NZ751398B2 - Spirocyclic compounds - Google Patents
Spirocyclic compounds Download PDFInfo
- Publication number
- NZ751398B2 NZ751398B2 NZ751398A NZ75139817A NZ751398B2 NZ 751398 B2 NZ751398 B2 NZ 751398B2 NZ 751398 A NZ751398 A NZ 751398A NZ 75139817 A NZ75139817 A NZ 75139817A NZ 751398 B2 NZ751398 B2 NZ 751398B2
- Authority
- NZ
- New Zealand
- Prior art keywords
- compound
- pharmaceutically acceptable
- acceptable salt
- cancer
- group
- Prior art date
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 487
- 201000011510 cancer Diseases 0.000 claims abstract description 95
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 56
- 230000002730 additional Effects 0.000 claims abstract description 24
- -1 methylbenzoxazolyl Chemical group 0.000 claims description 447
- 239000011780 sodium chloride Substances 0.000 claims description 160
- 150000003839 salts Chemical class 0.000 claims description 157
- 239000000203 mixture Substances 0.000 claims description 141
- 125000000217 alkyl group Chemical group 0.000 claims description 128
- 125000001424 substituent group Chemical group 0.000 claims description 71
- 101700083887 MAPK1 Proteins 0.000 claims description 60
- 102100016823 MAPK1 Human genes 0.000 claims description 60
- 125000001072 heteroaryl group Chemical group 0.000 claims description 58
- 125000000623 heterocyclic group Chemical group 0.000 claims description 53
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 52
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 44
- 229910052739 hydrogen Inorganic materials 0.000 claims description 41
- 239000001257 hydrogen Chemical group 0.000 claims description 41
- 206010028980 Neoplasm Diseases 0.000 claims description 39
- 230000002401 inhibitory effect Effects 0.000 claims description 39
- 101710024775 erkB Proteins 0.000 claims description 36
- 230000012010 growth Effects 0.000 claims description 35
- 229910052727 yttrium Inorganic materials 0.000 claims description 35
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 31
- 125000001153 fluoro group Chemical group F* 0.000 claims description 31
- 239000003814 drug Substances 0.000 claims description 28
- 230000003211 malignant Effects 0.000 claims description 28
- 230000000694 effects Effects 0.000 claims description 27
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 26
- 108040008097 MAP kinase activity proteins Proteins 0.000 claims description 25
- 102000019149 MAP kinase activity proteins Human genes 0.000 claims description 25
- 125000004076 pyridyl group Chemical group 0.000 claims description 23
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 23
- 125000004435 hydrogen atoms Chemical group [H]* 0.000 claims description 20
- 201000003793 myelodysplastic syndrome Diseases 0.000 claims description 20
- YZCKVEUIGOORGS-OUBTZVSYSA-N deuterium Chemical group [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 claims description 19
- 125000004205 trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 claims description 19
- 238000004519 manufacturing process Methods 0.000 claims description 18
- 229910052757 nitrogen Inorganic materials 0.000 claims description 18
- 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 18
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 17
- 229910052805 deuterium Chemical group 0.000 claims description 17
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 17
- 125000003545 alkoxy group Chemical group 0.000 claims description 16
- 229910052799 carbon Inorganic materials 0.000 claims description 15
- 208000008443 Pancreatic Carcinoma Diseases 0.000 claims description 14
- 201000001441 melanoma Diseases 0.000 claims description 14
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 14
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 14
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 13
- UFHFLCQGNIYNRP-UHFFFAOYSA-N hydrogen Chemical group [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 13
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- 125000003784 fluoroethyl group Chemical group [H]C([H])(F)C([H])([H])* 0.000 claims description 11
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- 206010038389 Renal cancer Diseases 0.000 claims description 10
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- 201000005216 brain cancer Diseases 0.000 claims description 10
- 201000009030 carcinoma Diseases 0.000 claims description 10
- 239000003085 diluting agent Substances 0.000 claims description 10
- 125000003386 piperidinyl group Chemical group 0.000 claims description 10
- 201000010174 renal carcinoma Diseases 0.000 claims description 10
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 10
- 125000005059 halophenyl group Chemical group 0.000 claims description 7
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 7
- 230000000051 modifying Effects 0.000 claims description 7
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 claims description 6
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 6
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- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 201
- 238000000034 method Methods 0.000 description 150
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- 239000000243 solution Substances 0.000 description 82
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- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 78
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- 125000003118 aryl group Chemical group 0.000 description 56
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- 125000000304 alkynyl group Chemical group 0.000 description 24
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- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 23
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- 238000007792 addition Methods 0.000 description 22
- 229910052763 palladium Inorganic materials 0.000 description 22
- 239000000460 chlorine Substances 0.000 description 21
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 20
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical class CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 19
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- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 18
- DHXVGJBLRPWPCS-UHFFFAOYSA-N THP Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 description 18
- NXQGGXCHGDYOHB-UHFFFAOYSA-L cyclopenta-1,4-dien-1-yl(diphenyl)phosphane;dichloropalladium;iron(2+) Chemical group [Fe+2].Cl[Pd]Cl.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 NXQGGXCHGDYOHB-UHFFFAOYSA-L 0.000 description 18
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 18
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- 125000004432 carbon atoms Chemical group C* 0.000 description 15
- 150000002431 hydrogen Chemical class 0.000 description 15
- 238000000746 purification Methods 0.000 description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
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- 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 9
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- LWIHDJKSTIGBAC-UHFFFAOYSA-K Tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 8
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- VVDCRJGWILREQH-UHFFFAOYSA-N tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCC(B2OC(C)(C)C(C)(C)O2)=C1 VVDCRJGWILREQH-UHFFFAOYSA-N 0.000 description 7
- 238000002560 therapeutic procedure Methods 0.000 description 7
- SBWKQMCGTSWDPE-UHFFFAOYSA-N 2-(4-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane Chemical compound O1C(C)(C)C(C)(C)OB1C1=CC=C(F)C=C1 SBWKQMCGTSWDPE-UHFFFAOYSA-N 0.000 description 6
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- LZPWAYBEOJRFAX-UHFFFAOYSA-N 4,4,5,5-tetramethyl-1,3,2$l^{2}-dioxaborolane Chemical compound CC1(C)O[B]OC1(C)C LZPWAYBEOJRFAX-UHFFFAOYSA-N 0.000 description 6
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- LSMVUNSQZOHKJB-UHFFFAOYSA-N 4,4,5,5-tetramethyl-2-(4-propan-2-yloxyphenyl)-1,3,2-dioxaborolane Chemical compound C1=CC(OC(C)C)=CC=C1B1OC(C)(C)C(C)(C)O1 LSMVUNSQZOHKJB-UHFFFAOYSA-N 0.000 description 5
- IPWKHHSGDUIRAH-UHFFFAOYSA-N Bis(pinacolato)diboron Chemical group O1C(C)(C)C(C)(C)OB1B1OC(C)(C)C(C)(C)O1 IPWKHHSGDUIRAH-UHFFFAOYSA-N 0.000 description 5
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- 208000002154 Non-Small-Cell Lung Carcinoma Diseases 0.000 description 4
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- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 4
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- LBJQKYPPYSCCBH-UHFFFAOYSA-N spiro[3.3]heptane Chemical group C1CCC21CCC2 LBJQKYPPYSCCBH-UHFFFAOYSA-N 0.000 description 1
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- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- 229960002317 succinimide Drugs 0.000 description 1
- 150000003871 sulfonates Chemical class 0.000 description 1
- 150000003457 sulfones Chemical class 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 230000002459 sustained Effects 0.000 description 1
- CWXPZXBSDSIRCS-UHFFFAOYSA-N tert-butyl piperazine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCNCC1 CWXPZXBSDSIRCS-UHFFFAOYSA-N 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
- YPWFISCTZQNZAU-UHFFFAOYSA-N tetrahydro-2H-thiopyran Chemical compound C1CCSCC1 YPWFISCTZQNZAU-UHFFFAOYSA-N 0.000 description 1
- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 description 1
- 150000003536 tetrazoles Chemical class 0.000 description 1
- 125000000858 thiocyanato group Chemical group *SC#N 0.000 description 1
- YTPLMLYBLZKORZ-UHFFFAOYSA-N thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 description 1
- 230000000699 topical Effects 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
- 231100000041 toxicology testing Toxicity 0.000 description 1
- 230000002103 transcriptional Effects 0.000 description 1
- 125000005270 trialkylamine group Chemical group 0.000 description 1
- 125000005039 triarylmethyl group Chemical group 0.000 description 1
- BSUNTQCMCCQSQH-UHFFFAOYSA-N triazine Chemical compound C1=CN=NN=C1.C1=CN=NN=C1 BSUNTQCMCCQSQH-UHFFFAOYSA-N 0.000 description 1
- QXTIBZLKQPJVII-UHFFFAOYSA-N triethylsilicon Chemical group CC[Si](CC)CC QXTIBZLKQPJVII-UHFFFAOYSA-N 0.000 description 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
- 125000004952 trihaloalkoxy group Chemical group 0.000 description 1
- 125000004385 trihaloalkyl group Chemical group 0.000 description 1
- 125000000025 triisopropylsilyl group Chemical group C(C)(C)[Si](C(C)C)(C(C)C)* 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- CCRMAATUKBYMPA-UHFFFAOYSA-N trimethyltin Chemical compound C[Sn](C)C.C[Sn](C)C CCRMAATUKBYMPA-UHFFFAOYSA-N 0.000 description 1
- KQBSGRWMSNFIPG-UHFFFAOYSA-N trioxane Chemical compound C1COOOC1 KQBSGRWMSNFIPG-UHFFFAOYSA-N 0.000 description 1
- 238000001665 trituration Methods 0.000 description 1
- 210000004881 tumor cells Anatomy 0.000 description 1
- 230000003827 upregulation Effects 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 230000036642 wellbeing Effects 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- 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
- C07D487/10—Spiro-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
Abstract
Disclosed herein are spirocyclic compounds of formula (I), together with pharmaceutical compositions and methods of ameliorating and/or treating a cancer described herein with one or more of the compounds described herein.
Description
SPIROCYCLIC COMPOUNDS
INCORPORATION BY REFERENCE TO ANY PRIORITY APPLICATIONS
Any and all applications for which a foreign or domestic priority claim is
identified, for example, in the Application Data Sheet or Request as filed with the present
application, are hereby incorporated by reference under 37 CFR 1.57, and Rules 4.18 and
.6.
BACKGROUND
Field
The present application relates to the fields of chemistry, biochemistry and
medicine. More particularly, disclosed herein are spirocyclic compounds, together with
pharmaceutical compositions, and methods of synthesizing the same. Also disclosed herein
are methods of ameliorating and/or treating a cancer described herein with one or more of the
compounds described herein.
Description
The RAS/MAPK pathway is activated in response to growth factor
binding and regulates cellular growth, differentiation and survival in a variety of cell types.
Activation of this pathway occurs via a cascade of protein phosphorylation events, which
culminates in the phosphorylation and activation of ERK (ERK1 and/or ERK2). ERK lies
downstream from the small GTPase RAS and the protein kinases RAF and MEK in the
RAS/MAPK pathway. Following its activation by RAS, RAF phosphorylates MEK, which
in turn phosphorylates ERK. Activated ERK phosphorylates other substrates that govern the
transcriptional output of cells.
SUMMARY
[0003a] In a first aspect, the invention provides a compound of Formula (I):
or a pharmaceutically acceptable salt thereof, wherein:
R is selected from the group consisting of C cycloalkyl, halophenyl, C
3-4 1-4
alkoxyphenyl, C alkoxyhalophenyl, C dialkoxyphenyl, halopyridinyl, C
1-4 1-4 1-4
alkoxypyridinyl, C alkylpyridinyl, C cycloalkoxypyridinyl, methylbenzoxazolyl and
1-4 3-5
tetrahydropyranyl;
R and R are each independently methyl, hydrogen or deuterium;
Y and Y are each independently CH or N;
Y is C, CH or N; and
9 10
Y and Y are each independently CH or N;
Z is C1-3 alkyl optionally substituted with hydroxy;
wherein -------- is a single bond when Y is N or CH and -------- is a double
bond when Y is C; and
wherein the compound of Formula (I) is not
[0003b] In a second aspect, the invention provides a compound of Formula (II):
(II)
or a pharmaceutically acceptable salt thereof, wherein:
R is a methyloxazolopyridinyl, or a pyridinyl substituted with one or two
substituents independently selected from the group consisting of methyl, C alkoxy,
isopropylthio, fluoro, chloro, cyano, trifluoromethyl, and -C(=O)NHCH ; or
R is a dimethylbenzodioxolyl, a methylbenzoxazolyl, or a phenyl substituted with
one or two substituents independently selected from the group consisting of methoxy, fluoro,
chloro, cyano, trifluoromethyl and -C(=O)NHCH ;
R is or ;
R and R are each independently hydrogen or deuterium;
R is H or methyl;
R is hydrogen;
Y is N, CH or CF;
Y is N, C, CH or CF; and
Y is N or CH;
wherein -------- is a single bond when Y is N, CH or CF and -------- is a double bond
when Y is C;
wherein the compound of Formula (II) is not selected from the group consisting of
N N N
N O N
HN HN
HN HN
N N N N
O O O O
, , , , ,
N N N N
HN HN
HN HN
N N N
, , , , ,
N N N
N N N
N N N
N N N
O O O
N N N
O O O
N N N
HN HN HN
N N N
N N N
O 3 O F F
, , , , , ,
N N N
O O O
N N N
O O O
HN HN
N N N
N N N
O 3 O
, , , , ,
N HN
3 F O N
, , , , ,
N O N
HN N HN
N O 3 O
, , , ,
O N O N
N O N N
HN HN
O HN N
N HN N
N N O
, , , and .
[0003c] In a third aspect, the invention provides a compound of Formula (III):
(III)
or a pharmaceutically acceptable salt thereof, wherein:
R is a heterocyclyl selected from the group consisting of piperidinyl, 1,1-
dioxidotetrahydrothiopyranyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl,
dihydropyranyl, 2-oxaazaspiro[3.5]nonanyl, and morpholino; wherein said heterocyclyl is
optionally substituted with one or two substituents selected from the group consisting of
methyl, fluoro and trifluoroethyl; or
R is a five-membered heteroaryl selected from the group consisting of thiazolyl,
pyrazolyl, and triazolyl; wherein said five-membered heteroaryl is substituted with methyl or
isopropyl;
R is or ;
11 12
R and R are each independently hydrogen or deuterium;
Y is N or CH; and
Y is N, C, or CH;
wherein -------- is a single bond when Y is N or CH and -------- is a double bond
when Y is C; and
wherein the compound of Formula (III) is not selected from the group consisting of
N N N N N N
N N N N N N
N N N O O
N N N N N
O O O O O
N N N N N
O O O O O
N N N N N
HN HN HN HN HN
N N N N N
O O O O O
, , , , , and .
[0003d] In a fourth aspect, the invention provides a pharmaceutical
composition comprising an effective amount of a compound of any one of the first, second,
or third aspects, or a pharmaceutically acceptable salt thereof, and a pharmaceutically
acceptable carrier, diluent, excipient, or combination thereof.
[0003e] In a fifth aspect, the invention provides a method for inhibiting the
activity of ERK1 and/or ERK2 comprising providing an effective amount of a compound of
any one of the first, second, or third aspects, or a pharmaceutically acceptable salt thereof, or
a pharmaceutical composition of the fourth aspect to a sample comprising a cancer cell,
wherein the cancer cell is selected from the group consisting of a lung cancer cell, a
pancreatic cancer cell, a colon cancer cell, a myeloid leukemia cell, a thyroid cancer cell,
myelodysplastic syndrome (MDS) cell, a bladder carcinoma cell, an epidermal carcinoma
cell, a melanoma cell, a breast cancer cell, a prostate cancer cell, a head and neck cancer cell,
an ovarian cancer cell, a brain cancer cell, a cancer of mesenchymal origin cell, a sarcoma
cell, a tetracarcinoma cell, a neuroblastoma cell, a kidney carcinoma cell, a hepatoma cell, a
non-Hodgkin's lymphoma cell, a multiple myeloma cell and an anaplastic thyroid carcinoma
cell and a neurofibromatosis cell.
[0003f] In a sixth aspect, the invention provides use of an effective amount of
a compound of any one of the first, second, or third aspects, or a pharmaceutically acceptable
salt thereof, or a pharmaceutical composition of the fourth aspect in the manufacture of a
medicament for ameliorating or treating a cancer through ERK1 and/or ERK2 modulation,
wherein the cancer is selected from the group consisting of a lung cancer, a pancreatic
cancer, a colon cancer, a myeloid leukemia, a thyroid cancer, myelodysplastic syndrome
(MDS), a bladder carcinoma, an epidermal carcinoma, a melanoma, a breast cancer, a
prostate cancer, a head and neck cancer, an ovarian cancer, a brain cancer, a cancer of
mesenchymal origin, a sarcoma, a tetracarcinoma, a neuroblastoma, a kidney carcinoma, a
hepatoma, a non-Hodgkin's lymphoma, a multiple myeloma, an anaplastic thyroid carcinoma
and neurofibromatosis.
[0003g] In a seventh aspect, the invention provides use of an effective amount
of a compound of any one of the first, second, or third aspects, or a pharmaceutically
acceptable salt thereof, or a pharmaceutical composition of the fourth aspect in the
manufacture of a medicament for inhibiting replication of a malignant growth or a tumor
through ERK1 and/or ERK2 modulation, wherein the malignant growth or tumor is due to a
cancer that is selected from the group consisting of a lung cancer, a pancreatic cancer, a
colon cancer, a myeloid leukemia, a thyroid cancer, myelodysplastic syndrome (MDS), a
bladder carcinoma, an epidermal carcinoma, a melanoma, a breast cancer, a prostate cancer, a
head and neck cancer, an ovarian cancer, a brain cancer, a cancer of mesenchymal origin, a
sarcoma, a tetracarcinoma, a neuroblastoma, a kidney carcinoma, a hepatoma, a non-
Hodgkin's lymphoma, a multiple myeloma, an anaplastic thyroid carcinoma and
neurofibromatosis.
[0003h] In an eighth aspect, the invention provides use of an effective amount
of a compound of any one of the first, second, or third aspects, or a pharmaceutically
acceptable salt thereof, or a pharmaceutical composition of the fourth aspect in the
manufacture of a medicament for ameliorating or treating a cancer through ERK1 and/or
ERK2 modulation, wherein the malignant growth or tumor is due to a cancer that is selected
from the group consisting of a lung cancer, a pancreatic cancer, a colon cancer, a myeloid
leukemia, a thyroid cancer, myelodysplastic syndrome (MDS), a bladder carcinoma, an
epidermal carcinoma, a melanoma, a breast cancer, a prostate cancer, a head and neck cancer,
an ovarian cancer, a brain cancer, a cancer of mesenchymal origin, a sarcoma, a
tetracarcinoma, a neuroblastoma, a kidney carcinoma, a hepatoma, a non-Hodgkin's
lymphoma, a multiple myeloma, an anaplastic thyroid carcinoma and neurofibromatosis.
Some embodiments disclosed herein relate to a compound of Formulae (I),
(II) or (III), or a pharmaceutically acceptable salt thereof.
Some embodiments described herein relate to a pharmaceutical
composition, that can include an effective amount of a compound of Formulae (I), (II) or
(III), or a pharmaceutically acceptable salt thereof.
Some embodiments described herein relate to a method for ameliorating
and/or treating a cancer described herein that can include administering an effective amount
of a compound described herein (for example, a compound of Formulae (I), (II) or (III), or a
pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes an
effective amount of a compound described herein (for example, a compound of Formulae (I),
(II) or (III), or a pharmaceutically acceptable salt thereof) to a subject having a cancer
described herein. Other embodiments described herein relate to the use of an effective
amount of a compound described herein (for example, a compound of Formulae (I), (II) or
(III), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that
includes an effective amount of a compound described herein (for example, a compound of
Formulae (I), (II) or (III), or a pharmaceutically acceptable salt thereof) in the manufacture of
a medicament for ameliorating and/or treating a cancer described herein. Still other
embodiments described herein relate to the use of an effective amount of a compound
described herein (for example, a compound of Formulae (I), (II) or (III), or a
pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes an
effective amount of a compound described herein (for example, a compound of Formulae (I),
(II) or (III), or a pharmaceutically acceptable salt thereof) for ameliorating and/or treating a
cancer described herein.
Some embodiments described herein relate to a method for inhibiting
replication of a malignant growth or a tumor that can include contacting the growth or the
tumor with an effective amount of a compound described herein (for example, a compound
of Formulae (I), (II) or (III), or a pharmaceutically acceptable salt thereof) or a
pharmaceutical composition that includes an effective amount of a compound described
herein (for example, a compound of Formulae (I), (II) or (III), or a pharmaceutically
acceptable salt thereof), wherein the malignant growth or tumor is due to a cancer described
herein. Other embodiments described herein relate to the use of an effective amount of a
compound described herein (for example, a compound of Formulae (I), (II) or (III), or a
pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes an
effective amount of a compound described herein (for example, a compound of Formulae (I),
(II) or (III), or a pharmaceutically acceptable salt thereof) in the manufacture of a
medicament for inhibiting replication of a malignant growth or a tumor, wherein the
malignant growth or tumor is due to a cancer described herein. Still other embodiments
described herein relate to the use of an effective amount of a compound described herein (for
example, a compound of Formulae (I), (II) or (III), or a pharmaceutically acceptable salt
thereof) or a pharmaceutical composition that includes an effective amount of a compound
described herein (for example, a compound of Formulae (I), (II) or (III), or a
pharmaceutically acceptable salt thereof) for inhibiting replication of a malignant growth or a
tumor, wherein the malignant growth or tumor is due to a cancer described herein.
Some embodiments described herein relate to a method for ameliorating or
treating a cancer described herein that can include contacting a malignant growth or a tumor
with an effective amount of a compound described herein (for example, a compound of
Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition
that includes an effective amount of a compound described herein (for example, a compound
of Formulae (I), (II) or (III), or a pharmaceutically acceptable salt thereof) in a subject having
a cancer described herein. Other embodiments described herein relate to the use of an
effective amount of a compound described herein (for example, a compound of Formulae (I),
(II) or (III), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition
that includes an effective amount of a compound described herein (for example, a compound
of Formulae (I), (II) or (III), or a pharmaceutically acceptable salt thereof) in the manufacture
of a medicament for ameliorating or treating a cancer described herein that can include
contacting with a malignant growth or a tumor, wherein the malignant growth or tumor is due
to a cancer described herein. Still other embodiments described herein relate to the use of an
effective amount of a compound described herein (for example, a compound of Formulae (I),
(II) or (III), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition
that includes an effective amount of a compound described herein (for example, a compound
of Formulae (I), (II) or (III), or a pharmaceutically acceptable salt thereof) for ameliorating or
treating a cancer described herein that can include contacting with a malignant growth or a
tumor, wherein the malignant growth or tumor is due to a cancer described herein.
Some embodiments described herein relate to a method for inhibiting the
activity of ERK1 and/or ERK2 that can include providing an effective amount of a
compound described herein (for example, a compound of Formulae (I), (II) or (III), or a
pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes an
effective amount of a compound described herein (for example, a compound of Formulae (I),
(II) or (III), or a pharmaceutically acceptable salt thereof) to a sample that includes a cancer
cell from a cancer described herein. Other embodiments described herein relate to the use of
an effective amount of a compound described herein (for example, a compound of Formulae
(I), (II) or (III), or a pharmaceutically acceptable salt thereof) or a pharmaceutical
composition that includes an effective amount of a compound described herein (for example,
a compound of Formulae (I), (II) or (III), or a pharmaceutically acceptable salt thereof) in the
manufacture of a medicament for inhibiting the activity of ERK1 and/or ERK2. Still other
embodiments described herein relate to the use of an effective amount of a compound
described herein (for example, a compound of Formulae (I), (II) or (III), or a
pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes an
effective amount of a compound described herein (for example, a compound of Formulae (I),
(II) or (III), or a pharmaceutically acceptable salt thereof) for inhibiting the activity of ERK1
and/or ERK2.
Some embodiments described herein relate to a method for ameliorating or
treating a cancer described herein that can include inhibiting the activity of ERK1 and/or
ERK2 using an effective amount of a compound described herein (for example, a compound
of Formulae (I), (II) or (III), or a pharmaceutically acceptable salt thereof) or a
pharmaceutical composition that includes an effective amount of a compound described
herein (for example, a compound of Formulae (I), (II) or (III), or a pharmaceutically
acceptable salt thereof). Other embodiments described herein relate to the use of an effective
amount of a compound described herein (for example, a compound of Formulae (I), (II) or
(III), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that
includes an effective amount of a compound described herein (for example, a compound of
Formulae (I), (II) or (III), or a pharmaceutically acceptable salt thereof) in the manufacture of
a medicament for ameliorating or treating a cancer described herein by inhibiting the activity
of ERK1 and/or ERK2. Still other embodiments described herein relate to the use of an
effective amount of a compound described herein (for example, a compound of Formulae (I),
(II) or (III), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition
that includes an effective amount of a compound described herein (for example, a compound
of Formulae (I), (II) or (III), or a pharmaceutically acceptable salt thereof) for ameliorating or
treating a cancer described herein by inhibiting the activity of ERK1 and/or ERK2.
[0010a] In this specification where reference has been made to patent
specifications, other external documents, or other sources of information, this is generally for
the purpose of providing a context for discussing the features of the invention. Unless
specifically stated otherwise, reference to such external documents is not to be construed as
an admission that such documents, or such sources of information, in any jurisdiction, are
prior art, or form part of the common general knowledge in the art.
[0010b] The invention is defined in the claims. However, the disclosure preceding
the claims may refer to other subject matter outside the scope of the present claims. This
disclosure is retained for technical purposes.
DETAILED DESCRIPTION
Inhibition of ERK can have therapeutic effects in the treatment of certain
types of cancer. It has been shown that the RAS/MAPK/ERK pathway can be aberrantly
activated in certain tumors via activating mutations in RAS and BRAF, and this activation
has been implicated in the growth and pathologic behavior of certain cancer cells.
Constitutive activation of this pathway has been observed in human cancers and has been
associated with high rates of cancer cell proliferation. Tumor cells that harbor either BRAF
or RAS mutations are generally dependent on the activity of the altered proteins for growth
and survival, a phenomenon described as “oncogene addiction.” Activating mutations of
RAS have been reported in ~30% of all cancers, with some, such as pancreatic and colon
cancer, harboring mutation rates of ~90% and ~50%, respectively. RAS mutations have been
identified in ~15% of melanomas and ~30% of NSCLCs (non-small cell lung cancers).
BRAF somatic mutations have been identified in 50–70% of malignant melanomas, where all
mutations are within the kinase domain and a single substitution (V600E) accounts for 80%
of mutations. Activating BRAF mutations have also been documented in a variety of human
cancers, including colorectal cancer (~10%), NSCLC (2-3%), and thyroid cancer (~36%).
The high frequency of mutations makes targeting this pathway a strategy for cancer therapy.
Accordingly, there is a large unmet medical need for improved therapies in these diseases
especially in the advanced, refractory setting.
Provided herein are compounds that can inhibit the kinase activity of
ERKl and/or the kinase activity of ERK2. The compounds described herein can also inhibit
the phosphorylation of ERKl and ERK2, and thus can be ERK inhibitors (for example, ERK1
inhibitors and/or ERK2 inhibitors). The compounds described herein may also effectively
inhibit MAPK signaling through a dual mechanism, via inhibiting both the phosphorylation
and activation of ERK by MEK, in addition to inhibiting ERK phosphorylation of RSK. As
ERK inhibitors, the compounds described herein can be used to ameliorate and/or treat a
variety of cancers, such as, lung cancer, pancreatic cancer, colon cancer, myeloid leukemia,
thyroid cancer, myelodysplastic syndrome (MDS), bladder carcinoma, epidermal carcinoma,
melanoma, breast cancer, prostate cancer, head and neck cancer, ovarian cancer, brain
cancer, cancer of mesenchymal origin, sarcoma, tetracarcinoma, neuroblastoma, kidney
carcinoma, hepatoma, non-Hodgkin's lymphoma, multiple myeloma and anaplastic thyroid
carcinoma.
Definitions
Unless defined otherwise, all technical and scientific terms used herein
have the same meaning as is commonly understood by one of ordinary skill in the art. All
patents, applications, published applications and other publications referenced herein are
incorporated by reference in their entirety unless stated otherwise. In the event that there are
a plurality of definitions for a term herein, those in this section prevail unless stated
otherwise.
As used herein, any "R", “Y” or “Z” group(s) such as, without limitation,
1 2 3 4 5 6 7 8 9 10 11 12 13 1 2 3 4 5 6 7 8 9, 10
R , R , R , R , R , R , R , R , R , R , R , R , R , Y , Y , Y , Y , Y , Y , Y , Y , Y Y
and Z represent substituents that can be attached to the indicated atom. Such R, Y and/or Z
groups may be referred to herein in a general way as “R” groups. An R group may be
substituted or unsubstituted. If two "R" groups are described as being "taken together" the R
groups and the atoms they are attached to can form a cycloalkyl, cycloalkenyl, aryl,
a b a b
heteroaryl or heterocycle. For example, without limitation, if R and R of an NR R group
are indicated to be "taken together," it means that they are covalently bonded to one another
to form a ring:
In addition, if two “R” groups are described as being “taken together” with the atom(s) to
which they are attached to form a ring as an alternative, the R groups are not limited to the
variables or substituents defined previously.
Whenever a group is described as being “optionally substituted” that
group may be unsubstituted or substituted with one or more of the indicated substituents.
Likewise, when a group is described as being “unsubstituted or substituted” if substituted, the
substituent(s) may be selected from one or more of the indicated substituents. If no
substituents are indicated, it is meant that the indicated “optionally substituted” or
“substituted” group may be substituted with one or more group(s) individually and
independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, acylalkyl,
hydroxy, alkoxy, alkoxyalkyl, aminoalkyl, amino acid, aryl, heteroaryl, heterocyclyl,
aryl(alkyl), heteroaryl(alkyl), heterocyclyl(alkyl), hydroxyalkyl, acyl, cyano, halogen,
thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido,
N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, isocyanato, thiocyanato,
isothiocyanato, azido, nitro, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy,
trihalomethanesulfonyl, trihalomethanesulfonamido, an amino, a mono-substituted amino
group and a di-substituted amino group.
As used herein, “C to C ” in which “a” and “b” are integers refer to the
number of carbon atoms in an alkyl, alkenyl or alkynyl group, or the number of carbon atoms
in the ring of a cycloalkyl, cycloalkenyl, aryl, heteroaryl or heteroalicyclyl group. That is,
the alkyl, alkenyl, alkynyl, ring(s) of the cycloalkyl, ring(s) of the cycloalkenyl, ring(s) of the
aryl, ring(s) of the heteroaryl or ring(s) of the heteroalicyclyl can contain from “a” to “b”,
inclusive, carbon atoms. Thus, for example, a “C to C alkyl” group refers to all alkyl
groups having from 1 to 4 carbons, that is, CH -, CH CH -, CH CH CH -, (CH ) CH-,
3 3 2 3 2 2 3 2
CH CH CH CH -, CH CH CH(CH )- and (CH ) C-. If no “a” and “b” are designated with
3 2 2 2 3 2 3 3 3
regard to an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl or
heteroalicyclyl group, the broadest range described in these definitions is to be assumed.
As used herein, “alkyl” refers to a straight or branched hydrocarbon chain
that comprises a fully saturated (no double or triple bonds) hydrocarbon group. The alkyl
group may have 1 to 20 carbon atoms (whenever it appears herein, a numerical range such as
“1 to 20” refers to each integer in the given range; e.g., “1 to 20 carbon atoms” means that
the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and
including 20 carbon atoms, although the present definition also covers the occurrence of the
term “alkyl” where no numerical range is designated). The alkyl group may also be a
medium size alkyl having 1 to 10 carbon atoms. The alkyl group could also be a lower alkyl
having 1 to 6 carbon atoms. The alkyl group of the compounds 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 methyl,
ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and t-butyl. Typical alkyl groups
include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary
butyl, pentyl and hexyl. The alkyl group may be substituted or unsubstituted.
As used herein, “alkenyl” refers to an alkyl group that contains in the
straight or branched hydrocarbon chain one or more double bonds. Examples of alkenyl
groups include allenyl, vinylmethyl and ethenyl. An alkenyl group may be unsubstituted or
substituted.
As used herein, “alkynyl” refers to an alkyl group that contains in the
straight or branched hydrocarbon chain one or more triple bonds. Examples of alkynyls
include ethynyl and propynyl. An alkynyl group may be unsubstituted or substituted.
As used herein, “cycloalkyl” refers to a completely saturated (no double or
triple bonds) mono- or multi- cyclic hydrocarbon ring system. When composed of two or
more rings, the rings may be joined together in a fused, bridged or spiro fashion. As used
herein, the term “fused” refers to two rings which have two atoms and one bond in common.
As used herein, the term “bridged cycloalkyl” refers to compounds wherein the cycloalkyl
contains a linkage of one or more atoms connecting non-adjacent atoms. As used herein, the
term “spiro” refers to two rings which have one atom in common and the two rings are not
linked by a bridge. Cycloalkyl groups can contain 3 to 30 atoms in the ring(s), 3 to 20 atoms
in the ring(s), 3 to 10 atoms in the ring(s), 3 to 8 atoms in the ring(s) or 3 to 6 atoms in the
ring(s). A cycloalkyl group may be unsubstituted or substituted. Typical mono-cycloalkyl
groups include, but are in no way limited to, cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, cycloheptyl and cyclooctyl. Examples of fused cycloalkyl groups are
decahydronaphthalenyl, dodecahydro-1H-phenalenyl and tetradecahydroanthracenyl;
examples of bridged cycloalkyl groups are bicyclo[1.1.1]pentyl, bicyclo[2.1.1]heptane,
adamantanyl, and norbornanyl; and examples of spiro cycloalkyl groups include
spiro[3.3]heptane and spiro[4.5]decane.
As used herein, “cycloalkenyl” refers to a mono- or multi- cyclic
hydrocarbon ring system that contains one or more double bonds in at least one ring;
although, if there is more than one, the double bonds cannot form a fully delocalized pi-
electron system throughout all the rings (otherwise the group would be “aryl,” as defined
herein). Cycloalkenyl groups can contain 3 to 10 atoms in the ring(s) or 3 to 8 atoms in the
ring(s). When composed of two or more rings, the rings may be connected together in a
fused fashion. A cycloalkenyl group may be unsubstituted or substituted.
As used herein, “aryl” refers to a carbocyclic (all carbon) monocyclic or
multicyclic aromatic ring system (including fused ring systems where two carbocyclic rings
share a chemical bond) that has a fully delocalized pi-electron system throughout all the
rings. The number of carbon atoms in an aryl group can vary. For example, the aryl group
can be a C -C aryl group, a C -C aryl group, or a C aryl group. Examples of aryl groups
6 14 6 10 6
include, but are not limited to, benzene, naphthalene and azulene. An aryl group may be
substituted or unsubstituted.
As used herein, “heteroaryl” refers to a monocyclic or multicyclic
aromatic ring system (a ring system with fully delocalized pi-electron system) that contain(s)
one, two, three or more heteroatoms, that is, an element other than carbon, including but not
limited to, nitrogen, oxygen and sulfur. The number of atoms in the ring(s) of a heteroaryl
group can vary. For example, the heteroaryl group can contain 4 to 14 atoms in the ring(s), 5
to 10 atoms in the ring(s) or 5 to 6 atoms in the ring(s). Furthermore, the term “heteroaryl”
includes fused ring systems where two rings, such as at least one aryl ring and at least one
heteroaryl ring, or at least two heteroaryl rings, share at least one chemical bond. Examples
of heteroaryl rings include, but are not limited to, those described herein and the following:
furan, furazan, thiophene, benzothiophene, phthalazine, pyrrole, oxazole, benzoxazole, 1,2,3-
oxadiazole, 1,2,4-oxadiazole, thiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, benzothiazole,
imidazole, benzimidazole, indole, indazole, pyrazole, benzopyrazole, isoxazole,
benzoisoxazole, isothiazole, triazole, benzotriazole, thiadiazole, tetrazole, pyridine,
pyridazine, pyrimidine, pyrazine, purine, pteridine, quinoline, isoquinoline, quinazoline,
quinoxaline, cinnoline and triazine. A heteroaryl group may be substituted or unsubstituted.
As used herein, “heterocyclyl” or “heteroalicyclyl” refers to three-, four-,
five-, six-, seven-, eight-, nine-, ten-, up to 18-membered monocyclic, bicyclic, and tricyclic
ring system wherein carbon atoms together with from 1 to 5 heteroatoms constitute said ring
system. A heterocycle may optionally contain one or more unsaturated bonds situated in
such a way, however, that a fully delocalized pi-electron system does not occur throughout
all the rings. The heteroatom(s) is an element other than carbon including, but not limited to,
oxygen, sulfur, and nitrogen. A heterocycle may further contain one or more carbonyl or
thiocarbonyl functionalities, so as to make the definition include oxo-systems and thio-
systems such as lactams, lactones, cyclic imides, cyclic thioimides and cyclic carbamates.
When composed of two or more rings, the rings may be joined together in a fused or spiro
fashion, as described herein with respect to “cycloalkyl.” Additionally, any nitrogens in a
heterocyclyl may be quaternized. Heterocyclyl or heteroalicyclic groups may be
unsubstituted or substituted. Examples of such “heterocyclyl” or “heteroalicyclyl” groups
include, but are not limited to, those described herein and the following: 1,3-dioxin, 1,3-
dioxane, 1,4-dioxane, 1,2-dioxolane, 1,3-dioxolane, 1,4-dioxolane, 1,3-oxathiane, 1,4-
oxathiin, 1,3,4-oxadiazol-2(3H)-one, 1,2,3-oxadiazol-5(2H)-one, 1,3-oxathiolane, 1,3-
dithiole, 1,3-dithiolane, 1,4-oxathiane, tetrahydro-1,4-thiazine, 1,3-thiazinane, 2H-1,2-
oxazine, maleimide, succinimide, barbituric acid, thiobarbituric acid, dioxopiperazine,
hydantoin, dihydrouracil, trioxane, hexahydro-1,3,5-triazine, imidazoline, imidazolidine,
isoxazoline, isoxazolidine, oxazoline, oxazolidine, oxazolidinone, thiazoline, thiazolidine,
morpholine, oxirane, piperidine N-Oxide, piperidine, piperazine, pyrrolidine, pyrrolidone,
pyrrolidione, 4-piperidone, pyrazoline, pyrazolidine, 2-oxopyrrolidine, tetrahydropyran, 4H-
pyran, tetrahydrothiopyran, thiamorpholine, thiamorpholine sulfoxide, thiamorpholine
sulfone, and their benzo-fused analogs (e.g., benzimidazolidinone, tetrahydroquinoline, and
3,4-methylenedioxyphenyl).
As used herein, “aralkyl” and “aryl(alkyl)” refer to an aryl group
connected, as a substituent, via a lower alkylene group. The lower alkylene and aryl group of
an aralkyl may be substituted or unsubstituted. Examples include but are not limited to
benzyl, 2-phenylalkyl, 3-phenylalkyl and naphthylalkyl.
As used herein, “heteroaralkyl” and “heteroaryl(alkyl)” refer to a
heteroaryl group connected, as a substituent, via a lower alkylene group. The lower alkylene
and heteroaryl group of heteroaralkyl may be substituted or unsubstituted. Examples include
but are not limited to 2-thienylalkyl, 3-thienylalkyl, furylalkyl, thienylalkyl, pyrrolylalkyl,
pyridylalkyl, isoxazolylalkyl, imidazolylalkyl and their benzo-fused analogs.
A “heteroalicyclyl(alkyl)” and “heterocyclyl(alkyl)” refer to a heterocyclic
or a heteroalicyclylic group connected, as a substituent, via a lower alkylene group. The
lower alkylene and heterocyclyl of a heteroalicyclyl(alkyl) may be substituted or
unsubstituted. Examples include but are not limited tetrahydro-2H-pyranyl(methyl),
piperidinyl(ethyl), piperidinyl(propyl), tetrahydro-2H-thiopyranyl(methyl), and 1,3-
thiazinanyl(methyl).
- tethering groups,
“Lower alkylene groups” are straight-chained -CH2
forming bonds to connect molecular fragments via their terminal carbon atoms. Examples
include but are not limited to methylene (-CH -), ethylene (-CH CH -), propylene (-
2 2 2
CH CH CH -), and butylene (-CH CH CH CH -). A lower alkylene group can be
2 2 2 2 2 2 2
substituted by replacing one or more hydrogen of the lower alkylene group with a
substituent(s) listed under the definition of “substituted.”
