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WO2017059252A1 - 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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Publication number
WO2017059252A1
WO2017059252A1 PCT/US2016/054780 US2016054780W WO2017059252A1 WO 2017059252 A1 WO2017059252 A1 WO 2017059252A1 US 2016054780 W US2016054780 W US 2016054780W WO 2017059252 A1 WO2017059252 A1 WO 2017059252A1
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Prior art keywords
inhibitor
group
compound
human
optionally substituted
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PCT/US2016/054780
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French (fr)
Inventor
Julie Di Paolo
David Breckenridge
Jamie BATES
Daniel Tumas
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Gilead Sciences, Inc.
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Priority to CA3000746A priority Critical patent/CA3000746A1/en
Priority to AU2016329075A priority patent/AU2016329075A1/en
Priority to JP2018516487A priority patent/JP2018534263A/en
Priority to EP16785022.1A priority patent/EP3355871A1/en
Priority to US15/764,687 priority patent/US20180311247A1/en
Priority to HK19101080.8A priority patent/HK1258762A1/en
Publication of WO2017059252A1 publication Critical patent/WO2017059252A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/541—Non-condensed thiazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
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    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
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    • A—HUMAN NECESSITIES
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Definitions

  • the present disclosure relates generally to therapeutics and compositions for treating cancers and allergic, autoimmune, and inflammatory disorders, and more specifically to the use of Bruton's Tyrosine Kinase (BTK) inhibitors
  • BTK Janus Kinase
  • ASK 1 Apopfcosis signal-regulating kinase 1
  • bromodomam-eonta nmg proteins bromodomam-eonta nmg proteins, or matrix metal lopeptidases 9
  • BTK inhibitors usefulm treating cancers such. as. hematological cancers and inflammatory conditions include those taught in U.S. Pat. No. 8,940,725 ⁇ Yamamoto et al.) s U.S. 2014/0330015 Yamamoto e( ai.) and U.S. Pat. No.
  • JAK Janus Kinase
  • beneficial combination therapies There remains a need for beneficial combination therapies.
  • Mitogen-activated protein kinase (MAFK) signaling cascades couple diverse extracellular and intracellular queues to appropriate cellular stress responses, including cell growth, differentiation, inflammation, and apoptosis (Kumar, S sharp Boehm, J,, and Lee,, J. C. (2003) Nat. Rev, Drug Dk 2:717-726;
  • MAPKs exist in three groups, MAP3&S, MAP2 s, and MAPKs, which are sequentially activated.
  • MAPK3s directly respond to environmental signals and phosphorylate MAP2Ks, which in torn phosphorylate specific MAPKs.
  • MAPKs then mediated the appropriate cellular response by phosphoryiatmg cellular substrates, including transcription factors that regulate gene expression.
  • ASKI Apoptosis signal-regulating kinase 1
  • ASKI is a member of the mitogen-, activated protein kinase kinase kinase ( ' 'MAF3K") family that activates the e-Jim N-termmal protein kinase ("JNK , ) and p38 MAP kinase, (ichijo, H. e et al. (1997) Science, .275. 0-94).
  • AS 1 is activated by a variety of stimuli including oxidative stress, reactive oxygen species ( OS), LPS, TNF-a, FasL, ER stress, and increased intracellular calcium concentrations (Hattori, K., et al.
  • ASK1 ' undergoes activatioa via autophospkjryiation at Thr838 in response to these signals and in turn phosphorylaf.es MAP2K.S, such as MKK3/6 and MK. 4/7, which then phosphorylate and activate p38 and JNK MAPKs, respectively.
  • AS 2 is a related MAP3K that shares 45% sequence homology with AS I (Wang, X. S., et al. (1998) Biochem. Biophys. Res. Common. 253, 33-37, Although A SK2 tissue distribution is restricted, in some cell, types ASKI and A SO have been reported to interact and function together in a protein complex (Takeda, . s et al. (2007) J. Bioi. Chem. 282: 7522-7531 ; Iriyama, T. 5 et al. (2009) Embo J.
  • ASK! activation and signaling have been reported to play an important role in a broad range of diseases including neurodegenerati ve, cardio vascular, kiilammatory, autoimmunity, and metabolic disorders.
  • ASKI has been implicate mediating organ damage following ischemia and reperthsion of the heart, brain, and kidney (Watanabe et al. (2005) BBRC 333 f 562-567: Zhang et ah, (2003) Life Sci 74-37-43; Terada et al. (2007)BBRC 364: 1043-49).
  • U.S. Publication No. 2007/0276050 describes methods for identifying ASK! inhibitors useful for preventing and/or treating cardiovascular disease and methods for preventing and/or treating cardiovascular disease in an animal. The methods comprise administering to the animal an ASK! 30 inhibitor and, optionally, a hypertensive compound.
  • U.S. Publication No. 2007/0167386 reports a drug for at least one of prevention and treatment of cardiac failure containing a compound that inhibits a functional expression of ASK! protein in a cardiomyocyte, and a method for screening the drug.
  • W02009027283 discloses iriazolopyridine compounds, methods for preparation thereof and methods for treating autoimmune disorders, inflammatory diseases, cardiovascular diseases and neurodegenerative diseases.
  • BET or BRD inhibitors- are a class of drugs with anti-cancer, immunosuppressive, and other effects demonstrated in clinical trials arid widely- used in research. They teversibiy bind the bromodomains of Bromodomain and Extra-Terminal motif (BET) proteins BRJD2, BR 3, BRD4 and B.RDT and prevent protein-protein interaction between BET proteins and aeetylated histories and transcription factors.
  • Bromodomain inhibitors include the benzimidazole derivatives taught in US 2014-03.36 ⁇ 90.
  • MMP9 tumor-associated macrophages i ' TAMsj, which support .metastasis and invasion in a complex co-activation loop via paracrine interaction with the primary tumor cells. This combination of the proteolytic breakdown -of physical barriers to cell invasion plus liberation of factors that activate growth and angiogenesis paves the way for tumor expansion, with the accompanying development of neovascularization to support tumor outgrowth.
  • MMP9 is a target of Oncogenic signaling pathways such as RAS/RAF, FB A T/NFkB, and WNT beta-catenin and functions as an upstream regulator of these pathways via modulation ofintegrin and receptor tyrosine kinase function.
  • MMP is also expressed by subsets of stromal cells (e.g. vasculature, fibroblasts) and turner-associated infiltrating cells, including myeloid-derived suppressor cells, macrophages and neutrophils.
  • MMF9 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 unregulated upon loss of several tumor suppressors, MMP9 is unregulated in many diverse tumor types and can promote primary growth and distal invasion of cancerous cells.
  • MMP9 inhibitors include the antibodies and fragments disclosed in U.S. 2015-0140580 (Smith et al.) and U.S. Patent Nos. 8,377,443 (MeAuley et al.), 8,501 ,916 (MeAuley et al,), and 9.120,863 (MeAuley et al.).
  • the BTK inhibitor is 6-amino-9-[(3R)-l- (23 ⁇ 4ttynoyl>3 ⁇ pym>jidiny
  • the BTK inhibitor is a hydrochloride salt of 6-ammo-9 ⁇ ( (3R)- l-(2-butyhoyl )-3- pyTralidinyl]-7-(4-phenoxyphenyl)-'7 i 9"dihydrO"8!:I''purin-8 ⁇ one, or a
  • 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 JA inhibitor.
  • the JAK inhibitor is selected from the group of momeJotmih, peficitinih, tofacitinib, oclacitinib, mxoUtitiib, baracitinib, lestaurtinib, pacritinib, filgotmib, 1 -[ l-[ 3-fluoro-2-(trifluoromethyl) ⁇ 4- pyricHnyl] -piperidinyl]-3- 4-(7H ⁇ yn , oio[23-i Jpyraiidjn-4-yi )-l K-pyrazal-l - ylj-S-azetidineacetonitrile, TGI 01348, JS-124, INCB3 110, INCB16562, CHZ86S, VX-509, XL019, NVP-BSK805, CEP33779, R-348, AC430, CDP ⁇ R723, BMS91
  • the ASK inhibitor is selected from the group of Compound CI, . Compound C2. or the compound of Formula (I), in some aspects, provided is a method for treating cancer in a human in need thereof, comprising administering to the human a therapeutically effective amount of a BTK inhibitor and a therapeutically effective amount of a BHD inhibitor,
  • the BRD inhibitor is the compound of Formula (II).
  • 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 immunoglobulin (l.g) hea vy chai (or functional fragment thereof ⁇ and an ig light chain (or functional fragment thereof), in certain embodiments, the MP9 inhibitor comprises the amino acid sequence selected from the group consisting of SEQ ID NOs: 3, 4, and 5-12.
  • kits that comprise the BTK inhibitor and one or more inhibitor selected from a JAK inhibitor, a ASK inhibitor, a BED inhibitor, and a MMP9 inhibitor.
  • methods comprising a BTK inhibitor and one or snore inhibitor selected from a JAK. inhibitor, a ASK nhibitor, a B D inhibitor, arid a P9 irihibitor for the use in therapy or in the manufacture of a medicament for cancer treatment,
  • FIG. 1 provides a chart of Mean SB Ankle Diameter for a rat collagen- induced arthritis model conducted using Compound Al and tofacitinib.
  • FIG, 2 depicts a heat map representing the percent of DLBCL cell growth inhibi tion for e very pairwise combination of Compound A I and a BET inhibitor 6-amino ⁇ T3R.)-l -(2-bufynoyl)- -pyrrolidinyl]-7-(4-pbenox phenyl)" 7.9-dihydro ⁇ 8H-purin- 8-one (Compound D) from one representative experiment.
  • FIG. 3 depicts a heatmap of the calculated Bliss excess over predicted addniv y for every pairwise combination using the percent growth inhibition shown in: PICT 2,
  • FIG. 4 depicts the average percent cell growth inhibition relative to a DMSO control (n ::: 3) for DLBCL ceils treated with a dilution series of
  • compositions including pharmaceutical compositions, formulations, or unit dosages
  • articles of manufacture and kits comprising a BTK inhibitor and one or more inhibitor selected from a JAK inhibitor, a ASK inhibitor, a B ' RD ' inhibitor, and a MMP9 inhibitor.
  • Combinations of pharmaceutically effecti ve amounts of the BTK inhibitor and one or more inhibitor selected from a JAK inhibitor, a ASK inhibitor, a BRD inhib tor, and a MMP inhibitor as described herein may be used to treat cancers, allergic disorders, autoimmune diseases and inflammatory diseases in a human, the method comprising administering to the human in need 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 MM.P9 inhibitor.
  • the combinations taught herein may be used for the treatment of allergic disorders, autoimmune diseases and inflammatory diseases such as; systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), multiple vasculites, idiopathic thrombocytopenic purpura (1TP), myasthenia gravis, allergic rhinitis, chronic obstructive pulmonary disease (COPD), adult respiratory distress syndrome CA Ds) and asthma.
  • SLE systemic lupus erythematosus
  • RA rheumatoid arthritis
  • TP idiopathic thrombocytopenic purpura
  • COPD chronic obstructive pulmonary disease
  • CA Ds adult respiratory distress syndrome
  • cancers such as hematologic malignancy, leukemia, lymphoma chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SIX), non-Hodgkin's lymphoma, indolent. non-Hodgfc l's lymphoma (iNHL), refractory iNHL. mantle cell lymphoma, follicular lymphoma (FL), lymphopksmacytic lymphoma, and. marginal zone lymphoma.
  • CLL chronic lymphocytic leukemia
  • SIX small lymphocytic lymphoma
  • iNHL non-Hodgkin's lymphoma
  • iNHL non-Hodgfc l's lymphoma
  • FL follicular lymphoma
  • lymphopksmacytic lymphoma and. marginal zone lymphoma.
  • 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 groitp.
  • a dashed line indicates an optional bond.
  • no directionality is indicated or implied by the order in which a chemical group is written. For instance, the group "-S0 2 CHr" is equivalent to JI- ⁇ SCV and both may be connected in either direction.
  • the prefix "(W indicates that the following group has from u to v carbon atoms, one or more of which, m certain groups (e.g.
  • heieroaikyl, heteroaryl, heteroarylalkyl, etc) may be replaced with one or more heteroatoms or heteroatomic groups.
  • " € ⁇ .,, alkyl” indicates that the alky! group has from 1 to 6 carbon atoms
  • a divalent group such as a divalent "alkyl” group, a divalent “aryl” group, etc., may also be referred to as an "aikylene” group or an “aikyienyf group, an "arylene” group or an “arylenyl” group, respectively.
  • A!kyJ refers to any aliphatic hydrocarbon group, is, .any linear, branched, cyclic, or spiro nonaromatie hydrocarbon group or an isomer or combination thereof.
  • alky 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), eyeloalkyi (a cyclic aliphatic group), alkylcycloalkyl (a linear or branched aliphatic group attached to a cyclic aliphatic group), and the like.
  • Alkyl groups include, but are not limited to, methyl; ethyl; propyls such as propan-l-yl, propan-2-yl (iso-propy) ), and cyclopropyls such as cyclopropan-l -yl, etc.; butyls such as buian-l -y!, butan-2-yl (sec-butyl), 2-methyI-propan ⁇ 1 -yl (iso-butyl), 2- mefhyI-propan-2-yl (t-butyl), eyciobutan-l-yi; butanes (e.g.
  • alkyl group comprises from 1 to about 10 carbon atoms, e.g., from 1 to 6 carbon atoms.
  • 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.
  • 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 10 carbon atoms, e.g., from 2 to 6 carbon atoms or 2 to 4 carbon atoms and having at least one site of vinyl unsaturation (>C ;;: C ⁇ j.
  • Alkenyl groups include ethenyl, propenyi, 1,.3-bu.tadienyl, 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.
  • Alkynyl is a subset of “alkyl” and refers to an aliphatic group containing at least one carbon -carbon triple bond.
  • alkynyl is also meant to include those groups having one triple bond and one double bond.
  • Alkoxy refers to the group -O-aikyl, wherein the alkyl group may be optionally substituted. Aikoxy includes, by way of example, methoxy, ethoxy, n-propoxy, isopropoxy, n » butoxy, t-buioxy, sec-butoxy, and n-pentoxy. 10026] "Acyr refers to a group - € ' ))R 5 where R is hydrogen, alkyl, cyeloalkyi, cycioheleroalkyi, aryl.
  • arylaikyi heieroalkyl, heteroaryl 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, cykohexylcarbonyl, cyclohexylineiiiyi- carboiiyl, benzoyl,
  • Amino refers; to tile group -NR3 ⁇ 4 S wherein R y and R are independentl selected from the group consisting of hydrogen, alkyl, aryl, heteraikyl, heteroaryl (each of which may be optionally substituted), and where R y and R z are optionally joined together with the nitrogen bound thereto to form a
  • heterocyeloaikyl or heteroaryl heteroaryl (each of which may be optionally substituted),
  • Amidino refers to the group -- €( ;:: E x )NiR R E where K ⁇ R y , and R 5 are independently selected from the group consisting of hydrogen, alkyl aryl heteraikyl, heteroaryl (each of which may be optionally substituted),, and where R y and R '" are optionally joined together with the nitrogen bound thereto to fonn a heterocyeloaikyl or heteroaryl (each of which may be optionally substituted).
  • 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 covIERly, or linked via one or more such as a methylene or ethylene moiety.
  • Aryl groups include., but are riot limited to, those groups derived from acenaphthylene, anthracene, azuiene, benzene, biphenyl, chrysene,
  • aryl group comprises from 5 to about 20 carbon atoms, e.g., from 5 to 20 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,
  • ArylalkyP refers to an aryl group attached to an alkyl group
  • Arylalkyi groups include, but are not limited to, benzyl, tolyl, dimethylphenyl, 2-ph.enyiet.han ⁇ 1 -yi, 2-naphthylmethyl, 2-naphthyiethan- 1 -yl, naphthobenzyi, plienylvinyl, diphenylmethyl, and the like.
  • the "arylalkyi” may be attached to the rest of the compound of formula (I) through the aryl group.
  • arylalkyP may be attached to the rest of the compound of formula ( !) through the alkyl group.
  • the nomenclature arylalkanyl, aryiaikenyl and/or arylalkynyl may be used.
  • An arylalkyi group comprises from 6 to about 30 carbon atoms, e.g. the alkyl portion of the arylalkyi group can comprise from 1 to about 10 carbon atoms and the aryl portion of the arylalkyi group can comprise from 5 to about 20 carbon atoms.
  • an arylalkyi group comprises from 6 to about 20 carbon atoms, e.g. the alkyl portion of the arylalkyi group can comprise from 1 to about 10 carbon atoms and the aryl portion of the arylalkyi group can comprise from 5 to about 10 carbon atoms.
  • Aryloxy refers to the group -O-aryl, including by way of example, phenoxy and naphthoxy.
  • Boromc acid refers to the group -B(OH) 2 .
  • Boronic acid ester refers to an ester derivative of a horonic acid compound.
  • Suitable boromc acid ester derivatives include those of the formula -
  • R is hydrogen, alkyl, aryl, arylalkyi, heteroaikyl, or heteroaryl, each of which may be optionally substituted.
  • boromc add ester may be pinacol ester or catechol ester.
  • CarbocyclyP refers to a saturated, partially unsaturated or aromatic ring having 3 to 7 carbon atoms as a monocycle, 7 to 12 carbon atoms as a bicycle, and up to about 20 carbon atoms as a polycycle, Monocyclic carbocycles have 3 to 6 ring atoms, still more typically 5 or 6 ring atoms, Bicychc 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 (6,6) system, Carboeycies includes aromatic and non-aromatic mono-, bi ⁇ , and poly-cyclic rings, whether fused, bridged, o spiro.
  • Non-limiting examples of monocyclic carboeycies include the cycloaJkyls group such as cyclopropyl, cyeJobutyl, cyclopentyi, l -cyclopent-l-enyk i --eyciope ) it-2-enyl i-cyclopemV3- enyl, cyclohexyi, l-cyclohex-l ⁇ cny ' j. l-cyclohex-2-enyl, l-cyclohex-3-enyl or aryl groups such as phenyl, and the like.
  • “carbocycle " as used herein, encompasses but is not limited to "aryl", “phenyl” and "biphenyl.”
  • Carbamoyl refers to the group ⁇ €(0) R y R. z where R y and R z are defined as in “amino" above.
  • CarhonyT refers to the divalent group -C(O)- which is equivalent ⁇ ⁇ ( . ' ( O r.
  • Carhoxyl or "earhoxy” refers to -COOH or salts thereof
  • Carboxyl ester 5 or ⁇ s carboxy ester refers. to the groups - €(0)011, wherein R is hydrogen, alkyl, aryl, aryialkyl, heteroalkyi, or heteroaryl, each of which may be optionally substituted, in one embodiment, R is alkyl, aryl, aryialkyl, heteroalkyi, or heteroaryl, each of which may be optionally substituted.
  • Cyano or “carbo Trile” refers to the group -C ,
  • 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.
  • eycloalkyT applies when the point of attachment is at a non-aromatic carbon atom (e.g., 5,6,7,8,- tetranydronaphthalene-5-yl).
  • the term "eycloalkyT includes cycloalkenyl groups.
  • cycloalkyl groups include, for instance, adaroantyl, cyeiopropyj, cyclobutyl, cyclopentyl, oyelooetyl, and cyclohexenyl.
  • Halo or "halogen” refers to fluoro, chl ' oro, bromo and iodo.
  • Haloalkyl refers to substitution of alkyl groups with 1. to 5 or, in some embodiments, 1 to 3 halo groups, e.g., -C3 ⁇ 4CL -C3 ⁇ 4F, ⁇ CHj.Br, -CFClBr, - C3 ⁇ 4CH 2 C1, ⁇ C.H2C.H2F, -CF 3 , -CFfeCFj, ⁇ C3 ⁇ 4CC3 ⁇ 4, and the like, and further includes those aikyl groups such as perifeoroalkyl in which all hydrogeri atoms are replaced by fluorine atoms,
  • Haloaryl* refers to aryl groups with one or more halo or halogen substiruents,
  • haloaryl groups include phenyl groups in which from 1 to 5 hydrogens are replaced with a halogen
  • Haloaryl groups include, for example, fluorophenyl, di fluorophenyl trifluorophenyl, chlorophenyl, clorofiuorophenyl, and the like.
  • Heteroalkyl refers to an aikyl group in which one or more of the carbon atoms (and any associated hydrogen atoms) are each independently replaced with the same or different heteroatorn or heteroatoraic group.
  • heteroalkyl may include 1 , 2 or 3 heteroato ic groups, e.g. I heteroaioinic group.
  • Heteroatoros include, but are not limited to, N, P, Q, S, etc.
  • Heteroatomic groups include, but are not limited to, -NR-, )-, -PH ⁇ , -P(0) 2 -. -S(0>, -S(0 .
  • heteroalkyl includes heterocyeloalkyl (a cyclic heteroalkyl group), alkyl-heterocycloalkyl (a linear or branched aliphatic group attached to a cyclic heteroalkyl group), and the like.
  • Heteroalkyl groups include, but are not limited to, -OCR,, ⁇ C3 ⁇ 4OC3 ⁇ 4 -SC3 ⁇ 4 » C3 ⁇ 4SCHj f -NRCH3, - CH2 RCH3, and the like, where R is hydrogen, aikyl, 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 i to 6 carbon, and hetero atoms.
  • 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 heteroatoms, as defined above.
  • heteroaryl may include i, 2 or 3 heteroatomic groups, e.g. 1 -heteroatomic group.
  • Heteroaryl groups include, but are not limited to, groups derived from acridine.
  • benzoimidazole benzothiophene, benzofuran, henzoxazole, benzothiazole, carbazole, earboline, cinnoline, furan, imidazole, imida3 ⁇ 4opyridine, indazoie, indole, indolme, indoiizme, isobenzofuran, isochromene, isoindoie, isoindotine, isoqutnolme, isothiazole, isoxazole, naphthyridme, oxadiazole, oxazole, perimidine, phenantJvridine, phenauthroline, phenazine, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrroiizine, qumazoime, quinoiine, quinoliziae
  • Heieroarylalkyl refers to an arylalkyl group in which one or snore carbon atoms (and any associated hydrogen atoms) are independently replaced with the same or different heteroaioms, as defined above.
  • heieroarylalkyl may include 1 , 2 or 3 heteroatomic groups.
  • Heteroarylalkyl groups include, but are no limited to, groups derived ftora heteroaryl groups with alkyl sitbstituents (e.g. methyipyndine, diroeihylisoxazole, etc.), hydrogenated heteroaryl groups (dihydioquinolines, e.g. 3,4-dihydroqrunoime,
  • dibydroisoquinolines e.g. ⁇ ,2-di : hydroisoquinoline, dihydroimidazole, tetrahydroimklazole, etc.
  • isoindoline iso dolones (e.g. isoindolin-1 -one), dihydrophthaiazine, quinolinone, spir0[cyclopropane ,14so ⁇ do ⁇ in]-3'-one, di(pyridm-2-yl)memyj., dt(pyridm-3-yl)methyl, di( ' pyridin-4-yl)methyl s and the like.
  • a heieroarylalkyl group comprises from 6 to about 30 carbon and hetero atoms, for example from 6 to about 20 carbon and hetero atoms.
  • Heterocycloalkyl is a subset of “heteroa!kyF and refers to a saturated or unsaturated ey oalkyl group in which one or more carbon atoms (and any associated hydrogen atoms) are independently replaced with the same or different heteroatom.
  • Heteroatoms include, but are not limited to, N, P, O, S, etc,
  • a heterocycloaikyl .group may also contain a charged heteroatom or group, e.g., a quatem.iz.ed ammonium group such as -N+ R)2- wherein R is alkyl, e.g., methyl, ethyl, etc,
  • Heterocycloaikyl groups include, but are not limited to, groups derived from epoxide, imidazolidine, morpholine, piperazine, piperidine, pyrazolidine, piperidine, pyrrolidine, pynolidinone, tetrahydroraran.
  • heterocycioalkyl group comprises from 3 to about. 10 carbon and hetero atoms in the ring or rings. In some embodiments, heterocycioalkyl includes 1, 2 or 3 heteroatomic groups,
  • Heterocycle or "heterocyelyr as used herein includes; by way of example and not limitation those heterocycles described in Paquette. Leo A,; Principles of Mo em 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 ponographs” (John Wiley & Sons, New York, 1950 to present), in particular Volumes 13, 14, 16, 19, and 28; and I, Am. Chem. Soc. (I960) 82:5566.
  • heteroeycle in one specific embodiment of the invention “heteroeycle” includes a “carbocyele” 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),
  • heteroatom e.g. 0, N, P or S
  • heteroeyele or “heterocYciyi” ' includes saturated rings, partially unsaturated rings, and aromatic rings (i.e., heteroaromatic rings), Heterocycles includes aromatic and non-aromatic mono-, bi-, and poly-cyclic rings, whether fused, bridged, or spiro.
  • 4 ⁇ heteroeycie encompasses, but is not limited to "heteroaryl.
  • Substituted heterocyclyis include, for example, heterocyclic rings substituted with any of the substituents disclosed herein including carbonyl groups.
  • heterocycles include by way of example and not limitation pyridyl, dihydroypyridyl.
  • tefrahydropyridyl (piperidyl), thiazoiyi, teirahydrothiophenyl, sulfur oxidized tetrahydrothiophenyl, pyrimidinyl, furanyl, thienyl, pyrroiy!, pyraxolyl, imidazolyl, tetrazoiyl, benzoftiranyl, mianaphthalenyl, indolyl, indolenyl, qiiinolinyf isoquinolinyl, bea imidazolyi, piperidinyl, 4-piperidonyl, pyrrolidinyl, azetidinyl, 2- pyrrolidonyl, pyrrolmyl, tetrahydroftiranyl, teirahydroquinolinyl,
  • imidazolidinyl imidazolinyl, pyrazolidmyl, pyrazoiiny!, piperazinyl, indolinyl, isoindoltnyl, quinuclidinyl, morpholinyl, oxazolidioyl, benzotriazolyj, benzisoxazolyl, oxindolyl, benzoxazolinyl, isatmoyl, and bis-tetrahydroiuranyi.
  • carbon bonded heterocycles are bonded at position 2. 3, 4, 5, or 6 of a pyridine, position 3, , 5, or 6 of a pyridazme, position 2, 4, 5, or 6 of a pyrrolidine., position 2, 3, 5, or 6 of a pyrazine, position 2, 3, 4, or 5 of a furan, tetrabydroftran, thiofuran, thiophene, pyrrole or tetrahydropyrrole, position 2, 4, or 5 of an oxazole, imidazole or thiazoie, position 3, 4, or 5 of an isoxazole, pyrazole, or isothiazole, position 2 or 3 of an aziridine, posiiion 2, 3, or 4 of an azetidine, position 2, , , 5, 6, 7, or 8 of a quinoline or position 1 , 3, 4, 5, , 7, or 8 of an isoquinoline.
  • carbon bonded heterocycles include 2 ⁇ pyridyl, 3-pyfidyl, 4 ⁇ pyridyl J S- pyridy], 6-pyndyl, 3-pyridazinyl, 4-pyridazmyl 5-pyridazmyL 6-pyndazinyl 2- pyrimitlmyl, 4-pyri.midmyl, 5-pyrimidmyl, 6-pyrimidinyl, 2-pyriiziny!, 3- pyrazinyi, 5-pyrazmyl, 6-pyrazinyl, 2-thiazoiyl, 4-ihiazolyl, or 5-thiazo.ly).
  • nitrogen bonded heterocycles are bonded at position 1.
  • nitrogen bonded heterocycles include l-aziridyb 1-azetedyl, 1-pyrrolyl, 1-imidazoiyl, 1 -pyrazolyl, and l-piperidmyl.
  • Imino refers to the group -C( » NR)- wherein.
  • R is hydrogen, alkyl atyl aryialkyl, hetero ikyl, or heieroaiyl, each of winch may be optionally substituted.
  • ' ⁇ Niiro :' refers to the group -NO.;.
  • Oxide refers to products resulting from the oxidation of one or more heteroatoms. Examples include N-oxides, sulfoxides, and suifones.
  • Oxo refers to a double-bonded oxygen (-0). In compounds where an oxo group is bound to an s ⁇ nitrogen atom, an N-oxide is indicated.
  • Racemates refers to a mixture of enantiomers.
  • 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, 1 92).
  • Substituted refers to a group wherein one or more hydrogens have been independently replaced with one or more substituents including, but not limited to, alky], alkenyl, alkynyl, alkoxy, acyi, amino, aniido.
  • substituted 5* may describe other chemical groups defined herein.
  • substituted aryl includes, but is not United to, “aryialkyl.”
  • substituted groups will have 1 to 5 substituems, 1. to 3 substituents, 1 or 2 suhstituents or 1 substitu nt.
  • the optionally substituted groups of the invention may be unsubstituted.
  • Tautomer refers t alternate forms of a compound that differ in the position of a proton, such as enoi-keto and iffiine ' -enamine tautomers, or the tautomeric forms of heteroaryl groups containing a ring atom attached to both a ring -NH ⁇ moiety and a ring :::: N- moiety such as pyrazoles. imidazoles, bendmidazoles, triazoies, and tetrazoles.
  • Tlfiocyanate refers to the group -SCN.
  • “Pharmaceuticaily acceptable” refers to compounds, salts, compositions, dosage forms and other materials which are useful in preparing a pharmaceutical composition that is suitable for veterinary or human pharmaceutical use.
  • “Pharmaeeutioaily 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, benzenesulfbnic acid, benzoic acid, camphoraulfomc acid, citric acid, ethanesul onic acid, turoarie acid, glucoheptonic acid, gluconic acid, lactic acid, maleic acid, malonic acid, mandelic acid, methanesulfonic acid, 2-napththalenesulfonic acid, oleic acid.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like
  • organic acids such as acetic acid, benzenesulfbnic acid, benzoic acid, camphoraulfomc acid, citric acid, ethanesul onic acid, turoarie acid
  • metbylglueamine and the like are ammonium and substituted or quatemized ammonium salts.
  • Representative non-limiting lists ofphannaceutically acceptable salts can be found in S.M. Berge et ah, J, Pharma Sci., 66(1). 1-19 ( 1977), and Remington: The Science and Practice of Pharmacy, R. Heodrickson, ed., 21 st edition, lipptneott, Williams & Wilkins, Philadelphia, PA, (2005), at p. 732, Table 38-5, both of which are hereby incorporated by reference herein.
  • riBuLi ?-bulyHithiur»; CC: column eliromatography; Q3 ⁇ 4COjj: cesium carbonate: C3 ⁇ 4C1 ⁇ 4 or DCJVf: dichlotomethane; CH 3 Mgi: methyl magnesium iodide; CuCk copper chloride; DAST: (diethylamino)sulfur trifluoride; DEAD: diethyl azodicarboxylate; DIB L: dnsobulyialuminum hydride; D1PEA:
  • lithium aluminum hydride LiOH: lithium hydroxide
  • M molar eCN
  • Effective amount or “therapeutically effective amount” means the amount of a compound or molecule described herein that may he 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.
  • 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 "re ractory” 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, tor 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 lias returned or the signs and symptoms of cancer have returned after a period of improvement, e.g. after a treatment has shown effective reduction in the cancer, such as after a subject is in remission or partial remission,
  • 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 (i) and (ii).
  • the human is refractory to at least two, at least three, or at least four anti-cancer therapies (including, for example, standard or experimental chemotherapies).
  • Subject and “subjects” refer to human in need thereof may be an individual who has or is suspected of having a cancer.
  • 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.
  • 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.
  • 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 ( g-., hereditary) considerations, and environmental exposure, in some embodiments, a human at risk for 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 al so be a risk factor for instances of cancer recurrence
  • treatment 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:
  • "delaying" the development of a disease or condition means to defer, hinder, slow, retard, stabilize, and/or 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 .
  • a method that "delays" development of a disease or condition is a method that reduces probability of disease or condition development in a given time frame and/or reduces the extent of the disease or condition in a given time frame, when compared to not using the method. Such comparisons are typically based on clinical studies, using a statistically significant number of subjects.
  • Disease or condition development can be detectable using standard methods, such as routine physical exams, mammography, imaging, or biopsy. Development may also refer to disease or condition progression that may be initially undetectable and includes occurrence, recurrence, and onset.
  • references to "about” a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se.
  • the term “about” includes the indicated amount ⁇ 10%.
  • the term “about” includes the indicated amount ⁇ 5%.
  • the term “about” includes the indicated amount ⁇ 1%.
  • 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.
  • antibody means an isolated or recombinant 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 mo.ooclon.ai antibodies (including full- length monoclonal antibodies), polyclonal antibodies, human antibodies, humanized antibodies, chimeric antibodies, nanobodies, diabodies, multispecifle antibodies [e.g. , bispeeific antibodies), and antibody fragments including but not limited to Fv, scFv, Fab. Fab' F(ab') 2 and Fab?., so long as they exhibit the desired biological activity.
  • 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).
  • an "antibody fragment” comprises; a portion of a full-length antibody, for example, the antigen bindi ng or variable region of a full -length antibody, Such antibody fragments may also be referred to herein as "functional fragments: or "antigen-binding fragments".
  • antibody fragments include Fab, Fab 1 , Fiab' . h, and Fv fragments; diabodies; linear antibodies (Zapata et al (1995) Protein Eng. 8(10): 1057-1062); single-chain antibody molecules; and mulrispeeific antibodies formed from antibody fragments.
  • Papain digestion of antibodies produces two identical antigen-binding fragments, called “Fab” fragments, each with a single antigen-binding site, and a residual "Fc” fragment, a designation reflecting the ability to crystallize readily.
  • Pepsin treatment yields an F(ab') 2 fragment that, has two antigen combining sites and is still capable of cross-linking antigen.
  • Fv is the minimum antibody fragment which contains a complete antigen-recognition and -binding site. This region consists of a dimer of one heavy- and one ' light-chain variable domain in tight, non-covalent association. It is in this configuration that the three complementarity-determining regions (CDRs) of each variable domain interact to define an antigen-binding site on the surface of the VH ⁇ VI, dimer. Collectively, the six CDRs confer antigen-binding specificity to the antibody.
  • variable domain or an isolated VH or V ' t region comprising only three of the six CDRs specific for an antigen
  • VH or V ' t region comprising only three of the six CDRs specific for an antigen
  • the -fragment also contains, in addition to heavy and light chain variable regions, the constant domain of the light chain and the first constant domain (CM)) of the heavy chain.
  • Fab fragments were originally observed following papain digestion of an antibody. Fair fragments differ from Fab fragments; in that F(ab') fragments contain several additional residues at the carboxy terminus of the heavy chain CHj domain, including one or more cysteines from the antibody hinge region. F(ab3 ⁇ 4 fragments contain two Fab fragments joined, near the hinge region, by disulfide bonds, and were originally- observed following pepsin digestion of an antibody.
  • Fab ' -SH is the designation herein for Fab' fragments in which the cysteine residue(s) of the constant domains bear a free thiol group. Other chemical couplings of antibody fragments are also known.
  • the "light chains" of antibodies (immunoglobulins) from any vertebrate species can he assigned to one of two clearly distinct types, called kappa and lambda, based on the amino acid sequences of their constant domains.
  • immunoglobulins can be assigned to five major classes: IgA, IgD, IgE, IgG, and IgM, and several of these may be further divided into subclasses (isotypes), e.g., igG L IgG2, lgG3, lgG4, IgAF and !gA2.
  • Single-chain Fv or “sFv” or “scFv” antibody fragments comprise the VH and Vi. domains of antibody, wherein these domains are present a single polypeptide chain.
  • the Fv polypeptide further comprises a polypeptide linker between the ⁇ 3 ⁇ 4 and 1 ⁇ 4. domains, which enables the sFv to form the desired structure for antigen binding.
  • diabodies refers to small antibody fragments with two antigen-binding sites, which fragments comprise a heavy-chain variable domain (V ' H) connected to a light-chain variable domain (Vj . ) in the same polypeptide chain (Vs.;- Vg.
  • V ' H heavy-chain variable domain
  • Vj . light-chain variable domain
  • Vs.;- Vg polypeptide chain
  • 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 antige -binding sites.
  • Diabodies are additionally described, for example, in EP 404,097; WO 93/1 .1 161 and HolHnger et aL ( 1993) Proc. Natl. Acad. Sci. USA 90:6444-6448.
  • 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.
  • 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 -terminal or internal amino, acid.
  • 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.
  • immunosorbent 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 or antigen binding fragment thereof.
  • An epitope can be a linear peptide sequence (i.e., ''continuous") or can be composed of noncontiguous amino acid sequences (i.e., "conformational” or “discontinuous”).
  • preferentially binds means that the binding agent binds to the binding site with greater affinity than it binds unrelated amino acid sequences.
  • CDR complementarity determining region
  • CDR complementarity determining region
  • nBtnbering follows ihe nomenclature of Kabat ct ai., supra
  • variable region when used its 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.
  • .framework region is intended to mean each domain of the framework that is separated by the CDRs.
  • Homology or “identity” or “similarity” as used herein in the context of nucleic acids and polypeptides refers to the relationship between two polypeptides or two nucleic acid molecules based on an alignment of the ammo 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 same, or a similar amino acid residue (e.g., similar in sterie and/or electronic nature), then the molecules can be referred io 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/sitnilariiy.
  • identity means th percentage of identical nucleotide or ami no 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 & designated region, e.g., a region al least about 20. 25, 30, 35, 40, 45, 50, 5, 0, 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.
  • test and reference sequences are input into a computer program, subsequence coordinates are designated, if necessary, and sequence algorithm program parameters are designated.
  • 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.
  • Residue positions which are not identical can differ by conservative amino acid substitutions.
  • Conservative amino add substitutions refer to the interchangeability of residues having similar side chains.
  • a group of amino acids having aliphatic side chains is gl cine, alanine, valine, leucine, and iso!eucine; a group of amino acids having aliphatic-hydroxy!
  • side chains is serine and threonine; a group of amino acids having amide-containing side chains is asparagine and glutamine; a group of amino acids having aromatic side chains is phenylalanine, tyrosine, and tryptophan; a group of amino acids having basic side chains is lysine, arginine, and histidine; and a group of amino acids having sulfur- containing side chains is cysteine and methionine.
  • 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.
  • 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 (TUPAC),
  • isotopicaiiy labeled forms of compounds detailed herein.
  • Isotopicaiiy 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.
  • isotopes thai can be incorporated into compounds of the disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as, but not.
  • isotopicaiiy labeled compounds of the present disclosure for example those into which radioactive isotopes such as ' ⁇ , "C and , C are incorporated, are provided.
  • isotopicaiiy labeled compounds may he useful in metabolic studies, reaction kinetic studies, detection or imaging techniques, such as positron emission tomography i PET) or single-photon emission computed, tomography (SPEC!) including drug or substrate tissue distribution assays or in radioactive treatment of subjects (e.g. humans).
  • isotopicaiiy labeled compounds described herein are any pharmaceutically acceptable salts, or hydrates, as the case may be.
  • 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 di half life of the compound when administered to a
  • Deuterium labeled or substituted therapeutic compounds of the disclosure may have improved DMP (drug metabolism and pharmacokinetics) properties, .relating to absorption, distribution, metabolism and excretion
  • 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,
  • the concentration .of such a hea greed isotope, specifically deuterium, may ⁇ be defined by an isoiopic enrichment factor.
  • any atom not specifically designated as a particular isotope is meant so represent any stable isotope of that atom.
  • a position is designated specifically as "H” or "hydrogen”
  • the position is understood to have hydrogen at its natural abundance isotopic composition.
  • any atom specifically designated as a deuterium (D) is meant to represent deuterium.
  • the BTK inhibitor is Compound AL or a pharmaceutically acceptable salt or hydrate thereof.
  • Compound Al has structure:
  • the BTK inhibitor is a hydrochloride salt of Compound Al , or a hydrate thereof.
  • Compound. A 1 may e synthesized according to the methods described in U.S. Patent No. 8,557,803 (Yamamoto et al) and US 2014/0330015.
  • Compound Al ma be referred to as (R)-6-araino-9- (l-(1wi-2->m i)pym)lidm-3-yl)-7-(4 ⁇ henoxyphenyl)-7H-purin-8(9H)-oxie or 6- amino-9-[(3Rj-!-(2"butyno>l)-3-py ⁇
  • Additional BTK inhibitors include, but are not limited to.
  • the JAK inhibitor is Compound B 1 ;! Compound .82, Compound B3, or Compound B4, or a pharmaceutically acceptable salt thereof.
  • Compound Bl which may be referred to as momeioiinib. CYTj 137, CYT387, or N- cyanometh l)-4 ⁇ [j -(4 » mo ⁇ holmyi) he yl] mmo]-4- pyrimidinyl] » benzamide or N-(cyanomethyl)-4-(2-((4"morphoiinophenyi) amino)pyrimidin-4-yl)benzainide 5 has the structure:
  • Compound B3 which has the Chemical Abstracts registry number 1334298-90-6, may be referred to as l-[ 1 -[ 3-lluoro «2- ⁇ irjfluoromethyi)-4- pyri.dmyi]carbony!] - ⁇
  • Compound B4 which may be referred to as tofacitinib,
  • piperidmepropanemtriie or 3-((3R,4R)-4-nisthyI-3-(methyl(7H-pynOio ⁇ 2 > 3- d]pyriroidin-4-yl)ammo)pi eridin-i -yl)-3 -ox opropanenitrile has the structure:
  • Compound B5 which, may be referred to as oclacitinib or N-methyl-1- iilr,4r)-4-i0iethyl(7H-p rro ⁇ o[2,3"d]pyrimidin-4- yi)amino)cyc!ohexy])methaneaidfonainids ! , has the structure:
  • Compound Bo which may be referred to as ruxolotinib (INC. ' 42.4, INCB 18424, JAKAFI®, JAKAVI®, a vailable from feeyte Pharmaceuticals and Novartis) or (3R.)-3-Cyc]opentyl-3-[4-(7H-p3aToio(23 ⁇ d]pyrimidin-4-yi)-iH- pyrazol-i•yljpropanenitrile has the structure:
  • Compound B7 which may be referred to as barackinib (LY300 104,
  • CoTnpound B8 which may be referred to as lestaurtinib (C.EP-703, .T5555, and A 154475.0) ⁇ ⁇ 2,3,9,10,1 l,i2-hexah dro-10 ⁇ hydroxy-10- (hydroxymethyl)-9-nie l-, (9SJ0S.12RV 9,12-Epoxy-l H-diindoio[ l,2 5 3-fg;3', 2',1 '-kljpyrroloj 3,4-i] [ 1 ,6]ben2odiazocm-l -one, has the structure:
  • Compound Bi 1 which may be referred to as JSl-124, Ciicurbitracin, Elalericin B, NSC-521777,.
  • Addiiional J AK inhibitor compounds that may be used, in the combinations, methods, kits, and articles of manufacture herein include
  • Compound B1 or a pharmaceutically aeceplab! salt thereof, is used in combination with Compound A 1, or a pharmaceutically acceptable salt or hydrate thereof, m other embodiments, Compound B2, or a pharmaceutically acceptable salt thereof, is used in combination with Compound Al , or a pharmaceutically acceptable salt or hydrate thereof.
  • Compound B3, 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 B4, or a pharmaceutically acceptable salt thereof, is used in combination with Compound Al, or a plmmiaceutieally acceptable salt or hydrate thereof.
  • Compound B5, or a phamiaceutically acceptable salt thereof is used in combination with Compound Al , or a pharmaceutically acceptable salt or hydrate thereof.
  • Compound B6. or a pharmaceutically acceptable salt thereof is used in combination with Compound A3, or a pharmaceutically acceptable salt or hydrate thereof, hi another embodiment, Compound B7, or a pharmaceutically acceptable salt thereof, is used in combination with Compound Al, or a pharmaceutically acceptable salt or hydrate thereof.
  • Compound .88, 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 B9 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 BIO, or a pharmaceutically acceptable salt thereof, is used in combination with Compound Al. or a pharmaceutically acceptable salt or hydrate thereof. In other embodiments. Compound Bl 1, or a pharmaceutically acceptable salt thereof, is used in combination with Compound Al , or a pharmaceutically acceptable salt or hydrate • thereof.
  • INCB-0391 10 (INCB-39110) may be prepared by the methods 30 seen in US 201 1/112662 and US 2015/1246046, pefkitmib may be prepared as described in U.S. Patent Nos, 7,879,844 and 8.779,140, and momeiotinib may be prepared as described in U.S. Patent No. 8.486,941,
  • the JA inhibitor is selected from the group of momeiotinib (CYT0387), ruxolitimb, fedratmib, baricitinih, lestaurtinib, pacritraib, XL019, AZD1480, LY27845 4, BMS911543, and NS01.8, or a pharmaceutically acceptable salt thereof.
  • the JAK inhibitor is selected from the group ofTG10l348, JS-12 , and INCB39110, CHZ868, and GS 2586I84, or a pharmaceutically acceptable salt thereof.
  • the JAK inhibitor is momeiotinib, or a pharmaceutically acceptable hydrochloride salt thereof.
  • the JAK inhibitor is fttgotinib, or a
  • the ASKl inhibiting compound is a compound of Formul ⁇ :
  • R is selected from aikyl of 1 -10 carbon atoms, alkenyl of 2-10 carbon atoms, a!kynyl of 2.-10 carbon, atoms, cycloalkyl of 3-8 carbon atoms, aryl, heteroaryl, or heterocyclyl, all of which are optionally substituted with 1 , 2, or 3 substituents selected from halo, oxo, aikyl, cycloalkyl, heterocyclyl, aryl, aryloxy, ⁇ NO?, R 6 , -CfO)R 6 , -OC(0)-R*, -OC(Q 0-R 6 5 A (0 ⁇ --N(R 6 i(R ).
