CA3000746A1 - 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 - Google Patents

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 Download PDF

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CA3000746A1
CA3000746A1 CA3000746A CA3000746A CA3000746A1 CA 3000746 A1 CA3000746 A1 CA 3000746A1 CA 3000746 A CA3000746 A CA 3000746A CA 3000746 A CA3000746 A CA 3000746A CA 3000746 A1 CA3000746 A1 CA 3000746A1
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inhibitor
group
mmp9
alkyl
compound
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Julie Di Paolo
David Breckenridge
Jamie BATES
Daniel Tumas
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Gilead Sciences Inc
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Gilead Sciences Inc
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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

2 PCT/US2016/054780 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
HUD OE INVENTION
[00011 Theptesent disclosure MAWS generally to therapeutics and 'compositions .for treating eancers and all autoimmunei and inflammatoty disorders, and more ;:pwifitally to the use of Bruton's Tyrosine =Kinase (DTI() inhibitors (hereinafter refml to BTK. or latk: inhibitors) in combination with one or more agent: which modulates Janus Kin as OAK)õ4,optesis giial-tegulating.kinase 1.
(A.SK1.)õ bromodomain-conta.ining prOteins, or matrix =tall peptidases. 9 (NIMP9).
BACKGROUND
[0002i BTKitibibitors useful in treating cancers suchaa hematological cancers and inflammatory conditions include those taught in U.S. Pat, No. 8,940,72.5 (Yamamoto et al.). U.S. 2014103:30015 Yamamoto et al.) and..1j,S, it. No..
.7,514,444 cflonigherg et al.).
100031 Janus Kidase (MK) inhibitors are known in the art,. including.
m tnektini tiitimh toTh.ftiib. ociaeitinib, LUX Olitinib, baracitinib,.
lentaurtinib, pactitinib, fflgcitinib4 T0101348, JS,424, and'INCB39110., CHZ868, and K2561GS 84. ihere remains a need for beneficial combination therapies.
100041 Mitogen-activatcd protein. kinase (MAK) signaling casca.d.es couple diverse extracellular and intracellaiar queues to appropriate cellular alms roponses, including cell growth, differentiation,. inflammation, .and apoptosig Boehm, j.õ ,apd 14eõ L C. (2003) Nat, Rev. Drag Dis, 1717-726;
Pimienta, G., and Pascual, J: (2007) Cell Cycle, 6: 2826,2632), MAPICa exist in time groups, NI:AH.1(s, MAPKs and,MAPK.s, which are sequel-100y activated.
MAPK3s direetly respond to environmental Opals and phosphorylateNIAP2Ks, which in Mill phosphorylate specific MAPKa. MAPKS then mediated the appropriate (titular response by phosphorylating cellular sulmtratesõ
including transcription factors that regulate gene expressinn.
SUBSTITUTE SHEET (RULE 26) WO 2017/(159252 [0005] Apoptosis signal-regulating kinase 1 (ASK]) is a member of the mitogen-activated protein kinase kinase kinase ("MAP3K") family that activates the c-Jun N-terminal protein kinase ("JNK") and p38 MAP kinase. (Ichijo, H., et at, (1997) Science, 275, 90-94). ASK1 is activated by a variety of stimuli including oxidative stress, reactive oxygen species (ROS), LPS,'INF-a, Fastõ ER. stress, and increased intracellular calcium concentrations (Hattori, K., et al. (2009) Cell Comm. Signal. 7:1-10; Takeda, K., et at, (2007) Annu. Rev. Phamiacal. Toxicol.

48: 1-8.27; Nagai, H., et al. (2007) J. Biochem. Mol. Biol, 40: 1-6). ASK!
'Undergoes activation via autophosphorylation at 1hr838 in response to these signals and in turn phosphorylates MAP2Ks, such as MKK3/6 and MKK4/7, which then phosphorylate and activate p38 and JNK MAPKs, respectively.
ASK2 is a related MAP3K that shares 45% sequence homology with ASK]
(Wang, X. S., e al. (1998) Biochem. Biophys. Res. Commun..253.,. 3.3-17, Although ASK2 tissue distribution is restricted, in some cell types ASK1 andASK2 have been reported to interact and function together in a protein complex (Takeda, K., et al. (2007) J. Biol. Chem. 282: 7522-7531; Iriyama, T., et al. (2009) Embo J. 28: 843-853) In non-stressed conditions, A SKI is kept in an inactive state through binding to its repressor Thioredoxin (Trx) (Saitoh, M., et al(1998) Embo J. 17:2596-2606), and through association with AK')' (Zhang, L., Chen, J. and Fu, H. (1999) Proc. Nat Acad. Sci. U.S.A 96:8511-8515).
Phosphorylation of ASK1 protein can lead to apoptosis or 10 other cellular responses depending on the cell type. ASK.1 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, ASK! has been implicate in mediating organ damage following ischemia and repetfusion of the heart, brain, and kidney (Watanabe et at (2005) BBRC 333, 562,567; Zhang et al., (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 ASK!, may play important roles in human diseases as well. Therefore, therapeutic agents that function as inhibitors of ASKI and signaling complexes have the potential to remedy or improve the lives of patients suffering from such conditions. U.S. Publication No. 2007/0276050 describes SUBSTITUTE SHEET (RULE 26) WO 2017/(159252
3 -methods for identifying A.SK1 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 ASK1 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 cardioniyoeyte, and a method for screening the drug.
W02009027283 discloses triazolopyridine compounds, methods for preparation thereof and methods for treating autoirmnune disorders, inflammatory diseases, cardiovascular diseases and neumdegenarative diseases, U.S. Patent Nos.
8,552,196 and 8,742,126 teach ASK] inhibiting compounds useful as pharmaceutical agents.
100061 BET or BRD inhibitors are a class of drugs with anti-cancer, immunosuppressive, and other effects demonstrated in el Mica] trials and widely used in research. They reversibly bind the bromodomains of Bromodomain and Extra-Terminal motif (BET) proteins 13RD2, BRD3, BRD4 and BRDT and prevent protein-protein interaction between BET proteins and acetylated histories and transcription factors. Bromodomain inhibitors include the benzimidazole derivatives taught in US 2014-0336190.
100071 Abnormal activity of certain IvIMPs plays a role in tumor growth, metastasis, inflammation, autoimmtuity, and vascular disease. See, for example, Hu et at. (2007) Nature Reviews: Drug Discovery 6:480-498. One notable source of MMP9 is tumor-associated macrophages ('FAMs), which support metastasis and invasion in a complex co-activation loop via paractine interaction with the primary tumor cells. This combination of the ptoteolytic breakdown of physical barriers to cell invasion plus liberation of factors that activate growth and angiogenesis paves the way for tumorexpansion, with the accompanying development of neovascularization to support tumor outgrowth.
100081 MMP9 is a target of oncogenic signaling pathways such as RAS/RAF, P13K/AKT/NFkB, and WNT/beta-catenin and fiinctions 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, SUBSTITUTE SHEET (RULE 26) WO 2017/(159252
4 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 cells.
100091 It can be desirable to inhibit the activity of one or more MMPs in certain therapeutic settings. However, the activity of certain other 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 MMPSõ use of available MMP inhibitors has caused side effects due to the inhibition of essential, non-pathogenically-related MMPs. Useful MMP9 inhibitors include the antibodies and fragments disclosed U.S.in 2015-0140580 (Smith et al.) and U.S. Patent Nos, 8,377,443 (McAuley et al.), 8,501,916 (McAuley et al.), and 9,120,863 (McAuley et al.).
100101 There remains a need for additional treatments for cancers.
BRIEF SUMMARY
100111 Provided herein are methods for treating cancers, allergic disorders, autoitmnune 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 BR!) inhibitor, and a MMP9 inhibitor. In some embodiments, the BTK. inhibitor is 6-amino-9-[(3R)-1-(2-butroy1),3-pyrrolidinyll-7-(4-phenoxyphenyl)-7,9-dihydro4H-purin-8-one, or a pharmaceutically acceptable salt or hydrate thereof. In some variations, the BTK inhibitor is a hydrochloride salt of6-amino-9-[(311.)-1--(2-butyno)1)-3-pyrrolidinyl]-7-(4-phenoxypheny1)-7,9-dihydro-8H-purin-8-one, or a pharmaceutically acceptable hydrate thereof.
100121 In some aspects, provided is a method for treating cancer in a human in need thereof, comprising administering to the human a therapeutically effective SUBSTITUTE SHEET (RULE 26) WO 2017/(159252 PCT/US2016/054780
- 5 -amount of .a I31K inhibitor and a therapeutically effective amount of a JAK
inhibitor, 10013) In some embodiments, the JAK inhibitor is selected from the group of momelotinib, peficitinib, tofacitinib, oclacitinib, ruxolitinib, baracitirdb, lestaurfinib, pacritinib, filgotinib, 1411[3-f1uoro-2-(trifluoromethyl)'4 pyridiny1]-4-piperidiny1]-344-(7H-pyrro1o[2,3-dippmidin-411)-111-pyrazol-1-y11-3-azetidineacetonitrile, TGI01348, JS-I24, INCB39110, INC,B16562, C117,868, VX-509, XL019, NVP-BSK805, CEP33779, R-348, AC-430, CDP-R723, .BMS911543, 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 efftcfive amount of a BTK inhibitor -and a therapeutically effective amount of a ASK inhibitor. In sonic embodiments, the ASK inhibitor is selected from the goup of Compound CI,. Compound (2, 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, comprising administering to the human a therapeutically effective amount of a BM inhibitor and a therapeutically effective amount of an MMP9 inhibitor.ln some embodiments, the MMP9 inhibitor is MMP9 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), wherein the binding proteins comprise an itmnunoglobulin (1g) 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 selected 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 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 SUBSTITUTE SHEET (RULE 26) WO 2017/(159252
- 6 -JAK inhibitor, a ASK inhibitor, a 11RD 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
100141 FIG. 1 provides a chart of Mean SE Ankle Diameter fOr a rat collagen-induced arthritis model conducted using Compound Al and tofacitinib.
1001.5j Ha 2: depicts a heat map representing the percent of DLBCI.: cell growth inhibition for every paiawise combination of Compound Al and a BET
inhibitor 6-amino-94 (3R.)- I -(2-butynoy1)-3-pyrro1idiny11-7-(4-phenoxyphenyl)-
7,9-dihydro-141-purin-8-one (Compound D) from one representative experiment.
100161 FIG, 3: depicts a heatmap of the calculated Bliss excess over predicted additivity for every pairwise combination using the. percent growth inhibition shown in Fla 2..
100171 PIG. 4: depicts the average percent-cell growth inhibition relative to a DM:SO control (n-3) for DLBC.I., 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 DESCRIPTION
100181 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 BR!) inhibitor, and a MMP9 inhibitor.
100.191 Combinations of pharmaceutically effective amounts of the BTK
inhibitor and one or more inhibitor selected from a MK inhibitor, a ASK
inhibitor, a BRD inhibitor, and a MMP9 inhibitor as described herein may be used to treat cancers, allergic disorders, autoimmtme diseases and inflammatory diseases in a human, the method comprising administering to the human in need SUBSTITUTE SHEET (RULE 26) WO 2017/(159252 thereof a pharmaceutically effective amount of the BTK inhibitor, or 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 MMP9 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 (LIP), myasthenia gravis, allergic rhinitis, chronic obstructive pulmonary disease (COPE)), 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. (S11), non-Hodgkin's lymphoma, indolent non-Hodgkin's lymphoma (iNHL), refractory NHL mantle cell lymphoma, follicular lymphoma (FL), lymphoplasmacytic lymphoma, and marginal 26tit lymphoma.
Definitions 1,00201 A dash at the front or end of a chemical group is a matter of convenience;
chemical groups may be 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 "-S02012-" is equivalent to "-CH2S02-" and both may be connected in either direction. The prefix "C" indicates that the following group has from 1,1 to v carbon atoms, one or more of which, in certain groups (e.g. heteroalkyl, beteroaryl, heteroarylalkyl, etc), may be replaced with one or more heteroatoms or heteroatomic groups. For example, "Caa, alkyl" indicates that the alkyl group has from I to 6 carbon atoms.
f00211 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. "arylenyl" group, respectively.
SUBSTITUTE SHEET (RULE 26) WO 2017/(159252
8 -100221 "Alkyl" refers to any aliphatic hydrocarbon group, i.e.. any linear, branched, cyclic, or spiro nonaromatic hydrocarbon group or an isomer or combination thereoL As used herein, the term "alkyl" includes terms used in the art to describe saturated and unsaturated 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 propari-l-yl, propan-2-y1 (iso-propyl), and cyclopropyls such as cyclopropan-1 -yl, etc.;
butyls such as butan-l-yl, butan-2-y1 (sec-butyl), 2-methyl-propan-1 -y1 (iso-butyl), methyl-propan-2-yi (i-butyl), cyclobutan4-y1; butanes (e.g. (E)-but-2-ene, (Z)-but-2-erte); panty's; pentanes; hexyls; hexenes; octyls; clecyls; 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, saturated aliphatic hydrocarbon group comprising from 1 to about 10 carbon atoms, e.g., from 1 to 6 carbon atoms.
[00231 "Alkenyl" is a subset of "alkyl" and refers to an aliphatic group containing at least one carbon-carbon double bond and having from 2 to about 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 Alkenyl groups include ethenyl, property!, 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.
100241 "Alkynyl" is a subset of "alkyl" and refers to an aliphatic group containing at least one carbon-carbon triple bond. The term "alkynyl" is also meant to include those groups having one triple bond and one double bond.
100251 "Alkoxy" refers to the group -0-alkyl, wherein the alkyl group may be optionally substituted. Alkoxy includes, by way of example, rnethoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy, sec-butoxy, and n-pentoxy.
SUBSTITUTE SHEET (RULE 26) WO 2017/(159252
- 9 -[0026] "Acyl" refers to a group ¶C(:e0)R, where R is hydrogen, alkyl, cycloalkyl, cyclohetemalkyl, aryl, arylalkyl, heteroalkyl, heteroatyl or heteroarylalkyl as defined herein, each of which may be optionally substituted, as defined herein. Representative examples include, but are not limited to formyl, acetyl, cylcohexylcarbonyl, cyclohexylmethyl-carbonyl, benzoyl, benzyloxycarbonyl and the like.
100271 "Amido" refers to both a "C-amido" group which refers to the group -C(=(Y)NRYRz and an "N-amido" group which refers to the group -NRYC())1e, wherein R.Y and le are independently selected from the group consisting of hydrogen, alkyl, aryl, heteralkyl, heteroaryl (each of which may be optionally substituted), and where le and R" are optionally joined together with the nitrogen or carbon bound thereto to form an optionally substituted heterocycloalkyl.
[00281 "Amino" refers to the group -Nlele wherein le and R' are independently selected from the group consisting of hydrogen, alkyl, aryl, heteralkylõ
heteroaryl (each of which may be optionally substituted), and where RY and R.7. are optionally joined together with the nitrogen bound thereto to form a heterocycloalkyl or heteroaryl heteroaryl (each of which may be optionally substituted).
[00291 "Amidino" refers to the group -((:Nle)NRYW where le, RY, and Rz are independently selected from the group consisting of hydrogen, alkyl, aryl, heteralkyl., heteroaryl (each of which may be optionally substituted), and where RY and le are optionally joined together with the nitrogen bound thereto to form a heterocycloalkyl or heteroaryl (each of which may be optionally substituted).
[0030] "Aryl" refers to a group with one or more aromatic rings. It 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 to, those groups derived from acenaphthylene, anthracene, azulene, benzene, biphenyl, chrysene, cyclopentadienyl anion, diphenylmethyl, tluoranthene, Nome, Mane, indene, naphthalene, perylene, phenalene, phenanthrene, pyretic, triphenylene, and the like. An aryl group comprises from 5 to about 20 carbon atoms, e.g., from 5 to SUBSTITUTE SHEET (RULE 26) WO 2017/(159252
- 10-2(j carbon atoms, e.g. from 5 to 10 carbon atoms. In some embodiments, aryl is a a single aromatic ring or multiple aromatic rings which are fused together, [0031] "Ary, !alkyl" (also "araikyl") refers to an aryl group attached to an alkyl group. Aiylalkyl groups include, but are not limited to, benzyl, tolyi, dimethylphenyl, 2-phenylethan-1.-yl, 2-naphthylmethyl, 2-naphthylethan-111, naphthoberrzyl, phenylvinyl, diphenylmethyl, and the like. For example, the "arylalkyl" may be attached to the rest of the compound of formula (I) through the aryl group. Alternatively, the "arylalkyl" may be attached to the rest of the compound of formula (1) through the alkyl group. Where specific alkyl moieties are intended, the nomenclature aryialkanyl, arylalkenyl and/or arylalkynyl may be used. An arylalkyl group comprises from 6 to about 30 carbon atoms, e.g.
the alkyl portion of the arylalkyl group can comprise from 1 to about 10 carbon atoms and the aryl portion of the arylalkyt group can. comprise from. 5 to about 20 carbon atoms. In sonic instances an arylalkyl group comprises from 6 to about carbon atoms, e.g. the alkyl portion of the arylalkyl group can comprise from 1 to about 10 carbon atoms and the aryl portion of the arylalkyl group can comprise from 5 to about 10 carbon atoms.
[0032] "Aryloxy" refers to the group -0-aryl, including by way of example, phenoxy and naphthoxy.
[0033] "Azido" refers to the group -N3.
[0034] "Boronie acid" refers to the group --B(011)2.
[0035] Boronic acid ester" refers to an ester derivative of a boronic acid compound. Suitable bomnic acid ester derivatives include those of the formula --B(OR)2 where R is hydrogen, alkyl, aryl, arylalkyl, heteroalkyl, or hetcroaryl, each of which may be optionally substituted. For example, boronic acid emt may be pinacol ester or -catechol ester.
[00361 Tarbocycle" or "carbocycly1" 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. Monocycle carbocycles have 3 to 6 ring atoms, still more typically 5 or 6 ring atoms.
Bicyclic 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 SUBSTITUTE SHEET (RULE 26) WO 2017/(159252
-11-(6,6) system. Carbocycles includes aromatic and non-aromatic mono-, hi-, and poly-cyclic rings, whether fused, bridged, or Spiro. Non-limiting examples of monocyclic carbocycles include the cycloalkyls group such as cyclopropyl, cyclobutyl, cyclopentyl, I -cyclopent-l-enyl, 1 -cyclopent-2-enyl, 1-cyclopent-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-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."
[00371 "Carbamoyl" refers to the group -C(0)NRYle where RY and le are defined as in "amino" above.
100381 "Carbonyl" refers to the divalent group -C(0)- which is equivalent to -C(-0)-, 10039j "Carboxyl" or "cartamy" refers to -COOH or salts thereof.
10041 "Carboxyl ester" or "carboxy ester" refers. to the groups -C(0)0R, wheminR is. hydrogen, alkyl, aryl, arylalkyl, heteroalkyli or heteroary.1, each of which may be optionally substituted. In one embodiment, R is alkyl, aryl, arylalkyl, heteroalkyl, or heteroaryl, each of which may be optionally substituted.
[0041 j "Cyano" or "carbonitrile" refers to the group -CN.
[00421 "Cycloalkyl" is a subset of "alkyl" and refers to a saturated or partially saturated cyclic group of from 3 to about 10 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 non-aromatic 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-y1). The term "cycloalkyl" includes cycloalkenyl groups. Examples of cycloalkyl groups include, for instance, adamantyl, cyclopropyi, cyclobutyl, cyclopentyl, cyclooctyl, and cyclohexenyl.
[00431 "Guanidine refers to the group -Nlig-NFON112.
[00441 "Halo" or "halogen" refers to fluor , chloro, bromo and iodo, 100451 "Haloalkyl" refers to substitution of alkyl groups with 1 to 5 or, in some embodiments, 1 to 3 halo groups, e.g., -CH2C1, -C.112F, -CH2Br, -CFC1Br, CH2C.H2C1, -C112C112F, -CH2CF3, -CH2CO3, and the like, and further SUBSTITUTE SHEET (RULE 26) WO 2017/(159252
12 -includca those alkyl groups such as perfluoroalkyl in which all hydrogen atoms are replaced by fluorine atoms.
100461 "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 $ hydrogens are replaced with a halogen, Haloaryl groups include, for example, fiuorophomyl, difluorophenyl, tritluorophenyl, chlorophenyl, clorofiuorophenyl, and the like.
100471 "Heteroalkyl" 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. 1 heteroatomic group.
Heteroatoms include, but are not limited to, N, P. 0, S. etc.. Heteroatomic groups include, but are not limited to, -NR-, -0-, -S-,la -P(0)2-, -S(0)-, -S(0)2-, and the like, where R. is H, alkyl, aryl, cycloalkyl., heteroalkylõ heteroaryl or cyclohetemalkyl. The term "heteroalkyl" includes heterocycloalkyl (a cyclic heteroalkyl group), alkyl-heterocycloalkyl (a linear or branched aliphatic group attached to a cyclic heteroalkyl group), and the like. Ileteroalkyl groups include, but are not limited to, -0C113, -CH2OCII3, -SCII3, -NRCH3, -CH2NRCH3, and the like, where It 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.
100481 "Heteroaryl" refers to an aryl group in which one or more of the carbon atoms (and any associated hydrogen atoms) are each independently replaced with the Same or different hettroatoms, as defined above. For example, heteroaryl may include 1, 2 or 3 heteroatomic groups, e.g. I heteroatomic group.
Heteroaryl groups include, but are not limited to, groups derived from acridine, benzoimidazole, benzothiophene, benzofuran, benzoxazole, benzothiazole, carbazole, carboline, dnnoline, furan, imidazole, imidazopyridine, indazole, indole, indoline, indolizine, isobenzofiiran, isochromene, isoindole, isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, perimidine, phenanthridine, phenanthroline, phenazine, phthalazine, pteridine, SUBSTITUTE SHEET (RULE 26) WO 2017/(159252
- 13 purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolizine, quinazoline, quinoline, quinolizine, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene, triazole, 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 more carbon atoms (and any associated hydrogen atoms) are independently replaced with the same or different heteroatoms, as defined above. For example, heteroarylalkyl may include 1, 2 or 3 heteroatomic groups.lIeteroarylalkyl groups include, but are no limited to, groups derived from heteroaryl groups with alkyl substituents (e.g. methylpyridine, ditnethylisoxazole, etc.), hydrogenated heteroaryl groups (dihydrequinolines, e.g. 3,4-dihydroquinoline, dihydroisoquinolines, e.g. 1,2-dihydroisoquinoline; dihydroimidazole, tetrahydroimidazole, etc.), isoindoline, isoindolones (e.g. isoindolin-1.-one), dihydrophthalazine, quinolinone, spiro[cyclopropane-1,1'-isoindolin]-3'-one, di(pyridin-2-yl)methyl, di(pyridin-3-yl)methyl, di(pyridin-11-Amethyl, 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.
100501 "lleterocycloalkyl" is a subset Of "heteroalkyr and refers to a saturated or unsaturated cycloalkyl 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. 0, S, etc. A
heterocycloalkyl group may also contain a charged heteroatom or group, e.g,, a quaternized ammonium group such as -N-(R)2- *herein R. is alkyl, e.g., methyl, ethyl, etc. Heterocycloalkyl gaups include, but are not limited to, groups derived from epoxide, imidazolidine, morpholine, piperazine, piperidine, pyTazolidine, piperidine, pyrrolidine, pyrrolidinone, tetrahydroftuan, tetrahydrothiophene, dihydropyridine, tetrahydropyridine, quinuclidine, N-bromoprrolidine, N-bromopiperidine, N-chloropyrrolidine, N-chloropiperidine, an N,N-dialkylpprolidinium, such as N,N-dimethylpyrrolidinium, a N,N-dialkylpiperidinium such as N,N-dimethylpiperidium, and the like. The SUBSTITUTE SHEET (RULE 26) WO 2017/(159252
- 14 -heterocycloalkyl group comprises from 3 to about 10 carbon and hetero atoms in the ring or rings. In some embodiments, heterocycloalkyl includes 1, 2 or 3 heteroatomic groups.
[00511 "Heterocycle" or "heterocycly1" as used herein includes by way of example and not limitation those heterocycles described in Paquette, Leo A.;
Principles of Modern Heterocyclic Chemistry W.A. Benjamin, New York, 1968), particularly Chapters 1, 3, 4, 6, 7, and 9; _The Chemistry of Heterocyclic 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.
(1.960) 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. 0, N, P or S). The terms "heterocycle" or "heterocycly.1" includes saturated rings, partially unsaturated rings, and aromatic rings (i.e., heteroaromaticrings).
Heterocycles includes aromatic and non-aromatic mono-, hi-, and poly-cyclic rings, whether fused, bridged, or Spiro. As used herein, the term "heterocycle" encompasses, but is not limited to "heteroaryl."Substituted heterocyclyls 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 (piperidy1), thiazolyl, tetrahydrothiophenyl, sulfur oxidized terahydrothiophenyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, thianaphthalenyl, indolyl, indolenyl, quinolinyl, isoquinolinyl, benzimidazolyl, piperidinyl, 4-piperidonyl, pyrrolidinyl, azetidinyl, 2, pyrrolidonyl, pyrrolinyl, tetrahydrofuranyl, tetrahydroquinolinyl, ttrahydroisoquinalinyl, decahydroquinolinyl, octahydroisoquinolinyl, azocirtyL

triazinyl, 6H,1,25-thiadiazinyl, 2H,6H-1,5,2-dithiazinyi, thienyl, thianthrenyl, pyranyl, isobenzofuranyl, chrotnenyl, xanthenyl, pheno.xathinyl, 2H.prrolyl, isothiazolyl, isoxaz.olyl, pyrazinyl, pyridazinyl, indolizinyl, isoindolyl, 31.1-indolyl, 1H-indazoly, purinyl, 4H-quinolizinyl, phthala2inyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cirmolinyl, pteridinyl, 4aH-carbazolyl, carba.zolyl, phenanthridinyl, acridity', pyrimidinyl, phenanthrolinyl, phenazinyl, SUBSTITUTE SHEET (RULE 26) WO 2017/(159252
- 15 -phenothiazinyl, thrazanyl, phenoxazinyl, isochromanyl, chromanyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperazinyl, indolinylõ
isoindolinyl, quinuclidinyl, morpholinyl, oxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, isatinoyl, and bis-tetrahydrofuranyl.
100521 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, 3, or 6 of a pyrimidine, position 2, 3, 5, or 6 of a pyrazine, position 2, 3, 4, or 5 of a ftwan, tetrahydrofuran, thiofuran, thiophene, pyirole 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 heterocycles include 2-pyridyl, 3-pyridyl, 4-pyridyl, pyridyl, 6-pyridyl, 3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyi, 6-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 6-pyrimidinyl, 2-pyrazinyl, 3-pyrazinyl, 5-pyrazinyl, 6-pyrazinyl, 4-thia2olyl, or 5-thiazolyl. By way of example and not limitation, nitrogen bonded heterocycles are bonded at position 1 of an aziridine, azetidine, pyrrole, pyrrolidine, 2-prroline, 3-pyrroline, imidazole, imiclazolidine, 2.-imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline, 1H-indazole, position 2 of a isoindole, or isoindoline, position 4 of a morpholine, and position 9 of a carbazole, or 13-carboline. Still more typically, nitrogen bonded heterocycles include 1-azitidyl, 1-azetedyl, 1-pyrrolyl, 1-imidazolyl, 1-pyrazolyl, and I -piperidinyl.
100531 "Hydrazino" refers to the group -NHNF12.
100541 "Hydroxy" or "hydroxyl" refers to the group -OH..
[00551 "Imino"refers to the group -(4-NR)- wherein R is hydrogen, alkyl, aryl, arylalkyl, heteroalkyl, or heteroatyl, each of which may be optionally substituted.
100561 "Nitro" refers to the group -NO2.
10057J The terms "optional" or "optionally" mean that the subsequently described event or circumstance may but need not occur, and that the description SUBSTITUTE SHEET (RULE 26) WO 2017/(159252
- 16 -includes instances where the event or circumstance occurs and instances in which it does not.
100581 "Oxide" refers to products resulting from the oxidation of one or more heteroatoms. Examples include N-oxides, sulfoxides, and sulfones.
100591 "Oxo" refers to a double-bonded oxygen (-0). In compounds where an oxo group is bound to an sp2 nitrogen atom, an N-oxide is indicated.
100601 "Racemates" refers to a mixture of enantiomers.
100611 "Stereoisomer" or "stereoisomers" refer to compounds that differ in the chirality of one or more stereocenters. 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).
100621 "Substituted" (as in, e.g., "substituted alkyl") refers to a group wherein one or more hydrogens have beenindependently replaced with one or more substituents including, but not limited to, alkyl, Amyl., alkynyl, alkoxy, acyl, amino, amido, amidino, aryl, azido, carbamoyl, carboxyl, carboxyl ester, cyan , guanidino, halo, haloalk.yl, heteroalkyl, heteroaryl, heterocycloalkyl, hydroxy, hydrazino, 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 substitmedwith 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 aryl-(substituted aryl)-substituted aryl. For example, in some embodiments, SUBSTITUTE SHEET (RULE 26) WO 2017/(159252
-17-.
when a group described above as being "optionally substituted" is substituted, that subsfituent is itself unsubstitnted.Similarly, it is understood that the above definitions are not intended to include impermissible substitution patterns 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 I imted to, "arylalkyl."
Generally, substituted groups will have 1 to 5 substituems, I. to 3 substituents, I or 2 su.bstituents or I substituent. Alternatively, the optionally substituted groups of the invention may be unsubstituted.
100631 "Sulfonyl" refers to the: divalent_ izroup -5(0)2-.
100641 "Tautomer refers VII alternate forms of a compound- that 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 :4\1- moiety such as pyrazoles, imidazoles, benzimida2oles, triazoles, and tetrazoles.
100651 "Thiocyanate" refers to the group -SC.:N..
100661 "Thiol" refers to the group -SH.
100671 Thione" refers to a thioketone (-S) group.
100681 "Pharmaceutically acceptable" refers to compounds, salts, compositions, dosage forms and other materials which are usefill in preparing a pharmaceutical composition that is suitable for veterinary or human pharmaceutical use.
100691 "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 acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fbmatic acid, glucoheptonic acid, &conic acid, lactic acid, maleic acid, malonic acid, mandelic acid, methariesulfonic acid, 2-napththalenesulfonic acid, oleic acid.
SUBSTITUTE SHEET (RULE 26) WO 2017/(159252
- 18 -pahnitic acidõ propinnic acid, stearic acid, weenie acid, tartaric acid, p-toluenesulfonic acid, trimethylacetic 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, N-methylglucamine and the like. Also included in this definition are ammonium and substituted or quatemized ammonium salts. Representative non-limiting lists of pharmaceutically acceptable salts can be found in S.M. Berge et al., J.
Pharma Sci., 66(1), 1-19 (1977), 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 by reference herein.
[00701 The following abbreviations may also be: used: Ac011: acetic acid;
n-butyllithium; CC: column chromatography; CsK;03: cesium carbonate;:
C11202 or DCM: dichloromethane; CH3.Mgl: methyl magnesium iodide; CuCh:
copper chloride; D.AST: (diethylamino)sulfur trifluoride; DEAD: diethyl azodicarboxylate; DIBAL: diisobtitylaltuninum hydride; D1PEA:
diisopropylethylamine; DMF: dimethylformamide; DMSO: dimethyl sulfoxide;
Et3N: triethylamine; Et0Ac: ethyl acetate; &OH: ethanol; g: gram(s); le hour;
H2: hydrogen; IIHr: hydrogen bromide; HQ: hydrogen chloride; 1120: water;
11202: hydrogen peroxide; HPLC: high performance liquid chromatography;
KCN: potassium cyanide; LHMDS: lithium hexamethyldisilazide; LiA1B4:
lithium aluminum hydride; LiOH: lithium hydroxide; M: molar; MeCN:
acetonitrile; Mel: methyl iodide.; Me0II: methanol; MgSO4: magnesium sulfate;
MgCO3: magnesium carbonate; mg: millilgram; Msa: mesyl chloride; mmol:
millimoles mL: milliliter; sodium hydrogen sulfite; maBA: meta-chloroperoxybenzoic acid; N: normality; N2: nitrogen; Na2CO3: sodium carbonate; NaliCO3: sodium bicarbonate; NaNO2: sodium nitrite; NaOH: sodium hydroxide; Na2S203: sodium bisulfate; Na2SO4: sodium sulfate; NBS: N-bromosuccinimide; NH4CI: ammonium chloride; .NI140Ac: ammonium acetate;
NMR: nuclear magnetic resonance; Pd/C: palladium on carbon; PPh3: triphenyl SUBSTITUTE SHEET (RULE 26) WO 2017/(159252 - -phosphine; iPrOff: isopropyl alcohol; RI: room temperature; SOC12: thionyl chloride; THF: tetrahydrofuran; TLC: thin layer chromatography; jile microliter.
100111 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.
100721 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.
10073] "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 be resistant to treatment from the beginning of treatment, or may become resistant during the course of treatment, for example after the treatment has shown some effect on the cancer, 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 returned atter 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 to at least one anti-cancer therapy, or (ii) in relapse after treatment with at least one anti-cancer therapy, or both (1) and (ii). in sonic of embodiments, the human is refractory to at least two, SUBSTITUTE SHEET (RULE 26) WO 2017/(159252 at 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 be an individual who has or is suspected of having a cancer. hi 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 fir 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 100771 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:
0) inhibiting the disease or condition (e.g., 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 SUBSTITUTE SHEET (RULE 26) WO 2017/(159252 (iii) relieving the disease, that is, causing the regression of clinical symptoms (e.g., ameliorating the disease state, providing partial or total remission of the disease or condition, enhancing effect of another medication, delaying, the progression of the disease, increasing the quality of life, and/or prolonging survival).
[00781 In some variations, "delaying" the development of a disease or condition means to defer, hinder, slow, retard, stabilize, andJor postpone development of the disease or condition. This delay can be of varying lengths 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 inchides occurrence, recurrence, and onset.