As used herein, “alkoxy” refers to the formula –OR wherein R is an alkyl,
an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl,
cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl) as defined herein. A
non-limiting list of alkoxys are methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy),
cyclopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, cyclobutoxy, phenoxy and
benzoxy. An alkoxy may be substituted or unsubstituted.
As used herein, “acyl” refers to a hydrogen, an alkyl, an alkenyl, an
alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl),
aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl) connected, as substituents, via a carbonyl
group. Examples include formyl, acetyl, propanoyl, benzoyl and acryl. An acyl may be
substituted or unsubstituted.
As used herein, “acylalkyl” refers to an acyl connected, as a substituent,
via a lower alkylene group. Examples include aryl-C(=O)-(CH ) - and heteroaryl-C(=O)-
(CH ) -, where n is an integer in the range of 1 to 6.
As used herein, “alkoxyalkyl” refers to an alkoxy group connected, as a
substituent, via a lower alkylene group. Examples include C alkyl-O-(CH ) - ,wherein n is
1-4 2 n
an integer in the range of 1 to 6.
As used herein, “aminoalkyl” refers to an optionally substituted amino
group connected, as a substituent, via a lower alkylene group. Examples include H N(CH ) -
2 2 n
,wherein n is an integer in the range of 1 to 6.
As used herein, “hydroxyalkyl” refers to an alkyl group in which one or
more of the hydrogen atoms are replaced by a hydroxy group. Exemplary hydroxyalkyl
groups include but are not limited to, 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl,
and 2,2-dihydroxyethyl. A hydroxyalkyl may be substituted or unsubstituted.
As used herein, “haloalkyl” refers to an alkyl group in which one or more
of the hydrogen atoms are replaced by a halogen (e.g., mono-haloalkyl, di-haloalkyl and tri-
haloalkyl). Such groups include but are not limited to, chloromethyl, fluoromethyl,
difluoromethyl, trifluoromethyl, chloro-fluoroalkyl, chloro-difluoroalkyl and 2-
fluoroisobutyl. A haloalkyl may be substituted or unsubstituted.
As used herein, “haloalkoxy” refers to an alkoxy group in which one or
more of the hydrogen atoms are replaced by a halogen (e.g., mono-haloalkoxy, di-
haloalkoxy and tri- haloalkoxy). Such groups include but are not limited to, chloromethoxy,
fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloro-fluoroalkyl, chloro-
difluoroalkoxy and 2-fluoroisobutoxy. A haloalkoxy may be substituted or unsubstituted.
A “sulfenyl” group refers to an “-SR” group in which R can be hydrogen,
an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl,
cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). A sulfenyl may be
substituted or unsubstituted.
A “sulfinyl” group refers to an “-S(=O)-R” group in which R can be the
same as defined with respect to sulfenyl. A sulfinyl may be substituted or unsubstituted.
A “sulfonyl” group refers to an “SO R” group in which R can be the same
as defined with respect to sulfenyl. A sulfonyl may be substituted or unsubstituted.
An “O-carboxy” group refers to a “RC(=O)O-” group in which R can be
hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl,
heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl), as
defined herein. An O-carboxy may be substituted or unsubstituted.
The terms “ester” and “C-carboxy” refer to a “-C(=O)OR” group in which
R can be the same as defined with respect to O-carboxy. An ester and C-carboxy may be
substituted or unsubstituted.
A “thiocarbonyl” group refers to a “-C(=S)R” group in which R can be the
same as defined with respect to O-carboxy. A thiocarbonyl may be substituted or
unsubstituted.
A “trihalomethanesulfonyl” group refers to an “X CSO -” group wherein
each X is a halogen.
A “trihalomethanesulfonamido” group refers to an “X CS(O) N(R )-”
3 2 A
group wherein each X is a halogen, and R hydrogen, an alkyl, an alkenyl, an alkynyl, a
cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl),
heteroaryl(alkyl) or heterocyclyl(alkyl).
The term “amino” as used herein refers to a –NH group.
As used herein, the term “hydroxy” refers to a –OH group.
A “cyano” group refers to a “-CN” group.
The term “azido” as used herein refers to a –N group.
An “isocyanato” group refers to a “-NCO” group.
A “thiocyanato” group refers to a “-CNS” group.
An “isothiocyanato” group refers to an “ -NCS” group.
A “carbonyl” group refers to a C=O group.
An “S-sulfonamido” group refers to a “-SO N(R R )” group in which R
2 A B A
and R can be independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a
cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl)
or heterocyclyl(alkyl). An S-sulfonamido may be substituted or unsubstituted.
An “N-sulfonamido” group refers to a “RSO N(R )-” group in which R
and R can be independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a
cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl)
or heterocyclyl(alkyl). An N-sulfonamido may be substituted or unsubstituted.
An “O-carbamyl” group refers to a “-OC(=O)N(R R )” group in which
R and R can be independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a
cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl)
or heterocyclyl(alkyl). An O-carbamyl may be substituted or unsubstituted.
An “N-carbamyl” group refers to an “ROC(=O)N(R )-” group in which R
and R can be independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a
cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl)
or heterocyclyl(alkyl). An N-carbamyl may be substituted or unsubstituted.
An “O-thiocarbamyl” group refers to a “-OC(=S)-N(R R )” group in
which R and R can be independently hydrogen, an alkyl, an alkenyl, an alkynyl, a
cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl),
heteroaryl(alkyl) or heterocyclyl(alkyl). An O-thiocarbamyl may be substituted or
unsubstituted.
An “N-thiocarbamyl” group refers to an “ROC(=S)N(R )-” group in
which R and R can be independently hydrogen, an alkyl, an alkenyl, an alkynyl, a
cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl),
heteroaryl(alkyl) or heterocyclyl(alkyl). An N-thiocarbamyl may be substituted or
unsubstituted.
A “C-amido” group refers to a “-C(=O)N(R R )” group in which R and
A B A
R can be independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a
cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl)
or heterocyclyl(alkyl). A C-amido may be substituted or unsubstituted.
An “N-amido” group refers to a “RC(=O)N(R )-” group in which R and
R can be independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a
cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl)
or heterocyclyl(alkyl). An N-amido may be substituted or unsubstituted.
A “urea” group refers to “N(R)-C(=O)-NR R group in which R can be
hydrogen or an alkyl, and R and R can be independently hydrogen, an alkyl, an alkenyl, an
alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl),
aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). A urea may be substituted or
unsubstituted.
” in which R can be
An “oxime” group refers to “-C(=N-OH)RA A
independently an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl,
heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). An
oxime may be substituted or unsubstituted.
An “acyl hydrozone” refers to “-C(=N-NH-acyl)-R .” in which the acyl
portion has the structure as provided herein for “acyl”, and R can be independently an alkyl,
an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl,
cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). An acyl hydrozone
may be substituted or unsubstituted.
A “hydrazine” refers to “-NHNR R ” in which R and R can be
A B A B
independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl,
heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or
heterocyclyl(alkyl). A hydrazine may be substituted or unsubstituted.
The term “halogen atom” or “halogen” as used herein, means any one of
the radio-stable atoms of column 7 of the Periodic Table of the Elements, such as, fluorine,
chlorine, bromine and iodine.
As used herein, “------” indicates a single or double bond, unless stated
otherwise.
Where the numbers of substituents is not specified (e.g. haloalkyl), there
may be one or more substituents present. For example “haloalkyl” may include one or more
of the same or different halogens. As another example, “C -C alkoxyphenyl” may include
one or more of the same or different alkoxy groups containing one, two or three atoms.
As used herein, the abbreviations for any protective groups, amino acids
and other compounds, are, unless indicated otherwise, in accord with their common usage,
recognized abbreviations, or the IUPAC-IUB Commission on Biochemical Nomenclature
(See, Biochem. 11:942-944 (1972)).
The terms “protecting group” and “protecting groups” (and the
abbreviation “PG”) as used herein refer to any atom or group of atoms that is added to a
molecule in order to prevent existing groups in the molecule from undergoing unwanted
chemical reactions. Examples of protecting group moieties are described in T. W. Greene and
P. G. M. Wuts, Protective Groups in Organic Synthesis, 3. Ed. John Wiley & Sons, 1999,
and in J.F.W. McOmie, Protective Groups in Organic Chemistry Plenum Press, 1973, both
of which are hereby incorporated by reference for the limited purpose of disclosing suitable
protecting groups. The protecting group moiety may be chosen in such a way, that they are
stable to certain reaction conditions and readily removed at a convenient stage using
methodology known from the art. A non-limiting list of protecting groups include benzyl;
substituted benzyl; alkylcarbonyls and alkoxycarbonyls (e.g., t-butoxycarbonyl (BOC),
acetyl, or isobutyryl); arylalkylcarbonyls and arylalkoxycarbonyls (e.g., benzyloxycarbonyl);
substituted methyl ether (e.g. methoxymethyl ether); substituted ethyl ether; a substituted
benzyl ether; tetrahydropyranyl ether; silyls (e.g., trimethylsilyl, triethylsilyl,
triisopropylsilyl, t-butyldimethylsilyl, tri-iso-propylsilyloxymethyl, [2-
(trimethylsilyl)ethoxy]methyl or t-butyldiphenylsilyl); esters (e.g. benzoate ester); carbonates
(e.g. methoxymethylcarbonate); sulfonates (e.g. tosylate or mesylate); acyclic ketal (e.g.
dimethyl acetal); cyclic ketals (e.g., 1,3-dioxane, 1,3-dioxolanes, and those described herein);
acyclic acetal; cyclic acetal (e.g., those described herein); acyclic hemiacetal; cyclic
hemiacetal; cyclic dithioketals (e.g., 1,3-dithiane or 1,3-dithiolane); orthoesters (e.g., those
described herein) and triarylmethyl groups (e.g., trityl; monomethoxytrityl (MMTr); 4,4'-
dimethoxytrityl (DMTr); 4,4',4"-trimethoxytrityl (TMTr); and those described herein).
The term “leaving group” (and the abbreviation “LG”) as used herein
refers to any atom or moiety that is capable of being displaced by another atom or moiety in a
chemical reaction. More specifically, in some embodiments, “leaving group” refers to the
atom or moiety that is displaced in a nucleophilic substitution reaction. In some
embodiments, “leaving groups” are any atoms or moieties that are conjugate bases of strong
acids. Examples of suitable leaving groups include, but are not limited to, tosylates,
mesylates, trifluoroacetates and halogens (e.g., I, Br, and Cl). Non-limiting characteristics
and examples of leaving groups can be found, for example in Organic Chemistry, 2d ed.,
Francis Carey (1992), pages 328-331; Introduction to Organic Chemistry, 2d ed., Andrew
Streitwieser and Clayton Heathcock (1981), pages 169-171; and Organic Chemistry, 5 ed.,
John McMurry (2000), pages 398 and 408; all of which are incorporated herein by reference
for the limited purpose of disclosing characteristics and examples of leaving groups.
The term “pharmaceutically acceptable salt” refers to a salt of a compound
that does not cause significant irritation to an organism to which it is administered and does
not abrogate the biological activity and properties of the compound. In some embodiments,
the salt is an acid addition salt of the compound. Pharmaceutical salts can be obtained by
reacting a compound with inorganic acids such as hydrohalic acid (e.g., hydrochloric acid or
hydrobromic acid), sulfuric acid, nitric acid and phosphoric acid. Pharmaceutical salts can
also be obtained by reacting a compound with an organic acid such as aliphatic or aromatic
carboxylic or sulfonic acids, for example formic, acetic, succinic, lactic, malic, tartaric, citric,
ascorbic, nicotinic, methanesulfonic, ethanesulfonic, p-toluenesulfonic, salicylic or
naphthalenesulfonic acid. Pharmaceutical salts can also be obtained by reacting a compound
with a base to form a salt such as an ammonium salt, an alkali metal salt, such as a sodium or
a potassium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of
organic bases such as dicyclohexylamine, N-methyl-D-glucamine,
tris(hydroxymethyl)methylamine, C -C alkylamine, cyclohexylamine, triethanolamine,
ethylenediamine, and salts with amino acids such as arginine and lysine.
Terms and phrases used in this application, and variations thereof,
especially in the appended claims, unless otherwise expressly stated, should be construed as
open ended as opposed to limiting. As examples of the foregoing, the term ‘including’
should be read to mean ‘including, without limitation,’ ‘including but not limited to,’ or the
like; the term ‘comprising’ as used herein is synonymous with ‘including,’ ‘containing,’ or
‘characterized by,’ and is inclusive or open-ended and does not exclude additional, unrecited
elements or method steps; the term ‘having’ should be interpreted as ‘having at least;’ the
term ‘includes’ should be interpreted as ‘includes but is not limited to;’ the term ‘example’ is
used to provide exemplary instances of the item in discussion, not an exhaustive or limiting
list thereof; and use of terms like ‘preferably,’ ‘preferred,’ ‘desired,’ or ‘desirable,’ and
words of similar meaning should not be understood as implying that certain features are
critical, essential, or even important to the structure or function, but instead as merely
intended to highlight alternative or additional features that may or may not be utilized in a
particular embodiment. In addition, the term “comprising” is to be interpreted synonymously
with the phrases "having at least" or "including at least". When used in the context of a
process, the term "comprising" means that the process includes at least the recited steps, but
may include additional steps. When used in the context of a compound, composition or
device, the term "comprising" means that the compound, composition or device includes at
least the recited features or components, but may also include additional features or
components. Likewise, a group of items linked with the conjunction ‘and’ should not be read
as requiring that each and every one of those items be present in the grouping, but rather
should be read as ‘and/or’ unless the context indicates otherwise. Similarly, a group of items
linked with the conjunction ‘or’ should not be read as requiring mutual exclusivity among
that group, but rather should be read as ‘and/or’ unless the context indicates otherwise.
With respect to the use of substantially any plural and/or singular terms
herein, those having skill in the art can translate from the plural to the singular and/or from
the singular to the plural as is appropriate to the context and/or application. The various
singular/plural permutations may be expressly set forth herein for sake of clarity. The
indefinite article “a” or “an” does not exclude a plurality. The mere fact that certain
measures are recited in mutually different dependent claims does not indicate that a
combination of these measures cannot be used to advantage. Any reference signs in the
claims should not be construed as limiting the scope.
It is understood that, in any compound described herein having one or
more chiral centers, if an absolute stereochemistry is not expressly indicated, then each
center may independently be of R-configuration or S-configuration or a mixture thereof.
Thus, the compounds provided herein may be enantiomerically pure, enantiomerically
enriched, racemic mixture, diastereomerically pure, diastereomerically enriched, or a
stereoisomeric mixture. In addition it is understood that, in any compound described herein
having one or more double bond(s) generating geometrical isomers that can be defined as E
or Z, each double bond may independently be E or Z, or a mixture thereof.
Likewise, it is understood that, in any compound described, all tautomeric
forms are also intended to be included.
It is to be understood that where compounds disclosed herein have unfilled
valencies, then the valencies are to be filled with hydrogens or isotopes thereof, e.g.,
hydrogen-1 (protium) and hydrogen-2 (deuterium).
It is understood that the compounds described herein can be labeled
isotopically. Substitution with isotopes such as deuterium may afford certain therapeutic
advantages resulting from greater metabolic stability, such as, for example, increased in vivo
half-life or reduced dosage requirements. Each chemical element as represented in a
compound structure may include any isotope of said element. For example, in a compound
structure a hydrogen atom may be explicitly disclosed or understood to be present in the
compound. At any position of the compound that a hydrogen atom may be present, the
hydrogen atom can be any isotope of hydrogen, including but not limited to hydrogen-1
(protium) and hydrogen-2 (deuterium). Thus, reference herein to a compound encompasses
all potential isotopic forms unless the context clearly dictates otherwise.
It is understood that the methods and combinations described herein
include crystalline forms (also known as polymorphs, which include the different crystal
packing arrangements of the same elemental composition of a compound), amorphous
phases, salts, solvates, and hydrates. In some embodiments, the compounds described herein
exist in solvated forms with pharmaceutically acceptable solvents such as water, ethanol, or
the like. In other embodiments, the compounds described herein exist in unsolvated form.
Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and may
be formed during the process of crystallization with pharmaceutically acceptable solvents
such as water, ethanol, or the like. Hydrates are formed when the solvent is water, or
alcoholates are formed when the solvent is alcohol. 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.
Where a range of values is provided, it is understood that the upper and
lower limit, and each intervening value between the upper and lower limit of the range is
encompassed within the embodiments.
Compounds
Formula (I)
Some embodiments disclosed herein relate to a compound of Formula (I),
or a pharmaceutically acceptable salt thereof, having the structure:
In various embodiments of Formula (I), R can be selected from C
cycloalkyl, halophenyl, C alkoxyphenyl, C alkoxyhalophenyl, C dialkoxyphenyl,
1-4 1-4 1-4
halopyridinyl, C alkoxypyridinyl (e.g., isopropoxypyridinyl), C alkylpyridinyl, C
1-4 1-4 3-5
cycloalkoxypyridinyl, methylbenzoxazolyl and tetraydropyranyl. In some embodiments, R
can be halophenyl. For example, in some embodiments R can be fluorophenyl. In other
embodiments, R can be halopyridinyl. For example, in some embodiments R can be
fluoropyridinyl. In some embodiments, R can be isopropoxypyridinyl. In other
embodiments, R is not isopropoxypyridinyl. In some embodiments, R can be C
alkoxypyridinyl. For example, in some embodiments R can be methoxypyridinyl,
ethoxypyridinyl, propoxypyridinyl, cycloproxypyridinyl, butoxypyridinyl or
cyclobutoxypyridinyl. In some embodiments, R can be C alkylpyridinyl. For example, in
some embodiments R can be methylpyridinyl, ethylpyridinyl, propylpyridinyl or
butylpyridinyl. In some embodiments, R can be methylbenzoxazolyl. In some
embodiments, R can be tetraydropyranyl.
In some embodiments, R and R are each independently methyl,
hydrogen or deuterium. For example, in an embodiment, R and R are both hydrogen. In
2 3 2 3
another embodiment, R is methyl and R is hydrogen. In another embodiment, R and R are
both deuterium.
In various embodiments of Formula (I), Y and Y are each independently
CH or N. For example, in an embodiment, Y is CH. In another embodiment, Y is N. In
another embodiment, Y is CH. In another embodiment, Y is N.
In various embodiments of Formula (I), Y is C, CH or N. The ring
structure that includes Y can include a double or a single bond from an atom adjacent to Y ,
depending on whether Y is C, CH or N. For example, in an embodiment, the -------- in the
ring structure is a single bond when Y is N. In another embodiment, the -------- in the ring
structure is a single bond when Y is CH. In another embodiment, the -------- in the ring
structure is a double bond when Y is C.
9 10
In various embodiments of Formula (I), Y and Y are each independently
CH or N. For example, in an embodiment, Y is CH. In another embodiment, Y is N. In
10
another embodiment, Y is CH. In another embodiment, Y is N. In an embodiment of
9 10
Formula (I), Y is N and Y is CH, as illustrated by the following Formula (IA):
(IA)
In various embodiments of Formula (IA), R is selected from the group
consisting of halophenyl, halopyridinyl, C alkoxypyridinyl, C alkylpyridinyl,
1-4 1-4
methylbenzoxazolyl and tetraydropyranyl. In various embodiments of Formula (IA), R and
R are each independently hydrogen or deuterium. In various embodiments of Formula (IA),
1 2 3
Y and Y are each independently CH or N. In various embodiments of Formula (IA), Y is
C, CH or N. In Formula (IA), -------- is a single bond when Y is N or CH and -------- is a
double bond when Y is C. In various embodiments of Formula (IA), Z is C alkyl
optionally substituted with hydroxyl.
In various embodiments of Formula (I), Z is C alkyl optionally
substituted with hydroxyl. For example, in an embodiment Z is methyl. In another
embodiment, Z is ethyl. In another embodiment, Z is hydroxyethyl.
In various embodiments, Formula (I) and/or Formula (IA) does not
represent a compound that is disclosed in International Application No.
, which is hereby incorporated herein by reference in its entirety,
including for the purpose of describing compounds that Formula (I) and/or Formula (IA)
does not represent. For example, in an embodiment, Formula (I) and/or Formula (IA) does
not represent the following compound: .
Examples of compounds of Formula (I), or pharmaceutically acceptable
salts thereof, include the following:
(Ia), (Id),
(Ib),
(Ie),
(Ic),
(If),
(Ig), (Ik),
(Ih),
(Il),
(Ii),
(Im),
(Ij),
or a pharmaceutically acceptable salt of the foregoing.
Those skilled in the art will recognize that compounds of the Formulae
(IA), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il) and (Im) are compounds of the
Formula (I). Therefore, reference herein to variables defined for Formula (I) (such as R , R ,
3 1 2 3 9 10 1
R , Y , Y , Y , Y , Y , and Z ) will also be understood as definitions for the corresponding
variables of the Formulae (IA), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), Ij), (Ik), (Il) and
(Im), and vice versa.
Examples of compounds of Formula (I) include, but are not limited to, the
following:
N N N N
N N N N
N N N N
N N N N
N S S S S
N N N N
O O O O
N N N N
O O O O
N N N N
N N N N
HN HN HN HN
N N N N
N N N N
O O O O
, , , , ,
N N N
N N N
N N N
N N N N
S S S
O O O
N N N N
O O O
N N N N
N N N N
HN HN HN HN
N N N N
O O O O
, , , , ,
N N N N
N N N N
N N N N
N N N N
S S S S
N N N N
O O O O
N N N N
O O O O
N N N N
N N N
HN HN HN HN
N N N N
O O O O
, , , , and , or a
pharmaceutically acceptable salt of the foregoing.
Examples of compounds of Formula (IA) (which are also compounds of
the Formula (I)) include, but are not limited to, the following:
N N N
N N N
N N N
O O O
N N N
HN HN
, , , , ,
N N N
S S S
N N N
HN HN
N N N
F F O
, , , , , and
, or a pharmaceutically acceptable salt of the foregoing.
Further examples of compounds of Formula (I) include, but are not limited
to, the compounds described in Example 120 below.
Formula (II)
Some embodiments disclosed herein relate to a compound of Formula (II),
or a pharmaceutically acceptable salt thereof, having the structure:
(II)
In various embodiments of Formula (II), R is:
a methyloxazolopyridinyl;
a dimethylbenzodioxolyl;
a methylbenzoxazolyl, an isopropylbenzoxazolyl, a methylindazolyl or a
methylbenzoisoxazolyl;
a pyridinyl substituted with one or two substituents independently selected
from the group consisting of methyl, C alkoxy, C cycloalkoxy, isopropylthio, fluoro,
1-4 3-5
chloro, cyano, trifluoromethyl, pyrrolidinyl and -C(=O)NHCH ; or
a phenyl substituted with one or two substituents independently selected
from the group consisting of methoxy, fluoro, chloro, cyano, trifluoromethyl and -
C(=O)NHCH .
In an embodiment of Formula (II), R is a methyloxazolopyridinyl. In
another embodiment, R is a dimethylbenzodioxolyl. In another embodiment, R is a
methylbenzoxazolyl. In another embodiment, R is a isopropylbenzoxazolyl. In another
embodiment, R is a methylindazolyl. In another embodiment, R is a
methylbenzoisoxazolyl.
In an embodiment of Formula (II), R is a pyridinyl substituted with one or
two substituents independently selected from the group consisting of methyl, C alkoxy,
isopropylthio, fluoro, chloro, cyano, trifluoromethyl, pyrrolidinyl and -C(=O)NHCH . For
example, in an embodiment R is a pyridinyl substituted with one or two methyl groups. In
an embodiment R is a pyridinyl substituted with one or two C alkoxy groups. For
example, in an embodiment R is a pyridinyl substituted with one or two groups
independently selected from methoxy, ethoxy, propoxy (e.g., isopropoxy), cyclopropoxy,
butoxy and cyclobutoxy. In an embodiment R is a pyridinyl substituted with one or two
isopropylthio groups. In an embodiment R is a pyridinyl substituted with one or two fluoro
groups. In an embodiment R is a pyridinyl substituted with one or two chloro groups. In an
embodiment R is a pyridinyl substituted with one or two cyano groups. In an embodiment
R is a pyridinyl substituted with one or two trifluoromethyl groups. In an embodiment R is
a pyridinyl substituted with one or two -C(=O)NHCH groups.
In various embodiments of Formula (II), R is a pyridinyl substituted with
two substituents selected from the group consisting of methyl, C alkoxy, isopropylthio,
fluoro, chloro, cyano, trifluoromethyl, pyrrolidinyl and -C(=O)NHCH , wherein both of the
substituents are the same. In other embodiments, R is a pyridinyl substituted with two
substituents selected from the group consisting of methyl, C alkoxy, isopropylthio, fluoro,
chloro, cyano, trifluoromethyl, pyrrolidinyl and -C(=O)NHCH , wherein both of the
substituents are different.
In an embodiment of Formula (II), R is a phenyl substituted with one or
two substituents independently selected from the group consisting of methoxy, fluoro, chloro,
cyano, trifluoromethyl and -C(=O)NHCH . For example, in an embodiment R is a phenyl
substituted with one or two methoxy groups. In an embodiment R is a phenyl substituted
with one or two fluoro groups. In an embodiment R is a phenyl substituted with one or two
chloro groups. In an embodiment R is a phenyl substituted with one or two cyano groups.
In an embodiment R is a phenyl substituted with one or two trifluoromethyl groups. In an
embodiment R is a phenyl substituted with one or two -C(=O)NHCH groups.
In various embodiments of Formula (II), R is a phenyl substituted with
two substituents selected from the group consisting of methoxy, fluoro, chloro, cyano,
trifluoromethyl and -C(=O)NHCH , wherein both of the substituents are the same. In other
embodiments, R is a phenyl substituted with two substituents selected from the group
consisting of methoxy, fluoro, chloro, cyano, trifluoromethyl and -C(=O)NHCH , wherein
both of the substituents are different.
In various embodiments of Formula (II), R is ,
, or . For example, in an embodiment R is
. In another embodiment, R is .
In various embodiments of Formula (II), R and R are each independently
hydrogen or deuterium. For example, in an embodiment, R and R are both hydrogen. In
another embodiment, R and R are both deuterium.
In various embodiments of Formula (II), R is H or methyl. For example,
in an embodiment R is H. In another embodiment, R is methyl.
In various embodiments, R is hydrogen or fluoro. For example, in an
embodiment of Formula (II), R is hydrogen as illustrated by the following Formula (IIA):
(IIA)
In various embodiments of the Formula (IIA), R is a
methyloxazolopyridinyl, or a pyridinyl substituted with one or two substituents
independently selected from the group consisting of methyl, C alkoxy, isopropylthio,
fluoro, chloro, cyano, trifluoromethyl, and -C(=O)NHCH ; or R is a dimethylbenzodioxolyl,
a methylbenzoxazolyl, or a phenyl substituted with one or two substituents independently
selected from the group consisting of methoxy, fluoro, chloro, cyano, trifluoromethyl and -
C(=O)NHCH ; and R is or . Those skilled in the art will recognize
that compounds of the Formula (IIA) are compounds of the Formula (II). Therefore,
4 5 6 7 8 13 4 5
reference herein to variables defined for Formula (II) (such as R , R , R , R , R , R ,Y , Y ,
and Y ) will also be understood as definitions for the corresponding variables of the
Formulae (IIA), and vice versa.
In various embodiments of Formula (II), Y is N, CH or CF. In an
4 4 4
embodiment, Y is N. In another embodiment, Y is CH. In another embodiment, Y is CF.
In various embodiments of Formula (II), Y is N, C, CH or CF. The ring
structure that includes Y can include a double or a single bond from an atom adjacent to Y ,
depending on whether Y is N, C, CH or CF. For example, in an embodiment, the -------- in
the ring structure is a single bond when Y is N. In another embodiment, the -------- in the
ring structure is a single bond when Y is CH. In another embodiment, the -------- in the ring
structure is a single bond when Y is CF. In another embodiment, the -------- in the ring
structure is a double bond when Y is C.
In various embodiments of Formula (II), the ring structure that includes Y
is bonded to a pyridinyl ring or a phenyl ring, and that pyridinyl ring or phenyl ring is bonded
6 6
to R . For example, in an embodiment Y is N or CH. In an embodiment, Y is N. In another
embodiment, Y is CH.
In various embodiments of Formula (II), when Y is CH and R is
, then R cannot be pyridinyl substituted with a single substituent selected from
the group consisting of methyl, methoxy, fluoro, trifluoromethyl and isopropoxy.
4 5 5
In various embodiments of Formula (II), when Y is CH, Y is C and R is
, then R cannot be phenyl substituted with a single substituent selected from the
group consisting of fluoro, methoxy and cyano.
4 5 5
In various embodiments of Formula (II), when Y is CH, Y is C and R is
, then R cannot be phenyl substituted with both a methoxy and a cyano and R
cannot be phenyl substituted with both a trifluoromethyl and a cyano
4 5 5
In various embodiments of Formula (II), when Y is CH, Y is C and R is
, then R cannot be pyridinyl substituted with a single isopropoxy and R cannot
be phenyl substituted with a single cyano.
4 5 5
In various embodiments of Formula (II), when Y is CH, Y is C and R is
, then R cannot be phenyl substituted with both a methoxy and a cyano.
4 5 5
In various embodiments of Formula (II), when Y is CH, Y is C and R is
or , then R cannot be a dimethylbenzodioxolyl and R cannot be a
methylbenzoxazolyl.
In various embodiments, Formula (II) does not represent a compound that
is disclosed in International Application No. , which is hereby
incorporated herein by reference in its entirety, including for the purpose of describing
compounds that Formula (II) does not represent. For example, in various embodiments,
Formula (II) does not represent one or more of the following compounds:
N O N
HN HN
HN HN
N N N N
O O O
, , , ,
HN HN
, , , , ,
N N N
N N N
N N N
N N N
O O O
N N N
O O O
N N N
HN HN HN
O 3 O F
, , , , ,
N N N
N N N
N N N
N N N
O O O
N N N
O O O
N N N
HN HN HN
N N N
N N N
F O 3 O
, , , , ,
HN HN
HN N
OC H
3 F O
, , , , ,
N O N
O HN HN
N N O 3 O
, , , , ,
O N O N
O N O
HN HN
HN N
, , , and .
Examples of compounds of Formula (II), or pharmaceutically acceptable
salts thereof, include the following:
(IIh),
(IIa),
(IIi),
(IIb),
(IIj),
(IIc),
(IIk),
(IId),
(IIe),
(IIl),
(IIf), (IIm),
(IIg),
(IIn),
or a pharmaceutically acceptable salt of the foregoing.
Examples of compounds of Formula (II) include, but are not limited to, the
following:
N N N
N N N
N N N
N N N
O O O
N N N
O O O
N N N
HN HN HN
N N N
O F S O
, , , ,
N N N
N N N
O O O
N N N
O O O
N N N
HN HN HN
N N N N
N N N
O O O
, , , ,
HN HN
O O O
, , , , ,
, , , , ,
O O O
N N N
HN HN
N N N
O O O
, , , , ,
O O O
N N N
HN HN
N F F
N N N
O O O
, , , , ,
and , or a pharmaceutically acceptable salt of the foregoing.
Examples of compounds of Formula (IIA) (which are also compounds of
the Formula (II)) include, but are not limited to, the following:
HN N
HN HN
N N N O N
O O O O
, , , , ,
, , , , ,
O N N N
N N N
O O O
O O O
N N N
O O O
HN HN HN
N N N
, , , , ,
HN HN
HN HN
O N F F N
, , , , ,
N N N
N N N
HN HN HN
N N N
F Cl O
, , , , , ,
N N N N
N N N N
N N N
N N N N
O O O
N N N N
O O O
N N N
HN HN N HN
N N N
N N N
O F N F O
, , , , ,
N N N N
N N N N
N N N N
N N N N
O O O O
N N N N
O O O O
N N N N
N N N N
HN HN HN HN
N N N N
O O Cl O
, , , , , or a
pharmaceutically acceptable salt of the foregoing.
Further examples of compounds of Formula (II) include, but are not
limited to, the compounds described in Example 121 below.
Formula (III)
Some embodiments disclosed herein relate to a compound of Formula
(III), or a pharmaceutically acceptable salt thereof, having the structure:
(III)
In various embodiments of Formula (III), R can be a heterocyclyl selected
from piperidinyl, 1,1-dioxidotetrahydrothiopyranyl, pyrrolidinyl, tetrahydrofuranyl,
tetrahydropyranyl, dihydropyranyl, 2-oxaazaspiro[3.5]nonanyl, and morpholino. In some
embodiments, the heterocyclyl can be optionally substituted with one or two substituents
selected from methyl, fluoro and trifluoroethyl.
In an embodiment of Formula (III), R is piperidinyl. In another
embodiment, R is piperidinyl substituted with a methyl. In another embodiment, R is
piperidinyl substituted with a fluoro. In another embodiment, R is piperidinyl substituted
with a trifluoroethyl. In an embodiment, R is piperidinyl substituted with two substituents
selected from methyl, fluoro and trifluoroethyl. In an embodiment, R is piperidinyl
substituted with two substituents that are the same. In an embodiment, R is piperidinyl
substituted with two substituents that are different.
In an embodiment of Formula (III), R is 1,1-
dioxidotetrahydrothiopyranyl. In another embodiment, R is 1,1-
dioxidotetrahydrothiopyranyl substituted with a methyl. In another embodiment, R is 1,1-
dioxidotetrahydrothiopyranyl substituted with a fluoro. In another embodiment, R is 1,1-
dioxidotetrahydrothiopyranyl substituted with a trifluoroethyl. In an embodiment, R is 1,1-
dioxidotetrahydrothiopyranyl substituted with two substituents selected from methyl, fluoro
and trifluoroethyl. In an embodiment, R is 1,1-dioxidotetrahydrothiopyranyl substituted
with two substituents that are the same. In an embodiment, R is 1,1-
dioxidotetrahydrothiopyranyl substituted with two substituents that are different.
In an embodiment of Formula (III), R is pyrrolidinyl. In another
embodiment, R is pyrrolidinyl substituted with a methyl. In another embodiment, R is
pyrrolidinyl substituted with a fluoro. In another embodiment, R is pyrrolidinyl substituted
with a trifluoroethyl. In an embodiment, R is pyrrolidinyl substituted with two substituents
selected from methyl, fluoro and trifluoroethyl. In an embodiment, R is pyrrolidinyl
substituted with two substituents that are the same. In an embodiment, R is pyrrolidinyl
substituted with two substituents that are different.
In an embodiment of Formula (III), R is tetrahydrofuranyl. In another
embodiment, R is tetrahydrofuranyl substituted with a methyl. In another embodiment, R is
tetrahydrofuranyl substituted with a fluoro. In another embodiment, R is tetrahydrofuranyl
substituted with a trifluoroethyl. In an embodiment, R is tetrahydrofuranyl substituted with
two substituents selected from methyl, fluoro and trifluoroethyl. In an embodiment, R is
tetrahydrofuranyl substituted with two substituents that are the same. In an embodiment, R
is tetrahydrofuranyl substituted with two substituents that are different.
In an embodiment of Formula (III), R is tetrahydropyranyl. In another
embodiment, R is tetrahydropyranyl substituted with a methyl. In another embodiment, R is
tetrahydropyranyl substituted with a fluoro. In another embodiment, R is tetrahydropyranyl
substituted with a trifluoroethyl. In an embodiment, R is tetrahydropyranyl substituted with
two substituents selected from methyl, fluoro and trifluoroethyl. In an embodiment, R is
tetrahydropyranyl substituted with two substituents that are the same. In an embodiment, R
is tetrahydropyranyl substituted with two substituents that are different.
In an embodiment of Formula (III), R is dihydropyranyl. In another
embodiment, R is dihydropyranyl substituted with a methyl. In another embodiment, R is
dihydropyranyl substituted with a fluoro. In another embodiment, R is dihydropyranyl
substituted with a trifluoroethyl. In an embodiment, R is dihydropyranyl substituted with
two substituents selected from methyl, fluoro and trifluoroethyl. In an embodiment, R is
dihydropyranyl substituted with two substituents that are the same. In an embodiment, R is
dihydropyranyl substituted with two substituents that are different.
In an embodiment of Formula (III), R is 2-oxaazaspiro[3.5]nonanyl. In
another embodiment, R is 2-oxaazaspiro[3.5]nonanyl substituted with a methyl. In another
embodiment, R is 2-oxaazaspiro[3.5]nonanyl substituted with a fluoro. In another
embodiment, R is 2-oxaazaspiro[3.5]nonanyl substituted with a trifluoroethyl. In an
embodiment, R is 2-oxaazaspiro[3.5]nonanyl substituted with two substituents selected from
methyl, fluoro and trifluoroethyl. In an embodiment, R is 2-oxaazaspiro[3.5]nonanyl
substituted with two substituents that are the same. In an embodiment, R is 2-
oxaazaspiro[3.5]nonanyl substituted with two substituents that are different.
In an embodiment of Formula (III), R is morpholino. In another
embodiment, R is morpholino substituted with a methyl. In another embodiment, R is
morpholino substituted with a fluoro. In another embodiment, R is morpholino substituted
with a trifluoroethyl. In an embodiment, R is morpholino substituted with two substituents
selected from methyl, fluoro and trifluoroethyl. In an embodiment, R is morpholino
substituted with two substituents that are the same. In an embodiment, R is morpholino
substituted with two substituents that are different.
In an embodiment of Formula (III), R is a five-membered heteroaryl
selected from the group consisting of thiazolyl, pyrazolyl, and triazolyl. In various
embodiments the five-membered heteroaryl is substituted with methyl or isopropyl. In an
embodiment, R is a methylthiazolyl. In an embodiment, R is a isopropylthiazolyl. In an
embodiment, R is a methyl pyrazolyl. In an embodiment, R is a isopropylpyrazolyl. In an
embodiment, R is a methyltriazolyl. In an embodiment, R is a isopropyltriazolyl.
In an embodiment of Formula (III), R is a , a
or a .
In various embodiments of Formula (III), R is or .
10
For example, in an embodiment R is . In another embodiment, R is
11 12
In various embodiments of Formula (III), R and R are each
11 12
independently hydrogen or deuterium. For example, in an embodiment, R and R are both
11 12
hydrogen. In another embodiment, R and R are both deuterium.
In various embodiments of Formula (III), Y is N or CH. In an
embodiment, Y is N. In another embodiment, Y is CH.
In various embodiments of Formula (III), Y is N, C, or CH. The ring
structure that includes Y can include a double or a single bond from an atom adjacent to Y ,
depending on whether Y is N, C, or CH. For example, in an embodiment, the -------- in the
ring structure is a single bond when Y is N. In another embodiment, the -------- in the ring
structure is a single bond when Y is CH. In another embodiment, the -------- in the ring
structure is a double bond when Y is C.
7 8 10
In various embodiments of Formula (III), when Y is CH, Y is C and R
is , then R cannot be tetrahydropyranyl, dihydropyranyl, methylpyrazolyl or
morpholino.
7 8 10
In various embodiments of Formula (III), when Y is CH, Y is C and R
is , then R cannot be tetrahydropyranyl or morpholino.
In various embodiments, Formula (III) does not represent a compound that
is disclosed in International Application No. , which is hereby
incorporated herein by reference in its entirety, including for the purpose of describing
compounds that Formula (III) does not represent. For example, in various embodiments,
Formula (III) does not represent one or more of the following compounds:
N N N N
N N N N
N O N O
N N N N
O O O O
N N N N
O O O O
N N N N
HN HN HN HN
N N N N
O O O
, , , , , and .
Examples of compounds of Formula (II), or pharmaceutically acceptable
salts thereof, include the following:
(IIIf),
(IIIa),
(IIIg),
(IIIb),
(IIIh),
(IIIc),
(IIIi),
(IIId),
(IIIj),
(IIIe),
or a pharmaceutically acceptable salt of the foregoing.
Examples of compounds of Formula (III), or pharmaceutically acceptable
salts thereof, include the following:
N HN
F O 3
, , , , , ,
N O N O N
N N N
N O O
N N N
O O O
N N N
O O O
N N N
HN HN HN
N N N
, , , , , ,
N N N
N N N
N N N
N N N
O O O
N N N
O O O
N N N
N N N
HN HN
N N N N
S N N
N N N
, , , , , ,
O O O
N N N
O O O
N N N
HN HN HN
N N N
, , , , ,
, , , and ; or a pharmaceutically
acceptable salt of the foregoing.
Further examples of compounds of Formula (III) include, but are not
limited to, the compound described in Example 122 below.