  • aikyl, cycloalkyl, heterocyclyl, phenyl, and phsnoxy are optionally substituted by 1 , 2, or 3 substituents selected .from aikyl, cycloalkyl alkoxy, hydroxyl, and halo; wherein R° and R " are independently selected from the group consisting of hydrogen, O-Cis alkyl, cycloalkyl, heterocyelyl, aryi, and heteroar l, all of which are optionally substituted with 1-3 substituents selected from halo, alkyl, mono- or diaikylamino, alkyl or aiy! or heteroaryl amide, -CN, lower alkoxy, -CF 3 , aryl, and heteroaryl; or
  • R ' is hydrogen, halo, cyano, alkoxy, or alkyl optionally substituted by halo; * is a ryl, heteroaryl, or heterocyelyl, all of which are optionally substituted with one or more substituents selected from alkyl. of 1-6 carbon atoms, alkoxy of 1 -6 carbon atoms, cycloalkyl of 3-8 carbon atoms, cycloalkylalkyi, aryl, aryl alkyl, heteroaryl, .
  • heteroarylalkyl heteroeyciyl, he erocyclylalkyl, halo, oxo, - N0 2 , haloalkyl, haloalkoxy, -CN, -O-R* -OC(0)-R (i , -OC(OK) ⁇ R -C(Q)- N(R 6 )(R 7 ), -S-R 6 , ⁇ N(R ft )(R 7 ), .
  • alkyl, alkoxy, cycloalkyl, aryi, heteroaryl, or heterocyelyl is further optionally substituted with one or more substituents selected from halo, oxo, ⁇ N ( 3 ⁇ 4, alkyl, haloalkyl, haloalkoxy, -N(R 6 )(R ?
  • heteroaryl or heterocyelyl moiety includes at least one nng nitrogen atom
  • X ! , X 2 , X 3 , X ⁇ X 5 , X 6 , X 7 , and X s are independently C(R 4 ) or N in which each R * is independently hydrogen, hydroxyl, halo, alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, or cycloalkyl of 3-8 carbon atoms, aryl, heteroaryl, heterocyelyl, halo, -NO2, haloalkyl, haloalkoxy, -CN, -OK", -S- R ⁇ .N(R 6 XR 7 ), ⁇ ' (; ⁇ ⁇ 3 ⁇ 4 - ( !
  • X 5 and X" or X" and X' are joined to provide optionally substituted fused aryl or optionally substituted fused heteroaryi; and with the proviso thai at least one of ", X ' ⁇ and * is C(l 4 ⁇ ; at least two of X ' ⁇ X°, X', and X 3 ⁇ 4 are is C(R*); and at least one of X * ' X ⁇ X 4 , X ' ⁇ X a , X", and X h is ; or a pharmaceutically acceptable salt or hydrate thereof.
  • An embodiment within each of the methods herein in which a compound of Formula .1 is used comprises use of a compound of Formula h as described above, or a pharmaceutically acceptable salt or hydrate thereof wherein R " is selected from the group of:
  • R 1 ' is selected from hydrogen, alkyl of 1-6 carton atoms, or cycloalkyi of 3-8 carbon atoms, wherein alkyl and cycloalky] are optionally substituted by hydroxy! or halo;
  • R : " is selected from hydrogen., alkyl of 1 -6 carbon atoms, or cycloalkyi of 3-8 carbon atoms, -S(-0)-R 6 or , --S( :: >) R 6 s wherein the alkyl and cycloalkyi are optionally substituted by bydroxyl or halo.
  • Another embodiment comprises use in the methods herein of a compound of Formula ⁇ , as described above, or a pharmaceutically acceptable salt or hydrate thereof in which.
  • ⁇ ', X 2 , and X 5 are all N, and X ⁇ X! X 6 , X ⁇ and X* are C(R 4 ).
  • This embodiment includes compounds in which R ! is optionally substituted alkyl of from I to 6 carbon atoms, optionally substituted cycloalkyi 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 bydroxyl, halo, or cycloalkyi of from 3 to 8 carbon atoms.
  • another embodiment includes compounds in which R J is optionally substituted ary , optionally substituted heteroaryl, or optionally substituted heterocyclyl, wherein the heteroaryl or heterocyclyl moieties contain, k 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, cycloalky i of from 3 to 8 carbon atom s, halo, cyano, or - ⁇ . ⁇ in which alklyl and cycloalkyi are optionally substituted by hydroxy! or halo.
  • a preferred group of R* moieties includes those non-limiting examples described above.
  • [00122 j] Another embodiment includes use in the methods herein of a compound of Formula ⁇ in which X 1 and X 5 are . and X% ⁇ X 4 , X 5 , X 6 , X 7 , and X s are C(R4).
  • T his group includes compounds in which R ' is optionally substituted alkyl of from 1 to 6 carbon atoms, optionally substituted cycloalky! .of from 3 to 8 carbon atoms, or optionally substituted heterocyclyl, particularly where the optional substituents are 1, 2, or 3 substituents chosen from hydroxy i, halo, or cycloalkyi of from 3 to 8 carbon atoms.
  • a subgroup includes compounds in which R ' ' is optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocyclyl, wherein the heteroaryl or heterocyclyl moieties contain 1 , 2, or 3 ring nitrogen atoms, and the aryl heteroaryl, . and heterocyelyi moieties contain I, 2, or 3 ring nitrogen atoms, and.
  • the aryi heteroaryl, and heterocydyl moieties are optionally substituted by alkyl of from 1 to 6 carbon atoms, cycloalkyi of from 3 to 8 carbon atoms, halo, cyano, or -OR in which alkyl and cycloalkyi are optionally substituted by hydroxy! or halo.
  • X ! and X 2 are N and ⁇ X 4 , X 5 , X 6 , X 7 , and X 8 are C(R4).
  • This group includes compounds in which R1 is optionally substituted alkyl of from 1 to 6 carbon atoms, optionally substituted cycloalkyi of from 3 to 8 carbo atoms, or optionally substituted heterocydyl, particularly where the optional substituents arc 1 , 2, or 3 substimenisehosen from hydroxyi, halo, or cycloalkyi.
  • a subgroup includes: compounds in which 3 is optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocydyl, wherein the heteroaryl or heterocydyl moieties contain 1 , 2, or 3 ring nitrogen atoms, arid the aryl, heteroaryl. and heterocyelyi moieties are optionally substituted by alkyl of from 1 to 6 carbon atoms, cycloalkyi of from 3 to 8 carbon atoms, halo, eyano, or -OR 11 , in which the alkyl and cycloalkyi are optionally substituted by hydroxyi or halo.
  • Another embodiment includes use in the methods herein of a compound of Formula I in which X ! is C(R ),
  • This group includes compounds in which R 1 is optionally substituted alkyl of from 1 to 6 carbon atoms, optionally substituted cycloalkyi of from 3 to 8 carbon atoms, or optionally substituted heterocydyl, particularly where the optional substituents are chosen from hydroxyi halo, or cycloalkyi of .from 3 to 8 carbon atoms.
  • a -subgroup includes compounds in which R' is optionally substituted heteroaryl or optionally substituted -heterocydyl, wherein the heteroaryl or heterocydyl moieties contain 1, 2, or 3 ring nitrogen atoms, and the aryl, heteroaryl, and heterocydyl moieties are optionally substituted by alkyl of from 1 to 6 carbon atoms, cycloalkyi of from 3 to 8 carbon atoms, halo, cyano, or -OR", in which, the alkyl and cycloalkyi groups are optionally substituted by hydroxyi or halo,
  • the ASKI inhibiting compounds for use in the methods herein include, but are not limited to, those compounds named below, which may be prepared by the methods described in U.S. Patent Nos, 8,552,1 6 arid 8,742,126, which are incorporated herein by reference:
  • N 3 (4 ⁇ yclopropyl-4H ,2 i 4 riazol -> )phenyl) - ⁇ 4-i2,2,2-irifluoro-l- hydroxyei hy I)- 1 H » imidazo j - 1 - yl jpicoiinam ide;
  • She ASKi inhibiting compound is a compound of the structure:
  • This compound may be referred to as 3-(4-cyclopropyl- i H-imidazoi- 1 -yi)-N-(6 ⁇ (4-cyclopropyl-4H- 1 ,2,4- triazoi-3-yl)pyridin-2-yl)-4-rnet ylbenzatmde or 3-(4-cyclopropy ⁇ -lH » imidazol- l-yl)- -[6-(4-tyclopropyM ⁇
  • benzamide... and has been assigned CAS Registry No. 12620 1 -67-7.
  • the compound and salts thereof including formic acid salt may be prepared by methods disclosed in US 2014/0228412 and U.S. Pat.
  • the ASKI inhibiting compound is a compound of the structure:
  • This compound may be referred to as 5-(4 yclopropyl"l H-imidazol-l-yl)-2-fluoro-N ⁇ (6-(4 » isopiOpyl- 4H ,2,4-teia2ol-3-yl ⁇ pyridin-2-yl)-4 ⁇ methyibeiizamide or 5 ⁇ (4-cyelopropyl-l H- imidazol-l -yl)-2 luoro-4-methyl-N-[6-[4-(l -rnethyletJhyiHH-.l ,2,4-triazoi-3-ylj- 2-pyiidinyl]-benzamide, and has been assigned CAS Registry No. 1448428-04-3.
  • No. 1448428-05-4) may be prepared by methods disclosed in US 2014/0228412 and U.S. Pat Mo. 9,067,933,
  • the terms 'Inhibitor' " , "inhibiting compound”, and the like refer to a compound or agent which presents a pharmaceutical activity to inhibit acti ity of certain target in a subject such as human,
  • ASKl inhibitor ''AS l inhibiting compound
  • ASK i inhibitor of ASK i
  • Compound C2 or a pharmaceutically acceptable salt thereof is used in combination with Compound Al, or a pharmaceutically acceptable salt or hydrate thereof
  • a compound of Formula t, or a pharmaceutically acceptable salt thereof * is used in combination with Compound Al, or a pharmaceutically acceptable -salt or hydrate thereof.
  • the ASKl inhibiting compound is 4-[4
  • the BET or BRD (bromotloroain-containiiig protein) inhibitor is an inhibitor of bromodomain ⁇ contamin3 ⁇ 4 protein 4 (BRIM).
  • the modulator of a hroraodomain-containing protein is a compound of Formula i l l ):
  • R ! " and R Ul are each independently C ⁇ . alkyl optionally substituted with from 1 to 5 R ⁇ ' groups;
  • R '1:' and R ':ft are each independently H or halo
  • CMO alkyl selected from the group consisting of CMO alkyl, CMO alkoxy, amino, C O aryl, C ⁇ o aiylalkyl, CMO heteroalkyl CMO heteroaryl, and C 6 . 2 o heteroarylalkyl, each of which is optionally substituted with from 1 to 5 R '3 ⁇ 4 ' groups;
  • R “ and R 1" is selected from the group consisting of H and alkyl optionally substituted with from 1 to 5 R AI groups, and the other is absent;
  • R 5 is ⁇ C(O)GR & , ⁇ NHC(0)OR ⁇ -NHS(0) 2 R 8 , or -S(G) 2 NR*R B ; or
  • R 3 ⁇ 4 is selected from the group consisting of H, C O alkyl, CMO haioalkyl.
  • each R A and R B is independently selected from the group consisting of 1R CMO al l O aryl, C ⁇ MO arylalkyl CMO heteroalkyl, (3 ⁇ 4.,io heteroaryl, and heteroarylalkyl, each of which is optionally substituted with from 1 to 5 R ''' ° groups; and
  • each E > is independently selected from the group consisting of acyi, CMO alkyl, CMO alkoxy, amino, amido, amidmo, C$.i ⁇ > aryl, C a* arylalkyl, azido, carbamoyl, carboxyl, carboxyl ester, cyarto, guariidmo, halo, Q.-. haioalkyl, i-.- heteroalkyl, Cue lietero-aryl, s-2 heteroaryklkyl, hydroxy, hydrazine imino, oxo, nitro, sulfmyl. sulfonic acid, sulfonyi, thioeyanate, thiol, and thione;
  • Cj.io alkyl, Cj-jo aryl., i arylalkyl, CHO heteroalkyl, C a heteroaryi, and C ( ;.?o heteroaiylaikyl groups are optionally substi luted with from 1 to 3 substituents independently selected from CM alkyl, C$. aryl, halo, Ct. ⁇ , haloalkyl, cyano, hydroxy, and Ci.g alkoxy;
  • Compounds of Formula (II) (which include compounds of any of Formulae ilia), (lib), (He), (lid) and (fie), described below) can include, independently, one or more of the following features. It will be recognized that features specified in each embodiment may be combined with other specified features to provide further embodiments,
  • R' 3 and R ;b are each independently a k l which, aa defined herein, includes alkeny!, alky yl and cycloalkyl. in some compounds, R la and R ) 0 ate different, and in other compounds R 1 : andR' b are the same.
  • R iK and R lb are each independently a alkyl optionally substituted with 1-5 II ' groups.
  • R f a and R h1 are both methyl.
  • one of R' A or R L " is a methyl and the other is a methyl substituted with a hydroxy.
  • R and R 10 are both methyl substituted with a hydroxy.
  • one ofR ia or !b is a niethyi and the other is a methyl substituted with an amine.
  • I 1 " and R lh are both methyl substituted with an amine,
  • R *' and " 'b are both halo.
  • one of R 2A and R “b is H and the other is halo.
  • the halo is -F or -CI ,
  • R ' is boronic acid, a boronic acid ester, or halo.
  • R 3 is -C(0)OR a , -NHCiOjOR 8 , - IS(0) 2 R a , or -S(0)2.
  • NR A R FC wherein R a and R >! are described above.
  • R J is -C(O R*, - NHC(0)OR 8 , ⁇ HS(0) 2 R a , or -S(0) ;; NR a R ⁇ wherein each R a and R is independently CJ-JO alkyl, C$.
  • R 3 is -C(0)OR a , -NHC(0)OR a , ⁇ NHS(0) 2 R 8 , or ⁇ S(0) 2 NR a R b , wherein each R a and R " is independently C5.10 aryl or heteroaryl.
  • R:' is selected from the group consisting of CMO alkyl, C O aikoxy, amino, C.s.10 aryl, C$.20 arylalkyl C O heteroalkyl, C io heteroaryl, and CV20 heteroarylalkyl, each of which is optionally substituted with from 1 to 5 R" 1 groups, wherein R '0 is described above, i some compounds, R '5 is CM alkyl, j .io aikoxy, or CM O heteroalkyl, each of which may be optionally substituted as described above.
  • the heteroalkyl is a heterocyeloa!kyl. In other compounds, R !
  • R 3 is C to aryl, C3 ⁇ 4.?o arylalkyl, C io heteroaryl, or C 6 . 20 heteroarylalkyl. each of which may be optionally substituted as described above.
  • R "1 is amino optionally substituted as described above.
  • R' is -N3 ⁇ 4, and in other compounds R :' ' is - J, R' ' . wherein W and R' together with the nitrogen to which the are bonded form a CMS heteroalkyl or CMO heteroaryl, each of which may be optionally substituted as described above, [00134]
  • R J include the following:
  • one of ' R '*: or R '4b is ii and the other is absent, that is, in some compounds R" J is H and R"° is absent, and in other compounds R TM is absent and R* is H.
  • one of R 3 ⁇ 4 and R 4b is alkyl and the other is absent, that is, in some compounds R. a is alkyl and R " is absent, and in other compounds R 4 * is absent and R 4 is alkyl.
  • the alkyl is methyl ,
  • R 5 is -C(G)GR a , -NHC(0)OR ⁇ -NHS(0) 2 R a , or - S(0) ⁇ NR a R n , wherein R a and R 8 are described above.
  • R ' is •-CiO)OR ' ⁇ -NHC(0)OR ; ⁇ - 1S(0) 2 R ⁇ or ⁇ S(0) .? NR s R , wherein each R 8 and R b is independently Cwo alkyl or C5.10 aryl, each of which may be optionally substituted as described above.
  • R:' is ⁇ NHC(0)O ⁇ !
  • R a is methyl
  • R ⁇ ' is -NHSiOj ⁇ " , wherein R a is C$.10 alkyl or C ⁇ m aryl, each of which may be optionally substituted as described above.
  • R " is - NHS(0) 2 R a
  • R" is eyelopropyl.
  • R 5 is selected from the group consisting of H, Ci.;o alkyl, Q.fo haloalkyk Ct-io alkoxy, amino, C ⁇ o aryl, CV20 aryialkyl, CMO heteroaikyl.
  • Cs_io heteroaryl, and heteroaryJalkyl each of which is optionally substituted with from i to 5 ⁇ w groups, wherein R 2,i is described above.
  • R 2,i is described above.
  • the Cj.jo alkyl is a Vio cycloalkyl, e.g. eyelopropyl.
  • R' is amino optionally substituted as described above.
  • R 5 is ⁇ ?
  • R .in other compounds R " is -NR y R ⁇ wherein R y is H and R '*: h alkyl, e.g. cyclopropyl
  • R " is -NR y R ⁇ wherein R y is H and R '*: h alkyl, e.g. cyclopropyl
  • R 5 is alkoxy, e.g. methoxy.
  • R ,a , R ! ⁇ ; ⁇ R* R 4b and R 5 are optionally substituted with from 1 to 5 (i.e. 1. 2, , 4 or 5 ⁇ R " ° groups as described above.
  • R ! ⁇ ⁇ R R ' , R 4s , R 40 and R 5 are optionally substituted with 1, 2, or 3 R '3 ⁇ 4> groups.
  • each R "'J is independently selected from the group consisting of alkyl, alkoxy, amino, cyano, halo, haloalkyl, heteroalkyl, hydroxy, and sulfonyl.
  • each is independently selected from the group consisting of aryl, alkylaryl, heteroaryl, and heteroalkylaryl.
  • R ia , tb , R i ( R 4 ° and are not. substituted.
  • R m is not substituted.
  • R and R' b are each independently CM alkyl optionally substituted with from 1 to 5 R 2 ' " ' groups;
  • Cj.jo alkyl selected from the group consisting of Cj.jo alkyl, Cj.ie alkoxy, amino, C5.10 aryl. arylalkyi, C .. ⁇ n heteroalkyl, C5.10 heteroaryl, atid C ao heteroarylalkyl, each of which is optionally substituted with from 1 to 5 R: '" ' groups;
  • R 4 is selected from the group consisting of H and C
  • each R a and R° is independently selected from the group consisting of H, Cj.io alkyl, C5.J0 aryl, G;, 3o arylalkyl, Q.JO heteroalkyl, C5.10 heteroaryl and Cg ⁇ o heteroarylalkyl, each of which is optionally substituted with from ]. to 5 R'° groups; and
  • each R '' is independently selected from the group consisting of acyl Cu ⁇ > alky I, CI.JO alkoxy, amino, amido, amidino, (3 ⁇ 4.] ⁇ aryl, 20 arylalkyl, azido, carbamoyl, carhoxyl carboxyl ester, cyano, guanidmo, halo, Cj.io haloalkyi, Cj.i heteroalkyl, C JO heteroaryl C ⁇ n heteroarylalkyl, hydroxy, hydrazine, homo, oxo, nitro, sulfuvyl, sulfonic acid, sulfbnyi, ihiocyanaie, thiol and thione;
  • CHO alkyl, Cs-ie aryl, C ⁇ o ar lalk l heteroalkyl, CMO heteroaryl, and C 20 heteroarylalkyl groups are optionally substituted with from 1 to 3 substituents independently selected from C alkyl, .10 aryl halo, C] .
  • R' 4 and R ! are each independently alkyl optionally substituted with from 1 to 5 R' ' groups;
  • R 2& and R " are each independently H or halo; boronic acid or halo; or
  • C(0)OR s , -NHC(0)OR 8 , -NHS(0) 2 R a , or ⁇ • S(0) 2 NR3 ⁇ 4 h ; or selected from the group consisting of C O alky], CJ .JO alkoxy, amino, C 5 .(o aryl, C 20 arylalkyl, CMO heteroaikyl. a heieroaryl, and 20 heteroarylalkyl, each of which is optionally substituted with from I to 5 R " ° groups;
  • each R* and R° is independently selected from the group consisting of H, C : .i aikyl, C$. ⁇ ⁇ , aryl, ( .2 arylalkyl CMO heteroaikyl, l. if. heteroary), and Q favor 2 o heieroaryl a Iky I each of which is optionally substituted with from 1 to 5 k ' ! " ' groups; and
  • each R ITJ is independently selected from the group consisting of airyl, e aikyl, CJ.JO alkoxy, amino, amido, amidino, C .10 aryl 20 arylalkyl, azido, carbamoyl earboxyl caxboxyl ester, cyano, goanidu o, halo, C[. ⁇ ⁇ , haloalkyl C;.
  • Cuo aikyl C e aryl, C f) .3 ⁇ 4 arylalkyl, C;.; heteroaikyl C5.10 heieroaryl, and C 2 0 heteroarylalkyl groups are ' optionally substituted with from 1 to 3 substituents independentl selected from CM aikyl, Cuo aryl, halo, C).c haloalkyl cyano, hydroxy, and . alkoxy;
  • R " are each independently Ci ⁇ aikyl optionally substituted with from 1 to 5 R" :,) groups;
  • heteroarylalkyl each of which is optionally substituted with fxor 1 to 5 R 2 ⁇ i groups;
  • each R* and R° is independently selected from the group consisting of H, Ci.j aikyl, ( ⁇ , aryl, (3 ⁇ 4. 2 ⁇ aryiaikyl, Ci-io heteroalkyl, C io heteroaryl, and Q.3 ⁇ 4j heteroarylalkyl, each of which is optional ly substituted with front 1 to 5 R 30 groups; and
  • each R M is independently selected from the group consisting ofacyl, Cwo aikyl Cf.io alkoxy, amino, amido, amidmo, Cs o aryl, C ⁇ >O aryiaikyl, azido, carbamoyl, carboxvl carboxyl ester, cyano, guanidino, halo, Cj.39 haloaikyl, Cj .; heteroalkyl, CYio heteroaryl, Q,.
  • Ct-jo alkyi, Cs.jo .aryl, Q. 2 o aryiaikyl, C ⁇ heteroalkyl, C5.18 heteroaryl, and C ⁇ o heteroaryiaikyi groups are opiionally substituted with from 1 to 3 substituents independentl selected from C1 aikyl, €5.10 aryl, halo, C ⁇ .(, haloaikyl, cyano, hydroxy, and Cj. f j alkoxy;
  • each R" and R: 1' is independently selected from the group consisting of H, Cj .j alkyl, C $ .50 aryl, Q.JO arylalkyl, 40 heteroalkyl C5.J0 heieroaryl, and C5.2 heteroaryialkyl, each of which is optionally substituted with from 1 to 5 R A ' groups; and
  • each R M is independently selected from the group consisting ofacyl, Cj.jo alkyl CM 0 aikoxy, .amino, amido, amidino, C3 ⁇ 4..,0 aryl, arylalkyl, nzk , carbamoyl, carboxyl, earhoxyl ester, eyano, guanidino, halo, C1..10 haloalkyl, Cj.to heteroalkyl, C5.J0 heteroaryl heteroaryialkyl hydroxy, hydrazino, imko, xo, nitro. sulfinyl, sulfonic acid, sulfanyl, thiocyanate, thiol, and thione;
  • heteroaryialkyl groups are optionally substituted with from 1 to 3 substituents independently selected from .4 alkyl, C5.J0 aryl, halo, C
  • each R a and R is independently selected from the group consisting of FL Cj .io alkyl, ⁇ -io aryl Q-so aryialkyl, C ⁇ o heteroalkyl, C .JO heteroaryl, and heteroarylalkyl each of which is optionally substituted with from 1 to 5 R 2 groups; and
  • each R"' 1 is independently selected from the group consisting of cyl, Cwo alkyl, Ch.io aikoxy. amino, amido, amidino, C5.10 aryl, C'MO aryialkyl, azido, carbamoyl carboxy caxboxyl ester, cyano, gnanidino, halo, C ⁇ .ta haloaikyl Cj.ig heteroalkyl, C5.1 heteroaryl, Q-y, heteroarylalkyl, hydroxy, hydrazine, imino, oxo, niiro, sulfinyl, sulfonic acid, sulfonyl, miocyanate, thiol and thione;
  • CMO alkyl C 5 ..i 0 aryl ( 3 ⁇ 4» aryialkyl C o heteroalkyl Cy ⁇ e heteroaryl, andC ⁇ o heteroarylalkyl groups are optionally substituted with from 1 to 3 substituents independently selected from C alkyl, ary halo, Cj. $ haloaikyl cyano, hydroxy, and C-i-g aikoxy;
  • a separate embodiment comprises a mi pound of Formula ⁇ I.e., as defined above, wherein R * IS CM aikyl, CM alkoxy, or C O heteroalkyl, each of which may be optionally substituted with from 1 to 5 R' x: 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 ' ' is C 5 . ;O aryl, Q..20 aryialkyl, CJ.JO heteroaryl, or C0..20 heteroarylalkyl, each of which may be optionally substituted with from 1 to 5 "1'1 groups, or a pharmaceutically acceptable salt thereof,
  • the modulator of a. bromodomain-containing protein is a compound selected from the group below, or a pharmaceutically acce table salt or hydrate thereof:
  • the modulator of a bromodomain-containing protein is (2 yclopropy ⁇ -6 » (3,5-a3 ⁇ 4meihy1isoxa2o ⁇ -y1)-dK"ben2o[d)imidazob4- yl)diipyi-azin ⁇ 2"-yl)methanol, or a pharmaceutically acceptable hydrate thereof.
  • the modulator of a broraodomain- containing protein is (2 ⁇ cyelopropyl ⁇ 6-(3,.5- ⁇
  • modulator of a bromodomain- containing protein is (2 ⁇ cyelQpropyl-6-(3,5-dimethyIisoxa
  • the modulator of a bromodomain-containing protein is (2-cyc!opropyl-6- (3 ,5-dimethyli soxazol-4-yl)- 1 H-ber «o[d]imia3 ⁇ 4zol"4-yi)di ⁇ yridin-3 -yl)methanol, or a pharmaceutically acceptable hydrate thereof.
  • the modulator of a bromodomain-containing protein is (2 ⁇ cyclopropyl ⁇ 6 ⁇ (3,5"dimeraylisoxa3 ⁇ 4ol ⁇ 4-y1)-lH ⁇
  • the modulator of a bromodomain-containing protein is (2- cyelopropyl-6-(3,5Klimethyiisoxazol-4-yl)-l H ⁇ benzo[d]imidazol-4- yl)( ' phenyjXpyridin » 3 » yl)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 2014-03361 0. MP9 Inhibiting Agents
  • Useful MMP9 inhibiting agents include comprises binding proteins, e.g., antibodies and antigen-binding fragments thereof, that bind to the matrix metalloproteinase-9 (MMP9) protein (M. P9 is also known as gelatinase-B), wherein the binding proteins comprise an immunoglobulin (ig) heavy chain (or functional fragment thereof) and an Ig light chain (or functional fragment thereof) disclosed in U.S. 20.15-0140580 (Smith et al.) and U.S. Patent Nos.
  • MMP9 matrix metalloproteinase-9
  • the present combinations provide binding proteins, e.g., antibodies and antigen-binding fragments thereof, that bind to the matrix metaUoproteinase-9 (MMP9) protein (MMP9 is also known as gelatinase-B).
  • the binding proteins of the present disclosure generally comprise an immunoglobulin (Ig) heavy chain (or functional fragment thereof) and an Ig light, chain (or functional fragment thereof) to be used in the methods, regimens, kits, and articles of manufacture herein, with a pharmaceutically effective amount, or with individual dose units containing a pharmaceutically effective amount, of Compound A 1.
  • MMP9 binding proteins thai bind specifically to MMP9 and not to other matrix metalioproteinases such as MMPL MMP2, MMP3, MMP7, MMP9, MMPK), MMP12, MMPJ.3.
  • matrix metalioproteinases such as MMPL MMP2, MMP3, MMP7, MMP9, MMPK), MMP12, MMPJ.3.
  • MMP9 binding proteins that specifically bind M P9 find use in applications in. which it is necessary or desirable to obtain specific modulation (e.g.. inhibition) ofMMF9. e.g., without directly affecting the activity of other matrix metalioproteinases.
  • an anti-MMP9 antibody is an inhibitor of the activity of MMP9, and can be a specific inhibitor of M P9.
  • the MMP9 binding proteins disclosed herein will be useful for inhibition of MP9 while allowing norma ⁇ function of other, related matrix metalioproteinases, "An inhibitor of MMP” or “inhibitor of MMP9 activity” can be an antibody or an antigen binding fragment thereof thai 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.
  • the present combinations also comprise MMP9 binding proteins that specifically bind to non-mouse MMP9, such as human M P9, Cyrtomolgus monkey MMP9, and rat M P9.
  • the combinations also comprise MM.P9 binding proteins (e.g., anti-MMP9 antibodies and functional fragments thereof) mat 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.
  • 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 thereof) that has at least about 80%, 85%, 0%, 95% or more ammo 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 maniactore, and kits include those that bind MM.P9, particularly human MMP9, and having a light polypeptide (or functional fragment thereof) that has ai least about 80%, 85%, 90%, 95% or more amino acid sequence identity to a heavy chain polypeptide disclosed herein.
  • MMP9 binding proteins (e.g., antibodies and functional fragments thereof) of the present disclosure include those that bind MMP9, particularly human MMP9, and have a heavy chain polypeptide (or functional fragment thereof) having the
  • CDRs complementarity determining regions
  • 10015 MMP9 binding proteins including antibodies and functional fragments thereof.
  • 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).
  • Sequence identity between two nucleic acids can also be described in terms of hybridization of two molecules to each other under stringent conditions.
  • the hybridization conditions are -selected following standard methods in the art (see, for example, Samhrook, et a-L, Molecular Cloning: A Labora tory Manual, Second Edition, (1989) Cold Spring Rarhor, ' N.Y .).
  • An example of stringent hybridization conditions is hybridization at 50°C or higher and 0.1 ⁇ SSC (15 mM sodium chloride/ .5 mM sodium citrate).
  • Another example of stringent hybridization, conditions is overnight incubation at 42 X.
  • Stringent hybridization conditions are hybridization conditions thai are at least as stringent as the above representative conditions, where conditions axe considered to be at least as stringent if ihey 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.
  • an antibody is a humanized antibody or a human antibody.
  • Humanized antibodies include human immununoglobulins (recipient antibody) in which residues from a
  • CD complementary-determinkg region
  • die 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.
  • donor antibody e.g., mouse, rat or rabbit having the: desired specificity, affinity and capacity.
  • humanized forms of non-human (e.g.,, murine) antibodies are chimeric immunoglobulins which contain minimal sequence derived from non-human immunoglobulin.
  • the non -human sequences are iocated primarily in the variable regions, particularly in the complemeniarity-determining regions (CDRs).
  • Fv framework residues of the human immunoglobulin are replaced by corresponding non-human residues.
  • Humanized antibodies can also comprise residues that are found neither in the recipient antibody nor in the imported CDR or framework sequences,
  • a humanized antibody comprises substantially ail of at least one, and typically two, variable domains, in which all or substantially all of the CDRs correspond to those of a non-huraan
  • immunogiobufin and all or substantially all of the framework regions are those of a human immunoglobulin consensus sequence.
  • humanized antibodies can also include immunoglobulin fragments, such as Fv, Fab, Fab', F(ab')2 or other antigen-binding subsequences of antibodies.
  • the humanized antibody can also comprise at least a portion of an immunoglobulin constant region (Fc), typically (hat of a human immunoglobulin. See, for example, Jones et al. (1986) Nature 321 :522--525; Rie iraa n et al. (1988) Nature 332:323-329; and Presta (1992) C rr. Op. Struct. Biol. 2:593-596.
  • Fc immunoglobulin constant region
  • a humanized antibody has one or more amino acid residues introduced into it from a source that is non-human. These non-huraan amino acid residues are- often referred to as "import” or “donor” residues, which are typically obtained from an "import” or “donor” variable domain.
  • import or "donor” residues
  • hum an mation can he 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; iechmann 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.
  • 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),
  • Human antibodies can also be produced, for example, by using phage display libraries. Hoogenboom et al. ( 1 91) J. Mol. Biol, 227:381 ; Marks et al (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. ( 1 1) J. Immunol. 147:86-95.
  • 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;
  • Antibodies can be affinity matured using known selection and/or mutagenesis methods as described above.
  • affinity matured antibodies have an affinity which is live times or more, ten times or more, twenty times or more, or thirty times or more than that of the starting antibody ⁇ generally murine, rabbit, chicken, humanized or human) from which the matured antibody is prepared,
  • An antibody can also be a bispecifie antibody, Bispecilk antibodies are monoclonal, and may be human or humanized antibodies that have binding specificities for at least two different antigens.
  • the two different binding specificities can be directed to two different MPs, or to two different epitopes on a single MM? (e.g. , MMP9).
  • An antibody as disclosed herein can also be an inmiunoconjugale.
  • Such immunoconjugates comprise an antibody (e.g., to M.MF9) conjugated to a second molecule, such as a reporter.
  • An imniurtoconjugate can also comprise an antibody conjugated to a cytotoxic agent such as a chemotherapeuric agent, a toxin (e.g.. an enxymaiieaily active toxin, of bacterial fungal, plant, or animal origin, or fragments thereof), or a radioactive isotope (i.e., a radioconjugatc).
  • 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 or polypeptide epitope.
  • an antibody of the present disclosure specifically binds to human MMP9 with a dissociation constant (K ⁇ s) equal to or lower than 100 nM, optionally lower than 10 nM, optionally lower than 1 nM, optionally lower than 0.5 nM, optionally lower than 0.1 nM, optionally lower than 0.01 nM, or optionally lower than 0.005 nM; in the form of monoclonal antibody, scFv, Fab, or other form of antibod measured at a temperature of about 4°C 25 C C, 3TC or 42°C.
  • K ⁇ s dissociation constant
  • use of an antibody of the present disclosure binds to on or more processing sites (e.g., sites of proteolytic cleavage) in. MMP9. thereby effecti vely blocking processing of the proenzyme or preproenzyrae 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 MM P. 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 ⁇ 3 ⁇ 4). equilibrium constant (K SK ) or any term in the art.
  • K SK equilibrium constant
  • 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. 100167] 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.
  • the present disclosure contemplates use of anti-MMP9 antibodies, and .functional fragments thereof, that compete for binding with, for example, an antibody having a heavy chain polypeptide of any of SEQ ID NOS: 1 or 5-8, a light chain polypeptide of SEQ ID OS:2 or 942, or combinations thereof.
  • the anti- MMP9 antibody, for functional fragment thereof competes for binding to human MMP9 with the antibody described herein as AB004I .
  • amino acid sequence of human M.MP9 protein is as follows:
  • Protein domains are shown schematically in Figure 3 and are indicated below:
  • the amino acid sequence of mature full-length human MMP9 (which is the atrii.no acid sequence of the propolypepiide of SEQ ID NO:27 withou t the signal peptide) is: PRQRQSTLVL FPGDLRT LT DRQLAEEYLY RY(5YTRVAEM RGESKSLGPA LLLLQKQLSl PBTGELD ' SAT L AMRTPRCG VPDLGRFQ P EGDLKWHHHN !TYWIQNYSE LPRAV DA FA.RAFALWSA VTPLTFrRVY SRDADiVlQF GVAEHGDGYP FDG DGLLAH AFPPGPG1QG DAHFDDDBLW SLG GVVVPT RFG ADGAAC HFPPIFEGRS YSACTTDGRS DGLPWCSTTA NYDTDDRFGF CPSERLYTRD GNADGKPCQF PFIFQGQSYS ACTTDGRSDG YRWCATTANY DRD LFGF
  • amino acid sequence of the signal peptide is MSLWQPLVLV
  • MMP9 binding proteins that, bind any portion of MM.P9, e.g., human MMP9, with MMP9 binding proteins that preferentially bind MMV9 relative to other M ' MPs being of particular interest, Ant MMP9 antibodies, and functional fragments thereof, can be generated accordingly to methods well known in the- art.
  • Examples of anti - MMP9 anti odies are provided below,
  • a mouse monoclonal antibody to human MMP9 was obtained as described in Example 2. This antibody contains a mouse- JgG2b heavy chain and a mouse kappa light, chain, and is denoted AB0041.
  • amino acid sequence of the.AB0041 Sight chain is as follows:
  • 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):
  • the following amino acid sequence comprises the framework regions and compiemenhirity-detenninmg regions (CDRs) of the variable region of the kappa light chain of ABG041 (with CDRs underlined):
  • TLVTVSS (SEQ ID NO:6)
  • Additional heavy chain variable region amino acid sequences having 75% or more, 80% or more, 90% or more, 95% or more, or 99% or more homology io the heavy chain variable region sequences disclosed herein are also provided.
  • additional light chain variable region amino acid sequences having 75% or more, 80% or more, 90% or more, 95% or more, or 99% or more homology to the light chain variable region sequences disclosed herein are also provided.
  • CDRs CompleTnentarity-determking regions
  • the CDRs of the heavy chain of an anti ⁇ MMP9 antibody as disclosed herein have the following amino acid sequences:
  • the CDRs of the light chain of an anti-MMP9 antibody as disclosed herein have the following amino acid sequences:
  • CDR 1 ASQDVRNTVA (SEQ ID NO: 16)
  • CDR2 SSSYRNT (SEQ ID NO: 17)
  • present disclosure provides use in the methods, regimens, kits, and articles of manufacture herein of nucleic acids encoding antidvfMP9 antibodies and functional fragments thereof. Accordingly, the present disclosure provides an isolated polynucleotide (nucieic acid) encoding an antibody or antigen- binding fragment as described herein, vectors containing such polynucleotides, and host cells and expression systems for transcribing and translating such polynucleotides into 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,
  • the present disclosure also provides the use of a recombinant host ceil 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 nucieic acid encoding a heavy chain polypeptide and a light chain polypeptide (in the same or different host cells, and from ike 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. 100190, Systems for cloning and expression of a polypeptide in a.
  • Suitable host cells include bacteria, mammalian cells, yeast, and baculo virus systems, Mammalian ceil lines available in the art for expression of a heterologous polypeptide include Ch inese hamster ovary cells, HeLa cells, baby hamster kidney cells. NSC) mouse melanoma cells and many others.
  • a common bacterial host is E. coli.
  • Suitable vectors can be chosen or constructed, containing appropriate regulatory sequences, including operably linked promoter sequences, terminator sequences, polyadersylation sequences, enhancer sequences, marker genes and/or other sequences as appropriate.
  • Vectors can be plasmids, viral e.g. 'phage, oi phagemid, . as appropriate.
  • Molecular Cloning a Laboratory Manual.: 2nd edition, Sambrook et al., 1989, Cold Spring Harbor Laboratory Press. Many known techniques and protocols for
  • nucleic acid for example rn preparation of nucleic acid constructs, mutagenesis, sequencing, introduction of D A into cells and gene expression, and analysis of proteins, are described in detail in Short Protocols in Molecular Biology, Second Edition, Ausubei el al. eds., John Wiiey & Sons, 1992. The disclosures of Sambrook et al. and Ausubei et al. are incorporated herein by reference in their entirety.
  • 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 episomai 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.
  • nucleic acid encoding a polypeptide of interest can e operabiy linked to a promoter, and provided in an expression construct far use in methods of prod uction of recombinant MMP9 proteins or portions ihereof.
  • nucleic acids encoding the antibody chains disclosed herein can be synthesized using standard knowledge and procedures in molecular biology.
  • nucleotide sequences encoding the heavy and light chain amino acid sequences disclosed herein are as follows: ⁇ ⁇ 1 0 ⁇
  • VH1 CAGGTGCAGC TGCAGGAATG CGGCCCTi SC
  • VH2 CAGGTGCAGC TGCAGGAATG CGGCCCTGGC
  • VH4 CAGGTGCAGC TGCAGGAATG CGGCCCTGGC
  • Vk2 GACATCGTGA TGACCCAGTC CCCCTCCAGC
  • Vk4 GACATCCAGA TGACCCAGTC CCCCTCCA.
  • nucleic acid sequences having at least. 75%, at least 80%, ai 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.
  • nucleic acid sequences having at least 75%, at least 80%, at least 85%, at least 90%, at. least 95%, at least 98% and at least 99% identity to any of the nucleotide sequences disclosed herein are also provided.
  • MMP9 binding proteins as well as nucleic acid (e.g., DNA or RNA) encoding MMP9 binding proteins, can be pro vided as a pharmaceutical composition, e.g., combined with a pharmaceutically acceptable earner or exeipieni.
  • 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.
  • Pharmaceutically acceptable carriers are physiologically acceptable to the administered patient and retain the therapeutic properties of the antibodies or peptides with which it is administered, Pha aceuiscaliy-aoceptabie carriers and their formulations are and generally described in, for example. Remington' pharmaceutical Sciences (18th Edition, ed. A. Gennaro, Mack Publishing Co., Easton, PA 1 90), One exemplary pharmaceutical earner 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 ihe patient,
  • compositions can be formulated to be compatible with a particular route of administration, systemic or local,
  • pharmaceutical compositions include carriers, diluents, or excipi nts suitable for administration by various routes.
  • compositions can include pharmaceutically acceptable additives,.
  • additives include, but are not limited to. a sugar such as marmiiol, 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.
  • 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, infra-arterial, intramuscular, or subcutaneous administration.
  • compositions for parenteral delivery include, for example, water, saline, phosphate buffered saline, Hank's solution. Ringer's solution, dextrose/saline, and giuco.se solutions.
  • the fomulations can contain auxiliary substances to approximate physiological conditions, such as buffering agents, tonicity adj usting agents, wetting agents, detergents and the like.
  • Additives can also include additional active ingredients such as bactericidal agents, or stabilizers.
  • the solution can contain sodium acetate, sodium lactate, sodium chloride, potassium chloride, calcium chloride, sorbitan monolaurate or trietbanolamine oleate.
  • Additional parenteral formulations and methods axe described in Bai ( 1997) J, Neuroimraunol. 80:65 75: Warren (1997) j. Neurol. Sci. 152:31 38; and Tonegawa (1997) J, Exp, Med. 1 6:507 515.
  • the parenteral preparation can be enclosed in ampules, disposable syringes or multiple dose vials made of glass or plastic.
  • compositions for intradermal or subcutaneous administration can include a sterile diluent, such as water, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parahens; antioxidants such as ascorbic acid, glutathione or sodium bisulfite; chelating agents such as ethylenedianiinetetra acetic acid; buffers such as acetates, citrates or phosphates and agents tor the adjustment of tonicity such as sodium chloride or dextrose.
  • a sterile diluent such as water, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents
  • antibacterial agents such as benzyl alcohol or methyl parahens
  • antioxidants such as ascorbic acid, glutathione or sodium bisulfite
  • chelating agents such as ethylenedianiinete
  • compositions for injection include aqueous solutions (where water soluble.) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion.
  • suitable carriers include physiological saline, bacteriostatic water, Cremophor El-TM (BASF, Parsippany, N.J.) or phosphate buffered saline (PBS),
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyetheyiene glycol, and the like), and suitable mixtures thereof.
  • Fluidity can be maintained, for example, by Ihe 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 surfactants.
  • Antibacterial and antifungal agents include, for example, parabens,
  • ehlorobutano! phenol, ascorbic acid and thimerosal, isotonic agents, for exampie, sugars, polyalcohols such as maniiol, sorbitol, and sodium chloride ma be included in the composition.
  • the resulting solutions can be packaged for use as is, or lyophiiized; the lyophilked preparation can later be combined with a sterile solution prior to administration,
  • Pharmaceutically acceptable carriers can contain a compound thai 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 raonostearate and gelatin. Detergents can also a s - be used to stabilize or to increase or decrease the absorption of the
  • compositions including liposomal carriers.
  • the compound can be compkxed 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 (1 96) Pharm R.es. 13:1760 1764; Samanen (1996) J. Pharm. Pharmacol. 48: 119 135; and U.S. Pat. No. 5,391 ,377, describing lipid compositions for oral delivery of therapeutic agents).
  • 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.
  • 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.
  • 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).
  • compositions can be formulated based on the physical characteristics of the patient/subject needing treatment, the route of
  • Such can be packaged in a suitable pharmaceutical package with appropriate labels forme 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.
  • compositions of the present invention can be included with the pharmaceutical packages and kits described below, Methods of Use and Treatments
  • 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.
  • the one or more inhibitor may be therapeutically effective amounts of a JAK inhibitor, an ASK.1 inhibitor, a BET inhibitor and a MM.P inhibitor, as described herein.
  • the method of use or treatment described herei n may comprise Compound A 1 , or a pharmaceutically acceptable salt or hydrate thereof, in combination with one or more inhibitor and another pharmaceutical or therapeutic, agent. Sn each of the methods described herein, pharmaceutically effective amounts of each inhibitor, and each pharmaceutical agent are used.
  • 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.
  • the disease or condition is chosen from rheumatoid arthritis, osteoarthritis, atherosclerosis, psoriasis, systemic lupus erythematosus, multiple sclerosis, inflammatory bowel disease, asthma, chronic obstructive airways disease, pneumonitis, dermatitis, alopecia, nephritis, vasculitis, atherosclerosis,
  • the disease or condition is cancer, including hematological cancers, lymphoma, multiple myelomas, leukemias, a neoplasm, cancer o ' tumor (for example a solid tumor), .
  • the cancer is carcinoma, sarcoma, melanoma, lymphoma or leukemia.
  • 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.
