NZ747854B2 - Egfr inhibitor compounds - Google Patents
Egfr inhibitor compounds Download PDFInfo
- Publication number
- NZ747854B2 NZ747854B2 NZ747854A NZ74785417A NZ747854B2 NZ 747854 B2 NZ747854 B2 NZ 747854B2 NZ 747854 A NZ747854 A NZ 747854A NZ 74785417 A NZ74785417 A NZ 74785417A NZ 747854 B2 NZ747854 B2 NZ 747854B2
- Authority
- NZ
- New Zealand
- Prior art keywords
- compound
- optionally substituted
- substituted
- alkyl
- cancer
- Prior art date
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 334
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- 230000035772 mutation Effects 0.000 claims description 60
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- LXNAVEXFUKBNMK-UHFFFAOYSA-N palladium(II) acetate Substances [Pd].CC(O)=O.CC(O)=O LXNAVEXFUKBNMK-UHFFFAOYSA-N 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
- 230000000737 periodic Effects 0.000 description 1
- 239000008177 pharmaceutical agent Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 239000002953 phosphate buffered saline Substances 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- GLUUGHFHXGJENI-UHFFFAOYSA-N piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 1
- JTHRRMFZHSDGNJ-UHFFFAOYSA-N piperazine-2,3-dione Chemical compound O=C1NCCNC1=O JTHRRMFZHSDGNJ-UHFFFAOYSA-N 0.000 description 1
- NQRYJNQNLNOLGT-UHFFFAOYSA-N piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920001467 poly(styrenesulfonates) Polymers 0.000 description 1
- 229920000728 polyester Polymers 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 239000001184 potassium carbonate Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- OFPTZWGZSRJCOT-MSPNRCMCSA-M potassium;2-[(1S,2S,3R,4S,5S,6R)-3-(diaminomethylideneamino)-4-[(2R,3R,4R,5S)-3-[(2S,3S,4S,5R,6S)-4,5-dihydroxy-6-(hydroxymethyl)-3-(methylamino)oxan-2-yl]oxy-4-formyl-4-hydroxy-5-methyloxolan-2-yl]oxy-2,5,6-trihydroxycyclohexyl]guanidine;(2S,5R,6R)-3,3-d Chemical compound [K+].N([C@H]1[C@H]2SC([C@@H](N2C1=O)C([O-])=O)(C)C)C(=O)CC1=CC=CC=C1.CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@H]1[C@H](N=C(N)N)[C@@H](O)[C@H](N=C(N)N)[C@@H](O)[C@@H]1O OFPTZWGZSRJCOT-MSPNRCMCSA-M 0.000 description 1
- 238000002953 preparative HPLC Methods 0.000 description 1
- 239000000955 prescription drug Substances 0.000 description 1
- 239000000092 prognostic biomarker Substances 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 230000000644 propagated Effects 0.000 description 1
- 125000001325 propanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- 230000005588 protonation Effects 0.000 description 1
- KYQCOXFCLRTKLS-UHFFFAOYSA-N pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- KAESVJOAVNADME-UHFFFAOYSA-N pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 1
- LISFMEBWQUVKPJ-UHFFFAOYSA-N quinolin-2(1H)-one Chemical compound C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 description 1
- SMWDFEZZVXVKRB-UHFFFAOYSA-N quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 230000001105 regulatory Effects 0.000 description 1
- 108700000006 regulatory domains Proteins 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 238000007790 scraping Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000009094 second-line therapy Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 235000015170 shellfish Nutrition 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- LBJQKYPPYSCCBH-UHFFFAOYSA-N spiro[3.3]heptane Chemical compound C1CCC21CCC2 LBJQKYPPYSCCBH-UHFFFAOYSA-N 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 229960002317 succinimide Drugs 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 230000004083 survival Effects 0.000 description 1
- 230000002459 sustained Effects 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- YPWFISCTZQNZAU-UHFFFAOYSA-N tetrahydro-2H-thiopyran Chemical compound C1CCSCC1 YPWFISCTZQNZAU-UHFFFAOYSA-N 0.000 description 1
- 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
- 238000010257 thawing Methods 0.000 description 1
- FZWLAAWBMGSTSO-UHFFFAOYSA-N thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 1
- YTPLMLYBLZKORZ-UHFFFAOYSA-N thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 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
- BSUNTQCMCCQSQH-UHFFFAOYSA-N triazine Chemical compound C1=CN=NN=C1.C1=CN=NN=C1 BSUNTQCMCCQSQH-UHFFFAOYSA-N 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 125000004952 trihaloalkoxy group Chemical group 0.000 description 1
- 125000004385 trihaloalkyl group Chemical group 0.000 description 1
- KQBSGRWMSNFIPG-UHFFFAOYSA-N trioxane Chemical compound C1COOOC1 KQBSGRWMSNFIPG-UHFFFAOYSA-N 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 231100000588 tumorigenic Toxicity 0.000 description 1
- 230000000381 tumorigenic Effects 0.000 description 1
- 230000036642 wellbeing Effects 0.000 description 1
- KPGXRSRHYNQIFN-UHFFFAOYSA-N α-Ketoglutaric acid Chemical compound OC(=O)CCC(=O)C(O)=O KPGXRSRHYNQIFN-UHFFFAOYSA-N 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
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Abstract
Disclosed herein are nitrogen-containing bicyclic compounds, 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
EGFR INHIBITOR 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 EGFR inhibitor compounds, together with
pharmaceutical compositions, and methods of synthesizing the same. Also disclosed herein
are methods of ameliorating and/or treating a cancer with one or more of the compounds
described herein.
Description
Overexpression of the EGFR gene has been identified in a variety of
cancers including head and neck, brain, breast, colon and lung. In addition to
overexpression, EGFR activating mutations have been detected in a subset of non-small cell
lung cancers (NSCLCs) tumors. The majority of patients who respond well to first and
second-generation EGFR inhibitors eventually develop resistance to these inhibitors. The
most common resistance mechanism is an acquired gatekeeper mutation of threonine-to-
methionine (T790M) in the EGFR gene. EGFR overexpression or activation, and acquired
EGFR T790M mutation is observed in human cancers and is associated with high rates of
cancer cell proliferation and drug resistance.
SUMMARY
[0003a] The present invention provides a compound of Formula (I), or a
pharmaceutically acceptable salt thereof, wherein Formula (I) has the structure:
(X )
R HN R
R is selected from hydrogen, halogen, hydroxy, cyano, an optionally substituted C -
alkyl, an optionally substituted C - haloalkyl, an optionally substituted C - alkoxy and an
1 4 1 4
optionally substituted C - haloalkoxy;
R is a substituted 6-15 membered heteroaryl or a substituted 6-15 membered
heterocyclyl, wherein the heteroaryl and the heterocyclyl independently contains 1-4
heteroatoms selected from N, O and S, and the heteroaryl and the heterocyclyl is substituted
with an optionally substituted bicyclo[1.1.1]pentyl;
R is selected from hydrogen, an optionally substituted C - alkyl, an optionally
substituted aryl, an optionally substituted heteroaryl and an optionally substituted
heterocyclyl, wherein when substituted, R is substituted by one or more substituents selected
from halogen, cyano, an unsubstituted C - alkyl, an optionally substituted aryl, -C(O)R , -
5B 5C 6A 6B 7A 7B
SO R , -NHC(O)R and -(CR R ) NR R ;
X is O, S or NR ;
R is selected from hydrogen, an optionally substituted C - alkyl, an optionally
substituted C1-4 haloalkyl and an optionally substituted C3-8 cycloalkyl;
5A 5B 5C
R , R and R are independently selected from hydrogen, an optionally substituted
C - alkyl, an optionally substituted C - haloalkyl, an optionally substituted C cycloalkyl,
1 4 1 4 3-8
an optionally substituted aryl, an optionally substituted heteroaryl and an optionally
substituted heterocyclyl;
6A 6B
R and R are independently selected from hydrogen, halogen, an optionally
substituted C - alkyl, an optionally substituted C - haloalkyl and an optionally substituted
1 4 1 4
C - cycloalkyl;
7A 7B
R and R are independently selected from hydrogen, an optionally substituted C -
alkyl, an optionally substituted C - haloalkyl and an optionally substituted C - cycloalkyl;
1 4 3 8
A is CR ;
R is selected from hydrogen, halogen, cyano, an optionally substituted C - alkyl, an
optionally substituted C - haloalkyl and an optionally substituted C cycloalkyl;
1 4 3-8
m is 0 or 1; and
n is 0, 1, 2 or 3; and
when a group is optionally substituted, the group can be substituted with one or more
groups individually and independently selected from D, halogen, hydroxy, C alkoxy, C
1-4 1-4
alkyl, C cycloalkyl, aryl, heteroaryl, C haloalkyl, cyano, alkenyl, alkynyl, cycloalkenyl,
3-8 1-6
aryl(alkyl), heteroaryl(alkyl), heterocyclyl(alkyl), acyl, thiocarbonyl, O-carbamyl,
N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, C-thioamido, N-
thioamido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, sulfenyl, sulfinyl,
sulfonyl, haloalkoxy, an amino, a mono-alkyl substituted amine group and a di-alkyl
substituted amine group.
[0003b] The present invention further provides a compound selected from the
group consisting of:
, , , and , or a
pharmaceutically acceptable salt of any of the foregoing.
[0003c] The present invention further provides pharmaceutical composition
comprising an effective amount of the compound of the invention, or a pharmaceutically
acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, excipient or
combination thereof.
[0003d] The present invention further provides use of an effective amount of a
compound of the invention, or a pharmaceutically acceptable salt thereof, or a
pharmaceutical composition of the invention in the manufacture of a medicament for
ameliorating or treating a cancer, wherein the cancer is selected from a lung cancer, a
pancreatic cancer, a colon cancer, a breast cancer, a prostate cancer, a head and neck cancer,
an ovarian cancer, a brain cancer and a kidney carcinoma.
[0003e] The present invention further provides use of an effective amount of a
compound of the invention, or a pharmaceutically acceptable salt thereof, or a
pharmaceutical composition of the invention 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 selected from a lung cancer, a pancreatic cancer, a colon cancer, a
breast cancer, a prostate cancer, a head and neck cancer, an ovarian cancer, a brain cancer
and a kidney carcinoma.
[0003f] The present invention further provides use of an effective amount of a
compound of the invention, or a pharmaceutically acceptable salt thereof, or a
pharmaceutical composition of the invention in the manufacture of a medicament for
ameliorating or treating a malignant growth or tumor, wherein the malignant growth or tumor
is due to a cancer selected from a lung cancer, a pancreatic cancer, a colon cancer, a breast
cancer, a prostate cancer, a head and neck cancer, an ovarian cancer, a brain cancer and a
kidney carcinoma.
[0003g] The present invention further provides use of an effective amount of a
compound of the invention, or a pharmaceutically acceptable salt thereof, or a
pharmaceutical composition of the invention in the manufacture of a medicament for
inhibiting the activity of EGFR, wherein the EGFR has one or more selected from a deletion
in exon 19, an insertion in exon 20, a mutation at L858R and an acquired EGFR T790M
mutation.
Some embodiments disclosed herein relate to a compound of Formula (I),
or a pharmaceutically acceptable salt thereof.
Some embodiments described herein relate to a pharmaceutical
composition, that can include an effective amount a compound of Formula (I), 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 Formula (I), or a
pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a
compound described herein (for example, a compound of Formula (I), 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 Formula (I), or a pharmaceutically acceptable salt thereof) or a
pharmaceutical composition that includes of a compound described herein (for example, a
compound of Formula (I), 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 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 of a compound described herein (for example, a
compound of Formula (I), 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 Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical
composition that includes of a compound described herein (for example, a compound of
Formula (I), 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
Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition
that includes of a compound described herein (for example, a compound of Formula (I), 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 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 of a
compound described herein (for example, a compound of Formula (I), 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 of a compound described herein (for example, a compound of Formula (I), 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 Formula (I), or a pharmaceutically acceptable
salt thereof) or a pharmaceutical composition that includes of a compound described herein
(for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) in
the manufacture of a medicament for ameliorating or treating a cancer described herein that
can include contacting 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
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 of a compound described herein (for example, a compound of Formula (I), or a
pharmaceutically acceptable salt thereof) for ameliorating or treating a cancer described
herein that can include contacting 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 EGFR (for example, inhibiting the activity of EGFR with acquired EGFR T790M
mutation, inhibiting the activity of EGFR with a deletion in exon 19 (such as A740-A750),
inhibiting the activity of EGFR with an insertion in exon 20, inhibiting the activity of EGFR
with a mutation at L858R, inhibiting the activity of wildtype EGFR and/or where EGFR is
overexpressed or activated) that can include providing 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 of a compound described herein
(for example, a compound of Formula (I), 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 Formula (I), or a pharmaceutically acceptable salt thereof) or a
pharmaceutical composition that includes of a compound described herein (for example, a
compound of Formula (I), or a pharmaceutically acceptable salt thereof) in the manufacture
of a medicament for inhibiting the activity of EGFR (for example, inhibiting the activity of
EGFR with acquired EGFR T790M mutation, inhibiting the activity of EGFR with a deletion
in exon 19 (such as A740-A750), inhibiting the activity of EGFR with an insertion in exon
, inhibiting the activity of EGFR with a mutation at L858R, inhibiting the activity of
wildtype EGFR and/or where EGFR is overexpressed or activated). Still other embodiments
described herein relate to 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 of a compound described herein (for example, a
compound of Formula (I), or a pharmaceutically acceptable salt thereof) for inhibiting the
activity of EGFR (for example, inhibiting the activity of EGFR with acquired EGFR T790M
mutation, inhibiting the activity of EGFR with a deletion in exon 19 (such as A740-A750),
inhibiting the activity of EGFR with an insertion in exon 20, inhibiting the activity of EGFR
with a mutation at L858R, inhibiting the activity of wildtype EGFR and/or where EGFR is
overexpressed or activated).
Some embodiments described herein relate to a method for ameliorating or
treating a cancer described herein that can include inhibiting the activity of EGFR (for
example, inhibiting the activity of EGFR with acquired EGFR T790M mutation, inhibiting
the activity of EGFR with a deletion in exon 19 (such as A740-A750), inhibiting the activity
of EGFR with an insertion in exon 20, inhibiting the activity of EGFR with a mutation at
L858R, inhibiting the activity of wildtype EGFR and/or where EGFR is overexpressed or
activated) using 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 of a compound described herein (for example, a compound of
Formula (I), 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 Formula (I), or a pharmaceutically acceptable salt thereof) or a
pharmaceutical composition that includes of a compound described herein (for example, a
compound of Formula (I), 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 EGFR (for example, inhibiting the activity of EGFR with acquired EGFR T790M
mutation, inhibiting the activity of EGFR with a deletion in exon 19 (such as A740-A750),
inhibiting the activity of EGFR with an insertion in exon 20, inhibiting the activity of EGFR
with a mutation at L858R, inhibiting the activity of wildtype EGFR and/or where EGFR is
overexpressed or activated). Still other embodiments described herein relate to 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 of a
compound described herein (for example, a compound of Formula (I), or a pharmaceutically
acceptable salt thereof) for ameliorating or treating a cancer described herein by inhibiting
the activity of EGFR (for example, inhibiting the activity of EGFR with acquired EGFR
T790M mutation, inhibiting the activity of EGFR with a deletion in exon 19 (such as A740-
A750), inhibiting the activity of EGFR with an insertion in exon 20, inhibiting the activity of
EGFR with a mutation at L858R, inhibiting the activity of wildtype EGFR and/or where
EGFR is overexpressed or activated).
DETAILED DESCRIPTION
Inhibition of EGFR can have therapeutic effects in the treatment of cancer.
It has been shown that EGFR can mutate and become activated, driving tumor growth.
Epidermal growth factor receptor (EGFR) has an extracellular ligand binding domain, a
transmembrane portion and intracellular tyrosine kinase and regulatory domains. Upon
binding of a specific ligand, EGFR undergoes conformational change and phosphorylation of
the intracellular domain occurs leading to downstream signal transduction that regulates
cellular proliferation. Constitutive activation of EGFR leads to increased intracellular
pathways activity which eventually leads to cell proliferation, angiogenesis, invasion and/or
metastasis.
Overexpression of the EGFR gene has been identified in a variety of
cancers including head and neck, brain, breast, colon and lung. In non-small cell lung
cancer, the frequency of EGFR overexpression has been determined to be 40% to 80%. In
addition to overexpression, EGFR activating mutations have been detected in a subset of
non-small cell lung cancers (NSCLCs) tumors, which represent 10% to 30% of all NSCLCs.
The mutations occur in exons 18, 19, 20 and 21 of the tyrosine kinase domain of the EGFR
gene. The majority of mutations in exon 21 are point mutations whereas exon 19 consists of
almost entirely in-frame deletions. The L858R point mutation and the deletion in exon 19
(such as delA740-A750), account up to 86% of all EGFR mutations. Also, EGFR exon 20
insertions comprise approximately 4–9.2% of all EGFR-mutated lung tumors (Arcila et al.,
Mol Cancer Ther. (2013) 12(2):220-229; Mitsudomi et al., FEBS J. (2010) 277(2):301-308;
and Oxnard et al., J Thorac Oncol. (2013) 8(2):179-184). These mutations result in increased
kinase activity of the EGF receptor in the absence of growth factors. The above-mentioned
mutations in EGF receptor were shown to be a predictive biomarker of efficacy in response
to EGFR tyrosine kinase inhibitors. These findings have revolutionized the way in which
EGFR inhibitors are used as therapy for NSCLC patients with activating EGFR mutations.
The EGFR inhibitors, erlotinib and gefitinib (considered first generation EGFR inhibitors)
were approved in the United States, initially as second-line therapies. However, subsequent
clinical trials of EGFR inhibitors, including the first-generation EGFR inhibitors (gefitinib)
and second-generation EGFR inhibitor (afatinib) demonstrated significant improvements in
overall response rates in NSCLC patients with EGFR activating mutations in the frontline
setting.
However, the majority of patients who respond well to the first and
second-generation EGFR inhibitors eventually develop resistance to these inhibitors. The
most common resistance mechanism, which is observed in approximately 50% of the
patients, is an acquired gatekeeper mutation of threonine-to-methionine (T790M) in the
EGFR gene. This mutation increases the receptor’s affinity for ATP and decreases the
effectiveness of first generation EGFR inhibitors. Therefore, the NSCLC patients who
refract on first and second-generation EGFR inhibitors need new therapies that can overcome
the acquired resistance associated with the T790M mutation.
