NZ747748A - Substituted pyridines as inhibitors of dnmt1 - Google Patents
Substituted pyridines as inhibitors of dnmt1Info
- Publication number
- NZ747748A NZ747748A NZ747748A NZ74774817A NZ747748A NZ 747748 A NZ747748 A NZ 747748A NZ 747748 A NZ747748 A NZ 747748A NZ 74774817 A NZ74774817 A NZ 74774817A NZ 747748 A NZ747748 A NZ 747748A
- Authority
- NZ
- New Zealand
- Prior art keywords
- dicyano
- thio
- phenylacetamide
- amino
- pyridin
- Prior art date
Links
- 230000002401 inhibitory effect Effects 0.000 title claims abstract description 34
- 239000003112 inhibitor Substances 0.000 title claims abstract description 16
- 150000003222 pyridines Chemical class 0.000 title abstract description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 169
- 150000003839 salts Chemical class 0.000 claims abstract description 79
- 239000011780 sodium chloride Substances 0.000 claims abstract description 79
- 208000007056 Sickle Cell Anemia Diseases 0.000 claims abstract description 41
- 239000000651 prodrug Substances 0.000 claims abstract description 40
- 229940002612 prodrugs Drugs 0.000 claims abstract description 40
- 101700070526 DNMT1 Proteins 0.000 claims abstract description 33
- 102100018208 DNMT1 Human genes 0.000 claims abstract description 33
- 201000011510 cancer Diseases 0.000 claims abstract description 26
- 201000010099 disease Diseases 0.000 claims abstract description 21
- 206010043391 Thalassaemia beta Diseases 0.000 claims abstract description 13
- 201000003923 hemoglobinopathy Diseases 0.000 claims abstract description 13
- 230000000694 effects Effects 0.000 claims abstract description 11
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 11
- 201000010874 syndrome Diseases 0.000 claims abstract description 11
- 208000001284 Hemoglobinopathy Diseases 0.000 claims abstract description 10
- -1 chloro, bromo, iodo Chemical group 0.000 claims description 880
- 125000001153 fluoro group Chemical group F* 0.000 claims description 757
- 125000001424 substituent group Chemical group 0.000 claims description 603
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 487
- 125000003118 aryl group Chemical group 0.000 claims description 456
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 446
- 125000004043 oxo group Chemical group O=* 0.000 claims description 383
- 125000001072 heteroaryl group Chemical group 0.000 claims description 376
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 357
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 216
- 229910052739 hydrogen Inorganic materials 0.000 claims description 209
- 239000001257 hydrogen Substances 0.000 claims description 209
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 135
- 150000002431 hydrogen Chemical class 0.000 claims description 126
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 116
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 112
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 95
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 90
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 81
- UFHFLCQGNIYNRP-UHFFFAOYSA-N hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 80
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 57
- 125000005885 heterocycloalkylalkyl group Chemical group 0.000 claims description 55
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 44
- 229910052757 nitrogen Inorganic materials 0.000 claims description 41
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 40
- 125000003386 piperidinyl group Chemical group 0.000 claims description 38
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 37
- 125000005842 heteroatoms Chemical group 0.000 claims description 30
- 229910052717 sulfur Inorganic materials 0.000 claims description 29
- 239000003795 chemical substances by application Substances 0.000 claims description 25
- 125000002757 morpholinyl group Chemical group 0.000 claims description 24
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 claims description 22
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 19
- 125000004193 piperazinyl group Chemical group 0.000 claims description 19
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 18
- 125000002883 imidazolyl group Chemical group 0.000 claims description 18
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 18
- 125000000999 tert-butyl group Chemical compound [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 18
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 17
- KOFZWWMCDUHEEM-UHFFFAOYSA-N 1-methylpyrrolidine Chemical group [CH2]N1CCCC1 KOFZWWMCDUHEEM-UHFFFAOYSA-N 0.000 claims description 17
- 125000002393 azetidinyl group Chemical group 0.000 claims description 17
- 125000000217 alkyl group Chemical group 0.000 claims description 16
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 13
- 125000003396 thiol group Chemical group [H]S* 0.000 claims description 13
- 239000000203 mixture Substances 0.000 claims description 12
- 125000001246 bromo group Chemical group Br* 0.000 claims description 11
- 238000004519 manufacturing process Methods 0.000 claims description 11
- 229910052760 oxygen Inorganic materials 0.000 claims description 11
- 229910003667 SRa Inorganic materials 0.000 claims description 8
- 125000002346 iodo group Chemical group I* 0.000 claims description 8
- 125000004573 morpholin-4-yl group Chemical compound N1(CCOCC1)* 0.000 claims description 8
- 208000005980 beta-Thalassemia Diseases 0.000 claims description 7
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 7
- 125000005960 1,4-diazepanyl group Chemical group 0.000 claims description 6
- TVMXDCGIABBOFY-UHFFFAOYSA-N Octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 claims description 6
- 210000004027 cells Anatomy 0.000 claims description 6
- 125000006311 cyclobutyl amino group Chemical group [H]N(*)C1([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 6
- 239000003814 drug Substances 0.000 claims description 6
- 125000002795 guanidino group Chemical group C(N)(=N)N* 0.000 claims description 6
- 125000000160 oxazolidinyl group Chemical group 0.000 claims description 6
- 239000002246 antineoplastic agent Substances 0.000 claims description 5
- 239000000546 pharmaceutic aid Substances 0.000 claims description 5
- 210000001178 Neural Stem Cells Anatomy 0.000 claims description 4
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 4
- 125000004076 pyridyl group Chemical group 0.000 claims description 4
- 125000001425 triazolyl group Chemical group 0.000 claims description 4
- 206010028980 Neoplasm Diseases 0.000 claims description 3
- 206010000880 Acute myeloid leukaemia Diseases 0.000 claims description 2
- 230000001154 acute Effects 0.000 claims description 2
- 230000022131 cell cycle Effects 0.000 claims description 2
- 238000000034 method Methods 0.000 claims description 2
- 125000003277 amino group Chemical compound 0.000 claims 214
- 150000003869 acetamides Chemical compound 0.000 claims 98
- DLFVBJFMPXGRIB-UHFFFAOYSA-N acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims 46
- 241000124008 Mammalia Species 0.000 claims 23
- 241000907681 Morpho Species 0.000 claims 20
- 125000000446 sulfanediyl group Chemical group *S* 0.000 claims 19
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 claims 18
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims 18
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims 14
- NBIIXXVUZAFLBC-UHFFFAOYSA-M dihydrogenphosphate Chemical compound OP(O)([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-M 0.000 claims 14
- VZCGEDTVPJTYHY-UHFFFAOYSA-N propanamide Chemical compound CCC(N)=O.CCC(N)=O VZCGEDTVPJTYHY-UHFFFAOYSA-N 0.000 claims 14
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims 10
- 125000002785 azepinyl group Chemical group 0.000 claims 10
- 125000003226 pyrazolyl group Chemical group 0.000 claims 10
- 150000004657 carbamic acid derivatives Chemical compound 0.000 claims 9
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 claims 9
- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 claims 8
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 claims 7
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims 7
- 125000000587 piperidin-1-yl group Chemical compound [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims 7
- KZSNJWFQEVHDMF-UHFFFAOYSA-M valinate Chemical compound CC(C)C(N)C([O-])=O KZSNJWFQEVHDMF-UHFFFAOYSA-M 0.000 claims 7
- 125000000979 2-amino-2-oxoethyl group Chemical group [H]C([*])([H])C(=O)N([H])[H] 0.000 claims 6
- 201000002847 Cowden syndrome Diseases 0.000 claims 6
- 208000009956 Adenocarcinoma Diseases 0.000 claims 5
- 206010025650 Malignant melanoma Diseases 0.000 claims 5
- 229910006074 SO2NH2 Inorganic materials 0.000 claims 5
- ZJXZSIYSNXKHEA-UHFFFAOYSA-N ethyl dihydrogen phosphate Chemical compound CCOP(O)(O)=O ZJXZSIYSNXKHEA-UHFFFAOYSA-N 0.000 claims 5
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims 5
- 201000001441 melanoma Diseases 0.000 claims 5
- 125000003566 oxetanyl group Chemical group 0.000 claims 5
- XLECGUSMKLPCGO-UHFFFAOYSA-N pyrrolidin-3-yl dihydrogen phosphate Chemical compound OP(O)(=O)OC1CCNC1 XLECGUSMKLPCGO-UHFFFAOYSA-N 0.000 claims 5
- 208000006336 Acinar Cell Carcinoma Diseases 0.000 claims 4
- 206010018404 Glucagonoma Diseases 0.000 claims 4
- 206010022498 Insulinoma Diseases 0.000 claims 4
- 206010024324 Leukaemias Diseases 0.000 claims 4
- 201000008395 adenosquamous carcinoma Diseases 0.000 claims 4
- 150000003936 benzamides Chemical compound 0.000 claims 4
- 125000006317 cyclopropyl amino group Chemical group 0.000 claims 4
- 201000010985 invasive ductal carcinoma Diseases 0.000 claims 4
- XPDWGBQVDMORPB-UHFFFAOYSA-N methyl trifluoride Chemical compound FC(F)F XPDWGBQVDMORPB-UHFFFAOYSA-N 0.000 claims 4
- NJYYWQHQUOODDL-UHFFFAOYSA-N oxetane-3-carboxamide Chemical compound NC(=O)C1COC1 NJYYWQHQUOODDL-UHFFFAOYSA-N 0.000 claims 4
- AGNMYVAFHGZZAZ-UHFFFAOYSA-N piperidin-4-yl dihydrogen phosphate Chemical compound OP(O)(=O)OC1CCNCC1 AGNMYVAFHGZZAZ-UHFFFAOYSA-N 0.000 claims 4
- DPBWFNDFMCCGGJ-UHFFFAOYSA-N piperidine-4-carboxamide Chemical compound NC(=O)C1CCNCC1 DPBWFNDFMCCGGJ-UHFFFAOYSA-N 0.000 claims 4
- 125000001544 thienyl group Chemical group 0.000 claims 4
- LSBDFXRDZJMBSC-UHFFFAOYSA-N 2-phenylacetamide Chemical compound NC(=O)CC1=CC=CC=C1 LSBDFXRDZJMBSC-UHFFFAOYSA-N 0.000 claims 3
- 206010003571 Astrocytoma Diseases 0.000 claims 3
- 201000007815 Bannayan-Riley-Ruvalcaba syndrome Diseases 0.000 claims 3
- 210000004556 Brain Anatomy 0.000 claims 3
- 210000001072 Colon Anatomy 0.000 claims 3
- 206010051906 Cowden's disease Diseases 0.000 claims 3
- 208000005017 Glioblastoma Diseases 0.000 claims 3
- 206010018338 Glioma Diseases 0.000 claims 3
- 210000003128 Head Anatomy 0.000 claims 3
- 210000003734 Kidney Anatomy 0.000 claims 3
- 210000004185 Liver Anatomy 0.000 claims 3
- 208000008770 Multiple Hamartoma Syndrome Diseases 0.000 claims 3
- 210000003739 Neck Anatomy 0.000 claims 3
- 210000002307 Prostate Anatomy 0.000 claims 3
- 206010039491 Sarcoma Diseases 0.000 claims 3
- 210000001685 Thyroid Gland Anatomy 0.000 claims 3
- 201000010915 glioblastoma multiforme Diseases 0.000 claims 3
- 230000002611 ovarian Effects 0.000 claims 3
- 125000006432 1-methyl cyclopropyl group Chemical compound [H]C([H])([H])C1(*)C([H])([H])C1([H])[H] 0.000 claims 2
- QOXOZONBQWIKDA-UHFFFAOYSA-N 3-hydroxypropyl Chemical compound [CH2]CCO QOXOZONBQWIKDA-UHFFFAOYSA-N 0.000 claims 2
- 210000000481 Breast Anatomy 0.000 claims 2
- DNSISZSEWVHGLH-UHFFFAOYSA-N Butyramide Chemical compound CCCC(N)=O DNSISZSEWVHGLH-UHFFFAOYSA-N 0.000 claims 2
- 208000010027 Carcinoma, Intraductal, Noninfiltrating Diseases 0.000 claims 2
- 206010051066 Gastrointestinal stromal tumour Diseases 0.000 claims 2
- 206010073094 Intraductal proliferative breast lesion Diseases 0.000 claims 2
- 210000004072 Lung Anatomy 0.000 claims 2
- ZZEYJFMVGDINRK-UHFFFAOYSA-N NCCCN(C1=C(C(=C(C(=N1)SC(C(=O)N)C1=CC=CC=C1)C#N)C1CC1)C#N)C Chemical compound NCCCN(C1=C(C(=C(C(=N1)SC(C(=O)N)C1=CC=CC=C1)C#N)C1CC1)C#N)C ZZEYJFMVGDINRK-UHFFFAOYSA-N 0.000 claims 2
- 206010035226 Plasma cell myeloma Diseases 0.000 claims 2
- 208000000389 T-Cell Leukemia Diseases 0.000 claims 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims 2
- 125000000218 acetic acid group Chemical compound C(C)(=O)* 0.000 claims 2
- AXJDEHNQPMZKOS-UHFFFAOYSA-N acetylazanium;chloride Chemical compound [Cl-].CC([NH3+])=O AXJDEHNQPMZKOS-UHFFFAOYSA-N 0.000 claims 2
- 150000001408 amides Chemical compound 0.000 claims 2
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims 2
- 230000003042 antagnostic Effects 0.000 claims 2
- 239000005557 antagonist Substances 0.000 claims 2
- 102000004965 antibodies Human genes 0.000 claims 2
- 108090001123 antibodies Proteins 0.000 claims 2
- GFVNJDIBQYYKGS-UHFFFAOYSA-N azetidin-3-yl carbamate Chemical compound NC(=O)OC1CNC1 GFVNJDIBQYYKGS-UHFFFAOYSA-N 0.000 claims 2
- 125000004567 azetidin-3-yl group Chemical compound N1CC(C1)* 0.000 claims 2
- 125000001664 diethylamino group Chemical compound [H]C([H])([H])C([H])([H])N(*)C([H])([H])C([H])([H])[H] 0.000 claims 2
- 125000002147 dimethylamino group Chemical compound [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims 2
- 201000007273 ductal carcinoma in situ Diseases 0.000 claims 2
- 201000011243 gastrointestinal stromal tumor Diseases 0.000 claims 2
- 239000002955 immunomodulating agent Substances 0.000 claims 2
- 201000004044 liver cirrhosis Diseases 0.000 claims 2
- MAJTXTYGACTQGY-UHFFFAOYSA-N methylcyclobutane Chemical compound [CH2+][C]1CCC1 MAJTXTYGACTQGY-UHFFFAOYSA-N 0.000 claims 2
- 125000004312 morpholin-2-yl group Chemical compound [H]N1C([H])([H])C([H])([H])OC([H])(*)C1([H])[H] 0.000 claims 2
- 201000009251 multiple myeloma Diseases 0.000 claims 2
- DGOYLVBDCVINQZ-UHFFFAOYSA-N oxane-4-carboxamide Chemical compound NC(=O)C1CCOCC1 DGOYLVBDCVINQZ-UHFFFAOYSA-N 0.000 claims 2
- 125000004194 piperazin-1-yl group Chemical compound [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 claims 2
- 125000004483 piperidin-3-yl group Chemical compound N1CC(CCC1)* 0.000 claims 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 claims 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims 2
- FGQIKVMUUPNDOL-CQSZACIVSA-N (2R)-2-(6-amino-3,5-dicyano-4-ethylpyridin-2-yl)sulfanyl-2-phenylacetamide Chemical compound CCC1=C(C#N)C(N)=NC(S[C@@H](C(N)=O)C=2C=CC=CC=2)=C1C#N FGQIKVMUUPNDOL-CQSZACIVSA-N 0.000 claims 1
- FGQIKVMUUPNDOL-UHFFFAOYSA-N 2-(6-amino-3,5-dicyano-4-ethylpyridin-2-yl)sulfanyl-2-phenylacetamide Chemical compound CCC1=C(C#N)C(N)=NC(SC(C(N)=O)C=2C=CC=CC=2)=C1C#N FGQIKVMUUPNDOL-UHFFFAOYSA-N 0.000 claims 1
- OKDGRDCXVWSXDC-UHFFFAOYSA-N 2-Chloropyridine Chemical group ClC1=CC=CC=N1 OKDGRDCXVWSXDC-UHFFFAOYSA-N 0.000 claims 1
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Abstract
The invention is directed to substituted pyridine derivatives. Specifically, the invention is directed to compounds according to Formula (Iar): (Iar) wherein Yar, X1ar, X2ar, R1ar, R2ar, R3ar, R4ar and R5ar are as defined herein; or a pharmaceutically acceptable salt or prodrug thereof. The compounds of the invention are selective inhibitors of DNMT1 and can be useful in the treatment of cancer, pre-cancerous syndromes, beta hemoglobinopathy disorders, sickle cell disease, sickle cell anemia, and beta thalassemia, and diseases associated with DNMT1 inhibition. Accordingly, the invention is further directed to pharmaceutical compositions comprising a compound of the invention. The invention is still further directed to methods of inhibiting DNMT1 activity and treatment of disorders associated therewith using a compound of the invention or a pharmaceutical composition comprising a compound of the invention. s of the invention are selective inhibitors of DNMT1 and can be useful in the treatment of cancer, pre-cancerous syndromes, beta hemoglobinopathy disorders, sickle cell disease, sickle cell anemia, and beta thalassemia, and diseases associated with DNMT1 inhibition. Accordingly, the invention is further directed to pharmaceutical compositions comprising a compound of the invention. The invention is still further directed to methods of inhibiting DNMT1 activity and treatment of disorders associated therewith using a compound of the invention or a pharmaceutical composition comprising a compound of the invention.
Description
SUBSTITUTED PYRIDINES AS INHIBITORS OF DNMT1
FIELD OF THE INVENTION
The present invention relates to substituted ne derivatives that are selective
tors of the activity of DNA methyltransferase1 (DNMT1). The present invention also
relates to pharmaceutical compositions comprising such compounds and methods of using
such compounds in the treatment of cancer, ncerous syndromes, beta
hemoglobinopathy disorders, sickle cell disease, sickle cell anaemia, and beta thalassemia,
and other diseases associated with DNMT1 inhibition.
OUND OF THE INVENTION
Epigenetics is a way to turn genes on and off independent of the underlaying DNA
sequence. DNA methylation occurring in gene promotors is an e of a repressive
epigenetic mark resulting in chromatin compaction and gene ing. DNA methylation
is mediated by the DNA methyltransferase (DNMT) family of proteins which is sed
of four family members. Three ofthe family members, DNMT1, DNMT3A and DNMTBB,
contain DNA methyltransferase activity. These three members are responsible for
establishing the de novo DNA methylation pattern, while DNMT1 is primarily responsible
for maintaining the ation pattern in daughter strands following DNA replication.
In cancer, DNA methylation patterns become aberrant resulting in global
hypomethylation and localized hypermethylation within promoter regions. This can result
in downstream silencing oftumor suppressor genes (Ting et al. Genes Dev. 2006;
:3215-3231). Additionally, silencing of DNMT1 results in DNA demethylation and
reexpression oftumor suppressor genes ing in tumor growth tion (Zhou et al.
Oncol. Lett. 2014; 5: 2130 — 2134).
DNA methylation inhibitors (termed DNA hypomethylating agents) are clinically
validated anti-cancertherapies ed forthe treatment of MDS, AML and CMML. While
these agents are available, there is still significant opportunity for improvement regarding
toxicity, y in solid tumors and oral bioavailability. Hence, a novel DNMT inhibitor
would be of interest forthe treatment of cancer and/or any disease or condition mediated
by DNA methylation. Of ular interest to this invention, is specifically targeting
DNMT1 to prevent propagation of abnormal methylation patterns (such as those that
occur in cancer) to daughter strands during replication.
WO 16727 2017/053511
US 132525 and describe inhibitors of DNA
methyltransferase. CA 2030875 bes methods and probes for detecting nucleoside
transporter and method for producing the probes.
Hemoglobinopathies
Hemoglobin disorders, such as sickle cell anemia and beta-thalassaemia,
represent the most common heritable blood diseases in the world. Sickle cell anemia and
beta-thalassemia are characterized by disorders of hemoglobin, which is the oxygen
carrying protein complex in red blood cells. Structurally, hemoglobin is normally
composed oftwo pairs of proteins plus four molecules of heme. Adults and children older
than about four months, express a form of hemoglobin referred to as adult hemoglobin,
which predominantly consists of two alpha-globin proteins paired with two beta-globin
proteins plus four molecules of heme. However, fetuses and infants typically express
mostly fetal hemoglobin, which is ed of two alpha-globin proteins paired with two
gamma-globin proteins plus four molecules of heme. Note that there are two forms of
gamma-globin, termed G-gamma and A-gamma, that are encoded by two different genes
(HBG1 and H362) but that are onally equivalent to a large degree; fetal hemoglobin
refers to any combination of a pair of G-gamma and/or A-gamma plus a pair of alpha-
globin proteins plus four molecules of heme.
In sickle cell anemia, the gene encoding for lobin contains a mutation which
results in an abnormal hemoglobin structure and causes red blood cells to adopt a
characteristic sickle shape under certain conditions. This sickle shape leads to reduced
red cell plasticity, longer capillary transit times, and frequent vaso-occlusive ses
that can damage tissues and result in patient morbidity. In contrast, halassemia is
characterized by inadequate beta-globin production to combine with normally produced
alpha-globin. The resulting lation of alpha globin is toxic to red blood cell
precursors, and results in ineffective erythropoiesis and extensive red blood cell
hemolysis.
There is currently no approved pharmacologic treatment to cure sickle cell anemia
or beta-thalassemia. However, increases in the number of red blood cells that produce
fetal hemoglobin, combined with l ses in the level of fetal hemoglobin per red
blood cell have been proven to provide clinical benefit in sickle cell anemia and sickle cell
disease patients by reducing the frequency of acute cclusive crises. Additionally,
although not clinically proven, the disease biology of beta-thalassemia suggests that
increasing fetal hemoglobin production to high levels may be a viable strategy forthe
therapy of this disease as well.
The object of this therapeutic approach, the de-repression of the silenced HBG1
and HBGZ genes, may be targeted through intervention in an epigenetic process in
opoiesis. Changes in DNA methylation are key determining events in the course of
poiesis, marking differentiation milestones that result in commitments to various
cell lineages. During opoiesis, a rapid decrease in global DNA methylation demarks
a commitment point toward the expression of erythroid specific regulators GATA1 and
KLF1, and suppression of hematopoietic progenitor tors GATA2 and PU.1 (1, 2).
For erythroid progenitor cells in adult bone marrow, DNA in the promoter region ofthe
beta-globin HBB gene becomes unmethylated, corresponding to high level expression of
beta-globin protein. In contrast, promoters ofthe H361 and H362 loci are highly
methylated, resulting in greatly diminished expression ofgamma-globin proteins (3).
Although DNA methyltransferases DNMT1, DNMT3A, and DNMT3B are each expressed
in erythroid progenitors, the relatively greater expression of DNMT1, particularly in the
final stages of erythroid differentiation suggests that it plays a dominant role in globin
gene tion (2). 5-azacytidine and 5-aza-2’-deoxycytidine (decitabine) are pan-DNMT
inhibitors that are known rs of fetal hemoglobin in erythroid progenitor cells. In
erythroid cell culture and in an in vivo model of fetal hemoglobin induction (4, 5),
treatment with these agents causes decreased methylation of CpG sites in the HBG
promoters with corresponding increases in the gamma globin protein expression.
er, in a limited set of clinical studies, both agents caused increases in fetal
hemoglobin in ts with sickle cell anemia, sickle cell disease and beta-thalassemia
(6-9). While effective at inducing fetal hemoglobin, these agents have not been widely
used to treat sickle cell , sickle cell disease, or beta-thalassemia due to concerns
over long-term safety, dose-limiting toxicities, and an unsuitable dosing route.
References
(1) Pop R, Shearstone JR, Shen Q, Liu Y, rom K, Koulnis M, et al. A key
commitment step in erythropoiesis is synchronized with the cell cycle clock through
mutual inhibition between PU.1 and e progression. 2010;8.
(2) Shearstone JR, Pop R, Bock C, Boyle P, Meissner A, vsky M. Global DNA
demethylation during mouse erythropoiesis in vivo. 2011;334:799-802.
2017/053511
(3) Mabaera R, Richardson CA, Johnson K, Hsu M, Fiering S, Lowrey CH.
Developmental- and differentiation-specific patterns of human +:- and +:-globin
promoter DNA methylation. 10:1343-52.
(4) Chin J, Singh M, Banzon V, Vaitkus K, Ibanez V, Kouznetsova T, et al.
Transcriptional activation of the +:-globin gene in baboons treated with decitabine
and in cultured erythroid progenitor cells involves different mechanisms.
2009;37:1131-42.
(5) Akpan l, Banzon V, Ibanez V, Vaitkus K, DeSimone J, Lavelle D. Decitabine
increases fetal hemoglobin in Papio anubis by sing bin gene
ription. 2010;38:989-93.
(6) Dover GJ, Charache SH, Boyer SH, Talbot J, Smith KD. 5-Azacytidine increases
fetal hemoglobin production in a patient with sickle cell disease. 34:475-88.
(7) Saunthararajah Y, Hillery CA, Lavelle D, Molokie R, Dorn L, Bressler L, et al. Effects
of 5-aza-2GC:-deoxycytidine on fetal hemoglobin levels, red cell adhesion, and
hematopoietic differentiation in patients with sickle cell disease. 2003;102:3865-70.
(8) Ley TJ, DeSimone J, Noguchi CT, Turner PH, Schechter AN, Heller P, et al. 5-
Azacytidine ses +:-globin synthesis and reduces the proportion ofdense cells
in patients with sickle cell anemia. 1983;62:370-80.
(9) Lowrey CH, Nienhuis AW. Brief report: Treatment with azacitidine of ts with
end-stage +:- thalassemia. 29:845-8.
It is an object of the present invention to provide novel compounds that are
selective inhibitors of DNMT1.
It is also an object of this invention to provide compounds which increase the
production of gamma globin, and thereby also increase the production of fetal
hemoglobin in human erythroid cells. The compounds of this invention may therefore
be useful to treat sickle cell anemia and sickle cell disease. Beta-thalassemia may
also be ameliorated by treatment with these compounds.
It is also an object ofthe present invention to provide pharmaceutical compositions
that comprise a pharmaceutical excipient and compounds of a (I).
It is also an object of the present invention to e a method for treating ,
pre-cancerous syndromes, beta obinopathies, such as sickle cell disease, sickle
cell anaemia, and beta thalassemia, that comprises administering novel selective inhibitors
of DNMT1 activity.
SUMMARY OF THE INVENTION
The invention is directed to substituted pyridine derivatives. Specifically, the
invention is directed to compounds ing to Formula (Iar):
(lar)
wherein Yar’ X1ar, X2ar, R15", R25", R33", R4ar and R5ar are as defined below; or a
pharmaceutically acceptable salt or prodrug thereof.
The present invention also relates to the discovery that the nds of Formula
(I) are active as inhibitors of DNMT1, and selective against DNMT3A and DNMT3B.
This invention also relates to a method of ng cancer, which comprises
administering to a subject in need thereof an effective amount of a DNMT1 inhibiting
compound of Formula (I); or a pharmaceutically acceptable salt thereof.
This invention also relates to a method oftreating pre-cancerous mes, which
comprises stering to a t in need thereof an effective amount of a DNMT1
inhibiting compound of Formula (I); or a pharmaceutically acceptable salt thereof.
This invention also relates to a method of treating beta hemoglobinopathies, which
ses stering to a subject in need thereof an effective amount of a DNMT1
inhibiting compound of Formula (I); or a pharmaceutically acceptable salt thereof.
This invention also relates to a method of treating sickle cell disease, which
comprises administering to a subject in need thereof an effective amount of a DNMT1
inhibiting compound of Formula (I); or a pharmaceutically acceptable salt thereof.
2017/053511
This invention also relates to a method of treating sickle cell anemia, which
comprises stering to a subject in need thereof an effective amount of a DNMT1
inhibiting compound of Formula (I); or a pharmaceutically acceptable salt thereof.
This invention also relates to a method of treating beta thalassemia, which
comprises administering to a subject in need thereof an effective amount of a DNMT1
inhibiting compound of Formula (I); or a ceutically acceptable salt f.
The invention also relates to a compound of Formula (I) or a pharmaceutically
able salt thereof for use in therapy.
The invention also s to a compound of Formula (I) or a pharmaceutically
acceptable salt thereof for use in the treatment of cancer.
The invention also relates to a compound of Formula (I) or a pharmaceutically
acceptable salt f for use in the treatment of pre-cancerous syndromes.
The invention also relates to a compound of Formula (I) or a pharmaceutically
acceptable salt thereof for use in the treatment of beta hemoglobinopathies.
The invention also relates to a compound of Formula (I) or a pharmaceutically
acceptable salt thereof for use in the treatment of sickle cell disease.
The invention also relates to a nd of Formula (I) or a pharmaceutically
acceptable salt thereof for use in the treatment of sickle cell anemia.
The invention also relates to a compound of Formula (I) or a pharmaceutically
able salt thereof for use in the treatment of beta semia.
The invention also relates to the use of a compound of Formula (I) or a
pharmaceutically acceptable salt thereof in the manufacture of a medicament for the
treatment of cancer.
The ion also relates to the use of a compound of Formula (I) or a
pharmaceutically acceptable salt thereof in the manufacture of a medicament for the
treatment of pre-cancerous syndromes.
The invention also relates to the use of a compound of Formula (I) or a
pharmaceutically acceptable salt thereof in the manufacture of a medicament for the
treatment of beta hemoglobinopathies.
The invention also relates to the use of a compound of Formula (I) or a
pharmaceutically acceptable salt thereof in the manufacture of a ment for the
treatment of sickle cell disease.
The invention also relates to the use of a nd of Formula (I) or a
pharmaceutically acceptable salt thereof in the manufacture of a medicament for the
treatment of sickle cell .
The invention also relates to the use of a compound of Formula (I) or a
pharmaceutically acceptable salt thereof in the manufacture of a medicament for the
treatment of beta thalassemia.
Included in the present invention are pharmaceutical compositions that comprise a
ceutical carrier and a compound of Formula (I) or a ceutically acceptable
salt thereof.
The ion also relates to a pharmaceutical composition as defined above for
use in therapy.
Also included in the present invention are methods of co-administering the
presently invented DNMT1 inhibiting compounds with a further anti-neoplastic agent or
.
Also included in the present invention are methods of co-administering the
tly invented DNMT1 inhibiting compounds with a further fetal hemoglobin inducing
agent or agents.
Also included in the present invention are s of co-administering the
presently invented DNMT1 ting compounds with a further agent or agents that
lessens the severity of beta hemoglobinopathies.
Also included in the present invention are methods of co-administering the
presently invented DNMT1 inhibiting compounds with a r agent or agents that
lessens the severity of sickle cell anemia.
Also ed in the present invention are s of co-administering the
presently invented DNMT1 inhibiting compounds with a further agent or agents that
s the severity of sickle cell disease.
Also ed in the present invention are methods of co-administering the
presently invented DNMT1 inhibiting compounds with a further agent or agents that
lessens the severity of beta thalassemia.
The invention also relates to a combination for use in therapy which comprises a
therapeutically effective amount of (i) a compound of Formula (I) or a pharmaceutically
acceptable salt thereof; and (ii) at least one anti-neoplastic agent.
The invention also relates to a combination for use in therapy which comprises a
therapeutically effective amount of (i) a compound of Formula (I) or a pharmaceutically
acceptable salt thereof; and (ii) at least one r fetal hemoglobin inducing agent.
The invention also relates to a combination for use in therapy which comprises a
therapeutically effective amount of (i) a compound of a (I) or a pharmaceutically
acceptable salt f; and (ii) at least one further agent that lessens the severity of beta
hemoglobinopathies.
The invention also relates to a ation for use in therapy which comprises a
therapeutically effective amount of (i) a compound of Formula (I) or a pharmaceutically
acceptable salt thereof; and (ii) at least one further agent that lessens the severity of
sickle cell anemia.
WO 16727
The invention also relates to a combination for use in therapy which ses a
therapeutically effective amount of (i) a compound of Formula (I) or a pharmaceutically
acceptable salt thereof; and (ii) at least one further agent that lessens the severity of
sickle cell disease.
The invention also relates to a combination for use in therapy which comprises a
therapeutically effective amount of (i) a compound of Formula (I) or a pharmaceutically
acceptable salt thereof; and (ii) at least one further agent that lessens the severity of beta
thalassemia.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure— 1A depicts the effect of Compound A on erythroid progenitor cells (EPCs).
Representative results (n=3 studies each) of 5 day treatment with
Compound A on fetal obin (HbF) ELISA (open s), and cell
growth assay (closed s).
Figure — 1B depicts the effect of Compound A on H361 and H362 DNA methylation.
oid progenitor cells (EPCs) were treated for 3 days with vehicle (gray
bars) or 5uM nd A (black bars), genomic DNA was extracted and
bisulfite sequenced for nine loci in the promoter regions of HBG1 and H362
that were previously described to be sites of DNMT1 cytosine methylation.
Sites of methylation are labeled as positions relative to respective start sites
Figure —2A s the effect of Compound A on fetal hemoglobin in the transgenic
mouse model. nd A administered orally to sickle cell disease (SCD)
model transgenic mice at 10 or 50 mgx’kg, BID daily caused dose dependent
increases in %HbF protein, measured by HPLC.
Figure —ZB depicts the effect of Compound A on fetal obin in the transgenic
mouse model. Compound A administered orally to SCD transgenic mice at
or 50 mg/kg, BID daily caused dose dependent increases in %F-
reticulocytes and %F-RBCs, measured by flow cytometry.
2017/053511
DETAILED DESCRIPTION OF THE INVENTION
This invention relates to compounds of Formula (lar) and to the use ofcompounds
of Formula (lar) in the methods ofthe invention:
Rlar
1ar Zar
X \X
I kR3ar /
R5ar N Yar R4ar
wherein:
X1ar and Xzar are independently selected from:
hydrogen,
cyano,
fluoro,
chloro,
bromo,
iodo,
C1-6alkyl,
-OC1-6a|ky|,
-OR§
cycloalkyl,
lkyl substituted from 1 to 4 times by Rd,
heterocycloalkyl,
heterocycloalkyl substituted from 1 to 4 times by Rd,
-SH, and
-SR%
Yar is selected from: 8, NH, NR2, 0, 8(0) and S(O)2;
R18" is ed from:
amino,
-NHR§
3o -NRbR9
cyano,
fluoro,
WO 16727
chloro,
bromo,
iodo,
C1-6alkyl,
-OC1-6alky|,
-ORe,
cycloalkyl,
cycloalkyl substituted from 1 to 4 times by Rd,
heterocycloalkyl,
heterocycloalkyl tuted from 1 to 4 times by Rd,
aryl,
aryl substituted from 1 to 4 times by Rd,
aryl,
heteroaryl substituted from 1 to 4 times by Rd,
-SH, and
-SRa;
R2ar is selected from:
hydrogen,
C1-6alkyl,
cycloalkyl,
cycloalkyl substituted from 1 to 4 times by Rd,
heterocycloalkyl,
heterocycloalkyl substituted from 1 to 4 times by Rd,
-C(O)ORa,
-C(O)NHRa, and
-C(O)NRbRC;
R38" is selected from:
hydrogen,
aryl,
aryl substituted from 1 to 4 times by Rd,
heteroaryl, and
heteroaryl substituted from 1 to 4 times by Rd;
R4ar is selected from:
hydrogen,
C1-6alkyl,
cycloalkyl,
cycloalkyl substituted from 1 to 4 times by Rd,
heterocycloalkyl,
heterocycloalkyl substituted from 1 to 4 times by Rd,
-c«»OR?
-C(O)NHRa, and
-C(O)NRbRC;
R5ar is selected from:
amino,
-NHRa,
,
aryl,
aryl substituted from 1 to 4 times by Rd,
-OC1-6alkyl,
-ORe,
-Oaryl,
-Oary| substituted from 1 to 4 times by Rd,
-Oheteroaryl,
-Oheteroary| substituted from 1 to 4 times by Rd,
-SH, and
-SRa;
where:
each Ra is independently selected from
C1-6alkyl,
Re,
aryl.
aryl tuted from 1 to 4 times by Rd,
aryl,
heteroaryl substituted from 1 to 4 times by Rd
cycloalkyl,
cycloalkyl tuted from 1 to 4 times by Rd,
heterocycloalkyl, and
heterocycloalkyl substituted from 1 to 4 times by Rd;
Rb and R0 are independently selected from:
C1-6alkyl,
aryl,
aryl substituted from 1 to 4 times by Rd,
heteroaryl,
heteroaryl substituted from 1 to 4 times by Rd;
cycloalkyl,
cycloalkyl tuted from 1 to 4 times by Rd,
heterocycloalkyl, and
heterocycloalkyl substituted from 1 to 4 times by Rd, or
Rb and RC are taken together with the nitrogen to which they are
attached, and optionally from 1 to 3 additional atoms, to form
a heterocycloalkyl, which is optionally substituted with from 1 to 5
substituents independently selected from:
fluoro,
chloro,
bromo,
iodo,
C1-6alkyl,
aryl,
aryl substituted from 1 to 4 times by Rd,
cycloalkyl,
cycloalkyl substituted from 1 to 4 times by Rd,
heterocycloalkyl, and
heterocycloalkyl substituted from 1 to 4 times by Rd,
C1-4alkoxy,
C1-4a|koxy substituted with from 1 to 6 substituents
independently selected from: fluoro, oxo, -OH,
2017/053511
-COOH, -NH2, and —-CN,
-N027
-NH2,
-N(H)C1-4a|kyl,
-N(H)Re,
-N(C1-4alkyl)2,
-NReRe,
SOzNHz,
CHs, and
SOzCH3;
each RCl is independently selected from:
fluoro,
chloro,
bromo,
iodo,
C1—63Ikyl,
heteroaryl,
heteroaryl substituted from 1 to 4 times by RX,
where RX is selected from aryl, heteroaryl, cycloalkyl,
heterocyloalkyl, C1-6alkyl, and C1-6alkyl substituted with
from 1 to 6 substituents independently selected from:
, 0x0, -OH, -COOH, -NH2, and —-CN,
cycloalkyl,
cycloalkyl substituted from 1 to 4 times by RX,
where RX is selected from aryl, heteroaryl, cycloalkyl,
heterocyloalkyl, C1-6alkyl, and C1-6alkyl substituted with
from 1 to 6 substituents ndently selected from:
fluoro, oxo, -OH, -COOH, -NH2, and —-CN,
heterocycloalkyl,
heterocycloalkyl substituted from 1 to 4 times by RX,
where RX is selected from aryl, heteroaryl, cycloalkyl,
heterocyloalkyl, C1-6alkyl, and C1-6alkyl substituted with
from 1 to 6 substituents independently selected from:
fluoro, 0x0, -OH, -COOH, -NH2, and —-CN,
aryl,
aryl substituted from 1 to 4 times by RX,
where RX is selected from aryl, heteroaryl, cycloalkyl,
heterocyloalkyl, kyl, and C1-6alkyl substituted with
from 1 to 6 substituents independently ed from:
fluoro, 0x0, -OH, -COOH, -NH2, and —-CN,
C1-4alkoxy,
C1_4alkoxy substituted from 1 to 4 times by fluoro,
-Oaryl,
-Oaryl substituted from 1 to 4 times by RX,
where RX is selected from aryl, heteroaryl, lkyl,
heterocyloalkyl, C1-6alkyl, and C1-6alkyl substituted with
from 1 to 6 substituents independently selected from:
, oxo, -OH, -COOH, -NH2, and —-CN,
-C(O)H,
-C(O)RZZ,
-C(O)aryl,
-C(O)aryl substituted from 1 to 4 times by R22,
-C(O)heteroaryl,
-C(O)heteroaryl substituted from 1 to 4 times by R22,
-OC(O)H,
-CO(O)RZZ,
aryl,
-CO(O)aryl substituted from 1 to 4 times by RZZ,
-OC(O)heteroaryl,
-OC(O)heteroaryl substituted from 1 to 4 times by R22,
-SRX,
where RX is selected from aryl, heteroaryl, cycloalkyl,
2017/053511
heterocyloalkyl, C1-6alkyl, and C1-6alkyl substituted with
from 1 to 6 substituents independently selected from:
fluoro, oxo, -OH, -COOH, -NH2, and —-CN,
-S(O)H,
-S(0)RX.
where RX is selected from aryl, heteroaryl, cycloalkyl,
heterocyloalkyl, C1-6alkyl, and kyl substituted with
from 1 to 6 substituents independently selected from:
fluoro, 0x0, -OH, -COOH, -NH2, and —-CN,
-S(O)2H,
where RX is selected from aryl, aryl, cycloalkyl,
heterocyloalkyl, C1-6alkyl, and C1-6alkyl substituted with
from 1 to 6 substituents independently selected from:
fluoro, 0x0, -OH, -COOH, -NH2, and —-CN,
-S(O)2NH2,
-S(O)2NHRX,
where RX is selected from aryl, heteroaryl, lkyl,
heterocyloalkyl, C1-6alkyl, and C1-6alky| substituted with
from 1 to 6 substituents independently selected from:
fluoro, 0x0, -OH, -COOH, -NH2, and —-CN,
-S(O)2NRX1RX2,
where RX1 and RX2 are each independently selected from
aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C1-6alkyl, and
kyl substituted with from 1 to 6 substituents
independently selected from: fluoro, oxo, -OH, -COOH,
-NH2, and —-CN,
-NHS(O)2H,
-NHS(O)2RX,
where RX is selected from aryl, heteroaryl, cycloalkyl,
heterocyloalkyl, kyl, and C1-6alkyl substituted with
from 1 to 6 substituents independently selected from:
fluoro, 0x0, -OH, -COOH, -NH2, and —-CN,
-NHC(O)H,
-NHC(O)RX,
where RX is selected from aryl, heteroaryl, lkyl,
heterocyloalkyl, C1-Balkyl, and C1-6alkyl substituted with
from 1 to 6 substituents independently selected from:
fluoro, 0x0, -OH, -COOH, -NH2, and —-CN,
-C(O)NH2,
-C(O)NHRX,
where RX is selected from aryl, heteroaryl, cycloalkyl,
heterocyloalkyl, C1-6alkyl, and C1-6alkyl substituted with
from 1 to 6 tuents independently selected from:
fluoro, oxo, -OH, -COOH, -NH2, and —-CN,
-C(O)NRX1RX2,
where RX1 and RX2 are each independently selected from
aryl, heteroaryl, cycloalkyl, cyloalkyl, C1-6alkyl, and
C1-ealkyl substituted with from 1 to 6 substituents
independently ed from: fluoro, oxo, -OH, -COOH,
-NH2, and —-CN,
-C(O)OH,
-C(O)ORX,
where RX is selected from aryl, aryl, cycloalkyl,
heterocyloalkyl, C1-6alkyl, and C1-6alkyl substituted with
from 1 to 6 substituents independently selected from:
fluoro, 0x0, -OH, -COOH, -NH2, and —-CN,
oxo,
hydroxy,
amino,
-NHRX,
where RX is selected from aryl, heteroaryl, cycloalkyl,
heterocyloalkyl, C1-6alkyl, and kyl substituted with
from 1 to 6 tuents independently selected from:
fluoro, oxo, -OH, -COOH, -NH2, and —-CN,
-NRX1RX2,
where RX1 and RX2 are each independently selected from
aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C1-ealkyl, and
C1-Balkyl substituted with from 1 to 6 substituents
independently selected from: fluoro, oxo, -OH, -COOH,
-NH2, and —-CN,
nitro,
cyano,
-NHC(O)NH2,
-NHC(O)NHRX,
where RX is selected from aryl, heteroaryl, cycloalkyl,
heterocyloalkyl, C1-6alky|, and C1-6alkyl substituted with
from 1 to 6 substituents independently selected from:
fluoro, 0x0, -OH, -COOH, -NH2, and —-CN,
-NHC(O)NRX1RX2,
where RX1 and RX2 are each independently ed from
aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C1-6alkyl, and
C1-6alkyl substituted with from 1 to 6 substituents
independently ed from: fluoro, oxo, -OH, -COOH,
-NH2, and —-CN,
each Re is independently selected from:
C1-6alkyl substituted with from 1 to 9 substitutents independently
selected from:
,
chloro,
bromo,
iodo,
C1-6alkyl,
a|ky|,
-OC1-6alkyl substituted with from 1 to 6 substituents
independently selected from: , oxo, -OH,
-COOH, -NH2, and —-CN,
mercapto,
-SRX,
where Rx is selected from aryl, aryl,
cycloalkyl, heterocyloalkyl, C1-6alkyl, and C1-6alkyl
substituted with from 1 to 6 substituents
independently selected from: fluoro, oxo, -OH,
-COOH, -NH2, and —-CN,
-S(O)H,
-S(0)RX,
where RX is selected from aryl, heteroaryl,
cycloalkyl, heterocyloalkyl, C1-6alkyl, and C1-6alky|
substituted with from 1 to 6 substituents
independently selected from: fluoro, oxo, -OH,
-COOH, -NH2, and —-CN,
-S(O)2H,
-S(O)2RX,
where RX is selected from aryl, heteroaryl,
cycloalkyl, heterocyloalkyl, kyl, and C1-6alkyl
substituted with from 1 to 6 substituents
independently selected from: fluoro, 0x0, -OH,
-COOH, -NH2, and —-CN,
oxo,
hydroxy,
amino,
-NHRXX,
where RXX is selected from aryl, heteroaryl,
cycloalkyl, cyloalkyl, C1-6alkyl,
and C1-6alkyl substituted with from 1 to 6
substituents independently selected from: fluoro,
oxo, -ORXV, -COOH, —-CN, alkyl, -OC1-5a|ky|
substituted from 1 to 6 times by fluoro and
—NRXVRXZ, where ny and R"Z are independently
selected from: en, aryl, C1-5alkyl and
C1-5alky| substituted with from 1 to 4 substituents
independently selected from: fluoro, oxo, -OH,
-OC1-5a|kyl, -OC1-5alkyl substituted from 1 to 6
times by fluoro and —COOH,
_NRX1RX2’
where RX1 and RX2 are each independently selected
from aryl, heteroaryl, cycloalkyl, heterocyloalkyl,
kyl, and C1-6alkyl substituted with from 1 to 6
Substituents independently selected from: fluoro,
oxo, -OH, -COOH, -NH2, and —-CN,
guanidino,
-C(O)OH,
-C(O)ORX,
where RX is selected from aryl, aryl,
cycloalkyl, heterocyloalkyl, C1-6alkyl, and C1-6alkyl
substituted with from 1 to 6 tuents
independently selected from: fluoro, oxo, -OH,
-COOH, -NH2, and —-CN,
-C(O)NH2,
-C(O)NHRX,
where RX is selected from aryl, heteroaryl,
cycloalkyl, heterocyloalkyl, kyl, and C1-ealkyl
substituted with from 1 to 6 substituents
independently selected from: fluoro, oxo, -OH,
-COOH, -NH2, and —-CN,
-C(O)NRX1RX2,
where RX1 and RX2 are each independently selected
from aryl, heteroaryl, cycloalkyl, heterocyloalkyl,
C1-6alkyl, and C1-6alkyl substituted with from 1 to 6
Substituents independently selected from: fluoro,
oxo, -OH, -COOH, -NH2, and —-CN,
aryl,
aryl substituted from 1 to 4 times by RX,
where RX is selected from aryl, heteroaryl,
cycloalkyl, cyloalkyl, C1-6alkyl, and C1-6alkyl
substituted with from 1 to 6 substituents
independently selected from: fluoro, 0x0, -OH,
-COOH, -NH2, and —-CN,
-Oaryl,
-Oaryl substituted from 1 to 4 times by RX,
where RX is selected from aryl, heteroaryl,
cycloalkyl, heterocyloalkyl, C1-6alkyl, and C1-6alkyl
substituted with from 1 to 6 substituents
independently selected from: fluoro, oxo, -OH,
-COOH, -NH2, and —-CN,
heteroaryl,
heteroaryl substituted from 1 to 4 times by RX,
where Rx is selected from aryl, aryl,
cycloalkyl, heterocyloalkyl, C1-6alkyl, and C1-6alky|
tuted with from 1 to 6 substituents
independently selected from: fluoro, oxo, -OH,
-COOH, -NH2, and —-CN,
roaryl,
-Oheteroaryl tuted from 1 to 4 times by RX,
where RX is selected from aryl, heteroaryl,
cycloalkyl, heterocyloalkyl, kyl, and kyl
substituted with from 1 to 6 substituents
independently selected from: fluoro, oxo, -OH,
-COOH, -NH2, and —-CN,
cycloalkyl,
cycloalkyl substituted from 1 to 4 times by RX,
where RX is selected from aryl, heteroaryl,
cycloalkyl, cyloalkyl, C1-6alkyl, and C1-6alkyl
substituted with from 1 to 6 substituents
independently selected from: fluoro, oxo, -OH,
-COOH, -NH2, and —-CN,
heterocycloalkyl,
heterocycloalkyl substituted from 1 to 4 times by RX,
where RX is selected from aryl, heteroaryl,
cycloalkyl, heterocyloalkyl, C1-6alkyl, and C1-6alky|
substituted with from 1 to 6 substituents
independently selected from: fluoro, 0x0, -OH,
-COOH, -NH2, and —-CN,
NH2,
-S(O)2NHRX,
where RX is selected from aryl, heteroaryl,
lkyl, heterocyloalkyl, C1-6alkyl, and C1-6alky|
substituted with from 1 to 6 substituents
independently selected from: fluoro, oxo, -OH,
-COOH, -NH2, and —-CN,
-S(O)2NRX1RX2,
where RX1 and RX2 are each independently selected
from aryl, heteroaryl, cycloalkyl, heterocyloalkyl,
C1-6alkyl, and C1-6alkyl substituted with from 1 to 6
Substituents independently selected from: fluoro,
oxo, -OH, -COOH, -NH2, and —-CN,
-NHS(O)2H,
-NHS(O)2RX,
where RX is selected from aryl, heteroaryl,
cycloalkyl, heterocyloalkyl, C1-6alkyl, and C1-6alky|
tuted with from 1 to 6 tuents
independently selected from: fluoro, 0x0, -OH,
-COOH, -NH2, and —-CN,
-NHC(O)NHRXp,
where RXp is selected from heteroaryl,
cycloalkyl, heterocyloalkyl, and C1-6alky|
substituted with from 1 to 4 substituents
independently selected from: -COOH, -NH2, and
—-CN,
-NHC(O)NRX3RX4,
where RX3 and RX4 are each independently ed
from heteroaryl, cycloalkyl, heterocyloalkyl,
and C1-6alky| substituted with from 1 to 6
Substituents ndently selected from:
-COOH, -NH2, and —-CN,
nitro, and
cyano;
each Rf is ndently C1-6alky| optionally substituted from 1 to 6 times
by Re;
each R9 is independently aryl ally substituted from 1 to 5 times by
RX
where RX is ndently selected from aryl, heteroaryl,
cycloalkyl, heterocyloalkyl, C1-6alkyl, and C1-6alkyl
substituted with from 1 to 6 substituents independently
ed from: fluoro, oxo, -OH, -COOH, -NH2, and —-CN,
each Rh is independently heteroaryl optionally substituted from 1 to 5
times by RX,
where RX is independently selected from aryl,
heteroaryl, cycloalkyl, heterocyloalkyl, C1-6alkyl, and
C1-6alkyl substituted with from 1 to 6 substituents
independently selected from: fluoro, oxo, -OH, -COOH,
-NH2, and —-CN, and
R2 is selected from
C1 —68|kyl,
cycloalkyl,
cycloalkyl substituted from 1 to 4 times by R ,
heterocycloalkyl, and
heterocycloalkyl substituted from 1 to 4 times by Rd;
R22 is selected from
kyl, and
Re;
provided that:
at least one of Rzar, R38" and R48", is hydrogen,
R28", R38" and R43" are not all hydrogen, and
X1ar and X25" are not both hydrogen;
or a pharmaceutically acceptable salt or prodrug thereof.
Suitably in the compounds of Formula (lar) R25" is -C(O)NH2.
Suitably in the compounds of Formula (lar) R3ar is aryl optionally substituted from 1
to 4 times by Rd.
ed in the compounds ofthe invention and used in the methods ofthe invention
are compounds of Formula (I):
x1 \ XZRZ
/ J<R3
R5 N Y R4
wherein:
X1 and X2 are independently selected from:
hydrogen,
cyano,
chloro,
bromo,
iodo,
C1-6alkyl,
alkyl,
-0R9
cycloalkyl,
cycloalkyl substituted from 1 to 4 times by Rd,
heterocycloalkyl,
heterocycloalkyl substituted from 1 to 4 times by Rd,
-SH, and
-SR%
Y is selected from: 8, NH, NRZ, 0, 8(0) and S(O)2;
R1 is selected from:
amino,
-NHR?
-NRbR9
cyano,
fluoro,
chloro,
bromo,
iodo,
C1-6alkyl,
-OC1-6a|ky|,
-OR§
cycloalkyl,
cycloalkyl substituted from 1 to 4 times by Rd,
heterocycloalkyl,
heterocycloalkyl substituted from 1 to 4 times by Rd,
-SH, and
-SR%
R2 is ed from:
hydrogen,
2017/053511
C1-6alkyl,
cycloalkyl,
cycloalkyl substituted from 1 to 4 times by Rd,
heterocycloalkyl,
heterocycloalkyl substituted from 1 to 4 times by Rd,
-C(O)ORa,
-C(O)NHRa, and
-C(O)NRbRC;
R3 is selected from:
hydrogen,
aryl,
aryl substituted from 1 to 4 times by Rd,
heteroaryl, and
heteroaryl substituted from 1 to 4 times by Rd;
R4 is ed from:
hydrogen,
C1-6alkyl,
cycloalkyl,
cycloalkyl substituted from 1 to 4 times by Rd,
heterocycloalkyl,
heterocycloalkyl substituted from 1 to 4 times by Rd,
-C(O)ORa,
-C(O)NHRa, and
-C(O)NRbRC;
R5 is ed from:
amino,
-NHRa,
-NRbRC,
aryl,
aryl substituted from 1 to 4 times by Rd,
-OC1-Ba|ky|,
-ORe,
-Oaryl,
-Oaryl substituted from 1 to 4 times by Rd,
-Oheteroaryl,
-Oheteroary| substituted from 1 to 4 times by Rd,
-SH, and
-SRa;
where:
each Ra is independently selected from
kyl,
aryl,
aryl tuted from 1 to 4 times by Rd,
heteroaryl,
heteroaryl substituted from 1 to 4 times by Rd
cycloalkyl,
cycloalkyl substituted from 1 to 4 times by Rd,
heterocycloalkyl, and
cycloalkyl substituted from 1 to 4 times by Rd;
Rb and R0 are independently selected from:
C1—6alkyl,
aryl,
aryl substituted from 1 to 4 times by Rd,
heteroaryl,
heteroaryl substituted from 1 to 4 times by Rd;
cycloalkyl,
cycloalkyl substituted from 1 to 4 times by Rd,
heterocycloalkyl, and
heterocycloalkyl substituted from 1 to 4 times by Rd, or
Rb and R0 are taken together with the nitrogen to which they are
attached, and optionally from 1 to 3 additional heteroatoms, to form
a cycloalkyl, which is optionally substituted with from 1 to 5
substituents independently selected from:
fluoro,
aryl substituted from 1 to 4 times by Rd,
cycloalkyl,
cycloalkyl substituted from 1 to 4 times by Rd,
heterocycloalkyl, and
heterocycloalkyl substituted from 1 to 4 times by Rd,
koxy,
C1-4alkoxy substituted with from 1 to 6 substituents
independently selected from: fluoro, oxo, -OH,
-COOH, -NH2, and —-CN,
-N02,
-NH2,
-N(H)C1-4alkyl,
-N(H)Re,
-N(Ct-4alkyl)2,
-NReRe,
SOzNHz,
CHs, and
SOzCHs;
each Rd is independently selected from:
WO 16727
fluoro,
chloro,
bromo,
iodo,
C1-6alkyl,
heteroaryl,
aryl substituted from 1 to 4 times by RX,
where RX is selected from aryl, heteroaryl, cycloalkyl,
heterocyloalkyl, C1-6alkyl, and C1-6alky| tuted with
from 1 to 6 substituents independently selected from:
fluoro, oxo, -OH, -COOH, -NH2, and —-CN,
cycloalkyl,
lkyl substituted from 1 to 4 times by RX,
where RX is selected from aryl, heteroaryl, cycloalkyl,
heterocyloalkyl, C1-6alkyl, and C1-6alkyl tuted with
from 1 to 6 substituents independently selected from:
fluoro, 0x0, -OH, -COOH, -NH2, and —-CN,
heterocycloalkyl,
heterocycloalkyl tuted from 1 to 4 times by RX,
where RX is selected from aryl, heteroaryl, cycloalkyl,
heterocyloalkyl, kyl, and C1-6alkyl substituted with
from 1 to 6 substituents independently selected from:
fluoro, 0x0, -OH, -COOH, -NH2, and —-CN,
aryl,
aryl substituted from 1 to 4 times by RX,
where RX is selected from aryl, heteroaryl, cycloalkyl,
heterocyloalkyl, C1-6alkyl, and C1-6alkyl substituted with
from 1 to 6 substituents independently selected from:
fluoro, 0x0, -OH, -COOH, -NH2, and —-CN,
C1_4alkoxy,
C1-4alkoxy substituted from 1 to 4 times by fluoro,
-Oaryl,
-Oaryl substituted from 1 to 4 times by RX,
where RX is selected from aryl, heteroaryl, cycloalkyl,
heterocyloalkyl, C1-6alkyl, and C1-6alkyl substituted with
from 1 to 6 substituents independently selected from:
fluoro, 0x0, -OH, -COOH, -NH2, and —-CN,
-C(O)H,
-C(O)RZZ,
-C(O)ary|,
-C(O)aryl substituted from 1 to 4 times by R22,
-C(O)heteroaryl,
-C(O)heteroaryl substituted from 1 to 4 times by R22,
-OC(O)H,
RZZ,
-OC(O)aryI,
-CO(O)aryl substituted from 1 to 4 times by R22,
-OC(O)heteroaryl,
heteroaryl substituted from 1 to 4 times by R22,
mercapto,
-SRX,
where RX is selected from aryl, heteroaryl, cycloalkyl,
heterocyloalkyl, C1-Balkyl, and C1-6alkyl substituted with
from 1 to 6 substituents independently selected from:
fluoro, 0x0, -OH, -COOH, -NH2, and —-CN,
-S(O)H,
-S(O)RX,
where RX is selected from aryl, heteroaryl, cycloalkyl,
heterocyloalkyl, C1-6alkyl, and C1-6alkyl tuted with
from 1 to 6 substituents independently selected from:
fluoro, oxo, -OH, -COOH, -NH2, and —-CN,
-S(O)2H,
where RX is selected from aryl, heteroaryl, cycloalkyl,
heterocyloalkyl, C1-6alkyl, and C1-6alkyl substituted with
from 1 to 6 substituents independently ed from:
, 0x0, -OH, -COOH, -NH2, and —-CN,
-S(O)2NH2,
-S(O)2NHRX,
where RX is selected from aryl, heteroaryl, lkyl,
heterocyloalkyl, C1-ealkyl, and C1-6alkyl substituted with
from 1 to 6 substituents independently selected from:
fluoro, oxo, -OH, -COOH, -NH2, and —-CN,
-S(O)2NRX1RX2,
where RX1 and RX2 are each independently selected from
aryl, heteroaryl, lkyl, heterocyloalkyl, C1-6alkyl, and
C1-6alkyl substituted with from 1 to 6 substituents
independently selected from: fluoro, 0x0, -OH, -COOH,
-NH2, and —-CN,
-NHS(O)2H,
-NHS(O)2RX,
where RX is selected from aryl, heteroaryl, cycloalkyl,
1O heterocyloalkyl, C1-ealkyl, and C1-6alkyl substituted with
from 1 to 6 substituents independently selected from:
fluoro, 0x0, -OH, -COOH, -NH2, and —-CN,
-NHC(O)H,
-NHC(O)RX,
where RX is selected from aryl, heteroaryl, cycloalkyl,
heterocyloalkyl, C1-6alkyl, and kyl substituted with
from 1 to 6 substituents independently selected from:
fluoro, oxo, -OH, -COOH, -NH2, and —-CN,
-C(O)NHRX,
where RX is ed from aryl, heteroaryl, cycloalkyl,
heterocyloalkyl, C1-6alkyl, and C1-6alkyl substituted with
from 1 to 6 substituents independently selected from:
fluoro, 0x0, -OH, -COOH, -NH2, and —-CN,
RX1RX2,
where RX1 and RX2 are each independently selected from
aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C1-6alky|, and
C1-6alkyl substituted with from 1 to 6 substituents
independently selected from: fluoro, oxo, -OH, -COOH,
-NH2, and —-CN,
-C(O)OH,
-C(O)ORX,
where RX is selected from aryl, heteroaryl, cycloalkyl,
heterocyloalkyl, C1-6alkyl, and C1-6alkyl substituted with
from 1 to 6 tuents independently selected from:
fluoro, 0x0, -OH, -COOH, -NH2, and —-CN,
oxo,
hydroxy,
amino,
-NHRX,
where RX is selected from aryl, heteroaryl, cycloalkyl,
heterocyloalkyl, C1-6alky|, and C1-6a|kyl substituted with
from 1 to 6 tuents independently selected from:
fluoro, 0x0, -OH, -COOH, -NH2, and —-CN,
-NRX1RX2,
where RX1 and RX2 are each independently selected from
aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C1-6alky|, and
C1-6alkyl substituted with from 1 to 6 substituents
independently selected from: fluoro, oxo, -OH, -COOH,
-NH2, and —-CN,
nitro,
cyano,
-NHC(O)NH2.
-NHC(O)NHRX,
where RX is selected from aryl, heteroaryl, cycloalkyl,
heterocyloalkyl, kyl, and C1-6alky| substituted with
from 1 to 6 substituents independently selected from:
fluoro, 0x0, -OH, -COOH, -NH2, and —-CN,
-NHC(O)NRX1RX2,
where RX1 and RX2 are each independently selected from
aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C1-6alkyl, and
kyl substituted with from 1 to 6 substituents
independently ed from: fluoro, oxo, -OH, -COOH,
-NH2, and —-CN,
each Re is independently selected from:
C1_6alkyl substituted with from 1 to 9 substitutents independently
selected from:
fluoro,
bromo,
iodo,
C1-68lkyl,
-OC1-6a|ky|,
-OC1-6alkyl substituted with from 1 to 6 substituents
ndently selected from: fluoro, oxo, -OH,
-COOH, -NH2, and —-CN,
mercapto,
-SRX,
where RX is selected from aryl, heteroaryl,
cycloalkyl, heterocyloalkyl, C1-6alkyl, and C1-6alkyl
substituted with from 1 to 6 substituents
independently selected from: fluoro, oxo, -OH,
-COOH, -NH2, and —-CN,
-S(O)H,
X,
where Rx is selected from aryl, heteroaryl,
cycloalkyl, heterocyloalkyl, C1-6alkyl, and C1-6alky|
substituted with from 1 to 6 substituents
independently ed from: fluoro, oxo, -OH,
-COOH, -NH2, and —-CN,
-S(O)2H,
-S(O)2RX,
where RX is selected from aryl, aryl,
cycloalkyl, heterocyloalkyl, C1-6alkyl, and C1-6alkyl
substituted with from 1 to 6 substituents
ndently selected from: fluoro, oxo, -OH,
-COOH, -NH2, and —-CN,
oxo,
hydroxy,
amino,
-NHRXX,
where RXX is selected from aryl, heteroaryl,
cycloalkyl, heterocyloalkyl, C1-6alkyl,
and C1-6alkyl tuted with from 1 to 6
substituents independently selected from: fluoro,
oxo, -ORXV, -COOH, —-CN, -OC1-5alkyl, -OC1-5alkyl
substituted from 1 to 6 times by fluoro and
—NRXyRXZ, where ny and RXZ are independently
selected from: hydrogen, aryl, C1-5alkyl and
C1-5alkyl tuted with from 1 to 4 substituents
independently selected from: fluoro, oxo, -OH,
-OC1-5alkyl, -OC1-5alky| substituted from 1 to 6
times by fluoro and —COOH,
-NRX1RX2,
where RX1 and RX2 are each independently selected
from aryl, heteroaryl, cycloalkyl, heterocyloalkyl,
C1-6alkyl, and kyl substituted with from 1 to 6
Substituents independently selected from: fluoro,
oxo, -OH, -COOH, -NH2, and —-CN,
guanidino,
1O -C(O)OH,
-C(O)ORX,
where RX is selected from aryl, heteroaryl,
cycloalkyl, heterocyloalkyl, C1-ealkyl, and C1-6alky|
tuted with from 1 to 6 substituents
independently selected from: fluoro, oxo, -OH,
-COOH, -NH2, and —-CN,
-C(O)NH2,
-C(O)NHRX,
where RX is selected from aryl, heteroaryl,
cycloalkyl, heterocyloalkyl, C1-6alkyl, and kyl
substituted with from 1 to 6 substituents
independently selected from: fluoro, 0x0, -OH,
-COOH, -NH2, and —-CN,
-C(O)NRX1RX2,
where RX1 and RX2 are each independently selected
from aryl, heteroaryl, cycloalkyl, heterocyloalkyl,
C1-6alkyl, and C1-ea|kyl substituted with from 1 to 6
tuents independently selected from: ,
0x0, -OH, -COOH, -NH2, and —-CN,
aryl,
aryl substituted from 1 to 4 times by RX,
where RX is selected from aryl, heteroaryl,
cycloalkyl, heterocyloalkyl, C1-ealkyl, and ky|
substituted with from 1 to 6 substituents
independently selected from: fluoro, oxo, -OH,
-COOH, -NH2, and —-CN,
-Oaryl,
-Oaryl substituted from 1 to 4 times by RX,
where RX is selected from aryl, heteroaryl,
cycloalkyl, heterocyloalkyl, C1-6alkyl, and C1-6alkyl
substituted with from 1 to 6 substituents
independently selected from: fluoro, 0x0, -OH,
-COOH, -NH2, and —-CN,
heteroaryl,
heteroaryl substituted from 1 to 4 times by RX,
where RX is selected from aryl, heteroaryl,
cycloalkyl, heterocyloalkyl, C1-ealkyl, and C1-6alkyl
substituted with from 1 to 6 substituents
independently selected from: fluoro, oxo, -OH,
-COOH, -NH2, and —-CN,
-Oheteroaryl,
-Oheteroary| substituted from 1 to 4 times by RX,
where Rx is selected from aryl, heteroaryl,
cycloalkyl, heterocyloalkyl, kyl, and C1-6alkyl
tuted with from 1 to 6 substituents
independently ed from: fluoro, oxo, -OH,
-COOH, -NH2, and —-CN,
lkyl,
lkyl substituted from 1 to 4 times by RX,
where RX is selected from aryl, heteroaryl,
cycloalkyl, cyloalkyl, C1-6alkyl, and C1-6alkyl
substituted with from 1 to 6 substituents
independently selected from: fluoro, oxo, -OH,
-COOH, -NH2, and —-CN,
heterocycloalkyl,
heterocycloalkyl substituted from 1 to 4 times by RX,
where RX is selected from aryl, heteroaryl,
cycloalkyl, heterocyloalkyl, C1-6alkyl, and C1-6alkyl
substituted with from 1 to 6 substituents
independently selected from: fluoro, 0x0, -OH,
-COOH, -NH2, and —-CN,
-S(O)2NH2,
-S(O)2NHRX,
where RX is selected from aryl, heteroaryl,
cycloalkyl, cyloalkyl, C1-6alkyl, and C1-6alkyl
substituted with from 1 to 6 tuents
independently selected from: fluoro, oxo, -OH,
-COOH, -NH2, and —-CN,
-S(O)2NRX1RX2,
where RX1 and RX2 are each independently selected
from aryl, heteroaryl, cycloalkyl, heterocyloalkyl,
C1-6alkyl, and C1-6alkyl substituted with from 1 to 6
Substituents independently selected from: fluoro,
oxo, -OH, -COOH, -NH2, and —-CN,
-NHS(O)2H,
-NHS(O)2RX,
where RX is selected from aryl, aryl,
cycloalkyl, heterocyloalkyl, C1-6alkyl, and C1-6alkyl
substituted with from 1 to 6 substituents
independently selected from: fluoro, oxo, -OH,
-COOH, -NH2, and —-CN,
-NHC(O)NHRXp,
where RXp is selected from heteroaryl,
cycloalkyl, heterocyloalkyl, and C1-6alkyl
tuted with from 1 to 4 substituents
independently selected from: -COOH, -NH2, and
—-CN,
-NHC(O)NRX3RX4,
where RX3 and RX4 are each independently selected
from heteroaryl, cycloalkyl, cyloalkyl,
and C1-6alkyl substituted with from 1 to 6
Substituents independently selected from:
-COOH, -NH2, and —-CN,
nitro, and
cyano;
each Rf is independently C1-6alkyl optionally tuted from 1 to 6 times
by Re;
each R9 is independently aryl optionally substituted from 1 to 5 times by
where RX is independently selected from aryl, heteroaryl,
cycloalkyl, heterocyloalkyl, kyl, and C1-6alkyl
substituted with from 1 to 6 substituents independently
selected from: fluoro, 0x0, -OH, -COOH, -NH2, and —-CN,
each Rh is independently heteroaryl optionally tuted from 1 to 5
times by RX,
where RX is independently ed from aryl,
heteroaryl, cycloalkyl, cyloalkyl, C1-6alkyl, and
C1-6alkyl substituted with from 1 to 6 substituents
independently selected from: fluoro, oxo, -OH, -COOH,
-NH2, and —-CN, and
RZ is ed from
C1—6alkyl,
cycloalkyl,
cycloalkyl substituted from 1 to 4 times by Rd,
heterocycloalkyl, and
heterocycloalkyl substituted from 1 to 4 times by Rd;
R22 is selected from
C1-6alkyl, and
provided that:
at least one of R2, R3 and R4, is hydrogen,
R2, R3 and R4 are not all hydrogen, and
X1 and X2 are not both hydrogen;
or a pharmaceutically acceptable salt or prodrug thereof.
Included in the compounds ofthe invention and used in the methods ofthe invention
are compounds of Formula (II):
21 22
X X
\ 22
/ J<R23
R25 N Y1 R24 (II)
wherein:
X21 and X22 are independently selected from:
hydrogen,
cyano,
fluoro,
chloro,
bromo,
iodo,
C1 -6a|kyl,
1O -OC1-6alkyl,
-OR§
cycloalkyl,
heterocycloalkyl, and
-SH;
Y1 is selected from: 8, NH, NRZ, 8(0) and S(O)2;
R21 is ed from:
amino,
cyano,
fluoro,
chloro,
bromo,
iodo,
C1-6alkyl,
-OC1-6alkyl,
-0R9
-NHR§
-NRbR9
cycloalkyl,
lkyl substituted with from 1 to 4 times by Rd,
heterocycloalkyl,
-SH, and
-SR%
R22 is selected from:
hydrogen,
C1-6alkyl,
cycloalkyl,
cycloalkyl substituted from 1 to 4 times by Rd,
heterocycloalkyl,
heterocycloalkyl tuted from 1 to 4 times by Rd,
-C(O)ORa, and
-C(O)NHRa;
R23 is selected from:
hydrogen,
aryl,
aryl substituted from 1 to 4 times by Rd,
heteroaryl, and
heteroaryl substituted from 1 to 4 times by Rd;
R24 is selected from:
hydrogen,
C1-6alkyl,
lkyl,
cycloalkyl substituted from 1 to 4 times by Rd,
heterocycloalkyl,
heterocycloalkyl substituted from 1 to 4 times by Rd,
-C(O)ORa, and
-C(O)NHRa;
R25 is ed from:
amino,
-NHRa,
-NRbRc,
aryl,
aryl substituted from 1 to 4 times by Rd,
-OC1-6alkyl,
-ORe,
-Oaryl,
-Oheteroaryl,
-SH, and
-SRa;
where:
each Ra is independently selected from
C1—6alkyl,
aryl,
aryl substituted from 1 to 4 times by Rd,
heteroaryl,
aryl substituted from 1 to 4 times by Rd
cycloalkyl,
cycloalkyl substituted from 1 to 4 times by Rd,
heterocycloalkyl, and
heterocycloalkyl substituted from 1 to 4 times by Rd;
Rb and R0 are independently selected from:
kyl,
Re,
aryl,
aryl substituted from 1 to 4 times by Rd,
heteroaryl,
heteroaryl substituted from 1 to 4 times by Rd;
cycloalkyl,
cycloalkyl substituted from 1 to 4 times by Rd,
heterocycloalkyl, and
heterocycloalkyl substituted from 1 to 4 times by Rd, or
Rb and RC are taken together with the nitrogen to which they are
attached, and optionally from 1 to 3 additional heteroatoms, to form
a cycloalkyl, which is optionally substituted with from 1 to 5
tuents independently selected from:
fluoro,
chloro,
bromo,
iodo,
aryl substituted from 1 to 4 times by Rd,
cycloalkyl,
cycloalkyl substituted from 1 to 4 times by Rd,
heterocycloalkyl, and
cycloalkyl substituted from 1 to 4 times by Rd,
C1-4alkoxy,
C1-4alkoxy substituted with from 1 to 6 substituents
independently selected from: fluoro, oxo, -OH,
-COOH, -NH2, and —-CN,
-OH,
-N021
-NH2,
-N(H)C1-4alkyl,
-N(H)Re,
-N(C1-4a|ky|)2,
SOzNHz,
SOzCHzCHs, and
SOzCH3;
each Rd is independently selected from:
chloro,
bromo,
iodo,
C1—6alkyl,
heteroaryl,
heteroaryl substituted from 1 to 4 times by RX,
where RX is selected from aryl, heteroaryl, cycloalkyl,
heterocyloalkyl, C1-6alkyl, and C1-6alkyl substituted with
from 1 to 6 substituents independently selected from:
fluoro, oxo, -OH, -COOH, -NH2, and —-CN,
cycloalkyl,
cycloalkyl substituted from 1 to 4 times by RX,
where RX is selected from aryl, heteroaryl, cycloalkyl,
heterocyloalkyl, C1-6alkyl, and C1-6alkyl substituted with
from 1 to 6 substituents independently selected from:
fluoro, 0x0, -OH, -COOH, -NH2, and —-CN,
heterocycloalkyl,
heterocycloalkyl substituted from 1 to 4 times by RX,
where RX is selected from aryl, heteroaryl, cycloalkyl,
heterocyloalkyl, C1-6alky|, and C1-6alkyl substituted with
from 1 to 6 substituents independently selected from:
fluoro, 0x0, -OH, -COOH, -NH2, and —-CN,
aryl,
aryl tuted from 1 to 4 times by RX,
where RX is selected from aryl, heteroaryl, cycloalkyl,
heterocyloalkyl, C1-6alkyl, and C1-6alkyl substituted with
from 1 to 6 substituents independently ed from:
fluoro, 0x0, -OH, -COOH, -NH2, and —-CN,
koxy,
C1-4a|koxy substituted from 1 to 4 times by fluoro,
-Oaryl,
-Oaryl substituted from 1 to 4 times by RX,
where RX is selected from aryl, aryl, cycloalkyl,
heterocyloalkyl, C1-6alkyl, and kyl substituted with
from 1 to 6 tuents independently selected from:
fluoro, 0x0, -OH, -COOH, -NH2, and —-CN,
-C(O)H,
-C(O)aryl,
-C(O)aryl substituted from 1 to 4 times by R22,
-C(O)heteroaryl,
-C(O)heteroaryl substituted from 1 to 4 times by R22,
-OC(O)H,
-CO(O)RZZ,
-OC(O)ary|,
-CO(O)aryl substituted from 1 to 4 times by R22,
-OC(O)heteroaryl,
-OC(O)heteroaryl substituted from 1 to 4 times by R22,
to,
-SRX,
where RX is selected from aryl, heteroaryl, cycloalkyl,
heterocyloalkyl, C1-ealkyl, and kyl substituted with
from 1 to 6 substituents independently selected from:
fluoro, 0x0, -OH, -COOH, -NH2, and —-CN,
-S(O)H,
-S(O)RX,
where RX is selected from aryl, heteroaryl, cycloalkyl,
cyloalkyl, C1-6alkyl, and C1-6alky| substituted with
from 1 to 6 substituents independently selected from:
fluoro, oxo, -OH, -COOH, -NH2, and —-CN,
-S(O)2H,
-S(O)2RX,
where RX is selected from aryl, heteroaryl, cycloalkyl,
heterocyloalkyl, C1-6alkyl, and C1-6alkyl substituted with
from 1 to 6 substituents independently selected from:
, 0x0, -OH, -COOH, -NH2, and —-CN,
NH2,
-S(O)2NHRX,
where RX is selected from aryl, heteroaryl, cycloalkyl,
heterocyloalkyl, C1-6alkyl, and C1-6alkyl substituted with
from 1 to 6 substituents independently selected from:
fluoro, oxo, -OH, -COOH, -NH2, and —-CN,
NRX1RX2,
where RX1 and RX2 are each independently selected from
aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C1-ealkyl, and
C1-ealkyl substituted with from 1 to 6 substituents
independently selected from: fluoro, oxo, -OH, -COOH,
-NH2, and —-CN,
-NHS(O)2H,
-NHS(O)2RX,
where RX is selected from aryl, heteroaryl, cycloalkyl,
heterocyloalkyl, C1-6alkyl, and C1-6alkyl substituted with
from 1 to 6 substituents ndently selected from:
fluoro, oxo, -OH, -COOH, -NH2, and —-CN,
-NHC(O)H,
-NHC(O)RX,
where RX is selected from aryl, heteroaryl, lkyl,
heterocyloalkyl, C1-6alkyl, and C1-6alkyl substituted with
from 1 to 6 substituents independently selected from:
fluoro, 0x0, -OH, -COOH, -NH2, and —-CN,
-C(O)NH2,
-C(O)NHRX,
where RX is selected from aryl, heteroaryl, cycloalkyl,
cyloalkyl, C1-6alky|, and C1-6alkyl substituted with
from 1 to 6 substituents ndently selected from:
fluoro, 0x0, -OH, -COOH, -NH2, and —-CN,
RX1RX2,
where RX1 and RX2 are each independently selected from
aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C1-6a|kyl, and
C1-6alkyl substituted with from 1 to 6 substituents
independently selected from: fluoro, oxo, -OH, -COOH,
-NH2, and —-CN,
-c«DOR{
where RX is selected from aryl, heteroaryl, cycloalkyl,
heterocyloalkyl, C1-6alkyl, and C1-6alkyl substituted with
from 1 to 6 substituents independently ed from:
fluoro, 0x0, -OH, -COOH, -NH2, and —-CN,
oxo,
hydroxy,
amino,
-NHRX,
where RX is selected from aryl, heteroaryl, cycloalkyl,
heterocyloalkyl, C1-6alkyl, and C1-6alkyl substituted with
from 1 to 6 tuents independently selected from:
fluoro, oxo, -OH, -COOH, -NH2, and —-CN,
-NRX1RX2,
where RX1 and RX2 are each independently selected from
aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C1-6alkyl, and
C1-6a|kyl substituted with from 1 to 6 tuents
independently selected from: fluoro, oxo, -OH, -COOH,
-NH2, and —-CN,
nitro,
cyano,
-NHC(O)NH2,
-NHC(O)NHRX,
where RX is selected from aryl, heteroaryl, cycloalkyl,
heterocyloalkyl, C1-6alky|, and kyl substituted with
from 1 to 6 substituents independently selected from:
fluoro, 0x0, -OH, -COOH, -NH2, and —-CN,
-NHC(O)NRX1RX2,
where RX1 and RX2 are each independently selected from
aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C1-6alkyl, and
C1-6alkyl substituted with from 1 to 6 substituents
independently selected from: fluoro, 0x0, -OH, -COOH,
-NH2, and —-CN,
each Re is independently selected from:
C1_6alkyl substituted with from 1 to 9 substitutents independently
selected from:
fluoro,
chloro,
bromo,
iodo,
C1-Balkyl,
-OC1-6a|kyl,
-OC1-6alkyl substituted with from 1 to 6 tuents
independently selected from: fluoro, oxo, -OH,
-COOH, -NH2, and —-CN,
mercapto,
-SRX,
where RX is ed from aryl, heteroaryl,
cycloalkyl, heterocyloalkyl, C1-ealkyl, and C1-6alkyl
substituted with from 1 to 6 substituents
independently selected from: , oxo, -OH,
-COOH, -NH2, and —-CN,
-S(O)H,
-S(0)RX,
where RX is selected from aryl, heteroaryl,
cycloalkyl, heterocyloalkyl, C1-6alkyl, and C1-6alkyl
substituted with from 1 to 6 substituents
independently selected from: fluoro, oxo, -OH,
-COOH, -NH2, and —-CN,
-S(O)2RX,
where RX is selected from aryl, heteroaryl,
cycloalkyl, heterocyloalkyl, C1-6alkyl, and kyl
substituted with from 1 to 6 substituents
independently selected from: fluoro, oxo, -OH,
-COOH, -NH2, and —-CN,
oxo,
hydroxy,
amino,
-NHRXX,
where RXX is selected from aryl, heteroaryl,
cycloalkyl, heterocyloalkyl, C1-ealkyl,
and C1-6alky| substituted with from 1 to 6
substituents independently ed from: fluoro,
oxo, -ORXV, -COOH, —-CN, -OC1-5alkyl, -OC1-5alkyl
substituted from 1 to 6 times by fluoro and
—NRXyRXZ, where ny and R"Z are independently
selected from: hydrogen, aryl, C1-5alkyl and
C1-5a|kyl tuted with from 1 to 4 substituents
independently selected from: fluoro, oxo, -OH,
-OC1-5alkyl, -OC1-5alky| substituted from 1 to 6
times by fluoro and —COOH,
_NRX1RX2’
where RX1 and RX2 are each independently selected
from aryl, heteroaryl, cycloalkyl, heterocyloalkyl,
C1-6alkyl, and C1-6alkyl tuted with from 1 to 6
Substituents independently selected from: fluoro,
oxo, -OH, -COOH, -NH2, and —-CN,
guanidino,
-C(O)OH,
-C(O)ORX,
where RX is selected from aryl, heteroaryl,
cycloalkyl, heterocyloalkyl, C1-6a|kyl, and kyl
substituted with from 1 to 6 substituents
independently selected from: , oxo, -OH,
-COOH, -NH2, and —-CN,
-C(O)NH2,
-C(O)NHRX,
where Rx is selected from aryl, heteroaryl,
cycloalkyl, heterocyloalkyl, C1-6a|kyl, and C1-6alkyl
substituted with from 1 to 6 substituents
independently selected from: , oxo, -OH,
-COOH, -NH2, and —-CN,
-C(O)NRX1RX2,
where RX1 and RX2 are each independently selected
from aryl, heteroaryl, cycloalkyl, heterocyloalkyl,
C1-6alkyl, and C1-6alkyl substituted with from 1 to 6
Substituents independently selected from: fluoro,
oxo, -OH, -COOH, -NH2, and —-CN,
aryl,
aryl substituted from 1 to 4 times by RX,
where RX is selected from aryl, heteroaryl,
cycloalkyl, cyloalkyl, C1-6a|kyl, and C1-6alkyl
substituted with from 1 to 6 substituents
independently selected from: fluoro, 0x0, -OH,
-COOH, -NH2, and —-CN,
-Oaryl,
-Oary| substituted from 1 to 4 times by RX,
where RX is selected from aryl, heteroaryl,
cycloalkyl, heterocyloalkyl, C1-6alkyl, and C1-6alkyl
tuted with from 1 to 6 substituents
independently selected from: fluoro, oxo, -OH,
-COOH, -NH2, and —-CN,
heteroaryl,
aryl substituted from 1 to 4 times by RX,
where RX is selected from aryl, heteroaryl,
cycloalkyl, heterocyloalkyl, C1-ealkyl, and C1-6alkyl
substituted with from 1 to 6 substituents
independently selected from: fluoro, oxo, -OH,
-COOH, -NH2, and —-CN,
-Oheteroaryl,
-Oheteroaryl substituted from 1 to 4 times by RX,
where RX is selected from aryl, heteroaryl,
cycloalkyl, heterocyloalkyl, C1-6alkyl, and C1-6alkyl
substituted with from 1 to 6 substituents
independently ed from: fluoro, oxo, -OH,
-COOH, -NH2, and —-CN,
cycloalkyl,
cycloalkyl substituted from 1 to 4 times by RX,
where RX is selected from aryl, heteroaryl,
cycloalkyl, heterocyloalkyl, C1-6alkyl, and C1-6alkyl
substituted with from 1 to 6 tuents
independently selected from: , 0x0, -OH,
-COOH, -NH2, and —-CN,
cycloalkyl,
heterocycloalkyl substituted from 1 to 4 times by RX,
where RX is selected from aryl, heteroaryl,
cycloalkyl, heterocyloalkyl, C1-6alkyl, and C1-6alkyl
substituted with from 1 to 6 substituents
independently ed from: fluoro, oxo, -OH,
-COOH, -NH2, and —-CN,
-S(O)2NH2,
-S(O)2NHRX,
where RX is selected from aryl, heteroaryl,
lkyl, heterocyloalkyl, C1-ealkyl, and C1-6alkyl
substituted with from 1 to 6 substituents
independently selected from: fluoro, oxo, -OH,
-COOH, -NH2, and —-CN,
-S(O)2NRX1RX2,
where RX1 and RX2 are each independently selected
from aryl, heteroaryl, cycloalkyl, heterocyloalkyl,
C1-6alkyl, and C1-6alkyl substituted with from 1 to 6
Substituents ndently selected from: fluoro,
oxo, -OH, -COOH, -NH2, and —-CN,
-NHS(O)2H,
-NHS(O)2RX,
where RX is selected from aryI, heteroaryl,
cycloalkyl, heterocyloalkyl, C1-6alkyl, and kyl
substituted with from 1 to 6 substituents
independently selected from: fluoro, oxo, -OH,
-COOH, -NH2, and —-CN,
-NHC(O)NHRXp,
where RXp is selected from heteroaryl,
cycloalkyl, cyloalkyl, and C1-6a|ky|
substituted with from 1 to 4 substituents
independently selected from: -COOH, -NH2, and
—-CN,
-NHC(O)NRX3RX4,
where RX3 and RX4 are each ndently selected
from heteroaryl, cycloalkyl, heterocyloalkyl,
and C1-6alkyl substituted with from 1 to 6
Substituents independently selected from:
-COOH, -NH2, and —-CN,
nitro, and
cyano;
each Rf is independently C1-6a|ky| optionally substituted from 1 to 6 times
by Re;
each R9 is ndently aryl optionally substituted from 1 to 5 times by
where RX is independently selected from aryl, heteroaryl,
cycloalkyl, heterocyloalkyl, kyl, and C1-6alkyl
substituted with from 1 to 6 substituents independently
selected from: fluoro, oxo, -OH, -COOH, -NH2, and —-CN,
each Rh is independently aryl optionally substituted from 1 to 5
times by RX,
where RX is independently selected from aryl,
heteroaryl, cycloalkyl, heterocyloalkyl, C1-6alkyl, and
C1-6alkyl substituted with from 1 to 6 substituents
ndently selected from: fluoro, 0x0, -OH, -COOH,
-NH2, and —-CN, and
R2 is selected from
C1 -6alkyl,
Re,
cycloalkyl,
cycloalkyl substituted from 1 to 4 times by Rd,
heterocycloalkyl, and
heterocycloalkyl tuted from 1 to 4 times by Rd;
R22 is selected from
C1_6alkyl, and
provided that:
at least one of R22, R23 and R24, is hydrogen,
R22, R23 and R24 are not all hydrogen, and
X21 and X22 are not both hydrogen;
or a pharmaceutically acceptable salt or prodrug thereof.
Included in the compounds ofthe invention and used in the methods ofthe invention
are nds of Formula (Ill):
X31 X132 32
I JR<R33
R35 N/ Y2 R34 (III)
wherein:
X31 and X32 are independently selected from:
hydrogen,
cyano,
fluoro,
chloro,
bromo,
iodo,
C1-6alkyl,
-OC1-6a|ky|,
cycloalkyl, and
-SH;
Y2 is selected from: 8, NH, NRZ and 8(0);
R31 is selected from:
Ct-6alkyl,
R61,
-OC1-6a|kyl,
-ORe1,
-NHRa1,
_NRb1Rc1,
lkyl,
cycloalkyl substituted from 1 to 4 times by Rd1,
-SH, and
-SRa1;
R32 is selected from:
hydrogen,
C1-6alkyl,
R91,
cycloalkyl,
lkyl substituted from 1 to 4 times by R“,
heterocycloalkyl, and
heterocycloalkyl substituted from 1 to 4 times by Rm;
R33 is selected from:
hydrogen,
aryl!
aryl substituted from 1 to 4 times by Rd1,
heteroaryl, and
heteroaryl substituted from 1 to 4 times by R“;
R34 is selected from:
hydrogen,
C1-6alkyl,
R91,
cycloalkyl,
cycloalkyl substituted from 1 to 4 times by Rd1,
heterocycloalkyl, and
heterocycloalkyl substituted from 1 to 4 times by R“;
R35 is ed from:
amino,
-NHRa1,
_NRb1Rc1
aryl,
aryl tuted from 1 to 4 times by Rd1,
-OC1-68|ky|,
_ORe1
-SH, and
-SRa1;
where:
each R811 is independently selected from
C1—68Ikyl,
R81,
aryl,
heteroaryl,
cycloalkyl, and
heterocycloalkyl;
Rb1 and R01 are independently selected from:
C1—68Ikyl,
Re1,
aryl,
aryl substituted from 1 to 4 times by Rm,
heteroaryl,
heteroaryl substituted from 1 to 4 times by Rm;
cycloalkyl,
cycloalkyl substituted from 1 to 4 times by R“,
heterocycloalkyl, and
heterocycloalkyl substituted from 1 to 4 times by Rd1, or
Rb1 and RC1 are taken er with the en to which they are
attached, and optionally from 1 to 3 additional heteroatoms, to form
a heterocycloalkyl, which is optionally substituted with from 1 to 5
substituents ndently selected from:
fluoro,
chloro,
bromo,
iodo,
C1-6alkyl,
Re11
aryl,
aryl tuted from 1 to 4 times by Rm,
cycloalkyl,
cycloalkyl substituted from 1 to 4 times by RC”,
heterocycloalkyl, and
heterocycloalkyl substituted from 1 to 4 times by R“,
C1-4alkoxy,
C1-4alkoxy substituted with from 1 to 6 substituents
independently selected from: fluoro, oxo, -OH,
-COOH, -NH2, and —-CN,
—-CN,
oxo,
-OH,
-COOH,
-N02,
-NH2,
-N(H)C1-4alkyl,
-N(H)Rel,
-N(Ct-4alky|)2,
SOzNHz,
SOzCHzCHs, and
each Rd1 is ndently selected from:
fluoro,
chloro,
bromo,
iodo,
C1—63Ikyl,
Re1,
heteroaryl,
heteroaryl substituted from 1 to 4 times by Rxa’
where Rxa is selected from aryl, heteroaryl, cycloalkyl,
heterocyloalkyl, C1-6alkyl, and C1-6alkyl substituted
from 1 to 6 times by fluoro,
cycloalkyl,
cycloalkyl substituted from 1 to 4 times by Rxa’
where Rxa is selected from aryl, heteroaryl, cycloalkyl,
heterocyloalkyl, kyl, and C1-6alkyl substituted
from 1 to 6 times by fluoro,
heterocycloalkyl,
heterocycloalkyl substituted from 1 to 4 times by Rxa’
where RXa is selected from aryl, heteroaryl, cycloalkyl,
heterocyloalkyl, C1-6alkyl, and C1-6alkyl tuted
from 1 to 6 times by fluoro,
aryl,
aryl substituted from 1 to 4 times by Rxa’
where RXa is selected from aryl, heteroaryl, cycloalkyl,
heterocyloalkyl, C1-6alkyl, and C1-6alkyl substituted
from 1 to 6 times by fluoro,
C1-4alkoxy,
C1_4alkoxy substituted from 1 to 4 times by fluoro,
-C(O)H,
-C(O)RZZ,
-C(O)ary|,
-C(O)heteroaryl,
-OC(O)H,
-CO(O)RZZ,
-OC(O)ary|,
heteroaryl,
mercapto,
-SRxa,
where Rxa is selected from aryl, aryl, cycloalkyl,
heterocyloalkyl, C1-6alkyl, and C1-6alkyl substituted
from 1 to 6 times by fluoro,
-S(O)H,
-S(O)Rxa,
where Rxa is selected from aryl, heteroaryl, cycloalkyl,
heterocyloalkyl, C1-6alkyl, and C1-6alkyl substituted
from 1 to 6 times by fluoro,
-S(O)2H,
-S(O)2Rxa,
where Rxa is selected from aryl, heteroaryl, cycloalkyl,
heterocyloalkyl, C1-6alkyl, and C1-6alkyl substituted
from 1 to 6 times by ,
-S(O)2NH2,
-S(O)2NHRxa,
where Rxa is selected from aryl, heteroaryl, cycloalkyl,
heterocyloalkyl, C1-6alkyl, and C1-6alkyl substituted
from 1 to 6 times by fluoro,
-NHS(O)2H,
-NHS(O)2Rxa,
where Rxa is selected from aryl, heteroaryl, cycloalkyl,
heterocyloalkyl, C1-Balkyl, and C1-6alkyl substituted
from 1 to 6 times by fluoro,
-NHC(O)H,
)Rxa,
where Rxa is selected from aryl, heteroaryl, cycloalkyl,
heterocyloalkyl, C1-6alkyl, and C1-6alkyl substituted
from 1 to 6 times by fluoro,
-C(O)NH2,
-C(O)NHRxa,
where Rxa is selected from aryl, heteroaryl, cycloalkyl,
heterocyloalkyl, C1-Balkyl, and C1-6alkyl substituted
from 1 to 6 times by fluoro,
-C(O)OH,
-C(O)ORxa,
where Rxa is selected from aryl, heteroaryl, cycloalkyl,
heterocyloalkyl, C1-6alkyl, and C1-6alkyl substituted
from 1 to 6 times by ,
oxo,
hydroxy,
amino,
,
where RXa is selected from aryl, heteroaryl, cycloalkyl,
heterocyloalkyl, C1-6alkyl, and C1-6alky| substituted
from 1 to 6 times by fluoro,
nitro,
cyano,
-NHC(O)NH2, and
)NHRxa,
where Rxa is selected from aryl, heteroaryl, cycloalkyl,
heterocyloalkyl, C1-6alkyl, and kyl tuted
from 1 to 6 times by fluoro;
each Re1 is independently selected from:
C1_6a|ky| substituted with from 1 to 9 substitutents independently
selected from:
fluoro,
chloro,
bromo,
iodo,
C1—6alkyl,
-OC1-6a|kyl,
-OC1-6a|ky| substituted with from 1 to 6 substituents
independently selected from: fluoro, oxo, -OH,
-COOH, -NH2, and —-CN,
mercapto,
_SRxa’
where Rxa is selected from aryl, heteroaryl,
cycloalkyl, heterocyloalkyl, C1-6alkyl, and C1-6alkyl
substituted from 1 to 6 times by fluoro,
-S(O)H,
where Rxa is selected from aryl, heteroaryl,
cycloalkyl, heterocyloalkyl, C1-6alkyl, and C1-6alkyl
substituted from 1 to 6 times by fluoro,
-S(O)2H,
-S(O)2Rxa,
where Rxa is selected from aryl, heteroaryl,
cycloalkyl, heterocyloalkyl, C1-6alkyl, and C1-6alkyl
substituted from 1 to 6 times by fluoro,
oxo,
hydroxy,
amino,
-NHRXX,
where RXX is selected from aryl, heteroaryl,
cycloalkyl, cyloalkyl, C1-ealkyl,
and C1-6alkyl substituted with from 1 to 6
substituents independently selected from: fluoro,
oxo, -ORXV, -COOH, —-CN, -OC1-5alkyl, alkyl
substituted from 1 to 6 times by fluoro and
XZ, where ny and R"Z are independently
selected from: en, aryl, C1-5alky| and
C1-5alkyl substituted with from 1 to 4 substituents
independently selected from: fluoro, oxo, -OH,
-OC1-5alkyl, -OC1-5alkyl substituted from 1 to 6
times by fluoro and —COOH,
-NRX1XRX2X,
where R and Rx2x are each independently
selected from ky|, and C1-4alkyl substituted
with from 1 to 4 substituents independently selected
from: fluoro, 0x0, and —OH,
guanidino,
-C(O)OH,
-C(O)ORxa,
where Rxa is ed from aryl, heteroaryl,
cycloalkyl, heterocyloalkyl, C1-ealkyl, and C1-6alky|
substituted from 1 to 6 times by fluoro,
-C(O)NHRxa,
where Rxa is selected from aryl, heteroaryl,
cycloalkyl, and heterocyloalkyl,
aryl,
aryl substituted from 1 to 4 times by Rxa,
where Rxa is ed from aryl, heteroaryl,
cycloalkyl, heterocyloalkyl, C1-ealkyl, and C1-6alky|
substituted from 1 to 6 times by fluoro,
-Oary|,
-Oary| tuted from 1 to 4 times by Rxa’
where Rxa is selected from aryl, heteroaryl,
cycloalkyl, heterocyloalkyl, C1-Galkyl, and C1-6alkyl
substituted from 1 to 6 times by fluoro,
heteroaryl,
heteroaryl substituted from 1 to 4 times by Rxa’
where Rxa is selected from aryl, heteroaryl,
cycloalkyl, heterocyloalkyl, C1-ealkyl, and C1-6alky|
substituted from 1 to 6 times by fluoro,
-Oheteroaryl,
-Oheteroary| substituted from 1 to 4 times by Rxa,
where Rxa is selected from aryl, heteroaryl,
cycloalkyl, heterocyloalkyl, C1-ealkyl, and C1-6alky|
substituted from 1 to 6 times by fluoro,
cycloalkyl,
cycloalkyl substituted from 1 to 4 times by RX,
where RX is selected from aryl, heteroaryl,
cycloalkyl, cyloalkyl, kyl, and C1-6alky|
substituted with from 1 to 6 substituents
independently selected from: , oxo, -OH,
-COOH, -NH2, and —-CN,
heterocycloalkyl,
WO 16727
heterocycloalkyl substituted from 1 to 4 times by RX,
where RX is ed from aryl, heteroaryl,
cycloalkyl, heterocyloalkyl, kyl, and C1-6alkyl
substituted with from 1 to 6 substituents
independently selected from: fluoro, oxo, -OH,
-COOH, -NH2, and —-CN,
-S(O)2NH2,
-S(O)2NHRX3,
where Rxa is selected from aryl, heteroaryl,
lkyl, heterocyloalkyl, kyl, and C1-6alkyl
substituted from 1 to 6 times by fluoro,
-NHS(O)2H,
-NHS(O)2RX3,
where Rxa is selected from aryl, heteroaryl,
cycloalkyl, heterocyloalkyl, C1-6alkyl, and C1-Galkyl
substituted from 1 to 6 times by fluoro,
-NHC(O)NHRxa,
where RX":l is selected from heteroaryl,
cycloalkyl, and heterocyloalkyl,
nitro, and
cyano;
each Rf is independently kyl optionally substituted from 1 to 6 times
by R61;
each R9 is independently aryl optionally substituted from 1 to 5 times by
where RX is independently selected from aryl, heteroaryl,
cycloalkyl, heterocyloalkyl, C1-6alkyl, and C1-6alkyl
substituted with from 1 to 6 substituents independently
selected from: fluoro, oxo, -OH, -COOH, -NH2, and —-CN,
each Rh is independently heteroaryl optionally substituted from 1 to 5
times by RX,
where RX is independently selected from aryl,
heteroaryl, cycloalkyl, heterocyloalkyl, C1-6alkyl, and
C1-6alkyl substituted with from 1 to 6 substituents
Independently ed from: fluoro, oxo, -OH, -COOH,
-NH2, and —-CN, and
R2 is selected from
C1—6alkyl,
Re1’
cycloalkyl,
cycloalkyl substituted from 1 to 4 times by R‘“,
heterocycloalkyl, and
heterocycloalkyl substituted from 1 to 4 times by R“;
R22 is selected from
ky|, and
Re1.
provided that:
at least one of R32, R33 and R34, is en,
R32, R33 and R34 are not all hydrogen, and
X31 and X32 are not both hydrogen;
or a pharmaceutically acceptable salt or prodrug thereof.
Suitably in the compounds of Formula (Ill), neither X31 nor X32 are hydrogen.
ed in the compounds ofthe invention and used in the methods ofthe invention
are compounds of Formula (IVar):
R41ar
41ar 42ar
R ft m WM
45ar R43ar
R (We r)
wherein:
X418" and X425" are independently selected from: --CN, fluoro, chloro, bromo and
iodo;
Y4“ is selected from: S and NH;
2017/053511
R418" is selected from:
C1-68Ikyl,
C1-6alkyl substituted with from 1 to 9 substituents
independently selected from: fluoro, chloro, bromo,
iodo, 0x0, kyloxy, -OH, -COOH, -NH2
-N(H)C1-4alkyl, -N(C1-4alkyl)2 and —-CN,
C1-4alkyl0xy,
C1-4alkyloxy substituted from 1 to 4 times by fluoro,
-N(H)C1-4a|kyl,
-N(C1-4a|ky|)2,
-SC1-4a|ky|,
aryl,
aryl substituted with from 1 to 4 substituents
independently selected from:
fluoro,
bromo,
iodo,
C1—6alkyl,
C1_6alkyl substituted with from 1 to 9 substituents
independently selected from: fluoro, chloro, bromo,
iodo, 0x0, -OH, -NH2 and —-CN,
C1-4alkoxy,
—-CN,
0x0,
WO 16727
heteroaryl,
heteroaryl substituted with from 1 to 4 substituents
independently selected from:
fluoro,
chloro,
bromo,
iodo,
C1—6alkyl,
C1-6alkyl substituted with from 1 to 9 substituents
independently selected from: fluoro, chloro, bromo,
iodo, oxo, -OH, -NH2 and —-CN,
C1—4alk0xy,
—-CN,
-OH,
-NH2,
cycloalkyl,
cycloalkyl substituted with from 1 to 4 substituents
independently selected from:
fluoro,
bromo,
iodo,
C1-6alkyl,
C1-6alkyl substituted with from 1 to 9 substituents
independently selected from: , chloro, bromo,
iodo, oxo, -OH, -NH2 and —-CN,
C1_4a|koxy,
—-CN,
0X0,
-NH2;
R428" is selected from:
hydrogen,
Ct-ealkyl,
C1-6alkyl substituted with from 1 to 9 substituents
independently selected from: fluoro, chloro, bromo,
iodo, oxo, -OH, -NH2, -N(H)C1-4alkyl, -N(C1—4alky|)2, and —-CN,
heterocycloalkyl, and
heterocycloalkyl substituted with from 1 to 4 substituents independently
ed from:
fluoro,
chloro,
bromo,
iodo,
C1-Balkyl,
C1-ealkyl substituted with from 1 to 9 substituents
independently selected from: fluoro, chloro, bromo,
iodo, 0x0, -OH, -NH2 and —-CN,
-NHC(O)H,
)Rxa1,
where Rxa1 is selected from aryl, heteroaryl,
cycloalkyl, cyloalkyl, C1-ealkyl, and C1-6alkyl
substituted from 1 to 6 times by fluoro,
C1-4alkoxy,
—-CN,
oxo,
-OH,
-N02, and
R438" is selected from:
hydrogen,
C1-6alkyl,
aryl,
aryl substituted with from 1 to 4 substituents independently selected
from:
fluoro,
chloro,
bromo,
iodo,
C1—68Ikyl,
C1-6alkyl substituted with from 1 to 9 tuents
independently selected from: fluoro, chloro, bromo,
iodo, oxo, --CN, -OR49 and 47,
where R46 and R47 are independently
selected from: hydrogen, -S(O)2CH3,
C1-5alkyl and C1-5alkyl substituted with from
1 to 4 substituents independently selected
from: fluoro, oxo, -OH, -OC1-5alkyl,
alkyl substituted from 1 to 6 times by
fluoro, —COOH and 49, where R48
and R49 are independently selected from:
hydrogen, phenyl, C1-5alky| and C1-5alky|
substituted with from 1 to 4 substituents
independently selected from: fluoro, oxo,
-OH, -OC1-5alkyl, -OC1—5alkyl substituted
from 1 to 6 times by fluoro and —COOH,
C1-4alk0xy,
—-CN,
-S(O)2NH2,
-S(O)2NHCH3,
-N02, and
-NH2,
heteroaryl, and
heteroaryl substituted with from 1 to 4 substituents independently selected
from:
fluoro,
bromo,
iodo,
C1-Galkyl,
C1-6alkyl substituted with from 1 to 9 tuents
independently selected from: fluoro, chloro, bromo,
iodo, 0x0, --CN, OR“ and —NR46R47,
where R46 and R47 are independently
ed from: hydrogen, -S(O)ZCH3,
C1-5a|ky| and C1-5alky| substituted with from
1 to 4 substituents independently selected
from: fluoro, 0x0, -OH, -OC1-5a|ky|,
-OC1-5alkyl substituted from 1 to 6 times by
fluoro, -COOH and —NR48R49, where R48
and R49 are independently selected from:
hydrogen, phenyl, C1-5alkyl and C1-5alky|
substituted with from 1 to 4 substituents
ndently selected from: fluoro, oxo,
-OH, -OC1—5a|ky|, -OC1—sa|ky| substituted
2017/053511
from 1 to 6 times by fluoro and —COOH,
C1-4a|koxy,
—-CN,
-S(O)2NH2,
-S(O)2NHCH3,
-N02, and
-NH2; and
R448" and R458" are independently selected from:
hydrogen,
C1-6alkyl,
C1-6alkyl substituted with from 1 to 9 substituents
independently selected from: fluoro, chloro, bromo,
iodo, heterocycloalkyl, C1-4alkoxy, 0x0, -OH, -NH2 and —-CN,
heterocycloalkyl, and
heterocycloalkyl substituted with from 1 to 5 substituents independently
selected from:
fluoro,
chloro,
bromo,
iodo,
kyl,
C1-ealkyl substituted with from 1 to 9 tuents
independently selected from: fluoro, chloro, bromo,
iodo, oxo, -OH, -NH2 and --CN,
aryl,
C1—4alkoxy,
—-CN,
-N021
-NH2, and
SOzNHz, or
R44ar and R45ar are taken together with the nitrogen to which they are
attached, and optionally from 1 to 3 additional atoms, to form
a cycloalkyl, which is optionally substituted with from 1 to 5
substituents independently selected
from:
fluoro,
chloro,
bromo,
iodo,
C1-68Ikyl,
C1-6alkyl substituted with from 1 to 9 tuents
independently selected from: fluoro, chloro, bromo,
iodo, Ct-4alkoxy, 0x0, phenyl, cycloalkyl,
heterocycloalkyl, methylheterocycloalkyl,
-OH, -NH2, -N(H)Ct-4alkyl, -N(C1-4alkyl)2, and
—-CN,
aryll
cycloalkyl,
cycloalkyl,
heterocycloalkyl substituted with from 1 to 9 substituents
independently selected from: C1-6alky|,
-C1-6alkyIOH, fluoro, -C1-6alkleH2,
chloro, bromo, iodo, oxo, -OH, -NH2 and —-CN,
C1-4alk0xy,
C1-4alkoxy tuted with from 1 to 4 substituents
independently selected from: fluoro, oxo, -OH,
-COOH, -NH2, and —-CN,
-N02,
-NH2,
-N(H)C1-4alkyl,
-N(H)C1-6alkyl substituted with from 1 to 9 substituents
independently selected from: fluoro, chloro, bromo,
iodo, C1-4alkoxy, oxo, phenyl, cycloalkyl,
heterocycloalkyl, methylheterocycloalkyl,
-OH, -NH2, -N(H)C1-4alkyl, -N(C1-4alkyl)2, and
—-CN,
-N(C1-4alky|)2,
SOzNHz,
SOzCHzCHs, and
SOzCH3;
provided that:
R42ar and R43ar are not both en;
or a pharmaceutically acceptable salt or prodrug thereof.
ly in the compounds of Formula (lVar) neither R445" nor R458r is hydrogen.
Suitably in the compounds of Formula (lVar) R425" is -C(O)NH2.
Suitably in the nds of Formula (lVar) R435" is aryl substituted with from 1 to
4 substituents independently selected from:
chloro,
bromo,
iodo,
C1—Balkyl,
C1-6alkyl substituted with from 1 to 9 substituents
independently selected from: fluoro, chloro, bromo,
iodo, 0x0, --CN, 012‘” and —NR46R47,
where R46 and R47 are independently
selected from: hydrogen, -S(O)zCH3,
C1-5a|ky| and C1-5a|ky| substituted with from
1 to 4 substituents independently ed
from: fluoro, oxo, -OH, -OC1-5alkyl,
-OC1-sa|ky| substituted from 1 to 6 times by
fluoro, —COOH and —NR48R49, where R48
and R49 are independently selected from:
hydrogen, phenyl, ky| and C1-5alky|
substituted with from 1 to 4 substituents
independently selected from: fluoro, oxo,
-OH, -OC1-5alky|, -OC1-5alkyl substituted
from 1 to 6 times by fluoro and —COOH.
Included in the compounds ofthe invention and used in the methods ofthe invention
are nds of Formula (IV):
41 42
\N N/ Y4/\
R45 R43
(IV)
wherein:
X41 and X42 are independently selected from: --CN, fluoro, chloro, bromo and iodo;
Y4 is selected from: S and NH;
R41 is selected from:
C1-6alkyl tuted with from 1 to 9 substituents
independently selected from: fluoro, chloro, bromo,
iodo, oxo, C1-4alkyloxy, -OH, -COOH, -NH2
-N(H)C1-4alkyl, -N(C1-4alkyl)2 and —-CN,
C1-4alkyloxy,
C1-4a|kyloxy substituted from 1 to 4 times by ,
-N(H)C1-4a|kyl,
-N(C1-4a|ky|)2,
-SC1-4a|ky|,
cycloalkyl,
cycloalkyl tuted with from 1 to 4 substituents
independently selected from:
fluoro,
chloro,
bromo,
iodo,
kyl,
C1_6alkyl substituted with from 1 to 9 substituents
independently selected from: fluoro, chloro, bromo,
iodo, 0x0, -OH, -NH2 and —-CN,
C1—4alk0xy,
—-CN,
-NH2;
R42 is selected from:
hydrogen,
C1-6alkyl,
C1-6alkyl substituted with from 1 to 9 substituents
independently selected from: fluoro, chloro, bromo,
iodo, oxo, -OH, -NH2, -N(H)C1-4a|kyl, -N(C1—4alkyl)2, and --CN,
heterocycloalkyl, and
cycloalkyl substituted with from 1 to 4 substituents independently
selected from:
fluoro,
chloro,
bromo,
iodo,
C1-Balkyl,
C1-6alkyl substituted with from 1 to 9 substituents
independently selected from: fluoro, chloro, bromo,
iodo, oxo, -OH, -NH2 and —-CN,
-NHC(O)H,
-NHC(O)Rxa1,
where Rxa1 is selected from aryl, heteroaryl,
lkyl, heterocyloalkyl, C1-ealkyl, and C1-6alkyl
tuted from 1 to 6 times by fluoro,
C1-4alkoxy,
—-CN,
0x0,
-OH,
-NH2;
R43 is selected from:
hydrogen,
C1-68lkyl,
aryl,
aryl tuted with from 1 to 4 substituents independently ed
from:
fluoro,
chloro,
bromo,
iodo,
C1-6alkyl,
C1-6alkyl substituted with from 1 to 9 substituents
independently selected from: fluoro, chloro, bromo,
iodo, oxo, --CN, -OR49 and —NR46R47,
where R46 and R47 are independently
selected from: hydrogen, -S(O)2CH3,
C1-5alkyl and kyl substituted with from
1 to 4 substituents independently selected
from: fluoro, oxo, -OH, -OC1-5alkyl,
-OC1-5alkyl substituted from 1 to 6 times by
fluoro, -COOH and —NR48R49, where R48
and R49 are independently selected from:
hydrogen, , C1-5alkyl and C1-5alkyl
substituted with from 1 to 4 substituents
independently selected from: fluoro, oxo,
-OH, -OC1-5alkyl, -OC1-5alkyl substituted
from 1 to 6 times by fluoro and —COOH,
C1-4alkoxy,
—-CN,
-S(O)2NH2,
-S(O)2NHCH3,
-N02, and
-NH2,
heteroaryl, and
heteroaryl substituted with from 1 to 4 substituents ndently selected
from:
fluoro,
chloro,
bromo,
iodo,
C1-Galkyl,
kyl substituted with from 1 to 9 substituents
ndently ed from: fluoro, chloro, bromo,
iodo, 0x0, --CN, -OR49 and —NR46R47,
where R46 and R47 are independently
selected from: hydrogen, -S(O)2CH3,
C1-5alky| and C1-5alky| substituted with from
1 to 4 substituents independently selected
from: fluoro, 0x0, -OH, -OC1-5alkyl,
-OC1-5alkyl substituted from 1 to 6 times by
fluoro, -COOH and —NR48R49, where R48
and R49 are independently selected from:
hydrogen, phenyl, C1-5alkyl and C1-5alkyl
substituted with from 1 to 4 substituents
independently selected from: fluoro, oxo,
-OH, -OC1-5alkyl, -OC1—5alkyl substituted
from 1 to 6 times by fluoro and —COOH,
C1-4alk0xy,
—-CN,
-S(O)2NH2,
-S(O)2NHCH3,
-N02, and
-NH2; and
R44 and R45 are independently ed from:
hydrogen,
C1-6alkyl,
C1-6alky| substituted with from 1 to 9 tuents
ndently selected from: fluoro, chloro, bromo,
iodo, heterocycloalkyl, C1-4alkoxy, 0x0, -OH, -NH2 and —-CN,
heterocycloalkyl, and
heterocycloalkyl substituted with from 1 to 5 substituents independently
selected from:
fluoro,
chloro,
bromo,
iodo,
C1-Salkyl,
C1-ealkyl substituted with from 1 to 9 substituents
independently selected from: fluoro, chloro, bromo,
iodo, oxo, -OH, -NH2 and —-CN,
C1-4alkoxy,
—-CN,
-N027
-NH2, and
SOzNHz, or
R44 and R45 are taken together with the nitrogen to which they are
attached, and optionally from 1 to 3 additional heteroatoms, to form
a heterocycloalkyl, which is optionally substituted with from 1 to 5
substituents independently selected
from:
fluoro,
chloro,
bromo,
iodo,
C1-Balkyl,
Ct-Balkyl substituted with from 1 to 9 substituents
independently selected from: fluoro, chloro, bromo,
iodo, koxy, oxo, phenyl, cycloalkyl,
heterocycloalkyl, methylheterocycloalkyl,
-OH, -NH2, 1-4alky|, -N(C1-4a|ky|)2, and
—-CN,
aryl,
cycloalkyl,
cycloalkyl,
heterocycloalkyl substituted with from 1 to 9 substituents
independently selected from: C1-6alky|,
-C1—6alkyIOH, fluoro, -C1—6a|ky|NH2,
chloro, bromo, iodo, oxo, -OH, -NH2 and —-CN,
C1-4a|koxy,
C1-4alkoxy substituted with from 1 to 4 substituents
independently ed from: fluoro, oxo, -OH,
-COOH, -NH2, and —-CN,
-N02,
-NH2,
-N(H)C1-4alkyl,
-N(H)C1-6alkyl substituted with from 1 to 9 substituents
independently selected from: fluoro, chloro, bromo,
iodo, C1-4alkoxy, oxo, phenyl, cycloalkyl,
heterocycloalkyl, methylheterocycloalkyl,
-OH, -NH2, 1-4a|kyl, -N(C1-4alkyl)2, and
—-CN,
-N(C1-4alky|)2,
SOzNHz,
SOzCHzCHs, and
SOzCH3;
provided that:
R42 and R43 are not both hydrogen;
or a pharmaceutically acceptable salt or prodrug thereof.
Suitably in the compounds of Formula (IV) r R44 nor R45 is hydrogen.
This invention relates to novel compounds of Formula ) and to the use of
compounds of Formula (IVaar) in the methods of the invention:
R41aar
44aarXMYYXQaar R42aar
%ng N/ Y4aar/KR43aar
R (IVaar)
wherein:
X4135" and X4235" are independently ed from: --CN, fluoro, chloro, bromo and
iodo;
Y4aar is selected from: S and NH;
R4135" is ed from:
C1-6alkyl,
C1-6alkyl substituted with from 1 to 9 substituents
ndently selected from: fluoro, chloro, bromo,
iodo, oxo, C1-4alkyloxy, -OH, -COOH, -NH2
-N(H)C1-4alkyl, -N(C1-4a|kyl)2 and —-CN,
C1-4alkyloxy,
C1-4alkyloxy substituted from 1 to 4 times by fluoro,
-N(H)C1-4alkyl,
-N(C1-4a|ky|)2,
-SC1-4alky|,
aryl,
aryl substituted with from 1 to 4 substituents
independently selected from:
fluoro,
chloro,
bromo,
iodo,
C1—6alkyl,
C1-6alkyl substituted with from 1 to 9 substituents
independently selected from: fluoro, , bromo,
iodo, 0x0, -OH, -NH2 and —-CN,
koxy,
—-CN,
-OH,
-NH2,
heteroaryl,
heteroaryl substituted with from 1 to 4 substituents
independently selected from:
fluoro,
chloro,
bromo,
iodo,
C1-6alkyl,
C1-6a|kyl substituted with from 1 to 9 substituents
independently selected from: fluoro, chloro, bromo,
iodo, oxo, -OH, -NH2 and —-CN,
C1_4alkoxy,
—-CN,
-NH2,
cycloalkyl,
cycloalkyl substituted with from 1 to 4 substituents
independently ed from:
fluoro,
chloro,
bromo,
iodo,
C1—68lkyl,
C1_6alkyl substituted with from 1 to 9 tuents
independently selected from: fluoro, chloro, bromo,
iodo, oxo, -OH, -NH2 and —-CN,
C1-4a|koxy,
—-CN,
-N02, and
-NH2;
R428m is selected from:
hydrogen,
C1-6alkyl,
C1-6a|ky| substituted with from 1 to 9 substituents
independently selected from: fluoro, chloro, bromo,
iodo, oxo, -OH, -NH2, -N(H)C1-4a|kyl, -N(C1-4alkyl)2, and —-CN,
heterocycloalkyl, and
heterocycloalkyl substituted with from 1 to 4 substituents independently
selected from:
chloro,
bromo,
iodo,
3o C1-68lkyl,
kyl substituted with from 1 to 9 substituents
independently selected from: fluoro, chloro, bromo,
iodo, 0x0, -OH, -NH2 and —-CN,
-NHC(O)H,
-NHC(O)Rxa1,
where Rxa1 is selected from aryl, heteroaryl,
cycloalkyl, heterocyloalkyl, C1-6alkyl, and C1-6alkyl
substituted from 1 to 6 times by fluoro,
C1-4alk0xy,
—-CN,
oxo,
-OH,
-N02, and
-NH2;
R4335" is selected from:
hydrogen,
C1-Galkyl,
aryl,
aryl tuted with from 1 to 4 substituents independently selected
from:
fluoro,
chloro,
bromo,
iodo,
C1-6alkyl,
C1-6alkyl substituted with from 1 to 9 substituents
independently selected from: fluoro, chloro, bromo,
iodo, 0x0, --CN, 012“9 and —NR46R47,
where R46 and R47 are ndently
selected from: hydrogen, -S(O)2CH3,
C1-5alky| and C1-5alkyl substituted with from
1 to 4 substituents independently selected
from: fluoro, oxo, -OH, -OC1-5alkyl,
alkyl substituted from 1 to 6 times by
fluoro, —COOH and 49, where R48
and R49 are independently selected from:
hydrogen, phenyl, kyl and C1-5alkyl
substituted with from 1 to 4 substituents
independently selected from: fluoro, 0x0,
-OH, -OC1-5alkyl, -OC1—5alkyl substituted
from 1 to 6 times by fluoro and —COOH,
C1-4alkoxy,
—-CN,
-OH,
-S(O)2NH2,
-S(O)2NHCH3,
-N02, and
-NH2,
heteroaryl, and
heteroaryl substituted with from 1 to 4 substituents ndently selected
from:
fluoro,
chloro,
bromo,
iodo,
C1-Galkyl,
C1-ealkyl substituted with from 1 to 9 substituents
independently selected from: fluoro, chloro, bromo,
iodo, oxo, --CN, 012” and —NR46R47,
where R46 and R47 are independently
selected from: hydrogen, -S(O)2CH3,
C1-5alkyl and C1-5alkyl substituted with from
1 to 4 substituents independently selected
from: fluoro, oxo, -OH, -OC1-5alkyl,
-OC1-5alkyl substituted from 1 to 6 times by
fluoro, -COOH and —NR48R49, where R48
and R49 are independently ed from:
hydrogen, phenyl, ky| and C1-5alkyl
substituted with from 1 to 4 substituents
independently selected from: fluoro, oxo,
-OH, -OC1-5a|kyl, -OC1-5a|kyl substituted
from 1 to 6 times by fluoro and —COOH,
C1-4alkoxy,
—-CN,
-S(O)2NH2,
-S(O)2NHCH3,
-N02, and
-NH2; and
R44aar and R45aar are independently ed from:
hydrogen,
C1-6alkyl,
kyl substituted with from 1 to 9 substituents
independently selected from: fluoro, chloro, bromo,
iodo, heterocycloalkyl, C1-4alkoxy, oxo, -OH, -NH2 and —-CN,
cycloalkyl, and
heterocycloalkyl substituted with from 1 to 5 substituents independently
selected from:
fluoro,
chloro,
bromo,
iodo,
C1-Balkyl,
C1-6alkyl substituted with from 1 to 9 tuents
ndently selected from: fluoro, , bromo,
iodo, oxo, -OH, -NH2 and —-CN,
aryl,
C1-4alkoxy,
C1-4alkoxy substituted with from 1 to 4 substituents
independently selected from: fluoro, oxo, -OH,
-COOH, -NH2, and —-CN,
-OH,
-N027
-NH2, and
SOzNHz, or
R4438" and R45alalr are taken together with the nitrogen to which they are
attached, and optionally from 1 to 3 additional heteroatoms, to form
a heterocycloalkyl, which is optionally substituted with from 1 to 5
substituents independently selected from:
fluoro,
chloro,
bromo,
iodo,
C1-Balkyl,
C1-6alkyl substituted with from 1 to 9 substituents
independently ed from: fluoro, chloro, bromo,
iodo, C1-4alkoxy, 0x0, phenyl, cycloalkyl,
heterocycloalkyl, methylheterocycloalkyl,
-OH, -NH2, -N(H)C1-4alkyl, -N(C1-4alkyl)2, and
—-CN,
aryl,
cycloalkyl,
heterocycloalkyl,
heterocycloalkyl tuted with from 1 to 9 substituents
independently selected from: C1-6alkyl,
-C1-6a|ky|OH, fluoro, -C1-6alky|NH2,
chloro, bromo, iodo, 0x0, -OH, -NH2 and —-CN,
C1—4alkoxy,
—-CN,
-COOH,
-N021
-NH2,
-N(H)C1-4alkyl,
-N(H)C1-6alkyl substituted with from 1 to 9 substituents
independently selected from: fluoro, chloro, bromo,
iodo, C1-4alkoxy, 0x0, , cycloalkyl,
heterocycloalkyl, heterocycloalkyl,
-OH, -NH2, -N(H)C1-4alkyl, -N(C1-4alkyl)2, and
—-CN,
-N(C1-4alky|)2,
SOzNHz,
SOzCHzCH3, and
provided that:
R4288" and R4333" are not both hydrogen, and
R4485" and R45alalr are not both hydrogen;
or a pharmaceutically acceptable salt or prodrug thereof.
Suitably in the compounds of Formula (lVaar) neither R445lalr nor R45am is en.
Suitably in the compounds of Formula (lVaar) R4Zaalr is -C(O)NH2.
Suitably in the compounds of Formula (lVaar) R43aar is aryl substituted with from 1
to 4 tuents independently selected from:
fluoro,
chloro,
bromo,
iodo,
C1-6alkyl,
C1-6alkyl substituted with from 1 to 9 substituents
independently selected from: fluoro, chloro, bromo,
iodo, oxo, --CN, -0R49 and 47,
where R46 and R47 are independently
ed from: hydrogen, -S(O)2CH3,
ky| and C1-5alkyl substituted with from
1 to 4 substituents independently selected
from: fluoro, oxo, -OH, -OC1-5alky|,
-OC1-5alkyl substituted from 1 to 6 times by
fluoro, -COOH and —NR48R49, where R48
and R49 are independently ed from:
hydrogen, phenyl, C1-5alky| and C1-5alky|
tuted with from 1 to 4 substituents
independently selected from: fluoro, oxo,
-OH, -OC1-5alkyI, -OC1-5alkyl substituted
from 1 to 6 times by fluoro and —COOH.
This invention relates to novel compounds of Formula (Na) and to the use of
compounds of Formula (Na) in the methods of the invention:
R413
41a 42a
R4ia /
,N N Y4a/k
45a R
R (lVa)
wherein:
X413 and X423 are independently selected from: --CN, , chloro, bromo and
iodo;
Y4a is selected from: S and NH;
R413 is selected from:
C1-Salkyl,
C1-6alkyl substituted with from 1 to 9 tuents
independently selected from: fluoro, chloro, bromo,
iodo, oxo, C1-4alkyloxy, -OH, -COOH, -NH2
-N(H)C1-4alkyl, -N(C1-4alkyl)2 and —-CN,
C1-4alkyloxy,
C1-4alkyloxy substituted from 1 to 4 times by fluoro,
WO 16727
-N(H)C1-4a|kyl,
4alky|)2,
-SC1-4a|ky|,
cycloalkyl,
cycloalkyl substituted with from 1 to 4 substituents
independently selected from:
fluoro,
chloro,
bromo,
iodo,
C1—6alkyl,
C1_6alkyl substituted with from 1 to 9 substituents
independently selected from: , chloro, bromo,
iodo, 0x0, -OH, -NH2 and —-CN,
C1-4alkoxy,
—-CN,
-NH2;
R423 is selected from:
hydrogen,
C1-6alkyl,
C1-6alky| tuted with from 1 to 9 substituents
independently selected from: fluoro, chloro, bromo,
iodo, oxo, -OH, -NH2, -N(H)C1-4alkyl, -N(C1—4alky|)2, and —-CN,
heterocycloalkyl, and
heterocycloalkyl substituted with from 1 to 4 substituents independently
selected from:
fluoro,
chloro,
bromo,
iodo,
C1—Balkyl,
C1-6alkyl substituted with from 1 to 9 substituents
ndently selected from: fluoro, chloro, bromo,
iodo, 0x0, -OH, -NH2 and —-CN,
-NHC(O)H,
-NHC(O)Rxa1,
where Rxa1 is selected from aryl, heteroaryl,
cycloalkyl, heterocyloalkyl, C1-6alkyl, and C1-6alkyl
substituted from 1 to 6 times by fluoro,
C1-4alkoxy,
—-CN,
is selected from:
hydrogen,
C1-6alkyl,
aryl,
aryl substituted with from 1 to 4 substituents independently selected
from:
fluoro,
bromo,
iodo,
C1—68Ikyl,
C1-6alkyl substituted with from 1 to 9 substituents
independently selected from: fluoro, chloro, bromo,
iodo, 0x0, --CN, 012‘” and —NR46R47,
where R46 and R47 are independently
selected from: hydrogen, -S(O)zCH3,
C1-5a|ky| and C1-5a|ky| substituted with from
1 to 4 substituents independently ed
from: fluoro, 0x0, -OH, -OC1-5alkyl,
-OC1-5a|kyl substituted from 1 to 6 times by
fluoro, —COOH and —NR48R49, where R48
and R49 are ndently selected from:
hydrogen, phenyl, C1-5alky| and C1-5alky|
substituted with from 1 to 4 substituents
independently selected from: fluoro, oxo,
-OH, -OC1-5alkyl, -OC1—5alkyl substituted
from 1 to 6 times by fluoro and —COOH,
C1-4alk0xy,
—-CN,
-S(O)2NH2,
NHCH3,
-N02, and
-NH2,
heteroaryl, and
heteroaryl substituted with from 1 to 4 substituents ndently selected
from:
fluoro,
chloro,
bromo,
iodo,
C1-Balkyl,
C1-6alkyl substituted with from 1 to 9 substituents
independently selected from: fluoro, chloro, bromo,
iodo, oxo, --CN, 012” and —NR46R47,
where R46 and R47 are independently
selected from: hydrogen, -S(O)2CH3,
C1-5alky| and C1-5alky| substituted with from
1 to 4 substituents independently selected
from: fluoro, oxo, -OH, -OC1-5alkyl,
-OC1-5a|kyl substituted from 1 to 6 times by
fluoro, -COOH and 49, where R48
and R49 are independently selected from:
hydrogen, phenyl, C1-5alkyl and kyl
tuted with from 1 to 4 substituents
independently selected from: fluoro, oxo,
-OH, -OC1-5alkyl, -OC1—5alkyl substituted
from 1 to 6 times by fluoro and —COOH,
C1-4alkoxy,
—-CN,
-S(O)2NH2,
-S(O)2NHCH3,
-N02, and
-NH2; and
R446‘ and R453 are ndently selected from:
hydrogen,
WO 16727
C1-6alkyl,
C1-6a|ky| substituted with from 1 to 9 substituents
independently selected from: fluoro, chloro, bromo,
iodo, heterocycloalkyl, C1-4alkoxy, oxo, -OH, -NH2 and —-CN,
heterocycloalkyl, ancl
heterocycloalkyl substituted with from 1 to 5 substituents independently
selected from:
fluoro,
chloro,
bromo,
iodo,
C1-68Ikyl,
C1-6alkyl substituted with from 1 to 9 substituents
independently ed from: fluoro, chloro, bromo,
iodo, 0x0, -OH, -NH2 and —-CN,
aryl,
koxy,
C1-4alkoxy substituted with from 1 to 4 substituents
independently selected from: fluoro, oxo, -OH,
-COOH, -NH2, and —-CN,
-N021
-NH2, and
SOzNHz, or
R446‘ and R458‘ are taken together with the nitrogen to which they are
attached, and optionally from 1 to 3 additional atoms, to form
a heterocycloalkyl, which is optionally substituted with from 1 to 5
substituents independently selected from:
fluoro,
chloro,
bromo,
iodo,
kyl,
C1-ealkyl substituted with from 1 to 9 substituents
independently selected from: fluoro, chloro, bromo,
iodo, koxy, oxo, phenyl, cycloalkyl,
heterocycloalkyl, methylheterocycloalkyl,
-OH, -NH2, 1-4alkyl, -N(C1-4alkyl)2, and
—-CN,
aryl,
cycloalkyl,
heterocycloalkyl,
heterocycloalkyl substituted with from 1 to 9 substituents
independently selected from: C1-6alkyl,
-C1-6a|kleH, fluoro, -C1-6alkleH2,
chloro, bromo, iodo, oxo, -OH, -NH2 and —-CN,
C1-4alkoxy,
—-CN,
-N02,
-NH2,
-N(H)C1-4alkyl,
-N(H)C1-6alkyl substituted with from 1 to 9 substituents
independently selected from: fluoro, , bromo,
iodo, C1-4alkoxy, oxo, phenyl, cycloalkyl,
heterocycloalkyl, methylheterocycloalkyl,
-OH, -NH2, -N(H)C1-4a|kyl, -N(C1-4alkyl)2, and
—-CN,
4alkyl)2,
SOzNHz,
SOzCHzCHs, and
SOzCH3;
provided that:
R428‘ and R438‘ are not both hydrogen, and
R448‘ and R458‘ are not both hydrogen;
or a ceutically acceptable salt or prodrug thereof.
ly in the compounds of Formula (lVa) neither R44a nor R45a is hydrogen.
Included in the compounds ofthe invention and used in the methods ofthe invention
are compounds of Formula (V):
51 52
R54 (V)
wherein:
X51 and X52 are independently selected from: --CN, fluoro and chloro;
Y5 is selected from: S and NH;
R50 is selected from:
Cl-Galkyl,
C1-6alkyl substituted with from 1 to 9 substituents
independently ed from: fluoro and chloro,
-N(H)C1-4alkyl,
4alkyl)2,
-SC1-4a|kyl,
C1-4alkyloxy,
cycloalkyl,
cycloalkyl substituted with from 1 to 5 substituents
independently selected from:
fluoro,
chloro,
-OH,
C1-6alkyl, and
C1-6a|ky| substituted with from 1 to 9 substituents
independently selected from: fluoro and chloro;
R51 is selected from:
hydrogen,
C1-6alkyl,
-C(O)NHR55, where R55 is selected from: hydrogen, C1-6alky|, kyl
substituted with from 1 to 9 substituents independently selected
from: fluoro and ,
heterocycloalkyl, and
heterocycloalkyl substituted with from 1 to 4 substituents independently
selected from:
fluoro,
chloro,
C1—Balkyl,
kyl substituted with from 1 to 6 substituents
independently selected from: fluoro, chloro, bromo,
oxo, -OH, -NH2 and —-CN,
-NHC(O)H,
-NHC(O)RX32,
where R”2 is selected from aryl, heteroaryl,
cycloalkyl, heterocyloalkyl, C1-6alkyl, and C1-6alkyl
substituted from 1 to 6 times by fluoro,
C1-4alk0xy,
—-CN,
oxo,
-OH, and
-NH2;
R52 is selected from:
hydrogen,
C1—Galkyl,
aryl,
aryl substituted with from 1 to 4 substituents independently selected
from:
fluoro,
chloro,
C1-68Ikyl,
C1-6alkyl substituted with from 1 to 9 substituents
independently selected from: fluoro, chloro, bromo,
iodo, 0x0, --CN, -OR59 and —NR56R57,
where R56 and R57 are independently
selected from: hydrogen, -S(O)2CH3,
kyl and kyl tuted with from
1 to 4 substituents independently selected
from: fluoro, oxo, -OH, -OC1-5alkyl,
-OC1-5alkyl substituted from 1 to 6 times by
fluoro, —COOH and —NR58R59, where R58
and R59 are independently selected from:
hydrogen, phenyl, C1-5alkyl and C1-5alkyl
substituted with from 1 to 4 substituents
independently selected from: fluoro, 0x0,
-OH, -OC1-5a|kyl, -OC1-sa|kyl substituted
from 1 to 6 times by fluoro and —COOH,
0x0,
--CN,
-S(O)2NH2,
-S(O)2NHCH3,
-OH;
heteroaryl, and
heteroaryl tuted with from 1 to 4 substituents independently selected
from:
fluoro,
chloro,
C1-68Ikyl,
C1-ealkyl tuted with from 1 to 9 substituents
independently ed from: fluoro, chloro, bromo,
iodo, 0x0, --CN, -OR59 and —NR56R57,
where R56 and R57 are independently
selected from: hydrogen, -S(O)2CH3,
C1-5alkyl and C1-5alkyl substituted with from
1 to 4 substituents independently selected
from: fluoro, oxo, -OH, -OC1-5alkyl,
-OC1-5alkyl substituted from 1 to 6 times by
fluoro, —COOH and 59, where R58
and R59 are independently selected from:
hydrogen, phenyl, C1-5alkyl and C1-5alkyl
substituted with from 1 to 4 substituents
ndently selected from: fluoro, oxo,
-OH, -OC1-5alkyl, -OC1-5a|kyl substituted
from 1 to 6 times by fluoro and —COOH,
oxo,
-S(O)2NH2,
NHCH3,
-OH; and
R53 and R54 are independently selected from:
hydrogen,
Ct-6alkyl,
C1-6alkyl substituted with from 1 to 6 substituents
independently selected from: fluoro, chloro, oxo,
heterocycloalkyl, C1-4alkoxy, -OH and -NH2,
heterocycloalkyl, and
heterocycloalkyl substituted with from 1 to 5 substituents independently
selected from:
fluoro,
chloro,
C1-Galkyl,
C1-6alkyl substituted with from 1 to 9 substituents
independently selected from: fluoro and chloro,
C1-4alkoxy, and
-OH, or
R53 and R54 are taken together with the nitrogen to which they are
attached, and optionally from 1 to 3 onal heteroatoms, to form
a cycloalkyl, which is optionally substituted with from 1 to 5
substituents ndently selected from:
fluoro,
chloro,
C1-Balkyl,
kyl substituted with from 1 to 9 substituents
independently selected from: fluoro, chloro,
C1-4alkoxy, 0x0, phenyl, lkyl,
heterocycloalkyl, methylheterocycloalkyl,
-OH, -NH2, -N(H)C1-4alkyl, -N(C1-4alkyl)2, and
—-CN,
heterocycloalkyl,
heterocycloalkyl tuted with from 1 to 9 substituents
independently selected from: C1-6alkyl,
-C1-6a|ky|OH, fluoro, -C1-6a|ky|NH2,
chloro, 0x0 and -OH,
C1-4alkoxy,
C1-4a|koxy substituted with from 1 to 4 substituents
independently selected from: fluoro, oxo, -OH,
-COOH, -NH2, and —-CN,
-OH,
-NH2,
1-4alky|,
-N(H)C1-6alkyl substituted with from 1 to 9 substituents
independently selected from: fluoro, chloro,
C1-4alkoxy, 0x0, phenyl, cycloalkyl,
heterocycloalkyl, methylheterocycloalkyl,
-OH, -NH2, -N(H)C1-4alkyl, -N(C1-4alkyl)2, and
—-CN, and
-N(C1-4alkyl)2;
provided that:
R51 and R52 are not both hydrogen;
or a pharmaceutically acceptable salt or prodrug thereof.
Suitably in the compounds of Formula (V) neither R53 nor R54 is hydrogen.