Synthesis
Compounds of Formulae (I), (II) or (III), and those described herein may
be prepared in various ways. Some compounds of Formulae (I), (II) or (III) can be obtained
commercially and/or prepared utilizing known synthetic procedures. General synthetic
routes to the compounds of Formulae (I), (II) or (III), and some examples of starting
materials used to synthesize the compounds of Formulae (I), (II) or (III) are shown and
described herein in Schemes 1-12. The routes shown and described herein are illustrative
only and are not intended, nor are they to be construed, to limit the scope of the claims in any
manner whatsoever. Those skilled in the art will be able to recognize modifications of the
disclosed syntheses and to devise alternate routes based on the disclosures herein; all such
modifications and alternate routes are within the scope of the claims.
Scheme 1
(1) (2)
Compounds of Formulae (I), (II) or (III) can be prepared as shown in
1 4 9
Scheme 1. In some embodiments, a suitable compound of Structure 1 (R = R , R or R ; Y =
1 4 7
Y , Y or Y ) and suitable electrophile compounds of Structure 2, where LG is a suitable
leaving group such as tosylates, mesylates, trifluoroacetates and halogens (e.g. LG = Cl, Br
and I) are coupled to form compounds of Formulae (I), (II) or (III). In some embodiments,
an amine base can be utilized in the reaction of compounds of Structure 1 and compounds of
Structure 2. Examples of suitable amine bases, include, but are not limited to, alkylamine
(including mono-, di- and tri-alkylamines (e.g., triethylamine), optionally substituted
pyridines (e.g. collidine) and optionally substituted imidazoles (e.g., N-methylimidazole). In
some embodiments, compounds of Structure 1 and compounds of Structure 2 can be coupled
in the presence of a suitable amine base in a solvent with optional heating. In some
embodiments, the solvent can be N,N-dimethylformamide.
1 5 10
In some embodiments, the triazoyl-Z , R or R group is attached the
remainder of the molecule after the reaction between compounds of Structure 1 and
compounds of Structure 2, wherein compounds of Structure 2 includes a leaving group. In
1 5 10
some embodiments, the pyrazoyl-Z , R or R group can be attached to the remainder of the
molecule by a Pd-mediated cross coupling reactions. Examples of suitable Pd-mediated
cross coupling reactions are Suzuki, Buchwald and/or Ullmann cross coupling reactions.
Scheme 2
N
N OH
(I), (II), (III)
(3) (4)
Another method for obtaining compounds of Formulae (I), (II) or (III) is
1 4 9 1 4 7 a
provided in Scheme 2. Compounds of Structure 3 (R = R , R or R ; Y = Y , Y or Y ; R
and R = H and/or D) and compounds of Structure 4 can be coupled with a suitable coupling
agent in a suitable solvent. A non-limiting list of suitable coupling agents include: 1-
[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid
hexafluorophosphate (HATU), N,N,N ′,N ′-tetramethyl-O-(1H-benzotriazolyl)uronium
hexafluorophosphate, O-(Benzotriazolyl)-N,N,N ′,N ′-tetramethyluronium
hexafluorophosphate (HBTU) and any such amide coupling agent known to those skilled in
the art. In some embodiments, a suitable solvent can be N,N-dimethylformamide. If desired,
the reaction can be carried out with heating.
Scheme 3
Compounds of Structure 13 can be prepared as outlined in Scheme 3. In
some embodiments, halide compounds of Structure 5 (where X can be Br or I and R can be
1 4 9
R , R or R ) are reacted with a boron reagent in the presence of a palladium catalyst and a
base in a suitable solvent with optional heating. A suitable example of a boron reagent is
bis(pinacolato)diboron, a suitable example of a palladium catalyst is [1,1′-
bis(diphenylphosphino)ferrocene] dichloropalladium(II) complex, and an example of a
suitable solvent is tetrahydrofuran. In some embodiments, a suitable base can be potassium
acetate and a suitable solvent can be 1,4-dioxane. In some embodiments, halide compounds
of Structure 5, bis(pinacolato)diboron, [1,1′-bis(diphenylphosphino)
ferrocene]dichloropalladium(II) complex with dichloromethane, potassium acetate can be
reacted in 1,4-dioxane with optional heating. In some embodiments, compounds of Structure
6 and compounds of Structure 7 (PG = protecting group such as trityl or THP) are reacted
under Suzuki cross coupling condition using a suitable palladium catalyst and a base in a
suitable solvent to prepare compounds of Structure 8. An example of a suitable palladium
catalyst is [1,1′-bis(diphenylphosphino) ferrocene]dichloropalladium(II) complex, an
example of a suitable solvent is tetrahydrofuran and an example of a suitable base is
potassium carbonate. In some embodiments, the solvent can be a mixture of 1,2-
dimethoxyethane and water. If desired, the reaction can be conducted with optional heating.
In some embodiments, compounds of Structure 8 can be hydrogenated using a palladium
catalyst in a suitable solvent such as methanol, ethanol or a mixture of methanol and toluene.
In some embodiments, aryl amine compounds of Structure 9 can be converted to aryl halides
of Structure 10 where X can be Br or I using a Sandmeyer reaction. In some embodiments,
compounds of Structure 9 can be reacted with sodium nitrite, hydrobromic acid in the
presence of copper (I) bromide catalyst to prepare compounds of Structure 10 where X is Br.
In some embodiments, compounds of Structure 9 can be reacted with sodium nitrite,
hydrochloric acid, sodium iodide in the presence of copper (I) iodide to prepare compounds
of Structure 10 where X is I. In some embodiments, aryl halides of compounds of Structure
where X is I and amides of Structure 11A (PG = Boc or Cbz) can be coupled under
Ullmann coupling conditions. In some embodiments, compounds of Structure 10 and amides
of Structure 11A (PG = Boc or Cbz) can be reacted in the presence of copper (I) iodide in a
suitable solvent (e.g. dimethylsulfoxide) in the presence of a suitable base (such as potassium
phosphate) with optimal heating. In some embodiments, compounds of Structure 10 (X = Br
or I) and amides of Structure 11A (PG = Boc or Cbz) can be reacted under Buchwald cross
coupling conditions using a suitable palladium catalyst and a suitable solvent with optional
heating to prepare compounds of Structure 12. In some embodiment, when PG is trityl or
2 1 2
THP and PG is Boc or Cbz, both PG and PG protecting groups can be removed
simultaneously with an acid (such as trifluoroacetic acid) in a suitable solvent (such as
dichloromethane). In some embodiments, when PG is Cbz, the Cbz group can be removed
under hydrogenation conditions catalyzed by palladium on carbon in a suitable solvent (for
example, methanol) followed by the removal of PG under acidic conditions to prepare
compounds of Structure 13.
Scheme 4
Compounds of Structure 19 can be prepared as outlined in Scheme 4. In
some embodiments, aryl halides of compounds of Structure 14 (PG = trityl or THP and X =
I) and amides of Structure 11A’ (PG = Boc or Cbz) can be coupled under Ullmann coupling
conditions. In some embodiments, compounds of Structure 14 and amides of Structure 11A’
(PG = Boc or Cbz) can be reacted with catalytic copper (I) iodide in the presence of a
suitable base (such as potassium phosphate) in a suitable solvent (for example, dimethyl
sulfoxide) at elevated temperature (such as 100 °C). In some embodiments, compounds of
Structure 14 where X is Br and amides of Structure 11A’ can be coupled under Buchwald
coupling conditions using a suitable palladium catalyst and a suitable base in a suitable
solvent. In some embodiments, compounds of Structure 15 where PG = trityl or THP and
PG = Cbz can be selectively deprotected under acidic conditions. In some embodiments,
compounds of Structure 15 can be deprotected with trifluoroacetic acid in a suitable solvent
(such as dichloromethane) at ambient temperature to prepare compounds of Structure 16.
In some embodiments, compounds of Structure 16 can be reacted with an
electrophilic halide reagent to prepare compounds of Structure 17 where X is Br or I. In
some embodiments, compounds of Structure 16 can be reacted with iodine in the presence of
a base (such as potassium hydroxide) in a suitable solvent (such as N,N-dimethylformamide)
with an optional heating. In some embodiments, compounds of Structure 16 can be reacted
with NBS in the presence of a suitable base in a suitable solvent (such as dichloromethane) to
prepare compounds of Structure 17. In some embodiments, compounds of Structure 17 can
be reacted with trityl chloride in the presence of a base (such as potassium carbonate) in a
suitable solvent(s) (such as acetonitrile) with optional heating to prepare compounds of
Structure 18. In some embodiments, compounds of Structure 18 can be reacted with boronic
esters of compounds of Structure 6 or boronic acids under Suzuki cross coupling conditions
to prepare compounds of Structure 19. In some embodiments, the palladium catalyst can be
[1,1′-bis(diphenylphosphino) ferrocene]dichloropalladium (II) complex with
dichloromethane and cesium carbonate as the base. In some embodiments, the solvent can be
a mixture of 1,2-dimethoxyethane and water, and the reaction can be conducted with optional
heating.
Scheme 5
Alternatively, compounds of Structure 25 can be prepared as shown in
Scheme 5. In some embodiments, compounds of Structure 20 can be reacted with an
electrophilic halide reagent to prepare compounds of Structure 21 where X1 is I or Br. In
some embodiments, compounds of Structure 20 can be reacted with NBS in the presence of a
suitable base in a suitable solvent (such as dichloromethane) to prepare compounds of
Structure 21 where X is Br or alternatively compounds of Structure 20 can be reacted with
NCS in the presence of a suitable base in a suitable solvent to prepare compounds of
Structure 21 where X is Cl. In some embodiments, compounds of Structure 21 can be
reacted with trityl chloride in the presence of a base (such as potassium carbonate) in a
suitable solvent(s) (such as acetonitrile) with optional heating to prepare compounds of
Structure 22.
In some embodiments, aryl halides of compounds of Structure 22 where
X1 is I and X2 = Br or Cl and amides of Structure 11A (PG = Boc or Cbz) can be coupled
under Ullmann coupling conditions. In some embodiments, compounds of Structure 22 and
amides of Structure 11A (PG = Boc or Cbz ) can be reacted in the presence of copper (I)
iodide in a suitable solvent (e.g. dimethylsulfoxide) in the presence of a suitable base (such
as potassium phosphate) with optional heating. In some embodiments, compounds of
Structure 22 ( X = I and X = Br or Cl) and amides of Structure 11A (PG = Boc or Cbz )
can be reacted under Buchwald cross coupling conditions using a suitable palladium catalyst
and a suitable solvent with optional heating to prepare compounds of Structure 23. In some
embodiments, compounds of Structure 23 can be reacted with boronic esters of compounds
of Structure 6 or boronic acids under Suzuki cross coupling conditions to prepare compounds
of Structure 24. In some embodiments, the palladium catalyst can be [1,1′-
bis(diphenylphosphino) ferrocene]dichloropalladium (II) complex with dichloromethane and
cesium carbonate as the base. In some embodiments, the solvent can be a mixture of 1,2-
dimethoxyethane and water, and the reaction can be conducted with optional heating. In
1 2 1 2
some embodiments, when PG is trityl or THP and PG is Boc or Cbz, both PG and PG
protecting groups can be removed simultaneously with an acid (such as trifluoroacetic acid)
in a suitable solvent (such as dichloromethane). In some embodiments, when PG is Cbz, the
Cbz group can be removed under hydrogenation conditions catalyzed by palladium on carbon
in a suitable solvent (for example, methanol) followed by the removal of PG under acidic
conditions to prepare compounds of Structure 25.
Scheme 6
Compounds of Structure 33 can be prepared as shown in Scheme 6. A
compound of Structure 26 can be protected with a suitable protecting group (PG = Trityl,
THP or acetyl). In some embodiments, a compound of Structure 26 can be reacted with trityl
chloride in the presence of a suitable base (such as potassium carbonate) in a suitable solvent
(such as acetonitrile) with optional heating. In some embodiments, compounds of Structure
27 can be reacted with mCPBA followed by POCl and PCl (or POBr ) to prepare
3 5 3
compounds of Structure 28 where X1 is Cl or Br. In some embodiments, PG (trity, THP or
acetyl) can be removed using acidic conditions (e.g. methanol and hydrochloric acid) to
afford compounds of Structure 28. In some embodiments, compounds of Structure 28 can be
reacted with an electrophilic halogen reagent to prepare compounds of Structure 29 where X
is Br or Cl. In some embodiments, compounds of Structure 28 can be reacted with NBS in a
suitable solvent to prepare compounds of Structure 29 where X is Br, or compounds of
Structure 28 can be reacted with NCS (or NaOCl) in a suitable solvent (such as
dichloromethane) with optional heating to prepare compounds of Structure 29 where X is
Cl. In some embodiments, compounds of Structure 30 can be prepared using a suitable
protecting group such as trityl, THP or acetyl as described in Scheme 3-5. In some
embodiments, compounds of Structure 30 (X = Br and X = Br or Cl) and amides of
Structure 11A (PG = Boc or Cbz) can be reacted under Buchwald cross coupling conditions
using a suitable palladium catalyst and a suitable solvent with optional heating to prepare
compounds of Structure 31. In some embodiments, compounds of Structure 30 and amides
of Structure 11A (PG = Boc or Cbz) can be reacted in the presence of copper (I) iodide in a
suitable solvent (e.g. dimethyl sulfoxide) in the presence of a suitable base (such as
potassium phosphate) with optional heating to prepare compounds of Structure 31.
In some embodiments, compounds of Structure 6 and compounds of
Structure 31 can be reacted under Suzuki cross coupling conditions using a suitable
palladium catalyst and a base in a suitable solvent to prepare compounds of Structure 32. An
example of a suitable palladium catalyst is [1,1′-bis(diphenylphosphino)
ferrocene]dichloropalladium (II) complex, an example of a suitable solvent is
dichloromethane and an example of a suitable base is potassium carbonate. In some
embodiments, the solvent can be a mixture of 1,2-dimethoxyethane and water, and the
reaction can be conducted with optional heating. In some embodiments, when PG is Boc,
the Boc group can be removed simultaneously with trifluoroacetic acid in a suitable solvent
(such as dichloromethane). In some embodiments, when PG is Cbz, Cbz group can be
removed under hydrogenation conditions catalyzed by palladium on carbon in a suitable
solvent (such as methanol) followed by removal of PG under acidic condition to prepare
compounds of Structure 33.
Scheme 7
In some embodiments, compounds of Structures 40 and 43 can be
prepared as outlined in Scheme 7. In some embodiments, a compound of Structure 34 can be
reacted with hydrochloric acid gas in an alcohol (such as ethanol) to prepare a compound of
Structure 35. In some embodiments, compound 35 can be reacted with a substituted
hydrazine in an alcoholic solvent (such as methanol) in the presence of a base (such as
sodium bicarbonate) to prepare compounds of Structure 36. In some embodiments,
compounds of Structure 36 can be cyclized to form a triazole ring in the presence of formic
acid to prepare compounds of Structure 37. In some embodiments, compounds of Structure
37 can be reacted under Suzuki cross coupling conditions using a suitable palladium catalyst
(for example, palladium catalyst is [1,1′-bis(diphenylphosphino) ferrocene]dichloropalladium
(II) complex) and a base (for example, potassium carbonate) in a suitable solvent (such as
tetrahydrofuran) to prepare compounds of Structure 38. In some embodiments, the solvent
can be a mixture of 1,2-dimethoxyethane and water, and the reaction can be conducted with
optional heating. In some embodiments, compounds of Structure 37 can be reacted under
Buchwald cross coupling conditions using a suitable palladium catalyst and a suitable solvent
with optional heating to prepare compounds of Structure 41. In some embodiments,
compounds of Structures 38 or 41 can be reacted with an acid (such as hydrochloric acid) in
a suitable solvent (such as 1,4-dioxane) to prepare compounds of Structures 39 or 42. In
some embodiments, compounds of Structures 39 or 42 can be reacted with chloroacetyl
chloride or chloroacetic anhydride in the presence of a suitable base (such as triethylamine)
in a suitable solvent (such as dichloromethane) to prepare compounds of Structures 40 and 43
where R is an alkyl or optionally substituted alkyl, e.g., an optionally substituted C alkyl .
Scheme 8
Compounds of Structure 50 can be prepared as outlined in Scheme 8. In
some embodiments, a compound of Structure 45 can be prepared using Suzuki cross coupling
conditions. In some embodiments, a compound of structure 44 can be coupled with tert-butyl
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-3,6-dihydropyridine-1(2H)-carboxylate in
the presence of palladium catalyst (such as bistriphenylphosphinepalladium(II) dichloride)
and a base (such as cesium carbonate) in a mixture of solvents (such as 1,2-dimethoxyethane
and water) with optional heating to prepare a compound of Structure 45. In some
embodiments, a compound of Structure 45 can be reacted with lithium hydroxide in a
suitable solvent (such as tetrahydrofuran and water) to prepare a compound of Structure 46.
In some embodiments, a compound of Structure 46 can be reacted with1,1′-
carbonyldiimidazole followed by tert-butyl 1-methylhydrazinecarboxylate (or other
suitably R-substituted hydrazinecarboxylate) in a suitable solvent (such as N,N-
dimethylformamide) with optional heating to prepare compounds of Structure 47. In some
embodiments, compounds of Structure 47 can be reacted with hydrochloric acid in a suitable
solvent (such as 1,4-dioxane). In some embodiments, compounds of Structure 48 can be
treated with a suitable reagent (such as bis(trichloromethyl) carbonate) and a base (such as
trimethylamine) in a suitable solvent (such as dichloromethane) to prepare compounds of
Structure 49.
In some embodiments, compounds of Structure 49 can be converted to
compounds of Structure 50 where R is an optionally substituted C alkyl group using
methods similar to those for preparing compounds of Structures 40 and 43 as outlined in
Scheme 7.
Scheme 9
Alternatively, compounds of Structure 50 can be prepared as outlined in
Scheme 9. In some embodiments, a compound of Structure 51 can be reacted with tert-butyl
1-methylhydrazinecarboxylate in a suitable solvent (such as tetrahydrofuran) and in the
presence of a suitable base (such as triethylamine) to prepare compounds of Structure 52. In
some embodiments, compounds of Structure 52 can be reacted with hydrochloric acid to
remove Boc group and then can be reacted with a suitable reagent (such as 4-
nitrophenylchloroformate) in a suitable solvent (such as dichloromethane) in the presence of
a suitable base (such as triethylamine) to prepare compounds of Structure 53. In some
embodiments, compounds of Structure 54 can be prepared using Suzuki cross coupling
conditions. In some embodiments, compounds of Structure 53 can be coupled with tert-butyl
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-3,6-dihydropyridine-1(2H)-carboxylate in
the presence of palladium catalyst (such as bistriphenylphosphinepalladium (II) dichloride)
and a base (such as cesium carbonate) in a mixture of solvents (such as 1,2-dimethoxyethane
and water) with optional heating to prepare compounds of Structure 54. In some
embodiments, compounds of Structure 54 can be converted to compounds of Structure 50 as
outlined in Scheme 9. Throughout the specification, groups and substituents thereof are
chosen by one skilled in the field to provide stable moieties and/or compounds.
Scheme 10
In some embodiments, compounds of Structure 62 can be prepared as
outlined in Scheme 10. In some embodiments, a compound of Structure 56 can be reacted
with hydrochloric acid gas in an alcohol (such as ethanol) to prepare a compound of
Structure 57. In some embodiments, compound 57 can be reacted with a substituted
hydrazine (e.g., R is optionally substituted C alkyl) in a suitable solvent (such as pyridine)
to prepare compounds of Structure 58. In some embodiments, compounds of Structure 58
can be cyclized to form a triazole ring in the presence of formic acid to prepare compounds
of Structure 59. In some embodiments, compounds of Structure 59 can be reacted under
Suzuki cross coupling conditions using a suitable palladium catalyst (for example, palladium
catalyst is [1,1′-bis(diphenylphosphino) ferrocene]dichloropalladium (II) complex) and a
base (for example, potassium carbonate) in a suitable solvent (such as tetrahydrofuran) to
prepare compounds of Structure 60. In some embodiments, the solvent can be a mixture of
1,2-dimethoxyethane and water, and the reaction can be conducted with optional heating. In
some embodiments, compounds of Structure 60 can be converted to compounds of Structure
62 as outlined in Scheme 7-9. Throughout the specification, groups and substituents thereof
are chosen by one skilled in the field to provide stable moieties and/or compounds.
Scheme 11
In some embodiments, compounds of Structure 69 can be prepared as
outlined in Scheme 11. In some embodiments, a compound of Structure 63 can be reacted
with sodium methoxide in methanol to prepare a compound of Structure 64. In some
embodiments, compound 64 can be reacted with a substituted hydrazine (e.g., R is optionally
substituted C alkyl) in a suitable solvent (such as pyridine) to prepare compounds of
Structure 65. In some embodiments, compounds of Structure 65 can be cyclized to form a
triazole ring in the presence of formic acid to prepare compounds of Structure 66. In some
embodiments, compounds of Structure 66 can be reacted with POCl to form compounds of
Structure 67. In some embodiments, compounds of Structure 67 can be reacted under Suzuki
cross coupling conditions using a suitable palladium catalyst (for example, palladium catalyst
is [1,1′-bis(diphenylphosphino) ferrocene]dichloropalladium (II) complex) and a base (for
example, potassium carbonate) in a suitable solvent (such as tetrahydrofuran) to prepare
compounds of Structure 68. In some embodiments, compounds of Structure 68 can be
converted to compounds of Structure 69 as outlined in Scheme 7-9. Throughout the
specification, groups and substituents thereof are chosen by one skilled in the field to provide
stable moieties and/or compounds.
Scheme 12
NH.HCl NH.HCl
Cl N Cl N
Cl N HO N
70 71 72 73
Cl N
74 76
In some embodiments, compounds of Structure 76 can be prepared as
outlined in Scheme 12. In some embodiments, a compound of Structure 70 can be reacted
with hydrochloric acid gas in an alcohol (such as ethanol) to prepare a compound of
Structure 71. In some embodiments, compound 71 can be reacted with a substituted
hydrazine (e.g., R is optionally substituted C alkyl) in a suitable solvent (such as pyridine)
to prepare compounds of Structure 72. In some embodiments, compounds of Structure 72
can be cyclized to form a triazole ring in the presence of formic acid to prepare compounds
of Structure 73. In some embodiments, compounds of Structure 73 can be treated with
POCl3 to form compounds of Structure 74. In some embodiments, compounds of Structure
74 can be converted to compounds of Structure 76 as outlined in Scheme 7-9. Throughout the
specification, groups and substituents thereof are chosen by one skilled in the field to provide
stable moieties and/or compounds.
Pharmaceutical Compositions
Some embodiments described herein relate to a pharmaceutical
composition, that can include an effective amount of one or more compounds described
herein (e.g., a compound of Formulae (I), (II) or (III), or a pharmaceutically acceptable salt
thereof) and a pharmaceutically acceptable carrier, diluent, excipient or combination thereof.
The term “pharmaceutical composition” refers to a mixture of one or more
compounds disclosed herein with other chemical components, such as diluents or carriers.
The pharmaceutical composition facilitates administration of the compound to an organism.
Pharmaceutical compositions can also be obtained by reacting compounds with inorganic or
organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,
phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and
salicylic acid. Pharmaceutical compositions will generally be tailored to the specific intended
route of administration.
The term “physiologically acceptable” defines a carrier, diluent or
excipient that does not abrogate the biological activity and properties of the compound nor
cause appreciable damage or injury to an animal to which delivery of the composition is
intended.
As used herein, a “carrier” refers to a compound that facilitates the
incorporation of a compound into cells or tissues. For example, without limitation, dimethyl
sulfoxide (DMSO) is a commonly utilized carrier that facilitates the uptake of many organic
compounds into cells or tissues of a subject.
As used herein, a “diluent” refers to an ingredient in a pharmaceutical
composition that lacks appreciable pharmacological activity but may be pharmaceutically
necessary or desirable. For example, a diluent may be used to increase the bulk of a potent
drug whose mass is too small for manufacture and/or administration. It may also be a liquid
for the dissolution of a drug to be administered by injection, ingestion or inhalation. A
common form of diluent in the art is a buffered aqueous solution such as, without limitation,
phosphate buffered saline that mimics the pH and isotonicity of human blood.
As used herein, an “excipient” refers to an essentially inert substance that
is added to a pharmaceutical composition to provide, without limitation, bulk, consistency,
stability, binding ability, lubrication, disintegrating ability etc., to the composition. A
“diluent” is a type of excipient.
The pharmaceutical compositions described herein can be administered to
a human patient per se, or in pharmaceutical compositions where they are mixed with other
active ingredients, as in combination therapy, or carriers, diluents, excipients or combinations
thereof. Proper formulation is dependent upon the route of administration chosen.
Techniques for formulation and administration of the compounds described herein are known
to those skilled in the art.
The pharmaceutical compositions disclosed herein may be manufactured
in a manner that is itself known, e.g., by means of conventional mixing, dissolving,
granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or tableting
processes. Additionally, the active ingredients are contained in an amount effective to
achieve its intended purpose. Many of the compounds used in the pharmaceutical
combinations disclosed herein may be provided as salts with pharmaceutically compatible
counterions.
Multiple techniques of administering a compound exist in the art
including, but not limited to, oral, rectal, pulmonary, topical, aerosol, injection and parenteral
delivery, including intramuscular, subcutaneous, intravenous, intramedullary injections,
intrathecal, direct intraventricular, intraperitoneal, intranasal and intraocular injections.
One may also administer the compound in a local rather than systemic
manner, for example, via injection or implantation of the compound directly into the affected
area, often in a depot or sustained release formulation. Furthermore, one may administer the
compound in a targeted drug delivery system, for example, in a liposome coated with a
tissue-specific antibody. The liposomes will be targeted to and taken up selectively by the
organ. For example, intranasal or pulmonary delivery to target a respiratory infection may be
desirable.
As described herein, compounds of Formulae (I), (II) or (III), or a
pharmaceutically acceptable salt thereof, can be administered by a variety of methods. In
some of the methods described herein, administration can be by injection, infusion and/or
intravenous administration over the course of 1 minute, 5 minutes, 10 minutes, 30 minutes, 1
hour, 2 hours, 6 hours, 12 hours, 24 hours or longer, or any intermediate time. Other
methods described herein can include oral, intravenous and/or intraperitoneal administration
to a subject in need thereof, for example, to a subject to treat a cancer described herein
responsive to an ERK inhibitor.
The compositions may, if desired, be presented in a pack or dispenser
device which may contain one or more unit dosage forms containing the active ingredient.
The pack may for example comprise metal or plastic foil, such as a blister pack. The pack or
dispenser device may be accompanied by instructions for administration. The pack or
dispenser may also be accompanied with a notice associated with the container in form
prescribed by a governmental agency regulating the manufacture, use, or sale of
pharmaceuticals, which notice is reflective of approval by the agency of the form of the drug
for human or veterinary administration. Such notice, for example, may be the labeling
approved by the U.S. Food and Drug Administration for prescription drugs, or the approved
product insert. Compositions that can include a compound described herein formulated in a
compatible pharmaceutical carrier may also be prepared, placed in an appropriate container,
and labeled for treatment of an indicated condition.
Methods of Use
Some embodiments described herein relate to a method for ameliorating
and/or treating a cancer described herein that can include administering an effective amount
of a compound described herein (for example, a compound of Formulae (I), (II) or (III), or a
pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes an
effective amount of a compound described herein (for example, a compound of Formulae (I),
(II) or (III), or a pharmaceutically acceptable salt thereof) to a subject having a cancer
described herein. Other embodiments described herein relate to the use of an effective
amount of a compound described herein (for example, a compound of Formulae (I), (II) or
(III), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that
includes an effective amount of a compound described herein (for example, a compound of
Formulae (I), (II) or (III), or a pharmaceutically acceptable salt thereof) in the manufacture of
a medicament for ameliorating and/or treating a cancer described herein. Still other
embodiments described herein relate to the use of an effective amount of a compound
described herein (for example, a compound of Formulae (I), (II) or (III), or a
pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a
compound described herein (for example, a compound of Formulae (I), (II) or (III), or a
pharmaceutically acceptable salt thereof) for ameliorating and/or treating a cancer described
herein.
Some embodiments described herein relate to a method for inhibiting
replication of a malignant growth or a tumor that can include contacting the growth or the
tumor with an effective amount of a compound described herein (for example, a compound
of Formulae (I), (II) or (III), or a pharmaceutically acceptable salt thereof) or a
pharmaceutical composition that includes an effective amount of a compound described
herein (for example, a compound of Formulae (I), (II) or (III), or a pharmaceutically
acceptable salt thereof), wherein the malignant growth or tumor is due to a cancer described
herein. Other embodiments described herein relate to the use of an effective amount of a
compound described herein (for example, a compound of Formulae (I), (II) or (III), or a
pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes an
effective amount of a compound described herein (for example, a compound of Formulae (I),
(II) or (III), or a pharmaceutically acceptable salt thereof) in the manufacture of a
medicament for inhibiting replication of a malignant growth or a tumor, wherein the
malignant growth or tumor is due to a cancer described herein. Still other embodiments
described herein relate to the use of an effective amount of a compound described herein (for
example, a compound of Formulae (I), (II) or (III), or a pharmaceutically acceptable salt
thereof) or a pharmaceutical composition that includes an effective amount of a compound
described herein (for example, a compound of Formulae (I), (II) or (III), or a
pharmaceutically acceptable salt thereof) for inhibiting replication of a malignant growth or a
tumor, wherein the malignant growth or tumor is due to a cancer described herein.
Some embodiments described herein relate to a method for ameliorating or
treating a cancer described herein that can include contacting a malignant growth or a tumor
with an effective amount of a compound described herein (for example, a compound of
Formulae (I), (II) or (III), or a pharmaceutically acceptable salt thereof) or a pharmaceutical
composition that includes an effective amount of a compound described herein (for example,
a compound of Formulae (I), (II) or (III), or a pharmaceutically acceptable salt thereof) in a
subject having a cancer described herein. Other embodiments described herein relate to the
use of an effective amount of a compound described herein (for example, a compound of
Formulae (I), (II) or (III), or a pharmaceutically acceptable salt thereof) or a pharmaceutical
composition that includes an effective amount of a compound described herein (for example,
a compound of Formulae (I), (II) or (III), or a pharmaceutically acceptable salt thereof) in the
manufacture of a medicament for ameliorating or treating a cancer that can include
contacting with a malignant growth or a tumor, wherein the malignant growth or tumor is due
to a cancer described herein. Still other embodiments described herein relate to the use of an
effective amount of a compound described herein (for example, a compound of Formulae (I),
(II) or (III), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition
that includes an effective amount of a compound described herein (for example, a compound
of Formulae (I), (II) or (III), or a pharmaceutically acceptable salt thereof) for ameliorating or
treating a cancer that can include contacting with a malignant growth or a tumor, wherein the
malignant growth or tumor is due to a cancer described herein.
Some embodiments described herein relate to a method for inhibiting the
activity of ERK1 and/or ERK2 that can include providing an effective amount of a
compound described herein (for example, a compound of Formulae (I), (II) or (III), or a
pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes an
effective amount of a compound described herein (for example, a compound of Formulae (I),
(II) or (III), or a pharmaceutically acceptable salt thereof) to a sample that includes a cancer
cell from a cancer described herein. Other embodiments described herein relate to the use of
an effective amount of a compound described herein (for example, a compound of Formulae
(I), (II) or (III), or a pharmaceutically acceptable salt thereof) or a pharmaceutical
composition that includes an effective amount of a compound described herein (for example,
a compound of Formulae (I), (II) or (III), or a pharmaceutically acceptable salt thereof) in the
manufacture of a medicament for inhibiting the activity of ERK1 and/or ERK2. Still other
embodiments described herein relate to the use of an effective amount of a compound
described herein (for example, a compound of Formulae (I), (II) or (III), or a
pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes an
effective amount of a compound described herein (for example, a compound of Formulae (I),
(II) or (III), or a pharmaceutically acceptable salt thereof) for inhibiting the activity of ERK1
and/or ERK2.
Some embodiments described herein relate to a method for ameliorating or
treating a cancer described herein that can include inhibiting the activity of ERK1 and/or
ERK2 using an effective amount of a compound described herein (for example, a compound
of Formulae (I), (II) or (III), or a pharmaceutically acceptable salt thereof) or a
pharmaceutical composition that includes an effective amount of a compound described
herein (for example, a compound of Formulae (I), (II) or (III), or a pharmaceutically
acceptable salt thereof). Other embodiments described herein relate to the use of an effective
amount of a compound described herein (for example, a compound of Formulae (I), (II) or
(III), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that
includes an effective amount of a compound described herein (for example, a compound of
Formulae (I), (II) or (III), or a pharmaceutically acceptable salt thereof) in the manufacture of
a medicament for ameliorating or treating a cancer described herein by inhibiting the activity
of ERK1 and/or ERK2. Still other embodiments described herein relate to the use of an
effective amount of a compound described herein (for example, a compound of Formulae (I),
(II) or (III), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition
that includes an effective amount of a compound described herein (for example, a compound
of Formulae (I), (II) or (III), or a pharmaceutically acceptable salt thereof) for ameliorating or
treating a cancer described herein by inhibiting the activity of ERK1 and/or ERK2.
Examples of suitable cancers include, but are not limited to: lung cancer
(e.g., lung adenocarcinoma and non-small cell lung cancer, see Adjei, A.A., “The role of
mitogen-activated ERK-kinase inhibitors in lung cancer therapy” Clin. Lung. Cancer (2005)
7(3):221-223 and Roberts et al., “Targeting the Raf-MEK-ERK mitogen-activated protein
kinase cascade for the treatment of cancer” Oncogene (2007) 26(22):3291-3310), pancreatic
cancers (e.g., pancreatic carcinoma such as, for example, exocrine pancreatic carcinoma, see
Hayes, et al., “Long-Term ERK Inhibition in KRAS-Mutant Pancreatic Cancer Is Associated
with MYC Degradation and Senescence-like Growth Suppression” Cancer Cell (2016)
29(1):75-89 and Morris et al., “Discovery of a novel ERK inhibitor with activity in models of
acquired resistance to BRAF and MEK inhibitors” Cancer Discov (2013) 3(7):742-750),
colon cancers (e.g., colorectal carcinomas, such as, for example, colon adenocarcinoma and
colon adenoma, see Fang et al., “The MAPK signalling pathways and colorectal cancer”
Lancet Oncol (2005) 6(5):322-327), myeloid leukemias (for example, acute myelogenous
leukemia (AML), CML, and CMML, see Steelman et al., “Roles of the Ras/Raf/MEK/ERK
pathway in leukemia therapy” Leukemia (2011) 25(7):1080-1094), thyroid cancer,
myelodysplastic syndrome (MDS), bladder carcinoma (see Noguchi et al., “Replacement
treatment with microRNA-143 and -145 induces synergistic inhibition of the growth of
human bladder cancer cells by regulating PI3K/Akt and MAPK signaling pathways” Cancer
Lett (2013) 328(2):353-361), epidermal carcinoma (see Khavari et al., “Ras/Erk MAPK
signaling in epidermal homeostasis and neoplasia” Cell Cycle (2007) 6(23)2928-2931),
melanoma (see Morris et al., “Discovery of a novel ERK inhibitor with activity in models of
acquired resistance to BRAF and MEK inhibitors” Cancer Discov (2013) 3(7):742-750),
breast cancer (see Maiello et al., “EGFR and MEK Blockade in Triple Negative Breast
Cancer Cells” J Cell Biochem (2015) 116(12):2778-2785), prostate cancer (see Rodriguez-
Berriguete et al., “Relationship between IL-6/ERK and NF-κB: a study in normal and
pathological human prostate gland” Eur Cytokine Netw (2010) 21(4):251-250), head and
neck cancers (e.g., squamous cell cancer of the head and neck, see Jimenez et al.,
“Mechanisms of Invasion in Head and Neck Cancer” Arch Pathol Lab Med (2015)
139(11):1334-1348), ovarian cancer (see Sheppard et al., “Synergistic inhibition of ovarian
cancer cell growth by combining selective PI3K/mTOR and RAS/ERK pathway inhibitors”
Eur J Cancer (2013) 49(18):3936-3944), brain cancers (e.g., gliomas, such as glioma
blastoma multiforme, see Chen et al., “Glioma cell proliferation controlled by ERK activity-
dependent surface expression of PDGFRA” PLoS One (2014) 9(1)e87281), cancers of
mesenchymal origin (e.g., fibrosarcomas and rhabdomyosarcomas, see Buonata et al.,
“ERK1/2 blockade prevents epithelial-mesenchymal transition in lung cancer cells and
promotes their sensitivity to EGFR inhibition” Cancer Res (2014) 74(1):309-319), sarcomas
(see Serrano et al., “RAS/MAPK pathway hyperactivation determines poor prognosis in
undifferentiated pleomorphic sarcomas” Cancer (2016) 122(1):99-107), tetracarcinomas (see
Chambers et al., “Self-renewal of teratocarcinoma and embryonic stem cells” Oncogene
(2004) 23(43):7150-7160), neuroblastomas (see Vieira et al., “LGR5 regulates pro-survival
MEK/ERK and proliferative Wnt/β-catenin signalling in neuroblastoma” Oncotarget (2015)
6(37):40053-40067), kidney carcinomas (see Chen et al., “Expression and prognostic role of
MEKK3 and pERK in patients with renal clear cell carcinoma” Asian Pac J Cancer Prev
(2015) 16(6):2495-2499), hepatomas (see Huang et al., “Apelin-13 induces autophagy in
hepatoma HepG2 cells through ERK1/2 signaling pathway-dependent upregulation of
Beclin1” Oncol Lett (2016) 11(2):1051-1056), non-Hodgkin's lymphoma (see Carlo-Stella et
al., “Sorafenib inhibits lymphoma xenografts by targeting MAPK/ERK and AKT pathways
in tumor and vascular cells” PLoS One (2013) 8(4):e61603), multiple myeloma (see Jin et
al., “USO1 promotes tumor progression via activating Erk pathway in multiple myeloma
cells” Biomed Pharmacother (2016) 78:264-271), anaplastic thyroid carcinoma (see
Milosevic et al., “Targeting RAS-MAPK-ERK and PI3K-AKT-mTOR signal transduction
pathways to chemosensitize anaplastic thyroid carcinoma” Transl Res (2014) 164(5):411-
423) and neurofibromatosis (NF-1) (see Wang et al., “ERK inhibition rescues defects in fate
specification of Nf1-deficient neural progenitors and brain abnormalities” Cell (2012)
150(4):816-830).
The compound(s) of Formulae (I), (II) or (III) or a pharmaceutically
acceptable salt thereof, that can be used can be any of the embodiments described in the
“Compounds” section above.
As used herein, a “subject” refers to an animal that is the object of
treatment, observation or experiment. “Animal” includes cold- and warm-blooded
vertebrates and invertebrates such as fish, shellfish, reptiles and, in particular, mammals.
“Mammal” includes, without limitation, mice, rats, rabbits, guinea pigs, dogs, cats, sheep,
goats, cows, horses, primates, such as monkeys, chimpanzees, and apes, and, in particular,
humans. In some embodiments, the subject can be human. In some embodiments, the
subject can be a child and/or an infant, for example, a child or infant. In other embodiments,
the subject can be an adult.
As used herein, the terms “treat,” “treating,” “treatment,” “therapeutic,”
and “therapy” do not necessarily mean total cure or abolition of the disease or condition. Any
alleviation of any undesired signs or symptoms of a disease or condition, to any extent can be
considered treatment and/or therapy. Furthermore, treatment may include acts that may
worsen the subject’s overall feeling of well-being or appearance, and may positively affect
one or more symptoms or aspects of the disease while having effects on other aspects of the
disease or on unrelated systems that may be considered undesireable.
The terms “therapeutically effective amount” and “effective amount” are
used to indicate an amount of an active compound, or pharmaceutical agent, that elicits the
biological or medicinal response indicated. For example, a therapeutically effective amount
of compound can be the amount needed to treat, alleviate or ameliorate one or more
symptoms or conditions of disease or prolong the survival of the subject being treated This
response may occur in a tissue, system, animal or human and includes alleviation of the signs
or symptoms of the disease being treated. Determination of an effective amount is well
within the capability of those skilled in the art, in view of the disclosure provided herein.
For example, an effective amount of a compound, or radiation, is the
amount that results in: (a) the reduction, alleviation or disappearance of one or more
symptoms caused by the cancer, (b) the reduction of tumor size, (c) the elimination of the
tumor, and/or (d) long-term disease stabilization (growth arrest) of the tumor. In the
treatment of lung cancer (such as non-small cell lung cancer) a therapeutically effective
amount is that amount that alleviates or eliminates cough, shortness of breath and/or pain.