100801 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 "about" includes the indicated amount 5%. In .certain other embodiments, the term "about" includes the indicated amount a, 1%. Also, to the term "about X" includes description of ":r. Also., the singular forms "e 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 SUBSTITUTE SHEET (RULE 26) WO 2017/(159252 [00811 As used herein, the term "antibody" means an isolated orrecombinant polypeptide binding agent that comprises peptide sequences (e.g., variable region sequences) that specifically bind an antigenic epitope. The term is used in its broadest sense and specifically covers monoclonal antibodies (including full-length monoclonal antibodies), polyclonal antibodies, human antibodies, humanized antibodies, chimeric antibodies, nanobodies, diabodies, multispecifk antibodies (e.g., bispecific antibodies), and antibody fragments including but not limited to Fv, scFv, Fab, Fab' F(abl)2 and Fab2, 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 (i.e.; does not induce the production of antibodies. to itself).
[00821 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(abr)2, and Fv fragments; diabodies; linear antibodies (Zapata etal. (1995) Protein .Eng. 8(10):1057-1062); 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 "Fe"
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 fight, non-covalent association.
It is in this configuration that the three complementarity-determining regions (CDRs) of each variable domain interact to define an antigen-binding site on the surface of the V1-V1, dimer. Collectively, the six CDRs confer antigen-binding specificity to the antibody. However, even a single variable domain (or an SUBSTITUTE SHEET (RULE 26) WO 2017/(159252 isolated V or Vt. region comprising only three of the six CDIts specific for an antigen) has the ability to recognize and bind antigen, although generally at a lower affinity than does the entire F., fragment.
[0084] The "Fab" fragment also contains, in addition to heavy and light chain variable regions, the constant domain of the light chain and the first constant domain (Clio of the heavy chain. Fab fragments were originally observed following papain digestion of an antibody. Fab' fragments differ from Fab fragments in that Nab') fragments contain several additional residues at the carboxy terminus of the heavy chain all domain, including one or more cysteines from the antibody hinge region. F(ab1)2 fragments contain two Fab fragments joined, near the hinge region, by disulfide bonds, and were originally observed following pepsin digestion of an antibody. Fab`-Sli is the designation herein for Fab' fragments in which the cysteine residue(s) of the constant domains bear a free third group. Other chemical couplings of antibody- fragments are also known.
100851 The "light chains" of antibodies (immunoglobulins) from any vertebrate species can be assigned to one of two clearly 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, IgG, and IgM, and several of these may be further divided into subclasses (isotypeo, e.g., IgGl, Ig02, IgG3, Ig64, IgAl , and IgA2.
[0086i "Single-chain Fe or "sFv" or "scFv" antibody fragments comprise the \ill and VI. domains of antibody, wherein these domains are present in a single polypeptide chain. In some embodiments, the Fv polypeptide further comprises a polyreptide linker between the Ve and V/. domains, which enables the sFv to form the desired structure for antigen binding. For a review of sFV, see Pluckthun, in The Pharmacology of Monoclonal Antibodies, vol. 113 (Rosenburg 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 heavy-chain variable domain (Ve) connected to a light-chain variable domain (VI) in the same polypeptide SUBSTITUTE SHEET (RULE 26) WO 2017/(159252 chain (Vki-V.I.,). By using a linker that is 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 are additionally described, for example, in EP 404,097; WO
93/11161 and Hollinger ei al. (1993) Proc. Natl. Acad. Sci. USA 90:6444-6448.
100881 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 nonreducingconditiorts, with detection by . Coomassie blue or silver stain. The tema "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.
100891 As used herein, "immunoreactive" refers to 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 orantigen 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 ¶prefereatially binds" means that the binding agent binds to the binding site with greater affinity than it binds 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 Kabat et al., I. Biol. Chem, 252;6609-SUBSTITUTE SHEET (RULE 26) 6616 (1.977); Kabat et al., U.S. Dept. of Health and Human Services, "Sequences of proteins of immunological interest" (1.991); by Chothia et al., J. Mal.
Bid, 196:901-917 (1987); and MacCallum et at,, J. Md. Biol.. 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 be 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.
[00911 'fable : CDR Definitions KAM'. Ch4ithia2 mateCatione cDRI 31-15 26-32 30-35 V, C:DR1 24-34 26-32 30-36 'Residue numbering follows the nomenclature of Kabat et al., supra ?Residue numbering follows the nomenclature of Chothia at al., supra 3Residue numbering follows the nomenclature of MacCallum at al., supra [00921 As used herein, the term "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 100-120 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.
[00931 "Homology" or "identity" or "similarity" as used herein in the context of nucleic acids and pelypeptideS refers to the relationship between two polypeptides or two nucleic acid molecules based on an alignment of the amino acid sequences or nucleic acid 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 SUBSTITUTE SHEET (RULE 26) WO 2017/(159252 same 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 homology/similarity.
10094) As used herein, "identity" 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(s) relative to the reference sequence, based on the designated program parameters.
j00951 Examples of algorithms that are suitable for determining percent sequence identity are the BIAST and BLAST 2.0 algorithms, which are described in Altschul et al. (19.90) J. MeL Biol. 21.5.: 403-410 and Altschul et al.
(1977)Nuc1eic Acids Res. 25: 3389-3402, respectively. Software for.perfonning BLAST analyses is publicly available through the National Center for Biotechnology Information (wwwmcbinlm.nihgov). Further exemplary algorithms include ClustalW (Higgins D., et al. (1994) Nucleic Acids Res 22:
4673-4680), available at www.ebi.ac.uk/Tools/clastahvlindex.html, [00961 Residue positions which are not identical can differ by conservative amino acid substitutions. Conservative amino acid substitutions refer to the interchangeability of residues having similar side chains. For example, a group of SUBSTITUTE SHEET (RULE 26) WO 2017/(159252 amino acids having aliphatic side chains is glycine, alanine, valine, leucine, and isoleucine; a group of amino acids having aliphatic-hydroxyl side chains is serine and tbreonine; a group of amino acids having amide-containing side chains is asparagine and glutamine; a group of amino acids having aromatic side chains is phenyialanine, tyrosine, and tryptophan; a group of amino acids having basic side chains is lysine, arginine, and histidine; and a group of amino acids having sulfur-containing side chains is cysteine and methionine.
Compounds [00971 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 commonly recognized nomenclature: systems and symbols. By way of example, the compound may be named or identified with common names, systematic or non-systematic 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 (IRAC).
(0098i Also provided herein are isotopically labeled forms of compounds detailed herein. Isotopically labeled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected 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 211 (deuterium, D), 3H (tritium), )1c, 13c, It, I5N, 15p, lip, 32p, 35s, 36CI and 1251. Various isotopically labeled compounds of the present disclosure, for example those into which radioactive isotopes such as 11i, 11C and 14. C
are incorporated, are 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 (SPECT) 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.
SUBSTITUTE SHEET (RULE 26) WO 2017/(159252 [00991 In some variations, the compounds disclosed herein may be varied such that from 1 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.
[001001 Deuterium labeled or substituted therapeutic compounds of the disclosure may have improved DMPK (drug metabolism and pharmacokinetics) properties, /elating 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 .81' labeled compound may be useful tbr PET or SPECT studies. Isotopically 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 isotopically labeled reagent for a non-isotopically labeled reagent.
It is understood that deuterium in this context is regarded as a substituent in the compounds provided herein.
[001011 The concentration of such a heavier isotope, specifically deuterium, may be defined by an isotopic enrichment factor. In the compounds of this disclosure any atom not specifically designated as a particular isotope is meant te.) 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.
SUBSTITUTE SHEET (RULE 26) -2.
B1 K inhibitor [001021 in some variations, the BTK inhibitor is.COmpoutid Al, or a pharmaceutically acceptable salt. or hydrate thereof. Compound Al 11A: the structure:
...=
i Y-) = .,õ.õ,4.5,,"
==
0.0 1001031 In SOW µAiriations, the BTK inhibitor is a hydivoliloride salt of Compound Al or a hydrate thereof. Compound.A1 may b.0 spthesind according to the methods described in U.S. Patent No. 8,55703 (Yamamoto et at) and US 2014/0330015, Co.mp.ound A.1 may be referred to as (R)-6-amino-9-(1--(bot,-2-yrtoy1)pyTro1idin-3-y1)-7-(4-phenoxyphenyl)-7H--purin-8(9H)-one or 6.-amino-940R)-1-(2-butynoy1)-3-pyrrolidinyll-7-(4-phenovpheny1)-7,9-dihydro-811. -purin-S-one. A.dditional BTK inhibitors include, but are notinuited. to, (S)-6-amino-9-(1-(but-Z-ynoyerpyrrolidin-3-y1)4-(4,phenoxyphenyl.)-7Iffurin-8(9 M.-one ibrutinib (1- f (3.4344-Amino-3-(4-phenox yph riy1)-4 .pyrazolo [3,4-djpyri tin din- I yIIpp&rith i I 1Ipip2eix 1 one), aeaj a brut ini b, j-ir471224, =ON0-4059, and CC-292 (speburtinib).
1.AK Inhibitor [OW 041 in some variations, the INK inhibitor i Compound Bl, Compound B2, Compound B3., orCom pound B4õ or a pharmaceuticallyacceptable It thereof.Compound B:1, which .may be referred to as momclotinib, ern137, CYT3g7, or N(eyanomethyl)-4-[24.4-(4-111orpholiny gthnyflaminoH-pyrimidinyll-bm ........ N-(cyanr3methy.1),--4-(24(4¶motpliolinophertyl) amino)pyrimidin-4-yl)be1Izamide, has the structure.:
SUBSTITUTE SHEET (RULE 26) -30-.
r [001051 Compound ,132, which may he Tamed to as filgotinib, GLPG0634, GI 46034, N -15,04(14 ,dioxidathiomorpholinOmethyl [1,2 Aqui azolo[1,5-a}pyridin-211)eydopmpanecarboxamide, 15-[44131-dilox0,1 ,4-tbiazinan-4-y1)methy1lpheny11_[1,2,411triazolo[1,54]pyridin,2, ylicyclopropanecarboxamide, or N-15-[ 4-[(1õ1-dioxido-4411j omorpb Any methyl phenyll [1 ,2341triazo]o[1.5-alpyridin-2-ylj-cyclepr(manecarboxamide and has the structure:
"
!
0.47, (S2) 1901061 Compound 133, which has the Chemical Abstracts fcgi sty number 1334298-90-6, may be referred to as 1 411341 u oro-,2-(trichl oromethyl).-4-pyTidinyi 1 carbonyl] i peri d iny11,344-(7H-pyrrolo[2,3-dipyrimidi )-pyrup1411j- 3,azendineacetoo itrile and has the structure ;
' (133) SUBSTITUTE SHEET (RULE 26) 1001071 Compound 1343 which maybe retbrred to as tolacithdb, (3R,4R)-1.-A-mothyl.-3-(0.1ethyl-7FI-uyrrolO12,,:W]pyrimidin4-ylamino)-0-oxo-piperidinepropanenitri1e or 34(.311,410-40erityi-3.4rnethyl(711-pyrrolo[2õ3-di pyrim idin-l-y1)amino)piperidin-1-y1)-loxoprOpanertittile has the 'structure:
("SA
40' (134) 1001081. Compound B5, which 1.hay be referred. to mi. oclacitinib or N -(11r,40-44methyl(7H-pyrro1o[2,341]pyrimiclin.4 A)mirio)oyelobekyl)methaT1esulfonamide has the structure:
A
t st4 = ' (kb) 100109j Compound B6, which may be referred to as ruxolotinib (IN0424, IN7B1.8424, JAKAFIV, JAKAVIV, available =from Incyte PliarmacetticalS and NovartiO or (3R)-3-Cycloperity1-34447ii-pyrrolo[243-4flpyrimidia-411)-1H-pyrvol-1 -yllpropancnitrile: has the: Mutate:
.4. ......
polo] Compound B7, .which may be referred to as bmluitinib (I,Y30091.04, INCB28050) 241.-ethylso1forty1444.-PII-pyrro1o[2,3,d]pyriintdin-4-3/1)pyrazo1-1-y1lazetidin-.3-y1lacotopitti1e or 2(3-(4-(71I-pyrro1o[2,3-dipyriTnidin-4-A-II
pyrazol- I -A)4 -(ethylstitimyl)azetidia-3-y1)aeetwitrilct,. has the structure:
SUBSTITUTE SHEET (RULE 26) .5.^
- ,,,, -u , =I'''''`'''n. I
N
11 <4 ...-x)-,;:-.'""''.`.4-0';'\ \ ):.=
.. 1 .. 1 ',.N.,N
(137) [091111 compound 138., which may be retrred to as 1Ø ----------- ih (CEP-701.
KT5555, akl A 154475.0) , 2,3,9,10,11,12-heuhydro40-hydrox y-10-(hydroxymethy1)+met hyl-, (9S,.108,12R)- 9,1.2-Epoxy-I1i-di in dolo[1.,M.-fg.:3', 2%.14;1}pyrrolor.i.,4-i]1.1,6Thenzodiazocin4-one:, has the structure:
=:N, .., ..... ..
. .
..., .%õ
ii. 1 . k= .:/:.
:N... .;...:.J, ---"P ;'1.===`"-"k-sõ ===;':
,::::.-'..= .?,... .,,. '.'x:,:µ,.:
,S. = = = ,..k.
[ ' ..
1 = ./
=e' 0'. 03 8) [001121 Compound B9, which may be referred. to as pacritinih (SB1518) or (16E)-I 1-[2-(t-pyrradinyoethoxyli-14,194oxa,5,7,26-triazatetracyclo=[ 03 ,1õ.12,6,1.8,121heptacosa-1(25),2(26.),3,5,8,10,12(27),16,;21,23-decaene, has the structure :rd.. ===:: = = .......,,..,....7-N.

..,::
.i"'e , ( .9 'N.'N.:''''':.,.,.... . 'f'k.:=`.,v .....
" r . "?'I. . (139).
[001131 Compound B10, which may In: rofored to as 1'o101348, SAR302505, .*tget-B01.-34$-Taethyl-24442-pyixolidit411--ethoxy)-phenylamirad.-pyrimiditi,4-y1amino } -henzenesulfonamideõ or N-aert-buty0-3-0-methy1-2-04-(-(pyrn.iiiilin - 1-yi)ethoxy)ph aiyiNDT) ino)pyrimi din-4-YOaminonzeriesulfonamide, has the structure:
SUBSTITUTE SHEET (RULE 26) 0.3 =
= I
. = .= ;;,4:0,=
H.
(FAV).
[001141 Compound B11, which may be referred to as JSI-124, Cucurbitracin, Elatehcin B. NSG-521777õ (0,98õ10R,13R,14R,16R, 7R)-1:7-((R,E),,2õ6.,.
dihydroxy-6-mediy1-3-oxohept-4--en-211)-2,16-dihydroxy4,4,8,9,1.3õ
hexamethy1h7,K,930,12J33.1435.,Kil -decohydro-3H--qc I open Ita{a]phenanthrente-3,11.(411)-di one or 2,16a,20,25-tetrabydt meth), i-19-Nor-91:;, do,lanosta- õ5,23.-tricne-.3,11.,224rione, has: the structure =
"*, =
' 4".
(1311) 001151 Additional JAK inhibitor compounds. that May housed. in the combinations, methods, kits, and articles of manufactinv. herein GSK2586184, INCB16562, X1,019, NV P-BSK805, CEP3:3779õ R,348, AC430, CDP-R723 oz BMS 911543, NVRESK805, CEP33779, as: well asthose disclosed in U.S.. Pat. No. 7,879,844, and the JAK inhibitor cyclodgxtrin-based.
polymer conjugates described in U.S. 2014-03.575.57.
SUBSTITUTE SHEET (RULE 26) -.11 .. 1...NH.:
,,,õ
õ*
,.,,, ..... ...., . ,..,,,,,,........õ) ."-- - ?.....' '::-.
k,,... .:.:,, VA -: 60t3 livivilf1Mit. te''''''.... .e....,-.=,,,, HI;i= - ,,, = :\ I
,./.

ft. ....:. \
;,...,:,;... .;;.:::,',=?'"1,k, / ., õ.:.,. '1. . .. tr. '...
A
I
ti.
\ BMS211.543H.
= = ..,,s=P
\.
.'....''''''''''....i i ?,.,-..:µ.=.'. lv:
...A.'i::::=,...../ :. = :. ..;,oM1 fr-U.

I ; NVP-8SK805 . s i H 11:s..., - 1.
/''=-=\-?-ir''' µN::-'7'''A:...k,.:
.,.., i L
,....4:
AZD',460 f , ( ,...,./
. =.'":- ' r."..Nr. HN .. ,........"??.',..,t,õ .
õ...) Xi-019 - 1 i -.1-t !: 11 .o ''...,,../
= ,e.:::-..-k1 .,,,, j\.,..
. -....,.., ''..::, ,.,,::'-'. if \
- T. GERM773 if¨A...4;
r4--/ \ .......................................... i ?e -`r.=;''''' \ ...
and 1 2? 1411 ...\/..':=.,\,;....,....;õ;,,I.4"*"...4.1 [001161 In some eniboditnents, Compound Bl, or a pliarmuentieally aceeptahle salt thereof, is tied in combination with C)arripouttd AL or a, pharmac::,:atioally acceptable salt or hydrate thereof, In other embodiments, Compound B2, or a SUBSTITUTE SHEET (RULE 26) WO 2017/(159252 pharmaceutically acceptable salt thereof, is used in combination with Compound Al., or a pharmaceutically acceptable salt or hydrate thereof In yet other embodiments, Compound133, 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 134, or a phannaceutically 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 Al, or a pharmaceutically acceptable salt or hydrate thereof, In still another embodiment, Compound 136, 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 .A1., or a pharmaceutically acceptable salt or hydrate thereof. In yet other embodiments, Compound 138, 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 1310, or a pharmaceutically acceptable salt thereof', is used in combination with CompouridA1, 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 [001171 Reference herein to "Compounds Bleat 1", "13.1 to /31.17, or "131 through 1311" is understood to include the full group ofB1, 132133, B4, 135, 136, B7, 138, B9, BIO, and B11. Compouinds fll - 1311 are commercially available or their methods of synthesis are generally known in the art. For instance, tofacitinib may be prepared as described in U.S. Patent No. 6,956,041, filgotinib may be prepared by the methods seen in U.S. Patent No. 8,853,240 and US
2015/0225398AI, I:NCB-039110 (1NCB-39110) may be prepared by the methods SUBSTITUTE SHEET (RULE 26) seen in U$ 20111112662 and U$ 20151 246.046, peficitinib may he propmd as:
described int.1,S. Patent:Nosõ 7,879,844. and R,779,140., and momelotinib may be prepared as: described in U.S. Patent No. 8:,06.,941..
1001181 in one em bodimont, the AK inhibitor is s:elected from the group of mornelotinill (CY10387),õ ruxolitinib, tedratinih, baricitinib, lestatalinib, paeritinibõ XL0.19õ .AZDI480, LY2784544, BMS911543, and 1...-6018, or a pharmaceutically acceptable salt thereof In one embodiment, the AK inhibitor iti scloctod from tiu.,, group of '1610.1348 J$-124, and INCB39 I 10,CHZ8.68, and 05.51K 25 6 I M., or apbannau:.utioally.aceeptable salt thereof. In another variatkIirt, the 1A1( inhibitor is momeintinib, or a pharmaceutically acceptable hydiochlotid.
.Salt tlicriVi. In another variation, the jAK inhibitor is filgotinib, or a phannaceutimily acceptable salt: thereof, ASK I Inhibitors 1001.191 in some vatiatiou$õ the ISM inhibiting compound is a compound of FO.M1Ula I
Fe 1,1:
c.,.
RP 11 -"N, 11 )' 1 V.71 x?
'µ,,, '1,' - (1) / =
.xe kl Wherein:.
R' is seleckõ=.4 frfiin alkyl of 1-10 carbon atoms, Amyl 012-10 carbon atoms,:alkynyl of 240 carbon atoms, cycloalkyl of3-13 carbon atoms,. aryl, hoteroarylc or hetorocyclyl, all of which are optionally :snbiOntectwith I,.
2, or 3 sobstiMents selected from halo, oxo, alkyl, cycloalkyl.õ.hoterocyclyl, aryl, aryloxyõ -NO2. W, -C(0)R6., -0C;(0.)-le, -K(0)-0-1e, -C(0)-N(R.6)(10, -S-r, -S(-0)-teõ
-S(-0)2-W, -wo)2.4400(g.)., 4(-01,...04e, .NR.)(1.0, -.N00-cm-R7, -N(0-C(0)-0-R7, ,N(R6),C(-0)N(R6)(R7), -N.(,)R6)-S(;;O:12-R6, CN,: and --OR;
wherein alkyl, cycloalkyl, heteroeyelyl, phenyl, and phemcy are optionally substituted by .1, 2, or a subs{ iments seiected from alkyl, :cykioalkylõ
alkoxy, hydroxyl, and halo;
SUBSTITUTE SHEET (RULE 26) wherein le and le are independently selected from the group consisting of hydrogen, C-C.alkyt, cycloalkyl, hete.rocyelyl, aryl, and be:term:17A all of Which.
are optionally substituted with 1-3 :substintents selected: from halo, alkyl, mono- or dialtYlamino, alkyl or aryl or heteroaryl amide, -CN, lower alkoxy; -Ch., aryl, and heteroaryl; or R.6 and R' Aen taken together ' with the nitrovn to which they are attached Coml. a.heterocycle;
1(2 is hydrogen, halo, cyano, alkoxy, or alkyl optionally substituted by halo;
1(3 aryl, hetaoaryl, or heterocyclyl, all of which are optionally substituted with one ornioig8ubstituents selected from alkyl of 1-6 carbon atoms, alkoxy oil -6 carbon. atom a, Ofei.Ogkyi of 3,8 carbon atoms, cycloalkyl alkyl, aryl, heteroarylõ heteroarylalkyl, heteroeyelyl, heterocyclylalkyl, halo, oxo, -NO2, haloalkyl, haloalkoxy, -CN, -0c(0)-R6, .o(.(o)-o-R6, Nut.NR7), -S(,:q2-N(R6)(R)., -N(Rdy.cmyR7,.,N(Rc(4))1\(R4)00, ,,N(R.,)(40)-0-R5% -N(R)-(,(=0)N(R.6)(R7)õ ,C(0)R6, ,c(9p-04es, ,c(o)-N(R)(g.7), and -N(R)-S0=:.0)2-R1, wherein the: alkyl, alkoxy.õeyeloalkylõ aryl, heteroaryl, Or heterocyclyl is further optionally subs titu WEI with one ormore SUbstituenv .seit.oted.from halo, oxoõ
haloalkyl., haloalkoxy, -N(1.4)(R), -C(0)R6, ,OC(0YR6, -C(0)-N(R)(R7),. -CN, cycloalkyl, aryl, heteroaryl, and heterocyclyl;
with the proviso that the heteroaryl othetefocyclylmoi(ty. includes at least one ring nitrogen. atom; X, X21, X. X4..X5j V% X% and X8 are independently C(R4) or N in which each R4 is independently hydrogen, hydroxyl, halo, alkyl of 1-6 carbon atoms:, alkoxy of 1-6 carbon atoms, or cycloalkylof3-8 carbon atoms., aryl, haorsywyt, heterocyclyl,. halo, NO2,- haloalkyl, haloalkoxy, -CN, -0-R6, -S-R6, -N(R6)(R7), -8(-)):R6, -S(-0)2-R6, -S())2-N(R6)(R7), -woyo-re, -wittiycwo-R7, -Noo-ce.owooao, 47,(0)-0-R6, -c(O.)-Noexio, wherein the AA, cyeloalkyl, atyt. heteroaryl, and heterocyclyl is further optionally substituted with one: or more sub.stitrients selected from halo, oxo, -NO2, -CF3, -N(R.4)(R7), -C(0).-R6, -C(0)-0,R7, -C(0)-N(R)(R7), -CN, -,C0-e; or SUBSTITUTE SHEET (RULE 26) X5 and X6. or V and X7 are to to provi&
optionany substituted fused aryl or optionally snbstituted -11.tsed heteroaryt. and with the proviso that at least.
one of X2, X. .and X=':` is C(lt4); at least two of X5, X. , X7,. and ).µe are is Coe); and at least one ot X2, X', X4, X. .X6, X7, and XS is. N; .or a pharmaceutically acceptable salt or hydrate thereof, [001201 An embodiment within each of the methods herein in which a compound of Formula.] is used witpriges use of a compound of Formula l, as described a.bove, or a pharmaceutically acceptable: salt or hydrate thereof, wile:win le is selected from the group of:
N-.
' 1 RI-e, k .
IVY
¨ St ' Ril N
1 =
)47-").,=,%1)V, -,,,,,,l, N.,..,./ ,-, , N , . = .,e. == ..-.- /.
gil 4 , .N.,,...i ...t.õ,õ1 ../
..--µ,..
( = =.- - --K --Nil f =ii %
../...Nis, N.,,:- ..ek.. :4 = = ..,..,,N.sss .1.-,,y, õ,..----,,..e.,--,..-=\
. = = ......,:j . I : ..s - :,,,i,/.. 131... N i = =\::,-.-=N r. ?"..s, re.= ,-,,,,,.,. NI,..., L., 1õs-,= z, . =%..... _ .." ..
N'''.4 = ...,,,,- ,,,, ,h. .4,,i----f .0- -si-I, =_,. ,.. :, \,...õ..õ.., nil = 0 = .., 1 N -. , N N.
= ,..,... .r.,,,,, ,.., ,. ..... 4-,..:, , is , ?. 1!
.. I
, Az;:...---=!...,.:04. 'N'''''4'.>-.1= (\, .. ,5 T V. .N.--;,,,õ
'N''''4,,,:==;.N.... It . "r: .....i :6 '1:: ===N',..
#1' 1... 4s Nw-:N. ,-e":11. ,=== .-t ,. .
,,,,,a*.',. == il .-= , 4....= =
::,= :;14.1:7N .= ,,,,,i.
....., ,,..
Ni ..
..-(.., =1 .1 \::,.,..... ,,i Ir. .,...-= 1.:4.4. and :. = . 7 l' ' ..... Nt = L-:-: . = 'V,..:,:z:=': ,/ .
..?=4:-:.:
wherein;
SUBSTITUTE SHEET (RULE 26) WO 2017/(159252 R11 is selected from hydrogen, alkyl of 1-,6 carbon atoms, or cycloalkyl of 3-8 carbon atoms, wherein alkyl and cycloalkyl are optionally substituted by hydroxyl or halo;
RI2 is selected from hydrogen, alkyl of 1-6 carbon atoms, or cycloalkyl of 3-8 carbon atoms, -53(.0)-R6 or, -S(.0)2.-R6, wherein the alkyl and cycloalkyl are optionally substituted by hydroxyl or halo.
[001211 Another embodiment comprises use in the methods herein of a compound of Formula 1, as described above, or a pharmaceutically acceptable salt or hydrate thereof, in which. XI, X2, and X.5 are all N, and X', X4, X6, X7, and X8 are C(R4). This embodiment 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 an optionally substituted heterocyclyl, particularly when the optional substituents are 1, 2, or 3 substituents chosen from hydroxyl, halo, or cycloalkyl of from 3 to 8 carbon atoms. Within the embodiment another embodiment includes compounds in which R3 is optionally substituted an, 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 MR, in which alklyl and cycloalkyl are optionally substituted by hydroxyl or halo. A preferred group of R3 moieties includes those non-limiting examples described above.
[001221 Another embodiment includes use in the methods herein of a compound of Formula in -which XI and X5 are N, and X2, X.3, X4, X5, X6., X7., and X8 are (3(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 substituents chosen from hydroxyl, halo, or cycloalkyl of from 3 to 8 carbon atoms. Within this group, a subgroup includes compounds in which R3 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, SUBSTITUTE SHEET (RULE 26) WO 2017/(159252 heteroaryl, and heterocyclyl moieties contain I, 2, or 3 ring nitrogen atoms, and the aryl, heteroaryl, and heterocyclyl moieties are optionally substituted by alkyl of from l to 6 carbon atoms, cycloalkyl of from 3 to 8 carbon atoms, halo, cyano, or --OR, in which alkyl and cycloalkyl are optionally substituted by hydroxyl or halo.
1001231 Another embodiment provides use in the methods he:rein of a compound of Formula I in which X1 and X2 are N and X3, X4, X. X6, X7, and X8 are C(R4).

