NZ619642B2 - Inhibitors of bruton's tyrosine kinase - Google Patents
Inhibitors of bruton's tyrosine kinase Download PDFInfo
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- NZ619642B2 NZ619642B2 NZ619642A NZ61964212A NZ619642B2 NZ 619642 B2 NZ619642 B2 NZ 619642B2 NZ 619642 A NZ619642 A NZ 619642A NZ 61964212 A NZ61964212 A NZ 61964212A NZ 619642 B2 NZ619642 B2 NZ 619642B2
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- 239000003638 reducing agent Substances 0.000 description 1
- 230000003307 reticuloendothelial Effects 0.000 description 1
- 229960000371 rofecoxib Drugs 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 150000003902 salicylic acid esters Chemical class 0.000 description 1
- 238000004626 scanning electron microscopy Methods 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000004904 shortening Methods 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 1
- 238000003530 single readout Methods 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- YOQDYZUWIQVZSF-UHFFFAOYSA-N sodium borohydride Substances [BH4-].[Na+] YOQDYZUWIQVZSF-UHFFFAOYSA-N 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000001187 sodium carbonate Substances 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- PZOHOALJQOFNTB-UHFFFAOYSA-M sodium;6-fluoro-2-[4-(2-fluorophenyl)phenyl]-3-methylquinoline-4-carboxylate Chemical compound [Na+].N1=C2C=CC(F)=CC2=C(C([O-])=O)C(C)=C1C(C=C1)=CC=C1C1=CC=CC=C1F PZOHOALJQOFNTB-UHFFFAOYSA-M 0.000 description 1
- XBUIKNRVGYFSHL-IAVQPKKASA-M sodium;[(1E,3R,4R,6R,7Z,9Z,11E)-3,6,13-trihydroxy-3-methyl-1-[(2R)-6-oxo-2,3-dihydropyran-2-yl]trideca-1,7,9,11-tetraen-4-yl] hydrogen phosphate Chemical compound [Na+].OC/C=C/C=C\C=C/[C@H](O)C[C@@H](OP(O)([O-])=O)[C@@](O)(C)\C=C\[C@H]1CC=CC(=O)O1 XBUIKNRVGYFSHL-IAVQPKKASA-M 0.000 description 1
- ODGROJYWQXFQOZ-UHFFFAOYSA-N sodium;boron(1-) Chemical compound [B-].[Na+] ODGROJYWQXFQOZ-UHFFFAOYSA-N 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 230000000392 somatic Effects 0.000 description 1
- 230000003595 spectral Effects 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000010911 splenectomy Methods 0.000 description 1
- 230000000087 stabilizing Effects 0.000 description 1
- 239000008117 stearic acid Chemical group 0.000 description 1
- 210000000130 stem cell Anatomy 0.000 description 1
- 230000004936 stimulating Effects 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- 229960002317 succinimide Drugs 0.000 description 1
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 description 1
- 125000004434 sulfur atoms Chemical group 0.000 description 1
- 230000000153 supplemental Effects 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 229960001367 tartaric acid Drugs 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229930003347 taxol Natural products 0.000 description 1
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 1
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- YPWFISCTZQNZAU-UHFFFAOYSA-N tetrahydro-2H-thiopyran Chemical compound C1CCSCC1 YPWFISCTZQNZAU-UHFFFAOYSA-N 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000005958 tetrahydrothienyl group Chemical group 0.000 description 1
- 125000004632 tetrahydrothiopyranyl group Chemical group S1C(CCCC1)* 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000005308 thiazepinyl group Chemical group S1N=C(C=CC=C1)* 0.000 description 1
- 125000001583 thiepanyl group Chemical group 0.000 description 1
- 125000002053 thietanyl group Chemical group 0.000 description 1
- 125000005309 thioalkoxy group Chemical group 0.000 description 1
- 125000002813 thiocarbonyl group Chemical group *C(*)=S 0.000 description 1
- 229940026752 topical Sulfonamides Drugs 0.000 description 1
- 231100000224 toxic side effect Toxicity 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 230000002103 transcriptional Effects 0.000 description 1
- 108091006091 transcriptional repressors Proteins 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- 230000001052 transient Effects 0.000 description 1
- LXZZYRPGZAFOLE-UHFFFAOYSA-L transplatin Chemical compound [H][N]([H])([H])[Pt](Cl)(Cl)[N]([H])([H])[H] LXZZYRPGZAFOLE-UHFFFAOYSA-L 0.000 description 1
- 229960000575 trastuzumab Drugs 0.000 description 1
- 229960005294 triamcinolone Drugs 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- KQBSGRWMSNFIPG-UHFFFAOYSA-N trioxane Chemical compound C1COOOC1 KQBSGRWMSNFIPG-UHFFFAOYSA-N 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 1
- 150000004917 tyrosine kinase inhibitor derivatives Chemical class 0.000 description 1
- 229940121358 tyrosine kinase inhibitors Drugs 0.000 description 1
- 230000004222 uncontrolled growth Effects 0.000 description 1
- 125000004417 unsaturated alkyl group Chemical group 0.000 description 1
- 238000011144 upstream manufacturing Methods 0.000 description 1
- 229960005486 vaccines Drugs 0.000 description 1
- 229960002004 valdecoxib Drugs 0.000 description 1
- LNPDTQAFDNKSHK-UHFFFAOYSA-N valdecoxib Chemical compound CC=1ON=C(C=2C=CC=CC=2)C=1C1=CC=C(S(N)(=O)=O)C=C1 LNPDTQAFDNKSHK-UHFFFAOYSA-N 0.000 description 1
- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 description 1
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
Classifications
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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
- A61K31/495—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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- A—HUMAN NECESSITIES
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-
- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
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- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
- C07D473/32—Nitrogen atom
- C07D473/34—Nitrogen atom attached in position 6, e.g. adenine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Abstract
Described herein are kinase inhibitor compounds, methods for synthesizing such inhibitors, and methods for using such inhibitors in the treatment of diseases. Further described herein are methods, assays and systems for determining an appropriate inhibitor of a protein, including a kinase.
Description
INHIBITORS OF BRUTON’S TYROSINE KINASE
RELATED APPLICATIONS
The present application claims the benefit of priority from U.S. Provisional Patent
Application No. 61/507,482 filed July 13, 2011, which is herein incorporated by reference
in its entirety.
FIELD OF THE INVENTION
Described herein are kinase inhibitor compounds, methods for synthesizing such
inhibitors, and methods for using such inhibitors in the treatment of diseases.
BACKGROUND OF THE INVENTION
A kinase, alternatively known as a phosphotransferase, is a type of enzyme that
transfers phosphate groups from high-energy donor molecules, such as ATP, to specific
target molecules; the process is termed phosphorylation. Protein kinases, which act on and
modify the activity of specific proteins, are used to transmit signals and control complex
processes in cells. Up to 518 different kinases have been identified in humans. Their
enormous diversity and role in signaling makes them attractive targets for drug discovery.
SUMMARY OF THE INVENTION
[0003a] A first aspect of the invention provides for a compound having the structure of
Formula (VI):
Formula (VI);
wherein:
a a b b b b
L is CR R , O, S, NR , N-OR , C=O, C=S, C=N-R or C=N-OR ;
W is a bond or optionally substituted C -C alkyl;
Z is C=O, SO or SO;
1 2 1 2
R and R are each independently H or C -C alkyl, wherein R and R have a cis
or trans relationship; or R and R join together to form a bond;
n and p are each independently an integer from 0 to 3;
m is an integer from 1 to 3;
R is H, substituted or unsubstituted C -C alkyl, substituted or unsubstituted
C -C cycloalkyl, substituted or unsubstituted C -C heteroalkyl, substituted or
3 6 1 6
unsubstituted C -C heterocycloalkyl, substituted or unsubstituted C -C aryl, or
2 6 6 12
substituted or unsubstituted C -C heteroaryl;
11
R is substituted or unsubstituted C -C cycloalkyl, substituted or unsubstituted
C -C heterocycloalkyl, substituted or unsubstituted C -C aryl, or substituted or
2 6 6 12
unsubstituted C -C heteroaryl;
11
b b b
R is H, OH, OR , NR R , halogen, C -C alkyl, C -C heteroalkyl,
1 6 1 6
C C cycloalkyl, or C -C heterocycloalkyl;
3 6 2 6
R is each independently H, C -C alkyl, C -C heteroalkyl, halogen, OR , or
1 6 1 6
NR R ;
R is each independently H, C -C alkyl, C -C heteroalkyl, C -C cycloalkyl, or
1 6 2 6 3 6
C -C heterocycloalkyl;
or a pharmaceutically acceptable salt, solvate, or N-oxide thereof.
[0003b] A second aspect of the invention provides for A compound having the structure
of Formula (VII)
Formula (VII);
wherein:
a a b b b b
L is CR R , O, S, NR , N-OR , C=O, C=S, C=N-R or C=N-OR ;
W is a bond or optionally substituted C -C alkyl;
Z is NR C=O, SO or SO;
1 2 1 2
R and R are each independently H or C -C alkyl, wherein R and R have a cis
or trans relationship; or R and R join together to form a bond;
p is an integer from 0 to 3;
R is H, substituted or unsubstituted C -C alkyl, substituted or unsubstituted
C -C cycloalkyl, substituted or unsubstituted C -C heteroalkyl, substituted or
3 6 1 6
unsubstituted C -C heterocycloalkyl, substituted or unsubstituted C -C aryl, or
2 6 6 12
substituted or unsubstituted C -C heteroaryl;
11
R is substituted or unsubstituted C -C cycloalkyl, substituted or unsubstituted
C -C heterocycloalkyl, substituted or unsubstituted C -C aryl, or substituted or
2 6 6 12
unsubstituted C -C heteroaryl;
11
b b b
R is H, OH, OR , NR R , halogen, C -C alkyl, C -C heteroalkyl,
1 6 1 6
C -C cycloalkyl or C -C heterocycloalkyl;
3 6 2 6
R is each independently H, C -C alkyl, C -C heteroalkyl, halogen, OR , or
1 6 1 6
NR R ;
R is each independently H, C -C alkyl, C -C heteroalkyl, C -C cycloalkyl or
1 6 2 6 3 6
C -C heterocycloalkyl;
R is H or C -C alkyl;
or a pharmaceutically acceptable salt, solvate, or N-oxide thereof.
[0003c] A third aspect of the invention provides for a compound having the structure of
Formula (VIII)
Formula (VIII);
wherein:
a a b b b b
L is CR R , O, S, NR , N-OR , C=O, C=S, C=N-R or C=N-OR ;
W is a bond or optionally substituted C -C alkyl;
Z is NR C=O, SO or SO;
1 2 1 2
R and R are each independently H or C -C alkyl, wherein R and R have a cis
or trans relationship; or R and R join together to form a bond;
p is an integer from 0 to 3;
R is H, substituted or unsubstituted C -C alkyl, substituted or unsubstituted
C C cycloalkyl, substituted or unsubstituted C -C heteroalkyl, substituted or
3- 6 1 6
unsubstituted C -C heterocycloalkyl, substituted or unsubstituted C -C aryl, or
2 6 6 12
substituted or unsubstituted C -C heteroaryl;
11
R is substituted or unsubstituted C -C cycloalkyl, substituted or unsubstituted
C -C heterocycloalkyl, substituted or unsubstituted C -C aryl, or substituted or
2 6 6 12
unsubstituted C -C heteroaryl;
11
b b b
R is H, OH, OR , NR R , halogen, C -C alkyl, C -C heteroalkyl,
1 6 1 6
C -C cycloalkyl or C -C heterocycloalkyl;
3 6 2 6
R is each independently H, C -C alkyl, C -C heteroalkyl, halogen, OR , or
1 6 1 6
NR R ;
R is each independently H, C -C alkyl, C -C heteroalkyl, C -C cycloalkyl or
1 6 2 6 3 6
C -C heterocycloalkyl;
R is H or C -C alkyl;
or a pharmaceutically acceptable salt, solvate, or N-oxide thereof.
[0003d] A fourth aspect of the invention provides for a compound having the structure of
Formula (X)
n R R
Formula (X);
wherein:
a a b b b b
L is CR R , O, S, NR , N-OR , C=O, C=S, C=N-R or C=N-OR ;
W is a bond or optionally substituted C -C alkyl;
Z is C=O, SO or SO;
1 2 1 2
R and R are each independently H or C -C alkyl, wherein R and R have a cis
or trans relationship; or R and R join together to form a bond;
n and p are each independently an integer from 0 to 3;
m is an integer from 1 to 3;
R is H, substituted or unsubstituted C -C alkyl, substituted or unsubstituted
C -C cycloalkyl, substituted or unsubstituted C -C heteroalkyl, substituted or
3 6 1 6
unsubstituted C -C heterocycloalkyl, substituted or unsubstituted C -C aryl, or
2 6 6 12
substituted or unsubstituted C -C heteroaryl;
11
R is substituted or unsubstituted C -C cycloalkyl, substituted or unsubstituted
C -C heterocycloalkyl, substituted or unsubstituted C -C aryl, or substituted or
2 6 6 12
unsubstituted C -C heteroaryl;
11
b b b
R is H, OH, OR , NR R , halogen, C -C alkyl, C -C heteroalkyl,
1 6 1 6
C -C cycloalkyl or C -C heterocycloalkyl;
3 6 2 6
R is each independently H, C -C alkyl, C -C heteroalkyl, halogen, OR , or
1 6 1 6
NR R ;
R is each independently H, C -C alkyl, C -C heteroalkyl, C -C cycloalkyl or
1 6 2 6 3 6
C -C heterocycloalkyl;
or a pharmaceutically acceptable salt, solvate, or N-oxide thereof.
[0003e] A fifth aspect of the invention provides for a compound having the structure
selected from:
NH NH
O , ,
NH NH
NH NH
O , O .
NH NH
, and ; or a
pharmaceutically acceptable salt, solvate, or N-oxide thereof.
[0003f] A sixth aspect of the invention provides for a compound having the structure
selected from:
NH NH
O , O ,
O H O
NH NH
NH NH
, and ; or a
pharmaceutically acceptable salt, solvate, or N-oxide thereof.
[0003g] A seventh aspect of the invention provides for a compound having the structure
selected from:
, O ,
O N O
, ,
N , ,
, and ; or a
pharmaceutically acceptable salt, solvate, or N-oxide thereof.
[0003h] An eighth aspect of the invention provides for a compound selected from:
O , , O ,
O , O ,
, O ,
O , ,
, O ,
O , O ,
O , O ,
O , O ,
O , O , O ,
O , O ,
O , O ,
O , O ,
O , O ,
O , O ,
O , O ,
, , ,
N OMe
N OMe
NH NH
N N N
O N O N
, , ,
NH NH
O O O
, , ,
N N N
, , ,
H N H N
, and or a
pharmaceutically acceptable salt, solvate, or N-oxide thereof.
[0003i] A ninth aspect of the invention provides for a pharmaceutical composition
comprising a compound of the first to eighth aspects of the invention, or a
pharmaceutically acceptable salt, solvate, or N-oxide thereof; and a pharmaceutically
acceptable excipient, binder or carrier.
[0003j] A tenth aspect of the invention provides the use of a compound of the first to
eighth aspects of the invention for the manufacture of a medicament for the treatment of
an autoimmune disease.
[0003k] An eleventh aspect of the invention provides the use of a compound of the first
to eighth aspects of the invention for the manufacture of a medicament for the treatment
of a heteroimmune condition.
[0003l] A twelfth aspect of the invention provides the use of a compound of the first to
eighth aspects of the invention for the manufacture of a medicament for the treatment of
an inflammatory disease.
[0003m] A thirteenth aspect of the invention provides the use of a compound of the first
to eighth aspects of the invention for the manufacture of a medicament for the treatment
of a cancer.
Described herein are inhibitors of Bruton’s tyrosine kinase (Btk). Also described
herein are methods for synthesizing such inhibitors, methods for using such inhibitors in
the treatment of diseases (including diseases wherein inhibition of Btk provides
therapeutic benefit to a patient having the disease). Further described are pharmaceutical
formulations that include an inhibitor of Btk.
In one aspect, provided herein are compounds of Formula (I) having the
structure:
L Ar R
Formula (I);
wherein:
a a b b b
L is each independently CR R , O, S, NR , N-OR , C=O, C=S, C=N-R , or C=N-
OR ;
R is each independently H, C -C alkyl, C -C heteroalkyl, halogen, OR , or
1 6 1 6
NR R ;
R is each independently H, C -C alkyl, C -C heteroalkyl, C -C cycloalkyl, or
1 6 2 6 3 6
C -C heterocycloalkyl;
1 2 b b b
R is L-Ar , OR , or NR R ;
2 b b b
R is H, OR , NR R , halogen, C -C alkyl, C -C heteroalkyl, C -C cycloalkyl,
1 6 1 6 3 6
or C -C heterocycloalkyl;
3 b b b b
R is optionally substituted alkyl, -(C=O)C -C alkyl, -(C=O)OR , -(C=O)NR R , -(C=O)SR ,
optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or
optionally substituted heteroaryl;
Ar and Ar are each independently C -C aryl or heteroaryl optionally substituted with halogen, OR ,
12
NR R , C -C alkyl, C -C heteroalkyl, C -C cycloalkyl, or C -C heterocycloalkyl;
1 6 1 6 3 6 2 6
or a pharmaceutically acceptable salt, solvate, N-oxide, or prodrug thereof.
In one aspect, provided herein are compounds of Formula (II) having the structure:
NH 1
2 Ar' R
Formula (II);
wherein:
R is L-Ar ;
a a b b b b
L is each independently CR R , O, S, NR , N-OR , C=O, C=S, C=N-R , or C=N-OR ;
2 b b b
R is H, OR , NR R , halogen, C -C alkyl, C -C heteroalkyl, C -C cycloalkyl, or C -C
1 6 1 6 3 6 2 6
heterocycloalkyl;
3 b b b b
R is optionally substituted alkyl, -(C=O)C -C alkyl, -(C=O)OR , -(C=O)NR R , -(C=O)SR ,
optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or
optionally substituted heteroaryl;
a b b b
R is each independently H, C -C alkyl, C -C heteroalkyl, halogen, OR , or NR R ;
1 6 1 6
R is each independently H, C -C alkyl, C -C heteroalkyl, C -C cycloalkyl, or C -C
1 6 2 6 3 6 2 6
heterocycloalkyl;
Ar’ is selected from furan, thiophene, oxazole, isoxazole, oxadiazole, thiazole, isothiazole,
thiadiazole, imidazole, triazole, pyrazole, thiodiazole, tetrazole, pyridine, pyrimidine, and pyrazine;
2 b b b
Ar is C -C aryl or heteroaryl optionally substituted with halogen, OR , NR R , C -C alkyl, C -C
12 1 6 1 6
heteroalkyl, C -C cycloalkyl or C -C heterocycloalkyl; or a pharmaceutically acceptable salt, solvate, N-
3 6 2 6
oxide, or prodrug thereof.
In one aspect, provided herein are compounds of Formula (III) having the structure:
Ar R
2a N
Formula (III);
wherein:
R is L-Ar ;
a a b b b b
L is CR R , O, S, NR , N-OR , C=O, C=S, C=N-R , or C=N-OR ;
a b b b
R is each independently H, C -C alkyl, C -C heteroalkyl, halogen, OR , or NR R ;
1 6 1 6
R is each independently H, C -C alkyl, C -C heteroalkyl, C -C cycloalkyl, or C -C
1 6 2 6 3 6 2 6
heterocycloalkyl;
2a b b b
R is OR , NR R , halogen, C -C alkyl, C -C heteroalkyl, C -C cycloalkyl, or C -C
1 6 1 6 3 6 2 6
heterocycloalkyl;
3 b b b b
R is optionally substituted alkyl, -(C=O)C -C alkyl, -(C=O)OR , -(C=O)NR R , -(C=O)SR ,
optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or
optionally substituted heteroaryl;
Ar and Ar are each independently C -C aryl or heteroaryl optionally substituted with halogen, OR ,
12
NR R , C -C alkyl, C -C heteroalkyl, C -C cycloalkyl, or C -C heterocycloalkyl; or a pharmaceutically
1 6 1 6 3 6 2 6
acceptable salt, solvate, N-oxide, or prodrug thereof.
In one aspect, provided herein are compounds of Formula (IV) having the structure:
Ar R
Formula (IV);
wherein:
X is hydrogen, hydroxy, alkoxy, thiol, halogen or C -C alkyl;
R is L-Ar ;
a a b b b b
L is CR R , O, S, NR , N-OR , C=O, C=S, C=N-R , or C=N-OR ;
a b b b
R is each independently H, C -C alkyl, C -C heteroalkyl, halogen, OR , or NR R ;
1 6 1 6
R is each independently H, C -C alkyl, C -C heteroalkyl, C -C cycloalkyl, or C -C
1 6 2 6 3 6 2 6
heterocycloalkyl;
2 b b b
R is H, OR , NR R , halogen, C -C alkyl, C -C heteroalkyl, C -C cycloalkyl, or C -C
1 6 1 6 3 6 2 6
heterocycloalkyl;
3 b b b b
R is optionally substituted alkyl, -(C=O)C -C alkyl, -(C=O)OR , -(C=O)NR R , -(C=O)SR ,
optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or
optionally substituted heteroaryl;
Ar and Ar is each independently C -C aryl or heteroaryl optionally substituted with halogen, OR ,
12
NR R , C -C alkyl, C -C heteroalkyl, C -C cycloalkyl, or C -C heterocycloalkyl;
1 6 1 6 3 6 2 6
or a pharmaceutically acceptable salt, solvate, N-oxide, or prodrug thereof.
In one aspect, provided herein are compounds of Formula (V) having the structure:
Formula (V);
wherein:
R is L-Ar ;
a a b b b b
L is CR R , O, S, NR , N-OR , C=O, C=S, C=N-R , or C=N-OR ;
a b b b
R is each independently H, C -C alkyl, C -C heteroalkyl, halogen, OR , or NR R ;
1 6 1 6
R is each independently H, C -C alkyl, C -C heteroalkyl, C -C cycloalkyl, or C -C
1 6 2 6 3 6 2 6
heterocycloalkyl;
2 b b b
R is H, OR , NR R , halogen, C -C alkyl, C -C heteroalkyl, C -C cycloalkyl or C -C
1 6 1 6 3 6 2 6
heterocycloalkyl;
N 5 N
R R n
R R N
R 6 6
R is selected from S , , , R , R ,
and ;
R is hydrogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxycarbonyl,
substituted or unsubstituted alkoxyalkyl, substituted or unsubstituted hydroxyalkyl, substituted or
unsubstituted aminocarbonyl, substituted or unsubstituted alkylcarbonyl or substituted or unsubstituted
arylalkyl group;
b b b
R is H, optionally substituted C -C alkyl, -(C=O)C -C alkyl, -(C=O)OR , -(C=O)NR R , -
1 6 1 6
(C=O)SR , cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
R is optionally substituted C -C alkyl or NR ;
R is each independently hydrogen, optionally substituted C -C alkyl, optionally substituted
cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted
heteroaryl;
Ar is C -C aryl or heteroaryl optionally substituted with halogen, hydroxy, amine, or C -C alkyl;
12 1 6
n is an integer from 0 to 3;
m is an integer from 0 to 6;
Y is O, S or NR ;
or a pharmaceutically acceptable salt, solvate, N-oxide, or prodrug thereof.
In one aspect, provided herein are compounds of Formula (VI) having the structure:
n R R
Formula (VI);
wherein:
a a b b b b
L is CR R , O, S, NR , N-OR , C=O, C=S, C=N-R or C=N-OR ;
W is a bond or optionally substituted C -C alkyl;
Z is C=O, SO or SO;
1 2 1 2
R and R are each independently H or C -C alkyl, wherein R and R have a cis or trans relationship;
or R and R join together to form a bond;
n and p are each independently an integer from 0 to 3;
m is an integer from 1 to 3;
R is H, substituted or unsubstituted C -C alkyl, substituted or unsubstituted C -C cycloalkyl,
1 3 3 6
substituted or unsubstituted C -C heteroalkyl, substituted or unsubstituted C -C heterocycloalkyl,
1 6 2 6
substituted or unsubstituted C -C aryl, or substituted or unsubstituted C -C heteroaryl;
6 12 5 11
R is substituted or unsubstituted C -C cycloalkyl, substituted or unsubstituted C -C
3 6 2 6
heterocycloalkyl, substituted or unsubstituted C -C aryl, or substituted or unsubstituted C -C
6 12 5 11
heteroaryl;
b b b
R is H, OH, OR , NR R , halogen, C -C alkyl, C -C heteroalkyl, C -C cycloalkyl, or C -C
1 6 1 6 3 6 2 6
heterocycloalkyl;
a b b b
R is each independently H, C -C alkyl, C -C heteroalkyl, halogen, OR , or NR R ;
1 6 1 6
R is each independently H, C -C alkyl, C -C heteroalkyl, C -C cycloalkyl, or C -C
1 6 2 6 3 6 2 6
heterocycloalkyl;
or a pharmaceutically acceptable salt, solvate, N-oxide, or prodrug thereof.
In one aspect, provided herein are compounds of Formula (VIA) having the structure:
n R R
Formula (VIA);
wherein:
a a b b b b
L is CR R , O, S, NR , N-OR , C=O, C=S, C=N-R or C=N-OR ;
W is a bond or optionally substituted C -C alkyl;
Z is C=O, SO or SO;
1 2 1 2
R and R are each independently H or C -C alkyl, wherein R and R have a cis or trans
relationship; or R and R join together to form a bond;
n and p are each independently an integer from 0 to 3;
m is an integer from 1 to 3;
R is H, substituted or unsubstituted C -C cycloalkyl, substituted or unsubstituted C -C
3 6 1 6
heteroalkyl, substituted or unsubstituted C -C heterocycloalkyl, substituted or unsubstituted C -C aryl,
2 6 6 12
or substituted or unsubstituted C -C heteroaryl;
11
R is substituted or unsubstituted C -C cycloalkyl, substituted or unsubstituted C -C
3 6 2 6
heterocycloalkyl, substituted or unsubstituted C -C aryl, or substituted or unsubstituted C -C
6 12 5 11
heteroaryl;
b b b
R is H, OH, OR , NR R , halogen, C -C alkyl, C -C heteroalkyl, C -C cycloalkyl or C -C
1 6 1 6 3 6 2 6
heterocycloalkyl;
a b b b
R is each independently H, C -C alkyl, C -C heteroalkyl, halogen, OR , or NR R ;
1 6 1 6
R is each independently H, C -C alkyl, C -C heteroalkyl, C -C cycloalkyl or C -C
1 6 2 6 3 6 2 6
heterocycloalkyl;
or a pharmaceutically acceptable salt, solvate, N-oxide, or prodrug thereof.
In one aspect, provided herein are compounds of Formula (VII) having the structure:
Formula (VII);
wherein:
a a b b b b
L is CR R , O, S, NR , N-OR , C=O, C=S, C=N-R or C=N-OR ;
W is a bond or optionally substituted C -C alkyl;
Z is NR C=O, SO or SO;
1 2 1 2
R and R are each independently H or C -C alkyl, wherein R and R have a cis or trans relationship;
or R and R join together to form a bond;
p is an integer from 0 to 3;
R is H, substituted or unsubstituted C -C alkyl, substituted or unsubstituted C -C cycloalkyl,
1 3 3 6
substituted or unsubstituted C -C heteroalkyl, substituted or unsubstituted C -C heterocycloalkyl,
1 6 2 6
substituted or unsubstituted C -C aryl, or substituted or unsubstituted C -C heteroaryl;
6 12 5 11
R is substituted or unsubstituted C -C cycloalkyl, substituted or unsubstituted C -C
3 6 2 6
heterocycloalkyl, substituted or unsubstituted C -C aryl, or substituted or unsubstituted C -C
6 12 5 11
heteroaryl;
b b b
R is H, OH, OR , NR R , halogen, C -C alkyl, C -C heteroalkyl, C -C cycloalkyl or C -C
1 6 1 6 3 6 2 6
heterocycloalkyl;
a b b b
R is each independently H, C -C alkyl, C -C heteroalkyl, halogen, OR , or NR R ;
1 6 1 6
R is each independently H, C -C alkyl, C -C heteroalkyl, C -C cycloalkyl or C -C
1 6 2 6 3 6 2 6
heterocycloalkyl;
R is H or C -C alkyl;
or a pharmaceutically acceptable salt, solvate, N-oxide, or prodrug thereof.
In one aspect, provided herein are compounds of Formula (VIII) having the structure:
Formula (VIII);
wherein:
a a b b b b
L is CR R , O, S, NR , N-OR , C=O, C=S, C=N-R or C=N-OR ;
W is a bond or optionally substituted C -C alkyl;
Z is NR C=O, SO or SO;
1 2 1 2
R and R are each independently H or C -C alkyl, wherein R and R have a cis or trans relationship;
or R and R join together to form a bond;
p is an integer from 0 to 3;
R is H, substituted or unsubstituted C -C alkyl, substituted or unsubstituted C -C cycloalkyl,
1 3 3 6
substituted or unsubstituted C -C heteroalkyl, substituted or unsubstituted C -C heterocycloalkyl,
1 6 2 6
substituted or unsubstituted C -C aryl, or substituted or unsubstituted C -C heteroaryl;
6 12 5 11
R is substituted or unsubstituted C -C cycloalkyl, substituted or unsubstituted C -C
3 6 2 6
heterocycloalkyl, substituted or unsubstituted C -C aryl, or substituted or unsubstituted C -C
6 12 5 11
heteroaryl;
b b b
R is H, OH, OR , NR R , halogen, C -C alkyl, C -C heteroalkyl, C -C cycloalkyl or C -C
1 6 1 6 3 6 2 6
heterocycloalkyl;
a b b b
R is each independently H, C -C alkyl, C -C heteroalkyl, halogen, OR , or NR R ;
1 6 1 6
R is each independently H, C -C alkyl, C -C heteroalkyl, C -C cycloalkyl or C -C
1 6 2 6 3 6 2 6
heterocycloalkyl;
R is H or C -C alkyl;
or a pharmaceutically acceptable salt, solvate, N-oxide, or prodrug thereof.
In one aspect, provided herein are compounds of Formula (IX) having the structure:
L Ar R
Formula (IX);
wherein:
a a b b b b
L is each independently CR R , O, S, NR , N-OR , C=O, C=S, C=N-R , or C=N-OR ;
a b b b
R is each independently H, C -C alkyl, C -C heteroalkyl, halogen, OR , or NR R ;
1 6 1 6
R is each independently H, C -C alkyl, C -C heteroalkyl, C -C cycloalkyl, or C -C
1 6 2 6 3 6 2 6
heterocycloalkyl;
1 2 b b b
R is L-Ar , OR , or NR R ;
2 b b b
R is H, OR , NR R , halogen, C -C alkyl, C -C heteroalkyl, C -C cycloalkyl, or C -C
1 6 1 6 3 6 2 6
heterocycloalkyl;
3 b b b b
R is optionally substituted alkyl, -(C=O)C -C alkyl, -(C=O)OR , -(C=O)NR R , -(C=O)SR ,
optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or
optionally substituted heteroaryl;
Ar and Ar are each independently C -C aryl or C -C heteroaryl optionally substituted with
12 5 11
b b b
halogen, OR , NR R , C -C alkyl, C -C heteroalkyl, C -C cycloalkyl, or C -C heterocycloalkyl;
1 6 1 6 3 6 2 6
or a pharmaceutically acceptable salt, solvate, N-oxide, or prodrug thereof.
In one aspect, provided herein are compounds of Formula (X) having the structure:
n R R
Formula (X);
wherein:
a a b b b b
L is CR R , O, S, NR , N-OR , C=O, C=S, C=N-R or C=N-OR ;
W is a bond or optionally substituted C -C alkyl;
Z is C=O, SO or SO;
1 2 1 2
R and R are each independently H or C -C alkyl, wherein R and R have a cis or trans
relationship; or R and R join together to form a bond;
n and p are each independently an integer from 0 to 3;
m is an integer from 1 to 3;
R is H, substituted or unsubstituted C -C alkyl, substituted or unsubstituted C -C cycloalkyl,
1 3 3 6
substituted or unsubstituted C -C heteroalkyl, substituted or unsubstituted C -C heterocycloalkyl,
1 6 2 6
substituted or unsubstituted C -C aryl, or substituted or unsubstituted C -C heteroaryl;
6 12 5 11
R is substituted or unsubstituted C -C cycloalkyl, substituted or unsubstituted C -C
3 6 2 6
heterocycloalkyl, substituted or unsubstituted C -C aryl, or substituted or unsubstituted C -C
6 12 5 11
heteroaryl;
b b b
R is H, OH, OR , NR R , halogen, C -C alkyl, C -C heteroalkyl, C -C cycloalkyl or C -C
1 6 1 6 3 6 2 6
heterocycloalkyl;
a b b b
R is each independently H, C -C alkyl, C -C heteroalkyl, halogen, OR , or NR R ;
1 6 1 6
R is each independently H, C -C alkyl, C -C heteroalkyl, C -C cycloalkyl or C -C
1 6 2 6 3 6 2 6
heterocycloalkyl;
or a pharmaceutically acceptable salt, solvate, N-oxide, or prodrug thereof.
In one aspect is a pharmaceutical composition comprising a compound having the structure of
Formula (I), (IA), (II), (III), (IV), (V), (VI), (VIA), (VIB), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), or
(XIV), or a pharmaceutically acceptable salt or solvate thereof; and a pharmaceutically acceptable
excipient, binder or carrier. In another aspect is a pharmaceutical composition comprising a compound
having the structure of Formula (VI) or a pharmaceutically acceptable salt or solvate thereof; and a
pharmaceutically acceptable excipient, binder or carrier.
In certain embodiments, provided herein is a pharmaceutical composition containing: i) a
physiologically acceptable carrier, diluent, and/or excipient; and ii) one or more compounds provided
herein.
Other objects, features and advantages of the methods and compositions described herein will
become apparent from the following detailed description. It should be understood, however, that the
detailed description and the specific examples, while indicating specific embodiments, are given by way
of illustration only. The section headings used herein are for organizational purposes only and are not to
be construed as limiting the subject matter described.
DETAILED DESCRIPTION OF THE INVENTION
The methods described herein include administering to a subject in need a composition
containing a therapeutically effective amount of one or more Btk inhibitor compounds described herein.
Without being bound by theory, the diverse roles played by Btk signaling in various hematopoietic cell
functions, e.g., B-cell receptor activation, suggests that small molecule Btk inhibitors are useful for
reducing the risk of or treating a variety of diseases affected by or affecting many cell types of the
hematopoetic lineage including, e.g., autoimmune diseases, heteroimmune conditions or diseases,
inflammatory diseases, cancer (e.g., B-cell proliferative disorders), and thromboembolic disorders.
Further, the Btk inhibitor compounds described herein can be used to inhibit a small subset of other
tyrosine kinases that share homology with Btk by having a cysteine residue (including a Cys 481 residue)
that can form a covalent bond with the inhibitor. Thus, a subset of tyrosine kinases other than Btk are also
expected to be useful as therapeutic targets in a number of health conditions.
In some embodiments, the methods described herein can be used to treat an autoimmune
disease, which includes, but is not limited to, rheumatoid arthritis, psoriatic arthritis, osteoarthritis, Still’s
disease, juvenile arthritis, lupus, diabetes, myasthenia gravis, Hashimoto's thyroiditis, Ord's thyroiditis,
Graves' disease Sjögren's syndrome, multiple sclerosis, Guillain-Barré syndrome, acute disseminated
encephalomyelitis, Addison's disease, opsoclonus-myoclonus syndrome, ankylosing spondylitisis,
antiphospholipid antibody syndrome, aplastic anemia, autoimmune hepatitis, coeliac disease,
Goodpasture's syndrome, idiopathic thrombocytopenic purpura, optic neuritis, scleroderma, primary
biliary cirrhosis, Reiter's syndrome, Takayasu's arteritis, temporal arteritis, warm autoimmune hemolytic
anemia, Wegener's granulomatosis, psoriasis, alopecia universalis, Behçet's disease, chronic fatigue,
dysautonomia, endometriosis, interstitial cystitis, neuromyotonia, scleroderma, and vulvodynia.
In some embodiments, the methods described herein can be used to treat heteroimmune
conditions or diseases, which include, but are not limited to graft versus host disease, transplantation,
transfusion, anaphylaxis, allergies (e.g., allergies to plant pollens, latex, drugs, foods, insect poisons,
animal hair, animal dander, dust mites, or cockroach calyx), type I hypersensitivity, allergic conjunctivitis,
allergic rhinitis, and atopic dermatitis.
In further embodiments, the methods described herein can be used to treat an inflammatory disease,
which includes, but is not limited to asthma, inflammatory bowel disease, appendicitis, blepharitis,
bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, colitis, conjunctivitis, cystitis,
dacryoadenitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis,
enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, hepatitis,
hidradenitis suppurativa, laryngitis, mastitis, meningitis, myelitis myocarditis, myositis, nephritis,
oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleuritis,
phlebitis, pneumonitis, pneumonia, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis,
stomatitis, synovitis, tendonitis, tonsillitis, uveitis, vaginitis, vasculitis, and vulvitis.
In yet other embodiments, the methods described herein can be used to treat a cancer, e.g., B-
cell proliferative disorders, which include, but are not limited to diffuse large B cell lymphoma, follicular
lymphoma, chronic lymphocytic lymphoma, chronic lymphocytic leukemia, B-cell prolymphocytic
leukemia, lymphoplasmacytic lymphoma/Waldenström macroglobulinemia, splenic marginal zone
lymphoma, plasma cell myeloma, plasmacytoma, extranodal marginal zone B cell lymphoma, nodal
marginal zone B cell lymphoma, mantle cell lymphoma, mediastinal (thymic) large B cell lymphoma,
intravascular large B cell lymphoma, primary effusion lymphoma, burkitt lymphoma/leukemia, and
lymphomatoid granulomatosis.
In further embodiments, the methods described herein can be used to treat thromboembolic disorders,
which include, but are not limited to myocardial infarct, angina pectoris (including unstable angina),
reocclusions or restenoses after angioplasty or aortocoronary bypass, stroke, transitory ischemia,
peripheral arterial occlusive disorders, pulmonary embolisms, and deep venous thromboses.
Hematological Malignancies
Disclosed herein, in certain embodiments, is a method for treating a hematological
malignancy in an individual in need thereof, comprising: administering to the individual a composition
containing a therapeutic amount of at least one compound having the structure of Formula (I), (IA), (II),
(III), (IV), (V), (VI), (VIA), (VIB), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), or (XIV).
In some embodiments, the hematological malignancy is a chronic lymphocytic leukemia
(CLL), small lymphocytic lymphoma (SLL), high risk CLL, or a non-CLL/SLL lymphoma. In some
embodiments, the hematological malignancy is follicular lymphoma, diffuse large B-cell lymphoma
(DLBCL), mantle cell lymphoma, Waldenstrom’s macroglobulinemia, multiple myeloma, marginal zone
lymphoma, Burkitt’s lymphoma, non-Burkitt high grade B cell lymphoma, or extranodal marginal zone B
cell lymphoma. In some embodiments, the hematological malignancy is acute or chronic myelogenous (or
myeloid) leukemia, myelodysplastic syndrome, or acute lymphoblastic leukemia. In some embodiments,
the hematological malignancy is relapsed or refractory diffuse large B-cell lymphoma (DLBCL), relapsed
or refractory mantle cell lymphoma, relapsed or refractory follicular lymphoma, relapsed or refractory
CLL; relapsed or refractory SLL; relapsed or refractory multiple myeloma. In some embodiments, the
hematological malignancy is a hematological malignancy that is classified as high-risk. In some
embodiments, the hematological malignancy is high risk CLL or high risk SLL.
B-cell lymphoproliferative disorders (BCLDs) are neoplasms of the blood and encompass,
inter alia, non-Hodgkin lymphoma, multiple myeloma, and leukemia. BCLDs can originate either in the
lymphatic tissues (as in the case of lymphoma) or in the bone marrow (as in the case of leukemia and
myeloma), and they all are involved with the uncontrolled growth of lymphocytes or white blood cells.
There are many subtypes of BCLD, e.g., chronic lymphocytic leukemia (CLL) and non-Hodgkin
lymphoma (NHL). The disease course and treatment of BCLD is dependent on the BCLD subtype;
however, even within each subtype the clinical presentation, morphologic appearance, and response to
therapy is heterogeneous.
Malignant lymphomas are neoplastic transformations of cells that reside predominantly
within lymphoid tissues. Two groups of malignant lymphomas are Hodgkin's lymphoma and non-
Hodgkin's lymphoma (NHL). Both types of lymphomas infiltrate reticuloendothelial tissues. However,
they differ in the neoplastic cell of origin, site of disease, presence of systemic symptoms, and response to
treatment (Freedman et al., "Non-Hodgkin's Lymphomas" Chapter 134, Cancer Medicine, (an approved
publication of the American Cancer Society, B.C. Decker Inc., Hamilton, Ontario, 2003).
Non-Hodgkin’s Lymphomas
Disclosed herein, in certain embodiments, is a method for treating a non-Hodgkin’s
lymphoma in an individual in need thereof, comprising: administering to the individual a composition
containing a therapeutic amount of at least one compound having the structure of Formula (I), (IA), (II),
(III), (IV), (V), (VI), (VIA), (VIB), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), or (XIV).
Further disclosed herein, in certain embodiments, is a method for treating relapsed or
refractory non-Hodgkin’s lymphoma in an individual in need thereof, comprising: administering to the
individual a composition containing a therapeutic amount of at least one compound having the structure
of Formula (I), (IA), (II), (III), (IV), (V), (VI), (VIA), (VIB), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), or
(XIV). In some embodiments, the non-Hodgkin’s lymphoma is relapsed or refractory diffuse large B-cell
lymphoma (DLBCL), relapsed or refractory mantle cell lymphoma, or relapsed or refractory follicular
lymphoma.
Non-Hodgkin lymphomas (NHL) are a diverse group of malignancies that are predominately
of B-cell origin. NHL may develop in any organs associated with lymphatic system such as spleen, lymph
nodes or tonsils and can occur at any age. NHL is often marked by enlarged lymph nodes, fever, and
weight loss. NHL is classified as either B-cell or T-cell NHL. Lymphomas related to lymphoproliferative
disorders following bone marrow or stem cell transplantation are usually B-cell NHL. In the Working
Formulation classification scheme, NHL has been divided into low-, intermediate-, and high-grade
categories by virtue of their natural histories (see "The Non-Hodgkin's Lymphoma Pathologic
Classification Project," Cancer 49(1982):2112-2135). The low-grade lymphomas are indolent, with a
median survival of 5 to 10 years (Horning and Rosenberg (1984) N. Engl. J. Med. 311:1471-1475).
Although chemotherapy can induce remissions in the majority of indolent lymphomas, cures are rare and
most patients eventually relapse, requiring further therapy. The intermediate- and high-grade lymphomas
are more aggressive tumors, but they have a greater chance for cure with chemotherapy. However, a
significant proportion of these patients will relapse and require further treatment.
A non-limiting list of the B-cell NHL includes Burkitt's lymphoma (e.g., Endemic Burkitt's
Lymphoma and Sporadic Burkitt's Lymphoma), Cutaneous B-Cell Lymphoma, Cutaneous Marginal Zone
Lymphoma (MZL), Diffuse Large Cell Lymphoma (DLBCL), Diffuse Mixed Small and Large Cell
Lympoma, Diffuse Small Cleaved Cell, Diffuse Small Lymphocytic Lymphoma, Extranodal Marginal
Zone B-cell lymphoma, follicular lymphoma, Follicular Small Cleaved Cell (Grade 1), Follicular Mixed
Small Cleaved and Large Cell (Grade 2), Follicular Large Cell (Grade 3), Intravascular Large B-Cell
Lymphoma, Intravascular Lymphomatosis, Large Cell Immunoblastic Lymphoma, Large Cell Lymphoma
(LCL), Lymphoblastic Lymphoma, MALT Lymphoma, Mantle Cell Lymphoma (MCL), immunoblastic
large cell lymphoma, precursor B-lymphoblastic lymphoma, mantle cell lymphoma, chronic lymphocytic
leukemia (CLL)/small lymphocytic lymphoma (SLL), extranodal marginal zone B-cell lymphoma-
mucosa-associated lymphoid tissue (MALT) lymphoma, Mediastinal Large B-Cell Lymphoma, nodal
marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma, primary mediastinal B-cell
lymphoma, lymphoplasmocytic lymphoma, hairy cell leukemia, Waldenstrom's Macroglobulinemia, and
primary central nervous system (CNS) lymphoma. Additional non-Hodgkin's lymphomas are
contemplated within the scope of the present invention and apparent to those of ordinary skill in the art.
DLBCL
Disclosed herein, in certain embodiments, is a method for treating a DLCBL in an individual
in need thereof, comprising: administering to the individual a composition containing a therapeutic
amount of at least one compound having the structure of Formula (I), (IA), (II), (III), (IV), (V), (VI),
(VIA), (VIB), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), or (XIV).
As used herein, the term “Diffuse large B-cell lymphoma (DLBCL)” refers to a neoplasm of
the germinal center B lymphocytes with a diffuse growth pattern and a high-intermediate proliferation
index. DLBCLs represent approximately 30% of all lymphomas and may present with several
morphological variants including the centroblastic, immunoblastic, T-cell/histiocyte rich, anaplastic and
plasmoblastic subtypes. Genetic tests have shown that there are different subtypes of DLBCL. These
subtypes seem to have different outlooks (prognoses) and responses to treatment. DLBCL can affect any
age group but occurs mostly in older people (the average age is mid-60s).
Disclosed herein, in certain embodiments, is a method for treating diffuse large B-cell
lymphoma, activated B cell-like subtype (ABC-DLBCL), in an individual in need thereof, comprising:
administering to the individual an irreversible Btk inhibitor in an amount from 300 mg/day up to, and
including, 1000 mg/day. The ABC subtype of diffuse large B-cell lymphoma (ABC-DLBCL) is thought to
arise from post germinal center B cells that are arrested during plasmatic differentiation. The ABC
subtype of DLBCL (ABC-DLBCL) accounts for approximately 30% total DLBCL diagnoses. It is
considered the least curable of the DLBCL molecular subtypes and, as such, patients diagnosed with the
ABC-DLBCL typically display significantly reduced survival rates compared with individuals with other
types of DLCBL. ABC-DLBCL is most commonly associated with chromosomal translocations
deregulating the germinal center master regulator BCL6 and with mutations inactivating the PRDM1
gene, which encodes a transcriptional repressor required for plasma cell differentiation.
A particularly relevant signaling pathway in the pathogenesis of ABC-DLBCL is the one
mediated by the nuclear factor (NF)-κB transcription complex. The NF-κB family comprises 5 members
(p50, p52, p65, c-rel and RelB) that form homo- and heterodimers and function as transcriptional factors
to mediate a variety of proliferation, apoptosis, inflammatory and immune responses and are critical for
normal B-cell development and survival. NF-κB is widely used by eukaryotic cells as a regulator of genes
that control cell proliferation and cell survival. As such, many different types of human tumors have
misregulated NF-κB: that is, NF-κB is constitutively active. Active NF-κB turns on the expression of
genes that keep the cell proliferating and protect the cell from conditions that would otherwise cause it to
die via apoptosis.
The dependence of ABC DLBCLs on NF-kB depends on a signaling pathway upstream of
IkB kinase comprised of CARD11, BCL10 and MALT1 (the CBM complex). Interference with the CBM
pathway extinguishes NF-kB signaling in ABC DLBCL cells and induces apoptosis. The molecular basis
for constitutive activity of the NF-kB pathway is a subject of current investigation but some somatic
alterations to the genome of ABC DLBCLs clearly invoke this pathway. For example, somatic mutations
of the coiled-coil domain of CARD11 in DLBCL render this signaling scaffold protein able to
spontaneously nucleate protein-protein interaction with MALT1 and BCL10, causing IKK activity and
NF-kB activation. Constitutive activity of the B cell receptor signaling pathway has been implicated in the
activation of NF-kB in ABC DLBCLs with wild type CARD11, and this is associated with mutations
within the cytoplasmic tails of the B cell receptor subunits CD79A and CD79B. Oncogenic activating
mutations in the signaling adapter MYD88 activate NF-kB and synergize with B cell receptor signaling in
sustaining the survival of ABC DLBCL cells. In addition, inactivating mutations in a negative regulator of
the NF-kB pathway, A20, occur almost exclusively in ABC DLBCL.
Indeed, genetic alterations affecting multiple components of the NF-κB signaling pathway
have been recently identified in more than 50% of ABC-DLBCL patients, where these lesions promote
constitutive NF-κB activation, thereby contributing to lymphoma growth. These include mutations of
CARD11 (~10% of the cases), a lymphocyte-specific cytoplasmic scaffolding protein that—together with
MALT1 and BCL10—forms the BCR signalosome, which relays signals from antigen receptors to the
downstream mediators of NF-κB activation. An even larger fraction of cases (~30%) carry biallelic
genetic lesions inactivating the negative NF-κB regulator A20. Further, high levels of expression of NF-
κB target genes have been observed in ABC-DLBCL tumor samples. See, e.g., U. Klein et al., (2008),
Nature Reviews Immunology 8:22-23; R.E. Davis et al., (2001), Journal of Experimental Medicine
194:1861-1874; G. Lentz et al., (2008), Science 319:1676-1679; M. Compagno et al., (2009), Nature
459:712-721; and L. Srinivasan et al., (2009), Cell 139:573-586).
