydopropyi4H-l,2₅4-triazol-3-yi)pbedyi)4-(4{peHliiffroethyl)IH-ttnidazol-1 -yl )pieolinaniide;

N-(6~(4~cyeiopropy{-4H-l,2,4-triazol-3-yl)pyridin2-yl)-4~(4(perfluoroethyi)-1H -imidazob 1 -yl)picolinamide;

3- (4-cyclopropyi-lH“imida20l-l-yl)-N-(6-(4-cyclopropyl-4H-1_s2,4-triazol3-yl)pyridffi-2-yl)-4-ffierbyibenzamide;

4- (3-cyclopropyl- 111-1,2,4-triazol- UyI)-N-(6-(4-cyclopropy 1-4H-1,2,4tri azol - 3 -yl ipy ri din-2 -yI )picolinamide;

4-(3-cycfopropyl-lH-l,2,4-triazol-1-y1)-N-(3-(4-cyclopropyi-4H-l ,2,4-. iriazol-3-yl)phenyl)picolinamide;

4-(5-eyclopropy1-'IH-l,2,4-triazoli“yl)“N-(3-(4~eyclopropyl-4H-l,2,4triazol-3-yl)phenyl)picolinamide;

N-(6-(4-eyelopropyl-4-H -1 ,2,4-triazol-3-yl^pyridin-2-yl)-3(6-(2-hydmxypwpan-2-y0pyridin-3-yi)henzamide; 3-<4-:cyelopropyl~lH-imidaz!ol-.l-yi)-N-(6-(4-cyelopropyl4 H -1 ,2,4-trmzol-3-yl)pyridin-2-y l)-5-fiu oro benzamide; N-(2-{‘l-cydopropyl-4'H-i,2,4-triazol-3-yl)pyridin-4-yl)'4(quinolin-3-yi)picoli.namide;

N-(3-(4-eyclopropyl-4H-i,2,4-triazoi3-yl)phenyl)-4-(5,6,7, 8-tetrahydro-1,6-naphihyndin-3-y1)picolinamide;

SUBSTITUTE SHEET (RULE 26)

WO 2017/059252

PCT/US2016/054780 · 54 6<yeiopropyl-NU(3.(4._ey^prQpyl4H.i_s2₅4.t_i-t_aZol-3-yl)-2-fl.uorophenyl>

V l'bipyfithik-2'-c_tirbo\.iraiik·,

5- cyelopropyTN-(3-(4-cyclopropyHH-l^^-triazol-'J -yl)phenyl)-3,4’bipyridine-2 ’ -carboxamide;

N--i3~(4<:ycdopr(>pyl-4H--I,2,44riazoi-3-y!.)-2'fluorophenyl)-3,4’bipyridme-2 ’-carboxamide;

N-(3-(4-cyclopropyl-4.H-1.,2,4-triazol-3-yl)phenyl)-4-(4-ethyl-lH -hmdazob- 1 -yi jpieolinamide;

N-(6-i4-cyclopropyb4H-l ,2,4-triazof-3-yl)pyridin-2-yl)-4“(4“methyl“lH imidazoM-yi)pieo3inamide;

'N-(6-(4“Cyclopropyl-4H-l,2,4-triazol-3-yl)pyridin-2“yl)-4-(4,5-dimethyi1 H-iraidazoi-1 -yl)picol inarn ide;

N-(3-(4-cyciopropyi~4H-IfeA-triazol-3-y()pbenyl)-4~(6-(2,2,2irifluor»eth.yl>5,6,7 ,8-tetrahydro-l ,6-naphthyridin-3-yl)picolinamide;

N-(3-(4-cyclopropyl-4H-l,2,4-triazol-3-yl)phenyl)-4-(4-isopropyl-lHimidazol-1 -yl)pjeohttarmde;

'N-(3-(4-cyclopropyl'4H-l,2,4tfia2ol-3-yl)phenyl)-6~(2’hydroxypropan-2·· yS)'-3,4ⁱ-bipyridine-27-Carboxandde;

N-(6-(4-cyclopropyJ-41 4-1,2,, 4-tii azol-3~yl)pyridin-2--)4)-6(2-hydroxypropan-2-yl)-3,4’“bipyridine-2’-Carboxamide;

N-(6-(4-cyclopropyl-4H-l,2,4-triazole~3-yl)pyridm-2-yl)-4-(4“isopropy{-lH

-imidazol-l -yl)picolmamide;

6- cyclopropyl-N-(3-(4-cyclopropyi-4H-l_s2,4-triazol-3-y!)-5-fluoropheny 1 )-3,4' -bipyridine-2 ’ -carboxaraide;

N - (3 -(4 -cy clopropyl ~4H -1,2,4-triazoE3 -yl)- 5 -11 uorophenyl)-3,4 ’ bipyri dine .-2 '-Car boxamide:

4^(4-cyc{opropyl- -IH-imidazol-1 -yi)-N46-(4~eyclopropyl-4H-l ,2,4-triazol3“yl)pyridiil-2-yl)picolinamide;

N-(3-(4-cyclof»ropyl-4H-l,2,4-triazol“3-yl)phenyl)-6-(2_!2_s2-irifluoroethy{)3,4’ -bipyri dine-2 ’ -carboxamide;

N-(3-(4-cyclopropyl-4H-1,2,4-triazol-3-yl)pfaenyi)-4-(6-isopropyl-5,6,7 ,8tetrahydro-l ,6-naphthyridm~3-yl)picolinamide;

SUBSTITUTE SHEET (RULE 26)

WO 2017/059252

PCT/US2016/054780 ··

N-(3-(4-cyeiopropyi--4H-l_!2,4-tnazo3-3-yl)pheny1)-4-(6-n-!ethy3-5,6,7,8tetrabydro-l,6-naphthyridin-3yl)picolmamide;

N-(3-(4-cyclopropyl-4I-I-L2,4~triazol3-yl)pheiiyl)-4-(3-hydiO.xypiperidin1 -yilpicolinamide;

N-(6-(4-eyclopropyl-4H-l,2,4-triazol-3-yi)pyridin-2-yl)~4-(3hydroxypiperidiN-1 -y 1 )picolinamide;

6-cyclopropyl-N-(6-(4-isopiOpyl-4H-1. ,2,4-triazol-3-yl)p.yridin-2·-yl )--3,4 ’ bipyridine-2 ’-carboxamide;

N-(3-(4-cyclopropyl-4H-l,2,4-6'iazol-3-yl)pheoyl)-4--(4-eihy 1-3oxopiperaziN-Uyl)pieolinamide;

'N'-{6-(4Cyclopropyl-*4H-l₉2<4~triazol-3-'yl)pyridiri-2.-y.l)~4(4-eihyl~3oxopjpsraziN-by I tpmol nsmide;

(R.)-6-cyclop) op> I 19-(6--(4-(1,1,1 -teifluoroptopan-2-yl)-4R-l,2,4-lriazol” 3-yl)pyridm-2-yl)-3,4’ -bipyridine>2'-cait)oxaratde;

N-(3-(4-isopropy!-4H-l,2,4-triazol-3“yl)phenyl)-3,4’-bipyridine-2’carboxamide;

6-cyclopentyl-'N'-(3-'i4-cyclopropyl-41i“l,2,4-(riazoi-3-yl4)li&nyl)-3,4⁵bipyridine-2' -carboxam ide;

N-(3-(4Cyclopfopyl-4H-l₅2,4-triazol-3-yl)phenyl)-6-(l-jnethyl-2oxopyrrolidin-3-yl)-3,4’”bipyridine-2’-Carboxamide;

N-i6-(4-eyciopropyl-4H-l_>2,4-fcriazol-3-yl)pyri.din-2-y1)-4-(4-(N-metliyl sulfamoyl iphenylipicolinami d.e;

N~(6-(4-cyelopropyl-4H-lA44riaz0l-3-yi)pyridin~2-yl)-4“(quitiolin“3yljpicohnamide;

N-(6-(4-cyclopropyl-4H-1,2,4-iriazol-3“yl)pyndim2-yl)-4-(4-phenyWH imidazoj-l~yl)picolinarnide;

N--(3-(4-cyclopropyMfI-1,2,4-triazo 1-3-ν1)ρίιεην1)-6-ρΐ'ορ) 4 i bipyri dine.-2 ’-Carboxamide:

N~(3~(4~cyciopropyl-4H-l,2,4-ir)azol”3-yi)pheoyi)-6-neope!riyi--3,4’bipyndine 2' - Carboxamide;

19-(3-(4-cyc1opropyl-4H-1,2,4-triazoi-3-yl)phenyl)-4-(l -methyl-2-phenyllHimidazoi-5-yl)pieoiinamide;

SUBSTITUTE SHEET (RULE 26)

WO 2017/059252

PCT/US2016/054780

.. 56 ..

Ν-(3-(4-ονε)ορΓορν1-4Η-1,2,44π&ζο1-3-γ1)ρ1κίηγ1)-4-(4-ύ&ν1 sulfonyOpheny 1 )-picolinamide;

N-(3-(4-cyc{opropyl-4H-l,2_s4-{riazoi-3-yl)phenyl)-4-(4“ (i sopropy) sul touyi )phe-ny f) p tc oli na m ids;

N-(344toyclopropyMH~l,2,4-friazoi-3-yi)pheiiyl)-6-( thylamino)-3,4’ bipyridine-2^; -carboxamide;

K43-(4-eyd0propy{-4H4,2<44riazoI-3-yi)phenyl)-6-( cyclopropylamino)3 _f4’-hipyridine-2⁵ -carboxamide;

M-(3-(4-cyclopropyl-4H-V,4-triazol-3-yl)phenyl)-4-(imidazo[2,1-b] [1 ,3,4]thiadiazol-5-yl)picolinamide;

4-(4-cbloro-lH -5ΐηίύ&ζο1-.1-γΙ}··Ν·-(3-·(4-ο>'4ορΓοργ]-4Η-1,2,4-ηίίίζο1-3yl)phenyl)picolinamide;

Κ-(3-(4-ογς1ορΓοργ1-4Η-1,2,4-ίτίηζο1-3^1)ρΕ«ηχ1)-4-(2cyclopropylpyrimidm-S-yDpicolmamkle:;

N-(3~(4-cycl0propyl-4H-l_>2_s4-iria2ol~3-yl)pheny{)-6’-(triiI'uorQmethyl)3,4 ’ -bipyridine-2 ’ -carboxamide;

N-(3(4-cyc1opropyl-4H-l₍2,4“triazol“3-yl)phenyl)-4-(quinoiin-3-yl)-6·· (iriiltiorometby!)pico]inamide;

Ν-(ϊ>-(1-cyclopropyl-HI -imidazol-5-yl)pyridin-2-yl}-4-(quinoiin-3yl)picolinamide;

6-cyclopropyl-N-(6-(l-cyciopropyl-lH -imidazol-5-yl)pyridin-2-yl)-3,4’bipyridine 2'-carboxamide;

N-(3-(4-cyciopropyl-4.H-l,2,4-trtazol-3-yl)phenyl)-4-(lHpynolo[3,2-b ]pyridin-6-yi)picolinamide;

Nr(3.’-(4-cycjopropyl-4H-l_J2_>4-triazol-3-yl)pheiiyl)~4-(4cyc 1 opropy1 phe fr yi )pi colinarn ide;

N--(6-(4-cyclopropyl-4H-1,2,4-4 03 4 -3-yi )pyridin--2“yl)-3-10 (pyridin-3 · yObenzamide;

.N-(3-(4-cycfopropyl-4H-0,4-iriazol~3-yl)phenyl)-6-(methyUhio)~3,4’bipyri dine -2 ’ -carboxamide;

N-(3-(4-cycloproi>yi-4H-V,4-triazol-3-yl)phenyl}-6-(isobutylihio )--3,4’bipyridine-2 ’-carboxamide;

SUBSTITUTE SHEET (RULE 26)

WO 2017/059252

PCT/US2016/054780

-- 57 15 N-(3--(4-cycIopropyi-4H-4 KyKriazoi-S-yljphenyO-d-fScydopropylpyrazin2-yl)picolinamide;

6Cyclopropyl”N(3f4-cyciopropyMH.-l_>2,4d'riazol’3-yi)phenyl)’5~.fluoro3,4’ -bi pyridine-2 ’ -carboxamide;

5“Chloro-6“Cyclop.ropyi-N-(3-(4-cyciopn)pyi-4H-l,2,4-{riazoi-3”yl)phenyl)3,4’ -bipyri dine-2' -carbox amide;

N-(3-(4-cye]opropy{-4H-l_s2,4-triazol-3-yl)phenyl)-6-(2methoxyethylarninoj-j/r -hi pyridme-2’-earhoxamide;

N-(3 -(4-cy clopropyi-4H -1,2,4-triazoi-3 -yl )phenyl)-4-(4(methyisulfonyl)piperazin-l-yl)picolmamide;

N-(3-(4-cyciopropyi4Hl,2_!4-triazol3-yl)phenyl)-6-ethyi-5»flu oro-3,4' bipyridine-2 ’ -carboxamide;

5- ehloro-N-(3”(4-cy€lopropyM'H-I_i2,4-iriazol-3^:“yi)pheRyi)-6-eihyWj4’'bipyri dine-2 ’-Carboxamide;

4-(4-cyclopropyl-lH -imidazol-1-yi)-N-{3-(4-cyciopropy!-4H-l,2,4-triazal~

3-yi)phenyl)picofinamide;

N-(3-(4-cyciopiOpyl-4H-l,2,4-triazol-3-yi)phenyl)-5,6-diethyi-3,4’bipyridine-2’-carboxamide;

N-(3-(4-cyciopropyl-4H-l,2,4-triazol-3~yl)pbenyl)-4-(furo[3,2-b]pyridin-6yl)picolinamide;

N-(4-cyclopropyi-4H~l,2,4-triazol-3-yl)pbenyl)-4-(3-methyl-3I-!imidazo[4,5-b]pyiidin-6-yl)picoiinamide;

N-(3-(4-cyclopropyl-4H-1.,2,4-triazol-3-yl)phenyl)-6“(6eye iopropylpyri din-3-yl )pyrimidins-4-earboxam ide,

6- cyciopropyl-NT-3.-(4.-cyclopropyl-4H-l.,2,4-iriazol-3-yi)pbenyl)-.6’ηιβΛγ1-3_!4’-Είργή41η6--2’-οα^οχ<ιηπύβ;

6”CyclopfOpyi-N-(3“(4-cyclopropy.l-4'H-i,2,4“triazol-3-yi)phenyl)“5'“ methyl-3,4’-bipyri dine-2’-carboxamide;

Ν·-(6-(4-ον(:.1ορϊΌρν1-4Η-1,2_;4-ώίϊ.ζο1-3~·νί)ργΓ!άίη2-γ1)~4-(5'·π36ΐ1ιγ1··4(trifluoromethyi)-4,5,6, 7 -tetrahydro-iH -iroidazo[ 4,5-e ]pyridin-lyi )picolinanride;

SUBSTITUTE SHEET (RULE 26)

WO 2017/059252

PCT/US2016/054780

8 N-i'3-(4-cyclPpropyi-4li-i,2,-4-tnazoU3-yl)phenyr)4-(5“inethyi4·· (trifiuororneihyl)-4,5,6, 7 -tetrabydro-ΙΗ -imidazo[4,5C ]pyridin-lyl)picoimamide;

6’-cyclopropyl-N-(6-(4-cyclopropyl-4H-l,2.4-triazoi“3yi)pyridin-2-y{)2,31 -bipyridine-6-carboxamide;

6^f-cydopropylN-(6-(4-cyclopropyl-4H-l,2,4-triazo1-3-yl)pyridin”2”yl)”

3.3 l-bipyridine-5-carboxamide;

6' -cyclopropyl-N-(6-(4-cyclopropyl-4H-1,2,4-triazoi-3-yOpyri din-2-y 1 )2,31 -bipyridine-4-carboxamide;

N-(6-(4-cyclopropyi-4H-l,2,4-ttiazol-3-yl)pyridin-2“yl)-5-(6 eye1opropy1pyridin-3-yi)-2,4diflu0robenzamide;

6’-cyelopropyi-N-(3-(4-cyclopropyl-4H -1 ,2_t4-tnaze.l-3-yl)phenyl)-2,31 bipyridme-6-earbQxanri.de;

fS)-4-(4~eycloptOpyl-lH-imidazoi-I-yl(-N-(3-(4-(3-meihylbutan-2-y0-4Hi,2,4-triazol-3-yl)phenyi)pieolinamide;

4-chloro-N-(6-f 4-cyclopropy1-4H-l, 2,4-triazol~3-yi)pyridin-2-yl )-5-(6cyclopropylpyridin-3-y 1 )-2~fluorobenzamide;

b-eyelopropyl-N-O-id-^-phenyicyclopropyiMH-1,2,4-triazol·3y!)phenyl)-3,4’-bipyridine-2 ’-carboxamide;

N-(3-(4-cycl.q)ropyl-4H-l_>2,4-triazol-3-yi)phenyl)“6”(cyclopropy1methyl)3.4 ’ -bipyridine-2 ’-carboxamide;

3- (4CyclopropyI- {H -1,2,3-triazol-1 -yl)-N-(6~(4-eyclopiOpyl-4H-1,2,4triazol“3-yl)pyridm-2-yl)benzanv_sde,

4- ( 5-cydopropyl-l ,3,4•tiiiadi,t2Ql-2-yl)-N-(3-(4-cyclopropyMH-1,2,4triazoi - 3-yl )phenyl)picolinamide;

6-cyclopropyl-N-{3-(4-pbenyl-4H 1,2,1 tnruol > vi)phcn>l)d 4'bipy.ridme-2’-carboxamide;

6-cyclopropyl-N-(3-(4-(pyridin-2-yl)-4H-i,2,4-triazol-3-yl) phenyl>3,4'-bipyridine-2'-carboxamide;

6-cyclopropyi-N -(3-(4-(pyridi q-3 -yl)-4H-1,2,4-iri azoi-3 ~yl)phenyi)-3,4'bipyridine-2'-carboxamide;

SUBSTITUTE SHEET (RULE 26)

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PCT/US2016/054780

6Cyciopropyl-N“(3-(4-(pyridiR”4-yl)-4H-l,2,4-ttiazol-3-yl)phenyl)-3,4^!bipyridine-2‘-carlx>xamide;

6-cyclopropyl-N-(3-(4-(pyrimidin-5-yi )-41-1-1,2,4»tfiazol“3“yl)phenyl)“3,4'bipyridine-2'-carboxamide:

4-(4-eyclopropyl-lii-imidazoi“l-yl)-N-(3-( 4-(pyridin-3-yl)-4H-l ,2.4-iriazol-3-yOphenyi )pico) inamide;

(l-cyUoinopyl HI iroidu/ol 1 vl) <_vpViriin-4-vl)-4H-t? 1 triazol-3-yl)phenyl)picolinamide;

4-(4-cyclopropyi-lHimida2ol-l-yl)-N-(3“( 4~(pyrimidin-5~yl}-4H -1,2,4triazol -3 -yl )phenyl )pico! inamide; and

N-(3-(4-(but-2-ynyi)-4H-.l,2,4-iriazo1-3-y{)phenyl)-4-('4-cyclopi‘opyl-lHmudazai-l-ylipieohnanude; or a pharmaceutically acceptable salt or solvate thereof, [00126) In some embodiments, the ASKi inhibiting compound is a compound of the structure:

v (cn or a pharmaceutically acceptable salt or hydrate thereof This compound may be referred io as 3-(4-cyclopropyl-1 H-imidazol-1 -yl)-N~(6-(4-cyciopropyl-4H-1,2,4triazol-3-yl)pyridin-2-yl)-4-methy1benzamide or 3-(4-cyclopiOpyl~l//-imidazoll-yl)--V-[6(4Cyclopropyl-4H-l,2,4-triazo{-3-yl)-2-pyridinyl)-4-methyl· benzamide, and .has been assigned CAS Registry No. 1262041 -67-7. The compound and sails thereof including formic acid salt (CAS Reg, No. 126204168-81 may be prepared by methods disclosed in US 2014/0228412 and U.S. Pat. No. 9,067,933.

[00127) in other embodiments, the ASKI inhibiting compound is a compound of the structure;

SUBSTITUTE SHEET (RULE 26)

WO 2017/059252

PCT/US2016/054780 v -<·, ~^:T r

toe i ..

'1' k/ (Cl) or a pharmaceutically acceptable salt or hydrate thereof. This compound may be referred to as 5'(4-eyclopropyl-l H-imidazol-l-yl)-2-fluoro-N(6-(4-isopiOpyl4H-l,2,4-tria2ol-3-yl)pyridin-2-yl)-4-methylbenzamide or 5-(4-cyclopropyl-l//imi dazol-1 -yl)-2'.fluoro-4-meihyi-;V- [6 - [4-(1 -methylethyi .)--4/7-1,2,4-triazoi-3 -yl ] 2-pyridinyf]-benzamide, and has been assigned CAS Registry No. 1448428--04--3. The compound and salts thereof, including hydrochloride salt (CAS Reg.

No. 14-48428--05-4) may he prepared by methods disclosed in US 2014/0228412 and UR. Eat. No. 9,067,933.

1110128) it will be understood that the terms “inhibitor”, “inhibiting compound”, and the like, refer to a compound or agent which presents a-pharmaceutical activity to inhibit activity of certain target in a subject such as human, For example, it will be understood that the terms “ASKI inhibitor”, “ASK ! inhibiting compound”, and “inhibitor of ASKI”, and the like, refer to compounds which present a pharmaceutical activity to inhibit activity of an apoptosis signalregulating kinase 1 in a human. In some embodiments of each of the methods herein, Compound C2 or a pharmaceutically acceptable salt thereof, is used in combination with Compound Al, or a pharmaceutically acceptable salt or hydrate thereof. In other embodiments of each of the methods herein, a compound of Formula 1, or a pharmaceutically acceptable salt thereof, is used in combination with Compound Al, or a phn tn.tveutieally acceptable salt or hydrate thereof, in another variation, the ASKI inhibiting compound is 4-[4-[(4’-ehloro[l,Γbiphenyl}-2-yl)methyl]-l-piperaz:inyi]-N-[[4-{[.(TR)-3-(dimethylammo)-l[(phenyl.thio)methyl]propyiJamino]--3’-ni'trophenyl3sdfony5] benzamide, ora pharmaceutically acceptable salt thereof.

Bromodomain inhibitors [00129] in some variations the BET or BRI) (bromodormiin-eontaming protein) inhibitor is an inhibitor of bromodomain-containing protein 4 (BRD4). In one

SUBSTITUTE SHEET (RULE 26)

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PCT/US2016/054780

- 61 aspect the modulator of a bromodomain-containing protein is a compound of Formula (11):

wherein

R¹* and R^!” are each independently C}.^ alkyl optionally substituted with from 1 to 5 R.^A° groups;

R^::' and R^:ft are each independently H or halo; ifr is

C(Q)OR\ -NHC(0)OR^S, -NHS(O)₂r, or -S(O)₂NrR^b; or selected .from the group consisting of Cm» alkyl, Cj.jo alkoxy, amino, C5-10 aryl, CY20 arylalkyl, Ci ao heteroalkyl, C<_!0 heteroaryl, and C^o heteroarylalkyl, each of which is optionally substituted wi th from 1 to 5 R²⁰ groups;

one of R^4i> and R⁴ is selected from the group consisting of H and Cu alkyl optionally substituted with from 1 to 5 R^A’ groups, and the other is absent;

R⁵ is -C(O)OR^a, -NHC(0)OR\ -NHS(O)₂Rh or -S(O),NR^aR^b; or

R⁵ is selected from the group consisting of H, Cmo alkyl, C,.·,₀ haloalkyl.

Cmo alkoxy, amino, C₅~so aryl, Q..?o arylalkyl, Cmo heteroalkyl, C5.10 heteroaryl, and C6.20 heteroarylalkyl, each of which is optionally substituted with from 1 to 5 groups;

each R⁸ and R^b is independently selected from the group consisting of 11,

Cmo alkyl, C₅.₁₉ aryl, C^o arylalkyl, C_W9 heteroalkyl, C₅.,_w heteroaryl, and CUy, ·»·\ heteroarylalkyl, each of which is optionally -substituted with from 1 to 5 R' groups; and each R²⁰ is independently selected from the group consisting of acyl, Cj-10 alkyl, Cmo alkoxy, amino, amido, arnidino, Cs-10 aryl, arylalkyl, azido, carbamoyl, carboxyl, carboxyl ester, cyano, guanidino, halo, Cj.-.o haloalkyl, Cwo

SUBSTITUTE SHEET (RULE 26)

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PCT/US2016/054780

-((2heteroalkyl, Qjo heteroaryl, Ce-2o heteroarylalkyl, hydroxy, hydrazine, imino, oxo, nitro, sulfinyl, sulfonic acid, sulfonyl, thiocyanate, thiol, and thione;

wherein the Cj.jo alkyl, Cs-jo Gwo arylalkyl, C1.·ο heteroalkyl, C₅-j0 heteroarvl, and C<w.o heteroarylalkyl groups are optionally substituted with from 1 to 3 substituents independently selected from Cm alkyl, 65.,0 aryl, halo, Cm haloalkyl, cyano, hydroxy, and Cm alkoxy;

or a pharmaceutically acceptable salt thereof.

[001301 Compounds of Formula (II) (which include compounds of any of Formulae (Ra), (fib), (He), (fid) and (fie), described below) can include, independently, one or more of the following features. It will be recognized that, features specified in each embodiment may be combined with other specified features to provide further embodiments..

[00131] In some compounds, R‘^a and R'^k are each independently Cm alkyl which, as: defined herein, includes alkenyl, alkynyl and cycloalkyl. In some compounds, R^la and R^{1 a} are different, and in other compounds R^la and R^ifc are the same. In some compounds, R^iK and R^lb are each independently a Cm alkyl optionally substituted with 1-5 R²⁰ groups. In some compounds, R^la and R^!o are both methyl. In some compounds, one of R’^a or R.’^:' is a methyl and the other is a methyl substituted with a hydroxy. In some compounds, R^la and R^ln are both methyl substituted with a hydroxy, in some compounds, one of R‘^a or R^l° is a methyl and the other is a methyl substituted with an amine. In some compounds, R‘^a and R^ls are both methyl substituted with an amine.

[00132] In some compounds, R^2i; and R^ib are both H. In some compounds, R^Ja and R^ib are both halo. In some compounds, one of R^la and R^b is H and the other is halo. In some compounds the halo is -F or -Cl, ·' [80133] In some compounds, R' is boronic -acid, a boronic add ester, or halo. In some compounds, R³ is -C(O)OR^a, -NHC(O)OR^a; -NHS(O)₂R^a, or -S{O)2.NR^aR^fcwherein R^a and R” are described above. In some compounds, R^J is -C(0)OR^a, NHC(O)OR^a, -NHS(O)2R^a, or -S(t))dsR^aR^b, wherein each R^a and R^k is independently Cj_io alkyl, C$.(9 aryl, Cmo heteroalkyl or C5.W heteroaryl, each of which may be optionally substituted as described above, For example, in some compounds R³ is -C(O)OR^a, -NHC(O)OR\ -NHS(O)2Rh or -S(O)₂NR^aR^b,

SUBSTITUTE SHEET (RULE 26)

WO 2017/059252

PCT/US2016/054780 wherein each R^a and R is independently €3. _w aryl or C-s.jo heteroaryl. In some compounds, R:’ is selected from the group consisting of Cj.w alkyl, C 1-:,.1 alkoxy, amino, C.s.}0 aryl, C$.20 arylalkyi, C:.r. heteroalkyl, C$.10 heteroaryl, and C$.20 heteroarylalkyl, each of which is optionally substituted with from 1 to 5 groups, wherein R' is described above. In some compounds, .R' is Cm,, alkyl,

Calkoxy, or Cfoio heteroalkyl, each of which may be optionally substituted as described above, in some compounds, the heteroalkyl is a heterocyeloaikyl. In other compounds, R³ is C$.20 arylalkyi or C$.33 heteroarylalkyl, each of which may be optionally substituted as described above. In other compounds, R³ is C$. 10 aryl, C«® arylalkyi, C$.10 heteroatyl, or C_ft.₂o heteroarylalkyl, each of which may be optionally substituted as described above. In some compounds, R³ is amino optionally substituted as described above. For example^ in some compounds R' is -Nflj, and in other compounds R’ is -NfCR') wherein R^y and R' together with the nitrogen to which they are bonded form a Cm® heteroalkyl or C5.50 heteroaryl, each of which maybe optionally substituted as described above, [00134] Other non-limiting examples of R'¹ include the following:

SUBSTITUTE SHEET (RULE 26)

WO 2017/059252

PCT/US2016/054780

,,Τ Ά'

OH

Γ 'ςζ e 7

HN >

?

v/VW

wAW

s? ¹ v

A

A'Ν' A.

/ /N

O' . Z·—,,···' <

A J AY .A-,/ ο*

X.

A:

N*A

ΑΧ ^f li N a >s

A~N

-,1 r⁵ T NH

AT

X ,$ . / c’S'xA'X r* Ί 1 r ϊ NH tes-»,/ / - 'N '•••Ζ e *^y Ί z* '

SUBSTITUTE SHEET (RULE 26)

WO 2017/059252

PCT/US2016/054780

SUBSTITUTE SHEET (RULE 26)

WO 2017/059252

PCT/US2016/054780

AB

v/ i

WV

Xc· X , ..*' ··

Άν vr !

^Ar

WV

A wv

^x0H

A/W

[00135] In some compounds, One of R^t!: or R^4b is H and the other is absent, that is, in some compounds R^4a is H and R⁴” is absent, and in other compounds R*⁸ is absent and R^4b is H. In other compounds, one of R'^i:i and R‘^vl' is alkyl and the other is absent, that is, in some compounds R^4a is alkyl and R^4,! is absent, and in other compounds R^4a is absent and R^4b is alkyl, In some compounds the alky] is methyl, [00136] In some compounds, R⁵ is -C(Q)OR^a, -NHC(O)OR^S, -NHSiO^R⁸, or S(O)jNR^aRⁿ, wherein R^a and R^s arc described above. In some compounds, R⁵ is -C(O)ORy -NHC(O)OR\ -NItS(OhR^s, or ~S(O),NR^aR^b, wherein each R⁸ and R^bis independently (?·ι_]o alkyl or C5.10 aryl, each.of which may be optionally substituted as described above. For example, in some compounds .R;' is NFIC(O)OR“, wherein R^a is methyl. In some compounds, R⁵ is -NHSO-tRb wherein R⁴ is alkyl or CAso aryl, each of which may be optionally substituted as described above. For example, in some compounds R^? is - NHS(O)2R^a, wherein R'^! is eyelopjopyl. In some compounds, R' is selected from the group consisting of'H, Cwo alkyl, Cwt a halealkyi, Cwo alkoxy, amino, CA10 aryl, (Aoq arylalkyl, Cwjo heteroalkyl, C5.10 heteroaryi, and C_;;.,?o heteroarylalkyl, each of which is optionally substituted with from 1 to 5 R^4W groups, wherein R^2,}is described above. In some compounds, R' is Ct..so alkyl optionally substituted as described above. In some compounds the Cj.jo alkyl is a Cj.jo cycloaikyl, e.g. cyclopropyl. In other compounds, R^J is amino optionally substituted as described

SUBSTITUTE SHEET (RULE 26)

WO 2017/059252

PCT/US2016/054780 (it?

above. For example, in some compounds R⁵ is -NH-?, and .in other compounds R^sis -NR^yR^z, wherein R^y is H and R^z is alkyl, e.g. cyclopropyl, in other compounds, R⁵ is alkoxy, e.g. methoxy.

[00137] In some compounds, R^ia, Rⁿ\ R’, RU R’¹’ and IF' are optionally substituted with from I to 5 (i.e. 1,2,3,4 or 5) R²⁰ groups as described above. In some compounds, R^u, R^i;\ R', R^4s, R^4ts and iV are optionally substituted with 1,

2, or 3 R^?'° groups. In some compounds, each R^’ is independently selected from the group consisting of alkyl, alkoxy, amino, cyano, halo, haioalkyl, heteroaikyl, hydroxy, and sulfonyl. In some comounds, each R^2b is independently selected from the group consisting of aryl, alkylaryl, heteroaryl, and heteroalkylaryl. In some compounds, R^!\ R^lb, R^J, RU R^k’ and R⁵ are not substituted. In some comounds, R^ is not substituted.