Provided herein are compounds that can inhibit the kinase activity of
EGFR. As EGFR inhibitors, the compounds described herein can be used to ameliorate
and/or treat a variety of cancers (including those with acquired EGFR T790M mutation, a
mutation at L858R, a deletion in exon 19 (such as A740-A750), inhibiting the activity of
EGFR with an insertion in exon 20, inhibiting the activity of wildtype EGFR and/or where
EGFR is overexpressed or activated) such as non-small cell lung, head and neck, brain,
breast and colon cancer.
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.
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 D (deuterium), halogen, hydroxy, C alkoxy, C alkyl, C
1-4 1-4 3-8
cycloalkyl, aryl, heteroaryl, C haloalkyl, cyano, alkenyl, alkynyl, cycloalkenyl, aryl(alkyl),
heteroaryl(alkyl), heterocyclyl(alkyl), acyl, thiocarbonyl, O-carbamyl, N-carbamyl,
O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, C-thioamido, N-thioamido, S-
sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, sulfenyl, sulfinyl, sulfonyl, haloalkoxy,
an amino, a mono-substituted amine group and a di-substituted amine group.
As used herein, “C to C ” in which “a” and “b” are integers refer to the
number of carbon atoms in a group. The indicated group 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, the
3 2 2 2 3 2 3 3 3
broadest range described in these definitions is to be assumed.
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, heteroaryl or
a b a b
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, either indirectly through
intermediate atoms, or directly to one another, to form a ring, for example:
As used herein, the term “alkyl” refers to a fully saturated aliphatic
hydrocarbon group. The alkyl moiety may be branched or straight chain. Examples of
branched alkyl groups include, but are not limited to, iso-propyl, sec-butyl, t-butyl and the
like. Examples of straight chain alkyl groups include, but are not limited to, methyl, ethyl, n-
propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl and the like. The alkyl group may have 1 to 30
carbon atoms (whenever it appears herein, a numerical range such as “1 to 30” refers to each
integer in the given range; e.g., “1 to 30 carbon atoms” means that the alkyl group may
consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 30 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 12 carbon atoms. The alkyl group could also be a lower alkyl having 1 to 6 carbon
atoms. An alkyl group may be substituted or unsubstituted.
The term “alkenyl” used herein refers to a monovalent straight or
branched chain radical containing one or more carbon double bonds. The alkenyl group may
have 2 to 30 carbon atoms, 2 to 12 carbon atoms or 2 to 6 carbon atoms. Examples of an
alkenyl include, but are not limited to, 1-propenyl, 2-propenyl, 2-methylpropenyl, 1-
butenyl, 2-butenyl and the like. An alkenyl group may be unsubstituted or substituted.
The term “alkynyl” used herein refers to a monovalent straight or
branched chain radical containing one or more carbon triple bonds. The alkynyl group may
have 2 to 30 carbon atoms, 2 to 12 carbon atoms or 2 to 6 carbon atoms. Examples of an
alkenyl include, but not limited to, 1-propynyl, 1-butynyl, 2-butynyl and the like. 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. 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.
As used herein, the term “fused” refers to a connectivity between two
rings in which two adjacent atoms sharing at least one bond (saturated or unsaturated) are
common to the rings. For example, in the following structure, rings A and B are fused
. Examples of fused ring structures include, but are not limited to,
decahydronaphthalene, 1H-indole, quinolone, chromane, bicyclo[2.1.0]pentane and 6,7,8,9-
tetrahydro-5H-benzo[7]annulene.
As used herein, the term “bridged” refers to a connectivity wherein three
or more atoms are shared between two rings. The following structures and
are examples of “bridged” rings because the indicated atoms are shared
between at least two rings. Examples of bridged ring structures include, but are not limited
to, bicyclo[1.1.1]pentane, 2-oxabicyclo[1.1.1]pentane, 5-azabicyclo[2.1.1]hexane, 6-
azabicyclo[3.1.1]heptane, adamantane and norbornane.
As used herein, the term “spiro” refers to a connectivity between two rings
wherein the rings have only one atom in common. For example, in the structure
rings C and D are joined by a spiro connection. Examples of spiro connected ring structures
include, but are not limited to, spiro[3.3]heptane, 2,6-diazaspiro[3.3]heptane, 2-oxa
azaspiro[3.3]heptane, spiro[4.5]decane and 2,6-dioxaspiro[3.3]heptane.
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 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).
When composed of two or more rings, the rings may be connected together in a fused,
bridged or spiro fashion. A cycloalkenyl group may be unsubstituted or substituted.
As used herein, “cycloalkynyl” refers to a mono- or multi- cyclic
hydrocarbon ring system that contains one or more triple bonds in at least one ring. If there
is more than one triple bond, the triple bonds cannot form a fully delocalized pi-electron
system throughout all the rings. Cycloalkynyl groups can contain 8 to 30 atoms in the
ring(s), 8 to 20 atoms in the ring(s) or 8 to 10 atoms in the ring(s). When composed of two
or more rings, the rings may be joined together in a fused, bridged or spiro fashion. A
cycloalkynyl 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, bicyclic and tricyclic
aromatic ring system (a ring system with fully delocalized pi-electron system) that contain(s)
one or more heteroatoms (for example, 1, 2, 3, 4 or 5 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. Examples of heteroaryl
rings include, but are not limited to, 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, bridged,
or spiro fashion. Additionally, any nitrogens in a heteroalicyclic 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, 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-oxathiolane, 1,3-dithiole, 1,3-dithiolane, 1,4-oxathiane, tetrahydro-1,4-thiazine,
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/or 3,4-methylenedioxyphenyl). Examples of bridged heterocyclic
compounds include, but are not limited to, 1,4-diazabicyclo[2.2.2]octane and 1,4-
diazabicyclo[3.1.1]heptane. Examples of spiro-connected heterocyclic compounds include,
but are not limited to, 2-azaspiro[3,3]heptane, 2,6-diazaspiro[3,3]heptane, and 2-oxa
azaspiro[3,3]heptane.
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 and 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).
“Lower alkylene groups” are straight-chained -CH - tethering groups,
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 substituted
2 2 2 2 2 2 2
by replacing one or more hydrogen of the lower alkylene group and/or by substituting both
hydrogens on the same carbon with a cycloalkyl group (e.g., ).
As used herein, the term “hydroxy” refers to a –OH group.
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) is defined herein. A
non-limiting list of alkoxys is methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n-
butoxy, iso-butoxy, sec-butoxy, tert-butoxy, phenoxy and benzoxy. An alkoxy may be
substituted or unsubstituted.
As used herein, “acyl” refers to a hydrogen, alkyl, alkenyl, alkynyl, aryl,
heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl) and heterocyclyl(alkyl) connected, as
substituents, via a carbonyl group. Examples include formyl, acetyl, propanoyl, benzoyl and
acryl. An acyl may be substituted or unsubstituted.
A “cyano” group refers to a “-CN” group.
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.
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.
R )” group in which
An “O-carbamyl” group refers to a “-OC(=O)N(RA B
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 “C-thioamido” group refers to a “-C(=S)N(R R )” group in which R
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). A C-thioamido may be substituted or unsubstituted.
An “N-thioamido” group refers to a “RC(=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-thioamido may be substituted or unsubstituted.
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-carboxy” group refers to a “RC(=O)O-” group in which R can be
hydrogen, an alkyl, an alkenyl, an alkynyl, an alkoxy, 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.
An “oxo” group refers to a “=O” group.
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.
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, 1-chlorofluoromethyl 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, 1-chlorofluoromethoxy and 2-
fluoroisobutoxy. A haloalkoxy may be substituted or unsubstituted.
The term “amino” as used herein refers to a –NH group.
A “mono-substituted amine” group refers to a “-NHR” group in which R
can be an alkyl, an alkenyl, an alkynyl, a haloalkyl, a cycloalkyl, a cycloalkenyl, aryl,
heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or
heterocyclyl(alkyl), as defined herein. A mono-substituted amino may be substituted or
unsubstituted. Examples of mono-substituted amino groups include, but are not limited to,
-NH(methyl), -NH(phenyl) and the like.
A “di-substituted amine” group refers to a “-NR R ” group in which R
A B A
and R can be independently an alkyl, an alkenyl, an alkynyl, a haloalkyl, a cycloalkyl, a
cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl)
or heterocyclyl(alkyl), as defined herein. A di-substituted amino may be substituted or
unsubstituted. Examples of di-substituted amino groups include, but are not limited to,
-N(methyl) , -N(phenyl)(methyl), -N(ethyl)(methyl) and the like.
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, a radical indicates species with a single, unpaired electron
such that the species containing the radical can be covalently bonded to another species.
Hence, in this context, a radical is not necessarily a free radical. Rather, a radical indicates a
specific portion of a larger molecule. The term “radical” can be used interchangeably with
the term “group.”
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), a sulfuric acid, a nitric acid and a phosphoric acid (such as 2,3-
dihydroxypropyl dihydrogen phosphate). 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, trifluoroacetic, benzoic, salicylic, 2-
oxopentanedioic, 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, a potassium or a lithium salt, an alkaline earth metal salt, such as a
calcium or a magnesium salt, a salt of a carbonate, a salt of a bicarbonate, 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. For compounds of Formula (I), those skilled in the art
understand that when a salt is formed by protonation of a nitrogen-based group (for example,
NH ), the nitrogen-based group can be associated with a positive charge (for example, NH
can become NH ) and the positive charge can be balanced by a negatively charged
counterion (such as Cl ).
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.
It is understood that, in any compound described, all tautomeric forms are
also intended to be included. For example, the following are tautomers:
and .
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.
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
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. A single processor or other unit
may fulfill the functions of several items recited in the claims. 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.
Compounds
Some embodiments described herein generally relate to a compound of
Formula (I), or a pharmaceutically acceptable salt thereof, wherein Formula (I) has the
structure:
R can be selected from hydrogen, halogen, hydroxy, cyano, an optionally substituted C -
alkyl, an optionally substituted C - haloalkyl, an optionally substituted C - alkoxy and an
1 4 1 4
optionally substituted C - haloalkoxy; R can be an optionally substituted 6-15 membered
heteroaryl or an optionally substituted 6-15 membered heterocyclyl, wherein the heteroaryl
and the heterocyclyl independently can contains 1-4 heteroatoms selected from N, O and S;
R can be selected from hydrogen, halogen, an optionally substituted C - alkyl, an optionally
substituted C cycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl
and an optionally substituted heterocyclyl, wherein when substituted, R can be substituted
by one or more substituents selected from halogen, cyano, an unsubstituted C - alkyl, an
5A 5B 5C 6A 6B 7A 7B 1
optionally substituted aryl, -C(O)R , -SO R , -NHC(O)R and -(CR R ) NR R ; X
can be O (oxygen), S (sulfur) or NR ; R can be selected from hydrogen, an optionally
substituted C - alkyl, an optionally substituted C - haloalkyl and an optionally substituted
1 4 1 4
5A 5B 5C
C cycloalkyl; R , R and R can be independently selected from hydrogen, an
optionally substituted C - alkyl, an optionally substituted C - haloalkyl, an optionally
1 4 1 4
substituted C cycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl
6A 6B
and an optionally substituted heterocyclyl; R and R can be independently selected from
hydrogen, halogen, an optionally substituted C - alkyl, an optionally substituted C -
1 4 1 4
7A 7B
haloalkyl and an optionally substituted C - cycloalkyl; R and R can be independently
selected from hydrogen, an optionally substituted C - alkyl, an optionally substituted C -
1 4 1 4
1 8 8
haloalkyl and an optionally substituted C - cycloalkyl; A can be N (nitrogen) or CR ; R
can be selected from hydrogen, halogen, cyano, an optionally substituted C - alkyl, an
optionally substituted C - haloalkyl and an optionally substituted C cycloalkyl; m can be 0
1 4 3-8
or 1; and n can be 0, 1, 2 or 3.
In some embodiments, R can be an optionally substituted 6-15 membered
heteroaryl. In other embodiments, R can be an optionally substituted 6-15 membered
heterocyclyl. A variety of heteroatoms can be present in one or more rings of the optionally
substituted 6-15 membered heteroaryl and/or the optionally substituted 6-15 membered
heterocyclyl. The number of heteroatoms can also vary. In some embodiments, 1
heteroatom can be present in one or more rings of the optionally substituted 6-15 membered
heteroaryl and/or the optionally substituted 6-15 membered heterocyclyl. In other
embodiments, 2 heteroatoms can be present in one or more rings of the optionally substituted
6-15 membered heteroaryl and/or the optionally substituted 6-15 membered heterocyclyl. In
still other embodiments, 3 heteroatoms can be present in one or more rings of the optionally
substituted 6-15 membered heteroaryl and/or the optionally substituted 6-15 membered
heterocyclyl. In yet still other embodiments, 4 heteroatoms can be present in one or more
rings of the optionally substituted 6-15 membered heteroaryl and/or the optionally substituted
6-15 membered heterocyclyl. In some embodiments, the heteroatom(s) can be independently
selected from N (nitrogen), O (oxygen) and S (sulfur).
The number of rings in the 6-15 membered heteroaryl and/or the
optionally substituted 6-15 membered heterocyclyl can vary. In some embodiments, the 6-15
membered heteroaryl and/or the optionally substituted 6-15 membered heterocyclyl can be
monocyclic. In other embodiments, the 6-15 membered heteroaryl and/or the optionally
substituted 6-15 membered heterocyclyl can be bicyclic. In some embodiments, R can be an
optionally substituted 5 or 6 membered monocyclic heteroaryl. In other embodiments, R
can be an optionally substituted 9 or 10 membered bicyclic heteroaryl. In still other
embodiments, R can be an optionally substituted 5 or 6 membered monocyclic heterocyclyl.
In yet still other embodiments, R can be an optionally substituted 9 or 10 membered bicyclic
heterocyclyl.
In some embodiments, R can be an optionally substituted indolyl. In
other embodiments, R can be an optionally substituted indazolyl. In still other
embodiments, R can be an optionally substituted 4,5,6,7-tetrahydroindazolyl. In yet still
other embodiments, R can be an optionally substituted . In some
embodiments, R can be an optionally substituted . The optionally substituted
indolyl, optionally substituted indazolyl, optionally substituted 4,5,6,7-tetrahydroindazolyl,
optionally substituted and optionally substituted can be attached
to of Formula (I) at any suitable position. In some embodiments, R can be
connected to via a carbon atom. In some embodiments, R can be an
optionally substituted , an optionally substituted , an
optionally substituted , an optionally substituted or an
2A 2B 2C
optionally substituted . In some embodiments, R , R and R can be
independently, halogen, cyano, an optionally substituted C - alkyl, an optionally substituted
C - haloalkyl, an optionally substituted C - alkoxy, an optionally substituted C -
1 4 1 4 3 8
cycloalkyl, an unsubstituted mono-substituted amine and an unsubstituted di-substituted
2A 2B 2C
amine. In some embodiments, R , R and/or R can be substituted by an optionally
substituted C - cycloalkyl, for example, an optionally substituted bicyclo[1.1.1]pentyl.
2A 2B 2C
When R , R and/or R is substituted, possible substituents include, but are not limited to,
halogen (such as fluoro and/or chloro), cyano and an optionally substituted C - alkyl (for
example, a substituted or unsubstituted methyl, a substituted or unsubstituted ethyl, a
substituted or unsubstituted n-propyl, a substituted or unsubstituted iso-propyl, a substituted
or unsubstituted n-butyl, a substituted or unsubstituted iso-butyl or a substituted or
unsubstituted tert-butyl).
Various substituents can be present when R is substituted, and the number
of substituents can also vary. In some embodiments, when R is substituted, R can be
substituted by one or more substituents selected from halogen, cyano, an optionally
substituted C - alkyl, an optionally substituted C - haloalkyl, an optionally substituted C -
1 4 1 4 1 4
alkoxy, an optionally substituted C - cycloalkyl, an unsubstituted mono-substituted amine
and an unsubstituted di-substituted amine. In some embodiments, R can be substituted by
an optionally substituted C - cycloalkyl. For example, R can be an optionally substituted
bicyclo[1.1.1]pentyl. In some embodiments, R can be an unsubstituted bicyclo[1.1.1]pentyl.
In other embodiments, R can be a substituted bicyclo[1.1.1]pentyl. Examples of substituted
bicyclo[1.1.1]pentyl moieties include fluoro-substituted bicyclo[1.1.1]pentyl, chloro-
substituted bicyclo[1.1.1]pentyl and cyano-substituted bicyclo[1.1.1]pentyl. In some
embodiments, R can be substituted by an optionally substituted C - alkyl. As an example,
R can be substituted by an unsubstituted C - alkyl. Examples of C - alkyls include methyl,
1 4 1 4
ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl and tert-butyl.
In some embodiments, m can be 0 such that R is directly bonded to the
phenyl ring shown in Formula (I). In other embodiments, m can be 1 and R can be
connected to the phenyl ring shown in Formula (I) through X . In some embodiments, X
can be O (oxygen). In other embodiments, X can be S (sulfur). In still other embodiments,
X can be –NH. In yet still other embodiments, X can be –N(an optionally substituted C -
alkyl). In some embodiments, X can be –N(an unsubstituted C - alkyl). As an example, X
can be –N(CH ). In some embodiments, X can be –N(an optionally substituted C -
3 1 4
haloalkyl). In some embodiments, X can be –N(an unsubstituted C - haloalkyl), such as
N(CF ). In other embodiments, X can be –N(an optionally substituted C cycloalkyl). In
3 3-8
some embodiments, X can be –N(an unsubstituted C cycloalkyl).
In some embodiments, R can be a substituted C - alkyl. In other
embodiments, R can be an unsubstituted C - alkyl. Examples of suitable optionally
substituted C - alkyls are described herein. In some embodiments, R can be a substituted
C cycloalkyl. In other embodiments, R can be an unsubstituted C cycloalkyl. As a non-
3-8 3-8
limiting example, R can be an optionally substituted C cycloalkyl, such as an optionally
substituted bicyclo[1.1.1]pentyl. In some embodiments, R can be a substituted aryl, such as
a substituted phenyl. In other embodiments, R can be an unsubstituted aryl, for example, an
unsubstituted phenyl. In some embodiments, R can be a substituted heteroaryl. In other
embodiments, R can be an unsubstituted heteroaryl. In some embodiments, R can be a
substituted heterocyclyl. In other embodiments, R can be an unsubstituted heterocyclyl.
When R is an optionally substituted heteroaryl or an optionally
substituted heterocyclyl, the heteroaryl and/or heterocyclyl can be monocyclic or bicyclic.