DLBCL cells of the ABC subtype, such as OCI-Ly10, have chronic active BCR signalling
and are very sensitive to the Btk inhibitor described herein. The irreversible Btk inhibitor described herein
potently and irreversibly inhibits the growth of OCI-Ly10 (EC continuous exposure = 10 nM, EC 1
50 50
hour pulse = 50 nM). In addition, induction of apoptosis, as shown by capsase activation, Annexin-V flow
cytometry and increase in sub-G0 fraction is observed in OCILy10. Both sensitive and resistant cells
express Btk at similar levels, and the active site of Btk is fully occupied by the inhibitor in both as shown
using a fluorescently labeled affinity probe. OCI-Ly10 cells are shown to have chronically active BCR
signalling to NF-kB which is dose dependently inhibited by the Btk inhibitors described herein. The
activity of Btk inhibitors in the cell lines studied herein are also characterized by comparing signal
transduction profiles (Btk, PLCγ, ERK, NF-kB, AKT), cytokine secretion profiles and mRNA expression
profiles, both with and without BCR stimulation, and observed significant differences in these profiles
that lead to clinical biomarkers that identify the most sensitive patient populations to Btk inhibitor
treatment. See U.S. Patent No. 7,711,492 and Staudt et al., Nature, Vol. 463, Jan. 7, 2010, pp. 88-92, the
contents of which are incorporated by reference in their entirety.
Follicular Lymphoma
Disclosed herein, in certain embodiments, is a method for treating a follicular lymphoma in
an individual in need thereof, comprising: administering to the individual a composition containing a
therapeutic amount of at least one compound having the structure of Formula (I), (IA), (II), (III), (IV),
(V), (VI), (VIA), (VIB), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), or (XIV).
As used herein, the term “follicular lymphoma” refers to any of several types of non-
Hodgkin's lymphoma in which the lymphomatous cells are clustered into nodules or follicles. The term
follicular is used because the cells tend to grow in a circular, or nodular, pattern in lymph nodes. The
average age for people with this lymphoma is about 60.
CLL/SLL
Disclosed herein, in certain embodiments, is a method for treating a CLL or SLL in an
individual in need thereof, comprising: administering to the individual a composition containing a
therapeutic amount of at least one compound having the structure of Formula (I), (IA), (II), (III), (IV),
(V), (VI), (VIA), (VIB), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), or (XIV).
Chronic lymphocytic leukemia and small lymphocytic lymphoma (CLL/SLL) are commonly
thought as the same disease with slightly different manifestations. Where the cancerous cells gather
determines whether it is called CLL or SLL. When the cancer cells are primarily found in the lymph
nodes, lima bean shaped structures of the lymphatic system (a system primarily of tiny vessels found in
the body), it is called SLL. SLL accounts for about 5% to 10% of all lymphomas. When most of the
cancer cells are in the bloodstream and the bone marrow, it is called CLL.
Both CLL and SLL are slow-growing diseases, although CLL, which is much more common,
tends to grow slower. CLL and SLL are treated the same way. They are usually not considered curable
with standard treatments, but depending on the stage and growth rate of the disease, most patients live
longer than 10 years. Occasionally over time, these slow-growing lymphomas may transform into a more
aggressive type of lymphoma.
Chronic lymphoid leukemia (CLL) is the most common type of leukemia. It is estimated that
100,760 people in the United States are living with or are in remission from CLL. Most (>75%) people
newly diagnosed with CLL are over the age of 50. Currently CLL treatment focuses on controlling the
disease and its symptoms rather than on an outright cure. CLL is treated by chemotherapy, radiation
therapy, biological therapy, or bone marrow transplantation. Symptoms are sometimes treated surgically
(splenectomy removal of enlarged spleen) or by radiation therapy ("de-bulking" swollen lymph nodes).
Though CLL progresses slowly in most cases, it is considered generally incurable. Certain CLLs are
classified as high-risk. As used herein, “high risk CLL” means CLL characterized by at least one of the
following 1) 17p13-; 2) 11q22-; 3) unmutated IgVH together with ZAP-70+ and/or CD38+; or 4) trisomy
CLL treatment is typically administered when the patient's clinical symptoms or blood counts
indicate that the disease has progressed to a point where it may affect the patient's quality of life.
Small lymphocytic leukemia (SLL) is very similar to CLL described supra, and is also a
cancer of B-cells. In SLL the abnormal lymphocytes mainly affect the lymph nodes. However, in CLL the
abnormal cells mainly affect the blood and the bone marrow. The spleen may be affected in both
conditions. SLL accounts for about 1in 25 of all cases of non-Hodgkin lymphoma. It can occur at any time
from young adulthood to old age, but is rare under the age of 50. SLL is considered an indolent
lymphoma. This means that the disease progresses very slowly, and patients tend to live many years after
diagnosis. However, most patients are diagnosed with advanced disease, and although SLL responds well
to a variety of chemotherapy drugs, it is generally considered to be incurable. Although some cancers tend
to occur more often in one gender or the other, cases and deaths due to SLL are evenly split between men
and women. The average age at the time of diagnosis is 60 years.
Although SLL is indolent, it is persistently progressive. The usual pattern of this disease is
one of high response rates to radiation therapy and/or chemotherapy, with a period of disease remission.
This is followed months or years later by an inevitable relapse. Re-treatment leads to a response again, but
again the disease will relapse. This means that although the short-term prognosis of SLL is quite good,
over time, many patients develop fatal complications of recurrent disease. Considering the age of the
individuals typically diagnosed with CLL and SLL, there is a need in the art for a simple and effective
treatment of the disease with minimum side-effects that do not impede on the patient’s quality of life. The
instant invention fulfills this long standing need in the art.
Mantle Cell Lymphoma
Disclosed herein, in certain embodiments, is a method for treating a Mantle cell lymphoma in
an individual in need thereof, comprising: administering to the individual a composition containing a
therapeutic amount of at least one compound having the structure of Formula (I), (IA), (II), (III), (IV),
(V), (VI), (VIA), (VIB), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), or (XIV).
As used herein, the term, “Mantle cell lymphoma” refers to a subtype of B-cell lymphoma,
due to CD5 positive antigen-naive pregerminal center B-cell within the mantle zone that surrounds normal
germinal center follicles. MCL cells generally over-express cyclin D1 due to a t(11:14) chromosomal
translocation in the DNA. More specifically, the translocation is at t(11;14)(q13;q32). Only about 5% of
lymphomas are of this type. The cells are small to medium in size. Men are affected most often. The
average age of patients is in the early 60s. The lymphoma is usually widespread when it is diagnosed,
involving lymph nodes, bone marrow, and, very often, the spleen. Mantle cell lymphoma is not a very fast
growing lymphoma, but is difficult to treat.
Marginal Zone B-cell Lymphoma
Disclosed herein, in certain embodiments, is a method for treating a marginal zone B-cell
lymphoma in an individual in need thereof, comprising: administering to the individual a composition
containing a therapeutic amount of at least one compound having the structure of Formula (I), (IA), (II),
(III), (IV), (V), (VI), (VIA), (VIB), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), or (XIV).
As used herein, the term “marginal zone B-cell lymphoma” refers to a group of related B-cell
neoplasms that involve the lymphoid tissues in the marginal zone, the patchy area outside the follicular
mantle zone. Marginal zone lymphomas account for about 5% to 10% of lymphomas. The cells in these
lymphomas look small under the microscope. There are 3 main types of marginal zone lymphomas
including extranodal marginal zone B-cell lymphomas, nodal marginal zone B-cell lymphoma, and
splenic marginal zone lymphoma.
MALT
Disclosed herein, in certain embodiments, is a method for treating a MALT in an individual in
need thereof, comprising: administering to the individual a composition containing a therapeutic amount
of at least one compound having the structure of Formula (I), (IA), (II), (III), (IV), (V), (VI), (VIA),
(VIB), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), or (XIV).
The term “mucosa-associated lymphoid tissue (MALT) lymphoma”, as used herein, refers to
extranodal manifestations of marginal-zone lymphomas. Most MALT lymphoma are a low grade,
although a minority either manifest initially as intermediate-grade non-Hodgkin lymphoma (NHL) or
evolve from the low-grade form. Most of the MALT lymphoma occur in the stomach, and roughly 70% of
gastric MALT lymphoma are associated with Helicobacter pylori infection. Several cytogenetic
abnormalities have been identified, the most common being trisomy 3 or t(11;18). Many of these other
MALT lymphoma have also been linked to infections with bacteria or viruses. The average age of patients
with MALT lymphoma is about 60.
Nodal Marginal Zone B-Cell Lymphoma
Disclosed herein, in certain embodiments, is a method for treating a nodal marginal zone B-
cell lymphoma in an individual in need thereof, comprising: administering to the individual a composition
containing a therapeutic amount of at least one compound having the structure of Formula (I), (IA), (II),
(III), (IV), (V), (VI), (VIA), (VIB), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), or (XIV).
The term “nodal marginal zone B-cell lymphoma” refers to an indolent B-cell lymphoma that
is found mostly in the lymph nodes. The disease is rare and only accounts for 1% of all Non-Hodgkin’s
Lymphomas (NHL). It is most commonly diagnosed in older patients, with women more susceptible than
men. The disease is classified as a marginal zone lymphoma because the mutation occurs in the marginal
zone of the B-cells. Due to its confinement in the lymph nodes, this disease is also classified as nodal.
Splenic Marginal Zone B-Cell Lymphoma
Disclosed herein, in certain embodiments, is a method for treating a splenic marginal zone B-
cell lymphoma in an individual in need thereof, comprising: administering to the individual a composition
containing a therapeutic amount of at least one compound having the structure of Formula (I), (IA), (II),
(III), (IV), (V), (VI), (VIA), (VIB), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), or (XIV).
The term “splenic marginal zone B-cell lymphoma” refers to specific low-grade small B-cell
lymphoma that is incorporated in the World Health Organization classification. Characteristic features are
splenomegaly, moderate lymphocytosis with villous morphology, intrasinusoidal pattern of involvement
of various organs, especially bone marrow, and relative indolent course. Tumor progression with increase
of blastic forms and aggressive behavior are observed in a minority of patients. Molecular and cytogenetic
studies have shown heterogeneous results probably because of the lack of standardized diagnostic criteria.
Burkitt Lymphoma
Disclosed herein, in certain embodiments, is a method for treating a Burkitt lymphoma in an
individual in need thereof, comprising: administering to the individual a composition containing a
therapeutic amount of at least one compound having the structure of Formula (I), (IA), (II), (III), (IV),
(V), (VI), (VIA), (VIB), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), or (XIV).
The term “Burkitt lymphoma” refers to a type of Non-Hodgkin Lymphoma (NHL) that
commonly affects children. It is a highly aggressive type of B-cell lymphoma that often starts and
involves body parts other than lymph nodes. In spite of its fast-growing nature, Burkitt’s lymphoma is
often curable with modern intensive therapies. There are two broad types of Burkitt’s lymphoma – the
sporadic and the endemic varieties:
Endemic Burkitt’s lymphoma: The disease involves children much more than adults, and is
related to Epstein Barr Virus (EBV) infection in 95% cases. It occurs primarily is equatorial Africa, where
about half of all childhood cancers are Burkitt’s lymphoma. It characteristically has a high chance of
involving the jawbone, a rather distinctive feature that is rare in sporadic Burkitt’s. It also commonly
involves the abdomen.
Sporadic Burkitt’s lymphoma: The type of Burkitt’s lymphoma that affects the rest of the
world, including Europe and the Americas is the sporadic type. Here too, it's mainly a disease in children.
The link between Epstein Barr Virus (EBV) is not as strong as with the endemic variety, though direct
evidence of EBV infection is present in one out of five patients. More than the involvement of lymph
nodes, it is the abdomen that is notably affected in more than 90% of the children. Bone marrow
involvement is more common than in the sporadic variety.
Waldenstrom Macroglobulinemia
Disclosed herein, in certain embodiments, is a method for treating a Waldenstrom
macroglobulinemia in an individual in need thereof, comprising: administering to the individual a
composition containing a therapeutic amount of at least one compound having the structure of Formula
(I), (IA), (II), (III), (IV), (V), (VI), (VIA), (VIB), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), or (XIV).
The term “Waldenstrom macroglobulinemia”, also known as lymphoplasmacytic lymphoma,
is cancer involving a subtype of white blood cells called lymphocytes. It is characterized by an
uncontrolled clonal proliferation of terminally differentiated B lymphocytes. It is also characterized by the
lymphoma cells making an antibody called immunoglobulin M (IgM). The IgM antibodies circulate in the
blood in large amounts, and cause the liquid part of the blood to thicken, like syrup. This can lead to
decreased blood flow to many organs, which can cause problems with vision (because of poor circulation
in blood vessels in the back of the eyes) and neurological problems (such as headache, dizziness, and
confusion) caused by poor blood flow within the brain. Other symptoms can include feeling tired and
weak, and a tendency to bleed easily. The underlying etiology is not fully understood but a number of risk
factors have been identified, including the locus 6p21.3 on chromosome 6. There is a 2- to 3-fold risk
increase of developing WM in people with a personal history of autoimmune diseases with autoantibodies
and particularly elevated risks associated with hepatitis, human immunodeficiency virus, and rickettsiosis.
Multiple Myeloma
Disclosed herein, in certain embodiments, is a method for treating a myeloma in an individual
in need thereof, comprising: administering to the individual a composition containing a therapeutic
amount of at least one compound having the structure of Formula (I), (IA), (II), (III), (IV), (V), (VI),
(VIA), (VIB), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), or (XIV).
Multiple myeloma, also known as MM, myeloma, plasma cell myeloma, or as Kahler's
disease (after Otto Kahler) is a cancer of the white blood cells known as plasma cells. A type of B cell,
plasma cells are a crucial part of the immune system responsible for the production of antibodies in
humans and other vertebrates. They are produced in the bone marrow and are transported through the
lymphatic system.
Leukemia
Disclosed herein, in certain embodiments, is a method for treating a leukemia in an individual
in need thereof, comprising: administering to the individual a composition containing a therapeutic
amount of at least one compound having the structure of Formula (I), (IA), (II), (III), (IV), (V), (VI),
(VIA), (VIB), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), or (XIV).
Leukemia is a cancer of the blood or bone marrow characterized by an abnormal increase of
blood cells, usually leukocytes (white blood cells). Leukemia is a broad term covering a spectrum of
diseases. The first division is between its acute and chronic forms: (i) acute leukemia is characterized by
the rapid increase of immature blood cells. This crowding makes the bone marrow unable to produce
healthy blood cells. Immediate treatment is required in acute leukemia due to the rapid progression and
accumulation of the malignant cells, which then spill over into the bloodstream and spread to other organs
of the body. Acute forms of leukemia are the most common forms of leukemia in children; (ii) chronic
leukemia is distinguished by the excessive build up of relatively mature, but still abnormal, white blood
cells. Typically taking months or years to progress, the cells are produced at a much higher rate than
normal cells, resulting in many abnormal white blood cells in the blood. Chronic leukemia mostly occurs
in older people, but can theoretically occur in any age group. Additionally, the diseases are subdivided
according to which kind of blood cell is affected. This split divides leukemias into lymphoblastic or
lymphocytic leukemias and myeloid or myelogenous leukemias: (i) lymphoblastic or lymphocytic
leukemias, the cancerous change takes place in a type of marrow cell that normally goes on to form
lymphocytes, which are infection-fighting immune system cells; (ii) myeloid or myelogenous leukemias,
the cancerous change takes place in a type of marrow cell that normally goes on to form red blood cells,
some other types of white cells, and platelets.
Within these main categories, there are several subcategories including, but not limited to,
Acute lymphoblastic leukemia (ALL), Acute myelogenous leukemia (AML), Chronic myelogenous
leukemia (CML), and Hairy cell leukemia (HCL).
Symptoms, diagnostic tests, and prognostic tests for each of the above-mentioned conditions
are known in the art. See, e.g., Harrison’s Principles of Internal Medicine ,” 16th ed., 2004, The
McGraw-Hill Companies, Inc. Dey et al. (2006), Cytojournal 3(24), and the “Revised European American
Lymphoma” (REAL) classification system (see, e.g., the website maintained by the National Cancer
Institute).
A number of animal models of are useful for establishing a range of therapeutically effective
doses of Btk inhibitor compounds for treating any of the foregoing diseases.
For example, dosing of Btk inhibitor compounds for treating an autoimmune disease can be
assessed in a mouse model of rheumatoid arthitis. In this model, arthritis is induced in Balb/c mice by
administering anti-collagen antibodies and lipopolysaccharide. See Nandakumar et al. (2003), Am. J.
Pathol 163:1827-1837.
In another example, dosing of Btk inhibitors for the treatment of B-cell proliferative disorders
can be examined in, e.g., a human-to-mouse xenograft model in which human B-cell lymphoma cells (e.g.
Ramos cells) are implanted into immunodefficient mice (e.g., “nude” mice) as described in, e.g., Pagel et
al. (2005), Clin Cancer Res 11(13):4857-4866.
Animal models for treatment of thromboembolic disorders are also known.
The therapeutic efficacy of the compound for one of the foregoing diseases can be optimized
during a course of treatment. For example, a subject being treated can undergo a diagnostic evaluation to
correlate the relief of disease symptoms or pathologies to inhibition of in vivo Btk activity achieved by
administering a given dose of an Btk inhibitor. Cellular assays known in the art can be used to determine
in vivo activity of Btk in the presence or absence of an Btk inhibitor. For example, since activated Btk is
phosphorylated at tyrosine 223 (Y223) and tyrosine 551 (Y551), phospho-specific immunocytochemical
staining of P-Y223 or P-Y551-positive cells can be used to detect or quantify activation of Bkt in a
population of cells (e.g., by FACS analysis of stained vs unstained cells). See, e.g., Nisitani et al. (1999),
Proc. Natl. Acad. Sci, USA 96:2221-2226. Thus, the amount of the Btk inhibitor inhibitor compound that
is administered to a subject can be increased or decreased as needed so as to maintain a level of Btk
inhibition optimal for treating the subject’s disease state.
Compounds disclosed herein can irreversibly inhibit Btk and may be used to treat mammals
suffering from Bruton’s tyrosine kinase-dependent or Bruton’s tyrosine kinase mediated conditions or
diseases, including, but not limited to, cancer, autoimmune and other inflammatory diseases. Compounds
disclosed herein have shown efficacy in a wide variety of diseases and conditions that are described
herein.
Certain Terminology
It is to be understood that the foregoing general description and the following detailed
description are exemplary and explanatory only and are not restrictive of any subject matter claimed. In
this application, the use of the singular includes the plural unless specifically stated otherwise. It must be
noted that, as used in the specification and the appended claims, the singular forms “a,” “an” and “the”
include plural referents unless the context clearly dictates otherwise. In this application, the use of “or”
means “and/or” unless stated otherwise. Furthermore, use of the term “including” as well as other forms,
such as “include”, “includes,” and “included,” is not limiting.
Definition of standard chemistry terms are found in reference works, including Carey and
Sundberg “ADVANCED ORGANIC CHEMISTRY 4 ED.” Vols. A (2000) and B (2001), Plenum Press, New
York. Unless otherwise indicated, conventional methods of mass spectroscopy, NMR, HPLC, protein
chemistry, biochemistry, recombinant DNA techniques and pharmacology, within the skill of the art are
employed. Unless specific definitions are provided, the nomenclature employed in connection with, and
the laboratory procedures and techniques of, analytical chemistry, synthetic organic chemistry, and
medicinal and pharmaceutical chemistry described herein are those known in the art. Standard techniques
are optionally used for chemical syntheses, chemical analyses, pharmaceutical preparation, formulation,
and delivery, and treatment of patients. Standard techniques are optionally used for recombinant DNA,
oligonucleotide synthesis, and tissue culture and transformation (e.g., electroporation, lipofection).
Reactions and purification techniques are performed using documented methodologies or as described
herein.
It is to be understood that the methods and compositions described herein are not limited to
the particular methodology, protocols, cell lines, constructs, and reagents described herein and as such
optionally vary. It is also to be understood that the terminology used herein is for the purpose of
describing particular embodiments only, and is not intended to limit the scope of the methods and
compositions described herein, which will be limited only by the appended claims.
An “alkyl” group refers to an aliphatic hydrocarbon group. The alkyl moiety includes a
“saturated alkyl” group, which means that it does not contain any alkene or alkyne moieties. The alkyl
moiety also includes an “unsaturated alkyl” moiety, which means that it contains at least one alkene or
alkyne moiety. An “alkene” moiety refers to a group that has at least one carbon-carbon double bond, and
an “alkyne” moiety refers to a group that has at least one carbon-carbon triple bond. The alkyl moiety,
whether saturated or unsaturated, includes branched, straight chain, or cyclic moieties. Depending on the
structure, an alkyl group includes a monoradical or a diradical (i.e., an alkylene group), and if a “lower
alkyl” having 1 to 6 carbon atoms.
As used herein, C -C includes C -C , C -C . . . C -C
1 x 1 2 1 3 1 x.
The “alkyl” moiety optionally has 1 to 10 carbon atoms (whenever it appears herein, a
numerical range such as “1 to 10” refers to each integer in the given range; e.g., “1 to 10 carbon atoms”
means that the alkyl group is selected from a moiety having 1 carbon atom, 2 carbon atoms, 3 carbon
atoms, etc., up to and including 10 carbon atoms, although the present definition also covers the
occurrence of the term “alkyl” where no numerical range is designated). The alkyl group of the
compounds described herein may be designated as “C -C alkyl” or similar designations. By way of
example only, “C -C alkyl” indicates that there are one to four carbon atoms in the alkyl chain, i.e., the
alkyl chain is selected from among methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and t-
butyl. Thus C -C alkyl includes C -C alkyl and C -C alkyl. Alkyl groups are optionally substituted or
1 4 1 2 1 3
unsubstituted. Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl,
butyl, isobutyl, tertiary butyl, pentyl, hexyl, ethenyl, propenyl, butenyl, cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, and the like.
An “alkoxy” group refers to a (alkyl)O- group, where alkyl is as defined herein.
“Alkoxyalkyl” refers to an alkyl radical, as defined herein, substituted with an alkoxy group,
as defined herein.
The term “ester” refers to a chemical moiety with formula –COOR, where R is selected from
among C -C alkyl, phenyl or benzyl. Any hydroxy, or carboxyl side chain on the compounds described
herein can be esterified. The procedures and specific groups to make such esters are found in sources such
as Greene and Wuts, Protective Groups in Organic Synthesis, 3 Ed., John Wiley & Sons, New York,
NY, 1999, which is incorporated herein by reference for this disclosure.
As used herein, the term “aryl” refers to an aromatic ring wherein each of the atoms forming
the ring is a carbon atom. Aryl rings can be formed by five, six, seven, eight, nine, or more than nine
carbon atoms. Aryl groups can be optionally substituted. Examples of aryl groups include, but are not
limited to phenyl, naphthalenyl, phenanthrenyl, anthracenyl, fluorenyl, and indenyl. Depending on the
structure, an aryl group can be a monoradical or a diradical (i.e., an arylene group).
The term “carbonyl” as used herein refers to a group containing a moiety selected from the
group consisting of -C(O)-, -S(O)-, -S(O)2-, and –C(S)-, including, but not limited to, groups containing a
least one ketone group, and/or at least one aldehyde group, and/or at least one ester group, and/or at least
one carboxylic acid group, and/or at least one thioester group. Such carbonyl groups include ketones,
aldehydes, carboxylic acids, esters, and thioesters. In some embodiments, such groups are a part of linear,
branched, or cyclic molecules.
The term “halo” or, alternatively, “halogen” or “halide” means fluoro, chloro, bromo and
iodo.
The term “cycloalkyl” refers to a monocyclic or polycyclic radical that contains only carbon
and hydrogen, and may be saturated, partially unsaturated, or fully unsaturated. Cycloalkyl groups include
groups having from 3 to 10 ring atoms. Illustrative examples of cycloalkyl groups include the following
moieties:
, , , , ,
, and the like. Depending on the structure, a cycloalkyl
group can be a monoradical or a diradical (e.g., an cycloalkylene group). The cycloalkyl group could also
be a “lower cycloalkyl” having 3 to 8 carbon atoms
The term “heteroatom” refers to an atom other than carbon or hydrogen. Heteroatoms are
typically independently selected from among oxygen, sulfur, nitrogen, silicon and phosphorus, but are not
limited to these atoms. In embodiments in which two or more heteroatoms are present, the two or more
heteroatoms can all be the same as one another, or some or all of the two or more heteroatoms can each be
different from the others.
The term “heterocycle” refers to heteroaromatic and heteroalicyclic groups containing one to
four heteroatoms each selected from O, S and N, wherein each heterocyclic group has from 4 to 10 atoms
in its ring system, and with the proviso that the ring of said group does not contain two adjacent O or S
atoms. Herein, whenever the number of carbon atoms in a heterocycle is indicated (e.g., C -C
heterocycle), at least one other atom (the heteroatom) must be present in the ring. Designations such as
“C -C heterocycle” refer only to the number of carbon atoms in the ring and do not refer to the total
number of atoms in the ring. It is understood that the heterocylic ring can have additional heteroatoms in
the ring. Designations such as “4-6 membered heterocycle” refer to the total number of atoms that are
contained in the ring (i.e., a four, five, or six membered ring, in which at least one atom is a carbon atom,
at least one atom is a heteroatom and the remaining two to four atoms are either carbon atoms or
heteroatoms). In heterocycles that have two or more heteroatoms, those two or more heteroatoms can be
the same or different from one another. Heterocycles can be optionally substituted. Binding to a
heterocycle can be at a heteroatom or via a carbon atom. Non-aromatic heterocyclic groups include groups
having only 4 atoms in their ring system, but aromatic heterocyclic groups must have at least 5 atoms in
their ring system. The heterocyclic groups include benzo-fused ring systems. An example of a 4-
membered heterocyclic group is azetidinyl (derived from azetidine). An example of a 5-membered
heterocyclic group is thiazolyl. An example of a 6-membered heterocyclic group is pyridyl, and an
example of a 10-membered heterocyclic group is quinolinyl. Examples of non-aromatic heterocyclic
groups are pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl,
dihydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino, thioxanyl, piperazinyl,
azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl,
1,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-
dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl,
pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, 3H-
indolyl and quinolizinyl. Examples of aromatic heterocyclic groups are pyridinyl, imidazolyl, pyrimidinyl,
pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl,
pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl,
indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl,
furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl,
naphthyridinyl, and furopyridinyl. The foregoing groups, as derived from the groups listed above, may be
C-attached or N-attached where such is possible. For instance, a group derived from pyrrole may be
pyrrolyl (N-attached) or pyrrolyl (C-attached). Further, a group derived from imidazole may be
imidazolyl or imidazolyl (both N-attached) or imidazolyl, imidazolyl or imidazolyl (all C-
attached). The heterocyclic groups include benzo-fused ring systems and ring systems substituted with
one or two oxo (=O) moieties such as pyrrolidinone. Depending on the structure, a heterocycle group
can be a monoradical or a diradical (i.e., a heterocyclene group).
The terms “heteroaryl” or, alternatively, “heteroaromatic” refers to an aryl group that includes
one or more ring heteroatoms selected from nitrogen, oxygen and sulfur. An N-containing
“heteroaromatic” or “heteroaryl” moiety refers to an aromatic group in which at least one of the skeletal
atoms of the ring is a nitrogen atom. Illustrative examples of heteroaryl groups include the following
moieties:
S O S
, N N
, , ,
, N N N
the like. Depending on the structure, a heteroaryl group can be a monoradical or a diradical (i.e., a
heteroarylene group).
As used herein, the term “non-aromatic heterocycle”, “heterocycloalkyl” or “heteroalicyclic”
refers to a non-aromatic ring wherein one or more atoms forming the ring is a heteroatom. A “non-
aromatic heterocycle” or “heterocycloalkyl” group refers to a cycloalkyl group that includes at least one
heteroatom selected from nitrogen, oxygen and sulfur. The radicals may be fused with an aryl or
heteroaryl. Heterocycloalkyl rings can be formed by three, four, five, six, seven, eight, nine, or more than
nine atoms. Heterocycloalkyl rings can be optionally substituted. In certain embodiments, non-aromatic
heterocycles contain one or more carbonyl or thiocarbonyl groups such as, for example, oxo- and thio-
containing groups. Examples of heterocycloalkyls include, but are not limited to, lactams, lactones, cyclic
imides, cyclic thioimides, cyclic carbamates, tetrahydrothiopyran, 4H-pyran, tetrahydropyran, piperidine,
1,3-dioxin, 1,3-dioxane, 1,4-dioxin, 1,4-dioxane, piperazine, 1,3-oxathiane, 1,4-oxathiin, 1,4-oxathiane,
tetrahydro-1,4-thiazine, 2H-1,2-oxazine, maleimide, succinimide, barbituric acid, thiobarbituric acid,
dioxopiperazine, hydantoin, dihydrouracil, morpholine, trioxane, hexahydro-1,3,5-triazine,
tetrahydrothiophene, tetrahydrofuran, pyrroline, pyrrolidine, pyrrolidone, pyrrolidione, pyrazoline,
pyrazolidine, imidazoline, imidazolidine, 1,3-dioxole, 1,3-dioxolane, 1,3-dithiole, 1,3-dithiolane,
isoxazoline, isoxazolidine, oxazoline, oxazolidine, oxazolidinone, thiazoline, thiazolidine, and 1,3-
oxathiolane. Illustrative examples of heterocycloalkyl groups, also referred to as non-aromatic
heterocycles, include:
S N N
, , , ,
N O O
N , , ,
N O S O O
N N ,
the like.
The term “bond” or “single bond” refers to a chemical bond between two atoms, or two
moieties when the atoms joined by the bond are considered to be part of larger substructure.
The term “moiety” refers to a specific segment or functional group of a molecule. Chemical
moieties are often recognized chemical entities embedded in or appended to a molecule.
A “thioalkoxy” or “alkylthio” group refers to a –S-alkyl group.
A “SH” group is also referred to either as a thiol group or a sulfhydryl group.
The term “acceptable” or “pharmaceutically acceptable”, with respect to a formulation,
composition or ingredient, as used herein, means having no persistent detrimental effect on the general
health of the subject being treated or does not abrogate the biological activity or properties of the
compound, and is relatively nontoxic.
As used herein, the term “agonist” refers to a compound, the presence of which results in a
biological activity of a protein that is the same as the biological activity resulting from the presence of a
naturally occurring ligand for the protein, such as, for example, Btk.
As used herein, the term “partial agonist” refers to a compound the presence of which results
in a biological activity of a protein that is of the same type as that resulting from the presence of a
naturally occurring ligand for the protein, but of a lower magnitude.
As used herein, the term “antagonist” refers to a compound, the presence of which results in a
decrease in the magnitude of a biological activity of a protein. In certain embodiments, the presence of an
antagonist results in complete inhibition of a biological activity of a protein, such as, for example, Btk. In
certain embodiments, an antagonist is an inhibitor.
As used herein, “amelioration” of the symptoms of a particular disease, disorder or condition
by administration of a particular compound or pharmaceutical composition refers to any lessening of
severity, delay in onset, slowing of progression, or shortening of duration, whether permanent or
temporary, lasting or transient that can be attributed to or associated with administration of the compound
or composition.
“Bioavailability” refers to the percentage of the weight of compounds disclosed herein, such
as, compounds of Formula (I), dosed that is delivered into the general circulation of the animal or human
being studied. The total exposure (AUC ) of a drug when administered intravenously is usually defined
(0-∞)
as 100% bioavailable (F%). “Oral bioavailability” refers to the extent to which compounds disclosed
herein, such as, compounds of Formula (I), are absorbed into the general circulation when the
pharmaceutical composition is taken orally as compared to intravenous injection.
“Blood plasma concentration” refers to the concentration of compounds disclosed herein,
such as, compounds of Formula (I), in the plasma component of blood of a subject. It is understood that
the plasma concentration of compounds of Formula (I), may vary significantly between subjects, due to
variability with respect to metabolism and/or possible interactions with other therapeutic agents. In
accordance with one embodiment disclosed herein, the blood plasma concentration of the compounds of
Formula (I), does vary from subject to subject. Likewise, values such as maximum plasma concentration
(C ) or time to reach maximum plasma concentration (T ), or total area under the plasma
max max
concentration time curve (AUC ) may vary from subject to subject. Due to this variability, the amount
(0-∞)
necessary to constitute “a therapeutically effective amount” of a compound of Formula (I), is expected to
vary from subject to subject.
The term “Bruton’s tyrosine kinase,” as used herein, refers to Bruton’s tyrosine kinase from
Homo sapiens, as disclosed in, e.g., U.S. Patent No. 6,326,469 (GenBank Accession No. NP_000052).
The term “Bruton’s tyrosine kinase homolog,” as used herein, refers to orthologs of Bruton’s
tyrosine kinase, e.g., the orthologs from mouse (GenBank Accession No. AAB47246), dog (GenBank
Accession No. XP_549139.), rat (GenBank Accession No. NP_001007799), chicken (GenBank Accession
No. NP_989564), or zebra fish (GenBank Accession No. XP_698117), and fusion proteins of any of the
foregoing that exhibit kinase activity towards one or more substrates of Bruton’s tyrosine kinase (e.g. a
peptide substrate having the amino acid sequence “AVLESEEELYSSARQ”).
The terms “co-administration” or the like, as used herein, are meant to encompass
administration of the selected therapeutic agents to a single patient, and are intended to include treatment
regimens in which the agents are administered by the same or different route of administration or at the
same or different time.
The terms “effective amount” or “therapeutically effective amount,” as used herein, refer to a
sufficient amount of an agent or a compound being administered which will relieve to some extent one or
more of the symptoms of the disease or condition being treated. The result can be reduction and/or
alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological
system. For example, an “effective amount” for therapeutic uses is the amount of the composition
including a compound as disclosed herein required to provide a clinically significant decrease in disease
symptoms without undue adverse side effects. An appropriate “effective amount” in any individual case is
optionally determined using techniques, such as a dose escalation study. The term “therapeutically
effective amount” includes, for example, a prophylactically effective amount. An “effective amount” of a
compound disclosed herein is an amount effective to achieve a desired pharmacologic effect or
therapeutic improvement without undue adverse side effects. It is understood that “an effect amount” or “a
therapeutically effective amount” can vary from subject to subject, due to variation in metabolism of the
of Formula (I), age, weight, general condition of the subject, the condition being treated, the severity of
the condition being treated, and the judgment of the prescribing physician.
The terms “enhance” or “enhancing” means to increase or prolong either in potency or
duration a desired effect. By way of example, “enhancing” the effect of therapeutic agents refers to the
ability to increase or prolong, either in potency or duration, the effect of therapeutic agents on during
treatment of a disease, disorder or condition. An “enhancing-effective amount,” as used herein, refers to
an amount adequate to enhance the effect of a therapeutic agent in the treatment of a disease, disorder or
condition. When used in a patient, amounts effective for this use will depend on the severity and course of
the disease, disorder or condition, previous therapy, the patient's health status and response to the drugs,
and the judgment of the treating physician.
The term “homologous cysteine,” as used herein refers to a cysteine residue found with in a
sequence position that is homologous to that of cysteine 481 of Bruton’s tyrosine kinase, as defined
herein. For example, cysteine 482 is the homologous cysteine of the rat ortholog of Bruton’s tyrosine
kinase; cysteine 479 is the homologous cysteine of the chicken ortholog; and cysteine 481 is the
homologous cysteine in the zebra fish ortholog. In another example, the homologous cysteine of TXK, a
Tec kinase family member related to Bruton’s tyrosine, is Cys 350. See also the sequence alignments of
tyrosine kinases (TK) published on the world wide web at kinase.com/human/kinome/phylogeny.html.
The terms “inhibits”, “inhibiting”, or “inhibitor” of a kinase, as used herein, refer to inhibition
of enzymatic phosphotransferase activity.
The term “modulate,” as used herein, means to interact with a target either directly or
indirectly so as to alter the activity of the target, including, by way of example only, to enhance the
activity of the target, to inhibit the activity of the target, to limit the activity of the target, or to extend the
activity of the target.
As used herein, the term “modulator” refers to a compound that alters an activity of a
molecule. For example, a modulator can cause an increase or decrease in the magnitude of a certain
activity of a molecule compared to the magnitude of the activity in the absence of the modulator. In
certain embodiments, a modulator is an inhibitor, which decreases the magnitude of one or more activities
of a molecule. In certain embodiments, an inhibitor completely prevents one or more activities of a
molecule. In certain embodiments, a modulator is an activator, which increases the magnitude of at least
one activity of a molecule. In certain embodiments the presence of a modulator results in an activity that
does not occur in the absence of the modulator.
The term “plasma half life,” as used herein refers to half-life in rat, dog or human as
determined by measure drug concentration over time in plasma following a single dose and fitting data to
standard pharmacokinetic models using software such as WinNonLin to determine the time at which drug
has been 50% eliminated from plasma.
The term “prophylactically effective amount,” as used herein, refers that amount of a
composition applied to a patient which will relieve to some extent one or more of the symptoms of a
disease, condition or disorder being treated. In such prophylactic applications, such amounts may depend
on the patient's state of health, weight, and the like.
As used herein, the term “selective binding compound” refers to a compound that selectively
binds to any portion of one or more target proteins.
As used herein, the term “selectively binds” refers to the ability of a selective binding
compound to bind to a target protein, such as, for example, Btk, with greater affinity than it binds to a
non-target protein. In certain embodiments, specific binding refers to binding to a target with an affinity
that is at least about 10, about 50, about 100, about 250, about 500, about 1000 or more times greater than
the affinity for a non-target.
As used herein, the term “selective modulator” refers to a compound that selectively
modulates a target activity relative to a non-target activity. In certain embodiments, specific modulator
refers to modulating a target activity at least about 10, about 50, about 100, about 250, about 500, about
1000 times more than a non-target activity.
The term “substantially purified,” as used herein, refers to a component of interest that may
be substantially or essentially free of other components which normally accompany or interact with the
component of interest prior to purification. By way of example only, a component of interest may be
“substantially purified” when the preparation of the component of interest contains less than about 30%,
less than about 25%, less than about 20%, less than about 15%, less than about 10%, less than about 5%,
less than about 4%, less than about 3%, less than about 2%, or less than about l% (by dry weight) of
contaminating components. Thus, a “substantially purified” component of interest may have a purity level
of about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about
98%, about 99% or greater.
The term “subject” as used herein, refers to an animal which is the object of treatment,
observation or experiment. By way of example only, a subject may be, but is not limited to, a mammal
including, but not limited to, a human.
As used herein, the term “target activity” refers to a biological activity capable of being
modulated by a selective modulator. Certain exemplary target activities include, but are not limited to,
binding affinity, signal transduction, enzymatic activity, tumor growth, inflammation or inflammation-
related processes, and amelioration of one or more symptoms associated with a disease or condition.
As used herein, the term “target protein” refers to a molecule or a portion of a protein capable
of being bound by a selective binding compound. In certain embodiments, a target protein is Btk.
The terms “treat,” “treating” or “treatment”, as used herein, include alleviating, abating or
ameliorating a disease or condition symptoms, preventing additional symptoms, ameliorating or
preventing the underlying metabolic causes of symptoms, inhibiting the disease or condition, e.g.,
arresting the development of the disease or condition, relieving the disease or condition, causing
regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping
the symptoms of the disease or condition. The terms “treat,” “treating” or “treatment”, include, but are not
limited to, prophylactic and/or therapeutic treatments.
As used herein, the IC refers to an amount, concentration or dosage of a particular test
compound that achieves a 50% inhibition of a maximal response, such as inhibition of Btk, in an assay
that measures such response.
As used herein, EC refers to a dosage, concentration or amount of a particular test
compound that elicits a dose-dependent response at 50% of maximal expression of a particular response
that is induced, provoked or potentiated by the particular test compound.
Inhibitor Compounds
In the following description of Btk compounds suitable for use in the methods described
herein, definitions of referred-to standard chemistry terms may be found in reference works (if not
otherwise defined herein), including Carey and Sundberg “Advanced Organic Chemistry 4th Ed.” Vols. A
(2000) and B (2001), Plenum Press, New York. Unless otherwise indicated, conventional methods of
mass spectroscopy, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniques and
pharmacology, within the ordinary skill of the art are employed. In addition, nucleic acid and amino acid
sequences for Btk (e.g., human Btk) are known in the art as disclosed in, e.g., U.S. Patent No. 6,326,469.
Unless specific definitions are provided, the nomenclature employed in connection with, and the
laboratory procedures and techniques of, analytical chemistry, synthetic organic chemistry, and medicinal
and pharmaceutical chemistry described herein are those known in the art. Standard techniques can be
used for chemical syntheses, chemical analyses, pharmaceutical preparation, formulation, and delivery,
and treatment of patients.
The Btk inhibitor compounds described herein are selective for Btk and kinases having a
cysteine residue in an amino acid sequence position of the tyrosine kinase that is homologous to the amino
acid sequence position of cysteine 481 in Btk.
Cellular functional assays for Btk inhibition include measuring one or more cellular endpoints
in response to stimulating a Btk-mediated pathway in a cell line (e.g., BCR activation in Ramos cells) in
the absence or presence of a range of concentrations of a candidate Btk inhibitor compound. Useful
endpoints for determining a response to BCR activation include, e.g., autophosphorylation of Btk,
phosphorylation of a Btk target protein (e.g., PLC- ), and cytoplasmic calcium flux.
High throughput assays for many acellular biochemical assays (e.g., kinase assays) and
cellular functional assays (e.g., calcium flux) are well known to those of ordinary skill in the art. In
addition, high throughput screening systems are commercially available (see, e.g., Zymark Corp.,
Hopkinton, MA; Air Technical Industries, Mentor, OH; Beckman Instruments, Inc. Fullerton, CA;
Precision Systems, Inc., Natick, MA, etc.). These systems typically automate entire procedures including
all sample and reagent pipetting, liquid dispensing, timed incubations, and final readings of the microplate
in detector(s) appropriate for the assay. Automated systems thereby allow the identification and
characterization of a large number of Btk compounds without undue effort.
Btk inhibitor compounds can be used for the manufacture of a medicament for treating any of
the foregoing conditions (e.g., autoimmune diseases, inflammatory diseases, allergy disorders, B-cell
proliferative disorders, or thromboembolic disorders).
In some embodiments, the Btk inhibitor compound used for the methods described herein
inhibits Btk or a Btk homolog kinase activity with an in vitro IC of less than 10 μM. (e.g., less than 1
μM, less than 0.5 μM, less than 0.4 μM, less than 0.3 μM, less than 0.1 μM, less than 0.08 μM, less than
0.06 μM, less than 0.05 μM, less than 0.04 μM, less than 0.03 μM, less than less than 0.02 μM, less than
0.01 μM, less than 0.008 μM, less than 0.006 μM, less than 0.005 μM, less than 0.004 μM, less than 0.003
μM, less than less than 0.002 μM, less than 0.001 μM, less than 0.00099 μM, less than 0.00098 μM, less
than 0.00097 μM, less than 0.00096 μM, less than 0.00095 μM, less than 0.00094 μM, less than 0.00093
μM, less than 0.00092, or less than 0.00090 μM).
In one embodiment, the Btk inhibitor compound selectively inhibits an activated form of its
target tyrosine kinase (e.g., a phosphorylated form of the tyrosine kinase). For example, activated Btk is
transphosphorylated at tyrosine 551. Thus, in these embodiments the Btk inhibitor inhibits the target
kinase in cells only once the target kinase is activated by the signaling events.
In the following description of kinase inhibitor compounds suitable for use in the methods
described herein. Unless specific definitions are provided, the nomenclature employed in connection with,
and the laboratory procedures and techniques of, analytical chemistry, synthetic organic chemistry, and
medicinal and pharmaceutical chemistry described herein are those known in the art. Standard techniques
can be used for chemical syntheses, chemical analyses, pharmaceutical preparation, formulation, and
delivery, and treatment of patients.
Described herein are compounds of any of Formula (I), (IA), (II), (III), (IV), (V), (VI), (VIA),
(VIB), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), or (XIV). Also described herein are pharmaceutically
acceptable salts, pharmaceutically acceptable solvates, pharmaceutically active metabolites, and
pharmaceutically acceptable prodrugs of such compounds. Pharmaceutical compositions that include at
least one such compound or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate,
pharmaceutically active metabolite or pharmaceutically acceptable prodrug of such compound, are
provided. In some embodiments, when compounds disclosed herein contain an oxidizable nitrogen atom,
the nitrogen atom can be converted to an N-oxide by methods well known in the art. In certain
embodiments, isomers and chemically protected forms of compounds having a structure represented by
any of Formula (I), (IA), (II), (III), (IV), (V), (VI), (VIA), (VIB), (VII), (VIII), (IX), (X), (XI), (XII),
(XIII), or (XIV) are also provided.
In one aspect, provided herein are compounds of Formula (I) having the structure:
L Ar R
Formula (I);
wherein:
a a b b b b
L is each independently CR R , O, S, NR , N-OR , C=O, C=S, C=N-R , or C=N-OR ;
a b b b
R is each independently H, C -C alkyl, C -C heteroalkyl, halogen, OR , or NR R ;
1 6 1 6
R is each independently H, C -C alkyl, C -C heteroalkyl, C -C cycloalkyl, or C -C
1 6 2 6 3 6 2 6
heterocycloalkyl;
1 2 b b b
R is L-Ar , OR , or NR R ;
2 b b b
R is H, OR , NR R , halogen, C -C alkyl, C -C heteroalkyl, C -C cycloalkyl, or C -C
1 6 1 6 3 6 2 6
heterocycloalkyl;
3 b b b b
R is optionally substituted alkyl, -(C=O)C -C alkyl, -(C=O)OR , -(C=O)NR R , -(C=O)SR ,
optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or
optionally substituted heteroaryl;
Ar and Ar are each independently C -C aryl or heteroaryl optionally substituted with halogen, OR ,
12
NR R , C -C alkyl, C -C heteroalkyl, C -C cycloalkyl, or C -C heterocycloalkyl;
1 6 1 6 3 6 2 6
or a pharmaceutically acceptable salt, solvate, N-oxide, or prodrug thereof.
In one embodiment is a compound of Formula (I) wherein L is CH or C=O. In another
embodiment is a compound of Formula (I) wherein Ar is phenyl. In yet another embodiment is a
compound of Formula (I) wherein R is H and R is optionally substituted cycloalkyl. In a further
embodiment is a compound of Formula (I) wherein R is O-Ph.
For any and all of the embodiments, substituents are selected from among from a subset of the
2 b b b
listed alternatives. For example, in some embodiments, R is H, OR , NR R , halogen, C -C alkyl, C -C
1 6 1 6
heteroalkyl, C -C cycloalkyl, or C -C heterocycloalkyl; wherein R is each independently H, C -C alkyl,
3 6 2 6 1 6
C -C heteroalkyl, C -C cycloalkyl, or C -C heterocycloalkyl. In some embodiments, R is H, OH, NH ,
2 6 3 6 2 6 2
halogen or C -C alkyl. In some embodiments, R is F, Cl, Br or I. In other embodiments, R is methyl,
ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, n-pentyl, or hexyl. In yet other embodiments, R
is H, OH, or NH . In other embodiments, R is H.
1 2 2
In some embodiments, R is O-Ar wherein Ar is C -C aryl or heteroaryl optionally
12
b b b
substituted with halogen, OR , NR R , C -C alkyl, C -C heteroalkyl, C -C cycloalkyl, or C -C
1 6 1 6 3 6 2 6
heterocycloalkyl; and R is each independently H, C -C alkyl, C -C heteroalkyl, C -C cycloalkyl, or C -
1 6 2 6 3 6 2
1 2 2
C heterocycloalkyl. In some embodiments, R is O-Ar wherein Ar is C -C aryl or heteroaryl
6 5 12
optionally substituted with halogen, hydroxy, amine, or C -C alkyl. In other embodiments, Ar is phenyl,
pyridinyl, pyridaznyl, pyrimidinyl, pyrazinyl, triazinyl, tetrazinyl, furanyl, thiophenyl, oxazolyl, thiazolyl,
pyrazolyl, quinolinyl, isoquinolinyl, indolyl, benzofuranyl, benzimidazolyl, or the like. In other
embodiments, Ar is phenyl, pyridinyl, furanyl, thiophenyl or quinolinyl. In certain embodiments, Ar is
phenyl or pyridinyl.
In some embodiments, R is optionally substituted alkyl, -(C=O)C -C alkyl, -(C=O)OR , -
b b b
(C=O)NR R , -(C=O)SR , optionally substituted cycloalkyl, optionally substituted heterocycloalkyl,
optionally substituted aryl, or optionally substituted heteroaryl. In other embodiments, R is methyl,
ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, and tert-butyl. In yet other embodiments, R is –C=O-Me, -
(C=O)Et, or -(C=O)Bu. In other embodiments, R is –COOH, -COOMe, -COOEt, -COOPr or –COOBu.