[00.138] One subset of compounds- of Formula (II) relates-to compounds of formula Ilia)

N-Q /Λ -.

Γ 1

.....

wherein

R^!,: and R^;b are each independently Ch.6 alkyl optionally substituted with from 1 io 5 R³'¹ groups;

R³ is boronic acid or halo; or

C(O)OR^!\ -NHCfOfOC -NHS(O)2R\ or -S(O)UK^;;Ry or selected from the group consisting of C:..₎₉ alkyl, Cj-io alkoxy, amino, C5.10 aryl, Cg.» arylaikyl, Cmo heteroaikyl, C5.10 heieroaryl, andQ.20 heteroarylalkyl, each of which is optionally substituted with from 1 to 5 IT ’ groups;

one of R^4a and R^4b is selected from the group consisting of H and €).?, alkyl optionally substituted with from 1 to 5 R^z0 groups, and the other is absent;

is

C(O)OR^a, -NHC(O)OR^S, -NHS(O.feR\ or -S(O)₂NR^aR^b; or

SUBSTITUTE SHEET (RULE 26)

WO 2017/059252

PCT/US2016/054780 selected from the group consisting of H, C·..jo alkyl, Cmo haloalkyi, C_Pf(> alkoxy, amino, C₅.j,) aryl, C₍mo arylalkyl, Cmo heteroalkyl, C₅.₁₀ heteroaryl, and C.\20 heteroarylalkyl, each of which is optionally substituted with from I to 5 R^w groups;

each R‘^! and R° is independently selected from the group consisting of H, Cj-ie alkyl, Cs-jo aryl, Gmc arylalkyl, Cmo heteroalkyl, Csuo heteroaryl, and C^o heteroarylalkyl, each of which is optionally substituted with from 1 to 5 R^/Jgroups; and each A is independently selected from the group consisting of acyl, Cmo alkyl, Ci_jo alkoxy, amino, amido, amidino, C540 aryl, C₆.₂₀ arylalkyl, azido, carbamoyl, carboxyl, carboxyl ester, cyano, guanidino, halo, Cmo haloalkyi, Cmo heteroallyl, heteroaryl, heteroarylalkyl, hydroxy, hydrazine, imino, oxo, nitro, sulfinyl, sulfonic acid, sulfonyl, thiocyanate, thiol, and thione:

wherein the Ci.m alkyl, Cfoie aryl, C_f,2o arylalkyl, Cmo heteroalky!, Cj-io heteroaryl, and C₆._2I) heteroarylalkyl groups are optionally substituted with from 1 to 3 substituents independently selected from Cm. alkyl, C5.10 aryl, halo, Cfo, haloalkyi, cyano, hydroxy, and Cu alkoxy;

or a pharmaceutically acceptable salt thereof, [00139] Another subset of compounds of Formula (II) relates io compounds of

Formula (lib)

N-o <7 \ ^RW*

Aw /-NH Ffr (lib) wherein

R*^a and R^:' are each independently Ci._(i alkyl optionally substituted with from 1 to 5 R^a' groups;

R²® and R^2b are each independently H or halo;

R³is boronic acid or halo; or

C(O)OR^S, -NHC(O)OR⁸, -NHS(O)2R^a, or -S(O>2NR®R^b; or

SUBSTITUTE SHEET (RULE 26)

WO 2017/059252

PCT/US2016/054780 selected from the group consisting of Cmo alkyl, Cmo alkoxy, amino, Cmo aryl, C$.20 arylalkyl, Cmo heieroalkyl, Cmo heieroaryl, and C$.20 heteroarylalkyl, each of which is optionally substituted with from 1 to 5 R'^<l) groups;

F is

C(O)OR\ -NHC(O)()R^a, -NHS(O)2R^a, or -S(O)2NR^aR^b; or selected from the group consisting of H, Ch.;o alkyl, Cmo haloalkyl, Cmo alkoxy, amino, C₅._{o aryl, C$.30 arylalkyl, Cmo heteroaikyl, (/5.-10 heieroaryl, and C_;>20 heteroarylalkyl, each of which is optionally substituted with from 1 to 5 R^ibgroups;

each R’and R” is independently selected from the group consisting of H,

Ch 455 alkyl, Cmo aryl, C$.20 arylalkyl, Cmo heteroaikyl, Cmo heieroaryl, and C$.20 ' t) heteroarylalkyl, each of which is optionally substituted with from 1 to 5 R* groups; and each R^iV is independently selected from the group consisting of acyl, Cms alkyl, Cj-ro alkoxy, amino, amido, amidino, C5.10 aryl, C$.20 arylalkyl, azido, carbamoyl, carboxyl, carboxyl ester, cyano, goanidtno, halo, Cmo haloalkyl, Ci.io heteroaikyl, C₅. μ, heieroaryl, C$.20 heteroarylalkyl, hydroxy, hydrazine, imino, oxo, nitro, sulfinyl, sulfonic acid, sulfonyl, thiocyanate, thiol, and.thione;

wherein the Ci.io alkyl, C5-10 aryh Oj-20 arylalkyl, C·.-so bctcroaH.*) 1, €5.-,0 heteroaryl, and C$.30 heteroarylalkyl groups are'optionally substituted with from 1 to 3 substituents independently selected from Cm5 alkyl, Cmo aryl, halo, C).$ haloalkyl, cyano, hydroxy, and C]..$ alkoxy;

or a pharmaceutically acceptable salt thereof.

[00140] /Another subset of compounds of Formula. (II.) relates to compounds of Formula (He)

wherein

SUBSTITUTE SHEET (RULE 26)

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PCT/US2016/054780

- 70 R'^! and R¹’ are each independently Cm alkyl optionally substituted with from 1 to 5 Rⁱ⁰ groups;

Itiw boronic acid or halo; or

C(Q)OR\ -NHC(O)OR^S, -NHS(O)2R⁸, or-S(O)2NR^aR^b; or selected from the group consisting of C-j-io alkyd, Cj.jo alkoxy, amino, C5-10 aryl, C₆.₂o arylalkyi, C,.jo heteroalkyl, C5-10 heteroaryl, and C«o heteroarylalkyl, each of which is optionally substituted with from 1 to 5 R‘^?o groups;

P.' is

C(O)OR\ -NHC(O)QR\ -NMS(O)₂R^a, or-S(O)₂NR^aR^b; or selected from the group consisting of H, C₃_«> alkyl, C>haloalkyl, Cj.jo alkoxy, amino, C₅.;o arvl, C«j arylalkyi, Ci,.i_C heteroalkyl, C5.10 heteroatyl, and C^. 20 heteroarylalkyl, each of which is optionally substituted with from 1 to 5 R^2<igroups;

each R^! and R° is independently selected from the group consisting of H, Ciao alkyl, C5.50 aryl, C₆..₂s arylalkyi, Ci„io heteroalkyl, C₅._K) heteroaryl, and C«.o heteroarylalkyl, each of which is optionally substituted with from 1 to 5 R^° groups; and each Κ'^υ is independently selected from the group consisting of acyl, C1-10 alkyl, Cmq alkoxy, amino, amido, amidino, C5.;,} aryl, €¢..20 arylalkyi, azido, carbamoyl, carboxyl, carboxyl ester, cyano, guanidino, halo, Cr-ίο haloalkyl, Cmo heteroalkyl, C5-10 heteroaryl, Q.™ heteroarylalkyl, hydroxy, hydrazino, imino, oxo, nitro, sulfinyl, sulfonic acid, sulfonyl, thiocyanate, thiol, and thione;

wherein the C_wo alkyl, C5.j0.aryl, Q.₂o arylalkyi, Cj-to heteroalkyl, C540 heteroaryl, and heteroarylaikyl groups are optionally substituted with from 1 to 3 substituents independently selected from Cm alkyl, C₅.j₀ aryl, halo. Cm haloalkyl, cyano, hydroxy, and 0-m alkoxy;

or a pharmaceutically acceptable salt thereof, [00141] Another subset of compounds of Formula (11) relates to compounds of formula (lid)

SUBSTITUTE SHEET (RULE 26)

WO 2017/059252

PCT/US2016/054780 '-J· ./

R^s uld) wherein

R³ is boronic add or halo; or

C(O)OR\ ~NHC(O)OR^a, -NHS<O)2R^a, or -8(O)2NR^sR^b; or selected uotu tk-'inup c,»n>,,·>.mg ol t .dUh? j <tikiw> amiim h ' aryl, Cf,..20 arylalkyl, Ci.·.}>heteroaikyl, ¢/5.:0 heteroaryl, and heteroarylaikyl, each of which is optionally substituted with from 1 to 5 R^a groups;

R' is

C(0)OR\ -NiIC(O)OR^a, -NHStOfeR⁸, or -S(O)₂NiCR^b; or selected from the group consisting of H, Cmo alkyl, Ckt<, haloalkyl, Cmo alkoxy, amino, C₅._i0 aryl, C^o arylalkyl, C:.._j3 heteroalkyl, C₅-io heteroaryl, and C«. 20 heteroarylaikyl, each of which is optionally anbstitnted with from 1 to S R²'³groups;

each R⁴ and R.^b is independently selected from the group consisting of H, Cj-fo alkyl, C5-10 aryl, C₃.jn arylalkyl, Cmo heteroaikyl, C5-jo heteroaryl, and C^-ao heteroarylaikyl, each of which is optionally substituted with from 1 to 5 R^K' groups; and each R‘^?o is independently selected from the group consisting of acyl, C j ,_i0alkyl, C: ,_!δ alkoxy, .amino, amido, amidine, Owe Wk Q-2q arylalkyl, azido, carbamoyl, carboxyl, carboxyl ester, cyano, guanidino, halo, C1..30 haloalkyl, Cuo heteroaikyl, ¢/5.:0 heteroaryl, C₀..?₃ heteroarylaikyl, hydroxy, hydrazine, imino, oxo, nitro, sulfinyl, sulfonic acid, sulfonyl, thiocyanate, thiol, and thione;

wherein the Cmo alkyl, C5.10 aryl, Cg.._2c arylalkyl, Ci-jo.heteroaikyl, C₅..;c heteroaryl, and Cg.?:. heteroarylaikyl groups are optionally substituted with from 1 to 3 substituents independently selected from Cm alkyl, C5.10 aryl, halo, Cm . haloalkyl, cyano, hydroxy, and Cm alkoxy;

or a pharmaceutically acceptable salt thereof.

SUBSTITUTE SHEET (RULE 26)

WO 2017/059252

PCT/US2016/054780 [00I42J Another subset of compounds of Formula (II) relates io compounds of Formula (He)

N-Q

HN J >

Wt wherein

H' is boronic acid or halo; or

C(O)OR^a, -NHC(O)OR^a, -NBS(O)₂R^a, or -8(0^1^; or selected from the group consisting of <· .·;; alkyl, €549 alkoxy, amino, C₅.io aryl, Co·, arylalkyl, Cm;, heteroalkyl, G49 he.teroaryl, and C₆..?o heteroarylalkyl, each of which is optionally substituted with, from 1 to 5 R^il! groups;

each R^aand R^b is independently selected from the group consisting of H, Ci.io alkyl, C5-10 aryl, Cfrco arylalkyl, Cue heteroalkyi, C5..J0 heteroaxyl, and C^o heteroarylalkyl, each of which is optionally substituted with from 1 to 5 R²⁰groups; and each R⁴’¹ is independently selected from the group consisting of acyl, Cmo alkyl, Cmo alkoxy, amino, amido, amidino, Cjuo aryl, C<>,20 arylalkyl, azido, carbamoyl, carboxyl, carboxyl ester, cyano, guanidino, halo, (/.-59 haloaikyl, Cj-ic heteroalkyi, C5-10 heteroaryl, Cs.₂o heteroarylalkyl, hydroxy, hydrazi.no, imino, oxo, nitro, sulfinyl, sulfonic acid, sulfonyl, thiocyanate, thiol, and thione;

wherein the Cj.jo alkyl, (fr.49 aryl.» Ccas arylalkyl, Cmo heteroalkyi, C5.jp heteroaryl, and €<_;,?9 heteroarylalkyl groups are optionally substituted with from 1 to 3 substituents independently selected from Cm alkyl, C5.1Q aryl, halo, Cm haloaikyl, cyano. hydroxy, anti Cm alkoxy;

or a pharmaceutically acceptable salt thereof [00143] In separate embodiments within each of the compounds described for Formulas If Ua, lib, and lie, there is another embodiment comprising a compound in which R^la and R^le are each independently Cm alkyl, or a

SUBSTITUTE SHEET (RULE 26)

WO 2017/059252

PCT/US2016/054780 pharmaceutically acceptable salt thereof.In separate embodiments within each of the compounds described for Formulas ΙΪ, Ila, fib, Ik, lid, and He, there is another embodiment comprising a compound in which R⁵ is Cj-w alkyl, Cmo alkoxy, or Cmo heteroalkyi, each of which may be optionally substituted with from 1 to 5 R⁴'³ groups, or a pharmaceutically acceptable salt thereofJn separate embodiments within each of the compounds described for Formulas II, Ila. lib, lie, lid, and lie, there is another embodiment comprising a compound in which R’ is an, Ckw aryl, Cfiee aryialkyl, C5.kl h net »aryl, or Cs-jo heteroarylalkyl, each of which may be optionally substituted wirn from 1 to 5 R²¹’ groups, or a pharmaceutically acceptable salt thereofJn separate embodiments within each of the compounds described for Formulas Π, Ila, lib, lie, and lid, there is another embodiment comprising a compound- in which R⁵ is (f. w alkyl, or a pharmaceutically acceptable salt thereof A separate embodiment comprises a compound of Formula fie, as defined above, wherein R is Cmo alkyl, Cmo alkoxy, or Cmo heteroalkyi, each of which may be optionally substituted with from I to 5 groups, or a pharmaceutically acceptable salt thereof.There is also provided a separate embodiment with each of the embodiments described herein comprising a compound of Formula lie, further in which R* is C₅.:₀ aryl, Cg..2o aryialkyl, Cj.jo hetennryl, or Cfjo heteroarylalkyl, each of which maybe optionally substituted with from I to 5 Rf '¹ groups, or a pharmaceutically acceptable salt thereof, [0(1144] In some embodiments, the modulator of a hromodomain-containing protein is a compound selected from the group below, or a pharmaceutically acceptable salt or hydrate thereof:

3-{2-at!rii;o-6U3,5-ditncihy!;soxazoh4-yl)-fiibsnzotd ]i t nidazoM - yhpentan· 3-ci] lBl-4-i2-i:yi;kipropyl-7-(hex-U'-en-3-yi)-1Hbenzotdlimidazol-S-ylM.S-dimethylisoMzois

SUBSTITUTE SHEET (RULE 26)

WO 2017/059252

PCT/US2016/054780 >·Λ _

N-0

l-('2-cyclopyopyl-6-<3,S'dnrxethyHsoxitzol-4-yl)l H-benzo[d]imidazol-4-yi)propa!) i -of

(Z)-4(2-eyc!i>pri)pyt -4-(peni-2-en-3'yl)-1Hbenzo[djimidaKol-6-yl)-3,5-dinKthyJisoxszoie

cyciopeniyi(2-cyclopropyi-6-(3-5dimethylisoxazol-4-yl)- iH-benzofd] imidazoM-

i8)-cyeloiwntyl{2-cyc!opropy!'&-{3,5dimeihy! «.oxazol -4-yl)- f H-benzo[ tn «lazes 1-4yi)raetha!!oi

3-{2-cyckipropyi-fc-(3 .S-diwc-thBisox vil 4 >1)« 1 H~benzo{d:jinidazoi-4-'' 1 -t>!

4-fe-cyckipropyi-4-'(pe;!iaic3--yi}-ifibe«zo[d]imidazol“6-yi)-3,5-dimethyiisoxa2:oie

dicvJnp'nt\It ''-^.vkoptopyi-ti-t V·· dimetbylihcxazul ^ά >0-¹H·l\'!i/>i|4]uind jzol-4vllinetbatjoi

(R i-t yclnpentyl(2-cyclopropy]~6-(3,5’ dimethyl isoxazn i-4-yl1 H-benzo[d] imidazo.1-4yijmethanol

SUBSTITUTE SHEET (RULE 26)

WO 2017/059252

PCT/US2016/054780

l-(2-cyclopropyl-6-(3_>5-dimethyiisox32.o!-4»yl>· 1H-tozo[d] irn i dazol-4-yi )-2-inethyipropan-1 -

4-(2->;yt iopi upyi -6-(3,5~iiiswetli xiisoxazc-i-'i-yS) IH-bcnznidjiniidaxoM-yOhspan-Wi

3-(2-ο>'οΙορΐΌργ1-6-(3,$-<ΐ!κΐδΛγϋ8θΧΒΖ0ΐ-4-γ1))H-benzo[d}imidazol-4-yi)-2,4-di!«ethyi|)eniaa-

benzofdjimidazoi o \'i < ' dt nctbyijsex&zole

4-(2-oyeiopropyl-4-(heptan-4-yl)-iHbsti2«[d]imidaz0l-6-y1)-3,5-dimelhylisoxaxo!e

-(2-.3yclopropy}“6-(3,5'dirtieUiyiisoxazoi4 .yi). 1 -raethyl-j H-ben2X)[d]iniidazoi-4-yl )peniao--3-ol

ί··(2-ί'νε;όρϊέιρ54··5'7,75''άι:ΐ!είήν17ίί):<ίΐζ(.4·4··νΙ)··

5-methYMH-bsnzo[dlirniilazoj7»ynpro!5an-1oi

SUBSTITUTE SHEET (RULE 26)

WO 2017/059252

PCT/US2016/054780

HN (2 i···) i lof i (i-i 3,5-dim Α)Ίκ.'.'\,ιζηί- hyl)1 ί 1 -bcnzo[d]iin5da^ol-4-yl.)dij»bcjiyitn<lbajiol

(?'CyJopiopyi-»H?,5-tliiiietliy)i&o\j/<)l-4 y))3 H-beiizo[d]j roida/t·] 4 yi i( phenyl ifpyr;din-3vDineihannl

N~O

X

KN

X-·' X j| •'%x^AxX%-'ⁿx / ho y ) (2-cyetopropyl-ii-(3,i-dimetPyi isoxa2oi-4-y) )1 H-bei)z.i.'[d](iniXiZ(il-4-yl)di(pyridir_I-3yl/meihanol

N“O .J X

(2-eye!opropyi-6-(3,S- di methYlisoxazol-4-yl)IH-ben/oi dlinddazol-d-yl )(pyridm-2y 1)(j ynd -n -3 -y i) moth ano)

Ν~Ο if 4,

XI

ΌΗ r n (2-cyclopropyl-6-(3,5-ditHethylisoxazol-4-yi>7fluoro- J H-bcnzo[d]imidazol-4-yl)di(pytidi>^ y!)ffl&ihaiiol

N”O / -fo < Xfo '

(2-eyciopj npyl-b-i 3,5-liiinethyiisoxazc'i-d-yl)3 H-bec < o[ dj in liilazoi -4- y 3)( plieny i i(pyridin-2y: imedunoi

N-0 // V ,·,Κ *x fox

(/-cvdoptnpvl'ii-i 1,5 dimvinvtntn s/N 3 ' iiH-b«i/nfdjui!)i·-/1)1 · /! iddpvoXn-'¹' yl Ksi-'Ί· · ·st)!

(2-eycii)propyi-6-i_i3,5-ij(nieihv)i‘,ox;t;:ol-4,y!). 1H- benzo[d!)find.!Z('3-4-y! Jipyri Jazin-3yi )(pyr!diii-2-yl Jmethanol

SUBSTITUTE SHEET (RULE 26)

WO 2017/059252

PCT/US2016/054780

Μ Ο // V

	J. ' \·.χ
...'O'; 1	{ OH N^sC
W \ J	M J A-· R, \ A
	/¾ N Y
V / NO',·.. '-ο.'-,Ο·

// //

N~O tf 4 . < ,K

....

--¾ [ οι-i / dN, / χ <- ί

Χι i'2-cycloprop>l-6-(3,5-diinethyiiM)xazol-4-yl)1 Η4·κηΊΖί3|'ΰ]ί!ΏΪίί;32θί-·4-·5'!Χρνί!ί8ΐί··2·y 1 χ py f ί midi n-2 -yl jmetbano:

NO

J V,

....... χ_Χίί,· .....

'N

Λ- ^v\ r ί VJ (2-cyciopiopvi-6(5,5-dhneihytisoKazol-4-yl)1 H-benzo(d]iinid3zol-4 -yijfpyridin .?.· yl )i'pyiimic!in-5-yl;mfc;ha!ioi

N“O

V J..

οχ' ) QH N^:

..--4, f Ί OH N'·

HN

L a a ‘1

Λ-VxLj //

HN / \ R.--N ^;N

V

C2-cyc]opr<)pyi-6-i'3,5-d5i)K-r?)yH»<)Xiizol-4-.yi)J b l/ι d i'l kL oi to!,'' Vi' ¹y!)ipyy:(iin-?.-yijini-:^:hi_;i?<)!

N~Q

N ' ' t

h > 7'\i i V

X,

V k, ' •'’ass/ (2-cyclopropyM-(3,5-dijriethviisoxa2ol-4-yl)lM-ben2ofd)itnd'/i)M-\biii(pyrazin-2·· \Bnxthbiol

N-O

X ' 0--0:

HN

VMA )“-”N

X.

t I

HR

N.

OH (2-eyctopiop\i-(. OO-diniHhyiisowizol-d.-yi)lH-bsri7n[d]iitiid-i.^Tol-^-yi)(pyrictin-2.yl)(py!ni!din-^-yi)nietlianol

N~“G

J V .,.v_:

Ό A/ (S-^yel^propyi-i-fJ^-steaeihyiiSKisazal-^yfti·?fliioio-! H.-bt:i!>?.(i[dji;ii!ciazoi'.4-yl)di(pyrkiiii-2yljmethanol

H-Ο

NH

-V

OH

F~ N

Ν 'V €J (2-cydofir<3py3-6-C3,5-diinetliyli»osazoi-4-yl)y])(tiiiazol-2-vi)n5ethsaol

OH

N-v < I ?F to (7.-cyclopropy)-6-(3,5-iiiniethyiisoxa2o!'4-yi)1ΗΤι5ηζο[!.1Ηηηίΐ3-ζοΐ.·4··νΙϊίί!(ίηί.·ΐ2θΙ··2·· yi Inicthanol

SUBSTITUTE SHEET (RULE 26)

WO 2017/059252

PCT/US2016/054780

,.···'

Ν“0

J X

Ν' i

Ό-...

(2-cyclupr<:pyh0~(.i,5-(ii tnetby lisoxaz.ul-4-yl}i H-benzo[djinntlazo!“4-y5 X6-mvthylpyridi{j-2yi)(i c!rjhydrnfi;ran-7-yDi!)c:b;]iic]

N~Q .,// A

N

Ui.u'ipfqvii p j iKthviisovi/uiP-vb1!{ t i e| hnikiiznl 4 yb,pvi J zin » y! ίίηνίΈηνύΐ'ητίΐί-'ϊηΡ-νΙ'ΐίηοίη.ιΐ'Οΐ

O“N . ki-.

w.

p i i

ΑΑΛχ

A

A .As in >•NH

H?N

5-(3,S-dnn;fh\hsn<..xol 4 yi' 7-_t phenylvinyb- i 1Ι-Κηζυ[4}.ΓΛΐ4,ΐζ(Ί-2- irtiine

H₂N

5-(3,5-thine th vi j *«oxa zol-4-yl)- 7~( Ϊ phen-ylethyl J-1 Η-Β0η7νΓύ1ϊίηίί1ηζ.ο1--2-<3ΓηΐΓ«?

N~0 y; y

t.X X I ./ V' '-<· A ϊ y

V—NH ^ss

(E)-4-(2-cyci0pt opyt-7-styry i -1Hbenzofdjanidazol-5-y!j~3..5-diniethylisoxazoie N“Q *«*κ· .-4 ,-;?x ,-F

NH

4-(3-Gyyiop!'opyS-7'0-pfeeiiy!yit)yl)-]Hbsrizofd]ii»uia/t;l-5-yl)-3,5-dimethyli3Oxa2ole

4-(2 lAtbpte ij 'il'li t oifn'-iii ,1 vinyl)It! lei 'u|4jin idiznl-*' ν’) i * dim< luyli. (w'),

4-(2-eyPopr<^!py!-7-( 1 -(4- fluorophenyl iviRyl)]} i-beiizo[d]iinidazoi-5-yn-3,5dinie{hy:is('.xaz<)le

SUBSTITUTE SHEET (RULE 26)

WO 2017/059252

PCT/US2016/054780

-79N0

>X\.

.-Aw

F

-NH

4-i 7 -( I ··( 4- ch} crop henyl lv in yl2-cyclopropylUi-bav-'I'ijiriiiiSa/ol * \i'>

diwetbylisoxazole

‘tfe-'Cydopropyl-? -(1-(4(-ri 1 hioronietiiyi Jpbejiyi j vinyl}-1Hbenzoj d |hmtl<J^fl-5-y t) -.1,5- dnnethyiisuxazole N~G

X

4-{ 2-cyciopiOpyl7-('l -phcnyletlayO- i Hbenzo[d]imi4azol-5-yO-3,5-dimethylisoxazole

1-C-< 'leprnpy: - ?-(! -(4-s bivi eph, nylk-thyl)11 ί - oen/Cij d jinnda/oi- yl)- '<5linnetbxbwxazoic

N~O •W, ..ijz ''

F ,ζίΑ y ^ f.·

NH

4-(2 -cyclopropy 1-7-( 1 -{3-flooropteny))8<liyi}· i H-benzoj djimid.izol-i-y!)-J.5JiinciliyHsoxazole

' (' Lyvlnpiopyl-? (?-i4,nd n, (iiu 1 i', tpb/ny: letbyli-i Hhen/u|d|inki /<>1 - > i-i S-iirnerliYlisoxazoie

N~Q .4 X.

HN / >

4¾ XX

O' l-(2-cy;:lopn;py!-6-(.1.5-dime! hyIisoxazol-4-yl)i H-benzo[d]iffiicazol-4-yl >~5-tneshyJpyrrol idi u2-one i -(.7-cyabniiopyl-0-(3,5- dni'itbybsoxazol-4-ylj^: Il-b/nz(i(d|i:iiid,-/(.4--4 -yi|-.i byipyrrolidni-2one

SUBSTITUTE SHEET (RULE 26)

WO 2017/059252

PCT/US2016/054780

- 80 NO //

A ° aJ, Λ

HN ? Un

UJ <i y·.(S)- 1 -(2'Cyvbptnpyl -6-( 3.5-diniclhy lisoKazoi-4v!)- 1IJ hi .]/(·! d fniida; oi-4-ylV*'(r tl i fur· jmerlivl jpyn oh dn i-2- disc

N~G.

J A

HN

i ! (i)j' iitphe:)'/¹ (° yl)-?-<vi k>ptnp\bo diiiydio 1 R-bcnzoidji'Wdj/ol fi-yilJj ditnethyhsoxazole

N-0

..X A, (2 > a Jo ,_u pvl I- (>,' (ho i it Ji ϋ\,ι oi 4 y!) Hi ΠΑ 11 mnti Ό -4 y )ocnzm iJi

HN

AU ^x\. .-y'-teX ,<··\ r r

Aa

NH?

V(2-cycii)p:Opy!-6R3,5-tliPiethyiiso\dZOl*4-yl)1H -btnzol d]i rn i da? ol-4-y Dbonzam ide

N“O // A

--'•'V X·A Α.Λ

Ύ--ΝΗ 2

OH·

4'-(;^,.-cyclop:'opvl’?'|3.5-dii!’.cthyhsoAazo!-'4--yi}·· } H- L>enzo(d]imi(jazo{- 7-yl ip honol

-(2- cycloptopvl-?· pbeiiyl- 0)boiii-oj J inunhizol-i-yl !-3J-diiri-,t)iy)i:,n,\azole

J-iz-cyrfopropyt-V-btj-dmieihoxyplienyO-iHbe-izo| ii)im:i)azol-5-'/i)~3.5-dime:hyhsox;v(i]c

SUBSTITUTE SHEET (RULE 26)

WO 2017/059252

PCT/US2016/054780

NX) X i·'

N-q . /

..A\ . .-.4.

η n'^? y χχ >=Ν l_%J

X SJ {1 (.' i n/vp, viblK ι\νΐ·ΐ),ωρ\1 1H be i:/o{ (.ijiiiud.izo! -6-vl ) i,5-ihweihyiisoAu,'!. ie

N-0

-X Aΐ r‘%

HK ) h

X* xxx „/ x

4-i /-cydopn’ipxM-f 2 · ihiiKZXh'zrnyi) 111υζίΐζψί]ι;ϊΐ!ώίζύ·1-ΐ'- vl)-3,5-dimethylisoxazo?c

N~O ,(/ 1 -- <;..

Λ ,-A .,-. hn y τ ' >N ,4,X

Λ n-vScv y-NH >z ..τί.

xX -QH

SJ

Η ιλ kp.opl ' to ,i U)!1 \ ι o apt) ib/(<l '! i t - di I ok

NO // 1

- A

AA ,, , y ¹ l y~NH ^{J J}

XZ

4-t.2-e\< iOpi opyl-7~{ 3, x-dr iieth ylptieuyi)-; Hbe)izo[dhii)id32.G-5->ri-3,5-Jiiricih\li''Ox.5zule ' Q-N ' •I t i’»' 'ipn,p\i ‘ ;\Xtin:X’„l ,o\.;/oP4-\!)IH twn/o[,l] n 0 j .Η ui- '-v.)-?,! -cut ethvlplif njl

'-6-i vt k - c, / i X lin KiiXpi i )iU) 1 ) I nzuldjm.kli zni i yl) i - uw’6 6<i\i/e, N“O ,k

Z-X ..•-'-s. ,.,\

X r ΐ κ >-’NH X4

A i ..)

XQ M' vvJuP <>pv 'I’iTfe jpwidm i vl) II) btn/'i [d]mui<,o' i yD X fhmzihvlkoxa/oie

7 \(bipiopy) XquroliiiSytUl· tesofdJimiilazoVS-ylH^-diraothylisoxazule

SUBSTITUTE SHEET (RULE 26)

WO 2017/059252

PCT/US2016/054780

Γ®

-<,Λί 1 .

U **' ψ ^f γ-NH

4- ί2-i.yclfpro! yl- ''-{quinolin- 5-yi J-Utfcjcn7o[d)iiriiriazo!-5-yi)-3.5-dimethylii,oxa2o]e

NO 4 Λ, .-· \' x.

\ I 1 ¥ • to'!··

4-( 2-uvc 1 opr op \)- 7-j lsyquiijoiii!- ?-yf) 1HUirofdliilikh/nj ^s yl) V dmu divltsoxa/ ik

-4-i2-cyclopiopYf-7-(iSv''t:»ui)in 4 l! IHbenzo[d jimidazol- 5- y1)-) 5-din wf 1 j luoxiuote

4-1 ? -cycl opropyl -4-{2-f>henyipyndi n-5-y 1)-1Hbc;izo(d]>mi<.lazol-i-yl i-.'.S-diraethy lisoxazoie

N~O // A..

V. Z·.1 aa

HN / 'An A{ 5 .//

4-(2-cyclopi opyi-4-t S-i-l-flm.·: oplien yl)-1Hpy razoM-y ί l-l H-benzojd jimid:iZoi-(>-yl}-3,5dimethybsoxaiole

4-ff -^vclo-Yopyl-l Ή-11,4'b bo ι/of. l])j( idazoi l-b'-yi)- 3,5 dimeiUhsox azole

N™G

A- A

A

ί, A

4-i.?-cyclopropyl-f,-( 3,4. JimetL _vj.i,o\jz»l-4vy[). 1H- xt· ·ιι[(Ι],ι!)ιΊ,ι/ό1 1 -yI n'b: d,i !a,jn-1(211) one

4-(4 (2 i)eii-biilo\v)p>ri<Un-4-y[/-?c.yclopropy:-lii-ber,zo[d]:niiilazol-6-yl)-;<5dimeihvlisoxazole

SUBSTITUTE SHEET (RULE 26)

WO 2017/059252

PCT/US2016/054780

N-Ό

(2 CVliopi ipvl )iAvlisuxizr.j--4'yl}1H beii.ji[djiir.id../Ol-l-',{ij)Y.)iii:i 2(i 11) one

0-N / w

--Ά to'··-.