This invention relates to novel compounds of Formula (Vaar) and to the use of
compounds of a (Vaar) in the methods ofthe invention:
R50aar
R5311]XMYistaar R51aarN/ Y5aar/KR52aar
R54aar (Vaar)
wherein:
X5185" and X5285" are ndently selected from: --CN, fluoro and chloro;
Y5aar is selected from: S and NH;
R5035" is selected from:
C1-6alkyl,
C1-6alkyl substituted with from 1 to 9 substituents
independently selected from: fluoro and ,
-N(H)C1-4a|kyl,
4a|ky|)2,
-SC1-4a|ky|,
C1-4alkyloxy,
aryli
alkyl substituted with from one to five substituents
independently selected from:
chloro,
-OH,
kyl, and
C1_6alkyl substituted with from 1 to 9 substituents
independently selected from: fluoro and chloro,
heteroaryl,
alkyl tuted with from one to five substituents
independently selected from:
fluoro,
chloro,
-OH,
C1-6alkyl, and
C1-6alky| substituted with from 1 to 9 substituents
independently selected from: fluoro and chloro,
cycloalkyl,
cycloalkyl substituted with from one to five substituents
independently selected from:
fluoro,
chloro,
-OH,
C1_6alkyl, and
C1-6alkyl substituted with from 1 to 9 substituents
independently selected from: fluoro and chloro;
R5135" is selected from:
hydrogen,
C1-6alkyl,
-C(O)NHR55, where R55 is selected from: hydrogen, C1-6a|kyl, C1-6alky|
substituted with from 1 to 9 substituents independently selected
from: fluoro and chloro,
heterocycloalkyl, and
heterocycloalkyl substituted with from 1 to 4 substituents ndently
selected from:
fluoro,
chloro,
C1-Galkyl,
C1_6alkyl substituted with from 1 to 6 substituents
independently selected from: fluoro, chloro, bromo,
oxo, -OH, -NH2 and —-CN,
-NHC(O)H,
-NHC(O)RX82,
where Rva is ed from aryl, heteroaryl,
cycloalkyl, heterocyloalkyl, C1-6a|kyl, and ky|
substituted from 1 to 6 times by fluoro,
C1-4alkoxy,
—-CN,
oxo,
-OH, and
-NH2;
R52aar is selected from:
hydrogen,
C1-6alkyl,
aryl,
aryl substituted with from 1 to 4 substituents independently selected
from:
fluoro,
,
C1-Balkyl,
C1-6alkyl substituted with from 1 to 9 substituents
independently selected from: fluoro, chloro, bromo,
iodo, 0x0, --CN, -OR59 and —NR56R57,
where R56 and R57 are independently
ed from: hydrogen, -S(O)2CH3,
ky| and C1-5alky| substituted with from
1 to 4 substituents independently selected
from: fluoro, oxo, -OH, -OC1-5alkyl,
-OC1-5a|kyl substituted from 1 to 6 times by
fluoro, —COOH and —NR58R59, where R58
and R59 are independently selected from:
hydrogen, phenyl, C1-5alkyl and C1-5alkyl
substituted with from 1 to 4 substituents
independently selected from: fluoro, 0x0,
-OH, 3|kyl, -OC‘| -5alkyl substituted
from 1 to 6 times by fluoro and —COOH,
oxo,
--CN,
NH2,
NHCH3,
-OH,
heteroaryl, and
heteroaryl substituted with from 1 to 4 substituents independently selected
from:
fluoro,
chloro,
C1-Balkyl,
C1-6alkyl substituted with from 1 to 9 substituents
independently selected from: fluoro, chloro, bromo,
2017/053511
iodo, oxo, --CN, 012‘” and —NR56R57,
where R56 and R57 are independently
selected from: hydrogen, -S(O)2CH3,
C1-5a|ky| and C1-5a|ky| substituted with from
1 to 4 substituents independently selected
from: , oxo, -OH, -OC1-5alkyl,
-OC1-5a|ky| tuted from 1 to 6 times by
fluoro, —COOH and —NR58R59, where R58
and R59 are independently selected from:
hydrogen, phenyl, C1-5alky| and C1-5alky|
substituted with from 1 to 4 substituents
independently selected from: fluoro, oxo,
-OH, -OC1-5a|kyl, -OCt-5a|ky| substituted
from 1 to 6 times by fluoro and —COOH,
0x0,
-S(O)2NH2,
-S(O)2NHCH3,
-OH; and
R5335" and R5433" are independently selected from:
hydrogen,
C1-6alkyl,
C1-6a|ky| substituted with from 1 to 6 substituents
independently ed from: fluoro, chloro, oxo,
heterocycloalkyl, C1 xy, -OH and -NH2,
heterocycloalkyl, and
heterocycloalkyl substituted with from 1 to 5 substituents independently
selected from:
fluoro,
chloro,
C1-Balkyl,
C1-6a|ky| substituted with from 1 to 9 substituents
independently selected from: fluoro and chloro,
koxy, and
-OH, or
R53aar and R54alalr are taken together with the nitrogen to which they are
attached, and optionally from 1 to 3 additional atoms, to form
a heterocycloalkyl, which is optionally tuted with from 1 to 5
substituents independently selected from:
fluoro,
chloro,
C1-Balkyl,
C1-6alkyl substituted with from 1 to 9 substituents
independently selected from: fluoro, chloro,
C1-4alkoxy, oxo, phenyl, cycloalkyl,
heterocycloalkyl, methylheterocycloalkyl,
-OH, -NH2, -N(H)C1-4alkyl, -N(C1-4alkyl)2, and
--CN,
heterocycloalkyl,
heterocycloalkyl tuted with from 1 to 9 substituents
independently selected from: C1-6alkyl,
-C1-6a|kyIOH, fluoro, -C1-6a|ky|NH2,
chloro, 0x0 and -OH,
C1-4alkoxy,
koxy substituted with from 1 to 4 substituents
independently selected from: fluoro, oxo, -OH,
-COOH, -NH2, and —-CN,
—-CN,
0X0,
-NH2,
-N(H)C1-4alkyl,
-N(H)C1-6alkyl substituted with from 1 to 9 substituents
independently selected from: fluoro, chloro,
C1-4alkoxy, oxo, phenyl, lkyl,
heterocycloalkyl, methylheterocycloalkyl,
-OH, -NH2, 1-4alkyl, -N(C1-4alkyl)2, and
—-CN, and
-N(C1-4alky|)2;
ed that:
R5138" and R5zalalr are not both hydrogen, and
R5335" and R5435" are not both hydrogen;
or a ceutically acceptable salt or prodrug thereof.
Suitably in the compounds of Formula (Vaar) neither R5335" nor R5433" is en.
Suitably in the compounds of Formula (Vaar) R5138" is -C(O)NH2.
Suitably in the compounds of Formula (Vaar) R5zalalr is aryl substituted with from 1
to 4 substituents independently selected from:
fluoro,
chloro,
C1-68Ikyl,
C1-6a|kyl substituted with from 1 to 9 substituents
independently selected from: fluoro, chloro, bromo,
iodo, oxo, --CN, -OR59 and —NR56R57,
where R56 and R57 are independently
selected from: hydrogen, -S(O)2CH3,
C1-5alky| and C1-5a|ky| substituted with from
1 to 4 substituents independently selected
from: fluoro, oxo, -OH, -OC1-5alkyl,
-OC1-5alkyl substituted from 1 to 6 times by
fluoro, —COOH and —NR58R59, where R58
and R59 are independently selected from:
hydrogen, phenyl, C1-5alkyl and C1-5alkyl
substituted with from 1 to 4 substituents
independently selected from: fluoro, oxo,
-OH, a|kyl, -OC1—5alkyl substituted
from 1 to 6 times by fluoro and —COOH.
This invention relates to novel nds of Formula (Va) and to the use of
compounds of Formula (Va) in the methods of the invention:
R503
R53“!Xsfj:X52aR51a
N/ Y5a’KR52a
[L54a (Va)
X518 and X5281 are independently selected from: --CN, fluoro and chloro;
Y5a is selected from: S and NH;
R503 is selected from:
kyl,
C1-6alky| substituted with from 1 to 9 substituents
independently selected from: fluoro and chloro,
-N(H)C1-4a|kyl,
-N(C1-4a|ky|)2,
-SC1-4alkyl,
C1 -4alkyloxy,
cycloalkyl,
cycloalkyl substituted with from one to five substituents
ndently selected from:
fluoro,
chloro,
-OH,
kyl, and
C1-6alkyl substituted with from 1 to 9 substituents
independently selected from: fluoro and chloro;
R513 is selected from:
hydrogen,
C1-6alkyl,
-C(O)NHR55, where R55 is selected from: hydrogen, kyl, C1-6alky|
substituted with from 1 to 9 tuents independently selected
from: fluoro and chloro,
heterocycloalkyl, and
heterocycloalkyl tuted with from 1 to 4 substituents independently
selected from:
fluoro,
chloro,
C1-Galkyl,
C1_6alkyl substituted with from 1 to 6 substituents
independently selected from: fluoro, chloro, bromo,
oxo, -OH, -NH2 and —-CN,
-NHC(O)H,
-NHC(O)RX32,
where Rva is selected from aryl, heteroaryl,
cycloalkyl, cyloalkyl, C1-6alkyl, and C1-6alkyl
substituted from 1 to 6 times by fluoro,
C1-4a|koxy,
—-CN,
oxo,
-OH, and
-NH2;
R523 is selected from:
hydrogen,
C1—Galkyl,
aryl,
aryl substituted with from 1 to 4 substituents independently selected
from:
fluoro,
chloro,
C1-6alkyl,
C1-6alkyl substituted with from 1 to 9 substituents
independently selected from: fluoro, chloro, bromo,
iodo, 0x0, --CN, -OR59 and —NR56R57,
where R56 and R57 are independently
ed from: hydrogen, -S(O)2CH3,
C1-5alky| and C1-5a|kyl substituted with from
1 to 4 substituents independently ed
from: fluoro, oxo, -OH, -OC1-5alkyl,
-OC1-5a|kyl substituted from 1 to 6 times by
fluoro, —COOH and —NR58R59, where R58
and R59 are independently selected from:
hydrogen, phenyl, C1-5alkyl and C1-5alkyl
tuted with from 1 to 4 tuents
independently selected from: fluoro, oxo,
-OH, -OC1-5alkyl, -OC1-sa|kyl substituted
from 1 to 6 times by fluoro and —COOH,
oxo,
--CN,
-S(O)2NH2,
-S(O)2NHCH3,
-OH,
heteroaryl, and
heteroaryl substituted with from 1 to 4 substituents independently selected
from:
fluoro,
,
C1-Galkyl,
C1-6alkyl substituted with from 1 to 9 substituents
independently selected from: fluoro, , bromo,
iodo, 0x0, --CN, -0R59 and —NR56R57,
where R56 and R57 are independently
selected from: hydrogen, -S(O)2CH3,
C1-5alky| and C1-5alky| substituted with from
1 to 4 substituents independently ed
from: fluoro, oxo, -OH, -OC1-5a|kyl,
-OC1-5alkyl substituted from 1 to 6 times by
fluoro, —COOH and —NR58R59, where R58
and R59 are independently selected from:
hydrogen, phenyl, C1-5alkyl and C1-5alkyl
substituted with from 1 to 4 substituents
independently selected from: fluoro, oxo,
-OH, -OC1-5alkyl, -OC1-5alkyl substituted
from 1 to 6 times by fluoro and —COOH,
0x0,
-S(O)2NH2,
-S(O)2NHCH3,
-OH; and
R538‘ and R543 are ndently selected from:
hydrogen,
C1-6alkyl,
C1-6alkyl substituted with from 1 to 6 substituents
ndently selected from: fluoro, chloro, oxo,
heterocycloalkyl, C1-4alkoxy, -OH and -NH2,
heterocycloalkyl, and
heterocycloalkyl substituted with from 1 to 5 substituents independently
selected from:
fluoro,
chloro,
C1-Galkyl,
kyl substituted with from 1 to 9 tuents
independently selected from: fluoro and chloro,
C1-4alkoxy, and
-OH, or
R538 and R548 are taken together with the nitrogen to which they are
attached, and optionally from 1 to 3 additional heteroatoms, to form
a heterocycloalkyl, which is optionally substituted with from 1 to 5
substituents independently selected from:
chloro,
3o C1-6alkyl.
C1-6alkyl substituted with from 1 to 9 substituents
independently ed from: fluoro, chloro,
C1-4alkoxy, 0x0, phenyl, cycloalkyl,
heterocycloalkyl, methylheterocycloalkyl,
-OH, -NH2, -N(H)C1-4alkyl, -N(C1-4alkyl)2, and
—-CN,
heterocycloalkyl,
cycloalkyl substituted with from 1 to 9 substituents
independently selected from: C1-6alkyl,
-C1-6alkyIOH, fluoro, -C1-6alkleH2,
chloro, 0x0 and -OH,
C1—4alkoxy,
C1-4alkoxy substituted with from 1 to 4 tuents
independently selected from: fluoro, oxo, -OH,
-COOH, -NH2, and —-CN,
-NH2,
-N(H)C1-4alky|,
-N(H)C1-6alkyl substituted with from 1 to 9 substituents
independently selected from: fluoro, chloro,
C1-4alkoxy, 0x0, phenyl, lkyl,
heterocycloalkyl, methylheterocycloalkyl,
-OH, -NH2, -N(H)C1-4alkyl, -N(C1-4alkyl)2, and
—-CN, and
-N(C1-4a|ky|)2;
provided that:
R513 and R523 are not both hydrogen, and
R538‘ and R548‘ are not both hydrogen;
or a pharmaceutically acceptable salt or prodrug thereof.
Suitably in the compounds of Formula (Va) neither R538 nor R543 is hydrogen.
Included in the compounds ofthe invention and used in the methods ofthe invention
are compounds of Formula (VI):
N~tcfic’//N
R64 (VI)
wherein:
Y6 is selected from: S and NH;
R60 is selected from:
kyl,
kyl substituted with from 1 to 6 substituents
independently selected from: fluoro and chloro,
-N(H)C1-3a|kyl,
-N(C1-3a|ky|)2,
-SC1-4a|ky|,
C1-3alkyloxy,
cycloalkyl,
cycloalkyl substituted with from one to 3 substituents
independently selected from:
fluoro,
chloro,
-OH, and
C1-3alkyl;
R61 is selected from:
hydrogen,
-C(O)NH2,
heterocycloalkyl, and
heterocycloalkyl substituted with from 1 to 4 substituents independently
selected from:
oxo,
C1-4alkyl substituted with from 1 to 4 tuents
independently selected from: fluoro, 0x0, and -NH2,
-NHC(O)H, and
-NHC(O)Rxa3,
where Rxal3 is selected from C1-6alky|, and C1-6a|kyl
substituted from 1 to 6 times by fluoro;
R62 is selected from:
en,
C1-Salkyl,
aryl,
aryl substituted with from 1 to 4 tuents independently selected
from:
fluoro,
chloro,
C1-Balkyl,
C1-6alkyl substituted with from 1 to 5 tuents
independently selected from: fluoro, chloro, bromo,
3o iodo, 0x0, --CN, -OR69 and —NR66R67,
where R66 and R67 are independently
selected from: hydrogen, -S(O)2CH3,
C1-5alky| and C1-5a|ky| substituted with from
1 to 4 substituents independently selected
from: fluoro, oxo, -OH, alkyl,
-OC1-5alkyl substituted from 1 to 6 times by
fluoro, —COOH and —NR68R69, where R68
and R69 are independently selected from:
hydrogen, phenyl, C1-5alkyl and C1-5alkyl
substituted with from 1 to 4 substituents
ndently selected from: fluoro, oxo,
-OH, -OC1-5a|kyl, -OC1—5alkyl substituted
from 1 to 6 times by fluoro and —COOH,
--CN,
-S(O)2NH2, and
NHCH3,
hetroaryl, and
hetroaryl substituted with from 1 to 4 substituents independently selected
from:
fluoro,
chloro,
C1-6alkyl,
C1-6alkyl substituted with from 1 to 5 substituents
independently selected from: fluoro, chloro, bromo,
iodo, oxo, --CN, -OR69 and —NR66R67,
where R66 and R67 are ndently
selected from: hydrogen, -S(O)2CH3,
C1-5alkyl and C1-5alkyl substituted with from
1 to 4 substituents independently selected
from: fluoro, oxo, -OH, alkyl,
-OC1-5a|ky| substituted from 1 to 6 times by
fluoro, —COOH and —NR58R69, where R68
and R69 are independently selected from:
hydrogen, phenyl, C1-5alkyl and C1-5alkyl
substituted with from 1 to 4 substituents
ndently selected from: fluoro, oxo,
-OH, -OC1-5alkyl, -OC1—5alkyl substituted
from 1 to 6 times by fluoro and —COOH,
NH2, and
-S(O)2NHCH3; and
R63 and R64 are independently selected from:
hydrogen,
C1-4alkyl,
C1-4alkyl substituted with from 1 to 6 substituents
independently selected from: fluoro, heterocycloalkyl,
oxo, -NH2, C1-4alkoxy, and -OH,
heterocycloalkyl, and
heterocycloalkyl substituted with from 1 to 5 substituents independently
selected from:
fluoro,
chloro,
-OH, and
C1-6alkyl, or
R63 and R64 are taken together with the nitrogen to which they are
attached, and optionally from 1 to 3 additional heteroatoms, to form
a heterocycloalkyl, which is optionally tuted with from 1 to 5
tuents independently selected from:
fluoro,
chloro,
kyl,
C1-6alkyl substituted with from 1 to 9 substituents
independently selected from: fluoro, chloro,
C1-4alkoxy, 0x0, phenyl, cycloalkyl, heterocycloalkyl,
methylheterocycloalkyl, -OH, -NH2, -N(H)C1-4alkyl,
-N(C1_4alkyl)2, and —-CN,
heterocycloalkyl,
heterocycloalkyl substituted with from 1 to 9 substituents
independently selected from: C1-6alkyl,
|kyIOH, fluoro, chloro, 0x0 and -OH,
C1-4alkoxy,
C1-4a|koxy substituted with from 1 to 4 substituents
independently selected from: fluoro, oxo, -OH,
-COOH, -NH2, and —-CN,
oxo,
-NH2,
-N(H)C1-4a|kyl,
-N(H)C1-6alkyl substituted with from 1 to 9 tuents
independently selected from: fluoro, chloro,
C1-4alkoxy, 0x0, phenyl, cycloalkyl,
heterocycloalkyl, methylheterocycloalkyl,
-OH, -NH2, -N(H)C1-4a|kyl, -N(C1-4alkyl)2, and
—-CN, and
-N(C1-4a|ky|)2;
ed that:
R61 and R62 are not both hydrogen;
or a pharmaceutically acceptable salt or g thereof.
ly in the compounds of Formula (VI) neither R63 nor R64 is hydrogen.
This invention relates to novel compounds of Formula ) and to the use of
compounds of Formula (Vlaar) in the methods of the invention:
R60aar N
N5 0/ 61aar
R63§r 3A R62aar
[ll N/ Y6
R64aar )
wherein:
Yeaar is selected from: S and NH;
Reoaar is selected from:
C1—3alkyl,
C1-3alkyl substituted with from 1 to 6 substituents
independently selected from: fluoro and chloro,
-N(H)C1-3alkyl,
-N(C1-3a|ky|)2,
-SC1-4a|ky|,
C1-3alkyloxy,
aryl,
aryl substituted with from one to 3 substituents
independently selected from:
fluoro,
chloro,
-OH, and
C1—3alkyl,
heteroaryl,
heteroaryl substituted with from one to 3 tuents
independently selected from:
fluoro,
chloro,
-OH, and
C1-33Ikyl,
cycloalkyl,
cycloalkyl substituted with from one to 3 substituents
independently ed from:
fluoro,
chloro,
-OH, and
C1 —Sa|kyl;
R61 aar is selected from:
hydrogen,
-C(O)NH2,
heterocycloalkyl, and
heterocycloalkyl substituted with from 1 to 4 substituents independently
ed from:
oxo,
C1-4alkyl substituted with from 1 to 4 substituents
independently selected from: fluoro, 0x0, and -NH2,
)H, and
-NHC(O)Rxa3,
where Rm3 is selected from C1-6alkyl, and C1-6a|kyl
substituted from 1 to 6 times by fluoro;
R62aar is selected from:
hydrogen,
C1—Salkyl,
aryl!
aryl tuted with from 1 to 4 substituents independently selected
from:
chloro,
kyl,
C1-ealkyl substituted with from 1 to 5 substituents
independently selected from: fluoro, chloro, bromo,
iodo, 0x0, --CN, -OR69 and —NR66R67,
where R66 and R67 are independently
selected from: hydrogen, -S(O)2CH3,
C1-5alky| and C1-5alky| substituted with from
1 to 4 substituents independently selected
from: fluoro, oxo, -OH, -OC1-5alkyl,
-OC1-5alkyl substituted from 1 to 6 times by
fluoro, —COOH and —NR68R69, where R68
and R69 are independently ed from:
hydrogen, phenyl, C1-5alkyl and C1-5alkyl
tuted with from 1 to 4 substituents
independently selected from: fluoro, 0x0,
-OH, -OC1-5a|kyl, -OC1-5a|kyl substituted
from 1 to 6 times by fluoro and —COOH,
--CN,
-S(O)2NH2, and
-S(O)2NHCH3,
hetroaryl, and
hetroaryl substituted with from 1 to 4 substituents independently selected
from:
fluoro,
chloro,
C1-68Ikyl,
C1-ealkyl tuted with from 1 to 5 substituents
independently selected from: fluoro, chloro, bromo,
iodo, oxo, --CN, -OR69 and —NR66R67,
where R66 and R67 are independently
selected from: en, -S(O)2CH3,
C1-5alky| and C1-5alkyl substituted with from
1 to 4 substituents independently ed
from: fluoro, oxo, -OH, -OC1-5alkyl,
-OC1-5alkyl substituted from 1 to 6 times by
fluoro, —COOH and —NR68R69, where R68
and R69 are independently selected from:
hydrogen, phenyl, C1-5alkyl and C1-5alkyl
substituted with from 1 to 4 substituents
independently selected from: fluoro, oxo,
-OH, -OC1-5alkyl, -OC1—5alkyl substituted
from 1 to 6 times by fluoro and —COOH,
-S(O)2NH2, and
-S(O)2NHCH3§
R6335" and R6433" are independently selected from:
C1-4alky|,
C1-4alkyl substituted with from 1 to 6 tuents
independently selected from: fluoro, heterocycloalkyl,
oxo, -NH2, C1-4alkoxy, and -OH,
heterocycloalkyl, and
heterocycloalkyl substituted with from 1 to 5 substituents independently
selected from:
fluoro,
chloro,
-OH, and
C1-6alkyl, or
R6388" and R64am are taken together with the nitrogen to which they are
attached, and optionally from 1 to 3 additional heteroatoms, to form
a heterocycloalkyl, which is optionally substituted with from 1 to 5
tuents independently selected from:
fluoro,
chloro,
C1-Balkyl,
C1-6alkyl substituted with from 1 to 9 tuents
independently selected from: fluoro, chloro,
C1-4alkoxy, oxo, phenyl, cycloalkyl, heterocycloalkyl,
methylheterocycloalkyl, -OH, -NH2, -N(H)C1-4alkyl,
-N(C1_4alky|)2, and —-CN,
heterocycloalkyl,
heterocycloalkyl substituted with from 1 to 9 tuents
independently selected from: C1-6alkyl,
-C1-BalkyIOH, fluoro, , 0x0 and -OH,
C1-4alkoxy,
C1-4alkoxy tuted with from 1 to 4 substituents
independently selected from: fluoro, oxo, -OH,
-COOH, -NH2, and —-CN,
0x0,
-NH2,
-N(H)C1-4alkyl,
-N(H)C1-6alkyl substituted with from 1 to 9 substituents
independently selected from: fluoro, chloro,
koxy, oxo, phenyl, cycloalkyl,
heterocycloalkyl, methylheterocycloalkyl,
-OH, -NH2, -N(H)C1-4a|kyl, -N(C1-4alkyl)2, and
—-CN, and
-N(Ct-4alky|)2;
provided that:
R6138" and R6235" are not both hydrogen, and
r and R64am are not both hydrogen;
or a pharmaceutically acceptable salt or g thereof.
Suitably in the compounds of Formula (Vlaar) neither R6335" nor R64aa|r is hydrogen.
Suitably in the compounds of Formula (Vlaar) R6133" is -C(O)NH2.
Suitably in the compounds of a (Vlaar) R6235" is aryl substituted with from 1
to 4 substituents independently selected from:
fluoro,
chloro,
kyl,
C1-6a|kyl substituted with from 1 to 5 substituents
independently selected from: fluoro, chloro, bromo,
iodo, oxo, --CN, -OR69 and 67,
where R66 and R67 are independently
selected from: hydrogen, -S(O)2CH3,
C1-5alkyl and C1-5alkyl substituted with from
1 to 4 substituents independently selected
from: fluoro, oxo, -OH, -OC1-5alkyl,
-OC1-5a|kyl substituted from 1 to 6 times by
2017/053511
fluoro, —COOH and —NR68R69, where R68
and R69 are independently selected from:
en, phenyl, C1-5alkyl and C1-5alkyl
substituted with from 1 to 4 substituents
ndently selected from: fluoro, oxo,
-OH, -OC1-5a|kyl, -OC1-5a|kyl substituted
from 1 to 6 times by fluoro and —COOH.
This invention s to novel compounds of Formula (Vla) and to the use of
compounds of Formula (Vla) in the methods ofthe invention:
R603
N\=CfirC///N
R61a
R6§N N/ Y6a/K R62a
A643 (Vla)
wherein:
Y6a is selected from: S and NH;
R603 is selected from:
C1-Salkyl,
C1-3alkyl substituted with from 1 to 6 substituents
independently selected from: fluoro and chloro,
-N(H)C1-3a|kyl,
-N(C1-3a|ky|)2,
-SC1-4a|ky|,
C1-3alkyloxy,
cycloalkyl,
cycloalkyl tuted with from one to 3 substituents
independently selected from:
fluoro,
chloro,
-OH, and
C1-3alkyl;
R6181 is selected from:
hydrogen,
-C(O)NH2,
heterocycloalkyl, and
heterocycloalkyl substituted with from 1 to 4 substituents independently
selected from:
oxo,
ky| substituted with from 1 to 4 substituents
independently selected from: fluoro, 0x0, and -NH2,
)H, and
-NHC(O)RX33,
where Rxa13 is selected from C1-6alkyl, and C1-6alkyl
substituted from 1 to 6 times by fluoro;
R623 is selected from:
hydrogen,
C1-Salkyl,
aryl,
aryl tuted with from 1 to 4 substituents independently selected
from:
fluoro,
chloro,
C1-Galkyl,
C1-ealkyl substituted with from 1 to 5 substituents
independently selected from: fluoro, chloro, bromo,
iodo, 0x0, --CN, -OR69 and —NR66R67,
where R66 and R67 are independently
selected from: hydrogen, -S(O)2CH3,
C1-5alkyl and C1-5alkyl substituted with from
1 to 4 substituents independently selected
from: fluoro, oxo, -OH, alkyl,
-OC1-5alkyl substituted from 1 to 6 times by
fluoro, —COOH and —NR68R69, where R68
and R69 are independently selected from:
en, , C1-5alky| and C1-5alky|
substituted with from 1 to 4 substituents
independently selected from: fluoro, oxo,
-OH, -OC1-5alkyI, -OC1-5alkyl substituted
from 1 to 6 times by fluoro and —COOH,
--CN,
-S(O)2NH2, and
-S(O)2NHCH3,
hetroaryl, and
hetroaryl tuted with from 1 to 4 substituents independently ed
from:
fluoro,
chloro,
C1—Balkyl,
C1-ealkyl substituted with from 1 to 5 substituents
independently selected from: fluoro, chloro, bromo,
iodo, oxo, --CN, -OR69 and —NR66R67,
where R66 and R67 are independently
selected from: hydrogen, -S(O)20H3,
C1-5alkyl and C1-5alkyl substituted with from
2017/053511
1 to 4 substituents independently selected
from: fluoro, oxo, -OH, -OC1-5alkyl,
alkyl substituted from 1 to 6 times by
fluoro, —COOH and —NR68R69, where R68
and R69 are independently selected from:
hydrogen, phenyl, C1-5alkyl and C1-5alkyl
substituted with from 1 to 4 substituents
independently selected from: fluoro, oxo,
-OH, -OC1-5alkyl, -OC1—5alkyl substituted
from 1 to 6 times by fluoro and —COOH,
-S(O)2NH2, and
-S(O)2NHCH3§
R638‘ and R643 are ndently selected from:
hydrogen,
C1—4alkyl,
C1-4alkyl substituted with from 1 to 6 substituents
independently selected from: fluoro, heterocycloalkyl,
oxo, -NH2, C1-4alkoxy, and -OH,
heterocycloalkyl, and
heterocycloalkyl substituted with from 1 to 5 substituents independently
selected from:
chloro,
-OH, and
C1-6a|kyl, or
R638‘ and R648‘ are taken er with the nitrogen to which they are
attached, and optionally from 1 to 3 additional heteroatoms, to form
a heterocycloalkyl, which is optionally substituted with from 1 to 5
substituents independently selected from:
fluoro,
chloro,
C1—Balkyl,
C1-Balkyl substituted with from 1 to 9 tuents
independently selected from: fluoro, chloro,
C1-4alkoxy, 0x0, phenyl, lkyl, heterocycloalkyl,
methylheterocycloalkyl, -OH, -NH2, -N(H)C1-4alkyl,
-N(C1_4a|kyl)2, and —-CN,
heterocycloalkyl,
1O heterocycloalkyl substituted with from 1 to 9 substituents
independently selected from: C1-6alkyl,
-C1-6a|kleH, fluoro, chloro, 0x0 and -OH,
koxy,
C1-4alkoxy substituted with from 1 to 4 substituents
ndently selected from: fluoro, oxo, -OH,
-COOH, -NH2, and —-CN,
oxo,
-NH2,
-N(H)C1-4alkyl,
-N(H)C1-6alkyl substituted with from 1 to 9 substituents
independently selected from: fluoro, ,
C1-4alkoxy, 0x0, phenyl, cycloalkyl,
heterocycloalkyl, methylheterocycloalkyl,
-OH, -NH2, -N(H)C1-4alkyl, -N(C1-4alkyl)2, and
—-CN, and
-N(C1-4a|ky|)2;
provided that:
R61a and R623 are not both hydrogen, and
R633 and R643 are not both hydrogen;
or a pharmaceutically acceptable salt or prodrug thereof.
Suitably in the compounds of Formula (Vla) r R638 nor R643 is hydrogen.
ed in the compounds ofthe invention and used in the methods ofthe invention
are compounds of Formula (VII):
N ///N
:C C R71
72 I
R\N N/ Y7J\ 77
l R
R73 (VII)
wherein:
Y7 is selected from: S and NH;
R70 is selected from:
ethyl,
-CH2CF3,
-NCH3,
-SCH3,
ethoxy, and
cyclopropyl;
R71 is selected from:
hydrogen,
-C(O)NH2,
heterocycloalkyl, and
heterocycloalkyl substituted by oxo, -C(O)CH3 or -NHC(O)CH3;
R77 is selected from:
hydrogen,
kyl, and
aryl,
aryl substituted with from 1 to 4 substituents independently selected
from:
fluoro,
chloro,
1o C1-6alkyl,
C1-ealkyl substituted with from 1 to 3 tuents
independently selected from: fluoro, , bromo,
iodo, oxo, --CN, -OR79 and 77,
where R76 and R77 are ndently
selected from: hydrogen, -S(O)zCH3,
C1-5alkyl and C1-5alkyl substituted with from
1 to 4 substituents independently selected
from: fluoro, oxo, -OH, -OC1-5alkyl,
-OC1-5alkyl substituted from 1 to 6 times by
fluoro, —COOH and —NR78R79, where R78
and R79 are independently selected from:
hydrogen, phenyl, C1-5alkyl and C1-5alkyl
substituted with from 1 to 4 substituents
independently selected from: fluoro, oxo,
-OH, -OC1-5alky|, -OC1-5alkyl substituted
from 1 to 6 times by fluoro and —COOH,
--CN,
H2, and
-S(O)2NHCH3,
pyridinyl,
thiazolyl, and
thiazolyl substituted by -C(O)CH3 or-NHC(O)CH3;
R72 and R73 are independently selected from:
hydrogen,
C1-Salkyl,
C1-3alkyl substituted with from 1 to 3 substituents independently selected
from: -OH, oxo, -NH2, morpholino and y,
-oxa-2azaspiro[3.4]octanyl, and
8-azabicyclo[3.2.1]octanyl, or
R72 and R73 are taken together with the nitrogen to which they are
attached, and optionally from 1 to 3 onal heteroatoms,
to form a heterocycloalkyl ed from:
pyrrolidinyl,
piperidinyl,
1,4diazepanyl,
piperazinyl,
2,9-diazaspiro[5.5]undecanyl,
2,8-diazaspiro[4.5]decanyl,
hexahydro-1H-pyrrolo[1,2a][1,4]diazepinyl,
morpholinyl,
1-oxaazaspiro[3.4]octanyl,
1,7-diazaspiro[3.5]nonanyl,
2,7-diazaspiro[3.5]nonanyl,
2,6-diazaspiro[3.4]octanyl,
azetidinyl,
1,8—diazaspiro[4.5]decanyl, and
-oxaazaspiro[3.4]octanyl,
all of which are optionally substituted with from 1 to 5
substituents independently selected from:
fluoro,
0x0,
-OH,
-CH3,
-CH20H,
methoxy,
-CH20H3,
1o -C(O)CH3,
-CH2CH20H,
-CHZCH2CH3,
-CH20H20CH3,
-CH20H(OH)CH3,
-CH20(O)OCH3,
-C(O)CH(CH3)2,
-CH20H2N(CH3)2,
-CHZCH2CH2N(CH3)2,
-OCH2CH2NH2,
-NH2,
-NHCH3,
-NHC(O)-CNH2(CH3)2,
)CH2NH2,
-NHC(O)CHCH3NH2,
-NHC(O)-CNH2(CH3)2,
-NHC(O)aminotetrahydropyranyl,
-CH2NH2,
-CHZCH2NH2,
ZCH2NH2,
-CH2N(CH3)2,
-C(O)aminooxetanyl,
-S(O)2CH2CH3,
-S(O)2CH3,
3-pyrrolidinylpropyl,
cyclopropylmethyl,
dinyl,
morpholinyl,
morpholinylmethyl,
methylpiperazinylmethyl,
pyrrolidinyl,
pyrrolidinylmethyl,
piperazinylmethyl,
oxoimidazolidinyl, and
2-hydroxyethylpiperidinyl;
provided that:
R71 and R77 are not both hydrogen;
or a pharmaceutically acceptable salt or prodrug thereof.
Suitably in the compounds of Formula (VII) neither R72 nor R73 is hydrogen.
This invention relates to novel compounds of a (Vllaar) and to the use of
compounds of Formula (Vllaar) in the methods of the invention:
R7Oaar N
NSC Co R71aar
R72§r / A
N N Y7aar R77aar
(Vllaar)
wherein:
Y7aar is selected from: S and NH;
R70am is selected from:
ethyl,
-CH2CF3,
-NCH3,
-SCH3,
ethoxy,
phenyL
l, and
cyclopropyl;
R71aar is selected from:
hydrogen,
-C(O)NH2,
heterocycloalkyl, and
heterocycloalkyl substituted by oxo, -C(O)CH3 or -NHC(O)CH3;
R77am is selected from:
hydrogen,
C1-3alkyl, and
aryl!
aryl substituted with from 1 to 4 substituents independently selected
from:
fluoro,
chloro,
C1-Balkyl,
C1-6alkyl substituted with from 1 to 3 substituents
independently selected from: fluoro, chloro, bromo,
iodo, 0x0, --CN, -OR793 and —NR768R773,
where R763 and R773 are independently
selected from: hydrogen, CH3,
C1-5alkyl and C1-5alkyl substituted with from
1 to 4 tuents independently selected
from: , oxo, -OH, -OC1-5alkyl,
-OC1-5a|kyl substituted from 1 to 6 times by
fluoro, —COOH and —NR788R793, where R788
and R79a are independently selected from:
hydrogen, phenyl, C1-5alkyl and C1-5alkyl
substituted with from 1 to 4 substituents
independently ed from: fluoro, 0x0,
-OH, -OC1-5a|kyl, -OCt-sa|ky| substituted
from 1 to 6 times by fluoro and —COOH,
--CN,
S(O)2NH2, and
-S(O)2NHCH3,
nyl,
thiazolyl, and
thiazolyl substituted by -C(O)CH3 or-NHC(O)CH3;
R72aar and R73aar are independently selected from:
hydrogen,
C1-Salkyl,
C1-3alkyl substituted with from 1 to 3 substituents ndently selected
from: -OH, oxo, -NH2, morpholino and methoxy,
-oxa-2azaspiro[3.4]octanyl, and
8-azabicyclo[3.2.1]octanyl, or
R72aar and R73aar are taken er with the nitrogen to which they are
attached, and optionally from 1 to 3 additional heteroatoms,
to form a heterocycloalkyl selected from:
pyrrolidinyl,
piperidinyl,
1,4diazepanyl,
piperazinyl,
2,9-diazaspiro[5.5]undecanyl,
2,8—diazaspiro[4.5]decanyl,
hexahydro-1H-pyrrolo[1,2a][1,4]diazepiny|,
morpholinyl,
1-oxaazaspiro[3.4]octany|,
1,7-diazaspiro[3.5]nonanyl,
2,7-diazaspiro[3.5]nonanyl,
azaspiro[3.4]octanyl,
azetidinyl,
1,8—diazaspiro[4.5]decany|, and
5-oxaazaspiro[3.4]octanyl,
all of which are ally substituted with from 1 to 5
substituents independently selected from:
fluoro,
0x0,
-OH,
-CH3,
-CH20H,
methoxy,
-CHZCH3,
-C(O)CH3,
-CHZCH20H,
-CH2CH2CH3,
-CH20H20CH3,
(OH)CH3,
-CH2C(O)OCH3,
-C(O)CH(CH3)2,
-CHZCH2N(CH3)2,
-CH2CH2CH2N(CH3)2,
-OCHZCH2NH2,
-OCH2CH20H,
-NH2,
-NHCH3,
-N(CH3)2,
-NHC(O)-CNH2(CH3)2,
-NHC(O)CH2NH2,
-NHC(O)CHCH3NH2,
-NHC(O)-CNH2(CH3)2,
-NHC(O)aminotetrahydropyranyl,
-CH2NH2,
-CHZCH2NH2,
2CH2NH2,
-CH2N(CH3)2.
-C(O)aminooxetanyl,
-C(O)aminotetrahyd ropyranyl,
CH20H3,
-S(O)2CH3,
benzoyl,
3-pyrrolidinylpropyl,
cyclopropylmethyl,
piperidinyl,
morpholinyl,
morpholinylmethyl,
methylpiperazinylmethyl,
methylpiperazinyl,
pyrrolidinyl,
pyrrolidinylmethyl,
piperazinylmethyl,
oxoimidazolidinyl, and
2-hydroxyethylpiperidinyl;
provided that:
R72aar and R73aar are not both hydrogen, and
R7138" and R7735" are not both hydrogen;
or a pharmaceutically acceptable salt or g thereof.
Suitably in the compounds of Formula (Vllaar) neither R72aar nor R73aar i s
hydrogen.
Suitably in the compounds of Formula (Vllaar) R7133" is -C(O)NH2.
ly in the compounds of Formula (Vllaar) R7735” is aryl tuted with from 1
to 4 substituents independently selected from:
fluoro,
chloro,
C1-Balkyl,
C1-6alkyl substituted with from 1 to 3 substituents
independently selected from: fluoro, chloro, bromo,
iodo, oxo, --CN, -OR793 and —NR763R773,
where R763 and R773 are independently
selected from: hydrogen, -S(O)2CH3,
C1-5alky| and C1-5a|ky| substituted with from
1 to 4 substituents independently selected
from: , oxo, -OH, -OC1-5alkyl,
-OC1-5a|kyl substituted from 1 to 6 times by
fluoro, —COOH and —NR783R793, where R78a
and R79a are independently selected from:
hydrogen, , C1-5alkyl and kyl
substituted with from 1 to 4 substituents
independently selected from: fluoro, oxo,
-OH, -OC1-5alkyl, alky| substituted
from 1 to 6 times by fluoro and —COOH.
This invention relates to novel compounds of Formula (Vlla) and to the use of
compounds of Formula (Vlla) in the methods ofthe invention:
N\ ’//N
R723 /
wherein:
Y73 is selected from: S and NH;
R703 is selected from:
WO 16727
ethyl,
-CH2CF3,
-NCH3,
-SCH3,
ethoxy, and
cyclopropyl;
R713 is ed from:
hydrogen,
-C(O)NH2,
heterocycloalkyl, and
heterocycloalkyl substituted by oxo, -C(O)CH3 or -NHC(O)CH3;
R773 is selected from:
hydrogen,
kyl, and
aryl,
aryl substituted with from 1 to 4 substituents independently selected
from:
fluoro,
chloro,
C1-6alkyl,
C1-6alkyl substituted with from 1 to 3 substituents
ndently selected from: fluoro, chloro, bromo,
iodo, oxo, --CN, -OR793 and —NR763R773,
where R763 and R773 are independently
selected from: hydrogen, -S(O)2CH3,
C1-5alkyl and C1-5alkyl substituted with from
1 to 4 substituents independently selected
from: fluoro, oxo, -OH, -OC1-5alkyl,
-OC1-5a|ky| substituted from 1 to 6 times by
fluoro, —COOH and R793, where R78a
and R798 are independently selected from:
hydrogen, phenyl, C1-5alkyl and kyl
substituted with from 1 to 4 substituents
independently selected from: fluoro, oxo,
-OH, -OC1-5alkyl, -OC1-5a|kyl tuted
from 1 to 6 times by fluoro and —COOH,
--CN,
S(O)2NH2, and
-S(O)2NHCH3,
pyridinyl,
thiazolyl, and
thiazolyl substituted by -C(O)CH3 or-NHC(O)CH3;
R723 and R733 are independently selected from:
hydrogen,
C1-Salkyl,
ky| substituted with from 1 to 3 substituents independently selected
from: -OH, oxo, -NH2, morpholino and methoxy,
-oxa-2azaspiro[3.4]octany|, and
8-azabicyclo[3.2.1]octanyl, or
R723 and R733 are taken together with the nitrogen to which they are
attached, and optionally from 1 to 3 additional heteroatoms,
to form a cycloalkyl selected from:
pyrrolidinyl,
piperidinyl,
1,4diazepanyl,
piperazinyl,
2,9-diazaspiro[5.5]undecanyl,
2,8—diazaspiro[4.5]decanyl,
dro-1H-pyrrolo[1,2a][1,4]diazepinyl,
morpholinyl,
1-oxaazaspiro[3.4]octanyl,
azaspiro[3.5]nonanyl,
azaspiro[3.5]nonanyl,
2,6-diazaspiro[3.4]octanyl,
azetidinyl,
1,8—diazaspiro[4.5]decany|, and
-oxaazaspiro[3.4]octanyl,
all of which are optionally substituted with from 1 to 5
substituents independently selected from:
fluoro,
0x0,
-OH,
-CH3,
-CH20H,
methoxy,
-CHZCH3,
-C(O)CH3,
-CH20H20H,
-CHZCH2CH3,
-CH2CH20CH3,
-CH20H(OH)CH3,
-CHZC(O)OCH3,
-C(O)CH(CH3)2,
-CH20H2N(CH3)2,
-CH20H2CH2N(CH3)2,
-OCH2CH2NH2,
-NH2,
-NHCH3,
-N(CH3)2,
-NHC(O)-CNH2(CH3)2,
-NHC(O)CH2NH2,
-NHC(O)CHCH3NH2,
-NHC(O)-CNH2(CH3)2,
-NHC(O)aminotetrahydropyranyl,
-CH2NH2,
-CHZCH2NH2,
-CHZCHZCH2NH2,
-CH2N(CH3)2.
-C(O)aminooxetany|,
-S(O)2CH2CH3,
-S(O)2CH3,
benzoyL
3-pyrrolidinylpropyl,
cyclopropylmethyl,
dinyl,
morpholinyl,
morpholinylmethyl,
piperazinylmethyl,
pyrrolidinyl,
pyrrolidinylmethyl,
piperazinylmethyl,
dazolidinyl, and
2-hydroxyethylpiperidinyl;
provided that:
R723 and R733 are not both hydrogen, and
R718‘ and R778‘ are not both hydrogen;
or a pharmaceutically acceptable salt or prodrug thereof.
Suitably in the compounds of Formula (Vlla) r R723 nor R733 is en.
Included in the compounds ofthe invention and used in the methods ofthe invention
are compounds of Formula (VIII):
N\ ’//N
:C C R81
82 I
R /
\N N Y8J\R87
R (VIII)
wherein:
Y8 is selected from: S and NH;
R80 is selected from:
ethyl,
-CH2CF3,
-NCH3,
-SCH3,
ethoxy, and
cyclopropyl;
R81 is selected from:
hydrogen,
-C(O)NH2,
heterocycloalkyl, and
heterocycloalkyl substituted by oxo, -C(O)CH3 or -NHC(O)CH3;
R87 is selected from:
hydrogen,
CH3,
phenyL
phenyl substituted with from 1 to 4 substituents independently selected
from:
chloro,
kyl,
C1-6alkyl substituted with from 1 to 3 substituents
independently selected from: fluoro, , bromo,
iodo, oxo, --CN, -0R89 and —NR86R87,
where R86 and R87 are independently
selected from: hydrogen, -S(O)2CH3,
C1-5a|ky| and C1-5alkyl substituted with from
1 to 4 substituents independently ed
from: fluoro, oxo, -OH, a|kyl,
-OC1-5alkyl substituted from 1 to 6 times by
fluoro, —COOH and —NR88R89, where R88
and R89 are independently selected from:
hydrogen, phenyl, C1-5alkyl and C1-5alkyl
substituted with from 1 to 4 substituents
independently selected from: fluoro, oxo,
-OH, -OC1-5alky|, -OC1-5alkyl substituted
from 1 to 6 times by fluoro and —COOH,
--CN,
S(O)2NH2, and
-S(O)2NHCH3,
nyl,
thiazolyl, and
thiazolyl substituted by -C(O)CH3 or-NHC(O)CH3;
R82 and R83 are independently selected from:
C1-3alkyl,
C1-3alkyl substituted with from 1 to 3 substituents independently selected
from: -OH, 0x0, -NH2, morpholino and methoxy,
-oxa-2azaspiro[3.4]octanyl, and
8-azabicyclo[3.2.1]octanyl, or
R82 and R83 are taken er with the nitrogen to which they are
attached, and optionally from 1 to 3 additional heteroatoms,
to form a heterocycloalkyl selected from:
pyrrolidinyl,
piperidinyl,
zepanyl,
piperazinyl,
2,9-diazaspiro[5.5]undecanyl,
2,8—diazaspiro[4.5]decanyl,
hexahydro-1H-pyrrolo[1,2a][1,4]diazepinyl,
morpholinyl,
1-oxaazaspiro[3.4]octany|,
1,7-diazaspiro[3.5]nonanyl,
2,7-diazaspiro[3.5]nonanyl,
2,6-diazaspiro[3.4]octanyl,
azetidinyl,
1,8—diazaspiro[4.5]decanyl, and
5-oxaazaspiro[3.4]octanyl,
all of which are optionally substituted with from 1 to 5
substituents independently selected from:
fluoro,
oxo,
-OH,
-CH3,
-CH20H,
methoxy,
-CHZCH3,
-C(O)CH3,
1o -CHZCH20H,
-CH2CH2CH3.
-CHZCH20CH3,
-CH2CH(OH)CH3,
-CH2C(O)OCH3,
-C(O)CH(CH3)2,
-CHZCH2N(CH3)2,
-CH2CH2CH2N(CH3)2,
-OCHZCH2NH2,
-NH2,
-NHCH3,
-N(CH3)2,
-NHC(O)-CNH2(CH3)2,
-NHC(O)CH2NH2,
-NHC(O)CHCH3NH2,
)-CNH2(CH3)2,
-NHC(O)aminotetrahydropyranyl,
'CHZNHZ!
-CHZCH2NH2,
-CH2CH2CH2NH2,
-CH2N(CH3)2,
-C(O)aminooxetanyl,
CH2CH3.
-S(O)2CH3,
benzoyL
3-pyrrolidinylpropyl,
cyclopropylmethyl,
dinyl,
morpholinyl,
morpholinylmethyl,
methylpiperazinylmethyl,
pyrrolidinyl,
pyrrolidinylmethyl,
piperazinylmethyl,
oxoimidazolidinyl, and
2-hydroxyethylpiperidinyl;
ed that:
R81 and R87 are not both hydrogen;
or a pharmaceutically acceptable salt or prodrug thereof.
Suitably in the compounds of a (Vlll) neither R82a nor R83a is hydrogen.
This invention relates to novel compounds of Formula (Vlllaar) and to the use of
compounds of Formula (Vlllaar) in the methods of the invention:
RSOaar N
s 0/
R82§r agk R87aar
lilNYs/
I283aar (Vlllaar)
wherein:
Yfsaar is selected from: S and NH;
Rsoaar is selected from:
ethyl,
-CH2CF3,
-NCH3,
-SCH3,
ethoxy,
methoxy,
phenyL
furanyl, and
ropyl;
R8135" is selected from:
hydrogen,
-C(O)NH2,
heterocycloalkyl, and
heterocycloalkyl substituted by oxo, -C(O)CH3 or -NHC(O)CH3;
R8735" is selected from:
hydrogen,
CH3,
phenyL
phenyl substituted with from 1 to 4 tuents independently selected
from:
fluoro,
WO 16727
chloro,
C1-Balkyl,
kyl substituted with from 1 to 3 substituents
independently ed from: fluoro, , bromo,
iodo, oxo, --CN, -OR89 and —NR86R87,
where R86 and R87 are independently
selected from: hydrogen, -S(O)2CH3,
C1-5alky| and C1-5alky| substituted with from
1 to 4 substituents independently selected
from: fluoro, oxo, -OH, -OC1-5alkyl,
-OC1-5a|kyl substituted from 1 to 6 times by
fluoro, —COOH and —NR88R89, where R88
and R89 are independently selected from:
hydrogen, phenyl, C1-5alkyl and C1-5alkyl
substituted with from 1 to 4 substituents
independently selected from: fluoro, oxo,
-OH, -OC1-5alkyl, -OC1-5a|ky| substituted
from 1 to 6 times by fluoro and —COOH,
--CN,
-S(O)2NH2, and
-S(O)2NHCH3,
nyl,
thiazolyl, and
thiazolyl substituted by -C(O)CH3 or -NHC(O)CH3;
R82aar and R83aar are independently selected from:
hydrogen,
C1-Salkyl,
C1-3alkyl substituted with from 1 to 3 substituents independently selected
from: -OH, oxo, -NH2, morpholino and y,
-oxa-2azaspiro[3.4]octany|, and
8-azabicyclo[3.2.1]octany|, or
Razaar and R8338" are taken together with the nitrogen to which they are
attached, and optionally from 1 to 3 additional heteroatoms,
to form a heterocycloalkyl selected from:
pyrrolidinyl,
piperidinyl,
1,4diazepanyl,
piperazinyl,
2,9-diazaspiro[5.5]undecanyl,
2,8-diazaspiro[4.5]decany|,
dro-1H-pyrrolo[1,2a][1,4]diazepinyl,
morpholinyl,
1-oxaazaspiro[3.4]octanyl,
1,7-diazaspiro[3.5]nonanyl,
2,7-diazaspiro[3.5]nonany|,
2,6-diazaspiro[3.4]octany|,
azetidinyl,
1,8—diazaspiro[4.5]decanyl, and
-oxaazaspiro[3.4]octanyl,
all of which are optionally substituted with from 1 to 5
substituents independently selected from:
,
-CH3,
-CH20H,
methoxy,
'CHZCH31
-C(O)CH3,
-CHZCH20H,
-CHZCH2CH3,
-CH20H20CH3,
(OH)CH3,
-CH20(O)OCH3,
-C(O)CH(CH3)2,
-CH20H2N(CH3)2,
-CHZCH2CH2N(CH3)2,
-OCH2CH2NH2,
-OCHZCH20H,
-NH2,
-NHCH3,
-N(CH3)2,
)-CNH2(CH3)2,
-NHC(O)CH2NH2,
-NHC(O)CHCH3NH2,
-NHC(O)-CNH2(CH3)2,
-NHC(O)aminotetrahydropyranyl,
'CHZNHZ!
-CHZCH2NH2,
-CHZCH2CH2NH2,
-CH2N(CH3)2,
-C(O)aminooxetany|,
-C(O)aminotetrahyd ropyranyl,
-S(O)2CH2CH3,
-S(O)2CH3,
benzoyL
3-pyrrolidinylpropyl,
cyclopropylmethyl,
piperidinyl,
morpholinyl,
morpholinylmethyl,
methylpiperazinylmethyl,
methylpiperazinyl,
pyrrolidinyl,
pyrrolidinylmethyl,
piperazinylmethyl,
oxoimidazolidinyl, and
oxyethylpiperidinyl;
provided that:
R8135" and R8738" are not both hydrogen, and
R82aar and R83alalr are not both en;
or a pharmaceutically acceptable salt or prodrug thereof.
Suitably in the compounds of Formula (Vlllaar) neither R8235" nor R83ala|r is
hydrogen.
Suitably in the compounds of Formula (Vlllaar) R81alar is -C(O)NH2.
ly in the nds of Formula (Vlllaar) R87aar is phenyl substituted with
from 1 to 4 substituents independently selected from:
fluoro,
chloro,
C1—Balkyl,
C1-6a|kyl substituted with from 1 to 3 tuents
independently selected from: fluoro, chloro, bromo,
iodo, oxo, --CN, -OR89 and —NR86R87,
where R86 and R87 are independently
selected from: hydrogen, -S(O)2CH3,
C1-5alkyl and C1-5alkyl substituted with from
1 to 4 substituents ndently selected
from: fluoro, oxo, -OH, alkyl,
-OC1-5alkyl substituted from 1 to 6 times by
fluoro, —COOH ancl —NR88R89, where R88
and R89 are independently selected from:
hydrogen, phenyl, C1-5alky| and C1-5alky|
substituted with from 1 to 4 substituents
independently selected from: fluoro, oxo,
-OH, -OC1-5alkyI, -OC1-5alkyl substituted
from 1 to 6 times by fluoro and —COOH.
This ion relates to novel compounds of Formula (Vllla) and to the use of
compounds of Formula (Vllla) in the methods ofthe invention:
R8Oa
82 l
R \aN N/ YSa/kR87a
(Vllla)
wherein:
Y8a is selected from: S and NH;
R803 is selected from:
ethyl,
-CH2CF3,
-NCH3,
-SCH3,
, and
cyclopropyl;
R813 is selected from:
hydrogen,
heterocycloalkyl, and
heterocycloalkyl substituted by oxo, -C(O)CH3 or -NHC(O)CH3;
R873 is selected from:
hydrogen,
CH3,
phenyL
phenyl substituted with from 1 to 4 substituents independently selected
from:
fluoro,
chloro,
C1-68Ikyl,
C1-6alkyl tuted with from 1 to 3 substituents
independently selected from: fluoro, chloro, bromo,
iodo, oxo, --CN, -0R89 and —NR36R87,
where R86 and R87 are independently
selected from: en, -S(O)2CH3,
C1-5alky| and C1-5alky| substituted with from
1 to 4 substituents independently selected
from: fluoro, 0x0, -OH, -OC1-5a|kyl,
-OC1-5alkyl substituted from 1 to 6 times by
fluoro, —COOH and —NR88R89, where R88
and R89 are independently selected from:
hydrogen, phenyl, C1-5alkyl and C1-5alkyl
substituted with from 1 to 4 tuents
independently selected from: fluoro, oxo,
-OH, -OC1-5a|kyl, a|kyl substituted
from 1 to 6 times by fluoro and —COOH,
--CN,
-S(O)2NH2, and
-S(O)2NHCH3,
pyridinyl,
thiazolyl, and
thiazolyl substituted by H3 or-NHC(O)CH3;
R823 and R833 are independently selected from:
hydrogen,
C1-Salkyl,
C1-3alkyl substituted with from 1 to 3 substituents independently selected
from: -OH, oxo, -NH2, morpholino and methoxy,
-oxa-2azaspiro[3.4]octanyl, and
8-azabicyclo[3.2.1]octanyl, or
R823 and R833 are taken together with the en to which they are
ed, and optionally from 1 to 3 additional heteroatoms,
to form a heterocycloalkyl selected from:
pyrrolidinyl,
piperidinyl,
1,4diazepanyl,
piperazinyl,
2,9-diazaspiro[5.5]undecanyl,
2,8-diazaspiro[4.5]decanyl,
hexahydro-1H-pyrrolo[1,2a][1,4]diazepiny|,
morpholinyl,
1-oxaazaspiro[3.4]octany|,
1,7-diazaspiro[3.5]nonany|,
2,7-diazaspiro[3.5]nonany|,
2,6-diazaspiro[3.4]octany|,
azetidinyl,
1,8—diazaspiro[4.5]decanyl, and
-oxaazaspiro[3.4]octanyl,
all of which are optionally substituted with from 1 to 5
tuents ndently selected from:
fluoro,
oxo,
-OH,
-CH3,
-CH20H,
methoxy,
-CH20H&
-c«»CH&
-CH20H20H,
-CHZCH2CH3,
-CH2CH20CH3,
-CH20H(OH)CH3,
-CH20(O)OCH3,
-C(O)CH(CH3)2,
-CH20HflMCH$2
ZCH2N(CH3)2,
-OCH2CH2NH2,
-NH2,
-NHCH3,
-N(CH3)2,
-NHC(O)-CNH2(CH3)2.
-NHC(O)CH2NH2,
-NHC(O)CHCH3NH2,
-NHC(O)-CNH2(CH3)2,
-NHC(O)aminotetrahydropyranyl,
'CH2NH21
-CHZCH2NH2,
-CHZCH2CH2NH2,
-CH2N(CH3)2,
-C(O)aminooxetany|,
-S(O)2CH2CH3,
CH3,
benzoyl,
3-pyrrolidinylpropyl,
cyclopropylmethyl,
dinyl,
morpholinyl,
morpholinylmethyl,
methylpiperazinylmethyl,
pyrrolidinyl,
pyrrolidinylmethyl,
piperazinylmethyl,
dazolidinyl, and
2-hydroxyethylpiperidinyl;
provided that:
R816‘ and R873 are not both hydrogen, and
R828‘ and R838‘ are not both hydrogen;
or a pharmaceutically acceptable salt or prodrug thereof.
Suitably in the compounds of Formula ) neither R823 nor R833 is hydrogen.
This invention s to novel compounds of Formula (Q) and to the use of
compounds of Formula (Q) in the methods ofthe invention:
wherein:
Y” is selected from: S and NH;
R703, is selected from:
ethyl,
-CH2CF3, and
cyclopropyl;
R713, is selected from:
hydrogen,
CH3,
phenyL
phenyl substituted with chloro, and
ne,
R773, is selected from:
-C(O)NH2, and
aryl,
aryl substituted with from 1 to 4 substituents independently selected
from:
fluoro,
chloro,
C1—Balkyl,
C1-Balkyl substituted with from 1 to 3 substituents
independently selected from: fluoro, chloro, bromo,
iodo, 0x0, --CN, ’ and —NR763’R773’,
where R763’ and R773’ are independently
selected form: hydrogen, -S(O)ZCH3,
C1-5alkyl and C1-5alkyl substituted with from
1 to 4 substituents ndently selected
from: fluoro, oxo, -OH, -OC1-5alky|,
-OC1-5alkyl substituted from 1 to 6 times by
fluoro, —COOH and —NR788’R793', where
R7Ba’ and R7Qa' are independently selected
form: hydrogen, phenyl, C1-5alkyl and
C1-5alkyl tuted with from 1 to 4
substituentsindependently selected from:
fluoro, oxo, -OH, -OC1-5a|kyl, -OC1-5alky|
substituted from 1 to 6 times by fluoro and
—COOH,
S(O)2NH2,
-S(O)2NHCH3, and
R723’ and R733’ are independently selected from:
hydrogen,
C1-Salkyl,
C1-3alkyl substituted with from 1 to 3 substituents
independently ed from: lino and methoxy,
WO 16727
-oxa-2azaspiro[3.4]octan, and
8-azabicyclo[3.2.1]octan, or
R728, and R733! are taken together with the nitrogen to which they are
attached, and optionally from 1 to 3 additional heteroatoms,
to form a heterocycloalkyl selected from:
pyrrolidinyl,
piperidinyl,
zepan,
piperazinyl,
2,9-diazaspiro[5.5]undecan,
2,8—diazaspiro[4.5]decan,
octahydro-1H-pyrrolo[1,2a][1,4]diazepin,
morpholin,
1-oxaazaspiro[3.4]octan,
azaspiro[3.5]nonan,
2,7-diazaspiro[3.5]nonan,
2,6-diazaspiro[3.4]octan,
azetidin,
1,8—diazaspiro[4.5]decan, and
5-oxaazaspiro[3.4]octan,
all of which are optionally substituted with from 1 to 5
substituents independently selected from:
fluoro,
0x0,
-OH,
-CH3,
-CH20H,
methoxy,
-CHZCH3,
-C(O)CH3,
-CHZCH20H,
-CH2CH2CH3,
-CH20H20CH3,
-CHZCH(OH)CH3,
-CH20(O)OCH3,
H(CH3)2.
-CH2CH2N(CH3)2,
-CH2CH2CH2N(CH3)2,
-NH2,
-NHCH3,
-N(CH3)2,
-CH2NH2,
-CH2CH2NH2,
-CH20HZCH2NH2,
CH3)2,
-S(O)2CH2CH3,
-S(O)2CH3,
benzoyL
3-pyrr0lidinylpropyl,
2-cyclopropylmethyl,
piperidinyl,
morpholinyl,
morpholinylmethyl,
methylpiperazinylmethyl,
pyrrolidinyl,
pyrrolidinylmethyl,
piperazinylmethyl,
oxoimidazolidinyl, and
2-hydroxyethylpiperidinyl;
provided that:
R728’ and R733’ are not both hydrogen;
or a pharmaceutically acceptable salts thereof.
Suitably in the nds of Formula (Q) neither R72a’ nor R738’ is hydrogen.
This invention relates to novel compounds of Formula (T) and to the use of
compounds of Formula (T) in the methods ofthe invention:
N //N
S /
C C 81
\ R
| NH
82 2
\N N/ 3N
| 0
R83 (T)
wherein:
R80 is selected from:
ethyl,
-CH2CF3, and
ropyl;
R81 is selected from:
, and
phenyl tuted with chloro or fluoro, and
R723, and R733, are independently selected from:
C1-Salkyl,
C1-3alky| substituted with from 1 to 3 substituents
independently selected from: 0x0, and NH2, or
R7Za' and R73a’ are taken together with the nitrogen to which they are
attached, and optionally from 1 to 3 additional heteroatoms,
to form a heterocycloalkyl ed from:
pyrrolidinyl,
piperidinyl,
1,4diazepan,
piperazinyl,
2,9-diazaspiro[5.5]undecan,
2,8-diazaspiro[4.5]decan,
octahydro-1H-pyrrolo[1,2a][1,4]diazepin,
morpholin,
1-oxaazaspiro[3.4]octan,
1,7-diazaspiro[3.5]nonan,
2,7-diazaspiro[3.5]nonan,
2,6-diazaspiro[3.4]octan,
azetidin,
1,8—diazaspiro[4.5]decan, and
-oxaazaspiro[3.4]octan,
all of which are optionally substituted with from 1 to 5
substituents ndently selected from:
fluoro,
0x0,
-OH,
-CH3,
-CH20H,
-CH20H3,
-C(O)CH3,
-CHZCH20H,
-CHZCHZCH3,
-CH2CH20CH3,
-CH20H(OH)CH3,
-CH20(O)OCH3,
-C(O)CH(CH3)2,
-CHZCH2N(CH3)2,
-CH20H2CH2N(CH3)2,
-NH2,
-NHCH3,
C(CH3)3,
-N(CH3)cycIobutane,
-CH2NH2,
-CH2CH2NH2,
-CH2CH2CH2NH2,
-CH2N(CH3)2,
-S(O)2CH2CH3,
-S(O)2CH3,
benzoyL
3-pyrrolidinylpropyl,
2-cyclopropylmethyl,
piperidinyl,
morpholinyl,
morpholinylmethyl,
methylpiperazinylmethyl,
pyrrolidinyl,
pyrrolidinylmethyl,
piperazinylmethyl,
oxoimidazolidinyl, and
2-hydroxyethylpiperidinyl;
or a ceutically acceptable salt or prodrug thereof.
Suitably in the compounds of Formula (T), the compounds are in the form of a
phosphate prodrug.
This invention relates to novel compounds of Formula (Ta) and to the use of
compounds of Formula (Ta) in the methods of the invention:
R80a
N5 /
c c 81
I aNH
R823 2
N N s
| 0
R838 (Ta)
wherein:
R803 is selected from:
ethyl,
-CH2CF3, and
cyclopropyl;
R813 is ed from:
phenyl, and
phenyl substituted with chloro or fluoro, and
R823 and R8381 are taken together with the en to which they are
attached, and optionally from 1 to 3 additional atoms,
to form a heterocycloalkyl selected from:
pyrrolidinyl,
piperidinyl,
1,4diazepan,
piperazinyl,
2,9-diazaspiro[5.5]undecan,
2,8-diazaspiro[4.5]decan,
dro-1H-pyrrolo[1,2a][1,4]diazepin,
morpholin,
2017/053511
1-oxaazaspiro[3.4]octan,
1,7-diazaspiro[3.5]nonan,
2,7-diazaspiro[3.5]nonan,
2,6-diazaspiro[3.4]octan,
azetidin,
1,8—diazaspiro[4.5]decan, and
-oxaazaspiro[3.4]octan,
all of which are optionally substituted with from 1 to 5
substituents independently selected from:
fluoro,
-CH3,
-CH20H,
methoxy,
'CHZCH31
-C(O)CH3,
-CHZCH20H,
-CH20H2CH3,
-CHZCH20CH3,
-CHZCH(OH)CH3,
-CH20(O)OCH3,
-C(O)CH(CH3)2,
-CH20H2N(CH3)2,
2CH2N(CH3)2,
-NH2,
-NHCH3,
-N(CH3)2,
C(CH3)3,
)cyclobutane,
-CH2NH2,
-CH20H2NH2,
-CHZCH2CH2NH2,
-CH2N(CH3)2,
-S(O)20HZCH3.
-S(O)2CH3,
benzoyL
3-pyrrolidinylpropyl,
2-cyclopropylmethyl,
piperidinyl,
morpholinyl,
morpholinylmethyl,
methylpiperazinylmethyl,
pyrrolidinyl,
pyrrolidinylmethyl,
piperazinylmethyl,
dazolidinyl, and
2-hydroxyethylpiperidinyl;
or a pharmaceutically acceptable salt or prodrug thereof.
Suitably in the compounds of Formula (Ta), the compounds are in the form of a
phosphate prodrug.
This invention relates to novel compounds of Formula (8) and to the use of
compounds of Formula (8) in the methods ofthe invention:
NSC c’
92 I
RN? N/ s/\RQ1
wherein:
R90 is selected from:
ethyl,
-CH2CF3, and
cyclopropyl;
R91 is selected from:
phenyl, and
phenyl substituted with from 1 to 2 substituents ndently selected
from:
fluoro,
chloro,
C1-4alkoxy,
C1-4alkoxy substituted with from 1 to 3 substituents
independently selected from: fluoro, , oxo,
-OH, -NH2, -NHCH3, and -N(CH3)2,
C1-Balkyl,
C1-6alkyl substituted with from 1 to 3 tuents
independently selected from: fluoro, chloro, bromo,
iodo, oxo, -S(O)zCH3, --CN, ’ and
_NR76a’R77a"
where R763, and R773, are independently
selected form: hydrogen, -S(O)2CH3,
C1-5alky| and ky| substituted with from
1 to 4 substituents independently selected
from: fluoro, oxo, -OH, alkyl,
-OC1-5alkyl substituted from 1 to 6 times by
fluoro, —COOH and —NR783’R793', where
R783, and R793, are independently selected
form: hydrogen, phenyl, C1-5alkyl and
C1-5alkyl tuted with from 1 to 4
substituentsindependently selected from:
fluoro, oxo, -OH, -OC1-5alkyl, -OC1-5alkyl
tuted from 1 to 6 times by fluoro and
—COOH,
tetrahydroisothiazolyl,
tetrahydroisothiazolyl substituted twice by OXO,
tetrahydro-1,2—thiazinyl,
tetrahydro-1,2—thiazinyl substituted twice by oxo,
-N(CH3)S(O)2CH3,
-N(CH3)S(O)ZCFH2,
-N(CH3)S(O)2CF2H,
-N(CH3)S(O)2CF3,
-OS(O)2CH3,
-S(O)2NH2, and
-S(O)2NHCH3, and
R92 and R93 are independently selected from:
C1-Salkyl,
2017/053511
C1-3alkyl substituted with from 1 to 3 substituents
ndently selected from: oxo, -N(CHzCH3)3,
2piperidinyl, and NH2, or
R92 and R93 are taken together with the nitrogen to which they are
attached, and optionally from 1 to 3 additional heteroatoms,
to form a heterocycloalkyl selected from:
pyrrolidinyl,
piperidinyl,
1,4diazepan,
piperazinyl,
2,9-diazaspiro[5.5]undecan,
2,8—diazaspiro[4.5]decan,
dro-1H-pyrrolo[1,2a][1,4]diazepin,
morpholin,
1-oxaazaspiro[3.4]octan,
1,7-diazaspiro[3.5]nonan,
2,7-diazaspiro[3.5]nonan,
2,6-diazaspiro[3.4]octan,
azetidin,
1,8-diazaspiro[4.5]decan, and
-oxaazaspiro[3.4]octan,
all of which are optionally substituted with from 1 to 5
substituents independently selected from:
fluoro,
0x0,
-OH,
-CH3,
-CH20H,
methoxy,
3O -CHZCH3,
-C(O)CH3,
-CH20H20H,
-CHZCH2CH3,
-CH20H20CH3,
-CH20H(OH)CH3,
-CH2C(O)OCH3,
-C(O)CH(CH3)2,
-CH20H2N(CH3)2,
-CH2N(CH3)2,
-CH20H2CH2N(CH3)2,
-NH2,
-NHCH3,
-N(CH3)2,
C(CH3)3,
-NHCH(CH3)2,
-NHC(O)CH(CH3)(NH2),
-NHC(O)C(CH3)3,
-N(CH3)cyclobutane,
-CH2NH2,
-CH2pyrrolidinyI,
-CH20H2NH2,
-CH20H2CH2NH2,
CH3)2,
-S(O)2CH2CH3.
-S(O)2CH3,
benzoyL
3-pyrrolidinylpropyl,
2-cyclopropylmethyl,
dinyl,
morpholinyl,
morpholinylmethyl,
methylpiperazinylmethyl,
pyrrolidinyl,
pyrrolidinylmethyl,
piperazinylmethyl,
oxoimidazolidinyl, and
2-hydroxyethylpiperidinyl;
or a pharmaceutically acceptable salt or prodrug thereof.
Suitably in the compounds of Formula (8), the compounds are in the form of a
phosphate prodrug.
This invention relates to novel compounds of a (Sa) and to the use of
compounds of Formula (Sa) in the methods of the invention:
NSC c’
923 I
\lil N/ SAR91a
wherein:
R903 is ed from:
ethyl,
-CH20F3, and
cyclopropyl;
R91a is selected from:
phenyl, and
phenyl substituted with from 1 to 2 substituents independently selected
from:
fluoro,
chloro,
C1-4alkoxy,
C1-4alkoxy substituted with from 1 to 3 substituents
ndently selected from: fluoro, chloro, 0x0,
-OH, -NH2, -NHCH3, and —N(CH3)2,
C1-Balkyl,
C1-6alkyl substituted with from 1 to 3 substituents
independently selected from: fluoro, chloro, bromo,
iodo, 0x0, -S(O)20H3, --CN, -OR793’ and
_NR76a‘R77a',
where R763, and R773, are independently
selected form: hydrogen, -S(O)2CH3,
C1-5alky| and C1-5alky| substituted with from
1 to 4 substituents independently ed
from: fluoro, oxo, -OH, -OC1-5alkyl,
-OC1-5alkyl substituted from 1 to 6 times by
fluoro, —COOH and —NR783’R793', where
R783, and R793, are independently selected
form: hydrogen, phenyl, C1-5alkyl and
C1-5alky| tuted with from 1 to 4
substituentsindependently selected from:
fluoro, 0x0, -OH, alkyl, -OC1-5alkyl
substituted from 1 to 6 times by fluoro and
—COOH,
tetrahydroisothiazolyl,
tetrahydroisothiazolyl substituted twice by oxo,
ydro-1,2—thiazinyl,
tetrahydro-1,2—thiaziny| tuted twice by 0x0,
-N(CH3)S(O)ZCH3,
-N(CH3)S(O)2CFH2,
-N(CH3)S(O)2CF2H,
-N(CH3)S(O)2CF3,
-OS(O)2CH3,
1o -S(O)2NH2, and
-S(O)2NHCH3, and
R923 and R933 are independently selected from:
kyl,
C1-3alky| substituted with from 1 to 3 substituents
independently selected from: oxo, -N(CHzCH3)3,
-CH2CH2piperidinyl, and NH2, or
R92a and R933 are taken er with the nitrogen to which they are
attached, and optionally from 1 to 3 additional heteroatoms,
to form a heterocycloalkyl selected from:
pyrrolidinyl,
piperidinyl,
1,4diazepan,
piperazinyl,
2,9—diazaspiro[5.5]undecan,
2,8—diazaspiro[4.5]decan,
octahydro-1H-pyrrolo[1,2a][1,4]diazepin,
morpholin,
1-oxaazaspiro[3.4]octan,
1,7-diazaspiro[3.5]nonan,
2017/053511
2,7-diazaspiro[3.5]nonan,
2,6-diazaspiro[3.4]octan,
azetidin,
1,8—diazaspiro[4.5]decan, and
5-oxaazaspiro[3.4]octan,
all of which are optionally substituted with from 1 to 5
substituents independently selected from:
fluoro,
0x0,
-OH,
-CH3,
-CH20H,
methoxy,
-CH20H3,
-C(O)CH3,
-CHZCH20H,
-CH20H2CH3,
-CH20H200H3,
-CH2CH(OH)CH3,
-CH20(O)OCH3,
-C(O)CH(CH3)2,
-CH2CH2N(CH3)2,
-CH2N(CH3)2,
-CH20H2CH2N(CH3)2,
-NH2,
-NHCH3,
-N(CH3)2,
WO 16727
-NHCH2C(CH3)3,
-NHCH(CH3)2,
-NHC(O)CH(CH3)(NH2),
-NHC(O)C(CH3)3,
-N(CH3)cycIobutane,
-CH2NH2,
-CH2pyrro|idiny|,
-CHZCH2NH2,
-CH20H2CH2NH2,
1O -CH2N(CH3)2,
-S(O)2CH2CH3,
-S(O)2CH3,
benzoyL
3-pyrrolidinylpropyl,
2-cyclopropylmethyl,
piperidinyl,
morpholinyl,
morpholinylmethyl,
methylpiperazinylmethyl,
pyrrolidinyl,
pyrrolidinylmethyl,
piperazinylmethyl,
oxoimidazolidinyl, and
2-hydroxyethylpiperidinyl;
or a pharmaceutically able salt or g thereof.
Suitably in the compounds of Formula (Sa), the compounds are in the form of a
phosphate prodrug.
Primary Amide
This invention relates to compounds of Formula (lbr) and to the use of compounds
of Formula (lbr) in the methods ofthe invention:
R1br
I NH 2
R5br N/ Ybr)\fl/
O (I bf)
wherein:
X1br and X2br are independently selected from:
--CN,
fluoro,
chloro,
bromo,
iodo,
C1-6alky|,
-OC1-6a|ky|,
-ORe,
cycloalkyl,
cycloalkyl tuted from 1 to 4 times by Rd,
heterocycloalkyl,
cycloalkyl substituted from 1 to 4 times by Rd,
-SH, and
-SRa;
Ybr is selected from: 8, NH, NRZ, 0, 8(0), and S(O)2;
R1br is selected from:
-NH2,
-NHR§
-NRbR9
--CN,
fluoro,
chloro,
bromo,
iodo,
C1-6a|ky|,
-OC1-6a|ky|,
-OR?
cycloalkyl,
cycloalkyl substituted from 1 to 4 times by Rd,
heterocycloalkyl,
heterocycloalkyl substituted from 1 to 4 times by Rd,
aryl.
aryl substituted from 1 to 4 times by Rd,
heteroaryl,
heteroaryl substituted from 1 to 4 times by Rd,
-SH, and
-SR%
R3br is selected from:
hydrogen,
C1-6alkyl,
heterocycloalkyl,
heterocycloalkyl tuted from 1 to 4 times by Rd,
aryl,
3O aryl substituted from 1 to 4 times by Rd,
heteroaryl, and
heteroaryl tuted from 1 to 4 times by Rd; and
R5br is selected from:
-NHz
-NHR?
-NRbRc,
aryl,
aryl substituted from 1 to 4 times by Rd,
-C1-6a|kyl,
-OC1-6a|ky|,
-ORe,
-Oaryl,
-Oaryl substituted from 1 to 4 times by Rd,
-Oheteroaryl,
-Oheteroary| substituted from 1 to 4 times by Rd,
-SH, and
-SRa;
where:
each Ra is independently selected from
C1-6alkyl,
aryl,
aryl substituted from 1 to 4 times by Rd,
heteroaryl,
heteroaryl substituted from 1 to 4 times by Rd
cycloalkyl,
lkyl substituted from 1 to 4 times by Rd,
heterocycloalkyl, and
heterocycloalkyl substituted from 1 to 4 times by Rd;
Rb and R0 are independently ed from:
C1—6alkyl,
aryl,
aryl substituted from 1 to 4 times by Rd,
heteroaryl,
heteroaryl substituted from 1 to 4 times by Rd;
lkyl,
cycloalkyl substituted from 1 to 4 times by Rd,
heterocycloalkyl, and
heterocycloalkyl substituted from 1 to 4 times by Rd, or
Rb and R0 are taken together with the nitrogen to which they are
attached, and optionally from 1 to 3 additional heteroatoms
independently selected from O, N, and 8,, to form a cycloalkyl,
which is optionally substituted with from 1 to 5 substituents
independently selected from:
fluoro,
chloro,
bromo,
iodo,
1o C1-Balkyl,
aryl substituted from 1 to 4 times by Rd,
lkyl,
cycloalkyl substituted from 1 to 4 times by Rd,
heterocycloalkyl, and
heterocycloalkyl substituted from 1 to 4 times by Rd,
C1-4alkoxy,
—-CN,
-N021
-NH2,
-N(H)C1-Salkyl,
-N(H)Re,
5alkyl)2,
-NReRe,
3o -N(Re)C1-5alkyl,
-ONHC(NH)NH2,
-Oheterocycloalkyl,
-NHcycloalkyl,
-N(C1-5alkyl)cycloalkyl,
-NHheterocycloalkyl,
-N(C1-5alkyl)heterocycloalkyl,
-S(O)2C1-4alkyl,
-S(O)2pheny|,
benzoyL
2-methylcyclopropyl,
imidazolyl,
(methoxypyridinylmethyl)amino,
(methylcyclopropylmethyl)amino,
(fluorophenylmethyl)amino,
(methyloxetanylmethyl)amino, and
(methylcyclobutylmethyl)amino,
each RCl is independently selected from:
fluoro,
chloro,
bromo,
iodo,
kyl,
heteroaryl,
heteroaryl substituted from 1 to 4 times by RX,
where RX is selected from aryl, heteroaryl, cycloalkyl,
heterocyloalkyl, C1-6alkyl, and C1-6alkyl substituted with
from 1 to 6 substituents independently selected from:
fluoro, 0x0, -OH, -COOH, -NH2, and -CN,
cycloalkyl,
cycloalkyl substituted from 1 to 4 times by RX,
where RX is selected from aryl, heteroaryl, cycloalkyl,
cyloalkyl, C1-6alky|, and C1-6alkyl substituted with
from 1 to 6 substituents independently selected from:
fluoro, 0x0, -OH, -COOH, -NH2, and -CN,
heterocycloalkyl,
heterocycloalkyl substituted from 1 to 4 times by RX,
where RX is selected from aryl, heteroaryl, cycloalkyl,
heterocyloalkyl, C1-6alkyl, and C1-6alkyl substituted with
from 1 to 6 substituents independently selected from:
fluoro, 0x0, -OH, -COOH, -NH2, and -CN,
aryl,
aryl substituted from 1 to 4 times by RX,
where RX is selected from aryl, heteroaryl, cycloalkyl,
heterocyloalkyl, C1-ealkyl, and C1-6a|kyl substituted with
from 1 to 6 substituents independently selected from:
fluoro, 0x0, -OH, -COOH, -NH2, and -CN,
C1-4a|koxy,
C1-4alkoxy substituted from 1 to 4 times by fluoro,
-Oaryl,
-Oary| substituted from 1 to 4 times by RX,
where RX is selected from aryl, heteroaryl, cycloalkyl,
heterocyloalkyl, C1-6alky|, and C1-6alkyl tuted with
from 1 to 6 substituents ndently selected from:
fluoro, 0x0, -OH, -COOH, -NH2, and -CN,
-ORe,
-C(O)RZZ,
-C(O)ary|,
-C(O)ary| substituted from 1 to 4 times by R22,
eteroaryl,
-C(O)heter0ary| substituted from 1 to 4 times by R22,
-OC(O)H,
RZZ,
-OC(O)ary|,
-CO(O)ary| substituted from 1 to 4 times by R22,
-OC(O)heteroaryl,
heteroaryl substituted from 1 to 4 times by R22
WO 16727
where RX is selected from aryl, heteroaryl, cycloalkyl,
heterocyloalkyl, C1-6alkyl, and C1-6alkyl substituted with
from 1 to 6 substituents independently selected from:
fluoro, 0x0, -OH, -COOH, -NH2, and -CN,
-S(O)H,
-S(O)RX,
where RX is selected from aryl, heteroaryl, cycloalkyl,
cyloalkyl, C1-6alky|, and C1-6a|kyl substituted with
from 1 to 6 substituents independently selected from:
fluoro, 0x0, -OH, -COOH, -NH2, and -CN,
-S(O)2H,
-S(O)2RX,
where RX is selected from aryl, heteroaryl, lkyl,
heterocyloalkyl, C1-6alkyl, and C1-6alkyl tuted with
from 1 to 6 substituents independently selected from:
fluoro, oxo, -OH, -COOH, -NH2, and -CN,
-S(O)2NH2.
-S(O)2NHRX,
where RX is selected from aryl, heteroaryl, cycloalkyl,
heterocyloalkyl, C1-6alkyl, and C1-6alkyl substituted with
from 1 to 6 substituents independently selected from:
fluoro, 0x0, -OH, -COOH, -NH2, and -CN,
-S(O)2NRX1RX2
where RX1 and RX2 are each independently ed from
aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C1-6a|kyl, and
C1-6alkyl substituted with from 1 to 6 tuents
independently selected from: fluoro, oxo, -OH, -COOH,
-NH2, and -CN,
-P(O)(CH3)2,
-NHS(O)2H,
-NHS(O)2RX,
where RX is selected from aryl, heteroaryl, cycloalkyl,
cyloalkyl, C1-6alkyl, and C1-6alkyl substituted with
from 1 to 6 substituents independently selected from:
fluoro, 0x0, -OH, -COOH, -NH2, and -CN,
-NHC(O)H,
-NHC(O)RX,
where RX is selected from aryl, heteroaryl, cycloalkyl,
heterocyloalkyl, C1-6alkyl, and C1-6alkyl substituted with
from 1 to 6 substituents independently selected from:
fluoro, 0x0, -OH, -COOH, -NH2, and -CN,
-C(O)NHRX,
where RX is selected from aryl, heteroaryl, cycloalkyl,
heterocyloalkyl, C1-6alkyl, and C1-6alkyl substituted with
from 1 to 6 substituents independently selected from:
fluoro, 0x0, -OH, -COOH, -NH2, and -CN,
-C(O)NRX1RX2,
where RX1 and RX2 are each independently selected from
aryl, heteroaryl, cycloalkyl, cyloalkyl, C1-6alkyl, and
kyl substituted with from 1 to 6 substituents
independently selected from: fluoro, 0x0, -OH, -COOH,
-NH2, and —-CN,
-C(O)OH,
-C(O)ORX,
where RX is selected from aryl, heteroaryl, cycloalkyl,
heterocyloalkyl, C1-6alkyl, and C1-6alkyl substituted with
from 1 to 6 substituents independently ed from:
fluoro, 0x0, -OH, -COOH, -NH2, and -CN,
-NH2,
-NHRX,
where RX is selected from aryl, heteroaryl, cycloalkyl,
3O heterocyloalkyl, C1-ealkyl, and C1-ealkyl substituted with
from 1 to 6 tuents independently selected from:
fluoro, 0x0, -OH, -COOH, -NH2, and -CN,
-NRX1RX2,
where RX1 and RX2 are each independently ed from
aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C1_6alkyl, and
kyl substituted with from 1 to 6 substituents
independently selected from: fluoro, 0x0, -OH, -COOH,
-NH2, and -CN,
-NH2,
-CN,
-NHC(O)NH2,
-NHC(O)NHRX,
where RX is ed from aryl, heteroaryl, cycloalkyl,
heterocyloalkyl, kyl, and C1-6alkyl substituted with
from 1 to 6 substituents independently selected from:
fluoro, 0x0, -OH, -COOH, -NH2, and —CN,
-NHC(O)NRX1RX2,
where RX1 and RX2 are each independently ed from
aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C1-6alkyl, and
C1-6alkyl substituted with from 1 to 6 substituents
independently selected from: fluoro, oxo, -OH, -COOH,
-NH2, and -CN,
each Re is independently selected from:
C1-6alkyl substituted with from 1 to 9 substitutents independently
selected from:
fluoro,
chloro,
bromo,
iodo,
-oc1-ealky|,
-OC1-6alkyl substituted with from 1 to 6 tuents
ndently selected from: fluoro, oxo, -OH,
-COOH, -NH2, and -CN,
-OC(O)C1-6alkyl,
-OC(O)C1-6alkyl substituted with from 1 to 6 substituents
independently selected from: fluoro, oxo, -OH,
-COOH, -NH2, and -CN,
-ONHC(NH)NH2,
-OP(O)(OH)2,
where RX is ed from aryl, heteroaryl,
cycloalkyl, heterocyloalkyl, C1-ealkyl, and C1-6alkyl
substituted with from 1 to 6 substituents
independently selected from: fluoro, oxo, -OH,
-COOH, -NH2, and —CN,
-S(O)H,
-S(0)RX,
where RX is selected from aryl, heteroaryl,
cycloalkyl, heterocyloalkyl, C1-6alkyl, and C1-6alkyl
substituted with from 1 to 6 substituents
independently selected from: fluoro, oxo, -OH,
-COOH, -NH2, and -CN,
-S(O)2 RX.
where RX is selected from aryl, heteroaryl,
cycloalkyl, heterocyloalkyl, C1-ealkyl, and C1-6alky|
substituted with from 1 to 6 substituents
independently selected from: fluoro, oxo, -OH,
-COOH, -NH2, and —CN,
-NH2,
-NHRXX,
where RXX is selected from aryl, heteroaryl,
cycloalkyl, cycloalkyl substituted with C1-4alkoxy,
C1-4alkoxy substituted with from 1 to 6 substituents
independently selected from: , triazolyl,
cyclopropyl,oxo, -ORXV, -COOH, -CN, and -NRXVRXZ,
where ny and RXZ are Independently selected from:
hydrogen, aryl, kyl heterocyloalkyl, C1-6alkyl,
and C1-6alkyl substituted with from 1 to 6 substituents
independently selected from: fluoro, 0x0, 0ny,
-COOH, —CN, and -NRXVRXZ, where ny and RXZ are
Independently selected from: hydrogen, aryl,
C1-5alkyl and C1-5alkyl substituted with from 1 to 4
substituents independently selected from: fluoro,
lyl, cyclopropyl,oxo, -OH, -OC1-5alkyl,
alkyl substituted from 1 to 6 times by fluoro
and —COOH,
_NRX1 Rx2
where RX1 and RX2 are each independently ed
from aryl, heteroaryl, cycloalkyl, heterocyloalkyl,
C1-4alkoxy, C1-6alkyl, and C1-6alkyl tuted with
from 1 to 6 substituents independently selected from:
fluoro, C1-4alkoxy, lyl, cyclopropyl, oxo, -OH, -
COOH,
-NH2, and -CN,
ino,
-C(O)OH,
-C(O)ORX,
where RX is selected from aryl, heteroaryl,
cycloalkyl, heterocyloalkyl, C1-6alkyl, and C1-6alky|
substituted with from 1 to 6 substituents
independently selected from: fluoro, oxo, -OH,
-COOH, -NH2, and —CN,
-C(O)NH2,
-C(O)NHRX,
where Rx is selected from aryl, heteroaryl, -OH,
C1-4alkoxy, cycloalkyl, cycloalkyl substituted with
HO-(C1-4alkyl)-, heterocyloalkyl, heterocyloalkyl
substituted with HO-(C1-4alkyI)-, C1-6alky|, and
C1-6alky| substituted with from 1 to 6 substituents
independently ed from: fluoro, oxo, -OH,
-COOH, heteroaryl, -NH2, and —-CN,
-C(O)NRX1RX2,
where RX1 and RX2 are each independently selected
from aryl, heteroaryl, lkyl, cycloalkyl substituted
with HO-(C1-4alkyI)-, heterocyloalkyl, C1-6alkyl, and
C1-6alkyl substituted with from 1 to 6 substituents
independently selected from: fluoro, oxo, -OH,
-COOH, -NH2, and —CN,
or RX1 and RX2 taken together with the nitrogen to
which they are attached, and optionally from 1 to 3
additional heteroatoms ndently selected from
O, N, and S, to form a heterocycloalkyl, which is
optionally substituted with from 1 to 5 tuents
independently selected from fluoro, 0x0, -OH, HO-
(C1-4alkyI)-, -COOH, -NH2, and -CN,
2017/053511
aryl substituted from 1 to 4 times by RX,
where RX is selected from fluoro, chloro, bromo, iodo,
aryl, heteroaryl, cycloalkyl, heterocyloalkyl, kyl,
and kyl substituted with from 1 to 6 substituents
independently selected from: fluoro, oxo, -OH,
-COOH, -NH2, -N(CH3)2, -NHC(O)C1-4a|kyl, and —
-Oaryl,
-Oaryl substituted from 1 to 4 times by RX,
where RX is ed from aryl, heteroaryl,
cycloalkyl, heterocyloalkyl, C1-ealkyl, and kyl
substituted with from 1 to 6 substituents
independently selected from: fluoro, oxo, -OH,
-COOH, -NH2, -N(CH3)2, and -CN,
heteroaryl,
heteroaryl substituted from 1 to 4 times by RX,
where RX is selected from aryl, heteroaryl,
cycloalkyl, heterocyloalkyl, C1-4alkoxy, C1-6alkyl,
and C1-6alkyl substituted with from 1 to 6 substituents
independently selected from: fluoro, 0x0, -OH,
-COOH, -NH2, and —CN,
-Oheteroaryl,
-Oheteroaryl substituted from 1 to 4 times by RX,
where RX is selected from aryl, heteroaryl,
cycloalkyl, heterocyloalkyl, C1-6alkyl, and C1-6alkyl
substituted with from 1 to 6 substituents
independently selected from: fluoro, oxo, -OH,
-COOH, -NH2, -N(CH3)2, and -CN,
cycloalkyl,
cycloalkyl substituted from 1 to 4 times by RX,
where Rx is selected from aryl, heteroaryl,
cycloalkyl, heterocyloalkyl, kyl, and C1-6alkyl
substituted with from 1 to 6 substituents
ndently ed from: fluoro, oxo, -OH,
-COOH, -NH2, -N(CH3)2, and -CN,
heterocycloalkyl,
heterocycloalkyl substituted from 1 to 4 times by RX,
where RX is selected from 0x0, -OH,
-N(C1-4alkyl)2, aryl, heteroaryl,
cycloalkyl, heterocyloalkyl, C1-ealkyl, and C1-6alky|
substituted with from 1 to 6 substituents
independently selected from: fluoro, oxo, -OH,
-COOH, -NH2, -N(CH3)2, and -CN,
NH2,
-S(O)2NHRX,
where RX is selected from aryl, heteroaryl,
cycloalkyl, heterocyloalkyl, C1-6alkyl, and C1-6alkyl
substituted with from 1 to 6 substituents
independently selected from: fluoro, oxo, -OH,
-COOH, -NH2, and —-CN,
-S(O)2NRX1RX2,
where RX1 and RX2 are each independently selected
from aryl, aryl, cycloalkyl, cyloalkyl,
C1-ealkyl, and C1-6alkyl substituted with from 1 to 6
Substituents independently selected from: fluoro,
oxo, -OH, -COOH, -NH2, and —CN,
-NHS(O)2H,
-NHS(O)2RX,
where RX is selected from aryl, heteroaryl,
cycloalkyl, heterocyloalkyl, C1-ealkyl, and C1-6alky|
substituted with from 1 to 6 tuents
independently selected from: fluoro, oxo, -OH,
-COOH, -NH2, and —CN,
-OC(O)NH2,
-NHC(O)RX,
where Rx is selected from aryl, heteroaryl,
cycloalkyl, heterocyloalkyl, C1-6alkyl, and C1-6alky|
substituted with from 1 to 6 substituents
ndently selected from: , oxo, -OH,
-COOH, -NH2, and -CN
-NHC(O)NHRXp,
where RXp is selected from heteroaryl,
cycloalkyl, heterocyloalkyl, and Ct-Salkyl
substituted with from 1 to 4 substituents
ndently selected from: -COOH, -NH2, and
—-CN,
-NHC(O)NRX3RX4,
where RX3 and RX4 are each independently selected
from heteroaryl, lkyl, heterocyloalkyl,
and C1-6alky| substituted with from 1 to 6
Substituents independently selected from:
-COOH, -NH2, and —-CN,
-NHC(O)C(O)NH2,
-N02, and
-CN; and
RZ is selected from
C1—68Ikyl,
cycloalkyl,
cycloalkyl substituted from 1 to 4 times by Rd,
heterocycloalkyl, and
heterocycloalkyl substituted from 1 to 4 times by Rd;
R22 is selected from
C1-6alkyl, and
ed that:
are not both hydrogen;
or a pharmaceutically acceptable salt or prodrug thereof.
Suitably in the compounds of Formula (lbr) R3hr is aryl ally substituted from 1
to 4 times by Rd.
Suitably in the compounds of Formula (lbr) neither x1br nor X2br are hydrogen.
ly in the compounds of a (lbr), the compounds are in the form of a
phosphate prodrug.
Suitably in the compounds of Formula (lbr), the compounds are in the form of a
—C(O)CH(NH2)CH(CH3)2 prodrug.
Included in the compounds ofthe invention and used in the methods ofthe invention
are compounds of Formula (Ilbr):
R21br
21 brit WW2N/ 22br
X X R23m
Y1br
R25” 0 (llbr)
wherein:
X21 br and X22br are independently selected from:
hydrogen,
cyano,
fluoro,
bromo,
iodo,
C1 -6a|kyl,
Re,
-OC1-6alkyl,
-ORe,
lkyl,
heterocycloalkyl, and
-SH;
Y1br is selected from: 8, NH, and NRZ;
R21hr is selected from:
amino,
cyano,
fluoro,
chloro,
bromo,
iodo,
C1-6alkyl,
Re,
-OCl-Galkyl,
2017/053511
-OR§
-NHR§
-NRbR9
cycloalkyl,
cycloalkyl substituted with from 1 to 4 times by Rd,
heterocycloalkyl,
heterocycloalkyl substituted from 1 to 4 times by Rd,
aryl,
aryl substituted from 1 to 4 times by Rd,
heteroaryl,
heteroaryl tuted from 1 to 4 times by Rd,
-SH, and
-SR%
R23hr is selected from:
C1-6alkyl,
C1-6alky| substituted with from 1 to 9 substituents
independently selected from: fluoro, chloro,
C1-4alkoxy, oxo, phenyl, cycloalkyl, heterocycloalkyl,
-OH, -NH2, -N(H)C1-4alkyl, -N(C1_4a|kyl)2, and —-CN,
heterocycloalkyl,
aryl,
aryl substituted from 1 to 4 times by Rd,
heteroaryl, and
heteroaryl substituted from 1 to 4 times by Rd; and
R25hr is ed from:
amino,
-NHR?
3o -NRbR9
aryl,
aryl substituted from 1 to 4 times by Rd,
-OC1-6a|ky|,
-OR?
-Oaryl,
-Oheteroaryl,
-SH, and
-SRa;
where:
each Ra is independently selected from
kyl,
aryl,
aryl substituted from 1 to 4 times by Rd,
heteroaryl,
heteroaryl substituted from 1 to 4 times by Rd
lkyl,
cycloalkyl substituted from 1 to 4 times by Rd,
heterocycloalkyl, and
heterocycloalkyl substituted from 1 to 4 times by Rd;
Rb and R0 are independently ed from:
C1—68Ikyl,
Re,
aryl,
aryl substituted from 1 to 4 times by Rd,
heteroaryl,
heteroaryl substituted from 1 to 4 times by Rd;
cycloalkyl,
cycloalkyl substituted from 1 to 4 times by Rd,
heterocycloalkyl, and
heterocycloalkyl substituted from 1 to 4 times by Rd, or
Rb and RC are taken together with the nitrogen to which they are
attached, and optionally from 1 to 3 additional heteroatoms, to form
a heterocycloalkyl, which is optionally substituted with from 1 to 5
tuents independently selected from:
fluoro,
chloro,
bromo,
iodo,
aryl substituted from 1 to 4 times by Rd,
cycloalkyl,
cycloalkyl substituted from 1 to 4 times by Rd,
cycloalkyl, and
heterocycloalkyl substituted from 1 to 4 times by Rd,
koxy,
C1-4alkoxy substituted with from 1 to 6 substituents
independently selected from: fluoro, 0x0, -OH,
-COOH, -NH2, and —-CN,
—-CN,
0x0,
-OH,
-COOH,
-N02,
-NH2,
-N(H)C1-4a|kyl,
-N(H)Re,
-N(C1-4alky|)2,
-ONHC(NH)NH2,
-Oheterocyc|oa|ky|,
-NHcyc|oa|kyl,
-NHheterocycloa|ky|,
-S(O)ZCH2CH3,
-S(O)2CH2CH2CH3,
-SOzNH2,
-S(O)2pheny|,
-S(O)2CH3.
benzoyL
benzylamino,
3-pyrrolidinylpropyl,
opropylmethyl,
cyclobutylamino,
cyclobutyI-N(CH3)-,
piperidinyl,
imidazolyl,
morpholinyl,
morpholinylmethyl,
methylpiperazinylmethyl,
methylpiperazinyl,
pyrrolidinyl,
pyrrolidinylmethyl,
methoxypyridinylmethylamino,
methylpyrrolidinyl,
opyrrolidinyl,
dimethylpyrrolidinyl,
methylcyclopropylmethylamino,
hyd roxymethylpyrrolidinyl,
fluoropyrrolidinyl,
fluorophenylmethylamino,
piperazinylmethyl,
oxazolidinyl,
methyloxetanmethylamino,
methylcyclobutylmethylamino,
dazolidinyl, and
2-hydroxyethylpiperidinyl;
each Rd is independently selected from:
fluoro,
bromo,
iodo,
C1—6alkyl,
heteroaryl,
heteroaryl substituted from 1 to 4 times by RX,
where RX is selected from aryl, aryl, cycloalkyl,
heterocyloalkyl, C1-6alkyl, and C1-6alkyl substituted with
1O from 1 to 6 substituents independently selected from:
fluoro, 0x0, -OH, -COOH, -NH2, and —-CN,
cycloalkyl,
cycloalkyl substituted from 1 to 4 times by RX,
where RX is selected from aryl, aryl, lkyl,
heterocyloalkyl, C1-6alkyl, and C1-6alkyl substituted with
from 1 to 6 substituents independently selected from:
fluoro, 0x0, -OH, -COOH, -NH2, and —-CN,
cycloalkyl,
heterocycloalkyl substituted from 1 to 4 times by RX,
where RX is selected from aryl, heteroaryl, cycloalkyl,
heterocyloalkyl, C1-6alkyl, and ky| substituted with
from 1 to 6 substituents independently selected from:
fluoro, oxo, -OH, -COOH, -NH2, and —-CN,
aryl,
aryl substituted from 1 to 4 times by RX,
where RX is selected from aryl, heteroaryl, cycloalkyl,
heterocyloalkyl, C1-6alkyl, and C1-6alkyl substituted with
from 1 to 6 substituents independently selected from:
fluoro, 0x0, -OH, -COOH, -NH2, and —-CN,
3O C1-4alkoxy,
C1-4alkoxy substituted from 1 to 4 times by fluoro,
-Oaryl,
-Oary| substituted from 1 to 4 times by RX,
where RX is selected from aryl, heteroaryl, cycloalkyl,
heterocyloalkyl, C1-6alkyl, and C1-ealkyl tuted with
from 1 to 6 substituents independently selected from:
fluoro, 0x0, -OH, -COOH, -NH2, and —-CN,
-C(0)RZZ,
-C(O)ary|,
-C(O)ary| substituted from 1 to 4 times by R22,
-C(O)heteroaryl,
-C(O)heteroaryl substituted from 1 to 4 times by R22,
-OC(O)H,
-CO(O)RZZ,
-OC(O)aryl,
-CO(O)ary| substituted from 1 to 4 times by R22,
-OC(O)heteroaryl,
heteroaryl substituted from 1 to 4 times by R22,
mercapto,
-SRX,
where RX is selected from aryl, aryl, cycloalkyl,
cyloalkyl, C1-6alky|, and kyl substituted with
from 1 to 6 substituents independently selected from:
fluoro, 0x0, -OH, -COOH, -NH2, and —-CN,
-S(O)H,
-S(O)RX,
where RX is selected from aryl, heteroaryl, cycloalkyl,
cyloalkyl, C1-6alkyl, and C1-6alkyl substituted with
from 1 to 6 substituents independently selected from:
fluoro, 0x0, -OH, -COOH, -NH2, and —-CN,
-S(O)2H,
-S(O)2RX,
where RX is selected from aryl, heteroaryl, cycloalkyl,
heterocyloalkyl, C1_ealkyl, and C1-6alkyl substituted with
from 1 to 6 substituents independently selected from:
fluoro, 0x0, -OH, -COOH, -NH2, and —-CN,
-S(O)2NH2,
-S(O)2NHRX,
where RX is selected from aryl, heteroaryl, cycloalkyl,
heterocyloalkyl, C1-6alkyl, and C1-6alkyl tuted with
from 1 to 6 substituents independently selected from:
fluoro, oxo, -OH, -COOH, -NH2, and —-CN,
-S(O)2NRX1RX2,
where RX1 and RX2 are each independently selected from
aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C1-6alkyl, and
kyl substituted with from 1 to 6 substituents
independently ed from: fluoro, oxo, -OH, -COOH,
-NH2, and —-CN,
-P(O)(CH3)2,
)2H,
-NHS(O)2RX,
where RX is ed from aryl, heteroaryl, cycloalkyl,
1O heterocyloalkyl, C1-ealkyl, and C1-6alkyl substituted with
from 1 to 6 substituents independently selected from:
fluoro, 0x0, -OH, -COOH, -NH2, and —-CN,
-NHC(O)H,
-NHC(O)RX,
where RX is selected from aryl, heteroaryl, cycloalkyl,
heterocyloalkyl, C1-6alkyl, and C1-6alkyl substituted with
from 1 to 6 substituents independently selected from:
fluoro, oxo, -OH, -COOH, -NH2, and —-CN,
-C(O)NH2.
-C(O)NHRX,
where RX is selected from aryl, heteroaryl, lkyl,
heterocyloalkyl, C1-6alkyl, and C1-6alkyl substituted with
from 1 to 6 substituents independently selected from:
fluoro, 0x0, -OH, -COOH, -NH2, and —-CN,
-C(O)NRX1RX2,
where RX1 and RX2 are each independently ed from
aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C1-6alky|, and
C1-6alkyl substituted with from 1 to 6 substituents
independently selected from: fluoro, oxo, -OH, -COOH,
-NH2, and —-CN,
-C(O)OH,
where RX is selected from aryl, heteroaryl, cycloalkyl,
heterocyloalkyl, C1-6alkyl, and C1-6alkyl substituted with
from 1 to 6 substituents independently selected from:
fluoro, 0x0, -OH, -COOH, -NH2, and —-CN,
oxo,
hydroxy,
amino,
-NHRX,
where RX is selected from aryl, heteroaryl, cycloalkyl,
heterocyloalkyl, C1-6alky|, and C1-6a|kyl substituted with
from 1 to 6 substituents independently selected from:
fluoro, 0x0, -OH, -COOH, -NH2, and —-CN,
-NRX1RX2,
where RX1 and RX2 are each independently selected from
aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C1-6alky|, and
C1-6alkyl substituted with from 1 to 6 substituents
independently ed from: fluoro, oxo, -OH, -COOH,
-NH2, and —-CN,
nitro,
cyano,
-NHC(O)NH2.
-NHC(O)NHRX,
where RX is selected from aryl, heteroaryl, lkyl,
heterocyloalkyl, C1-6alkyl, and C1-6alky| substituted with
from 1 to 6 tuents independently selected from:
fluoro, 0x0, -OH, -COOH, -NH2, and —-CN,
-NHC(O)NRX1RX2,
where RX1 and RX2 are each independently ed from
aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C1-6alkyl, and
C1-6a|kyl substituted with from 1 to 6 substituents
independently selected from: fluoro, oxo, -OH, -COOH,
-NH2, and —-CN,
each Re is independently selected from:
C1_6alkyl substituted with from 1 to 9 substitutents independently
selected from:
chloro,
bromo,
iodo,
C1-68lkyl,
-OC1-6a|ky|,
-OC1-6alkyl substituted with from 1 to 6 substituents
independently ed from: fluoro, oxo, -OH,
WO 16727
-COOH, -NH2, and —-CN,
mercapto,
-SRX,
where RX is selected from aryl, heteroaryl,
cycloalkyl, heterocyloalkyl, C1-6alkyl, and C1-6alkyl
substituted with from 1 to 6 tuents
independently ed from: fluoro, oxo, -OH,
-COOH, -NH2, and —-CN,
-S(O)H,
-S(O)RX,
where Rx is selected from aryl, heteroaryl,
cycloalkyl, heterocyloalkyl, kyl, and C1-6alky|
substituted with from 1 to 6 substituents
independently selected from: fluoro, oxo, -OH,
-COOH, -NH2, and —-CN,
-S(O)2H,
-S(O)2RX,
where RX is selected from aryl, aryl,
cycloalkyl, heterocyloalkyl, C1-6alkyl, and C1-6alkyl
substituted with from 1 to 6 substituents
independently selected from: fluoro, oxo, -OH,
-COOH, -NH2, and —-CN,
oxo,
hydroxy,
amino,
-NHRXX,
where RXX is selected from aryl, aryl,
cycloalkyl, heterocyloalkyl, C1-6alkyl,
and C1-6alkyl substituted with from 1 to 6
substituents independently selected from: fluoro,
oxo, -ORXV, -COOH, —-CN, -OC1-5alkyl, -OC1-5alkyl
substituted from 1 to 6 times by fluoro and
—NRXyRXZ, where ny and RXZ are independently
selected from: hydrogen, aryl, C1-5alkyl and
C1-5alkyl substituted with from 1 to 4 substituents
independently selected from: fluoro, oxo, -OH,
-OC1-5alkyl, -OC1-5alky| substituted from 1 to 6
times by fluoro and —COOH,
-NRX1RX2,
where RX1 and RX2 are each ndently selected
from aryl, heteroaryl, cycloalkyl, heterocyloalkyl,
C1-6alkyl, and C1-6alkyl substituted with from 1 to 6
tuents independently selected from: fluoro,
oxo, -OH, -COOH, -NH2, and —-CN,
guanidino,
1O H,
-C(O)ORX,
where RX is selected from aryl, heteroaryl,
lkyl, cyloalkyl, C1-ealkyl, and C1-6alky|
substituted with from 1 to 6 tuents
independently selected from: fluoro, oxo, -OH,
-COOH, -NH2, and —-CN,
-C(O)NH2,
-C(O)NHRX,
where RX is selected from aryl, heteroaryl,
cycloalkyl, heterocyloalkyl, C1-6alkyl, and C1-6alkyl
substituted with from 1 to 6 substituents
independently selected from: fluoro, 0x0, -OH,
-COOH, -NH2, and —-CN,
RX1RX2,
where RX1 and RX2 are each independently selected
from aryl, heteroaryl, cycloalkyl, heterocyloalkyl,
C1-6alkyl, and C1-ea|kyl substituted with from 1 to 6
Substituents independently selected from: fluoro,
0x0, -OH, -COOH, -NH2, and —-CN,
aryl,
aryl substituted from 1 to 4 times by RX,
where RX is selected from aryl, heteroaryl,
cycloalkyl, heterocyloalkyl, C1-ealkyl, and C1-6alky|
substituted with from 1 to 6 substituents
independently selected from: fluoro, oxo, -OH,
-COOH, -NH2, and —-CN,
-Oaryl,
WO 16727
-Oaryl substituted from 1 to 4 times by RX,
where RX is selected from aryl, heteroaryl,
cycloalkyl, heterocyloalkyl, C1-6alkyl, and C1-6alkyl
substituted with from 1 to 6 tuents
independently selected from: fluoro, 0x0, -OH,
-COOH, -NH2, and —-CN,
heteroaryl,
heteroaryl substituted from 1 to 4 times by RX,
where RX is selected from aryl, heteroaryl,
cycloalkyl, heterocyloalkyl, C1-ealkyl, and C1-6alkyl
substituted with from 1 to 6 substituents
independently selected from: , oxo, -OH,
-COOH, -NH2, and —-CN,
-Oheteroaryl,
-Oheteroary| substituted from 1 to 4 times by RX,
where Rx is ed from aryl, heteroaryl,
cycloalkyl, heterocyloalkyl, C1-6alkyl, and C1-6alkyl
substituted with from 1 to 6 substituents
independently selected from: fluoro, oxo, -OH,
-COOH, -NH2, and —-CN,
cycloalkyl,
cycloalkyl substituted from 1 to 4 times by RX,
where RX is selected from aryl, aryl,
cycloalkyl, heterocyloalkyl, C1-6alkyl, and C1-6alkyl
substituted with from 1 to 6 substituents
independently selected from: fluoro, oxo, -OH,
-COOH, -NH2, and —-CN,
heterocycloalkyl,
cycloalkyl substituted from 1 to 4 times by RX,
where RX is selected from aryl, heteroaryl,
cycloalkyl, heterocyloalkyl, C1-6alkyl, and C1-6alkyl
substituted with from 1 to 6 substituents
independently selected from: fluoro, 0x0, -OH,
-COOH, -NH2, and —-CN,
NH2,
-S(O)2NHRX,
where RX is selected from aryl, heteroaryl,
cycloalkyl, heterocyloalkyl, C1-6alkyl, and C1-6alkyl
substituted with from 1 to 6 substituents
independently selected from: fluoro, oxo, -OH,
-COOH, -NH2, and —-CN,
-S(O)2NRX1RX2,
where RX1 and RX2 are each independently selected
from aryl, heteroaryl, cycloalkyl, cyloalkyl,
C1-6alkyl, and C1-6alkyl substituted with from 1 to 6
Substituents ndently selected from: fluoro,
oxo, -OH, -COOH, -NH2, and —-CN,
-NHS(O)2H,
-NHS(O)2RX,
where RX is selected from aryl, heteroaryl,
lkyl, heterocyloalkyl, C1-6alkyl, and C1-6alkyl
substituted with from 1 to 6 substituents
independently ed from: fluoro, oxo, -OH,
-COOH, -NH2, and —-CN,
-NHC(O)NHRXp,
where RXp is selected from heteroaryl,
cycloalkyl, heterocyloalkyl, and C1-6alkyl
substituted with from 1 to 4 tuents
independently selected from: -COOH, -NH2, and
—-CN,
-NHC(O)NRX3RX4,
where RX3 and RX4 are each independently selected
from heteroaryl, cycloalkyl, heterocyloalkyl,
and C1-6alkyl substituted with from 1 to 6
Substituents independently selected from:
-COOH, -NH2, and —-CN,
nitro, and
cyano;and
R2 is selected from
C1 —68|ky|,
cycloalkyl,
cycloalkyl substituted from 1 to 4 times by Rd,
heterocycloalkyl, and
heterocycloalkyl substituted from 1 to 4 times by R ;
R22 is selected from
C1_6alkyl, and
provided that:
X21 br and X22br are not both en;
or a pharmaceutically acceptable salt or prodrug thereof.
Suitably in the compounds of Formula (llbr) R23br is aryl optionally substituted from
1 to 4 times by Rd.
Suitably in the compounds of Formula (llbr) neither X21br nor X22hr are hydrogen.
Suitably in the compounds of Formula (llbr), the compounds are in the form of a
ate prodrug.
Suitably in the compounds of Formula (llbr), the nds are in the form of a
—C(O)CH(NH2)CH(CH3)2 g.
ed in the compounds ofthe invention and used in the methods ofthe invention
are compounds of Formula (lllbr):
R31br
X31br X32br R r
/ 2brWNHZ
R35br N Y O (lllbr)
wherein:
X31hr and X32hr are independently selected from:
hydrogen,
cyano,
fluoro,
chloro,
3O bromo,
iodo,
C1-6alkyl,
-OC1-6a|kyl,
cycloalkyl, and
-SH;
Y2br is selected from: 8, NH, and NRZ;
R31blr is selected from:
C1—6alkyl,
R61,
-OC1-6alkyl,
-ORe1,
-NHRa1,
-NRb1RC1,
cycloalkyl,
cycloalkyl substituted from 1 to 4 times by RM,
heterocycloalkyl,
heterocycloalkyl substituted from 1 to 4 times by Rm,
aryl,
aryl substituted from 1 to 4 times by Rd1,
heteroaryl,
aryl substituted from 1 to 4 times by R“,
-SH, and
-SRa1;
R33hr is selected from:
C1-6alkyl,
heterocycloalkyl,
aryl,
aryl substituted from 1 to 4 times by R“,
heteroaryl, and
aryl substituted from 1 to 4 times by R“; and
R35hr is selected from:
amino,
2017/053511
-NHRa1,
-NRb1RC1,
aryl,
aryl substituted from 1 to 4 times by R“,
-OC1-6a|kyl,
where:
each R811 is independently selected from
C1—Galkyl,
Re1’
aryl,
heteroaryl,
cycloalkyl, and
heterocycloalkyl;
R and R01 are independently ed from:
aryl substituted from 1 to 4 times by Rm,
heteroaryl,
heteroaryl substituted from 1 to 4 times by Rm;
cycloalkyl,
cycloalkyl substituted from 1 to 4 times by R“,
heterocycloalkyl, and
heterocycloalkyl substituted from 1 to 4 times by R“, or
R and RC1 are taken together with the nitrogen to which they are
attached, and optionally from 1 to 3 additional heteroatoms, to form
a heterocycloalkyl, which is optionally substituted with from 1 to 5
tuents independently selected from:
fluoro,
chloro,
bromo,
iodo,
WO 16727
C1-68Ikyl,
aryl,
aryl substituted from 1 to 4 times by R“,
cycloalkyl,
cycloalkyl substituted from 1 to 4 times by Rm,
heterocycloalkyl, and
heterocycloalkyl substituted from 1 to 4 times by R“,
C1-4a|koxy,
C1-4alkoxy substituted with from 1 to 6 substituents
independently selected from: fluoro, oxo, -OH,
-COOH, -NH2, and —-CN,
-OH,
-N021
-NH2,
-N(H)C1-4a|ky|,
-N(H)Re1,
-N(C1-4a|ky|)2,
-ONHC(NH)NH2,
-Oheterocyc|oa|ky|,
-NHcycIoalkyl,
-NHheterocycIoa|ky|,
-S(O)ZCHZCH3,
CH2CH2CH3,
-SOzNH2,
-S(O)2phenyl,
-S(O)2CH3,
benzoyL
benzylamino,
3-pyrrolidinylpropyl,
2-cyclopropyl methyl,
utylamino,
utyI-N(CH3)-,
piperidinyl,
imidazolyl,
morpholinyl,
morpholinylmethyl,
methylpiperazinylmethyl,
methylpiperazinyl,
pyrrolidinyl,
pyrrolidinylmethyl,
methoxypyridinylmethylamino,
methylpyrrolidinyl,
difluoropyrrolidinyl,
dimethylpyrrolidinyl,
cyclopropylmethylamino,
hyd roxymethylpyrrolidinyl,
fluoropyrrolidinyl,
fluorophenylmethylamino,
piperazinylmethyl,
oxazolidinyl,
methyloxetanmethylamino,
methylcyclobutylmethylamino,
oxoimidazolidinyl, and
2-hydroxyethylpiperidinyl;
each Rd1 is independently selected from:
fluoro,
chloro,
bromo,
iodo,
kyl,
Re1’
heteroaryl,
heteroaryl substituted from 1 to 4 times by Rxa’
where Rxa is ed from aryl, heteroaryl, cycloalkyl,
heterocyloalkyl, C1-6alkyl, and C1-ealkyl substituted
from 1 to 6 times by fluoro,
cycloalkyl,
lkyl substituted from 1 to 4 times by Rxa’
where Rxa is selected from aryl, heteroaryl, cycloalkyl,
heterocyloalkyl, C1-ealkyl, and C1-6alkyl substituted
from 1 to 6 times by fluoro,
heterocycloalkyl,
heterocycloalkyl substituted from 1 to 4 times by Rxa’
where Rxa is selected from aryl, heteroaryl, cycloalkyl,
heterocyloalkyl, C1-ealkyl, and C1-ealkyl substituted
from 1 to 6 times by fluoro,
aryl,
aryl substituted from 1 to 4 times by Rxa,
where Rxa is selected from aryl, heteroaryl, cycloalkyl,
heterocyloalkyl, C1-6alkyl, and C1-6alkyl substituted
from 1 to 6 times by fluoro,
C1_4alkoxy,
C1-4alkoxy substituted from 1 to 4 times by fluoro,
-Oaryl,
-C(O)aryl,
-C(O)heteroaryl,
-OC(O)H,
-CO(O)RZZ,
ary|,
-OC(O)heteroaryl,
mercapto,
-SRxa,
where Rxa is selected from aryl, heteroaryl, cycloalkyl,
heterocyloalkyl, C1-6alkyl, and C1-6alkyl substituted
from 1 to 6 times by fluoro,
-S(O)H,
-S(O)Rxa,
where Rxa is selected from aryl, heteroaryl, cycloalkyl,
heterocyloalkyl, C1-ealkyl, and C1-6alkyl substituted
from 1 to 6 times by fluoro,
-S(O)2H,
-S(O)2Rxa,
where Rxa is selected from aryl, aryl, cycloalkyl,
heterocyloalkyl, C1-6alkyl, and C1-6alkyl substituted
from 1 to 6 times by ,
-S(O)2NH2,
NHRxa,
where Rxa is selected from aryl, heteroaryl, cycloalkyl,
heterocyloalkyl, C1-6alkyl, and C1-6alkyl substituted
from 1 to 6 times by fluoro,
-P(O)(CH3)2.
-NHS(O)2H,
-NHS(O)2Rxa,
where Rxa is selected from aryl, heteroaryl, cycloalkyl,
heterocyloalkyl, kyl, and C1-6alkyl substituted
from 1 to 6 times by ,
-NHC(O)H,
-NHC(O)RX3,
where Rxa is ed from aryl, heteroaryl, cycloalkyl,
heterocyloalkyl, C1-6alkyl, and C1-6alkyl substituted
from 1 to 6 times by fluoro,
-C(O)NH2,
3O -C(O)NHRxa,
where Rxa is selected from aryl, heteroaryl, cycloalkyl,
heterocyloalkyl, C1-6alkyl, and C1-6alkyl substituted
from 1 to 6 times by fluoro,
-C(O)OH,
-C(O)ORxa,
where Rxa is ed from aryl, heteroaryl, cycloalkyl,
heterocyloalkyl, C1-6alkyl, and C1-6alkyl substituted
from 1 to 6 times by fluoro,
0x0,
hydroxy,
amino,
-NHRxa,
where RXa is selected from aryl, aryl, cycloalkyl,
heterocyloalkyl, C1-6alkyl, and C1-6alkyl substituted
from 1 to 6 times by fluoro,
nitro,
cyano,
-NHC(O)NH2, and
-NHC(O)NHRxa,
where Rxa is selected from aryl, heteroaryl, cycloalkyl,
heterocyloalkyl, C1-6alkyl, and C1-6alkyl substituted
from 1 to 6 times by fluoro;
each Re1 is independently selected from:
C1_6a|ky| substituted with from 1 to 9 substitutents independently
ed from:
fluoro,
chloro,
bromo,
iodo,
C1—Balkyl,
-OC1-6a|kyl,
-OC1-6alky| substituted with from 1 to 6 substituents
independently selected from: fluoro, oxo, -OH,
-COOH, -NH2, and —-CN,
mercapto,
-SRxa,
where Rxa is selected from aryl, heteroaryl,
lkyl, heterocyloalkyl, C1-ealkyl, and C1-6alkyl
substituted from 1 to 6 times by fluoro,
-S(O)H,
-S(0)Rxa,
where Rxa is selected from aryl, heteroaryl,
cycloalkyl, cyloalkyl, C1-ealkyl, and C1-6alkyl
substituted from 1 to 6 times by fluoro,
-S(O)2H,
-S(O)2Rxa,
where Rxa is ed from aryl, heteroaryl,
cycloalkyl, heterocyloalkyl, C1-6alkyl, and C1-6alky|
substituted from 1 to 6 times by fluoro,
oxo,
hydroxy,
amino,
-NHRXX,
where RXX is selected from aryl, heteroaryl,
cycloalkyl, heterocyloalkyl, C1-ealkyl,
and C1-6alkyl substituted with from 1 to 6
substituents independently selected from: fluoro,
oxo, -ORXV, -COOH, —-CN, alkyl, -OC1-5alkyl
substituted from 1 to 6 times by fluoro and
—NRXyRXZ, where ny and R"Z are independently
selected from: hydrogen, aryl, ky| and
kyl substituted with from 1 to 4 substituents
independently selected from: fluoro, oxo, -OH,
-OC1-5a|kyl, -OC1-5a|ky| substituted from 1 to 6
times by fluoro and —COOH,
-NRX1XRX2X,
where RX1X and RXZX are each independently
selected from C1-4alkyl, and kyl substituted
with from 1 to 4 substituents independently selected
from: fluoro, 0x0, and —OH,
guanidino,
-C(O)OH,
-C(O)ORxa,
where Rxa is selected from aryl, heteroaryl,
cycloalkyl, heterocyloalkyl, C1-6alkyl, and C1-6a|kyl
tuted from 1 to 6 times by fluoro,
-C(O)NHRxa,
where Rxa is selected from aryl, heteroaryl,
cycloalkyl, and heterocyloalkyl,
2017/053511
aryl,
aryl substituted from 1 to 4 times by Rxa,
where Rxa is selected from aryl, heteroaryl,
lkyl, heterocyloalkyl, C1-6alkyl, and C1-6alkyl
substituted from 1 to 6 times by fluoro,
-Oaryl,
-Oary| substituted from 1 to 4 times by Rxa’
where Rxa is ed from aryl, heteroaryl,
cycloalkyl, heterocyloalkyl, C1-6alkyl, and C1-6alkyl
substituted from 1 to 6 times by fluoro,
heteroaryl,
heteroaryl substituted from 1 to 4 times by Rxa’
where Rxa is selected from aryl, heteroaryl,
cycloalkyl, heterocyloalkyl, C1-6alkyl, and C1-6alkyl
substituted from 1 to 6 times by fluoro,
-Oheteroaryl,
-Oheteroaryl substituted from 1 to 4 times by Rxa,
where RXE‘l is selected from aryl, heteroaryl,
cycloalkyl, heterocyloalkyl, kyl, and C1-6alkyl
substituted from 1 to 6 times by fluoro,
cycloalkyl,
cycloalkyl substituted from 1 to 4 times by RX,
where RX is selected from aryl, heteroaryl,
cycloalkyl, heterocyloalkyl, C1-6alkyl, and C1-6alkyl
substituted with from 1 to 6 substituents
ndently selected from: fluoro, oxo, -OH,
-COOH, -NH2, and —-CN,
heterocycloalkyl,
heterocycloalkyl substituted from 1 to 4 times by RX,
where RX is selected from aryl, heteroaryl,
cycloalkyl, heterocyloalkyl, C1-6alkyl, and C1-6alkyl
tuted with from 1 to 6 substituents
independently selected from: fluoro, 0x0, -OH,
-COOH, -NH2, and —-CN,
-S(O)2NH2,
NHRxa,
where Rxa is selected from aryl, heteroaryl,
cycloalkyl, heterocyloalkyl, C1-6alkyl, and C1-6alkyl
2017/053511
substituted from 1 to 6 times by fluoro,
)2H,
)2Rxa,
where Rxa is selected from aryl, heteroaryl,
cycloalkyl, heterocyloalkyl, C1-6alkyl, and C1-6a|kyl
substituted from 1 to 6 times by fluoro,
-NHC(O)NHRxa,
where Rxa is selected from heteroaryl,
cycloalkyl, and heterocyloalkyl,
nitro, and
cyano;and
RZ is selected from
C1-6alkyl,
R91,
cycloalkyl,
cycloalkyl substituted from 1 to 4 times by R“,
heterocycloalkyl, and
heterocycloalkyl substituted from 1 to 4 times by R“;
R22 is selected from
C1-6alkyl, and
Re1.
provided that:
X31hr and X32hr are not both hydrogen;
or a pharmaceutically acceptable salt or prodrug thereof.
Suitably in the compounds of Formula (lllbr), neither X31 br nor X32br are hydrogen.
Suitably in the compounds of Formula (lllbr) R33hr is aryl optionally substituted from
1 to 4 times by R‘“.
Suitably in the compounds of Formula ), the compounds are in the form of a
phosphate g.
Suitably in the compounds of Formula (lllbr), the compounds are in the form ofa
—C(O)CH(NH2)CH(CH3)2 g.
This ion relates to novel compounds of Formula (IVbbr) and to the use of
compounds of Formula (IVbbr) in the methods of the invention:
R41bbr
X41b\/bfi\/[X42bbr R43bbr'N/
R45bbr WW2
(IVbbr)
wherein:
X41bbr and X42bblr are independently selected from: --CN, methyl, fluoro, chloro,
bromo and iodo;
Y4bbr is selected from: S and NH;
R41bbr is selected from:
C1-6alkyl,
C1-6alky| substituted with from 1 to 9 substituents
independently selected from: fluoro, chloro, bromo,
iodo, oxo, C1-4alkyloxy, -OH, -COOH, -NH2
1-4alkyl, -N(C1-4a|kyl)2 and -CN,
C1-4alkyloxy,
C1-4alkyloxy substituted from 1 to 4 times by fluoro,
1-4alkyl,
-N(C1-4a|ky|)2,
-SC1-4a|ky|,
aryl,
aryl substituted with from 1 to 4 substituents
independently selected from:
fluoro,
chloro,
bromo,
iodo,
C1-6alkyl,
C1_6alkyl substituted with from 1 to 9 tuents
independently selected from: fluoro, chloro, bromo,
iodo, 0x0, -OH, -NH2 and —CN,
C1-4alkoxy,
—CN,
-NH21
heteroaryl,
heteroaryl substituted with from 1 to 4 substituents
independently selected from:
fluoro,
bromo,
iodo,
C1—6alkyl,
ky| substituted with from 1 to 9 substituents
independently selected from: fluoro, chloro, bromo,
iodo, oxo, -OH, -NH2 and —CN,
C1_4alkoxy,
—CN,
0x0,
-OH,
-N02, and
lkyl,
cycloalkyl substituted with from 1 to 4 substituents
independently selected from:
fluoro,
,
bromo,
iodo,
C1—6alkyl,
C1-6alkyl substituted with from 1 to 9 substituents
independently ed from: fluoro, chloro, bromo,
iodo, oxo, -OH, -NH2 and -CN,
C1—4alk0xy,
-OH,
-NH2;
R43bbr is selected from:
C1-4alkyl,
phenyl,
phenyl substituted with 1 or 2 substituents independently selected
from: fluoro, -CH3, -CF3, chloro, -C(O)phenyl, pyrrolidinyl,
-P(O)(CH3)2, -C(O)NH2, -S(O)2NHCH3, -OCH2CH2N(CH3)2 and
—CH2C(O)NH2,
l,
piperidinyl,
pyridine, and
pyridine substituted with 1 or 2 substituents independently selected
from: fluoro, -CH3, -CF3, and -OCH3;
R44bbr and R45bbr are independently selected from:
hydrogen,
Cl—Galkyl,
C1-6alkyl substituted with from 1 to 9 substituents
independently selected from: , morpholino, lyl,
imidazolyl, pyrrolidinyl, -OC(O)NH2, -OCH2CH2NH2,
-ONHC(NH2)NH2, -NHCHZC(CH3)3, -NOCH3, -NHOH,
-NHCH2CH2F, -N(CH3)CHZCH20CH3, -N(CHZCH3)2,
-NCH(CH20H)2, CH20H)2, -NHCH2CH20H,
-NHCH20H2NH2, -N(CH3)C(CH3)2CH20H, -NHCH20H3,
-NHCH2CH20CH3, -N(CH3)CH2CH20H, -NHC(O)C(O)NH2,
-N(CH3)CH2CH2CH20H, -N(CH3)CH2CH(OH)CH20H,
-N(CH3)CHZCH2NH2, 0X0, -NHCHZC(CH3)ZCH20H, -OH, -NH2,
-NHCH3, -NHCH2CH2CH20H, -N(CH3)2, -N(CH3)CHZCH3,
-NHOC(CH3)2NH2, -N(CH3)CH20yclopropyl, -NHCH20yclopropyl,
-NHoxetanyl, -NCHzCH2triazole, piperazinyl, piperidinyl, pyrazolyl,
azepinyl, azetidinyl, methoxy, and cyclopropylamino,
where said phenyl, morpholino, triazolyl, imidazolyl, azepinyl,
inyl, pyrrolidinyl, piperazinyl, dinyl,
oxetanyl, cyclopropyl, and pyrazolyl are optionally
substituted with from 1 to 4 substituents
independently selected from: , , -NH2,
-N(CH3)2, hydroxymethyl, oxo, -OH, and -CH2NH2,
lkyl,
cycloalkyl substituted with from one to five substituents
independently selected from:
fluoro,
chloro,
-OH,
C1-6alkyl, and
C1-6a|ky| substituted with from 1 to 9 substituents
independently selected from: fluoro and chloro;
heterocycloalkyl, and
heterocycloalkyl substituted with from 1 to 5 substituents independently
selected from:
fluoro,
bromo,
iodo,
C1_6alkyl,
C1-6alkyl tuted with from 1 to 9 substituents
ndently selected from: fluoro, chloro, bromo,
iodo, oxo, -OH, -NH2 and —-CN,
aryl,
C1-4alkoxy,
C1-4alkoxy substituted with from 1 to 4 substituents
independently selected from: fluoro, oxo, -OH,
-COOH, -NH2, and —-CN,
-N02,
-NH2, and
SOzNHz, or
R44bbr and R45bbr are taken together with the nitrogen to which they are
attached, and optionally from 1 to 3 additional heteroatoms
ndently selected from O, N, and S, to form a heterocycloalkyl,
which is optionally substituted with from 1 to 5 substituents
independently selected from:
fluoro,
chloro,
bromo,
iodo,
kyl,
C1-ealkyl substituted with from 1 to 9 substituents
independently selected from: fluoro, chloro,
C1-4alkoxy, oxo, phenyl, cycloalkyl, heterocycloalkyl,
methylheterocycloalkyl-, -OH, -NH2, -N(H)C1-5alkyl,
aminoheterocycloalkyl-, -N(C1-5alkyl)2, --CN,
-N(C1-4a|ky|)(CHZOCH3), and -NHC1-4alkyl
substituted by one ortwo tuents independently
selected from oxo, NH2, and -OH,
aryl,
cycloalkyl,
heterocycloalkyl,
heterocycloalkyl substituted with from 1 to 9 substituents
independently selected from: C1-6alkyl,
|ky|OH, fluoro, lkyINH2,
chloro, bromo, iodo, oxo, -OH, -NH2 and —CN,
C1-4alkoxy,
C1-4a|koxy substituted with from 1 to 4 substituents
independently selected from: fluoro, oxo, -OH,
-COOH, -NH2, and -CN,
-OP(O)(OH)2,
WO 16727
-COOH,
-N02.
-NH2,
-N(H)C1-5alky|,
-N(H)C1-6alkyl substituted with from 1 to 9 substituents
independently selected from: fluoro, chloro, bromo,
iodo, C1-4alkoxy, oxo, phenyl, cycloalkyl,
aminoC1-4a|koxy, heterocycloalkyl,
methylheterocycloalkyI-, -OH, -NH2, -N(H)C1-4a|ky|,
-N(C1-4a|ky|)2, and -CN,
-Ooxetany|,
-ONHC(NH)NH2,
-NHcyclopropyI,
-NHoxetany|,
-N(C1-5a|ky|)2,
-S(O)2CHZCH3.
S(O)2CH2CH2CH3,
-S(O)2CH3,
-SOzNH2,
phenyl,
benzoyL
benzylamino,
-propy|pyrro|idiny|,
-methy|cyc|opropy|,
cyclobutylamino,
cyclobutyI-N(CH3)-,
piperidinyl,
imidazolyl,
morpholinyl,
morpholinylmethyl,
methylpiperazinylmethyl,
methylpiperazinyl,
pyrrolidinyl,
pyrrolidinylmethyl,
(methoxypyridinylmethyl)amino,
methylpyrrolidinyl,
difluoropyrrolidinyl,
dimethylpyrrolidinyl,
(methylcyclopropylmethyl)amino,
hyd roxymethylpyrrolidinyl,
fluoropyrrolidinyl,
fluorophenylmethylamino,
piperazinylmethyl,
oxazolidinyl,
(methyloxetanmethyl)amino,
lcyclobutylmethyl)amino,
oxoimidazolidinyl, and
2-hydroxyethylpiperidinyl;
provided that:
X41bbr and X42bbr are not both hydrogen, and
R44bbr and R45bbr are not both hydrogen;
or a pharmaceutically acceptable salt or prodrug thereof.
Suitably in the compounds of Formula (lVbbr) neither R44bbr nor R45bbr is hydrogen.
Suitably in the nds of Formula (lVbbr) R43br is phenyl.
Suitably in the compounds of a ) neither X41 bbr nor X42bbr are
hydrogen.
2017/053511
Suitably in the compounds of Formula (lVbbr), the nds are in the form ofa
phosphate prodrug.
Suitably in the compounds of Formula (lVbbr), the compounds are in the form ofa
—C(O)CH(NH2)CH(CH3)2 prodrug.
This invention relates to novel compounds of Formula (Vbbr) and to the use of
compounds of Formula (Vbbr) in the methods ofthe invention:
50bbr
N R N
\\\ //x
C C 51bbr
\ R
R5357? N/ Y5bbr/S1/NH2
R54bbr (Vbbr)
wherein:
Y5bbr is selected from: S and NH;
R5Obbr is selected from:
Cl-6alkyl,
C1-6alkyl tuted with from 1 to 9 substituents
independently selected from: fluoro and chloro,
-N(H)C1-4a|kyl,
-N(Cl-4a|kyl)2,
a|ky|,
C1-4alkyloxy,
aryl,
alkyl substituted with from one to five substituents
independently selected from:
fluoro,
chloro,
-OH,
kyl, and
C1-6a|kyl substituted with from 1 to 9 substituents
independently selected from: fluoro and ,
heteroaryl,
heteroalkyl substituted with from one to five substituents
independently selected from:
fluoro,
chloro,
-OH,
C1_6alkyl, and
C1-6alkyl tuted with from 1 to 9 tuents
independently selected from: fluoro and chloro,
cycloalkyl,
cycloalkyl substituted with from one to five substituents
independently selected from:
fluoro,
chloro,
-OH,
C1-6alkyl, and
C1_6alkyl substituted with from 1 to 9 substituents
independently selected from: fluoro and chloro;
R51bbr is selected from:
-CH3,
phenyL
phenyl substituted with 1 or2 substituents independently selected
from: fluoro, -CH3, -CF3, chloro, -C(O)pheny|, pyrrolidinyl,
-C(O)NH2, -S(O)2NHCH3, -OCH2CH2N(CH3)2 and -CH2C(O)NH2,
piperidinyl,
pyridine, and
pyridine substituted with 1 or 2 substituents independently ed
from: fluoro, -CH3, -CF3, and -OCH3;
R53bbr and R54bbr are independently selected from:
hydrogen,
C1-68Ikyl,
C1-6alkyl substituted with from 1 to 9 substituents
independently selected from: phenyl, morpholino, triazolyl,
olyl, -CH2CH2pyrrolidinyl, -OC(O)NH2, -OCH2CH2NH2,
-ONHC(NH2)NH2, -NHCH20(CH3)3, -NOCH3, -NHOH,
-NHCHZCH2F, -N(CH3)CHZCHZOCH3, -N(CHZCH3)2,
-NCH(CH20H)2, -N(CH2CH20H)2, -NHCH2CH20H,
-NHCH2CH2NH2, -N(CH3)CH2(CH3)2CH20H, -NHCH2CH3,
-NHCH2CH20CH3, -N(CH3)CH2CH20H, -NHC(O)C(O)NH2,
-N(CH3)CH2CH2CH20H, -N(CH3)CH2CH(OH)CH20H,
-N(CH3)CHZCH2NH2, 0x0, -NHCHZC(CH3)ZCH20H, -OH, -NH2,
, CH2CH20H, -N(CH3)2, )CH20H3,
-NHOC(CH3)2NH2, -N(CH3)CH20yclopropyl, -NHCH20yclopropyl,
-NHoxetanyl, -NCHzCH2triazole, piperazinyl, dinyl, lyl,
azepinyl, azetidinyl, y, and cyclopropylamino,
where said phenyl, morpholino, triazolyl, imidazolyl, azepinyl,
azetidinyl, pyrrolidinyl piperazinyl, piperidinyl,
oxetanyl, cyclopropyl, and pyrazolyl are optionally
substituted with from 1 to 4 substituents
independently selected from: methyl, fluoro, -NH2,
-N(CH3)2, hydroxymethyl, oxo, -OH, and -CH2NH2,
cycloalkyl,
cycloalkyl substituted with from one to five tuents
independently selected from:
chloro,
-OH,
C1-6alkyl, and
C1-6a|ky| substituted with from 1 to 9 substituents
independently selected from: fluoro and ;
heterocycloalkyl, and
heterocycloalkyl substituted with from 1 to 5 substituents independently
ed from:
fluoro,
chloro,
C1-Balkyl,
C1-6alkyl substituted with from 1 to 9 substituents
independently selected from: fluoro and chloro,
C1-4alkoxy, and
-OH, or
R53bbr and R54bbr are taken together with the nitrogen to which they are
attached, and optionally from 1 to 3 additional heteroatoms
independenfly
selected from O, N, and S, to form a heterocycloalkyl, to form
a heterocycloalkyl, which is optionally substituted with from 1 to 5
substituents independently selected from:
fluoro,
C1-6alkyl,
C1-6alkyl substituted with from 1 to 9 substituents
independently selected from: fluoro, chloro,
C1-4alkoxy, oxo, phenyl, cycloalkyl, heterocycloalkyl,
methylheterocycloalkyl, -OH, -NH2, -N(H)C1-5a|kyl,
aminoheterocycloalkyl, -N(C1-5alkyl)2, -CN,
-N(C1-4a|kyl)(CHzoCH3), and -NHC1-4alkyl
substituted by one ortwo substituents independently
selected from 0x0, NH2, and -OH,
cycloalkyl,
heterocycloalkyl substituted with from 1 to 9 substituents
independently selected from: C1-6alkyl,
|kyIOH, fluoro, -C1-6alkyINH2,
chloro, 0x0 and -OH,
C1-4alkoxy,
koxy substituted with from 1 to 4 substituents
Independently selected from: , oxo, -OH,
-COOH, -NH2, and -CN,
-OP(O)(OH)2,
-COOH,
-CONH2,
-NH2,
-N(H)C1-4alkyl,
-N(H)C1-6alkyl substituted with from 1 to 9 substituents
independently selected from: fluoro, chloro,
C1-4alkoxy, 0x0, phenyl, cycloalkyl,
aminoC1-4alkoxy, heterocycloalkyl,
methylheterocycloalkyl, -OH, -NH2, -N(H)C1-4a|kyl,
-N(C1_4a|ky|)2, and -CN,
-Ooxetanyl,
-ONHC(NH)NH2,
-NHcyclopropy|,
-NHoxetanyI,
-N(C1-4alky|)2,
-S(O)2CHZCH3,
S(O)2CH2CH2CH3,
-S(O)ZCH3,
-S(O)2pheny|,
benzoyL
amino,
-propy|pyrrolidiny|,
-methylcyclopropyl,
cyclobutylamino,
cyclobutyI-N(CH3)-,
piperidinyl,
imidazolyl,
morpholinyl,
morpholinylmethyl,
piperazinylmethyl,
methylpiperazinyll
pyrrolidinyl,
pyrrolidinylmethyl,
(methoxypyridinylmethy|)amino,
pyrrolidinyl,
difluoropyrrolidinyl,
dimethylpyrrolidinyl,
(methyIcyclopropylmethy|)amino,
hyd roxymethylpyrrolidinyl,
fluoropyrrolidinyl,
fluorophenylmethylamino,
piperazinylmethyl,
idinyl,
(methyloxetanylmethyl)amino,
(methylcyclobutylmethy|)amino,
oxoimidazolidinyl, and
2-hydroxyethylpiperidinyl;
ed that:
R53bbr and R54bbr are not both hydrogen;
or a pharmaceutically acceptable salt or prodrug thereof.