In yet other embodiments, R is –CONH , -CONHMe, -CONHEt or –CONHBu. In other embodiments,
R is –C=O-SMe, -(C=O)SEt or –C=O-SPr. In yet other embodiments, R is optionally substituted
cyclobutyl, cyclopentyl, cyclohexyl, or the like. In yet other embodiments, R is optionally substituted
azetidinyl, pyrrolidinyl, piperidinyl or the like. In yet other embodiments, R is optionally substituted
phenyl, pyridinyl, pyridaznyl, pyrimidinyl, pyrazinyl, triazinyl, tetrazinyl, furanyl, thiophenyl, oxazolyl,
thiazolyl, pyrazolyl, quinolinyl, isoquinolinyl, indolyl, benzofuranyl, benzimidazolyl, or the like.
In another embodiment is a compound of Formula (I) wherein R is optionally substituted
with at least one substituent selected from halogen, -CN, -NO , -OH, -OCF , -OCF H, -OCH F, -CF , -
2 3 2 2 3
8 9 9 10 9 10 10 9 9 10
SR , -S(=O)R , -S(=O) R , -NR S(=O) R , -S(=O) N(R ) , -OR , -C(=O)R , -OC(=O)R , -CO R ,
2 2 2 2 2
10 10 10 10 10 10 10
-N(R ) , -C(=O)N(R ) , -NR C(=O)R , -N R C(=O)OR , -NR C(=O)N(R ) , substituted or
2 2 2
unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl or
substituted or unsubstituted heterocycloalkyl; wherein R is H or substituted or unsubstituted alkyl; R is
substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; and each R
is independently H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted
or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted
heteroaryl, or two R together with the atoms to which they are attached form a heterocycle. In one
embodiment, R is substituted with halogen, -CN, -NO , -OH, -OCF , -OCF H, -OCH F, -CF , -SH. In
2 3 2 2 3
3 9 9
another embodiment is a compound of Formula (I) wherein R is substituted with -S(=O)R , -S(=O) R , -
9 10 9 10 10 9
NR S(=O) R , -S(=O) N(R ) , -C(=O)R , -CO R , -C(=O)N(R ) . In another embodiment, R is an
2 2 2 2 2
unsubstituted or substituted alkyl selected from methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl or
tert-butyl. In another embodiment, is a compound of Formula (I) wherein R is a substituted or
unsubstituted cycloalkyl. In a further embodiment, the cycloalkyl is selected from cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. In another embodiment R is a substituted or
unsubstituted heterocycloalkyl. In another embodiment, R is a substituted or unsustituted aryl. In a
further embodiment, the aryl is a phenyl group. In a further embodiment, the aryl is a naphthalene group.
In yet a further embodiment, R is a substituted or unsubstituted heteroaryl. In yet another embodiment
the heteroaryl is selected from pyrrole, furan, thiophene, pyrazole, imidazole, isoxazole, oxazole,
isothiazole, thiazole, 1,2,3-triazole, 1,3,4-triazole, 1-oxa-2,3-diazole, 1-oxa-2,4-diazole, 1-oxa-2,5-diazole,
1-oxa-3,4-diazole, 1-thia-2,3-diazole, 1-thia-2,4-diazole, 1-thia-2,5-diazole, 1-thia-3,4-diazole, tetrazole,
pyridine, pyridazine, pyrimidine, and pyrazine.
a a b b
In some embodiments, L is each independently CR R , O, S, NR , C=O, C=S, C=N-R or
b a b b b
C=N-OR wherein R is each independently H, C -C alkyl, C -C heteroalkyl, halogen, OR , or NR R ;
1 6 1 6
and R is each independently H, C -C alkyl, C -C heteroalkyl, C -C cycloalkyl, or C -C
1 6 2 6 3 6 2 6
a a b b
heterocycloalkyl. In some embodiments, L is each independently CR R , O, S, NR , C=O, C=S, C=N-R
b a b
or C=N-OR wherein R is each independently H, C -C alkyl, or halogen; and R is each independently H
or C -C alkyl. In other embodiments, L is CH , O, S, NH, C=O, C=S, C=N-H or C=N-OH. In other
1 6 2
embodiments, L is –CH(Me) or –CH(Cl). In yet other embodiments, L is C=N-Me, C=N-OMe, C=N-Et,
n- n-
C=N-OEt, C=N- Pr, or C=N-O Pr.
In some embodiments, Ar is C -C aryl or heteroaryl optionally substituted with halogen,
12
b b b b
OR , NR R , C -C alkyl, C -C heteroalkyl, C -C cycloalkyl, or C -C heterocycloalkyl; and R is each
1 6 1 6 3 6 2 6
independently H, C -C alkyl, C -C heteroalkyl, C -C cycloalkyl, or C -C heterocycloalkyl. In some
1 6 2 6 3 6 2 6
embodiments, Ar is C -C aryl or heteroaryl optionally substituted with halogen, hydroxy, amine, or C -
12 1
C alkyl. In other embodiments, Ar is phenyl, pyridinyl, pyridaznyl, pyrimidinyl, pyrazinyl, triazinyl,
tetrazinyl, furanyl, thiophenyl, oxazolyl, thiazolyl, pyrazolyl, quinolinyl, isoquinolinyl, indolyl,
benzofuranyl, benzimidazolyl, or the like. In certain embodiments, Ar is phenyl, or pyridinyl optionally
substituted with amine or hydroxy. In certain embodiments, Ar is phenyl, or pyridinyl optionally
substituted with methyl, ethyl, propyl, or the like.
In another aspect, provided herein are compounds of Formula (II) having the structure:
Ar' R
Formula (II);
wherein:
R is L-Ar ;
a a b b b b
L is each independently CR R , O, S, NR , N-OR , C=O, C=S, C=N-R , or C=N-OR ;
2 b b b
R is H, OR , NR R , halogen, C -C alkyl, C -C heteroalkyl, C -C cycloalkyl, or C -C
1 6 1 6 3 6 2 6
heterocycloalkyl;
3 b b b b
R is optionally substituted alkyl, -(C=O)C -C alkyl, -(C=O)OR , -(C=O)NR R , -(C=O)SR ,
optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or
optionally substituted heteroaryl;
a b b b
R is each independently H, C -C alkyl, C -C heteroalkyl, halogen, OR , or NR R ;
1 6 1 6
R is each independently H, C -C alkyl, C -C heteroalkyl, C -C cycloalkyl, or C -C
1 6 2 6 3 6 2 6
heterocycloalkyl;
Ar’ is selected from furan, thiophene, oxazole, isoxazole, oxadiazole, thiazole, isothiazole,
thiadiazole, imidazole, triazole, pyrazole, thiodiazole, tetrazole, pyridine, pyrimidine, and pyrazine;
2 b b b
Ar is C -C aryl or heteroaryl optionally substituted with halogen, OR , NR R , C -C alkyl, C -C
12 1 6 1 6
heteroalkyl, C -C cycloalkyl or C -C heterocycloalkyl; or a pharmaceutically acceptable salt, solvate, N-
3 6 2 6
oxide, or prodrug thereof.
In one embodiment is a compound of Formula (II) wherein Ar’ is oxazole, isoxazole, or
oxadiazole. In another embodiment is a compound of Formula (II) wherein R is H. In yet another
embodiment is a compound of Formula (II) wherein R is H and R is optionally substituted cycloalkyl.
In a further embodiment is a compound of Formula (II) wherein R is O-Ph.
1 2 2
In some embodiments, R is O-Ar wherein Ar is C -C aryl or heteroaryl optionally
12
b b b
substituted with halogen, OR , NR R , C -C alkyl, C -C heteroalkyl, C -C cycloalkyl, or C -C
1 6 1 6 3 6 2 6
heterocycloalkyl; and R is each independently H, C -C alkyl, C -C heteroalkyl, C -C cycloalkyl, or C -
1 6 2 6 3 6 2
1 2 2
C heterocycloalkyl. In some embodiments, R is O-Ar wherein Ar is C -C aryl or heteroaryl
6 5 12
optionally substituted with halogen, hydroxy, amine, or C -C alkyl. In other embodiments, Ar is phenyl,
pyridinyl, pyridaznyl, pyrimidinyl, pyrazinyl, triazinyl, tetrazinyl, furanyl, thiophenyl, oxazolyl, thiazolyl,
pyrazolyl, quinolinyl, isoquinolinyl, indolyl, benzofuranyl, benzimidazolyl, or the like. In other
embodiments, Ar is phenyl, pyridinyl, furanyl, thiophenyl or quinolinyl. In certain embodiments, Ar is
phenyl or pyridinyl.
2 b b b
In some embodiments, R is H, OR , NR R , halogen, C -C alkyl, C -C heteroalkyl, C -C
1 6 1 6 3 6
cycloalkyl, or C -C heterocycloalkyl; wherein R is each independently H, C -C alkyl, C -C heteroalkyl,
2 6 1 6 2 6
C -C cycloalkyl, or C -C heterocycloalkyl. In some embodiments, R is H, OH, NH , halogen or C -C
3 6 2 6 2 1 6
alkyl. In other embodiments, R is F, Cl, Br or I. In other embodiments, R is methyl, ethyl, n-propyl, iso-
propyl, n-butyl, sec-butyl, iso-butyl, n-pentyl, or hexyl. In yet other embodiments, R is H, OH, or NH . In
other embodiments, R is H.
In some embodiments, R is optionally substituted alkyl, -(C=O)C -C alkyl, -(C=O)OR , -
b b b
(C=O)NR R , -(C=O)SR , optionally substituted cycloalkyl, optionally substituted heterocycloalkyl,
optionally substituted aryl, or optionally substituted heteroaryl. In other embodiments, R is methyl,
ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, and tert-butyl. In yet other embodiments, R is –C=O-Me, -
(C=O)Et, or -(C=O)Bu. In other embodiments, R is –COOH, -COOMe, -COOEt, -COOPr or –COOBu.
In yet other embodiments, R is –CONH , -CONHMe, -CONHEt or –CONHBu. In other embodiments,
R is –C=O-SMe, -(C=O)SEt or –C=O-SPr. In yet other embodiments, R is optionally substituted
cyclobutyl, cyclopentyl, cyclohexyl, or the like. In yet other embodiments, R is optionally substituted
azetidinyl, pyrrolidinyl, piperidinyl or the like. In yet other embodiments, R is optionally substituted
phenyl, pyridinyl, pyridaznyl, pyrimidinyl, pyrazinyl, triazinyl, tetrazinyl, furanyl, thiophenyl, oxazolyl,
thiazolyl, pyrazolyl, quinolinyl, isoquinolinyl, indolyl, benzofuranyl, benzimidazolyl, or the like.
In another embodiment is a compound of Formula (II) wherein R is optionally substituted
with at least one substituent selected from halogen, -CN, -NO , -OH, -OCF , -OCF H, -OCH F, -CF , -
2 3 2 2 3
8 9 9 10 9 10 10 9 9 10
SR , -S(=O)R , -S(=O) R , -NR S(=O) R , -S(=O) N(R ) , -OR , -C(=O)R , -OC(=O)R , -CO R ,
2 2 2 2 2
10 10 10 10 10 10 10
-N(R ) , -C(=O)N(R ) , -NR C(=O)R , -N R C(=O)OR , -NR C(=O)N(R ) , substituted or
2 2 2
unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl or
substituted or unsubstituted heterocycloalkyl; wherein R is H or substituted or unsubstituted alkyl; R is
substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; and each R
is independently H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted
or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted
heteroaryl, or two R together with the atoms to which they are attached form a heterocycle. In one
embodiment, R is substituted with halogen, -CN, -NO , -OH, -OCF , -OCF H, -OCH F, -CF , -SH. In
2 3 2 2 3
3 9 9
another embodiment is a compound of Formula (II) wherein R is substituted with -S(=O)R , -S(=O) R , -
9 10 9 10 10 9
NR S(=O) R , -S(=O) N(R ) , -C(=O)R , -CO R , -C(=O)N(R ) . In another embodiment, R is an
2 2 2 2 2
unsubstituted or substituted alkyl selected from methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl or
tert-butyl. In another embodiment, is a compound of Formula (II) wherein R is a substituted or
unsubstituted cycloalkyl. In a further embodiment, the cycloalkyl is selected from cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. In another embodiment R is a substituted or
unsubstituted heterocycloalkyl. In another embodiment, R is a substituted or unsustituted aryl. In a
further embodiment, the aryl is a phenyl group. In a further embodiment, the aryl is a naphthalene group.
In yet a further embodiment, R is a substituted or unsubstituted heteroaryl. In yet another embodiment
the heteroaryl is selected from pyrrole, furan, thiophene, pyrazole, imidazole, isoxazole, oxazole,
isothiazole, thiazole, 1,2,3-triazole, 1,3,4-triazole, 1-oxa-2,3-diazole, 1-oxa-2,4-diazole, 1-oxa-2,5-diazole,
1-oxa-3,4-diazole, 1-thia-2,3-diazole, 1-thia-2,4-diazole, 1-thia-2,5-diazole, 1-thia-3,4-diazole, tetrazole,
pyridine, pyridazine, pyrimidine, and pyrazine.
In some embodiments, Ar’ is selected from furan, thiophene, oxazole, isooxazole, oxadiazole,
thiazole, isothiazole, and thiadiazole. In other embodiments, Ar’ is oxazole, isooxazole or oxadiazole.
In one aspect, provided herein are compounds of Formula (III) having the structure:
Ar R
2a N
Formula (III);
wherein:
wherein:
R is L-Ar ;
a a b b b b
L is CR R , O, S, NR , N-OR , C=O, C=S, C=N-R , or C=N-OR ;
a b b b
R is each independently H, C -C alkyl, C -C heteroalkyl, halogen, OR , or NR R ;
1 6 1 6
R is each independently H, C -C alkyl, C -C heteroalkyl, C -C cycloalkyl, or C -C
1 6 2 6 3 6 2 6
heterocycloalkyl;
2a b b b
R is OR , NR R , halogen, C -C alkyl, C -C heteroalkyl, C -C cycloalkyl, or C -C
1 6 1 6 3 6 2 6
heterocycloalkyl;
3 b b b b
R is optionally substituted alkyl, -(C=O)C -C alkyl, -(C=O)OR , -(C=O)NR R , -(C=O)SR ,
optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or
optionally substituted heteroaryl;
Ar and Ar are each independently C -C aryl or heteroaryl optionally substituted with halogen, OR ,
12
NR R , C -C alkyl, C -C heteroalkyl, C -C cycloalkyl, or C -C heterocycloalkyl; or a pharmaceutically
1 6 1 6 3 6 2 6
acceptable salt, solvate, N-oxide, or prodrug thereof.
In one embodiment is a compound of Formula (III) wherein Ar is phenyl. In another
embodiment is a compound of Formula (III) wherein R is CH or OH. In yet another embodiment is a
compound of Formula (III) wherein R is optionally substituted cycloalkyl. In a further embodiment is a
compound of Formula (III) wherein R is O-Ph.
2a b b b
In some embodiments, R is OR , NR R , halogen, C -C alkyl, C -C heteroalkyl, C -C
1 6 1 6 3 6
cycloalkyl, or C -C heterocycloalkyl. In some embodiments, R is OH, NH , halogen, or C -C alkyl. In
2 6 2 1 6
2a 2a
other embodiments, R is OH, NH , F, Cl, Br or I. In yet other embodiments, R is methyl, ethyl, n-
propyl, iso-propyl, n-butyl, iso-butyl, and tert-butyl.
1 2 2
In some embodiments, R is O-Ar wherein Ar is C -C aryl or heteroaryl optionally
12
b b b
substituted with halogen, OR , NR R , C -C alkyl, C -C heteroalkyl, C -C cycloalkyl, or C -C
1 6 1 6 3 6 2 6
heterocycloalkyl; and R is each independently H, C -C alkyl, C -C heteroalkyl, C -C cycloalkyl, or C -
1 6 2 6 3 6 2
1 2 2
C heterocycloalkyl. In some embodiments, R is O-Ar wherein Ar is C -C aryl or heteroaryl
6 5 12
optionally substituted with halogen, hydroxy, amine, or C -C alkyl. In other embodiments, Ar is
phenyl, pyridinyl, pyridaznyl, pyrimidinyl, pyrazinyl, triazinyl, tetrazinyl, furanyl, thiophenyl, oxazolyl,
thiazolyl, pyrazolyl, quinolinyl, isoquinolinyl, indolyl, benzofuranyl, benzimidazolyl, or the like. In other
embodiments, Ar is phenyl, pyridinyl, furanyl, thiophenyl or quinolinyl. In certain embodiments, Ar is
phenyl or pyridinyl.
In some embodiments, R is optionally substituted alkyl, -(C=O)C -C alkyl, -(C=O)OR , -
b b b
(C=O)NR R , -(C=O)SR , optionally substituted cycloalkyl, optionally substituted heterocycloalkyl,
optionally substituted aryl, or optionally substituted heteroaryl. In other embodiments, R is methyl,
ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, and tert-butyl. In yet other embodiments, R is –C=O-Me, -
(C=O)Et, or -(C=O)Bu. In other embodiments, R is –COOH, -COOMe, -COOEt, -COOPr or –COOBu.
In yet other embodiments, R is –CONH , -CONHMe, -CONHEt or –CONHBu. In other embodiments,
R is –C=O-SMe, -(C=O)SEt or –C=O-SPr. In yet other embodiments, R is optionally substituted
cyclobutyl, cyclopentyl, cyclohexyl, or the like. In yet other embodiments, R is optionally substituted
azetidinyl, pyrrolidinyl, piperidinyl or the like. In yet other embodiments, R is optionally substituted
phenyl, pyridinyl, pyridaznyl, pyrimidinyl, pyrazinyl, triazinyl, tetrazinyl, furanyl, thiophenyl, oxazolyl,
thiazolyl, pyrazolyl, quinolinyl, isoquinolinyl, indolyl, benzofuranyl, benzimidazolyl, or the like.
In another embodiment is a compound of Formula (III) wherein R is optionally substituted
with at least one substituent selected from halogen, -CN, -NO , -OH, -OCF , -OCF H, -OCH F, -CF , -
2 3 2 2 3
8 9 9 10 9 10 10 9 9 10
SR , -S(=O)R , -S(=O) R , -NR S(=O) R , -S(=O) N(R ) , -OR , -C(=O)R , -OC(=O)R , -CO R ,
2 2 2 2 2
10 10 10 10 10 10 10
-N(R ) , -C(=O)N(R ) , -NR C(=O)R , -N R C(=O)OR , -NR C(=O)N(R ) , substituted or
2 2 2
unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl or
substituted or unsubstituted heterocycloalkyl; wherein R is H or substituted or unsubstituted alkyl; R is
substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; and each R
is independently H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted
or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted
heteroaryl, or two R together with the atoms to which they are attached form a heterocycle. In one
embodiment, R is substituted with halogen, -CN, -NO , -OH, -OCF , -OCF H, -OCH F, -CF , -SH. In
2 3 2 2 3
3 9 9
another embodiment is a compound of Formula (III) wherein R is substituted with -S(=O)R , -S(=O) R ,
9 10 9 10 10 9
-NR S(=O) R , -S(=O) N(R ) , -C(=O)R , -CO R , -C(=O)N(R ) . In another embodiment, R is an
2 2 2 2 2
unsubstituted or substituted alkyl selected from methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl or
tert-butyl. In another embodiment, is a compound of Formula (III) wherein R is a substituted or
unsubstituted cycloalkyl. In a further embodiment, the cycloalkyl is selected from cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. In another embodiment R is a substituted or
unsubstituted heterocycloalkyl. In another embodiment, R is a substituted or unsustituted aryl. In a
further embodiment, the aryl is a phenyl group. In a further embodiment, the aryl is a naphthalene group.
In yet a further embodiment, R is a substituted or unsubstituted heteroaryl. In yet another embodiment
the heteroaryl is selected from pyrrole, furan, thiophene, pyrazole, imidazole, isoxazole, oxazole,
isothiazole, thiazole, 1,2,3-triazole, 1,3,4-triazole, 1-oxa-2,3-diazole, 1-oxa-2,4-diazole, 1-oxa-2,5-diazole,
1-oxa-3,4-diazole, 1-thia-2,3-diazole, 1-thia-2,4-diazole, 1-thia-2,5-diazole, 1-thia-3,4-diazole, tetrazole,
pyridine, pyridazine, pyrimidine, and pyrazine.
In some embodiments, Ar is C -C aryl or heteroaryl optionally substituted with halogen,
12
b b b b
OR , NR R , C -C alkyl, C -C heteroalkyl, C -C cycloalkyl, or C -C heterocycloalkyl; and R is each
1 6 1 6 3 6 2 6
independently H, C -C alkyl, C -C heteroalkyl, C -C cycloalkyl, or C -C heterocycloalkyl. In some
1 6 2 6 3 6 2 6
embodiments, Ar is C -C aryl or heteroaryl optionally substituted with halogen, hydroxy, amine, or C -
12 1
C alkyl. In other embodiments, Ar is phenyl, pyridinyl, pyridaznyl, pyrimidinyl, pyrazinyl, triazinyl,
tetrazinyl, furanyl, thiophenyl, oxazolyl, thiazolyl, pyrazolyl, quinolinyl, isoquinolinyl, indolyl,
benzofuranyl, benzimidazolyl, or the like. In certain embodiments, Ar is phenyl, or pyridinyl optionally
substituted with amine or hydroxy. In certain embodiments, Ar is phenyl, or pyridinyl optionally
substituted with methyl, ethyl, propyl, or the like.
In one aspect, provided herein are compounds of Formula (IV) having the structure:
Ar R
Formula (IV);
wherein:
X is hydrogen, hydroxy, alkoxy, thiol, halogen or C -C alkyl;
R is L-Ar ;
a a b b b b
L is CR R , O, S, NR , N-OR , C=O, C=S, C=N-R , or C=N-OR ;
a b b b
R is each independently H, C -C alkyl, C -C heteroalkyl, halogen, OR , or NR R ;
1 6 1 6
R is each independently H, C -C alkyl, C -C heteroalkyl, C -C cycloalkyl, or C -C
1 6 2 6 3 6 2 6
heterocycloalkyl;
2 b b b
R is H, OR , NR R , halogen, C -C alkyl, C -C heteroalkyl, C -C cycloalkyl, or C -C
1 6 1 6 3 6 2 6
heterocycloalkyl;
3 b b b b
R is optionally substituted alkyl, -(C=O)C -C alkyl, -(C=O)OR , -(C=O)NR R , -(C=O)SR ,
optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or
optionally substituted heteroaryl;
Ar and Ar is each independently C -C aryl or heteroaryl optionally substituted with halogen, OR ,
12
NR R , C -C alkyl, C -C heteroalkyl, C -C cycloalkyl, or C -C heterocycloalkyl;
1 6 1 6 3 6 2 6
or a pharmaceutically acceptable salt, solvate, N-oxide, or prodrug thereof.
1 2 2
In some embodiments, R is O-Ar wherein Ar is C -C aryl or heteroaryl optionally
12
substituted with halogen, hydroxy, amine, or C -C alkyl. In other embodiments, Ar is phenyl, pyridinyl,
pyridaznyl, pyrimidinyl, pyrazinyl, triazinyl, tetrazinyl, furanyl, thiophenyl, oxazolyl, thiazolyl, pyrazolyl,
quinolinyl, isoquinolinyl, indolyl, benzofuranyl, benzimidazolyl, or the like. In other embodiments, Ar is
phenyl, pyridinyl, furanyl, thiophenyl or quinolinyl. In certain embodiments, Ar is phenyl or pyridinyl.
In some embodiments, R is optionally substituted alkyl, -(C=O)C -C alkyl, -(C=O)OR , -
b b b
(C=O)NR R , -(C=O)SR , optionally substituted cycloalkyl, optionally substituted heterocycloalkyl,
optionally substituted aryl, or optionally substituted heteroaryl. In other embodiments, R is methyl,
ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, and tert-butyl. In yet other embodiments, R is –C=O-Me, -
(C=O)Et, or -(C=O)Bu. In other embodiments, R is –COOH, -COOMe, -COOEt, -COOPr or –COOBu.
In yet other embodiments, R is –CONH , -CONHMe, -CONHEt or –CONHBu. In other embodiments,
R is –C=O-SMe, -(C=O)SEt or –C=O-SPr. In yet other embodiments, R is optionally substituted
cyclobutyl, cyclopentyl, cyclohexyl, or the like. In yet other embodiments, R is optionally substituted
azetidinyl, pyrrolidinyl, piperidinyl or the like. In yet other embodiments, R is optionally substituted
phenyl, pyridinyl, pyridaznyl, pyrimidinyl, pyrazinyl, triazinyl, tetrazinyl, furanyl, thiophenyl, oxazolyl,
thiazolyl, pyrazolyl, quinolinyl, isoquinolinyl, indolyl, benzofuranyl, benzimidazolyl, or the like.
In another embodiment is a compound of Formula (IV) wherein R is optionally substituted
with at least one substituent selected from halogen, -CN, -NO , -OH, -OCF , -OCF H, -OCH F, -CF , -
2 3 2 2 3
8 9 9 10 9 10 10 9 9 10
SR , -S(=O)R , -S(=O) R , -NR S(=O) R , -S(=O) N(R ) , -OR , -C(=O)R , -OC(=O)R , -CO R ,
2 2 2 2 2
10 10 10 10 10 10 10
-N(R ) , -C(=O)N(R ) , -NR C(=O)R , -N R C(=O)OR , -NR C(=O)N(R ) , substituted or
2 2 2
unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl or
substituted or unsubstituted heterocycloalkyl; wherein R is H or substituted or unsubstituted alkyl; R is
substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; and each R
is independently H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted
or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted
heteroaryl, or two R together with the atoms to which they are attached form a heterocycle. In one
embodiment, R is substituted with halogen, -CN, -NO , -OH, -OCF , -OCF H, -OCH F, -CF , -SH. In
2 3 2 2 3
3 9 9
another embodiment is a compound of Formula (IV) wherein R is substituted with -S(=O)R , -S(=O) R ,
9 10 9 10 10 9
-NR S(=O) R , -S(=O) N(R ) , -C(=O)R , -CO R , -C(=O)N(R ) . In another embodiment, R is an
2 2 2 2 2
unsubstituted or substituted alkyl selected from methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl or
tert-butyl. In another embodiment, is a compound of Formula (IV) wherein R is a substituted or
unsubstituted cycloalkyl. In a further embodiment, the cycloalkyl is selected from cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. In another embodiment R is a substituted or
unsubstituted heterocycloalkyl. In another embodiment, R is a substituted or unsustituted aryl. In a
further embodiment, the aryl is a phenyl group. In a further embodiment, the aryl is a naphthalene group.
In yet a further embodiment, R is a substituted or unsubstituted heteroaryl. In yet another embodiment
the heteroaryl is selected from pyrrole, furan, thiophene, pyrazole, imidazole, isoxazole, oxazole,
isothiazole, thiazole, 1,2,3-triazole, 1,3,4-triazole, 1-oxa-2,3-diazole, 1-oxa-2,4-diazole, 1-oxa-2,5-diazole,
1-oxa-3,4-diazole, 1-thia-2,3-diazole, 1-thia-2,4-diazole, 1-thia-2,5-diazole, 1-thia-3,4-diazole, tetrazole,
pyridine, pyridazine, pyrimidine, and pyrazine.
In one embodiment is a compound of Formula (IV) wherein Ar is phenyl. In another
embodiment is a compound of Formula (IV) wherein X is hydroxy or alkoxy. In yet another embodiment
is a compound of Formula (IV) wherein R is optionally substituted cycloalkyl. In a further embodiment
is a compound of Formula (IV) wherein R is O-Ph.
In some embodiments, X is hydroxy, methoxy, ethoxy or butoxy. In other embodiments, X is
F, Cl, Br or I. In yet other embodiments, X is methyl, ethyl, propyl, or the like.
In one aspect, provided herein are compounds of Formula (V) having the structure:
Formula (V);
wherein:
R is L-Ar ;
a a b b b b
L is CR R , O, S, NR , N-OR , C=O, C=S, C=N-R , or C=N-OR ;
a b b b
R is each independently H, C -C alkyl, C -C heteroalkyl, halogen, OR , or NR R ;
1 6 1 6
R is each independently H, C -C alkyl, C -C heteroalkyl, C -C cycloalkyl, or C -C
1 6 2 6 3 6 2 6
heterocycloalkyl;
2 b b b
R is H, OR , NR R , halogen, C -C alkyl, C -C heteroalkyl, C -C cycloalkyl or C -C
1 6 1 6 3 6 2 6
heterocycloalkyl;
N 5 N
R R n
R R N
R 6 6
O O R
R is selected from S , , , , R ,
and ;
R is hydrogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxycarbonyl,
substituted or unsubstituted alkoxyalkyl, substituted or unsubstituted hydroxyalkyl, substituted or
unsubstituted aminocarbonyl, substituted or unsubstituted alkylcarbonyl or substituted or unsubstituted
arylalkyl group;
b b b
R is H, optionally substituted C -C alkyl, -(C=O)C -C alkyl, -(C=O)OR , -(C=O)NR R , -
1 6 1 6
(C=O)SR , cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
R is optionally substituted C -C alkyl or NR ;
R is each independently hydrogen, optionally substituted C -C alkyl, optionally substituted
cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted
heteroaryl;
Ar is C -C aryl or heteroaryl optionally substituted with halogen, hydroxy, amine, or C -C alkyl;
12 1 6
n is an integer from 0 to 3;
m is an integer from 0 to 6;
Y is O, S or NR ;
or a pharmaceutically acceptable salt, solvate, N-oxide, or prodrug thereof.
In one embodiment is a compound of Formula (V) wherein R is . In
N N HN N
another embodiment is a compound of Formula (V) wherein R is O , O ,
HN NH N N HN N HN NH
HN NH
O , S , S , S , or NH . In yet another
embodiment is a compound of Formula (V) wherein R is H or CH . In a further embodiment is a
compound of Formula (V) wherein R is O-Ph.
In one aspect, provided herein are compounds of Formula (VI) having the structure:
n R R
Formula (VI);
wherein:
a a b b b b
L is CR R , O, S, NR , N-OR , C=O, C=S, C=N-R or C=N-OR ;
W is a bond or optionally substituted C -C alkyl;
Z is C=O, SO or SO;
1 2 1 2
R and R are each independently H or C -C alkyl, wherein R and R have a cis or trans relationship;
or R and R join together to form a bond;
n and p are each independently an integer from 0 to 3;
m is an integer from 1 to 3;
R is H, substituted or unsubstituted C -C alkyl, substituted or unsubstituted C -C cycloalkyl,
1 3 3 6
substituted or unsubstituted C -C heteroalkyl, substituted or unsubstituted C -C heterocycloalkyl,
1 6 2 6
substituted or unsubstituted C -C aryl, or substituted or unsubstituted C -C heteroaryl;
6 12 5 11
R is substituted or unsubstituted C -C cycloalkyl, substituted or unsubstituted C -C
3 6 2 6
heterocycloalkyl, substituted or unsubstituted C -C aryl, or substituted or unsubstituted C -C
6 12 5 11
heteroaryl;
b b b
R is H, OH, OR , NR R , halogen, C -C alkyl, C -C heteroalkyl, C -C cycloalkyl, or C -C
1 6 1 6 3 6 2 6
heterocycloalkyl;
a b b b
R is each independently H, C -C alkyl, C -C heteroalkyl, halogen, OR , or NR R ;
1 6 1 6
R is each independently H, C -C alkyl, C -C heteroalkyl, C -C cycloalkyl, or C -C
1 6 2 6 3 6 2 6
heterocycloalkyl;
or a pharmaceutically acceptable salt, solvate, N-oxide, or prodrug thereof.
In one embodiment is a compound of Formula (VI) wherein L is CH or C=O. In another
embodiment is a compound of Formula (VI) wherein L is O. In another embodiment is a compound of
Formula (VI) wherein W is a bond. In another embodiment is a compound of Formula (VI) wherein W is
optionally substituted C -C alkyl. In another embodiment is a compound of Formula (VI) wherein R is
H. In another embodiment is a compound of Formula (VI) wherein R is H. In yet another embodiment is
a compound of Formula (VI) wherein R is H and R is H. In another embodiment is a compound of
Formula (VI) wherein R and R have a trans relationship. In another embodiment is a compound of
Formula (VI) wherein R and R have a cis relationship. In another embodiment is a compound of
Formula (VI) wherein m is 2. In another embodiment is a compound of Formula (VI) wherein n is 1. In
another embodiment is a compound of Formula (VI) wherein n is 2. In another embodiment is a
compound of Formula (VI) wherein n is 2 and m is 1. In another embodiment is a compound of Formula
(VI) wherein n is 3 and m is 1. In another embodiment is a compound of Formula (VI) wherein n is 2 and
m is 2. In another embodiment is a compound of Formula (VI) wherein p is 1. In another embodiment is a
compound of Formula (VI) wherein R is H. In another embodiment is a compound of Formula (VI)
wherein R is CH . In a further embodiment is a compound of Formula (VI) wherein R is not substituted
or unsubstituted C -C alkyl. In another embodiment is a compound of Formula (VI) wherein R is H,
methyl, ethyl, or isopropyl. In another embodiment is a compound of Formula (VI) wherein R is
substituted or unsubstituted C -C cycloalkyl. In a further embodiment is a compound of Formula (VI)
wherein R is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. In another embodiment is a compound
of Formula (VI) wherein R is substituted or unsubstituted C -C heterocycloalkyl. In a further
embodiment is a compound of Formula (VI) wherein R is tetrahydropyran, tetrahydrofuran, oxetane, or
. In another embodiment is a compound of Formula (VI) wherein R is substituted or
unsubstituted C -C heteroaryl. In a further embodiment is a compound of Formula (VI) wherein R is
11
pyridyl.
In another embodiment is a compound of Formula (VI) wherein L is O, W is a bond, R is H,
2 3 4
R is H, p is 1, Z is C=O, R is H, and R is substituted or unsubstituted C -C cycloalkyl. In another
embodiment is a compound of Formula (VI) wherein L is O, W is a bond, R is H, R is H, p is 1, Z is
C=O, R is H, and R is substituted or unsubstituted C -C heterocycloalkyl. In another embodiment is a
1 2 3
compound of Formula (VI) wherein L is O, W is a bond, R is H, R is H, p is 1, Z is C=O, R is methyl,
and R is substituted or unsubstituted C -C cycloalkyl. In another embodiment is a compound of Formula
1 2 3 4
(VI) wherein L is O, W is a bond, R is H, R is H, p is 1, Z is C=O, R is methyl, and R is substituted or
unsubstituted C -C heterocycloalkyl. In another embodiment is a compound of Formula (VI) wherein L is
1 2 3 4
O, W is a bond, R is H, R is H, p is 1, Z is C=O, R is ethyl, and R is substituted or unsubstituted C -C
cycloalkyl. In another embodiment is a compound of Formula (VI) wherein L is O, W is a bond, R is H,
2 3 4
R is H, p is 1, Z is C=O, R is ethyl, and R is substituted or unsubstituted C -C heterocycloalkyl. In
another embodiment is a compound of Formula (VI) wherein L is O, W is a bond, R is H, R is H, p is 1,
Z is C=O, R is H, and R is substituted or unsubstituted C -C aryl. In another embodiment is a
6 12
1 2 3 4
compound of Formula (VI) wherein L is O, W is a bond, R is H, R is H, p is 1, Z is C=O, R is H, and R
is substituted or unsubstituted C -C heteroaryl. In another embodiment is a compound of Formula (VI)
11
1 2 3 4
wherein L is O, W is a bond, R is H, R is H, p is 1, Z is C=O, R is methyl, and R is substituted or
unsubstituted C -C aryl. In another embodiment is a compound of Formula (VI) wherein L is O, W is a
6 12
1 2 3 4
bond, R is H, R is H, p is 1, Z is C=O, R is methyl, and R is substituted or unsubstituted C -C
11
heteroaryl.
In one aspect, provided herein are compounds of Formula (VIA) having the structure:
n R R
Formula (VIA);
wherein:
a a b b b b
L is CR R , O, S, NR , N-OR , C=O, C=S, C=N-R or C=N-OR ;
W is a bond or optionally substituted C -C alkyl;
Z is C=O, SO or SO;
1 2 1 2
R and R are each independently H or C -C alkyl, wherein R and R have a cis or trans
relationship; or R and R join together to form a bond;
n and p are each independently an integer from 0 to 3;
m is an integer from 1 to 3;
R is H, substituted or unsubstituted C -C cycloalkyl, substituted or unsubstituted C -C
3 6 1 6
heteroalkyl, substituted or unsubstituted C -C heterocycloalkyl, substituted or unsubstituted C -C aryl,
2 6 6 12
or substituted or unsubstituted C -C heteroaryl;
11
R is substituted or unsubstituted C -C cycloalkyl, substituted or unsubstituted C -C
3 6 2 6
heterocycloalkyl, substituted or unsubstituted C -C aryl, or substituted or unsubstituted C -C
6 12 5 11
heteroaryl;
b b b
R is H, OH, OR , NR R , halogen, C -C alkyl, C -C heteroalkyl, C -C cycloalkyl or C -C
1 6 1 6 3 6 2 6
heterocycloalkyl;
a b b b
R is each independently H, C -C alkyl, C -C heteroalkyl, halogen, OR , or NR R ;
1 6 1 6
R is each independently H, C -C alkyl, C -C heteroalkyl, C -C cycloalkyl or C -C
1 6 2 6 3 6 2 6
heterocycloalkyl;
or a pharmaceutically acceptable salt, solvate, N-oxide, or prodrug thereof.
In one embodiment is a compound of Formula (VIA) wherein L is CH or C=O. In another
embodiment is a compound of Formula (VIA) wherein L is O. In another embodiment is a compound of
Formula (VIA) wherein W is a bond. In another embodiment is a compound of Formula (VIA) wherein
W is optionally substituted C -C alkyl. In another embodiment is a compound of Formula (VIA) wherein
R is H. In another embodiment is a compound of Formula (VIA) wherein R is H. In yet another
embodiment is a compound of Formula (VIA) wherein R is H and R is H. In another embodiment is a
compound of Formula (VIA) wherein R and R have a trans relationship. In another embodiment is a
compound of Formula (VIA) wherein R and R have a cis relationship. In another embodiment is a
compound of Formula (VIA) wherein m is 2. In another embodiment is a compound of Formula (VIA)
wherein n is 1. In another embodiment is a compound of Formula (VIA) wherein n is 2. In another
embodiment is a compound of Formula (VIA) wherein n is 2 and m is 1. In another embodiment is a
compound of Formula (VIA) wherein n is 3 and m is 1. In another embodiment is a compound of Formula
(VIA) wherein n is 2 and m is 2. In another embodiment is a compound of Formula (VIA) wherein p is 1.
In another embodiment is a compound of Formula (VIA) wherein R is H. In another embodiment is a
compound of Formula (VIA) wherein R and R are each independently substituted or unsubstituted C -C
cycloalkyl.
In another embodiment is a compound of Formula (VIA) wherein L is O, W is a bond, R is
2 3 4
H, R is H, p is 1, Z is C=O, R is H and R is substituted or unsubstituted C -C cycloalkyl. In another
embodiment is a compound of Formula (VIA) wherein L is O, W is a bond, R is H, R is H, p is 1, Z is
C=O, R is H and R is substituted or unsubstituted C -C heterocycloalkyl. In another embodiment is a
1 2 3
compound of Formula (VIA) wherein L is O, W is a bond, R is H, R is H, p is 1, Z is C=O, R is H and
R is substituted or unsubstituted C -C aryl. In another embodiment is a compound of Formula (VIA)
6 12
1 2 3 4
wherein L is O, W is a bond, R is H, R is H, p is 1, Z is C=O, R is H and R is substituted or
unsubstituted C -C heteroaryl.
11
In another embodiment is a compound of Formula (VIA) wherein L is O, W is a bond, R is
2 3 4
H, R is H, p is 1, Z is C=O, R is substituted or unsubstituted C -C cycloalkyl and R is substituted or
unsubstituted C -C cycloalkyl. In another embodiment is a compound of Formula (VIA) wherein L is O,
1 2 3 4
W is a bond, R is H, R is H, p is 1, Z is C=O, R is substituted or unsubstituted C -C cycloalkyl and R
is substituted or unsubstituted C -C heterocycloalkyl. In another embodiment is a compound of Formula
1 2 3
(VIA) wherein L is O, W is a bond, R is H, R is H, p is 1, Z is C=O, R is substituted or unsubstituted
C -C cycloalkyl and R is substituted or unsubstituted C -C aryl. In another embodiment is a compound
3 6 6 12
1 2 3
of Formula (VIA) wherein L is O, W is a bond, R is H, R is H, p is 1, Z is C=O, R is substituted or
unsubstituted C -C cycloalkyl and R is substituted or unsubstituted C -C heteroaryl.
3 6 5 11
In one aspect, provided herein are compounds of Formula (VIB) having the structure:
Formula (VIB);
wherein:
Z is selected from or R ;
R is C -C cycloalkyl, pyridine, tetrahydrofuran, tetrahydropyran, or ;
R is H or CH ;
or a pharmaceutically acceptable salt, solvate, N-oxide, or prodrug thereof.
In some embodiments is a compound of Formula (VIB) wherein Z is
R N R
or . In one embodiment is a compound of Formula
(VIB) wherein R is C -C cycloalkyl and R is H. In another embodiment is a compound of Formula
(VIB) wherein R is C -C cycloalkyl and R is CH . In another embodiment is a compound of Formula
3 6 3
(VIB) wherein R is pyridine and R is H. In another embodiment is a compound of Formula (VIB)
wherein R is pyridine and R is CH . In another embodiment is a compound of Formula (VIB) wherein
R is tetrahydrofuran, tetrahydropyran or ; and R is H. In yet another embodiment is a
compound of Formula (VIB) wherein R is tetrahydrofuran, tetrahydropyran or ; and R is
CH . In another embodiment is a compound of Formula (VIB) wherein R is tetrahydrofuran or
tetrahydropyran; and R is H. In a further embodiment is a compound of Formula (VIB) wherein R is
tetrahydrofuran or tetrahydropyran; and R is CH .
In certain aspect, provided here are compounds of Formula (IA) having the structure:
L Ar R
Formula (IA);
wherein:
a a b b b b
L is each independently CR R , O, S, NR , N-OR , C=O, C=S, C=N-R , or C=N-OR ;
a b b b
R is each independently H, C -C alkyl, C -C heteroalkyl, halogen, OR , or NR R ;
1 6 1 6
R is each independently H, C -C alkyl, C -C heteroalkyl, C -C cycloalkyl, or C -C
1 6 2 6 3 6 2 6
heterocycloalkyl;
1 2 b b b
R is L-Ar , OR , or NR R ;
2 b b b
R is H, OR , NR R , halogen, C -C alkyl, C -C heteroalkyl, C -C cycloalkyl, or C -C
1 6 1 6 3 6 2 6
heterocycloalkyl;
3 b b b b
R is optionally substituted alkyl, -(C=O)C -C alkyl, -(C=O)OR , -(C=O)NR R , -(C=O)SR ,
optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or
optionally substituted heteroaryl;
Ar and Ar are each independently C -C aryl or heteroaryl optionally substituted with halogen, OR ,
12
NR R , C -C alkyl, C -C heteroalkyl, C -C cycloalkyl, or C -C heterocycloalkyl;
1 6 1 6 3 6 2 6
X is hydrogen, hydroxy, alkoxy, thiol, halogen or C -C alkyl;
or a pharmaceutically acceptable salt, solvate, N-oxide, or prodrug thereof.
In one aspect, provided herein are compounds of Formula (VII) having the structure:
Formula (VII);
wherein:
a a b b b b
L is CR R , O, S, NR , N-OR , C=O, C=S, C=N-R or C=N-OR ;
W is a bond or optionally substituted C -C alkyl;
Z is NR C=O, SO or SO;
1 2 1 2
R and R are each independently H or C -C alkyl, wherein R and R have a cis or trans relationship;
or R and R join together to form a bond;
p is an integer from 0 to 3;
R is H, substituted or unsubstituted C -C alkyl, substituted or unsubstituted C -C cycloalkyl,
1 3 3 6
substituted or unsubstituted C -C heteroalkyl, substituted or unsubstituted C -C heterocycloalkyl,
1 6 2 6
substituted or unsubstituted C -C aryl, or substituted or unsubstituted C -C heteroaryl;
6 12 5 11
R is substituted or unsubstituted C -C cycloalkyl, substituted or unsubstituted C -C
3 6 2 6
heterocycloalkyl, substituted or unsubstituted C -C aryl, or substituted or unsubstituted C -C
6 12 5 11
heteroaryl;
b b b
R is H, OH, OR , NR R , halogen, C -C alkyl, C -C heteroalkyl, C -C cycloalkyl or C -C
1 6 1 6 3 6 2 6
heterocycloalkyl;
a b b b
R is each independently H, C -C alkyl, C -C heteroalkyl, halogen, OR , or NR R ;
1 6 1 6
R is each independently H, C -C alkyl, C -C heteroalkyl, C -C cycloalkyl or C -C
1 6 2 6 3 6 2 6
heterocycloalkyl;
R is H or C -C alkyl;
or a pharmaceutically acceptable salt, solvate, N-oxide, or prodrug thereof.
In one embodiment is a compound of Formula (VII) wherein L is CH or C=O. In another
embodiment is a compound of Formula (VII) wherein L is O. In another embodiment is a compound of
Formula (VII) wherein W is a bond. In another embodiment is a compound of Formula (VII) wherein W
is optionally substituted C -C alkyl. In another embodiment is a compound of Formula (VII) wherein R
is H. In another embodiment is a compound of Formula (VII) wherein R is H. In yet another
embodiment is a compound of Formula (VII) wherein R is H and R is H. In another embodiment is a
compound of Formula (VII) wherein R and R have a trans relationship. In another embodiment is a
compound of Formula (VII) wherein R and R have a cis relationship. In another embodiment is a
compound of Formula (VII) wherein p is 1. In a further embodiment is a compound of Formula (VII)
wherein R is not substituted or unsubstituted C -C alkyl. In another embodiment is a compound of
Formula (VII) wherein R is H, methyl, ethyl, or isopropyl. In another embodiment is a compound of
Formula (VII) wherein R is H. In another embodiment is a compound of Formula (VII) wherein R is
CH . In another embodiment is a compound of Formula (VII) wherein R is substituted or unsubstituted
C -C cycloalkyl. In a further embodiment is a compound of Formula (VII) wherein R is cyclopropyl,
cyclobutyl, cyclopentyl or cyclohexyl. In another embodiment is a compound of Formula (VII) wherein
R is substituted or unsubstituted C -C heterocycloalkyl. In a further embodiment is a compound of
Formula (VII) wherein R is tetrahydropyran, tetrahydrofuran, oxetane, or . In another
embodiment is a compound of Formula (VII) wherein R is substituted or unsubstituted C -C heteroaryl.
11
In a further embodiment is a compound of Formula (VII) wherein R is pyridyl.
In another embodiment is a compound of Formula (VII) wherein L is O, W is a bond, R is H,
2 3 4
R is H, p is 1, Z is C=O, R is H, and R is substituted or unsubstituted C -C cycloalkyl. In another
embodiment is a compound of Formula (VII) wherein L is O, W is a bond, R is H, R is H, p is 1, Z is
C=O, R is methyl, and R is substituted or unsubstituted C -C cycloalkyl. In another embodiment is a
1 2 3
compound of Formula (VII) wherein L is O, W is a bond, R is H, R is H, p is 1, Z is C=O, R is ethyl,
and R is substituted or unsubstituted C -C cycloalkyl. In another embodiment is a compound of Formula
1 2 3 4
(VII) wherein L is O, W is a bond, R is H, R is H, p is 1, Z is C=O, R is H, and R is substituted or
unsubstituted C -C heterocycloalkyl. In another embodiment is a compound of Formula (VII) wherein L
1 2 3 4
is O, W is a bond, R is H, R is H, p is 1, Z is C=O, R is methyl, and R is substituted or unsubstituted
C -C heterocycloalkyl. In another embodiment is a compound of Formula (VII) wherein L is O, W is a
1 2 3 4
bond, R is H, R is H, p is 1, Z is C=O, R is ethyl, and R is substituted or unsubstituted C -C
heterocycloalkyl. In another embodiment is a compound of Formula (VII) wherein L is O, W is a bond, R
2 3 4
is H, R is H, p is 1, Z is C=O, R is H, and R is substituted or unsubstituted C -C aryl. In another
6 12
embodiment is a compound of Formula (VII) wherein L is O, W is a bond, R is H, R is H, p is 1, Z is
C=O, R is methyl, and R is substituted or unsubstituted C -C aryl. In another embodiment is a
6 12
1 2 3
compound of Formula (VII) wherein L is O, W is a bond, R is H, R is H, p is 1, Z is C=O, R is ethyl,
and R is substituted or unsubstituted C -C aryl. In another embodiment is a compound of Formula (VII)
6 12
1 2 3 4
wherein L is O, W is a bond, R is H, R is H, p is 1, Z is C=O, R is H, and R is substituted or
unsubstituted C -C heteroaryl. In another embodiment is a compound of Formula (VII) wherein L is O,
11
1 2 3 4
W is a bond, R is H, R is H, p is 1, Z is C=O, R is methyl, and R is substituted or unsubstituted C -C
11
heteroaryl. In another embodiment is a compound of Formula (VII) wherein L is O, W is a bond, R is H,
2 3 4
R is H, p is 1, Z is C=O, R is ethyl, and R is substituted or unsubstituted C -C heteroaryl.