As another example, an effective amount, or a therapeutically effective amount of an ERK
inhibitor is the amount which results in the reduction in ERK (ERKI and/or ERK2) activity
and/or phosphorylation. The reduction in ERK activity are known to those skilled in the art
and can be determined by the analysis of pharmacodynamic markers such as phosphorylated
RSKI,2 and phosphorylated ERKI,2 and/or or gene expression profile (mRNA).
The therapeutically effective amount of the compounds disclosed herein
required as a dose will depend on the route of administration, the type of animal, including
human, being treated, and the physical characteristics of the specific animal under
consideration. The dose can be tailored to achieve a desired effect, but will depend on such
factors as weight, diet, concurrent medication and other factors which those skilled in the
medical arts will recognize.
Various indicators for determining the effectiveness of a method for
treating a cancer, are known to those skilled in the art. Example of suitable indicators
include, but are not limited to, the reduction, alleviation or disappearance of one or more
symptoms caused by the cancer, the reduction of tumor size, the elimination of the tumor,
and/or long-term disease stabilization (growth arrest) of the tumor.
As will be readily apparent to one skilled in the art, the useful in vivo
dosage to be administered and the particular mode of administration will vary depending
upon the age, weight, the severity of the affliction, and mammalian species treated, the
particular compounds employed, and the specific use for which these compounds are
employed. The determination of effective dosage levels, that is the dosage levels necessary
to achieve the desired result, can be accomplished by one skilled in the art using routine
methods, for example, human clinical trials and in vitro studies.
The dosage may range broadly, depending upon the desired effects and the
therapeutic indication. Alternatively, dosages may be based and calculated upon the surface
area of the patient, as understood by those of skill in the art. Although the exact dosage will
be determined on a drug-by-drug basis, in most cases, some generalizations regarding the
dosage can be made. The daily dosage regimen for an adult human patient may be, for
example, an oral dose of between 0.01 mg and 3000 mg of each active ingredient, preferably
between 1 mg and 700 mg, e.g. 5 to 200 mg. The dosage may be a single one or a series of
two or more given in the course of one or more days, as is needed by the subject. In some
embodiments, the compounds will be administered for a period of continuous therapy, for
example for a week or more, or for months or years.
In instances where human dosages for compounds have been established
for at least some condition, those same dosages may be used, or dosages that are between
about 0.1% and 500%, more preferably between about 25% and 250% of the established
human dosage. Where no human dosage is established, as will be the case for newly-
discovered pharmaceutical compositions, a suitable human dosage can be inferred from ED50
or ID values, or other appropriate values derived from in vitro or in vivo studies, as
qualified by toxicity studies and efficacy studies in animals.
In cases of administration of a pharmaceutically acceptable salt, dosages
may be calculated as the free base. As will be understood by those of skill in the art, in
certain situations it may be necessary to administer the compounds disclosed herein in
amounts that exceed, or even far exceed, the above-stated, preferred dosage range in order to
effectively and aggressively treat particularly aggressive diseases or infections.
Dosage amount and interval may be adjusted individually to provide
plasma levels of the active moiety which are sufficient to maintain the modulating effects, or
minimal effective concentration (MEC). The MEC will vary for each compound but can be
estimated from in vitro data. Dosages necessary to achieve the MEC will depend on
individual characteristics and route of administration. However, HPLC assays or bioassays
can be used to determine plasma concentrations. Dosage intervals can also be determined
using MEC value. Compositions should be administered using a regimen which maintains
plasma levels above the MEC for 10-90% of the time, preferably between 30-90% and most
preferably between 50-90%. In cases of local administration or selective uptake, the
effective local concentration of the drug may not be related to plasma concentration.
It should be noted that the attending physician would know how to and
when to terminate, interrupt, or adjust administration due to toxicity or organ dysfunctions.
Conversely, the attending physician would also know to adjust treatment to higher levels if
the clinical response were not adequate (precluding toxicity). The magnitude of an
administrated dose in the management of the disorder of interest will vary with the severity
of the condition to be treated and to the route of administration. The severity of the condition
may, for example, be evaluated, in part, by standard prognostic evaluation methods. Further,
the dose and perhaps dose frequency, will also vary according to the age, body weight, and
response of the individual patient. A program comparable to that discussed above may be
used in veterinary medicine.
Compounds disclosed herein can be evaluated for efficacy and toxicity
using known methods. For example, the toxicology of a particular compound, or of a subset
of the compounds, sharing certain chemical moieties, may be established by determining in
vitro toxicity towards a cell line, such as a mammalian, and preferably human, cell line. The
results of such studies are often predictive of toxicity in animals, such as mammals, or more
specifically, humans. Alternatively, the toxicity of particular compounds in an animal model,
such as mice, rats, rabbits, or monkeys, may be determined using known methods. The
efficacy of a particular compound may be established using several recognized methods,
such as in vitro methods, animal models, or human clinical trials. When selecting a model to
determine efficacy, the skilled artisan can be guided by the state of the art to choose an
appropriate model, dose, route of administration and/or regime.
EXAMPLES
Additional embodiments are disclosed in further detail in the following
examples, which are not in any way intended to limit the scope of the claims.
Intermediate 1
Intermediate 1 was prepared following a procedure decribed in a patent
WO2016/161160A1. LCMS: 275.3 [M+H] .
Intermediate 1A
Intermediate 1A was prepared following a procedure decribed in a patent
WO2016/161160A1. LCMS: 275.09 [M+H] .
Intermediate 1B
Intermediate 1B was prepared following a procedure decribed in a patent
WO2016/161160A1. LCMS: 275.09 [M+H] .
Intermediate 2
Intermediate 2 was prepared following a procedure decribed in a patent
WO2016/161160A1. LCMS: 759.25 [M+H] .
Intermediate 3
Intermediate 3 was prepared following a procedure decribed in a patent
WO2016/161160A1 using 3-bromoiodo(tetrahydro-2H-pyranyl)-1H-indazole and
Intermediate 1A. LCMS: 554.95 [M+H] .
Intermediate 4
Intermediate 4 was prepared following a procedure decribed in a patent
WO2016/161160A1 using 3,5-dibromo-1H-pyrazolo[4,3-b]pyridine and Intermediate 1A.
LCMS: 555.92 [M+H] .
Intermediate 5
5-Bromochloro-1H-pyrazolo[4,3-b]pyridine (5-#1): To a stirred
solution of 5-bromo-1H-pyrazolo[4,3-b]pyridine (5.0 g, 25.3 mmol) in water (100 mL) was
added NaOH (4.06 g, 101.5 mmol) at rt. The reaction was stirred at 70 C and cooled to 0ºC
followed by the addition of NaOCl (11.26 mL, 151.8 mmol) at 0°C. After being stirred at
room temperature for 16h, the reaction was quenched by cold water and extracted with
EtOAc. The combined organic layers were washed with water and brine, dried over Na SO
and concentrated to afford 5-#1 (4.2 g, 18.2 mmol, 72%) as a yellow solid. LCMS: 233.75
[M+H] .
5-Bromochloro(tetrahydro-2H-pyranyl)-1H-pyrazolo[4,3-
b]pyridine (Intermediate 5): To a stirred solution of 5-#1(3.0 g, 12.8 mmol) in DCM (20
mL) were added DHP (3.5 mL, 38.6 mmol) and PTSA (220 mg, 1.28 mmol) at 0 C. After
being stirred at rt for 1h, the reaction was quenched by cold water and extracted with DCM.
The combined organic layers were washed with brine, dried over Na SO and concentrated.
The crude product was purified by column chromatography using 15% EtOAc in petroleum
ether to afford Intermediate 5 (1.3 g, 32%) as an off white solid. mp: 80–82ºC; LCMS:
315.83 [M+H] .
Intermediate 6
Benzyl (R)(3-(4-fluorophenyl)trityl-1H-indazolyl)oxo-2,7-
diazaspiro[4.4]nonanecarboxylate (6-#1): To a stirred solution of Intermediate 2 (1.8 g,
2.37 mmol) and 2-(4-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.398 g, 2.84
mmol) in ethanol/toluene/water (1:1:1 ratio, 60 mL) was added K CO (1.63 g, 11.85 mmol).
The mixture was degassed for 10 min, followed by the addition of Pd(dppf) Cl -DCM (0.273
g, 0.237 mmol), and degassed for another 10 mins. The resulting mixture was refluxing for
3h. Upon completion, the mixture was cooled to rt and filtered through a Celite pad. The
filtrate was diluted with cold water and extracted with EtOAc. The combined organic layers
were washed with water and brine, dried over Na SO and concentrated. The residue was
purified by column chromatography using 50% EtOAc/hexanes to afford 6-#1 (1.5 g, 87%).
LCMS: 727.29 [M+H] .
(S)(3-(4-Fluorophenyl)trityl-1H-indazolyl)-2,7-
diazaspiro[4.4]nonanone (Intermediate 6): To a solution of 6-#1 (0.5 g, 0.688 mmol) in
toluene (3.44 mL) and methanol (3.44 mL) was added HCl (1.720 mL, 3.44 mmol). The
solution was degassed, followed by addition of Pd/C (0.073 g, 0.069 mmol), and stirred at rt
under hydrogen atmosphere overnight. The mixture was filtered through Celite and washed
with methanol. The solvents were removed to afford Intermediate 6 as hydrochloride salt
(0.46 g of crude material) as pale yellow foam. This material was used without further
purification. LCMS: 593.30 [M+H] .
Intermediate 7
Intermediate 7 was prepared following a procedure described for
Intermediate 6 using Intermediate 2 and 2-methoxy(4,4,5,5-tetramethyl-1,3,2-
dioxaborolanyl)pyridine. LCMS: 606.52 [M+H] .
Intermediate 8
Intermediate 8 was prepared following a procedure described in a patent
WO2016/161160A1 using 4-bromobenzonitrile, t-butyl 1-methylhydrazinecarboxylate and
tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-5,6-dihydropyridine-1(2H)-
carboxylate. LCMS: 241.34 [M+H] .
Intermediate 9
Intermediate 9 was prepared following a procedure described in a patent
WO2016/161160A1 using 4-(4-(1-methyl-1H-1,2,4-triazolyl)phenyl)-1,2,3,6-
tetrahydropyridine hydrochloride and chloroacetyl chloride. LCMS: 317.12 [M+H] .
Intermediate 10
Intermediate 10 was prepared following a procedure described in a patent
WO2016/161160A1 using 1-(4-(1-methyl-1H-1,2,4-triazolyl)phenyl)piperazine and
chloroacetic anhydride. LCMS: 320.19 [M+H] .
Intermediate 11
Intermediate 11 was prepared following a procedure described in a patent
WO2016/161160A1 using 4-(4-(1-methyl-1H-1,2,4-triazolyl)phenyl)piperidine
hydrochloride and chloroacetyl chloride. LCMS: 319.08 [M+H] .
Intermediate 12
Intermediate 12 was prepared following a procedure described in a patent
WO2016/161160A1 using 1-(5-(1-methyl-1H-1,2,4-triazolyl)pyridinyl)piperazine
hydrochloride and chloroacetyl chloride. LCMS: 320.9 [M+1] .
Intermediate 13
Intermediate 13 was prepared following a procedure described in a patent
WO2011/041152A1 using 5-(1-methyl-1H-1,2,4-triazolyl)(1,2,3,6-tetrahydropyridin
yl)thiazole hydrochloride and chloroacetyl chloride. LCMS: 324.25 [M+H] .
Intermediate 14
Intermediate 14 was prepared following a procedure described in a patent
WO2011/041152A1 using 4-(5-(1-methyl-1H-1,2,4-triazolyl)thiophenyl)-1,2,3,6-
tetrahydropyridine hydrochloride and chloroacetyl chloride. . LCMS: 322.92 [M+H] .
Intermediate 15
4-Iodobenzohydrazide (15-#1): To a solution of 4-iodobenzoic acid (6 g,
24.19 mmol) in DCM (300 mL) was added 1,1-carbonyldiimidazole (4.315 g, 26.61 mmol) at
0 C. After being stirred at rt for 2h, hydrazine monohydrate (7.26 g, 145.15 mmol) was
added and the mixture was stirred at rt for 5h. The mixture was then concentrated under
reduced pressure followed by the addition of water to precipitate out the product. The
product was collected by filtration and dried under reduced pressure to afford 15-#1 (5.2 g,
82%) as an off white solid. LCMS: 263.05 [M+H] .
5-(4-Iodophenyl)-1,3,4-oxadiazol-2(3H)-one (15-#2): To a stirred
solution of 15-#1 (5 g, 19.08 mmol) in THF (480 mL) at rt was added 1,1-
carbonyldiimidazole (3.40 g, 20.99 mmol) at 0°C. After being stirred at rt for 2h, the
reaction mixture was concentrated and extracted with EtOAc. The combined organic layers
were washed with 1 M hydrochloric acid and brine, dried over Na SO , and concentrated to
afford 15-#2 (4.95 g, 90%) as an off white solid. LCMS: 288.86 [M+H] .
5-(4-Iodophenyl)methyl-1,3,4-oxadiazol-2(3H)-one (15-#3): To a
solution of 15-#2 (4.95 g, 17.24 mmol) in dimethylformamide (350 mL) were added K CO
(4.75 g, 34.48 mmol) and methyl iodide (4.89 g, 34.48 mmol) at rt. After being stirred at rt
for 2h, the reaction was quenched by ice water. The solid was collected by filtration and
dried under reduced pressure to afford 15-#3 (4.3 g, 82%) as an off white solid. LCMS:
303.13 [M+H] .
tert-butyl 4-(4-(4-Methyloxo-4,5-dihydro-1,3,4-oxadiazol
yl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate (15-#4): To a stirred solution of 15-#3
(4.3 g, 14.23 mmol) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-5,6-
dihydropyridine-1(2H)-carboxylate (5.71 g, 18.50 mmol) in 1,4-dioxane/water (3:1 ratio, 200
mL) was added Na CO (3.01 g, 28.46 mmol). The mixture was degassed for 10 min,
followed by the addition of Pd(dppf) Cl -DCM (1.161 g, 1.42 mmol), and degassed for
another 10 min. After being refluxed for 16h, the mixture was cooled to rt and filtered
through a Celite pad. The filtrate was diluted with cold water and extracted with EtOAc. The
combined organic layers were washed with waterand brine, dried over Na SO and
concentrated. The residue was purified by column chromatographyusing 50%
EtOAc/hexanes to afford 15-#4(3.9 g, 76%). LCMS: 357.98 [M+H] .
3-Methyl(4-(1,2,3,6-tetrahydropyridinyl)phenyl)-1,3,4-oxadiazol-
2(3H)-one hydrochloride (15-#5): To a solution of 15-#4 (3.9 g, 10.08 mmol) in 1,4-
dioxane (100 mL) was added 4 M HCl in 1,4-dioxane (50 mL) at 0 C. After being stirred at
rt for 3h, the mixture was concentrated and triturated with diethyl etherto afford 15-#5 (2.5 g,
78%) as an off white solid. LCMS: 258.5 [M+H]
5-(4-(1-(2-Chloroacetyl)-1,2,3,6-tetrahydropyridinyl)phenyl)
methyl-1,3,4-oxadiazol-2(3H)-one (Intermediate 15): To a stirred solution of 15-#5 (2.5 g,
8.51 mmol) in DCM (100 mL) was added triethylamine (1.03 g, 10.21 mmol) followed by
chloroacetyl chloride (1.24 g, 11.06 mmol) at 0°C. After being stirred at 0°C for 1h, the
mixture was diluted with water and extracted with DCM. The combined organic layers were
washed with brine, dried over Na SO and concentrated under reduced pressure. The residue
was purified by column chromatography using 70% EtOAc/hexanes to afford Intermediate
(2.2 g, 77%) as an off white solid. LCMS: 334.18 [M+H] .
Intermediate 16
To a solution of chloroacetic acid-d (250 mg, 2.57 mmol) in toluene (5
mL) was added a drop of DMF followed by addition of oxalyl chloride (0.4 mL, 3.86 mmol)
at 0°C and stirred at rt for 1h. The resulting clear solution was added to DCM (15 mL)
solution of Intermediate 8 (500 mg, 1.80 mmol) and N,N-diisopropylethylamine (0.4 mL,
2.57 mmol) at 0°C drop wise and the reaction was stirred at rt for 1h. The reaction mixture
was quenched with NaHCO (10 mL) and extracted with EtOAc. The combined organic
layers were washed with water, brine, dried over Na SO and concentrated. The resulting
crude compound was purified by column chromatography using 5% of methanol/DCM to
afford Intermediate 16 (200 mg, 20%) as an off-white solid. H NMR (300 MHz, DMSO-d )
δ 8.51 (s, 1H), 7.96 (d, 2H), 7.56 – 7.52 (m, 2H), 6.28 (s, 1H), 4.20–4.14 (m, 2H), 3.91 (s,
3H), 3.72 – 3.66 (m, 2H), 2.73 – 2.61 (m, 2H); LCMS: 319.0 [M+H] .
Intermediate 17
3-Methyl(4-(1-methyl-1H-1,2,4-triazolyl)phenyl)piperazine (17-
#1): A solution of 3-(4-bromophenyl)methyl-1H-1,2,4-triazole (2.0 g, 8.43 mmol) and 2-
methylpiperazine (1.68 g, 16.87 mmol) in dioxane : water (5:1, 60 mL) was degassed three
times with nitrogen/vacuum cycles. To this mixture was added Cs CO (4.11 g, 12.65 mmol)
followed by 2-di-tert-(butylphosphino)-biphenyl (0.755 g, 2.531 mmol) and Pd(OAc) (0.189
mg, 0.843 mmol). The mixture was further degassed for additional 10 min followed by
heating at 100°C for 48h. After completion of the reaction, the mixture was cooled to room
temperature, filtered through celite and washed with DCM. Filtrate was treated with 1N
aqueous HCl solution and extracted with DCM. The aqueous solution was neutralized with
5N NaOH (10 mL) solution, then extracted with 5% methanol/DCM. The combined organic
fractions were dried over Na SO and concentrated to afford 17-#1 (900 mg, 42%) as a
brown liquid. LCMS: 258.32 [M+H] .
2-Chloro(2-methyl(4-(1-methyl-1H-1,2,4-triazol
yl)phenyl)piperazinyl)ethanone (Intermediate 17): Intermediate 17 was prepared
following the procedure described for Intermediate 10 using 17-#1 and chloroacetic
anhydride to afford Intermediate 17. LCMS: 334.05 [M+H] .
Intermediate 18
Tert-butyl 4-(5-(1-methyl-1H-1,2,4-triazolyl)thiazol
yl)piperazinecarboxylate (18-#1): A mixture of 2-chloro(1-methyl-1H-1,2,4-triazol
yl)thiazole (600 mg, 3.0 mmol) and tert-butyl piperazinecarboxylate (1.78 g, 9.0 mmol)
in NMP (5 mL) was refluxed for 24h. The mixture was diluted with water and extracted with
ethyl acetate. The combined organic layers were washed with brine, dried over Na SO and
concentrated under reduced pressure. The residue was purified by column chromatography
eluted with 8% methanol/ DCM to afford 18-#1. (0.4 g, 40%) as an off white solid. LCMS:
351.04 [M+H] .
5-(1-Methyl-1H-1,2,4-triazolyl)(piperazinyl)thiazole
hydrochloride (18-#2): To a solution of 18-#1 (400 g, 1.14 mmol) in 1,4-dioxane (5 mL)
was added 4 M HCl in 1,4-dioxane (5 mL) and stirred at rt for 3h. The mixture was
concentrated and triturated with diethyl ether to afford 18-#2 (200 mg, 75%) as an off white
solid. LCMS: 250.95 [M+H] .
2-Chloro(4-(5-(1-methyl-1H-1,2,4-triazolyl)thiazol
yl)piperazinyl)ethanone (Intermediate 18): Intermediate 18 was prepared following the
procedure described for Intermediate 10 using 18-#2 and chloroacetyl chloride to afford
Intermediate 18. LCMS: 327.30 [M+H] .
Intermediate 19
Intermediate 19 was prepared following the procedure described for
Intermediate 13 using 2-methoxythiazolecarbimidate and ethyl hydrazine oxalate in Step 2
to afford Intermediate 19. LCMS: 338.23 [M+H] .
Intermediate 20
Intermediate 20 was prepared following the procedure described in
WO2016161160A1. LCMS: 347.22 [M+H] .
Intermediate 21
Tert-butyl 4-(4-(1-(2-hydroxyethyl)-1H-1,2,4-triazolyl)phenyl)-
,6-dihydropyridine-1(2H)-carboxylate (21-#1): To a stirred solution of 2-(3-(4-(1,2,3,6-
tetrahydropyridinyl)phenyl)-1H-1,2,4-triazolyl)ethanol hydrochloride (2.5 g, 7.911
mmol) in DCM (50 mL) was added triethylamine (3.99 g, 39.555 mmol), Boc anhydride
(1.89 g, 8.702 mmol) and stirred at rt for 3h. The mixture was quenched with ice-cold water
and extracted with DCM. The combined organic layer was washed with water and dried over
Na SO and concentrated under reduced pressure to afford a residue, which was purified by
column chromatography eluted with 5-10% methanol/DCM to afford 21-#1. (2.6 g, 86%) as
an off-white solid. LCMS: 371.17 [M+H] .
Tert-butyl 4-(4-(1-(2-bromoethyl)-1H-1,2,4-triazolyl)phenyl)-
,6-dihydropyridine-1(2H)-carboxylate (21-#2): To a stirred solution of 21-#1 (2.4 g,
6.486 mmol) in DCM (50 mL) was added Ph P (2.04 g, 7.783 mmol) and CBr (4.301
g,12.972 mmol) at 0°C and stirred at rt for 3h. The mixture was concentrated under reduced
pressure to afford a residue, which was purified by column chromatography eluted with 5-
% methanol/DCM to afford 21-#2 (1.63 g, 58%) as an off-white solid. LCMS: 433.24
[M+H] .
Tert-butyl 4-(4-(1-(2-(dimethylamino)ethyl)-1H-1,2,4-triazol
yl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate (21-#3): To a stirred solution of 21-#2
(0.750 g, 1.739 mmol) in DMF (20 mL) was added K CO (0.720 g, 5.219 mmol),
dimethylamine in THF (2.0 M) (2.17 mL, 4.349 mmol) at rt and stirred at rt for 16h. The
mixture was quenched with ice-cold water and extracted with EtOAc. The combined organic
layer was washed with water and dried over Na SO , concentrated under reduced pressure to
afford a residue, which was purified by column chromatography eluted with 5-10%
methanol/DCM to afford 21-#3 (0.5 g, 72%) as an off-white solid. LCMS: 398.36 M+H] .
2-Chloro(4-(4-(1-(2-(dimethylamino)ethyl)-1H-1,2,4-triazol
yl)phenyl)-5,6-dihydropyridin-1(2H)-yl)ethanone (Intermediate 21): Intermediate 21 was
prepared following the procedures described for Intermediate 9 using 21-#3 to afford 21.
LCMS: 374.11 [M+H] .
Intermediate 22
Intermediate 22 was prepared following the procedures described for
Intermediate 9 using 6-chloronicotinonitrile to afford Intermediate 22. LCMS: 318.2
[M+H] .
Intermediate 23
Intermediate 23 was prepared following the procedures described for
Intermediate 9 using 5-bromonicotinonitrile to afford Intermediate 23. LCMS: 318.1
[M+H] .
Intermediate 24
Intermediate 24 was prepared following the procedure described for
Intermediate 13 using 5-bromo-1,3,4-thiadiazolecarbonitrile to afford Intermediate 24.
LCMS: 325.28 [M+H] .
Intermediate 25
Intermediate 25 was prepared following the procedure described in
WO2016161160A1. LCMS: 335.10 [M+H] .
Intermediate 26
To a stirred solution of 5-(1-methyl-1H-1,2,4-triazolyl)(1,2,3,6-
tetrahydropyridinyl)thiazole hydrochloride (0.7 g, 2.472 mmol) in DCM (20 mL) was
added triethylamine (1.24 g, 12.36 mmol), 2-chloropropanoyl chloride (0.467 g, 3.708 mmol)
at 0°C. The mixture was stirred at 0°C for 2h. The mixture was quenched with ice-cold water
and extracted with DCM. The combined organic layers were washed with water and dried
over Na SO , concentrated under reduced pressure to afford a residue, which was purified by
column chromatography eluted with 5-10% methanol/DCM to afford Intermediate 26.
LCMS: 337.9[M+H] .
Intermediate 27
Tert-butyl 4-(5-Bromothiazolyl)-5,6-dihydropyridine-1(2H)-
carboxylate (27-#1): A solution of 2,5-dibromothiazole (5 g, 20.57 mmol) and tert-butyl 4-
(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-5,6-dihydropyridine-1(2H)-carboxylate (3.17
g, 16.46 mmol) in mixture of benzene : methanol (4 : 1, 50 mL) was added Na CO (6.5 g,
61.71 mmol) and degassed for 20 min. To this reaction mixture was then added Pd(Ph P)
(1.1 g, 1.02 mmol) and continued degassing for additional 10 min. Then, the mixture was
heated at 80°C for 12h. The mixture was cooled to rt and filtered through the Celite pad. To
the filtrate was added cold water and extracted with EtOAc. The combined organic layers
were washed with water, brine, dried over Na SO and concentrated. The residue was
purified by column chromatography eluted with 20% EtOAc/hexanes to afford 27-#1 (3 g,
42%) as yellow solid. LCMS: 345.18 [M+H] .
Tert-butyl 4-(5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolanyl)thiazol-
2-yl)-5,6-dihydro pyridine-1(2H)-carboxylate (27-#2): To a solution of 27-#1 (3 g, 8.72
mmol) in dioxane (30 mL) was added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-
dioxaborolane) (4.4 g, 17.44 mmol), AcOK (1.7 g, 17.44 mmol) and degassed for 15 min. To
this mixture was then added tricyclohexylphosphine (0.48 g, 1.74 mmol), Pd (dba) (0.39 g,
0.43 mmol) and continued degassing for additional 10 min. This mixture was heated at
110 C for 3h. TLC indicated full consumption of starting material and formation of a polar
spot. The reaction mixture was used in the next step without purification.
Tert-butyl 4-(5-(1-Methyl-1H-imidazolyl)thiazolyl)-5,6-
dihydropyridine-1(2H)-carboxylate (27-#3): To a crude mixture of 27-#2 in dioxane was
added 4-iodomethyl-1H-imidazole (1.2 g, 6.97 mmol), K CO (2.8 g, 20.91 mmol) and
degassed for 15 min. To this mixture was added Pd(Ph P) (0.4 g, 0.34 mmol) and continued
degassing for additional 10 min. This mixture was then heated at 100 C for 16h. The mixture
was cooled to rt and filtered through the Celite pad. To the filtrate was added cold water and
extracted with EtOAc. The combined organic layers were washed with water, brine, dried
over Na SO and concentrated. The residue was purified by column chromatography eluted
with 6% methanol/DCM to afford 27-#3 (700 mg, 25% for 2 steps). LCMS: 347.34 [M+H] .
2-Chloro(4-(5-(1-methyl-1H-imidazolyl)thiazolyl)-5,6-
dihydropyridin-1(2H)-yl)ethanone (intermediate 27): Intermediate 27 was prepared
following a procedure described for Intermediate 13 using tert-butyl 4-(5-(1-Methyl-1H-
imidazolyl)thiazolyl)-5,6-dihydropyridine-1(2H)-carboxylate. LCMS: 323.23 [M+1] .
General Procedure A: Suzuki cross coupling when PG = Trt or THP and PG = Cbz
or Boc
(A) (B)
To a solution of corresponding halide A (X = Cl, Br or I; Y = Y , Y or
Y ) (1.0 equiv) and appropriate boronic acid or boronic ester (1.0-1.2 equiv. Note #1) in
ethanol/toluene/water (0.2-0.5 M, 1:1:1 ratio, Note #2) was added K CO (2-4 equiv). The
mixture was degassed with vacuum/nitrogen purge three times, followed by the addition of
Pd(dppf) Cl -DCM (0.05-0.2 equiv Note #3). The resulting mixture was heated to reflux for
2-16h. Upon completion as determined by LCMS (or TLC), the mixture was cooled to rt and
diluted with EtOAc. The combined organic layers were washed with water and brine, dried
1 4 9
over Na SO and concentrated. The crude product B (R = R , R or R ) was either 1) purified
by column chromatography using silica gel, or 2) used directly in the next step without
further purification.
Note #1: In some instances, additional quantities of boronic acid or
boronic ester were added.
Note #2: In some instances, a mixture of DME/water, THF/water,
dioxane/water or 2-methyl THF/water mixture were used as solvent mixtures.
Note #3: In some instances, Pd(Ph P) or Pd(Ph P) Cl was used as
3 4 3 2 2
catalyst.
General Procedure B1: N-Deprotection when PG = Trt or THP and PG = CBz
(B) (C)
To a solution of corresponding protected amine B (PG = Trt or THP; PG
= Cbz) (1.0 equiv) in MeOH (or ethanol, or acetic acid) was added 10% Pd/C (0.1 equiv) and
stirred at rt for 6h under hydrogen atmosphere. The mixture was filtered through Celite pad
and washed with 10% MeOH/DCM. The filtrate was concentrated under reduced pressure to
afford the crude product C. This product was either 1) purified on a silica gel column or RP
HPLC; or 2) used directly in the next step without further purification.
General Procedure B2: Bis-deprotection when PG = Trt or THP and PG = CBz or Boc
A solution of corresponding protected amine B (PG = Trt or THP; PG =
Cbz or Boc) (1.0 equiv) in TFA (0.1-0.5M solution) was stirred at rt for 24h. The reaction
mixture was concentrated under reduced pressure to afford crude product C (where PG = H;
PG = H). This crude product was either 1) purified on a silica gel column or RP HPLC; or
2) used directly in the next step without further purification.
General Procedure C: Alkylation of secondary amine when PG = Trt, THP or H
Z
Y 1 3
PG Y
Y 2 R
Y 13
3 13
R Y N
N 5 PG
N H N
+ O N
R N 8
R Y N R
LG 8
Y 1 8
PG Y
O Y N
(C) (ID), (IID), (IIID) (IE), (IIE), (IIIE)
To a solution of corresponding secondary amine C (1 equiv) in N,N-
dimethylformamide (0.1-0.5 M, initial concentration of secondary amine in DMF varied from
0.1 M to 0.5 M based on solubility) at rt were added neat N-ethyl-N-isopropylpropan
amine (3-6 equiv, excess N-ethyl-N-isopropylpropanamine was used, or N-ethyl-N-
isopropylpropanamine was replaced for trimethylamine) and the corresponding alkylating
agent ID, IID or IIID (1.0-1.1 equiv, preferably 1.0 equiv of alkylating agent was used in
order to minimize over alkylation) in one portion. The mixture was stirred at rt for 6-24h (if
needed, the mixture was heated at 50°C). Upon completion as determined by LCMS (or
TLC), the mixture was either 1) concentrated directly on a rotary evaporator to give the crude
mixture that was used in the next step without further purification, or 2) purified on a silica
gel column eluted with methanol/DCM or purified on a RP-C18 column eluted with
acetonitrile/water in the presence of 0.1% formic acid to afford the desired corresponding
compound IE, IIE or IIIE.
General Procedure D: Deprotection of indazole when PG = Trt or THP
(IE), (IIE), (IIIE) (I), (II), (III)
A solution of trityl or THP protected indazole IE, IIE or IIIE (1 equiv) in
DCM/TFA/water (0.05 or 0.5 M, 3:1:0.5 ratio, conditions varied based on solubility of
staring material, a mixed DCM/TFA solvent was used in some preparations, Note #1) was
stirred at 25°C 6-16h. Upon completion as determined by LCMS, the reaction was quenched
with sat’d aqueous NaHCO and extracted with DCM (or extracted with EtOAc or
EtOAc/THF). The combined organic layers were dried over Na SO , filtered and
concentrated to afford the crude product I, II or III. Crude product I, II, or III was then
either 1) purified on a silica gel column eluted with 0-100% (0-10% 7 M NH in
methanol)/DCM or 2) purified on a RP-C18 column eluted with 0-100% acetonitrile/water in
the presence of 0.1% formic acid to afford the pure compound I, II, or III. When crude
material was purified on RP-C18 HPLC column or C-18 cartridges, compounds were free-
based using sat’d aqueous NaHCO and extracted with either DCM, EtOAc or EtOAc/THF
mixture.
Note #1: In some cases, PG (Trt or THP) was deprotected using neat
trifluoroacetic acid at room temperature.
General Procedure E: Preparation of hydrochloride salt
Compound I, II or III was dissolved in a suitable solvent (0.1-0.5 M,
DCM, MeOH or i-PrOH). At 0 C, hydrochloric acid (1-3 equiv., 2.0 M in diethyl ether) was
added via a syringe. In some cases, small amount of methanol was added prior to the
addition of hydrochloric acid. The precipitate was stirred for 5-10 mins at 0°C. Excess
solvent(s) and hydrochloric acid were removed using a rotary evaporator at 0°C. The
product was dried to afford the corresponding compound I, II or III as a hydrochloric acid
salt (equivalence of hydrochloride salt was determined by H NMR analysis).
Example 1
3-Fluoroiodomethylaniline (1-1): To a stirred solution of 3-fluoro-
2-methylaniline (10.0 g, 0.080 mmol) in acetic acid/water (1:1 ratio, 100 mL) was added
NaBO .4H O (12.3 g, 0.080 mmol). At 0°C, a solution of KI (13.3 g, 0.080 mmol) in 100 mL
water was added dropwise over 30 min. After being stirred at rt for 1h, the mixture was
diluted with water, filtered, and air dried to afford 1-1 (15.0 g, 75%) as a brown solid.
LCMS: 251.86 [M+H] .
4-Fluoroiodo-1H-indazole (1-2): To a stirred solution of 1-1 (10.0 g,
0.038 mmol) in acetic acid (400 mL) at 0°C was added a solution of NaNO (2.67 g, 0.038
mmol) in 10 mL water. After being stirred at rt for 6h, the mixture was directly concentrated
under reduced pressure. The residue was dissolved in EtOAc and washed with water.
Organic layer was dried over Na SO and concentrated under reduced pressure to afford 1-2
(9.0 g, 90%) as a brown solid. LCMS: 262.65 [M+H] .
3-Bromofluoroiodo-1H-indazole (1-3): To a stirred solution of 1-2
(9.0 g, 0.033 mmol) in DMF at 0°C was added bromine (5.86 g, 0.036 mmol) dropwise.
After being stirred at rt for 1h, the mixture was then poured into water, filtered, and air dried
to 1-3 (10.0 g, 85%) as a brown solid. LCMS: 340.78 [M+H] .
3-Bromofluoroiodo(tetrahydro-2H-pyranyl)-1H-indazole
(1-4): To a stirred solution of 1-3 (2.0 g, 0.005 mmol) in DCM (20 mL) at 0°C was added
PTSA (0.1 g, 0.0005 mmol). After being stirred at rt for 1h, the mixture was then poured into
sat’d solution of NaHCO and extracted with EtOAc. Combined organic layers were dried
over Na SO and concentrated under reduced pressure. The residue was purified by column
chromatography to afford 1-4 (1.4 g, 56%) as an orange solid. LCMS: 424.66 [M+H] .
(5R)-Benzyl 7-(3-bromofluoro(tetrahydro-2H-pyranyl)-1H-
indazolyl)oxo-2,7-diazaspiro[4.4]nonanecarboxylate (1-5): To a stirred solution
(15 min) of 1-5 (1.2 g, 4.370 mmol), Intermediate 1A (676 mg, 3.060 mmol) in dry DMSO
(15 mL) was added CuI (83 mg, 0.437 mmol) followed by K PO (1.1 g, 8.74 mmol). The
mixture was degassed for 30 min and heated at 100°C for 36h. The mixture was cooled to rt ,
diluted with water, and extracted with EtOAc . The combined organic layers were washed
with waterand brine, dried over Na SO and concentrated under reduced pressure. The
residue was purified by column chromatographyto afford 1-5 (550 mg, 22%) as a pale yellow
solid. LCMS: 572.88 [M+1] .
(5R)-Benzyl 7-(4-fluoro(6-isopropoxypyridinyl)(tetrahydro-
2H-pyranyl)-1H-indazolyl)oxo-2,7-diazaspiro[4.4]nonanecarboxylate (1-6):
To a stirred solution of 1-5 (500 mg, 0.877 mmol) and 2-isopropoxy(4,4,5,5-tetramethyl-
1,3,2-dioxaborolanyl)pyridine (253 mg, 0.964 mmol) in toluene/water/EtOH (1:1:1 ratio,
9 mL) was added K CO (605 mg, 4.385 mmol). The mixture was degassed for 10 min,
followed by addition of Pd(PPh ) (101 mg, 0.088 mmol), and degassed for another 10 min.
After being heated at 100°C for 3h, the mixture was cooled to room temperature, diluted with
water (30 mL), extracted with EtOAc. Combined organic layers were dried over Na SO and
concentrated under reduced pressure. The residue was purified by column chromatography to
afford 1-6 (350 mg, 63%) as an off white solid. LCMS: 628.07 [M+H] .
(S)(4-Fluoro(6-isopropoxypyridinyl)-1H-indazolyl)-2,7-
diazaspiro[4.4]nonanon (1-7): A solution of 1-6 (330 mg, 0.526 mmol) in TFA (5 mL)
was stirred at rt for 16h. The reaction mixture was directly concentrated under reduced
pressure to afford crude 1-7 (120 mg, 22%) as a pale yellow sticky liquid. This crude
compound was used in the next step without further purification. LCMS: 409.97 [M+H] .
(S)(4-Fluoro(6-isopropoxypyridinyl)-1H-indazolyl)(2-(4-
(4-(1-methyl-1H-1, 2, 4 -triazolyl) phenyl)-5,6-dihydropyridin-1(2H)-yl)oxoethyl)-
2,7-diazaspiro[4.4]nonanone (1): To a stirred solution of 1-7 (120 mg, 0.293 mmol) in
DMF (5 mL) was added DIPEA (0.315 mL, 1.75 mmol) followed by Intermediate 9 (101 mg,
0.322 mmol). After being stirred at rt for 16h, the mixture was diluted with cold water (10
mL) and extracted with EtOAc. The combined organic layers were washed with brine, dried
over Na SO and concentrated under reduced pressure. The residue was purified by column
chromatography using 10% MeOH/DCM to afford Example 1. (60 mg, 29%) as an off white
solid. mp: 138-140 °C; H NMR (400 MHz, DMSO-d ) δ 13.62 (s, 1H), 8.56 (s, 1H), 8.50 (s,
1H), 8.07 (d, 1H), 7.98–7.92 (m, 2H), 7.57–7.50 (m, 2H), 7.46–7.36 (m, 2H), 6.87 (d, 1H),
6.30–6.26 (m, 1H), 5.36–5.26 (m, 1H), 4.29 – 4.12 (m, 2H), 3.91 (s, 3H), 3.79–3.43 (m, 7H),
3.16–3.11 (m, 1H), 2.65–2.60 (m, 4H), 2.33–2.15 (m, 3H), 1.93–1.78 (m, 1H), 1.34–1.30 (m,
6H); LCMS: 690.06 [M+H]
Example 2
Example 2 was prepared following General Procedures C and D using
Intermediate 7 and Intermediate 9. H NMR (400 MHz, DMSO-d ) δ 13.23 (s, 1H), 8.76 (d,
1H), 8.5 (s, 1H), 8.26-8.23 (dd,1H), 8.16 (s, 1H), 7.96 (d, 2H), 7.78-7.75 (m, 1H), 7.60-7.53
(m, 3H), 6.98 (d,1H), 6.28 (s,1H), 4.28 (br s, 1H), 4.19-4.09 (m, 3H), 3.92-3.91 (m, 8H),
3.76-3.67 (m, 2H), 3.50-3.36 (m, 2H), 2.97 (br s, 3H), 2.67-2.62 (m, 2H), 2.21-2.18 (m, 3H).
LCMS: 644.45 [M+H] .
Example 3
(R)-Benzyl 7-(3-(4, 4-difluoropiperidinyl)trityl-1H-indazolyl)-
6-oxo-2,7-diaza spiro[4.4]nonanecarboxylate (3-1): To a stirred solution of
Intermediate 2 (500 mg, 0.659 mmol) and 4,4-difluoropiperidine (95 mg, 0.791 mmol) in
dioxane/water (9 mL, 2:1 ratio) was added K CO (272.8 mg, 1.977 mmol). The mixture was
degassed for 10 min, followed by addition of L-proline (22.7 mg, 0.197 mmol) and CuI (12.5
mg, 0.0659 mmol), and degassed again for another 10 min. After being stirred at 100 C for
16h, the mixture was diluted with water and extracted with EtOAc. The combined organic
layers were dried over Na SO and concentrated under reduced pressure. The residue was
purified by column chromatography to afford 3-1. (250mg, 50%) as an off white solid.