Suitably in the compounds of Formula (Vbbr) neither R53bbr nor R54bblr is hydrogen.
Suitably in the compounds of Formula (Vbbr) R51bbr is phenyl.
Suitably in the compounds of Formula (Vbbr), the compounds are in the form of a
phosphate prodrug.
Suitably in the compounds of Formula (Vbbr), the compounds are in the form of a
—C(O)CH(NH2)CH(CH3)2 g.
This invention relates to novel compounds of Formula ) and to the use of
compounds of Formula ) in the methods of the invention:
63bbr I NHZ
\N N/ S/Si/
| O
R64bbr (Vlbbr)
wherein:
R60bbr is selected from:
C1-3alkyl,
kyl substituted with from 1 to 6 substituents
independently selected from: fluoro and chloro,
-N(H)C1-3alkyl,
-N(C1-3alkyl)2,
-SC1-4a|kyl,
C1-3alkyloxy,
aryl,
aryl substituted with from one to 3 substituents
independently ed from:
fluoro,
chloro,
-OH, and
C1-3alkyl,
heteroaryl,
aryl substituted with from one to 3 substituents
independently selected from:
fluoro,
chloro,
-OH, and
C1-3alkyl,
cycloalkyl,
cycloalkyl substituted with from one to three substituents
independently selected from:
fluoro,
chloro,
-OH, and
Cl-Salkyl;
R61bbr is selected from:
-CH3,
phenyl,
phenyl substituted with 1 or 2 tuents independently selected
from: fluoro, -CH3, -CF3, chloro, -C(O)phenyl, pyrrolidinyl,
-C(O)NH2, NHCH3, -OCH2CH2N(CH3)2 and -CH2C(O)NH2,
thienyl,
dinyl,
pyridine, and
pyridine substituted with 1 or 2 substituents independently selected
from: fluoro, -CH3, -CF3, and -OCH3;
R63bbr and R64bblr are independently selected from:
en,
C1-4alkyl,
C1-4alkyl substituted with from 1 to 4 substituents
independently selected from: phenyl, morpholino, triazolyl,
imidazolyl, -CH2CH2pyrrolidinyl, -OC(O)NH2, -OCH2CH2NH2,
-ONHC(NH2)NH2, C(CH3)3, -NOCH3, -NHOH,
-NHCH2CH2F, -N(CH3)CH2CH20CH3, -N(CH2CH3)2,
-NCH(CH20H)2, -N(CH2CH20H)2, 0H20H,
-NHCH2CH2NH2, -N(CH3)CH2(CH3)ZCH20H, -NHCHZCH3,
-NHCH2CH20CH3, -N(CH3)CH2CH20H, -NHC(O)C(O)NH2,
-N(CH3)CH2CHZCH20H, -N(CH3)CHZCH(OH)CH20H,
-N(CH3)CH2CH2NH2, 0x0, C(CH3)2CH20H, -OH, -NH2,
-NHCH3, CH2CH20H, -N(CH3)2, -N(CH3)CH2CH3,
-NHOC(CH3)2NH2, -N(CH3)CH20yclopropyl, -NHCH20yclopropyl,
-NHoxetanyl, -NCH2CH2triazole, piperazinyl, piperidinyl, pyrazolyl,
azepinyl, azetidinyl, methoxy, and cyclopropylamino,
where said phenyl, morpholino, triazolyl, imidazolyl, azepinyl,
azetidinyl, pyrrolidinyl piperazinyl, piperidinyl,
oxetanyl, cyclopropyl, and pyrazolyl are optionally
substituted with from 1 to 4 substituents
independently selected from: methyl, fluoro, -NH2,
-N(CH3)2, hydroxymethyl, oxo, -OH, and -CH2NH2,
cycloalkyl,
lkyl substituted with from 1 to 5 substituents independently
selected from:
fluoro,
chloro,
-OH, and
C1_6alkyl,
cycloalkyl, and
heterocycloalkyl substituted with from 1 to 5 substituents independently
selected from:
fluoro,
chloro,
-OH, and
kyl, or
R63bbr and R64bbr are taken together with the nitrogen to which they are
attached, and optionally from 1 to 3 additional heteroatoms
independenfly
selected from O, N, and S, to form a heterocycloalkyl, to form
a heterocycloalkyl, which is optionally tuted with from 1 to 5
substituents independently selected from:
fluoro,
chloro,
-OH,
-OP(O)(OH)2,
-CN,
3O kyl,
C1-6alkyl substituted with from 1 to 9 substituents
independently selected from: fluoro, chloro,
C1-4alkoxy, 0x0, phenyl, cycloalkyl, heterocycloalkyl,
methylheterocycloalkyl, -OH, -NH2, -N(H)C1-5alkyl,
aminoheterocycloalkyl, -N(C1-5alkyl)2, -CN,
-N(C1-4alkyl)(CH20CH3), and 4alkyl
substituted by one ortwo substituents ndently
selected from 0x0, NH2, and -OH,
heterocycloalkyl,
heterocycloalkyl substituted with from 1 to 9 substituents
independently ed from: C1-6alkyl,
-C1-6a|kyIOH, fluoro, chloro, 0x0 and -OH,
C1-4alkoxy,
C1-4a|koxy substituted with from 1 to 4 substituents
independently selected from: fluoro, oxo, -OH,
-COOH, -NH2, and -CN,
oxo,
-NH2,
-N(H)C1-6a|kyl,
-N(H)C1-6alkyl substituted with from 1 to 9 substituents
ndently selected from: fluoro, chloro,
C1-4alkoxy, 0x0, phenyl, cycloalkyl,
aminoC1-4alkoxy, cycloalkyl,
methylheterocycloalkyl, -OH, -NH2, -N(H)C1-4alkyl,
-N(C1-4a|kyl)2, and -CN,
-ONHC(NH)NH2,
-Ooxetanyl,
WO 16727
-ONHC(NH)NH2,
-NHcycIopropy|,
-NHoxetanyI,
-N(C1-4a|ky|)2,
-S(O)2CH2CH3,
S(O)ZCHZCHZCH3,
-S(O)2CH3,
-S(O)2phenyl,
benzoyL
benzylamino,
-propy|pyrrolidiny|,
-methy|cyclopropy|,
cyclobutylamino,
cyclobutyI-N(CH3)-,
piperidinyl,
imidazolyl,
morpholinyl,
linylmethyl,
methylpiperazinylmethyl,
methylpiperazinyl,
pyrrolidinyl,
idinylmethyl,
(methoxypyridinylmethy|)amino,
methylpyrrolidinyl,
difluoropyrrolidinyl,
dimethylpyrrolidinyl,
(methylcyclopropylmethyl)amino,
hyd roxymethylpyrrolidinyl,
fluoropyrrolidinyl,
(fluorophenylmethy|)amino,
piperazinylmethyl,
oxazolidinyl,
WO 16727
(methyloxetanylmethyl)amino,
(methylcyclobutylmethyl)amino,
oxoimidazolidinyl, and
2-hydroxyethylpiperidinyl;
provided that:
R63“r and R64bbr are not both hydrogen;
or a pharmaceutically acceptable salt or prodrug thereof.
Suitably in the compounds of a (Vlbbr) neither R63bbr nor R64bbr is hydrogen.
Suitably in the compounds of Formula (Vlbbr) R61bbr is .
Suitably in the compounds of Formula (Vlbbr), the compounds are in the form ofa
ate prodrug.
Suitably in the compounds of Formula (Vlbbr), the compounds are in the form ofa
—C(O)CH(NH2)CH(CH3)2 prodrug.
This invention s to novel compounds of Formula (Vllbbr) and to the use of
compounds of Formula (Vllbbr) in the methods ofthe invention:
R70bbr//N
NSC (3/
\ R71bbr
72bbr I NH2
I73bb O
R r
(Vllbbr)
wherein:
R70bbr is selected from:
ethyl,
ethyl substituted from 1 to 4 times by fluoro,
-NCH3,
-SCH3,
methoxy,
PFOPOXY.
phenyl,
cyclopropyl, and
ropyl substituted once or twice by fluoro;
R71bbr is selected from:
,
phenyl substituted with 1 or2 substituents independently selected
from: fluoro, -CH3, -CF3, chloro, -C(O)phenyl, pyrrolidinyl,
-C(O)NH2, NHCH3, -OCH2CH2N(CH3)2 and —CH2C(O)NH2,
thienyl,
piperidinyl,
pyridine, and
pyridine substituted with 1 or 2 substituents independently selected
from: , -CH3, -CF3, and -OCH3; and
R72bb|r and R73bb|r are independently selected from:
hydrogen,
C1-4alkyl,
C1-4alky| substituted with from 1 to 4 substituents
independently selected from: phenyl, morpholino, triazolyl,
imidazolyl, -CHZCH2pyrro|idinyl, -OC(O)NH2, -OCHZCH2NH2,
-ONHC(NH2)NH2, -NHCH2C(CH3)3, -NOCH3, -NHOH,
-NHCH2CH2F, -N(CH3)CH20H20CH3, -N(CH2CH3)2,
-NCH(CH20H)2, -N(CH2CH20H)2. -NHCHZCH20H,
-NHCH2CH2NH2, -N(CH3)CH2(CH3)2CHZOH, -NHCH2CH3,
-NHCH2CH20CH3, -N(CH3)CH2CH20H, -NHC(O)C(O)NH2,
-N(CH3)CH2CHZCH20H, -N(CH3)CHZCH(OH)CH20H,
-N(CH3)CH2CH2NH2, 0X0, -NHCH2C(CH3)2CH20H, -OH, -NH2,
-NHCH3, -NHCH20H2CH20H, -N(CH3)2, -N(CH3)CH20H3,
-NHOC(CH3)2NH2, -N(CH3)CH20yclopropyl, -NHCH20yclopropyl,
-NHoxetanyl, -NCH2CH2triazole, zinyl, piperidinyl, pyrazolyl,
azepinyl, azetidinyl, methoxy, and cyclopropylamino,
where said phenyl, morpholino, triazolyl, imidazolyl, azepinyl,
azetidinyl, pyrrolidinyl piperazinyl, piperidinyl,
oxetanyl, cyclopropyl, and pyrazolyl are optionally
substituted with from 1 to 4 substituents
independently selected from: methyl, , -NH2,
-N(CH3)2, hydroxymethyl, oxo, -OH, and 2,
cyclobutyl,
aminocyclobutyl,
tetrahydrofu ran,
-oxa-2azaspiro[3.4]octan, and
8-azabicyclo[3.2.1]octan, or
R72bbr and R73bbr are taken together with the nitrogen to which they are
attached, and optionally from 1 to 3 onal heteroatoms,
to form a heterocycloalkyl selected from:
pyrrolidinyl,
pyrrolo[3,4-c]pyrazolyl,
piperidinyl,
1,4diazepanyl,
piperazinyl,
6,7-dihydro-triazolo[4,5-c]pyridinyl,
2,9-diazaspiro[5.5]undecanyl,
azaspiro[4.5]decanyl,
dro-1H-pyrrolo[1,2a][1,4]diazepinyl,
oxa-diazaspiro[4.5]decanyl,
WO 16727
morpholinyl,
1-oxaazaspiro[3.4]octanyl,
2-oxaazaspiro[3.4]octanyl,
1,7-diazaspiro[3.5]nonany|,
2,7-diazaspiro[3.5]nonanyl,
2,6-diazaspiro[3.4]octanyl,
azetidinyl,
hexahydropyrrolo[3,4-b]oxaziny|,
dihydronaphthyridinyl,
diazabicycloheptanyl,
1,8-diazaspiro[4.5]decanyl, and
-oxaazaspiro[3.4]octanyl,
all of which are optionally substituted with from 1 to 5
substituents independently selected from:
fluoro,
--CN,
'CH31
-CH20H,
methoxy,
-CHZCH3,
-C(O)CH3,
-C(O)NH2.
-OCH2CH20H,
-OCH2CH2NH2,
-ONHC(NH)NH2,
-OC(O)NH2,
-Ooxetanyl,
-CH20H20H,
-CH20H2CH20H,
-CH20H2CH3,
-CH20H20CH3,
-CHZCH(OH)CH3,
-CH2CH(OH)CH20H,
-CH20(O)OCH3,
-CHZC(O)NH2,
-C(O)CH(CH3)2,
1O -CH20H2N(CH3)2,
-CH20H2NHCH2CH3,
-CH20H2CH2N(CH3)2,
-CH20H2NHCHZC(CH3)3,
-CH2CH2N(CH3)CH20CH3,
)2CH20H,
-CH20(CH3)2OH,
-CH2C(CH3)20CH3,
-C(O)CH20H,
-CH2isothiazoly|,
iazolyI,
-CHzpyrazon|,
-CH2imidazolyl,
-CH2pyridiny|,
-CH20xazo|y|,
2017/053511
-CH2pyrro|y|,
-CH2isoxazon,
-CH2furany|,
-CH20H2morpho|inyl,
-CH20H2pyrrolidinyI,
-CH2CH2Pyrro|idinyICH3,
-CH20H2CH2Pyrr0|idinyI,
-C(O)pheny|,
-C(O)C(tetrahyd ropyrany|)NH2,
-NH2,
-NHCH3,
-N(CH3)2,
-NHC(O)CH3,
-NHCH2CHF2,
-NHCH2C(CH3)3,
-NHCH2CH(CH3)2,
-NHCHZCH20CH3,
-NHCH2CH20H,
-NHCH2CH2NH2,
C(O)OH,
-NHC(O)CH2NH2,
-NHC(O)CH2CH2CH2NH2,
-NHCH2C(O)NH2,
-NHCHZC(OH)(CH3)2,
-NHC(O)CH(CH3)NH2,
-NHC(O)OCH(CH3)NH2,
-NHC(O)CH(CH3)2,
-NHC(O)C(CH3)2NH2,
-NHC(O)CH20H,
-NHC(O)CH(CH20H)NH2,
-NHC(O)(oxetanyI)NH2,
-NHC(O)OC(CH3)3,
-NHC(CH3)2C(O)OCH3,
-NHcyclopropyl,
-NHoxetany|,
-CH2NH2,
-CH2CH2NH2,
-CHZCH2CH2NH2,
-CH2NHCHZC(CH3)3,
-CH2NHC(O)C(CH3)3,
-CH2NHC(O)CH2NH2,
-CH2NHC(O)CH20H,
-CH2N(CH3)2,
CH3,
-CH2N(CH2CH3)2,
-CH20H2N(CH3)2,
CH2CH3,
-S(O)2CHZCH2CH3,
-S(O)2pheny|,
-S(O)2CH3,
benzoyL
benzylamino,
3-pyrrolidinylpropyl,
2-cyclopropylmethyl,
utylamino,
cyclobutyI-N(CH3)-,
piperidinyl,
imidazolyl,
morpholinyl,
linylmethyl,
methylpiperazinylmethyl,
methylpiperazinyl,
pyrrolidinyl,
pyrrolidinylmethyl,
methoxypyridinylmethylamino,
methylpyrrolidinyl,
difluoropyrrolidinyl,
dimethylpyrrolidinyl,
methylcyclopropylmethylamino,
hydroxymethylpyrrolidinyl,
fluoropyrrolidinyl,
fluorophenylmethylamino,
piperazinylmethyl,
oxazolidinyl,
methyloxetanmethylamino,
methylcyclobutylmethylamino,
dazolidinyl, and
2-hydroxyethylpiperidinyl;
provided that:
R72bbr and R73bbr are not both hydrogen,
or a pharmaceutically acceptable salt or prodrug thereof.
Suitably in the nds of Formula (Vllbbr) neither R72bbr nor R73bbr is
hydrogen.
Suitably in the compounds of Formula (Vllbbr) R71bbr is phenyl.
Suitably in the compounds of a (Vllbbr), the compounds are in the form of a
phosphate prodrug.
Suitably in the nds of Formula r), the compounds are in the form of a
—C(O)CH(NH2)CH(CH3)2 prodrug.
This invention relates to novel compounds of Formula (Qb) and to the use of
compounds of Formula (Qb) in the methods of the invention:
R703" N
N: 0/
\C C 71"
R a
72a" I
R s/SfNH2 \N N/
I73 O
R a
(Qb)
wherein:
R703" is selected from:
ethyl,
-OCH3,
-CH2CF3, and
cyclopropyl;
R713" is selected from:
phenyL
phenyl substituted with 1 or2 substituents independently selected
from: fluoro, -CH3, -CF3, and chloro,
pyridine, and
pyridine substituted with 1 or 2 substituents independently ed
from: fluoro, -CH3, -CF3, and -OCH3; and
R723" and R733" are independently selected from:
hydrogen,
C1-4alkyl,
C1-4alkyl tuted with from 1 to 4 substituents
independently selected from: phenyl, lino, lyl,
imidazolyl, 2pyrrolidinyl, -OC(O)NH2, -OCH2CH2NH2,
-ONHC(NH2)NH2, -NHCHZC(CH3)3, -NOCH3, -NHOH,
-NHCH2CH2F, -N(CH3)CH20H20CH3, -N(CH2CH3)2,
-NCH(CH20H)2, -N(CHZCH20H)2, -NHCHZCH20H,
-NHCH2CH2NH2, -N(CH3)CH2(CH3)ZCH20H, -NHCHZCH3,
-NHCH2CH20CH3, -N(CH3)CH2CH20H, -NHC(O)C(O)NH2,
-N(CH3)CH2CH2CH20H, -N(CH3)CH2CH(OH)CH20H,
-N(CH3)CH2CH2NH2, 0X0, -NHCH2C(CH3)2CH20H, -OH, -NH2,
-NHCH3, -NHCHZCH2CH20H, -N(CH3)2, -N(CH3)CH20H3,
-NHOC(CH3)2NH2, -N(CH3)CH20yclopropyl, -NHCH20yclopropyl,
-NHoxetany|, -NCH2CH2triazole, zinyl, piperidinyl, pyrazolyl,
azepinyl, azetidinyl, methoxy, and cyclopropylamino,
where said phenyl, morpholino, triazolyl, imidazolyl, azepinyl,
azetidinyl, idinyl piperazinyl, piperidinyl,
oxetanyl, cyclopropyl, and pyrazolyl are optionally
substituted with from 1 to 4 substituents
independently selected from: methyl, fluoro, -NH2,
-N(CH3)2, hydroxymethyl, oxo, -OH, and -CH2NH2,
utyl,
aminocyclobutyl,
tetrahydrofu ran,
-oxa-2azaspiro[3.4]octan, and
8-azabicyclo[3.2.1]octan, or
R723" and R733" are taken together with the nitrogen to which they are
attached, and optionally from 1 to 3 onal heteroatoms
independenfly
selected from O, N, and S, to form a heterocycloalkyl selected from:
pyrrolidinyl,
pyrrolo[3,4-c]pyrazolyl,
piperidinyl,
zepanyl,
zinyl,
6,7-dihydro-triazolo[4,5-c]pyridinyl,
2,9-diazaspiro[5.5]undecanyl,
2,8—diazaspiro[4.5]decanyl,
octahydro-1H-pyrrolo[1,2a][1,4]diazepinyl,
oxa-diazaspiro[4.5]decanyl,
oxazolyl,
morpholinyl,
1-oxaazaspiro[3.4]octanyl,
2—oxaazaspiro[3.4]octanyl,
1,7-diazaspiro[3.5]nonanyl,
2,7-diazaspiro[3.5]nonanyl,
2,6-diazaspiro[3.4]octanyl,
inyl,
hexahydropyrrolo[3,4-b]oxazinyl,
dihydronaphthyridinyl,
diazabicycloheptanyl,
1,8—diazaspiro[4.5]decanyl, and
-oxaazaspiro[3.4]octanyl,
all of which are optionally substituted with from 1 to 5
substituents independently selected from:
fluoro,
chloro,
oxo,
-OH,
-OP(O)(OH)2,
-CN,
-CH3,
-CH20H,
methoxy,
-CH20H3,
-C(O)CH3,
-C(O)NH2,
-OCHZCH20H,
1o H2NH2,
-ONHC(NH)NH2,
-OC(O)NH2,
-Ooxetanyl,
-CHZCH20H,
-CH2CH2CH20H,
-CH20H2CH3,
20CH3,
-CH2CH(OH)CH3,
-CH20H(OH)CH20H,
-CHZC(O)OCH3,
-CH20(O)NH2,
-C(O)CH(CH3)2,
-CH2CH2N(CH3)2,
-CH20H2NHCH2CH3,
-CHZCH2CH2N(CH3)2,
2017/053511
-CHZCH2NHCHZC(CH3)3,
-CH2CH2N(CH3)CHZOCH3,
-C(CH3)2CH20H,
-CH20(CH3)2OH,
-CHZC(CH3)ZOCH3,
-C(O)CH20H,
-CH2isothiazoly|,
-CH2thiazolyI,
-CH2pyrazolyI,
1O -CH2imidazolyl,
-CH2pyridiny|,
-CH20xazo|y|,
-CH2pyrroly|,
-CH2isoxazoly,
-CH2furany|,
-CHZCH2morpholinyl,
-CH20H2pyrrolidinyl,
-CH20H2pyrrolidinyICH3,
-CHZCH2CH2pyrro|idinyl,
-C(O)pheny|,
-C(O)C(tetrahyd ropyrany|)NH2,
-NH2,
-N(CH3)2,
-NHC(O)CH3,
-NHCH2CHF2,
C(CH3)3,
-NHCH2CH(CH3)2,
-NHCHZCHZOCH3,
-NHCH2CH20H,
-NHCH2CH2NH2,
-NHCH2C(O)OH,
-NHC(O)CH2NH2,
1O )CHZCHZCH2NH2,
-NHCH2C(O)NH2,
-NHCH2C(OH)(CH3)2,
-NHC(O)CH(CH3)NH2,
-NHC(O)OCH(CH3)NH2,
-NHC(O)CH(CH3)2,
-NHC(O)C(CH3)2NH2,
-NHC(O)CH20H,
-NHC(O)CH(CH20H)NH2,
-NHC(O)(oxetanyI)NH2,
-NHC(O)OC(CH3)3,
-NHC(CH3)ZC(O)OCH3,
-NHcyclopropyl,
-NHoxetany|,
'CH2NH21
-CHZCH2NH2,
-CHZCH2CH2NH2,
-CH2NHCHZC(CH3)3.
-CH2NHC(O)C(CH3)3,
-CH2NHC(O)CH2NH2,
-CH2NHC(O)CH20H,
-CH2N(CH3)2,
-CH2NHCH3,
-CH2N(CH2CH3)2,
-CHZCH2N(CH3)2,
1o -S(O)2CH20H3,
-S(O)2CH2CH2CH3,
—S(0)2pheny|,
-S(O)2CH3.
benzoyL
benzylamino,
-propylpyrrolidinyl,
-methy|cyclopropy|,
cyclobutylamino,
cyclobutyI-N(CH3)-,
piperidinyl,
imidazolyl,
morpholinyl,
morpholinylmethyl,
methylpiperazinylmethyl,
piperazinyl,
pyrrolidinyl,
idinylmethyl,
(methoxypyridinylmethy|)amino,
2017/053511
methylpyrrolidinyl,
difluoropyrrolidinyl,
dimethylpyrrolidinyl,
(methylcyclopropylmethy|)amino,
hydroxymethylpyrrolidinyl,
fluoropyrrolidinyl,
(fluorophenylmethyl)amino,
piperazinylmethyl,
oxazolidinyl,
(methyloxetanylmethyl)amino,
(methylcyclobutylmethyl)amino,
oxoimidazolidinyl, and
oxyethylpiperidinyl;
provided that:
R726‘ and R733 are not both hydrogen;
or a pharmaceutically acceptable salt or prodrug f.
Suitably in the compounds of Formula (Qb) neither R72a" nor R733" is hydrogen.
ly in the compounds of Formula (Qb) R71a" is phenyl.
Suitably in the compounds of Formula (Qb), the compounds are in the form of a
ate prodrug.
Suitably in the compounds of Formula (Qb), the compounds are in the form of a
—C(O)CH(NH2)CH(CH3)2 prodrug.
This invention relates to novel compounds of Formula (Qb1) and to the use of
compounds of Formula (Qb1) in the methods of the invention:
wherein:
R7Ob" is selected from:
ethyl,
-OCH3,
-CH2CF3, and
cyclopropyl;
R71b" is selected from:
phenyL
phenyl substituted with 1 or2 substituents independently selected
from: fluoro, -CH3, -CF3, and chloro,
pyridine, and
ne tuted with 1 or 2 substituents independently selected
from: fluoro, -CH3, -CF3, and -OCH3; and
Rub" and R73b" are independently selected from:
C1-4alkyl,
C1-4alky| substituted with from 1 to 4 substituents
independently selected from: , morpholino, triazolyl,
imidazolyl, -CH2CH2pyrrolidiny|, -OC(O)NH2, -OCHZCH2NH2,
-ONHC(NH2)NH2, C(CH3)3, -NOCH3, -NHOH,
-NHCH2CH2F, -N(CH3)CH20H20CH3, -N(CH2CH3)2,
-NCH(CH20H)2, -N(CH2CH20H)2, -NHCH2CH20H,
-NHCH2CH2NH2, -N(CH3)CH2(CH3)2CH20H, CH3,
-NHCHZCHZOCH3, -N(CH3)CH20H20H, -NHC(O)C(O)NH2,
WO 16727
-N(CH3)CH2CH2CH20H, -N(CH3)CH2CH(OH)CH20H,
-N(CH3)CH2CH2NH2, oxo, -NHCHZC(CH3)ZCH20H, -OH, -NH2,
-NHCH3, -NHCH2CH2CH20H, -N(CH3)2, -N(CH3)CH2CH3,
-NHOC(CH3)2NH2, -N(CH3)CH20yclopropyl, -NHCH20yclopropyl,
-NHoxetanyl, -NCHzCH2triazole, piperazinyl, piperidinyl, pyrazolyl,
azepinyl, azetidinyl, methoxy, and cyclopropylamino,
where said , morpholino, triazolyl, olyl, azepinyl,
azetidinyl, pyrrolidinyl piperazinyl, piperidinyl,
oxetanyl, cyclopropyl, and pyrazolyl are optionally
substituted with from 1 to 4 substituents
independently selected from: methyl, fluoro, -NH2,
-N(CH3)2, hydroxymethyl, oxo, -OH, and -CH2NH2,
cyclobutyl,
yclobutyl,
tetrahydrofu ran,
-oxa-2azaspiro[3.4]octan, and
8-azabicyclo[3.2.1]octan, or
R72b" and R73b" are taken together with the nitrogen to which they are
attached, and optionally from 1 to 3 additional atoms,
to form a heterocycloalkyl selected from:
pyrrolidinyl,
pyrrolo[3,4-c]pyrazolyl,
piperidinyl,
1,4diazepanyl,
piperazinyl,
6,7-dihydro-triazolo[4,5-c]pyridinyl,
2,9-diazaspiro[5.5]undecany|,
2,8—diazaspiro[4.5]decanyl,
dro-1H-pyrrolo[1,2a][1,4]diazepinyl,
oxa-diazaspiro[4.5]decanyl,
oxazolyl,
morpholinyl,
1-oxaazaspiro[3.4]octanyl,
2-oxaazaspiro[3.4]octanyl,
azaspiro[3.5]nonanyl,
2,7-diazaspiro[3.5]nonany|,
2,6-diazaspiro[3.4]octanyl,
azetidinyl,
dropyrrolo[3,4-b]oxazinyl,
onaphthyridinyl,
diazabicycloheptanyl,
1,8—diazaspiro[4.5]decanyl, and
-oxaazaspiro[3.4]octanyl,
all of which are optionally substituted with from 1 to 5
substituents independently selected from:
fluoro,
chloro,
oxo,
-OH,
--CN,
-CH3,
-CH20H,
methoxy,
-CH20H3,
-C(O)CH3,
-C(O)NH2,
-OCH2CH20H,
-OCH2CH2NH2,
-ONHC(NH)NH2,
-OC(O)NH2,
-Ooxetanyl,
-CH20H20H,
2CH20H,
-CH20H2CH3,
-CH20H20CH3,
(OH)CH3,
-CH2CH(OH)CH20H,
-CH20(O)OCH3,
-CHZC(O)NH2,
-C(O)CH(CH3)2,
1O -CH20H2N(CH3)2,
-CH20H2NHCH2CH3,
-CH20H2CH2N(CH3)2,
-CH20H2NHCHZC(CH3)3,
-CH2CH2N(CH3)CH20CH3,
-C(CH3)2CH20H,
-CH20(CH3)2OH,
-CH2C(CH3)20CH3,
-C(O)CH20H,
-CH2isothiazoly|,
-CH2thiazolyI,
-CHzpyrazon|,
-CH2imidazolyl,
-CH2pyridiny|,
-CH20xazo|y|,
-CH2pyrro|y|,
-CH2isoxazon,
-CH2furany|,
-CH20H2morpho|inyl,
-CH20H2pyrrolidinyI,
-CH2CH2Pyrro|idinyICH3,
-CH20H2CH2Pyrr0|idinyI,
-C(O)pheny|,
-C(O)C(tetrahyd ny|)NH2,
-NH2,
-NHCH3,
-N(CH3)2,
-NHC(O)CH3,
-NHCH2CHF2,
C(CH3)3,
-NHCH2CH(CH3)2,
-NHCHZCH20CH3,
-NHCH2CH20H,
-NHCH2CH2NH2,
-NHCH2C(O)OH,
-NHC(O)CH2NH2,
-NHC(O)CH2CH2CH2NH2,
-NHCH2C(O)NH2,
-NHCHZC(OH)(CH3)2,
-NHC(O)CH(CH3)NH2,
-NHC(O)OCH(CH3)NH2,
)CH(CH3)2,
-NHC(O)C(CH3)2NH2,
-NHC(O)CH20H,
-NHC(O)CH(CH20H)NH2,
-NHC(O)(oxetanyI)NH2,
-NHC(O)OC(CH3)3,
-NHC(CH3)2C(O)OCH3,
-NHcyclopropyl,
-NHoxetany|,
-CH2NH2,
-CH2CH2NH2,
-CHZCH2CH2NH2,
-CH2NHCHZC(CH3)3,
-CH2NHC(O)C(CH3)3,
-CH2NHC(O)CH2NH2,
C(O)CH20H,
-CH2N(CH3)2,
-CH2NHCH3,
-CH2N(CH2CH3)2,
-CH20H2N(CH3)2,
-S(O)ZCH2CH3,
-S(O)2CHZCH2CH3,
-S(O)2pheny|,
CH3,
benzoyL
benzylamino,
3-pyrrolidinylpropyl,
opropylmethyl,
cyclobutylamino,
cyclobutyI-N(CH3)-,
piperidinyl,
imidazolyl,
morpholinyl,
morpholinylmethyl,
methylpiperazinylmethyl,
methylpiperazinyl,
pyrrolidinyl,
pyrrolidinylmethyl,
methoxypyridinylmethylamino,
methylpyrrolidinyl,
difluoropyrrolidinyl,
dimethylpyrrolidinyl,
methylcyclopropylmethylamino,
hydroxymethylpyrrolidinyl,
fluoropyrrolidinyl,
fluorophenylmethylamino,
piperazinylmethyl,
oxazolidinyl,
methyloxetanmethylamino,
methylcyclobutylmethylamino,
oxoimidazolidinyl, and
2-hydroxyethylpiperidinyl;
provided that:
R72b" and R73b" are not both unsubstituted alkyl;
or a ceutically acceptable salt or prodrug thereof.
Suitably in the compounds of Formula (Qb1) R71 is phenyl.
Suitably in the compounds of Formula (Qb1), the compounds are in the form of a
phosphate prodrug.
ly in the compounds of Formula (Qb1), the compounds are in the form of a
-C(O)CH(NH2)CH(CH3)2 prodrug.
This invention s to novel compounds of Formula (Qb2) and to the use of
compounds of a (Qb2) in the methods of the invention:
R70c"
72c"
R NH2
\N N/ 34
l 0
R730.. (Qb2)
R70C" is selected from:
ethyl,
-OCH3,
-CH2CF3, and
cyclopropyl;
R716" is selected from:
phenyL
phenyl substituted with 1 or2 substituents independently selected
from: fluoro, -CH3, -CF3, and chloro,
pyridine, and
pyridine substituted with 1 or 2 substituents independently selected
from: fluoro, -CH3, -CF3, and -OCH3; and
R72C" and R730" are are taken together with the nitrogen to which they are
2017/053511
attached, and optionally from 1 to 3 additional heteroatoms,
to form a heterocycloalkyl selected from:
pyrrolidinyl,
pyrrolo[3,4-c]pyrazolyl,
piperidinyl,
1,4diazepanyl,
piperazinyl,
6,7-dihydro-triazolo[4,5-c]pyridinyl,
2,9—diazaspiro[5.5]undecanyl,
2,8—diazaspiro[4.5]decany|,
octahydro-1H-pyrrolo[1,2a][1,4]diazepiny|,
oxa-diazaspiro[4.5]decany|,
oxazolyl,
morpholinyl,
6-azaspiro[3.4]octanyl,
2-oxaazaspiro[3.4]octanyl,
1,7-diazaspiro[3.5]nonanyl,
2,7-diazaspiro[3.5]nonanyl,
2,6-diazaspiro[3.4]octany|,
azetidinyl,
hexahydropyrrolo[3,4-b]oxazinyl,
dihydronaphthyridinyl,
diazabicycloheptanyl,
1,8—diazaspiro[4.5]decanyl, and
5-oxaazaspiro[3.4]octanyl,
all of which are optionally substituted with from 1 to 5
substituents independently selected from:
fluoro,
0x0,
-OH,
--CN,
-CH3,
-CH20H,
methoxy,
-C(O)CH3,
-C(O)NH2,
-OCH2CH20H,
-OCH2CH2NH2,
-ONHC(NH)NH2,
NH2,
-Ooxetany|,
-CHZCH20H,
-CH20H2CH20H,
-CHZCH2CH3,
-CH2CH20CH3,
-CHZCH(OH)CH3,
-CH20H(OH)CH20H,
-CH20(O)OCH3,
-CHZC(O)NH2,
-C(O)CH(CH3)2,
-CH20H2N(CH3)2,
-CHZCH2NHCHZCH3,
-CH2CH2CH2N(CH3)2,
-CH20H2NHCH2C(CH3)3,
-CH20H2N(CH3)CHzoCH3,
-C(CH3)2CH20H,
-CH20(CH3)2OH,
-CH20(CH3)20CH3,
-C(O)CH20H,
othiazolyl,
-CH2thiazolyI,
-CH2pyrazoly|,
-CH2imidazolyl,
-CH2pyridiny|,
-CH20xazo|y|,
-CH2pyrro|y|,
-CH2isoxazoly,
-CH2furany|,
-CHZCH2morpholinyl,
-CH2CH2pyrrolidinyl,
-CH2CH2pyrrolidinyICH3,
-CH20H2CH2pyrro|idiny|,
-C(O)pheny|,
-C(O)C(tetrahyd ropyrany|)NH2,
-NH2,
-NHCH3,
)2,
-NHC(O)CH3,
-NHCH2CHF2,
-NHCH2C(CH3)3,
-NHCH2CH(CH3)2,
-NHCH2CH20CH3,
-NHCH2CH20H,
-NHCH2CH2NH2,
-NHCH2C(O)OH,
-NHC(O)CH2NH2,
-NHC(O)CH20H2CH2NH2,
-NHCH2C(O)NH2,
-NHCH2C(OH)(CH3)2,
-NHC(O)CH(CH3)NH2,
-NHC(O)OCH(CH3)NH2.
-NHC(O)CH(CH3)2,
-NHC(O)C(CH3)2NH2,
-NHC(O)CH20H,
-NHC(O)CH(CH20H)NH2,
-NHC(O)(oxetanyI)NH2,
)OC(CH3)3,
-NHC(CH3)ZC(O)OCH3,
-NHcyclopropyl,
-NHoxetany|,
-CH2NH2,
-CH2CH2NH2,
-CHZCH2CH2NH2,
-CH2NHCHZC(CH3)3,
C(O)C(CH3)3,
-CH2NHC(O)CH2NH2,
-CH2NHC(O)CH20H,
-CH2N(CH3)2,
-CH2NHCH3,
-CH2N(CH2CH3)2,
-CHZCH2N(CH3)2,
-S(O)2CH2CH3,
-S(O)2CH20HZCH3,
-S(O)2pheny|,
-S(O)2CH3,
benzoyl,
benzylamino,
3-pyrrolidinylpropyl,
opropylmethyl,
utylamino,
cyclobutyI-N(CH3)-,
piperidinyl,
imidazolyl,
morpholinyl,
morpholinylmethyl,
methylpiperazinylmethyl,
methylpiperazinyl,
pyrrolidinyl,
pyrrolidinylmethyl,
methoxypyridinylmethylamino,
methylpyrrolidinyl,
difluoropyrrolidinyl,
dimethylpyrrolidinyl,
methylcyclopropylmethylamino,
ymethylpyrrolidinyl,
fluoropyrrolidinyl,
fluorophenylmethylamino,
zinylmethyl,
oxazolidinyl,
oxetanmethylamino,
methylcyclobutylmethylamino,
oxoimidazolidinyl, and
2-hydroxyethylpiperidinyl;
or a pharmaceutically acceptable salt or prodrug thereof.
ly in the compounds of Formula (Qb2) R716 is phenyl.
Suitably in the compounds of a (Qb2), the compounds are in the form of a
phosphate prodrug.
Suitably in the compounds of Formula (Qb2), the compounds are in the form of a
—C(O)CH(NH2)CH(CH3)2 prodrug.
Non primary amide:
This invention relates to compounds of Formula (lcr) and to the use of compounds
of Formula (lcr) in the methods of the invention:
R’lcr
X1cr Zor
X Zcr
/ JR< R3Cr
R4cr
R5cr N Ycr (lcr)
wherein:
X1cr and XZCr are independently selected from:
hydrogen,
cyano,
fluoro,
chloro,
bromo,
iodo,
C1-6alkyl,
-OC1-6a|ky|,
-ORe,
cycloalkyl,
cycloalkyl substituted from 1 to 4 times by Rd,
heterocycle,
heterocycle substituted from 1 to 4 times by Rd,
-SH, and
-SRa;
Ycr is selected from: 3, NH, NR2, 0, 3(0) and S(O)2;
R1cr is selected from:
amino,
-NHRa,
-NRbRC,
cyano,
fluoro,
chloro,
bromo,
iodo,
C1-6alkyl,
-OC1-6a|kyl,
-ORe,
cycloalkyl,
cycloalkyl substituted from 1 to 4 times by Rd,
heterocycle,
cycle substituted from 1 to 4 times by Rd,
aryl,
aryl substituted from 1 to 4 times by Rd,
heteroaryl,
aryl substituted from 1 to 4 times by Rd,
-SH, and
-SRa;
RZCr is selected from:
hydrogen,
C1-6alkyl, and
C1-6alky| substituted with from 1 to 6 substituents
independently selected from: n, -OH, -COOH;
R3cr is selected from:
aryl,
aryl substituted from 1 to 4 times by Rd,
heteroaryl, and
heteroaryl tuted from 1 to 4 times by Rd;
R4” is selected from:
hydrogen,
C1-6alky|, and
C1-6alky| substituted with from 1 to 6 substituents
independently selected from: halogen, -OH, -COOH;
R5cr is selected from:
amino,
-NHRa,
-NRbRC,
aryl,
aryl substituted from 1 to 4 times by Rd,
-C1-6a|ky|,
-OC1-6alkyl,
-ORe,
-Oaryl,
-Oary| substituted from 1 to 4 times by Rd,
-Oheteroaryl,
-Oheteroaryl substituted from 1 to 4 times by Rd,
-SH, and
-SRa;
where:
each Ra is independently ed from
C1—68Ikyl,
aryl,
aryl substituted from 1 to 4 times by Rd,
heteroaryl,
heteroaryl tuted from 1 to 4 times by Rd
cycloalkyl,
cycloalkyl substituted from 1 to 4 times by Rd,
heterocycloalkyl, and
cycloalkyl substituted from 1 to 4 times by Rd;
R and R0 are independently selected from:
C1-6alkyl,
aryl,
aryl substituted from 1 to 4 times by Rd,
heteroaryl,
aryl substituted from 1 to 4 times by Rd;
cycloalkyl,
cycloalkyl substituted from 1 to 4 times by Rd,
heterocycloalkyl, and
heterocycloalkyl substituted from 1 to 4 times by Rd, or
Rb and R0 are taken together with the nitrogen to which they are
attached, and optionally from 1 to 3 additional heteroatoms
independently selected from O, N, and S, to form
a heterocycloalkyl, which is optionally substituted with from 1 to 5
substituents independently selected from:
fluoro,
chloro,
bromo,
iodo,
C1-Balkyl,
-ORe,
aryl,
aryl substituted from 1 to 4 times by Rd,
heteroaryl,
heteroaryl substituted from 1 to 4 times by Rd,
cycloalkyl,
cycloalkyl substituted from 1 to 4 times by Rd,
heterocycloalkyl, and
heterocycloalkyl substituted from 1 to 4 times by Rd,
C1-4alkoxy,
—-CN,
-N021
-NH2,
-N(H)C1-Salkyl,
-N(H)Re,
-N(C1-5a|ky|)2,
-NReRe,
-N(Re)C1-5a|kyl,
-ONHC(NH)NH2,
-Oheterocyc|oa|ky|,
-NHcyc|oa|kyl,
5a|ky|)cycloa|kyl,
erocycIoa|ky|,
-N(C1-5alkyl)heterocycloa|kyl,
-S(O)2C1-4a|kyl,
-SOzNH2
-S(O)2phenyl,
benzoyL
2-methylcyclopropyl,
imidazolyl,
(methoxypyridinylmethyl)amino,
lcyclopropylmethyl)amino,
(fluorophenylmethyl)amino,
(methyloxetanylmethyl)amino, and
(methylcyclobutylmethy|)amino;
each Rd is independently selected from:
fluoro,
bromo,
iodo,
kyl,
heteroaryl,
heteroaryl substituted from 1 to 4 times by RX,
where RX is selected from aryl, heteroaryl, cycloalkyl,
heterocyloalkyl, C1-ealkyl, and C1-6alkyl substituted with
from 1 to 6 substituents independently selected from:
fluoro, oxo, -OH, -COOH, -NH2, and —-CN,
cycloalkyl,
cycloalkyl substituted from 1 to 4 times by RX,
where RX is selected from aryl, aryl, cycloalkyl,
heterocyloalkyl, C1-6alkyl, and C1-6alkyl substituted with
from 1 to 6 substituents independently selected from:
fluoro, 0x0, -OH, -COOH, -NH2, and —-CN,
heterocycloalkyl,
heterocycloalkyl substituted from 1 to 4 times by RX,
where RX is selected from aryl, heteroaryl, cycloalkyl,
heterocyloalkyl, fluoro, oxo, C1-6alkyl, and C1-6alkyl
tuted
with from 1 to 6 substituents independently selected from:
fluoro, oxo, -OH, -COOH, -NH2, and —-CN,
aryl,
aryl substituted from 1 to 4 times by RX,
where RX is selected from aryl, heteroaryl, cycloalkyl,
heterocyloalkyl, C1-6alkyl, and C1-6alkyl substituted with
from 1 to 6 substituents independently selected from:
fluoro, 0x0, -OH, -COOH, -NH2, and —-CN,
Ci_4a|koxy,
koxy substituted with from 1 to 4 substituents independently
selected from: fluoro, oxo, -OH, -COOH, -NH2, -NHC1-4alkyl,
-N(C1-4alky|)2 and —-CN,
-Oaryl,
-Oary| substituted from 1 to 4 times by RX,
where RX is selected from aryl, heteroaryl, cycloalkyl,
cyloalkyl, C1-6alkyl, and C1-6alkyl substituted with
from 1 to 6 substituents independently selected from:
fluoro, 0x0, -OH, -COOH, -NH2, and —-CN,
-ORe,
-C(O)H,
-C(O)RZZ,
-C(O)ary|,
ry| substituted from 1 to 4 times by R22,
eteroary|,
-C(O)heteroaryl substituted from 1 to 4 times by R22,
-OC(O)H,
-CO(O)RZZ,
-OC(O)aryl,
-CO(O)ary| tuted from 1 to 4 times by RZZ,
-OC(O)heteroaryl,
-OC(O)heteroaryl substituted from 1 to 4 times by R22,
mercapto,
-SRX,
where RX is selected from aryl, heteroaryl, cycloalkyl,
heterocyloalkyl, C1-ealkyl, and C1-6alkyl substituted with
from 1 to 6 tuents independently selected from:
fluoro, oxo, -OH, -COOH, -NH2, and —-CN,
-S(O)H,
-S(0)RX,
where RX is selected from aryl, aryl, cycloalkyl,
heterocyloalkyl, C1-6alkyl, and C1-6alkyl substituted with
from 1 to 6 substituents independently selected from:
fluoro, 0x0, -OH, -COOH, -NH2, and —-CN,
-S(O)2H,
-S(O)2RX,
where RX is selected from aryl, heteroaryl, cycloalkyl,
heterocyloalkyl, C1-ealkyl, and C1-salkyl substituted with
from 1 to 6 substituents independently ed from:
fluoro, 0x0, -OH, -COOH, -NH2, and —-CN,
-OS(O)2RX,
where RX is selected from aryl, heteroaryl, cycloalkyl,
1O heterocyloalkyl, C1-ealkyl, and C1-6alkyl substituted with
from 1 to 6 substituents independently selected from:
fluoro, 0x0, -OH, -COOH, -NH2, and —-CN,
NH2,
-S(O)2NHRX,
where RX is selected from aryl, heteroaryl, cycloalkyl,
heterocyloalkyl, C1-6alkyl, and C1-6alkyl substituted with
from 1 to 6 substituents ndently selected from:
fluoro, 0x0, -OH, -COOH, -NH2, and —-CN,
-S(O)2NRX1RX2,
where RX1 and RX2 are each independently selected from
aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C1-6alkyl, and
C1-Balkyl substituted with from 1 to 6 substituents
independently selected from: fluoro, oxo, -OH, -COOH,
-NH2, and —-CN,
-P(O)(CH3)2,
-NHS(O)2H,
)2RX,
where RX is selected from aryl, heteroaryl, cycloalkyl,
heterocyloalkyl, C1-6alkyl, and kyl tuted with
from 1 to 6 substituents independently selected from:
fluoro, 0x0, -OH, -COOH, -NH2, and —-CN,
-NHC(O)H,
-NHC(O)RX,
where RX is selected from aryl, aryl, cycloalkyl,
heterocyloalkyl, C1-6alkyl, and C1-6alkyl substituted with
from 1 to 6 substituents independently selected from:
fluoro, 0x0, -OH, -COOH, -NH2, and —-CN,
-C(O)NH2,
-C(O)NHRX,
where RX is selected from aryl, heteroaryl, cycloalkyl,
heterocyloalkyl, C1-6alkyl, and C1-6alkyl substituted with
from 1 to 6 substituents independently selected from:
fluoro, 0x0, -OH, -COOH, -NH2, and —-CN,
-C(O)NRX1RX2,
where RX1 and RX2 are each independently selected from
aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C1-6a|kyl, and
1O kyl substituted with from 1 to 6 tuents
independently ed from: fluoro, oxo, -OH, -COOH,
-NH2, and —-CN,
-C(O)OH,
-c«30R§
where RX is selected from aryl, aryl, cycloalkyl,
heterocyloalkyl, C1-6alkyl, and C1-6alkyl substituted with
from 1 to 6 substituents independently selected from:
fluoro, oxo, -OH, -COOH, -NH2, and —-CN,
oxo,
hydroxy,
amino,
-NHRX,
where RX is selected from aryl, heteroaryl, cycloalkyl,
heterocyloalkyl, C1-6alkyl, C1-6alkyl substituted with
from 1 to 6 substituents independently selected from:
, 0x0, -OH, -COOH, -NH2, and -CN, C1-6alkoxy, and
koxy tuted with from 1 to 6 substituents
Independently selected from: fluoro, oxo, -OH, -COOH,
-NH2, and —CN
-NRX1RX2,
where RX1 and RX2 are each independently selected from
aryl, heteroaryl, cycloalkyl, heterocyloalkyl, -S(O)2C1-6a|kyl,
-S(O)2C1-6alkyl substituted with from 1 to 6 substituents
independently selected from: fluoro, oxo, -OH, -COOH, -NH2,
and -CN, C1-6alkyl, and C1-6alkyl substituted with from 1 to
6 substituents independently selected from: fluoro, 0x0, -OH,
-COOH, -NH2, and -CN,
boronic acid,
nitro,
cyano,
-NHC(O)NH2,
-NHC(O)NHRX,
where RX is ed from aryl, heteroaryl, cycloalkyl,
heterocyloalkyl, C1-6alkyl, and C1-ealkyl substituted with
from 1 to 6 substituents ndently selected from:
fluoro, 0x0, -OH, -COOH, -NH2, and —-CN,
)NRX1RX2,
where RX1 and RX2 are each independently selected from
aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C1-6alkyl, and
C1-6alkyl substituted with from 1 to 6 substituents
independently selected from: fluoro, 0x0, -OH, -COOH,
-NH2, and —-CN,
each Re is independently selected from:
C1-6alkyl substituted with from 1 to 9 substitutents independently
selected from:
fluoro,
chloro,
bromo,
iodo,
-OC1-6a|kyl,
-OC1-6alkyl substituted with from 1 to 6 substituents
independently selected from: fluoro, oxo, -OH,
-COOH, -NH2, and —-CN,
-OC(O)C1-6alky|,
C1-6alkyl substituted with from 1 to 6 substituents
independently selected from: fluoro, oxo, -OH,
-COOH, -NH2, and -CN,
-ONHC(NH)NH2,
(OH)2,
mercapto,
-SRX,
where RX is selected from aryl, heteroaryl,
cycloalkyl, heterocyloalkyl, C1-6alkyl, and C1-6alkyl
substituted with from 1 to 6 substituents
independently selected from: fluoro, oxo, -OH,
-COOH, -NH2, and —-CN,
-S(0)H.
-S(O)RX,
where RX is selected from aryl, heteroaryl,
cycloalkyl, heterocyloalkyl, C1-ealkyl, and C1-6alkyl
substituted with from 1 to 6 substituents
independently selected from: fluoro, oxo, -OH,
-COOH, -NH2, and —-CN,
-S(O)2H,
-S(0)2RX,
where RX is ed from aryl, heteroaryl,
cycloalkyl, heterocyloalkyl, C1-6alkyl, and C1-6alkyl
substituted with from 1 to 6 substituents
independently selected from: , oxo, -OH,
-COOH, -NH2, and —-CN,
oxo,
hyd roxy,
amino,
-NHRXX,
where Rxx is selected from aryl, heteroaryl,
cycloalkyl, cycloalkyl substituted with C1-4alkoxy,
C1-4alkoxy substituted with from 1 to 6 substituents
independently selected from: fluoro, triazolyl,
cyclopropyl,oxo, -ORXV, -COOH, —CN, and -NRXVRXZ,
where ny and RXZ are Independently selected from:
hydrogen, aryl, C1-5alkyl heterocyloalkyl, C1-6alkyl,
and C1-6alky| tuted with from 1 to 6 substituents
ndently selected from: fluoro, oxo, -ORXV,
-COOH, —CN, and XZ, where ny and RXZ are
Independently selected from: hydrogen, aryl,
C1-5alkyl and C1-5alkyl substituted with from 1 to 4
tuents independently selected from: fluoro,
triazolyl, cyclopropyl,oxo, -OH, -OC1-5alkyl,
-OC1-5alkyl substituted from 1 to 6 times by fluoro
and —COOH,
_NRX1 Rx2
where RX1 and RX2 are each independently selected
from aryl, heteroaryl, cycloalkyl, heterocyloalkyl,
C1-6alkyl, and C1-6alkyl substituted with from 1 to 6
substituents independently selected from: fluoro,
oxo, -OH, -COOH, -NH2, and —-CN,
guanidino,
-C(O)OH,
where RX is selected from aryl, heteroaryl,
cycloalkyl, heterocyloalkyl, kyl, and kyl
substituted with from 1 to 6 substituents
independently selected from: , oxo, -OH,
-COOH, -NH2, and —-CN,
-C(O)NHRX,
where RX is selected from aryl, heteroaryl, -OH,
C1-4alkoxy, cycloalkyl, cycloalkyl substituted with
HO-(C1-4alkyl)-, heterocyloalkyl, heterocyloalkyl
substituted with HO-(C1-4alkyI)-, C1-6alkyl, and
C1-6alkyl substituted with from 1 to 6 substituents
independently selected from: fluoro, oxo, -OH,
-COOH, heteroaryl, -NH2, and —-CN,
-C(O)NRX1RX2,
where RX1 and RX2 are each independently selected
from aryl, heteroaryl, cycloalkyl, cycloalkyl substituted
with HO-(C1-4a|kyI)-, heterocyloalkyl, C1-6a|kyl, and
C1-6alkyl tuted with from 1 to 6 substituents
independently selected from: , oxo, -OH,
-COOH, -NH2, and —CN,
or RX1 and RX2 taken together with the nitrogen to
which they are attached, and optionally from 1 to 3
additional heteroatoms independently selected from
O, N, and S, to form a heterocycloalkyl, which is
ally substituted with from 1 to 5 substituents
independently selected from fluoro, oxo, -OH, HO-
(C1-4alkyI)-, -COOH, -NH2, and —CN,
aryl,
aryl substituted from 1 to 4 times by RX,
where RX is selected from fluoro, chloro, bromo, iodo,
aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C1-6alky|,
and C1-6alkyl substituted with from 1 to 6 substituents
independently selected from: fluoro, oxo, -OH,
-COOH, -NH2, -N(CH3)2, -NHC(O)C1-4alkyl, and
-CN,
-Oary|,
-Oary| substituted from 1 to 4 times by RX,
where RX is selected from aryl, heteroaryl,
cycloalkyl, heterocyloalkyl, C1-6alkyl, and C1-6alkyl
substituted with from 1 to 6 substituents
independently selected from: fluoro, oxo, -OH,
-COOH, -NH2, and —-CN,
heteroaryl,
heteroaryl substituted from 1 to 4 times by RX,
where RX is selected from aryl, heteroaryl,
cycloalkyl, heterocyloalkyl, C1-4alkoxy C1-6alkyl, and
kyl substituted with from 1 to 6 tuents
independently selected from: fluoro, oxo, -OH,
-COOH, -NH2, and -CN,
-Oheteroary|,
-Oheteroaryl substituted from 1 to 4 times by RX,
where RX is selected from aryl, aryl,
cycloalkyl, heterocyloalkyl, C1-6alkyl, and C1-6alkyl
substituted with from 1 to 6 substituents
independently selected from: fluoro, oxo, -OH,
-COOH, -NH2, and —-CN,
cycloalkyl,
cycloalkyl substituted from 1 to 4 times by RX,
where RX is ed from aryl, heteroaryl,
cycloalkyl, cyloalkyl, C1-6a|kyl, and C1-6alky|
tuted with from 1 to 6 substituents
independently selected from: fluoro, 0x0, -OH,
-COOH, -NH2, and —-CN,
heterocycloalkyl,
heterocycloalkyl substituted from 1 to 4 times by RX,
where RX is selected from oxo, -OH,
-N(C1-4a|kyl)2, aryl, aryl,
cycloalkyl, heterocyloalkyl, C1-6alkyl, and Ct-6alkyl
substituted with from 1 to 6 substituents
independently selected from: fluoro, oxo, -OH,
-COOH, -NH2, -N(CH3)2, and -CN,
-S(O)2NH2,
-S(O)2NHRX,
where RX is selected from aryl, heteroaryl,
cycloalkyl, heterocyloalkyl, C1-6alkyl, and C1-6alky|
substituted with from 1 to 6 substituents
independently selected from: fluoro, oxo, -OH,
-COOH, -NH2, and —-CN,
-S(O)2NRX1RX2,
where RX1 and RX2 are each independently selected
from aryl, heteroaryl, cycloalkyl, heterocyloalkyl,
C1-6alkyl, and C1-6alkyl substituted with from 1 to 6
substituents ndently selected from: ,
oxo, -OH, -COOH, -NH2, and —-CN,
-NHS(O)2H,
-NHS(O)2RX,
where RX is selected from aryl, heteroaryl,
cycloalkyl, heterocyloalkyl, C1-6alkyl, and C1-6alkyl
substituted with from 1 to 6 substituents
independently selected from: , oxo, -OH,
-COOH, -NH2, and —-CN,
-OC(O)NH2,
-NHC(O)RX,
where RX is selected from aryl, heteroaryl,
cycloalkyl, cyloalkyl, C1-ealkyl, and ky|
tuted with from 1 to 6 substituents
independently ed from: fluoro, oxo, -OH,
-COOH, -NH2, and -CN
-NHC(O)NHRXp,
where RXp is selected from heteroaryl,
cycloalkyl, heterocyloalkyl, and C1-6alkyl
substituted with from 1 to 4 substituents
independently selected from: -COOH, -NH2, and
—-CN,
-NHC(O)NRX3RX4,
where RX3 and RX4 are each independently selected
from heteroaryl, cycloalkyl, heterocyloalkyl,
and C1-6alkyl substituted with from 1 to 6
substituents independently selected from:
-COOH, -NH2, and —-CN,
)C(O)NH2,
-N02, and
-CN; and
RZ is selected from
C1—6alkyl,
cycloalkyl,
cycloalkyl substituted from 1 to 4 times by Rd,
heterocycloalkyl, and
heterocycloalkyl substituted from 1 to 4 times by Rd; and
R22 is selected from
C1-6alkyl, and
provided that:
X1cr and Xzcr are not both hydrogen;
or a pharmaceutically acceptable salt or prodrug thereof.
Suitably in the nds of Formula (lcr) neither X1cr nor X2cr are hydrogen.
Suitably in the compounds of Formula (lcr), the nds are in the form of a
ate prodrug.
Suitably in the compounds of Formula (lcr), the compounds are in the form of a
-C(O)CH(NH2)CH(CH3)2 prodrug.
Included in the compounds ofthe invention and used in the methods ofthe invention
are compounds of Formula (llcr):
R21cr
21 cr 220r
X X R22cr
/ %R23cr24cr
R25or N R
Y1 cr (Ilcr)
X21cr and X22cr are independently selected from:
cyano,
fluoro,
chloro,
bromo,
iodo,
C1 -6a|kyl,
-OC1-6alkyl,
-OR?
cycloalkyl,
heterocycle, and
-SH;
Y1cr is selected from: 8, NH, and NR2;
R21cr is selected from:
amino,
cyano,
fluoro,
chloro,
bromo,
iodo,
C1-6alkyl,
-OC1_6alkyI,
-OR§
-NHR?
3o -NRbR9
aryl,
aryl substituted from 1 to 4 times by Rd,
heteroaryl,
heteroaryl substituted from 1 to 4 times by Rd,
cycloalkyl,
cycloalkyl substituted with from 1 to 4 times by Rd,
cycle,
heterocycle substituted with from 1 to 4 times by Rd,
-SH, and
-SRa;
R22Cr is selected from:
hydrogen,
C1-6alkyl, and
C1-6alkyl substituted with from 1 to 6 substituents
independently selected from: fluoro, chloro, and bromo;
R230r is selected from:
aryl!
aryl substituted from 1 to 4 times by Rd,
heteroaryl, and
heteroaryl substituted from 1 to 4 times by Rd;
R24cr is ed from:
hydrogen,
C1-6alkyl, and
ky| tuted with from 1 to 6 substituents
independently selected from: fluoro, chloro, and bromo;
R250r is selected from:
amino,
-NHRa,
-NRbRC,
aryl.
aryl substituted from 1 to 4 times by Rd,
-OC1-68Ikyl,
-ORe,
-Oaryl,
-Oheteroaryl,
-SH, and
-SRa;
where:
each Ra is independently selected from
C1—6alkyl,
Re,
aryl,
aryl substituted from 1 to 4 times by Rd,
heteroaryl,
heteroaryl tuted from 1 to 4 times by Rd
cycloalkyl,
cycloalkyl substituted from 1 to 4 times by Rd,
heterocycloalkyl, and
heterocycloalkyl substituted from 1 to 4 times by Rd;
Rb and R0 are ndently selected from:
C1-6alkyl,
aryl,
aryl tuted from 1 to 4 times by Rd,
heteroaryl,
heteroaryl substituted from 1 to 4 times by Rd;
cycloalkyl,
cycloalkyl substituted from 1 to 4 times by Rd,
heterocycloalkyl, and
heterocycloalkyl substituted from 1 to 4 times by Rd, or
Rb and RC are taken together with the nitrogen to which they are
attached, and optionally from 1 to 3 additional heteroatoms, to form
a cycloalkyl, which is optionally substituted with from 1 to 5
substituents independently selected from:
fluoro,
chloro,
bromo,
aryl substituted from 1 to 4 times by Rd,
heteroaryl,
heteroaryl substituted from 1 to 4 times by Rd,
cycloalkyl,
cycloalkyl substituted from 1 to 4 times by Rd,
heterocycloalkyl, and
heterocycloalkyl substituted from 1 to 4 times by Rd,
C1-4a|koxy,
C1-4alkoxy substituted with from 1 to 6 substituents
independently selected from: fluoro, oxo, -OH,
-COOH, -NH2, and —-CN,
-COOH,
-N021
-NH2,
1-4a|ky|,
-N(H)Re,
-N(C1-4a|ky|)2,
NH)NH2,
-Oheterocyc|oa|ky|,
-NHcyc|oa|kyl,
-NHheterocycIoa|ky|,
3o -S(O)2CHZCH3,
-S(O)2CH2CH2CH3,
-S(O)2pheny|,
-S(O)2CH3,
benzoyL
benzylamino,
3-pyrrolidinylpropyl,
2-cyclopropylmethyl,
cyclobutylamino,
utyI-N(CH3)-,
piperidinyl,
imidazolyl,
morpholinyl,
morpholinylmethyl,
methylpiperazinylmethyl,
methylpiperazinyl,
pyrrolidinyl,
pyrrolidinylmethyl,
methoxypyridinylmethylamino,
methylpyrrolidinyl,
difluoropyrrolidinyl,
ylpyrrolidinyl,
methylcyclopropylmethylamino,
hyd roxymethylpyrrolidinyl,
pyrrolidinyl,
fluorophenylmethylamino,
piperazinylmethyl,
oxazolidinyl,
methyloxetanmethylamino,
methylcyclobutylmethylamino,
oxoimidazolidinyl, and
2-hydroxyethylpiperidinyl;
each Rd is independently selected from:
WO 16727
fluoro,
chloro,
bromo,
iodo,
C1-6alkyl,
aryl,
heteroaryl substituted from 1 to 4 times by RX,
where RX is selected from aryl, heteroaryl, cycloalkyl,
heterocyloalkyl, C1-6alkyl, and C1-6alky| tuted with
from 1 to 6 substituents independently selected from:
fluoro, oxo, -OH, -COOH, -NH2, and —-CN,
cycloalkyl,
cycloalkyl tuted from 1 to 4 times by RX,
where RX is selected from aryl, heteroaryl, cycloalkyl,
heterocyloalkyl, C1-6alkyl, and C1-6alkyl substituted with
from 1 to 6 substituents independently selected from:
fluoro, 0x0, -OH, -COOH, -NH2, and —-CN,
heterocycloalkyl,
heterocycloalkyl substituted from 1 to 4 times by RX,
where RX is selected from aryl, heteroaryl, cycloalkyl,
heterocyloalkyl, fluoro, oxo, C1-6alkyl, and C1-6alkyl
substituted
with from 1 to 6 substituents independently selected from:
fluoro, 0x0, -OH, -COOH, -NH2, and —-CN,
aryl,
aryl substituted from 1 to 4 times by RX,
where RX is selected from aryl, heteroaryl, cycloalkyl,
heterocyloalkyl, C1-6alkyl, and C1-6alkyl substituted with
from 1 to 6 substituents independently selected from:
, 0x0, -OH, -COOH, -NH2, and —-CN,
C1-4alkoxy,
C1_4alkoxy substituted with from 1 to 4 substituents independently
selected
from: fluoro, oxo, -OH, -COOH, -NH2, and —-CN,
-Oaryl,
-Oary| substituted from 1 to 4 times by RX,
where RX is selected from aryl, aryl, cycloalkyl,
heterocyloalkyl, C1-6alky|, and C1-6alkyl substituted with
from 1 to 6 substituents independently selected from:
fluoro, 0x0, -OH, -COOH, -NH2, and —-CN,
-C(O)H,
-C(O)RZZ,
-C(O)aryl,
ry| substituted from 1 to 4 times by R22,
-C(O)heteroaryl,
-C(O)heteroaryl substituted from 1 to 4 times by R22,
-OC(O)H,
-CO(O)RZZ,
-OC(O)aryl,
-CO(O)ary| substituted from 1 to 4 times by RZZ,
-OC(O)heteroaryl,
-OC(O)heteroaryl substituted from 1 to 4 times by R22,
mercapto,
where RX is selected from aryl, heteroaryl, cycloalkyl,
heterocyloalkyl, kyl, and kyl substituted with
from 1 to 6 substituents independently selected from:
fluoro, 0x0, -OH, -COOH, -NH2, and —-CN,
-S(O)H,
-S(O)RX,
where RX is selected from aryl, heteroaryl, cycloalkyl,
cyloalkyl, C1-6alkyl, and C1-6alky| substituted with
from 1 to 6 substituents independently selected from:
fluoro, 0x0, -OH, -COOH, -NH2, and —-CN,
-S(O)2H,
-S(O)2RX,
where RX is selected from aryl, heteroaryl, cycloalkyl,
heterocyloalkyl, C1-6alkyl, and C1-6alkyl substituted with
from 1 to 6 tuents independently selected from:
fluoro, 0x0, -OH, -COOH, -NH2, and —-CN,
2RX,
where RX is selected from aryl, heteroaryl, cycloalkyl,
heterocyloalkyl, C1-6alkyl, and C1-6alkyl substituted with
from 1 to 6 substituents independently selected from:
fluoro, oxo, -OH, -COOH, -NH2, and —-CN,
-S(O)2NH2,
-S(O)2NHRX,
where RX is selected from aryl, heteroaryl, cycloalkyl,
heterocyloalkyl, C1-6alkyl, and C1-6alkyl substituted with
from 1 to 6 substituents independently selected from:
fluoro, 0x0, -OH, -COOH, -NH2, and —-CN,
-S(O)2NRX1RX2,
where RX1 and RX2 are each independently selected from
aryl, heteroaryl, cycloalkyl, heterocyloalkyl, kyl, and
kyl substituted with from 1 to 6 substituents
independently selected from: fluoro, oxo, -OH, -COOH,
-NH2, and —-CN,
-NHS(O)2H,
-NHS(O)2RX,
where RX is selected from aryl, heteroaryl, cycloalkyl,
heterocyloalkyl, C1-6alkyl, and C1-6alkyl substituted with
from 1 to 6 substituents independently selected from:
fluoro, 0x0, -OH, -COOH, -NH2, and —-CN,
-NHC(O)H,
-NHC(O)RX,
where RX is selected from aryl, heteroaryl, lkyl,
heterocyloalkyl, C1-6alkyl, and C1-6alkyl substituted with
from 1 to 6 substituents independently selected from:
fluoro, 0x0, -OH, -COOH, -NH2, and —-CN,
-C(O)NH2,
-C(O)NHRX,
where RX is selected from aryl, heteroaryl, cycloalkyl,
heterocyloalkyl, C1-6alkyl, and kyl substituted with
from 1 to 6 substituents ndently selected from:
fluoro, 0x0, -OH, -COOH, -NH2, and —-CN,
RX1RX2,
where RX1 and RX2 are each independently selected from
aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C1-6alkyl, and
C1-6alkyl substituted with from 1 to 6 substituents
independently selected from: fluoro, oxo, -OH, -COOH,
-NH2, and —-CN,
-C(O)OH,
-C(O)ORX,
where RX is selected from aryl, heteroaryl, cycloalkyl,
heterocyloalkyl, C1-6alkyl, and C1-6alkyl substituted with
from 1 to 6 substituents independently ed from:
, oxo, -OH, -COOH, -NH2, and —-CN,
oxo,
hydroxy,
amino,
-NHRX,
where RX is selected from aryl, heteroaryl, cycloalkyl,
heterocyloalkyl, C1-6alkyl, and C1-6alkyl substituted with
from 1 to 6 substituents independently ed from:
fluoro, oxo, -OH, -COOH, -NH2, and —-CN,
where RX1 and RX2 are each independently selected from
aryl, heteroaryl, cycloalkyl, heterocyloalkyl, -S(O)2C1-6alkyl,
-S(O)ZC1-6alkyl substituted with from 1 to 6 substituents
ndently selected from: fluoro, oxo, -OH, -COOH, -NH2,
—-CN, C1-6alkyl, and C1-6alkyl substituted with from 1 to 6
tuents independently ed from: fluoro, oxo, -OH, -
COOH,
-NH2, and —-CN,
boronic acid,
nitro,
cyano,
-NHC(O)NH2,
-NHC(O)NHRX,
where RX is selected from aryl, heteroaryl, cycloalkyl,
heterocyloalkyl, C1-6alky|, and C1-6a|kyl substituted with
from 1 to 6 substituents independently selected from:
fluoro, 0x0, -OH, -COOH, -NH2, and —-CN,
-NHC(O)NRX1RX2,
where RX1 and RX2 are each independently selected from
aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C1-6alkyl, and
kyl substituted with from 1 to 6 substituents
independently selected from: fluoro, oxo, -OH, -COOH,
-NH2, and —-CN,
each Re is independently selected from:
C1_6a|kyl tuted with from 1 to 9 substitutents ndently
selected from:
fluoro,
bromo,
iodo,
C1—Balkyl,
-OC1-6a|kyl,
-OC1-6alkyl substituted with from 1 to 6 substituents
independently selected from: fluoro, oxo, -OH,
-COOH, -NH2, and —-CN,
mercapto,
-SRX,
where RX is selected from aryl, heteroaryl,
cycloalkyl, heterocyloalkyl, C1-Galkyl, and C1-6alkyl
substituted with from 1 to 6 substituents
independently selected from: fluoro, oxo, -OH,
-COOH, -NH2, and —-CN,
-S(O)H,
-S(O)RX,
where RX is selected from aryl, heteroaryl,
cycloalkyl, heterocyloalkyl, C1-6alkyl, and C1-6alkyl
substituted with from 1 to 6 substituents
independently selected from: fluoro, oxo, -OH,
-COOH, -NH2, and —-CN,
H,
-S(O)2RX,
where RX is selected from aryl, aryl,
cycloalkyl, heterocyloalkyl, C1-6a|ky|, and C1-6alkyl
substituted with from 1 to 6 substituents
independently selected from: fluoro, oxo, -OH,
-COOH, -NH2, and —-CN,
oxo,
hyd roxy,
amino,
-NHRXX,
where RXX is selected from aryl, heteroaryl,
cycloalkyl, cyloalkyl, C1-6alkyl,
and C1-6alky| substituted with from 1 to 6
substituents ndently ed from: fluoro,
oxo, -ORXV, -COOH, —-CN, alkyl, -OC1-5alkyl
substituted from 1 to 6 times by fluoro and
—NRXyRXZ, where ny and R"Z are ndently
selected from: hydrogen, aryl, C1-5alky| and
C1-5alkyl substituted with from 1 to 4 substituents
ndently selected from: fluoro, oxo, -OH,
-OC1-5a|kyl, -OC1-5a|ky| substituted from 1 to 6
times by fluoro and —COOH,
-NRX1RX2,
where RX1 and RX2 are each independently selected
from aryl, heteroaryl, cycloalkyl, heterocyloalkyl,
C1-6alkyl, and C1-6alkyl substituted with from 1 to 6
substituents independently selected from: fluoro,
oxo, -OH, -COOH, -NH2, and —-CN,
guanidino,
-C(O)OH,
-C(O)ORX,
where RX is selected from aryl, heteroaryl,
cycloalkyl, heterocyloalkyl, C1-6a|kyl, and C1-6a|ky|
substituted with from 1 to 6 substituents
independently selected from: fluoro, oxo, -OH,
-COOH, -NH2, and —-CN,
-C(O)NHRX,
where Rx is selected from aryl, heteroaryl,
cycloalkyl, heterocyloalkyl, C1-6a|kyl, and C1-6alky|
substituted with from 1 to 6 substituents
independently selected from: fluoro, oxo, -OH,
-COOH, -NH2, and —-CN,
-C(O)NRX1RX2,
where RX1 and RX2 are each independently selected
from aryl, heteroaryl, cycloalkyl, heterocyloalkyl,
C1-6alkyl, and C1-6alkyl substituted with from 1 to 6
substituents independently selected from: ,
oxo, -OH, -COOH, -NH2, and —-CN,
aryl,
aryl substituted from 1 to 4 times by RX,
where RX is selected from aryl, heteroaryl,
cycloalkyl, cyloalkyl, C1-ealkyl, and C1-6a|kyl
substituted with from 1 to 6 substituents
ndently selected from: fluoro, oxo, -OH,
-COOH, -NH2, and —-CN,
-Oaryl,
-Oaryl substituted from 1 to 4 times by RX,
where Rx is selected from aryl, heteroaryl,
cycloalkyl, heterocyloalkyl, C1-6alkyl, and C1-6alkyl
substituted with from 1 to 6 substituents
ndently selected from: , oxo, -OH,
-COOH, -NH2, and —-CN,
heteroaryl,
heteroaryl tuted from 1 to 4 times by RX,
where RX is selected from aryl, heteroaryl,
cycloalkyl, cyloalkyl, C1-6alkyl, and C1-6alkyl
substituted with from 1 to 6 substituents
independently selected from: fluoro, oxo, -OH,
-COOH, -NH2, and —-CN,
-Oheteroary|,
-Oheteroaryl substituted from 1 to 4 times by RX,
where RX is selected from aryl, heteroaryl,
cycloalkyl, heterocyloalkyl, C1-6alkyl, and C1-6alkyl
substituted with from 1 to 6 substituents
independently selected from: fluoro, 0x0, -OH,
-COOH, -NH2, and —-CN,
cycloalkyl,
cycloalkyl substituted from 1 to 4 times by RX,
where RX is selected from aryl, heteroaryl,
cycloalkyl, heterocyloalkyl, C1-ealkyl, and C1-6a|kyl
2017/053511
substituted with from 1 to 6 substituents
independently selected from: fluoro, oxo, -OH,
-COOH, -NH2, and —-CN,
heterocycloalkyl,
heterocycloalkyl tuted from 1 to 4 times by RX,
where Rx is selected from aryl, heteroaryl,
cycloalkyl, heterocyloalkyl, C1-6alkyl, and C1-6alkyl
tuted with from 1 to 6 tuents
independently selected from: fluoro, oxo, -OH,
-COOH, -NH2, and —-CN,
-S(O)2NH2,
-S(O)2NHRX,
where RX is selected from aryl, aryl,
cycloalkyl, heterocyloalkyl, C1-6alkyl, and C1-6alkyl
substituted with from 1 to 6 substituents
independently selected from: fluoro, oxo, -OH,
-COOH, -NH2, and —-CN,
NRX1RX2,
where RX1 and RX2 are each independently selected
from aryl, heteroaryl, cycloalkyl, heterocyloalkyl,
C1-6alkyl, and C1-6alkyl substituted with from 1 to 6
substituents independently selected from: fluoro,
oxo, -OH, -COOH, -NH2, and —-CN,
-NHS(O)2H,
-NHS(O)2RX,
where Rx is selected from aryl, heteroaryl,
cycloalkyl, heterocyloalkyl, C1-6alkyl, and C1-6alky|
substituted with from 1 to 6 substituents
independently selected from: fluoro, oxo, -OH,
-COOH, -NH2, and —-CN,
-NHC(O)NHRXp,
where RXp is selected from heteroaryl,
cycloalkyl, heterocyloalkyl, and C1-6alkyl
substituted with from 1 to 4 substituents
independently selected from: -COOH, -NH2, and
—-CN,
-NHC(O)NRX3RX4,
where RX3 and RX4 are each independently selected
from heteroaryl, cycloalkyl, heterocyloalkyl,
and C1-6alkyl substituted with from 1 to 6
substituents independently selected from:
-COOH, -NH2, and —-CN,
nitro, and
cyano;
R2 is selected from
C1 -6alkyl,
cycloalkyl,
cycloalkyl substituted from 1 to 4 times by Rd,
heterocycloalkyl, and
heterocycloalkyl substituted from 1 to 4 times by Rd;
R22 is selected from
kyl, and
provided that:
X21cr and X22” are not both hydrogen;
or a pharmaceutically acceptable salt or g thereof.
Suitably in the compounds of Formula (llcr) neither X21cr nor X22cr are hydrogen.
Suitably in the nds of Formula (llcr), the compounds are in the form of a
phosphate prodrug.
Suitably in the compounds of Formula (llcr), the compounds are in the form of a
—C(O)CH(NH2)CH(CH3)2 prodrug.
Included in the compounds ofthe invention and used in the s ofthe invention
are nds of Formula (lllcr):
R31cr
31 cr 32cr
X X RSZCr
l R33cr
R35cr N/ XR34cr
Y (I l Icr)
wherein:
X31cr and X32cr are ndently selected from:
hydrogen,
cyano,
fluoro,
chloro,
bromo,
iodo,
C1-6alkyl,
-OC1-6alkyl,
cycloalkyl, and
-SH;
Y2” is selected from: 8, NH, and NR2;
R31CIr is selected from:
Ct—68lkyl,
Ret’
-OC1-6alkyl,
-ORe1,
-NHRa1,
aryl,
aryl substituted from 1 to 4 times by R“,
heteroaryl,
heteroaryl substituted from 1 to 4 times by R“,
cycloalkyl,
cycloalkyl substituted from 1 to 4 times by Rd1,
heterocycloalkyl,
heterocycloalkyl substituted from 1 to 4 times by R“,
-SH, and
-SRa1;
R32” is selected from:
hydrogen,
C1-3alkyl, and
C1-3alkyl substituted from 1 to 4 times by fluoro;
R33cr is selected from:
aryl,
aryl tuted from 1 to 4 times by Rd1,
heteroaryl, and
heteroaryl substituted from 1 to 4 times by R“;
R3‘1rCr is selected from:
hydrogen,
C1-3alky|, and
C1-3alky| substituted from 1 to 4 times by fluoro;
R35‘” is selected from:
amino,
-NHRa1,
C1,
aryl,
aryl substituted from 1 to 4 times by Rd1,
-OC1-6a|kyl,
-SH, and
where:
each Ra1 is independently selected from
C1-6alkyl,
aryl,
heteroaryl,
cycloalkyl,
heterocycloalkyl, and
heterocycloalkyl substituted from 1 to 4 times by R“;
Rb1 and RC1 are ndently selected from:
C1-6alkyl,
Re1’
-ORe1,
aryl,
aryl substituted from 1 to 4 times by Rm,
heteroaryl,
heteroaryl substituted from 1 to 4 times by Rm;
cycloalkyl,
lkyl substituted from 1 to 4 times by R“,
heterocycloalkyl, and
heterocycloalkyl substituted from 1 to 4 times by Rd1, or
Rb1 and RC1 are taken together with the nitrogen to which they are
attached, and optionally from 1 to 3 additional atoms, to form
a heterocycloalkyl, which is optionally substituted with from 1 to 5
substituents independently selected from:
fluoro,
chloro,
bromo,
iodo,
C1-6alkyl,
R61,
aryl,
aryl substituted from 1 to 4 times by Rm,
cycloalkyl,
cycloalkyl substituted from 1 to 4 times by Rm,
heterocycloalkyl, and
heterocycloalkyl substituted from 1 to 4 times by Rd1,
koxy,
C1-4alkoxy substituted with from 1 to 6 substituents
independently selected from: fluoro, oxo, -OH,
-COOH, -NH2, and —-CN,
—-CN,
oxo,
-OH,
-COOH,
-N027
-NH2,
-N(H)C1-4a|kyl,
-N(H)Re1,
-N(C1-4alkyl)2,
-ONHC(NH)NH2,
-Oheterocyc|oa|ky|,
-NHcyc|oa|kyl,
-NHheterocycloa|ky|,
-S(O)2CH2CH3,
-S(O)2CHZCH2CH3,
-S(O)2pheny|,
-S(O)2CH3,
benzoyL
benzylamino,
3-pyrrolidinylpropyl,
2-cyclopropyl methyl,
utylamino,
cyclobutyI-N(CH3)-,
piperidinyl,
imidazolyl,
morpholinyl,
morpholinylmethyl,
piperazinylmethyl,
methylpiperazinyl,
pyrrolidinyl,
pyrrolidinylmethyl,
methoxypyridinylmethylamino,
methylpyrrolidinyl,
difluoropyrrolidinyl,
dimethylpyrrolidinyl,
methylcyclopropylmethylamino,
hyd roxymethylpyrrolidinyl,
fluoropyrrolidinyl,
1O fluorophenylmethylamino,
piperazinylmethyl,
oxazolidinyl,
methyloxetanmethylamino,
methylcyclobutylmethylamino,
oxoimidazolidinyl, and
oxyethylpiperidinyl;
each Rd1 is independently ed from:
fluoro,
chloro,
bromo,
iodo,
C1—Salkyl,
Re1
heteroaryl,
heteroaryl substituted from 1 to 4 times by Rxa
where Rxa is selected from aryl, heteroaryl, lkyl,
heterocyloalkyl, C1-6alkyl, and C1-6alkyl substituted
from 1 to 6 times by fluoro,
cycloalkyl,
cycloalkyl substituted from 1 to 4 times by Rxa'
where Rxa is selected from aryl, heteroaryl, lkyl,
heterocyloalkyl, C1-6alkyl, and C1-6alkyl substituted
from 1 to 6 times by fluoro,
heterocycloalkyl,
heterocycloalkyl substituted from 1 to 4 times by RX,
where RX is selected from: fluoro, oxo, C1-6alkyl, and C1-
6alkyl
substituted with from 1 to 6 substituents independently
selected
from: fluoro, 0x0, -OH, -COOH, -NH2, and —-CN,
aryl,
aryl substituted from 1 to 4 times by Rxa’
where Rxa is selected from aryl, heteroaryl, cycloalkyl,
heterocyloalkyl, kyl, and C1-6alkyl tuted
from 1 to 6 times by ,
C1-4alkoxy,
C1_4alkoxy substituted with from 1 to 4 substituents independently
selected from: fluoro and -NH2,
-Oaryl,
-C(0)H,
-C(O)RZZ,
-C(0)aryl,
-C(O)heteroaryl,
-OC(O)H,
-CO(O)RZZ,
-OC(O)ary|,
-OC(O)heteroaryl,
mercapto,
-SRxa,
where Rxa is selected from aryl, heteroaryl, cycloalkyl,
heterocyloalkyl, C1-6alkyl, and C1-6alkyl substituted
from 1 to 6 times by fluoro,
-S(O)H,
-S(O)Rxa,
where Rxa is selected from aryl, heteroaryl, cycloalkyl,
heterocyloalkyl, C1_6alkyl, and C1-6alkyl substituted
from 1 to 6 times by fluoro,
-S(O)2H,
-S(O)2Rxa,
where Rxa is ed from aryl, heteroaryl, cycloalkyl,
heterocyloalkyl, C1-6alkyl, and kyl substituted
from 1 to 6 times by ,
-OS(O)2RX3,
2017/053511
where Rxa is selected from aryl, heteroaryl, cycloalkyl,
heterocyloalkyl, C1-6alkyl, and C1-6alkyl tuted
from 1 to 6 times by fluoro,
-S(O)2NH2,
-S(O)2NHRXa,
where Rxa is selected from aryl, heteroaryl, cycloalkyl,
heterocyloalkyl, C1-6alkyl, and C1-6alkyl substituted
from 1 to 6 times by fluoro,
-NHS(O)2H,
1o -NHS(O)2Rxa,
where Rxa is selected from aryl, heteroaryl, lkyl,
cyloalkyl, C1-6alkyl, and C1-6alkyl substituted
from 1 to 6 times by fluoro,
-NHC(O)H,
-NHC(O)RX3,
where Rxa is selected from aryl, heteroaryl, cycloalkyl,
heterocyloalkyl, C1-6alkyl, and C1-6alkyl substituted
from 1 to 6 times by fluoro,
-C(O)NH2,
-C(O)NHRX3,
where Rxa is selected from aryl, heteroaryl, cycloalkyl,
heterocyloalkyl, C1-6alkyl, and C1-6alkyl substituted
from 1 to 6 times by fluoro,
-C(O)OH,
-C(O)ORxa,
where Rxa is selected from aryl, heteroaryl, cycloalkyl,
heterocyloalkyl, C1-6alkyl, and C1-6alkyl substituted
from 1 to 6 times by fluoro,
0x0,
hydroxy,
amino,
-NRX1aRX2a,
where Rx1 a and Rx2a are each independently selected from
-S(O)2C1-6a|kyl, and C1-6alkyl,
-NHRxa,
where Rxa is selected from aryl, aryl, cycloalkyl,
cyloalkyl, C1-6alkyl, and C1-6alkyl substituted
2017/053511
from 1 to 6 times by fluoro,
nitro,
cyano,
boronic acid,
-NHC(O)NH2, and
-NHC(O)NHRxa,
where Rxa is selected from aryl, heteroaryl, cycloalkyl,
heterocyloalkyl, C1-ealkyl, and C1-ealkyl substituted
from 1 to 6 times by fluoro;
each R‘31 is independently selected from:
C1-6alkyl substituted with from 1 to 9 tutents independently
selected from:
fluoro,
chloro,
bromo,
iodo,
C1-Balkyl,
a|ky|,
-OC1-6alkyl substituted with from 1 to 6 substituents
independently selected from: fluoro, oxo, -OH,
-COOH, -NH2, and —-CN,
mercapto,
_SRxa,
where Rxa is selected from aryl, heteroaryl,
cycloalkyl, cyloalkyl, C1-6alkyl, and C1-6alkyl
substituted from 1 to 6 times by fluoro,
-S(O)H,
-S(0)Rxa,
where Rxa is selected from aryl, heteroaryl,
cycloalkyl, heterocyloalkyl, C1-6alkyl, and C1-6alkyl
substituted from 1 to 6 times by fluoro,
-S(O)2Rxa,
where Rxa is selected from aryl, heteroaryl,
cycloalkyl, heterocyloalkyl, C1-6alkyl, and C1-ealkyl
substituted from 1 to 6 times by fluoro,
oxo,
hydroxy,
amino,
-NHRXX,
where RXX is selected from aryl, heteroaryl,
cycloalkyl, cyloalkyl, C1-5alkyl,
and C1-6alkyl substituted with from 1 to 6
substituents independently selected from: fluoro,
oxo, -Ony, -COOH, —-CN, -OC1-5alkyl, -OC1-5alky|
substituted from 1 to 6 times by fluoro and
1O -NRXVRXZ, where ny and R"Z are ndently
selected from: hydrogen, aryl, C1-5alkyl and
C1-5alkyl substituted with from 1 to 4 substituents
independently selected from: fluoro, oxo, -OH,
-OC1-5alkyl, alkyl substituted from 1 to 6
times by fluoro and —COOH,
-NRX1XRX2X,
where R and Rx2x are each independently
selected from C1-4alkyl, and C1-4alkyl substituted
with from 1 to 4 substituents ndently selected
from: fluoro, 0x0, and —OH,
guanidino,
-C(O)OH,
-C(O)ORxa,
where Rxa is selected from aryl, heteroaryl,
cycloalkyl, heterocyloalkyl, C1-6alkyl, and C1-6alky|
substituted from 1 to 6 times by fluoro,
-C(O)NHRxa,
where Rxa is ed from aryl, heteroaryl,
cycloalkyl, and heterocyloalkyl,
aryl,
aryl tuted from 1 to 4 times by Rxa,
where Rxa is selected from aryl, heteroaryl,
cycloalkyl, heterocyloalkyl, C1-6alkyl, and C1-6alkyl
substituted from 1 to 6 times by fluoro,
-Oaryl,
-Oary| substituted from 1 to 4 times by Rxa’
where Rxa is selected from aryl, heteroaryl,
cycloalkyl, heterocyloalkyl, C1-6alkyl, and C1-6alkyl
substituted from 1 to 6 times by fluoro,
heteroaryl,
heteroaryl substituted from 1 to 4 times by Rxa’
where Rxa is selected from aryl, heteroaryl,
cycloalkyl, heterocyloalkyl, C1-6alkyl, and C1-6alkyl
substituted from 1 to 6 times by fluoro,
-Oheteroary|,
-Oheteroary| substituted from 1 to 4 times by Rxa,
where Rxa is selected from aryl, heteroaryl,
cycloalkyl, heterocyloalkyl, kyl, and C1-6alkyl
substituted from 1 to 6 times by fluoro,
cycloalkyl,
cycloalkyl substituted from 1 to 4 times by RX,
where RX is selected from aryl, aryl,
lkyl, heterocyloalkyl, C1-6alkyl, and C1-6alkyl
substituted with from 1 to 6 substituents
independently selected from: fluoro, oxo, -OH,
-COOH, -NH2, and —-CN,
heterocycloalkyl,
heterocycloalkyl tuted from 1 to 4 times by RX,
where RX is selected from aryl, heteroaryl,
cycloalkyl, heterocyloalkyl, C1-6alkyl, and kyl
substituted with from 1 to 6 substituents
ndently selected from: fluoro, 0x0, -OH,
-COOH, -NH2, and —-CN,
-S(O)2NH2,
-S(O)2NHRxa,
where Rx":l is selected from aryl, heteroaryl,
cycloalkyl, heterocyloalkyl, C1-6alkyl, and C1-6alkyl
substituted from 1 to 6 times by fluoro,
-NHS(O)2H,
-NHS(O)2Rxa,
where RXa is selected from aryl, heteroaryl,
cycloalkyl, heterocyloalkyl, C1-6alkyl, and C1-6alkyl
tuted from 1 to 6 times by fluoro,
-NHC(O)NHRxa,
where Rxa is selected from heteroaryl,
lkyl, and cyloalkyl,
nitro, and
cyano;
R2 is selected from
C1-68lkyl,
Re1’
cycloalkyl,
cycloalkyl substituted from 1 to 4 times by RC”,
heterocycloalkyl, and
cycloalkyl tuted from 1 to 4 times by R“;
R22 is selected from
C1-6a|kyl, and
R61;
provided that:
X31 cr and X320r are not both hydrogen;
or a pharmaceutically acceptable salt or prodrug thereof.
Suitably in the compounds of Formula (lllcr), neither X31cr nor X32m are hydrogen.
Suitably in the compounds of a (lllcr), the compounds are in the form of a
phosphate prodrug.
Suitably in the compounds of Formula (lllcr), the compounds are in the form of a
—C(O)CH(NH2)CH(CH3)2 prodrug.
This invention relates to novel compounds of Formula (chcr) and to the use of
compounds of Formula (chcr) in the methods ofthe invention:
R41 ccr
41 ccr 420cr
X X
R44$r I
N N Y4CCF
/ R4300r
R4500r (IVCCF)
wherein:
X41ccr and X42ccr are independently selected from: --CN, , fluoro, chloro,
bromo and
iodo;
Y4ccr is selected from: S and NH;
R41 ccr is selected from:
C1-6alkyl,
C1-6alkyl substituted with from 1 to 9 substituents
independently selected from: fluoro, chloro, bromo,
iodo, oxo, C1-4alkyloxy, -OH, -COOH, -NH2
1-4alkyl, -N(C1-4alkyl)2 and —-CN,
C1-4alkyloxy,
C1-4alkyloxy substituted from 1 to 4 times by fluoro,
1-4a|kyl,
-N(C1-4a|kyl)2,
-SC1-4a|ky|,
aryl,
aryl substituted with from 1 to 4 substituents
independently selected from:
fluoro,
chloro,
bromo,
iodo,
C1—6alkyl,
C1-6a|kyl substituted with from 1 to 9 substituents
independently selected from: fluoro, chloro, bromo,
iodo, oxo, -OH, -NH2 and —-CN,
k0xy,
—-CN,
-NH2,
heteroaryl,
heteroaryl substituted with from 1 to 4 substituents
independently selected from:
fluoro,
chloro,
bromo,
iodo,
C1—6alkyl,
C1-6alkyl substituted with from 1 to 9 substituents
independently selected from: fluoro, , bromo,
iodo, oxo, -OH, -NH2 and —-CN,
C1_4alkoxy,
—-CN,
-OH,
-NH2,
cycloalkyl,
cycloalkyl tuted with from 1 to 4 substituents
independently selected from:
fluoro,
chloro,
bromo,
iodo,
C1-6alkyl,
C1_6alkyl substituted with from 1 to 9 substituents
independently selected from: fluoro, chloro, bromo,
iodo, 0x0, -OH, -NH2 and —-CN,
C1-4alkoxy,
—-CN,
-NH2;
R43ccr is ed from:
aryl,
aryl substituted with from 1 to 4 substituents independently selected
from:
fluoro,
chloro,
bromo,
iodo,
C1-4alkoxy,
C1-4alkoxy substituted with from 1 to 3 substituents
independently selected from: fluoro, chloro, oxo,
-OH, -NH2, -NHCH3, and —N(CH3)2,
C1-68Ikyl,
C1-6alky| substituted with from 1 to 9 tuents
independently ed from: fluoro, chloro, bromo,
iodo, oxo, -S(O)2C1-4alkyl, --CN, -OR49 and —
NR46R47
where R46 and R47 are independently
selected from: hydrogen, -S(O)2CH3,
pyrazole, C1 -5alkyl and C1 -5alkyl substituted
with from 1 to 4 substituents independently
selected from: fluoro, oxo, -OH, -OC1-5alkyl,
-OC1-5alkyl substituted from 1 to 6 times by
fluoro, —COOH and 49, where R“8
and R49 are independently ed from:
hydrogen, phenyl, C1-5alkyl and C1-5alkyl
substituted with from 1 to 4 substituents
independently selected from: fluoro, oxo,
-OH, -OC1-5alkyl, alkyl substituted
from 1 to 6 times by fluoro and —COOH,
heterocycloalkyl,
heterocycloalkyl independently tuted once ortwice with
a substituent selected from: fluoro and 0x0,
-N(CH3)S(O)ZCFH2,
-N(CH3)S(O)2CF2H,
-N(CH3)S(O)ZCF3.
-OS(O)2CH3,
-S(O)2NH2,
-S(O)2NHCH3,
_NR303’R813’ where R803, and R813, are independently
selected form: hydrogen, CH3, phenyl,
C1-5alkyl and C1-5alky| substituted with from 1 to 4
substituents independently selected from: fluoro, 0x0,
-OH, -NH2, -OC1-5alkyI, -OC1-5alkyl substituted from
1 to 6 times by fluoro and —COOH,
c acid,
-N02, and
-NH2,
aryl, and
heteroaryl substituted with from 1 to 4 substituents independently selected
from:
fluoro,
chloro,
bromo,
iodo,
kyl,
C1-ealkyl substituted with from 1 to 9 substituents
independently ed from: fluoro, chloro, bromo,
iodo, 0x0, --CN, -OR49 and —NR46R47,
where R46 and R47 are independently
selected from: hydrogen, -S(O)2CH3,
C1-5a|kyl and C1-5alky| substituted with from
1 to 4 substituents independently selected
from: fluoro, 0x0, -OH, -OC1-5a|kyl,
-OC1-5alkyl substituted from 1 to 6 times by
fluoro, -COOH and —NR48R49, where R48
and R49 are independently selected from:
hydrogen, phenyl, kyl and C1-5alky|
substituted with from 1 to 4 substituents
2017/053511
independently selected from: fluoro, oxo,
-OH, -OC1-5alkyl, -OC1—5alkyl substituted
from 1 to 6 times by fluoro and —COOH,
k0xy,
—-CN,
-OH,
NH2,
-S(O)2NHCH3,
-N02, and
-NH2; and
R446” and R45ccr are ndently selected from:
hydrogen,
C1-6alkyl,
C1-6alky| substituted with from 1 to 9 substituents
independently selected from: phenyl, morpholino, lyl,
imidazolyl, pyrrolidinyl, -OC(O)NH2, -OCHZCH2NH2.
-ONHC(NH2)NH2, -NHCH2C(CH3)3, -NOCH3, -NHOH,
-NHCH2CH2F, -N(CH3)CH20H200H3, -N(CH2CH3)2,
-NCH(CH20H)2, -N(CH2CH20H)2, -NHCH2CH20H,
-NHCH2CH2NH2, -N(CH3)C(CH3)2CH20H, -NHCH2CH3,
-NHCH20HZOCH3, -N(CH3)CH20H20H, -NHC(O)C(O)NH2,
-N(CH3)CH2CH2CH20H, -N(CH3)CH2CH(OH)CH20H,
-N(CH3)CH2CH2NH2, oxo, -NHCH2C(CH3)2CH20H, -OH, -NH2,
-NHCH3, -NHCHZCH2CH20H, -N(CH3)2, -N(CH3)CHZCH3,
-NHOC(CH3)2NH2, -N(CH3)CH2cyclopropyl, -NHCH2cyclopropyl,
-NHoxetanyl, -NCH2CH2triazoIe, zinyl, piperidinyl, pyrazolyl,
yl, azetidinyl, methoxy, and cyclopropylamino,
where said phenyl, morpholino, triazolyl, imidazolyl, azepinyl,
azetidinyl, pyrrolidinyl piperazinyl, piperidinyl,
oxetanyl, cyclopropyl, and pyrazolyl are optionally
substituted with from 1 to 4 substituents
independently selected from: methyl, fluoro, -NH2,
-N(CH3)2, ymethyl, oxo, -OH, and 2,
cycloalkyl,
cycloalkyl substituted with from one to five substituents
independently selected from:
chloro,
-OH,
C1-6alkyl, and
C1_6alkyl substituted with from 1 to 9 substituents
independently ed from: fluoro and chloro;
heterocycloalkyl, and
heterocycloalkyl substituted with from 1 to 5 substituents independently
selected from:
fluoro,
chloro,
bromo,
iodo,
C1-6alkyl,
C1-6alkyl substituted with from 1 to 9 substituents
independently selected from: fluoro, chloro, bromo,
iodo, oxo, -OH, -NH2 and —-CN,
aryl,
C1-4alkoxy,
C1-4alkoxy substituted with from 1 to 4 substituents
ndently selected from: fluoro, oxo, -OH,
-COOH, -NH2, and —-CN,
-N02,
-NH2, and
SOzNHz, or
R44ccr and R45ccr are taken together with the en to which they are
attached, and optionally from 1 to 3 additional heteroatoms
independently selected from O, N, and S, to form
a heterocycloalkyl, which is optionally substituted with from 1 to 5
substituents independently selected from:
fluoro,
chloro,
bromo,
iodo,
C1-Balkyl,
C1-6alkyl substituted with from 1 to 9 substituents
independently selected from: fluoro, chloro,
C1-4alkoxy, 0x0, phenyl, cycloalkyl, cycloalkyl,
methylheterocycloalkyl-, -OH, -NH2, -N(H)C1-5alkyl,
aminoheterocycloalkyl-, -N(C1-5a|kyl)2, --CN,
-N(C1-4alkyl)(CH20CH3), and -NHC1-4alkyl
substituted by one ortwo substituents independently
selected from oxo, NH2, and -OH,
aryl,
lkyl,
heterocycloalkyl,
heterocycloalkyl substituted with from 1 to 9 substituents
independently selected from: C1-6alkyl,
|kleH, fluoro, -C1-6alkleH2,
chloro, bromo, iodo, 0x0, -OH, -NH2 and —-CN,
C1-4alk0xy,
C1-4alkoxy substituted with from 1 to 4 substituents
independently ed from: fluoro, oxo, -OH,
-COOH, -NH2, and —-CN,
-OP(O)(OH)2,
-COOH,
-N021
-NH2,
-N(H)C1-5alkyl,
-N(H)C1-6alkyl substituted with from 1 to 9 substituents
independently selected from: fluoro, chloro, bromo,
iodo, koxy, oxo, phenyl, cycloalkyl,
aminoC1-4alkoxy, heterocycloalkyl,
methylheterocycloalkyl, -OH, -NH2, -N(H)C1-4alkyl,
-N(C1_4a|ky|)2, and -CN,
-Ooxetanyl,
-ONHC(NH)NH2,
-NHcyclopropyl,
-NHoxetany|,
-N(C1-5a|ky|)2,
-S(O)2CHZCH3.
2017/053511
S(O)2CH2CH2CH3,
-S(0)ZCH3,
-SOzNH2,
-S(O)2phenyl,
benzoyL
benzylamino,
-propy|pyrrolidiny|,
-methy|cyclopropy|,
cyclobutylamino,
cyclobutyI-N(CH3)-,
piperidinyl,
imidazolyl,
morpholinyl,
morpholinylmethyl,
methylpiperazinylmethyl,
methylpiperazinyl,
pyrrolidinyl,
pyrrolidinylmethyl,
(methoxypyridinylmethy|)amino,
pyrrolidinyl,
difluoropyrrolidinyl,
dimethylpyrrolidinyl,
(methylcyclopropylmethy|)amino,
hyd thylpyrrolidinyl,
fluoropyrrolidinyl,
fluorophenylmethylamino,
piperazinlymethyl,
oxazolidinyl,
(methyloxetanmethyl)amino,
(methylcyclobutylmethy|)amino,
oxoimidazolidinyl, and
2-hydroxyethylpiperidinyl;
provided that:
R44ccr and R45ccr are not both hydrogen;
or a pharmaceutically acceptable salt or prodrug f.
ly in the compounds of Formula (chcr), the compounds are in the form of a
phosphate prodrug.
Suitably in the compounds of Formula (chcr), the compounds are in the form of
a —C(O)CH(NH2)CH(CH3)2 prodrug.
1O Suitably in the compounds of Formula (chcr) neither R44ccr nor R45ccr is hydrogen.
Suitably in the compounds of Formula (chcr) R43ccr is aryl substituted with from 1
to 4 substituents independently selected from:
fluoro,
chloro,
bromo,
iodo,
heterocycloalkyl,
heterocycloalkyl independently substituted once e a
substituent selected from: fluoro and 0x0,
-OS(O)2CH3,
)S(O)ZCH3,
C1-Galkyl,
C1-6alkyl substituted with from 1 to 9 substituents
independently selected from: fluoro, chloro, bromo,
iodo, oxo, -S(O)2C1-4alkyl, --CN, -0R49 and —
NR46R47
where R46 and R47 are independently
selected from: hydrogen, -S(O)20H3,
C1-5alkyl and kyl substituted with from
1 to 4 substituents independently selected
from: fluoro, oxo, -OH, -OC1-5alkyl,
-OC1-5a|ky| substituted from 1 to 6 times by
fluoro, —COOH and 49, where R48
and R49 are ndently selected from:
hydrogen, phenyl, C1-5alkyl and C1-5alkyl
substituted with from 1 to 4 tuents
independently selected from: fluoro, oxo,
-OH, -OC1-5alkyl, -OC1-5a|kyl substituted
from 1 to 6 times by fluoro and —COOH.
This ion relates to novel compounds of Formula (Vccr) and to the use of
compounds of Formula (Vccr) in the methods ofthe invention:
R50ccr N
N \\”fie///
R533:r / Y5ccr/\R52ccr
[I] N
R54ccr (VCCF)
wherein:
Y5ccr is selected from: S and NH;
R50ccr is selected from:
C1-6alkyl,
C1-6alky| substituted with from 1 to 9 substituents
independently selected from: fluoro and chloro,
-N(H)C1-4alkyl,
-N(C1-4alky|)2,
-SC1-4a|ky|,
C1-4alkyloxy,
aryl!
aryl substituted with from one to five substituents
independently selected from:
fluoro,
chloro,
-OH,
kyl, and
C1_6alkyl substituted with from 1 to 9 substituents
independently selected from: fluoro and ,
heteroaryl,
heteroaryl substituted with from one to five substituents
independently selected from:
chloro,
-OH,
C1-6alkyl, and
C1-6alky| substituted with from 1 to 9 substituents
independently selected from: fluoro and chloro,
cycloalkyl,
cycloalkyl substituted with from one to five substituents
independently selected from:
fluoro,
chloro,
-OH,
C1_6alkyl, and
C1-6alkyl substituted with from 1 to 9 substituents
independently selected from: fluoro and ;
R52ccr is ed from:
aryl,
aryl substituted with from 1 to 4 substituents independently selected
from:
fluoro,
chloro,
C1-4alkoxy,
C1-4alkoxy substituted with from 1 to 3 substituents
independently selected from: fluoro, chloro, oxo,
-OH, -NH2. -NHCH3, and —N(CH3)2,
kyl,
C1-ealkyl substituted with from 1 to 9 substituents
independently selected from: fluoro, chloro, bromo,
iodo, 0x0, -S(O)2CH3, --CN, -OR59 and —NR56R57,
where R56 and R57 are independently
selected from: hydrogen, CH3,
kyl and C1-5alkyl substituted with from
1 to 4 substituents independently selected
from: fluoro, oxo, -OH, -OC1-5alkyl,
-OC1-5alkyl substituted from 1 to 6 times by
fluoro, —COOH and —NR58R59, where R58
and R59 are independently selected from:
en, phenyl, C1-5alkyl and C1-5alkyl
substituted with from 1 to 4 substituents
independently ed from: fluoro, 0x0,
-OH, -OC1-5a|kyl, -OC1-5a|kyl substituted
from 1 to 6 times by fluoro and —COOH,
oxo,
--CN,
tetrahydroisothiazolyl,
tetrahydroisothiazolyl substituted twice by oxo,
tetrahydro-1,2—thiazinyl,
tetrahydro-1,2—thiazinyl substituted twice by oxo,
2017/053511
-N(CH3)S(O)2CH3,
-N(CH3)S(O)2CFH2,
-N(CH3)S(O)2CF2H,
)S(O)2CF3,
-OS(O)ZCH3,
-S(O)2NH2,
-S(O)2NHCH3,
—NR803’R813! where R803, and R813, are independently
selected form: hydrogen, CH3, phenyl,
C1-5alkyl and C1-5alkyl tuted with from 1 to 4
substituents independently selected from: fluoro, 0x0,
-OH, -NH2, -OC1-5alkyl, -OC1-5a|kyl substituted from
1 to 6 times by fluoro and —COOH, and
-OH;
heteroaryl, and
heteroaryl substituted with from 1 to 4 substituents independently selected
from:
fluoro,
chloro,
C1-Galkyl,
C1-ealkyl substituted with from 1 to 9 substituents
independently selected from: fluoro, chloro, bromo,
iodo, 0x0, --CN, -OR59 and —NR56R57,
where R56 and R57 are independently
selected from: hydrogen, -S(O)ZCH3,
C1-5alkyl and kyl substituted with from
1 to 4 substituents independently selected
from: fluoro, 0x0, -OH, -OC1-5alkyl,
alkyl substituted from 1 to 6 times by
fluoro, —COOH and —NR58R59, where R58
and R59 are independently selected from:
hydrogen, phenyl, C1-5alkyl and C1-5alkyl
substituted with from 1 to 4 substituents
independently selected from: fluoro, 0x0,
-OH, -OC1-5alkyl, -OC1-5alky| substituted
from 1 to 6 times by fluoro and —COOH,
0x0,
-S(O)2NH2,
-S(O)2NHCH3,
-OH; and
R53ccr and R54CClr are independently ed from:
hydrogen,
C1-6alkyl,
kyl substituted with from 1 to 9 substituents
independently ed from: , morpholino, triazolyl,
imidazolyl, -CH2CH2pyrrolidinyl, -OC(O)NH2, -OCH2CH2NH2,
-ONHC(NH2)NH2, -NHCHZC(CH3)3, -NOCH3, -NHOH,
-NHCH2CH2F, -N(CH3)CH20H20CH3, CH3)2,
-NCH(CH20H)2, -N(CH2CH20H)2, -NHCH2CH20H,
-NHCH2CH2NH2, -N(CH3)CH2(CH3)2CH20H, -NHCHZCH3.
-NHCH2CH20CH3, -N(CH3)CH2CH20H, -NHC(O)C(O)NH2,
-N(CH3)CH2CH2CH20H, -N(CH3)CH2CH(OH)CH20H,
-N(CH3)CH2CH2NH2, oxo, -NHCHZC(CH3)ZCH20H, -OH, -NH2,
-NHCH3, -NHCH2CH2CH20H, -N(CH3)2, -N(CH3)CHZCH3,
-NHOC(CH3)2NH2, -N(CH3)CH2cyclopropyl, -NHCH2cyclopropyl,
tanyl, -NCHzCH2triazole, piperazinyl, piperidinyl, pyrazolyl,
azepinyl, azetidinyl, methoxy, and cyclopropylamino,
where said , morpholino, triazolyl, imidazolyl, azepinyl,
azetidinyl, pyrrolidinyl piperazinyl, piperidinyl,
oxetanyl, cyclopropyl, and pyrazolyl are optionally
substituted with from 1 to 4 substituents
independently selected from: methyl, fluoro, -NH2,
-N(CH3)2, hydroxymethyl, oxo, -OH, and —CH2NH2,
cycloalkyl,
cycloalkyl substituted with from one to five substituents
independently selected from:
fluoro,
chloro,
-OH,
C1_6alkyl, and
C1-6alkyl substituted with from 1 to 9 substituents
independently selected from: fluoro and ;
heterocycloalkyl, and
heterocycloalkyl substituted with from 1 to 5 substituents independently
ed from:
fluoro,
chloro,
C1-Galkyl,
C1-6alkyl substituted with from 1 to 9 substituents
independently selected from: fluoro and chloro,
C1-4alkoxy, and
-OH, or
R53ccr and R54ccr are taken together with the nitrogen to which they are
ed, and ally from 1 to 3 additional heteroatoms, to form
a heterocycloalkyl, which is optionally substituted with from 1 to 5
substituents independently selected from:
fluoro,
chloro,
C1eamw,
kyl substituted with from 1 to 9 substituents
ndently selected from: fluoro, chloro,
C1-4alkoxy, 0x0, , cycloalkyl, heterocycloalkyl,
methylheterocycloalkyl, -OH, -NH2, -N(H)C1-5alkyl,
aminoheterocycloalkyl, -N(C1-5alkyl)2, --CN,
-N(C1-4alkyl)(CH20CH3), and -NHC1-4alkyl
substituted by one ortwo substituents independently
selected from 0x0, NH2, and -OH,
heterocycloalkyl,
heterocycloalkyl tuted with from 1 to 9 substituents
independently selected from: C1-6alkyl,
-C1-6a|kleH, fluoro, -C1-6alky|NH2,
chloro, 0x0 and -OH,
C1-4alkoxy,
C1-4alkoxy substituted with from 1 to 4 substituents
independently selected from: fluoro, oxo, -OH,
-COOH, -NH2, and —-CN,
-OH,
-omoxomz
-cooH
-CONHz
-NH2,
-N(H)C1-4a|ky|,
-N(H)C1-6alky| substituted with from 1 to 9 substituents
independently selected from: fluoro, chloro,
C1-4alkoxy, 0x0, phenyl, cycloalkyl,
aminoC1-4a|koxy, heterocycloalkyl,
methylheterocycloalkyl, -OH, -NH2, -N(H)C1-4a|kyl,
-N(C1-4a|ky|)2, and —-CN,
any|,
-ONHC(NH)NH2,
-NHcyclopropy|,
tanyI,
-N(Ct-4a|ky|)2,
-S(O)2CH2CH3,
S(O)2CH2CH2CH3,
CH3.
-S(O)2phenyl,
benzoyL
benzylamino,
-propy|pyrro|idiny|,
-methy|cyc|opropy|,
cyclobutylamino,
cyclobutyI-N(CH3)-,
piperidinyl,
imidazolyl,
morpholinyl,
morpholinylmethyl,
methylpiperazinylmethyl,
methylpiperazinlyl
pyrrolidinyl,
pyrrolidinylmethyl,
(methoxypyridinylmethyl)amino,
methylpyrrolidinyl,
difluoropyrrolidinyl,
dimethylpyrrolidinyl,
(methylcyclopropylmethyl)amino,
hyd roxymethylpyrrolidinyl,
fluoropyrrolidinyl,
fluorophenylmethylamino,
piperazinylmethyl,
oxazolidinyl,
(methyloxetanylmethyl)amino,
(methylcyclobutylmethy|)amino,
oxoimidazolidinyl, and
2-hydroxyethylpiperidinyl;
provided that:
R53ccr and R54ccr are not both hydrogen;
or a pharmaceutically acceptable salt or prodrug thereof.
Suitably in the nds of Formula (Vccr), the compounds are in the form of a
phosphate prodrug.
Suitably in the compounds of a , the compounds are in the form ofa
—C(O)CH(NH2)CH(CH3)2 prodrug.
Suitably in the nds of Formula (Vccr) neither R530cr nor R54ccr is en.
Suitably in the compounds of Formula (Vccr) R5200r is aryl substituted with from 1
to 4 substituents independently selected from:
fluoro,
chloro,
tetrahydrothiazolyl,
tetrahydrothiazolyl substituted twice by oxo,
tetrahydrothiazinyl,
tetrahydrothiazinyl tuted twice by oxo,
-N(CH3)S(O)2CH3,
-OS(O)20H3,
C1-Galkyl,
C1-6alkyl substituted with from 1 to 9 substituents
independently selected from: fluoro, chloro, bromo,
iodo, oxo, -S(O)2CH3, --CN, -0R59 and —NR56R57,
where R56 and R57 are independently
ed from: hydrogen, -S(O)2CH3,
C1-5alkyl and C1-5alkyl substituted with from
1 to 4 tuents independently selected
from: fluoro, oxo, -OH, -OC1-5alkyl,
-OC1-5alkyl substituted from 1 to 6 times by
fluoro, —COOH and —NR58R59, where R58
and R59 are independently selected from:
hydrogen, phenyl, kyl and C1-5alkyl
tuted with from 1 to 4 substituents
independently selected from: fluoro, oxo,
-OH, -OC1-5a|kyl, -OC1—5alkyl substituted
from 1 to 6 times by fluoro and —COOH.
This invention relates to novel compounds of Formula (Vlccr) and to the use of
compounds of Formula (Vlccr) in the methods ofthe invention:
R64ccr (Vlccr)
wherein:
Yeccr is selected from: S and NH;
R60cm is selected from:
C1-Salkyl,
C1-3alky| substituted with from 1 to 6 substituents
independently selected from: fluoro and chloro,
-N(H)C1-3a|kyl,
-N(C1-3a|ky|)2,
-SC1-4alkyl,
kyloxy,
aryl!
aryl substituted with from one to 3 substituents
independently selected from:
fluoro,
-OH, and
kyl,
heteroaryl,
heteroaryl substituted with from one to 3 substituents
independently selected from:
fluoro,
chloro,
-OH, and
C1-salkyl,
cycloalkyl,
cycloalkyl substituted with from one to 3 substituents
independently selected from:
fluoro,
chloro,
-OH, and
C1—Salkyl;
R62ccr is ed from:
phenyL
phenyl substituted with from 1 to 4 tuents independently selected
from:
fluoro,
chloro,
--CN,
0x0,
C1-4alkoxy,
C1-4a|koxy substituted with from 1 to 3 tuents
independently selected from: fluoro, chloro, oxo,
-OH, -NH2, -NHCH3, and —N(CH3)2,
C1-68Ikyl,
C1-6alkyl substituted with from 1 to 5 substituents
independently selected from: fluoro, chloro, bromo,
iodo, 0x0, -S(O)zCH3, --CN, -OR69 and 67,
where R66 and Re‘7 are independently
selected from: hydrogen, -S(O)2CH3,
kyl and C1-5alky| substituted with from
1 to 4 substituents independently selected
from: fluoro, oxo, -OH, -OC1-5alkyl,
-OC1-5a|kyl substituted from 1 to 6 times by
fluoro, —COOH and —NR68R69, where R68
and R69 are independently selected from:
en, phenyl, C1-5alkyl and C1-5alkyl
tuted with from 1 to 4 substituents
independently selected from: fluoro, 0x0,
-OH, -OC1-5a|kyl, -OC1-sa|kyl substituted
from 1 to 6 times by fluoro and —COOH,
tetrahydroisothiazolyl,
tetrahydroisothiazolyl substituted twice by OXO,
tetrahydro-1,2—thiazinyl,
tetrahydro-1,2—thiazinyl substituted twice by oxo,
-N(CH3)S(O)2CH3,
-N(CH3)S(O)2CFH2,
-N(CH3)S(O)2CF2H,
-N(CH3)S(O)ZCF3,
-OS(O)2CH3,
-S(O)2NH2,
-S(O)2NHCH3, and
—NR803’R81a’ where R803, and R813, are independently
selected form: hydrogen, -S(O)2CH3, ,
C1-5alkyl and C1-5alkyl substituted with from 1 to 4
substituents independently selected from: fluoro, oxo,
-OH, -NH2, -OC1-5alkyl, -OC1-5alkyl substituted from
1 to 6 times by fluoro and —COOH,
hetroaryl, and
ryl tuted with from 1 to 4 substituents independently selected
from:
fluoro,
chloro,
C1-68Ikyl,
kyl substituted with from 1 to 5 substituents
independently selected from: fluoro, chloro, bromo,
iodo, oxo, -S(O)20H3, --CN, -OR69 and —NR66R67,
where R66 and R67 are independently
selected from: en, -S(O)2CH3,
C1-5alky| and ky| substituted with from
1 to 4 substituents independently selected
from: fluoro, oxo, -OH, -OC1-5a|kyl,
-OC1-5alkyl substituted from 1 to 6 times by
fluoro, —COOH and —NR68R69, where R68
and R69 are independently selected from:
hydrogen, phenyl, C1-5alkyl and C1-5alkyl
substituted with from 1 to 4 substituents
independently selected from: fluoro, oxo,
-OH, -OC1-5alkyl, -OC1-5alkyl substituted
from 1 to 6 times by fluoro and —COOH,
-S(O)2NH2, and
-S(O)2NHCH3; and
R63ccr and R64ccr are independently selected from:
hydrogen,
C1-4alkyl,
C1-4alkyl substituted with from 1 to 4 tuents
ndently selected from: phenyl, morpholino, triazolyl,
imidazolyl, 2pyrrolidinyl, -OC(O)NH2, -OCH2CH2NH2,
-ONHC(NH2)NH2, -NHCH2C(CH3)3, -NOCH3, -NHOH,
-NHCHZCH2F, -N(CH3)CHZCHZOCH3, -N(CHZCH3)2,
-NCH(CH20H)2, -N(CH2CH20H)2, -NHCH2CH20H,
-NHCHZCH2NH2, -N(CH3)CH2(CH3)2CH20H, -NHCHZCH3,
-NHCH2CH20CH3, -N(CH3)CH2CH20H, -NHC(O)C(O)NH2,
)CH2CH2CH20H, -N(CH3)CH2CH(OH)CH20H,
-N(CH3)CH2CH2NH2, oxo, -NHCHZC(CH3)ZCH20H, -OH, -NH2,
-NHCH3, -NHCH2CH2CH20H, -N(CH3)2, -N(CH3)CH2CH3,
-NHOC(CH3)2NH2, )CH20yclopropyl, -NHCH20yclopropyl,
-NHoxetanyl, -NCHzCH2triazole, piperazinyl, piperidinyl, pyrazolyl,
azepinyl, azetidinyl, methoxy, and cyclopropylamino,
where said , lino, triazolyl, imidazolyl, azepinyl,
azetidinyl, pyrrolidinyl piperazinyl, piperidinyl,
oxetanyl, cyclopropyl, and pyrazolyl are optionally
substituted with from 1 to 4 substituents
independently selected from: methyl, fluoro, -NH2,
-N(CH3)2, hydroxymethyl, oxo, -OH, and -CH2NH2,
cycloalkyl,
cycloalkyl substituted with from 1 to 5 substituents independently
selected from:
fluoro,
chloro,
-OH, and
C1-Galkyl,
heterocycloalkyl, and
heterocycloalkyl substituted with from 1 to 5 tuents independently
selected from:
fluoro,
chloro,
-OH, and
C1-6alkyl, or
R63ccr and R64ccr are taken together with the nitrogen to which they are
attached, and optionally from 1 to 3 additional heteroatoms
independently ed from O, N, and S, to form a heterocycloalkyl,
to form a heterocycloalkyl, which is optionally substituted with from 1
to 5 tuents independently selected from:
fluoro,
chloro,
-OH,
-OP(O)(OH)2,
--CN,
C1-Balkyl,
C1-6alkyl substituted with from 1 to 9 substituents
independently selected from: fluoro, chloro,
C1-4alkoxy, oxo, phenyl, cycloalkyl, heterocycloalkyl,
methylheterocycloalkyl, -OH, -NH2, 1-5alkyl,
aminoheterocycloalkyl, -N(C1-5alkyl)2, --CN,
-N(C1-4alkyl)(CH20CH3), and -NHC1-4alkyl
tuted by one ortwo substituents independently
selected from oxo, NH2, and -OH,
heterocycloalkyl,
heterocycloalkyl substituted with from 1 to 9 substituents
independently selected from: C1-6alkyl,
-C1-6alkyIOH, fluoro, chloro, 0x0 and -OH,
C1-4alkoxy,
koxy substituted with from 1 to 4 substituents
independently selected from: fluoro, oxo, -OH,
-COOH, -NH2, and —-CN,
oxo,
-NH2,
-N(H)C1-4a|ky|,
-N(H)C1-6alky| substituted with from 1 to 9 substituents
independently selected from: fluoro, ,
C1-4alkoxy, oxo, phenyl, cycloalkyl,
aminoC1-4a|koxy, heterocycloalkyl,
heterocycloalkyl, -OH, -NH2, -N(H)C1-4a|kyl,
-N(C1-4a|ky|)2, and —-CN,
-ONHC(NH)NH2,
-Ooxetanyl,
-ONHC(NH)NH2,
-NHcyc|opropy|,
-NHoxetanyI,
-N(C1-4a|ky|)2,
-S(O)2CH2CH3,
S(O)ZCHZCHZCH3,
-S(O)2CH3,
-S(O)2phenyl,
benzoyL
benzylamino,
-propy|pyrrolidiny|,
-methy|cyc|opropy|,
cyclobutylamino,
cyclobutyI-N(CH3)-,
piperidinyl,
imidazolyl,
linyl,
morpholinylmethyl,
methylpiperazinylmethyl,
methylpiperazinyl,
pyrrolidinyl,
pyrrolidinylmethyl,
(methoxypyridinylmethy|)amino,
methylpyrrolidinyl,
difluoropyrrolidinyl,
dimethylpyrrolidinyl,
(methylcyclopropylmethyl)amino,
hyd roxymethylpyrrolidinyl,
pyrrolidinyl,
(fluorophenylmethyl)amino,
piperazinylmethyl,
oxazolidinyl,
(methyloxetanylmethyl)amino,
(methylcyclobutylmethy|)amino,
oxoimidazolidinyl, and
2-hydroxyethylpiperidinyl;
provided that:
i263ccr and RB“ccr are not both hydrogen;
or a pharmaceutically able salt or prodrug thereof.
Suitably in the compounds of Formula ), the compounds are in the form of a
phosphate prodrug.
Suitably in the compounds of Formula (Vlccr), the compounds are in the form of
a H(NH2)CH(CH3)2 prodrug.
Suitably in the compounds of Formula (Vlccr) neither R6300r nor R64ccr is en.
3O Suitably in the compounds of Formula (Vlccr) R62ccr is phenyl substituted with from
1 to 4 substituents independently selected from:
fluoro,
chloro,
tetrahydroisothiazolyl,
tetrahydroisothiazolyl substituted twice by oxo,
tetrahydro-1,2—thiazinyl,
tetrahydro-1,2—thiazinyl substituted twice by oxo,
-N(CH3)S(O)2CH3,
-OS(O)2CH3,
C1-68Ikyl,
C1-6a|kyl substituted with from 1 to 5 substituents
independently selected from: fluoro, chloro, bromo,
iodo, oxo, 0H3, --CN, -OR69 and —NR66R67,
where R66 and R67 are independently
selected from: hydrogen, -S(O)2CH3,
C1-5a|ky| and C1-5alky| substituted with from
1 to 4 substituents independently selected
from: fluoro, oxo, -OH, -OC1-5a|kyl,
-OC1-5alkyl substituted from 1 to 6 times by
fluoro, —COOH and —NR68R69, where R68
and R69 are independently ed from:
en, , C1—5alkyl and C1-5alkyl
substituted with from 1 to 4 substituents
independently selected from: fluoro, oxo,
-OH, -OC1-5alky|, alkyl substituted
from 1 to 6 times by fluoro and —COOH.
This invention relates to novel compounds of Formula (Vllccr) and to the use of
compounds of Formula (Vllccr) in the methods ofthe invention:
700m
N=c‘ fl0/”N
R72??? N/ S/\ R77ccr
R730” (Vllccr)
wherein:
R70ccr is selected from:
ethyl,
ethyl substituted from 1 to 4 times by fluoro,
-NCH3,
-SCH3,
ethoxy,
methoxy,
phenyL
furanyl,
cyclopropyl,
cyclopropyl substituted once or twice by fluoro;
R77ccr is selected from:
phenyL
phenyl substituted with from 1 to 4 substituents independently selected
from:
fluoro,
,
--CN,
oxo,
C1-4alkoxy,
C1-4alkoxy substituted with from 1 to 3 tuents
independently selected from: fluoro, chloro, oxo,
-OH, -NH2, , and —N(CH3)2,
C1-68Ikyl,
C1-ealkyl substituted with from 1 to 3 tuents
independently selected from: fluoro, chloro, bromo,
iodo, oxo, -S(O)zCH3, --CN, -0R79al and —
77a,
where R768‘ and R778 are independently
selected from: hydrogen, -S(O)2CH3,
C1-5alkyl and C1-5alkyl substituted with from
1 to 4 substituents independently selected
from: fluoro, oxo, -OH, -OC1-5alky|,
-OC1-Salkyl substituted from 1 to 6 times by
fluoro, —COOH and R793, where R783
and R793 are independently selected from:
hydrogen, phenyl, C1-5alkyl and C1-5alky|
substituted with from 1 to 4 substituents
independently selected from: fluoro, 0x0,
-OH, -OC1-5alkyI, -OC1-5alkyl substituted
from 1 to 6 times by fluoro and —COOH,
tetrahydroisothiazolyl,
tetrahydroisothiazolyl substituted twice by OXO,
tetrahydro-1,2—thiazinyl,
tetrahydro-1,2—thiazinyl substituted twice by oxo,
-N(CH3)S(O)2CH3,
-N(CH3)S(O)2CFH2,
-N(CH3)S(O)ZCF2H,
)S(O)2CF3,
-OS(O)2CH3,
-S(O)2NH2,
-S(O)2NHCH3, and
WO 16727
_NR808’R813’ where R808, and R813, are independently
selected form: hydrogen, -S(O)20H3, phenyl,
C1-5alkyl and C1-5alky| substituted with from 1 to 4
substituents independently selected from: fluoro, 0x0,
-OH, -NH2, -OC1-5alkyl, -OC1-5alkyl substituted from
1 to 6 times by fluoro and —COOH,
dihydropyridinyl,
oxo-dihydropyridinyl,
tetrahydroisoquinolinyl,
tetrahydroisoquinolinyl substituted by —C(O)CH3,
thiazolyl, and
thiazolyl substituted by a substituent selected from: -C(O)CH3 and
-NHC(O)CH3;
R720” and R73°°r are ndently selected from:
en,
kyl,
C1-4alky| substituted with from 1 to 4 substituents
independently selected from: phenyl, morpholino, triazolyl,
imidazolyl, 2pyrrolidinyl, -OC(O)NH2, -OCH20H2NH2,
-ONHC(NH2)NH2, -NHCH2C(CH3)3, -NOCH3, -NHOH,
-NHCH2CH2F, -N(CH3)CH2CH20CH3, -N(CH2CH3)2,
-NCH(CH20H)2. -N(CH2CH20H)2, -NHCHZCH20H,
-NHCH2CH2NH2, -N(CH3)CH2(CH3)2CH20H, -NHCHzCH3,
-NHCH2CH20CH3, -N(CH3)CH2CH20H, )C(O)NH2,
-N(CH3)CH2CH2CH20H, -N(CH3)CHZCH(OH)CH20H,
-N(CH3)CH2CH2NH2, oxo, C(CH3)2CH20H, -OH, -NH2,
-NHCH3, -NHCH20HzCH20H, -N(CH3)2, -N(CH3)CH20H3,
-NHOC(CH3)2NH2, -N(CH3)CH20yclopropyl, -NHCH20yclopropyl,
-NHoxetanyl, -NCH2CH2triazole, zinyl, piperidinyl, pyrazolyl,
azepinyl, azetidinyl, methoxy, and cyclopropylamino,
where said phenyl, morpholino, triazolyl, imidazolyl, azepinyl,
azetidinyl, pyrrolidinyl piperazinyl, piperidinyl,
oxetanyl, ropyl, and lyl are optionally
substituted with from 1 to 4 substituents
independently selected from: , fluoro, -NH2,
-N(CH3)2, hydroxymethyl, oxo, -OH, and —CH2NH2,
cyclobutyl,
yclobutyl,
tetrahydrofu ran,
2azaspiro[3.4]octan, and
8-azabicyclo[3.2.1]octan, or
R72cm and R73ccr are taken together with the nitrogen to which they are
attached, and optionally from 1 to 3 additional heteroatoms
independently selected from O, N, and S, to form a heterocycloalkyl,
to form a heterocycloalkyl selected from:
pyrrolidinyl,
pyrrolo[3,4-c]pyrazolyl,
piperidinyl,
1,4diazepanyl,
piperazinyl,
6,7-dihydro-triazolo[4,5-c]pyridinyl,
2,9—diazaspiro[5.5]undecanyl,
2,8—diazaspiro[4.5]decanyl,
octahydro-1H-pyrrolo[1,2a][1,4]diazepiny|,
3O oxa-diazaspiro[4.5]decanyl,
oxazolyl,
morpholinyl,
WO 16727
1-oxaazaspiro[3.4]octanyl,
2-oxaazaspiro[3.4]octanyl,
1,7-diazaspiro[3.5]nonanyl,
azaspiro[3.5]nonanyl,
2,6-diazaspiro[3.4]octany|,
azetidinyl,
hexahydropyrrolo[3,4-b]oxaziny|,
dihydronaphthyridinyl,
diazabicycloheptanyl,
1,8—diazaspiro[4.5]decany|, and
-oxaazaspiro[3.4]octanyl,
all of which are optionally substituted with from 1 to 5
substituents independently ed from:
fluoro,
chloro,
oxo,
-OH,
-OP(O)(OH)2,
-CN,
-CH3,
-CH20H,
methoxy,
-CH2CH3,
-C(O)CH3,
-C(O)NH2,
-OCH2CH20H,
-OCHZCH2NH2,
-ONHC(NH)NH2,
-OC(O)NH2,
-Ooxetanyl,
-CH20H20H,
2CH20H,
-CH20H2CH3,
-CH20H20CH3,
-CHZCH(OH)CH3,
-CH2CH(OH)CH20H,
-CH20(O)OCH3,
-CHZC(O)NH2,
-C(O)CH(CH3)2,
1O -CH20H2N(CH3)2,
-CH20H2NHCH2CH3,
-CH20H2CH2N(CH3)2,
-CH20H2NHCHZC(CH3)3,
-CH2CH2N(CH3)CH20CH3,
-C(CH3)2CH20H,
-CH20(CH3)2OH,
-CH2C(CH3)20CH3,
-C(O)CH20H,
-CH2isothiazoly|,
-CH2thiazolyI,
-CHzpyrazon|,
-CH2imidazolyl,
ridiny|,
-CH20xazo|y|,
-CH2pyrro|y|,
-CHZPyrrolidinyl,
-CH2isoxazoly,
-CH2furanyI,
-CH2CH2morph0|inyl.
-CH2CH2pyrrolidinyl,
-CH20H2pyrrolidinyICH3,
-CHZCH2CH2pyrro|idinyl,
-C(O)pheny|,
-C(O)C(tetrahyd ropyrany|)NH2,
-NH2,
-NHCH3,
-N(CH3)2,
-NHC(O)CH3,
-NHCH(CH3)2,
-NHCH2CHF2,
-NHCHZC(CH3)3,
CH(CH3)2,
-NHCH2CHZOCH3,
-NHCH2CH20H,
-NHCH2CH2NH2,
C(O)OH,
-NHC(O)CH2NH2,
-NHC(O)CH2CH2CH2NH2,
-NHCH2C(O)NH2,
-NHCH2C(OH)(CH3)2.
-NHC(O)CH(CH3)NH2.
-NHC(O)OCH(CH3)NH2,
-NHC(O)CH(CH3)2,
-NHC(O)C(CH3)3,
-NHC(O)C(CH3)2NH2,
-NHC(O)CH20H,
)CH(CH20H)NH2,
-NHC(O)(oxetanyl)NH2,
-NHC(O)OC(CH3)3,
-NHC(CH3)ZC(O)OCH3,
lopropyl,
-NHoxetany|,
-CH2NH2,
-CHZCH2NH2,
-CHZCHZCH2NH2,
-CH2NHCH2C(CH3)3,
-CH2NHC(O)C(CH3)3,
-CH2NHC(O)CH2NH2,
-CH2NHC(O)CH20H,
-CH2N(CH3)2,
-CH2NHCH3,
-CH2N(CH2CH3)2,
-CHZCH2N(CH3)2,
WO 16727
-S(O)2CH2CH3,
-S(O)2CH20H2CH3.
-S(O)2pheny|,
-S(O)2CH3,
benzoyl,
benzylamino,
-propy|pyrrolidinyl,
-methylcyclopropyl,
utylamino,
1o cyclobutyI-N(CH3)-,
piperidinyl,
imidazolyl,
morpholinyl,
morpholinylmethyl,
methylpiperazinylmethyl,
methylpiperazinyl,
pyrrolidinyl,
pyrrolidinylmethyl,
(methoxypyridinylmethyl)amino,
methylpyrrolidinyl,
difluoropyrrolidinyl,
dimethylpyrrolidinyl,
(methylcyclopropylmethyl)amino,
hydroxymethylpyrrolidinyl,
pyrrolidinyl,
(fluorophenylmethyl)amino,
piperazinylmethyl,
oxazolidinyl,
(methyloxetanylmethyl)amino,
(methylcyclobutylmethyl)amino,
oxoimidazolidinyl, and
2-hydroxyethylpiperidinyl;
provided that:
R72ccr and R73ccr are not both hydrogen;
or a ceutically acceptable salt or prodrug thereof.
Suitably in the compounds of Formula (Vllccr), the compounds are in the form of a
phosphate prodrug.
Suitably in the compounds of Formula r), the compounds are in the form of
a —C(O)CH(NH2)CH(CH3)2 prodrug.
Suitably in the compounds of Formula r) neither R72ccr nor R73ccr is hydrogen.
Suitably in the compounds of Formula r) r is phenyl substituted with from
1 to 4 substituents independently selected from:
fluoro,
chloro,
--CN,
oxo,
C1-4alkoxy,
C1-4alkoxy substituted with from 1 to 3 substituents
independently selected from: fluoro, chloro, oxo,
-OH, -NH2, -NHCH3, and —N(CH3)2,
tetrahydroisothiazolyl,
tetrahydroisothiazolyl substituted twice by oxo,
tetrahydro-1,2—thiazinyl,
tetrahydro-1,2—thiaziny| substituted twice by oxo,
-N(CH3)S(O)2CH3,
-OS(O)2CH3,
C1-Balkyl,
C1-6alkyl substituted with from 1 to 3 substituents
2017/053511
independently selected from: fluoro, chloro, bromo,
iodo, oxo, -S(O)2CH3, --CN, -OR793 and —
N R763R77a
where R763 and R773 are independently
selected from: hydrogen, -S(O)2CH3,
C1-5alky| and C1-5a|kyl substituted with from
1 to 4 substituents independently selected
from: fluoro, oxo, -OH, -OC1-5alkyl,
-OC1-5a|kyl substituted from 1 to 6 times by
fluoro, —COOH and —NR783R793, where R78a
and R79a are independently selected from:
hydrogen, phenyl, C1-5alkyl and C1-5alkyl
substituted with from 1 to 4 substituents
independently selected from: fluoro, 0x0,
-OH, -OC1-5alkyl, -OC1-5alkyI substituted
from 1 to 6 times by fluoro and —COOH.
This ion relates to novel nds of a (Qc) and to the use of
compounds of Formula (Qc) in the methods ofthe invention:
R700a"
N‘ ’//N
~C C
72 " I
R c\aN N/ SARWca”
R73ca (QC)
wherein:
R7063" is selected from:
ethyl,
-OCH3,
-CH2CF3, and
cyclopropyl;
R7763" is selected from:
phenyL
phenyl substituted with from 1 to 4 substituents ndently selected
from:
fluoro,
chloro,
C1-4alkoxy,
C1-4alkoxy substituted with from 1 to 3 tuents
independently selected from: fluoro, chloro, oxo,
-OH, -NH2, -NHCH3, and —N(CH3)2,
C1—Balkyl,
C1-6alkyl substituted with from 1 to 3 substituents
independently selected from: fluoro, chloro, bromo,
iodo, 0x0, -S(O)2CH3, -CN, -OR793’ and —
NR76a’R77a”
where R763, and R773, are independently
selected form: hydrogen, -S(O)2CH3,
C1-5alkyl and C1-5alkyl substituted with from
1 to 4 substituents independently ed
from: fluoro, oxo, -OH, -OC1-5alkyl,
-OC1-5alkyl substituted from 1 to 6 times by
fluoro, —COOH and —NR788’R793', where
R783, and R793. are ndently selected
form: hydrogen, phenyl, C1-5alkyl and
C1-5alky| substituted with from 1 to 4
substituentsindependently selected from:
fluoro, 0x0, -OH, -OC1-5alkyl, -OC1-5alkyl
substituted from 1 to 6 times by fluoro and
—COOH,
tetrahydroisothiazolyl,
tetrahydroisothiazolyl substituted twice by OXO,
tetrahydro-1,2—thiazinyl,
tetrahydro-1,2—thiaziny| tuted twice by oxo,
-N(CH3)S(O)2CFH2,
-N(CH3)S(O)2CF2H,
-N(CH3)S(O)2CF3,
-OS(O)2CH3,
-S(O)2NH2,
-S(O)2NHCH3, and
_NR8031R813’ where R803! and R813! are independently
selected
form: en, -S(O)2CH3, phenyl, C1-5alkyl and
C1-5alkyl substituted with from 1 to 4
substituentsindependently selected from: fluoro, 0x0,
-OH,
-NH2, -OC1-5alkyl, alky| tuted from 1 to
times by fluoro and —COOH, and
R7263" and R7363" are independently selected from:
hydrogen,
C1—4alkyl,
C1-4alky| substituted with from 1 to 4 substituents
independently selected from: phenyl, morpholino, triazolyl,
imidazolyl, -CH2CH2pyrrolidinyl, -OC(O)NH2, -OCH2CH2NH2,
NH2)NH2, C(CH3)3, -NOCH3, -NHOH,
-NHCH2CH2F, -N(CH3)CH20H20CH3, -N(CH2CH3)2,
-NCH(CH20H)2, -N(CH2CH20H)2, CH20H,
-NHCH20H2NH2, -N(CH3)CH2(CH3)2CH20H, -NHCHZCH3.