For example, the optionally substituted heteroaryl and/or the an optionally substituted
heterocyclyl can be an optionally substituted 4-membered monocyclic heteroaryl, an
optionally substituted 4-membered monocyclic heterocyclyl, an optionally substituted 5-
membered monocyclic heteroaryl, an optionally substituted 5-membered monocyclic
heterocyclyl, an optionally substituted 6-membered monocyclic heteroaryl, an optionally
substituted 6-membered monocyclic heterocyclyl, an optionally substituted 9-membered
bicyclic heteroaryl, an optionally substituted 9-membered bicyclic heterocyclyl, an optionally
substituted 10-membered bicyclic heteroaryl or an optionally substituted 10-membered
bicyclic heterocyclyl.
As described herein, a heteroaryl and/or a heterocyclyl can include one or
more heteroatoms in the ring(s) of the heteroaryl and/or the heterocyclyl. In some
embodiments, R can be an optionally substituted heteroaryl containing 1 heteroatom. In
other embodiments, R can be an optionally substituted heterocyclyl containing 1
heteroatom. In still other embodiments, R can be an optionally substituted heteroaryl
containing 2 heteroatoms. In yet still other embodiments, R can be an optionally substituted
heterocyclyl containing 2 heteroatoms. In some embodiments, R can be an optionally
substituted heteroaryl containing 3 or more heteroatoms. In other embodiments, R can be an
optionally substituted heterocyclyl containing 3 or more heteroatoms. Various heteroatoms
can be present in the optionally substituted heteroaryl and/or the an optionally substituted
heterocyclyl of R . Examples of suitable heteroatoms include N (nitrogen), O (oxygen) and
S (sulfur).
In some embodiments, R can be an optionally substituted 4-membered
nitrogen-containing heterocyclyl. In other embodiments, R can be an optionally substituted
-membered nitrogen-containing heterocyclyl. In still other embodiments, R can be an
optionally substituted 6-membered nitrogen-containing heterocyclyl. The following are
examples of suitable nitrogen containing monocyclic heterocyclyls: an optionally substituted
azetidinyl, an optionally substituted pyrrolidinyl and an optionally substituted piperazinyl.
The optionally substituted heteroaryl and/or the optionally substituted
heterocyclyl can be connected to X or the shown phenyl ring of Formula (I) at any suitable
position. In some embodiments, the optionally substituted heteroaryl and/or the optionally
substituted heterocyclyl can be connected to X or the shown phenyl ring of Formula (I) via a
carbon. In other embodiments, the optionally substituted heteroaryl and/or the optionally
substituted heterocyclyl can be connected to X or the shown phenyl ring of Formula (I) via a
nitrogen. In some embodiments, R can be one of the following, wherein any of the moieties
shown can be optionally substituted: , and .
When R is substituted, a variety and number of substituents can be
present. In some embodiments, R can be substituted with 1 substituent. In other
embodiments, R can be substituted with 2 substituents. In still other embodiments, R can
be substituted with 3 or more substituents. When more than 1 substituent is present on R ,
the substituent(s) can be the same as another substituent(s) or different from another
substituent(s).
In some embodiments, R can be substituted by halogen, such as fluoro
and/or chloro. In some embodiments, R can be substituted by cyano. In some
embodiments, R can be substituted by an unsubstituted C - alkyl. Examples of
unsubstituted C - alkyls include methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl and
tert-butyl. In some embodiments, R can be substituted by an optionally substituted aryl,
such as an optionally substituted phenyl and/or an optionally substituted naphthyl.
In some embodiments, R can be substituted by an optionally substituted
5A 5A
acyl. The optionally substituted acyl can have the formula -C(O)R , wherein R can be
hydrogen, an optionally substituted C - alkyl, an optionally substituted C - haloalkyl, an
1 4 1 4
optionally substituted C cycloalkyl, an optionally substituted aryl, an optionally substituted
heteroaryl or an optionally substituted heterocyclyl. In some embodiments, R can be
substituted by C(O)-(an optionally substituted C - alkyl). Suitable optionally substituted C -
1 4 1
alkyls are described herein. In some embodiments, R can be an unsubstituted C - alkyl.
4 1 4
When R is an unsubstituted C - alkyl, an example of acyl group that can be substituted on
3 5A
R is –C(O)CH . In other embodiments, R can be a substituted C - alkyl. For example,
3 1 4
R can be C - alkyl substituted by a mono-alkyl substituted amine and/or a di-alkyl
substituted amine. In some embodiments, R can be substituted by –C(O)CH N(CH ) .
2 3 2
In some embodiments, R can be substituted by an optionally substituted
C - alkyl that can be substituted with a mono-alkyl substituted amine and/or a di-alkyl
substituted amine. The alkyl group(s) that can be present on a mono-alkyl substituted amine
and/or a di-alkyl substituted amine include an unsubstituted C alkyl. In some
embodiments, the optionally substituted C - alkyl that is substituted with a di-alkyl
substituted amine can have the structure –(CH ) N(CH ) .
2 2 3 2
3 5B 5B
In some embodiments, R can be substituted by -SO R , wherein R can
be selected from hydrogen, an optionally substituted C - alkyl, an optionally substituted C -
1 4 1 4
haloalkyl, an optionally substituted C cycloalkyl, an optionally substituted aryl, an
optionally substituted heteroaryl and an optionally substituted heterocyclyl. In some
3 5C 5C
embodiments, R can be substituted by -NHC(O)R , wherein R can be selected from
hydrogen, an optionally substituted C - alkyl, an optionally substituted C - haloalkyl, an
1 4 1 4
optionally substituted C cycloalkyl, an optionally substituted aryl, an optionally substituted
heteroaryl and an optionally substituted heterocyclyl.
3 6A 6B 7A 7B
In some embodiments, R can be substituted by -(CR R ) NR R ,
6A 6B
wherein R and R can be independently selected from hydrogen, halogen, an optionally
substituted C - alkyl, an optionally substituted C - haloalkyl and an optionally substituted
1 4 1 4
7A 7B
C - cycloalkyl; R and R can be independently selected from hydrogen, an optionally
substituted C - alkyl, an optionally substituted C - haloalkyl and an optionally substituted
1 4 1 4
C - cycloalkyl; and n can be 0, 1, 2 or 3. In some embodiments, n can be 0. In other
embodiments, n can be 1. In still other embodiments, n can be 2. In yet still other
6A 6B
embodiments, n can be 3. In some embodiments, each R and each R can be
independently hydrogen, halogen or an unsubstituted C - alkyl. In some embodiments, each
6A 6B
R and each R can be independently hydrogen or an unsubstituted C - alkyl. In some
6A 6B 6A
embodiments, at least one of R and R can be hydrogen. In some embodiments, each R
6B 7A 7B
and each R can be hydrogen. In some embodiments, R and R can be independently
hydrogen or an optionally substituted C - alkyl. In some embodiments, at least one of R
7B 7A 7B
and R can be hydrogen. In some embodiments, R and R can be each an optionally
7A 7B
substituted C - alkyl. In some embodiments, R and R can be each an unsubstituted C -
1 4 1 4
3 6A 6B 7A 7B 6A 6B 7A 7B
alkyl. When R is substituted by -(CR R ) NR R , -(CR R ) NR R can be –
N(CH ) , –(CH )N(CH ) or–(CH ) N(CH ) . In some embodiments, R can be a lower
3 2 2 3 2 2 2 3 2
alkylene-(mono-substituted alkyl amine). In other embodiments, R can be a lower alkylene-
(di-substituted alkyl amine).
Examples of R moieties include, but are not limited to, the following:
, , , , an optionally substituted (for example,
), an optionally substituted (for example, ) and an optionally substituted
(for example, , and ).
In some embodiments, R can be hydrogen. In other embodiments, R can
be halogen. In still other embodiments, R can be hydroxy. In yet still other embodiments,
R can be cyano. In some embodiments, R can be a substituted C - alkyl. In other
embodiments, R can be an unsubstituted C - alkyl. In still other embodiments, R can be a
substituted C - haloalkyl. In yet still other embodiments, R can be an unsubstituted C -
1 4 1 4
haloalkyl. In some embodiments, R can be a substituted C - alkoxy. In other
embodiments, R can be an unsubstituted C - alkoxy. In still other embodiments, R can be
a substituted C - haloalkoxy. In yet other embodiments, R can be an unsubstituted C -
1 4 1 4
haloalkoxy. Example of suitable R moieties include, but are not limited to, the following:
chloro, fluoro, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, -CF , -CHF ,
-CH F, -CH CF , methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, tert-
2 2 3
butoxy, -OCF , -OCHF , -OCH F and -OCH CF .
3 2 2 2 3
In some embodiments, A can be N (nitrogen) such that the ring shown in
2 1 8
Formula (I) has the structure: . In some embodiments, A can be CR such that
the ring shown in Formula (I) has the structure: . In some embodiments,
8 8 8
R can be hydrogen. In other embodiments, R can be halogen. For example, R can be
chloro or fluoro. In still other embodiments, R can be cyano. In yet still other
embodiments, R can be an optionally substituted C - alkyl. In some embodiments, R can
be an unsubstituted C - alkyl. In some embodiments, R can be an unsubstituted C -
1 4 1 4
haloalkyl or a substituted C - haloalkyl. An example of a suitable C - haloalkyl is CF . In
1 4 1 4 3
some embodiments, R can be an optionally substituted C cycloalkyl. Examples of
optionally substituted C cycloalkyls are described herein and include, but are not limited
to, an optionally substituted cyclopropyl, an optionally substituted cyclobutyl, an optionally
substituted cyclopentyl, an optionally substituted bicyclo[1.1.1]pentyl, an optionally
substituted cyclohexyl, an optionally substituted cycloheptyl and an optionally substituted
cyclooctyl.
Examples of compounds of Formula (I) include the following:
HN N HN N
HO O
NH NH
O O F
, , ,
N N N
HN N HN N
NH NH
O CN O
, , ,
HN N HN N
O N O N
NH NH
O O F
, , ,
HN N HN N
O N O
NH NH
N NH
O CN O
, , ,
HN N
, , ,
, , ,
, and
, or a pharmaceutically acceptable salt of any of the
foregoing.
In some embodiments, R can be substituted with bicyclo[1.1.1]pentyl. In
some embodiments, R can be a substituted bicyclo[1.1.1]pentyl.
Synthesis
Compounds of Formula (I), or a pharmaceutically acceptable salt thereof,
and those described herein may be prepared in various ways. Some compounds of Formula
(I), or a pharmaceutically acceptable salt thereof, can be obtained utilizing known synthetic
procedures. General synthetic routes to the compounds of Formula (I), or a pharmaceutically
acceptable salt thereof, and some examples of starting materials used to synthesize the
compounds of Formula (I), or a pharmaceutically acceptable salt thereof, are shown and
described herein. One example is shown below in Scheme 1. 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
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 Formula (I), 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 Formula (I), 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 EGFR 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 Formula (I), or a
pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a
compound described herein (for example, a compound of Formula (I), 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 Formula (I), or a pharmaceutically acceptable salt thereof) or a
pharmaceutical composition that includes of a compound described herein (for example, a
compound of Formula (I), 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 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 of a compound described herein (for example, a
compound of Formula (I), 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 Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical
composition that includes of a compound described herein (for example, a compound of
Formula (I), 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
Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition
that includes of a compound described herein (for example, a compound of Formula (I), 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 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 of a
compound described herein (for example, a compound of Formula (I), 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 of a compound described herein (for example, a compound of Formula (I), 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 Formula (I), or a pharmaceutically acceptable
salt thereof) or a pharmaceutical composition that includes of a compound described herein
(for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) in
the manufacture of a medicament for ameliorating or treating a cancer that can include
contacting 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 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 of a
compound described herein (for example, a compound of Formula (I), or a pharmaceutically
acceptable salt thereof) for ameliorating or treating a cancer that can include contacting 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 EGFR (for example, inhibiting the activity of EGFR with acquired EGFR T790M
mutation, inhibiting the activity of EGFR with a deletion in exon 19 (such as A740-A750),
inhibiting the activity of EGFR with an insertion in exon 20, inhibiting the activity of EGFR
with a mutation at L858R, inhibiting the activity of wildtype EGFR and/or where EGFR is
overexpressed or activated) that can include providing 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 of a compound described herein
(for example, a compound of Formula (I), 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 Formula (I), or a pharmaceutically acceptable salt thereof) or a
pharmaceutical composition that includes of a compound described herein (for example, a
compound of Formula (I), or a pharmaceutically acceptable salt thereof) in the manufacture
of a medicament for inhibiting the activity of EGFR (for example, inhibiting the activity of
EGFR with acquired EGFR T790M mutation, inhibiting the activity of EGFR with a deletion
in exon 19 (such as A740-A750), inhibiting the activity of EGFR with an insertion in exon
, inhibiting the activity of EGFR with a mutation at L858R, inhibiting the activity of
wildtype EGFR and/or where EGFR is overexpressed or activated). Still other embodiments
described herein relate to 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 of a compound described herein (for example, a
compound of Formula (I), or a pharmaceutically acceptable salt thereof) for inhibiting the
activity of EGFR (for example, inhibiting the activity of EGFR with acquired EGFR T790M
mutation, inhibiting the activity of EGFR with a deletion in exon 19 (such as A740-A750),
inhibiting the activity of EGFR with an insertion in exon 20, inhibiting the activity of EGFR
with a mutation at L858R, inhibiting the activity of wildtype EGFR and/or where EGFR is
overexpressed or activated). Some embodiments described herein relate to a method for
inhibiting the activity of EGFR (for example, inhibiting the activity of EGFR with acquired
EGFR T790M mutation, inhibiting the activity of EGFR with a deletion in exon 19 (such as
A740-A750), inhibiting the activity of EGFR with an insertion in exon 20, inhibiting the
activity of EGFR with a mutation at L858R, inhibiting the activity of wildtype EGFR and/or
where EGFR is overexpressed or activated) that can include providing 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 of a
compound described herein (for example, a compound of Formula (I), or a pharmaceutically
acceptable salt thereof) to a cancer cell from a cancer described herein. Other embodiments
described herein relate to a method for inhibiting the activity of EGFR (for example,
inhibiting the activity of EGFR with acquired EGFR T790M mutation, inhibiting the activity
of EGFR with a deletion in exon 19 (such as A740-A750), inhibiting the activity of EGFR
with an insertion in exon 20, inhibiting the activity of EGFR with a mutation at L858R,
inhibiting the activity of wildtype EGFR and/or where EGFR is overexpressed or activated)
that can include contacting a cancer cell from a cancer described herein 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 of a
compound described herein (for example, a compound of Formula (I), or a pharmaceutically
acceptable salt thereof), and thereby inhibiting the activity of EGFR.
Some embodiments described herein relate to a method for ameliorating or
treating a cancer described herein that can include inhibiting the activity of EGFR (for
example, inhibiting the activity of EGFR with acquired EGFR T790M mutation, inhibiting
the activity of EGFR with a deletion in exon 19 (such as A740-A750), inhibiting the activity
of EGFR with an insertion in exon 20, inhibiting the activity of EGFR with a mutation at
L858R, inhibiting the activity of wildtype EGFR and/or where EGFR is overexpressed or
activated) using 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 of a compound described herein (for example, a compound of
Formula (I), 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 Formula (I), or a pharmaceutically acceptable salt thereof) or a
pharmaceutical composition that includes of a compound described herein (for example, a
compound of Formula (I), 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 EGFR (for example, inhibiting the activity of EGFR with acquired EGFR T790M
mutation, inhibiting the activity of EGFR with a deletion in exon 19 (such as A740-A750),
inhibiting the activity of EGFR with an insertion in exon 20, inhibiting the activity of EGFR
with a mutation at L858R, inhibiting the activity of wildtype EGFR and/or where EGFR is
overexpressed or activated). Still other embodiments described herein relate to 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 of a
compound described herein (for example, a compound of Formula (I), or a pharmaceutically
acceptable salt thereof) for ameliorating or treating a cancer described herein by inhibiting
the activity of EGFR (for example, inhibiting the activity of EGFR with acquired EGFR
T790M mutation, inhibiting the activity of EGFR with a deletion in exon 19 (such as A740-
A750), inhibiting the activity of EGFR with an insertion in exon 20, inhibiting the activity of
EGFR with a mutation at L858R, inhibiting the activity of wildtype EGFR and/or where
EGFR is overexpressed or activated). Some embodiments described herein relate to a
method for ameliorating or treating a cancer described herein that can include contacting a
cancer cell 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 of a compound described herein (for example, a compound of
Formula (I), or a pharmaceutically acceptable salt thereof), wherein the compound inhibits
the activity of EGFR (for example, a compound described herein can inhibits the activity of
EGFR with acquired EGFR T790M mutation, inhibis the activity of EGFR with a deletion in
exon 19 (such as A740-A750), inhibits the activity of EGFR with an insertion in exon 20,
inhibits the activity of EGFR with a mutation at L858R, inhibits the activity of wildtype
EGFR and/or where EGFR is overexpressed or activated).
Some embodiments disclosed herein relate to a method for inhibiting the
activity of EGFR that can include providing 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 of a compound described herein (for
example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) to a
subject or sample having a cancer cell selected from a lung cancer cell, a pancreatic cancer
cell, a colon cancer cell, a breast cancer cell, a prostate cancer cell, a head and neck cancer
cell, an ovarian cancer cell, a brain cancer cell and a kidney carcinoma cell, and wherein the
EGFR has one or more selected from a deletion in exon 19, an insertion in exon 20, a
mutation at L858R and an acquired EGFR T790M mutation. Other embodiments disclosed
herein relate to the use of 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 of a compound described herein (for example, a
compound of Formula (I), or a pharmaceutically acceptable salt thereof) in the manufacture
of a medicament for inhibiting the activity of EGFR, wherein the EGFR can have one or
more selected from a deletion in exon 19, an insertion in exon 20, a mutation at L858R and
an acquired EGFR T790M mutation. Still other embodiments disclosed herein relate to a
compound described herein (for example, a compound of Formula (I), or a pharmaceutically
acceptable salt thereof) or a pharmaceutical composition that includes of a compound
described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable
salt thereof) for inhibiting the activity of EGFR, wherein the EGFR can have one or more
selected from a deletion in exon 19, an insertion in exon 20, a mutation at L858R and an
acquired EGFR T790M mutation.