11
In one aspect, provided herein are compounds of Formula (VIII) having the structure:
Formula (VIII);
wherein:
a a b b b b
L is CR R , O, S, NR , N-OR , C=O, C=S, C=N-R or C=N-OR ;
W is a bond or optionally substituted C -C alkyl;
Z is NR C=O, SO or SO;
1 2 1 2
R and R are each independently H or C -C alkyl, wherein R and R have a cis or trans relationship;
or R and R join together to form a bond;
p is an integer from 0 to 3;
R is H, substituted or unsubstituted C -C alkyl, substituted or unsubstituted C -C cycloalkyl,
1 3 3 6
substituted or unsubstituted C -C heteroalkyl, substituted or unsubstituted C -C heterocycloalkyl,
1 6 2 6
substituted or unsubstituted C -C aryl, or substituted or unsubstituted C -C heteroaryl;
6 12 5 11
R is substituted or unsubstituted C -C cycloalkyl, substituted or unsubstituted C -C
3 6 2 6
heterocycloalkyl, substituted or unsubstituted C -C aryl, or substituted or unsubstituted C -C
6 12 5 11
heteroaryl;
b b b
R is H, OH, OR , NR R , halogen, C -C alkyl, C -C heteroalkyl, C -C cycloalkyl or C -C
1 6 1 6 3 6 2 6
heterocycloalkyl;
a b b b
R is each independently H, C -C alkyl, C -C heteroalkyl, halogen, OR , or NR R ;
1 6 1 6
R is each independently H, C -C alkyl, C -C heteroalkyl, C -C cycloalkyl or C -C
1 6 2 6 3 6 2 6
heterocycloalkyl;
R is H or C -C alkyl;
or a pharmaceutically acceptable salt, solvate, N-oxide, or prodrug thereof.
In one embodiment is a compound of Formula (VIII) wherein L is CH or C=O. In another
embodiment is a compound of Formula (VIII) wherein L is O. In another embodiment is a compound of
Formula (VIII) wherein W is a bond. In another embodiment is a compound of Formula (VIII) wherein
W is optionally substituted C -C alkyl. In another embodiment is a compound of Formula (VIII) wherein
R is H. In another embodiment is a compound of Formula (VIII) wherein R is H. In yet another
embodiment is a compound of Formula (VIII) wherein R is H and R is H. In another embodiment is a
compound of Formula (VIII) wherein R and R have a trans relationship. In another embodiment is a
compound of Formula (VIII) wherein R and R have a cis relationship. In another embodiment is a
compound of Formula (VIII) wherein p is 1. In a further embodiment is a compound of Formula (VIII)
wherein R is not substituted or unsubstituted C -C alkyl. In another embodiment is a compound of
Formula (VIII) wherein R is H, methyl, ethyl, or isopropyl. In another embodiment is a compound of
Formula (VIII) wherein R is H. In another embodiment is a compound of Formula (VIII) wherein R is
CH . In another embodiment is a compound of Formula (VIII) wherein R is substituted or unsubstituted
C -C cycloalkyl. In a further embodiment is a compound of Formula (VIII) wherein R is cyclopropyl,
cyclobutyl, cyclopentyl or cyclohexyl. In another embodiment is a compound of Formula (VIII) wherein
R is substituted or unsubstituted C -C heterocycloalkyl. In a further embodiment is a compound of
Formula (VIII) wherein R is tetrahydropyran, tetrahydrofuran, oxetane, or . In another
embodiment is a compound of Formula (VIII) wherein R is substituted or unsubstituted C -C
11
heteroaryl. In a further embodiment is a compound of Formula (VIII) wherein R is pyridyl.
In another embodiment is a compound of Formula (VIII) wherein L is O, W is a bond, R is
2 3 4
H, R is H, p is 1, Z is C=O, R is H, and R is substituted or unsubstituted C -C cycloalkyl. In another
embodiment is a compound of Formula (VIII) wherein L is O, W is a bond, R is H, R is H, p is 1, Z is
C=O, R is methyl, and R is substituted or unsubstituted C -C cycloalkyl. In another embodiment is a
1 2 3
compound of Formula (VIII) wherein L is O, W is a bond, R is H, R is H, p is 1, Z is C=O, R is ethyl,
and R is substituted or unsubstituted C -C cycloalkyl. In another embodiment is a compound of Formula
1 2 3 4
(VIII) wherein L is O, W is a bond, R is H, R is H, p is 1, Z is C=O, R is H, and R is substituted or
unsubstituted C -C heterocycloalkyl. In another embodiment is a compound of Formula (VIII) wherein L
1 2 3 4
is O, W is a bond, R is H, R is H, p is 1, Z is C=O, R is methyl, and R is substituted or unsubstituted
C -C heterocycloalkyl. In another embodiment is a compound of Formula (VIII) wherein L is O, W is a
1 2 3 4
bond, R is H, R is H, p is 1, Z is C=O, R is ethyl, and R is substituted or unsubstituted C -C
heterocycloalkyl. In another embodiment is a compound of Formula (VIII) wherein L is O, W is a bond,
1 2 3 4
R is H, R is H, p is 1, Z is C=O, R is H, and R is substituted or unsubstituted C -C aryl. In another
6 12
embodiment is a compound of Formula (VIII) wherein L is O, W is a bond, R is H, R is H, p is 1, Z is
C=O, R is methyl, and R is substituted or unsubstituted C -C aryl. In another embodiment is a
6 12
1 2 3
compound of Formula (VIII) wherein L is O, W is a bond, R is H, R is H, p is 1, Z is C=O, R is ethyl,
and R is substituted or unsubstituted C -C aryl. In another embodiment is a compound of Formula
6 12
1 2 3 4
(VIII) wherein L is O, W is a bond, R is H, R is H, p is 1, Z is C=O, R is H, and R is substituted or
unsubstituted C -C heteroaryl. In another embodiment is a compound of Formula (VIII) wherein L is O,
11
1 2 3 4
W is a bond, R is H, R is H, p is 1, Z is C=O, R is methyl, and R is substituted or unsubstituted C -C
11
heteroaryl. In another embodiment is a compound of Formula (VIII) wherein L is O, W is a bond, R is H,
2 3 4
R is H, p is 1, Z is C=O, R is ethyl, and R is substituted or unsubstituted C -C heteroaryl.
11
In one aspect, provided herein are compounds of Formula (IX) having the structure:
NH 1
L Ar R
Formula (IX);
wherein:
a a b b b b
L is each independently CR R , O, S, NR , N-OR , C=O, C=S, C=N-R , or C=N-OR ;
a b b b
R is each independently H, C -C alkyl, C -C heteroalkyl, halogen, OR , or NR R ;
1 6 1 6
R is each independently H, C -C alkyl, C -C heteroalkyl, C -C cycloalkyl, or C -C
1 6 2 6 3 6 2 6
heterocycloalkyl;
1 2 b b b
R is L-Ar , OR , or NR R ;
2 b b b
R is H, OR , NR R , halogen, C -C alkyl, C -C heteroalkyl, C -C cycloalkyl, or C -C
1 6 1 6 3 6 2 6
heterocycloalkyl;
3 b b b b
R is optionally substituted alkyl, -(C=O)C -C alkyl, -(C=O)OR , -(C=O)NR R , -(C=O)SR ,
optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or
optionally substituted heteroaryl;
Ar and Ar are each independently C -C aryl or C -C heteroaryl optionally substituted with
12 5 11
b b b
halogen, OR , NR R , C -C alkyl, C -C heteroalkyl, C -C cycloalkyl, or C -C heterocycloalkyl;
1 6 1 6 3 6 2 6
or a pharmaceutically acceptable salt, solvate, N-oxide, or prodrug thereof.
In one embodiment is a compound of Formula (IX) wherein L is CH or C=O. In another
embodiment is a compound of Formula (IX) wherein Ar is phenyl. In yet another embodiment is a
compound of Formula (IX) wherein R is H and R is optionally substituted cycloalkyl. In a further
embodiment is a compound of Formula (IX) wherein R is O-Ph.
For any and all of the embodiments, substituents are selected from among from a subset of the
2 b b b
listed alternatives. For example, in some embodiments, R is H, OR , NR R , halogen, C -C alkyl, C -C
1 6 1 6
heteroalkyl, C -C cycloalkyl, or C -C heterocycloalkyl; wherein R is each independently H, C -C alkyl,
3 6 2 6 1 6
C -C heteroalkyl, C -C cycloalkyl, or C -C heterocycloalkyl. In some embodiments, R is H, OH, NH ,
2 6 3 6 2 6 2
halogen or C -C alkyl. In some embodiments, R is F, Cl, Br or I. In other embodiments, R is methyl,
ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, n-pentyl, or hexyl. In yet other embodiments, R
is H, OH, or NH . In other embodiments, R is H.
1 2 2
In some embodiments, R is O-Ar wherein Ar is C -C aryl or heteroaryl optionally
12
b b b
substituted with halogen, OR , NR R , C -C alkyl, C -C heteroalkyl, C -C cycloalkyl, or C -C
1 6 1 6 3 6 2 6
heterocycloalkyl; and R is each independently H, C -C alkyl, C -C heteroalkyl, C -C cycloalkyl, or C -
1 6 2 6 3 6 2
1 2 2
C heterocycloalkyl. In some embodiments, R is O-Ar wherein Ar is C -C aryl or heteroaryl
6 5 12
optionally substituted with halogen, hydroxy, amine, or C -C alkyl. In other embodiments, Ar is phenyl,
pyridinyl, pyridaznyl, pyrimidinyl, pyrazinyl, triazinyl, tetrazinyl, furanyl, thiophenyl, oxazolyl, thiazolyl,
pyrazolyl, quinolinyl, isoquinolinyl, indolyl, benzofuranyl, benzimidazolyl, or the like. In other
embodiments, Ar is phenyl, pyridinyl, furanyl, thiophenyl or quinolinyl. In certain embodiments, Ar is
phenyl or pyridinyl.
In some embodiments, R is optionally substituted alkyl, -(C=O)C -C alkyl, -(C=O)OR , -
b b b
(C=O)NR R , -(C=O)SR , optionally substituted cycloalkyl, optionally substituted heterocycloalkyl,
optionally substituted aryl, or optionally substituted heteroaryl. In other embodiments, R is methyl,
ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, and tert-butyl. In yet other embodiments, R is –C=O-Me, -
(C=O)Et, or -(C=O)Bu. In other embodiments, R is –COOH, -COOMe, -COOEt, -COOPr or –COOBu.
In yet other embodiments, R is –CONH , -CONHMe, -CONHEt or –CONHBu. In other embodiments,
R is –C=O-SMe, -(C=O)SEt or –C=O-SPr. In yet other embodiments, R is optionally substituted
cyclobutyl, cyclopentyl, cyclohexyl, or the like. In yet other embodiments, R is optionally substituted
azetidinyl, pyrrolidinyl, piperidinyl or the like. In yet other embodiments, R is optionally substituted
phenyl, pyridinyl, pyridaznyl, pyrimidinyl, pyrazinyl, triazinyl, tetrazinyl, furanyl, thiophenyl, oxazolyl,
thiazolyl, pyrazolyl, quinolinyl, isoquinolinyl, indolyl, benzofuranyl, benzimidazolyl, or the like.
In another embodiment is a compound of Formula (IX) wherein R is optionally substituted
with at least one substituent selected from halogen, -CN, -NO , -OH, -OCF , -OCF H, -OCH F, -CF , -
2 3 2 2 3
8 9 9 10 9 10 10 9 9 10
SR , -S(=O)R , -S(=O) R , -NR S(=O) R , -S(=O) N(R ) , -OR , -C(=O)R , -OC(=O)R , -CO R ,
2 2 2 2 2
10 10 10 10 10 10 10
-N(R ) , -C(=O)N(R ) , -NR C(=O)R , -N R C(=O)OR , -NR C(=O)N(R ) , substituted or
2 2 2
unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl or
substituted or unsubstituted heterocycloalkyl; wherein R is H or substituted or unsubstituted alkyl; R is
substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; and each R
is independently H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted
or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted
heteroaryl, or two R together with the atoms to which they are attached form a heterocycle. In one
embodiment, R is substituted with halogen, -CN, -NO , -OH, -OCF , -OCF H, -OCH F, -CF , -SH. In
2 3 2 2 3
3 9 9
another embodiment is a compound of Formula (IX) wherein R is substituted with -S(=O)R , -S(=O) R ,
9 10 9 10 10 9
-NR S(=O) R , -S(=O) N(R ) , -C(=O)R , -CO R , -C(=O)N(R ) . In another embodiment, R is an
2 2 2 2 2
unsubstituted or substituted alkyl selected from methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl or
tert-butyl. In another embodiment, is a compound of Formula (IX) wherein R is a substituted or
unsubstituted cycloalkyl. In a further embodiment, the cycloalkyl is selected from cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. In another embodiment R is a substituted or
unsubstituted heterocycloalkyl. In another embodiment, R is a substituted or unsustituted aryl. In a
further embodiment, the aryl is a phenyl group. In a further embodiment, the aryl is a naphthalene group.
In yet a further embodiment, R is a substituted or unsubstituted heteroaryl. In yet another embodiment
the heteroaryl is selected from pyrrole, furan, thiophene, pyrazole, imidazole, isoxazole, oxazole,
isothiazole, thiazole, 1,2,3-triazole, 1,3,4-triazole, 1-oxa-2,3-diazole, 1-oxa-2,4-diazole, 1-oxa-2,5-diazole,
1-oxa-3,4-diazole, 1-thia-2,3-diazole, 1-thia-2,4-diazole, 1-thia-2,5-diazole, 1-thia-3,4-diazole, tetrazole,
pyridine, pyridazine, pyrimidine, and pyrazine.
a a b b
In some embodiments, L is each independently CR R , O, S, NR , C=O, C=S, C=N-R or
b a b b b
C=N-OR wherein R is each independently H, C -C alkyl, C -C heteroalkyl, halogen, OR , or NR R ;
1 6 1 6
and R is each independently H, C -C alkyl, C -C heteroalkyl, C -C cycloalkyl, or C -C
1 6 2 6 3 6 2 6
a a b b
heterocycloalkyl. In some embodiments, L is each independently CR R , O, S, NR , C=O, C=S, C=N-R
b a b
or C=N-OR wherein R is each independently H, C -C alkyl, or halogen; and R is each independently H
or C -C alkyl. In other embodiments, L is CH , O, S, NH, C=O, C=S, C=N-H or C=N-OH. In other
1 6 2
embodiments, L is –CH(Me) or –CH(Cl). In yet other embodiments, L is C=N-Me, C=N-OMe, C=N-Et,
n- n-
C=N-OEt, C=N- Pr, or C=N-O Pr.
In some embodiments, Ar is C -C aryl or C -C heteroaryl optionally substituted with
12 5 11
b b b b
halogen, OR , NR R , C -C alkyl, C -C heteroalkyl, C -C cycloalkyl, or C -C heterocycloalkyl; and R
1 6 1 6 3 6 2 6
is each independently H, C -C alkyl, C -C heteroalkyl, C -C cycloalkyl, or C -C heterocycloalkyl. In
1 6 2 6 3 6 2 6
some embodiments, Ar is C -C aryl or heteroaryl optionally substituted with halogen, hydroxy, amine,
12
or C -C alkyl. In other embodiments, Ar is phenyl, pyridinyl, pyridaznyl, pyrimidinyl, pyrazinyl,
triazinyl, tetrazinyl, furanyl, thiophenyl, oxazolyl, thiazolyl, pyrazolyl, quinolinyl, isoquinolinyl, indolyl,
benzofuranyl, benzimidazolyl, or the like. In certain embodiments, Ar is phenyl, or pyridinyl optionally
substituted with amine or hydroxy. In certain embodiments, Ar is phenyl, or pyridinyl optionally
substituted with methyl, ethyl, propyl, or the like.
In one aspect, provided herein are compounds of Formula (X) having the structure:
n R R
Formula (X);
wherein:
a a b b b b
L is CR R , O, S, NR , N-OR , C=O, C=S, C=N-R or C=N-OR ;
W is a bond or optionally substituted C -C alkyl;
Z is C=O, SO or SO;
1 2 1 2
R and R are each independently H or C -C alkyl, wherein R and R have a cis or trans
relationship; or R and R join together to form a bond;
n and p are each independently an integer from 0 to 3;
m is an integer from 1 to 3;
R is H, substituted or unsubstituted C -C alkyl, substituted or unsubstituted C -C cycloalkyl,
1 3 3 6
substituted or unsubstituted C -C heteroalkyl, substituted or unsubstituted C -C heterocycloalkyl,
1 6 2 6
substituted or unsubstituted C -C aryl, or substituted or unsubstituted C -C heteroaryl;
6 12 5 11
R is substituted or unsubstituted C -C cycloalkyl, substituted or unsubstituted C -C
3 6 2 6
heterocycloalkyl, substituted or unsubstituted C -C aryl, or substituted or unsubstituted C -C
6 12 5 11
heteroaryl;
b b b
R is H, OH, OR , NR R , halogen, C -C alkyl, C -C heteroalkyl, C -C cycloalkyl or C -C
1 6 1 6 3 6 2 6
heterocycloalkyl;
a b b b
R is each independently H, C -C alkyl, C -C heteroalkyl, halogen, OR , or NR R ;
1 6 1 6
R is each independently H, C -C alkyl, C -C heteroalkyl, C -C cycloalkyl or C -C
1 6 2 6 3 6 2 6
heterocycloalkyl;
or a pharmaceutically acceptable salt, solvate, N-oxide, or prodrug thereof.
In one embodiment is a compound of Formula (X) wherein L is CH or C=O. In another
embodiment is a compound of Formula (X) wherein L is O. In another embodiment is a compound of
Formula (X) wherein W is a bond. In another embodiment is a compound of Formula (X) wherein W is
optionally substituted C -C alkyl. In another embodiment is a compound of Formula (X) wherein R is
H. In another embodiment is a compound of Formula (X) wherein R is H. In yet another embodiment is
a compound of Formula (X) wherein R is H and R is H. In another embodiment is a compound of
Formula (X) wherein R and R have a trans relationship. In another embodiment is a compound of
Formula (X) wherein R and R have a cis relationship. In another embodiment is a compound of
Formula (X) wherein m is 2. In another embodiment is a compound of Formula (X) wherein n is 1. In
another embodiment is a compound of Formula (X) wherein n is 2. In another embodiment is a
compound of Formula (X) wherein p is 1. In another embodiment is a compound of Formula (X) wherein
R is H. In another embodiment is a compound of Formula (X) wherein R is CH . In a further
embodiment is a compound of Formula (X) wherein R is not substituted or unsubstituted C -C alkyl. In
another embodiment is a compound of Formula (X) wherein R is H, methyl, ethyl, or isopropyl. In
another embodiment is a compound of Formula (X) wherein R is substituted or unsubstituted C -C
cycloalkyl. In a further embodiment is a compound of Formula (X) wherein R is cyclopropyl,
cyclobutyl, cyclopentyl or cyclohexyl. In another embodiment is a compound of Formula (X) wherein R
is substituted or unsubstituted C -C heterocycloalkyl. In a further embodiment is a compound of
Formula (X) wherein R is tetrahydropyran, tetrahydrofuran, oxetane, or . In another
embodiment is a compound of Formula (X) wherein R is substituted or unsubstituted C -C heteroaryl.
11
In a further embodiment is a compound of Formula (X) wherein R is pyridyl. In another embodiment is a
compound of Formula (X) wherein R and R are each independently substituted or unsubstituted C -C
cycloalkyl.
In another embodiment is a compound of Formula (X) wherein L is O, W is a bond, R is H,
2 3 4
R is H, p is 1, Z is C=O, R is H, and R is substituted or unsubstituted C -C cycloalkyl. In another
embodiment is a compound of Formula (X) wherein L is O, W is a bond, R is H, R is H, p is 1, Z is
C=O, R is methyl, and R is substituted or unsubstituted C -C cycloalkyl. In another embodiment is a
1 2 3
compound of Formula (X) wherein L is O, W is a bond, R is H, R is H, p is 1, Z is C=O, R is ethyl, and
R is substituted or unsubstituted C -C cycloalkyl. In another embodiment is a compound of Formula (X)
1 2 3 4
wherein L is O, W is a bond, R is H, R is H, p is 1, Z is C=O, R is H, and R is substituted or
unsubstituted C -C heterocycloalkyl. In another embodiment is a compound of Formula (X) wherein L is
1 2 3 4
O, W is a bond, R is H, R is H, p is 1, Z is C=O, R is methyl, and R is substituted or unsubstituted C -
C heterocycloalkyl. In another embodiment is a compound of Formula (X) wherein L is O, W is a bond,
1 2 3 4
R is H, R is H, p is 1, Z is C=O, R is ethyl, and R is substituted or unsubstituted C -C
heterocycloalkyl. In another embodiment is a compound of Formula (X) wherein L is O, W is a bond, R
2 3 4
is H, R is H, p is 1, Z is C=O, R is H, and R is substituted or unsubstituted C -C aryl. In another
6 12
embodiment is a compound of Formula (X) wherein L is O, W is a bond, R is H, R is H, p is 1, Z is
C=O, R is methyl, and R is substituted or unsubstituted C -C aryl. In another embodiment is a
6 12
1 2 3
compound of Formula (X) wherein L is O, W is a bond, R is H, R is H, p is 1, Z is C=O, R is ethyl, and
R is substituted or unsubstituted C -C aryl. In another embodiment is a compound of Formula (X)
6 12
1 2 3 4
wherein L is O, W is a bond, R is H, R is H, p is 1, Z is C=O, R is H, and R is substituted or
unsubstituted C -C heteroaryl. In another embodiment is a compound of Formula (X) wherein L is O, W
11
1 2 3 4
is a bond, R is H, R is H, p is 1, Z is C=O, R is methyl, and R is substituted or unsubstituted C -C
11
heteroaryl. In another embodiment is a compound of Formula (X) wherein L is O, W is a bond, R is H,
2 3 4
R is H, p is 1, Z is C=O, R is ethyl, and R is substituted or unsubstituted C -C heteroaryl.
11
In another aspect, provided herein are compounds of Formula (XI) having the structure:
NH 1
Ar' R
Formula (XI);
wherein:
R is L-Ar ;
a a b b b b
L is each independently CR R , O, S, NR , N-OR , C=O, C=S, C=N-R , or C=N-OR ;
2 b b b
R is H, OR , NR R , halogen, C -C alkyl, C -C heteroalkyl, C -C cycloalkyl, or C -C
1 6 1 6 3 6 2 6
heterocycloalkyl;
3 b b b b
R is optionally substituted alkyl, -(C=O)C -C alkyl, -(C=O)OR , -(C=O)NR R , -(C=O)SR ,
optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or
optionally substituted heteroaryl;
a b b b
R is each independently H, C -C alkyl, C -C heteroalkyl, halogen, OR , or NR R ;
1 6 1 6
R is each independently H, C -C alkyl, C -C heteroalkyl, C -C cycloalkyl, or C -C
1 6 2 6 3 6 2 6
heterocycloalkyl;
Ar’ is selected from furan, thiophene, oxazole, isooxazole, oxadiazole, thiazole, isothiazole,
thiadiazole, imidazole, triazole, pyrazole, thiodiazole and tetrazole, pyridine, pyrimidine, pyrazine;
2 b b b
Ar is C -C aryl or heteroaryl optionally substituted with halogen, OR , NR R , C -C alkyl, C -C
12 1 6 1 6
heteroalkyl, C -C cycloalkyl or C -C heterocycloalkyl;
3 6 2 6
or a pharmaceutically acceptable salt, solvate, N-oxide, or prodrug thereof.
In one embodiment is a compound of Formula (XI) wherein Ar’ is oxazole, isooxazole, or
oxadiazole. In another embodiment is a compound of Formula (XI) wherein R is H. In yet another
embodiment is a compound of Formula (XI) wherein R is H and R is optionally substituted cycloalkyl.
In a further embodiment is a compound of Formula (XI) wherein R is O-Ph.
1 2 2
In some embodiments, R is O-Ar wherein Ar is C -C aryl or heteroaryl optionally
12
b b b
substituted with halogen, OR , NR R , C -C alkyl, C -C heteroalkyl, C -C cycloalkyl, or C -C
1 6 1 6 3 6 2 6
heterocycloalkyl; and R is each independently H, C -C alkyl, C -C heteroalkyl, C -C cycloalkyl, or C -
1 6 2 6 3 6 2
1 2 2
C heterocycloalkyl. In some embodiments, R is O-Ar wherein Ar is C -C aryl or heteroaryl
6 5 12
optionally substituted with halogen, hydroxy, amine, or C -C alkyl. In other embodiments, Ar is phenyl,
pyridinyl, pyridaznyl, pyrimidinyl, pyrazinyl, triazinyl, tetrazinyl, furanyl, thiophenyl, oxazolyl, thiazolyl,
pyrazolyl, quinolinyl, isoquinolinyl, indolyl, benzofuranyl, benzimidazolyl, or the like. In other
embodiments, Ar is phenyl, pyridinyl, furanyl, thiophenyl or quinolinyl. In certain embodiments, Ar is
phenyl or pyridinyl.
2 b b b
In some embodiments, R is H, OR , NR R , halogen, C -C alkyl, C -C heteroalkyl, C -C
1 6 1 6 3 6
cycloalkyl, or C -C heterocycloalkyl; wherein R is each independently H, C -C alkyl, C -C heteroalkyl,
2 6 1 6 2 6
C -C cycloalkyl, or C -C heterocycloalkyl. In some embodiments, R is H, OH, NH , halogen or C -C
3 6 2 6 2 1 6
alkyl. In other embodiments, R is F, Cl, Br or I. In other embodiments, R is methyl, ethyl, n-propyl, iso-
propyl, n-butyl, sec-butyl, iso-butyl, n-pentyl, or hexyl. In yet other embodiments, R is H, OH, or NH . In
other embodiments, R is H.
In some embodiments, R is optionally substituted alkyl, -(C=O)C -C alkyl, -(C=O)OR , -
b b b
(C=O)NR R , -(C=O)SR , optionally substituted cycloalkyl, optionally substituted heterocycloalkyl,
optionally substituted aryl, or optionally substituted heteroaryl. In other embodiments, R is methyl,
ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, and tert-butyl. In yet other embodiments, R is –C=O-Me, -
(C=O)Et, or -(C=O)Bu. In other embodiments, R is –COOH, -COOMe, -COOEt, -COOPr or –COOBu.
In yet other embodiments, R is –CONH , -CONHMe, -CONHEt or –CONHBu. In other embodiments,
R is –C=O-SMe, -(C=O)SEt or –C=O-SPr. In yet other embodiments, R is optionally substituted
cyclobutyl, cyclopentyl, cyclohexyl, or the like. In yet other embodiments, R is optionally substituted
azetidinyl, pyrrolidinyl, piperidinyl or the like. In yet other embodiments, R is optionally substituted
phenyl, pyridinyl, pyridaznyl, pyrimidinyl, pyrazinyl, triazinyl, tetrazinyl, furanyl, thiophenyl, oxazolyl,
thiazolyl, pyrazolyl, quinolinyl, isoquinolinyl, indolyl, benzofuranyl, benzimidazolyl, or the like.
In another embodiment is a compound of Formula (XI) wherein R is optionally substituted
with at least one substituent selected from halogen, -CN, -NO , -OH, -OCF , -OCF H, -OCH F, -CF , -
2 3 2 2 3
8 9 9 10 9 10 10 9 9 10
SR , -S(=O)R , -S(=O) R , -NR S(=O) R , -S(=O) N(R ) , -OR , -C(=O)R , -OC(=O)R , -CO R ,
2 2 2 2 2
10 10 10 10 10 10 10
-N(R ) , -C(=O)N(R ) , -NR C(=O)R , -N R C(=O)OR , -NR C(=O)N(R ) , substituted or
2 2 2
unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl or
substituted or unsubstituted heterocycloalkyl; wherein R is H or substituted or unsubstituted alkyl; R is
substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; and each R
is independently H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted
or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted
heteroaryl, or two R together with the atoms to which they are attached form a heterocycle. In one
embodiment, R is substituted with halogen, -CN, -NO , -OH, -OCF , -OCF H, -OCH F, -CF , -SH. In
2 3 2 2 3
3 9 9
another embodiment is a compound of Formula (XI) wherein R is substituted with -S(=O)R , -S(=O) R ,
9 10 9 10 10 9
-NR S(=O) R , -S(=O) N(R ) , -C(=O)R , -CO R , -C(=O)N(R ) . In another embodiment, R is an
2 2 2 2 2
unsubstituted or substituted alkyl selected from methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl or
tert-butyl. In another embodiment, is a compound of Formula (IX) wherein R is a substituted or
unsubstituted cycloalkyl. In a further embodiment, the cycloalkyl is selected from cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. In another embodiment R is a substituted or
unsubstituted heterocycloalkyl. In another embodiment, R is a substituted or unsustituted aryl. In a
further embodiment, the aryl is a phenyl group. In a further embodiment, the aryl is a naphthalene group.
In yet a further embodiment, R is a substituted or unsubstituted heteroaryl. In yet another embodiment
the heteroaryl is selected from pyrrole, furan, thiophene, pyrazole, imidazole, isoxazole, oxazole,
isothiazole, thiazole, 1,2,3-triazole, 1,3,4-triazole, 1-oxa-2,3-diazole, 1-oxa-2,4-diazole, 1-oxa-2,5-diazole,
1-oxa-3,4-diazole, 1-thia-2,3-diazole, 1-thia-2,4-diazole, 1-thia-2,5-diazole, 1-thia-3,4-diazole, tetrazole,
pyridine, pyridazine, pyrimidine, and pyrazine.
In some embodiments, Ar’ is selected from furan, thiophene, oxazole, isooxazole, oxadiazole,
thiazole, isothiazole, and thiadiazole. In other embodiments, Ar’ is oxazole, isooxazole or oxadiazole.
In one aspect, provided herein are compounds of Formula (XII) having the structure:
NH 1
Ar R
Formula (XII);
wherein:
R is L-Ar ;
a a b b b b
L is CR R , O, S, NR , N-OR , C=O, C=S, C=N-R , or C=N-OR ;
a b b b
R is each independently H, C -C alkyl, C -C heteroalkyl, halogen, OR , or NR R ;
1 6 1 6
R is each independently H, C -C alkyl, C -C heteroalkyl, C -C cycloalkyl, or C -C
1 6 2 6 3 6 2 6
heterocycloalkyl;
2a b b b
R is OR , NR R , halogen, C -C alkyl, C -C heteroalkyl, C -C cycloalkyl, or C -C
1 6 1 6 3 6 2 6
heterocycloalkyl;
3 b b b b
R is optionally substituted alkyl, -(C=O)C -C alkyl, -(C=O)OR , -(C=O)NR R , -(C=O)SR ,
optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or
optionally substituted heteroaryl;
Ar and Ar are each independently C -C aryl or heteroaryl optionally substituted with halogen, OR ,
12
NR R , C -C alkyl, C -C heteroalkyl, C -C cycloalkyl, or C -C heterocycloalkyl; or a pharmaceutically
1 6 1 6 3 6 2 6
acceptable salt, solvate, N-oxide, or prodrug thereof.
In one embodiment is a compound of Formula (XII) wherein Ar is phenyl. In another
embodiment is a compound of Formula (XII) wherein R is CH or OH. In yet another embodiment is a
compound of Formula (XII) wherein R is optionally substituted cycloalkyl. In a further embodiment is a
compound of Formula (XII) wherein R is O-Ph.
2a b b b
In some embodiments, R is OR , NR R , halogen, C -C alkyl, C -C heteroalkyl, C -C
1 6 1 6 3 6
cycloalkyl, or C -C heterocycloalkyl. In some embodiments, R is OH, NH , halogen, or C -C alkyl. In
2 6 2 1 6
2a 2a
other embodiments, R is OH, NH , F, Cl, Br or I. In yet other embodiments, R is methyl, ethyl, n-
propyl, iso-propyl, n-butyl, iso-butyl, and tert-butyl.
1 2 2
In some embodiments, R is O-Ar wherein Ar is C -C aryl or heteroaryl optionally
12
b b b
substituted with halogen, OR , NR R , C -C alkyl, C -C heteroalkyl, C -C cycloalkyl, or C -C
1 6 1 6 3 6 2 6
heterocycloalkyl; and R is each independently H, C -C alkyl, C -C heteroalkyl, C -C cycloalkyl, or C -
1 6 2 6 3 6 2
1 2 2
C heterocycloalkyl. In some embodiments, R is O-Ar wherein Ar is C -C aryl or heteroaryl
6 5 12
optionally substituted with halogen, hydroxy, amine, or C -C alkyl. In other embodiments, Ar is
phenyl, pyridinyl, pyridaznyl, pyrimidinyl, pyrazinyl, triazinyl, tetrazinyl, furanyl, thiophenyl, oxazolyl,
thiazolyl, pyrazolyl, quinolinyl, isoquinolinyl, indolyl, benzofuranyl, benzimidazolyl, or the like. In other
embodiments, Ar is phenyl, pyridinyl, furanyl, thiophenyl or quinolinyl. In certain embodiments, Ar is
phenyl or pyridinyl.
In some embodiments, R is optionally substituted alkyl, -(C=O)C -C alkyl, -(C=O)OR , -
b b b
(C=O)NR R , -(C=O)SR , optionally substituted cycloalkyl, optionally substituted heterocycloalkyl,
optionally substituted aryl, or optionally substituted heteroaryl. In other embodiments, R is methyl,
ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, and tert-butyl. In yet other embodiments, R is –C=O-Me, -
(C=O)Et, or -(C=O)Bu. In other embodiments, R is –COOH, -COOMe, -COOEt, -COOPr or –COOBu.
In yet other embodiments, R is –CONH , -CONHMe, -CONHEt or –CONHBu. In other embodiments,
R is –C=O-SMe, -(C=O)SEt or –C=O-SPr. In yet other embodiments, R is optionally substituted
cyclobutyl, cyclopentyl, cyclohexyl, or the like. In yet other embodiments, R is optionally substituted
azetidinyl, pyrrolidinyl, piperidinyl or the like. In yet other embodiments, R is optionally substituted
phenyl, pyridinyl, pyridaznyl, pyrimidinyl, pyrazinyl, triazinyl, tetrazinyl, furanyl, thiophenyl, oxazolyl,
thiazolyl, pyrazolyl, quinolinyl, isoquinolinyl, indolyl, benzofuranyl, benzimidazolyl, or the like.
In another embodiment is a compound of Formula (XII) wherein R is optionally substituted
with at least one substituent selected from halogen, -CN, -NO , -OH, -OCF , -OCF H, -OCH F, -CF , -
2 3 2 2 3
8 9 9 10 9 10 10 9 9 10
SR , -S(=O)R , -S(=O) R , -NR S(=O) R , -S(=O) N(R ) , -OR , -C(=O)R , -OC(=O)R , -CO R ,
2 2 2 2 2
10 10 10 10 10 10 10
-N(R ) , -C(=O)N(R ) , -NR C(=O)R , -N R C(=O)OR , -NR C(=O)N(R ) , substituted or
2 2 2
unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl or
substituted or unsubstituted heterocycloalkyl; wherein R is H or substituted or unsubstituted alkyl; R is
substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; and each R
is independently H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted
or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted
heteroaryl, or two R together with the atoms to which they are attached form a heterocycle. In one
embodiment, R is substituted with halogen, -CN, -NO , -OH, -OCF , -OCF H, -OCH F, -CF , -SH. In
2 3 2 2 3
3 9 9
another embodiment is a compound of Formula (XII) wherein R is substituted with -S(=O)R , -S(=O) R ,
9 10 9 10 10 9
-NR S(=O) R , -S(=O) N(R ) , -C(=O)R , -CO R , -C(=O)N(R ) . In another embodiment, R is an
2 2 2 2 2
unsubstituted or substituted alkyl selected from methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl or
tert-butyl. In another embodiment, is a compound of Formula (XII) wherein R is a substituted or
unsubstituted cycloalkyl. In a further embodiment, the cycloalkyl is selected from cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. In another embodiment R is a substituted or
unsubstituted heterocycloalkyl. In another embodiment, R is a substituted or unsustituted aryl. In a
further embodiment, the aryl is a phenyl group. In a further embodiment, the aryl is a naphthalene group.
In yet a further embodiment, R is a substituted or unsubstituted heteroaryl. In yet another embodiment
the heteroaryl is selected from pyrrole, furan, thiophene, pyrazole, imidazole, isoxazole, oxazole,
isothiazole, thiazole, 1,2,3-triazole, 1,3,4-triazole, 1-oxa-2,3-diazole, 1-oxa-2,4-diazole, 1-oxa-2,5-diazole,
1-oxa-3,4-diazole, 1-thia-2,3-diazole, 1-thia-2,4-diazole, 1-thia-2,5-diazole, 1-thia-3,4-diazole, tetrazole,
pyridine, pyridazine, pyrimidine, and pyrazine.
In some embodiments, Ar is C -C aryl or heteroaryl optionally substituted with halogen,
12
b b b b
OR , NR R , C -C alkyl, C -C heteroalkyl, C -C cycloalkyl, or C -C heterocycloalkyl; and R is each
1 6 1 6 3 6 2 6
independently H, C -C alkyl, C -C heteroalkyl, C -C cycloalkyl, or C -C heterocycloalkyl. In some
1 6 2 6 3 6 2 6
embodiments, Ar is C -C aryl or heteroaryl optionally substituted with halogen, hydroxy, amine, or C -
12 1
C alkyl. In other embodiments, Ar is phenyl, pyridinyl, pyridaznyl, pyrimidinyl, pyrazinyl, triazinyl,
tetrazinyl, furanyl, thiophenyl, oxazolyl, thiazolyl, pyrazolyl, quinolinyl, isoquinolinyl, indolyl,
benzofuranyl, benzimidazolyl, or the like. In certain embodiments, Ar is phenyl, or pyridinyl optionally
substituted with amine or hydroxy. In certain embodiments, Ar is phenyl, or pyridinyl optionally
substituted with methyl, ethyl, propyl, or the like.
In one aspect, provided herein are compounds of Formula (XIII) having the structure:
Ar R
Formula (XIII);
wherein:
X is hydrogen, hydroxy, alkoxy, thiol, halogen or C -C alkyl;
R is L-Ar ;
a a b b b b
L is CR R , O, S, NR , N-OR , C=O, C=S, C=N-R , or C=N-OR ;
a b b b
R is each independently H, C -C alkyl, C -C heteroalkyl, halogen, OR , or NR R ;
1 6 1 6
R is each independently H, C -C alkyl, C -C heteroalkyl, C -C cycloalkyl, or C -C
1 6 2 6 3 6 2 6
heterocycloalkyl;
2 b b b
R is H, OR , NR R , halogen, C -C alkyl, C -C heteroalkyl, C -C cycloalkyl, or C -C
1 6 1 6 3 6 2 6
heterocycloalkyl;
3 b b b b
R is optionally substituted alkyl, -(C=O)C -C alkyl, -(C=O)OR , -(C=O)NR R , -(C=O)SR ,
optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or
optionally substituted heteroaryl;
Ar and Ar is each independently C -C aryl or heteroaryl optionally substituted with halogen, OR ,
12
NR R , C -C alkyl, C -C heteroalkyl, C -C cycloalkyl, or C -C heterocycloalkyl;
1 6 1 6 3 6 2 6
or a pharmaceutically acceptable salt, solvate, N-oxide, or prodrug thereof.
1 2 2
In some embodiments, R is O-Ar wherein Ar is C -C aryl or heteroaryl optionally
12
substituted with halogen, hydroxy, amine, or C -C alkyl. In other embodiments, Ar is phenyl, pyridinyl,
pyridaznyl, pyrimidinyl, pyrazinyl, triazinyl, tetrazinyl, furanyl, thiophenyl, oxazolyl, thiazolyl, pyrazolyl,
quinolinyl, isoquinolinyl, indolyl, benzofuranyl, benzimidazolyl, or the like. In other embodiments, Ar is
phenyl, pyridinyl, furanyl, thiophenyl or quinolinyl. In certain embodiments, Ar is phenyl or pyridinyl.
In some embodiments, R is optionally substituted alkyl, -(C=O)C -C alkyl, -(C=O)OR , -
b b b
(C=O)NR R , -(C=O)SR , optionally substituted cycloalkyl, optionally substituted heterocycloalkyl,
optionally substituted aryl, or optionally substituted heteroaryl. In other embodiments, R is methyl,
ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, and tert-butyl. In yet other embodiments, R is –C=O-Me, -
(C=O)Et, or -(C=O)Bu. In other embodiments, R is –COOH, -COOMe, -COOEt, -COOPr or –COOBu.
In yet other embodiments, R is –CONH , -CONHMe, -CONHEt or –CONHBu. In other embodiments,
R is –C=O-SMe, -(C=O)SEt or –C=O-SPr. In yet other embodiments, R is optionally substituted
cyclobutyl, cyclopentyl, cyclohexyl, or the like. In yet other embodiments, R is optionally substituted
azetidinyl, pyrrolidinyl, piperidinyl or the like. In yet other embodiments, R is optionally substituted
phenyl, pyridinyl, pyridaznyl, pyrimidinyl, pyrazinyl, triazinyl, tetrazinyl, furanyl, thiophenyl, oxazolyl,
thiazolyl, pyrazolyl, quinolinyl, isoquinolinyl, indolyl, benzofuranyl, benzimidazolyl, or the like.
In another embodiment is a compound of Formula (XIII) wherein R is optionally substituted
with at least one substituent selected from halogen, -CN, -NO , -OH, -OCF , -OCF H, -OCH F, -CF , -
2 3 2 2 3
8 9 9 10 9 10 10 9 9 10
SR , -S(=O)R , -S(=O) R , -NR S(=O) R , -S(=O) N(R ) , -OR , -C(=O)R , -OC(=O)R , -CO R ,
2 2 2 2 2
10 10 10 10 10 10 10
-N(R ) , -C(=O)N(R ) , -NR C(=O)R , -N R C(=O)OR , -NR C(=O)N(R ) , substituted or
2 2 2
unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl or
substituted or unsubstituted heterocycloalkyl; wherein R is H or substituted or unsubstituted alkyl; R is
substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; and each R
is independently H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted
or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted
heteroaryl, or two R together with the atoms to which they are attached form a heterocycle. In one
embodiment, R is substituted with halogen, -CN, -NO , -OH, -OCF , -OCF H, -OCH F, -CF , -SH. In
2 3 2 2 3
another embodiment is a compound of Formula (XIII) wherein R is substituted with -S(=O)R , -
9 10 9 10 9 10 10
S(=O) R , -NR S(=O) R , -S(=O) N(R ) , -C(=O)R , -CO R , -C(=O)N(R ) . In another embodiment,
2 2 2 2 2 2
R is an unsubstituted or substituted alkyl selected from methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-
butyl or tert-butyl. In another embodiment, is a compound of Formula (XIII) wherein R is a substituted
or unsubstituted cycloalkyl. In a further embodiment, the cycloalkyl is selected from cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. In another embodiment R is a substituted or
unsubstituted heterocycloalkyl. In another embodiment, R is a substituted or unsustituted aryl. In a
further embodiment, the aryl is a phenyl group. In a further embodiment, the aryl is a naphthalene group.
In yet a further embodiment, R is a substituted or unsubstituted heteroaryl. In yet another embodiment
the heteroaryl is selected from pyrrole, furan, thiophene, pyrazole, imidazole, isoxazole, oxazole,
isothiazole, thiazole, 1,2,3-triazole, 1,3,4-triazole, 1-oxa-2,3-diazole, 1-oxa-2,4-diazole, 1-oxa-2,5-diazole,
1-oxa-3,4-diazole, 1-thia-2,3-diazole, 1-thia-2,4-diazole, 1-thia-2,5-diazole, 1-thia-3,4-diazole, tetrazole,
pyridine, pyridazine, pyrimidine, and pyrazine.
In one embodiment is a compound of Formula (XIII) wherein Ar is phenyl. In another
embodiment is a compound of Formula (XIII) wherein X is hydroxy or alkoxy. In yet another
embodiment is a compound of Formula (XIII) wherein R is optionally substituted cycloalkyl. In a further
embodiment is a compound of Formula (XIII) wherein R is O-Ph.
In some embodiments, X is hydroxy, methoxy, ethoxy or butoxy. In other embodiments, X is
F, Cl, Br or I. In yet other embodiments, X is methyl, ethyl, propyl, or the like.
In one aspect, provided herein are compounds of Formula (XIV) having the structure:
Formula (XIV);
wherein:
R is L-Ar ;
a a b b b b
L is CR R , O, S, NR , N-OR , C=O, C=S, C=N-R , or C=N-OR ;
a b b b
R is each independently H, C -C alkyl, C -C heteroalkyl, halogen, OR , or NR R ;
1 6 1 6
R is each independently H, C -C alkyl, C -C heteroalkyl, C -C cycloalkyl, or C -C
1 6 2 6 3 6 2 6
heterocycloalkyl;
2 b b b
R is H, OR , NR R , halogen, C -C alkyl, C -C heteroalkyl, C -C cycloalkyl or C -C
1 6 1 6 3 6 2 6
heterocycloalkyl;
N R N R
3a O
R is selected from R , , , ,
O O R
R , and ;
R is hydrogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxycarbonyl,
substituted or unsubstituted alkoxyalkyl, substituted or unsubstituted hydroxyalkyl, substituted or
unsubstituted aminocarbonyl, substituted or unsubstituted alkylcarbonyl or substituted or unsubstituted
arylalkyl group;
b b b
R is H, optionally substituted C -C alkyl, -(C=O)C -C alkyl, -(C=O)OR , -(C=O)NR R , -
1 6 1 6
(C=O)SR , cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
R is optionally substituted C -C alkyl or NR ;
R is each independently hydrogen, optionally substituted C -C alkyl, optionally substituted
cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted
heteroaryl;
Ar is C -C aryl or heteroaryl optionally substituted with halogen, hydroxy, amine, or C -C alkyl;
12 1 6
n is an integer from 0 to 3;
m is an integer from 0 to 6;
Y is O, S or NR ;
or a pharmaceutically acceptable salt, solvate, N-oxide, or prodrug thereof.
In one embodiment is a compound of Formula (XIV) wherein R is . In
N HN
another embodiment is a compound of Formula (XIV) wherein R is , ,
NH N N NH NH
2 2 2
HN N HN HN HN
O S S S
, , , or NH . In yet another
embodiment is a compound of Formula (XIV) wherein R is H or CH . In a further embodiment is a
compound of Formula (XIV) wherein R is O-Ph.
In one embodiment is a compound having the structure selected from
NH NH
2 O 2 O OPh
N N N
N N N
N N N
N N N
, , ,
NH OPh OPh
NH NH NH
2 2 2 2
N N N
N N N N
N N N N
N N N N
, , , ,
NH OPh OPh
NH NH NH
2 2 2 2
N N N N
N N N N
N N N N
, , , ,
NH 2 S OPh
NH OPh 2 HN NH
2 2 HN
, , ,
2 N OPh
NH NH
2 O 2 S
HO N
H N N
N , , ,
NH NH NH
2 O OPh 2
N N N
Cl N N
, , ,
HN OPh OPh
NH NH NH
2 2 2
N N N
N N N
F N N HO N
, , ,
HN S
OPh OPh
NH NH NH
2 2 2
N N N
N N N
N N N
H N N HO N Cl N
, , ,
2 HN NH
2 HN
HO N
, and
2 HN O
H N N
N ; or a pharmaceutically acceptable salt, solvate, N-oxide, or prodrug
thereof.
In another embodiment, provided herein is a compound selected from:
OPh OPh OPh
O O O
NH NH NH NH
2 2 2
N N N N
N N N N
N N N N
N N N N
, , , ,
OPh OPh OPh
O S S S
NH NH NH NH
2 2 2
N N N N
N N N N
N N N N
N N N N
, , , ,
O N O
O O S
NH NH NH
2 2 2
N N N
N N O
, , , ,
OPh OPh
O O O
NH NH
NH N N
2 2 2
N N N
N N N
N N N
HO N H N N Cl N
, , , and
; or a pharmaceutically acceptable salt, solvate, N-oxide, or prodrug thereof.