-NHCH2CH20CH3, -N(CH3)CH2CH20H, -NHC(O)C(O)NH2,
-N(CH3)CH2CH2CH20H, -N(CH3)CH2CH(OH)CH20H,
-N(CH3)CH2CH2NH2, oxo, -NHCHZC(CH3)ZCHZOH, -OH, -NH2,
-NHCH3, -NHCH2CH2CH20H, -N(CH3)2, -N(CH3)CH2CH3,
-NHOC(CH3)2NH2, -N(CH3)CH2cyclopropyl, -NHCH2cyclopropyl,
-NHoxetanyl, -NCHzCH2triazole, piperazinyl, piperidinyl, pyrazolyl,
azepinyl, azetidinyl, methoxy, and cyclopropylamino,
where said phenyl, morpholino, triazolyl, imidazolyl, azepinyl,
azetidinyl, pyrrolidinyl piperazinyl, piperidinyl,
oxetanyl, ropyl, and pyrazolyl are ally
substituted with from 1 to 4 tuents
independently selected from: methyl, fluoro, -NH2,
-N(CH3)2, hydroxymethyl, oxo, -OH, and 2,
cyclobutyl,
aminocyclobutyl,
tetrahydrofu ran,
-oxa-2azaspiro[3.4]octan, and
icyclo[3.2.1]octan, or
R723" and R733" are taken together with the nitrogen to which they are
attached, and optionally from 1 to 3 additional heteroatoms
independently selected from O, N, and S, to form a heterocycloalkyl
2017/053511
selected from:
pyrrolidinyl,
pyrrolo[3,4-c]pyrazolyl,
piperidinyl,
1,4diazepanyl,
piperazinyl,
6,7-dihydro-triazolo[4,5-c]pyridinyl,
2,9-diazaspiro[5.5]undecanyl,
2,8—diazaspiro[4.5]decanyl,
octahydro-1H-pyrrolo[1,2a][1,4]diazepinyl,
oxa-diazaspiro[4.5]decanyl,
oxazolyl,
morpholinyl,
1-oxaazaspiro[3.4]octanyl,
2-oxaazaspiro[3.4]octanyl,
1,7-diazaspiro[3.5]nonanyl,
2,7-diazaspiro[3.5]nonanyl,
2,6-diazaspiro[3.4]octanyl,
inyl,
hexahydropyrrolo[3,4-b]oxaziny|,
dihydronaphthyridinyl,
icycloheptanyl,
1,8—diazaspiro[4.5]decanyl, and
-oxaazaspiro[3.4]octanyl,
all of which are optionally substituted with from 1 to 5
substituents independently selected from:
fluoro,
chloro,
0x0,
-OH,
-OP(O)(OH)2,
-CN,
-CH3,
-CH20H,
methoxy,
-CHZCH3,
-C(O)CH3,
-C(O)NH2,
-OCH2CH20H,
-OCH2CH2NH2,
NH)NH2,
-OC(O)NH2,
-Ooxetany|,
-CHZCH20H,
-CH20H2CH20H,
-CHZCH2CH3,
-CH2CH20CH3,
-CHZCH(OH)CH3,
-CH20H(OH)CH20H,
-CH20(O)OCH3,
-CHZC(O)NH2,
-C(O)CH(CH3)2,
-CH20H2N(CH3)2,
-CHZCH2NHCHZCH3,
-CH2CH2CH2N(CH3)2,
-CH20H2NHCH2C(CH3)3,
2N(CH3)CHzoCH3,
-C(CH3)2CH20H,
-CH20(CH3)2OH,
-CH20(CH3)20CH3,
-C(O)CH20H,
-CH2isothiazolyl,
-CH2thiazolyI,
-CH2pyrazoly|,
-CH2imidazolyl,
-CH2pyridiny|,
-CH20xazo|y|,
rro|y|,
-CH2pyrrolidinyI,
oxazoly,
-CH2furanyI,
-CH2CH2morpholiny|,
-CH2CH2pyrrolidinyl,
-CH20H2pyrrolidinyICH3,
-CH20H2CH2pyrro|idinyl,
-C(O)pheny|,
-C(O)C(tetrahyd ropyranyl)NH2,
-NH2,
-NHCH3,
-N(CH3)2,
-NHC(O)CH3,
-NHCH(CH3)2,
-NHCH2CHF2,
-NHCH2C(CH3)3,
-NHCH2CH(CH3)2,
-NHCH2CHZOCH3,
-NHCH2CH20H,
-NHCH2CH2NH2,
-NHCH2C(O)OH,
-NHC(O)CH2NH2,
)CHZCH2CH2NH2,
C(O)NH2,
-NHCHZC(OH)(CH3)2,
-NHC(O)CH(CH3)NH2.
-NHC(O)OCH(CH3)NH2,
-NHC(O)CH(CH3)2.
-NHC(O)C(CH3)3,
-NHC(O)C(CH3)2NH2,
-NHC(O)CH20H,
-NHC(O)CH(CH20H)NH2,
-NHC(O)(oxetanyI)NH2,
-NHC(O)OC(CH3)3,
-NHC(CH3)ZC(O)OCH3,
-NHcyclopropyl,
-NHoxetany|,
-CH2NH2,
-CH2CH2NH2,
-CHZCHZCH2NH2,
-CH2NHCHZC(CH3)3,
-CH2NHC(O)C(CH3)3.
-CH2NHC(O)CH2NH2,
-CH2NHC(O)CH20H,
-CH2N(CH3)2,
-CH2NHCH3,
-CH2N(CHZCH3)2,
-CHZCH2N(CH3)2,
-S(O)2CH2CH3,
CHZCHZCH3,
—S(O)2phenyl,
-S(O)2CH3,
benzoyL
benzylamino,
-propylpyrrolidinyl,
-methy|cyclopropyl,
cyclobutylamino,
cyclobutyI-N(CH3)-,
piperidinyl,
imidazolyl,
morpholinyl,
morpholinylmethyl,
methylpiperazinylmethyl,
methylpiperazinyl,
pyrrolidinyl,
idinylmethyl,
(methoxypyridinylmethyl)amino,
methylpyrrolidinyl,
difluoropyrrolidinyl,
dimethylpyrrolidinyl,
(methylcyclopropylmethyl)amino,
ymethylpyrrolidinyl,
fluoropyrrolidinyl,
(fluorophenylmethyl)amino,
piperazinylmethyl,
oxazolidinyl,
(methyloxetanylmethyl)amino,
(methylcyclobutylmethyl)amino,
oxoimidazolidinyl, and
2-hydroxyethylpiperidinyl;
provided that:
R72a” and R733" are not both en;
or a pharmaceutically acceptable salt or prodrug thereof.
Suitably in the compounds of Formula (Qc), the compounds are in the form of a
phosphate prodrug.
Suitably in the compounds of Formula (Qc), the compounds are in the form of a
-C(O)CH(NH2)CH(CH3)2 prodrug.
ly in the compounds of Formula (Qc) neither R728” nor R733" is hydrogen.
This invention relates to novel compounds of Formula (Qc1) and to the use of
compounds of Formula (001) in the methods of the invention:
R70ca1;N
72 1" I
R (3N N/ SAR77C81"
R73ca1" (Qc1)
wherein:
" is selected from:
ethyl,
-OCH3,
-CHzCF3, and
cyclopropyl;
R77ca1" is selected from:
phenyL
phenyl substituted with from 1 to 4 substituents independently selected
from:
fluoro,
--CN,
oxo,
C1-4alkoxy,
C1-4alkoxy substituted with from 1 to 3 substituents
independently selected from: fluoro, chloro, oxo,
-OH, -NH2, -NHCH3, and —N(CH3)2,
C1—Balkyl,
C1-ealkyl substituted with from 1 to 3 substituents
independently selected from: fluoro, chloro, bromo,
iodo, 0x0, -S(O)2CH3, --CN, ’ and —
NR76a’R77a”
where R763! and R773! are independently
selected form: hydrogen, -S(O)2CH3,
C1-5alkyl and C1-5alkyl substituted with from
1 to 4 substituents independently selected
from: , oxo, -OH, -OC1-5alkyl,
-OC1-5alkyl substituted from 1 to 6 times by
fluoro, —COOH and —NR783’R793', where
R783, and R793, are independently selected
form: hydrogen, phenyl, C1-5alkyl and
C1-5alkyl substituted with from 1 to 4
substituentsindependently selected from:
fluoro, oxo, -OH, -OC1-5alkyl, -OC1-5alkyl
substituted from 1 to 6 times by fluoro and
-COOH,
tetrahydroisothiazolyl,
tetrahydroisothiazolyl substituted twice by OXO,
tetrahydro-1,2—thiazinyl,
tetrahydro-1,2—thiazinyl substituted twice by oxo,
-OS(O)2CH3,
-N(CH3)S(O)2CH3,
)S(O)2CFH2,
-N(CH3)S(O)2CF2H,
-N(CH3)S(O)2CF3,
-S(O)2NH2,
-S(O)2NHCH3, and
—NR803!R813' where R803, and R813, are independently
selected form: en, -S(O)2CH3, ,
C1-5alkyl and C1-5alky| substituted with from 1 to 4
substituents independently selected from: fluoro, 0x0,
-OH, -NH2, -OC1-5alkyl, -OC1-5a|kyl substituted from
1 to 6 times by fluoro and —COOH, and
R720a1" and " are independently selected from:
C1-4alkyl,
C1-4alky| substituted with from 1 to 4 substituents
independently selected from: phenyl, morpholino, triazolyl,
imidazolyl, -CH2CH2pyrrolidinyl, -OC(O)NH2, -OCH2CH2NH2,
-ONHC(NH2)NH2, -NHCHZC(CH3)3, -NOCH3, -NHOH,
-NHCH2CH2F, -N(CH3)CH20H20CH3, -N(CH2CH3)2,
H20H)2, -N(CH2CH20H)2, -NHCH2CH20H,
-NHCH20H2NH2, -N(CH3)CH2(CH3)2CH20H, -NHCHZCH3.
-NHCH2CH20CH3, -N(CH3)CH2CH20H, -NHC(O)C(O)NH2,
-N(CH3)CH2CH2CH20H, -N(CH3)CH2CH(OH)CH20H,
-N(CH3)CH2CH2NH2, oxo, -NHCHZC(CH3)ZCHZOH, -OH, -NH2,
-NHCH3, -NHCH2CH2CH20H, -N(CH3)2, -N(CH3)CH2CH3,
-NHOC(CH3)2NH2, -N(CH3)CH2cyclopropyl, -NHCH2cyclopropyl,
-NHoxetanyl, -NCHzCH2triazole, piperazinyl, piperidinyl, pyrazolyl,
azepinyl, inyl, methoxy, and cyclopropylamino,
where said , morpholino, triazolyl, imidazolyl, yl,
inyl, pyrrolidinyl zinyl, piperidinyl,
oxetanyl, cyclopropyl, and pyrazolyl are optionally
substituted with from 1 to 4 substituents
ndently selected from: methyl, fluoro, -NH2,
-N(CH3)2, hydroxymethyl, oxo, -OH, and -CH2NH2,
cyclobutyl,
aminocyclobutyl,
tetrahydrofu ran,
-oxa-2azaspiro[3.4]octan, and
8-azabicyclo[3.2.1]octan, or
R720a1" and R73ca1" are taken together with the nitrogen to which they are
attached, and ally from 1 to 3 additional heteroatoms,
to form a heterocycloalkyl selected from:
pyrrolidinyl,
pyrrolo[3,4-c]pyrazoly|,
piperidinyl,
zepanyl,
piperazinyl,
6,7-dihydro-triazolo[4,5-c]pyridinyl,
2,9—diazaspiro[5.5]undecanyl,
2,8—diazaspiro[4.5]decany|,
octahydro-1H-pyrrolo[1,2a][1,4]diazepiny|,
oxa-diazaspiro[4.5]decany|,
oxazolyl,
morpholinyl,
6-azaspiro[3.4]octany|,
2-oxaazaspiro[3.4]octanyl,
1,7-diazaspiro[3.5]nonany|,
2,7-diazaspiro[3.5]nonany|,
2,6-diazaspiro[3.4]octany|,
inyl,
hexahydropyrro|o[3,4-b]oxazinyl,
dihydronaphthyridinyl,
diazabicycloheptanyl,
1,8—diazaspiro[4.5]decany|, and
-oxaazaspiro[3.4]octanyl,
all of which are optionally substituted with from 1 to 5
substituents independently selected from:
fluoro,
chloro,
oxo,
-OH,
--CN,
-CH3,
-CH20H,
methoxy,
'CHZCHS!
2017/053511
-C(O)CH3,
-C(O)NH2,
-OCH2CH20H,
-OCH2CH2NH2,
-ONHC(NH)NH2,
-OC(O)NH2,
-Ooxetany|,
20H,
-CH20H2CH20H,
-CHZCH2CH3,
-CH2CH20CH3,
-CH20H(OH)CH3.
-CH20H(OH)CH20H,
-CH20(O)OCH3,
-CH20(O)NH2,
-C(O)CH(CH3)2,
-CH20H2N(CH3)2,
-CH20H2NHCH2CH3,
-CH2CH2CH2N(CH3)2,
-CH20H2NHCH2C(CH3)3,
-CHZCH2N(CH3)CHZOCH3,
-C(CH3)2CH20H,
-CH20(CH3)20H,
-CHZC(CH3)20CH3,
2017/053511
-C(O)CH20H,
-CH2isothiazoly|,
-CH2thiazolyI,
-CH2pyrazolyI,
-CH2imidazolyl,
-CH2pyridiny|,
-CH20xazo|y|,
rro|y|,
-CH2pyrrolidinyI,
-CH2isoxazoly,
-CH2furany|,
-CHZCH2morpholinyl,
-CH2CH2pyrrolidinyl,
-CH2CH2pyrrolidinyICH3,
-CH20H2CH2pyrro|idiny|,
-C(O)pheny|,
-C(O)C(tetrahyd ropyrany|)NH2,
-NH2,
-NHCH3,
-N(CH3)2,
-NHC(O)CH3,
-NHCH(CH3)2,
-NHCH2CHF2,
-NHCH2C(CH3)3,
-NHCHZCH(CH3)2,
-NHCH2CH20CH3,
-NHCH2CH20H,
-NHCH2CH2NH2,
-NHCH2C(O)OH,
-NHC(O)CH2NH2,
-NHC(O)CHZCH2CH2NH2,
-NHCH2C(O)NH2,
-NHCH2C(OH)(CH3)2,
1o -NHC(O)CH(CH3)NH2,
-NHC(O)OCH(CH3)NH2,
-NHC(O)CH(CH3)2,
-NHC(O)C(CH3)3,
-NHC(O)C(CH3)2NH2,
-NHC(O)CH20H,
-NHC(O)CH(CH20H)NH2,
-NHC(O)(oxetanyI)NH2,
-NHC(O)OC(CH3)3,
-NHC(CH3)2C(O)OCH3,
-NHcyclopropyl,
-NHoxetany|,
2NH2,
-CH2CH2CH2NH2,
-CH2NHCHZC(CH3)3,
-CH2NHC(O)C(CH3)3,
-CH2NHC(O)CH2NH2,
-CH2NHC(O)CH20H,
-CH2N(CH3)2,
-CH2NHCH3,
-CH2N(CH2CH3)2,
-CH20H2N(CH3)2,
CH2CH3,
-S(O)2CHZCH2CH3,
1o pheny|,
-S(O)2CH3,
benzylamino,
3-pyrr0lidinylpropyl,
2-cyclopropylmethyl,
cyclobutylamino,
cyclobutyI-N(CH3)-,
piperidinyl,
imidazolyl,
morpholinyl,
morpholinylmethyl,
methylpiperazinylmethyl,
methylpiperazinyl,
pyrrolidinyl,
pyrrolidinylmethyl,
methoxypyridinylmethylamino,
methylpyrrolidinyl,
difluoropyrrolidinyl,
dimethylpyrrolidinyl,
WO 16727
methylcyclopropylmethylamino,
hydroxymethylpyrrolidinyl,
fluoropyrrolidinyl,
fluorophenylmethylamino,
zinylmethyl,
oxazolidinyl,
methyloxetanmethylamino,
methylcyclobutylmethylamino,
dazolidinyl, and
1O 2-hydroxyethylpiperidinyl;
provided that:
R72ca1” and R73ca1" are not both unsubstituted alkyl;
or a pharmaceutically acceptable salt or prodrug thereof.
Suitably in the compounds of Formula (Qc1), the compounds are in the form of a
phosphate g.
Suitably in the compounds of Formula (Qc1), the compounds are in the form of a
—C(O)CH(NH2)CH(CH3)2 prodrug.
This invention relates to novel compounds of Formula (002) and to the use of
compounds of Formula (002) in the methods of the invention:
R70ca2"
N ~ ’0N
=C C
Rmai", N’ s/\ R77ca2"
$73ca2" (Q02)
wherein:
R70032" is selected from:
ethyl,
-OCH3,
3, and
cyclopropyl;
R77”? is selected from:
phenyL
phenyl substituted with from 1 to 4 substituents independently ed
from:
fluoro,
chloro,
--CN,
0x0,
C1-4alkoxy,
C1-4a|koxy substituted with from 1 to 3 substituents
independently selected from: fluoro, chloro, oxo,
-OH, -NH2, -NHCH3. and —N(CH3)2,
C1-Galkyl,
kyl tuted with from 1 to 3 substituents
ndently selected from: fluoro, chloro, bromo,
iodo, 0x0, -S(O)2CH3, --CN, -OR793’ and —
NR76a’R77a”
where R763’ and R773’ are independently
selected form: hydrogen, -S(O)zCH3,
C1-5alkyl and C1-5alkyl substituted with from
1 to 4 substituents independently selected
from: fluoro, oxo, -OH, -OC1-5alkyl,
-OC1-5alkyl substituted from 1 to 6 times by
fluoro, —COOH and —NR783’R793’, where
R7Ba’ and R7Qa' are independently selected
form: hydrogen, phenyl, C1-5alkyl and
C1-5alkyl substituted with from 1 to 4
substituentsindependently selected from:
fluoro, oxo, -OH, -OC1-5alkyl, -OC1-5alkyl
substituted from 1 to 6 times by fluoro and
—COOH,
ydroisothiazolyl,
tetrahydroisothiazolyl substituted twice by oxo,
tetrahydro-1,2—thiazinyl,
tetrahydro-1,2—thiazinyl substituted twice by 0x0,
)S(O)2CH3,
-N(CH3)S(O)ZCFH2,
-N(CH3)S(O)2CF2H,
-N(CH3)S(O)ZCF3.
2CH3,
-S(O)2NH2,
-S(O)2NHCH3, and
—NR8oa’R81a’ where R803, and R813, are independently
selected form: hydrogen, -S(O)20H3, phenyl,
C1-5alkyl and C1-5alkyl substituted with from 1 to 4
substituents ndently ed from: fluoro, oxo,
-OH, -NH2, -OC1-5alkyl, -OC1-5a|kyl substituted from
1 to 6 times by fluoro and —COOH, and
R720a2" and R73ca2" are taken together with the nitrogen to which they are
attached, and optionally from 1 to 3 additional heteroatoms,
to form a heterocycloalkyl selected from:
pyrrolidinyl,
pyrrolo[3,4-c]pyrazolyl,
piperidinyl,
1,4diazepanyl,
WO 16727
piperazinyl,
6,7-dihydro-triazolo[4,5-c]pyridinyl,
2,9-diazaspiro[5.5]undecanyl,
2,8—diazaspiro[4.5]decany|,
octahydro-1H-pyrro|o[1,2a][1,4]diazepiny|,
oxa-diazaspiro[4.5]decany|,
oxazolyl,
morpholinyl,
1-oxaazaspiro[3.4]octany|,
6-azaspiro[3.4]octanyI,
1,7-diazaspiro[3.5]nonany|,
2,7-diazaspiro[3.5]nonany|,
2,6-diazaspiro[3.4]octany|,
azetidinyl,
hexahydropyrrolo[3,4-b]oxaziny|,
dihydronaphthyridinyl,
diazabicycloheptanyl,
1,8—diazaspiro[4.5]decany|, and
-oxaazaspiro[3.4]octany|,
all of which are optionally substituted with from 1 to 5
substituents independently selected from:
chloro,
0x0,
-OH,
--CN,
-CH3,
-CH20H,
methoxy,
3o -CH20H3,
-C(O)CH3.
-C(O)NH2,
-OCH2CH20H,
-OCHZCH2NH2,
-ONHC(NH)NH2,
-OC(O)NH2,
-Ooxetany|,
-CH20H20H,
-CH20H2CH20H,
-CH2CH2CH3,
-CH20H20CH3,
-CHZCH(OH)CH3,
-CH2CH(OH)CH20H,
-CHZC(O)OCH3,
O)NH2,
-C(O)CH(CH3)2,
-CHZCH2N(CH3)2,
-CH20H2NHCH2CH3,
-CH20H2CH2N(CH3)2,
2NHCH2C(CH3)3,
-CH2CH2N(CH3)CH20CH3,
-C(CH3)2CH20H.
-CHZC(CH3)20H,
-CHZC(CH3)20CH3,
-C(O)CH20H,
-CH2isothiazolyl,
WO 16727
-CH2flflazoWL
-CHZPyrazolyI,
-CH2imidazolyl,
-CH2pyridiny|,
-CH20xazo|y|,
-CH2pyrro|y|,
-CH2pyrro|idiny|,
-CH2isoxazoly,
-CH2furanyI,
-CHZCH2momhmmw,
-CH2CH2pyrrolidinyI,
-CH20H2pyrrolidinyICH3,
-CHZCH2CH2pyrro|idinyl,
-C(O)pheny|,
(tetrahyd ropyranyI)NH2,
-NH2,
-NHCH3,
-N(CH3)2,
-NHC(O)CH3,
-NHCH(CH3)2,
-NHCH2CHFZ
-NHCH2C(CH3)3,
-NHCH2CH(CH3)2,
-NHCH2CH20CH3,
CH20H,
-NHCH2CH2NH2,
-NHCH2C(O)OH,
-NHC(O)CH2NH2,
-NHC(O)CH20H2CH2NH2,
-NHCH2C(O)NH2,
-NHCH2C(OH)(CH3)2,
-NHC(O)CH(CH3)NH2,
-NHC(O)OCH(CH3)NH2,
1o -NHC(O)CH(CH3)2,
-NHC(O)C(CH3)3,
-NHC(O)C(CH3)2NH2,
-NHC(O)CH20H,
-NHC(O)CH(CH20H)NH2,
-NHC(O)(oxetanyI)NH2,
-NHC(O)OC(CH3)3,
-NHC(CH3)ZC(O)OCH3,
-NHcyclopropyl,
-NHoxetany|,
-CH2NH2,
-CH2CH2NH2,
-CHZCH2CH2NH2,
-CH2NHCHZC(CH3)3,
-CH2NHC(O)C(CH3)3,
-CH2NHC(O)CH2NH2,
2017/053511
-CH2NHC(O)CH20H,
-CH2N(CH3)2,
-CH2NHCH3,
-CH2N(CH2CH3)2,
-CHZCH2N(CH3)2,
-S(O)2CH2CH3,
-S(O)2CH20HZCH3,
-S(O)2pheny|,
-S(O)2CH3,
benzoyl,
benzylamino,
3-pyrrolidinylpropyl,
2-cyclopropylmethyl,
cyclobutylamino,
cyclobutyI-N(CH3)-,
piperidinyl,
imidazolyl,
linyl,
linylmethyl,
methylpiperazinylmethyl,
methylpiperazinyl,
pyrrolidinyl,
pyrrolidinylmethyl,
methoxypyridinylmethylamino,
methylpyrrolidinyl,
difluoropyrrolidinyl,
dimethylpyrrolidinyl,
methylcyclopropylmethylamino,
hydroxymethylpyrrolidinyl,
fluoropyrrolidinyl,
fluorophenylmethylamino,
piperazinylmethyl,
oxazolidinyl,
methyloxetanmethylamino,
methylcyclobutylmethylamino,
oxoimidazolidinyl, and
2-hydroxyethylpiperidinyl;
or a pharmaceutically acceptable salt or prodrug thereof.
Suitably in the compounds of Formula (Qc2), the nds are in the form of a
phosphate prodrug.
ly in the compounds of Formula (Qc2), the compounds are in the form of a
—C(O)CH(NH2)CH(CH3)2 prodrug.
In an ment, X51a is selected from: --CN, fluoro and chloro. In an
embodiment, X52a is selected from: --CN, fluoro and chloro. In an embodiment, X513 is
--CN. In an embodiment, X5281 is --CN.
In an embodiment, Y53 is selected from: S and NH. In an embodiment, Y53 is S.
In an embodiment, Y5bblr is S.
In an embodiment, R503 is selected from: C1—6alkyl, C1-6alkyl substituted with from
1 to 9 substituents independently selected from: fluoro and chloro, and cycloalkyl. In an
embodiment, R50a is selected from ethyl, cyclopropyl and 2,2,2,trifluoroethyl. In an
ment, R508 is ethyl.
In an embodiment, R50bbr is selected from: C1-6alkyl, C1-6alky| substituted with
from 1 to 9 substituents ndently selected from: fluoro and , and cycloalkyl. In
an embodiment, R50bbr is selected from ethyl, cyclopropyl and 2,2,2,trifluoroethy|. In an
embodiment, R50IObr is ethyl.
WO 16727
In an embodiment, R50aar is selected from: phenyl, furanyl, C1-6alkyl, C1-6alkyl
substituted with from 1 to 9 substituents independently selected from: fluoro and ,
and cycloalkyl. In an embodiment, R5oaar is selected from phenyl, furanyl, ethyl,
cyclopropyl and trifluoroethyl. In an embodiment, R50aar is ethyl. In an embodiment,
R50alallr is phenyl. In an embodiment, R50aar iS furanyl.
In an embodiment R5” is selected from: hydrogen, kyl, aryl, phenyl
and heteroaryl. In an embodiment R513 is selected from: hydrogen, methyl, phenyl,
chlorophenyl and pyridine. In an embodiment R5121 is phenyl. In an embodiment R5121 is
hydrogen.
In an embodiment R51bbr is selected from: en, C1-6alkyl, aryl, chlorophenyl
and heteroaryl. In an embodiment R51bbr is selected from: hydrogen, methyl, phenyl,
chlorophenyl, piperidinyl and pyridinyl. In an embodiment R51bbr is phenyl. In an
embodiment R51bbr is pyridinyl.
In an embodiment R523 is selected from: -C(O)NH2 and
eH2NHC(O)CH3. In an embodiment R5221 is -C(O)NH2. In an embodiment R528
is —phenleH2NHC(O)CH3.
In an ment R538‘ and R543 are independently selected from: hydrogen,
methyl, morpholinethyl, methoxyethyl, oxaazaspiro[3.4]octan, 5-oxaazaspiro[3.4]octan,
aminoethyl, aminooxoethyl and hydroxyethyl.
In an embodiment R533 and R543 are taken together with the nitrogen to which they
are attached to form: pyrrolidinyl, hydroxypyrrolidinyl, piperidinyl, hydroxypiperidinyl, 1,4-
diazepanyl, methyl-1,4-diazepanyl, yethyl-1,4-diazepanyl, hydroxypropyl-1,4-
diazepanyl, methyl-1,4-diazepanacetate, (methyl)oxo-1,4-diazepanyl,
(methyl)oxopiperazinyl, propylpiperazinyl, aminopyrrolidinyl, oxo-1,4-diazepanyl,
piperidinylpiperazinyl, hydroxymethylpiperazinyl, oxopiperazinyl, morpholinpiperidinyl,
yethyl1,4diazepanyl, dimethylaminopropylpiperazinyl, pyrrolidinpiperidinyl,
piperidinpiperidinyl, pyrrolidinpropyl-1,4-diazepanyl, methylpiperazinyl,
dimethylaminopiperidinyl, ylpiperazinyl, dimethylmorpholinyl,
(aminomethyl)hydroxypiperidinyl, aminopiperidinyl, methylaminopiperidinyl, piperazinyl,
2017/053511
aminoethylpiperazinyl, ethylpiperazinyl, morpholinmethylpiperidinyl,
aminopropylpiperazinyl, methylpiperazinmethylpiperidinyl, pyrrolidinmethylpiperidinyl,
methylpiperazinpiperidinyl, ethyl1,4diazepanyl, imidazolidinpiperidinyl,
oxoimidazolidinpiperidinyl, l1,4-diazepanyl, azetidinyl, methoxyazetidinyl,
piperazinyl, hydroxyethylpiperazinyl, morpholinyl, ylpropanoylpiperazinyl,
ethanesulfonylpiperazinyl, methanesulfonylpiperazinyl, lpiperazinyl, oxopiperidinyl,
hydroxyethylpiperidinpiperidinyl, ymethylmorpholinyl or difluoropiperidinyl,
In an embodiment R53 and R54 are taken er with the nitrogen to which they
are attached to form: diazaspiroundecanyl, 2,9—diazaspiro[5.5]undecanyl,
diazaspirodecanyl, azaspiro[4.5]decanyl, hexahydropyrrolo-1,4-diazepanyl, methyl-
2,9-diazaspiro[5.5]undecanyl, cyclopropylmethyl-2,9-diazaspiro[5.5]undecanyl,
oxaazaspirooctanyl, oxaazaspiro[3.4]octanyl, diazaspirononanyl, diazaspiro[3.5]nonanyl,
1,7-diazaspiro[3.5]nonanyl, 2,7-diazaspiro[3.5]nonanyl, diazaspirooctanyl,
diazaspiro[3.4]octanyl, 2,6-diazaspiro[3.4]octanyl, methanesulfonyl-1,8-
diazaspiro[4.5]decanyl, azabicyclooctanyl, 8-azabicyclo[3.2.1]octanyl, 4-amino
methylpiperidinyl, NHZCHZC(O)NH-piperidinyl, NHZCH(CH3)C(O)NH-piperidinyl, 3-
aminooxetanecarbonyl)piperazinyl, 4-amino-(piperidinyl)tetrahydro-2H-pyran
carboxamide, 4—amino-(piperazinyl)tetrahydro-2H-pyran-4—carboxamide, hyd roxyethyl-
1,4-diazepanyl, aminopiperidinyl, yazetidinyl, hydroxypyrrolidinyl or
hydroxyethoxypiperidinyl.
In an embodiment R53bbr and R54bbr are independently selected from: hydrogen,
methyl, morpholinethyl, methoxyethyl, oxaazaspiro[3.4]octan, 2-azaspiro[3.4]octan,
aminoethyl, aminooxoethyl and hydroxyethyl.
In an embodiment R53bbr and R54bbr are taken together with the nitrogen to which
they are attached to form: pyrrolidinyl, hydroxypyrrolidinyl, piperidinyl, hydroxypiperidinyl,
1,4-diazepanyl, methyl-1,4-diazepanyl, methoxyethyl-1,4-diazepanyl, ypropyl-1,4-
diazepanyl, methyl-1,4-diazepanacetate, (methyl)oxo-1,4-diazepanyl,
(methyl)oxopiperazinyl, propylpiperazinyl, aminopyrrolidinyl, oxo-1,4-diazepanyl,
piperidinylpiperazinyl, hydroxymethylpiperazinyl, oxopiperazinyl, morpholinpiperidinyl,
hydroxyethyl1,4diazepanyl, dimethylaminopropylpiperazinyl, pyrrolidinpiperidinyl,
piperidinpiperidinyl, pyrrolidinpropyl-1,4-diazepanyl, methylpiperazinyl,
dimethylaminopiperidinyl, dimethylpiperazinyl, dimethylmorpholinyl,
(aminomethyl)hydroxypiperidinyl, aminopiperidinyl, methylaminopiperidinyl, piperazinyl,
aminoethylpiperazinyl, ethylpiperazinyl, morpholinmethylpiperidinyl,
aminopropylpiperazinyl, methylpiperazinmethylpiperidinyl, pyrrolidinmethylpiperidinyl,
methylpiperazinpiperidinyl, ethyl1,4diazepanyl, imidazolidinpiperidinyl,
oxoimidazolidinpiperidinyl, propy-I1,4-diazepanyl, azetidinyl, methoxyazetidinyl,
acetylpiperazinyl, hydroxyethylpiperazinyl, linyl, 2-methylpropanoylpiperazinyl,
ethanesuIfonylpiperazinyl, methanesuIfonylpiperazinyl, lpiperazinyl, oxopiperidinyl,
hydroxyethylpiperidinpiperidinyI, hydroxymethylmorpholinyl or difluoropiperidinyl,
In an embodiment R53bbr and R54bbr are taken together with the nitrogen to which
they are attached to form: diazaspiroundecanyl, 2,9-diazaspiro[5.5]undecany|,
diazaspirodecanyl, 2,8—diazaspiro[4.5]decanyl, hexahydropyrrolo-1,4—diazepanyl, methyl-
2,9-diazaspiro[5.5]undecanyl, cyclopropylmethyl-2,9-diazaspiro[5.5]undecany|,
oxaazaspirooctanyl, oxaazaspiro[3.4]octanyl, diazaspirononanyl, diazaspiro[3.5]nonanyl,
1,7-diazaspiro[3.5]nonany|, 2,7-diazaspiro[3.5]nonany|, diazaspirooctanyl,
diazaspiro[3.4]octanyl, 2,6-diazaspiro[3.4]octanyl, methanesulfonyI-1,8-
diazaspiro[4.5]decany|, yclooctanyl, 8-azabicyclo[3.2.1]octanyl, 4-amino
methylpiperidinyl, NH2CH2C(O)NH-piperidinyl, CH3)C(O)NH-piperidinyI, 3-
aminooxetanecarbonyl)piperazinyl, 4-amino-(piperidinyl)tetrahydro-2H-pyran
carboxamide, 4-amino-(piperazinyl)tetrahydro-2H-pyran-4—carboxamide, hydroxyethyl-
1,4-diazepany|, aminopiperidinyl, hydroxyazetidinyl, hydroxypyrrolidinyl or
yethoxypiperidinyl.
In an embodiment, X41 ccr is selected from: --CN, fluoro and chloro. In an
embodiment, X42” is selected from: --CN, fluoro and chloro. In an embodiment, X41ccr is
--CN. In an embodiment, X42ccr is --CN.
In an embodiment, Y4ccr is selected from: S and NH. In an ment, Y4ccr is 8.
In an embodiment, R41 ccr is selected from: kyl, C1-6alkyl substituted with
from 1 to 9 substituents independently selected from: fluoro and chloro, and cycloalkyl. In
an embodiment, R41ccr is selected from ethyl, ropyl and 2,2,2,trifluoroethyl. In an
embodiment, R41ccr is ethyl.
In an embodiment, R43ccr is selected from: phenyl, phenyl subsitituted with 1 or 2
substituents independently selected form: -OS(O)2CH3, -N(CH3)S(O)2CH3,
-CH2NHC(O)CH3, -CH2NHC(O)CH2NH2, -CH2NHC(O)CH3, tetrahydrothiazolyl,
tetrehydrothiazolyl substituted once or twice by oxo, tetrahydrothiazinyl, tetrahydrothiazinyl
substituted once ortwice by 0x0, and -CH28(O)2CH3,
In an embodiment R44ccr and R45ccr are independently selected from: en,
methyl, and C1-6alkyl substituted with from 1 to 9 substituents independently selected
from: -N(CHZCH3)2, and -NHOC(CH3)2NH2.
In an embodiment R44ccr and R45ccr are taken er with the nitrogen to which
they are attached to form: piperidinyl, piperidinyl tuted by one or two substituents
independently selected from: amino, CH3), pyrrolidinyl, -NHC(O)C(CH3)3,
-NH(O)CH(CH3)(NH2), , chloro, and CH2N(CH3)2, morpholinyl, morpholinyl
substituted by CH2pyrrolidinyl, zepanyl, and methyl1,4diazepanyl.
In an embodiment, X41bbr is selected from: --CN, fluoro and chloro. In an
ment, X42bbr is selected from: --CN, fluoro and . In an embodiment, X41 bbr is
--CN. In an embodiment, X42bbr is --CN.
In an embodiment, Y4bbr is selected from: S and NH. In an embodiment, Y4bblr is
In an embodiment, R41bbr is ed from: C1-6alkyl, C1-6alkyl substituted with
from 1 to 9 substituents independently selected from: fluoro and chloro, and cycloalkyl. In
an embodiment, R41bbr is selected from ethyl, cyclopropyl and 2,2,2,trifluoroethyl. In an
embodiment, R41bbr is ethyl.
In an embodiment, R43bbr is selected from: phenyl, and phenyl subsitituted with 1
or 2 substituents independently ed form: fluoro and chloro.
In an embodiment R44bbr and R45bbr are independently selected from: methyl, and
-CH2C(O)NH2.
In an embodiment R44bbr and R45bbr are taken together with the nitrogen to which
they are attached to form: piperidinyl, piperidinyl substituted by one or two substituents
independently selected from: amino, -NHCH2C(CH3)3, flouro, chloro, and
-N(CH3)cycIobutyI, pyrrolidinyl, and idinyl substituted by hydroxy.
Included in the compounds of Formula (I) and in the methods of the invention are:
2-[(6-amin0-3,5-dicyanoethylpyridiny|)su|fany|]pheny|acetamide;
(R)-[(6-amin0-3,5-dicyanoethylpyridinyl)suIfany|]phenylacetamide;
2-{[3,5-dicyano(dimethylamino)ethy|pyridiny|]su|fany|}phenylacetamide;
2-((3,5-dicyanocyclopropyI(1 ,4-diazepany|)pyridiny|)thio)
phenylacetamide;
-dicyanocyclopropyI(4-ethyl-1 ,4-diazepany|)pyridiny|]su|fany|}
phenylacetamide;
2-((3,5-dicyanoethyI(4-propyI-1,4-diazepany|)pyridiny|)thio)-2—
phenylacetamide;
2-{[3,5-dicyanoethyI(4-ethyI-1 ,4-diazepany|)pyridinyl]su|fanyl}
phenylacetamide;
2-{[3,5-dicyanoethyI(5-oxo-1 ,4-diazepany|)pyridiny|]su|fany|}
phenylacetamide;
2-((3,5-dicyanocyclopropyImorphoIinopyridinyl)thio)(pyridin
y|)acetamide;
2-{[3,5-dicyanoethyI(4-methyIoxopiperaziny|)pyridiny|]su|fany|}
(pyridiny|)acetamide;
2-[(3,5-dicyanoethyI{methyl[2-(morpho|iny|)ethy|]amino}pyridin
fany|]pheny|acetamide;
2-{[3,5-dicyanoethyI(4-propylpiperaziny|)pyridiny|]sulfany|}
acetamide;
2-({3,5-dicyanoethyI[4-(piperidinyI)piperaziny|]pyridiny|}su|fany|)
phenylacetamide;
2-({3,5-dicyanocyclopropyI[3-(hydroxymethyl)piperaziny|]pyridin
y|}suIfany|)pheny|acetamide;
2-{[3,5-dicyanocyclopropyI(3-oxopiperaziny|)pyridinyl]su|fanyl}
phenylacetamide;
2-({3,5-dicyanocyclopropyI[4-(morpholinyl)piperidiny|]pyridin
y|}suIfany|)pheny|acetamide;
-dicyanoethyI(2,8-d iazaspiro[4.5]decany|)pyridiny|)th io)
acetamide; 2,2,2-trifluoroacetic acid;
2-((3,5-DicyanocyclopropyI(3-(dimethylamino)piperidiny|)pyridiny|)thio)-
2-phenylacetamide;
2-((3,5-DicyanocyclopropyI(3-methylpiperaziny|)pyridiny|)thio)
phenylacetamide;
-DicyanocyclopropyI(2-(hydroxymethyl)morpholino)pyridiny|)thio)
phenylacetamide;
2-((3,5-DicyanocyclopropyI(2,6-dimethylmorpholino)pyridinyl)thio)
phenylacetamide;
2-((3,5-DicyanocyclopropyI(3-(dimethylamino)piperidiny|)pyridiny|)thio)-
2-phenylacetamide;
2-((6-(4-(Aminomethy|)hydroxypiperidiny|)-3,5-dicyanocyclopropylpyridin-
2-y|)thio)pheny|acetamide;
2-((3,5-dicyanocyclopropyI(3-(methylamino)piperidiny|)pyridiny|)thio)
phenylacetamide;
2-((6-(3-aminopiperidiny|)-3,5-dicyanocyclopropylpyridinyl)thio)
phenylacetamide;
2-((3,5-dicyanocyclopropyI(dimethylamino)pyridiny|)thio)(pyridin
y|)acetamide;
2-((3,5-dicyano(dimethylamino)ethy|pyridiny|)thio)(pyridin
y|)acetamide;
2-((6-(4-aminopiperidiny|)-3,5-dicyanocyclopropylpyridinyl)thio)
phenylacetamide;
2-((3,5-dicyanocyclopropyI(4-(dimethylamino)piperidiny|)pyridiny|)thio)-
2-phenylacetamide;
-dicyano—4-cyclopropyI(piperaziny|)pyridiny|)thio)(pyridin
tamide;
2-((3,5-dicyanocyclopropyI(1 ,4-diazepany|)pyridiny|)thio)(pyridin
y|)acetamide;
2-((3,5-dicyanocyclopropyI((R)hyd roxypiperidiny|)pyridinyl)thio)
phenylacetamide;
2-(3,5-dicyanocyclopropyI((S)hydroxypiperidiny|)pyridiny|thio)
phenylacetamide;
2-((3,5-dicyanocyclopropyI((S)hydroxypyrrolidiny|)pyridin-Z-yl)thio)
(pyrid iny|)acetamide;
2-((3,5-dicyanoethyI(4-ethylpiperaziny|)pyridiny|)thio)
phenylacetamide;
-DicyanoethyI(1-oxaazaspiro[3.4]octany|)pyridin-Z-yl)thio)
phenylacetamide;
2-((6-(4-(3-aminopropy|)piperaziny|)-3,5-dicyanoethylpyridinyl)thio)
phenylacetamide;
2-((3,5-Dicyano—4-ethyI(1,7-diazaspiro[3.5]nonany|)pyridiny|)thio)
phenylacetamide trifluoroacetate;
2-((3,5-DicyanocyclopropyI(4-(pyrrolidiny|methy|)piperidiny|)pyridin
y|)thio)pheny|acetamide;
2-((3,5-DicyanocyclopropyI(4-(4-methylpiperaziny|)piperidinyl)pyridin
y|)thio)pheny|acetamide;
(R)((3,5-dicyano(1,4-diazepany|)ethy|pyridin-Z-yl)amino)
phenylacetamide;
2-((3,5-DicyanocyclopropyI(4-(pyrrolidiny|)piperidiny|)pyridiny|)thio)-
2-phenylacetamide trifluoroacetate;
2-((3,5-DicyanoethyI(2,7-diazaspiro[3.5]nonany|)pyridiny|)thio)
phenylacetamide;
2-((3,5-DicyanoethyI(2,6-d iazaspiro[3.4]octany|)pyrid iny|)th io)
phenylacetamide;
2-((3,5-dicyano—4-cyclopropyI(1,4-diazepany|)pyridiny|)thio)propanamide;
2-((3,5-DicyanoethyI(4-(2-oxoimidazoIidiny|)piperidiny|)pyridin
y|)thio)phenylacetamide;
2-((3,5-DicyanoethyI(4-hydroxypiperidiny|)pyridinyl)thio)
phenylacetamide;
2-((3,5-DicyanoethyI((S)hydroxypyrrolidiny|)pyridiny|)thio)
phenylacetamide;
2-((3,5-Dicyano-4—ethyI(3-oxopiperaziny|)pyridiny|)thio)
phenylacetamide;
2-[(6-amino-3,5-dicyanocyclopropylpyridy|)su|fany|]pheny|—acetamide;
2-((3,5-DicyanoethyI(methylamino)pyridiny|)thio)phenylacetamide;
2-((3,5-DicyanoethyI((2-meth oxyethy|)(methy|)amino)pyridiny|)thio)
phenylacetamide;
2-((3,5-DicyanoethyI(3-methoxyazetidiny|)pyridiny|)thio)
phenylacetamide;
2-((3,5-DicyanoethyI(piperaziny|)pyridiny|)thio)pheny|acetamide;
2-((3,5-DicyanoethyI(4-methyI-1 ,4-diazepanyl)pyridin-2—y|)thio)
phenylacetamide;
2-((3,5-DicyanoethyImorpholinopyridiny|)thio)phenylacetamide;
2-[[6-(azetidiny|)-3,5-dicyano—4-ethyIpyridy|]suIfanyI]phenyI-acetamide;
2-((3,5-dicyanoethyI(4-oxopiperidiny|)pyridiny|)thio)pheny|acetamide;
2-((3,5-dicyanoethyI(1 '-(2-hyd hy|)-[4,4'-bipipe rid in]-1 ridin
o)pheny|acetamide;
2-((3,5-Dicyano((3S,5R)—3,5-dimethylpiperazinyl)ethy|pyridiny|)thio)
phenylacetamide;
2-((6-(8-azabicyc|o[3.2.1]octany|(methy|)amino)-3,5-dicyanoethylpyridin
y|)thio)pheny|acetamide;
2-((3,5-Dicyano—4-cyclopropyI(2-(hydroxymethyl)morpholino)pyridiny|)thio)
phenylacetamide;
(R)((3,5-dicyano(dimethylamino)ethy|pyridiny|)thio)phenylacetamide;
(R)[(3,5-Dicyanoethyl-6—morpholinopyridyl)sulfany|]—2-phenyI-acetamide;
N-(4-((3,5-DicyanoethyI(4-(pyrrolidiny|)piperidiny|)pyridin
ylthio)methyl)benzy|)acetamide trifluoroacetate;
2-{[3,5-dicyanoethyI(5-methyI-1 ,4-diazepany|)pyridiny|]su|fany|}
acetamide;
2-(4-(Aminomethyl)benzylthio)ethy|—6-(4-(pyrrolidiny|)piperidinyl)pyridine-
3,5-dicarbonitrile;
tert-Butyl 4-(((3,5-dicyano-4—ethyI(4-methyl-1,4-diazepany|)pyridin
y|)thio)methyl)benzy|carbamate;
4-(((3,5-DicyanoethyI(4-methyl-1 ,4-diazepanyl)pyridin
o)methy|)benzamide;
2-((4-(Aminomethy|)benzyl)thio)ethy|—6-(4—methy|-1,4-diazepany|)pyridine-
carbonitrile, 2Hydrochloride;
2-(4-(((3,5-Dicyanoethyl(4-methyl-1 ,4-diazepany|)pyridin
y|)thio)methy|)pheny|)acetic acid;
4-(((3,5-DicyanoethyI(4-methyl-1 ,4-diazepanyl)pyridin
y|)thio)methy|)benzoic acid;
2-(Dimethylamino)ethy|(((6-oxo-1 ,6-dihydropyridinyl)methyl)thio)pyridine-
3,5-dicarbonitrile;
N-(4-(((3,5-Dicyanoethyl—6-(4-methyl-1 ,4-diazepany|)pyridin
o)methy|)thiazoIy|)acetamide;
4-(((3,5-Dicyanoethyl(4-methyl—1 ,4-diazepanyl)pyridin
y|)thio)methy|)benzenesulfonamide;
N-(4-(((3,5-Dicyanoethyl—6-(4-methyl-1 ,4-diazepany|)pyridin
y|)thio)methyl)benzy|)acetamide;
tert-Butyl(2-((4-(((3,5-dicyanoethyl-6—(4-methyI-1 ,4—diazepany|)pyridin
y|)thio)methyl)benzy|)amino)oxoethyl)carbamate;
N-(4-(((3,5-Dicyanoethyl(4-methyl-1 ,4-diazepany|)pyridin
y|)thio)methy|)benzy|)methanesulfonamide;
2-Amino-N-(4-(((3,5-dicyanoethyl(4-methyl-1 ,4-diazepany|)pyridin
y|)thio)methyl)benzy|)acetamide;
2-(4-Aminopiperidiny|)(benzy|thio)ethy|pyridine-3, 5-dicarbonitrile;
4-(((3,5-DicyanoethyI(4-methyl-1 ,4-diazepany|)pyridin
o)methy|)benzy| acetate;
2-(4-(((3,5-Dicyanoethyl—6-(4-methyl-1 ,4-diazepany|)pyridin
y|)thio)methy|)pheny| ide;
2-(4-(((3,5-Dicyanoethyl—6-(4-methyl-1 ,4-diazepany|)pyridin
y|)thio)methyl)phenyI)-N-methylacetamide;
4-Ethyl-2—((4-(hydroxymethyl)benzyl)thio)—6-(4-methy|—1 ,4-diazepanyl)pyridine-
3,5-dicarbonitrile;
N-(4-(((3,5-Dicyanoethyl—6—(4-methyI-1 ,4-diazepany|)pyridin
o)methy|)benzyI)hydroxyacetamide;
N-(4-(((3,5-Dicyanoethyl—6—(4-methyI-1 ,4-diazepany|)pyridin
y|)thio)methy|)benzy|)propionamide;
N-(4-(((3,5-Dicyanoethyl—6-(4-methyI-1 ,4-diazepany|)pyridin
y|)thio)methy|)benzy|)isobutyramide;
N-(4-(((3,5-Dicyanoethyl—6-(4-methyI-1 ,4-diazepany|)pyridin
o)methyl)benzyI)methylbutanamide;
4-Ethyl-2—((4-(((2-hydroxyethy|)amino)methyl)benzyl)thio)(4-methy|-1,4-
diazepany|)pyridine-3,5-dicarbonitrile;
N-(4-(((3,5-Dicyano(4-methyI-1,4—diazepany|)(methy|amino)pyridin
y|)thio)methyl)benzy|)acetamide;
2-(((2-Acety|—1 ,2,3,4-tetrahydroisoquinolinyl)methyl)thio)(dimethy|amino)
ethylpyridine-3,5-dicarbonitrile;
2-((4-Cyanobenzyl)thio)ethy|—6-(4-methyI-1,4-diazepany|)pyridine-3,5-
dicarbonitrile;
2-Amino-N-(1 -(6-(benzy|thio)-3,5-d icyanoethylpyridinyl) pipe ridin
y|)acetamide, Trifluoroacetic acid salt;
o-N-(1-(6-(benzy|thio)—3,5-dicyanoethylpyridinyl)piperidin-4—yl)—2-
methylpropanamide, Formic acid salt;
3-Amino-N-(4-(((3,5-dicyanoethyl(4-methyl-1 ,4-diazepany|)pyridin
y|)thio)methyl)benzy|)propanamide;
Amino-N-(4-(((3,5-dicyanoethyI(4-methyI-1,4-diazepany|)pyridin
y|)thio)methyl)benzy|)propanamide;
(R)Amino-N-(4-(((3,5-dicyanoethyI(4-methyI-1,4-diazepany|)pyridin
y|)thio)methyl)benzy|)propanamide;
1-(4-(((3,5-DicyanoethyI(4-methyl-1,4-diazepany|)pyridin
o)methy|)benzy|)ethy|urea;
1-(4-(((3,5-DicyanoethyI(4-methyl-1,4-diazepany|)pyridin
y|)thio)methyl)benzyI)phenylurea;
N-(4-(((3,5-Dicyano(4-methyI-1,4-diazepany|)(methy|thio)pyridin
o)methy|)benzy|)acetamide;
(E)(4-(((3,5-Dicyano(dimethylamino)ethy|pyridin
y|)thio)methy|)pheny|)acrylic acid, Trifluoroacetic acid salt;
N-(4-(((3,5-Dicyano—4-ethyl((2-hydroxyethy|)(methyl)amino)pyridin
y|)thio)methy|)benzy|)acetamide;
4-(((3,5-DicyanoethyI(4-methyl-1,4-diazepany|)pyridiny|)thio)methy|)-N-
methylbenzenesuIfonamide;
N-(4-(((3,5-Dicyanoethoxy(4-methyl-1,4-diazepany|)pyridin
y|)thio)methy|)benzy|)acetamide;
2-({3,5-DicyanoethyI[4-(2-methoxyethyl)-1 ,4-diazepany|]pyridin
y|}suIfany|)pheny|acetamide;
2-((3,5-dicyanoethyI(4-(2-hyd roxypropyl)-1 ,4-diazepany|)pyridiny|)thio)-
2-phenylacetamide;
Methyl 2-[4-(6-{[carbamoyl(pheny|)methy|]su|fany|}-3,5-dicyanoethylpyridin
y|)-1 ,4-diazepany|]acetate;
2-{[3,5-DicyanocyclopropyI(4-methyIoxo-1,4-diazepany|)pyridin
fany|}phenylacetamide;
2-{[3,5-Dicyanocyclopropyl(5-oxo—1 ,4-diazepany|)pyridinyl]su|fany|}
phenylacetamide;
2-{[3,5-DicyanoethyI(4-methyIoxo-1 ,4-diazepany|)pyridinyl]su|fany|}-
2-phenylacetamide;
-Dicyano(1,4-diazepanyl)ethylpyridiny|]su|fany|}
phenylacetamide;
2-({3,5-Dicyano[4-(2-hydroxyethyl)-1,4-diazepany|](2,2,2-
trifluoroethyl)pyridiny|}su|fany|)phenylacetamide;
(2R)({3,5-DicyanoethyI[4-(2-hydroxyethyI)-1,4-diazepany|]pyridin
y|}amino)phenylacetamide;
2-({6-[(3S)AminopyrroIidiny|]-3,5-dicyanocyclopropylpyridinyl}su|fany|)-
2-phenylacetamide;
2-((3,5-DicyanoethyI(2,9-diazaspiro[5.5]undecanyl)pyridin-Z-yl)thio)
phenylacetamide;
2-((3,5-DicyanoethyI(hexahydro-1H-pyrro|o[1,2-a][1 ,4]diazepin-2(3H)-
y|)pyridiny|)thio)phenylacetamide;
2-((3,5-DicyanoethyI(2-methyI-2,9-diazaspiro[5.5]undecany|)pyridin
y|)thio)pheny|acetamide;
2-((3,5-Dicyano(2-(cyclopropylmethyI)-2,9-diazaspiro[5.5]undecanyI)
ethylpyridiny|)thio)phenylacetamide hydrochloride;
2-((3,5-Dicyano(4-(3-(dimethylamino)propy|)piperaziny|)ethy|pyridin
y|)thio)pheny|acetamide;
5-DicyanoethyI(4-(pyrroIidinyl)piperidiny|)pyridiny|)thio)
phenylacetamide; 2,2,2-trifluoroacetic acid;
2-((6-([4,4'-Bipiperidin]—1-yl)-3,5-dicyanoethylpyridiny|)thio)
phenylacetamide; 2,2,2-trifluoroacetic acid;
2-((6-(4-(2-Aminoethy|)piperaziny|)-3,5-dicyanoethylpyridiny|)thio)
phenylacetamide;
(4-(3-Aminopropyl)piperaziny|)-3,5-dicyanocyclopropylpyridiny|)thio)-
2-phenylacetamide;
-DicyanocyclopropyI(4-((4-methylpiperaziny|)methy|)piperidin
yI)pyridiny|)thio)phenylacetamide trifluoroacetate;
2-((6-(4-Acetylpiperaziny|)-3,5-dicyanoethylpyridin-Z-yl)thio)
phenylacetamide;
2-((3,5-DicyanocyclopropyI(dimethylamino)pyridiny|)thio)-2—
phenylacetamide;
h|orophenyl)((3,5-dicyano(dimethylamino)ethy|pyridin
y|)thio)acetamide;
2-((3,5-DicyanoethyI(4-(2-hydroxyethy|)piperaziny|)pyridiny|)thio)
phenylacetamide;
2-[(3,5-Dicyano—4-cyclopropyImorpholinopyridy|)su|fany|]phenyl-
acetamide;
2-((6-(4-Benzoy|piperaziny|)-3,5-dicyanoethylpyridinyl)thio)
phenylacetamide;
2-((3,5-DicyanoethyI((5S,6S)hydroxy(methy|su|fonyI)-1,8-
diazaspiro[4.5]decan-8—y|)pyridin-2—yl)thio)pheny|acetamide;
2-((3,5-Dicyano(4,4-difluoropiperidiny|)ethy|pyridinyl)thio)
phenylacetamide;
(R)((3,5-Dicyanoethyl((R)hydroxypyrrolidiny|)pyridinyl)thio)
phenylacetamide;
2-((6-(4-aminomethylpiperidiny|)-3,5-dicyanoethylpyridiny|)thio)
phenylacetamide;
2-amino-N-(1-(6-((2-aminooxophenylethyl)thio)-3,5-dicyanoethylpyridin-2—
y|)piperidinyl)acetamide 2,2,2-trifluoroacetate;
(ZS)amino-N-(1-(6-((2-aminooxophenylethyl)thio)-3,5-dicyano
ethylpyridiny|)piperidiny|)propanamide 2,2,2-trifluoroacetate;
2-((6-(4-(3-aminooxetanecarbonyl)piperaziny|)-3,5-dicyanoethylpyridin
o)pheny|acetamide formate;
4-amino-N-(1-(6-((2-aminooxopheny|ethy|)thio)-3,5-dicyanoethylpyridin
y|)piperidinyl)tetrahydro-2H-pyrancarboxamide 2,2,2-trifluoroacetate;
2-((6-(4-(4-aminotetrahydro-2H-pyrancarbonyl)piperazinyl)-3,5-dicyano
ethylpyridiny|)thio)phenylacetamide 2,2,2-trifluoroacetate;
2-((3,5-dicyano(4-(2-hydroxyethyl)-1 ,4-diazepany|)methoxypyridin
y|)thio)pheny|acetamide;
2-((6-(4-aminopiperidinyI)-3,5-dicyanoethylpyridiny|)thio)
phenylacetamide;
2-((6-((2-aminoethyl)(methy|)amino)-3 ,5-dicyanoethylpyrid inyl)th io)
phenylacetamide 2,2,2-trifluoroacetate;
2-((6-((2-aminooxoethy|)(methy|)amino)-3,5-dicyanoethylpyridiny|)thio)
phenylacetamide;
2-((3,5-dicyanoethyI(3-hydroxyazetidiny|)pyridinyl)thio)—2-
phenylacetamide;
2-((3,5-dicyanoethyI((2-hyd hyl)(methy|)amino)pyridinyl)thio)
phenylacetamide;
2-amino-N-(1-(6-((2-aminooxophenylethyl)thio)-3,5-dicyanoethylpyridin
eridiny|)methylpropanamide;
2-((6-(4-(2-aminoethoxy)piperidiny|)-3,5-dicyanoethylpyridinyl)thio)
phenylacetamide 2,2,2-trifluoroacetate;
2-((3,5-dicyanoethyI(3-hydroxypyrroIidiny|)pyridinyl)thio)
phenylacetamide;
2-((3,5-dicyanoethyI(4-(2-hydroxyethoxy)piperidiny|)pyridinyl)thio)
phenylacetamide;
N-(4-(((6-(4-aminopiperidiny|)-3,5-dicyanoethylpyridin
y|)thio)methyl)benzy|)acetamide 2,2,2-trifluoroacetate; and
2-((3,5-dicyano(dimethylamino)ethy|pyridiny|)thio)(piperidin-4—
y|)acetamide;
or a pharmaceutically acceptable salt or g thereof.
Included prodrugs of Formula (I) ofthe invention are:
1-(6-((2-aminooxophenylethyl)thio)-3,5-dicyanoethylpyridinyl)pyrrolidin-
3-yl dihydrogen phosphate;
2-((6-((2-aminooxophenylethyl)thio)-3,5-dicyanoethylpyridin
yl)(methy|)amino)ethyl dihydrogen phosphate;
1-(6-((2-aminooxophenylethyl)thio)-3,5-dicyanoethylpyridinyl)azetidin-
3-yl dihydrogen phosphate;
(ZS)((1-(6-((2-aminooxophenylethyl)thio)-3,5-dicyanoethylpyridin
yl)piperidinyl)oxy)ethyl 2-aminomethylbutanoate;
2-((1-(6-((2-aminooxophenylethyl)thio)-3,5-dicyanoethylpyridin
eridinyl)oxy)ethyl ogen phosphate;
1-(6-((2-aminooxophenylethyl)thio)-3,5-dicyanoethylpyridinyl)piperidin-
4-yl dihydrogen phosphate;
or a pharmaceutically acceptable salt thereof.
Suitably, the presently invented novel nds of Formula (lVa) are selected
from:
2-{[3,5-dicyano(dimethylamino)-4—ethylpyridinyl]sulfanyl}phenylacetamide;
2-((3,5-dicyanocyclopropyl(1 ,4-diazepany|)pyridinyl)thio)
phenylacetamide;
2-{[3,5-dicyanocyclopropyl(4-ethyl-1 ,4-diazepanyl)pyridinyl]sulfanyl}
acetamide;
2-((3,5-dicyanoethyl(4-propyl-1,4-diazepanyl)pyridiny|)thio)
phenylacetamide;
2-{[3,5-dicyanoethyl(4-ethyl-1 ,4-diazepanyl)pyridinyl]sulfanyl}
phenylacetamide;
2-{[3,5-dicyanoethyI(5-oxo-1 ,4-diazepany|)pyridiny|]su|fany|}
phenylacetamide;
2-((3,5-dicyanocyclopropyImorphoIinopyridiny|)thio)(pyridin
y|)acetamide;
2-{[3,5-dicyanoethyI(4-methyIoxopiperaziny|)pyridiny|]su|fany|}
(pyrid iny|)acetamide;
2-[(3,5-dicyanoethyI{methyl[2-(morpho|iny|)ethy|]amino}pyridin
y|)su|fany|]pheny|acetamide;
2-{[3,5-dicyanoethyI(4-propylpiperaziny|)pyridinyl]su|fany|}
phenylacetamide;
2-({3,5-dicyanoethyI[4-(piperidinyl)piperaziny|]pyridiny|}su|fany|)
phenylacetamide;
2-({3,5-dicyanocyclopropyI[3-(hydroxymethyl)piperaziny|]pyridin
y|}suIfany|)pheny|acetamide;
2-{[3,5-dicyanocyclopropyI(3-oxopiperaziny|)pyridinyl]su|fanyl}
phenylacetamide;
-dicyanocyclopropyI[4-(morpholinyl)piperidinyl]pyridin
y|}suIfany|)pheny|acetamide;
2-((3,5-dicyanoethyI(2,8-d iazaspiro[4.5]decany|)pyridiny|)th io)
phenylacetamide; 2,2,2-trifluoroacetic acid;
2-((3,5-DicyanocyclopropyI(3-(dimethylamino)piperidiny|)pyridiny|)thio)-
2-phenylacetamide;
2-((3,5-DicyanocyclopropyI(3-methylpiperaziny|)pyridiny|)thio)
acetamide;
2-((3,5-DicyanocyclopropyI(2-(hydroxymethyl)morpholino)pyridiny|)thio)
acetamide;
2-((3,5-DicyanocyclopropyI(2,6-dimethylmorpholino)pyridiny|)thio)
phenylacetamide;
2-((3,5-DicyanocyclopropyI(3-(dimethylamino)piperidiny|)pyridiny|)thio)-
2-phenylacetamide;
2-((6-(4-(Aminomethy|)hydroxypiperidiny|)-3,5-dicyanocyclopropylpyridin-
2-y|)thio)pheny|acetamide;
2-((3,5-dicyanocyclopropyI(3-(methylamino)piperidiny|)pyridiny|)thio)
phenylacetamide;
2-((6-(3-aminopiperidiny|)-3,5-dicyanocyclopropylpyridinyl)thio)
acetamide;
2-((3,5-dicyanocyclopropyI(d imethylamino)pyridiny|)thio)(pyridin
y|)acetamide;
-dicyano(dimethylamino)ethy|pyridiny|)thio)(pyridin
y|)acetamide;
2-((6-(4-aminopiperidiny|)-3,5-dicyanocyclopropylpyridinyl)thio)
phenylacetamide;
2-((3,5-dicyanocyclopropyI(4-(dimethylamino)piperidiny|)pyridiny|)thio)-
2-phenylacetamide;
2-((3,5-dicyanocyclopropyI(piperaziny|)pyridiny|)thio)(pyridin
y|)acetamide;
2-((3,5-dicyanocyclopropyI(1 ,4-diazepany|)pyridiny|)thio)(pyridin
y|)acetamide;
2-((3,5-dicyanocyclopropyl((R)—3-hyd roxypiperidiny|)pyridinyl)thio)
phenylacetamide;
2-(3,5-dicyanocyclopropyI((S)hydroxypiperidiny|)pyridiny|thio)
phenylacetamide;
2-((3,5-dicyanocyclopropyI((S)hydroxypyrrolidiny|)pyridin-Z-yl)thio)
(pyrid iny|)acetamide;
2-((3,5-dicyanoethyI(4-ethylpiperaziny|)pyridiny|)thio)
phenylacetamide;
2-((3,5-DicyanoethyI(1 -oxaazaspiro [3 .4]octany|)pyridinyl)th io)
phenylacetamide;
(4-(3-aminopropy|)piperaziny|)-3,5-dicyanoethylpyridinyl)thio)
phenylacetamide;
2017/053511
2-((3,5-DicyanoethyI(1,7-diazaspiro[3.5]nonany|)pyridiny|)thio)
phenylacetamide oroacetate;
2-((3,5-DicyanocyclopropyI(4-(pyrrolidiny|methy|)piperidiny|)pyridin
y|)thio)pheny|acetamide;
2-((3,5-DicyanocyclopropyI(4-(4-methylpiperaziny|)piperidinyl)pyridin
y|)thio)pheny|acetamide;
(R)((3,5-dicyano(1,4-diazepany|)ethy|pyridin-Z-yl)amino)
phenylacetamide;
2-((3,5-DicyanocyclopropyI(4-(pyrrolidiny|)piperidiny|)pyridiny|)thio)-
2-phenylacetamide trifluoroacetate;
2-((3,5-DicyanoethyI(2,7-diazaspiro[3.5]nonany|)pyridiny|)thio)
phenylacetamide;
2-((3,5-DicyanoethyI(2,6-diazaspiro[3.4]octanyl)pyridinyl)thio)
phenylacetamide;
2-((3,5-dicyanocyclopropyI(1,4-diazepany|)pyridiny|)thio)propanamide;
2-((3,5-DicyanoethyI(4-(2-oxoimidazoIidiny|)piperidiny|)pyridin
y|)thio)phenylacetamide;
2-((3,5-DicyanoethyI(4-hydroxypiperidiny|)pyridinyl)thio)
phenylacetamide;
2-((3,5-DicyanoethyI((S)hydroxypyrrolidiny|)pyridiny|)thio)
phenylacetamide;
2-((3,5-Dicyano-4—ethyI(3-oxopiperaziny|)pyridiny|)thio)
acetamide;
2-((3,5-DicyanoethyI((2-meth oxyethy|)(methy|)amino)pyridinyl)thio)
phenylacetamide;
2-((3,5-DicyanoethyI(3-methoxyazetidiny|)pyridinyl)thio)
phenylacetamide;
2-((3,5-DicyanoethyI(piperaziny|)pyridinyl)thio)phenylacetamide;
2-((3,5-DicyanoethyI(4-methyI-1 ,4-diazepanyl)pyridiny|)thio)
phenylacetamide;
2-((3,5-DicyanoethyImorpholinopyridinyl)thio)—2-phenylacetamide;
2-[[6-(azetidiny|)-3,5-dicyanoethyIpyridyl]suIfanyl]pheny|—acetamide;
2-((3,5-dicyanoethyI(4-oxopiperidinyl)pyridiny|)thio)phenylacetamide;
2-((3,5-dicyanoethyI(1 '-(2-hyd roxyethy|)-[4,4'-bipipe rid in]-1 -y|)pyridin
o)phenylacetamide;
2-((3,5-Dicyano((38,5R)—3,5-dimethylpiperaziny|)ethy|pyridiny|)thio)
phenylacetamide;
2-((6-(8-azabicyclo[3.2.1]octany|(methy|)amino)-3,5-dicyanoethylpyridin
y|)thio)phenylacetamide;
2-((3,5-Dicyano-4—cyclopropyl(2-(hydroxymethyl)morpholino)pyridin-2—y|)thio)
phenylacetamide;
(R)((3,5-dicya no(d imethylamino)ethylpyridiny|)th io)—2-phenylacetamide;
(R)[(3,5-DicyanoethyImorpholinopyridyl)sulfany|]—2-phenyI-acetamide;
N-(4-((3,5-DicyanoethyI(4-(pyrrolidiny|)piperidiny|)pyridin
ylthio)methyl)benzy|)acetamide trifluoroacetate;
2-{[3,5-dicyanoethyI(5-methyI-1,4-diazepany|)pyridiny|]su|fany|}
phenylacetamide;
2-(4-(Aminomethyl)benzylthio)ethyI(4-(pyrrolidiny|)piperidinyl)pyridine-
3,5-dicarbonitrile;
tert-Butyl 4-(((3,5-dicyanoethyI(4-methyl-1,4-diazepany|)pyridin
y|)thi0)methy|)benzylcarbamate;
4-(((3,5-DicyanoethyI(4-methyl-1 ,4-diazepanyl)pyridin
o)methy|)benzamide;
2-((4-(Aminomethy|)benzyl)thio)ethy|(4-methyI-1,4-diazepany|)pyridine-
3,5-dicarbonitrile, 2Hydrochloride;
2-(4-(((3,5-Dicyanoethyl—6-(4-methyl-1,4-diazepany|)pyridin
y|)thio)methy|)pheny|)acetic acid;
,5-DicyanoethyI(4-methyl-1 ,4-diazepanyl)pyridin
y|)thio)methy|)benzoic acid;
2-(Dimethy|amino)ethy|—6-(((6-oxo-1 ,6-dihydropyridinyl)methy|)thio)pyridine-
carbonitrile;
N-(4-(((3,5-Dicyanoethyl(4-methyl-1 ,4-diazepany|)pyridin
y|)thio)methy|)thiazoIy|)acetamide;
4-(((3,5-DicyanoethyI(4-methyl-1 ,4-diazepanyl)pyridin
y|)thio)methy|)benzenesulfonamide;
N-(4-(((3,5-Dicyanoethyl(4-methyl-1 ,4-diazepany|)pyridin
y|)thio)methyl)benzy|)acetamide;
te rt-Butyl(2-((4-(((3,5-dicyanoethyI(4-methyI-1 ,4-diazepany|)pyridin
y|)thi0)methyl)benzy|)amino)oxoethyl)carbamate;
N-(4-(((3,5-Dicyanoethyl(4-methyl-1 ,4-diazepany|)pyridin
y|)thio)methy|)benzy|)methanesulfonamide;
2-Amino-N-(4-(((3,5-dicyanoethyl(4-methyl-1 ,4-diazepany|)pyridin
y|)thio)methyl)benzy|)acetamide;
2-(4-Aminopiperidiny|)(benzy|thio)ethy|pyridine-3, 5-dicarbonitrile;
4-(((3,5-DicyanoethyI(4-methyl-1 ,4-diazepany|)pyridin
y|)thio)methy|)benzy| acetate;
2-(4-(((3,5-Dicyanoethyl—6-(4-methyl-1 ,4-diazepany|)pyridin
y|)thio)methy|)pheny| ide;
2-(4-(((3,5-Dicyanoethyl—6-(4-methyl-1 ,4-diazepany|)pyridin
y|)thio)methyl)phenyI)-N-methylacetamide;
4-Ethyl-2—((4-(hydroxymethyl)benzyl)thio)—6-(4-methy|—1 ,4-diazepanyl)pyridine-
3,5-dicarbonitrile;
N-(4-(((3,5-Dicyanoethyl—6—(4-methyI-1 ,4-diazepany|)pyridin
o)methy|)benzyI)hydroxyacetamide;
N-(4-(((3,5-Dicyanoethyl—6—(4-methyI-1 ,4-diazepany|)pyridin
y|)thio)methy|)benzy|)propionamide;
N-(4-(((3,5-Dicyanoethyl—6—(4-methyI-1 ,4-diazepany|)pyridin
y|)thio)methy|)benzy|)isobutyramide;
2017/053511
N-(4-(((3,5-Dicyanoethyl(4-methyl-1 ,4-diazepany|)pyridin
y|)thio)methyl)benzyI)methylbutanamide;
I((4-(((2-hydroxyethy|)amino)methyl)benzyl)thio)(4-methyI-1,4-
diazepany|)pyridine-3,5-dicarbonitrile;
N-(4-(((3,5-Dicyano(4-methyl-1,4-diazepany|)(methy|amino)pyridin
y|)thio)methy|)benzy|)acetamide;
2-(((2-Acety|-1 ,2,3,4-tetrahydroisoquinolinyl)methyl)thio)(dimethy|amino)
ethylpyridine-3,5-dicarbonitrile;
2-((4-Cyanobenzyl)thio)ethy|—6-(4-methyI-1,4-diazepany|)pyridine-3,5-
dicarbonitrile;
2-Amino-N-(1 -(6-(benzy|thio)-3,5-d ethylpyridinyl) pipe ridin
y|)acetamide, Trifluoroacetic acid salt;
2-Amino-N-(1-(6-(benzy|thio)—3,5-dicyanoethylpyridinyl)piperidin-4—yl)—2-
methylpropanamide, Formic acid salt;
3-Amino-N-(4-(((3,5-dicyanoethyl(4-methyl-1 ,4-diazepany|)pyridin
y|)thio)methyl)benzy|)propanamide;
Amino-N-(4-(((3,5-dicyanoethyI(4-methyI-1,4-diazepany|)pyridin
y|)thio)methyl)benzy|)propanamide;
(R)Amino-N-(4-(((3,5-dicyanoethyI(4-methyI-1,4-diazepany|)pyridin
y|)thio)methyl)benzy|)propanamide;
1-(4-(((3,5-DicyanoethyI(4-methyl-1,4-diazepany|)pyridin
y|)thio)methy|)benzy|)ethy|urea;
1-(4-(((3,5-DicyanoethyI(4-methyl-1,4-diazepany|)pyridin
y|)thio)methyl)benzyI)phenylurea;
N-(4-(((3,5-Dicyano—6-(4-methyI-1 ,4-diazepany|)(methy|thio)pyridin
y|)thio)methy|)benzy|)acetamide;
(E)(4-(((3,5-Dicyano(dimethylamino)ethy|pyridin
y|)thio)methy|)pheny|)acrylic acid, Trifluoroacetic acid salt;
N-(4-(((3,5-Dicyano—4-ethyl((2-hyd roxyethyl)(methyl)amino)pyridin
y|)thio)methy|)benzy|)acetamide;
2017/053511
4-(((3,5-DicyanoethyI(4-methyl-1,4-diazepanyl)pyridiny|)thio)methy|)-N-
methylbenzenesuIfonamide;
N-(4-(((3,5-Dicyanoethoxy(4-methyl-1,4-diazepany|)pyridin
y|)thio)methyl)benzy|)acetamide;
2-({3,5-Dicyano-4—ethyI[4-(2-methoxyethyl)—1 ,4-diazepanyl]pyridin
y|}suIfany|)pheny|acetamide;
2-((3,5-dicyanoethyI(4-(2-hyd roxypropyI)-1 ,4-diazepany|)pyridiny|)thio)—
ylacetamide;
Methyl 2-[4-(6-{[carbamoyl(pheny|)methyl]su|fany|}-3,5-dicyanoethylpyridin
y|)-1 ,4-diazepany|]acetate;
2-{[3,5-DicyanocyclopropyI(4-methyIoxo-1,4-diazepany|)pyridin
y|]su|fany|}pheny|acetamide;
2-{[3,5-Dicyano-4—cyclo propyI(5-oxo-1 ,4-diazepany|)pyridiny|]sulfany|}
acetamide;
2-{[3,5-Dicyano-4—ethyI(4-methyIoxo-1 ,4-diazepany|)pyridinyl]su|fany|}-
2-phenylacetamide;
2-{[3,5-Dicyano(1,4-diazepanyl)ethylpyridin-2—yl]su|fany|}
phenylacetamide;
2-({3,5-Dicyano[4-(2-hydroxyethyl)-1,4-diazepany|](2,2,2-
trifluoroethyl)pyridiny|}su|fanyI)phenylacetamide;
(2R)({3,5-Dicyanoethyl[4-(2-hydroxyethy|)-1,4-diazepany|]pyridin
y|}amino)phenylacetamide;
2-({6-[(3S)AminopyrroIidiny|]-3,5-dicyanocyclopropylpyridinyl}su|fany|)—
2-phenylacetamide;
2-((3,5-Dicyano-4—ethyI(2,9-diazaspiro[5.5]undecany|)pyridiny|)thio)
phenylacetamide;
2-((3,5-DicyanoethyI(hexahydro-1H-pyrrolo[1,2-a][1 ,4]diazepin-2(3H)—
y|)pyridiny|)thio)phenylacetamide;
2-((3,5-DicyanoethyI(2-methyI-2,9-diazaspiro[5.5]undecany|)pyridin
y|)thio)pheny|acetamide;
2-((3,5-Dicyano(2-(cyclopropylmethyI)-2,9-diazaspiro[5.5]undecanyI)
ethylpyridiny|)thio)phenylacetamide hydrochloride;
2-((3,5-Dicyano(4-(3-(dimethylamino)propy|)piperaziny|)ethy|pyridin
y|)thio)pheny|acetamide;
2-((3,5-DicyanoethyI(4-(pyrroIidinyl)piperidiny|)pyridinyl)thio)-2—
acetamide; 2,2,2-trifluoroacetic acid;
2-((6-([4,4'-Bipiperidin]—1-yl)-3,5-dicyanoethylpyridiny|)thio)
phenylacetamide; 2,2,2-trifluoroacetic acid;
2-((6-(4-(2-Aminoethy|)piperaziny|)-3,5-dicyanoethylpyridin-Z-yl)thio)-2—
phenylacetamide;
2-((6-(4-(3-Aminopropyl)piperaziny|)-3,5-dicyanocyclopropylpyridiny|)thio)-
2-phenylacetamide;
2-((3,5-DicyanocyclopropyI(4-((4-methylpiperaziny|)methy|)piperidin
yI)pyridiny|)thio)phenylacetamide trifluoroacetate;
(4-Acetylpiperaziny|)-3,5-dicyanoethylpyridin-Z-yl)thio)
phenylacetamide;
2-((3,5-DicyanocyclopropyI(dimethylamino)pyridiny|)thio)
phenylacetamide;
2-(4-Ch|orophenyl)((3,5-dicyano(dimethylamino)ethy|pyridin
y|)thio)acetamide;
2-((3,5-DicyanoethyI(4-(2-hydroxyethy|)piperaziny|)pyridinyl)thio)
acetamide;
2-[(3,5-DicyanocyclopropyImorpholinopyridy|)su|fany|]phenyl-
acetamide;
2-((6-(4-Benzoy|piperaziny|)-3,5-dicyanoethylpyridinyl)thio)
phenylacetamide;
2-((3,5-DicyanoethyI((5S,6S)hydroxy(methy|su|fonyI)-1,8-
diazaspiro[4.5]decany|)pyridin-2—yl)thio)pheny|acetamide;
2-((3,5-Dicyano(4,4-difluoropiperidiny|)ethy|pyridinyl)thio)
acetamide;
(R)((3,5-Dicyanoethyl—6-((R)hydroxypyrrolidiny|)pyridinyl)thio)
phenylacetamide;
2-((6-(4-aminomethylpiperidinyI)-3,5-dicyanoethylpyridiny|)thio)
phenylacetamide;
2-amino-N-(1-(6-((2-aminooxophenylethyl)thio)-3,5-dicyanoethylpyridin-2—
y|)piperidinyl)acetamide 2,2,2-trifluoroacetate;
-amino-N-(1-(6-((2-aminooxopheny|ethy|)thio)-3,5-dicyano
ethylpyridiny|)piperidiny|)propanamide 2,2,2-trifluoroacetate;
2-((6-(4-(3-aminooxetanecarbonyl)piperaziny|)-3,5-dicyanoethylpyridin
y|)thio)pheny|acetamide formate;
4-amino-N-(1-(6-((2-aminooxophenylethyl)thio)-3,5-dicyanoethylpyridin-2—
y|)piperidinyl)tetrahydro-2H-pyrancarboxamide 2,2,2-trifluoroacetate;
(4-(4-aminotetrahydro-2H-pyrancarbonyl)piperaziny|)-3,5-dicyano
ethylpyridiny|)thio)phenylacetamide 2,2,2-trifluoroacetate;
2-((3,5-dicyano(4-(2-hydroxyethy|)-1 ,4-diazepany|)methoxypyridin
y|)thio)pheny|acetamide;
2-((6-(4-aminopiperidiny|)-3,5-dicyanoethylpyridiny|)thio)
acetamide;
2-((6-((2-aminoethyl)(methy|)amino)-3 ,5-dicyanoethylpyrid inyl)th io)
phenylacetamide 2,2,2-trifluoroacetate;
2-((6-((2-aminooxoethy|)(methy|)amino)-3,5-dicyanoethylpyridiny|)thio)
phenylacetamide;
2-((3,5-dicyanoethyI(3-hydroxyazetidiny|)pyridinyl)thio)
phenylacetamide;
2-((3,5-dicyanoethyI((2-hyd roxyethyl)(methy|)amino)pyridiny|)thio)
phenylacetamide;
o-N-(1-(6-((2-aminooxophenylethyl)thio)-3,5-dicyanoethylpyridin
y|)piperidinyl)methy|propanamide;
2-((6-(4-(2-aminoethoxy)piperidiny|)-3,5-dicyanoethylpyridinyl)thio)
phenylacetamide 2,2,2-trifluoroacetate;
-dicyanoethyl(3-hydroxypyrrolidinyl)pyridinyl)thio)
phenylacetamide;
2-((3,5-dicyanoethyl(4-(2-hydroxyethoxy)piperidiny|)pyridinyl)thio)
phenylacetamide;
N-(4-(((6-(4-aminopiperidinyl)-3,5-dicyanoethylpyridin
y|)thio)methyl)benzyl)acetamide 2,2,2-trifluoroacetate; and
2-((3,5-dicyano(dimethylamino)ethylpyridinyl)thio)(piperidin-4—
y|)acetamide;
or a ceutically acceptable salt or prodrug thereof.
Included prodrugs of Formula (lVa) ofthe invention are:
1-(6-((2-aminooxophenylethyl)thio)-3,5-dicyanoethylpyridinyl)pyrrolidin-
3-yl dihydrogen phosphate;
2-((6-((2-aminooxophenylethyl)thio)-3,5-dicyanoethylpyridin
y|)(methy|)amino)ethyl dihydrogen phosphate;
1-(6-((2-aminooxophenylethyl)thio)-3,5-dicyanoethylpyridiny|)azetidin-
3-yl dihydrogen phosphate;
(ZS)((1-(6-((2-aminooxophenylethyl)thio)-3,5-dicyanoethylpyridin
y|)piperidinyl)oxy)ethyl 2-aminomethylbutanoate;
2-((1-(6-((2-aminooxophenylethyl)thio)-3,5-dicyanoethylpyridin
y|)piperidinyl)oxy)ethyl dihydrogen phosphate;
1-(6-((2-aminooxophenylethyl)thio)-3,5-dicyanoethylpyridinyl)piperidin-
4-yl dihydrogen phosphate;
or a pharmaceutically acceptable salt thereof.
Primary amide:
Included in the nds of Formula (Ibr) and in the methods ofthe invention are:
2-[(6-amino-3,5-dicyanoethylpyridinyl)su|fany|]pheny|acetamide;
(R)-[(6-amin0-3,5-dicyanoethylpyridinyl)suIfanyl]phenylacetamide;
2-{[3,5-dicyano(dimethylamino)-4—ethy|pyridiny|]su|fany|}phenylacetamide;
2-((3,5-dicyanocyclopropyI(1 ,4-diazepany|)pyridiny|)thio)
phenylacetamide;
2-{[3,5-dicyanocyclopropyI(4-ethyI-1 ,4-diazepany|)pyridiny|]su|fany|}
acetamide;
2-((3,5-dicyanoethyI(4-propyI-1,4-diazepany|)pyridiny|)thio)
phenylacetamide;
2-{[3,5-dicyanoethyI(4-ethyI-1 ,4-diazepany|)pyridinyl]su|fany|}
phenylacetamide;
2-{[3,5-dicyanoethyI(5-oxo-1 ,4-diazepany|)pyridiny|]su|fany|}
acetamide;
2-((3,5-dicyanocyclopropyImorphoIinopyridiny|)thio)(pyridin
yl)acetamide;
2-{[3,5-dicyanoethyI(4-methyIoxo pipe razin-1 -y|)pyridiny|]su|fa ny|}
(pyrid inyl)acetamide;
2-[(3,5-dicyanoethyI{methyl[2-(morpho|iny|)ethy|]amino}pyridin
y|)su|fany|]pheny|acetamide;
2-{[3,5-dicyanoethyI(4-propylpiperaziny|)pyridiny|]su|fany|}
phenylacetamide;
2-({3,5-dicyanoethyI[4-(piperidiny|)piperaziny|]pyridiny|}su|fany|)
phenylacetamide;
2-({3,5-dicyanocyclopropyI[3-(hydroxymethyl)piperaziny|]pyridin
fany|)phenylacetamide;
2-{[3,5-dicyanocyclopropyI(3-oxopiperaziny|)pyridinyl]su|fany|}
phenylacetamide;
2-({3,5-dicyanocyclopropyI[4-(morpholinyl)piperidiny|]pyridin
y|}suIfany|)pheny|acetamide;
2-((3,5-dicyanoethyI(2,8-diazaspiro[4.5]decany|)pyridiny|)thio)
phenylacetamide;
2-((3,5-DicyanocyclopropyI(3-(dimethylamino)piperidiny|)pyridiny|)thio)-
2-phenylacetamide;
2-((3,5-DicyanocyclopropyI(3-methylpiperaziny|)pyridiny|)thio)
phenylacetamide;
2-((3,5-DicyanocyclopropyI(2-(hydroxymethyl)morpholino)pyridiny|)thio)
phenylacetamide;
2-((3,5-DicyanocyclopropyI(2,6-dimethylmorpholino)pyridinyl)thio)
phenylacetamide;
-DicyanocyclopropyI(3-(dimethylamino)piperidiny|)pyridiny|)thio)-
ylacetamide;
2-((6-(4-(Aminomethy|)hydroxypiperidiny|)-3,5-dicyanocyclopropylpyridin-
2-y|)thio)pheny|acetamide;
2-((3,5-dicyanocyclopropyI(3-(methylamino)piperidiny|)pyridiny|)thio)
phenylacetamide;
2-((6-(3-aminopiperidiny|)-3,5-dicyanocyclopropylpyridinyl)thio)
phenylacetamide;
2-((3,5-dicyanocyclopropyI(dimethylamino)pyridiny|)thio)(pyridin
tamide;
2-((3,5-dicyano(dimethylamino)ethy|pyridiny|)thio)(pyridin
y|)acetamide;
2-((6-(4-aminopiperidiny|)-3,5-dicyanocyclopropylpyridinyl)thio)
phenylacetamide;
2-((3,5-dicyanocyclopropyI(4-(dimethylamino)piperidiny|)pyridiny|)thio)-
2-phenylacetamide;
2-((3,5-dicyanocyclopropyI(piperaziny|)pyridiny|)thio)(pyridin
y|)acetamide;
2-((3,5-dicyanocyclopropyI(1 ,4-diazepany|)pyridiny|)thio)(pyridin
y|)acetamide;
2-((3,5-dicyanocyclopropyI((R)hyd roxypiperidiny|)pyridinyl)thio)
phenylacetamide;
2-(3,5-dicyanocyclopropyI((S)hydroxypiperidiny|)pyridiny|thio)
phenylacetamide;
2-((3,5-dicyanocyclopropyI((S)hydroxypyrrolidiny|)pyridinyl)thio)
(pyrid iny|)acetamide;
2-((3,5-dicyanoethyI(4-ethylpiperaziny|)pyridiny|)thio)
phenylacetamide;
2-((3,5-DicyanoethyI(1 -oxaazaspiro [3 any|)pyridinyl)th io)
phenylacetamide;
2-((6-(4-(3-aminopropy|)piperaziny|)-3,5-dicyanoethylpyridinyl)thio)
phenylacetamide;
2-((3,5-Dicyano—4-ethyI(1,7-diazaspiro[3.5]nonany|)pyridiny|)thio)
phenylacetamide;
2-((3,5-DicyanocyclopropyI(4-(pyrrolidiny|methy|)piperidiny|)pyridin
y|)thio)pheny|acetamide;
2-((3,5-DicyanocyclopropyI(4-(4-methylpiperaziny|)piperidinyl)pyridin
y|)thio)pheny|acetamide;
(R)((3,5-dicyano(1,4-diazepany|)ethy|pyridin-Z-y|)amino)
phenylacetamide;
-DicyanocyclopropyI(4-(pyrrolidiny|)piperidiny|)pyridiny|)thio)-
2-phenylacetamide;
2-((3,5-DicyanoethyI(2,7-diazaspiro[3.5]nonany|)pyridin-Z-y|)thio)
phenylacetamide;
2-((3,5-DicyanoethyI(2,6-d iazaspiro[3.4]octany|)pyrid iny|)th io)
acetamide;
2-((3,5-dicyanocyclopropyI(1,4-diazepany|)pyridiny|)thio)propanamide;
2-((3,5-DicyanoethyI(4-(2-oxoimidazoIidiny|)piperidiny|)pyridin
y|)thio)pheny|acetamide;
2-((3,5-DicyanoethyI(4-hydroxypiperidiny|)pyridinyl)thio)
acetamide;
2-((3,5-DicyanoethyI((S)hydroxypyrrolidiny|)pyridiny|)thio)
phenylacetamide;
2-((3,5-DicyanoethyI(3-oxopiperaziny|)pyridiny|)thio)
phenylacetamide;
2-[(6-amino—3,5-dicyanocyclopropyIpyridy|)su|fany|]pheny|—acetamide;
2-((3,5-DicyanoethyI(methylamino)pyridinyl)thio)phenylacetamide;
2-((3,5-DicyanoethyI((2-meth y|)(methy|)amino)pyridinyl)thio)
phenylacetamide;
2-((3,5-DicyanoethyI(3-methoxyazetidiny|)pyridinyl)thio)
phenylacetamide;
2-((3,5-DicyanoethyI(piperaziny|)pyridinyl)thio)phenylacetamide;
2-((3,5-DicyanoethyI(4-methyI-1,4-diazepanyl)pyridin-2—y|)thio)
phenylacetamide;
2-((3,5-DicyanoethyImorpholinopyridiny|)thio)—2-phenylacetamide;
2-[[6-(azetidiny|)-3,5-dicyanoethyIpyridyl]suIfanyl]pheny|—acetamide;
2-((3,5-dicyanoethyI(4-oxopiperidiny|)pyridiny|)thio)phenylacetamide;
2-((3,5-dicyanoethyI(1 '-(2-hyd roxyethy|)-[4,4'-bipipe rid in]-1 -y|)pyridin
y|)thio)phenylacetamide;
2-((3,5-Dicyano((3S,5R)-3,5-dimethylpiperaziny|)ethy|pyridiny|)thio)
phenylacetamide;
2-((6-(8-azabicyclo[3.2.1]octany|(methy|)amino)-3,5-dicyanoethylpyridin
y|)thio)phenylacetamide;
2-((3,5-Dicyano-4—cyclopropyI(2-(hydroxymethy|)morpho|ino)pyridin-Z-y|)thio)
acetamide;
(R)((3,5-dicyano(dimethylamino)ethylpyridiny|)thio)pheny|acetamide;
(R)[(3,5-Dicyanoethylmorpholinopyridyl)sulfanyI]phenyI-acetamide;
-dicyanoethyI(5-methyI-1,4-diazepany|)pyridin-2—y|]su|fany|}
phenylacetamide;
2-({3,5-Dicyano-4—ethyI[4-(2-methoxyethyl)—1 ,4-diazepanyl]pyridin
y|}suIfany|)pheny|acetamide;
2-((3,5-dicyanoethyI(4-(2-hyd roxypropyI)-1 ,4-diazepany|)pyridiny|)thio)—
2-phenylacetamide;
Methyl 2-[4-(6-{[carbamoyl(pheny|)methyl]su|fany|}-3,5-dicyanoethylpyridin
y|)-1 ,4-diazepany|]acetate;
5-DicyanocyclopropyI(4-methyIoxo-1,4-diazepany|)pyridin
y|]su|fany|}phenylacetamide;
2-{[3,5-Dicyano-4—cyclo propyI(5-oxo-1 ,4-diazepany|)pyridiny|]su|fany|}
phenylacetamide;
2-{[3,5-Dicyano-4—ethyI(4-methyIoxo-1 ,4-diazepany|)pyridinyl]su|fany|}-
2-phenylacetamide;
2-{[3,5-Dicyano(1,4-diazepany|)ethylpyridin-2—yl]su|fany|}
phenylacetamide;
2-({3,5-Dicyano[4-(2-hydroxyethyl)-1,4-diazepany|](2,2,2-
trifluoroethyl)pyridiny|}su|fanyI)phenylacetamide;
(2R)({3,5-Dicyanoethyl[4-(2—hydroxyethy|)-1,4—diazepany|]pyridin
y|}amino)phenylacetamide;
2-({6-[(3S)Aminopyrro|idiny|]-3,5-dicyanocyclopropylpyridinyl}su|fany|)—
2-phenylacetamide;
2-((3,5-Dicyano-4—ethyI(2,9-diazaspiro[5.5]undecany|)pyridiny|)thio)
phenylacetamide;
2-((3,5-DicyanoethyI(hexahydro-1H-pyrrolo[1,2-a][1 ,4]diazepin-2(3H)—
y|)pyridiny|)thio)phenylacetamide;
-Dicyanoethyl(2-methyl—2,9-diazaspiro[5.5]undecanyl)pyridin
y|)thio)phenylacetamide;
2017/053511
2-((3,5-Dicyano(2—(cyclopropylmethyI)-2,9-diazaspiro[5.5]undecanyI)
ethylpyridiny|)thio)phenylacetamide;
2-((3,5-Dicyano(4-(3-(dimethylamino)propy|)piperaziny|)ethy|pyridin
y|)thio)pheny|acetamide;
2-((3,5-DicyanoethyI(4-(pyrroIidinyl)piperidiny|)pyridinyl)thio)-2—
phenylacetamide;
2-((6-([4,4'-Bipiperidin]—1-yl)-3,5-dicyanoethylpyridiny|)thio)
acetamide;
2-((6-(4-(2-Aminoethy|)piperaziny|)-3,5-dicyanoethylpyridin-Z-yl)thio)
phenylacetamide;
2-((6-(4-(3-Aminopropyl)piperaziny|)-3,5-dicyanocyclopropylpyridiny|)thio)-
2-phenylacetamide;
2-((3,5-DicyanocyclopropyI(4-((4-methylpiperaziny|)methy|)piperidin
y|)pyridiny|)thio)phenylacetamide;
2-((6-(4-Acetylpiperaziny|)-3,5-dicyanoethylpyridin-Z-yl)thio)
phenylacetamide;
2-((3,5-DicyanocyclopropyI(dimethylamino)pyridiny|)thio)
phenylacetamide;
2-(4-Ch|orophenyl)((3,5-dicyano(dimethylamino)ethy|pyridin
y|)thio)acetamide;
2-((3,5-Dicyano—4-ethyI(4-(2-hydroxyethy|)piperaziny|)pyridinyl)thio)
acetamide;
2-[(3,5-DicyanocyclopropyImorpholinopyridy|)su|fany|]phenyl-
acetamide;
2-((6-(4-Benzoy|piperaziny|)-3,5-dicyanoethylpyridinyl)thio)
phenylacetamide;
2-((3,5-DicyanoethyI((5S,6S)hydroxy(methy|su|fonyI)-1,8-
diazaspiro[4.5]decan-8—y|)pyridin-2—yl)thio)pheny|acetamide;
2-((3,5-Dicyano(4,4-difluoropiperidiny|)ethy|pyridinyl)thio)
phenylacetamide;
(R)((3,5-Dicyanoethyl—6-((R)hydroxypyrrolidiny|)pyridinyl)thio)
phenylacetamide;
2-((3,5-dicyano(fu ranyI)(4-methyI-1 ,4-diazepany|)pyridinyl)thio)
phenylacetamide;
2-((6-(4-Aminomethylpiperidiny|)-3,5-dicyanoethylpyridin-Z-yl)thio)
phenylacetamide;
2-Amino-N-(1-(6-((2-aminooxopheny|ethy|)thio)-3,5-dicyano—4-ethylpyridin
y|)piperidinyl)acetamide;
(28)Amino-N-(1-(6-((2-aminooxophenylethyl)thio)-3,5-dicyano-4—
ethylpyridiny|)piperidiny|)propanamide;
2-((6-(4-(3-Aminooxetanecarbony|)piperaziny|)-3,5-dicyanoethylpyridin
y|)thio)pheny|acetamide;
4-Amino-N-(1-(6-((2-aminooxopheny|ethy|)thio)-3,5-dicyano—4-ethylpyridin
y|)piperidinyl)tetrahydro-2H-pyrancarboxamide;
2-((6-(4-(4-Aminotetrahyd pyrancarbony|)piperaziny|)-3,5-dicyano
ethylpyridiny|)thio)phenylacetamide;
2-((3,5-Dicyano—6-(4-(2-hydroxyethy|)-1 ,4-diaze pa n-1 -y|)methoxypyridin
y|)thio)pheny|acetamide;
(4-Aminopiperidiny|)-3,5-dicyanoethylpyridinyl)thio)
phenylacetamide;
2-((6-((2-Aminoethy|)(methy|)amino)-3 ,5-dicyanoethylpyrid iny|)th io)-2—
phenylacetamide;
2-((6-((2-Aminooxoethyl)(methyl)amino)-3,5-dicyano—4-ethylpyridiny|)thio)
phenylacetamide;
2-((3,5-DicyanoethyI(3-hydroxyazetidiny|)pyridinyl)thio)
phenylacetamide;
2-(3,5-DicyanoethyI((2-hydroxyethyl)(methy|)amino)pyridinylthio)
phenylacetamide;
o-N-(1-(6-((2-aminooxophenylethyl)thio)-3,5-dicyano—4-ethylpyridin
y|)piperidiny|)methylpropanamide;
(4-(2-Aminoethoxy)piperidiny|)-3,5-dicyanoethylpyridinyl)thio)
phenylacetamide;
(2-Aminooxopheny|ethy|)thio)-3,5-dicyanoethylpyridinyl)pyrro|idin-
3-yl dihydrogen phosphate;
2-((6-((2-Aminooxopheny|ethyl)thio)-3,5-dicyanoethylpyridin
y|)(methy|)amino)ethy| dihydrogen phosphate;
1-(6-((2-Aminooxopheny|ethy|)thio)-3,5-dicyanoethylpyridinyl)azetidin-
3-yl dihydrogen phosphate;
(28)((1-(6-((2-Aminooxopheny|ethy|)thio)-3,5-dicyanoethylpyridin
y|)piperidiny|)oxy)ethy| 2-aminomethylbutanoate;
(6-((2-Aminooxopheny|ethy|)thio)-3,5-dicyanoethylpyridin
y|)piperidiny|)oxy)ethy| dihydrogen phosphate;
(2-Aminooxo-1 -pheny|ethy|)thio)-3,5-d icyanoethylpyrid inyl) pipe rid in-
4-y| dihydrogen phosphate;
2-((3,5-Dicyano(dimethylamino)ethylpyridiny|)thio)(piperidin
y|)acetamide;
2-((3,5-DicyanoethyI(4-(propylsu|fony|)piperaziny|)pyridinyl)thio)
phenylacetamide;
2-((3,5-DicyanoethyI(4-(phenylsulfony|)piperaziny|)pyridinyl)thio)
phenylacetamide;
2-((3,5-DicyanoethyI((R)hydroxypyrro|idiny|)pyridiny|)thio)
phenylacetamide;
2-((3,5-DicyanoethyI(2-oxaazaspiro [3 .4]octany|)pyridinyl)th io)
phenylacetamide;
(R)((3,5-Dicyanoethyl(4-ethyI-1 ,4-diazepany|)pyridiny|)amino)
phenylacetamide;
(R)((3,5-Dicyanoethyl(4-(3-(pyrrolidiny|)propy|)-1,4-diazepan
y|)pyridiny|)amino)phenylacetamide;
2-(3,5-DicyanocyclopropyI(3-hydroxypiperidiny|)pyridiny|thio)
phenylacetamide;
2-((3,5-DichIoroethyI(4-methyI-1 ,4-diazepanyl) pyridiny|)thio)
phenylacetamide;
2-((3,5-Dicyano(1,1-dioxidothiomorpholino)ethylpyridinyl)thio)
phenylacetamide;
2-((3,5-DicyanoethyI(methy|(2-(piperaziny|)ethy|)amino)pyridiny|)thio)-
2-phenylacetamide;
(R)((3,5-Dicyanoethyl((S)hyd roxypyrrolidiny|)pyridinyl)thio)—2-
phenylacetamide;
2-((6-((2-(4-(AminomethyI)hydroxypiperidiny|)ethy|)(methy|)amino)-3,5-
dicyanoethylpyridiny|)thio)phenylacetamide;
2-((4-Cyano(1 ,4-diazepany|)-6,7-dihydro-5H-cyclopenta[c]pyridiny|)thio)
phenylacetamide;
2-((6-(4-(1H-ImidazoIy|)piperidiny|)-3,5-dicyanoethylpyridinyl)thio)
phenylacetamide;
2-((3,5-DicyanoethyI(4-(pyridinylmethyl)piperaziny|)pyridiny|)thio)
phenylacetamide;
-Dicyano(2-(dimethylamino)ethoxy)ethy|pyridiny|)thio)
phenylacetamide;
2-((1-(6-((2-Aminooxopheny|ethy|)thio)-3,5-dicyanocyclopropylpyridin
eridinyl)amino)acetic acid;
2-((3,5-DicyanoethyI(4-(oxazolylmethyl)piperaziny|)pyridinyl)thio)
phenylacetamide;
(4-((1H-PyrroI-Z-yl) methyl) piperaziny|)-3,5-dicyanoethylpyridin
y|)thio)pheny|acetamide;
2-((3,5-Dicyano(3,4-dihydro-2,7-naphthyridin-2 (1 H)-y|)ethy|pyridin-2—y|)thio)-
2-phenylacetamide;
2-((3,5-DicyanoethyI((S)hydroxypyrrolidiny|)pyridiny|)thio)(pyridin-
3-y|)acetamide;
2-((6-(4-((1H-PyrroIyl)methy|)piperaziny|)-3,5-dicyanoethylpyridin
y|)thio)pheny|acetamide;
2-((3,5-DicyanoethyI(4-(isoxazo|y|methy|)piperazinyl)pyridiny|)thio)-
2-phenylacetamide;
2-((3,5-DicyanoethyI(4-(oxazolylmethyl)piperaziny|)pyridinyl)thio)
phenylacetamide;
2-((3,5-DicyanoethyI(4-(isoxazo|y|methy|)piperazinyl)pyridiny|)thio)-
2-phenylacetamide;
3-Amino-N-(1-(6-((2-aminooxopheny|ethy|)thio)-3,5-dicyano—4-ethylpyridin
y|)piperidinyl)oxetanecarboxamide;
2-((6-(4-((1H-PyrazoIyl)methyl)piperaziny|)-3,5-dicyanoethylpyridin
y|)thio)pheny|acetamide;
2-((6-(4-((1H-|midazoIy|)methy|)piperaziny|)-3,5-dicyanoethylpyridin
y|)thio)pheny|acetamide;
2-((3,5-DicyanoethyI(4-(1-hydroxymethy|propanyl)piperazin
y|)pyridiny|)thio)phenylacetamide;
2-((6-(4-((1H-|midazoIy|)methyl)piperaziny|)-3,5-dicyanoethylpyridin
y|)thio)pheny|acetamide;
2-((3,5-Dicyano(dimethylamino)methoxypyridinyl)thio)phenylacetamide;
-Dicyano(dimethylamino)-4—ethoxypyridiny|)thio)phenylacetamide;
2-((3,5-Dicyanoethoxy(4-(2-hydroxyethy|)-1 zepanyl) pyridin
y|)thio)pheny|acetamide;
2-((3,5-DicyanoethyI(4-(2-hydroxymethylpropyI)-1 ,4-diazepany|)pyridin-
2-y|)thio)pheny|acetamide;
2-((3,5-DicyanoethyI(4-(thiazolylmethyl)piperaziny|)pyridinyl)thio)
acetamide;
2-((3,5-DicyanoethyI(piperaziny|)pyridiny|)thio)(4-
fluorophenyl)acetamide;
2-((3,5-DicyanoethyI(4-(isothiazoIylmethyl)piperaziny|)pyridiny|)thio)-
2-phenylacetamide;
2-((3,5-Dicyano(dimethylamino)-4—ethylpyrid iny|)thio)(4-
fluorophenyl)acetamide;
2-((3,5-Dicyano(dimethylamino)-4—ethy|pyridiny|)thio) (5-fluoropyridin
y|)acetamide;
2-((3,5-DicyanoethyI(4-(furanylmethy|)piperaziny|)pyridinyl)thio)
phenylacetamide;
2-((3,5-DicyanoethyI((2-mo rpholinoethyl)th io)pyridinyl)th io)
phenylacetamide;
2-((3,5-Dicyano(4-methyI-1 ,4-diazepany|)(methy|thio)pyridiny|)thio)
phenylacetamide;
2-((3,5-DichIoroethyI(4-(2-hydroxyethy|)-1 ,4-diazepany|)pyridiny|)thio)-
2-phenylacetamide;
2-((3,5-DicyanoethyI(hexahydropyrro|o[3,4-b][1,4]oxazin-6(2H)-y|)pyridin
y|)thio)pheny|acetamide;
-DicyanoethyI(4-methyI-1 ,4-diazepanyl)pyridiny|)thio)(5-
methylpyridiny|)acetamide;
2-((3,5-DicyanoethyI(4-methyI-1 ,4-diazepanyl)pyridiny|)thio)(6-
fluoropyridinyl)acetamide;
2-((3,5-Dicyano(4-(dimethylamino)piperidiny|)ethy|pyridiny|)thio)(4-
fluorophenyl)acetamide;
2-((3,5-DicyanoethyI(4-methyI-1,4-diazepanyl) pyridin-Z-yl) thio)(4-
methylpyridin-Z-yl) acetamide;
2-((3,5-DicyanoethyI(4-methyI-1 ,4-diazepanyl)pyridiny|)thio)(3-
ypyridiny|)acetamide;
2-((3,5-Dicyano(4-(dimethylamino)piperidiny|)ethy|pyridinyl)thio)(2,4-
difluoropheny|)acetamide;
2-((3,5-DicyanoethyI(4-(pyrrolidin-1 -y|)pipe rid in-1 -y|)pyridiny|)thio)(5-
fluoropyridinyl)acetamide;
2-((3,5-Dicyanoethoxy(4-(2-hyd hyI)-1 ,4-diazepany|)pyridin
o)propanamide;
2-((3,5-Dicyano(4-(2-hydroxyethy|)-1 ,4-diazepany|)propoxypyridin
y|)thio)pheny|acetamide;
WO 16727
2-((3,5-DicyanoethyI(4-methyI-1 ,4-diazepanyl)pyridiny|)thio)(4-
methoxypyridiny|)acetamide;
2-((3,5-DicyanoethyI(2-methyI-2,8—diazaspiro[4.5]decany|)pyridin
y|)thio)pheny|acetamide;
-Dicyano(4-(dimethylamino)piperidiny|)ethy|pyridinyl)thio)(3,4-
difluoropheny|)acetamide;
1-(6-((2-Aminooxopheny|ethy|)thio)-3,5-dicyanoethylpyridin
y|)piperidinecarboxamide;
2-((3,5-Dicyano((2-(dimethylamino)ethyl)thio)ethy|pyridiny|)thio)
phenylacetamide;
2-((3,5-Dicyano((3S,4R)-3,4-dihydroxypyrrolidinyI)ethylpyridinyl)thio)
phenylacetamide;
2-((3,5-DicyanoethyI(4-methyI-1 ,4-diazepanyl)pyridiny|)thio)(3-
fluoropyridin-Z-yl) acetamide;
2-((3,5-DicyanoethyI(4-methyI-1 ,4-diazepanyl)pyridiny|)thio)(5-
meth oxypyrid iny|)acetamide;
2-((3,5-DicyanoethyI(4-(1-hydroxymethy|propanyl)piperazin
yI)pyridiny|)thio)(4-f|uorophenyl)acetamide;
2-((3,5-DicyanoethyI(4-methyI-1 ,4-diazepanyl)pyridiny|)thio)(3-
(trifluoromethyl)pheny|)acetamide;
2-((3,5-DicyanoethyI(4-(2-hydroxyethoxy)piperidiny|)pyridinyl)thio)
phenylacetamide;
2-((3,5-DicyanoethyI(4-methyI-1 ,4-diazepanyl) pyridin-Z-yl)thio)(2-
fluoropyridinyl)acetamide;
2-((3,5-DicyanoethyI(4-methyI-1 ,4-diazepanyl) n-Z-yl)thio)(6-
fluoropyridinyl)acetamide;
3-((6-(2-Aminooxopheny|ethy|thio)-3,5-dicyanoethylpyridin
thy|)amino)propanamide;
2-((3,5-DicyanoethyI(4-(oxetanyloxy)piperidiny|)pyridiny|)thio)
phenylacetamide;
2-((3,5-Dicyano(4-((2,2-difluoroethyl) methy|piperidiny|)
yridin-Z-yl) thio)phenylacetamide;
2-((3,5-DicyanoethyI(4-methyI-1 ,4-diazepanyl)pyridiny|)thio)(4-
(trifluoromethyl)pheny|)acetamide;
2-((6-(4-Aminopiperaziny|)-3,5-dicyanoethylpyridin-Z-yl)thio)
phenylacetamide;
2-((6-((2-Aminooxoethy|)th io)-3,5-dicyanoethylpyridinyl)th io)
phenylacetamide;
2-((3,5-DicyanoethyI(pyrro|o[3,4-c]pyrazoI-5(1H,4H,6H)-yl)pyridiny|)thio)-
2-phenylacetamide;
2-((3,5-Dicyano(dimethylamino)-4—ethylpyridiny|)thio)(5-methoxypyridin
y|)acetamide;
2-((3,5-Dicyano(dimethylamino)ethy|pyridiny|)thio)(5-methy|pyridin
y|)acetamide;
2-((3,5-DicyanoethyI(4-methyI-1 zepanyl)pyridiny|)thio)(2-
fluoropyridinyl)acetamide;
2-((3,5-Dicyano—4-ethyI(4-hyd roxy(hyd roxymethyl) pipe ridin-1 -y|)pyridin
y|)thio)pheny|acetamide;
2-((3,5-DicyanoethyI(2-oxooxa-1 ,8—diazaspiro[4.5]decan-8—y|)pyridin
y|)thio)pheny|acetamide;
2-((6-(4-Amino(hyd roxymethy|)pipe rid in-1 -y|)-3 ,5-dicyanoethylpyrid in
o)pheny|acetamide;
2-((6-(4-(Aminomethy|)hydroxypiperidiny|)-3,5-dicyanoethylpyridin
y|)thio)pheny|acetamide;
2-(3-BenzoylphenyI)((3,5-dicyanoethyI(4-(2-hydroxyethy|)-1,4-diazepan
y|)pyridiny|)thio)acetamide;
2-(4-BenzoylphenyI)((3,5-dicyanoethyI(4-(2-hydroxyethy|)-1,4-diazepan
y|)pyridiny|)thio)acetamide;
2-((3,5-DicyanoethyI(4-methyI-1 ,4-diazepanyl)pyridiny|)thio)(2-
methylpyridiny|)acetamide;
2-((3,5-DicyanoethyI(4-methyI-1 ,4-diazepanyl)pyridiny|)thio)(3-
(pyrrolidiny|)pheny|)acetamide;
2-((3,5-DicyanoethyI(4-methyI-1 ,4-diazepanyl)pyridiny|)thio)(3-
fluoropyridinyl)acetamide;
2-((3,5-DicyanoethyI(4-methyI-1,4-diazepanyl)pyridiny|)thio)(2,5-
ropyridiny|)acetamide;
2-((3,5-Dicyano(4-(2,5-dioxoimidazolidiny|)piperidiny|)ethy|pyridin
y|)thio)pheny|acetamide;
4-Amino(6-((2-aminooxopheny|ethy|) thio)-3, 5-dicyanoethylpyridinyl)
piperidinecarboxamide;
2-((3,5-Dicyano(4-(2,5-dioxopyrrolidinyl)piperidiny|)ethy|pyridin
o)pheny|acetamide;
2-((3,5-dicyanoethyI(4-methyI-1 ,4-diazepany|)pyridin-2—yl)thio)
phenylacetamide (isomer 1);
5-dicyanoethyI(4-methyI-1 ,4-diazepany|)pyridin-2—yl)thio)
phenylacetamide (Isomer 2) ;
2-((3,5-DicyanoethyI(2-oxooxa-3,8-diazaspiro[4.5]decan-8—y|)pyridin
y|)thio)pheny|acetamide;
1-(6-((2-Aminooxopheny|ethy|)thio)-3,5-dicyanoethylpyridinyI)
hydroxy piperidinecarboxamide;
1-(6-((2-Aminooxopheny|ethy|)thio)-3,5-dicyanoethylpyridinyl)azetidin-
3-yl carbamate;
2-((3,5-Dicyano(4-(2,4-dioxooxazolidiny|)piperidiny|)ethy|pyridin
y|)thio)pheny|acetamide;
3-((6-((2-Aminooxopheny|ethyl)thio)-3,5-dicyanoethylpyridin
yI)(methy|)amino)hydroxymethylpropanamide;
-DicyanoethyI(3-(hyd roxymethy|)azetidiny|)pyridinyl)thio)
phenylacetamide;
2-(3,5-DicyanoethyI(piperaziny|)pyridinylthio)(thiophen
y|)acetamide;
2-((3,5-DicyanoethyI(4-methyI-1,4-diazepanyl) pyridin-Z-yl) thio)(5-
methylpyridin-B-yl) acetamide;
2-((6-(4-(3-Aminooxopyrrolidiny|)piperidiny|)-3,5-dicyano—4-ethylpyridin
y|)thio)pheny|acetamide;
1-(6-((2-Aminooxo-1 -pheny|ethy|)thio)-3,5-d icyanoethylpyrid inyl) pipe rid in-
4-y| (28)aminomethylbutanoate;
2-((6-((2-Aminooxophenylethyl)thio)-3,5-dicyanoethylpyridinyl) (methyl)
amino)ethy| (28)aminomethylbutanoate;
2,2'-((3,5-Dicyanoethylpyridine-2,6-diy|)bis(suIfanediy|))bis(2-pheny|acetamide);
(28)-(1-(6-((2-Aminooxophenylethy|)thio)-3,5-dicyano-4 —ethy| pyridin
y|)azetidiny|)methy| 2-aminomethylbutanoate;
2-((6-(3-Aminoazetidiny|)-3,5-dicyanoethylpyridiny|)thio)
acetamide;
2-((3,5-DicyanoethyImethylpyridinyl)thio)phenylacetamide;
N-(1-(6-((2-Aminooxopheny|ethy|)thio)-3,5-dicyanoethylpyridin
y|)piperidinyl)—2-hydroxyacetamide;
6-((2-Aminooxopheny|ethy|)thio)-3,5-dicyanoethylpyridin
y|)azetidinyI)hyd roxyacetamide;
2-((3-CyanoethyImethyI(piperaziny|)pyridiny|)thio)
phenylacetamide;
-DicyanoethyI(5-methyI-2,5-diazabicyclo[2.2.1]heptan-Z-y|)pyridin
y|)thio)pheny|acetamide;
2-((3,5-DicyanoethyI(4-(2-(pyrrolidiny|)ethy|)piperaziny|)pyridin
o)pheny|acetamide;
2-((3,5-Dicyano(dimethylamino)-4—ethy|pyridiny|)thio)phenylacetamide
(R)((3,5-Dicyano(dimethylamino)ethy|pyridiny|)thio)
phenylacetamide-Z-d;
2-((6-(4-(4-Bromobenzoyl)piperaziny|)-3,5-dicyanoethylpyridinyl)thio)
phenylacetamide;
2-((3,5-DicyanoethyI(4-(2-hydroxyethy|)-1 ,4-diazepanyl)pyridiny|)thio)-
2-phenylacetamide;
2-((3,5-Dicyano(4-cyanopiperidiny|)ethy|pyridinyl)thio)
phenylacetamide;
(S)—2-((3,5-Dicyanoethyl—6-((S)hyd roxypyrrolidiny|)pyridiny|)thio)
phenylacetamide;
(4-AminomethylpiperidinyI)-3,5-dicyanocyclopropylpyridin-Z-y|)thio)-
2-phenylacetamide;
2-((3,5-DicyanoethyI((S)hydroxypyrrolidiny|)pyridiny|)thio)(pyridin-
2-y|)acetamide;
2-((3,5-DichIoroethyI(piperaziny|)pyridiny|)thio)phenylacetamide;
utyl (1-(6-((2-aminooxopheny|ethy|)thio)—3,5-dicyanoethylpyridin
y|)piperidiny|)carbamate;
2-((6-(3-(2-Aminooxoethyl)azetidiny|)-3,5-dicyanoethylpyridiny|)thio)
phenylacetamide;
(2R)(6-((2-Aminooxophenylethy|)thio)-3,5-dicyanoethylpyridin
y|)azetidiny| omethylbutanoate;
2-((3,5-DicyanoethyI(methy|((5-oxo-4,5-dihydro-1H-1 ,2,4-triazo|—3-
y|)methy|)amino)pyridiny|)thio)pheny|acetamide;
2-((6-(((4H-1 ,2,4-TriazoIyl)methyl)(methy|)amino)-3,5-dicyanoethylpyridin
y|)thio)phenylacetamide;
2-((3,5-Dicyanoethoxy-6—methylpyridiny|)thio)phenylacetamide;
2-((3,5-Dicyano-4,6-diethylpyridin-Z-y|)thio)phenylacetamide;
2-((6-((2-(4H-1,2,4-Triazo|—4-y|)ethy|)(methy|)amino)—3,5-dicyanoethylpyridin-Z-yl)thio)-
2-phenylacetamide;
2-((6-(((1H-Pyrazolyl)methy|)(methyl)amino)-3,5-dicyanoethylpyridin
y|)thio)phenylacetamide;
2-((3,5-Dicyano(6,7-dihydro-1H-[1,2,3]triazolo[4,5-c]pyridin-5(4H)-y|)—4-
ethylpyridiny|)thio)phenylacetamide;
(((1H-ImidazoIyl)methy|)(methy|)amino)-3,5-dicyanoethylpyridin
y|)thio)pheny|acetamide;
2-((6-(((1H-ImidazoIyl)methy|)(methy|)amino)-3,5-dicyanoethylpyridin
y|)thio)pheny|acetamide;
(2R)Amino-N-(1-(6-((2-aminooxo—1-phenylethyl)thio)-3,5-dicyano
ethylpyridiny|)piperidiny|)propanamide;
mino((3,5-dicyanoethyI(4-methyI-1,4-diazepany|)pyridin
y|)thio)oxoethy|)benzamide;
2-((3,5-DicyanocyclopropyI(3-hydroxypyrrolidiny|)pyridinyl)thio)-2—
phenylacetamide;
2-((3,5-DicyanoethyI(3-hydroxypyrrolidiny|)pyridiny|)thio)
phenylacetamide;
(2R)Amino-N-(1-(6-((2-aminooxo—1-phenylethyl)thio)-3,5-dicyano
cyclopropyl pyridiny|)piperidin-4—yl)propanamide;
2-((6-((2-Aminoethy|)(methy|)amino)-3,5-dicyanocyclopropylpyridin-2—yl)thio)
acetamide;
2-Amino-N-(1-(6-((2-aminooxopheny|ethy|) thio)-3,5-d icyano
cyclopropylpyridiny|)piperidiny|)methy|propanamide;
4-(2-Amino((3,5-dicyano(dimethylamino)ethylpyridinyl)thio)
oxoethyl)benzamide;
2-(6-(4-Aminopiperidiny|)cyanoethyImethylpyridinylthio)
phenylacetamide;
2-((3,5-DicyanoethyI(4-methyI-1,4-diazepanyl)pyridiny|)thio)(4-(N-
methylsulfamoyl)phenyl)acetamide;
2-((3,5-DicyanoethyI(6-fluoro-1,4-diazepany|)pyridiny|)thio)
phenylacetamide;
2-((6-(4-Amino-3,3-difluoropiperidiny|)-3,5-dicyanoethylpyridinyl)thio)
phenylacetamide;
tert—Butyl (1-(6-((2-aminooxopheny|ethy|) thio)-3,5-dicyanoethylpyridin
yI)-3,3-diquoropiperidin-4—yl) carbamate;
2017/053511
2-((3,5-DicyanocyclopropyI((2-hyd roxyethyl)(methy|)amino)pyridiny|)thio)-
2-phenylacetamide;
2-((3,5-DicyanocyclopropyI(3-hydroxyazetidiny|)pyridiny|)thio)
phenylacetamide;
1-(6-((2-Aminooxopheny|ethy|)thio)-3,5-dicyanoethylpyridin
y|)pyrro|idinecarboxamide;
2-((6-((3-Aminopropy|) l) amino)-3, 5-dicyanocyclopropylpyridinyl)
thio)phenylacetamide;
2-((3,5-DicyanocyclopropyI((2-(3-hyd roxyazetidinyI)
oxoethyl)(methyl)amino) ny|)thio)phenylacetamide;
2-((6-(4-((2-Aminooxoethy|)amino)piperidiny|)-3,5-dicyanoethylpyridin
y|)thio)pheny|acetamide;
2-((6-((2-Aminooxoethyl)(methyl)amino)-3,5-dicyanocyclopropylpyridin
y|)thio)pheny|acetamide;
2-((6-((2-Aminooxopheny|ethyl) thio)-3, 5-dicyanocyclopropylpyridin
y|)(methy|)amino)ethy| carbamate;
(2R)Amino-N-(1-(6-((2-aminooxo—1-phenylethyl)thio)-3,5-dicyano
ethylpyridiny|)piperidinyI)hydroxypropanamide;
(28)Amino-N-(1-(6-((2-aminooxopheny|ethy|) thio)—3, 5-dicyano
ethylpyridin-Z-yl) piperidiny|)hydroxypropanamide;
2-(4-(2-Aminooxoethyl)phenyI)(3,5-dicyanoethyI(4-methyl-1 ,4-
diazepany|)pyridinylthio)acetamide;
2-(4-(2-Aminooxoethyl)pheny|)(3,5-dicyano(dimethylamino)ethy|pyridin-
2-ylthio)acetamide;
2-((3,5-Dicyano(dimethylamino)ethy|pyridiny|)thio)(4-(N-
methylsulfamoyl)phenyl)acetamide;
-Dicyano(dimethylamino-d6)ethylpyridiny|)thio)-2—phenylacetamide;
(R)((3,5-Dicya noethyl—6—(4-(pyrrolidiny|)piperidiny|)pyridinyl)thio)
phenylacetamide;
(R)((3,5-Dicyano(4-(dimethylamino)piperidinyI)ethylpyridiny|)thio)
phenylacetamide;
-dicyano(dimethylamino)ethy|pyridinylthio)(3-(2-
(dimethylamino)ethoxy)pheny|)acetamide;
2-((3,5-DicyanoethyI(4-(neopentylamino)piperidiny|)pyridiny|)thio)(4-
fluorophenyl)acetamide;
2-((3,5-dicyanoethyI(3-fluoroA(neopentylamino)piperidiny|)pyridin
y|)thio)pheny|acetamide;
2-((6-(4-aminopiperidinyI)-3,5-dicyanoethylpyridiny|)thio)(4-
(trifluoromethyl)pheny|)acetamide;
2-((3,5-DicyanoethyI(4-(pyrroIidiny|)piperidiny|)pyridinyl)thio)
phenylacetamide;
(R)((6-(4-aminopiperidiny|)-3,5-dicyanoethylpyridinyl)thio)
phenylacetamide;
2-((6-((2-aminooxoethy|)(methy|)amino)-3,5-dicyanoethylpyridiny|)thio)
phenylacetamide; (single omer)
(38)(6-((2-aminooxopheny|ethy|) thio)-3, 5-dicyanoethylpyridinyl)
idinyl dihydrogen phosphate;
(3R)(6-((2-aminooxopheny|ethy|)thio)-3,5-dicyanoethylpyridin
y|)pyrrolidiny| dihydrogen phosphate;
(S)(6-(((S)aminooxopheny|ethy|)thio)-3,5-dicyanoethylpyridin
y|)pyrrolidiny| dihydrogen phosphate;
(S)(6-(((R)aminooxopheny|ethy|) thio)-3,5-dicyanoethylpyridinyl)
pyrrolidinyl dihydrogen phosphate;
2-((3,5-Dicyano(dimethylamino)ethylpyridiny|)thio)(3-
(dimethylphosphory|)pheny|)acetamide;
2-((3,5-DicyanoethyI((S)hydroxypyrrolidiny|)pyridiny|)thio)(3-(
ylphosphory|)phenyl)acetamide;
(R)((6-((2-aminooxopheny|ethy|)thio)-3,5-dicyanoethylpyridin
y|)(methy|)amino)ethy| dihydrogen phosphate;
(R)((3,5-dicyanoethyI((S)hydroxypyrrolidiny|)pyridin-Z-yl)thio)(4-
methoxyphenyl)acetamide;
(R)(4-chIorophenyI)((3,5-dicyanoethyI((S)hydroxypyrrolidin
y|)pyridiny|)thio)acetamide;
(R)((3,5-dicyanoethyI((S)hydroxypyrrolidiny|)pyridin-Z-yl)thio)(4-
fluoro pheny|)acetamide;
(S)(6-(((R)amino(4-f|uorophenyI)oxoethy|)thio)-3,5-dicyano
ethylpyridiny|)pyrro|idiny| dihydrogen phosphate;
2-((3, 5-dicyanoethyI((S)hydroxypyrrolidiny|) pyridinyl) thio)(4-
henyl) acetamide;
2-((3,5-dicyanoethyI((S)hydroxypyrro|idinyl) pyridinyl) thio)(2, 6-
difluorophenyl) ide;
2-((3, anoethyI((S)hydroxypyrrolidiny|) pyridinyl) thio)(2, 3-
difluorophenyl) acetamide;
2-((3, 5-dicyanoethyI((S)hydroxypyrrolidiny|) pyridinyl) thio)(2, 4-
difluorophenyl) ide;
2-((3,5-dicyanoethyI(4-((S)(hydroxymethy|)pyrrolidiny|)piperidin
y|)pyridiny|)thio)phenylacetamide;
2-((3,5-dicyanoethyI(4-((2-hydroxyethy|)(methy|)amino)piperidiny|)pyridin-
2-y|)thio)pheny|acetamide;
2-((3,5-dicyanoethyI(4-((2-hydroxymethylpropyl)(methyl)amino)piperidin
y|)pyridiny|)thio)phenylacetamide;
2-((3,5-dicyanoethyI(4-(pyrroIidiny|methy|)piperidinyl)pyridiny|)thio)-
2-phenylacetamide;
2-((3,5-dicyanoethyI(4-((2-methoxymethylpropy|)amino)piperidin
y|)pyridiny|)thio)phenylacetamide;
2-((3,5-dicyanoethyI(4-((2-hydroxymethylpropy|)amino)piperidin
y|)pyridiny|)thio)phenylacetamide;
2-((3,5-dicyano(4-(cyclobutylamino)piperidiny|)ethy|pyridinyl)thio)
phenylacetamide;
2-((3,5-dicyanoethyI(4-(((3-methyloxetanyl)methy|)amino)piperidin
y|)pyridiny|)thio)phenylacetamide;
2-((3,5-dicyanoethyI(4-(4-methylpiperaziny|)piperidiny|)pyridin
y|)thio)pheny|acetamide;
2-((3,5-dicyanoethyI(4-((R)methy|pyrrolidiny|)piperidiny|)pyridin
y|)thio)pheny|acetamide;
2-((3,5-dicyano(4-((2R,5S)-2,5-dimethylpyrrolidiny|)piperidiny|)
ethylpyridiny|)thio)phenylacetamide;
2-((3,5-dicyanoethyI(4-((S)methy|pyrro|idiny|)piperidiny|)pyridin
o)pheny|acetamide;
2-((3,5-dicyan0(4-(cyclobutyl(methy|)amino)piperidiny|)ethy|pyridin
y|)thio)pheny|acetamide;
2-(6-(4-(benzylamino)piperidiny|)-3,5-dicyanoethylpyridinylthio)—2-
phenylacetamide;
5-dicyanoethy|(4-(((6-methoxypyridinyl)methy|)amino)piperidin
y|)pyridiny|)thio)phenylacetamide;
2-((3,5-dicyanoethyI(4-((S)fluoropyrrolidiny|)piperidiny|)pyridin
y|)thio)pheny|acetamide;
2-((3,5-dicyanoethyI(methyl(2-((R)methy|pyrro|idin
y|)ethy|)amino)pyrid iny|)th io)pheny|acetamide;
2-((3,5-dicyanoethyI(4-((R)fluoropyrrolidinyl)piperidiny|)pyridin
y|)thio)pheny|acetamide;
2-((3,5-dicyano(4-((ZS,5S)-2,5-dimethylpyrrolidiny|)piperidiny|)
ethylpyridiny|)thio)phenylacetamide;
2-((3,5-dicyanoethyI(methy|(2-((S)methy|pyrro|idin
y|)ethy|)amino)pyrid iny|)th io)pheny|acetamide;
-dicyanoethyI(4-((R)(hydroxymethy|)pyrrolidiny|)piperidin
y|)pyridiny|)thio)phenylacetamide;
2-((3,5-dicyano(4-(dimethylamino)piperidiny|)ethy|pyridinyl)thio)(4-
fluorophenyl)acetamide;
2-((3,5-dicyanoethyI(4-(((1-methy|cyc|obuty|)methy|)amino)piperidin
y|)pyridiny|)thio)phenylacetamide;
-dicyanoethy|(4-(((6-methoxypyridinyl)methyl)amino)piperidin
idiny|)thio)phenylacetamide;
2-(3,5-dicyanoethyI((2-(ethylamino)ethy|)(methyl)amino)pyridinylthio)
phenylacetamide;
2-((3,5-dicyanoethyI(4-((4-methy|piperaziny|)methy|)piperidiny|)pyridin-
2-y|)thio)pheny|acetamide;
2-((3,5-dicyanoethyI(methy|(2-(methy|amino)ethy|)amino)pyridiny|)thio)
phenylacetamide;
2-((3,5-dicyano(4-((2R,5R)—2,5-dimethylpyrrolidiny|)piperidinyI)
yridiny|)thio)phenylacetamide;
2-((3,5-dicyanoethyI(4-(((1-methy|cyc|opropy|)methy|)amino)piperidin
y|)pyridiny|)thio)phenylacetamide;
2-((3,5-dicyanoethyI(4-((4-fluorobenzy|)amino)piperidiny|)pyridiny|)thio)-
2-phenylacetamide;
2-((3,5-dicyanoethyI((2-((S)(hyd roxymethy|)pyrro|idin
y|)ethy|)(methy|)amino)pyridiny|)thio)pheny|acetamide;
2-(3,5-dicyano((2—((ZS,5R)-2,5-dimethylpyrrolidiny|)ethyl)(methyl)amino)
ethylpyridinylthio)phenylacetamide;
2-((6-((2-(azepany|)ethyl)(methy|)amino)-3,5-dicyanoethylpyridiny|)thio)
phenylacetamide;
2-((3,5-dicyanoethyI(methy|(2-(pipe rid in-1 -y|)ethy|)amino)pyrid iny|)thio)
phenylacetamide;
2-((3,5-dicyanoethy|((2-((R)(hydroxymethy|)pyrro|idin
y|)ethy|)(methy|)amino)pyridiny|)thio)phenylacetamide;
2-(3,5-dicyanoethyI((2-(ethy|(methy|)amino)ethyl)(methy|)amino)pyridin
ylthio)-2—phenylacetamide;
2-((3,5-dicyano((2-((2R,5R)-2,5-dimethylpyrrolidiny|)ethyl)(methy|)amino)-4—
ethylpyridiny|)thio)phenylacetamide;
2-(3,5-dicyanoethyI((2-((S)hydroxypyrrolidin
y|)ethy|)(methy|)amino)pyridinylthio)phenylacetamide;
methyl 2-((1-(6-((2-aminooxopheny|ethy|)thio)-3,5-dicyano—4-ethylpyridin
y|)piperidinyl)amino)-2—methy|propanoate;
2-((3,5-dicyanoethyI(methy|(2-(neopentylamino)ethy|)amino)pyridin
o)pheny|acetamide;
2-(3,5-dicyanoethyI(methy|(2-(1-methy|cyc|opropylamino)ethy|)amino)pyridin-
2-ylthio)—2-pheny|acetamide;
2-((3,5-dicyano((2-((ZS,58)-2,5-dimethylpyrrolidiny|)ethy|)(methy|)amino)
ethylpyridiny|)thio)phenylacetamide;
2-((3,5-dicyanoethyI((2-((2-methoxyethy|)amino)ethy|)(methy|)amino)pyridin-
2-y|)thio)pheny|acetamide;
2-((3,5-dicyanoethyI(4-((2-methoxymethylpropyl)(methy|)amino)piperidin-
yrid inyl)th io)pheny|acetamide;
2-((3,5-dicyano((2-(dimethylamino)ethy|)(methy|)amino)ethy|pyridin
y|)thio)pheny|acetamide;
2-(3,5-dicyanoethyI((2-((R)hyd roxypyrrolidin
y|)ethy|)(methy|)amino)pyridinylthio)phenylacetamide;
2-((3,5-dicyanoethyI((2-((2-fluoroethy|)amino)ethy|)(methyl)amino)pyridin-2—
y|)thio)pheny|acetamide;
2-((3,5-dicyano(4-(3,3-difluoropyrrolidiny|)piperidiny|)ethy|pyridin
y|)thio)pheny|acetamide;
2-((1-(6-((2-aminooxopheny|ethy|)thio)-3,5-dicyanoethylpyridin
y|)piperidinyl)amino)acetic acid;
((3-aminocyclobutyl)(methyl)amino)-3,5-dicyanoethylpyridin-Z-y|)thio)
phenylacetamide;
(R)(3,5-dicyanoethyI(methyl((R)-tetrahyd rofurany|)amino)pyridin
ylthio)-2—phenylacetamide;
(S)(3,5-dicyanoethyI(methyl((R)-tetrahydrofu rany|)amino)pyridin
ylthio)-2—phenylacetamide;
WO 16727
2-((3,5-dicyano—4-ethyI(4-morpholinopiperidiny|)pyridiny|)thio)
phenylacetamide;
2-((3,5-dicyanoethyI(4-(2-hydroxyethyI)oxopiperaziny|)pyridiny|)thio)-
2-phenylacetamide;
2-((3,5-dicyanoethyI(4-(pyrroIidiny|)piperidiny|)pyridiny|)thio)—2-(4-
fluorophenyl)acetamide;
(R)((6-((3S,4R)aminofluoropiperidiny|)-3,5-dicyanoethylpyridin
y|)thio)pheny|acetamide;
2-((3,5-dicyanoethyI(3-fluoro(methylamino)piperidiny|)pyridiny|)thio)-
2-phenylacetamide;
((6-(trans)aminofluoropiperidinyI)-3,5-dicyanoethylpyridin
y|)thio)pheny|acetamide;
(R)((6-((3R,4S)aminofluoropipe rid in-1 -y|)-3 ,5-dicyanoethylpyrid in
y|)thio)pheny|acetamide;
2-((3,5-dicyanoethyI(3-fluoro((2-methoxyethyl)amino)piperidiny|)pyridin-
2-y|)thio)pheny|acetamide;
2-((3,5-dicyanoethyI(methy|(2-(pyrrolidiny|)ethy|)amino)pyridiny|)thio)
phenylacetamide;
2-((3,5-dicyano(3-((dimethylamino)methy|)pyrro|idiny|)ethy|pyridin
y|)thio)pheny|acetamide;
2-((3,5-dicyanoethyI(4-((2-hydroxymethylpropy|)amino)piperidin
yI)pyridiny|)thio)(4-f|uorophenyl)acetamide;
(R)((6-((3S,4R)aminohydroxypiperidiny|)-3,5-dicyanoethylpyridin
y|)thio)pheny|acetamide;
2-((3,5-dicyano((2-(diethylamino)ethy|)(methy|)amino)ethy|pyridiny|)thio)-
ylacetamide;
2-((3,5-dicyano((2-((R)(dimethylamino)pyrro|idiny|)ethy|)(methyl)amino)
ethylpyridiny|)thio)phenylacetamide;
2-((3,5-dicyano((2-((S)(dimethylamino)pyrrolidiny|)ethy|)(methyl)amino)
ethylpyridiny|)thio)phenylacetamide;
(R)((6-((3R,4R)aminofluoropiperidiny|)-3,5-dicyanoethylpyridin
y|)thio)pheny|acetamide;
(R)((6-((3S,4S)aminofluoropiperidiny|)-3,5-dicyanoethylpyridin
y|)thio)pheny|acetamide;
2-((3,5-dicyanoethyI(3-(methylamino)pyrro|idiny|)pyridiny|)thio)
acetamide;
2-((6-(4-aminopiperidinyI)-3,5-dicyanoethylpyridiny|)thio)(4-
fluorophenyl)acetamide;
(R)((6-((3R,4R)—4-aminohydroxypiperidiny|)-3,5-dicyanoethylpyridin
y|)thio)pheny|acetamide;
2-((6-((R)aminopyrroIidiny|)-3,5-dicyanoethylpyridiny|)thio)
phenylacetamide;
2-((6-(3-(aminomethyl)pyrro|idinyI)-3,5-dicyanoethylpyridiny|)thio)
acetamide;
2-((3,5-dicyanoethyI(4-(methylamino)piperidiny|)pyridiny|)thio)(4-
fluorophenyl)acetamide;
2-((3,5-dicyano(4-(cyclopropylamino)fluoropiperidiny|)ethy|pyridin
y|)thio)pheny|acetamide;
2-((6-((S)aminopyrrolidiny|)-3,5-dicyanoethylpyridiny|)thio)
phenylacetamide;
2-((6-((2-((R)aminopyrrolidiny|)ethy|)(methyl)amino)-3,5-dicyano
ethylpyridiny|)thio)phenylacetamide;
3,5-dicyano((R)(dimethylamino)pyrrolidiny|)ethy|pyridinyl)thio)(4-
fluorophenyl)acetamide;
(S)((6-((3S,4R)—4-aminofluoropiperidiny|)-3,5-dicyanoethylpyridin
y|)thio)pheny|acetamide;
2-((3,5-dicyanoethyI(4-(neopentylamino)piperidiny|)pyridinyl)thio)(4-
(trifluoromethyl)pheny|)acetamide;
tert—butyl ((38,4R)(6-(((R)aminooxophenylethyl)thio)-3,5-dicyano
yridin-Z-yl)—3-hyd roxypiperidiny|)carbamate;
rel-tert-butyl (cis)(6-((2-aminooxophenylethyl)thio)-3,5-dicyano
ethylpyrid iny|)f|uoropipe ridinyl)ca rba mate;
2-((6-((2-((S)aminopyrrolidiny|)ethy|)(methy|)amino)-3,5-dicyano-4—
ethylpyridiny|)thio)phenylacetamide;
-dicyano((R)(dimethy|amino)pyrrolidinyI)ethylpyridin-2—y|)thio)
acetamide;
te rt-butyl ((3R,4S)(6-(((R)aminooxophenylethyl)thio)-3,5-dicyano
ethylpyridin-Z-yl)—3-hyd roxypiperidinyl)carbamate;
rel-tert-butyl (cis)(6-((2-aminooxophenylethyl)thio)-3,5-dicyano
ethylpyridiny|)f|uoropiperidinyl)carbamate;
2-((3,5-dicyano((S)(dimethy|amino)pyrrolidinyI)ethylpyridiny|)thio)
phenylacetamide;
(S)((6-((3R,4S)—4-aminofluoropiperidiny|)-3,5-dicyanoethylpyridin
y|)thio)pheny|acetamide;
2-((3,5-dicyanoethyI((S)((2-hydroxymethylpropy|)amino)pyrrolidin
y|)pyridiny|)thio)phenylacetamide;
tert—butyl ((3R,4R)(6-(((R)aminooxophenylethyl)thio)-3,5-dicyano
ethylpyridin-Z-yl)—3-hyd roxypiperidiny|)carbamate;
2-((3,5-dicyano((S)(dimethy|amino)pyrrolidinyI)ethylpyridiny|)thio)
(4-fluoropheny|)acetamide;
rel((6-cisaminofluoropiperidiny|)-3,5-dicyanoethylpyridiny|)thio)
phenylacetamide;
-dicyanoethyI(4-(methylamino)piperidiny|)pyridiny|)thio)
phenylacetamide;
2-((3,5-dicyano(4-(dimethylamino)piperidiny|)ethy|pyridinyl)thio)
acetamide;
2-((3,5-dicyanoethy|(4-(ethy|(methy|)amino)piperidiny|)pyridin-2—y|)thio)
phenylacetamide;
2-((3,5-dicyanoethyI(4-(neopentylamino)piperidiny|)pyridiny|)thio)
phenylacetamide;
2017/053511
2-((3,5-dicyanoethyI(4-(methyl(neopentyl)amino)piperidiny|)pyridin
y|)thio)pheny|acetamide;
2-((3,5-dicyano(4-(cyclopropylamino)piperidiny|)ethy|pyridinyl)thio)
phenylacetamide;
2-((3,5-dicyanoethyI(4-((2-methoxyethyl)amino)piperidiny|)pyridin
y|)thio)pheny|acetamide;
2-((3,5-dicyano(4-((2,2-difluoroethy|)amino)piperidiny|)ethy|pyridin
y|)thio)pheny|acetamide;
2-((3,5-dicyanoethyI((R)((neope ino)methyl)mo rpholino)pyridin
y|)thio)pheny|acetamide;
-dicyano(2-((dimethylamino)methyl)morpholino)ethy|pyridiny|)thio)-
2-phenylacetamide;
2-((3,5-dicyano(2-((diethylamino)methyl)morpholino)ethylpyridin-2—y|)thio)
phenylacetamide;
2-((3,5-dicyanoethyI(2-(pyrrolidiny|methy|)morpholino)pyridiny|)thio)
phenylacetamide;
(R)((6-((R)—2-(aminomethyl)morpholino)-3,5-d icyanoethylpyrid iny|)th io)
phenylacetamide;
2-((6-(2-(aminomethy|)morpholino)-3,5-dicyanoethylpyridiny|)thio)
phenylacetamide;
2-((3,5-dicyanoethyI(2-((methy|amino)methyl)morpholino)pyridiny|)thio)
phenylacetamide;
2-((6-((R)(aminomethyl)morpho|ino)-3,5-dicyanoethylpyridinyl)thio)
phenylacetamide;
2-((3,5-dicyano(3-((dimethylamino)methy|)piperidiny|)ethy|pyridin
y|)thio)pheny|acetamide;
2-((3,5-dicyanoethyI(3-((methy|amino)methyl)piperidiny|)pyridiny|)thio)-
2-phenylacetamide;
2-((3,5-dicyanoethyI((S)((neopentylamino)methyl)morpholino)pyridin
y|)thio)pheny|acetamide;
2-((3,5-dicyanoethyI((S)((neopentylamino)methy|)piperidiny|)pyridin
y|)thio)pheny|acetamide;
2-amino-N-(((ZS)(6-((2-aminooxo—1-pheny|ethy|)thio)-3,5-dicyano
ethylpyridiny|)morpho|iny|)methyI)methy|propanamide;
2-((6-((S)(aminomethyl)piperidiny|)-3,5-dicyanoethylpyridinyl)thio)
phenylacetamide;
2-((3,5-dicyano((R)((diethylamino)methyl)morpholino)ethy|pyridin
y|)thio)pheny|acetamide;
o-N-(((2R)(6-((2-aminooxopheny|ethy|)thio)-3,5-dicyano
ethylpyridiny|)morpho|iny|)methyI)methy|propanamide;
2-((6-(4-aminopiperidinyl)-3,5-dicyanoethylpyridiny|)thio)(3-
fluoropyridinyl)acetamide;
2-((6-((S)(aminomethy|)morpholino)-3,5-dicyanoethylpyridinyl)thio)
phenylacetamide;
2-amino-N-(((3S)(6-((2-aminooxopheny|ethy|)thio)-3,5-dicyano
ethylpyridiny|)piperidinyl)methyI)methy|propanamide;
2-amino-N-(((3S)(6-((2-aminooxopheny|ethy|)thio)-3,5-dicyano
ethylpyridiny|)piperidiny|)methy|)acetamide;
2-amino-N-(((2R)(6-((2-aminooxopheny|ethy|)thio)-3,5-dicyano
ethylpyridinyl)morpholinyl)methyl)acetamide;
2-((6-((R)(aminomethyl)piperidiny|)-3,5-dicyanoethylpyridinyl)thio)(4-
fluorophenyl)acetamide;
2-((3,5-dicyanoethyI((R)((neopentylamino)methy|)piperidiny|)pyridin
y|)thio)(4-f|uoropheny|)acetamide;
o-N-(((ZS)(6-((2-aminooxopheny|ethy|)thio)-3,5-dicyano
yridinyl)morpholinyl)methyl)acetamide;
N-(((R)(6-(((R)aminooxopheny|ethy|)thio)-3,5-dicyano—4-ethylpyridin
yI)morphoIinyl)methyI)hyd roxyacetamide;
(S)((6-(4-aminopiperidiny|)-3,5-dicyanoethylpyridinyl)thio)
phenylacetamide;
((2-aminooxophenylethyl)thio)-3,5-dicyanoethylpyridin
yI)(methy|)amino)-N-(2-hyd roxyethy|)-N-methylacetamide;
2-((3,5-dicyanoethy|((S)(methy|amino)piperidiny|)pyridinyl)thio)
phenylacetamide;
2-((6-(4-aminomethylpiperidinyI)-3,5-dicyanoethylpyridinyl)thio)-2—
phenylacetamide;
2-((6-((2-aminooxophenylethyl)thio)-3,5-dicyanoethylpyridin
y|)(methy|)amino)—N-((1-(hydroxymethy|)cyclopropyl)methyI)-N-methylacetamide;
o-N-(1-(6-((2-aminooxopheny|ethy|)thio)-3,5-dicyano
cyclopropylpyridinyl)azetidiny|)acetamide;
(28)amino-N-(1-(6-((2-aminooxopheny|ethy|)thio)-3,5-dicyano
cyclopropylpyridinyl)azetidinyI)hydroxypropanamide;
((S)aminopiperidiny|)-3,5-dicyanoethylpyridinyl)thio)
phenylacetamide;
2-((3,5-dicyanoethyI((2-((R)hydroxypyrrolidiny|)
oxoethyl)(methyl)amino)pyridinyl)thio)pheny|acetamide;
(2R)amino-N-(1-(6-((2-aminooxopheny|ethy|)thio)-3,5-dicyano
cyclopropylpyridinyl)azetidinyI)hydroxypropanamide;
2-((6-((2-aminooxophenylethyl)thio)-3,5-dicyanoethylpyridin
yI)(methyl)amino)-N-(3-hyd roxy-2,2-dimethylpropyl)-N-methylacetamide;
2-((3,5-dicyanoethyI((2-((S)hydroxypyrrolidiny|)
oxoethyl)(methyl)amino)pyridinyl)thio)pheny|acetamide;
2-((6-(4-aminomethylpiperidinyI)-3,5-dicyanoethylpyridinyl)thio)
phenylacetamide;
2-((6-(4-(aminomethyI)fluoropiperidiny|)-3,5-dicyanoethylpyridiny|)thio)-
2-phenylacetamide hydrochloride;
2-((6-((2-aminooxopheny|ethyl)thio)-3,5-dicyanocyclopropylpyridin
yI)(methy|)amino)-N-(2-aminoethyl)acetamide hydrochloride;
2-((3,5-dicyanoethyI(methy|(2-oxo(pyrrolidiny|)ethy|)amino)pyridin
y|)thio)pheny|acetamide;
2-((3,5-dicyanoethyI((2-(4-hydroxypiperidiny|)
yl)(methyl)amino)pyridiny|)thio)phenylacetamide;
2-((3,5-dicyanoethyI(methy|(2-oxo(piperaziny|)ethy|)amino)pyridin
y|)thio)pheny|acetamide;
2-((3,5-dicyanoethyI(methy|(2-morpho|inooxoethy|)amino)pyridin
y|)thio)pheny|acetamide;
(R)((6-((S)(aminomethyI)hydroxypyrrolidinyI)-3,5-dicyano
ethylpyridiny|)thio)phenylacetamide;
2-((3,5-dicyanoethyI((S)(g uanidinooxy)pyrro|idiny|)pyridiny|)thio)
phenylacetamide;
2-amino-N-(2-((6-((2-aminooxopheny|ethy|)thio)-3,5-dicyanoethylpyridin
yI)(methy|)amino)ethy|)-2—methy|propanamide;
((2-(2-aminoethoxy)ethy|)(methyl)amino)-3,5-dicyanoethylpyridin
y|)thio)pheny|acetamide;
4-amino-N-(1-(6-((2-aminooxophenylethyl)thio)-3,5-dicyanoethylpyridin
y|)piperidinyl)butanamide;
2-((6-((2-aminooxophenylethyl)thio)-3,5-dicyanoethylpyridin
y|)(methy|)amino)-N-(2-aminoethyl)acetamide;
2-((6-((2-(azetidiny|)oxoethy|)(methyl)amino)-3,5-dicyanoethylpyridin
y|)thio)pheny|acetamide;
2-((6-((R)(aminomethy|)f|uoropyrro|idiny|)-3,5-dicyanoethylpyridin
y|)thio)pheny|acetamide;
2-((3,5-dicyanoethyI((2-(3-hydroxyazetidiny|)
oxoethyl)(methyl)amino)pyridinyl)thio)phenylacetamide;
2-((3,5-dicyanoethyI(4-(guanidinooxy)piperidiny|)pyridiny|)thio)
phenylacetamide;
2-((6-(3-aminoazetidiny|)-3,5-dicyanoethylpyridinyl)thio)
acetamide; (single stereoisomer)
2-((3,5-dicyanoethyI((R)(methy|amino)piperidiny|)pyridinyl)thio)
phenylacetamide;
2-((3,5-dicyano—4-ethyI((2-((3R,4S)hydroxy(hydroxymethy|)pyrrolidiny|)-
2-oxoethyl)(methy|)amino)pyridiny|)thio)phenylacetamide;
(R)((6-((S)(aminomethy|)f|uoropyrro|idiny|)-3,5-dicyano—4-ethylpyridin
y|)thio)pheny|acetamide;
2-((6-((2-aminooxophenylethyl)thio)-3,5-dicyanocyclopropylpyridin
y|)(methy|)amino)-N-(1,3-dihydroxypropan-Z-y|)acetamide;
2-((3,5-dicyanoethyI((S)(oxetany|amino)piperidiny|)pyridiny|)thio)-
2-phenylacetamide;
2-((6-((2-aminooxophenylethyl)thio)-3,5-dicyanocyclopropylpyridin
y|)(methy|)amino)-N,N-bis(2-hydroxyethyl)acetamide;
2-amino-N-(1-(6-((2-aminooxopheny|ethy|)thio)-3,5-dicyano
cyclopropylpyridinyl)piperidiny|)acetamide;
2-((3,5-dicyanoethyI(4-((2-hydroxyethyl)amino)methy|piperidin
y|)pyridiny|)thio)phenylacetamide;
5-dicyanoethyI((2-(g uan idinooxy) ethyl)(methyl)amino)pyrid iny|)thio)-
2-phenylacetamide;
2-((6-(4-((2-aminoethy|)amino)piperidiny|)-3,5-dicyanoethylpyridiny|)thio)-
2-phenylacetamide;
2-((3,5-dicyanoethyI((2-((S)(hyd thy|)mo rpholino)
oxoethyl)(methyl)amino)pyridinyl)thio)phenylacetamide;
2-((3,5-dicyano((2-((cis)-3,4-dihydroxypyrrolidiny|)
oxoethyl)(methyl)amino)ethy|pyridiny|)thio)phenylacetamide;
2-((3,5-dicyanoethy|((2-((S)(hydroxymethy|)pyrrolidiny|)
oxoethyl)(methyl)amino)pyridinyl)thio)phenylacetamide;
2-((3,5-dicyanoethyI((2-((3S,4S)hydroxy(hydroxymethy|)pyrro|idiny|)-
2-oxoethyl)(methy|)amino)pyridiny|)thio)phenylacetamide;
2-((3,5-dicyanoethyI((S)(neopentylamino)piperidinyl)pyridiny|)thio)
acetamide;
2-((3,5-dicyanoethyI((2-((R)(hydroxymethyl)pyrrolidiny|)
oxoethyl)(methyl)amino)pyridinyl)thio)phenylacetamide;
2-((3,5-dicyano—6-((2-((3R,4R)-3,4-dihydroxypyrrolidiny|)
oxoethyl)(methyl)amino)ethy|pyridiny|)thio)phenylacetamide;
(R)((3,5-dicyanoethyI((S)hyd roxy(hyd roxymethy|)pyrro|idin
y|)pyridiny|)thio)phenylacetamide;
(28)amino-N-(1-(6-((2-aminooxopheny|ethy|)thio)-3,5-dicyano
cyclopropylpyridinyl)piperidinyl)propanamide;
2-((6-(4-(2-aminoethoxy)piperidiny|)-3,5-dicyanocyclopropylpyridiny|)thi0)-
2-phenylacetamide;
2-((3,5-dicyanocyclopropyI(4-((2-hyd roxyethyl)amino)piperidiny|)pyridin
y|)thio)pheny|acetamide;
2-((6-((2-aminooxophenylethyl)thio)-3,5-dicyanoethylpyridin
y|)(methy|)amino)—N-(1,3-dihydroxypropan-Z-y|)acetamide;
2-((3,5-dicyano((2-((3R,SS)-3 ,5-dihyd roxypiperidiny|)
oxoethyl)(methyl)amino)ethy|pyridiny|)thio)phenylacetamide;
2-((3,5-dicyano((2-((3S,4S)-3,4-dihydroxypyrrolidiny|)
oxoethyl)(methyl)amino)ethy|pyridiny|)thio)phenylacetamide;
2-((3,5-dicyanoethyI(4-((2-hydroxyethyl)amino)(hydroxymethy|)piperidin
y|)pyridiny|)thio)phenylacetamide;
-dicyanoethyI((2-((R)(hyd roxymethyl)morpholino)
oxoethyl)(methyl)amino)pyridinyl)thio)phenylacetamide;
2-((6-((2-aminooxophenylethyl)thio)-3,5-dicyanoethylpyridin
yI)(methy|)amino)-N-methoxyacetamide;
2-((3,5-dicyanoethyI((2-((3R,4R)hydroxy—4-(hydroxymethy|)pyrro|idiny|)-
2-oxoethyl)(methy|)amino)pyridiny|)thio)phenylacetamide;
((2-aminooxophenylethyl)thio)-3,5-dicyanoethylpyridin
yI)(methy|)amino)-N-(3-hyd opy|)-N-methylacetamide;
2-((6-((2-aminooxophenylethyl)thio)-3,5-dicyanoethylpyridin
y|)(methy|)amino)-N-((R)-2,3-dihydroxypropy|)acetamide;
2-((6-(4-((2-aminooxoethyl)amino)piperidiny|)-3,5-dicyano
cyclopropylpyridiny|)thio)phenylacetamide;
2-((6-((2-aminooxophenylethyl)thio)-3,5-dicyanoethylpyridin
thy|)amino)—N,N-bis(2-hydroxyethy|)acetamide;
2-((6-((2-aminooxophenylethyl)thio)-3,5-dicyanoethylpyridin
yI)(methy|)amino)-N-(2-hydroxyethyl)acetamide;
2-((6-((3-aminopropy|)(methy|)amino)-3,5-dicyanoethylpyridinyl)thio)
phenylacetamide;
2-((6-(3-(aminomethy|)azetidiny|)-3,5-dicyanoethylpyridinyl)thio)
phenylacetamide;
2-((6-((2-aminooxophenylethyl)thio)-3,5-dicyanoethylpyridin
y|)(methy|)amino)—N-((1-(hydroxymethyl)cyclopropy|)methy|)acetamide;
((3,5-dicyanoethyI((S)hydroxypyrrolidiny|)pyridinyl)thio)(2,4-
difluoropheny|)acetamide;
2-((6-((2-aminooxophenylethyl)thio)-3,5-dicyanoethylpyridin
yI)(methy|)amino)-N-(3-(hydroxymethy|)oxetanyl)acetamide;
2-((3,5-dicyanoethyI(3-(guanidinooxy)azetidiny|)pyridiny|)thio)
phenylacetamide;
2-((6-((2-aminooxophenylethyl)thio)-3,5-dicyanoethylpyridin
yI)(methy|)amino)-N-(3-hyd roxypropy|)acetamide;
2-((3,5-dicyano(4-(2,3-dihydroxypropy|)-1,4-diazepany|)ethy|pyridin
y|)thio)pheny|acetamide;
2-((6-((2-aminooxophenylethyl)thio)-3,5-dicyanoethylpyridin
thy|)amino)-N-hydroxyacetamide;
3-amino-N-(1-(6-((2-aminooxopheny|ethy|)thio)-3,5-dicyano
cyclopropylpyridinyl)azetid iny|)oxetanecarboxamide;
2-((3,5-dicyanoethyI((S)hydroxypyrro|idinyl)pyridiny|)thio)(2-
fluorophenyl)acetamide;
2-((3,5-dicyano((S)(cyclopropylamino)piperidiny|)ethy|pyridiny|)thi0)-
2-phenylacetamide;
2-((6-((2-aminooxophenylethyl)thio)-3,5-dicyanoethylpyridin
yl)(methy|)amino)-N-(3-hydroxy-2,2-dimethylpropyl)acetamide;
N-(2-(4H-1,2,4-triazo|y|)ethy|)((6-((2-aminooxopheny|ethy|)thio)-3,5-
dicyanoethylpyridinyl)(methy|)amino)acetamide;
N1 -(2-((6-((2-aminooxopheny|ethy|)thio)-3,5-dicyanoethylpyridin
yI)(methy|)amino)ethy|)oxa|amide;
2-((6-(3-(aminomethyI)fluoroazetidiny|)-3,5-dicyanoethylpyridiny|)thio)-
2-phenylacetamide;
(R)((3,5-dicyanoethyl—6-((R)hyd roxy(hyd roxymethy|)pyrro|idin
y|)pyridiny|)thio)phenylacetamide;
2-((3,5-dicyano((S)((2,2—difluoroethy|)amino)piperidiny|)ethy|pyridin
y|)thio)pheny|acetamide;
2-((6-((R)aminopiperidiny|)-3,5-dicyanoethylpyridinyl)thio)
acetamide;
2-((6-(4-aminopiperidinyl)-3,5-dicyanomethoxypyridinyl)thio)
phenylacetamide;
2-((3,5-dicyanoethyI((S)hyd roxyisoxazolid l)pyridinyl)thio)
phenylacetamide;
(R)((3,5-dicyanoethyI((3-hydroxypropyl)(methy|)amino)pyridin-2—y|)thio)
phenylacetamide;
2-((3,5-dicyano((S)hydroxypyrrolidiny|)methoxypyridiny|)thio)
acetamide;
2-((3,5-dicyanoethyI(4-(3-methoxyazetidiny|)piperidiny|)pyridin
y|)thio)pheny|acetamide;
2-((3,5-dicyanoethyI(4-(3-methoxyazetidiny|)piperidiny|)pyridin
y|)thio)(4-f|uoropheny|)acetamide;
(R)((3,5-dicyanoethyI((2-hydroxyethy|)(methyl)amino) pyridiny|)thio)
phenylacetamide;
(R)((6-((R)(aminomethyI)hydroxypyrrolidinyI)-3,5-dicyano
ethylpyridiny|)thio)phenylacetamide;
2-((3,5-Dicyano(4-(cyclobutyl(methy|)amino)piperidiny|)ethy|pyridin
y|)thio)(4-f|uoropheny|)acetamide; and
2-((3,5-dicyanoethyl(methyl(1-methylpyrrolidinyl)amino)pyridinyl)thio)-
2-phenylacetamide;
or a pharmaceutically able salt or prodrug thereof.