<7~N / % • x*<·

HN ₍ /=0 fee

V-fll:1X:hy) 4 (4 i,!illli<lll’l-tov. )-2(ii'ifii!or<iinetbyO-lH'beizv|d]imidazoi-6ylpsoMA'Se

N-i.i .7

V.XX A'^N

Ά .A* Αχ -γ ¢1 λ --to HN /

A i .°

HN, if ,-A<

to •NH /Άί

XA //^ b (ί) ί V~ inn tbvb <x i/ol -0)4( pbeiiylpYiidiii 2 vl) i 1 l-bcox(filf riitdaTtjl-?Itv 1, γ ο, ,)\sidtn i id 0”N

A A,

.. to

A A

A' X /' (-i2-e!l:ux\ -}-(ι'-!lΊcι:lyχ;ιί^!χ)b!',-5-0)ΊH ^x'iχ)i d lniiid.i/i«! -0-^vB- 2,5 -inn-vtliyliiOxazolc

N-Q .A/'HN to to , ,1 / XA 'to \ 4 to

V NH Z^teN

4-(4-(3, i-diniethyi-l H-pyrazoS-·-yl)-2(vtllpe Η X! 3<)[d xMld Izd OVli'' liitaetbYbsownie

N-f<yolfpiopyliiK-tbyiJ-l.fi-bi.ί 2 ‘ ,lii xxb H svi - ί u 4 toi-lh ciiift! d] inn / 1 ’ 331138

ON

A fto Ii J feto * . ··· xi

HN I

Ό

4( ,ιι,ιΐιω v 4 (p in, d’H-piintiliii > yij Hi Ixr ujd μη.id ιζιψρ-νΐ) d.mefl \ i

O~N \X

4, to to, , to·-· \ 1 /> An

HN 7

A

Π \

1(1 1 d nxtby’ 1H ,)t , υ¹ Hi n 41 n’liL nx,]d|mi d, ol ( vl) > s dimethyl iSfixaziiie

SUBSTITUTE SHEET (RULE 26)

WO 2017/059252

PCT/US2016/054780

.. 84 /

N 'NH

447-(3.5 ihiiid Is yl- ] H -pyraz-M-4~yl)~?,-nii^foyl-. 1 H~benzo(djimtda7oi-3-yB- 45 dimcdtyiboxazoli

O~N γΑ'-ΖΎ 8 s

HN

4-i4-(2₎4-d^|i:)eihy!py!'iJiii-3-yl}-2-ii'jetbyl- 5 Hbenzotd j imidazol-6-yl )-3,5-din icfhyi isoxazo te

N~Q // \

XZ-.--,

Χ<^ζ

3,i-dimethyi-H-td-methyl- -Ift'-uiethviquinolin* 5- y 1 i- ϊ H - benzol d limidazol-O-y! Jisnxazole

OH !-(i) (ί,5-affiielhyiispx,. 4-4-4)-4-(tiniethylqnuioiiu-5-yi)-1 H-berizo[d]imidazol-2y I jpropane- i ,3-cbol

HN γλ | ,NH

Z^N

Tiri

HiN

Z z ,

AZyl ^ri 1 T NH >-NH te_NN-cyelO{Hopyl-'4-t3,^s-dtntctf(yl IH pviazoi yB-b-i2 5 όΐ'ίιοΗινΙοο^ϊ/οΐ-.ί.

beuz-ihi jimiiiazot-d-anijne

N“O & X· ’ t V-dimi thyi-1 H-pyrazol-4-yB-5-(,3,5dimi';hyli,rr,j Ό-4-yl)-! H-ben/<.,[d]tmiiiazo!-2·* amine

N x 'NH HN

0--8---0

Z.\

N-(⁷43,5-itimctitv!'H{ pyt.voi 4-yB ''-{ί.'ιd ) t 1 'vh 'λ f ol 4 vp Hi b“ 1/45 imi j ’o) 2 y! ky lopi'paiie^ulfonamide >

NH

N~Q

N-(cyck(piopylmethyi44-i 3,5-dimethyl-1 HpyrazoMyyB-(i43,5--dimeihy|tso.\szcd-4 yl')-1Hberi7o|d|ui’)iLi/o· ?-;mmu·

SUBSTITUTE SHEET (RULE 26)

WO 2017/059252

PCT/US2016/054780

N'O

X χ^χ -·

4-('2--i:yclopii.-p>^;i“4--(?,5-di]‘r!it;!yl· JH-pyrazoMvl)-l H-bmo[d junidazol -6-yl)-3,5diracihviisoxszole

·. \

4-(2-cyeioprtjpy!-4^(3-ingihy!pyT)iijH-4-yi)-)Hbeo2o[d]i!nidazol-6-yl)3,5-diraetkylisoxazole

O~N A 1

4-i2-cyciupropy!-4-i? inetb' ip'ndw 5-νϊ)-1 Hbenzofdjnrjidszoi -6-yi'i- \? -<v un*th vb ,i/o)e p~N . X

4Τ2-βϊείορΓ^Ί*444-Ε«βίίθ?ίρ^Γϊώί>.3-^)-ίΗ?

benzo(d]iniiilazol»6yl)-3,5-din3etbyiisoxaz0le

O“N

..Λ V .V'· \\ V’ '•'S

I • N.

X ·' /-NH

4-(2-cye!'ipivpyi-7 -(1.4- dimethyl· 1 H-pymoi-S·yl)-j }-i-beii>:o[d]tint-lazol-5->4,)-3,5dk'ircihylisox3?.uk‘

N-0 A A wJx

X··'·· iX s «ΎΥ^Χ4

N ..

X,

4-(2-cyclopropy!4-(?.i)5ethox.y-4·· rie:hyipyiid!ri-3-'yJ)--iH'bi;!K()5djir;;id3Zii!“6-'yl)3.5 - d i methyl i s oxaz o i e

XJ X_?; N 4-('2-cycSoptopyl· 7-('6-rneth'.· iuutnol i ti- ί-y 1 ; H« benzo[d}imidazoI-5-yi)-5,?-di!nt-;hy!i,oxaz.)ie

NO Y A Χ,-ΐ? -

4-(2-cyckipri'>pyl~4'('2-eiiiosy-4'mt;’!iytpy;-jdb-i3-y])-! H-benzo[d jimidazo!-6-yi)-3,5dunefbyXoMZi.'ie

SUBSTITUTE SHEET (RULE 26)

WO 2017/059252

PCT/US2016/054780 pro $ X fe.A

3-(2*cyclop!npyl-6-(3,5-dijTiethylisvx:uOl-4-yJE 1H-benzo! d (imi dazol-4-yi)-4-rncthylpynihn-Uol

N-0

ΧΛ4-{2-cye3ei)t'epyi -1 -{2 4- diTfietliyiffiiazol-S-yi)IH -benzo[ii]und;iZoi-6-yi)-3,5dinKthyluoxazoIe

N-0

^V<:

,<.U.

HN

X;

HN

I

JΛ fed

I (

i to vVC.ojimp'i ¹ i 3,4 '.jiiiieiii'J-iH-iniidiUwi -v P- 3) 1-S5CH. n[dJiniiiiaZol-{)- γ! I- \5 di:nvthvlii.(>xazok4-(2-cy lopiopy] J (? S-dimeihyt-ίH-4,2,4«ίο/οι-1-yl )-3 H-benZ(i(d]in'i'da/d-6-y!)-O₅5· dtmethylis>oxrfz(>fe <1

N”O // A ^x;-'- -

Ax .-rife , r	3 A
	c-
' A	N

Hn Z

4-i2-<yc)opropyt -3 -(3.5-dimethyl-4H-1,2,4iriazol-4-yi)-! H-benzn[d]iniidazoi-6-y3)-3,5dimethyl isc-x azole N-0

--γ....

hi I

AWfe

4-(4-tyeiopropyl 4 _s2,5 d't-idhyl- lH-iniOuol!-y{}-·H-ben„oiajuradazol ( v]) < 5diniLtby' sc\.:/i'^!e

HN

4-(2’-eyc lopi opyl-2-.nethyi - > Ή-{ 1,4bibf!;\i[djirt!i.3,,/(41 <>' v])- < 4 dl!i;Sft(V!!SOK;!„o!o ydopropy[-4-(2-methyl- lH--nudazoi- ί ylfe ;lTbenzQ[d]irii)d<wi ft ylj-3,?· dinielltylisoKazoie

SUBSTITUTE SHEET (RULE 26)

WO 2017/059252

PCT/US2016/054780

-.87Ν~0

A ,α

Q-N ί Λ

Λγ,ζ ΗΝ /

ΥΛ ζΗ

V / ,Λ\, .· _χ

- Υ

Ν ? ϊ ~ΝΗ .A A <.«*·.· ·<·Ζ

9-(2'-cyck'[iro;.jι-ί,.ί,ο /-ienabydio- dH-flY biben?o[d jimidazul j-ύ’-yl )-3.5dimcthyiisoxdznle

4-(2-i.\Uoprupyl-7-i2 4-dhtictlrUpvi idui-3-yi)i H bciiyoYimiduZidYyJ)-3,5dun. thvk oxazole

N”O ί /

../

MM <1

v.

Υ'Ν

4-i2-cycloprnpyt-4-{5-cyelop’Opyl-3-hiediyi ί H-pvt azo) -4-yi)- j H -benzofd](!?.idazoi-6-yl )4.5-d)!i?eii)yiis(na/i>!c

difktb ί λ z<ii NC

ΑΛΙ.

λ-(2-cyc iopt opyM-t 3- nieihylYphenyM Hpyrazos-4-y ϊ ί 1 Η-Μινψΐ hnj’da2ol--6--yi )-3.5HiTK’hdl OM. 'lie

		NO λ» V Aza ί	-,
		J- - - u Αχ .A	νΆ
	hn	J
	>	“~N ,, S'j	,,z€ zyV V
	<1	ί	, X
R-	Ύ W OJ tupvl ‘i		N 0 H i b' bsii\ i/<4 t yt'
) 3-	til b, j οΓ4]πΐι'<.	z 1	t so mioh i 11 4
		U1 i N-0 A A r

ΛΑλ.

<1 )‘

Α/^λν%

HN / Ϊ) ) γ ..--ΆΑ

Λ. -Y Ν Ο Η

5~(2 .’γ,1ορίυρ\! 6(5^ diliR-tbybsi.'.’Zf'l-d-yl)1 H-bcrzu|iijiiniU-j/vl - yi) ) '^l ddt.d uisiki’iinuhii-li ;ii)-cix·

5-i ?-yy4opinpvl-t'-( V )-di.jk-^:hsit^st>y u) -t yl·IH-bi-n/oldjimidazol-l-yϊiqu’m br ' Hi <n “

SUBSTITUTE SHEET (RULE 26)

WO 2017/059252

PCT/US2016/054780

-88N~q ί'ί \ !

/*$· - \

N~0 # X

KN T · ~N > N , J l Ά.

N OK <5

Ute m pio( \ (> 1 ti 11> tii',hs<'va/ul-f-»b liI-beuzniiijinndazol-4-y! )-4,6d i met ii y; pyo ο! ci n- 2- ol

N”0 iz s j/ -A·.

•''^Λ -x·..

5-(7«cydi'piopyl-6 (3,5 dunetbylisoxazol-T-yl)IH'benzol d | !mi4azol-4-yl)«4-?nethylpy i imidin2-ol

N~0

Λ \ ./ -,_v

RN

Ay ,a..Z.

y ύ>'·'

XT;

NK

X, <1

5‘-(2- tvelopropy 1-i-13,5 dmiethvlisoxazol-dy 1 j -1H- benzoj d jimid.izoMy i ispBt.|, yclopropanv-1, ί¹ -isoindobn]- V-one:

5-(2«cycjopropyl-6-i3,5-iltinethyHsoxaznl-4-yl)1B -be nzo[ d] imidazol -4-y!)-1 -methyl- 3,4dihydroqiimolin-2f 1 H)-onc

4-{2'v»ck'pro[) ¹ ( Jut Jl'! JH-pyrazoM)1)-i-melhyl ill i ndpJ-5-vls-3.5IBi, ibvl su zoic N-Q

4-(2-cycI«propyl-7-O.4-(hiBetbvl-IH-pyr.)2(..S“5yl)-i-lnetbyb 3 H-bef:zo[d]wiidg;.ui-5-y;'j-3,5dimetbyhsox azole

4-i2-cyck(prep5d--l-iii«thyl-7-(6-metbylqiiinoii!l·· 5-yh-1 U-benzo[d]iinidazoi r y:.)--3,5diriici by lisoxazoie (’ ,>ck)bity' - (\ ihi'ietby -IH pi'n/o! 1 R) ’’l-bertzoRlnm i/ol 6 \B A iliineibyliscx.s/oie

SUBSTITUTE SHEET (RULE 26)

WO 2017/059252

PCT/US2016/054780

Ν“Ό // V

N“O <·/ Ύ /N

NH \<w \\ χΑ\

4-(4-(3.5 - J niiediyi-1 H-gyras? i- 4-y ] )-2-(! fluoroeyc)upiv>pyl)-l H-ben?:o(d]ireklszol-6-yl)V-dimethylisoxazoie

NO

Λ 1.

4,4’-(2-«yciopropyl-lH-bcD2oiiiji!nidazok-4,6diy()bis(3_s5-iHraethyiisox3z«ie)

NO

J A -· ·?’ ·’ Y

Hri

4-(4(2i4-dimsthy)i!yT!din-3-y!!“IHbiiiizofd Jteidazoi-i.-ylyiAS-dirfiethyhsexawle ν··ο // 3

3, S-dirnethyi-4-f4-{d-n['.it(iv4ii-i!ii(4n)-;i-y i). IHbeazoj d) imidd/ot-o- yl psoxszole ri‘ //

Q

ΑΒΑ'

YY_;

A Ύ f^ANH Mfi

../: ^z'^:

4-(2-(2,2-dif!uonwyi:lo(»Opy})-7-(3,5-ilimethyl3 H-pyrazol-4-yl)- 3 H-benzoi i’’[ntiidazo i-5·· yl)··

d.S-iijinetbylssaxszoji:

HN

K:

4-(4-( 3.,4-dimsl ky I -1 H-pysazol-5-yi)-l H~ benzold jimidazoi-fi-yl t-.iA-dniX'iiiyiisoxazide:

ri “Q .ΛΑ.

,K_NNH

4-(2-(43 flnoromeihy i) ·? -(3. 5-dknsthyl- 3 H pyrazol-4-yi j-1 H-bsnz<)[djm»dazol-5-yl 1-3,5ditneibybxiJiazolfc

O'N

-άα'-

F,C

33,5-d3ri'!?thyi-4-;'4-(6-!rs(;tliylq'aino!i (1-5-)4)-2(ixi ikiororaethy 3)-1 H-benzo[d]jni idazol-Ayljisoxasole

SUBSTITUTE SHEET (RULE 26)

WO 2017/059252

PCT/US2016/054780

5-(.6-(3,5--diti)eih\hsox4zol-4-yl )-2(i-rifinoromeihyl)-1 i i-bcnzol Ujifflidazol-4-yi)3Adihydr<XjUi;i<)iin ?i iH)-oiie

N -(6-(3, S-dimefhylisnxiizoi- 1 - yi )-4-) 6inetliy)quinnlin-5-yi)~!H-bcn/('f 1] )iin.U.-:yl-2yDcyclopropanest If) u< Hire

•5-<2-cyclopropyl-6-(3,5-diincthynsox8zof)*4--yI)«·· S H-bcnz.(i[dl;niidazoi-4- yi)-3,4 d> hy tiroquin obii-21 ’ H )-onc

ON

V

HN

NF,C

4-(4 (1,1 di.nt4iy!-iΗ p\i,i/ol-5-\i)-’(iri fluei ontel hy t)-1 [-{-ben;:of J jnnidazoi-f-yi )3,5~dnK>S'iyltp<wazok'

3,5 -din icihyl -4 -(2-( 1 -met b yi -1 H-pyrazol-d-yi) 4-(() ]\Ή4,,.ιΐικΊ·ιΐι-^-ν1'ι-ΐ H bcnzvld]imiduzol-6- yijjsoxazok

SUBSTITUTE SHEET (RULE 26)

WO 2017/059252

PCT/US2016/054780

HN

Ν~ϋ / 1

JUG .,..4.

N-eyulopontyl-6-<3,5-dinnithyli»oxa2oI-4-yn-2· (ii i fi uorome th yl }· 1B -beuzo[d]imitlazoIe-4stijfonamide

dime 'hyh ova.»ol-4-yl,-lΠ-bt ii/ojd jinudazole't-sultniiainide

N~Q .J X ·*·' >' . 4 w _t

HN ) ^p'

HN 'NH

χ.i

M-cytHpmit' 1 J ,ί-'γιΗρηryliiiethyDdnmol-S· ; Ί S-diii-'ti \tiM>< i/ri 5 yl) IK ben. c'dHjtin/ok·-'¹ -mi loiidnmk

NO

ΛΛ

1.

HN

V

N HN,

H_aN i 4

U,y

..: -3:iiH!O-N-eyekmenry!-6-!7,5dn'iiediybsozazol-d-yl)-] H-heiizt.klhiitkiaziiled-svdibnsfflide

N-cy, ktpenivl-ft-l j.S-duneihy ίίί,οκ;ιζο1-4- yl ) 2(hydroxymethyl)-1 H-bciizuj d Jimid,izole-4st(lfor,atB(de

methyl ί 4-(. N-cyclopentv Isutfamoyl)-ti-(3,5dimcdiyl isoxaόΙ·4- J; ¹ ίi-l civ o[d]imklazoi- 2\l)td' , licit·

N“O

X-

N-cyclopentvl-i'-l 3, i-biiiiethyll&oxjy.il-d-y!}·?.· !' (2 -methcxyethyl pimrn ο > -1Hhen:;y[d}imuiizn1e-t-suifnfiamide

N-cyvlopentyl-i-I3, S-dimetfaylisoxdZol-4- yl )-2(pbenvlammo}-1H -heir.tefd] nn idaznle-4Millonanhik’

SUBSTITUTE SHEET (RULE 26)

WO 2017/059252

PCT/US2016/054780 o-

HN.

Ο N 2......./

N“C

2-ibei)zyiann«o>N-cyclopeiityi-6-(3,5dimethylisoxazoi-4-yi}- S H-bcnzo[d}iinidazo)t;^x , yvlox.ityl o t.k. dii.iei.p,!isi'\,/i«i 4 Hi ' i/d-moi phaiiiiovthylijmiin.-')- Ήhenzffdki) dv.'le 1 m Irish Hide

NO

HN

V

NH

S i

HN '’’λ

N-cyc!Gpcrityl-2-(cyciitpiOpyid:riiiX')-6-(?j,?·' d ueri .('fiviA-d <, ) 1H lx v< [J sm ( '< 4

N-e\ik>peii!\i-R-( i S-dmictlnlisiRa.'-’H vH-2 ((z-metbceyciiiffpiiHii’O!· bc(’ ’i)[d]nnttlazt-k- 1 Slt'iolXi.llW

N-.:\c !o}'ciityi-(i-i3.j-i}!iik4hyiieozaZ.G!-4-yl)-2(((tef! .ihydiORir:iri'2-yi)mctbyi):in'iiri(i)- IBbeiizofd] ii'iidiizi'le -4 -.sulfonn snide

N-eyei(tpenf yl-6-(3,S-din:el liylj.'ioxszoi-kyl ,)-2|Π ^.ιπίΙυ.χοΗπ'ΉιιιυΉ Ή be!i?i’[d]ir:'!!d;izc>le-4-sii] foisssmick.

SUBSTITUTE SHEET (RULE 26)

WO 2017/059252

PCT/US2016/054780

N-0

i ((1 < ιΛ>ι\Ί tyhilf ui'u\I> t> (\Y daw' hvtisu' ι/t. 1 νΐι H inan>[d]inuih7 1 ?.yl giiRiiifi/prctpntiflic ;ic;t1

ethvl 7-((-1 {N-cvt.'up··mg IsniUdiiiyp a (Vcinu'ih Jiao^.ui'il-Byii-l i-i-i.eivold [nnnNt. «1 1.yi) j man ·))«<. p mmin'

N”Q •^k' -ιΊ

-¼ ? N HN.

N-.;ydopeRtyB6-).h.')-di:nithy!is«xaziil-4-y])-'2m it pt IH~b i.. lun.izeli 1 »lkninnk

N“O

T \

-^Λ [I . I o

HN >

™s

S'„ ^{1 (} “N HN, < iiipentvi-M \.'i-liinvihv)ii,oxdzol-4-yl}-2irntiylst.ifny I Hi t 'vzoj3jpure*s/uie 1sultf-nafinde

n'O y / o

N'cyclopcmyl a-t.yi-tiimei'itYis'nixazoJ-d-yl)-;?(nn'tliyisuHoiiy! }-l H-bcn<.n[ lJmtidazulc-4sai'lwnsrmiliNO

H₂N .-¼ .,- % .-0

Fn i il' I ¹ a i ί (i i t i (i nt hyli’-u'' a nl 4 .Ns ¹ P-Ka/_lt|d|iuad;.. nl© -¹ ;iilnmylik niBth'i I I-benzyl -CYid(n'i())n I ^s t Y dimeihyhsoxazol-d-vi j -1H- ben, o(d]urn«,)/fle 7-e<j:-pdxyi.;te

SUBSTITUTE SHEET (RULE 26)

WO 2017/059252

PCT/US2016/054780 • 94N-0 ri'*''-,, ri ,Ζ.Η / Η

Ο

V, ri / ,-V ;(

..,0,

N ”0

methyl 5 - benzyl -2~cyclopropyl-6-*(3_>5~ <litnetbyl5sox«zol-4-yl}-lH-benzo[d]int3da-zole·· 4-carboxylate Ν' υ i? V ,_χ.. ,

Ά 'ri' v^: y

<4 /'“N methyl 2--eych)pii(pyi-U-f3,;5'-diinethylist)xazi>l4-y 1)- J ..methyl·· 1 H-benzo[d]imidazole-4carboxyiate

O'N

-''•’Sri®' methyl 2-cyckspropy! -6-(3,5-dimethylisoxa2<,l4-y 1)-1 H-benzo(d]imidazole-4-carboxylate

N“0

methyl S-eyclot'i-i’pyiri-i 3,5 -himefeyksexaxoi4-yl)-1 -methyl·· 1H- benzofti Jimidazote-?carboxylate N~0

-Ά .ri'” <ri hn r ¹

HN

I λΧ*. . Λ·'·.'·'··., ,»·· \/;-·· n_x

HN: i 1 }ri

Ν.'(6·'63₍5··ί§ίΗίίΗγΗχ(ίχ&χο;·-4-νί)-4-!(ί£}{!-Π·Γ· benzoi'tlJimidazol-2yi jcyciopropaeesuffonatnide

N'O .y A y·’·*'”··'X>' •(2-cyciopTopyl-4-iodo-lH-benzol'd]iffitdazoi6-yi)-3,5-dimethy!iioxazole

N -eye lope nt v 1-2- eye k»propyl-6-(3,5 ditnethyhsoxazoi-4-yi)- 3 H-be)izo[d]?mjda2oi-4· amine

SUBSTITUTE SHEET (RULE 26)

WO 2017/059252

PCT/US2016/054780

- 95 [001451 It is understood that separate, single embodiments comprise the methods, regi mens, kits, -and articles of manufacture in which the modulator of a bromodomain-containing protein is each separate compound listed in the table above. For instance, in one embodiment of each of the methods, regimens, kits, and articles of manufacture discussed herein, there is an embodiment in which the modulator of a bromodomain-containing protein is, (2-cyclopropyS-6- (3,5·· dimethylisoxazol -4-yl)·· 1H•benzo[d3imidazol-4-yl)di(pyridin-2-yl)methanol, or a pharmaceutically acceptable hydrate thereof. In separate other embodiments for each of the methods, regimens, kits, and articles of manufacture discussed herein, there is an embodiment in which the modulator of a broraodomain-contaming protein is .(2-cyclopTopyl-6-(3,5-diinethy1isoxazol-4-yl)-lH“henzo[d]imidazoi’4yl)di(pyraztn~2-yl)methanoi, or a pharmaceutically acceptable hydrate thereof. There are also embodiments in which the modulator of a bromodomain containing protein is (2^cyctopri)pyl~6-(3,5-dimethylisoxazol-4-yi)-lHbenzo[d]imidazol-4-yl)(pyridin-2-yl)(pyrimidin-5-y1)methanol, ora pharmaceutically acceptable hydrate thereof, [00146] There are also embodiments in which the modulator of a bromodomaincontaining protein is (2-cyclopropyl-6-(3,5-dimeihyIisoxazoi-4-yi)-lUbenzo[d]imidazol-4-yl)(pyridin-2-yl)(pyrimidin-2-yi)methano'i_> ora pharmaceutically acceptable hydrate thereof. There are also embodiments in which the modulator of a bromodomain-containing protein is (2-cyc1opropyl-6f3,5-dimethylisoxazol-4-yl)-lH-benzo[d]imidazol“4-yl)di(pyridin-3-yl)methant)L or a pharmaceutically acceptable hydrate thereof. There are also embodiments in which the modulator of a bromodomain-containing protei n i s (2-cyclopropyl-6(3,5-dimethylisoxazol-4-yl)-lH-benzo[d}imidazol-4syl)(phenylXpyridin-2yl)msihanol, or a pharmaceutically acceptable hydrate thereof. 'There are also embodiments in which the modulator of a hroroodomainreontaining protein is (2cyclopropyl-6-(3,5dimethyiisoxazol-4-yl)-lH~benzo[d]imidazol-4yl)(phenylXpyridin-3“yl)methanol, or a pharmaceutically acceptable hydrate thereof. The compounds which are inodulniots of a bromain-domain containing protein described above may be prepared as taught in US 2014-0336.190.

SUBSTITUTE SHEET (RULE 26)

WO 2017/059252

PCT/US2016/054780

-MMP9 Inhibiting Agents [00147} Useful MMP9 inhibiting agents include comprises binding proteins, e.g., antibodies and antigen-binding fragments thereof, that bind to the matrix metalloproteinase-9 (MMP9) protein (MMF9 is also known as gelatinase-B), wherein the binding proteins comprise an immunoglobulin (Ig) heavy chain (or functional fragment thereof) and an Ig light chain (or functional fragment thereof) disclosed in U.S. 20.15-0140580 (Smith et ai.) and U.S. Patent Nos. 8,377,443 (McAuley et al.), 8,501,916 (McAuley et ah), and 9,120,863 (McAuley et al.), each of which is incorporated herein by reference.

[00148] Practice of the present disclosure employs, unless otherwise indicated, standard methods and conventional techniques in the fields of ceil biology, toxicology, molecular biology, biochemistry, cell culture, immunology, oncology, recombinant DNA and related fields as. are within, die skill of the. art. Such techniques are described in the literature and thereby available: to those of skill in the art. See, for example, Alberts, B. et ai, “Molecular Biology of the Cell,” 5¹⁸ edition, Garland Science, New York, NY, 2008; Voet, D. et al. “Fundamentals of Biochemistry: Life at the Molecular Level,” 3^,Q edition, John Wiley & Sons, Hoboken, NJ, 2008; Sambrook, J. et al, “Molecular Cloning: A Laboratory Manual,” 3'° edition. Cold Spring Harbor Laboratory Press, 2001; Ausubel, F. et al., “Current Protocols in Molecular Biology,” John Wiley & Sons, New York, 1987 and periodic updates; Freshney, R.I., “Culture of Animal Cells: A Manual of Basic Technique,” 4^A edition, John Wiley & Sons, Somerset, NJ, 2000; and the series “Methods in Enzymology,” Academic Press, San Diego, CA. .Set- also, for example, “Current Protocols in Immunology,” (R. Coico, series editor), Wiley, last updated August 2010, [•00149] The present combinations provide binding proteins, e,g„ antibodies and antigen-binding fragments thereof, that bind to the matrix metalloproteinase-9 (MMP9) protein (MMP9 is also known as gelatinase-B). The binding proteins of the present disclosure generally comprise an immunoglobulin (Ig) heavy chain (or functional fragment thereof) and an ig light chain (or functional fragment thereof) io be used in the methods, regimens, kits, and articles of manufacture

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- 97 herein with a pharmaceutically effective amount, or with individual dose units containing a pharmaceutically effective amount, of Compound A1.

[091S0] The combinations include MMP9 binding proteins that hind specifically to MMP9 and not to other mauE metalloproteinases such as MMP1, MMP2, MMP3, MMP7, MMP9, MMP 10, MMP12, MMP 13. Such specific MMP9 binding proteins are thus generally not significantly or delectably crossreactive with non-MMP9 matrix metalloproteinases. MMP9 binding proteins that specifically bind MMP9 find use in applications in which ii is necessary or desirable to obtain specific modulation (e.g., inhibition) of MMF9. e.g., without directly affecting the activity of other matrix metalloproteinases.

[00151] In certain embodiments of the present disclosure an anti-MMP9 antibody is an inhibitor of the· activity of MMP9, and can be a specific inhibitor of MMP9. In particular, the MMP9 binding proteins disclosed'herein will be useful for inhibition of MMP9 white allowing normal function of other, related matrix metalloproteinases. An inhibitor of MMP” or “inhibitor of MMP9 activity can be an antibody or an antigen binding fragment thereof that directly or indirectly inhibits activity of MMP9, including but not limited to enzymatic processing, inhibiting action of MMP9 on it substrate (e.g., by inhibiting substrate binding, substrate cleavage, and the like), and the like.

)00152] The present combinations also comprise MMP9 binding proteins that specifically bind to non-mouse MMP9, such as human MMP9, Cyaornolgus monkey MMP9, and rat MMP9.The combinations also comprise MMP9 binding proteins (e.g., anti-.MMP9 antibodies and functional fragments thereof) that act as non-competitive inhibitors. A “non-competitive inhibitor” refers Io an inhibitor binds at site away from substrate binding site of an enzyme, and thus can bind the enzyme and effect inhibitory activity regardless of whether or not .the enzyme is bound to its substrate, Such non-competitive inhibitors can, for example, provide for a level of inhibition that can be substantially independent of substrate concentration.

[00153] MMP9 binding proteins (e.g., antibodies and functional fragments thereof) of the present disclosure include those that bind MMP9, particularly human MMP9, and having a heavy chain polypeptide (or functional fragment

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-98thereof) that has at least about 80%, 85%, 90%, 95% or more amino add sequence identity to a heavy chain polypeptide disclosed herein.MMP9 binding proteins (e.g., antibodies and functional fragments thereof) of the present combinations, methods, articles manfacture, and kits include those that bind MMP9, particularly human MMP9, and having a light polypeptide (or functional fragment thereof) that has ai least about 80%, 85%, 90%, 95%· or more amino acid sequence identity to a heavy chain polypeptide disclosed berein.MMP9 binding proteins (e.g., antibodies and functional fragments thereof) of the present disclosure include those that bind MMP9, particularly human MMP9, and have a heavy chain polypeptide (or functional fragment thereof) having the complementarity determining regions (“CDRs”) of heavy chain polypeptide and the CDRs of a light chain polypeptide (or functional fragment thereof} as disclosed herein, (00154) MMP9 binding proteins including antibodies and functional fragments thereof. Accordingly, the present disclosure provides embodiments comprising, for example, antibodies or antigen binding fragments thereof, comprising a heavy chain variable region polypeptide having at least 80%, 85%, 90%, 95%, or greater amino acid sequence identity to an amino acid sequence of a heavy chain vanable region described herein (e.g,, SEQ ID NOS:1 or 5-8), and a variable light chain polypeptide having at least 80%, 85%, 90%, 95%, or greater amino acid sequence identity to an amino acid sequence of a tight chain polypeptide as set forth herein (e.g,, SEQ ID NOS :2 or 9-12).