  • the cancer is small lymphocytic lymphoma, no.o- Hodgkin's lymphoma, indolent non-Hodgkin's lymphoma (i ' NHL), refractory 1.17 - iNHL, mantle cell lymphoma, follicular lym h m , lymphopiasmaeytic lymphoma, marginal zone lymphoma, immunoblastic large cell lymphoma, lymphoblastic lymphoma, Splenic marginal zone B-cell lymphoma ( ⁇ + -/- villous lymphocytes), nodal marginal zone lymphoma (+ - monocytoid B-cell s), e lranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue type, cutaneous T-cell lymphoma, extranodal T-cell lymphoma, anapiastic large cell lymphoma, angioim unoblastic T-cell
  • T-cell acute lymphoblastic leukemia B-cell acute lymphoblastic leukemia, B-ce31 prolymphocyte c leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, juvenile
  • ⁇ myelomonoeytic leukemia minimal residual disease, hairy cell leukemia, primary myelofibrosis, secondary myelofibrosis, chronic myeloid leukemia, myelodysplastic syndrome, myeloproliferative disease, or Waldenstrom's maerogiobttlinemia.
  • the cancer is pancreatic cancer, urological cancer, bladder cancer, colorectal cancer, colon cancer, breast cancer, prostate cancer, renal cancer, hepatocellular cancer, thyroid cancer, gal! 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, C S cancer, brain tumors (e.g., glioma, anaplastic oligodendroglioma, adult glioblastoma multiforme, and adult anapiastic astrocytoma), bone cancer, soft tissue sarcoma, retinoblastomas, neuroblastomas, peritonea! effusions, malignant pleural effusions,
  • brain tumors e.g., glioma, anaplastic oligodendroglioma, adult glioblastoma multiforme, and adult anapiastic astrocytoma
  • bone cancer soft tissue sarcoma, retinoblastomas, neuroblastomas, peritonea! effusions, malignant pleural effusions,
  • mesotheliomas Wilms tumors, trophoblastic neoplasms, hemangiopericytomas, Kaposi's sarcomas, myxoid carcinoma, round cell carcinoma, squamous cell carcinomas, esophageal squamous cell carcinomas, oral carcinomas, cancers of the adrenal cortex, or ACTH-producing tumors.
  • provided herein is a method for treating a human who exhibits one or more symptoms associated with cancer (e.g. , a hematologic malignancy).
  • the human is at an early stage of cancer. In other embodiments, the human is at an advanced stage of cancer.
  • a method for treating a human who is undergoing one or more standard therapies for treating cancer such as chemotherapy, radiotherapy, immunotherapy, and/or surgery.
  • cancer e.g. , a hematologic malignancy
  • 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.
  • the one or more inhibitor may be a JAK inhibitor, an ASKI inhibitor, a BET inhibitor and a MMP9 inhibitor, as described herein.
  • Compound Al may be used in combination with a JAK inhibitor such as Compound B 1 and
  • Compound B in other embodiments, Compound Al may be used in combination with a BRD inhibitor such as (2 :yeio:p:ropy3-6-- ⁇ 3,5 - dimethyiisoxazoi -4-yl)- 1 H )eiu»[d]imida ⁇
  • a BRD inhibitor such as (2 :yeio:p:ropy3-6-- ⁇ 3,5 - dimethyiisoxazoi -4-yl)- 1 H )eiu»[d]imida ⁇
  • 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.
  • the on or more inhibitor may be a JA inhibitor, an ASKI inhibitor, a BET inhibitor and/or a MMP9 inhibitor, as described herein.
  • Fludarabine (Fludara ®);
  • rituximab (Rituxan ®) combined with fludarabine (sometimes abbreviated as FR): cyclophosphamide (Cytoxan®) combined with fiudarabine;
  • cyclophosphamide combined with rituximab and fiudarabine (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, ohirmtuzumab, or ofatur umab
  • cyclophosphamide and rituximab (sometimes abbreviated as FCR);
  • bendarmistine (Tmandaii ) combined with .rituximab ((sometimes abbreviated as BR);
  • fiudarabine plus cyclophosphamide bendamustine, or chlorambucil
  • fiudarabine plus cyclophosphamide bendamustme, or ch.iorainbuc.il, combined with an anti » CD20 antibody, such as rituximab, ofatumurnab, veltuzumab, lurailuximab or obinutuzumab.
  • 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 die cancer.
  • the BTK inhbitor, Compound Al,or a pharmaceutically acceptable salt or hydrate thereof may be combined with known agents and regimens useful in the treatment of allergic, autoimmune, and inflammatory disorders, as can the combinations herein of Compound A1 with one or more inhibitoras described herein.
  • Compound l may be combined include tumor necrosis factor inhibitors (TNFi i, such as infliximab (sold under the REMICADE® mark), etaiiercept (ENBREb certoUzumab pegol fCIMZIA®), golimumab
  • TNFi i tumor necrosis factor inhibitors
  • infliximab sold under the REMICADE® mark
  • etaiiercept ENBREb certoUzumab pegol fCIMZIA®
  • a therapeutically effective amount refers to an amount that is sufficient to effeci treatment, as defined, below, when administered to a subject ( e.g., a human) in need of such treatment.
  • the therapeutically effectiv 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.
  • a therapeutically effective amount of Compound Al, or a pharmaceutically acceptable salt or hydra te thereof is an amount sufficient to modulate BT K expression, and thereby treat a human suffering an indication, or to ameliorate or alleviate the existing symptoms of the indication,
  • the therapeutically effective amount of the BTK inhibitor such as Compound Al , or a pharmaceutically acceptable salt or hydrate thereof, may be an amount sufficient to decrease a symptom of a disease or condition responsive to inhibition of BTK activity.
  • the compound, inhibitor, or therapeutic agent described herein may be administered using any suitable methods known in the art.
  • the compounds may be administered bucaily, ophthalmic-ally, orally, osniotieali.y, parenteral!' (intramuscularly, intraperiioneally intrasternally, intravenously, subcutaneous! ⁇ '), rectaily, topically, transdermaily, or vaginally, in certain embodiments, the Btk inhibitor is administered orally.
  • 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, r ISOmg, In some embodiments, the Btk inhibitor is Compound Al or hydrochloride salt thereof, which is administered orally, twice a day, to a subject at a dose of 20 mg, 40mg, or 75 mg.
  • the therapeutically effective amount of the BTK inhibitor is a dose corresponding to 1 nmoi to 10,000 nmoi of the BTK. inhibitor used in an apoptosis assay run with 10% serum which approximately relates to a blood plasma concentration of 500 nmoi to 2500 nmoi of the BTK inhibitor.
  • the therapeutically effective amount of the one or more inhibitor is a dose corresponding to 1 nmoi to 200 nmoi of the one or more inhibitor used in an apoptosis assay run with 10% serum.
  • Specific examples include nM, 5 nM, 30 n , 20 nM and 30 .oM concentrations when combined with one or more inhibitor described herein.
  • the therapeutically effective amount of the inhibitors described herein may also be determined based on data obtained from assays known in the art, including for example, an apoptosis assay, in one variation, the therapeutically effective amount of the BTK inhibitor in a human is a dose of from about 1 mg to about 200 mg. In another embodiment the BTK in a human is administered at a dose of from about 10 mg to about 200 mg. In another embodiment the BTK in a human is administered at a dose of from about 20 mg to about 160 rag. 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 2.0 mg to about 150 mg, d) from about 75 mg to about 100 mg, and e) fr m about 100 mg to about 200 mg.
  • individual doses of the BTK. inhibitor that may be administered to a human in need thereof include individual doses of Img, 5 mg, 10 mg, 20 mg, 30 mg, 40 rag, 50 mg, 60 mg, 70 mg, 75 mg, 80 mg, 901 mg, 100 mg, l i O mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 175 mg, and 200 mg.
  • the doses of the BTK inhibitor may be administered as determined by a medical professional and may be administered once daily or may be delivered twice daily, three times daily., or four tiroes daily.
  • the BTK inhibitor such as Compound Al , or a pharmaceutically acceptable salt or hydrate thereof
  • the BTK 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% BTK target inhibition.
  • the one or more inhibitor such as JAK inhibitor, ASK inhibitor, BRD inhibitor, and MMP9 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 inhibition.
  • the BTK inhibitor such as Compound AL or a pharmaceutically acceptable salt or hydrate theieof
  • the BTK inhibitor is administered to the human at a dose between 40 mg and 1 00 mg, between 40 mg and 800 mg, between 40 mg and 600 mg, between 40 mg and 40 mg, about 1 0 rag, about 100 mg, about 200 mg, about 300 mg, about 400 rag, about 500 mg, about 600 mg, about 700 mg, or about 800 mg.
  • the JAK inhibitor such as Compound B I, Compound B2, Compound B3, or Compound B4, or a pbarmaee «tically acceptable salt thereof, is administered to the human at a dose between 20 to 600 mg, between 20 to 400 mg, between 20 to 200 mg, about 20 mg, about 50 mg, about 100 mg, about 200 mg, about 300 mg. about 400 mg, about 500 mg, about 600 mg, about 700 tag, or about 800 mg.
  • the JAK inhibitor is momelotmib (Compound B l) or a hydrochloride salt there of is administered orally at a dose of 50 mg, 100 mg. 200 mg, or 400 mg.
  • (he JAK inhibitor is filgotimb (Compound B2) or a
  • phariunceuueaily sal there of is administered orally at a dose of 3:0 mg. 50 mg, 75 mg, 100 mg, 1 50 mg, 200 mg, or 300 mg.
  • the J AK inhibitor is administered once daily or twice daily.
  • 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 endpoini.
  • dose refers to the total amount of an active ingredient to be taken each time by a human.
  • the dose administered fox example for oral administration described above, may be administered once weekly, once daily (QD), twice daily (BID), three times daily, four times daily, or more than four times daily.
  • the BTK and/or the one or more inhibitor may be administered once daily. ID.
  • the BTK and/or the one or moreinbibitor may be administered twice daily.
  • the one or more inhibitor may be
  • the therapeuiically effective amount of the ASKl inhibiting compound is a dose corresponding to 1 nmol to 200 nmol of the ASKl inhibiting compound used in an. apoptosis assay run with 10% serum.
  • the Askl inhibiting compounds hereii), .including compounds of formula 0.) and Compound CL may be admniisiered in a pharmaceutically effective amount.
  • each dosage unit preferably contains from 1 rag to 500 mg of the A SKI inhibiting compound.
  • a more preferred dose is from 1 mg to 250 mg of the compound of the AS i inhibiting compound.
  • the ASK. inhibitor is Compound C2 which is administered orally at a dose of 2 mg, 6 mg, 10 rag, 18 mg, or 50 mg.
  • the ASK inhibitor is administered once daily or twice daily, it wili 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 io be treated, the chosen route of administration, coadministration compound if applicable, the age, weight, response of the individual patient, the seventy of the patient ' s symptoms,, and iive like.
  • 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 rag and 600 mg, between 40 mg and 40 mg, about 100 rag, 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.
  • the ASK ! inhibiting compound such as Compound CI, 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 mg, between 20 to 400 mg, between 20 to 200 mg, about 20 rag, about 50 mg, about 100 mg, about 200 mg, about 300 rag, about 400 mg, about 500 mg, about 600 mg, about 700 mg, or about 800 mg.
  • 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 rag, 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 m , about 700 mg, or about 800 mg.
  • the MMP9 inhibitor is administered once every two weeks at a single dose of from about 600 mg to ⁇ ,000 mg.
  • the M P 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.
  • 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.
  • the MMP9 inhibitor, particularly including an anti- P antibody i administered once every two weeks at a single dose of about BOO mg.
  • tire MMP9 inhibitor is administered once every three weeks at a single dose of from about 1,000 mg to 1,400 mg.
  • 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 mg.
  • the M.V1P9 inhibitor is administered once every three weeks at a single dose of about 1 ,200 mg
  • the MMP9 inhibitor is an &nti-MMP9 antibody having the amino acid sequence of SEQ ID os: 7 and 12, which is administered intravenously or subcutaneously at a dose of 150 mg, 300 mg, or 600 mg.
  • the MMP9 inhibitor is administered once a week or once every two weeks,
  • compositions for use in connection with such methods.
  • Compositions can be suitable for administration locally or systemically b any suitable route.
  • normal dosage amounts can vary from about 10 ng/kg to up to 100 nig/kg of mammal body weight or more per day, preferably about 1 pg/kg day to 50 rng/kg/day, optionally about 100 pg kg day to 20 mg/kg/day, 500 pg/kg day to 10 mg/kg/day, or 1 mg/kg/day to 10 mg/kg/day, depending upon the route of administration,
  • the selected dosage regimen will depend upon a variety of factors including the activity of the MMP binding protein, the route of administration, the time of administration, the rate of excretion of the particular compound being employed, the duration of die 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.
  • a clinician having ordinary skill in the art can readily determine and prescribe the effective amount (BD50) of the pharmaceutical, composition required.
  • the physician or veterinarian can start doses of the compounds of the invention employed in the pharmaceutical composition at levels lower .than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.
  • methods can further include surgical removal of the cancer and/or administration of an ami -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.
  • a BTK inhibitor such as Compound Al
  • the one or more inhibitor to be combined with a BTK inhibitor may be a I K inhibitor, such as Compound Bl, Compound ,82, Compound B 3, CompouiKi 84, Compound 85, Compound B6.
  • Compound B7, Compound B8, Compound B9, Compound Bit or Compound B1 i .
  • the one or more inhibitor may be an ASK i inhibitor, such as Compound C.1 , Compound C2 or a compound of Formula L
  • the one or more inhbitior may be a modulator of a bromodomain-containing protein such as (2-cyelopropyl-6 ⁇ (3,5- dimethylisoxazol --yJ)-dH-beiKo[d] nidazol-4-y1)di(pyridin-2-y1)memanol.
  • the one or more inhibitor may be a MMP9 inhibitor such as an anti-M P antibody.
  • the compounds may be administered bucally,

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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

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
FIELD OF THE INVENTION
(0001 J The present disclosure relates generally to therapeutics and compositions for treating cancers and allergic, autoimmune, and inflammatory disorders, and more specifically to the use of Bruton's Tyrosine Kinase (BTK) inhibitors
(hereinafter refered to BTK or Btk inhibitors) in combination with one or more agent which modulates Janus Kinase (JAK), Apopfcosis signal-regulating kinase 1 (ASK 1 ), bromodomam-eonta nmg proteins, or matrix metal lopeptidases 9
(MMP9).
BACKGKOUND
[0002] BTK inhibitors usefulm treating cancers such. as. hematological cancers and inflammatory conditions include those taught in U.S. Pat. No. 8,940,725 {Yamamoto et al.)s U.S. 2014/0330015 Yamamoto e( ai.) and U.S. Pat. No.
7,514,444 (Honigberg et al.).
[0 Θ3] Janus Kinase (JAK) inhibitors are known in the art, including
momelotmib, peficitinib, toiacitinib, oelacitinib, ruxolitinib. baracitinib, lestaurtimb, pacritmib, fiigotmib, TG101348, JS-124, and I CB391 10, CHZ868, and GSK2586184. There remains a need for beneficial combination therapies.
[0004] Mitogen-activated protein kinase (MAFK) signaling cascades couple diverse extracellular and intracellular queues to appropriate cellular stress responses, including cell growth, differentiation, inflammation, and apoptosis (Kumar, S„ Boehm, J,, and Lee,, J. C. (2003) Nat. Rev, Drug Dk 2:717-726;
Piraienta, G.s and Paseual, J. (2007) Cell Cycle. 6: 2826-2632). MAPKs exist in three groups, MAP3&S, MAP2 s, and MAPKs, which are sequentially activated. MAPK3s directly respond to environmental signals and phosphorylate MAP2Ks, which in torn phosphorylate specific MAPKs. MAPKs then mediated the appropriate cellular response by phosphoryiatmg cellular substrates, including transcription factors that regulate gene expression. lO OS'j Apoptosis signal-regulating kinase 1 (ASKI ) is a member of the mitogen-, activated protein kinase kinase kinase (''MAF3K") family that activates the e-Jim N-termmal protein kinase ("JNK, ) and p38 MAP kinase, (ichijo, H.e et al. (1997) Science, .275. 0-94). AS 1 is activated by a variety of stimuli including oxidative stress, reactive oxygen species ( OS), LPS, TNF-a, FasL, ER stress, and increased intracellular calcium concentrations (Hattori, K., et al. (2009) Cell Comm. Signal. 7: 1- 10; Takeda, K., et al. (2007) Annu. Rev. Pharmacal. Toxicol. 48: 1-8.27; Nagat, H., et al. (2007) J. Biochem. Mol. Biol. 40: 1-6). ASK1 'undergoes activatioa via autophospkjryiation at Thr838 in response to these signals and in turn phosphorylaf.es MAP2K.S, such as MKK3/6 and MK. 4/7, which then phosphorylate and activate p38 and JNK MAPKs, respectively.
AS 2 is a related MAP3K that shares 45% sequence homology with AS I (Wang, X. S., et al. (1998) Biochem. Biophys. Res. Common. 253, 33-37, Although A SK2 tissue distribution is restricted, in some cell, types ASKI and A SO have been reported to interact and function together in a protein complex (Takeda, .s et al. (2007) J. Bioi. Chem. 282: 7522-7531 ; Iriyama, T.5 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.C 1998) Embo J. 1 7:2596-2606), and through association with ART (Zhang. L, Chen, J. and Fu, II (\ 999) Proe. Nal Acad. Sci. U.S.A 96:8511-8515).
Phosphorylation of ASK 1 protein can lead to apoptosis or 10 other cellular responses depending on the cell type. ASK! activation and signaling have been reported to play an important role in a broad range of diseases including neurodegenerati ve, cardio vascular, kiilammatory, autoimmunity, and metabolic disorders. In addition, ASKI has been implicate mediating organ damage following ischemia and reperthsion of the heart, brain, and kidney (Watanabe et al. (2005) BBRC 333 f 562-567: Zhang et ah, (2003) Life Sci 74-37-43; Terada et al. (2007)BBRC 364: 1043-49). Emerging evidence suggests mat ASK2, either alone or in a complex with ASKI, may play important roles in human diseases as well. Therefore, therapeutic agents that function as inhibitors of ASKI and ASK2 signaling complexes have the potential to remedy or improve the lives of patients suffering from such conditions. U.S. Publication No. 2007/0276050 describes methods for identifying ASK! inhibitors useful for preventing and/or treating cardiovascular disease and methods for preventing and/or treating cardiovascular disease in an animal. The methods comprise administering to the animal an ASK! 30 inhibitor and, optionally, a hypertensive compound. U.S. Publication No. 2007/0167386 reports a drug for at least one of prevention and treatment of cardiac failure containing a compound that inhibits a functional expression of ASK! protein in a cardiomyocyte, and a method for screening the drug.
W02009027283 discloses iriazolopyridine compounds, methods for preparation thereof and methods for treating autoimmune disorders, inflammatory diseases, cardiovascular diseases and neurodegenerative diseases. U.S. Patent Nos.
8,552,196 and 8,742,126 teach AS 1 inhibiting compounds useful as pharmaceutical agents.
[6006] BET or BRD inhibitors- are a class of drugs with anti-cancer, immunosuppressive, and other effects demonstrated in clinical trials arid widely- used in research. They teversibiy bind the bromodomains of Bromodomain and Extra-Terminal motif (BET) proteins BRJD2, BR 3, BRD4 and B.RDT and prevent protein-protein interaction between BET proteins and aeetylated histories and transcription factors. Bromodomain inhibitors include the benzimidazole derivatives taught in US 2014-03.36 ί 90.
[0007] Abnormal activity of certain MMPs plays a role in tumor growth, metastasis, inflammation, autoimmunity, and vascular disease. See, for example, Hu ei ah (2007) Nature Reviews: Drug Discovery 6:480-498, One notable source of MMP9 is tumor-associated macrophages i'TAMsj, which support .metastasis and invasion in a complex co-activation loop via paracrine interaction with the primary tumor cells. This combination of the proteolytic breakdown -of physical barriers to cell invasion plus liberation of factors that activate growth and angiogenesis paves the way for tumor expansion, with the accompanying development of neovascularization to support tumor outgrowth.
[6008] MMP9 is a target of Oncogenic signaling pathways such as RAS/RAF, FB A T/NFkB, and WNT beta-catenin and functions as an upstream regulator of these pathways via modulation ofintegrin and receptor tyrosine kinase function. MMP is also expressed by subsets of stromal cells (e.g. vasculature, fibroblasts) and turner-associated infiltrating cells, including myeloid-derived suppressor cells, macrophages and neutrophils. MMF9 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 unregulated upon loss of several tumor suppressors, MMP9 is unregulated in many diverse tumor types and can promote primary growth and distal invasion of cancerous cells.
{0009J 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 MMPS., use of available MMP inhibitors has caused side effects due to the inhibition of essential, non^pathogenicaily-rekfced MMPs. Useful MMP9 inhibitors include the antibodies and fragments disclosed in U.S. 2015-0140580 (Smith et al.) and U.S. Patent Nos. 8,377,443 (MeAuley et al.), 8,501 ,916 (MeAuley et al,), and 9.120,863 (MeAuley et al.).
{0010} There remains a need for additional treatments for cancers.
BRIEF SUMMARY
(001 ί I Provided herein are methods for treating cancers, allergic disorders, autoimmune diseases and inflammatory diseases that involve the administration of a BTK inhibitor in combination with one or more inhibitor selected from the group consisting of a JAK inhibitor, a ASK inhibitor, a BRD inhibitor, and a MMP9 inhibitor, In some embodiments, the BTK inhibitor is 6-amino-9-[(3R)-l- (2¾ttynoyl>3~pym>jidiny
or a pharmaceutically acceptable -salt or hydrate thereof. In. some variations, the BTK inhibitor is a hydrochloride salt of 6-ammo-9~( (3R)- l-(2-butyhoyl )-3- pyTralidinyl]-7-(4-phenoxyphenyl)-'7i9"dihydrO"8!:I''purin-8~one, or a
pharmaceutically acceptable hydrate thereof
10012] 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 ofa JA inhibitor.
[0013] in some embodiments, the JAK inhibitor is selected from the group of momeJotmih, peficitinih, tofacitinib, oclacitinib, mxoUtitiib, baracitinib, lestaurtinib, pacritinib, filgotmib, 1 -[ l-[ 3-fluoro-2-(trifluoromethyl)~4- pyricHnyl] -piperidinyl]-3- 4-(7H^yn,oio[23-i Jpyraiidjn-4-yi )-l K-pyrazal-l - ylj-S-azetidineacetonitrile, TGI 01348, JS-124, INCB3 110, INCB16562, CHZ86S, VX-509, XL019, NVP-BSK805, CEP33779, R-348, AC430, 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 effective amount of a BTK inhibitor and a therapeutically effective amount of a ASK inhibitor. In some embodiments, the ASK inhibitor is selected from the group of Compound CI,. Compound C2. or the compound of Formula (I), in some aspects, provided is a method for treating cancer in a human in need thereof, comprising administering to the human a therapeutically effective amount of a BTK inhibitor and a therapeutically effective amount of a BHD 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 BTK inhibitor and a therapeutically effective amount of an MMP9 mhibitor.tn 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 immunoglobulin (l.g) hea vy chai (or functional fragment thereof} and an ig light chain (or functional fragment thereof), in certain embodiments, the MP9 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 BTK inhibitor and one or more inhibitor selected from a JAK inhibitor, a ASK inhibitor, a BED inhibitor, and a MMP9 inhibitor. Also provided herein are methods comprising a BTK inhibitor and one or snore inhibitor selected from a JAK. inhibitor, a ASK nhibitor, a B D inhibitor, arid a P9 irihibitor for the use in therapy or in the manufacture of a medicament for cancer treatment,
BRIEF DESCRIPTION OF THE DRAWINGS
[0014] FIG. 1 provides a chart of Mean SB Ankle Diameter for a rat collagen- induced arthritis model conducted using Compound Al and tofacitinib.
[ OlSj FIG, 2: depicts a heat map representing the percent of DLBCL cell growth inhibi tion for e very pairwise combination of Compound A I and a BET inhibitor 6-amino~ T3R.)-l -(2-bufynoyl)- -pyrrolidinyl]-7-(4-pbenox phenyl)" 7.9-dihydro~8H-purin- 8-one (Compound D) from one representative experiment.
[0016] FIG. 3: depicts a heatmap of the calculated Bliss excess over predicted addniv y for every pairwise combination using the percent growth inhibition shown in: PICT 2,
[0017] FIG. 4: depicts the average percent cell growth inhibition relative to a DMSO control (n:::3) for DLBCL ceils treated with a dilution series of
Compound D either alone or in the presence of 5.5 nM or 1 1 nM of Compound
AL
DETAILED DESCRIPTION
[0018] The following description sets forth exemplary methods, parameters and the like, it should b recognized, however, that such description is not intended s a limitation on the scope of the present di sclosure but is instead provided as a description of exemplar embodiments. Provided are methods, compositions (including pharmaceutical compositions, formulations, or unit dosages), articles of manufacture and kits comprising a BTK inhibitor and one or more inhibitor selected from a JAK inhibitor, a ASK inhibitor, a B'RD 'inhibitor, and a MMP9 inhibitor.
[0019] Combinations of pharmaceutically effecti ve amounts of the BTK inhibitor and one or more inhibitor selected from a JAK inhibitor, a ASK inhibitor, a BRD inhib tor, and a MMP inhibitor as described herein may be used to treat cancers, allergic disorders, autoimmune diseases and inflammatory diseases in a human, the method comprising administering to the human in need 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 MM.P9 inhibitor. The combinations taught herein may be used for the treatment of allergic disorders, autoimmune diseases and inflammatory diseases such as; systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), multiple vasculites, idiopathic thrombocytopenic purpura (1TP), myasthenia gravis, allergic rhinitis, chronic obstructive pulmonary disease (COPD), adult respiratory distress syndrome CA Ds) 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 (SIX), non-Hodgkin's lymphoma, indolent. non-Hodgfc l's lymphoma (iNHL), refractory iNHL. mantle cell lymphoma, follicular lymphoma (FL), lymphopksmacytic lymphoma, and. marginal zone lymphoma.
Definitions
[9020] 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 groitp. 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 "-S02CHr" is equivalent to JI-^SCV and both may be connected in either direction. The prefix "(W indicates that the following group has from u to v carbon atoms, one or more of which, m certain groups (e.g. heieroaikyl, heteroaryl, heteroarylalkyl, etc), may be replaced with one or more heteroatoms or heteroatomic groups. For example, "€·.,, alkyl" indicates that the alky! group has from 1 to 6 carbon atoms,
{00211 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 "aikylene" group or an "aikyienyf group, an "arylene" group or an "arylenyl" group, respectively. [0022) "A!kyJ" refers to any aliphatic hydrocarbon group, is, .any linear, branched, cyclic, or spiro nonaromatie hydrocarbon group or an isomer or combination thereof. As used herein, the term "alky!" 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), eyeloalkyi (a cyclic aliphatic group), alkylcycloalkyl (a linear or branched aliphatic group attached to a cyclic aliphatic group), and the like. Alkyl groups include, but are not limited to, methyl; ethyl; propyls such as propan-l-yl, propan-2-yl (iso-propy) ), and cyclopropyls such as cyclopropan-l -yl, etc.; butyls such as buian-l -y!, butan-2-yl (sec-butyl), 2-methyI-propan~ 1 -yl (iso-butyl), 2- mefhyI-propan-2-yl (t-butyl), eyciobutan-l-yi; butanes (e.g. (E)-but~2~ &, Z)- bui-2-ene); pentyls; pentenes; hexyls; hexenes; oety!s; decyls; cyclopropyl, eyclobutyl, eyclopentyl, cyclohexyl methylcyclohexyl, spiro 2.4]heptyl5 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.
{.0023J "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 10 carbon atoms, e.g., from 2 to 6 carbon atoms or 2 to 4 carbon atoms and having at least one site of vinyl unsaturation (>C ;;: C<j. Alkenyl groups include ethenyl, propenyi, 1,.3-bu.tadienyl, and the like, Alkynyl may have from 2 to about 10 carbon .atoms, e.g. from 2 to 6 carbon atoms or 2 to 4 carbon atoms.
[0024] "Alkynyl" is a subset of "alkyl" and refers to an aliphatic group containing at least one carbon -carbon triple bond. The term "alkynyl" is also meant to include those groups having one triple bond and one double bond.
[0025) "Aikoxy" refers to the group -O-aikyl, wherein the alkyl group may be optionally substituted. Aikoxy includes, by way of example, methoxy, ethoxy, n-propoxy, isopropoxy, n»butoxy, t-buioxy, sec-butoxy, and n-pentoxy. 10026] "Acyr refers to a group -€ '))R5 where R is hydrogen, alkyl, cyeloalkyi, cycioheleroalkyi, aryl. arylaikyi, heieroalkyl, heteroaryl 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, cykohexylcarbonyl, cyclohexylineiiiyi- carboiiyl, benzoyl,
benzyk ycarbonyi and the like.
(0O27J "Amide1* refers to both a "C-amido" group which refers to the group - 0(=Ο) Ι¾* and an "N-amido" group which refers to the group -NRyC(===0)R2, wherein Ry and R;i are independently selected from the group consisting of hydrogen, alkyl, aryl, heteralkyh heieroaryi (each of which may be optionally substituted), and where Ry and R* are optionally joined, together with the nitrogen or carbon bound thereto to form an optionally substituted heterocyeloaikyl.
[0028] "Amino" refers; to tile group -NR¾S wherein Ry and R are independentl selected from the group consisting of hydrogen, alkyl, aryl, heteraikyl, heteroaryl (each of which may be optionally substituted), and where Ry and Rz are optionally joined together with the nitrogen bound thereto to form a
heterocyeloaikyl or heteroaryl heteroaryl (each of which may be optionally substituted),
[0029] "Amidino" refers to the group --€(;:: Ex)NiR RE where K\ Ry, and R5 are independently selected from the group consisting of hydrogen, alkyl aryl heteraikyl, heteroaryl (each of which may be optionally substituted),, and where Ry and R'" are optionally joined together with the nitrogen bound thereto to fonn a heterocyeloaikyl 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 covaiently, or linked via one or more such as a methylene or ethylene moiety. Aryl groups include., but are riot limited to, those groups derived from acenaphthylene, anthracene, azuiene, benzene, biphenyl, chrysene,
cyclopentadienyl anion, diphenylmethy!, fluoranthene, fluorene, mdane, indene, naphthalene, perylene, phenalene, phenanihrene, pyrene, ttiphenylene, and the like. An aryl group comprises from 5 to about 20 carbon atoms, e.g., from 5 to 20 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,
[00311 "ArylalkyP (also "araikyP) refers to an aryl group attached to an alkyl group, Arylalkyi groups include, but are not limited to, benzyl, tolyl, dimethylphenyl, 2-ph.enyiet.han· 1 -yi, 2-naphthylmethyl, 2-naphthyiethan- 1 -yl, naphthobenzyi, plienylvinyl, diphenylmethyl, and the like. For example, the "arylalkyi" may be attached to the rest of the compound of formula (I) through the aryl group. Alternatively, the "arylalkyP may be attached to the rest of the compound of formula ( !) through the alkyl group. Where specific alkyl moieties are intended, the nomenclature arylalkanyl, aryiaikenyl and/or arylalkynyl may be used. An arylalkyi group comprises from 6 to about 30 carbon atoms, e.g. the alkyl portion of the arylalkyi group can comprise from 1 to about 10 carbon atoms and the aryl portion of the arylalkyi group can comprise from 5 to about 20 carbon atoms. In some instances an arylalkyi group comprises from 6 to about 20 carbon atoms, e.g. the alkyl portion of the arylalkyi group can comprise from 1 to about 10 carbon atoms and the aryl portion of the arylalkyi group can comprise from 5 to about 10 carbon atoms.
{0032] "Aryloxy" refers to the group -O-aryl, including by way of example, phenoxy and naphthoxy.
[0033] "Azido" refers to the group -N3.
[Θ034] "Boromc acid" refers to the group -B(OH)2.
[0035] Boronic acid ester" refers to an ester derivative of a horonic acid compound. Suitable boromc acid ester derivatives include those of the formula -
B(OR)? where R is hydrogen, alkyl, aryl, arylalkyi, heteroaikyl, or heteroaryl, each of which may be optionally substituted. For example, boromc add ester may be pinacol ester or catechol ester.
[003#j "Cafbocyele" or "carbocyclyP refers to a saturated, partially unsaturated or aromatic ring having 3 to 7 carbon atoms as a monocycle, 7 to 12 carbon atoms as a bicycle, and up to about 20 carbon atoms as a polycycle, Monocyclic carbocycles have 3 to 6 ring atoms, still more typically 5 or 6 ring atoms, Bicychc 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 (6,6) system, Carboeycies includes aromatic and non-aromatic mono-, bi~, and poly-cyclic rings, whether fused, bridged, o spiro. Non-limiting examples of monocyclic carboeycies include the cycloaJkyls group such as cyclopropyl, cyeJobutyl, cyclopentyi, l -cyclopent-l-enyk i --eyciope)it-2-enyl i-cyclopemV3- enyl, cyclohexyi, l-cyclohex-l~cny'j. l-cyclohex-2-enyl, l-cyclohex-3-enyl or aryl groups such as phenyl, and the like. Thus, "carbocycle " as used herein, encompasses but is not limited to "aryl", "phenyl" and "biphenyl."
[00371 "Carbamoyl" refers to the group ~€(0) RyR.z where Ry and Rz are defined as in "amino" above.
(00381 "CarhonyT refers to the divalent group -C(O)- which is equivalent ίθ · (.' ( O r.
(00 1 "Carhoxyl" or "earhoxy" refers to -COOH or salts thereof
[0046] "Carboxyl ester5 or <scarboxy ester" refers. to the groups -€(0)011, wherein R is hydrogen, alkyl, aryl, aryialkyl, heteroalkyi, or heteroaryl, each of which may be optionally substituted, in one embodiment, R is alkyl, aryl, aryialkyl, heteroalkyi, or heteroaryl, each of which may be optionally substituted.
[0041 ] "Cyano" or "carbo Trile" refers to the group -C ,
[0042] "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 "eycloalkyT applies when the point of attachment is at a non-aromatic carbon atom (e.g., 5,6,7,8,- tetranydronaphthalene-5-yl). The term "eycloalkyT includes cycloalkenyl groups. Examples of cycloalkyl groups include, for instance, adaroantyl, cyeiopropyj, cyclobutyl, cyclopentyl, oyelooetyl, and cyclohexenyl.
[00431 "Guanidinb" refers to the group -NMC(-N.H)N¾.
[0044] "Halo" or "halogen" refers to fluoro, chl'oro, bromo and iodo.
[00451 "Haloalkyl" refers to substitution of alkyl groups with 1. to 5 or, in some embodiments, 1 to 3 halo groups, e.g., -C¾CL -C¾F, ~CHj.Br, -CFClBr, - C¾CH2C1, ~C.H2C.H2F, -CF3, -CFfeCFj, ~C¾CC¾, and the like, and further includes those aikyl groups such as perifeoroalkyl in which all hydrogeri atoms are replaced by fluorine atoms,
[0046] "Haloaryl* refers to aryl groups with one or more halo or halogen substiruents, For example, haloaryl groups include phenyl groups in which from 1 to 5 hydrogens are replaced with a halogen, Haloaryl groups include, for example, fluorophenyl, di fluorophenyl trifluorophenyl, chlorophenyl, clorofiuorophenyl, and the like.
[0047] "Heteroalkyl" refers to an aikyl group in which one or more of the carbon atoms (and any associated hydrogen atoms) are each independently replaced with the same or different heteroatorn or heteroatoraic group. For example, heteroalkyl may include 1 , 2 or 3 heteroato ic groups, e.g. I heteroaioinic group. Heteroatoros include, but are not limited to, N, P, Q, S, etc. Heteroatomic groups include, but are not limited to, -NR-, )-, -PH~, -P(0)2-. -S(0>, -S(0.fe-, and the like, where R is H, aikyl, aryl, eycioaikyl. heteroalkyl,. heteroaryl or oyctoheteroalkyl. The terra "heteroalkyl" includes heterocyeloalkyl (a cyclic heteroalkyl group), alkyl-heterocycloalkyl (a linear or branched aliphatic group attached to a cyclic heteroalkyl group), and the like. Heteroalkyl groups include, but are not limited to, -OCR,, ~C¾OC¾ -SC¾ »C¾SCHjf -NRCH3, - CH2 RCH3, and the like, where R is hydrogen, aikyl, 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 i to 6 carbon, and hetero atoms.
[0048] "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 heteroatoms, as defined above. For example, heteroaryl may include i, 2 or 3 heteroatomic groups, e.g. 1 -heteroatomic group. Heteroaryl groups include, but are not limited to, groups derived from acridine.
benzoimidazole, benzothiophene, benzofuran, henzoxazole, benzothiazole, carbazole, earboline, cinnoline, furan, imidazole, imida¾opyridine, indazoie, indole, indolme, indoiizme, isobenzofuran, isochromene, isoindoie, isoindotine, isoqutnolme, isothiazole, isoxazole, naphthyridme, oxadiazole, oxazole, perimidine, phenantJvridine, phenauthroline, phenazine, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrroiizine, qumazoime, quinoiine, quinoliziae, quinoxaline, tetrazole, thiadiazoie, thiazole, thiophene, triazoie, 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 helero atoms.
[0049] "Heieroarylalkyl" .refers to an arylalkyl group in which one or snore carbon atoms (and any associated hydrogen atoms) are independently replaced with the same or different heteroaioms, as defined above. For example, heieroarylalkyl may include 1 , 2 or 3 heteroatomic groups.Heteroarylalkyl groups include, but are no limited to, groups derived ftora heteroaryl groups with alkyl sitbstituents (e.g. methyipyndine, diroeihylisoxazole, etc.), hydrogenated heteroaryl groups (dihydioquinolines, e.g. 3,4-dihydroqrunoime,
dibydroisoquinolines, e.g. { ,2-di:hydroisoquinoline, dihydroimidazole, tetrahydroimklazole, etc.), isoindoline, iso dolones (e.g. isoindolin-1 -one), dihydrophthaiazine, quinolinone, spir0[cyclopropane ,14so∞do}in]-3'-one, di(pyridm-2-yl)memyj., dt(pyridm-3-yl)methyl, di('pyridin-4-yl)methyls and the like. A heieroarylalkyl group comprises from 6 to about 30 carbon and hetero atoms, for example from 6 to about 20 carbon and hetero atoms.
{O SOJ "Heterocycloalkyl" is a subset of "heteroa!kyF and refers to a saturated or unsaturated ey oalkyl group in which one or more carbon atoms (and any associated hydrogen atoms) are independently replaced with the same or different heteroatom. Heteroatoms include, but are not limited to, N, P, O, S, etc, A heterocycloaikyl .group may also contain a charged heteroatom or group, e.g., a quatem.iz.ed ammonium group such as -N+ R)2- wherein R is alkyl, e.g., methyl, ethyl, etc, Heterocycloaikyl groups include, but are not limited to, groups derived from epoxide, imidazolidine, morpholine, piperazine, piperidine, pyrazolidine, piperidine, pyrrolidine, pynolidinone, tetrahydroraran.
tetrahydrothiophene, dihydropyridine, teirahydropyridme, quinuciidine, N- bro.mopyrrojidine, N-bromopiperidine, N-chloiOpyrrolidine, -chloropiperid ne, an Ν, -dialkylpyrrolidinium, such as
Figure imgf000014_0001
a N,N- dialkylpiperidinium such as N, -dimeihylpiperidium , and the like. The heterocycioalkyl group comprises from 3 to about. 10 carbon and hetero atoms in the ring or rings. In some embodiments, heterocycioalkyl includes 1, 2 or 3 heteroatomic groups,
{OOSJ'j "Heterocycle" or "heterocyelyr as used herein includes; by way of example and not limitation those heterocycles described in Paquette. Leo A,; Principles of Mo em 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 ponographs" (John Wiley & Sons, New York, 1950 to present), in particular Volumes 13, 14, 16, 19, and 28; and I, Am. Chem. Soc. (I960) 82:5566. in one specific embodiment of the invention "heteroeycle" includes a "carbocyele" 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 "heteroeyele" or "heterocYciyi"' includes saturated rings, partially unsaturated rings, and aromatic rings (i.e., heteroaromatic rings), Heterocycles includes aromatic and non-aromatic mono-, bi-, and poly-cyclic rings, whether fused, bridged, or spiro. As used herein, the term 4<heteroeycie" encompasses, but is not limited to "heteroaryl. "Substituted heterocyclyis 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. tefrahydropyridyl (piperidyl), thiazoiyi, teirahydrothiophenyl, sulfur oxidized tetrahydrothiophenyl, pyrimidinyl, furanyl, thienyl, pyrroiy!, pyraxolyl, imidazolyl, tetrazoiyl, benzoftiranyl, mianaphthalenyl, indolyl, indolenyl, qiiinolinyf isoquinolinyl, bea imidazolyi, piperidinyl, 4-piperidonyl, pyrrolidinyl, azetidinyl, 2- pyrrolidonyl, pyrrolmyl, tetrahydroftiranyl, teirahydroquinolinyl,
tetrahydroisoquinolinyl, decahydroquinolinyl, octahydroisoquinohnyl, azocinyf triazinyl, 6H-l,2,5-thia<hazinyi, 2.H,6H .5,2 lithiazinyls thienyl, thianthrenyl, pyranyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxathinyi, 2H~pyrrolyL isothiazolyl, isoxazolyl, pyraz.inyl, pyrklazmy!, indolizinyl, isoindolyl, 3H- mdalyL 1 H-indazoiy, purinyl, 4H-qi.¾i « oii iny 1 , phthaiazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyi, pieridinyl, 4aH-carbazoiyl, earbazolyl, β- carboiinyl, phenanthridinyl, acridinyl, pyrimidinyl, phenanthrolinyl, phenazinyL phenothiazinyl, furazany!, phenoxaziayl, isoehroraanyl, ehromanyl,
imidazolidinyl, imidazolinyl, pyrazolidmyl, pyrazoiiny!, piperazinyl, indolinyl, isoindoltnyl, quinuclidinyl, morpholinyl, oxazolidioyl, benzotriazolyj, benzisoxazolyl, oxindolyl, benzoxazolinyl, isatmoyl, and bis-tetrahydroiuranyi.
[0052] By way of example and not limitation, carbon bonded heterocycles are bonded at position 2. 3, 4, 5, or 6 of a pyridine, position 3, , 5, or 6 of a pyridazme, position 2, 4, 5, or 6 of a pyrrolidine., position 2, 3, 5, or 6 of a pyrazine, position 2, 3, 4, or 5 of a furan, tetrabydroftran, thiofuran, thiophene, pyrrole or tetrahydropyrrole, position 2, 4, or 5 of an oxazole, imidazole or thiazoie, position 3, 4, or 5 of an isoxazole, pyrazole, or isothiazole, position 2 or 3 of an aziridine, posiiion 2, 3, or 4 of an azetidine, position 2, , , 5, 6, 7, or 8 of a quinoline or position 1 , 3, 4, 5, , 7, or 8 of an isoquinoline. Still more typieally, carbon bonded heterocycles include 2~pyridyl, 3-pyfidyl, 4~pyridylJ S- pyridy], 6-pyndyl, 3-pyridazinyl, 4-pyridazmyl 5-pyridazmyL 6-pyndazinyl 2- pyrimitlmyl, 4-pyri.midmyl, 5-pyrimidmyl, 6-pyrimidinyl, 2-pyriiziny!, 3- pyrazinyi, 5-pyrazmyl, 6-pyrazinyl, 2-thiazoiyl, 4-ihiazolyl, or 5-thiazo.ly). By way of example and not limitation, nitrogen bonded heterocycles are bonded at position 1. of an aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrro!ine, 3-pyrroiine, imidazole, imidazolidine, 2-ii¾ida¾oline5 3-imidazoline, pyrazole, pyrazoline, 2- pyrazoline, 3-pyrazoltne, piperidine, piperazine, indole, indoline, lH-indazole, position 2 of a isoindole, or isoindoline, position 4 of a morpholine, and position 9 of a carbazole, or β-carboiine. Still more typically, nitrogen bonded heterocycles include l-aziridyb 1-azetedyl, 1-pyrrolyl, 1-imidazoiyl, 1 -pyrazolyl, and l-piperidmyl.
(D0S3) ''Hydrazmo" refers to the group -NHNHj.
PS4{ "ffydroxy" or "hydroxyi" refers to the gronp -OH..
[0055] "Imino" refers to the group -C(»NR)- wherein. R is hydrogen, alkyl atyl aryialkyl, hetero ikyl, or heieroaiyl, each of winch may be optionally substituted.
[0056] '\Niiro:' refers to the group -NO.;.
[0057J The tenns "optional" or "optionally" mean that the subsequently descr bed event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances in wh ch it does not.
[0058 j "Oxide" refers to products resulting from the oxidation of one or more heteroatoms. Examples include N-oxides, sulfoxides, and suifones.
[00.69] "Oxo" refers to a double-bonded oxygen (-0). In compounds where an oxo group is bound to an s ^ nitrogen atom, an N-oxide is indicated.
[0060] "Racemates" refers to a mixture of enantiomers.
[0061 J "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, 1 92).