Suitably, presently invented novel compounds of Formula (lVbbr) are selected from:
2-{[3,5-dicyano(dimethylamino)ethylpyridinyl]sulfanyl}phenylacetamide;
2-((3,5-dicyanocyclopropyl(1 zepanyl)pyridinyl)thio)
phenylacetamide;
2-{[3,5-dicyanocyclopropyl(4-ethyl-1 ,4-diazepany|)pyridinyl]sulfany|}
phenylacetamide;
2-((3,5-dicyanoethyl(4-propyl-1,4-diazepanyl)pyridiny|)thio)-2—
phenylacetamide;
2-{[3,5-dicyanoethyl(4—ethyl-1 ,4-diazepany|)pyridinyl]sulfanyl}
phenylacetamide;
2-{[3,5-dicyanoethyl(5-oxo-1 ,4—diazepanyl)pyridinyl]sulfany|}
phenylacetamide;
-dicyanocyclopropylmorpholinopyridinyl)thio)(pyridin
yl)acetamide;
2-{[3,5-dicyanoethyl(4-methyloxopiperaziny|)pyridinyl]su|fany|}
(pyrid inyl)acetamide;
2-[(3,5-dicyanoethyl{methyl[2-(morpholinyl)ethyl]amino}pyridin
yl)sulfanyl]phenylacetamide;
2-{[3,5-dicyanoethyl(4-propylpiperaziny|)pyridinyl]sulfanyl}-2—
phenylacetamide;
2-({3,5-dicyanoethyl[4—(piperidinyl)piperazinyl]pyridiny|}sulfanyl)
acetamide;
2-({3,5-dicyanocyclopropyl[3-(hydroxymethyl)piperazinyl]pyridin
yl}sulfanyl)phenylacetamide;
WO 16727
2-{[3,5-dicyanocyclopropyI(3-oxopiperaziny|)pyridinyl]su|fanyl}
phenylacetamide;
2-({3,5-dicyanocyclopropyI[4-(morpholinyl)piperidiny|]pyridin
y|}suIfany|)pheny|acetamide;
2-((3,5-dicyanoethyI(2,8-diazaspiro[4.5]decany|)pyridiny|)thio)
phenylacetamide;
2-((3,5-DicyanocyclopropyI(3-(dimethylamino)piperidiny|)pyridiny|)thio)-
2-phenylacetamide;
2-((3,5-DicyanocyclopropyI(3-methylpiperaziny|)pyridiny|)thio)
phenylacetamide;
2-((3,5-DicyanocyclopropyI(2-(hydroxymethyl)morpholino)pyridiny|)thio)
acetamide;
-DicyanocyclopropyI(2,6-dimethylmorpholino)pyridinyl)thio)
phenylacetamide;
2-((3,5-DicyanocyclopropyI(3-(dimethylamino)piperidiny|)pyridiny|)thio)-
2-phenylacetamide;
2-((6-(4-(Aminomethy|)hydroxypiperidiny|)-3,5-dicyanocyclopropylpyridin-
2-y|)thio)pheny|acetamide;
2-((3,5-dicyanocyclopropyI(3-(methylamino)piperidiny|)pyridiny|)thio)
phenylacetamide;
2-((6-(3-aminopiperidiny|)-3,5-dicyanocyclopropylpyridinyl)thio)
phenylacetamide;
2-((3,5-dicyanocyclopropyI(dimethylamino)pyridiny|)thio)(pyridin
y|)acetamide;
2-((3,5-dicyano(dimethylamino)ethy|pyridiny|)thio)(pyridin
y|)acetamide;
2-((6-(4-aminopiperidiny|)-3,5-dicyanocyclopropylpyridinyl)thio)
phenylacetamide;
2-((3,5-dicyanocyclopropyI(4-(dimethylamino)piperidiny|)pyridiny|)thio)-
2-phenylacetamide;
2-((3,5-dicyano—4-cyclopropyI(piperaziny|)pyridiny|)thio)(pyridin
y|)acetamide;
-dicyanocyclopropyI(1 ,4-diazepany|)pyridiny|)thio)(pyridin
y|)acetamide;
2-((3,5-dicyanocyclopropyI((R)hyd roxypiperidiny|)pyridinyl)thio)
phenylacetamide;
2-(3,5-dicyanocyclopropyI((S)hydroxypiperidiny|)pyridiny|thio)
phenylacetamide;
-dicyanocyclopropyI((S)hydroxypyrrolidiny|)pyridinyl)thio)
(pyrid iny|)acetamide;
2-((3,5-dicyanoethyI(4-ethylpiperaziny|)pyridiny|)thio)
phenylacetamide;
2-((3,5-DicyanoethyI(1-oxaazaspiro[3.4]octany|)pyridin-Z-yl)thio)
phenylacetamide;
2-((6-(4-(3-aminopropy|)piperaziny|)-3,5-dicyanoethylpyridinyl)thio)
phenylacetamide;
2-((3,5-Dicyano—4-ethyI(1,7-diazaspiro[3.5]nonany|)pyridiny|)thio)
phenylacetamide;
2-((3,5-DicyanocyclopropyI(4-(pyrrolidiny|methy|)piperidiny|)pyridin
y|)thio)pheny|acetamide;
2-((3,5-DicyanocyclopropyI(4-(4-methylpiperaziny|)piperidinyl)pyridin
y|)thio)pheny|acetamide;
(R)((3,5-dicyano(1,4-diazepany|)ethy|pyridin-Z-yl)amino)
phenylacetamide;
2-((3,5-DicyanocyclopropyI(4-(pyrrolidiny|)piperidiny|)pyridiny|)thio)-
2-phenylacetamide;
2-((3,5-DicyanoethyI(2,7-diazaspiro[3.5]nonany|)pyridiny|)thio)
phenylacetamide;
2-((3,5-DicyanoethyI(2,6-d iazaspiro[3.4]octany|)pyrid iny|)th io)
phenylacetamide;
2-((3,5-dicyanocyclopropyI(1,4-diazepany|)pyridiny|)thio)propanamide;
2-((3,5-DicyanoethyI(4-(2-oxoimidazoIidiny|)piperidiny|)pyridin
y|)thio)phenylacetamide;
2-((3,5-DicyanoethyI(4-hydroxypiperidiny|)pyridinyl)thio)
acetamide;
2-((3,5-DicyanoethyI((S)hydroxypyrrolidiny|)pyridiny|)thio)
acetamide;
2-((3,5-Dicyano-4—ethyI(3-oxopiperaziny|)pyridiny|)thio)
phenylacetamide;
5-DicyanoethyI((2-meth oxyethy|)(methy|)amino)pyridinyl)thio)
phenylacetamide;
2-((3,5-DicyanoethyI(3-methoxyazetidiny|)pyridinyl)thio)
phenylacetamide;
2-((3,5-DicyanoethyI(piperaziny|)pyridinyl)thio)phenylacetamide;
2-((3,5-DicyanoethyI(4-methyI-1 ,4-diazepanyl)pyridin-2—y|)thio)
phenylacetamide;
2-((3,5-DicyanoethyImorpholinopyridinyl)thio)phenylacetamide;
2-[[6-(azetidiny|)-3,5-dicyanoethylpyridyl]suIfanyl]phenyl-acetamide;
2-((3,5-dicyanoethyI(4-oxopiperidinyl)pyridiny|)thio)phenylacetamide;
2-((3,5-dicyanoethyI(1'-(2-hydroxyethy|)-[4,4'-bipiperidin]y|)pyridin
y|)thio)pheny|acetamide;
2-((3,5-Dicyano((3S,5R)—3,5-dimethylpiperazinyl)ethylpyridiny|)thio)
phenylacetamide;
2-((6-(8-azabicyc|o[3.2.1]octany|(methy|)amino)-3,5-dicyanoethylpyridin
y|)thio)pheny|acetamide;
2-((3,5-DicyanocyclopropyI(2-(hydroxymethyl)morpholino)pyridiny|)thio)
phenylacetamide;
(R)((3,5-dicyano(dimethylamino)ethylpyridiny|)thio)phenylacetamide;
(R)[(3,5-Dicyanoethylmorpholinopyridyl)sulfany|]—2-phenyI-acetamide;
2-{[3,5-dicyanoethyI(5-methyI-1 ,4-diazepany|)pyridiny|]su|fany|}
phenylacetamide;
-DicyanoethyI[4-(2-methoxyethyl)-1 ,4-diazepanyl]pyridin
y|}suIfany|)pheny|acetamide;
2-((3,5-dicyanoethyI(4-(2-hyd roxypropyI)-1 ,4-diazepany|)pyridiny|)thio)-
2-phenylacetamide;
Methyl 2—[4-(6-{[carbamoyl(pheny|)methy|]su|fany|}-3,5-dicyanoethylpyridin
y|)-1 ,4-diazepany|]acetate;
2-{[3,5-DicyanocyclopropyI(4-methyIoxo-1,4-diazepany|)pyridin
y|]suIfany|}phenylacetamide;
2-{[3,5-DicyanocyclopropyI(5-oxo-1 ,4-diazepany|)pyridinyl]su|fany|}
phenylacetamide;
2-{[3,5-DicyanoethyI(4-methyIoxo-1 ,4-diazepany|)pyridinyl]su|fany|}-
2-phenylacetamide;
5-Dicyano(1,4-diazepanyl)ethylpyridiny|]su|fany|}
phenylacetamide;
2-({3,5-Dicyano[4-(2-hydroxyethyl)-1,4-diazepany|](2,2,2-
trifluoroethyl)pyridiny|}su|fany|)phenylacetamide;
(2R)({3,5-DicyanoethyI[4-(2-hydroxyethy|)-1,4-diazepany|]pyridin
no)phenylacetamide;
2-({6-[(3S)AminopyrroIidiny|]-3,5-dicyanocyclopropylpyridinyl}su|fany|)-
2-phenylacetamide;
2-((3,5-DicyanoethyI(2,9-diazaspiro[5.5]undecanyl)pyridinyl)thio)
acetamide;
2-((3,5-DicyanoethyI(hexahydro-1H-pyrro|o[1 ,2-a][1 ,4]diazepin-2(3H)-
y|)pyridiny|)thio)phenylacetamide;
2-((3,5-DicyanoethyI(2-methyI-2,9-diazaspiro[5.5]undecany|)pyridin
y|)thio)pheny|acetamide;
2-((3,5-Dicyano(2-(cyclopropylmethyI)-2,9-diazaspiro[5.5]undecanyI)
ethylpyridiny|)thio)phenylacetamide;
2-((3,5-Dicyano(4-(3-(dimethylamino)propy|)piperaziny|)ethy|pyridin
y|)thio)pheny|acetamide;
2-((3,5-DicyanoethyI(4-(pyrroIidinyl)piperidiny|)pyridinyl)thio)-2—
phenylacetamide;
2-((6-([4,4'-Bipiperidin]—1-yl)-3,5-dicyanoethylpyridiny|)thio)
phenylacetamide;
2-((6-(4-(2-Aminoethy|)piperaziny|)-3,5-dicyanoethylpyridin-Z-yl)thio)
phenylacetamide;
2-((6-(4-(3-Aminopropyl)piperaziny|)-3,5-dicyanocyclopropylpyridiny|)thio)-
2-phenylacetamide;
2-((3,5-DicyanocyclopropyI(4-((4-methylpiperaziny|)methy|)piperidin
y|)pyridiny|)thio)phenylacetamide;
2-((6-(4-Acetylpiperaziny|)-3,5-dicyanoethylpyridin-Z-yl)thio)
phenylacetamide;
2-((3,5-DicyanocyclopropyI(dimethylamino)pyridiny|)thio)
phenylacetamide;
h|orophenyl)((3,5-dicyano(dimethylamino)ethy|pyridin
y|)thio)acetamide;
2-((3,5-Dicyano—4-ethyI(4-(2-hydroxyethy|)piperaziny|)pyridinyl)thio)
phenylacetamide;
2-[(3,5-DicyanocyclopropyImorpholinopyridy|)su|fany|]phenyl-
acetamide;
2-((6-(4-Benzoy|piperaziny|)-3,5-dicyanoethylpyridinyl)thio)
phenylacetamide;
5-DicyanoethyI((5S,6S)hydroxy(methy|su|fonyI)-1,8-
piro[4.5]decan-8—y|)pyridin-2—yl)thio)pheny|acetamide;
2-((3,5-Dicyano(4,4-difluoropiperidiny|)ethy|pyridin-Z-yl)thio)
phenylacetamide;
(R)((3,5-Dicyanoethyl((R)hydroxypyrrolidiny|)pyridinyl)thio)
phenylacetamide;
-dicyano(fu ranyI)(4-methyI-1 ,4-diazepany|)pyridinyl)thio)
phenylacetamide;
2-((6-(4-Aminomethylpiperidiny|)-3,5-dicyanoethylpyridin-Z-yl)thio)
phenylacetamide;
2-Amino-N-(1-(6-((2-aminooxopheny|ethy|)thio)-3,5-dicyano—4-ethylpyridin
y|)piperidinyl)acetamide;
(28)Amino-N-(1-(6-((2-aminooxophenylethyl)thio)-3,5-dicyano-4—
yridiny|)piperidiny|)propanamide;
2-((6-(4-(3-Aminooxetanecarbony|)piperaziny|)-3,5-dicyanoethylpyridin
o)pheny|acetamide;
4-Amino-N-(1-(6-((2-aminooxophenylethy|)thio)-3,5-dicyano—4-ethylpyridin
y|)piperidinyl)tetrahydro-2H-pyrancarboxamide;
2-((6-(4-(4-Aminotetrahyd ro-2H-pyrancarbony|)piperaziny|)-3,5-dicyano
ethylpyridiny|)thio)phenylacetamide;
2-((3,5-Dicyano—6-(4-(2-hydroxyethy|)-1 ,4-diaze pa n-1 -y|)methoxypyridin
y|)thio)pheny|acetamide;
2-((6-(4-AminopiperidinyI)-3,5-dicyanoethylpyridinyl)thio)
phenylacetamide;
2-((6-((2-Aminoethy|)(methy|)amino)-3 ,5-dicyanoethylpyrid iny|)th io)-2—
phenylacetamide;
2-((6-((2-Aminooxoethyl)(methyl)amino)-3,5-dicyanoethylpyridiny|)thio)
phenylacetamide;
2-((3,5-DicyanoethyI(3-hydroxyazetidiny|)pyridinyl)thio)
phenylacetamide;
2-(3,5-DicyanoethyI((2-hydroxyethy|)(methy|)amino)pyridinylthio)
phenylacetamide;
2-Amino-N-(1-(6-((2-aminooxophenylethyl)thio)-3,5-dicyano—4-ethylpyridin
y|)piperidiny|)methylpropanamide;
2-((6-(4-(2-Aminoethoxy)piperidiny|)-3,5-dicyanoethylpyridinyl)thio)
phenylacetamide;
1-(6-((2-Aminooxopheny|ethy|)thio)-3,5-dicyanoethylpyridinyl)pyrro|idin-
3-yl dihydrogen phosphate;
2-((6-((2-Aminooxopheny|ethyl)thio)-3,5-dicyanoethylpyridin
thy|)amino)ethy| dihydrogen phosphate;
1-(6-((2-Aminooxopheny|ethy|)thio)-3,5-dicyanoethylpyridinyl)azetidin-
3-yl dihydrogen phosphate;
(28)((1-(6-((2-Aminooxopheny|ethy|)thio)-3,5-dicyanoethylpyridin
y|)piperidiny|)oxy)ethy| 2-aminomethylbutanoate;
2-((1-(6-((2-Amino-2—oxopheny|ethy|)thio)-3,5-dicyanoethylpyridin
y|)piperidiny|)oxy)ethy| dihydrogen phosphate;
1-(6-((2-Aminooxo-1 -pheny|ethy|)thio)-3,5-d icyanoethylpyrid inyl) pipe rid in-
4-y| dihydrogen phosphate;
2-((3,5-Dicyano(dimethylamino)ethylpyridiny|)thio)(piperidin
y|)acetamide;
2-((3,5-DicyanoethyI(4-(propylsu|fony|)piperaziny|)pyridinyl)thio)
phenylacetamide;
2-((3,5-DicyanoethyI(4-(phenylsulfony|)piperaziny|)pyridinyl)thio)
phenylacetamide;
2-((3,5-DicyanoethyI((R)hydroxypyrro|idiny|)pyridiny|)thio)
phenylacetamide;
2-((3,5-DicyanoethyI(2-oxaazaspiro [3 any|)pyridinyl)th io)
phenylacetamide;
(R)((3,5-Dicyanoethyl(4-ethyI-1 ,4-diazepany|)pyridiny|)amino)
phenylacetamide;
(R)((3,5-Dicyanoethyl(4-(3-(pyrrolidiny|)propy|)-1,4-diazepan
idiny|)amino)phenylacetamide;
2-(3,5-DicyanocyclopropyI(3-hydroxypiperidiny|)pyridiny|thio)
acetamide;
2-((3,5-Dich|oroethyI(4-methyI-1 ,4-diazepanyl) pyridiny|)thio)
phenylacetamide;
2-((3,5-Dicyano(1,1-dioxidothiomorpholino)ethylpyridinyl)thio)
phenylacetamide;
2-((3,5-DicyanoethyI(methy|(2-(piperaziny|)ethy|)amino)pyridiny|)thio)-
2-phenylacetamide;
(R)((3,5-Dicyanoethyl((S)hydroxypyrro|idiny|)pyridiny|)thio)
phenylacetamide;
2-((6-((2-(4-(AminomethyI)hyd roxypiperidiny|)ethy|)(methy|)amino)-3,5-
dicyanoethylpyridiny|)thio)phenylacetamide;
2-((4-Cyano(1 ,4-diazepany|)-6,7-dihydro-5H-cyclopenta[c]pyridiny|)thio)
acetamide;
2-((6-(4-(1H-ImidazoIy|)piperidiny|)-3,5-dicyanoethylpyridinyl)thio)
phenylacetamide;
2-((3,5-DicyanoethyI(4-(pyridinylmethyl)piperaziny|)pyridiny|)thio)
phenylacetamide;
2-((3,5-Dicyano(2-(dimethylamino)ethoxy)ethy|pyridiny|)thio)
phenylacetamide;
(6-((2-Aminooxopheny|ethy|)thio)-3,5-dicyanocyclopropylpyridin
y|)piperidinyl)amino)acetic acid;
-DicyanoethyI(4-(oxazolylmethyl)piperaziny|)pyridinyl)thio)
phenylacetamide;
2-((6-(4-((1H-PyrroI-Z-yl) methyl) piperaziny|)-3,5-dicyanoethylpyridin
y|)thio)pheny|acetamide;
2-((3,5-Dicyano(3,4-dihydro-2,7-naphthyridin-2 (1 H)-y|)ethy|pyridiny|)thio)-
2-phenylacetamide;
2-((3,5-DicyanoethyI((S)hydroxypyrrolidiny|)pyridiny|)thio)(pyridin-
3-y|)acetamide;
2-((6-(4-((1H-PyrroIyl)methy|)piperaziny|)-3,5-dicyanoethylpyridin
y|)thio)pheny|acetamide;
2-((3,5-DicyanoethyI(4-(isoxazo|y|methy|)piperazinyl)pyridiny|)thio)-
2-phenylacetamide;
2-((3,5-DicyanoethyI(4-(oxazolylmethyl)piperaziny|)pyridinyl)thio)
phenylacetamide;
2-((3,5-DicyanoethyI(4-(isoxazo|y|methy|)piperazinyl)pyridiny|)thio)-
2-phenylacetamide;
3-Amino-N-(1-(6-((2-aminooxopheny|ethy|)thio)-3,5-dicyano—4-ethylpyridin
y|)piperidinyl)oxetanecarboxamide;
2-((6-(4-((1H-PyrazoIyl)methyl)piperaziny|)-3,5-dicyanoethylpyridin
y|)thio)pheny|acetamide;
2-((6-(4-((1H-|midazoIy|)methy|)piperaziny|)-3,5-dicyanoethylpyridin
y|)thio)pheny|acetamide;
2-((3,5-DicyanoethyI(4-(1-hydroxymethy|propanyl)piperazin
idiny|)thio)phenylacetamide;
(4-((1H-|midazoIy|)methy|)piperaziny|)-3,5-dicyanoethylpyridin
y|)thio)pheny|acetamide;
2-((3,5-Dicyano(dimethylamino)methoxypyridinyl)thio)phenylacetamide;
-Dicyano(dimethylamino)-4—ethoxypyridin-Z-y|)thio)phenylacetamide;
2-((3,5-Dicyanoethoxy(4-(2-hydroxyethy|)-1 ,4-diazepanyl) pyridin
y|)thio)pheny|acetamide;
2-((3,5-DicyanoethyI(4-(2-hydroxymethylpropyI)-1 ,4-diazepany|)pyridin-
2-y|)thio)pheny|acetamide;
2-((3,5-DicyanoethyI(4-(thiazolylmethyl)piperaziny|)pyridinyl)thio)
phenylacetamide;
2-((3,5-DicyanoethyI(piperaziny|)pyridiny|)thio)(4-
fluorophenyl)acetamide;
2-((3,5-DicyanoethyI(4-(isothiazoIylmethyl)piperaziny|)pyridiny|)thio)-
2-phenylacetamide;
2-((3,5-Dicyano(dimethylamino)-4—ethylpyrid iny|)thio)(4-
fluorophenyl)acetamide;
2-((3,5-Dicyano(dimethylamino)-4—ethylpyridiny|)thio) (5-fluoropyridin
y|)acetamide;
-DicyanoethyI(4-(furanylmethy|)piperaziny|)pyridinyl)thio)
phenylacetamide;
2-((3,5-DicyanoethyI((2-morpholinoethyl)thio)pyridinyl)thio)
phenylacetamide;
2-((3,5-Dicyano(4-methyI-1 ,4-diazepany|)(methy|thio)pyridiny|)thio)
phenylacetamide;
-DichIoroethyI(4-(2-hydroxyethy|)-1 ,4-diazepany|)pyridiny|)thio)-
2-phenylacetamide;
2-((3,5-DicyanoethyI(hexahydropyrro|o[3,4-b][1,4]oxazin-6(2H)-y|)pyridin
y|)thio)pheny|acetamide;
2-((3,5-DicyanoethyI(4-methyI-1 ,4-diazepanyl)pyridiny|)thio)(5-
methylpyridiny|)acetamide;
2-((3,5-DicyanoethyI(4-methyI-1 ,4-diazepanyl)pyridiny|)thio)(6-
yridinyl)acetamide;
2-((3,5-Dicyano(4-(dimethylamino)piperidiny|)ethy|pyridiny|)thio)(4-
fluorophenyl)acetamide;
2-((3,5-DicyanoethyI(4-methyI-1,4-diazepanyl) pyridin-Z-yl) 2-(4-
methylpyridin-Z-yl) acetamide;
2-((3,5-DicyanoethyI(4-methyI-1 ,4-diazepanyl)pyridiny|)thio)(3-
methoxypyridiny|)acetamide;
2-((3,5-Dicyano(4-(dimethylamino)piperidiny|)ethy|pyridiny|)thio)(2,4-
difluoropheny|)acetamide;
2-((3,5-DicyanoethyI(4-(pyrrolidin-1 -y|)pipe rid in-1 -y|)pyridiny|)thio)(5-
fluoropyridinyl)acetamide;
2-((3,5-Dicyanoethoxy(4-(2-hyd roxyethyI)-1 ,4-diazepany|)pyridin
y|)thio)propanamide;
2-((3,5-Dicyano(4-(2-hydroxyethy|)-1 ,4-diazepany|)propoxypyridin
y|)thio)pheny|acetamide;
2-((3,5-DicyanoethyI(4-methyI-1 ,4-diazepanyl)pyridiny|)thio)(4-
meth oxypyrid iny|)acetamide;
2-((3,5-DicyanoethyI(2-methyI-2,8—diazaspiro[4.5]decany|)pyridin
y|)thio)pheny|acetamide;
-Dicyano(4-(dimethylamino)piperidiny|)ethy|pyridinyl)thio)(3,4-
difluoropheny|)acetamide;
1-(6-((2-Aminooxopheny|ethy|)thio)-3,5-dicyanoethylpyridin
y|)piperid ineca rboxa mide;
2-((3,5-Dicyano((2-(dimethylamino)ethyl)thio)ethy|pyridiny|)thio)
phenylacetamide;
2-((3,5-Dicyano((3S,4R)-3,4-dihydroxypyrrolidinyI)ethylpyridinyl)thio)
phenylacetamide;
-DicyanoethyI(4-methyI-1 zepanyl)pyridiny|)thio)(3-
fluoropyridin-Z-yl) ide;
2-((3,5-DicyanoethyI(4-methyI-1 ,4-diazepanyl)pyridiny|)thio)(5-
meth oxypyrid iny|)acetamide;
2-((3,5-DicyanoethyI(4-(1-hydroxymethy|propanyl)piperazin
yI)pyridiny|)thio)(4-f|uorophenyl)acetamide;
2-((3,5-DicyanoethyI(4-methyI-1 ,4-diazepanyl)pyridiny|)thio)(3-
(trifluoromethyl)pheny|)acetamide;
2-((3,5-DicyanoethyI(4-(2-hydroxyethoxy)piperidiny|)pyridinyl)thio)
phenylacetamide;
2-((3,5-DicyanoethyI(4-methyI-1 ,4-diazepanyl) pyridin-Z-yl)thio)(2-
fluoropyridinyl)acetamide;
2-((3,5-DicyanoethyI(4-methyI-1 ,4-diazepanyl) pyridin-Z-yl)thio)(6-
fluoropyridinyl)acetamide;
3-((6-(2-Aminooxopheny|ethy|thio)-3,5-dicyanoethylpyridin
yI)(methy|)amino)propanamide;
2-((3,5-DicyanoethyI(4-(oxetanyloxy)piperidiny|)pyridiny|)thio)
phenylacetamide;
2-((3,5-Dicyano(4-((2,2-difluoroethyl) amino)methy|piperidiny|)
ethylpyridin-Z-yl) thio)phenylacetamide;
2-((3,5-DicyanoethyI(4-methyI-1 ,4-diazepanyl)pyridiny|)thio)(4-
(trifluoromethyl)pheny|)acetamide;
2-((6-(4-Aminopiperaziny|)-3,5-dicyanoethylpyridin-Z-yl)thio)
phenylacetamide;
((2-Aminooxoethy|)thio)-3,5-dicyanoethylpyridinyl)thio)
phenylacetamide;
2-((3,5-DicyanoethyI(pyrro|o[3,4-c]pyrazoI-5(1H,4H,6H)-yl)pyridiny|)thio)-
2-phenylacetamide;
2-((3,5-Dicyano(dimethylamino)-4—ethy|pyridiny|)thio)(5-methoxypyridin
y|)acetamide;
2-((3,5-Dicyano(dimethylamino)ethylpyridiny|)thio)(5-methy|pyridin
y|)acetamide;
-DicyanoethyI(4-methyI-1 ,4-diazepanyl)pyridiny|)thio)(2-
fluoropyrid inyl)acetamide;
2-((3,5-Dicyano—4-ethyI(4-hyd roxy(hyd roxymethyl) pipe 1 -y|)pyridin
y|)thio)pheny|acetamide;
2-((3,5-DicyanoethyI(2-oxooxa-1 ,8-diazaspiro[4.5]decan-8—y|)pyridin
y|)thio)pheny|acetamide;
2-((6-(4-Amino(hyd roxymethy|)pipe rid in-1 -y|)-3 ,5-dicyanoethylpyrid in
y|)thio)pheny|acetamide;
2-((6-(4-(Aminomethy|)hydroxypiperidiny|)-3,5-dicyanoethylpyridin
y|)thio)pheny|acetamide;
enzoylphenyI)((3,5-dicyanoethyI(4-(2-hydroxyethy|)-1,4-diazepan
y|)pyridiny|)thio)acetamide;
2-(4-BenzoylphenyI)((3,5-dicyanoethyI(4-(2-hydroxyethy|)-1,4-diazepan
y|)pyridiny|)thio)acetamide;
2-((3,5-DicyanoethyI(4-methyI-1 ,4-diazepanyl)pyridiny|)thio)(2-
methylpyridiny|)acetamide;
2-((3,5-DicyanoethyI(4-methyI-1 ,4-diazepanyl)pyridiny|)thio)(3-
(pyrrolidiny|)pheny|)acetamide;
2-((3,5-DicyanoethyI(4-methyI-1 ,4-diazepanyl)pyridiny|)thio)(3-
fluoropyrid l)acetamide;
2-((3,5-DicyanoethyI(4-methyI-1,4-diazepanyl)pyridiny|)thio)(2,5-
difluoropyridiny|)acetamide;
2-((3,5-Dicyano(4-(2,5-dioxoimidazolidiny|)piperidiny|)ethy|pyridin
y|)thio)pheny|acetamide;
4-Amino(6-((2-aminooxopheny|ethy|) thio)-3, 5-dicyanoethylpyridinyl)
piperidinecarboxamide;
-Dicyano(4-(2,5-dioxopyrrolidinyl)piperidiny|)ethy|pyridin
y|)thio)pheny|acetamide;
2-((3,5-dicyanoethyI(4-methyI-1 ,4-diazepany|)pyridin-2—yl)thio)
phenylacetamide (isomer 1);
2-((3,5-dicyanoethyI(4-methyI-1 ,4-diazepany|)pyridin-2—yl)thio)
phenylacetamide (Isomer 2) ;
2-((3,5-DicyanoethyI(2-oxooxa-3,8-diazaspiro[4.5]decan-8—y|)pyridin
y|)thio)pheny|acetamide;
1-(6-((2-Aminooxopheny|ethy|)thio)-3,5-dicyanoethylpyridinyI)
hydroxy piperidinecarboxamide;
(2-Aminooxopheny|ethy|)thio)-3,5-dicyanoethylpyridinyl)azetidin-
3-yl carbamate;
2-((3,5-Dicyano(4-(2,4-dioxooxazolidiny|)piperidiny|)ethy|pyridin
y|)thio)pheny|acetamide;
3-((6-((2-Aminooxopheny|ethyl)thio)-3,5-dicyanoethylpyridin
y|)(methy|)amino)hydroxymethylpropanamide;
2-((3,5-DicyanoethyI(3-(hyd roxymethy|)azetidiny|)pyridin-Z-yl)thio)
phenylacetamide;
-DicyanoethyI(piperaziny|)pyridinylthio)(thiophen
y|)acetamide;
2-((3,5-DicyanoethyI(4-methyI-1,4-diazepanyl) pyridin-Z-yl) thio)(5-
methylpyridinyl) acetamide;
2-((6-(4-(3-Aminooxopyrrolidiny|)piperidiny|)-3,5-dicyano—4-ethylpyridin
y|)thio)pheny|acetamide;
1-(6-((2-Aminooxo-1 -pheny|ethy|)thio)-3,5-d icyanoethylpyrid inyl) pipe rid in-
4-y| (28)aminomethylbutanoate;
2-((6-((2-Aminooxophenylethyl)thio)-3,5-dicyanoethylpyridinyl) l)
amino)ethy| (28)aminomethylbutanoate;
2,2'-((3,5-Dicyanoethylpyridine-2,6-diy|)bis(suIfanediy|))bis(2-pheny|acetamide)
(28)-(1-(6-((2-Amino—2-oxophenylethy|)thio)-3,5-dicyano-4 —ethy| n
y|)azetidinyl)methy| 2-aminomethylbutanoate;
2-((6-(3-Aminoazetidiny|)-3,5-dicyanoethylpyridiny|)thio)
phenylacetamide;
2-((3,5-DicyanoethyImethylpyridiny|)thio)phenylacetamide;
N-(1-(6-((2-Amino—2-oxopheny|ethy|)thio)-3,5-dicyanoethylpyridin
y|)piperidiny|)hydroxyacetamide;
N-(1-(6-((2-Amino—2-oxopheny|ethy|)thio)-3,5-dicyanoethylpyridin
y|)azetidinyI)hydroxyacetamide;
2-((3-Cyanoethylmethyl(piperaziny|)pyridiny|)thio)
phenylacetamide;
2-((3,5-Dicyanoethyl(5-methyl—2,5-diazabicyclo[2.2.1]heptan-Z-y|)pyridin
y|)thio)phenylacetamide;
2-((3,5-DicyanoethyI(4-(2-(pyrrolidiny|)ethy|)piperaziny|)pyridin
o)phenylacetamide;
2-((3,5-Dicyano(dimethylamino)-4—ethy|pyridiny|)thio)pheny|acetamide-2—
(R)((3,5-Dicyano(dimethylamino)ethy|pyridiny|)thio)—2-
phenylacetamide-Z-d;
2-((6-(4-(4-Bromobenzoy|)piperaziny|)-3,5-dicyanoethylpyridiny|)thio)
phenylacetamide;
2-((3,5-DicyanoethyI(4-(2-hydroxyethy|)-1 ,4-diazepanyl)pyridiny|)thio)-
2-phenylacetamide;
2-((3,5-Dicyano(4-cyanopiperidiny|)ethy|pyridinyl)thio)
phenylacetamide;
(S)—2-((3,5-Dicyanoethyl—6-((S)hyd roxypyrrolidiny|)pyridiny|)thio)
phenylacetamide;
2-((6-(4-AminomethylpiperidinyI)-3,5-dicyanocyclopropylpyridin-Z-y|)thio)-
2-phenylacetamide;
2-((3,5-DicyanoethyI((S)hydroxypyrrolidiny|)pyridiny|)thio)(pyridin-
2-y|)acetamide;
2-((3,5-DichIoroethyI(piperaziny|)pyridiny|)thio)phenylacetamide;
utyl (1-(6-((2-aminooxopheny|ethy|)thio)—3,5-dicyanoethylpyridin
y|)piperidiny|)carbamate;
2-((6-(3-(2-Aminooxoethyl)azetidiny|)-3,5-dicyanoethylpyridiny|)thio)
acetamide;
(2R)(6-((2-Aminooxophenylethy|)thio)-3,5-dicyanoethylpyridin
y|)azetidiny| 2-aminomethylbutanoate;
2-((3,5-Dicyano-4—ethyI(methyl((5-oxo-4,5-dihyd ro-1 H-1 ,2,4-triazo|—3-
y|)methy|)amino)pyridiny|)thio)pheny|acetamide;
2-((6-(((4H-1 ,2,4-TriazoIyl)methyl)(methy|)amino)-3,5-dicyanoethylpyridin
y|)thio)phenylacetamide;
2-((3,5-Dicyanoethoxy-6—methylpyridiny|)thio)phenylacetamide;
2-((3,5-Dicyano-4,6-diethylpyridin-Z-y|)thio)phenylacetamide;
2-((6-((2-(4H-1,2,4-Triazo|—4-y|)ethy|)(methy|)amino)—3,5-dicyanoethylpyridin-Z-yl)thio)-
2-
phenylacetamide;
(((1H-PyrazoIyl)methy|)(methyl)amino)-3,5-dicyanoethylpyridin
y|)thio)pheny|acetamide;
2-((3,5-Dicyano(6,7-dihydro-1H-[1,2,3]triazolo[4,5-c]pyridin-5(4H)-y|)
ethylpyridiny|)thio)pheny|acetamide;
2-((6-(((1H-ImidazoIyl)methy|)(methy|)amino)-3,5-dicyanoethylpyridin
y|)thio)pheny|acetamide;
2-((6-(((1H-ImidazoIyl)methy|)(methy|)amino)-3,5-dicyanoethylpyridin
y|)thio)pheny|acetamide;
(2R)Amino-N-(1-(6-((2-aminooxo—1-phenylethyl)thio)-3,5-dicyano
ethylpyridiny|)piperidiny|)propanamide;
4-(2-Amino((3,5-dicyanoethyI(4-methyI-1,4-diazepany|)pyridin
y|)thio)oxoethy|)benzamide;
2-((3,5-DicyanocyclopropyI(3-hydroxypyrrolidiny|)pyridinyl)thio)-2—
phenylacetamide;
2-((3,5-DicyanoethyI(3-hydroxypyrrolidiny|)pyridiny|)thio)
phenylacetamide;
(2R)Amino-N-(1-(6-((2-aminooxo—1-phenylethyl)thio)-3,5-dicyano
cyclopropyl pyridiny|)piperidin-4—yl)propanamide;
((2-Aminoethy|)(methy|)amino)-3,5-dicyanocyclopropylpyridin-2—yl)thio)
acetamide;
2-Amino-N-(1-(6-((2-aminooxopheny|ethy|) thio)-3,5-d icyano
ropylpyridiny|)piperidiny|)methy|propanamide;
4-(2-Amino((3,5-dicyano(dimethylamino)ethylpyridinyl)thio)
oxoethyl)benzamide;
2-(6-(4-Aminopiperidiny|)cyanoethyImethylpyridinylthio)
phenylacetamide;
2-((3,5-DicyanoethyI(4-methyI-1,4-diazepanyl)pyridiny|)thio)(4-(N-
methylsulfamoyl)phenyl)acetamide;
2-((3,5-DicyanoethyI(6-fluoro-1,4-diazepany|)pyridiny|)thio)
phenylacetamide;
2-((6-(4-Amino-3,3-difluoropiperidiny|)-3,5-dicyanoethylpyridinyl)thio)
phenylacetamide;
tert—Butyl (1-(6-((2-aminooxopheny|ethy|) thio)-3,5-dicyanoethylpyridin
yI)-3,3-diquoropiperidin-4—yl) carbamate;
2-((3,5-DicyanocyclopropyI((2-hyd roxyethyl)(methy|)amino)pyridiny|)thio)-
2-phenylacetamide;
2-((3,5-DicyanocyclopropyI(3-hydroxyazetidiny|)pyridiny|)thio)
phenylacetamide;
(2-Aminooxopheny|ethy|)thio)-3,5-dicyanoethylpyridin
y|)pyrro|idinecarboxamide;
2-((6-((3-Aminopropy|) (methyl) amino)-3, 5-dicyanocyclopropylpyridinyl)
thio)phenylacetamide;
2-((3,5-DicyanocyclopropyI((2-(3-hyd roxyazetidinyI)
oxoethyl)(methyl)amino) pyridiny|)thio)phenylacetamide;
2-((6-(4-((2-Aminooxoethy|)amino)piperidiny|)-3,5-dicyanoethylpyridin
y|)thio)pheny|acetamide;
2-((6-((2-Aminooxoethyl)(methyl)amino)-3,5-dicyanocyclopropylpyridin
y|)thio)pheny|acetamide;
2-((6-((2-Aminooxopheny|ethyl) thio)-3, 5-dicyanocyclopropylpyridin
y|)(methy|)amino)ethy| carbamate;
-Amino-N-(1-(6-((2-aminooxo—1-phenylethyl)thio)-3,5-dicyano
ethylpyridiny|)piperidinyI)hydroxypropanamide;
(28)Amino-N-(1-(6-((2-aminooxopheny|ethy|) thio)—3, ano
yridin-Z-yl) piperidiny|)hydroxypropanamide;
2-(4-(2-Aminooxoethyl)phenyI)(3,5-dicyanoethyI(4-methyl-1 ,4-
diazepany|)pyridinylthio)acetamide;
2-(4-(2-Aminooxoethyl)pheny|)(3,5-dicyano(dimethylamino)ethy|pyridin-
2-ylthio)acetamide;
2-((3,5-Dicyano(dimethylamino)ethy|pyridiny|)thio)(4-(N-
methylsulfamoyl)phenyl)acetamide;
2-((3,5-Dicyano(dimethylamino-d6)ethylpyridiny|)thio)-2—phenylacetamide;
(R)((3,5-Dicya noethyl—6—(4-(pyrrolidiny|)piperidiny|)pyridinyl)thio)
phenylacetamide;
(R)((3,5-Dicyano(4-(dimethylamino)piperidinyI)ethylpyridiny|)thio)
phenylacetamide;
2-(3,5-dicyano(dimethylamino)ethy|pyridinylthio)(3-(2-
(dimethylamino)ethoxy)pheny|)acetamide;
2-((3,5-DicyanoethyI(4-(neopentylamino)piperidiny|)pyridiny|)thio)(4-
fluorophenyl)acetamide;
2-((3,5-dicyanoethyI(3-fluoroA(neopentylamino)piperidiny|)pyridin
y|)thio)pheny|acetamide;
2-((6-(4-aminopiperidinyI)-3,5-dicyanoethylpyridiny|)thio)(4-
(trifluoromethyl)pheny|)acetamide;
2-((3,5-DicyanoethyI(4-(pyrroIidiny|)piperidiny|)pyridinyl)thio)
phenylacetamide;
(R)((6-(4-aminopiperidiny|)-3,5-dicyanoethylpyridinyl)thio)
phenylacetamide;
2-((6-((2-aminooxoethy|)(methy|)amino)-3,5-dicyanoethylpyridiny|)thio)
phenylacetamide; (single enantiomer)
(38)(6-((2-aminooxopheny|ethy|) thio)-3, 5-dicyanoethylpyridinyl)
Pyrrolidinyl ogen phosphate;
(3R)(6-((2-aminooxopheny|ethy|)thio)-3,5-dicyanoethylpyridin
y|)pyrrolidiny| dihydrogen ate;
(S)(6-(((S)aminooxopheny|ethy|)thio)-3,5-dicyanoethylpyridin
y|)pyrrolidiny| dihydrogen phosphate;
(6-(((R)aminooxopheny|ethy|) thio)-3,5-dicyanoethylpyridinyl)
idinyl dihydrogen phosphate;
2-((3,5-Dicyano(dimethylamino)ethylpyridiny|)thio)(3-
(dimethylphosphory|)pheny|)acetamide;
2-((3,5-DicyanoethyI((S)hydroxypyrrolidiny|)pyridiny|)thio)(3-(
dimethylphosphory|)phenyl)acetamide;
(R)((6-((2-aminooxopheny|ethy|)thio)-3,5-dicyanoethylpyridin
y|)(methy|)amino)ethy| dihydrogen phosphate;
2017/053511
(R)((3,5-dicyanoethyI((S)hydroxypyrrolidiny|)pyridin-Z-yl)thio)(4-
methoxyphenyl)acetamide;
(R)(4-chIorophenyI)((3,5-dicyanoethyI((S)hydroxypyrrolidin
y|)pyridiny|)thio)acetamide;
(R)((3,5-dicyanoethyI((S)hydroxypyrrolidiny|)pyridin-Z-yl)thio)(4-
fluoro pheny|)acetamide;
(S)(6-(((R)amino(4-f|uorophenyI)oxoethy|)thio)-3,5-dicyano
ethylpyridiny|)pyrro|idiny| dihydrogen phosphate;
2-((3, 5-dicyanoethyI((S)hydroxypyrrolidiny|) pyridinyl) thio)(4-
fluorophenyl) acetamide;
2-((3,5-dicyanoethyI((S)hydroxypyrro|idinyl) pyridinyl) 2-(2, 6-
difluorophenyl) acetamide;
2-((3, 5-dicyanoethyI((S)hydroxypyrrolidiny|) pyridinyl) thio)(2, 3-
difluorophenyl) acetamide;
2-((3, 5-dicyanoethyI((S)hydroxypyrrolidiny|) nyl) thio)(2, 4-
difluorophenyl) acetamide;
2-((3,5-dicyanoethyI(4-((S)(hydroxymethy|)pyrrolidiny|)piperidin
y|)pyridiny|)thio)phenylacetamide;
2-((3,5-dicyanoethyI(4-((2-hydroxyethy|)(methy|)amino)piperidiny|)pyridin-
2-y|)thio)pheny|acetamide;
2-((3,5-dicyanoethyI(4-((2-hydroxymethylpropyl)(methyl)amino)piperidin
y|)pyridiny|)thio)phenylacetamide;
2-((3,5-dicyanoethyI(4-(pyrroIidiny|methy|)piperidinyl)pyridiny|)thio)-
2-phenylacetamide;
2-((3,5-dicyanoethyI(4-((2-methoxymethylpropy|)amino)piperidin
idiny|)thio)phenylacetamide;
2-((3,5-dicyanoethyI(4-((2-hydroxymethylpropy|)amino)piperidin
y|)pyridiny|)thio)phenylacetamide;
2-((3,5-dicyano(4-(cyclobutylamino)piperidiny|)ethy|pyridinyl)thio)
phenylacetamide;
2-((3,5-dicyanoethyI(4-(((3-methyloxetanyl)methy|)amino)piperidin
y|)pyridiny|)thio)phenylacetamide;
2-((3,5-dicyanoethyI(4-(4-methylpiperaziny|)piperidiny|)pyridin
o)pheny|acetamide;
2-((3,5-dicyanoethyI(4-((R)methy|pyrrolidiny|)piperidiny|)pyridin
y|)thio)pheny|acetamide;
2-((3,5-dicyano(4-((2R,5S)-2,5-dimethylpyrrolidiny|)piperidiny|)
ethylpyridiny|)thio)phenylacetamide;
2-((3,5-dicyanoethyI(4-((S)methy|pyrro|idiny|)piperidiny|)pyridin
y|)thio)pheny|acetamide;
2-((3,5-dicyan0(4-(cyclobutyl(methy|)amino)piperidiny|)ethy|pyridin
y|)thio)pheny|acetamide;
2-(6-(4-(benzylamino)piperidiny|)-3,5-dicyanoethylpyridinylthio)—2-
phenylacetamide;
2-((3,5-dicyanoethy|(4-(((6-methoxypyridinyl)methy|)amino)piperidin
y|)pyridiny|)thio)phenylacetamide;
2-((3,5-dicyanoethyI(4-((S)fluoropyrrolidiny|)piperidiny|)pyridin
y|)thio)pheny|acetamide;
-dicyanoethyI(methyl(2-((R)methy|pyrro|idin
y|)ethy|)amino)pyrid iny|)th io)pheny|acetamide;
2-((3,5-dicyanoethyI(4-((R)fluoropyrrolidinyl)piperidiny|)pyridin
y|)thio)pheny|acetamide;
2-((3,5-dicyano(4-((ZS,5S)-2,5-dimethylpyrrolidiny|)piperidiny|)
ethylpyridiny|)thio)phenylacetamide;
2-((3,5-dicyanoethyI(methy|(2-((S)methy|pyrro|idin
y|)amino)pyrid iny|)th io)pheny|acetamide;
2-((3,5-dicyanoethyI(4-((R)(hydroxymethy|)pyrrolidiny|)piperidin
y|)pyridiny|)thio)phenylacetamide;
2-((3,5-dicyano(4-(dimethylamino)piperidiny|)ethy|pyridinyl)thio)(4-
fluorophenyl)acetamide;
2-((3,5-dicyanoethyI(4-(((1-methy|cyc|obuty|)methy|)amino)piperidin
y|)pyridiny|)thio)phenylacetamide;
-dicyanoethy|(4-(((6-methoxypyridinyl)methyl)amino)piperidin
y|)pyridiny|)thio)phenylacetamide;
2-(3,5-dicyanoethyI((2-(ethylamino)ethy|)(methyl)amino)pyridinylthio)
phenylacetamide;
-dicyanoethyI(4-((4-methy|piperaziny|)methy|)piperidiny|)pyridin-
2-y|)thio)pheny|acetamide;
2-((3,5-dicyanoethyI(methy|(2-(methy|amino)ethy|)amino)pyridiny|)thio)
phenylacetamide;
2-((3,5-dicyano(4-((2R,5R)—2,5-dimethylpyrrolidiny|)piperidinyI)
ethylpyridiny|)thio)phenylacetamide;
2-((3,5-dicyanoethyI(4-(((1-methy|cyc|opropy|)methy|)amino)piperidin
y|)pyridiny|)thio)phenylacetamide;
2-((3,5-dicyanoethyI(4-((4-fluorobenzy|)amino)piperidiny|)pyridiny|)thio)-
2-phenylacetamide;
2-((3,5-dicyanoethyI((2-((S)(hyd roxymethy|)pyrro|idin
y|)ethy|)(methy|)amino)pyridiny|)thio)pheny|acetamide;
2-(3,5-dicyano((2—((ZS,5R)-2,5-dimethylpyrrolidiny|)ethyl)(methyl)amino)
ethylpyridinylthio)phenylacetamide;
2-((6-((2-(azepany|)ethyl)(methy|)amino)-3,5-dicyanoethylpyridiny|)thio)
phenylacetamide;
2-((3,5-dicyanoethyI(methy|(2-(pipe rid in-1 -y|)ethy|)amino)pyrid iny|)thio)
phenylacetamide;
2-((3,5-dicyanoethy|((2-((R)(hydroxymethy|)pyrro|idin
y|)ethy|)(methy|)amino)pyridiny|)thio)phenylacetamide;
-dicyanoethyI((2-(ethy|(methy|)amino)ethyl)(methy|)amino)pyridin
ylthio)-2—phenylacetamide;
2-((3,5-dicyano((2-((2R,5R)-2,5-dimethylpyrrolidiny|)ethyl)(methy|)amino)-4—
ethylpyridiny|)thio)phenylacetamide;
2-(3,5-dicyanoethyI((2-((S)hydroxypyrrolidin
y|)ethy|)(methy|)amino)pyridinylthio)phenylacetamide;
methyl 2-((1-(6-((2-aminooxopheny|ethy|)thio)-3,5-dicyano—4-ethylpyridin
y|)piperidinyl)amino)-2—methy|propanoate;
-dicyanoethyI(methy|(2-(neopentylamino)ethy|)amino)pyridin
o)pheny|acetamide;
2-(3,5-dicyanoethyI(methy|(2-(1-methy|cyc|opropylamino)ethy|)amino)pyridin-
2-ylthio)—2-pheny|acetamide;
2-((3,5-dicyano((2-((ZS,58)-2,5-dimethylpyrrolidiny|)ethyl)(methyl)amino)
ethylpyridiny|)thio)phenylacetamide;
2-((3,5-dicyanoethyI((2-((2-methoxyethy|)amino)ethy|)(methy|)amino)pyridin-
hio)pheny|acetamide;
2-((3,5-dicyanoethyI(4-((2-methoxymethylpropyl)(methy|)amino)piperidin-
1-y|)pyrid inyl)th io)pheny|acetamide;
2-((3,5-dicyano((2-(dimethylamino)ethy|)(methy|)amino)ethy|pyridin
y|)thio)pheny|acetamide;
2-(3,5-dicyanoethyI((2-((R)hyd roxypyrrolidin
y|)ethy|)(methy|)amino)pyridinylthio)phenylacetamide;
2-((3,5-dicyanoethyI((2-((2-fluoroethy|)amino)ethy|)(methyl)amino)pyridin-2—
y|)thio)pheny|acetamide;
2-((3,5-dicyano(4-(3,3-difluoropyrrolidiny|)piperidiny|)ethy|pyridin
y|)thio)pheny|acetamide;
2-((1-(6-((2-aminooxopheny|ethy|)thio)-3,5-dicyanoethylpyridin
y|)piperidinyl)amino)acetic acid;
2-((6-((3-aminocyclobutyl)(methyl)amino)-3,5-dicyanoethylpyridin-Z-y|)thio)
phenylacetamide;
(R)(3,5-dicyanoethyI(methyl((R)-tetrahyd rofurany|)amino)pyridin
ylthio)-2—phenylacetamide;
(S)(3,5-dicyanoethyI(methyl((R)-tetrahydrofu rany|)amino)pyridin
ylthio)-2—phenylacetamide;
2-((3,5-dicyano—4-ethyI(4-morpholinopiperidiny|)pyridiny|)thio)
phenylacetamide;
2-((3,5-dicyanoethyI(4-(2-hydroxyethyI)oxopiperaziny|)pyridiny|)thio)-
2-phenylacetamide;
2-((3,5-dicyanoethyI(4-(pyrroIidiny|)piperidiny|)pyridiny|)thio)—2-(4-
fluorophenyl)acetamide;
(R)((6-((3S,4R)aminofluoropiperidiny|)-3,5-dicyanoethylpyridin
y|)thio)pheny|acetamide;
2-((3,5-dicyanoethyI(3-fluoro(methylamino)piperidiny|)pyridiny|)thio)-
2-phenylacetamide;
rel((6-(trans)aminofluoropiperidinyI)-3,5-dicyanoethylpyridin
y|)thio)pheny|acetamide;
(R)((6-((3R,4S)aminofluoropipe rid in-1 -y|)-3 yanoethylpyrid in
y|)thio)pheny|acetamide;
2-((3,5-dicyanoethyI(3-fluoro((2-methoxyethyl)amino)piperidiny|)pyridin-
2-y|)thio)pheny|acetamide;
2-((3,5-dicyanoethyI(methy|(2-(pyrrolidiny|)ethy|)amino)pyridiny|)thio)
phenylacetamide;
2-((3,5-dicyano(3-((dimethylamino)methy|)pyrro|idiny|)ethy|pyridin
y|)thio)pheny|acetamide;
-dicyanoethyI(4-((2-hydroxymethylpropy|)amino)piperidin
yI)pyridiny|)thio)(4-f|uorophenyl)acetamide;
((6-((3S,4R)aminohydroxypiperidiny|)-3,5-dicyanoethylpyridin
y|)thio)pheny|acetamide;
2-((3,5-dicyano((2-(diethylamino)ethy|)(methy|)amino)ethy|pyridiny|)thio)-
2-phenylacetamide;
2-((3,5-dicyano((2-((R)(dimethylamino)pyrro|idiny|)ethy|)(methyl)amino)
ethylpyridiny|)thio)phenylacetamide;
2-((3,5-dicyano((2-((S)(dimethylamino)pyrrolidiny|)ethy|)(methyl)amino)
ethylpyridiny|)thio)phenylacetamide;
(R)((6-((3R,4R)aminofluoropiperidiny|)-3,5-dicyanoethylpyridin
y|)thio)pheny|acetamide;
(R)((6-((3S,4S)aminofluoropiperidiny|)-3,5-dicyanoethylpyridin
y|)thio)pheny|acetamide;
2-((3,5-dicyanoethyI(3-(methylamino)pyrro|idiny|)pyridiny|)thio)
phenylacetamide;
2-((6-(4-aminopiperidinyI)-3,5-dicyanoethylpyridiny|)thio)(4-
fluorophenyl)acetamide;
(R)((6-((3R,4R)—4-aminohydroxypiperidiny|)-3,5-dicyanoethylpyridin
y|)thio)pheny|acetamide;
2-((6-((R)aminopyrroIidiny|)-3,5-dicyanoethylpyridiny|)thio)
phenylacetamide;
2-((6-(3-(aminomethyl)pyrro|idinyI)-3,5-dicyanoethylpyridiny|)thio)
phenylacetamide;
2-((3,5-dicyanoethyI(4-(methylamino)piperidiny|)pyridiny|)thio)(4-
henyl)acetamide;
2-((3,5-dicyano(4-(cyclopropylamino)fluoropiperidiny|)ethy|pyridin
y|)thio)pheny|acetamide;
2-((6-((S)aminopyrrolidiny|)-3,5-dicyanoethylpyridiny|)thio)
phenylacetamide;
((2-((R)aminopyrrolidiny|)ethy|)(methyl)amino)-3,5-dicyano
ethylpyridiny|)thio)phenylacetamide;
cyano((R)(dimethylamino)pyrrolidiny|)ethy|pyridinyl)thio)(4-
fluorophenyl)acetamide;
(S)((6-((3S,4R)—4-aminofluoropiperidiny|)-3,5-dicyanoethylpyridin
y|)thio)pheny|acetamide;
2-((3,5-dicyanoethyI(4-(neopentylamino)piperidiny|)pyridinyl)thio)(4-
(trifluoromethyl)pheny|)acetamide;
tert—butyl ((38,4R)(6-(((R)aminooxophenylethyl)thio)-3,5-dicyano
ethylpyridin-Z-yl)—3-hyd roxypiperidiny|)carbamate;
rt-butyl (cis)(6-((2-aminooxophenylethyl)thio)-3,5-dicyano
ethylpyrid iny|)f|uoropipe ridinyl)ca rba mate;
2-((6-((2-((S)aminopyrrolidiny|)ethy|)(methy|)amino)-3,5-dicyano-4—
ethylpyridiny|)thio)phenylacetamide;
2-((3,5-dicyano((R)(dimethy|amino)pyrrolidinyI)ethylpyridin-2—y|)thio)
phenylacetamide;
te rt-butyl ((3R,4S)(6-(((R)aminooxophenylethyl)thio)-3,5-dicyano
ethylpyridin-Z-yl)—3-hyd roxypiperidinyl)carbamate;
rel-tert-butyl (cis)(6-((2-aminooxophenylethyl)thio)-3,5-dicyano
ethylpyridiny|)f|uoropiperidinyl)carbamate;
2-((3,5-dicyano((S)(dimethy|amino)pyrrolidinyI)ethylpyridiny|)thio)
phenylacetamide;
(S)((6-((3R,4S)—4-aminofluoropiperidiny|)-3,5-dicyanoethylpyridin
y|)thio)pheny|acetamide;
2-((3,5-dicyanoethyI((S)((2-hydroxymethylpropy|)amino)pyrrolidin
idiny|)thio)phenylacetamide;
tert—butyl ((3R,4R)(6-(((R)aminooxophenylethyl)thio)-3,5-dicyano
ethylpyridin-Z-yl)—3-hyd roxypiperidiny|)carbamate;
2-((3,5-dicyano((S)(dimethy|amino)pyrrolidinyI)ethylpyridiny|)thio)
(4-fluoropheny|)acetamide;
rel((6-cisaminofluoropiperidiny|)-3,5-dicyanoethylpyridiny|)thio)
phenylacetamide;
2-((3,5-dicyanoethyI(4-(methylamino)piperidiny|)pyridiny|)thio)
acetamide;
2-((3,5-dicyano(4-(dimethylamino)piperidiny|)ethy|pyridinyl)thio)
phenylacetamide;
2-((3,5-dicyanoethy|(4-(ethy|(methy|)amino)piperidiny|)pyridin-2—y|)thio)
phenylacetamide;
-dicyanoethyI(4-(neopentylamino)piperidiny|)pyridiny|)thio)
phenylacetamide;
2-((3,5-dicyanoethyI(4-(methyl(neopentyl)amino)piperidiny|)pyridin
y|)thio)pheny|acetamide;
2-((3,5-dicyano(4-(cyclopropylamino)piperidiny|)ethy|pyridinyl)thio)
phenylacetamide;
-dicyanoethyI(4-((2-methoxyethyl)amino)piperidiny|)pyridin
y|)thio)pheny|acetamide;
2-((3,5-dicyano(4-((2,2-difluoroethy|)amino)piperidiny|)ethy|pyridin
y|)thio)pheny|acetamide;
2-((3,5-dicyanoethyI((R)((neope ntylamino)methyl)mo rpholino)pyridin
y|)thio)pheny|acetamide;
-dicyano(2-((dimethylamino)methyl)morpholino)ethy|pyridiny|)thio)-
2-phenylacetamide;
2-((3,5-dicyano(2-((diethylamino)methyl)morpholino)ethylpyridin-2—y|)thio)
phenylacetamide;
5-dicyanoethyI(2-(pyrrolidiny|methy|)morpholino)pyridiny|)thio)
phenylacetamide;
(R)((6-((R)—2-(aminomethyl)morpholino)-3,5-d icyanoethylpyrid iny|)th io)
phenylacetamide;
2-((6-(2-(aminomethy|)morpholino)-3,5-dicyanoethylpyridiny|)thio)
phenylacetamide;
2-((3,5-dicyanoethyI(2-((methy|amino)methyl)morpholino)pyridiny|)thio)
phenylacetamide;
2-((6-((R)(aminomethyl)morpho|ino)-3,5-dicyanoethylpyridinyl)thio)
phenylacetamide;
2-((3,5-dicyano(3-((dimethylamino)methy|)piperidiny|)ethy|pyridin
y|)thio)pheny|acetamide;
2-((3,5-dicyanoethyI(3-((methy|amino)methyl)piperidiny|)pyridiny|)thio)-
2-phenylacetamide;
2-((3,5-dicyanoethyI((S)((neopentylamino)methyl)morpholino)pyridin
y|)thio)pheny|acetamide;
2017/053511
2-((3,5-dicyanoethyI((S)((neopentylamino)methy|)piperidiny|)pyridin
y|)thio)pheny|acetamide;
2-amino-N-(((ZS)(6-((2-aminooxo—1-pheny|ethy|)thio)-3,5-dicyano
ethylpyridiny|)morpho|iny|)methyI)methy|propanamide;
2-((6-((S)(aminomethyl)piperidiny|)-3,5-dicyanoethylpyridinyl)thio)
phenylacetamide;
2-((3,5-dicyano((R)((diethylamino)methyl)morpholino)ethy|pyridin
y|)thio)pheny|acetamide;
2-amino-N-(((2R)(6-((2-aminooxopheny|ethy|)thio)-3,5-dicyano
ethylpyridiny|)morpho|iny|)methyI)methy|propanamide;
2-((6-(4-aminopiperidinyl)-3,5-dicyanoethylpyridiny|)thio)(3-
fluoropyridinyl)acetamide;
2-((6-((S)(aminomethy|)morpholino)-3,5-dicyanoethylpyridinyl)thio)
acetamide;
2-amino-N-(((3S)(6-((2-aminooxopheny|ethy|)thio)-3,5-dicyano
ethylpyridiny|)piperidiny|)methyI)methy|propanamide;
2-amino-N-(((3S)(6-((2-aminooxopheny|ethy|)thio)-3,5-dicyano
ethylpyridiny|)piperidiny|)methy|)acetamide;
2-amino-N-(((2R)(6-((2-aminooxopheny|ethy|)thio)-3,5-dicyano
ethylpyridinyl)morpholinyl)methyl)acetamide;
2-((6-((R)(aminomethyl)piperidiny|)-3,5-dicyanoethylpyridinyl)thio)(4-
fluorophenyl)acetamide;
2-((3,5-dicyanoethyI((R)((neopentylamino)methy|)piperidiny|)pyridin
y|)thio)(4-f|uoropheny|)acetamide;
2-amino-N-(((ZS)(6-((2-aminooxopheny|ethy|)thio)-3,5-dicyano
ethylpyridinyl)morpholinyl)methyl)acetamide;
N-(((R)(6-(((R)aminooxopheny|ethy|)thio)-3,5-dicyano—4-ethylpyridin
yI)morphoIinyl)methyI)hyd roxyacetamide;
(S)((6-(4-aminopiperidiny|)-3,5-dicyanoethylpyridinyl)thio)
phenylacetamide;
((2-aminooxophenylethyl)thio)-3,5-dicyanoethylpyridin
yI)(methy|)amino)-N-(2-hyd hy|)-N-methylacetamide;
2-((3,5-dicyanoethy|((S)(methy|amino)piperidiny|)pyridinyl)thio)
phenylacetamide;
(4-aminomethylpiperidinyI)-3,5-dicyanoethylpyridinyl)thio)-2—
phenylacetamide;
2-((6-((2-aminooxophenylethyl)thio)-3,5-dicyanoethylpyridin
y|)(methy|)amino)—N-((1-(hydroxymethy|)cyclopropyl)methyI)-N-methylacetamide;
2-amino-N-(1-(6-((2-aminooxopheny|ethy|)thio)-3,5-dicyano
cyclopropylpyridinyl)azetidiny|)acetamide;
(28)amino-N-(1-(6-((2-aminooxopheny|ethy|)thio)-3,5-dicyano
cyclopropylpyridinyl)azetidinyI)hydroxypropanamide;
2-((6-((S)aminopiperidiny|)-3,5-dicyanoethylpyridinyl)thio)
phenylacetamide;
2-((3,5-dicyanoethyI((2-((R)hydroxypyrrolidiny|)
oxoethyl)(methyl)amino)pyridinyl)thio)pheny|acetamide;
(2R)amino-N-(1-(6-((2-aminooxopheny|ethy|)thio)-3,5-dicyano
cyclopropylpyridinyl)azetidinyI)hydroxypropanamide;
2-((6-((2-aminooxophenylethyl)thio)-3,5-dicyanoethylpyridin
yI)(methyl)amino)-N-(3-hyd roxy-2,2-dimethylpropyl)-N-methylacetamide;
2-((3,5-dicyanoethyI((2-((S)hydroxypyrrolidiny|)
oxoethyl)(methyl)amino)pyridinyl)thio)pheny|acetamide;
2-((6-(4-aminomethylpiperidinyI)-3,5-dicyanoethylpyridinyl)thio)
phenylacetamide;
2-((6-(4-(aminomethyI)fluoropiperidiny|)-3,5-dicyanoethylpyridiny|)thio)-
2-phenylacetamide hydrochloride;
2-((6-((2-aminooxopheny|ethyl)thio)-3,5-dicyanocyclopropylpyridin
yI)(methy|)amino)-N-(2-aminoethyl)acetamide hydrochloride;
2-((3,5-dicyanoethyI(methy|(2-oxo(pyrrolidiny|)ethy|)amino)pyridin
y|)thio)pheny|acetamide;
2-((3,5-dicyanoethyI((2-(4-hydroxypiperidiny|)
oxoethyl)(methyl)amino)pyridiny|)thio)phenylacetamide;
2-((3,5-dicyanoethyI(methy|(2-oxo(piperaziny|)ethy|)amino)pyridin
y|)thio)pheny|acetamide;
2-((3,5-dicyanoethyI(methy|(2-morpho|inooxoethy|)amino)pyridin
y|)thio)pheny|acetamide;
(R)((6-((S)(aminomethyI)hydroxypyrrolidinyI)-3,5-dicyano
ethylpyridiny|)thio)phenylacetamide;
2-((3,5-dicyanoethyI((S)(g uanidinooxy)pyrro|idiny|)pyridiny|)thio)
acetamide;
2-amino-N-(2-((6-((2-aminooxopheny|ethy|)thio)-3,5-dicyanoethylpyridin
yI)(methy|)amino)ethy|)-2—methy|propanamide;
2-((6-((2-(2-aminoethoxy)ethy|)(methyl)amino)-3,5-dicyanoethylpyridin
y|)thio)pheny|acetamide;
4-amino-N-(1-(6-((2-aminooxophenylethyl)thio)-3,5-dicyanoethylpyridin
y|)piperidinyl)butanamide;
((2-aminooxophenylethyl)thio)-3,5-dicyanoethylpyridin
y|)(methy|)amino)-N-(2-aminoethyl)acetamide;
2-((6-((2-(azetidiny|)oxoethy|)(methyl)amino)-3,5-dicyanoethylpyridin
y|)thio)pheny|acetamide;
2-((6-((R)(aminomethy|)f|uoropyrro|idiny|)-3,5-dicyanoethylpyridin
y|)thio)pheny|acetamide;
2-((3,5-dicyanoethyI((2-(3-hydroxyazetidiny|)
oxoethyl)(methyl)amino)pyridinyl)thio)phenylacetamide;
2-((3,5-dicyanoethyI(4-(guanidinooxy)piperidiny|)pyridiny|)thio)
phenylacetamide;
2-((6-(3-aminoazetidiny|)-3,5-dicyanoethylpyridinyl)thio)
phenylacetamide; (single isomer)
2-((3,5-dicyanoethyI((R)(methy|amino)piperidiny|)pyridinyl)thio)
phenylacetamide;
2-((3,5-dicyano—4-ethyI((2-((3R,4S)hydroxy(hydroxymethy|)pyrrolidiny|)-
2-oxoethyl)(methy|)amino)pyridiny|)thio)phenylacetamide;
(R)((6-((S)(aminomethy|)f|uoropyrro|idiny|)-3,5-dicyano—4-ethylpyridin
y|)thio)pheny|acetamide;
((2-aminooxophenylethyl)thio)-3,5-dicyanocyclopropylpyridin
y|)(methy|)amino)-N-(1,3-dihydroxypropan-Z-y|)acetamide;
2-((3,5-dicyanoethyI((S)(oxetany|amino)piperidiny|)pyridiny|)thio)-
2-phenylacetamide;
2-((6-((2-aminooxophenylethyl)thio)-3,5-dicyanocyclopropylpyridin
y|)(methy|)amino)-N,N-bis(2-hydroxyethyl)acetamide;
2-amino-N-(1-(6-((2-aminooxopheny|ethy|)thio)-3,5-dicyano
cyclopropylpyridinyl)piperidiny|)acetamide;
2-((3,5-dicyanoethyI(4-((2-hydroxyethyl)amino)methy|piperidin
y|)pyridiny|)thio)phenylacetamide;
5-dicyanoethyI((2-(g uan idinooxy) ethyl)(methyl)amino)pyrid iny|)thio)-
2-phenylacetamide;
2-((6-(4-((2-aminoethy|)amino)piperidiny|)-3,5-dicyanoethylpyridiny|)thio)-
2-phenylacetamide;
2-((3,5-dicyanoethyI((2-((S)(hyd thy|)mo rpholino)
oxoethyl)(methyl)amino)pyridinyl)thio)phenylacetamide;
2-((3,5-dicyano((2-((cis)-3,4-dihydroxypyrrolidiny|)
oxoethyl)(methyl)amino)ethy|pyridiny|)thio)phenylacetamide;
2-((3,5-dicyanoethy|((2-((S)(hydroxymethy|)pyrrolidiny|)
oxoethyl)(methyl)amino)pyridinyl)thio)phenylacetamide;
2-((3,5-dicyanoethyI((2-((3S,4S)hydroxy(hydroxymethy|)pyrro|idiny|)-
2-oxoethyl)(methy|)amino)pyridiny|)thio)phenylacetamide;
2-((3,5-dicyanoethyI((S)(neopentylamino)piperidinyl)pyridiny|)thio)
phenylacetamide;
2-((3,5-dicyanoethyI((2-((R)(hydroxymethyl)pyrrolidiny|)
oxoethyl)(methyl)amino)pyridinyl)thio)phenylacetamide;
2-((3,5-dicyano—6-((2-((3R,4R)-3,4-dihydroxypyrrolidiny|)
oxoethyl)(methyl)amino)ethy|pyridiny|)thio)phenylacetamide;
(R)((3,5-dicyanoethyI((S)hyd roxy(hyd roxymethy|)pyrro|idin
y|)pyridiny|)thio)phenylacetamide;
(28)amino-N-(1-(6-((2-aminooxopheny|ethy|)thio)-3,5-dicyano
cyclopropylpyridinyl)piperidinyl)propanamide;
(4-(2-aminoethoxy)piperidiny|)-3,5-dicyanocyclopropylpyridiny|)thi0)-
2-phenylacetamide;
2-((3,5-dicyanocyclopropyI(4-((2-hyd roxyethyl)amino)piperidiny|)pyridin
y|)thio)pheny|acetamide;
2-((6-((2-aminooxophenylethyl)thio)-3,5-dicyanoethylpyridin
y|)(methy|)amino)—N-(1,3-dihydroxypropan-Z-y|)acetamide;
2-((3,5-dicyano((2-((3R,SS)-3 ,5-dihyd roxypiperidiny|)
oxoethyl)(methyl)amino)ethy|pyridiny|)thio)phenylacetamide;
2-((3,5-dicyano((2-((3S,4S)-3,4-dihydroxypyrrolidiny|)
oxoethyl)(methyl)amino)ethy|pyridiny|)thio)phenylacetamide;
2-((3,5-dicyanoethyI(4-((2-hydroxyethyl)amino)(hydroxymethy|)piperidin
idiny|)thio)phenylacetamide;
2-((3,5-dicyanoethyI((2-((R)(hyd roxymethyl)morpholino)
oxoethyl)(methyl)amino)pyridinyl)thio)phenylacetamide;
2-((6-((2-aminooxophenylethyl)thio)-3,5-dicyanoethylpyridin
yI)(methy|)amino)-N-methoxyacetamide;
2-((3,5-dicyanoethyI((2-((3R,4R)hydroxy—4-(hydroxymethy|)pyrro|idiny|)-
2-oxoethyl)(methy|)amino)pyridiny|)thio)phenylacetamide;
2-((6-((2-aminooxophenylethyl)thio)-3,5-dicyanoethylpyridin
yI)(methy|)amino)-N-(3-hyd roxypropy|)-N-methylacetamide;
((2-aminooxophenylethyl)thio)-3,5-dicyanoethylpyridin
y|)(methy|)amino)-N-((R)-2,3-dihydroxypropy|)acetamide;
2-((6-(4-((2-aminooxoethyl)amino)piperidiny|)-3,5-dicyano
cyclopropylpyridiny|)thio)phenylacetamide;
WO 16727
2-((6-((2-aminooxophenylethyl)thio)-3,5-dicyanoethylpyridin
y|)(methy|)amino)—N,N-bis(2-hydroxyethy|)acetamide;
2-((6-((2-aminooxophenylethyl)thio)-3,5-dicyanoethylpyridin
yI)(methy|)amino)-N-(2-hydroxyethyl)acetamide;
2-((6-((3-aminopropy|)(methy|)amino)-3,5-dicyanoethylpyridinyl)thio)
acetamide;
2-((6-(3-(aminomethy|)azetidiny|)-3,5-dicyanoethylpyridinyl)thio)
phenylacetamide;
2-((6-((2-aminooxophenylethyl)thio)-3,5-dicyanoethylpyridin
y|)(methy|)amino)—N-((1-(hydroxymethyl)cyclopropy|)methy|)acetamide;
(R)((3,5-dicyanoethyI((S)hydroxypyrrolidiny|)pyridinyl)thio)(2,4-
difluoropheny|)acetamide;
2-((6-((2-aminooxophenylethyl)thio)-3,5-dicyanoethylpyridin
yI)(methy|)amino)-N-(3-(hydroxymethy|)oxetanyl)acetamide;
2-((3,5-dicyanoethyI(3-(guanidinooxy)azetidiny|)pyridiny|)thio)
phenylacetamide;
2-((6-((2-aminooxophenylethyl)thio)-3,5-dicyanoethylpyridin
yI)(methy|)amino)-N-(3-hyd roxypropy|)acetamide;
2-((3,5-dicyano(4-(2,3-dihydroxypropy|)-1,4-diazepany|)ethy|pyridin
y|)thio)pheny|acetamide;
2-((6-((2-aminooxophenylethyl)thio)-3,5-dicyanoethylpyridin
y|)(methy|)amino)-N-hydroxyacetamide;
3-amino-N-(1-(6-((2-aminooxopheny|ethy|)thio)-3,5-dicyano
cyclopropylpyridinyl)azetid iny|)oxetanecarboxamide;
2-((3,5-dicyanoethyI((S)hydroxypyrro|idinyl)pyridiny|)thio)(2-
fluorophenyl)acetamide;
2-((3,5-dicyano((S)(cyclopropylamino)piperidiny|)ethy|pyridiny|)thi0)-
2-phenylacetamide;
2-((6-((2-aminooxophenylethyl)thio)-3,5-dicyanoethylpyridin
yl)(methy|)amino)-N-(3-hydroxy-2,2-dimethylpropyl)acetamide;
4H-1,2,4-triazolyl)ethyl)((6-((2-aminooxophenylethyl)thio)-3,5-
dicyanoethylpyridinyl)(methyl)amino)acetamide;
N1 -(2-((6-((2-aminooxophenylethyl)thio)-3,5-dicyanoethylpyridin
yl)(methyl)amino)ethyl)oxalamide;
2-((6-(3-(aminomethyI)fluoroazetidinyl)-3,5-dicyanoethylpyridinyl)thio)-
2-phenylacetamide;
((3,5-dicyanoethyl((R)hyd roxy(hyd roxymethyl)pyrrolidin
yl)pyridinyl)thio)phenylacetamide;
2-((3,5-dicyano((S)((2,2—difluoroethyl)amino)piperidinyl)ethylpyridin
yl)thio)phenylacetamide;
((R)aminopiperidinyl)-3,5-dicyanoethylpyridinyl)thio)
phenylacetamide;
2-((6-(4-aminopiperidinyl)-3,5-dicyanomethoxypyridinyl)thio)
phenylacetamide;
2-((3,5-dicyanoethyl((S)hyd roxyisoxazolid in-2—yl)pyridinyl)thio)
phenylacetamide;
(R)((3,5-dicyanoethyl((3-hydroxypropyl)(methyl)amino)pyridin-2—yl)thio)
phenylacetamide;
2-((3,5-dicyano((S)hydroxypyrrolidiny|)methoxypyridinyl)thio)
phenylacetamide;
2-((3,5-dicyanoethyl(4-(3-methoxyazetidinyl)piperidinyl)pyridin
yl)thio)phenylacetamide; and
2-((3,5-dicyanoethyl(4-(3-methoxyazetidinyl)piperidinyl)pyridin
yl)thio)(4-fluorophenyl)acetamide;
or a pharmaceutically acceptable salt or prodrug thereof.
Suitably, presently invented novel compounds of a (lVbbr) are selected from:
2-{[3,5-dicyano(dimethylamino)ethylpyridinyl]sulfanyl}phenylacetamide;
2-((6-((2-Aminooxoethyl)(methyl)amino)-3,5-dicyanoethylpyridiny|)thio)
acetamide;
(R)((3,5-Dicyanoethyl((S)hydroxypyrrolidinyl)pyridinyl)thio)
phenylacetamide;
2-((6-(4-Aminopiperidinyl)-3,5-dicyanoethylpyridinyl)thio)
phenylacetamide;
(4-aminopiperidinyl)-3,5-dicyanoethylpyridinyl)thio)(4-
fluorophenyl)acetamide;
2-((3,5-dicyan0(4-(cyclobutyl(methyl)amino)piperidinyl)ethylpyridin
yl)thio)phenylacetamide;
2-((3,5-dicyanoethyl(3-fluoroA(neopentylamino)piperidinyl)pyridin
yl)thio)phenylacetamide;
(R)((3,5-dicyanoethyl((2-hydroxyethyl)(methyl)amino)pyridinyl)thio)
phenylacetamide;
2-((3,5-Dicyano(4-(cyclobutyl(methyl)amino)piperidinyl)ethylpyridin
yl)thio)(4-fluorophenyl)acetamide; and
2-((3,5-dicyanoethyl(methyl(1-methylpyrrolidinyl)amino)pyridiny|)thi0)-
2-phenylacetamide;
or a pharmaceutically acceptable salt or prodrug thereof.
Suitably, presently invented novel compounds of Formula (lVbbr) are selected from:
(R)((3,5-dicyanoethyl((2-hydroxyethyl)(methy|)amino)pyridinyl)thio)
phenylacetamide;
-Dicyano(4-(cyclobutyl(methyl)amino)piperidiny|)ethylpyridin
yl)thio)(4-fluorophenyl)acetamide; and
2-((3,5-dicyanoethyl(methyl(1-methy|pyrrolidinyl)amino)pyridiny|)thi0)-
2-phenylacetamide;
or a pharmaceutically acceptable salt or prodrug thereof.
Suitably, presently invented novel compounds of Formula (Vbbr) are selected from:
2-((3,5-dicyanocyclopropyl(1 ,4-diazepanyl)pyridinyl)thio)
phenylacetamide;
2-{[3,5-dicyanocyclopropyl(4-ethyl-1 ,4-diazepanyl)pyridinyl]sulfanyl}
acetamide;
2-((3,5-dicyanoethyl(4-propyl-1 zepany|)pyridinyl)thio)
phenylacetamide;
2-{[3,5-dicyanoethyl(4-ethyl-1 ,4-diazepanyl)pyridinyl]sulfanyl}
phenylacetamide;
2-{[3,5-dicyanoethyl(5-oxo-1 ,4-diazepanyl)pyridinyl]sulfany|}
acetamide;
2-((3,5-dicyanocyclopropylmorpholinopyridinyl)thio)(pyridin
yl)acetamide;
2-{[3,5-dicyanoethyl(4-methyloxo pipe razin-1 -yl)pyridinyl]sulfa nyl}
(pyrid inyl)acetamide;
2-[(3,5-dicyanoethyl{methyl[2-(morpholinyl)ethyl]amino}pyridin
yl)sulfanyl]phenylacetamide;
2-{[3,5-dicyanoethyl(4-propylpiperazinyl)pyridinyl]sulfanyl}
phenylacetamide;
2-({3,5-dicyanoethyl[4-(piperidinyl)piperazinyl]pyridinyl}sulfanyl)
phenylacetamide;
2-({3,5-dicyanocyclopropyl[3-(hydroxymethyl)piperazinyl]pyridin
yl}sulfanyl)phenylacetamide;
2-{[3,5-dicyanocyclopropyl(3-oxopiperazinyl)pyridinyl]sulfanyl}
phenylacetamide;
2-({3,5-dicyanocyclopropyl[4-(morpholinyl)piperidinyl]pyridin
yl}sulfanyl)phenylacetamide;
2017/053511
2-((3,5-dicyano—4-ethyI(2,8-d iazaspiro[4.5]decany|)pyridiny|)th io)
phenylacetamide;
2-((3,5-DicyanocyclopropyI(3-(dimethylamino)piperidiny|)pyridiny|)thio)-
2-phenylacetamide;
2-((3,5-DicyanocyclopropyI(3-methylpiperaziny|)pyridiny|)thio)
phenylacetamide;
2-((3,5-DicyanocyclopropyI(2-(hydroxymethyl)morpholino)pyridiny|)thio)
phenylacetamide;
2-((3,5-DicyanocyclopropyI(2,6-dimethylmorpholino)pyridinyl)thio)-2—
phenylacetamide;
2-((3,5-DicyanocyclopropyI(3-(dimethylamino)piperidiny|)pyridiny|)thio)-
2-phenylacetamide;
2-((6-(4-(Aminomethy|)hydroxypiperidiny|)-3,5-dicyanocyclopropylpyridin-
2-y|)thio)pheny|acetamide;
2-((3,5-dicyanocyclopropyI(3-(methylamino)piperidiny|)pyridiny|)thio)
phenylacetamide;
2-((6-(3-aminopiperidiny|)-3,5-dicyanocyclopropylpyridinyl)thio)
phenylacetamide;
2-((6-(4-aminopiperidiny|)-3,5-dicyanocyclopropylpyridinyl)thio)
phenylacetamide;
2-((3,5-dicyanocyclopropyI(4-(dimethylamino)piperidiny|)pyridiny|)thio)-
2-phenylacetamide;
2-((3,5-dicyanocyclopropyI(piperaziny|)pyridiny|)thio)(pyridin
y|)acetamide;
2-((3,5-dicyanocyclopropyI(1 zepany|)pyridiny|)thio)(pyridin
tamide;
2-((3,5-dicyanocyclopropyl((R)—3-hyd roxypiperidiny|)pyridinyl)thio)
phenylacetamide;
2-(3,5-dicyanocyclopropyI((S)hydroxypiperidiny|)pyridiny|thio)
phenylacetamide;
2-((3,5-dicyanocyclopropyI((S)hydroxypyrrolidiny|)pyridinyl)thio)
(pyrid iny|)acetamide;
-dicyanoethyI(4-ethylpiperaziny|)pyridiny|)thio)
phenylacetamide;
2-((3,5-DicyanoethyI(1-oxaazaspiro[3.4]octany|)pyridin-Z-yl)thio)
phenylacetamide;
2-((6-(4-(3-aminopropy|)piperaziny|)-3,5-dicyanoethylpyridinyl)thio)
phenylacetamide;
2-((3,5-DicyanoethyI(1,7-diazaspiro[3.5]nonany|)pyridiny|)thio)
acetamide;
2-((3,5-DicyanocyclopropyI(4-(pyrrolidiny|methy|)piperidiny|)pyridin
y|)thio)pheny|acetamide;
2-((3,5-DicyanocyclopropyI(4-(4-methylpiperaziny|)piperidinyl)pyridin
y|)thio)pheny|acetamide;
(R)((3,5-dicyano(1,4-diazepany|)ethy|pyridin-Z-yl)amino)
phenylacetamide;
2-((3,5-DicyanocyclopropyI(4-(pyrrolidiny|)piperidiny|)pyridiny|)thio)-
2-phenylacetamide;
2-((3,5-Dicyano—4-ethyI(2,7-diazaspiro[3.5]nonany|)pyridiny|)thio)
acetamide;
2-((3,5-DicyanoethyI(2,6-diazaspiro[3.4]octany|)pyridinyl)thio)
phenylacetamide;
2-((3,5-dicyanocyclopropyI(1,4-diazepany|)pyridiny|)thio)propanamide;
2-((3,5-DicyanoethyI(4-(2-oxoimidazoIidiny|)piperidiny|)pyridin
y|)thio)phenylacetamide;
2-((3,5-DicyanoethyI(4-hydroxypiperidiny|)pyridinyl)thio)
phenylacetamide;
2-((3,5-DicyanoethyI((S)hydroxypyrrolidiny|)pyridiny|)thio)
phenylacetamide;
2-((3,5-DicyanoethyI(3-oxopiperaziny|)pyridiny|)thio)
acetamide;
2-((3,5-DicyanoethyI((2-meth oxyethyl)(methyl)amino)pyridiny|)thio)
phenylacetamide;
2-((3,5-DicyanoethyI(3-methoxyazetidiny|)pyridinyl)thio)
phenylacetamide;
2-((3,5-DicyanoethyI(piperaziny|)pyridiny|)thio)pheny|acetamide;
2-((3,5-DicyanoethyI(4-methyI-1 ,4-diazepanyl)pyridin-2—y|)thio)
phenylacetamide;
2-((3,5-DicyanoethyImorpholinopyridinyl)thio)—2-phenylacetamide;
2-[[6-(azetidiny|)-3,5-dicyanoethyIpyridyl]suIfanyl]pheny|—acetamide;
2-((3,5-dicyanoethyI(4-oxopiperidiny|)pyridiny|)thio)—2-phenylacetamide;
2-((3,5-dicyanoethyI(1 yd roxyethy|)-[4,4'-bipipe rid in]-1 -y|)pyridin
y|)thio)pheny|acetamide;
2-((3,5-Dicyano((3S,5R)-3,5-dimethylpiperaziny|)ethy|pyridiny|)thio)
acetamide;
2-((6-(8-azabicyclo[3.2.1]octanyl(methy|)amino)-3,5-dicyanoethylpyridin
y|)thio)pheny|acetamide;
2-((3,5-DicyanocyclopropyI(2-(hydroxymethyl)morpholino)pyridin-2—y|)thio)
phenylacetamide;
(R)[(3,5-DicyanoethyImorpholinopyridyl)sulfany|]—2-phenyI-acetamide;
N-(4-((3,5-DicyanoethyI(4-(pyrrolidiny|)piperidiny|)pyridin
ylthio)methyl)benzy|)acetamide trifluoroacetate;
2-{[3,5-dicyanoethyI(5-methyI-1,4-diazepany|)pyridiny|]su|fany|}
phenylacetamide;
2-({3,5-Dicyano-4—ethyI[4-(2-methoxyethyl)-1 ,4-diazepanyl]pyridin
y|}suIfany|)pheny|acetamide;
-dicyano—4-ethyI(4-(2-hyd roxypropyI)-1 ,4-diazepany|)pyridiny|)thio)-
2-phenylacetamide;
Methyl 2—[4-(6-{[carbamoyl(pheny|)methy|]su|fany|}-3,5-dicyano—4-ethylpyridin
y|)-1 ,4-diazepany|]acetate;
2-{[3,5-DicyanocyclopropyI(4-methyIoxo-1,4-diazepany|)pyridin
y|]suIfany|}phenylacetamide;
2-{[3,5-Dicyanocyclopropyl(5-oxo—1 ,4-diazepany|)pyridinyl]su|fany|}
phenylacetamide;
2-{[3,5-DicyanoethyI(4-methyIoxo-1 ,4-diazepany|)pyridinyl]su|fany|}-
ylacetamide;
2-{[3,5-Dicyano(1,4-diazepanyl)ethylpyridiny|]su|fany|}
phenylacetamide;
2-({3,5-Dicyano[4-(2-hydroxyethyl)-1,4-diazepany|](2,2,2-
trifluoroethyl)pyridiny|}su|fany|)phenylacetamide;
(2R)({3,5-DicyanoethyI[4-(2-hydroxyethy|)-1,4-diazepany|]pyridin
y|}amino)phenylacetamide;
2-({6-[(3S)AminopyrroIidiny|]-3,5-dicyanocyclopropylpyridinyl}su|fany|)-
2-phenylacetamide;
2-((3,5-DicyanoethyI(2,9-diazaspiro[5.5]undecanyl)pyridin-Z-yl)thio)
phenylacetamide;
2-((3,5-DicyanoethyI(hexahydro-1H-pyrro|o[1 ,2-a][1 ,4]diazepin-2(3H)-
y|)pyridiny|)thio)phenylacetamide;
2-((3,5-DicyanoethyI(2-methyI-2,9-diazaspiro[5.5]undecany|)pyridin
y|)thio)pheny|acetamide;
2-((3,5-Dicyano(2-(cyclopropylmethyI)-2,9-diazaspiro[5.5]undecanyI)
ethylpyridiny|)thio)phenylacetamide hloride;
2-((3,5-Dicyano(4-(3-(dimethylamino)propy|)piperaziny|)ethy|pyridin
y|)thio)pheny|acetamide;
2-((3,5-DicyanoethyI(4-(pyrroIidinyl)piperidiny|)pyridiny|)thio)
phenylacetamide; 2,2,2-trifluoroacetic acid;
([4,4'-Bipiperidin]—1-yl)-3,5-dicyanoethylpyridiny|)thio)
phenylacetamide;
2-((6-(4-(2-Aminoethy|)piperaziny|)-3,5-dicyanoethylpyridinyl)thio)
phenylacetamide;
2-((6-(4-(3-Aminopropyl)piperaziny|)-3,5-dicyanocyclopropylpyridiny|)thio)-
2-phenylacetamide;
-DicyanocyclopropyI(4-((4-methylpiperaziny|)methy|)piperidin
y|)pyridiny|)thio)phenylacetamide;
2-((6-(4-Acetylpiperaziny|)-3,5-dicyanoethylpyridin-Z-yl)thio)
phenylacetamide;
2-((3,5-DicyanoethyI(4-(2-hydroxyethy|)piperaziny|)pyridiny|)thio)
phenylacetamide;
2-[(3,5-Dicyano—4-cyclopropyImorpholinopyridy|)su|fany|]phenyl-
ide;
2-((6-(4-Benzoy|piperaziny|)-3,5-dicyanoethylpyridinyl)thio)
phenylacetamide;
2-((3,5-DicyanoethyI((5S,6S)hydroxy(methy|su|fonyI)-1,8-
diazaspiro[4.5]decan-8—y|)pyridin-2—yl)thio)pheny|acetamide;
2-((3,5-Dicyano(4,4-difluoropiperidiny|)ethy|pyridinyl)thio)
phenylacetamide;
(R)((3,5-Dicyanoethyl((R)hydroxypyrrolidiny|)pyridinyl)thio)
phenylacetamide;
2-((3,5-dicyano(fu ranyI)(4-methyI-1 ,4-diazepany|)pyridinyl)thio)
phenylacetamide;
2-((6-(4-aminomethylpiperidinyI)-3,5-dicyanoethylpyridinyl)thio)
phenylacetamide;
2-amino-N-(1-(6-((2-aminooxophenylethyl)thio)-3,5-dicyanoethylpyridin-2—
y|)piperidiny|)acetamide;
(28)amino-N-(1-(6-((2-aminooxo—1-pheny|ethy|)thio)-3,5-dicyano
ethylpyridiny|)piperidiny|)propanamide;
(4-(3-aminooxetanecarbony|)piperaziny|)-3,5-dicyanoethylpyridin
y|)thio)pheny|acetamide;
4-amino-N-(1-(6-((2-aminooxopheny|ethy|)thio)-3,5-dicyanoethylpyridin
y|)piperidinyl)tetrahydro-2H-pyrancarboxamide;
2-((6-(4-(4-aminotetrahydro-2H-pyrancarbonyl)piperazinyl)-3,5-dicyano
ethylpyridiny|)thio)phenylacetamide;
2-((3,5-dicyano(4-(2-hydroxyethyl)-1 zepany|)methoxypyridin
y|)thio)pheny|acetamide;
2-((6-(4-aminopiperidiny|)-3,5-dicyanoethylpyridiny|)thio)
phenylacetamide;
2-((6-((2-aminoethyl)(methy|)amino)-3 ,5-dicyanoethylpyrid iny|)th io)
phenylacetamide;
2-((6-((2-aminooxoethy|)(methy|)amino)-3,5-dicyanoethylpyridiny|)thio)
phenylacetamide;
2-((3,5-dicyanoethyI(3-hydroxyazetidiny|)pyridinyl)thio)
phenylacetamide;
2-((3,5-dicyanoethyI((2-hyd roxyethyl)(methy|)amino)pyridinyl)thio)
acetamide;
2-amino-N-(1-(6-((2-aminooxopheny|ethy|)thio)-3,5-dicyanoethylpyridin
y|)piperidiny|)methy|propanamide;
2-((6-(4-(2-aminoethoxy)piperidiny|)-3,5-dicyanoethylpyridinyl)thio)
phenylacetamide;
2-((3,5-dicyanoethyI(3-hydroxypyrroIidiny|)pyridinyl)thio)
phenylacetamide;
2-((3,5-dicyanoethyI(4-(2-hydroxyethoxy)piperidiny|)pyridinyl)thio)
phenylacetamide;
or a pharmaceutically acceptable salt or prodrug thereof.
Included prodrugs of Formula (Vbbr) ofthe invention are:
(2-aminooxophenylethyl)thio)-3,5-dicyanoethylpyridinyl)pyrrolidin-
3-yl dihydrogen phosphate;
((2-aminooxophenylethyl)thio)-3,5-dicyanoethylpyridin
thyl)amino)ethyl dihydrogen phosphate;
1-(6-((2-aminooxophenylethyl)thio)-3,5-dicyanoethylpyridinyl)azetidin-
3-yl dihydrogen phosphate;
(28)((1-(6-((2-aminooxophenylethyl)thio)-3,5-dicyanoethylpyridin
yl)piperidinyl)oxy)ethyl omethylbutanoate;
(S)(6-(((S)aminooxophenylethyl)thio)-3,5-dicyanoethylpyridin
yl)pyrro|idinyl dihydrogen phosphate;
2-((1-(6-((2-aminooxophenylethyl)thio)-3,5-dicyanoethylpyridin
yl)piperidinyl)oxy)ethyl dihydrogen phosphate; and
1-(6-((2-aminooxophenylethyl)thio)-3,5-dicyanoethylpyridinyl)piperidin-
4-yl dihydrogen phosphate;
or a pharmaceutically acceptable salt thereof.
Non primary amide:
ly, presently invented novel compounds of Formula (lcr) are selected from:
2-amino-N-(1-(3,5-dicyanoethyl((4-(N-
methylmethylsulfonamido)benzyl)thio)pyridinyl)piperidin-4—y|)methy|propanamide;
(R)amino-N-(1-(3,5-dicyanoethyl((4-(N-
methylmethylsulfonamido)benzyl)thio)pyridinyl)piperidin-4—y|)propanamide;
N-(4-(((3,5-dicyanoethyl(methyl(2-(piperidinyl)ethyl)amino)pyridin
yl)thio)methyl)phenyl)-N-methylmethanesulfonamide;
N-(4-(((6-(4-Aminopiperidinyl)-3,5-dicyanoethylpyridin
y|)thio)methyl)benzyl)acetamide;
2-(4-aminopiperidinyl)((4-(1,1-dioxidoisothiazolidinyl)benzyl)thio)
ethylpyridine-3,5-dicarbonitrile;
2-(4-aminopiperidinyl)((4-(1,1-dioxido-1,2-thiazinanyl)benzyl)thio)—4-
ethylpyridine-3,5-dicarbonitrile;
2-(4-aminopiperidinyl)ethyl((4-
((methylsulfony|)methyl) benzyl)thio)pyridine-3 ,5-dica rbon itrile;
4-(((6-(4-aminopiperidinyl)-3,5-dicyanoethylpyridinyl)thio)methyl)phenyl
methanesulfonate;
N-(4-(((3,5-dicyanoethyl(4-(isopropylamino)piperidinyl)pyridin
yl)thio)methyl)phenyl)-N-methylmethanesulfonamide;
N-(4-(((6-(4-aminopiperidinyl)-3,5-dicyanoethylpyridin
yl)thio)methyl)phenyl)-N-methylmethanesulfonamide;
N-(4-((3,5-Dicyanoethyl(4-(pyrrolidinyl)piperidinyl)pyridin
ylthio)methyl)benzyl)acetamide;
2-amino-N-(4-(((3,5-dicyano((2-(diethylamino)ethyl)(methyl)amino)-4—
yridiny|)thio)methyl)benzy|)acetamide;
relamino-N-(4-(((6-(cisaminofluoropiperidinyl)-3,5-dicyano
ethylpyrid iny|)th io)methyl)benzy|)acetamide;
((3,5-dicyanoethyl(2-(pyrrolidiny|methyl)morpholino)pyridin
yl)thio)methyl)phenyl)-N-methylmethanesulfonamide;
N-(4-(((3,5-Dicyanoethyl(4-methyl-1 ,4-diazepanyl)pyridin
yl)thio)methyl)benzyl) acetamide; and
N-(4-(((3,5-dicyano(3-((dimethylamino)methyl)piperidinyl)ethylpyridin
o)methyl)phenyl)-N-methylmethanesulfonamide;
or a pharmaceutically acceptable salt or prodrug thereof.
Suitably, presently invented novel compounds of Formula (lcr) are ed from:
N-(4-((3,5-Dicyanoethyl(4-(pyrrolidinyl)piperidinyl)pyridin
ylthio)methyl)benzyl)acetamide;
2-(4-(Aminomethyl)benzylthio)ethyl(4-(pyrrolidinyl)piperidiny|)pyridine-
3,5-dicarbonitrile;
utyl 4-(((3,5-dicyanoethyI(4-methyl-1 zepany|)pyridin
y|)thio)methy|)benzy|carbamate;
4-(((3,5-DicyanoethyI(4-methyl-1 ,4-diazepanyl)pyridin
y|)thio)methy|)benzamide;
(Aminomethy|)benzyl)thio)ethy|—6-(4-methyI-1,4-diazepany|)pyridine-
3,5-dicarbonitrile;
2-(4-(((3,5-Dicyanoethyl—6-(4-methyl-1 ,4-diazepany|)pyridin
y|)thio)methy|)pheny|)acetic acid;
4-(((3,5-DicyanoethyI(4-methyl-1 ,4-diazepanyl)pyridin
y|)thio)methy|)benzoic acid;
2-(Dimethy|amino)ethy|—6-(((6-oxo-1 ,6-dihydropyridinyl)methy|)thio)pyridine-
3,5-dicarbonitrile;
N-(4-(((3,5-Dicyanoethyl(4-methyl-1 ,4-diazepany|)pyridin
y|)thio)methy|)thiazoIy|)acetamide;
4-(((3,5-DicyanoethyI(4-methyl-1 ,4-diazepanyl)pyridin
y|)thi0)methy|)benzenesulfonamide;
N-(4-(((3,5-Dicyanoethyl(4-methyl-1 ,4-diazepany|)pyridin
y|)thio)methy|)benzy|) acetamide;
tert—Butyl (2-((4-(((3,5-dicyanoethyI(4-methyl-1 ,4-diazepany|)pyridin
y|)thi0)methyl)benzy|)amino)oxoethy|)carbamate;
N-(4-(((3,5-Dicyanoethyl(4-methyl-1 ,4-diazepany|)pyridin
y|)thio)methy|)benzy|)methanesulfonamide;
2-Amino-N-(4-(((3,5-dicyanoethyl(4-methyl-1 ,4-diazepany|)pyridin
y|)thio)methy|)benzy|)acetamide;
2-(4-Aminopiperidiny|)(benzy|thio)ethy|pyridine-3, 5-dicarbonitrile;
4-(((3,5-DicyanoethyI(4-methyl-1 zepanyl)pyridin
y|)thio)methy|)benzy| acetate;
2-(4-(((3,5-Dicyanoethyl—6-(4-methyl-1 ,4-diazepany|)pyridin
y|)thio)methy|)pheny| acetamide;
2-(4-(((3,5-Dicyanoethyl—6-(4-methyl-1 ,4-diazepany|)pyridin
y|)thio)methyl)phenyI)-N-methylacetamide;
4-EthyI((4-(hydroxymethy|)benzyl)thio)(4-methyI-1 ,4-diazepanyl)pyridine-
3,5-dicarbonitrile;
N-(4-(((3,5-Dicyanoethyl(4-methyl-1 ,4-diazepany|)pyridin
y|)thio)methy|)benzyI)hydroxyacetamide;
e 87N-(4-(((3,5-DicyanoethyI(4-methyI-1,4-diazepany|)pyridiny|)thio)
methy|)benzy|)propionamide;
N-(4-(((3,5-Dicyanoethyl(4-methyl-1 ,4-diazepany|)pyridin
y|)thio)methy|)benzy|)isobutyramide;
N-(4-(((3,5-Dicyanoethyl(4-methyl-1 ,4-diazepany|)pyridin
y|)thio)methyl)benzyI)methylbutanamide;
4-EthyI((4-(((2-hydroxyethy|)amino)methyl)benzyl)thio)(4-methyI-1,4-
diazepany|)pyridine-3,5-dicarbonitrile;
N-(4-(((3,5-Dicyano—6-(4-methyl-1,4-diazepany|)(methy|amino)pyridin
y|)thio)methyl)benzy|)acetamide;
2-(((2-Acety|—1 ,2,3,4-tetrahydroisoquinolinyl)methyl)thio)(dimethy|amino)
ethylpyridine-3,5-dicarbonitrile;
2-((4-Cyanobenzy|)thio)ethyI(4-methy|-1,4-diazepany|)pyridine-3,5-
dicarbonitrile;
o-N-(1 -(6-(benzy|thio)-3,5-d icyanoethylpyridinyl) pipe ridin
y|)acetamide;
2-Amino-N-(1-(6-(benzy|thio)—3,5-dicyanoethylpyridinyl)piperidin-4—yl)—2-
methylpropanamide;
3-Amino-N-(4-(((3,5-dicyanoethyl(4-methyl-1 ,4-diazepany|)pyridin
y|)thio)methyl)benzy|)propanamide;
(S)Amino-N-(4-(((3,5-dicyanoethyI(4-methyI-1,4-diazepany|)pyridin
o)methyl)benzy|)propanamide;
(R)Amino-N-(4-(((3,5-dicyanoethyI(4-methyI-1,4-diazepany|)pyridin
y|)thio)methyl)benzy|)propanamide;
WO 16727
1-(4-(((3,5-DicyanoethyI(4-methyl-1,4-diazepany|)pyridin
y|)thio)methy|)benzy|)ethy|urea;
1-(4-(((3,5-DicyanoethyI(4-methyl-1,4-diazepany|)pyridin
y|)thio)methyl)benzyI)phenylurea;
N-(4-(((3,5-Dicyano(4-methyI-1,4-diazepany|)(methy|thio)pyridin
y|)thio)methyl)benzy|)acetamide;
(E)(4-(((3,5-Dicyano(dimethylamino)ethy|pyridin-2—
y|)thio)methy|)pheny|)acrylic acid;
N-(4-(((3,5-Dicyanoethyl((2-hyd roxyethyl)(methyl)amino)pyridin
y|)thio)methyl)benzy|)acetamide;
4-(((3,5-DicyanoethyI(4-methyl-1,4-diazepanyl)pyridiny|)thio)methyI)-N-
methylbenzenesuIfonamide;
N-(4-(((3,5-Dicyanoethoxy(4-methyl-1,4-diazepany|)pyridin
y|)thio)methyl)benzy|)acetamide;
N-(4-(((6-(4-Aminopiperidiny|)-3,5-dicyanoethylpyridin
y|)thio)methyl)benzy|)acetamide;
(S)—2-((1-(6-((4-(Acetamidomethyl)benzyl)thio)-3,5-dicyanoethylpyridin
y|)piperidiny|)oxy)ethy| 2-aminomethylbutanoate;
(S)((6-((4-(Acetamidomethy|)be nzyl)th io)-3,5-d icyanoethylpyrid in
thy|)amino)ethy| 2-aminomethylbutanoate;
2-Amino-N-(4-(((3,5-dicyano(dimethy|amino)ethy|pyridin
y|)thio)methyl)benzy|)acetamide;
4-EthyI(4-methyI-1,4-diazepany|)((4-((2-oxopyrrolidin
yI)methy|)benzyl)thio)pyridine-3,5-dicarbonitrile;
(Aminomethyl)benzyl)thio)(dimethylamino)ethy|pyridine-3,5-
dicarbonitrile;
((3,5-Dicyano—6-(dimethylamino)ethy|pyridiny|) thio) methyl) phenyl)
acetamide;
N-(4-(((3,5-Dicyano(dimethylamino)ethy|pyridiny|)thio)methyl)benzyI)
hydroxyacetamide;
3-Amino-N-(4-(((3,5-dicyano(dimethylamino)ethy|pyridin
y|)thio)methyl)benzy|)propanamide;
(S)(6-((4-(Acetamidomethy|)benzy|)thio)-3,5-dicyanoethylpyridin-2—
y|)azetidiny| 2—aminomethylbutanoate;
N-(4-(((3,5-Dicyanoethylmethylpyridiny|)thio)methyl)benzy|)acetamide;
2-(4-(((3,5-Dicyano(dimethylamino)ethy|pyridiny|)thio)methyI)-1H-pyrazol—
1-y|)acetamide;
((3,5-Dicyano(dimethylamino)ethy|pyridiny|)thio)methy|)pheny|)
methanesulfonamide;
(S)(6-((4-(Acetamidomethyl)benzyl)thio)-3,5-dicyanoethylpyridin-2—
y|)piperidiny| 2-aminomethylbutanoate;
6-((4-(Acetamidomethyl)benzy|)thio)-3,5-dicyanoethylpyridin
y|)piperidiny|)acetamide;
2-(4-(((3,5-Dicyano(dimethylamino)ethylpyridiny|)thio)methy|)pheny|)-N-(2-
hydroxyethyl)acetamide;
4-(((3,5-Dicyano(dimethylamino)—4-ethy|pyridinyl)thio)methyI)-N-(2-
hydroxyethy|)benzamide;
2-((4-(1H-lmidazoly|)benzy|)thio)—4-ethyI(4-methyl-1 ,4-diazepan
y|)pyridine-3,5-dicarbonitrile;
2-((4-Cyanomethylbenzy|)thio)-4—ethy|—6-(4-methyI-1 ,4-diazepany|)pyridine-
3,5-dicarbonitrile;
tert-Butyl(4-(((3,5-dicyanoethyI(4-methyl-1 ,4-diazepany|)pyridin
y|)thio)methyl)pheny|)carbamate;
2-((4-Aminobenzyl)thio)ethy|—6-(4-methyI-1,4-diazepany|)pyridine-3,5-
dicarbonitrile;
N-(4-(((3,5-Dicyanoethyl—6—(4-methyI-1 ,4-diazepany|)pyridin
y|)thio)methyl)pheny|)acetamide;
N-(4-(((3,5-Dicyanoethyl—6—(4-methyI-1 ,4-diazepany|)pyridin
y|)thio)methy|)pheny|) methanesulfonamide;
WO 16727
2-(((6-Aminopyridinyl)methyl)thio)ethy|(4-methy|—1 ,4-diazepan
y|)pyridine-3,5-dicarbonitrile;
N-(4-(((3,5-Dicyanoethyl(4-methyl-1 ,4-diazepany|)pyridin
y|)thio)methy|)phenyI)hyd roxyacetamide;
2-Amino-N-(4-(((3,5-dicyanoethyl(4-methyl-1 ,4-diazepany|)pyridin
y|)thi0)methyl)pheny|)acetamide;
N-(4-(((3,5-Dicyanoethyl—6-(3-oxopiperaziny|)pyridiny|)thio) methyl) benzyl)
acetamide;
N-(4-(((3,5-Dicyanoethyl—6-(3-hydroxypyrrolidinyl)pyridin
y|)thio)methyl)benzy|)acetamide;
N-(4-(1-(3,5-Dicyano(4-(dimethylamino)piperidiny|)ethy|pyridin
ylthio)propyl)benzy|)acetamide;
N-(5-(((3,5-dicyanoethyI(4-methyl-1 ,4-diazepany|)pyridin
y|)thio)methy|)pyridinyl)methanesulfonamide;
2-(6-(4-(Acetamidomethyl)benzy|th io)-3,5-dicyanoethylpyridinylth io)
acetamide;
I((4-(pyridinyl)benzyl)thio)(4-(pyrro|idiny|)piperidiny|)pyridine-
3,5-dicarbonitrile;
4-EthyI((4-(pyridinyl)benzyl)thio)(4-(pyrro|idiny|)piperidiny|)pyridine-
3,5-dicarbonitrile;
2-Amino-N-(1-(3,5-dicyanoethyI((4-su|famoy|benzy|)thio)pyridin
y|)piperidinyl)acetamide;
2-(4-(((3,5-Dicyanoethyl—6-(4-methyl-1 ,4-diazepany|)pyridin
y|)thio)methy|)pheny|)-N-(2-hydroxyethyl)acetamide;
2-(((1H-|ndoIyI)methyl)thio)ethyI(4-(pyrrolidiny|)piperidiny|)pyridine-
3,5-dicarbonitrile;
4-(((6-(4-Aminopiperidiny|)-3,5-dicyanoethylpyridinyl)thio)methyl)
benzenesulfonamide;
2-((Benzo[d][1 ,3]dioonylmethy|)thio)ethyI(4-methy|-1 ,4-diazepan
y|)pyridine-3,5-dicarbonitrile;
2-(((3,3-Dimethoxyoxoindolinyl)methy|)thio)ethyI(4-methy|-1,4-
diazepany|)pyridine-3,5-dicarbonitrile;
2-(((2,3-Dioxoindolinyl)methy|)thio)ethyl(4-methy|—1 ,4-diazepan
y|)pyridine-3,5-dicarbonitrile;
((6-(((4H-1,2,4-Triazo|—3-y|)methyl)(methy|)amino)-3,5-dicyano
ethylpyridiny|)thi0)methy|)benzyl)acetamide;
4-EthyI((4-(pyridinyl)benzyl)thio)(4-(pyrro|idiny|)piperidiny|)pyridine-
carbonitrile;
N-(4-(((3,5-Dicyanoethyl(4-methyl-1 ,4-diazepany|)pyridin
y|)thi0)methyl)phenyI)-N-methylacetamide;
((3,5-Dicyanoethyl(4-methyl-1 ,4-diazepany|)pyridiny|)
thio)methyl)phenyI)-N-methy|methanesuIfonamide;
4-((3,5-DicyanoethyI(4-methyI-1 ,4-diazepanyl)pyridin
ylthio)methyl)pheny|boronic acid;
N-(4-(((3,5-Dicyanoethyl(4-methyl-1 ,4-diazepany|)pyridin
y|)thi0)methyl)benzy|)(methy|amino)acetamide;
2-((4-Aminofluorobenzyl)thio)ethy|—6-(4-methy|-1,4-diazepany|)pyridine-
3,5-dicarbonitrile;
N-(4-(((3,5-Dicyanoethyl(4-methyl-1 ,4-diazepany|)pyridin
0)methyI)fluoropheny|)methanesulfonamide;
N-(4-(((3,5-Dicyanoethyl(4-methyl-1 ,4-diazepany|)pyridiny|)
thio)methyI)fluorophenyl)acetamide;
2-(4-Aminopiperidiny|)ethy|(((1-(2-hydroxyethyI)-1H-pyrazoI
y|)methy|)thio)pyridine-3,5-dicarbonitrile;
N-(4-(((3,5-Dicyano—4-ethyl—6-(3-hydroxypyrrolidiny|)pyridin
y|)thio)methy|)benzyI)hydroxyacetamide;
N-(4-(((6-((2-Aminooxoethyl) (methyl) amino)-3, 5-dicyanoethylpyridinyl)
thio) methyl) benzyI)hydroxyacetamide;
2-(4-(2-(Dimethylamino)ethoxy)benzylthio)ethy|—6-(4-methyI-1 ,4-diazepan
yI)pyridine-3,5-dicarbonitrile;
4-EthyI(4-methyI-1 ,4-diazepanyl)((4-(methy|suIfonyl)benzy|)thio)pyridin
e-3,5-dicarbonitri|e;
minopiperidiny|)(((1-(2, 3-dihydroxypropyI)-1H-pyrazoI
yI)methy|)thio)-4—ethy|pyridine-3,5-dicarbonitrile;
4-EthyI(4-methyI-1,4-diazepany|)((4-(4-methylpiperazin
y|)benzy|)thio)pyridine-3,5-d icarbon itrile;
4-EthyI(4-methyI-1,4-diazepany|)((4-(((2-oxopyrroIidin
no)methy|)benzy|)thio)pyridine-3,5-dicarbonitrile;
2-(((1H-Benzo[d]imidazoIyl)methy|)thio)ethy|—6-(4-methyI-1 ,4-diazepan
y|)pyridine-3,5-dicarbonitrile;
4-EthyI(4-methyI-1,4-diazepanyI)(4-
(methylsulfonylmethyl)benzylth io)pyrid ine-3,5-dicarbon itrile;
2-{[3,5-dicyano(dimethylamino)ethy|pyridiny|]su|fany|}phenylacetamide;
N-(4-(((3,5-dicyanoethyl—6-(methyl(2-(neopentylamino)ethyl)amino)pyridin
y|)thio)methy|)pheny|)-N-methy|methanesulfonamide;
N-(4-(((3,5-dicyanoethyl—6—((2-((2—
methoxyethyl)(methyl)amino)ethy|)(methy|)amino)pyridinyl)thio)methyl)phenyI)-N-
methanesulfonamide;
N-(4-(((3,5-dicyanoethyI(methyl(2-(methylamino)ethy|)amino)pyridin
y|)thi0)methy|)pheny|)-N-methy|methanesulfonamide;
N-(4-(((3,5-dicyanoethyl—6-((2-((2-
yethy|)amino)ethyl)(methy|)amino)pyridin-Z-yl)thio)methy|)pheny|)-N-
methylmethanesulfonamide;
N-(4-(((3,5-dicyanoethyl—6—(methyl(2-((1 -
methylcyclopropy|)amino)ethyl)amino)pyridinyl)thio)methyl)phenyI)-N-
methylmethanesulfonamide;
N-(4-(((3,5-dicyano((2-(dimethy|amino)ethyl)(methyl)amino)ethy|pyridin
y|)thi0)methy|)pheny|)-N-methy|methanesulfonamide;
N-(4-(((6-((2-aminoethyl)(methyl)amino)-3,5-dicyanoethylpyridin
y|)thio)methy|)pheny|)-N-methy|methanesulfonamide;
WO 16727
2-(4-aminopiperidiny|)ethy|((4-
((methylsulfony|)methy|) benzy|)thio)pyridine-3 ,5-dica rbon itrile;
N-(4-(((3,5-dicyanoethyl—6-((2-((2-
fluoroethy|)amino)ethy|)(methy|)amino)pyridiny|)thio)methyl)pheny|)—N-
methylmethanesulfonamide;
2-amino-N-(4-(((3,5-dicyano((2-(diethylamino)ethy|)(methy|)amino)
ethylpyridiny|)thio)methy|)benzyl)acetamide;
4-(((3,5-dicyanoethyI(4-methyl-1 ,4-diazepany|)pyridiny|)thio)methy|)-N-
(1 H-pyrazoIy|)benzamide;
relamino-N-(4-(((6-(cisaminofluoropiperidiny|)-3,5-dicyano
ethylpyridiny|)thio)methy|)benzyl)acetamide;
N-(4-(((3,5-dicyanoethyI(4-(isopropylamino)piperidiny|)pyridin-2—
y|)thio)methyl)phenyI)-N-methy|methanesulfonamide;
N-(4-(((3,5-dicyanoethyI(4-((2-methoxyethy|)amino)piperidiny|)pyridin
y|)thio)methyl)phenyI)-N-methy|methanesulfonamide;
N-(4-(((3,5-dicyanoethyl—6—(4-(neopentylamino)piperidiny|)pyridin
y|)thio)methyl)phenyI)-N-methy|methanesulfonamide;
N-(4-(((3,5-dicyanoethy|(methy|(2-(pyrro|idiny|)ethy|)amino)pyridin
y|)thio)methyl)phenyI)-N-methy|methanesulfonamide;
N-(4-(((3,5-dicyano(2-((dimethy|amino)methy|)morpholino)-4—ethy|pyridin
y|)thio)methyl)phenyI)-N-methy|methanesulfonamide;
2-amino-N-(1-(3,5-dicyanoethyI((4-(N-
methylmethylsulfonamido)benzy|)thio)pyridin-2—yl)piperidinyI)methylpropanamide;
N-(4-(((3,5-dicyano(4-(cyclopropylamino)piperidiny|)ethy|pyridin
o)methyl)phenyI)-N-methy|methanesulfonamide;
N-(4-(((3,5-dicyanoethyI(2-(pyrrolidiny|methyl)morpholino)pyridin
y|)thio)methyl)phenyI)-N-methy|methanesulfonamide;
N-(4-(((3,5-dicyanoethyl—6-(methyl(2-(piperidiny|)ethy|)amino)pyridin
y|)thio)methyl)phenyI)-N-methy|methanesulfonamide;
2017/053511
N-(4-(((3,5-dicyano((2-(diethylamino)ethy|)(methy|)amino)ethy|pyridin
yI)thi0)methy|)pheny|)-N-methy|methanesulfonamide;
N-(4-(((3,5-dicyano(2-((diethy|amino)methy|)morpho|ino)ethy|pyridin
0)methyl)phenyI)-N-methy|methanesulfonamide;
N-(4-(((3,5-dicyanoethyI(4-(pyrrolidiny|)piperidiny|)pyridin
yI)thi0)methy|)pheny|)-N-methy|methanesulfonamide;
(R)amino-N-(1-(3,5-dicyanoethyI((4-(N-
methylmethylsulfonamido)benzyl)thio)pyridiny|)piperidiny|)propanamide;
(S)amino-N-(1-(3,5-dicyanoethyI((4-(N-
methylmethylsulfonamido)benzyl)thio)pyridiny|)piperidiny|)propanamide;
N-(4-(((6-(4-aminopiperidiny|)-3,5-dicyanoethylpyridin
yI)thi0)methy|)pheny|)-N-methy|methanesulfonamide;
2-amino-N-(1-(3,5-dicyanoethyI((4-(N-
methylmethylsuIfonamido)benzyl)thio)pyridinyl)piperidinyl)acetamide;
N-(4-(((6-(2-(aminomethyl)morpholino)-3,5-dicyanoethylpyridin
yI)thi0)methy|)pheny|)-N-methy|methanesulfonamide;
N-(4-(((3,5-dicyanoethyI(4-methyl-1 ,4-diazepany|)pyridin
yI)thio)methyI)phenyI)fluoro-N-methy|methanesulfonamide;
N-(4-(((3,5-dicyanoethyI(2-((methy|amino)methyl)morpholino)pyridin
yI)thi0)methy|)pheny|)-N-methy|methanesulfonamide;
N-(4-(((3,5-dicyano(3-((dimethy|amino)methy|)piperidiny|)ethy|pyridin
yI)thio)methy|)pheny|)-N-methy|methanesulfonamide;
2-(4-aminopiperidiny|)((4-(1,1-dioxidoisothiazolidin-Z-yl)benzy|)thio)
ethylpyridine-3,5-dicarbonitrile;
minopiperidiny|)((4-(1,1-dioxido-1,2-thiazinan-Z-yl)benzy|)thio)
ethylpyridine-3,5-dicarbonitrile;
N-(4-(((3,5-dicyanoethyI(4-methyl-1 ,4-diazepany|)pyridin
yI)thio)methyI)phenyI)-1,1-difluoro-N-methylmethanesulfonamide;
2-((4-(1,1-dioxidoisothiazolidiny|)benzy|)thio)ethyI(4-
(neopentylamino)piperidiny|)pyridine-3,5-dicarbonitrile;
2-((4-(1 ,1 -dioxido-1 ,2-thiazinanyl)benzyl)thio)ethyl(4-
(neopentylamino)piperidinyl)pyridine-3,5-dicarbonitrile;
4-(((6-(4-aminopiperidinyl)-3,5-dicyanoethylpyridinyl)thio)methyl)phenyl
methanesulfonate;
(R)amino-N-((1-(3,5-dicyanoethyl((4-(N-
methylmethylsulfonamido)benzyl)thio)pyridinyl)pyrrolidinyl)methy|)acetamide;
(S)amino-N-((1-(3,5-dicyanoethyl((4-(N-
methylmethylsulfonamido)benzyl)thio)pyridinyl)pyrrolidinyl)methy|)acetamide;
N-(4-(1-((6-(4-aminopiperidinyl)-3,5-dicyanoethylpyridin-2—
o)ethyl)phenyl)-N-methylmethanesulfonamide;
N-(4-(((6-(4-aminopiperidinyl)-3,5-dicyanomethoxypyridin
yl)thio)methyl)phenyl)-N-methylmethanesulfonamide; and
N-(4-(((3,5-dicyanoethyl(4-((2-hyd roxyethyl)amino)piperidinyl)pyridin
yl)thio)methyl)phenyl)-N-methylmethanesulfonamide;
or a pharmaceutically acceptable salt or prodrug thereof.