This group includes compounds in which RI is optionally substituted alkyl of from I to 6 carbon atoms, optionally substituted cycloalkyl of from 3 to 8 carbon.
atoms, or optionally substituted heterocyclyl, particularly where the optional substituents are I, 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 l to 6 carbon atoms, cycloalkyl of from 3 to 8 carbon atoms, halo, cyano, or ---OR6, in which the alkyl and cycloalkyl are optionally substituted by hydroxyl or halo.
[001241 Another embodiment includes use in the methods herein of a compound of Formula I in which XI is C(R4). This group includes compounds in which is optionally substituted alkyl of from l 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 R3 is optionally substituted heteroaryl or optionally substituted heterocyclyl, wherein the heteroaryl or heterocyclyl moieties contain I, 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.
[001251 The ASICI inhibiting compounds for use in the methods herein include, but are not limited to, those compounds named below, which may be prepared by SUBSTITUTE SHEET (RULE 26) the methods deseribed in U,S. Pat Nos, 8,552,196 and 8,:742,õ126, which are incorporatod herein by tat reritC.
542,5-di flu oropheayi)--N--(3 44-amtb y1-411-y )phenyDnicotinamide;
zl-(imidazo[ I ;2-4 jpyridin -3-y1)-N -(3-(4-methyl-4 ,2õ4-txiaml-3-ylVheny1)-pieutinato id 442-aminopyrimidin-5-AN-N4-cyclopropyialit- 42,4--thiazol3-yi)phenyl)picol n a mi de;
(3(4-me thy1-41- 1,2 ,4 azo I -3-y1 vheny-1)--5-phenyht ieotinamide;
N-:(3-(4-eyolopropy1-4H-1,2õ4-friazol-3-yOphenyl)-4-phenylpicolin.amide;
N- (3,(4,(tetrahydrio- 2 11-pyrah-4 10-4H- 1 ,2 4-triazo1-311)pheny1)-3 bipyridine -earboxamide 2-hydroxy-N*(4-methyl-4II-1.,2õ4-triazoL3,Apherty.1).-6-phenyipyrimidine-4-carboxamide;
N-(344-cyclopmpyl-41-172,4-triazol-311)phenyl)-3,4'-lipyridline-eatrbaxamide;
N-(3.44-eyeloprop y1-411-1 2,4-tria201-3 yi mida yOpimlinamide;
N-(3 44-methyl 111 1õ2,4-tri'azol.--31)phenyl),4-phenyIpicolinamide;
N-(344-(3,amino-3-oxotropy1)-411-1õ2,4-tiazol-311)pheny1)-3,4?-bipyridine-earboxami de;
ti,(344-cyc1opropy1-4I- 1;2,4-ttiazol-3-yi)pherty1)-4-( 1 1 ,2,44riaio1-1-y1)pieolinamik N,;(3444ttedly1,41E1-- 1 ,2,44riazo),3-y1Vhen yl),61henylpi colinamide;
N-(3,(4-P-acettimidoethyt)-411-1.õ2õ4-triazol-311)Oheny1).1,,P-bipyridine, carboxamide;
N 1,2,4-triazol-3 11)p h my1)-4-(4-re o thy i p1perazin- 1 --yl)picolinamide;
N-(3,(4-methyl-414, 1 ,2,4,triaw1 -3.11)photoi),1,3 -hipytidine,6-carboxamide;
N-(3-(4-methyl- 4IT- 1,2,4-triazo1-31 Opheny1)-4-morph opi inam ;
SUBSTITUTE SHEET (RULE 26) ¨42 -N-(3-(4-methyl-1. fl-I ,,2,444-491-3-Apivity1).4040001.113-6-yi Vicolinamide;
(.1Z:)-N-0-(4-( 1-hy dtax. ypropan,.2-y1)-411- 1 ,2A-triazo1-111)pheny0-3,4' pyi e-nearboxami& ;
N-.{3 -(4-eyelopropy1-41-1- 1 ,2944ri az61-314.)phorty1)-6-11ydroXy-3;4'.-bipyridine-T-carboxamide;
-( 3 -(4-m ethy1-411,1,2,41.-tria zel-311)ph carboxamik (S)-N-(3-(4-41.,1ythex. ypropali -2-y1)-41-1-1,2,4-triazol-111)pheny1)-3.,4' -bipyridine,ncarboxamicte;
N-(3-.(4-rnethy1-41-1-1,2,4-triazol-3--yl)phprty1)-4-(3-e,..topjpppz1r1- I..
yl)pichlitiamide;
N.-(3-(4-toothy1-411-1,2,4444z01411)pheny1)-1,4'Aipyridim-2 N,(3-(4-tycl opropyi 411- 1 ,2,4 -t r i a yl)ph erty1)-6-me the -bipyridine.-2'-carboxamide;
4-(3-aminopyrro1 -y1)-N-(3-(4.-rnothy1-4 1 ,2,4-tria zo1-3-Apliertyppirol n ami de ;
N-(3-(4-methyl - H. 1,2,4-triazol-3 -y1)oheny1),2.-pltml sorticotiramik 0-arnirto-N- 4-cyc lop ropy1-41I-1 ,2,4-tria201-3-y1)pherty1)4,4'-bipyridine2'-earbaxarnide;
(R.)-N-(3-(4-(2-hydrox ypropy1)-4II- 1 , 2,44riazo14-yOph eny1)-3,4 rpyridite-2 '-carboxa d e;
5-methoxy-N thy1-411-192.,4-triazol-3-y1)phmy1)-3,4'-hipyridino, r-carboxamide;
methyl 2 -(3,..(4-qek,propyl-4H- I A4-ttiazol,311)phanylearbamoy1)-3,4:'-hipyridiO4-y1eatb3mat%
5-methoxy-N-(3.44,methjii-lii-1.,2,4-triazo1-3-yl)pheny1)-3,4'-bipyri dine-2 -carboxamide;
methyl 2 -(344-eyelopropy1-411-1 -ybphenylca tbarnoy bipyri di h-6-11 carbamate;
SUBSTITUTE SHEET (RULE 26) (SPN-(3,(442-hydroxypropy0-411- 1,2,4 -,:triazol-3-Aphady0-3,4'=-bityyridine-2 '-eafboxatilide;
.4-(1 -methyl - 1 -imi da )-N-(344-mothy1-4H- 1 ;2.;44.6 azo -3, ipheriyOpi ell ami d e;
N(,344-eyel orropy1-4H-1. -Apheny1)-441 -m ethyl- HI
imida2ol-5-y1)picoli nal') ide; =
44111-berizo[d1imithrzo1- I-A-N4.3-,(4-eyelopropy",..4 - 1 , az 01-3 Aphen34 ol inamide;
N-(3(4-erlopropy1-4 H- 1 ,2,4-triazo1-311)ph eny1)-4-(Z4-di m=ethoxypyrimidiN-5-Apieolinamide;
N.(3-(4.((1 -11 yd to xycy dopropyl)methy1)-4H-1 ,2 --3/1)p hen yl 334' --bipyridirinearboxamide;
1H.
iinidazol-1-y1)pieolinamicle;
0-cyclopropy1-N-(344.-eyeloprop y1-4 H-1 ,2,4-triazol-3.11).pheny.473 bipyridine-T -earboxamide;
($)-N-(34442-bydrox=mopy.4)-4H-1,2,4-trianil-3-ylvhenyl)-3,4'-hipyidine-,2='-earboxamido;
N-(3-(4-eyelobuty1-41I-1,2,4-thazo1,311)pheny1)--3,4' ipyri carboxamik 1N2 '4344-eyel ()prop yl H -bipy 4.earboxamide;
($)N41344-(1 ,1 J 4itirPropropall-2-y1)-41-1-1,20-triazoir3-y1)phertyl).-3,4'=-bipridine-2='-earbomunide N--(3-(4-cyclopenty1-4H-1.,2,4-0640/-41)pbmil.)-3,4'-bipyridirie-2%
carbox amide;
N-4.3-(4-cyclopropyl-41:1-1 ,2,4-triazol-3-yltheny1)-6-(trilluorometity1)-3,4'-bipyriditie,2 ' -darbox amide;
N2' --(344-eyoloptopy1,411.1 ,2,44riazol-3 -y1 )phony4-3,4 bipyridine-2' ditaiboxamide;
N-(344-cycl opropy1-4H-.1,2,4-triazok,311)ph enyl.)-4,-(2,methyi- H. -Mi.-Max:A-1 -yi)plooli ami de;
SUBSTITUTE SHEET (RULE 26) N43-0-eyel optop y1-411- FA4-niazol,31f)phettyl)-6-mehyl-3 '-hipyridine-T-Carboxamide;
5-eyano-N4344,,cyclopropy1-4II- ,2A-triazol-3-Apheny1)-3,4'-bipyridMe-2'-earboxamide;
N4344-eyelopropy1-4!:!- ,2,4-tria zol,-311)phetyl )4444nethy1 -IP -imidaze1-1 -Apieo n am id e;
N -(644-eyc I op opy1-411- 1.,2/14ri a zo1,311)pyridi n-211)-3 -hipyri dine-2 '-carboxamik 2-amino-N-(344-cyclopwpyl-4II- 1)phmy1)-3,4' bipyri dine-2'-earbox am ide;
44-cycloprop34-4 H.- I ,2,4- tri,azell-y0pbeny1).-4-(4,5-ditn$hyl- 1 FT
in) -ylVieolinamitie;
.N4344-((1 S.,28)-2-methyloyclopropy0-41-1-I 2 ,4 -Triazot-3-yflpheny1)-1,4)-bipyridino,2'-carbox amide;
N43(4-cyclopropy1-41- I,2,4-Triazol-3-yl)pbetly1)-Z-rnetili)o-3,4'-bipridine-T-cattoxamide;
N4344-cyclopropy1-4II- ny1)-444-ari neremothyl)-H 1 .0 a ide ;
N-0-(4-oyeloprop y1-41-1- ,2,4-triozol..311)phoy1)-64 2,2,2-0 orne thoxy )-3,4' -hipyridine-2'-earboxami de;
N4344,cyc1 opKopy1-41-1- azo1,311)pherty1)-44 1 -methyl- 1 pyro zoi -Apicol in am i de;
N 43(4,eyeloprop y1-414- 1 ,2,4-triazol-311)phetly1)-442-victiioxypOmidin-5-y1)pico1inamide;
N-(344-eyelopropy1,4414,.2,4-trinol-311.)phenyl),21-methyl-3,4'-bipyridine-2"-Carboxamide;
N(344-tyelopropy1-4 I.,2,4-triazo1-3 -yl)pheny1)-44imichtzo [ 1,2-pyridit011)picolinami de;
:ethyl -N 43 44-methy1-41-t- Iidino,r2'-carboxamide;
N-(3 (4(2,2 a-tri fluoreethyl)-4H- I 224-triazo1-1:11)photkyl)-3,4'-hipyricline-2.' -.earbosmnide;
SUBSTITUTE SHEET (RULE 26) - 45 -6--chloro-[3,2',5' 'Wiwi dift-2",carboxylic acid[3,(4 -cyc1optopyl-4i1-{1,2,4jtriazol -3-y1).-pbg nyl] amide N-(3-(4-cyclopropy1-411-1,2,44riaza3-0)phenyl)-6-(pyrro1idia-1-3/1)-3,40-bipyTidine-2'.-Carboxamide;
N-(3-(4-pyclopropy1-4II, ,2,44riv,01-311)plicrly1)-5-(tri u mom t hyt -oat boxamide;
N-(3-(1-cyclopropyi-111 siraidazol-5-y1)01-ieny1)-3,4%-hipyridine-r-carboxami de;
N -(3-(4-cyck$propy1-411-1,2,4-triazot-311)pheny1)-4-(1,2-dimahyl- 1 I
imidazol-5-Dp icolinalyti4;
4-(114 -benzti[ di [1 ,2,3]tria2041)--N43,(4-cyclopropy1-41-1-1,2,4-triazol-3-yi)pheny1) picolinitruldq:
N-(344-cyc1opropy1-411-1,2,44riazo1-3-ylvlienyl)-4-(4-gui filmy 'phony )picolinamide:,;
N-(344-;.eyelqprop31.-4F1- ,2,44iipm17-3 --Apileuy1)-5-methoxy-3,4'-bipytidine-2'-catboxamide;
N-(3-(4-cyclopropy1-4.11- :,2,44.riamI-3 )pheny1)4-fitioto-5-oitivy1-3,4'-bipridine-2'-earboxamide;
1. )-5- flu ora-3,4' b 6:10 din'-carboxam idtt;
N-(344,cycJ op rop y1-4f ,2,4-qiitzel--311)pheny1)--2-methyl--.3,4,'-bipyridirte-2'-Carbotamide;
N-(3-(4-cyclopropy1411-1,2,4-triaM-3-yl)pheuyi ).-4-(4,5,674e trahyttro-111 -benczol djimidazol-111)pioolitanide;
N-(344-cyclopropyl-41-I-1,2,4-triazal-3,11)pheny I )-4-(4-(Nmethy1aulfamoy1)pheny1) pi calla-nu*
N5-tert-butyl-N2'.(3(4.--eyeioptopy1411-1,2.,44riazo1-341)pheny1.),34-bipyridine-2',5-dicatbi ?viol ide;
N-(3-(4-cyclopropy1-41:1-1,2,4-triazol-3:11)phouyi)-4-Tywin,2, yppicolitimidc;
iM-41-I-1 ,2,4-triazol-311)pli eny1)-4-(4-(NiwpropybuMmoy1) phenylVicolinataide:
SUBSTITUTE SHEET (RULE 26) =46 -0110roN,(3-(4-eydepropyi ,2A-tri awl-111)0 eny1),- -bipyridine-22-carboxa rni de;
4-(111-benzo[ dijimidazob- 1 --y1) -N-(3-(1 -cyclopropyl- 1 1-1-inndazol-5-y1)phtlnyl)pi e 0 i na mid%
6-eyeloprop+N---(644-cyclopropy1411- 1,2,4-triazol-311)pyridi p-2-y1)-3 ,4' -bipyridine-2 '-oarbommide;
N-(3 -(4-oyk:I opyi-,41f-12,44riaz01-3,y9phenyl)-4-(3-(Inethylsulfonyl)pilerky-Opi Go Imamidc;
-oyclopropy1-41I- 1 ,2 ,4-trizzo1-3-yOphen y1)-4-(isog u yi)pi colinamide N-(6-(4-eyelopropyk 1-1- 1 ,Z4-triazol-3-yOpyti aini-2-0)-4 (rnethylsulknyl)phenyl)picoli Milli de;
.N-(344-eyelopropy1-411.- 1,2,44riaZol-3.11)pheny1)-4-(2-(rnothylmlAny1)phenyl vied hum Me;
1443-(4-eyelopropyl-41-1-1.24-biazoi-3-yppheny1)-4-(1,5-ditndily1-I 1-1 pyrazo1-4-y1 )pico i n amide;
6-cyc1obuty144-(3-(4-cycklipropy1-4H-132,4-1riazol,311)pheny1),3,4'-bipyridine-2-carboximide;
N-(.3-(4-eyeloprop y1-41-1- 1,2,4-triazoP )pbeny1)-64sopropy1,3,4?
ip yridine.-.2cattaxamidq N-(344-eyelnpropyl-514- ,2,4-triazol-3..yl)pliony1).4-(4-(methylsulfony1)phenyl)pico1inainide;
N-(3 -(4-eyel opropy1-4.1- 1 52,4-1-xiazol-3-y1 iphony1)-6-( dimethylamino)-3,4'w bipyridine-2' -earbox amide;
N-(344-eyc1opavyt-4F1,1,2/1-411 02 1,311)0 enyI)-4,-(pytan-3-yi)quitiolinecarbexamik N-a-(4--f;yelopropyl-4H,1: 2,4-triazol-3 -3(1)pheny1)-4411-1pyrrolo [2,3-hipyridin-511)pi inamide;
6-cyclopropoxy-N-(3-(4-eyclopmpykii 1,2,41-tri /A )1-3,11)phenyi)-3,4' bipyridine-T .,.earboxami de;
N-(3 -(4-eyeliopropyl-4II- 1,2,44rkrzo1-3-yi)Ohenyl)-44 11-1-imida zo [
olimarnide;
SUBSTITUTE SHEET (RULE 26) N43-(4-cycloptopy1-4I1-1,2,4-triazo1-3-yOphenyly-6,fiuoroa,4' --carboxamide;
N-(3 -(4-cyel opropyI-4 El- ,2,4-tri a zoi.-3,11)pheny1)-4 - (442-oxoimidazol idin- 1 -yi )phenApicolinami de;
1-(344-eyc1opropyl.4.14,2,44Vdazo1-311)ptieny1Y4-(M1ni91a1o[4, 5-1 flpyrid1m-3-0i colin amide;
N-(3-(4,cycloprop y1-4H- /1- tri a zot-3-yivb.010).-6-iwpropoxy-3,4' b ipy ri --carbox amide;
"N -(3-(4-cyel oprop y1-21H- I 2,4-triazoi-311)pheriA)-6-ethyi-3 2'-earboxami de;
N4.344-eyc1opropy1-41-1,1,2,44iazok3 -yltthenyl )-44 11-imidazo [4,5-c] pyridin- -Apicoliomide;
6-cyclabutoxy-N-(3-(4.cyclopropyl-4H-1,2,4-triazotall)pheny1)-3,4'-bipyridine-2'-earboxamide;
(i-cyclopmpyl -N-Cl1 -cyreloprop -imidazol-5--y1)pheny1),3,4'-bipyridine,2',0al bilxamide;
N-(3-(4-cyc1opropyl-41:1 - 1 )phony1)-44 Onolin-3 yOpicolinamide;
N-(3-(4-cycl oprop y1-4 ,2,4-triazol-311)pheny1)-4-(4-(Nyclopropylgtfamoy1) pheny Dpicolina mide;
N--(141 QycIoprtpy I1-1-imi d :.01-5-3,1 )phonyl )-4-(qui vicotin am id 6--cyclopentyl-N-(3-(4-eyelopropyl,4114 ,2,44Tiazol-3,Aphenyty3,4'-:bipridine-2!-carboxamide;
N-(3-(4-tyeiopropy1-4H-1 ,2,4-tiazol-311)phen y1)-4,-(imidam [2, I -1)1 [
,3,41thi adia261-511)pi o I inamide;
N-(3 44-cyolopro p y1-411 - 02 014311 )plietly1)-4-(5 cyclopropy1pyrazin-2-Apico1inamide;
N-(3-(4-cydepro1 -41-t- ,2,4-triazol÷3-y1)phenyi)-6.--(1-methyl.-2, nopynolidin-311)-3,4' -bipyridine-T-Carboxami de;
SUBSTITUTE SHEET (RULE 26) - I H =nnidazol- 1 -y1)-N43-(4-gclopropy1-4H-1,2,4-4.10101-3 yl)phenyl)picolin anti de;
6-cyclopropyl-N-(3,(4-cyclopropyl-411-1,2,4-tri azol-311)phetly1)-5-fluoro-d -oath ox a in ide;
(S)-4-(4-uclopropy1,1H.- dazol- 1 -3/11),N-C3-(4-(3-- m ethylbutan-2 -y1)-4H -32,4-tria.m1-3 -y1 )plionyi )picolinamide;
6--cyclepropyl-N-(3-(4-cycl opropyi -µ1T-1- 1,2 ,4-(ria zoI-3 -yi )phenyi )-.2,3 1 hipyridine-6-eatboxarn i de ;
(i-ivdopropyl-N-( 3 -(4-Qyclopropyl-4H- 1 ,2,44riarm1-3,Ap1ieny1)-2,3 1 -hoxamide N 4644-eydopropy1-411- 1 õ2,4-triazol-3-y1 )pyri -(6-golopropylpytidiml-y1)÷2 A-d aorthenzami de ;
6-cyclopropy1-N-(6-(4-cyclopropy1 -4.H - 1,294-triazol-3 -yl)p yiidin-2-y 1 2,31 -hipyridine--4-carboxamide,;
6.-cyclopropyl-N-(644-cyclopropyl-4 FL- 1 ,244riazol-3-Apyri din-2,14)-3,3 1 -bipyritfinp.-5-carimamide;
0-cyclopropyl-N-05-(4-wc opropy1-4H-1,2,4-triazol-.3-yppyridin-2--y1 )-2,3 1 -b dino--(),carboxamidct;
N-(3-(4-cyclopropy1-411-1õ2,4-triazol-311)phopy1)-4-(5-metliy1.-4-(ix( f1uoromethy0-4,5,6, 7 -tetrahydro-iff -imidazo1455-c j pyri din- 1 Apirolinanii de;
(4-cyclopropy1-4H- 1 ,24-tiazal -Apyri di n-211)-4-(5-methy1-4-(trifittoromethyl)-4,5,6, 7 4,0111ydro-1111 -imidazof 4,5-c lpyridin- 1 -yl)pioolimmide;
4-( 5-wiopropy14-,methyi -411-- 1 ,2 ,4-triazol-311)-N43-(4 -oyeklip ropy: 1.4 Fl - ,2,4--triazol-3-yOphenyOpicoliirkarnide;
443 -eyel opropy1-1 ,2,4-axadiam1,5-0)-N-(344-Qyclopropy1-4H-tri azo1-3 -ypplIon34)pi oli na m de;
N,(3-(4-cyc lo propy1-45- 1,2,444mo:1-3 m e th yl-- 1 ,2,4-madiazo1-5-y1)picolinarnide;
6.-tyc lopropyl-N(3..(4..(3 -11 ydrox ybutan-2-y1)-4H- 1 2,44riazol-3 -yi)pheny1)-3,4' bipyri di ne-2' -carboxami da;
SUBSTITUTE SHEET (RULE 26) 4.thloto-N-(6-(4-cycloptopyl-4H- 1 24, tiazt1,3 -yl)py ri 1 ),5 cyclopropy ipyridin-3-y 1)-2-flu oro benzamide;
6-cyclopropy 1 -N--(6-(4( ps,3 R )-3-hydroxybutan-2-y 1)-4 114,2,4-triazol- 341)pyrIdin-2 y )- 3,4' -hipytidine-T -carboxamide;
6-cyclQpropy 1:-N,(644-( (2$,.3 $)-3-hydroxybutan-24 1 )-4 114,2,4-thazol ri --hipytidine-T-catboxam i de;
6-cycloprop 1 -(pyrrolidin-.1 -Apropa,o,-2-11)-4 1,2,44.0 yl)p yridia-211)-3 -carboxarnide;
N-(3 -cyclopropy1411- 1 :2,4-thazol411)pheny1)-4-(1 -(232,2=
-tri 11 u ormittyl).- UT-pp 01 015 ,24) Ipyridin-6-y1 N-(3(4-CyClOprOpyi,4H,1 ,2,44fiazo1,3 -;y1)phen y1)-44i sop ro p 1 pyrrolo [
S)-6-cyclopropyl-N--(3-(4-(3,3-dimethylbutan.2-34)-4H- 1 2 ,4-triazo1-3 yppix-my0-3,4"-bipyridine-2 -carboxamide;
6-cydopropyl --N-(44-( --methylpiperidip-i-1-0)-4H-- i.2,44riazoi3, yl)p pyridihne-2 -carbox amide;
N-(3 -(4-sec-buty1-4H- 1:;2.,4-ttiazol-a-yl)phQny1)-6-cyciop; opyl -bipyri dine-2' -cathoxamide;
( S)-6-rytlapropyl-N-(3 -(44 -cyolopropylethy1)-4 1:22944iazo1-3 )plieny1)-3,4bipyridinp-2' -carbox amide;
6,cyclopropyl-N4344-(pentan-3-34)-411-1,2,44riazol-311.)phonyl)-3,41'-bip,?ri d ine-2 -Øalbaarnide;.
(S),6-cyclopropyl-N-(3-(44I -me thoxypropan-2,10-411- 1 ,2,441.10 7,01-3 eny1)-3,4 ' -hi pyridine-2'-carboxamide;
6--cyclopropy1-N-(6-(4-eyclopropyl-431-1õ2,4-triazol-311)pridin-211)-W-ITOily1-3,4'-hipytidine-2' -caebommide;
($)-6-cyclopropyl-N-(6444 -rnetboxYpropw-211)411-1,2,4-triazol-3-rbournide;
(S)-N-{3 -(4-sec-butyi-411 -- ,2,4-triazol-3-Aphenyl) -6 ,cyclopropy1,:3:54' -bipyridinp-2'-Catboxamide;
NI-(6-(4-cyclopropy1 4I 1 ,2,44riazo1-311)pyridin72-y1)-3 4442,2 fluoro- 1 =-methoxyethyl -imidazol- 1 -Abenzaraide;
SUBSTITUTE SHEET (RULE 26) WO 2017/(159252 N-(6-(4-cyclopropy1-4I-1-1,2,44riazol-3-34)pyridia-2-y1)-4-(6-cyclopropylpyridin-311)-7 ,8-dimethyl quinoline-2-carboxamide;
(S )-6-cyclopropyl-N-(3-(4-(3-metbyl buta 11-2-y1)-411-1 ,2,4-triam1-3-yl)pheny1)-3,4'-bipyridine-2'-carboxamide;
(R)=4cyclopropyl-N43-(4-(1 -(2,6-dimethylphenoxy )propan-2-y1)-411-1.,2,4-triazo1-3-y1)pheny1)-3,4'-bipy-ridine-2'-carboxamide;
N-(3-(4-cyclopropy1-41I- 1 ,2,4-triazo1-3-Apheny1)-446-cyclopropylpyridin-3-y1)-7,8-dimettylquinoline-2-carboxamide;
3-(4-cyclopropyi 1 1f-imidazol-1 -y1)-N-(6-(4-eycl opropy1-41i- 1,2,446 azol-3-y1)pyri din-2-y1)-4-metboxybenzamide;
4-ehloro-3 -(4-cyclopropyl- 1 EL-imidazol - 1 11)-N-(6-(4-cyclopropy1-4H-1,2,44riazo1-3-Apyridin-2-Abenzamide;
4-(4.-cyclopropy1-1H -imidazo1-1-y1)-N-(6-(4-oyc1opropyl tri azol-3 -y1.)pyridin-2-yl)quinoline-2-carboxami de; -N-(6-(4-cyclopropy1-4H-1.2,4-triazol-3-yl)pridin-2-y1)-4-(6-cyclopropylpyridin-3-y1)quinoline-2-carboxamide;
N-(6-(4-cyclopropy1-411- 1 ,2,4-triazol-3-Apyridin-2-y1)-5-(6-cyclopropylpyridin-3-y1)-2-fluorobenzamide;
(S)-6-oyc1opropyl-N -(3 444 1, 1, 1 -tri iltioropropan-2-y1)-4H-Apheny0-3,4'-bipyridine-22-carbox amide;
(S )-tert -butyl 2-(3-(3-(6-cyclopropy1-3,4'-bipyridine-2'-earboxamido)phenyl)-4H-1,2,4-tritazol-4-y1)propanoate;
N-(3-(4-cyclobuty1-414-1,2,4-triazol-3-yl)pbeny1)-6-cyclopropyl-3,4'-bipyridine-2'-carboxamide;
(S)-6-cy.T1 opropyl-N 434441 -pheny1etity1),411-1,2,4-triazo1-3-yl)phenyl) 3,4'-bipyridine-2'-carboxamide;
6-cyclopr.opyl-N-(3-(4-isopropyi-41-1;2,4-triazol-3-yOpheny1)-3,4' bipyri dine-2' -carboxamide;
3-(4-cyclopropyl- 1 II4midazo1-1 -y1)-N-(6-(4-isopropy1-4H-1,2,4-triazol-3-Apyridin-2 -y1.)benzami de;
N-(6-(4-cyclopropy1-4H-1 trill uoro-1. -hydroxyethyl)- 111 -imidazol-1 -y1)pi colinam ide;
SUBSTITUTE SHEET (RULE 26) (S)-3-(4-cyclopropy dazobl. -3,1),N,(644-(1Thenykethyl.)-411-1õ2,4-triazo1-3i1)pyridim-2-ylpenzamide;
N-(3-(4-tyclopropy1-41T- 1,2,4-triazol-3-Aphonyl )-4-(442,2,,24 r fl u hydroxye thyD- H-imidazol- -ylvicoi n am i de;
N46-(1-pyelopropyi- 1 II -imidazol 411)pylid 2 -y1 )-4-(4,5-dimethyl- I
i1flida,O1 1 -y1 )pi colin amide;
N-(6-(4.-cyclopropy -411 1,2,4,triazol-3-ybpyridin-211)-3-(442,2,2-triftuoro-1-11ydroxyethyl)- i midazol -111)benzamide;
N(6(1-cyciopropyl- 111 din-211)-642- benzamide;
hydroxypropari,241)414'-bipyridirlo-2' -orttoNarn i de;
3-(4-cyci opropyl - 1 -imidazo1-1 ,y1),N46-(4-0y0 opy r )-5 -methy ibenzamik N-(6-(4-eyelopropyi-41- ,2,4-triazol-3-Apyridin-211)-3-0,5 I rnkIazo1 1-y1penzamide;
N-(3-(4-(0yel opro pyrim I) -L111-1õ2,4- ( r if, 1-11-3,1)p1en y1)-3.34' -bipyridi n Orboxamide;
4-(44:yelopropyl-2-4nothyt-lll-imidazo1-111)-N-(3-(44yc1opropy1-4H-1;44-triazoI-3-y1)pherlyi)picolinamideq 4-(4-oyci opropy1-2 -me thy I -111-inlida Z01- 1 --y1)-N4644-cyclopropy1 -411-1,2,4,trizol-311)pyridio-21.1)picolinamide;
444-cyclopropy - I= i-imidazol,111),N43-(4-isoprepyl-411-L2,4-triazol-3-y1.)phenyOpicolinamide;
4-(4-oyel opropyl-.,Iiint da zol-111)-N-(3.-(4-( .eyolopropylinerhyl )411, 1,2,4-triazoi-311.)phenyl)pieolinaraide;
4-(4-pyclopropy1-14midazot- 1 - y1).-N-N4-(1 -pheny1ethy1)-4 1.A4-tiazoll-311)phonytticolinamide;
N-(44-cydompyl-4fr-12,4-tria01-1-Y1)pyridin-2.11)-4-(4.,5,0,7-irtrahydro-..1IPbenzot c ()barn itie N-(6-(4-cyc1opropyl lT 1,2,4-triazol-3-yi)pyTidit- 211 (tau oromiethyI)- 1 fi -imidazol- 1 11)picolinamide;
N,-(6,(44,yelopropy1-4II 2,4-triazo1-3-yi tetra hydro- 1.4erizof imi dazol -1.11)bmizamide;
SUBSTITUTE SHEET (RULE 26) 1-(3-(644-cyclopropy1-4-if yl carbam oyi whony1)-5,methyl- 1 il-imidazo104-tarboxy1icacid;
(S).-3(4-.ydoptopyl -1H-imidazol-1 )4)--N-0-(44 1 -pi lenylethyl 411 1 a tri azol-3,11)pyridirt--2-yOlvazatnide;
6-cycloprcpyl-N-(6--(4-cyQlopropyl-4114-4,2,44riazol-,311)pytidin-211)--5'-niethy1--3,4'-hipyridit'-carboxamide;
(S)--34 4,5 -dirnothyl-W-itili da v)1,1 11).--N4 6,04 Arifluoropropan-2-y1)-4H-1,2,4-triazol-3.11)pyridio--2-y1)batzamid N-(.3(4--gy(..,,topropy1-4H- 1 ,2,4-triand-3 Vheny1)-4-(2.-ethylpyrim i yl)picol na mik (R)-444--cyc1opropyl4Wirnidazo1-1.10,*(3 -(441, 1, 1 OfQp1 van-.-1-y1H11-1,2,4-triazo1-3-11)phen,y1)picOlinotnide N-(344 -cyciinppyi-441, õ2,4--triam jpheny1)-5-ethyl--3,4' - bipyr i dine-23-mboxm 8--eyelopropyl-N oyelopropyl 411-i ,2,4--triazol--3-11)--441 Wropho --Carboxamide;
Ni--(3(4-zyclopropy1-41I-1 ,2,4-triazol-3-Apilenyiy-C(1,5-tapi II
yJ)picolinamide;
N46-(4-cy0opro py1-411- ,24 41-iszol 11)pyridip-2,.y1),3--(1,5,, naphtivridin-3 -yl)benza nide;
3-(4-cycloptopyl- 1 H- i awl-- 1--y1).-N-(644-0 y clopropyi-41- 1,2,4-tri azol-311)pyridit,2.-Aber Izam idc ;
N--(3(4,cyc1opropy1 -4f1-1.3234.--triazo1-311)-4-finorophtliy0-0-ethy 11-3,4'-bilpridin cabman ide;
64r1.-butyl-N-(3-(4-eyelopropy1-414,1,2,4--ttiazol,34Dplit-myt)314 bipyri dine-2'-carbax amide;
N-(6-(4,ypioloopytAff- ,2,44riani-3-Apyridin-2-34)-3-(quinoiin-3-Aberizamide;
N-(6-(4-c)'clopropy1-41-1,2,4-triazol-310pyrinlin-241) (44p)propyl-I H
N-(6-(4-cyc1opropy1-4H-1,2,44tiaz01-3-Appidia--2,11)-346-cyclop ropylmiciin -3 - y40enzainide;
SUBSTITUTE SHEET (RULE 26) -6-cyc1 opropyl-N-(2(4-cylopropyl-4 I I- I ,2,4-triazot,3-y1) 344 -cyclopropyl- 1 midazol- I-yI)-N-(6-(4 -cyclopropyi- pyrittin-4-y1).
3 prddin e-2 ,carbox amide;
4 11- 1.,2,44riaml-311)pyri dia-2-yI y2-methylbenzamide;
14-(614-f:.µ,yclopropyl-41 102,4-triazot-1-70)pyri din-2-34)-444-(trifluarom oth y1)-4,5,6,74c rahydro- I H Ili dam [4.,5-elpy in- I --yl)picol in amide;
N -(3(4-cyclopropyl-411- 1 2,44rivo1-3-y1)phenyl (trifluoromethy0-4,5,6, 7 -tetrahydp +- H Wow [4 5,01pyri 441-1 -yOpiciAinattlide;
544-owlopropyl-I H-imidazokl -y1)-N-(6-(4-cyclopropyl-4 II 1 16a201-311)pyridin.a-y 1),2-1fiethylbeill;itir:idt;
N-(3.,.(4-cyc1opropyl-4H- .1õ7,4-0jazol-311)pheriy1)-444(perfluorciethyl)-1H-imidazol-1.-11 )0M:it-amide;
N-(6-(4-cydopropy1-4H- 1,2,44ri azo1-3,Apyri d 2-0.)-4- (4-(pul1 u yI)- 114 -Pp i da zol- 1 -Agicolinamide;
3-(4-cycl ro py IH-imidazol-110-N-(6-(4-cyc1opropyl-4I1-1 3.-Apyridth - 2-y1 )-4--meetyi Nnzamide;
4(3-.cyclopropyl- I IT ,2,4-triazol -1,:y1)-N-(6-(4-cyclopropyl-4tH,2,4-triazo1141)pyridin-211)picolitiarnide;.
4-(3,cycl opmpyl- I H-1õ2,44riazo1-1 -(.47cyciopropy1-4H- 1 frivol-311)0 enyi Vico] imam" de;
4-(5-0yolopropyl- 111-1 ,2õ4=4riazol- I -y1)-N-(37(4-cyclopropyi -4 - 2 tfiazol-3-y1)piamyppico1inamiole;
.N,(6-(4--eyelopropyl-4-H , I: ,2õ4-triazoll -,y0pyri d 0-(2-hydtoxypnvan-2-11)pyridin,3-y1)benzamidc;
3,(4,0ye opropyl- I il-imidazol-1-11)-N-(6-(4.-cyclopropy1-4 E -I ,2,4-triozol-3-y1)pyridin-21 oro. benzamik N,(244- cyclopiwy1-4H- 12,4-triazol,311)pyridin-4-y1)-4-( quinol -3-10pi co lina de.;
45 N-(3 -(4-cyclopropyl-41-1- 1,2,4-triazol-3-yOphmy1)-4-0 7, 8.4.etra hydro- I. kolpirthyridin-3-Apicolinaini de ;
SUBSTITUTE SHEET (RULE 26) 6-cplopropyt,N,(3-(kyWompyi-4H-1.,2,4-triazol-3-y072-11.uoroplimy1).-3 ,4) yri dine-r-carbox amidt;
5-oiclopropyl -(4-eyoloptupy1-4H-1,2,4-tria zol -3.11)pliony1)-3,4' b ipyri d in o-2' -carboxami de ;
N-(3-(4-eyel op rop y1-411- I ,2,4-triazO1-311)-2.-flor oplieny1)-3,4'-lipyTidine-29-emtoxitro ick;
ti,(344,0ydor ropy1-411, r iazol-311)phrzyl )-4-(4-ethyl 1 idazoi - I -ylipicolinamide;
N-(6-(4q3yclopropyt-4II- 2,4-triazol -3 -Apyri d ti-241),4-(4-m ethyl- I 11 -imidazol4-ylVicolinardide;
N-(6-(4-cyclopropy1 -411- 1,2,4-tri -y1)pyridin-2-y1)-4 -(4 dirt] 0134.
I 1- imid 111)piceJ Mao ido=.;
N.-.(344-4;y0Qpropyl-411:- 144iazol-3,y0pheny1)-44(-(23291, trifitovetby4-5,6, 7 A-tct ra hydro- I knaphihyriditi-311)picol n a lid de;
N-(1(4-cyclopropyl-41-1-1 ,2,44ri aZ01-311)pheny1).- mop:0 lh inn I -yl)picolin amide ;
N-(344-eyclopropyl-4H= I,2,4,triazol -3 - )phetly1),6(2,hydrelypropati-2-y1)-31,4'-limidine-2Carbox traide;
N-(6-(4-cyc p rop -41-1- 1 ,2,4,triazol,3-Apyridin-2,11)-6, (2-hydroxypropau-210,-3,4'-bipyridine-T -Carboxami de ;
N-044-eycl opropy1-411- 1,2,4-tOszole-3,-yOpyticlitOil (4-isdpropy -imidazO1-1-Apicanamide;
6-eyeloprop yl-N-(344-oyelopropy I-4117 I. ,4-triazol-311).-541uo rop heny 1)4;4' -bipyridipe-2 ' -orboxami de;
........ apropy1,41.1- 1 ,2,44riazol,-3,11)-5 uorop h erty1)-3õ4' bipyri dine:-T-Catboxatl lick;
4,(47q0I0propy1- 1H-imidazoi-111)-N46-(4-cyc1opropyl-411- 1;2 ,4-tliazol, 311)pyriditi,2111)pi coli o amide=;:
N-(3-(4-cyclopropyl-4H- ,2,44 ri a zo1,3-yl)p uoroethyi) 3,4'4,py ridine-2 -catbox mg de ;
N 44-cyc1o1ro1y1-4H- 1,2,44607,014-0)phenyl)-4-(04sopropyl-5A 7 tOnthydro4 hyri eolina i de;
SUBSTITUTE SHEET (RULE 26) ¨55 N-(3-0-cycloprop y1-41:1- 1 ,20-tritizol-3-yOphertyl)-4-(6,-methyl,5,6:,7,8, t rah yak).- lfii-loplithy.4din-3,,y1)pi coin) a mide N (3 44-eyelopropyl,4144,2,44tiazol,3-Aphenyl)-443-hydrox ypiperidin-linamide;
N-(6-(4-0yelopropyl-4H-1,20-tri azot-311)p yr i d hydtoxypiper idi N I Vic olinamide;
6-scyclopropyi-N-(6,(4,i5opropyl-4H- I,2,4-triazol-3-yl)pridin-2-yD-3.0'-bipyridine2'-carboxamide.;
N43-(4-cyclopropyl-C-1,1,20-biazol-3-yi)pheoy0-444-ethy I -3-oxopiperaziN - -Apieolin amide;
N-(0-(4k1Pelopropyl-41I-1.,20-triazol-311)pyridin.2.11)-4,(4,ethyl-3-, oxopiperaziN,11 1 vicojimnide;
(R)-6-cyc1opropyIN-(6*(1, I. 14d u oropropaa-2.11)-41'14.,2,4-tiazol-3 -Apyridin-2-y1.Y3 -bipyridine-2'-catboxantidp.;
N-(3-(44sopropyl -41I- ,2,4-triazot,:3--yOphonyI)-3:0' -bipyrid carboxamide;
6-eyel p:Aityl:-N-(3-(4-geloprppylAft-1.,20-triazol-311,)p h yI)-3 hipyriditie-2'=box i de;
N-(3 -(4-cydoptopyl-4 HP I,,2,4-tria zol-311)pbenyl )-6-( -methyl-2-oxopyrrolidin-3i1)-30' -bipyridine-T -Carbox a de.;
Is(6-(4-cyelopropyl-411-1,20-triazol-311)pyridin,241)-4-(4-(N4methyl adfamoyOphenyDpipolinamide;.
N-(6-(4.-eyc1opropyl-414- 1,20-triazol-3-y)py ri din,2-0)-4-(quino lin-3 Apicolinami&;
N-(644-cyclopcapy1-4ti- 1420-triazol4yDpytidifrly1)-4-(4-pbenyi - I
midazol- )p namide., N(.344-g1opropy1-414-1,204riazol-311)01my1)--6,propyllfi -bipyridirte,2'.-Carbox.n.1 i de ;
-(4-eyclopropyl-4$4,20-trigad-311Viteny1)-6,neoperityl-3 bi pyridine-2' ,4:_arboxamide;
N-(3-(4-cyclopropyl-41i- 1,20-tri azol,314)phenyi }-4.4 ettiy1,2 p henyl-1 171-i midazol-5-yOpieolinamide;
SUBSTITUTE SHEET (RULE 26) N.(44-0yClOprOpy1-4B-1,2A-triaz61-3-34)pheny,1)-444-( ethyl sulfanyl)pheny 1 )-picolitarnide;
N -(3,(4-eyclopropy1-4 H- ,244,,triozol-3.-yi)phenyi )-41-(4-(isopropylgultbnyl)pbehyl)picolinam ide;
N-(3-(4-eyolopropyl 411- 42,4-triazol -yl)pheny1)-6-( thylarthrio)-3,4' -hip yri d ine-2 ' -eat hum:nide;
N-(3-(4-eyelopropy1-41-f- 1 ,2,44ri a zoI-3-yl)phenyl),64 eye] opfopyi amino)-30'-hipyridine-2'-carboxamide;
N-(3-0-eyelopropyl- 411, 1,2,4-triazol,3 -Aphenyl )-4-( imi da zo [2 , 1 [I
11)pic lin a roide;
I (A 0-1H -lin id no1-1 11)-N- (3 (4-cyclopropyl -41-1,2,4-tritizok-3-yOpiteny1)piadiriamide;
INV-(4-eyc1opropy1-411-1,2õ4-tiazol-3-0)phaoy1)-4,-(2.
oydopropylpoitnidin-510picolinamide.;
N-(3.-(4-eyeltv rop y1-4H- 1,2 4 -ftiazo.1-3 -yi)ph eny1)-&(rorome y 1 )-3.4'-bipyridinc-2 -earb amide;
N-(3--(4--eye1opJ.opyl,411,1,2,4-trigzol-3-Apheny1)-4-(quiflolin 1-y 1 )-6-wrometh ylipicolirtamide;
N46,(1-cyclopacy1 El n id .1,zol,,5-y1)pyrid in-111) -,1-(quipolin Apioolinami de ;
6-cyclopropyl-N-0-0 -oy i:lopropyl- 1 FT -imi d -yl)p yridin -2-34)-3,4 ' bipyri -carbo x amide N-(344 -eyclopfop p yrro o [3 ,2-b jpyridin-6-$)picolimmia;
N,(344-cytlopropy1,414-1,2 A-tri az01-3-yt)phoily1), 4 -(4-eyclopropylphenyl)picolibam ide;
N-(6-(41,cyclopropyi-41l- 1,2,4-triazol-311)pyriditi-2-y0-3- 10 (pyri y Obenzamide;
yci opropy1-411- 42,4-lriazol-3-yl)plienyl),6-Onethyithio)-3,4'-bipyridine-nmtboxamide;
N-(3-4-eyelopropyi,4I1-1,2,4--triazol-3-y1)pheny1)-6--(isobutylthio )_3,4'_ bip yridine-2 '-earborx a m ide.;
SUBSTITUTE SHEET (RULE 26) 15 N,(3,(4-OydopropyMI1.4,2,4,(riaz01111)phet0)-445-cyc1opropylpyrazin-2-yl)pico1inamide;
6-cyclopropyi-N-(344-cyclopropyl-4 zol-310ph en yi ),5 3,4 -b 4::.a.tbox an 4.,.;
5-chloro-6-tyclopropy-VN,(3,(4,cyclopropyl4f zo1,311)phertyl),, 3,4' -bipyri dine-2 -oarboxamide;
N-(3-(4-cycl op rop y1-4H-I,2,4-triazA-311)pheny1)-6-(2-mothmyethylamino)-3.,4' -hi pyridine-2' -carbox amide;
N--(3,(4,oyciopropyl-4H-1,2.,44ri z01-3-yl)pbeny04, -(metivisulfonyi)piperazin,l,yi)piallitami.d N-(3 -(4-cyclopropy1-4 FT- 1.,2õ4-trittzoi-310pheny1)-6,ethy1-5-flu or0,3,4' -bippidine-2'-carboxamide;
-thioio-N-C1 -(4-oyelopropy14.11-1,,2,4-triazol-3-Apheny1)-6-ethy173$
bipyri diu ,-,r-Cafbo.onikk;
4--(4,eyelopropy I- Hii-1y1)-'N...........': opropyi -4H--1;44-4Eiazol-37y1)phem/Opicotinamide;
N-(3 -(4-cycl opropy1-4H-4,2,4-triazol--3-0 Junyl)-5 th X-bipyridine-2' -carboxamide;
N-0,-(4-cyc1opropy14TI- L2,4-friazol -314)pheny1)-4 4 furo[3,2-hipyridin-6-yi)pi colinamide;
N-(41-cyclopropy1-4H-1,2,4-thazol:4-y1 )p 0 iy1)-4-(3-malyi imidazof4,5-b1pytidin-611)ploolinamide;
N-(34:4-cyclopropy!4H-1:,2,44-fiazol--3-Aphenyl),6-(6-oNlopropylpyriditi-311)pyrip1id1ne-4,carboxamide.
6-eye lopropyl-N,(344.-eyolopropyl.-4H-1.,2,4-triazol-311)phznyq-e -rnothy1:-.3N-bipridine-2'-c4rhoxamide;
6-cycIapropyl-N,(3,(4-cyclopropyl-41I,L,2,4-triozol-311)plmoyD-5'-vothy3N -*pi -earboxamide;
N-(6-(4-cyclopropykIH- L2,4-tTiazol-a-yI)pyridin-1-yO4-(5-methyl,4-(trifluoromethyl),4,5, 7 -tetrahydro-lli -imidazo[ 4,5 ]pyTidtu- -Apic .........
SUBSTITUTE SHEET (RULE 26) 5.18 -N-.(3 -(4-ryolopropy1-4H-1,2,4-triazol-3-y1)phenyl)-4.-(5-metl*-4.-uorom ethyl)-4,5A 7 -tettabydro- 1 H -imid azo õ5-c I pyri di D- I -yl)picolinamik 6' -cycloprppyl-N-(6-(4--oydopropyl-43, 2,4-triazO1-3-yOmi din-2-y1)-2,3 1 - bipyridiw-6.-oarboxamid0 6 =-=(..!yelopropyl-N-(6-(4-eydopropy1-411-1,2,4-triazol-3-y1pyridin.-21-1)-3,3 1 -bipyri dine-5-carboxarnide;
6' -cyclopropyi N-(6-(4-c ye lopropy1-41H ,2,4-46001-3.11)pyr idin -2 -y1)-2,3 1 -bi pyridine-4-car b( yx id.0;
N dopropy1-4H- ,2,44riazO1-3-Apyridin-2-0)-5-(6-cydopropylpytdia-.3-y1)-2,4-difluorobenzamide;
6'-cyc1opropy1-N (3-(4-cyc1opropyl-41I- 1 ,2,4-triazol-3 -yi)phe ny1)-23 1, b yridine-6-carboxami de;
(S)-4-(4-eyo1opropyl- IH-imidazol.-111HV,(3.(4-(3.metbyibutaA-2-y1).41J-1,2,4-triazol-3-)4)phenyl)picolinami(*
4-c hloto-N-(644-qclopropyl 1 294-tria zo1-3 .-yOpyridin-2.-y 1 )-5-(6-QyelQpropylp ithn-3-y )-2-11 oro benzami de;
6-0ydopropyl -.N-(3-(4-(2-pheo yl cycl opropy1)-4H- 1 ,2,4.-triazol -3-yi)phonyl -bipyridine-2'-carboxamide;
N-(3-(4-eydopropyl-411- 1 ,2,4-triazol-3 syl)phony )-6-(cyclopropy1r lett y I
)-3 A pyridine-27 -carboxami de ;
3-(4-.eydopropyl- H -1 ,2,3-triozo1- 1 11)-N,(6-(4--cyclopropy1-414 - 1 ,2,4-tri azol-311)pyi idin-2-yl)bertzam de;
44 5-cyclopropyl,1 3,441riadiazo1-2.11)-N-(3-(4-eydopropy-414-1.,,2 4-triazal-3 il)plionyl)picolinarnide;
6-cyclopropyi-N4144-ph enyl -4H- ny10,4'-bipyridine-T-quiooxamido;
6-eydopropy144-(3-(4-(pyridin-2,y1)-4H-I ,2,4iazol-3-0) pherty1)-3 ,4'-bipyridipe,2'-c rboxamide;
6-cy-clopropyi -N43-(4--(pyridin-3-y1)-4.H-1,2,4-triazol-31)phenyl)-3,4r.
.bipyri dine-T-ca rboxamide;
SUBSTITUTE SHEET (RULE 26) 6,=cyclopropyl-N-(3-0-(pyridin-411)-41I- 1 ,234-triazol-3-11)pheny1)-3,4,-bipyridine-2'-carboxamide;
6,eyelopropyl-N43-(4,(wirnidin-f41)-411,1.,2,4-triazol,311)phenyl).3,4,-1ipytidine-2'-carboxamide;
4-( 4-cyclopropyiill-imidazol-1.-ArN-(34 4-(pyridin-3-y1)-4H- I
triazo1-311)ph enyppicol inamide;
4(4-cyclopropy -1II-imidazal- 1 --y1)-N-(3-(4-(pyTidin-4.0)-41I-1 /44-tria.zo1.411)phenyl)picolituntiide;:
4-(44,:yelopropyl-ili-imida461-111)-N-(34 4-(0Timidin-511)-41I -1 ,2,4-triazot-3-y4phenApico1inamide; and N-(3-(4-(but-)-yny1)4H-1,234-triazoi-3-y1.)pbeny14-4-(4-cyclopropyi-II-1-imidazot-l-y1)picolinumide; or a pharmaceutically .acceptable salt or solvate thereat [90126J in Kane: embodiments:, the ASK1 inhibiting compound is a Compound of the strucblre jr.v ¨.1 'Nt I.N
N s N
(C1.) or a phatmaccutically .acceptable salt orhydrate 'thereof,. This COMpound maybc referred to as 3-(4-cycl opropy1-1H-i inidazol-1-y1)-4-(044-cyclopropy1-4H4,2,4-triazol-3-17.1)pridin-2-y1)-4,mothylbenzamide or 3-(4,cyc1opropy1-111-imidavol-1-y1)HAL-t6-(4-cyclopropyl-4H-I94-triazoI-3-y1)-2-pyridinyl]-44fletbyl-benzamidt; and has been assigned CAS Registry No. 1262041-67-7. The compound and salts: thereof including %rink; acid salt (CAS Rog. No, 1262041 -68-8) may be .prepared by methods &dosed in US 201.4/022841:2 and US. Pat.
No. 9,067,933.
[001271 mother embodiments, the: ASK1 inhibiting annpoundis a compound of the structure:.
SUBSTITUTE SHEET (RULE 26) WO 2017/(159252 PCT/US2016/054780 tA
...4, It ....
1..
. < \ i I7."...' \ lq. . .1 = N r .
. -: ..,r - Si ..,e," \ ....i./ ' . h...- tes. . -=-..sltrA
H
1., ti ...
\ (C2) or a pharmaceutically acceptable salt or hydrate thereof. This compound may be referred to as 5-(4-cycloprop0-1H-imidazol-1-0)-2-fluoro-N-(6-(4-isopropy1-411-1,2,4-triazol-311)pyridin-211)-4-methy1benzamide or 5-(4-cyc1opropy1-1 li-imidazol-1-y1)-2-fluoro-4-methyl-N-1644-(1-methylethy0-411-1,2,4-triazol-3-0]-2-pyridinyll-benzamide, and has been assigned CAS Registry No. 1448428-04-3.
The compound and salts thereof, including hydrochloride salt (CAS Reg.
No. 1448428-05-4) may be prepared by methods disclosed in US 2014/0228412 and 'US. Pat. No: 9,067,933:
190128) 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.1 inhibiting compound", and "inhibitor of ASK1", and the like, refer to compounds which present a pharmaceutical activity to inhibit activity of an apoptosis signal-regulating 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 I, or a pharmaceutically acceptable salt thereof, is used in combination with Compound Al, or a pharmaceutically acceptable salt or hydrate thereof In another variation, the ASK.1 inhibiting con pound is 444-[(4'-chloro[1,1'-hiphenyll-2-Aniethy1l--1-piperaziny1]-N4144[0R)-3-(dimethy1arnino)- I -[(phenylthio)methyllpropyliaminol-3-nitrophenylisulfonyli benzamide, ora pharmaceutically acceptable salt thereof.
Bromodomain Inhibitors 1001291 In some variations the BET or BRD (bromodomain-containing protein) inhibitor is an inhibitor of bromodomain,containing protein 4 (BRD4). In one SUBSTITUTE SHEET (RULE 26) opect the modulator of a brornodomain-containing protein is a compound of Formula N
,sies, re 4 õ
(11) wherein le' and le .are 6,ach independently alkyi optionally substituted with from I to 5 le groups;
R and Ra are each independently U or halo;
C(())0R.,, -IgHC(0)OR8, -NITS(0)2:le, or -S(00re; or sclected.from the group consisting, of C1..10 alkyl, C.140.aikaxy, amino, C5..1.0 aryl, C.,f.Q0 arylalkyl, Cno hetet:mkt C5.40 betcroaryl, and C6a.heteroarylalkyl, each of 'which is optionally substituted .with from I to 5: groups;
one of le and R4b is selected ifforct the group consisting of H and C.1,6 alkyl optionally substituted with from 1 to 5 lea groups, and the other is absent;
R5 i8 -c(0)0Ra, -NHC(0)OR4.;. -NHS(0)R8, or .S.(0)2Nn.b; or is selected from the group consisting of FL C.1.40alkyl, Cno haloalkyl, C14.0 alk,..qiy, amino, C5.10 aryl, Ciwa arylaIkyi C heteroalkyl, C5.10 heteroaryt and C6..2f, heteroarylalkyl, each of which is optionally substituted with from 1 to 5 .R2c) groups;
each R, and Rh is independently selected from Inc group consisting of e1.1.0 alicyi. C5.10 aryl, C.6,20 al-AalkY1,. C1,10 hettroalky4C540 hetematyl, and C.6.20 heteroarylancyt each of which is optionally substituted with from 1 to 5 1(79 groups; and.
each le is independently selected from the 1?,roup consisting of aoyl, CjA0 alkYL: C1-1.0 alkoxy, amino, amido, amiditioõ.C540. aryl, C arylalkylõ
azido, carbarnoYL carboxyl, carboxyl ester; craw, guanidino, halo, Cmo haklalkyl, C1:40 SUBSTITUTE SHEET (RULE 26) WO 2017/(159252 heteroalkyl, Cs,n, heteroaryl, C6.20 heteroarylalkyl, hydroxy, hydrazino, imino, oxo, nitro, sulfinyl, sulfonic acid, sulfonyl, thiocyanate, thiol, and thione;
wherein the Ci_joalkyl, C5.J0 aryl, C6.20 arylalkylõ C1.10 heteroalkyl, C5.40 heteroaryl, and C6.20 heteroatylalkyl groups are optionally substituted with from 1 to 3 substituents independently selected from C)..6 alkyl, Co aryl, halo, Ci..6 haloalkyl, cyano, hydroxy, and C1.6 alkoxy;
or a pharmaceutically acceptable salt thereof.
1001301 Compounds of Formula (H) (which include compounds of any of Formulae (Ha), (lib), (He), (lid) and (11e), 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..
1001311 In some compounds, R'a and Rib are each independently C1..6 alkyl which, as defined herein, includes alkenylõ alkynyl and cycloalkyl. In some compounds, RI and Rib are different, and in other compounds Ria and Rib are the same, In some compounds, R ja and Rib are each independently a C1.6 alkyl optionally substituted with 1-5 R20 groups. In some compounds, RI' and RR' are both methyl. In some compounds, one of R1 or Ril) is a methyl and the other is a methyl substituted with a hydroxy. In some compounds, Rh' and Rib are both methyl substituted with a hydroxy. In some compounds, one of R." or Rib is a methyl and the other is a methyl substituted with an amine. In some compounds, Ria and Rib are both methyl substituted with an amine, [001321 in some compounds, e and R2b are both H. In some compounds, R2a and le are bothhalo. In some compounds, one of R2a and 11Th is H and the other is halo. in some compounds the halo is -F or ÷Cl, 1001331 In some compounds, R3 is boronic acid, a boronic acid ester, or halo.
In -some compounds, R3 is -C.(0)01e, -NIIS(0)21e, or -S(0)2.NR6Rb wherein R" and Rb are described above. In some compounds, R3 is -C(0)0Ra, -NHC(0)0r, -N11.S0)2Ra, or -S(0)2Nritb, wherein each Ra and Rb is independently C1.10 alkyl, C5_j0 aryl, C1.10 heteroalkyl or C5-10 heteroaryl, each of which may be optionally substituted as described above. For example, in some compounds R3 is -C(0)011", -NHC(0)0ie, -NHS(0)2R', or -S(0)2NRalt1' , SUBSTITUTE SHEET (RULE 26) - :63 -wherein each le and le is independently C540 aryl or C5-10 hetemityl. In some compounds, le is selected from the group consisting of el a alkyl, CI,D, alkoxy, amino, C.5õID aryl, Q..20 arylalkyi, Ci_io heteroalkyl, C5.0 heterowl, and C6-heterwrylalkyl, each Of Which is optionally substituted with from I to 5 R.2 groups, wherein R2t) is described above, hi some compounds, R. is CFR, alkyl, C.140. alkoxy, or CI 40 betemalkyl, each of which may be optionally substituted as described above. in some compounds, the heteroalkyl is a heterooyeloalkyi. In other compounds, R3 is C6.90 arylalkyl or (74q0 heteroatylalkyl, each of Which may be optionally substituted as described above. In other compounds, E3 is C5.
jo aryl, CfAa aryialkyl, C5_13) beteroaryl, or C6,20 :heteroatylatkyl, each of which may be optionally substituted as described above In some compounds, E3 is amino optionally substituted as described above. For example, in some compounds R3 is -NIII, and in other compounds R3 is -NRYle, wherein R. and le together with .the nitrogen to Which they are bonded form a 014 heteroalkyl of Cs.to heteroaryl, each of which may be optionally substituted as described above.
WO134l Other non-limiting nattipt,'S of le include the following:
, 4"
,...sAt.,,,,,,õ r it µ.S.,,,,,,-,,,,, r k,... ...,,õ, -4/..T.""Ns, 05' .'"==ik,sµ. =,,,,, :S `y,'N 'e-S -,,t,'''' ,,.e of-1 ...is 0H1, i t vx.ri...6, 0:: H:De==''r'r-: ..
. = c=== = \
¨ '....:' LI 5H
:* i. p=
\
jj-I. ...11..,, ; ':-- ':
, I
\` '''''''''k''''' kes . NI' 'K `-'-:, - - . N.
01.i ,,,,......,..
OH0 .. : i old '=,,,----,,,,, 11 0171 Oi-i II
14 ,, õ -."7 , 'N , SUBSTITUTE SHEET (RULE 26) v 64 -....,..;
µ 0.4 6 ` r,J -.'7'')= µ ..õ.5 19 '';'.1. 4 . ... t r, i , I ,, , ! ,,, , ;õ , : ....=
\ ' '''': N:
-,:>, = N k -.., ...... = l'=*::.
,,...
ot.i 11 1. OH Ti ot.i \g- ..',1 OH li t,,I
Fill ' NI
., e , N
N , -..,.. ,=N , ...,, .;
N , oh: ..:1 1 ..,...) .., 5 , -_ c-, \., ,, ....cgs 9..õ
, ,,,,,õ,,,, r"..), , "
C. I