In another embodiments, provided herein is a compound selected from
NH OH
O 2 S O OPh
N N N
N N N
HO N H N N Cl N
, , ,
HN OPh
SH Cl
N F N
, , ,
N HO N
, , ,
HN S N
OPh OPh
HO N
HO N Cl N
, , ,
HN O
N H N N
, N , ,
OPh OPh OPh
N N N
O O O
OH Cl
N N N N
, , , ,
OPh OPh
S S S
F Cl
N N N
N N N
N N N
N HO N F N
, , ,
O N O
F N H N N
, , ,
OPh OPh
O OH
N N N
N N N
N O N N
N HO N H N N
, , ,
SH O
N N N
N N N
N N N
F N H N N HO N
, , ,
OH NH
H N N
, , ,
HO N
HO N
H N N
, , and ; or a
pharmaceutically acceptable salt, solvate, N-oxide, or prodrug thereof.
In another embodiment, provided herein is a compound selected from
OPh OPh OPh OPh
NH NH NH NH
2 2 2
N N N N
N N N N
N N N N
N N N N
N N HN N N N HN N
O , O , O , O ,
OPh OPh OPh
NH NH NH
2 2 2
N N N
N N N
N N N
N NH HN NH N N
O , O , O ,
OPh OPh
NH NH
HO N
N HN N
N NH
O , , ,
N NH
O , H , ,
NH NH
HN N
, , ,
OPh OPh OPh
NH NH NH
2 2 2
N N N
H H H
HN N HN N HN N
O , O , O ,
O OPh OPh
NH NH NH
2 2 2
N N N
N N N
N N N
N HO N H N N
HN NH HN NH N N
O , O , O ,
NH NH
HO N
H N N
HN N
, O , ,
H N N
, O , and
; or a pharmaceutically acceptable salt, solvate, N-oxide, or prodrug
thereof.
In another embodiment is a compound selected from:
O , , O
, , ,
, O ,
, ,
, O ,
, O , and
O ; or a
pharmaceutically acceptable salt, solvate, N-oxide, or prodrug thereof.
In another embodiment is a compound selected from:
, ,
NH NH
O , O ,
O H O
, ,
NH NH
, ,
NH 2
, ,
NH NH
, and ; or a
pharmaceutically acceptable salt, solvate, N-oxide, or prodrug thereof.
In another embodiment is a compound selected from:
NH NH
, ,
, ,
NH 2
, ,
, and ; or a
pharmaceutically acceptable salt, solvate, N-oxide, or prodrug thereof.
In another embodiment is a compound selected from:
, ,
, ,
, ,
NH NH
O , ,
NH NH
O O H
, and ; or a
pharmaceutically acceptable salt, solvate, N-oxide, or prodrug thereof.
In another embodiment is a compound selected from:
NH NH
, , O ,
NH 2
O , O , ,
NH NH
N N N N
O , O , O ,
NH NH
, O , ,
NH NH
O O O
, , ,
NH NH
O , O , O ,
NH NH
O , O , O ,
NH NH
O , O , O ,
NH NH
O , O , O ,
NH NH
O , O , O ,
NH NH
N O N
O O O
, , ,
NH NH
O , O , O ,
O , , O ,
N OMe
, , ,
NH NH
N OMe N
, , ,
NH O
, , H ,
NH NH
NH 2 2
H , , ,
NH NH
O O O
, , ,
N N N
, , ,
H N H N
, and or a
pharmaceutically acceptable salt, solvate, N-oxide, or prodrug thereof.
In another embodiment is a compound selected from:
NH NH
O , , O ,
NH NH
, O , ,
O , , ,
NH NH
O , O , O ,
NH NH
O , O , O ,
NH NH
O , , O ,
NH NH
, O , ,
NH NH
O O O
, , ,
NH NH
O , O , O ,
NH NH
O , O , O ,
O O O
, , ,
NH NH
N O N
O O O
, , ,
, , ,
N N OMe
OMe N
O , , O ,
, O , ,
N N N N
O O O
, , , , and
O or a pharmaceutically acceptable salt, solvate, N-oxide, or prodrug thereof.
In another embodiment is a compound selected from:
N N N N
O , O , , and
, or a pharmaceutically acceptable salt, solvate, N-oxide, or prodrug thereof.
In another embodiment is a compound selected from:
O and , or a pharmaceutically acceptable
salt, solvate, N-oxide, or prodrug thereof.
In another embodiment is a compound selected from:
NH NH
O O N
, , ,
NH N N
, , and , or a pharmaceutically
acceptable salt, solvate, N-oxide, or prodrug thereof.
In one aspect is a pharmaceutical composition comprising a compound having the structure of
Formula (I), (IA), (II), (III), (IV), (V), (VI), (VIA), (VIB), (VII), (VIII), (IX), (X), (XI), (XII), (XIII),
(XIV), or a pharmaceutically acceptable salt or solvate thereof; and a pharmaceutically acceptable
excipient, binder or carrier. In one aspect is a pharmaceutical composition comprising a compound having
the structure of Formula (I), (IA), (II), (III), (IV), (V), (VI), (VIA), (VIB), (VII), (VIII), (IX), (X), or a
pharmaceutically acceptable salt or solvate thereof; and a pharmaceutically acceptable excipient, binder or
carrier. In another aspect is a pharmaceutical composition comprising a compound having the structure of
Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), or (X), or a pharmaceutically acceptable salt,
solvate, N-oxide, or prodrug thereof; and a pharmaceutically acceptable excipient, binder or carrier. In
another aspect is a pharmaceutical composition comprising a compound having the structure of Formula
(VI) or a pharmaceutically acceptable salt, solvate, N-oxide, or prodrug thereof; and a pharmaceutically
acceptable excipient, binder or carrier. In another aspect is a pharmaceutical composition comprising a
compound having the structure of Formula (VII) or a pharmaceutically acceptable salt, solvate, N-oxide,
or prodrug thereof; and a pharmaceutically acceptable excipient, binder or carrier. In another aspect is a
pharmaceutical composition comprising a compound having the structure of Formula (VIII) or a
pharmaceutically acceptable salt, solvate, N-oxide, or prodrug thereof; and a pharmaceutically acceptable
excipient, binder or carrier. In another aspect is a pharmaceutical composition comprising a compound
having the structure of Formula (X) or a pharmaceutically acceptable salt, solvate, N-oxide, or prodrug
thereof; and a pharmaceutically acceptable excipient, binder or carrier.
In certain embodiments, provided herein is a pharmaceutical composition containing: i) a
physiologically acceptable carrier, diluent, and/or excipient; and ii) one or more compounds provided
herein.
In some embodiments, the inhibitors described herein are used for the manufacture of a
medicament for treating any of the foregoing conditions (e.g., autoimmune diseases, inflammatory
diseases, allergy disorders, B-cell proliferative disorders, or thromboembolic disorders).
In some embodiments, the inhibitor compound used for the methods described herein inhibits
a Kinase activity with an in vitro IC of less than about 10 μM. (e.g., less than about 1 μM, less than
about 0.5 μM, less than about 0.4 μM, less than about 0.3 μM, less than about 0.1, less than about 0.08
μM, less than about 0.06 μM, less than about 0.05 μM, less than about 0.04 μM, less than about 0.03 μM,
less than about 0.02 μM, less than about 0.01, less than about 0.008 μM, less than about 0.006 μM, less
than about 0.005 μM, less than about 0.004 μM, less than about 0.003 μM, less than about 0.002 μM, less
than about 0.001, less than about 0.00099 μM, less than about 0.00098 μM, less than about 0.00097 μM,
less than about 0.00096 μM, less than about 0.00095 μM, less than about 0.00094 μM, less than about
0.00093 μM, less than about 0.00092, or less than about 0.00090 μM).
In one embodiment, the inhibitor compound selectively inhibits an activated form of its target
tyrosine kinase (e.g., a phosphorylated form of the tyrosine kinase). For example, activated Btk is
transphosphorylated at tyrosine 551. Thus, in these embodiments the Btk inhibitor inhibits the target
kinase in cells only once the target kinase is activated by the signaling events.
Preparation of Compounds
Compounds of any of Formula (I), (IA), (II), (III), (IV), (V), (VI), (VIA), (VIB), (VII), (VIII),
(IX), (X), (XI), (XII), (XIII), or (XIV) are optionally synthesized using standard synthetic techniques or
using such methods known in combination with methods described herein. In additions, solvents,
temperatures and other reaction conditions are presented herein for illustration only, and not to limit the
scope of the methods and compositions described herein. As a further guide the following synthetic
methods may also be utilized.
The reactions are optionally employed in a linear sequence to provide the compounds
described herein or used to synthesize fragments which are subsequently joined by the methods described
herein and/or documented elsewhere.
Formation of Covalent Linkages by Reaction of an Electrophile with a Nucleophile
The compounds described herein can be modified using various electrophiles or nucleophiles
to form new functional groups or substituents. Table 1 entitled “Examples of Covalent Linkages and
Precursors Thereof” lists selected examples of covalent linkages and precursor functional groups which
yield and can be used as guidance toward the variety of electrophiles and nucleophiles combinations
available. Precursor functional groups are shown as electrophilic groups and nucleophilic groups.
Table 1: Examples of Covalent Linkages and Precursors Thereof
Covalent Linkage Product Electrophile Nucleophile
Carboxamides Activated esters amines/anilines
Carboxamides acyl azides amines/anilines
Carboxamides acyl halides amines/anilines
Esters acyl halides alcohols/phenols
Esters acyl nitriles alcohols/phenols
Carboxamides acyl nitriles amines/anilines
Imines Aldehydes amines/anilines
Hydrazones aldehydes or ketones Hydrazines
Oximes aldehydes or ketones Hydroxylamines
Alkyl amines alkyl halides amines/anilines
Esters alkyl halides carboxylic acids
Thioethers alkyl halides Thiols
Ethers alkyl halides alcohols/phenols
Thioethers alkyl sulfonates Thiols
Esters alkyl sulfonates carboxylic acids
Ethers alkyl sulfonates alcohols/phenols
Esters Anhydrides alcohols/phenols
Carboxamides Anhydrides amines/anilines
Thiophenols aryl halides Thiols
Aryl amines aryl halides Amines
Thioethers Azindines Thiols
Boronate esters Boronates Glycols
Carboxamides carboxylic acids amines/anilines
Esters carboxylic acids Alcohols
hydrazines Hydrazides carboxylic acids
N-acylureas or Anhydrides carbodiimides carboxylic acids
Esters diazoalkanes carboxylic acids
Thioethers Epoxides Thiols
Thioethers haloacetamides Thiols
Ammotriazines halotriazines amines/anilines
Triazinyl ethers halotriazines alcohols/phenols
Amidines imido esters amines/anilines
Ureas Isocyanates amines/anilines
Urethanes Isocyanates alcohols/phenols
Thioureas isothiocyanates amines/anilines
Thioethers Maleimides Thiols
Phosphite esters phosphoramidites Alcohols
Silyl ethers silyl halides Alcohols
Alkyl amines sulfonate esters amines/anilines
Thioethers sulfonate esters Thiols
Esters sulfonate esters carboxylic acids
Ethers sulfonate esters Alcohols
Sulfonamides sulfonyl halides amines/anilines
Sulfonate esters sulfonyl halides phenols/alcohols
Alkyl thiol α,β-unsaturated ester thiols
Alkyl ethers α,β-unsaturated ester alcohols
Alkyl amines α,β-unsaturated ester amines
Alkyl thiol Vinyl sulfone thiols
Alkyl ethers Vinyl sulfone alcohols
Alkyl amines Vinyl sulfone amines
Vinyl sulfide Propargyl amide thiol
Use of Protecting Groups
In the reactions described, it may be necessary to protect reactive functional groups, for
example hydroxy, amino, imino, thio or carboxy groups, where these are desired in the final product, to
avoid their unwanted participation in the reactions. Protecting groups are used to block some or all
reactive moieties and prevent such groups from participating in chemical reactions until the protective
group is removed. In one embodiment, each protective group be removable by a different means.
Protective groups that are cleaved under totally disparate reaction conditions fulfill the requirement of
differential removal. Protective groups can be removed by acid, base, and hydrogenolysis. Groups such as
trityl, dimethoxytrityl, acetal and t-butyldimethylsilyl are acid labile and may be used to protect carboxy
and hydroxy reactive moieties in the presence of amino groups protected with Cbz groups, which are
removable by hydrogenolysis, and Fmoc groups, which are base labile. Carboxylic acid and hydroxy
reactive moieties may be blocked with base labile groups such as, but not limited to, methyl, ethyl, and
acetyl in the presence of amines blocked with acid labile groups such as t-butyl carbamate or with
carbamates that are both acid and base stable but hydrolytically removable.
Carboxylic acid and hydroxy reactive moieties may also be blocked with hydrolytically
removable protective groups such as the benzyl group, while amine groups capable of hydrogen bonding
with acids may be blocked with base labile groups such as Fmoc. Carboxylic acid reactive moieties may
be protected by conversion to simple ester compounds as exemplified herein, or they may be blocked with
oxidatively-removable protective groups such as 2,4-dimethoxybenzyl, while co-existing amino groups
may be blocked with fluoride labile silyl carbamates.
Allyl blocking groups are useful in then presence of acid- and base- protecting groups since
the former are stable and can be subsequently removed by metal or pi-acid catalysts. For example, an
allyl-blocked carboxylic acid can be deprotected with a Pd -catalyzed reaction in the presence of acid
labile t-butyl carbamate or base-labile acetate amine protecting groups. Yet another form of protecting
group is a resin to which a compound or intermediate may be attached. As long as the residue is attached
to the resin, that functional group is blocked and cannot react. Once released from the resin, the functional
group is available to react.
Typically blocking/protecting groups may be selected from:
H C H
allyl Cbz alloc
H C CH
H 3 3 O
(H C) C
(H C) C
H C 3 3
(CH ) C O
t-butyl
TBDMS
Teoc
O H C
(C H ) C
(CH ) C 6 5 3
H CO
trityl acetyl
Fmoc
Other protecting groups, plus a detailed description of techniques applicable to the creation of
protecting groups and their removal are described in Greene and Wuts, Protective Groups in Organic
Synthesis, 3rd Ed., John Wiley & Sons, New York, NY, 1999, and Kocienski, Protective Groups, Thieme
Verlag, New York, NY, 1994, which are incorporated herein by reference for such disclosure.
Synthesis of Compounds
In certain embodiments, provided herein are methods of making the tyrosine kinase inhibitor
compounds described herein. In certain embodiments, compounds described herein are synthesized using
the following synthetic schemes. In other embodiments, compounds are synthesized using methodologies
analogous to those described below by the use of appropriate alternative starting materials.
The starting material used for the synthesis of the compounds described herein is either
synthesized or obtained from commercial sources, such as, but not limited to, Bachem (Torrance,
California), or Sigma-Aldrich Chemical Co. (St. Louis, Mo.). The compounds described herein, and other
related compounds having different substituents are optionally synthesized using techniques and
materials, such as described, for example, in March, ADVANCED ORGANIC CHEMISTRY 4 Ed., (Wiley
1992); Carey and Sundberg, ADVANCED ORGANIC CHEMISTRY 4 Ed., Vols. A and B (Plenum 2000,
2001); Green and Wuts, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS 3 Ed., (Wiley 1999); Fieser and
Fieser’s Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd’s Chemistry
of Carbon Compounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989); Organic
Reactions, Volumes 1-40 (John Wiley and Sons, 1991); and Larock’s Comprehensive Organic
Transformations (VCH Publishers Inc., 1989). Other methods for the synthesis of compounds described
herein may be found in International Patent Publication No. WO 01/01982901, Arnold et al. Bioorganic
& Medicinal Chemistry Letters 10 (2000) 2167-2170; Burchat et al. Bioorganic & Medicinal Chemistry
Letters 12 (2002) 1687-1690. As a guide the following synthetic methods may be utilized.
The products of the reactions are optionally isolated and purified, if desired, using
conventional techniques, including, but not limited to, filtration, distillation, crystallization,
chromatography and the like. Such materials are optionally characterized using conventional means,
including physical constants and spectral data.
Compounds described herein are optionally prepared using the synthetic methods described
herein as a single isomer or a mixture of isomers.
A non-limiting example of a synthetic approach towards the preparation of compounds of
Formula (I), (IA), (II), (III), (IV), (V), (VI), (VIA), (VIB), and (VII), focusing on the core ring preparation
is shown in Scheme 1.
Scheme 1.
NC CN
R COOH
R COCl
DIEA, THF
R = Ar or CR R Ar
NH NH
Me SO 2 2 formamide
EtOH
R NH
mitsunobu or
N alkylation
Referring to Scheme 1, the carboxylic acid 1 is converted to acid chloride by the known
procedures, for example, using reagents such as oxalyl chloride or thionyl chloride in an inert solvent such
as dichloromethane. The acid chloride intermediate 2 is then converted to the corresponding pyrazole 3
by, for example, reacting with malononitrile and methane sulfate followed by hydrazine. The formation of
pyrimidine ring (e.g. compound 4) is accomplished, in one embodiment, by heating the pyrazole with
formamide as a solvent. One of skilled in the art would readily find other suitable conditions to prepare
pyrimidine ring. Derivatization at ring nitrogen of compound 4, e.g. alkylation, is completed using
standard Mitsunobu condition with the corresponding alcohol or under standard alkylation conditions with
corresponding electrophile such as alkyl mesylate or alkyl halide. (All of the name reactions referenced
here could be found in Li, “Name Reactions: A Collection of Detailed Reaction Mechanisms” (Springer,
2003))
A non-limiting example of a synthetic approach towards the preparation of compounds of
Formula (II) is shown in Scheme 2. The 3-iodo-1H-pyrazolo[3,4-d]pyrimidine intermediates 5a are
versatile under a variety of known conditions for the installation of aromatic groups or aromatic groups
with linker at C-3 position. Specific designed heteroaryl derivative at C-3 position are prepared in on
embodiment via Mitsunobu reaction. In some embodiments, the heteroaryl groups are derivatized via its
aldehyde precursors. In other embodiments, the heteroaryl groups are derivatized via its carboxylic acid
precursors.
Scheme 2.
NH NH
I CN
Zn(CN)2
[I ]
[Pd]
N N N
[Pd]
NH NH
COOH 2
HetAr NH
HetAr
mitsunobu or
alkylation
Referring to Scheme 2, in one embodiment, commercially available 1H-pyrazolo[3,4-
d]pyrimidinamine (R = H) is reacted with N-iodosuccinamide to give 3-iodo-1H-pyrazolo[3,4-
d]pyrimidinamine. In some embodiments, the 3-iodo-1H-pyrazolo[3,4-d]pyrimidine intermediates 6
are converted to nitrile compounds 7 using palladium catalyst under known procedures. The nitrile group
is converted to aldehyde by, for example, reducing reagent such as DIBAL or it is converted to acid by
hydrolysis in basic or acid media. In some embodiments, the 3-iodo-1H-pyrazolo[3,4-d]pyrimidine
intermediates 6 are derivatized by conversion of iodo to heteroaromatic substituents using palladium
catalyzed cross-coupling condition such as Suzuki reaction. In other embodiments, the acid or aldehyde
group is converted to heteroaromatic group using procedures/methods outlined in Joule and Mills,
“Heterocyclic Chemistry” (Wiley-Blackwell, 2010).
A non-limiting example of a synthetic approach towards the preparation of compounds of
Formula (I) is shown in Scheme 3. In some embodiments, after converting the nitrile precursor 7 to a
carboxylic acids (11 or 12), the corresponding acids are converted to acylaromatic compounds (13 or 14)
by Friedel-Krafts reaction. The resulting compounds 14 serve as precursor to the corresponding thionyl, or
iminyl analogs.
Scheme 3.
2 CN CN
COOH
mitsunobu or
alkylation
11 R
2 NH
COOH Ar
NH Ar
N mitsunobu or
2 N alkylation
2 NH
I NH Ar
[Pd] or [Cu]
a a b
L = CR R , O, S, NR
R N N
In some embodiments, the 3-iodo-1H-pyrazolo[3,4-d]pyrimidine intermediates 15 undergo
Suzuki and Stille coupling reaction to provide compounds 16 with L = CR R (palladium catalyst);
compounds with L = O or S (copper(I) catalyst). The intermediates undergo Buckwald-Hartwig coupling
reaction with palladium catalyst to provide compounds with L = NR . (Scheme 3)
A non-limiting example of a synthetic approach towards the preparation of compounds of
Formula (III) is shown in Scheme 4. In some embodiments, R group is installed after derivatization at C-
3 and at N-1.
Scheme 4.
Cl NH
N POCl N N
HO N MeOH
Cl N Cl N
oxypurine
17 18
R NH
NH NH
[Pd] or [Cu]
N N N
2 N N
R N N
Cl N
3 Cl N
Cl N
R = OH, NH , alkyl
19
In some embodiments, starting from commercially available oxypurine followed known
procedures provide compounds 21 with 6-halide moiety (i.e. 6-chloro-1H-pyrazolo[3,4-d]pyrimidine
analogs). In some embodiments, palladium catalyst coupling reaction such as Suzuki reaction converts
the 6-halide to alkyl group. Copper (I) catalyst coupling reaction converts the 6-halide to OH or NH
group (Scheme 4).
A non-limiting example of a synthetic approach towards the preparation of certain
compounds of Formula (IV) is shown in Scheme 5.
Scheme 5
NH 2
2 2 N
R N 2
R = OH, NH , alkyl, halogen
X = OH, alkoxy, thiol, halogen
N [Pd] 2 N
2 N R
R X = alkyl
In some embodiments, 4-amino precursors 22 are converted to halide, hydroxy, alkoxy, thiol
compounds by Sandmeyer reaction (22 to 23a). In other embodiments, Suziki reaction with the 4-
bromide precursors 24 provide the corresponding alkyl compounds 23b.
The compounds prepared by the methods disclosed herein are purified by conventional
means, such as, for example, filtration, recrystallization, chromatography, distillation, and combinations
thereof.
Any combination of the groups described above for the various variables is contemplated
herein. It is understood that substituents and substitution patterns on the compounds provided herein can
be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can
be synthesized by techniques known in the art, as well as those set forth herein.
Further Forms of Compounds
Compounds disclosed herein have a structure of Formula (I), (IA), (II), (III), (IV), (V), (VI),
(VIA), (VIB), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), or (XIV). It is understood that when reference is
made to compounds described herein, it is meant to include compounds of any of Formula (I), (IA), (II),
(III), (IV), (V), (VI), (VIA), (VIB), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), or (XIV), as well as to all
of the specific compounds that fall within the scope of these generic formulae, unless otherwise indicated.
In some embodiments, the compounds described herein possess one or more stereocenters and
in further embodiments, each center exists in the R or S configuration. The compounds presented herein
include all diastereomeric, enantiomeric, and epimeric forms as well as the appropriate mixtures thereof.
In other embodiments, stereoisomers are obtained, if desired, by methods such as, for example, the
separation of stereoisomers by chiral chromatographic columns.
In further embodiments, diasteromeric mixtures are separated into their individual
diastereomers on the basis of their physical chemical differences by methods known, for example, by
chromatography and/or fractional crystallization. In one embodiment, enantiomers can be separated by
chiral chromatographic columns. In other embodiments, enantiomers can be separated by converting the
enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active
compound (e.g., alcohol), separating the diastereomers and converting (e.g., hydrolyzing) the individual
diastereomers to the corresponding pure enantiomers. All such isomers, including diastereomers,
enantiomers, and mixtures thereof are considered as part of the compositions described herein.
The methods and formulations described herein include the use of N-oxides, crystalline forms
(also known as polymorphs), or pharmaceutically acceptable salts of compounds described herein. In
some situations, compounds exist as tautomers. All tautomers are included within the scope of the
compounds presented herein. In addition, the compounds described herein can exist in unsolvated as well
as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. The
solvated forms of the compounds presented herein are also considered to be disclosed herein.
In further embodiments, compounds of any of Formula (I), (IA), (II), (III), (IV), (V), (VI),
(VIA), (VIB), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), or (XIV) in unoxidized form are prepared from
N-oxides of compounds of any of Formula (I), (IA), (II), (III), (IV), (V), (VI), (VIA), (VIB), (VII), (VIII),
(IX), (X), (XI), (XII), (XIII), or (XIV) by treating with a reducing agent, such as, but not limited to, sulfur,
sulfur dioxide, triphenyl phosphine, lithium borohydride, sodium borohydride, phosphorus trichloride,
tribromide, or the like in a suitable inert organic solvent, such as, but not limited to, acetonitrile, ethanol,
aqueous dioxane, or the like at 0 to 80°C.
Compounds described herein include isotopically-labeled compounds, which are identical to
those recited in the various formulas and structures presented herein, but for the fact that one or more
atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or
mass number usually found in nature. Examples of isotopes that can be incorporated into the present
compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine and chlorine, such as
2 3 13 14 15 18 17 35 18 36
H, H, C, C, N, O, O, S, F, Cl, respectively. Certain isotopically-labeled compounds
3 14
described herein, for example those into which radioactive isotopes such as H and C are incorporated,
are useful in drug and/or substrate tissue distribution assays. Further, substitution with isotopes such as
deuterium, i.e., H, can afford certain therapeutic advantages resulting from greater metabolic stability, for
example increased in vivo half-life or reduced dosage requirements.
In one embodiment is an isolated and/or pure form of a compound of Formula (I), (IA), (II),
(III), (IV), (V), (VI), (VIA), (VIB), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), or (XIV). In another
embodiment, is a compound of Formula (I), (IA), (II), (III), (IV), (V), (VI), (VIA), (VIB), (VII), (VIII),
(IX), (X), (XI), (XII), (XIII), or (XIV) wherein the compound is at least about 40% pure. In another
embodiment, is a compound of Formula (I), (IA), (II), (III), (IV), (V), (VI), (VIA), (VIB), (VII), (VIII),
(IX), (X), (XI), (XII), (XIII), or (XIV) wherein the compound is at least about 50%, about 60%, about
70%, about 80%, about 90%, about 95% pure. In yet another embodiment is a compound of Formula (I),
(IA), (II), (III), (IV), (V), (VI), (VIA), (VIB), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), or (XIV) in an
isolated form. In yet another embodiment, is a compound of Formula (I), (IA), (II), (III), (IV), (V), (VI),
(VIA), (VIB), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), or (XIV) wherein the compound is purified by
chromatography.
Compounds described herein (for example, compounds of Formula (I), (IA), (II), (III), (IV),
(V), (VI), (VIA), (VIB), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), or (XIV)) are optionally in the form
of, and/or used as, pharmaceutically acceptable salts. The type of pharmaceutical acceptable salts, include,
but are not limited to: (1) acid addition salts, formed ) by reacting the free base form of the compound
with a pharmaceutically acceptable: inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric
acid, nitric acid, phosphoric acid, metaphosphoric acid, and the like; or with an organic acid such as acetic
acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid,
malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, trifluoroacetic acid, tartaric acid, citric
acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic
acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid,
toluenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo-[2.2.2]octenecarboxylic acid,
glucoheptonic acid, 4,4’-methylenebis-(3-hydroxyene-1 -carboxylic acid), 3-phenylpropionic acid,
trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid,
hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; (2) salts formed when an
acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion
(e.g. lithium, sodium, potassium), an alkaline earth ion (e.g. magnesium, or calcium), or an aluminum ion;
or coordinates with an organic base. Acceptable organic bases include ethanolamine, diethanolamine,
triethanolamine, tromethamine, N-methylglucamine, and the like. Acceptable inorganic bases include
aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, and
the like.
The corresponding counterions of the pharmaceutically acceptable salts are optionally
analyzed and identified using various methods including, but not limited to, ion exchange
chromatography, ion chromatography, capillary electrophoresis, inductively coupled plasma, atomic
absorption spectroscopy, mass spectrometry, or any combination thereof.
The salts are recovered by using at least one of the following techniques: filtration,
precipitation with a non-solvent followed by filtration, evaporation of the solvent, or, in the case of
aqueous solutions, lyophilization.
It should be understood that a reference to a pharmaceutically acceptable salt includes the
solvent addition forms or crystal forms thereof, particularly solvates or polymorphs. Solvates contain
either stoichiometric or non-stoichiometric amounts of a solvent, and are optionally formed during the
process of crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like.
Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol.
Solvates of compounds described herein can be conveniently prepared or formed during the processes
described herein. In addition, the compounds provided herein can exist in unsolvated as well as solvated
forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of
the compounds and methods provided herein.
It should be understood that a reference to a salt includes the solvent addition forms or crystal
forms thereof, particularly solvates or polymorphs. Solvates contain either stoichiometric or non-
stoichiometric amounts of a solvent, and are often formed during the process of crystallization with
pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the
solvent is water, or alcoholates are formed when the solvent is alcohol. Polymorphs include the different
crystal packing arrangements of the same elemental composition of a compound. Polymorphs usually
have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape,
optical and electrical properties, stability, and solubility. Various factors such as the recrystallization
solvent, rate of crystallization, and storage temperature may cause a single crystal form to dominate.
Compounds described herein are optionally in various forms, including but not limited to,
amorphous forms, milled forms and nano-particulate forms. In addition, compounds described herein
include crystalline forms, also known as polymorphs. Polymorphs include the different crystal packing
arrangements of the same elemental composition of a compound. Polymorphs usually have different X-
ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and
electrical properties, stability, and solubility. Various factors such as the recrystallization solvent, rate of
crystallization, and storage temperature may cause a single crystal form to dominate.
The screening and characterization of the pharmaceutically acceptable salts, polymorphs
and/or solvates may be accomplished using a variety of techniques including, but not limited to, thermal
analysis, x-ray diffraction, spectroscopy, vapor sorption, and microscopy. Thermal analysis methods
address thermo chemical degradation or thermo physical processes including, but not limited to,
polymorphic transitions, and such methods are used to analyze the relationships between polymorphic
forms, determine weight loss, to find the glass transition temperature, or for excipient compatibility
studies. Such methods include, but are not limited to, Differential scanning calorimetry (DSC), Modulated
Differential Scanning Calorimetry (MDCS), Thermogravimetric analysis (TGA), and Thermogravi-metric
and Infrared analysis (TG/IR). X-ray diffraction methods include, but are not limited to, single crystal and
powder diffractometers and synchrotron sources. The various spectroscopic techniques used include, but
are not limited to, Raman, FTIR, UVIS, and NMR (liquid and solid state). The various microscopy
techniques include, but are not limited to, polarized light microscopy, Scanning Electron Microscopy
(SEM) with Energy Dispersive X-Ray Analysis (EDX), Environmental Scanning Electron Microscopy
with EDX (in gas or water vapor atmosphere), IR microscopy, and Raman microscopy.
Therapeutic Uses of Inhibitor Compounds
In one aspect, provided herein are methods for treating a patient by administering a compound
provided herein. In some embodiments, provided herein is a method of inhibiting the activity of tyrosine
kinase(s), such as Btk, or of treating a disease, disorder, or condition, which benefit from inhibition of
tyrosine kinase(s), such as Btk, in a patient, which includes administering to the patient a therapeutically
effective amount of at least one of any of the compounds described herein, or pharmaceutically acceptable
salt, pharmaceutically acceptable tautomer, pharmaceutically acceptable prodrug, or pharmaceutically
acceptable solvate.
In another aspect, provided herein is the use of a compound disclosed herein for inhibiting
Bruton’s tyrosine kinase (Btk) activity or for the treatment of a disease, disorder, or condition, which
benefit from inhibition of Bruton’s tyrosine kinase (Btk) activity.
In one aspect, provided herein is the use of a compound of Formula (I), (IA), (II), (III), (IV),
(V), (VI), (VIA), (VIB), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), or (XIV) in the manufacture of a
medicament for the treatment of an autoimmune disease. In another aspect, provided herein is the use of a
compound of Formula (I), (IA), (II), (III), (IV), (V), (VI), (VIA), (VIB), (VII), (VIII), (IX), (X), (XI),
(XII), (XIII), or (XIV) in the manufacture of a medicament for the treatment of a heteroimmune disease.
In another aspect, provided herein is the use of a compound of Formula (I), (IA), (II), (III), (IV), (V), (VI),
(VIA), (VIB), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), or (XIV) in the manufacture of a medicament for
the treatment of an inflammatory disease. In another aspect, provided herein is the use of a compound of
Formula (I), (IA), (II), (III), (IV), (V), (VI), (VIA), (VIB), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), or
(XIV) in the manufacture of a medicament for the treatment of a cancer. In another aspect, provided
herein is the use of a compound of Formula (I), (IA), (II), (III), (IV), (V), (VI), (VIA), (VIB), (VII),
(VIII), (IX), (X), (XI), (XII), (XIII), or (XIV) in the manufacture of a medicament for the treatment of a
thromboembolic disorder. In another aspect, provided herein is the use of a compound of Formula (I),
(IA), (II), (III), (IV), (V), (VI), (VIA), (VIB), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), or (XIV) in the
manufacture of a medicament for the treatment of mastocytosis. In another aspect, provided herein is the
use of a compound of Formula (I), (IA), (II), (III), (IV), (V), (VI), (VIA), (VIB), (VII), (VIII), (IX), (X),
(XI), (XII), (XIII), or (XIV) in the manufacture of a medicament for the treatment of a bone resorption
disorder. In another aspect, provided herein is the use of a compound of Formula (I), (IA), (II), (III), (IV),
(V), (VI), (VIA), (VIB), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), or (XIV) in the manufacture of a
medicament for the treatment of osteoporosis. In another aspect, provided herein is the use of a compound
of Formula (I), (IA), (II), (III), (IV), (V), (VI), (VIA), (VIB), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), or
(XIV) in the manufacture of a medicament for the treatment of a hematological malignancy.
In some embodiments, compounds provided herein are administered to a human. In some
embodiments, compounds provided herein are orally administered. In other embodiments, the
pharmaceutical formulation that is formulated for a route of administration is selected from oral
administration, parenteral administration, buccal administration, nasal administration, topical
administration, or rectal administration.
In other embodiments, compounds provided herein are used for the formulation of a
medicament for the inhibition of tyrosine kinase activity. In some other embodiments, compounds
provided herein are used for the formulation of a medicament for the inhibition of Bruton’s tyrosine
kinase (Btk) activity.
In a further aspect, provided herein is a method for treating an autoimmune disease by
administering to a subject in need thereof a composition containing a therapeutically effective amount of
at least one compound having the structure of Formula (I), (IA), (II), (III), (IV), (V), (VI), (VIA), (VIB),
(VII), (VIII), (IX), (X), (XI), (XII), (XIII), or (XIV). In one embodiment, the autoimmune disease is
arthritis. In another embodiment, the autoimmune disease is lupus. In some embodiments, the
autoimmune disease is inflammatory bowel disease (including Crohn’s disease and ulcerative colitis),
rheumatoid arthritis, psoriatic arthritis, osteoarthritis, Still’s disease, juvenile arthritis, lupus, diabetes,
myasthenia gravis, Hashimoto's thyroiditis, Ord's thyroiditis, Graves' disease Sjögren's syndrome, multiple
sclerosis, Guillain-Barré syndrome, acute disseminated encephalomyelitis, Addison's disease, opsoclonus-
myoclonus syndrome, ankylosing spondylitisis, antiphospholipid antibody syndrome, aplastic anemia,
autoimmune hepatitis, coeliac disease, Goodpasture's syndrome, idiopathic thrombocytopenic purpura,
optic neuritis, scleroderma, primary biliary cirrhosis, Reiter's syndrome, Takayasu's arteritis, temporal
arteritis, warm autoimmune hemolytic anemia, Wegener's granulomatosis, psoriasis, alopecia universalis,
Behçet's disease, chronic fatigue, dysautonomia, endometriosis, interstitial cystitis, neuromyotonia,
scleroderma, or vulvodynia.
In a further aspect, provided herein is a method for treating a heteroimmune condition or
disease by administering to a subject in need thereof a composition containing a therapeutically effective
amount of at least one compound having the structure of Formula (I), (IA), (II), (III), (IV), (V), (VI),
(VIA), (VIB), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), or (XIV). In some embodiments, the
heteroimmune condition or disease is graft versus host disease, transplantation, transfusion, anaphylaxis,
allergy, type I hypersensitivity, allergic conjunctivitis, allergic rhinitis, or atopic dermatitis.
In a further aspect, provided herein is a method for treating an inflammatory disease by
administering to a subject in need thereof a composition containing a therapeutically effective amount of
at least one compound having the structure of Formula (I), (IA), (II), (III), (IV), (V), (VI), (VIA), (VIB),
(VII), (VIII), (IX), (X), (XI), (XII), (XIII), or (XIV). In some embodiments, the inflammatory disease is
asthma, inflammatory bowel disease (including Crohn’s disease and ulcerative colitis), appendicitis,
blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, colitis, conjunctivitis,
cystitis, dacryoadenitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis,
enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, hepatitis,
hidradenitis suppurativa, laryngitis, mastitis, meningitis, myelitis myocarditis, myositis, nephritis,
oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleuritis,
phlebitis, pneumonitis, pneumonia, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis,
stomatitis, synovitis, tendonitis, tonsillitis, uveitis, vaginitis, vasculitis, or vulvitis.
In yet another aspect, provided herein is a method for treating a cancer by administering to a
subject in need thereof a composition containing a therapeutically effective amount of at least one
compound having the structure of Formula (I), (IA), (II), (III), (IV), (V), (VI), (VIA), (VIB), (VII), (VIII),
(IX), (X), (XI), (XII), (XIII), or (XIV). In one embodiment, the cancer is a B-cell proliferative disorder,
e.g., diffuse large B cell lymphoma, follicular lymphoma, chronic lymphocytic lymphoma, chronic
lymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma/Waldenström
macroglobulinemia, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, extranodal
marginal zone B cell lymphoma, nodal marginal zone B cell lymphoma, mantle cell lymphoma,
mediastinal (thymic) large B cell lymphoma, intravascular large B cell lymphoma, primary effusion
lymphoma, Burkitt’s lymphoma/leukemia, or lymphomatoid granulomatosis. In some embodiments,
where the subject is suffering from a cancer, an anti-cancer agent is administered to the subject in addition
to one of the above-mentioned compounds. In one embodiment, the anti-cancer agent is an inhibitor of
mitogen-activated protein kinase signaling, e.g., U0126, PD98059, PD184352, PD0325901, ARRY-
142886, SB239063, SP600125, BAY 43-9006, wortmannin, or LY294002.
In another aspect, provided herein is a method for treating a thromboembolic disorder by
administering to a subject in need thereof a composition containing a therapeutically effective amount of
at least one compound having the structure of Formula (I), (IA), (II), (III), (IV), (V), (VI), (VIA), (VIB),
(VII), (VIII), (IX), (X), (XI), (XII), (XIII), or (XIV). In some embodiments, the thromboembolic disorder
is myocardial infarct, angina pectoris, reocclusion after angioplasty, restenosis after angioplasty,
reocclusion after aortocoronary bypass, restenosis after aortocoronary bypass, stroke, transitory ischemia,
a peripheral arterial occlusive disorder, pulmonary embolism, or deep venous thrombosis.
In another aspect, provided herein is a method for treating a mastocytosis by administering to
a subject in need thereof a composition containing a therapeutically effective amount of at least one
compound having the structure of Formula (I), (IA), (II), (III), (IV), (V), (VI), (VIA), (VIB), (VII), (VIII),
(IX), (X), (XI), (XII), (XIII), or (XIV).
In yet another aspect, provided herein is a method for treating an osteoporosis or bone
resorption disorders by administering to a subject in need thereof a composition containing a
therapeutically effective amount of at least one compound having the structure of Formula (I), (IA), (II),
(III), (IV), (V), (VI), (VIA), (VIB), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), or (XIV).
In another aspect, provided herein is a method for treating a hematological malignancy by
administering to a subject in need thereof a composition containing a therapeutically effective amount of
at least one compound having the structure of Formula (I), (IA), (II), (III), (IV), (V), (VI), (VIA), (VIB),
(VII), (VIII), (IX), (X), (XI), (XII), (XIII), or (XIV). In some embodiments, the hematological malignancy
is a chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), high risk CLL, a non-
CLL/SLL lymphoma, follicular lymphoma, diffuse large B-cell lymphoma (DLBCL), mantle cell
lymphoma, Waldenstrom’s macroglobulinemia, multiple myeloma, marginal zone lymphoma, Burkitt’s
lymphoma, non-Burkitt high grade B cell lymphoma, extranodal marginal zone B cell lymphoma, acute or
chronic myelogenous (or myeloid) leukemia, myelodysplastic syndrome, acute lymphoblastic leukemia,
relapsed or refractory diffuse large B-cell lymphoma (DLBCL), relapsed or refractory mantle cell
lymphoma, relapsed or refractory follicular lymphoma, relapsed or refractory CLL, relapsed or refractory
SLL, relapsed or refractory multiple myeloma, Hodgkin's lymphoma or non-Hodgkin's lymphoma (NHL).
In further embodiments, the compound inhibits the Bruton’s tyrosine kinase.
Also described herein are kinase inhibitors that selectively bind to a protein tyrosine kinase
selected from Btk, a Btk homolog, and a Btk kinase cysteine homolog, in which the kinase inhibitor
reversibly and non-selectively binds to a multiplicity of protein tyrosine kinases. In one embodiment the
plasma half life of the kinase inhibitor is less than about 4 hours. In another embodiment the plasma half
life of the kinase inhibitor is less than about 3 hours.
In a further embodiment are kinase inhibitors that selectively bind to at least one of Btk, Jak3,
Blk, Bmx, Tec, and Itk. In another embodiment are kinase inhibitors that selectively bind to Btk. In
another embodiment are kinase inhibitors that selectively bind to Jak3. In another embodiment are kinase
inhibitors that selectively bind to Tec. In another embodiment are kinase inhibitors that selectively bind to
Itk. In another embodiment are kinase inhibitors that selectively bind to Btk and Tec. In another
embodiment are kinase inhibitors that selectively bind to Blk. In yet a further embodiment are kinase
inhibitors that reversibly and non-selectively bind to a multiplicity of src-family protein kinase inhibitors.
Also described herein are inhibitors that are identified using such methods, assays and
systems. In some embodiments, the inhibitor is a selective inhibitor, including selectivity for a particular
Btk kinase cysteine homolog over other Btk kinase cysteine homologs.
Further described herein are pharmaceutical formulations comprising the kinase inhibitors of
any kinase inhibitor compound previously listed. In one embodiment the pharmaceutical formulation
includes a pharmaceutical acceptable excipient. In some embodiments, pharmaceutical formulations
provided herein are administered to a human. In some embodiments, the selective kinase inhibitors
provided herein are orally administered. In other embodiments, the selective kinase inhibitors provided
herein are used for the formulation of a medicament for the inhibition of tyrosine kinase activity. In some
other embodiments, the selective kinase inhibitors provided herein are used for the formulation of a
medicament for the inhibition of a kinase activity, including a tyrosine kinase activity, including a Btk
activity, including a Btk homolog activity, including a Btk kinase cysteine homolog activity.
In any of the aforementioned aspects are further embodiments in which administration is
enteral, parenteral, or both, and wherein (a) the effective amount of the compound is systemically
administered to the mammal; (b) the effective amount of the compound is administered orally to the
mammal; (c) the effective amount of the compound is intravenously administered to the mammal; (d) the
effective amount of the compound administered by inhalation; (e) the effective amount of the compound
is administered by nasal administration; or (f) the effective amount of the compound is administered by
injection to the mammal; (g) the effective amount of the compound is administered topically (dermal) to
the mammal; (h) the effective amount of the compound is administered by ophthalmic administration; or
(i) the effective amount of the compound is administered rectally to the mammal. In further embodiments
the pharmaceutical formulation is formulated for a route of administration selected from oral
administration, parenteral administration, buccal administration, nasal administration, topical
administration, or rectal administration.
In any of the aforementioned aspects are further embodiments comprising single
administrations of the effective amount of the pharmaceutical formulation, including further embodiments
in which (i) the pharmaceutical formulations is administered once; (ii) the pharmaceutical formulations is
administered to the mammal once a day; (iii) the pharmaceutical formulations is administered to the
mammal multiple times over the span of one day; (iv) continually; or (v) continuously.
In any of the aforementioned aspects are further embodiments comprising multiple
administrations of the effective amount of the pharmaceutical formulations, including further
embodiments in which (i) the pharmaceutical formulations is administered in a single dose; (ii) the time
between multiple administrations is every 6 hours; (iii) the pharmaceutical formulations is administered to
the mammal every 8 hours. In further or alternative embodiments, the method comprises a drug holiday,
wherein the administration of the pharmaceutical formulations is temporarily suspended or the dose of the
pharmaceutical formulations being administered is temporarily reduced; at the end of the drug holiday,
dosing of the pharmaceutical formulations is resumed. The length of the drug holiday varies from 2 days
to 1 year.
In some aspects described herein the inhibitor is selective for one kinase selected from Btk, a
Btk homolog, and a Btk kinase cysteine homolog over at least one other kinase selected from Btk, a Btk
homolog, and a Btk kinase cysteine homolog. In other aspects described herein the inhibitor is selective
for at least one kinase selected from Btk, a Btk homolog, and a Btk kinase cysteine homolog over at least
one other non-kinase molecule having an accessible SH group.
Described herein are methods, compositions, uses and medicaments for the treatment of
disorders comprising administering to a patient in need an inhibitor of an ACK. In some embodiments, the
ACK is Btk or a Btk homolog. In further embodiments, the ACK is Blk or a Blk homolog. In yet further
embodiments, the ACK is tyrosine kinases that share homology with Btk by having a cysteine residue
(including a Cys 481 residue) that can form a covalent bond with the inhibitor.
The methods described herein (which includes uses of a pharmaceutical composition to treat a
disease or disorder, or uses of a compound to form a medicament for treating a disease or disorder)
include administering to a subject in need a composition containing a therapeutically effective amount of
one or more Btk inhibitor compounds described herein. Without being bound by theory, the diverse roles
played by Btk signaling in various hematopoietic cell functions, e.g., B-cell receptor activation, show that
small molecule Btk inhibitors are useful for reducing the risk of or treating a variety of diseases affected
by or affecting many cell types of the hematopoietic lineage including, e.g., autoimmune diseases,
heteroimmune conditions or diseases, inflammatory diseases, cancer (e.g., B-cell proliferative disorders),
and thromboembolic disorders.
In some embodiments, are methods for treating an autoimmune disease or condition
comprising administering to a patient in need a pharmaceutical formulation of any inhibitor of Btk (or a
Btk homolog) of Formula (I), (IA), (II), (III), (IV), (V), (VI), (VIA), (VIB), (VII), (VIII), (IX), (X), (XI),
(XII), (XIII), or (XIV). Such an autoimmune disease or condition includes, but is not limited to,
rheumatoid arthritis, psoriatic arthritis, osteoarthritis, Still’s disease, juvenile arthritis, lupus, diabetes,
myasthenia gravis, Hashimoto's thyroiditis, Ord's thyroiditis, Graves' disease Sjögren's syndrome, multiple
sclerosis, Guillain-Barré syndrome, acute disseminated encephalomyelitis, Addison's disease, opsoclonus-
myoclonus syndrome, ankylosing spondylitisis, antiphospholipid antibody syndrome, aplastic anemia,
autoimmune hepatitis, coeliac disease, Goodpasture's syndrome, idiopathic thrombocytopenic purpura,
optic neuritis, scleroderma, primary biliary cirrhosis, Reiter's syndrome, Takayasu's arteritis, temporal
arteritis, warm autoimmune hemolytic anemia, Wegener's granulomatosis, psoriasis, alopecia universalis,
Behçet's disease, chronic fatigue, dysautonomia, endometriosis, interstitial cystitis, neuromyotonia,
scleroderma, and vulvodynia. In some embodiments, the autoimmune disease is selected from rheumatoid
arthritis or lupus.
In some embodiments, are methods for treating a heteroimmune disease or condition
comprising administering to a patient in need a pharmaceutical formulation of any inhibitor of Btk (or a
Btk homolog) of Formula (I), (IA), (II), (III), (IV), (V), (VI), (VIA), (VIB), (VII), (VIII), (IX), (X), (XI),
(XII), (XIII), or (XIV). Such a heteroimmune condition or disease includes, but is not limited to graft
versus host disease, transplantation, transfusion, anaphylaxis, allergies (e.g., allergies to plant pollens,
latex, drugs, foods, insect poisons, animal hair, animal dander, dust mites, or cockroach calyx), type I
hypersensitivity, allergic conjunctivitis, allergic rhinitis, and atopic dermatitis.
In some embodiments, are methods for treating a cancer comprising administering to a patient
in need a pharmaceutical formulation of any inhibitor of Btk (or a Btk homolog) of Formula (I), (IA), (II),
(III), (IV), (V), (VI), (VIA), (VIB), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), or (XIV). Such a cancer,
e.g., B-cell proliferative disorders, includes but is not limited to diffuse large B cell lymphoma, follicular
lymphoma, chronic lymphocytic lymphoma, chronic lymphocytic leukemia, B-cell prolymphocytic
leukemia, lymphoplasmacytic lymphoma/Waldenström macroglobulinemia, splenic marginal zone
lymphoma, plasma cell myeloma, plasmacytoma, extranodal marginal zone B cell lymphoma, nodal
marginal zone B cell lymphoma, mantle cell lymphoma, mediastinal (thymic) large B cell lymphoma,
intravascular large B cell lymphoma, primary effusion lymphoma, burkitt lymphoma/leukemia, and
lymphomatoid granulomatosis.