LCMS: 752.55 [M+H] .
(S)(3-(4,4-Difluoropiperidinyl)trityl-1H-indazolyl)-2,7-
diazaspiro[4.4]nonanone (3-2): To a stirred solution of 3-1 (250 mg, 0.332 mmol) in
THF (10 mL) was added 10% Pd/C (500 mg). After being stirred at rt under hydrogen
atmosphere for 16h, the mixture was filtered through a Celite pad and washed with 10%
MeOH/DCM. The combined organic layers were concentrated under reduced pressure to
afford 3-2 (100 mg, 48%) which used in the next step without any purification. LCMS:
618.49 [M+H] .
(S)(3-(4,4-Difluoropiperidinyl)trityl-1H-indazolyl)(2-(4-
(4-(1-methyl-1H-1,2,4-triazolyl)phenyl)-5,6-dihydropyridin-1(2H)-yl)oxoethyl)-
2,7-diazaspiro[4.4]nonanone (3-3): To a stirred solution 3-2 (100 mg, 0.162 mmol) in
DMF (5 mL) was added DIPEA (125 mg, 0.972 mmol) followed by Intermediate 9 (51.2 mg,
0.162 mmol). After being stirred at rt for 16h, the mixture was diluted with cold water and
extracted with EtOAc. The combined organic layers were washed with brine, dried over
Na SO and concentrated under reduced pressure. The residue was purified by column
chromatography using 5% methanol/DCM to afford 3-3 (70 mg, 48%) as an off white solid.
LCMS: 898.74 [M+H] .
(S)(3-(4,4-difluoropiperidinyl)-1H-indazolyl)(2-(4-(4-(1-
methyl-1H-1,2,4-triazolyl)phenyl)-5,6-dihydropyridin-1(2H)-yl)oxoethyl)-2,7-
diazaspiro[4.4]nonanone (Example 3): To a stirred solution of 3-3 (70 mg, 0.077 mmol)
in DCM (4 mL) at 0°C was added TFA (3 ml). After being stirred at rt for 3 h, the mixture
was quenched with sat’d NaHCO solution and extracted with EtOAc. The combined
organic layers were dried over Na SO and concentrated under reduced pressure. The residue
was purified by column chromatography to afford Example 3 (25 mg, 45% yield) as an off
white solid. H NMR (400 MHz, DMSO-d ) δ 12.08 (s, 1H), 8.50 (s, 1H), 7.96 (d, 2H), 7.83
(d, 1H), 7.63 (d, 1H), 7.54 (d, 2H), 7.36 (d, 1H), 6.28 (br s, 1H), 4.33 – 4.10 (m, 3H), 3.91 (s,
3H), 3.88–3.60 (m, 4H), 3.46–3.43 (m, 5H), 2.95–2.90 (m, 2H), 2.85–2.80 (m, 2H), 2.70–
2.60 (m, 1H), 2.20–2.07 (m, 8H), 1.85–1.78 (m, 1H); LCMS: 656.45 [M+H] .
Example 4
4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolanyl)-1,2,3,6-
tetrahydropyridine hydrochloride (4-1): To a stirred solution of tert-butyl 4-(4,4,5,5-
tetramethyl-1,3,2-dioxaborolanyl)-5,6-dihydropyridine-1(2H)-carboxylate (2.0 g, 6.472
mmol) in MTBE (16 mL) was added 2 M HCl in Et O (48 mL). After being stirred at rt for
16h, the mixture was filtered. The obtained residue was washed with Et O and air dried to
afford 4-1 (1.2 g, 75%) as an off white solid.
1-Methyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1,2,3,6-
tetrahydropyridine (4-2): To a stirred solution of 4-1 (500mg, 2.040 mmol) in MeOH (8
mL) was added Et N (0.58 mL, 4.08 mmol) followed by formaldehyde (3 mL) and 10% Pd/C
(100 mg, wet). After being stirred at rt for 5h under hydrogen atmosphere, the mixture was
filtered through a Celite pad and washed with 10% MeOH/DCM. The organic layer was
concentrated under reduced pressure to afford 4-2 (400 mg, crude) which was used in the
next step without further purification.
(R)-Benzyl 7-(3-(1-methyl-1,2,3,6-tetrahydropyridinyl)trityl-1H-
indazolyl)oxo-2,7-diazaspiro[4.4]nonanecarboxylate (4-3): To a stirred solution
of Intermediate 2 (300 mg, 0.395 mmol) in toluene/EtOH/water (9 mL, 1:1:1 ratio) were
added K CO (273 mg, 1.978 mmol) and N-methyl(4,4,5,5-tetramethyl-1,3,2-
dioxaborolanyl)picolinamide (176 mg, 0.791 mmol). The mixture was degassed for 10
min, followed by addition of Pd(PPh ) (22 mg, 0.0197 mmol), and degassed again for
another 10 min. After being stirred at 90°C for 3h, the mixture was diluted with water and
extracted with EtOAc. The combined organic layers were dried over Na SO and
concentrated under reduced pressure to afford 4-3 (200 mg, 69%) as a brown thick liquid.
LCMS: 728.57 [M+H] .
(S)(2-(4-(4-(1-methyl-1H-1,2,4-triazolyl)phenyl)-3,6-
dihydropyridin-1(2H)-yl)oxoethyl)(3-(1-methylpiperidinyl)-1H-indazolyl)-
2,7-diazaspiro[4.4]nonanone (Example 4): Example 4 was prepared following General
Procedures B, C and D using (S)(3-(1-methylpiperidinyl)trityl-1H-indazolyl)-2,7-
diazaspiro[4.4]nonanone and Intermediate 9. H NMR (400 MHz, DMSO-d ) δ 12.86 (br
s, 1H), 10.70–10.22 (m, 2H), 8.52 (s, 1H), 8.00–7.95 (m, 2H), 7.82–7.72 (m, 1H), 7.59 -
7.48(m, 2H), 6.31 (s, 1H), 4.6 –4.50 (m, 2H), 4.22–4.10 (m, 2H), 4.09–3.90 (m, 6H), 3.65–
3.25 (m, 8H), 3.12 (dd, 2H), 2.80–2.55 (m, 5H), 2.44–2.08 (m, 8H); LCMS: 634.08 [M+H] .
Example 5
4-Bromopicolinoyl chloride (5-1): A mixture of 4-bromopicolinic acid
(2.0 g, 9.90 mmol) and thionylchloride (15 mL) were stirred at 90°C for 5h. The reaction was
then quenched with methanol and concentrated under reduced pressure to afford crude 5-1 (2
g) which was directly used in the next step without further purification.
4-Bromo-N-methylpicolinamide (5-2): To a stirred solution of 5-1 (2.0
g, 9.09 mmol) in THF (20 mL) was added methylamine (2 M in THF) solution at 0°C. After
being stirred at rt overnight, the mixture was concentrated under reduced pressure. The
resulting residue was dissolved in EtOAc and washed with water. The organic layer was
dried over Na SO and concentrated under reduced pressure to afford 5-2 (1.5 g, 70% over 2
steps) which was used in the next step without further purification.
N-Methyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)picolinamide
(5-3): To a stirred solution of 5-2 (600 mg, 1.0 eq.) in 1,4 dioxane (8 mL) were added
bis(pinacalato)diboron (1.5 eq.) and KOAc (3.0 eq.). The mixture was degassed for 10 min,
followed by the addition of PdCl (dppf)-DCM (0.1 eq.), and degassed again for 10 min. After
being stirred at 80°C for 3h, TLC indicated formation of a new polar spot with complete
consumption of starting material. The mixture was cooled to rt and the crude 5-3 was used in
the next step without any workup and purification.
(S)-N-methyl(5-(7-(2-(4-(4-(1-methyl-1H-1,2,4-triazolyl)phenyl)-
,6-dihydropyridin-1(2H)-yl)oxoethyl)oxo-2,7-diazaspiro[4.4]nonanyl)trityl-
1H-indazolyl)picolinamide (Example 5): Example 5 prepared following General
Procedures A, B2, C and D using 5-3, (S)-N-Methyl(5-(1-oxo-2,7-diazaspiro[4.4]nonan
H NMR (400 MHz, DMSO-
yl)trityl-1H-indazolyl)picolinamide and Intermediate 9.
d ) δ 13.78 (s, 1H), 8.83 (d, 1H), 8.76 – 8.872 (m, 1H), 8.59 (s, 1H), 8.50 (s, 1H), 8.29 (s,
1H), 8.15 (dd, 1H), 7.95 (d, 2H), 7.82 (t, 1H), 7.67 (d, 1H), 7.58–7.52 (m, 2H), 6.28 (s, 1H),
4.35–4.28 (m, 1H), 4.16–4.00 (m, 1H), 3-98–3.75 (m, 5H), 3.80–3.65 (m, 2H), 3.48–3.30 (m,
2H), 3.00–2.82 (m, 5H), 2.75–2.50 (m, 4H), 2.30–2.10 (m, 3H), 1.86–1.79 (m, 1H); LCMS:
671.47 [M+H] .
Example 6
Example 6 was prepared following the procedure described for Example 5
using N-methyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)picolinamide, Intermediate 2,
and Intermediate 9. H NMR (400 MHz, DMSO-d ) δ 13.60 (s, 1H), 9.21 (d, 1H), 8.84 (br d,
1H), 8.54-8.50 (m, 2H), 8.27 (s, 1H), 8.16 (d, 1H), 7.95 (d, 2H), 7.81 (t, 1H), 7.66 (d, 1H),
7.55 (t, 2H), 6.28 (s, 1H), 4.28 - 4.13 (m, 2H), 3.91 (s, 5H), 3.77-3.73 (m, 3H), 3.51-3.41 (m,
2H), 2.95-2.85 (m, 6H), 2.67-2.61 (m, 2H), 2.35-2.17 (m, 3H), 1.84 - 1.83 (m, 1H). ); LCMS:
671.47 [M+H] .
Example 7
(R)-Benzyl 7-(3-(3,6-dihydro-2H-thiopyranyl)trityl-1H-indazol-
-yl)oxo-2,7-diazaspiro[4.4]nonanecarboxylate (7-1): The title compound was
prepared following a General Procedure A using Intermediate 2 and 4-(4,4,5,5-tetramethyl-
1,3,2-dioxaborolanyl)(2,2,2-trifluoroethyl)-1,2,3,6-tetrahydropyridine to afford 7-1.
(300 mg, 78%) as an off white solid. LC-MS (ESI) m/z 731.08 [M+H] .
(R)-Benzyl 7-(3-(1,1-dioxido-3,6-dihydro-2H-thiopyranyl)trityl-
1H-indazolyl)oxo-2,7-diazaspiro[4.4]nonanecarboxylate (7-2): To a stirred
solution of 7-1 (300 mg, 0.410 mmol) in acetone/water (15 mL, 2:1 ratio) was added oxone
(252.0 mg, 0.821 mmol) at 0 C. After being stirred at rt for 3h, the mixture was diluted with
water and extracted with EtOAc. The combined organic layers were dried over Na SO and
concentrated under reduced pressure to 7-2 (220 mg, 70% ) which was used in the next step
without further purification. LCMS: 763.06 [M+H] .
(S)(3-(1,1-Dioxidotetrahydro-2H-thiopyranyl)trityl-1H-
indazolyl)-2,7-diazaspiro[4.4]nonanone (7-3): The title compound was prepared
following General Procedure B using 7-2 . LCMS: 631.65 [M+H] .
(S)(2-(4-(4-(1-Methyl-1H-1,2,4-triazolyl)phenyl)-5,6-
dihydropyridin-1(2H)-yl)oxoethyl)(3-(tetrahydro-2H-thiopyran 1,1-dioxideyl)-
1H-indazolyl)-2,7-diazaspiro[4.4]nonanone (Example 7): Example 7 was prepared
following General Procedures C and D using 7-3 and Intermediate 9. H NMR (400 MHz,
DMSO-d ) δ 12.79 (s, 1H), 8.50 (s, 1H), 7.96 (d, 2H), 7.89 (s, 1H), 7.68–7.65 (m, 1H), 7.56–
7.49 (m, 2H), 7.48 (d, 1H), 6.28 (s, 1H), 4.32 – 4.10 (m, 3H), 3.91 (s, 3H), 3.88–3.60 (m,
4H), 3.50–3.30 (m, 3H), 3.22–3.15 (m, 2H), 3.10-2.75 (m, 5H), 2.70–2.55 (m, 2H), 2.40–
2.10 (m, 7H), 1.90–1.75 (m, 1H); LCMS: 669.04 [M+H] .
Example 8
Example 8 was prepared following General Procedures A, B2, and C
using Intermediate 2, 2-methoxy(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)
(trifluoromethyl)pyridine and Intermediate 9. H NMR (400 MHz, DMSO-d ) δ 13.41 (s,
1H), 9.04 (d, 1H), 8.51 (s, 1H), 8.50 (s, 1H), 8.19 (s, 1H), 7.97 – 7.94 (m, 2H), 7.84 – 7.80
(m, 1H), 7.62 (d, 1H), 7.57–7.52 (m, 2H), 6.28 (s, 1H), 4.33–4.28 (m, 1H), 4.18–4.09 (m,
1H), 4.07 (s, 3H), 3.91 (s, 3H), 3.90 – 3.85 (m, 1H), 3.80–3.60 (m, 3H), 3.50–3.35 (m, 2H),
2.95–2.80 (m, 3H), 2.70–2.58 (m, 3H), 2.25–2.10 (m, 3H), 1.85–1.75 (m, 1H); LCMS: 712.4
[M+H] .
Example 9
Example 9 was prepared following General Procedures A, B2, and C
using Intermediate 2 and 3-chloro(4,4,5,5-tetramethyl-1,3,2-dioxaborolan
yl)picolinonitrile and Intermediate 9. H NMR (400 MHz, DMSO-d ) δ 13.90 (s, 1H), 9.32
(d, 1H), 8.68 (s, 1H), 8.50 (s, 1H), 8.21 (d, 1H), 7.95-7.90 (m, 3H), 7.68 (d, 1H), 7.54-7.52
(m, 2H), 6.28 (s, 1H), 4.36-4.30 (m, 1H), 4.14-4.10 (m, 2H), 3.91 (s, 5H), 3.79-3.72 (m, 2H),
3.44-3.36 (m, 2H), 3.01-2.80 (m, 3H), 2.70-2.63 (m, 2H), 2.28-2.12 (m, 3H), 1.86-1.77 (m,
1H); LCMS: 673.30 [M+H] .
Example 10
Example 10 was prepared following General Procedures A, B2, and C
using Intermediate 2 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)
(trifluoromethyl)picolinonitrile and Intermediate 9. H NMR (400 MHz, DMSO-d ) δ 12.98
(s, 1H), 9.63 (s, 1H), 8.80 (s, 1H), 8.50 (s, 1H), 8.27 (s, 1H), 7.97–7.90 (m, 3H), 7.70 (d, 1H),
7.57–7.52 (m, 2H), 6.27 (s, 1H), 4.32–4.10 (m, 2H), 3.98–3.90 (m, 2H), 3.91 (s, 3H), 3.85–
3.60 (m, 2H), 3.50–3.31 (m, 2H), 3.00–2.80 (m, 3H), 2.75–2.51 (m, 3H), 2.78–2.60 (m, 3H),
1.80–1.75 (m, 1H); LCMS: 707.3 [M+H] .
Example 11
(R)-Benzyl 6-oxo(3-(pyrrolidinyl)trityl-1H-indazolyl)-2,7-
diazaspiro[4.4] nonanecarboxylate (11-1): To a stirred solution of Intermediate 2 (400
mg, 0.527 mmol) in DMSO (6 mL) were added K CO (218 mg, 1.581 mmol), pyrrolidine
(44 mg, 0.633 mmol), and L-proline (18 mg, 0.158 mmol). The mixture was degassed for 10
min, followed by the addition of CuI (10 mg, 0.052 mmol), and degassed again for another
min. The mixture was warmed up and stirred at 90 C for 36h. The mixture was diluted
with water (20 mL) and extracted with EtOAc. The combined organic layers were dried over
Na SO and concentrated under reduced pressure to afford 11-1 (400 mg, crude) as a brown
thick liquid. LCMS: 702.16 [M+H] .
(S)(3-(Pyrrolidinyl)-1H-indazolyl)-2,7-diazaspiro[4.4]nonan-
1-one (11-2) : A mixture of 11-1 in TFA (5 mL) was stirred at rt for 16h. The mixture was
concentrated under reduced pressure to afford 11-2 (200 mg, crude TFA salt) which was used
in the next step without further purification. LCMS: 326.10 [M+H] .
(S)(2-(4-(4-(1-Methyl-1H-1,2,4-triazolyl)phenyl)-5,6-
dihydropyridin-1(2H)-yl)oxoethyl)(3-(pyrrolidinyl)-1H-indazolyl)-2,7-
diazaspiro[4.4]nonanone (Example 11): Example 11 was prepared following General
Procedure C and D using 11-2 and Intermediate 9. H NMR (400 MHz, DMSO-d ) δ 11.65
(s, 1H), 8.50 (s, 1H), 7.99–7.91 (m, 3H), 7.58–7.49(m, 3H), 7.26 (d,1H), 6.28 (s, 1H), 4.36–
4.25 (m, 1H), 4.20–4.05 (m, 1H), 3.91 (s, 3H), 3.85–3.60 (m, 4H), 3.55–3.30 (m, 7H), 2.96–
2.85 (m, 1H), 2.84–2.77 (m, 1H), 2.68–2.55 (m, 2H), 2.20–2.05 (m, 4H), 1.98–1.90 (m, 4H),
1.84–1.72 (m, 1H); LCMS: 606.16 [M+H] .
Example 12
4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolanyl)-1,2,3,6-
tetrahydropyridine hydrochloride (12-1): To a stirred solution of tert-butyl 4-(4,4,5,5-
tetramethyl-1,3,2-dioxaborolanyl)-5,6-dihydropyridine-1(2H)-carboxylate (2.0 g, 6.472
mmol) in MTBE (16 mL) was added 2 M HCl in Et O (48 mL). After being stirred at rt for
16h, the mixture was filtered. The residue was washed with Et O and air dried to afford 12-1
(1.2 g, 75%) as an off white solid.
Step 2: 4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolanyl)(2,2,2-
trifluoroethyl)-1,2,3,6-tetrahydropyridine (12-2): To a stirred solution of 12-1 (500 mg,
2.040 mmol) in THF (5 mL) was added TEA (1.4 mL, 10.2 mmol). After being stirred at rt
for 10 min, 2,2,2-trifluoroethyl trifluoromethane sulfonate (473 mg, 2.040 mmol) was added
and stirred at rt for 16h. The mixture was poured into a sat’d NaHCO solution and extracted
with EtOAc. The combined organic layers were dried over Na SO and concentrated under
reduced pressure to afford 12-2 (300 mg, 51%) which was used in the next step without
further purification. GCMS: 291.1 [M]
(S)(2-(4-(4-(1-Methyl-1H-1,2,4-triazolyl)phenyl)-5,6-
dihydropyridin-1(2H)-yl)oxoethyl)(3-(1-(2,2,2-trifluoroethyl)piperidinyl)-1H-
indazolyl)-2,7-diazaspiro[4.4]nonanone (Example 12): Example 12 was prepared as
described in Example 11 using 12-2 and (R)-benzyl 7-(3-iodotrityl-1H-indazolyl)
oxo-2,7-diazaspiro[4.4]nonanecarboxylate followed by General Procedures C and D using
Intermediate 9. H NMR (400 MHz, DMSO-d ) δ 12.62 (s, 1H), 8.50 (s, 1H), 7.96 (d, 2H),
7.90–7.88 (m, 1H), 7.64–7.61 (m, 1H), 7.59–7.53 (m, 2H), 7.44 (d, 1H), 6.28 (s, 1H), 4.32–
4.20 (m, 3H), 3.91 (s, 3H), 3.88–3.60 (m, 4H), 3.50–3.30 (m, 3H), 3.25–3.15 (m, 2H), 3.05-
2.98 (m, 5H), 2.70–2.60 (m, 4H), 2.23–2.05 (m, 3H), 1.95–1.75 (m, 5H); LCMS: 702.5
[M+H] .
Example 13
(R)-Benzyl 7-(3-(furanyl)trityl-1H-indazolyl)oxo-2,7-
diazaspiro[4.4]nonanecarboxylate (13-1): To a stirred solution Intermediate 2 (1.5 g,
1.981 mmol) and 2-(furanyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.38 g, 1.981
mmol) in toluene/water/ethanol (30 mL, 1:1:1 ratio) were added K CO (1.36 g, 9.840 mmol)
and Pd(Ph P) (0.22 g, 0.198 mmol). The mixture was degassed for 10 min followed by
heating at 80 C for 2h. The mixture was cooled to room temperature, diluted with cold water,
and extracted with EtOAc. The combined organic layers were washed with water, brine,
dried over Na SO and concentrated. The residue was purified by column chromatography
using 50% EtOAc/hexanes to afford 13-1(1.02 g, 73%) as an off white solid. LCMS: 699.10
[M+H] .
(5S)(3-(Tetrahydrofuranyl)trityl-1H-indazolyl)-2,7-
diazaspiro[4.4]nonanone (13-2): To a solution of 13-1 (1.02 g, 1.461 mmol) in THF (60
mL) was added wet Pd/C (2.04 g). After being stirred at rt under H atmosphere for 3h, the
mixture was filtered through a Celite pad and concentrated to afford 13-2 (0.57 g,68%) as an
off white solid. LCMS: 569.68 [M+H] .
(5S)(2-(4-(4-(1-Methyl-1H-1,2,4-triazolyl)phenyl)-5,6-
dihydropyridin-1(2H)-yl)oxoethyl)(3-(tetrahydrofuranyl)-1H-indazolyl)-2,7-
diazaspiro[4.4]nonanone (Example 13): Example 13 was prepared following General
Procedures C and D using 13-2 and Intermediate 9 H NMR (DMSO–d , 400 MHz) δ 12.75
(s, 1H), 8.50 (s, 1H), 7.96 (d,2H), 7.88–7.84 (m, 1H), 7.72–7.66 (m, 1H), 7.54 (d,2H), 7.48–
7.44 (m, 1H), 6.31–6.25 (m, 1H), 4.38–4.23 (m, 1H), 4.20–4.05 (m, 2H), 3.99–3.92 (m, 1H),
3.91 (s, 3H), 3.86–3.61 (m, 7H), 3.48–3.34 (m, 3H), 2.98 – 2.86 (m, 1H), 2.85–2.78 (m, 1H),
2.70–2.52 (m, 3H), 2.45–2.30 (m, 1H), 2.27–2.05 (m, 4H), 1.84–1.73 (m, 1H); LCMS:
607.17 [M+H] .
Example 14
Example 14 was prepared following General Procedures A, B2, and C
using Intermediate 3, 2-chloro(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)benzonitrile,
and Intermediate 15. Data for 1.0 HCl salt: H NMR (DMSO–d , 400 MHz) δ 13.80 (s, 1H),
.40 (d, 1H), 8.26 (d, 2H), 8.16-8.11 (m, 2H), 7.85-7.78 (m, 3H), 7.73-7.63 (m, 3H), 6.41 (s,
1H), 4.64-4.53 (m, 2H), 4.22-4.15 (m, 2H), 4.10-3.95 (m, 2H), 3.81-3.75 (m, 2H), 3.61 (br,
1H), 3.50-3.43 (br, 2H), 3.42 (s, 2H), 3.40-3.30 (m, 3H), 2.67 (br, 1H), 2.56 (br, 1H), 2.44-
2.27 (m, 3H), 2.20 -2.15 (m, 1H); LCMS: 689.20 [M+H] .
Example 15
Example 15 was prepared following General Procedures A, B2, C, and E
using Intermediate 3, (4-cyano(trifluoromethyl)phenyl)boronic acid, and Intermediate 15.
Data for 1.0 HCl salt: H NMR (DMSO–d , 400 MHz) δ 13.88 (s, 1H), 10.39 (d, 1H), 8.50
(d, 2H), 8.34 (br, 2H), 7.88-7.64 (m, 6H), 6.41 (s, 1H), 4.65-4.52 (m, 2H), 4.22-4.15 (m, 2H),
4.11-3.97 (m, 2H), 3.81-3.75 (m, 2H), 3.61 (br, 1H), 3.50-3.43 (br, 2H), 3.42 (s, 3H), 3.40-
3.30 (m, 2H), 2.67 (br, 1H), 2.57 (br, 1H), 2.44-2.28 (m, 3H), 2.22-2.16 (m, 1H); LCMS:
723.20 [M+H] .
Example 16
Example 16 was prepared following General Procedures A, B1, C, D and
E using Intermediate 3, 2-fluoro-N-methyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolan
yl)benzamide, and Intermediate 15. Data for 1.0 HCl salt: H NMR (DMSO–d , 400 MHz) δ
13.45 (s, 1H), 10.40 (d, 1H), 8.20-8.14 (m, 2H), 8.08-8.06 (br, 1H), 7.81-7.77 (m, 3H), 7.67-
7.63 (m, 3H), 7.49-7.43 (m, 1H), 6.40 (s, 1H), 4.65-4.52 (m, 2H), 4.22-4.15 (m, 2H), 4.11-
3.97 (m, 2H), 3.81-3.75 (m, 2H), 3.61 (br, 1H), 3.50-3.43 (br, 2H), 3.42 (s, 3H), 3.40-3.30
(m, 2H), 2.83 (d, 3H), 2.67 (br, 1H), 2.57 (br, 1H), 2.44-2.28 (m, 3H), 2.22 -2.16 (m, 1H);
LCMS: 705.30 [M+H] .
Example 17
Example 17 was prepared following General Procedures A, B2, and C
using Intermediate 3, 2-(4-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, and
Intermediate 13. H NMR (400 MHz, DMSO-d ) δ 13.25 (s, 1H), 8.56 (s, 1H), 8.18 (s, 1H),
8.15 (s, 1H), 8.01 - 7.97 (m, 2H), 7.75 (d, 1H), 7.59 (d, 1H), 7.35 (t, 2H), 6.71 (s, 1H), 4.38-
4.17 (m, 2H), 3.90-3.64 (m, 7H), 3.45-3.36 (m, 3H), 2.94-2.82 (m, 2H), 2.72 (s, 1H), 2.67-
2.49 (m, 2H), 2.23-2.11 (m, 3H), 1.82-1.77 (m, 1H); LCMS: 638.01 [M+H] .
Example 18
Example 18 was prepared following General Procedures A, B2, and C
using Intermediate 3, 2-(4-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, and
Intermediate 15. H NMR (DMSO-d , 300 MHz) δ 13.65 (br s, 1H), 8.16 (s, 1H), 8.02–7.96
(m, 2H), 7.77–7.72 (m, 3H), 7.68–7.54 (m, 3H), 7.38–7.31 (m, 2H), 6.39–6.35 (m, 1H), 4.32
– 3.62 (m, 6H), 3.50–3.35 (m, 6H), 2.98–2.78 (m, 2H), 2.73–2.56 (m, 3H), 2.30–2.06 (m,
3H), 1.84–1.75 (m, 1H); LCMS: 648.41 [M+H] .
Example 19
Example 19 was prepared following General Procedures A, B2, and C
using Intermediate 3, 2-methoxy(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)pyridine,
and Intermediate 15. H NMR (DMSO-d , 400 MHz) δ 13.26 (s, 1H), 8.75 (d, 1H), 8.24 (dd,
1H), 8.15 (br d, 1H), 7.78–7.71 (m, 3H), 7.66–7.55 (m, 3H), 6.98 (dd, 1H), 6.38–6.34 (m,
1H), 4.39–4.28 (m, 1H), 4.25–4.05 (m, 1H), 3.93 (s, 3H), 3.92–3.62 (m, 5H), 3.50–3.42 (m,
2H), 3.40 (s, 3H), 2.98–2.75 (m, 3H), 2.73–2.55 (m, 2H), 2.25–2.05 (m, 3H), 1.85–1.76 (m,
1H); LCMS 661.41 [M+H] .
Example 20
Example 20 was prepared following General Procedures A, B2, and
Cusing Intermediate 4, 2-methyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)pyridine,
and Intermediate 9. H NMR (DMSO–d , 400 MHz) δ 13.50 (s, 1H), 9.50 (s, 1H), 8.60 (dd,
1H ), 8.49 (d, 2H), 8.11 (d, 1H), 7.97 (d, 2H), 7.55 (d, 2H), 7.38 (d, 1H), 6.28 (s, 1H), 4.31(s,
1H), 4.14–4.11 (m, 3H), 3.92 (s, 3H), 3.80–3.67 (m, 2H), 3.50–3.47 (m, 1H), 3.40–3.28 (m,
2H), 293–2.69 (m, 3H), 2.62–2.49 (m, 5H), 2.32–2.15 (m, 3H), 1.87–1.85 (m, 1H); LCMS:
629.1[M+H]
Example 21
Example 21 was prepared following General Procedures A, B2, and C
using Intermediate 4, 2-methoxy(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)pyridine,
and Intermediate 9. H NMR (DMSO–d , 400 MHz) δ 13.51 (s, 1H), 9.29 (s, 1H), 8.62 (dd,
1H), 8.53–8.46 (m, 2H), 8.10 (d, 1H), 7.97 (d, 2H), 7.55 (d, 2H), 6.97 (d, 1H), 6.30–6.26
(m, 1H), 4.33–4.29 (m, 1H), 4.21–4.05 (m, 3H), 3.92 (s, 5H), 3.86–3.78 (m, 1H), 3.74–3.65
(m, 2H), 3.52–3.45 (m, 1H), 3.41–3.36 (m, 1H), 2.97–2.81 (m, 2H), 2.78–2.55 (m, 4H),
2.30–2.10 (m, 3H), 1.91–1.80 (m, 1H); LCMS: 645.46 [M+H] .
Example 22
(5R)-Benzyl 7-(3-(3,6-dihydro-2H-pyranyl)(tetrahydro-2H-
pyranyl)-1H-pyrazolo[4,3-b]pyridinyl)oxo-2,7-diazaspiro[4.4]nonane
carboxylate (22-1): To a stirred solution of Intermediate 4 (2.3 g, 4.151 mmol) and 2-(3,6-
dihydro-2H-pyranyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.87 g, 4.147 mmol) in
toluene/ethanol/water (60 mL, 1:1:1 ratio) were added K CO (2.86 g, 20.694 mmol) and
Pd(Ph P) (0.23 g, 0.206 mmol). The mixture was degassed for 10 min, followed by heating
at 100ºC for 16h. The mixture was cooled to rt, diluted with cold water, and extracted with
EtOAc. The combined organic layers were washed with water and brine, dried over Na SO
and concentrated. The crude compound was purified by column chromatography using 50%
EtOAc/hexanes to afford 22-1. LCMS: 558.05 [M+H] .
(5S)(1-(Tetrahydro-2H-pyranyl)(tetrahydro-2H-pyranyl)-
1H-pyrazolo[4,3-b]pyridinyl)-2,7-diazaspiro[4.4]nonanone (22-2): To a stirred
solution of 22-1 (1.2 g, 2.154 mmol) in THF was added Pd(OH) (3.6 g). After being stirred
at rt for 3h under hydrogen atmosphere, the mixture was filtered through a Celite pad and
washed with 30% MeOH/DCM. The organic layers were combined and concentrated under
reduced pressure to afford 22-2 (765 mg, 84%) as a colorless gummy liquid. LCMS: 425.99
[M+H] .
(S)(3-(Tetrahydro-2H-pyranyl)-1H-pyrazolo[4,3-b]pyridinyl)-
2,7-diazaspiro[4.4]nonanone (22-3): A solution of 22-2 (760 mg, 1.788 mmol) in TFA (3
mL) was stirred at rt for 1h. The TFA solvent was evaporated under reduced pressure. The
residue was triturated with diethyl ether to afford 22-3 (480 mg, 78%). LCMS: 342.09
[M+H] .
(S)(2-(4-(4-(1-Methyl-1H-1,2,4-triazolyl)phenyl)-5,6-
dihydropyridin-1(2H)-yl)oxoethyl)(3-(tetrahydro-2H-pyranyl)-1H-
pyrazolo[4,3-b]pyridinyl)-2,7-diazaspiro[4.4]nonanone (Example 22): Example 22
was prepared following General Procedure C using 22-3 and Intermediate 9. H NMR
(DMSO–d , 400 MHz) δ 12.89 (s, 1H), 8.51 (s, 1H), 8.36 (d, 1H), 8.02–7.93 (m, 3H), 7.55
(d, 2H), 6.32–6.25 (m, 1H), 4.34–4.28 (m, 1H), 4.22–4.09 (m, 1H), 4.08–3.88 (m, 7H), 3.87–
3.60 (m, 3H), 3.58–3.42 (m, 3H), 3.41–3.31 (m, 2H), 2.98–2.85 (m, 1H), 2.84–2.76 (m, 1H),
2.75–2.59 (m, 3H), 2.24–1.92 (m, 7H), 1.88–1.78 (m, 1H). LCMS: 622.49 [M+H] .
Example 23
Example 23 was prepared following General Procedures A, B2, and C
using (S)(3-(tetrahydro-2H-pyranyl)-1H-pyrazolo[4,3-b]pyridinyl)-2,7-
diazaspiro[4.4]nonanone (Step 2, Example 22) and Intermediate 15. H NMR (DMSO–d ,
400 MHz) δ 12.93 (s, 1H), 8.35 (d, 1H), 7.96 (d, 1H), 7.77 (d, 2H), 7.64 (d, 2H), 6.40–6.35
(m, 1H), 4.35–4.31 (m, 1H), 4.26–3.91 (m, 6H), 3.89–3.61 (m, 2H), 3.54–3.43 (m, 3H), 3.41
(s, 3H), 3.39–3.34 (m, 2H), 2.94–2.78 (m, 2H), 2.75–2.55 (m, 3H), 2.22–1.90 (m, 7H), 1.89–
1.78 (m, 1H); LCMS: 639.45 [M+H] .
Example 24
Example 24 was prepared following General Procedures A, B1, C and D
using Intermediate 4, 2-methyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolan
yl)benzo[d]oxazole, and Intermediate 9. H NMR (400 MHz, DMSO-d ) δ 8.77 (br, 1H),
8.52-8.45 (m, 3H), 8.13-8.10 (m, 1H), 7.99-7.97 (m, 2H), 7.78-7.75 (m, 1H), 7.57-7.55 (m,
2H), 6.29 (br, 1H), 4.32 (br, 1H), 4.20 -411 (m, 3H), 3.93 (s, 3H), 3.87-3.80 (m, 1H), 3.75-
3.63 (m, 2H), 3.52-3.34 (m, 3H), 2.96-2.84 (m, 3H), 2.78-2.69 (m, 1H), 2.65 (s, 3H), 2.60-
2.55 (m, 1H), 2.32-2.15 (m, 3H), 1.92-1.82 (m, 1H); LCMS: 669.20 [M+H] .
Example 25
Example 25 was prepared following General Procedures A, B2, and C
using Intermediate 4, 2-isopropoxy(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)pyridine,
and Intermediate 13. H NMR (400 MHz, DMSO-d6) δ 13.4 (s, 1H), 9.25 (d, 1H), 8.58 (s,
1H), 8.56 (s, 1H), 8.47 (d, 1H), 8.19 (s, 1H), 8.09 (d, 1H), 6.88 (d, 1H), 6.71 (s, 1H), 5.32 (t,
1H), 4.37-4.11 (m, 4H), 3.91 (s, 3H), 3.81-3.68 (m, 2H), 3.49-3.31 (m, 2H), 2.90-2.82 (m,
2H), 2.74 - 2.69 (m, 2H), 2.59-2.49 (m, 2H), 2.25-2.17 (m, 3H), 1.90 -1.82 (m, 1H), 1.33 (d,
6H); LCMS: 680.13 [M+H] .
Example 26
Example 26 was prepared following General Procedures A, B2, and C
using Intermediate 4, 2-(3,6-dihydro-2H-pyranyl)-4,4,5,5-tetramethyl-1,3,2-
dioxaborolane, and Intermediate 9. H NMR (DMSO–d , 400 MHz) δ 13.15 (s, 1H), 8.51 (s,
1H), 8.41 (d, 1H), 8.02 (d, 1H), 7.96 (d, 2H), 7.55 (d, 2H), 7.36–7.31 (m, 1H), 6.30–6.25 (m,
1H), 4.58–4.69 (m, 3H), 4.42–3.97 (m, 4H), 3.92 (s, 3H), 3.86 (t, 2H), 3.82–3.60 (m, 2H),
3.55–3.36 (m, 2H), 2.98 – 2.76 (m, 2H), 2.75–2.55 (m, 5H), 2.25–2.03 (m, 3H), 1.89–1.67
(m, 1H); LCMS: 620.44 [M+H] .
Example 27
Example 27 was prepared following General Procedures A, B2, and C
using Intermediate 4, 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)benzonitrile, and
Intermediate 9. H NMR (400 MHz, DMSO-d ) δ 13.75 (s, 1H), 8.65 (d, 2H), 8.52 (d, 2H),
8.15 (d, 1H), 7.98-7.95 (m, 4H), 7.55 (d, 2H), 6.29 (s, 1H), 4.31-4.11 (m, 4H), 3.92 (s, 3H),
3.80-3.73 (m, 2H), 3.50-3.35 (m, 2H), 2.95 - 2.83 (m, 3H), 2.74 - 2.49 (m, 3H), 2.26-2.18 (m,
3H), 1.89 -1.84 (m, 1H); LCMS: 639.41 [M+H] .
Example 28
(R)-Benzyl 7-(3-(5-fluoropyridinyl)trityl-1H-indazolyl)oxo-
2,7-diazaspiro [4.4] nonanecarboxylate (28-1): To a stirred solution of 2-bromo
fluoropyridine (0.5 g, 2.840 mmol) in DME (10 mL) was added hexamethylditin (0.9, 2.839
mmol). The mixture was degassed for 10 min, followed by the addition of Pd(Ph P) (0.16 g,
0.138 mmol), and degassed again for another 10 min. The reaction mixture was sealed,
heated to 80°C for 16h, and cooled to rt. To the mixture were added Intermediate 2 (0.53 g,
0.709 mmol), CuI (0.05 g, 0.284 mmol) and CsF (0.86 g, 5.661 mmol). The was degassed for
min, followed by the addition of Pd(Ph P) (0.16 g, 0.138 mmol), and degassed again for
another 10 min. The mixture was then sealed and heated at 80°C for 5h. Upon completion,
the mixture was cooled to room temperature, diluted with cold water, and extracted with
EtOAc. The combined organic layers were washed with water and brine, dried over Na SO
and concentrated. The crude compound was purified by column chromatography using 50%
EtOAc/Hexanes to afford 28-1 (0.26 g, 52%) as an off white solid. LCMS: 728.08 [M+H] .
(S)(3-(5-Fluoropyridinyl)-1H-indazolyl)-2, 7-diazaspiro [4.4]
nonanone (28-2): A solution of 28-1 (0.26 g, 0.357 mmol) in TFA (8.6 mL) was stirred
at rt for 16h. Upon completion, the mixture was concentrated followed by trituration with
diethyl ether to afford 28-1 (0.075 g, 60%) as an off white solid. LCMS: 352.00 [M+H] .
Step 3: (S)(3-(5-Fluoropyridinyl)-1H-indazolyl)(2-(4-(4-(1-
methyl-1H-1,2,4-triazolyl)phenyl)-5,6-dihydropyridin-1(2H)-yl)oxoethyl)-2,7-
diazaspiro[4.4]nonanone (Example 28): Example 28 was prepared following General
Procedure C using 28-2 and Intermediate 9. H NMR (DMSO–d , 400 MHz) δ 13.41 (s, 1H),
8.72–8.67 (m, 1H), 8.58–8.54 (m, 1H), 8.50 (s, 1H), 8.21 (q, 1H), 7.95 (d, 2H), 7.87–7.78 (m,
2H), 7.62–7.51 (m, 3H), 6.31–6.25 (m, 1H), 4.35–4.27 (m, 1H), 4.18–4.08 (m, 1H), 3.91 (s,
3H), 3.89–3.64 (m, 4H), 3.50–3.30 (m, 3H), 2.99–2.80 (m, 2H), 2.72–2.53 (m, 3H), 2.27–
2.08 (m, 3H), 1.87–1.77 (m, 1H); LCMS: 632.16 [M+H] .