0 ' 0 ? -µ, OH L, ...) 1 ..
, t tS
... .., ...APJAP
- H (6' ' N'''''',;\ 5 I
..J-- ''sS5 ,õ N N -....cs,..õ....,..,..,:õ.
0'. '0 r NI

:1)'''''''...
..... . .
o..-v)f (3.55 N ----.
....õ . ? NH

cs...., .1= ' N '''''''\, N-/
....õ, 1, C
.., t / A.,,, \----...) F F , SUBSTITUTE SHEET (RULE 26) ,- 65 -F

.(t.......'-=.-z-,,,,,/ !.......::::,,/ i. ''' N .:',.' \ .=
..... ,.., .
l''''.( N H
\ . d) \ : .,..
/ : :./4µ.Ni ' 1 NH
, - O.-, - . ' N ' 's...,...,S5 I ,,,,, , I c3 :`N, cS ..,<,_ )55 J.,, ID
, s5 11 ',I_ .,..."====;:. N : 'N.rj,'"===,.; N
css--.....r. N
' .e .N" OH. Nµ NJ '"OH ."
, t., S =
c -4- -..=
,..S: ,, µ,....' = ...,,,,õ . ;µ'..1 1 . 1,S ' . ': ' r. 1 =µ--i 1 .., . .,..
1., .,,,,,,,,,,,,,,' , N ' = ,'':'' 1 ' ,....."'Ny.";
'=,.5 .-...4. . .0' . : .,:,...,..,..... ,,,0 : ,,."., -..=.- N".'..--s-..- : H ,.. -"... , ..-.-.7::;N:
' ' N C1.
0 .'.. tkl \ X' V. N IN i c- ......... ::),,...
, ...
5..... .., -.-: = 1 . ' i ,ri ;
. .. .... ,-,.., ', .õ.:4.
i.. - : "*N...õ,..;:::),.,,,õ.. NH e --,---:
N ¨
.: ''st . I

õ..,.,....- ,,,,,,, =,;-,A "7: , i : ' I...
=,,.;,..
':-.--').;...: ,IIII.AP !../VVIP
"C' :1 t :
1,4 1: 1 iik>.
I : qltolp ,Vttior., .....- ".. -,.....,.,õ,I
-) :

OH
, I , .,1i12 O' NH
11 '''' '',..i.-""
ii .1 ,...
1 ' SUBSTITUTE SHEET (RULE 26) WO 2017/(159252 PCT/US2016/054780 V .=
-µ5r. ;pi (: CI
kttnrµ ' ." =
Ip 1\ I
j = I:

futikr vs\ S
rfr '====''SA: 7.µ,1 q- =
õ
F = OH
F ,and =CF3 1001351 In some compounds, one of R' or R4b is H and the other is absent, that is, in some compounds R4' is H and R4b is absent, and in other compounds R4 is absent and R4b is H. hi other compounds, one of .R42 and e is alkyl and the other is absent, that is, in some compounds R.4a is alkyl and R4b is absent, and in other compounds R4a is absent and e is alkyl. In some compounds the alkyl is methyl.
[00136] In some compounds, R5 is -C(0)0W, -NBC(0)OR', -NIIS(0)2W, or -S(0)2NRaltb, wherein le and Rb are described above. In some compounds, R5 is =(.:(0)0W, -NB.C.(0)01e, -NHS(0)2W, or -S(0)2NWRb, wherein each le and le is independently C1..10 alkyl or C5.10 aryl, each. of which may be optionally substituted as described above. For example, in some compounds R.5 is MIC(0)0W, wherein W is methyl. hi some compounds, R5 is -NIIS(0)2W, wherein W is C1..10 alkyl or C5.10 aryl, each of which may be optionally substituted as described above. For example, in some compounds 11.5 is -1\11.1.$(0)21r, wherein W is eyelopropyl, In some compounds, R5 is selected from the gout) consisting of H, C1,10 alkyl, C1.40 haloalkyl, C1.. alkoxy, amino, C5.10 aryl, C6.20 arylalkyl, C1.10 heteroalkyl, C5.10 heteroatyl, and C640 lieteroarylalkyl, each of which is optionally substituted with from I to 5 R2 groups, wherein is described above. In some compounds. Rs is C1..10 alkyl optionally substituted as described above. In some compounds the Cwo alkyl is a C1_10 cycloalkyl, e.g.
cyclopropyl. In other compounds, R5 is amino optionally substituted as described SUBSTITUTE SHEET (RULE 26) above. For example., in some compo.unds le is -NH2., and .in other compounds Rs is -NWT!, wherein RY i5H and. R i.sakyi,e:g; cyclopropyl,. In other compounds, le. is alkoxy, eg.. methoxy.
100137,1 In some. co.mpounds, .R lbs te, 7 4a, =
K R41' And R.5 are optionally subsiitataiNAiith from. Ito 5 (i,e. 1,2, 3, 4.or 5) R.2 groups as described above in Some compounds, le, Rib, R3õ R4: and le are optionally substituted with 1, 2, or 3 lea groups. hi SON compounds, each RN is independently selected from the group consisting of alkyl, alkoxy, amino., cyan% halo, haloalkyl, heteroalkyI, hydroxy, and sulfonyl. In some comounds, each R.21' is independently selected from the; goup consisting of aryl, alkyl:aryl, hetemaryl, and heteroalkylaryl,In some compounds. R lb, .R3., R. R4b and le are not substituted. In some comoundsõ R2(' is not substituted.
[001381 One subset of compounds of Formula (II) relates to coniponnds of Formula (Ha) = .:1./
Ro¨N
/ =
(Ila) wherein and R'b are each independently Cl..6 alkyl optionally suhsitut,d from 1 to 5 le groups.;:
R3 is boronie acid or halo; or C(0)0R8, -NHS(0)R3, or -S(0),AR8In selected from the group consisting of Q..0 alkyl, Ci,io alkoxy, imino C.5.10 Cfia arylalkyl, C heteroalkyl, C540 heteroaryl, and C6.2. heteroarylalkylõ
each of which is optionally Atbstitated with from 1 to 5 0 groups;
one ale and km is selected from the group consisting of H. and C74..6 alkyl optionally substituted with .from I to 5 R'.4a groups, and the other is absent.;
R5 is C(0)OR, -NIIC(0)0R3, -.NHS(0)0, or -S(0)2NR.aRb; or SUBSTITUTE SHEET (RULE 26) WOO from the group consisting of.H, CI40 alkyl, C1.10 haloskyl, alkoxy, amino,. C5.10 aryl, C6..16 arylalkyl.õCwo heteroalkyl, C5..10 heteroarylõ and C.
20 heteroarylalkyl, each of which is optionally substituted with from I to 5 R.2 groups;
each R" and R' is independently selected from the group consisting of Hõ
C=140 alkyl, C5,10: aryl,. C6_20 atylalkyl, C1-10 .brA01001kYi., C.,....i0 heteroaryl, and. C6,.2.0 hetoroarylalkyl, each rjf which, is optionally substituted with from I to 5R' groups; arid each R2f) is independently selected from the group coniisting of acyl, C1.10.
alkyl, C140 alkoxyõ amino, amido am i di no; c540 aryl, C6..m wylalkyl, azido, carhamoyl, carboxyl, carboxyl e$W f , (...y ano, guani.dino., halo. Ci-ia haloalkYl, C1-10 hetcroalkyl, Q3-10. hater =y, C6õa heteroarylalkylõ hydroxy, hydrazino imino, oxo, nitro, stilfinyl, sultOnic acid, .sulfony/, thiocyanate, thiol, and thione;
wherein the Cmo alkyl, e_it?, aryl, Q4,0 aryialkyl, Chio heteroalkyl, es.40 heft:oat% and C0,20 heteroarylalky4 groups are optionally '$4bstitotod with from I
to 3 substituents independently selected from (.).6 alkyl, C5-10 arYi, halo., C=14., halealkylõ cyanoõ hydroxy, am! C1_6 :alkoxy;
or .a pharmaceutically acceptable salt thereof [901391 Another subset of compounds of F01111111 a (II) relates to compounds of Formula (lib) N.-9 .
.:F1:4). R1P
Fc):=.. w..$
1 :
=6,1}N.: :.....:. R3:
::,,r.i, ===
.0 . (lib) wherein R1' And le' are each independently C1,..6 alkyl ppttimally suhslituted with :Nail Ito 5 le groups;
12' and R.21 are each independently H or halo;
R3 is:
botanic. acid. or halo; or C(0)0r, ,1\ifIC(0)0R8, -NIAS(0)2:, or -S(0)iNleRb.; or SUBSTITUTE SHEET (RULE 26) seletta from the group consisting of Ciõ.j0 alkyl, C1.40 alkoxy, amino, C5.111 .arytõ Coo arylalkyl, Cmo heimalkyl, c.0 hete.roaryl, and Co beteroarylalkyl, each of which. is optionally substituted With from 1 to 5 R24 groups;
..te is C(0)Q.E, -INII-1Q0)0Ra, -NIIS(0)21e, or -S(0)2:Nlele; or selected from the .group consisting of H, Ci_jo alkyl, Ci.4.0 haloalkyl, e1...10 alkoxyõ amino, C,...1.0 aryl, (1...10=ary.lalkyl, Cl..10 heteroalkyl, G540 heteroaryl, and. 1116_ beteroarylalkyt, each of which is optionally substituted with from 1 to 5 R2 groups;
each Jr and R' is independently selected from the group consisting of H, C1.40 AAA C5-Ri aryl; Cti-20 arylalkyl, C..1 heteroalkyl, C0 heteroaryl, and C6-2a:
hetenoatylalkylõ each of which is optionally substituted with from I to 5 le groups; and each R20. is independently selected from the group consign* of anyl, C14 alkyl, CjAa alkoxy, amino, amid , .amidino, C10 aryl, Coo aryialkyl, azido,.
carbzunoyi, carboxyl, carboxyl ester, cyanoõ guanidino, halo, Q,F.j.
haloalkyl, C1.4 beteroalkyl, C.3.10 heteroaryl, C6.,20. heteroarylalkyl,.hydroxy, hplrazino, inlinoõ oxo, nitro:, sultinyl, sultonio acid, sulfonyk.thiocyanate, thiol, and thione;
wherein the C1.10: alkyl, C71,.i 0 aryl, C64:6 atylalkyl,. C1.10 he.u.,,wikyl, C.3.1.0 heteroaryl, and Cwo beteroarylalkyl groups are optionally substituted with from I
to 3 substituents independently selected from el.6 alkyl, C5.10 aryl, halo, halo.alkylõ cyanoõ hydroxy, and ci,,6 alkoxY";
or a pharmaceutically acceptable salt thereof [OW d01 Another subset of compounds of Formula (II) relates to. compounds of Formula (ik) N.,-Ø.
sksci.1414,,...... 0,...,: = ..470-}
Sn!:: N :=
le (.U.C) wherein SUBSTITUTE SHEET (RULE 26) WO 2017/(159252 :RI' and Rib are each independently C1.6 alkyl optionally substituted with from I to 5 R20 groups;
R3 is boronic acid or halo; or C(.0)01e, -N1-1C(0)0fe, -NHS(0)2R3, or -S(0)2NleRb; or selected from the group consisting of C1.40 alkyl, Co alkoxy, amino, C5_10 aryl, C6.20 arylalkyl, Cia0 heteroalkyl, C5-10 hettroary4, and C6-20 heteroatylalkyl, each of which is optionally substituted with from Ito 5 R2 groups;
R5 is C(0)0R% -NI1C(0)01e, -NHS(0)2R', or -S(0)2NR8Rb; or selected from the group consisting of H, C3.10 alkyl, C1.40 haloalkyl, C1.10 alkoxy, amino, C5.10 aryl, C-6..20aiylalkyl, C140 heteroalkyt, C5.1.0 heteroaryl, and C.6õ.
20 heteroarylalkyl, each of whichis optionally substituted with frora I to 5 groups;
each le and Rh is independently selected from the group consisting, of H, Ci.10 alkyl, C5.16 aryl, C6.20 arylalkYl, Co heteroalkyl, C5.10 heteroaryl, and Cii-20 heteroarylalkyl, each of which is optionally substituted with from I to 5 le groups; and each R2 is independently selected from the group consisting of acyl, C1.10 CI.10 alkoxy, amino, amido, amidino, C540 aryl, C6,20 arylalkyl, azido, carbamoyl, carboxyl, carboxyl ester, cyano, guanidino, halo, Ci.j0 haloalkyl, C1.10 heteroalkyl, C5.10 hetetparyl, C6.20 heteroarylalkyl, hydroxy, hydrazino, imino, oxo, nitro, sulfinyl, sulfonic acid, sultbnyl, tbiocyanate, thiol, and thione;
wherein the C1.40.alkyl, C5.10 atyl, C6.20 arylalkyl, Ci..10.heteroalkyl, C540 heteroarylõ and C6.20 kelt roarylalkyl groups are optionally substituted with from I
to 3 substituents independently selected from C1.6 alkyl, C540 aryl, halo, Ci.6 haloalkyl, cyano, hydroxy, and C1.6 alkoxy;
or a pharmaceutically acceptable salt thereof 1001.411 Another subset of compounds of Formula (11) relates to compounds of Formula (lid) .=
SUBSTITUTE SHEET (RULE 26) AiL

' "
RS (IId) wherein R.3 is boronie, acid or halo; or C(0)01e., -NHC(0)0r, --N1I$(0)2R.', or -fi:(0).2Nre; Or selected from the group consisting of Cl..10 alkyl, Co alkoxy, amino, C540:
ati.13.Q.20 arylalkyl, C heteroalkyl, C heteroaryl, and C6,.2,0 heteroatylalkyl, each of which is optionally substituted with from 1 to 5 RN. groups;
le is C(0)01e, -VIC,(0)04. -NHS(0)2g.', or -5(0)2Nlele; or selected from the group consisting of H, alkyl, Cl.10 haloalkyl, C1-10 alkoxyõ amino, C540 aryl, GAO arylalkyl, C1-10 .hCterOalkyt, C.0 hetcroaryl, and. C6-20 bete; oaryialkyl, each of which is optionally substituted. with from I to 5 R2.
groups;
each P,! and le is hid:pendently selected from the group consisting of H, C)..to alkyl, C540 aryl, C6:.21)arylalkyl, Cj heteioalkyl, C5_10 heteroaryl, and C6.20.
heteroaryialkyl, each of which is optionally substituted with from .1 to 5 R.2 .
groups; and each leis independently selected from the group consisting of acyl, C1 40 alkyl, CI .to alkoxy, amino, amido, atnidine, C5..to aryl, C.6.20 arylalkyl, carbamoyl, carboxyl, carboxyl ester, cyano, guanidino, halo. Ci.o haloalkyl, heteroalkyl, C heteroarylõ C6.20 heteroarylalkylõ hydtoxy, .hydrazino, imino, oxo,:
nitro, sultinyl, si.ilfonic acid, sulfonyl, thiocyn rate, thiol, and thione;
wherein the C1 alkyl, C10 aryl, C6-2,Q arylalkyl, Ci-io.heteroalkyl, Cõ -10 heteroaryl, and Coh heteroarylalkyl groups are optionally substituted with from I
to 3 substituents independently selected from C1,6 alkyl, C5.10 aryl, halo, C.4..6 haloalkyl, cyanoõ hydcoxy, and C alkoxy;
or a pharmaceutically amptable saltthemtfõ.
SUBSTITUTE SHEET (RULE 26) [001421 Another subset of compounds of Formula (11) relates to compounds of Formula (re) N - C) II V
. t ..:;.:'....' Hi4 . . = ' 133 \t*
(lie) wherein J1 is boronle acid or halo; or C(0)0118, -MIC,(0)0R", -NHS(0)2R8, or -8(0)2NRaltb; or selected .from the group consisting of C140 alkyl, C14:0 alkoxy, amino,. C5.40 aryl, C6,..x, arylalkyl, ('i.10 heteroalkyl, C.ID heteroaryl, and C6:20 heteroatylalkyl, each of which is optionally substituted with from 1 to 5 le groups;
each R" and 'Ka is independently &'I.ecied horn the group consisting of H, C140 alkyl, C540 aryl, C6.10 aryl alkyl, C1,40..heteroalkyl, C5-10 het-crawl, and. C6.2.0 haer(gOlaikA, V.,'He.h. of which is optionally substituted with from 1 to 5 R2 mum and each le is independently selected from the gottp consisting amyl, CI _Jo alkylõ el_malkoxy, amino, amide, antidinoõ C5,,to aryl, Co arylalkyl, azido, carbamoyl, carboxyl, carboxyl ester, cram, guanidinoõ halo, C. hal ottlkyiõ
Ci.t.o beteroalkyl, C5,...10 .hetmaryl, C640 heteroarylalkyl, hydroxy, hydrazi no, train , .oxo, nito, sulfinyl, sulfonic acid, sulfonylõ,.thiocyamae, thioi, and thione;
.1.k:herein the Cno alkyl, C5..10 aryl,: C6,20 aryialkyl, (:.:.4.0 hereroalkyl, C.5 Jo hotoroaryl, and C6.2.0 heteroaryialkyl groups are: optionally r;nhstituted with from 1 to 3 substituents independontly setecicil from CIA alkyl C5.10 aryl, halo, C1.6 haloalkyl,.cyano, hydroxy, and C.I.6 a.lktnty or :a pharmaceutically acceptable salt thereof [001431 In separate .embodiments within each of the compounds described for Formulas ii. Ilaõ lib, and lie, there is another embodiment comprising a compound in which R1' and R1b are each independently Q.6. alkyl, or a SUBSTITUTE SHEET (RULE 26) WO 2017/(159252 PCT/US2016/054780 pharmaceutically acceptable salt thereof:In separate embodiments within each of the compounds described for Formulas II, Ha, 11b, Ile, lid, and lie, there is another embodiment comprising a compound in which R3 is C1.10 alkyl, C1.10 alkoxy, or C1.10 heteroal.kyl, each of which may be optionally substituted with from 1 to 5 R2 groups, or a pharmaceutically acceptable salt thereofin separate embodiments within each of the compounds described for Formulas 11, Ha, lid, and lie, there is another embodiment comprising a compound in which . R3 is an, C5.10 aryl, C6=20 aryialkyl, C5.)oheteroatyl, or C6.20 heteromylalkyl, each of which may be optionally substituted. with from 1 to 5 R2 groups, or a pharmaceutically acceptable salt thereofin separate embodiments within each of the compounds described for Formulas 11,1.1a, lib, He, and lid, there is another embodiment comprising a compound in which R5 is C1.10 alkyl, or a pharmaceutically acceptable salt thereof A separate embodiment comprises a compound of Formula Ile, as defined above, wherein R3 is Cm alkyl, C-1.40 alkoxy, or CIA0 heteroalkyl, each of which may be optionally substituted with from 1 to 5 R2 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 R3 is C5.10 aryl, C6-20 aryialkyl, C5.10 hetcroaryl, or C6..20 heteroarylalkyl, each of which may be optionally substituted with from 1 to 5 'le ?pups, or a pharmaceutically acceptable salt thereof.
[001441 in some embodiments, the modulator of a bromodomain-containing protein is a compound selected from the group below, or a pharmaceutically acceptable salt or hydrate thereof:
--trk N-o H.