(00155) Sequence identity between two nucleic acids can also be described in terms of hybridization of two molecules to each other under stringent conditions. The hybridization conditions are selected following standard methods in the art (see, for example, Sambrook, et al., Molecular Cloning: A Laboratory Manual, Second Edition, (1989) Cold Spring Harbor,'N.Y.), An example of stringent hybridization conditions is hybridization at 50°C or higher and 0.1 x SSC (15 mM sodium chloride/1.5 mM sodium citrate). Another example of stringent hybridization conditions is overnight incubation at 42 *C in a solution: 50 % fbrmamide, 5 x SSC (150 roMNaCl, 15 mM trisodium citrate), 50 mM sodium phosphate (pH7.6), 5 x Denhardt’s solution, 10%) dextran sulfate, and 20 mg/mi

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- 99 denatured, sheared salmon sperm DNA, followed by washing the filters in 0.1 x SSC at about 65 ⁿC. Stringent hybridization conditions are hybridization conditions that are at least as stringent as tire above representative conditions, where conditions are considered to be at least as stringent if they are at least about. 80% as stringent, typically at least 90% as stringent as the above specific stringent conditions. Examples of anti-MMP9 antibodies of the present disclosure are described in more detail below.

[00156] Anti-MMP9 antibodies can he described in terms ofi.be CDRs of the heavy and light chains. In some embodiments, an antibody is a humanized antibody or a human antibody. Humanized antibodies include human immununogJobulins (recipient antibody) in which residues from a complementary-determining region (CDR) of the recipient ate replaced by residues-from a CDR of a non-human species (donor antibody) such as mouse, rat or rabbit having the: desired specificity, affinity and capacity. Thus, humanized forms of non-human (kg., murine) antibodies are chimeric immunoglobulins which contain minimal sequence derived from non-human immunoglobulin. The non-human sequences are located primarily in the variable regions, particularly in the »ontpk it'rnunh »k tumuing wgioiw i( 1 tifirt In some embodiments, Fv framework residues of the human immunoglobulin are replaced by corresponding non-human residues. Humanized antibodies can also comprise residues that are found, neither in the recipient antibody nor in the imported CDR or framework sequences. In certain embodiments, a humanized antibody comprises substantially all of at least one, and typically two, variable domains, in which all or substantially all of the CDRs correspond to those of a non-human immunoglobulin and all or substantially all of fits framework regions are those of a human muiumoglnbutin ei>nwn,m\ .kquoncr J oi the purposes ot the pmsuh disclosure, humanized antibodies can also include immunoglobulin fragments, such as Fv, Fab, Fab', F(afr)·? or other antigen-binding subsequences of antibodies.

|00157] The humanized antibody can also comprise at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin.

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See, for example, Jones e? «/. (1986) Neftcre 321:522-525: Riecbmaim el al. (.1988) Nature 332:328-329; and Presta (.1992) Curr. Op. Struct. Biol. 2:593-596. (OfilSS] Methods for humanizing non-human antibodies are known .in the art. Generally, a humanized antibody has one or more amino acid residues introduced into ii from a source that is non-human. These non-human amino acid residues are often referred to as import or “donor⁵ residues, which are typically obtained from an import or “donor” variable domain. For example, humanization can be performed essentially according to the method of Winter and co-workers by substituting rodent CDRs or CDR sequences for the corresponding sequences of a human antibody. See, for example, Jones et al., supra; Riechmann e! al., supra and Verhoeyen ei al. (.1988) &fo?zee 239:1534-1536. Accordingly, such 'humanized antibodies include chimeric antibodies (US. Patent No. 4,816,567), wherein, substantially less, than an intact human variable domain has been substituted by the corresponding sequence from a non-human s \ t In certain embodiments, humanized antibodies are human antibodies in which some CDR. residues and optionally some framework region residues are substituted by residues from analogous sites in rodent antibodies (e.g., murine monoclonal antibodies).

(0(1159] Human antibodies can also be produced, for example, by using phage display libraries. Hoogenboom et al. (1991) J. Mol. Biol, 227:381: Marks et al. (1991)7. Mol. Biol. 222:581, Other methods for preparing human monoclonal antibodies are described by Cole et al. (1985) “Monoclonal Antibodies and Cancer Therapy,” Alan R. Liss, p. 77 and Boerner et al. (1991) J. Immunol.

.147:86-95.

(00160] Human antibodies can be made by introducing human immunoglobulin loci into transgenic animals mice) in which the endogenous immunoglobulin genes have been partially or completely inactivated. Upon immunological challenge, human antibody production is observed, which closely resembles that seen in humans in all respects, including gene rearrangement, assembly, and antibody repertoire. This approach is described, for example, in U.S. Patent Nos. 5,545,807; 5,545,806; 5,569,825; 5,625,126; 5,633,425; 5,661,016, and in the following scientific publications; Marks et al. (1992)

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PCT/US2016/054780 ιοί foo/Mnofegy 10:779-78.3 (1992); Lonberg a ai. (1994) Nature 368: 856-859; Morrison (1994) Nature 368:812-813; Fishwald et al. (1996) Nature Biotechnology 14:845-851; Neuberger (1996) Afe/ure Biotechnology 14:826; and Lonberg;etai. (1995) In.tern. Rev. Immunol. 13:65-93, [00.161 ] Antibodies can be affinity matured using known selection and/or mutagenesis methods as described above. In some embodiments, affinity matured antibodies have an affinity which is five times or more, ten times or more, twenty times or more·, or thirty times or more than that of the starting antibody (generally murine, rabbit, chicken, humanized or human) from which the matured antibody is prepared, [00162] An antibody can also be a bispecific antibody, Bispeeilie antibodies are monoclonal, and may be human or humanized antibodies that have binding specificities-for at least two different antigens. In the present case, the two different binding specificities can be directed to two different MMPs, or to two different epitopes on a single MMP (e.g., MMP9).

[00163] An antibody as disclosed herein can also be an immunoconjugate. Such immunoconjugates comprise an antibody (e.g,, to M.M.P9) conjugated to a second molecule, such as a reporter. An immunoconjugate can also comprise an antibody conjugated to a cytotoxic agent such as a chemotherapeutic agent, a toxin (eg., an enzymatically active toxin of bacterial, fungal, plant, or animal origin, or .fragments thereof), or a radioactive isotope (i.e., a radioconjugate). [(10164] Au antibody that specifically binds to or is specific for a particular polypeptide or an epitope on a particular polypeptide is one that binds to that particular polypeptide or epitope without substantially binding to any other polypeptide or polypeptide epitope. In some embodiments, an antibody of the present disclosure specifically binds to human M.MP9 with a dissociation constant (K_ts) equal to or lower than 100 »M, optionally lower than 10 nM, optionally lower than 1 nM, optionally lower than. 0.5 nM, optionally lower than 0.1 nM, optionally lower than 0.01 nM, or optionally lower than 0.005 n.vl in the form of monoclonal antibody, sc.Fv, 'Fab, or other form of antibody measured at a temperature of about 4°C, 25^CC, 37X1 or 42°C.

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- 102 [0016SI in certain embodiments, use of an antibody of the present disclosure binds to one or more processing sites (e.g., sites of proteolytic cleavage) in MMP9, thereby effecti vely blocking processing of the proenzyme or preproenzyme to the catalytically active enzyme, and thus reducing the proteolytic activity of the MMF9.in certain embodiments, use of an antibody according to the present disclosure binds to MMP9 with an affinity at least 2 times, at. least 5 times, at least. 10 times, at least 2.5 times, at least 50 times, at. least 100 times, at least 500 times, or at least. 1000 times greater than its binding affinity for another M.MP. Binding affinity can be measured by any method known in the art and can be expressed as, for example, on-rate, off-rate, dissociation constant (K_d). equilibrium constant (K^) or any term in the art, [00166] in certain embodimen ts, use of an antibody according to the present disclosure is a non-competitive: inhibitor of the catalytic activity of MMP9. In certain: embodiments, an antibody according to the present disclosure binds within the catalytic domain of MMP9. In additional embodiments, an antibody according to the present disclosure binds outside the catalytic domain of MMP9. [00167] The present disclosure also contemplates use in the methods, regimens, kits, and articles of manufacture herein of antibodies, or antigen binding fragments thereof, that compete with anti«MMP9 antibodies or antigen binding fragments thereof described herein for binding to MMP9. Thus, the present disclosure contemplates use of anti-MMP9 antibodies, and functional fragments thereof, that compete for binding with, for example, an antibody having a heavy chain polypeptide of any of SEQ ID NOS: 1 or 5-8, a light chain polypeptide of SEQ ID N.OS:2 or 9-12, or combinations thereof. In one embodiment, the antiMMP9 antibody, for functional fragment thereof, competes for binding to human MMP9 with the antibody described herein as AB004-1.

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MMP9 sequence

I00168] The amino acid sequence, of human M.MP9 protein is as follows: MSLWQPL.VLV LLVLGCCFAA PRQRQSTLVL- FPGDLRTNLT DRQLAEEYLY 50 RYGYTRVAEM RCESKSLGPA LLLLQKQLSL PETGELDSAT LKAMR.TPRCG 100 VPDLGRFQTF EGDLRWHRHNITYW1QNYSE DLPRAV1DDA FARAFAL.WSA 150

VTPLTFTRVY SR.DAD1 ViQF GVAEHGDGYP FDGKDGLLAH AFPPGPGIQG 200 DAHFDDDELW SLGKGVVVPT RPGNADGAAC HFPFiFEGRS YSACTTDGRS 250

DGLPWCSTTA NYDTDDRFGF CPSERLYTRD GNADGKPCQF PPIFQGQSYS 300

ACTTDGRSDG YRWCATTANY DRDKLFGFCP TRADSTVMGG NSAGELCVFP 350 FTFLGKEYST CTSEGRGDGR LWCATISNFD SOKKWGFCPD QGYSLFLVAA 40-0 HEFGHA.LGLD HSSVPEALMY PMYRFTEGPP LHKDDVNGIR HLYGPRPEPE 450

PRPPTTTTPQ ptapptvcpt GPPTVHPSER PTAGPTGPPS AGPTGPPTAG 500 PSTAT7V'PLS PVDDACNVNi PDA1AEIGNQ LYLFKDGK YW RFSEGRGSRP 550

QGPFUADKW P.AJ,PR.K,LDSV FEEPLSKKLF FPSGRQVWVY TG.ASVl.GPRR 600

LDKLGLGADV AQ'VTGALRSG RGKMLLFSGR RLWRFDVKAQ MVDPRSASEV 650 DRMFPGVPL'D THDVFQYREK AYFCQDRTYW RVSSRSELNQ VDQVGYVTYD

700ILQCPED (SEQ ID NQ:27) (00169] Protein domains are shown schematically in Figure 3 and are indicated below;

Amino Acid #

1-19

38-98

R98/C99

112-445

223-271

281-329

340-388

400-411

521-565

567-608

613-659

661-704 feature

Peptidogiycan Binding Domain

Propetide cleavage site (dependent on cleavage enzyme) Zn dependent. metalloproteinase domain Fibronectin type II domain (gelatin binding domain) Fibronectin type Π domain (gelatin binding domain) Fibronectin type Π domain (gelatin binding domain)

Zn binding region

Hemopexin-like domain

Hemopexin-like domasn

Hemopexin-like domain

Hemopexin-fike domain [60170] The amino acid sequence of mature full-length human MMP9 (which is the amino acid sequence of the propolypeptide of SEQ ID NO:27 without the signal peptide) is:

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-104 ·

PRQRQSTLVL FPGDLRTNtT DR'QLAEEYLY RYGYTRVAEM RGESKSEGPA LLLLQKQLSl PETGELDSAT LKAMRTPRCG VPDLGRFQTF EGDtKWHHHN ITYW1QNYSE DITRAVJDDA FARAFALWSA VTPLTFTRVY SRDAD1V1QF GVAEHGDGYP FDGKiXILLAH AFPPGPG1QG DAHFDDDBLW SLGKGVVVPT RFGNADGAAC HFPP1FEGRS YSACTTDGRS DGLPWCS1TA NYDTDDRFGF CPSERLYTRD GNADGKPCQF PFIFQGQSYS ACTTDGRSDG YRWCATTANY DRDKLFGFCP TRADSTVMGG NSAGELCVFP FTFLGKEYST CTSEGRGDGR LWCATTSNPD SDKKWGFCPD QGYSLFLVAA HEFGHALGLD HSSVPEALMY PMYRFTEGPP LHKDDVNG1R HLYGPRPEPE PRPHTri'PQ PTAPPTVCPT GPPTVHPSERPTAGPTGPPS AGPTGPPTAG PSTATTVPLS PVDDACNVN1 FDAIAEIGNQ LYLFKDGKYW RFSEGRGSRP QGPFLIADK.W PALPRKLDSV FEEPLSKKLFFPSGRQVWVYTGASVLGPRR LDKLGLGADV AQVTGALRSG RGKMLLFSGR RLWRFDVKAQ MVDPRSASEV DRMFPGVPLD THDVFQYREK AYFCQDR.FYW RVSSRSELNQ VDQVGYVTYD ILQCPED (SEQ ID NO:28) [00171] The: amino acid sequence of the signal peptide is MSLWQPLVLV LLVLGCCFAA (SEQ ID NQ:29).

[00172] The present disclosure contemplate the use of MMP9 binding proteins that hind any portion of MMP9, e.g., human MMP9, with MMP9 binding proteins that preferentially bind MMP9 relative to other MMPs being of particular interest.Anti-MMP9 antibodies, and functional fragments thereof, can be generated accordingly to methods well known in the art. Examples of antiMMP9 antibodies are provided below.

Mouse monoclonal anti-MMP9 [001.73] A mouse monoclonal antibody to human MMP9 was obtained as described in Example 2, This antibody contains a mouse IgG2h heavy chain and a mouse kappa light chain, and is denoted AB0041.

]00174J The amino acid sequence of the AB0041. heavy chain is as fellows:

MAVLVTFLCLVAFPSCVIEOVOLOSGFGLVA.PSQSLSITCTVSGES

LLSYGVHWVRqpPGKGLBWLGVIWTGGTTNYNSALMSRLSISKDDSK.Sq VFLKJ^SLQTDDTAIYYCARyYYGMDYWGQGTSVTVSSAK77PRYnyZ^ m?G2MTG5,STTLG'a FKG1FPFYFYFI 'feMGYLSSSUfJFiMLLgSGL 17M kT^SST^SQTVTCSVim^SSTmKKLl’PSGP/STINPt/PPCEECRKmPN /_JFGGPSFF/?Y^;)FG2FDFW/Sin^>KF7L?FFFDFSE.DDM)FSfeH<FUVVFFFin2i

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- 105 L VRAPQ VYiLPPPAEQLSRKD YSLTCL rVGFNPGDISVEWTSNGHTEENYEDTA. PVLDSDGSYFiYSKLDIKTSKWEKrDSFSCEVRHEGlJiNYYIJiKnSRSPGK (SEQ ID NOT) (00175] The signal sequence is underlined, and the sequence of the lgG2b constant region is presented italics.

[00176] The amino acid sequence of theAB0041 light chain is as follows:

MESQIQVFVFVFL.WL.SGVDGDIVMTQSHKI’'MSTSVGDRVS1TC.KAS

QDVRNTVAWYQQKT<.iQSPKl.LlYSSSYRNTGVPDRFT<)SGSGn.)FTFT.ISS

VQAEDLAVYFCQQHYITPYTFGGUIXLErOTZX4d7^;’7'T57F?P5W£LS^IGG.4

SYVCFLNNFYPKDINVKWKIDGSERQNGYLFSWTDQDSKDSEYSMSSTLTLTKD EYERHNSYTCEATHETSIEPJFKYFNRNEC (SEQ ID NO:2j [00177) The signal sequence is underlined, and the sequence of the kappa constant region is presented in italics.

)0(1178) The following amino acid sequence comprises- the framework regions and complementarity-determining regions (CDRs) of the variable region of the IgGSb heavy chain of AB0041 (with CDRs underlined):

OVOLKESGPGLVAPSOSLSITCTVSGESLLSYGVHWVRQPPGKGLE

WLGYIWTGGTTNYNSALMSRLSISKDDSKSOVFLKMNSLQTDDTAIYYCA

RYYYGMDYWGQGTSVTVSS (SEQ ID NOG) [00179] The following amino acid sequence comprises the framework regions and complementarity-determining regions (CDRs) of the variable region of tire kappa light chain of AB0041 (with CDRs underlined):

DIVED

UJ\hS<YRNIGVPDRFrGSGSGTDFTFTfSSVQAEDIAVYFCQQHY.nZnF GGGTKLEIK (SEQ ID NON)

Heavy-chain variants [00180] As noted in U.S. Patent Nos. 8,377,443 (McAuley et ah), 8,501,916 (McAuley et al.), and 9,120,863 (McAuley et ah), the amino acid sequences of the variable regions of the AB0041 heavy and light chains were separately modified, by altering framework region sequences in the heavy and light chain variable regions. The effect of these sequence alterations was to deplete the

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PCT/US2016/054780 • H )6 -antibody of human T-cell epitopes, thereby reducing or.abolishing i ts immunogenicity in humans (Antitope, Babraham, UK).

(0018J j Four heavy-chain variants were constructed, in a human IgG4 heavy chain background containing a S241P amino acid change that stabilises the hinge domain (Angal el al. (1993) Molec. Immunol. 30:105 -108), and are denoted VH1, VH2, VH3 and VH4, The amino acid sequences of their framework regions and CDRs are as follows:

ViH

QVQLQBSGPGLVKPSETLStTCTVSGFSLLSYGVHWVRQPPGKGLEWLGVIWTGG TtNYNSALMSRLTlSKDDSKSTVYLKMNSLkTEDTM'YYCARYYYGMDYWGQGT SVTVSS (SEQ ID NOG

QVQLQESGPGLVKPSE'I LSLTCTVSGFShtS YOVH W VRQPPGKGLEWLG V1WTGG: TTNWSALMSSLTlSKDDSKNTVYLKMNSLKTEDTAPrYCARYVYGMOYWGQG TLVTVSS (SEQiDNOfo)

VH3

QVQLQESGPGLVKPSETESETCTVSGiYLLSYGVHWVRQPPGKGLE WLGV1WTGGTTNYNSAIMSRFHSKDDSKNTVYLKMNSLKTEDTA IYYCARYYYGMDYWGQGTLVTVSS (SEQ ID NO: 7)

VH4

QVQLQESGPGLVKPSETLSLTCTVSGESLLSYGVHWVRQPPGKGLE . WLGVIWTGGTTNYNSALMSR.FriSKDDSKOTLYLKMNSIXTEDTAl

YYCARYYYGMDYWGQGTLVTVS8 (SEQ ID NO:8)

Li ght-chain van ants [90182] Four light-chain variants were constructed, in a human kappa chain background, and are denoted Vkl, Vk2, Vk3 and Vk4. The amino acid sequences of their framework regions and CDRs are as follows:

Vkl

DIVMTQSPSFIYASVGDRVTITCOSQDVRNTVAWYQQKTGKAPK

LLIYSSSYRNTGVPDRFTGSGSGTDFTUHSSLQAEDVAVYFCQQHYI TPYTFGGGTKVEIK (SEQ ID NO:9)

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- 107 Vk2

DIVMTQSPSSLSASVGDRVTITCKASQDVRNTVAW'YQQKI’GKAI’K LLIYSSSYRNTGVPDRFTGSGSGTDFTLTISSLQAEDVAVYFCQQFIYI TPYTFGGGTKVBIK (SEQ ID NO: 10)

Vk3

DIQMTQSPSSLSASVGDRVTITCKASQDVRNTVAWYQQKPGKAPK LLIYSSSYRNTGVPDRFSGSGSGTDFTLTISSLQAEDVAVYFCQQHYI TPY rFGGGTKVEIK (SEQ ID NO:11)

Vk4

DIQMTQSPSSLSASVGDRVTrfCKASQDVRNTVAWYQQKPGKAPK LLIYS-SSYRNTGVPDRFSGSGSGTDFTLTISSLQABDVAWYCQQ'HY ITPYTFGGGTKVEIK (SEQ ID NO: 12) [00183( The humanized heavy and light chains -.are combined in all possible pairwise combinations io generate a number of functional humanized anti-MMP9 antibodies.

[00184j Additional heavy chain variable region amino acid sequences having 75% or more, 80% or more, 90% or more, 95% or more, or 99% or more homology io the heavy chain variable region sequences disclosed herein are also provided. Furthermore, additional light chain variable region amino acid sequences having 75% or more, 80% or more, 90% or more, 95% or more, or 99% or more homology io the light chain variable region sequences disclosed herein are also provided.

[0018SJ Additional heavy chain variable region amino add sequences having 75% or more, 80% or more, 90% or more, 95% or more, or 99% or more sequence- identity to the heavy chain variable region .sequences disclosed herein are also provided, furthermore, additional light chain variable region amino acid sequences having 75% or more, 80% or more, 90% or more, 95% or more, or 99% or more sequence identity to the light chain variable region sequences disclosed herein are also provided.

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- 108 Complementarity-determinuig reguns ί( 'DIG) [00186] The CDRs of the hea>y chum of un antt-MMP9 antibody as disclosed herein have the following amino acid sequences:

CDRI: GFSLLSYGVH (SEQ ID NO: 13)

CDR2: VIWTGGTTNYNSALMS (SEQ ID NO: 14)

CDR3: YYYGMDY (SEQ ID NO: 15) {00187] The CDRs of the light, chain of an anti-MMP9 antibody as disclosed herein have the following amino acid sequences:

CDRI: KASQDVRNTVA (SEQ ID NO; 16)

CDR2: SSSYRNT (SEQ ID NO: 17)

CDR3: QQHYITPYT (SEQ ID NO: 18)

Nucleic acids encoding anti-MMP9 antibodies [001881 The present disclosure provides use in the methods, regimens, kits, and articles of manufacture herein of nucleic acids encoding anti-MMP9 antibodies and functional .fragments thereof. Accordingly, the present disclosure provides an isolated polynucleotide (nucleic acid) encoding an antibody or antigen-binding fragment as described herein, vectors containing such polynucleotides, and host cells and expression systems for transcribing and translating such polynucleotides into pol ypeptides.The present disclosure also contemplates the use of constructs in the form of plasmids, vectors, transcription or expression cassettes which comprise at least one polynucleotide as above.

[00189] The present, disclosure also provides the use of a recombinant host cell which comprises one or more constructs as above, as well as methods of production of the an tibody or antigen -binding fragments thereof described herein which method comprises expression of nucleic a cid encoding a hea vy chain polypeptide and a light chain polypeptide (in the same or different host cells, and from the same or different constructs) in a recombination host cell. Expression can be achieved by culturing under appropriate conditions recombinant host cells containing the nucleic acid. Following production by expression, an antibody or antigen-binding fragment can. be isolated and/or purified using any suitable technique, then used as appropriate.

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109 [00190) Systems for cloning sad expression of a polypeptide in a. variety of different host cells are well known, Suitable host cells include bacteria, mammalian cells, yeast, and 'ba culovirus systems. Mammalian cell lines available in the art for expression of a heterologous polypeptide include Chinese hamster ovary cells, HeLa cells, baby hamster kidney cells, NSO mouse melanoma cells and many others. A common bacterial host is E. coli.

I00191J Suitable vectors can be chosen or constructed, containing appropriate regulatory sequences, including operably linked promoter sequences, terminator sequences, polyadenylation sequences, enhancer sequences, marker genes and/or other sequences as appropriate. Vectors can be plasmids, viral e.g, ‘phage, or phagemid, as appropriate. For farther details see, for example, Molecular Cloning: a Laboratory Manual: 2nd edition, Sambrook et al,, 1989, Cold Spring Harbor laboratory Press. Many known teehniqucs and protocols for manipulation of nucleic acid, for example in preparation of nucleic acid constructs, mutagenesis, sequencing, introduction of DNA into cells and gene picssion, and •iiulypis ol pi oh ms, ,no dmeui od in detail in Short Protocols in Molecular Biology, Second Edition, Ausubei el al. eds., John Wiley & Sons,

1992. The disclosures of Sambrook et al. and Ausubei et al. are incorporated herein by reference in their entirety.

[00192'j The nucleic acid encoding a polypeptide of interest is integrated into the genome of the host cell or can be maintained as a stable or transient episomal element. Any of a wide variety of expression control sequences - sequences that control the expression of a DNA sequence operatively linked to it --- can be used in these vectors to express the DNA sequences. For example, a nucleic acid encoding a polypeptide of interest can he operably linked to a promoter, and provided in an expression construct for use in methods of production of' recombinant MMP9 proteins or portions thereof Those of skill in the art axe aware that nucleic acids encoding the antibody chains disclosed herein can be synthesized using standard knowledge and procedures in molecular biology. [0(1193( Examples of nucleotide sequences encoding the heavy and light chain amino acid sequences disclosed herein, are as follows:

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- i ii·.·

VITE CAGGTGCAGC TGCAGGAATC CGGCCC'TGGC CTGGTCAAGC CCTCCGAGAC ACTGTCCCTG ACCTGCACCG TGTCCGGCTT CTCCCTGCTG TCCTACGGCG TGCACTGGGT CCGACAGCCT ccagggaagg gcctggaatg gctgggcgtg ATCTGGACCG GGGGCACCAC CAACTACAAC TCCGCCCTGA TGTCCCGGCT gaccatctcc AAGGACGACT CCAAGTCCAC CGTGTACCTG AAGATGAACT CCCTGAAAAC CGAGGACACC GCCATCTACT ACTGCGCCCG GTACTACTAC GGCATGGACT ACTGGGGCCA. GGGCACCTCC GTGACCGTGT CCTCA (SEQ ID NO: 19)

VH2: CAGGTGCAGC TGCAGGAATC CGGCCC'TGGC CTGGTCAAGC CCTCCGAGAC ACTGTCCCTG ACCTGCACCG TGTCCGGCTT CTCCCTGCTG TCCTACGGCG TGCACTGGGT CCGACAGCCT CCAGGCAAAG GCCTGGAATG GCTGGGCGTG ATCTGGACCG GGGGCACCAC CAACTACAAC TCCGCCCTGA TGTCCCGGCT GACCATCTCC AAGGACGACT CCAAGAACAC CGTGTACCTG AAGATGAACT CCCTGAAAAC CGAGGACACC GCCATCTACT ACTGCGCCCG GTACTACTAC GGCATGGACT ACTGGGGCCA GGGCACCCTG GTGACCGTGT CCTCA (SEQ ID NO:20)

VID: CAGGTGCAGC TGCAGGAATC CGGCCCTGGC CTGGTCAAGC CCTCCGAGAC ACTGTCCCTG ACCTGCACCG TGTCCGGCTT CTCCCTGCTG TCCT ACGGCG TGCACTGGGT CCGACAGCCT CCAGGCAAAG GCCTGGAATG GCTGGGCGTG ATCTGGACCG GGGGCACCAC CAACTACAAC TCCGCCCTGA TGTCCCGGTT GACCATCTCC AAGGACGACT CCAAGAACAC CGTGTACCTG AAGATGAACT CCCTGAAAAC CGAGGACACC GCCATCTACT ACTGCGCCCG GTACTACTAC GGCATGGACT ACTGGGGCCA GGGCACCCTG GTGACCGTGT CCTCA (SEQ ID NO:21)

VIM: CAGGTGCAGC TGCAGGAATC CGGCCCTGGC CTGGTCAAGC CCTCCGAGAC ACTGTCCCTG ACCTGCACCG

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.. 1 · : TGTCCGGCTi CTCCCTGCTG TCCTACGGCG TGCACTGGGT CCGACAGCCT CCAGGCAAAG GCCTGGAATG GCTGGGCGTG ATCTGGACCG GCGGCACCAC CAACTACAAC TCCGCCCTGA TGTCCCGGTT CACCATCTCC AAGGACGACT CCAAGAACAC CCTGTACCTG AAGATGAACT CCCTGAAAA.C CGAGGACACC GCCATC'fACT ACTGCGCCCG GTACTACTAC GGCATGGACT ACTGGGGCCA GGGCACCCTG GTCACCGTGT CCTCA (SEQ ID NO:22)

Vki: GACATCGTGA TGACCCAGTC CCCCAGCTTC CTGTCCGCCT CCGTGGGCGA CAGAGTGACC ATCACATGCA AGGCCTCTCA GGACGTGCGG AACACCGTGG CCTGGTATCA GCAGAAAACC GGCAAGGCCC CCAAGCTGCT GATCTACTCC TCCTCCTACC GGAACACCGG· CGTGCCCGAC CGGTnACCG GCTCTGGCTC CGGCACCGAC TTTACCCTGA CCATCAGCTC CCTGCAGGCC GAGGACGTGG CCGTGTACTT CTGCCAGCAG CACTACATCA CCCCCTACAC GTTCGGCGGA GGCACCAAGG TGGAAATAAA A ISEQ ID NO;23)

Vk2: GACATCGTGA TGACCCAGTC CCCCTCCAGC CTGTCCGCCT CTGTGGGCGA CAGAGTGACC ATCACATGCA AGGCCTCTCA GGACGTGCGG AACACCGTGG CCTGGTATCA GCAGAAGCCC GGCAAGGCCC CCAAGCTGCT GATCTACTCC TCCTCCTACC GGAACACCGG CGTGCCCGAC CGGTTTACCG GCTCTGGCTC CGGCACCGAC TTTACCCTGA CCATCAGCTC CCTGCAGGCC GAGGACGTGG CCGTGTACTT¹ CTGCCAGCAG CACTACATCA CCCCCTACAC CTTC.GGCGGA GGCACCAAGG TGGAAATAAA A (SEQ ID NO:24)

Vk3; GACATCCAGA TGACCCAGTC CCCCTCCAGC CTGTCCGCCT CTGTGGGCGA CAGAGTGACC ATCACATGCA AGGCCTCCCA GGACGTGCGG AACACCGTGG CCTGGTATCA GCAGAAGCCC GGCAAGGCCC CCAAGCTGCT GATCTACTCC TCCTCCTACC GGAACACCGG CGTGCCCGAC CGGTTCTCTG GCTCTGGAAG CGGCACCGAC TTTACCCTGA CCATCAGCTC

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--112CCTCiGAGGCC GAGGACGTGG CCGTGTACTT CTGCCAGCAG CACTACATCA CCCCCTACAC CTTCGGCGGA GGCACCAAGG TGGAAATAAA A (SEQ Π) NO;25)

VU4; GACATCCAGA TGACCCAGTC CCCCTCCA.GC CTGTCCGCCT ctgtgggcga cagagtgacc atcacatgca AGGCCTCTCA GGACGTGCGG AACACCGTGG CCTGGTATCA GCAGAAGCCC GGCAAGGCCC CCAAGCTGCT GATCTACTCC TCCTCCTACC GGAACACCGG CGTGCCCGAC CGGTTCTCTG GCTCTGGAAG CGGCACCGA.C TTTACCCTGA CCATCAGCTC CCTGCAGGCC GAGGACGTGG CCGTGTACTA CTGCCAGCAG CACTACATCA CCCCCTACAC CTTCGGCGGA GGCACCAAGG TGGAAATAAA A (SEQ ID NO:26) [00194] Because the structure of antibodies, including the juxtaposition of CDRs and .framework regions in the variable region, the structure of framework regions and the structure of heavy- and light-chain constant regions, is well-known in the art; it is well within the skill of the art io obtain related nucleic acids that encode anti-MMP-9 antibodies. Accordingly, polynucleotides comprising nucleic acid sequences having at least 75%, at least 8078, at least 85*%, at least 90%, at least 95%, at least 98% and at least 99% homology to any of the nucleotide sequences disclosed herein are also provided. Accordingly, polynucleotides comprising nucleic acid sequences having at least 75%, at least 80%, at least 85%, at. least 90%, at least 95%, at least 98% and at least 99% identity to any of the nucleotide sequences disclosed herein are also provided, [00195] MMP9 binding proteins, as well as nucleic acid (e.g,, DNA or RNA) encoding MMP9 binding proteins, can be provided as a pharmaceutical composition, e,g., combined with a pharmaceutically acceptable carrier or excipient. Such pharmaceutical compositions are useful for, for example, administration to a subject in vivo or ex vivo, and for diagnosing and/or treating a subject with the MMP9 binding proteins, [00196j Pharmaceutically acceptable carriers are physiologically acceptable to the administered patient and retain the therapeutic properties of the antibodies or

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-113peptides with which ii is administered, Pharmaeeuticaiiy-acceptabie carriers and their formulations are and generally described in, for example, Remington’ pharmaceutical Sciences (18th Edition., cd. A. Gennaro, Mack Publishing Co., Easton, PA 1 «μο·, One exemplary pharmaceutical carrier is physiological saline. Each carrier is “pharmaceutically acceptable” in the sense of being compatible with the other ingredients of the formulation and not substantially injurious to the patient, [001973 Pharmaceutical compositions can be formulated to be compatible with a particular route of administration, systemic or local. Thus, pharmaceutical compositions include carriers, diluents, or excipients suitable for administration by various routes.