Example 29
Example 29 was prepared following procedures described for Example 28
using Intermediate 2, 6-bromonicotinonitrile, and Intermediate 9. H NMR (400 MHz,
DMSO-d ) δ 13.78 (s, 1H), 9.12 (s, 1H), 8.61 (s, 1H), 8.50 (s, 1H), 8.36–8.30 (m, 2H), 8.00–
7.94 (m, 2H), 7.87–7.84 (m,1H), 7.65 (d, 1H), 7.57–7.52 (m, 2H), 6.28 (s, 1H), 4.35–4.05
(m, 2H), 3.91 (s, 3H), 3.89–3.60 (m, 4H), 3.50–3.35 (m, 2H), 3.00–2.80 (m, 3H), 2.72–2.60
(m, 3H), 2.80–2.60 (m, 3H), 1.89–1.80 (m, 1H); LCMS: 639.14 [M+H] .
Example 30
Example 30 was prepared following procedures described for Example 28
using Intermediate 4, 5-bromomethylthiazole, and Intermediate 9. H NMR (400 MHz,
DMSO-d ) δ 13.49 (s, 1H), 8.53–8.48 (m, 3H), 8.11 (d, 1H), 7.97 (d, 2H), 7.55 (d, 2H), 6.28
(s, 1H), 4.35–4.09 (m, 4H), 3.92 (s, 3H), 3.85–3.65 (m, 2H), 3.10–2.80 (m, 4H), 2.72 (s, 3H),
2.70–2.60 (m, 1H), 2.50–2.40 (m, 2H), 2.30–2.10 (m, 4H), 1.95–1.85 (m, 1H); LCMS:
633.13 [M+H] .
Example 31
Example 31 was prepared following General Procedures A, B2, and C
using Intermediate 3, 1-isopropyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1H-
pyrazole, and Intermediate 15. Data for 1.0 HCl salt: H NMR (DMSO–d , 400 MHz) δ
13.00 (br, 1H), 10.40 (d, 1H), 8.31 (s, 1H), 8.02-7.95 (m, 2H), 7.81-7.78 (m, 3H), 7.68-7.63
(m, 2H), 7.58-7.55 (m, 1H), 6.40 (br, 1H), 4.64–4.58 (m, 3H), 4.22 (br, 1H), 4.15 (br, 1H),
4.01–3.93 (m, 3H), 3.77 (br, 2H), 3.61-3.60 (m, 1H), 3.45–3.38 (m, 2H), 3.40 (s, 3H), 2.73
(br, 1H), 2.56-2.54 (m, 1H), 2.42-2.38 (m, 3H), 2.20-2.18 (m, 1H), 1.50 (d, 6H); LCMS:
662.30 [M+H] .
Example 32
Example 32 was prepared following General Procedures A, B2, and C
Intermediate 3, 2-(3,6-dihydro-2H-pyranyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, and
Intermediate 15. Data for 1.0 HCl salt: H NMR (DMSO–d , 400 MHz) δ 13.08 (s, 1H),
.40 (d, 2H), 8.12 (s, 1H), 7.80-7.78 (m, 2H), 7.74-7.63 (m, 3H), 7.58-7.55 (m, 1H), 6.54
(br, 1H), 6.41 (br, 1H), 4.63 – 4.51 (m, 3H), 4.33 (m, 2H), 4.22 (br, 2H), 4.14 (m, 2H), 4.00-
3.86 (m, 4H), 3.76 (br, 2H), 3.59 (br, 1H), 3.42 (s, 3H), 2.66 (m, 2H), 2.56 (br, 1H), 2.42-
2.26 (m, 3H), 2.17 (br, 1H); LCMS: 636.30 [M+H] .
Example 33
Example 33 was prepared following General Procedures A, B2, and C
using Intermediate 3, (2-methylthiazolyl)boronic acid, and (Intermediate 15. LCMS:
651.30 [M+H] .
Example 34
Example 34 was prepared following General Procedures A, B2, and C
using Intermediate 4, 2-(3,6-dihydro-2H-pyranyl)-4,4,5,5-tetramethyl-1,3,2-
dioxaborolane, and Intermediate 13. H NMR (DMSO–d , 400 MHz) δ 12.91 (s, 1H), 8.56 (s,
1H), 8.35 (d, 1H), 8.19 (s, 1H), 7.96 (d, 1H), 6.74–6.68 (m, 1H), 4.40–4.36 (m, 1H), 4.24–
4.09 (m, 2H), 4.05–3.89 (m, 7H), 3.87–3.60 (m, 3H), 3.55–3.46 (m, 2H), 3.43–3.38 (m, 1H),
3.29–3.24 (m, 1H), 2.93–2.86 (m, 1H), 2.84–2.78 (m, 1H), 2.75–2.65 (m, 2H), 2.63–2.54 (m,
1H), 2.22–1.92 (m, 7H), 1.87–1.80 (m, 1H). ); LCMS: 629.04 [M+H] ;
Example 35
Example 35 was prepared following General Procedures A, B2, and C
using Intermediate 4, 2-methyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)pyridine, and
Intermediate 15. H NMR (DMSO–d6, 400 MHz) δ 13.50 (s, 1H), 9.50 (s, 1H), 8.59 (d, 1H ),
8.49 (d, 1H), 8.11 (d, 1H), 7.77 (d, 2H), 7.64 (d, 2H), 7.39 (d, 1H), 6.40 (s, 1H), 4.33–4.06
(m, 4H), 3.82–3.67 (m, 2H), 3.51–3.35 (m, 5H), 2.93–2.70 (m, 4H), 267–2.49 (m, 5H), 2.32–
2.13 (m, 3H), 1.88–1.83 (m, 1H). LCMS: 646.4[M+H] .
Example 36
Example 36 was prepared following General Procedures A, B2, and C
using Intermediate 4, 2-methoxy(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)pyridine,
and Intermediate 13. H NMR (DMSO–d , 400 MHz) δ 13.42 (s, 1H), 9.29 (s, 1H), 8.61–
8.56 (m, 2H), 8.47 (d, 1H), 8.19 (s, 1H), 8.09 (d, 1H), 6.97 (d, 1H), 6.73–6.69 (m, 1H), 4.41–
4.36 (m, 1H), 4.25–4.06 (m, 3H), 3.92 (s, 3H), 3.91 (s, 3H), 3.86–3.62 (m, 2H), 3.53–3.37
(m, 2H), 2.98–2.81 (m, 2H), 2.78–2.68 (m, 2H), 2.62–2.57 (m, 2H), 2.28–2.12 (m, 3H),
1.89–1.81 (m, 1H); LCMS: 652.11 [M+H] .
Example 37
Example 37 was prepared following General Procedures A, B1, C and D
using Intermediate 4, 1-methyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1H-pyrazole,
Intermediate 9. H NMR (DMSO–d6, 300 MHz) δ 13.11 (s, 1H), 8.51 (s, 1H), 8.43 (d, 1H),
8.38 (s, 1H), 8.10 (s, 1H), 8.03–7.95 (m, 3H), 7.55 (d, 2H), 6.28 (s, 1H), 4.30 (s, 1H), 4.14 (s,
3H), 3.93 (d, 6H), 3.89–3.64 (m, 2H), 3.50 – 3.39 (m, 2H), 2.99–2.80 (m, 3H), 2.78–2.53
(m, 3H), 2.27–2.17 (m, 3H), 1.87–1.79 (m, 1H). LCMS: 618.1 [M+H] .
Example 38
Example 38 was prepared following General Procedures A, B2, and C
using Intermediate 4, 2-methyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)pyridine and
Intermediate 9. H NMR (DMSO–d , 400 MHz) δ 13.80 (s, 1H), 8.57–8.49 (m, 3H), 8.26–
8.20 (m, 2H), 8.14 (d, 1H), 7.97 (d, 2H), 7.55 (d, 2H), 6.28 (br s, 1H), 4.31(s, 1H), 4.20–4.09
(m, 3H), 3.92 (s, 3H), 3.81–3.64 (m, 2H), 3.51–3.37 (m, 2H), 2.94–2.83 (m, 2H), 2.75–2.60
(m, 3H), 2.57–2.54 (m, 4H), 2.29–2.10 (m, 3H), 1.90–1.83 (m, 1H); LCMS: 629.21 [M+H] .
Example 39
Example 39 was prepared following General Procedures A, B2, and C
using Intermediate 4, 1-methyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1H-pyrazole,
and Intermediate 9. H NMR (400 MHz, DMSO-d ) δ 13.25 (s, 1H), 8.51 (s, 1H), 8.43 (d,
1H), 8.04 (d, 1H), 7.97 (d, 2H), 7.79 (s, 1H), 7.55 (d, 2H), 7.11 (s, 1H), 6.28 (s, 1H), 4.32-
4.06 (m, 4H), 3.92 (d, 6H), 3.83-3.64 (m, 2H), 3.50-3.36 (m, 2H), 2.94-2.58 (m, 6H), 2.24-
2.11 (m, 3H), 1.90-1.83 (m, 1H): LCMS: 618.15 [M+H] .
Example 40
Example 40 was prepared following General Procedures A, B1, C, D and
E using Intermediate 4, 1-isopropyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1H-
pyrazole, and Intermediate 9. Data for 1.0 HCl salt: H NMR (DMSO–d , 400 MHz) δ N-H
proton not observed, 10.50 (d, 1H), 8.57 (s, 1H), 8.45–8.42 (m, 2H), 8.19–8.18 (m, 1H),
8.10-8.08 (m, 1H), 8.00–7.98 (m, 2H), 7.58-7.55 (m, 2H), 6.32 (br, 1H), 4.65–4.57 (m, 3H),
4.31-4.14 (m, 4H), 3.93 (m, 3H), 3.83-3.77 (br, 2H), 3.62-3.61 (m, 1H), 3.41–3.36 (m, 3H),
2.67 (br, 1H), 2.56-2.54 (m, 1H), 2.43-2.33 (m, 3H), 2.23-2.21 (m, 1H), 1.50 (d, 6H); LCMS:
646.30 [M+H] .
Example 41
Example 41 was prepared following General Procedures A, B1, C and D
using Intermediate 4, 1-isopropyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1H-
pyrazole, and Intermediate 10. H NMR (DMSO–d , 400 MHz) δ 13.08 (s, 1H), 8.45–8.41
(m, 3H), 8.15 (s, 1H), 8.02 (d, 1H), 7.85 (s, 2H), 7.04 (d, 2H), 4.64–4.59 (m, 1H), 4.16-4.11
(m, 2H), 3.89 (s, 3H), 3.74-3.58 (m, 4H), 3.44–3.33 (m, 3H), 3.22-3.17 (m, 3H), 2.92-2.90
(m, 1H), 2.78 (dd, 2H), 2.56-2.55 (m, 1H), 2.26-2.13 (m, 3H), 1.87 1.84 (m, 1H), 1.49 (d,
6H); LCMS: 649.30 [M+H] .
Example 42
Step 1: (5R)-Benzyl 7-(3-(2-oxaazaspiro[3.5]nonanyl)
(tetrahydro-2H-pyranyl)-1H-pyrazolo[4,3-b]pyridinyl)oxo-2,7-
diazaspiro[4.4]nonanecarboxylate (42-1): To a stirred solution of Intermediate 4 (400
mg, 0.722 mmol) in DMSO (8 mL) were added K CO (299 mg, 2.166 mmol), 2-oxa
azaspiro[3.5]nonane (110 mg, 0.866 mmol) and L-proline (25 mg, 0.216 mmol). The mixture
was degassed for 10 min, followed by the addition of CuI (13 mg, 0.072 mmol), and
degassed again for another 10 min. The mixture was warmed up and stirred at 80°C for 36h.
Upon completion, the mixture was cooled to 0 C, diluted with water, and extracted with
EtOAc. The combined organic layers were dried over Na SO and concentrated under
reduced pressure to afford 42-1 (140 mg, 89%) as a colorless thick liquid. MS (ESI) m/z
601.07 [M+H] .
Step 2: (S)(3-(2-oxaazaspiro[3.5]nonanyl)-1H-pyrazolo[4,3-
b]pyridinyl)(2-(4-(4-(1-methyl-1H-1,2,4-triazolyl)phenyl)-3,6-dihydropyridin-
1(2H)-yl)oxoethyl)-2,7-diazaspiro[4.4]nonanone (Example 42): Example 42 was
prepared following General Procedures B2, and C using 42-1 and Intermediate 9. H NMR
(300 MHz, DMSO-d ) δ 14.10 (s, 1H), 8.60–8.53 (m, 1H), 8.49 (s, 1H), 8.27 (d, 1H), 7.14 (s,
2H), 6.97 (s, 2H), 6.29 (s, 1H), 4.65–4.50 (m, 2H), 4.51–4.38 (m, 2H), 4.30–4.15 (m, 4H),
4.15–4.00 (m, 4H), 3.89 (s, 3H), 3.80–3.60 (m, 4H), 3.62–3.50 (m, 5H), 2.70–2.60 (m, 1H),
2.58–2.50 (m, 2H), 2.39–2.23 (m, 3H), 2.20–2.10 (m, 1H), 2.00–1.88 (m, 2H); LCMS:
663.16 [M+H] .
Example 43
Example 43 was prepared following General Procedures A, B2, and C
using Intermediate 4, 2-methyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)pyridine, and
Intermediate 13. H NMR (DMSO–d , 400 MHz) δ 13.50 (s, 1H), 9.51 (s, 1H), 8.59 (d, 1H),
8.57 (s, 1H), 8.49 (d, 1H), 8.20 (s, 1H), 8.12 (d, 1H), 7.39 (d, 1H), 6.71 (s, 1H), 4.35–4.12
(m, 5H), 3.9 (s, 3H), 3.77–3.71 (m, 3H), 2.93–2.70 (m, 3H), 2.73–2.60 (m, 3H), 2.53 (s, 3H),
2.32–2.18 (m, 3H), 1.90–1.80 (m, 1H); LCMS: 636.4 [M+H] .
Example 44
Example 44 was prepared following General Procedures A, B2, and C
using Intermediate 4, 2-methyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)pyridine
Intermediate 12. H NMR (DMSO–d6, 400 MHz) δ 13.70 (s, 1H), 8.72 (d, 1H), 8.67 – 8.45
(m, 3H), 8.25–8.20 (m, 2H), 8.15 (d, 1H), 8.07 (dd, 1H), 6.95 (d, 1H), 4.16–4.13 (m, 2H),
3.89 (s, 3H), 3.77–3.51 (m, 8H), 3.47–3.35 (m, 2H), 2.97–2.84 (m, 2H), 2.74–2.66 (m, 1H),
2.54–2.58 (m, 4H), 2.38–2.24 (m, 1H), 2.19–2.15 (m, 2H), 2.0–1.80 (m, 1H); LCMS: 633.3
[M+H] .
Example 45
Example 45 was prepared following General Procedures A, B2, and C
using Intermediate 4, 2-(4-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, and
Intermediate 12. H NMR (400 MHz, DMSO-d ) δ 13.61 (s, 1H), 8.72 (d, 1H), 8.52–8.46 (m,
4H), 8.11–8.05 (m, 2H), 7.34 (t, 2H), 6.95 (d, 1H), 4.14 – 4.11 (m, 2H), 3.89 (s, 3H), 3.69–
3.53 (m, 8H), 3.43–3.37 (m, 2H), 2.94–2.92 (m, 1H), 2.85 (d, 1H), 2.71 (d, 1H), 2.56–2.54
(m, 1H), 2.27–2.13 (m, 3H), 1.87–1.84 (m, 1H); LCMS: 636.16 [M+H] .
Example 46
Example 46 was prepared following General Procedures A, B2, and C
using Intermediate 4, 2-methoxy(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)pyridine,
and Intermediate 12. H NMR (DMSO–d6, 400 MHz) δ 13.50 (s, 1H), 9.29 (d, 1H), 8.72 (d,
1H), 8.61 (dd, 1H), 8.49 (s, 1H), 8.46 (d, 1H), 8.13–8.04 (m, 2H), 6.96 (t, 2H), 4.13–4.10 (m,
2H), 3.91 (s, 3H), 3.89 (s, 3H), 3.68–3.52 (m, 8H), 3.42–3.36 (m, 2H), 2.92–2.82 (m, 2H),
2.71–2.60 (m, 1H), 2.55–2.54 (m, 1H), 2.31–2.10 (m, 3H), 1.90–1.84 (m, 1H); LCMS:
649.16 [M+H] .
Example 47
Example 47 was prepared following General Procedures A, B2, and C
using Intermediate 4, 2-(4-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, and
Intermediate 13. H NMR (400MHz, DMSO-d ) δ 13.4 (s, 1H), 8.57 (s, 1H), 8.52–8.46 (m,
3H), 8.20 (s, 1H), 8.09 (d, 1H), 7.36–7.31 (m, 2H), 6.71 (s, 1H), 4.38–4.08 (m, 4H), 3.91 (s,
3H), 3.83–3.64 (m, 2H), 3.49–3.36 (m, 2H), 2.92–2.83 (m, 2H), 2.74–2.59 (m, 2H), 2.57–
2.54 (m, 2H), 2.26–2.15 (m, 3H), 1.87–1.82 (m, 1H); LCMS: 639.10 [M+H] .
Example 48
Example 48 was prepared as described in Example 42 using Intermediate
4, (2S,6R)-2,6-dimethylmorpholine, and Intermediate 9. H NMR (400 MHz, DMSO-d ) δ
12.19 (s, 1H), 8.51 (s, 1H), 8.35–8.29 (m, 1H), 7.98 (d, 2H), 7.90 (d, 1H), 7.56 (t, 2H), 6.31
(s, 1H), 4.65–4.50 (m, 2H), 4.35–4.18 (m, 4H), 4.10–3.94 (m, 4H), 3.91 (s, 3H), 3.82–3.74
(m, 4H), 3.65–3.55 (m, 2H), 3.52–3.45 (m, 1H), 3.40–3.30 (m, 2H), 2.57–2.46 (m, 2H),
2.32–2.15 (m, 3H), 1.16 (d, 6H); LCMS: 651.4 [M+H] .
Example 49
Example 49 was prepared as described in Example 42 using Intermediate
4, morpholine, and Intermediate 9. H NMR (400 MHz, DMSO-d ) δ 12.13 (s, 1H), 8.51 (s,
1H), 8.32 (d, 1H), 7.96 (d, 2H), 7.84 (d, 1H), 7.55 (d, 2H), 5.92 (d, 1H), 4.35–4.05 (m, 2H),
4.00–3.90 (m, 5H), 3.85–3.65 (m, 7H), 3.60–3.52 (m, 4H), 3.50–3.35 (m, 2H), 3.00–2.85 (m,
1H), 2.85–2.70 (m, 2H), 2.65–2.50 (m, 2H), 2.20–2.05 (m, 3H), 1.86–1.78 (m, 1H); LCMS:
623.16 [M+H] .
Example 50
Example 50 was prepared as described in Example 28 using Intermediate
4, 2-bromofluoropyridine and Intermediate 9. H NMR (400 MHz, DMSO-d ) δ 13.69 (s,
1H), 8.73–8.69 (m, 2H), 8.51–8.47 (m, 2H), 8.15 (br s, 1H), 7.97 (d, 2H), 7.89 (br s, 1H),
7.55 (d, 2H), 6.28 (s, 1H), 4.30–4.11 (m, 4H), 3.92 (s, 3H), 3.81–3.66 (m, 2H), 3.50–3.38
(m, 3H), 2.95–2.82 (m, 2H), 2.70–2.56 (m, 3H), 2.24–2.13 (m, 3H), 1.88–1.83 (m, 1H);
LCMS: 633.15 [M+H] .
Example 51
Example 51 was prepared as described in Example 50 using Intermediate
4, 6-bromonicotinonitrile, and Intermediate 9. H NMR (400 MHz, DMSO-d ) δ 14.00 (s,
1H), 9.11 (d, 1H), 8.83–8.80 (m, 1H), 8.54–8.50 (m, 2H), 8.43 (d, 1H), 8.19 (br s, 1H), 7.97
(d, 2H), 7.55 (d, 2H), 6.28 (s, 1H), 4.31 (s, 1H), 4.20–4.05 (m, 3H), 3.92 (s, 3H), 3.85–3.60
(m, 2H), 3.50–3.30 (m, 3H), 3.00–2.50 (s, 5H), 2.30–2.10 (m, 3H), 1.90–1.80 (m, 1H);
LCMS: 640.15 [M+H] .
Example 52
Example 52 was prepared following General Procedures A, B2, and C
using Intermediate 4, 2-((2S,6R)-2,6-dimethyl-3,6-dihydro-2H-pyranyl)-4,4,5,5-
tetramethyl-1,3,2-dioxaborolane, and Intermediate 15. LCMS: 667.30 [M+H] .
Example 53
Example 53 was prepared following General Procedures A, B2, and C
using Intermediate 4, 1-methyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1H-pyrazole,
and Intermediate 15. LCMS: 635.30 [M+H] .
Example 54
Example 54 was prepared following procedures described for Example 28
using Intermediate 3 and Intermediate 13. H NMR (400 MHz, DMSO–d ) δ 13.51 (s, 1H),
8.70 (d, 1H), 8.57–8.52 (m, 2H), 8.25–8.18 (m, 2H), 8.87–7.78 (m, 2H), 7.59 (d, 1H), 6.74–
6.70 (m, 1H), 4.45–4.35 (m, 1H), 4.21–4.16 (m, 1H), 3.92–3.61 (m, 7H), 3.49–3.35 (m, 3H),
2.95–2.88 (m, 1H), 2.86–2.82 (m, 1H), 2.74–2.69 (m, 1H), 2.68–2.57 (m, 2H), 2.27–2.08 (m,
3H), 1.87–1.77 (m, 1H); LCMS: 639.11 [M+H] .
Example 55
Example 55 was prepared following procedures described for Example 54
using Intermediate 3, 2-bromofluoropyridine, Intermediate 14. H NMR (DMSO–d , 400
MHz) δ 13.51 (s, 1H), 8.70 (d, 1H), 8.57–8.54 (m, 1H), 8.48 (s, 1H), 8.24–8.18 (m, 1H),
7.87–7.77 (m, 2H), 7.59 (d, 1H), 7.47–7.41 (m, 1H), 7.13–7.08 (m, 1H), 6.23–6.18 (m, 1H),
4.35–4.27 (m, 1H), 4.14–4.09 (m, 1H), 3.90–3.64 (m, 7H), 3.48–3.35 (m, 3H), 2.95–2.80 (m,
3H), 2.66–2.58 (m, 2H), 2.25–2.11 (m, 3H), 1.87–1.79 (m, 1H); LCMS: 638.10 [M+H] .
Example 56
Example 56 was prepared following procedures described for Example 28
using Intermediate 3, 2-bromofluoropyridine and Intermediate 10. H NMR (400 MHz,
DMSO–d ) δ 13.51 (s, 1H), 8.70 (d, 1H), 8.57–8.54 (m, 1H), 8.42 (s, 1H), 8.25–8.18 (m,
1H), 7.88–7.77 (m, 4H), 7.60 (d, 1H), 7.03 (d, 2H), 3.91–3.85 (m, 5H), 3.73–3.68 (m, 2H),
3.65–3.59 (m, 2H), 3.44–3.35 (m, 2H), 3.29–3.26 (m, 3H), 3.25–3.19 (m, 2H), 3.03–2.84
(m, 3H), 2.28–2.12 (m, 3H), 1.78–1.92 (m, 1H); LCMS: 635.15 [M+H] .
Example 57
Example 57 was prepared as described in Example 28 using Intermediate
3, 2-bromofluoropyridine and Intermediate 12. H NMR (400 MHz, DMSO–d ) δ 13.51
(s, 1H), 8.71 (m, 2H), 8.55 (d, 1H), 8.46 (s, 1H), 8.21 (q, 1H), 8.05 (dd, 1H), 7.87–7.77 (m,
2H), 7.59 (d, 1H), 6.94 (d, 1H), 3.90–3.81 (m, 5H), 3.71–3.54 (m, 8H), 3.37 (s, 2H), 2.98–
2.90 (m, 1H), 2.88–2.83 (m, 1H), 2.68–2.61 (m, 1H), 2.53–2.51 (m, 1H), 2.28–2.07 (m, 3H),
1.87–1.78 (m, 1H); LCMS: 636.16 [M+H] .
Example 58
(5R)-Benzyl 7-(3-(2-methyl-2H-1,2,3-triazolyl)(tetrahydro-2H-
pyranyl)-1H-indazolyl)oxo-2,7-diazaspiro[4.4]nonanecarboxylate (58-1): To a
solution of 4-bromomethyl-2H-1,2,3-triazole (250 mg, 1.543 mmol) in 1,4-dioxane (20
mL) were added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (780.9 mg, 3.086
mmol) and KOAc (454.8 mg, 4.630 mmol). The mixture was degassed for 10 min, followed
by addition of Pd(Ph P) (126.0 mg, 0.154 mmol), and degassed for another 10 min. The
reaction mixture was sealed, stirred at 80°C for 3h, and cooled to rt. To the mixture was
added a mixture of Intermediate 3 (426.7 mg, 0.771 mmol) and K CO (1.064 g, 7.717
mmol) in toluene/H O/ethanol (30 mL). The mixture was degassed for 10 min, followed by
addition of Pd(Ph P) (178.2 mg, 0.154 mmol), and degassed for another10 min. After being
stirred at 80°C for 16h, the mixture was cooled to rt, diluted with cold water, and extracted
with EtOAc. The combined organic layers were washed with water and brine, dried over
Na SO and concentrated. The crude compound was purified by column chromatography
using 60% EtOAc/hexanes to afford 58-1 (300 mg, 35%). LCMS: 556.1 [M+H] .
(S)(2-(4-(4-(1-methyl-1H-1,2,4-triazolyl)phenyl)-3,6-
dihydropyridin-1(2H)-yl)oxoethyl)(3-(2-methyl-2H-1,2,3-triazolyl)-1H-indazol-
-yl)-2,7-diazaspiro[4.4]nonanone (Example 58): Example 58 was prepared following
H NMR (DMSO–d , 400
General Procedures B2, and C using 58-1 and Intermediate 9. 6
MHz) δ 13.40 (s, 1H), 8.50 (s, 1H), 8.24 (br s, 1H), 8.18 (s, 1H), 7.96 (d, 2H), 7.96 (t, 1H),
7.70–7.40 (m, 3H), 6.28 (br s, 1H), 4.40–4.09 (m, 5H), 3.91 (s, 3H), 3.90–3.70 (m, 5H),
3.48–3.30 (m, 2H), 2.96–2.89 (m, 1H), 2.87–2.80 (m, 1H), 2.70–2.60 (m, 2H), 2.57–2.50 (m,
1H), 2.30–2.10 (m, 3H), 1.87–1.80 (m, 1H); LCMS: 618.15 [M+H] .
Example 59
Example 59 was prepared following General Procedures A, B2, C and D
using 2-methyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-2H-1,2,3-triazole,
Intermediate 4 and Intermediate 9. H NMR (400 MHz, DMSO–d ) δ 13.55 (s, 1H), 8.55–
8.42 (m, 3H), 8.12 (d, 1H), 7.97 (d, 2H), 7.60–7.53 (m, 2H), 6.29 (br s, 1H), 4.30– 4.10 (m,
7H), 3.92 (s, 3H), 3.80–3.70 (m, 3H), 3.20–2.7 (m, 4H), 2.60–2.64 (m, 1H), 2.55–2.40 (m,
2H), 2.32–2.22 (m, 3H), 2.10–1.19 (m, 1H); LCMS: 619.16 [M+H] .
Example 60
Example 60 was prepared following procedures described for Example 56
using Intermediate 3, 2-bromomethoxy pyridine and Intermediate 9. H NMR (400 MHz,
DMSO–d ) δ 13.21 (s, 1H), 8.57 (s, 1H), 8.50 (s, 1H), 8.43 (s, 1H), 8.10 (d, 1H), 7.96 (d,
2H), 7.77 (t, 1H), 7.60–7.45 (m, 4H), 6.28 (br s, 1H), 4.40–4.10 (m, 2H), 3.95–3.64 (m,
10H), 3.50–3.30 (m, 2H), 2.95–2.82 (m, 2H), 2.70–2.61 (m, 2H), 2.56–2.40 (m, 2H), 2.25–
2.10 (m, 3H), 1.90–1.80 (m, 1H); LCMS: 644.15 [M+H] .
Example 61
Example 61 was prepared following General Procedures A, B2, and C
using Intermediate 3, 6-methoxypyridinylboronic acid, and Intermediate 9. H NMR (400
MHz, DMSO-d ) δ 13.38 (s, 1H), 8.82 (s, 1H), 8.51 (s, 1H), 7.96 (d, 2H), 7.94–7.85 (m, 1H),
7.82–7.75 (m, 2H), 7.62–7.52 (m, 3H), 6.78 (d, 1H), 6.29 (s, 1H), 4.30–4.12 (m, 2H), 4.08 (s,
3H), 3.94–3.83 (m, 5H), 3.80–3.60 (m, 4H), 3.15–2.80 (m, 4H), 2.70–2.60 (m, 2H), 2.30–
2.10 (m, 3H), 2.00–1.80 (m, 1H); LCMS: 644.49 [M+H] .
Example 62
Example 62 was prepared following General Procedures A, B1, C and D
using Intermediate 4, 2-(2,2-dimethylbenzo[d][1,3]dioxolyl)-4,4,5,5-tetramethyl-1,3,2-
dioxaborolane, and Intermediate 9. H NMR (400 MHz, DMSO-d ) δ 13.23 (s, 1H), 8.50 (s,
1H), 8.45 (d, 1H), 8.05 (d, 1H), 8.00–7.96 (m, 3H), 7.90 (s, 1H), 7.55 (d, 2H), 6.95 (d, 1H),
6.28 (s, 1H), 4.31–4.10 (m, 4H), 3.92 (s, 3H), 3.85–3.69 (m, 2H), 3.50–3.37 (m, 3H), 2.91–
2.82 (m, 2H), 2.76–2.57 (m, 3H), 2.24–1.85 (m, 4H), 1.60 (s, 6H); LCMS: 686.50 [M+H] .
Example 63
Example 63 was prepared following General Procedures A, B2, and C
using Intermediate 4, 2-(4-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, and
Intermediate 9. H NMR (DMSO–d , 300 MHz) δ 13.31 (s, 1H), 8.52–8.38 (m, 4H), 8.06 (d,
1H), 7.97 (d, 2H), 7.55 (d, 2H), 7.07 (d, 2H), 6.28 (br s, 1H), 4.31 (br s, 1H), 4.15 – 4.12 (m,
3H), 3.92 (s, 3H), 3.81 (s, 3H), 3.73-3.71 (m, 2H), 3.50–3.37 (m, 2H), 2.90–2.70 (m, 4H),
2.63–2.50 (m, 2H), 2.30–2.12 (m, 3H), 1.89–1.80 (m, 1H); LCMS: 644.15 [M+H] .
Example 64
Example 64 was prepared following General Procedures A, B2, and C
using Intermediate 4, 2-(3,6-dihydro-2H-pyranyl)-4,4,5,5-tetramethyl-1,3,2-
dioxaborolane, and Intermediate 14. H NMR (DMSO–d , 400 MHz) δ 12.89 (s, 1H), 8.49
(s, 1H), 8.35 (d, 1H), 7.96 (d, 1H), 7.45 (d, 1H), 7.11 (d, 1H), 6.19 (br s, 1H), 4.30–4.28 (m,
1H), 4.15–3.87 (m, 9H), 3.80–3.63 (m, 2H), 3.55–3.44 (m, 3H), 3.38–3.30 (m, 1H), 2.89–
2.85 (m, 1H), 2.81–2.77 (m, 1H), 2.73–2.66 (m, 1H), 2.61–2.54(m, 2H), 2.20–1.94 (m, 8H),
1.85–1.81 (m, 1H); LCMS: 628.46 [M+H] .
Example 65
Example 65 was prepared following General Procedures A, B2, and C
using Intermediate 4, 2-isopropoxy(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)pyridine,
and Intermediate 14. H NMR (DMSO–d , 400 MHz) δ 13.42 (s, 1H), 9.26 (d, 1H), 8.57 (dd,
1H), 8.50–8.44 (m, 2H), 8.09 (d, 1H), 7.46 (d, 1H), 7.11 (d, 1H), 6.88 (d, 1H), 6.22–6.18 (m,
1H), 5.36–5.29 (m, 1H), 4.31–4.28 (m, 1H), 4.19–4.04 (m, 3H), 3.86 (s, 3H), 3.85–3.62 (m,
2H), 3.52–3.43 (m, 1H), 3.39–3.34 (m, 1H), 2.94–2.79 (m, 2H), 2.76–2.65 (m, 1H), 2.64–
2.55 (m, 3H), 2.27–2.09 (m, 3H), 1.91–1.80 (m, 1H), 132 (d,6H); LCMS: 679.12 [M+H] .
Example 66
Example 66 was prepared following General Procedures A, B2, and C
using Intermediate 4, 2-methoxy(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)pyridine,
and Intermediate 14. H NMR (DMSO–d , 400 MHz) δ 13.43 (s, 1H), 9.29 (s, 1H), 8.60 (dd,
1H), 8.51–8.44 (m, 2H), 8.10 (d, 1H), 7.46 (d, 1H), 7.11 (d, 1H), 6.97 (d, 1H), 6.23–6.18 (m,
1H), 4.31–4.27 (m, 1H), 4.19–4.02 (m, 3H), 3.92 (s, 3H), 3.88 (s, 3H), 3.84–3.62 (m, 2H),
3.51–3.44 (m, 1H), 3.41–3.35 (m, 1H), 2.96–2.79 (m, 2H), 2.77–2.54 (m, 4H), 2.28–2.10 (m,
3H), 1.91–1.80 (m, 1H); LCMS: 651.45 [M+H] .
Example 67
Example 67 was prepared following General Procedures A, B2, and C
using Intermediate 4), 2-cyclopropoxy(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)
pyridine, and Intermediate 9. H NMR (400 MHz, DMSO-d ) δ 13.38 (s, 1H), 9.29 (d, 1H),
8.65–8.60 (m, 1H), 8.50 (s, 1H), 8.47 (s, 1H), 8.10 (d, 1H), 7.97 (d, 2H), 7.55 (d, 2H), 7.00
(d, 1H), 6.28 (s, 1H), 4.32–4.25 (m, 2H), 4.20–4.05 (m, 3H), 3.91 (s, 3H), 3.82–3.65 (m, 2H),
3.52–3.35 (m, 2H), 2.95–2.55 (m, 6H), 2.30 – 2.10 (m, 3H), 1.90–1.80 (m, 1H), 0.83–0.76
(m, 2H), 0.75–0.68 (m, 2H); LCMS: 671.51 [M+H] .
Example 68
Example 68 was prepared following General Procedures A, B1, C and D
using Intermediate 4, 2-(4-chlorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, and
Intermediate 9. H NMR (DMSO–d , 400 MHz) δ 13.51 (s, 1H), 8.52-8.48 (m, 4H), 8.12 (d,
1H), 7.78 (d, 2H), 7.58-7.55 (m, 4H), 6.29 (br, 1H), 4.31 (m, 1H), 4.15-4.07 (m, 3H), 3.92
(m, 3H), 3.83–3.65 (m, 2H), 3.49-3.37 (m, 2H), 3.32-3.27 (m, 1H), 2.92–2.84 (m, 2H), 2.78
(m, 1H), 2.66-2.62 (m, 2H), 2.33-2.12 (m, 3H), 1.91-1.85 (br, 1H); LCMS: 648.10 [M+H] .
Example 69
Example 69 was prepared following General Procedures A, B1, C and D
using Intermediate 4, 2-(4-chlorofluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane,
and Intermediate 9. H NMR (DMSO–d , 400 MHz) δ 13.64 (s, 1H), 8.52-8.39 (m, 4H), 8.15
(d, 1H), 7.97 (d, 2H), 7.61-7.55 (m, 3H), 6.29 (br, 1H), 4.30 (m, 1H), 4.15-4.07 (m, 3H), 3.92
(m, 3H), 3.83–3.65 (m, 2H), 3.49-3.37 (m, 2H), 3.32-3.27 (m, 1H), 2.92–2.84 (m, 2H), 2.78
(m, 1H), 2.66-2.62 (m, 2H), 2.23-2.09 (m, 3H), 1.88-1.83 (br, 1H); LCMS: 666.10 [M+H] .
Example 70
Example 70 was prepared following General Procedure B1 and E using
Example 21. Data for 1.0 acetate salt: H NMR (DMSO–d , 400 MHz) δ 9.30 (br, 1H), 8.50
(br, 1H), 8.52-8.42 (m, 2H), 8.14 (d, 1H), 7.94 (d, 2H), 7.36 (d, 2H), 6.91- 6.88 (m, 1H),
4.54-4.51 (m, 2H), 4.22-4.13 (m, 3H), 3.92 (m, 6H), 3.54-3.43 (m, 2H), 3.29-3.08 (m, 4H),
2.93–2.64 (m, 6H), 2.28-2.21 (m, 3H), 1.86 (s, 3H), 1.23 (br, 2H); LCMS: 647.20 [M+H] .
Example 71
Example 71 was prepared following General Procedure B1 using (S)(3-
(6-isopropoxypyridinyl)-1H-pyrazolo[4,3-b]pyridinyl)(2-(4-(4-(1-methyl-1H-1,2,4-
triazolyl)phenyl)-3,6-dihydropyridin-1(2H)-yl)oxoethyl)-2,7-diazaspiro[4.4]nonan
one. Data for 1.0 acetate salt: H NMR (DMSO–d , 400 MHz) δ 9.27 (br, 1H), 8.59 (br, 1H),
8.52-8.42 (m, 2H), 8.12 (d, 1H), 7.93 (d, 2H), 7.35 (d, 2H), 6.91-6.88 (m, 1H), 5.34–5.30 (m,
1H), 4.54-4.51 (m, 1H), 4.22-4.13 (m, 3H), 3.92 (m, 4H), 3.54 -3.43 (m, 2H), 3.29-3.08 (m,
4H), 2.93–2.64 (m, 6H), 2.28-2.21 (m, 3H), 1.86 (s, 3H), 1.33 (d, 6H), 1.23 (br, 2H); LCMS:
675.20 [M+H]
Example 72
Methyl 3-(chlorocarbonyl)bicyclo[1.1.1]pentanecarboxylate (72-1):
To a stirred solution of 3-(methoxycarbonyl)bicyclo[1.1.1]pentanecarboxylic acid (1.5 g,
8.823 mmol) in DCM (20 mL) was added oxalyl chloride (1.19 mL, 13.235 mmol) and a
drop of DMF at 0 C and continued stirring at rt for 3h. The mixture was evaporated to
dryness to afford 72-1 (1.6 g crude, 100%) as a gummy liquid which was used for the next
step directly.
Methyl 3-(2-fluorobenzoyl)bicyclo[1.1.1]pentanecarboxylate (72-2):
To a stirred solution of fluorobenzene (200 mg, 2.220 mmol) in THF (10 mL) was added sec-
Buli (1.6 mL, 2.260 mmol, 1.4 M in cyclohexane) drop wise at -78 C and the mixture was
further stirred at same temperature for 30 min. To this mixture was then ZnCl (2.2 mL,
2.220 mmol, 1M in THF) was added and continued stirring at same temperature for 15 min.
To the resulting mixture, CuCl (21 mg, 0.220 mmol) was added followed by 72-1 (200 mg,
1.063 mmol) in THF (10 mL) at -60 C slowly. The mixture was allowed to warm to rt and
stirred at rt for 16h. The reaction was quenched with 1N HCl, extracted with EtOAc (3 x 100
mL). The combined organic layers were washed with brine, dried Na SO and concentrated.
The crude compound was purified by column chromatography using 20% EtOAc/hexane to
afford 72-2 (65 mg, 25%) as an oil. LCMS: 248.98 [M+H] .
3-(2-Fluorobenzoyl)bicyclo[1.1.1]pentanecarboxylic acid (72-3): To
a solution of 72-2 (50 mg, 0.201 mmol) in THF: MeOH (1:1, 6 mL) was added LiOH (42
mg, 1.008 mmol) at 0°C and stirred at rt for 5h. After completion of the reaction, the mixture
was quenched with KHSO and extracted with EtOAc. The combined organic layers were
washed with water, brine, dried Na SO and concentrated to afford 72-3 (33 mg, 70%) as an
off white solid. LCMS: 234.86 [M+H] .