"(I
te\\ `
N, =;= r---NH
IµS-1.1 3-(2-amino-6-(3,5-dimethylisoxazol-4-y1)-1 If (6)-4-(2-cydopropyl-7-(hex-3-en-311)- 1H- =
benzo[dlimidazo1-411)pentan-3-o1 benzoKlimidazol-5-y1)-3.5-dimothyliwxazole SUBSTITUTE SHEET (RULE 26) WO 2017/(159252 PCT/US2016/054780 - N-0. - N - 0 ...t.- -q ,....,....... s,.: \

<4)-*"N OH
-7:"N HO
1.42- eyel opropy1-643,5-dimethylisoxazol-4-y1)- 3-(2-cycl oprop yi-6-(3,5-d imethyl isox azoi-4-y1)-1 H-benzo[d]im i dazol-4-y)propan- 1 -01 1 11-benzokflimiciazoi-elsyl)pentan-3 =ol )1 N0 +
....,-( ...4)--,..
, i Y
,--- N,.. - \\.1 .
jty,-1 ) II ., I
, t....., \ . -.
i-IN, if FIN 1 ,.........,;=.=
<(/)., <I' )0.11It,.4' ") , (7..)-4-1:2-cyclopropy1-4..(pent-2-en-311)- 1 H- 4-(2-cyclopropy.1.4-(pcigan-3-A- I H-benzo[d] imidazo1-6-y1)-3,5-dimethy1isoxazole benzo[d]imidazol-6-y1)-3,5-dir1ethylisoxazo1e ..--- - S `-=====
= ,..,,,,(..N-Q
..õ-.. .....7,,, ,,..õ ....- ,....-\., õ=SC, ,....-.. ...J.., kõ,, -, tc.' 1,1 õ.
H N 1 i HN i =
OH
4).:::=..z.N , . .
cycioperdy4(2-eye1opropyi-6-(3,5- dicyc1openty1(2-cyc1opropyl-6-(3,5-dimethyl isoxazol-4-y1)-1H-be mold) imi dazol-4- dimethyl isoxazol-4-y1)-1 H-benzo[d]im ida zo1-4-y1001;1110 yl)methanol õ---I4 \ 4:0=-====, # :\,,, '-.1.,..-1.... \
1 il i 1 ,M -Li i ) ,IN -.:=:;:::"k%=-\õ?`'N, . - , .....,.,---='-' ,...--',,,..0 <1 <1),----: N OH
(S)-cyclopenty1(2-cycloivopy1-6-(3,5- (R..)-cyclopenty1(2-cyclopropy1-6-(3,5-dimethylisoxazo1-4-y1)- 1 H-benzo[d]imidazol-4- dimothylisoxazol-4-y!)- I IT-benzo[d] im idazol-4-yOmelhatiot ylimethanol SUBSTITUTE SHEET (RULE 26) -, 75 ¨
N."'q ...k.,.õ-: ..
.,, i.
HNI
i .... . , tr'll 6H
......:µ,, ..<1 1...(2 ..,.?r,7,1 Op 1 , i)...%1 - 6.0,5- dimethylisoK ',.i Z 01., 4..yi), 'i.(2:.c)..c.1-643. 5-dirwthylis e X2, 7:014;y0-111-ii....,11zortll imi dazi-.4 -4-y1)--2-met1vi propa n=..I - 111--bz:
iizokijimidazo1-4- yi):-2.,4-dheillyipetitati-ol 3-of NO
l'.
i., .;
N
( 1 H : ? = , = /
fr.-I N J. . MN
. .
<....,,:l 4-(2-cyeinpi JI)), 643, 5-di wil ) I ko K n 7:o1.411), (E)-4,(2-cycipp:
opy1.4-0*p0,m21.-yt) -1H-11I-1-?cni:f,[diiraidaw1-4-y1)1:4r.-4,0 berao[dl1Tt3idazoi..6-.:, j-3,541.imahyliscaazolo tl¨f ...q :: N ." C.) t . 7.'"..
..
., i, it t ) ,,,.....--7--1 MM 1 --N f t:'''''' k =
ks,,,i) i'..
,:, ...., -.....
442.. .yc iopropy1-4-(heptatt,4-11)- I I-I- 3-(?. -,:.:yul opropy1-6-(3., 5 -di methyl isoxazol-4-y1), betizo[djiinidazol-6-yr)-3,5,climetitylisoxir..zole I -tit ethy1,111-bitztir (I] imiciaz6I-4-ylVe. iltm,3,o1 "Y.
1 .. õ
J:r o H
N\
.,..
142-cyclopropyl- 543,5-d itnethyl i soxazo1,441).-I -methyl-1 II-berotilj hid azo1-711)propan- 1 -SUBSTITUTE SHEET (RULE 26) WO 2017/(159252 PCT/US2016/054780 ,1µ1- =k, s, . = k ,---- N= õ" ....-- ...?-c.....,.:
==;.=<'' , -,-;=`` F. \ :,,l',,1 - - .:1'µ%'N

,,,Ass,_',.) . ,...."-1IN.,\\ !
) - = - IN II
: = ,,,,µ,T,Ir:A====:(3,'= =,..c.,,,-;µ= -HN I 1 H)...õ-ri . , 'OH
--.'N OH !...
<I
\ s., ,,, cr7 :- 'Al t 11 (2-ty(:lopropyl-.6-(3,5-dimpthylisoxazol-4-y1)- (2.-cyc lopropy1-6-(3,5-dimethyl isoxiizo1-4-y1)-7-I H-benzo[d] imi dazol-4-yl)dip heilyini et hanol fluoro- I H-benzo[d] i midazo1-4-yl)di(pr idin-2-yl)iliethatio I
N-( , .
/' (I
N. H 1---- .
i .., ) 1 i.
, .
H N i HN i µ \)N....-.. -/)::.'s- 1+.4 H 0 =-===-. -- N ).-, .-.:
< . .
(2-cyclopropyl-6-(3,5.dimethylisoxitzol-411)- (2-cyclopropy1-64.3,5-(limethylisoxazol-4-y1)-1H-benzoglitnidazol-4-y1)(phenyl)(pyridin-3- I 1-1-betuo[d)Iinidazol-4-y1)(phen yl)(pyridin-2-yl)methanol y)metlianol N ¨0N¨ 0 T
:

.\-1:=' , ===="--",\
.1==== , I. 1 11 : : OH fm' : s= . /
= :i ,k1 .1='"\\, ,,,,, N ,S".=-.õ..õ' HN t'. -.N4, ....'N FIN i A" ' --1 = N*
...\
Nze \-=======
"':=:..:N HO 0 .1 <1 o , ...,, ,..,....7 N µ
.-.1µi N4es'-:',,.... µ
I 2- c yei opropy1-6-(3,5 -d imethyl isoxazoi-4-A- (2-0. yclopropy1-6-(3,5-dimethyl isox azo14-y1)--111-benzo[djimidazA)1-4-y1)iIi(pyridin-3- 1H-Fierrzo[d] irn i dazoi-elli1di(pyri din-2-yi)metNinol ylkdettizowl N 0 NO.
I/ \
,-====-c,\ is=-==,õ
:
i' i OH '''. N
il 1 4 p FIN I \ r's.,.,--- HU. . ,...õ.--=
''''''''r's1 e.'='--, <1 4=` ksk Nk.s.õ...õ) "-- N Ni,õ.µ
L. '''' (2-cycl opropy1-6-(3i-dimethyli sox-no' -4-yI)- (2-cyclopropy1-6-(3,5-11imethyl isoxazol-411).
1H-benzoitilimidazol-4-y1)(pyridin-2- .1H-rhenzoril .1 i mulazoi-4-y1)(pyridazin-3-yl)(pyridin-3-yl)methanol yl )(pyridin-2-y1)methanol SUBSTITUTE SHEET (RULE 26) WO 2017/(159252 PCT/US2016/054780 N -0 N -= 0 ji \ it ) N
II 1 OH his:''''..\\. 1 OH t ) õ
3' = i /
'N=zs ::: .... \ N.).:i =-'4,, 1 ./K ,,-..=:=-'^' '", .
,..' = -, \
FIN i , H N õ1., ..t...-N.,........ N
\
2r4's'N' 7 ,õ "'N s =X ' < ilk. iS N 1 (2-e yclopropy1-6-(3,5-di methyl i6ox azol-4-y1)- (2-cyclopropy1-6-(3,5-dimethyl isoxazol-4-y1)-I H-benzokilimidazol-4-y1)(pridin-2- 1 H-benzo( d]imidazol-411)(pyrid i n-yl)(pyrimidin-211)methanol Y1)(Pyrimidin-5-yOrnethanoi :
.
1 1 il.i-i r - r I (:)H
.,,I,.õ;1=:' 1" \
HN 1 -, N.,,N UN ; .-- N
N . \\
_....., µ,,,.........,../N
µ= =
(2-cyc1opropy1-6-(3,5-dimetily1i6oxazol-4-5)- (2-cyclopropy1-6-(3,5-dimethyt isoxazol-d-y1)-I ii-benzoircliimidazol--411)(prazin-2- 111-benzotdiimidazol-411)di(pyrazin.2-yi)(p)TW in-2-yl)methanoi yl)methano I

F.,..:1 111 .. <1;;;;N, .:, -,.i... .. - =.-........1 I ; . / ,i) ......:"., .....,..&\ it 2- : It HN. -r .. .....-.--.14 H. i \':OH.
....¨_,. ..
¨N ........-.,,..:4 e)---r*-P1 . = --- .
s-4 ..VA,........" <4.: ''' \- - = ' ' '.e.'': =
(2-c yc lopropyt-6-(3,5 -dirnoi 41 isoxitzol-4-y1)- (2-cycloprop y1-6-(3,5-dimetivi i soxszo)-4. yl.)- 7-1 ti-benzo[d]imidazol-4-y1)(pyridin-2- fluor*. 1 Ii-benzo[d] ilnidazoi-4-y1)di(inal din-2-yl)(pyrimicljn-5-Apiethanol ylOrtethanel NO..
c)õ,õ :t.4 = - (":;''.
..A...-- # - -,-:0.
-. .NØ.... =,...
:
....., N.,.....
I H
. Ws., ..0 l= 714 tµ1"`N
,./N\ .,,,,s,;g2:: = . - - .. I =:=== N..4:1".
'',....1_ ..." 11 )..tr,:.V...1;sti ..s...;,.... . s ...---- '1q4 4\ \''''-=
/ N d (.\\i il if s<
= = '''.N.,,,,,,,,,-(2-cyclopropy3-6-13,5-dimahyliiioxazo.1-4-y1)- (2-cyclopropyl-643,541irnethylisoxazol-4-yi).
I H-benzo[dlitnidazoi-4-y1)(pyridin-2- 1H-benzo(djimidazol-4-yi)di(1ltiazol-y))(thiazol-2-Dmethano1 yi)inothanol SUBSTITUTE SHEET (RULE 26) - 78.
N ¨= Q N -- 0 \;=:, ' õ.k,x, ...."- Nk...
ti 1 H
A. ,,.=:: J)--,=i i ? R 1 oi-i 1, o -.
, -......3::_i I
NH/N\e'''''`,4õõõ/ '1 N H .= \ t I \ ...-1 < ,,, ,,,!--N/ 'T
..I 7`,. ,H
N
N:%I 11.
, (2-cyclopropyl-6-(3,5-dimethylisoxawl-4-y1)- (2-cyclopropyl -643,5-dimethyl isoxazo14-y1)-I H- bertzokijim i da zo1,4-y1)(6-methylpyr id 41-2- .114-benzoidlimidazcil-4-y1)(pyridazin-3-y)itetrahydrofuran-2-y1).rnethancl y1)(tetrahydrofutan-2-yl)methanot 4-N .
...-...-V.

:

-"L.... 1.- = = ..,Feikk., f;IN",) ) 1J i 1 i A.... . .i-s--..õ:
N

5-(3,5-dimettlylisoxazol-4-A-74 i - 5-(3,5-di1neth A isinazol-4-y1)-7-( I-pherxyl v in yi)- 1 H-benzo[d] imidazol-2.-arn int'. phenylethyl)-1H-benzordlimidazol-2-amine -1.,õ. % .
. - --N. ' - s= =
....
.1 Is'N & :1)..\\
. .: . =77 == = ...,,,,,...,,,-;µ;. , 0 ,,,,,,,,, - 791r-r e". No N . N - - = P.
= <
(E)-4-(2-cyclopropy1-7-styryl-IH, 4-(2-cyclopropy1-7-(i Theilylvinyl)-benzo[d]imidazol-5-y1)-3,5-dunethytisonzole benzo[d]imidazol-ft-y1)-3,5-dimethylisoxazele :,.., === - ../..
F
...t,r\ .....11 I
il t r I
....T
,,,õ.....õ ;.a.ky;),,,,,=:¨",;,.,,, N T 1r = N , it F
NH k' 4-(2-cyclopropy1-7-(1-(4- fluoropiienyOvinyl)- 41-(2-cycl o prop yl -7.(1-(3-il unrop hertyl)vi nyi).=
1.1{-benzo[d]itnidzol-5-0)-3,5- 111-benzo[i]imidazol-5-y0-3,5-dirnethyliSOKUOIC dimethylisoxamle SUBSTITUTE SHEET (RULE 26) WO 2017/(159252 PCT/US2016/054780 -~ ''"'"" *N.-0 ' , -e= = - .15.' f i Z ..., \ :ie.
,.....õ ,,õ,,,,..c, I-, 1 = ' õ ^....,i,-;./ N. ,.., ..;,......." ,...4=Ne.... N...,,,`
4: 1\., : li k 1 ¨NH N
4-(7-(1-(4-ehloroptienyl)viny1)-2-cyclopropyl- 4-(2-cyclopropy1-7-( 1-(4-I H-benzoidlimidazol-51)-3,5- (trill uoromethyl)phaiyijvi ny1)-1H-dimethyl isoxazole benzo[illimidazoi-5-y1)-3,5-ilimethylisoxazole rc.
.õ,..../.....
t, = ..õ.õ, - 9 .
.......,- .." " =
- .. ...: :
- F
- `-=1/4. - :' , = ,- :.' r'''.. ''''k' e::" .z; .
ILI '.
/ A,4: Xõ,..,,,, sk,...,,,,, N t 1 )---. 41 i .4).--- NH
<
4-(2-,eyelopropy/-7-(1-pheny1ethy1)-1.1i. 4-(2.-eyelopropyk-7-( I -(441uoropheny)cilly1)-benzo[dlimidazol-5-y1)-3,5-climethylisoxazole 1H-benzo[d] innclazo1-5- y 0-3,5-iiimethyli soxazole A
I
,......, . . . .. . -.F' .
/ ==Ne, \\,^=^N,c,,,'''` -. 442-cyclopropyl-741-(3-fluorophenyOethyl),- 11-(2-eyelopropy1-7-(1-(4-. I H-benzogjimidazo1-5-y1)-3,5- (triflooromethyl )phertyljethyl)-dimethylisonzole benzo[d] imida zo1-511)-3,5-dirn et h yli so xazole N- 0 .N _5õ..õ...., , . , ..
.:............;µ,.õ..=.:
i - 1 .. - õ...-: ...." -,.., H N. = = [ N- '' HN . ' . 1.? .. - .-=
44).
0 .4 (5, 142-cyclopropyI-6-(3,5-dime.thylisoxazol-4-y1)- I -(2-cycloprop y1-6-(3,5-diro eth ylisomo1-4-y1)-111-benzotd]imi dazo1-4-y1)-5-tnethylpyrrol idin- 1H-benzo[d] inndazol-4-yi)-5-ethylpyrrol idi n-2-2-one one SUBSTITUTE SHEET (RULE 26) WO 2017/(159252 -- :80 -N ¨ 0 I/ 'k i %

õAN
HN ) <!..=
r\1 =====N .ki---=/
/
F. 3 r '.,j4 (S)-1-(2-cyclopropy1-6-(3,5-dirriethylisoKazol-4-y1)-1H-beirm[d]imidazol-4-y1)-5-(trifluoromethyl)pyrrolidiri-2-one N¨Q. N - 0 .1õ.. ..µ,...,,:.
li -a , H ikµr Nk).
N K
HN p 1 Z .----==N \,..,....k,. ..

== it 4 f i N-4--(4,(0 , 1-'--b iphenyi I -:2- y1)-2.--cyclOropy1-6,7- 4-(2:=cyclopr:Ty1.4:(3i;5,-dimilfhy1isoklizot.4..y1).
dihydro-11-1-benzo[d]imidazol-6-y0-3,5- I FL-benw[d]imidazol-4,11)benzami de ditnethytistinzole ,....--= 1 )--s., ),..s.

a .. ...N., ., . ... - -T 1 = = -11112 "L
- . .se.=;== -.., õ,,,,z,õ
<-11Ar-14 = - = \ ¨441-1 L d-... .
..
, :3-(2-cyc I opropy1-643,5-dirnethylisonzol-4-y1)- 11-(2-cyclopropy1-7-phenyl-11-1, Ill-benzoidlinridazol-4-yObenzanide benzo[d] inii dazo1-5-y1)-3,5-di methyl isoxazole N ¨0 ,..... i. "..),,y,.....
al 1.1.
N, ' -Ø.. . ie'k,.. \ . .
.= ,:..-:='-',-,õ.----,:,,,,,,-0.., \
1 , at \ s 1 4y....\ NH \,,,,,,t,õ
OH.
4-(2-cyclopropy1-5-(3,5-dirn ethyl isoxazo1-4.y1)- 4-(2.cyclopropy1-7-(3.,5-dirnethoxypheny1)-1H-I11-bonzo[d]imidazol-7-y1)phenol benzo[dlimidazol-5-y1)-3,5-diniethyl Isonzo] e õ.
. SUBSTITUTE SHEET (RULE 26) WO 2017/(159252 N-Q N¨ 0 it s, ...., / ....,4..õ.õ,.
f ....- \ t :, N.., .
E
' i HN \...., I I, kN =<1, =
.0A==\.... 1 .,-;,.. \ .,,,,=;;;\
;) H 1 11 1 ' 4 ij ...re, N A.,=,<.,..,.,'...
I
. = '"'N =-k ..^4 ...., \ .....,.., . .
'''`...1 = =
4-(4-(2-benzylpheny1)-2-cyclopropy1- I 11- 4-0-cyclopropy1-4-(2,(-di met hylph eny1).- Ill-be ezof dilimidazoi-6-y1)- 3.5-di methylisoxazoie benzo[d] imi dazol-6-y1)-3,5-dim ethyl i sonzoie *(1....õ4,v.
A'.."... . . . .= õ .
µ4;
..,,..,?..0%

4) H NI - t 0 NH.4,, \,, .
1 OH.
442- e yelopropy1-4-0-toly!)- III- . 44.2-eyetopropyl-.5-(3,5.41hydhyliiioie2e1-4-y1)--benzo[d limidazol-6-y1),3,5,disnethylisokszete . l H-benzoidlimidazol.-7-y1)-2,6-dimethylphenol ..... .. = . ,. .- .., = ,,,f, (1/4 p,... NI ,==== =\-,=,c\
,(2--\ NH . ... . . :
NI i. itt ..
4-(2-eye4opropy1-7-(3,5-dimeth.ylpheny) )== 1 1-1- 442-eyelopropy14-(1,3-dimethy1pheny1)-1 II-benze[d] imidazoi-5-y1)-3,5-dimethyl isexazole benzo[d]imidazo1-5-y1)-3,5-dimethylisoxanie 0¨N N-0 ... .. N. µ .. =
--- Y -.-sk , N ...õ...-.),;,,,õ.. N sfµ
....v.-;-\,,,,,,,,,,, i :.N ;I !.
'-`11H N= ./ )NH ..,,,,,....;;;O; -J,..
<4 4 4-(2.-eyclo.propy)-7-(imidazo[ 1 ,2-a]pyridin-3- 4-(2-cyc1opropy1-7-(qui nol M-81.1)-1 H-yi)-111 =beazo[d]imidazol-5-y1)-3,5- benza[diirnidazol-5-y1)-3:5-dimethy1isexazole dimeshyl isoxstzole ..
SUBSTITUTE SHEET (RULE 26) - 82 , 4,1, II , ' N H "L ,-.=:=:',"
4(1-\-\\,,,,.. N 1¨ NH ,,,e) - = .
.e. ..
zi 4-(2,cyclopropy1-7.(quino1in-5-y1)-11-1- 4-(2-eyelopropy1.7-(isoquinolin-5-y1)-1.1-1-benzoknitnidazo1-5-y1)-3,5-dimethy1isonzole benzo[dlimidazo1.5-y1)-:3,5-dimalvligoxazole ...--'c.:,*=---õ, , it 1,,,;
C \) ,-4"k' .:Nk :;=P i 7--:.0-t4 :
A ;
", õ...¨' = ',,,,,,- .k.,,...4,r,-, . --N H ..,...- ,;;;:se=
<1 .,.
1 ..
442-cydopropyl-7-(isoquino144-yly1.11- . 4-(2-cyclopropy1-4-(2--phertylIvritli a-3- y1)- 11.1, benza[dlimidazol,511)-3,5-dinteiltylisoxazo1e, bovo[diinnidazol-6-111)-3,5-dirativlisimazole N'O
...Ar)õ,;...
...-- ,...õ,,õ..fr .-.... ...õ..,4\ : ..;.. ..
tr\i' ..::::" '` '),=:.---:,1 ic '\.;
..."4.=k,,... 0.:=,,,,, ,,,,.
-,,....--L. ......\

= - - 1 .IN
</-- ....4 ).:4.. /( <NI' 4-(2-cyclopmpy1-4-(5-(4-f1uoroplteny1)- iii- 4-(2*-cyclopropyl- 1 'H-[ 1,4'-p yrazol-4-y1)- 111-berizo[d] int idazol-6-y1)-3,5- bibenzoldlitriidazoil-6'-y1)-3,5-dimethylisexazoIe dimethyl ism azole '"µk! s',"==
,,,r\õ,..
,-.-z=V
..4 "\=
i l' .../"kN-4,,,õ,,,= : . ,.....N. s, .õ .., , 1.iN
<1 4-(2-cyclopropy1-6-(3,5-dimethylisoxazo1-411). 4-(4-12,(leirt-buiox myri din-4-11)-2-1 H-benzo[d] imiclazol-4-y1)plithlazin-1 (21-1)- cydopropy1-1 H-berzo[d]
imida2oI-6-y1)-3,S-one dimeilly1 iSOXitZOIC
SUBSTITUTE SHEET (RULE 26) .

WO 2017/(159252 PCT/US2016/054780 N.¨ 0 ON
= .--"' -...rx s --- .-- =-\..../.---I i !
..3.1-,,,=
I If /L,!:',N, .0,0. .-...:0 õA \ \r",.= '':',.' =
.,,,,,,,;',.\ ,...õ- N
ri L\\,... IV H )".,N IL., F.3C
=
4-(2.-cyclopropy1-6-(3,5-dirnethylisoxazo1-4-y1)- 3,5-dimethy1-4-(4-(quinolin-5-yi)-2-1H-benzo[dlinfidazol-4-yOpyridirt-2( 11-1)-orte (trifluoromethyl)-1H-benzo[djimidazol-6-0)isox3zol:e ..,.----e, õ..r. --..... 0,.? .. \\ ...'::...sr.x, .:====*''V..''',N .

..õ .,..,.

e.---k..s: .,,..r.:f-P r=-= N \ -,,, 1 - I .t., k 4:0...\\\,õA.õ
H . : .t N.,..N HN )''. 'to.:-..*' .
512-4-14 I I Y.:- N ,,,-sN
- :
s clit¨ NH

N-(643,5-dimethylisoxazol-4-A-4-(2- N-(eyei opropylmothyi),(4,6-bh.;(3,5 phenyl pyr i di rt-311)- ) H-benzo[d]imidazol-2- dirnethylisoxazol-4-y1)-1/1,,benzo[dJimidazol-2-yijeyelopropanestil.fonarnide amine 0. -N 0 - N
. 1 .k1 = 1 sef, =
0,...r...= = .,>. '....- .st ,...'.4., 11 i " 64 .. ....t, - -.....--;=.. / ,,,,,;.,,,,,,, =
,..=:-,c HN , .$,, = .
sc =--'N ::,õ."
/ . s 1-13 ¨0 4-(2-ethoxy-4-(6-metftylquinolin-5-y1)-1H- 4-(2-methox y-4-(6-methyl qu inolin-5-y1)-11-1-berizokilimidazol-6-y1)-3,5-illincthytisnxazo le benzortilitnidazoi-6-y1)-3,5-dirnethy1isoxazole . = / -:
Ask-- - -Ns.,',---;:.=
.-.....'\:,..,.... .ietN
A ,41 k /
y'N
¨0 0 \
4-(4-(3,5-dirnethyi- I H-pyrazni-4-y1).-2.- 4444 I ,4-ditnethy1-1H-pyrazo!-5-y1)-2-rnethoxy- i H-benzo[clinnidazol-6-y1)-3,5- methoxr-1H-benzobilirni dazol-6-y1)-3,5-dinuAllyi ism az.ole dimethyllsoxazole SUBSTITUTE SHEET (RULE 26) WO 2017/(159252 - 84 =
0 ¨N Q ¨ N
.--- '\: -A`==-=
1:
L.

,, ' ,-,...., .),õ 1 i 4,..e. . .., N i 1,1 s N H Wµ IL 1 1)--k.1 =.= ,.., NH 1),-.-...1=N ......_ .
õ...-./. , .1, I
447.(3,5-dimeth y1-1H-pyrazo1-4-11)-2-methyl- 3,5-di methy1-4-(2-methyl-41-( 6-methyl quinolin-111-benzo[d] im idazol-5-y1)-3,5- 5-y1)-1H-benzo[d]imidazol-611)isnazole dimethyl isoxazo le :,,..,......,,,, liNf ''N
T
TN( µzN HN =====is \--=::r rz.-:; =
1 i.
> = tki :.--;;;=' ''.i HO -1 k\,, .
.' = s.;=.=+INI
,,..
.,õ
) OH
444-(2,4-dimethy1pyridin-3-y1)-2-methy1-IH- 14643,5 -dim ethyl iso.azol-4-y1)-4-(6-benzo(d] imidazol-6-y1)-3,5-dimethyl isoxazole me th yl q u inolin-5-yi)-111-benzo[djimidazol-2-' yl)propane-1,3-diol e=-=
S ¨
. I. .- .
..., == =.=
r, 1 ) i ;.,,, .....c ...,- ,,,s;:\
HN f* . \ r NH N \ i 1 'NH
)=='N lz.'=>,= /,''''-zzN
/ - N
i >,-= H;iN
N-cyclopropy1-4-(3,5-di methyl., I ii-pyfazoi.4- 743,5.dimethy1-111-pyrazoi4-y1)-5-(3,5-y1)-6-(3,5-dimethyligomol-41))-1H- dimethy1isoxazol-4-y1)-1H-benzo[d]imidazoi,2, benzoldjimidazoi-2-arnine amine .,4õ,,,,..d.Lõ. ...-.="4 Nis 10X-===,, I I
1--- ,...., 1 I frTh HN
fiy-Ni' ,N H
)---- N H 4' / ' N H )'..?..N ,/k.'N
H N /.-- N H

0',*='S=0 0(31 N-(7-(3,5-dimethy1-111-pyrazoi-4-y1)-541,5- N4tyclopropylmethyl)-4-(3,5-dimethyl-1H-dimethylisoxazot-4-y1),1.1-1-benzo[djimidazol-2- pyrazo1-4-y1)-6-(3,5-dimethy1isoxazo1-411)- I H-y11cyclopropanestilfonamide benzo[d]imidazol-2-amine SUBSTITUTE SHEET (RULE 26) ...:$.5. ==-=
;WO. -TN.
i .......::: ... \\....:
:.,=: .: N. ?.--,õ
.:: == = .....õ. . ... .
.r. -1:
.1 .: i .,, i'1..:
.õ-,073-,,,,....,,k ..õ:õ..f.k.õ...õõ.,., 1-1N. ).. ',1-- Nft ... -.7.'N ..:.,...".., :.
....-= .
H. = i II i'l , .....,.N
4-(2-c- yclwropyi-'4,.(3,, S- dimethy1-1H-pyrazot -4- 442- :: =y=:. op ropyl- 4- (2-mothyipri .y1)-111-benzo[djimidaz(l-.611),3,5- b.enzolk I n i (.N.wi=-11-:;,/1)-2..,:',--,i :i 3: ct[hy :soy2.e.ol e di In ethyl i Oxazolt ON N 0 ¨ N
.'1 I : ...':'. . . ...
. -11 = ==== : :
=
liN.:== .= I ..' I === = HN . f = 1. = == ..
'''''' N === :.......:.... IN
<I). . 17::: N cõ.......0, =
.--- .14-4-,(liz-yelopr6pyi -443- tIle hylpyri cth.1.4414-114- 4-12-c yclopropy1-4-(4-nwthylpyr5=dirt.:3-34)- In.
betazofdli3nitiazo1-6-y1 )--3,5-dirmethy4isoxazole benzo[d]inlidazol-6-yl)-3,5-dixo.abylisoxat6le 0 ¨N
..õ...-4... ''sx..
."..) N 1 1,1 = N N( ' = 1:
= . \ _ . , . 1,...t iy=-=
<r)..
=- NO ig...'74!.. ''''-- '.q. :ii e:
..=.- .... ''..,..: = 4.
õ,,,, 11 =
=-=--,,,2=N
4,-(2-0yolopropyl-7-(1,.4-dir(1ethyl-IH-pyrazol-5, 4-1'2 -c. yi!,1,3 propyl-`,T-=(6 - : , ;:.-:=liy I (i 1.: i ;) c i : i--5-y1)-1K-yl)- I .1.1--beh?...okliiinii,lazol.-5-yi.)-V- bowoi di imiduol . '5- yi)-''.,,:f! = (Li:1-w ; h yl.i.soxazoId klin=io:hyi koxazole N- 0 NO.
=:=.,=,,J ,='... = 1, . . -:_,,, . =
:::r.;=i ,. =:..
L =
.7.. .1; ....:
.: -N.. . k>.
, =.. a. il cl--.:i. \ tr...N .... :-....
4...
P....
, 4-{7:-Q,,c1opt6pyl-4-(2-il= tilx.y-4.- 4-(2-cyciopropy1-442-etho=xy,-1-mettylpyriclirt-i:rehy1pyidin-311)-11-1-be;lzokijilitlazol-6-A)- 3.11),11I-bm2..ofdinidazoJ,6-yly'.3,5-3,5-dimothyl isoxvole. dilm.thyb )zok:
SUBSTITUTE SHEET (RULE 26) WO 2017/(159252 PCT/US2016/054780 1:. "C) i k \y/ N - 0 ....,, = ,,,,Aõ \ . . -------- ...:P^',-,-.
===.k.
,--.:\õ.. ,,,,A
H N 'I 4 HN , r, \ ¨
, 11 4r---Th H õA. N) : -.)- ¨
0 ''''N ==''¨ =
/ NI
<-3-(2-cycloprop y1-6-(3,5- d imohyl ism( azo1-4-y1)- 4-(2-cyclopropyl -4-(2,4-diniethylthiazol-5-y0-1H-henzo[dlintidaz01-4-y1)-4-methylpyridin-2.- 1H-benzokliimidazol-15-y1)-3,5-ol dimethyli manic N¨ 0 .N¨Q
= 1 ..,. - :.õ , == . -= ' ' 1 - =
1 . -. i R
N..
.>':. õ.....
ON..-4 c \ 1.\
i Ni yel-op to py1.-444;5-di tlitliy1-:11-1-i fa i da z-cil- - 4-(2-c ycloilirop yl.-4.:(3,5d finethy1-1H--1,2.4.-I -y1)-1.11-benzo[djimidazo1-6-y1)-3,5- triaz.01-1-34)-1H-benzo[d]imidazol6-y1)-3,5.
dimethylisoxazole &methyl isexanle ../ .
3, ),,,,, 1.----'4,7 A
if:.
.;;;'''N. = ,ey ,...1,..4 4 /L.
'N . et Ni <I.
4-(2-cyclopropy1,4-(3,5-dimetliy1-411-1,2,4- 4-(2-cyclopropyl-4-(2,5-ditnothyl-IH-irnidazol-tri azol-4-y1)-1}1-benzo[d] imidazo1-6- y1)-3,5- 1-y1)-1 H-benzo[d]
imidazol-6-y1)-3,S-din:ethyl isox awle dimethylisoxazole -f;,-.,,, / ) ' 1 ,-; i"
i = r IN,\,..A= .-A, j\".\\..1., I-1N 1 yµ \-N
<I0 1.,:õ:õ/
4-(2-cyclopropy1-2-methyl- i 'H-[I ,T- 4-(2-cyclopropy1-4--(2-methyl- 1 11-imidazol- i -bibenzo[d] im i d azol 1-('- yl)-3,5- yi)- I H-benzo[d]imidazol-6-y1)-3,5-dirriethylisoKazole dimeitty1isoxazote SUBSTITUTE SHEET (RULE 26) WO 2017/(159252 PCT/US2016/054780 -.87 -¨0 --i - =
y ON
-t , i . kk --- \N, ,-----, ...J.:') H N .. L. , `,(N
LN
I . .. ,:==T : 1. . , 1,-.
= 4%.,:, A, N = - 1 *s N
-.1.....9ki , ...,:. ' NH = AI
V-a) 4Ø'-cyclopropy1-4,5,63-tetrahydro, I '11.1 1.4'- 4-(2-eye1opropy1-7-(2,4-dirnethylpyridin-3-y1)-bibenzo[djimidazoq-6'-y1)-3,5- 1 11-bonzo[d]iniidazol-5-y1)-3,5-dimethylisonzole dimethylisoxazole ON NO
= N ,....) ----: .-= (.......44 - = = .s.`?
1- 'Ns_ V' :. =
'N - .=-=---i /
. : t ti .g :--..
.:.= -::.:-...=-=," 2.. i , _,,,:::-:-k NH HN t I
t,.. NH
õ.,.2.-- <., :"'N /s=-'N
4,(2-cyclopropy1-4-(5-erlopropy1-3-methyl- 4-(2-cyc lopropy1-4-(3-methyl-5-phenyl- 1 H-I H-praml--411). I H-benzo[dlitnid2zol-6-y1)- mazol-4-y1)-I fl-benzo[illinndazoi-6-3,1)-3,5-3,5-dimethyl isoxazole dimethyl isoxazo le N - a 5r5,:..,õ...
,....:õ..,,,..,, , , .
......
,.. , ,.,....,,,... =.
HN ' II IA 11 N
=
= 1st' 0 H
4-(2-cyc1opropyl-44.3,5.dicyclopropy1- 1H- 5-(2-cyclopropy1-6-(3,5-dirnethylisoKazol-4-y1)-pyrazol-4-yI)- 1 H-benzo[d lirnidazoI-6-y1)-3,5- I H-benzo[dlimiciazol-4-y1 ii soquinol in- I(2H)-dimanyi isoxazole one N
c,), 4 .)..
04? =
L'µ
. P
:..,;,1-,k,N_...)..\.,.... , ,.......\.?õ,. `.\\ ....AN As'N=
H Nic) I
fi N T 1 '''''N ---3\s, -,.Ø
<11- e' =4'.?
i N.. =-=(`,..\ ,ir., ,,,,,,,i' õ..;:.) it ....11' , NH
N 4 '0 5-(2-cyclopropyI-6.(3,5-dimethylisoxazo1-4-y1)- 542-cycIori1opy1-6-(3,5-climethylis3xazol 4 yl).
I H-benzo[djimidazol-4-y1)-3,4- I H-benzo[d]inlidazol-4-yDquinohn-2(1H)-one dittydmisocioinolin-1(.2H)-one SUBSTITUTE SHEET (RULE 26) WO 2017/(159252 PCT/US2016/054780 4=G'''''' = ...,,, -...
i 11 HN./'k--k`-µ
iNy--N
<I
N OH
N OH
542-eyelopr.,o,...ip,1yr v.N./...lA- .-, . ¨.6.. -0-,( = 5:- ,d.
m ethyli1soxazol-4-y1)- 5-(2-cycl opro pyi- 6-(13,=¨,..5.. ..-=d, i m.
e.
th ylisoxazol -4 -y1)-1 1i-berzo[llimidazol-4-y)-4,6- 11-benzo[d]imidazo1-4-y1)-4-methylpyriIidin-dmethylpyrimich-.2-ol 2-01 0 .1 ,....L..õ...k.\
...,>.õ ,I( ,,,, ...õ..,...=.,...., ., I I, NH FIN 1 -i---% ==,k,,-- kle. 7...' N . -... ---,,...--- = -. -i =

5`-(2-eyelopropy1-64.3,5-dimethylisoxazo1-4- 5(2-eyelopropy1-6-(3,5-dimethy)isoxazo1-411)-y1)- 111-benzo[d] imidazol-4- I 11-benzoi d]imidarA)14-y1)-1-methy1-3,4-yl)spiro[e yelopreparie-1,1'-isoMblin]-3'-one dihydroquirto1in-2( 1 1-1)-one .õ,....(y),..,.
.. . .
,...--L
,,,,Q i E.11 N-I /
. = ,I\ ,..-N 5 \ N N'µ I. 1 ,N
%
NH
<1--\ /
4-(2-cyclopropy1-7-(3,5-dimethyl- 1 11-pyraz)1-4- 442-cyclopropy1-7-(1,44dimethyl- I 1-1-pyrazol-5-yl)- 1 -m ethyl - 1 If4betrzokl1imidazol-5-y1)-3,5- y1)- 1-methyl- I H-betizo[djimidazol-5-y1)-3,5-dimethylismazole dimethylisoxazole ¨
i r II
e s'== -le i , N . i ,.....,c.:;.( NTNH
\ ,--' \ v.:- ¨"'N s',=-=-=,-- N' ....-4-(1-eyciapropyl-l-methyl-746-methylquirtolin- 4-(2-eyelobtity1-4-(3,5-dimethyl-ili-prazol-4-5-y1)-111-benzo[djimidazol-511)-3,5- y1)-1H-betizo[d] imidazol-6-y1)-3,5-di methyl isexazole d imethyli soxazole SUBSTITUTE SHEET (RULE 26) N'r. Q. NC) .t s.
..,=..= ..._ ,...A. ..õ,:eõ,,,...õ
ri..),..õ ..., ..,.:
- -......,:,...-='..--,....2...-.,õ
NI-I Ht. i 'I' 0 \,:-.;;%, 3=:-.:::: ,. Ny-......:1,1 .1.7...õ
, F , , / NI
V / N
....-1 4-0 -(35--;11-lie.t.hy1-11 -pyr:AZ01-4,11)724 1- 4,4'42.4: yclopropyi, In-bctrzakqimidazolz-41,6-fluorocyclorropy1)- I H-lx.mz of dlitnidaz61-6-y.1)- diyi)bis(3,5-dirnettiylisoxazole) VA:lin:ethyl isimazoie N - = N -0 i( ., A, I' =
: I,ilk, i UN i = . = f. T)...1: : HN ' := 't=
N
k="-t:i ,Li.
y)-1.H- 4-(4-(1,4-diittothy1, I }-i ..pgazo1,514)- I H-bemoki.limidazol,6- yl)3.õ5,(Iira.otbyliscixazde benzoDijimidazo[-6-:03,5,-diroethy.limcnole:
NO
. I
..... \.,õ.:: : ...4 ...
, F
--.,õ-.-, 3,5- dim (tly1-4-(4-(6-n :...i :.:,,i i u inolin-5.- y1)-11-1- 4-(`..-is clifl'uoron-i.:AyI)-75-climethyl-114, bozo[dlituidani-6-y1)i so x ;Izolc. pyrazoi-4-,l :- 1 Ã1-1),T,.,)1.(i.jiaidazoi-511)-3,.5.
N - Q
,=;.'; . = 4>" ' ',s,.
, ....õ
'7?).. .õ
: / - : . i:::;::-.= .: . ., :. ,,,.,:iN
1 =
. ... .,,,...; i:
.:
FqC
di ill soi.os).,:: ftspropy1)-7Ø-din-litsysl- 3,5,4 methy-14-(4-(6,mettr;
i p.(!ii3-5-yi)-2-In-!) yr ..:zol..4- -... i-. i .(i.dii1t..;;ZOI..'.;=11).=
(1.1jillioromethyi)-111- ben zo[d:ii:: il.ifiazo i.,6-3,5-,dimethyl ho x ::; zoitr, yi).ians,m4le SUBSTITUTE SHEET (RULE 26) , 90==
0.-N 0.-N
,õ::::=.H =:.. t. ......õ.
=
= =
P: i -,,,µ,:',K,c c, ),,,,,,,, :... :,:.: ... , ,,)'-'t ;,i-/ N
F3C Fie :,.. ...-- NH

dw,3ei-liviiso.,;;A:1-.1._y1)....2, 4-(4-(1,,I-dii1cthyl-IH-pcwol-5-yr.k?-(trifi.w,rony.:thyl ).. I 1 i-i.-,(J17.c:i (11 im i dn., ol-4-y1),:-ettifiL:03.0)TIElliy!)- i 7.5.,,1 H
p - N o -1,1 ,,k:, ' :. I. :-;....f;..,...:: . .
. '''. ..µ"''''*
0 . .. , ..
. ..