[00198] Pharmaceutical compositions can include pharmaceutically acceptable additives, Examples of additives include, but are not limited to, a sugar such as mannitol, sorbitol, glucose, xylitol, trehalose, sorbose, sucrose, galactose, dextran, dextrose, fructose, lactose and mixtures thereof. Pharmaceutically acceptable additives can be combined with pharmaceutically acceptable carriers and/or excipients such as dextrose. Additives also include surfactants such as polysorbate 20 or polysorbate 80.

[00199] The formulation and delivery methods will generally be adapted according to the site and the disease to he treated. Exemplary form illations include, but are not limited to, those suitable for parenteral administration, e.g., intravenous, intra-arterial, intramuscular, or subcutaneous administration.

[00280] Pharmaceutical compositions for parenteral delivery include, for example, water, saline, phosphate buffered saline, Hank’s solution, Ringer’s solution, dextrose/saline, and glucose solutions, The formulations can contain auxiliary substances to approximate physiological conditions, such as buffering agents, tonicity adjusting agents, wetting agents, detergents and the like. Additives can also include additional active ingredients such as bactericidal agents, or stabilizers. For example, the solution can contain sodium acetate, sodium lactate, sodium chloride, potassium chloride, calcium chloride, sorhitan monolaurate or triethanolamine oleate. Additional parenteral formulations and methods are described in. Bai {1997) J. Neuroimmunol. 80:65 75; Warren (1997)

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- 114j. Neurol. Sci, 152:31 38; and Tonegawa (1997) J, Exp. Med, 186:507 5.15. The parenteral preparation can be enclosed in ampules, disposable syringes or multiple dose vials made of glass or plastic.

(0020.1] Pharmaceutical compositions for intradermal or subcutaneous administration can include a sterile diluent, such as water, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parahens; antioxidants such as ascorbic acid, glutathione or sodium bisulfite; chelating agents such as ethylenediaminetetraacetie acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose. (00202] Pharmaceutical compositions for injection include aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion, For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor ELTM (BASF, Parsippany, N.J.) or phosphate buffered saline (PBS), The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyetheylene glycol, and the like), and suitable mixtures thereof. Fluidity can be maintained, for example, by the use of a coating such as lecithin, by die maintenance of the required particle size in the case of dispersion and by the use of surfactants. Antibacterial and antifungal agents include, for example, parabens, ehlorohutanol, phenol, ascorbic acid and. thimerosal, Isotonic agents, for example, sugars, polyalcohols such as manitol, sorbitol, and sodium chloride may be included in the composition. The resulting solutions can be packaged for use as is, .or lyophilized; the lyophilized preparation can later be combined with a sterile solution prior to administration.

]00203] Pharmaceutically acceptable carriers can contain a compound that stabilizes, increases or delays absorption or clearance. Such compounds include, for example, carbohydrates, such as glucose, sucrose, or dextrans; low molecular weight proteins; compositions that reduce the clearance or hydrolysis of peptides; or excipients or other stabil izers and/or buffers. Agents that delay absorption include, for example, aluminum monostearate and gelatin. Detergents can also

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I15 be used io stabilize or to increase or decrease the absorption of the pharmaceutical composition, including liposomal carriers. To protect from digestion the compound can he complexed with a composition to render it resistant to acidic and enzymatic hydrolysis, or the compound can he complexed in an appropriately resistant carrier such as a liposome. Means of protecting compounds from digestion are known in the art (see, e.g., Fix (.1996) Pharm Res. 13:1760 1764; Samanen (1996) J. Pharm. Pharmacol. 48:119 135; and U.S, Pat. No. 5,391,377, describing lipid compositions for oral delivery of therapeutic agents).

[002041 Compositions of'the present invention can be combined with other therapeutic moieties or imaging/diagnostic moieties as provided herein. Therapeutic moieties and/or imaging moieties can he provided as a separate composition, or as a >.o sm-gated moiety present on an MMP9 binding protein, (00205] Formulations for in. vivo-administration are generally sterile·. In one embodiment, the pharmaceutical compositions are formulated to be free of pyrogens such that they are acceptable for administration to human patients. (00206] Various other pharmaceutical compositions and techniques for their preparation and use will be known to those of skill in the art in light of the present disclosure. For a detailed listing of suitable pharmacological compositions and associated administrative techniques one can refer to the detailed teachings herein, which can he further supplemented by texts such as Remington: The Science and Practice of Pharmacy 20th Ed. (Lippincott, Williams & Wilkins 2003).

(00207] Pharmaceutical compositions can be formulated based on the physical characteristics of the patient/subject needing treatment, the ro ute of administration, and the like. Such can be packaged in a suitable pharmaceutical package with appropriate labels for the distribution to hospitals and clinics wherein the label is for the indication of treating a disorder as described herein in a subject. Medicaments can be packaged as a single or multiple units. Instructions lor the dosage and administration of the pharmaceutical compositions of the present invention can be included with the pharmaceutical packages and kits described below,

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Methods of Use and Treatments [00208] The methods disclosed herein may he used for treating cancer in a human in need thereof comprising administering to the human a therapeutically effective amount of a BTK inhibitor in combination with one or more inhibitor. For example, the one or more inhibitor may be therapeutically effective amounts of a JAK inhibitor, an ASKT inhibitor, a BET inhibitor and a MM.P9 inhibitor, as described herein.

[00209] The method of use or treatment described herein may comprise Compound A I, or a pharmaceutically acceptable salt or hydrate thereof, in combination with one or more inhibitor and another pharmaceutical or therapeutic agent. In each of the methods described herein, pharmaceutically effective amounts of each inhibitor, and each pharmaceutical agent are used.

Diseases [00210] In some aspects, the disease or condition is chosen from an autoimmune disease, an inflammatory disease, a neurodegenerative disease, a cardiovascular disorder, a renal disorder, a viral infection, and obesity. In some aspects, the disease or condition is chosen from rheumatoid arthritis, osteoarthritis, atherosclerosis, psoriasis, systemic lupus erythematosus, muHiple sclerosis, inflammatory bowel disease, asthma, chronic obstructive airways disease, pneumonitis, dermatitis, alopecia, nephritis, vasculitis, atherosclerosis, Alzheimer’s disease, hepatitis,, primary biliary cirrhosis, sclerosing cholangitis, diabetes (including type I diabetes), and acute rejection of transplanted organs, in some aspects the disease or condition is cancer, including hematological cancers, lymphoma, multiple myelomas, leukemias, a neoplasm, cancer or tumor ifor example a solid tumor), .

[00211] In some embodiments, the cancer is carcinoma, sarcoma, melanoma, lymphoma or leukemia. In other embodiments, the cancer is a hematologic malignancy. In some embodiments, the cancer is leukemia (e.g., chronic lymphocytic leukemia), lymphoma (e.g, non-Hodgkin’s lymphoma), or multiple myeloma. In other embodiments, the cancer is a solid tumor.

[00212] lit some variations, the cancer is small lymphocytic lymphoma, nonHodgkin’s lymphoma, indolent non-Hodgkin’s lymphoma (iNHL), refractory

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-1.17iNHL, mantle cell lymphoma, follicular lymphoma, lymphoplasmaeytic lymphoma, marginal zone lymphoma, immunoblastie large cell lymphoma, lymphoblastic lymphoma, Splenic marginal zone B-cell lymphoma ft·/- villous lymphocytes), nodal marginal zone lymphoma (+/~ monocytoid B-cells), ex tranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue type, cutaneous T-cell lymphoma, extranodal T-cell lymphoma, anaplastic large cell lymphoma, angioimmunoblastic ϊ-cell lymphoma, mycosis fungoides, B-cell lymphoma, diffuse large B-cell lymphoma, Mediastinal large B-cell lymphoma, Intravascular large B-cell lymphoma, Primary effusion lymphoma, small non-cleavedcell lymphoma, Burkitt’s lymphoma, multiple myeloma, plasmacytoma, acute lymphocytic leukemia. T-cell acute lymphoblastic leukemia, B-cell acute lymphoblastic leukemia, B-cell prolymphocytic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, juvenile •myelomonocytic leukemia, minimal residual disease, hairy cell leukemia, primary myelofibrosis, secondary myelofibrosis, chronic myeloid leukemia, ms JmK rohVk roedwm*,'lutomobtoMfo Ίι ro,, m \\ ehleffto u > macrogiobulinemia.

[002131 1» ote variations, the cancer is pancreatic cancer, urological cancer, bladder cancer, colorectal cancer, colon cancer, breast cancer, prostate cancer, renal cancer, hepatocellular cancer, thyroid cancer, gall bladder cancer, lung cancer (e.g. non-small cell lung cancer, small-cell lung cancer), ovarian cancer, cervical cancer, gastric cancer, endometrial cancer, esophageal cancer, head and neck cancer, melanoma, neuroendocrine cancer, CNS cancer, brain tumors (e.g., glioma, anaplastic oligodendroglioma, adult glioblastoma multiforme, and adult anaplastic astrocytoma), bone cancer, soft tissue sarcoma, retinoblastomas, neuroblastomas, peritoneal effusions, malignant pleural effusions, mesotheliomas, Wilms tumors, trophoblastic neoplasms, hemangiopericytomas, Kaposi's sarcomas, myxoid carcinoma, round cell carcinoma, squamous cell carcinomas, esophageal squamous cell carcinomas, oral carcinomas, cancers of the adrenal cortex, or zkCTH-producing tumors, [00214j In some embodiments, provided herein is a method for heating a human who exhibits one or more symptoms associated with cancer (e.g, a hematologic

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- .118malignancy). In some-embodiments, the human i‘ it η ^Ί\9«ι·χ -Emu In other embodiments, the human is at an advanced stage of cancer.

100215] In some embodiments, provided herein is a method for treating a human who is undergoing one or more standard therapies for treating cancer (e.g., a hematologic malignancy), such as chemotherapy, radiotherapy, immunotherapy, and/or surgery. Thus, in some foregoing embodiments, the combination of a BTK inhibitor and one or more inhibitor as described herein, may be administered before, during, or after administration of chemotherapy, radiotherapy, immunotherapy, and/or surgery, For example, the one or more inhibitor may be a .TAK inhibitor, an ASKI inhibitor, a BET inhibitor and a M'MP9 inhibitor, as described herein. In some embodiments, Compound Al may be used in combination with a TAK inhibitor such as Compound BI and Compound B2. In other embodiments, Compound.A1 may be used in combination with a BRD inhibitor such as (2<yel0pmpyl-d<3.,5dirnethylisoxazol -4-y})-lH-benzo[d]imidazol~4-yl)di(pyfidin-2-yl)meihanol. [00216] In another aspect, provided is a method for sensitizing a human who is (i) refractory to at least one chemotherapy treatment, or (ii) in relapse after treatment with chemotherapy, or both (i) and fit), wherein the method comprises administering a BTK. inhibitor in combination with one or more inhibitor, as described herein, to the human. A human who is sensitized is a human who is responsive to the treatment involving administration of a BTK inhibitor in combination with one or more inhibitor, as described herein, or who has not developed resistance to such treatment. For example, the on or more inhibitor may be a J AK inhibitor, an ASKI inhibitor, a BET inhibitor and/or a MMP9 inhibitor, as described herein.

[00217] For chronic lymphocytic leukemia the prior treatments a human, may have received include regimens of:

fludarabine (Fludara ®); ri tuximab (Ri tuxan®);

rituximab (Rituxan ®) combined with fludarabine (sometimes abbreviated as FR):

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-119 cyclophosphamide (Cytoxan®) combined with fludarabine; cyclophosphamide combined with rituximab and fludarabine (sometimes abbreviated as FCR);

cyclophosphamide combined with vincristine and prednisone (sometimes abbreviated as CVP);

cyclophosphamide combined with vincristine, prednisone, and rituximab; combination of cyclophosphamide, doxorubicin, vincristine (Oncovin), and prednisone (sometimes referred to as CHOP);

Chlorambucil combined with prednisone, rituximab, obinutuzumab, or ofatumumab pentostatin combined with cyclophosphamide and rituximab (sometimes abbreviated as FCR);

bendamustine ffrsanda®) combined with.rituximab ((sometimes abbreviated as BR);

aiemtuzumab (Campath®);

fludarabine plus cyclophosphamide, bendamustine, or chlorambucil; and fludarabine- plus cyclophosphamide, bendamustine, or chlorambucil, combined with an anti-CD20 antibody, such as rituximab, ofatumumab, veltuzumab, lumtluxiraab or obinutuzumab.

[00218] In another aspect, provided herein is a methods for treating a human for a cancer, with comorbidity, wherein the treatment is also effective in treating the comorbidity, A “comorbidity” to cancer is a disease that occurs at the same time as the cancer.

[00219] The BTK tnhbitor, Compound Al,or a pharmaceutically acceptable salt or hydrate thereof, may be combined with known agents and regimens useful in the treatment of allergic, autoimmune, and inflammatory disorders, as can the combinations herein of Compound Al with one or more inhibitors -described herein, in addition, Compound Al may be combined include tumor necrosis factor inhibitors (TNFi), such as infliximab (sold under the RBM1CADE® mark), etanercept (ENBREL®), certolizumab pegol fCIMZIA®), golimumab (SIMPON1®), adalimumab (HIIMIRA®), and ozoalizumab.

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-120 Therapeutically Effective Amounts [00220) In some variations, a therapeutically effective amount refers to an amount that is sufficient to effect treatment, as defined below, when administered to a subject (e.g., a. human) in. need of such treatment. The therapeutically effective amount will vary depending upon the subject and disease condition being treated, the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art. For example, in one variation, a therapeutically effective amount of Compound Al, or a pharmaceutically acceptable salt or hydrate thereof, is an amount sufficient to modulate BTK expression, and thereby treat a human suffering an indication, or to ameliorate or alleviate the existing symptoms of the indication, [00221) In another variation, the therapeutically effective amount of the BTK inhibitor, such as: Compound Al, or a pharmaceutically acceptable salt or hydrate thereof, may be an amount sufficient to decrease a symptom of a disease or condition responsive to inhibition of BTK activity.

[002:22) The compound, inhibitor, or therapeutic agent described herein may be administered using any suitable methods known in the art. For example, the compounds may be administered bucally, ophthahnicaliy, orally, osmotically, parenterally (intramuscularly, intraperitoneally intrastemally, intravenously, subcutaneously), rectally, topically, transdermaily, or vaginally. in certain embodiments, the Btk inhibitor is administered orally. In one embodiment, the Btk inhibitor is Compound Al or hydrochloride salt thereof, which is administered orally, once a day, to a subject in need thereof at a dose of 20 mg, mg, 80 mg, or 150mg. In some embodiments, the Btk inhibitor is Compound Al or hydrochloride salt thereof, which is administered orally, twice a day, to a subject at a dose of 20 mg, 40mg, or 75 mg. In one variation, the therapeutically effective amount of the BTK inhibitor is a dose corresponding to 1 nmol to 10,000 nmol of the BTK. inhibitor used in an apoptosis assay run with 10% serum which approximately relates to a blood plasma concentration of 500 nmol to 2.500 nmol of the BTK. inhibitor. In one variation, the therapeutically effective amount of the one or more inhibitor is a dose corresponding to 1 nmol to 200 nmol of the

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-121 one or more inhibitor used in an apoptosis assay run with 10% serum. Specific examples include 3 nM, 5 n.M, 10 nM, 20 nM and 30 nM concentrations when combined with one or more inhibitor described herein.

[00223] The therapeutically effective amount of the inhibitors described herein may also be determined based on data obtained from assays known in the art, including for example, an apoptosis assay. In one variation, the therapeutically effective amount of the BTK inhibitor in a human is a dose of from about 1 mg to about 200 mg. In another embodiment the BTK. in a human is administered at a dose of from about 10 mg to about 200 mg. In another embodiment the BTK. in a human is administered at a dose of from about 20 mg to about 160 mg. In other separate embodiments the BTK inhibitor is administered to a human at a dose of: a) from about 10 mg to about 100 rug, b) from about 50 mg to about 175 mg, c) from about 20 mg to about 150 mg, d) from about 75 mg to about 100 mg, and e) from about 100 mg to about 200 mg. individual doses of the BTK. inhibitor that may be administered to a human in need thereof include individual doses of 1 mg, 5 mg, 10 mg, 20 mg, 30 mg, 40 rag, 50 mg, 60 mg, 70 mg, 75 mg, 80 mg, 901 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 175 mg, and 200 mg. The doses of the BTK inhibitor may be administered as determined by a medical professional and may be administered once daily or may be delivered twice daily, three times daily, or four times daily.

(002241 in another variation, the BTK inhibitor, such as Compound Al, or a pharmaceutically acceptable salt or hydrate thereof, is administered to the human at a dose resulting in about 50%, about 55%, about 60%, about 65%, about 70%, about 7566, about 80%, about 90%, about 95%, or about 99% BTK target inhibition. In another variation, the one or more inhibitor, such as JAK. inhibitor, ASK inhibitor, BR.D inhibitor, and MMP9 inhibitor, is administered to the human ai a dose resulting in about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 90%, about. 95%, or about 99% target inhibition.

[00225] In some variations, the BTK inhibitor, such as Compound Al, or a pharmaceutically acceptable salt or hydrate thereof, is administered to the human, at a dose between 40 mg and 1200 rug, between 40 mg and 800 mg, between 40

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PCT/US2016/054780 mg and 600 mg, between 40 mg and 40 mg, about 1 Of) mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, or about 800 mg. In some variations, the JAK inhibitor, such as Compound BI, Compound B2, Compound B3, or Compound B4, or a pharmaceutically acceptable salt thereof, is administered to the human at a dose between 20 to 600 mg, between 20 to 400 mg, between 20 to 200 mg, about 20 mg, about 50 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, or about 800 mg. in some embodiments, the JAK inhibitor is momelotinib i Compound BI) or a hydrochloride salt there of is administered orally at a dose of 50 mg, 100 mg, 200 mg, or 400 mg. In certain embodiments, the JAK. inhibitor is filgotiuib (Compound B2) or a pharamceudeally salt there of is administered orally at a dose of 30 mg. 5:0 mg, mg, 100 mg, 15() mg, 200 mg, or 300 mg. In certain embodiments, the J AK inhibitor Is administered once daily or twice daily, [00226) The therapeutically effective amount of the BTK and one or more inhibitor described herein may be provided in a single dose or multiple doses to achieve the desired treatment endpoint. As used herein, “dose” refers to the total amount of an active ingredient to be taken each time by a hitman. The dose administered, for example for oral administration described above, may be administered once weekly, once daily (QD), twice daily (BID), three times daily, four times daily, or more than four times daily. In some embodiments, the BTK. and/or the one or more inhibitor may be administered once daily. In some embodiments, the BTK and/or the one or moreinhibitor may be administered twice daily. In some embodiments, the one or more inhibitor may be administered ones weekly or with a frequency that can vary between dally, every other day, once every 5 days, daily for 1, 2,3,4, 5, 6 or 7 days and then weekly or with a regimen that can combine these different frequencies and doses to result in a final dose and regimen that is tolerated and efficacious.

[002271 fo one variation, the therapeutically effective amount of the ASK1 inhibiting compound is a dose corresponding to 1 nmol to 200 nmol of the ASK I inhibiting compound used in an apoptosis assay run with 10% serum. The Ask 1 inhibiting compounds herein, including compounds of formula (I) and Compound

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-123 CL may be administered in a pharmaceutically effective amount, For oral administration, each dosage unit preferably contains from 1 mg to 500 mg of the AS.K1 inhibiting compound. A more preferred dose is from 1 mg to 250 mg of the compound of the AS.K1 inhibiting compound. Particularly preferred is a dose of the ASK1 inhibiting compound ranging from about 20 rug twice a day to about 50 mg twice a day, In some embodiments, the ASK. inhibitor is Compound C2 which is administered orally at a dose of 2 mg, 6 mg, 10 mg, .18 mg, or 50 mg. In certain embodiments, the ASK inhibitor is administered once daily or twice daily. It will be understood, however, that the amount of the compound actually administered usually wilt he determined by a physician in light of the relevant circumstances including the condition to be treated, the chosen route of administration, co-administration compound if applicable, the age, weight, response of the individual patient, the seventy of the patient’s- symptoms, and the like.

[00228] in some variations, the Btk inhibitor, such as Compound Al, or a pharmaceutically acceptable salt or hydrate thereof, is administered to the human at a dose between 40 mg and 1200 mg, between 40 mg and 800 mg, between 40 mg and 600 .tug, between 40 mg and 40 mg, about 100 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, or about. 800 mg. In some variations, the ASK'l inhibiting compound, such as Compound CI, Compound C2 or a compound of Formula 1, or a pharmaceutically acceptable salt thereof is administered to the human at a dose between 20 to 600 mg, between 20 to 400 mg, between 20 to 200 mg, about 20 mg, about SO mg, about 100 mg, about 2.00 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, or about 800 mg.

[00229] In some variations, the BET inhibitor, such as a modulator of a bromodomain-containing protein, or a pharmaceutically acceptable salt thereof as described herein, is administered to the human at a dose between 20 to 600 mg, between 20 to 400 mg, between 20 to 200 mg, about 20 mg, about 50 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, or about 800 mg.

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- 124-[ΌΌ23Θ3 In some variations, the MMP9 inhibitor, is administered to tbs human at a dose between 20 to 600 mg, between 20 to 400 rng, between 20 to 200 mg, about 20 mg, about 50 mg, about 100 mg, about 200 mg, about 300 mg, about 400 rag. about 500 mg, about 600 mg, about 700 mg, or about 800 mg, [00231] in another embodiment, the MMP9 inhibitor, particularly including an anti-MMP9 antibody, is administered once every two weeks at a single dose of from about 600 mg to 1,000 mg. In another embodiment, the MMP9 inhibitor, particularly including an anti-MMP9 antibody, is administered once every two weeks at a single dose of from about 700 mg to about 900 mg. hi another embodiment, the MMP9 inhibitor, particularly including an anti-MMP9 antibody, is administered once every two weeks at a single dose of from about 750 mg to about 850 mg. In another embodiment, the MMP9 inhibitor, particularly including an anti-MMP9 antibody, is administered once every two. weeks at a single dose of about 800 mg. In another embodiment, the MMP9 inhibitor, particularly including art anti-MMP9 antibody, is administered once every three weeks at a single dose of from about 1,000 mg to 1,400 mg. in another embodiment, the MMP9 inhibitor, particularly including an anti~M.MP9 antibody, is administered once every three weeks at a single dose of from about 1,100 mg to 1,300 mg. In another embodiment, the MM.P9 inhibitor, particularly including an antf-M.MP9 antibody, is administered once every three weeks at a single dose of about 1,200 mg, hi one embodiment, the MMP9 inhibitor is an anti-MMPO antibody having the amino acid sequence of SEQ ID Nos: 7 and 12, which is administered intravenously or subcutaneously at a dose of 150 mg, 300 mg, or 600 mg. In certain embodiment, the MMP9 inhibitor is administered once a week or once every two weeks, [00232] The present disclosure contemplates pharmaceutical compositions for use in connection with such methods. Compositions can he suitable for administration locally or systemically by any suitable route.

[002-33] For example, when in vivo administration of an anti-MMP9 antibody is employed, normal dosage amounts can vary from about 10 ng/kg to up to 100 mg/kg of mammal body weight or more per day, preferably about 1 p.g/kg/day to 50 rng/kg/day, optionally about 100 pg/kg/day to 2.0 mg/kg/day, 500 pg/kg/day to

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-· 125 10 mg/kg/day, or .1 mg/kg/day to 10 mg/kg/day, depending upon (he route of administration, [00234] The selected dosage regimen Will depend upon a variety of factors including the activity of the MMP9 binding protein, the route of administration, the time of administration, the rate of excretion of the particular compound being employed, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular composition employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts, [00235] A clinician having ordinary skill in the art can readily determine and prescribe the effective amount (ΕΌ50) of the pharmaceutical composition required. For example, the physician or veterinarian can start doses of the compounds of the invention employed in the pharmaceutical composition at levels: lower .than that, required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.

[00236] If needed, for cancer treatments, methods can further include surgical removal of the cancer and/or administration of an anti-cancer agent or treatment in addition to an MMP9 binding protein. Administration of such an anti-cancer agent, or treatment can be concurrent with administration of the compositions disclosed herein.

Administration [00237] A BTK inhibitor, such a Compound Al, can be administered with one or more inhibitor using any suitable .methods known, in the art. For example, the one or more inhibitor to be combined with a BTK inhibitor may be a JAK inhibitor, such as Compound Bl, Compound B2, Compound B3, Compound B4, Compound B5, Compound B6, Compound B7, Compound B8, Compound B9, Compound BIO or Compound Bl 1, In some embodiments, the one or more inhibitor may be an ASK1 inhibitor, such as Compound Cl, Compound C2 or a compound of Formula I. In other embodiments, the one or more inhbitior may be a modulator of a bromodomain-containing protein such as (2.-cyelopropyl-6~(3,5dimethyiisoxazol -4-yl)-lH-benzo[d]imidazol-4-yl)di(pyridin-2-y1)metlianol. In

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-126yet other embodiments, the one or more inhibitor may be a MMP.9 inhibitor such as an anti-MMP9 antibody.

(00238] For example, the compounds may be administered bucally, ophthalmieaily, orally, osmotically, parenterally (intramuscularly, intraperitoneaily intrastemaliy, intravenously, subcutaneously), rectally, topically, transderma lly, or vaginally. Further, in certain variations, the BTK inhibitor described herein may be administered prior, after or concurrently with one or more inhibitor wherein the one or more inhibitor may be a JAK. inhibitor, an ASK'1 inhibitor, a BET inhibitor and a MMP9 inhibitor, as described herein, (00239( In one aspect, the compounds described herein may be administered orally. Oral administration may be via, lor example, capsule or enteric coated tablets, hi making the pharmaceutical compositions that include- at least one eompounddescribed herein, or a pharmaceutically acceptable salt thereof, the active ingredient is usually diluted by an excipient and/or enclosed wiihm such a carrier that can be in the form of a capsule, sachet, paper or other eontamei When the excipient serves as a diluent, it can he in the form of a solid, semi-solid, or liquid material (as above), which acts as a vehicle, earner or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, sterile injectable solutions, and sterile packaged powders, (00240] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragaeanth, gelatin, calcium Mluatc, munouvshdliue cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methyl cellulose. The formulations can additionally.include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl and propylhydroxy-benzoates; sweetening agents; and flavoring agents, (00241] The compositions that include at least one compound of the compounds described herein, or a pharmaceutically acceptable salt thereof, can be formulated

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- 12.7 sp as to provide quick, sustained or delayed release of the active ingredient after administration to the subject by employing procedures known in the art. Controlled release drug delivery systems tor oral administration include osmotic pump systems and dissolutional systems containing polymer-coated reservoirs or drug-polymer matrix formulations. Examples of controlled release systems arc given in U.S. Patent Nos. 3,845,770; 4,326,525; 4,902,514: and 5,616,345. Another formulation for use in the methods of the present invention employs transdermal delivery devices (“patches”). Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds of the present invention in controlled amounts, The construction, and use of transdermal patches for die delivery of pharmaceutical agents is well known in die art. See, e.g., U.S. Patent Nos. 5,023,252, 4,992,445 and 5,001,139, Such patches maybe constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.

[002421 The compositions may, in some embodiments, be formulated in a unit dosage form. The term “unit dosage forms” refers io physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient (e.g.. a tablet, capsule, ampoule). The compounds are generally administered in a pharmaceutically effective amount, in some embodiments, for oral administration, each dosage unit contains from about 10 mg to about 1000 rag of a compound described herein, for example from about 50 mg to about 500 rag, .for example about 50 mg, about 75 mg, about 100 mg, about 150 rag, about 200 mg, about 250 mg, or about 300 mg, In other embodiments, for parenteral administration, each dosage unit contains from 0.1 to 700 mg of a compound :a compound described herein. It will be understood, however, that the .amount of the compound actually administered usually will be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered and its relative activity, the age, weight, and response of the individual subject, and the severity of the subject's symptoms.

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- 128 {00243J in certain embodiments, dosage levels may be from 0.1 mg to 100 rag per kilogram of body weight per day, for example from about 1 mg to about 50 mg per kilogram, for example from about 5 mg io about 30 mg per kilogram. Such dosage levels may, in certain instances, be useful in the treatment of the above-indicated conditions. In other embodiments, dosage levels may be from about IO mg to about 2000 mg per subject per day. The amount of active ingredient that may he com dined with the vehicle to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. Dosage unit forms may contain from ί mg to 500 mg of an active ingredient.

[00244] Frequency of dosage may also vary depending on the compound used and the particular disease or condition treated.. In some embodiments, for example, for the treatment of an. autoimmune and/or inflammatory disease, a dosage regimen of 4 times daily or less is used. In some embodiments, a dosage regimen of 1 or 2 times daily is used. It will be understood, however, that the specific dose level for any particular subject will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination and the severity of the particular disease in the subject undergoing therapy.

(00245] For preparing solid compositions such as tablets, the principal active ingredient may be mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound of Formula (II), or a pharmaceutically acceptable salt thereof When referring to these preformulation compositions as homogeneous, the active ingredient may be dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.

[00246] The tablets or pills of the compounds described herein may be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action, or to protect from the acid conditions of the stomach. For example, the tablet or pill can comprise an inner dosage and an outer dosage

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- 129 component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer that serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to he delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate,

100247] The pharmaceutical compositions may be administered in either single or multiple doses by any of the accepted modes of administration of agents having similar utilities, for example as described in those patents and patent .applications incorporated by reference, including rectal, buccal, intranasal and transdermaf routes, by intra-arterial injection, intravenously, mtraperitonealiy, parenteraliy, intramuscularly, subcutaneously, orally, topically, as an inhalant, or via an impregnated or coated device such as a stent, for example, or an artery-’ inserted cylindrical polymer

Pharmaceutical Compositions {00248} The BTK inhibitor and one or more inhibitor may he administered in the form of pharmaceutical compositions. For example, in some variations, the BTK inhibitor described herein may be present in a pharmaceutical composition comprising the BTK inhibitor, and at least one pharmaceutically acceptable vehicle. In some variations, the inhibitors described herein may be present in a pharmaceutical composition comprising the one or more inhibitor, and at least one pharmaceutically acceptable vehicle. For example, the one or more inliibitor maybe a JAK inhibitor, an ASKI inhibitor, a BET inhibitor and a MMP9 inhibitor, Pharmaceutically acceptable vehicles may include pharmaceutically acceptable carriers, adjuvants and/or excipients, and other ingredients can be deemed pharmaceutically acceptable insofar as they are compatible with other ingredients of the formulation and not deleterious to the recipient thereof, [00249] This disclosure therefore provides pharmaceutical compositions that contain a BTK inhibitor and one or more inhibitor, wherein the one or more inhibitor may be a JAK inhibitor, an ASK I inhibitor, a BET inhibitor and a MMP9 inhibitor as described herein, and one or more pharmaceutically

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- nO.aceeptable vehicle, -such as excipients, carriers, including inert solid diluents and fillers, diluents, including sterile aqueous solution and various organic solvents, permeation enhancers, solubilizers and adjuvants. The pharmaceutical compositions may be administered alone or in combination with other inhibitors. Such compositions are prepared in a manner well known in the pharmaceutical art (see, e.g., Remington’s Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, PA 17th Ed. (1985); and Modern Pharmaceutics, Marcel Dekker, Inc. 3rd Ed, (G.S. Banker & C.T, Rhodes, Eds,).