Examples of suitable cancers include, but are not limited to: lung cancers
(e.g., lung adenocarcinoma and non-small cell lung cancer), pancreatic cancers (e.g.,
pancreatic carcinoma such as, for example, exocrine pancreatic carcinoma), colon cancers
(e.g., colorectal carcinomas, such as, for example, colon adenocarcinoma and colon
adenoma), breast cancers, prostate cancers, head and neck cancers (e.g., squamous cell
cancer of the head and neck), ovarian cancers, brain cancers (e.g., gliomas, such as glioma
blastoma multiforme), and kidney carcinomas.
As described herein, a cancer can become resistant to one or more anti-
cancer agents. In some embodiments, a compound described herein (for example, a
compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical
composition that includes of a compound described herein (for example, a compound of
Formula (I), or a pharmaceutically acceptable salt thereof) can be used to treat and/or
ameliorate a cancer that has become resistant to one or more anti-cancer agents (such as one
or more EGFR inhibitors). Examples of anti-cancer agents that a subject may have
developed resistance to include, but are not limited to, first generation EGFR inhibitors (such
as gefitinib and erlotinib) and second generation EGFR inhibitors (for example, afatinib). In
some embodiments, the cancer that has become resistant to one or more anti-cancer agents
can be a cancer described herein.
Several known EGFR inhibitors can cause one or more undesirable side
effects in the subject being treated. Two examples of these side effects are hyperglacemia
and a rash. The rash can be characterized by mild scaling, pimples, roughness, a feeling of
tightness, itching and/or burning. In some embodiments, a compound described herein (for
example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) can
decrease the number and/or severity of one or more side effects associated with a known
EGFR inhibitor. In some embodiments, a compound of Formula (I), or a pharmaceutically
acceptable salt thereof, can result in a severity of a side effect (such as one of those described
herein) that is 25% less than compared to the severity of the same side effect experienced by
a subject receiving a known EGFR inhibitor (such as gefitinib, erlotinib and/or afatinib). In
some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt
thereof, results in a number of side effects that is 25% less than compared to the number of
side effects experienced by a subject receiving a known EGFR inhibitor (for example,
gefitinib, erlotinib and/or afatinib). In some embodiments, a compound of Formula (I), or a
pharmaceutically acceptable salt thereof, results in a severity of a side effect (such as one of
those described herein) that is less in the range of about 10% to about 30% compared to the
severity of the same side effect experienced by a subject receiving a known EGFR inhibitor
(such as gefitinib, erlotinib and/or afatinib). In some embodiments, a compound of Formula
(I), or a pharmaceutically acceptable salt thereof, results in a number of side effects that is in
the range of about 10% to about 30% less than compared to the number of side effects
experienced by a subject receiving a known EGFR inhibitor (for example, gefitinib, erlotinib
and/or afatinib).
The one or more compounds of Formula (I), or a pharmaceutically
acceptable salt thereof, that can be used to treat, ameliorate and/or inhibit the growth of a
cancer wherein inhibiting the activity of EGFR is beneficial is provided in any of the
embodiments described in paragraphs [0073]-[0094], under the heading titled “Compounds.”
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 with a fever. 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 EGFR
inhibitor is the amount which results in the reduction in EGFR activity and/or
phosphorylation. The reduction in EGFR activity are known to those skilled in the art and
can be determined by the analysis of EGFR intrinsic kinase activity and downstream
substrate phosphorylation.
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 ED
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
1-(bicyclo[1.1.1]pentanyl)indolinone
Step 1: A solution of 2-(2-bromophenyl)acetic acid (22.0 g, 102.32 mmol)
in DCM (400 mL) at 0 °C was treated with Hünig's base (53.47 mL, 306.97 mmol) followed
by N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine (29.42 g, 153.48
mmol), HOBt (21.41 g, 153.48 mmol), and bicyclo[1.1.1]pentanamine hydrochloride
(14.6 g, 122.78 mmol). The reaction was warmed to room temperature (RT) and stirred
overnight. The reaction was concentrated in vacuo, adsorbed onto silica and purified by
column chromatography (SiO2, Hexanes/EtOAc) to provide the N-(bicyclo[1.1.1]pentan
yl)(2-bromophenyl)acetamide (23.0 g, 80%) as a white solid. LC/MS (APCI) m/z 280.0
[M+H] .
Step 2: To a flame dried vial with stir bar was added compound N-
(bicyclo[1.1.1]pentanyl)(2-bromophenyl)acetamide (5.0 g, 17.92 mmol), followed by
Pd(OAc) (1.2 g, 1.79 mmol), tri-tert-butylphosphonium tetrafluoroborate (1.03 g, 3.58
mmol), and Cs CO (8.75 g, 26.88 mmol). The reaction vial was purged with Ar and
degassed toluene (180 mL) was added. The mixture was heated at 100 °C for 4 h. The
reaction was cooled to RT, and concentrated in vacuo to provide the crude product.
Purification of the crude product by column chromatography (SiO2, Hexanes/EtOAc)
afforded 1-(bicyclo[1.1.1]pentanyl)indolinone (2.88 g, 81%) as a yellow solid. H
NMR (400 MHz, CDCl ) d 7.26 – 7.19 (m, 2H), 7.09 (d, J = 8.0 Hz, 1H), 7.01 (t, J = 7.6,
1H), 3.46 (s, 2H), 2.59 (s, 1H), 2.46 (s, 6H); LC/MS (APCI) m/z 200.1 [M+H] .
Intermediate 2
1-(bicyclo[1.1.1]pentanyl)indoline
Step 1: A flame-dried pressure tube was charged with 1,1-dibromo-2,2-
bis(chloromethyl)cyclopropane (15 g, 50.5 mmol) and dibutyl ether (15 mL). The reaction
was cooled to –45 °C and PhLi (53.2 mL, 101 mmol, 1.8M in dibutyl ether) was added
slowly via syringe. The mixture was stirred at the same temperature for 5 mins. The
reaction temperature was allowed to warm to 0 °C and stirred for 2 h in an ice bath at which
point the reaction was brought to RT to provide a solution of crude [1.1.1]propellane.
Step 2: In a separate flask, a solution of indoline (11.4 mL, 101 mmol) in
dibutyl ether (15 mL) was treated with iPrMgCl•LiCl (92 mL, 102 mmol, 1.11M in THF) via
a dropping funnel at RT. After 2 h stirring at RT, the solution was added portion-wise to the
aforementioned crude [1.1.1]propellane solution. The reaction vessel was capped with a
Teflon™ pressure cap. The reaction was transferred to an oil bath and stirred at 60 °C for 16
h. The reaction was then removed from the oil bath, cooled in an ice bath and quenched
slowly with sat. aq. NH Cl. The reaction was then diluted with EtOAc and transferred into a
separation funnel. The layers were separated, and the combined organic layers were dried
with Na SO , filtered, and concentrated under reduced pressure. The residual solvent was
removed under vacuum, and the crude material was purified by column chromatography
(SiO2, Hexanes/EtOAc) to provide 1-(bicyclo[1.1.1]pentanyl)indoline (2.20 g, 23%) as a
yellow oil. H NMR (400 MHz, CDCl ) d 7.13–6.89 (m, 2H), 6.76 (d, J = 7.8 Hz, 1H), 6.67
(dt, J = 7.4, 0.9 Hz, 1H), 3.36 (t, J = 8.4 Hz, 2H), 2.93 (t, J = 8.4 Hz, 2H), 2.48 (s, 1H), 2.10
(s, 6H).
Intermediate 3
1-(bicyclo[1.1.1]pentanyl)-1H-indole
Method A.
A solution of 1-(bicyclo[1.1.1]pentanyl)indolinone (3.6 g, 18.09
mmol) was cooled to 0 °C and treated with diisobutylaluminum hydride (1 M in toulene, 20.3
mL, 32.6 mmol) dropwise. The reaction was warmed to RT and stirred for 2 h. The mixture
was cooled to 0 °C and quenched with MeOH (10 mL). The mixture was filtered through a
celite pad with dichloromethane, dried over Na SO and concentrated in vacuo. The residue
was purified by column chromatography (SiO2, Hexanes/EtOAc) to afford 1-
(bicyclo[1.1.1]pentanyl)-1H-indole (1.98 g, 60%) as a pale yellow oil. H NMR (400
MHz, CDCl ) d 7.62 (d, J = 7.8 Hz, 1H), 7.56 (d, J = 8.2 Hz, 1H), 7.22 – 7.18 (m, 1H), 7.13
– 7.08 (m, 1H), 7.07 (d, J = 3.2 Hz, 1H), 6.46 (d, J = 3.2 Hz, 1H), 2.67 (s, 1H), 2.42 (s, 6H);
LC/MS (APCI) m/z 184.1 [M+H] .
Method B.
A solution of compound 1-(bicyclo[1.1.1]pentanyl)indoline (100 mg,
0.54 mmol) in CH Cl (5 mL) was treated with MnO and stirred at RT. After 20 h, the
2 2 2
reaction was filtered over Celite, and the Celite was washed with CH Cl . The combined
filtrates were concentrated under vacuum to obtain 1-(bicyclo[1.1.1]pentanyl)-1H-indole
(79 mg, 80%) as a brown oil.
Example 1
N-(5-((4-(1-(bicyclo[1.1.1]pentanyl)-1H-indolyl)pyrimidinyl)amino)((2-
(dimethylamino)ethyl)(methyl)amino)methoxyphenyl)acrylamide
Step 1: To a stirred solution of 1-(bicyclo[1.1.1]pentanyl)-1H-indole
(580 mg, 3.27 mmol) in DME (10 mL) at RT was added 2,4-dichloropyrimidine (430 mg,
3.27 mmol) and aluminum chloride (654 mg, 4.90 mmol). The reaction was heated to 80 °C
and stirred for 16 h. The mixture was then poured into ice cold water (100 mL), and the
precipitate was collected by filtration to afford 1-(bicyclo[1.1.1]pentanyl)(2-
chloropyrimidinyl)-1H-indole (500 mg, 1.69 mmol, 53%) as off-white solid. LC/MS
(ESI) m/z 296.1 [M+H] .
Step 2: To a stirred solution of 1-(bicyclo[1.1.1]pentanyl)(2-
chloropyrimidinyl)-1H-indole (525 mg, 1.77 mmol) in 2-pentanol (20 mL) at RT was
added 4-fluoromethoxynitroaniline (331 mg, 1.77 mmol) and p-toluenesulfonic acid
(33 mg, 0.17 mmol). The reaction was heated to 80 °C and stirred for 16 h. The mixture
was then poured into ice cold water (100 mL), and the precipitate was collected by filtration
to afford 4-(1-(bicyclo[1.1.1]pentanyl)-1H-indolyl)-N-(4-fluoromethoxy
nitrophenyl)pyrimidinamine (400 mg, 0.89 mmol, 80% ) as off-white solid. LC/MS (ESI)
m/z 446.1 [M+H] .
Step 3: To a stirred solution of 4-(1-(bicyclo[1.1.1]pentanyl)-1H-indol-
3-yl)-N-(4-fluoromethoxynitrophenyl)pyrimidinamine (420 mg, 0.943 mmol) in
DMA (15 mL) at RT was added N1,N1,N2-trimethylethane-1,2-diamine (0.2 mL, 1.42
mmol) and DIPEA (0.3 mL, 1.22 mmol). The mixture was warmed to 90 °C. After 5 h, the
reaction was cooled to RT, diluted with water (40 mL) and extracted with ethyl acetate (3 x
mL). The combined organic layers were washed with water (20 mL) and brine (20 mL),
dried over sodium sulphate and concentrated to afford N1-(4-(1-(bicyclo[1.1.1]pentanyl)-
1H-indolyl)pyrimidinyl)-N4-(2-(dimethylamino)ethyl)methoxy-N4-methyl
nitrobenzene-1,4-diamine (350 mg, 0.66 mmol, 70%) as a bright red colored solid. LC/MS
(ESI) m/z 528.1 [M+H] .
Step 4: To a stirred solution of N1-(4-(1-(bicyclo[1.1.1]pentanyl)-1H-
indolyl)pyrimidinyl)-N4-(2-(dimethylamino)ethyl)methoxy-N4-methyl
nitrobenzene-1,4-diamine (380 mg, 0.72 mmol) in THF:EtOAc (1:1, 10 mL) was added 10%
Pd/C (150 mg), and the reaction was stirred at RT under hydrogen (1 atm) for 2 h. The
mixture was filtered through celite and was concentrated in vacuo to afford N4-(4-(1-
(bicyclo[1.1.1]pentanyl)-1H-indolyl)pyrimidinyl)-N1-(2-(dimethylamino)ethyl)
methoxy-N1-methylbenzene-1,2,4-triamine (350 mg, 0.70 mmol, 96%) as an off-white solid.
LC/MS (ESI) m/z 498.4 [M+H] .
Step 5: To a stirred solution of N4-(4-(1-(bicyclo[1.1.1]pentanyl)-1H-
indolyl)pyrimidinyl)-N1-(2-(dimethylamino)ethyl)methoxy-N1-methylbenzene-
1,2,4-triamine (200 mg, 0.40 mmol) in THF and water (1:1, 10 mL) at 0 °C was added
DIPEA (0.2 mL, 0.80 mmol) followed by acryloyl chloride (0.05 mL, 0.60 mmol). After 30
mins, the mixture was diluted with water (30 mL) and extracted with ethyl acetate (3 x 20
mL). The combined organic layers were washed with water (20 mL) and brine (20 mL),
dried over sodium sulphate and concentrated in vacuo. The resultant residue was purified by
Reveleris C-18 reverse phase column using 30% aqueous formic acid (0.1%) in acetonitrile
to afford N-(5-(4-(1-(bicyclo[1.1.1]pentanyl)-1H-indolyl)pyrimidinylamino)((2-
(dimethyl amino)ethyl)(methyl)amino)methoxyphenyl)acrylamide (70 mg, 0.12 mmol,
%) as an off-white solid. H NMR (300 MHz, DMSO-d ) d 10.1 (s, 1H), 8.84 (s, 1H), 8.32
– 8.16 (m, 3H), 7.99 (s, 1H), 7.66 (d, J = 8.4 Hz, 1H), 7.26 (d, J = 5.4 Hz, 1H), 7.19 (dd, J =
7.2, 7.2 Hz, 1H), 7.09 (dd, J = 7.2, 7.8 Hz, 1H), 7.01 (s, 1H), 6.44 – 6.35 (m, 1H), 6.19 (dd, J
= 1.8, 16.8 Hz, 1H), 5.70 (dd, J = 1.8, 10.2 Hz, 1H), 3.80 (s, 3H), 2.88 (t, J = 5.4 Hz, 2H),
2.70 (s, 3H), 2.69 (s, 1H), 2.43 (s, 6H), 2.32 (t, J = 5.4 Hz, 2H), 2.21 (s, 6H); LC/MS (ESI)
m/z 552.5 [M+H] .
Intermediate 4
3-(1H-indolyl)bicyclo[1.1.1]pentanecarbonitrile
Step 1: To a solution of 2-(2-bromophenyl)acetic acid (1.17 g, 5.44
mmol) in DCM (18.14 mL) was added N,N-Diisopropylethylamine (2.369 mL, 13.60 mmol),
followed by N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide (1.267 g, 8.16 mmol) and
HOBt(monohydrate) (1.250 g, 8.16 mmol). To this mixture was added methyl 3-
aminobicyclo[1.1.1]pentanecarboxylate hydrochloride (0.966 g, 5.44 mmol). The mixture
was stirred overnight at RT. LCMS showed the formation of product. The reaction was
diluted with ethyl acetate and water. The organic layer was separated and washed with sat.
aq. ammonium chloride. The organic layer was dried over Na SO , concentrated and
purified by column chromatography (SiO , hexanes/EtOAc) to afford methyl 3-(2-(2-
bromophenyl)acetamido)bicyclo[1.1.1]pentanecarboxylate (1.51 g, 4.46 mmol, 82 %).
LC/MS (ESI) m/z 338.0 [M+H] .
Step 2: To a mixture of methyl 3-(2-(2-
bromophenyl)acetamido)bicyclo[1.1.1]pentanecarboxylate (1.58g, 4.67 mmol), tri-t-
butylphosphonium tetrafluoroborate, 99% (0.271 g, 0.934 mmol), palladium(II) acetate
(0.105 g, 0.467 mmol) and cesium carbonate (1.352 g, 7.01 mmol), was added toluene (23.36
mL). The mixture was flushed with N for several minutes and then heated at 100 °C for 4 h.
The mixture was then filtered through pad of celite. The filtrate was concentrated in vacuo,
adsorbed on celite and purified by column chromatography (SiO , hexanes/EtOAc) to afford
methyl 3-(2-oxoindolinyl)bicyclo[1.1.1]pentanecarboxylate (639 mg, 2.484 mmol, 53.2
%). LC/MS (ESI) m/z 258.1 [M+H] .
Step 3: To a solution of methyl 3-(2-oxoindolin
yl)bicyclo[1.1.1]pentanecarboxylate (1.28 g, 4.98 mmol) in THF (24.88 mL) was added
Diisobutylaluminum hydride solution (1M in THF, 29.9 mL, 29.9 mmol) at 0 °C. The
reaction was slowly warmed to RT and stirred for 1 h. The reaction was quenched with
MeOH (6 mL) and then diluted with ethyl acetate and sat. aq. ammonium chloride. An
emulsion was formed which was passed through a celite pad. The filtrate was collected,
concentrated and purified by column chromatography (SiO , hexanes/EtOAc) to afford (3-
(1H-indolyl)bicyclo[1.1.1]pentanyl)methanol (720 mg, 3.38 mmol, 67 %). LC/MS
(ESI) m/z 214.1 [M+H] .
Step 4: To a solution of (3-(1H-indolyl)bicyclo[1.1.1]pentan
yl)methanol (100 mg, 0.469 mmol) in acetonitrile (1407 µl) and water (156 µl) was added
2,2,6,6-Tetramethylpiperdine 1-oxly (7.33 mg, 0.047 mmol) and ammonium acetate (181
mg, 2.344 mmol). Iodosobenzene I,I-diacetate (332 mg, 1.032 mmol) was then added. The
mixture was stirred at RT for 2 h and then concentrated in vacuo. The crude product was
diluted with ethyl acetate and water. The organic layer was separated, washed with sat. aq.
sodium thiosulfate, dried over Na SO , concentrated and purified by column chromatography
(SiO , hexanes/EtOAc) to afford 3-(1H-indolyl)bicyclo[1.1.1]pentanecarbonitrile (21
mg, 0.101 mmol, 21%). H NMR (400 MHz, CDCl ) d 7.65–7.60 (m, 1H), 7.42–7.40 (m,
1H), 7.26–7.25 (m, 1H), 7.16–7.14 (m, 1H), 6.97 (s, 1H), 6.50 (s, 1H), 2.87 (s, 6H); LC/MS
(ESI) m/z 209.1 [M+H] .