0 : . N
- N .
:?: ............. \sõ
N-Y;=i....i,z1"-dini::.111:yli:.,0Nu./.0 --I - ,....1)-4-i (1- 3,5:-dinik:ii-cyi-ii -(2-; 1 - 3-=:;.11.),:-metli,,,it.iiiH.µThl -.µ....1).1.11-t,,1-1;:o[..ilklicia.zol--, ,.,1)....:ioi)r.:-T.:ii10,....i;i..:.Kiiltiiic. 1>co.:;..01,1iin-ii,...=!!
(, µ')is,..::=,.::::::ie .., ............. -S. .,-..-;..?...c....:.
Y
[IN µ1 )N c.' õ...,.xf-':
õ
Q.
5.47.-c.yclop:-,1Dy1-6-1,5-dirr.ictipil1sr)xtrzat.411 li i- i..f.:n;

ti4lyc.I.voquil.aQ i .:- ...:( I 1r SUBSTITUTE SHEET (RULE 26) WO 2017/(159252 .. .4......---:., õ4: 11.}
FIN
¨ N HN
F HO

F F. = .:-...., N-eyelopenty1-643,5-dimethylisoxazol-4-y1)-2- Nacyclopenty1-6-(3,5-dimethylisoxazol-411)-2-(ttilluoromethyl)-11-1-benzo[d]imidszo1e-4- (hydt oxymethy.1)-1H-benzo[d]
imida zole.-4-sulfima m i de sulfonamide HN ::
..: = - . 1.,11,0 õ,. . _ .0 .. rr.....0 yr - .- . 14 FIN HN
¨0 2,benzyl-N=-eyelopentyl--643,5- methyl (.40-eyelopentylsulfamoy1)-6-(3,5-dimethyliwxazolal-y1)-1H-beirzof (Iliad dazole- dimeihyl isoxazol411}-1H-benzo[d] im idazel-2-4-su I fonamide Aearbamate N - =
.. / . rv ..........õ,".õ.

..e.7'N,... e=-k1 ,A 0 = = - rs.."

-X:=== N 11 !Lc-) \ Htk \\f N HN-%
? l'''' <sir NH
=
N-cycl openty1-24(eyelopropylmethyi)amino)4 N-cyc1openty1-643,5-thmethylisoxam.1-411)-2-(3,5-dintethylisoxazol-4=11)4 H- ((2-methoxyethy1)amino)-1H-benzo[d] imi dazole-47su ifimami de benzo[dii midazole-4-sulfonami de - ... Ni -,e1-..,e T
i :
*.
= - - 9,0 ..",,,;;O:-.
FIN H N / S
- r r H2N (1). HN )N FIN
\::=1" NH
2 -a.min o-N=cyclopentyl-6-(3,5- N-cyclopenty1-6(3,5-dimethylisoxazol-4-y1)-dim et b.yl iso x azol-4-y1)-11-1-benzo[djimidazolo- (phenylamino)l H-benzo[d]imidazo1e4-4-sulfonamide sultbnamide SUBSTITUTE SHEET (RULE 26) WO 2017/(159252 N - 0 N.- 0 / ......'" = 1 ,. t< \\*, Ii JO ) ?.
,...?=== ....:.'"' II, 0 1-1 \1)..=.: NT HNõID
e ---il- ..i.-,..÷

:I I
N HN
FIN r \
, . r---, _7----N1-1 . ili 0 N
\ ......./
2-4.benzyiarnino)-N-cyclopentyl-6-(3,5- N-cyclope1ty1-6-(3,5-climethylisoxazol-4-yi)-2-ctimethy1isokazol-4-y1)- I H-benzo[d)imidazole= ((2-morpho1inoet.hyl)amino)- I H-4-su ifonamide benzo[d]imidazole-4-sulfonamide N--) N- 0 .....: --....
, "1\
) it 1N .,i 1- ' S
'1 H.14 I f?
1........D
>--- N H
ce N-cyc1openty1-2-(cyc1opropyiamiao)-6-(3,5- N-cyc lopenty1-6-(3,5-dimethylisouzol-4-y1)-2-dimethylisoxazol-4-y0-1 H -be [riot (I) i m idazole- (atetrahydrofuran-2-yOmethylpmino)- I II-4-sulfonamide benzo[d] im idazol e -4-su I fonann de I
11 1 0 4 .1 0 ,. A. ii 0 ,...,,,,.......-..õ,,,,.,0 = N.;,,l, s'.. ,I.; ._ HN ./-' y- HN /.
)::----N 1-1N)N HN_..f.-N H
ar F F
N-cyclopenty1-6-(33-dimethylisoxazo1-4-11)-2- N-cyclopenty1-6(3,.5-dirtietlyfisoxazo1-4-y1)-2--((2-methoxyckl).x.pi n6).= LW-(.<7,2,17trifiti9ropthyDatn.inc:).)-.1H-:
benzo[djimiti32:ole -4,sulftmarrii de -benzold]irnidiv.61e-4-mffortarnide!.
=
=
SUBSTITUTE SHEET (RULE 26) WO 2017/(159252 PCT/US2016/054780 . - 1-...:/....=--A.
..x 4 'N..1 0 e ,,11:',', \ & 11,0 A ,-;:,,..11.;.0 - ',...- ..,-.v.. - y , i-iN / y H N / 'i) x-N H N , , ,. ) ):::---= N HN
0 r¨N H 0)......r NH 1 -HO Lõ) f-- "
3-0/1-(N-eyelopentylsulfamoy1)-6-(3,5- ethyl 34(44N-cyclopentylsu1 fam oy1)-(-(3,5-dirtied] yl i soxazu1.4-y1), I 11-benzo[d]imidazol-2- dirnethyl isoxazol-4-yl)-1H-benz.u[dli III idazol-2-yl)amino)propanoic acid ypamino)propanottte N"' HN7 ..,:s,-1 _0 . (110.'=9:.,0 -... . = .11.ov ... :
= =
KS
I--i S\
N-cyciopenty1-643,54itnothylismazol.4-y1)-2- N-cyc1opentyl-6-(3,5-dimethylisoxazol-4-y1)-2-mere&pto-1H-benzo[djimidazole-4-stilfonamide (nethylthin)-113-benzo[dliinidazole-4-su.lfOrtarnide N -l....,k ..".....7::::^ , . :-..0 /1/4\ --s.',':"..\=.":-..0 H N f i3 114 T . i3 0SHN,...,........\
"
Li 1::) \ "to N-cycl openty1-6-(3,5-dimethylisuxazol-4- y1)-2- N-cycl openty1-6-(3,5-ditnethyli soxazol-4-y1)-2-(methyl suifinyi)-1 El-benzurdjimidazoloal- (mothylsol fooy1)-111-benzo[dj imidazole-it-sulfonamide sulfonamide !I :
is H N
..,,,iõ,....,,, ,..,.....,. ....(), 0 \ 0 i ,*
1,:ksz, I
methyl 2-tint ino,6-(3,5-d imetyl ixota zol-et-y1). methyl I -ben41-2.-cyclopropy1-5-(3,5-1H-benzu[d] imi dazole-4-carimyl ate dimethylisoxazol-4-y0-1H-benzo[dInnidazole-7,carboxyiate SUBSTITUTE SHEET (RULE 26) - 94..
.:.:
. . .
, .. , sil - - NN
, ,======,,,,µ= ,. .. 7...wi. 6.
= .,--,s.:::/. ,,. ' ( : ---N 0 ,--..--, methyl 1 - ix,. i 3Zy.-2.-eye 1opropy14',,-(3,5- methyl 2 -ey'alopropyl-643,5. -dim ethyli s o K 3201-dith e thy I &ck.1., ;:?.o1-1--y1)-1 R-bono[illimidazole, 4.-y1)-111,benzo[d]imithrzoie-4-earboxylate 4-carboxy1ate N - q Nr 0 :
A\r 1 ..
. =
0 N., 1 .
i.,---..!:N. .:6.
<el <1.
methyl 1-e yc.: lopt opyl- 6-.0 ,5 .,,linIc.1:11y1lsomtzol- may' 2-µ`,yeh).-propyl.,5(3,5wilimthyl l',!n.a.z.61.-411)- 1 --me. thyt-TE- bc 31Z,C RI I I II iitta010-4- 4-y])-1 -owl:11y] - 1 H- b ,i-ce.o[.,:ljlimiskizole-7-carhosyl aie mit oxyl,:i e i% "... ..ti.
t t:
or!' -,...1::::",,, ..;
IN f I , ,...,..., s ¨ I-1N i ' I
is''''N - ' .'---.N

1 ..'1 A
(.) = ii Zkk N.(6.(3,5..dinit,thylis 0 Y. 3 7.01,41)-4Hiodo-11:1- 4-(244yei op i0\ I -4-ip d o- ITT, t=,, .;1 ]=:,)i- di imi &mil-1.- lizoi di imidaz01-2-yijo:yi:iiyi,.;)=ati.;suifonatilitie . . =
. . .. .
leNs.. )0 ." ,.---.. N
. " .
FIN T
/-7-4st <
tkl-cyclopenty1,2,-eyelopropy--.)-0,5, dip = t h yi isoxazol-4-y1)- i II- lnzo[d] :.r!idazol:-.4--arr,IMe SUBSTITUTE SHEET (RULE 26) WO 2017/(159252 -95...
1001451 it is understood that separate, single embodiments comprise the methods, regimens, 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-cyclopropy1-6-(3,5-dimethylisoxazol -4-y1)-III-benzo[d]imidazol-4-Adi(pyridin-2-Amethanol, 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 bronuxiomain-containing protein is .(2-cyclopropy14(3,5-dimethylisoxazol-4.y1)-11-1-benzo( dji idazol-311)dicpyrazin-2-y1)methanol, or a pharmaceutically acceptable hydrate thereof. There are also embodiments in which the modulator of a bromodomain-containing protein is (2-eyclopropy1-6-(3,5-dimethylisoxazoL-410-111-berizo[d]imidazol-4-34)(pyridin-2-y1)(pyrimidin-5-Amethanol, or a pharmaceutically acceptable hydrate thereof.
1001461 There are also embodiments in which the modulator of a bromodomain-containing protein is (2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-1171-berrzo[d]imidazol-4-y1)(pyridin-2-y1)(pyrimidin-2-yOmethanol, or a pharmaceutically acceptable hydrate thereof There are also embodiments in which the modulator of a bromodomain-containing protein is (2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-11I-benzo[dlimidazol-4-Adi(pyridin-3-Amethanol, or a pharmaceutically acceptable hydrate thereof There are also embodiments in which the modulator of a bromodomain-containing protein is (2-cyclopropy1-6-(3õ5-dimethylismazol-4-y1)-1H-benzoidlimidazol-411)(phenylApyridin-2-Dmethanol, or a phannaceutically acceptable hydrate thereof There are also embodiments in which the modulator of a bromodomain-containing protein is (2-cyclopropy1-6-(3,5-dimethylisoxazol-4-y1)-11I-benzo[d]imidazo1-4-yl)(phenyl)(pyridin-3-y1)methanol, or a pharmaceutically acceptable hydrate thereof. The compounds which are modulators of a bromain-domain containing protein described above may be prepared as taught in US 2014-0336190.
SUBSTITUTE SHEET (RULE 26) WO 2017/(159252 MMP9 Inhibiting Agents [001471 Useful MMP9 inhibiting agents include comprises binding proteins, e.g., antibodies and antigen-binding fragments thereof, that bind to the matrix metailoproteinase-9 (MMP9) protein (MMP9 is also known as gelatinase-B), wherein the binding proteins comprise an immunoglobulin (1g) heavy chain (or functional fragment thereof) and. an Ig light chain (or functional fragment thereof) disclosed in U.S. 2015-0140580 (Smith et al.) and U.S. Patent Nos. 8,377,443 (McAuley et al,), 8,501,916 (McAuley et al.), and 9,120,863 (McAuley et al.), each of which is incorporated herein by reference.
1001481 Practice of the present disclosure employs, unless otherwise indicated, standard methods and conventional techniques in the fields of cell biology, toxicology, molecular biology, biochemistry, cell culture, immunology, oncology, recombinant DNA and related fields as. are within, the 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 al., "Molecular Biology of the Cell," 5th edition, Garland Science, New York, NY, 2008; Voet, D. et aL
"Fundamentals of Biochemistry: Life at the Molecular Level," 3'd edition, John Wiley & Sons, Hoboken, NJ, 2008; Sambrook, J. et at, "Molecular Cloning: A
Laboratory Manual," 3rd 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; Freafmey, R,1., "Culture of Animal Cells:

A Manual of Basic Technique," 4th edition, John Wiley & Sons, Somerset, Nj, 2000; and the series "Methods in Enzymology," Academic Press, San Diego, CA.
Sec also, fbr example, "Current Protocols in Immunology," (R.. Coico, series editor), Wiley, last updated August 2010.
1901491 The /mem 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 lg light chain (or functional fragment thereof) to be used in the methods, regimens, kits, and articles of manufacture SUBSTITUTE SHEET (RULE 26) WO 2017/(159252 herein with a pharmaceutically effective amount, or with individual dose units containing a pharmaceutically effective amount, of Compound Al.
1001501 The combinations include MMP9 binding proteins that bind specifically to MMP9 and not to other matrix metalloproteinases such as MMPI. MMP2, MMP3, MMP7, MMP9, M.MP10, .MMP12, MMP13. Such specific MMP9 binding proteins are thus generally not significantly or detectably crossreacfive with non-MMP9 matrix metalloproteinases. MMP9 binding proteins that specifically bind MMP9 find use in applications in which it is necessary or desirable to obtain specific modulation (e.g., inhibition) of MMP9, e.g., without directly affecting the activity of other matrix metalloproteinases.
1001511 In certain embodiments of the present disclosure an anti-MMP9 antibody is an inhibitor of the activity of MMP9, and can ben specific inhibitor of MMP9. In particular, the MMP9 binding proteins disclosed herein will be useful, for inhibition of MMP9 while 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.
1001521 The present combinations also comprise MMP9 binding proteins that specifically bind to nou-mouse MMP9, such as human MMP9, Cynomolgus monkey MMP9, and rat MMP9.The combinations also comprise MMP9 binding proteins (e.g.õ anti-MMP9 antibodies and functional fragments thereof) that act as non-competitive inhibitors. A "non-competitive inhibitor" refers to 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 SUBSTITUTE SHEET (RULE 26) WO 2017/(159252 thereof) that has at least about $0%, 85%, 90%, 95% or more amino acid 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 at least about 80%, 85%, 90%, 95% or more amino acid sequence identity to a heavy chain polypeptide disclosed herein.MMP9 binding proteins (e.g., antibodies and functional fragments thereof) of the present disclosure include those that hind 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.
1001541 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 variable 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 light chain polypeptide as set forth herein (e.g., SEQ ID NOS:2 or 9-12).
1001551 Sequence identity between two nucleic acids cart 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, (19:89) Cold Spring Harbor, N.Y.). An example of stringent hybridization conditions is hybridization at SOT 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 %
fonnamide, 5 x SSC (150 mM NaC1, 15 natal trisodium citrate), 50 mM sodium phosphate (017.6), 5 x Denhardt's solution, 10% dextral) sulfate, and 20 mg/m1 SUBSTITUTE SHEET (RULE 26) 99..
denatured, sheared salmon sperm DNA, followed by washing the fitters in 0.1 SSC at about 65 T. Stringent hybridization conditions are hybridization conditions that are at least as stringent as the 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.
1001561 Anti-MM.P9 antibodies can be described in terms of the CURB of the heavy and light chains. In sonic embodiments, an antibody is a humanized antibody or a human antibody. Humanized antibodies include human immununoglobulins (recipient antibody) in which residues from a complementary-determining region (CDR)-of the recipient are 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 flu= of non-human (e.g.; murine) antibodies are chimeric immtmoglobulins which contain minimal sequence derived from non-human immunoglobulin. The non-human sequences are located primarily in the variable regions, particularly in the coniplementarity-determining regions (Cl)Rs). 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 fbwid 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 al.l of the framework regions are those of a human immunoglobulin consensus sequence. For the purposes of the present disclosure, humanized antibodies can also include immunogiobulin fragments, such as Fv, Fab, Fab', le(ab'h or other antigen-binding subsequences of antibodies.
1001571 The humanized antibody can also comprise at least a portion of an immunoglobulin constant region (Fe), typically that of a human immunoglobulin.
SUBSTITUTE SHEET (RULE 26) WO 2017/(159252 - -See, for example, ;ones Vi at. (1986) Nature 321:522-525; Riechmann et al.
(1988) Nature 332:323-329; and Presta (1992) Carr. Op. Struet Biol. 2:593-596, [001581 Methods for humanizing non-human antibodies are known in the art.
Generally, a humanized antibody has one or more amino acid residues introduced into it from a source that is non-human. These non-human amino acid residues are often referred to as "import" or "donor" 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; Riechmatm et al., supra and Verhoeyen et al. (1988) Science 239:1534-1536. Accordingly, such "humanized" antibodies include chimeric antibodies (U.S. 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 species. 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).
1001591 Human antibodies can also be produced, for example, by using phage display libraries. Hoogenboom et al. (1991) .1. Mol. Rio!, 227;381; Marks etal.
(1991) J. 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.
1001601 Human antibodies can be made by introducing human immunoglobulin loci into transgenic animals (e.g.., 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) SUBSTITUTE SHEET (RULE 26) WO 2017/(159252 Bio/Technology 10:779-783 (1992); Lonberg eta!, (1994) Nature 368:: 85:6-859;
Morrison (1994) Nature 368:812-813; Fishwald et (1996) Nature Biotechnology 14:845-851; Neuberger (1996) Nature Blotechnokw 14:826; and Lonberg et al. (199$) Intern. Rev. Inanunot 13:65-93.
[001611 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 marine, rabbit, chicken, humanized or human) from which the matured antibody is prepared..
100162] An antibody can also be a bispecific antibody. Bispecilic 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).
1001631 An antibody as disclosed herein can also be an immunoconjugate. Such immunoconjugates comprise an antibody (e.g, to MMP9) 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 (e.g., an enzymatically active toxin of bacterial, fungal, plant, or animal origin, or fragments thereof), or a radioactive isotope (i.e., a radioconjugate).
[00164] An 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 orpolypeptide epitope. In some embodiments, an antibody of the present disclosure specifically binds to human MMP9 with a dissociation constant (K,1) equal to or lower than 100 nM, optionally lower than 10 nM, optionally lower than I riM, optionally lower than 0.5 nM, optionally lower than 0.1 nM, optionally lower than 0.01 nM, or optionally lower than 0.005 nM; in the .fomi of monoclonal antibody, scFv, Fab, or other firm of antibody measured at a temperature of about 4 C, 25 C, 37 C or 42 C.
SUBSTITUTE SHEET (RULE 26) WO 2017/(159252 - :102 -1001651 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 effectively blocking processing of the proenzyme or preproenzyme to the catalytically active enzyme, and thus reducing the proteolytic activity of the MMP9.1n 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 25 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 MMP. 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 (Kd), equilibrium constant (Keq) or any term in the art, [00166] In certain embodiments, 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.
1001671 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, 1hr example, an antibody having a heavy chain polypeptide of any of SEQ ID NOS:1 or 5-8, a light chain poly-peptide of SEQ ID NOS:2 or 9-1.2, or combinations thereof, In one embodiment, the anti-MMP9 antibody, for functional fragment thereof, competes for binding to human M.MP9 with the antibody described herein as AB0041 SUBSTITUTE SHEET (RULE 26) MMP9 sequence 1001681 The amino acid sequence of human MIMP9 protein is as follows:

VPDLGRFQFP EGIILKWHIIHN ITYWIQNYSE DLPRAVIDDA PARAFALWSA ISO

DAHFDDDELW KoKovvvpi RPGNADGAAC HFPFIFEGRS YSACTIDORS 250 DupwarrA NYDTDDREGP CPSERLYTRD GNADGKPCQF PPIFQGQSYS 300 ACTTDGRSDG YR.WCATTANY DRDKLFGFCP TRADSTVNIGG NSAGELEVFP 350 FTPLGKE Y crsEotwocR LVICATTSNFD SDK KWGFCPD QG Y SLY L VAA 400 HEFGHALCILD HSSVPEALMY PMYRFTEGPP LHKDDVNGIR HINGPRPEPE: 450 PRPPTTITPQ PTAPPTVCPT GPPTVHPSER PTAGPTGPPS AGPTOPVI'AG 500 PSTAT1VPLS PVDDACNVNI PDAIAEIGNQ LYLFKIXiK YW RESEGRGSRP 550 LDKLGLGADV AQVTGALRSG RCiKNILLFSGR RI.,WPSDNIKAQ leIVIIPRSASEV 65:0 7001QCPED (SEQ ID NO:27) [00169) Protein domains are shown schematically in Figure 3 and are indicated below:
Amino Acid # Feature 1-19 Signal Peptide 38-98 Peptidoglycan Binding Domain R98/C99 Propetide cleavage site (dependent on cleavage =yaw) 112-445 Zn dependent metalloptoteinase domain 223-271 Fibronectin type II domain (gelatin binding domain) 281-329 Fibronectin type II domain (gelatin binding domain) 340-388 Fibronectin type II domain (gelatin binding domain) 400-411 Zit binding region 521-565 Hemopexin-like domain 567-608 Hemopexim-like domain 613-659 Hemopexin-like domain 661-704 Heinopexin-like domain [001701 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:
SUBSTITUTE SHEET (RULE 26) WO 2017/(159252 PRONSILVI, PPGDLRTNUT DRQLAEEYLY RYOYTRVAEM RGESKSLGPA
1.11-1-QKQI.SL PETGELDSAT LKAMRTPRCG VPDLGRFQTF EGDIAWHHITN
ITYW1QNYSE DLPRAVIDDA FARAFALWSA VTPLIFTRYY S.RDADIVIQF
GVAEHGDGYP FDGKDGLLAH APPGPGIQG DAHFDDDELW SLOKGWVPI
RFONAIXIAAC HFPFIFEGRS YSACTTDGRS DGLPWCSTTA NYDTDDRFGF

DRDKI,FGFCP TRADSTVMGG NSAGELCVFP FIFLOKEYST CTSEGRGDGR
LWCATTSNED SDKKWOMPD QGYSLFLVAA HEFGHALGIA) HSSVPEALMY
PMYRFFEOPP IIIKDDVNG1R. HINGPRPEPE PRIPITITPQ PTAPPTVCPT
GPPTVHPSER PTAGPTOPPS AGPTGPPTAG PSTATIVPLS PVDDACNVNI
FDA IAEIGNQ LYLFKIXIKYW RFSEGRGSRP QGPFLIADKW PALPRKLDSV
FEEPLSICKLF FFSORQVWVY TGASVI,GPRR LDIUGLGADV AQVTGAIRSG
RGKMLISSOR RIWRFIWKAQ MVDPRSASEV DRMFPG VFW THDVFQYREK
AYFCQDRFYW RVSSRSELNQ VDQVGYVIYD11,QCPED (SEQ 1.D NO:28) 1001711 The: amino acid sequence of the signal peptide is MSLWQPININ
UNLGCCFAA (SEQ11) NO:29).
1001721 The present disclosure contemplate the use of MMP9 binding proteins that bind 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 at Examples of anti-IvIMP9 antibodies are provided below.
Mouse monoclonal anti-MMP9 [001731 A mouse monoclonal antibody to human MMP9 was obtained as described in Example 2. This antibody contains a mouse 102h heavy chain and a mouse kappa light chain, and is denoted AB0041.
1001741 The amino acid sequence of the AB004i heavy chain is as follows:

LISYGVHWIIRQPNAGLEWLOVIWTGGTTNYNSALMSRLSISKDDSKSQ
VELKMNSI,QTDDTAITYCARYYYGMDYWCiQGTSVIVSSAKITPPSTIPLA
.PGCGDTTGSSVTLGCLVKGYFPESVTVTWNSGSLSSSVHTFPALLQSGLYTMSSS
PTVPSSTWPSQTVWSWIPASSITVLYKKLEPSGPISTIPIPCPPCKECHKCPAPN
LEGGPSTTIPPPNIKDVI,MISLTPKVTCVVVDVSEDDPDVRISKTINNVEVIITA
(2712THREDYNS7IRVTISALPIQIIQUWAISGKEFKOZYNNKALPSPIERTISKIKG
SUBSTITUTE SHEET (RULE 26) WO 2017/(159252 LVRAPQMPPPAEOLSRKDVSLT(1171-1GfiNPGDISVEWTSNGHTEENYKDTA

(SEQ ID NO:1) 1001751 The signal sequence is underlined, and the sequence of the IgG2b constant region is presented italics.
1001761 The amino acid sequence of theAB0041 light chain is as follows:
MESQIQVFVFVFLWLSGVDGDIVMTQSHUMSTSVGDRYSITCKAS
QDVIINTVAWYQQKTGQSPKI..1,1YSSSYRNIGVPDRFRISGSGIDFTIMSS
NIQAEDLAVYFCQQIIYITPY1'FGGC.iTKLEI.KRADA4PTVSIFPPSSEQLTSGG.4 SIIVCPLNNFYPKDINVKWKIDGSERQNGVLNSWTDQDSKDSTYSMSSTLTLTKD
EYERHNSYTC'EATHKTSTSPTVKSFNRNEC (SEQ ID NO:2) 1001771 The signal sequence is underlined, and the sequence of the kappa constant region is presented in italics.
1001781 The following amino acid sequence comprises the framework regions and complementarity-determining regions (CDRs) of the variable region of the IgG2b heavy chain of AB0041 (with CDRs underlined):
QVQLKESGPGLVAPSQSLSffcrvSGFSUSYGVHWVRQPPGKGLE
WI,GVINVIGOTTNYNSALMSRLSISKDDSKSQVITAKMNSLQTDDTANYCA
RYYYGMDYWOQGTSATIVSS (SEQ NO:3) 1001791 The following amino acid sequence comprises the framework regions and complementaiity-determining regions (CI)Rs) of the variable =lion of the kappa light chain of AB0041 (with CDRs underlined):
DIVMTQSHIUMSTSVGDRVSUCKASQPVRNIVAWYQQKTGQSPI( YSSS YR NTGVPDRFTGSGSGTDFTHISSVQAEDIA VYPCQQR.Y.13PYIF
GGGTKLEIK (SEQ ID .0:4) Heavy-chain variants [001801 As noted in U.S. Patent Nos. 8377,443 (McAuley et al.), 8,501,916 (McAuley et al.), and 9,120,863 (McAuley et al.), the amino acid sequences of the variable regions of the ABOO4 I 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 SUBSTITUTE SHEET (RULE 26) antibody of human T1epitepes thereby reducing or abolishing its immunagenicity in humans (Antitope, Babraham, UK).
[00181 j lour heavy-ehain variants were constructed, in a human IgG4 heavy chain background containing a S241P amino acid change that stabilizes the hinge domain (Angal a at. (1993)AI:dec. iintotmoi, 3010.5-10.8), and are denotcd VII2, VII3 and VI-14. The amino acid sequeneca of their framework regions and CDRs are as follows:
VIII
QVQ):1.)ESO PGINKRSETISLICryso FSILSYGVHW v QPPCIK (MENLO V VIM
ITN YN SALM L1 ISK DDSKSIVYLKMNS LEMMA' Y(:: OW GMDYA..
SVTVSS: (SEQ ID NO:5 QVQL,QESGPGINK P SEILS urcr VSG F.:SUSI( UV W V RQPPG KGIEWLGVIWTO
TTNYNSALMSRIMSK KNTVYLKMN SLKTEDTAIYYCARYYYM4DYWOQ(.1 nyrvs8 (SEQ ID NO:6) QVQLQU(.iKII.,YXPSETIHL,TC,TYSGFSUSYOVHWVRQPPGKGLE
WLGVEWTGGTTNYNSALMSRFTISKDDSI<NTVYLKMNSLKTEDTA
WYCARYYYGNIDYWGQGTINTVSS tiSEQ ID NO: 7) QNTQLQESGPOLVKP SETIS LTCTV.SOFSLI,SYGVII WYRQ PPG KOLE
WIBVINVIGGTTNYNS.A LAI S RFTISKDD SKNTLYLKMNSISTE DTA1 YYCARYYYGMDYWGQGTuvrviSS (SR) ID NO1) Light-chain variants WI 821 four light-chain variants were constructed, in a human kappa chain background, and are denoted Vkl., µ12, VL3 and Vk4. The amino acid sequences (.4 Their frameworkregions and CDRs are as followa;
VU
DIVNINSPSFLSASVCDRVIIICKASQDVRNTVAWYQQKTGRAPK
ILIYSSSYRNTOVPDRFTOSGSGTDFTLIISSLQAE.DVAVYFCQQIIYI
TPYTFOGOTKVEIK (SEQ ID NO:9) SUBSTITUTE SHEET (RULE 26) Via Di YMIQSPSSI:SA.S.VOION'IYI CKASQDVRNTVAWYQQKPGKAPK:
WYSSSYRNTGVPDRFTGSGSGTDFTLTISSLQAEDVAVY.FCQQI1Y1 TPYTFai(jTKVEIK. (SN NO:10) V.k3 -1,,La SS S YRNT(IVPDIOSOSGSPIDFTI,TISSLQIVEDVAVYFCQQIIY
TPYTFGGGTKVEIK. (SEQ ID NO: I I) k4 IY$SSYRNTGVPDRFSGSGSGTDFILIISSLQAEDVA.VYYCQQHY
ITITTIk300TYLVEM (SEC) ID NO:12.) I 001811 The:humanized heavy wad light Oaths, are combined in all possible pair-wise combinations to generate a number of functional humanized oti-IVIMP9 antibodies, [001.84j Additional hq.avy chain variabloregion amino acid sequences having 75% or more, 80% or more, 90% or more, 95% or more, or 99% or more homology to the heavy chain variable region sequences disclosed herein are also provided. Furthermon; addiiional 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 to the light chain variable region sequences disclosed herein are also provided.
[00185] Additional heavy chain viable: region amino acid sequences having 75% or more, 80% or more, 90% or more, 05% or 111004 or 99% or more.
sequence identity to the heavy chain variable region sequences di ;,:losed 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 99t; or more sequence identity to the light chain variable region sequences disclosed herein are also provided.
SUBSTITUTE SHEET (RULE 26) WO 2017/(159252 Complementarity-determining regions (CI)Rs) 1001861 The CDRs of the heavy chain of an anti-MMP9 antibody as disclosed herein have the following amino acid sequences:
CDR1: CiFSILSYGVII (SEQ ID NO:13) CDR2: VIWTGCiTINYNSALMS (SEQ. ID NO:14) CDR3: YYYGMDY (SEQ ID NO:15) 1001871 The CDRs of the light chain of an anti-MMP9 antibody as disclosed herein have the following amino acid sequences:
CDR 1: KASQDVRNTVA (SEQ ID NO:16) CDR2: SSSYRNT (SEQ ID NO:17) CDR3: QQINITPYT (SEQ ID NO:18) Nucleic acids encoding anti-MMP9 antibodies 100188] The: present disclosure provides use in the methods, regimens, kits, and articles of manufacture herein of nucleic acids encoding anti-MMP9 antibodies and functional fragment 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 fiat transcribing and translating such polynucleotides into polypeptides.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.
1001891 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 antibody or antigen-binding fragments thereof described herein which method comprises expression of nucleic acid encoding a heavy 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.
SUBSTITUTE SHEET (RULE 26) WO 2017/(159252 1901901 Systems for cloning and expression of a polypeptide in a variety of different host cells are well known, Suitable host cells include bacteria, mammalian cells, yeast, andbaculovirus systems. Mammalian cell lines available in the art for expression of a heterologous polypeptide include Chinese hamster ovary cells, TieI.a cells, baby hamster kidney cells, NSO mouse melanoma cells and many others. A common bacterial host is E. coll.
10019.11 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 plasmic's, viral e.g. 'phage, or phagemidõ as appropriate. For further details see, tbr example, Molecular Cloning: a Laboratory Manual: 2nd edition, Sambrook et ale 1989,- Cold Spring Harbor laboratory Press. Many known teaniques and protocols for manipulation of nucleic acid, for example in preparation of nucleic acid constructs, mutagenesis, sequencing, introduction of DNA into cells and gene expression, and analysis of proteins, are described in detail in Short Protocols in Molecular Biology, Second Edition, Ausubel et al. eds., John Wiley & Sons, 1992. The disclosures of Sambrook et al. and Ausubel et al. are incorporated herein by reference in their entirety.
[00192] 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 be operably linked to a promoter, and provided in an expression construct for use in methods of production of recombinant MMP9 proteins or portions thereofThose of skill in the art are aware that nucleic acids encoding the antibody chains disclosed herein can be synthesized using standard knowledge and procedures in molecular biology.
[00193] Examples of nucleotide sequences encoding the heavy and light chain amino acid sequences disclosed herein, are as follows:
SUBSTITUTE SHEET (RULE 26) CAGQTQCAGC TOCAGGAJATC CGOCCCTGOC
C:TGGTCAAGC CCICCGAGAC ACTGTCCCTG Accra::Acai TOTCCGGCTI. CTCCCTGCTO TeCTACGGC0 TOCACFGGGT
CCOACAGCCT CCAGOGAAGG GCCFGGAATG GCFOGGCGTG
ATCTGGACCG GCGGCACCAC CAACTACAA.0 TCCGCCC.TGA
TGTCCCGGCT GACCATCTCC: AAGGACGACT CCAAGTCCAC
CGTGTACCTG AAGATGAACT CCCTGAAAAC CGAGGACACC
GCCATCTACT ACTGCGCCCG GTACTACTAC GOCATGOACT
ACTGOGGCCA OGGCACCTCC GTGACCGTGT ccrcA (SR) ID
NO: 19) 11111 CAGGTGCAGC TGCACKiAATC CGGCCCTGGC
CTGOTCAAGC CCTCCGAGAC ACTGICCCTG ACCTOCAcco ATCTGGACCG GCGGCACCAC CAACTACAAC TCCOCCCIGA
TOTCCCGGCT GACCATCTCC AAGGACOACT C.:CAM:IAA:CAC
CGTOTACCTG AAGATGAACT CCCTGAAAAC CGAGGACACC
GCCATCTACT ACIGCGCCCG QTACTACTAC GOCATGGACT
ACTGGGGCCA OGGCACCCIO (iICACCO'LGT CCTCA (SEQ
NO:20) CAGGTOCAGC TGCAGGANrC CGGCCCIGGC