The skilled artisan will appreciate that pharmaceutically acceptable salts, of the
compounds according to Formula (I) may be prepared. , in certain embodiments of
the invention pharmaceutically acceptable salts ofthe compounds according to Formula (I)
may be red over the tive free or unsalted compound. Accordingly, the
invention is further directed to pharmaceutically acceptable salts, of the compounds
according to Formula (I). The invention is further directed to free or unsalted compounds
of a (I).
The pharmaceutically acceptable salts ofthe compounds ofthe invention are readily
ed by those of skill in the art.
Representative ceutically acceptable acid addition salts e, but are not
limited to, 4-acetamidobenzoate, acetate, adipate, alginate, ascorbate, ate,
benzenesulfonate ate), benzoate, bisulfate, bitartrate, butyrate, calcium edetate,
camphorate, camphorsulfonate (camsylate), caprate (decanoate), caproate (hexanoate),
caprylate (octanoate), cinnamate, citrate, cyclamate, digluconate, 2,5-dihydroxybenzoate,
disuccinate, dodecylsulfate (estolate), e enediaminetetraacetate), estolate
(lauryl sulfate), ethane-1,2-disulfonate (edisylate), ethanesulfonate (esylate), formate,
fumarate, galactarate (mucate), gentisate (2,5-dihydroxybenzoate), glucoheptonate
(gluceptate), gluconate, glucuronate, glutamate, glutarate, glycerophosphorate, glycolate,
hexylresorcinate, hippurate, hydrabamine (N,N’-di(dehydroabietyl)-ethylenediamine),
hydrobromide, hydrochloride, hydroiodide, hydroxynaphthoate, yrate, lactate,
lactobionate, laurate, , maleate, malonate, mandelate, methanesulfonate
(mesylate), methylsulfate, mucate, alene-1,5-disulfonate (napadisylate),
naphthalenesulfonate (napsylate), nicotinate, nitrate, oleate, palmitate, p-
aminobenzenesulfonate, p—aminosalicyclate, pamoate (embonate), pantothenate,
pectinate, persulfate, phenylacetate, phenylethylbarbiturate, phosphate,
polygalacturonate, propionate, enesulfonate (tosylate), pyroglutamate, pyruvate,
salicylate, sebacate, stearate, subacetate, succinate, sulfamate, sulfate, e, tartrate,
teoclate (8-chlorotheophyllinate), thiocyanate, triethiodide, undecanoate, undecylenate,
and valerate.
Representative pharmaceutically acceptable base addition salts include, but are not
d to, aluminium, 2-amino(hydroxymethyl)-1,3-propanediol (TRIS, tromethamine),
arginine, benethamine (N-benzylphenethylamine), benzathine (N,N’-
dibenzylethylenediamine), bis-(2-hydroxyethyl)amine, bismuth, calcium, chloroprocaine,
choline, ole (1 -p chlorobenzylpyrrolildine-1’-y|methylbenzimidazole),
cyclohexylamine, dibenzylethylenediamine, diethylamine, diethyltriamine, dimethylamine,
dimethylethanolamine, dopamine, ethanolamine, ethylenediamine, L-histidine, iron,
isoquinoline, lepidine, lithium, lysine, magnesium, meglumine (N-methylglucamine),
piperazine, dine, potassium, procaine, quinine, quinoline, sodium, strontium, t-
butylamine, and zinc.
The compounds according to Formula (I) may contain one or more asymmetric
s (also referred to as a chiral center) and may, therefore, exist as individual
enantiomers, reomers, or other stereoisomeric forms, or as es thereof. Chiral
centers, such as chiral carbon atoms, may be t in a substituent such as an alkyl
group. Where the stereochemistry of a chiral center t in a compound of Formula (I),
or in any chemical structure illustrated herein, is not specified the structure is intended to
encompass all dual stereoisomers and all mixtures thereof. Thus, compounds
ing to Formula (I) containing one or more chiral centers may be used as racemic
mixtures, enantiomerically enriched mixtures, or as enantiomerically pure individual
stereoisomers.
The compounds according to Formula (I) and pharmaceutically acceptable salts
thereof may contain isotopically-labelled compounds, which are identical to those recited in
Formula (I) and following, but forthe fact that one or more atoms are replaced by an atom
having an atomic mass or mass number different from the atomic mass or mass number
usually found in nature. Examples of such es include isotopes of hydrogen, carbon,
nitrogen, oxygen, phosphorous, sulphur, fluorine, iodine, and chlorine, such as 2H, 3H, 11C,
13C, 14C,15N,17O, 180’ 31p, 32p, 358, 18F, 360', 123' and 125|_
lsotopically-labelled compounds, for e those into which radioactive es
such as 3H or 14C are incorporated, are useful in drug and/or substrate tissue distribution
. Tritium, i.e., 3H, and carbon-14, i.e., 14C, isotopes are ularly preferred fortheir
ease of preparation and detectability. 11C and 18F isotopes are particularly useful in PET
(positron emission tomography), and 125| isotopes are particularly useful in SPECT (single
photon emission computerized tomography), both are useful in brain g. Further,
substitution with heavier isotopes such as ium, i.e., 2H, can afford certain therapeutic
advantages resulting from greater metabolic stability, for e increased in vivo half-life
or reduced dosage requirements and, hence, may be preferred in some circumstances.
lsotopically labelled compounds can generally be prepared by substituting a readily
available isotopically labelled reagent for a non-isotopically labelled reagent.
The compounds according to Formula (I) may also contain double bonds or other
centers of geometric try. Where the stereochemistry of a center of geometric
asymmetry present in Formula (I), or in any chemical structure illustrated herein, is not
specified, the structure is ed to encompass the trans (E) geometric isomer, the cis
(Z) geometric isomer, and all mixtures thereof. Likewise, all eric forms are also
included in Formula (I) whether such tautomers exist in brium or inately in one
form.
The compounds ofthe invention may exist in solid or liquid form. In solid form, compound
of the ion may exist in a continuum of solid states ranging from fully amorphous to
fully crystalline. The term ‘amorphous’ refers to a state in which the material lacks long
range order at the molecular level and, depending upon the temperature, may t the
physical properties of a solid or a liquid. Typically such materials do not give distinctive X-
ray diffraction patterns and, while exhibiting the properties of a solid, are more formally
described as a . Upon g, a change from solid to liquid ties occurs which
is characterized by a change of state, typically second order (‘glass transition’). The term
‘crystalline’ refers to a solid phase in which the material has a regular d internal
structure at the molecular level and gives a distinctive X-ray diffraction pattern with defined
peaks. Such als when heated sufficiently will also exhibit the properties of a liquid,
but the change from solid to liquid is characterized by a phase change, typically first order
(‘melting point’).
The compounds of the invention may have the ability to crystallize in more than one form,
a characteristic, which is known as polymorphism (“polymorphs”). Polymorphism generally
can occur as a response to changes in temperature or pressure or both and can also result
from variations in the crystallization process. Polymorphs can be distinguished by various
physical characteristics known in the art such as x—ray diffraction patterns, solubility and
melting point.
The compounds of Formula (I) may exist in solvated and unsolvated forms. As used herein,
the term te” refers to a x of variable stoichiometry formed by a solute (in this
invention, a compound of Formula (I) or a salt) and a solvent. Such solvents, for the
purpose of the ion, may not interfere with the biological activity of the solute. The
skilled artisan will appreciate that pharmaceutically acceptable es may be formed for
crystalline compounds wherein solvent molecules are incorporated into the crystalline
lattice during crystallization. The incorporated solvent molecules may be water molecules
or non-aqueous such as ethanol, isopropanol, DMSO, acetic acid, ethanolamine, and ethyl
acetate les. Crystalline lattice structures incorporated with water molecules are
typically referred to as “hydrates”. Hydrates include stoichiometric es as well as
compositions containing le amounts of water.
It is also noted that the compounds of Formula (I) may form tautomers. ‘Tautomers’ refer
to compounds that are interchangeable forms of a particular compound structure, and that
vary in the displacement of hydrogen atoms and electrons. Thus, two structures may be in
equilibrium through the movement of TI' ons and an atom (usually H). For example,
enols and ketones are tautomers because they are rapidly interconverted by treatment with
either acid or base. It is understood that all tautomers and mixtures of tautomers of the
nds ofthe t invention are ed within the scope ofthe compounds of the
present invention.
While aspects for each variable have generally been listed above separately for
each variable this invention includes those compounds in which several or each aspect in
a (I) is selected from each of the aspects listed above. Therefore, this invention is
intended to include all combinations of aspects for each variable.
DEFINITIONS
It will be appreciated that the ing tions apply to each of the
aforementioned formulae and to all instances of these terms, unless the context dictates
othen/vise.
“Alkyl” refers to a hydrocarbon chain having the specified number of “member atoms”. For
example, C1-C6 alkyl refers to an alkyl group having from 1 to 6 member atoms. Alkyl
groups may be saturated, unsaturated, straight or branched. Representative branched
alkyl groups have one, two, or three branches. Alkyl includes but is not limited to: methyl,
ethyl, ethylenyl, propyl (n-propyl and isopropyl), butenyl, butyl (n-butyl, isobutyl, and t-butyl),
pentyl and hexyl.
y” refers to an -O-alky| group wherein “alkyl” is as defined herein. For e,
C1-C4alkoxy refers to an alkoxy group having from 1 to 4 carbon member atoms.
Examples of such groups include but is not d to: methoxy, ethoxy, propoxy, butoxy,
and t-butoxy.
“Aryl” refers to an aromatic hydrocarbon ring system. Aryl groups are monocyclic, bicyclic,
and tricyclic ring s having a total of five to fourteen ring member atoms, wherein at
least one ring system is aromatic and wherein each ring in the system contains 3 to 7
member atoms, such as but no limited to: phenyl, dihydroindene, naphthalene,
tetrahydronaphthalene and biphenyl. Suitably aryl is phenyI.
“Cycloalkyl”, unless otherwise defined, refers to a saturated or rated non aromatic
hydrocarbon ring or rings having from three to seven carbon atoms. Cycloalkyl groups are
monocyclic or spiro ring systems. For example, 03-C7 cycloalkyl refers to a cycloalkyl
group having from 3 to 7 member atoms. Examples of cycloalkyl as used herein include
but is not limited to: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclobutenyl,
cyclopentenyl, cyclohexenyl, spiro heptanyl and cycloheptyl. Suitably lkyl is selected
from: cyclopropyl, entyl and cyclohexyl.
"Heteroaryl” refers to a monocyclic ic 4 to 8 member ring containing from 1 to 7
carbon atoms and containing from 1 to 4 heteroatoms independently selected from
nitrogen, oxygen and sulfur, provided that when the number of carbon atoms is 3, the
ic ring contains at least two heteroatoms, or to such aromatic ring is fused one or
more rings, such as heteroaryl rings, aryl rings, heterocyclic rings, or cycloalkyl rings.
Heteroaryl groups containing more than one heteroatom may contain different
heteroatoms. Heteroaryl includes but is not limited to: benzoimidazolyl, benzothiazolyl,
benzothiophenyl, benzopyrazinyl, riazolyl, benzotriazinyl, benzo[1,4]dioxanyl,
uranyl, 9H—a-carbolinyl, cinnolinyl, furanyl, imidazolyl, oxazoly, indazolyl, indolizinyl,
indolyl, olyl, isothiazolyl, isoquinolinyl, isoxazolyl, indolizinyl, naphthyridinyl, oxazolyl,
oxothiadiazolyl, oxadiazolyl, phthalazinyl, pyridyl, pyrrolyl, purinyl, pteridinyl, phenazinyl,
pyrazolyl, pyrazolopyrimidinyl, pyrazolopyridinyl, pyrrolizinyl, pyridazyl, pyrazinyl, pyrimidyl,
quinoxalinyl, quinazolinyl, quinolinyl, quinolizinyl, thienyl, thiophenyl, lyl, triazinyl,
tetrazolopyrimidinyl, triazolopyrimidinyl, tetrazolyl, thiadiazolyl, thiazolyl and thiazolidinyl.
Suitably heteroaryl is selected from: l, pyrazolyl, pyrrolyl, imidazoiyl. isoxazolyl,
isothiazolyl, oxazolyl, triazolyl, thiazolyl and thienyl. ly heteroaryl is a pyridyl group
or an imidazolyl group. Suitably heteroaryl is a pyridyl.
“Heterocyclic” or “heterocycloalkyl”, as used herein, unless otherwise defined,
refers to a saturated or unsaturated omatic ring containing 4 to 12 member atoms,
of which 1 to 11 are carbon atoms and from 1 to 6 are heteroatoms independently selected
from nitrogen, oxygen and sulfur. cycloalkyl groups ning more than one
atom may contain different heteroatoms. Such ring may be optionally fused to one
or more other “heterocyclic” rings, aryl rings, heteroaryl rings, or cycloalkyl rings. Such rings
may be d bicyclic or spiro. Examples of “heterocyclic” groups include, but are not
d to: 1,4diazepanyl, azetidinyl, yl, 1,4-dioxanyl, 1,3-dioxanyl, pyrrolidinyl,
pyrrolidinonyl, piperidinyl, zinyl, piperazinyl-2,5-dionyl, morpholinyl,
dihydropyranyl, dihydrocinnolinyl, dihydropyridinyl, tetrahydropyranyl, 2,3-dihydrofuranyl,
2,3-dihydrobenzofuranyl, dihydroisoxazolyl, tetrahydrooxazolyl, tetrahydrofuranyl,
tetrahydrothiazolyl, tetrahydrothiazinyl, tetrahydrothiopyranyl, tetrahydrothiophenyl,
oquinoxalinyl, tetrahydroquinoxalinyl, tetrahydroisoquinolinyl, tetrahydropyridinyl,
tetrahydrocarbolinyl, 2,9-diazaspiro[5.5]undecanyl, 1,8-diazaspiro[4.5]decanyl, 2,8-
piro[4.5]decanyl, hexahydropyrrolo-1,4-diazepanyl, 1-oxaazaspiro[3.4]octany|, 5-
oxaazaspiro[3.4]octany|, 1,7-diazaspiro[3.5]nonanyl, 2,7-diazaspiro[3.5]nonanyl, 2,6-
diazaspiro[3.4]octanyl, 1,8-diazaspiro[4.5]decany| and 8-azabicyclo[3.2.1]octanyl. Suitably
heterocyclic is selected from: 1,4-diazepanyl, azetidinyl, oxetanyl, pyrrolidinyl,
dihydropyridinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydroisoquinolinyl,
tetrahydropyranyl, 2,9-diazaspiro[5.5]undecanyl, 1,8—diazaspiro[4.5]decanyl, 2,8-
diazaspiro[4.5]decany|, hexahydropyrrolo-1,4-diazepanyl, 1-oxa6-azaspiro[3.4]octany|, 5-
oxaazaspiro[3.4]octanyl, 1,7-diazaspiro[3.5]nonanyl, 2,7-diazaspiro[3.5]nonanyl, 2,6-
diazaspiro[3.4]octanyl, 1,8-diazaspiro[4.5]decanyl and 8-azabicyclo[3.2.1]octany|.
“Heteroatom” refers to a nitrogen, sulphur or oxygen atom.
“Halogen” and “halo” refers to a fluorine, chlorine, e, or iodine atom.
As used , the term pto” refers to the group —SH.
As used herein, the term “oxo” refers to the group =O.
As used herein, the term “hydroxy” refers to the group —OH.
As used herein, the term “amino” refers to the group —NH2.
As used herein, the term “aminocarbonyl” refers to the group —C(O)NH2.
As used herein, the term “guanidino” refers to the group —NHC(=NH)NH2.
As used herein, the term “carboxy” refers to the group —C(O)OH.
As used herein, the term “cyano” refers to the group —-CN.
As used herein, the term “prodrug” refers to a nd that is metaboiizeo in the body
to produce a biologicaiiy active compound. This more bioiogicaiiy active compound is
refereci to herein as an “active compound”. An exampie of a prodrug oi'the invention is the
compound of Example 151. An exampie of the corresponding active compound is the
compound of Example 147.
As used , the term “active nd“ refers to a compound inhibits the activity of
DNMT1, ly a compound that is a seiective inhibitor of .
As used herein, the term “selective”, when referring to chemical compounds,
suitably the active nds of the present invention, means the compounds exhibit an
|C50 over 30 times more active, suitably over 50 times more , suitably over 100 times
more active as an tor against DNMT1, than DNMT3A or DNMT3B in the Breaklight
Assay described herein or a similar assay.
As used herein, the term “Compound A” refers to: 2-{[3,5-dicyano
(dimethylamino)—4-ethy|pyridinyl]su|fanyl}phenylacetamide, the compound of
Example 3.
As used herein the symbols and conventions used in these processes, schemes
and examples are consistent with those used in the contemporary scientific literature, for
example, the l of the American Chemical Society or the Journal of Biological
Chemistry. Standard single-letter or letter abbreviations are generally used to
designate amino acid residues, which are assumed to be in the L-configuration unless
otherwise noted. Unless otherwise noted, all ng materials were obtained from
commercial suppliers and used without further purification. Specifically, the ing
abbreviations may be used in the examples and throughout the cation:
A0 l);
A020 (acetic anhydride);
A-CN (acetonitrile);
AIBN (azobis(isobutyronitrile));
BINAP (2,2'-bis(diphenylphosphino)-1,1'-binaphthy|);
BMS (borane - dimethyl sulphide complex);
Bn (benzyl);
Boc (tert—Butoxycarbonyl);
80020 (di-tert-butyl dicarbonate);
BOP (BenzotriazoIey|-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate);
CAN (cerric um nitrate);
Cbz (benzyloxycarbonyl);
CSI (chlorosulfonyl isocyanate);
CSF (cesium fluoride);
DABCO (1 ,4-Diazabi0y0lo[2.2.2]octane);
DAST (Diethylamino)su|fur trifluoride);
DBU (1,8-Diazabicy0lo[5.4.0]unde0—7-ene);
DCC (Dicyclohexyl Carbodiimide);
DCE (1 ,2-di0hloroethane);
DCM (dichloromethane);
DDQ (2,3-Di0hloro-5,6-dicyano-1,4-benzoquinone);
ATP (adenosine triphosphate);
WO 16727
Bis-pinacolatodiboron (4,4,4',4',5,5,5',5'-Octamethyl-2,2'-bi-1,3,2-dioxaborolane);
BSA (bovine serum albumin);
C18 (refers to 18-carbon alkyl groups on silicon in HPLC stationary phase)
CHs-CN (acetonitrile) Cy (cyclohexyl);
DCM (dichloromethane);
DIEA (diisopropylethylamine);
DIPEA (Htinig’s base, N-ethyl-N-(1-methylethyl)propanamine);
Dioxane (1 ,4-dioxane);
DMAP (4-dimethylaminopyridine);
DME (1 ,2-dimethoxyethane);
DMEDA dimethylethylenediamine);
DMF (N,N-dimethylformamide);
DMSO (dimethylsulfoxide);
DPPA (diphenyl phosphoryl azide);
EDC (N-(3-dimethylaminopropyl)-N’ethylcarbodiimide) hydrochloride salt;
EDTA (ethylenediaminetetraacetic acid);
EtOAc (ethyl acetate);
EtOH (ethanol);
Et20 (diethyl ether);
HEPES (4-(2-hydroxyethyl)piperazinyl ethane sulfonic acid);
HATU (O-(7-Azabenzotriazolyl)-N,N,N',N'-tetramethyluronium hexafluorophosphate);
HOAt (1 -hyd roxy—7-azabenzotriazole);
HOBt (1 -hyd nzotriazole);
HOAc (acetic acid);
HPLC (high re liquid chromatography);
HMDS (hexamethyldisilazide);
Hunig’s Base (N,N-Diisopropylethylamine);
IPA (isopropyl alcohol);
Indoline (2,3-dihydro-1H-indole);
KHMDS (potassium hexamethyldisilazide);
LAH (lithium aluminum hydride);
LDA (lithium diisopropylamide);
LHMDS (lithium hexamethyldisilazide);
MeOH (methanol);
MTBE (methyl utyl ether);
mcM molar);
mCPBA oroperbezoic acid);
NaHMDS (sodium thyldisilazide);
NCS (N-chlorosuccinimide);
NBS (N-bromosuccinimide);
PE (petroleum ether);
Pd2(dba)3 (Tris(dibenzylideneacetone)dipalladium(0);
Pd(dppf)C|2.DCM Complex ([1,1'-
Bis(diphenylphosphino)ferrocene]dichloropalladium(l|).dichloromethane complex);
PyBOP (benzotriazoly|-oxytripyrrolidinophosphonium hexafluorophosphate);
PyBrOP (bromotripyrrolidinophosphonium hexafluorophosphate);
RPHPLC (reverse phase high pressure liquid tography);
RT (room temperature);
Sat. (saturated);
SFC (supercritical fluid chromatography);
SGC (silica gel chromatography);
SM (starting material);
TLC (thin layer chromatography);
TEA (triethylamine);
2017/053511
TEMPO (2,2,6,6-Tetramethylpiperidinyl 1-oxyl, free radical);
TFA (trifluoroacetic acid);
THF hydrofuran); and
Ts-Cl (p-toluenesulfonyl chloride).
All references to ether are to diethyl ether and brine refers to a saturated aqueous solution
of NaCl.
COMPOUND PREPARATION
The compounds ing to Formula (I) are prepared using conventional organic
synthetic s. Suitable synthetic routes are depicted below in the following general
reaction schemes. All of the starting materials are commercially available or are readily
prepared from commercially ble starting materials by those of skill in the art.
The skilled artisan will appreciate that if a substituent described herein is not
ible with the synthetic s described herein, the substituent may be protected
with a suitable protecting group that is stable to the reaction conditions. The protecting
group may be removed at a le point in the reaction sequence to provide a desired
intermediate or target compound. Suitable protecting groups and the methods for
protecting and tecting different substituents using such suitable protecting groups
are well known to those skilled in the art; es of which may be found in T. Greene
and P. Wuts, Protecting Groups in Organic Synthesis (4th ed.), John Wiley & Sons, NY
(2006). In some instances, a substituent may be specifically selected to be reactive under
the reaction conditions used. Under these circumstances, the reaction conditions convert
the selected substituent into another substituent that is either useful as an intermediate
compound or is a desired substituent in a target compound.
Scheme 1
r \NH
M r
NH2 N\ N 1
NMO A+
// t5
NHs_>-H20 POCIa \ NC C“
| \
O r |
0‘ [‘4
150°C or N/ TEA DMF
CI \N N/ CI
1 2 4 5
0 soM
TMSCN, ZnI2 HZSO4rt
OTMS Mscl
\o —> 0H—> NH2
CHZCIZ, rt Et3N THF rt
7 9
NC CN
r4\ /
r4\ii )KSAc DMF 'I‘ N 5
r5 0
2)TEA
10
In some cases intermediate of formula 13, is used to obtain intermediate of formula 4, as
shown in Scheme 2, and used in subsequent steps as shown in Scheme 1 and Scheme
2.
Scheme 2
)0: SOClz/DCE j? NaBH4/EtOH SNa
CONH2
,2 ,2 CONH2 —> CONH2
3 11
NCVCN
ne, 120°C NC C”
HCI 50 °c \
+ —>
EtOH
_ /
OEt :e\ CN MeZCO
H H2N CI
\i/OEt 13
OEt r1
r1 r1 "KNH NC CN
tBuONO, NC CN \
I \ SNa
NC CN NC EtOH,rt r4 |
\ CuClz CN
\ r5 I +
| | —> r4 A \N N/ S
CONH2
/ \N N/ Cl , 2 I
MeCNI THF | r NH
HZN N CI CI N CI 5 2
70°C rt r5 2
13 O
4 14 12
In other cases intermediate of formula 13 is used to obtain compound of formula 16, which
is used in subsequent steps to give compounds of formula 18 as described in Scheme 3.
Scheme 3
l r2)\c0NH2 HN IN/ s
HN N/ CI EtOH,70°C 2
12 r2NNHZ
13 16
r1 r1
BuONO (or amleNO), '1“
NC 0“ NC CN
CUX2 \ r5 \
—p | |
r4\ /
x N 'i‘ N S
MeCN] s THF, rt
NH2 r5
7000
X=C| r2WNW
=Br O O
In some cases compounds of formula 19 and 20 are used to give the compounds of a
21 as bed in Scheme 4.
Scheme 4
r1 r1
NC CN NC CN
\ CI \
“R +
N/ SH QACONHz —’ r4\N N/ s
is 20 Nchog, DMF, rt l5
19 r22Y0
Compounds of formula 24 are prepared by the tic route shown in Scheme 5.
Intermediates of formula 22 are commercially available compounds, that could be or could
not be single enantiomers. When compounds of formula 22 are single enantiomers, so are
the corresponding compounds of formula 23 and formula 24.
Scheme 5
WO 16727
r1 r4\ r1
r1 NC CN Nc CN
\ NH \
NC CN “”2 | r r
\ 5 |
| + r/J\CONH2 THE“ CI N/ NH 4\N N/ NH
/ 2 fl
Cl N CI NNHZ THF,rt r5
r2 r2/SrNH2
4 22 0 0
For compounds of formula 26, intermediate of formula 14 and intermediate of formula 25
have been used as shown in Scheme 6. Intermediates of formula 25 are commercially
available or are synthesized using conventional organic synthesis procedures that can be
uced by any skilled artisan.
Scheme 6
NC CN
NC CN \
\ Cl KSAc |
| j “K /
r4\N +
N/ N S
CI r2 [ll
I DMF, r1
r5 |\
Alternatively for compounds of formula 26, intermediate of formula 14 and intermediate of
formula 27 have been used as in Scheme 7. Intermediates of a 27 are commercially
available or are synthesized using conventional organic synthesis ures that can be
reproduced by any skilled artisan.
Scheme?
NC CN
NC 0N \
\ SH DMF, rt
r |
r4\ +
/ J 4\N N/ s
N N Cl r2 }5 K
r5 r2
14 27 26
nds of formulas 33 and 34 have been prepared by the synthetic routes shown in
Scheme 8. Intermediates 28 and 29 are commercially available compounds. Intermediates
of formula 31 are commercial or are sized using conventional organic synthesis
procedures that can be reproduced by any skilled artisan.
Scheme 8
\i Et3N,r.t. NC CN
NC —> \
NH2 l Br—r2
HZN N SH
29 30
1. CuCI2, t»BuONO
MeCN,40—45°C NC CN
NCflCN |\
2'r4r5NH r4\N N/ s’r2
/ —§
H2N N s’r2 I5
32 33
1. CuCIZ, t-BuONO
/ MeCN, 4045 °c
s Nc CN
2. \
r r NH
NC CN
\ ° l
/ r
I 3. NHzMe, 50 C I'4\
N N s/ 2
H2N N s’r2 —> I5
32 34
Compounds of formula 40 have been prepared by the synthetic routes shown in Scheme
9. ediates 35 and 36 are commercially available compounds. Intermediates of
formula 31 are commercial or are synthesized using conventional organic synthesis
ures that can be reproduced by any skilled artisan.
Scheme 9
EtOH, then acetone, HCI,
° 0
KSAC
NCVCN 50 C, 2 hours NC CN _
I Br—r2
HZN N CI
36 37
CuCI2, t—BuONO /r1
MeCN 40-50 ”c 0’“ WNH
'—, —’ NC CN
NC CN \
I r4\ l
/ r2
CI N/ S/rz IT] N
38 39 40
Compounds of formula 43 have been prepared by the synthetic routes shown in Scheme
. ediate 41 is commercial.
Scheme 10
DMFrt \
F N s
41 9
r 42
DMFrt
Compounds of formula 48 have been prepared by the synthetic routes shown in scheme
11. Intermediates 1 and 44 are commercially available.
Scheme 11
r rn
ZNJJ\/// N o KOH, H20
NC r. Pool3
' /
o o I 1500
reflux
HO \N OH
1 44 45
n 1 r”
r r\
. NH NC I"
NC '
KSAc / I2 /
I —r> 1 |
\ I’\ \
CI N S N S
DMF rt DMF rt
v T
0 r2 O
NH2 NH2
47 48
Compounds of formula 52 have been prepared by the synthetic routes shown in scheme
12. ediate 49 is commercial and intermediate 46 is shown above in shceme 11.
Scheme 12
SAC NaBH4, SH
r —> r
NH2 NH2
11 50
46 51 50 52
Compounds of a 58 have been prepared by the tic routes shown in scheme
13. Intermediates 1 and 53 are commercially available.
Scheme 13
0 o o NH3 H20 CN NBS Br CN
N \ CuCN
HZNM/ re‘>)J\/U\r7—> I —>
170 c, NMP
7 N o
r H
1 53 54 55
6 6 6
l' r SH l'
EtSN
Poms
NC|\ CN _,Nc|\ CN 0$9
_, NC|\ CN
N/ NH2 DMF’ rt
r7 N O r7 C] r7 N/ S
0 3
56 57 50 Ykr
Methods of Use
The compounds according to Formula (I) and pharmaceutically acceptable salts
thereof are selective inhibitors of DNMT1. These compounds are potentially useful in the
treatment of conditions that respond to the selective inhibition of DNMT1. These include
but are not limited to, cancer and pre-cancerous mes and beta hemoglobinopathies
such as sickle cell disease, sickle cell , and beta thalassemia. Accordingly, in
r aspect the invention is directed to methods of ng such conditions.
Suitably, the present invention relates to a method for treating breast cancer,
including inflammatory breast cancer, ductal carcinoma, and lobular carcinoma.
Suitably the present invention relates to a method for treating colon cancer.
Suitably the present invention relates to a method for treating pancreatic cancer,
including insulinomas, adenocarcinoma, ductal adenocarcinoma, adenosquamous
oma, acinar cell carcinoma, and glucagonoma.
Suitably the present invention relates to a method fortreating skin cancer, including
ma, including metastatic melanoma.
Suitably the present invention relates to a method fortreating lung cancer including
small cell lung cancer, all cell lung cancer, squamous cell carcinoma,
adenocarcinoma, and large cell carcinoma.
Suitably the present invention relates to a method fortreating cancers selected from
the group consisting of: cancers of the lung, bone, pancreas, skin, head, neck, uterus,
ovaries, stomach, colon, breast, esophagus, small intestine, bowel, endocrine system,
thyroid glad, parathyroid gland, adrenal gland, urethra, te, penis, testes, ureter,
bladder, kidney or liver; rectal ; cancer ofthe anal region; omas of the fallopian
tubes, endometrium, cervix, , vulva, renal pelvis, renal cell; sarcoma of soft tissue;
myxoma; rhabdomyoma; fibroma; lipoma; teratoma; cholangiocarcinoma; hepatoblastoma;
angiosarcoma; hemagioma; hepatoma; fibrosarcoma; chondrosarcoma; myeloma; c
or acute leukemia; cytic lymphomas; primary -CNS lymphoma; neoplasms of the -
CNS; spinal axis tumours; squamous cell carcinomas; synovial sarcoma; ant pleural
mesotheliomas; brain stem glioma; pituitary adenoma; bronchial adenoma; omatous
toma; inesothelioma; and Hodgkin’s Disease.
Suitably the present invention relates to a method fortreating cancers ed from
the group consisting of brain (gliomas), glioblastomas, astrocytomas, glioblastoma
multiforme, Bannayan-Zonana syndrome, Cowden disease, Lhermitte-Duclos disease,
Vlfilm's tumor, Ewing's sarcoma, Rhabdomyosarcoma, ependymoma, medulloblastoma,
head and neck, kidney, liver, melanoma, ovarian, pancreatic, adenocarcinoma, ductal
adenocarcinoma, adenosquamous carcinoma, acinar cell carcinoma, glucagonoma,
insulinoma, prostate, sarcoma, osteosarcoma, giant cell tumor of bone, thyroid,
blastic T cell leukemia, c myelogenous leukemia, chronic lymphocytic
leukemia, hairy-cell leukemia, acute lymphoblastic leukemia, acute myelogenous leukemia,
c philic leukemia, acute lymphoblastic T cell leukemia, cytoma,
Immunoblastic large cell leukemia, mantle cell leukemia, multiple a,
megakaryoblastic leukemia, multiple myeloma, acute megakaryocytic leukemia,
1O promyelocytic leukemia, erythroleukemia, malignant lymphoma, hodgkins lymphoma, non-
hodgkins lymphoma, lymphoblastic T cell ma, Burkitt’s lymphoma, follicular
lymphoma, neuroblastoma, bladder cancer, urothelial cancer, vulval cancer, cervical
cancer, trial cancer, renal cancer, mesothelioma, esophageal cancer, ry
gland cancer, hepatocellular cancer, gastric cancer, nasopharangeal cancer, buccal
cancer, cancer of the mouth, GIST (gastrointestinal l tumor), neuroendocrine
cancers and testicular cancer.
ly the present invention relates to a method for treating ncerous
syndromes in a mammal, including a human, wherein the pre-cancerous syndrome is
selected from: cervical intraepithelial neoplasia, monoclonal gammapathy of unknown
significance (MGUS), myelodysplastic syndrome, aplastic anemia, cervical lesions, skin
nevi (pre-melanoma), tic intraepithleial (intraductal) neoplasia (PIN), Ductal
Carcinoma in situ (DCIS), colon polyps and severe hepatitis or cirrhosis.
In some embodiments, the nds of the ion can be used to me
T-cell tolerance.
In some embodiments, the compounds ofthe invention can be used to treat diabetic
nephropathy, diabetes, podocyte injury, atherosclerosis, psoriasis, idiopathic pulmonary
fibrosis, soieroderma, iiver cirrhosis, rheumatoid arthritis, and Alzheimer’s disease.
Compounds of the invention can also be used to increase or enhance an immune
response, including increasing the immune se to an antigen; to improve
immunization, including increasing vaccine cy; and to increase inflammation. In some
embodiments, the compounds of the invention can be used to enhance the immune
WO 16727
se to vaccines including, but not limited, Listeria vaccines, oncolytic viarl vaccines,
and cancer vaccines such as GV AX® locyte-macrophage colony-stimulating factor
(GM-CF) gene-transfected tumor cell vaccine).
Further diseases and ers treatable with nds of the invention include,
but are not limited to, treating beta hemoglobinopathies, such as sickle cell disease, sickle
cell anemia, and beta thalassemia.
The methods of treatment of the invention comprise stering an effective
amount of a compound according to Formula (I) or a pharmaceutically acceptable salt,
thereof to a patient in need thereof.
By the term "treating" and derivatives thereof as used herein, in reference to a
condition means: (1) to ameliorate the condition or one or more of the biological
manifestations of the condition, (2) to interfere with (a) one or more points in the biological
cascade that leads to or is responsible forthe condition or (b) one or more ofthe biological
manifestations of the condition, (3) to alleviate one or more of the symptoms or effects
associated with the condition, or (4) to slow the progression of the condition or one or more
ofthe biological manifestations of the condition.
The term “treating" and derivatives thereof refers to therapeutic therapy.
Therapeutic therapy is appropriate to ate ms or to treat at early signs of
disease or its progression.
The skilled artisan will appreciate that "prevention" is not an absolute term. In
medicine, "prevention" is understood to referto the prophylactic administration of a drug to
substantially diminish the likelihood or severity of a condition or biological manifestation
thereof, orto delay the onset of such ion or biological manifestation thereof.
Prophylactictherapy is appropriate when a t has, for example, a strong family
history of cancer or is ise ered at high risk for developing cancer, or when a
subject has been exposed to a carcinogen or when the subject has a strong family history
of a beta-hemoglobinopathy such as sickle cell disease, sickle cell anemia, or beta-
thalassemia.
As used herein, the term "effective amount" and derivatives thereof means that
amount of a drug or pharmaceutical agent that will elicit the biological or medical response
of a tissue, system, animal or human that is being sought, for instance, by a researcher or
clinician. Furthermore, the term “therapeutically effective amount” and derivatives thereof
means any amount which, as compared to a corresponding t who has not received
such amount, results in improved treatment, healing, prevention, or amelioration of a
disease, disorder, or side effect, or a decrease in the rate of advancement of a disease or
disorder. The term also includes within its scope amounts effective to e normal
physiological function.
As used , "patient" or “subject" refers to a human or other mammal. Suitably
the t or subject is a human.
The compounds of Formula (I) or pharmaceutically acceptable salts thereof may be
administered by any suitable route of administration, ing systemic administration.
Systemic administration includes oral administration and parenteral administration.
Parenteral administration refers to routes of administration otherthan enteral, transdermal,
or by inhalation, and is typically by injection or infusion. Parenteral administration includes
intravenous, intramuscular, and subcutaneous injection or infusion.
The compounds of Formula (I) or pharmaceutically able salts f may be
administered once or according to a dosing regimen wherein a number of doses are
stered at varying intervals of time for a given period of time. For example, doses
may be administered one, two, three, or four times per day. Doses may be administered
until the desired therapeutic effect is ed or indefinitely to maintain the desired
therapeutic effect. Suitable dosing regimens for a compound of the invention depend on
the cokinetic properties ofthat nd, such as absorption, distribution, and half-
life, which can be determined by the skilled artisan. In addition, suitable dosing regimens,
including the duration such ns are administered, for a compound of the invention
depend on the condition being treated, the severity of the condition being treated, the age
and physical condition of the patient being treated, the l y of the patient to be
treated, the nature of concurrent therapy, the desired therapeutic effect, and like s
within the knowledge and expertise of the skilled artisan. It will be further understood by
such skilled ns that suitable dosing regimens may require adjustment given an
individual patient's response to the dosing regimen or overtime as individual patient needs
change.
Typical daily dosages may vary ing upon the particular route of
administration . Typical dosages for oral administration range from 1 mg to 1000
mg per person per dose. red dosages are 1 — 500 mg once daily or BID per
person.
Additionally, the compounds of Formula (I) or pharmaceutically acceptable salts
thereof may be administered as prodrugs. As used herein, a "prodrug" of a compound of
the ion is a functional derivative of the compound which, upon administration to a
patient, eventually liberates the compound of the invention in vivo. Administration of a
compound of the invention as a prodrug may enable the skilled artisan to do one or more
of the following: (a) modify the onset of the compound in vivo; (b) modify the duration of
action ofthe compound in vivo; (0) modify the transportation or distribution ofthe compound
in vivo; (d) modify the solubility of the compound in vivo; and (e) overcome a side effect or
other difficulty encountered with the compound. Typical functional derivatives used to
prepare prodrugs include modifications of the compound that are chemically or
enzymatically cleaved in vivo. Such modifications, include the preparation of phosphates,
amides, ethers, esters, thioesters, carbonates, and carbamate. Where a -COOH or -OH
group is t, pharmaceutically able esters can be employed, for e methyl,
ethyl, and the like for -COOH, and e maleate and the like for -OH, and those esters
known in the art for modifying solubility or hydrolysis characteristics.
Accordingly, the invention is further directed to prodrugs of the compounds
according to Formula (I). Suitably, the prodrug is a dihydrogen ate. Suitably, the
prodrug is a 2-aminomethylbutanoate.
Included in the gs of Formula (I) are:
1-(6-((2-aminooxophenylethyl)thio)-3,5-dicyanoethylpyridiny|)pyrrolidin-
3-yl ogen phosphate;
((2-aminooxophenylethyl)thio)-3,5-dicyanoethylpyridin
yl)(methyl)amino)ethyl dihydrogen phosphate;
1-(6-((2-aminooxophenylethyl)thio)-3,5-dicyanoethylpyridinyl)azetidin-
3-yl dihydrogen phosphate;
(28)((1-(6-((2-aminooxophenylethyl)thio)-3,5-dicyanoethylpyridin
yl)piperidinyl)oxy)ethy| 2-aminomethylbutanoate;
2-((1-(6-((2-aminooxophenylethyl)thio)-3,5-dicyanoethylpyridin
yl)piperidinyl)oxy)ethy| dihydrogen phosphate; and
1-(6-((2-aminooxophenylethyl)thio)-3,5-dicyanoethylpyridinyl)piperidin-
4-yl dihydrogen ate;
a ceutically acceptable salt thereof.
Prodrugs of the compounds ofthe invention are readily prepared by those of skill in
mean
The compounds of Formula (I) and pharmaceutically acceptable salts f may
be co-administered with at least one other active agent known to be useful in the treatment
Of Cancer or pre-cancerous syndromes.
By the term "co-administration" as used herein is meant either simultaneous
administration or any manner of separate sequential administration of an inhibitor of the
activity of DMNT1, as described herein, and a further active agent or agents, known to be
useful in the treatment of cancer, including chemotherapy and radiation treatment. The
term r active agent or agents, as used herein, includes any compound ortherapeutic
agent known to or that demonstrates advantageous properties when administered to a
patient in need oftreatment for cancer. Preferably, ifthe administration is not simultaneous,
the compounds are administered in a close time ity to each other. Furthermore, it
does not matter if the compounds are administered in the same dosage form, e.g. one
compound may be administered by injection and another compound may be administered
orally.
Examples of a further active ingredient or ingredients (anti-neoplastic agent) for use
in ation or co-administered with the presently invented combinations are indicated
below. This list is non-limiting. Additional anti-neoplastic agents are contemplated for use
with the presently invented compounds.
Typically, any anti-neoplastic agent that has activity versus a tible tumor
being treated may be co-administered in the treatment of cancer in the present invention.
Examples of such agents can be found in Cancer Principles and Practice of Oncology by
V.T. Devita and S. Hellman (editors), 6‘“ edition ary 15, 2001), Lippincott Williams &
Vlfilkins Publishers. Typical anti-neoplastic agents useful in the present invention include,
but are not limited to, icrotubule agents such as diterpenoids and vinca alkaloids;
platinum coordination xes; alkylating agents such as nitrogen mustards,
oxazaphosphorines, alkylsulfonates, nitrosoureas, and triazenes; antibiotic agents such as
anthracyclins, mycins and bleomycins; omerase II inhibitors such as
epipodophyllotoxins; antimetabolites such as purine and dine analogues and anti-
folate compounds; topoisomerase I inhibitors such as camptothecins; hormones and
hormonal analogues; signal transduction pathway inhibitors; non-receptor ne kinase
angiogenesis inhibitors; immunotherapeutic agents; ptotic agents; cell cycle
signaling inhibitors; proteasome inhibitors; and inhibitors of cancer lism.
Examples of a further active ingredient or ingredients (anti-neoplastic agent) for use
in combination or co-administered with the presently invented combinations are
chemotherapeutic agents.
Anti-microtubule or anti-mitotic agents are phase specific agents active against the
microtubules of tumor cells during M or the mitosis phase of the cell cycle. Examples of
anti-microtubule agents include, but are not limited to, diterpenoids and vinca alkaloids.
enoids, which are derived from natural sources, are phase specific anti-cancer agents
that operate at the G2/M phases ofthe cell cycle. It is believed thatthe enoids stabilize
the B-tubulin subunit of the microtubules, by binding with this n. Disassembly of the
protein appears then to be inhibited with mitosis being arrested and cell death following.
Examples ofditerpenoids include, but are not limited to, paclitaxel and its analog docetaxel.
Paclitaxel, 513,20-epoxy-1,20c,4,7[3,1013,13oc-hexa-hydroxytaxenone 4,10-
diacetate 2-benzoate 13-ester with (2R,38)-N-benzoylphenylisoserine; is a natural
diterpene t isolated from the Pacific yew tree Taxus olia and is commercially
available as an injectable solution TAXOL®. It is a member of the taxane family of
terpenes. Paclitaxel has been approved for clinical use in the treatment of refractory
n and breast cancer in the United .
Docetaxel, )- oxyphenylisoserine,N-terf—butyl ester, 13-ester with
epoxy-1,20a,4,7[3,10[3,13oc-hexahydroxytaxenone 4-acetate 2—benzoate,
trihydrate; is commercially ble as an injectable solution as TAXOTERE®. xel
is indicated for the treatment of breast cancer. Docetaxel is a semisynthetic derivative of
paclitaxel q.v., prepared using a natural precursor, 10-deacetyl-baccatin lll, extracted from
the needle ofthe European Yew tree. The dose limiting toxicity ofdocetaxel is neutropenia.
Vinca alkaloids are phase specific anti-neoplastic agents derived from the
periwinkle plant. Vinca alkaloids act at the M phase (mitosis) of the cell cycle by binding
specifically to tubulin. Consequently, the bound tubulin molecule is unable to polymerize
into microtubules. Mitosis is believed to be arrested in metaphase with cell death following.
Examples of vinca alkaloids include, but are not limited to, vinblastine, vincristine, and
vinorelbine.
Vinblastine, vincaleukoblastine sulfate, is cially available as VELBAN® as
an injectable solution. Although, it has possible indication as a second line therapy of
various solid tumors, it is primarily indicated in the treatment oftesticular cancer and various
lymphomas including Hodgkin’s e; and lymphocytic and histiocytic lymphomas.
Myelosuppression is the dose limiting side effect of stine.
Vincristine, vincaleukoblastine, 22-oxo-, sulfate, is commercially available as ONCOV|N®
as an injectable solution. Vincristine is indicated forthe ent of acute leukemias and
has also found use in treatment regimens for Hodgkin’s and non-Hodgkin’s malignant
lymphomas. Alopecia and neurologic s are the most common side effect ofvincristine
and to a lesser extent myelosupression and gastrointestinal mucositis effects occur.
Vinorelbine, 3’,4’-didehydro -4’-deoxy-C’-norvincaleukoblastine [R-(R*,R*)-2,3-
dihydroxybutanedioate (1 :2)(salt)], commercially ble as an injectable solution of
vinorelbine te (NAVELBINE®), is a semisynthetic vinca alkaloid. Vinorelbine is
indicated as a single agent or in combination with other chemotherapeutic agents, such as
cisplatin, in the treatment of various solid tumors, ularly non-small cell lung, advanced
breast, and hormone refractory prostate cancers. Myelosuppression is the most common
dose limiting side effect of vinorelbine.
Platinum coordination complexes are non-phase specific anti-cancer agents, which
40 are interactive with DNA. The platinum complexes enter tumor cells, o, aquation
and form intra- and interstrand crosslinks with DNA causing adverse biological effects to
the tumor. Examples of um coordination complexes include, but are not limited to,
tin and carboplatin.
Cisplatin, cis-diamminedichloroplatinum, is commercially available as PLATINOL®
as an injectable on. tin is primarily indicated in the treatment of metastatic
testicular and ovarian cancer and advanced bladder cancer. The primary dose limiting side
effects of cisplatin are nephrotoxicity, which may be controlled by hydration and diuresis,
and icity.
Carboplatin, platinum, diammine [1,1-cyclobutane-dicarboxylate(2-)-0,0’], is
commercially available as PARAPLAT|N® as an injectable solution. Carboplatin is
primarily indicated in the first and second line treatment of advanced ovarian carcinoma.
Bone marrow suppression is the dose ng toxicity of carboplatin.
Alkylating agents are non-phase anti-cancer specific agents and strong electrophiles.
Typically, alkylating agents form covalent linkages, by alkylation, to DNA through
philic moieties ofthe DNA le such as phosphate, amino, sulfhydryl, hydroxyl,
carboxyl, and imidazole groups. Such alkylation disrupts nucleic acid on leading to
cell death. Examples of alkylating agents include, but are not limited to, nitrogen mustards
such as cyclophosphamide, lan, and chlorambucil; alkyl sulfonates such as
busulfan; nitrosoureas such as carmustine; and triazenes such as dacarbazine.
Cyclophosphamide, 2-[bis(2-ch|oroethy|)amino]tetrahydro-2H-1,3,2-
oxazaphosphorine 2-oxide monohydrate, is commercially available as an able
solution ortablets as CYTOXAN®. Cyclophosphamide is indicated as a single agent or in
ation with other chemotherapeutic agents, in the treatment of malignant mas,
multiple myeloma, and leukemias. Alopecia, nausea, vomiting and leukopenia are the most
common dose limiting side effects of cyclophosphamide.
Melphalan, 4-[bis(2-chloroethyl)amino]-L-phenylalanine, is commercially available
as an injectable solution or tablets as N®. Melphalan is indicated for the palliative
treatment of multiple myeloma and non-resectable epithelial carcinoma of the ovary. Bone
marrow suppression is the most common dose limiting side effect of lan.
Chlorambucil, 4-[bis(2-chloroethyl)amino]benzenebutanoic acid, is commercially available
as LEUKERAN® tablets. Chlorambucil is indicated for the palliative treatment of chronic
lymphatic leukemia, and malignant lymphomas such as lymphosarcoma, giant follicular
lymphoma, and Hodgkin’s disease. Bone marrow suppression is the most common dose
limiting side effect of chlorambucil.
Busulfan, 1,4-butanediol dimethanesulfonate, is commercially available as
40 MYLERAN® TABLETS. Busulfan is ted for the palliative treatment of chronic
myelogenous leukemia. Bone marrow suppression is the most common dose limiting side
effects of busulfan.
Carmustine, 1,3-[bis(2-chloroethyl)nitrosourea, is commercially ble as
single vials of lyophilized material as Bi-CNU®. Carmustine is ted for the palliative
treatment as a single agent or in combination with other agents for brain tumors, multiple
a, Hodgkin’s disease, and non-Hodgkin’s lymphomas. Delayed myelosuppression
is the most common dose limiting side effects of carmustine.
Dacarbazine, 5-(3,3-dimethyltriazeno)-imidazolecarboxamide, is
cially available as single vials of material as DTlC-Dome®. Dacarbazine is
ted forthe treatment of metastatic malignant melanoma and in combination with other
agents forthe second line treatment of Hodgkin’s Disease. Nausea, vomiting, and anorexia
are the most common dose limiting side effects of dacarbazine.
Antibiotic anti-neoplastics are ase specific agents, which bind or intercalate
with DNA. Typically, such action results in stable DNA complexes or strand breakage,
which disrupts ordinary function of the nucleic acids, leading to cell death. Examples of
antibiotic anti-neoplastic agents include, but are not limited to, actinomycins such as
dactinomycin, anthrocyclins such as daunorubicin and doxorubicin; and bleomycins.
Dactinomycin, also know as Actinomycin D, is commercially available in injectable form as
COSMEGEN®. Dactinomycin is indicated for the treatment of Vlfilm’s tumor and
myosarcoma. Nausea, vomiting, and anorexia are the most common dose limiting
side s of dactinomycin.
Daunorubicin, (88-cis-)acetyl[(3-amin0-2,3,6-trideoxy-oc-L-lyxo-
hexopyranosyl)oxy]—7,8,9,10-tetrahydro-6,8,1 1-trihydroxymethoxy-5,12
naphthacenedione hydrochloride, is commercially ble as a liposomal able form
as DAUNOXOME® or as an able as CERUBIDINE®. Daunorubicin is indicated for
remission induction in the treatment of acute nonlymphocytic leukemia and advanced HlV
associated 's sarcoma. Myelosuppression is the most common dose limiting side
effect of daunorubicin.
Doxorubicin, (88, 108)[(3-amino-2,3,6-trideoxy-oc-L-lyxo-hexopyranosyl)oxy]
glycoloyl, 7,8,9,10-tetrahydro-6,8,11-trihydroxymethoxy-5,12 naphthacenedione
hydrochloride, is commercially available as an injectable form as RUBEX® or
ADRIAMYCIN RDF®. Doxorubicin is primarily indicated for the treatment of acute
lymphoblastic leukemia and acute myeloblastic leukemia, but is also a useful component
in the treatment of some solid tumors and lymphomas. uppression is the most
common dose limiting side effect of doxorubicin.
40 Bleomycin, a mixture of cytotoxic glycopeptide otics isolated from a strain of
Streptomyces ven‘icillus, is commercially available as BLENOXANE®. Bleomycin is
indicated as a palliative treatment, as a single agent or in combination with other agents, of
squamous cell carcinoma, lymphomas, and testicular carcinomas. Pulmonary and
cutaneous toxicities are the most common dose limiting side effects of bleomycin.
Topoisomerase ll inhibitors e, but are not limited to, epipodophyllotoxins.
ophyllotoxins are phase specific anti-neoplastic agents derived from the
mandrake plant. Epipodophyllotoxins lly affect cells in the S and G2 phases of the
cell cycle by forming a ternary complex with topoisomerase II and DNA causing DNA strand
breaks. The strand breaks accumulate and cell death follows. Examples of
epipodophyllotoxins include, but are not limited to, etoposide and teniposide.
ide, 4’-demethyl-epipodophyllotoxin 9[4,6(R)-ethylidene-[3-D-
yranoside], is commercially available as an injectable solution or capsules as
D® and is commonly known as VP-16. Etoposide is indicated as a single agent or
in combination with other chemotherapy agents in the treatment oftesticular and non-small
cell lung s. Myelosuppression is the most common side effect of etoposide. The
incidence of leucopenia tends to be more severe than thrombocytopenia.
Teniposide, 4’-demethyl-epipodophyllotoxin 9[4,6(R)-thenylidene-B-D-
glucopyranoside], is commercially available as an injectable solution as VUMON® and is
commonly known as VM-26. Teniposide is indicated as a single agent or in combination
with other chemotherapy agents in the ent of acute ia in children.
Myelosuppression is the most common dose limiting side effect of teniposide. Teniposide
can induce both leucopenia and thrombocytopenia.
Antimetabolite neoplastic agents are phase specific anti-neoplastic agents that act
at S phase (DNA synthesis) of the cell cycle by inhibiting DNA synthesis or by inhibiting
purine or pyrimidine base synthesis and thereby limiting DNA synthesis. Consequently, S
phase does not proceed and cell death s. Examples metabolite anti-neoplastic
agents include, but are not limited to, fluorouracil, methotrexate, cytarabine,
mecaptopurine, thioguanine, and gemcitabine.
-fluorouracil, 5-fluoro-2,4- (1H,3H) pyrimidinedione, is cially available as
fluorouracil. Administration of 5-fluorouracil leads to inhibition ofthymidylate synthesis and
is also incorporated into both RNA and DNA. The result typically is cell death. 5-fluorouracil
is indicated as a single agent or in ation with other chemotherapy agents in the
treatment of carcinomas of the breast, colon, rectum, stomach and pancreas.
Myelosuppression and mucositis are dose limiting side effects of 5-fluorouracil. Other
fluoropyrimidine analogs include 5-fluoro deoxyuridine (floxuridine) and 5-
40 fluorodeoxyuridine monophosphate.
WO 16727
Cytarabine, 4-amino[3-D-arabinofuranosyI-2 (1 H)-pyrimidinone, is commercially
available as R-U® and is commonly known as Ara-C. It is believed that bine
exhibits cell phase specificity at S-phase by inhibiting DNA chain elongation by terminal
incorporation of cytarabine into the growing DNA chain. Cytarabine is indicated as a single
agent or in combination with other chemotherapy agents in the treatment of acute leukemia.
Other cytidine analogs include 5-azacytidine and 2’,2‘-difluorodeoxycytidine (gemcitabine).
Cytarabine induces leucopenia, thrombocytopenia, and mucositis.
Mercaptopurine, hydro-6H-purinethione monohydrate, is commercially
available as PURINETHOL®. Mercaptopurine exhibits cell phase specificity at S-phase by
inhibiting DNA synthesis by an as of yet unspecified mechanism. topurine is
ted as a single agent or in combination with other chemotherapy agents in the
treatment of acute leukemia. Myelosuppression and gastrointestinal mucositis are
expected side effects of mercaptopurine at high doses. A useful mercaptopurine analog is
azathioprine.
Thioguanine, 2-amino-1,7-dihydro-6H-purinethione, is commercially available as
TABLOID®. Thioguanine exhibits cell phase specificity at S-phase by inhibiting DNA
synthesis by an as of yet unspecified ism. Thioguanine is indicated as a single
agent or in combination with other chemotherapy agents in the treatment of acute leukemia.
Myelosuppression, including leucopenia, thrombocytopenia, and , is the most
common dose ng side effect of thioguanine administration. However, gastrointestinal
side effects occur and can be dose limiting. Other purine analogs include pentostatin,
erythrohydroxynonyladenine, fludarabine phosphate, and cladribine.
Gemcitabine, 2’-deoxy-2’, 2’-dif|uorocytidine monohydrochloride (B-isomer), is
commercially available as GEMZAR®. Gemcitabine exhibits cell phase city at S-
phase and by blocking progression of cells through the G118 boundary. Gemcitabine is
indicated in combination with cisplatin in the treatment of locally advanced non-small cell
lung cancer and alone in the treatment of locally ed pancreatic cancer.
Myelosuppression, including leucopenia, thrombocytopenia, and anemia, is the most
common dose limiting side effect of gemcitabine administration.
Methotrexate, N-[4[[(2,4-diaminopteridinyl) methyl]methylamino] benzoyl]-L-
glutamic acid, is commercially available as methotrexate sodium. Methotrexate exhibits
cell phase s specifically at S-phase by inhibiting DNA synthesis, repair and/or
replication through the inhibition of dyhydrofolic acid reductase which is required for
synthesis of purine nucleotides and thymidylate. Methotrexate is indicated as a single
agent or in combination with other chemotherapy agents in the treatment of
40 choriocarcinoma, meningeal leukemia, dgkin’s lymphoma, and carcinomas of the
breast, head, neck, ovary and bladder. uppression (leucopenia, thrombocytopenia,
and anemia) and tis are expected side effect of methotrexate administration.
Camptothecins, including, camptothecin and camptothecin derivatives are available
or under development as Topoisomerase | inhibitors. Camptothecins cytotoxic ty is
believed to be related to its Topoisomerase | inhibitory activity. Examples of camptothecins
include, but are not d to irinotecan, topotecan, and the various optical forms of 7-(4-
methylpiperazino-methylene)—10,11-ethylenedioxycamptothecin described below.
lrinotecan HCI, (4S)-4,11-diethylhydroxy[(4-piperidinopiperidino) carbonyloxy]-1H-
pyrano[3’,4’,6,7]indolizino[1,2-b]quinoline-3,14(4H,12H)-dione hydrochloride, is
commercially available as the injectable solution CAMPTOSAR®.
lrinotecan is a derivative of camptothecin which binds, along with its active
metabolite SN-38, to the omerase I - DNA complex. It is ed that cytotoxicity
occurs as a result of irreparable double strand breaks caused by interaction of the
topoisomerase I : DNA : irintecan or SN-38 y complex with ation enzymes.
lrinotecan is indicated fortreatment of atic cancer ofthe colon or rectum. The dose
limiting side effects of irinotecan HCI are myelosuppression, ing neutropenia, and GI
effects, including diarrhea.
Topotecan HCI, (S)[(dimethylamino)methyl]ethyl-4,9-dihydroxy-1H-
pyrano[3‘,4’,6,7]indolizino[1,2-b]quinoline-3,14-(4H,12H)-dione monohydrochloride, is
commercially available as the injectable solution HYCAMTIN®. Topotecan is a derivative
of camptothecin which binds to the topoisomerase I— DNA complex and ts religation
of singles strand breaks caused by Topoisomerase l in response to torsional strain of the
DNA molecule. Topotecan is indicated for second line treatment of atic oma
of the ovary and small cell lung cancer. The dose limiting side effect of topotecan HCI is
myelosuppression, primarily penia.
Also of interest, is the camptothecin derivative of Formula A following, including the
racemic mixture (R,S) form as well as the R and S enantiomers:
(\N/CH3
known by the chemical name “7-(4-methylpiperazino-methylene)-10,11-ethylenedioxy-
(R,S)—camptothecin (racemic mixture) or “7-(4-methylpiperazino-methylene)-10,11-
ethylenedioxy-20(R)-camptothecin (R enantiomer) or “7-(4-methylpiperazino-methylene)-
,11-ethylenedioxy-20(S)-camptothecin (S enantiomer). Such compound as well as
related nds are described, ing s of making, in US. Patent Nos.
6,063,923; 5,342,947; 235; and 5,491,237.
Hormones and hormonal analogues are useful compounds for ng cancers in
which there is a relationship between the hormone(s) and growth andlor lack of growth of
the . Examples of hormones and hormonal analogues useful in cancer ent
include, but are not limited to, adrenocorticosteroids such as prednisone and prednisolone
which are useful in the treatment of malignant lymphoma and acute ia in children;
aminoglutethimide and other aromatase inhibitors such as anastrozole, ole, vorazole,
and exemestane useful in the treatment of adrenocortical carcinoma and hormone
dependent breast carcinoma containing estrogen receptors; progestrins such as megestrol
acetate useful in the treatment of hormone dependent breast cancer and endometrial
carcinoma; estrogens, androgens, and anti-androgens such as flutamide, mide,
bicalutamide, cyproterone acetate and 5oc-reductases such as finasteride and dutasteride,
useful in the treatment of prostatic carcinoma and benign prostatic hypertrophy; anti-
estrogens such as tamoxifen, toremifene, raloxifene, ifene, iodoxyfene, as well as
ive estrogen or modulators (SERMS) such those described in US. Patent Nos.
,681,835, 5,877,219, and 6,207,716, useful in the treatment of hormone dependent breast
carcinoma and other susceptible cancers; and gonadotropin-releasing hormone (GnRH)
and analogues thereof which stimulate the release of leutinizing hormone (LH) and/or
follicle stimulating hormone (FSH) for the ent prostatic carcinoma, for instance,
LHRH agonists and antagagonists such as goserelin acetate and luprolide.
Signal transduction pathway inhibitors are those inhibitors, which block or inhibit a
chemical process which evokes an intracellular change. As used herein this change is cell
proliferation or differentiation. Signal tranduction inhibitors useful in the present invention
include inhibitors of receptor tyrosine kinases, non-receptor tyrosine kinases, SH2/SH3
domain blockers, serinelthreonine kinases, phosphotidylinositol-3 kinases, myo-inositol
signaling, and Ras oncogenes.
Several protein tyrosine kinases catalyse the phosphorylation of specific tyrosyl
es in various proteins involved in the regulation of cell growth. Such protein tyrosine
kinases can be broadly classified as or or non-receptor kinases.
Receptor tyrosine kinases are embrane proteins having an extracellular
ligand binding domain, a transmembrane domain, and a ne kinase . Receptor
tyrosine kinases are involved in the regulation of cell growth and are generally termed
growth factor ors. Inappropriate or uncontrolled activation of many ofthese kinases,
40 i.e. aberrant kinase growth factor receptor activity, for example by over-expression or
mutation, has been shown to result in uncontrolled cell growth. Accordingly, the aberrant
activity of such kinases has been linked to malignant tissue growth. Consequently,
inhibitors ofsuch kinases could provide cancertreatment methods. Growth factor receptors
include, for example, epidermal growth factor receptor , platelet derived growth
factor receptor (PDGFr), erbBZ, erbB4, vascular endothelial growth factor receptor
(VEGFr), tyrosine kinase with immunoglobulin-Iike and epidermal growth factor homology
domains (TIE-2), insulin growth factor —I (IGFI) receptor, macrophage colony stimulating
factor (cfms), BTK, ckit, cmet, last growth factor (FGF) receptors, Trk receptors (TrkA,
TrkB, and TrkC), ephrin (eph) receptors, and the RET protooncogene. Several inhibitors
of growth receptors are under development and e ligand antagonists, antibodies,
tyrosine kinase tors and anti-sense oligonucleotides. Growth factor receptors and
agents that inhibit growth factor receptor function are described, for instance, in Kath, John
C., Exp. Opin. Ther. s (2000) 10(6):803-818; Shawver et al DDT Vol 2, No. 2
February 1997; and Lofts, F. J. et al, “Growth factor receptors as targets“, New lar
Targets for Cancer Chemotherapy, ed. Workman, Paul and Kerr, David, CRC press 1994,
London.
Suitably, the ceutically active compounds of the invention are used in
combination with a VEGFR inhibitor, suitably [(2,3-dimethyl-2H-indazol
yl)methylamino]pyrimidinyl]amino]methylbenzenesulfonamide, or a pharmaceutically
able salt, suitably the monohyd rochloride salt f, which is disclosed and claimed
in in International Application No. PCT/USO1/49367, having an International filing date of
December 19, 2001, International Publication Number W002!059110 and an ational
Publication date of August 1, 2002, the entire disclosure of which is hereby incorporated by
reference, and which is the compound of Example 69. 5-[[4-[(2,3-dimethyl-2H-indazol
yl)methylamino]pyrimidinyl]amino]methylbenzenesulfonamide can be prepared as
described in International Application No. O1/49367.
Suitably, 5-[[4-[(2,3-dimethyl-2H-indazolyl)methylamino]pyrimidinyl]amino]
methylbenzenesulfonamide is in the form of a monohydrochloride salt. This salt form can
be prepared by one of skill in the art from the description in International Application No.
PCT/USO1/49367, having an International filing date of December 19, 2001.
-[[4-[(2,3-dimethyl-2H-indazoIyl)methylamino]pyrimidiny|]amino]
methylbenzenesulfonamide is sold commercially as the monohydrochloride salt and is
known by the generic name nib and the trade name Votrient®.
Pazopanib is implicated in the treatment of cancer and ocular
diseases/angiogenesis. Suitably the present invention relates to the treatment of cancer
WO 16727
and ocular diseases/angiogenesis, suitably age-related macular degeneration, which
method comprises the administration ofa compound of Formula (I) alone or in ation
with pazopanib.
Tyrosine kinases, which are not growth factor receptor kinases are termed nonreceptor
tyrosine kinases. Non-receptortyrosine kinases for use in the present invention,
which are targets or potential targets ofanti-cancer drugs, include cSrc, Lck, Fyn, Yes, Jak,
cAbI, FAK (Focal adhesion kinase), Brutons tyrosine kinase, and Bcr-Abl. Such non-
receptor kinases and agents which inhibit non-receptor tyrosine kinase function are
described in Sinh, S. and Corey, S.J., (1999) Journal of Hematotherapy and Stem Cell
Research 8 (5): 465 — 80; and Bolen, J.B., Brugge, J.S., (1997) Annual review of
logy. 15: 371-404.
SH2/SH3 domain blockers are agents that disrupt SH2 or SH3 domain g in a
variety of enzymes or adaptor proteins ing, PI3-K p85 subunit, Src family kinases,
r molecules (Shc, Crk, ch, Grb2) and Ras-GAP. SH2/SH3 domains as targets for
anti-cancer drugs are discussed in Smithgall, TE. (1995), Journal of cological and
Toxicological Methods. 34(3) 125-32.
Inhibitors of /Threonine Kinases including MAP kinase cascade blockers
which include blockers of Raf kinases (rafk), Mitogen or Extracellular Regulated Kinase
(MEKs), and Extracellular Regulated Kinases (ERKs); and Protein kinase C family member
blockers including blockers of PKCs (alpha, beta, gamma, epsilon, mu, lambda, iota, zeta).
IkB kinase family (lKKa, IKKb), PKB family kinases, akt kinase family s, PDK1 and
TGF beta receptor kinases. Such SerineiThreonine kinases and inhibitors thereof are
described in Yamamoto, T., Taya, S., Kaibuchi, K., (1999), Journal of Biochemistry. 126 (5)
799-803; Brodt, P, Samani, A., and Navab, R. (2000), Biochemical Pharmacology, 60.
1101-1107; ue, J., Weis-Garcia, F. (1996) Cancer Surveys. 64; Philip, P.A.,
and , A.L. (1995), Cancer Treatment and ch. 78: 3-27, Lackey, K. et aI
Bioorganic and Medicinal Chemistry Letters, (10), 2000, 223-226; US. Patent No.
6,268,391; Pearce, L.R et al. Nature Reviews Molecular Cell Biology (2010) 11, 9-22. and
Martinez-Iacaci, L., et al, Int. J. Cancer (2000), 88(1), 44-52.
ly, the ceutically active compounds of the invention are used in
combination with a MEK inhibitor. Suitably, N-{3-[3-cyclopropyI(2-fluoroiodo-
phenylamino)-6,8-dimethyI-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin
nyl}acetamide, or a pharmaceutically acceptable salt or solvate, suitably the dimethyl
sulfoxide solvate, thereof, which is disclosed and claimed in International Application No.
, having an International filing date of June 10, 2005; International
40 Publication Number and an International Publication date of December
22, 2005, the entire disclosure of which is hereby incorporated by nce. N-{3-[3-
cyclopropyl(2-fluoroiodo-phenylamino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-
2H-pyrido[4,3-d]pyrimidinyl]phenyl}acetamide, can be prepared as bed in United
States Patent Publication No. US 2006/0014768, Published January 19, 2006, the entire
disclosure ofwhich is hereby incorporated by reference.
Suitably, the pharmaceutically active compounds of the invention are used in
combination with a B-Raf inhibitor. Suitably, N-{3-[5-(2-Aminopyrimidinyl)(1,1-
dimethylethyl)-1,3-thiazolyl]fluorophenyl}-2,6-difluorobenzenesulfonamide, or a
pharmaceutically acceptable salt thereof, which is disclosed and claimed, in International
Application No. 2009/042682, having an International filing date of May 4, 2009,
the entire disclosure of which is hereby incorporated by reference. N-{3-[5-(2-Amino
pyrimidinyl)(1,1-dimethylethyl)-1,3-thiazolyl]fluorophenyl}-2,6-
difluorobenzenesulfonamide can be prepared as described in International Application No.
PCT/U82009/042682.
Suitably, the pharmaceutically active compounds of the invention are used in
combination with an Akt inhibitor. Suitably, N-{(1S)amino[(3,4-
difluorophenyl)methyl]ethyl}chIoro(4-chloromethyl-1H-pyrazoIyl)
furancarboxamide or a pharmaceutically acceptable salt thereof, which is sed and
claimed in International ation No. PCT/U82008/053269, having an International filing
date of ry 7, 2008; International Publication Number and an
International Publication date of August 14, 2008, the entire sure of which is hereby
incorporated by reference. N-{(1S)amino[(3,4—difluorophenyl)methyl]ethyl}chloro-
4-(4-chloromethyl-1H-pyrazolyl)furancarboxamide is the compound of example
224 and can be prepared as described in International Application No.
PCT/U82008/053269.
ly, the pharmaceutically active compounds of the invention are used in
combination with an Akt inhibitor. Suitably, N-{(1S)amino[(3-
fluorophenyl)methyl]ethy|}chloro(4-chloromethyl-1H-pyrazolyl)
thiophenecarboxamide or a pharmaceutically acceptable salt f, which is disclosed
and claimed in International Application No. PCT/U82008/053269, having an International
filing date of February 7,2008; International Publication Number and an
International Publication date of August 14, 2008, the entire sure of which is hereby
incorporated by nce. N-{(1S)amino[(3-fluoropheny|)methyl]ethyl}chloro(4-
chloromethyI-1H-pyrazolyl)thiophenecarboxamide is the compound of example 96
and can be prepared as described in ational Application No. 2008/053269.
Suitably, N-{(1S)amino[(3-fluorophenyl)methyl]ethyI}chloro(4-chIoromethyl-
1H-pyrazolyl)thiophenecarboxamide is in the form of a hydrochloride salt. The salt
40 form can be prepared by one of skill in the art from the description in International
Application No. PCT/U82010/022323, having an International filing date of January 28,
2010.
Inhibitors of Phosphotidylinositol-3 Kinase family members including rs of
Pl3-kinase, ATM, DNA-PK, and Ku may also be useful in the t invention. Such
kinases are discussed in Abraham, R.T. (1996), Current n in Immunology. 8 (3) 412-
8; Canman, C.E., Lim, DS. (1998), Oncogene 17 (25) 3301-3308; Jackson, SP. (1997),
International Journal of Biochemistry and Cell Biology. 29 (7):935-8; and Zhong, H. et al,
Cancer res, (2000) 60(6), 1541-1545.
Also of interest in the present invention are Myo-inositol signaling inhibitors such as
phospholipase C blockers and Myoinositol analogues. Such signal tors are described
in Powis, G., and Kozikowski A., (1994) New Molecular Targets for Cancer Chemotherapy
ed., Paul Workman and David Kerr, CRC press 1994, London.
Another group of signal transduction pathway inhibitors are inhibitors of R35
Oncogene. Such inhibitors include inhibitors of farnesyltransferase, geranyl-geranyl
transferase, and CAAX proteases as well as anti-sense oligonucleotides, ribozymes and
immunotherapy. Such inhibitors have been shown to block ras activation in cells containing
wild type mutant ras, thereby acting as antiproliferation agents. Ras oncogene inhibition is
discussed in Scharovsky, O.G., Rozados, V.R., Gervasoni, S.l. Matar, P. (2000), l
of Biomedical Science. 7(4) 292-8; Ashby, MN. (1998), Current Opinion in logy. 9 (2)
99 — 102; and BioChim. Biophys. Acta, (19899) 1423(3):19-30.
As ned above, antibody antagonists to receptor kinase ligand binding may
also serve as signal transduction inhibitors. This group of signal transduction pathway
inhibitors includes the use of zed antibodies to the ellular ligand g
domain of receptor tyrosine kinases. For example Imclone 0225 EGFR ic dy
(see Green, MC. et al, Monoclonal Antibody Therapy for Solid Tumors, Cancer Treat. Rev.,
(2000), 26(4), 269-286); Herceptin ® erbB2 antibody (see Tyrosine Kinase Signalling in
Breast cancerzerbB Family Receptor ne Kniases, Breast cancer Res., 2000, 2(3),
176-183); and 2GB VEGFR2 ic antibody (see n, RA. et al, Selective Inhibition
of VEGFR2 Activity by a monoclonal Anti-VEGF antibody blocks tumor growth in mice,
Cancer Res. (2000) 60, 5117-5124).
Non-receptor kinase angiogenesis inhibitors may also be useful in the present
invention. Inhibitors of angiogenesis related VEGFR and T|E2 are discussed above in
regard to signal transduction inhibitors (both ors are receptor tyrosine kinases).
enesis in general is linked to erbB2IEGFR signaling since inhibitors of erbBZ and
40 EGFR have been shown to inhibit angiogenesis, primarily VEGF expression. Accordingly,
non-receptortyrosine kinase inhibitors may be used in combination with the compounds of
the present invention. For example, anti-VEGF antibodies, which do not recognize VEGFR
(the receptor tyrosine kinase), but bind to the ; small molecule inhibitors of integrin
(alphaV betas) that will inhibit angiogenesis; endostatin and angiostatin (non-RTK) may also
prove useful in combination with the disclosed compounds. (See Bruns CJ et al (2000),
Cancer Res., 60: 2926-2935; Schreiber AB, Winkler ME, and Derynck R. (1986), e,
232: 1250-1253; Yen L et al. (2000), ne 19: 3460-3469).
Agents used in immunotherapeutic regimens may also be useful in combination with
the compounds of Formula (I). There are a number of immunologic strategies to generate
an immune response. These strategies are generally in the realm of tumor vaccinations.
The efficacy of immunologic ches may be greatly ed through combined
inhibition of signaling pathways using a small molecule inhibitor. Discussion of the
immunologic/tumor vaccine approach against erbB2/EGFR are found in Reilly RT et al.
(2000), Cancer Res. 60: 3569-3576.
Agents used in proapoptotic regimens (e.g., bcl-2 antisense oligonucleotides) may
also be used in the ation of the present invention. Members of the Bcl-2 family of
proteins block apoptosis. Upregulation of bcl-2 has therefore been linked to
chemoresistance. Studies have shown that the epidermal growth factor (EGF) stimulates
anti-apoptotic members of the bcl-2 family (i.e., mcl-1). Therefore, strategies designed to
downregulate the expression of bcl-2 in tumors have trated clinical t and are
now in Phase ll/lll trials, namely Genta's G3139 bcl-2 nse oligonucleotide. Such
proapoptotic strategies using the antisense oligonucleotide strategy for bcl-2 are discussed
in Water JS et al. (2000), J. Clin. Oncol. 18: 1812-1823.
Cell cycle signalling inhibitors inhibit molecules involved in the control of the cell
cycle. A family of protein kinases called cyclin dependent s (CDK5) and their
interaction with a family of proteins termed cyclins controls progression through the
eukaryotic cell cycle. The coordinate activation and inactivation of different /CDK
complexes is necessary for normal ssion h the cell cycle. Several inhibitors
of cell cycle signalling are under development. For instance, examples of cyclin dependent
kinases, including CDK2, CDK4, and CDK6 and inhibitors for the same are described in,
for instance, Rosania et al, Exp. Opin. Ther. Patents (2000) 10(2):215-230. Further,
p21WAF1/CIP1 has been described as a potent and universal inhibitor of cyclin-dependent
kinases (Cdks) (Ball et al., Progress in Cell Cycle Res, 3: 125 ). Compounds that
are known to induce sion of p21 WAF1/CIP1 have been implicated in the suppression
of cell proliferation and as having tumor suppressing activity (Richon et al., Proc. Nat Acad.
Sci. USA. 97(18): 10014-10019 (2000)), and are included as cell cycle signaling inhibitors.
Histone deacetylase (HDAC) inhibitors are ated in the transcriptional activation of
p21WAF1/CIP1 (Vigushin et al., AnticancerDrugs, 13(1): 1-13 (Jan 2002)), and are suitable
40 cell cycle signaling inhibitors for use in combination herein.
Examples of such HDAC inhibitors include:
1. Vorinostat, including pharmaceutically acceptable salts thereof. Marks et al., Nature
Biotechnology 25, 84 to 90 (2007); Stenger, Community Oncology 4, 384-386 (2007).
Vorinostat has the following chemical ure and name:
4-“ \’§-
353 M
".43" \ .61K .-'\ ,t-a
Pa \,¢“\‘\,_~4“"‘\
13 "
H "gE’ \m.
oxy-N'-phenyl-octanediamide
2. Romidepsin, including pharmaceutically acceptable salts thereof.
Vinodhkumar et al., Biomedicine & cotherapy 62 (2008) 85-93.
1O Romidepsin, has the following chemical ure and name:
A i? ,I' ,0
sf N \i
liV"“\\NH Y03 /\~/
U)“. 4 '
\V—’
(1S,4S,7Z,1OS,16E,21R)ethy|idene-4,21-di(propanyI)oxa-12,13-dithia-5,8,20,23-
tetrazabicyclo[8.7.6]tricos—16-ene-3,6,9,19,22-pentone
3. Panobinostat, including pharmaceutically acceptable salts thereof. Drugs of the
Future 32(4): 315-322 (2007).
Panobinostat, has the following al structure and name:
-hydroxy[4-({[2—(2-methyl-1H-indolyl)ethyl]amino}methyl)phenyl]acrylamide
4. Valproic acid, including pharmaceutically acceptable salts thereof. Gottlicher, et al.,
EMBO J. 20(24): 6969-6978 (2001).
Valproic acid, has the following chemical structure and name:
CH3 «w» CR: N“ CHE
56)('
\\ 4.};
CH """"" 3
1'" "x -
CHS “““ Ct‘ig """ {DH-5‘ L3H
2—propylpentanoic acid
. Mocetinostat 103), including pharmaceutically acceptable salts thereof.
Balasubramanian et al., Cancer Letters 280: 211-221 (2009).
Mocetinostat, has the following chemical ure and name:
\J'\
N\ NN NH2
H H
N-(2-Aminophenyl)[[(4-pyridinylpyrimidinyl)amino]methyl] benzamide
Further examples of such HDAC inhibitors are included in Bertrand European Journal of
Medicinal Chemistry 45, (2010) 2095-2116, particularly the nds of table 3 therein
as indicated below.
WO 16727
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Proteasome inhibitors are drugs that block the action of proteasomes, cellular
complexes that break down proteins, like the p53 protein. Several proteasome tors
are marketed or are being studied in the treatment of cancer. Suitable proteasome
inhibitors for use in combination herein include:
1. omib (Velcade®), including pharmaceutically acceptable salts thereof.
Adams J, an M (2004), Cancer Invest 22 (2): 304—1 1.
Bortezomib has the following chemical structure and name.
[(1R)methyl({(2S)phenyl[(pyrazin
ylcarbonyl)amino]propanoyl}amino)butyl]boronic acid
2. Disulfiram, including pharmaceutically acceptable salts thereof.
Bouma et al. (1998). J. Antimicrob. her. 42 (6): 817—20.
iram has the following chemical structure and name.
Say-\Wo‘}
1,1 ',1 ",1 "'-[disulfanediylbis(carbonothioylnitrilo)]tetraethane
3. Epigallocatechin gallate (EGCG), including pharmaceutically acceptable salts
thereof. Vlfilliamson et al., (December 2006), The Joumal of Allergy and Clinical
Immunology 118 (6): 1369—74.
locatechin gallate has the following chemical structure and name.
{33%
§: ”3380 .
€13"?
[(2R,3R)-5,7-dihydroxy(3,4,5-trihydroxyphenyl)chromanyl]3,4,5-trihydroxybenzoate
4. Salinosporamide A, ing pharmaceutically acceptable salts thereof. Feling et
at., (2003), Angew. Chem. Int. Ed. Eng]. 42 (3): 355—7.
Salinosporamide A has the following chemical structure and name.
Q9“:R;
O f0
‘3 (“:1
(4R,5S)(2-ch|oroethyl)((1S)—cyclohex—2-enyl(hydroxy)methyl) methyloxa
azabicyclo3.2.0heptane-3,7-dione
5. Carfilzomib, including pharmaceutically acceptable salts thereof. Kuhn DJ, et al,
Blood, 2007, 110:3281-3290.
zomib has the following chemical structure and name.
“Tfiwwh
OJ G
(S)methyl-N-((S)(((S)methyl((R)methyloxiranyl)oxopentanyl)amino)-
1-oxophenylpropanyl)((S)(2-morpholinoacetamido)
phenylbutanamido)pentanamide
The 70 kilodalton heat shock proteins (Hsp705) and 90 kilodalton heat shock proteins
(Hsp90s) are a family of ubiquitously sed heat shock proteins. Hsp70$ and Hsp90$
are over expressed certain cancertypes. Several Hsp70s and Hsp90$ inhibitors are being
studied in the treatment of cancer. Suitable Hsp70$ and Hsp90$ inhibitors for use in
combination herein include:
1. 17—AAG(Geldanamycin), ing pharmaceutically acceptable salts thereof. Jia W et
al. Blood. 2003 Sep 1;102(5):1824—32.
17—AAG(Geldanamycin) has the following chemical structure and name.
1 7—(Allylamino)-1 thoxygeldanamycin
2. Radicicol, including pharmaceutically able salts thereof. (Lee et al.,
Mol Cell Endocrinol. 2002, 188,47-54)
Radicicol has the following chemical structure and name.
(1aR,2Z,4E,14R,15aR)chloro-9,11-dihydroxymethyI-15,15a-dihydro-1aH-
benzo[c]oxireno[2,3-k][1]oxacyclotetradecine-6,12(7H,14H)-dione
Inhibitors of cancer metabolism - Many tumor cells show a markedly different
lism from that of normal tissues. For example, the rate ofglycolysis, the metabolic
process that converts glucose to pyruvate, is increased, and the pyruvate generated is
reduced to lactate, rather than being further oxidized in the ondria via the
tricarboxylic acid (TCA) cycle. This effect is often seen even under c conditions and
is known as the Warburg Effect.
Lactate dehyd rogenase A (LDH-A), an isoform of lactate ogenase expressed
in muscle cells, plays a pivotal role in tumor cell metabolism by performing the reduction of
pyruvate to lactate, which can then be exported out of the cell. The enzyme has been
shown to be upregulated in many tumor types. The alteration of glucose metabolism
described in the Warburg effect is critical for growth and eration of cancer cells and
knocking down LDH-A using RNA-i has been shown to lead to a reduction in cell
proliferation and tumor growth in xenograft models.
D. A. Tennant et. al., Nature Reviews, 2010, 267.
P. Leder, et. al., Cancer Cell, 2006, 9, 425.
High levels of fatty acid synthase (FAS) have been found in cancer precursor
lesions. Pharmacological inhibition of FAS affects the expression of key oncogenes
involved in both cancer development and maintenance. Alli et al. Oncogene (2005) 24,
39—46. doi:10.1038
Inhibitors of cancer metabolism, including inhibitors of LDH-A and inhibitors of
fatty acid thesis (or FAS inhibitors), are suitable for use in combination with the
compounds of this invention.
Additional examples of a r active ingredient or ingredients (anti-neoplastic
agent) for use in combination or co-administered with the presently invented CD73
inhibiting nds are anti-PD-L1 agents.
Anti-PD-L1 antibodies and methods of making the same are known in the art.
Such antibodies to PD-L1 may be polyclonal or monoclonal, and/or recombinant,
and/or humanized.
Exemplary PD-L1 antibodies are disclosed in:
US Patent No. 8,217,149; ,339;
US Patent No. 8,383,796; 13/091,936;
US Patent No 8,552,154; 13/120,406;
US patent publication No. 20110280877; 13/068337;
US Patent Publication No. 20130309250; 13/892671;
W02013019906;
079174;
US Application No. ,538 (filed August 7, 2012), which is the
US National Phase of International Application No. PCT/US10/58007 (filed 2010);
US Application No. 13/478,511 (filed May 23, 2012).
Additional exemplary dies to PD-L1 (also ed to as CD274 or B7-H1) and
methods for use are disclosed in US Patent No. 743; U820130034559,
W02014055897, US Patent No. 8,168,179; and US Patent No. 7,595,048. PD-L1
antibodies are in development as immuno-modulatory agents forthe treatment of cancer.
In one embodiment, the antibody to PD-L1 is an antibody disclosed in US Patent
No. 8,217,149. In another embodiment, the anti-PD-L1 antibody comprises the CDRs of
an antibody disclosed in US Patent No. 8,217,149.
In r embodiment, the antibody to PD-L1 is an antibody disclosed in US
Application No. 13/511,538. In another embodiment, the anti-PD-L1 antibody comprises
the CDRs of an antibody disclosed in US Application No. 13/511,538.
In another embodiment, the antibody to PD-L1 is an dy disclosed in
Application No. 13/478,511. In another embodiment, the anti-PD-L1 antibody comprises
the CDRs of an antibody disclosed in US Application No. ,511.
In one embodiment, the anti-PD-L1 antibody is EMS-936559 (MDX-1105). In
r ment, the anti-PD-L1 antibody is MPDL3280A (RG7446). In another
embodiment, the anti-PD-L1 antibody is MEDI4736.
Additional es of a further active ingredient or ingredients (anti-neoplastic
agent) for use in combination or co-administered with the presently invented CD73
inhibiting compounds are PD-1 antagonist.
"PD-1 antagonist" means any chemical compound or biological molecule that blocks
binding of PD-L1 expressed on a cancer cell to PD-1 expressed on an immune cell (T
cell, B cell or NKT cell) and preferably also blocks binding of PD-L2 expressed on a
cancer cell to the immune-cell expressed PD-1. Alternative names or synonyms for PD-
1 and its ligands include: PDCD1, PD1, CD279 and SLEBZ for PD-1; PDCD1L1, PDL1,
B7H1, B7-4, CD274 and B7-H for PD-L1; and PDCD1L2, PDL2, B7-DC, Btdc and
CD273 for PD-L2. In any embodiments of the aspects or embodiments of the present
invention in which a human individual is to be d, the PD-1 antagonist blocks binding
of human PD-L1 to human PD-1, and preferably blocks binding of both human PD-L1
and PD-L2 to human PD-1. Human PD-1 amino acid sequences can be found in NCBI
Locus No.: NP_005009. Human PD-L1 and PD-L2 amino acid sequences can be found
in NCBI Locus No.: 862 and NP_079515, respectively.
PD-1 antagonists useful in the any of the aspects of the present invention include
a monoclonal antibody (mAb), or antigen binding fragment thereof, which specifically binds
to PD-1 or PD-L1, and preferably specifically binds to human PD-1 or human PD-L1.
The mAb may be a human dy, a humanized antibody or a chimeric antibody,
and may include a human constant . In some embodiments, the human constant
region is selected from the group consisting of IgG1, IgG2, IgG3 and IgG4 nt
regions, and in preferred ments, the human constant region is an IgG1 or IgG4
constant region. In some ments, the antigen binding fragment is selected from
the group consisting of Fab, Fab'-SH, F(ab')2, scFv and Fv fragments.
Examples of mAbs that bind to human PD-1, and useful in the vario us aspects
and embodiments of the present invention, are described in US7488802, 051,
U88008449, USS354509, U88168757, W02004/004771, W02004/O72286,
W02004/056875, and USZO11/0271358.
ic anti-human PD-1 mAbs useful as the PD-1 antagonist in any ofthe s
and embodiments of the present invention e: MK—3475, a humanized lgG4 mAb
with the structure described in WHO Drug Information, Vol. 27, No. 2, pages 161-162
(2013) and which comprises the heavy and light chain amino acid sequences shown in
Figure 6; nivolumab, a human lgG4 mAb with the structure bed in WHO Drug
ation, Vol. 27, No. 1, pages 68-69 (2013) and which comprises the heavy and
light chain amino acid sequences shown in Figure 7; the humanized antibodies h409A11,
h409A16 and h409A17, which are described in W02008/156712, and AMP-514, which
is being developed by Medimmune.
Other PD-1 antagonists useful in the any of the aspects and embodiments of
the present invention include an immunoadhesin that specifically binds to PD-1, and
preferably specifically binds to human PD-1, e.g., a fusion protein containing the
extracellular or PD-1 binding portion of PD-L1 or PD-L2 fused to a constant region
such as an Fc region of an immunoglobulin molecule. Examples of immunoadhesion
molecules that specifically bind to PD-1 are described in W02010/027827 and
/066342. Specific fusion proteins useful as the PD-1 antagonist in the treatment
method, medicaments and uses of the present invention include AMP-224 (also known
as g), which is a PD-L2-FC fusion protein and binds to human PD-1.
Other examples of mAbs that bind to human PD-L1, and useful in the treatment
method, medicaments and uses of the present invention, are described in
W02013/019906, /077634 A1 and U88383796. Specific anti-human PD-L1 mAbs
useful as the PD-1 antagonist in the treatment method, medicaments and uses of the
present invention include MPDL3280A, EMS-936559, MEDI4736, MSBOO10718C.
KEYTRUDA/pembrolizumab is an anti-PD-1 antibody ed forthe treatment of
lung cancer by Merck. The amino acid sequence of pembrolizumab and methods of using
are disclosed in US Patent No. 8,168,757.
Opdivo/nivolumab is a fuiiy human monocional antibody marketed by Bristoi Myers
Squibb directed against. the negative ii‘nmunoregtiiatory human ceii surface or PCs—i
(programmed death-t or programmed ceii deatti—i/PCD-i) with immbnopotentiation
activity. Niveiumab binds to and blocks the activation of PIE—i, an if; superfamiiy
transmembrane protein, by its Iigands PDvLi and , resetting in the activation of T—
ceiie and oeilvmediated immune ses against tumor ceiis or pathogens. Antivated
PDw‘i veiy tes Tvceii activation and effector function through the ssion of
PiEk/Akt y activation. Other names for nivolumab inoiude: BMS~938558, MD) n
1106, and ONO/4538. The amino acid ce for nivolumab and methods of using and
1O making are disclosed in US Patent No. US 8,008,449.
Additional examples of a r active ingredient or ingredients (anti-neoplastic
agent) for use in combination or co-administered with the presently invented CD73
inhibiting nds are immuno-modulators.
As used herein “immune-modulators“ refer to any substance including monoclonal
antibodies that affects the immune . The ICOS binding proteins of the present
invention can be considered immune-modulators. Immuno-modulators can be used as
anti-neoplastic agents for the treatment of cancer. For example, -modulators
include, but are not limited to, anti-CTLA-4 antibodies such as ipilimumab (YERVOY) and
anti-PD-1 antibodies (Opdivo/nivolumab and Keytruda/pembrolizumab). Other immuno-
modulators include, but are not limited to, OX-4O antibodies, PD-L1 antibodies, LAG3
antibodies, TIM-3 antibodies, 41 BB antibodies and GITR antibodies.
Yervoy (ipilimumab) is a fully human CTLA-4 antibody marketed by Bristol Myers
Squibb. The n structure of ipilimumab and methods are using are described in US
Patent Nos. 720 and 7,605,238.
CD134, also known as ANTIBODIES TO OX40, is a member of the TNFR-
superfamily of receptors which is not constitutively expressed on resting naive T cells,
unlike CD28. ANTIBODIES TO OX40 is a secondary costimulatory molecule, expressed
after 24 to 72 hours following activation; its ligand, ANTIBODIES TO OX40L, is also not
expressed on resting antigen presenting cells, but is following their activation. Expression
of ANTIBODIES TO OX40 is dependent on full activation of the T cell; without CD28,
expression of ANTIBODIES TO OX40 is delayed and of fourfold lower levels. OX-40
antibodies, OX-40 fusion proteins and methods of using them are disclosed in US Patent
Nos: US 7,504,101; US 7,758,852; US 7,858,765; US 7,550,140; US 7,960,515;
W02012027328; WO2013028231.
Additional examples of a further active ingredient or ingredients (anti-neoplastic
agent) for use in combination or co-administered with the presently invented CD73
inhibiting compounds are Toll-like Receptor4 (TLR4) antagonists.
Aminoalkyl aminide phosphates (AGPs) are known to be useful as vaccine
adjuvants and immunostimulatory agents for stimulating cytokine production, activating
hages, promoting innate immune response, and augmenting antibody production in
immunized animals. Aminoalkyl glucosaminide phosphates (AGPs) are synthetic ligands
ofthe Toll-like Receptor 4 (TLR4). AGPs and their immunomodulating s via TLR4 are
disclosed in patent publications such as , , and/or US.
Patent No. 6,113,918 and have been reported in the literature. Additional AGP derivatives
are disclosed in US. Patent No. 7,129,219, US. Patent No. 6,525,028 and US. Patent No
6,911,434. Certain AGPs act as agonists of TLR4, while others are recognized as TLR4
antagonists.
onal examples of a further active ient or ingredients (anti-neoplastic
agent) for use in combination or co-administered with the presently invented CD73
inhibiting compounds are antibodies to ICOS.
CDRs for murine dies to human ICOS having agonist activity are shown in
(VVO 2012/131004). Antibodies to ICOS are also disclosed in WO
2008/137915, , EP 1374902, EP1374901, and EP1125585.
Additional es of a r active ingredient or ingredients (anti-neoplastic
agent) for use in combination or co-administered with the presently invented compound of
Formula (I) are STING ting compounds, CD39 inhibitors and A2a and A2a
adenosine antagonists.
In one embodiment, the cancertreatment method of the claimed ion includes
the co-administration a compound of Formula (I) and/or a pharmaceutically acceptable salt
thereof and at least one anti-neoplastic agent, such as one selected from the group
ting of anti-microtubule agents, platinum coordination complexes, alkylating agents,
antibiotic , topoisomerase II inhibitors, antimetabolites, topoisomerase I inhibitors,
2017/053511
hormones and hormonal analogues, signal transduction y inhibitors, non-receptor
tyrosine kinase angiogenesis inhibitors, immunotherapeutic , proapoptotic agents,
cell cycle signaling tors; proteasome inhibitors; and inhibitors of cancer metabolism.
The compounds of Formula (I) and pharmaceutically acceptable salts thereof may
be inistered with at least one other active agent known to be useful fortreating beta
hemoglobinopathies, such as sickle cell disease, sickle cell anemia, and beta thalassemia.
Examples of a further active ingredient or ingredients for use in combination or co-
administered with the presently invented combinations is hydroxyurea.
Compositions
The pharmaceutically active compounds within the scope ofthis invention are useful
as selective DNMT1 tors in mammals, particularly humans, in need thereof.
The present invention provides a pharmaceutical composition containing a
pharmaceutically acceptable ent and an effective amount of a compound of Formula
(I) as described above or a pharmaceutically acceptable salt f.
The present invention provides a process for preparing a pharmaceutical
composition containing a pharmaceutically acceptable excipient and an effective amount
of a compound of Formula (I) as described above or a pharmaceutically acceptable salt
thereof, which process comprises bringing the nd of Formula (I) or a
pharmaceutically acceptable salt thereof into association with a pharmaceutically
acceptable excipient.
The t invention therefore provides a method of treating cancer, pre-
cancerous mes and other conditions requiring DNMT1 inhibition, which comprises
administering an effective amount of a compound of a (I) or a pharmaceutically
able salt thereof. The compounds of Formula (I) also provide fora method oftreating
the above indicated disease states because oftheir demonstrated ability to act as DNMT1
inhibitors. The drug may be administered to a patient in need thereof by any conventional
route of administration, including, but not limited to, intravenous, intramuscular, oral, topical,
aneous, intradermal, intraocular and parenteral.
The pharmaceutically active compounds of the present invention are incorporated
into convenient dosage forms such as capsules, tablets, or injectable preparations. Solid
or liquid pharmaceutical carriers are employed. Solid carriers include, starch, lactose,
calcium sulfate dihydrate, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium
stearate, and c acid. Liquid rs include syrup, peanut oil, olive oil, saline, and
water. Similarly, the carrier or diluent may include any prolonged e material, such as
yl monostearate or glyceryl distearate, alone or with a wax. The amount of solid
carrier varies widely but, preferably, will be from about 25 mg to about 1 g per dosage unit.
When a liquid carrier is used, the preparation will be in the form of a syrup, elixir, emulsion,
soft gelatin capsule, sterile injectable liquid such as an ampoule, or an aqueous or
nonaqueous liquid suspension.
The pharmaceutical compositions are made following conventional techniques ofa
pharmaceutical chemist ing mixing, granulating, and compressing, when necessary,
fortablet forms, or , filling and dissolving the ingredients, as appropriate, to give the
desired oral or parenteral products.
Doses of the presently invented pharmaceutically active nds in a
pharmaceutical dosage unit as described above will be an cious, nontoxic quantity
preferably selected from the range of 0.001 - 500 mg/kg of active compound, ably
0.01 - 100 mg/kg. When treating a human patient in need of a DNMT1 inhibitor, the
selected dose is administered preferably from 1-6 times daily, orally or parenterally.
red forms of parenteral administration include topically, rectally, transdermally, by
injection and continuously by infusion. Oral dosage units for human administration
ably contain from 0.5 to 3500 mg of active compound. Suitably oral dosage units for
human administration preferably contain from 0.5 to 1,000 mg of active compound. Oral
stration, which uses lower dosages, is preferred. Parenteral administration, at high
dosages, however, also can be used when safe and convenient forthe patient.
Optimal dosages to be administered may be readily determined by those skilled in
the art, and will vary with the particular DMNT1 tor in use, the strength of the
preparation, the mode of administration, and the advancement of the disease condition.
Additional factors depending on the particular patient being treated will result in a need to
adjust s, including patient age, weight, diet, and time of administration.
The method of this invention of inducing DNMT1 inhibitory activity in mammals,
ing humans, comprises stering to a subject in need ofsuch activity an effective
DNMT1 ting amount of a pharmaceutically active nd ofthe present invention.
The invention also provides for the use of a compound of Formula (I) or a
pharmaceutically acceptable salt f in the manufacture of a medicament for use as a
DNMT1 inhibitor.
The invention also provides a compound of Formula (I) or a pharmaceutically
able salt thereof for use in therapy.
The invention also provides a compound of Formula (I) or a pharmaceutically
acceptable salt thereof for use in treating cancer and pre-cancerous syndromes.
The invention also provides the use of a compound of a (I) or a
pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating
cancer and pre-cancerous mes.
The invention also provides a compound of Formula (I) or a pharmaceutically
acceptable salt thereof for use in ng a emoglobinopathy such as sickle cell
disease, sickle cell anemia, or beta-thalassemia.
The invention also provides the use of a compound of Formula (I) or a
ceutically acceptable salt thereof in the manufacture of a medicament for treating a
beta-hemoglobinopathy such as sickle cell disease, sickle cell anemia, or beta-
thalassemia.
The invention also provides for a pharmaceutical composition for use as a DNMT1
inhibitor which comprises a compound of Formula (I) or a pharmaceutically acceptable salt
thereof and a pharmaceutically acceptable carrier.
The invention also provides for a pharmaceutical composition for use in the
treatment of cancer which comprises a compound of Formula (I) or a pharmaceutically
acceptable salt thereof and a pharmaceutically acceptable carrier.
In addition, the pharmaceutically active compounds ofthe present invention can be
co-administered with further active ingredients, such as other compounds known to treat
cancer, or compounds known to have utility when used in combination with a DNMT1
inhibitor.
The invention also provides a pharmaceutical composition comprising from 0.5 to
1,000 mg of a nd of Formula (I) or pharmaceutically acceptable salt thereof and
from 0.5 to 1,000 mg of a pharmaceutically acceptable excipient.
Vlfithout further elaboration, it is believed that one skilled in the art can, using the
preceding description, utilize the t invention to its t extent. The following
Examples are, ore, to be construed as merely illustrative and not a limitation of the
scope ofthe present invention in any way.
EXAMPLES
The following Examples rate the invention. These examples are not intended
to limit the scope of the present invention, but rather to provide guidance to the skilled
artisan to e and use the compounds, compositions, and methods of the present
invention. While ular embodiments ofthe present invention are described, the skilled
artisan will appreciate that various s and modifications can be made without
departing from the spirit and scope ofthe invention.
Example 1:
2- 6-amino-3 5-dic anoeth | ridin lsulfan l hen lacetamide
This compound was purchased from a commercial source; CAS 1845301. This
compound may also be prepared according to the method of V. D. Dyachenko, S. G.
Krivokolysko, V. P. Litvinov, Chemistry of Heterocyclic Compounds, Vol. 32, No. 8, 1996.
Example 2:
R - 6-amino-3 5-dic anoeth l ridin lsulfan l hen lacetamide
Racemic 2-[(6-amino-3,5-dicyanoethylpyridinyl)sulfany|]phenylacetamide (39 mg)
was dissolved in 4 mg portions in 1000 volumes using 1.30 mL of g methanol with
sonication, followed by 1.30 mL of ethanol, followed by 1.30 mL of n-heptane for each 4
mg. Carried out about 10 chiral preps at 4 mg each (4 mL each). The sample was resolved
by chiral HPLC using a Chiralpack, IC, 5 microns, (21 mm x 250 mm) eluting with 70:30 n-
heptane: methanol (20 mL/min). Collected a total ofabout 300 mL of product solution which
was concentrated to near dryness and then the product was dried at 40 °C under high
vacuum to afford (R)[(3,5-dicyanoethylmorpholinopyridyl)sulfanyl]phenyl-
acetamide (18 mg) as a white solid. LCMS m/z = 338.3 . 98% ee chiral purity.
Optical Rotation: -336 s (C = 0.1, DMSO-de, 23 °C). 1H NMR (DMSO—ds) 6 ppm
7.91 (br. s., 2H), 7.75 (s, 1H), 7.59 (d, J=6.8 Hz, 2H), 7.27-7.40 (m, 4H), 5.56 (s, 1H), 2.69
(q, J=7.4 Hz, 2H), 1.18 (t, J=7.6 Hz, 3H).
Example 3:
2- 35-dic ano dimeth lamino eth | 2- n | hen lacetamide
Step 1: um 3,5-dicyanoethylhydroxypyridin-Z-olate
NC \CN
'/ 9 <9
HO N 0 NH4
To a solution of 2-cyanoacetamide (28.6 g, 0.34 mol) in water (190 mL) was added
ammonium hydroxide (25%, aqueous, 10 mL) and propionaldehyde (10 g, 0.17 mol). Then
the reaction on was stirred at room temperature overnight. The solid was filtered and
washed with cold methanol, then dried under reduced pressure to give ammonium 3,5-
dicyano—4-ethyl-6—hydroxypyridin-2—olate (12 g, 34.3%) as a white solid. LCMS m/z = 187.9
[M]—.
Step 2: chloroethylpyridine-3,5-dicarbonitrile
NO ON
CI N CI
Ammonium 3,5-dicyanoethylhydroxypyridinolate (12 g, 58.2 mmol) was added
slowly to POCIs (100 mL) in a sealed tube. The mixture was stirred at 150 °C for 15 hours.
The solvent was removed under reduced pressure. The residue was poured into ice-water.
The solid was filtered and dried to give 2,6-dichloroethylpyridine-3,5-dicarbonitrile (10.8
g, 83%) as a light yellow solid. 1H NMR (400 MHz, CDCls) 6 ppm 3.13 (d, J = 7.7 Hz, 2H),
1.42 (t, J = 7.7 Hz, 3H).
Step 3: ro(dimethylamino)—4-ethy|pyridine-3,5-dicarbonitrile
NC ON
\T N/ CI
To a solution of 2,6-dichloroethylpyridine-3,5-dicarbonitrile (1 g, 4.44 mmol) in NM-
dimethylformamide (10 mL) was added dimethylamine (2 M in tetrahydrofuran, 2.2 mL, 4.44
mmol) and triethylamine (0.62 mL, 4.44 mmol). The reaction was stirred at room
temperature for 5 minutes. Water was added to the reaction. The solid was filtered and
purified by flash column chromatography eluted by petroleum ether:ethyl acetate = 3:1 to
give ro(dimethylamino)-4—ethylpyridine-3,5-dicarbonitrile (900 mg, 87%). LCMS
m/z = 234.9 [M+H]".
Step 4: 2-hydroxyphenylacetamide
To a solution of 2-hydroxyphenylacetic acid (20 g, 0.13mol) in MeOH (140 mL) was
added CH3COC| (27.9 g, 0.36 mol) dropwise. Then the solution was stirred at room
temperature for 20 hours. The ing solution was concentrated to give solid which was
dissolved in MeOH (60 mL). NH3-H20 (140 mL) was added. The mixture was stirred at 4
°C for 18 hours. The mixture was trated to give 2-hydroxyphenylacetamide (20
g, 100% yield) as a white solid. LCMS m/z = 152.0 [M+H]+.
Step 5: 2-aminooxophenylethy| esulfonate
To a on of 2-hydroxyphenylacetamide (20 g, 0.13mmol) in CHs-CN (400 mL) was
added triethylamine (36 mL, 0.26 mmol) and MsCl (18.2 g, 0.16 mol). Then the mixture was
stirred at 40 °C for 6 hours. The solvent was removed and the residue was resolved with
DCM and H20, the organic layer was washed with brine, dried and concentrated to give 2-
aminooxophenylethy| esulfonate (15 g) as a white solid. LCMS m/z = 247
[M+Na]*.
Step 6: 2-{[3,5-dicyano(dimethylamino)ethylpyridinyl]sulfanyl}
phenylacetamide
A solution of 2-chloro(dimethylamino)ethylpyridine-3,5-dicarbonitrile (450 mg, 1.92
mmol) and KSAc (263 mg, 2.31 mmol) in N,N-dimethylformamide (20 mL) was stirred at
room temperature for 30 minutes then 2-aminooxopheny|ethyl methanesulfonate (528
mg, 1.06 mmol) and triethylamine (0.53 mL, 3.84 mmol) were added to the solution. The
mixture was stirred at room temperature overnight then diluted with water (20 mL). The
precipitated solid was ted by filtration and purified by silica gel column
chromatography (eluted by DCM:MeOH = 20:1) to give 2-{[3,5-dicyano(dimethylamino)-
4-ethylpyridinyl]sulfanyl}phenylacetamide (400 mg, 57%). LCMS m/z = 365.9 .
1H NMR (400 MHz, CDCIs) 6 ppm 7.47 — 7.43 (m, 2H), 7.42 — 7.34 (m, 3H), 6.55 (b rs, 1H),
.60 (br s, 1H), 5.43 (s, 1H), 3.40 (s, 6H), 2.92 (q, J = 7.6 Hz, 2H), 1.32 (t, J = 7.6 Hz, 3H).
Example 4:
2- 35-dic anoc clo ro |14-diaze an l ridin Ithio
phenylacetamide
Step 1: Ammonium 3,5-dicyanocyclopropylhydroxypyridinolate
NC CN
HO N O"
NH4”
To a mixture of cyclopropanecarbaldehyde (47.3 g, 562 mmol) in H20 (320 mL) was added
NH3~H20 (16 mL) and oacetamide (20 g, 285 mmol). The mixture was stirred at room
temperature overnight. The solid was filtered and washed with cold MeOH to give
ammonium 3,5-dicyanocyclopropylhydroxypyridinolate as a white solid (20 g,
32%). LCMS m/z = 199.9 [M]—.
Step 2: 2,6-Dichlorocyclopropylpyridine-3,5-dicarbonitrile
NC CN
CI N Cl
Ammonium 3,5-dicyanocyclopropylhydroxypyridinolate (20 g, 91.7 mmol) was
added to POC|3 (500 mL), then the e was stirred at 150 °C in a sealed tube overnight.
The solvent was removed under vacuo. The residue was poured into ice-water. The solid
formed was filtered, washed with water, dried to give 2,6-dichlorocyclopropylpyridine-
3,5-dicarbonitrile (21 g) as a yellow solid. 1H NMR (400 MHz, CDCI3) 6 ppm 2.36 — 2.27
(m, 1H), 1.51 — 1.44 (m, 4H).
Step 3: tert-butyl 4-(6-chloro-3,5-dicyanocyclopropylpyridinyl)-1,4-diazepane
carboxylate
NC ON
(\N /
N Cl
To a solution of 2,6-dichIorocyclopropylpyridine-3,5-dicarbonitrile (2.37 g, 10 mmol) in
N.N-dimethylformamide (50 mL) was added tert-butyl 1,4-diazepanecarboxylate (2 g, 10
mmol) and triethylamine (1.4 mL, 10 mmol). Then the mixture was stirred at room
temperature for 5 minutes. Water was added to the reaction, extracted with ethyl acetate.
The organic layer was washed with water and brine, dried, trated and purified by
flash column chromatography (eluted by petroleum ethyl acetate = 5:1) to give tertbutyl
4-(6-chloro-3,5-dicyanocyclopropylpyridinyl)-1,4-diazepanecarboxylate (3.4
g, 85%) as a white solid. LCMS m/z = 424.0 [M+H]“.
Step 4: tert-butyl 4-(6-((2-aminooxophenylethy|)thio)-3,5-dicyano
cyclopropylpyridinyI)-1,4-diazepanecarboxylate
tert-Butyl 4-(6-chloro-3,5-dicyan0cyclopropylpyridinyl)—1 ,4-diazepanecarboxylate
(600 mg, 1.5 mmol) and KSAc (205 mg, 1.8 mmol) in N,N-dimethylformamide (15 mL) were
stirred at room temperature for 30 minutes. 2-Aminooxophenylethyl
esulfonate (synthesis described in example 3 step 5, 377 mg, 1.6 mmol) was added
followed by triethylamine (0.42 mL, 3 mmol), then the mixture was d at room
temperature for 2 hours. Water was added, the solid was stirrred, d and purified by
flash column chromatography (eluted by petroleum ether:ethyl acetate = 2:3) to give tert-
butyl 4-(6-((2-aminooxophenylethyl)thio)-3,5-dicyanocyclopropylpyridinyl)-1,4-
diazepanecarboxylate (300 mg, 38%) as white solid. LCMS m/z = 533.0 [M+H]+.
Step 5: 2-((3,5-dicyanocyclopropyl(1,4-diazepanyl)pyridiny|)thio)
phenylacetamide
NC CN
rN /
N s
To a solution of tert-butyl 4-(6-((2-aminooxophenylethyl)thio)-3,5—dicyano
cyclopropylpyridinyl)-1,4-diazepanecarboxylate (300 mg, 0.56 mmol) in DCM (10 mL)
was added trifluoroacetic acid (1 mL). The reaction solution was stirred at room temperature
ght. The solvent was washed with saturated aqueous NaHCOs solution and brine,
concentrated and d by flash column chromatography (eluted by DCM:MeOH = 10:1)
to give 2-((3,5-dicyanocyclopropyl(1,4-diazepanyl)pyridinyl)thio)
acetamide (170 mg, 70%) as a white solid. LCMS m/z = 433.0 [M+H]*. 1H NMR
(400 MHz, CDCIs) 6 ppm 7.46 — 7.33 (m, 5H), 6.66 (br s, 1H), 5.78 (br s, 1H), 5.34 (s, 1H),
4.10 — 3.88 (m, 4H), 3.19 (t, J = 5.3 Hz, 2H), 2.99 — 2.91 (m, 2H), 2.12 - 1.94 (m, 4H), 1.33
— 1.24 (m, 2H), 1.15 — 1.06 (m, 2H).
Example 5:
2- 35-dic anoc clo ro l 4-eth ldiaze an | ridin n l
phenylacetamide
NC ON
//\N N/
\ng) s
To a solution of 2-((3,5-dicyano—4-cyclopropyl(1,4-diazepanyl)pyridinyl)thio)—2-
phenylacetamide (synthesis bed in example 4, step 5, 120 mg, 0.28 mmol) in DCM
(5 mL) was added CH3CHO (37 mg, 0.84 mmol) and NaBH(OAc)3 (119 mg, 0.56 mmol).
The reaction was stirred at room temperature overnight. The resulting solution was washed
with saturated aqueous NaHCOs solution, water and brine. The solvent was removed and
the residue was purified by flash column chromatography (eluted by DCMzMeOH = 10:1)
to give 2-{[3,5-dicyanocyclopropyl(4-ethyl-1,4-diazepanyl)pyridinyl]sulfanyl}
phenylacetamide (17 mg, 13%) as a white solid. LCMS m/z = 460.8 [M+H]+. 1H NMR (400
MHz, CDClg) 5 ppm 7.48 — 7.31 (m, 5H), 6.64 (br s, 1H), 5.91 (br s, 1H), 5.36 (s, 1H), 4.08
— 3.34 (m, 4H), 2.97 — 2.33 (m, 2H), 2.75 — 2.58 (m, 4H), 2.15 — 2.01 , 1.31 — 1.24
(m,2H), 1.15 - 1.04 (m, 5H).
Example 6:
2- 35-dic anoeth | 4- r0 ldiaze an l ridin Ithio
phenylacetamide
Step 1: 2-[(6-bromo-3,5-dicyanoethylpyridyl)sulfanyl]phenyl-acetamide
NC CN
W0””2
A d suspension of 2-[(6-amino-3,5-dicyanoethyl—2-pyridyl)sulfanyl]phenyl-
acetamide (synthesis described in example 2, 150 mg, 0.44 mmol) in dry itrile (8 mL)
was treated with copper(|l) e (168 mg, 0.75 mmol) and tert-butylnitrite (0.09 mL, 0.78
mmol) then heated at 70 °C for 15 minutes under an atmosphere of nitrogen. The product
mixture was cooled to ambient temperature, dry loaded onto Si02 (1 g) and
chromatographed on SiOz (4 g RediSep cartridge) eluting with 20-100% EtOAc/isohexane
to give 2-[(6-bromo-3,5-dicyanoethylpyridyl)sulfanyl]phenyl-acetamide (55 mg,
31% yield) as an off-white solid. LCMS m/z = 401.0 [M—H]—.
Step 2: 2-((3,5-dicyanoethyl(4-propy|-1,4-diazepany|)pyridiny|)thio)
phenylacetamide
:91:
H0 m:
A solution of 2-[(6-bromo-3,5-dicyanoethylpyridyl)sulfanyl]phenyl-acetamide (31
mg, 0.08 mmol) in tetrahydrofuran (1 mL) was treated with 1-propyl-1,4-diazepane (0.03
mL, 0.19 mmol) and stirred at room temperature for2 hours. The product mixture was
concentrated and loaded onto SiOz (0.9 g) and chromatographed on Si02 (4 g RediSep
cartridge, eluting with 0-10% MeOH, 0-0.1% NH3/CH2CI2) and triturated with diethyl ether to
afford 2-[[3,5-dicyanoethyl(4-propyl-1,4-diazepanyl)pyridyl]sulfanyl]phenyl-
acetamide (27 mg, 76% yield) as a white solid. LCMS m/z = 461.2 [M—H]‘. 1H NMR (300
MHz, e) 6 ppm 7.92 (s, 1H), 7.54 - 7.45 (m, 2H), 7.43 - 7.30 (m, 4H), 5.51 (s, 1H),
3.89 (br s, 4H), 2.77 (q, J=7.4 Hz, 4H), 2.68 - 2.53 (m, 2H), 2.47 - 2.17 (m, 2H), 1.91 (brs,
2H), 1.42 (br s, 2H), 1.20 (t, J=7.5 Hz, 3H), 0.83 (br t, J=7.3 Hz, 3H).
e 7:
2- 35-dic anoeth | 4-eth |diaze an | ridin lsulfan |
phenylacetamide
A solution of 2-[(6-bromo-3,5-dicyanoethylpyridyl)sulfanyl]phenyl-acetamide
(synthesis described in example 6, step 1, 32 mg, 0.08 mmol) in tetrahydrofuran (1 mL)
was treated with N-ethylhomopiperazinyl (0.03 mL, 0.20 mmol) and stirred at t
temperature for2 hours. The product mixture was loaded onto Si02 (0.9 g) and
chromatographed on SiOz (4 g p cartridge eluting with 0-10% MeOH, 0-0.1%
NHs/CH2CI2) to furnish 2-[[3,5-dicyanoethyl(4-ethyl-1,4-diazepanyl)
pyridyl]sulfanyl]phenyl-acetamide (33 mg, 94% yield) as a white solid. LCMS m/z =
447.2 [M-H]—. 1H NMR (300 MHz, DMSO-da) 6 ppm 7.93 (s, 1H), 7.54 - 7.42 (m, 2H), 7.47
- 7.30 (m, 4H), 5.51 (s, 1H), 4.09 - 3.79 (m, 4H), 3.02 - 2.64 (m, 8H), 2.02 (brs, 2H), 1.22
(t, J=7.5 Hz, 3H), 1.08 (brt, J=6.8 Hz, 3H).
Example 8:
acetamide
Step 1: Ch|oroethyl(5-oxo-1,4-diazepanyl)pyridine-3,5-dicarbonitrile
NC \CN
N N CI
To a stirred solution of 2,6-dichloroethylpyridine-3,5-dicarbonitrile (synthesis described
in example 3, step 2, 225 mg, 1 mmol) and triethylamine (202 mg, 2 mmol) in
dichloromethane (10 mL) was added 1,4-diazepanone (114 mg, 1 mmol) dropwise. The
resulting solution was stirred at room temperature overnight. The reaction was quenched
with HCI solution (6 N), then extracted with dichloromethane (40 mL). The organic layer
was washed with brine (30 mL) then dried over anhydrous sodium sulfate, filtered, and
concentrated under reduced pressure. The residue was purified by silica gel
chromatograph (petroleum ether/ethyl acetate = 5:1) to afford chloroethyl(5-oxo-1,4-
diazepanyl)pyridine-3,5-dicarbonitrile (150 mg, 50%). LCMS m/z = 304 [M+H]+.
Step 2: 2-{[3,5-dicyanoethyl(5-oxo-1,4-diazepany|)pyridinyl]su|fany|}
phenylacetamide
N N S
o J o
To a stirred solution of potassium thioacetate (114 mg, 1.0 mmol) in N,N-
dimethylformamide (20 mL) was added dropwise a on of chloroethyl(5-oxo-1,4-
any|)pyridine-3,5-dicarbonitrile (150 mg, 0.5 mmol) in N,N-dimethylformamide (5
mL) at 0 °C. The resulting on was stirred at ambient temperature for2 hours followed
by the addition of potassium carbonate (138 mg, 1.0 mmol) and ooxo
ethyl methanesulfonate (synthesis described in example 3 step 5, 344 mg, 3.0
mmol). The resulting mixture was stirred at room temperature overnight. The reaction was
quenched with HCI solution (1 N, 60 mL), then ted with ethyl acetate (40 mL). The
organic layer was washed with brine (30 mL) and concentrated to dryness. The residue
was d by prep-HPLC to give 2-{[3,5-dicyanoethyl(5-oxo-1,4-diazepan
yl)pyridinyl]sulfany|}phenylacetamide (85 mg) as a white solid. LCMS m/z = 435
[M+H]*. 1H NMR (400 MHz, DMSO-de) 6 ppm 1.23 (m, 3H), 2.68 (s, 2H), 2.79 (m, 2H),
3.35 (s, 2H), 4.00 (s, 4H), 5.53 (s, 1H), 7.40 (m, 3H), 7.51 (m, 2H), 7.74 (s, 1H), 7.93 (s,
1H).
Example 9:
2- 35-dic anoc clo ro lmor holino ridin lthio ridin
yl lacetamide
Step 1: idinyl)((trimethylsilyl)oxy)acetonitrile
OTMS
A mixture of isonicotinaldehyde (3.5 g, 32.7 mmol), TMS-CN (163.3 mmol) in CHC|3 (50
mL) was stirred at 50 °C for 12 hours. The resulting mixture was concentrated. The e
was purified by silica gel column eluting with petroleum ether/ethyl acetate = 20/1 to give
2-(pyridinyl)((trimethylsi|y|)oxy)acetonitrile (1.8 g, 22% yield) as colorless oil. LCMS
m/z = 207 [M+H]".
Step 2: 2-hydroxy(pyridinyl)acetamide
N/ 0
To a stirring solution of conc. H2804 (90%, 10 mL) was added 2-(pyridinyl)
((trimethylsily|)oxy)acetonitrile (1.8 g, 8.72 mmol). The resulting mixture was stirred at room
temperature for 5 hours. then poured into ice water, and made basic by NHg'Hzo to pH 9.
The solution was concentrated, the residue was ed by silica gel column eluting with
CH2C|2l MeOH (30/1) to give 2-hydroxy(pyridiny|)acetamide(900 mg, 53% yield) as a
white solid. LCMS m/z = 153 [M+H]".
Step 3: 2-aminooxo(pyridinyl)ethyl methanesulfonate
N/ NH2
To a stirring mixture of 2-hydroxy(pyridinyl)acetamide (900 mg, 5.91 mmol) EtaN (1.79
g, 17.7 mmol) in tetrahydrofuran (25 mL) was added MsCl (745 mg, 6.5 mmol) at 0 °C. The
resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was
concentrated. The residue was purified by silica gel column eluting with CH2Cl2/MeOH
) to give 2—aminooxo(pyridinyl)ethyl esulfonate (800 mg, 59% yield)
as brown oil. LCMS m/z = 231 [M+H]*.
Step 4: ro—4-cycIopropyI-B-morpholinopyridine-3,5-dicarbonitrile
To a solution of2,6-dichlorocyclopropylpyridine-3,5-dicarbonitrile (10 g, 42.2 mmol) in
N,N-dimethylformamide (200 mL) was added morpholine (3.7 g, 42.2 mmol) and
triethylamine (4.3 g, 42.2 mmol). the reaction on was stirred at room temperature for
minutes. Water was added to the reaction, and the resulting solid was filtered, washed
with water and dried to give 2-chlorocyclopropylmorpholinopyridine-3,5-dicarbonitrile
as a yellow solid (9.3 g, 77% yield). LCMS m/z = 289 [M+H]+.
Step 5: 2-((3,5-dicyanocyclopropylmorpholinopyridinyl)thio)(pyridin
yl)acetamide
(\N N/ 3
Cd o
A mixture of 2-chlorocyclopropylmorpholinopyridine-3,5-dicarbonitrile (200 mg, 0.69
mmol), KSAc (788 mg, 0.69 mmol) in N,N-dimethylformamide (8 mL) was stirred at room
temperature for 30 minutes. Then ooxo(pyridinyl)ethy| methanesulfonate
(191 mg, 0.83 mmol) and triethylamine (209 mg, 202 mmol) were added. The resulting
mixture was stirred at room temperature for 12 hours. The reaction mixture was poured into
water (50 mL), then extracted with EtOAc (50 mL x 2). The combined organic layers were
dried, concentrated and the e was ed by silica gel column eluting with
CH2C|2/MeOH (50/1) to give 2-((3,5-dicyanocyclopropylmorpholinopyridinyl)thio)-
2-(pyridinyl)acetamide (100 mg, 34% yield) as a white solid. LCMS m/z = 421 .
1H NMR (400 MHz, DMSO) 6 ppm 8.58 (dd, J = 4.6, 1.4 Hz, 2H), 8.04 (br s, 1H), 7.55 —
7.45 (m, 3H), 5.57 (s, 1H), 3.80 (m, 4H), 3.71 — 3.56 (m, 4H), 2.16 — 2.08 (m, 1H), 1.16 —
1.07 (m, 2H), 1.02 — 0.93 (m, 2H).
e 10
2- 35-dic anoeth l 4-meth loxo i erazin I ridin lsulfan |
(pyridinyllacetamide
Step 1: 2-chloroethyl(4-methyloxopiperazinyl)pyridine-3,5-dicarbonitrile
OVN N/ CI
A solution of2,6-dichloroethylpyridine-3,5-dicarbonitrile (synthesis described in example
3 step 2, 226 mg, 1.000 mmol), 1-methylpiperazinone (114 mg, 1.000 mmol) and
triethylamine (0.167 mL, 1.200 mmol) in N,N-dimethylformamide (8 mL) was stirred at room
temperature for 30 minutes. The reaction mixture was poured into water (50 mL), and
extracted with ethyl acetate (50 mL x 2), the combined organic layers were dried,
concentrated to give desired product (270 mg, 89% yield) as a white solid. LCMS m/z =
304.0 [M+H]+.
Step 2: 2-{[3,5-dicyanoethyl(4-methyloxopiperazinyl)pyridin
yl]sulfany|}(pyridiny|)acetamide
oYN /
N s
/N\) O
N/ NH2
A on of potassium thioacetate (122 mg, 1.067 mmol), 2-chIoroethyl(4-methyl
oxopiperazinyl)pyridine—3,5-dicarbonitrile (synthesis described in example 9 step 3, 270
mg, 0.889 mmol) in N,N-dimethy|formamide (10 mL) was stirred at room temperature for
minutes, then 2-aminooxo(pyridinyl)ethyl methanesulfonate (246 mg, 1.067
mmol) and triethylamine (0.248 mL, 1.778 mmol) was added to the solution. The on
mixture was stirred at room ature for 12 hours. The reaction mixture was poured into
water (50 mL), and extracted with ethyl acetate (50 mL x 2), the combined organic layers
were dried, concentrated, the residue was purified by silica gel column eluting with
DCM/MeOH (30/1) to give 2-{[3,5-dicyanoethyl(4-methyloxopiperaziny|)pyridin-
2-yl]su|fany|}(pyridinyl)acetamide (50 mg, 13% yield) as a white solid. LCMS m/z =
435.8 [M+H]+. 1H NMR (400 MHz, CDCls) 6 ppm 8.64 (d, J = 3.8 Hz, 2H), 7.47 (d, J = 5.3
Hz, 2H), 7.25 (brs, 1H), 6.14 (brs, 1H), 5.50 (s, 1H), 4.43 (dd, J = 569,173 Hz, 2H), 4.26
— 4.17 (m, 1H), 4.18 — 4.08 (m, 1H), 3.58 — 3.47 (m, 2H), 3.03 (s, 3H), 2.96 (q, J = 7.6 Hz,
2H), 1.34 (t, J = 7.6 Hz, 3H).
Example 11
2- 35-dic anoeth l meth l2- mor 4- leth lamino ridin
yl)sulfanyl|phenylacetamide
Step 1: 2-chloroethyl(methy|(2-morpho|inoethyl)amino)pyridine-3,5-
dicarbonitrile
NC CN
0 \
K/N I
N CI
\An
To a solution of 2,6-dichIoroethylpyridine-3,5-dicarbonitrile (synthesis described in
e 3 step 2, 300 mg, 1.327 mmol) and N-methylmorpholinoethanamine (191 mg,
1.327 mmol) in N,N-dimethylformamide (15 mL) was added EtsN (0.185 mL, 1.327 mmol)
at room temperature and the resulting mixture was stirred at room temperature for 1 hour.
The reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (50
mL x 2), the combined organic layers were dried and concentrated to give desired product
(320 mg, 72% yield) as a pale solid. LCMS m/z = 334 [M+H]*.
Step 2: 2-[(3,5-dicyanoethyl{methyl[2-(morpholinyl)ethyl]amino}pyridin
yl)sulfanyl]phenylacetamide
A solution of potassium thioacetate (82 mg, 0.719 mmol), 2-chloroethyl(methyl(2-
morpholinoethyl)amino)pyridine-3,5-dicarbonitrile (200 mg, 0.599 mmol) in NM-
dimethylformamide (10 mL) was d at room temperature for 30 minutes, then o-
2-oxophenylethyl methanesulfonate (synthesis described in example 3 step 5, 165 mg,
0.719 mmol) and triethylamine (0.167 mL, 1.198 mmol) was added to the solution. The
reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was
poured into water (50 mL), and extracted with ethyl acetate (50 mL x 2), the combined
organic layers were dried, concentrated, the residue was purified by silica gel column
eluting with DCM/MeOH (30/1) to give 2-[(3,5-dicyanoethyl{methyl[2-(morpho|in
yl)ethyl]amino}pyridinyl)su|fany|]phenylacetamide (75 mg, 27% yield) as a white solid.
LCMS m/z = 465.0 [M+H]". 1H NMR (400 MHz, CDCIg) 6 ppm 7.48 — 7.32 (m, 5H), 6.98
(br s, 1H), 5.84 (br s, 1H), 5.41 (s, 1H), 4.20 — 4.06 (m, 1H), 3.78 — 3.60 (m, 5H), 3.45 (s,
3H), 2.91 (q, J = 7.6 Hz, 2H), 2.80 - , 2H), 2.62 — 2.45(m, 4H), 1.32 (t, J = 7.6 Hz,
3H).
e 12
2- 35-dic eth | 4- r0 I i erazin | ridin lsulfan l
acetamide
Step 1: 2-chloroethyl(4-propylpiperazinyl)pyridine-3,5-dicarbonitrile
A/Nx)
A mixture dichloroethylpyridine-3,5-dicarbonitrile (synthesis described in example
3 step 2, 300 mg, 1.32 mmol), 1-propylpiperazinyl hydrochloride (217.8 mg, 1.32 mmol)
and EN (133.3 mg, 1.32 mmol) in N,N-dimethylformamide (10 mL) was stirred at room
temperature for1 hour. The resulting mixture was poured into water (50 mL), then extracted
with EtOAc (50 mL x 2), the combined organic layer was dried and concentrated to give 2-
ethyl(4-propylpiperazinyl)pyridine-3,5-dicarbonitrile (310 mg, 74%) as a
brown oil. LCMS m/z = 318.0 [M+H]".
Step 2: 2-{[3,5-dicyanoethyl(4-propylpiperaziny|)pyridinyl]sulfanyl}
phenylacetamide
NC CN
N N S
/\/N\) O
A solution of roethyl(4-propylpiperazinyl)pyridine-3,5-dicarbonitrile (310 mg,
0.97 mmol) and KSAc (134 mg, 1.17 mmol) in N,N-dimethylformamide (10 mL) was stirred
at room temperature for 30 minutes then 2-aminooxophenylethyl methanesulfonate
(synthesis described in example 3 step 5, 268 mg, 0.97 mmol) and Eth (196 mg, 1.94
mmol) in N,N-dimethylformamide were added. The mixture was stirred at room temperature
for 12 hours. The reaction mixture was poured into water (50 mL), then extracted with
EtOAc (50 mL x 2), the combined organic layer was dried and concentrated. The e
was purified by silica gel column chromatography 2:MeOH 20:1) to give 2-{[3,5-
dicyano—4-ethyl(4-propylpiperazinyl)pyridinyl]sulfany|}phenylacetamide (100
mg, 23%) as a white solid. LCMS m/z = 488.8 [M+H]". 1H NMR (400 MHz, CDCIs) 6 ppm
7.48 — 7.42 (m, 2H), 7.41 — 7.35 (m, 3H), 6.51 (br s, 1H), 5.68 (br s, 1H), 5.36 (s, 1H), 4.04
— 3.91 (m, 4H), 2.91 (q, J = 7.6 Hz, 2H), 2.65 — 2.50 (m, 4H), 2.41 — 2.31 (m, 2H), 1.61 —
1.47 (m, 2H), 1.32 (t, J = 7.6 Hz, 3H), 0.93 (t, J = 7.4 Hz, 3H).
e 13:
2- 35-dic anoeth l 4- i eridin | i erazin I ridin lsulfan |
phenylacetamide
NCfiCN
(\N N/ 8
NJ 0
To a mixture of 2-[(6-bromo-3,5—dicyano—4-ethylpyridy|)su|fany|]phenyl—acetamide
(synthesis described in example 6 step 1, 28 mg, 0.0700 mmol) and tert-butyl razin-
1-ylpiperidinylcarboxy|ate (20.68 mg, 0.0800 mmol) in tetrahydrofuran (2 mL) was
added triethylamine (19.4 pL, 0.1400 mmol). The mixture was stirred for6 hours. Additional
tert-butyl razinylpiperidinyIcarboxy|ate (4.6 mg. 0.25 eq.) and Eth (9.7 pL, 1
eq.) added and the mixture stirred for a r 16 hours. The mixture was diluted with
EtOAc (20 mL), washed with water (3 x 20 mL), brine (25 mL), filtered h a
hydrophobic frit and the solvent removed under reduced pressure. The residue was
dissolved in DCM and chromatographed on Si02 (4 g RediSep cartridge) using 0 - 10 %
MeOH in DCM as eluent to afford 25 mg ofa colorless residue. The residue was dissolved
in DCM (2 mL) and trifluoroacetic acid (0.5 mL, 6.73 mmol) was added. The mixture was
stirred at room temperature for 1 hour, the solvent removed under reduced re, the
residue triturated with Etzo and dried in vacuo at 50 °C to afford an off-white powder, which
was dissolved in DMSO and purified by prep HPLC to afford 2-[[3,5-dicyanoethyl[4-
(4-piperidyl)piperaziny|]pyridyl]su|fany|]phenyl-acetamide (12 mg, 0.0245 mmol,
%) as a white powder. LCMS m/z = 488.3 [M—H]‘. 1H NMR (300MHz, DMSO-ds) 6 ppm
8.37 (s, 1H), 7.94 (s, 1H), 7.52 (d, J=6.7 Hz, 2H), 7.45 - 7.29 (m, 4H), 5.53 (s, 1H), 3.90 -
3.82 (m, 4H), 3.18 - 3.04 (m, 2H), 2.96 - 2.61 (m, 6H), 2.61 - 2.53 (m, 2H), 2.48 - 2.16 (m,
1H), 1.81 (br d, J=12.4 Hz, 2H), 1.54 (brs, 2H), 1.20 (t, J=7.6 Hz, 3H).
yl}sulfanyl)—2-phenylacetamide
Step 1: 4-(6-chloro-3,5-dicyanocyclopropylpyridinyl)
(hydroxymethyl)piperazinylcarboxylate
NC ON
Ho/YN N/ Cl
Boc/Nd
To a solution of 2,6-dichlorocyclopropylpyridine-3,5-dicarbonitrile (synthesis described
in example 4 step 2, 238 mg, 1 mmol) in N,N-dimethylformamide (8 mL) at room
temperature was added tert-butyl 2-(hydroxymethyl)piperazinylcarboxylate (216 mg, 1
mmol), followed by Eth (101 mg, 1 mmol). The mixture was stirred at room temperature
for 1 hour. The reaction mixture was poured into water (50 mL) and extracted with EtOAc
(50 mL x 2). The combined organic layers were dried and concentrated, and the e
was purified by silica gel column eluting with CHzC|2:MeOH 50:1to give 4-(6-chloro-3,5-
dicyanocyclopropylpyridinyI)(hydroxymethyl)piperazinylcarboxylate (260 mg,
82%) as a brown oil. LCMS m/z = 318.0 [M+H—Boc]".
Step 2: tert-Butyl 4-(6-((2-aminooxophenylethy|)thio)-3,5-dicyano
cyclopropylpyridinyI)(hydroxymethyl)piperazinyIcarboxylate
NC ON
HO/Y\N /
N s
Boc’Nd O
A solution of tert-Butyl 4-(6-chloro-3,5-dicyanocyclopropylpyridinyl)—2-
(hydroxymethyl)piperazinylcarboxylate (260 mg, 0.62 mmol) and KSAc (85 mg, 0.74
mmol) in N,N-dimethylformamide (10 mL) was stirred at room temperature for 30 minutes
then 2-aminooxophenylethyl methanesulfonate esis described in example 3
step 5, 170 mg, 0.74 mmol) and Eth (125 mg, 1.24 mmol) were added to the solution. The
mixture was stirred at room ature for 12 hours then poured into water (50 mL), and
extracted with EtOAc (50 mL x 2). The ed organic layers were dried, trated
and purified by silica gel column chromatography (CH20I2:MeOH 40:1) to give tert-Butyl 4-
(6-((2-aminooxophenylethyl)thio)-3,5-dicyanocyclopropylpyridiny|)
(hydroxymethyl)piperazinylcarboxylate (280 mg, 82%) as a white solid. LCMS m/z =
570.7 [M+Na]+.