[00250] The pharmaceutical compositions may be administered in either single or multiple doses by any of the accepted modes of administration of agents having similar utilities, including rectal, buccal, intranasal and transdermal routes, by intra-arterial injection, intravenously, intraperitoneally, parenteraliy, intramuscularly, subcutaneously, orally, topically, as an inhalant, or via an impregnated or coated device such as:a stent, for example, or an artery-inserted cylindrical polymer.

[00251J In some embodiments, the pharmaceutical compositions described herein are formulated in a unit dosage form. The term “unit dosage forms” refers to physically discrete units suitable as unitary dosages for human subjects, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient. In some variations, the pharmaceutical compositions described herein are in the form of a tablet, capsule, or ampoule.

[00252] In certain embodiments, the BTK Inhibitor described .herein, such as Compound Al, or a pharmaceutically acceptable salt or hydrate thereof, is formulated as a. tablet. In some variations, such tablet may comprise a hydrochloride salt of Compound AT Such tablet comprising Compound. Al, for example, may be prepared by suitable methods known in the art, -such as spraydrving and granulation (e.g., dry granulation).

Articles of Manufacture and Kits [00253J Compositions (including, tor example, formulations and unit dosages) comprising a BTK inhibitor, as described herein, and compositions comprising one or more inhibitor, such as J AK inhibitors, ASK1 inhibitors, BET Inhibitor

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- 131 and MMP9 inhibitors, as described herein, can be prepared and placed in -an appropriate container, and labeled for treatment of an indicated condition. Accordingly, provided is also an article of manufacture, such as a container corcpnsmg a unit dosage form of a BTK inhibitor and a unit dosage form of a inhibitor, as described herein, and a. label containing instructions for use of the compounds. In some embodiments, the article of manufacture is a container comprising (i) a unit dosage form of a BTK inhibitor, as described herein, and one or more pharmaceutically acceptable carriers, adjuvants or excipients; and (ii) a unit dosage form of a inhibitor, as described herein, and one or more pharmaceutically acceptable carriers, adjuvants or excipients, in one embodiment, the unit dosage form for both the BTK inhibitor and the one or more inhibitor is a tablet.

[00254] Kits also are contemplated- For example, a kit can comprise unit dosage forms of a BTK .inhibitor, as described herein, and compositions comprising one or more inhibitor, as described herein, and a package insert containing instructions for use of the composition in treatment of a medical condition. For example, the one or more inhibitor' may be a J AK inhibitor, an ASKI inhibitor, a BET inhibitor and an MMP9 inhibitor. In some embodiments, the kits comprises (i) a unit dosage form of the BTK inhibitor, as described herein, and one or more pharmaceutically acceptable carriers, adjuvants or excipients; and (ii) a unit dosage form of a inhibitor, as described herein, and one or more pharmaceutically acceptable carriers, adjuvants or excipients. In one embodiment, the unit dosage form for both the BTK inhibitor and the inhibitor is a tablet, [00255] The instructions for use in the kit may be for treating a cancer, including, for example, a hematologic malignancy, as further described herein.The instructions for use in the kit may be for treating a cancer, including, for example, a 'hematologic malignancy or an allergic, autoimmune, or inflammatory disorder, as further described herein.

Other Therapeutic Agents [00256] In the present, disclosure, in some aspects, the combination therapies and methods described herein may he used or combined with an additional agents selected from the group of a chemotherapeutic agent, an anti-cancer agent, an

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-132-anti-rengioycnu. agent, -in antt-libwuc agent an nmmmotherapeufic agent, a therapeutic antibody, a radiothcrapeutie agent, an anti-neoplastic agent, an antiproliferation agent, or any combination thereof.

[00257] The combination therapies and methods described herein may he used or combined with an additional one or more of the following additional therapeutic agents: an adenosine A2B receptor (A2B) inhibitor, a BETbromodomain 4 (BRIM) inhibitor, an isocitrate dehydrogenase 1 (1DH1.) inhibitor, an IKK inhibitor, a protein kinase C (PKC) activator or inhibitor, a ΤΡ.Ϊ.2 inhibitor, a serine/thrconine-protein kinase 1 (TBK1) inhibitor, agents that activate or reactivate latent human immunodeficiency virus (HIV) such as panobinostat or romidepsin. an anti-CD20 antibody such as obinutuzumab, an anti-PD-1 antibody such, as nivolimumab (BMS-936558, MDX1106, or MK34775), and anti-PD-Ll antibodies such as.BM8-93.6559, MPDL3280A, MEDI4736, MSB00107J 8C, and MDX11054)1, [00258] The combination therapies and methods disclosed herein and the additional one or more therapeutic agents (e.g, an A2B inhibitor, an apoptosis signal-regulating kinase (ASK) inhibitor, a BRIM inhibitor, a discoidin domain receptor 1 (DDR I) inhibitor, a histone deacetylase (HDAC) inhibitor, an isocitrate dehydrogenase (IDH) inhibitor, a Janus kinase (JAK) inhibitor, a lysyl oxidase-like protein 2 (LOXI.,2) inhibitor, a matrix metalloprotease 9 (MMP9) inhibitor, a phosphatidylinositol 3-kmasc (ΡΪ3Κ) inhibitor, a PKC activator or inhibitor, a spleen tyrosine kinase (SYK) inhibitor, a TPL2 inhibitor, or a TBK inhibitor) may be further used or combined with a chemotherapeutic agent, an anti-cancer agent, an anti-angiogenic agent, an anti-fibrotic agent, an immunotherapeutic agent, a therapeutic antibody, a radiothcrapeutie agent, an anti-neoplastic agent, or any combination thereof.

[00259] It is understood that the combinations and methods herein may be used with standard therapies, including neoadjuvant chemotherapy, intraoperative radiotherapy (IORT), adjuvant chemotherapy (such as with 5U), adjuvant radiotherapy, adjuvant cliemoradiotherapy, palliative radiotherapy, and palliativeintent procedures, which in regard to gastrointestinal conditions may include

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- B 3 wide local excision, partial -gastrectomy, total gastrectomy, simple laparotomy, i jstinmiestingal anastomosis, or bypass.

Chem otherapeutic A gents [00260J As used herein, the term chemotherapeutic agent or chemotherapeutic (or chemotherapy in the case of treatment with a chemotherapeutic agent) is meant to encompass any non-proteinaceous (i.e., nonpeptidic } chemical compound useful in the treatment of cancer.

Chemotherapeutic agents may be categorized by their mechanism of action into, for example, the following groups: anti-metabolitea-'and-cancer agents such as pyrimidine analogs floxuridine, capecitahine, and eytarabine:purine analogs, folate antagonists, and related inhibitors; autiproliforative/antiiniiotic agents including natural products such as vinca alkaloid (vinblastine, vincristine) and microtubule such as taxane (paclitaxel, docetaxel), vmblastin, nocodazole, epothtlones, vinorelbine (NAVELBlNiT'), and epipodophyllotoxins (etoposide, teniposide); DNA. damaging agents such as actinomycin, amsacrine, busulfan, carbopiatin, chlorambucil, cispiatin, cyclophosphamide (CYTOXAN j, dactinomycin, daunoruhicin, doxorubicin, eptrubicin, iphosphamide, meiphalan, merclrlorethamine, mitomycin, mitoxantrone, nitrosourea, procarbazine, taxol, taxotere, teniposide, etoposide, and fcriethylenethiophosphoramide; antibiotics such as dactinomycin, daunoruhicin, doxorubicin, idarubicin, anthracyclines, mitoxantrone, bleomycins, plicamycin (mithramycin), and mitomycin; enzymes such as Uasparaginase which systemic-ally metabolizes L-asparagine and deprives cells which do not. have the capacity to synthesize their own asparagine; antiplatelet agents; antiproliferative/antimitotic alkylating agents such as nitrogen mustards cyclophosphamide and analogs (meiphalan, chlorambucil, hexamethylmelamine, -and thiotepa), alkyl nitrosoureas (canuustine) and analogs, streptozocin, and triazenes (daearbazine); antiproliferati ve/antimitotic antimeiaboiites such as folic acid analogs (methotrexate); platinum coordination complexes such as cispiatin, oxiloplatinim, and carbopiatin), procarbazine, hydroxyurea, mitotane, and aminoglutethimide; hormones and hormone analogs such as estrogen, tamoxifen, goserelin, bicaiutamide, and nilutamide, and aromatase inhibitors such as letrozole and artastrozole; anticoagulants such as

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-134 heparin, synthetic heparin salts, and other inhibitors of thrombin: fibrinolytic agents such as tissue plasminogen activator, streptokinase, urokinase, aspirin, dipyridamole, ticlopidine, and clopidogrel; antmiigratory agents; antisecretory agents such as breveldin; immunosuppressives such as tacrolimus, strolimus, azathioprine, andmycophenolate; compounds (TNP--470, genisteiiu and growth factor inhibitors (vascular endothelial growth factor inhibitors and fibroblast growth factor inhibitors); angiotensin receptor blockers, nitric oxide donors; antisense oligonucleotides; antibodies such as tiastuzumab and rituximab; cell cycle inhibitors and differentiation inducers such as tretinoin; inhibitors includingtopoisomerase inhibitors such as doxorubicin, daunorubicin, dactinomycin, eniposide, epirubicin, etoposide, idarubicin, irinotecan, mitexantiene, topoieean, and irinotecan, and corticosteroids such, as cortisone, dexamethasone, hydrocortisone, methylprednisolone, prednisone, and prednisolone; growth factor signal transduction kinase: inhibitors; dysfunction inducers; toxins such as Cholera toxin, ricin, Pseudomonas exotoxin, Bordetella pertussis adenylate cyclase toxin, diphtheria toxin, and caspase activators; and chromatin, [00261] Further examples of chemotherapeutic agents include: alkylating agents such as thiotepa and cyclophosphamide (CYTOXAN'¹''); alkyl sulfonates such as busulfan, improsulfan, and piposulfan; aziridines such as benzodopa, carboqoone, meturedopa, and uredopa; emylerumines and memylamelamines including alfretaraine, triemylenemelamine, triethylenephosphorantide, triethylenethiophosphoramide, and triraemylolomelatnine; acetogenins, especially buliaiaein and bullatacinone; a camptotheein, including synthetic analog topoieean; bryostatin; callystatin; CC--1065, including its adozelesin, earzelesin, and bizelesin synthetic analogs; cryptopliyciris, particularly cryptophycin 1 and cryptophycin 8; dolastatin; duocarmycin, including the synthetic analogs KW-2189 and CBI-TM1; eleutherobin; pancraiistatin; a sarcodictyin; spongistatin; nitrogen mustards such as chlorambucil, chlornaphazine, cyclophosphamide, estramustioe, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, meiphaian, novembiehin, phenesterine, prednimustine, trofosfamide, and uracil mustard; nitrosoureas such as carmustine,

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-135 · chlorozotocin, foremusime, iomustine, nimustine, and raninmstine; antibiotics such as the enediyne antibiotics (e.g., caiicheamicin, especially caiicheamicin gammal! and caiicheamicin phill), dynemicin including dynemicin A, bisphosphonates such as elodronate, an esperamicin, neocarzinostatin chromophore and related chromoprotein enediyne antibiotic chromomophores, aclacinomycins, actinomycin, authramycin, azase'rine, bleomycins, cactinomycin, catabjem, carmiuornjum cruvinopbilin, chromomycins, dactinomycin, daunoruhicin, detorubicin, 6-diazo-5-oxo-L-norleueine, doxorubicin 1 including morpholino-doxorubicin, cyanomoipholino-doxorubicin, 2-pyrroIinodoxorubicin, and deoxydoxorubicin), epirubicin, esombicin, idarubicin, marceflomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalaroyein, olivomycins,.peplomycin,.porfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozoein, tubereidin, ubenimex, zinostatin, and zorubiein; antrimetabolites such as methotrexate and 5-fluorouracil (5--FU); folic acid analogs such as demopterin, methotrexate, pteropterin, and trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, and thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxy uridine, doxifl uridine, enocitabine, and floxuridine; androgens such as calusferone, dromostanolone propionate, epitiostanol, mepitiostane, and testolactone; anti-adrenals such as aminoglutethimide, mitotane, and trilostane; folic acidreplinishers such as frolinicacid; trichothecenes, especially T-2 toxin, verracurin A, roridin A, and anguidine; taxoids such as paclitaxel (TAXOLfo and docetaxel (TAXOTERE⁴'); platinum analogs such as cispiatin and carbopiatin; aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; hestrahucil; bisautrene; edatraxate; defofamine; demeeolcine; -diaziquone; eltormthine; elliptimum acetate; an epothiione; efoglucid; gallium nitrate; hydroxyurea; lentinan; leucovorin; lonidamine; maytansinoids such as maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidamoi; nitracrine; pentostatin; phenamet; pirarubicin; iosoxantrone; fluoropyrimidine; fblinic acid; podophyllinic acid; 2ethylhydrazide; procarbazine; polysaccharide-K (PSK); razoxane; rhizoxin; sizofiran; spirogennanium; tenuazonic acid; triaziquone; 2,2',2’'SUBSTITUTE SHEET (RULE 26)

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-136 tricUorobfemyiamine; urethane; vindesine; daearbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside (Ara-C); cyclophosphamide; thiopeta; chlorambucil; gemcitabine (GEMZAR*); 6ibioguanine; mercaptopurins; methotrexate; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitroxantrone; vancristine; vinorelbine (NAVEEBINE^); novantrone; teniposide; edatrexate; daunomycin; atninopterin; xeoloda; ibandronate; CPT-ί 1; topoisomerase inhibitor RPS 2000;

difluoromethylomithine (DEMO); retinoids such as retinoic acid; capecitabine; FOLFIRI (fluorouracil, leucovorin, and irinoiecan); and pharmaceutically acceptable salts, acids, or derivatives of any of the above.

Anti-hormonal Agents [002621 Also included in the definition of chemotherapeutic agent are antihormonal agents such as anti-estrogens and selective estrogen, receptor modulators (SERMs), inhibitors of the enzyme aromatase, anti-androgens, and pharmaceutically acceptable salts, acids or derivatives of any of the above that act io regulate or inhibit hormone action on tumors. Examples of anti-estrogens and SERMs include, for example, tamoxifen (including NOLVADEX^iM), raloxifene, droloxifene, 4-hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone, and torenufene (FARESTON¹'). Inhibitors of the enzyme aromatase regulate estrogen production in the adrenal glands. Examples include 4(5)-imidazoles, aminoglutethimide, megestrol acetate (M.EGACE*^<;), exeroestane, formestane, fadrozole, vorozole (RIVISOR’³''), letrozole (EEMAKA''), and anastrozole (ARiMIDEX'ⁱ‘^;). Examples of anti-androgens include flutamide, nilutamide, bicabtamide, leuprohde, and goserslin.

Anti-angiogenic Agents [00263] Anu-angiogenic agents include, but are not limited to, retinoid acid and derivatives thereof, 2-methoxyestradiol, ANGIOSTATiM^, ENDOST'ATIN*, suramin, squalamine, tissue inhibitor of metalloproteinase-1, tissue inhibitor of metalloproteinase-2, plasminogen activator inhibitor-1, plasminogen activator inhibitor-2, cartilage-derived inhibitor, paclitaxel (nab-paclitaxel), platelet factor 4, protamine sulphate (clupeine), sulphated chitin derivatives (prepared from

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PCT/US2016/054780 queen crab shells), sulphated polysaccharide peptidoglycan complex (sp-pg), staurosporine, modulators of matrix metabolism including proline analogs ((1azetidme-2-carboxylic add (LACA)), cishydroxyproline, d,I-3,4-dehydroprolin©, thiaproline, «,α’-dipyridyl, beta-aminopropionitrile fumarate, 4-propyl-5-(4pyrldinyl )-2(3h)-oxazolone, methotrexate, mitoxantrone, heparin, interferons, 2 macroglobulin-serum, chicken inhibitor of metalloproteinase-3 (ChIMP-3), chymostatin, beta-cyelodextrin tetradecasulfate, eponemycin, fiimagillin, gold sodium thiomalate, d-peniciilamine, beta-l-anticollagenase-serum, alpha-2·· antiplasmin, bisantrene, lobenzarit disodium, n-2~earboxyphenyl-4chloroanihronihc acid disodium or CCA, thalidomide, angiostatic steroid, carboxy aminoimidazole, and metalloproteinase inhibitors such as BB-94. Other anti -angiogenesis agents include antibodies,preferably monoclonal antibodies against these angiogenic growth factors: heta-FGF, alpha-FGF, PGF-5, VEGF isoforms, VEGF-G, RGF/SP, and Ang-I/Ang-2.

Anti-fibrotic Agents [00264) Anti-fibrotic agents include, but are not limited to, the compounds such as beta-aminoproprionitrile (BAPN), as well as the compounds disclosed in US 4,965,288 relating to inhibitors of lysyl oxidase and their use in the treatment of diseases and conditions associated with the abnormal deposition of collagen, and US 4,997,854 relating to compounds which inhibit LOX for the treatment of various pathological fibrotic states, which are herein incorporated by reference. Further exemplary inhibitors are described in US 4,943,593 relating to compounds such as 2-isobutyl-3-fluoro··, chloro-, or brorao-allylamine, US 5,021,456, US 5,059,714, US 5,120,764, US 5,182,297, US 5,252,608 relating to 2-(1 -naphthylox'ymemyi)-3-fluoroally1arame, and. US 2004-02.48871, -which are herein incorporated by reference.

[00265) Exemplary anti-fibrotic agents also include the primary amines reacting with the carbonyl group of the active site of the lysyl oxidases, and more particularly those which produce, after binding with the carbonyl, a product stabilized by resonance, such as the following primary amines: emylenemamine, hydrazine, phenylhydrazine, and their derivatives; semicarbazide and urea derivatives: ammonitriles such as BAPN or 2-mtroethylamine; unsaturated or

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-138saturated haloamineg such as 2-bromo-ethylamine, 2-chloroethylamine, 2triiluoroethylarnine, 3-b.romopropylamine, and p-halobenzylamines; and selenohomocysteine lactone.Other anti-fibrotic agents are copper chelating agents penetrating or not penetrating the cells. Exemplary compounds include indirect inhibitors which block the aldehyde derivatives originating from the oxidative deamination of the lysyl and hydroxylvsyl residues by the lysyl oxidases. Examples include the tbioiamines, particularly D-peniciilaroine, and its analogs such as 2-amino-5-mercapto-5-methy1hexanoic acid, D-2-aminO3-methyl-3-((2acetaraidoethyl)dithio)butanoic acid, p-2-amino-3-methyl-3-((2aminoethyl)diIhio)butanoic acid, sodium-4-((p-1 -dimethyl -2-amino-2carboxyethyl)dithio)butane sulphurate, 2-aceiamidoethyl-2-acetamidoethanethioi sulphonate, and sodium-4-m.ercaptobu.tanesulphinate: trihydrate.

ImmunotherapeuticAgents [00266] The immunotherapeftiic agents include and are not limited to therapeutic antibodies suitable for treating patients. Some examples of therapeutic antibodies include simtuzumab, abagovomab, adecatumumab, afutuzumab, alerotuzumab, altumomab, amatuxiraab, anatumomab, areitumomab, bavituximab, bectumomab, bevacizumab, bivatuzumab, blinatumomab, brentuximab, cantuzumab, catumaxomab, cetuximab, citatuzumab, cixutumumab, clivatuzumab, conatumumab, daratumumab, drozitumab, duligotumab, dusigitumab, detumotnab, dacetuzumab, daloiuzumab, ecromeximab. elotuzumab, ensituximab, ertumaxomah, etaracizumab, farietuzumab, fielatuzumab, figitumumab, flanvotumab, futuximab, ganitumab, gemtuzumab, girentuximab, glembatumumab, ibritumomab, igovomab. imgatuzumab, indatuximab, inotuzumab, intetumumab, ipilimumab, iralumumab, labeteumab, lexatumuraab, liniuzomab. lorvotuzumab, lucatumumab, mapatumumab, matuzumab, tthlaiuzumab, minretumomab, mitumomab, rnoxetumoma b, namatumab, naptumomab, necitumumab,, nimotuzumab, nofetumomab, ocaratuzumab, ofatumumab, olaratumab, onartuzumab, oportuzumab, oregovomab, panitumumab, parsatuzumab, patriiumah, pemtumomab, pertuzumab, pintumomab, pritumumab, racotumomab, radretumab, rilotumumab, rituximab, robaiumumab, satumomab, sihrotuzumab, siltuximab, solitoraab, tacatuzumab,

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-139taplitumomab, tenatumomab, teprotumumab, tigatuzumab, tositumomab, irastuzumab, tucotuzomab, ublituximab, veltuzumab, vorsetuzumab, votumumab, zalutumumab, CC49, and 3F8. Rituximab can be used for treating indolent Bcell cancers, including marginal-zone lymphoma, WM, CLL and small lymphocytic lymphoma. -A combination of Rituximab and chemotherapy agents is especially effective.

[00267] The exemplified therapeutic antibodies may be further labeled or combined with a radioisotope particle such as indium-111, yttrium-90, or iodine131.In a certain embodiments, the additional therapeutic agent is a nitrogen mustard alkylating agent. Nonlimiting examples of nitrogen mustard alkylating agents include chlorambucil.

Lymphoma or Leukemia Combination Therapy [00268[ Same chemotherapy agents are Suitable for treating, lymphoma or leukemia. Ihese agents include aldesleukin, alvocidib, antmeopl&ston AS2-1, antineoplaston A10, anti-thymocyte globulin, amifostine trihydrate, aminocamptoihecin, arsenic trioxide, beta alethine, Bel-2 family protein inhibitor ABT-263, ABT-I99, ABT-737, BMS-345541, bortezomib (VELCADE^, bryostatin 1, busulfan, carboplatin, campath-ΙΗ, CC-5103, carmustine, easpoftngin acetate, clofarabine, cisplatin, cladribine, chlorambucil, curcumin, cyclosporine·, cyclophosphamide, cytarabine, denileukin diftitox, dexamethasone, DT-PACE (dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide, and etoposide), docetaxel, dolastatin 10, doxorubicin, doxorubicin hydrochloride, enzastaurin, epoetin alia, etoposide, everolimus (RAD00T), feoretini'de, filgrastim, melphalan, mesna, flavopiridol, fludarabine, geldanamydn (17-AA.G), ifosfamide, irinotecan hydrochloride, ixahepilone, lenalidomide (REVLIMID¹⁸’, .CC-5G13), lymphokine-activated killer cells, melphalan, methotrexate, mitoxantrone hydrochloride, motexafin gadolinium, mycophenolate mofetil, nelarabine, oblimersen, obatoclax (GX15-070), oblimersen, octreotide acetate, omega-3 fatty acids, oxaliplatin, paclitaxel, PD033299!, PEGylated liposomal doxorubicin hydrochloride, peglilgrastim, pentostaiin, perifosine, prednisolone, prednisone, R-roscovitine (seiicichb, CYC202), recombinant interferon alia, recombinant interleukin-12, recombinant

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- 140interleukin-11., recorabinant fit3 ligand, recombinant human thrombopoietin, rituximab, sargramostim, sildenafil citrate, simvastatin, siroliraus, styryl sulphones, tacrolimus, tanespimycin, temsirolimus (CCl-779), thalidomide, therapeutic allogeneic lymphocytes, tliiotepa, tipifaniib, hortezomib (VELCADE^X) PS-341), vincristine, vincristine sulfate, vinorclhine ditartrate, SAHA (suberanilohydroxamic acid, or suberoyl, anilide, and hydroxamic acid), FR (fludarabine and rituximab), CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), CVP (cyclophosphamide, vincristine, and prednisone), FCM (fludarabine, cyclophosphamide, and mitoxantrone), FCR (fludarabine, cyclophosphamide, and rituximab), hyperCVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone, methotrexate, and cytarabine), 105 (iphospharaide, earbopiatin, and etoposide), MCP (mitoxantrone, chlorambucil, and .prednisolone), R-CHOP (rituximab and CHOP), R-CVP (rituximab: and CVP), R-FCM (rituximab and FCM), R-ICE (rituximab and ICE), and R-MCP (rituximab and MCP), [00269] One modified approach is radioimmunotherapy, wherein a monoclonal antibody is combined with a radioisotope particle, such as indium-111, yttrium90, and iodine-131. Examples of combination therapies include, but are not limited to, iodine-131 tositumomab (BEXXAR''), yttrium-90 ibritumomab tiuxetan (ZEVALIN*), and BEXXAR' with CHOP.

[00270] The abovementioned therapies can he supplemented or combined with stem cell transplantation or treatment. Therapeutic procedures include peripheral blood stem cell transplantation, autologous hematopoietic stem cell transplantation, autologous bone marrow transplantation, antibody therapy, biological therapy, enzyme inhibitor therapy, total body Irradiation, infusion of stem cells, bone marrow ablation with stem cell support, ra v/nv-treated peripheral blood stem cell transplantation, umbilical cord blood transplantation, immunoenzyme technique, low-LBT cobalt-60 gamma ray therapy, bleomycin, conventional surgery, radiation therapy, and nonmyeloablalive allogeneic hematopoietic stem cell transplantation.

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-14!

Non4Iodgkin’s Lymphomas Combination Therapy [00271] Treatment of non-Hodgkin’s lymphomas (NHL), especially those of B cell origin, includes using monoclonal antibodies, standard chemotherapy approaches (e.g., CHOP, CVP, FCM, MCP, and the like), radioimmunotherapy, and combinations thereof, especially integration of an antibody therapy with chemotherapy. Examples of unconj ugated monoclonal antibodies for the treatment of NHL/B-celi cancers include rituximab, alemtuzumab, human or humanized anli-CD20 antibodies, lumiliximab, anti-TNF-reiated apoptosisinducing ligand (anti-TRAIL), bevacizumab, galixitnab, epratuzuroab, SGN-40. and anti~CD74, Examples of experimental antibody agents used in treatment of NHL/B-eell cancers include ofatumumab, ha20, PRO 131921, alemtuzumab, ;aln nub Kbfviil OUR HO' eptaiu mini) temhximfo upoluumub, milatuzumab, and 'bevacizumab.Examples of stautiard regimens of chemotherapy for NHL/B-eell cancers include CHOP, FCM, vAP, MCP, R-CHOP, R-FCM, RCVP, and R-MCP.Examples of radioimmunotherapy for NHUB-cell cancers include yttrium-90 ibritumomab tiuxetan (ZEVALIN'Q and iodine-131 tositumomab (BE.XXAtU).

Mantle Cell Lymphoma Combination Therapy [00272] Therapeutic treatments for mantle cell lymphoma (MCL) include combination chemotherapies such as CHOP, hyperCVAD, and FCM. These regimens can also be supplemented with the monoclonal antibody rituximab to form combination therapies R-CHOP, hyperCVAD-R, and R- FCM. Any of the abovementioned therapies may be combined with stem cell transplantation or ICE in order to teat MCI.,.

[00273] An alternative approach to treating MCL is immunotherapy.. One immunotherapy uses monoclonal, antibodies like rituximab. Another uses cancer vaccines, such as GTOP-99, which are based on the genetic makeup of an individual patient’s tumor.

[00274] .A modified approach to treat MCI, is radioimmunotherapy, wherein a monoclonal antibody is combined with a radioisotope particle, such as iodine-.13.1 tositumomab (BBX.XARU and yttrium-90 ibritumomab tiuxetan i XEVALFN'’ ).

In another example, BEXXAIV is used in sequential treatment with CHOP.

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- 142 -[00275] Other approaches to tea Ong MCI, include autologous stem ceil transplantation coupled with high-dose chemotherapy, administering proteasome inhibitors such as bortezomib (YELCADB''' or PS-341), or administering antiangiogenesis agents such as thalidomide, especially in combination with rituximab, [00276{ Another treatment approach is administering drugs that lead to the degradation of Bel-2 protein and increase cancer cell sensitivity to chemotherapy, such as oblimersen, in combination with other chemotherapeutic agen ts, [00277] A further treatment approach includes administering mTOR inhibitors, which can lead to inhibition of cell growth and even cell death. Non-limiting examples are temsiroiimus (TORISEL'% CCI-779) and temsiroiimus in combination with R1TUXAN“', VELCADEfe or other chemotherapeutic agents. [00278] Other recent therapies for MCL have been disclosed. Such examples include flavopiridoi, PDO332991, R-roscovitine (selieieilib, CYC202), styryl sulphones, obatoclax (GX15-070), TRAIL, Anti-TRATL death receptors DR4 and DR5 antibodies, temsiroiimus (TORISBL'y CCI-779), everolimus (RAD001), BMS-345541, corcumin, SAHA, thalidomide, lenalidomide (RBVLIMIDfe CC5013), and geldanamycin (17-AAG).

Waldenstrom’s Maeroglobulinemia Combination Therapy [00279] Therapeutic agents used to treat Waldenstrom’s Maeroglobulinemia (WM) include perifosine, bortezomib (VELCADE'fe, rituximab, sildenafil citrate (VIAGRA'¹'’), CC-5103, thalidomide, epratuzumab (hLL2~ anti-CD22 humanized antibody), simvastatin, enzastaurin, eampath-lH, dexamethasone, DT-PACE, oblimersen, antineoplasion A10, antineoplaston AS2-1, alemteumab, beta alethine, cyclophosphamide, doxorubicin hydrochloride, prednisone, vincristine sulfate, fiudarabine, filgrastim, me-lpbalan, recombinant interferon alia, carmustine, cispiatin, cyclophosphamide, cytarabine, etoposide, melphalan, dolastalin 10, indium-111 monoclonal antibody MN-14, yttrium-90 humanized epratuzumab, anti-thymocyte globulin, busulfiiu ·. ydosp-mne, methotrexate, mycophenolate mofetil, therapeutic allogeneic lymphocytes, yttrium-90 ibritumomab tiuxetan, sirolimus, tacrolimus, carboplatm, thiotepa, paclitaxel, aldesleukin, docetaxel, ifbsfamide, mesna, recombinant interleukin-11,

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- 143 recombinant intetleukin-12, Bci-2 family protein inhibitor ABT-263, deniteukin diflitox, tanespimyein, everolimus, pegfdgrastim, vorinostat, alvocidib, recombinant flt3 ligand, recombinant human thrombopoietki, lymphokhieactivated killer cells, amifostine irihydrate. aminocamptothecin, irinotecan hydrochloride, caspofungin acetate, clofarahine, epoetin aifa, nelarabine, pentosiatin, sargramostim, vinorelhine ditarirate, WT-1 analog peptide vaccine. WT1 126-134 peptide vaccine, fenretinide, ixabepilone, oxaliplatin, monoclonal antibody CD19, monoclonal antibody C.D20, omega-3 fatty acids, mitoxantrone hydrochloride, octreotide acetate, tositomomab, iodine-13.1 tositumomab, motexafm gadolinium, arsenic trioxide, tipiiarnib, autologous human tumorderived HSPPC-96, veltuzumab,.hryostatin 1, PFbyMtcd liposomal dowtuhi» m hydrochloride, and any combination thereof.

(00280] Examples of therapeutic procedures used to treat WM include peripheral blood, stern, cell transplantation, autologous hematopoietic stem cell transplantation, autologous bone marrow transplantation, antibody therapy, biological therapy, enzyme inhibitor therapy, total body irradiation, infusion of stem cells, bone marrow ablation with stem cell support, in virro-treated peripheral blood stem cell transplantation, umbilical cord blood transplantation, immunoenzyme techniques, low-LET cobalt-60 gamma ray therapy, bleomycin, conventional surgery, radiation therapy, and nonmyeloablative allogeneic hematopoietic stem cell transplantation.