IGTCOGGCIT CTCCCTGCTO TCCIACGOCG TGCACTGOOT
CCGACAGCCT CCAGGCAAAQ OCCTGGAATG GCTGOGCGIG
ATCTGGACCG GCGGCACCAC CAACTACAAC TCXXICCCTGA
TGICCCOGIT CACCATCTCC AAGOACOACT CCAAGAACAC
CGTGTACCTO AAGAT"GAACT CCCTGAAAAC CGAGGACACC
CFCCATCFACT ACT GCGCCCG GTACTACTAC GGCATGGACT
AC TGGGGCCA GGOCACCCTG (TTCACCGTGT CCTCA (SEQ ID
NO:21) N1-14: C.AGGIGCAGC TGCAGQAATC CGOCCCTGGC
C TGGTCAAGC CCTCCCiAGAC AC'IGTCCCTG AMGCACCG
SUBSTITUTE SHEET (RULE 26) i I
TGTCEGGCTI CICC.CTGCTG TCCTAEOGai TGCACTGGGT
CMACAGCCT CCAGGCAAAG GCCTOGAATG GCTGGGCGTG
ATCTGGACCG GCGGCACCAC CAACTACAAC TCCGCCCTGA
TGTCCCGOTT CACCATCTCC AAGGACCIACT CCAAGAACAC
CrIGTACCTG AAGATGAACT CCCTGAAAAC CGAGGACACC
GCCATCTACT ACTGCGCCCO GTACTACTAC GGCATGGACT
ACTGGGGCCA GGGCACCCIG OTCACCGTGT (CICA (SEQ
N 0:22) Vki: GACATCGTGA TGACCCAGR. CCCCAGCTTC
CTGICCCiCCT CCGIGGGCOA CAGAGTGACC ATCACATGCA
AGGCCICTCA GOACGTGCGG AACACCM GO CCIGGIATCA
GCAGAAAACC GGCAAGGCCC CCAAGCTOCT CiATCTACICC
TCCTCCTACC GGAACACCGG CGTGCCCGAC COGITIACCO
OCR:T(10CW CGGCACCGAC TTIACCCTGA CCATCAGCTC
CCTGCAGGCC GAGGACGIGG CCOTGTACTI CIGCCAGCAG
CACTACATCA CCCCCTACAC CTIVGGCGGA GGCACCAAGG
T(GAAATAAA A (SEQ NO:23) Vk2: GA CATCGTGA TGACCCAGIC CCCCTCCAGC
CTGTCCGCCT CTGIGGGCGA CAGAGTGACC ATCACATGCA
AGGCCTCTCA GOACGTOCGG AACACCGTOG CCTGGTATCA
GCAGAACiCCC OGCAAGGCCC CCAAGCTGCT GATCTACFCC
'TCCICCTACC GOAACACCGG CGTGCCCGAC CGGITTACCG
GCICTGGCTC CGGCACCGAC TTTACCCTGA CCATCAGCTC
CCTGCAGGCC GAGGAMTGG CCGTGTACIT CTGCCAGCAG
CACTACATCA CCCCCTACAC CITCGGCGGA GGCACCAAGG
TGGAAATAAA A (SEQ ID NO:24) Vk3; GACATCCAGA TGACCCACITC.. ccccrcoka:
crarcooca crarthaicGA CAGAGTCiACC ATCACATGCA
AGGCCTCCCA GGACGTGC:GG AACACCGTGG CCTGGTATCA
GCAGAA.GCCC GGCAAGGCCC CCAAGCTGC r GATurAcitc TccrrcrAcc GGAACACCGO COTGCCCGAC CCIGTICTCTCi GCTCIGGAAO CGGCACCGAC TTIACCCTGA CCATCA.GCTC
SUBSTITUTE SHEET (RULE 26) WO 2017/(159252 CCTGCAGGCC GAGGACGTGG CCGTGTACIT CMCCAGCAO
CACTACATCA C.:CCCCIACAC CITCGGCGGA GGCACC.A.AGO
TG/CiAAATAAA A (SEQ ID NO:25) V1(4: GACATCCAGA TGACCCAGTC CCCC.7CCAGC, maccoca CTGIGGGCGA CAGAGTGACC ATCACATGCA
AGGCCTCTCA GGACGTGCGG AACACCGTGG CCIGGTATCA
GCAGAAGCCC GGCAAGGCCC CCAAGCTGCT GATCTACICC
TCCICCIACC GGAACACCGG CGTGCCCGAC CGGTICTCTG
GCTCTGGAAG CGGCACCGAC TTTACCCTGA CCATCAGCTC
CCTGCAGGCC GAGGACGTGG CCGTGTACTA CTGCCAGCAG
CACTACATCA CCCCCIACAC CTICGGCGGA GGCACCAAGG
TGGAAATAAA A (SEQ ID NO:26) 1001941 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 to obtain related nucleic acids that encode anti-MMP-9 antibodies. 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% homology to any of the nucleotide sequences disclosed herein are also provided. Accordingly, polynucleofides comprising nucleic acid sequences baying 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.
= [001.951 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 witha 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.
1001961 Pharmaceutically acceptable carriers are physiologically acceptable to the administered patient and retain the therapeutic properties of the antibodies or SUBSTITUTE SHEET (RULE 26) WO 2017/(159252 PCT/US2016/054780 peptides with which it is administered. Pharmaceuthally-acceptable carriers and their formulations are and generally described in, for example, Remington' pharmaceutical Sciences (18th Edition, ed. A. Gennaro, Mack Publishing Co., Easton, PA 1990). 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.
1001971 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.
1001991 The formulation and delivery methods will generally be adapted according to the site and the disease to be treated. Exemplary formulations =
include, but are not limited to, those suitable for parenteral administration, e.g., intravenous, intra-arterial, intramuscular, or subcutaneous administration.
1002001 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 tbnnulations 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, sorbitan monolaurate or triethanolamine oleate. Additional parenteral formulations and methods are described in Bai (1997) J. Neuroimmunol. 80:65 75; Warren (1997) SUBSTITUTE SHEET (RULE 26) WO 2017/(159252 -114..
Nonni, Set. 152:31 38; and Tonegawa (1997) L Exp.. Med. 186.:507 515. The parenteral preparation can be enclosed in ampules, disposable syringes or multiple dose vials made of glass or plastic.
1002011 Pharmaceutical compositions tbr intmdermal 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 parabens; antioxidants such =
as ascorbic acid, glutathione or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose.

1002021 Pharmaceutical compositions for injection include aqueous solutions (where water soluble) or dispersions and sterile powders thrthe extemporaneous preparation of sterile injectable. solutions or dispersion. For intravenous administration, suitable: carriers include physiological saline, bacteriostatic water, Cremophor EL114 (BASF, Parsippany, NJ) 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 the maintenance of the -required particle size in the case of dispersion and by the use of stufactants.
Antibacterial and antifwagal agents include, for example, parabens, chlorobutanol, phenol, ascorbic acid and. thimerosal. Isotonic agents, for example, sugars, polyalcohols such as manitol, sorbitot, and sodium chloride may be included in the composition. The remitting solutions can be packaged for use as is, or lyophilized; the lyophilized preparation can later be combined with a sterile solution prior to administration.
1002031 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 stabilizers and/or buffers. Agents that delay absorption include, for example, aluminum monostearate and gelatin. Detergents can also SUBSTITUTE SHEET (RULE 26) WO 2017/(159252 - 11.5 be used to stabilize or to increase or decrease the absorption of the pharmaceutical composition, including liposomal carriers. To protect from digestion the compound can be complexed with a composition to render it resistant to acidic and enzymatic hydrolysis, or the compound can be 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) Phalan Res.
13:1760 1764; Samanen (1996).1. Phalan. Pharmacol. 48:119 135; and U.S. Pat.
No. 5,391,377, describing lipid compositions for oral delivery of therapeutic agents).
100204j 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 be provided as a separate composition, or as a conjugated moiety present on an MMP9 binding protein.
1002051 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.
1002061 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 be further supplemented by texts such as Remington: The Science and Practice of Pharmacy 20th Ed. (Lippincott, Williams & Wilkins 2003).
0002071 Pharmaceutical compositions can be formulated based on the physical characteristics of the patient/subject needing treatment, the route of administration, and the like. Such can be packaged in a suitable pharmaceutical package with appropriate libels 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 for the dosage and administration of the pharmaceutical compositions of the present invention can be included with the pharmaceutical packages and kits described below, SUBSTITUTE SHEET (RULE 26) WO 2017/(159252 Methods of Use and Treatments [00208] The methods disclosed herein may be 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 ASK! inhibitor, a BET inhibitor and a lvIMP9 inhibitor, as described herein.
1002091 The method of use or treatment described herein may comprise Compound A). 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 100210] 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 eryahematosus, multiple sclerosis, inflammatory bowel disease, asthma, chronic obstructive airways disease, pneum.onitisõ 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, leuk.emiaa, a neoplasm, cancer or tumor (for example a solid tumor), .
[002111 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.
[002121 In some variations, the cancer is small lymphocytic lymphoma, non-Hodgkin's lymphoma, indolent non-Hodgkin's lymphoma (NHL), refractory SUBSTITUTE SHEET (RULE 26) WO 2017/(159252 i NHL mantle cell lymphoma, follicular lymphoma, lymphoplasmacytic lymphoma, marginal zone lymphoma, immunoblastic large cell lymphoma., lymphoblastic lymphoma, Splenic marginal zone B-cell lymphoma (+1- villous lymphocytes), nodal marginal zone lymphoma (+1- monocytoid B-cells), extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue type, cutaneous T-cell lymphoma, extranodal 1-cell lymphoma, anaplastic large cell lymphoma, angioimmunoblastic lymphoma, mycosis fimgoides, B-cell lymphoma, diffuse large B-cell lymphoma, Mediastinal large B-cell lymphoma, intravascular large B-cell lymphoma, Primary effusion lymphoma, small non-cleaved cell lymphoma, Burkitt's lymphoma, multiple myeloma, phismacytorna, acute lymphocytic leukemia, T-cell acute lymphoblastic leukemia, B-cell acute lymphoblastic leukemia, 13-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, myelodysplastic syndrome, nyeloprolifemtive disease, or Waldestrom's macroglobulinemia.
[002131 In other 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, mesoltheliomas, 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 ACTH-producing tumors.
[002141 in some embodiments, provided herein is a method for treating a human who exhibits one or more symptoms associated with cancer (e.g., a hematologic SUBSTITUTE SHEET (RULE 26) WO 2017/(159252 malignancy). In some embodiments, the human is at an early stage &cancer. In other embodiments, the human is at an advanced stage of cancer.
[002151 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 hematoloizic malignancy), such as chemotherapy, radiotherapy, immunotherapy, and/or surgery.. Thus, in some tbregoing 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 JAK inhibitor, an ASK1 inhibitor, a BET inhibitor and a MMP9 inhibitor, as described herein. In some embodiments, Compound Al may be used in combination with a JAK inhibitor such as Compound B1 and Compound 82. In other embodiments, Compound.AI maybe used in combination with a BRD inhibitor such as (2-cyclopropy1-6-(3.,5-dimethylisoxazol -4-y1)-1H-benzo[d]imidazol-4-34)di(pyridin-2-yl)methanol.
[002161 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 (ii), 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 MK inhibitor, an ASKI inhibitor, a BET inhibitor and/or a MMP9 inhibitor, as described herein.
[002171 For -chronic lymphocytic leukemia the prior treatments &human may have received include regimens of:
fludarabine (Fludara 6);
rituximab (Rituxant);
rituximab (Rituxan *) combined with fludarabine (sometimes abbreviated as FR);
=
SUBSTITUTE SHEET (RULE 26) cyclophosphamide (CytoxanO) 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 datum umab pento.statin combined with cyclophosphamide and rituximab (sometimes abbreviated as PCR).;
bendamustine (Treandat) combined with.rituximah ((sometimes abbreviated as BR);
alemtuzumab (Campath0);
fludarabine plus cyclophosphamide, bendamustine, or chlorambucil; and fludarabine plus cyclophosphamide, bendamustine, or chlorambucil, combined with an anti-CD20 antibody, such as rituximab, ofatumumab, vehuzumab, lumiluximab or obinutuzumab.
[002181 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.
[002191 The BTK inhbitor, Compound. A I,or a pharmaceutically acceptable salt or hydrate thereof, may be combined with known agents and regimens useful in the treatment ofallergic, autoimmune, and inflammatory disorders, as can the combinations herein of Compound Al with one or more inhibitoras described --herein. In addition, Compound Al may be combined include tumor necrosis factor inhibitors (FM:0, such as infliximab (sold under the REMICADIND mark), etanercept (INBREI)), cettolizumab pegol (CIMZIAV), golimumab (SIMPON10), adalimumab (HUMIRAV), and ozoalizumab.
SUBSTITUTE SHEET (RULE 26) WO 2017/(159252 Therapeutically Effective Amounts 1002201 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, 1002211 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 MK activity.
1002221 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, ophthalmically, orally, osmotically, paxenterally (intramuscularly, intraperitoneally intrastemally, intravenously, subcutaneously), rectally., topically, transdermally, 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, 40 Mg, 80 mg, or 150mg. In some embodiments, the Btk inhibitor is Compound Al orhydrochloride 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 WK. inhibitor is a dose corresponding to I nmol to 10,000 nmol of the BTK inhibitor used in an apoptosis assay run with 10% swim which approximately relates to a blood plasma concentration of 500 nmol to nmol of the BTK inhibitor. In one variation, the therapeutically effective amount of the one or more inhibitor is a dose corresponding to I mnol to 200 nmol of the SUBSTITUTE SHEET (RULE 26) WO 2017/(159252 - 121 , one or more inhibitor used in an apoptosis assay run with 10% serum. :Specific examples include 3 ntvl, 5 riM, 10 rila4, 20nM and 30 IN concentrations when combined with one or more inhibitor described herein.
1902231 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 BM inhibitor in a human is a dose of from about 1 mg to about 2.00 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 .51..K .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 mg, 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 1(X) mg, and e) from about 100 mg to about 200 mg: Individual doses of the 51K inhibitor that may be administered to a human in need thereof include individual doses of lmg, Sing, 10 mg, 20 mg, 30 M2, 40 mg, 50 mg, 60 mg, 70 mg, 75 mg, 80 mg, 901 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 1.60 mg, 170 mg, 175 mg, and 200 mg. The doses of the BM 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.
1002241 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 75%, 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, SRI) inhibitor, and M.MP9 inhibitor, is administered to the human at 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 (00225j 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 SUBSTITUTE SHEET (RULE 26) WO 2017/(159252 nag and 600 mg, 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 MK inhibitor, such as Compound B I, Compound B2, Compound B3, or Compound 134, or a pharmaceutically acceptable salt thereof, is administered to the human at a dose between 20 to 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 emIxxiiments, the IAK
inhibitor is momelotinib (Compound B1) 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 MK inhibitor is filgotinib (Compound 132) or a pharamceutically salt there of is administered orally at a dose of 3:0 mg. 5:0 mg, 75 mg, 100 mg, 150 mg, 200 mg, or 300 mg. In certain embodiments, the JAK
inhibitor is administered once daily or twice daily.
[002261 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 human. The dose administered, for example fbr 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 moreinbibitor may be administered twice daily. In some embodiments, the one or more inhibitor may be administered once weekly or with a frequency that can vary between daily, every other day, once every 5 days, daily tbr 1, 2, 3, 4, 5, 6 or? days and then weekly or witha regimen that can combine these different frequencies and doses to result in a final dose and regimen that is tolerated and efficacious.
1002271 In one variation, the therapeutically effective amount of the ASKI
inhibiting compound is a dose corresponding to 1 nrnol to 200 nmol of the ASK1 inhibiting compound used in an apoptosis assay run with 10% serum. The Askl inhibiting compounds herein, including compounds of formula (1) and Compound SUBSTITUTE SHEET (RULE 26) WO 2017/(159252 C1, may be administered in a pharmaceutically effective amount For oral administration, each dosage unit preferably contains from 1 mg to 500 mg of the ASK1 inhibiting compound. A more preferred dose is from I mg to 250 mg of the compound of the ASK1 inhibiting compound. Particularly preferred is a dose of the ASK] inhibiting compound ranging from about 20 mg 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 will be 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 severity of the patient's symptoms,, and the 1002281 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 mg, 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 ASK1 inhibiting compound, such as Compound Cl, Compound C2 or a compound of Formula I, or a pharmaceutically acceptable salt thereof, is administered to the human at a dose between 20 to 600 me, 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.
1002291 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 nig, about 500 mg, about 600 mg, about 700 mg, or about 800 mg.
SUBSTITUTE SHEET (RULE 26) WO 2017/(159252 1002301 In some variations, the MMP9 inhibitor, is administered to the human at a dose between 20 to 600 mg, between 20 to 400 mg, between 2.0 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 me, or about 800 mg.
1002311 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. 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 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 an 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-MMP9 antibody, is administered once every three weeks at a single dose of from about 1,100 mg to 1,300 fig. In another embodiment, the MMP9 inhibitor, particularly including an anti-MMP9 antibody, is administered once every three weeks at a single dose of about 1,200 mg. In one embodiment, the MMP9 inhibitor is an anti-MMP9 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.
1002321 The present disclosure contemplates pharmaceutical compositions for use in connection with such methods. Compositions can be suitable for administration locally or systemically by any suitable route.
[002331 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 fig/kg/day to 50 mg/kg/day, optionally about 100 1g/kg/day to 20 mg/kg/day, 50014/kg/day to SUBSTITUTE SHEET (RULE 26) WO 2017/(159252 mg/kg/day, or 1 mg/kg/day to 10 mgl- 'day, depending upon the route of administration, [002341 The selected dosage regimen will depend upon a variety of factors including the activity of the MM.P9 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.
[002351 A clinician having ordinary skill in the art can readily determine and prescribe the effective amount (ED50) of the pharmaceutical composition required. For example the physician or veterinarian can start doses of the compounds of the invention employed in the phamiaceutical composition at lower than thatrequired in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.
[002361 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 BM 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 AK
inhibitor, such as Compound 13.1, Compound B2, Compound133., Compound 134, Compound 135, Compound B6, Compound 131, Compound :B8, Compound 139, Compound.1310 or Compound 1311. In sonic 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 inhhitior may be a modulator of a bromodomain-containing protein such as (2-cyelopropy1-643,5-dimethylisoxazol -4-3/0-1H-benzo[d]imidazol-4-yDdi(pyridin-2-yOmethanol. In SUBSTITUTE SHEET (RULE 26) WO 2017/(159252 yet. other embodiments, the OM or more inhibitor may be a MM.P.9 inhibitor such as an anti-MMP9 antibody.
[002381 For example, the compounds may be administered bucally, ophthalmically, orally, osmotically, parenterally (intramuscularly, intraperitoneally intmstemally, intravenously, subcutaneously), rectally, topically, transdennally, 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 ASK1 inhibitor, a BET inhibitor and a MMP9 inhibitor, as described herein, [002391 In one aspect, the compounds described herein may be administered orally. Oral administration may be via, for example, capsule or enteric coated tablets. In making the pharmaceutical compositions that include at least one-compounddescribed herein, or a pharmaceutically acceptable salt thereof, the active ingredient is usually diluted by an excipient and/or enclosed within such a carrier that can be in the form of a capsule, sachet, paper or other container.
When the excipiem serves as a diluent, it can be in the form of a solid, semi-solid, or liquid material (as above), which acts as a vehicle, carrier or medium tbr the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, sr-ups, 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.
1002401 Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, marmitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methyl cellulose: The formulations can additionallyinclude: 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.
[00241.1 The compositions that include at least one compound of the compounds described herein, or a pharmaceutically acceptable salt thereof, can be formulated SUBSTITUTE SHEET (RULE 26) WO 2017/(159252 12.7 s0 21$ 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 for oral administration include osmotic pump systems and dissolutional systems containing polymer-coated reservoirs or drug-polymer matrix tbrmulations. Examples of controlled release systems are given in U.S. Patent Nos. 3,845,770; 4326,525; 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 the delivery of pharmaceutical agents is well known in the art.
See, U.S. Patent Nos. 5,023,252, 4,992,445 and 5,001,139. Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents, 1002421 The compositions may, in some embodiments, be formulated in a unit dosage form. The term "unit dosage forms" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient (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 mg of a compound described herein, for example from. about 50 mg to about 500 mg, for example about SO mg, about 75 rug, about 1.00 mg, about 150 mg, about 200 mg, about 250 mg, or about 3-00-mg. In other embodiments, for parentend 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.
SUBSTITUTE SHEET (RULE 26) WO 2017/(159252 -128..
1002431 in certain embodiments, dosage levels may be from 0.1 mg to 100 mg per kilogram of body weight per day, for example from about 1 me to about 50 rug per kilogram, for example from about 5 mg to about 30 mg per kilogram.
Such dosage levels may, in certain instances, be usefill in the treatment of the above-indicated conditions. In other embodiments, dosage levels may be from about 10 mg to about 2000 mg per subject per day. The amount of active ingredient that may be combined with the vehicle to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. Dosage unit fbrins may contain from I mg to 500 mg of an active ingredient.
1002441 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. autoimm one 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.
[02451 For preparing solid compositions such as tablets, the principal active ingredient may be mixed with a pharmaceutical excipient to fbmi 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 con positioe may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.
002461 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 SUBSTITUTE SHEET (RULE 26) WO 2017/(159252 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 be 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, eetyl alcohol, and cellulose acetate.
[002471 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 transdermal routes, by intra-arterial injection, intravenously, intraperitoneally, parenterally, 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 be 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 inhibitor may be 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 ether ingredients can he deemed pharmaceutically acceptable insofar as they are compatible with other ingredients of the formulation and not deleterious to the recipient thereof, [002491 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 ASKI inhibitor, a BET inhibitor and a MMP9 inhibitor as described herein, and one or more pharmaceutically SUBSTITUTE SHEET (RULE 26) WO 2017/(159252 acceptable 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 Modem Pharmaceutics, Marcel Dekker, Inc. 3rd Ed. (G.S. Banker & CJ. Rhodes, Eds.).
1002501 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, intaperitoneally, parenterally, intramuscularly, Subcutaneously, orally, topically, as an inhalant, or via an impregnated or coated device such as:a stem, for example, or an artery-inserted cylindrical polymer.
1002511 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.
1002521 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 AL Such tablet comprising Compound Al, for example, may be prepared by suitable methods known in the art, such as spray-drying and granulation (e.g., dry granulation). =
Articles of Manufacture and Kits 1002531 Compositions (including, for example, formulations and unit dosages) comprising a BTK. inhibitor, as described herein, and compositions comprising one or more inhibitor, such as JAK inhibitors, ASK1 inhibitors, BET inhibitor SUBSTITUTE SHEET (RULE 26) WO 2017/(159252 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 comprising 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.
100254] 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 JAK inhibitor, an ASK1 inhibitor, a BET inhibitor and an MMP9 inhibitor. In some embodiments, the kits comprises (1) 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.
100255] 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, ahematologic malignancy or an allergic, autoimmune, or inflammatory disorder, as further described herein.
Other Therapeutic Agents (002561 In the present disclosure, in some aspects, the combination therapies and methods described herein may be used or combined with an additional agents selected from the group of a chemotherapeutic agent, an anti-cancer agent, an SUBSTITUTE SHEET (RULE 26) WO 2017/(159252 - -anti-aagiogen ic agent, an anti-fibrotic agent, an immunotherapeutic agent, a therapeutic antibody, a radiotherapeutic agent, an anti-neoplastic agent, an anti-proliferation anent, or any combination thereof.
1002571 The combination therapies and methods described herein may be used or combined with an additional one or more of the following additional therapeutic agents: an adenosine A2B receptor (A2B) inhibitor, a BET-bromodomain 4 (BRD4) inhibitor, an isocitrate dehydrogenase 1 (1D111.) inhibitor, an MK inhibitor, a protein kinase C (PKC) activator or inhibitor, a TPI.2 inhibitor, a scrinelthreonine-protein kinase 1 (TBK1) inhibitor, agents that activate or reactivate latent human immunodeficiency vims (111V) such as panobinostat or romidepsin, an anti-CD20 antibody such as obinutuzumab, an anti-PD-1 antibody sueh.as nivolimumab (BMS-936.5-58, MDX11.06, or MK-34775), and anti-PD-1,1 antibodies such as.BMS-93.6559, MPD1.32:80A, MED14736, MSB001071 8C, and MDX1.105-01.
1002581 The combination therapies and methods disclosed herein and the additional one or more therapeutic agents (e.g, an A213 inhibitor, an apoptosis signal-regulating kinase (ASK) inhibitor, a 13R1)4 inhibitor, a discoidin domain receptor I (DDR I.) inhibitor, a histone deacetylase (HDAC) inhibitor, an isocitrate dehydrogenase (1DII) inhibitor, a Janus kinase (JAK) inhibitor, a lysyl oxidase-like protein 2 (LON:12) inhibitor, a matrix metalloprotease 9 (MMP9) inhibitor, a phosphatidylinositol 3-kinase (PI3K) inhibitor, a PKC activator or inhibitor, a spleen tyrosine kinase (SYK) inhibitor, a TP1,2 inhibitor, or a inhibitor) may be further used or combined with a chemotherapeutic agent, an anticancer agent, an anti-arigiogenic agent, an anti-fibrotic agent, an immunotherapeutic agent, a therapeutic antibody, a radiotherapeutic agent, an anti-neoplastic agent, or any combination thereof.
1002591 It is understood that the combinations and methods herein may be used with standard therapies, including neoadjuvant chemotherapy, intraoperative radiotherapy (1ORT), adjuvant chemotherapy (such as with 5U), adjuvant radiotherapy, adjuvant chemoradiotherapy, palliative radiotherapy, and palliative-intent procedures, which in regard to gastrointestinal conditions may include SUBSTITUTE SHEET (RULE 26) WO 2017/(159252 - 1.3.3 -wide local exdsion, partial gastrectomy, total gastrectomy, simple laparotomy, gastrointestingal anastomosis, or bypass.
Chemotherapeutic Agents [00260] 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., non-peptidic) 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-metabolites/anti-cancer agents such as pyrimidine analogs floxaridine, capecitabine, and cytarabine:purine analogs, folate antagonists, and related inhibitors; antipttaliferative/antimitotic agents including natural products such as vinca alkaloid (vinblastine, vincristine) and microtubule such as taxane (paclitaxel, docetaxel.) vinblastinõ nocodazole, epothilones, vinorelbine (NAVELBENie), and epipodophyllotox ins (etoposide, teniposide); 'DNA. damaging agents such as actinomycin, amsacrine, busulfan, carboplatin, chlorambucil, cisplatin, cyclophosphamide (CYTOX,A,10), dactinomycin, daunorubicin, doxorubicin, epirubicin, iphosphamide, melphalan, merchlorethamine, mitomycin, mitoxantrone, nitrosourea, procarbazine, taxol, taxotere, ternposide, etoposide, and triethylenethiophosphoramide; antibiotics such as dactinomycin, daunorubicin, doxorubicin, idarubicin, andracyclines, mitoxantrone, bleomycins, plicamycin (mithramycin), and mitomycin; enzymes such as Laasparaginase which systemically metabolizes laasparagine and deprives cells which do not have the capacity to synthesize their own asparagine;
antiplatelet agents; antiproliferativelantimitotic alkylating agents such as nitrogen mustards cyclophosphamide and analogs (melphalan, chlorambucil, hexamethylmelamine, and thiotepa), alk.yl nitrosoureas (carmustinc) and analogs,.
streptozocin, and triazenes (dacarbazine); antiproliferativelantimitotic antimetabolites such as folic acid analogs (methotrexate); platinum coordination complexes such as cisplatin., oxiloplatinim, and carboplatin), procarbazine, hydtnxyturea, mitotane, and aminogiutethimide; hormones and hormone analogs such as estrogen, tamoxifen, goserelin, bicalutamide, and nil utamide, and aromatase inhibitors such as letrozole and anastrozole; anticoagulants such as SUBSTITUTE SHEET (RULE 26) WO 2017/(159252 heparin, synthetic heparin salts, and other inhibitors of thrombin;
fibrinolyfic agents such as tissue plasminogen activator, streptokinase, urokinase, aspirin, dipyridamole, ticlopidine, and clopidogrel; antimigratory agents; anti secretory agents such as breveldin; immtmosuppressives such as tacrolimus, sirolimus, azathioptine, and mycophenolate; compounds (f1siP-470, genistein) and growth factor inhibitors (vascular endothelial growth factor inhibitors and fibroblast growth factor inhibitors); angioten sin receptor blockers, nitric oxide donors; anti-sense oligonucleotides; antibodies such as trastuzumab and rituximab; cell cycle inhibitors and differentiation inducers such as tTetinoin; inhibitors includingtopoisomerase inhibitors such as doxorubicin, dannombicin, dactinomycin, eniposide, epimbicin, etoposide, idarubicin, irinotecan, mitoxantrone, topoincan, and irinotecan, and corticosteroids such. as cortisone, dexamethasone, hydrocortisone, methylprednisolone, prednisone, and prednisoIone; growth factor signal transduction kinase inhibitors; dysfunction inducers; toxins such. as Cholera toxin, ricin, Pseudomonas exotoxin, I3ordetella 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 (CYTOXAN4); alkyl sulfonates such as busulfan, improsulfan, and piposulfaxi; aziridines such as benzodopa, carboquorte, meturedopa, and uredopa; emylerumines and memylarnelamines including alfretamine, triemylen.ernelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimemylolomelamine; acetogenins, especially b.ullatacin and bullatacinone; a camptothecin, including synthetic analog topotecan; bryostatin; cally-statin; CC,1065, including its aclozelesin, carzelesin, and biz,elesin synthetic analogs; cryptophycins, particularly cryptophycin 1 and cryptophycin 8; dolastatin; duocannycin, including the synthetic analogs KW-2189 and CBI-IMI.; eleutherobin; pancratistatin; a sarcodictyin; spongistatin; nitrogen mustards such as chlorarnbucil, chlomaphazine, cyclophosphamide, estrarnustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prechinnustine, trofosfamide, and uracil mustard; nitrosoureas such as carrnustine, SUBSTITUTE SHEET (RULE 26) WO 2017/(159252 chlorozotociti, foremustine, lomustine, nimustineõ and ranimustine;
antibiotics such as the enediyne antibiotics (e.g., calicheamicin, especially calicheamicin gamma' and calicheamicin phill), dynemicin including dynemicin A, bisphosphonates such as clodronate, an esperamicin, neocarzinostatin chromophore and related chromoprotein (=dire antibiotic chromornophores, aclacinomycins, actinomycin, audiramycin, azasetine, bleomycins, cactinomycin, cambicin, camiinomycin, carzinophilin, chromomycins, dactinornycin, daunorubicin, detorubicin, 6-diazo-5-oxo4.-nor1eucine, doxonibicin (including morpholino-doxorubicin, cyanommpholino-doxorubicin, 2-pyrmlino-cloxorubicin, and deoxydoxorubicin), epirubicin, esonibicin, idaruhicin, marcellomycin, mitomycins such as mitomycin C. mycophenolic acid, nogalamycin, olivomycins,. peplomycin, portiromycin, puromynin, quelamycin, rodoruhicin, streptonigrin, streptozoein, tubercidin, ubenimex, zinostatin, and zorubicin; anti-metabolites such as inethotrexate and 5-fluorouraeil (5-FU);
folic acid analogs such as demopterin, methotrexate, pteropterin, and trimetrexate;
purine analogs such as tludarabine, 6-mercaptopurine, thiamiprine, and thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azautidine, caxmofur, cytarabineõ dideoxyuridine, doxifluridine, enocitabine, and floxuridine;
androgens such as cal.usterone, dromostanolone propionate, epitiostanol, mepitiostane, and testolactone; anti-adrenals such as aminoglutethimide, mitotane, and trilostane; fblic acid replinishers such as frolinic acid;
trichothecenes, especially1-2 toxin, venacurin A, roridin A, and anguidine;
taxolds such as paclitaxel (TAX009) and docetaxel (TAXOTERO; platinum analogs such as cisplatin and carboplatin; aceglatone; aldophosphamide glycoside; an inolevulinie acid; eniluracil; amsacrine; hestrabucil;
bisantrene;
edatraxate; defofamine; dememlcine; diaziquone; elfomithine; elliptinium acetate; an epothilone; etogiucid; gallium nitrate; hydroxyurea; lentinan;
leucovorin; lonidamine; maytansinoids such as maytansine and ansamitocins;
mitoguazone; mitoxantrone; mopidamol; nitracrine; pentostatin; phenamet;
pirarubicin; losoxantrone; fluoroprimidine; folinic acid; podophyllinic acid;