Step 3: 2-({3,5-dicyanocyc|opropyl[3-(hydroxymethyl)piperazinyl]pyridin
yl}suIfanyl)pheny|acetamide
NC ON
Ho/Y\N N/ s
HNQ o
To a solution of tert-Butyl 4-(6-((2-aminooxophenylethyl)thio)-3,5-dicyano
cyclopropylpyridinyl)(hydroxymethyl)piperazinylcarboxylate (280 mg, 0.61 mmol)
in DCM (10 mL) at room temperature was added trifluoroacetic acid (3 mL). The mixture
was stirred at room temperature for 12 hours then concentrated under vacuum, basified
with sat. NaHCOs solution and ted with DCM (50 mL x 2). The combined organic
layers were dried concentrated and purified by silica gel column chromatography
(CH2ClzzMeOH 30:1) to give 2-({3,5-dicyanocyclopropyl[3-(hydroxymethy|)piperazin-
1-yl]pyridinyl}sulfanyl)phenylacetamide (90 mg, 32%) as a white solid. LCMS m/z =
448.8 . 1H NMR (400 MHz, CDsOD) 6 ppm 7.60 — 7.50 (m, 2H), 7.50 — 7.31 (m, 3H),
.54 (s, 1H), 4.69 — 4.44 (m, 2H), 3.72 — 3.55 (m, 2H), 3.32 — 3.25 (m, 1H), 3.21 — 2.89 (m,
4H), 2.20 — 2.10 (m, 1H), 1.28 — 1.20 (m, 2H), 1.15 — 1.05 (m, 2H).
e 15:
2- 35-dic anoc clo ro | 3-oxo i erazin | ridin n |
phenylacetamide
Step 1: 2-ChIorocycIopropyI-G-(3-oxopiperaziny|)pyridine-3,5-dicarbonitrile
NC CN
OYN /
N CI
To a solution of 2,6-dich|orocyclopropylpyridine-3,5-dicarbonitrile (synthesis described
in example 4 step 2, 237 mg, 1 mmol) in N,N-dimethylformamide (10 mL) at room
temperature was added piperazinone (100 mg, 1 mmol), followed by EtsN (0.14 mL, 1
mmol). The mixture was stirred at room temperature for 5 minutes, then diluted with water
and ted with EtOAc. The combined organic layers were washed with water and brine,
dried and concentrated to give 2-chlorocyclopropyl(3-oxopiperazinyl)pyridine-3,5-
dicarbonitrile (290 mg, 96%). LCMS m/z = 301.9 [M+H]+.
Step 2: 2-{[3,5-dicyanocyclopropyl(3-oxopiperaziny|)pyridinyl]sulfanyI}
phenylacetamide
A solution of rocyclopropyl(3-oxopiperazinyl)pyridine-3,5-dicarbonitrile (290
mg, 0.96 mmol) and KSAc (132 mg, 1.16 mmol) in N,N-dimethylformamide (10 mL) was
stirred at room ature for 30 minutes then 2-aminooxopheny|ethyl
methanesulfonate (synthesis described in example 3 step 5, 265 mg, 1.16 mmol) and EN
(0.27 mL, 1.92 mmol) were added to the solution. The mixture was stirred at room
temperature overnight then diluted with water (20 mL). The precipitated solid was collected
by tion and purified by silica gel column chromatography (MeOHzDCM = 10:1) to give
2-{[3,5-dicyanocyclopropyl(3-oxopiperaziny|)pyridinyl]sulfanyl}
phenylacetamide (48 mg, 12%). LCMS m/z = 432.8 [M+H]+. 1H NMR (400 MHz, CD30D)
6 ppm 7.56 (d, J = 6.8 Hz, 2H), 7.45 — 7.35 (m, 3H), 5.57 (s, 1H), 4.48 (q, J = 17.8 Hz, 2H),
4.21 —4.04 (m, 2H), 3.50 (t, J = 5.2 Hz, 2H), 2.21 —2.11 (m, 1H), 1.30— 1.22 (m, 2H), 1.14
- 1.06 (m, 2H).
e 16
2- 35-dic anoc clo ro | 4- mar holin | i eridin | ridin
yl{sulfanyl1Qhenylacetamide
Step 1: 2-ch|orocyclopropyl(4-morpholinopiperidiny|)pyridine-3,5-
dicarbonitrile
2017/053511
NC ON
O / N CI
A mixture of 2,6-dichlorocyclopropylpyridine-3,5-dicarbonitrile (synthesis described in
example 4 step 2, 238 mg, 1 mmol) eridinyl)morpholine dihydrochloride (115 mg,
1 mmol) and Eth (303 mg, 3 mmol) in N,N-dimethylformamide (8 mL) at was stirred at
room temperature for 30 minutes. The reaction mixture was poured into water (50 mL) and
extracted with EtOAc (50 mL x 2). The combined organic layers were dried and
concentrated to give 2—ch|orocyclopropyl(4—morpholinopiperidinyl)pyridine-3,5-
dicarbonitrile (320 mg, 86%) as a brown solid. LCMS m/z = 372.1 [M+H]".
Step 2: 2-({3,5-dicyanocyclopropyl-G-[4-(morpholinyl)piperidinyl]pyridin
y|}su|fany|)phenylacetamide
NO ON
00m:/N 8
A solution of 2-chlorocyclopropyl(4-morpholinopiperidinyl)pyridine-3,5-
dicarbonitrile (320 mg, 0.86 mmol) and KSAc (117 3 mmol) in N,N-
dimethylformamide (10 mL) was stirred at room temperature for 30 minutes then 2-amino-
2-oxophenylethyl methanesulfonate (synthesis described in example 3 step 5, 236 mg,
1.03 mmol) and EtsN (174 mg, 1.72 mmol) were added. The resulting e was d
at room temperature for 12 hours. The mixture was poured into water (50 mL), and
extracted with EtOAc (50 mL x 2). The combined organic layers were dried concentrated,
and the residue was purified by silica gel column chromatography (CH2CI2:MeOH = 50:1)
to give 2-({3,5-dicyanocyclopropyl[4-(morpholinyl)pipe rid in-1 -yl]pyridin
y|}sulfany|)phenylacetamide (130 mg, 30%) as a white solid. LCMS m/z = 502.8 [M+H]+.
1H NMR (400 MHz, CDCIs) 6 ppm 7.50 — 7.43 (m, 2H), 7.43 — 7.35 (m, 3H), 6.57 (br s, 1H),
.68 (brs, 1H), 5.37 (s, 1H), 4.65 (d, J = 14.1 Hz, 2H), 3.82 —3.70 (m, 4H), 3.19 (t, J = 12.7
Hz, 2H), 2.66 — 2.45 (m, 5H), 2.13 — 2.02 (m, 3H), 1.70 — 1.59 (m, 2H), 1.32 — 1.27 (m, 2H),
.14 (m, 2H).
Example 17
2- 35-dic anoeth l 28-diazas iro 4.5 decan I ridin Ithio
hen lacetamide' 2 2 2-trifluoroacetic acid
NC ON
N N S
HN W0NH2 531OH
F F
To a mixture of 2-[(6-bromo-3,5-dicyanoethylpyridy|)su|fany|]phenyl—acetamide
(synthesis bed in example 6 step 1, 30 mg, 0.07 mmol) and tert-butyl 2,8-
diazaspiro[4.5]decanecarboxylate hloride (23 mg, 0.08 mmol) in tetrahydrofuran
(2 mL) was added triethylamine (0.03 mL, 0.25 mmol). The reaction mixture was stirred for
1 hour. The mixture was diluted with EtOAc (20 mL), washed with water (3 x 20 mL),
saturated sodium chloride (25 mL), filtered through a hydrophobic frit and the solvent was
removed under reduced pressure. The crude product was chromatographed on Si02 (4 g
RediSep cartridge) using 0-10 % MeOH in CH2C|2 as eluent. The resulting residue was
dissolved in CH2CI2 (2 mL) followed by the addition of trifluoroacetic acid (0.5 mL,
ol) and the subsequent mixture was stirred at ambient temperature for1 hour. The
solvent was removed under reduced pressure and the product was triturated with l
ether, dried in vacuo at 50 °C to afford 2-[[3,5-dicyano(2,8-diazaspiro[4.5]decanyl)
ethylpyridyl]su|fany|]phenyI-acetamide; 2,2,2-trifluoroacetic acid (38 mg, 88% yield)
as a white solid. LCMS m/z = 459.3 [M—H]‘. 1H NMR (300 MHz, DMSO-de) 6 ppm 8.79 (br
s, 2H), 7.92 (s, 1H), 7.57 - 7.47 (m, 2H), 7.44 - 7.30 (m, 4H), 5.53 (s, 1H), 4.30 - 3.98 (m,
2H), 3.91 - 3.60 (m, 2H), 3.43 - 3.12 (m, 4H), 2.78 (q, J=7.5 Hz, 2H), 2.11 - 1.81 (m, 6H),
1.22 (t, J=7.6 Hz, 3H).
Exam ple 18:
I 3- dimeth lamino i eridin I
Z-phenylacetamide
WO 16727
Step 1: tert-butyl ethylamino)piperidinylcarboxylate
/NU,BOC
To a solution of tert-butyl iperidinylcarboxylate (500 mg, 2.5 mmol) in
dichloromethane (10 mL) was added a solution of dimethylamine in tetrahydrofuran (3.8
mL, 2 M, 7.5 mmol). After stirring at room temperature for 5 minutes, NaBH(OAc)3 (1.06 g,
mmol) was added to the mixture. The mixture was stirred at room temperature overnight
then concentrated under vacuum and purified by silica gel column chromatography
(CH2ClzzMeOH = 10:1) to give tert-butyl 3-(dimethylamino)piperidinyl—1-carboxylate (500
mg, 88%) as a white solid. LCMS m/z = 229.0 [M+H]*.
Step 2: N,N-dimethylpiperidinamine
/N\©\1H
To a solution of tert-butyl 3-(dimethylamino)piperidinylcarboxylate (500 mg, 2.19 mmol)
in dichloromethane (4 mL) was added trifluoroacetic acid (4 mL). The mixture was stirred
at room temperature overnight then concentrated under vacuum, basified with saturated
aqueous NaHCOs solution and extracted with dichloromethane. The combined organic
layers were concentrated under vacuum to give N,N-dimethylpiperidinamine (250 mg).
LCMS m/z = 129.1 [M+H]+.
Step 3: 2-Chlorocyclopropyl(3-(dimethylamino)piperidiny|)pyridine-3,5-
onitrile
To a solution of 2,6-dichIorocyclopropylpyridine-3,5-dicarbonitrile (synthesis described
in example 4 step 2, 236 mg, 1 mmol) in methylformamide (10 mL) at room
temperature was added N,N-dimethylpiperidinamine (128 mg, 1 mmol), followed by
ylamine (0.14 mL1 mmol). The mixture was stirred at room temperature for5 minutes,
then diluted with water. The precipitated solid was collected by filtration and purified by
silica gel column chromatography (CH2CI2:ethyl acetate = 1:1) to give ro
cyclopropyl(3-(dimethylamino)piperidinyl)pyridine-3,5-dicarbonitrile (190 mg, 58%).
LCMS m/z = 329.8 [M+H]".
Step 4: 2-((3,5-Dicyanocyc|opropyl(3-(dimethylamino)piperidiny|)pyridin
y|)thio)phenylacetamide
A solution of 2-ch|orocyclopropyl(3-(dimethylamino)piperidiny|)pyridine-3,5-
dicarbonitrile (190 mg, 0.58 mmol) and KSAc (80 mg, 0.7 mmol) in N,N-dimethylformamide
(6 mL) was d at room temperature for 30 minutes then 2-aminooxophenylethy|
methanesulfonate esis described in example 3 step 5, 159 mg, 0.7 mmol) and
triethylamine (0.16 mL, 1.16 mmol) were. The mixture was stirred at room temperature
overnight then diluted with water. The precipitated solid was collected by filtration and
purified by silica gel column chromatography (dichloromethane:methano| = 20:1) to give 2-
((3 yanocyclo pro pyl(3-(dimethylamino)piperid in-1 -yl)pyrid inyl)th io)—2-
phenylacetamide (132 mg, 49%). LCMS m/z = 460.9 [M+H]*. 1H NMR (400 MHz, CDCI3)
6 ppm 7.49 — 7.44 (m, 2H), 7.40 — 7.34 (m, 3H), 5.54 (s, 1H), 5.42 (s, 1H), 4.89 — 4.76 (m,
1H), 4.55 (d, J = 13.6 Hz, 1H), 3.16 — 3.06 (m, 1H), 3.00 — 2.92 (m, 1H), 2.75 - 2.64 (m,
1H), 2.41 (s, 6H), 2.12 — 2.03 (m, 2H), 2.00 — 1.93 (m, 1H), 1.68 — 1.45 (m, 3H), 1.30 — 1.24
(m, 2H), 1.19 — 1.07 (m, 2H).
Example 19:
2- 35-Dic anoc clo ro | 3-meth | i erazin | 2- Ithio
phenylacetamide
Step 1: 4-(6-chIoro-3,5-dicyanocyclopropylpyridinyI)methy|piperazinyl
carboxylate
NC CN
YN /
N CI
Boc’N
To a solution of 2,6-dichlorocyclopropylpyridine-3,5-dicarbonitrile (synthesis described
in example 4 step 2, 236 mg, 1 mmol) in N,N-dimethylformamide (10 mL) was added tert-
butyI 2-methylpiperazinyIcarboxylate (200 mg, 1 mmol), followed by ylamine (0.14
mL,1 mmol). The mixture was stirred at room temperature for 5 minutes, then diluted with
water. The precipitated solid was collected by filtration and dried in an oven to give 4-(6-
chloro-3,5-dicyanocyclopropylpyridiny|)methy|piperazinylcarboxylate (330 mg,
82%). LCMS m/z = 301.9 [M+H—Boc]+.
Step 2: tert-Butyl 4-(6-((2-aminooxophenylethy|)thio)-3,5-dicyano
ropylpyridiny|)methylpiperazinylcarboxylate
Boc’Nd O
A solution of tert-butyl 4-(6-chloro-3,5-dicyanocyclopropylpyridinyI)
methylpiperazinylcarboxylate (330 mg, 0.82 mmol) and KSAc (113 mg, 0.99 mmol) in
N,N-dimethylformamide (9 mL) was stirred at room temperature for 30 minutes then 2-
aminooxophenylethyl methanesulfonate (synthesis described in example 3 step 5,
226 mg, 0.99 mmol) and triethylamine (0.23 mL, 1.64 mmol) were added to the solution.
The mixture was stirred at room temperature overnight then d with water. The
precipitated solid was collected by filtration and purified by silica gel column
tography (dichloromethanezmethanol = 20:1) to give tert-butyl 4-(6-((2-amino
oxophenylethyl)thio)-3,5-dicyanocyclopropylpyridiny|)methy|piperazinyl
carboxylate (280 mg, 64%). 1H NMR (400 MHz, CDCIa) 6 ppm 7.49 — 7.45 (m, 2H), 7.44 -
7.36 (m, 3H), 6.58 — 6.48 (m, 1H), 5.62 (brs, 1H), 5.40 — 5.35 (m, 1H), 4.49 — 4.27 (m, 3H),
4.03 — 3.95 (m, 1H), 3.62 — 3.53 (m, 1H), 3.43 — 3.27 (m, 2H), 2.16 — 2.08 (m, 1H), 1.50 (s,
9H),1.35 — 1.28 (m, 2H), 1.27 — 1.22 (m, 3H), 1.21 — 1.11 (m, 2H).
Step 3: 2-((3,5-Dicyanocyclopropyl-G-(s-methylpiperaziny|)pyridinyl)thio)
phenylacetamide
NCj\L/LCNl /
N N s
To a solution of tert-Butyl (2-aminooxophenylethyl)thio)-3,5-dicyano
cyclopropylpyridinyl)methylpiperazinylcarboxylate (280 mg, 0.53 mmol) in
dichloromethane (5 mL) at room temperature was added trifluoroacetic acid (4 mL). The
mixture was stirred at room temperature overnight then concentrated under vacuum,
basified with sat. NaHCOs solution, and extracted with dichloromethane (20 mL x 3). The
combined c layers were concentrated under vacuum, and purified by silica gel
column chromatography (dichloromethane2methanol = 20:1) to give 2-((3,5-dicyano
cyclopropyl(3-methylpiperazinyl)pyridinyl)thio)phenylacetamide (194.5 mg,
86%). LCMS m/z = 432.8 [M+H]". 1H NMR (400 MHz, CDCI3) 6 ppm 7.48 — 7.42 (m, 2H),
7.41 — 7.31 (m, 3H), 6.53 (s, 1H), 5.82 — 5.72 (m, 1H), 5.34 (s, 1H), 4.58 — 4.46 (m, 2H),
3.26 — 3.12 (m, 2H), 2.99 — 2.78 (m, 3H), 2.15 — 2.03 (m, 2H), 1.33 — 1.24 (m, 2H), 1.20 —
1.09 (m, 5H).
Example 20:
phenylacetamide
Step 1: 2-ChIorocycIopropyI-G-(3,5-dimethylpiperazinyl)pyridine-3,5-
dicarbonitrile
To a solution of 2,6-dichlorocyclopropylpyridine-3,5-dicarbonitrile (synthesis described
in example 4 step 2, 237 mg, 1 mmol) in N,N-dimethylformamide (10 mL) was added 2,6-
dimethylpiperazinyl (114 mg, 1 mmol), followed by triethylamine (0.14 mL, 1 mmol). The
mixture was stirred at room temperature for 5 minutes, then diluted with water. The
itated solid was collected by filtration and dried in an oven to give 2-chloro
cyclopropyl(3,5-dimethylpiperazinyl)pyridine-3,5-dicarbonitrile (280 mg, 89%) as a
white solid. LCMS m/z = 316.0 [M+H]+.
Step 2: 2-((3,5-Dicyanocyc|opropyl(2-(hydroxymethyl)morpho|ino)pyridin
yl)thio)phenylacetamide
NC CN
Y\NlN/S
HNW) o
A solution of 2-chlorocyclopropyl(3,5-dimethylpiperazinyl)pyridine-3,5-
dicarbonitrile (280 mg, 0.89 mmol) and KSAc (122 mg, 1.07 mmol) in N,N-
ylformamide (9 mL) was stirred at room temperature for 30 minutes then 2-amino
oxophenylethyl methanesulfonate (synthesis described in example 3 step 5, 245 mg,
1.07 mmol) and triethylamine (0.25 mL, 1.78 mmol) were added to the on. The mixture
was stirred at room temperature overnight then diluted with water. The precipitated solid
was collected by tion and d by silica gel column chromatography (CH2CI2:MeOH
10:1) to give 2-((3,5-dicyanocyclopropyl(2-(hydroxymethyl)morpholino)pyridin
yl)thio)phenylacetamide (43 mg, 11%) as a gray solid. LCMS m/z = 446.6 [M+H]". 1H
NMR (400 MHz, CDCls) 6 ppm 7.49 — 7.42 (m, 2H), 7.41 — 7.32 (m, 3H), 6.55 (br s, 1H),
.65 (br s, 1H), 5.34 (s, 1H), 4.61 —4.49 (m, 2H), 3.10 —2.75 (m, 4H), 2.12 —2.04 (m, 1H),
1.37 — 1.18 (m, 8H), 1.18 -1.11 (m, 2H). 1H not observed.
Example 21:
2- 35-Dic anoc clo ro -dimeth lmor holino ridin-Z- Ithio
phenylacetamide
2017/053511
Step 1: 2-Chlorocyc|opropy|(2,6-dimethylmorpholino)pyridine-3,5-
onitrile
YN N/ Cl
A mixture of 2,6-dichlorocyclopropylpyridine-3,5-dicarbonitrile (synthesis described in
example 4 step 2, 238 mg, 1 mmol) 2,6-dimethylmorpholine (115 mg, 1 mmol), and
triethylamine (101 mg, 1 mmol) N,N-dimethylformamide (8 mL) was d at room
temperature for 30 minutes. The reaction was poured into water (50 mL) and extracted with
ethyl acetate (50 mL x2). The combined organic layers were dried and concentrated under
vacuum to give 2-chlorocyclopropyl(2,6-dimethylmorpholino)pyridine-3,5-
dicarbonitrile (280 mg, 89%) as a white solid. LCMS m/z = 317.0 [M+H]*.
Step 2: 2-((3,5-DicyanocycIopropyI-B-(Z,6-dimethylmorpholino)pyridiny|)thio)-
2-phenylacetamide
A solution of 2-chlorocyclopropyl(2,6-dimethylmorpholino)pyridine-3,5-dicarbonitrile
(280 mg, 0.88 mmol) and KSAc (121 mg,1.06 mmol) in N,N-dimethylformamide (10 mL)
was stirred at room temperature for 30 minutes then 2-aminooxophenylethyl
methanesulfonate (synthesis described in example 3 step 5, 242 mg, 1.06 mmol) and
ylamine (178 mg, 1.76 mmol) were added to the solution. The mixture was stirred at
room temperature for 12 hours then diluted with water (50 mL), and extracted with ethyl
e (50 mL x 2). The combined organic layers were, concentrated under vacuum, and
purified by silica gel column chromatography (CH2ClzzMeOH 50:1) to give 2-((3,5-dicyano-
4-cyclopropyl(2,6-dimethylmorpholino)pyridinyl)thio)phenylacetamide (120 mg,
30%) as a white solid. LCMS m/z = 447.8 [M+H]+. 1H NMR (400 MHz, CDCls) 6 ppm 7.49
- 7.42 (m, 2H), 7.42 — 7.33 (m, 3H), 6.51 (br s, 1H), 5.52 (br s, 1H), 5.31 (s, 1H), 4.56 -
4.45 (m, 2H), 3.75 — 3.60 (m, 2H), 2.94 — 2.81 (m, 2H), 2.14 — 2.04 (m, 1H), 1.36 — 1.22 (m,
8H), 1.18— 1.12 (m, 2H).
Example 22:
2- 35-Dic anoc clo ro I 3- dimeth lamino i eridin I ridin lthio -
2-phenylacetamide
Step 1: 2-Chlorocyclopropyl(4-methyloxopiperaziny|)pyridine-3,5-
dicarbonitrile
(\N N/ Cl
A solution of 2,6—dichlorocyclopropylpyridine-3,5-dicarbonitrile (synthesis described in
example 4 step 2, 238 mg, 1 mmol) 1-methylpiperazinone (114 mg, 1 mmol), and
triethylamine (121 mg, 1.2 mmol) in N,N-dimethylformamide (8 mL) was stirred at room
temperature for 30 minutes, then diluted with water (50 mL) and ted with ethyl acetate
(50 mL x 2). The combined organic layers were dried and concentrated under vacuum to
give 2-chlor0cyclopropyl(4-methyloxopiperaziny|)pyridine-3,5-dicarbonitrile
(260 mg, 83%) as a brown solid. LCMS m/z = 315.8 [M+H]+.
Step 2: 2-((3,5-Dicyanocyc|opropyl(3-(dimethylamino)piperidiny|)pyridin
yl)thio)phenylacetamide
A solution of 2-Ch|orocyclopropyI(4-methyloxopiperazinyl)pyridine-3,5-
onitrile (260 mg, 0.82 mmol) and KSAc (122 mg,1.07 mmol) in NM-
dimethylformamide (6 mL) was d at room temperature for 30 minutes then 2-amino
oxophenylethyl methanesulfonate (synthesis described in example 3 step 5, 244 mg,
1.07 mmol) and ylamine (166 mg, 1.64 mmol) were added to the solution. The mixture
was stirred at room ature for 12 hours then diluted with water (50 mL), and extracted
with ethyl e (50 mL x2). The combined organic layers were dried, concentrated under
vacuum, and purified by silica gel column chromatography (CH2ClzzMeOH 40:1) to give 2-
((3,5-dicyanocyclopropyl(3-(dimethylamino)piperidiny|)pyridinyl)thio)—2-
acetamide (110 mg, 30%) as a white solid. LCMS m/z = 446.8 [M+H]+.1H NMR (400
MHz, CDCIs) 6 ppm 7.53 - 7.44 (m, 2H), 7.44 — 7.33 (m, 3H), 6.87 (br s, 1H), 5.76 (br s,
1H), 5.41 (s, 1H), 4.52 (d, J = 17.4 Hz, 1H), 4.34 (d, J =17.4 Hz, 1H), 4.25 — 4.15 (m, 1H),
4.12 — 3.99 (m, 1H), 3.50 (s, 2H), 3.03 (s, 3H), 2.15 - 2.06 (m, 1H), 1.36 — 1.27 (m, 2H),
1.23 — 1.12 (m, 2H).
Example 23:
2- 6- 4- Aminometh Ih drox i eridin I-3 5-dic anoc clo ro I ridin
yl)thio)—2-phenylacetamide
Step 1: 4-(Aminomethyl)benzylpiperidinol
To a oled solution (20 °C) of 1-benzylpiperidinone (1.0 g, 5.3 mmol) and
triethylamine (0.15 mL 1.1 mmol) was added TMS-CN (0.63 g, 6.4 mmol). The mixture was
stirred at room temperature for 3 hours then cautiously added to a mixture of LiAlH4 (0.23
g, 6.1 mmol) in tetrahydrofuran (50 mL). The mixture was refluxed for 1 .5 hours then cooled
to room temperature, quenched with water (0.23 mL), followed by NaOH solution (1 N,
0.23 mL) and water (0.46 mL). The mixture was stirred overnightthen filtered and the filtrate
was concentrated under vacuum to give 4-(aminomethyl)—1-benzylpiperidin-4—o| (1.2 g).
LCMS m/z = 221.0 [M+H]*.
Step 2: tert-Butyl ((1-benzy|hydroxypiperidiny|)methy|)carbamate
.opoo
To a solution of 4-(aminomethy|)benzy|piperidinol (1.2 g, crude) in dichloromethane
(25 mL) was added (Boc)20 (1.4 g, 6.4 mmol). The mixture was stirred at room temperature
overnight then concentrated under vacuum and purified by silica gel column
tography (petroleum etherzethyl e (2:1) to give to give tert-butyl ((1-benzyl
hydroxypiperidinyl)methy|)carbamate (1.2 g, 71%). 1H NMR (400 MHz, CDCI3) 6 ppm
7.38 — 7.31 (m, 4H), 7.28 - 7.24 (m, 1H), 4.92 (brs, 1H), 3.56 (s, 2H), 3.20 — 3.10 (m, 2H),
2.69 — 2.57 (m, 2H), 2.49 — 2.29 (m, 3H), 1.72 — 1.57 (m, 4H), 1.46 (s, 9H).
Step 3: tert-Butyl ((4-hydroxypiperidiny|)methyl)carbamate
To a solution of tert-butyl ((1-benzylhydroxypiperidinyl)methy|)carbamate (800 mg,
2.5 mmol) in ethanol (25 mL) were added hydrazine hydrate (0.25 mL, 5 mmol) and Pd/C
(280 mg). The mixture was refluxed for 3 hours. The mixture was filtered through Celite®
and the e was concentrated under vacuum and purified by silica gel column
chromatography (CH2CI21MeOH 20:1) to give to give tert—butyl ((4-hydroxypiperidin
yl)methyl)carbamate (400 mg, 70%). 1H NMR (400 MHz, CDCIs) 6 ppm 5.08 (br s, 1H),
3.17 — 3.08 (m, 2H), 3.01 — 2.92 (m, 2H), 2.90 — 2.82 (m, 2H), 2.45 (brs, 2H), 1.61 — 1.50
(m, 4H), 1.45 (s, 9H).
Step 4: tert-Butyl ((1-(6-((2-aminooxophenylethyl)thio)-3,5-dicyano
cyclopropylpyridiny|)hydroxypiperidiny|)methy|)carbamate
NC CN
N N/ 8
HO 0
>4 HN NH2
To a solution of chlorocyclopropylpyridine-3,5-dicarbonitrile (synthesis bed
in example 4 step 2, 237 mg, 1 mmol) in N,N-dimethylformamide (10 mL) was added tert-
2017/053511
butyl droxypiperidinyl)methyl)carbamate (230 mg, 1 mmol), followed by Eth (0.14
mL 1 mmol). The mixture was stirred at room temperature for 5 minutes, then diluted with
water . The precipitated solid was collected by filtration and purified by silica gel column
chromatography (DCM:ethyl acetate 1:1) to afford 300 mg of a residue. A solution the
e and KSAc (96 mg, 0.84 mmol) in N,N-dimethylformamide (7 mL) was stirred at
room temperature for 30 s then 2-aminooxophenylethy| methanesulfonate
(synthesis described in example 3 step 5, 191 mg, 0.84 mmol) and Eth (0.19 mL, 1.4
mmol) were added to the solution. The mixture was stirred at room temperature overnight
then diluted with water. The precipitated solid was collected by tion and purified by
silica gel column chromatography (CH20I2:MeOH 20:1) to give tert-butyl ((1-(6-((2-amino-
2-oxophenylethyl)thio)-3,5-dicyanocyclopropylpyridinyl)hydroxypiperidin
hy|)carbamate (233 mg) as a yellow solid. LCMS m/z = 562.8 [M+H]+.
Step 5: 2-((6-(4-(Aminomethyl)hydroxypiperidiny|)-3,5-dicyano
cyclopropylpyridinyl)thio)phenylacetamide
N N 8
HO 0
H2” NH2
To a solution of tert—butyl -((2-aminooxophenylethyl)thio)-3,5-dicyano
cyclopropylpyridinyl)hydroxypiperidinyl)methyl)carbamate (233 mg, 0.41 mmol) in
dichloromethane (4 mL) at room temperature was added trifluoroacetic acid (3 mL). The
mixture was stirred at room temperature overnight then concentrated under vacuum,
basified with saturated aqueous NaHCOs solution, and extracted with dichloromethane (20
mL x 3). The combined organic layers were concentrated under vacuum, and purified by
silica gel column tography (DCMzMeOH 10:1) to give 2-((6-(4-(Aminomethyl)—4-
hydroxypiperidinyl)-3,5-dicyanocyclopropylpyridinyl)thio)phenylacetamide (62.2
mg, 33%). LCMS m/z = 462.7 [M+H]+. 1H NMR (400 MHz, CDsoD) 6 ppm 7.54 (d, J = 6.8
Hz, 2H), 7.44 — 7.35 (m, 3H), 5.51 (s, 1H), 4.44 (dd, J = 17.5, 14.3 Hz, 2H), 3.56 (dd, J =
240,107 Hz, 2H), 2.63 (s, 2H), 2.17 — 2.07 (m, 1H), 1.77 — 1.60 (m, 4H), 1.27 — 1.20 (m,
2H),1.11 - 1.05 (m, 2H). 5H not observed.
Example 24
2017/053511
2- 35-dic anoc clo ro l 3- meth lamino i eridin l ridin lthio
phenylacetamide
Step 1: 1-benzyl-N-methylpiperidinamine
/N\©l/\©
To a solution of 1-benzylpiperidinone (1.0 g, 5.3 mmol) in dichloromethane (25 mL) was
added a solution of methylamine in tetrahydrofuran (5.3 mL, 2 M, 10.6 mmol). The mixture
was stirred at room temperature for 5 minutes then NaBH(OAc)3 (2.2 g, 10.6 mmol) was
added to the solution. The e was stirred at room temperature overnight then washed
with saturated aqueous NaHCOs solution, dried and concentrated under vacuum to give 1-
benzyl-N-methylpiperidinamine (1.0 g, crude). LCMS m/z = 205.1 [M+H]+.
Step 2: tert-butyl (1-benzylpiperidinyl)(methyl)carbamate
O O
/N\©l/\©
To a solution of1-benzyl-N-methylpiperidinamine (1.0 g) and triethylamine (1.36 mL, 9.8
mmol) in dichloromethane (25 mL) was added (Boc)2O (1.26 g, 5.9 mmol). The mixture was
stirred at room temperature overnight then concentrated under vacuum and purified by
silica gel column chromatography leum ethyl acetate 4:1) to give to give tert-
butyl (1-benzylpiperidinyl)(methyl)carbamate (1.3 g). LCMS m/z = 305.0 [M+H]+.
Step 3: tert-butyl (1 -(6-chloro-3,5-dicyanocyclopropylpyridinyl)piperidin
yl)(methyl)carbamate
OONC\ CN
”U N/ Cl
To a solution of tert-butyl ((1-benzylhydroxypiperidinyl)methyl)carbamate (1.3 g, 4.3
mmol) in methanol (20 mL) was added PdlC (130 mg). The mixture was stirred at room
ature under H2 atmosphere (1 atm) overnight then filtered. The filtrate was
trated under vacuum to give to give crude utyl methyl(piperidinyl)carbamate
as a residue. To a solution of 2,6-dichlorocyclopropylpyridine-3,5-dicarbonitrile
(synthesis described in example 4 step 2, 236 mg, 1 mmol) in N,N-dimethylformamide (10
mL) was added tert-butyl methyl(piperidinyl)carbamate (214 mg of crude residue above),
followed by triethylamine (0.14 mL 1 mmol). The mixture was stirred at room temperature
for 5 minutes, then diluted with water. The itated solid was collected by filtration and
purified by silica gel column chromatography (dichloromethane:ethyl acetate 1:1) to give
te rt-butyl (1 -(6-chloro-3,5-dicyanocyclopropylpyridinyl)piperidin
y|)(methy|)carbamate (320 mg, 77%). LCMS m/z = 315.8 [M+H—Boc]“.
Step 4: tert-butyl (1 -(6-((2-aminooxo-1 -phenylethyl)thio)-3,5-dicyano
cyclopropylpyridiny|)piperidiny|)(methy|)carbamate
t 0 NC CN
Y \
/N\©l N/ s
A solution of tert-butyl (1-(6-chloro-3,5-dicyanocyclopropylpyridinyl)piperidin
y|)(methy|)carbamate (320 mg, 0.77 mmol) and KSAc (106 mg, 0.93 mmol) in NM-
dimethylformamide (8 mL) was stirred at room temperature for 30 minutes then 2-amino
oxophenylethyl esulfonate (synthesis bed in example 3 step 5, 212 mg,
0.93 mmol) and triethylamine (0.21 mL, 1.54 mmol) were added to the solution. The e
was stirred at room temperature ght then diluted with water. The precipitated solid
was collected by filtration and purified by silica gel column chromatography
(dichloromethane:methanol 20:1) to give tert-butyl (1-(6-((2-aminooxo
phenylethyl)thio)—3,5-dicyanocyclopropylpyridinyl)piperidinyl)(methyl)carbamate
(250 mg, 60%). LCMS mIz = 446.8 [M+H—Boc]+.
Step 5: 2-((3,5-dicyanocyclopropyl(3-(methylamino)piperidiny|)pyridin
y|)thio)phenylacetamide
To a solution of tert—butyl (1-(6-((2-aminooxophenylethyl)thio)-3,5-dicyano
cyclopropylpyridinyl)piperidinyl)(methyl)carbamate (250 mg, 0.46 mmol) in DCM (5
mL) was added trifluoroacetic acid (3 mL). The mixture was stirred at room temperature
overnight then concentrated under vacuum, basified with saturated aqueous NaH003
solution, and extracted with DCM. The c layer was concentrated under , and
purified by silica gel column chromatography (DCMzMeOH 20:1) to give 2-((3,5-dicyano
cyclopropyl(3-(methylamino)piperidinyl)pyridinyl)thio)—2-phenylacetamide (180
mg, 88%). LCMS m/z = 446.7 [M+H]+. 1H NMR (400 MHz, CDsoD) 6 ppm 7.48 — 7.42 (m,
2H), 7.36 - 7.26 (m, 3H), 5.45 (s, 1H), 4.54 - 4.45 (m, 1H), 4.41 — 4.27 (m, 1 H), 3.19 — 3.11
(m, 1H), 3.02 — 2.93 (m, 1H), 2.72 —2.60 (m, 1H), 2.41 (d, J = 5.6 Hz, 3H), 2.11 — 2.01 (m,
2H), 1.87 —1.78 (m, 1H), 1.65— 1.52 (m, 1H), 1.42 —1.31 (m, 1H), .11(m,2H), 1.05
— 0.94 (m, 2H). 3H not observed.
Example 25
2 6- 3-amino i eridin l-3 5-dic anoc clo r0 | ridin Ithio
phenylacetamide
Step 1: tert-butyl (1 -(6-((2-aminooxophenylethyl)thio)-3,5-dicyano
cyclopropylpyridiny|)piperidinyl)carbamate
NC CN
\‘/0 H /
\ll/ N N s
o o
To a solution of 2,6-dichlorocyclopropylpyridine-3,5-dicarbonitrile (synthesis described
in example 4 step 2, 236 mg, 1 mmol) in N,N-dimethylformamide (10 mL) was added tert-
butyl dinylcarbamate (200 mg, 1 mmol) and triethylamine (0.14 mL, 1 mmol). The
mixture was stirred at room temperature for 5 minutes. Water was added to the reaction
and the ing mixture filtered to afford a crude solid. A solution of the crude solid (401
mg) and KSAc (137 mg, 1.2 mmol) in N,N-dimethylformamide (10 mL) was stirred at room
temperature for 30 minutes. Then 2-aminooxophenylethy| methanesulfonate
(synthesis described in example 3 step 5, 275 mg, 1.2 mmol) and triethylamine (0.28 mL,
2 mmol) were added to the reaction. The resulting solution was stirred at room temperature
overnight. Water was added to the reaction. The solid was filtered and purified by flash
column chromatography (dichloromethane: ethyl acetate 1:1) to give tert—butyl (1-(6-((2-
aminooxophenylethyl)thio)-3,5-dicyanocyclopropylpyridinyl)piperidin
y|)carbamate (230 mg, 43%). LCMS m/z = 554.8 [M+Na]+.
Step 2: 2-((6-(3-aminopiperidinyl)-3,5-dicyanocyclopropylpyridinyl)thio)
phenylacetamide
To a solution of tert—butyl (1-(6-((2-aminooxophenylethyl)thio)-3,5-dicyano
cyclopropylpyridinyl)piperidinyl)carbamate (230 mg, 0.43 mL), in dichloromethane (4
mL) was added trifluoroacetic acid (4 mL). the reaction was stirred at room temperature
overnight. The resulting on was concentrated and lized with saturated aqueous
NaHCOa solution, ted with dichloromethane, the c layer was washed with
brine, concentrated and purified by flash column chromatography (eluted by DCMzMeOH
10:1) to give 2-((6-(3-aminopiperidiny|)-3,5-dicyanocyclopropylpyridinyl)thio)
phenylacetamide (180.5 mg, 92%). LCMS m/z = 432.7 [M+H]+. 1H NMR (400 MHz,
CDsOD) 6 ppm 7.55 (d, J = 7.0 Hz, 2H), 7.45 — 7.35 (m, 3H), 5.50 (d, J = 6.4 Hz, 1H), 4.61
— 4.47 (m, 1H), 4.46 — 4.38 (m, 1H), 3.31 — 3.23 (m, 1H), 3.07 — 2.84 (m, 2H), 2.18 — 2.03
(m, 2H), 1.94 — 1.85 (m, 1H), 1.73- 1.60 (m, 1H), 1.52 — 1.41 (m, 1H), 1.28 — 1.20 (m, 2H),
1.15 — 1.04 (m, 2H). 4H not ed.
Example 26:
2- 35-dic anoc clo ro l dimeth lamino ridin Ithio ridin
yl )acetamide
Step 1: 2-chloro—4-cyclopropyl(dimethylamino)pyridine-3,5-dicarbonitrile
To a solution of 2,6-dichlorocyclopropylpyridine-3,5-dicarbonitrile (synthesis described
in example 4 step 2, 4.8 g, 20.3 mmol) in N,N-dimethylformamide (100 mL) was added
dimethylamine (2 M in tetrahydrofuran, 10 mL, 20.3 mmol) and triethylamine (2.8 mL, 20.3
mmol). The reaction was stirred at room temperature for 5 s. Water was added to
the reaction. The solid was filtered and washed with water and dried to give ro
cyclopropyl(dimethylamino)pyridine-3,5-dicarbonitrile (4.6 g, 92%) as a pink solid. LCMS
m/z = 246.9 [M+H]+.
Step 2: 2-((3,5-dicyanocyclopropyl(dimethylamino)pyridinyl)thio)(pyridin-
4-yl)acetamide
/ Z\/
/ NH2
A mixture of 2-chlorocyclopropyl(dimethylamino)pyridine-3,5-dicarbonitrile (400 mg,
1.62 mL), KSAc (221 mg, 1.94 mmol) in N,N-dimethylformamide (10 mL) was stirred at
room temperature for 30 minutes. Then 2-aminooxo(pyridinyl)ethy|
methanesulfonate (synthesis described in example 9 step 3, 448 mg, 1.94 mmol), E13N
(327 mg, 3.24 mmol) was added. The resulting mixture was stirred at room temperature for
12 hours. The on mixture was poured into water (50 mL), and extracted with ethyl
acetate (50 mL x2). The combined organic layers was dried and concentrated. The residue
was purified by silica gel column g with romethane/methanol (60/1) to give 2-
((3,5-dicyanocyclopropyl(dimethylamino)pyridinyl)thio)(pyridinyl)acetamide
(220 mg, 36% yield) as a white solid. LCMS m/z = 378.9 [M+H]+. 1H NMR (400 MHz,
DMSO) 6 ppm 8.57 (d, J = 4.9 Hz, 2H), 3.07 (s, 1H), 7.53 (d, J = 4.9 Hz, 2H), 7.49 (s, 1H),
.65 (s, 1H), 3.27 (s, 6H), 2.15 — 2.03 (m, 1H), 1.19 —1.03 (m, 2H), 0.93 — 0.88 (m, 2H).
e 27:
2- 35-dic ano—6- dimeth lamino eth I ridin lthio ridin Iacetamide
2-((3,5-dicyano—6-(dimethylamino)ethylpyridinyl)thio)(pyridinyl)acetamide
A mixture of 2-chloro—6-(dimethylamino)ethy|pyridine-3,5-dicarbonitrile (synthesis
described in example 3 step 3, 234.7 mg, 1 mmol), KSAc (137 mg, 1.2 mmol) in NM-
dimethylformamide (10 mL) was stirred at room temperature for 30 s. then 2-amino-
2-oxo(pyridinyl)ethyl methanesulfonate (synthesis described in example 9 step 3, 276
mg, 1.2 mmol) ylamine (202 mg, 20 mmol) was added. The resulting mixture was
stirred at room temperature for 12 hours. The reaction mixture was poured into water (50
mL), and extracted with ethyl acetate (50 mL x 2). The combined organic layers was dried
and concentrated. The residue was purified by silica gel column eluting with
dichloromethane:methanol 40:1 to give 2-((3,5-dicyano(dimethylamino)ethy|pyridin-
2-yl)thio)(pyridinyl)acetamide (120 mg, 33% yield) as a white solid. LCMS m/z =
366.9 [M+H]+. 1H NMR (400 MHz, DMSO) 6 ppm 8.57 (dd, J = 45,15 Hz, 2H), 8.07 (br s,
1H), 7.53 (dd, J = 45,15 Hz, 2H), 7.49 (br s, 1H), 5.66 (s, 1H), 3.30 (s, 6H), 2.75 (q, J =
7.5 Hz, 2H), 1.20 (t, J = 7.6 Hz, 3H).
e 28:
2- 6- 4-amino i eridin l-3 5-dic anoc clo ro l ridin lthio
phenylacetamide
Step 1: tert-butyl chloro-3,5-dicyanocyclopropylpyridin-Z-yl)piperidin
yl)carbamate
To a solution of 2,6-dichlorocyclopropylpyridine-3,5-dicarbonitrile esis described
in example 4 step 2, 236 mg, 1 mmol) in N,N-dimethylformamide (10 mL) was added tert-
butyl piperidin-4—ylcarbamate (200 mg, 1 mmol) and triethylamine (0.14 mL, 1 mmol). The
mixture was stirred at room temperature for 5 minutes. water was added to the reaction.
The solid was filtered and dried to give tert-butyl (1-(6-chloro-3,5-dicyano
cyclopropylpyridinyl)piperidinyl)carbamate (390 mg, 97%). LCMS mlz = 423.7
[M+Na]*.
Step 2: utyl (1 -(6-((2-aminooxo-1 -phenylethy|)thio)-3,5-dicyano
cyclopropylpyridinyl)piperidinyl)carbamate
To a solution of 2-aminooxophenylethyl esulfonate (synthesis described in
example 3 step 5, 390 mg, 0.97 mmol) in N,N-dimethylformamide (10 mL) was added KSAc
(133 mg, 117 mmol). The reaction was stirred at room temperature for 30 minutes, then
tert-butyl (1-(6-chloro-3,5-dicyano—4-cyclopropylpyridinyl)piperidinyl)carbamate (267
mg, 1.17 mmol) and ylamine (0.27 mL, 1.94 mmol) were added to the reaction. The
reaction was stirred at room temperature overnight. Water was added to the reaction, the
solid was filtered and purified by flash column chromatography d by DCMzMeOH =
:1) to give tert-butyl (1-(6-((2-aminooxophenylethyl)thio)-3,5-dicyano
cyclopropylpyridinyl)piperidin-4—yl)carbamate (36 mg). LCMS m/z = 476.7 [M+H—
isobutylene]+ (major), 554.7 [M+Na]+ (minor).
WO 16727
Step 3: 2-((6-(4-aminopiperidiny|)-3,5-dicyanocyclopropylpyridiny|)thio)
phenylacetamide
A mixture of tert—butyl (1-(6-((2-aminooxophenylethyl)thio)-3,5—dicyano
cyclopropylpyridinyl)piperidinyl)carbamate (360 mg, 0.68 mmol), in DCM (7 mL) was
added trifluoroacetic acid (4 mL). The reaction was stirred at room temperature overnight.
The solvent was removed and the residue was neutralized by saturated aqueous NaHCOs
solution and extracted with DCM. The organic layer was concentrated and purified by flash
column tography (eluted by DCM:MeOH = 10:1) to give (200 mg, 68%). LCMS m/z
= 432.8 [M+H]+. 1H NMR (400 MHz, CDCIa) 6 ppm 7.48 — 7.42 (m, 2H), 7.41 — 7.32 (m,
3H), 6.54 (br s, 1H), 5.75 (br s, 1H), 5.35 (s, 1H), 4.57 - 4.46 (m, 2H), 3.30 — 3.19 (m, 2H),
3.10 — 3.00 (m, 1H), 2.12 — 2.04 (m, 1H), 2.04 — 1.94 (m, 2H), 1.79 (br s, 2H), 1.52 — 1.39
(m,2H), 1.33 — 1.24 (m, 2H), 1.18 — 1.11 (m, 2H).
e 29:
2- 35-dic anoc clo ro | 4- dimeth lamino i eridin l ridin Ithio-
Z-phenylacetamide
Step 1: 2-chlorocyclopropyl(4-(dimethylamino)piperidiny|)pyridine-3,5-
dicarbonitrile
To a solution of2,6-dichlorocyclopropylpyridine-3,5-dicarbonitrile (synthesis described
in example 4 step 2, 200 mg, 0.85 mmol) in N,N-dimethylformamide (9 mL) was added N,N-
ylpiperidinamine (108 mg, 0.85 mmol) and triethylamine (0.12 mL, 0.85 mmol).
The mixture was stirred at room temperature for 5 minutes. Water was added to the
reaction. The solid was filtered and dried to give 2-chlorocyclopropyl(4-
(dimethylamino)piperidinyl)pyridine-3,5-dicarbonitrile (210 mg, 75% yield). LCMS m/z =
330.3 [M+H]+.
Step 2: 2-((3,5-dicyanocyclopropyl(4-(dimethylamino)piperidiny|)pyridin
yl)thio)phenylacetamide
A solution of 2-chlorocyclopropyl(4-(dimethylamino)piperidinyl)pyridine-3,5-
dicarbonitrile (210 mg, 0.64 mmol) and KSAc (88 mg, 0.77 mmol) in NM-
dimethylformamide (7 mL) was stirred at room temperature for 30 minutes. 2-Aminooxo-
1-phenylethyl methanesulfonate esis described in e 3 step 5, 176 mg, 0.77
mmol) and triethylamine (0.81 mL, 1.28 mmol) were added to the reaction. The e was
stirred at room temperature overnight. Water was added to the reaction, the solid was
filtered and purified by flash column chromatography (eluted by DCMzMeOH = 20:1) to
give 2-((3,5-dicyanocyclopropyl(4-(dimethylamino)piperidinyl)pyridinyl)thio)
phenylacetamide (180 mg, 61% yield). LCMS m/z = 460.9 [M+H]+. 1H NMR (400 MHz,
CDCIs) 6 ppm 7.50 — 7.45 (m, 2H), 7.44 — 7.35 (m, 3H), 6.54 (br s, 1H), 5.57 (br s, 1H),
5.39 (s, 1H), 4.69 — 4.62 (m, 2H), 3.19 (t, J = 12.6 Hz, 2H), 2.52 — 2.43 (m, 1H), 2.36 (s,
6H), 2.14 - 2.01 (m, 3H), 1.65 — 1.58 (m, 2H), 1.34 — 1.27 (m, 2H), 1.20 - 1.13 (m, 2H).
Example 30:
2- 35-dic c clo ro l i erazin l ridin lthio ridin
yl )acetamide
Step 1: tert-butyl hloro-3,5-dicyanocyclopropylpyridinyl)piperazinyl
carboxylate
A mixture of 2,6-dichlorocyclopropylpyridine-3,5-dicarbonitrile (synthesis described in
example 4 step 2, 1.0 g, 4.2 mmol), tert-butyl piperazinylcarboxylate (782 mg, 4.2 mmol),
and Et3N (424 mg, 1.2 mmol) in N,N-dimethylformamide (20 mL) was d at room
temperature for 30 minutes. The reaction mixture was poured into water (100 mL) and
extracted with EtOAc (100 mL x 2). The combined organic layers were dried, and
concentrated to give tert-butyl 4-(6-chloro-3,5-dicyanocyclopropylpyridin
y|)piperazinylcarboxylate (1.3 g, 80%) as a white solid. LCMS m/z = 288.0 [M+H-Boc]*.
Step 2: tert-butyl (2-aminooxo(pyridiny|)ethyl)thio)-3,5-dicyano
cyclopropylpyridin-Z-yl)piperazinylcarboxy|ate
N/ s
W cm0O N01 NH
N/ O
A solution of tert-butyl 4-(6-chloro-3,5-dicyanocyclopropylpyridinyl)piperazinyl
carboxylate (400 mg, 1.03 mmol) and potassium thioacetate (142 mg, 1.24 mmol) in NM-
dimethylformamide (10 mL) was stirred at room temperature for 30 minutes, then 2-amino-
1-(pyridinyl)ethy| esulfonate (synthesis described in example 9 step 3, 285
mg, 1.24 mmol) and EtsN (208 mg, 2.08 mmol) were added to the reaction. The mixture
was d at room temperature for 12 hours, then poured into water (50 mL), and extracted
with EtOAc (50 mL x 2). The combined organic layers were dried and concentrated. The
remaining residue was purified by silica gel column chromatography (MeOH:CH2CI2 1:70)
to give tert-butyl 4-(6-((2-aminooxo(pyridinyl)ethyl)thio)-3,5-dicyano—4-
cyclopropylpyridinyl)piperazinylcarboxy|ate (380 mg, 71%) as a white solid. LCMS
m/z = 519.9 [M+H]+.
Step 3: 2-((3,5-dicyanocyclopropyl-G-(piperaziny|)pyridinyl)thio)(pyridin-
4-yl)acetamide
A mixture of tert—butyl 4-(6-((2-aminooxo(pyridinyl)ethyl)thio)-3,5-dicyano
cyclopropylpyridinyl)piperazinylcarboxylate (5) (380 mg, 0.73 mmol) and
oroacetic acid (2 mL) in dichloromethane (8 mL) was stirred at room temperature for
12 hours. After the on mixture was concentrated, the remaining residue was poured
into water (50 mL), made basic with , solution, and extracted with dichloromethane
(50 mL x 2). The combined organic layers were dried and concentrated. The remaining
residue was purified by silica gel column chromatography (MeOH:DCM 1:30) to give 2-
((3,5-dicyanocyclopropyl(piperazinyl)pyridinyl)thio)—2-(pyridinyl)acetamide
(110 mg, 36%) as a white solid. LCMS m/z = 442.0 *. 1H NMR (400 MHz, DMSO) 6
ppm 8.57 (d, J = 5.3 Hz, 2H), 8.09 (brs, 1H), 7.60 — 7.42 (m, 3H), 5.59 (s, 1H), 3.81 — 3.65
(m, 4H), 3.34 (brs, 1H), 2.89 —2.68 (m, 4H), 2.19 —2.04 (m, 1H), 1.18— 1.07 (m, 2H), 1.00
— 0.93 (m, 2H).
Example 31:
2- 35-dic anoc clo ro I14-diaze an | ridin Ithio ridin
1| )acetamide
Step 1: tert-butyl 4-(6-((2-aminooxo(pyridinyl)ethyl)thio)-3,5-dicyano
cyclopropylpyridinyl)-1,4-diazepanecarboxylate
A mixture of tert-butyl 4-(6-chloro-3,5-dicyanocyclopropylpyridinyl)-1,4-diazepane
carboxylate (synthesis described in example 4 step 3, 402 mg, 1.0 mmol) and potassium
thioacetate (137 mg, 1.2 mmol) in N,N-dimethylformamide (10 mL) was stirred at room
temperature for 30 minutes, then 2-aminooxo(pyridinyl)ethyl methanesulfonate
esis described in example 9 step 3, 345 mg, 1.5 mmol) and Et3N (202 mg, 2.0 mmol)
were added to the reaction. The mixture was stirred at room temperature for 12 hours, then
poured into water (50 mL) and extracted with ethyl acetate (50 mL x 2). The combined
organic layers were dried and concentrated. The ing residue was purified by silica
gel column tography (MeOH:CH2C|2 1:80) to give tert-butyl (2-aminooxo
(pyridinyl)ethyl)thio)-3,5-dicyanocyclopropylpyridinyl)-1 ,4-diazepane
carboxylate(380 mg, 71%) as a brown solid. LCMS m/z = 533.9 [M+H]".
Step 2: 2-((3,5-dicyanocyclopropyl(1,4-diazepanyl)pyridinyl)thio)
(pyridinyl)acetamide
NC CN
rN /
N s
NH2
A mixture of tert-butyl 4-(6-((2-aminooxo(pyridin-4—yl)ethyl)thio)-3,5-dicyano—4-
ropylpyridinyl)-1,4-diazepanecarboxylate (380 mg, 0.71 mmol) and
trifluoroacetic acid (2 mL) in dichloromethane (10 mL) was d at room temperature for
12 hours. After the reaction mixture was concentrated, the remaining residue was poured
into water (50 mL), made basic with NaHCOs solution, and extracted with dichloromethane
(50 mL x 2). The combined organic layers were dried and concentrated. The remaining
residue was purified by silica gel column chromatography (MeOH:DCM 1:30) to give 2-
((3,5-dicyanocyclopro pyl(1 ,4—diazepanyl)pyridinyl)thio)—2-(pyridin
yl)acetamide (120 mg, 40%) as a white solid. LCMS m/z = 433.9 . 1H NMR (400
MHz, DMSO-ds) 6 ppm 8.58 (d, J = 5.6 Hz, 2H), 8.10 (br s, 1H), 7.55 — 7.47(m, 3H), 5.56
(s, 1H), 3.92 — 3.75 (m, 4H), 3.33 (br s, 1H), 2.98 — 2.84 (m, 2H), 2.80 - 2.73 (m, 2H), 2.15
— 2.07 (m, 1H), 1.85 — 1.70 (m, 2H), 1.18 — 1.09 (m, 2H), 0.98 — 0.92 (m, 2H).
Example 32:
phenylacetamide
Step 1: (R)chlorocyclopropyl(3-hydroxypiperidiny|)pyridine-3,5-
dicarbonitrile
NC CN
HOU N/ CI
To a solution of 2,6-dichIorocyclopropylpyridine-3,5-dicarbonitrile (synthesis described
in example 4 step 2, 237 mg, 0.995 mmol) in N,N-dimethylformamide (10 mL) were added
(R)-piperidino| (101 mg, 0.995 mmol) and Eth (0.139 mL, 0.995 mmol). The reaction
mixture was stirred at 25 °C overnight. After ng the on with water, the precipitated
solid was collected by filtration and dried in an oven to give (R)chlorocyclopropyl
(3-hydroxypiperidinyl)pyridine-3,5-dicarbonitrile (275 mg, 91%). LCMS m/z = 303.1
[M+H]".
Step 2: 2-((3,5-dicyanocycIopropyl((R)hydroxypiperidinyl)pyridin
yl)thio)phenylacetamide
NC ON
HO /
N N 8
A solution of (R)chlorocyclopropyl(3-hydroxypiperidinyl)pyridine-3,5-
dicarbonitrile (275 mg, 0.908 mmol) and potassium thioacetate (124 mg, 1.09 mmol) in
N,N-dimethylformamide (8 mL) was stirred at room temperature for 30 minutes.
Triethylamine (0.253 mL, 1.817 mmol) and 2-aminooxophenylethyl methanesulfonate
esis described in example 3 step 5, 250 mg, 1.09 mmol) were then added and the
reaction mixture stirred at 25 °C overnight. After diluting the on with water, the
precipitated solid was collected by filtration and purified by silica gel column
chromatography (MeOHzDCM 1:20) to give 2-((3,5-dicyanocyclopropyl((R)
hydroxypiperidinyl)pyridinyl)thio)phenylacetamide (80 mg, 20%). LCMS m/z =
434.2 [M+H]+. 1H NMR (400 MHz, CDCIs) 5 ppm 7.52 — 7.43 (m, 2H), 7.43 — 7.32 (m, 3H),
6.93 — 6.79 (m, 1H), 5.83 — 5.68 (m, 1H), 5.28 — 5.20 (m, 1H), 4.65 — 4.44 (m, 1H), 4.05 —
3.98 (m, 0.5H), 3.94 — 3.87 (m, 1.5H), 3.81 — 3.75 (m, 0.5H), 3.66 — 3.55 (m, 0.5H), 3.48 —
3.38 (m, 0.5H), 3.07 — 2.99 (m, 0.5H), 2.29 (br s, 1H), 2.12 — 1.89 (m, 3H), 1.78 — 1.48 (m,
2H),1.34 — 1.23 (m, 2H), 1.20 — 1.08 (m, 2H).
Example 33:
phenylacetamide
Step 1: (S)chlorocyclopropyl(3-hydroxypiperidinyl)pyridine-3,5-
dicarbonitrile
NC CN
H0301 N/ Cl
To a solution of 2,6-dichIorocyclopropylpyridine-3,5-dicarbonitrile (synthesis described
in example 4 step 2, 237 mg, 0.995 mmol), in N,N-dimethy|formamide (10 mL) were added
(S)-piperidinol (101 mg, 0.995 mmol) and triethylamine (0.139 mL, 0.995 mmol). The
reaction mixture was stirred at 25 °C overnight. After diluting the reaction with water, the
precipitated solid was ted by filtration and dried to give chlorocyclopropyl
roxypiperidinyl)pyridine-3,5-dicarbonitrile (275 mg, 91%). LCMS m/z = 303.1
[M+H]".
Step 2 : 2-(3,5-dicyanocyclopropyl((S)hydroxypiperidinyl)pyridin
ylthio)phenylacetamide
NC ON
H00,”O /
N N S
A solution of (S)chlorocyclopropyl(3-hydroxypiperidinyl)pyridine-3,5-
dicarbonitrile (275 mg, 0.908 mmol) and potassium thioacetate (124 mg, 1.09 mmol) in
2017/053511
N,N-dimethylformamide (8 mL) was stirred at room ature for 30 minutes.
Triethylamine (0.253 mL, 1.817 mmol) and 2-aminooxophenylethy| methanesulfonate
(synthesis described in example 3 step 5, 250 mg, 1.09 mmol) were then added and the
reaction mixture stirred at 25 °C overnight. After diluting the reaction with water, the
precipitated solid was ted by filtration and purified by silica gel column
chromatography (MeOH:DCM 1 :20) to give 2-(3,5-dicyanocyclopropyl((S)
hydroxypiperidinyl)pyridinylthio)phenylacetamide (110 mg, 28%). LCMS m/z =
434.1 [M+H]+. 1H NMR (400 MHz, CDCIs) 6 ppm 7.50 — 7.43 (m, 2H), 7.42 — 7.34 (m, 3H),
6.92 — 6.79 (m, 1H), 5.77 — 5.64 (m, 1H), 5.28 — 5.21 (m, 1H), 4.63 — 4.46 (m, 1H), 4.05 —
3.98 (m, 0.5H), 3.95 — 3.88 (m, 15H), 3.81 - 3.75 (m, 0.5H), 3.65 — 3.56 (m, 0.5H), 3.49 -
3.39 (m, 0.5H), 3.07 — 2.99 (m, 0.5H), 2.12 — 2.03 (m, 2H), 2.00 — 1.88 (m, 2H), 1.79 — 1.54
(m, 2H), 1.32 — 1.24 (m, 2H), 1.20 — 1.08 (m, 2H).
Example 34:
(pyridinyl)acetamide
Step 1: chlorocyc|opropyl(3-hydroxypyrrolidiny|)pyridine-3,5-
dicarbonitrile
NC CN
N N CI
HO
A mixture of 2,6-dichlorocyclopropylpyridine-3,5-dicarbonitrile (synthesis bed in
example 4 step 2, 400 mg, 1.68 mmol), (S)-pyrro|idinol (146 mg, 1.68 mmol), and
triethylamine (170 mg, 1.68 mmol) in N,N-dimethylformamide (10 mL) was stirred at room
temperature for 30 minutes. The reaction mixture was poured into water (50 mL) and
extracted with EtOAc (50 mL x 2). The combined organic layers were dried and
concentrated. The remaining residue was purified by silica gel column chromatography
(MeOH2CH2CI2 1:80) to give (S)-2—chlorocyclopropyl(3-hydroxypyrrolidin
yl)pyridine-3,5-dicarbonitrile (320 mg, 66%) as a white solid. LCMS mlz = 288.9 [M+H]".
Step 2: 2-((3,5-dicyanocyclopropyl((S)hydroxypyrrolidiny|)pyridin
yl)thio)(pyridinyl)acetamide
A solution of ch|orocyclopropyI(3-hydroxypyrrolidiny|)pyridine-3,5-
dicarbonitrile (320 mg, 1.11 mmol) and potassium thioacetate (152 mg, 1.33 mmol) in NM-
dimethylformamide (10 mL) was stirred at room temperature for 30 minutes, then 2-amino-
2-oxo(pyridinyl)ethy| methanesulfonate (synthesis described in example 3 step 5, 306
mg, 1.33 mmol) and Eth (224 mg, 2.22 mmol) were added to the reaction. The mixture
was stirred at room ature for 12 hours, then poured into water (50 mL), and
extracted with EtOAc (50 mL x 2). The combined organic layers were dried and
concentrated. The remaining residue was purified by silica gel column chromatography
CH2CI2 1:40) to give 2-((3,5-dicyanocyclopropyl((S)hydroxypyrrolidin
yl)pyridinyl)thio)(pyridinyl)acetamide_(180 mg, 38%) as a white solid. LCMS m/z =
420.8 [M+H]+. 1H NMR (400 MHz, CDsOD) 6 ppm 8.57 (d, J = 5.1 Hz, 2H), 7.63 (d, J = 5.6
Hz, 2H), 5.70 (s, 1H), 4.53 (s, 1H), 4.10 — 3.72 (m, 4H), 2.16 — 2.02 (m, 3H), 1.27 — 1.18
(m, 2H), 1.12 — 1.00 (m, 2H). 3H not observed.
e 35:
2- 35-dic anoeth | 4-eth I i erazin | ridin Ithio hen Iacetamide
A solution of 2-[(6-bromo-3,5-dicyanoethylpyridyl)su|fany|]phenyl-acetamide
esis described in example 6 step 1, 16 mg, 0.04 mmol) in tetrahydrofuran (1 mL)
was treated with 1-ethylpiperazinyl (0.011 mL, 0.089mmol) and stirred at room temperature
for 16 hours. The reaction mixture was dry loaded onto Si02 (0.9 g) and purified by silica
gel chromatography (4 g RediSep cartridge; 0-10% MeOH, 0-1% NH3/CH2CI2) to give 2-
[[3,5-dicyanoethyl(4—ethylpiperazinyl)pyridyl]sulfanyl]pheny|—acetamide (14
2017/053511
mg, 81%), as a white solid. LCMS m/z = 435 ‘ 1H NMR (300 MHz, DMSO-de) 5 ppm
7.92 (s, 1H), 7.52 (br d, J=6.9 Hz, 2H), 7.46 - 7.29 (m, 4H), 5.53 (s, 1H), 3.37 - 3.30 (m,
4H), 2.84 - 2.54 (m, 2H), 2.48 - 2.32 (m, 6H), 1.20 (t, J=7.6 Hz, 3H), 1.04 (t, J=7.1 Hz, 3H).
Example 36:
2- 35-Dic anoeth |1-oxaazas iro 3.4 octan | ridin Ithio
phenylacetamide
Step 1: Benzyl 3-hydroxypyrrolidinylcarboxy|ate
HO
To a solution of pyrrolidinol (10.45 9, 120.1 mmol) in dichloromethane (300 mL) was
added benzyl chloroformate (24.6 g, 144 mmol) and triethylamine (24.3 g, 240.2 mmol).
The resulting solution was stirred at room temperature for 12 hours. After trating the
reaction, the remaining al was partitioned between ethyl acetate (100 mL) and water
(60 mL). The layers were separated. The organic layer was washed with water (60 mL),
aqueous saturated sodium chloride solution (60 mL), dried and trated. The residue
was purified by silica gel column chromatography (petroleum ether:ethyl acetate 2:1) to
give benzyl oxypyrrolidinylcarboxylate (15.2 g, 57%) as a colorless gum. LCMS
m/z = 222.1 [M+H]+.
Step 2: Benzyl 3-oxopyrrolidinylcarboxy|ate
A mixture of benzyl 3-hydroxypyrrolidinylcarboxylate (14 g, 63.3 mmol) and IBX (21.3 g,
76 mmol) in acetonitrile (200 mL) was stirred at 70 °C for 2 hours. The mixture was filtered
and the filtrate concentrated. The remaining residue was purified by silica gel column
chromatography (petroleum etherzethyl acetate 1:1) to give benzyl 3-oxopyrrolidinyl
carboxylate (11 g, 79%) as a colorless oil. 1H NMR (400 MHz, DMSO-de) 6 ppm 7.46 - 7.25
(m, 5H), 5.13 (s, 2H), 3.83 - 3.64 (m, 4H), 2.57 (s, 2H).
2017/053511
Step 3: Benzyl 1-oxaazaspiro[3.4]octanecarboxylate
To a solution of trimethylsulfoxonium iodide (25.86 g, 117.5 mmol) in tert-butanol (78 mL)
was added ium tert-butanolate (11.6 g, 103.4 mmol). The mixture was stirred at 50
°C for 1 hour and then benzyl 3-oxopyrrolidinylcarboxylate (10.3 g, 47 mmol) was added.
The mixture was stirred at 50 °C for an additional 48 hours. The reaction was quenched
with saturated ammonium chloride solution (200 mL) and extracted with ethyl acetate (50
mL x 3). The combined organic layers were washed with saturated sodium chloride solution
(100 mL), dried, and trated. The remaining residue was purified by silica gel column
chromatography leum ethy| acetate 3:1) to give benzyl 1-oxa
azaspiro[3.4]octanecarboxylate (1.5 g, 12%) as a light yellow oil. LCMS m/z = 248.0
[M+H]".
Step 4: 1-Oxaazaspiro[3.4]octane
A mixture of benzyl 1-oxaazaspiro[3.4]octanecarboxy|ate (1 g, 4 mmol) and 10%
palladium on carbon (100 mg) in methanol (20 mL) was stirred at room temperature under
a en atmosphere for 12 hours. The mixture was filtered and the filtrate concentrated.
The remaining residue was purified by silica gel column chromatography
(dichloromethane:methanol 20:1) to give 1-oxaazaspiro[3.4]octane (700 mg, crude) as
a colorless oil. LCMS m/z = 114.0 [M+H]".
Step 5: 2-Chloroethyl(1-oxaazaspiro[3.4]octanyl)pyridine-3,5-
dicarbonitrile
NC CN
N N Cl
To a solution of 2,6-dichloroethylpyridine-3,5-dicarbonitrile (678 mg, 3.01 mmol) in
dichloromethane (20 mL) was added 1-oxaazaspiro[3.4]octane (340 mg, 3.01 mmol)
ed by triethylamine (303 mg, 3.01 mmol). The solution was stirred at room
ature for 12 hours. The reaction was partitioned between dichloromethane (40 mL)
and water (30 mL). The layers were separated. The organic layer was washed with brine
(30 mL), dried, and concentrated to afford 2-chloroethyl(1-oxaazaspiro[3.4]octan-
6-y|)pyridine-3,5-dicarbonitrile (910 mg, crude) as a brown oil. LCMS m/z = 303.0 [M+H]*.
Step 6: 4-Ethylmercapto(1-oxaazaspiro[3.4]octanyl)pyridine-3,5-
dicarbonitrile
NC CN
N N SH
A mixture of 2-chloroethyl(1-oxaazaspiro[3.4]octanyl)pyridine-3,5-dicarbonitrile
(synthesis described in example 3 step 2, 910 mg, 3.01 mmol) and potassium thioacetate
(514 mg, 4.51 mmol) in N,N-dimethylformamide (10 mL) was d at room temperature
for 1.5 hours and used ly in the next step. LCMS m/z = 300.8 [M+H]+
Step 7: 2-((3,5-Dicyanoethyl(1-oxaazaspiro[3.4]octanyl)pyridinyl)thio)-
2-phenylacetamide
NC ON
N N s
To the above mixture was added potassium carbonate (826 mg, 6.00 mmol) and the
reaction allowed to stir at room temperature for 1 hour, then 2-aminooxophenylethyl
methanesulfonate (synthesis described in example 3 step 5, 825 mg, 3.60 mmol) was
added. The resulting mixture was d at room temperature for an additional 12 hours
then was concentrated. The residue was ed by silica gel column chromatography
(CH2CI2:Methanol 30:1) to provide 2-((3,5-dicyanoethyl(1-oxaazaspiro[3.4]octan-
6—yl)pyridiny|)thio)phenylacetamide (107 mg, 8%) as a pale solid. LCMS m/z = 433.8
2017/053511
[M+H]*.1H NMR (400 MHz, DMSO-de) 5 ppm 1.21 (t, J = 7.6 Hz, 3H), 2.17 - 2.06 (m, 1H),
2.41 - 2.33 (m, 1H), 2.85 - 2.63 (m, 4H), 4.05 - 3.71 (m, 3H), 4.13 (dd, J = 28.3, 12.7 Hz,
1H), 4.52 - 4.40 (m, 2H), 5.61 (d, J = 4.9 Hz, 1H), 7.45 - 7.31 (m, 4H), 7.54 (d, J = 7.5 Hz,
2H), 7.93 (d, J = 6.6 Hz, 1H).
Example 37:
2- 6- 4- 3-amino r0 | i erazin l-3 5-dic anoeth | 2- Ithio
phenylacetamide
Step 1: tert-butyl (3-(4-benzylpiperazinyl)propyl)carbamate
To a on of 1-benzylpiperazinyl (500 mg, 2.84 mmol) in CHs-CN (30 mL) was added
tert-butyl (3-bromopropyl)carbamate (1.0 g, 4.26 mmol) and K2C03 (784 mg, 5.68 mmol).
he reaction was heated at 70 °C for 12 hours, the mixture was concentrated and the
remaining al purified by silica gel column chromatography (CHzclzzmethanol 10:1) to
give tert-butyl (3-(4-benzylpiperaziny|)propy|)carbamate (900 mg, 95%). LCMS m/z =
334 [M+H].
Step 2: tert-butyl (3-(piperaziny|)propyl)carbamate
K/NWHTCKN/O
A mixture oftert-butyl (3-(4-benzylpiperaziny|)propy|)carbamate (900 mg, 2.7 mmol) and
palladium on carbon (90 mg) in methanol (30 mL) was stirred at room temperature under a
hydrogen atmosphere overnight. The reaction mixture was filtered, the filtrate concentrated,
and the remaining residue purified by silica gel column chromatography (CH2CI2:methanol
:1) to give tert-butyl (3-(piperaziny|)propy|)carbamate (460 mg, 70% yield). LCMS m/z
= 244 [M+H]+.
Step 3: tert-butyl (3-(4-(6-chloro-3,5-dicyanoethylpyridin-Z-yl)piperazin
yl)propyl)carbamate
WO 16727
(\N N/ Cl
To a solution of 2,6-dichloroethylpyridine-3,5-dicarbonitrile (synthesis described in
example 3 step 2, 426 mg, 1.89 mmol) in N,N-dimethylformamide (10 mL) was added tert-
butyl (3-(piperazinyl)propyl)carbamate (460 mg, 1.89 mmol) and triethylamine (0.26 mL,
1.89 mmol). The on mixture was stirred at room temperature for 5 minutes, then was
partitioned between ethyl acetate and water. The layers were separated. The organic layer
was washed with water, brine, dried, and concentrated. The remaining residue was purified
by silica gel column chromatography (petroleum ethyl acetate 40:60) to give tert-butyl
(3-(4-(6-chloro-3,5-dicyanoethylpyridin-2—yl)piperazinyl)propyl)carbamate (600 mg,
74%). LCMS mlz = 433 [M+H]+.
Step 4: tert-butyl (3-(4-(6-((2-aminooxophenylethyl)thio)-3,5-dicyano
ethylpyridinyl)piperaziny|)propyl)carbamate
To a solution of tert-butyl (3-(4-(6-chloro-3,5-dicyanoethylpyridinyl)piperazin
pyl)carbamate (300 mg, 0.69 mmol) in N,N-dimethylformamide (7 mL) was added
potassium thioacetate (95 mg, 0.83 mmol). The reaction was stirred at room temperature
for 30 minutes, then 2-aminooxophenylethy| methanesulfonate (synthesis described
in example 3 step 5, 191 mg, 0.83 mmol) and triethylamine (0.19 mL, 1.38 mmol) were
added to the reaction. The mixture was stirred at room temperature overnight. After the
addition of water to the reaction, the precipitated solid was collected by ion and was
purified by silica gel column chromatography (CH2CI2:methanol 20:1) to give utyl (3-
(4-(6-((2-aminooxophenylethyl)thio)-3,5-dicyanoethylpyridin-2—yl)piperazin
yl)propyl)carbamate (280 mg, 72%) as yellow solid. LCMS m/z = 564 [M+H]+.
Step 5: 2-((6-(4-(3-aminopropyl)piperaziny|)-3,5-dicyanoethylpyridiny|)thio)-
2-phenylacetamide
NC \CN
(\N N s
HZNWNJ WNW
A solution of tert-butyl (3-(4-(6-((2-aminooxophenylethyl)thio)-3,5-dicyano
ethylpyridinyl)piperazinyl)propyl)carbamate (280 mg, 0.50 mmol) and trifluoroacetic
acid (3 mL) in dichloromethane (5 mL) was stirred at room temperature overnight. The
t was removed, the remaining material lized with saturated aqueous NaHCOe,
solution, and extracted with dichloromethane. The organic layer was washed with aqueous
saturated sodium chloride solution and concentrated. The crude material was purified by
silica gel column chromatography (CHzClzzmethanol 5:1) to give (4-(3-
aminopropyl)piperaziny|)-3,5-dicyanoethylpyridinyl)thio)phenylacetamide (91
mg, 39%) as a white solid. LCMS m/z = 464 [M+H]*. 1H NMR (400 MHz, CD30D) 6 ppm
7.55 (d, J = 6.7 Hz, 2H), 7.45 - 7.36 (m, 3H), 5.49 (s, 1H), 4.05 - 3.94 (m, 4H), 3.09 (t, J =
7.1 Hz, 2H), 2.92 (q, J = 7.6 Hz, 2H), 2.68 - 2.53 (m, 6H), 1.94 - 1.85 (m, 2H), 1.32 (t, J =
7.6 Hz, 3H). 4H not observed.
e 38:
2- 35-Dic anoeth |17-diazas iro 3.5 nonan | ridin Ithio
hen lacetamide trifluoroacetate
Step 1: tert-Butyl 4-methylenepiperidinylcarboxylate
JG“0
To a solution of methyltriphenylphosphonium bromide (9.5 g, 26.7 mmol) in tetrahydrofuran
(30 mL) was added sodium hydride (60%, 1.07 g, 26.7 mmol) followed by the addition of
dimethyl sulfoxide (33 mL). The ing mixture was stirred at ambient ature for 10
minutes and then treated with a solution oftert-butyl 4-oxopiperidinylcarboxylate (5 g, 25
mmol) in tetrahydrofuran (20 mL) dropwise. The resulting mixture was stirred at t
temperature for 30 minutes and then diluted with ethyl acetate (60 mL). The mixture washed
with water (60 mL) and brine (60 mL), dried over sodium sulfate and concentrated under
reduced pressure. The residue was purified with chromatography (petroleum ether:ethyl
acetate = 30:1) to afford the title compound (4 g, 80%) as a yellow oil. 1H NMR (400 MHz,
chloroform-d) 6 ppm 1.48 (s, 9H), 2.23 - 2.14 (m, 4H), 3.47 - 3.38 (m, 4H), 4.75 (s, 2H).
Step 2: tert-Butyl 1,7-diazaspiro[3.5]nonanecarboxylate
To a solution of tert-butyl 4-methylenepiperidinylcarboxylate (4 g, 20 mmol) in
dichloromethane (50 mL) was added sulfurisocyanatidic chloride (3.4 g, 24 mmol) at 0 °C.
The resultant mixture was stirred at t ature overnight and then diluted with
diethyl ether (100 mL) and cooled to 0 °C. The mixture was treated with a on of sodium
thiosulfate (9.5 g, 60 mmol) and potassium hydroxide (2.24 g, 40 mmol) in water (50 mL)
at 0 °C. The resultant mixture was stirred at 0 °C for 3 hours and extracted with ethyl e
(2 x 50 mL). The organic phase was dried anhydrous sodium e and concentrated
under reduced pressure to give a yellow oil (4.1 g . The oil was dissolved in
tetrahydrofuran (30 mL) and borane-dimethyl sulfide x (2 M, 15 mL, 30 mmol) was
added. The resultant mixture as stirred at 70 °C overnight. The mixture was cooled to
ambient temperature and concentrated under reduced pressure to give the title compound
(4.5 g, crude) as a yellow oil which was used in the next step without further purification.
LCMS m/z = 227.1 [M+H]+.
Step 3: tert-Butyl 1-(6-chloro-3,5-dicyanoethylpyridinyl)-1,7-
diazaspiro[3.5]nonanecarboxylate
N NC CN
N N CI
tert-Butyl 1,7-diazaspiro[3.5]nonanecarboxylate (1.5 g, crude) and 2,6-dichloro
ethylpyridine-3,5-dicarbonitrile (synthesis described in example 3 step 2, 1 g, 4.5 mmol)
were dissolved in tetrahydrofuran (20 mL) and triethylamine (1.14 g, 11.25 mmol) was
added at 0 °C. The resultant e was stirred at ambient temperature for 2 hours and
then diluted with ethyl acetate (60 mL). The mixture was washed with water (40 mL) and
brine (40 mL), dried over anhydrous sodium e and concentrated under reduced
pressure to afford the title compound (2.1 g, crude) as a yellow oil which was used in the
next step without further purification. LCMS m/z = 437.8 [M+Na]+.
Step 4: tert-Butyl 1-(6-((2-aminooxophenylethyl)thio)-3,5-dicyano
ethylpyridin-Z-yl)-1, aspiro[3.5]nonanecarboxylate
134: NC CN
To a solution of tert-butyl 1-(6-chloro-3,5-dicyanoethylpyridinyl)-1,7-diazaspiro[3.
]nonanecarboxylate (2.1 g, crude) in anhydrous N,N-dimethylformamide (30 mL) was
added potassium thioacetate (0.7 g, 6 mmol). The resultant mixture was stirred at room
temperature for 3 hours and then potassium carbonate (1.65 g, 12 mmol) was added and
the reaction stirred for 2 hours at room temperature. Then 2-aminooxophenylethyl
methanesulfonate (synthesis described in example 3 step 5, 2.75 g, 12 mmol) was added
and the resultant mixture was stirred at room temperature overnight, then diluted with ethyl
acetate (80 mL), washed with water (60 mL) and brine (60 mL). The organic phase was
dried over ous sodium sulfate and concentrated under d pressure. The
residue was purified by column chromatography (petroleum ether:ethyl e = 1:1—1 :2)
to give the title compound (1 g, crude). LCMS m/z = 546.8 [M+H]+.
Step 5: 2-((3,5-DicyanoethyI(1,7-diazaspiro[3.5]nonany|)pyridinyl)thio)
phenylacetamide trifluoroacetate
HN NC CN
N N S
““2 i
F30 OH
To a solution of tert-butyl 1-(6-((2-aminooxophenylethyl)thio)-3,5-dicyano
ethylpyridinyl)—1,7-diazaspiro[3.5]nonanecarboxylate (0.9 g, crude) in 1,4-dioxane (20
mL) was bubbled in HCl(g) at 0 °C for 10 minutes. The resultant mixture was trated
under reduced pressure and the residue was purified with prep-HPLC to give the title
compound (120 mg, 15%) as a white solid. LCMS mfz = 447.1 [M+H]”. 1H NMR (400 MHz,
DMSO-de) 6 ppm 1.2 (t, J=6 Hz, 3H), 2.36 - 2.18 (m, 4 H), 2.70 (q, J=6 Hz, 2H), 3.18-3.12
(m, 2 H), 3.54-3.46 (m, 4H), 3.65-3.57 (m, 2 H), 5.55 - 5.44 (m, 2H), 7.53 - 7.35 (m, 4H),
7.95 - 7.88 (m, 1H), 8.71 - 8.59 (br, 2H).
Example 39:
rrolidin Imeth | i |
lthio hen lacetamide
Step 1: tert-Butyl 4-(pyrrolidinylmethyl)piperidinylcarboxylate
ofiw
To a solution of utyl 4-formylpiperidinyIcarboxylate (1 g, 4.69 mmol) and pyrrolidinyl
(0.3 g, 4.22 mmol) in dichloromethane (20 mL) was added 2 drops of acetic acid. The
mixture was d for one hour and then sodium triacetoxyborohydride (1 g, 4.7 mmol)
was added. The mixture was stirred for one hour, and was then washed with aqueous
sodium hydroxide (2 M, 2 x50 mL) and aqueous HCI (2 M, 2 x50 mL), dried over anhydrous
sodium sulfate, filtered, and concentrated to afford the title compound (1 g, 80% yield).
LCMS m/z = 269 [M+H]*.
Step 2: 4-(Pyrrolidinylmethyl)piperidinyl hydrochloride
To a solution of hydrochloric acid in dioxane (4 M, 20 mL, 80 mmol) was added tert-butyl
4-(pyrrolidinylmethyl)piperidinylcarboxylate (1 g, 3.73 mmol). The mixture was stirred
for2 hours and the ing solid was ted by filtration, washed with ethyl acetate, and
dried to give the crude title compound (0.8 g, >100% crude yield). LCMS m/z =169[M+H]+.
Step 3: 2-Chlorocyclopropyl(4-(pyrrolidiny|methy|)piperidinyl)pyridine-
3,5-dicarbonitrile
NC CN
QfiN N CI
To a solution of 2,6-dichlorocyclopropylpyridine-3,5-dicarbonitrile (synthesis described
in example 4 step 2, 500 mg, 2.1 mmol) and 4-(pyrrolidinylmethyl)piperidiny|
hydrochloride (500 mg, 2.4 mmol) in dichloromethane (20 mL) was added ylamine
(750 mg, 7.5 mmol). The mixture was stirred for one hour, and was then washed with brine
(2 x 100 mL), dried over ous sodium sulfate, and trated. The residue was
then purified by silica gel chromatography eluting with ethyl acetate:petroleum ether (1:3)
to afford the title compound (750 mg, 96% yield). LCMS m/z = 370 [M+H]+.
Step 4: 4-Cyclopropylmercapto(4-(pyrrolidiny|methy|)piperidin
yl)pyridine-3,5-dicarbonitrile
NC CN
CNVQN N SH
To a solution of 2-chloro—4-cyclopropyl(4-(pyrrolidinylmethyl)piperidiny|) pyridine-
3,5-dicarbonitri|e (750 mg, 2.0 mmol) in N,N-dimethylformamide (20 mL) was added
potassium thioacetate (250 mg, 2.2 mmol). The mixture was stirred for two hours and was
then diluted with ethyl acetate (200 mL), washed with brine (2 x 100 mL), dried over
anhydrous sodium sulfate and concentrated to give the crude title compound (700 mg, 95%
crude . LCMS m/z = 368 [M+H]+.
Step 5: 2-((3,5-Dicyanocyclopropyl(4-(pyrrolidinylmethy|)piperidin
yl)pyridin-Z-yl)thio)phenylacetamide
To a solution of opropylmercapto(4-(pyrrolidinylmethyl)piperidin
yl)pyridine-3,5-dicarbonitrile (700 mg, 1.9 mmol) in N,N-dimethylformamide (50 mL) was
added 2-aminooxophenylethyl esulfonate (synthesis bed in example 3
step 5, 500 mg, 2.2 mmol) and potassium carbonate (300 mg, 2.2 mmol). The reaction
mixture was stirred overnight at ambient temperature. The mixture was diluted with ethyl
acetate (200 mL) and washed with brine (2 x 100 mL), dried over anhydrous sodium sulfate
and concentrated. The residue was purified by prep-HPLC to give the title compound (15
mg, 1.5% yield). LCMS m/z = 501 [M+H]*. 1H NMR (400 MHz, DMSO-de) 6 ppm 7.92 (s,
1H), 7.52 (d, J = 7.0 Hz, 2H), 7.41 - 7.34 (m, 3H), 5.53 (s, 1H), 4.53 (t, J = 12.2 Hz, 2H),
3.60 (br s, 3H), 3.17 — 3.10 (m, 3H), 3.04 (br s, 2H), 2.18 — 1.99 (m, 4H), 1.93 - 1.86 (m,
3H), 1.34 — 1.22 (m, 3H), 1.18 — 1.09 (m, 2H), 0.98 (dt, J = 10.2, 5.2 Hz, 2H).
Example 40:
2- 35-Dic anoc clo ro I 4- 4-meth | i erazin I i eridin I ridin
Ithio hen mide
To a solution of 2,6-dichlorocyclopropylpyridine-3,5-dicarbonitrile (synthesis described
in example 4 step 2, 300 mg, 1.26 mmol) and 1-methyl(piperidin-4 -yl)piperazinyl
hydrochloride (243 mg, 1.10 mmol) in romethane (50 mL) was added triethylamine
(300 mg, 2.75 mmol). The mixture was d for one hour and then concentrated. To a
solution ofthe residue in N,N-dimethylformamide (50 mL) was added potassium thioacetate
(144 mg, 1.26 mmol), and the mixture was d overnight. To the mixture was added
potassium carbonate (500 mg, 3.62 mmol) and 2-aminooxophenylethyl
methanesulfonate (synthesis described in example 3 step 5, 1 g, 4.46 mmol). The reaction
was d at ambient temperature overnight and was then diluted with water (30 mL). The
resulting solid was collected by filtration, and was then purified by prep-HPLC to give the
title compound (200 mg, 37% yield). LCMS m/z = 516 [M+H]*. 1H NMR (400 MHz, DMSO-
de) 6 ppm 7.94 (s, 1H), 7.53 (d, J = 7.1 Hz, 2H), 7.43 - 7.30 (m, 4H), 5.54 (s, 1H), 4.61 (s,
4H)8&L298Un8H)283@3HL2D8—195mrfifl154de=245112HL2m,
114th=8831HL2H)1D4-092mm2m.
Example 41:
R 3 5-dic ano 1 4-diaze an I eth I ridin lamino
phenylacetamide
Step 1: (R)((6-chloro-3,5-dicyanoethylpyridin-Z-yl)amino)phenylacetamide
NC CN
CI N NH
A stirred solution of 2,6-dichloroethylpyridine-3,5-dicarbonitrile (synthesis described in
e 3 step 2, 148.5 mg, 0.657 mmol) ved in tetrahydrofuran (10 mL) was treated
with (R)aminophenylacetamide (118 mg, 0.788 mmol) in one portion at 20 °C. After
2 hours, the e was diluted with EtOAc (50 mL), washed with water (3 x 50 mL), brine,
dried, then concentrated to provide (R)((6-chloro-3,5-dicyanoethylpyridin-2—yl)amino)-
2-phenylacetamide (177 mg, 0.521 mmol, 79% yield) as a light yellow solid. LCMS m/z =
340 [M+H]+.
Step 2: (R)((3,5-dicyano(1,4-diazepanyl)ethylpyridinyl)amino)—2-
phenylacetamide
NC CN
{/A\N /
N NH
HN\J)
[::j/l\f%3NH2
A solution of (R)((8-chloro-3,5-dicyanoethylpyridinyl)amino)—2-phenylacetamide
(39 mg, 0.115 mmol) in tetrahydrofuran (5 mL) was treated with a solution of 1 ,4-diazepane
(184 mg, 1.836 mmol) in tetrahydrofuran (5 mL) in one portion at room temperature. The
ing suspension was stirred at room temperature for 1 hour, then the reaction mixture
was diluted with ethyl e (20 mL), washed with water (2 x 20 mL), brine, then dried
over sodium sulfate to provide the crude product. This material was purified on a 24 g
Analogix column that had been preconditioned with dichloromethane, then eluted with
100% DCM (4 minutes) followed by a gradient from 0-100% (methanol containing 10%
um hydroxide)/ dichloromethane over 25 minutes. The desired fractions were
combined, concentrated in vacuo, then dried under vacuum to provide (R)((3,5-dicyano-
6-(1,4-diazepany|)ethy|pyridinyl)amino)phenylacetamide (23 mg, 0.057 mmol,
50% yield) as a white solid. LCMS m/z = 404 [M+H]+. 1H NMR (400 MHz, DMSO-de): 6
ppm 7.83 (s, 1 H), 7.49 - 7.42 (m, 3 H), 7.38 - 7.31 (m, 2 H), 7.31 - 7.25 (m, 1 H), 7.07 (d,
J = 6.1 Hz, 1 H), 5.42 (d, J = 6.1 Hz, 1 H), 3.86 - 3.61 (m, 5 H), 2.90 - 2.79 (m, 1 H), 2.71
(q, J = 7.7 Hz, 3 H), 2.61 (t, J = 5.7 Hz, 2 H), 1.72 (dd, J = 13.3, 7.5 Hz, 1 H), 1.65 - 1.55
(m, 1 H), 1.20 (t, J = 7.6 Hz, 3 H).
Example 42:
2- 35-Dic anoc clo ro | 4- in l i eridin | ridin Ithio
hen lacetamide trifluoroacetate
NC CN
/ CF3COOH
Q HZN
To a solution of 2,6-dichlorocyclopropylpyridine-3,5-dicarbonitrile (synthesis described
in example 4 step 2, 500 mg, 2.10 mmol) and rolidinyl)piperidinyl (325 mg, 2.11
mmol) in dichloromethane (50 mL) was added triethylamine (230 mg, 2.28 mmol). The
on was stirred at room temperature until LCMS showed the product. The mixture was
concentrated to give a light yellow solid which was dissolved in N,N-dimethylformamide (50
mL) and potassium thioacetate (144 mg, 1.26 mmol) was added. The mixture was stirred
at 25 °C for six hours and then ium carbonate (500 mg, 3.60 mmol) and 2-amino
oxophenylethyl methanesulfonate (synthesis described in example 3 step 5, 1.0 g, 4.36
mmol) were added. The mixture was stirred overnight at room temperature. The mixture
was diluted with water (30 mL) and extracted with ethyl acetate (30 mL). The organic phase
was concentrated, and the e was purified by prep-HPLC to give the title compound
(120 mg, 22% yield). LCMS m/z = 487 [M+H]+. 1H NMR (400 MHz, CDCIa) 6 ppm 12.25 (s,
1H), 7.54 - 7.45 (m, 2H), 7.44 — 7.34 (m, 3H), 6.95 (s, 1H), 6.88 (s, 1H), 5.30 (s, 1H), 4.72
(t, J = 12.3 Hz, 2H), 3.92 (d, J = 38.7 Hz, 2H), 3.32 (t, J = 13.1 Hz, 1H), 3.12 (s, 1H), 3.06
— 2.94 (m, 1H), 2.84 (s, 4H), 2.24 — 2.12 (m, 6H), 1.92 (d, J = 8.3 Hz,1H), 1.36 -1.14 (m,
4H).
e 43:
2- 35-Dic anoeth l 27-diazas iro 3.5 nonan I ridin Ithio
phenylacetamide
Step 1: tert-Butyl hloro-3,5-dicyanoethylpyridinyl)-2,7-
diazaspiro[3.5]nonane carboxylate
To a solution of 2,6-dichloroethylpyridine-3,5-dicarbonitrile (synthesis described in
example 3 step 2, 452 mg, 2 mmol) in dichloromethane (20 mL) was added tert-butyl 2,7-
diazaspiro[3.5]nonanecarboxylate (452 mg, 2 mmol) followed by triethylamine (202 mg,
2 mmol). The on was stirred for 12 hours and was diluted with dichloromethane (40
mL) and washed with water (25 mL) and brine (25 mL). The organic layer was dried over
sodium sulfate, and concentrated to afford the crude title compound (820 mg) as a yellow
solid. LCMS m/z = 438 [M+Na]+.
Step 2: tert-Butyl 7-(3,5-dicyanoethylmercaptopyridin-Z-yl)-2,7-
piro[3.5]nonane carboxylate
To a solution of crude tert-butyl 7-(6-chloro-3,5-dicyanoethy|pyridiny|)-2,7-
diazaspiro[3.5]nonanecarboxylate (820 mg, assumed 1.97 mmol) in N,N-
dimethylformamide (8 mL) was added potassium thioacetate (271 mg, 2.36 mmol). The
resulting mixture was stirred at ambient ature for 2 hours. The mixture was then
diluted with water (25 mL) and extracted with ethyl acetate (40 mL). The organic phase
was washed with brine (25 mL), dried, and concentrated to afford the crude title compound
(890 mg) as a brown oil. LCMS mfz = 414 [M+H]*.
Step 3: tert-Butyl 7-(6-((2-aminooxophenylethyl)thio)-3,5-dicyano
ethylpyridin-Z-yl)-2,7-diazaspiro[3.5]nonane-Z-carboxylate
To a on of crude tert—butyl 7-(3,5-dicyanoethylmercaptopyridiny|)-2,7-
diazaspiro[3.5]nonane carboxylate (890 mg) in N,N-dimethylformamide (6 mL) was
added potassium carbonate (594 mg, 4.3 mmol). The e was stirred at ambient
temperature for one hour followed by the addition of 2-aminooxophenylethy|
methanesulfonate (synthesis described in example 3 step 5, 741 mg, 3.23 mmol). The
resulting mixture was stirred at ambient temperature for 12 hours. The mixture was then
diluted with ethyl acetate (60 mL), washed with water (30 mL) and brine (30 mL), dried, and
concentrated. The residue was purified by silica gel chromatography eluting with eum
ether-ethyl acetate (2:1) to give the title compound (600 mg, 55% yield over 3 steps) as a
brown solid. LCMS m/z = 547 .
Step 4: 2-((3,5-Dicyanoethyl(2,7-diazaspiro[3.5]nonanyl)pyridinyl)thio)
phenylacetamide
NC CN
HN H2”
To a solution of tert-butyl 7-(6-((2-aminooxophenylethy|)thio)-3,5-dicyano
ethylpyridinyl)—2,7-diazaspiro[3.5]nonanecarboxylate (600 mg, 1.1 mmol) in
dichloromethane (20 mL) was added trifluoroacetic acid (2 mL). The ing solution was
stirred at ambient temperature for 5 hours and trated under reduced pressure. The
residue was d with ethyl acetate (60 mL) and was washed with aqueous sodium
bicarbonate (40 mL), dried, and concentrated under reduced re. The residue was
purified by silica gel chromatography eluting with dichloromethane-methanol (10:1) to give
a solid that was washed with diethyl ether and dried to afford the title compound (90.8 mg,
18% yield) as a light yellow solid. LCMS mfz = 447 [M+H]". 1H NMR (400 MHz, DMSO-de)
6 ppm 9.09 (br s, 2H), 7.99 (s, 1H), 7.53 (d, J = 7.1 Hz, 2H), 7.45 - 7.26 (m, 4H), 5.55 (s,
1H), 3.81 (t, J = 5.3 Hz, 4H), 3.77 (s, 4H), 2.76 (q, J = 7.5 Hz,2H), 1.97 - 1.82 (m, 4H), 1.21
(t, J = 7.6 Hz, 3H).
Example 44:
2- 35-Dic anoeth |26-diazas iro 3.4 octan | ridin Ithio
phenylacetamide
Step 1: tert-Butyl(6-chloro-3,5-dicyanoethylpyridinyl)-2,6-
diazaspiro[3.4]octanecarboxylate
NC CN
7*) /
)‘NOQ N CI
To a on of chloroethylpyridine-3,5-dicarbonitrile (synthesis described in
example 3 step 2, 900 mg, 4 mmol) and tert—butyl 2,6-diazaspiro[3.4]octanecarboxylate
(840 mg, 4 mmol) in dichloromethane (100 mL) was added triethylamine (400 mg, 4 mmol).
The reaction was stirred for 30 minutes, was then washed with brine (2 x 100 mL), and the
organic phase was dried over sodium sulfate and concentrated. The residue was purified
by silica gel chromatography eluting with petroleum ether — ethyl acetate (3:1) to give the
title compound (1.3 g, 81% yield). LCMS m/z = 346 [M+H—isobutylene]*.
Step 2: utyl 6-(3,5-dicyanoethyImercaptopyridin-Z-yI)-2,6-
diazaspiro[3.4]octane-2 —carboxylate
NC CN
)0 /
\J N SH
To a solution of tert-butyl 6-(6-chloro-3,5-dicyanoethylpyridinyl)-2,6-
diazaspiro[3.4]octanecarboxylate (1.3 g, 3.2 mmol) in N,N-dimethylformamide (20 mL)
was added potassium thioacetate (554 mg, 4.8 mmol). The reaction was d for 3 hours,
and the mixture was then diluted with ethyl acetate (200 mL) and washed with brine (2 x
100 mL). The organic phase was concentrated to afford the crude title compound (1 g, 78%
crude yield). LCMS m/z = 344 [M+H—isobutylene]+.
Step 3: tert-Butyl 6-(6-((2-aminooxophenylethyl)thio)-3,5-dicyano
ethylpyridin-Z-yl)-2, 6-diazaspiro[3.4]octanecarboxylate
NC CN
)0 /
HOG N S
o H2N
To a solution of crude tert-butyl 6-(3,5-dicyanoethyImercaptopyridinyl)-2,6-
diazaspiro[3.4]octanecarboxylate (1 g, assumed 2.5 mmol) in N,N-dimethylformamide
(100 mL) was added 2-aminooxophenylethyl methanesulfonate (synthesis described
in example 3 step 5, 0.572 g, 2.5 mmol) and potassium carbonate (1.0 g, 7.2 mmol). The
reaction was stirred ght, and was then diluted with ethyl acetate (200 mL) and
washed with brine (2 x 100 mL). The organic phase was dried over sodium e, filtered,
and concentrated to afford the crude title compound (0.8 g, 60% crude yield). LCMS m/z
= 477 [M+H—isobutylene]*.
Step 4: 2-((3,5-Dicyanoethyl(2,6-diazaspiro[3.4]octanyl)pyridinyl)thio)
phenylacetamide
NC CN
N S
To a solution of crude utyl 6-(6-((2-aminooxophenylethy|)thio)-3,5-dicyano
ethylpyridinyl)-2,6-diazaspiro[3.4]octanecarboxylate (0.8 g, assumed 1.5 mmol) in
dichloromethane (10 mL) was added trifluoroacetic acid (2 mL). The reaction was stirred
ght, and was then concentrated. The residue was purified by prep-HPLC to give the
title compound (520 mg, 80% yield). LCMS m/z = 433 [M+H]*. 1H NMR (400 MHz, DMSO-
de) 6 ppm 8.48 (s, 1H), 8.08 (s, 1H), 7.54 (d, J = 7.3 Hz, 2H), 7.42 - 7.31 (m, 4H), 5.63 (s,
1H), 4.22 — 3.77 (m, 8H), 2.75 (q, J = 7.4 Hz, 2H), 2.26 (s,2H), 1.29 - 1.10 (m, 3H).
Example 46:
l14-diaze an I re anamide
Step 1: tert-Butyl 4-(6-((1-aminooxopropan-Z-yl)thio)-3,5-dicyano
cyclopropylpyridinyI)-1,4-diazepanecarboxylate
7<0—<O NH2
A mixture of tert-butyl 4-(6-chloro-3,5-dicyanocyclopropylpyridinyl)-1,4-diazepane
carboxylate (synthesis described in example 4 step 3, 300 mg, 0.74 mmol), KSAc (93 mg,
0.81 mmol) in N,N-dimethylformamide (8 mL) was stirred at room temperature for 30
minutes, then 2-bromopropanamide (136 mg, 0.89 mmol) was added. The resulting mixture
was stirred at room temperature for 12 hours. The reaction mixture was poured into water
(50 mL), then extracted with ethyl acetate (2 x 50 mL). The ed c layer was
dried, concentrated, and the residue was purified by silica gel chromatography using
:MeOH (100:1) to give the title compound (290 mg, 83% yield) as a white solid.
LCMS m/z = 371.0 [M+H—Boc]+.
Step 2: 2-((3,5-Dicyanocyclopropyl(1,4-diazepanyl)pyridin
yl)thio)propanamide
A mixture of tert-butyl (1-aminooxopropanyl)thio)-3,5-dicyano
cyclopropylpyridinyl)-1,4-diazepanecarboxylate (synthesis described in example 6
step 1, 260 mg, 0.55 mmol) and trifluoroacetic acid (1 mL) in CH20|2 (6 mL) was stirred at
room ature for 12 hours. The resulting mixture was concentrated. The residue was
poured into water (50 mL) and made basic by the addition of aqueous NaHC03, then
extracted with CH2CI2 (2 x 50 mL). The combined organic layers were dried and
concentrated. The residue was purified by silica gel chromatography eluting with
CH2CI2:MeOH (30:1) to give the title compound (80 mg, 39% yield) as a white solid. LCMS
m/z = 371 . 1H NMR (400 MHz, CDCls) 6 ppm 6.44 (br s, 1H), 5.35 (brs, 1H), 4.22
(q, J = 7.6 Hz, 1H), 4.06 - 3.97 (m, 1H), 3.97 — 3.87 (m, 3H), 3.16 — 3.10 (m, 2H), 2.97 -
2.85 (m, 2H), 2.10 —2.02 (m, 1H), 2.01 — 1.94 (m, 2H), 1.86 (br s, 2H), 1.64 (d, J = 7.6 Hz,
3H),1.35 — 1.23 (m, 2H), 1.15 — 1.05 (m, 2H).
Example 47:
2- 35-Dic anoeth l 4- midazolidin | i eridin I ridin Ithio -
Z-phenylacetamide
NC ON
O / N S
HN’g (WNHz
A solution of 2-((6-bromo-3,5-dicyanoethylpyridinyl)thio)phenylacetamide
esis described in example 6 step 1, 15 mg, 0.04 mmol) in tetrahydrofuran (1 mL) was
treated with 1-(piperidinyl)imidazolidinone hydrochloride (12 mg, 0.06 mmol) and
triethylamine (0.013 mL, 0.09 mmol) and stirred at ambient temperature for 72 hours. The
product e was dry loaded onto SiOz (0.9 g) and chromatographed on Si02 (4 g
RediSep cartridge, eluting with 0-15% MeOH/CH20I2) to give the title compound (15 mg,
82% yield) as an off-white solid. LCMS m/z = 490 [M+H]+. 1H NMR (300 MHz, DMSO-de)
6 ppm 7.93 (br s, 1H), 7.52 (br d, J = 6.8 Hz, 2H), 7.46 - 7.30 (m, 4H), 6.32 (s, 1H), 5.54 (s,
1H), 4.67 (br d, J = 12.9 Hz, 2H), 3.93 - 3.64 (m, 2H), 3.30 - 3.06 (m, 7H), 2.76 (q, J = 7.0
Hz, 2H), 1.82 - 1.50 (m, 2H), 1.19 (t, J = 7.5 Hz, 3H).
Example 48:
NC CN
A solution of 2-((6-bromo-3,5-dicyanoethylpyridinyl)thio)phenylacetamide
(synthesis described in example 6 step 1, 16 mg, 0.04 mmol) in tetrahydrofuran (1 mL) was
treated with 4-hydroxypiperidinyl (14 mg, 0.14 mmol) and stirred at ambient
temperature for 3 hours. The on was then loaded onto Si02 (0.9 g) and
tographed on Si02 (4 g RediSep cartridge, eluting with 0-15% MeOHICH2CI2) to
give the title compound (15 mg, 88% yield) as a white solid. LCMS m/z = 420 [M—H]‘. 1H
NMR (300 MHz, DMSO-de) 6 ppm 7.92 (s, 1H), 7.57 - 7.46 (m, 2H), 7.44 - 7.28 (m, 4H),
.53 (s, 1H), 4.85 (d, J = 4.1 Hz, 1H), 4.24 - 4.05 (m, 2H), 3.91 - 3.70 (m, 1H), 3.65 - 3.47
(m, 2H), 2.75 (q, J = 7.4 Hz, 2H), 1.84 (brs, 2H), 1.61 - 1.34 (m, 2H), 1.20 (t, J = 7.6 Hz,
3H).
Example 49:
2- 35-Dic anoeth l S h drox rrolidin l ridin lthio
phenylacetamide
NC CN
“WC/q N s
A solution of 2-((6-bromo-3,5-dicyanoethylpyridinyl)thio)phenylacetamide
(synthesis bed in e 6 step 1, 17 mg, 0.04 mmol) in tetrahydrofuran (1 mL) was
treated with (S)pyrrolidinol (0.009 mL, 0.11 mmol) and stirred at ambient
temperature for3 hours. The reaction was then loaded onto Si02 (0.9 g) and
chromatographed on SiOz (4 g RediSep cartridge, eluting with 0-15% MeOHlCH2C|2) to
give the title compound (12 mg, 70% yield) as a white solid. LCMS m/z = 408 [M+H]+. 1H
NMR (300 MHz, DMSO-de) 6 ppm 7.91 (br s, 1H), 7.52 (br d, J = 7.2 Hz, 2H), 7.44 - 7.26
(m, 4H), 5.61 (s, 1H), 5.15 (brs, 1H), 4.42 (brs, 1H), 3.90 (br s, 2H), 3.35 - 3.64 (m, 2H),
2.89 - 2.56 (m, 2H), 1.95 (br s, 2H), 1.20 (brt, J = 7.3 Hz, 3H).
Example 50:
2- 35-Dic anoeth I 3-oxo i erazin I ridin lthio hen Iacetamide
Step 1: 2-Chloroethyl(3-oxopiperazinyl)pyridine-3,5-dicarbonitrile
NC CN
OYN /
N Cl
To a solution of 2,6-dichloroethylpyridine-3,5-dicarbonitrile esis described in
example 3 step 2, 2.26 g, 10.00 mmol) in dichloromethane (30 mL) was added piperazin-
2-one (1.001 g, 10.00 mmol) and triethylamine (1.012 g, 10.00 mmol). The mixture was
stirred at 25 °C for 12 hours. The reaction mixture was diluted with dichloromethane (30
mL), washed with water (30 mL) and brine (30 mL), dried, and concentrated to give the title
compound (2.4 g, 83% yield) as a light yellow solid. LCMS m/z = 290 [M+H]+.
Step 2: 4-Ethylmercapto(3-oxopiperazinyl)pyridine-3,5-dicarbonitrile
NC CN
GYM N/ SH
To a solution of 2—chloroethyl(3-oxopiperaziny|)pyridine-3,5-dicarbonitrile (290 mg,
1.001 mmol) in N,N-dimethylformamide (5 mL) was added potassium thioacetate (229 mg,
2.002 mmol). The mixture was stirred at room ature for 12 hours, diluted with ethyl
acetate (60 mL), and washed with ted aqueous ammonium chloride solution (60 mL).
The c phase was washed with brine (60 mL), dried, and concentrated to give crude
4-ethylmercapto(3-oxopiperaziny|)pyridine-3,5-dicarbonitrile (300 mg) as a brown
solid. LCMS m/z = 288 [M+H]+.
Step 3: 2-((3,5-Dicyanoethyl(3-oxopiperazinyl)pyridinyl)thio)
phenylacetamide
WO 16727
To a solution of crude 4-ethylmercapto(3-oxopiperazinyl)pyridine-3,5-dicarbonitrile
(300 mg, 1.044 mmol) in N,N-dimethylformamide (6 mL) was added potassium carbonate
esis described in e 3 step 5, 289 mg, 2.088 mmol). The mixture was stirred at
room temperature for 2 hours, and 2—amino-2—oxophenylethyl methanesulfonate
(synthesis described in example 3 step 5, 287 mg, 1.253 mmol) was then added. The
mixture was stirred at room temperature for 12 hours. The on solution was diluted
with ethyl e (60 mL), washed with water (60 mL) and brine (60 mL), dried,
concentrated and purified by prep-HPLC to give 2-((3,5-dicyanoethyl(3-oxopiperazin-
1-yl)pyridinyl)thio)phenylacetamide (35 mg, 8% yield) as a light brown solid. LCMS
m/z = 421.0 [M+H]+. 1H NMR (400 MHz, DMSO-de) 8.30 (s, 1H), 7.95 (s, 1H), 7.54 (d, J =
7.1 Hz, 2H), 7.46-7.24 (m, 4H), 5.57 (s, 1H), 4.39 (s, 2H), 4.07-3.97 (m, 2H), 2.78 (dd, J =
8 Hz, 7.5 Hz, 2H), 1.22 (t, J = 7.5 Hz, 3H).
Example 51:
2- 6-amino-3 5-dic anoc clo ro l rid lsulfan | hen l-acetamide
Step 1: 2-Aminocyclopropylmercaptopyridine-3,5-dicarbonitrile; 4-
methylmorpholine
“3% |
\N 0
HZN SH
2-Cyanothioacetamide (860 mg, 8.56 mmol), N-methylmorpholine (2.2 mL, 20 mmol) and
cyclopropane carboxaldehyde (0.32 mL, 4.28 mmol) were mixed and dissolved in ethanol
(10 mL). The resulting solution was stirred at ambient temperature for 16 hours. The
precipitate formed was washed with ethanol and dried under reduced pressure to furnish
the title compound (322 mg, 24% yield) as a cream d solid. LCMS m/z = 217 [M+H]*.
Step 2: 2-((6-Amino-3,5-dicyano—4-cyclopropylpyridinyl)thio)phenylacetamide
WO 16727
NC ON
H2N N s
2-Amino—4-cyclopropylmercaptopyridine-3,5-dicarbonitrile; 4-methylmorpholine, (316
mg, 1 mmol) and 2-chlorophenyl—acetamide (174 mg, 1.02 mmol) were dissolved in NM-
dimethylformamide (10 mL) and the reaction e was allowed to stir at ambient
temperature for 16 hours. The mixture was d with EtOAc (50 mL) and washed with
water (3 x 10 mL), saturated sodium chloride (10 mL) and then water (10 mL). The organic
layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure.
The crude product was purified by ative HPLC to furnish the title compound (7 mg,
2% yield) as a white solid. LCMS m/z = 348 [M—H]‘. 1H NMR (300 MHz, DMSO—ds) 6 ppm
7.80 (br s, 2H), 7.73 (s, 1H), 7.58 (dd, J = 1.6, 7.9 Hz, 2H), 7.39 - 7.26 (m, 4H), 5.54 (s,
1H), 2.15 - 2.00 (m, 1H), 1.25 - 0.95 (m, 4H).
Example 52:
2- 35-Dic eth l meth lamino ridin lthio hen lacetamide
NC CN
A stirred suspension of amino-3,5-dicyanoethylpyridinyl)thio)—2-
phenylacetamide (synthesis described in example 1, 74 mg, 0.22 mmol) in dry acetonitrile
(10 mL) was treated with copper(l|) chloride (52 mg, 0.39 mmol) and isoamyl nitrite (0.052
mL, 0.39 mmol) then heated to 70 °C for 45 minutes under an atmosphere of nitrogen gas.
More copper(ll) chloride (52 mg, 0.39 mmol) and isoamyl nitrite (0.052 mL, 0.39 mmol)
were then added. After 40 minutes a third series of additions was made: copper(|l) chloride
(52 mg, 0.39 mmol) then isoamyl nitrite (0.052 mL, 0.39 mmol). After1 hour the reaction
mixture was evaporated to dryness under vacuum to give the crude title nd that
was used without further purification. LCMS m/z = 355 [M—H]‘.
Step 2: 2-((3,5-Dicyanoethyl(methylamino)pyridiny|)thio)phenylacetamide
A solution of crude 2-((6-chloro-3,5-dicyanoethylpyridinyl)thio)phenylacetamide,
(39.25 mg, 0.11 mmol) in tetrahydrofuran (3 mL) and ethanol (1.5 mL) was treated with
methylamine solution (2 M in tetrahydrofuran, 0.44 mL, 0.88 mmol) then heated at 65 °C.
After 45 minutes more methylamine solution (2 M in tetrahydrofuran, 0.11 mL, 0.22 mmol)
was added and heating was continued another 45 minutes. The reaction mixture was then
allowed to cool and was loaded onto Si02 (1 g). Chromatography on Si02 (12 g RediSep
cartridge, eluting with 0-10% MeOH/CH2C|2) furnished 14 mg material that was then
dissolved in DMSO (0.4 mL), diluted with 50% CH3-CN/H20 (0.4 mL), and the resulting
solid was collected and washed with 50% CHs-CN/Hzo (5 mL) to give the title compound
(7 mg), as an off-white solid. LCMS m/z = 350 [M—H]—. 1H NMR (300 MHz, DMSO-de) 6
ppm 8.08 (br d, J = 4.3 Hz, 1H), 7.91 (br s, 1H), 7.64 - 7.46 (m, 2H), 7.45 - 7.29 (m, 4H),
.64 (s, 1H), 2.99 (br d, J = 4.5 Hz, 3H), 2.69 (d, J = 7.4 Hz, 2H), 1.17 (t, J = 7.5 Hz, 3H).
e 53:
2- 35-Dic anoeth | 2-methox eth | meth lamino 2- Ithio
phenylacetamide
NC CN
\N /
N S
A solution of 2-((6-bromo-3,5-dicyanoethylpyridinyl)thio)—2-phenylacetamide
esis described in e 6 step 1, 20 mg, 0.05 mmol) in tetrahydrofuran (1 mL) was
treated with (2-methoxyethyl)-methylamine (0.012 mL, 0.11 mmol) at t temperature
WO 16727
for 18 hours, loaded onto Si02 (4 g) and chromatographed on Si02 (4 g RediSep cartridge,
eluting with 0-5% MeOH/CH2CI2) to furnish the title compound (16 mg, 78% yield), as a
white solid. LCMS m/z = 410 [M+H]*. 1H NMR (300 MHz, DMSO-de) 6 ppm 7.90 (s, 1H),
7.55 - 7.45 (m, 2H), 7.43 - 7.30 (m, 4H), 5.53 (s, 1H), 4.00 (s, 1H), 3.93 (s, 1H), 3.56 (t, J =
.2 Hz, 2H), 3.37 (s, 3H), 3.26 (s, 3H), 2.76 (q, J = 7.5 Hz, 2H), 1.20 (t, J = 7.6 Hz, 3H).
Example 54:
2- 35-Dic anoeth l 3-methox azetidin l ridin Ithio
phenylacetamide
NC CN
\OL“ N S
1O NH2
A solution of 2-[(6-bromo-3,5-dicyanoethylpyridyl)sulfanyl]phenyl-acetamide
(synthesis described in example 6 step 1, 20 mg, 0.05 mmol) in tetrahydrofuran (1 mL) was
treated with oxyazetidine hydrochloride (16 mg, 0.13 mmol) and ylamine (0.02
mL, 0.13 mmol). The resultant solution was stirred at ambient ature for 45 minutes,
dry loaded onto Si02 (0.9 g) and chromatographed on Si02 (4 g RediSep cartridge) eluting
with 0-5% MeOH/CH2CI2 to give 2-[[3,5-dicyanoethyl(3-methoxyazetidinyl)
pyridyl]sulfanyl]phenyl-acetamide (20 mg, 100% yield) as a white solid. LCMS m/z = 408
[M+H]*. 1H NMR (300 MHz, DMSO-de) 6 ppm 7.86 (s, 1H), 7.57 - 7.46 (m, 2H), 7.44 - 7.28
(m, 4H), 5.55 (s, 1H), 4.60 (br s, 2H), 4.39 - 4.09 (m, 3H), 3.28 (br s, 3H), 2.69 (q, J=7.5
Hz, 2H), 1.19 (t, J=7.5 Hz, 3H).
Example 55:
2- 35-Dic anoeth | i erazin | ridin Ithio hen lacetamide
A solution of 2-[(6-bromo-3,5-dicyanoethylpyridyl)su|fanyl]phenyl-acetamide
(synthesis described in example 6 step 1, 137 mg, 0.34 mmol) in tetrahydrofuran (5 mL)
was treated with a solution of piperazinyl (350 mg, 4.06 mmol) in tetrahydrofuran (5 mL)
warmed to dissolve then re-cooled all at once at ambient temperature. The resultant
suspension was stirred for 20 minutes. The product mixture was diluted with EtOAc (80
mL), washed with water (3 x 50 mL), saturated sodium de and dried through a
hydrophobic frit to give 2-[(3,5-dicyanoethyl—6-piperaziny|pyridy|)su|fany|]
phenyl-acetamide (123 mg, 88% yield) as an off-white solid. LCMS mfz = 407 [M+H]+. 1H
NMR (300 MHz, s) 6 ppm 7.91 (s, 1H), 7.62 - 7.46 (m, 2H), 7.44 - 7.30 (m, 4H),
5.52 (s, 1H), 3.79 (brs, 4H), 3.43 - 3.37 (m, 1H), 2.88 - 2.67 (m, 6H), 1.20 (t, J=7.5 Hz, 3H).
Example 56:
2- 35-Dic anoeth | 4-meth ldiaze an l ridin Ithio
phenylacetamide
A solution of 2-[(6-bromo-3,5-dicyanoethylpyridyl)su|fany|]phenyl-acetamide
(synthesis described in example 6 step 1, 467 mg, 1.16 mmol) in tetrahydrofuran (25 mL)
was treated with N-methylhomopiperazinyl (0.36mL, 2.91mmol) and d at t
temperature for 1.5 hours under an atmosphere of nitrogen. The product mixture was dry
loaded onto SiOz (2 g) and chromatographed on SiOz (12 g p cartridge, eluting with
0-10% MeOH, 0-1% NH3/CH20I2) to afford 5-dicyanoethyI(4-methyI-1,4-
diazepany|)pyridy|]su|fany|]phenyl-acetamide (445 mg, 88% yield), as a white
solid. LCMS m/z = 435 [M+H]*. 1H NMR (300 MHz, DMSO-de) 6 ppm 7.91 (s, 1H), 7.54 -
7.45 (m, 2H), 7.43 - 7.29 (m, 4H), 5.51 (s, 1H), 4.01 - 3.79 (m, 4H), 2.84 - 2.55 (m, 6H),
2.26 (s, 3H), 2.08 - 1.79 (m, 2H), 1.21 (t, J=7.6 Hz, 3H).
Example 57:
2- 35-Dic anoeth |mor holino ridin Ithio hen lacetamide
NC CN
{\N /
N s
(V Me
A solution of 2-[(6-bromo-3,5-dicyanoethylpyridyl)sulfanyl]phenyl-acetamide
(synthesis described in example 6 step 1, 28 mg, 0.07 mmol) in tetrahydrofuran (1 mL) and
ethanol (0.5 mL) was treated with morpholine (0.009 mL, 0.1 mmol) with stirring at ambient
temperature for 1 hour. The product mixture was dry loaded onto 3102 (0.8 g).
tography on Si02 (4 g RediSep cartridge, eluting with 0-5% MeOH/CH2CI2) followed
by trituration with diethyl ether afforded 2—[(3,5-dicyanoethylmorpholino
pyridyl)sulfanyl]phenyl-acetamide (19 mg, 0.0466 mmol, 67% yield), as a white solid.
LCMS m/z = 408 [M+H]+. 1H NMR (300 MHz, DMSO—de) 6 ppm 7.90 (br s, 1H), 7.65 - 7.46
(m, 2H), 7.46 - 7.31 (m, 4H), 5.76 - 5.49 (m, 1H), 3.99 - 3.78 (m, 4H), 3.77 - 3.39 (m, 4H),
2.76 (q, J=7.3 Hz, 2H), 1.21 (t, J=7.6 Hz, 3H).
Example 58:
2- 6- azetidin l-3 5-dic anoeth l rid lsulfan | hen l-acetamide
A solution of 2-[(6-bromo-3,5-dicyanoethylpyridyl)sulfanyl]phenyl-acetamide
(synthesis described in example 6 step 1, 23 mg, 0.06 mmol) in tetrahydrofuran (1 mL) was
treated with azetidine hloride (11.8 mg, 0.13 mmol) and triethylamine (0.02 mL, 0.15
mmol). The resultant solution was stirred at ambient temperature for 16 hours, dry loaded
onto 3102 (0.9 g) and tographed on Si02 (4 g p dge, eluting with 0-5%
MeOH/CH2CI2) to afford 2-[[6-(azetidinyl)-3,5-dicyanoethylpyridyl]sulfanyl]
phenyl-acetamide (19 mg, 0.0503 mmol, 86% yield) as a white solid. LCMS m/z = 376 [M—
H]‘. 1H NMR (300 MHz, DMSO-de) 6 ppm 7.86 (s, 1H), 7.55 - 7.39 (m, 2H), 7.39 - 7.25 (m,
4H), 5.55 (s, 1H), 4.56 - 4.28 (m, 4H), 2.68 (q, J=7.5 Hz, 2H), 2.47 - 2.26 (m, 2H), 1.17 (t,
J=7.6 Hz, 3H).
Example 59:
2- 35-dic anoeth l 4-oxo i eridin l ridin lthio hen lacetamide
A solution of 2-[(6-bromo-3,5-dicyanoethylpyridyl)su|fany|]phenyl-acetamide
(synthesis described in example 6 step 1, 20 mg, 0.05 mmol) in tetrahydrofuran (1 mL) was
treated with 4-piperidinone hydrochloride hydrate (11 mg, 0.07 mmol) and triethylamine
(0.017 mL, 0.12 mmol) then stirred at ambient temperature for 72 hours. The product
e was dry loaded onto SiOz (0.9 g) and chromatographed on SiOz (4 g RediSep
dge, eluting with 0-15% MeOH/CH2CI2) to give 5-dicyanoethyl(4-
eridinyl)pyridinyl)thio)pheny|acetamide (15 mg, 0.0358 mmol, 73%) as a
white solid. LCMS m/z = 418 [M—H]‘. 1H NMR (300 MHz, CD30D with a drop of CDCIs) 6
ppm 7.55 - 7.41 (m, 4H), 7.41 - 7.31 (m, 3H), 5.40 (s, 1H), 3.99 - 3.80 (m, 4H), 2.88 (q,
J=7.6 Hz,2H), 1.95 - 1.77 (m, 4H), 1.30 (t, J=7.6 Hz, 3H).
Example 60:
2- 35-dic anoeth |1'- 2-h drox eth |-44'-bi i eridin l ridin lthio -
Z-phenylacetamide
NC ON
HO/\/N NH2
To a mixture of 2-[(6-bromo-3,5-dicyanoethylpyridy|)su|fany|]phenyI-acetamide
esis described in example 6 step 1, 25 mg, 0.06 mmol) and 2-[4-(4-piperidyl)
piperidyl]ethanol dihydrochloride (20 mg, 0.07 mmol) in tetrahydrofuran (2 mL) was added
triethylamine (0.035 mL, 0.25 mmol). The reaction mixture was stirred for 90 hours. The
product mixture was diluted with EtOAc (20 mL), washed with water (3 x 20 mL), brine (25
mL), filtered through a hydrophobic frit and the solvent was removed under reduced
pressure. The residue was dissolved in DMSO and purified by preparative HPLC to furnish
-dicyano-4—ethyl[4-[1-(2-hydroxyethyl)piperidyl]piperidy|]pyridyl]sulfany|]-
yl-acetamide (10 mg, 30% yield) as a white powder. LCMS m/z = 531 [M—H]‘. 1H
NMR (300 MHz, DMSO-de) 6 ppm 8.22 (s, 1H), 7.92 (s, 1H), 7.57 - 7.46 (m, 2H), 7.44 -
7.28 (m, 4H), 5.53 (s, 1H), 4.62 (brd, J=11.6 Hz, 2H), 3.74 (br s, 4H), 3.53 (br t, J=6.1 Hz,
2H), 3.31 - 2.94 (m, 3H), 2.75 (q, J=7.3 Hz, 2H), 2.48 - 2.36 (m, 1H), 2.27 (brs, 1H), 2.07
(brt, J=11.0 Hz,2H), 1.80 (brd, J=11.5 , 1.67 (brd, J=12.2 Hz,2H), 1.41 H),
1.25 - 1.15 (m, 5H).
Example 61:
2- 35-Dic ano 38 SR -3 5-dimeth I i erazin leth | ridin Ithio
acetamide
NC CN
NAN /
N S
w m:
To a mixture of 2-[(6-bromo-3,5-dicyanoethylpyridyl)sulfanyl]phenyl-acetamide
(synthesis described in example 6 step 1, 30 mg, 0.07 mmol) and triethylamine (0.02 mL,
0.15 mmol) in tetrahydrofuran (2 mL) was added cis-2,6-dimethylpiperazinyl (9 mg, 0.08
mmol). The reaction mixture was allowed to stir for 1.5 hours. The product mixture was
diluted with EtOAc (20 mL), washed with water (3 x 20 mL), ted sodium chloride (25
mL), filtered through a hydrophobic frit and the solvent was removed under reduced
pressure. The resulting solid was triturated with diethyl ether and dried in vacuo at 50 °C to
give 2-[[3,5-dicyano[(3R,5S)-3,5-dimethylpiperazinyl]ethylpyridyl]sulfanyl]
phenyl-acetamide (27 mg, 83% yield), as a white solid. LCMS m/z = 433 [M—H]‘. 1H NMR
(300 MHz, DMSO-de) 6 ppm 7.94 (s, 1H), 7.58 - 7.46 (m, 2H), 7.44 - 7.31 (m, 4H), 5.50 (s,
1H), 4.46 (br d, J=12.4 Hz, 2H), 2.75 (q, J=7.4 Hz, 4H), 2.67 - 2.53 (m, 3H), 1.20 (t, J=7.8
Hz, 3H), 1.10 - 0.96 (m, 6H).
Example 62:
2- 6- 8-azabic clo 3.2.1 octan Imeth lamino -3 5-dic anoeth l ridin
Ithio hen lacetamide
Step 1: (1 S)—tert-butyl 3-(((benzyloxy)carbonyl)amino)
azabicyclo[3.2.1]octanecarboxylate
@HOJkN
(@1800
(1R,3r,58)-tert-butyl 3-aminoazabicyclo[3.2.1]octanecarboxylate (1 g, 4.42 mmol)
was dissolved in dichloromethane (15 mL) and triethylamine (1.23 mL, 8.84 mmol) was
added. The solution was cooled to 0 °C and benzyl chloroformate (0.662 mL, 4.64 mmol)
was added dropwise. The reaction was allowed to warm to room temperature overnight.
The solvent was evaporated and the remaining al purified by silica gel column
chromatography (10-75% ethyl acetate-hexane) to obtain ,5S)-tert-butyl 3-
(((benzyloxy)carbonyl)amino)-8—azabicyclo[3.2.1]octanecarboxylate (1.3 g, 82 %).
LCMS m/z = 383 [M+Na]*.
Step 2: (1 $)-tert-butyl enzyloxy)carbonyl)(methyl)amino)
azabicyclo[3.2.1]octanecarboxylate
OAOAT(@1800
(1 R,3r,58)-tert—butyl 3-(((benzyloxy)carbonyl)amino)azabicyclo[3.2.1]octane
carboxylate (700 mg, 1.94 mmol) was dissolved in tetrahydrofuran (15 mL) and NM-
dimethylformamide (5 mL) then sodium e (51.5 mg, 2.039 mmol) was added. The
solution was stirred 15 minutes. The effervescence stopped and methyl iodide (0.158 mL,
2.52 mmol) was added dropwise. The reaction was allowed to stir at 25 °C for 2 hours.
The solvents were evaporated and the crude dissolved in ethyl acetate, washed with water
and dried over sodium sulfate. The crude compound was purified by silica gel
chromatography (10-75% ethyl acetate-hexane) to give (1 R,3r,5S)-tert-butyl 3-
(((benzyloxy)carbonyl)(methyl)amino)azabicyclo[3.2.1]octanecarboxylate (600 mg,
83 %). LCMS m/z = 397 [M+Na]*.
Step 3: (1 R,3r,5S)-tert-butyl 3-(methylamino)azabicyclo[3.2.1]octane
ylate
HN($1Boc
(1 R,3r,SS)-tert-butyl 3-(((benzyloxy)carbonyl)(methy|)amino)azabicyclo[3.2.1]octane
carboxylate (350 mg, 0.935 mmol) was dissolved in ethanol (20 mL) and 10% Pd/C (5 mg)
was added and the reaction mixture exposed to hydrogen at 30 psi for3 hours. The mixture
was filtered and the filtrate concentrated to give (1R,3r,5S)-tert—butyl 3-(methylamino)
azabicyclo[3.2.1]octanecarboxylate (215 mg, 96 %). LCMS m/z = 241 [M+H]*.
Step 4: tert-butyl chIoro-3,5-dicyanoethy|pyridinyl)(methyl)amino)
azabicyclo[3.2.1]octanecarboxy|ate
NC CN
\ I
N CI
2,6-Dichloroethylpyridine-3,5-dicarbonitrile (synthesis described in example 3 step 2,
200 mg, 0.885 mmol) was dissolved in tetrahydrofuran (20 mL) and tert-butyl 3-
(methylamino)-8—azabicyclo[3.2.1]octanecarboxy|ate (213 mg, 0.885 mmol) was added
followed by ofdiisopropylethylamine (0.308 mL, 1.77 mmol). The solution was stirred for 4
hours at 40 °C. The reaction was concentrated, the residue taken up in water, and the
ble solid collected by filtration (135 mg of desired t). The filtrate was
concentrated to give a solid that was purified by silica gel column chromatography (20-75%
ethyl acetate-hexane) to afford another 115 mg of desired product. The two amounts were
combined to e tert-butyl chloro-3,5-dicyanoethylpyridinyl)(methy|)amino)-
8-azabicyclo[3.2.1]octanecarboxylate (250 mg, 66 %). LCMS m/z = 452 [M+Na]+.
Step 5: S-(2-Aminooxophenylethy|) ethanethioate
To a on of 2-chlorophenyl-acetamide (6 g, 35 mmol) in acetone (120 mL) was
added potassium thioacetate (4.08 g, 36 mmol) and the reaction was stirred and heated at
reflux under an here of nitrogen for2 hours. The mixture was cooled and the solvent
was removed under reduced pressure. The resulting solid was partitioned between water
(200 mL) and EtOAc (200 mL), filtered and the phases separated. The c phase was
washed with brine (200 mL), filtered through a hydrophobic frit and the solvent removed
under reduced pressure. The resulting solid was triturated with diethyl ether, filtered,
washed with minimal diethyl ether and air dried to afford S-(2-aminooxophenyl-
ethyl)ethanethioate (2.8 g, 38% yield) as a beige powder. LCMS m/z = 208.0 [M-H]‘.
Step 6: 2-((6-(8-azabicyclo[3.2.1]octanyl(methyl)amino)-3,5-dicyano
ethylpyridinyl)thio)pheny|acetamide
S-(2-aminooxophenylethyl) ethanethioate (synthesis described in example 3 step 5,
120 mg, 0.575 mmol) was dissolved in ethanol (10 mL) and NaBH4 (27.2 mg, 0.719 mmol)
was added. The solution was stirred for 6 minutes at 70 °C. The reaction was cooled and
a solution of tert-butyl 3-((6-chloro-3,5-dicyanoethylpyridinyl)(methyl)amino)—8-
azabicyclo[3.2.1]octanecarboxylate (206 mg, 0.479 mmol) in N,N-dimethylformamide
(15 mL) was added and the reaction mixture heated for 4 minutes at 70 °C. The reaction
e was concentrated under d pressure and the crude material purified by silica
gel column chromatography % ethyl acetate-hexane). The purified material was
dissolved in dichloromethane (5 mL) and trifluoroacetic acid (5 mL) and the reaction stirred
at roomtemperature for one hour. The on was concentrated under reduced pressure.
The remaining residue was dissolved in romethane and washed with ted
sodium bicarbonate solution. The organic layer was concentrated to provide 2-((6-(8-
azabicyclo[3.2.1]octanyl(methyl)amino)-3,5-dicyanoethylpyridin-2—yl)thio)
phenylacetamide (63 mg, 28%). LCMS m/z = 481 [M+H]+. 1H NMR (400 MHz, DMSO-da)
6 ppm 1.22 (t, J=7.58 Hz, 3 H) 1.57 (t, J=11.75 Hz, 2 H) 1.78 - 2.00 (m, 4 H) 2.18 - 2.37 (m,
2 H) 2.78 (q, J=7.58 Hz, 2 H) 3.18 (s, 4 H) 3.86 (br. s., 2 H) 5.00 (t, J=7.83 Hz, 1 H) 5.49
(s, 1 H) 7.34 - 7.48 (m, 3 H) 7.54 (d, J=7.07 Hz, 2 H) 7.88 (br. s.,1 H) 8.12 (s, 1 H).
Example 63:
phenylacetamide
Step 1: 2-Chlorocyclopropyl-G-(Z-(hydroxymethyl)morpholino)pyridine-3,5-
dicarbonitrile
(\N N/ c1
To a solution of 2,6-dichlorocyclopropylpyridine-3,5-dicarbonitrile (synthesis described
in example 3 step 2, 237 mg, 1 mmol) in N,N-dimethylformamide (10 mL) was added
morpholinylmethanol (117 mg, 1 mmol), followed by Eth (0.14 mL, 1 mmol). The
reaction was d at room temperature for 30 minutes, and then diluted with water (20
mL). The precipitated solid was ted by filtration and dried in an oven to afford 2-chloro-
4-cyclopropyl(2-(hydroxymethy|)morpholino)pyridine-3,5-dicarbonitrile (280 mg, 88%).
LCMS m/z = 319 [M+H]*.
Step 2: 5-Dicyanocyclopropyl(2-(hydroxymethyl)morpholino)pyridin
yl)thio)phenylacetamide
NC ON
{\N /
N s
0]) WW2O
A solution of 2-chlorocyclopropyl(2-(hydroxymethyl)morpho|ino)pyridine-3,5-
dicarbonitrile (280 mg, 0.88 mmol) and potassium thioacetate (121 mg, 1.06 mmol) in NM-
dimethylformamide (9 mL) was stirred at room temperature for 30 minutes, then 2-amino-
2-oxophenylethyl methanesulfonate (synthesis described in example 3 step 5, 242 mg,
1.06 mmol) and Et3N (0.25 mL, 1.76 mmol) were added. The reaction mixture was stirred
at room temperature overnight then diluted with water (20 mL). The itated solid was
collected by filtration and purified by silica gel column chromatography (MeOHzDCM 1:20)
to afford 2-((3,5-dicyanocyclopropyl(2-(hydroxymethyl)morpholino)pyridinyl)thi0)-
ylacetamide (102 mg, 26%). LCMS m/z = 450 [M+H]”. 1H NMR (400 MHz, CDCIs)
6 ppm 7.50 — 7.33 (m, 5H), 6.75 (d, J = 22.0 Hz, 1H), 5.91 (cl, J = 38.7 Hz, 1H), 5.31 (d, J
= 7.3 Hz, 1H), 4.73 (dd, J = 352,135 Hz, 1H), 4.45 (t, J = 14.5 Hz, 1H), 4.02 (d, J = 11.5
Hz, 1H), 3.77 — 3.56 (m, 4H), 3.52 - 3.42 (m, 1H), 3.07 — 2.95 (m, 1H), 2.19 (br s, 1H), 2.13
— 2.05 (m, 1H), 1.35 — 1.26 (m, 2H), 1.22 — 1.11 (m, 2H).
Example 64:
R 35-dic ano dimeth lamino eth | ridin lthio hen Iacetamide
2-[[3,5-Dicyano(dimethylamino)ethylpyridyl]sulfanyl]phenyl-acetamide
(synthesis described in example 3 step 6, 496 mg), was dissolved in 30 mg portions in 300
volumes of g methanol (9 mL) and resolved by chiral HPLC on a Lux-2 cellulose, 5
microns column (30 mm x250 mm) and eluted with 100% methanol (50 mL/min). Collected
a total of about 900 mL of product solution which was concentrated to dryness. The solid
was dried at 40 °C under high vacuum to a final, constant weight to afford (R)((3,5-
o(dimethylamino)ethylpyridiny|)thio)phenylacetamide (232 mg) as a
white solid. LCMS m/z = 366 [M+H]+. Chiral HPLC: >99.8% ee chiral purity. Optical
Rotation: -316 s , chloroform-d, 21 °C). 1H NMR (DMSO-de) 6 ppm 7.91 (s,
1H), 7.52 (d, J=7.1 Hz, 2H), 7.29-7.42 (m, 4H), 5.59 (s, 1H), 3.34 (s, J=7.8 Hz, 6H), 2.76
(q, J=7.4 Hz, 2H), 1.20 (t, J=7.6 Hz, 3H).
Example 64(a) alternative route
R 35-dic ano dimeth lamino eth | ridin lthio hen Iacetamide
To a solution of (S)aminooxo—1-pheny|ethyl 4-methylbenzenesulfonate esis
described in e 418 step 3, 65.7 mg, 0.215 mmol), 2-(dimethylamino)ethyl
mercaptopyridine-3,5-dicarbonitrile (synthesis described in example 92, step 3, 50 mg,
0.215 mmol) in N,N-dimethylformamide (1 mL) was added triethylamine (0.060 mL, 0.430
mmol). The reaction was stirred at room temperature for six hours. The mixture was
poured into H20 (5 mL), and stirred for 10 minutes, then filtered and washed with
additional H20 (5 mL), dried at the pump overnight to afford 67 mg of crude. The sample
was ed by flash chromatography (0-100% EtOAc in . The product fractions
1O were concentrated, and the residue was triturated with DCM and filtered to afford (R)
((3,5-dicyano(dimethylamino)ethylpyridinyl)thio)phenylacetamide (40 mg,
0.109 mmol, 51% yield) as a white solid. LCMS(ES) m/z = 388.0 [M+Na]+. 1H NMR
(DMSO—de) 6 ppm 7.93 (s, 1H), 7.46-7.56 (m, 2H), .44 (m, 4H), 5.59 (s, 1H), 3.32-
3.36 (m, 6H), 2.76 (q, J=7.4 Hz, 2H), 1.21 (t, J=7.5 Hz, 3H). Chiral HPLC indicated
99.5% ee.
Example 65
R 35-Dic anoeth lmor holino rid lsulfan l hen l-acetamide
Step 1: 2-Chloroethylmorpholinopyridine-3,5-dicarbonitrile
NC CN
(\N /
N Cl
To a solution of 2,6-dichloroethyl-pyridine-3,5-dicarbonitrile (synthesis described in
example 3 step 2, 1.0 g, 4.42 mmol) in tetrahydrofuran (25 mL) was added morpholine
(0.386 mL, 4.42 mmol) at room temperature. The e was stirred for 15 minutes then
an additional one equivalent of morpholine (0.386 mL, 4.42 mmol) was added. The mixture
was then stirred for 75 minutes before the addition of 0.5 equivalents more of morpholine
(0.19 mL, 2.21 mmol). After 30 s, the reaction mixture was filtered, the collected solid
WO 16727
washed with tetrahydrofuran (2 x 25 mL), and the filtrate concentrated under reduced
pressure. The resulting solid was dissolved in ethyl acetate (25 mL), ed through a
hydrophobic frit, dry loaded onto Si02, and purified by silica gel column chromatography
(0-30% ethyl acetate/hexane) to give 2-chloroethylmorpholino-pyridine-3,5-
dicarbonitrile (926 mg, 76%) as a white powder. LCMS m/z = 275 [M—H]‘.