Example 2
N-(5-((4-(1-(3-cyanobicyclo[1.1.1]pentanyl)-1H-indolyl)pyrimidinyl)amino)((2-
(dimethylamino)ethyl)(methyl)amino)methoxyphenyl)acrylamide
Step 1: To a solution of 2,4-dichloropyrimidine (172 mg, 1.152 mmol) in
DME (3201 µL) was added 3-(1H-indolyl)bicyclo[1.1.1]pentanecarbonitrile (200 mg,
0.960 mmol) and aluminum trichloride (192 mg, 1.441 mmol). The mixture was heated to 80
°C and stirred for 10 h. The mixture was diluted with ethyl acetate and water, and then
passed through a pad of celite. The organic layer from the collected filtrate was separated,
dried over Na SO , concentrated and purified by column chromatography (SiO ,
2 4 2
hexanes/EtOAc) to afford 3-(3-(2-chloropyrimidinyl)-1H-indol
yl)bicyclo[1.1.1]pentanecarbonitrile (168 mg, 0.524 mmol, 54 %). LC/MS (ESI) m/z
321.1 [M+H] .
Step 2: To a solution of 3-(3-(2-chloropyrimidinyl)-1H-indol
yl)bicyclo[1.1.1]pentanecarbonitrile (168 mg, 0.524 mmol) in 2-propanol (5.23 mL) was
added 4-fluoromethoxynitroaniline (97 mg, 0.524 mmol) followed by 4-
methylbenzenesulfonic acid hydrate (19.92 mg, 0.105 mmol). The mixture was heated at 80
°C for 10 h. Additional 4-fluoromethoxynitroaniline (19.4 mg, 0.104 mmol) and 2-
propanol (2 mL) was added to the reaction, and the mixture was heated for 3 h at 80 °C. The
reaction was cooled to RT and concentrated in vacuo. The resulting residue was diluted with
ethyl acetate and water. The organic layer was separated, washed with sat. aq. sodium
bicarbonate and brine, dried over Na SO and concentrated. The resulting residue was
triturated with diethyl ether to afford 3-(3-(2-((4-fluoromethoxy
nitrophenyl)amino)pyrimidinyl)-1H-indolyl)bicyclo[1.1.1]pentanecarbonitrile (182
mg, 0.387 mmol, 73%). LC/MS (ESI) m/z 471.1 [M+H] .
Step 3: To a solution of 3-(3-(2-((4-fluoromethoxy
nitrophenyl)amino)pyrimidinyl)-1H-indolyl)bicyclo[1.1.1]pentanecarbonitrile (180
mg, 0.383 mmol) in DMA (3826 µL) was added N,N-Diisopropylethylamine (133 µL, 0.765
mmol) followed by N1,N1,N2-trimethylethane-1,2-diamine (58.6 mg, 0.574 mmol). The
mixture was heated at 70 °C for 2 h. The mixture was then poured into cold water and
extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with
water and brine, dried over Na SO , and concentrated. The crude product was purified by
column chromatography (SiO , CH Cl /MeOH) to afford 3-(3-(2-((4-((2-
2 2 2
(dimethylamino)ethyl)(methyl)amino)methoxynitrophenyl)amino)pyrimidinyl)-1H-
indolyl)bicyclo[1.1.1]pentanecarbonitrile (120 mg, 0.217 mmol, 56 %). LC/MS (ESI)
m/z 553.3 [M+H] .
Step 4: To a solution of 3-(3-(2-((4-((2-
(dimethylamino)ethyl)(methyl)amino)methoxynitrophenyl)amino)pyrimidinyl)-1H-
indolyl)bicyclo[1.1.1]pentanecarbonitrile (50 mg, 0.090 mmol) in 6 N aq. HCl (1.81
mL) was added Iron (50.5 mg, 0.905 mmol). The mixture was heated at 60 °C for 45 mins.
The reaction was then cooled to RT and filtered. The solvents were evaporated, and the
residue was triturated with ether. The precipitate formed was filtered and dried to afford 3-
(3-(2-((5-amino((2-(dimethylamino)ethyl)(methyl)amino)
methoxyphenyl)amino)pyrimidinyl)-1H-indolyl)bicyclo[1.1.1]pentanecarbonitrile
hydrochloride (50 mg, 0.089 mmol, 99%), which was used in the next step without further
purification. LC/MS (ESI) m/z 523.3 [M+H] .
Step 5: To a solution of 3-(3-(2-((5-amino((2-
(dimethylamino)ethyl)(methyl)amino)methoxyphenyl)amino)pyrimidinyl)-1H-indol
yl)bicyclo[1.1.1]pentanecarbonitrile hydrochloride (50 mg, 0.089 mmol) in THF (1.72
mL) and DMF (0.52 mL) was added DIPEA (156 µl, 0.894 mmol) at 0 °C. To this mixture
was added acryloyl chloride (8.09 mg, 0.089 mmol) in THF (0.2 mL). The mixture was
stirred at 0 °C for 10 mins and then diluted with ethyl acetate and water. The organic layer
was separated, dried over Na SO , and concentrated. The crude product was purified by
HPLC (10:90 to 80:20 0.1% HCO H (aq):MeCN) to afford N-(5-((4-(1-(3-
cyanobicyclo[1.1.1]pentanyl)-1H-indolyl)pyrimidinyl)amino)((2-
(dimethylamino)ethyl)(methyl)amino)methoxyphenyl)acrylamide (6 mg, 10.40 µmol, 11
%). H NMR (400 MHz, DMSO-d ) d 10.05 (s, 1H), 8.81 (s, 1H), 8.40–8.30 (m, 3H), 8.19
(s, 1H), 7.72–7.70 (m, 1H), 7.33–7.31 (m, 2H), 7.29–7.27 (m, 1H), 7.06 (s, 1H), 6.55–6.47
(m, 1H), 5.81–5.78 (m, 1H), 3.87 (s, 3H), 3.02–3.01 (m, 8H), 2.75 (s, 3H), 2.60–2.28 (m,
9H); LC/MS (ESI) m/z 577.3 [M+H]
Example 3
N-(5-((4-(1-(bicyclo[1.1.1]pentanyl)-1H-indolyl)cyanopyrimidinyl)amino)((2-
(dimethylamino)ethyl)(methyl)amino)methoxyphenyl)acrylamide
Step 1: To a solution of 2,4-dichloropyrimidinecarbonitrile (500 mg,
2.87 mmol) in dimethoxy ethane (14.4 mL) was added 1-(bicyclo[1.1.1]pentanyl)-1H-
indole (527 mg, 2.87 mmol, from example 1, step-3) and aluminum trichloride (575 mg, 4.31
mmol). The mixture was heated at 80 °C for 2h, cooled to RT, and diluted with ethyl
acetate/water. The organic layer was separated, dried over Na SO , concentrated and purified
by column chromatography using 0-20% ethyl acetate in hexane to afford impure product
(eluting along with dialkylated product). The impure compound was again purified by silica
gel chromatography (SiO , hexanes/EtOAc) to afford 4-(1-(bicyclo[1.1.1]pentanyl)-1H-
indolyl)chloropyrimidinecarbonitrile (195 mg, 0.608 mmol, 21%). LC/MS (ESI)
m/z 321.1 [M+H] .
Step 2: To a solution of 4-(1-(bicyclo[1.1.1]pentanyl)-1H-indolyl)-
2-chloropyrimidinecarbonitrile (20 mg, 0.062 mmol) in 2-propanol (0.623 mL) was added
4-fluoromethoxynitroaniline (11.61 mg, 0.062 mmol) followed by 4-
methylbenzenesulfonic acid hydrate (2.372 mg, 0.012 mmol). The mixture was heated at 80
°C for 6 h. The reaction was cooled to RT. The resulting precipitate was filtered, washed
with cold 2-propanol and dried to afford 4-(1-(bicyclo[1.1.1]pentanyl)-1H-indolyl)
((4-fluoromethoxynitrophenyl)amino)pyrimidinecarbonitrile (21 mg, 0.045 mmol,
71%), which was used in the next step without purification. LC/MS (ESI) m/z 471.2
[M+H] .
Step 3: To a solution of 4-(1-(bicyclo[1.1.1]pentanyl)-1H-indolyl)-
2-((4-fluoromethoxynitrophenyl)amino)pyrimidinecarbonitrile (100 mg, 0.213
mmol) in DMA (3 mL) was added N,N-Diisopropylethylamine (0.074 mL, 0.425 mmol)
followed by N1,N1,N2-trimethylethane-1,2-diamine (21.72 mg, 0.213 mmol) in DMA (0.2
mL). The mixture was heated at 70 °C for 1 h. The mixture was then cooled to RT, poured
into cold water and extracted with ethyl acetate. The combined organic layers were washed
with brine, dried over Na SO , concentrated and purified by column chromatography (SiO ,
2 4 2
CH Cl /MeOH) to afford 4-(1-(bicyclo[1.1.1]pentanyl)-1H-indolyl)((4-((2-
(dimethylamino)ethyl)(methyl)amino)methoxynitrophenyl)amino)pyrimidine
carbonitrile (78 mg, 0.141 mmol, 66%). LC/MS (ESI) m/z 553.1 [M+H] .
Step 4: To a solution of 4-(1-(bicyclo[1.1.1]pentanyl)-1H-indolyl)-
2-((4-((2-(dimethylamino)ethyl)(methyl)amino)methoxynitrophenyl)amino)pyrimidine-
-carbonitrile (50 mg, 0.090 mmol) in aq. HCl (2 mL, 12.0 mmol) was added Iron (50 mg,
0.895 mmol). The mixture was heated to 70 °C. After 30 mins the reaction was cooled to
RT. The reaction was concentrated in vacuo, and the resulting residue was triturated with
ether. The precipitate was collected and dried to afford 2-((5-amino((2-
(dimethylamino)ethyl)(methyl)amino)methoxyphenyl)amino)(1-(bicyclo[1.1.1]pentan-
1-yl)-1H-indolyl)pyrimidinecarbonitrile hydrochloride (50 mg, 0.089 mmol, 99%),
which was used in the next step without further purification. LC/MS (ESI) m/z 523.1
[M+H] .
Step 5: To a solution of 2-((5-amino((2-
(dimethylamino)ethyl)(methyl)amino)methoxyphenyl)amino)(1-(bicyclo[1.1.1]pentan-
1-yl)-1H-indolyl)pyrimidinecarbonitrile (47 mg, 0.090 mmol) in tetrahydrofuran (4
mL) was added N,N-Diisopropylethylamine (0.078 mL, 0.450 mmol) at 0 °C followed by
acryloyl chloride (8.14 mg, 0.090 mmol) in THF (0.2 mL). The mixture was stirred at 0 °C
for 10 mins at which point additional acryloyl chloride (1.62 mg, 0.018 mmol) was added at
0 °C. After 10 mins, the reaction was diluted with ethyl acetate and water. The organic layer
was washed with water and brine, dried over Na SO , concentrated and was purified by
HPLC (10:90 to 80:20 0.1% HCO H (aq): MeCN) to afford N-(5-((4-(1-
(bicyclo[1.1.1]pentanyl)-1H-indolyl)cyanopyrimidinyl)amino)((2-
(dimethylamino)ethyl)(methyl)amino)methoxyphenyl)acrylamide (15 mg, 0.026 mmol,
28.9 %). H NMR (400 MHz, CDCl ) d 10.08 (s, 1H), 9.47 (s, 1H), 8.70 (s, 1H), 8.38–8.35
(m, 2H), 7.71–7.69 (m, 1H), 7.23–7.20 (m, 1H), 7.07–7.05 (m, 1H), 6.43–6.39 (m, 1H),
6.20–6.16 (m, 1H), 5.74–5.71 (m, 1H), 3.73 (s, 3H), 2.93–2.92 (m, 2H), 2.76 (s, 3H), 2.75 (s,
1H), 2.49 (s, 6H), 2.48–2.38 (m, 2H), 2.21 (s, 6H); LC/MS (ESI) m/z 577.3 [M+H] .
Intermediate 5
3-((dimethylamino)methyl)-N-methylbicyclo[1.1.1]pentanamine
Step 1: To a solution of 3-(methoxycarbonyl)bicyclo[1.1.1]pentane
carboxylic acid (5 g, 29.4 mmol) at 0 °C was added oxalyl chloride (7.57 mL, 88 mmol) and
dimethylformamide (0.023 mL, 0.294 mmol). The mixture was stirred at RT for 2 h. The
solvents were evaporated. The crude was re-dissolved in dichloromethane (50 mL) and a
solution of dimethylamine (2M in MeOH, 29.4 mL, 58.8 mmol) in dichloromethane (50 mL)
was added at 0 °C. The mixture was stirred at 0 °C for 1 h and then partitioned between
DCM/water. The organic layer was separated, dried over Na SO , and concentrated in vacuo
to afford methyl 3-(dimethylcarbamoyl)bicyclo[1.1.1]pentanecarboxylate (5.67 g, 28.7
mmol, 98%) as an off-white solid. LC/MS (APCI) m/z 198.1 [M+H] .
Step 2: To a solution of methyl 3-
(dimethylcarbamoyl)bicyclo[1.1.1]pentanecarboxylate (5.67 g, 28.7 mmol) in
tetrahydrofuran (40.0 mL) and H O (13.3 mL) was added lithium hydroxide monohydrate
(1.810 g, 43.1 mmol) at 0 °C. The mixture warmed RT and stirred over 2 days. The organic
solvent was removed in vacuo, and the reaction was diluted with water. To this mixture was
added Dowex® Marathon C hydrogen form (60 g), and the reaction was stirred for 1 h.
The reaction was filtered, and the filtrate was concentrated to afford 3-
(dimethylcarbamoyl)bicyclo[1.1.1]pentanecarboxylic acid (5.1 g, 27.8 mmol, 97 %) as a
white solid. LC/MS (APCI) m/z 184.1 [M+H] .
Step 3: To a solution of 3-(dimethylcarbamoyl)bicyclo[1.1.1]pentane
carboxylic acid (331 mg, 1.81mmol)in tBuOH (9.0 mL) was added 3Å molecular sieves (400
mg) followed by triethylamine (0.504 mL, 3.61 mmol) and diphenyl phosphorazidate (0.466
mL, 2.17 mmol). The mixture was stirred at 30 °C for 2 h and then heated to 85 °C
overnight. The reaction was concentrated in vacuo and purified by column chromatography
, DCM/MeOH) to afford tert-butyl (3-(dimethylcarbamoyl)bicyclo[1.1.1]pentan
(SiO2
yl)carbamate (160 mg, 1.81 mmol, 35%) as a colorless oil. LC/MS (APCI) m/z 155.1
[C H N O -C H O +H ] .
13 22 2 3 5 9 2
Step 4: A solution of tert-butyl (3-
(dimethylcarbamoyl)bicyclo[1.1.1]pentanyl)carbamate (350 mg, 1.38 mmol) in THF (6.9
mL) was cooled to 0 °C and treated with NaH (60% dispersion in mineral oil, 83 mg, 2.06
mmol). After 10 mins, iodomethane (258 µL, 4.1 mmol) was added. After 16 h, additional
iodomethane (258 µL, 4.1 mmol) was added. After 2 h, the reaction was quenched by the
addition of water. The mixture was diluted with EtOAc and H O, and extracted with EtOAc.
The combined organic layers were dried over Na sO and concentrated in vacuo to afford the
crude product which was purified by column chromatography (SiO , DCM/MeOH) to afford
tert-butyl (3-(dimethylcarbamoyl)bicyclo[1.1.1]pentanyl)(methyl)carbamate (209.4 mg,
57%) as a colorless oil. LC/MS (APCI) m/z 169.1 [C H N O -C H O +H] .
14 24 2 3 5 9 2
Step 5: A solution of tert-butyl (3-
(dimethylcarbamoyl)bicyclo[1.1.1]pentanyl)(methyl)carbamate (209.0 mg, 1.38 mmol) in
THF (3.1 mL) was cooled to 0 °C and then was treated with BH ·THF (1M in THF, 3.12 mL,
3.12 mmol). The reaction was warmed to 35 °C and stirred for 3 h, and then for 4 days at 45
°C. The reaction was quenched at 0 °C by the addition of MeOH. The mixture was
concentrated in vacuo, diluted with MeOH and reconcentrated (3x). The crude product was
purified by reverse phase HPLC using 20-60% acetonitrile in water to afford tert-butyl (3-
((dimethylamino)methyl)bicyclo[1.1.1]pentanyl)(methyl)carbamate (196 mg, 99%) as a
colorless oil. LC/MS (APCI) m/z 255.2 [M+H] .
Step 6: A solution of tert-butyl (3-
((dimethylamino)methyl)bicyclo[1.1.1]pentanyl)(methyl)carbamate (198 mg, 0.778
mmol) in EtOAc (3.89 mL) was cooled to 0 °C and treated with hydrogen chloride (4M in
Dioxane, 1.95 mL, 7.78 mmol). The mixture was stirred for 2 h at RT. The reaction was
then concentrated to provide 3-((dimethylamino)methyl)-N-methylbicyclo[1.1.1]pentan
amine dihydrochloride (170 mg, 96%) as an off-white solid. LC/MS (APCI) m/z 155.2
[M+H] .
Example 4
N-(2-((3-((dimethylamino)methyl)bicyclo[1.1.1]pentanyl)(methyl)amino)methoxy
((4-(1-methyl-1H-indolyl)pyrimidinyl)amino)phenyl)acrylamide
Step 1: 3-(2-chloropyrimidinyl)methyl-1H-indole was synthesized
by following the same procedure as described in step 1 from Example 1 by reacting 1-
methyl-1H-indole instead 1-(bicyclo[1.1.1]pentanyl)-1H-indole to afford 3-(2-
chloropyrimidinyl)methyl-1H-indole (15%). H NMR (400 MHz, CDCl3): d 8.43 (d, J
= 5.2 Hz, 1H,), 8.31 – 8.30 (m, 1H), 7.92 (s, 1H), 7.46 (d, J = 5.2 Hz, 1H,), 7.40 – 7.32 (m,
3H), 3.86 (s, 3H).
Step 2: To a solution of 3-(2-chloropyrimidinyl)methyl-1H-indole
(50 mg, 0.205 mmol), and 4-fluoromethoxynitroaniline (40 mg, 0.215 mmol) in
isopropyl alcohol (10 mL) was added 4-methylbenzenesulfonic acid (45 mg, 0.261 mmol).