ethylhydrazide; procarbazine; polysaccharide-K. (PSK); razoxane; rhizoxin;
sizofiran; spirogermanium; tenuazonic acid.; triaziquone; 2,2',2"-SUBSTITUTE SHEET (RULE 26) WO 2017/(159252 triclionotriemylamine; urethane; vindesine; dacarbazine; mannomustine;
mitobronitol; mitolactol; pipolmoman; gacytosine; arabinoside ("Ara-C");
cyclophosphamide; thiopeta; ehlorambucil; gemcitabine (GEMZ,AR'); 6-thioguanine; mercaptopurine; methotrexate; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitroxantrone; vancristine; vinorelbine (NAVEL:BINE);
novantrone; teniposide; echttrexate; daunomycin; aminopterin; xeoloda;
ibaminmate; CPT-11; topoisomerase inhibitor RFS 2000;
ditluoromethylomithine (DFM0); retinoids such as retinoic acid; capecitabine;
FOLFIRI (fluorouracil, leucovorin, and irinotecan); 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 anti-hormonal agents such as anti-estrogens and selective estrogen. receptor modulators (SEM), inhibitors of the enzyme aromatase, anti-androgens, and pharmaceutically acceptable salts, acids or derivatives of any of the above that act to regulate or inhibit hormone action on tumors. Examples of anti-estrogens and SERMs include, for example, tamoxifen (including NOLVADEXTm), raloxifene, droloxifene, 4-hydroxytamoxifen, trioxifene, keoxifene. LY117018, onapristone, and toremifene (FARESION4). Inhibitors of the enzyme aromatase regulate estrogen production in the adrenal glands. Examples include 4(5)-imidazoles, aminoglutethimide, meg,estrol acetate (MEGACO, exemestane, form estane, fadrozole, vorozole (RIVISOle), letrozole (FEMARA*), and anastroZole (ARIMIDEle). Examples of anti-androgens include flutamide, nilutamide, bicalutamid.e, le.uprohde., and gos.erelin.
Anti-angiogenic, Agents [002631 Anti-angiogenic agents include, but are not limited to, retinoid acid and derivatives thereof, 2-methoxyestradiol, ANGIOSTATINI% ENDOSTATlle, suramin, squalamine, tissue inhibitor of metalloproteinase-1, tissue inhibitor of metalloproteinase-2, plasminogen activator inhibitor-1, plasminogen activator inbibitor-2, cartilage-derived inhibitor, paclitaxel (nab-paclitaxel), platelet factor 4, protamine sulphate (clupeine), sulphated chitin derivatives (prepared from SUBSTITUTE SHEET (RULE 26) WO 2017/(159252 queen -crab shells), sulphated polysaccharide peptidoglycan complex (sp-pg), staurosporine, modulators of matrix metabolism including proline analogs ((1-azetidine-2-carboxylic acid (LACA)), eishydroxyproline, d,I-3,4-dehydroprolincõ
thiaproline, beta-am inopropionitrile fumarate, 4-propy1-5-(4-pridiny1)-2(3h)-oxazolone, methotrexate, mitoxantrone, heparin, interferons, 2 macroglobulin-serum, chicken inhibitor of metalloproteinase-3 (ChIMP-3), chymostatin, beta-cyclodextrin tetradecasulfate, eponemycin, fumagillin, gold sodium thiomalate, d-pertieillamine, beta-l-anticollagenase-serum, alpha-2-antiplasmin, bisantrene, lobenzarit disodium, n-2-carboxypheny1-4-chloroanthronilic acid disodium or "CCA", thalidomide, angiostatic steroid, carboxy aminoimidazole, and metallopmteinase inhibitors such as 1313-94. Other anti-angiogenesis agents include antibodies,.preferably monoclonal antibodies against these angiogenic growth factors: heta-FGF, alpha-FOP, FOP-5, VEGP
isolbrms, VEOP-C., HOF/SF, and Ang-1/Ang-2.
Anti-fibrotic Agents 1002641 Anti-fibrotic agents include, but are not limited to, the compounds such as beta-aminoproprionitrile (BAIN), as well as the compounds disclosed in US
4,965,288 relating to inhibitors of lys)4 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-isobuty1-3-f1uoro-, chloro-, or bromo-allylamine, US
5,021,456, US 5,059,714, US 5,120,764, US 5,182,297, US 5,252,608 relating to s2-(1-naphthyloxymemyI)-34luoroallylamine, and US 2004-0248871, -which are herein incorporated by reference.
100265] Exemplary anti-fibrotic agents also include the primary amines reacting with the carbonyl group of the active site of the lysyl oxidasesõ and more particularly those Which produce, after binding with the carbonyl, a product stabilized by resonance, such as the following primary amines: emylenemamine, hydrazine, phenythydrazine, and their derivatives; semicarbazide and urea derivatives; aminonitriles such as BAIN or 2-nitroethylaraine; unsaturated or SUBSTITUTE SHEET (RULE 26) WO 2017/(159252 - 138..
saturated haloamines such as 2-bromo-ethylarnine, 2-chloroethylamine, 2-trifluoroethylamine, 3-bromopropylamine, and p-halobenzylamines; and selenohomocysteine lactone.Other anti-fibrotic agents are copper cheiating 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 hydroxylysyl residues by the lysyl oxidases.
Examples include the tbiolamines, particularly D-penieillamine, and its analogs such as 2-amino-5-mercapto-5-methylhexanoic acid, D-2-amino-3-methy1-342-acetamidoethyl)didlio)butanoic acid, p-2-arnino-3-methy1-34(2-aminoethyl)dithio)butanoic acid, sodium-4-((p-1-dimethyl-2-amino-2-carboxyenhyDdithio)butane sulphurate, 2-acetainidoethy1-2-acetamidoethanethiol sulphanate, and sodium-4-mercaptobutanesulphinate trihydrate.
Immunotherapeutic Agents 1902661 'the immunotherapeutic agents include and are not limited to therapeutic antibodies suitable for treating patients. Some examples of therapeutic antibodies include sinnuzutriab, abagovomab, adecatumumab, afutuzumab, alemtuzinnab, altumomab, amatuxirnab, anatumomab, arcitumomab, bavituximab, bectumomab, bevaciztmiab, bivatuzumab, blinatumomab, brentuximab, cantuzumab, catumaxomab, cetuximab, citatitzumab, cixutumumab, clivatuzumab, conatumumab, daratumumab, drozitumab, duligotumab, dusigiturnab, detumomab, dacetuzumab, dalotuzumab, ecromeximab, elotuzumab, ensituximab, ertumaxomab, etaracizumab, farlettizumab, ticlatuzumab, tigiturnumab, flanvotumab, futuximab, ganitumab, gerntuzumab, airenttutimab, glemhatumumab, ibritumomab, igovornab, imgatuzumabõ indatuximab, inotuzumab, intetumumab, ipilimumab, imtumumab, labetuzumab, lexatutnumab, lintuzumab, lorvotuzumab, lucatumumab, mapatumumab, matuzurnab, milatuzumab, minretumomab, mitumomab, moxetuniomab, narnatumab, naptumom.ab, necitumumabõ nimotuzumab, nofetumomab, ocaratuzumab, ofatumumab, olaratumab, onartuzumab, oportuzumab, oregovomab, panitumuniab, paxsatuzumab, patriturnab, pemtumomab, pertuzumab, pintumornab, pritumumab, racotumomab, radretumab, rilotumumab, rituximab, robatumumab, satumomab, sibrotuzumab, siltuximab, solitomab, tacatuzumab, SUBSTITUTE SHEET (RULE 26) WO 2017/(159252 taplitumornab, tenatumomab, teprotumumab, tigatuzumab, tositumomab, trastuzumab, tucotuzumab, ublituximab, veltuzumab, vorsetuzumab, votunrumab, zalutumumab. CC.,449, and 3F8. Rituximab can be used for treating indolent B-cell cancers, including marginal-zone lymphoma, WM, CLL and small lymphocytic lymphoma. A combination of Rituximab and chemotherapy agents is especially effective.
1002671 The exemplified therapeutic antibodies may be further labeled or combined with a. radioisotope particle such as indium-111, yttrium-90, or iodine-131.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 [00268j Some chemotherapy agents are suitable for treating lymphoma or leukemia. These agents include aldesleukin, alvocidib, anfineoplaston AS2-1, antineoplaston A10, anti-thymocyte globulin, amifostine tiihydrate, aminoca.mptothecin, arsenic trioxide, beta alethine, Bc1-2 family protein inhibitor ABT-263, ABT-199, ABT-737, BMS-345541, bortez.omib (VELCADO, bryostatin 1, busulfan, carboplatin, campath-Ill, carmustine, caspofimgin acetate, clothrabine, cisplatin, cladribine, chlorambucil, eurcumin, cyclosporine, cyclophosphamide, cytarabine, denileukin diftitox, dexamethasone, DT-PACE (dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide, and etoposide), docetaxel, dolastatin 10, doxorubicin, doxorubicin hydrochloride, enzastaurin, epoetin alfa, etoposide, everolimus (RA0001), fenretinide., filgrastim, melphalan, mesna., flavopiridol, fludarabine, .geldanamycin (17-AAG), ifosfamide, irinotecan hydrochloride, ixabepilone, lenalidomide (REVLIMII) , C(-50.13), lymphokine-activated killer cells., tnelphalanonethotrexate, mitoxantrone hydrochloride, motexafin gadolinium, mycophenolitte mofetil, nelarabine, oblimersen, obatoclax (GX15-070), oblimersen, octreotide acetate, omega-3 fatty acids, oxaliplatin, paclitaxel, P00332991, PEGylated liposomal doxorubicin hydrochloride, pegfilgrastim, pentostatin, perifosine, prednisolone, preclnisone, R-roscovitine (seliciclib, CYC202), recombinant interferon Ala, recombinant interleukin-12, recombinant SUBSTITUTE SHEET (RULE 26) WO 2017/(159252 PCT/US2016/054780 interleukin-11, -recombinant flt3 ligand, recombinant human thrombopoietin, rituximab, sargamostim, sildenafil citrate, simvastatin, sirolimus, styryl sulphones, tacrolimus, utnespimycin, temsirolimus (CC1-779), thalidomide, therapeutic allogeneic lymphocytes, thiotepa, tipifamib, bortezomib (VELCADe, PS-341), vincristine, vincristine sulfate, vinorelbine ditartrate, SAHA (suberanilohydroxamic acid, or suberoyl, anilide, and hydroxamic acid), FR (fludarabine and rituximab), CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), (VP (cyclophosphamide, vincristine, and prednisone), .FCM (fludarabine, cyclophosphamide, and mitoxantrone), .FCR
(fludarabine, cyclophosphamide, and rituximab), hyperCVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone, metbotrexate, and =
eytarabine), ICE (iphosphamide, carboplatin, and etoposide), MCP
, (mitoxantrone, chlorambucil, andprednisolone), R-CHOP (rituximab. and CHOP),.R-CVP (rituximab: and CVP), R-PCM (rituxim.ab and FCM), R-ICE
(rituximab and ICE), and R-MCP (rituximab and MCP).
100269) One modified approach is radioimmunotherapy, wherein a monoclonal antibody is combined with a radioisotope particle, such as indium-111, yttrium..
90, and iodine-131. Examples of combination therapies include, but are not limited to, iodine-1.31 tositumomab (13IMARv), yttrium-90 ibritumomab tiuxetan (ZEVALIN'), and BEXXAle with CHOP.
1002701 The abovementioned therapies can be 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, in vitro-teated peripheral blood stem cell transplantation, umbilical cord blood transplantation, immtmoenzyme technique, low-Lin' cobalt-60 gamma ray therapy. Neomycin, conventional surgery, radiation therapy, and nonmyeloablative aliment*
hematopoietic stem cell transplantation.
SUBSTITUTE SHEET (RULE 26) WO 2017/(159252 -.141 -Non-Hodgkin's lymphomas Combination Therapy [002711 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 unconjugated monoclonal antibodies for the treatment of NHL.43-cell cancers include rituximab, alemtuzumab, human or humanized anti-CD20 antibodies, lumiliximab, anti-TNE-related apoptosis-inducing ligand (anti-TRAIL), bevacizumab, galiximab, epratuzumah, SGN-40, and anti-CD74.Examples of experimental antibody agents used in treatment of NH:IA-cell cancers include ofatumumab, ha20. PRO131921, alemtuzumab, kaliximab, SON-40, CHIR-12.12, eptatuzumab lumiliximab, apolizumab, milatuzumab, and bevaciztnab.Examples of standard regimens of chemotherapy for MIA-cell cancers include CTIOP, ECM., CVP, MCP, It-CHOP, R-FCM, R-CVP, and R-M.CP.Examples of radioimmunotherapy for NHL/B-cell cancers include yttrium-90 ibritumomab tiuxetan (ZEVALIN') and iodine-I 31 tositumomab (BEXXAR1).
Mantle Cell Lymphoma Combination Therapy 1002721 Therapeutic treatments for mantle cell lymphoma (MCI.) include combination chemotherapies such as CHOP, hyperCVAD, and ECM. These regimens can also be supplemented with the monoclonal antibody rituximab to form combination therapies R-CHOP, hyperCVAD-R., and R.-ECM. Any of the abovementioned therapies may be combined with stem cell transplantation or ICE in order to treat MCI_ [00273j 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.
1002741 A modified approach to treat MCI, is radioimmunotherapy, wherein a monoclonal antibody is combined with a radioisotope particle, such as iodine-tositumomab (BEXXA10 and yttrium-90 ibritumomab titixetan (ZEVALENe).
hi another example, BEXXAle is used in sequential treatment with CHOP.
SUBSTITUTE SHEET (RULE 26) WO 2017/(159252 1002751 Other app aches to treating Mei, include. autologous stem cell transplantation coupled with high-dose chemotherapy, administering proteasome inhibitors such as bortezomib (VEL(.:ADIe or PS-341), or administering antiangiogenesis agents such as thalidomide, especially in combination with rituximab.
1002761 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 agents.
1002771 A further treatment approach includes administering mTOR inhibitors, which can lead to inhibition of cell growth and even cell death. Non-limiting examples are temsirolimus (TORISEO. CCI-779) and temsirolimus in combination with R1T1JXAN4', VELCADe, or other chemotherapeutic agents.
10e2781 Other recent therapieslar MCL have been disclosed. Such examples include flavopiridol, P.00332991, R-roscovitine (selicicilib, CYC202), styryl sulphortes, obatoclax (GX15-070), TRAIL Anti-TRAIL death receptors DRA and DR.5 antibodies, temsirolimus (TORISEO. CC1-779), everolimus (RAD001).
BMS-345541, curcumin, SAHA, thalidomide, lenalidomide (REVIIMID6, CC.
5013), and geldanamycin (17-AAG).
Waldenstrom's Macroglobalinemia Combination Therapy 1002791 Therapeutic agents used to treat Waldenstrom's Macroglobulinemia (WM) include perifosine, bortezomib (VEIX.ADE), ritwtimab, sildenafil citrate (VIAGRA4), CC-5103, thalidomide, epratuzumab (111.12- anti-CD22 humanized antibody), simvastatin, enzastaurin, campath-111, dexamethasone, DT-PACE, oblimersen,.amineoplaston A10, antineoplaston AS2-1, alemtuzumab, beta alethine, cyciophosphamide, doxorubicin hydrochloride, prednisone, vincristine sulfate, fludarabine, filgrastim, melphalan, recombinant interferon alfa, carmustine, cisplatin, cyclophosphamide, cytarabine, etoposide, melphalan, dolastatin 10, indium-111 monoclonal antibody MN-14, yttrium-90 humanized epratuzumab, anti-thymocyte globulin, busulfan, cyclosporine, methotrexate, mycophenolate mofetil, therapeutic allogeneic lymphocytes, yttrium-90 ibritumomab tiuxetan, sirolimus, tacrolimus, carboplatin, thiotepa, paclitaxel, aldesieukin, docetaxel, ifosfamide, mesna, recombinant interleukin-11, SUBSTITUTE SHEET (RULE 26) WO 2017/(159252 recombinant intedeukin-I2, Bc1-2 family protein inhibitor ABT-263, denileukin diffitox, tanespimycin, everolimus, pegfilgrastim, vorinostat, alvocidib, recombinant fit3 ligand, recombinant human thrombopoietin, lymphokine-activated killer cells, amifostine trihydrate, am inocamptothecin, irinotecan hydrochloride, caspofimgirt acetate, clofarabine, epoetin alfa, nelarabine, pentostatin, sargamostim, vinorelbine ditartrate, WT-1 analog peptide vaccine, WTI 126-134 peptide vaccine, fenretinide, ixabepilone, oxaliplatin, monoclonal antibody C1)19, monoclonal antibody CD20, omega-3 fatty acids, mitoxantrone hydrochloride, octreotide acetate, tositumomab, iodine-131 tositurnomah, motexafin gadolinium, arsenic trioxide, tipifamib, autologous human tumor-derived IISPPC-96, veltuzumabõ biyostatin 1, PEGylated liposomal doxorubicin hydrochloride., and any combination thereof 100280] Examples of therapeutic procedures used to treat WM include peripheral bloodatem. cell transplantation, autologous hematopoiefic 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 vitro-treated peripheral blood stem cell transplantation, umbilical cord blood transplantation, immunoenzyme techniques, low-LET cobalt-60 gamma ray therapy, bleomycirt, conventional surgery, radiation therapy, and nonmyeloablative allogeneic hematopoietic stem cell transplantation.
Diffuse Large 13-cell 'Lymphoma Combination Therapy 1002811 Therapeutic agents used to treat ditbse large B-cell lymphoma (DLBCL) include cyclophosphamide, doxorubicin, vineristine, prednisone, anti-CD20 monoclonal antibodies, etoposide, bleomycin, many of the agents listed for WM, and any combination thereof, such as ICE and 1-ICE.
Chronic Lymphocytic Leukemia Combination Therapy 1002821 Examples of therapeutic agents used to treat chronic lymphocytic leukemia (CLL) include chlorambucil, cyclophosphamide, fludarabine, pentostatin, cladribine, doxorubicin, vincristine, prednisone, prednisolone, alemtuzumab, many of the agents listed for WM, and combination chemotherapy SUBSTITUTE SHEET (RULE 26) WO 2017/(159252 and chemoimmunotherapy, including the following common combination regimens: CVP, R-CVP, ICE, R-ICE, ECR, and FR..
Myelotibrosis Combination Therapy [002831 Myelotibrosis inhibiting agents include, but are not limited to, hedgehog inhibitors, histone deacetylase (HDAC) inhibitors, and tyrosine kinase inhibitors.
A non-limiting example of hedgehog inhibitors is saridegib.Examples of MAC
inhibitors include, but are not limited to, pracinostat and panobinostat.A non-limiting example of a tyrosine kinase inhibitor is lestaurtinib, Kinase Inhibitors 1002841 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 Ahl,.activated CDC kinase (ACK), adenosine A213 receptor (A213), apoptosis signal-regulating kinase (ASK), Auroa kinase, BET-bromodOmain (BRD) such as BRD4, c-Kit, c-Met, CDK-activating kinase ((.:AK), calmodulin-dependent protein kinase (CaMK), cyclin-dependent kinase (CDK), casein kinase (CK), discoidin domain receptor (DDR), epidermal growth factor receptors (EGER), focal adhesion kinase (EAK), Flt-3, FYN, glycogen synthase kinase (GSK.), FICK, histone deacetylase (H1)AC), 1KK such as IKKiie, isocitrate dehydrogenase (1DH) such as IDE I, Janus kinase KDR, lymphocyte-specific protein tyrosine kinase (LEK), lysyl oxidase protein, lysyl oxidase-like protein (LOXL), LYN, matrix.
metal loprotease (MM?), MEK, mitogen-activated protein kinase (MAPK), NEK9, NPM-ALK, p38 kinase, platelet-derived growth factor (PDGF), phosphorylase kinase (PK), polo-like kinase (PLK), phosphatidylinositol 3-kinase (P1.3K), protein kinase (PK) such as protein kinase A, 13, and/or C, PYK, spleen tyrosine kinase (SYK), serinethreonine kinase TPL2, serinelthreonine kinase STK, signal transduction and transcription (STAT), SRC, serineithreonine-protein kinase (TBK) such as TBK1, TIE, tyrosine kinase (TK), vascular endothelial growth factor receptor (VEGER), YES, or any combination thereof.
SUBSTITUTE SHEET (RULE 26) Apoptosis Signal-Regulating Kinase (ASK) Inhibitors 100201 ASK inhibitors include ASK1 inhibitors. Examples of ASK1 inhibitor's include, but am not limited to, those :described in WO 2011/008709 (Gilead Sciences) and W0.2:0111.112741 Kijlead Sciences):õ
Discoidin Domain RectITtor (D.DR) Inhibitors [002861 DDR inhibitors include inhibitors of'DDR1 andlor DDR2:. Examples of DDR inhibitors 'include, but are not limited to, those disclosed in WO
2014/047.624 (Gilead Soknocs),. US 2009-0.1.42345 (Takeda Pharmaceutica4, US
2011-0287011 (Named .Plia 010, WO 2013/027802: (Chugai Pharmaceutical), and WO '2013/034933 (Imperial 'Innovations).
Historic Deaeetylase (lIDAC) Inhibitors [002871 Examples of law inhibitors. include, but are not limited w, pmeinostat and panobinostat, Jams Kinase: (JAK) inhibitors [002831 .JAK,. inhibitors inhibit RW1, JAK2, and/or JA1F3., E.xamples. of 'MK
inhibitora include, but are not limited to, Compound A,ruoiitinib tdratiaib, tolacifinib, baricitintb, lestatirtinib, paeritinib, XLO1 9, AZD1480, INCB039110õ
LY2784544, I 6'!L543, and NSW 8, 401 Oxidase-Like Protein (LOXL) Inhibitors 1002891 LOXI,, inhibitors include inhibitim of I.DX.LA, LOX1.4 LOX13, LOXIA, andlorT,OX1:,5.. Examples of LOXL inhibitors include, but are not limited to, the antibodies described M WO 2009/017813 (Arresto Bioseiences).Examplea of LOXI,2 inhibiims include, but are not limited to, the antibodies described in 'WO 2009/(j17833 (Attesto Bioscieneog), WO
2009/035791 (Arcot Biosciences), and WO 20111097513: (Gilead. Biologics).
Mattix Metalloprotease (1,AMP) Inhibitors [002901 MIVIP inhibitors include inhibitors. of.MMPI through 10, Examples of mmp9 inhibitors. iodide; but are..., not limited to, marimastatill.4-251(), SUBSTITUTE SHEET (RULE 26) WO 2017/(159252 cipemastat (Ro 32-3555), and those de:scribed in WO 20121027721 (Gilead Biologics).
Phosphatidylinositol 3-kinase (1113K) Inhibitors 100291] PI3K inhibitors include inhibitors of MKT, MK& PI3Kj3, P13Ka, and/or pan-MK.. Examples of MK. inhibitors include, but are not limited to, wortmannin, BKM120, C115132799, XL756, and GDC-0980.Examples of PI3Ky inhibitors include, but are not limited to, ZSTK474, AS252424, LY294002, and TG100115.Examples of PI3K5 inhibitors include, but are not limited to, Pl3K
TGR-I202, AMG-319, GSK2269557, X.-339, X-414, RP5090, KAR41.41, XIA99, OXY111A, IPI-145,1P1-443, and the compounds described in WO
'.2005/11.3556 (ICOS), WO 2013/052699 (Gilead Calistotta), WO 2013/116562 (Gilead C.alistoga), WO 2014/100765 (Gilead Calistogal, WO 2014/100767 (Gilead Calistoga), and WO 2014/101409 (Gilead Sciences). Examples of NIKO
inhibitors include, but are not limited to, 0SK2636771, BAY 10824391, and IGX221.Examples of PI3Ka inhibitors include, but are not limited to, buparlisib, BAY 80-6946, BYL719, PX-866, RG7604, MLN1117, WX-037, AEZA.-129, and PA799.Examples of pan-P13K inhibitors include, but are not limited to, LY294002, BEZ235, XL147 (SAR245408), and GDC-0941.
Spleen Tyrosine Kinase (SYK) Inhibitors [002921 Examples of SYK inhibitors include, but are not limited to, tamatinib (R406), fostamatinib (R788), PRT062607, BAY-61-3606, NVP-QAB 205 AA, R112, R343, and those described in US 8450321 (Gilead Connecticut).
Tyrosine-kinase Inhibitors (TKIs) 1002931 TKIs may target -epidermal growth factor receptors (EGFR.$) and receptors for fibroblast growth factor (FOT), platelet-derived growth fackn (PDGF), and vascular endothelial growth factor (VEGF). Examples of TKIs that target EGER include, but are not limited to, gefitinib and erlotinib.
Santini]) is a non-limiting example of a TKI that targets receptors for FGF, PIXiF, and VEGF.

1002941 Combinations of pharmaceutically effective amounts of the BTK
inhibitor and an ASK' inhibitor as described herein may also be used to treat an SUBSTITUTE SHEET (RULE 26) 147=
allergic 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 n phatinaccutically acceptable salt or hydrate thereof, and a pharmaceutically effective amount of an ASKI inhibitor, or a pharmaceutically acceptable salt or hydrate t1-1.ttwf.
Partietlarly; the combinations taught herein may be used for the treatment Of allergic disorders, wenn/mine diseases and inflammatory diseases such as:
Systemic lupus erytheruatosus (SLE), rheumatoid arthritis, multiple vaseulitides, idiopathic thrombocytopenic purpura (1TP), myastheaitt gavis, al1e0c rhinitts, chronic Obstructive pulmonary disease (COPD), adult respiratory distress syndrome (ARDs) and asthma.
SUBSTITUTE SHEET (RULE 26) WO 2017/(159252 - 14$ -EXAMPLES
The following examples are provided to further aid in understanding the embodiments disclosed in the application, and presuppose an understanding of conventional methods well known to those persons having ordinary skill in the art to which the examples pertain. The particular materials and conditions described hereunder are intended to 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.
Example 1 [002951 This study evaluated the potential effects of BTK inhibitor in combination with JAI( inhibitor in treating arthritis. Lewis rats were injected intradermally/subcutaneously (ID/SC) with porcine type II collagen to induce arthritis. Arthritic rats were treated with vehicle (20% Cremophor EL/10%
Et011/70% saline), Compound Al (a RIX inhibitor), Compound B4 (a õPAK
inhibitor), Compound Al and Compound B4, or Dex (dexamethasone).
Compound Al was administered orally either twice daily at 3, 10, or 20 nag/kg or once daily at 20 mg/kg; Compound 134 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 on body weights, daily ankle caliper measurements, ankle diameter expressed as area under the curve (AIM), terminal hind paw weights, and histopathologic evaluation .of right ankles.
[002961 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;
SUBSTITUTE SHEET (RULE 26) WO 2017/(159252 the results obtained may be used in evaluating chronic, highly destructive macrophage-mediated phase of this model.
1002971 Ankle diameters were measured and compared for potential treatment effects. FIG. I depicts the measurements taken on Day 9, 13-34 for ankle diameter (in.) (mean standard error) tbr the tbllowing groups; control (normal and disease), Compound Al (20 mg/k2, daily), Compound Al (3 mg/kg, twice daily). Compound 134 (2.5 mg/kg, twice daily), Compound Al (20 mg/kg, daily) with Compound 134 (2.5 mg/kg, twice daily), Compound Al (3 mg/kg, twice daily) with Compound 134 (2.5 mg/kg, twice daily) and Dex (0.075 mg/kg daily).

In addition, the AUC total sum (day 17-34) (mean standard error) was measured. The MC total sum for the control (normal) was 4.5 0.008; for control (disease), 6.1 0.058; for Compound AI (20 mg/kg, daily), 5.9 0.096;
for Compound Al (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 134 (2,5 mg/kg, twice daily), 5.3 0.063;
for Compound Al (10 ingikk,), twice daily) with Compound 134 (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.
1002981 Also, the percent inhibition of the AIX 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); 9% for Compound Al (10 mg/kg, twice daily); 13% 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 134 (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% tbr Compound Al (3 mg/kg, twice daily) with Compound B4 (2.5 mg/kg, twice daily),; and 56% for Dex (0.075 inWkg).
f002991 the following score systems were used to evaluate ankle inflammation, ankle pannus, ankle cartilage. damage, ankle bone resorption, and periosteal new SUBSTITUTE SHEET (RULE 26) WO 2017/(159252 bone formation, which may represent treatmera effects toatikle histology. The sum of the summed ankle histology scores for day 34, are provided herein.
1003001 Ankle inflammatiortscores as used herein have the following meaning:
0- normal; 0.5= minimal focus inflammation; I= minimal infiltration of inflammatory cells in synovium/periarficular 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 ibllowing 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 and subchondral bone, primarily affects marginal zones; 2= mild infiltration (<25% of tibia or tarsals at marginal zones); 3- moderate infiltration (26% - 50% of tibia or small tarsals affected at marginal zones); 4semarked infiltration (51% - 75% of tibia or tarsals affected at marginal zones); 5e-severe infiltration (>75% of tibia or tarsals affected at marginal zones, severe distortion of overall architecture).
1003011 Ankle cartifiage 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; Is mild loss of toluidine blue staining with focal mild (superficial) chondrocyte loss and/or collagen disruption; 3= moderate loss of toluidine blue staining with multifoceal moderate (depth to middle zone) chondrocyte loss and/or collagen disruption, smaller tarsals affected to 50% to 75% depth with rare areas of NI

thickness loss; 4= marked loss of toluidine blue staining with multifocal marked (depth to deep zone) chondrocyte loss and/or collagen disruption, 1 or 2 small tarsals surfaces have full thickness loss of cartilage; 5= severe diffuse loss of toluidine blue staining withmultifocal severe (depth to tide mark) chondrocyte loss and/or collagen dismption affecting more than 2 cartilage surfaces.
1003021 Ankle bone 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; lss small areas of resorption, not readily apparent on low magnification, rare osteoclasts; le more numerous areas of resorption, not readily SUBSTITUTE SHEET (RULE 26) WO 2017/(159252 apparent on low magnification, osteoclasts more numerous, <25% of tibia or tarsals at marginal zones resorbed; 3-: obvious resorption of medullary tra.becular 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 bone, often with distortion of profile of remaining 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.
[003031 Periosteal new bone formation scores..as used herein have the following meaning: 0- normal, no periosteal proliferation; 0.5:::: minimal focal or multifocal proliferation, measures less- than 127 tun width (1-2 units at 16x) at any location;
minimal muhifocal 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 1(ix); 3- moderate multifocal on tarsals, diffuse in most other locations, width at any location measures 442-630 tun (8-units at 1(ix); 4- marked multifocal on tarsals, diffuse at most other locations, width at any location measures 630-819 urn (11-13 units at 1(ix); 5::: severe, multifocal on tarsals, diffuse at most other locations, width at any location measures >819 um (>13 units at 16x).
[003041 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 25. 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 134 (2.5 mg/kg, twice daily), 19 1.4; for Compound Al (20 mg/kg, daily) with Compound 84 (2.5 mg/kg, twice daily), 10 1.2; for Compound Al (10 mg/kg, twice daily) with Compound 134 SUBSTITUTE SHEET (RULE 26) WO 2017/(159252 - 152..
(2.5 mg/kg, twice daily), 11 1.6; for Compound Al (3 mg/kg, twice daily) with Compound 134 (2.5 mg/kg, twice daily), 10 2.0; and for Dex (0,075 mg/kg daily), 12 1Ø
[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/kgõ 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 134 (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 C.s.ompound 134 (2.5 mg/kg, twice daily); 60% for Compound Al (3 mg/kg, twice daily) with Compound 134 (2.5 mg/kg, twice daily); and 51% for Dex (0.075 mg/kg)..
1003061 In addition, the ED-1 immunopositive osteoclast. count (mean -1 standard error) was measured. The ED-1 immunopositive osteoclast count for the control (normal) was 1 0.2; for the control (disease), 19 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 Al (10 nag/kg, twice daily) with Compound B4 (2.5 mg/kg, twicedaily), 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 ma/kg, twice daily), 65%; for Compound 134 (2.5 mg/kg, twice daily), 14%; for Compound Al (20 mg/kg, daily) with Compound 134 (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) WO 2017/(159252 1.5.3 -ing/kg, twice daily) with Compound 84 (2.5 mg/kg, twice daily), 90%; and for Dex (0.075 ing4), 85%.
Example 2 1003071 Material and Methods: The effect of the combination of a BET
inhibitor, (2-cyclopropy1-6-(3,5-dimethylisoxazo1 -4-y1)-111-benzo[d]imidazol-4-yl)di(pyridin-2-yl)methanol (Compound D), and BTK. inhibitor (Compound Al) on growth inhibition of the human activated B cell (ABC) subtype DI.BCL cell line, IMD8, was evaluated in vitro. TMD8 cells were dosed with a matrix of Compound D (0 --- 90 nM) andcompound Al (0 22 ad) and treated for four days, after which cell viability was measured by a CellTiWr Glo assay. A
representative heatmap of this dose matrix for cell growth inhibition is shown in 2 (0% to 100% growth inhibition). Both compounds reduced cell growth over the dose range; synergy was observed at concentrations of 5.8 -- 90 rth4 of Compound D and 03 - 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 D alone or in the presence of 5.5 nM or 11 nM of Compound Al is shown inFIG. 4 . The average IC50 values (concentration that causes half maximal inhibition of cell growth) for Compound D were decreased from 25 nlvi to 11 nM and 8 nM by the presence of 5.5 nIVI and II nM of Compound Al., respectively, and is consistent with a synergistic interaction, Cell Viability Assay:
1003081 Cells were plated at a density of 4,000 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 DM.S0 concentration of 0.14%). Cells treated with DM50 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-fold dilution series ranging from 0.3 22 nM) for each dose of Compounda Cells were incubated at 37`1C for 96 how s and viability was measured using CellTiterGlo reagent as per the vendor's SUBSTITUTE SHEET (RULE 26) protocol. Curves were plotted in prism and no values were calculated with a 4-parameter variable hilklope mu-linear fit. The predicted response under Bliss additivity for any combination of drugs at a given concentration pair was determined by Ra Ra Rb, where Ra and Rb are the responses of Compounds D and Al cell growth inhibition); The total Bliss 5MM:was determined by .summing the diftkences 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.
SUBSTITUTE SHEET (RULE 26)

Claims (13)

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)-1-(2-butynoyl)-3-pyrrolidinyl]-7-(4-phenoxyphenyl)-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 JAK 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 wherein the disease is selected from the group consisting of a hematologic malignancy, leukemia, lymphoma chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), non-Hodgkin's lymphoma, indolent non-Hodgkin's lymphoma (iNHL), mantle cell lymphoma, follicular lymphoma (FL), lymphoplasmacytic 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 atter treatment with at least one anti-cancer therapy selected from 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) Chlorambucil combined with prednisone, rituximab, obinutuzumab, or ofatumumab; pentostatin combined with cyclophosphamide and rituximab, (k) bendamustine (Treande®) combined with rituximab; (1) alemtuzumab; (m) fludarabine plus cyclophosphamide, bendamustine, or chlorambucil; and (n) fudarabine plus cyclophosphamide, bendamustine, or chlorambucil, combined with 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 (ii), 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 ASKl 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, 1-[1-[[3-fluoro-2-(trifluoromethyl)-4-pyridinyl]-4 -piperidinyl]-3-[4-(7H-pyrrolo[2,3-d]pyrmidin-4-yl)-1H-pyrazol-yl]-3-azetidineacetonitrile, tofacitinib, oclacitinib, ruxolotinib, baracitinib, lestaurtinib, pacritinib, TO101348, JSI-124, GSK2585184, VX-509, INCB16562, XL019, NVP-BSK805, CEP33779, R-348, AC-430, CDP-R723, BMS911543, or a pharmaceutically acceptable salt thereof.
8. The method of claims 1 or 6 wherein the ASKI inhibitor is 5-(4-cyclopropyl-1H-imidazol-1-yl)-2-fluoro-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-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 bromodomain-containing protein is a compound of Formula II:

wherein R1a and R1b are each independently C1-6 alkyl optionally substituted with from 1 to R20 groups;
R2a and R2b are each independently H or halo;
R3 is -C(O)OR3, NHC(O)ORe, -NHS(O)2Ra, or -S(O)2NR3Rb; or selected from the group consisting of C1-10 alkyl, C1-10 alkoxy, amino, C5-10 aryl, C6-20 arylalkyl, C1-10 heteroalkyl, C5-10 heteroaryl, and C6-20 heteroarylalkyl, each of which is optionally substituted with from 1 to 5R20 groups;
one R4a and R4b is selected from the group consisting of H and C1-6 alkyl optionally substituted with from 1 to 5 R20 groups; and the other is absent;
R5 is C(O)ORa, NHC(O)ORa,-NHS(O)2R3, or -S(O)2NRaRb; or R5 is selected from the group consisting of H, C1-10 alkyl, C1-10 haloalkyl, alkoxy, amino, C5-10 aryl, C6-20 arylalkyl, C1-10 heteroalkyl, C5-10 heteroaryl, and C6-20 heteroarylalkyl, each of which is optionally substituted with from 1 to 5 groups;
each Ra and Rb is independently selected from the group consisting of H, C1-10 alkyl, C5-10 aryl, C6-20 arylalkyl, C6-10, heteroalkyl, C5-10 heteroaryl, and heteroarylalkyl, each of which is optionally substituted with from I to S R-20 groups; and each R20 is independently selected from the group consisting of acyl, C1-10 alkyl, C1-10 alkoxy, amino, amido, amidino, C5-10 aryl, C6-20 arylalkyl, azido, carbamoyl, carboxyl, carboxyl ester, cyano, guanidino, halo, C1-10 haloalkyl, C1-10 heteroalkyl, C5-10 heteroaryl, C6-20 heteroarylalkyl, hydroxy, hydrazino, imino, oxo, nitro, sulfonic acid, sulfonyl, thiocyanate, thiol, and thione; and wherein the C1-10 alkyl, C5-10 aryl, C6-20 arylalkyl, C1-10 heteroalkyl, C5-10, heteroaryl, and C6-20 heteroarylalkyl groups are optionally substituted with from 1 to 3 substituents independently selected from C1-6 alkyl, C5-10 aryl, halo, C1-haloalkyl, cyano, hydroxy, and C1-6 alkoxy;
or a pharmaceutically acceptable salt thereof:
10. the method of claims 1 or 6 wherein the MMP9 inhibitor comprises a MMP9 binding protein comprising:
an immunoglobulin heavy chain polypeptide, or a functional fragment thereof; and an immunogloblulin light chain polypeptide, or a functional fragment thereof; wherein the MMP9 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 chain CDRs of SEQ .11) Nos. 16-18.
11. 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 6-amino-9-[(3R)-1-(2-butynoyl)-3-pyrrolidinyl)-7-(4-phenoxyphenyl)-7,9-dihydro-8H -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 ASKI inhibitor, a BRD inhibitor, and a MMP9 inhibitor;
a label containing instructions for use in treating a disease selected from the group of cancers, allergic disorders, autoimmune diseases, and inflammatory diseases.
13. A kit comprising:
a pharmaceutical composition comprising a pharmaceutically effective amount of a BTK inhibitor, wherein the BTK inhibitor is 6-amino-9-[(3R)-1-(2-butynoyl)-3-pyrrolidinyl]-7-(4-phenoxyphenyl)-7,9-dihydro-8H -purin-8-one, or a 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 the 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.
CA3000746A 2015-10-02 2016-09-30 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 Abandoned CA3000746A1 (en)

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