[0062] "Substituted" (as in, e.g., "substituted alkyF) refers to a group wherein one or more hydrogens have been independently replaced with one or more substituents including, but not limited to, alky], alkenyl, alkynyl, alkoxy, acyi, amino, aniido. amidi.no, aryi, azido, carbamoyl, carboxyl, carboxyl ester, cyano, guanidino, halo, haloalkyi, heteroalkyl, heteroaryl, heterocyeloalky), hydroxy, hydrazino, hydroxy., imino, oxo, nitro, sulfmyl, 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 alkyi which is itself substituted with a siibstiiuted aryl group, which is further siibstiiuted by a substituted heteroalkyl group, etc.) arc 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 aryi groups are limited io -substituted aryl»(substituted aryi)-substituted aryl. For example, in some embodiments, when a group described above as being "optionally substituted" is substituted, that substituerit is itself unsubstituted-Simiiarly, it is understood that the above definitions are not intended to include impermissible substitution patterns' (e.g., methyl substituted with 5 fluoro groups or heteroaryl groups having two adjacent oxygen ring atoms;. Such impermissible substitution patterns are well known to the skilled artisan. When used to modify a chemical group, the term
"substituted5* may describe other chemical groups defined herein. For example, the term "substituted aryl" includes, but is not United to, "aryialkyl." Generally, substituted groups will have 1 to 5 substituems, 1. to 3 substituents, 1 or 2 suhstituents or 1 substitu nt. Alternatively, the optionally substituted groups of the invention may be unsubstituted.
(0063] "Suifottyf refers to the divalent- rou ~S(0) .
(0064] "Tautomer" refers t alternate forms of a compound that differ in the position of a proton, such as enoi-keto and iffiine'-enamine tautomers, or the tautomeric forms of heteroaryl groups containing a ring atom attached to both a ring -NH~ moiety and a ring ::::N- moiety such as pyrazoles. imidazoles, bendmidazoles, triazoies, and tetrazoles.
(0065] "Tlfiocyanate" refers to the group -SCN.
(0066] "Thiol" refers to the group -SH.
[0067] Thiorie" refers to a ihtoketone (=S) group.
|0068] "Pharmaceuticaily acceptable" refers to compounds, salts, compositions, dosage forms and other materials which are useful in preparing a pharmaceutical composition that is suitable for veterinary or human pharmaceutical use.
{0069] "Pharmaeeutioaily 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, benzenesulfbnic acid, benzoic acid, camphoraulfomc acid, citric acid, ethanesul onic acid, turoarie acid, glucoheptonic acid, gluconic acid, lactic acid, maleic acid, malonic acid, mandelic acid, methanesulfonic acid, 2-napththalenesulfonic acid, oleic acid. palmitic acid, propionic acid, stearic acid, succinic add, tartaric acid, p- toluenesuh me 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 son; or coordinates with an organic base such as diethanoiamine, triethanolamine, N~
metbylglueamine and the like. Also included in this definition are ammonium and substituted or quatemized ammonium salts. Representative non-limiting lists ofphannaceutically acceptable salts can be found in S.M. Berge et ah, J, Pharma Sci., 66(1). 1-19 ( 1977), and Remington: The Science and Practice of Pharmacy, R. Heodrickson, ed., 21 st edition, lipptneott, Williams & Wilkins, Philadelphia, PA, (2005), at p. 732, Table 38-5, both of which are hereby incorporated by reference herein.
[0'Θ7Θ'| The following abbreviations may also be: used: AcGl-I: acetic acid;
riBuLi: ?-bulyHithiur»; CC: column eliromatography; Q¾COjj: cesium carbonate: C¾C¼ or DCJVf: dichlotomethane; CH3Mgi: methyl magnesium iodide; CuCk copper chloride; DAST: (diethylamino)sulfur trifluoride; DEAD: diethyl azodicarboxylate; DIB L: dnsobulyialuminum hydride; D1PEA:
diisopropylethyiamine; DMF: dimethylforrnamide: DMSO: dimethyl sulfoxide; Et¾N: triethylamine; BtOAc: ethyl acetate; EtOH: ethanol; g: gram(s); h: hour; ¾: hydrogen; HBr: hydrogen bromide; HC1: hydrogen chloride; ¾0: water; ¾¾: hydrogen peroxide; HPLC: high performance liquid chromatography; KCN: potassium cyanide; LHMDS: lithium hexamethyklisilaside; L1AIH4:
lithium aluminum hydride; LiOH: lithium hydroxide; M: molar eCN;
acetonitrile; Mel: methyl iodide; MeOH: methanol; MgS04: magnesium sulfate; MgC.'Q : magnesium carbonate; rng: milligram; MsCI; mesyl chloride; mmol: miilimoies mL: milliliter; sodium hydrogen sulfite; rnCPBA: meta- chloroperoxybenzoic acid; : normality; N?.: nitrogen; Na2CO¾: sodium carbonate; NaHC(¼: sodium bicarbonate; NO sodium nitrite; NaOH: sodium hydroxide: NajSjO?: sodium bisulfate; Ν¾804: sodium sulfate; NBS: N- biOmosuccinimide; NEjCl: ammonium chloride; NIIsOAc: ammonium acetate; NMR: nuclear magnetic resonance; Pd/C: palladium on carbon; PPh¾: triphenyl phosphine; tPrOH; isopropyl alcohol; RT: room temperature; SOC¾: thionyl chloride; THF: tetrahyckofuran; TI..€: thin layer chromatography; μΐ : microliter, [0071] It is understood that combinations of chemical groups may be used arid will be recognized by persons of ordinary skill in the art. For instance, the group "hydroxyalkyl" would refer to a hydroxy! group attached to an alky! group. A great number of such combinations may be readily envisaged.
{0072| 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 otherwi se specified.
[0073] "Effective amount" or "therapeutically effective amount" means the amount of a compound or molecule described herein that may he 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 "re ractory" 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, tor 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 lias returned or the signs and symptoms of cancer have returned after a period of improvement, e.g. after a treatment has shown effective reduction in the cancer, such as after a subject is in remission or partial remission,
[0075] In some variations, the human is (i) refractory to at least one anti-cancer therapy, or (ii) in relapse after treatment with at least one anti-cancer therapy, or both (i) and (ii). In some of embodiments, the human is refractory to at least two, at least three, or at least four anti-cancer therapies (including, for example, standard or experimental chemotherapies).
[0076] "Subject" and "subjects" refer to human in need thereof may be an individual who has or is suspected of having a cancer. In some of variations, the human is at risk of developing a cancer (e.g., a human who is genetically or otherwise predisposed to developing a cancer) and who has or has not been diagnosed with the cancer. As used herein, an "at risk" subject is a subject who is at risk of developing cancer (e.g., a hematologic malignancy.). The subject may. or may not have detectable disease, and may or may not have displayed detectable disease prior to the treatment methods described herein. An at risk subject may have one or more so-called risk factors, which are measurable parameters that, correlate with development, of cancer, such as described. -herein, A subject having one or more of these risk factors has: a higher probability of developing cancer than an individual without, these risk factor(s). These risk factors may include, for example, age, sex, race, diet, history of previous disease, presence of precursor disease, genetic ( g-., hereditary) considerations, and environmental exposure, in some embodiments, a human at risk for 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 al so be a risk factor for instances of cancer recurrence
[0077] As used herein, "treatment" or "treating" is an approach for obtaining beneficial or desired results including clinical results. Beneficial or desired clinical results .may include one or more of the following:
(i) inhibiting the disease or condition (e.g. , decreasing one ox 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 (eg., 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 (in) relievmg 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).
(0Θ78) In some variations, "delaying" the development of a disease or condition means to defer, hinder, slow, retard, stabilize, and/or 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 includes occurrence, recurrence, and onset.
[0079]
{0080] Reference to "about" a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se. In certain embodiments, the term "about" includes the indicated amount ± 10%. In other embodiments, the term "about" includes the indicated amount ·± 5%. In certain other embodiments, the term "about" includes the indicated amount ± 1%, Also, to the term "about includes description &P-X , Also* the singular-forms "a" and "the" include plural references unless the context clearly dictates otherwise. Thus, e.g., reference to "the compound" includes a plurality of such compounds and reference to "the assay" includes reference to one or more assays and equivalents thereof known to those skilled in the art.
Antibodies [0081] As used herein, the term "antibody" means an isolated or recombinant 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 mo.ooclon.ai antibodies (including full- length monoclonal antibodies), polyclonal antibodies, human antibodies, humanized antibodies, chimeric antibodies, nanobodies, diabodies, multispecifle antibodies [e.g. , bispeeific antibodies), and antibody fragments including but not limited to Fv, scFv, Fab. Fab' F(ab')2 and Fab?., so long as they exhibit the desired biological activity. The term "human antibody"' refers to antibodies containing sequences of human origin, except, for possible non-human CDR regions, and does not imply that the full structure of an immunoglobulin molecule be present, only that the antibody has minimal immunogenic effect, in. a human {i.e., does not induce the production of antibodies to itself).
{'0082] An "antibody fragment" comprises; a portion of a full-length antibody, for example, the antigen bindi ng 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, Fab1, Fiab'.h, and Fv fragments; diabodies; linear antibodies (Zapata et al (1995) Protein Eng. 8(10): 1057-1062); single-chain antibody molecules; and mulrispeeific antibodies formed from antibody fragments. Papain digestion of antibodies produces two identical antigen-binding fragments, called "Fab" fragments, each with a single antigen-binding site, and a residual "Fc" fragment, a designation reflecting the ability to crystallize readily. Pepsin treatment yields an F(ab')2 fragment that, has two antigen combining sites and is still capable of cross-linking antigen.
i0083| "Fv" is the minimum antibody fragment which contains a complete antigen-recognition and -binding site. This region consists of a dimer of one heavy- and one 'light-chain variable domain in tight, non-covalent association. It is in this configuration that the three complementarity-determining regions (CDRs) of each variable domain interact to define an antigen-binding site on the surface of the VH~VI, dimer. Collectively, the six CDRs confer antigen-binding specificity to the antibody. However, even a single variable domain (or an isolated VH or V't region comprising only three of the six CDRs specific for an antigen) has the ability to recognize and bind antigen, although generally at a lower affinity than does the entire FY fragment.
[0084] The -fragment also contains, in addition to heavy and light chain variable regions, the constant domain of the light chain and the first constant domain (CM)) of the heavy chain. Fab fragments were originally observed following papain digestion of an antibody. Fair fragments differ from Fab fragments; in that F(ab') fragments contain several additional residues at the carboxy terminus of the heavy chain CHj domain, including one or more cysteines from the antibody hinge region. F(ab¾ fragments contain two Fab fragments joined, near the hinge region, by disulfide bonds, and were originally- observed following pepsin digestion of an antibody. Fab' -SH is the designation herein for Fab' fragments in which the cysteine residue(s) of the constant domains bear a free thiol group. Other chemical couplings of antibody fragments are also known.
(0085] The "light chains" of antibodies (immunoglobulins) from any vertebrate species can he assigned to one of two 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, IgE, IgG, and IgM, and several of these may be further divided into subclasses (isotypes), e.g., igG L IgG2, lgG3, lgG4, IgAF and !gA2.
[0086] "Single-chain Fv" or "sFv" or "scFv" antibody fragments comprise the VH and Vi. domains of antibody, wherein these domains are present a single polypeptide chain. In some embodiments, the Fv polypeptide further comprises a polypeptide linker between the \¾ and ¼. 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 (Rosenborg and Moore eds.) Springer-Vedag, New York, pp. 269-31 5 (1994).
[0087] The term "diabodies" refers to small antibody fragments with two antigen-binding sites, which fragments comprise a heavy-chain variable domain (V'H) connected to a light-chain variable domain (Vj.) in the same polypeptide chain (Vs.;- Vg. 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 antige -binding sites. Diabodies are additionally described, for example, in EP 404,097; WO 93/1 .1 161 and HolHnger et aL ( 1993) Proc. Natl. Acad. Sci. USA 90:6444-6448.
[0088] An "isolated" antibody is one that, has been identified and separated and/or recovered from a component of its natural environment. Components of its natural environment may include enzymes, hormones, and other proteinaceous or nonproteinaceous solutes. In some embodiments, an isolated antibody is purified (1) to greater than 95% by weight of antibody as determined by the Lowry method, for example, more than 99% by weight. (2) to a degree sufficient to obtain at least 15 residues of -terminal or internal amino, acid. sequence, e.g., by use of a spinning, cup sequenator, or (3) to homogeneity by gel electrophoresis (e.g,} SDS-PAGE) under reducing or nonreducing- conditions, with detection by Coomassie bine or silver stain. The term "isolated antibody" includes an antibody in situ within recombinant cells, since at least one component of the antibody's natural environment will not be present. In certain embodiments, isolated antibody is prepared by at least one purification step.
[0089] As used herein, "immunoreactive" refers 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 or antigen binding fragment thereof. An epitope can be a linear peptide sequence (i.e., ''continuous") or can be composed of noncontiguous amino acid sequences (i.e., "conformational" or "discontinuous"). The term "preferentially binds" means that the binding agent binds to the binding site with greater affinity than it 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 J. Biol. Chem. 252:6609- 6616 (1977); Kabat et al., U.S. Dept. of Heal to and Human Services, "Sequences of proteins of immunological interest" (1 91 ): by Chothia et al.s I Mol. Biol. 196:901-917 (1987); and MacCalksni et aL, J. Mol. Bio!. 262:732-745 (1996), where the definitions include overlapping or subsets of ammo 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 def ned by each of the above cited references are set forth below in Table 1 as a comparison.
[0091] fable \ : CDR Definitions
Kabat1' a his1 Mee allufflf5
3I--35 26-32 30-35
VH CD 2 50-65 5345 7-SS
V ; CDRS 95-102 96-101 93- 101
V, CDR I 24-34 26 -32 30-36 , CDR2 50-56 50-52 46-55
VL. CDR3 89-97 91-96 89-96
'Residue nBtnbering follows ihe nomenclature of Kabat ct ai., supra
''Residue numberin follows the nomenclature of Chothia et si., supra :' Residue numbering follows the nomenclature of MacCaiium et si,, supra [0092] As used herein, the term "framework" when used its 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.
[0093] "Homology" or "identity" or "similarity" as used herein in the context of nucleic acids and polypeptides refers to the relationship between two polypeptides or two nucleic acid molecules based on an alignment of the ammo 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 same, or a similar amino acid residue (e.g., similar in sterie and/or electronic nature), then the molecules can be referred io 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/sitnilariiy.
10094] As used herein, "identity" means th percentage of identical nucleotide or ami no 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 & designated region, e.g., a region al least about 20. 25, 30, 35, 40, 45, 50, 5, 0, 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 usi 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.
|009S] Examples of algorithms that are suitable for determining percent sequence identity are the BLAST and BLAST 2,0 algorithms, which are described in AJ.ts.chui et al. (1 90) I Mol. Biol. 215: 403-410 and Altschiil et a . (1977) Nucleic. Acids Res. 25: 3389-3402, respectively. Software for perfo ming BLAST -analyses is publicly available through the National Center for
Biotechnology Information (www;nebi.nlm.nih,gov). Further exemplary algorithms include ChistalW (Biggins D., et al (1994) Nucleic Acids Res 22: 4673 -4680), avail a ble a t www.ebt . ac ,uk/Tool s/clus tai w/index.html ,
[0096] Residue positions which are not identical can differ by conservative amino acid substitutions. Conservative amino add substitutions refer to the interchangeability of residues having similar side chains. For example, a group of amino acids having aliphatic side chains is gl cine, alanine, valine, leucine, and iso!eucine; a group of amino acids having aliphatic-hydroxy! side chains is serine and threonine; a group of amino acids having amide-containing side chains is asparagine and glutamine; a group of amino acids having aromatic side chains is phenylalanine, tyrosine, and tryptophan; a group of amino acids having basic side chains is lysine, arginine, and histidine; and a group of amino acids having sulfur- containing side chains is cysteine and methionine.
Compounds
[0097] 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 (TUPAC),
[0098} Also provided herein are isotopicaiiy labeled forms of compounds detailed herein. Isotopicaiiy 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 thai 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 :JH (deuterium, D), ¾ (tritium), nC, ¾, 54C, 15N, l P, ¾P, y "CI and 1 Various isotopicaiiy labeled compounds of the present disclosure, for example those into which radioactive isotopes such as 'Ή, "C and , C are incorporated, are provided. Such isotopicaiiy. labeled compounds may he useful in metabolic studies, reaction kinetic studies, detection or imaging techniques, such as positron emission tomography i PET) or single-photon emission computed, tomography (SPEC!) including drug or substrate tissue distribution assays or in radioactive treatment of subjects (e.g. humans). Also provided for isotopicaiiy labeled compounds described herein are any pharmaceutically acceptable salts, or hydrates, as the case may be. [0099] 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 di 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 ait, for example by employing starting materials in which one or more hydrogens have been replaced by deuterium.
[60100} Deuterium labeled or substituted therapeutic compounds of the disclosure may have improved DMP (drug metabolism and pharmacokinetics) properties, .relating to absorption, distribution, metabolism and excretion
(ADME). Substitution with heavier isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life, reduced dosage requirements and/or an improvement in therapeutic index. An ¾*F labeled compound may be useful for 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,
100101} The concentration .of such a hea vier isotope, specifically deuterium, may¬ be defined by an isoiopic enrichment factor. In the compounds of this disclosure any atom not specifically designated as a particular isotope is meant so 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. ΒΊ Κ inhibitor
[09102) in some variations, the BTK inhibitor is Compound AL or a pharmaceutically acceptable salt or hydrate thereof. Compound Al has structure:
Figure imgf000030_0001
(00103) in some variations, the BTK inhibitor is a hydrochloride salt of Compound Al , or a hydrate thereof. Compound. A 1 may e synthesized according to the methods described in U.S. Patent No. 8,557,803 (Yamamoto et al) and US 2014/0330015. Compound Al ma be referred to as (R)-6-araino-9- (l-(1wi-2->m i)pym)lidm-3-yl)-7-(4^henoxyphenyl)-7H-purin-8(9H)-oxie or 6- amino-9-[(3Rj-!-(2"butyno>l)-3-py^
811 -purin-8-one. Additional BTK inhibitors include, but are not limited to. (S
Figure imgf000030_0002
8(9B one ibrutinib (l~[(3R)";>-[4"Ainino-3~(4"phenoxyphenyl)~lH- pyrazoio[ 3 ,4 djpyrij.r.udin - 1 -yijpiperidin- 1 -yl]prop-2-e ·· 1 -one), acala brutinib, HM71224, CNX-774, RN486, ONO-4059, and CC-292 (speburtinib).
JAK Inhibitor
[00104] In .some variations, the JAK inhibitor is Compound B 1 ;! Compound .82, Compound B3, or Compound B4, or a pharmaceutically acceptable salt thereof. Compound Bl, which may be referred to as momeioiinib. CYTj 137, CYT387, or N- cyanometh l)-4 ~[j -(4»moφholmyi) he yl] mmo]-4- pyrimidinyl]»benzamide or N-(cyanomethyl)-4-(2-((4"morphoiinophenyi) amino)pyrimidin-4-yl)benzainide5 has the structure:
Figure imgf000031_0001
[Θ 105] Compound B2, which may be referred to as filgotinib, GLPG0634,
(jl46034, N-{5-(4-((l ,l-dk)xidothiomorpholino.)methyl)phenyi.)-
[1 ,2,4]triazoto[ 1 ,5-aJpyridin-2-yl)cyclopropanecarboxamide, N-{5-[4-[(l,l- dioxo-1 ,4~thiazman-4-yi)methyl]phenyl]-[ 1 ,2,4]triazo3o[l,5-a)pyridin-2- yl ]cyci opropanecarboxamide, or N~ 15 ·■ [ 4-[ (1,1 -dioxido -4- tin omorphol iny! )
Figure imgf000031_0002
has die structure:
Figure imgf000031_0003
iB2)
[001061 Compound B3, which has the Chemical Abstracts registry number 1334298-90-6, may be referred to as l-[ 1 -[ 3-lluoro«2-{irjfluoromethyi)-4- pyri.dmyi]carbony!] -^
pyrazoi-l-ylj- 3-azetidineacet.onitrile and has the structure:
Figure imgf000031_0004
[00107] Compound B4, which may be referred to as tofacitinib,
Figure imgf000032_0001
piperidmepropanemtriie or 3-((3R,4R)-4-nisthyI-3-(methyl(7H-pynOio{2>3- d]pyriroidin-4-yl)ammo)pi eridin-i -yl)-3 -ox opropanenitrile has the structure:
Figure imgf000032_0002
[00108] Compound B5, which, may be referred to as oclacitinib or N-methyl-1- iilr,4r)-4-i0iethyl(7H-p rro{o[2,3"d]pyrimidin-4- yi)amino)cyc!ohexy])methaneaidfonainids!, has the structure:
Figure imgf000032_0003
[00109} Compound Bo, which may be referred to as ruxolotinib (INC. '42.4, INCB 18424, JAKAFI®, JAKAVI®, a vailable from feeyte Pharmaceuticals and Novartis) or (3R.)-3-Cyc]opentyl-3-[4-(7H-p3aToio(23~d]pyrimidin-4-yi)-iH- pyrazol-i•yljpropanenitrile has the structure:
Figure imgf000032_0004
[00110] Compound B7, which may be referred to as barackinib (LY300 104,
Figure imgf000032_0005
.l-yl]azetidiii-3»yl]acetomtriie or 2-(3-(4-(7H-pyrroio[2 -d]pyriraidin-4-yl)-lH- pyr zol~ 1 -yl )- 1 -(ethyl sul fonyl }azetidin-3 -yi )aceton itrik, ha s the structure :
Figure imgf000033_0001
[ΘΘΠ1] CoTnpound B8, which may be referred to as lestaurtinib (C.EP-703, .T5555, and A 154475.0)■· 2,3,9,10,1 l,i2-hexah dro-10~hydroxy-10- (hydroxymethyl)-9-nie l-, (9SJ0S.12RV 9,12-Epoxy-l H-diindoio[ l,253-fg;3', 2',1 '-kljpyrroloj 3,4-i] [ 1 ,6]ben2odiazocm-l -one, has the structure:
Figure imgf000033_0002
[001121 Compound B9, which may be referred to as paeritm b (SB 1518} or (16E)-n-[2-{i-Pyrrolidinyl)ethoxy]-14,19-ilioxa-5)7>26- tnazatetracyci f .19.3.1.12,6.18,12]heptacosa- 1(25),2(26),3 ,5,8,10,12(27) J 6,21,23-decaene, has the structure:
Figure imgf000033_0003
[00133? Compound B10, which may be referred to as TG101348, SA.R302503,
.¥-ter ¾styl"3"{5-meihyi-2~[4~(2--pym lidi
pyriro idin-4-ylamino } -beiizenesulf namide, or N-(tert~butyl)-3~((5-metliyl-2-{'(4-
(2~(pwolidin-l'yl)ethoxy)pbenyl)aramo)pyrimidin-4- yi)aniiBo)berszcnesulfonamides has the struciure:
Figure imgf000034_0001
[00114] Compound Bi 1 , which may be referred to as JSl-124, Ciicurbitracin, Elalericin B, NSC-521777,. < 8S,9S ,10R J3RJ 4R ,16RS 17R> 17-((R,E)~2,6~ dihydro.xy-6~methyl-3K>xohept-4-en-2-y])~2, .16-d!hydroxy--4,4,8,9, 13, 14- hexamethyi-7,8,9,10, 12J 3J4J 5J6J 7-deca ydro-3.H- cyelopenta[a]phenanthrene~3,l l(4H)-dione or 2 i6a,2i),25 -i.eirahydroxy-9- methyl- i ··Νοί··9β, 1 Ga~ianosra- 1 ,5 ,23 -triene-3 , 1 1.22-trione, has the structure:
Figure imgf000034_0002
[00115] Addiiional J AK inhibitor compounds that may be used, in the combinations, methods, kits, and articles of manufacture herein include
GSK2586184, VX-509, TNCB 16562, XL019, VP-BS 805, CEP33779, R-348, AC-430, CDP-R723 or BMS 911543, NVP-BSK805, CEP33779, as well as those disclosed io U.S. Pat. No. 7,879,844, and the JAK inhibitor cyclo&xtrin-based polymer conjugates described in U.S. 2014-0357557.
Figure imgf000035_0001
In some embodiments, Compound B1 , or a pharmaceutically aeceplab! salt thereof, is used in combination with Compound A 1, or a pharmaceutically acceptable salt or hydrate thereof, m other embodiments, Compound B2, 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 B3, 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 B4, or a pharmaceutically acceptable salt thereof, is used in combination with Compound Al, or a plmmiaceutieally acceptable salt or hydrate thereof. In yet other embodiments, Compound B5, or a phamiaceutically acceptable salt thereof, is used in combination with Compound Al , or a pharmaceutically acceptable salt or hydrate thereof. In still another embodiment, Compound B6. or a pharmaceutically acceptable salt thereof, is used in combination with Compound A3, or a pharmaceutically acceptable salt or hydrate thereof, hi another embodiment, Compound B7, 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 .88, 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 B9, 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 BIO, or a pharmaceutically acceptable salt thereof, is used in combination with Compound Al. or a pharmaceutically acceptable salt or hydrate thereof. In other embodiments. Compound Bl 1, or a pharmaceutically acceptable salt thereof, is used in combination with Compound Al , or a pharmaceutically acceptable salt or hydrate •thereof.
(00117) Reference herein to "Compounds Bl -dBl l", "Bl Bl Γ, or "Bl through Bl Γ is understood to include the Ml group of Bl, B2 B3, B4, B5, B6, B7, B8, B9, BIO, and Bl i. Compoumds Bi- Bl ! 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, iilgotinib may be prepared by the methods seen in U.S. Patent No. 8,853,240 and US 2015/0225398 Al , INCB-0391 10 (INCB-39110) may be prepared by the methods 30 seen in US 201 1/112662 and US 2015/1246046, pefkitmib may be prepared as described in U.S. Patent Nos, 7,879,844 and 8.779,140, and momeiotinib may be prepared as described in U.S. Patent No. 8.486,941,
[00118] In one embodiment, the JA inhibitor is selected from the group of momeiotinib (CYT0387), ruxolitimb, fedratmib, baricitinih, lestaurtinib, pacritraib, XL019, AZD1480, LY27845 4, BMS911543, and NS01.8, or a pharmaceutically acceptable salt thereof. In one embodiment, the JAK inhibitor is selected from the group ofTG10l348, JS-12 , and INCB39110, CHZ868, and GS 2586I84, or a pharmaceutically acceptable salt thereof. In another variation, the JAK inhibitor is momeiotinib, or a pharmaceutically acceptable hydrochloride salt thereof. In another variation, the JAK inhibitor is fttgotinib, or a
pharmaceutically acceptable salt, thereof,
AS l Inhibitors
(00119] In some variations, the ASKl inhibiting compound is a compound of Formul Ϊ:
Figure imgf000037_0001
Wherein:
R is selected from aikyl of 1 -10 carbon atoms, alkenyl of 2-10 carbon atoms, a!kynyl of 2.-10 carbon, atoms, cycloalkyl of 3-8 carbon atoms, aryl, heteroaryl, or heterocyclyl, all of which are optionally substituted with 1 , 2, or 3 substituents selected from halo, oxo, aikyl, cycloalkyl, heterocyclyl, aryl, aryloxy, ·· NO?, R6, -CfO)R6, -OC(0)-R*, -OC(Q 0-R6 5 A (0}--N(R6i(R ). ~$-R.\ -$f 0)-RE, -S{=--0)2-R6, -S( ¾~ (Rd)(R?), -S(-0)2-0-R6, -N(R6)(R7), -Ni.R6)-C(0)-R7, - N{RVX0)-0-R7,•• (Ri C(-0}N(Rii){R7), -N{R6)-S{-0)2-R6, CN, and -OR.6; wherein aikyl, cycloalkyl, heterocyclyl, phenyl, and phsnoxy are optionally substituted by 1 , 2, or 3 substituents selected .from aikyl, cycloalkyl alkoxy, hydroxyl, and halo; wherein R° and R " are independently selected from the group consisting of hydrogen, O-Cis alkyl, cycloalkyl, heterocyelyl, aryi, and heteroar l, all of which are optionally substituted with 1-3 substituents selected from halo, alkyl, mono- or diaikylamino, alkyl or aiy! or heteroaryl amide, -CN, lower alkoxy, -CF3, aryl, and heteroaryl; or
R" and R' when taken, together with the nitrogen to which they are attached form a heterocycle;
R' is hydrogen, halo, cyano, alkoxy, or alkyl optionally substituted by halo; * is a ryl, heteroaryl, or heterocyelyl, all of which are optionally substituted with one or more substituents selected from alkyl. of 1-6 carbon atoms, alkoxy of 1 -6 carbon atoms, cycloalkyl of 3-8 carbon atoms, cycloalkylalkyi, aryl, aryl alkyl, heteroaryl,. heteroarylalkyl, heteroeyciyl, he erocyclylalkyl, halo, oxo, - N02, haloalkyl, haloalkoxy, -CN, -O-R* -OC(0)-R(i, -OC(OK)~R -C(Q)- N(R6)(R7), -S-R6, ~N(Rft)(R7), . -S(Oj-Rf', -S(=0)2~R*, -S(-0)2-N(R6)(R7)5 -S(-O)- O-R6, -N(R6)-C(0)-R7 s - (R6)-C(:0)N(R6)(R7), -N(R6K¾0)-O-R7, -N{R6)- C«))N(R6)(R?), -C(0)R6, -C(0 0~R6, -C(())^(R'5)(R7), and •• (Ri)-S(-0)2-R7 ; wherein the alkyl, alkoxy, cycloalkyl, aryi, heteroaryl, or heterocyelyl is further optionally substituted with one or more substituents selected from halo, oxo, ~N(¾, alkyl, haloalkyl, haloalkoxy, -N(R6)(R?), -C(0)R6, -OC(0)-R6, -C(0)-N(R6}(R7}, ·· CN, -OR0, cycloalkyl, aryl, heteroaryl, and heterocyelyl;
with the proviso that the heteroaryl or heterocyelyl moiety includes at least one nng nitrogen atom; X!, X2, X3, X\ X5, X6, X7, and Xs are independently C(R4) or N in which each R* is independently hydrogen, hydroxyl, halo, alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, or cycloalkyl of 3-8 carbon atoms, aryl, heteroaryl, heterocyelyl, halo, -NO2, haloalkyl, haloalkoxy, -CN, -OK", -S- R\ .N(R6XR7), ■■' (;■■{ ¾ -( ! -R&, -S(=0> N(Re)(.R7), -Sl-Qf-O-R6, -N(Rfc}- C(0)-Rs, ■ i i )..(■(( ) hi ) -N(R6)-( -0)N(R¾(R7), -C(0)-R6, -C(0)-0-R6,■■ C(0)- (R-)CR7), - (R-)-S^O)rRv, wherein the alkyl, cycloalkyl, aryl, heteroaryl, and heterocyelyl is further optionally substituted with one or more substituents selected from halo, oxo, -N<¾, -CF¾ -0-0% -N(Ri;)iR7}, ~C{0}-R6, -C(0 -0»R?, - C(0)- (R6)(R7), -CN, -CO-R6; or X5 and X" or X" and X' are joined to provide optionally substituted fused aryl or optionally substituted fused heteroaryi; and with the proviso thai at least one of ", X'\ and * is C(l 4}; at least two of X'\ X°, X', and X¾ are is C(R*); and at least one of X*' X\ X4, X'\ Xa, X", and Xh is ; or a pharmaceutically acceptable salt or hydrate thereof.
[00120] An embodiment within each of the methods herein in which a compound of Formula .1 is used comprises use of a compound of Formula h as described above, or a pharmaceutically acceptable salt or hydrate thereof wherein R" is selected from the group of:
Figure imgf000039_0001
wherein R1 ' is selected from hydrogen, alkyl of 1-6 carton atoms, or cycloalkyi of 3-8 carbon atoms, wherein alkyl and cycloalky] are optionally substituted by hydroxy! or halo;
R :": is selected from hydrogen., alkyl of 1 -6 carbon atoms, or cycloalkyi of 3-8 carbon atoms, -S(-0)-R6 or , --S(:: >) R6 s wherein the alkyl and cycloalkyi are optionally substituted by bydroxyl or halo.
[0012.1] Another embodiment comprises use in the methods herein of a compound of Formula Ϊ, as described above, or a pharmaceutically acceptable salt or hydrate thereof in which. Χ', X2, and X5 are all N, and X\ X! X6, X\ and X* are C(R4). This embodiment includes compounds in which R! is optionally substituted alkyl of from I to 6 carbon atoms, optionally substituted cycloalkyi 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 bydroxyl, halo, or cycloalkyi of from 3 to 8 carbon atoms. Within the embodiment another embodiment includes compounds in which RJ is optionally substituted ary , optionally substituted heteroaryl, or optionally substituted heterocyclyl, wherein the heteroaryl or heterocyclyl moieties contain, k 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, cycloalky i of from 3 to 8 carbon atom s, halo, cyano, or -Ο.Ρ in which alklyl and cycloalkyi are optionally substituted by hydroxy! or halo. A preferred group of R* moieties includes those non-limiting examples described above.
[00122 j Another embodiment includes use in the methods herein of a compound of Formula ί in which X1 and X5 are . and X% \ X4, X5, X6, X7, and Xs are C(R4). T his group includes compounds in which R ' is optionally substituted alkyl of from 1 to 6 carbon atoms, optionally substituted cycloalky! .of from 3 to 8 carbon atoms, or optionally substituted heterocyclyl, particularly where the optional substituents are 1, 2, or 3 substituents chosen from hydroxy i, halo, or cycloalkyi of from 3 to 8 carbon atoms. Within this group, a subgroup includes compounds in which R '' is optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocyclyl, wherein the heteroaryl or heterocyclyl moieties contain 1 , 2, or 3 ring nitrogen atoms, and the aryl heteroaryl,. and heterocyelyi moieties contain I, 2, or 3 ring nitrogen atoms, and. the aryi heteroaryl, and heterocydyl moieties are optionally substituted by alkyl of from 1 to 6 carbon atoms, cycloalkyi of from 3 to 8 carbon atoms, halo, cyano, or -OR in which alkyl and cycloalkyi are optionally substituted by hydroxy! or halo.
[00123] .Another embodiment provides use in the methods herein of a compound of Formula I in which X! and X2 are N and \ X4, X5, X6, X7, and X8 are C(R4). This group includes compounds in which R1 is optionally substituted alkyl of from 1 to 6 carbon atoms, optionally substituted cycloalkyi of from 3 to 8 carbo atoms, or optionally substituted heterocydyl, particularly where the optional substituents arc 1 , 2, or 3 substimenisehosen from hydroxyi, halo, or cycloalkyi. Within this group, a subgroup: includes: compounds in which 3 is optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocydyl, wherein the heteroaryl or heterocydyl moieties contain 1 , 2, or 3 ring nitrogen atoms, arid the aryl, heteroaryl. and heterocyelyi moieties are optionally substituted by alkyl of from 1 to 6 carbon atoms, cycloalkyi of from 3 to 8 carbon atoms, halo, eyano, or -OR11, in which the alkyl and cycloalkyi are optionally substituted by hydroxyi or halo.
[00124] Another embodiment includes use in the methods herein of a compound of Formula I in which X! is C(R ), This group includes compounds in which R1 is optionally substituted alkyl of from 1 to 6 carbon atoms, optionally substituted cycloalkyi of from 3 to 8 carbon atoms, or optionally substituted heterocydyl, particularly where the optional substituents are chosen from hydroxyi halo, or cycloalkyi of .from 3 to 8 carbon atoms. Within this group, a -subgroup includes compounds in which R' is optionally substituted heteroaryl or optionally substituted -heterocydyl, wherein the heteroaryl or heterocydyl moieties contain 1, 2, or 3 ring nitrogen atoms, and the aryl, heteroaryl, and heterocydyl moieties are optionally substituted by alkyl of from 1 to 6 carbon atoms, cycloalkyi of from 3 to 8 carbon atoms, halo, cyano, or -OR", in which, the alkyl and cycloalkyi groups are optionally substituted by hydroxyi or halo,
( 12S'| The ASKI inhibiting compounds for use in the methods herein include, but are not limited to, those compounds named below, which may be prepared by the methods described in U.S. Patent Nos, 8,552,1 6 arid 8,742,126, which are incorporated herein by reference:
5-(2,5~difluorophenyl ~(3-{4-mctby}-4H-l52,4 riazol-3- y I )pheny 1 )ttieotmarni de;
4~(imidazo[ I ,2-a ]pyridin-3-yi)- -(3-(4-metbyl-4H-152,4-triazo]-3- yl )phen yl )-pi col inara ide ;
4- 2-aminopyrinudin~5~yl)-^^
yj)phenyl)picolinamide;
N-(3-(4-raeihyl-4H-l)2s4-iria2:oi-3-yl)phei)yl)-5"pheflylnic tinaim
N-(3~(4-cyclopropyl-4H-l,2,4-iaia¾ol-3-yl)phenyl)-4-phenylpi∞{i«aroide;
N 4- teirahy r -2ft- r^^^^
bipyridine 2'-carbo amide;
2-hydrGxy»N H4»m€ MH»ls2,4 riaml-3-yl)pheny])-6~
pheny'Spyrimidine-4-carboxamide;
N~(3-(4-cydopropyi-4H ^4-triazok^^^
carboxamid ;
N-(3-i4-eyciopiOpyl-4H- 1,2,4-^
>'l)picolinamide;
Figure imgf000042_0001
N-(3 4-(3-'amin --oxopfopyl)-4>Ld,2s4-triazol-3-yl)phei)yl)--3,4'" bipyridine-carboxamide;
N-(3 "(4-cyclopropyl"4H" 152,4-triazol-3 - yl )phenyl) -4 -( 1 H - 1 ,2,4-triazol - 1 - yl)picolinamide;
-(3 4~ eth MH-i ^
N~(3 4-(2-acetamidoethy^^
carboxamide;
N"{3-(4"methyh4H- 1 ,2,4-tri8∞l-3-y!)phen(yl)-4~(4-raeth lpjpera¾n- 1 ·- yl)picolinamide;
N-(3-(4~methyl-4H-l,2,4-triazo1-3-yi)phenyl)-2, 1 -bipyridind-6- carboxaraide;
N-(3-(4-methyl- H4,2,4 ria:zol"3-y^ "N~(3-(4-metbyl» H» 1 ,2,4-tri a¾ol -3-yl)phenyl 6^'quino{m - yi!pic linamide;
(R)~N-( 4-iI iy<irox> ro an^^
bi pyridin - 2 * -carbox amid ;
N-(3-(4-cyclopropyl-4H-l,2,4 n3zol~:^yJ.)pbenyl)^)~hydroxy-3,4>- bipyridine-2'-carboxamjde;
N-(3-i4-raethyi H-l ,2>4-triazoI-3-yl)pheny1>3,3,-bip>Tidme-5- carboxamide:
(S)-N-(3-(4~(1 iydroxypropan-2^
bipyridine-2'-carboxamide;
N-(3-(4-methyl-4H-l,24 ria∞i-3~yl)pb.enyl)-4-(3-oxopiperazin~i- y])picolmamide;
-B-(4-methyl-4H -2,4-triazol»3-yl)phenyl)-3,4'-bipyri
earboxamide;
N~(3 -(4-cycl opropyi-4H- 1 ,2 ,4 -tri az I-3 «yi)ph enyl) -6-me(lioxy-3 ,4'- bipyndme-2'-earboxamide;
4- (3-ammopyrrolidm- 1 -yl)-N-(3-(4~mei;hy1-4H-l .2,4-triazo3~3- y 1 )pl leny l)picoli n ami d ;
NK '^-medr W
6-ainino-N-(3-(4-cyclopropyMH-l ,2,4-{riazol-3-yl)phe^
bipyridin.e~2'-carboxamide;
(R N-{3 ~(4~(2-hydroxypropyl)-4H-l ,2,4-triazol · -3-yl)pheny1 3,4'- bipyridine-2'-carboxamide;
5- rn hoxy-lN-{3-(4~raeihy1~4H^
2 -carbox amide;
methyl 2'-(3- 4-eye!apix>pyl-4H-l,2^
bipyridm-6-ykarbamate;
5 -meihoxy -N -{ -{4-meihyj -4 H- 1 ,2 ,4-tri azol -3 -yl)phenyl)-3i4,-bipyridine" ^'-earboxamide;
methyl 2 ' -(3 -(4-cyclopropyI-4H- 1 ,2,4-triazoi -3 -yl)phenylearbamoyl)»3,4' ·· bipyridin-6-yl carbamate; bipyridi.ne-2 ' -carboxamide;
4■( ί -methyl -1 H-imi dazol -5-y! N -(3 -(4-meth l-4H-l ,2,4-triazo!-3 - yl)phenyl)pieolinamide;
N-(3»(4»cycJopropyl-4H- ,4-txiaz«j^-yl)phenyl 4-(l-methyl«lH■· imidazol-5-yl)picolinaraide;
4-(iH-benzo[d]imid¾oi-l-A^^
y!)phenyi)piooUnaniid.e;
N-(3-(4-cycl propyl-4H-l,2,4-ti-!azol--3-yl)phejiyj)-4-(2,4- <¾methoxypyrimidiN-5-y])picolmamide;
Ν··(3-ί4··( 14>ydroxycyclopt^
3,4'- bipy ridme - 2 · - carbo am id .