The resulting mixture was heated at 105 °C for 2.5 h. The mixture was cooled to RT. The
precipitate was collected by filtration, washed with 2-pentanol (50 mL), and dried under
vacuum to afford N-(4-fluoromethoxynitrophenyl)(1-methyl-1H-indol
yl)pyrimidinamine as a yellow solid (51 mg, 62%). LC/MS (ESI) m/z 394.1 [M+H] .
Step 3: To a solution of N-(4-fluoromethoxynitrophenyl)(1-
methyl-1H-indolyl)pyrimidinamine (200 mg, 0.508 mmol) and diisopropylethylamine
(0.328 mg, 2.54 mmol) in dimethyl sulfoxide (4 mL) was added 3-((dimethylamino)methyl)-
N-methylbicyclo[1.1.1]pentanamine (117 mg, 0.762 mmol). The mixture was heated at
100 C for 24 h. The mixture was cooled to RT and diluted with dichloromethane and water.
The organic layer was separated, dried over Na SO and concentrated in vacuo. The crude
product was purified by HPLC (10:90 to 80:20 0.1% HCO H (aq):MeCN) to afford N1-(3-
((dimethylamino)methyl)bicyclo[1.1.1]pentanyl)methoxy-N1-methyl-N4-(4-(1-methyl-
1H-indolyl)pyrimidinyl)nitrobenzene-1,4-diamine (140 mg, 52%). LC/MS (ESI)
m/z 528.6 [M+H] .
Step 4: To the solution of N1-(3-
((dimethylamino)methyl)bicyclo[1.1.1]pentanyl)methoxy-N1-methyl-N4-(4-(1-methyl-
1H-indolyl)pyrimidinyl)nitrobenzene-1,4-diamine (50 mg, 0.095 mmol) in acetic
acid (1 mL) under argon was added iron powder (27 mg, 0.475 mmol). The mixture was
stirred at 50 C for 1 h. The mixture was then cooled to RT and filtered to afford N1-(3-
((dimethylamino)methyl)bicyclo[1.1.1]pentanyl)methoxy-N1-methyl-N4-(4-(1-methyl-
1H-indolyl)pyrimidinyl)benzene-1,2,4-triamine as solution in acetic acid, which was
used in the next step without further purification. LC/MS (ESI) m/z 498.7 [M+H] .
Step 5: To the solution of N1-(3-
((dimethylamino)methyl)bicyclo[1.1.1]pentanyl)methoxy-N1-methyl-N4-(4-(1-methyl-
1H-indolyl)pyrimidinyl)benzene-1,2,4-triamine in acetic acid (obtained from step 4) at
0 C was added acryloyl chloride (8.59 mg, 0.095 mmol) in DCM (0.2 mL). After 15 min,
the reaction mixture was diluted with ethyl acetate and water. The organic layer was
separated, dried over Na SO , concentrated and purified by HPLC (10:90 to 80:20 0.1%
HCO H (aq): MeCN) to afford N-(2-((3-((dimethylamino)methyl)bicyclo[1.1.1]pentan
yl)(methyl)amino)methoxy((4-(1-methyl-1H-indolyl)pyrimidin
yl)amino)phenyl)acrylamide (20 mg, 42%). H NMR (400 MHz, DMSO-d ): d 9.38 (s, 1H),
9.20 (s, 1H), 8.97 (s, 1H), 8.69 (s, 1H), 8.32 (d, J = 5.6 Hz, 1H), 8.25 (m, 1H), 7.54 (d, J =
8.4 Hz, 1H), 7.29–7.24 (m, 2H), 7.17 (t, J = 7.2 Hz, 1H), 6.92 (s, 1H), 6.80–6.73 (m, 1H),
6.24 (dd, J = 16.8, 1.6 Hz, 1H), 5.73 (d, J = 10.0 Hz, 1H), 3.92 (s, 3H), 3.86 (s, 3H), 3.29 (d,
J = 4.8Hz, 2H), 2.73 (s, 9H), 1.87 (s, 6H); LC/MS (ESI) m/z 552.6 [M+H] .
Example 5
N-(5-((4-(1-(bicyclo[1.1.1]pentanyl)-1H-indazolyl)pyrimidinyl)amino)((2-
(dimethylamino)ethyl)(methyl)amino)methoxyphenyl)acrylamide
Step 1: Sodium hydride (60% dispersion in mineral oil, 598 mg, 14.94
mmol) was added to a stirring solution of 4-chloromethylthiopyrimidine (1.45 mL, 12.45
mmol), 2-fluoro-benzaldehyde (1.57 mL, 14.94 mmol) and 1,3-dimethylimidazolium iodide
(4.15 mmol). The resulting mixture was heated at reflux for 4 h. The mixture was cooled to
RT, and then partitioned between ethyl acetate and water. The organic layer was separated,
dried over Na SO , filtered and evaporated under reduced pressure. The crude residue was
purified by column chromatography (SiO , hexanes/EtOAc) to afford (2-fluorophenyl)-(2-
methylsulfanyl-pyrimidinyl)-methanone as a pale yellow solid (2 g, 64%). LC/MS (ESI)
m/z 249.2 [M+H] .
Step 2: A mixture of (2-Fluoro-phenyl)-(2-methylsulfanyl-pyrimidin
yl)-methanone (50 mg, 0.2 mmol), bicyclo[1.1.1]pentanylhydrazine (23.5 mg, 0.24 mmol)
and cesium carbonate (282.25 mg, 0.8 mmol) in dimethyl acetamide (3 mL) was heated at
150 C for 8 h. The mixture was then diluted with dichloromethane (50 mL) and washed
with water (2 x 20 mL). The organic layer was separated, dried over Na SO and
concentrated. The residue was purified by HPLC (10:90 to 80:20 0.1% HCO H (aq):MeCN)
to afford 1-(bicyclo[1.1.1]pentanyl)(2-(methylthio)pyrimidinyl)-1H-indazole as a
red oil (30 mg, 0.097 mmol, 48%). LC/MS (ESI) m/z 309.4 [M+H] .
Step 3: To a solution of 1-(bicyclo[1.1.1]pentanyl)(2-
(methylthio)pyrimidinyl)-1H-indazole (1.2 g, 3.89 mmol) in dichloromethane (10 mL)
was added 2-chlorobenzoic acid (1.21 g, 7.78 mmol). The mixture was stirred at RT
overnight. The resulting suspension was filtered and washed with dichloromethane. The
filtrate was concentrated to afford 1-(bicyclo[1.1.1]pentanyl)(2-
(methylsulfonyl)pyrimidinyl)-1H-indazole as a pale yellow solid (1.25 g, 3.68 mmol,
94%), which was used directly in the next step. LC/MS (ESI) m/z 341.4 [M+H] .
Step 4: To a solution of 1-(bicyclo[1.1.1]pentanyl)(2-
(methylsulfonyl)pyrimidinyl)-1H-indazole (340 mg, 1.0 mmol) and 4-Fluoromethoxy-
-nitro-phenylamine (223.2 mg, 1.2 mmol) in anhydrous THF (5 mL) was added sodium
hydride (60 mg, 1.5 mmol, 60% dispersion in mineral oil). The mixture was stirred at 60 C
overnight. The mixture was then diluted with water and extracted with DCM. The organic
layer was dried over Na SO and concentrated. The residue was purified by HPLC (10:90 to
80:20 0.1% HCO H (aq): MeCN) to afford 4-(1-(bicyclo[1.1.1]pentanyl)-1H-indazol
yl)-N-(4-fluoromethoxynitrophenyl)pyrimidinamine (98 mg, 0.22 mmol, 22%).
LC/MS (ESI) m/z 447.5 [M+H]
Step 5: To a solution of 4-(1-(bicyclo[1.1.1]pentanyl)-1H-indazol
yl)-N-(4-fluoromethoxynitrophenyl)pyrimidinamine (100 mg, 0.224 mmol) in
1 1 2
dimethyl acetamide (3 mL) was added N ,N ,N -trimethylethane-1,2-diamine (45.7 mg,
0.448 mmol). The mixture was stirred at 100 C for 2 h and then cooled to RT. The mixture
was diluted with water and extracted with dichloromethane (2 x 50 mL). The combined
organic layers were dried over Na SO and concentrated. The residue was purified by HPLC
(10:90 to 80:20 0.1% HCO H (aq): MeCN) to afford N1-(4-(1-(bicyclo[1.1.1]pentanyl)-
1H-indazolyl)pyrimidinyl)-N4-(2-(dimethylamino)ethyl)methoxy-N4-methyl
nitrobenzene-1,4-diamine (60 mg, 0.114 mmol, 50%). LC/MS (ESI) m/z 529.3 [M+H] .
Step 6: To a solution of N1-(4-(1-(bicyclo[1.1.1]pentanyl)-1H-indazol-
3-yl)pyrimidinyl)-N4-(2-(dimethylamino)ethyl)methoxy-N4-methylnitrobenzene-
1,4-diamine (60 mg, 0.114 mmol) in acetic acid ( 2 mL) under Ar, was added Iron powder
(31 mg, 0.57 mmol). The mixture was stirred at 60 C for 1 h. The mixture was then cooled
to RT and filtered. It was used directly as a solution of N4-(4-(1-(bicyclo[1.1.1]pentanyl)-
1H-indazolyl)pyrimidinyl)-N1-(2-(dimethylamino)ethyl)methoxy-N1-
methylbenzene-1,2,4-triamine in acetic acid. LC/MS (ESI) m/z 499.7 [M+H] .
Step 7: To a solution of N4-(4-(1-(bicyclo[1.1.1]pentanyl)-1H-
indazolyl)pyrimidinyl)-N1-(2-(dimethylamino)ethyl)methoxy-N1-methylbenzene-
1,2,4-triamine in acetic acid obtained in step 6 (Example 5), was added acryloyl chloride
(12.32 mg, 0.137 mmol) in dichloromethane (0.2 mL). The mixture was stirred at RT for 15
mins. The mixture was then filtered, and the filtrate was concentrated. The residue was
purified by HPLC (10:90 to 80:20 0.1% HCO H (aq):MeCN) to afford N-(5-((4-(1-
(bicyclo[1.1.1]pentanyl)-1H-indazolyl)pyrimidinyl)amino)((2-
(dimethylamino)ethyl)(methyl)amino)methoxyphenyl)acrylamide as a brownish solid (20
mg, 0.036 mmol, 31% over two steps). H NMR (400 MHz, DMSO-d ): d 9.61 (s, 1H), 8.58
(s, 1H), 8.47 – 8.44 (m, 2H), 8.34 (s, 1H), 7.83 (d, J = 8.4 Hz, 1H), 7.46–7.43 (m, 2H), 7.21–
7.18 (m, 1H), 7.02 (s, 1H), 6.68 – 6.60 (m, 1H), 6.28 (d, J = 16.8 Hz, 1H), 5.78 (d, J = 10.0
Hz, 1H), 3.86 (s, 3H), 3.33–3.27 (m, 4H), 2.82–2.81 (m, 6H), 2.76 (s, 1H), 2.52 (s, 3H), 2.51
(s, 6H); LC/MS (ESI) m/z 553.4 [M+H] .
Example 6
N-(2-((3-(dimethylamino)bicyclo[1.1.1]pentanyl)(methyl)amino)methoxy((4-(1-
methyl-1H-indolyl)pyrimidinyl)amino)phenyl)acrylamide
Step 1: To a stirred suspension of 2,4-dichloropyrimidine (2.637 g, 20.13
mmol) in dimethoxyethane (30 mL) was added aluminum trichloride (2.67 g, 20.134 mmol)
at 10 °C. The mixture was stirred at 10 °C for 15 mins. 1-methyl-1H-indole (3.0 g, 20.13
mmol) was added, and the mixture was heated under reflux for 2 h. The mixture was cooled
to RT, poured into water (30 mL) and extracted with ethyl acetate (3 x 50 mL). The
combined organic layers were washed with water (30 mL) and brine (30 mL), dried over
sodium sulphate and concentrated to afford 3-(2-chloropyrimidinyl)methyl-1H-indole
(3.0 g, 12.34 mmol, 61%). LC/MS (ESI) m/z 244.3 [M+H] .
Step 2: To a stirred solution of 3-(2-chloropyrimidinyl)methyl-1H-
indole (4g, 16.46 mmol) in 2-pentanone (40 mL) was added 4-fluoromethoxy
nitroaniline (3.06 g, 16.46 mmol) and p- toluenesulfonic acid (0.312 g, 1.65 mmol). The
reaction was heated to 80 °C. After 16h, the mixture cooled to RT and diluted with water (40
mL). The resulting solid was filtered and dried to afford N-(4-fluoromethoxy
nitrophenyl)(1-methyl-1H-indolyl)pyrimidinamine (4.0 g, 10.18 mmol, 62%).
LC/MS (ESI) m/z 394.20 [M+H] .
Step 3: To a stirred solution of N-(4-fluoromethoxynitrophenyl)
(1-methyl-1H-indolyl)pyrimidinamine (1.0 g, 2.54 mmol) in dimethyl sulfoxide (50
mL) was added N1,N1,N3-trimethylbicyclo[1.1.1]pentane-1,3-diamine hydrochloride (0.537
g, 3.05 mmol, intermediate 1, Step-10) and potassium carbonate (0.701 g, 5.08 mmol). The
mixture was heated at 65 °C for 16 h. The mixture was then cooled to RT, poured into water
(20 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were
washed with water (20 mL) and brine (20 mL), dried over sodium sulphate and concentrated
to afford N1-(5-methoxy(4-(1-methyl-1H-indolyl)pyrimidinylamino)
nitrophenyl)-N1,N3,N3-trimethylbicyclo[1.1.1]pentane-1,3-diamine (0.420 g, 0.818 mmol,
32%). LC/MS (ESI) m/z 514.1 [M+H] .
Step 4: To a stirred solution N1-(5-methoxy(4-(1-methyl-1H-indol
yl)pyrimidinylamino)nitrophenyl)-N1,N3,N3-trimethylbicyclo[1.1.1]pentane-1,3-
diamine (0.400 g, 0.779 mmol) in ethyl acetate:tetrahydrofuran (10 mL) was added 10% wet
Pd/C (100 mg). The reaction was stirred at RT under hydrogen atmosphere (60 psi) for 6 h.
The mixture was filtered through celite, and the organic fractions were concentrated to afford
N1-(3-(dimethylamino)bicyclo[1.1.1]pentanyl)methoxy-N1-methyl-N4-(4-(1-methyl-
1H-indolyl)pyrimidinyl)benzene-1,2,4-triamine (260 g, 0.538 mmol, 69%). LC/MS
(ESI) m/z 484.1 [M+H] .
Step 5: To a stirred suspension of N1-(3-
(dimethylamino)bicyclo[1.1.1]pentanyl)methoxy-N1-methyl-N4-(4-(1-methyl-1H-
indolyl)pyrimidinyl)benzene-1,2,4-triamine (0.270 g, 0.559 mmol) in
tetrahydrofuran:water (25 mL) was added 3-chloropropanoyl chloride (7.10 mg, 0.559
mmol). The reaction was stirred at 5 °C for 15 mins. To this mixture was added sodium
hydroxide (89.0 mg, 2.236 mmol), and the mixture was stirred at RT for 16 h. The mixture
was poured into water (5 mL) and extracted with ethyl acetate (3 x 30 mL). The combined
organic layers were washed with water (10 mL) and brine (10 mL), dried over sodium
sulphate and concentrated to afford N-(2-((3-(dimethylamino)bicyclo[1.1.1]pentan
yl)(methyl)amino)methoxy((4-(1-methyl-1H-indolyl)pyrimidin
yl)amino)phenyl)acrylamide (0.110 g, 0.204 mmol, 37%). H NMR (300 MHz, CDCl ) d
9.86 (s, 1H), 9.07 (s, 1H), 8.78 (s, 1H), 8.38 (d, J = 5.6 Hz, 1H), 8.14-8.04 (m, 2H), 7.81 (s,
1H), 7.40 (d, J = 7.2 Hz, 1H), 7.28–7.26 (m, 1H), 7.22 (d, J = 5.2 Hz, 1H), 6.71 (s, 1H),
6.45–6.37 (m, 2H), 5.77 (dd, J = 7.2, 2.0 Hz, 1H), 4.0 (s, 3H), 3.88 (s, 3H), 2.70 (s, 3H), 2.27
(s, 6H), 1.82 (s, 6H); LC/MS (ESI) m/z 538.5 [M+H] .
Intermediate 6
1-(3-fluorobicyclo[1.1.1]pentanyl)-1H-indole
Step 1: To a solution of 2-(2-bromophenyl)acetic acid (2.0 g, 9.30 mmol)
in CH Cl (40 mL) at 0 °C was added Hunig's base (4.8 mL, 27.90 mmol), N1-
((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine (2.67 g, 13.95 mmol) and
HOBt (2.1g, 13.90 mmol) followed by bicyclo[1.1.1]pentanamine hydrochloride (1.52 g,
11.16 mmol). The mixture was stirred at RT for 16 h. After the completion of the reaction,
the mixture was concentrated under reduced pressure to afford a residue that was purified by
chromatography on SiO (100-200 mesh, eluent: 15% ethyl acetate in petroleum ether) to
afford of 2-(2-bromophenyl)-N-(3-fluorobicyclo[1.1.1]pentanyl)acetamide as a white solid
(1.2 g, 43%). MS (ESI) m/z 298.11 [M+H] .
Step 2: To a flame dried vial with stir bar was added 2-(2-bromophenyl)-
N-(3-fluorobicyclo[1.1.1]pentanyl)acetamide (0.85 g, 2.86 mmol), followed by Pd(OAc)
(0.19 g, 0.28 mmol), tri-tert-butylphosphonium tetrafluoroborate (0.16 g, 0.57 mmol) and
Cs CO (1.39 g, 4.29 mmol). The reaction vial was purged with argon. Degassed toluene
(30 mL) was added, and the mixture was heated at 100 °C for 4 h. After the reaction
completed (TLC), the mixture was filtered through a pad of celite and washed with EtOAc
(30 mL). The filtrate was concentrated under reduced pressure to afford a residue that was
purified by chromatography on SiO (100-200 mesh, eluent: 5% ethyl acetate in petroleum
ether) to afford 1-(3-fluorobicyclo[1.1.1]pentanyl)indolinone as an off-white solid
(0.37 g, 60%). MS (ESI) m/z 218.32 [M+H] .