Diffuse Large B-ceH Lymphoma Combination Therapy [00281] Therapeutic agents used io treat difftise large B-ce.ll lymphoma (DLBCL) include cyclophosphamide, doxorubicin, vincristine, prednisone, antiCD20 monoclonal antibodies, etoposide, bleomycin, many of-the agents listed for WM, and any combination thereof such as ICE and R-1CE,

Chronic Lymphocytic Leukemia Combination Therapy [00282] 'Examples of therapeutic agents used to treat chronic lymphocytic leukemia (C-LL) include chlorambucil, cyclophosphamide, fiudarabine, pentosiatin, cladribine, doxorubicin, vincristine, prednisone, prednisolone, alemtuzumah, many of the agents listed for WM, and combination chemotherapy

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- 144 and diernoinwunotherapv, including the following common combination regimens: CVP, .R-CVP, ICE, R-ICE, FCR, and FR..

Myelofibrosis Combination Therapy [00283( Myelofibrosis inhibiting agents include, but are not limited to, hedgehog inhibitors, histone deacetyiase (HDAC) inhibitors, and tyrosine kinase inhibitors. A non-limiting example of hedgehog inhibitors is saridegih.Examples of HDAC inhibitors include, but are not limited to, pracinostat and panobinostatA nonlimiting example of a tyrosine kinase inhibitor is lestaurtinib.

Kinase Inhibitors [00284] In one embodiment, the compound described herein may be used or combined with one or more additional therapeutic agents. The one or more therapeutic agents include, but are not limited to, an inhibitor of AM,.activated GDC kinase (ACK), adenosine A2B receptor (A2B), apoptosis signal-regulating kinase (ASK), Auroa kinase. BET-bromoddmain (BRD) such as BRD4, e-Kit, cMet, CDK-activating kinase (CAK), calmodulin-dependent protein kinase (CaMK), eyclin-dependent kinase (CDK), casein kinase (CK), discoidin domain receptor (DDR), epidermal growth factor receptors (EGFR), focal adhesion kinase (FAK), Flt-3, FYN, glycogen synthase kinase (GSK), HCK, histone deacetyiase (HDAC), IKK such as ΙΚΚβε, isocitrate dehydrogenase (IDH) such as IDH1, Janus kinase (JAK), KDR, lymphocyte-specific protein tyrosine kinase CLCK), lysyl oxidase protein, lysyl oxidase-like protein (LOXL), LYN, matrix metal loprotease (MMP), MEK, mitogen-activated protein kinase (MAPK),

NEK9, NPM-ALK, p38 kinase, platelet-derived growth factor (PDGF), phosphorylase kinase (PK), ροίο-like kinase (PLK), phosphatidylinositol 3-kinase (PI3K), protein kinase (PK) such as protein kinase A, B, and/or C, PYK, spleen tyrosine kinase (SYK), serine/threonine kinase TPI.,2, serine/threonine kinase STK, signal transduction and transcription (STAT), SRC, serine/threonineprotein kinase (TBK) such as TBK1, TIE, tyrosine kinase (TK), vascular endothelial growth factor receptor (VEGFR), YES, or any combination thereof

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PCT/US2016/054780 • 145 Apoptosis Signal-Regulating Kinase (ASK) Inhibitors [00285] ASK inhibitors include ASK1 inhibitors. Examples of ASK1 inhibitors include, but are noi limited to, those described in WO 201 '1/008709 (Gilead Sciences) and WO-2013/112741 (Gilead Sciences),

Discoidin Domain Receptor (DDR) Inhibitors [00286] DDR inhibitors include inhibitors of DDR.I and/or DDR2. Examples of DDR inhibitors include, but are not limited to, those disclosed in WO 2014/047624 (Gilead Sciences), US 2009-0142345 (Takeda Pharmaceutical), US 2011-0287011 (Oncoraed Pharmaceuticals), WO 2013/027802 (Chugai Pharmaceutical), and WO 2013/034933 (imperial Innovations.).

Histone Deacetvlase (HDAC) Inhibitors [00287] Examples of HDAC inhibitors incl ude, but are not li mited to, praeinostat and panobinostat.

Janus Kinase (JAK) inhibitors [01)288] JAK inhibitors inhibit JAK!, JAK2, and/or JAK3, Examples of JAK inhibitors include, but are not limited to, Compound A, ruxolitinib, .tedrathrib., tofecitimb, baricitinib, lestaurtinib, pacri tinib, XL0.19, AZD1480, INCB039110, LY2784544, BMS9H543, andNSOW.

Lysyl Oxidase-Like Protein (LOXL) Inhibitors [00289] LOXL inhibitors include inhibitors ofLOXLl, LOXL2. LOXL3, LOXL4, and/or LOXL5. Examples of LOXL inhibitors include, but are not limited to, the antibodies described in. WO 2009/017833 (Arresto Bfoschn ¢0 i ' ? tples of LO.XL2 inhibitors include, but are not limited to, the antibodies described in WO 2009/017833 (Arresto Bioscienees), WO 2009/035791 (Arresto Biosciences), and WO 2011/097513 (‘Gilead Biologies).

Matrix Metalloprotease (MMP) Inhibitors [1)6290] MMP inhibitors include inhibitors of MM'P 1 through 10, Examples of MMP9 inhibitors include, but. are not limited to, marimastat (BB-2516),

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- ] 4:6 cipemasiat (Ro 32-3555), and those described in WO 2012/027721 (Gilead Biologies),

Phosphatidylinositol 3-kinase (PI3K) Inhibitors [00291) PI3K inhibitors include inhibitors of Ρΐ3Κγ, PI3KS, Ρ.Ι3Κβ, ΡΙ3Κα, and/or pan-PBK. Examples of PI3K inhibitors include, but are not limited to, wortaannirt, BKM120, CHS 132799, XL756, and GDC-0980.Exaraples of ΡΙ3Κγ inhibitors include, but are not limited to, ZSTK474, AS252424, LY294002, and TGI00115,Examples of ΡΙ3Κδ inhibitors include, but are not limited to.. PI3K Π, TGR-1202, AMG-319, GSK2269557,X.-339, X-414, RP5090, KAR4141, XL499, OXY111 A. IPI-145, ΓΡ1-443, and the compounds described in WO 2005/113556 (R Ofo WO 2013/052699 (Gilead Calistoga), WO 2013/116562 (Gilead Calistoga), WO 2Θ14/100765 (Gilead Calistoga), WO 2014/100767 (Gilead Calistoga), and WO 2014/201409 (Gilead Sciences). Examples οίΡΤΙΚβ inhibitors include, but are not limited to, GSK2636771, B AY 10824391, and TGX221 .Examples of PI3K« inhibitors include, but are not limited to, buparlisib, BAY 80-6946, BYL719, P.X-866, RG7604, MLN1117, WX-037, AEZA-129, and PA799.Examples of pan-PI3K inhibitors include, but are not limited to, LY2940O2, BEZ235, XL 147 (SAR245408), and GDC-0941.

Spleen Tyrosine Kinase (SYK) Inhibitors [00292] Examples of SYK inhibitors include, hut are not limited to, tamatinib (144(16), fostamatinib (R7S8), PRT062607, BAY-6E3606, NVP-QAB 205 AA, RI 12, R343, and those described in US 8450321 (Gilead Connecticut).

Tyrosine-kinase Inhibitors (TKIs) [00293] TKIs may target epidermal growth factor receptors (EGERs) and receptors for fibroblast growth factor (FGF), platelet-derived growth factor (PDG.F), and vascular endothelial growth factor (VEGF). Examples of TKIs that target EGER include, but are not limited to, gefitinib and ertotinib. Sunitinib is a non-limiting example of a TKI that targets receptors for FGF, EDGE, and VEGF. [00294] Combinations of pharmaceutically effective amounts of the BTK inhibitor and an ASKI inhibitor as described herein may also he used to treat an

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PCT/US2016/054780 · 147allergic disorders, autoimmune diseases and inflammatory diseases in a human, the method comprising administering to the human in need thereof a pharmaceutically effective amount of the BTK inhibitor, or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically effective amount of an ASK! inhibitor, or a pharmaceutically acceptable salt or hydrate thereof. Particularly, the combinations taught herein may be used for the treatment of allergic disorders, autoimmune diseases and inflammatory diseases such as: systemic lupus erythematosus (SLE), rheumatoid arthritis,, multiple vasculitides, idiopathic thrombocytopenic purpura (HP), myasthenia gravis, allergic rhinitis, chronic obstructive pulmonary disease (COPD), adult respiratory distress syndrome (ARDs) and asthma.

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- ί 48 EXAMPLES

The following examples are provided to further aid in understanding the embodiments disclosed in the appl ieati on, and presuppose an understanding of conventional methods well known io those persons having ordinary skill in the art to which the examples pertain. The particular materials anti conditions described hereunder are intended io exemplify particular aspects of embodiments disclosed herein and should not be construed to limit the reasonable scope thereof. It is understood that the conditions (such as the reagent concentration or the incubation temperature) of the assay or study may be varied and the results of the assay or study may vary. In some instances, the value may vary within a range of one to three-fold.

[06295] This study evaluated the potential effects of BTK inhibitor in combination with JAK inhibitor in treating arthritis. Lewis rats were injected intradermally/subcutaneously (TD/SC) with porcine type II collagen to induce arthritis. Arthritic rats were treated with vehicle (20% Cremophor EI.710% EtOH/70% saline), Compound Al (a BTK inhibitor}, Compound B4 (a JAK inhibitor), Compound Al and Compound B4, or Dex (dexamethasone). Compound Al was administered orally either twice daily at 3.10, or 20 mg/kg or once daily at 20 mg/kg; Compound B4 was administered orally daily at 2.5 mg/kg; dex was administered daily at 0.075 mg/kg, initiated on day 17. The study was terminated at day 34. Efficacy evaluation was based or body weights, daily ankle caliper measurements, ankle diameter expressed as area under the curve (AtJC), terminal hind paw weights, and histopathologic evaluation of right ankles, [00296] This model may reflect certain clinical and histopathologic parameters, such as inflammation, cartilage destruction, and bone resorption that occur in established type II collagen arthritis in female Lewis rats. As the treatment was initiated at the peak of established disease and continued into the chronic phase;

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- nrthe results obtained may be used in evaluating chronic, highly destructive macrophage-mediated phase of this model.

[002,97] Ankle diameters were measured and compared for potential treatment effects. FIG. 1 depicts the measurements taken on Day 9,13-34 for ankle diameter (in.) (mean* standard error) for the following groups: control (normal and disease), Compound Al (20 mg/kg, daily), Compound A l (3 mg/kg, twice daily), Compound B4 (2.5 mg/kg, twice daily). Compound Al (20 mg/kg, daily) with Compound B4 (2.5 mg/kg, twice daily). Compound Al (3 mg/kg, twice daily) with Compound B4 (2.5 mg/kg, twice daily) and Dex (0.()75 mg/kg daily). In addition, the AUC total sum (day 17-34) (mean * standard error) was measured. The AUC total sum for the control (normal) was 4.5 + 0.008; for couth4 (disease?, 6.1 ± 0.058; for Compound Al (20 mg/kg, daily), 5.9 ± 0,096; for Compound A1 (20 mg/kg, twice daily), 5.8 ± 0.124; for Compound Al (10 mg/kg, twice daily), 5,9 ± 0.102; for Compound Al (3 mg/kg, twice daily), 5.9 ± 0.079; for Compound B4 (2,5 mg/kg, twice daily), 5.6 ± 0.083; for Compound Al (20 mg/kg, daily) with Compound B4 (2.5 mg/kg, twice daily), 5.3 ± 0.063; for Compound AI (10 mg/kg, twice daily) with Compound B4 (2,5 mg/kg, twice daily), 5.3 ± 0.093; for Compound Al (3 mg/kg, twice daily) with Compound B4 (2,5 mg/kg, twice daily), 5,3 ± 0.082; and for .Dex (0,075 mg/kg daily), 5.2 + 0.069, [00298] Also, the percent inhibition of the AUC total sum (day 17 -34) was determined. The percent inhibition was 100% for the control (normal); 0% for the control (disease); 13% for Compound Al (20 mg/kg, daily); 15% for Compound Al (20 mg/kg, twice daily); 95¾ for Compound Al (10 mg/kg, twice daily); {3% for Compound Al (3 mg/kg, twice daily); 28% for -Compound B4 (2.5 mg/kg, twice daily); 50% for Compound Al (20 mg/kg, daily) with Compound B4 (2.5 mg/kg, twice daily); 49% for Compound Al (10 mg/kg, twice daily) with Compound 134 (2.5 mg/kg, twice daily); 48% for Compound Al (3 mg/kg, twice daily) with Compound B4 (2.5 mg/kg, twice daily),; and 56% for Dex (0.075 mg/kg).

[00299]’ the following score systems were used to evaluate ankle inflammation, ankle pannus, ankle cartilage damage, ankle bone resotption, and periosteal new

SUBSTITUTE SHEET (RULE 26)

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PCT/US2016/054780 • 150 bone formation, which may represent treatment effects roankle histology. The sum of the summed ankle histology scores for day 34, are provided herein. |OO300] Ankle inflamroatioifscores as used herein have the following meaning: 0=== normal; 0.5=== minimal focus inflammation; T- minimal infiltration of inflammatory cells in synovium/periarticular tissue; 2^:::: mild infiltration; 3= moderate infiltration with moderate edema; 4^::: marked infiltration with marked edema; 5 severe infiltration with severe edema. Ankle pannus scores as used herein have the foil owing meaning: 0=== normal; 0.5==== minimal infiltration of pannus in cartilage and subchondral bone, affects only marginal zones and affects only a few joints; 1==== minimal infiltration of pannus in cartilage ami subchondral b·me pi manly dfetb mammal zones, ? mild mfihmtmn t w%, phi i or tarsal's at marginal zones); 3- moderate infiltration (26% -- 50% of tibia or small tarsals affected at marginal zones); 4- marked infilttafiem (51% - 75% of tibia or tarsals affected at marginal zones); 5- severe infiltration (>75% of tibia or tarsals affected at marginal zones, severe distortion of overall architecture).

100301] Ankle earth iage damage scores as used herein have the following meaning: 0=== normal; 0.5=- minimal decrease in T blue staining, affects only marginal zones and affects only a few joints; 1==== minimal to mild loss of toluidine blue staining with no obvious chondrocyte loss or collagen disruption; 2=== mild loss of toluidine blue staining with focal mild (superficial) chondrocyte loss and/or collagen disruption; 3=== moderate loss of toluidine blue staining with multifocal moderate (depth to middle zone) chondrocyte loss and/or collagen disruption, smaller tarsals affected to 50% to 75% depth with rare areas of frill thickness loss; 4==== marked few’ of to iyidme blue Matmug with multifocal marked (depth to deep zone) chondrocyte loss and/or collagen disruption, 1 or 2 small tarsals surfaces have full thickness fess of cartilage; 5==== severe diffuse fess of toluidine ’blue staining with multifocal severe (depth to tide mark) chondrocyte loss and/or collagen disruption affecting more than 2 cartilage surfaces.

[00302] /Ankle hone resorption scores as used herein have the following meaning: 0=== normal; 0.5=== minimal resorption affects only marginal zones and affects only a few joints; 1==== small areas of resorption, not readily apparent on low magnification, rare osteoclasts; 2=== more numerous areas of resorption, not readily

SUBSTITUTE SHEET (RULE 26)

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PCT/US2016/054780 apparent'on low magnification, osteoclasts more numerous, <25% of tibia or tarsals at marginal zones resorbed; 3^;::: obvious resorption of medullary trabecular and cortical bone without full thickness defects in cortex, loss of some medullary trabeculae, lesion apparent on low magnification, osteoclasts more numerous, 25% to 50% of tibia or tarsals affected at marginal zones; 4== full thickness defects in cortical hon>\ ottcn v>iih distortion nf prolife oi rcnwinuig cortical surface, marked loss of medullary bone, numerous osteoclasts, 51% to 75% of tibia or tarsals affected at marginal zones; 5= full thickness defects in cortical bone, often with distortion of profile of remaining cortical surface, marked loss of medullary bone, numerous osteoclasts, >75% of tibia or tarsals affected at marginal zones, severe distortion, of overall architecture, (00303) Periosteal new bone formation scores..as used herein have the following meaning: O normal, no periosteal proliferation; 0.5== minimal focal or multifocal proliferation, measures less-than 127 um width (1---2 units at 16.x) at any location; 1^:::: minimal multifocal proliferation, width at any location measures 127-252 um (3-4 units at 16x); 2== mild multifocal on tarsals, diffuse in some locations, width at. any location 253-441 um (5™7 units at 16x); 3-=-- moderate multifocal on tarsals, diffuse in most other locations, width at any location measures 442.-630 um (810 units at 16x); 4- marked multifocal on tarsals, diffuse at most other locations, width at any location measures 630-819 urn (1 ί-l 3 units at 16x); 5== severe, multifocal on tarsals, diffuse at. most other locations, width at any location measures --'819 um (>13 units at 16x).

[00304] The summed ankle histopathology (mean < standard error) was measured by histopathology scores. The sum of inflammation, pannus, cartilage damage, bone resorption and peristeal new bone formation was calculated for each ankle, with a maximum value of 23. The summed ankle histopathology for the control (normal) was 0 ± 0.0; for control (disease), 25 ± 0,0; for Compound Al (20 mg/kg, daily), 21 ± 0.7; for Compound Al (20 mg/kg, twice daily), 21 ± 0,6; for Compound Al (10 mg/kg, twice daily), 21 ± 1.4, for Compound Al (3 mg/kg, twice daily), 23 ± 0,6; for Compound B4 (2,5 mg/kg, twice daily), .19 ± 1.4; for Compound Al (.20 mg/kg, daily) with. Compound B4 (2,5 mg/kg, twice daily), 1.0 ± 1.2; for Compound Al (10 mg/kg, twice daily) with Compound B4

SUBSTITUTE SHEET (RULE 26)

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PCT/US2016/054780 (2..5 mg/kg, twice daily). 1 ί ± 1,6; for Compound Al (3 mg/kg, twice, daily) with Compound B4 (2.5 mg/kg, twice daily), 10 ± 2,0; and for Dex (0,075 mg/kg daily), 12 + 1.0.

[00305] For the summed ankle histopathology; the percent inhibition was determined. The percent inhibition was 100% for the control (normal); 0% for the control (disease); 15% for Compound Al (20 mg/kg, daily); 18% for Compound Al (20 mg/kg, twice daily); 16% for Compound Al (10 mg/kg, twice daily); 10% for Compound Al (3 mg/kg, twice daily); 23% for Compound B4 (2.5 mg/kg, twice daily); 60% for Compound Al (20 mg/kg, daily) with Compound B4 (2.5 mg/kg. twice daily): 57% for Compound Al (10 mg/kg, twice daily) with Compound B4 (2..5 mg/kg, twice daily); 60% for .Compound Al (3 mg/kg, twice daily) with Compound B4 (2,5 mg/kg, twice daily); and 51% for Dex (0.075 mg/kg), (09306( In addition, the ED-1 immunopositive osteoclast count (mean ± standard error) was measured. The ED-1 immunopositive osteoclast count for the control (normal) was 1 + 0,2; for the control (disease), 19 i 1.0; for Compound Al (20 mg/kg, daily), 9 ± 1.5; for Compound Al (20 mg/kg, twice daily), 4 ± 0.7; for Compound Al (10 mg/kg, twice daily), 8 + 1.9; for Compound Al (3 mg/kg, twice daily), 7 ± 1,3; for Compound B4 (2.5 mg/kg, twice daily), 16 + 1.7 for Compound Al (20 mg/kg, daily) with Compound B4 (2,5 mg/kg, twice daily), 4 ± 0.4; Compound A1 (10 mg/kg, twice daily) with Compound B4 (2.5 mg/kg, twice daily), 3 + 0.4; Compound Al (3 mg/kg, twice daily) with Compound B4 (2.5 mg/kg, twice daily), 3 ± 0.4; and for Dex (0.075 mg/kg), 4 ± 1.4. For the ED-1 immunopositive osteoclast count, the percent inhibition was also measured. The percent inhibition for the control (normal) was 100%; for the control (disease), 0%; for Compound Al (20 mg/kg, daily), 56%; for Compound Al (20 mg/kg, twice daily), 83%; for Compound Al (10 mg/kg, twice daily), 62%; for Compound Al (3 mg/kg, twice daily), 65%; for Compound B4 (2.5 mg/kg, twice daily), 14%; for Compound Al (20 mg/kg, daily) with Compound B4 (2,5 mg/kg, twice daily), 85%; Compound Al (10 mg/kg, twice daily) with Compound B4 (2,5 mg/kg, twice daily), 91%; Compound Al (3

SUBSTITUTE SHEET (RULE 26)

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PCT/US2016/054780

- 153 mg/kg, twice daily) with Compound B4 (2.5 mg/kg, twice daily), 90%; and for Bex (0.075 mg/kg), 85%.

Example 2 [00307] Material and Methods; The effect of the combination of a BET inhibitor, (2-cyclopropyl-6-(3,5-dimethylisoxazol -4-yl)-lH~henzo[d]imidaz.ol-4yl)di(pyridin-2-yl)methanol (Compound D), and BTK inhibitor (Compound Al) on growth inhibition of the human activated B ceil (ABC) subtype DLBCL ceil line, TMD8, was evaluated in vitro, TMD8 ceils were dosed with a matrix of Compound D (0 --- 90 nM) andeompound Al (0 - 22 nM) and treated for four days, after which cell viability was measured by a CeliTiter Gio assay. A representative heatmap of thi s dose matrix for cell growth inhibition is shown in TIG. 2 (0% to HX)% growth inhibition). Both compounds reduced cell growth over the dose range; synergy was observed at concentrations of 5,8 -- 90 nM of Compound D and 0.3 - 22 nM of Compound .Al (FIG, 3). Synergy was defined as the excess over the predicted additive interaction between the compounds using Bliss analysis. The dose response curve for growth inhibition of Compound I) alone or in the presence of 5,5 nM or 11 nM of Compound Al is shown inFIG. 4 . I he «nciuge k% values (i otieuihanon that causes half maximal inhibition of cell growth) for Compound Γ) were decreased from 25 nM io 11 nM and 8 nM by the presence of 5.5 nM and 11 n.M of Compound Al, respectively, and is consistent with a synergistic interaction,

Ceil Viability Assay:

[06368] Cells were plated at a density of 4,0QQ cells per well in 384-well (Grenier 781086) tissue culture black well plates already spotted with compounds by a Labcyte Echo liquid handler. Cells were treated with an 8-point 2-fold dilution series of (Compound D starting at 90 nM (final DMSO concentration of 0.14%). Cells treated with DMSO alone were used as a positive control for 100% cell growth. Cells were treated with Compound D alone or in the presence of a dose range of Compound Al (6-point 2-fokl dilution series ranging from 0.3 - 22 nM) for each dose of CompoundD. Ceils were incubated at 37'³C for 96 hours and viability was measured using Cell'TiterGlo reagent as per the vendor’s

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- 154 protocol Curves were plotted in prism and values were calculated. with a 4parameter vanable biilslope non-linear fit. The predicted response under Bliss additivity for any combination of drugs at a given concentration pair was determined by Ra * Rb - Ra * Rb, where Ra and Rb are the responses of Compounds D and Al (i.e,, cell growth inhibition). The total Bliss score was determined by summing the differences between the observed values and the predicted additive value at each pair of concentrations assayed. Only values where the difference is greater than the 95% confidence interval of the measurements are included in the sum.

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- 155 -

Claims

WHAT IS CLAIMED IS:

1. A method for treating in a human in need thereof a disease selected from the group of cancers, allergic disorders, autoimmune diseases, and inflammatory diseases, comprising administering to the human a therapeutically effective amount of a BTK inhibitor and a therapeutically effective amount of one or more inhibitor, wherein the BTK inhibitor is 6-amino-9-[(3R)-l-(2-butynoyl)-3-pyrrolidinyl]-7-(4phenoxyphenyl)-7,.9-dihydro-8H -purin-8-one, or a pharmaceutically acceptable salt or hydrate thereof, and wherein the one or more inhibitor is selected from the group consisting of a TAK inhibitor, an ASKI inhibitor, a BRD inhibitor, and a MMP9 inhibitor.
2, The method, of claim 1 wherein the BTK inhibitor and/or the: one or more inhibitor is administered intravenously, intramuscularly, parenterally, nasally or orally.
3. The method of claim 1 wherein the BTK inhibitor is administered prior, after or concurrently with the one or more inhibitor.
4. The method of claim 1 whcicm the hwav is wk'w.cd iio-u th·', omn consisting of a hematologic malignancy, leukemia, lymphoma chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma fSLL), non-Hodgkin’s lymphoma, indolent non-Hodgkin’s lymphoma (iNHL), mantle cell lymphoma, follicular lymphoma (FL·), lymphoplasmacytie lymphoma, and marginal zone lymphoma, rheumatoid arthritis, systemic lupus erythematosus, chronic- obstructive pulmonary disease (CORD), adult respiratory distress syndrome and asthma.
5. The method of claim 1 wherein the human is in refractory to at least one of the cancer therapies, or is in relapse after treatment with at least one anti-cancer therapy selected front the group consisting of: (a) fludarabine; (b) rituximab; (c) rituximab combined with fludarabine; (d) cyclophosphamide combined with fludarabine; (e) cyclophosphamide combined with rituximab and fludarabine; (f) cyclophosphamide combined with vincristine and prednisone; (g) cyclophosphamide combined with vincristine, prednisone, and rituximab; (h) a combination of cyclophosphamide, doxorubicin, vincristine, and prednisone; (i)

SUBSTITUTE SHEET (RULE 26)

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- 156Chlorambncil combined with prednisone, rituximab, obinutuzumab, or ofatumumab; (j) pentostatin combined with cyclophosphamide and rituximab. (k) bendamustine (Treandafe) combined with rituximab; (1} alemtuzuraab; (m) fludarabine plus cyclophosphamide, bendamustine, or chlorambucil; and (n) fludarabine plus cyclophosphamide, bendamustine, or chlorambucil, combined wife an anti-CD20 antibody.
6. A method for sensitizing a human who is (i) refractory to at least one chemotherapy treatment, or (Ii) in relapse after treatment with chemotherapy, or both (i) and iii), wherein the method comprises administering a Btk inhibitor in combination with an inhibitor to the human, and wherein the inhibitor is selected from the group consisting of a JAK inhibitor, an ASK1 inhibitor, a BRD inhibitor, and a MMP9 inhibitor.
7, 'The method of claims 1 or 6 wherein the JAK inhibitor is selected from the group consisting of of momelotinib, filgotinib, i-[l-[[3-fluoro-2~(trifluoromethyl)“ 4-pyri.dinyl]-4-piperidinyl]-3“{4-(7/7-pyrroio[2,3-i/}pyrraidin-4-yl)-lH-pyrdzol-lyfj-3-azetidineacetonitrile, tofacitinib, oclacitinib, ruxoloiinib, baraeitinib, lestaurtinib, pacritinib. TGI 01348, JSI-124, GSK2585184, VX-509, INCB16562, \1OA A'Pfbfoo\i U‘”> /- R '11 \· :fo (DPR/?; _Ora pharmaceutically acceptable salt thereof.
8, The method of claims 1 or 6 wherein the ASK1 inhibitor is 5-(4cyclopropyHH-!midazoM»yl)2”fluorO“N“(6-(4”isopropyMH-l₍2,4-triazol-3yi)pyridm-2-yl)'4»methylbenzamide, or a pharmaceutically acceptable salt or hydrate thereof
9, The method of claims 1 or 6 wherein the modulator of the hromodomaincontaining protein is a compound of Formula II:

SUBSTITUTE SHEET (RULE 26)

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PCT/US2016/054780

-157 - (Π) wherein

R^ta and R¹* are each independently C|._(i alkyl optionally substituted with from 1 to 5 R^J|' groups;

R^z3 and R^z0 are each independently H or halo;

R Is ••G(O)OR^K, -NHC(O)Or, YH8(O)₂R^a, or Y(O.hNR^aR^b; or selected from the group- consisting of Cwo alkyl, Cm «.alkoxy, amino, C^o aryl, C6.20 arylalkyl, Cm« heteroaikyl, C₅..io heteroaryl, and heteroarylaikyl, each of which is optionally substituted with from 1 to 5 R^AI groups;

one of R⁴* and R⁴⁵* is selected from the group consisting of 11 and CY, alkyl optionally substituted with from 1 to 5 R“ groups, and the other is absent;

R⁵ is -C(O)OR\ -NHC(O)OR³, -NHS(O)2R⁸, or -S(O)2NR^aR^b; or R is selected from the group consisting of H, Cmo alkyl, C).)« haloalkyl, Cho alkoxy, amino, Gj-kj aryl, Ce-ao arylalkyl, Gf.jo heteroaikyl, C5.J0 heteroaryl, and Q. 2o heteroarylaikyl, each of which is optionally substituted with from 1 to 5 R^zt' groups;

each R^a and R^b is independently selected from the group consisting of H, Cm« alkyl, G5.se aryl, €«<., arylalkyl, Gj.io heteroaikyl, C_s~so heteroaryl, and C«0 heteroarylaikyl, each of which is optionally substituted with from 1 to 5 R^zdgroups; and each R^AI is independently selected from the group consisting of acyl, Gi-ίθ alkyl, Cj..io alkoxy, amino, amido, amidino, C^o aryl, C^o arylalkyl, azido, carbamoyl, carboxyl, carboxyl ester, cyano, guanidino, halo, Cj.so haloalkyl, Guo heteroaikyl, C5.10 heteroaryl, C5.20 heteroarylaikyl, hydroxy, hydrazino, imino, oxo, nitro, sulfinyl, sulfonic acid, sulfonyl, thiocyanate, thiol, and thione; and

SUBSTITUTE SHEET (RULE 26)

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PCT/US2016/054780

-- Ϊ58 wherein the (%,<; alkyl, C5..1» C0-20 arylalkyl, Cwe heteroalkyl, €5.-.0 heteroaryl, and Cg.^o heteroarylalkyl groups are optionally substituted with from 1 io 3 substituents independently selected from Cm alkyl, C-5.10 aryl, halo, Cm haloalkyi, cyano, hydroxy, and Cj.e alkoxy;

or a pharmaceutically acceptable salt thereof
10. The method of claims 1 or 6 wherein the MMP9 inhibitor comprises a M.MP9 binding protein comprising:

an immunoglobulin heavy chain polypeptide, or a functional fragment thereof; and aii immunogloblulin light chain polypeptide, or a functional fragment thereof; wherein the MMP'9 binding protein specifically binds to human MMP9, and wherein the. MMP9 binding protein competes for binding to human MMP9 with an antibody comprising heavy chain CDRs of SEQ ID NOs: 13-15 or light cham CDRs of SEQ ID Nos. 16-18.

J. 1. The method of claim 10 wherein the immunoglobulin heavy chain comprises an amino acid sequence SEQ ID NO. 7 and wherein the immunoglobulin light chain polypeptide or functional fragment thereof comprises an amino acid sequence SEQ ID NO. 12,

12, An article of manufacture comprising:

a unit dosage form of a BTK. inhibitor, wherein the BTK inhibitor is is 6amino-9-[(3R)-l“(2“butynoyl)-3-pyrrolidin>4]-7-(4-phenoxyphenyi)-7,9-dihydro8H -purin-8-one, or a pharmaceutically acceptable salt or hydrate thereof; and a unit dosage form of one or more inhibitor, wherein the inhibitor is selected from the group consisting a JAK inhibitor, an ASK1 inhibitor, a BRD inhibitor, and a M.MP9 inhibitor:

a label containing instructions for use in treating a disease selected from the group of cancers, allergic disorders, autoimmune diseases, and Inflammatory diseases.

SUBSTITUTE SHEET (RULE 26)

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PCT/US2016/054780

-15913, A kit comprising:

a pharmaceutical composition comprising a pharmaceutically effective amount of a BTK inhibitor, wherein the ΒΪΚ inhibitor is 6-amino~9~[(311)-1-(2butynoyl)-3-pyrrolidinyl]-7-(4-phenoxyphenyl)-7,9“dihydro-8H -purin-8-one, ora pharmaceutically acceptable salt or hydrate thereof;

a pharmaceutical composition comprising a pharmaceutically effective amount of one or more inhibitor, wherein the inhibitor is selected from (he group consisting a JAK inhibitor, an ASKi inhibitor, a BRD inhibitor, and a MMP9 inhibitor; and instructions for use in treating a disease selected from the group of a cancer, allergic disorders, autoimmune diseases, and inflammatory diseases.