3-(2-Fluorobenzoyl)bicyclo[1.1.1]pentanecarbonyl chloride (72-4):
To a stirred solution of 72-3 (200 mg, 0.858 mmol) in DCM (10 mL) was added oxalyl
chloride (0.1 mL, 1.287 mmol) and a drop of DMF at 0 C. Resulting mixture was stirred at rt
for 3h. After completion of the reaction, the mixture was concentrated under nitrogen
atmosphere to afford 72-4 (200 mg, 100%) as a gummy solid. This material was used for the
next step directly.
Bicyclo[1.1.1]pentanyl(2-fluorophenyl)methanone (72-5): To a
stirred solution of sodium 2-thioxopyridin-1(2H)-olate (50 mg, 0.33 mmol) in CHCl (5 mL)
was added DMAP (4 mg, 0.033 mmol) at rt and then heated at 60 C for 30 min. To this
mixture was then added 72-4 (77 mg, 0.305 mmol) in THF (5 mL) drop wise at 60°C. The
mixture was then irradiated under U.V light at 60 C for 16h. 1N HCl (50 mL) was added to
the mixture and extracted with DCM. The combined organic layers were washed with brine,
dried over Na SO and concentrated. The crude was purified by column chromatography
eluted with 10% EtOAc/petroleum ether to afford 72-5 (9 mg, 25%) as an off white solid.
LCMS: 190.87 [M+H] .
3-(Bicyclo[1.1.1]pentanyl)-1H-indazole (72-6): To a solution of 72-5
(200 mg, 1.05 mmol) in DMSO (5 mL) was added hydrazine solution (10 mL, 1.0 M in THF)
at rt and stirred at 120 C for 6h. The mixture was then cooled to room temperature and
dissolved in water and extracted with EtOAc. The combined organic layers were washed
with water, dried over Na SO and concentrated. The residue was purified by column
chromatography using 4-6% MeOH/DCM to afford 72-6 (44 mg, 0.228 mmol, 22%) as a
brown solid. LCMS: 184.86 [M+H] .
3-(Bicyclo[1.1.1]pentanyl)bromo-1H-indazole (72-7): To a
solution of 72-6 (300 mg, 1.630 mmol) in acetic acid (5 mL) was added bromine (0.1 mL in
acetic acid (1.0 mL), 1.956 mmol) at 0 C and stirred at rt for 5h. After completion of the
reaction, cold sat’d NaHSO was added to the mixture and extracted with EtOAc. The
combined organic layers were washed with water, brine, dried over Na SO and concentrated
to afford 72-7 (200 mg, 46%) as an off white solid. LCMS: 264.85 [M+H] .
3-(Bicyclo[1.1.1]pentanyl)bromo(tetrahydro-2H-pyranyl)-
1H-indazole (72-8): To a stirred solution of 72-7 (200 mg, 0.763 mmol) in DCM (10 mL)
was added DHP (0.348 mL, 3.816 mmol) followed by p-TSA (13.12 g, 0.076 mmol) at 0ºC.
Resulting mixture was stirred at rt for 3h. After completion of the reaction, cold water was
added to the reaction mixture and extracted with DCM. The combined organic layers were
washed with brine, dried over Na SO and concentrated. The residue was purified by silica
gel column chromatography eluted with 20% EtOAc/petroleum ether to afford 72-8 (150 mg,
0.433 mmol, 56%) as an off white solid. LCMS: 348.95 [M+H] .
(5R)-Benzyl 7-(3-(bicyclo[1.1.1]pentanyl)(tetrahydro-2H-pyran-
2-yl)-1H-indazolyl)oxo-2,7-diazaspiro[4.4]nonanecarboxylate (72-9): A mixture
of 72-8 (80 mg, 0.231 mmol), benzyl (R)oxo-2,7-diazaspiro[4.4]nonanecarboxylate
(189 mg, 0.693 mmol), K CO (63.7 mg, 0.462 mmol), CuI (8.77 mg, 0.0462 mmol) and
N,N̍'-dimethyl ethylenediamine (0.008 mL, 0.0924 mmol) in dioxane (8 mL) was degassed
with nitrogen/vacuum cycles. The reaction mixture was heated at 110 C for 4 days. The
reaction mixture was cooled to rt followed by addition of cold water and then extracted with
EtOAc. The combined organic layers were washed with water, brine, dried over Na SO , and
concentrated. The residue was purified by column chromatography using 5% MeOH/DCM to
afford 72-9 (65 mg, 52%) as an off-white solid. LCMS: 541.45 [M+H] .
(S)(3-(Bicyclo[1.1.1]pentanyl)-1H-indazolyl)(2-(4-(4-(1-
methyl-1H-1,2,4-triazolyl)phenyl)-5,6-dihydropyridin-1(2H)-yl)oxoethyl)-2,7-
diazaspiro[4.4]nonanone (Example 72) Example 72 was prepared following General
Procedures B2 and C using 72-9 and Intermediate 9. H NMR (DMSO–d , 400 MHz) δ
12.67 (s, 1H), 8.49 (s, 1H), 7.96 (d, 2H), 7.88 (d, 1H), 7.63 (d, 1H), 7.54 (d, 2H), 7.45 (d,
1H), 6.30–6.26 (m, 1H), 4.10–4.38 (m, 2H), 3.91 (s, 3H), 3.88–3.63 (m, 4H), 3.55–3.30 (m,
3H), 2.98–2.88 (m, 1H), 2.85–2.80 (m, 1H), 2.72–2.55 (m, 4H), 2.25 (s, 6H), 2.22–2.05 (m,
3H), 1.88–1.75 (m, 1H). LCMS: 603.19 [M+H] ;
Example 73
3-(2-Fluorobenzoyl)bicyclo[1.1.1]pentanecarboxamide (73-1): To a
stirred solution of methyl 3-(2-fluorobenzoyl)bicyclo[1.1.1]pentanecarboxylate (50 mg,
0.201 mmol) in MeOH (3 mL) was added methanolic ammonia (5 mL, 7N) at 0°C and the
mixture was heated at 100°C in a sealed tube for 16h. After completion of the reaction, the
mixture cooled to rt and concentrated to afford 73-1 which was further washed with diethyl
ether to afford 73-1 (33 mg, 70%) as an off white solid. LCMS: 234.86 [M+H] .
3-(2-Fluorobenzoyl)bicyclo[1.1.1]pentanecarbonitrile (73-2): To a
stirred solution of 73-1 (50 mg, 2.145 mmol) in DMF (3 mL) was added thionylchloride
(0.04 mL, 6.437 mmol) at 0 C and continued stirring at rt for 3h. After completion of the
reaction, the mixture was diluted with ice water and extracted with EtOAc. The combined
organic layers were washed with water, brine, dried over Na SO and concentrated to obtain
residue. Residue was purified by column chromatography using 10-20% EtOAc/petroleum
ether to afford 73-2 (18 mg, 40%). LCMS: 216.02 [M+H] .
3-(1H-Indazolyl)bicyclo[1.1.1]pentanecarbonitrile (73-3): To a
solution of 73-2 (200 mg, 0.853 mmol) in dimethyl sulfoxide (5 mL) was added hydrazine
solution (10 mL, 1.0 M in THF) at rt and stirred at 120 C for 6h. The mixture was then
cooled to rt and dissolved in water and extracted with EtOAc. The combined organic layers
were washed with water, brine, dried over Na SO and concentrated. The residue was
purified by column chromatography using 4-6% MeOH/DCM to afford 73-3 (0.1 g, 22%) as
an oil. LCMS: 209.91 [M+H] .
3-(5-Iodo-1H-indazolyl)bicyclo[1.1.1]pentanecarbonitrile (73-4):
To a stirred solution of 73-3 (50 mg, 0.239 mmol) in acetic acid (5 mL) was added ICl (0.1
mL in acetic acid (1.0 mL) 1.916 mmol) at 0ºC and continued stirring at rt for 3h. After
completion of the reaction, cold sat’d NaHS O was added followed by extraction with
EtOAc. The combined organic layers were washed with water, brine, dried over Na SO and
concentrated to afford 73-4 (60 mg, 31%) as a brown color liquid. LCMS: 336.13 [M+H] .
(S)(5-(7-(2-(4-(4-(1-Methyl-1H-1,2,4-triazolyl)phenyl)-5,6-
dihydropyridin-1(2H)-yl)oxoethyl)oxo-2,7-diazaspiro[4.4]nonanyl)-1H-indazol-
3-yl)bicyclo[1.1.1]pentanecarbonitrile (Example 73): Example 73 was prepared
following procedures described for Example 72 using 73-4 and Intermediate 9. H NMR
(DMSO–d , 400 MHz) δ 12.98 (s, 1H), 8.50 (s, 1H), 7.96 (d, 2H), 7.82–7.80 (m, 1H), 7.76–
7.69 (m, 1H), 7.57–7.51 (m, 2H), 7.50–7.47 (m, 1H), 6.30–6.27 (m, 1H), 4.34–4.29 (m, 1H),
4.15–4.10 (m, 2H), 3.91 (s, 3H), 3.88–3.65 (m, 4H), 3.50–3.40 (m, 2H), 2.95–2.90 (m, 1H),
2.85–2.78 (m, 1H), 2.72 (s, 6H), 2.65–2.55 (m, 3H), 2.23–2.09 (m, 3H), 1.87–1.72 (m, 1H).
LCMS: 628.12 [M+H] .
Example 74
Example 74 was prepared following General Procedures A, B2, and C
using Intermediate 4, 2-bromofluoromethoxypyridine, and Intermediate 9. H NMR
(400 MHz, DMSO-d ) δ 13.38 (s, 1H), 8.50 (s, 1H), 8.40–8.36 (m, 2H), 7.98–7.93 (m, 2H),
7.81–7.75 (m, 1H), 7.61–7.52 (m, 4H), 6.30–6.26 (m, 1H), 4.35–4.10 (m, 3H), 3.95–3.90 (m,
6H), 3.87–3.63 (m, 4H), 3.48–3.35 (m, 2H), 2.96–2.80 (m, 2H), 2.70–2.56 (m, 3H), 2.25–
2.05 (m, 3H), 1.85–1.76 (m, 1H). LCMS: 662.47 [M+H] .
Example 75
Example 75 was prepared following General Procedures A, B2, and C
using Intermediate 4, 2-bromofluoromethoxypyridine, and Intermediate 9. H NMR
(DMSO–d , 400 MHz) δ 13.52 (s, 1H), 8.72–8.68 (m, 1H), 8.50 (s, 1H), 7.95 (d, 2H), 7.89
(d, 1H), 7.78 (t, 1H), 7.62 (d, 1H), 7.54 (d, 2H), 6.85 (d, 1H), 6.30–6.26 (m, 1H), 4.36–4.22
(m, 1H), 4.20–4.03 (m, 4H), 3.93–3.60 (m, 8H), 3.49–3.35 (m, 2H), 2.97–2.79 (m, 2H),
2.70–2.58 (m, 3H), 2.26–2.03 (m, 3H), 1.88–1.75 (m, 1H). LCMS: 662.47 [M+H] .
Example 76
Example 76 was prepared following General Procedures A, B2, and C
using Intermediate 4, 2-(isopropylthio)(4,4,5,5-tetramethyl-1,3,2-dioxaborolan
yl)pyridine, and Intermediate 9. H NMR (DMSO–d , 400 MHz) δ 13.51 (s, 1H), 9.50 (s,
1H), 8.53 (dd, 1H), 8.49 (d, 2H), 8.11 (d, 1H), 7.97 (d, 2H), 7.55 (d, 2H), 7.39 (d, 1H), 6.30–
6.26 (m, 1H), 4.33–4.29 (m, 1H), 4.16–4.06 (m, 3H), 4.04–3.95 (m, 1H), 3.92 (s, 3H), 3.88–
3.78 (m, 1H), 3.75–3.67 (m, 1H), 3.52–3.03 (m, 2H), 2.97–2.53 (m, 6H), 2.29–2.03 (m, 3H),
1.91–1.80 (m, 1H), 1.38 (d, 6H). LCMS: 689.16 [M+H] .
Example 77
Example 77 was prepared following General Procedures A, B2, and C
using Intermediate 4, 2-cyclobutoxy(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)pyridine,
and Intermediate 9. H NMR (400 MHz, DMSO-d ) δ 13.41 (s, 1H), 9.23 (d, 1H), 8.59 (dd,
1H), 8.51–8.47 (m, 2H), 8.09 (d, 1H), 7.97 (d, 2H), 7.55 (d, 2H), 6.92 (d, 1H), 6.30–6.26 (m,
1H), 5.21 (qt, 1H), 4.31 (s, 1H), 4.14–4.11 (m, 3H), 3.92 (s, 3H), 3.80–3.70 (m, 2H), 3.47–
3.37 (m, 3H), 3.32–2.84 (m, 2H), 2.76–2.74 (m, 1H), 2.67–2.58 (m, 2H), 2.50–2.39 (m, 2H),
2.32–2.06 (m, 5H), 1.88–1.78 (m, 2H), 1.69–1.64 (m, 1H). LCMS: 685.49 [M+H] .
Example 78
Example 78 was prepared following General Procedures A, B2, and C
using Intermediate 4, 2-bromofluoromethoxypyridine, and Intermediate 9. H NMR
(400 MHz, DMSO-d ) δ 13.38 (s, 1H), 8.50 (s, 1H), 8.34 (d, 2H), 7.95 (d, 2H), 7.80–7.74 (m,
1H), 7.62–7.52 (m, 4H), 6.28 (s, 1H), 4.85–4.78 (m, 1H), 4.33–4.28 (m, 1H), 4.15–4.10 (m,
2H), 3.91 (s, 3H), 3.85–3.63 (m, 4H), 3.00–2.80 (m, 3H), 2.70–2.50 (m, 4H), 2.35–2.05 (m,
3H), 1.85–1.65 (m, 1H), 1.33 (d, 6H). LCMS: 690.46 [M+H] .
Example 79
Example 79 was prepared following General Procedures A, B2, and C
using Intermediate 4, 2-chloro(4-(4-(1-methyl-1H-1,2,4-triazolyl)phenyl)piperidin
yl)ethanone (prepared via Pd(OH) -mediated hydrogenation of Intermediate 9 in THF at rt).
H NMR (DMSO–d , 400 MHz) δ 13.50 (s, 1H), 9.51 (s, 1H), 8.63–8.58 (m, 1H), 8.52–8.50
(m, 2H), 8.13 (d, 1H), 7.92 (d, 2H), 7.40–7.38 (m, 3H), 4.52 (d, 1H), 4.17–4.11 (m, 3H), 3.91
(d, 3H), 3.61–3.38 (m, 2H) 3.15–3.09 (m, 1H), 2.98–2.81(m, 4H), 2.68–2.61 (m, 2H), 2.53–
2.51 (m, 3H), 2.34–2.12 (m, 3H), 1.93–1.79 (m, 3H), 1.74–1.63 (m, 1H), 1.52–1.42 (m, 1H).
LCMS: 631.17 [M+H] .
Example 80
Example 80 was prepared following General Procedures A, B2, and C
using Intermediate 4, 2-chloro(4-(5-(1-methyl-1H-1,2,4-triazolyl)thiazol
yl)piperidinyl)ethanone (prepared via Pd(OH) -mediated hydrogenation of Intermediate
13 in THF at rt). H NMR (DMSO–d , 400 MHz) δ 13.50 (s, 1H), 9.51 (s, 1H), 8.60 (dd,
1H), 8.54 (s, 1H), 8.49 (d, 1H), 8.15–8.08 (m, 2H), 7.3 (d, 1H), 4.43–4.38 (m, 1H), 4.17–4.09
(m, 3H), 3.89 (d, 3H), 3.52–3.41 (m, 1H), 3.23–3.17 (m, 3H), 2.92–2.88 (m, 1H), 2.83–2.65
(m, 3H), 2.53–2.51 (m, 4H), 2.33–2.06 (m, 5H), 1.88–1.74 (m, 2H), 1.59–1.53 (m, 1H).
LCMS: 638.44 [M+H] .
Example 81
Example 81 was prepared following General Procedures A, B2, and C
using Intermediate 4, 2-ethoxy(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)pyridine and
Intermediate 9. H NMR (DMSO–d , 300 MHz) δ 13.35 (s, 1H), 9.27 (s, 1H), 8.60 (dd, 1H),
8.52–8.45 (m, 2H), 8.10 (d, 1H), 7.97 (d, 2H), 7.55 (d, 2H), 6.94 (d, 1H), 6.28 (br s, 1H),
4.41–4.30 (m, 3H), 4.13–4.09 (m, 3H), 3.92 (s, 3H), 3.81–3.67 (m, 2H), 3.52–3.46 (m, 1H),
3.97–3.37 (m, 2H), 2.92–2.80 (m, 2H), 2.77–2.69 (m, 1H), 2.63–2.56 (m, 2H), 2.28–2.13 (m,
3H), 1.89–1.85 (m, 1H), 1.35 (t, 3H). LCMS: 659.21 [M+H] .
Example 82
Example 82 was prepared following General Procedures A, B2, and C
using Intermediate 4, 2-isopropoxy(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)pyridine,
and Intermediate 9. H NMR (400 MHz, DMSO-d ) δ 13.39 (s, 1H), 9.24 (d, 1H), 8.57 (dd,
1H), 8.47 (d, 1H), 8.41 (s, 1H), 8.09 (d, 1H), 7.84 (d, 2H), 7.03 (d, 2H), 6.88 (d, 1H), 5.35–
.29 (m, 1H), 4.14–4.10 (m, 2H), 3.88 (s, 3H), 3.72–3.59 (m, 5H), 3.44–3.34 (m, 2H), 3.23–
3.18 (m, 3H), 2.93–2.56 (m, 4H), 2.28–2.12 (m, 3H), 1.89–1.83 (m, 1H), 1.32 (d, 6H).
LCMS: 676.20 [M+H] .
Example 83
Example 83 was prepared following General Procedures A, B2, and C
using Intermediate 4, 2-isopropoxy(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)pyridine,
and Intermediate 16. H NMR (400 MHz, DMSO-d ) δ 13.40 (s, 1H), 9.25 (s, 1H), 8.57 (dd,
1H), 8.50 (s, 1H), 8.47 (d, 1H), 8.09 (d, 1H), 7.97 (d, 2H), 7.55 (d, 2H), 6.88 (d, 1H), 6.28 (s,
1H), 5.36–5.29 (m, 1H), 4.31–4.11 (m, 4H), 3.92 (s, 3H), 3.84–3.70 (m, 2H), 2.91–2.75 (m,
4H), 2.66–2.59 (m, 2H), 2.24–2.19 (m, 3H), 1.90–1.85 (m, 1H), 1.33 (d, 6H). LCMS: 675.16
[M+1] .
Example 84
Example 84 was prepared following General Procedures A, B2, and C
using Intermediate 4, 2-isopropoxy(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)pyridine,
and Intermediate 12. H NMR (400 MHz, DMSO-d ) δ 13.60 (s, 1H), 9.26 (d, 1H), 8.72 (d,
1H), 8.58 (dd, 1H), 8.49–8.47 (m, 2H), 8.11–8.05 (m, 2H), 6.95 (d, 1H), 6.88 (d, 1H), 5.34–
.31 (m, 1H), 4.14–4.11 (m, 2H), 3.89 (s, 3H), 3.69–3.53 (m, 8H), 3.40–3.31 (m, 2H), 2.94–
2.84 (m, 2H), 2.72–2.55 (m, 2H), 2.27–2.13 (m, 3H), 1.87–1.84 (m, 1H), 1.33 (d, 6H).
LCMS: 677.49 [M+H] .
Example 85
Example 85 was prepared following General Procedures A, B2, and C
using Intermediate 4, 2-isopropoxy(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)pyridine,
and Intermediate 17. H NMR (DMSO–d , 400 MHz) δ 13.38 (s, 1H), 9.22 (s, 1H), 8.53 (d,
1H), 8.44 (d, 1H), 8.38 (s, 1H), 8.07 (d, 1H), 7.80 (d, 2H), 6.97 (d, 2H), 6.91 (d, 1H), 5.35–
.25 (m, 1H), 4.65–4.45 (m, 1H), 4.32–3.60 (m, 3H), 3.84 (s, 3H), 3.72–3.52 (m, 2H), 3.50–
3.30 (m, 3H), 3.10–2.72 (m, 5H), 2.71–3.45 (m, 1H), 2.30–2.05 (m, 3H), 1.90–1.75 (m, 1H),
1.40–1.10 (m, 9H). LCMS: 690.46 [M+H] .
Example 86
Example 86 was prepared following General Procedures A, B2, and C
using Intermediate 4, 2-isopropoxy(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)pyridine,
and 2-chloro(4-(5-(1-methyl-1H-1,2,4-triazolyl)thiazolyl)piperidinyl)ethanone
(prepared via Pd(OH) -mediated hydrogenation of Intermediate 13 in THF at rt). H NMR
(400 MHz, DMSO-d ) δ 13.40 (s, 1H), 9.25 (s, 1H), 8.58 (dd, 1H), 8.53 (s, 1H), 8.47 (d, 1H),
8.10–8.06 (m, 2H), 6.88 (d, 1H), 5.34–5.31 (m, 1H), 4.40–4.11 (m, 4H), 3.89 (s, 3H), 3.50–
3.19 (m, 4H), 2.90–2.56 (m, 5H), 2.43–2.11 (m, 5H), 1.85–1.56 (m, 3H), 1.33 (d, 6H).
LCMS: 682.54 [M+H] .
Example 87
Example 87 was prepared following General Procedures A, B2, and C
using Intermediate 4, 2-isopropoxy(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)pyridine,
and Intermediate 18. H NMR (400 MHz, DMSO-d ) δ 13.40 (s, 1H), 9.26 (d, 1H), 8.57 (dd,
1H), 8.49–8.42 (m, 2H), 8.10 (d, 1H), 7.63 (s, 1H), 6.88 (d, 1H), 5.37–5.28 (m, 1H), 4.15–
4.10 (m, 2H), 3.85 (s, 3H), 3.75–3.36 (m, 10H), 2.97–2.81 (m, 2H), 2.75–2.56 (m, 2H), 2.29–
2.12 (m, 3H), 1.91–1.83 (m, 1H), 1.33 (d, 6H). LCMS: 683.42 [M+H] .
Example 88
Example 88 was prepared following General Procedures A, B2, and C
using Intermediate 4, 2-isopropoxy(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)pyridine,
and Intermediate 19. H NMR (DMSO–d6, 400 MHz) δ 13.40 (s, 1H), 9.54 (d, 1H), 8.61 (s,
1H), 8.57 (dd, 1H), 8.47 (d, 1H), 8.19 (s, 1H), 8.08 (d, 1H), 6.87 (d, 1H), 6.73–6.70 (m, 1H),
.40–5.28 (m, 1H), 4.39–4.36 (m, 1H), 4.29–4.09 (m, 5H), 3.88–3.58 (m, 2H), 3.51–3.38 (m,
2H), 2.93–2.80 (m, 2H), 2.78–2.66 (m, 2H), 2.62–2.51 (m, 2H), 2.27–2.13 (m, 3H), 1.90–
1.80 (m, 1H), 1.42 (t, 3H), 1.32 (d, 6H). LCMS 694.32[M+H] .
Example 89
Example 89 was prepared following General Procedures A, B2, and C
using Intermediate 4, 2-isopropoxy(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)pyridine,
and Intermediate 20. H NMR (400 MHz, DMSO-d ) δ 13.4 (s, 1H), 9.26 (d, 1H), 8.58 (dd,
1H), 8.50–8.47 (m, 2H), 8.10 (d, 1H), 7.98 (d, 2H), 7.56 (d, 2H), 6.88 (d, 1H), 6.29 (s, 1H),
.34–5.31 (m, 1H), 5.01–4.98 (m, 1H), 4.30–4.10 (m, 6H), 3.80–3.68 (m, 4H), 3.51–3.36 (m,
3H), 3.31–2.82 (m, 2H), 2.76–2.57 (m, 3H), 2.24–2.15 (m, 3H), 1.89–1.84 (m, 1H), 1.33 (d,
6H). LCMS: 703.47 [M+H] .
Example 90
Example 90 was prepared following General Procedures A, B2, and C
using Intermediate 4, 2-cyclobutoxy(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)pyridine,
and Intermediate 13. H NMR (400 MHz, DMSO-d ) δ 13.41 (s, 1H), 9.23 (d, 1H), 8.61–8.57
(m, 2H), 8.47 (d 1H), 8.20 (s, 1H), 8.09 (d, 1H), 6.92 (d, 1H), 6.71 (s, 1H), 5.21 (qt, 1H),
4.39–4.37(m, 1H), 4.21–4.05 (m, 3H), 3.91 (s, 3H), 3.83–3.62 (m, 2H), 3.52–3.37 (m, 2H),
2.96–2.81 (m, 2H), 2.74–2.69 (m, 2H), 2.62–2.53 (m, 2H), 2.45–2.37 (m, 2H), 2.29–2.02 (m,
5H), 1.90–1.62 (m, 3H). LCMS: 692.15 [M+H] .
Example 91
Example 91 was prepared following General Procedures A, B1, C and D
using Intermediate 4, 2-isopropyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolan
yl)benzo[d]oxazole and Intermediate 9. H NMR (400 MHz, DMSO-d ) δ 13.4 (s, 1H), 8.80
(s, 1H), 8.52-8.45 (m, 3H), 8.29 (s, 1H), 8.12 (d, 1H), 7.98 (d, 2H), 7.56 (d, 2H), 6.29 (s, 1H),
4.32 (br, 1H), 4.18-4.06 (m, 3H), 3.93 (s, 3H), 3.85-3.82 (m, 1H), 3.71-3.66 (m, 2H), 3.52-
3.27 (m, 2H), 2.96-2.85 (m, 2H), 2.77-2.72 (m, 1H), 2.67-2.55 (m, 3H), 2.33-2.19 (m, 3H),
1.90-1.85 (m, 1H), 1.42 (d, 6H). LCMS: 697.20 [M+H] .
Example 92
Example 92 was prepared following General Procedures A, B1, C and D
using Intermediate 4, 2-(3,4-dimethoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane and
Intermediate 9. H NMR (400 MHz, DMSO-d ) δ 13.27 (s, 1H), 8.51-8.46 (m, 2H), 8.09-8.03
(m, 2H), 7.97 (d, 2H), 7.56 (d, 2H), 7.09 (d, 1H), 6.29 (s, 1H), 4.31 (br, 1H), 4.20-4.11 (m,
3H), 3.92 (s, 3H), 3.88 (s, 3H), 3.81 (s, 3H), 3.74-3.66 (m, 2H), 3.52-3.48 (m, 1H), 3.41-3.31
(m, 2H), 2.93-2.83 (m, 2H), 2.77-2.72 (m, 1H), 2.67-2.56 (m, 3H), 2.23-2.15 (m, 3H), 1.87-
1.86 (m, 1H). LCMS: 674.20 [M+H] .
Example 93
Example 93 was prepared following General Procedures A, B1, C and D
using Intermediate 4, 2,3-dimethoxy(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)pyridine
and Intermediate 9. H NMR (400 MHz, DMSO-d ) δ 13.16 (s, 1H), 8.77 (s, 1H), 8.51 (s,
1H), 8.19 (s, 1H), 7.96 (d, 2H), 7.87 (t, 1H), 7.71 (d, 1H), 7.55 (m, 3H), 7.41 (d, 1H), 6.29 (s,
1H), 4.32 (br, 1H), 4.20-4.10 (m, 4H), 3.92 (s, 3H), 3.84 (m, 6H), 3.50-3.35 (m, 4H), 3.02-
2.91 (m, 2H), 2.69-2.62 (m, 2H), 2.23-2.14 (m, 3H), 1.86-1.79 (m, 1H). LCMS: 674.15
[M+H] .
Example 94
Example 94 was prepared following General Procedures A, B2, and C
using Intermediate 4, 2-(4-isopropoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane and
Intermediate 13. H NMR (400 MHz, DMSO-d ) δ 13.20 (s, 1H), 8.56 (s, 1H), 8.44 (d, 1H),
8.37 (d, 2H),8.19 (s, 1H), 8.05 (d, 1H) 7.03 (d, 2H), 6.71 (s, 1H), 4.72–4.62 (m, 1H), 4.37 (s,
1H), 4.25–4.05 (m, 3H), 3.91 (s, 3H), 3.85–3.65 (m, 3H), 3.51–3.30 (m, 2H), 2.95–2.82 (m,
2H), 2.78–2.65 (m, 2H), 2.61–2.50 (m, 2H), 2.30–2.10 (m, 2H), 1.90–1.80 (m, 1H), 1.30 (d,
6H). LCMS: 679.58 [M+H] .
Example 95
Example 95 was prepared following General Procedures A, B2, and C
using Intermediate 4, 2-isopropoxy(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)pyridine,
and Intermediate 26. H NMR (400 MHz, DMSO-d ) δ 13.4 (s, 1H), 9.28–9.22 (m, 1H),
8.59–8.53 (m, 2H), 8.49–8.43 (m, 2H), 8.20–8.16 (m, 1H), 8.11–8.05 (m, 1H), 6.89–6.86 (m,
1H), 6.73–6.69 (m, 1H), 5.35–5.30 (m, 1H), 4.56–4.52 (m, 1H), 4.31–3.98 (m, 4H), 3.91 (s,
3H), 3.85–3.68 (m, 2H), 2.83–2.53 (m, 6H), 2.30–2.09 (m, 3H), 1.85–1.80 (m, 1H), 1.34–
1.31 (m, 6H), 1.24–1.15 (m, 3H). LCMS: 694.4 [M+H] .
Example 96
Example 96 was prepared following General Procedures A, B2, and C
using Intermediate 4, 2-(4-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, and
Intermediate 26. H NMR (400 MHz, DMSO-d ) δ 13.40 (s, 1H), 8.58–8.44 (m, 4H), 8.20–
8.16 (m, 1H), 8.12–8.04 (m, 1H), 7.38–7.26 (m, 2H), 6.76–6.69 (m, 1H), 4.60–4.50 (m, 1H),
4.40–4.00 (m, 4H), 3.91 (s, 3H), 3.80–3.60 (m, 2H), 2.90–2.52 (m, 6H), 2.30–2.05 (m, 3H),
1.88–1.76 (m, 1H), 1.24–1.15 (m, 3H). LCMS: 653.20 [M+H] .
Example 97
Example 97 was prepared following General Procedures A, B2, and C
using Intermediate 4, 2-isopropoxy(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)pyridine,
and Intermediate 21. H NMR (400 MHz, DMSO-d ) δ 13.40 (s, 1H), 9.25 (d, 1H), 8.59–8.52
(m, 2H), 8.47 (d, 1H), 8.09 (d, 1H), 7.97 (d, 2H), 7.55 (d, 2H), 6.88 (d, 1H), 6.30–6.26 (m,
1H), 5.35–5.29 (m, 1H), 4.35–4.29 (m, 3H), 4.15–4.10 (m, 3H), 3.83–3.68 (m, 2H), 3.58–
3.40 (m, 2H), 3.01–2.80 (m, 4H), 2.73–2.62 (m, 4H), 2.30–2.13 (m, 9H), 1.96–1.73 (m, 1H),
1.33 (d, 6H). LCMS: 728.44 [M+H] .
Example 98
Example 98 was prepared following General Procedures A, B2, and C
using Intermediate 4, 2-isopropoxy(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)pyridine,
and 2-chloro(4-(4-(1-methyl-1H-imidazolyl)phenyl)-5,6-dihydropyridin-1(2H)-
yl)ethanone which was prepared as described in patent WO2016161160A1. H NMR (400
MHz, DMSO-d ) δ 13.38 (s, 1H), 9.26 (d, 1H), 8.58 (dd, 1H), 8.47 (d, 1H), 8.09 (d, 1H), 7.71
(d, 2H), 7.60 (d, 2H), 7.44 (d, 2H), 6.88 (d, 1H), 6.20 (s, 1H), 5.36–5.29 (m, 1H), 4.31–4.26
(m, 1H), 4.18–4.07 (m, 3H), 3.83–3.68 (m, 5H), 3.54–3.41 (m, 2H), 2.95–2.76 (m, 3H),
2.66–2.60 (m, 3H), 2.26–2.16 (m, 3H), 1.91–2.85 (m, 1H), 1.33 (d, 6H). LCMS: 672.47
[M+H] .
Example 99
Example 99 was prepared following General Procedures A, B2, and C
using Intermediate 4, 2-isopropoxy(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)pyridine,
and Intermediate 27. H NMR (400 MHz, DMSO-d ) δ 13.41 (s, 1H), 9.25 (d, 1H), 8.57 (dd,
1H), 8.47 (d, 1H), 8.09 (d, 1H), 7.90 (s, 1H), 7.65 (s, 1H), 7.57 (s, 1H), 6.88 (d, 1H), 6.56 (s,
1H), 5.36–5.30 (m, 1H), 4.34–4.13 (m, 4H), 3.78–3.72 (m, 2H), 3.68 (s, 3H), 3.45–3.39 (m,
2H), 2.93–2.82 (m, 2H), 2.74–2.70 (m, 2H), 2.59–2.56 (m, 2H), 2.23–2.15 (m, 3H), 1.90–
1.86 (m, 1H), 1.33 (d, 6H). LCMS: 679.14 [M+H] .
Example 100
Example 100 was prepared following General Procedures A, B2, and C
using Intermediate 4, 3-methyl(tetrahydro-2H-pyranyl)(4,4,5,5-tetramethyl-1,3,2-
dioxaborolanyl)-1H-indazole and Intermediate 9. H NMR (400 MHz, DMSO-d ) δ 13.25
(s, 1H), 12.70 (s, 1H), 8.92 (br s, 1H), 8.48 (d, 2H), 8.41 (d, 1H), 8.08 (d, 1H), 7.97 (d, 2H),
7.60–7.50 (m, 3H), 6.28 (br s, 1H), 4.40–4.30 (m, 1H), 4.25–4.0 (m, 3H), 3.92 (s, 3H), 3.90–
3.60 (m, 2H), 3.55–3.20 (m, 2H), 3.00–2.80 (m, 3H), 2.79–2.70 (m, 1H), 2.65–2.50 (m, 5H),
2.40–2.15 (m, 3H), 2.00–1.80 (m, 1H). LCMS: 668.47 [M+H] .
Example 101
Example 101 was prepared following General Procedures A, B2, and C
using Intermediate 4, 3-methyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolan
yl)benzo[d]isoxazole and Intermediate 9. H NMR (300 MHz, DMSO-d ) δ 13.05 (s, 1H),
8.93 (s, 1H), 8.75 (d, 1H), 8.51 (s, 2H), 8.13 (d, 1H), 7.97 (d, 2H), 7.83 (d, 1H), 7.55 (d, 2H),
6.28 (s, 1H), 4.40–4.10 (m, 4H), 3.92 (m, 3H), 3.85–3.60 (m, 3H), 3.10–2.80 (m, 3H), 2.72–
2.55 (m, 7H), 2.30–2.10 (m, 3H), 2.0–1.80 (m, 1H). LCMS: 669.07 [M+H] .
Example 102
Example 102 was prepared following General Procedures A, B2, and C
using benzyl Intermediate 3, 3-cyclopropoxymethoxy(4,4,5,5-tetramethyl-1,3,2-
dioxaborolanyl)pyridine and Intermediate 9. H NMR (400 MHz, DMSO-d ) δ 13.18 (s,
1H), 8.76 (s, 1H), 8.49 (s, 1H), 7.95 (d, 2H), 7.86 (t, 1H), 7.73 (d, 1H), 7.65 (d, 1H), 7.60–
7.50 (m, 3H), 6.27 (s, 1H), 4.30–4.12 (m, 2H), 4.08 (s, 3H), 4.0–3.88 (m, 4H), 3.85–3.65 (m,
4H), 3.50–3.40 (m, 2H), 2.90–2.75 (m, 3H), 2.75–2.52 (m, 3H), 2.32–2.05 (m, 3H), 1.85–
1.75 (m, 1H), 0.80–0.40 (m, 4H). LCMS: 700.46 [M+H] .
Example 103
Example 103 was prepared following General Procedures A, B2, and C
using Intermediate 4, 2-(4-isopropoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane and
Intermediate 9. H NMR (DMSO–d , 400 MHz) δ 13.33 (s, 1H), 8.50 (s, 1H), 8.44 (d, 1H),
8.37 (d, 2H), 8.05 (d, 1H), 7.97 (d, 2H), 7.55 (d, 2H), 7.03 (d, 2H), 6.32–6.25 (m, 1H), 4.80–
4.60 (m, 1H), 4.40–4.00 (m, 4H), 3.92 (s, 3H), 3.90–3.60 (m, 2H), 3.60–3.20 (m, 2H), 3.0–
2.68 (m, 4H), 2.67–2.40 (m, 2H), 2.40–2.10 (m, 3H), 1.90–1.80 (m, 1H), 1.30 (d, 6H).
LCMS: 672.47 [M+H] .
Example 104
Example 104 was prepared following General Procedures A, B2, and C
using Intermediate 4, 2-(4-isopropoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane and
Intermediate 22. H NMR (400 MHz, DMSO-d ) δ 13.25 (s, 1H), 9.12 (d, 1H), 8.58 (s, 1H),
8.44 (d, 1H), 8.37 (d, 2H), 8.35–8.20 (m, 1H), 8.06 (d, 1H), 7.68 (d, 1H), 7.03 (d, 2H), 6.90–
6.80 (m, 1H), 4.75–4.60 (m, 1H), 4.40–4.30 (m, 1H), 4.25–4.10 (m, 3H), 3.94 (s, 3H), 3.80–
3.60 (m, 4H), 3.40–2.70 (m, 3H), 2.75–2.72 (m, 2H), 2.68–2.50 (m, 1H), 2.40–2.15 (m, 3H),
2.00–1.80 (m, 1H), 1.30 (d, 6H). LCMS: 673.4 [M+H] .
Example 105
Example 105 was prepared following General Procedures A, B2, and C
using Intermediate 4, 2-(4-isopropoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane and
Intermediate 23. H NMR (400 MHz, DMSO-d ) δ 13.20 (s, 1H), 8.76 (s, 1H), 8.55 (s, 1H),
8.44 (d, 1H), 8.37 (d, 2H), 8.08–7.92 (m, 3H), 7.03 (d, 2H), 6.42–6.37 (m, 1H), 4.71–4.64
(m, 1H), 4.35–4.31 (m, 1H), 4.21–4.09 (m, 3H), 3.95 (s, 3H), 3.91–3.64 (m, 2H), 3.53–3.47
(m, 1H), 3.43–3.38 (m, 1H), 2.97–2.70 (m, 4H), 2.62–2.53 (m, 2H), 2.29–2.10 (m, 3H),
1.91–1.82 (m, 1H), 1.30 (d, 6H). LCMS: 673.11 [M+H] .
Example 106
Example 106 was prepared following General Procedures A, B2, and C
using Intermediate 4, 2-(4-isopropoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane and
Intermediate 24. H NMR (400 MHz, DMSO-d ) δ 13.25 (s, 1H), 8.72 (s, 1H), 8.45–8.37 (m,
3H), 8.07 (d, 1H), 7.04 (d, 2H), 6.81 (s, 1H), 4.69–4.66 (m, 1H), 4.35–4.15 (m, 4H), 3.99 (s,
3H), 3.81–3.72 (m, 3H), 3.39–3.34 (m, 1H), 3.10–2.82 (m, 5H), 2.75–2.67 (m, 1H), 2.34–
1.95 (m, 4H), 1.31 (d, 6H). LCMS: 680.66 [M+H] .
Example 107
Example 107 was prepared following General Procedures A, B2, and C
using Intermediate 4, 2-(4-isopropoxymethoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-
dioxaborolane and Intermediate 9. H NMR (400 MHz, DMSO-d ) δ 13.23 (s, 1H), 8.53–
8.43 (m, 2H), 8.17 (d, 1H), 8.10–7.93 (m, 4H), 7.55 (d, 2H), 7.07 (d, 1H), 6.30–6.26 (m, 1H),
4.66–4.54 (m, 1H), 4.32–4.28 (m, 1H), 4.18–4.06 (m, 3H), 3.92 (s, 3H), 3.87 (s, 3H), 3.82–
3.65 (m, 2H), 3.54–3.37 (m, 2H), 2.95–2.70 (m, 3H), 2.69–2.55 (m, 3H), 2.28–2.15 (m, 3H),
1.91–1.82 (m, 1H), 1.28 (d, 6H). LCMS: 702.4 [M+H] .