N-(3»(4»cyclopropyl - H- 1 ,2,4-triazol-3-yI)phenyj H-('4-phenyl-ffi- imidazole 1 -yl)pkolinamide;
0-cydopropyl- ~(3-(4-cyclopropy^
bipyridi.ne-2 '-carboxamid ;
(S)-N-(3-(4~ -hydiOxypropyi)-4H-l,254 ria?>]-3-yl}phen>)-3,4'-- bipyridiiie-"2,"Carb xamids;
N 3 4--cycl biityl-4H-],2!4-tria l-3-yl)phenyl)-3,4,-bipyri«ime-2,» carboxamide;
2M3-(4-cydopropyl-4H~¼4-tria^^
di carboxamide;
Figure imgf000044_0001
bipyri dine -2 f -earboxa mi de ;
'N~(3-(4-eyclopeotyMH-i,^
carboxamide;
N»i3"{4-cydopropyi-4H~152,4 ria^
3,4'-bipyridine-2'-carboxa ide;
Figure imgf000044_0002
dicarboxamide;
Figure imgf000044_0003
invi dazol - 1 -yl )pi colin ami de ;
Figure imgf000045_0001
bipyridine-2' -Carboxaraide;
5-cyano-N-f 3 -(4~eyclopropyI-4H- 1 -tiiazol-3-yl)phejt)yl)-3 ,4 ' - bipyridine-2 ! -carboxamide;
N 3-(4-cydopropyl-4H-l,2,4-iriazoi-3-yl)phenyl) -(4-raeihyi-lil - iraidazol- 1 -yl)picolinamide;
N·< -ί4-c c3o Γo l H-l,2,4-triazol- - l yridil 2- {)- >4, ip τidine-2,- carboxamide;
2~ammo- "(3-{ clop φyl H-L2,4 ria¾')l-3- 1)pheny])- ,4!'- bipyri dine -2 ' -carboxamide ;
N-(3-(4-cyclopropyl-4H-1.2,4 riazol-3-yl)pb8nyl)4-(4,5-dimethyl4H iniidazol-'l-yljpjcoiinamide;
Κ-ί3 {(1 S.,2S)4-me%lcyciopropyl) H-1 4-ttiazoi »yi)pknyi) (4)- b ipyri di«e-2 ' -carbox amide ;
N-(3-(4"Cydopropyi4H-1^4-iria2»l-3-yi)pheny1)-2-meAoxy-3,4'- bipyridine-2'-earboxaraide;
N-i3-(4-cyciopropyl4H-lJ2,4-triazol-^- l)phen>)4- 4-(triiluoromethyl)- 1H -imidfizol-i -yl)picoli.oamide;
N-(3-(4-cyclopix>pyMH-l}2,4 ri^^
)-θ,4' -bipyridiiie-2'-caTboxamide;
N-(3-i4-cycIopropyl4H- 1 ;2,4 riazol-3-yi)phenyl)4-(1 -methyl- 1H - pyra zo! -4~yl )pi cdiinanii de;
-(3•(4-cyelopropyl-4H-l s2 -t^'¾oi-3-yl)pheiiyl)-4~(2-meilioxypyrimidiii~ 5-yl)picol.mamide;
N~( -i4-c :o ro yl H4,2 ^^
bipyridice-l-' -Carboxamide;
'N-(3-(4~cyclopropyl~4H„ l,2!4-triazol-3-yl)phenyl)4-(imidazo[ 1 ,2» a]pyridin-3-yl)picolinamide;
ethy]-N-(3-i4-methyl4M4,24"iri^^^
carboxamide;
N- 3 4-(252!2 rifluoroethyl)-4H4,24 riazol--3-yi)pheByl}-3,4'- bipyri.dine-J.'-carboxamide;
Figure imgf000046_0001
"jiei:pyndme-2"-carboxylic acid[3-(4 -cyciopropyi- 4} l-[ l,2?4jiriazoi-3-ylS-phenyl]amide bipyridiiie-2 ! -Carboxamide:
N^3-(4-cyclopro yl-4H-l 52,4- azol-3-yl) henyl)-5-(triflιlorometh l)-3.ϊ , -bipyridiRie-2'-carboxami(le;
N-(3-(l-cydopropyi H raida2»l-5-yi)phenyi)-3,4<-btpyridine-2'- carboxamide;
N. 3..(4H:yClopropyl-4H-L2,4-triazoi~3-y1)phenyl) -(l)2-dimethyl-lH- traidazo3-5-y{)pic.olinainide;
4-flH -benzo[ d] [1 ,2!3]tria∞l-yl)-N 3,(4-cyclopTOpyl !:i-.l)2,4-triazol-3- yi)phenyi) picoiinarnide;
N-{3^4-cydoprQpyi-4H }.2,4 Tia^l-3-yl)phenyl) "(4-suifan^ iplieny I )pico3inamide;
5 N-(3-(4-cydopropyl -4H- .1 ,2,4-triazol -3 ~yl)phenyl)-5-metb.oxy-3 ,4 ' - bipyridine-2 * -carboxam ide ;
N"i3"(4-cyclopropyl-4H-i ,2s4-iriazoi-3 )phejiyl)-6-fluoro-5-metliyl-3,4'- bi pyi'i di ne-2 * -caiboxamide ;
N-(3-(4--cydopropy1-4H-l,2:,4-irjaz;ol-3-yl)phenyl)»5-41uoro-3>4'- bipyri dine - 25 - carboxam ide;
Figure imgf000046_0002
bipyridine-2 '-Carboxamide;
N-i3-(4~cydopropyl"4H-i,2,4-tri^
IH -bertzo[ d)imidazol -yl)picoHnamide:;
N-0~(4"Cydopropyl-4H-l.^,4-ida?.ol-3-yi)ph8nyl)- -(4- (Nraetliylsulfa«ioyl)phenyl) picoiinarnide;
5-tert-buiyj-N2-,-(3(4-cydopropyWH-l>2^^
bipyridine-2 ',5 -dicarboxamide;
N-(3 y4-eydoprapyl H4,2.44ria^
ylipicoimamide;
43 4"Cyciopropyi-4H4.s24 nazol~3-y1)phenyl)-4-{4-'
(Nisopropyl sulf ainoyl) pbenyl)picolinamide;
Figure imgf000047_0001
2*-earboxamide;
4-(lH~benzo[ d]imidazol-l-yl)-N-(3-(l -cyclopropyH -imidas:ol-5- ])phenyl)picolinamidc;
6-cyclopropyRH6-(4-cyelopro^^
,4' -bipyri dine-2 ' - carbox am ί de ;
i -(3-(4-cyclopropyl-4H-l,2,4-triazol-3-yl)phenyl)-4-(3"
(methylsulfonyi)phenyi)picolinamide;
N-(3'-(4-cyciopropyl-4H» 1 >2«4 riazol-3-yl)pbeny] )-4-(.tsoqumolm-4- yi)picolinamide;
N»(6 4 clopropyl-4H-.1.2>4 riazol -3»yl)pyTidin-2-yl)-4-(4- {m thy{salfonyl)phenyl)picolinamide;
-(3-(4 *yciopropyl-4H~ 1
Figure imgf000047_0002
( methyi.su I fonyl jphenyl )pi coTinam i de ;
N~{:M4^yc!opro y ■· pyrazoi-4-yl}picolinamide;
6-cyclobutyl-N-(3-(4-cyclopropyl-4H-l,2,4 riazol-3-yl)pbenyl)-3}4!- bipyridine-S'-carboxamidc;
N-(3-(4"Cyclopropyl-4H-i>2,4-triazol-3>yl)phenyJ)-6-isopropyi-3,4' · bipyri dine -2 ' -carboxarnide;
N-(3-(4«cyc1opropyl-5H- 1 ,2s4-triazol-3-yl)phenyl)-4-(4- (TnethylsoIfonyl)phenyl)picolinamide;
N-(3-(4-cyclopropyl-4K-l !2,4-tiiazo].-3-yl)phenyl)-6-(dime
bipyri dine -2 ! -carboxarnide;
N~(3-(4^y io.propyi H ,254-triazol-3-y1)phenyl)-4-(pyridm"3- yi)qtiinoline-i2-carboxaiaide;
N-(3-i4-cyelopropyl-4^
b]pyridii>5~yi)picolmafflide;
6"Cyciopropoxy-N-(3-(4-cyclopropyl-4H-l,2,4-triazo3--3-yl)phenyl)-3,4?- bipyridine-2 ' -carboxarnide;
43^4 ,ycl propyHH4,2,4-triazoi-3-yl)phenyI) -(lH-M
bjpyridi«4-yl)picoiinamide;
Figure imgf000048_0001
bipyridine-2'-carboxamide;
N^^-cyclo ro l^H-i^^-tiiazol-S-y phenyl)^'^^?^
oxoimidazolidin-l-yl)phenyl)pico!inamide;
N-{3-(4-cydopropyi H ,2,4-^ 5-1 )]pyridm-3-yl)picoiinamide;
N'(3 4"Cydopropyl-4H-i)2,4-triazol-3-yl)phenyj)-6-isopropt)xy-3,4'- bipyri dine-2 ' - carboxam ide ;
N-(3 -(4-cydopropyl-4H- 1 ,2,4-triazoi-3 -yl)phenyl)■ 6 -eth yl- , '■ bipyridine■ 2'-carboxamide
N-'f3-(4~cyciopropyl H !2,4 ria»^^-y!)phenyii -<iH- mida204!5" cjpyri-din- 1 »yl)picoimamidei
6 ydobatoxy-N-(3-(4^ydGpropyl»4H-lf2,4 ria∞l»3»yi)pbeiiy])-3,4i- bipyridme~2'~earboxaixude;
6-cydopropyl~ -{3-(l-cydopropyl-lH -imidazol-5-yl)pheny{)-3,4'- bipyridine-2 ' -carboxaraide
N-(3-(4-cydopropy!-4H-l,2s4-iriazol-3-yl)phe»yl.)-4-( quinolio-3- yl)picolmamide;
N-(3-(4-cyclopropyl-4H-l,2>4-ttiazol~3-yl)phefiy])-4-(4- (Ncydopropylsiilfamoyl)
pheny pico!inamide;
N-(3-(1^ydopropyl H-iinidazol-5-yr)phenyr)-4-{quinol!n-3-- yl)picoimamide;
6-ey'clopentyl-N~(3-(4-eydo
bipyrldme~2 * -carb xamid ;
N-<3-(4~e o r^ MH-!^ 1-bj [1
J54]tliiadiazol--5~yi)picoimaraide;
'N~(3-(4-cyciopropyl-4H-i,2,4-irja2:ol-3-yl.)phenyl)»4-(5- cydopropylpyrazk"2"yl)pico1inamide;
-( -ί4~ονο1ο Γο χ1· Η4,2;4 π8ζο1· ··ν1) 1ι¾ην1)^^(1^ε{1 -2- oxopytrolidin~3"yi)-3,4,-bipyridine-2'-Carb xainjde; 4-{4 -chloro■ 1 H -tmidazol- 1 -yl)-N-(3 -(4-Gyclopr pyl-4H~l s2;4 n&2ol-3- yl)phenyl)picol«iamide;
6- :ycJopropyl"N'-(3"(4"Cyclopropyi"4I'i ,2!4 ri
3 ,4 ' -bipyridine-2 ' -carboxamide;
(S)-4-{4-c clopropyl4H½iidazol4^
1 ,2,4-ίπ&»)1-3-ν1 )phenyl)picoimamide;
6-cyclopropyl-N-(3 -(4-cycl opropyj -4H- 1 ,2 ,4 -iriazol-3 -yl )phenyi )-2,31■■ bipy ridine-6-carboxam ide ;
6-cyoJop.ropyj- -(3■■( 4-■7 lopropyl-4H-l52,4-triaz i-3-yl)phenyl)~2i 1" bipyridiiie-4-carboxamide;
N-(6-(4-t ck^ropyl-4H~lJ2!4-iria'-tol-3-yl)pyridin»2-yl)-5»(6- cyc]opropy{pyridj!i-3-yl)»2,4-difluofobenzamide;
6»eyclopropyl-N-(i544-cyc{opropy] H-l,2,4 riazol-3"yl)pyri !)· 2,31 "btpyridjne-4-carboxani ide;
6-cyelopropyl4\40^4-cycl pro^^
3, 1 -bipyrid e-5-earboxamid ;
6-cyciopropyl- -{6-(4-cyc iopropyi-4H4 ,2 ,44nazol4~yi)pyridiri-2~y 1 )- 2, 1 -bipyridine4>-carboxaraide;
N~(3~(4-cyc!opiOpyl-4J-l-i;,2,44ria2:oi-3-yi)phenyl)-4-(5-!iiethyl-4- (mfliioromethy'0-4,5,6, 7 4etxahydro-lH -imidazo[4,5-c ]pyridin-l- yI)picolraamide;
-(6^4" yclopropyI 1i-li2s44Tiazol-3-yl")pyridin-2-yl)-4-(^
(trifl-uoiOttiethyl)-4,5}6} 7 4etrahydro4H 4it)idazo[4,5-c '|pyridin4- yl)picqimanude;
44 5-€yclopropyl-4-rai hyi-4H ,2,44ria∞1^3^y))-N-i3-(4-cy.clopfopy 1-4 H -1 )2,4-triazol-3-yl.)pheny))picolmamide.;
4-(3-cyclopropyi ,2,4--oxadiazoi- -yl)--N--(3-(4"Cyclopropyl~4H4,2!4- iriazol-3-yl)phenyl)picoli)iainide;
N-(344-cyclopropyl H4.,244nazol4-yi)ph nyl)443-inethyl4 ,2,4- oxadiazol-5-yl)picolmamide;
6-cyck^ropyl-N-(3K44'.3-hydroxybutan-2-yl)^H4' /2.4-triazol-3- yljphenyl )-3 , ' -bipyridifie-2 ' -carboxami de;
Figure imgf000050_0001
cyclopropy Ipyridin-3-y ί)-2-ί)υ oro benzamide
ό-cyclopropy 3-N-(6-(4-( (2S53 R 3-hydroxybutan-2-y l)-4 H- 1,2,4- triazol-3 -yl)pyridra-2~y l)-3.4 ' -bipyridine-25 -carboxam ide ;
6-cyclopropy 1 ~N~(6-(4-( (2SS3 S)-3-hydroxybuian»2»y I H H-1,2,4- triazol -3 -yl)pyridin-2-y i )- ,4'-bipyridme-2' -carbox amide;
6-cydopropyl-N-(6-(4-(l-(pynOlidia-l-yl)propan-2-yl)-4 H-l,2,4-triazol-3» yl)pytidin-2-yl)-3,4,-bipyrj.diiie-2'-carboxanude;
N-(3-(4-cyclopropyl-4H-l>2>4- ria2;ol-3-yl)phsnyl)-4-(l-(2,2,2- trifluoroeihyl)-lH-pyiTojo(3,2-b ]pyridin-6-yl)picolinaraide;
N-(3-(4-cycl propyb4H ,2!4-iriazo]-3-yl)phenyl )-4-(i
pyrro Jo [ 3 , 2■■ b jpyrid i « -6 - 3 ipicoi ami dc;
S)-6-eydopropyl-N 3~(4-(3 im^
yi)phenyl)-3{4 ' -bipyridi.oe-2 ' -carboxamide;
6-cydQprQpyi-N-(6-(4<l-methy^^^
yl)pyridm-2-yl)-3,4>-bipyridine-2'-carboxamide;
N 3 4'-seC"buiyi-4H ,2s4 riazoi-3-yi)pheny:)- -cyci propyb3!4! - bi pyridme-2 ' - carboxaniick
(S)-6-cydopropyl-NHl-(4~( -cyc propykthyi)-4H4\2,4"triazol-3- yl)phenyl)~ ,4 ' -bipyridine-2 ' -carboxamide;
6 :y oprop l4 (3-Y4-( enta^^^^^
bipyridine-2*-carboxamide;
(S)-6-cyclopropyl-N-(3-( -( 1 -methoxypropan *2~yl)-4H» 1 ,2,4-triazo! -3 - yl)pheny!)-3,4'-b'ipyndir!e-2!-cai'b xami(fe;
:6-cydopropylrN-(6-{4-cydopmpyl-4fr
mellwi"3,4'~bipyrid:me-2' -carboxamide;
(S)-6~cyclopropyb.N-(' 6-(4-( I -meih.oxypr pan-2-yl)-4H-l ,2,4--tfiazol-3- yi)pyi din-2"yl)-dine--2^carbosaniide;
(S)-N »sec-bui ] Hd^^
bipyridine»2'"Catboxaro.ide;
~(6-(4^ydopropyMH ,2s4 ria^^
mfiuoro - 1 -meihoxyethyj)-3H -imidazol- 1 -y benzasnide; N~(6~(4-cyclopropyl-4i1 ,2>4 riazol-3-yl)pyridin-2-yl) -(6- cyclopropy3pyridin»3-yl)-7 ,8-dimethyl quinoIine~2-carboxamide;
(S i-6-cyclopropyl-N~(3-(4-(3-methylbutan-2-yl)--4H- l ,2,4-inaz S-3- yl)phenyl)-3,45 -bipyndine-2 ' -carboxamide;
(R)-6-cyclopropyl- -{3-(4-(1 -(2,6~dimethylphenoxy )propan-2-yl)-4H- ] !2>4 nazol -yl)pheny!j^,4'4?ipyridioe-2>"Carboxamide:
N-(3-(4-cyciopropyl-4H-l ,254-triazoi-3-yl)phenyl}-4-{6- cyciopiOpylpyridja-3-yl)-7,8-dimeihyiquinoline-2-carix)xamid
3~(4-cyclopropyi-lH midazoi-l -yl.)"N"(6-(4-cyciopropy]--4H-l,2,4-triazol~ 3~yi¾pyridin-2-yl)-4~meihoxybenzajnide;
4"eh!oro-3-(4~cycIopropy
1 ,2,44riazi>i-3~>l)pyridm-2~yl jbeoza ide;
4-(4-cyclopropyi-l;H ½ ikzoi-l-yl)-N- -(4-cydopropyl'4H ,2>4-friazol- B-yi jpyridin-^-y!jqu!Boime-Z-carboxamide;
N-(6-(4-cyclopropyl-4H- 1 ,2,4-tria2:ol-3-yl)pyridin-2-yi)~4-(6- cydopropylpyridin-3-yl)quinoline-2-carboxamide;
N"(6H'4-cydopropyl-4H- l ,2>4-triaz i-3-yl.)pyridin-2--yl,)-5-(6- cydopropylpyridin-3-yi.)-2-tluorobenzamide;
(S)-6-eydopropyl-N-(3-(4-(l, 1 . 14rifluoropropatx-2- l)-4H- i ,2,4-iria2:ol-3- yl)phenyl)-3(4'«bipyTjdme-2'-carboxamide;
(S ) eri -butyl X^-iS-^-cydo fo l-S^'- i yridtne^'- c^oxaniido)phenyl) H-J }2s4-triaEol-4- l)propaiioate;
-{3 4--cyclobutyi H4,2,44riazol-3--yi)pheiwi}--6--cyclopropyl--3,4^. bipyridine-2'-carboxamide;
(S)-6-cydopropyl~N-{3 -(4-( 1 -p henylethy!)r4H-l i2J4-triazoI-3-yl)phenyi)- 3,4' -bipyridiiie^' -carboxamide;
6~cydopropyl-N-(3-(4-isopropyi-4H-i,2^
bipyridii.ie-2!-carboxatnide;
3"(4"Cyclopropyl4 H-imidazoM -yl)~N~(6"(4"isopropyl 1i4 ,2,4 riazol-3- yi)pyridin-2-yl)benzamide;
N-(6K'4-cycl propyMH ^,4 Tiaz ]-3-yi)pyridn-2-yl)-4-i4-(2,2,2- trifl uoro 1 -hy droxyethyi)-- 1 H -irnidazol- 1 -y!)pi colinam kk ;
Figure imgf000052_0001
tria5r.ol"3-yl)pyridin-2-y!)bei\zainide;
N 3»(4^yclopropyl-4H ,2i4 riazol -> )phenyl) -{4-i2,2,2-irifluoro-l- hydroxyei hy I)- 1 H»imidazo j - 1 - yl jpicoiinam ide;
-('6-{ 1 -cyelopropyl- IH -iimdazol-5-y!)pyfidSa"2-yl)-4-(4,5-dimeihyl- 1 H- imidazoH~yI)picolinamide;
N~(6 4~cyclopropyi 1^d,2,4-iriazol-3-yi)pyndin-2-yl)-3-(4~(2,2,2- trifluorO"l-hydroxyet yl)-lH -imidazol - 1 ~yi)benzamide
N-(6-(l -cyelopropyl- IH -imj dazol -5 -yl jpyridin-2-yl)~6 -(2- benzamide; hy<froxypropan-2-yl)~3,4 ' -bipyri dine-2 -carboxat de;
- (4 -cyelopropyl- ill. -imidazol-l -yl)- -( -(4-cyclopropyl ·4Η··1,254 Π8Ζθ1- 3-y{}pyridin-2-y1 )-5 -meihy !benzaaiide;
1 Hdroidazol- 1 --yl)benzamide;
N--(3"(4--ieyc]opropy^
earhoxamid ;
4- (4-cyclopropyi--2-mer yi-lH-imidazol- 1 ~yl)"N-{3-(4-cyciopfopyl-4H- l.,2,4-triazoi-3-yl)phe.iiyi)picolinamide;
4~{4-cyc)opropyl-2-roeihyl-lH½iidazol-l-yl)-^-(Y-(4--cyclopfopyj--4H- l,2,4-friazol-3-yl)pyridin-2-y!)picoljjiamide;
4- 4~cyc1opropyl"lH»ifflidazol-d-yl)'- -(3-(4 sopropyl H ,2i4driazoi-3» yl )pheny )pi col inamide ;
4 -(4-cycIopropyl -IH-imidazol- 1 -yl )» -( ~(4-( cyclopropylmethyj)-4H- ls2,4--triazol-3~yl)phei5y piooiinamide;
4-(4«cyciopfOpyl- 1 -iaudazol- 1 -yi)~N-(3-(4-( 1 -phenyletiiyl >4H- 1,2,4- iriazol-3 -yl )pheny! )pico!inam Ide
N'"(6-i4-cy opi«pyl~4f:i-5^^
tetra hydro- 1 H - benzo [ d j imidazol - 1 -yl )pi coi n amide ;
N~(6~(4--cycIopropyl- H ,2J4-Tiazo]- 'yi)pyridin~2"yl)-4-(4- (trijfluoroffieihyl)-lH midazQM-yl)pkoHnamide
N-(6-(4-cyc]opropyl-4e-li2)4 riazol'3-yl)pyridin»2-yl)-3-(4>5,6i7» tetrahydro- 1 -beozo[ djimidazol-l -yl)ben_tamkle; 1 -p-(6-(4-cye-lopropyl-4H- 1 ,2,4-triazol"3-yl)pyridin-2- ylcarbamoylphenyi)-5-rae4hyl-lH-in3tdazole-4-carb xylicacid;
(S) -(4^yc{opropyl-lH-imida2.oi-l-yl)-^-{6-<4-(l-phenytethylHH triazol«3-yl)pyridin-2-yl)benzamide;
{)-cyclopropyl- -(6-(4-cyclopfopyHH- 1 ,2 ,4-triazol -3 -· yl)pyii diiv-2-y !)-55 ~ methyl-3,4'-bipyridine-2*-carboxamide;
(S)~3-( 4>5-dimethyWH-imidazol-l -y1)-N-('6~(4-(l ,1 ,.l-triiluoropropaii-2- yl}"4]-i"l,2>4 riazol^3-yi)pyridin-2-y))benzamid ;
N-i3-(4-cyciopropyl-4H" 1 ^,4-triaz0l-3•yi)pheny!) -(2-eihylpynmidin-5- yl)picolmamide;
(R 4..(4-cydopropyl-lH-imidazfjl-l.-yj)--N--i'3-(4--{l, 1, l- i-lluoropropan-2~ yl 41i-i,2,4 Tiazol-3-yl)phenyl)picolinaroide
N -(3 -(A -cyclopr pyI H- ί ,2,4-tfiazoi -3-yl }phenyl)-5 -ethyl - , » - bipyridine- 2'-earboxamide;
6-cyclopropyl-N-(3»(4-cyciopropyl-4H-l52,4-tria2ol-3-yl)-
4-fluoropheiiy1j-3,4,"bipyriditie-2'-€afboxamide;
-(3-(4-cydopr pyl-4H-l ,2,44.riazol-3-yl )phenyl )-4-( l,5-naphthyridm-3- y])picol amide;
N-(6 4-cyd^ropyl~4il >2i4-tTja2ol-3->4)pyridiii '-yl)-3-(l,5» naphthyridm-3 - -yl)benzami de;
3- 4 yd propyl-1H midazol-l-yl)~N»(6-{4-cyclopropyl-4H-i,2,44riazol~ 3-yl¾pyridin-2«yl)benzaniide;
-{3-(4-cyclopropyl-4H-l,2,4-(riaz i-:vyl)-4-f3« fophenyl)-6-e 1-3,4'- ipyii din carboxamide.;
ert- utyl-N-f3-( ^^^^^
bipyridine- '-carboxamide;
Figure imgf000053_0001
yl)benzarmde;
-(6-(4-cycfopropy I-4H- 1 ,2544riazoi"3-y1)pyridin~2»yl)-3-(4-isopropyl- 1 H -iratdazol-i -yl)benzainide;
N-ie^-c do ro MH-l^^-iri zoi-S- ll yridin^-yl^i-CS- cydopropyipyriditi-3»yr)beii2:amide 6- cyclopropyi -N-( 2-{ 4--eyc1 opr pyl- 1- 1 , .4-iriazol- -yi)
3-(4 -cyciopropyl"lH-imidazoi-l-yl)-N-(6-(4 -cyclopropyi- pyridin-4-yl)-
3.4* -bipyxidine-2 ' -carboxamide;
4 H- 1 ,2,4-tri azoS- ~yl)pyridm-2-y 1 )-2-methyibenzamide;
N-(6-(4-cyclopropyl-4H-l ,2,4-MazoI-3"yl)p>Tidin-2-yl)-4-i4-
( ifluorome l)-4,5,6,7-teirahyd
IS -(3 -(4 -cyclopropyi --4H-- 1 ,2,4-triazol.-3-yl )phenyl)-4-(4- (tnfluorornethyl)-4i 6, 7 4eixahydro-lH -imida£o[4s5-c]pyridm-l - yl}picoirMrmde;
5-{ -cyclo fo yl·dH"ίmid a l-l- l)-N-(6-(4-c c·lo ro yl·4 H -1 ,2,4- triazo}-3-yl)pyTidin-2-y 1 )-2-metbylbenzamide;
Figure imgf000054_0001
IH-imidazoi- l-yl )pieolinamjde:
-(6~(4-cyelopropyl-4H ,2,44riazol yl)pyridia-2-yl)»4»(4.
(peril uoroethyl)- 1 II --imidazol- 1 -yl)pico!tnarmde;
3- {'4-cyclopropyj-dli-4mida20l-l-yl)-N ^6-(4-cyclopropyl-4B'-l ,2.44ria2:oi- 3"yi)pyridin~2~yl}-4--methy!benzamide;
4 - (3 -cyclopropyi- 1H- 1 ,2,4-tri azol- I-yl)-N-(6-(4-cyclopropy 1 -4H- 1 ,2,4- tr i a : · > ! ·· 3 - yl )py ri din - 2 -y I ) pi ol inam ide ;
4-(3-cyclopropyl- 1 H-1 ,2,4-fna ol- 1 -yl)-N-i3-(4-cycloptx)pyl-4H-l ,2,4-. triazol-3-yl)phenyl)picoimarftide;
4-(5-cyclopropy1-lH >254- iazol»i"yl)-N'(3~(4~cyclopiOpyl-4B'-l.,2,4- tfiaz«l"3- yl)phenyl)picoSinamide;
N-(6~(4~cyelopropyi-4-l:I - 1 >2,4-tri.azoj-3-yl)pyridin-2~yl)~3«
(6--(2--hydroxypropan-2--yl}pyndin--3-yi) enzaraide;
3--i4-^cyclopi'Opyl B n)idaz ^l"y1)--N--f6-(4-cyclQprQpyl-
4 H --1 52,4-tnazol-3 -y!)pyridin-2--y i)-5-ilu oro benzamide;
-(2-(4-cyclopropyl-4H-l,2,4-triazoI-3-yl)pytidm-4-y3)-4-
( qumolin-3-yi)picoImamide;
45 N-(3-{4-cyclopiOpyl-4H-l .2?4-triazoi-3-yl)phenyl)~4-(5s6, 7,
8-tetrahydro- 1 ,6-naphthyridm»3-yl)picolitiaraide; 6-cye{opropyl- ~(3--(4-cy4^
3 , ' -bi pyridine-2 ' -earboxaro ids;
5- cydopropyl- H3-(4~ yclopropyl4¾
bipyridine^'-earboxamide;
N-(3-(4-cyclopropyl-4H-l,2,4-tria2:ob3-y!)-2-fluoropheny1)-3<4'- bipyridme-2*-carboxamide;
N-(3-(4-c ck>propyl-4H-L2,4-trtazol-3-yl)phenyl) -(4-ethyl-lH ·- imidazoi- 1 -yi jpieolmamide;
55 N- 6-i4-cydopro !4H4 ^
■•imidazoi- 1 -yi)pico3inani.ide;
N-(6-(4^yclopropyl I14,2,4-triazol-3-yl)pyridin-2-y])-4-(4,5-^ iH4mdazei -yi)picojinarmde;
Figure imgf000055_0001
trifluoroethyl y$,6> 7 ,8 -tetrahydro-l ^iaphihyrrdin- -yDpicoIinaffiide;
N 3-(4"Cyclopropy!4H4,254 riazol-3-yl)phenyl)4-(4 sopropyl-lH- imi<fezol-l-yl)pieo3inarmde;
N-{3-(4-cyclopropyl4iI- ] 2?4-Mazo]-3-yl)pb.enyl)-6-(2diydr xypropan-'2" ylfS^'-bipyridine^'-Carboxamide
Figure imgf000055_0002
(2 iydroxypropaB^2~yr}--34' )ipyridine"2-Carboxamide;
~(64'4'Cyvlopropyl41i-l,2,4 riaz l.e-3-y
-imidazol-l-yi)pkolraajtnide;
6- cydopropyl-N-(3-(4-cydopropyi4H ^^
.1 )-3 ,4' -bipytidine-2 ' -earboxamide;
N-(3- 4--ey lopropyl4iJ 1244na2oi4"yl)4-dluorophenylV34'-' bipyridine -2 "-Carboxamide ;
4~{4-i:yciopropyl- IH-imidasoi-l -y!)-N-^'6-(4~cyclopropyl4H4J214»1xiaz l» 3-yl)pyridin-2-yl)picolinamide;
K-(3-(4-cyclopropyl4il4,2,4 i½zol -yl)phenyl)-6-(2>2s2-{rifluoro^^^ 3 ,4*-bipyri dine~2 " -car boxamide ;
-(3-(4 yclopropyl4H-l,2,4-triazoJ-3-yi)pfaenyl)4-(6-isopropyl-5,6, 7 ,8- tetrahydro-1 ,6-naphthyridin~3-yl)ptc;oliaamide; »(;H4„eydo ro yl^
tetrabydro- 1 ,6-naphthyridin-3 -yl)picolmamide;
N-(3"i -cycloprq:ty]-4H-L2 i na^
1 -y! ipico!inamide;
-(6-(4-cyclopropyl-4H-l,2,4-triazol-3-yi)pyridin-2-yl)~4-(3- hydroxypiperidiN-1 -y 1 )picolmaraide;
6-cyelopropyi- -(6-(4-isopropyl^^^
bipyridin e»2 ' -carboxatnide ;
N^3-( -cyck)propyi-4H i-lriazoj-3-yl)phenvi)-4-i4»ethy I -3- oxopiperaziN-l-yl)picoiiflaraide;
-(6-(4-cyclopropyl-4H« 1 ,2}44ri azol -3-y I )pyridin-2 «yl)-4-(4-ethyl-3 - oxopiperaziN-l^y I tpic linsmide:
iR)--6-cydopropy]-N-(6- 4-'{l, 1, l~dfluoropropan-2-yl)-4H-l,254-lTiaiioi« 3-yl)pyridiii-2-y] )-3?4' -bipyridine '-caii QMrntde-;
-i3-(4 s propy!4H-l,2,4-triajRo)-3-yl)phenyl)-3,4'-bipyridi∞ carboxamide;
6-cyclopentyi -N ··(' 3 ~{4 - -cyclopropyl -41:1» 1 ,2,4-lxia2o! -3 - yl )phenyl)-3 , * - bipyridine-2*-carboxamide;
M"(3"(4-cyciop.fopyl-4H- 152,4-triazol-3-yl)phenyl)-6-(l ~roethyl-2- oxopyrrolidin-S-ylVS^'-bipyridine^'-Carboxamide; suliaffi yl)phenyl)pscolinamide;
N~(6-(4 :yekspropyl4H^^
yi)picoliii¾fflide;
N»(6-(4-cy¾lopropyMH^ ,2,4-tria^^ - imidazol~l~yI)pieolinain'ide;
N-(3-(4~cyclopropyl-4H- 1 ,2,4-lri azol-3 -yi )phenyl )-6 -pro 1 ~ 354s - bipyridine-2' -Carboxamide ;
N~(3-(4-cyciopropyl-4H-l^,4-triazol-3-yl)phenyl)-6-neopentyl-3,4>- bipyndine -2 " ·· Carboxamide;
-(;H -cycio ro l-4H-0A'^
lH-imida2of-5-yl)picolin.amide; H-(3-{4-cycloprQpyl-4H-ls2,4-triazol-:Vyl)phenyl)- -(4--(eihyl sulfony])pheny l)-pieolmarnide;
N-(3-(4-cyclopropyl-4H~l)254-triazol-3-yl)phenyl)-4-(4- (ts pro yj sul f bnyi)pheny f )p i oli nam ids;
N-(3-{4-cyclopropyl-4H-l.,2>4~ riazol»3-yl)phenyl)-6-( thylamino)"3,4' - bipyridine-2 ' -carboxamide;
N-(3-(4-cyclopropyl-4H-l,2,4-triazol-3-yi)phenyl)-6-( cyclopropylamino)- 3 '-bipyridine-25 -carhox am de;
^(3-(4-cyck)propyMH 52,4-txia :ol-3-yl)piienyl) 1 -b] [ 1
,3.4]tWadiazol-5-yl)picoliaamiile;
4-(4-cbloro-lH -iraidazoi-l-yl}-N-(3-(4-cycloprop>4-4H-L254-triazol"3- yl)pheayl)picol-inaraide;
N~(3-(4-cyclopropy!-4H-lJ2,4-triazol-3-yl)phfii)yl)-4-(2- cycioprop5 pyri:midm-5-yl)plcoljnainide:;
N-(3-(4-cyclopropyl-4H >2s4»tria?Oi-3-y])phenyj)-6 irifluorojme&yl.^ 3 ,4 ' -bipyridine-25 -carboxamide ;
N··( -(4-c·yclo ro yj-4H ( , t azo^ »yl)phenyl)-4-(φiinoiin- -yl }-6·· (trifluoromethyl)picoiinamide;
N »('6-( 1 -cyclopropyl- 1 H 4raidazol-5-yl)pyridin-2-yl} -(quinQlin-3- yOpicolinamide;
6-cyclopropyl-N-(6-(l-cyciopropyl-I H -iraida¾ol-5-yl)pyridin-2-yl)-3,4'- bipyri dine- ' -carboxamide ;
5 N-(3"(4"Cyclopropy! };i4,2 44riazol"3"yI)phen>4)-4
]pyridin-6-yt.)picolinaTnide;
NK3 4-cycjopropyb4H4J2>4-triaz0l-3-yl)ph6iiyl)~4"(4~
cycl opr pylpherxyijpi eoHiiam id ;
Figure imgf000057_0001
yi)be«zamide;
N 3~(4"cyciopropyl-4H4 ~tria:∞^^
bipyri dine -2 ' -carboxamide ;
N-(3-i4-cyciopropyl4H4^4 riazol-3-yi)phenyl}-6-iisobuiy!ihio )-3,4'- bipyridine-2 '-carboxamide; 15 N^3"(4-cyclopropyK4H ,2,4 riazol^^l)phenyl)-4K5- cydopropylpyrazin-
2-yl)picoliaamide;
6-cy lopropyi-N"(3"! 4-cydopropyM.l S-l .2 4-iriazoN-3~yi}pheR} )-5~fluorO" 3 s4'-bipyridin.e-2 ' -carboxamide;
5~cUoix)-6 yclopropyl-N-(3-(4-cydopropyl-4H-l J2,4-triazol-3-yl)pheny^ 3,4' -bipyri dine-25 -carbox amide;
N-(3-(4-cyclopropyl-4H-ls2(4-lTjazoj-3--yl)phenyl)-6-(2- met oxyethylaniino)-3>4'' -hi pyridine^'-carboxamide;
N-(3-(4-cyclopr pyi-4H-l,2s4 riazol-3--yl)phenyl)-4-f4'
(methyisiilfonyi)piperazin-l-yl)picolmaraide;
N-(3-(4..Cyclopropyl H )2!4-triazol»3-yl)pbenyl)-6-c i-5^ oro-3,4' - bipyridjne-2 ' -carboxamide
5- -ddoro-^H4-c do ro ! M
bipyri dine-2 ' -Carboxamide;
4-(4-cyclopropyl- 1 H -imida ol-l-yi}-N-{3--f4-cyciopropyl-4I-i-I,2>4-iriazol- 3 -y p snyl )picoi raamkle ;
N-(3-(4-cycioprop>4-4H-l,2,4-iriazol-3-yi)pheiiyl)-5s6-di«t yl-3,4'- bipyridine-2 '-carboxamide:
Figure imgf000058_0001
ytypicoliriamkls;
^-c cio ro yl^H-l^^^azol-S- hen ^-i'S-meth l-SH- imida2o[4,5»b]pyiidin-6-yl)picoiinamide;
3-(4-cyclopropyl-4H-l,2)4-triazol-3-yl}phenyl)-6-(6»
cydopropylpyridin"3">4)pyritsidjix 4-carboxamide..
6- eydopropyi-N"(3-(4-cydopropy^
methyl-3.4'-bipyridine-.2,-carboxamide;
6-cydopropyl"N-(3"(4-cydopropyl-4H-l >2,4-triazol-3-yl)phenyi)-5'- ffiethyl-3,4' -bipyri dine"2'-carboxainide:
Figure imgf000058_0002
(irifluororoethy])-4,5,6, 7 -ieirahydr -lH -imidazo[ 4,5-c jpyridin-l- y picolinamide; 8 ·
N■■( 3 · (4 -cycloprop yl-4M- 1 ,2,4-triazoI ~3 -yl)phenyl)-4-( 5■ methy!-4- (tniIuoroinelhyl)~4,5,6, 7 -tetrabydro- 1 H -imidazol^S-e Jpyridin- 1 - yljpicolinamide;
6' ;yclopropyl-N-(6-(4 ycJopropyl-4H-l,2,4-triazol-3-yi)pyridin-2-yl)- 2 ,3 1, -bipyridine-6-carboxamide;
6'-cyclopfopyl-N-(6-(4-cyclopropyl-4H-l,2,4-ti¾zol-3-y!)pyridin--2-yl)- 3,3 l-bipyridine-S-carboxamide;
6 ' -cyciopropyl-N-(6-(4-cyclopropyi-4H- 1 ,2,4-triazoi-3 -yl)pyri din-2 -yl)- 2, 1 -bipyridit e-4-carboxainide;
Figure imgf000059_0001
,2J4-Maz»l-3-yl)pyridin"2-yl)-5-(6- cyclopropy]pyridia-3~yl)-2,4"difluoroben2ainide;
6'--cyciopropyl-N-i 3 -(4-cyclopropyk4H- 152;4-tna¾ol-3-yl)phenyl)-2., 1 - bipyridine-6-earbcxami.de;
fS)-4-(4-cyclopropyl-lH mtda? l-i-yi.)-N-(3-(4^3^
l ,2,4-{ri82ol-3-yi)phenyl)picolmamide;
4-cWoro-N-(6-f4-cyci propyl-4H-l,2,4-tmzol~3"yl)pyridin--2-yl )-S-(6- eyeiopropylpyridin-3-y 1 )~2~fluorobenzamide;
6-cyclopfopyl-N 3-(4-(2-phenyicyclopropyi)-4H-l,2,4-triazo!-3- yl)phenyl} 3,45-bipyridine-2'-carboxamide;
N-(3 -(4-cyclopropyl-4H-l (2,4-{iia2ol-3»yl)phenyi)-6-fcyclopropy]methyl)- 3 , ' -bipyridine-2 ' -carboxamide;
3»(4-cyclopropyl- 1 H - 1 ,2,3-triazol- 1 -yl)~N-(6-(4-cyclopropyl-4H- 1 ,2,4- tnazol-3-yl)pyrjdin-2-yl)benzaraide;
4-( 5-cycIopropyk 1 ^thiadiazal^- rj-N-CS^-cyclo ro yi^H-l^^- tnaxol -3 -y 1 jphenyl)pko! inam ids;
6-cyclopropyi-N-i3 4-phenyMH^^
bipyridme-2'~carboxamide;
6-cyclopropyl-N 3^4-(pyridm-2-yl)-4H-152,4-iriazol-3-yl)
phenylj- 3,4'-bipyridine-2i~carboxamide;
6-cycloptopyl- -( -( 4-(pyridin- -yl) -411- i ,2 , -iri azol -3 -yl¾ihenyJ)-3,4'- bipyridme-2'-earboxamide; 6- yclopropyl»N»(3»(4-(pyridia -yl) H-l s2,4- azol-3-yl)phenyl)-3J4,~ bipyri dine -2 '-carboxarn ide ;
6-cydopropyl~N-(3-(4-(pvTirmdin-5~y^^^
bipyTidme-2'-carbcfxamide;
4-( 4-cyclopropyl-lH-irnidazoH-yl)-N-(3-( 4-ipyfidin-3-yl -4H-l ,2,4- iriazol-3 -yfjphenyJ )pieol inamide ;
4-(4-cyclopropyl-lH-imicte2ol- 1 -yl N-(3-(4~(pyridin-4-yl)-4H-l }2,4- triazol-3-yl)phenyl)picolinamide;
4'-(4»cycl piOpyl-3H»imida?.oj-l-yl)-N-(3-( 4~(pyrimidi n-5 ~yi }~4ll -1 ,2,4- iriazol · ' · y: yphexi yl )pico!inamide; and
N-{3-(4~(but-2-wy!MH-i,2^
inaidazoi-l-yl pisoHnsniide; or a pharmaceutically acceptable salt or solvate thereof,
[00126] In m embodiments, She ASKi inhibiting compound is a compound of the structure:
Figure imgf000060_0001
or a pharmaceutically acceptable salt, o hydrate thereof This compound may be referred to as 3-(4-cyclopropyl- i H-imidazoi- 1 -yi)-N-(6~(4-cyclopropyl-4H- 1 ,2,4- triazoi-3-yl)pyridin-2-yl)-4-rnet ylbenzatmde or 3-(4-cyclopropy{-lH»imidazol- l-yl)- -[6-(4-tyclopropyM^
benzamide... and has been assigned CAS Registry No. 12620 1 -67-7. The compound and salts thereof including formic acid salt (CAS Reg, No. 1262041- 68-8 may be prepared by methods disclosed in US 2014/0228412 and U.S. Pat.
No. 9,067,933.
[00127] in other embodiments, the ASKI inhibiting compound is a compound of the structure:
Figure imgf000061_0001
or a pharmaceutically acceptable salt or hydrate thereof. This compound may be referred to as 5-(4 yclopropyl"l H-imidazol-l-yl)-2-fluoro-N~(6-(4»isopiOpyl- 4H ,2,4-teia2ol-3-yl }pyridin-2-yl)-4~methyibeiizamide or 5~(4-cyelopropyl-l H- imidazol-l -yl)-2 luoro-4-methyl-N-[6-[4-(l -rnethyletJhyiHH-.l ,2,4-triazoi-3-ylj- 2-pyiidinyl]-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 U.S. Pat Mo. 9,067,933,
[00128) 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 acti ity of certain target in a subject such as human, For example, it will be understood that the terms "ASKl inhibitor", ''AS l inhibiting compound", and "inhibitor of ASK i", and the like, refer io compounds which present a pharmaceutical activity to inhibit activity of an apoptosis signal- regulating kinase I 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 t, 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 ASKl inhibiting compound is 4-[4-[(4'-chlot'oj , - biphenylj~2-yl)me^
[(phenylmio)memyl]propyi]amino]-3-flitrophenyl]sdforiyl) benmmide, or a pharmaceutically acceptable salt thereof.
Brornodomam Inhibitors
100129) In some variations the BET or BRD (bromotloroain-containiiig protein) inhibitor is an inhibitor of bromodomain~contamin¾ protein 4 (BRIM). In one aspect the modulator of a hroraodomain-containing protein is a compound of Formula i l l ):
Figure imgf000062_0001
wherein
R!" and RUl are each independently C\. alkyl optionally substituted with from 1 to 5 R~ ' groups;
R'1:' and R':ft are each independently H or halo;
R3 is
C(0)ORA, - HC(0)ORS, -NHS(0)2 *, or -S(<%NR*RB; or
selected from the group consisting of CMO alkyl, CMO alkoxy, amino, C O aryl, C^o aiylalkyl, CMO heteroalkyl CMO heteroaryl, and C6.2o heteroarylalkyl, each of which is optionally substituted with from 1 to 5 R'¾' groups;
one of R " and R1" is selected from the group consisting of H and alkyl optionally substituted with from 1 to 5 RAI groups, and the other is absent;
R5 is ~C(O)GR&, ~NHC(0)OR\ -NHS(0)2R8, or -S(G)2NR*RB; or
R¾ is selected from the group consisting of H, C O alkyl, CMO haioalkyl. C MO alkoxy, amino, Cs-jo aryl, arylalkyl, C heteroalkyl, C5.1 heteroaryl, and Q 2o heteroarylalkyl, each of which is optionally substituted with from 1 to 5 R groups;
each RA and RB is independently selected from the group consisting of 1R CMO al l O aryl, C<MO arylalkyl CMO heteroalkyl, (¾.,io heteroaryl, and heteroarylalkyl, each of which is optionally substituted with from 1 to 5 R'''° groups; and
each E > is independently selected from the group consisting of acyi, CMO alkyl, CMO alkoxy, amino, amido, amidmo, C$.i<> aryl, C a* arylalkyl, azido, carbamoyl, carboxyl, carboxyl ester, cyarto, guariidmo, halo, Q.-. haioalkyl, i-.- heteroalkyl, Cue lietero-aryl, s-2 heteroaryklkyl, hydroxy, hydrazine imino, oxo, nitro, sulfmyl. sulfonic acid, sulfonyi, thioeyanate, thiol, and thione;
wherein the Cj.io alkyl, Cj-jo aryl., i arylalkyl, CHO heteroalkyl, C a heteroaryi, and C(;.?o heteroaiylaikyl groups are optionally substi luted with from 1 to 3 substituents independently selected from CM alkyl, C$. aryl, halo, Ct.<, haloalkyl, cyano, hydroxy, and Ci.g alkoxy;
or a pharmaceutically acceptable salt thereof.
[00130] Compounds of Formula (II) (which include compounds of any of Formulae ilia), (lib), (He), (lid) and (fie), described below) can include, independently, one or more of the following features. It will be recognized that features specified in each embodiment may be combined with other specified features to provide further embodiments,
(00131) in some compounds, R'3 and R;b are each independently a k l which, aa defined herein, includes alkeny!, alky yl and cycloalkyl. in some compounds, Rla and R) 0 ate different, and in other compounds R1 : andR'b are the same. In some compounds, R iK and Rlb are each independently a
Figure imgf000063_0001
alkyl optionally substituted with 1-5 II ' groups. In some compounds. Rf a and Rh1 are both methyl. In some compounds, one of R'A or RL" is a methyl and the other is a methyl substituted with a hydroxy. In some compounds, R and R 10 are both methyl substituted with a hydroxy. In some compounds, one ofRia or !b is a niethyi and the other is a methyl substituted with an amine. In some compounds, I 1" and Rlh are both methyl substituted with an amine,
[00132} in some compounds,. " and R"1 are both H. In some compounds, R*' and "'b are both halo. In some compounds, one of R2A and R"b is H and the other is halo. In some compounds the halo is -F or -CI ,
(.00133) In -some compounds, R ' is boronic acid, a boronic acid ester, or halo. In some compounds, R3 is -C(0)ORa, -NHCiOjOR8, - IS(0)2Ra, or -S(0)2.NRARFC wherein Ra and R>! are described above. In some compounds, RJ is -C(O R*, - NHC(0)OR8, ~ HS(0)2Ra, or -S(0);;NRaR\ wherein each Ra and R is independently CJ-JO alkyl, C$.fa aryl, C O heteroalkyl or C3.10 heteroaryi, each of which may be optionally substituted as described above. For example, in some compounds R3 is -C(0)ORa, -NHC(0)ORa, ~NHS(0)2R8, or ~S(0)2NRaRb, wherein each Ra and R" is independently C5.10 aryl or heteroaryl. h some compounds, R:' is selected from the group consisting of CMO alkyl, C O aikoxy, amino, C.s.10 aryl, C$.20 arylalkyl C O heteroalkyl, C io heteroaryl, and CV20 heteroarylalkyl, each of which is optionally substituted with from 1 to 5 R"1 groups, wherein R'0 is described above, i some compounds, R'5 is CM alkyl, j .io aikoxy, or CM O heteroalkyl, each of which may be optionally substituted as described above. In some compounds, the heteroalkyl is a heterocyeloa!kyl. In other compounds, R! is Q.20 arylalkyl or C^o heieroarylalkyl, each of which may be optionally substituted as described above. In other compounds, R3 is C to aryl, C¾.?o arylalkyl, C io heteroaryl, or C6.20 heteroarylalkyl. each of which may be optionally substituted as described above. In some compounds, R"1 is amino optionally substituted as described above. For example, in some compounds R' is -N¾, and in other compounds R:'' is - J,R''. wherein W and R' together with the nitrogen to which the are bonded form a CMS heteroalkyl or CMO heteroaryl, each of which may be optionally substituted as described above, [00134] Other non-limiting examples of RJ include the following:
Figure imgf000064_0001
Figure imgf000065_0001
Figure imgf000066_0001
Figure imgf000067_0001
(0 13S] In some compounds, one of' R'*: or R'4b is ii and the other is absent, that is, in some compounds R"J is H and R"° is absent, and in other compounds R™ is absent and R* is H. In other compounds, one of R¾ and R4b is alkyl and the other is absent, that is, in some compounds R. a is alkyl and R " is absent, and in other compounds R4* is absent and R4 is alkyl. In some compounds the alkyl is methyl ,
[00136] in some compounds, R5 is -C(G)GRa, -NHC(0)OR\ -NHS(0)2Ra, or - S(0)}NRaRn, wherein Ra and R8 are described above. In some compounds, R' is •-CiO)OR'\ -NHC(0)OR;\ - 1S(0)2R\ or ~S(0).?NRsR , wherein each R8 and Rb is independently Cwo alkyl or C5.10 aryl, each of which may be optionally substituted as described above. For example, in some compounds R:' is ~ NHC(0)O <!, wherein Ra is methyl, in some compounds, R~' is -NHSiOj^ ", wherein Ra is C$.10 alkyl or C^m aryl, each of which may be optionally substituted as described above. For example, in some compounds R" is - NHS(0)2Ra, wherein R" is eyelopropyl. In some compounds, R5 is selected from the group consisting of H, Ci.;o alkyl, Q.fo haloalkyk Ct-io alkoxy, amino, C^o aryl, CV20 aryialkyl, CMO heteroaikyl. Cs_io heteroaryl, and heteroaryJalkyl, each of which is optionally substituted with from i to 5 ~w groups, wherein R2,i is described above. In some compounds, is Ci..¾ alkyl optionally substituted as described above. In some compounds the Cj.jo alkyl is a Vio cycloalkyl, e.g. eyelopropyl. In other compounds, R' is amino optionally substituted as described above. For example, in some compounds R5 is ·ΝΗ?, and .in other compounds R" is -NRyR\ wherein Ry is H and R'*: h alkyl, e.g. cyclopropyl In other
compounds, R5 is alkoxy, e.g. methoxy.