In some embodiments, are methods for treating mastocytosis comprising administering to a
patient in need a pharmaceutical formulation of any inhibitor of Btk (or a Btk homolog) of Formula (I),
(IA), (II), (III), (IV), (V), (VI), (VIA), (VIB), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), or (XIV).
Mastocytosis includes but is not limited to diseases characterized by hyperactive mast cells.
In some embodiments, are methods for treating osteoporosis or bone resorption disorders
comprising administering to a patient in need a pharmaceutical formulation of any inhibitor of Btk (or a
Btk homolog) of Formula (I), (IA), (II), (III), (IV), (V), (VI), (VIA), (VIB), (VII), (VIII), (IX), (X), (XI),
(XII), (XIII), or (XIV). Bone resorption disorders include but are not limted to Paget's disease of bone,
osteoporosis, and the bone changes secondary to cancer, such as occur in myeloma and metastases from
breast cancer.
In some embodiments, are methods for treating inflammatory diseases comprising
administering to a patient in need a pharmaceutical formulation of any inhibitor of Btk (or a Btk homolog)
of Formula (I), (IA), (II), (III), (IV), (V), (VI), (VIA), (VIB), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), or
(XIV). Inflammatory diseases include but are not limited to asthma, inflammatory bowel disease,
appendicitis, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, colitis,
conjunctivitis, cystitis, dacryoadenitis, dermatitis, dermatomyositis, encephalitis, endocarditis,
endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis,
gastroenteritis, hepatitis, hidradenitis suppurativa, laryngitis, mastitis, meningitis, myelitis myocarditis,
myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, peritonitis,
pharyngitis, pleuritis, phlebitis, pneumonitis, pneumonia, proctitis, prostatitis, pyelonephritis, rhinitis,
salpingitis, sinusitis, stomatitis, synovitis, tendonitis, tonsillitis, uveitis, vaginitis, vasculitis, and vulvitis.
In another aspect, are methods for treating hematological malignancies by administering to a
patient in need a pharmaceutical formulation of any inhibitor of Btk (or a Btk homolog) of Formula (I),
(IA), (II), (III), (IV), (V), (VI), (VIA), (VIB), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), or (XIV). The
hematological malignancies include but are not limited to chronic lymphocytic leukemia (CLL), small
lymphocytic lymphoma (SLL), high risk CLL, non-CLL/SLL lymphoma, follicular lymphoma, diffuse
large B-cell lymphoma (DLBCL), mantle cell lymphoma, Waldenstrom’s macroglobulinemia, multiple
myeloma, marginal zone lymphoma, Burkitt’s lymphoma, non-Burkitt high grade B cell lymphoma,
extranodal marginal zone B cell lymphoma, acute or chronic myelogenous (or myeloid) leukemia,
myelodysplastic syndrome, acute lymphoblastic leukemia, relapsed or refractory diffuse large B-cell
lymphoma (DLBCL), relapsed or refractory mantle cell lymphoma, relapsed or refractory follicular
lymphoma, relapsed or refractory CLL, relapsed or refractory SLL, relapsed or refractory multiple
myeloma, Hodgkin's lymphoma and non-Hodgkin's lymphoma (NHL).
A subset of tyrosine kinases other than Btk are also expected to be useful as therapeutic
targets in a number of health conditions, including:
autoimmune diseases, which include, but are not limited to, rheumatoid arthritis, psoriatic
arthritis, osteoarthritis, Still’s disease, juvenile arthritis, lupus, diabetes, myasthenia gravis,
Hashimoto's thyroiditis, Ord's thyroiditis, Graves' disease Sjögren's syndrome, multiple sclerosis,
Guillain-Barré syndrome, acute disseminated encephalomyelitis, Addison's disease, opsoclonus-
myoclonus syndrome, ankylosing spondylitisis, antiphospholipid antibody syndrome, aplastic
anemia, autoimmune hepatitis, coeliac disease, Goodpasture's syndrome, idiopathic
thrombocytopenic purpura, optic neuritis, scleroderma, primary biliary cirrhosis, Reiter's
syndrome, Takayasu's arteritis, temporal arteritis, warm autoimmune hemolytic anemia,
Wegener's granulomatosis, psoriasis, alopecia universalis, Behçet's disease, chronic fatigue,
dysautonomia, endometriosis, interstitial cystitis, neuromyotonia, scleroderma, and vulvodynia.
heteroimmune conditions or diseases, which include, but are not limited to graft versus host
disease, transplantation, transfusion, anaphylaxis, allergies (e.g., allergies to plant pollens, latex,
drugs, foods, insect poisons, animal hair, animal dander, dust mites, or cockroach calyx), type I
hypersensitivity, allergic conjunctivitis, allergic rhinitis, and atopic dermatitis.
inflammatory diseases, which include, but are not limited to asthma, inflammatory bowel disease,
appendicitis, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis,
colitis, conjunctivitis, cystitis, dacryoadenitis, dermatitis, dermatomyositis, encephalitis,
endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis,
gastritis, gastroenteritis, hepatitis, hidradenitis suppurativa, laryngitis, mastitis, meningitis,
myelitis myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis,
pericarditis, peritonitis, pharyngitis, pleuritis, phlebitis, pneumonitis, pneumonia, proctitis,
prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendonitis, tonsillitis,
uveitis, vaginitis, vasculitis, and vulvitis.
a cancer, e.g., B-cell proliferative disorders, which include, but are not limited to diffuse large B
cell lymphoma, follicular lymphoma, chronic lymphocytic lymphoma, chronic lymphocytic
leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma/Waldenström
macroglobulinemia, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma,
extranodal marginal zone B cell lymphoma, nodal marginal zone B cell lymphoma, mantle cell
lymphoma, mediastinal (thymic) large B cell lymphoma, intravascular large B cell lymphoma,
primary effusion lymphoma, burkitt lymphoma/leukemia, and lymphomatoid granulomatosis.
thromboembolic disorders, which include, but are not limited to myocardial infarct, angina
pectoris (including unstable angina), reocclusions or restenoses after angioplasty or aortocoronary
bypass, stroke, transitory ischemia, peripheral arterial occlusive disorders, pulmonary embolisms,
and deep venous thromboses.
mastocytosis, which include but are not limited to diseases characterized by hyperactive mast
cells.
bone resorption disorders, which include but are not limted to Paget's disease of bone,
osteoporosis, and the bone changes secondary to cancer, such as occur in myeloma and metastases
from breast cancer.
Symptoms, diagnostic tests, and prognostic tests for each of the above-mentioned conditions
include, e.g., Harrison’s Principles of Internal Medicine ,” 16th ed., 2004, The McGraw-Hill Companies,
Inc. Dey et al. (2006), Cytojournal 3(24), and the “Revised European American Lymphoma” (REAL)
classification system (see, e.g., the website maintained by the National Cancer Institute).
A number of animal models are useful for establishing a range of therapeutically effective
doses of inhibitors, including Btk inhibitor compounds for treating any of the foregoing diseases. Also, for
example, dosing of inhibitor compounds for treating an autoimmune disease can be assessed in a mouse
model of rheumatoid arthitis. In this model, arthritis is induced in Balb/c mice by administering anti-
collagen antibodies and lipopolysaccharide. See Nandakumar et al. (2003), Am. J. Pathol 163:1827-1837.
In another example, dosing of inhibitors for the treatment of B-cell proliferative disorders can be
examined in, e.g., a human-to-mouse xenograft model in which human B-cell lymphoma cells (e.g.
Ramos cells) are implanted into immunodefficient mice (e.g., “nude” mice) as described in, e.g., Pagel et
al. (2005), Clin Cancer Res 11(13):4857-4866. Animal models for treatment of thromboembolic disorders
are also known.
In one embodiment, the therapeutic efficacy of the compound for one of the foregoing
diseases is optimized during a course of treatment. For example, a subject being treated optionally
undergoes a diagnostic evaluation to correlate the relief of disease symptoms or pathologies to inhibition
of in vivo Btk activity achieved by administering a given dose of a Btk inhibitor. Cellular assays are used
to determine in vivo activity of Btk in the presence or absence of an Btk inhibitor. For example, since
activated Btk is phosphorylated at tyrosine 223 (Y223) and tyrosine 551 (Y551), phospho-specific
immunocytochemical staining of P-Y223 or P-Y551-positive cells are used to detect or quantify activation
of Bkt in a population of cells (e.g., by FACS analysis of stained vs unstained cells). See, e.g., Nisitani et
al. (1999), Proc. Natl. Acad. Sci, USA 96:2221-2226. Thus, the amount of the Btk inhibitor inhibitor
compound that is administered to a subject is optionally increased or decreased as needed so as to
maintain a level of Btk inhibition optimal for treating the subject’s disease state.
Combination Treatments
In some embodiments, the Btk inhibitor compositions described herein are used in
combination with other well known therapeutic reagents that are selected for their therapeutic value for
the condition to be treated. In general, the compositions described herein and, in embodiments where
combinational therapy is employed, other agents do not have to be administered in the same
pharmaceutical composition, and are optionally, because of different physical and chemical
characteristics, have to be administered by different routes. The initial administration is made, for
example, according to established protocols, and then, based upon the observed effects, the dosage, modes
of administration and times of administration are modified.
In certain instances, it is appropriate to administer at least one Btk inhibitor compound
described herein in combination with another therapeutic agent. By way of example only, if one of the
side effects experienced by a patient upon receiving one of the Btk inhibitor compounds described herein
is nausea, then it is appropriate to administer an anti-nausea agent in combination with the initial
therapeutic agent. Or, by way of example only, the therapeutic effectiveness of one of the compounds
described herein is enhanced by administration of an adjuvant (i.e., by itself the adjuvant has minimal
therapeutic benefit, but in combination with another therapeutic agent, the overall therapeutic benefit to
the patient is enhanced). Or, by way of example only, the benefit experienced by a patient is increased by
administering one of the compounds described herein with another therapeutic agent (which also includes
a therapeutic regimen) that also has therapeutic benefit. In any case, regardless of the disease, disorder or
condition being treated, the overall benefit experienced by the patient is in some embodiments simply
additive of the two therapeutic agents or in other embodiments, the patient experiences a synergistic
benefit.
The particular choice of compounds used will depend upon the diagnosis of the attending
physicians and their judgment of the condition of the patient and the appropriate treatment protocol. The
compounds are optionally administered concurrently (e.g., simultaneously, essentially simultaneously or
within the same treatment protocol) or sequentially, depending upon the nature of the disease, disorder, or
condition, the condition of the patient, and the actual choice of compounds used. The determination of the
order of administration, and the number of repetitions of administration of each therapeutic agent during a
treatment protocol, is based on an evaluation of the disease being treated and the condition of the patient.
Therapeutically-effective dosages can vary when the drugs are used in treatment
combinations. Methods for experimentally determining therapeutically-effective dosages of drugs and
other agents for use in combination treatment regimens are described in the literature. For example, the
use of metronomic dosing, i.e., providing more frequent, lower doses in order to minimize toxic side
effects, has been described extensively in the literature Combination treatment further includes periodic
treatments that start and stop at various times to assist with the clinical management of the patient.
For combination therapies described herein, dosages of the co-administered compounds will
of course vary depending on the type of co-drug employed, on the specific drug employed, on the disease
or condition being treated and so forth. In addition, when co-administered with one or more biologically
active agents, the compound provided herein may be administered either simultaneously with the
biologically active agent(s), or sequentially. If administered sequentially, the attending physician will
decide on the appropriate sequence of administering protein in combination with the biologically active
agent(s).
In any case, the multiple therapeutic agents (one of which is a compound of Formula (I)
described herein) are optionally administered in any order or even simultaneously. If simultaneously, the
multiple therapeutic agents are optionally provided in a single, unified form, or in multiple forms (by way
of example only, either as a single pill or as two separate pills). One of the therapeutic agents may be
given in multiple doses, or both may be given as multiple doses. If not simultaneous, the timing between
the multiple doses may vary from more than zero weeks to less than four weeks. In addition, the
combination methods, compositions and formulations are not to be limited to the use of only two agents;
the use of multiple therapeutic combinations are also envisioned.
It is understood that the dosage regimen to treat, prevent, or ameliorate the condition(s) for
which relief is sought, can be modified in accordance with a variety of factors. These factors include the
disorder from which the subject suffers, as well as the age, weight, sex, diet, and medical condition of the
subject. Thus, the dosage regimen actually employed can vary widely and therefore can deviate from the
dosage regimens set forth herein.
The pharmaceutical agents which make up the combination therapy disclosed herein may be a
combined dosage form or in separate dosage forms intended for substantially simultaneous administration.
The pharmaceutical agents that make up the combination therapy may also be administered sequentially,
with either therapeutic compound being administered by a regimen calling for two-step administration.
The two-step administration regimen may call for sequential administration of the active agents or spaced-
apart administration of the separate active agents. The time period between the multiple administration
steps may range from, a few minutes to several hours, depending upon the properties of each
pharmaceutical agent, such as potency, solubility, bioavailability, plasma half-life and kinetic profile of
the pharmaceutical agent. Circadian variation of the target molecule concentration may also determine the
optimal dose interval.
In addition, the compounds described herein also are optionally used in combination with
procedures that provide additional or synergistic benefit to the patient. By way of example only, patients
are expected to find therapeutic and/or prophylactic benefit in the methods described herein, wherein
pharmaceutical composition of a compound disclosed herein and /or combinations with other therapeutics
are combined with genetic testing to determine whether that individual is a carrier of a mutant gene that is
known to be correlated with certain diseases or conditions.
In some embodiments, the compounds described herein and combination therapies are
administered before, during or after the occurrence of a disease or condition, and the timing of
administering the composition containing a compound can vary. Thus, for example, the compounds can
be used as a prophylactic and can be administered continuously to subjects with a propensity to develop
conditions or diseases in order to prevent the occurrence of the disease or condition. The compounds and
compositions can be administered to a subject during or as soon as possible after the onset of the
symptoms. The administration of the compounds can be initiated within the first 48 hours of the onset of
the symptoms, within the first 6 hours of the onset of the symptoms, or within 3 hours of the onset of the
symptoms. The initial administration can be via any route practical, such as, for example, an intravenous
injection, a bolus injection, infusion over 5 minutes to about 5 hours, a pill, a capsule, transdermal patch,
buccal delivery, and the like, or combination thereof. A compound should be administered as soon as is
practicable after the onset of a disease or condition is detected or suspected, and for a length of time
necessary for the treatment of the disease, such as, for example, from about 1 month to about 3 months.
The length of treatment can vary for each subject, and the length can be determined using the known
criteria. For example, the compound or a formulation containing the compound can be administered for at
least 2 weeks, between about 1 month to about 5 years, or from about 1 month to about 3 years.
Therapeutic Agents for Use in Combination with an Inhibitor Compound
In some embodiments, where the subject is suffering from or at risk of suffering from an
autoimmune disease, an inflammatory disease, or an allergy disease, a Btk inhibitor compound is used in
with one or more of the following therapeutic agents in any combination: immunosuppressants (e.g.,
tacrolimus, cyclosporin, rapamicin, methotrexate, cyclophosphamide, azathioprine, mercaptopurine,
mycophenolate, or FTY720), glucocorticoids (e.g., prednisone, cortisone acetate, prednisolone,
methylprednisolone, dexamethasone, betamethasone, triamcinolone, beclometasone, fludrocortisone
acetate, deoxycorticosterone acetate, aldosterone), non-steroidal anti-inflammatory drugs (e.g., salicylates,
arylalkanoic acids, 2-arylpropionic acids, N-arylanthranilic acids, oxicams, coxibs, or sulphonanilides),
Coxspecific inhibitors (e.g., valdecoxib, celecoxib, or rofecoxib), leflunomide, gold thioglucose, gold
thiomalate, aurofin, sulfasalazine, hydroxychloroquinine, minocycline, TNF-α binding proteins (e.g.,
infliximab, etanercept, or adalimumab), abatacept, anakinra, interferon- , interferon- , interleukin-2,
allergy vaccines, antihistamines, antileukotrienes, beta-agonists, theophylline, anticholinergics or other
selective kinase inhibitors (e.g p38 inhibitors, Syk inhibitors, PKC inhibitors).
In yet other embodiments, where the subject is suffering from or at risk of suffering from a B-
cell proliferative disorder (e.g., plasma cell myeloma), the subjected is treated with a Btk inhibitor
compound in any combination with one or more other anti-cancer agents. In some embodiments, one or
more of the anti-cancer agents are proapoptotic agents. Examples of anti-cancer agents include, but are
not limited to, any of the following: gossyphol, genasense®, polyphenol E, Chlorofusin, all trans-retinoic
acid (ATRA), bryostatin, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), 5-aza-2’-
deoxycytidine, all trans retinoic acid, doxorubicin, vincristine, etoposide, gemcitabine, imatinib
(Gleevec®), geldanamycin, 17-N-AllylaminoDemethoxygeldanamycin (17-AAG), flavopiridol,
LY294002, bortezomib, trastuzumab, BAY 11-7082, PKC412, or PD184352, Taxol™, also referred to as
“paclitaxel”, which is a well-known anti-cancer drug which acts by enhancing and stabilizing microtubule
formation, and analogs of Taxol™, such as Taxotere™. Compounds that have the basic taxane skeleton as
a common structure feature, have also been shown to have the ability to arrest cells in the G2-M phases
due to stabilized microtubules and may be useful for treating cancer in combination with the compounds
described herein.
Further examples of anti-cancer agents for use in combination with an Btk inhibitor
compound include inhibitors of mitogen-activated protein kinase signaling, e.g., U0126, PD98059,
PD184352, PD0325901, ARRY-142886, SB239063, SP600125, BAY 43-9006, wortmannin, or
LY294002; Syk inhibitors; mTOR inhibitors; and antibodies (e.g., rituxan).
In further embodiments, other anti-cancer agents are employed in combination with an Btk
inhibitor compound include Adriamycin, Dactinomycin, Bleomycin, Vinblastine, Cisplatin, acivicin;
aclarubicin; acodazole hydrochloride; acronine; adozelesin; aldesleukin; altretamine; ambomycin;
ametantrone acetate; aminoglutethimide; amsacrine; anastrozole; anthramycin; asparaginase; asperlin;
azacitidine; azetepa; azotomycin; batimastat; benzodepa; bicalutamide; bisantrene hydrochloride;
bisnafide dimesylate; bizelesin; bleomycin sulfate; brequinar sodium; bropirimine; busulfan;
cactinomycin; calusterone; caracemide; carbetimer; carboplatin; carmustine; carubicin hydrochloride;
carzelesin; cedefingol; chlorambucil; cirolemycin; cladribine; crisnatol mesylate; cyclophosphamide;
cytarabine; dacarbazine; daunorubicin hydrochloride; decitabine; dexormaplatin; dezaguanine;
dezaguanine mesylate; diaziquone; doxorubicin; doxorubicin hydrochloride; droloxifene; droloxifene
citrate; dromostanolone propionate; duazomycin; edatrexate; eflornithine hydrochloride; elsamitrucin;
enloplatin; enpromate; epipropidine; epirubicin hydrochloride; erbulozole; esorubicin hydrochloride;
estramustine; estramustine phosphate sodium; etanidazole; etoposide; etoposide phosphate; etoprine;
fadrozole hydrochloride; fazarabine; fenretinide; floxuridine; fludarabine phosphate; fluorouracil;
flurocitabine; fosquidone; fostriecin sodium; gemcitabine; gemcitabine hydrochloride; hydroxyurea;
idarubicin hydrochloride; ifosfamide; iimofosine; interleukin Il (including recombinant interleukin II, or
rlL2), interferon alfa-2a; interferon alfa-2b; interferon alfa-n1; interferon alfa-n3; interferon beta-la;
interferon gamma-l b; iproplatin; irinotecan hydrochloride; lanreotide acetate; letrozole; leuprolide
acetate; liarozole hydrochloride; lometrexol sodium; lomustine; losoxantrone hydrochloride; masoprocol;
maytansine; mechlorethamine hydrochloride; megestrol acetate; melengestrol acetate; melphalan;
menogaril; mercaptopurine; methotrexate; methotrexate sodium; metoprine; meturedepa; mitindomide;
mitocarcin; mitocromin; mitogillin; mitomalcin; mitomycin; mitosper; mitotane; mitoxantrone
hydrochloride; mycophenolic acid; nocodazoie; nogalamycin; ormaplatin; oxisuran; pegaspargase;
peliomycin; pentamustine; peplomycin sulfate; perfosfamide; pipobroman; piposulfan; piroxantrone
hydrochloride; plicamycin; plomestane; porfimer sodium; porfiromycin; prednimustine; procarbazine
hydrochloride; puromycin; puromycin hydrochloride; pyrazofurin; riboprine; rogletimide; safingol;
safingol hydrochloride; semustine; simtrazene; sparfosate sodium; sparsomycin; spirogermanium
hydrochloride; spiromustine; spiroplatin; streptonigrin; streptozocin; sulofenur; talisomycin; tecogalan
sodium; tegafur; teloxantrone hydrochloride; temoporfin; teniposide; teroxirone; testolactone; thiamiprine;
thioguanine; thiotepa; tiazofurin; tirapazamine; toremifene citrate; trestolone acetate; triciribine
phosphate; trimetrexate; trimetrexate glucuronate; triptorelin; tubulozole hydrochloride; uracil mustard;
uredepa; vapreotide; verteporfin; vinblastine sulfate; vincristine sulfate; vindesine; vindesine sulfate;
vinepidine sulfate; vinglycinate sulfate; vinleurosine sulfate; vinorelbine tartrate; vinrosidine sulfate;
vinzolidine sulfate; vorozole; zeniplatin; zinostatin; zorubicin hydrochloride.
In yet other embodiments, other anti-cancer agents are employed in combination with an Btk
inhibitor compound include: 20-epi-1,25 dihydroxyvitamin D3; 5-ethynyl uracil; abiraterone; aclarubicin;
acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TK antagonists; altretamine; ambamustine;
amidox; amifostine; aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole; andrographolide;
angiogenesis inhibitors; antagonist D; antagonist G; antarelix; anti-dorsalizing morphogenetic protein-1;
antiandrogen, prostatic carcinoma; antiestrogen; antineoplaston; antisense oligonucleotides; aphidicolin
glycinate; apoptosis gene modulators; apoptosis regulators; apurinic acid; ara-CDP-DL-PTBA; arginine
deaminase; asulacrine; atamestane; atrimustine; axinastatin 1; axinastatin 2; axinastatin 3; azasetron;
azatoxin; azatyrosine; baccatin III derivatives; balanol; batimastat; BCR/ABL antagonists; benzochlorins;
benzoylstaurosporine; beta lactam derivatives; beta-alethine; betaclamycin B; betulinic acid; bFGF
inhibitor; bicalutamide; bisantrene; bisaziridinylspermine; bisnafide; bistratene A; bizelesin; breflate;
bropirimine; budotitane; buthionine sulfoximine; calcipotriol; calphostin C; camptothecin derivatives;
canarypox IL-2; capecitabine; carboxamide-amino-triazole; carboxyamidotriazole; CaRest M3; CARN
700; cartilage derived inhibitor; carzelesin; casein kinase inhibitors (ICOS); castanospermine; cecropin B;
cetrorelix; chlorins; chloroquinoxaline sulfonamide; cicaprost; cis-porphyrin; cladribine; clomifene
analogues; clotrimazole; collismycin A; collismycin B; combretastatin A4; combretastatin analogue;
conagenin; crambescidin 816; crisnatol; cryptophycin 8; cryptophycin A derivatives; curacin A;
cyclopentanthraquinones; cycloplatam; cypemycin; cytarabine ocfosfate; cytolytic factor; cytostatin;
dacliximab; decitabine; dehydrodidemnin B; deslorelin; dexamethasone; dexifosfamide; dexrazoxane;
dexverapamil; diaziquone; didemnin B; didox; diethylnorspermine; dihydroazacytidine; 9- dioxamycin;
diphenyl spiromustine; docosanol; dolasetron; doxifluridine; droloxifene; dronabinol; duocarmycin SA;
ebselen; ecomustine; edelfosine; edrecolomab; eflornithine; elemene; emitefur; epirubicin; epristeride;
estramustine analogue; estrogen agonists; estrogen antagonists; etanidazole; etoposide phosphate;
exemestane; fadrozole; fazarabine; fenretinide; filgrastim; finasteride; flavopiridol; flezelastine;
fluasterone; fludarabine; fluorodaunorunicin hydrochloride; forfenimex; formestane; fostriecin;
fotemustine; gadolinium texaphyrin; gallium nitrate; galocitabine; ganirelix; gelatinase inhibitors;
gemcitabine; glutathione inhibitors; hepsulfam; heregulin; hexamethylene bisacetamide; hypericin;
ibandronic acid; idarubicin; idoxifene; idramantone; ilmofosine; ilomastat; imidazoacridones; imiquimod;
immunostimulant peptides; insulin-like growth factor-1 receptor inhibitor; interferon agonists; interferons;
interleukins; iobenguane; iododoxorubicin; 4-ipomeanol; iroplact; irsogladine; isobengazole;
isohomohalicondrin B; itasetron; jasplakinolide; kahalalide F; lamellarin-N triacetate; lanreotide;
leinamycin; lenograstim; lentinan sulfate; leptolstatin; letrozole; leukemia inhibiting factor; leukocyte
alpha interferon; leuprolide+estrogen+progesterone; leuprorelin; levamisole; liarozole; linear polyamine
analogue; lipophilic disaccharide peptide; lipophilic platinum compounds; lissoclinamide 7; lobaplatin;
lombricine; lometrexol; lonidamine; losoxantrone; lovastatin; loxoribine; lurtotecan; lutetium texaphyrin;
lysofylline; lytic peptides; maitansine; mannostatin A; marimastat; masoprocol; maspin; matrilysin
inhibitors; matrix metalloproteinase inhibitors; menogaril; merbarone; meterelin; methioninase;
metoclopramide; MIF inhibitor; mifepristone; miltefosine; mirimostim; mismatched double stranded
RNA; mitoguazone; mitolactol; mitomycin analogues; mitonafide; mitotoxin fibroblast growth factor-
saporin; mitoxantrone; mofarotene; molgramostim; monoclonal antibody, human chorionic
gonadotrophin; monophosphoryl lipid A+myobacterium cell wall sk; mopidamol; multiple drug resistance
gene inhibitor; multiple tumor suppressor 1 -based therapy; mustard anticancer agent; mycaperoxide B;
mycobacterial cell wall extract; myriaporone; N-acetyldinaline; N-substituted benzamides; nafarelin;
nagrestip; naloxone+pentazocine; napavin; naphterpin; nartograstim; nedaplatin; nemorubicin; neridronic
acid; neutral endopeptidase; nilutamide; nisamycin; nitric oxide modulators; nitroxide antioxidant;
nitrullyn; O6-benzylguanine; octreotide; okicenone; oligonucleotides; onapristone; ondansetron; oracin;
oral cytokine inducer; ormaplatin; osaterone; oxaliplatin; oxaunomycin; palauamine; palmitoylrhizoxin;
pamidronic acid; panaxytriol; panomifene; parabactin; pazelliptine; pegaspargase; peldesine; pentosan
polysulfate sodium; pentostatin; pentrozole; perflubron; perfosfamide; perillyl alcohol; phenazinomycin;
phenylacetate; phosphatase inhibitors; picibanil; pilocarpine hydrochloride; pirarubicin; piritrexim;
placetin A; placetin B; plasminogen activator inhibitor; platinum complex; platinum compounds;
platinum-triamine complex; porfimer sodium; porfiromycin; prednisone; propyl bis-acridone;
prostaglandin J2; proteasome inhibitors; protein A-based immune modulator; protein kinase C inhibitor;
protein kinase C inhibitors, microalgal; protein tyrosine phosphatase inhibitors; purine nucleoside
phosphorylase inhibitors; purpurins; pyrazoloacridine; pyridoxylated hemoglobin polyoxyethylerie
conjugate; raf antagonists; raltitrexed; ramosetron; ras farnesyl protein transferase inhibitors; ras
inhibitors; ras-GAP inhibitor; retelliptine demethylated; rhenium Re 186 etidronate; rhizoxin; ribozymes;
RII retinamide; rogletimide; rohitukine; romurtide; roquinimex; rubiginone B1; ruboxyl; safingol;
saintopin; SarCNU; sarcophytol A; sargramostim; Sdi 1 mimetics; semustine; senescence derived
inhibitor 1; sense oligonucleotides; signal transduction inhibitors; signal transduction modulators; single
chain antigen-binding protein; sizofiran; sobuzoxane; sodium borocaptate; sodium phenylacetate;
solverol; somatomedin binding protein; sonermin; sparfosic acid; spicamycin D; spiromustine;
splenopentin; spongistatin 1; squalamine; stem cell inhibitor; stem-cell division inhibitors; stipiamide;
stromelysin inhibitors; sulfinosine; superactive vasoactive intestinal peptide antagonist; suradista;
suramin; swainsonine; synthetic glycosaminoglycans; tallimustine; tamoxifen methiodide; tauromustine;
tazarotene; tecogalan sodium; tegafur; tellurapyrylium; telomerase inhibitors; temoporfin; temozolomide;
teniposide; tetrachlorodecaoxide; tetrazomine; thaliblastine; thiocoraline; thrombopoietin; thrombopoietin
mimetic; thymalfasin; thymopoietin receptor agonist; thymotrinan; thyroid stimulating hormone; tin ethyl
etiopurpurin; tirapazamine; titanocene bichloride; topsentin; toremifene; totipotent stem cell factor;
translation inhibitors; tretinoin; triacetyluridine; triciribine; trimetrexate; triptorelin; tropisetron;
turosteride; tyrosine kinase inhibitors; tyrphostins; UBC inhibitors; ubenimex; urogenital sinus-derived
growth inhibitory factor; urokinase receptor antagonists; vapreotide; variolin B; vector system,
erythrocyte gene therapy; velaresol; veramine; verdins; verteporfin; vinorelbine; vinxaltine; vitaxin;
vorozole; zanoterone; zeniplatin; zilascorb; and zinostatin stimalamer.
Yet other anticancer agents that can be employed in combination with a Btk inhibitor
compound include alkylating agents, antimetabolites, natural products, or hormones, e.g., nitrogen
mustards (e.g., mechloroethamine, cyclophosphamide, chlorambucil, etc.), alkyl sulfonates (e.g.,
busulfan), nitrosoureas (e.g., carmustine, lomusitne, ete.), or triazenes (decarbazine, etc.). Examples of
antimetabolites include but are not limited to folic acid analog (e.g., methotrexate), or pyrimidine analogs
(e.g., Cytarabine), purine analogs (e.g., mercaptopurine, thioguanine, pentostatin).
Examples of natural products useful in combination with a Btk inhibitor compound include
but are not limited to vinca alkaloids (e.g., vinblastin, vincristine), epipodophyllotoxins (e.g., etoposide),
antibiotics (e.g., daunorubicin, doxorubicin, bleomycin), enzymes (e.g., L-asparaginase), or biological
response modifiers (e.g., interferon alpha).
Examples of alkylating agents that are employed in combination a Btk inhibitor compound in
some embodiments, include, but are not limited to, nitrogen mustards (e.g., mechloroethamine,
cyclophosphamide, chlorambucil, meiphalan, etc.), ethylenimine and methylmelamines (e.g.,
hexamethlymelamine, thiotepa), alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine,
lomusitne, semustine, streptozocin, etc.), or triazenes (decarbazine, ete.). Examples of antimetabolites
include, but are not limited to folic acid analog (e.g., methotrexate), or pyrimidine analogs (e.g.,
fluorouracil, floxouridine, Cytarabine), purine analogs (e.g., mercaptopurine, thioguanine, pentostatin).
Examples of hormones and antagonists useful in combination with a Btk inhibitor compound
include, but are not limited to, adrenocorticosteroids (e.g., prednisone), progestins (e.g.,
hydroxyprogesterone caproate, megestrol acetate, medroxyprogesterone acetate), estrogens (e.g.,
diethlystilbestrol, ethinyl estradiol), antiestrogen (e.g., tamoxifen), androgens (e.g., testosterone
propionate, fluoxymesterone), antiandrogen (e.g., flutamide), gonadotropin releasing hormone analog
(e.g., leuprolide). Other agents that can be used in the methods and compositions described herein for the
treatment or prevention of cancer include platinum coordination complexes (e.g., cisplatin, carboblatin),
anthracenedione (e.g., mitoxantrone), substituted urea (e.g., hydroxyurea), methyl hydrazine derivative
(e.g., procarbazine), adrenocortical suppressant (e.g., mitotane, aminoglutethimide).
Examples of anti-cancer agents which act by arresting cells in the G2-M phases due to
stabilized microtubules and which are used in some embodiments, in combination with a Btk inhibitor
compound include without limitation marketed drugs and drugs in development.
Where the subject is suffering from or at risk of suffering from a thromboembolic disorder
(e.g., stroke), the subject, in some embodiments is treated with a Btk inhibitor compound in any
combination with one or more other anti-thromboembolic agents. Examples of anti-thromboembolic
agents include, but are not limited any of the following: thrombolytic agents (e.g., alteplase anistreplase,
streptokinase, urokinase, or tissue plasminogen activator), heparin, tinzaparin, warfarin, dabigatran (e.g.,
dabigatran etexilate), factor Xa inhibitors (e.g., fondaparinux, draparinux, rivaroxaban, DX-9065a,
otamixaban, LY517717, or YM150), factor VIIa inhibitors, ticlopidine, clopidogrel, CS-747 (prasugrel,
LY640315), ximelagatran, or BIBR 1048.
Pharmaceutical Composition/Formulation
In a further aspect are provided pharmaceutical compositions, which include a therapeutically
effective amount of at least one of any of the compounds described herein, or a pharmaceutically
acceptable salt, pharmaceutically acceptable tautomer, pharmaceutically acceptable prodrug, or
pharmaceutically acceptable solvate. In certain embodiments, compositions provided herein further
include a pharmaceutically acceptable diluent, excipient and/or binder.
Pharmaceutical compositions formulated for administration by an appropriate route and
means containing effective concentrations of one or more of the compounds provided herein, or
pharmaceutically effective derivatives thereof, that deliver amounts effective for the treatment,
prevention, or amelioration of one or more symptoms of diseases, disorders or conditions that are
modulated or otherwise affected by tyrosine kinase activity, or in which tyrosine kinase activity is
implicated, are provided. The effective amounts and concentrations are effective for ameliorating any of
the symptoms of any of the diseases, disorders or conditions disclosed herein.
Pharmaceutical compositions are formulated in a conventional manner using one or more
physiologically acceptable carriers including excipients and auxiliaries which facilitate processing of the
active compounds into preparations which can be used pharmaceutically. Proper formulation is dependent
upon the route of administration chosen. A summary of pharmaceutical compositions described herein is
found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.:
Mack Publishing Company, 1995); Hoover, John E., Remington’s Pharmaceutical Sciences, Mack
Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical
Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug
Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins1999).
A pharmaceutical composition, as used herein, refers to a mixture of a compound described
herein, such as, for example, compounds of any of Formula (I), (IA), (II), (III), (IV), (V), (VI), (VIA),
(VIB), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), or (XIV), with other chemical components, such as
carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, and/or excipients.
The pharmaceutical composition facilitates administration of the compound to an organism. In practicing
the methods of treatment or use provided herein, therapeutically effective amounts of compounds
described herein are administered in a pharmaceutical composition to a mammal having a disease,
disorder, or condition to be treated. Preferably, the mammal is a human. The compounds, in some
embodiments, are used singly or in combination with one or more therapeutic agents as components of
mixtures.
The pharmaceutical formulations described herein in some embodiments, is administered to a
subject by multiple administration routes, including but not limited to, oral, parenteral (e.g., intravenous,
subcutaneous, intramuscular), intranasal, buccal, topical, rectal, or transdermal administration routes. The
pharmaceutical formulations described herein include, but are not limited to, aqueous liquid dispersions,
self-emulsifying dispersions, solid solutions, liposomal dispersions, aerosols, solid dosage forms,
powders, immediate release formulations, controlled release formulations, fast melt formulations, tablets,
capsules, pills, delayed release formulations, extended release formulations, pulsatile release formulations,
multiparticulate formulations, and mixed immediate and controlled release formulations.
Pharmaceutical compositions including a compound described herein are optionally
manufactured in a conventional manner, such as, by way of example only, by means of conventional
mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or
compression processes.
A “carrier” or “carrier materials” includes excipients in pharmaceutics and is selected on the
basis of compatibility with compounds disclosed herein, such as, compounds of Formula (I), (IA), (II),
(III), (IV), (V), (VI), (VIA), (VIB), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), or (XIV), and the release
profile properties of the desired dosage form. Exemplary carrier materials include, e.g., binders,
suspending agents, disintegration agents, filling agents, surfactants, solubilizers, stabilizers, lubricants,
wetting agents, diluents, and the like. See, e.g., Remington: The Science and Practice of Pharmacy,
Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington’s
Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and
Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and
Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams &
Wilkins1999).
A “measurable serum concentration” or “measurable plasma concentration” describes the
blood serum or blood plasma concentration, typically measured in mg, g, or ng of therapeutic agent per
ml, dl, or l of blood serum, absorbed into the bloodstream after administration. As used herein,
measurable plasma concentrations are typically measured in ng/ml or g/ml.
“Pharmacodynamics” refers to the factors which determine the biologic response observed
relative to the concentration of drug at a site of action. “Pharmacokinetics” refers to the factors which
determine the attainment and maintenance of the appropriate concentration of drug at a site of action.
“Steady state,” as used herein, is when the amount of drug administered is equal to the
amount of drug eliminated within one dosing interval resulting in a plateau or constant plasma drug
exposure.
Dosage Forms
Moreover, the pharmaceutical compositions described herein, which include a compound of
Formula (I), (IA), (II), (III), (IV), (V), (VI), (VIA), (VIB), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), or
(XIV) are, in some embodiments, formulated into any suitable dosage form, including but not limited to,
aqueous oral dispersions, liquids, gels, syrups, elixirs, slurries, suspensions and the like, for oral ingestion
by a patient to be treated, solid oral dosage forms, aerosols, controlled release formulations, fast melt
formulations, effervescent formulations, lyophilized formulations, tablets, powders, pills, dragees,
capsules, delayed release formulations, extended release formulations, pulsatile release formulations,
multiparticulate formulations, and mixed immediate release and controlled release formulations.
The pharmaceutical solid dosage forms described herein optionally include a compound
described herein and one or more pharmaceutically acceptable additives such as a compatible carrier,
binder, filling agent, suspending agent, flavoring agent, sweetening agent, disintegrating agent, dispersing
agent, surfactant, lubricant, colorant, diluent, solubilizer, moistening agent, plasticizer, stabilizer,
penetration enhancer, wetting agent, anti-foaming agent, antioxidant, preservative, or one or more
combination thereof. In still other aspects, using standard coating procedures, such as those described in
Remington's Pharmaceutical Sciences, 20th Edition (2000), a film coating is provided around the
formulation of the compound of Formula (I), (IA), (II), (III), (IV), (V), (VI), (VIA), (VIB), (VII), (VIII),
(IX), (X), (XI), (XII), (XIII), or (XIV). In one embodiment, some or all of the particles of the compound
of Formula (I), (IA), (II), (III), (IV), (V), (VI), (VIA), (VIB), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), or
(XIV), are coated. In another embodiment, some or all of the particles of the compound of Formula (I),
(IA), (II), (III), (IV), (V), (VI), (VIA), (VIB), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), or (XIV), are
microencapsulated. In still another embodiment, the particles of the compound of Formula (I), (IA), (II),
(III), (IV), (V), (VI), (VIA), (VIB), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), or (XIV), are not
microencapsulated and are uncoated.
Examples of Methods of Dosing and Treatment Regimens
The compounds described herein, in some embodiments, is used in the preparation of
medicaments for the inhibition of Btk or a homolog thereof, or for the treatment of diseases or conditions
that benefit, at least in part, from inhibition of Btk or a homolog thereof. In addition, a method for treating
any of the diseases or conditions described herein in a subject in need of such treatment, involves
administration of pharmaceutical compositions containing at least one compound of any of Formula (I),
(IA), (II), (III), (IV), (V), (VI), (VIA), (VIB), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), or (XIV),
described herein, or a pharmaceutically acceptable salt, pharmaceutically acceptable N-oxide,
pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof, in therapeutically
effective amounts to said subject.
The compositions containing the compound(s) described herein, in other embodiments, are
administered for prophylactic and/or therapeutic treatments. In therapeutic applications, the compositions
are administered to a patient already suffering from a disease or condition, in an amount sufficient to cure
or at least partially arrest the symptoms of the disease or condition. Amounts effective for this use will
depend on the severity and course of the disease or condition, previous therapy, the patient's health status,
weight, and response to the drugs, and the judgment of the treating physician.
In prophylactic applications, compositions containing the compounds described herein are
administered to a patient susceptible to or otherwise at risk of a particular disease, disorder or condition.
Such an amount is defined to be a “prophylactically effective amount or dose.” In this use, the precise
amounts also depend on the patient's state of health, weight, and the like. When used in a patient, effective
amounts for this use will depend on the severity and course of the disease, disorder or condition, previous
therapy, the patient's health status and response to the drugs, and the judgment of the treating physician.
In some embodiments, the kinase inhibitor is administered to the patient on a regular basis,
e.g., three times a day, two times a day, once a day, every other day or every 3 days. In other
embodiments, the kinase inhibitor is administered to the patient on an intermittent basis, e.g., twice a day
followed by once a day followed by three times a day; or the first two days of every week; or the first,
second and third day of a week. In some embodiments, intermittent dosing is as effective as regular
dosing. In further or alternative embodiments, the kinase inhibitor is administered only when the patient
exhibits a particular symptom, e.g., the onset of pain, or the onset of a fever, or the onset of an
inflammation, or the onset of a skin disorder.
In the case wherein the patient’s condition does not improve, upon the doctor’s discretion the
administration of the compounds may be administered chronically, that is, for an extended period of time,
including throughout the duration of the patient’s life in order to ameliorate or otherwise control or limit
the symptoms of the patient’s disease or condition.
In the case wherein the patient’s status does improve, upon the doctor’s discretion the
administration of the compounds may be given continuously; alternatively, the dose of drug being
administered may be temporarily reduced or temporarily suspended for a certain length of time (i.e., a
“drug holiday”). The length of the drug holiday can vary between 2 days and 1 year, including by way of
example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days,
days, 50 days, 70 days, 100 days, 120 days, 150 days, 180 days, 200 days, 250 days, 280 days, 300
days, 320 days, 350 days, or 365 days. The dose reduction during a drug holiday may be from about 10%-
about 100%, including, by way of example only, about 10%, about 15%, about 20%, about 25%, about
%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%,
about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%.
Once improvement of the patient's conditions has occurred, a maintenance dose is
administered if necessary. Subsequently, the dosage or the frequency of administration, or both, can be
reduced, as a function of the symptoms, to a level at which the improved disease, disorder or condition is
retained. Patients can, however, require intermittent treatment on a long-term basis upon any recurrence of
symptoms.
The amount of a given agent that will correspond to such an amount will vary depending
upon factors such as the particular compound, disease or condition and its severity, the identity (e.g.,
weight) of the subject or host in need of treatment, and is determined according to the particular
circumstances surrounding the case, including, e.g., the specific agent being administered, the route of
administration, the condition being treated, and the subject or host being treated. In general, however,
doses employed for adult human treatment will typically be in the range of about 0.02- about 5000 mg per
day, or from about 1- about 1500 mg per day. The desired dose may conveniently be presented in a single
dose or as divided doses administered simultaneously (or over a short period of time) or at appropriate
intervals, for example as two, three, four or more sub-doses per day.
The pharmaceutical composition described herein may be in unit dosage forms suitable for
single administration of precise dosages. In unit dosage form, the formulation is divided into unit doses
containing appropriate quantities of one or more compound. The unit dosage may be in the form of a
package containing discrete quantities of the formulation. Non-limiting examples are packaged tablets or
capsules, and powders in vials or ampoules. Aqueous suspension compositions can be packaged in single-
dose non-reclosable containers. Alternatively, multiple-dose reclosable containers can be used, in which
case it is typical to include a preservative in the composition. By way of example only, formulations for
parenteral injection may be presented in unit dosage form, which include, but are not limited to ampoules,
or in multi-dose containers, with an added preservative.
The foregoing ranges are merely suggestive, as the number of variables in regard to an
individual treatment regime is large, and considerable excursions from these recommended values are not
uncommon. Such dosages may be altered depending on a number of variables, not limited to the activity
of the compound used, the disease or condition to be treated, the mode of administration, the requirements
of the individual subject, the severity of the disease or condition being treated, and the judgment of the
practitioner.
Toxicity and therapeutic efficacy of such therapeutic regimens can be determined by standard
pharmaceutical procedures in cell cultures or experimental animals, including, but not limited to, the
determination of the LD (the dose lethal to 50% of the population) and the ED (the dose
50 50
therapeutically effective in 50% of the population). The dose ratio between the toxic and therapeutic
effects is the therapeutic index and it can be expressed as the ratio between LD and ED . Compounds
50 50
exhibiting high therapeutic indices are preferred. The data obtained from cell culture assays and animal
studies can be used in formulating a range of dosage for use in human. The dosage of such compounds
lies preferably within a range of circulating concentrations that include the ED with minimal toxicity.
The dosage may vary within this range depending upon the dosage form employed and the route of
administration utilized.
Kits/Articles of Manufacture
Articles of manufacture including packaging material, a compound or composition or
pharmaceutically acceptable derivative thereof provided herein, which is effective for inhibiting the
activity of tyrosine kinase(s), such as Btk, within the packaging material, and a label that indicates that the
compound or composition, or pharmaceutically acceptable salt, pharmaceutically acceptable tautomer,
pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate thereof, is used for
inhibiting the activity of tyrosine kinase(s), such as Btk, are provided.
EXAMPLES
The following specific and non-limiting examples are to be construed as merely illustrative,
and do not limit the present disclosure in any way whatsoever.
Synthesis of Compounds
Example 1: Preparation of 4-Amino(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine
4-Amino(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine is prepared as disclosed in
International Patent Publication No. WO 01/019829. Briefly, 4-phenoxybenzoic acid (48 g) is added to
thionyl chloride (100 mL) and heated under gentle reflux for 1h. Thionyl chloride is removed by
distillation, the residual oil dissolved in toluene and volatile material removed at 80 °C/20 mbar. The
resulting acid chloride is dissolved in toluene (200 mL) and tetrahydrofuran (35 mL). Malononitrile (14.8
g) is added and the solution and stirred at -10 °C while adding diisopropylethylethylamine (57.9 g) in
toluene (150mL), while maintaining the temperature below 0 °C. After 1 h at 0 °C, the mixture is stirred
at 20°C overnight. Amine hydrochloride is removed by filtration and the filtrate evaporated in vacuo. The
residue is taken up in ethyl acetate (EA) and washed with 1.25 M sulphuric acid, then with brine and dried
over sodium sulfate. Evaporation of the solvents gives a semisolid residue which is treated with a little EA
to give 4.1 g of 1,1-dicyanohydroxy(4-phenoxyphenyl)ethene as a white solid (m.p. 160- 162°C).
The filtrate on evaporation gives 56.58 (96%) of 1,1-dicyanohydroxy(4-phenoxypheny1)ethene as a
grey-brown solid, which is sufficiently pure for further use.
1,1-Dicyanohydroxy(4-phenoxyphenyl)ethene (56.5 g) in acetonitrile (780 mL) and
methanol (85 mL) is stirred under nitrogen at 0°C while adding diisopropylethylamine (52.5 mL)
followed by 2M trimethylsilyldiazomethane (150 mL) in THF. The reaction is stirred for 2 days at 20°C,
and then 2 g of silica is added (for chromatography). The brown-red solution is evaporated in vacuo, the
residue dissolved in EA and washed well with water then brine, dried and evaporated. The residue is
extracted with diethyl ether (3x250 mL), decanting from insoluble oil. Evaporation of the ether extracts
gives 22.5 g of 1,1-dicyanomethoxy(4-phenoxyphenyl)ethene as a pale orange solid. The insoluble
oil is purified by flash chromatography to give 15.0 g of a red-orange oil.
1,1-Dicyanomethoxy(4-phenoxyphenyl)ethene (22.5 g) and 1,1-dicyanomethoxy
(4-phenoxyphenyl)ethene oil (15 g) are treated with a solution of hydrazine hydrate (18 mL) in ethanol
(25 mL) and heated on the steambath for 1 h. Ethanol (15 mL) is added followed by water (10 mL). The
precipitated solid is collected and washed with ethanol:water (4:1) and then dried in air to give 3-amino
cyano(4-phenoxypheny1)pyrazole as a pale orange solid.
3-Aminocyano(4-phenoxyphenyl)pyrazole (29.5 g) is suspended in formamide (300
mL) and heated under nitrogen at 180 °C for 4 h. The reaction mixture is cooled to 30 °C and water (300
mL) is added. The solid is collected, washed well with water, then with methanol and dried in air to give
of 4-amino(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine.