Example 108
Example 108 was prepared following General Procedures A, B2, and C
using Intermediate 4, 2-(4-isopropoxymethoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-
dioxaborolane and Intermediate 13. H NMR (400 MHz, DMSO-d ) δ 13.23 (s, 1H), 8.56 (s,
1H), 8.46 (d, 1H), 8.18 (dd, 2H), 8.06 (d, 1H), 7.99 (d, 1H), 7.07 (d, 1H), 6.75–6.69 (m, 1H),
4.65–4.55 (m, 1H), 4.39–4.35 (m, 1H), 4.23–4.03 (m, 3H), 3.91 (s, 3H), 3.87 (s, 3H), 3.84–
3.62 (m, 2H), 3.52–3.36 (m, 2H), 2.95–2.81 (m, 2H), 2.75–2.72 (m, 2H), 2.62–2.57 (m, 2H),
2.29–2.12 (m, 3H), 1.91–1.82 (m, 1H), 1.28 (d, 6H). LCMS: 709.4 [M+H] .
Example 109
Example 109 was prepared following General Procedures A, B2, and C
using Intermediate 3, 4-isopropoxyphenylboronic acid and Intermediate 9. H NMR (400
MHz, DMSO-d ) δ 13.01 (s, 1H), 8.49 (s, 1H), 8.15 (s, 1H), 7.96 (d, 2H), 7.85 (d, 2H), 7.70
(t, 1H), 7.60–7.50 (m, 3H), 7.05 (d, 2H), 6.28 (s, 1H), 4.75–4.65 (m, 1H), 4.40–4.22 (m, 1H),
4.20–4.05 (m, 1H), 3.91 (s, 3H), 3.90–3.80 (m, 2H), 3.80–3.60 (m, 2H), 3.48–3.38 (m, 2H),
2.98–2.80 (m, 2H), 2.75–2.50 (m, 4H), 2.30–2.05 (m, 3H), 1.90–1.70 (m, 1H), 1.38–1.25 (m,
6H). LCMS: 671.49 [M+H] .
Example 110
Example 110 was prepared following General Procedures A, B2, and C
using Intermediate 3, 4-isopropoxyphenylboronic acid and Intermediate 13. H NMR (400
MHz, DMSO-d ) δ 13.10 (s, 1H), 8.55 (s, 1H), 8.18 (s, 1H), 8.15 (s, 1H), 7.85 (d, 2H), 7.76–
7.66 (m, 1H), 7.55 (d, 1H), 7.05 (d, 2H), 6.71 (s, 1H), 4.75–4.65 (m, 1H), 4.45–4.30 (m, 1H),
4.22–4.15 (m, 1H), 3.90 (s, 3H), 3.90–3.82 (m, 2H), 3.81–3.65 (m, 2H), 3.48–3.35 (m, 2H),
2.98–2.88 (m, 1H), 2.87–2.80 (m, 1H), 2.75–2.55 (m, 4H), 2.30–2.05 (m, 3H), 2.85–2.75 (m,
1H), 1.33 (d, 6H). LCMS: 678.45 [M+H] .
Example 111
Example 111 was prepared following General Procedures A, B2, and C
using Intermediate 4, 1-isopropyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)pyridin-
2(1H)-one Intermediate 9. H NMR (400 MHz, DMSO-d ) δ 13.25 (s, 1H), 8.89 (d, 1H),
8.48–8.46 (m, 2H), 8.15 (dd, 1H), 8.05 (d, 1H), 7.94 (d, 2H), 7.51 (d, 2H ), 6.52 (d, 1H), 6.25
(s, 1H), 5.12–5.09 (m, 1H), 4.30–4.25 (m, 1H), 4.10–4.08 (m, 3H), 3.88 (s, 3H), 3.79–3.58
(m, 2H), 3.47–3.33 (m, 2H), 2.90–2.71 (m, 3H), 2.63–2.57 (m, 3H), 2.22–2.13 (m, 3H),
2.86–2.83 (m, 1H), 1.36 (d, 6H). LCMS: 673.44 [M+H] .
Example 112
Example 112 was prepared following General Procedures A, B2, and C
using Intermediate 4, 4-isopropoxyphenylboronic acid and Intermediate 18. H NMR
(DMSO–d , 400 MHz) δ 13.22 (s, 1H), 8.44 (d, 2H), 8.38 (d, 2H), 8.05 (d, 1H), 7.62 (s, 1H),
7.03 (d, 2H), 4.75–4.60 (m, 1H), 4.20–4.09 (m, 2H), 3.85 (s, 3H), 3.80–3.42 (m, 8H), 3.40–
3.20 (m, 2H), 3.00–2.87 (m, 1H), 2.86–2.80 (m, 1H), 2.75–2.65(m, 1H), 2.60–2.40 (m, 1H),
2.30–2.10 (m, 3H), 1.90–1.80 (m, 1H), 1.30 (d, 6H). LCMS: 682.41 [M+H] .
Example 113
Example 113 was prepared following General Procedures A, B2, and C
using Intermediate 4, potassium cyclopropyltrifluoroborate and Intermediate 13. H NMR
(400 MHz, DMSO-d ) δ 12.79 (s, 1H), 8.56 (s, 1H), 8.33 (d, 1H), 8.19 (s, 1H), 7.92 (d, 1H),
6.74–6.68 (m, 1H), 4.39–4.35 (m, 1H), 4.20–4.10 (m, 1H), 4.05–3.95 (m, 2H), 3.91 (s, 3H),
3.80–3.60 (m, 2H), 3.52–3.35 (m, 2H), 2.95–2.82 (m, 2H), 2.79–2.70 (m, 2H), 2.62–2.57 (m,
2H), 2.29–2.10 (m, 4H), 1.90–1.80 (m, 1H), 1.29–1.16 (m, 2H), 1.00–0.94 (m, 2H). LCMS:
585.20 [M+H] .
Example 114
Example 114 was prepared by chiral SFC separation of Example 85 using
a chiral column (Chiralpak-IE (250 X30 )mm, 5u) eluted with 0.2% TFA in n-Hexane:
Ethanol: Methanol (20:40:40) to afford Example 114 as the first eluted isomer.
Stereochemisty is arbitrarily assigned. H NMR (DMSO–d , 400 MHz) δ 13.50 (s, 1H),
.60–10.20 (m, 1H), 9.27 (d, 1H), 8.57 (d, 1H), 8.50–8.40 (m, 2H), 8.15 (d, 1H), 7.85 (d,
2H), 7.10–6.95 (m, 2H), 6.89 (d, 1H), 5.4–5.25 (m, 1H), 4.80–4.45 (m, 3H), 4.40–4.05 (m,
4H), 3.88 (s, 3H), 3.85–3.70 (m, 4H), 3.45–3.25 (m, 2H), 3.15–2.82 (m, 3H), 2.48–2.32 (m,
3H), 2.28–2.10 (m, 1H), 1.45–1.20 (m, 9H). LCMS: 688.46 [M-H] .
Example 115
Example 115 was prepared by chiral SFC separation of Example 85 using
a chiral column (Chiralpak-IE (250 X30 )mm, 5u) eluted with 0.2% TFA in n-Hexane:
Ethanol: Methanol (20:40:40) to afford Example 115 as the second eluted isomer.
Stereochemistry is arbitrarily assigned. H NMR (DMSO–d , 400 MHz) δ 13.50 (s, 1H),
.60–10.20 (m, 1H), 9.27 (d, 1H), 8.57 (d, 1H), 8.50–8.40 (m, 2H), 8.15 (d, 1H), 7.85 (d,
2H), 7.10–6.95 (m, 2H), 6.89 (d, 1H), 5.40–5.25 (m, 1H), 4.80–4.40 (m, 3H), 4.40–4.0 (m,
4H), 3.88 (s, 3H), 3.85–3.70 (m, 4H), 3.45–3.25 (m, 2H), 3.25–2.95 (m, 3H), 2.48–2.32 (m,
3H), 2.28–2.10 (m, 1H), 1.45–1.20 (m, 9H). LCMS: 690.51 [M+H]
Example 116
Example 116 was prepared following General Procedures A, B1, C, D and
E using Intermediate 4, (3-fluoroisopropoxyphenyl)boronic acid and Intermediate 9. Data
for 1.0-HCl salt: H NMR (DMSO–d , 400 MHz) δ 13.60 (s, 1H), 10.50 (d, 1H), 8.56 (br,
1H), 8.48-8.44 (m, 1H), 8.26-8.23 (m, 2H), 8.17-8.14 (m, 1H), 8.00 (d, 2H), 6.31 (s, 1H),
4.74-4.70 (m, 1H), 4.66-4.64 (m, 1H), 4.41 (br, 7H), 4.21 (br, 1H), 4.16-4.11 (m, 3H), 3.93
(s, 3H), 3.88-3.77 (m, 2H), 3.63-3.59 (m, 1H), 3.39-3.34 (m, 1H), 2.51-2.49 (br, 1H), 2.38-
2.33 (m, 2H), 2.24-2.19 (m, 1H), 1.34 (d, 6H). LCMS: 690.30 [M+H] .
Example 117
Example 117 was prepared following General Procedures A, B1, C, D and
E using Intermediate 4, (3-fluoroisopropoxyphenyl)boronic acid and Intermediate 25.
Data for 1.0-HCl salt: H NMR (DMSO–d , 400 MHz) δ 13.49 (br, 1H), 10.40 (d, 1H), 8.58
(s, 1H), 8.48-8.44 (m, 1H), 8.28-8.23 (m, 2H), 8.17-8.14 (m, 1H), 7.99 (t, 1H), 7.48-7.41 (m,
2H), 7.35-7.30 (m, 1H), 6.43 (s, 1H), 4.74-4.68 (m, 1H), 4.61-4.55 (m, 2H), 4.29-4.10 (m,
5H), 3.94 (s, 3H), 3.83-3.78 (m, 3H), 3.51 (m, 2H), 2.68-2.66 (m, 2H), 2.40-2.33 (m, 3H),
1.34 (d, 6H). LCMS: 708.30 [M+H] .
Example 118
Example 118 was prepared following General Procedures A, B2, and C
using Intermediate 4, (3-fluoroisopropoxyphenyl)boronic acid and Intermediate 13. H
NMR (400 MHz, DMSO-d ) δ 13.21 (s, 1H), 8.57 (s, 1H), 8.47 (d, 1H), 8.26–8.19 (m, 3H),
8.09 (d, 1H), 7.31 (t, 1H), 6.71 (s, 1H), 4.73–4.69 (m, 1H), 4.38–4.36 (m, 1H), 4.20–4.12 (m,
3H), 3.91 (s, 3H), 3.81–3.69 (m, 2H), 3.52–3.45 (m, 2H), 2.95–2.87 (m, 2H), 2.75–2.67 (m,
2H), 2.63–2.58 (m, 2H), 2.32–2.18 (m, 3H), 1.92–2.88 (m, 1H), 1.33 (d, 6H). LCMS: 697.43
[M+H] .
Example 119
Example 119 was prepared following General Procedures A, B1, C and D
using Intermediate 3, 3-fluoro(pyrrolidinyl)(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-
2-yl)pyridine and Intermediate 9. H NMR (DMSO–d , 400 MHz) δ 13.27 (br, 1H), 10.35 (d,
1H), 8.77-8.76 (m, 1H), 8.53 (s, 1H), 8.00-797 (m, 2H), 7.87-7.85 (m, 1H), 7.61-7.54 (m,
3H), 7.51-7.45 (m, 1H), 7.39-7.36 (m, 1H), 6.32 (br, 1H), 4.64-4.58 (m, 2H), 4.22 (br, 1H),
4.13-4.08 (m, 2H), 3.93 (s, 3H), 3.82-3.74 (br, 3H), 3.61-3.60 (m, 2H), 3.46 -3.35 (m, 3H),
2.68-2.67 (m, 1H), 2.56-2.53 (m, 2H), 2.39-2.29 (m, 4H), 2.22-2.17 (m, 1H), 1.99-1.97 (m,
4H). LCMS: 701.30 [M+H] .
Example 120
Compounds of Formula (I)
For some compounds, the foregoing syntheses are exemplary and can be
used as a starting point to prepare additional compounds of Formula (I). Examples of
additional compounds of Formula (I) are described below. These compounds can be prepared
in various ways, including by those synthetic schemes shown and described herein. Those
skilled in the art will be able to recognize modifications of the disclosed syntheses and to
devise routes based on the disclosures herein; all such modifications and alternate routes are
within the scope of the claims.
(S)(2-(4-(5-(1-(2-hydroxyethyl)-1H-1,2,4-triazolyl)thiazolyl)-3,6-
dihydropyridin-1(2H)-yl)oxoethyl)(3-(6-isopropoxypyridinyl)-1H-pyrazolo[4,3-
b]pyridinyl)-2,7-diazaspiro[4.4]nonanone, or a pharmaceutically acceptable salt
thereof.
(S)(2-(4-(5-(1-methyl-1H-1,2,4-triazolyl)thiazolyl)-3,6-
dihydropyridin-1(2H)-yl)oxoethyl)(3-(2-methylbenzo[d]oxazolyl)-1H-pyrazolo[4,3-
b]pyridinyl)-2,7-diazaspiro[4.4]nonanone, or a pharmaceutically acceptable salt
thereof.
(S)(3-(6-isopropoxypyridinyl)-1H-pyrazolo[4,3-b]pyridinyl)
(2-(4-(5-(1-methyl-1H-1,2,4-triazolyl)thiazolyl)-3,6-dihydropyridin-1(2H)-yl)
oxoethyl-1,1-d2)-2,7-diazaspiro[4.4]nonanone, or a pharmaceutically acceptable salt
thereof.
(S)(2-(4-(5-(1-methyl-1H-1,2,4-triazolyl)thiazolyl)-3,6-
dihydropyridin-1(2H)-yl)oxoethyl)(3-(2-methylpyridinyl)-1H-pyrazolo[4,3-
b]pyridinyl)-2,7-diazaspiro[4.4]nonanone, pharmaceutically acceptable salt thereof.
Example 121
Compounds of Formula (II)
For some compounds, the foregoing syntheses are exemplary and can be
used as a starting point to prepare additional compounds of Formula (II). Examples of
additional compounds of Formula (II) are described below. These compounds can be
prepared in various ways, including by those synthetic schemes shown and described herein.
Those skilled in the art will be able to recognize modifications of the disclosed syntheses and
to devise routes based on the disclosures herein; all such modifications and alternate routes
are within the scope of the claims.
(S)(3-(5-fluoropyridinyl)-1H-indazolyl)(2-(4-(4-(1-methyl-
1H-1,2,4-triazolyl)phenyl)-3,6-dihydropyridin-1(2H)-yl)oxoethyl-1,1-d2)-2,7-
diazaspiro[4.4]nonanone, or a pharmaceutically acceptable salt thereof.
(S)(2-(4-(4-(1-Methyl-1H-1,2,4-triazolyl)phenyl)-3,6-
dihydropyridin-1(2H)-yl)oxoethyl)(3-(2-methyloxazolo[4,5-b]pyridinyl)-1H-
indazolyl)-2,7-diazaspiro[4.4]nonanone, or a pharmaceutically acceptable salt thereof.
Example 122
Compounds of Formula (III)
For some compounds, the foregoing syntheses are exemplary and can be
used as a starting point to prepare additional compounds of Formula (III), such as (S)(2-
(4-(4-(1-methyl-1H-1,2,4-triazolyl)phenyl)-3,6-dihydropyridin-1(2H)-yl)oxoethyl-1,1-
d2)(3-(tetrahydro-2H-pyranyl)-1H-indazolyl)-2,7-diazaspiro[4.4]nonanone, or a
pharmaceutically acceptable salt thereof. These compounds can be prepared in various ways,
including by those synthetic schemes shown and described herein. Those skilled in the art
will be able to recognize modifications of the disclosed syntheses and to devise routes based
on the disclosures herein; all such modifications and alternate routes are within the scope of
the claims.
Example 123
Active ERK1 and ERK2 Kinase Assay
Activated ERK1 and ERK2 activity was determined in a Mobility Shift
Assay (MSA) format as follows: Compound and kinase solution were prepared with assay
buffer (20 mM HEPES, 0.01% Triton X-100, 2 mM DTT, pH7.5) and mixed and incubated
in for 30 mins at rt . ERK1 & ERK2 were then activated by the addition of Fl-Substrate, ATP
and metal solution and incubated for 1 h at rt . After 1 h, the reaction was terminated by the
addition of 70 mL of Termination Buffer (QuickScout Screening Assist MSA; Carna
Biosciences) to the well. The reaction mixture was applied to LabChip ™ system
(PerkinElmer), and the product and substrate peptide peaks were separated, analyzed and
quantitated. The kinase reaction is evaluated by the product ratio calculated from peak
heights of product (P) and substrate(S) peptides (P/(P+S)).
Compounds of Formulae (I), (II) and (III) are active in this assay as
indicated in Table 1, where A = a single IC ≤50 nM; B = a single IC ≥50 nM and ≤ 250
50 50
nM; C = a single IC50 ≥250 nM.
Table 1
Example # ERK2 Example # ERK2 Example # ERK2 Example # ERK2
IC50 IC50 IC50 IC50
(nM) (nM) (nM) (nM)
GDC-0994 A 13 A 28 A 43 A
BVD-523 A 14 A 29 A 44 A
SCH772984 A 15 A 30 A 45 A
1 C 16 A 31 A 46 A
2 A 17 A 32 A 47 A
3 A 18 A 33 A 48 A
4 C 19 A 34 A 49 A
A 20 A 35 A 50 A
6 A 21 A 36 A 51 A
7 A 22 A 37 A 52 A
8 A 23 A 38 A 53 A
9 A 24 A 39 B 54 A
A 25 A 40 A 55 A
11 A 26 A 41 A 56 A
12 A 27 A 42 C 57 A
Example # ERK2 Example # ERK2 Example # ERK2 Example # ERK2
IC50 IC50 IC50 IC50
(nM) (nM) (nM) (nM)
58 A 74 A 90
59 A 75 - 91 A 107 -
60 A 76 A 92 A 108 -
A A A -
61 77 93 109
62 A 78 110 -
63 A 79 A 95
64 A 80 A 96
65 A 81 A 97
66 A 82 A 98
67 A 83 115 -
68 A 84 A 100
69 A 85 117 -
70 A 86 118 -
71 A 87 119 -
72 A 88
73 A 89 A 105 -
Example 124
ERK and RSK Target Engagement Biomarker (pERK and pRSK Western Blot)
Protocols
BRAF mutant melanoma cells A375 are plated at approximately 1 x 106
cells per 10 cm dish in growth media (RPMI 1640, 10% FBS, non-essential amino acids and
glutamine). The next day the media is removed and replaced with serum free media (RPMI
1640, 0.1% FBS, non-essential amino acids and glutamine) and allowed to incubate
overnight. The following day the serum free media is removed and replaced with fresh serum
free media containing compound. Typical concentrations for drug treatments are 300 nM,
100 nM, 30 nM, 10 nM, 3 nM and 1 nM, with a final DMSO concentration of 0.1%. The
controls include one plate with DMSO alone at 0.1% final concentration and another plate
treated with a compound control at 10 nM final concentration. The cells are treated for 24 h.
At the time of harvest, the cells are scraped directly into the media and spun down at 1800
rpm in order to capture the floating dead or dying cells as well. One wash with 5 mL of PBS
is done, and the cell pellet are frozen or lysed immediately in lysis buffer. The protein
concentrations of the lysates are determined using the Pierce BCA protein assay kit and 50
µg of total cell lysate is loaded per lane of a 15 well, 1.5 mm width Tris glycine gel. The gels
are run at 125 Volts constant voltage until the dye just runs off the gel. They are transferred
using the Invitrogen transfer apparatus onto nitrocellulose membranes at 25 Volts for 2 h.
The nitrocellulose membrane is blocked in 5% (wt/vol) non-fat dried milk protein in
TBS/Tween for 30 mins at rt. The blot is incubated with anti-RSK or with anti-ERK
antibodies. The nitrocellulose membrane is washed 3 times for 10 minutes with vigorous
rocking in 50 mL TBS/Tween then incubated 1 h with HRPx-labeled secondary antibody at
room temperature. The secondary antibodies are diluted in 2% non-fat dried milk protein in
TBS/Tween.
The nitrocellulose is washed as above then developed with freshly
prepared ECL reagent. The nitrocellulose membranes are incubated for 1 minute with 5 mL
ECL reagent. Excess reagent is removed by blotting on a clean paper towel, and the
membrane is wrapped in cellophane before exposing to film. Several exposures of film are
made for each blot. (The western blots may be developed and/or quantitated by other means
if available.) Band densities are quantitated by densitometry, and the scanned densities are
plotted using XLfit to give dose response curves.
Example 125
Proliferation Assay
A375 (melanoma), Colo-205 (colon cancer), Miapaca (pancreatic),
HPAFII (pancreatic), sNF02.0 (neurofibromatosis type 1), sNF96.2 (neurofibromatosis type
1) and 8505 (Thyroid) cells were grown and maintained in RPMI-1640 medium containing
100 U/mL penicillin−streptomycin and 10% fetal bovine serum. Cells were in growth
medium in 96-well opaque-walled clear bottom plates and incubated in the CO incubator
overnight before treatment. Cells were treated with compounds diluted in DMSO and a 10
point 3-fold serial dilutions were done. Plates were placed in 37°C, 5% CO to incubate for 3
days. Before they were developed by adding 100 μL of CellTiter-Glo reagent (Promega) to
the assay plate, plates were shaken briefly for 2 mins and allowed to incubate at room
temperature for 10 mins. The bottom of the plates was pasted with white back seal and
luminescence was recorded with Flexstation3 with setting of luminescence, integration time
500 ms.
Compounds of Formula (I), (II) and (III) are active in this assay as noted
in Table 2. In Table 2: A = a single IC ≤500 nM; B = a single IC ≥500 nM and ≤ 1.0 μM;
50 50
C = a single IC ≥1.0 μM.
Table 2
Example # A375 Example # A375 Example # A375 Example # A375
IC IC IC IC
50 50 50 50
(nM) (nM) (nM) (nM)
GDC-0994 B 16 A 34 A 52 A
BVD-523 A 17 A 35 A 53 A
SCH772984 A 18 A 36 A 54 A
1 C 19 A 37 A 55 A
2 A 20 A 38 A 56 A
3 B 21 A 39 C 57 A
4 C 22 A 40 A 58 A
A 23 A 41 A 59 B
6 A 24 A 42 C 60 A
7 C 25 A 43 A 61 A
8 C 26 A 44 A 62 B
9 A 27 A 45 A 63 A
B 28 A 46 A 64 A
11 C 29 A 47 A 65 A
12 B 30 A 48 B 66 A
13 A 31 A 49 A 67 A
14 A 32 A 50 B 68 A
B 33 A 51 A 69 B
Example # A375 Example # A375 Example # A375 Example # A375
IC50 IC50 IC50 IC50
(nM) (nM) (nM) (nM)
70 B 83 A 96 C 109 A
71 B 84 A 97 A 110 A
72 B 85 A 98 C 111 A
B A A A
73 86 99 112
74 B 87 A 100 A 113 A
75 A 88 A 101 A 114 C
76 A 89 A 102 A 115 A
77 A 90 A 103 A 116 A
78 C 91 B 104 A 117 A
79 A 92 A 105 B 118 A
80 A 93 A 106 A 119 B
81 A 94 A 107 A
82 A 95 C 108 A
Furthermore, although the foregoing has been described in some detail by
way of illustrations and examples for purposes of clarity and understanding, it will be
understood by those of skill in the art that numerous and various modifications can be made
without departing from the spirit of the present disclosure. Therefore, it should be clearly
understood that the forms disclosed herein are illustrative only and are not intended to limit
the scope of the present disclosure, but rather to also cover all modification and alternatives
coming with the true scope and spirit of the invention.
Claims (53)
1. A compound of Formula (I): or a pharmaceutically acceptable salt thereof, wherein: R is selected from the group consisting of C cycloalkyl, halophenyl, C 3-4 1-4 alkoxyphenyl, C alkoxyhalophenyl, C dialkoxyphenyl, halopyridinyl, C 1-4 1-4 1-4 alkoxypyridinyl, C alkylpyridinyl, C cycloalkoxypyridinyl, methylbenzoxazolyl and 1-4 3-5 tetrahydropyranyl; R and R are each independently methyl, hydrogen or deuterium; Y and Y are each independently CH or N; Y is C, CH or N; and 9 10 Y and Y are each independently CH or N; Z is C alkyl optionally substituted with hydroxy; wherein -------- is a single bond when Y is N or CH and -------- is a double bond when Y is C; and wherein the compound of Formula (I) is not
2. The compound of Claim 1, or a pharmaceutically acceptable salt thereof, of the Formula (IA): (IA) wherein: R is selected from the group consisting of halophenyl, halopyridinyl, C alkoxypyridinyl, C alkylpyridinyl, methylbenzoxazolyl and tetrahydropyranyl; and R and R are each independently hydrogen or deuterium.
3. The compound of Claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R is halophenyl or halopyridinyl.
4. The compound of Claim 3, or a pharmaceutically acceptable salt thereof, wherein R is fluorophenyl or fluoropyridinyl.
5. The compound of Claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R is C alkoxypyridinyl or C alkylpyridinyl. 1-4 1-4
6. The compound of Claim 5, or a pharmaceutically acceptable salt thereof, wherein R is isopropoxypyridinyl, methoxypyridinyl or methylpyridinyl.
7. The compound of Claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R is methylbenzoxazolyl or tetrahydropyranyl.
8. The compound of Claim 1, or a pharmaceutically acceptable salt thereof, wherein R is selected from the group consisting of C cycloalkyl, C alkoxyphenyl, C 3-4 1-4 1-4 alkoxyhalophenyl, C dialkoxyphenyl, and C cycloalkoxypyridinyl. 1-4 3-5
9. The compound of any one of Claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein -------- is a double bond.
10. The compound of any one of Claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein -------- is a single bond.
11. The compound of any one of Claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein Y is CH.
12. The compound of any one of Claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein Y is N.
13. The compound of any one of Claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein Y is CH.
14. The compound of any one of Claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein Y is N.
15. The compound of any one of Claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein Y is C.
16. The compound of any one of Claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein Y is CH.
17. The compound of any one of Claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein Y is N.
18. The compound of Claim 1, or a pharmaceutically acceptable salt thereof, wherein Y is N or CH.
19. The compound of Claim 1, or a pharmaceutically acceptable salt thereof, wherein Y is N or CH.
20. The compound of Claim 1, selected from the group consisting of N N N N N N N N N N N N N N N N S S S N N N N O O O N N N N O O O O N N N N N N N N HN HN HN HN N N N N N N N N N O O O O , , , , , N N N N N N S S S N N N O O O O O O N N N N N N N N HN HN HN HN N N N N O O F O , , , , N N N N N N N N N N N N N N N N N S S S S N N N N O O O O N N N N O O O O N N N N N N N HN HN HN HN N N N N O O O O , , , , , and , or a pharmaceutically acceptable salt of the foregoing.
21. The compound of Claim 2, selected from the group consisting of , S N S N HN HN HN HN N N N , , , , , , , , , and , or a or a pharmaceutically acceptable salt of the foregoing.
22. The compound of Claim 1 or 2, selected from the group consisting of (S)(2-(4-(5-(1-(2-hydroxyethyl)-1H-1,2,4-triazolyl)thiazolyl)-3,6- dihydropyridin-1(2H)-yl)oxoethyl)(3-(6-isopropoxypyridinyl)-1H-pyrazolo[4,3- b]pyridinyl)-2,7-diazaspiro[4.4]nonanone; (S)(2-(4-(5-(1-methyl-1H-1,2,4-triazolyl)thiazolyl)-3,6-dihydropyridin- 1(2H)-yl)oxoethyl)(3-(2-methylbenzo[d]oxazolyl)-1H-pyrazolo[4,3-b]pyridinyl)- 2,7-diazaspiro[4.4]nonanone; (S)(3-(6-isopropoxypyridinyl)-1H-pyrazolo[4,3-b]pyridinyl)(2-(4-(5-(1- methyl-1H-1,2,4-triazolyl)thiazolyl)-3,6-dihydropyridin-1(2H)-yl)oxoethyl-1,1-d2)- 2,7-diazaspiro[4.4]nonanone; and (S)(2-(4-(5-(1-methyl-1H-1,2,4-triazolyl)thiazolyl)-3,6-dihydropyridin- 1(2H)-yl)oxoethyl)(3-(2-methylpyridinyl)-1H-pyrazolo[4,3-b]pyridinyl)-2,7- diazaspiro[4.4]nonanone; or a pharmaceutically acceptable salt of the foregoing.
23. A compound of Formula (II): (II) or a pharmaceutically acceptable salt thereof, wherein: R is a methyloxazolopyridinyl, or a pyridinyl substituted with one or two substituents independently selected from the group consisting of methyl, C alkoxy, isopropylthio, fluoro, chloro, cyano, trifluoromethyl, and -C(=O)NHCH ; or R is a dimethylbenzodioxolyl, a methylbenzoxazolyl, or a phenyl substituted with one or two substituents independently selected from the group consisting of methoxy, fluoro, chloro, cyano, trifluoromethyl and -C(=O)NHCH ; R is or ; R and R are each independently hydrogen or deuterium; R is H or methyl; R is hydrogen; Y is N, CH or CF; Y is N, C, CH or CF; and Y is N or CH; wherein -------- is a single bond when Y is N, CH or CF and -------- is a double bond when Y is C; wherein the compound of Formula (II) is not selected from the group consisting of N O N HN HN HN HN N N N N O O O O , , , , , N N N N N O O HN HN HN HN , , , , , N N N N N N N N N N N N O O O N N N O O O N N N HN HN HN N N N N N N O 3 O F F , , , , , , N N N O O O N N N O O O HN HN N N N N N N O 3 O , , , , , N HN 3 F O N , , , , , N O N O HN N HN N O 3 O , , , , O N O N N O N N O N O HN HN O HN N N HN N N N N O , , , and .
24. The compound of Claim 23, or a pharmaceutically acceptable salt thereof, 4 5 4 wherein when Y is CH and R is , then R cannot be pyridinyl substituted with a single substituent selected from the group consisting of methyl, methoxy, fluoro, trifluoromethyl and isopropoxy.
25. The compound of Claim 23, or a pharmaceutically acceptable salt thereof, 4 5 5 4 wherein when Y is CH, Y is C and R is , then R cannot be phenyl substituted with a single substituent selected from the group consisting of fluoro, methoxy and cyano.
26. The compound of Claim 23, or a pharmaceutically acceptable salt thereof, 4 5 5 4 wherein when Y is CH, Y is C and R is , then R cannot be phenyl substituted with both a methoxy and a cyano and R cannot be phenyl substituted with both a trifluoromethyl and a cyano.
27. The compound of Claim 23, or a pharmaceutically acceptable salt thereof, 4 5 5 4 wherein when Y is CH, Y is C and R is , then R cannot be pyridinyl substituted with a single isopropoxy and R cannot be phenyl substituted with a single cyano.
28. The compound of Claim 23, or a pharmaceutically acceptable salt thereof, 4 5 5 4 wherein when Y is CH, Y is C and R is , then R cannot be phenyl substituted with both a methoxy and a cyano.
29. The compound of Claim 23, or a pharmaceutically acceptable salt thereof, 4 5 5 4 wherein when Y is CH, Y is C and R is or , then R cannot be a dimethylbenzodioxolyl and R cannot be a methylbenzoxazolyl.
30. The compound of any one of Claims 23 to 29, or a pharmaceutically acceptable salt thereof, wherein R is a methyloxazolopyridinyl, or a pyridinyl substituted with one or two substituents independently selected from the group consisting of methyl, C alkoxy, isopropylthio, fluoro, chloro, cyano, trifluoromethyl, and -C(=O)NHCH .
31. The compound of any one of Claims 23 to 29, or a pharmaceutically acceptable salt thereof, wherein R is a dimethylbenzodioxolyl, a methylbenzoxazolyl, or a phenyl substituted with one or two substituents independently selected from the group consisting of methoxy, fluoro, chloro, cyano, trifluoromethyl and -C(=O)NHCH .
32. The compound of any one of Claims 23 to 31, or a pharmaceutically acceptable salt thereof, wherein R is .
33. The compound of any one of Claims 23 to 31, or a pharmaceutically acceptable salt thereof, wherein R is .
34. The compound of Claim 23, selected from the group consisting of N N O HN N HN HN N N N O O O O O , , , , , HN HN HN HN O N N F F N F Cl F Cl , , , , , O N N N N N N O O O N N N O O O N N N O O O N N N HN HN HN N N N F F F O , , , , , HN HN HN HN N F F N , , , , , N N N O O O O O O N N N O O O N N N N N N HN HN HN HN HN N N N N N N F Cl O , , , , , , N N N N N N N N N N N N N N N O O O N N N N O O O N N N N HN HN N HN N N N O F N F O , , , , , N N N N N N N N N N N N N N N O O O O N N N N O O O O N N N N N N HN HN HN N N N N N N N O Cl O , , , , and , or a pharmaceutically acceptable salt of the foregoing.
35. The compound of Claim 23, selected from the group consisting of (S)(3-(5-fluoropyridinyl)-1H-indazolyl)(2-(4-(4-(1-methyl-1H-1,2,4- triazolyl)phenyl)-3,6-dihydropyridin-1(2H)-yl)oxoethyl-1,1-d2)-2,7- diazaspiro[4.4]nonanone; and (S)(2-(4-(4-(1-methyl-1H-1,2,4-triazolyl)phenyl)-3,6-dihydropyridin-1(2H)-yl)- 2-oxoethyl)(3-(2-methyloxazolo[4,5-b]pyridinyl)-1H-indazolyl)-2,7- diazaspiro[4.4]nonanone; or a pharmaceutically acceptable salt of the foregoing.
36. A compound of Formula (III): (III) or a pharmaceutically acceptable salt thereof, wherein: R is a heterocyclyl selected from the group consisting of piperidinyl, 1,1- dioxidotetrahydrothiopyranyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, dihydropyranyl, 2-oxaazaspiro[3.5]nonanyl, and morpholino; wherein said heterocyclyl is optionally substituted with one or two substituents selected from the group consisting of methyl, fluoro and trifluoroethyl; or R is a five-membered heteroaryl selected from the group consisting of thiazolyl, pyrazolyl, and triazolyl; wherein said five-membered heteroaryl is substituted with methyl or isopropyl; R is or ; 11 12 R and R are each independently hydrogen or deuterium; Y is N or CH; and Y is N, C, or CH; wherein -------- is a single bond when Y is N or CH and -------- is a double bond when Y is C; and wherein the compound of Formula (III) is not selected from the group consisting of N N N O N O N N N N N N N N N O N O N N N N N O O O O O N N N N N O O O O O N N N N N HN HN HN HN HN N N N N N N O O O O O , , , , , and .
37. The compound of Claim 36, or a pharmaceutically acceptable salt thereof, 7 8 10 9 wherein when Y is CH, Y is C and R is , then R cannot be tetrahydropyranyl, dihydropyranyl, methylpyrazolyl or morpholino.
38. The compound of Claim 36, or a pharmaceutically acceptable salt thereof, 7 8 10 9 wherein when Y is CH, Y is C and R is then R cannot be tetrahydropyranyl or morpholino.
39. The compound of any one of Claims 36 to 38, or a pharmaceutically acceptable salt thereof, wherein R is heterocyclyl.
40. The compound of any one of Claims 36 to 38, or a pharmaceutically acceptable salt thereof, wherein R is five-membered heteroaryl.
41. The compound of any one of Claims 36 to 40, or a pharmaceutically acceptable salt thereof, wherein R is .
42. The compound of any one of Claims 36 to 40, or a pharmaceutically acceptable salt thereof, wherein R is .
43. The compound of Claim 36, selected from the group consisting of , N NCF , , , , , , O N N O N N O N N N N N N N N N N HN HN HN N HN N N N O O O , , , , , , N N N N N N N N N N N N N O O O O N N N N O O O O N N N N N N N N N HN HN HN HN HN N N N N N N N N N N N N N , , , , , , HN HN , , , , and , or a pharmaceutically acceptable salt of the foregoing.
44. The compound of Claim 36, which is (S)(2-(4-(4-(1-methyl-1H-1,2,4-triazol yl)phenyl)-3,6-dihydropyridin-1(2H)-yl)oxoethyl-1,1-d2)(3-(tetrahydro-2H-pyran yl)-1H-indazolyl)-2,7-diazaspiro[4.4]nonanone, or a pharmaceutically acceptable salt thereof.
45. A pharmaceutical composition comprising an effective amount of a compound of any one of Claims 1 to 44, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, excipient, or combination thereof.
46. A method for inhibiting the activity of ERK1 and/or ERK2 comprising providing an effective amount of a compound of any one of Claims 1 to 44, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of Claim 45 to a sample comprising a cancer cell, wherein the cancer cell is selected from the group consisting of a lung cancer cell, a pancreatic cancer cell, a colon cancer cell, a myeloid leukemia cell, a thyroid cancer cell, myelodysplastic syndrome (MDS) cell, a bladder carcinoma cell, an epidermal carcinoma cell, a melanoma cell, a breast cancer cell, a prostate cancer cell, a head and neck cancer cell, an ovarian cancer cell, a brain cancer cell, a cancer of mesenchymal origin cell, a sarcoma cell, a tetracarcinoma cell, a neuroblastoma cell, a kidney carcinoma cell, a hepatoma cell, a non-Hodgkin's lymphoma cell, a multiple myeloma cell and an anaplastic thyroid carcinoma cell and a neurofibromatosis cell.
47. Use of an effective amount of a compound of any one of Claims 1 to 44, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of Claim 45 in the manufacture of a medicament for ameliorating or treating a cancer through ERK1 and/or ERK2 modulation, wherein the cancer is selected from the group consisting of a lung cancer, a pancreatic cancer, a colon cancer, a myeloid leukemia, a thyroid cancer, myelodysplastic syndrome (MDS), a bladder carcinoma, an epidermal carcinoma, a melanoma, a breast cancer, a prostate cancer, a head and neck cancer, an ovarian cancer, a brain cancer, a cancer of mesenchymal origin, a sarcoma, a tetracarcinoma, a neuroblastoma, a kidney carcinoma, a hepatoma, a non-Hodgkin's lymphoma, a multiple myeloma, an anaplastic thyroid carcinoma and neurofibromatosis.
48. Use of an effective amount of a compound of any one of Claims 1 to 44, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of Claim 45 in the manufacture of a medicament for inhibiting replication of a malignant growth or a tumor through ERK1 and/or ERK2 modulation, wherein the malignant growth or tumor is due to a cancer that is selected from the group consisting of a lung cancer, a pancreatic cancer, a colon cancer, a myeloid leukemia, a thyroid cancer, myelodysplastic syndrome (MDS), a bladder carcinoma, an epidermal carcinoma, a melanoma, a breast cancer, a prostate cancer, a head and neck cancer, an ovarian cancer, a brain cancer, a cancer of mesenchymal origin, a sarcoma, a tetracarcinoma, a neuroblastoma, a kidney carcinoma, a hepatoma, a non- Hodgkin's lymphoma, a multiple myeloma, an anaplastic thyroid carcinoma and neurofibromatosis.
49. Use of an effective amount of a compound of any one of Claims 1 to 44, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of Claim 45 in the manufacture of a medicament for ameliorating or treating a cancer through ERK1 and/or ERK2 modulation, wherein the malignant growth or tumor is due to a cancer that is selected from the group consisting of a lung cancer, a pancreatic cancer, a colon cancer, a myeloid leukemia, a thyroid cancer, myelodysplastic syndrome (MDS), a bladder carcinoma, an epidermal carcinoma, a melanoma, a breast cancer, a prostate cancer, a head and neck cancer, an ovarian cancer, a brain cancer, a cancer of mesenchymal origin, a sarcoma, a tetracarcinoma, a neuroblastoma, a kidney carcinoma, a hepatoma, a non-Hodgkin's lymphoma, a multiple myeloma, an anaplastic thyroid carcinoma and neurofibromatosis.
50. The compound of any one of Claims 1 to 44, substantially as herein described with reference to any example thereof.
51. The pharmaceutical composition of Claim 45, substantially as herein described with reference to any example thereof.
52. The method of Claim 46, substantially as herein described with reference to any example thereof.
53. Use of any one of Claims 47 to 49, substantially as herein described with reference to any example thereof.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201662404668P | 2016-10-05 | 2016-10-05 | |
US62/404,668 | 2016-10-05 | ||
PCT/US2017/054865 WO2018067512A1 (en) | 2016-10-05 | 2017-10-03 | Spirocyclic compounds |
Publications (2)
Publication Number | Publication Date |
---|---|
NZ751398A NZ751398A (en) | 2021-03-26 |
NZ751398B2 true NZ751398B2 (en) | 2021-06-29 |
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