[0013η In some compounds, R,a, R!\ ;\ R* R4b and R5 are optionally substituted with from 1 to 5 (i.e. 1. 2, , 4 or 5} R"° groups as described above. In some compounds, R!<\ R R ', R4s, R40 and R5 are optionally substituted with 1, 2, or 3 R'¾> groups. In some compounds, each R"'J is independently selected from the group consisting of alkyl, alkoxy, amino, cyano, halo, haloalkyl, heteroalkyl, hydroxy, and sulfonyl. In some comounds, each is independently selected from the group consisting of aryl, alkylaryl, heteroaryl, and heteroalkylaryl. In some compounds, Ria, tb, R i ( R4° and are not. substituted. In some comounds,. Rm is not substituted.
[00138] One subset of compounds- of Formula (II) relates- to compounds of Formula (Ha)
Figure imgf000068_0001
wherein
R and R'b are each independently CM alkyl optionally substituted with from 1 to 5 R2'"' groups;
I is
boronie acid or halo; or
C(Q)(M\ -NI:fCiO)GR* -NHS(Q):2R\ or -8({¾NR¾¾; or
selected from the group consisting of Cj.jo alkyl, Cj.ie alkoxy, amino, C5.10 aryl. arylalkyi, C ..\n heteroalkyl, C5.10 heteroaryl, atid C ao heteroarylalkyl, each of which is optionally substituted with from 1 to 5 R:'" ' groups;
one of R4,: and R b is selected from the group consisting of H and C| .s alky! optionally substituted with .from 1 to 5 R''° groups, and the other is absent;
k ' is
C(0)ORa 5 -NIICiO)ORs, -NHS(0.feR¾, or -S(Q)2NRaRb; or selected from the group consisting of H, Gs-jo alkyl, CI.JO haloalkyi, C^o alkoxy, amino. C5.ii> aryl Q..20 arylalkyl, Cj.io heteroalkyl,€5.10 heteroaryl, and C . 20 heteroarylalkyl, each of which is optionally substituted with from 1 to 5 Ri0 groups;
each Ra and R° is independently selected from the group consisting of H, Cj.io alkyl, C5.J0 aryl, G;, 3o arylalkyl, Q.JO heteroalkyl, C5.10 heteroaryl and Cg^o heteroarylalkyl, each of which is optionally substituted with from ]. to 5 R'° groups; and
each R '' is independently selected from the group consisting of acyl Cu<> alky I, CI.JO alkoxy, amino, amido, amidino, (¾.]ø aryl, 20 arylalkyl, azido, carbamoyl, carhoxyl carboxyl ester, cyano, guanidmo, halo, Cj.io haloalkyi, Cj.i heteroalkyl, C JO heteroaryl C^n heteroarylalkyl, hydroxy, hydrazine, homo, oxo, nitro, sulfuvyl, sulfonic acid, sulfbnyi, ihiocyanaie, thiol and thione;
wherein the CHO alkyl, Cs-ie aryl, C< o ar lalk l
Figure imgf000069_0001
heteroalkyl, CMO heteroaryl, and C 20 heteroarylalkyl groups are optionally substituted with from 1 to 3 substituents independently selected from C alkyl, .10 aryl halo, C] .
haloalkyi cyano, hydroxy, and t, alkoxy,
or a pharmaceutically acceptable salt thereof,
100139] Another subset of compounds of Formula (II) relates to compounds of Formula (lib)
Figure imgf000069_0002
wherein
R'4 and R! are each independently alkyl optionally substituted with from 1 to 5 R' ' groups;
R2& and R" are each independently H or halo; boronic acid or halo; or
C(0)ORs, -NHC(0)OR8, -NHS(0)2Ra, or■•S(0)2NR¾h; or selected from the group consisting of C O alky], CJ .JO alkoxy, amino, C5.(o aryl, C 20 arylalkyl, CMO heteroaikyl. a heieroaryl, and 20 heteroarylalkyl, each of which is optionally substituted with from I to 5 R"° groups;
is
CiO)OR\ -NHC(0)ORA, -NHS(0)2RA, or -S(0)2NRAR ; or
selected from the group consisting of H, CMO aikyl, C j _ :> haloalkyl, Cue alkoxy, amino, C$.to aryl, Q.20 arylalkyl, Ct.jo heteroaikyl, C io heieroaryl, and .
20 heieroaryl aikyl, each of which is optionally substituted with from I to 5 R''° groups;
each R* and R° is independently selected from the group consisting of H, C : .i aikyl, C$.\<, aryl, ( .2 arylalkyl CMO heteroaikyl, l. if. heteroary), and Q„2o heieroaryl a Iky I each of which is optionally substituted with from 1 to 5 k' !"' groups; and
each RITJ is independently selected from the group consisting of airyl, e aikyl, CJ.JO alkoxy, amino, amido, amidino, C .10 aryl 20 arylalkyl, azido, carbamoyl earboxyl caxboxyl ester, cyano, goanidu o, halo, C[.\<, haloalkyl C;. ;o heteroaikyl, C5.10 heieroaryl, C$.20 heteroarylalkyl, hydroxy, hydrazines imino, oxo, nitro, sulfinyl, sulfonic acid, sulfonyl, thiocyanate, thiol, and thione;
wherein the Cuo aikyl C e aryl, Cf).¾ arylalkyl, C;.; heteroaikyl C5.10 heieroaryl, and C 20 heteroarylalkyl groups are'optionally substituted with from 1 to 3 substituents independentl selected from CM aikyl, Cuo aryl, halo, C).c haloalkyl cyano, hydroxy, and . alkoxy;
or a pharmaceutically acceptable salt thereof.
j'O j 40) Another subset of compounds of Formula. (II) relates to compounds of Formula (lie !
Figure imgf000070_0001
and R " are each independently Ci^ aikyl optionally substituted with from 1 to 5 R":,) groups;
R3 is
boronic aesd or halo; or
QQjOR8, -M-l€iO)ORs, -NHS(0)2Rs, o -S(0)2NRaRb; or
selected from the group consisting of Cj-jo aikyl, CJ .JO alkoxy, amino, C5..10 aryl, Q.™ aryiaikyl C.h-io heteroalkyl, C5..jo heteroatyl, and C«o heteroarylalkyl, each of which is optionally substituted with f om 1 to 5 R''° groups;
R5 is
QO}OR\ ~NHC(0)0R4, -NHS(0)2Ra, or -S(0)2NR*Rb; or
selected from the group consisting of H, CJ.JO aikyl, Cj.io haloaikyl, Cj.; alkoxy, amino, C5.-.0 aryl . aryiaikyl, ί¾ο heteroalkyl, C5 0 heteroaryl and Q.
20 heteroarylalkyl, each of which is optionally substituted with fxor 1 to 5 R2<i groups;
each R* and R° is independently selected from the group consisting of H, Ci.j aikyl, (Χκ, aryl, (¾.2ο aryiaikyl, Ci-io heteroalkyl, C io heteroaryl, and Q.¾j heteroarylalkyl, each of which is optional ly substituted with front 1 to 5 R30 groups; and
each RM is independently selected from the group consisting ofacyl, Cwo aikyl Cf.io alkoxy, amino, amido, amidmo, Cs o aryl, C< >O aryiaikyl, azido, carbamoyl, carboxvl carboxyl ester, cyano, guanidino, halo, Cj.39 haloaikyl, Cj .; heteroalkyl, CYio heteroaryl, Q,.2o heteroarylalkyl, hydroxy, hydrazino, imina, oxo, nitro, sulfrayl, sulfonic acid, sulfonyl, thiocyanate, thiol, and thione;
wherein the Ct-jo alkyi, Cs.jo .aryl, Q.2o aryiaikyl, C\ heteroalkyl, C5.18 heteroaryl, and C^o heteroaryiaikyi groups are opiionally substituted with from 1 to 3 substituents independentl selected from C1 aikyl,€5.10 aryl, halo, C\.(, haloaikyl, cyano, hydroxy, and Cj.fj alkoxy;
or a pharmaceutically acceptable salt thereof.
[00141] Another subset of compounds of Formula (Π) relates to compounds of Formula (lid)
Figure imgf000072_0001
wherein
R3 is
boromc acid or halo; or
C(G)OR\ ~NHC(0)ORa, -NHStOfcR*, or -S(0)2NRs ; or
selected from the group consisting of C;. u. alky], C|.so aikoxy, amino, Cs-io aryl, CV20 arylalkyl, Cj.;i> heteroalkyl C^w heieroaryl. and heteroaryialkyl, each of which is optionally substituted with from 1 to 5 R"° groups;
R5 is
C(0)OR\ -NHCfOjOR*, -NHS(OfeR", or -8(0)2ΝΕ¾¾; or
selected from the group consisting of H, C O alkyl, CMO haloalkyl, CMO aikoxy, amino, C$.10 aryl 0>.2 arylalkyl, CWQ heteroalkyl, C >e heteroaryl, and Q.
20 heteroaryialkyl. each of which is optionally substituted with from 1 to 5 R"'J groups;
each R" and R:1' is independently selected from the group consisting of H, Cj .j alkyl, C$.50 aryl, Q.JO arylalkyl, 40 heteroalkyl C5.J0 heieroaryl, and C5.2 heteroaryialkyl, each of which is optionally substituted with from 1 to 5 RA' groups; and
each RM is independently selected from the group consisting ofacyl, Cj.jo alkyl CM0 aikoxy, .amino, amido, amidino, C¾..,0 aryl,
Figure imgf000072_0002
arylalkyl, nzk , carbamoyl, carboxyl, earhoxyl ester, eyano, guanidino, halo, C1..10 haloalkyl, Cj.to heteroalkyl, C5.J0 heteroaryl heteroaryialkyl hydroxy, hydrazino, imko, xo, nitro. sulfinyl, sulfonic acid, sulfanyl, thiocyanate, thiol, and thione;
wherein the CMO alkyl, C5-10 aryl, .w arylalkyl, (>.. so heteroalkyl, C5..10 heteroaryl, and Q.:>{, heteroaryialkyl groups are optionally substituted with from 1 to 3 substituents independently selected from .4 alkyl, C5.J0 aryl, halo, C|..6 haloalkyl, cyano, hydroxy, and aikoxy;
or a pharmaceutically acceptable salt thereof. [00142] Another subset of compounds of Formula (11) relates to compounds of Formula (He)
Figure imgf000073_0001
wherein
R3 is
boronic acid or halo; or
C(0)C)R\••NHC(0)(}Ra J ~NHS(0)2Ra, or -S(0)iNRt b; or
selected from the group consisting of C O alkyl, Cuo aikoxy, amino,. C5.1 aryl Cf.j(, aryialkyl, CM*, heteroalkyl, C5.ro heteroaryl rid€' ¾¾ heteroarylalkyl each of which is optionally substituted with, from 1 to 5 groups;
each Ra and R is independently selected from the group consisting of FL Cj .io alkyl, ^-io aryl Q-so aryialkyl, C^o heteroalkyl, C .JO heteroaryl, and heteroarylalkyl each of which is optionally substituted with from 1 to 5 R2 groups; and
each R"'1 is independently selected from the group consisting of cyl, Cwo alkyl, Ch.io aikoxy. amino, amido, amidino, C5.10 aryl, C'MO aryialkyl, azido, carbamoyl carboxy caxboxyl ester, cyano, gnanidino, halo, C<.ta haloaikyl Cj.ig heteroalkyl, C5.1 heteroaryl, Q-y, heteroarylalkyl, hydroxy, hydrazine, imino, oxo, niiro, sulfinyl, sulfonic acid, sulfonyl, miocyanate, thiol and thione;
wherein the CMO alkyl C5..i0 aryl (¾» aryialkyl C o heteroalkyl Cy{e heteroaryl, andC^o heteroarylalkyl groups are optionally substituted with from 1 to 3 substituents independently selected from C alkyl, ary halo, Cj.$ haloaikyl cyano, hydroxy, and C-i-g aikoxy;
or a pharmaceutically acceptable salt thereof
[00143] In separate embodiments within each of the compounds described for Formulas If Ha, lib, and He, there is another embodiment comprising a compound in which Rid and R!" are each independently
Figure imgf000073_0002
or a pharmaceutically acceptable salt the.reof.In separate embodiments within each of the compounds described for Formulas 11, 11% ib, ifc,, lid, and ie, there is another embodiment comprising a compound in which ' is C O alky], C\-u> alkoxy, or C O heteroalkyl, each of which may be optionally substituted with from 1 to 5 R''° groups, or a pharmaceutically acceptable salt thereof!n separate embodiments within each of the compounds described for Formulas If, 11a, lib, l i e, lid, and lie, there is another embodiment coniprising a compound in which R' is an, C O aryl, C5.20 aryialkyl, heteroaryl, or Q.20 beteroarylalkyl, each of which may be optionally substituted with from 1 to 5 R.^' groups, or a pharmaceutically acceptable salt thereof In separate embodiments within each of the compounds described for Formulas SI, Ha, lib, lie, and lid, there is another embodiment comprising a compound in which R5 is CMO alk i, or a
pharmaceutically acceptable salt thereof.A separate embodiment comprises a mi pound of Formula ί I.e., as defined above, wherein R * IS CM aikyl, CM alkoxy, or C O heteroalkyl, each of which may be optionally substituted with from 1 to 5 R'x: 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 '' is C5.;O aryl, Q..20 aryialkyl, CJ.JO heteroaryl, or C0..20 heteroarylalkyl, each of which may be optionally substituted with from 1 to 5 "1'1 groups, or a pharmaceutically acceptable salt thereof,
[00144] In some embodiments, the modulator of a. bromodomain-containing protein is a compound selected from the group below, or a pharmaceutically acce table salt or hydrate thereof:
Figure imgf000074_0001
Figure imgf000075_0001
!^-cyc!opropy!-<>-(3,5-dimehyli8 xaz i-4-yl)-' 3-'{2-cyGk!propyi-6-(3!S-iiimeihy!isox :!i-4--yl}- i H-bcn7.o[d]tmidazol- -yi)propan- ί -ol 1 H" snxo[dijnidazoi~-1-yi)peni«n - -oi
enzoEd raicazo-6-yl.l-3,5-dimethyiisoxa2;ois
cyci pentyi(2-cyclopropyl"6"(3,5- ditnethy!isox3zol4-yl)- lH-benzo[d] imidazoH- di l-4- yitrfieth rso]
Figure imgf000075_0002
(S)-cyciopentyl('2-cyciop»Opyl-6-(3,5- (Rj-t:yclopentyl(2-cyclq>ropyl-6-(3!5- dimetfcylisoxazol-4-yl)- i H-be«zo[d jjtni(!3zo]»4- dintethylisoxazo!-4yi)- Ϊ fM»nzo[d] imidazoi-4- yOraethanoi vljmethanol l~
l
Figure imgf000076_0001
Figure imgf000076_0002
-c ciopriipyi-6-(3,S-diniet{iyfis0ji82ioJ"4-y{ (BH»(2-cyciopropyl-4-(¾8pt-3-en-4-yi)- 1 H- lH-be«zo[dj!raid¾5ol-4-yi}hsptaR-4-oi benzo[djiinidaz l»fr-yi)-3,5-diTnetbyijsoxsizole
xa !-4-yl)- pet)tan-3»ol
I
Figure imgf000076_0003
Figure imgf000077_0001
(2-cyciopropyi-6-(3,.5-dln-ie iisox{!z.ol"4-yi)- I H-benzo[d]iinidazol-4-yi)ipyriciin-2-
Figure imgf000078_0001
yl)(py il« ift-5-yl)nicthaGol
a2o!4-yi)- a?.o!"2-
Figure imgf000078_0002
It
Figure imgf000079_0001
dimeihviisoxazoie imet y isoxazde
Figure imgf000080_0001
Figure imgf000081_0001
Figure imgf000081_0002
ei) |d}i id l 5 l)35 di h ] l 8!
Figure imgf000082_0001
-din!e!hyi
Figure imgf000083_0001
-
Figure imgf000084_0001
■■ B4
4-(7-(3,5-din quin()!iii- lH-b
Figure imgf000085_0001
xazole diitteihyiisoxazoic:
i)-4-(
Figure imgf000085_0002
y) .(cycopropanes onamde enze m fazo!--2-amne
Figure imgf000086_0001
!nelhylpyridiri-3-yl iH-beiiZ()(djirajd3?.o)-6-ylV 3-y])- 1 H-ber)zo[d] imidaz0l-6-yl)-3(5- 3.5-dimethvl isoxazoie ditnetbvlisosazoie
Figure imgf000087_0001
Figure imgf000088_0001
- H . ~
-(2-cyclopropyi-?-(3,5-(iinsetiiyl- 1 H-pyrazoI-4- yl)- i -methyl- J H--be i i¾o[ d ] irn i d 32 o 1- 5 - yl)-3 , 5 - oimethylisoxazoie
Figure imgf000089_0001
-(2-cyclopr«py}- 1 -methyl-7-(6-metbylquinolin- ••(2-cycIobi:tyl-4-(3,5-dini0thyl-lH-pyf:«:o]-4- 5-yl)- 1 H-bcnzo[d])mida2oi"3-y; )··3,5- yl)-lH-benzo[d]m-Hda2el-6-yl)-3,5- dirnethylisoxazo!e diraethylisoxazole 8:9
dazols-4,6- fl iie)
Figure imgf000090_0001
Figure imgf000090_0002
)-2- i-6-yi-,)-
M-yj)
Figure imgf000091_0001
-cycl pen!yi-6-(3,5-ditf»gthySfSoxazol-4-yl)- (hydtoxyB3eihyl)-lH-benzo[d3t{Kidazoi6-4-
Figure imgf000092_0001
sulfonaniide
3,5 zot
yl)-2-
Figure imgf000092_0002
xazoi-4-y:|>-2.- du'iietbyl!Soxaz I- -yl)-] H-benzoldliinidazole- (pheaylamino)*} H-beiKo[d] imidazoles- 4-sulf namide sulfonamide
Figure imgf000093_0001
Figure imgf000094_0001
~ methyl 2-cyckspropyS -(3,5-dimethylisoxa;iol- dim 2oie- 4.y[ 1 H-benzo[d]in!idazc e~4-c&rhoxy!ate
methyl 2-cyc.lopt«pyi-6-{3i,5-i¾meti.ylisoxazd- 4-yl)-l-tnethyi-lH-b6!)zo[d'Jimidazoie-4~
carboxyiate
N»(6-n( H"benzad]imidazoi-
Figure imgf000095_0001
y )cyc opropan ssu onaro e
j5- dime da:i i--4--
Figure imgf000095_0002
[00145] it is understood that separate, single embodiments comprise the methods, regimens, kits, and articles of manufacture in which the modulator of a hromodomam-contaming 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, i2-cyclopropyl-6-(345- dirnethylisoxazol -4-yl>- 1 li"beiKo[d3imidazol-4-y])di(pyridin-2-yl)me hanol, 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 bromodomain-containing protein is (2 yclopropy{-6»(3,5-a¾meihy1isoxa2o{ -y1)-dK"ben2o[d)imidazob4- yl)diipyi-azin~2"-yl)methanol, or a pharmaceutically acceptable hydrate thereof. There are also embodiments in which the modulator of a broraodomain- containing protein is (2^cyelopropyl~6-(3,.5-^
be«2o[d]imidazoi -yl.!(pyridin"2"y!)fpyrinud or a
pharmaceutically acceptable hydrate thereof.
(86146) There are also embodiments in which the modulator of a bromodomain- containing protein is (2~cyelQpropyl-6-(3,5-dimethyIisoxa
beazo d]inuda7X)l.--4-yl}(pyridvn-2 -yi){p>iimidi or a
pharmaceutically acceptable hydrate thereof. There are also embodiments in which the modulator of a bromodomain-containing protein is (2-cyc!opropyl-6- (3 ,5-dimethyli soxazol-4-yl)- 1 H-ber«o[d]imia¾zol"4-yi)di^yridin-3 -yl)methanol, or a pharmaceutically acceptable hydrate thereof. There are also embodiments in which the modulator of a bromodomain-containing protein is (2~cyclopropyl~6~ (3,5"dimeraylisoxa¾ol~4-y1)-lH^^
yl)meihattol. or a pharmaceutically acceptable hydrate thereof. There are also embodiments in which the modulator of a bromodomain-containing protein is (2- cyelopropyl-6-(3,5Klimethyiisoxazol-4-yl)-l H~benzo[d]imidazol-4- yl)('phenyjXpyridin»3»yl)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 2014-03361 0. MP9 Inhibiting Agents
[00.147] Useful MMP9 inhibiting agents include comprises binding proteins, e.g., antibodies and antigen-binding fragments thereof, that bind to the matrix metalloproteinase-9 (MMP9) protein (M. P9 is also known as gelatinase-B), wherein the binding proteins comprise an immunoglobulin (ig) heavy chain (or functional fragment thereof) and an Ig light chain (or functional fragment thereof) disclosed in U.S. 20.15-0140580 (Smith et 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.)s each of which is incorporated herein by reference.
[001 8 j Practice of the present disclosure employs, unless otherwise indicated, standard methods and conventional techniques in the fields of celt biology, toxicology, molecular biology, biochemistry, cell culture, immunology, oncology, recombinant D A and related fields as are within, the skill of the art, Such techniques are described m the literature and thereby available: to those of skill in the art. See, for example, Alberts, B, el lt "Molecular Biology of the Cell" 5th edition, Garland Science, New York, NY, 2008; Voei, D. et al.
"Fundamentals of Biochemistry: Life at the Molecular Level " 3ie edition, John Wiley & Sons, Boboken, NJ, 2008; Sambrook, J. et al,, "Molecular Cloning: A Laboratory Manual," 3'° edition, Cold Spring Harbor Laboratory Press, 2001 ; AusuheL F. et al., "Current Protocols in Molecular Biology," John Wiley & Sons, New York, 1987 and periodic updates; Freshney, R.I., "Culture of Animal Cells: A Manual of Basic Technique," 4!¾ edition, John Wiley & Sons, Somerset, NJ, 2000; and the series "Methods in Enzymology," Academic Press, San Diego, CA. See also, for example, "Current Protocols in Immunology," (II. Coico, series editor), Wiley, last updated August 2010.
10149] The present combinations provide binding proteins, e.g., antibodies and antigen-binding fragments thereof, that bind to the matrix metaUoproteinase-9 (MMP9) protein (MMP9 is also known as gelatinase-B). The binding proteins of the present disclosure generally comprise an immunoglobulin (Ig) heavy chain (or functional fragment thereof) and an Ig light, chain (or functional fragment thereof) to be used in the methods, regimens, kits, and articles of manufacture herein, with a pharmaceutically effective amount, or with individual dose units containing a pharmaceutically effective amount, of Compound A 1.
(001501 The combinations include MMP9 binding proteins thai bind specifically to MMP9 and not to other matrix metalioproteinases such as MMPL MMP2, MMP3, MMP7, MMP9, MMPK), MMP12, MMPJ.3. Such specific MMP9 binding proteins are thus generally not significantly or deteciably crossreactive with non-MMP9 matrix meiailoprotekiases. MMP9 binding proteins that specifically bind M P9 find use in applications in. which it is necessary or desirable to obtain specific modulation (e.g.. inhibition) ofMMF9. e.g., without directly affecting the activity of other matrix metalioproteinases.
[00151] lit certain embodiments of the present disclosure an anti-MMP9 antibody is an inhibitor of the activity of MMP9, and can be a specific inhibitor of M P9. In particular, the MMP9 binding proteins disclosed herein will be useful for inhibition of MP9 while allowing norma} function of other, related matrix metalioproteinases, "An inhibitor of MMP" or "inhibitor of MMP9 activity" can be an antibody or an antigen binding fragment thereof thai directly or indirectly inhibits activity of MMP9, including but not limited to enzymatic processing, inhibiting action of MMP9 on it substrate (e.g., by inhibiting substrate binding, substrate cleavage, and the like), and the like.
[00152] The present combinations also comprise MMP9 binding proteins that specifically bind to non-mouse MMP9, such as human M P9, Cyrtomolgus monkey MMP9, and rat M P9.The combinations also comprise MM.P9 binding proteins (e.g., anti-MMP9 antibodies and functional fragments thereof) mat 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.
[001 S3] 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 thereof) that has at least about 80%, 85%, 0%, 95% or more ammo 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 maniactore, and kits include those that bind MM.P9, particularly human MMP9, and having a light polypeptide (or functional fragment thereof) that has ai least about 80%, 85%, 90%, 95% or more amino acid sequence identity to a heavy chain polypeptide disclosed herein. MMP9 binding proteins (e.g., antibodies and functional fragments thereof) of the present disclosure include those that bind MMP9, particularly human MMP9, and have a heavy chain polypeptide (or functional fragment thereof) having the
complementarity determining regions ("CDRs ) of heavy chain polypeptide and the CDRs of a light chain polypeptide (or functional fragment thereof) as disclosed .herein,.
10015 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).
[001551 Sequence identity between two nucleic acids can also be described in terms of hybridization of two molecules to each other under stringent conditions. The hybridization conditions are -selected following standard methods in the art (see, for example, Samhrook, et a-L, Molecular Cloning: A Labora tory Manual, Second Edition, (1989) Cold Spring Rarhor,'N.Y .). An example of stringent hybridization conditions is hybridization at 50°C or higher and 0.1 χ SSC (15 mM sodium chloride/ .5 mM sodium citrate). Another example of stringent hybridization, conditions is overnight incubation at 42 X. in a solution: 50 % formamide, 5 x SSC (150 roM aCL 15 mM tnsodium citrate), 50 mM sodium phosphate (pH7.6), 5 * Denhardfs solution, 10% dextran sulfate, and 20 mg/mi - - denatured, sheared salmon sperm DMA, followed by washing the fitters in 0.1 x SSC at about 65 . Stringent hybridization conditions are hybridization conditions thai are at least as stringent as the above representative conditions, where conditions axe considered to be at least as stringent if ihey are at least about 80% as stringent, typically at least 90% as stringent as the above specific stringent conditions. Examples of anti-MMP9 antibodies of the present disclosure are described in more detail below.
[00156] Anii~MMP9 antibodies can he described in terms of the CDRs of the heavy and light chains. In some embodiments, an antibody is a humanized antibody or a human antibody. Humanized antibodies include human immununoglobulins (recipient antibody) in which residues from a
complementary-determinkg region (CD ) of die 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 forms of non-human (e.g.,, murine) antibodies are chimeric immunoglobulins which contain minimal sequence derived from non-human immunoglobulin. The non -human sequences are iocated primarily in the variable regions, particularly in the complemeniarity-determining regions (CDRs). In some embodiments, Fv framework residues of the human immunoglobulin are replaced by corresponding non-human residues. Humanized antibodies can also comprise residues that are found neither in the recipient antibody nor in the imported CDR or framework sequences, In certain embodiments, a humanized antibody comprises substantially ail of at least one, and typically two, variable domains, in which all or substantially all of the CDRs correspond to those of a non-huraan
immunogiobufin and all or substantially all of the framework regions are those of a human immunoglobulin consensus sequence. For the purposes of the present disclosure, humanized antibodies can also include immunoglobulin fragments, such as Fv, Fab, Fab', F(ab')2 or other antigen-binding subsequences of antibodies.
[00157] The humanized antibody can also comprise at least a portion of an immunoglobulin constant region (Fc), typically (hat of a human immunoglobulin. See, for example, Jones et al. (1986) Nature 321 :522--525; Rie iraa n et al. (1988) Nature 332:323-329; and Presta (1992) C rr. Op. Struct. Biol. 2:593-596.
[06158) 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-huraan 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, hum an mation can he 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; iechmann 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),
[00159] Human antibodies can also be produced, for example, by using phage display libraries. Hoogenboom et al. ( 1 91) J. Mol. Biol, 227:381 ; Marks et al (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. ( 1 1) J. Immunol. 147:86-95.
[00160] 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) Bio/Technology 10:779-783 (1992); Lonberg m at (1994) Nature 368: 856-859; Morrison (J 994) Nature 368:812-813; Fishwaid et l f 1996) Nature
Biotechnology 14:845-851 ; Neuberger (1996) Nature Biotechnology 14:826; and Lonberg a al (] 99S) Intern. Rev. Immunol 13:65-93.
[00161 j 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 live times or more, ten times or more, twenty times or more, or thirty times or more than that of the starting antibody ί generally murine, rabbit, chicken, humanized or human) from which the matured antibody is prepared,
[00162] An antibody can also be a bispecifie antibody, Bispecilk 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 MPs, or to two different epitopes on a single MM? (e.g. , MMP9).
[00 J 63] An antibody as disclosed herein can also be an inmiunoconjugale. Such immunoconjugates comprise an antibody (e.g., to M.MF9) conjugated to a second molecule, such as a reporter. An imniurtoconjugate can also comprise an antibody conjugated to a cytotoxic agent such as a chemotherapeuric agent, a toxin (e.g.. an enxymaiieaily active toxin, of bacterial fungal, plant, or animal origin, or fragments thereof), or a radioactive isotope (i.e., a radioconjugatc).
[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 or polypeptide epitope. In same embodiments, an antibody of the present disclosure specifically binds to human MMP9 with a dissociation constant (K<s) equal to or lower than 100 nM, optionally lower than 10 nM, optionally lower than 1 nM, optionally lower than 0.5 nM, optionally lower than 0.1 nM, optionally lower than 0.01 nM, or optionally lower than 0.005 nM; in the form of monoclonal antibody, scFv, Fab, or other form of antibod measured at a temperature of about 4°C 25CC, 3TC or 42°C. |00I6S| In certain embodiments, use of an antibody of the present disclosure binds to on or more processing sites (e.g., sites of proteolytic cleavage) in. MMP9. thereby effecti vely blocking processing of the proenzyme or preproenzyrae 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 MM P. 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 {¾). equilibrium constant (KSK) 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. 100167] The present disclosure also contemplates use in the methods, regimens, kits, and articles of manufacture herein of antibodies, or antigen binding fragments thereof, that compete with anti«MMP9 antibodies or antigen binding fragments thereof described herein for binding to MMP9. Thus, the present disclosure contemplates use of anti-MMP9 antibodies, and .functional fragments thereof, that compete for binding with, for example, an antibody having a heavy chain polypeptide of any of SEQ ID NOS: 1 or 5-8, a light chain polypeptide of SEQ ID OS:2 or 942, or combinations thereof. In one embodiment, the anti- MMP9 antibody, for functional fragment thereof, competes for binding to human MMP9 with the antibody described herein as AB004I . MMP9 sequence
[00168] The amino acid sequence of human M.MP9 protein is as follows:
MSLWQPLVLV LLVLGCCFAA P Q QSTLV1, FPGDLRTNLT DRQLAEEY LY 50
RYGYT VAE RGES S(..GPA LLLLQKQLSL PETOELDSAT I..KAMRTPRCG 100
VPDLGRFQTF EGDL WHRHN JTYW!QNYSE DLPRAVIDDA FARAFALWSA ISO
VTPLTFTRVY SRDADIVIQP GVAEHGDGYP FDG DGLLAH AFPPGPGIQG 200
DAHFDDDELW SLGKGVVVPT RFGNADGAAC HFPFIFEGRS YSACTTDGR8 250
DGLPWCSTTA NYDTDDRFGF CPSERLYTRD GNADGKPCQF PPIFQGQSYS 300
ACTTDGRSDG YRWCATTANY DRDKLFGFCP TRADSTV GG NSAGELCVFP 350
FTFLGKEYST CTSEGRGDGR LWCATTSNFD SDKKWGFCPD QGYSLFLVAA 400
HEFGHALGLD HSSWEAL Y PMYRFTEGPP LH .DDVNGIR HLYGPRPEPB 450
PRPPTTTTPQ PTAPPTVCPT GPPTVHPSER PTAGPTGPPS AGPTGPPTAG 500
PSTATI VPLS PVD ACNVNI PDAiABIGNQ LYLFKDGK Y RFSBGRGSRP 550
QGPFLSA W PALPRKLDSV PEEPLSKKLF FFSGRQVWVY TGASVLGPRR 600
LD LGLGA V AQVTGALRSG RGK LLFSGR RLWRPDV AQ MVDPRSASEV 650 DR FPGVPL'D THDVPQYREK. AYFCQDRFYW RVSSRSELNQ V!X)VGYVTY
70aiLQCPED (SEQ ID NO:27)
(00169] Protein domains are shown schematically in Figure 3 and are indicated below:
Amino Acid # Pe re
1-19 Signal Peptide
38- 8 Peptidoglycan Binding Domain
R98/C99 Propeij.de cleavage site (dependent on cleavage- enzyme)
1 12445 Zn dependent metailopjoteinase domain
223-271 Fibronectin type 11 domain (gelatin binding domain)
281-329 Fibrotiectin type 11 domain (gelatin binding domaio)
340-388 Fibronectin type 11 domain (gelatin binding domain)
40(1- 1 1 Zn binding region
521-565 He opexi:n -like domain
567-608 Hemopexin-like domain
613-659 Hemopesirs-like domain
661 -704 Hemopexm-Hke domain
[00170] The amino acid sequence of mature full-length human MMP9 (which is the atrii.no acid sequence of the propolypepiide of SEQ ID NO:27 withou t the signal peptide) is: PRQRQSTLVL FPGDLRT LT DRQLAEEYLY RY(5YTRVAEM RGESKSLGPA LLLLQKQLSl PBTGELD'SAT L AMRTPRCG VPDLGRFQ P EGDLKWHHHN !TYWIQNYSE LPRAV DA FA.RAFALWSA VTPLTFrRVY SRDADiVlQF GVAEHGDGYP FDG DGLLAH AFPPGPG1QG DAHFDDDBLW SLG GVVVPT RFG ADGAAC HFPPIFEGRS YSACTTDGRS DGLPWCSTTA NYDTDDRFGF CPSERLYTRD GNADGKPCQF PFIFQGQSYS ACTTDGRSDG YRWCATTANY DRD LFGFCP TRADSTVMG S GELCVFP FTFLGKKYST CTSEGRGiXiR LWCATTS FO S K WGFCPD QGYSLFLVAA HEFGHALGLi) HSSVPEALMY P YRFTEGPP LHKDDVNG1R HLYGPRPEPE PRPPTTTTPQ PTAPPWCPT
GPPTVHPSER PTAGPTGPPS AGPTGPPTAG PSTA'Il VPL-S PVDDACNVN1
FDAIAEIGNQ L YLF GKY W R PSEGRGS RP QGPFLJAD PAEPR LDSV FEEPLSKKLF FPSGRQVWYY TGASVLGPRR LDKLGLGADV AQVTGALRSG RGKMLLFSGR Rl.WRFDVK.AO VDPRSASEV DR FPGVPLD THDVFQYREK AYFCQDRFYW RVSSRSELNQ VDQVGYVTYD IL.QGPED (SBQ ID NO:28)
[00.171 J The: amino acid sequence of the signal peptide is MSLWQPLVLV
LLVLGCCFAA (SEQ ID NO:29).
[00172] The present disclosure contemplate the use of MMP9 binding proteins that, bind any portion of MM.P9, e.g., human MMP9, with MMP9 binding proteins that preferentially bind MMV9 relative to other M'MPs being of particular interest, Ant MMP9 antibodies, and functional fragments thereof, can be generated accordingly to methods well known in the- art. Examples of anti - MMP9 anti odies are provided below,
Mouse monoclonal anti-MMP9
(00173) A mouse monoclonal antibody to human MMP9 was obtained as described in Example 2. This antibody contains a mouse- JgG2b heavy chain and a mouse kappa light, chain, and is denoted AB0041.
[001 4J The amino acid sequence of the AR00 I heavy chain is as follows;
MAVLVXFLCLVAFPSCVLSOVOLKI-SGPGLVAPSQSLSiTCTVSCTFS LLSYGVHWV QPPGKGLEWLGVIWTCiC rrTNY SAI SRLSIS DSKSQ VFL. MNSLQTDDTAiYYCARyYYGMDYWGQGTSYTYSS^iCITP/^ ZPL^ PGCGDTTGSSVTLGCL VKGYFPESVrVTWN' SGSLSSSVHTFPALLQSGL YTMSSS VTyPSSIWPSQTVTCWAHPASSTTyDKKLEPSGPISTINPCPPCKECHKCPAPN LEGGPSVF!FPPNIKDVlMlSLTPKyJVVVVDVSEDDPDrRISWFVNNVEVHTA OTQTHR£DYNSTIRpySALPIQHQDW 4SGKEFKCKVNNKDLPSPIERmnKG - 1 C'5 ·
L VRAPO VYILPPPAEQLSRKD VSLTCL VVGFNPGDISVEWTSNGHTEENYKDTA PVLDSDGSVFiYSKLDIKTSKWEKTDSFSCNVRHEGlJiNYYLKKT!SRSPGK (SEQ ID NOT)
(00175] The signal sequence is underlined, and the sequence of the IgG2b constant region is presented italics,.
[00176] The amino acid sequence of the.AB0041 Sight chain is as follows:
M£SOIOVF^FVFi.,WL.SGVDGDiVMTOSHKi-MSTSVGD VSiTCKAS
QDVI^TVAWYQQ TGQSP ITJYSSSYRNTCiVPDRFTGSGSGTDFTFnSS VQAEDLAVYFCQQHYiTPYTFGGGTKLEiK^^
5 VVCFLNNFYPKDINVKWKIDGSERQNG yLNSWTDQDSKDSTYSMSSTLTLTKD EYERHNSYTGEATHKTSTSPIVKSFNRNEC { SEQ ID NO: 2)
[00177] The signal sequence is underlined, and the sequence of the kappa constant region is presented in italics.
[0017$] 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):
OV )LKESCd)GLVAPSOSLSrfCIA/SGFSLL^Y(:iVTlWVRQPPG GLE WLGVIWTGGTTNYNSA^
RYYYGMDYWGOGTSVTVSS (SEQ ID NO:3)
[00179] The following amino acid sequence comprises the framework regions and compiemenhirity-detenninmg regions (CDRs) of the variable region of the kappa light chain of ABG041 (with CDRs underlined):
DIVMTQSHKFM STSVGDRV S1TC ASODVR TVAWOOKTGOSPK •lJJYSSSYR.NTCA^DRFrGSGSGTDm ISSVOAEDLAV /PCOOHYrfPYTF GGGTKLE1K (SEQ ID O:4)
Heavy-chain variants
[00180] As noted in U.S. Patent Nos. 8,377,443 (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 AB0041 heavy and .light chains were separately modified, by altering framework region sequences in the heavy and light chain variable regions. The effect f these sequence alterations was to deplete the antibody of human T-eelS epitopes, thereby reducing or abolishing its
immunogenicit in humans (Antitope, Babrahani, UK).
[0018.1 j Four heavy-chain variants were constructed, in human ]gGA heavy chain background containing a S241P amino acid change thai stabilizes the hinge domain (Angal <?/ ai (1993) Moiec. Immunol. 30: 105 -108 ). and are denoted VH1, VH2, VH3 and VH4. The amino acid sequences of their framework regions and CDRs are as follows:
VH1
QVQLQBSGPGLV PSETLSLTCTVSGFSLI^YGVHWVRQPPGKGLEWLGVIWTGG r{^YNSALMS l lS DDS STVYi, M S{, EDTAiYY ARYYYGMDYWGQGT SVTVSS (SEQ ID NO: 5
VH2
QVQLQESGPGLV PSBll.SLTCTVSGFSiLSYGVHWVRQPPGKGL£VY iV!:WTGG: TTNYN8ALMSRi;]lSKDi>S NTVYIJiMNSL TEDTAiYYCA YYYG^i)YWGQG
TLVTVSS (SEQ ID NO:6)
QVQI.QESGPGI,V PSETLSL;rcrVSGFSLI.SYGVHWVROPPGK iLE WLGV.iWTG(iT'rNYNSAI,MSRFiISKDDSKNTVYLKMNSL TED'rA IYYCARYYYGMDYWGQGTLVTVSS (SEQ ID NO: 7)
VH4
QVQLOESGPGLVKPSETLSETCTVSGFSELSYGVHWY QPPCiKGLE . WLGViWTGGTTOWSALMSRFnSKDDSK lIAXKMNSLKl rAI. YYCARYYYGMDYWGQGTLVTVSS (SEQ ID NO:8)
Li gh ί -chain van ants
[00182] Four light-chain variants were constructed, in a human kappa chain background, and are denoted Vkl, Vk2„ Vk3 and Vk4. The amino acid sequences of their framework regions and CDRs are as follows::
Vkl
Di\WQSPSFLSASVGDRVTITCKASQDVRNl,VAWYQQ TG AI»K
LIJYSSSYRNTGVPDRFTGSGSGTDFTUnSSLQAEDVAVYFCQQFiYI TPYTFGGGTKVEIK (SEQ ID NO:9) Vk2
DIVMTQSPSSLSASVGDRVinCKASQDVRN'TVAWYQQ^GKAP UJYSSSYRNTGVPD FTCiSGSGTDFTLTiSSLQAEDVAVYFCQQHYI TP YTFG GGTK VE1K (SEQ ID NO: 10)
Vk3
DIQMTQSPSSLSASVGDRWITC ASQDVI NTV'AWYQQKPGKAPK
UJ.YSSSYRNTi}VPDRFSGSGSGTDFTLTISSLQAEDVAVYFCQQHYI
TPYTFGGGT .VEI (SEQ ID NO: 11)
Vk4
DlQMTOSPSSLSASVGDRVTiTCKASQDVRNTVAWYQQKPGKAPK iTiYSSSY RN'l'GVPDRFSGSGSiTrDFl LTTSSL.QAEDVAVYYCQQSiY iTPY FOGGTKVEIK (SEQ ID NO: 12.) j 001831 The humanized heavy and light chains are combined in all possible pair- wise combinations io generate a number of functional humanized a.«ti--MMP9 antibodies.
[00184] Additional heavy chain variable region amino acid sequences having 75% or more, 80% or more, 90% or more, 95% or more, or 99% or more homology io the heavy chain variable region sequences disclosed herein are also provided. Furthermore, additional light chain variable region amino acid sequences having 75% or more, 80% or more, 90% or more, 95% or more, or 99% or more homology to the light chain variable region sequences disclosed herein are also provided.
[001851 Additional heavy chain variable region amino acid sequences having
75% or more, 80% or more, 90% or more, 95% or more, or 99% or more sequence identity to the heavy chain yariabie region sequences disclosed herein are also provided. Furthermore, additional light chain variable region amino acid sequences having 75% or more, 80% or more, 90% or more, 95% or more, or 99% or more sequence identity to the light chain variable region sequences disclosed herein are also provided. CompleTnentarity-determking regions (CDRs)
{00186] The CDRs of the heavy chain of an anti~MMP9 antibody as disclosed herein have the following amino acid sequences:
CDR1 : GFSLLSYGVH (SEQ I'D NO: 13)
CDR2: VIWTGGT N YN S ALMS (SEQ ID NO: 14)
CDR3: YYYGMDY (SEQ 1.D NO: 15)
(00187'j The CDRs of the light chain of an anti-MMP9 antibody as disclosed herein have the following amino acid sequences:
CDR 1 : ASQDVRNTVA (SEQ ID NO: 16)
CDR2: SSSYRNT (SEQ ID NO: 17)
CDR3: QQHYITPYT (SEQ ID NO: 18}
Nucleic acids encoding a:nti- MP9 antibodies
(0.0188) The: present disclosure provides use in the methods, regimens, kits, and articles of manufacture herein of nucleic acids encoding antidvfMP9 antibodies and functional fragments thereof. Accordingly, the present disclosure provides an isolated polynucleotide (nucieic acid) encoding an antibody or antigen- binding fragment as described herein, vectors containing such polynucleotides, and host cells and expression systems for transcribing and translating such polynucleotides into 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,
(00189) The present disclosure also provides the use of a recombinant host ceil 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 nucieic acid encoding a heavy chain polypeptide and a light chain polypeptide (in the same or different host cells, and from ike 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. 100190, 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, and baculo virus systems, Mammalian ceil lines available in the art for expression of a heterologous polypeptide include Ch inese hamster ovary cells, HeLa cells, baby hamster kidney cells. NSC) mouse melanoma cells and many others. A common bacterial host is E. coli.