Example 1-1: Preparation of (R)(4-phenoxyphenyl)(pyrrolidinyl)-1H-pyrazolo[3,4-
d]pyrimidinamine (Compound A)
To a mixture of 4-amino(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine (45.50 g, 150
mmol, 1.0 eq), (S)-pyrrolidinol (bought from CNH, 51.95g, 277.5 mmol, 1.85 eq) and Ph P (72.79g,
277.5 mmol, 1.85 eq) in THF (400 mL) at rt was added DIAD (57.6 mL, 292.5mmol, 1.95 eq) dropwise
over 1.5 h. The mixture was stirred another 30 min and concentrated HCl solution (100 mL) was added
dropwise over 30 min. The mixture was stirred overnight at rt. The mixture was then heated to 50 °C for 1
h to push the de-Boc to completion. THF was removed by rotavap. The crude was diluted with toluene
and water. The aqueous solution was further washed with EtOAc and toluene. MeOH (70 mL, 10% v/v to
the aqueous solution) was added followed by KOH solution (100 g in 100 mL water). The mixture
became warm and precipitate immediately formed. The mixture was cooled in a 4 °C fridge for 2 h and
filtered. The solid was washed with water, air-dried and then dried under high-vac for 3 days. Yield 49.45
g (89%), HPLC purity 95%.
Example 1-2: Preparation of (R)(4-phenoxyphenyl)(piperidineyl)-1H-pyrazolo[3,4-
d]pyrimidinamine (Compound B)
The title compound was made in the similar fashion as Compound A.
Example 1a: Synthesis of N-((4-(4-amino(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin
yl)tetrahydrofuranyl)methyl)-N-methylpropionamide
a) polymer-bound triphenylphosphine (TPP), diisopropyl diazodicarboxylate (DIAD), tetrahydrofuran
(THF)
4-amino(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine and polymer-bound
triphenylphosphine(TPP) (polymerlab) are mixed together with 5 mL of tetrahydrofuran (THF). N-((4-(4-
amino(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidinyl)tetrahydrofuranyl)methyl)-N-
methylpropionamide is added to the mixture followed by the addition of diisopropyl diazodicarboxylate.
The reaction mixture is stirred at room temperature overnight. The reaction mixture is filtered to remove
the resins and the reaction mixture is concentrated and purified by flash chromatography (pentane/ethyl
acetate = 1/1) to give the title compound.
Example 1b: Synthesis of 1-(6-(4-amino(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidinyl)-
1,4-oxazepanyl)butanone
I NH O
Boc O
Na CO
2 3 N
NH Boc N
Pd Boc
a) tert-butyl 6-(4-aminoiodo-1H-pyrazolo[3,4-d]pyrimidinyl)-1,4-oxazepanecarboxylate
Di-tert-butyl dicarbonate (1.32 mmol) is added to a mixture of 3-iodo(1,4-oxazepanyl)-
1H-pyrazolo[3,4-d]pyrimidinamine (1.20 mmol) and sodium carbonate (4.20 mmol) in dioxane (10
mL) and water (10 mL) and the reaction is stirred for 18 h. Dichloromethane (100 mL) is added and the
organic layer is washed with water (30 mL) and brine (30 mL), dried (Na SO ) and concentrated in vacuo
to afford the title compound.
b) tert-butyl 6-(4-amino(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidinyl)-1,4-oxazepane
carboxylate
tert-butyl 6-(4-aminoiodo-1H-pyrazolo[3,4-d]pyrimidinyl)-1,4-oxazepanecarboxylate
(1.18 mmol) is dissolved in ethylene glycol dimethylether (50 mL) and water (10 mL). 4,4,5,5-
tetramethyl(4-phenoxyphenyl)-1,3,2-dioxaborolane (1.47 mmol), palladium tetrakistriphenylphosphine
(0.059 mmol) and sodium carbonate (2.95 mmol) are added and the reaction is heated for 12-20 hours.
Additional boronate and palladium tetrakistriphenylphosphine are added and the reaction is heated at 60-
90 C for a further 20-24 hours. The reaction is concentrated under reduced pressure. The remaining
residue was partitioned between dichloromethane and water. The organic layer is dried then concentrated
under reduced pressure to yield the title comound.
c). 1-(1,4-oxazepanyl)(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidinamine
tert-butyl 6-(4-amino(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidinyl)-1,4-
oxazepanecarboxylate is dissolved in acetone and 6N aqueous hydrochloric acid. The reaction is then
heated at 45 C. which yielded a precipitate. After 2.5 hours, the precipitate is collected by vacuum
filtration, washed with a minimal amount of acetone and dried on the lyophilizer to afford title compound.
d). 1-(6-(4-amino(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidinyl)-1,4-oxazepanyl)butan
1-(1,4-oxazepanyl)(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidinamine is coupled
with butyric acid under basic condition to afford title compound in good yield.
Example 1c: Synthesis of (R,E)(3-(4-amino(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin
yl)pyrrolidinyl)(2-methoxyethylamino)butenone (1c)
O Boc O
(Boc) O, Na CO
2 2 3
2 N N
Br O
0 O O O O
THF, 25 C, 12h 0
THF/H O, 25 C, 3h
1 2 3
Boc O N
(E) Boc
LiOH.H O
N HATU, DIPEA
O OH
DMA, 25 C, 3h
THF/H O, 25 C, 12h N (R)
DCM, 25 C, 3h (E)
N (R)
Step 1
To a solution of compound 2 (1.9 g, 25 mmol) in 20 mL of THF was added 4-bromo-methyl-
crotonate 1 (450 mg, 2.5 mmol), and the mixture was stirred at 25 C for 12h. The reaction was monitored
by TLC. After the reaction was complete, the reaction mixture was diluted with 20 mL of ethyl acetate.
Then it was washed with brine several times, dried over MgSO and concentrated under reduced pressure
to give 150 mg of 3 as a crude product, which was used directly in the next step without further
purification.
Step 2
To a solution of compound 3 (150 mg, 0.87 mmol) and Na CO (180 mg, 1.74 mmol) in
THF/H O (10 mL/ 10 mL) was added (Boc) O (375 mg, 1.74 mmol), and the mixture was stirred at 25 C
for 3h. Then the mixture was diluted with dichloromethane (20 mL), washed with brine several times,
dried over MgSO4 and concentrated under reduced pressure to give 202 mg of 4 as a crude product,
which was used directly in the next step without further purification.
Step 3
To a solution of compound 4 (200 mg, 0.73 mmol) in THF/H O was added LiOH.H O (60
mg, 1.47 mmol), and the mixture was stirred at 25 C for 12h. Then the pH value of the mixture was
adjusted to about 7, and the solvent was removed under reduced pressure to give 189 mg of 5 as a crude
product, which was used directly in the next step without further purification.
Step 4
A solution of compound 5 (100 mg, 0.38 mmol) and HATU (146 mg, .38 mmol) in DMA (5
mL) was stirred at 25 C for 10min. Then it was added to a solution of (R)(4-phenoxyphenyl)
(pyrrolidinyl)-1H-pyrazolo[3,4-d]pyrimidinamine (compound A) (144 mg, 0.38 mmol, prepared as
disclosed in US 7,514,444) and DIPEA (100 mg, 0.76 mmol) in DMA (5 mL), and the mixture was stirred
at 25 C for 3h. The reaction was monitored by LC-MS, and purified by prep-HPLC to give 110 mg of 6.
Step 5
Compound 6 (110 mg, 0.18 mmol) was dissolved in 10 mL of DCM, and then TFA (1 mL)
was added. After stirring at 25 C for 3h, the solvent was removed under reduced pressure. The residue
was dissolved by DCM again, and treated with aqueous NaHCO . The organic phase separated and was
dried over MgSO , concentrated under reduced pressure to give 80 mg of the title compound (1c). MS
(ESI) m/e (M+1H) : 514.1.
Example 1d: Synthesis of (R,E)(3-(4-amino(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin
yl)pyrrolidinyl)(tetrahydro-2H-pyranylamino)butenone (1d)
Similarly, compound 1d was prepared by substituting tetrahydro-2H-pyranamine for
compound 2 in Step 1 of Example 1c. MS (ESI) m/e (M+1H) : 540.1.
Example 1e: Synthesis of (R,E)(3-(4-amino(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin
yl)piperidinyl)(2-methoxyethylamino)butenone (1e)
Similarly, compound 1e was prepared by substituting (R)(4-phenoxyphenyl)(piperidin-
3-yl)-1H-pyrazolo[3,4-d]pyrimidinamine (compound B, prepared as disclosed in US 7,514,444) for
compound A in Step 4 of Example 1c. MS (ESI) m/e (M+1H) : 528.1.
Example 1f: Synthesis of (R,E)(3-(4-amino(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin
yl)piperidinyl)(tetrahydro-2H-pyranylamino)butenone (1f)
Similarly, compound 1f was prepared by substituting tetrahydro-2H-pyranamine for
compound 2 in Step 1 of Example 1c and by substituting compound B for compound A in Step 4 of
Example 1c. MS (ESI) m/e (M+1H) : 554.1.
Example 1g: Synthesis of (R,E)(3-(4-amino(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin
yl)pyrrolidinyl)((2-methoxyethyl)(methyl)amino)butenone (1g)
LiOH.H O
Br N
O THF, 25 C, 12h O OH
THF/H O, 25 C, 12h
1 8 9 10
HATU, DIPEA
DMA, 25 C, 3h N
Step 1
To a solution of compound 8 (765 mg, 8.6 mmol) in 20 mL of THF was added 4-bromo-
methyl-crotonate 1 (700 mg, 3.9 mmol), and the mixture was stirred at 25 C for 12h. The reaction was
monitored by TLC. After the reaction finished, it was diluted by ethyl acetate (20 mL). Then it was
washed with brine several times, dried over MgSO and concentrated under reduced pressure to give 500
mg of 9 as a crude product, which was used directly in the next step without further purification.
Step 2
To a solution of compound 9 (400 mg, 2.1 mmol) in THF/H O (10 mL/10 mL) was added
LiOH.H O (175 mg, 4.3 mmol), and the mixture was stirred at 25 C for 12h. Then the pH value of the
mixture was adjusted to about 7. The solvent was removed under reduced pressure to give 360 mg of 10
as a crude product, which was used for the next step directly without further purification.
Step 3
The solution of compound 10 (200 mg, 1.1 mmol) and HATU (439 mg, 1.1 mmol) in 10 mL
of DMA was stirred at 25 C for 10mins. Then it was added to the solution of compound A (400 mg, 1.1
mmol) and DIPEA (298 mg, 2.3 mmol) in 10 mL of DMA, and the mixture was stirred at 25 C for 3h.
The reaction was monitored by LC-MS, and purified by prep-HPLC to give 76 mg of the title compound
(1g). MS (ESI) m/e (M+1H) : 528.3.
Example 1h: Synthesis of (R,E)(3-(4-amino(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin
yl)pyrrolidinyl)(ethyl(methyl)amino)butenone (1h)
Similarly, compound 1h was prepared by substituting ethyl(methyl)amine for compound 8 in
Step 1 of Example 1g. MS (ESI) m/e (M+1H) : 498.1.
Example 1i: Synthesis of (R,E)(3-(4-amino(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin
yl)pyrrolidinyl)(isopropyl(methyl)amino)butenone (1i)
Similarly, compound 1i was prepared by substituting isopropyl(methyl)amine for compound 8
in Step 1 of Example 1g. MS (ESI) m/e (M+1H) : 512.3.
Example 1j: Synthesis of (R,E)(3-(4-amino(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin
yl)pyrrolidinyl)(diethylamino)butenone (1j)
Similarly, compound 1j was prepared by substituting diethylamine for compound 8 in Step 1
of Example 1g. MS (ESI) m/e (M+1H) : 512.1.
Example 1k: Synthesis of (R,E)(3-(4-amino(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin
yl)pyrrolidinyl)(methyl(tetrahydro-2H-pyranyl)amino)butenone (1k)
Similarly, compound 1k was prepared by substituting N-methyltetrahydro-2H-pyranamine
for compound 8 in Step 1 of Example 1g. MS (ESI) m/e (M+1H) : 554.1.
Example 1m: Synthesis of (R,E)(3-(4-amino(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-
1-yl)piperidinyl)((2-methoxyethyl)(methyl)amino)butenone (1m)
Similarly, compound 1m was prepared by substituting compound B for compound A in Step
3 of Example 1g. MS (ESI) m/e (M+1H) : 542.3.
Example 1n: Synthesis of (R,E)(3-(4-amino(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin
yl)piperidinyl)(ethyl(methyl)amino)butenone (1n)
Similarly, compound 1n was prepared by substituting ethyl(methyl)amine for compound 8 in
Step 1 of Example 1g and by substituting compound B for compound A in Step 3 of Example 1g. MS
(ESI) m/e (M+1H) : 512.1.
Example 1o: Synthesis of (R,E)(3-(4-amino(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin
yl)piperidinyl)(isopropyl(methyl)amino)butenone (1o)
Similarly, compound 1o was prepared by substituting isopropyl(methyl)amine for compound
8 in Step 1 of Example 1g and by substituting compound B for compound A in Step 3 of Example 1g.
MS (ESI) m/e (M+1H) : 526.2.
Example 1p: Synthesis of (R,E)(3-(4-amino(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin
yl)piperidinyl)(diethylamino)butenone (1p)
Similarly, compound 1p was prepared by substituting diethylamine for compound 8 in Step 1
of Example 1g and by substituting compound B for compound A in Step 3 of Example 1g. MS (ESI) m/e
(M+1H) : 526.3.
Example 1q: Synthesis of (R,E)(3-(4-amino(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin
yl)piperidinyl)(methyl(tetrahydro-2H-pyranyl)amino)butenone (1q)
Similarly, compound 1q was prepared by substituting N-methyltetrahydro-2H-pyranamine
for compound 8 in Step 1 of Example 1g and by substituting compound B for compound A in Step 3 of
Example 1g. MS (ESI) m/e (M+1H) : 568.3.
Example 1r: Synthesis of (R,E)(3-(4-amino(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin
yl)pyrrolidinyl)(methyl(pyridinyl)amino)butenone (1r)
O O O
(COCl)
NBS, BPO
Br DIPEA
HO HO 0 Cl 0
N (R)
DCM, 25 C, 4h THF, 0 C, 3h
CCl , 80 C, 4h
13 14
DIPEA
DMF, 30 C, 12h
Step 1
To a solution of compound 11 (10 g, 116 mmol) and bromosuccinimide (13.7 g, 116 mmol) in
200 mL of CCl was added benzoyl peroxide (3.37 g, 13.9 mmol), and the mixture was stirred at 100 C
for 4h. Then the solvent was removed under reduced pressure to give a crude product, which was purified
by silica gel column (Eluent: EA) to give 4.2 g of 12.
Steps 2 and 3
To a solution of compound 12 (652 mg, 4 mmol) in 10 mL of DCM was added oxalyl
chloride (10 mL), and the mixture was stirred at 25 C for 4h. Then the solvent and excess oxalyl chloride
was removed under reduced pressure to give the crude product. One-sixteenth of the crude product was
added to a solution of compound A (110 mg, 0.25 mmol) in THF (10 mL) in the presence of DIPEA (129
mg, 1 mmol) at 0 C. After stirring for 3h, the mixture was diluted with EA (20 mL), washed with brine,
dried over MgSO and concentrated under reduced pressure to give the crude 110 mg of 14, which was
used in the next step directly without further purification.
Step 4
To a solution of compound 14 (110 mg, 0.21 mmol) and DIPEA (55 mg, 0.43 mmol) in DMF
(3 mL) was added N-methylpyridinamine (45 mg, 0.43 mmol), and the mixture was stirred at 30 C for
12h. The mixture was purified by prep-HPLC to give 49 mg of the title compound (1r). MS (ESI) m/e
(M+1H) : 547.1.
Example 1s: Synthesis of (R,E)(3-(4-amino(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin
yl)pyrrolidinyl)(pyridinylamino)butenone (1s)
Similarly, compound 1s was prepared by substituting pyridinamine for N-methylpyridin
amine in Step 4 of Example 1r. MS (ESI) m/e (M+1H) : 533.1.
Example 1t: Synthesis of (R,E)(3-(4-amino(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin
yl)piperidinyl)(methyl(pyridinyl)amino)butenone (1t)
Similarly, compound 1t was prepared by substituting compound B for compound A in Step 3
of Example 1r. MS (ESI) m/e (M+1H) : 561.0.
Example 1u: Synthesis of (R,E)(3-(4-amino(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin
yl)piperidinyl)(pyridinylamino)butenone (1u)
Similarly, compound 1u was prepared by substituting compound B for compound A in Step 3
of Example 1r and substituting pyridinamine for N-methylpyridinamine in Step 4 of Example 1r.
MS (ESI) m/e (M+1H) : 547.0.
Example 2a: Synthesis of (R,E)(3-(4-amino(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin
yl)pyrrolidinyl)(dicyclopropylamino)butenone (2a)
(COCl)
2 DIPEA
Br o
DCM, 20 C, 3h
THF, 0 C, 10 min
Br N
DIPEA
H N (E) H N (E)
DMF, 30 C, 1h
(R) (R)
N N N N
14 2a
Steps 1 and 2
To a solution of compound 12 (2.0 g, 7.9 mmol) in DCM (10 mL), oxalyl chloride (20 ml)
was added, and the mixture was stirred at 20 C for 3h. Excess oxalyl chloride and solvent were removed
in vacuo to give the crude product 13. Half of crude 13 was added to a solution of compound A (1.2 g, 2.6
mmol) in THF (10 ml) in the presence of DIPEA (1 g, 7.8 mmol) at 0 C. After stirring for 10 min, the
mixture was diluted with EA(20 mL), washed with brine, dried over Na SO , concentrated in vacuo to
give 0.65 g of the crude compound 14, which was used in the next step directly without further
purification.
Step 3
To a solution of 14 (100 mg, 0.19 mmol) and DIPEA (49 mg, 0.38 mmol) in DMF (2 ml) was
added dicyclopropylamine (37 mg, 0.38 mmol). The mixture was stirred at 30 C for 1h and then purified
by prep-HPLC to give 24 mg of the title compound (2a). MS (ESI) m/e (M+1H) : 536.3.
Example 2b: Synthesis of (E)((R)(4-amino(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-
1-yl)pyrrolidinyl)(methyl((R)-tetrahydrofuranyl)amino)butenone (2b)
Similarly, compound 2b was prepared by substituting (R)-N-methyltetrahydrofuranamine
for dicyclopropylamine in Step 3 of Example 2a. MS (ESI) m/e (M+1H) : 540.1.
Example 2c: Synthesis of (E)((R)(4-amino(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-
1-yl)pyrrolidinyl)((R)-tetrahydrofuranylamino)butenone (2c)
Similarly, compound 2c was prepared by substituting (R)-tetrahydrofuranamine for
dicyclopropylamine in Step 3 of Example 2a. MS (ESI) m/e (M+1H) : 526.1.
Example 2d: Synthesis of (E)((R)(4-amino(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-
1-yl)pyrrolidinyl)(methyl((S)-tetrahydrofuranyl)amino)butenone (2d)
Similarly, compound 2d was prepared by substituting (S)-N-methyltetrahydrofuranamine
for dicyclopropylamine in Step 3 of Example 2a. MS (ESI) m/e (M+1H) : 540.3.
Example 2e: Synthesis of (E)((R)(4-amino(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-
1-yl)pyrrolidinyl)((S)-tetrahydrofuranylamino)butenone (2e)
Similarly, compound 2e was prepared by substituting (S)-tetrahydrofuranamine for
dicyclopropylamine in Step 3 of Example 2a. MS (ESI) m/e (M+1H) : 526.0.
Example 2f: Synthesis of (R,E)(3-(4-amino(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin
yl)pyrrolidinyl)(methyl(oxetanyl)amino)butenone (2f)
Similarly, compound 2f was prepared by substituting N-methyloxetanamine for
dicyclopropylamine in Step 3 of Example 2a. MS (ESI) m/e (M+1H) : 526.1.
Example 2g: Synthesis of (R,E)(3-(4-amino(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin
yl)pyrrolidinyl)(oxetanylamino)butenone (2g)
Similarly, compound 2g was prepared by substituting oxetanamine for dicyclopropylamine
in Step 3 of Example 2a. MS (ESI) m/e (M+1H) : 512.1.
Example 2h: Synthesis of (E)((R)(4-amino(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-
1-yl)piperidinyl)(methyl((R)-tetrahydrofuranyl)amino)butenone (2h)
Similarly, compound 2h was prepared by substituting compound B for compound A in Step 2
of Example 2a and substituting (R)-N-methyltetrahydrofuranamine for dicyclopropylamine in Step 3 of
Example 2a. MS (ESI) m/e (M+1H) : 554.1.
Example 2i: Synthesis of (E)((R)(4-amino(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-
1-yl)piperidinyl)((R)-tetrahydrofuranylamino)butenone (2i)
Similarly, compound 2i was prepared by substituting compound B for compound A in Step 2
of Example 2a and substituting (R)-tetrahydrofuranamine for dicyclopropylamine in Step 3 of Example
2a. MS (ESI) m/e (M+1H) : 540.1.
Example 2j: Synthesis of (E)((R)(4-amino(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-
1-yl)piperidinyl)(methyl((S)-tetrahydrofuranyl)amino)butenone (2j)
Similarly, compound 2j was prepared by substituting compound B for compound A in Step 2
of Example 2a and substituting (S)-N-methyltetrahydrofuranamine for dicyclopropylamine in Step 3 of
Example 2a. MS (ESI) m/e (M+1H) : 554.1.
Example 2k: Synthesis of (E)((R)(4-amino(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-
1-yl)piperidinyl)((S)-tetrahydrofuranylamino)butenone (2k)
Similarly, compound 2k was prepared by substituting compound B for compound A in Step 2
of Example 2a and substituting (S)-tetrahydrofuranamine for dicyclopropylamine in Step 3 of Example
2a. MS (ESI) m/e (M+1H) : 540.1.
Example 2m: Synthesis of (R,E)(3-(4-amino(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-
1-yl)piperidinyl)(methyl(oxetanyl)amino)butenone (2m)
Similarly, compound 2m was prepared by substituting compound B for compound A in Step
2 of Example 2a and substituting N-methyloxetanamine for dicyclopropylamine in Step 3 of Example
2a. MS (ESI) m/e (M+1H) : 540.1.
Example 2n: Synthesis of (R,E)(3-(4-amino(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin
yl)piperidinyl)(oxetanylamino)butenone (2n)
Similarly, compound 2n was prepared by substituting compound B for compound A in Step 2
of Example 2a and substituting oxetanamine for dicyclopropylamine in Step 3 of Example 2a. MS
(ESI) m/e (M+1H) : 526.1.
Example 2o: Synthesis of (R,E)(3-(4-amino(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin
yl)pyrrolidinyl)(ethyl(2-methoxyethyl)amino)butenone (2o)
Similarly, compound 2o was prepared by substituting ethyl-(2-methoxyethyl)-amine for
dicyclopropylamine in Step 3 of Example 2a. MS (ESI) m/e (M+1H) : 542.1. H NMR (CDCl 400
MHz): 8.43 (s, 1H), 7.67 (dd, J =2.0 Hz, J =6.8 Hz, 2H), 7.43 (t, J = 8.0Hz, 2H), 7.21-7.09 (m, 5H), 6.88-
6.77 (m, 2H), 5.71 (m, 1H), 4.22 (d, J = 5.6Hz, 1H), 4.23-3.67 (m, 7H), 3.41-3.25 (m, 7H), 2.65-2.54(m,
2H), 1.35-1.29 (m, 3H).
Example 2p: Synthesis of (R,E)(3-(4-amino(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin
yl)pyrrolidinyl)(cyclopropyl(2-methoxyethyl)amino)butenone (2p)
Similarly, compound 2p was prepared by substituting N-(2-methoxyethyl)cyclopropanamine
for dicyclopropylamine in Step 3 of Example 2a. MS (ESI) m/e (M+1H) : 554.3.
Example 2q: Synthesis of (R,E)(3-(4-amino(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin
yl)pyrrolidinyl)(cyclopropyl(isopropyl)amino)butenone (2q)
Similarly, compound 2q was prepared by substituting N-isopropylcyclopropanamine for
dicyclopropylamine in Step 3 of Example 2a. MS (ESI) m/e (M+1H) : 538.2.
Example 2r: Synthesis of (R,E)(3-(4-amino(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin
yl)piperidinyl)(dicyclopropylamino)butenone (2r)
Similarly, compound 2r was prepared by substituting compound B for compound A in Step 2
of Example 2a. MS (ESI) m/e (M+1H) : 550.4.
Example 2s: Synthesis of (R,E)(3-(4-amino(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin
yl)piperidinyl)(cyclopropyl(2-methoxyethyl)amino)butenone (2s)
Similarly, compound 2s was prepared by substituting compound B for compound A in Step 2
of Example 2a and substituting N-(2-methoxyethyl)cyclopropanamine for dicyclopropylamine in Step 3
of Example 2a. MS (ESI) m/e (M+1H) : 568.3.
Example 2t: Synthesis of (R,E)(3-(4-amino(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin
yl)piperidinyl)(cyclopropyl(isopropyl)amino)butenone (2t)
Similarly, compound 2t was prepared by substituting compound B for compound A in Step 2
of Example 2a and substituting N-isopropylcyclopropanamine for dicyclopropylamine in Step 3 of
Example 2a. MS (ESI) m/e (M+1H) : 552.3.
Example 2u: Synthesis of (R,E)(3-(4-amino(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin
yl)pyrrolidinyl)(cyclopropyl(methyl)amino)butenone (2u)
Similarly, compound 2u was prepared by substituting N-methylcyclopropanamine for
dicyclopropylamine in Step 3 of Example 2a. MS (ESI) m/e (M+1H) : 510.1.
Example 2v: Synthesis of (R,E)(3-(4-amino(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin
yl)pyrrolidinyl)(cyclopropyl(ethyl)amino)butenone (2v)
Similarly, compound 2v was prepared by substituting N-ethylcyclopropanamine for
dicyclopropylamine in Step 3 of Example 2a. MS (ESI) m/e (M+1H) : 524.1.
Example 2w: Synthesis of (R,E)(3-(4-amino(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-
1-yl)pyrrolidinyl)(cyclohexyl(methyl)amino)butenone (2w)
Similarly, compound 2w was prepared by substituting N-methylcyclohexanamine for
dicyclopropylamine in Step 3 of Example 2a. MS (ESI) m/e (M+1H) : 552.1.
Example 2x: Synthesis of (R,E)(3-(4-amino(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin
yl)pyrrolidinyl)(cyclohexylamino)butenone (2x)
Similarly, compound 2x was prepared by substituting cyclohexanamine for
dicyclopropylamine in Step 3 of Example 2a. MS (ESI) m/e (M+1H) : 538.1.
Example 2y: Synthesis of (R,E)(3-(4-amino(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin
yl)pyrrolidinyl)(cyclopentyl(methyl)amino)butenone (2y)
Similarly, compound 2y was prepared by substituting N-methylcyclopentanamine for
dicyclopropylamine in Step 3 of Example 2a. MS (ESI) m/e (M+1H) : 538.4.
Example 2z: Synthesis of (R,E)(3-(4-amino(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin
yl)pyrrolidinyl)(cyclopentylamino)butenone (2z)
Similarly, compound 2z was prepared by substituting cyclopentanamine for
dicyclopropylamine in Step 3 of Example 2a. MS (ESI) m/e (M+1H) : 524.2.
Example 2aa: Synthesis of (R,E)(3-(4-amino(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-
1-yl)pyrrolidinyl)(cyclobutyl(methyl)amino)butenone (2aa)
Similarly, compound 2aa was prepared by substituting N-methylcyclobutanamine for
dicyclopropylamine in Step 3 of Example 2a. MS (ESI) m/e (M+1H) : 524.1.
Example 2ab: Synthesis of (R,E)(3-(4-amino(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-
1-yl)pyrrolidinyl)(cyclobutylamino)butenone (2ab)
Similarly, compound 2ab was prepared by substituting cyclobutanamine for
dicyclopropylamine in Step 3 of Example 2a. MS (ESI) m/e (M+1H) : 510.1.
Example 2ac: Synthesis of (R,E)(3-(4-amino(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-
1-yl)pyrrolidinyl)(methyl(1-methylpiperidinyl)amino)butenone (2ac)
Similarly, compound 2ac was prepared by substituting N,1-dimethylpiperidinamine for
dicyclopropylamine in Step 3 of Example 2a. MS (ESI) m/e (M+1H) : 567.3.
Example 2ad: Synthesis of (R,E)(3-(4-amino(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-
1-yl)pyrrolidinyl)(1-methylpiperidinylamino)butenone (2ad)
Similarly, compound 2ad was prepared by substituting 1-methylpiperidinamine for
dicyclopropylamine in Step 3 of Example 2a. MS (ESI) m/e (M+1H) : 553.1.
Example 2ae: Synthesis of (R,E)(3-(4-amino(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-
1-yl)piperidinyl)(cyclopropyl(methyl)amino)butenone (2ae)
Similarly, compound 2ae was prepared by substituting compound B for compound A in Step
2 of Example 2a and substituting N-methylcyclopropanamine for dicyclopropylamine in Step 3 of
Example 2a. MS (ESI) m/e (M+1H) : 524.3.
Example 2af: Synthesis of (R,E)(3-(4-amino(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-
1-yl)piperidinyl)(cyclopropylamino)butenone (2af)
Similarly, compound 2af was prepared by substituting compound B for compound A in Step
2 of Example 2a and substituting cyclopropanamine for dicyclopropylamine in Step 3 of Example 2a.
MS (ESI) m/e (M+1H) : 509.4.
Example 2ag: Synthesis of (R,E)(3-(4-amino(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-
1-yl)piperidinyl)(cyclohexyl(methyl)amino)butenone (2ag)
Similarly, compound 2ag was prepared by substituting compound B for compound A in Step
2 of Example 2a and substituting N-methylcyclohexanamine for dicyclopropylamine in Step 3 of
Example 2a. MS (ESI) m/e (M+1H) : 566.1.
Example 2ah: Synthesis of (R,E)(3-(4-amino(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-
1-yl)piperidinyl)(cyclohexylamino)butenone (2ah)
Similarly, compound 2ah was prepared by substituting compound B for compound A in Step
2 of Example 2a and substituting cyclohexanamine for dicyclopropylamine in Step 3 of Example 2a. MS
(ESI) m/e (M+1H) : 552.4.
Example 2ai: Synthesis of (R,E)(3-(4-amino(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-
1-yl)piperidinyl)(cyclopentyl(methyl)amino)butenone (2ai)
Similarly, compound 2ai was prepared by substituting compound B for compound A in Step 2
of Example 2a and substituting N-methylcyclopentanamine for dicyclopropylamine in Step 3 of Example
2a. MS (ESI) m/e (M+1H) : 552.1.
Example 2aj: Synthesis of (R,E)(3-(4-amino(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-
1-yl)piperidinyl)(cyclopentylamino)butenone (2aj)
Similarly, compound 2aj was prepared by substituting compound B for compound A in Step
2 of Example 2a and substituting cyclopentanamine for dicyclopropylamine in Step 3 of Example 2a. MS
(ESI) m/e (M+1H) : 538.4.
Example 2ak: Synthesis of (R,E)(3-(4-amino(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-
1-yl)piperidinyl)(cyclobutyl(methyl)amino)butenone (2ak)
Similarly, compound 2ak was prepared by substituting compound B for compound A in Step
2 of Example 2a and substituting N-methylcyclobutanamine for dicyclopropylamine in Step 3 of Example
2a. MS (ESI) m/e (M+1H) : 538.1.
Example 2am: Synthesis of (R,E)(3-(4-amino(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-
1-yl)piperidinyl)(cyclobutylamino)butenone (2am)
Similarly, compound 2am was prepared by substituting compound B for compound A in Step
2 of Example 2a and substituting cyclobutanamine for dicyclopropylamine in Step 3 of Example 2a. MS
(ESI) m/e (M+1H) : 524.1.
Example 2an: Synthesis of (R,E)(3-(4-amino(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-
1-yl)piperidinyl)(methyl(1-methylpiperidinyl)amino)butenone (2an)
Similarly, compound 2an was prepared by substituting compound B for compound A in Step
2 of Example 2a and substituting N,1-dimethylpiperidinamine for dicyclopropylamine in Step 3 of
Example 2a. MS (ESI) m/e (M+1H) : 581.1.
Example 2ao: Synthesis of (R,E)(3-(4-amino(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-
1-yl)piperidinyl)(1-methylpiperidinylamino)butenone (2ao)
Similarly, compound 2ao was prepared by substituting compound B for compound A in Step
2 of Example 2a and substituting 1-methylpiperidinamine for dicyclopropylamine in Step 3 of
Example 2a. MS (ESI) m/e (M+1H) : 567.2.
Example 2ap: Synthesis of (R,E)(3-(4-amino(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-
1-yl)pyrrolidinyl)(cyclobutyl(ethyl)amino)butenone (2ap)
Similarly, compound 2ap was prepared by substituting N-ethylcyclobutanamine for
dicyclopropylamine in Step 3 of Example 2a. MS (ESI) m/e (M+1H) : 538.2.
Example 2aq: Synthesis of (R,E)(3-(4-amino(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-
1-yl)pyrrolidinyl)(cyclobutyl(isopropyl)amino)butenone (2aq)
Similarly, compound 2aq was prepared by substituting N-isopropylcyclobutanamine for
dicyclopropylamine in Step 3 of Example 2a. MS (ESI) m/e (M+1H) : 552.4.
Example 2ar: Synthesis of (R,E)(3-(4-amino(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-
1-yl)pyrrolidinyl)(isopropyl(2-methoxyethyl)amino)butenone (2ar)
Similarly, compound 2ar was prepared by substituting N-(2-methoxyethyl)propanamine
for dicyclopropylamine in Step 3 of Example 2a.
Example 2as: Synthesis of (R,E)(3-(4-amino(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-
1-yl)piperidinyl)(isopropyl(2-methoxyethyl)amino)butenone (2as)
Similarly, compound 2as was prepared by substituting compound B for compound A in Step
2 of Example 2a and substituting N-(2-methoxyethyl)propanamine for dicyclopropylamine in Step 3 of
Example 2a.
Example 2at: Synthesis of (R,E)(3-(4-amino(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-
1-yl)pyrrolidinyl)(bis(2-methoxyethyl)amino)butenone (2at)
Similarly, compound 2at was prepared by substituting bis(2-methoxyethyl)amine for
dicyclopropylamine in Step 3 of Example 2a.
Example 2au: Synthesis of (R,E)(3-(4-amino(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-
1-yl)piperidinyl)(bis(2-methoxyethyl)amino)butenone (2au)
Similarly, compound 2au was prepared by substituting compound B for compound A in Step
2 of Example 2a and substituting bis(2-methoxyethyl)amine for dicyclopropylamine in Step 3 of Example
Example 3a: Synthesis of (R,E)(3-(4-amino(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin
yl)pyrrolidinyl)(cyclopropylamino)butenone (3a)
LiOH,
O (Boc) O
Br 2
Boc THF/H O
1 15 16
NH 2
HO HCl
Boc N
EA N
O HATU, DIPEA N
DMA, 25 C, 3h
N (E)
18 3a
Step 1
To a solution of cyclopropylamine (12.8 g, 0.22 mol) in THF (20 mL) was added 1 (20 g,
0.11 mol), and the mixture was stirred at 25 C for 12h. The reaction was monitored by LCMS. Upon
reaction completion, the solvent was removed under reduced pressure, re-dissolved in DCM, washed with
brine several times, dried over Na SO and concentrated under reduced pressure to give 10 g of 15 as a
crude product, which was used directly in the next step without further purification. MS (ESI) m/e
(M+1H) : 156.0.
Step 2
To a solution of 15 (10 g, 64.5 mmol) and Na CO (13.6 g, 129 mmol) in THF/H O (30 mL/
2 3 2
mL) was added (Boc) O (28.1 g, 129 mmol), and the mixture was stirred at 25 C for 3h. Upon reaction
completion, the mixture was diluted with DCM (50 mL), washed with brine several times, dried over
Na SO and concentrated under reduced pressure to give 15 g of 16 as a crude product, which was used
directly in the next step without further purification.
Step 3
To a solution of 16 (15 g, 58 mmol) in THF/H O (15 mL/ 15 mL) was added LiOH•H O (4.9
g, 117 mmol), and the mixture was stirred at 25 C for 12h. Upon reaction completion, the pH of the
mixture was adjusted to about pH = 7, and the solvent was removed under reduced pressure to give 8.0 g
of 17 as a crude product, which was used directly in the next step without further purification.
Step 4
A solution of 17 (8.0 g, 33.2 mmol) and HATU (17.1 g, 45 mmol) in DMA (5 mL) was
stirred at 25 C for 10 min. To this solution was added a solution of compound A (10 g, 22.5 mmol) and
DIPEA (5.8 g, 45 mmol) in DMA (5 mL). The mixture was stirred at 25 C for 3h and monitored by LC-
MS. Upon reaction completion, the reaction mixture was poured into water and extracted with EA three
times, dried over Na SO and concentrated under reduced pressure to give 8.0 g of 18 as a crude product.
MS (ESI) m/e (M+1H) : 596.1.
Step 5
To a solution of 18 (8.0 g, 13.4 mmol) in EA (20 mL), was added HCl/EA (10 mL). After
stirring at 25 C for 3h, the solvent was removed under reduced pressure. The residue was purified by
prep-HPLC to give 2.6 g of 3a. MS (ESI) m/e (M+1H) : 496.1.
Example 3b: Synthesis of (R,E)(3-(4-amino(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin
yl)pyrrolidinyl)((2-methoxyethyl)(methyl)amino)butenone (3b)
Similarly, compound 3b was prepared in an analogous manner as Example 3a.
Example 4a: Synthesis of (R)(4-(3-fluorophenoxy)phenyl)(pyrrolidinyl)-1H-pyrazolo[3,4-
d]pyrimidinamine (4a)
1) COCl
2) malononitrile,
K CO , 1) NaOH
DIPEA
DMF 2) HCl
3) dimethylsulfate
CN F
HO C
19 20 21 22 23
NC OMe
formamide
NH NH 1) PPh , DIAD, THF
2 2 NH NH
NC 2
N N N
N NBoc N
2) HCl
24 25
3) KOH
Step 1
A mixture of 19 (25.0 g, 206.4 mmol), 20 (20.4 mL, 227.0 mmol) and K CO (31.38 g, 227.0
mmol) in DMF (200 mL) was heated to 150 °C for 3 h. The mixture was cooled to rt and water (800 mL)
was added with stirring. White precipitate was formed during this exothermic process. The mixture was
cooled to rt and filtered. The solid was washed with water (500 mL) and air-dried. After further drying
under reduced pressure, 44.4 g of 21 was obtained and used without additional purification.
Step 2
A mixture of 21 (10.66 g, 50.0 mmol) and aq. NaOH solution (60 mL) was heated to reflux
for 2.5 h. HPLC monitoring of the reaction revealed a large amount of unreacted starting material.
Additional aq. NaOH solution (80 mL) was added, and the reaction mixture was heated to reflux for
another 2.5 h. The mixture became a homogeneous clear solution. HPLC monitoring indicated complete
consumption of the starting material but also showed two major peaks likely corresponding to the amide
intermediate and the desired product. Heating was continued for another 5 h before the mixture was
cooled to rt, during which the mixture remained a homogeneous clear solution. HPLC analysis indicated
complete conversion to final carboxylic acid. Concentrated HCl solution was added to the mixture to
adjust the pH to approximately pH = 0. The mixture was cooled to rt and filtered. The solid was further
washed with water (150 mL) and air dried. The solid was further dried under reduced pressure to provide
11.61 g of 22 as a white solid.
Steps 3 and 4
To a mixture of 22 (44.31 g, 190.8 mmol) and DMF (0.20 mL) in THF (300 mL) stirring in an
ice bath was slowly added oxalyl chloride (19.4 mL, 229.0 mmol) over 10 min. The reaction mixture was
warmed up to rt and stirred for 2 h. An additional amount of DMF (0.20 mL) was added and the mixture
was heated to 40 °C for 2 h. The solvent was removed under reduced pressure, and the residue was mixed
with with THF (200 mL) and malononitrile (13.2 mL, 209.9 mmol) and cooled in an ice bath. DIPEA
(83.1 mL, 477.0 mmol) was added slowly over 1 h. The mixture was warmed up to rt and stirred for 2 h.
After dimethylsulfate (54.2 mL, 572.5 mmol) was added in one portion, the mixture was heated to 70 °C
for 2 h, cooled to rt and stirred overnight (note: stirring overnight is not necessary). Ethanol (100 mL) was
added in one portion to the mixture. The mixture was cooled in an ice bath followed by the addition of
hydrazine hydrate (27.8 mL, 572.5 mmol) in one portion. The mixture was warmed up to rt and stirred for
2 h after which more hydrazine hydrate (9.0 mL, 190.0 mmol) was added and the mixture was stirred for
an additional 2 h. Water (300 mL) was added in one portion to the mixture and an additional amount of
water (300 mL) was added dropwise over 2 h. The mixture was stirred at rt overnight. More water (500
mL) was added and the precipitate was filtered. The solid was washed with MeOH/H O (1:1, 200 mL) and
water (100 mL), air-dried and then dried in a vacuum oven at 50 °C overnight to provide 38.77 g of 24,
which was used without additional purification.
Step 5
A mixture of 24 (35.30 g, 120.0 mmol) and formamide (250 mL) was heated to 175 °C for 3.5
h. Some precipitate was formed at the end of the heating. The mixture was cooled to 80 °C, and water (75
mL) was added. The mixture was stirred at 80 °C for 3 h, cooled to rt and stirred overnight. The mixture
was filtered and the solid collected was washed with water (100 mL), MTBE (100 mL) and ether (100
mL). The solid was air-dried and then dried in a vacuum oven at 50 °C overnight to provide 33.55 g of 25,
which was used without additional purification.
Step 6
To a mixture of 25 (30.51g, 95.0 mmol), Ph P (44.83g, 170.9 mmol) and (S)-tert-butyl 3-
hydroxypyrrolidinecarboxylate (32.0 g, 170.9 mmol) in THF (500 mL) stirring at rt was added
dropwise DIAD (37.0 mL, 188.0 mmol) over 2 h. The mixture became a homogeneous solution and was
stirred an additional 1 h at rt followed by the addition of HCl in dioxane (4 M, 250 mL, 1.0 mol) and
MeOH (20 mL). The solution was stirred at rt overnight and became a cloudy mixture. The mixture was
filtered. The solid collected was washed with EA (50 mL) and ether (50 mL). The solid was then
dissolved in a mixture of water (300 mL) and MeOH (30 mL) and the resulting solution was filtered.
KOH (15 g) was added in one portion to the filtrate with stirring, resulting in a cloudy mixture (pH ~11).
The mixture was cooled in an ice bath for 1 h and filtered. The solid was washed with water, air-dried and
then dried in a vacuum oven at 50 °C overnight to provide 26.14 g of 4a, which was used without
additional purification.
Example 4b: Synthesis of (R,E)(3-(4-amino(4-(3-fluorophenoxy)phenyl)-1H-pyrazolo[3,4-
d]pyrimidinyl)pyrrolidinyl)(cyclobutyl(methyl)amino)butenone (4b)
To a solution of 4a (134 mg, 0.344mmol), (E)(cyclobutyl(methyl)amino)butenoic acid
hydrochloride (0.344 mmol) and HATU ( 122 mg, 0.38 mmol) in DMF (1.5 ml) was dropwise added
DIPEA (134 mg, 1.032 mmol) at rt. Stirring was continued for 30 min at rt (monitored by HPLC). The
reaction mixture was diluted with EA, washed with water and brine, and dried over sodium sulfate.
Filtration followed by concentration under reduced pressure provided a residue which was purified by
flash chromatography using silica gel (1-12% MeOH /DCM) to give 32 mg of the title compound (4b).
MS (ESI) m/e (M+1H) : 542.1.
Example 4c: Synthesis of (R,E)(3-(4-amino(4-(3-fluorophenoxy)phenyl)-1H-pyrazolo[3,4-
d]pyrimidinyl)pyrrolidinyl)(cyclopropyl(methyl)amino)butenone (4c)
Similarly, compound 4c was prepared by substituting (E)(cyclopropyl(methyl)amino)but-
2-enoic acid for (E)(cyclobutyl(methyl)amino)butenoic acid hydrochloride in Example 4b. MS
(ESI) m/e (M+1H) : 528.3.
Example 5a: Synthesis of (R,E)(3-(4-amino(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin
yl)piperidinyl)(cyclopropyl(ethyl)amino)butenone (5a)
Example 5a was prepared using analogous methods of the preceding examples. MS (ESI)
m/e (M+1H) : 538.1.
Example 5b: Synthesis of (E)(4-(4-amino(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin
yl)piperidinyl)(cyclopropyl(methyl)amino)butenone (5b)
Example 5b was prepared using analogous methods of the preceding examples. MS (ESI)
m/e (M+1H) : 524.3.
Example 5c: Synthesis of (E)(3-(4-amino(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin
yl)azetidinyl)(cyclopropyl(methyl)amino)butenone (5c)
Example 5c was prepared using analogous methods of the preceding examples. MS (ESI)
m/e (M+1H) : 496.2.
Example 6a: Synthesis of (R,E)(3-(4-amino(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin
yl)pyrrolidinyl)(dimethylamino)butenone (6a)
Boc N
o Pd(dppf)Cl , K PO , N o
2 3 4 N
DIAD, PPh , THF, -10 C Et N, dioxane, 140 C
H DME/H O, 80 C
69% N
27 28
NH 2 N
O HCl
TFA, 60 C
HBTU, DMF, 0 C to rt N
29 30
Step 1
To a stirred solution of 26 (20 g, 71.6 mmol), (S)-tert-butyl 3-hydroxypyrrolidine
carboxylate (20.1 g, 107.4 mmol) and PPh (33.8 g, 128.8 mmol) in anhydrous THF (350 mL) was slowly
added DIAD (18.8 g, 93.03 mmol) over 1 h at -10 C and under N atmosphere. The resulting reaction
mixture was subsequently warmed up to rt and stirred for additional 2 h. Once yellow precipitation was
generated, the reaction mixture was cooled back to -5 C and stirred overnight. While the solution was still
cold, the yellow precipitation was quickly filtered and washed with cold THF (30 mL) to afford 22.7 g of
27 as light yellow powder. MS (ESI) m/e (M+2H) : 451.0.
Step 2
To a suspension of 27 (22.6 g, 50.4 mmol), 4-phenoxyphenylboronic acid (11.3 g. 53 mmol),
K PO •3H O (40.2 g, 151.2 mmol) in DME (240 mL) and water (60 mL) was added Pd(dppf)Cl (1.24 g,
3 4 2 2
1.51 mmol). The resulting mixture was purged with N (3x) before heated to 80 C overnight under N
atmosphere. The mixture was cooled down to rt. The organic layer was separated and the aqueous layer
was extracted with EA (20 mL x 2). The combined organic phase was dried over Na SO and
concentrated in vacuo. The residue was purified flash chromatography using silica gel (15% to 59% EA in
petroleum ether) to give 17.0 g of 28 as a white solid. MS (ESI) m/e (M+2H) : 493.1.
Step 3
A solution of 28 (11.2 g, 22.8 mmol), (4-methoxyphenyl) methanamine (4 g, 29.6 g) and Et N
(6.4 mL, 45.6 mmol) in dioxane (150 mL) was stirred at 140 C for 16 h in a 350-mL sealed tube. After
the reaction mixture was cooled down to rt, the precipitation was filtered and the filtrate was concentrated
in vacuo. The residue was purified by flash chromatography using silica gel (30% to 50% EA in
petroleum ether) to give 11.0 g of 29 as a white solid. MS (ESI) m/e (M+H) : 592.3.
Step 4
Compound 29 (16 g, 27.1 mmol) was dissolved in TFA (100 mL). The mixture was stirred at
60 C for 6 h before the solvent was removed under reduced pressure. The residue was dissoved in EA
(200 mL), adjusted pH to > 7 with sat’d. aq. NaHCO and extracted with EA (50 mL x 3). The combined
organic phase was dried over Na SO and concentrated in vacuo. The residue was purified by flash
chromatography using silica gel (5% MeOH in DCM with 0.3% Et N) to obtain 4.65 g of 30 as a white
solid. MS (ESI) m/e (M+H) : 372.3.