SUBSTITUTE SHEET (RULE 26)

WO 2017/059252

PCT/US2016/054780 (in) japttiBiQ aj >juy gs *

Study Day

SUBSTITUTE SHEET (RULE 26)

WO 2017/059252

PCT/US2016/054780 ,-Λ'», rt

U aa

2M

SUBSTITUTE SHEET (RULE 26)

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PCT/US2016/054780

3/4

BLISS excess over theoretical at 95% confidence

BETi (nM)

SUBSTITUTE SHEET (RULE 26)

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PCT/US2016/054780

4/4 no 4

O o

03956101140_PC_09122016_SequenceListing_ST25 SEQUENCE LISTING <110> Gilead Sciences, Inc.

<120> Combination Therapies for Treating Cancer <130> 03956.101140.PC <150> US 62/236,729 <151> 2015-10-02 <150> US 62/236,345 <151> 2015-10-02 <150> US 62/236,409 <151> 2015-10-02 <150> US 62/236,741 <151> 2015-10-02 <160> 29 <170> PatentIn version 3.5 <210> 1 <211> 470 <212> PRT <213> mouse <400> 1

Met Ala 1 Val Leu Val 5 Leu Phe Leu Cys Leu 10 Val Ala Phe Pro Ser 15 Cys Val Leu Ser Gln Val Gln Leu Lys Glu Ser Gly Pro Gly Leu Val Ala 20 25 30 Pro Ser Gln Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu 35 40 45 Leu Ser Tyr Gly Val His Trp Val Arg Gln Pro Pro Gly Lys Gly Leu 50 55 60 Glu Trp Leu Gly Val Ile Trp Thr Gly Gly Thr Thr Asn Tyr Asn Ser 65 70 75 80 Ala Leu Met Ser Arg Leu Ser Ile Ser Lys Asp Asp Ser Lys Ser Gln 85 90 95 Val Phe Leu Lys Met Asn Ser Leu Gln Thr Asp Asp Thr Ala Ile Tyr 100 105 110 Tyr Cys Ala Arg Tyr Tyr Tyr Gly Met Asp Tyr Trp Gly Gln Gly Thr 115 120 125 Ser Val Thr Val Ser Ser Ala Lys Thr Thr Pro Pro Ser Val Tyr Pro 130 135 140 Leu Ala Pro Gly Cys Gly Asp Thr Thr Gly Ser Ser Val Thr Leu Gly Page 1

03956101140_PC_09122016_SequenceListing_ST25 145 150 155 160

Cys Leu Val Lys Gly 165 Tyr Phe Pro Glu Ser 170 Val Thr Val Thr Trp 175 Asn Ser Gly Ser Leu Ser Ser Ser Val His Thr Phe Pro Ala Leu Leu Gln 180 185 190 Ser Gly Leu Tyr Thr Met Ser Ser Ser Val Thr Val Pro Ser Ser Thr 195 200 205 Trp Pro Ser Gln Thr Val Thr Cys Ser Val Ala His Pro Ala Ser Ser 210 215 220 Thr Thr Val Asp Lys Lys Leu Glu Pro Ser Gly Pro Ile Ser Thr Ile 225 230 235 240 Asn Pro Cys Pro Pro Cys Lys Glu Cys His Lys Cys Pro Ala Pro Asn 245 250 255 Leu Glu Gly Gly Pro Ser Val Phe Ile Phe Pro Pro Asn Ile Lys Asp 260 265 270 Val Leu Met Ile Ser Leu Thr Pro Lys Val Thr Cys Val Val Val Asp 275 280 285 Val Ser Glu Asp Asp Pro Asp Val Arg Ile Ser Trp Phe Val Asn Asn 290 295 300 Val Glu Val His Thr Ala Gln Thr Gln Thr His Arg Glu Asp Tyr Asn 305 310 315 320 Ser Thr Ile Arg Val Val Ser Ala Leu Pro Ile Gln His Gln Asp Trp 325 330 335 Met Ser Gly Lys Glu Phe Lys Cys Lys Val Asn Asn Lys Asp Leu Pro 340 345 350 Ser Pro Ile Glu Arg Thr Ile Ser Lys Ile Lys Gly Leu Val Arg Ala 355 360 365 Pro Gln Val Tyr Ile Leu Pro Pro Pro Ala Glu Gln Leu Ser Arg Lys 370 375 380 Asp Val Ser Leu Thr Cys Leu Val Val Gly Phe Asn Pro Gly Asp Ile 385 390 395 400 Ser Val Glu Trp Thr Ser Asn Gly His Thr Glu Glu Asn Tyr Lys Asp 405 410 415 Thr Ala Pro Val Leu Asp Ser Asp Gly Ser Tyr Phe Ile Tyr Ser Lys

Page 2

420 03956101140 PC 09122016 SequenceListi i 425 430 ng_ST25 Leu Asp Ile Lys Thr Ser Lys Trp Glu Lys Thr Asp Ser Phe Ser Cys 435 440 445 Asn Val Arg His Glu Gly Leu Lys Asn Tyr Tyr Leu Lys Lys Thr Ile 450 455 460 Ser Arg Ser Pro Gly Lys 465 470 <210> : 2 <211> : 234 <212> PRT <213> i mouse <400> 2 Met Glu Ser Gln Ile Gln Val Phe Val Phe Val Phe Leu Trp Leu Ser 1 5 10 15 Gly Val Asp Gly Asp Ile Val Met Thr Gln Ser His Lys Phe Met Ser 20 25 30 Thr Ser Val Gly Asp Arg Val Ser Ile Thr Cys Lys Ala Ser Gln Asp 35 40 45 Val Arg Asn Thr Val Ala Trp Tyr Gln Gln Lys Thr Gly Gln Ser Pro 50 55 60 Lys Leu Leu Ile Tyr Ser Ser Ser Tyr Arg Asn Thr Gly Val Pro Asp 65 70 75 80 Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser 85 90 95 Ser Val Gln Ala Glu Asp Leu Ala Val Tyr Phe Cys Gln Gln His Tyr 100 105 110 Ile Thr Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg 115 120 125 Ala Asp Ala Ala Pro Thr Val Ser Ile Phe Pro Pro Ser Ser Glu Gln 130 135 140 Leu Thr Ser Gly Gly Ala Ser Val Val Cys Phe Leu Asn Asn Phe Tyr 145 150 155 160 Pro Lys Asp Ile Asn Val Lys Trp Lys Ile Asp Gly Ser Glu Arg Gln 165 170 175 Asn Gly Val Leu Asn Ser Trp Thr Asp Gln Asp Ser Lys Asp Ser Thr 180 185 190

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03956101140_PC_09122016_SequenceListing_ST25

Tyr Ser Met Ser Ser Thr Leu Thr Leu Thr Lys Asp Glu Tyr Glu Arg 195 200 205 His Asn Ser Tyr Thr Cys Glu Ala Thr His Lys Thr Ser Thr Ser Pro 210 215 220 Ile Val Lys Ser Phe Asn Arg Asn Glu Cys 225 230 <210> 3 <211> 115 <212> PRT <213> mouse <400> 3 Gln Val Gln Leu Lys Glu Ser Gly Pro Gly Leu Val Ala Pro Ser Gln 1 5 10 15 Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Leu Ser Tyr 20 25 30 Gly Val His Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Leu 35 40 45 Gly Val Ile Trp Thr Gly Gly Thr Thr Asn Tyr Asn Ser Ala Leu Met 50 55 60 Ser Arg Leu Ser Ile Ser Lys Asp Asp Ser Lys Ser Gln Val Phe Leu 65 70 75 80 Lys Met Asn Ser Leu Gln Thr Asp Asp Thr Ala Ile Tyr Tyr Cys Ala 85 90 95 Arg Tyr Tyr Tyr Gly Met Asp Tyr Trp Gly Gln Gly Thr Ser Val Thr 100 105 110 Val Ser Ser 115 <210> 4 <211> 107 <212> PRT <213> mouse <400> 4 Asp Ile Val Met Thr Gln Ser His Lys Phe Met Ser Thr Ser Val Gly 1 5 10 15 Asp Arg Val Ser Ile Thr Cys Lys Ala Ser Gln Asp Val Arg Asn Thr 20 25 30

Page 4

Val Ala Trp 35 Tyr 03956101140_PC_09122016_SequenceListi i ng_ST25 Leu Ile Gln Gln Lys Thr Gly Gln Ser 40 Pro Lys 45 Leu Tyr Ser Ser Ser Tyr Arg Asn Thr Gly Val Pro Asp Arg Phe Thr Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Val Gln Ala 65 70 75 80 Glu Asp Leu Ala Val Tyr Phe Cys Gln Gln His Tyr Ile Thr Pro Tyr 85 90 95 Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 <210> 5 <211> 115 <212> PRT <213> human <400> 5 Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Leu Ser Tyr 20 25 30 Gly Val His Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Leu 35 40 45 Gly Val Ile Trp Thr Gly Gly Thr Thr Asn Tyr Asn Ser Ala Leu Met 50 55 60 Ser Arg Leu Thr Ile Ser Lys Asp Asp Ser Lys Ser Thr Val Tyr Leu 65 70 75 80 Lys Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Ile Tyr Tyr Cys Ala 85 90 95 Arg Tyr Tyr Tyr Gly Met Asp Tyr Trp Gly Gln Gly Thr Ser Val Thr 100 105 110 Val Ser Ser 115 <210> 6 <211> 115 <212> PRT <213> human <400> 6 Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu 1 5 10 15 Page 5

03956101140_PC_09122016_SequenceListing_ST25

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Leu Ser Tyr 20 25 30 Gly Val His Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Leu 35 40 45 Gly Val Ile Trp Thr Gly Gly Thr Thr Asn Tyr Asn Ser Ala Leu Met 50 55 60 Ser Arg Leu Thr Ile Ser Lys Asp Asp Ser Lys Asn Thr Val Tyr Leu 65 70 75 80 Lys Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Ile Tyr Tyr Cys Ala 85 90 95 Arg Tyr Tyr Tyr Gly Met Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr 100 105 110 Val Ser Ser 115 <210> 7 <211> 115 <212> PRT <213> human <400> 7 Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Leu Ser Tyr 20 25 30 Gly Val His Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Leu 35 40 45 Gly Val Ile Trp Thr Gly Gly Thr Thr Asn Tyr Asn Ser Ala Leu Met 50 55 60 Ser Arg Phe Thr Ile Ser Lys Asp Asp Ser Lys Asn Thr Val Tyr Leu 65 70 75 80 Lys Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Ile Tyr Tyr Cys Ala 85 90 95 Arg Tyr Tyr Tyr Gly Met Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr 100 105 110

Val Ser Ser 115

Page 6

03956101140_PC_09122016_SequenceListing_ST25 <210> 8 <211> 115 <212> PRT <213> human

<400> Gln Val 1 8 Glu Ser Gly Pro Gly 10 Leu Val Lys Pro Ser 15 Glu Gln Leu Gln 5 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Leu Ser Tyr 20 25 30 Gly Val His Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Leu 35 40 45 Gly Val Ile Trp Thr Gly Gly Thr Thr Asn Tyr Asn Ser Ala Leu Met 50 55 60 Ser Arg Phe Thr Ile Ser Lys Asp Asp Ser Lys Asn Thr Leu Tyr Leu 65 70 75 80 Lys Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Ile Tyr Tyr Cys Ala 85 90 95 Arg Tyr Tyr Tyr Gly Met Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr 100 105 110 Val Ser Ser 115 <210> 9 <211> 107 <212> PRT <213> human <400> 9 Asp Ile Val Met Thr Gln Ser Pro Ser Phe Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asp Val Arg Asn Thr 20 25 30 Val Ala Trp Tyr Gln Gln Lys Thr Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ser Ser Ser Tyr Arg Asn Thr Gly Val Pro Asp Arg Phe Thr Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Ala 65 70 75 80 Glu Asp Val Ala Val Tyr Phe Cys Gln Gln His Tyr Ile Thr Pro Tyr

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03956101140_PC_09122016_SequenceListing_ST25

85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 <210> 10 <211> 107 <212> PRT <213> human <400> 10 Asp Ile Val Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asp Val Arg Asn Thr 20 25 30 Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ser Ser Ser Tyr Arg Asn Thr Gly Val Pro Asp Arg Phe Thr Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Ala 65 70 75 80 Glu Asp Val Ala Val Tyr Phe Cys Gln Gln His Tyr Ile Thr Pro Tyr 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys

100 105 <210> 11 <211> 107 <212> PRT <213> human

<400> 11 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asp Val Arg Asn Thr 20 25 30 Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ser Ser Ser Tyr Arg Asn Thr Gly Val Pro Asp Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Ala 65 70 75 80

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Glu Asp Val Ala 03956101140_PC_09122016_SequenceListi i ng_ST25 Pro Tyr 95 Val 85 Tyr Phe Cys Gln Gln 90 His Tyr Ile Thr Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 <210> 12 <211> 107 <212> PRT <213> human <400> 12 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asp Val Arg Asn Thr 20 25 30 Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ser Ser Ser Tyr Arg Asn Thr Gly Val Pro Asp Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Ala 65 70 75 80 Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln His Tyr Ile Thr Pro Tyr 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 <210> 13 <211> 10 <212> PRT <213> human <400> 13 Gly Phe Ser Leu Leu Ser Tyr Gly Val His 1 5 10 <210> 14 <211> 16 <212> PRT <213> human <400> 14 Val Ile Trp Thr Gly Gly Thr Thr Asn Tyr Asn Ser Ala Leu Met Ser 1 5 10 15

<210> 15 <211> 7

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03956101140_PC_09122016_SequenceListing_ST25

<212> PRT <213> human <400> 15 Tyr Tyr Tyr Gly Met Asp Tyr 1 5 <210> 16 <211> 11 <212> PRT <213> human <400> 16 Lys Ala Ser Gln Asp Val Arg Asn Thr Val Ala

1 5 10 <210> 17 <211> 7 <212> PRT <213> human <400> 17

Ser Ser Ser Tyr Arg Asn Thr 1 5 <210> 18 <211> 9 <212> PRT <213> human <400> 18

Gln Gln His Tyr Ile Thr Pro Tyr Thr 1 5 <210> 19 <211> 345 <212> DNA <213> human <400> 19

caggtgcagc tgcaggaatc cggccctggc ctggtcaagc cctccgagac actgtccctg 60 acctgcaccg tgtccggctt ctccctgctg tcctacggcg tgcactgggt ccgacagcct 120 ccagggaagg gcctggaatg gctgggcgtg atctggaccg gcggcaccac caactacaac 180 tccgccctga tgtcccggct gaccatctcc aaggacgact ccaagtccac cgtgtacctg 240 aagatgaact ccctgaaaac cgaggacacc gccatctact actgcgcccg gtactactac 300 ggcatggact actggggcca gggcacctcc gtgaccgtgt cctca 345

<210> 20 <211> 345 <212> DNA <213> human <400> 20 caggtgcagc tgcaggaatc cggccctggc ctggtcaagc cctccgagac actgtccctg 60

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03956101140_PC_09122016_SequenceListing_ST25 acctgcaccg tgtccggctt ctccctgctg tcctacggcg tgcactgggt ccgacagcct 120 ccaggcaaag gcctggaatg gctgggcgtg atctggaccg gcggcaccac caactacaac 180 tccgccctga tgtcccggct gaccatctcc aaggacgact ccaagaacac cgtgtacctg 240 aagatgaact ccctgaaaac cgaggacacc gccatctact actgcgcccg gtactactac 300 ggcatggact actggggcca gggcaccctg gtcaccgtgt cctca 345 <210> 21 <211> 345 <212> DNA <213> human <400> 21 caggtgcagc tgcaggaatc cggccctggc ctggtcaagc cctccgagac actgtccctg 60 acctgcaccg tgtccggctt ctccctgctg tcctacggcg tgcactgggt ccgacagcct 120 ccaggcaaag gcctggaatg gctgggcgtg atctggaccg gcggcaccac caactacaac 180 tccgccctga tgtcccggtt caccatctcc aaggacgact ccaagaacac cgtgtacctg 240 aagatgaact ccctgaaaac cgaggacacc gccatctact actgcgcccg gtactactac 300 ggcatggact actggggcca gggcaccctg gtcaccgtgt cctca 345 <210> 22 <211> 345 <212> DNA <213> human <400> 22 caggtgcagc tgcaggaatc cggccctggc ctggtcaagc cctccgagac actgtccctg 60 acctgcaccg tgtccggctt ctccctgctg tcctacggcg tgcactgggt ccgacagcct 120 ccaggcaaag gcctggaatg gctgggcgtg atctggaccg gcggcaccac caactacaac 180 tccgccctga tgtcccggtt caccatctcc aaggacgact ccaagaacac cctgtacctg 240 aagatgaact ccctgaaaac cgaggacacc gccatctact actgcgcccg gtactactac 300 ggcatggact actggggcca gggcaccctg gtcaccgtgt cctca 345 <210> 23 <211> 321 <212> DNA <213> human <400> 23 gacatcgtga tgacccagtc ccccagcttc ctgtccgcct ccgtgggcga cagagtgacc 60 atcacatgca aggcctctca ggacgtgcgg aacaccgtgg cctggtatca gcagaaaacc 120 ggcaaggccc ccaagctgct gatctactcc tcctcctacc ggaacaccgg cgtgcccgac 180 cggtttaccg gctctggctc cggcaccgac tttaccctga ccatcagctc cctgcaggcc 240 gaggacgtgg ccgtgtactt ctgccagcag cactacatca ccccctacac cttcggcgga 300 ggcaccaagg tggaaataaa a 321

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03956101140_PC_09122016_SequenceListing_ST25 <210> 24 <211> 321 <212> DNA <213> human <400> 24

gacatcgtga tgacccagtc cccctccagc ctgtccgcct ctgtgggcga cagagtgacc 60 atcacatgca aggcctctca ggacgtgcgg aacaccgtgg cctggtatca gcagaagccc 120 ggcaaggccc ccaagctgct gatctactcc tcctcctacc ggaacaccgg cgtgcccgac 180 cggtttaccg gctctggctc cggcaccgac tttaccctga ccatcagctc cctgcaggcc 240 gaggacgtgg ccgtgtactt ctgccagcag cactacatca ccccctacac cttcggcgga 300 ggcaccaagg tggaaataaa a 321

<210> 25 <211> 321 <212> DNA <213> human

<400> 25 gacatccaga tgacccagtc cccctccagc ctgtccgcct ctgtgggcga cagagtgacc 60 atcacatgca aggcctccca ggacgtgcgg aacaccgtgg cctggtatca gcagaagccc 120 ggcaaggccc ccaagctgct gatctactcc tcctcctacc ggaacaccgg cgtgcccgac 180 cggttctctg gctctggaag cggcaccgac tttaccctga ccatcagctc cctgcaggcc 240 gaggacgtgg ccgtgtactt ctgccagcag cactacatca ccccctacac cttcggcgga 300 ggcaccaagg tggaaataaa a 321

<210> 26 <211> 321 <212> DNA <213> human

<400> 26 gacatccaga tgacccagtc cccctccagc ctgtccgcct ctgtgggcga cagagtgacc 60 atcacatgca aggcctctca ggacgtgcgg aacaccgtgg cctggtatca gcagaagccc 120 ggcaaggccc ccaagctgct gatctactcc tcctcctacc ggaacaccgg cgtgcccgac 180 cggttctctg gctctggaag cggcaccgac tttaccctga ccatcagctc cctgcaggcc 240 gaggacgtgg ccgtgtacta ctgccagcag cactacatca ccccctacac cttcggcgga 300

ggcaccaagg tggaaataaa a 321 <210> 27 <211> 707 <212> PRT <213> human <400> 27

Met Ser Leu Trp Gln Pro Leu Val Leu Val Leu Leu Val Leu Gly Cys 1 5 10 15

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03956101140_PC_09122016_SequenceListing_ST25

Cys Phe Ala Ala Pro Arg Gln Arg 20 Gln 25 Ser Thr Leu Val Leu 30 Phe Pro Gly Asp Leu Arg Thr Asn Leu Thr Asp Arg Gln Leu Ala Glu Glu Tyr 35 40 45 Leu Tyr Arg Tyr Gly Tyr Thr Arg Val Ala Glu Met Arg Gly Glu Ser 50 55 60 Lys Ser Leu Gly Pro Ala Leu Leu Leu Leu Gln Lys Gln Leu Ser Leu 65 70 75 80 Pro Glu Thr Gly Glu Leu Asp Ser Ala Thr Leu Lys Ala Met Arg Thr 85 90 95 Pro Arg Cys Gly Val Pro Asp Leu Gly Arg Phe Gln Thr Phe Glu Gly 100 105 110 Asp Leu Lys Trp His His His Asn Ile Thr Tyr Trp Ile Gln Asn Tyr 115 120 125 Ser Glu Asp Leu Pro Arg Ala Val Ile Asp Asp Ala Phe Ala Arg Ala 130 135 140 Phe Ala Leu Trp Ser Ala Val Thr Pro Leu Thr Phe Thr Arg Val Tyr 145 150 155 160 Ser Arg Asp Ala Asp Ile Val Ile Gln Phe Gly Val Ala Glu His Gly 165 170 175 Asp Gly Tyr Pro Phe Asp Gly Lys Asp Gly Leu Leu Ala His Ala Phe 180 185 190 Pro Pro Gly Pro Gly Ile Gln Gly Asp Ala His Phe Asp Asp Asp Glu 195 200 205 Leu Trp Ser Leu Gly Lys Gly Val Val Val Pro Thr Arg Phe Gly Asn 210 215 220 Ala Asp Gly Ala Ala Cys His Phe Pro Phe Ile Phe Glu Gly Arg Ser 225 230 235 240 Tyr Ser Ala Cys Thr Thr Asp Gly Arg Ser Asp Gly Leu Pro Trp Cys 245 250 255 Ser Thr Thr Ala Asn Tyr Asp Thr Asp Asp Arg Phe Gly Phe Cys Pro 260 265 270 Ser Glu Arg Leu Tyr Thr Arg Asp Gly Asn Ala Asp Gly Lys Pro Cys 275 280 285

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03956101140_PC_09122016_SequenceListing_ST25

Gln Phe 290 Pro Phe Ile Phe Gln 295 Gly Gln Ser Tyr Ser 300 Ala Cys Thr Thr Asp Gly Arg Ser Asp Gly Tyr Arg Trp Cys Ala Thr Thr Ala Asn Tyr 305 310 315 320 Asp Arg Asp Lys Leu Phe Gly Phe Cys Pro Thr Arg Ala Asp Ser Thr 325 330 335 Val Met Gly Gly Asn Ser Ala Gly Glu Leu Cys Val Phe Pro Phe Thr 340 345 350 Phe Leu Gly Lys Glu Tyr Ser Thr Cys Thr Ser Glu Gly Arg Gly Asp 355 360 365 Gly Arg Leu Trp Cys Ala Thr Thr Ser Asn Phe Asp Ser Asp Lys Lys 370 375 380 Trp Gly Phe Cys Pro Asp Gln Gly Tyr Ser Leu Phe Leu Val Ala Ala 385 390 395 400 His Glu Phe Gly His Ala Leu Gly Leu Asp His Ser Ser Val Pro Glu 405 410 415 Ala Leu Met Tyr Pro Met Tyr Arg Phe Thr Glu Gly Pro Pro Leu His 420 425 430 Lys Asp Asp Val Asn Gly Ile Arg His Leu Tyr Gly Pro Arg Pro Glu 435 440 445 Pro Glu Pro Arg Pro Pro Thr Thr Thr Thr Pro Gln Pro Thr Ala Pro 450 455 460 Pro Thr Val Cys Pro Thr Gly Pro Pro Thr Val His Pro Ser Glu Arg 465 470 475 480 Pro Thr Ala Gly Pro Thr Gly Pro Pro Ser Ala Gly Pro Thr Gly Pro 485 490 495 Pro Thr Ala Gly Pro Ser Thr Ala Thr Thr Val Pro Leu Ser Pro Val 500 505 510 Asp Asp Ala Cys Asn Val Asn Ile Phe Asp Ala Ile Ala Glu Ile Gly 515 520 525 Asn Gln Leu Tyr Leu Phe Lys Asp Gly Lys Tyr Trp Arg Phe Ser Glu 530 535 540 Gly Arg Gly Ser Arg Pro Gln Gly Pro Phe Leu Ile Ala Asp Lys Trp 545 550 555 560

Page 14

Pro Ala Leu Pro 03956101140_PC_09122016_SequenceListi ι ng_ST25 Leu Ser 575 Arg Lys 565 Leu Asp Ser Val 570 Phe Glu Glu Pro Lys Lys Leu Phe Phe Phe Ser Gly Arg Gln Val Trp Val Tyr Thr Gly 580 585 590 Ala Ser Val Leu Gly Pro Arg Arg Leu Asp Lys Leu Gly Leu Gly Ala 595 600 605 Asp Val Ala Gln Val Thr Gly Ala Leu Arg Ser Gly Arg Gly Lys Met 610 615 620 Leu Leu Phe Ser Gly Arg Arg Leu Trp Arg Phe Asp Val Lys Ala Gln 625 630 635 640 Met Val Asp Pro Arg Ser Ala Ser Glu Val Asp Arg Met Phe Pro Gly 645 650 655 Val Pro Leu Asp Thr His Asp Val Phe Gln Tyr Arg Glu Lys Ala Tyr 660 665 670 Phe Cys Gln Asp Arg Phe Tyr Trp Arg Val Ser Ser Arg Ser Glu Leu 675 680 685 Asn Gln Val Asp Gln Val Gly Tyr Val Thr Tyr Asp Ile Leu Gln Cys 690 695 700 Pro Glu Asp 705 <210> 28 <211> 687 <212> PRT <213> human <400> 28 Pro Arg Gln Arg Gln Ser Thr Leu Val Leu Phe Pro Gly Asp Leu Arg 1 5 10 15 Thr Asn Leu Thr Asp Arg Gln Leu Ala Glu Glu Tyr Leu Tyr Arg Tyr 20 25 30 Gly Tyr Thr Arg Val Ala Glu Met Arg Gly Glu Ser Lys Ser Leu Gly 35 40 45 Pro Ala Leu Leu Leu Leu Gln Lys Gln Leu Ser Leu Pro Glu Thr Gly 50 55 60 Glu Leu Asp Ser Ala Thr Leu Lys Ala Met Arg Thr Pro Arg Cys Gly 65 70 75 80

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03956101140_PC_09122016_SequenceListing_ST25

Val Pro Asp Leu Gly Arg Phe Gln Thr 85 Phe 90 Glu Gly Asp Leu Lys 95 Trp His His His Asn Ile Thr Tyr Trp Ile Gln Asn Tyr Ser Glu Asp Leu 100 105 110 Pro Arg Ala Val Ile Asp Asp Ala Phe Ala Arg Ala Phe Ala Leu Trp 115 120 125 Ser Ala Val Thr Pro Leu Thr Phe Thr Arg Val Tyr Ser Arg Asp Ala 130 135 140 Asp Ile Val Ile Gln Phe Gly Val Ala Glu His Gly Asp Gly Tyr Pro 145 150 155 160 Phe Asp Gly Lys Asp Gly Leu Leu Ala His Ala Phe Pro Pro Gly Pro 165 170 175 Gly Ile Gln Gly Asp Ala His Phe Asp Asp Asp Glu Leu Trp Ser Leu 180 185 190 Gly Lys Gly Val Val Val Pro Thr Arg Phe Gly Asn Ala Asp Gly Ala 195 200 205 Ala Cys His Phe Pro Phe Ile Phe Glu Gly Arg Ser Tyr Ser Ala Cys 210 215 220 Thr Thr Asp Gly Arg Ser Asp Gly Leu Pro Trp Cys Ser Thr Thr Ala 225 230 235 240 Asn Tyr Asp Thr Asp Asp Arg Phe Gly Phe Cys Pro Ser Glu Arg Leu 245 250 255 Tyr Thr Arg Asp Gly Asn Ala Asp Gly Lys Pro Cys Gln Phe Pro Phe 260 265 270 Ile Phe Gln Gly Gln Ser Tyr Ser Ala Cys Thr Thr Asp Gly Arg Ser 275 280 285 Asp Gly Tyr Arg Trp Cys Ala Thr Thr Ala Asn Tyr Asp Arg Asp Lys 290 295 300 Leu Phe Gly Phe Cys Pro Thr Arg Ala Asp Ser Thr Val Met Gly Gly 305 310 315 320 Asn Ser Ala Gly Glu Leu Cys Val Phe Pro Phe Thr Phe Leu Gly Lys 325 330 335 Glu Tyr Ser Thr Cys Thr Ser Glu Gly Arg Gly Asp Gly Arg Leu Trp 340 345 350

Page 16

03956101140_PC_09122016_SequenceListing_ST25 Cys Ala Thr Thr Ser Asn Phe Asp Ser Asp Lys Lys Trp Gly Phe Cys

355 360 Pro Asp 370 Gln Gly Tyr Ser Leu 375 Phe His 385 Ala Leu Gly Leu Asp 390 His Ser Pro Met Tyr Arg Phe 405 Thr Glu Gly Asn Gly Ile Arg 420 His Leu Tyr Gly Pro Pro Thr 435 Thr Thr Thr Pro Gln 440 Pro Thr 450 Gly Pro Pro Thr Val 455 His Pro 465 Thr Gly Pro Pro Ser 470 Ala Gly Pro Ser Thr Ala Thr 485 Thr Val Pro Asn Val Asn Ile 500 Phe Asp Ala Ile Leu Phe Lys 515 Asp Gly Lys Tyr Trp 520 Arg Pro 530 Gln Gly Pro Phe Leu 535 Ile Arg 545 Lys Leu Asp Ser Val 550 Phe Glu Phe Phe Ser Gly Arg 565 Gln Val Trp Gly Pro Arg Arg 580 Leu Asp Lys Leu Val Thr Gly 595 Ala Leu Arg Ser Gly 600 Gly Arg 610 Arg Leu Trp Arg Phe 615 Asp

365 Leu Val Ala Ala 380 His Glu Phe Gly Ser Val Pro 395 Glu Ala Leu Met Tyr 400 Pro Pro 410 Leu His Lys Asp Asp 415 Val Pro 425 Arg Pro Glu Pro Glu 430 Pro Arg Pro Thr Ala Pro Pro 445 Thr Val Cys Pro Ser Glu Arg 460 Pro Thr Ala Gly Pro Thr Gly 475 Pro Pro Thr Ala Gly 480 Leu Ser 490 Pro Val Asp Asp Ala 495 Cys Ala 505 Glu Ile Gly Asn Gln 510 Leu Tyr Arg Phe Ser Glu Gly 525 Arg Gly Ser Ala Asp Lys Trp 540 Pro Ala Leu Pro Glu Pro Leu 555 Ser Lys Lys Leu Phe 560 Val Tyr 570 Thr Gly Ala Ser Val 575 Leu Gly 585 Leu Gly Ala Asp Val 590 Ala Gln Arg Gly Lys Met Leu 605 Leu Phe Ser Val Lys Ala Gln 620 Met Val Asp Pro

Page 17

03956101140_PC_09122016_SequenceListing_ST25

Arg 625 Ser Ala Ser Glu Val 630 Asp Arg Met Phe Pro Gly 635 Val Pro Leu Asp 640 Thr His Asp Val Phe Gln Tyr Arg Glu Lys Ala Tyr Phe Cys Gln Asp 645 650 655 Arg Phe Tyr Trp Arg Val Ser Ser Arg Ser Glu Leu Asn Gln Val Asp 660 665 670 Gln Val Gly Tyr Val Thr Tyr Asp Ile Leu Gln Cys Pro Glu Asp 675 680 685

<210> 29 <211> 20 <212> PRT <213> human <400> 29

Met Ser Leu Trp Gln Pro Leu Val Leu Val Leu Leu Val Leu Gly Cys 1 5 10 15

Cys Phe Ala Ala 20

Page 18