Step 3: To a solution of 1-(bicyclo[1.1.1]pentanyl)indolinone (0.5 g,
2.48 mmol) in THF (10 mL) at -78 °C was added DIBAL-H (1M toluene, 6.2 mL, 6.21
mmol) dropwise. The mixture was stirred at -78 °C for 2 h. After the completion of the
reaction (TLC), the mixture was cooled to 0 °C, and the reaction was quenched with MeOH
(10 mL). The mixture was filtered through a pad of celite, washed with EtOAc (30 mL),
dried over Na SO and concentrated under reduced pressure. The resulting residue was
purified by chromatography on SiO (100-200 mesh, eluent: 2% ethyl acetate in petroleum
ether) to afford 1-(3-fluorobicyclo[1.1.1]pentanyl)-1H-indole as a pale yellow liquid (0.27
g, 58%). H NMR (400 MHz, CDCl ) d 7.61 (d, J = 7.6 Hz, 1H), 7.42 (d, J = 7.6 Hz, 1H),
7.21 (t, J = 8.0 Hz, 1H), 7.13 (t, J = 8.0 Hz, 1H), 6.98 (d, J = 3.6 Hz, 1H), 6.50 (d, J = 3.6 Hz,
1H), 2.73 (s, 6H); MS (ESI) m/z 202.1 [M+H] .
Example 7
N-(2-((2-(dimethylamino)ethyl)(methyl)amino)((4-(1-(3-fluorobicyclo[1.1.1]pentanyl)-
1H-indolyl)pyrimidinyl)amino)methoxyphenyl)acrylamide
Step 1: To a stirred solution of 1-(3-fluorobicyclo[1.1.1]pentanyl)-1H-
indole (100 mg, 0.49 mmol) in DME (1.6 mL) at RT was added 2,4-dichloropyrimidine (74
mg, 0.49 mmol) followed by AlCl (99 mg, 0,74 mmol). The mixture was stirred at 80 °C
for 16 h. After completion of reaction (TLC), the mixture was diluted with dichloromethane
(5 mL), washed with water followed by brine, dried over Na2SO4 and concentrated under
reduced pressure. The residue was purified by chromatography on SiO (100-200 mesh,
eluent: 10% ethyl acetate in petroleum ether) to afford 3-(2-chloropyrimidinyl)(3-
fluorobicyclo[1.1.1]pentanyl)-1H-indole as a yellow solid (80 mg, 51%). MS (ESI) m/z
313.92 [M+H] .
Step 2: To a stirred solution of 3-(2-chloropyrimidinyl)(3-
fluorobicyclo[1.1.1]pentanyl)-1H-indole (180 mg, 0.57 mmol) in 2-pentanol (8 mL) at RT
was added 4-fluoromethoxynitroaniline (107 mg, 0.57 mmol) and PTSA (10 mg, 0.05
mmol). The mixture was stirred at 80 °C for 16 h. After completion of reaction, the mixture
O (2 x 5 mL) and brine (5 mL), dried over
was diluted with EtOAc (5 mL), washed with H2
Na SO and concentrated under reduced pressure. The residue was purified by
chromatography on SiO (100-200 mesh, eluent: 20% ethyl acetate in petroleum) to afford N-
(4-fluoromethoxynitrophenyl)(1-(3-fluorobicyclo[1.1.1]pentanyl)-1H-indol
yl)pyrimidinamine as a dark green color solid (160 mg, 60%). MS (ESI) m/z 464.01
[M+H] .
Step 3: To a stirred solution of N-(4-fluoromethoxynitrophenyl)
(1-(3-fluorobicyclo[1.1.1]pentanyl)-1H-indolyl)pyrimidinamine (160 mg, 0.34
mmol) in DMA (6 mL) at RT was added N1,N1,N2-trimethylethane-1,2-diamine (0.06 mL,
0.51 mmol) followed by DIPEA (0.08 mL, 0.44 mmol). The mixture was stirred at 85 °C for
h. After completion of reaction, the mixture was diluted with EtOAc (10 mL), washed with
ice cold H O (10 mL) and brine (5 mL), dried over Na SO and concentrated. The residue
2 2 4
was purified by chromatography on SiO (100-200 mesh, eluent: 5% methanol in
dichloromethane) to afford 160 mg (85%) of N-(4-fluoromethoxynitrophenyl)(1-(3-
fluorobicyclo[1.1.1]pentanyl)-1H-indolyl)pyrimidinamine as a bright red solid. MS
(ESI) m/z 546.09 [M+H] .
Step 4: To a stirred solution of N1-(2-(dimethylamino)ethyl)-N4-(4-(1-(3-
fluorobicyclo[1.1.1]pentanyl)-1H-indolyl)pyrimidinyl)methoxy-N1-methyl
nitrobenzene-1,4-diamine (160 mg, 0.294 mmol) in THF:EtOAc (1:1, 10 mL) was added
Pd/C (10% w/w, wet, 80 mg). The mixture was stirred at RT under H (1 atm) for 2 h. After
the completion of the reaction, the mixture was filtered through a pad of celite, washed with
EtOAc (50 mL) and concentrated under reduced pressure. The residue was purified by
chromatography on SiO (100-200 mesh, eluent: 15% methanol in dichloromethane) to
afford N1-(2-(dimethylamino)ethyl)-N4-(4-(1-(3-fluorobicyclo[1.1.1]pentanyl)-1H-indol-
3-yl)pyrimidinyl)methoxy-N1-methylbenzene-1,2,4-triamine as a pale brown solid
(140 mg, 92%). MS (ESI) m/z 516.43 [M+H] .
Step 5: To a stirred solution of N1-(2-(dimethylamino)ethyl)-N4-(4-(1-(3-
fluorobicyclo[1.1.1]pentanyl)-1H-indolyl)pyrimidinyl)methoxy-N1-
methylbenzene-1,2,4-triamine (140 mg, 0.26 mmol) in THF (10 mL) was added DIPEA
(0.14 mL, 0.89 mmol) followed by acryloyl chloride (0.02 mL, 0.26 mmol). The mixture
was stirred at 0 °C for 10 mins. Upon the completion of reaction, the reaction was quenched
with water (30 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers
were washed with water (10 mL) and brine (10 mL), dried over Na SO and concentrated
under reduced pressure. The residue was purified by a reverse phase HPLC using
acetonitrile (contains 0.05% formic acid) in water (contains 0.05% formic acid) to afford N-
(2-((2-(dimethylamino)ethyl)(methyl)amino)((4-(1-(3-fluorobicyclo[1.1.1]pentanyl)-
1H-indolyl)pyrimidinyl)amino)methoxyphenyl)acrylamide as an off-white solid (13
mg, 8.4%). H NMR (300 MHz, DMSO-d ) d 10.14 (s, 1H), 8.87 (s, 1H), 8.39 – 8.30 (m,
2H), 8.27 (s, 1H), 8.04 (s, 1H), 7.66 (d, J = 7.8 Hz, 1H), 7.28 (d, J = 5.4 Hz, 1H), 7.24 (d, J =
7.5 Hz, 1H), 7.13 (t, J = 7.5 Hz, 1H), 7.03 (s, 1H), 6.41 (dd, J = 16.8, 10.2 Hz, 1H), 6.19 (dd,
J = 16.8, 2.0 Hz, 1H), 5.74 (dd, J = 10.2, 2.0 Hz, 1H), 3.82 (s, 3H), 2.94–2.81 (m, 8H), 2.73
(s, 3H), 2.36–2.26 (m, 2H), 2.21 (s, 6H); MS (ESI) m/z 570.43 [M+H]
Example 8
N-(5-((4-(1-(Bicyclo[1.1.1]pentanyl)-1H-indolyl)pyrimidinyl)amino)methoxy
(methyl(2-(methylamino)ethyl)amino)phenyl)acrylamide
Step1: To a stirred solution of 4-(1-(bicyclo[1.1.1]pentanyl)-1H-indol-
3-yl)-N-(4-fluoromethoxynitrophenyl)pyrimidinamine (3.0 g, 6.73 mmol) in DMA
(100 mL) were added N1,N2-dimethylethane-1,2-diamine (1.09 mL, 10.09 mmol) and
DIPEA (1.45 mL, 8.75 mmol) at RT. After being stirred at 85 °C for 5 h, the mixture was
diluted with EtOAc (300 mL), washed with ice cold H O (100 mL) and brine (50 mL), dried
over Na SO , and concentrated under reduced pressure. The residue was purified by
chromatography on SiO (100-200 mesh, eluent: 5% methanol in CH Cl ) to afford N1-(4-(1-
2 2 2
(bicyclo[1.1.1]pentanyl)-1H-indolyl)pyrimidinyl)methoxy-N4-methyl-N4-(2-
(methylamino)ethyl)nitrobenzene-1,4-diamine (1.9 g, 55%) as a bright red solid. MS
(ESI) m/z 514.14 [M+H] .
Step 2: To a stirred solution of N1-(4-(1-(bicyclo[1.1.1]pentanyl)-1H-
indolyl)pyrimidinyl)methoxy-N4-methyl-N4-(2-(methylamino)ethyl)
nitrobenzene-1,4-diamine (1.9 g, 3.69 mmol) in THF (50 mL) were added Et N (1.56 mL,
11.08 mmol), (Boc) O (0.85 mL, 3.69 mmol) and DMAP (45 mg, 0.36 mmol). After being
stirred at 70 °C for 8 h, the mixture was cooled to RT, diluted with EtOAc (100 mL), washed
with H O (25 mL) and brine (25 mL), dried over Na SO , and concentrated. The residue was
2 2 4
purified by chromatography on SiO (100-200 mesh, eluent: 5% methanol in CH Cl ) to
2 2 2
afford tert-butyl (2-((4-((4-(1-(bicyclo[1.1.1]pentanyl)-1H-indolyl)pyrimidin
yl)amino)methoxynitrophenyl)(methyl)amino)ethyl)(methyl)carbamate (1.4 g, 61%) as
a pale yellow solid. MS (ESI) m/z 614.10 [M+H] .
Step 3: To a stirred solution of tert-butyl (2-((4-((4-(1-
(bicyclo[1.1.1]pentanyl)-1H-indolyl)pyrimidinyl)amino)methoxy
nitrophenyl)(methyl)amino)ethyl)(methyl) carbamate (1.4 g, 2.28 mmol) in THF:EtOAc (1:1
ratio, 40 mL) was added Pd/C (10% w/w, wet, 400 mg). After being stirred at RT under H
(1 atm) for 8 h, the mixture was filtered through a pad of celite, washed with EtOAc (100
mL) and concentrated under reduced pressure. The residue was purified by chromatography
on SiO (100-200 mesh, eluent: 15% methanol in dichloromethane) to afford tert-butyl(2-((2-
amino((4-(1-(bicyclo[1.1.1]pentanyl)-1H-indolyl)pyrimidinyl)amino)
methoxyphenyl)(methyl) amino)ethyl)(methyl)carbamate (1.0 g, 75%) as a pale yellow solid.
MS (ESI) m/z 584.08 [M+H] .
Step 4: To a stirred solution of tert-butyl (2-((2-amino((4-(1-
(bicyclo[1.1.1]pentanyl)-1H-indolyl)pyrimidinyl)amino)
methoxyphenyl)(methyl)amino)ethyl)(methyl) carbamate (400 mg, 0.68 mmol) in THF (100
mL) were added DIPEA (0.36 mL, 2.05 mmol) and acryloyl chloride (0.044 mL, 0.54
mmol). After being stirred at 0 °C for 10 min, the reaction was quenched by water (50 mL)
and the mixture was extracted with EtOAc (5 x 20 mL). The combined organic layers were
washed with water (30 mL) and brine (50 mL), dried over Na SO , and concentrated under
reduced pressure. The residue was purified by chromatography (Grace-normal phase, eluent:
% methanol in CH Cl ) to afford tert-butyl (2-((2-acrylamido((4-(1-
(bicyclo[1.1.1]pentanyl)-1H-indolyl)pyrimidinyl)amino)
methoxyphenyl)(methyl)amino)ethyl)(methyl)carbamate (360 mg, 82%) as an off-white
solid. MS (ESI) m/z 638.11 [M+H]
Step 5: To a stirred solution of tert-butyl (2-((2-acrylamido((4-(1-
(bicyclo[1.1.1]pentanyl)-1H-indolyl)pyrimidinyl)amino)methoxyphenyl)(methyl)
amino)ethyl)(methyl)carbamate (260 mg, 0.407 mmol) in CH Cl (5 mL) was added TFA
(0.3 mL, 4.07 mmol) at 0 °C. After being stirred at 0 °C for 1 h, the reaction was quenched
by sat. aq. NaHCO solution (5 mL) and the mixture was extracted with CH OH:CH Cl
3 3 2 2
(10:1 ratio, 3 x 10 mL). The combined organic layers were washed with water (10 mL) and
brine (10 mL), dried over Na SO , and concentrated under reduced pressure. The residue
was purified by preparative HPLC [Mobile phase: (A) Water contains 0.1% Formic acid (B)
Acetonitrile contains 0.1% Formic acid Flow: 19mL/min Gradient -
O+THF Column
(T/%B):0/10,0.1/25,11/25,11.1/98,13/98,13.1/10,15/10 Solubility:ACN+H2
used: Symmetry C18 (300x19) mm 7u] to afford N-(5-((4-(1-(bicyclo[1.1.1]pentanyl)-1H-
indolyl)pyrimidinyl)amino)methoxy(methyl(2-
(methylamino)ethyl)amino)phenyl) acrylamide (51 mg, 23%) as an off-white solid. H NMR
(300 MHz, DMSO-d ) d 10.12 (s, 1H), 8.8 (s, 1H), 8.4-8.2 (m, 4H), 8.02 (s, 1H), 7.68 (d, J =
8.1 Hz, 1H), 7.28 (d, J = 5.4 Hz, 1H), 7.21 (t, J = 7.2 Hz, 1H), 7.11 (t, J = 7.2 Hz, 1H), 6.96
(s, 1H), 6.7–6.58 (m, 1H), 6.19 (d, J = 16.2 Hz, 1H), 5.71 (d, J = 12.0 Hz, 1H), 3.83 (s, 3H),
3.02-2.94 (m, 2H), 2.8-2.72 (m, 2H), 2.71 (s, 1H), 2.67 (s, 3H), 2.45 (s, 6H), 2.42 (s, 3H).
MS (ESI) m/z 538.17 [M+H] .
General methods and conditions for preparing compounds of Formula (I),
or a pharmaceutically acceptable salt thereof, are described herein. Additional compounds of
Formula (I), or a pharmaceutically acceptable salt thereof, that can be prepared using one of
more of methods described herein include the following:
N N N
HN N HN N
O HO
NH NH
, , ,
N N N
HN N HN N HN N
O N O N O
N N N
NH NH NH
N N NH
O F O CN O
N N N
, , ,
HN N
, , ,
, , ,
and .
EXAMPLE A
EGFR Biochemical Enzyme Assay Protocol:
The inhibitory activity of a compound against EGFR (T790M/L858R)
were determined with CisBio HTRF (homogenous time-resolved fluorescence) KinEASE TK
(#62TKOPEC). The enzyme reaction contained recombinant N-terminal GST-tagged human
EGFR (T790M/L858R), which phosphorylates the HTRF tyrosine kinase biotinylated
substrate.
The sequence of the substrate is proprietary to CisBio. Test compounds
were serially diluted in 100% (v/v) DMSO before being acoustically dispensed from an Echo
555 (Labcyte) into black Corning 1536-well assay plates. Kinase activity assays were
performed in a total reaction volume of 3 µL per well. A 1.5 µL enzyme reaction consisted
of 1.6 nM EGFR (T970M, L858R), 1 mM DTT, and 10 mM MgCl . A 1.5 µL substrate mix
consisted of 1 µM TK substrate, 30 µM ATP, 1 mM DTT, and 10 mM MgCl . Following a
50 mins incubation, 3 µL of stop mix was added, which consisted of 250 nM Strep-XL665
and TK Ab-Cryptate diluted in kit detection buffer. The plates were incubated for 1 h before
being read on Pherastar using standard HTRF settings. N-terminal GST-tagged recombinant
human EGF receptor, with amino acids 696-end containing the T790M and L858R
mutations, was obtained from Millipore.
Compounds of Formula (I) are active in this assay as provided in Table 1,
where A = IC =10 nM; B = IC >10 nM and <100 nM; and C = IC = 100 nM.
50 50 50
Table 1
T790M/L
L858R Del-19 Wt IGF1R INSR
Example # 858R
(nM) (nM) (nM) (nM) (nM)
(nM)
1 A A A A C C
2 A -- A A C C
3 A -- A A C C
4 C -- C B C C
A -- A A C C
6 A C C C C C
7 A A A A -- --
8 A -- A B C C
EXAMPLE B
p-EGFR: Target Engagement Assay (cell-based phospho-EGFR assay) Western Blot
Cell lines used as follows: A431 (WT), H1975 (L858R/T790M), PC9
(E746–A750 deletion): cells are grown in 12-well plates to 90% confluence and then
incubated in low-serum (0.1% FBS) media for 16-18 h. Cells are then treated with varying
concentration of test compounds (5, 1.25, 0.31, 0.078, 0.020 µM) or 0.5% DMSO in low-
serum (0.1% FBS) media for 1 h. A431 cells are then stimulated with 50 ng/mL EGF for 15
mins. After treatment, cell monolayers are washed with cold PBS and immediately lysed by
scraping into 50 µL cold Cell Extraction Buffer supplemented with Complete Protease
inhibitors and phosphatase inhibitors. Lysate protein concentrations are determined by BCA
assay and approximately 50 µg of each lysate were separated by 4-12% gradient SDS-PAGE
transferred to nitrocellulose membrane and probed with specific antibodies. Phosphoprotein
signals are visualized by western blot detection system or quantitated using Odyssey Infrared
Imaging (Li-Cor Biosciences, Lincoln, NE). To assess phospho-signaling, blots are
immunoblotted with phospho and total antibodies for EGFR (Y1068), AKT, pS6RP and
Erk1/2. Phospho-signals are normalized to total protein expression for each biomarker.
Results are indicated as % DMSO control. Normalized data are fitted using a sigmoidal
curve analysis program (Graph Pad Prism version 5) with variable Hill slope to determine the
EC values.
Antibodies: All primary antibodies are obtained from Cell Signaling
(Danvers, MA) and used at 1:1000. Secondary antibodies are used at 1:20,000. Goat anti-
mouse IgG IRDye 800CW antibody is obtained from LiCor Biosciences (Lincoln, NE) and
goat anti-rabbit IgG Alexa Fluor 680 is obtained from Invitrogen (Carlsbad, CA).