Step 5
To a solution of 30 (7.4 g, 19.9 mmol), (E)(dimethylamino)but- 2-enoic acid hydrochloride
(3.5 g, 20.9 mmol) and DIPEA (18 mL, 99.5 mmol) in DMF (70 mL) was added HBTU (11.6 g, 29.9
mmol) portionwise at -10 C. The mixture was stirred at rt for 3 h before the addition of water (200 mL)
and EA (80 mL). The organic layer was separated, and the aqueous layer was extracted with EA (80 mL x
4). The combined organic phase was washed with brine and dried over Na SO . The solvent was removed
in vacuo and the residue was pre-purified by flash chromatography using silica gel (15:1 to 10:1
DCM/MeOH) followed by HPLC (C18, 40-60 μm, 60Å, on CombiFlash, 40% to 100% MeOH in water
(0.2% NH /H O)) to give 5.1 g of 6a as a light yellow solid. MS (ESI) m/e (M+H) : 483.2. H NMR
(DMSO-d , 400 MHz,) 8.15 (s, 1H), 7.47 – 7.33 (m, 5 H), 7.16 – 7.04 (m, 5 H), 6.62 (dd, J = 14.3, 6.2 Hz,
1H), 6.38 (dd, J = 23.5, 15.2 Hz, 1H), 6.15 (br, 2 H), 5.34 (dt, J = 13.2, 6.9 Hz, 1 H), 4.11 – 3.45 (m, 4 H),
3.00 (dd, J = 17.1, 6.0 Hz, 2 H), 2.39 (dd, J = 33.6, 7.1 Hz, 2 H), 2.13 (s, 3 H), 2.10 (s, 3 H).
Example 6b: Synthesis of (R,E)(3-(4-amino(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin
yl)pyrrolidinyl)(cyclopropyl(methyl)amino)butenone (6b)
Similarly, compound 6b was prepared by substituting (E)(cyclopropyl(methyl)amino)but-
2-enoic acid for (E)(dimethylamino)but- 2-enoic acid hydrochloride in Step 5 of Example 6a. MS
(ESI) m/e (M+1H) :509.3.
Example 7a: Synthesis of (E)-N-(4-(4-amino(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin
yl)phenyl)(dimethylamino)-N-methylbutenamide (7a)
NH NH
Fe/NH Cl
1) LiHMDS, THF, -40 C 4
MeOH/THF/H O
K CO , DMF
N 2) (Boc) O, -40 C to rt N
N N o
60 C
100 C
NO NO
31 32 33
Boc 2
HCHO, NaBH(OAc)
N N 2) TFA, DCM
2 HN
Step 1
To a solution of 31 (15 g, 49.45 mmol) and 1-fluoronitrobenzene (7.33 g, 51.9 mmol) in
DMF (200 mL) was added K CO (20.5 g, 148.4 mmol). After the mixture was stirred at 120 C under a
N atmosphere for 48 h, the mixture was slowly poured into stirred water (1L). The resulting precipitate
was collected by filtration, washed with MeOH (200 mL x 5), and dried in vacuo to afford 16 g of 32 as a
gray solid. MS (ESI) m/e (M+H) : 425.2.
Step 2
To a stirred solution of 32 (16 g, 37.7 mmol) in THF (300 mL) under a N atmosphere was
added LiHMDS (1M, 76 mL, 76 mmol) dropwise at -40 C. The resulting mixture was stirred at -40 C
for 30 min before the addition of (Boc) O (12.33 g, 56.55 mmol). The reaction mixture was warmed up to
rt and was stirred at rt for 1 h before a quench with sat’d. aq. NH Cl (30 mL). EA (200 mL) was added to
the mixture and a precipitate was generated. The resulting precipitate was collected by filtration, washed
with EA (50 mL), and dried in vacuo to afford 18.5 g of 33 as a gray solid that was used without further
purification. MS (ESI) m/e (M+H) : 525.3.
Step 3
To a solution of 33 (18.5 g, 35.3 mmol) in a mixture of MeOH/THF/H O (5/10/1, 350 mL)
was added Fe (9.9 g, 176.5 mmol) and NH Cl (18.9 g, 353 mmol). The mixture was stirred at 60 C under
a N atmosphere for 3 h and then filtered through a Celite pad. The filtrate was concentrated in vacuo.
The residue was purified by flash chromatography using silica gel (0 to 25% EA in DCM) to give 14 g of
34 as a light yellow solid. MS (ESI) m/e (M+H) : 495.2.
Step 4
To a solution of 34 (14 g, 28.3 mmol) in DCM (150 mL) was added HCHO (38% aqueous,
3.4 g, 42.45 mmol). The mixture was stirred at rt overnight before NaBH(OAc) (18 g, 84.9 mmol) was
added in several portions. Stirring was continued at rt for 5 h before a quench with water (10 mL).
Solvents were removed in vacuo. The residue was purified by flash chromatography using silica gel (0 to
% EA in DCM) to provide 6 g of 35 as a yellow solid. MS (ESI) m/e (M+H) : 509.3.
Step 5
To a suspension of (E)(dimethylamino)butenoic acid (2.35 g, 14.2 mmol) and a drop of
DMF in dry DCM (20 mL) was added oxalyl dichloride (4.5 g, 35.4 mmol) slowly. The mixture was
stirred at rt for 2 h before the solvent was removed in vacuo. The freshly generated acid chloride was
dissolved in dry DCM (50 mL) and was added dropwise into a solution of 35 (6 g, 11.8 mmol) in DCM
(50 mL) at 0 C. The resulting mixture was stirred at rt for 3 h. TFA (20 mL) was added and the mixture
was stirred at rt for 5 h. The solvent was removed under reduced pressure. The resulting residue was
partitioned between DCM (100 mL) and water (50 mL), and the pH was adjusted to pH = 8-9 with sat’d.
aq. NaHCO . The aqueous layer was extracted with DCM (100 mL x 5). The combined organic phase
was washed with brine, dried over Na SO , and concentrated in vacuo. The residue was purified by flash
chromatography using silca gel (0 to 7% MeOH in DCM) to provide 5.4 g of the title compound (7a) as a
white solid. MS (ESI) m/e (M+H) : 520.3. 1H NMR (DMSO, 400 MHz) 9.77 (s, 1H), 8.38 (d, J = 1.8
Hz, 1H), 8.33 (d, J = 7.2 Hz, 2H), 7.74 (dd, J = 8.5, 1.8 Hz, 2H), 7.50 (dd, J = 8.7, 1.8 Hz, 2H), 7.44 (t, J
= 7.0 Hz, 2H), 7.24 – 7.09 (m, 5H), 6.64 (dd, J = 14.4, 6.3 Hz, 1H), 6.30 – 6.10 (m, 1H), 3.77 (d, J = 6.0
Hz, 2H), 3.30 (s, 3H), 2.68 (s, 6H).
Example 7b: Synthesis of (E)-N-(4-(4-amino(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin
yl)phenyl)(cyclopropyl(methyl)amino)-N-methylbutenamide (7b)
Similarly, compound 7b was prepared by substituting (E)(cyclopropyl(methyl)amino)but-
2-enoic acid for (E)(dimethylamino)butenoic acid in Step 5 of Example 7a. MS (ESI) m/e
(M+1H) : 546.2.
Example 7c: Synthesis of (E)-N-(4-(4-amino(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin
yl)phenyl)(cyclobutyl(methyl)amino)-N-methylbutenamide (7c)
Similarly, compound 7c was prepared by substituting (E)(cyclobutyl(methyl)amino)but
enoic acid for (E)(dimethylamino)butenoic acid in Step 5 of Example 7a. MS (ESI) m/e (M+1H) :
560.2.
Example 7d: Synthesis of (E)-N-(3-(4-amino(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin
yl)phenyl)(cyclopropyl(methyl)amino)-N-methylbutenamide (7d)
Similarly, compound 7d was prepared by substituting 1-fluoronitrobenzene for 1-fluoro
nitrobenzene in Step 1 and (E)(cyclopropyl(methyl)amino)butenoic acid for (E)
(dimethylamino)butenoic acid in Step 5 of Example 7a. MS (ESI) m/e (M+1H) : 546.2.
Example 7e: Synthesis of (E)-N-(3-(4-amino(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin
yl)phenyl)(cyclobutyl(methyl)amino)-N-methylbutenamide (7e)
Similarly, compound 7e was prepared by substituting 1-fluoronitrobenzene for 1-fluoro
nitrobenzene in Step 1 and (E)(cyclobutyl(methyl)amino)butenoic acid for (E)
(dimethylamino)butenoic acid in Step 5 of Example 7a. MS (ESI) m/e (M+1H) : 560.2.
Example 7f: Synthesis of (E)-N-(3-(4-amino(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin
yl)phenyl)(cyclopropyl(methyl)amino)butenamide (7f)
Compound 7f was prepared in an analogous manner as Example 7d, but Step 4 was omitted.
MS (ESI) m/e (M+1H) : 532.2.
Example 7g: Synthesis of (E)-N-(3-(4-amino(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin
yl)phenyl)(cyclobutyl(methyl)amino)butenamide (7g)
Compound 7g was prepared in an analogous manner as Example 7e, but Step 4 was omitted.
MS (ESI) m/e (M+1H) : 546.5.
Example 8a: Synthesis of 1-cyclopentyl-N -phenyl-1H-pyrazolo[3,4-d]pyrimidine-3,4-diamine (8a)
NHBoc
Cl NH NHBoc
I 2 I I
(HO) B NO
N N N
NH /dioxane Fe
3 LiHMDS
N N N
N N N
MW, 120 C
Cu(OAc) , pyridine, (Boc) O
2 2 NH Cl
H DCM, O (g)
NO NO
NO 2
2 2 2
26 36 37 39
NHBoc
Cl N
HCHO Pd(dppf)Cl
2) TFA
Step 1
To a solution of 26 (5.58 g, 20 mmol) in DCM (200 mL) were added 3-nitrophenylboronic
acid (5 g, 30 mmol), pyridine (9.49 g, 120 mmol), anhydrous Cu(OAc) (3.64 g, 20 mmol) and 4Å MS (20
g). The resulting suspension was stirred at rt overnight under O atmosphere. After quenching with water,
the mixture was filtered through a Celite pad. The filtrate was concentrated down under vacuum. The
crude product was purified by flash chromatography using silica gel (0-30% EA in petroleum ether) to
provide 5.9 g of 36. MS (ESI) m/e (M+1H) : 401.
Step 2
A solution of 36 (500 mg, 1.25 mmol), NH •H O (3 mL) and dioxane (6 mL) in a sealed tube
was heated to 120 C in a microwave reactor for 40 min. The yellow precipitate was collected by
filtration to provide 460 mg of 37. MS (ESI) m/e (M+1H) : 382.
Step 3
Compound 38 was prepared in an analogous manner as compound 33 in Step 2 of Example
7a. MS (ESI) m/e (M+1H) : 482.
Step 4
Compound 39 was prepared in an analogous manner as compound 34 in Step 3 of Example
7a. MS (ESI) m/e (M+1H) : 453.
Step 5
Compound 40 was prepared in an analogous manner as compound 35 in Step 4 of Example
7a. MS (ESI) m/e (M+1H) : 467.
Step 6
Compound 41 was prepared in an analogous manner as Example 7a. MS (ESI) m/e (M+1H) :
503.
Step 7
Compound 8a was prepared in an analogous manner as compound 28 in Step 2 of Example
6a. MS (ESI) m/e (M+1H) : 545.3. H NMR (DMSO, 400 MHz) 9.61 (br, 1H), 8.40 (s, 1H), 7.95 (m,
2H), 7.88 (s, 1H), 7.65 (t, J = 8.1 Hz, 1H), 7.56 (d, J = 8.4 Hz, 1H), 7.46 – 7.34 (m, 3H), 7.20 – 7.07 (m,
5H), 6.70 (dt, J = 14.6, 7.2 Hz, 1H), 6.32 (m, 1H), 3.94 (s, 2H), 3.33 (s, 3H), 2.74 (s, 4H), 0.93 – 0.63 (m,
4H).
Therapeutic Uses of Inhibitor Compounds
Example 9: Inhibition of Btk
The properties of the compounds disclosed herein are further characterized by assaying a
number of cellular biochemical and functional endpoints. In particular, we sought to assess the selectivity
of these compounds for inhibition of Btk versus the closely related protein kinases Lck, Lyn, and Syk. In
anti-IgM-stimulated Ramos cells (a human B cell line), are assayed Btk-dependent phosphorylation of
PLC- 1; Lyn and Syk-dependent phosphorylation of tyrosine 551 on Btk; and BCR-activated calcium
flux. The effect of compounds disclosed herein on Jurkat cells are measured wherein a human T cell line
in which Lck and Itk, but not Btk are required for T cell receptor mediated Ca flux.
Example 9a: Btk in vitro Inhibitory Activity
The Btk IC s of compounds disclosed herein is determined in both an acellular kinase assay
and in a cellular functional assay of BCR-induced calcium flux as described below.
Btk kinase activity is determined using a time-resolved fluorescence resonance energy
transfer (TR-FRET) methodology. Measurements are performed in a reaction volume of 50 L using 96-
well assay plates. Kinase enzyme, inhibitor, ATP (at the K for the kinase), and 1 M peptide substrate
(Biotin-AVLESEEELYSSARQ-NH ) are incubated in a reaction buffer composed of 20 mM Tris, 50 mM
NaCl, MgCl (5-25 mM depending on the kinase), MnCl (0-10 mM), 1 mM DTT, 0.1 mM EDTA, 0.01%
bovine serum albumin, 0.005% Tween-20, and 10% DMSO at pH 7.4 for one hour. The reaction is
quenched by the addition of 1.2 equivalents of EDTA (relative to divalent cation) in 25 L of 1x Lance
buffer (Perkin-Elmer). Streptavidin-APC (Perkin-Elmer) and Eu-labeled p-Tyr100 antibody (Perkin-
Elmer) in 1x Lance buffer are added in a 25 L volume to give final concentrations of 100 nM and 2.5
nM, respectively, and the mixture is allowed to incubate for one hour. The TR-FRET signal is measured
on a multimode plate reader with an excitation wavelength ( ) of 330 nm and detection wavelengths
( ) of 615 and 665 nm. Activity is determined by the ratio of the fluorescence at 665 nm to that at 615
nm. For each compound, enzyme activity is measured at various concentrations of compound. Negative
control reactions are performed in the absence of inhibitor in replicates of six, and two no-enzyme
controls were used to determine baseline fluorescence levels. Inhibition constants, K (app), are obtained
using the program BatchK (Kuzmic et al. (2000), Anal. Biochem. 286:45-50). IC s are obtained
i 50
according to the equation:
IC = {Ki(app)/(1+[ATP]/K )} + [E] /2;
50 m total
For all kinases, [ATP] = K , [Btk] = 0.5 nM and [Lck] = 6 nM.
m total total
Calcium flux fluoresence-based assays are performed in a FlexStation II384 fluorometric
imaging plate reader (Molecular Devices) according to manufacturer instructions. In brief, actively
growing Ramos cells (ATCC) in RPM1 medium supplemented with 10% FBS (Invitrogen) are washed
and re-plated in low serum medium at approximately 5 X 10 cells per 100 µl per well in a 96-well plate.
Compounds to be assayed are dissolved in DMSO and then diluted in low serum medium to final
concentrations ranging from 0 to 10 µM (at a dilution factor of 0.3). The diluted compounds are then
added to each well (final DMSO concentration is 0.01%) and incubate at 37 degree in 5% CO incubator
for one hour. Afterwards, 100 µl of a calcium-sensitive dye (from the Calcium 3 assay kit, Molecular
Devices) is added to each well and incubated for an additional hour. The compound-treated cells are
stimulated with a goat anti-human IgM antibody (80ug/ml; Jackson ImmunoResearch) and read in the
FlexStation II384 using a = 485nm and = 538nm for 200 seconds. The relative fluorescence unit
Ex Em
(RFU) and the IC are recorded and analyzed using a built-in SoftMax program (Molecular devices).
Table 2.
Example Btk IC * Example Btk IC * Example Btk IC *
50 50 50
1d A 2p A 2ak A
1f A 2q A 2am A
1k A 2r A 2an A
1q A 2s A 2ao A
1r A 2t A 2ap A
1s A 2u A 2aq A
1t A 2v A 3a A
1u A 2w A 4b A
2a A 2x A 4c A
2b A 2y A 5a A
2c A 2z A 5b A
2d A 2aa A 5c A
2e A 2ab A 6b A
2f A 2ac A 7b A
2g A 2ad A 7c A
2h A 2ae A 7d A
2i A 2af A 7e A
2j A 2ag A 7f A
2k A 2ah A 7g A
2m A 2ai A 8a A
2n A 2aj A
*A: < 100 nM
Example 10: Use of a Compound of Formula (I), (IA), (II), (III), (IV), (V), (VI), (VIA), (VIB), (VII),
(VIII), (IX), (X), (XI), (XII), (XIII), or (XIV) to treat rheumatoid arthritis
The in vivo efficacy of the compounds described herein are evaluated in a mouse model of
rheumatoid arthitis. Arthritis is induced in Balb/c mice by administration of anti-collagen antibodies and
lipopolysaccharide (LPS). See Nandakumar et al. (2003), Am. J. Pathol. 163:1827-1837. Female Balb/c
mice are treated with 100 mg/kg of Chemicon mAb cocktail to Type II collagen intravenously on Day 0
and 1.25 mg/kg of LPS intraperitoneally on Day 1. A test compound is administered orally in a
methylcellulose-based aqueous suspension formulation at 1, 3, 10 and 30 mg/kg once daily starting on
Day 2 through Day 12. Blood samples are collected at 0.5 and 2 hours post dose of the test compound
administration on Day 12. The serum concentrations of the test compound are quantified by LC/MS/MS.
Twenty four hours post dose, levels of the test compound below the level of quantitation.
Example 11: Inhibition of Mast Cell Degranulation
Human CD34+ cells differentiated to mast cells by 9 weeks in culture in the presence of
1ng/ml IL-3, 50 ng/ml IL-6, 100 ng/ml SCF. Cells are incubated with IgE + IL-4 for 4 days and then
degranulation is induced by cross-linking with anti-IgE. Degranulation quantitated using hexosaminidase
assay. The IC in MC degranulation of the compounds are determined. Compounds with desired IC
50 50
values are used for the treatment of inflammatory diseases, such as asthma.
Example 12: Inhibition of Lyphoma Tumor Cell Growth
An inhibitor disclosed herein is evaluated for inhibition of lymphoma tumor cell growth. A
variety of lymphoma cell lines are incubated with a range of concentrations of an inhibitor disclosed
herein to determine the GI50, the concentration that results in 50% decrease in cell proliferation.
For in vitro cell proliferation assays, cells are seeded in 96-well plates in standard growth
media (in most cases RPMI + 10% fetal calf serum) and an inhibitor disclosed herein is added in a 9-point
dilution series ranging from 10uM to 0.04 uM with DMSO at 0.1% final concentration in all wells. After
72 hours, cell number is measured using Alamar Blue using manufacturer’s protocol. A dilution series of
untreated cells is run in parallel to verify that the Alamar Blue assay reliably reflected cell number and
that growth conditions are not limiting. The GI50, the concentration that results in a 50% decrease in cell
number, is calculated using Calcusyn to fit the dose-response curve. GI50 values are confirmed in two or
more separate experiments for each cell line.
For in vivo lymphoma xenograft studies, 5E6 DOHH2 or DLCL2 cells in 50% matrigel are
implanted subcutaneously in SCID mice and dosed orally with an inhibitor disclosed herein beginning
when tumor size reaches 100 mm2.
Example 13: Inhibition of Collagen-Induced Arthritis in a Mouse
An inhibitor disclosed herein is evaluated for inhibition of collagen-induced arthritis in the
mouse. Male DBA/1OlaHsd mice are injected intradermally with 150 microliters of 2 mg/mL Type II
collagen in Freund’s complete adjuvant with supplemental M. tuberculosis, 4 mg/mL and boosted with the
same injection 21 days later. After paw inflammation is established, animals are randomized and an
inhibitor disclosed herein or vehicle is dosed orally once per day starting at day 1. Paw inflammation is
scored from 0-5 and averaged across all paws from all animals for each group in the study. Examples of
doses to be used in this study are 3.125mg/kg, 12.5 mg/kg and 50 mg/kg. Dexamethasone is included as a
positive control.
In another study, an inhibitor disclosed herein is dosed at 12.5 mg/kg or 50 mg/kg to such
mice over: (a) each day of an 11-day period; (b) days 1, 2, and 3 of an 11-day period; or (c) days 9, 10,
and 11 of an 11-day period.
Example 14: Inhibition of Lupus in a Mouse Model
An inhibitor disclosed herein is evaluated for inhibition of disease progression in the mouse
MRL/lpr model of lupus. Paw inflammation is scored from 0-5 and averaged across all paws from all
animals for each group in the study. Examples of doses to be used in this study are 3.125mg/kg, 12.5
mg/kg and 50 mg/kg. MRL/lpr mice (Jax strain 000485) are dosed orally once per day from 12 weeks of
age until 20 weeks of age and urine protein levels are measured weekly using Clinitech Multistick
dipstick.
Example 15: Pharmaceutical Compositions:
The compositions described below are presented with a compound of Formula (I), (IA), (II),
(III), (IV), (V), (VI), (VIA), (VIB), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), or (XIV) for illustrative
purposes; any of the compounds of any of Formula (I), (IA), (II), (III), (IV), (V), (VI), (VIA), (VIB),
(VII), (VIII), (IX), (X), (XI), (XII), (XIII), or (XIV) are optionally used in such pharmaceutical
compositions.
Example 15a: Parenteral Composition
To prepare a parenteral pharmaceutical composition suitable for administration by injection,
100 mg of a water-soluble salt of a compound of Formula (I), (IA), (II), (III), (IV), (V), (VI), (VIA),
(VIB), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), or (XIV) is dissolved in DMSO and then mixed with 10
mL of 0.9% sterile saline. The mixture is incorporated into a dosage unit form suitable for administration
by injection.
Example 15b: Oral Composition
To prepare a pharmaceutical composition for oral delivery, 100 mg of a compound of
Formula (I), (IA), (II), (III), (IV), (V), (VI), (VIA), (VIB), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), or
(XIV) is mixed with 750 mg of starch. The mixture is incorporated into an oral dosage unit for, such as a
hard gelatin capsule, which is suitable for oral administration.
Example 15c: Sublingual (Hard Lozenge) Composition
To prepare a pharmaceutical composition for buccal delivery, such as a hard lozenge, mix 100
mg of a compound of Formula (I), (IA), (II), (III), (IV), (V), (VI), (VIA), (VIB), (VII), (VIII), (IX), (X),
(XI), (XII), (XIII), or (XIV), with 420 mg of powdered sugar mixed, with 1.6 mL of light corn syrup, 2.4
mL distilled water, and 0.42 mL mint extract. The mixture is gently blended and poured into a mold to
form a lozenge suitable for buccal administration.
Example 15d: Inhalation Composition
To prepare a pharmaceutical composition for inhalation delivery, 20 mg of a compound of
Formula (I), (IA), (II), (III), (IV), (V), (VI), (VIA), (VIB), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), or
(XIV) is mixed with 50 mg of anhydrous citric acid and 100 mL of 0.9% sodium chloride solution. The
mixture is incorporated into an inhalation delivery unit, such as a nebulizer, which is suitable for
inhalation administration.
Example 15e: Rectal Gel Composition
To prepare a pharmaceutical composition for rectal delivery, 100 mg of a compound of
Formula (I), (IA), (II), (III), (IV), (V), (VI), (VIA), (VIB), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), or
(XIV) is mixed with 2.5 g of methylcellulose (1500 mPa), 100 mg of methylparaben, 5 g of glycerin and
100 mL of purified water. The resulting gel mixture is then incorporated into rectal delivery units, such as
syringes, which are suitable for rectal administration.
Example 15f: Topical Gel Composition
To prepare a pharmaceutical topical gel composition, 100 mg of a compound of Formula (I),
(IA), (II), (III), (IV), (V), (VI), (VIA), (VIB), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), or (XIV) is
mixed with 1.75 g of hydroxypropyl cellulose, 10 mL of propylene glycol, 10 mL of isopropyl myristate
and 100 mL of purified alcohol USP. The resulting gel mixture is then incorporated into containers, such
as tubes, which are suitable for topical administration.
Example 15g: Ophthalmic Solution Composition
To prepare a pharmaceutical ophthalmic solution composition, 100 mg of a compound of
Formula (I), (IA), (II), (III), (IV), (V), (VI), (VIA), (VIB), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), or
(XIV) is mixed with 0.9 g of NaCl in 100 mL of purified water and filtered using a 0.2 micron filter. The
resulting isotonic solution is then incorporated into ophthalmic delivery units, such as eye drop containers,
which are suitable for ophthalmic administration.
Example 16: Clinical Trial to Determine Safety and Efficacy of an inhibitor disclosed herein
The purpose of this clinical trial is to study the side effects and best dose of a compound of
Formula (I), (IA), (II), (III), (IV), (V), (VI), (VIA), (VIB), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), or
(XIV) and to determine its efficacy in the treatment of patients diagnosed with recurrent B-cell
lymphoma.
STUDY DESIGN
Cohorts of 6 patients each receive a compound of Formula (I), (IA), (II), (III), (IV), (V), (VI),
(VIA), (VIB), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), or (XIV) at 1.25, 2.5, 5.0, 8.3, 12.5, 17.5
mg/kg/d until the MTD is established. In cases where MTD is not reached, dosing levels are increased
beyond 17.5mg/kg/d by 33% increments. Patients receive daily treatment for 28 days followed by a 7 day
rest period (one cycle). Tests for Btk occupancy by the compound of Formula (I), (IA), (II), (III), (IV),
(V), (VI), (VIA), (VIB), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), or (XIV) (“occupancy”) are
performed on Day 1, 2, 8, 15 and 29 during Cycle 1 and on Day 1 and 15 of Cycles 3, 5, 7, 9, and 11. If ≤
1 DLT (“dose-limiting toxicity”) is observed in the cohort during Cycle 1, escalation to the next cohort
will proceed. Patients are enrolled in the next cohort if four of the six patients enrolled in the cohort
completed Cycle 1 without experiencing a DLT, while the remaining two patients are completing
evaluation. If ≥ 2 DLTs are observed during Cycle 1, dosing at that dose and higher is suspended and the
MTD is established as the previous cohort. Patients are allowed to continue dosing at the MTD. If ≥ 2
DLTs are seen at the 5.0 mg/kg/d cohort an additional cohort of 6 patients can be added at 3.75 mg/kg/d.
Upon determination of the MTD, a cohort of 6 patients is enrolled to receive a compound of
Formula (I), (IA), (II), (III), (IV), (V), (VI), (VIA), (VIB), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), or
(XIV) at the MTD or “preferred occupying dose” continuously for 35 days with no rest period (one cycle).
STUDY POPULATION
Up to 52 patients with recurrent surface immunoglobulin positive B cell non-Hodgkin’s
lymphoma according to WHO classification (including small lymphocytic lymphoma /chronic
lymphocytic leukemia.
STUDY OBJECTIVES
1. Primary Objectives include:
A. Determine pharmacokinetics (PK) of an orally administered compound of Formula (I),
(IA), (II), (III), (IV), (V), (VI), (VIA), (VIB), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), or (XIV).
B. Evaluate tumor response. Patients have screening (i.e., baseline) disease assessments
within 30 days before beginning treatment. Patients undergo follow-up disease assessments following
specified dosing cycles. Patients without evidence of disease progression on treatment are followed for a
maximum of 6 months off treatment for disease progression. At screening, a computed tomography (CT)
(with contrast unless contraindicated) and positron-emission tomography (PET) or CT/PET scan of the
chest, abdomen, and pelvis are required. At other visits, a CT (with contrast unless contraindicated) scan
of the chest, abdomen, and pelvis are obtained. A CT/PET or PET is required to confirm a complete
response. Bone marrow biopsy is optional. In patients known to have positive bone marrow before
treatment with a compound of Formula (I), (IA), (II), (III), (IV), (V), (VI), (VIA), (VIB), (VII), (VIII),
(IX), (X), (XI), (XII), (XIII), or (XIV), a repeat biopsy should be done to confirm a complete response
following treatment. All patients are evaluated for response based on International Working Group
Revised Response Criteria for Malignant Lymphoma, Guidelines for the diagnosis and treatment of
chronic lymphocytic leukemia14, or Uniform Response Criteria in Waldenstrom’s Macroglobulinemia.
C. Measure pharmacodynamic (PD) parameters to include drug occupancy of Btk, the target
enzyme, and effect on biological markers of B cell function. Specifically, this study examines the
pharmacodynamics (PD) of the compound of Formula (I), (IA), (II), (III), (IV), (V), (VI), (VIA), (VIB),
(VII), (VIII), (IX), (X), (XI), (XII), (XIII), or (XIV) in peripheral blood mononuclear cells (PBMCs)
using two PD assays. The first PD assay measures occupancy of the Btk active site by the compound of
Formula (I), (IA), (II), (III), (IV), (V), (VI), (VIA), (VIB), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), or
(XIV) using a specially designed fluorescent probe. The second PD assay measures inhibition of B cell
activation by stimulating the PBMCs ex vivo at the BCR with anti-IgM/IgG, and then assaying cell
surface expression of the activation marker CD69 by flow cytometry The PD biomarkers are measured in
vitro from a blood sample removed from patients 4-6 hours following an oral dose of the compound of
Formula (I), (IA), (II), (III), (IV), (V), (VI), (VIA), (VIB), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), or
(XIV). These assays determine what levels of a compound of Formula (I), (IA), (II), (III), (IV), (V), (VI),
(VIA), (VIB), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), or (XIV) are required to achieve maximal
occupancy of Btk and maximal inhibition of BCR signaling. When possible, similar studies are conducted
on circulating tumor cells isolated from blood of patients.
2. Secondary Objectives include:
A. To analyze tumor biopsy samples (when possible) for apoptotic biomarker expression
analysis.
Inclusion Criteria
To be eligible to participate in this study, a patient must meet the following criteria:
Women and men ≥ 18 years of age
Body weight ≥ 40 kg
Recurrent surface immunoglobulin positive B cell non-Hodgkin’s lymphoma (NHL)
according to WHO classification, including small lymphocytic lymphoma/ chronic
lymphocytic leukemia (SLL/CLL) and lymphoplasmacytic lymphoma, including
Waldenstrom's Macroglobulinemia (WM)
Measurable disease (for NHL, bidimensional disease ≥ 2 cm diameter in at least one
dimension, for CLL ≥ 5000 leukemia cells/mm3, and for WM presence of immunoglobulin M
paraprotein with a minimum IgM level ≥ 1000 mg/dL and infiltration of bone marrow by
lymphoplasmacytic cells)
Have failed ≥ 1 previous treatment for lymphoma and no standard therapy is available.
Patients with diffuse large B cell lymphoma must have failed, refused or be ineligible for
autologous stem cell transplant
ECOG performance status of ≤ 1
Ability to swallow oral capsules without difficulty
Willing and able to sign a written informed consent
Exclusion Criteria
A patient meeting any of the following criteria will be excluded from this study:
More than four prior systemic therapies (not counting maintenance rituximab), except for
CLL patients. Salvage therapy/conditioning regimen leading up to autologous bone marrow
transplantation is considered to be one regimen
Prior allogeneic bone marrow transplant
Immunotherapy, chemotherapy, radiotherapy or experimental therapy within 4 weeks before
first day of study drug dosing
Major surgery within 4 weeks before first day of study drug dosing
CNS involvement by lymphoma
Active opportunistic infection or treatment for opportunistic infection within 4 weeks before
first day of study drug dosing
Uncontrolled illness including but not limited to: ongoing or active infection, symptomatic
congestive heart failure (New York Heart Association Class III or IV heart failure), unstable
angina pectoris, cardiac arrhythmia, and psychiatric illness that would limit compliance with
study requirements
History of myocardial infarction, acute coronary syndromes (including unstable angina),
coronary angioplasty and/or stenting within the past 6 months
Known HIV infection
Hepatitis B sAg or Hepatitis C positive
Other medical or psychiatric illness or organ dysfunction which, in the opinion of the
investigator, would either compromise the patient’s safety or interfere with the evaluation of
the safety of the study agent
Pregnant or lactating women (female patients of child-bearing potential must have a negative
serum pregnancy test within 14 days of first day of drug dosing, or, if positive, a pregnancy
ruled out by ultrasound)
History of prior cancer < 2 years ago, except for basal cell or squamous cell carcinoma of the
skin, cervical cancer in situ or other in situ carcinomas
Example 17: Safety and Tolerability Study of an inhibitor disclosed herein in Chronic Lymphocytic
Leukemia
Purpose: The purpose of this study is to establish the safety and optimal dose of orally
administered a compound of Formula (I), (IA), (II), (III), (IV), (V), (VI), (VIA), (VIB), (VII), (VIII), (IX),
(X), (XI), (XII), (XIII), or (XIV) in patients with B-cell chronic lymphocytic leukemia/small lymphocytic
lymphoma/diffuse well-differentiated lymphocytic lymphoma.
Primary Outcome Measures: Safety and tolerability of a compound of Formula (I), (IA), (II),
(III), (IV), (V), (VI), (VIA), (VIB), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), or (XIV) (frequency,
severity, and relatedness of adverse events).
Secondary Outcome Measures: Pharmacokinetic/ Pharmacodynamic assessments. Tumor
response - overall response rate as defined by recent guidelines on CLL and SLL (B cell lymphoma) and
duration of response.
Eligibility: 18 Years and older; both genders are eligible.
Inclusion Criteria: 1. For treatment-naive group only: Men and women ≥ 65 years of age with
confirmed diagnosis of CLL/SLL, who require treatment per NCI or International Working Group
guidelines11-14. 2. For relapsed/refractory group only: Men and women ≥ 18 years of age with a
confirmed diagnosis of relapsed/refractory CLL/SLL unresponsive to therapy (ie, failed ≥ 2 previous
treatments for CLL/SLL and at least 1 regimen had to have had a purine analog [eg, fludarabine] for
subjects with CLL). 3. Body weight ≥ 40 kg. 4. ECOG performance status of ≤ 2. 5. Agreement to use
contraception during the study and for 30 days after the last dose of study drug if sexually active and able
to bear children. 6. Willing and able to participate in all required evaluations and procedures in this study
protocol including swallowing capsules without difficulty. 7. Ability to understand the purpose and risks
of the study and provide signed and dated informed consent and authorization to use protected health
information (in accordance with national and local subject privacy regulations).
Exclusion Criteria: 1. A life-threatening illness, medical condition or organ system
dysfunction which, in the investigator's opinion, could compromise the subject's safety, interfere with the
absorption or metabolism of a compound of Formula (I), (IA), (II), (III), (IV), (V), (VI), (VIA), (VIB),
(VII), (VIII), (IX), (X), (XI), (XII), (XIII), or (XIV) PO, or put the study outcomes at undue risk. 2. Any
immunotherapy, chemotherapy, radiotherapy, or experimental therapy within 4 weeks before first dose of
study drug (corticosteroids for disease-related symptoms allowed but require 1-week washout before
study drug administration). 3. Central nervous system (CNS) involvement by lymphoma. 4. Major
surgery within 4 weeks before first dose of study drug. 5. Creatinine > 1.5 x institutional upper limit of
normal (ULN); total bilirubin > 1.5 x ULN (unless due to Gilbert's disease); and aspartate
aminotransferase (AST) or alanine aminotransferase (ALT) > 2.5 x ULN unless disease related. 6.
Concomitant use of medicines known to cause QT prolongation or torsades de pointes. 7. Significant
screening electrocardiogram (ECG) abnormalities including left bundle branch block, 2nd degree AV
block type II, 3rd degree block, bradycardia, and QTc > 470 msec. 8. Lactating or pregnant.
Example 18: Safety and Efficacy of an inhibitor disclosed herein in Subjects With
Relapsed/Refractory Mantle Cell Lymphoma (MCL)
The primary objective of this trial is to evaluate the efficacy of a compound of Formula (I),
(IA), (II), (III), (IV), (V), (VI), (VIA), (VIB), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), or (XIV) in
relapsed/refractory subjects with Mantle Cell Lymphoma (MCL). The secondary objective is to evaluate
the safety of a fixed daily dosing regimen of a compound of Formula (I), (IA), (II), (III), (IV), (V), (VI),
(VIA), (VIB), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), or (XIV) in this population.
Primary Outcome Measures: To measure the number of participants with a response to a
compound of Formula (I), (IA), (II), (III), (IV), (V), (VI), (VIA), (VIB), (VII), (VIII), (IX), (X), (XI),
(XII), (XIII), or (XIV).
Secondary Outcome Measures: To measure the number of participants with adverse events as
a measure of safety and tolerability. To measure pharmacokinetics to assist in determining how the body
responds to the compound of Formula (I), (IA), (II), (III), (IV), (V), (VI), (VIA), (VIB), (VII), (VIII),
(IX), (X), (XI), (XII), (XIII), or (XIV). Patient reported outcomes (to measure the number of participants
reported outcomes in determing the health related quality of life).
Eligibility: 18 Years and older; both genders are eligible.
Inclusion Criteria: Men and women ≥ 18 years of age. ECOG performance status of ≤ 2.
Pathologically confirmed MCL, with documentation of either overexpression of cyclin D1 or t(11;14),
and measurable disease on cross sectional imaging that is ≥ 2 cm in the longest diameter and measurable
in 2 perpendicular dimensions. Documented failure to achieve at least partial response (PR) with, or
documented disease progression disease after, the most recent treatment regimen. At least 1, but no more
than 5, prior treatment regimens for MCL (Note: Subjects having received ≥2 cycles of prior treatment
with bortezomib, either as a single agent or as part of a combination therapy regimen, will be considered
to be bortezomib-exposed.). Willing and able to participate in all required evaluations and procedures in
this study protocol including swallowing capsules without difficulty. Ability to understand the purpose
and risks of the study and provide signed and dated informed consent and authorization to use protected
health information (in accordance with national and local subject privacy regulations).
Major exclusion criteria: Prior chemotherapy within 3 weeks, nitrosoureas within 6 weeks,
therapeutic anticancer antibodies within 4 weeks, radio- or toxin-immunoconjugates within 10 weeks,
radiation therapy within 3 weeks, or major surgery within 2 weeks of first dose of study drug. Any life-
threatening illness, medical condition or organ system dysfunction which, in the investigator's opinion,
could compromise the subject's safety, interfere with the absorption or metabolism of a compound of
Formula (I), (IA), (II), (III), (IV), (V), (VI), (VIA), (VIB), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), or
(XIV), or put the study outcomes at undue risk. Clinically significant cardiovascular disease such as
uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6
months of screening, or any Class 3 or 4 cardiac disease as defined by the New York Heart Association
Functional Classification. Malabsorption syndrome, disease significantly affecting gastrointestinal
function, or resection of the stomach or small bowel or ulcerative colitis, symptomatic inflammatory
bowel disease, or partial or complete bowel obstruction. Any of the following laboratory abnormalities: 1.
Absolute neutrophil count (ANC) < 750 cells/mm3 (0.75 x 109/L) unless there is documented bone
marrow involvement. 2. Platelet count < 50,000 cells/mm3 (50 x 109/L) independent of transfusion
support unless there is documented bone marrow involvement. 3. Serum aspartate transaminase
(AST/SGOT) or alanine transaminase (ALT/SGPT) ≥ 3.0 x upper limit of normal (ULN). 4. Creatinine >
2.0 x ULN.
Claims (35)
1. A compound having the structure of Formula (VI): Formula (VI); wherein: a a b b b b L is CR R , O, S, NR , N-OR , C=O, C=S, C=N-R or C=N-OR ; W is a bond or optionally substituted C -C alkyl; Z is C=O, SO or SO; 1 2 1 2 R and R are each independently H or C -C alkyl, wherein R and R have a cis or trans relationship; or R and R join together to form a bond; n and p are each independently an integer from 0 to 3; m is an integer from 1 to 3; R is H, substituted or unsubstituted C -C alkyl, substituted or unsubstituted C -C cycloalkyl, substituted or unsubstituted C -C heteroalkyl, substituted or 3 6 1 6 unsubstituted C -C heterocycloalkyl, substituted or unsubstituted C -C aryl, or 2 6 6 12 substituted or unsubstituted C -C heteroaryl; 5 11 R is substituted or unsubstituted C -C cycloalkyl, substituted or unsubstituted C -C heterocycloalkyl, substituted or unsubstituted C -C aryl, or substituted or 2 6 6 12 unsubstituted C -C heteroaryl; 5 11 5 b b b R is H, OH, OR , NR R , halogen, C -C alkyl, C -C heteroalkyl, 1 6 1 6 C C cycloalkyl, or C -C heterocycloalkyl; 3 6 2 6 R is each independently H, C -C alkyl, C -C heteroalkyl, halogen, OR , or 1 6 1 6 NR R ; R is each independently H, C -C alkyl, C -C heteroalkyl, C -C cycloalkyl, or 1 6 2 6 3 6 C -C heterocycloalkyl; or a pharmaceutically acceptable salt, solvate, or N-oxide thereof.
2. The compound of claim 1 wherein R is C -C cycloalkyl.
3. The compound of claim 1 wherein R is tetrahydrofuran, tetrahydropyran, oxetane, or .
4. The compound of claim 1 wherein R is pyridine.
5. The compound of any one of claims 1 to 4 wherein L is O.
6. The compound of any one of claims 1 to 5 wherein W is a bond.
7. The compound of any one of claims 1 to 6 wherein R is H.
8. The compound of any one of claims 1 to 7 wherein R is H.
9. The compound of any one of claims 1 to 8 wherein R and R have a trans relationship.
10. The compound of any one of claims 1 to 9 wherein m is 2.
11. The compound of any one of claims 1 to 10 wherein n is 1 or 2.
12. The compound of any one of claims 1 to 9 wherein m is 3 and n is 1.
13. The compound of any one of claims 1 to 12 wherein p is 1.
14. The compound of any one of claims 1 to 13 wherein R is H or CH .
15. A compound having the structure of Formula (VII) Formula (VII); wherein: a a b b b b L is CR R , O, S, NR , N-OR , C=O, C=S, C=N-R or C=N-OR ; W is a bond or optionally substituted C -C alkyl; Z is NR C=O, SO or SO; 1 2 1 2 R and R are each independently H or C -C alkyl, wherein R and R have a cis or trans relationship; or R and R join together to form a bond; p is an integer from 0 to 3; R is H, substituted or unsubstituted C -C alkyl, substituted or unsubstituted C -C cycloalkyl, substituted or unsubstituted C -C heteroalkyl, substituted or 3 6 1 6 unsubstituted C -C heterocycloalkyl, substituted or unsubstituted C -C aryl, or 2 6 6 12 substituted or unsubstituted C -C heteroaryl; 5 11 R is substituted or unsubstituted C -C cycloalkyl, substituted or unsubstituted C -C heterocycloalkyl, substituted or unsubstituted C -C aryl, or substituted or 2 6 6 12 unsubstituted C -C heteroaryl; 5 11 5 b b b R is H, OH, OR , NR R , halogen, C -C alkyl, C -C heteroalkyl, 1 6 1 6 C -C cycloalkyl or C -C heterocycloalkyl; 3 6 2 6 R is each independently H, C -C alkyl, C -C heteroalkyl, halogen, OR , or 1 6 1 6 NR R ; R is each independently H, C -C alkyl, C -C heteroalkyl, C -C cycloalkyl or 1 6 2 6 3 6 C -C heterocycloalkyl; R is H or C -C alkyl; or a pharmaceutically acceptable salt, solvate, or N-oxide thereof.
16. A compound having the structure of Formula (VIII) Formula (VIII); wherein: a a b b b b L is CR R , O, S, NR , N-OR , C=O, C=S, C=N-R or C=N-OR ; W is a bond or optionally substituted C -C alkyl; Z is NR C=O, SO or SO; 1 2 1 2 R and R are each independently H or C -C alkyl, wherein R and R have a cis or trans relationship; or R and R join together to form a bond; p is an integer from 0 to 3; R is H, substituted or unsubstituted C -C alkyl, substituted or unsubstituted C C cycloalkyl, substituted or unsubstituted C -C heteroalkyl, substituted or 3- 6 1 6 unsubstituted C -C heterocycloalkyl, substituted or unsubstituted C -C aryl, or 2 6 6 12 substituted or unsubstituted C -C heteroaryl; 5 11 R is substituted or unsubstituted C -C cycloalkyl, substituted or unsubstituted C -C heterocycloalkyl, substituted or unsubstituted C -C aryl, or substituted or 2 6 6 12 unsubstituted C -C heteroaryl; 5 11 5 b b b R is H, OH, OR , NR R , halogen, C -C alkyl, C -C heteroalkyl, 1 6 1 6 C -C cycloalkyl or C -C heterocycloalkyl; 3 6 2 6 R is each independently H, C -C alkyl, C -C heteroalkyl, halogen, OR , or 1 6 1 6 NR R ; R is each independently H, C -C alkyl, C -C heteroalkyl, C -C cycloalkyl or 1 6 2 6 3 6 C -C heterocycloalkyl; R is H or C -C alkyl; or a pharmaceutically acceptable salt, solvate, or N-oxide thereof.
17. A compound having the structure of Formula (X) n R R Formula (X); wherein: a a b b b b L is CR R , O, S, NR , N-OR , C=O, C=S, C=N-R or C=N-OR ; W is a bond or optionally substituted C -C alkyl; Z is C=O, SO or SO; 1 2 1 2 R and R are each independently H or C -C alkyl, wherein R and R have a cis or trans relationship; or R and R join together to form a bond; n and p are each independently an integer from 0 to 3; m is an integer from 1 to 3; R is H, substituted or unsubstituted C -C alkyl, substituted or unsubstituted C -C cycloalkyl, substituted or unsubstituted C -C heteroalkyl, substituted or 3 6 1 6 unsubstituted C -C heterocycloalkyl, substituted or unsubstituted C -C aryl, or 2 6 6 12 substituted or unsubstituted C -C heteroaryl; 5 11 R is substituted or unsubstituted C -C cycloalkyl, substituted or unsubstituted C -C heterocycloalkyl, substituted or unsubstituted C -C aryl, or substituted or 2 6 6 12 unsubstituted C -C heteroaryl; 5 11 5 b b b R is H, OH, OR , NR R , halogen, C -C alkyl, C -C heteroalkyl, 1 6 1 6 C -C cycloalkyl or C -C heterocycloalkyl; 3 6 2 6 R is each independently H, C -C alkyl, C -C heteroalkyl, halogen, OR , or 1 6 1 6 NR R ; R is each independently H, C -C alkyl, C -C heteroalkyl, C -C cycloalkyl or 1 6 2 6 3 6 C -C heterocycloalkyl; or a pharmaceutically acceptable salt, solvate, or N-oxide thereof.
18. The compound of any one of claims 15 to 17 wherein R is C -C cycloalkyl.
19. The compound of any one of claims 15 to 17 wherein L is O.
20. The compound of any one of claims 15 to 17 wherein W is a bond.
21. The compound of any one of claims 15 to 17 wherein R is H.
22. The compound of any one of claims 15 to 17 wherein R is H.
23. The compound of any one of claims 15 to 17 wherein R and R have a trans relationship.
24. The compound of any one of claims 15 to 17 wherein R is H or CH .
25. A compound having the structure selected from: NH NH O , , NH NH NH NH NH NH , and ; or a pharmaceutically acceptable salt, solvate, or N-oxide thereof.
26. A compound having the structure selected from: NH NH O , O , O H O NH NH NH NH , and ; or a pharmaceutically acceptable salt, solvate, or N-oxide thereof.
27. A compound having the structure selected from: NH NH , O , O N O , , N , , , and ; or a pharmaceutically acceptable salt, solvate, or N-oxide thereof.
28. A compound selected from: O , , O , O , O , , O , O , , , O , O , O , O , O , O , O , O , O , O , O , O , O , O , O , O , O , O , O , O , O , O , , , , N OMe N OMe NH NH N N N O N O N , , , NH NH O O O , , , N N N , , , H N H N , and or a pharmaceutically acceptable salt, solvate, or N-oxide thereof.
29. A pharmaceutical composition comprising a compound of any one of claims 1 to 28, or a pharmaceutically acceptable salt, solvate, or N-oxide thereof; and a pharmaceutically acceptable excipient, binder or carrier.
30. Use of a compound of any one of claims 1 to 28 for the manufacture of a medicament for the treatment of an autoimmune disease.
31. Use of a compound of any one of claims 1 to 28 for the manufacture of a medicament for the treatment of a heteroimmune condition or disease.
32. Use of a compound of any one of claims 1 to 28 for the manufacture of a medicament for the treatment of an inflammatory disease.
33. Use of a compound of any one of claims 1 to 28 for the manufacture of a medicament for the treatment of a cancer.
34. The use of claim 33, wherein the cancer is a B-cell proliferative disorder.
35. The use of claim 34, wherein the B-cell proliferative disorder is chronic lymphocytic lymphoma, diffuse large B cell lymphoma, follicular lymphoma or chronic lymphocytic leukemia. Pharmacyclics, LLC. Patent Attorneys for the Applicant/Nominated Person SPRUSON & FERGUSON
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201161507482P | 2011-07-13 | 2011-07-13 | |
US61/507,482 | 2011-07-13 | ||
PCT/US2012/046779 WO2013010136A2 (en) | 2011-07-13 | 2012-07-13 | Inhibitors of bruton's tyrosine kinase |
Publications (2)
Publication Number | Publication Date |
---|---|
NZ619642A NZ619642A (en) | 2016-04-29 |
NZ619642B2 true NZ619642B2 (en) | 2016-08-02 |
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