[00191) Suitable vectors can be chosen or constructed, containing appropriate regulatory sequences, including operably linked promoter sequences, terminator sequences, polyadersylation sequences, enhancer sequences, marker genes and/or other sequences as appropriate. Vectors can be plasmids, viral e.g. 'phage, oi phagemid,. as appropriate. For further details see, for example, Molecular Cloning: a Laboratory Manual.: 2nd edition, Sambrook et al., 1989, Cold Spring Harbor Laboratory Press. Many known techniques and protocols for
manipulation of nucleic acid, for example rn preparation of nucleic acid constructs, mutagenesis, sequencing, introduction of D A into cells and gene expression, and analysis of proteins, are described in detail in Short Protocols in Molecular Biology, Second Edition, Ausubei el al. eds., John Wiiey & Sons, 1992. The disclosures of Sambrook et al. and Ausubei et al. are incorporated herein by reference in their entirety.
[001 2] 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 episomai 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 e operabiy linked to a promoter, and provided in an expression construct far use in methods of prod uction of recombinant MMP9 proteins or portions ihereof.Those 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: ■ ί 1 0 ·
VH1 : CAGGTGCAGC TGCAGGAATG CGGCCCTi SC
CTGGTCAAGC CCTCCGAGAC ACTGTCCCTG ACCTGCACCG TGTCCGGCTT CTGCCTGCI G TCCTACGGCG TGCACTGGGT CCGACAGCCT CCAGGGAAGG GCCTGGAATG GCTGGGCGTG ATCTGGACCG GCGGCACCAC CAACTACAAC TCCGCCCTGA TGTCCCGGCT GACCATCTCC AAGGACGACT CCAAGTCCAC CGTGTACCTG AAGATGAACT CCCTGAAAAC CGAGGACACC GCCATCTACT ACTGCGCCCG GTACTACTAC GGCATGGACT ACTGGGGCCA GGGCACCTCC GTGACCGTGT CCTCA (SEQ ID NO: 1 )
VH2: CAGGTGCAGC TGCAGGAATG CGGCCCTGGC
CTGGTCAAGC CCTCCGAGAC ACTGTCCCTG ACCTGCACCG TGTCCGGCTT CTCCCTGCTG TCCTACGGCG TGCACTGGGT CCGACAGCCT CCAGGCAAAG GCCTGGAATG GCTGGGCGTG ATCT GGACCG GCGGCACCAC CAACTACAAC TCCGCCCTGA TGTCCCGGCT GACCATCTCC AAGGACGACT CCAAGAACAC CGTGTACCTG AAGATG ACT CCCTGAAAAC CGAGGACACC GCCATCTACT ACTGCGCCCG GTACTACTAC GGCATGGACT ACTGGGGCCA GGGCACCCTG GTGACCGTGT CCTCA (SEQ ID NO;20)
\Ή3: CAGGTGCAGC TGCAGGAATG CGGCCCTGGC
CTGGTCAAGC CCTCCGAGAC ACTGTCCCTG ACCI'GCACCG TGTCCGGCTT CTCCCTGCTG TCCI ACGGCG TGCACTGGGT CCGACAGCCT CCAGGCAAAG GCCTGGAATG GCTGGGCGTG ATCTGGACCG GCGGCACCAC CAACTACAAC TCCGCCCTGA TGTCCCGGTT GACCATCTCC AAGGACGACT CCAAGAACAC CGTGTACCTG AAGATGAACT CCCTGAAAAC CGAGGACACC GCCATCTACT ACTGCGCCCG GTACTACTAC GGCATGGACT ACTGGGGCCA GGGCACCCTG GTGACCGTGT CCTCA (SEQ ID G.2 i )
VH4: CAGGTGCAGC TGCAGGAATG CGGCCCTGGC
CTGGTCAAGC CCTCCGAGAC ACTGTCCCTG ACCTGCACCG TGTCCGGCT7 CTCCCTGCTG TCCTACGGCG TGCACTGGGT CCGACAGCCT CXAGGCAAAG GGCTGGAATG GCTGGGCGTG ATCTGGACCG GCGGCACCAC CAACTACAAC TCCGCCCTGA TGTCCCGGTT CACCATCTCC AAGGACGACT CCAAGAACAC CCTGTACCTG AAGATGAACT CCCTGAAAA.C CGAGGACACC GCCATC'f ACT ACTGCGCCCG GTACTACTAC GGCATGGACT ACTGGGGCCA GGGCACCCTG GIX14CCGTGT CCTCA (SEQ ID NO:22)
Vkl ί GACATCGTGA TGACCCAGTC CCCCAGCTTG
CTGTCCGCCT CCGTGGGCGA CAGAGTGACC ATCACATGCA AGGCCTCTCA GGACGTGCGG A CAGCGIGG CCTGGTATCA GCAGAAAAGC GGCAAGGCCC CCAAGCTGCT GATCTACTCC TCCTCCTACC GGAACAC'CGG CGTGCCCGAC CGGTTTACCG GCTCTGGCTC CGGCACCGAG TTTACCCTGA CCATCAGGTC CCTGCAGGCC GAGGACGTGG CCGTGTA.CTT CTGCCAGCAG CACTACATCA CCCCCTACAC CTTCGGCGGA GGCA.CCAAGG TGGAAATAAA A (SEQ ID O:23)
Vk2: GACATCGTGA TGACCCAGTC CCCCTCCAGC
CTGTCCGCCT CTGTGGGCGA CAGAGTGACC ATCACATGCA AGGCCTCTCA GGACGTGCGG AACACCGTGG CCTGGTATCA GCAGAAGCCC GGCAAGGCCC CCAAGCTGCT GATCTACTCC TCCTCCTACC GGAACACCGG CGTGCCCGAC CGGTTTACCG GCTCTGGCTC CGGCACCGAG TTTACCCTGA CCATCAGGTC CCTGCAGGCC GAGGACGTGG CCGTGTACTT CTGCCAGCAG CACTACATCA CCCCCTACAC CTTCGGCGGA GGCACCAAGG TGGAAATAAA A (SEQ ID NO: 24)
Aid: GACATCCAGA TGACCCAGTC CCCCTCCAGC
CTGTCCGCCT CTGTGGGCGA CAGAGTGACC ATCACATGCA AGGCCTCCCA GGACGTGCGG AACACCGTGG CCTGGTATCA GCAGAAGCCC GGCAAGGCCC CCAAGCTGCT GATCTACTCC TCCTCCTACC GGAACACCGG CGTGCCCGAC CGGTTCTCTG GCTCTGGAAG CGGCACCGAC TTTACCCTGA CCATCAGGTC CCTGCAGGCC GAGGACGTGG CCGTGTACTT CTGCCAGCAG CACTACATCA CCCCCTACAC C'TTCGGCGGA. GGCACCAAGG TGGAAATAAA A (SEQ Π) NO:25 }
Vk4: GACATCCAGA TGACCCAGTC CCCCTCCA.GC
CTGTCCGCCT CTGTGGGCGA CAGAGTGACC ATCACATGCA AGGCCTCTCA GGACGiGCGG AACACCGTGG CCTGGTATCA GCAGAAGCCC GGCAAGGCCC CCAAGCTGCT GATCTACTCC TCCTCCTACC GGAACACCGG CGTGCCCGAC CGGTTCTCTC GCTCTGGAAG CGGCACCGAC TTTACCCTGA CCATCAGCTC CCTGCAGGCC GAG<}ACGTGG CCGTGTACTA CTGCCAGCAG CACTACATCA CCCCCTACAC C'TTCGGCGGA GGCACCAAGG TGGAAATAAA A (SEQ I'D NO:26)
[00194] Because the structure of antibodies, including the juxtaposition ofCDRs 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-M P -9 antibodies. Accordingly, polynucleotides comprising nucleic acid sequences having at least. 75%, at least 80%, ai least 85%, at least 90%, at least 95%, at least 98% and at least 99% homology to any of the nucleotide sequences disclosed herein are also provided. Accordingly, polynucleotides comprising nucleic acid sequences having at least 75%, at least 80%, at least 85%, at least 90%, at. least 95%, at least 98% and at least 99% identity to any of the nucleotide sequences disclosed herein are also provided,
100195] MMP9 binding proteins, as well as nucleic acid (e.g., DNA or RNA) encoding MMP9 binding proteins, can be pro vided as a pharmaceutical composition, e.g., combined with a pharmaceutically acceptable earner or exeipieni. 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.
[00196] Pharmaceutically acceptable carriers are physiologically acceptable to the administered patient and retain the therapeutic properties of the antibodies or peptides with which it is administered, Pha aceuiscaliy-aoceptabie carriers and their formulations are and generally described in, for example. Remington' pharmaceutical Sciences (18th Edition, ed. A. Gennaro, Mack Publishing Co., Easton, PA 1 90), One exemplary pharmaceutical earner 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 ihe patient,
[00197] Pharmaceutical compositions can be formulated to be compatible with a particular route of administration, systemic or local, Thus, pharmaceutical compositions include carriers, diluents, or excipi nts suitable for administration by various routes.
[001 8] Pharmaceutical compositions can include pharmaceutically acceptable additives,. Examples of additives include, but are not limited to. a sugar such as marmiiol, sorbitol, glucose, xylitol, trehalose, sorbose, sucrose, galactose, dextran, dextrose, fructose, lactose and mixtures thereof. Pharmaceutically acceptable additives can be combined with pharmaceutically acceptable carriers and/or excipients such as dextrose. Additives also include surfactants such as polysorbate 20 or polysorbate 80.
[00199] The formulation and delivery methods will generally be adapted according to the site and the disease to be treated. Exemplary formulations include, but are not limited to, those suitable for parenteral administration, e.g., intravenous, infra-arterial, intramuscular, or subcutaneous administration.
[00200] Pharmaceutical compositions for parenteral delivery include, for example, water, saline, phosphate buffered saline, Hank's solution. Ringer's solution, dextrose/saline, and giuco.se solutions. The fomulations can contain auxiliary substances to approximate physiological conditions, such as buffering agents, tonicity adj usting 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 trietbanolamine oleate. Additional parenteral formulations and methods axe described in Bai ( 1997) J, Neuroimraunol. 80:65 75: Warren (1997) j. Neurol. Sci. 152:31 38; and Tonegawa (1997) J, Exp, Med. 1 6:507 515. The parenteral preparation can be enclosed in ampules, disposable syringes or multiple dose vials made of glass or plastic.
(00201) Pharmaceutical compositions for intradermal or subcutaneous administration can include a sterile diluent, such as water, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parahens; antioxidants such as ascorbic acid, glutathione or sodium bisulfite; chelating agents such as ethylenedianiinetetra acetic acid; buffers such as acetates, citrates or phosphates and agents tor the adjustment of tonicity such as sodium chloride or dextrose.
(00202) Pharmaceutical compositions for injection include aqueous solutions (where water soluble.) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor El-TM (BASF, Parsippany, N.J.) or phosphate buffered saline (PBS), The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyetheyiene glycol, and the like), and suitable mixtures thereof. Fluidity can be maintained, for example, by Ihe 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 surfactants. Antibacterial and antifungal agents include, for example, parabens,
ehlorobutano!, phenol, ascorbic acid and thimerosal, isotonic agents, for exampie, sugars, polyalcohols such as maniiol, sorbitol, and sodium chloride ma be included in the composition. The resulting solutions can be packaged for use as is, or lyophiiized; the lyophilked preparation can later be combined with a sterile solution prior to administration,
(00203) Pharmaceutically acceptable carriers can contain a compound thai 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 raonostearate and gelatin. Detergents can also a s - 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 compkxed 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 (1 96) Pharm R.es. 13:1760 1764; Samanen (1996) J. Pharm. Pharmacol. 48: 119 135; and U.S. Pat. No. 5,391 ,377, describing lipid compositions for oral delivery of therapeutic agents).
|OO204] 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.
[00205] Formulations for in vivo administration are generally sterile-, in one embodiment, the pharmaceutical compositions are formulated to be free of pyrogens such that they are acceptable for administration to human patients. 100206] 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).
[00207] 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 labels forme 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, Methods of Use and Treatments
1.00208] 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.1 inhibitor, a BET inhibitor and a MM.P inhibitor, as described herein.
[002091 The method of use or treatment described herei n may comprise Compound A 1 , or a pharmaceutically acceptable salt or hydrate thereof, in combination with one or more inhibitor and another pharmaceutical or therapeutic, agent. Sn each of the methods described herein, pharmaceutically effective amounts of each inhibitor, and each pharmaceutical agent are used.
Diseases
[ΟΌ210] In some aspects, the disease or condition is chosen from an autoimmune disease, an inflammatory disease, a neurodegenerative disease, a cardiovascular disorder, a renal disorder, a viral infection, and obesity. In some aspects, the disease or condition is chosen from rheumatoid arthritis, osteoarthritis, atherosclerosis, psoriasis, systemic lupus erythematosus, multiple sclerosis, inflammatory bowel disease, asthma, chronic obstructive airways disease, pneumonitis, dermatitis, alopecia, nephritis, vasculitis, atherosclerosis,
Alzheimer's disease, hepatitis, primary biliary cirrhosis, sclerosing cholangitis, diabetes {including type Ϊ diabetes), and acute rejection of transplanted organs, in some aspects the disease or condition is cancer, including hematological cancers, lymphoma, multiple myelomas, leukemias, a neoplasm, cancer o 'tumor (for example a solid tumor), .
[00211] ¾ some embodiments, the cancer is carcinoma, sarcoma, melanoma, lymphoma or leukemia. In other embodiments, the cancer is a hematologic malignancy, in some embodiments, the cancer is leukemia (e.g., chronic lymphocytic leukemia), lymphoma (e.g., non-Hodgkin's lymphoma), or multiple myeloma, In other embodiments, the cancer is a solid tumor.
[00212] In some variations, the cancer is small lymphocytic lymphoma, no.o- Hodgkin's lymphoma, indolent non-Hodgkin's lymphoma (i'NHL), refractory 1.17 - iNHL, mantle cell lymphoma, follicular lym h m , lymphopiasmaeytic lymphoma, marginal zone lymphoma, immunoblastic large cell lymphoma, lymphoblastic lymphoma, Splenic marginal zone B-cell lymphoma (·+-/- villous lymphocytes), nodal marginal zone lymphoma (+ - monocytoid B-cell s), e lranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue type, cutaneous T-cell lymphoma, extranodal T-cell lymphoma, anapiastic large cell lymphoma, angioim unoblastic T-cell lymphoma, mycosis fungoides, B -cell lymphoma, diffuse large B-cell lymphoma. Mediastinal large B-cell lymphoma, Intravascular large B-cell lymphoma, Primary effusion lymphoma, small non-cleaved cell lymphoma, Bufkitt's lymphoma, multiple myeloma, plasmacytoma, acute lymphocytic leukemia. T-cell acute lymphoblastic leukemia, B-cell acute lymphoblastic leukemia, B-ce31 prolymphocyte c leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, juvenile
■myelomonoeytic leukemia, minimal residual disease, hairy cell leukemia, primary myelofibrosis, secondary myelofibrosis, chronic myeloid leukemia, myelodysplastic syndrome, myeloproliferative disease, or Waldenstrom's maerogiobttlinemia.
[00213] 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, gal! 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, C S cancer, brain tumors (e.g., glioma, anaplastic oligodendroglioma, adult glioblastoma multiforme, and adult anapiastic astrocytoma), bone cancer, soft tissue sarcoma, retinoblastomas, neuroblastomas, peritonea! effusions, malignant pleural effusions,
mesotheliomas, Wilms tumors, trophoblastic neoplasms, hemangiopericytomas, Kaposi's sarcomas, myxoid carcinoma, round cell carcinoma, squamous cell carcinomas, esophageal squamous cell carcinomas, oral carcinomas, cancers of the adrenal cortex, or ACTH-producing tumors.
[60214] 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 malignancy). In some embodiments, the human is at an early stage of cancer. In other embodiments, the human is at an advanced stage of cancer.
[00215] In some embodiments, provided herein is a method for treating a human who is undergoing one or more standard therapies for treating cancer (e.g. , a hematologic malignancy), such as chemotherapy, radiotherapy, immunotherapy, and/or surgery. Thus, in some foregoing embodiments, the combination of a BTK inhibitor and one or more inhibitor as described herein, may be administered before, during, or after administration of chemotherapy, radiotherapy, immunotherapy, and/or surgery. For example, the one or more inhibitor may be a JAK inhibitor, an ASKI 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 B 1 and
Compound B . in other embodiments, Compound Al may be used in combination with a BRD inhibitor such as (2 :yeio:p:ropy3-6--{3,5 - dimethyiisoxazoi -4-yl)- 1 H )eiu»[d]imida^^
[00216] In another aspect, provided is a method for sensitizing a human who is (i) refractory to at least one chemotherapy treatment, or (ii) in relapse after treatment with chemotherapy, or both (i) and (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 JA inhibitor, an ASKI inhibitor, a BET inhibitor and/or a MMP9 inhibitor, as described herein.
[00217] For chrome lymphocytic leukemia th prior treatments a human may have received include regimens of:
fludarabine (Fludara ®);
ri tuxrma b (Ri tuxan¾ ) ;
rituximab (Rituxan ®) combined with fludarabine (sometimes abbreviated as FR): cyclophosphamide (Cytoxan®) combined with fiudarabine;
cyclophosphamide combined with rituximab and fiudarabine (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, ohirmtuzumab, or ofatur umab
pentostatm combined with cyclophosphamide and rituximab (sometimes abbreviated as FCR);
bendarmistine (Tmandaii ) combined with .rituximab ((sometimes abbreviated as BR);
a!emtuzumab (Campaih®);
fiudarabine plus cyclophosphamide, bendamustine, or chlorambucil; and fiudarabine plus cyclophosphamide, bendamustme, or ch.iorainbuc.il, combined with an anti»CD20 antibody, such as rituximab, ofatumurnab, veltuzumab, lurailuximab or obinutuzumab.
[00248] 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 die cancer.
[002191 The BTK inhbitor, Compound Al,or a pharmaceutically acceptable salt or hydrate thereof, may be combined with known agents and regimens useful in the treatment of allergic, autoimmune, and inflammatory disorders, as can the combinations herein of Compound A1 with one or more inhibitoras described herein. In addition, Compound l may be combined include tumor necrosis factor inhibitors (TNFi i, such as infliximab (sold under the REMICADE® mark), etaiiercept (ENBREb certoUzumab pegol fCIMZIA®), golimumab
(SIMPONS'f), adaliaramab (ΗΟΜΪΚΑ ), and ozoalizunub. Therapeutically Effective Amounts
[00220] In some variations, a therapeutically effective amount refers to an amount that is sufficient to effeci treatment, as defined, below, when administered to a subject ( e.g., a human) in need of such treatment, The therapeutically effectiv 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 hydra te thereof, is an amount sufficient to modulate BT K expression, and thereby treat a human suffering an indication, or to ameliorate or alleviate the existing symptoms of the indication,
[002211 In another variation, the therapeutically effective amount of the BTK inhibitor, such as Compound Al , or a pharmaceutically acceptable salt or hydrate thereof, may be an amount sufficient to decrease a symptom of a disease or condition responsive to inhibition of BTK activity.
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 bucaily, ophthalmic-ally, orally, osniotieali.y, parenteral!)' (intramuscularly, intraperiioneally intrasternally, intravenously, subcutaneous!}'), rectaily, topically, transdermaily, or vaginally, in certain embodiments, the Btk inhibitor is administered orally. In one embodiment, the Btk inhibitor is Compound Al or hydrochloride salt thereof which is administered orally, once a day, to a subject in need thereof at a dose of 20 mg, 40 mg, 80 mg, r ISOmg, In some embodiments, the Btk inhibitor is Compound Al or hydrochloride salt thereof, which is administered orally, twice a day, to a subject at a dose of 20 mg, 40mg, or 75 mg. in one variation, the therapeutically effective amount of the BTK inhibitor is a dose corresponding to 1 nmoi to 10,000 nmoi of the BTK. inhibitor used in an apoptosis assay run with 10% serum which approximately relates to a blood plasma concentration of 500 nmoi to 2500 nmoi of the BTK inhibitor. In one variation, the therapeutically effective amount of the one or more inhibitor is a dose corresponding to 1 nmoi to 200 nmoi of the one or more inhibitor used in an apoptosis assay run with 10% serum. Specific examples include nM, 5 nM, 30 n , 20 nM and 30 .oM concentrations when combined with one or more inhibitor described herein.
[00223] The therapeutically effective amount of the inhibitors described herein may also be determined based on data obtained from assays known in the art, including for example, an apoptosis assay, in one variation, the therapeutically effective amount of the BTK inhibitor in a human is a dose of from about 1 mg to about 200 mg. In another embodiment the BTK in a human is administered at a dose of from about 10 mg to about 200 mg. In another embodiment the BTK in a human is administered at a dose of from about 20 mg to about 160 rag. 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 2.0 mg to about 150 mg, d) from about 75 mg to about 100 mg, and e) fr m about 100 mg to about 200 mg. individual doses of the BTK. inhibitor that may be administered to a human in need thereof include individual doses of Img, 5 mg, 10 mg, 20 mg, 30 mg, 40 rag, 50 mg, 60 mg, 70 mg, 75 mg, 80 mg, 901 mg, 100 mg, l i O mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 175 mg, and 200 mg. The doses of the BTK inhibitor may be administered as determined by a medical professional and may be administered once daily or may be delivered twice daily, three times daily., or four tiroes daily.
£00224) 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, BRD inhibitor, and MMP9 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 inhibition.
10 2251 in some variations, the BTK inhibitor, such as Compound AL or a pharmaceutically acceptable salt or hydrate theieof, is administered to the human at a dose between 40 mg and 1 00 mg, between 40 mg and 800 mg, between 40 mg and 600 mg, between 40 mg and 40 mg, about 1 0 rag, about 100 mg, about 200 mg, about 300 mg, about 400 rag, about 500 mg, about 600 mg, about 700 mg, or about 800 mg. in some variations, the JAK inhibitor, such as Compound B I, Compound B2, Compound B3, or Compound B4, or a pbarmaee«tically acceptable salt thereof, is administered to the human at a dose between 20 to 600 mg, between 20 to 400 mg, between 20 to 200 mg, about 20 mg, about 50 mg, about 100 mg, about 200 mg, about 300 mg. about 400 mg, about 500 mg, about 600 mg, about 700 tag, or about 800 mg. in some embodiments, the JAK inhibitor is momelotmib (Compound B l) or a hydrochloride salt there of is administered orally at a dose of 50 mg, 100 mg. 200 mg, or 400 mg. In certam embodiments, (he JAK inhibitor is filgotimb (Compound B2) or a
phariunceuueaily sal there of is administered orally at a dose of 3:0 mg. 50 mg, 75 mg, 100 mg, 1 50 mg, 200 mg, or 300 mg. In certain embodiments, the J AK inhibitor is administered once daily or twice daily.
[00226] The therapeutically effective amount of the BTK and one or more inhibitor described herein may be provided in a single dose or multiple doses to achieve the desired treatment endpoini. As used herein, "dose" refers to the total amount of an active ingredient to be taken each time by a human. The dose administered, fox example for oral administration described above, may be administered once weekly, once daily (QD), twice daily (BID), three times daily, four times daily, or more than four times daily. In some embodiments, the BTK and/or the one or more inhibitor may be administered once daily. ID. 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 for 1 , 2, 3, 4, 5, 6 or ? days and then weekly or with a regimen that can combine these different frequencies and doses to result in a final dose and regimen that is tolerated and efficacious.
[00227] In one variation, the therapeuiically effective amount of the ASKl inhibiting compound is a dose corresponding to 1 nmol to 200 nmol of the ASKl inhibiting compound used in an. apoptosis assay run with 10% serum. The Askl inhibiting compounds hereii), .including compounds of formula 0.) and Compound CL may be admniisiered in a pharmaceutically effective amount. For oral administration, each dosage unit preferably contains from 1 rag to 500 mg of the A SKI inhibiting compound. A more preferred dose is from 1 mg to 250 mg of the compound of the AS i inhibiting compound. Particularly preferred is a dose of the ASKI inhibiting compound ranging from about 20 rag twice a day io 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 rag, 18 mg, or 50 mg. In certain embodiments, the ASK inhibitor is administered once daily or twice daily, it wili 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 io be treated, the chosen route of administration, coadministration compound if applicable, the age, weight, response of the individual patient, the seventy of the patient's symptoms,, and iive like.
100228] 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 rag and 600 mg, between 40 mg and 40 mg, about 100 rag, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, or about 800 mg. In some variations, the ASK ! inhibiting compound, such as Compound CI, 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 mg, between 20 to 400 mg, between 20 to 200 mg, about 20 rag, about 50 mg, about 100 mg, about 200 mg, about 300 rag, about 400 mg, about 500 mg, about 600 mg, about 700 mg, or about 800 mg.
{00229] in some variations, the BET inhibitor, such as a modulator of a bromodomain-containing protein, or a pharmaceutically acceptable salt thereof as described herein, is administered to the human at a dose between 20 to 600 rag, 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 m , about 700 mg, or about 800 mg. [Ο023Θ] in some variations, the MMP9 inhib or, k administered to the human at a dose between 20 to 600 mg, between 20 to 400 rag, between 20 to 200 mg, about 20 rag, about 50 nig, about 100 mg, about 200 mg, about 300 rag, about 400 rag. about 500 mg, about 600 rag. about 700 mg, or about 800 rag,
[00231] in another embodiment, the MMP9 inhibitor, particularly including an anti- MP antibody, is administered once every two weeks at a single dose of from about 600 mg to { ,000 mg. In another embodiment, the M P 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- P antibody, i administered once every two weeks at a single dose of about BOO mg. in another embodiment,, tire MMP9 inhibitor, particularly including an an†i-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 mg. In another embodiment, the M.V1P9 inhibitor, particularly including an antf-M P9 antibody, is administered once every three weeks at a single dose of about 1 ,200 mg, in one embodiment, the MMP9 inhibitor is an &nti-MMP9 antibody having the amino acid sequence of SEQ ID os: 7 and 12, which is administered intravenously or subcutaneously at a dose of 150 mg, 300 mg, or 600 mg. In certain embodiment, the MMP9 inhibitor is administered once a week or once every two weeks,
[00232] The present disclosure contemplates pharmaceutical compositions for use in connection with such methods. Compositions can be suitable for administration locally or systemically b any suitable route.
[00233 j 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 nig/kg of mammal body weight or more per day, preferably about 1 pg/kg day to 50 rng/kg/day, optionally about 100 pg kg day to 20 mg/kg/day, 500 pg/kg day to 10 mg/kg/day, or 1 mg/kg/day to 10 mg/kg/day, depending upon the route of administration,
[00234] The selected dosage regimen will depend upon a variety of factors including the activity of the MMP binding protein, the route of administration, the time of administration, the rate of excretion of the particular compound being employed, the duration of die treatment, other drugs, compounds and'Or materials used in combination with the particular composition employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.
[00235] A clinician having ordinary skill in the art can readily determine and prescribe the effective amount (BD50) of the pharmaceutical, composition required. For example, the physician or veterinarian can start doses of the compounds of the invention employed in the pharmaceutical composition at levels lower .than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.
[00236] If needed, for cancer treatments, methods can further include surgical removal of the cancer and/or administration of an ami -cancer agent or treatment in addition to an MMP9 binding protein. Administration of such an anti-cancer agent or treatment can be concurrent with administration of the compositions disclosed herein.
Administration
[00237] A BTK inhibitor, such a Compound Al, can be administered with one or more inhibitor using any suitable methods know in the art. For example, the one or more inhibitor to be combined with a BTK inhibitor may be a I K inhibitor, such as Compound Bl, Compound ,82, Compound B 3, CompouiKi 84, Compound 85, Compound B6. Compound B7, Compound B8, Compound B9, Compound Bit) or Compound B1 i . in some embodiments, the one or more inhibitor may be an ASK i inhibitor, such as Compound C.1 , Compound C2 or a compound of Formula L In other embodiments, the one or more inhbitior may be a modulator of a bromodomain-containing protein such as (2-cyelopropyl-6~(3,5- dimethylisoxazol --yJ)-dH-beiKo[d] nidazol-4-y1)di(pyridin-2-y1)memanol. in yet other embodiments, the one or more inhibitor may be a MMP9 inhibitor such as an anti-M P antibody.
[00238] For example, the compounds may be administered bucally,
ophthalmieally, orally, osmotieally, parenterally (intramuscularly,
iniraperi toneall y in trasiernally, intraveno usiy , subcutaneousiy), rectally, topically, transdermal!}', or vaginally. Further, in certain variations, the BT inhibitor described herein may be administered prior, after or concurrently with one or more inhibitor wherein the one or more inhibitor may be a JA inhibitor, an ASK1 inhibitor, a BET inhibitor and a MP9 inhibitor, as described herein, {00239] in one aspect, the compounds described herein may be administered orally. Oral administration may be via, for example, capsule or enteric coated tablets, h making the pharmaceutical compositions that include at least one eompounddescribed herein, or a pharmaceutically acceptable salt thereof, the active ingredient is usually diluted by an excipient and/or enclosed within such a carrier that can be in the form of a capsule, sachet, paper or other container. When the excipient 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 for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the acti ve compound, soft and. hard gelatin capsules, sterile injectable solutions, and sterile packaged powders.
[00240] Some examples of suitable excipients incl ude lactose, dextrose, sucrose, sorbitol, manmiol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, mierocrystaliine cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methyl cellulose. The formulations ca additionally, include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents: preserving agents such as methyl and propylhydroxy-benzoates; sweetening agents; and flavoring agents.
[002411 The compositions thai include at least one compound of the compounds described herein, or a pharmaceutically acceptable salt thereof, can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the subject by employing procedures known in the art.
Controlled release drug delivery systems for oral administration include osmotic pump systems and dissolutions.! systems containing polymer-coated reservoirs or drug-polymer matrix formulations. Examples of controlled release systems are given in U.S. Patent Nos. 3,845,770; 4,326,525; 4,902,514; and 5,616,345. Another formulation for use in the methods of the present invention employs transdermal delivery devices ("patches")- Such transdermal patches may be used to provide conti nuous 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, e.g., 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,
[00242] The compositions may, in some embodiments, be formulated m 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 uitable 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 50 mg, about 75 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, or about 300 mg, In other embodiments, for parenteral •administration, each dosage unit -contains from 0.1 to 700 mg of a compound a compound described herein. It will be understood, however, that the amount of the compound actually administered usually will be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered and its relative activity, the age, weight, and response of the individual subject, and the severity of the subject's symptoms. [00243] in certain embodiments, dosage levels may be from 0. i rag to 100 mg per kilogram of body weight per day. for example from about 1 mg to about 50 mg per kilogram, for example from about 5 mg to about 30 mg per kilogram. Such dosage levels may, in certain instances, be useful in the treatment of the above-indicated conditions, In other embodiments, dosage levels may be from about 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 forms may contain from 1 mg to 500 mg of an active ingredient.
[90244] Frequency of dosage may also vary depending on the compound used and the particular disease or condition treated. In some embodiments, for example, for the treatment of an . autoimmune and/or inflammatory disease, a dosage regimen of 4 times daily or less is used. In some embodiments, a dosage regimen of 1 or 2 times daily is used. It. will be understood, however, that the specific dose level for any particular subject will depend upon a variety of factors including the activity of the specific compound employed, ihe age. body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination and the severity of the particular disease in the subject undergoing therapy.
[00245] For preparing solid compositions such as tablets, the principal active ingredient may be mixed with a pharmaceutical excipieni to form a solid prefbrmulation composition containing a homogeneous mixture o a compound of Formula (ΙΪ), or a pharmaceutically acceptable salt thereof When referring to these preformulatkm compositions as homogeneous, the active ingredient may be dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.
[00246] 'The tablets or pills of the compounds described herein may be coaled 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 ; 2v · 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, cetyl alcohol, and cellulose acetate.
[00247] 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-arierial injection, intravenously, intraperiionealiy, parenteral!}', intramuscularly, subeutaneously, orally, topically, as an i halant, or via an impregnated or coated device such as a stent, for example, or an artery- inserted cylindrical polymer
Pharrn aceutieal Compositions
[002481 The BTK inhibitor and one or raore inhibitor may be administered in the form of pharmaceutical compositions. For example, in some variations, the B K 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 ASK i inhibitor, a BET. inhibitor and a MMP9 inhibitor, Pharmaceutically acceptable vehicles may include pharmaceutically acceptable carriers, adjuvants and/or exeipients, and other ingredients can be deemed pharmaceutically acceptable insofar as they are compatible with other ingredients of the formulation and not deleterious to the recipient thereof
[00249} This disclosure therefore provides pharmaceutical compositions that contain a BTK inhibitor and one or more inhibitor, wherein the one or more inhibitor may be a JAK inhibitor, an ASK.i inhibitor, a BET inhibitor and a MMP9 inhibitor as described herein, and one or more pharmaceutically acceptable vehicle, such as excipients, carriers, including inert solid diluents and fillers, diluents, including sterile aqueous solution and various organic solvents, permeation enhancers, soiubilizers and adjuvants. The pharmaceutical compositions may be administered, alone or in combination with other inhibitors. Such compositions are prepared in a manner well known in the. pharmaceutical art (see, e.g., Remington's Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, PA 17th Ed. (1985); and Modern Pharmaceutics, Marcel Dekker, Inc. 3rd Ed. (G.S. Banker & C.T. Rhodes. Eds.).
[00250] The pharmaceutical compositions may he 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 inira-arteriai injection, intravenously, iniiaperitoneally, parenteraliy, intramuscularly, subcutaneously, orally, topically, as an inhalant, or via an impregnated or coated device such as a stent, for example, or an artery-inserted cylindrical polymer.
100251] In some embodiments, the pharmaceutical compositions described herein are formulated in a unit dosage form. The term "unit dosage forms" reters to physically discrete units suitable as unitary dosages for human subjects, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient. In some variations, the pharmaceutical compositions described herein are in the form of a tablet, capsule, or ampoule.
[00252] In certain embodiments, the BTK inhibitor described herein, such as Compound A l , 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 Compoimd A L 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
{00253] 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, ASK! inhibitors, BET inhibitor \ M - and M P9 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 idrra 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 exeipients; and t it ) a unit, dosage form of a inhibitor, as described herein, and one or more pharmaceutically acceptable carriers, adjuvants or exeipients. In one embodiment, the unit, dosage form for both the BTK inhibitor and the one or more inhibitor is a tablet.
SII2S4] 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 JA inhibitor, an ASK1 inhibitor, a BET inhibitor and an MMF9 inhibitor. In some embodiments, the kits comprises ft) a unit dosage form of the BTK iiihibiior, as described herein, and one or more pharmaceutically acceptable carriers, adjuvants or exeipients; and (ii) a unit dosage form of a inhibitor, as described herein, and one or more pharmaceutically acceptable carriers, adjuvants or exeipients. In one embodiment, the unit dosage form for both the BTK inhibitor and the inhibitor is a tablet..
[80255] The instructions for use in the kit may be for treating a cancer, including, for example, a hematologic malignancy, as further described herein .The instructions for use in the kit may be for treating a cancer, including, for example, a hematologic malignancy or an allergic, autoimmune, or inflammatory disorder, as further described herein.
Other Therapeutic Agents
00256] In the present disclosure, in some aspects, the combination therapies and methods described herein may be used or combined with an additional agents selected from the group of a chemotherapeutic agent, an anti-cancer agent, an ant! -angiogenic agent an :anti-ybrotic agent, m imnv notherapeuiic agent, a therapeutic antibody, a radiotherapeutie agent, an anti-neoplastie agent, an anti- proliferation agent, or any combination thereof.
[00257] 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- hromodomain 4 (B D4) inhibitor, an isocitrate dehydrogenase i (1DH1 ) inhibitor, an Ϊ Κ inhibitor, a protein kinase C (PKC) activator or inhibitor, a TPI.,2 inhibitor, a serine/threonine-proiein kinase 1 (TBK1) inhibitor, agents that activate or reactivate latent human immunodeficiency virus (HIV) such as panobinostat or roraidepsin. an anti~CD20 antibody such as obin tuzumab, an anti -PI i antibody such as mVolimumab (BMS-9365S8, MDX1106, or K- 34775), and anti-PD-Li antibodies such as BMS-936559, MPDL3280A,
EDI4736, MSB00.107J 8C, and MDX1105-01.
[00258] The combination therapies and methods disclosed herein and the additional one or more therapeutic agents (e.g. an A2B inhibitor, an apopiosis signal -regulating kinase (ASK) inhibitor, a BRIM inhibitor, a discoidiii domain receptor 1 (DDK S ) inhibitor, a historic deacetylase (HDAC) inhibitor, an isocitrate dehydrogenase (IDH) inhibitor, a Janus kinase (JAK t inhibitor, a lysyl oxidase-like protein 2 (LOXL2) inhibitor, a matrix metalloprotease 9 (MMP9) inhibitor, a phosphatidyiinositol 3-kinase (PI3 ) inhibitor, a PKC activator or inhibitor, a spleen tyrosine kinase (SYK) inhibitor, a TPL2 inhibitor, or a TBK inhibitor) may be further used or combined with a chemotherapeutic agent, an anti-cancer agent, an anti -angiogenic agent, .an anii-fibroric agent, an
imm unotherapeutic agent, a, therapeutic antibody, a .radiotherapeutie agent, an •anti-neopiastic agent., or any combination thereof.
[00259] It is understood that the combinations and methods herein may be used with standard therapies, including neoadjuvant chemotherapy, intraoperative radiotherapy (IORT), adjuvant chemotherapy (such as with 511), adjuvant radiotherapy, adjuvant chemoradiotherapy, palliative radiotherapy, and palliative- inten procedures, which in regard to gastrointestinal conditions may include - ; n - wide local excision, partial -gastrectomy, total gastrectomy, simple laparotomy, gastrointestingal anastomosis, or bypass,
Chemotherapeutic A gents
[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- peptidtc ) 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/anii -cancer agents such as pyrimidine analogs iloxuridine, capeciiahine, and eytarabine:purine analogs, folate antagonists, and related inhibitors; antiproliferati ve/aittiffti totic- agents including natural products such as vinca alkaloid (vinblastine, vincristine) and microtubule such as taxane (paclitaxel, docetaxel), vinblastin,. nocodazole, epothikmes, vinorelbine (NAVELBl f' and epipodophyllotoxins (etoposide. teniposide); ΌΝΑ. damaging agents such as actinomycin, amsacrine, busulfan, carboplatin, chlorambucil, cisplatin, cyclophosphamide (CYTOXAN 1 ), dactinomycui, daunoruhicin, doxorubicin, epirubicm, iphosphamide, meiphalan, merchlorethamine, mitomycin, mitoxantrone, nitrosourea , procarbazine, taxol, taxotere, teniposide, etoposide, and triemylenemiophosphoramide; antibiotics such as dactinomycin, daunorubicin, doxorabiein, idarubicin, amhraeyelmes, mitoxantrone, bleomycins, pHcamyctn (mithramycin), and mitomycin.; enzymes such as ^asparaginase which systemic-ally metabolizes L-asparagine and deprives cells which do not have the capacity to synthesize their own asparagine; antiplatelet agents; atitiproliferative antimitolic alkylating agents such as nitrogen mustards cyclophosphamide and analogs (melphaiati. chloramh.uci.1,
Isexamethylmelaniine, and thiotepa), alkyl nitrosoureas (camtusttne) and aaalogs, streptozocin, and triazenes (dacarbazine); antiproliferati ve/antiiniiotic antimetabolites such as folic acid analogs (methotrexate); platinum coordination complexes such as cisplatin., oxiloplatinim, and carboplatin), procarbazine, hydroxyurea, mitoiane, and am mogJutethimide; hormones and hormone analogs such as estrogen, tamoxifen, goserelin, bicaiutamide, and nilutamide, and aromatase inhibitors such as letrozoie and anastrozole; anticoagulants such as heparin, synthetic 'heparin salts, and oilier inhibitors of thrombin: fibrinolytic agents such as tissue plasminogen activator, streptokinase, urokinase, aspirin, dipyridamole, ticlopidine, and clopidogre!; antimigratory agents; antisecretory agents such as breveldin; immunosuppressives such as tacroiinius, sirolitnus, azathioprme, and mycophenolate; compounds (TNP-470, genistein) and growth factor inhibitors (vascular endothelial growth factor inhibitors and fibroblast growth factor inhibitors); angiotensin receptor blockers, nitric oxide donors; anti- sense oligonucleotides; antibodies such as trastuzumab and rituximab; cell cycle inhibitors and differentiation inducers such as tretinoin; inhibitors
mcludingtopoisomerase inhibitors such as doxorubicin, daunorabicin, daciinomyein, emposide, epirubicm, etoposide, idambicin, irinotecan, mitoxantrone, topoteean, and irinotecan, and corticosteroids such as cortisone, dexametbasone, hydrocortisone, raeihylprednisolone, prednisone, and prednisolone; growth factor s gnal transduction kinase: inhibitors; dysfunction inducers; toxins such as Cholera toxin, ricin, Pseudomonas exotoxin, Bordetella pertussis adenylate cyclase toxin, diphtheria toxin, and caspase activators; and chromatin.
[00261] Further examples of chemotherapeutic agents include: alkylating agents such as thiotepa and cyclophosphamide (CYTOXAN '); alkyl sulfonates such as busulfan, improsulfan} and piposulfan; aziridines such as benzodopa, carboquone, mcturedopa, and wedopa; emylerumines and memylarnelamines including alfretaraine, triemylenemelamine, triethylenephosphoraroide,
iiiethylenefhiophosphoramide, and trimemyloiomelamine; acetoge ms, especially biiliaiacin and buliaiacinone; a campiotheem, including synthetic analog topoteean; bryostatin; caUystatm; CC-I063, including its adozelesin, carzelesin, and bizelesin synthetic analogs; cryptophycins, particularl cryptophycm 1 and cryptophycin 8; dolastatin; duocarmycm, including the synthetic analogs KW-2189 and CB1-TMI; eleutherobin; pancratistatin; a sarcodictyin; spongisiatin; nitrogen mustards such as chlorambucil,
chloriiaphaziiie, cyclophosphamide, estramustine, ifosfamide, mechlorethamine, mechloreihamine oxide hydrochloride, melphaian, novembichin, phenesterine, prednimustine, trofostamide, and uracil mustard; nitrosoureas such as cannustine, chlofOTOtocirij f remusdne, lomusiine. irimustine, and ranina'ttstme: antibiotics such as the enediyne antibiotics (e.g., caltcheamicin, especially calicheamicin gammali and calicheamicin phil 1), dynemicin including dynemiek A, bisphosphonates such as clodronate, an esperarnic , neoearzkostatin chroraophore and related chromoproteiii enediyne antibiotic chromornophores, aclacinomycins, actinomycin, authramycin, azase'rine, bleomycins, cactraomyck, earabick, camikomyck, cardnopbilk, chromomycins, daciinomyek, daunorwbicinj detorubicin, 6-diazo-5-oxo-L~norleucine, doxorubicin (including morpholko-doxorubick, cyanomoipholino-doxorubicin, 2-pyrrolino- doxorubick, and deoxydoxorabicsn), epirubiek, esorubick, idarubick, marceltomyck, mitomycins such as mitomycin€, mycophenolic acid, nogalamyein, olivomycins, peplomycin, porfiromyck, puromyek, qn amycin, radorubiek, strepionigrm, streptozoem, tubercklin, abenimsx, zinostatin, and zorabiem antimetabolites such as methotrexate and 5-fluorouraeil (5-FU); folic acid analogs such as demopterm, methotrexate, pteropterin, and trimetrexate; purine analogs such as fludarabke, 6-mercaptopurine, ihiamiprine, and ihioguanine; pyrimidine analogs such as ancitabirie, azacitidke, 6-azauridine, caimoiur, cytarabine, dideoxyuridke, doxifiuridine, enocitabke., and floxuridke; androgens such as calusterone, dromostanolone propionate, epiiiostano!, mepitiostane, and testolactone; anti-adrenals such as ammoglutethimide.
rn totane, and irilostane; folic acid replkishers such as frolinic acid;
trichotheccnes, especially T-2 toxin, verracurin A, roridin A, and anguidine; taxoid such as paclitaxel (TAXOL*1) and docetaxel (TAXOTERE*); platinum analogs such as cisplatin and carboplatk; aceglatone aldophosphamide glycoside; aminolevulinic acid; emluracil; amsacrke; hestrabacil; bisaatrene; edatraxate; defofamine; demecoldne; -diaziquone; eltbrmthke; ellipt him- acetate; an epothilone; etoglucid; gallium nitrate; hydroxyurea; iendnan;
leucovorin; lonidamine; maytanskoids such as rnayiansine and ansamitocins; miloguazone; miioxanrnme; mopidamol ; oitracrine; pentostatin; phenamei:
pirarubicin; iosoxantrone; fluoropyriniidine; folkic acid; podophyllkic acid; 2- eihylhydrazide; procarbazine; polysaccharide-K (PSR ; razoxane; rhizoxk; sizofiran; spirogemiamum; ieraia onic acid: iiiaziquone 2.2',2"- tnclJorotxieray iamine; methane; yindesine daearbazirse; mamiomustme;
mitobronitol; mitolactol; pipobroman; gaeytosine; arahinoside ("Ara-C");
cyclophosphamide; thiopeta; chlorambucil; gemeitabrae (GEMZAR*); 6~ thiogiianme; mercaptopurine methotrexate; vinblastine: platinum; etoposide (VIM 6); ifosfaraide; tnitroxantrone; vancristine; vinorelbine (NAVELBINE"*); novantrone; tenyposide; edatrexate; daunomycin; aminopterin; xeoioda;
ibandronate; CPT-11; topoisomerase inhibitor RFS 2000;
difiuoromethyloraithine (DFMO); retinoids such as retinoic acid; capecitabine; OLFIRI (fluorouracil, ieucovorin, and irinoteean); and pharmaceutically acceptable salts, acids, or derivatives of any of the above.