EXAMPLE C
EGFR Cell Proliferation Assays
Cell Lines: A431 (WT), H1975 (L858R/T790M), PC9 (E746–A750
deletion): A431 cells were grown in DMEM (Invitrogen, Carlsbad, CA) supplemented with
% FBS (HyClone, South Logan, UT) and 1% Penicillin-Streptomycin (P/S, Lonza,
Walkersville, MD). H1975 cells were grown in RPMI 1640 (Invitrogen) supplemented with
% FBS and 1% P/S. Culture Collection (Manassas, VA), and PC-9 cells were obtained
from Japan. All cells were maintained and propagated as monolayer cultures at 37 °C in a
humidified 5% CO incubator. All cells were cultured according to recommendations.
In order to profile the effect of EGFR inhibitors in various tumorigenic
cell lines, the cell lines were tested in the cell proliferation assay that exhibit different EGFR
mutation status. Cell proliferation was measured using the CellTiter-Glo® Luminescent Cell
Viability Assay. The assay involved the addition of a single reagent (CellTiter-Glo®
Reagent) directly to cells cultured in serum-supplemented medium. The assay used a one-
step addition to induce cell lysis and generate a luminescent signal proportional to the
amount of ATP present, which is directly proportional to the number of metabolically active
cells present in culture.
Each compound evaluated was prepared as a DMSO stock solution (10
mM). Compounds were tested in duplicate on each plate, with an 11-point serial dilution
curve (1:3 dilution). Compound treatment (50 µL) was added from the compound dilution
plate to the cell plate. The highest compound concentration was 1 or 10 µM (final), with a
0.3% final DMSO (#D-5879, Sigma, St Louis, MO) concentration. Plates were then
incubated at 37 °C, 5% CO . After 3-5 days of compound treatment, CellTiter-Glo®
Reagent (#G7573, Promega, Madison, WI) was prepared in one of two ways. If thawing a
frozen aliquot of CellTiter-Glo® Reagent, the aliquot was thawed and equilibrated to RT
prior to use while keeping it protected from light. Alternatively, new bottles of CellTiter-
Glo® Buffer and CellTiter-Glo® Substrate were thawed and equilibrated to RT prior to use.
CellTiter-Glo® Buffer (100 mL) was transferred into the amber bottle containing CellTiter-
Glo® Substrate to reconstitute the lyophilized enzyme/substrate mixture, forming the
CellTiter-Glo® Reagent. The reconstituted reagent was mixed by gently inverting the
contents to obtain a homogeneous solution, and went into solution easily in less than 1 min.
Any unused reconstituted CellTiter-Glo® Reagent was immediately aliquoted and frozen at -
°C, and protected from light. Cell plates were equilibrated at RT for approximately 30
mins. An equi-volume amount of CellTiter-Glo® Reagent (100 µL) was added to each well.
Plates were mixed for 2 mins on an orbital shaker to induce cell lysis, and then were allowed
to incubate at RT for 10 mins to stabilize the luminescent signal. Luminescence was
recorded using the PerkinElmer EnVision Excite Multilabel Reader used for endpoint
reading for luminescence detection (Waltham, MA). Data was analyzed using a four-
parameter fit in Microsoft Excel.
Compounds of Formula (I) were active in this assay as provided in Table
2, where A = IC =50 nM; B = IC >50 nM and < 300 nM; and C = IC =300 nM.
50 50 50
Table 2
H1975 PC9 A431
Example #
(nM) (nM) (nM)
1 A A C
2 B B C
3 A A B
4 C C C
A B C
6 C C C
7 A C C
8 A A C
EXAMPLE D
Metabolite identification in hepatocytes of mouse rat, dog and human
Suspended hepatocytes in enough incubation medium to yield ~1.5 × 10
cells/mL. Pipetted 199 µL of viable hepatocytes or the boiled hepatocytes into each wells of
a 96 -well non -coated plate. Placed the plate in the incubator on an orbital shaker to allow the
hepatocytes to warm for 10 minutes. Pipetted 1 µL of the 2 mM test compound(s) into
respective wells of the 96 -well non -coated plate to start the reaction with final concentration
of 10 µM. Returned the plate to the incubator and placed on an orbital shaker. Incubated at
37 °C, 5% CO and 90 -95% relative humidity with shaking at 500 rpm on the shaker for 240
min. After incubation, transferred media from each well to a tube containing 400 µL cold
methanol, washed the well with 200 µL cold methanol and then transferred the media to the
corresponding tube. Centrifuged tubes for 10 minutes at 16,000 g. Aliquots of 200 µL of the
supernatants were mixed with 200 µL of pure water and used for LC -MS/MS analysis.
UHPLC -MS/MS analysis was conducted using a Dionex UltiMate 3000 UHPLC system
(Thermo Fisher Scientific, USA) and Thermo Scientific Q Exactive (Thermo Fisher
Scientific, USA) fitted with a HESI probe. Data was acquired using Xcaliur® v3.0 software
(Thermo Fisher Scientific) and processed using Xcaliur® v3.0 software (Thermo Fisher
Scientific) and Metworks® v1.3 software (Thermo Fisher Scientific), and metabolite was
elucidated by Mass Frontier® v7.0 predictive fragmentation software (Thermo Fisher
Scientific).
As shown by the results in Table 3, the compound of Example 1 did not
lead to the formation of the less selective metabolite AZ5104 in human hepatocyte cells.
Table 3 – Metabolite Identification study: formation of AZ5104 via de-alkylation on the
indole ring.
HN N
HN N
HN N
de-alkyation
de-alkylation N
(de-methylation)
NH X
A Z D9291
E xam p le 1
A Z 5104
Compound Metabolite AZ5104
Incubated
Mouse Rat Dog Human
hepatocytes
AZD9291 - - - Observed
Not Not Not
Example 1 observe
observed observed observed
Inhibition of wild-type EGFR (WT EGFR) has been shown to cause side
effects such as rash and diarrhea. AZ5104, a major human metabolite of AZD9291, is
oberserved both in vitro and in vivo. AZ5104 is a more potent inhibitor of WT EGFR
compared toAZD9291 as demonstrated by the data in Table 4. This difference in potency
between AZD9291 and AZ5104 is believed to account and/or contribute to the clinical side
effects of diarrhea (42%) and rash (41%) observed with AZD9291 treatment. As AZ5104 is
not observed as a metabolite of the compound of Example 1, compounds of Formula (I), and
pharmaceutically acceptable salts thereof, have fewer side effects (e.g., rash and/or diarrhea)
and/or the severity of the side effect(s) is to a lesser degree.
Table 4 - In vitro and in vivo data for AZD9291 and its metabolite AZ5104*
WT EGFR Cell H1975 Cell Mouse Human
Compound
IC50 (nM) IC50 (nM) exposure exposure
AZD9291 480 15 - -
Roughly 10% Roughly 10%
AZ5104 33 2 of AZD9291 of AZD9291
exposure exposure
*Data from Raymond et al., J. Med. Chem. (2014) 57(20):8249-8267 and Cross et al., Cancer
Discovery, (2014) 4(9):1046-1061
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 (70)
1. A compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Formula (I) has the structure: R is selected from hydrogen, halogen, hydroxy, cyano, an optionally substituted C - alkyl, an optionally substituted C - haloalkyl, an optionally substituted C - alkoxy and an 1 4 1 4 optionally substituted C - haloalkoxy; R is a substituted 6-15 membered heteroaryl or a substituted 6-15 membered heterocyclyl, wherein the heteroaryl and the heterocyclyl independently contains 1-4 heteroatoms selected from N, O and S, and the heteroaryl and the heterocyclyl is substituted with an optionally substituted bicyclo[1.1.1]pentyl; is selected from hydrogen, an optionally substituted C - alkyl, an optionally R 1 4 substituted aryl, an optionally substituted heteroaryl and an optionally substituted heterocyclyl, wherein when substituted, R is substituted by one or more substituents selected from halogen, cyano, an unsubstituted C - alkyl, an optionally substituted aryl, -C(O)R , - 5B 5C 6A 6B 7A 7B SO R , -NHC(O)R and -(CR R ) NR R ; X is O, S or NR ; R is selected from hydrogen, an optionally substituted C - alkyl, an optionally substituted C - haloalkyl and an optionally substituted C cycloalkyl; 1 4 3-8 5A 5B 5C R , R and R are independently selected from hydrogen, an optionally substituted C - alkyl, an optionally substituted C - haloalkyl, an optionally substituted C cycloalkyl, 1 4 1 4 3-8 an optionally substituted aryl, an optionally substituted heteroaryl and an optionally substituted heterocyclyl; 6A 6B R and R are independently selected from hydrogen, halogen, an optionally substituted C - alkyl, an optionally substituted C - haloalkyl and an optionally substituted 1 4 1 4 C - cycloalkyl; 7A 7B R and R are independently selected from hydrogen, an optionally substituted C - alkyl, an optionally substituted C - haloalkyl and an optionally substituted C - cycloalkyl; 1 4 3 8 A is CR ; R is selected from hydrogen, halogen, cyano, an optionally substituted C - alkyl, an optionally substituted C - haloalkyl and an optionally substituted C cycloalkyl; 1 4 3-8 m is 0 or 1; and n is 0, 1, 2 or 3; and when a group is optionally substituted, the group can be substituted with one or more groups individually and independently selected from D, halogen, hydroxy, C alkoxy, C 1-4 1-4 alkyl, C cycloalkyl, aryl, heteroaryl, C haloalkyl, cyano, alkenyl, alkynyl, cycloalkenyl, 3-8 1-6 aryl(alkyl), heteroaryl(alkyl), heterocyclyl(alkyl), acyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, C-thioamido, N- thioamido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, sulfenyl, sulfinyl, sulfonyl, haloalkoxy, an amino, a mono-alkyl substituted amine group and a di-alkyl substituted amine group.
2. The compound of Claim 1, wherein R is selected from a substituted indolyl, a substituted indazolyl, a substituted 4,5,6,7-tetrahydroindazolyl, a substituted and a substituted .
3. The compound of Claim 1 or 2, wherein the optionally substituted bicyclo[1.1.1]pentyl substituted on R is a fluoro-substituted bicyclo[1.1.1]pentyl, a chloro- substituted bicyclo[1.1.1]pentyl or a cyano-substituted bicyclo[1.1.1]pentyl.
4. The compound of Claim 1, wherein R is selected from and 2A 2B , wherein R and R are independently an optionally substituted bicyclo[1.1.1]pentyl. 2A 2B
5. The compound of Claim 4, wherein R and R are independently an unsubstituted bicyclo[1.1.1]pentyl. 2A 2B
6. The compound of Claim 4, wherein R and R are independently a fluoro- substituted bicyclo[1.1.1]pentyl, a chloro-substituted bicyclo[1.1.1]pentyl or a cyano- substituted bicyclo[1.1.1]pentyl.
7. The compound of Claim 1 or 2, wherein the optionally substituted bicyclo[1.1.1]pentyl on R is an unsubstituted bicyclo[1.1.1]pentyl.
8. The compound of any one of Claims 1-7, wherein m is 0.
9. The compound of any one of Claims 1-7, wherein m is 1.
10. The compound of Claim 9, wherein X is O.
11. The compound of Claim 9, wherein X is S.
12. The compound of Claim 9, wherein X is NR .
13. The compound of Claim 12, wherein R is hydrogen.
14. The compound of Claim 12, wherein R is an optionally substituted C - alkyl.
15. The compound of Claim 14, wherein R is an unsubstituted C - alkyl.
16. The compound of Claim 12, wherein R is an optionally substituted C - haloalkyl.
17. The compound of Claim 12, wherein R is an optionally substituted C cycloalkyl.
18. The compound of any one of Claims 1-17, wherein R is an optionally substituted C - alkyl.
19. The compound of any one of Claims 1-17, wherein R is an optionally substituted aryl.
20. The compound of any one of Claims 1-17, wherein R is an optionally substituted heteroaryl.
21. The compound of any one of Claims 1-17, wherein R is an optionally substituted heterocyclyl.
22. The compound of Claim 21, wherein the optionally substituted heterocyclyl is an optionally substituted monocyclic heterocyclyl.
23. The compound of Claim 22, wherein the optionally substituted monocyclic heterocyclyl is an optionally substituted 4-membered nitrogen-containing heterocyclyl, an optionally substituted 5-membered nitrogen-containing heterocyclyl or an optionally substituted 6-membered nitrogen-containing heterocyclyl.
24. The compound of Claim 23, wherein the optionally substituted 4-membered nitrogen-containing heterocyclyl, the optionally substituted 5-membered nitrogen-containing heterocyclyl or the optionally substituted 6-membered nitrogen-containing heterocyclyl is selected from the group consisting of an optionally substituted azetidinyl, an optionally substituted pyrrolidinyl and an optionally substituted piperazinyl. is substituted by
25. The compound of any one of Claims 18-24, wherein R halogen.
26. The compound of any one of Claims 18-24, wherein R is substituted by cyano.
27. The compound of any one of Claims 18-24, wherein R is substituted by an unsubstituted C - alkyl.
28. The compound of any one of Claims 18-24, wherein R is substituted by an optionally substituted aryl.
29. The compound of any one of Claims 18-24, wherein R is substituted by - C(O)R .
30. The compound of Claim 29, wherein R is an optionally substituted C - alkyl.
31. The compound of Claim 30, wherein the optionally substituted C - alkyl is an unsubstituted C - alkyl.
32. The compound of Claim 30, wherein the optionally substituted C - alkyl is a substituted C - alkyl substituted with a mono-alkyl substituted amine or a di-alkyl substituted amine.
33. The compound of any one of Claims 18-24, wherein R is substituted by -SO R .
34. The compound of any one of Claims 18-24, wherein R is substituted by -NHC(O)R .
35. The compound of any one of Claims 18-24, wherein R is substituted by 6A 6B 7A 7B -CR R ) NR R .
36. The compound of Claim 35, wherein n is 0.
37. The compound of Claim 35, wherein n is 1.
38. The compound of Claim 35, wherein n is 2.
39. The compound of Claim 35, wherein n is 3.
40. The compound of any one of Claims 35-39, wherein at least one of R and R is hydrogen. 6A 6B
41. The compound of any one of Claims 35-39, wherein R and R are each hydrogen. 7A 7B and R are
42. The compound of any one of Claims 35-41, wherein R independently hydrogen or an optionally substituted C - alkyl.
43. The compound of any one of Claims 35-41, wherein at least one of R and R is hydrogen. 7A 7B
44. The compound of any one of Claims 35-41, wherein R and R are each an optionally substituted C - alkyl.
45. The compound of Claim 44, wherein the optionally substituted C - alkyl is an unsubstituted C - alkyl.
46. The compound of any one of Claims 1-45, wherein R is an optionally substituted C - alkoxy.
47. The compound of Claim 46, wherein the optionally substituted C - alkoxy is an unsubstituted C - alkoxy.
48. The compound of Claim 47, wherein the unsubstituted C - alkoxy is methoxy.
49. The compound of any one of Claims 1-45, wherein R is hydroxy.
50. The compound of any one of Claims 1-49, wherein R is hydrogen.
51. The compound of any one of Claims 1-49, wherein R is halogen.
52. The compound of any one of Claims 1-49, wherein R is cyano.
53. The compound of any one of Claims 1-49, wherein R is an optionally substituted C - alkyl, an optionally substituted C haloalkyl or an optionally substituted C 1 4 1-4 3- cycloalkyl.
54. The compound of any one of Claim 53, wherein R is an unsubstituted C alkyl, an unsubstituted C - haloalkyl or an unsubstituted C cycloalkyl. 1 4 3-8
55. The compound of Claim 1, wherein the compound is selected from: , , , , , , , , , HN N , , , , , , and HN N , or a pharmaceutically acceptable salt of any of the foregoing.
56. The compound of Claim 55, wherein the compound is , or a pharmaceutically acceptable salt thereof.
57. The compound of Claim 55, wherein the compound is , or a pharmaceutically acceptable salt thereof.
58. The compound of Claim 55, wherein the compound is , or a pharmaceutically acceptable salt thereof.
59. The compound of Claim 55, wherein the compound is , or a pharmaceutically acceptable salt thereof.
60. The compound of Claim 55, wherein the compound is , or a pharmaceutically acceptable salt thereof.
61. The compound of Claim 55, wherein the compound is , or a pharmaceutically acceptable salt thereof.
62. A compound selected from the group consisting of: , , , and , or a pharmaceutically acceptable salt of any of the foregoing.
63. A pharmaceutical composition comprising an effective amount of the compound of any one of any one of Claims 1-61, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, excipient or combination thereof.
64. Use of an effective amount of a compound of any one of Claims 1-61, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of Claim 63 in the manufacture of a medicament for ameliorating or treating a cancer, wherein the cancer is selected from a lung cancer, a pancreatic cancer, a colon cancer, a breast cancer, a prostate cancer, a head and neck cancer, an ovarian cancer, a brain cancer and a kidney carcinoma.
65. Use of an effective amount of a compound of any one of Claims 1-61, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of Claim 63 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 selected from a lung cancer, a pancreatic cancer, a colon cancer, a breast cancer, a prostate cancer, a head and neck cancer, an ovarian cancer, a brain cancer and a kidney carcinoma.
66. Use of an effective amount of a compound of any one of Claims 1-61, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of Claim 63 in the manufacture of a medicament for ameliorating or treating a malignant growth or tumor, wherein the malignant growth or tumor is due to a cancer selected from a lung cancer, a pancreatic cancer, a colon cancer, a breast cancer, a prostate cancer, a head and neck cancer, an ovarian cancer, a brain cancer and a kidney carcinoma.
67. Use of an effective amount of a compound of any one of Claims 1-61, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of Claim 63 in the manufacture of a medicament for inhibiting the activity of EGFR, wherein the EGFR has one or more selected from a deletion in exon 19, an insertion in exon 20, a mutation at L858R and an acquired EGFR T790M mutation.
68. The compound of any one of Claims 1-62, or pharmaceutically acceptable salt thereof, substantially as herein described with reference to any example thereof.
69. The pharmaceutical composition of Claim 63, substantially as herein described with reference to any example thereof.
70. Use of any one of Claims 64-67, substantially as herein described with reference to any example thereof.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201662342141P | 2016-05-26 | 2016-05-26 | |
US62/342,141 | 2016-05-26 | ||
PCT/US2017/034163 WO2017205459A1 (en) | 2016-05-26 | 2017-05-24 | Egfr inhibitor compounds |
Publications (2)
Publication Number | Publication Date |
---|---|
NZ747854A NZ747854A (en) | 2020-09-25 |
NZ747854B2 true NZ747854B2 (en) | 2021-01-06 |
Family
ID=
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