Anti-hormonal Agents
[00262] Also included in the definition of "ehemomerapeutk agent" are anti- hormonal agents such as anti-estrogens and selective estrogen receptor modulators (SERMs), inhibitors of the enzyme aromatase, anti -androgens, and pharmaceutically acceptable salts, acids or derivatives of any of the above that act (o regulate or inhibit hormone action on tumors. Examples of anti -estrogens and SERMs include, for example, tamoxifen (including NOLVADEX i M), raloxifene, droloxifene, 4-hydroxytamoxifen, trioxifeiie, keoxifene, LYl 17018, onapristone, and toiemifene (FAKESTON*). inhibitors of the enzyme aromatase regulate estrogen production in the adrenal glands. Examples include 4(5 imidazoles, aminoglutethimide, megestrol acetate (MEGACE*' , exemestane, formestane, fadrozole, vorozole (RJVISOR®), letrozole (FEMARAi¾), and anastrozole (AR IDEX*). Examples ofanti-androgens include flutamide, ifutamide, bieahitaniide, leuprohde, and goserelin.
Anli-angiogenie Agents
[00263] Anti-angiogenic agents i clude, but are not limited to, retinoid acid and derivatives thereof 2-methoxyestradiol, ANGIOSTATIN®, ENDOSTATINf suramin, squa!amine, tissue inhibitor of metalloproteinase- 1 , tissue inhibitor of metalloprotetnase-2, plasminogen activator inhibi tor- 1, plasminogen activator mbtbitor-2, cartilage-derived inhibitor, paclitaxel (nab-paclitaxel), platelet factor 4, protamine sulphate (e!upeme), sulphated chitin derivatives (prepared from queen crab shells), sulphated polysaccharide peptidoglycan complex (sp~pg), staurosponne, modulators of matrix metabolism including proline analogs ((1- azetidine-2-carboxyiic add (LACA)). cishydroxyproline, dJ-S^-dehydroprolinc, thiaproline, rx5a'»dipyridyl. beta-aminopropionitrile fomarate, 4-propyl-5-(4- pyridinyl)-2(3h)-oxazo1one, methotrexate, mitoxantrone, heparin, interferons, 2 macroglobulm-serum, chicken inhibitor of metail.oproteinase-3 (ChiMP-3), chymostarin, beta-cyciodextrm terradecasulfate, eponemycin, fumagillin, gold sodium thiomaiate, d-pentcillamine, beta-l-amticoUagenase-seriim, alpha-2- antiplasrnin, bisantrene, lobenzarit disodium, n-2-earboxyphenyi-4- chloroantlironi 'c acid disodium or "CCA", thalidomide, angiostatic steroid, carboxy aminoimidazole, and metalloproteinase inhibitors such as BB-94. Other anti-aogiogenesis agents include antibodies, preferably monoclonal antibodies against these angiogenic growth factors: heia-FGF, alpha- FOF, PGF-5, VEGF isoforms, VBGF-C, HGF/SF, and Ang-l:/Ang-2.
Anti-fibrofic Agents
[00264] Anti-fibrotic agents include, but are not limited to, the compounds such as beta-aminopropri onitrile (BAPN), as well as the compounds disclosed in US 4,965,288 relating to inhibitors oflysyl 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-isobu.yl-3-fluoro~, ehioro-, 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 2--(i -nap hyloxymemyi)--3-flt! !roallylaniine, and. US 2004-0248871 , which are herein incorporated by reference.
{00265] Exemplary anti-fibrotic agents also include the primary amines reacting with the carbonyl group of the active site of the lysyi oxidases, and more particularly those which produce, after binding with the carbonyl, a product stabilized by resonance, such as the following primary amines: emylenemamine, hydrazine, phenylhydrazine, and their derivatives; sernicarbazide and urea derivatives; ammonitriles such as BAPN or 2-nitroethylamine; unsaturated or saturated hajoamines such as 2-bromo--eih !ainiiie, 2-ehlaroethy!am ine, 2- triil uoroethylamine, 3-bromapropyia me, and p-halobenzylammes; and selen ©homocysteine lactone. Other aati-fibrotic agents are copper chelating agents penetrating or not penetrating the cells. Exemplary compounds include indirect inhibitors which block the aldehyde derivatives originating from the oxidative deamination of the lysyl and hydroxy! syl residues by the lysy! oxidases.
Examples include the thiamines, particularly D-penicil!amtne, and its analogs such as 2-aniitto-5-inercapto-5-methylhexanoic acid, D-2»amino-3-methyl-3-((2- acetaraidoethyl)dithio)butano)c acid, p-2-amino-3 -methyl-3-((2- aminoethyl)diihio)buianoic acid, sodium-4-((p-i-diniethyl-2-amino-2- carboxyethyi)dithio)bi3tane sulphurate, 2-aceiamidoethyl-2-acctamidoeihaneihiol su!phanate, and sodium-4-rn.ercapi.obtttanesulphinate trihydraie. inimunotherapeirtic Agents
[00266] The immraotherapeotie agents include and are not limited to therapeutic antibodies suitable for treating patients. Some examples of therapeutic antibodies include simtuzumab, abagovomab, adecatumiunab, aiutuzumab, aleroiuzumab, aitumomab, amatuxiraab, anatumomab, areitumomab, bavituxiraab, bectumomab, bevacizumab, bivatuzumab, blinatumomab, brentuxiroab, cantuzumab, catumaxomab, cetuximab, citatuzumab, cixutu umab, clivatuzumab, conaiumumab, daratumumab, drozitumab, duligotumab, dusigitumab, detumo ab, daeetuzumab, dalotuzumab, ecromsximab. e!otuzumab,
eusituximab. ertumaxomab, etaraci¾umab, farletuzumab, ficlatummab, ftgituinumab, flanvotumab, ftituxiniab, ganiiuniab, gemtuzumab, girentuximab, glemhat.umumab, ibritumomab, igovomab, imgatuxumab, indatuxknab, motuzumah, inteiumumab, ipilimumah, irahumimab, !ahetuzumah, lexatumiiraab, lintuzumab, !orvoruzumab, lucatumamab, mapatumumab, matuzumab, rnilaiuzumab, minretumomab, raitumornab, rnoxetumoma b, narnatumab, naptumomab, necitumumab, , niraotuzumab, nofetumomab, ocaratozumab, ofatumumab, olaratumab, onartuzumab, oportuzumab, oregovoraab,
paniiumumab, parsatuzumab, patritumab, peratumornab, pertuzumab, piniumomab, pritumumab, racotumomab, radretumab, riioturaumab, rituximab, robatumumab, satumornab, sibrotuzumab, si!tuximab, solitoraab, tacatuzutnab, 39 - taplitumomah, tenatumomab, teptoturnumab, tigaiuzumab, tositwnomab, trastuzumab, tucotuzomab, ublituximab, velt zumab, vorsetuziimab, votumamab, zalutumumab, CC49, and 3F8. Rituximab can be used for treating indolent B- eell cancers, including marginal-zone lymphoma, WM, CLL and small lymphocytic lymphoma. A combination of Rituximab and chemotherapy agents is especially effective.
[00267J The exemplified therapeutic antibodies may be further labeled or combmed with a. radioisotope particle such as indium-l 1 1 , yttrium-90, or iodine- 1 1 .In a certain embodiments, the additional therapeutic agent is a nitrogen mustard alkylating agent. Nonltmitmg examples of nitrogen mustard alkylating agents include chlorambucil.
Lymphoma or Leukemia Combination Therapy
[ΘΘ268] Some chemotherapy agents are suitable for treating lymphoma or leukemia. These agents include aldesleukin, alvocidib, antineoplaston. AS2-1, antineoplaston A 10, anti-thymocyte globulin, aroifosrine tnhydrate,
aminocamptothecin, arsenic trioxide, beta aleihine, Bcl-2 family protein inhibitor ΑΒΪ-263, ABT-199, ABT-737, BMS-345541 , bortezomib (VELCADEa?), bryostatm j , busulfan, carbopMn, eampath-lH, CC-5103, carmustine, caspofungin acetate, clofarabine, ci platin, cladribine, chlorambucil, eurcumm, cyclosporine, cyclophosphamide, cytokine, denileukin diftitox, dexamethasone, DT-PACE (dexamethasone, thalidomide, cisplatin, doxorubicin,
cyclophosphamide, and etoposide), docetaxel, dolastatin 10, doxorubicin, doxorubicin hydrochloride, enzastaurin, epoetin alia, etoposide, everolimus (RADOOi), fenretinkte, filgrastim, mejphalan, mesna, ilavopiridc!, fladarabme, geidanamyci (17-A .G), ifosfamide, irinotecan hydrochloride, ixahep lone, lenalidomi.de (R VLIMID®, CC-5013X !ymphokine-activafed killer cells, melphalan, methotrexate, mitoxantrone hydrochloride, motexafin gadolinium, mycophenolate mofetil, nelarabine, oblimersen, obatoclax (GX15-070), obliraersen, octreotide acetate, omega-3 fatty acids, oxaliplatm, pachtaxei, PD0332991 , PEGylaied liposomal doxorubicin hydrochloride, pegfilgrastim, pent.ostai.in, peri osine, prednisolone, prednisone, R-roscoviiine (seliciclib, CYC202), recombinant interferon alia, recombinant inierleukin-12, recombinant inierleukin-l 1 , ret?¾mbinMt ϋ ligand, recombinant human thrombopoietm, rituximab, sargramostirn, sildenafil citrate, simvastatin, sirolrraus, styryl sulpb.on.es, tacrolimus, tanespimyein, temsirolimus (CCl-779), thalidomide, therapeutic allogeneic lymphocytes, thiotepa, tipifarnib, hortezomib
(VELCADE^, PS-341), vincristine, vincristine sulfate, vinorelhine di tartrate, SAHA (suberanilohydroxamic acid, or suberoyl, anilide, and hydroxamic acid), ! (fludarabine and rit.uximab)f (.'HOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), CVP (cyclophosphamide, vincristine, and prednisone), FCM (fludarabine, cyclophosphamide, and mitoxantrone), FCR (fludarabine, cyclophosphamide, and rituximab), hyperCVAD (hyperfractionaied cyclophosphamide, vincristine, doxorubicin, dexamethasone, methotrexate, and. eytarabiiie), ICE iiphosphamide, carboplatin, and etoposide), MCP
(mitoxantrone, chlorambucil, and predn isolone), R-CHOP (rituxirrtsb and CHOP), R-CVP (rituximab: and CVP), R-FC.M (rituximab 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- 1 1 1 , yttrium- 90, and iodine- 131. Examples of combination therapies include, but are not limited to, iodine- 1.31 tosttumomab (BEXXAR*). yttrium -90 ibritumomab tiuxetan (ZEVAEIN®), and BE'XXAR* with CHOP.
[00270] The abovementioned therapies can be supplemented or combined with stern 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 viir -treated peripheral blood stem cell transplantation, umbilical cord blood transplantation, immunoenzyme technique, low -LET cohalt-60 gamma ray therapy, bleomycin, conventional surgery, radiation therapy, and nonnryeloabl alive allogeneic hematopoietic stem cell transplantation. NomHodgk vs Lymphomas Combination Therapy
[00271J Treatment of nori-Flodgkin's lymphomas (NHL), especially those of B cell origin, includes using monoclonal antibodies, standard chemotherapy- approaches {e.g. , CHOP, CVP, FCM, MCP, and the like), radioimmunotherapy, and combinations thereof, especially integration of an antibody therapy with chemotherapy. Examples of unconj ugated .monoclonal antibodies for the treatment of HL/B-celi cancers include rituximab. alemtuzumah, human or humanized a.n i--CD20 antibodies, himiliximab, anti-TNF-reiated apoptosis- inducing ligand (anti-TRAIL ), bevaeizurnab, galiximab, epratuzu uab, SGN- 40. and anti~CD74,Examples of experimental antibody agents used in treatment of NHL B-ce!l cancers include otatumumab, ha20, PR0131921 , aiemtuzumab, galixmiab, SGN-40, CHIR~12.12, epratosumab !umili iniab, apoli umab, milatuzumab, and bevackumab .Examples of standard regimens of chemotherapy for NHL/B-ce!l cancers include CHOP, FCM, CVP, MCP, R-CHOP, R--FCM, R- CVP, and R-MCP.Examples of radioimrounotherapy for H UB-ceil cancers include yttrium -90 ibritumoroab iiuxeiaii (ZEVALIN*) and iodine- 131 tositirmo.mab (BEXXAR^).
Mantle Cell Lymphoma Combination Therapy
[00272] Therapeutic treatments for mantle ceil lymphoma (MCL) include combination chemotherapies such as CHOP, hyperCVAD, and FCM. These regimens can also be supplemented with the monoclonal antibody rituximab to form combination therapies R-CHOP, by erCVAD-R, and R.-FCM. Any of the abovementioned therapies may be combined with stem cell transplantation or ICE in order to teat MCL,
[00273] An alternative approach to treating MCL is iinmimotherapy . One immunotherapy uses monoclonal antibodies like rituximab. Another uses cancer vaccines, such as GTOP-99, which are based on. the genetic makeup of an individual patient's tumor,
[00274] A modified approach to trea MCL is radioimmunotherapy, wherein a monoclonal antibody is combined with a radioisotope particle, such as iodine-131 tositumomab (BEXXAR.'*) and yttmmv-90 ibritumomab tiuxetan iZEVALu *'). In another example, BBX.XAR " is used in sequential treatment with CHOP. [00275] Other approaches to treating MC , include autologous stem cell transplantation coupled with high-dose chemotherapy, administering proteasome inhibitors such as borteaomib (YEECADE ' or PS-34.1), or adniimstering antiangiogenesis agents such as thalidomide, especially in combination with rituximab,
[00276] Another treatment approach is administering drugs that lead to the degradation oi Bcl-2 protein and increase cancer cell sensitivity so chemotherapy, such as oblimersen, in combination with other chemotiherapeutie agents,
[00277] A further treatment approach includes administering m'l'OR inhibitors, which can lead to inhibition of cell growth and even cell death. Non -limiting examples are temsiroitmus (TORISEI, '', CCI-779) and temsirolmms in combination with RITUXAN*', VELCADE® or other ehemoiherapeutic agents.
[00278] Other recent therapies for MCL have been disclosed. Such examples include ilavopiridof PD0332991, R-roseovitine (selicicilib, CYC202), sryry] sulphones, obaioclax (GX15-070), TRAIL,, Anti-TRAIL death receptors DR4 and DR. antibodies, temsirolimus (TORfSEL®, CCI-779), evcrolimus (RAD001 ), BMS-345541 , curcumin, SAHA, thalidomide, lenalidomide (REVLJM!D* CC- 5013), and geldanarnycin ί 17-AAGi.
Waldenstrom's Macroglobulinemia Combination Therapy
[00279] Therapeutic agents used to treat Waldenstrom's Macroglobulinemi (WM) include perifosine, bortezomib (VELCADE' '), rituximab, sildenafil citrate (VIAGRA*), CC-5103, thalidomide, epratuzumab (hi.,L2~ anii-CD22 humanized antibody), simvastatin, enzastaurin, eampath-lH, dexamethasone, DT-PACE, oblimersen, antineop!astoa A 10, antineoplaston AS2- I , alemtuzumab, beta alethine, cyclophosphamide, doxorubicin hydrochloride, prednisone, vincristine sulfate, fludarabine, filgrastim, me-lpbaian, recombinant interferon alia,
cammstme, cispiatra, cyclophosphamide, cytarabiue, etoposide, melphalan, dolastatin 10, indium - 1 1 1 monoclonal antibody MN-14, yttrium-90 humanized eptateumab, anii-thymocyte globulin, busulfan, eyciosporine, methotrexate, mycophenokte mofeii!, therapeutic allogeneic lymphocytes, yttriu.m-90 ibritumomab tiuxetan, sirolimus, tacrolimus, carboplatin, hiotepa, paelitaxei, aldesleukin, docetaxei, iibsfamide, mesna, recombinant interleukin-l l, recombinant inCerieukin-12, Bci-2 family protein inhibitor ABT--263, denileukin difiitox, tanespimycm, everoliraua, pegfilgrastim, vorinostat, alvocidib, recombinant flt3 ligand, recombinant human thrombopoietiii, lymphokiiie- activ ted killer cells, amifostine trihydrate. am inocamptothecin, irinotecan hydrochloride, caspofu gin acetate, clofarabine, epoetin alia, nelarabine, peniosiaim, sargraraostim, vinorelbine ditarirate, WT-1 analog peptide vaccine, WTl 126- 134 peptide vaccine, fenretinide, ixabepiione, oxaliplatin, monoclonal antibody CD1 , monoclonal antibody CD20, omega-3 fatty acids, mitoxantrone hydrochloride, octreotide acetate, tositumomab, iodi e- 131 tositumomab, motexafin gadolinium, arsenic trioxide, tipifar b, autologous human tumor- derived HS.PPC-96, veliuzumab, hryostatin 1 , PEGylated liposomal doxorubicin hydrochloride, ami any combination thereof.
(00280) Examples of therapeutic procedures used to treat WM 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, bon marrow ablation with stem cell support, in virr -trealed peripheral blood stem cell transplantation, umbilical cord blood transplantation, immunoenzyme techniques, low-LET cobalt-60 gamma ray therapy, bleomycin, conventional surgery, radiation therapy, and nonmyeloablati ve allogeneic hematopoietic stem cell transplantation.
Diffuse Large B-cell Lymphoma Combination Therapy
[00281] Therapeutic agents used to treat diffuse large B-cell lymphoma
(DLBCL) include cyclophosphamide, doxorubicin, vincristine, prednisone, anti- CD20 monoclonal antibodies, etoposide, bleomycin, many of the agents l isted for WM, and any combination thereof such as ICE and MCE.
Chronic Lymphocytic Leukemia Combination Therapy
[00282] Examples of therapeutic agents used to treat chronic lymphocytic leukemia (CLL) include chlorambucil, cyclophosphamide, fiudarahme, pentostatin, cladribine, doxorubicin, vincristine, prednisone, prednisolone, alemtuzumab, .many of the agents listed for 'WM, and combination chemotherapy and ehemoirnmuno therapy, including the following common combination regimens: CVP, R-CV.P, ICE, R-ICE, FOR, and FR.
Myelofibrosis Combination Therapy
[00283 Myelofibrosis inhibiting agents include, but are not limited to, hedgehog inhibitors, histone deacetyiase (HDAC) iiihibitors, and tyrosine kinase inhibitors. A non -1 imi ting example of hedgehog inhibitors is saridegib.Examples of HDAC inhibitors include, but are not limited to, pracinostat and panobinostat.A non- limiting example of a tyrosine kinase inhibitor is iestaurtmib.
Kinase Inhibitors
1.00284] In one embodiment, the compound described herein may be used or combined with one or more additional therapeutic agents. The one or more therapeutic agents include, but are not limited to, an inhibitor of Abl, activated GDC kinase (ACK), adenosine A2B receptor (A2B), apoptosis signal-regulating kinase (ASK), Auroa kinase, BET-hromodomam (BRD) such as BRD4, e-Kit, c- Met, CDK-aclivating kinase (CAK), calmod ulin-dependent protein kinase (CaMK), eyclin-dependeni kinase (CD ), casein kinase (C ), discoidin domain receptor (DDR), epidermal growth factor receptors (EGFR), focal adhesion kinase (FAK), Flt-3, FY. , glycogen synthase kinase (GSK), HCK, histone deacetyiase (HDAC), IKK. such as Ι Κβε, isocitrate dehydrogenase (IDE) such as IDHl, Janus kinase (JA.K), KDR, lymphocyte-specific protein tyrosine kinase (LCK), iysyl oxidase protein, lysyl oxidase-like protein (LOXL), LYN, matrix metal loprotease (MMP). MEK, mitogen-activated protein kinase (MAPK). NE , NPM-ALK, p 8 kinase, platelet-derived growth factor (PDGF), phosphorylas kinase (PK), polo-like kinase (PLK), phosphatidylinosi ol 3-kinase (PBK), protein kinase (PK) such as protein kinase A, B, and/or C, PYK, spleen tyrosine kinase (SYK), serine/threanine kinase TPI.,2, serine/threonine kinase STK, signal transduction and transcription (STAT), SRC, serine/threonine- protein kinase (TBK) such as TBR1 , TIE, tyrosine kinase (TK), vascular endothelial growth factor receptor (VEGFR), YES, or any combination thereof. Apoptosis Signal -Regulating Kinase (ASK) inhibitors
[00285] ASK inhibitors include ASK1 inhibitors. Examples of ASK1 inhibitors include, but are noi limited to, those described m WO 2011/008709 (Giiead Sciences) and WO - 2013/1 12741 (Giiead Sciences).
Discoidin Domain Receptor (D.DR) Inhibitors
[00286] DDR inhibitors include inhibitors o f DDR I and/or DDR2. Examples of DDR inhibitors include, but are not limited to, those disclosed in WO
2014/047624 (Giiead Sciences), US 2009-0142345 (Takeda Pharmaceutical), US 201 1-02870! 1 (Oncomed Pharmaceuticals), WO 2013/027802 (Chugai Pharmaceutical), and WO 20.13/034933 (imperial Innovations).
Historic Deaeetylase (MDAC) Inhibitors
[00287] Examples- of HDAC inhibitors- include, but are not limited to, praeinostat and paaobinostat.
Janus Kinase (JAK) inhibitors
[00288] JAK inhibitors inhibit JAK i, JA 2, and/or JAK3, Examples of JAK inhibitors include, but are not limited to, Compound A, nixolitimh, fedratmib, tofacitinib, baricitmib. lestaurtmib, pacrumib, XL019, AZDI480, INCB03 H0, LY27845 4, BMS91 1543, and NS018.
Lysyl Oxidase-Like Protein (LOXL.) Inhibitors
[00289] LOXL inhibitors include inhibitors ofLOXLl , LOXL2, 1,0X1,3, LOXL4, and/or LOXL5. Examples of LOXL inhibitors include, but are not limited to, the antibodies described in WO 2009/017833 (Arresto
Biosciences), Examples ofLO.XL2 inhibitors include, but are not limited to, the antibodies described in WO 2009/017833 (Arresto Biosciences), WO
2009/035791 (Arresto Biosciences), and WO 201,1 /097513 (Giiead Biologies).
Matrix Metalioprotease (MMP) inhibitors
[00290] MMP inhibitors include inhibitors of MMP! through 10. Examples of MMP9 inhibitors include, but are not limited to, marimastat i'BB-2516), cipeniastat (Ro 32-3555), and those described in WO 2012/027721 (Gilead Biologies),
Phosphatidyl inositol 3 -kinase (PS3K) Inhibitors
[00291] FI3K inhibitors include inhibitors; of Ρ13Κγ, PI3K5, Ρϊ3Κβ, ΡΙ3Κ , and/or pan-PI3K. Examples of PI3K inhibitors include, but are not limited to, wortmannin, BKM120, CHS 132799, XL756, and GDC-0980.Exaraples of ΡΙ3Κγ inhibitors include, but are not limited to, ZSTK474, AS252424, LY294002, and TGI 001 5. Examples of ΡΒΚδ inhibitors include, but are not limited to, , PI3K IE TGR-1202, AMG- 19, GSK2269557, X-339, X- I4, RP5090, KAR4141 , XL499, OXY11 1 A, IPI-145, 1P1-443, and the compounds described in WO 2005/11 556 (ICOS), WO 2013/052699 (Gilead Calistoga), WO 2013/1 16562 (Gilead Calistoga), WO 2014/ 100765 (Gilead Calistoga ), WO 2014/1 QQ767 (Gilead Calistoga), and WO 2014/201409 (Gilead Sciences). Examples of ΡΪ3Κβ inhibitors include, but are not limited to, GSK2636771 , BAY 10824391, and TGX221 .Examples ofPDK inhibitors include, but are not limited to, huparlisib, BAY 80-6946, BYL71 , PX-866, RG7604, MEN 3 1 17, WX-037, AEZA-129, and PA79 .Examples of pan-PDK inhibitors include, but are not limited to, LY294002, BEZ235, XL 147 (SAR245408), and GDC-0941.
Spleen Tyrosine Kinase (SYK) Inhibitors
292| Examples of SYK inhibitors include, but are not limited to, tamatinib (R4G6), fostamatinib (R7SSI PRT062607, BAY-6I-3606, NVP-QAB 205 AA, Rl 12, R343, and those described in US 8450321 (Gilead Connecticut).
Tyrosine-kinase Inhibitors (TKIs)
[00293} TKIs ma target epidermal growth factor receptors (EGFRs) and receptors for fibroblast growth factor (FGF), platelet-derived growth factor (PDGF), and vascular endothelial growth factor (VEGF). Examples of TKIs that target EGFR include, but are not limited to, gefitinib and erlotmib. Sunitinib is a non-limiting example of a TKI that targets receptors for FGF, PDGF, and VEGF.
[00294] Combinations of pharmaceutically effective amounts of the BTK inhibitor and an ASKl inhibitor as described herein may also be used to treat an allergic disorders, autoimmune diseases and infiamma'tory diseases in a human, the method comprising administering to the human in need thereof a pharmaceutically effective amount of the BTK inhibitor, or a pkamiaceuticaity acceptable salt or hydrate thereof, and a pharmaceutically effective amount of an AS.K1 inhibitor, or a pharmaceutically acceptable salt or hydrate thereof.
Particularly, the combinations taught herein may be used for the treatment of allergic disorders, autoimmune diseases and inflammatory diseases such as: systemic lupus erythematosus (SLE), rheumatoid arthritis, multiple vasculitide-s, idiopathic thrombocytopenic purpura (II P), myasthenia gravis, allergic rhinitis, chronic obstructive pulmonary disease (COPD), adult respiratory distress syndrome (A Ds) and asthma.
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 result of the assay or study may vary. In some instances, the value may vary within a range of one to three -fold.
Example 1
|O029S] This study evaluated the potential effects of BTK inhibitor in combination with J AK inhibitor in treating arthritis. Lewis rats were injected mtradermally/subeutaneously f !D SC) with porcine type II collagen to induce arthritis. Arthritic rats were treated with vehicle (20% Cremophor EL 10% EtOH/70% saline), Compound Al ia BTK inhibitor}. Compound B4 (a JAK inhibitor), Compound Al and Compound B4, or ex (dexameihasone).
Compound Al was administered orally either twice daily at 3. 10, or 20 mg/kg or once daily at 20 mg/kg; Compound B4 was administered orally daily at 2.5 mg kg; dex was administered daily at 0.075 mg/kg, initiated on day 17. The study was terminated at day 34. Efficacy evaluation was based on body weights, daily ankle- caliper measurements, ankle diameter expressed as area under the carve (AUC), terminal hind paw weights, and histopathologic evaluation of right ankles,
[00296] This model may reflect certain clinical and histopathologic parameters, such as inflammation, cartilage destruction, and bone resorption that occur in established type II collagen arthritis in female Lewis rats. As the treatment was initiated at the peak of established disease and continued into the chronic phase; the results obtained may be used in evaluating chronic, highly destructive maerophage-oiediated phase of this model.
[1)0297] Ankle diameters were measured and compared for potential treatment effects. FIG. 1 depicts the measurements taken on Day 9, 13-34 for ankle diameter (in.) (mean * standard error) tor the following groups: control (normal and disease). Compound Al (20 mg/kg, daily), Compound Al (3 mg/kg, twice daily), Compound B4 (2,5 mg/kg, twice daily), Compound Al (20 mg/kg, daily) with Compound B4 (2.5 mg/kg, twice daily), Compound Al (3 mg/kg, twice daily) with Compound B4 (2.5 mg/kg, twice datly) and Dex (0.075 mg/kg daily). In addition, the AUC total sum (day 17-34) (mean ± standard error) was .measured. The AUC total sum for the control ('normal) was 4.5 ± 0.008; for control (disease), 6.1 ± 0.058; for Compound Al (20 mg/kg, daily), 5.9 ± 0,096: for Compound A 1 (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 Compoimd B4 (2.5 mg/kg, twice daily), 5.6 ± 0.083; for Compound Al (20 mg/kg. daily) with Compound B4 (2.5 mg kg, twice daily), 5.3 ± 0.063; for Compound A l (10 mg kg, twice daily) with Compound B4 (2.5 mg/kg, twice daily), 5.3 ± 0.093; for Compound Al (3 mg/kg, twice daily) with Compound B4 (2.5 mg/kg, iwice datly), 5.3 ± 0.082; and for Dex (0.075 mg kg daily), 5.2 ± 0.069.
[00298'j Also, the percent inhibition of the AUC total sum (day 17-34) was determined. The percent inhibition was 100% for the control (normal); 0% for the control (disease); 13% for Compound Al (20 mg/kg, daily); 15% for Compound Al (20 mg kg, twice daily); 9% for Compound Al (10 mg/kg, twice daily); 1 % for Compound Al (3 mg kg, twice daily); 28% for Compound .84 (2.5 mg/kg, twice daily): 50% for Compound At (20 mg/kg, daily) with
Compound B4 (2.5 mg/kg, twice daily): 49% for Compound Al (10 mg/kg, twice daily) with Compound B4 (2.5 mg/kg, twice daily); 48% for Compound Al (3 mg kg, twice daily) with Compound B4 (2.5 mg/kg, twice daily),; and 56% for Dex (0.075 mg/kg).
10 299] the following score systems were used to evaluate ankle inflammation, ankle pannus, ankle cartilage damage, ankle hone resorption, and periosteal new bone formation,, which may represent treatment, effects toarikle histology. The sum of the summed ankle histology scores tor day 34, are provided herein.
|00300] Ankle mflammatioi scores as used herein have the following meaning: <■' normal; 0. minimal focus inflammation; 1 ~ minimal infiltration of inflammatory cells in synovium/periarticular tissue; 2:::: mild infiltration; 3= moderate infiltration with moderate edema; 4::= marked infiltration with marked edema; 5~ severe infiltration with severe edema. Ankle pannus scores as used herein ha ve the following meaning: 0- normal; 0.5~: minimal infiltration of pannus in cartilage and subchondral bone, affects only marginal zones and affects only a few joints; 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 infiHration (26% - 50% of tibia or small tarsals affected at marginal zones); 4::; marked infiltration (51%■· 75% of tibia or tarsals affected at marginal zones); ™· severe infiltration (>75% of tibia or tarsals affected at marginal zones, severe distortion of overall architecture).
100301] Ankle cartiliage 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; l:::- minimal to mild loss of tohndine blue staining with no obvious chondrocyte loss or collagen disruption; 2~ mild loss of toluidine blue staining with focal mild (superficial) chondrocyte loss and/or collage disruption; 3~ moderate loss of toluidine blue staining with multifocal moderate (depth to middle zone) chondrocyte loss and/or collagen disruption, smaller tarsals affected to 50% to 75% depth with rare areas of full 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 with multifocal severe (depth to tide mark) chondrocyte loss and/or collagen disruption affecting more than 2 cartilage surfaces.
100302] 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; 1:::; small areas of resorption, not readily apparent on low magnification, rare osteoclasts; 2~ more numerous areas of resorption, not readily apparent on low magnification, osteoclasts more numerous, 25% of tibia or tarsals at marginal zones resorbed; 3:::: obvious resorption oi'meduilary trabecular and cortical bone without full thickness defects in cortex, loss of some medullary trahecul&e, 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.
[0.03031 Periosteal new bone formation scores as used herein have the following meaning: normal, no periosteal proliferation; Q.5:::: minimal focal or multifocal proliferation, measures less than 127 um width (1-2 units at 16x) at any location; 1::; minimal multifocal proliferation, width at any location measures 127 -252 urn (3-4 units at 1 6x); 2- mild multifocal on tarsals, diffuse in some locations, width at any location 253 -441 um (5-7 units at 16s); - moderate multifocal on tarsals, diffuse in moss other locations, width at any location measures 442-630 um (8- 10 units at 16x); 4~ marked multifocal on tarsals, diffuse at most other locations, width at any location measures 630-819 um (1 i— 13 units at 16x); 5 ::: severe, multifocal on tarsals, diffuse at. most other locations, width at any location measures >81 um (>13 units at 16x).
[00304] The summed ankle histopat.ho.logy (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 Ai (20 mg kg, twice daily), 21 ± 0.6; for Compound A 1 (10 mg/kg, twice daily), 21 ± 1.4, for Compound A i (3 mg kg, twice daily), 23 ± 0,6; for Compound B4 (2,5 mg/kg, twice daily), .1 ± 1.4; for Compound Al (20 mg/kg, daily) with Compound B4 (2,5 mg/kg, twice daily), 1.0 ± .1.2; for Compound Al (10 mg/kg, twice daiiy) with Compound B4 (2.5 mg/kg, twice daily), 1 1 ± L6; for Compound Al (3 mg/kg, twice daily) with Compound B4 (2.5 mg kg, twice daily), 10 ± 2.0; and for Dex (0,075 rag/kg daily), 12 ± 1.0.
[00305] For th summed ankle histoparhoiogy. the percent inhibition was determined. The percent inhibition was 100% for the control (normal); 0% for the control (disease); 15% for Compound Al (20 mg/kg. daily); 18% for Compound A i (20 mg kg, twice daily); 16% for Compound Al (10 mg/kg, twice daily); 10% for Compound Al (3 mg kg, twice daily); 23% for Compound B4 (2.5 mg/kg, twice daily); 60% for Compound Al (20 mg/kg, daily) with
Compound B4 (2.5 mg/kg. twice daily); 57% for Compound Al (10 mg/kg, twice daily) with Compound B4 (2.5 mg/kg, twice daily); 60% for Compound Al (3 mg/kg, twice daily) with Compound 4 (2,5 mg/kg, twice daily); and 51% for Dex (0.075 mg/kg),
|00306) in addition, the ED-1 immunopositive osteoclast, count (mean -.t standard error) was measured. The ED-1 immunopositive osteoclast count for the control (normal) was 1 ± 0.2; for the control (disease), 19 i 1.0; for Compound Al (20 mg/kg, daily), 9 ± 1.5; for Compound Al (2.0 mg/kg, twice daily), 4 ± 0.7; for Compound Al (10 mg kg, twice daily), 8 ± 1.9; for
Compound Ai (3 mg/kg, twice daily), 7 ± 1 .3; for Compound B4 (2.5 mg/kg, twice daily), .1 ± 1 ,7 for Compound Al (20 mg/kg, daily) with Compound B4 (2.5 mg/kg, twice daily), 4 ± 0.4; Compound A 1 (10 mgkg, twice daily) with Compound B4 (2.5 mg/kg, twice daily), 3 ± 0.4; Compound Al (3 mg kg, twice daily) with Compound B4 (2.5 mg kg, twice daily), 3 ± 0.4; and for Dex (0.075 mg/kg), 1 1.4. For the ED-1 immunopositive osteoclast count, the percent inhibition was also measured. The percent inhibition for the control (normal) was 100%; for the control (disease), 0%; for Compound Al (20 mg kg, daily), 56%; for Compound Al (20 mg kg, twice daily), 83%; for Compound Al (10 mg/kg, twice daily), 62%; for Compound Al (3 mg/kg, twice daily), 65%; for Compound B4 (2.5 mg/kg, twice daily), 14%; for Compound Al (20 rag/kg, daily) with Compound B4 (2,5 mg/kg, twice daily), 85%; Compound A i (10 mg/kg, twice daily) with Compound B4 (2,5 mg/kg, twice daily), 1%; Compound Al (3 mg/kg, twice daily) with Compound B4 (2.5 mg/fcg, twice daily), 90%; and for Dex (0.075 mg/kgl 85%.
Example 2
[00307) Material and Methods: The effect of the Combination of a BET inhibitor, (2-cyelopropyl-6-(3,5-dimethylisoxazol -4-yl)-lH-beit)¾)[d]imidazoI-4- yl)d"i(pyridin-2-yl)methanol (Compound D)„ and BTK inhibitor (Compound Al) on growth inhibition of the human activated B cell (ABC) subtype DLBCL ceil line. TMD8, was evaluated in vitro. TMD8 cells were dosed with a matrix of Compound D (0 - 90 nM) andeompound Al (0 - 22 nM) and treated for four days, after which eel! viability was measured by a CeHTiter Glo assay. A representative heatmap of this dose matrix for cell growth inhibition is shown in FIG. 2 (0% to 100% growth inhibition). Both compounds reduced ceil growth over- he dose range; synergy was observed at concentrations of 5.8 - 90 nM of Compound D and 0.3 - 22 tM of Compound Al (FIG. 3). Synergy was defined as the excess over the predicted additive interaction between the compounds using Bliss analysis. The dose response curve for growth inhibition of
Compound I) alone or in the presence of 5.5 nM or 1 1 nM of Compound Al is shown inFIG. 4 . The average 1C¾ values (concentration that causes half maximal inhibition of cell growth} for Compound. D were decreased from 25 nM to 11 nM and 8 nM by the presence of 5.5 nM and 1 i nM of Compound Al, respectively, and is consistent with a synergistic interaction.
Cell Viability Assay:
100308] Cells were plated at a density of 4,000 ceils per well in 384- well (Grenier 7 1086} tissue culture black well plates already spotted with compounds b a Labcy e Echo liquid handler. Cells were treated with an 8-point 2-fold dilution series of (Compound D starting at 90 nM (final DMSO concentration of 0.14%). Cells treated with DMSO alone were used as a positive control for 100% cell growth. Cells were treated with Compound D alone or in the presence of a dose range of Compound Al (6»poini 2-fold dilution series ranging from 0.3 - 22 nM) for each dose of CompoundD. Ceils were incubated at 37*C for 96 hours and viability was measured using CellTiterG!o reagent as per the vendor's protocol. Curves were plotted in prism and IC½ valises were calculated with a 4- parameter variable biilslope non-linear fit. The predicted response under Bliss additivit for any combination of drugs at a given concentration pair was determined by a * Kb ~ Ra * Rb, where Ra and. Rb are the responses of Compounds D and Al (i.e., cell growth inhibition). The total Bliss score was determined by summing the differences between the observed values and the predicted additive value at each pair of concentrations assayed. Only values where the difference is greater than the 95% confidence interval of the measurements are included in the sum.

Claims

WHAT IS CLAIMED IS:
1. A method for treating m 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-pyrroUdinyl]-?-(4- phenoxyphenyl)-7,9-dihydro-8H -purin-8-one, or a pharmaceutically acceptable sail or hydrate thereof, and
wherein the one or more inhibitor is selected from the group consisting of a iAK inhibitor, an ASKl 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, mtmmusculariy, parenteral!}', 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 fSLL), non-Hodgkin's lymphoma, indolent non-Hodgkin's lymphoma (iNHL), mantle cell lymphoma, follicular lymphoma (FL), lyrnphoplasmaeytic lymphoma, and marginal zone lymphoma, rheumatoid arthritis, systemic lupus erythematosus, chronic obstructive pulmonary disease (CORD), -adult respiratory distress syndrome and asthma.
5. The method of claim 1 wherein the human is in refractory to at least one of the cancer therapies, or is in relapse after t eatment with at least one anti-cancer therapy selected from the group consisting of: (a) fludarabine; fb) 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, riinxiniab, ohinuiir/umab, or ofatumumab; (j ) peiitostatin combined with cyclophosphamide and riruximab. (k) bendamustine (Treamia& combined with rituxiraab; (1) alemtuzumab; (m) ftudarabine plus cyclophosphamide, bendamustine, or chlorambucil; and (n) fludarabine phis cyclophosphamide, bendamustme, 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 adm nistering a Btk inhibitor in combination with an inhibitor to the human, and wherein the inhibitor is selected from the group consisting of a JA inhibitor, an ASK1 inhibitor, a BED inhibitor, and a MM.P inhibitor,
7. The method of claims 1 or 6 wherein !he JAK inhibitor is selected from the group consisting of of mo.mel0tin.ib, Jfilgotinib, .l-[l-[[3-.fluoro-2~(irif!uorom
Figure imgf000157_0001
y i-3-azetidmeacetonitrile, tofacitinib, oclacirinib, ruxolotit b, baraeitinib, lestaurtmib, pacritmib, TGI 01348, JSi-124, GSK25851 4, VX-509, I CB 16562, XL059} NVP-BS 805, CEP33779, R-348, AC-430, CDP-R723, BMS91 1 543, or a pharmaceutically acceptable salt thereof.
8, The method of claims 1 or 6 wherein the ASK..1 inhibitor is 5-(4- cyclopropyM H-imidazol · 1 -yi)-2 "fluoro-N-(6-i4-isopropyi-4H-l !2,4~triazol-: - yl)pyridin"2~y{)-4-methyibenzara.ide, or a pharmaceutically acceptable salt or hydrate thereof
9. The method of claims 1 or 6 wherein the modulator of the komodomaitt- containing protein is a compound of Formula H:
Figure imgf000158_0001
wherein
Ria and Ru' are each independently C :, alky] optionally substituted with from 1 to
5 R" ' groups;
k"' and R"" are each independently H or halo;
R is
••CiO)OR\ -NHC(Q)OR¾, »MHS(0)2R*5 or ^S(Oj Ra b; or
selected from the grou consisting of Cuo alkyl, C O alkoxy, amino, Q.;o aryl
Q;.2o aiylaikyi, CMO heteroalkyl, C5.10 heteroaryl, and (.¾.;,;, heteroaryialkyl, each of which is optionally substituted with from 1 to 5 RAI groups;
one of R½ and R4¾ is selected from the group consisting of H and C -> alkyl optionally substituted with from 1 to 5 R" groups, and the other is absent;
R5 is -C(0)OR*, -NHC(0)OR*, -NHS(0)2R8, or -S(0)2NRaRb; or
R5 is selected from the group consisting of H, CMO alkyl, C haloalkyl, Cuo alkoxy, amino, C.vio aryl, C« aryiaikyi, CMO heteroalkyl, C5.10 heteroaryl, and Cg.
20 heteroaryialkyl, each of which is optionally substituted with from 1 to 5 R:il' groups;
each Ra and Rb is independently selected from, the group consisting of H, CMO alkyl, CMO aryl, Q.20 aryialkyl, .io heteroalkyl, C5-10 heteroaryl and (¾.¾, heteroaryialkyl, each of which is optionally substituted with from 1 to 5 R<:i) groups; arid
each RAI is independently selected from the group consisting ofacyi, C O alkyl, CMO alkoxy, amino, amido, amidino, Cs..; aryl, Q.20 aryialkyl, azido, carbamoyl, carhoxyi, carboxyl ester, cyano, guanidino, halo, CMO haloalkyl, C heteroalkyl, Cs-io heteroaryl, Q.20 heteroaryialkyl, hydroxy, hydrazino, irairio, oxo, n ro, suli nyl, sulfonic acid, sulfonyi, thioeyanate, thiol, and thione; and wherein the Ci-;<; alkyl, C$.u, aryl, (¾.¾) arylalkyl, io heteroalkyl, Cs-io heteroar ], and Q..20 heteroaiylalkyi groups are optionally substituted with from .1 to 3 substituents independently selected from C;..6 alky], C.¾.; aryl, halo, Ci^ haloalkyl. cyano, hydroxy, and C1 alkoxy;
or a pharmaceutically acceptable salt thereof.
10. The method of claims 1 or 6 wherein the MP9 inhibitor comprises a
M. P9 binding protein comprising;
an immunoglobulin heavy chain polypeptide, or a ilmctiona) fragment thereof; and
an immunogloblulin light chain polypeptide, or a functional fragment thereof; wherein the .MP9 binding protein specifically binds to human. MM.P9, and
wherein th M P9 binding protein competes for binding to human MMP9 with an antibody comprising heavy chain CDRs ofSEQ ID NOs: 13-15 or light chain CDRs of SEQ I'D oe. 16 8.
1 1 . The method of claim 10 wherein the immunoglobulin heavy chain comprises an amino acid sequence SEQ ID NO. 7 and wherein the
immunoglobulin light chain polypeptide or functional fragment thereof comprises an amino acid sequence SEQ I'D NO. 12.
12. An article of manufacture comprising:
a unit dosage form of a BT inhibitor, wherein the BTK inhibitor is is 6- amino-9-[(3R l-(2-butynoyl^
81.1 -purin-S-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 ASIC! 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)-l-(2~ bu!ynoyl)-3-pyrroiidi^ -purin-8-on.e, 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 MMP inhibitor; and
instructions for use in treating a disease selected from the group of a cancer, allergic disorders, autoimmune diseases, and inflammatory diseases.
PCT/US2016/054780 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 WO2017059252A1 (en)

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CA3000746A CA3000746A1 (en) 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
AU2016329075A AU2016329075A1 (en) 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
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US15/764,687 US20180311247A1 (en) 2015-10-02 2016-09-30 Combination therapies for treating cancers
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CN110403944A (en) * 2019-08-07 2019-11-05 中南大学湘雅医院 Application, medicine and preparation method of Decernotinib in preparation of external medicine for treating psoriasis

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