Step 2: 2-((3,5-DicyanoethyImorpholinopyridinyl)thio)phenylacetamide
NC CN
(\N /
N s
0d We
Sodium dride (114 mg, 3.01 mmol) was added portionwise over 5 minutes to a
solution of S-(2-aminooxophenyl-ethyl)ethanethioate, (synthesis described in
example 3 step 5, 0.46 g, 2.2 mmol) in ethanol (20 mL) at 70 °C. The reaction mixture was
stirred at 70—80 °C for 15 minutes. The reaction was d from the heat source and 2-
chloroethylmorpholino-pyridine-3,5-dicarbonitrile (590 mg, 2.13 mmol) was added.
The ant mixture was heated at 80 °C for 15 minutes, allowed to cool to room
temperature, then further cooled with an ice/water bath. The solid that was present was
collected by filtration and washed with ice-cold ethanol (5 mL), cold s ethanol (50%
aqueous, 10 mL), water (2 x 15 mL), and dried in vacuo. The solid was then washed with
diethyl ether/hexane (1:1, 10 mL), hexane (10 mL), and dried in vacuo at 50 °C to afford
racemic 2-[(3,5-dicyano-4—ethylmorpholinopyridy|)sulfanyl]phenyl-acetamide (542
mg, 62%) as a white solid. LCMS m/z = 408 [M+H]“.
Step 3: (R)[(3,5-Dicyanoethylmorpholinopyridyl)sulfanyl]phenyl-
acetamide
Racemic 2-[(3,5-dicyanoethylmorpholinopyridyl)sulfanyl]phenyl-acetamide (232
mg), was dissolved in 20 mg portions in 400 volumes (8 mL) of boiling methanol and filtered.
WO 16727
The sample was resolved by chiral HPLC using a Chromega Chiral, 004, 5 microns column
(30 mm x250 mm) g with 100% methanol (42 mL/min). Collected a total of about 400
mL of product solution which was concentrated to near dryness to afford a white slurry.
The slurry was filtered, rinsed with a minimum amount of methanol and dried at 40 °C under
high vacuum to a final, constant weight to afford [(3,5-dicyanoethylmorpholino-
2-pyridyl)sulfany|]phenyl-acetamide (102 mg) as a white solid. LCMS m/z = 408 [M+H]".
99.2% ee chiral . Optical Rotation: —285 degrees (C = 0.20, DMSO-de, 23 °C). 1H
NMR de) 6 ppm 7.89 (s, 1H), 7.47-7.56 (m, 2H), 7.28-7.44 (m, 4H), 5.52 (s, 1H),
3.90 (t, J=4.7 Hz, 4H), 3.60-3.75 (m, 4H), 2.77 (q, J=7.6 Hz, 2H), 1.21 (t, J=7.6 Hz, 3H)
Example 66
N- 4- 35-Dic anoeth [ 4- rrolidin l i eridin I ridin
Step 1: 2-Ch|oroethyl(4-(pyrrolidiny|)piperidiny|)pyridine-3,5-
dicarbonitrile
A solution of 4-(pyrrolidinyl)piperidinyl (1.5 g, 9.72 mmol) in dichloromethane (30 mL)
was added to a mixture of 2,6-dichIoroethylpyridine-3,5-dicarbonitrile (synthesis
described in example 3 step 2, 2.198 g, 9.72 mmol) and triethylamine (1.355 mL, 9.72
mmol) in dichloromethane (30 mL) at 0 °C. The resultant e was warmed to 25 °C and
stirred for 12 hours. The reaction mixture was partitioned with water (30 mL) and the layers
separated. The organic layer was concentrated and the remaining residue purified by silica
gel column chromatography (petroleum ether:ethy| acetate 2:1) to give 2-chloroethyI
(4-(pyrrolidinyl)piperidinyl)pyridine-3,5-dicarbonitrile (3.6 g). LCMS m/z = 344 [M+H]*.
Step 2: 4-(Aminomethyl)phenyl)methanol
K|£:\/NHZ
To a cooled suspension of lithium aluminum hydride (5.79 g, 153 mmol) in ydrofuran
(50 mL) at 0 °C was added a solution of 4-formylbenzonitrile (5 g, 38.1 mmol) in
tetrahydrofuran (50 mL). The resultant mixture was stirred at room temperature overnight
then recooled to 0 °C and treated with a solution of aqueous sodium ide solution (5
N, 32.1 mL). The resultant mixture was then filtrated and the e concentrated in vacuo
to e (4-(aminomethyl)phenyl)methanol (4.5 g, 73 %) as a white solid. LCMS m/z =
138.1 [M+H]+.
Step 3: N-(4-(Hydroxymethyl)benzyl)acetamide
A solution of (4-(aminomethyl)phenyl)methanol (0.96 g, 7.00 mmol) and acetic anhydride
(7.14 g, 70.0 mmol) in acetic acid (20 mL) was stirred in a sealed tube at 1 10 °C for6 hours.
After cooling to room temperature, the on was concentrated in vacuo. The residue
was diluted with methanol (15 mL), treated with lithium hydroxide (0.838 g, 35.0 mmol), and
stirred at room temperature overnight. The reaction was concentrated and the remaining
material partitioned between ethyl acetate (50 mL) and water (25 mL). The layers were
separated and the organic layer washed with saturated sodium chloride solution (25 mL),
dried over sodium e, and concentrated in vacuo to give the crude product. The crude
product was purified by silica gel column chromatography oromethane:methanol 15:1)
to give N-(4-(hydroxymethyl)benzyl)acetamide (0.23 g, 17%). 1H NMR (400 MHz, DMSO-
de) 6 ppm 8.32 (br. s, 1H), 7.23 (dd, J = 24.5, 8.0 Hz, 4H), 5.14 (t, J = 5.7 Hz, 1H), 4.47 (d,
J = 5.6 Hz, 2H), 4.22 (d, J = 5.9 Hz, 2H), 1.86 (s, 3H).
Step 4: N-(4-((3,5-Dicyanoethyl(4-(pyrrolidinyl)piperidinyl)pyridin
ylthio)methyl)benzyl)acetamide trifluoroacetate
2017/053511
To a on of N-(4-(hydroxymethyl)benzyl)acetamide (180 mg, 1.004 mmol) and
ylamine (305 mg, 3.01 mmol) in tetrahydrofuran (8 mL) was added methanesulfonyl
chloride (173 mg, 1.507 mmol) at 0 °C. The resultant mixture was stirred at 0 °C for 0.5
hour and at room temperature for an additional 1 hour. The reaction was partitioned
between ethyl acetate (50 mL) and water (25 mL). The layers were ted and the
organic layer washed with saturated sodium chloride solution (25 mL), dried over sodium
sulfate, and concentrated in vacuo to give crude 4-(acetamidomethyl)benzyl
methanesulfonate (0.27 g) as a brown solid. To a solution of 2-chloroethyl(4-
(pyrrolidinyl)piperidinyl)pyridine-3,5-dicarbonitrile (0.361 g, 1.049 mmol) in N,N-
ylformamide (10 mL) was added potassium thioacetate (0.180 g, 1.574 mmol). The
reaction mixture was stirred at room temperature for two hours and then was treated with
ium carbonate (0.145 g, 1.049 mmol). After stirring at room temperature for1 hour,
crude 4-(acetamidomethyl)benzyl methanesulfonate (0.27 g, 1.049 mmol) was added and
the mixture was stirred at room temperature ght. The reaction was concentrated in
vacuo and the residue partitioned between ethyl acetate (50 mL) and water (25 mL). The
layers were separated. The organic layer was washed with saturated sodium chloride
solution (25 mL), dried over sodium sulfate, and concentrated in vacuo to give the crude
product as a brown solid. The crude product was purified by prep-HPLC to provide N-(4-
(((3,5-dicyano-4—ethyl(4-(pyrrolidinyl)piperidinyl)pyridin
yl)thio)methyl)benzyl)acetamide trifluoroacetate (120 mg). LCMS m/z = 503 [M+H]*. 1H
NMR (400 MHz, DMSO-de) 6 ppm 1.22 (t, J = 7.6 Hz, 3H), 1.66 (dd, J = 212,122 Hz, 2H),
1.87 (s, 5H), 2.02 (s, 2H), 2.21 (d, J = 10.7 Hz, 2H), 2.79 (q, J = 7.5 Hz, 2H), 3.25 - 3.04
(m, 4H), 3.60-3.40 (m, 3H), 4.22 (d, J = 5.9 Hz, 2H), 4.50 (s, 2H), 4.61 (d, J = 13.6 Hz, 2H),
7.22 (d, J = 8.0 Hz, 2H), 7.37 (d, J = 8.0 Hz, 2H), 8.37 (t, J = 5.7 Hz, 1H), 9.92 (s, 1H).
Example 67
2- 35-dic anoeth | 5-meth |diaze an l ridin lsulfan |
phenylacetamide
WO 16727 2017/053511
NC CN
fN / N s
To a solution of 2-[(6-bromo-3,5-dicyano—4-ethyIpyridy|)sulfany|]phenyl-acetamide
(synthesis described in example 6 step 1, 30 mg, 0.07 mmol) and triethylamine (0.02 mL,
0.16 mmol) in tetrahydrofuran (2 mL) was added 5-methyl—[1,4]diazepene (9 mg, 0.08
mmol). The mixture was allowed to stir at ambient temperature for 17 hours. The product
mixture was diluted water (7.5 mL), filtered, washed with water (2 x 10 mL) and dried in
vacuo at 50 °C to afford 2-[[3,5-dicyanoethyl(5-methyl-1,4-diazepanyl)
pyridyl]sulfanyl]phenyl-acetamide as a complex mix ofdiastereomers (24 mg, 74% yield)
as an off-white solid. 1H NMR (300 MHz, DMSO-ds) 6 ppm 7.91 (br s, 1H), 7.54 - 7.44 (m,
2H), 7.44 - 7.28 (m, 4H), 5.52 (d, J=2.3 Hz, 1H), 4.19 - 4.03 (m, 1H), 4.01 - 3.85 (m, 1H),
3.84 - 3.58 (m, 2H), 3.22 - 3.03 (m, 1H), 2.89 (br d, J=10.5 Hz, 1H), 2.84 - 2.69 (m, 3H),
1.89 (br s, 1H), 1.45 (br d, J=13.7 Hz, 1H), 1.36 (s, 1H), 1.28 - 1.09 (m, 3H), 1.09 - 0.87 (m,
3H). LCMS m/z = 433 [M—H]‘.
Example 68
2- 4- Aminometh lbenz Ithio eth | 4- rrolidin | i eridin l ridine-
3 5-dicarbonitrile 2 2 2-trifluoroacetate
Step 1: 2-chloroethyI(4-(pyrrolidiny|)piperidinyl)pyridine-3,5-dicarbonitrile
A solution of 4-(pyrrolidiny|)piperidine (1.5 g, 9.72 mmol) in romethane (30 mL)
was added to a mixture of 2,6-dichIoroethylpyridine-3,5-dicarbonitrile (synthesis
described in example 3, step 2, 2.19 g, 9.72 mmol) and triethylamine (1.355 mL, 9.72 mmol)
in dichloromethane (30 mL) at 0 °C. The mixture was warmed to 25 °C and stirred for 12
2017/053511
hours. The mixture was washed with water (30 mL), the organic phase was concentrated
and purified by column chromatography (PE:EA = 2:1) to give 2—chloro-4—ethyl(4-
(pyrrolidinyl)piperidinyl)pyridine-3,5-dicarbonitrile (3.6 g). LCMS m/z = 344.1 [M+H]*.
Step 2: (4-(Aminomethyl)pheny|)methanol
To a cooled suspension of LiAlH4 (5.79 g, 153 mmol) in tetrahydrofuran (50 mL) was added
a solution of 4-formylbenzonitrile (5 g, 38.1 mmol) in ydrofuran (50 mL) at 0 °C. The
resultant mixture was stirred at room temperature overnight then cooled and treated with a
solution of s sodium hydroxide solution (5 N, 32.1 mL) at 0 °C. The resultant mixture
was filtrated and concentrated under reduced pressure to give (4-
(aminomethyl)phenyl)methanol (4.5 g, 27.9 mmol, 73% yield) as a gray solid. LCMS m/z =
138.1 [M+H]+.
Step 3: utyl 4-(hydroxymethyl)benzylcarbamate
‘Boc
The mixture of (4-(aminomethyl)phenyl)methanol (1 g, 7.29 mmol) and di-tert-butyl
dicarbonate (1.59 g, 7.29 mmol) in dichloromethane (30 mL) was stirred at room
temperature overnight then concentrated under d pressure and the crude product
was added to a silica gel column and was eluted with dichloromethane:ethyl acetate (1:1)
to give tert-butyl 4-(hydroxymethyl)benzylcarbamate (0.8 g, 2.28 mmol, 31% yield) as a
white solid. 1H NMR (400 MHz, DMSO-de) 6 ppm 7.37 (s, 1H), 7.22 (dd, J = 27.8, 8.0 Hz,
4H), 5.13 (t, J = 5.7 Hz, 1H), 4.46 (d, J = 5.7 Hz, 2H), 4.10 (d, J = 6.1 Hz, 2H), 1.36 (s, 9H).
Step 4: tert-Butyl 4-((3,5-dicyanoethyI(4-(pyrrolidiny|)piperidinyl)pyridin
ylthio)methyl)benzylcarbamate
Q 2\ U)
‘Boc
To a solution of utyl 4-(hydroxymethyl)benzylcarbamate (350 mg, 1.47 mmol) and
triethylamine (448 mg, 4.42 mmol) in tetrahydrofuran (10 mL) was added methanesulfonyl
chloride (253 mg, 2.212 mmol) at 0 °C. The ant mixture was stirred at 0 °C for 0.5
hourand at room temperature for1 hourthen diluted with ethyl acetate (50 mL). The organic
phase was washed with water (25 mL) and saturated brine (25 mL), dried over sodium
sulfate and evaporated in vacuo to afford crude 4-(((tert-
butoxycarbonyl)amino)methyl)benzyl methanesulfonate (500 mg) as a brown solid. To a
solution of 2-chloroethyl(4-(pyrrolidinyl)piperidiny|)pyridine-3,5-dicarbonitrile
(545 mg) in N,N-dimethy|formamide (15 mL) was added potassium thioate (272 mg,
2.37 mmol). The mixture was stirred at room temperature for 2 hours then treated with
potassium ate (438 mg, 3.17 mmol). The resultant mixture was stirred at room
temperature for 1 hour then treated with the brown solid of crude 4-(((tert-
butoxycarbonyl)amino)methyl)benzyl methanesulfonate (500 mg). The mixture was stirred
at room temperature overnight then concentrated under reduced pressure. The residue
was diluted with ethyl acetate (100 mL). The organic phase was washed with water (50 mL)
and saturated brine (50 mL), dried over sodium sulfate and evaporated in vacuo to give
crude tert-butyl 4-((3,5-dicyanoethyl(4-(pyrroIidinyl)piperidinyl)pyridin
ylthio)methyl)benzylcarbamate (0.8 g) as a brown solid, which was used in next step
without further purification. LCMS m/z = 561.2 [M+H]+.
Step 6: 2-((4-(Aminomethyl)benzyl)thio)ethyl(4-(pyrro|idiny|)piperidin
yl)pyridine-3,5-dicarbonitrile, Trifluoroacetic acid salt
To a solution of crude utyl 4-(((3,5-dicyanoethyl(4-(pyrrolidinyl)piperidin
yl)pyridin- 2-yl)thio)methyl)benzylcarbamate (0.78 g) in dichloromethane (20 mL) was
added 2,2,2-trifluoroacetic acid (1.58 g, 13.9 mmol) at room temperature. The ant
mixture was stirred at room ature overnight, then trated under reduced
re and the crude product was purified by prep-HPLC to give 2-((4-
(aminomethyl)benzyl)thio)ethy|(4-(pyrrolidinyl)piperidinyl)pyridine-3,5-
dicarbonitrile, trifluoroacetic acid salt (150 mg, 0.261 mmol) as a white solid. LCMS m/z =
460.7 [M+H]". 1H NMR (400 MHz, DMSO) 6 ppm 10.30 (s, 1H), 8.28 (s, 2H), 7.45 (q, J =
NC CN
TlH 0 k
N NJkO
NC CN
\ 0 |
0 //\N N s
”Q NH2
NC\CN
H2NNS
N\\ \//N
CI N S
NC ON
Homav N s
O /
/ NH2
N\ NH2
/ 0
W0 16727
N N
(\N /
J N N \
/ |
/ NH2
/ NH2
N\ NH2
/ o
NC ON
N N Cl
BocHN
NC CN
//\N \
N 5
”NJ NH2
ethy|)thio)-3,5-dicyanoethylpyridinyl)azetidiny| 2-((tert-
butoxycarbony|)amino)methy|butanoate (250 mg) as a brown solid. LCMS m/z = 593.4
[M+H]+.
N N
(AN /
/ \S/p
NC CN
N /
W0 16727
NC CN
(\N \ N s
/N\/ O
HZN NH2
NC ON
o N N s
LN H2N
i H
\OH O
NC CN
W0 16727
1078
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Claims (40)
1. A method oftreating a disease selected from: cancer, pre-cancerous syndromes, beta haemoglobinopathy disorders, sickle cell disease, sickle cell anemia, and beta thalassemia, in a mammal in need thereof, which comprises administering to such mammal a therapeutically effective amount of a compound of Formula (|br): R1br 1b 2b X X ’R3br R5” m ybrfi 2 0 (lbr) wherein: X1” and X2” are independently selected from: hydrogen, -CN, fluoro, chloro, bromo, iodo, C1—6alky|, -OC1-ealkyl, -OR? cycloalkyl, cycloalkyl substituted from 1 to 4 times by Rd, heterocycloalkyl, heterocycloalkyl substituted from 1 to 4 times by Rd, -SH, and —sR% Yb’ is selected from: S, NH, NRZ, O, S(O), and S(O)2; R1” is selected from: -NH; -NHR? WO 2017/216727 R3br R5br 1193 -NRbR9 -CN, fluoro, chloro, bromo, iodo, C1—6a|ky|, -OC1—6a|ky|, -OR? cycloalkyl, cycloalkyl substituted from 1 to 4 times by Rd, heterocycloalkyl, heterocycloalkyl substituted from 1 to 4 times by Rd, aryl, aryl substituted from 1 to 4 times by Rd, heteroaryl, heteroaryl substituted from 1 to 4 times by Rd, -SH, and -SR3 is selected from: hydrogen, C1-Balkyl, heterocycloalkyl, heterocycloalkyl substituted from 1 to 4 times by Rd, aryl, aryl substituted from 1 to 4 times by Rd, heteroaryl, and heteroaryl substituted from 1 to 4 times by Rd; and is selected from: -NHZ -NHR? -NRbR9 30". PCT/IB2017/053511 WO 2017/216727 where: PCT/IB2017/053511 1194 aryl substituted from 1 to 4 times by Rd, -C1—6a|ky|, -OC1—6a|kyl, -ORe, -Oaryl, -Oaryl substituted from 1 to 4 times by Rd, -Oheteroaryl, -Oheteroaryl substituted from 1 to 4 times by Rd, -SH, and -SRa; each R3 is independently selected from C1—6alkyl, aryl, aryl substituted from 1 to 4 times by Rd, heteroaryl, heteroaryl substituted from 1 to 4 times by Rd cycloalkyl, cycloalkyl substituted from 1 to 4 times by Rd, heterocycloalkyl, and heterocycloalkyl substituted from 1 to 4 times by Rd; Rb and R0 are independently selected from: C1—6alkyl, aryl, aryl substituted from 1 to 4 times by Rd, heteroaryl, heteroaryl substituted from 1 to 4 times by Rd; cycloalkyl, cycloalkyl substituted from 1 to 4 times by Rd, heterocycloalkyl, and heterocycloalkyl substituted from 1 to 4 times by Rd, or Rb and RC are taken together with the nitrogen to which they are attached, and optionally from 1 to 3 additional heteroatoms independently selected from O, N, and S,, to form a heterocycloalkyl, WO 2017/216727 PCT/IB2017/053511 1195 which is optionally substituted with from 1 to 5 substituents independently selected from: fluoro, chloro, bromo, iodo, C1—6a|ky|, -ORe, aryl, aryl substituted from 1 to 4 times by Rd, cycloalkyl, cycloalkyl substituted from 1 to 4 times by Rd, heterocycloalkyl, and heterocycloalkyl substituted from 1 to 4 times by Rd, C1-4a|koxy, —-CN, OX0, -OH, -COOH, -NO2, -NH2, -N(H)C1—5a|ky|, -N(H)Re, -N(C1-5a|ky|)2, -NReRe, -N(Re)C1-5alky|, -ONHC(NH)NH2, -Oheterocycloalkyl, -NHcyc|oa|ky|, -N(C1—5a|ky|)cyc|oa|ky|, WO 2017/216727 PCT/IB2017/053511 1196 -NHheterocycloalkyl, -N(C1-5alkyl)heterocycloalkyl, -S(O)2C1—4aIky|, -SO2NH2 -S(O)2phenyl, benzoyL 2-methylcyclopropyl, imidazolyl, (methoxypyridinylmethyl)amino, (methylcyclopropylmethy|)amino, (f|uoropheny|methyl)amino, (methyloxetanylmethyl)amino, and (methylcyclobutylmethy|)amino; each Rd is independently selected from: fluoro, chloro, bromo, iodo, C1—6a|ky|, heteroaryl, heteroaryl substituted from 1 to 4 times by RX, where RX is selected from aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C1—6a|ky|, and C1—6a|ky| substituted with from 1 to 6 substituents independently selected from: fluoro, oxo, -OH, -COOH, -NH2, and -CN, cycloalkyl, cycloalkyl substituted from 1 to 4 times by RX, where RX is selected from aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C1—6a|ky|, and C1—6a|ky| substituted with from 1 to 6 substituents independently selected from: fluoro, oxo, -OH, -COOH, -NH2, and -CN, heterocycloalkyl, WO 2017/216727 PCT/IB2017/053511 1197 heterocycloalkyl substituted from 1 to 4 times by RX, where RX is selected from aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C1-6a|ky|, and C1_6a|ky| substituted with from 1 to 6 substituents independently selected from: fluoro, oxo, -OH, -COOH, -NH2, and -CN, aryl, aryl substituted from 1 to 4 times by RX, where RX is selected from aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C1-6a|ky|, and C1—6a|ky| substituted with from 1 to 6 substituents independently selected from: fluoro, oxo, -OH, -COOH, -NH2, and -CN, C1-4a|koxy, C1-4a|koxy substituted from 1 to 4 times by fluoro, -Oaryl, -Oaryl substituted from 1 to 4 times by RX, where RX is selected from aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C1-6a|kyl, and C1-6a|ky| substituted with from 1 to 6 substituents independently selected from: fluoro, oxo, -OH, -COOH, -NH2, and -CN, -ORe, -C(O)H. -C(O)RZZ, -C(O)ary|, -C(O)aryl substituted from 1 to 4 times by R22, -C(O)heteroary|, -C(O)heteroary| substituted from 1 to 4 times by R22, -OC(O)H, -CO(O)RZZ, -OC(O)ary|, -CO(O)ary| substituted from 1 to 4 times by R22, -OC(O)heteroary|, -OC(O)heteroary| substituted from 1 to 4 times by R22, -SRX, where RX is selected from aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C1-6a|ky|, and C1_6a|ky| substituted with from 1 to 6 substituents independently selected from: fluoro, oxo, -OH, -COOH, -NH2, and -CN, -S(O)H, WO 2017/216727 PCT/IB2017/053511 1198 -S(O)RX, where RX is selected from aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C1-6a|ky|, and C1_6a|ky| substituted with from 1 to 6 substituents independently selected from: fluoro, oxo, -OH, -COOH, -NH2, and -CN, -S(O)2H. -S(O)2RX, where RX is selected from aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C1-6alky|, and C1_6a|ky| substituted with from 1 to 6 substituents independently selected from: fluoro, oxo, -OH, -COOH, -NH2, and -CN, -S(O)2NH2, -S(O)2NHRX, where RX is selected from aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C1-6alky|, and C1_6a|ky| substituted with from 1 to 6 substituents independently selected from: fluoro, oxo, -OH, -COOH, -NH2, and -CN, -S(O)2NRX1 RX2, where RX1 and RX2 are each independently selected from aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C1-6a|ky|, and C1-6a|ky| substituted with from 1 to 6 substituents independently selected from: fluoro, oxo, -OH, -COOH, -NH2, and -CN, -P(O)(CH3)2, -NHS(O)2H, -NHS(O)2RX, where RX is selected from aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C1-6a|kyl, and C1-6a|ky| substituted with from 1 to 6 substituents independently selected from: fluoro, oxo, -OH, -COOH, -NH2, and -CN, -NHC(O)H, -NHC(O)RX, where RX is selected from aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C1-6a|ky|, and C1-6a|ky| substituted with from 1 to 6 substituents independently selected from: fluoro, oxo, -OH, -COOH, -NH2, and -CN, -C(O)NH2, -C(O)NHRX, WO 2017/216727 PCT/IB2017/053511 1199 where RX is selected from aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C1-6alky|, and C1-6alkyl substituted with from 1 to 6 substituents independently selected from: fluoro, oxo, -OH, -COOH, -NH2, and -CN, -C(O)NRX1RX2, where RX1 and RX2 are each independently selected from aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C1-ealkyl, and C1-6alkyl substituted with from 1 to 6 substituents independently selected from: fluoro, oxo, -OH, -COOH, -NH2, and —-CN, -C(O)OH, -C(O)ORX, -NH2, -NHRX -NRX1 R , -NH2, -CN, where RX is selected from aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C1-6alkyl, and C1-6alkyl substituted with from 1 to 6 substituents independently selected from: fluoro, oxo, -OH, -COOH, -NH2, and -CN, where RX is selected from aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C1-6alky|, and C1-6a|kyl substituted with from 1 to 6 substituents independently selected from: fluoro, oxo, -OH, -COOH, -NH2, and -CN, where RX1 and RX2 are each independently selected from aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C1-6alky|, and C1-6alkyl substituted with from 1 to 6 substituents independently selected from: fluoro, oxo, -OH, -COOH, -NH2, and -CN, -NHC(O)NH2, -NHC(O)NHRX, where RX is selected from aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C1-6alky|, and C1-6a|kyl substituted with from 1 to 6 substituents independently selected from: fluoro, oxo, -OH, -COOH, -NH2, and -CN, WO 2017/216727 PCT/IB2017/053511 1200 -NHC(O)NRX1RX2, where RX1 and RX2 are each independently selected from aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C1-6alkyl, and C1-6a|ky| substituted with from 1 to 6 substituents independently selected from: fluoro, oxo, -OH, -COOH, -NH2, and -CN, each Re is independently selected from: C1-6alkyl substituted with from 1 to 9 substitutents independently selected from: fluoro, chloro, bromo, iodo, -OC1—6alkyl, -OC1-6alkyl substituted with from 1 to 6 substituents independently selected from: fluoro, oxo, -OH, -COOH, -NH2, and -CN, -OC(O)C1-6a|kyl, -OC(O)C1-6alkyl substituted with from 1 to 6 substituents independently selected from: fluoro, oxo, -OH, -COOH, -NH2, and -CN, -ONHC(NH)NH2. -OP(O)(OH)2, -SH, -SRX, where RX is selected from aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C1-6alky|, and C1-5a|kyl substituted with from 1 to 6 substituents independently selected from: fluoro, oxo, -OH, -COOH, -NH2, and -CN, -S(O)H, -S(O)RX, where RX is selected from aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C1-6alkyl, and C1-6a|ky| substituted with from 1 to 6 substituents independently selected from: fluoro, oxo, -OH, -COOH, -NH2, and -CN, -S(0)2H, -S(O)2RX, WO 2017/216727 -NH2, PCT/IB2017/053511 1201 where RX is selected from aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C1-6a|ky|, and C1-6alky| substituted with from 1 to 6 substituents independently selected from: fluoro, oxo, -OH, -COOH, -NH2, and —CN, -NHRXX, where RXX is selected from aryl, heteroaryl, cycloalkyl, cycloalkyl substituted with C1-4a|koxy, C1-4a|koxy substituted with from 1 to 6 substituents independently selected from: fluoro, triazolyl, cyc|opropy|,oxo, -ORXV, -COOH, —CN, and -NRXVRXZ, where RXV and RXZ are Independently selected from: hydrogen, aryl, C1-5a|kyl heterocyloalkyl, C1-6alkyl, and C1-6a|ky| substituted with from 1 to 6 substituents independently selected from: fluoro, oxo, -ORXV, -COOH, —CN, and -NRXVRXZ, where RXV and R” are Independently selected from: hydrogen, aryl, C1-5a|kyl and C1-5a|ky| substituted with from 1 to 4 substituents independently selected from: fluoro, triazolyl, cyc|opropy|,oxo, -OH, -OC1-5a|ky|, -OC1-5a|ky| substituted from 1 to 6 times by fluoro and -COOH, _NRx1Rx2’ COOH, where RX1 and RX2 are each independently selected from aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C1-4alkoxy, C1-6a|ky|, and C1-6a|ky| substituted with from 1 to 6 substituents independently selected from: fluoro, C1-4alkoxy, triazolyl, cyclopropyl, oxo, -OH, - -NH2, and —CN, guanidino, -C(O)OH, -C(O)ORX, where RX is selected from aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C1-6alky|, and C1-6alky| substituted with from 1 to 6 substituents WO 2017/216727 PCT/IB2017/053511 1202 independently selected from: fluoro, oxo, -OH, -COOH, -NH2, and —CN, -C(O)NH2, -C(O)NHRX, where RX is selected from aryl, heteroaryl, -OH, C1-4a|koxy, cycloalkyl, cycloalkyl substituted with HO-(C1-4alkyl)-, heterocyloalkyl, heterocyloalkyl substituted with HO-(C1-4a|kyl)-, C1—6alkyl, and C1—6alkyl substituted with from 1 to 6 substituents independently selected from: fluoro, oxo, -OH, -COOH, heteroaryl, -NH2, and —-CN, -C(O)NRX1RX2, aryl, where RX1 and RX2 are each independently selected from aryl, heteroaryl, cycloalkyl, cycloalkyl substituted with HO-(C1—4a|ky|)-, heterocyloalkyl, C1—6alkyl, and C1—6alkyl substituted with from 1 to 6 substituents independently selected from: fluoro, oxo, -OH, -COOH, -NH2, and —CN, or RX1 and RX2 taken together with the nitrogen to which they are attached, and optionally from 1 to 3 additional heteroatoms independently selected from O, N, and S, to form a heterocycloalkyl, which is optionally substituted with from 1 to 5 substituents independently selected from fluoro, oxo, -OH, HO- (C1—4a|ky|)-, -COOH, -NH2, and —CN, aryl substituted from 1 to 4 times by RX, -Oaryl, where RX is selected from fluoro, chloro, bromo, iodo, aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C1-5a|kyl, and C1—6alkyl substituted with from 1 to 6 substituents independently selected from: fluoro, oxo, -OH, -COOH, -NH2, -N(CH3)2, -NHC(O)C1-4a|kyI, and — -Oaryl substituted from 1 to 4 times by RX, where RX is selected from aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C1—6alkyl, and C1—6alkyl substituted with from 1 to 6 substituents WO 2017/216727 PCT/IB2017/053511 1203 independently selected from: fluoro, oxo, -OH, -COOH, -NH2, -N(CH3)2, and -CN, heteroaryl, heteroaryl substituted from 1 to 4 times by RX, where Rx is selected from aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C1-4alkoxy, C1-6alkyl, and C1-6a|ky| substituted with from 1 to 6 substituents independently selected from: fluoro, oxo, -OH, -COOH, -NH2, and —CN, -Oheteroaryl, -Oheteroaryl substituted from 1 to 4 times by RX, where RX is selected from aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C1-6alkyl, and C1-6alkyl substituted with from 1 to 6 substituents independently selected from: fluoro, oxo, -OH, -COOH, -NH2, -N(CH3)2, and -CN, cycloalkyl, cycloalkyl substituted from 1 to 4 times by RX, where RX is selected from aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C1—6a|kyl, and C1-6alkyl substituted with from 1 to 6 substituents independently selected from: fluoro, oxo, -OH, -COOH, -NH2, -N(CH3)2, and -CN, heterocycloalkyl, heterocycloalkyl substituted from 1 to 4 times by RX, where RX is selected from oxo, -OH, -N(C1-4alkyl)2, aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C1-6alkyl, and C1-6a|ky| substituted with from 1 to 6 substituents independently selected from: fluoro, oxo, -OH, -COOH, -NH2, -N(CH3)2, and -CN, -S(O)2NH2, -S(O)2NHRX, where RX is selected from aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C1-6alkyl, and C1-6alkyl substituted with from 1 to 6 substituents independently selected from: fluoro, oxo, -OH, -COOH, -NH2, and —-CN, -S(O)2NRX1RX2, WO 2017/216727 PCT/IB2017/053511 1204 where RX1 and RX2 are each independently selected from aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C1—6a|kyl, and C1-6a|ky| substituted with from 1 to 6 Substituents independently selected from: fluoro, oxo, -OH, -COOH, -NH2, and —CN, -NHS(O)2H, -NHS(O)2RX, where RX is selected from aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C1—6a|kyl, and C1-6a|kyl substituted with from 1 to 6 substituents independently selected from: fluoro, oxo, -OH, -COOH, -NH2, and —CN, -OC(O)NH2, -NHC(O)RX, where RX is selected from aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C1-6alkyl, and C1-6a|ky| substituted with from 1 to 6 substituents independently selected from: fluoro, oxo, -OH, -COOH, -NH2, and —CN, -NHC(O)NHRXp, where Rxp is selected from heteroaryl, cycloalkyl, heterocyloalkyl, and C1-6a|kyl substituted with from 1 to 4 substituents independently selected from: -COOH, -NH2, and —-CN, -NHC(O)NRX3RX4, where RX3 and RX4 are each independently selected from heteroaryl, cycloalkyl, heterocyloalkyl, and C1-6alkyl substituted with from 1 to 6 Substituents independently selected from: -COOH, -NH2, and —-CN, -NHC(O)C(O)NH2, -N02, and -CN; and R2 is selected from C1—6alky|, WO 2017/216727 PCT/IB2017/053511 1205 cycloalkyl, cycloalkyl substituted from 1 to 4 times by Rd, heterocycloalkyl, and heterocycloalkyl substituted from 1 to 4 times by Rd; R22 is selected from C1-6alky|, and provided that: are not both hydrogen; or a pharmaceutically acceptable salt or prodrug thereof.
2. A method oftreating a disease selected from: cancer, pre-cancerous syndromes, beta haemoglobinopathy disorders, sickle cell disease, sickle cell anemia, and beta thalassemia, in a mammal in need thereof, which comprises administering to such mammal a therapeutically effective amount of a compound of Formula (|Vbbr): R41bbr X41 X42bbr R43bbr R44£,)kl)\lr N/ Y4bbr/‘wTNH2 R45bbr 0 lVbb ( r) wherein: X41bb' and X42bb' are independently selected from: --CN, methyl, fluoro, chloro, bromo and iodo; Y4bb' is selected from: S and NH; R41bb' is selected from: C1—6aIky|, C1-6a|ky| substituted with from 1 to 9 substituents independently selected from: fluoro, chloro, bromo, iodo, oxo, C1-4alky|oxy, -OH, -COOH, -NH2 WO 2017/216727 PCT/IB2017/053511 1206 -N(H)C1—4a|kyl, -N(C1—4a|ky|)2 and -CN, C1-4a|ky|oxy, C1-4a|ky|oxy substituted from 1 to 4 times by fluoro, -N(H)C1-4a|ky|, -N(C1—4a|ky|)2, -SC1—4a|ky|, aryl, aryl substituted with from 1 to 4 substituents independently selected from: fluoro, chloro, bromo, iodo, C1—6alky|, C1-6a|ky| substituted with from 1 to 9 substituents independently selected from: fluoro, chloro, bromo, iodo, oxo, -OH, -NH2 and -CN, C1 -4a|koxy, -NO2, and -NH2, heteroaryl, heteroaryl substituted with from 1 to 4 substituents independently selected from: fluoro, chloro, bromo, iodo, WO 2017/216727 PCT/IB2017/053511 1207 C1 -6aIky|, C1-6a|ky| substituted with from 1 to 9 substituents independently selected from: fluoro, chloro, bromo, iodo, oxo, -OH, -NH2 and -CN, C1 —4a|koxy, -NO2, and -NH2, cycloalkyl, cycloalkyl substituted with from 1 to 4 substituents independently selected from: fluoro, chloro, bromo, iodo, C1—6aIky|, C1-6a|kyl substituted with from 1 to 9 substituents independently selected from: fluoro, chloro, bromo, iodo, oxo, -OH, -NH2 and -CN, C1 -4a|koxy, -NO2, and -NH2; R43bb' is selected from: C1—4aIkyI, phenyL WO 2017/216727 PCT/IB2017/053511 1208 phenyl substituted with 1 or 2 substituents independently selected from: fluoro, -CH3, -CF3, chloro, -C(O)phenyl, pyrrolidinyl, -P(O)(CH3)2, -C(O)NH2, -S(O)2NHCH3, -OCH2CH2N(CH3)2 and -CH2C(O)NH2, thienyl, piperidinyl, pyridine, and pyridine substituted with 1 or 2 substituents independently selected from: fluoro, -CH3, -CF3, and -OCH3; R44bb' and R45bb' are independently selected from: hydrogen, C1—6a|ky|, C1-6alkyl substituted with from 1 to 9 substituents independently selected from: phenyl, morpholino, triazolyl, imidazolyl, pyrrolidinyl, -OC(O)NH2, -OCH2CH2NH2, -ONHC(NH2)NH2, -NHCH2C(CH3)3, -NOCH3, -NHOH, -NHCH2CH2F, -N(CH3)CH2CH2OCH3, -N(CH2CH3)2, -NCH(CH2OH)2. -N(CH2CH2OH)2, -NHCH2CH2OH, -NHCH2CH2NH2, -N(CH3)C(CH3)2CH2OH, -NHCH2CH3, -NHCH2CH2OCH3, -N(CH3)CH2CH2OH, -NHC(O)C(O)NH2, -N(CH3)CH2CH2CH2OH, -N(CH3)CH2CH(OH)CH2OH, -N(CH3)CH2CH2NH2, oxo, -NHCH2C(CH3)2CH2OH, -OH, -NH2, -NHCH3, -NHCH2CH2CH2OH, -N(CH3)2, -N(CH3)CH2CH3, -NHOC(CH3)2NH2, -N(CH3)CH2cyc|opropy|, -NHCH2cyclopropy|, -NHoxetanyl, -NCH2CH2triazo|e, piperazinyl, piperidinyl, pyrazolyl, azepinyl, azetidinyl, methoxy, and cyclopropylamino, where said phenyl, morpholino, triazolyl, imidazolyl, azepinyl, azetidinyl, pyrrolidinyl, piperazinyl, piperidinyl, WO 2017/216727 PCT/IB2017/053511 1209 oxetanyl, cyclopropyl, and pyrazolyl are optionally substituted with from 1 to 4 substituents independently selected from: methyl, fluoro, -NH2, -N(CH3)2, hydroxymethyl, oxo, -OH, and -CH2NH2, cycloalkyl, cycloalkyl substituted with from one to five substituents independently selected from: fluoro, chloro, -OH, C1-6a|kyl, and C1-6alkyl substituted with from 1 to 9 substituents independently selected from: fluoro and chloro; heterocycloalkyl, and heterocycloalkyl substituted with from 1 to 5 substituents independently selected from: fluoro, chloro, bromo, iodo, C1—6a|ky|, C1-6alkyl substituted with from 1 to 9 substituents independently selected from: fluoro, chloro, bromo, iodo, oxo, -OH, -NH2 and —-CN, aryl, C1-4alkoxy, C1—4a|koxy substituted with from 1 to 4 substituents independently selected from: fluoro, oxo, -OH, -COOH, -NH2, and —-CN, WO 2017/216727 PCT/IB2017/053511 1210 -NO2, -NH2, and SO2NH2, or R44bbr R45bbr and are taken together with the nitrogen to which they are attached, and optionally from 1 to 3 additional heteroatoms independenfly selected from O, N, and S, to form a heterocycloalkyl, which is optionally substituted with from 1 to 5 substituents independently selected from: fluoro, chloro, bromo, iodo, C1—6alkyl, C1-6alkyl substituted with from 1 to 9 substituents independently selected from: fluoro, chloro, C1-4a|koxy, oxo, phenyl, cycloalkyl, heterocycloalkyl, methylheterocycloalkyl-, -OH, -NH2, -N(H)C1—5alkyl, aminoheterocycloalkyl-, -N(C1-5alky|)2, --CN, -N(C1—4alkyl)(CH2OCH3), and -NHC1—4alkyl substituted by one or two substituents independently selected from oxo, NH2, and -OH, aryl, cycloalkyl, heterocycloalkyl, heterocycloalkyl substituted with from 1 to 9 substituents independently selected from: C1-6alkyl, -C1—6a|ky|OH, fluoro, -C1—6a|ky|NH2, WO 2017/216727 PCT/IB2017/053511 1211 chloro, bromo, iodo, oxo, -OH, -NH2 and -CN, C1-4alkoxy, C1-4a|koxy substituted with from 1 to 4 substituents independently selected from: fluoro, oxo, -OH, -COOH, -NH2, and -CN, -OP(O)(OH)2, -COOH, -CONH2, -N02, -NH2, -N(H)C1—5a|ky|, -N(H)C1-6alkyl substituted with from 1 to 9 substituents independently selected from: fluoro, chloro, bromo, iodo, C1-4alkoxy, oxo, phenyl, cycloalkyl, aminoC1-4alkoxy, heterocycloalkyl, methylheterocycloalkyl-, -OH, -NH2, -N(H)C1-4a|kyl, -N(C1—4aIky|)2, and -CN, -Ooxetanyl, -ONHC(NH)NH2, -NHcyclopropyl, -NHoxetanyl, -N(C1—5alky|)2, -S(O)2CH2CH3, S(O)2CH2CH2CH3, -3(0)2CH3, WO 2017/216727 provided that: X41 bbr X42bbr 1212 -SO2NH2, -S(O)2Dheny|, benzoyL benzylamino, -propylpyrrolidinyl, -methylcyclopropyl, cyclobutylamino, cyclobutyl-N(CH3)-, piperidinyl, imidazolyl, morpholinyl, morpholinylmethyl, methylpiperazinylmethyl, methylpiperazinyl, pyrrolidinyl, pyrrolidinylmethyl, (methoxypyridiny|methy|)amino, methylpyrrolidinyl, difluoropyrrolidinyl, dimethylpyrrolidinyl, (methylcyc|opropy|methy|)amino, hydroxymethylpyrrolidinyl, fluoropyrrolidinyl, fluorophenylmethylamino, piperazinlymethyl, oxazolidinyl, (methyloxetanmethy|)amino, (methylcyclobutylmethy|)amino, oxoimidazolidinyl, and 2-hydroxyethylpiperidinyl; are not both hydrogen, and R44bb' and R45bb' are not both hydrogen; PCT/IB2017/053511 WO 2017/216727 PCT/IB2017/053511 1213 or a pharmaceutically acceptable salt or prodrug thereof.
3. The method of claim 2 wherein the mammal is a human.
4. A method of inhibiting DNMT1 activity in a mammal in need thereof, which comprises administering to such mammal a therapeutically effective amount of a compound of Formula (lvbbr), as described in claim 2 or a pharmaceutically acceptable salt thereof.
5. The method of claim 4 wherein the mammal is a human.
6. The method of claim 1 wherein the compound is selected from: 2-[(6-amino-3,5-dicyano-4-ethylpyridin-2-yl)sulfanyl]-2-phenylacetamide; (R)-[(6-amino-3,5-dicyano-4-ethylpyridin-2-yl)sulfanyl]-2-phenylacetamide; 2-{[3,5-dicyano-6-(dimethylamino)-4-ethylpyridin-2-yl]sulfanyl}-2-phenylacetamide; 2-((3,5-dicyano-4-cyclopropyl-6-(1 ,4-diazepan-1-yl)pyridin-2-yl)thio)-2- phenylacetamide; 2-{[3,5-dicyano-4-cyclopropyl-6-(4-ethyl-1 ,4-diazepan-1-yl)pyridin-2-y|]sulfanyl}-2- phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-(4-propyl-1,4-diazepan-1-yl)pyridin-2-yl)thio)-2- phenylacetamide; 2-{[3,5-dicyano-4-ethyl-6-(4-ethyl-1 ,4-diazepan-1-yl)pyridin-2-yl]sulfanyl}-2- phenylacetamide; 2-{[3,5-dicyano-4-ethyl-6-(5-oxo-1 ,4-diazepan-1-yl)pyridin-2-yl]su|fanyl}-2- phenylacetamide; 2-((3,5-dicyano-4-cyclopropyl-6-morpholinopyridin-2-yl)thio)-2-(pyridin-4- y|)acetamide; 2-{[3,5-dicyano-4-ethyl-6-(4-methyl-3-oxopiperazin-1-yl)pyridin-2-y|]sulfanyl}-2- (pyridin-4-y|)acetamide; WO 2017/216727 PCT/IB2017/053511 1214 2-[(3,5-dicyan0-4-ethyl-6-{methy|[2-(morpholin-4-y|)ethy|]amino}pyridin-2- y|)suIfanyl]-2-phenylacetamide; 2-{[3,5-dicyano-4-ethyl-6-(4-propylpiperazin-1-y|)pyridin-2-y|]su|fany|}-2- phenylacetamide; 2-({3,5-dicyano-4-ethyl-6-[4-(piperidin-4-yl)piperazin-1-y|]pyridin-2-y|}su|fany|)-2- phenylacetamide; 2-({3,5-dicyano-4-cyclopropyl-6-[3-(hydroxymethy|)piperazin-1-y|]pyridin-2- y|}suIfanyl)-2-phenylacetamide; 2-{[3,5-dicyano-4-cyclopropyl-6-(3-oxopiperazin-1-yl)pyridin-2-y|]su|fany|}-2- phenylacetamide; 2-({3,5-dicyano-4-cyclopropyl-6-[4-(morpholin-4-y|)piperidin-1-y|]pyridin-2- y|}suIfanyl)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-(2 ,8-d iazaspiro[4.5]decan-8-y|)pyridin-2-y|)th io)-2- phenylacetamide; 2-((3,5-Dicyano-4-cyclopropyl-6-(3-(dimethylamino)piperidin-1-y|)pyridin-2-y|)thio)- 2-phenylacetamide; 2-((3,5-Dicyano-4-cyclopropy|-6-(3-methy|piperazin-1-y|)pyridin-2-y|)thio)-2- phenylacetamide; 2-((3,5-Dicyano-4-cyclopropyl-6-(2-(hydroxymethyl)morpholino)pyridin-2-y|)thio)-2- phenylacetamide; 2-((3,5-Dicyano-4-cyclopropyl-6-(2,6-dimethy|morpho|ino)pyridin-2-y|)thio)-2- phenylacetamide; 2-((3,5-Dicyano-4-cyclopropyl-6-(3-(dimethylamino)piperidin-1-y|)pyridin-2-y|)thio)- 2-phenylacetamide; 2-((6-(4-(Aminomethyl)-4-h yd roxypipe ridin-1 -yl)-3,5-d icyano-4-cyclopropy|pyridin- 2-y|)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-cyc|opropy|-6-(3-(methylamino)piperidin-1-yl)pyridin-2-y|)thio)-2- phenylacetamide; 2-((6-(3-aminopiperidin-1-yl)-3,5-dicyano-4-cyclopropylpyridin-2-y|)thio)-2- phenylacetamide; WO 2017/216727 PCT/IB2017/053511 1215 2-((3,5-dicyano-4-cyclopropyl-6-(dimethylamino)pyridin-2-y|)thio)-2-(pyridin-4- y|)acetamide; 2-((3,5-dicyano-6-(dimethylamin0)-4-ethylpyridin-2-y|)thio)-2-(pyridin-4- y|)acetamide; 2-((6-(4-aminopiperidin-1-yl)-3,5-dicyano-4-cyclopropylpyridin-2-y|)thio)-2- phenylacetamide; 2-((3,5-dicyano-4-cyclopropyl-6-(4-(dimethy|amino)piperidin-1-y|)pyridin-2-y|)thio)- 2-phenylacetamide; 2-((3,5-dicyano-4-cyclopropyl-6-(piperazin-1-y|)pyridin-2-y|)thio)-2-(pyridin-4- y|)acetamide; 2-((3,5-dicyano-4-cyclopropyl-6-(1 ,4-diazepan-1-y|)pyridin-2-y|)thio)-2-(pyridin-4- y|)acetamide; 2-((3,5-dicyano-4-cyc|opropy|-6-((R)-3-hyd roxypiperidin-1-y|)pyridin-2-y|)thio)-2- phenylacetamide; 2-(3,5-dicyan0-4-cyclopropyl-6-((S)-3-hydroxypiperidin-1-y|)pyridin-2-y|thio)-2- phenylacetamide; 2-((3,5-dicyan0-4-cyclopropyl-6-((S)-3-hydroxypyrrolidin-1-y|)pyridin-2-y|)thio)-2- (pyridin-4-y|)acetamide; 2-((3,5-dicyano-4-ethyl-6-(4-ethylpiperazin-1-y|)pyridin-2-y|)thio)-2- phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-(1-oxa-6-azaspiro[3.4]octan-6-yl)pyridin-2-y|)thio)-2- phenylacetamide; 2-((6-(4-(3-aminopropy|)piperazin-1-yl)-3,5-dicyano-4-ethylpyridin-2-y|)thio)-2- phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-(1,7-diazaspiro[3.5]nonan-1-y|)pyridin-2-y|)thio)-2- phenylacetamide; 2-((3,5-Dicyano-4-cyclopropyl-6-(4-(pyrrolidin-1-y|methyl)piperidin-1-y|)pyridin-2- y|)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-cyclopropy|-6-(4-(4-methy|piperazin-1-y|)piperidin-1-y|)pyridin-2- y|)thio)-2-phenylacetamide; WO 2017/216727 PCT/IB2017/053511 1216 (R)-2-((3,5-dicyano-6-(1,4-diazepan-1-yl)-4-ethylpyridin-2-y|)amino)-2- phenylacetamide; 2-((3,5-Dicyano-4-cyclopropyl-6-(4-(pyrrolidin-1-y|)piperidin-1-y|)pyridin-2-y|)thio)- 2-phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-(2,7-diazaspiro[3.5]nonan-7-y|)pyridin-2-y|)thio)-2- phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-(2,6-d iazaspiro[3.4]octan-6-y|)pyrid in-2-y|)th io)-2- phenylacetamide; 2-((3,5-dicyano-4-cyclopropyl-6-(1,4-diazepan-1-yl)pyridin-2-y|)thio)propanamide; 2-((3,5-Dicyano-4-ethy|-6-(4-(2-oxoimidazolidin-1-y|)piperidin-1-y|)pyridin-2- y|)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-(4-hydroxypiperidin-1-y|)pyridin-2-y|)thio)-2- phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-((S)-3-hydroxypyrrolidin-1-y|)pyridin-2-y|)thio)-2- phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-(3-oxopiperazin-1-y|)pyridin-2-y|)thio)-2- phenylacetamide; 2-[(6-amino-3,5-dicyano-4-cyclopropyl-2-pyridy|)suIfanyl]-2-phenyl-acetamide; 2-((3,5-Dicyano-4-ethyl-6-(methylamino)pyridin-2-y|)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-((2-methoxyethyl)(methy|)amino)pyridin-2-y|)thio)-2- phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-(3-methoxyazetidin-1-y|)pyridin-2-y|)thio)-2- phenylacetamide; 2-((3,5-Dicya n0-4-ethyl-6-(piperazin-1-y|)pyridin-2-y|)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-(4-methyl-1 ,4-diazepan-1-y|)pyridin-2-y|)thio)-2- phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-morpholinopyridin-2-y|)thio)-2-phenylacetamide; 2-[[6-(azetidin-1-yl)-3,5-dicyano-4-ethyl-2-pyridy|]suIfanyl]-2-phenyl-acetamide; 2-((3,5-dicyano-4-ethyl-6-(4-oxopiperidin-1-y|)pyridin-2-y|)thio)-2-phenylacetamide; WO 2017/216727 PCT/IB2017/053511 1217 2-((3,5-dicyano-4-ethyl-6-(1'-(2-hydroxyethyl)-[4,4'-bipiperidin]-1-y|)pyridin-2- y|)thio)-2-phenylacetamide; 2-((3,5-Dicyano-6-((3S,5R)-3,5-dimethylpiperazin-1-yl)-4-ethylpyridin-2-y|)thio)-2- phenylacetamide; 2-((6-(8-azabicyc|o[3.2.1]octan-3-y|(methy|)amino)-3,5-dicyano-4-ethylpyridin-2- y|)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-cyclopro pyl-6-(2-(hyd roxymethyl)morpholino)pyridin-2-y|)thio)-2- phenylacetamide; (R)-2-((3,5-dicyano-6-(dimethylamino)-4-ethylpyridin-2-y|)thio)-2-phenylacetamide; (R)-2-[(3,5-Dicyano-4-ethyl-6-morpholino-2-pyridy|)suIfanyl]-2-phenyl-acetamide; 2-{[3,5-dicyano-4-ethyl-6-(5-methyl-1,4-diazepan-1-y|)pyridin-2-y|]su|fany|}-2- phenylacetamide; 2-({3,5-Dicyano-4-ethy|-6-[4-(2-methoxyethyl)-1,4-diazepan-1-y|]pyridin-2- y|}suIfanyl)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-(4-(2-hydroxypropyl)-1 ,4-diazepan-1-y|)pyridin-2-y|)thio)- 2-phenylacetamide; Methyl 2-[4-(6-{[carbamoy|(pheny|)methy|]sulfanyl}-3,5-dicyano-4-ethylpyridin-2- yl)-1 ,4-diazepan-1-y|]acetate; 2-{[3,5-Dicyan0-4-cyclopropy|-6-(4-methy|-5-oxo-1,4-diazepan-1-y|)pyridin-2- y|]suIfanyl}-2-phenylacetamide; 2-{[3,5-Dicyano-4-cyclopropyl-6-(5-oxo-1 ,4-diazepan-1-yl)pyridin-2-y|]su|fany|}-2- phenylacetamide; 2-{[3,5-Dicyano-4-ethy|-6-(4-methy|-5-oxo-1 ,4-diazepan-1-y|)pyridin-2-y|]su|fany|}- 2-phenylacetamide; 2-{[3,5-Dicyano-6-(1,4-diazepan-1-yl)-4-ethylpyridin-2-y|]su|fany|}-2- phenylacetamide; 2-({3,5-Dicyano-6-[4-(2-hydroxyethyl)-1,4-diazepan-1-y|]-4-(2,2,2- trifluoroethy|)pyridin-2-y|}su|fany|)-2-phenylacetamide; (2R)-2-({3,5-Dicyano-4-eth yl-6-[4-(2-hyd roxyethyl)-1 ,4-diazepan-1-y|]pyridin-2- y|}amino)-2-phenylacetamide; WO 2017/216727 PCT/IB2017/053511 1218 2-({6-[(38)-3-Aminopyrrolidin-1-yl]-3,5-dicyan0-4-cyclopropylpyridin-2-y|}su|fany|)- 2-phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-(2,9-diazaspiro[5.5]undecan-9-yl)pyridin-2-y|)thio)-2- phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-(hexahydro-1H-pyrro|o[1,2-a][1,4]diazepin-2(3H)- y|)pyridin-2-y|)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-(2-methyl-2,9-diazaspiro[5.5]undecan-9-y|)pyridin-2- y|)thio)-2-phenylacetamide; 2-((3,5-Dicyano-6-(2-(cyclopropylmethyl)-2,9-diazaspiro[5.5]undecan-9-y|)-4- ethylpyridin-2-y|)thio)-2-phenylacetamide; 2-((3,5-Dicyano-6-(4-(3-(dimethylamino)propy|)piperazin-1-y|)-4-ethy|pyridin-2- y|)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-(4-(pyrroIidin-3-y|)piperidin-1-y|)pyridin-2-y|)thio)-2- phenylacetamide; 2-((6-([4,4'-Bipiperidin]-1-yl)-3,5-dicyano-4-ethylpyridin-2-y|)thio)-2- phenylacetamide; 2-((6-(4-(2-Aminoethyl)piperazin-1-yl)-3,5-dicyano-4-ethylpyridin-2-y|)thio)-2- phenylacetamide; 2-((6-(4-(3-Aminopropy|)piperazin-1-yl)-3,5-dicyano-4-cyclopropylpyridin-2-y|)thio)- 2-phenylacetamide; 2-((3,5-Dicyano-4-cyclopropy|-6-(4-((4-methylpiperazin-1-y|)methy|)piperidin-1- y|)pyridin-2-y|)thio)-2-phenylacetamide; 2-((6-(4-Acetylpiperazin-1-yl)-3,5-dicyano-4-ethylpyridin-2-y|)thio)-2- phenylacetamide; 2-((3,5-Dicyano-4-cyclopropyl-6-(dimethy|amino)pyridin-2-y|)thio)-2- phenylacetamide; 2-(4-ChIorophenyl)-2-((3,5-dicyano-6-(dimethylamino)-4-ethy|pyridin-2- y|)thio)acetamide; 2-((3,5-Dicyano-4-ethy|-6-(4-(2-hydroxyethyl)piperazin-1-y|)pyridin-2-y|)thio)-2- phenylacetamide; WO 2017/216727 PCT/IB2017/053511 1219 2-[(3,5-Dicyano-4-cyclopropyl-6-morpholino-2-pyridy|)su|fany|]-2-pheny|- acetamide; 2-((6-(4-Benzoylpiperazin-1-yl)-3,5-dicyano-4-ethylpyridin-2-y|)thio)-2- phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-((5S,6S)-6-hydroxy-1-(methylsulfonyl)-1,8- diazaspiro[4.5]decan-8-y|)pyridin-2-y|)thio)-2-phenylacetamide; 2-((3,5-Dicyano-6-(4,4-difluoropiperidin-1-yl)-4-ethylpyridin-2-y|)thio)-2- phenylacetamide; (R)-2-((3,5-Dicyano-4-ethyl-6-((R)-3-hydroxypyrro|idin-1-y|)pyridin-2-y|)thio)-2- phenylacetamide; 2-((3,5-dicyano-4-(furan-2-y|)-6-(4-methy|-1,4-diazepan-1-y|)pyridin-2-y|)thio)-2- phenylacetamide; 2-((6-(4-Amino-4-methylpiperidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-y|)thio)-2- phenylacetamide; 2-Amino-N-(1-(6-((2-amino-2-oxo-1-pheny|ethy|)thio)-3,5-dicyano-4-ethy|pyridin-2- y|)piperidin-4-y|)acetamide; (28)-2-Amino-N-(1-(6-((2-amino-2-oxo-1-pheny|ethy|)thio)-3,5-dicyano-4- ethylpyridin-2-yl)piperidin-4-yl)propanamide; 2-((6-(4-(3-Aminooxetane-3-carbony|)piperazin-1-yl)-3,5-dicyano-4-ethy|pyridin-2- y|)thio)-2-phenylacetamide; 4-Amino-N-(1-(6-((2-amino-2-oxo-1-pheny|ethy|)thio)-3,5-dicyano-4-ethy|pyridin-2- y|)piperidin-4-y|)tetrahydro-2H-pyran-4-carboxamide; 2-((6-(4-(4-Aminotetrahydro-2H-pyran-4-carbony|)piperazin-1-y|)-3,5-dicyano-4- ethylpyridin-2-y|)thio)-2-phenylacetamide; 2-((3,5-Dicyano-6-(4-(2-hydroxyethyl)-1,4-diazepan-1-y|)-4-methoxypyridin-2- y|)thio)-2-phenylacetamide; 2-((6-(4-Aminopiperidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-y|)thio)-2- phenylacetamide; 2-((6-((2-Aminoethy|)(methy|)amino)-3 ,5-dicyano-4-ethylpyrid in-2-y|)th io)-2- phenylacetamide; WO 2017/216727 PCT/IB2017/053511 1220 2-((6-((2-Amino-2-oxoethyl)(methy|)amino)-3,5-dicyano-4-ethylpyridin-2-y|)thio)-2- phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-(3-hydroxyazetidin-1-y|)pyridin-2-y|)thio)-2- phenylacetamide; 2-(3,5-Dicyano-4-ethyl-6-((2-hydroxyethy|)(methy|)amino)pyridin-2-y|thio)-2- phenylacetamide; 2-Amino-N-(1-(6-((2-amino-2-oxo-1-pheny|ethy|)thio)-3,5-dicyano-4-ethy|pyridin-2- y|)piperidin-4-yl)-2-methylpropanamide; 2-((6-(4-(2-Aminoethoxy)piperidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-y|)thio)-2- phenylacetamide; 1-(6-((2-Amino-2-oxo-1-pheny|ethy|)thio)-3,5-dicyano-4-ethylpyridin-2-y|)pyrro|idin- 3-yl dihydrogen phosphate; 2-((6-((2-Amino-2-oxo-1-pheny|ethy|)thio)-3,5-dicyano-4-ethy|pyridin-2- y|)(methy|)amino)ethy| dihydrogen phosphate; 1-(6-((2-Amino-2-oxo-1-pheny|ethy|)thio)-3,5-dicyano-4-ethylpyridin-2-y|)azetidin- 3-yl dihydrogen phosphate; (28)-2-((1-(6-((2-Amino-2-oxo-1-pheny|ethy|)thio)-3,5-dicyano-4-ethylpyridin-2- y|)piperidin-4-y|)oxy)ethy| 2-amino-3-methylbutanoate; 2-((1-(6-((2-Amino-2-oxo-1-pheny|ethy|)thio)-3,5-dicyano-4-ethylpyridin-2- y|)piperidin-4-y|)oxy)ethy| dihydrogen phosphate; 1-(6-((2-Amino-2-oxo-1-pheny|ethy|)thio)-3,5-dicyano-4-ethylpyridin-2-y|)piperidin- 4-yl dihydrogen phosphate; 2-((3,5-Dicyano-6-(dimethylamino)-4-ethylpyridin-2-y|)thio)-2-(piperidin-4- y|)acetamide; 2-((3,5-Dicyano-4-ethyl-6-(4-(propylsu|fony|)piperazin-1-y|)pyridin-2-y|)thio)-2- phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-(4-(phenylsulfony|)piperazin-1-y|)pyridin-2-y|)thio)-2- phenylacetamide; 2-((3,5-Dicyano-4-ethy|-6-((R)-3-hydroxypyrrolidin-1-y|)pyridin-2-y|)thio)-2- phenylacetamide; WO 2017/216727 PCT/IB2017/053511 1221 2-((3,5-Dicyan0-4-ethyl-6-(2-oxa-6-azaspiro[3.4]octan-6-yl)pyridin-2-y|)thio)-2- phenylacetamide; (R)-2-((3,5-Dicyano-4-ethy|-6-(4-ethy|-1 ,4-diazepan-1-y|)pyridin-2-y|)amino)-2- phenylacetamide; (R)-2-((3,5-Dicyano-4-ethyl-6-(4-(3-(pyrrolidin-1-y|)propy|)-1,4-diazepan-1- y|)pyridin-2-y|)amino)-2-phenylacetamide; 2-(3,5-Dicyano-4-cyc|opropy|-6-(3-hydroxypiperidin-1-y|)pyridin-2-y|thio)-2- phenylacetamide; 2-((3,5-Dich|oro-4-ethy|-6-(4-methyl-1 ,4-diazepan-1-yl) pyridin-2-y|)thio)-2- phenylacetamide; 2-((3,5-Dicyano-6-(1,1-dioxidothiomorpholino)-4-ethylpyridin-2-y|)thio)-2- phenylacetamide; 2-((3,5-Dicyano-4-ethy|-6-(methy|(2-(piperazin-1-y|)ethy|)amino)pyridin-2-y|)thio)-2- phenylacetamide; (R)-2-((3,5-Dicyano-4-ethyl-6-((S)-3-hyd roxypyrrolidin-1-y|)pyridin-2-y|)thio)-2- phenylacetamide; 2-((6-((2-(4-(Aminomethyl)-4-hydroxypiperidin-1-y|)ethy|)(methy|)amino)-3,5- dicyano-4-ethylpyridin-2-y|)thio)-2-phenylacetamide; 2-((4-Cyano-3-(1 ,4-diazepan-1-yl)-6,7-dihydro-5H-cyc|openta[c]pyridin-1-y|)thio)-2- phenylacetamide; 2-((6-(4-(1H-Imidazol-1-y|)piperidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-y|)thio)-2- phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-(4-(pyridin-4-ylmethyl)piperazin-1-y|)pyridin-2-y|)thio)-2- phenylacetamide; 2-((3,5-Dicyano-6-(2-(dimethylamino)ethoxy)-4-ethylpyridin-2-y|)thio)-2- phenylacetamide; 2-((1-(6-((2-Amino-2-oxo-1-pheny|ethy|)thio)-3,5-dicyano-4-cyclopropylpyridin-2- y|)piperidin-3-y|)amino)acetic acid; 2-((3,5-Dicyan0-4-ethyl-6-(4-(oxazol-2-ylmethyl)piperazin-1-y|)pyridin-2-y|)thio)-2- phenylacetamide; WO 2017/216727 PCT/IB2017/053511 1222 2-((6-(4-((1H-Pyrrol-2-yl) methyl) piperazin-1-yl)-3,5-dicyano-4-ethy|pyridin-2- y|)thio)-2-phenylacetamide; 2-((3,5-Dicyano-6-(3,4-dihydro-2,7-naphthyridin-2 (1 H)-yl)-4-ethylpyridin-2-y|)thio)- 2-phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-((S)-3-hyd roxypyrrolid in-1 -y|)pyrid in-2-y|)thio)-2-(pyrid in- 3-y|)acetamide; 2-((6-(4-((1H-PyrroI-3-yl)methy|)piperazin-1-yl)-3,5-dicyano-4-ethylpyridin-2- y|)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-(4-(isoxazoI-3-y|methy|)piperazin-1-y|)pyridin-2-y|)thio)- 2-phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-(4-(oxazol-5-ylmethyl)piperazin-1-y|)pyridin-2-y|)thio)-2- phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-(4-(isoxazoI-4-y|methy|)piperazin-1-y|)pyridin-2-y|)thio)- 2-phenylacetamide; 3-Amino-N-(1-(6-((2-amino-2-oxo-1-pheny|ethy|)thio)-3,5-dicyano-4-ethylpyridin-2- y|)piperidin-4-y|)oxetane-3-carboxamide; 2-((6-(4-((1H-Pyrazol-4-y|)methy|)piperazin-1-yl)-3,5-dicyano-4-ethy|pyridin-2- y|)thio)-2-phenylacetamide; 2-((6-(4-((1H-Imidazol-5-y|)methy|)piperazin-1-yl)-3,5-dicyano-4-ethy|pyridin-2- y|)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-(4-(1-hydroxy-2-methylpropan-2-y|)piperazin-1- y|)pyridin-2-y|)thio)-2-phenylacetamide; 2-((6-(4-((1H-Imidazol-2-y|)methy|)piperazin-1-yl)-3,5-dicyano-4-ethy|pyridin-2- y|)thio)-2-phenylacetamide; 2-((3,5-Dicyano-6-(dimethylamino)-4-methoxypyridin-2-y|)thio)-2-phenylacetamide; 2-((3,5-Dicyano-6-(dimethylamino)-4-ethoxypyridin-2-y|)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-ethoxy-6-(4-(2-hyd roxyethyl)-1 ,4-diazepan-1-yl) pyridin-2- y|)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-ethy|-6-(4-(2-hydroxy-2-methylpropyl)-1,4-diazepan-1-y|)pyridin- 2-y|)thio)-2-phenylacetamide; WO 2017/216727 PCT/IB2017/053511 1223 2-((3,5-Dicyano-4-ethyl-6-(4-(thiazol-5-ylmethyl)piperazin-1-y|)pyridin-2-y|)thio)-2- phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-(piperazin-1-y|)pyridin-2-y|)thio)-2-(4- fluorophenyl)acetamide; 2-((3,5-Dicyano-4-ethyl-6-(4-(isothiazol-4-ylmethy|)piperazin-1-y|)pyridin-2-y|)thio)- 2-phenylacetamide; 2-((3,5-Dicyano-6-(dimethylamino)-4-ethylpyridin-2-y|)thio)-2-(4- fluorophenyl)acetamide; 2-((3,5-Dicyano-6-(dimethylamino)-4-ethylpyridin-2-y|)thio)-2- (5-f|uoropyridin-2- y|)acetamide; 2-((3,5-Dicyano-4-ethyl-6-(4-(furan-3-y|methy|)piperazin-1-y|)pyridin-2-y|)thio)-2- phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-((2-morpho|inoethy|)thio)pyridin-2-y|)thio)-2- phenylacetamide; 2-((3,5-Dicyano-6-(4-methyl-1 ,4-diazepan-1-yl)-4-(methylthio)pyridin-2-y|)thio)-2- phenylacetamide; 2-((3,5-DichIoro-4-ethyl-6-(4-(2-hydroxyethyl)-1,4-diazepan-1-y|)pyridin-2-y|)thio)- 2-phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-(hexahydropyrro|o[3,4-b][1 ,4]oxazin-6(2H)-y|)pyridin-2- y|)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-(4-methyl-1 ,4-diazepan-1-y|)pyridin-2-y|)thio)-2-(5- methylpyridin-2-y|)acetamide; 2-((3,5-Dicyano-4-ethyl-6-(4-methyl-1 ,4-diazepan-1-y|)pyridin-2-y|)thio)-2-(6- fluoropyridin-2-y|)acetamide; 2-((3,5-Dicyano-6-(4-(dimethy|amino)piperidin-1-yl)-4-ethylpyridin-2-y|)thio)-2-(4- fluorophenyl)acetamide; 2-((3,5-Dicyano-4-ethy|-6-(4-methy|-1,4-diazepan-1-yl) pyridin-2-yl) thio)-2-(4- methylpyridin-2-yl) acetamide; 2-((3,5-Dicyano-4-ethyl-6-(4-methyl-1 ,4-diazepan-1-y|)pyridin-2-y|)thio)-2-(3- methoxypyridin-2-y|)acetamide; WO 2017/216727 PCT/IB2017/053511 1224 2-((3,5-Dicyano-6-(4-(dimethy|amino)piperidin-1-yl)-4-ethylpyridin-2-y|)thio)-2-(2,4- difluoropheny|)acetamide; 2-((3,5-Dicyan0-4-ethyl-6-(4-(pyrrolidin-1 -y|)pipe rid in-1 -y|)pyridin-2-y|)thio)-2-(5- fluoropyridin-2-y|)acetamide; 2-((3,5-Dicyano-4-ethoxy-6-(4-(2-hyd roxyethyl)-1 ,4-diazepan-1-y|)pyridin-2- y|)thio)propanamide; 2-((3,5-Dicyano-6-(4-(2-hyd roxyethyl)-1 ,4-diazepan-1-y|)-4-propoxypyridin-2- y|)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-(4-methyl-1 ,4-diazepan-1-y|)pyridin-2-y|)thio)-2-(4- methoxypyridin-2-y|)acetamide; 2-((3,5-Dicyano-4-ethyl-6-(2-methyl-2,8-diazaspiro[4.5]decan-8-y|)pyridin-2- y|)thio)-2-phenylacetamide; 2-((3,5-Dicyano-6-(4-(dimethy|amino)piperidin-1-yl)-4-ethylpyridin-2-y|)thio)-2-(3,4- dif|uoropheny|)acetamide; 1-(6-((2-Amino-2-oxo-1-pheny|ethy|)thio)-3,5-dicyano-4-ethylpyridin-2- y|)piperidine-4-carboxamide; 2-((3,5-Dicyano-6-((2-(dimethy|amino)ethy|)thio)-4-ethylpyridin-2-y|)thio)-2- phenylacetamide; 2-((3,5-Dicyano-6-((3S,4R)-3,4-d ihyd roxypyrrolidin-1-yl)-4-ethylpyridin-2-y|)thio)-2- phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-(4-methyl-1 ,4-diazepan-1-y|)pyridin-2-y|)thio)-2-(3- fluoropyridin-2-yl) acetamide; 2-((3,5-Dicyano-4-ethyl-6-(4-methyl-1 ,4-diazepan-1-y|)pyridin-2-y|)thio)-2-(5- methoxypyridin-2-y|)acetamide; 2-((3,5-Dicyano-4-ethyl-6-(4-(1-hydroxy-2-methylpropan-2-y|)piperazin-1- y|)pyrid in-2-y|)th io)-2-(4-fluoropheny|)acetamide; 2-((3,5-Dicyano-4-ethyl-6-(4-methyl-1 ,4-diazepan-1-y|)pyridin-2-y|)thio)-2-(3- (trifluoromethyl)pheny|)acetamide; 2-((3,5-Dicyano-4-ethy|-6-(4-(2-hydroxyethoxy)piperidin-1-y|)pyridin-2-y|)thio)-2- phenylacetamide; WO 2017/216727 PCT/IB2017/053511 1225 2-((3,5-Dicyano-4-ethyl-6-(4-methyl-1 ,4-diazepan-1-yl) pyridin-2-y|)thio)-2-(2- fluoropyridin-3-y|)acetamide; 2-((3,5-Dicyano-4-ethyl-6-(4-methyl-1 ,4-diazepan-1-yl) pyridin-2-y|)thio)-2-(6- fluoropyridin-3-y|)acetamide; 3-((6-(2-Amino-2-oxo-1-phenylethylthio)-3,5-dicyano-4-ethylpyridin-2- y|)(methy|)amino)propanamide; 2-((3,5-Dicyano-4-ethyl-6-(4-(oxetan-3-y|oxy)piperidin-1-y|)pyridin-2-y|)thio)-2- phenylacetamide; 2-((3,5-Dicyano-6-(4-((2,2-difluoroethyl) amino)-4-methylpiperidin-1-y|)-4- ethylpyridin-2-yl) thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-(4-methyl-1 ,4-diazepan-1-y|)pyridin-2-y|)thio)-2-(4- (trifluoromethyl)pheny|)acetamide; 2-((6-(4-Aminopiperazin-1-yl)-3,5-dicyano-4-ethylpyridin-2-y|)thio)-2- phenylacetamide; 2-((6-((2-Amin0-2-oxoethy|)thio)-3,5-dicyan0-4-ethylpyridin-2-y|)thio)-2- phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-(pyrro|o[3,4-c]pyrazol-5(1H,4H,6H)-y|)pyridin-2-y|)thio)- 2-phenylacetamide; 2-((3,5-Dicyano-6-(dimethylamino)-4-ethylpyridin-2-y|)thio)-2-(5-methoxypyridin-2- y|)acetamide; 2-((3,5-Dicyano-6-(dimethylamino)-4-ethylpyridin-2-y|)thio)-2-(5-methylpyridin-2- y|)acetamide; 2-((3,5-Dicyano-4-ethyl-6-(4-methyl-1 ,4-diazepan-1-y|)pyridin-2-y|)thio)-2-(2- fluoropyridin-4-y|)acetamide; 2-((3,5-Dicyano-4-ethyl-6-(4-hydroxy-4-(hydroxymethyl)piperidin-1-y|)pyridin-2- y|)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-ethy|-6-(2-oxo-3-oxa-1 ,8-diazaspiro[4.5]decan-8-y|)pyridin-2- y|)thio)-2-phenylacetamide; 2-((6-(4-Amino-4-(hyd roxymethy|)pipe rid in-1 -yl)-3 ,5-dicyano-4-ethylpyrid in-2- y|)thio)-2-phenylacetamide; WO 2017/216727 PCT/IB2017/053511 1226 2-((6-(4-(Aminomethyl)-4-hydroxypiperidin-1-yl)-3,5-dicyano-4-ethylpyridin-2- y|)thio)-2-phenylacetamide; 2-(3-Benzoylphenyl)-2-((3,5-dicyan0-4-ethyl-6-(4-(2-hydroxyethyl)-1,4-diazepan-1- y|)pyridin-2-y|)thio)acetamide; 2-(4-Benzoylphenyl)-2-((3,5-dicyano-4-ethyl-6-(4-(2-hydroxyethyl)-1,4-diazepan-1- y|)pyridin-2-y|)thio)acetamide; 2-((3,5-Dicyano-4-ethyl-6-(4-methyl-1 ,4-diazepan-1-y|)pyridin-2-y|)thio)-2-(2- methylpyridin-4-y|)acetamide; 2-((3,5-Dicyano-4-ethyl-6-(4-methyl-1 ,4-diazepan-1-y|)pyridin-2-y|)thio)-2-(3- (pyrrolidin-1-y|)pheny|)acetamide; 2-((3,5-Dicyano-4-ethyl-6-(4-methyl-1 ,4-diazepan-1-y|)pyridin-2-y|)thio)-2-(3- fluoropyridin-4-y|)acetamide; 2-((3,5-Dicyano-4-ethyl-6-(4-methyl-1,4-diazepan-1-y|)pyridin-2-y|)thio)-2-(2,5- difluoropyridin-4-y|)acetamide; 2-((3,5-Dicyano-6-(4-(2,5-dioxoimidazolidin-1-y|)piperidin-1-y|)-4-ethy|pyridin-2- y|)thio)-2-phenylacetamide; 4-Amino-1-(6-((2-amino-2-oxo-1-phenylethyl) thio)-3, 5-dicyano-4-ethylpyridin-2-yl) piperidine-4-carboxamide; 2-((3,5-Dicyano-6-(4-(2,5-dioxopyrrolidin-1-y|)piperidin-1-y|)-4-ethy|pyridin-2- y|)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-(4-methyl-1,4-diazepan-1-y|)pyridin-2-y|)thio)-2- phenylacetamide (isomer 1); 2-((3,5-dicyano-4-ethyl-6-(4-methyl-1,4-diazepan-1-y|)pyridin-2-y|)thio)-2- phenylacetamide (lsomer 2) ; 2-((3,5-Dicyano-4-ethyl-6-(2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-8-y|)pyridin-2- y|)thio)-2-phenylacetamide; 1-(6-((2-Amino-2-oxo-1-pheny|ethy|)thio)-3,5-dicyano-4-ethylpyridin-2-y|)-4- hydroxy piperidine-4-carboxamide; 1-(6-((2-Amino-2-oxo-1-pheny|ethy|)thio)-3,5-dicyano-4-ethylpyridin-2-y|)azetidin- 3-yl carbamate; WO 2017/216727 PCT/IB2017/053511 1227 2-((3,5-Dicyano-6-(4-(2,4-dioxooxazolidin-3-y|)piperidin-1-y|)-4-ethy|pyridin-2- y|)thio)-2-phenylacetamide; 3-((6-((2-Amino-2-oxo-1-pheny|ethy|)thio)-3,5-dicyano-4-ethy|pyridin-2- y|)(methy|)amino)-2-hydroxy-2-methylpropanamide; 2-((3,5-Dicyano-4-ethyl-6-(3-(hyd roxymethy|)azetidin-1-y|)pyridin-2-y|)thio)-2- phenylacetamide; 2-(3,5-Dicyano-4-ethyl-6-(piperazin-1-y|)pyridin-2-ylthio)-2-(thiophen-3- y|)acetamide; 2-((3,5-Dicyano-4-ethyl-6-(4-methyl-1,4-diazepan-1-yl) pyridin-2-yl) thio)-2-(5- methylpyridin-3-yl) acetamide; 2-((6-(4-(3-Amino-2-oxopyrrolidin-1-y|)piperidin-1-yl)-3,5-dicyano-4-ethy|pyridin-2- y|)thio)-2-phenylacetamide; 1-(6-((2-Amino-2-oxo-1 -pheny|ethy|)thio)-3,5-dicyano-4-ethylpyrid in-2-yl) piperid in- 4-yl (28)-2-amino-3-methylbutanoate; 2-((6-((2-Amino-2-oxo-1-pheny|ethy|)thio)-3,5-dicyano-4-ethylpyridin-2-yl) (methyl) amino)ethy| (28)-2-amino-3-methylbutanoate; 2,2‘-((3,5-Dicyano-4-ethylpyridine-2,6-diy|)bis(suIfanediy|))bis(2-phenylacetamide) (28)-(1-(6-((2-Amino-2-oxo-1-pheny|ethy|)thio)-3,5-dicyano-4 —ethy| pyridin-2- y|)azetidin-3-y|)methy| 2-amino-3-methylbutanoate; 2-((6-(3-Aminoazetidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-y|)thio)-2- phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-methylpyridin-2-y|)thio)-2-phenylacetamide; N-(1-(6-((2-Amino-2-oxo-1-pheny|ethy|)thio)-3,5-dicyano-4-ethylpyridin-2- y|)piperidin-4-y|)-2-hydroxyacetamide; N-(1-(6-((2-Amino-2-oxo-1-pheny|ethy|)thio)-3,5-dicyano-4-ethylpyridin-2- y|)azetidin-3-yl)-2-hydroxyaceta mide; 2-((3-Cyano-4-ethy|-5-methyl-6-(piperazin-1-y|)pyridin-2-y|)thio)-2- phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-(5-methyl-2,5-diazabicyc|o[2.2.1]heptan-2-y|)pyridin-2- y|)thio)-2-phenylacetamide; WO 2017/216727 PCT/IB2017/053511 1228 2-((3,5-Dicyan0-4-ethyl-6-(4-(2-(pyrrolidin-1-y|)ethy|)piperazin-1-yl)pyridin-2- y|)thio)-2-phenylacetamide; 2-((3,5-Dicyano-6-(dimethylamino)-4-ethylpyridin-2-y|)thio)-2-pheny|acetamide-2- (R)-2-((3,5-Dicyano-6-(dimethylamino)-4-ethylpyridin-2-y|)thio)-2- phenylacetamide-2-d; 2-((6-(4-(4-Bromobenzoy|)piperazin-1-yl)-3,5-dicyano-4-ethylpyridin-2-y|)thio)-2- phenylacetamide; 2-((3,5-Dicyano-4-ethy|-6-(4-(2-hydroxyethyl)-1,4-diazepan-1-yl)pyridin-2-y|)thio)- 2-phenylacetamide; 2-((3,5-Dicyano-6-(4-cyanopiperidin-1-yl)-4-ethylpyridin-2-y|)thio)-2- phenylacetamide; (S)-2-((3,5-Dicyano-4-ethyl-6-((S)-3-hyd roxypyrrolidin-1-y|)pyridin-2-y|)thio)-2- phenylacetamide; 2-((6-(4-Amino-4-methylpiperidin-1-yl)-3,5-dicyano-4-cyclopropylpyridin-2-y|)thio)- 2-phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-((S)-3-hyd roxypyrrolid in-1 -y|)pyrid in-2-y|)thio)-2-(pyrid in- 2-y|)aceta mide; 2-((3,5-DichIoro-4-ethyl-6-(piperazin-1-yl)pyridin-2-y|)thio)-2-phenylacetamide; tert-Butyl (1-(6-((2-amino-2-oxo-1-pheny|ethy|)thio)-3,5-dicyano-4-ethylpyridin-2- y|)piperidin-4-y|)carbamate; 2-((6-(3-(2-Amino-2-oxoethy|)azetidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-y|)thio)-2- phenylacetamide; (2R)-1-(6-((2-Amino-2-oxo-1-phenylethy|)thio)-3,5-dicyano-4-ethylpyridin-2- y|)azetidin-3-yl 2-amino-3-methylbutanoate; 2-((3,5-Dicyano-4-ethyl-6-(methy|((5-oxo-4,5-dihydro-1H-1 ,2,4-triazo|-3- y|)methy|)a mino)pyrid in-2-y|)th io)-2-phenylacetamide; 2-((6-(((4H-1 ,2,4-Triazol-3-yl)methy|)(methy|)amino)-3,5-dicyano-4-ethylpyridin-2- y|)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-ethoxy-6-methylpyridin-2-y|)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4,6-diethylpyridin-2-y|)thio)-2-phenylacetamide; WO 2017/216727 PCT/IB2017/053511 1229 2-((6-((2-(4H-1 ,2,4-Triazol-4-y|)ethy|)(methy|)amino)-3,5-dicyano-4-ethylpyridin-2-y|)thio)- phenylacetamide; 2-((6-(((1H-Pyrazol-3-y|)methy|)(methy|)amino)-3,5-dicyano-4-ethylpyridin-2- y|)thio)-2-phenylacetamide; 2-((3,5-Dicyano-6-(6.7-dihydro-1H-[1,2,3]triazo|o[4,5-c]pyridin-5(4H)-y|)-4- ethylpyridin-2-y|)thio)-2-phenylacetamide; 2-((6-(((1H-Imidazol-2-y|)methy|)(methy|)amino)-3,5-dicyano-4-ethy|pyridin-2- y|)thio)-2-phenylacetamide; 2-((6-(((1H-Imidazol-5-y|)methy|)(methy|)amino)-3,5-dicyano-4-ethy|pyridin-2- y|)thio)-2-phenylacetamide; (2R)-2-Amino-N-(1-(6-((2-amino-2-oxo-1-pheny|ethy|)thio)-3,5-dicyano-4- ethylpyridin-2-yl)piperidin-4-yl)propanamide; 4-(2-Amino-1-((3,5-dicyano-4-ethy|-6-(4-methy|-1,4-diazepan-1-y|)pyridin-2- y|)thio)-2-oxoethy|)benzamide; 2-((3,5-Dicyano-4-cyclopropyl-6-(3-hydroxypyrrolidin-1-y|)pyridin-2-y|)thio)-2- phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-(3-hydroxypyrrolidin-1-y|)pyridin-2-y|)thio)-2- phenylacetamide; (2R)-2-Amino-N-(1-(6-((2-amino-2-oxo-1-pheny|ethy|)thio)-3,5-dicyano-4- cyclopropyl pyridin-2-y|)piperidin-4-y|)propanamide; 2-((6-((2-Aminoethy|)(methy|)amino)-3,5-dicyano-4-cyclopropylpyridin-2-y|)thio)-2- phenylacetamide; 2-Amino-N-(1-(6-((2-amino-2-oxo-1-phenylethyl) thio)-3,5-d icyano-4 cyclopropylpyrid in-2-yl)piperid in-4-yl)-2-methylpropa namide; 4-(2-Amino-1-((3,5-dicyano-6-(dimethylamin0)-4-ethylpyridin-2-y|)thio)-2- oxoethy|)benzamide; 2-(6-(4-Aminopiperidin-1-yl)-3-cyano-4-ethyl-5-methylpyridin-2-y|thio)-2- phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-(4-methyl-1,4-diazepan-1-y|)pyridin-2-y|)thio)-2-(4-(N- methylsulfamoyl)pheny|)acetamide; WO 2017/216727 PCT/IB2017/053511 1230 2-((3,5-Dicyano-4-ethyl-6-(6-fluoro-1 ,4-diazepan-1-yl)pyridin-2-y|)thio)-2- phenylacetamide; 2-((6-(4-Amino-3,3-difluoropiperidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-y|)thio)-2- phenylacetamide; tert-Butyl (1-(6-((2-amino-2-oxo-1-phenylethyl) thio)-3,5-dicyano-4-ethy|pyridin-2- yl)-3,3-difluoropiperidin-4-yl) carbamate; 2-((3,5-Dicyano-4-cyclopropyl-6-((2-hydroxyethyl)(methy|)amino)pyridin-2-y|)thio)- 2-phenylacetamide; 2-((3,5-Dicyano-4-cyclopropyl-6-(3-hydroxyazetidin-1-y|)pyridin-2-y|)thio)-2- phenylacetamide; 1-(6-((2-Amino-2-oxo-1-pheny|ethy|)thio)-3,5-dicyano-4-ethylpyridin-2- y|)pyrro|idine-3-carboxamide; 2-((6-((3-Aminopropyl) (methyl) amino)-3, 5-dicyano-4-cyclopropylpyridin-2-yl) thio)-2-phenylacetamide; 2-((3,5-Dicyan0-4-cyclopropyl-6-((2-(3-hydroxyazetidin-1-y|)-2- oxoethy|)(methy|)amino) pyridin-2-y|)thio)-2-phenylacetamide; 2-((6-(4-((2-Amino-2-oxoethy|)amino)piperidin-1-yl)-3,5-dicyano-4-ethylpyridin-2- y|)thio)-2-phenylacetamide; 2-((6-((2-Amino-2-oxoethyl)(methy|)amino)-3,5-dicyano-4-cyclopropylpyridin-2- y|)thio)-2-phenylacetamide; 2-((6-((2-Amino-2-oxo-1-phenylethyl) thio)-3, 5-dicyano-4-cyclopropylpyridin-2- y|)(methy|)amino)ethy| carbamate; (2R)-2-Amino-N-(1-(6-((2-amino-2-oxo-1-pheny|ethy|)thio)-3,5-dicyano-4- ethylpyridin-2-y|)piperidin-4-yl)-3-hydroxypropanamide; (ZS)-2-Amino-N-(1-(6-((2-amino-2-oxo-1-phenylethyl) thio)-3, 5-dicyano-4- ethylpyridin-2-yl) piperidin-4-yl)-3-hydroxypropanamide; 2-(4-(2-Amino-2-oxoethyl)phenyl)-2-(3,5-dicyano-4-ethyl-6-(4-methyl-1 ,4- diazepan-1-y|)pyridin-2-y|thio)acetamide; 2-(4-(2-Amin0-2-oxoethyl)phenyl)-2-(3,5-dicyano-6-(dimethylamino)-4-ethylpyridin- 2-y|thio)acetamide; WO 2017/216727 PCT/IB2017/053511 1231 2-((3,5-Dicyano-6-(dimethylamino)-4-ethylpyridin-2-y|)thio)-2-(4-(N- methylsulfamoyl)pheny|)acetamide; 2-((3,5-Dicyano-6-(dimethylamino-de)-4-ethylpyridin-2-y|)thio)-2-phenylacetamide; (R)-2-((3,5-Dicyano-4-ethy|-6-(4-(pyrrolidin-1-yl)piperidin-1-y|)pyridin-2-y|)thio)-2- phenylacetamide; (R)-2-((3,5-Dicyano-6-(4-(dimethy|amino)piperidin-1-yl)-4-ethylpyridin-2-y|)thio)-2- phenylacetamide; 2-(3,5-dicyano-6-(dimethylamino)-4-ethylpyridin-2-ylthio)-2-(3-(2- (dimethy|amino)ethoxy)pheny|)acetamide; 2-((3,5-Dicyano-4-ethyl-6-(4-(neopentylamino)piperidin-1-y|)pyridin-2-y|)thio)-2-(4- fluorophenyl)acetamide; 2-((3,5-dicyano-4-ethyl-6-(3-fluoro-4-A(neopenty|amino)piperidin-1-y|)pyridin-2- y|)thio)-2-phenylacetamide; 2-((6-(4-aminopiperidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-y|)thio)-2-(4- (trifluoromethyl)phenyl)acetamide; 2-((3,5-Dicyano-4-ethyl-6-(4-(pyrroIidin-1-y|)piperidin-1-y|)pyridin-2-y|)thio)-2- phenylacetamide; (R)-2-((6-(4-aminopiperidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-y|)thio)-2- phenylacetamide; 2-((6-((2-amino-2-oxoethyl)(methy|)amino)-3,5-dicyano-4-ethylpyridin-2-y|)thio)-2- phenylacetamide; (single enantiomer) (38)-1-(6-((2-amino-2-oxo-1-phenylethyl) thio)-3, 5-dicyano-4-ethylpyridin-2-yl) Pyrrolidin-3-yl dihydrogen phosphate; (3R)-1-(6-((2-amino-2-oxo-1-pheny|ethy|)thio)-3,5-dicyano-4-ethylpyridin-2- y|)pyrro|idin-3-yl dihydrogen phosphate; (S)-1-(6-(((S)-2-amino-2-oxo-1-pheny|ethy|)thio)-3,5-dicyano-4-ethylpyridin-2- y|)pyrro|idin-3-yl dihydrogen phosphate; (S)-1-(6-(((R)-2-amino-2-oxo-1-phenylethyl) thio)-3,5-dicyano-4-ethylpyridin-2-yl) pyrrolidin-3-yl dihydrogen phosphate; 2-((3,5-Dicyano-6-(dimethylamino)-4-ethylpyridin-2-y|)thio)-2-(3- (dimethylphosphory|)pheny|)acetamide; WO 2017/216727 PCT/IB2017/053511 1232 2-((3,5-Dicyano-4-ethyl-6-((8)-3-hydroxypyrrolidin-1-y|)pyridin-2-y|)thio)-2-(3-( dimethylphosphory|)pheny|)acetamide; (R)-2-((6-((2-amino-2-oxo-1-pheny|ethy|)thio)-3,5-dicyano-4-ethy|pyridin-2- y|)(methy|)amino)ethyl dihydrogen phosphate; (R)-2-((3,5-dicyano-4-ethyl-6-((S)-3-hydroxypyrro|idin-1-y|)pyridin-2-y|)thio)-2-(4- methoxypheny|)acetamide; (R)-2-(4-chIorophenyl)-2-((3,5-dicyano-4-ethyl-6-((S)-3-hydroxypyrrolidin-1- y|)pyridin-2-y|)thio)acetamide; (R)-2-((3,5-dicyano-4-ethyl-6-((S)-3-hydroxypyrro|idin-1-y|)pyridin-2-y|)thio)-2-(4- fluoro pheny|)acetamide; (S)-1-(6-(((R)-2-amino-1-(4-fluorophenyl)-2-oxoethy|)thio)-3,5-dicyano-4- ethylpyridin-2-y|)pyrro|idin-3-yl dihydrogen phosphate; 2-((3, 5-dicyano-4-ethy|-6-((S)-3-hydroxypyrro|idin-1-yl) pyridin-2-yl) thio)-2-(4- fluorophenyl) acetamide; 2-((3,5-dicyan0-4-ethy|-6-((S)-3-hydroxypyrrolidin-1-yl) pyridin-2-yl) thio)-2-(2, 6- difluorophenyl) acetamide; 2-((3, 5-dicyano-4-ethyl-6-((S)-3-hydroxypyrrolidin-1-yl) pyridin-2-yl) thio)-2-(2, 3- difluorophenyl) acetamide; 2-((3, 5-dicyano-4-ethyl-6-((S)-3-hydroxypyrrolidin-1-yl) pyridin-2-yl) thio)-2-(2, 4- difluorophenyl) acetamide; 2-((3,5-dicyano-4-ethy|-6-(4-((S)-2-(hydroxymethy|)pyrro|idin-1-y|)piperidin-1- y|)pyridin-2-y|)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-(4-((2-hydroxyethy|)(methy|)amino)piperidin-1-y|)pyridin- 2-y|)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-(4-((2-hydroxy-2-methy|propy|)(methy|)amino)piperidin-1- y|)pyridin-2-y|)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-(4-(pyrroIidin-1-y|methy|)piperidin-1-y|)pyridin-2-y|)thio)- 2-phenylacetamide; 2-((3,5-dicyano-4-ethy|-6-(4-((2-methoxy-2-methylpropy|)amino)piperidin-1- y|)pyridin-2-y|)thio)-2-phenylacetamide; WO 2017/216727 PCT/IB2017/053511 1233 2-((3,5-dicyano-4-ethy|-6-(4-((2-hydroxy-2-methy|propy|)amino)piperidin-1- y|)pyridin-2-y|)thio)-2-phenylacetamide; 2-((3,5-dicyano-6-(4-(cyclobuty|amino)piperidin-1-yl)-4-ethylpyridin-2-y|)thio)-2- phenylacetamide; 2-((3,5-dicyano-4-ethy|-6-(4-(((3-methyloxetan-3-yl)methy|)amino)piperidin-1- y|)pyridin-2-y|)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-(4-(4-methylpiperazin-1-y|)piperidin-1-y|)pyridin-2- y|)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethy|-6-(4-((R)-2-methylpyrrolidin-1-y|)piperidin-1-y|)pyridin-2- y|)thio)-2-phenylacetamide; 2-((3,5-dicyano-6-(4-((2R,5S)-2,5-dimethylpyrrolidin-1-y|)piperidin-1-y|)-4- ethylpyridin-2-y|)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethy|-6-(4-((S)-2-methylpyrrolidin-1-y|)piperidin-1-y|)pyridin-2- y|)thio)-2-phenylacetamide; 2-((3,5-dicyan0-6-(4-(cyclobuty|(methy|)amino)piperidin-1-y|)-4-ethy|pyridin-2- y|)thio)-2-phenylacetamide; 2-(6-(4-(benzylamino)piperidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-y|thio)-2- phenylacetamide; 2-((3,5-dicyano-4-ethy|-6-(4-(((6-methoxypyridin-2-yl)methy|)amino)piperidin-1- y|)pyridin-2-y|)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethy|-6-(4-((S)-3-fluoropyrrolidin-1-y|)piperidin-1-y|)pyridin-2- y|)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-(methyl(2-((R)-2-methylpyrrolidin-1- y|)ethy|)amino)pyrid in-2-y|)th io)-2-phenylacetamide; 2-((3,5-dicyano-4-ethy|-6-(4-((R)-3-fluoropyrrolidin-1-y|)piperidin-1-y|)pyridin-2- y|)thio)-2-phenylacetamide; 2-((3,5-dicyano-6-(4-((2S,5S)-2,5-dimethylpyrrolidin-1-y|)piperidin-1-y|)-4- ethylpyridin-2-y|)thio)-2-phenylacetamide; 2-((3,5-dicyan0-4-ethyl-6-(methy|(2-((8)-2-methylpyrrolidin-1- y|)ethy|)amino)pyrid in-2-y|)th io)-2-phenylacetamide; WO 2017/216727 PCT/IB2017/053511 1234 2-((3,5-dicyan0-4-ethyl-6-(4-((R)-2-(hydroxymethy|)pyrro|idin-1-y|)piperidin-1- y|)pyridin-2-y|)thio)-2-phenylacetamide; 2-((3,5-dicyano-6-(4-(dimethy|amino)piperidin-1-yl)-4-ethylpyridin-2-y|)thio)-2-(4- fluorophenyl)acetamide; 2-((3,5-dicyano-4-ethyl-6-(4-(((1-methylcyclobutyl)methy|)amino)piperidin-1- y|)pyridin-2-y|)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethy|-6-(4-(((6-methoxypyridin-3-yl)methy|)amino)piperidin-1- y|)pyridin-2-y|)thio)-2-phenylacetamide; 2-(3,5-dicyano-4-ethy|-6-((2-(ethylamino)ethy|)(methy|)amino)pyridin-2-y|thio)-2- phenylacetamide; 2-((3,5-dicyano-4-ethy|-6-(4-((4-methy|piperazin-1 -y|)methy|) piperidin-1 -yl) pyridin- 2-y|)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethy|-6-(methy|(2-(methylamino)ethy|)amino)pyridin-2-y|)thio)-2- phenylacetamide; 2-((3,5-dicyano-6-(4-((2R,5R)-2,5-dimethylpyrrolidin-1-y|)piperidin-1-y|)-4- ethylpyridin-2-y|)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-(4-(((1-methylcyclopropyl)methy|)amino)piperidin-1- y|)pyridin-2-y|)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethy|-6-(4-((4-fluorobenzy|)amino)piperidin-1-y|)pyridin-2-y|)thio)- 2-phenylacetamide; 2-((3,5-dicyano-4-ethy|-6-((2-((S)-2-(hyd roxymethy|)pyrro|idin-1- y|)ethy|)(methy|)amino)pyridin-2-y|)thio)-2-phenylacetamide; 2-(3,5-dicyano-6-((2-((2S,5R)-2,5-dimethylpyrrolidin-1-y|)ethy|)(methy|)amino)-4- ethylpyridin-2-ylthio)-2-phenylacetamide; 2-((6-((2-(azepan-1-y|)ethy|)(methy|)amino)-3,5-dicyano-4-ethylpyridin-2-y|)thio)-2- phenylacetamide; 2-((3,5-dicyano-4-ethy|-6-(methy|(2-(piperidin-1-y|)ethy|)amino)pyridin-2-y|)thio)-2- phenylacetamide; 2-((3,5-dicyano-4-ethy|-6-((2-((R)-2-(hydroxymethy|)pyrro|idin-1- y|)ethy|)(methy|)amino)pyridin-2-y|)thio)-2-phenylacetamide; WO 2017/216727 PCT/IB2017/053511 1235 2-(3,5-dicyano-4-ethy|-6-((2-(ethy|(methy|)amino)ethy|)(methy|)amino)pyridin-2- ylthio)-2-phenylacetamide; 2-((3,5-dicyano-6-((2-((2R,5R)-2,5-dimethylpyrrolidin-1-y|)ethy|)(methy|)amino)-4- ethylpyridin-2-y|)thio)-2-phenylacetamide; 2-(3,5-dicyano-4-ethy|-6-((2-((S)-3-hydroxypyrrolidin-1- y|)ethy|)(methy|)amino)pyridin-2-ylthio)-2-phenylacetamide; methyl 2-((1-(6-((2-amino-2-oxo-1-pheny|ethy|)thio)-3,5-dicyano-4-ethylpyridin-2- y|)piperidin-4-y|)amin0)-2-methylpropanoate; 2-((3,5-dicyano-4-ethyl-6-(methy|(2-(neopentylamino)ethy|)amino)pyridin-2-y|)thio)- 2-phenylacetamide; 2-(3,5-dicyano-4-ethyl-6-(methy|(2-(1-methylcyclopropylamino)ethyl)amino)pyridin- 2-ylthio)-2-phenylacetamide; 2-((3,5-dicyano-6-((2-((2S,5S)-2,5-dimethylpyrrolidin-1-y|)ethy|)(methy|)amino)-4- ethylpyridin-2-y|)thio)-2-phenylacetamide; 2-((3,5-dicyan0-4-ethy|-6-((2-((2-methoxyethyl)amino)ethy|)(methyl)amino)pyridin- 2-y|)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethy|-6-(4-((2-methoxy-2-methy|propy|)(methy|)amino)piperidin- 1-y|)pyrid in-2-y|)th io)-2-phenylacetamide; 2-((3,5-dicyano-6-((2-(dimethylamino)ethyl)(methy|)amino)-4-ethylpyridin-2- y|)thio)-2-phenylacetamide; 2-(3,5-dicyano-4-ethy|-6-((2-((R)-3-hydroxypyrrolidin-1- y|)ethy|)(methy|)amino)pyridin-2-ylthio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-((2-((2-fluoroethy|)amino)ethy|)(methy|)amino)pyridin-2- y|)thio)-2-phenylacetamide; 2-((3,5-dicyano-6-(4-(3,3-difluoropyrrolidin-1-y|)piperidin-1-y|)-4-ethy|pyridin-2- y|)thio)-2-phenylacetamide; 2-((1-(6-((2-amino-2-oxo-1-pheny|ethy|)thio)-3,5-dicyano-4-ethylpyridin-2- y|)piperidin-4-y|)amino)acetic acid; 2-((6-((3-aminocyclobuty|)(methy|)amino)-3,5-dicyano-4-ethylpyridin-2-y|)thio)-2- phenylacetamide; WO 2017/216727 PCT/IB2017/053511 1236 (R)-2-(3,5-dicyano-4-ethyl-6-(methy|((R)-tetrahyd rofuran-3-y|)amino)pyridin-2- ylthio)-2-phenylacetamide; (S)-2-(3,5-dicyano-4-ethy|-6-(methy|((R)-tetrahydrofu ran-3-y|)amino)pyridin-2- ylthio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-(4-morpholinopiperidin-1-yl)pyridin-2-y|)thio)-2- phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-(4-(2-hyd roxyethyl)-3-oxopiperazin-1-y|)pyridin-2-y|)thio)- 2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-(4-(pyrroIidin-1-y|)piperidin-1-y|)pyridin-2-y|)thio)-2-(4- fluoropheny|)acetamide; (R)-2-((6-((38,4R)-4-amino-3-fluoropiperidin-1-yl)-3,5-dicyano-4-ethylpyridin-2- y|)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-(3-fluoro-4-(methy|amino)piperidin-1-y|)pyridin-2-y|)thio)- 2-phenylacetamide; rel-2-((6-(trans)-4-amin0-3-fluoropiperidin-1-yl)-3,5-dicyano-4-ethylpyridin-2- y|)thio)-2-phenylacetamide; (R)-2-((6-((3R,4S)-4-amino-3-fluoropipe rid in-1 -yl)-3 ,5-dicyano-4-ethylpyrid in-2- y|)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-(3-fluoro-4-((2-methoxyethy|)amino)piperidin-1-y|)pyridin- 2-y|)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-(methyl(2-(pyrrolidin-1-y|)ethy|)amino)pyridin-2-y|)thio)-2- phenylacetamide; 2-((3,5-dicyano-6-(3-((dimethy|amino)methy|)pyrro|idin-1-y|)-4-ethy|pyridin-2- y|)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethy|-6-(4-((2-hydroxy-2-methy|propy|)amino)piperidin-1- y|)pyrid in-2-y|)th io)-2-(4-fluoropheny|)acetamide; (R)-2-((6-((38,4R)-4-amino-3-hydroxypiperidin-1-yl)-3,5-dicyano-4-ethy|pyridin-2- y|)thio)-2-phenylacetamide; 2-((3,5-dicyano-6-((2-(diethy|amino)ethy|)(methy|)amino)-4-ethylpyridin-2-y|)thio)- 2-phenylacetamide; WO 2017/216727 PCT/IB2017/053511 1237 2-((3,5-dicyano-6-((2-((R)-3-(dimethy|amino)pyrro|idin-1-y|)ethy|)(methy|)amino)-4- ethylpyridin-2-y|)thio)-2-phenylacetamide; 2-((3,5-dicyano-6-((2-((8)-3-(dimethylamino)pyrrolidin-1-y|)ethy|)(methy|)amino)-4- ethylpyridin-2-y|)thio)-2-phenylacetamide; (R)-2-((6-((3R,4R)-4-amino-3-fluoropiperidin-1-yl)-3,5-dicyano-4-ethylpyridin-2- y|)thio)-2-phenylacetamide; (R)-2-((6-((38,4S)-4-amino-3-fluoropipe rid in-1 -yl)-3,5-dicyano-4-ethylpyrid in-2- y|)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-(3-(methylamino)pyrro|idin-1-y|)pyridin-2-y|)thio)-2- phenylacetamide; 2-((6-(4-aminopiperidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-y|)thio)-2-(4- fluorophenyl)acetamide; (R)-2-((6-((3R,4R)-4-amino-3-hydroxypiperidin-1-yl)-3,5-dicyano-4-ethy|pyridin-2- y|)thio)-2-phenylacetamide; 2-((6-((R)-3-aminopyrrolidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-y|)thio)-2- phenylacetamide; 2-((6-(3-(aminomethyl)pyrrolidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-y|)thio)-2- phenylacetamide; 2-((3,5-dicyano-4-ethy|-6-(4-(methylamino)piperidin-1-y|)pyridin-2-y|)thio)-2-(4- fluorophenyl)acetamide; 2-((3,5-dicyano-6-(4-(cyclopropylamino)-3-fluoropiperidin-1-y|)-4-ethy|pyridin-2- y|)thio)-2-phenylacetamide; 2-((6-((S)-3-aminopyrrolidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-y|)thio)-2- phenylacetamide; 2-((6-((2-((R)-3-aminopyrrolidin-1-y|)ethy|)(methy|)amino)-3,5-dicyano-4- ethylpyridin-2-y|)thio)-2-phenylacetamide; 3,5-dicyano-6-((R)-3-(dimethylamino)pyrrolidin-1-yl)-4-ethylpyridin-2-y|)thio)-2-(4- fluorophenyl)acetamide; (S)-2-((6-((38,4R)-4-amino-3-fluoropipe rid in-1 -yl)-3,5-dicyano-4-ethylpyrid in-2- y|)thio)-2-phenylacetamide; WO 2017/216727 PCT/IB2017/053511 1238 2-((3,5-dicyano-4-ethyl-6-(4-(neopenty|amino)piperidin-1-y|)pyridin-2-y|)thio)-2-(4- (trifluoromethyl)pheny|)acetamide; tert-butyl ((3S,4R)-1-(6-(((R)-2-amino-2-oxo-1-pheny|ethy|)thio)-3,5-dicyano-4- ethylpyrid in-2-yl)-3-hyd roxypiperid in-4-y|)ca rba mate; rel-tert-butyl (cis)-1-(6-((2-amino-2-oxo-1-pheny|ethy|)thio)-3,5-dicyano-4- ethylpyridin-2-yl)-3-fluoropiperidin-4-y|)ca rbamate; 2-((6-((2-((S)-3-aminopyrrolidin-1-y|)ethy|)(methy|)amino)-3,5-dicyano-4- ethylpyridin-2-y|)thio)-2-phenylacetamide; 2-((3,5-dicyano-6-((R)-3-(dimethy|amino)pyrro|idin-1-yl)-4-ethylpyridin-2-y|)thio)-2- phenylacetamide; tert-butyl ((3R,4S)-1-(6-(((R)-2-amino-2-oxo-1-pheny|ethy|)thio)-3,5-dicyano-4- ethylpyrid in-2-yl)-3-hyd roxypiperid in-4-y|)ca rba mate; rel-ten-butyl (cis)-1-(6-((2-amino-2-oxo-1-pheny|ethy|)thio)-3,5-dicyano-4- ethylpyridin-2-yl)-3-fluoropiperidin-4-y|)carbamate; 2-((3,5-dicyano-6-((S)-3-(dimethylamino)pyrro|idin-1-yl)-4-ethylpyridin-2-y|)thio)-2- phenylacetamide; (S)-2-((6-((3R,4S)-4-amino-3-fluoropipe rid in-1 -yl)-3,5-dicyano-4-ethylpyrid in-2- y|)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethy|-6-((S)-3-((2-hydroxy-2-methylpropy|)amino)pyrro|idin-1- y|)pyridin-2-y|)thio)-2-phenylacetamide; tert-butyl ((3R,4R)-1-(6-(((R)-2-amino-2-oxo-1-pheny|ethy|)thio)-3,5-dicyano-4- ethylpyrid in-2-yl)-3-hyd roxypiperid in-4-y|)ca rba mate; 2-((3,5-dicyano-6-((S)-3-(dimethy|amino)pyrro|idin-1-yl)-4-ethylpyridin-2-y|)thio)-2- (4-fluoropheny|)acetamide; rel-2-((6-cis-4-amino-3-fluoropiperidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-y|)thio)-2- phenylacetamide; 2-((3,5-dicyan0-4-ethyl-6-(4-(methylamino)piperidin-1-y|)pyridin-2-y|)thio)-2- phenylacetamide; 2-((3,5-dicyano-6-(4-(dimethy|amino)piperidin-1-yl)-4-ethylpyridin-2-y|)thio)-2- phenylacetamide; WO 2017/216727 PCT/IB2017/053511 1239 2-((3,5-dicyan0-4-ethyl-6-(4-(ethy|(methy|)amino)piperidin-1-yl)pyridin-2-y|)thio)-2- phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-(4-(neopenty|amino)piperidin-1-y|)pyridin-2-y|)thio)-2- phenylacetamide; 2-((3,5-dicyano-4-ethy|-6-(4-(methy|(neopenty|)amino)piperidin-1-yl)pyridin-2- y|)thio)-2-phenylacetamide; 2-((3,5-dicyano-6-(4-(cyclopropy|amino)piperidin-1-yl)-4-ethylpyridin-2-y|)thio)-2- phenylacetamide; 2-((3,5-dicyano-4-ethy|-6-(4-((2-methoxyethy|)amin0)piperidin-1-yl)pyridin-2- y|)thio)-2-phenylacetamide; 2-((3,5-dicyano-6-(4-((2,2-difluoroethy|)amino)piperidin-1-yl)-4-ethylpyridin-2- y|)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethy|-6-((R)-2-((neopentylamin0)methyl)morpho|ino)pyridin-2- y|)thio)-2-phenylacetamide; 2-((3,5-dicyano-6-(2-((dimethy|amino)methy|)morpholino)-4-ethylpyridin-2-y|)thio)- 2-phenylacetamide; 2-((3,5-dicyano-6-(2-((diethy|amino)methy|)morpholin0)-4-ethylpyridin-2-y|)thio)-2- phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-(2-(pyrrolidin-1-ylmethyl)morpholino)pyridin-2-y|)thio)-2- phenylacetamide; (R)-2-((6-((R)-2-(aminomethyl)morpholino)-3 ,5-d icyano-4-ethylpyridin-2-y|)th io)-2- phenylacetamide; 2-((6-(2-(aminomethyl)morpholino)-3,5-dicyano-4-ethylpyridin-2-y|)thio)-2- phenylacetamide; 2-((3,5-dicyano-4-ethy|-6-(2-((methy|amino)methy|)morpholino)pyridin-2-y|)thio)-2- phenylacetamide; 2-((6-((R)-2-(a minomethy|)morpho|ino)-3 ,5-dicyano-4-ethylpyrid in-2-y|)th io)-2- phenylacetamide; 2-((3,5-dicyano-6-(3-((dimethylamino)methy|)piperidin-1-yl)-4-ethylpyridin-2- y|)thio)-2-phenylacetamide; WO 2017/216727 PCT/IB2017/053511 1240 2-((3,5-dicyano-4-ethy|-6-(3-((methy|amino)methyl)piperidin-1-y|)pyridin-2-y|)thio)- 2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-((S)-2-((neopentylamino)methy|)morpho|ino)pyridin-2- y|)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-((S)-3-((neopenty|amino)methy|)piperidin-1-y|)pyridin-2- y|)thio)-2-phenylacetamide; 2-amino-N-(((2S)-4-(6-((2-amino-2-oxo-1-pheny|ethy|)thio)-3,5-dicyano-4- ethylpyridin-2-y|)morpho|in-2-yl)methyl)-2-methylpropanamide; 2-((6-((S)-3-(aminomethy|)piperidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-y|)thio)-2- phenylacetamide; 2-((3,5-dicyano-6-((R)-2-((diethylamino)methy|)morpholino)-4-ethylpyridin-2- y|)thio)-2-phenylacetamide; 2-amino-N-(((2R)-4-(6-((2-amino-2-oxo-1-pheny|ethy|)thio)-3,5-dicyano-4- ethylpyridin-2-y|)morpho|in-2-yl)methyl)-2-methylpropanamide; 2-((6-(4-aminopiperidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-y|)thio)-2-(3- fluoropyridin-2-y|)acetamide; 2-((6-((S)-2-(aminomethy|)morpho|ino)-3,5-dicyano-4-ethylpyridin-2-y|)thio)-2- phenylacetamide; 2-amino-N-(((3S)-1-(6-((2-amino-2-oxo-1-pheny|ethy|)thio)-3,5-dicyano-4- ethylpyridin-2-y|)piperidin-3-yl)methyl)-2-methylpropanamide; 2-amino-N-(((3S)-1-(6-((2-amino-2-oxo-1-pheny|ethy|)thio)-3,5-dicyano-4- ethylpyridin-2-y|)piperidin-3-y|)methy|)acetamide; 2-amino-N-(((2R)-4-(6-((2-amino-2-oxo-1-pheny|ethy|)thio)-3,5-dicyano-4- ethylpyridin-2-yl)morpholin-2-yl)methy|)acetamide; 2-((6-((R)-3-(aminomethy|)piperidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-y|)thio)-2-(4- fluoropheny|)acetamide; 2-((3,5-dicyano-4-ethy|-6-((R)-3-((neopenty|amino)methyl)piperidin-1-y|)pyridin-2- y|)thio)-2-(4-fluoropheny|)acetamide; 2-amin0-N-(((2S)-4-(6-((2-amino-2-oxo-1-pheny|ethy|)thio)-3,5-dicyano-4- ethylpyridin-2-y|)morpho|in-2-yl)methy|)acetamide; WO 2017/216727 PCT/IB2017/053511 1241 N-(((R)-4-(6-(((R)-2-amino-2-oxo-1-pheny|ethy|)thio)-3,5-dicyano-4-ethy|pyridin-2- y|)morphoIin-2-y|)methy|)-2-hydroxyacetamide; (S)-2-((6-(4-aminopiperidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-y|)thio)-2- phenylacetamide; 2-((6-((2-amino-2-oxo-1-pheny|ethy|)thio)-3,5-dicyano-4-ethy|pyridin-2- y|)(methy|)amino)-N-(2-hyd roxyethyl)-N-methylacetamide; 2-((3,5-dicyano-4-ethyl-6-((S)-3-(methylamino)piperidin-1-yl)pyridin-2-y|)thio)-2- phenylacetamide; 2-((6-(4-amino-4-methylpiperidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-y|)thio)-2- phenylacetamide; 2-((6-((2-amino-2-oxo-1-pheny|ethy|)thio)-3,5-dicyano-4-ethy|pyridin-2- y|)(methy|)amino)-N-((1-(hydroxymethy|)cyc|opropyl)methyl)-N-methylacetamide; 2-amino-N-(1-(6-((2-amino-2-oxo-1-pheny|ethy|)thio)-3,5-dicyano-4- cyclopropylpyridin-2-y|)azetidin-3-y|)acetamide; (ZS)-2-amino-N-(1-(6-((2-amino-2-oxo-1-pheny|ethy|)thio)-3,5-dicyano-4- cyclopropylpyridin-2-y|)azetidin-3-yl)-3-hydroxypropanamide; 2-((6-((S)-3-aminopiperidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-y|)thio)-2- phenylacetamide; 2-((3,5-dicyano-4-ethy|-6-((2-((R)-3-hydroxypyrrolidin-1-y|)-2- oxoethy|)(methy|)amino)pyridin-2-y|)thio)-2-phenylacetamide; (2R)-2-amino-N-(1-(6-((2-amino-2-oxo-1-pheny|ethy|)thio)-3,5-dicyano-4- cyclopropylpyridin-2-y|)azetidin-3-yl)-3-hydroxypropanamide; 2-((6-((2-amino-2-oxo-1-pheny|ethy|)thio)-3,5-dicyano-4-ethy|pyridin-2- y|)(methy|)amino)-N-(3-hyd roxy-2,2-dimethylpropyl)-N-methylacetamide; 2-((3,5-dicyano-4-ethy|-6-((2-((S)-3-hydroxypyrrolidin-1-y|)-2- oxoethy|)(methy|)amino)pyridin-2-y|)thio)-2-phenylacetamide; 2-((6-(4-amino-4-methylpiperidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-y|)thio)-2- phenylacetamide; 2-((6-(4-(aminomethyl)-4-fluoropiperidin-1-yl)-3,5-dicya no-4-ethylpyridin-2-y|)th io)- 2-phenylacetamide hydrochloride; WO 2017/216727 PCT/IB2017/053511 1242 2-((6-((2-amino-2-oxo-1-pheny|ethy|)thio)-3,5-dicyano-4-cyclopropylpyridin-2- y|)(methy|)amino)-N-(2-aminoethy|)acetamide hydrochloride; 2-((3,5-dicyan0-4-ethyl-6-(methy|(2-oxo-2-(pyrrolidin-1-y|)ethy|)amino)pyridin-2- y|)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-((2-(4-hydroxypiperidin-1-y|)-2- oxoethyl)(methy|)amino)pyridin-2-y|)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-(methy|(2-oxo-2-(piperazin-1-y|)ethy|)amino)pyridin-2- y|)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-(methyl(2-morpholino-2-oxoethy|)amino)pyridin-2- y|)thio)-2-phenylacetamide; (R)-2-((6-((S)-3-(aminomethyl)-3-hydroxypyrrolidin-1-y|)-3,5-dicyano-4- ethylpyridin-2-y|)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-((8)-3-(g uanidinooxy)pyrro|idin-1-y|)pyridin-2-y|)thio)-2- phenylacetamide; 2-amino-N-(2-((6-((2-amino-2-oxo-1-pheny|ethy|)thio)-3,5-dicyano-4-ethy|pyridin-2- y|)(methy|)amino)ethy|)-2-methylpropanamide; 2-((6-((2-(2-aminoethoxy)ethy|)(methy|)amino)-3,5-dicyano-4-ethy|pyridin-2- y|)thio)-2-phenylacetamide; 4-amino-N-(1-(6-((2-amino-2-oxo-1-pheny|ethy|)thio)-3,5-dicyano-4-ethy|pyridin-2- y|)piperidin-4-y|)butanamide; 2-((6-((2-amino-2-oxo-1-pheny|ethy|)thio)-3,5-dicyano-4-ethy|pyridin-2- y|)(methy|)amino)-N-(2-aminoethyl)acetamide; 2-((6-((2-(azetidin-1-yl)-2-oxoethyl)(methy|)amino)-3,5-dicyano-4-ethylpyridin-2- y|)thio)-2-phenylacetamide; 2-((6-((R)-3-(aminomethyl)-3-fluoropyrrolidin-1-yl)-3,5-dicyano-4-ethy|pyridin-2- y|)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethy|-6-((2-(3-hydroxyazetidin-1-y|)-2- oxoethy|)(methy|)amino)pyridin-2-y|)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-(4-(guanidinooxy)piperidin-1-y|)pyridin-2-y|)thio)-2- phenylacetamide; WO 2017/216727 PCT/IB2017/053511 1243 2-((6-(3-aminoazetidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-y|)thio)-2- phenylacetamide; (single stereoisomer) 2-((3,5-dicyano-4-ethy|-6-((R)-3-(methylamino)piperidin-1-y|)pyridin-2-y|)thio)-2- phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-((2-((3R,4S)-3-hyd roxy-4-(hydroxymethy|)pyrro|idin-1-y|)- 2-oxoethy|)(methy|)amino)pyridin-2-y|)thio)-2-phenylacetamide; (R)-2-((6-((S)-3-(aminomethyl)-3-fluoropyrrolidin-1-yl)-3,5-dicyano-4-ethylpyridin-2- y|)thio)-2-phenylacetamide; 2-((6-((2-amino-2-oxo-1-pheny|ethy|)thio)-3,5-dicyano-4-cyclopropylpyridin-2- y|)(methy|)amino)-N-(1,3-dihydroxypropan-2-y|)acetamide; 2-((3,5-dicyano-4-ethy|-6-((S)-3-(oxetan-3-ylamino)piperidin-1-y|)pyridin-2-y|)thio)- 2-phenylacetamide; 2-((6-((2-amino-2-oxo-1-pheny|ethy|)thio)-3,5-dicyano-4-cyclopropylpyridin-2- y|)(methy|)amino)-N,N-bis(2-hydroxyethy|)acetamide; 2-amino-N-(1-(6-((2-amino-2-oxo-1-pheny|ethy|)thio)-3,5-dicyano-4- cyclopropylpyridin-2-y|)piperidin-4-y|)acetamide; 2-((3,5-dicyano-4-ethyl-6-(4-((2-hydroxyethy|)amino)-4-methylpiperidin-1- y|)pyridin-2-y|)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-((2-(guanidinooxy)ethy|)(methy|)amino)pyridin-2-y|)thio)- 2-phenylacetamide; 2-((6-(4-((2-aminoethy|)amino)piperidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-y|)thio)- 2-phenylacetamide; 2-((3,5-dicyano-4-ethy|-6-((2-((S)-2-(hyd roxymethy|)morpho|ino)-2- oxoethy|)(methy|)amino)pyridin-2-y|)thio)-2-phenylacetamide; 2-((3,5-dicyano-6-((2-((cis)-3,4-dihydroxypyrrolidin-1-y|)-2- oxoethyl)(methy|)amino)-4-ethylpyridin-2-y|)thio)-2-phenylacetamide; 2-((3,5-dicyan0-4-ethyl-6-((2-((8)-3-(hydroxymethy|)pyrrolidin-1-y|)-2- oxoethy|)(methy|)amino)pyridin-2-y|)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-((2-((38,4S)-3-hydroxy-4-(hydroxymethy|)pyrro|idin-1-y|)- 2-oxoethyl)(methy|)amino)pyridin-2-y|)thio)-2-phenylacetamide; WO 2017/216727 PCT/IB2017/053511 1244 2-((3,5-dicyano-4-ethyl-6-((8)-3-(neopentylamino)piperidin-1-yl)pyridin-2-y|)thio)-2- phenylacetamide; 2-((3,5-dicyano-4-ethy|-6-((2-((R)-3-(hydroxymethyl)pyrrolidin-1-y|)-2- oxoethy|)(methy|)amino)pyridin-2-y|)thio)-2-phenylacetamide; 2-((3,5-dicyano-6-((2-((3R,4R)-3,4-dihydroxypyrrolidin-1-y|)-2- oxoethyl)(methy|)amino)-4-ethylpyridin-2-y|)thio)-2-phenylacetamide; (R)-2-((3,5-dicyano-4-ethyl-6-((S)-3-hyd roxy-3-(hyd roxymethy|)pyrro|idin-1- y|)pyridin-2-y|)thio)-2-phenylacetamide; (28)-2-amino-N-(1-(6-((2-amino-2-oxo-1-pheny|ethy|)thio)-3,5-dicyano-4- cyclopropylpyridin-2-y|)piperidin-4-y|)propanamide; 2-((6-(4-(2-aminoethoxy)piperidin-1-yl)-3,5-dicyano-4-cyclopropylpyridin-2-y|)thio)- 2-phenylacetamide; 2-((3,5-dicyano-4-cyc|opropy|-6-(4-((2-hydroxyethy|)amino)piperidin-1-y|)pyridin-2- y|)thio)-2-phenylacetamide; 2-((6-((2-amino-2-oxo-1-pheny|ethy|)thio)-3,5-dicyano-4-ethy|pyridin-2- y|)(methy|)amino)-N-(1,3-dihydroxypropan-2-y|)acetamide; 2-((3,5-dicyano-6-((2-((3R,5S)-3 ,5-dihyd roxypiperidin-1-y|)-2- oxoethyl)(methy|)amino)-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-6-((2-((3S,4S)-3,4-dihydroxypyrrolidin-1-y|)-2- oxoethyl)(methy|)amino)-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-(4-((2-hydroxyethy|)amino)-4-(hydroxymethy|)piperidin-1- y|)pyridin-2-y|)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethy|-6-((2-((R)-2-(hyd roxymethyl)morpho|ino)-2- oxoethy|)(methy|)amino)pyridin-2-y|)thio)-2-phenylacetamide; 2-((6-((2-amino-2-oxo-1-pheny|ethy|)thio)-3,5-dicyano-4-ethy|pyridin-2- y|)(methy|)amino)-N-methoxyacetamide; 2-((3,5-dicyano-4-ethyl-6-((2-((3R,4R)-3-hydroxy-4-(hydroxymethyl)pyrro|idin-1-y|)- 2-oxoethyl)(methy|)amino)pyridin-2-y|)thio)-2-phenylacetamide; 2-((6-((2-amino-2-oxo-1-pheny|ethy|)thio)-3,5-dicyano-4-ethy|pyridin-2- y|)(methy|)amino)-N-(3-hyd roxypropyl)-N-methylacetamide; WO 2017/216727 PCT/IB2017/053511 1245 2-((6-((2-amino-2-oxo-1-pheny|ethy|)thio)-3,5-dicyano-4-ethy|pyridin-2- y|)(methy|)amino)-N-((R)-2,3-dihydroxypropy|)acetamide; 2-((6-(4-((2-amino-2-oxoethy|)amino)piperidin-1-y|)-3,5-dicyano-4- cyclopropylpyridin-2-yl)thio)-2-phenylacetamide; 2-((6-((2-amino-2-oxo-1-pheny|ethy|)thio)-3,5-dicyano-4-ethy|pyridin-2- y|)(methy|)amino)-N,N-bis(2-hydroxyethy|)acetamide; 2-((6-((2-amino-2-oxo-1-pheny|ethy|)thio)-3,5-dicyano-4-ethy|pyridin-2- y|)(methy|)amino)-N-(2-hydroxyethy|)acetamide; 2-((6-((3-aminopropy|)(methy|)amino)-3,5-dicyano-4-ethylpyridin-2-y|)thio)-2- phenylacetamide; 2-((6-(3-(aminomethy|)azetidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-y|)thio)-2- phenylacetamide; 2-((6-((2-amino-2-oxo-1-pheny|ethy|)thio)-3,5-dicyano-4-ethy|pyridin-2- y|)(methy|)amino)-N-((1 -(hyd roxymethy|)cyc|o pro py|)methy|)acetamide; (R)-2-((3,5-dicyano-4-ethyl-6-((S)-3-hydroxypyrrolidin-1-y|)pyridin-2-y|)thio)-2-(2,4- difluoropheny|)acetamide; 2-((6-((2-amino-2-oxo-1-pheny|ethy|)thio)-3,5-dicyano-4-ethy|pyridin-2- y|)(methy|)amino)-N-(3-(hydroxymethyl)oxetan-3-y|)acetamide; 2-((3,5-dicyano-4-ethyl-6-(3-(guanidinooxy)azetidin-1-y|)pyridin-2-y|)thio)-2- phenylacetamide; 2-((6-((2-amino-2-oxo-1-pheny|ethy|)thio)-3,5-dicyano-4-ethy|pyridin-2- yl)(methy|)amino)-N-(3-hyd roxypropy|)acetamide; 2-((3,5-dicyano-6-(4-(2,3-dihyd roxypropyl)-1 ,4-diazepan-1-y|)-4-ethy|pyridin-2- y|)thio)-2-phenylacetamide; 2-((6-((2-amino-2-oxo-1-pheny|ethy|)thio)-3,5-dicyano-4-ethy|pyridin-2- y|)(methy|)amino)-N-hydroxyacetamide; 3-amino-N-(1-(6-((2-amino-2-oxo-1-pheny|ethy|)thio)-3,5-dicyano-4- cyclopropylpyridin-2-y|)azetidin-3-y|)oxetane-3-carboxamide; 2-((3,5-dicyano-4-ethy|-6-((S)-3-hydroxypyrrolidin-1-y|)pyridin-2-y|)thio)-2-(2- fluorophenyl)acetamide; WO 2017/216727 PCT/IB2017/053511 1246 2-((3,5-dicyano-6-((S)-3-(cyclopropylamino)piperidin-1-yl)-4-ethylpyridin-2-y|)thio)- 2-phenylacetamide; 2-((6-((2-amino-2-oxo-1-pheny|ethy|)thio)-3,5-dicyano-4-ethy|pyridin-2- y|)(methy|)amino)-N-(3-hydroxy-2,2-dimethy|propy|)acetamide; N-(2-(4H-1,2,4-triazoI-4-yl)ethy|)-2-((6-((2-amino-2-oxo-1-pheny|ethy|)thio)-3,5- dicyano-4-ethylpyridin-2-y|)(methy|)amino)acetamide; N1 -(2-((6-((2-amino-2-oxo-1 -pheny|ethy|)thio)-3,5-dicyano-4-ethylpyrid in-2- y|)(methy|)amino)ethy|)oxa|amide; 2-((6-(3-(aminomethyl)-3-fluoroazetidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-y|)thio)- 2-phenylacetamide; (R)-2-((3,5-dicyano-4-ethyl-6-((R)-3-hyd roxy-3-(hyd roxymethy|)pyrro|idin-1- y|)pyridin-2-y|)thio)-2-phenylacetamide; 2-((3,5-dicyano-6-((S)-3-((2,2-difluoroethy|)amino)piperidin-1-yl)-4-ethylpyridin-2- y|)thio)-2-phenylacetamide; 2-((6-((R)-3-aminopiperidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-y|)thio)-2- phenylacetamide; 2-((6-(4-aminopiperidin-1-yl)-3,5-dicyano-4-methoxypyridin-2-y|)thio)-2- phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-((S)-4-hydroxyisoxazolidin-2-y|)pyridin-2-y|)thio)-2- phenylacetamide; (R)-2-((3,5-dicyano-4-ethyl-6-((3-hydroxypro pyl)(methy|)amino)pyridin-2-y|)thio)-2- phenylacetamide; 2-((3,5-dicyano-6-((S)-3-hydroxypyrrolidin-1-yl)-4-methoxypyridin-2-y|)thio)-2- phenylacetamide; 2-((3,5-dicyano-4-ethy|-6-(4-(3-methoxyazetidin-1-y|)piperidin-1-y|)pyridin-2- y|)thio)-2-phenylacetamide; 2-((3,5-dicyan0-4-ethy|-6-(4-(3-methoxyazetidin-1-y|)piperidin-1-y|)pyridin-2- y|)thio)-2-(4-fluoropheny|)acetamide; (R)-2-((3,5-dicyano-4-ethy|-6-((2-hydroxyethy|)(methy|)amino)pyridin-2-y|)thio)-2- phenylacetamide; WO 2017/216727 PCT/IB2017/053511 1247 (R)-2-((3,5-dicyano-4-ethyl-6-((S)-3-hydroxypyrrolidin-1-y|)pyridin-2-y|)thio)-2-(4- fluorophenyl)acetamide; (R)-2-((6-((R)-3-(aminomethyl)-3-hydroxypyrrolidin-1-yl)-3,5-dicyano-4- ethylpyridin-2-y|)thio)-2-phenylacetamide; 2-((3,5-Dicyano-6-(4-(cyclobutyl(methyl)amino)piperidin-1-yl)-4-ethylpyridin-2- y|)thio)-2-(4-fluoropheny|)acetamide; and 2-((3,5-dicyano-4-ethyl-6-(methyl(1-methylpyrrolidin-3-yl)amino)pyridin-2-yl)thio)-2- phenylacetamide; or a pharmaceutically acceptable salt or prodrug thereof.
7. A compound according to Formula (lVbbr): R41bbr 41bbr 42bbr X j|\)\/[X R43bbr N/ Y«mf~H2 R45bbr 0 lVbb ( r) wherein: X41bb' and X42bb' are independently selected from: --CN, methyl, fluoro, chloro, bromo and iodo; Y4bb' is selected from: S and NH; R41bb' is selected from: C1—6aIky|, C1-5a|ky| substituted with from 1 to 9 substituents independently selected from: fluoro, chloro, bromo, iodo, oxo, C1-4a|ky|oxy, -OH, -COOH, -NH2 -N(H)C1-4alkyl, -N(C1-4alkyl)2 and -CN, WO 2017/216727 PCT/IB2017/053511 1248 C1-4a|ky|oxy, C1-4a|ky|oxy substituted from 1 to 4 times by fluoro, -N(H)C1-4a|ky|, -N(C1-4alky|)2, -SC1—4alky|, aryl, aryl substituted with from 1 to 4 substituents independently selected from: fluoro, chloro, bromo, iodo, C1—6alkyI, C1-6a|ky| substituted with from 1 to 9 substituents independently selected from: fluoro, chloro, bromo, iodo, oxo, -OH, -NH2 and —CN, C1 —4a|koxy, -NO2, and —NH2, heteroaryl, heteroaryl substituted with from 1 to 4 substituents independently selected from: fluoro, chloro, bromo, iodo, C1—6alky|, WO 2017/216727 PCT/IB2017/053511 1249 C1-6a|ky| substituted with from 1 to 9 substituents independently selected from: fluoro, chloro, bromo, iodo, oxo, -OH, -NH2 and —CN, C1 —4a|koxy, -NO2, and -NH2, cycloalkyl, cycloalkyl substituted with from 1 to 4 substituents independently selected from: fluoro, chloro, bromo, iodo, C1—6alky|, C1-6alkyl substituted with from 1 to 9 substituents independently selected from: fluoro, chloro, bromo, iodo, oxo, -OH, -NH2 and —CN, C1 -4a|koxy, -NO2, and -NH2; R43bb' is selected from: C1—4aIky|, phenyL phenyl substituted with 1 or 2 substituents independently selected WO 2017/216727 PCT/IB2017/053511 1250 from: fluoro, -CH3, -CF3, chloro, -C(O)pheny|, pyrrolidinyl, -P(O)(CH3)2, -C(O)NH2, -S(O)2NHCH3, -OCH2CH2N(CH3)2 and —CH2C(O)NH2, thienyl, piperidinyl, pyridine, and pyridine substituted with 1 or 2 substituents independently selected from: fluoro, -CH3, -CF3, and -OCH3; R44bb' and R45bb' are independently selected from: hydrogen, C1—6alkyl, C1-6a|ky| substituted with from 1 to 9 substituents independently selected from: phenyl, morpholino, triazolyl, imidazolyl, pyrrolidinyl, -OC(O)NH2, -OCH2CH2NH2, -ONHC(NH2)NH2, -NHCH2C(CH3)3, -NOCH3, -NHOH, -NHCH2CH2F, -N(CH3)CH2CH2OCH3, -N(CH2CH3)2, -NCH(CH2OH)2, -N(CH2CH2OH)2, -NHCH2CH2OH, -NHCH2CH2NH2, -N(CH3)C(CH3)2CH2OH, -NHCH2CH3, -NHCH2CH2OCH3, -N(CH3)CH2CH2OH, -NHC(O)C(O)NH2. -N(CH3)CH2CH2CH2OH, -N(CH3)CH2CH(OH)CH2OH, -N(CH3)CH2CH2NH2, oxo, -NHCH2C(CH3)2CH2OH, -OH, -NH2, -NHCH3, -NHCH2CH2CH2OH, -N(CH3)2, -N(CH3)CH2CH3, -NHOC(CH3)2NH2, -N(CH3)CH2cyc|opropy|, -NHCH2cyclopropy|, -NHoxetany|, -NCH2CH2triazo|e, piperazinyl, piperidinyl, pyrazolyl, azepinyl, azetidinyl, methoxy, and cyclopropylamino, where said phenyl, morpholino, triazolyl, imidazolyl, azepinyl, azetidinyl, pyrrolidinyl, piperazinyl, piperidinyl, oxetanyl, cyclopropyl, and pyrazolyl are optionally WO 2017/216727 cycloalkyl, PCT/IB2017/053511 1251 substituted with from 1 to 4 substituents independently selected from: methyl, fluoro, -NH2, -N(CH3)2, hydroxymethyl, oxo, -OH, and —CH2NH2, cycloalkyl substituted with from one to five substituents independently selected from: fluoro, chloro, -OH, C1-6alkyl, and C1-6alkyl substituted with from 1 to 9 substituents independently selected from: fluoro and chloro; heterocycloalkyl, and heterocycloalkyl substituted with from 1 to 5 substituents independently selected from: fluoro, chloro, bromo, iodo, C1—6alky|, C1-6alkyl substituted with from 1 to 9 substituents independently selected from: fluoro, chloro, bromo, iodo, oxo, -OH, -NH2 and —-CN, aryl, C1-4a|koxy, C1-4alkoxy substituted with from 1 to 4 substituents independently selected from: fluoro, oxo, -OH, -COOH, -NH2, and —-CN, WO 2017/216727 PCT/IB2017/053511 1252 -COOH, -NO2, -NH2, and SO2NH2, or R44bbr R45bbr and are taken together with the nitrogen to which they are attached, and optionally from 1 to 3 additional heteroatoms independenfly selected from O, N, and S, to form a heterocycloalkyl, which is optionally substituted with from 1 to 5 substituents independently selected from: fluoro, chloro, bromo, iodo, C1—6a|kyl, C1-6a|ky| substituted with from 1 to 9 substituents independently selected from: fluoro, chloro, C1-4alkoxy, oxo, phenyl, cycloalkyl, heterocycloalkyl, methylheterocycloalkyl-, -OH, -NH2, -N(H)C1-5a|ky|, aminoheterocycloalkyl-, -N(C1-5a|ky|)2, --CN, -N(C1-4a|ky|)(CH2OCH3), and -NHC1-4a|ky| substituted by one ortwo substituents independently selected from oxo, NH2, and -OH, aryl, cycloalkyl, heterocycloalkyl, heterocycloalkyl substituted with from 1 to 9 substituents independently selected from: C1—6a|ky|, -C1-6a|kylOH, fluoro, -C1-6alkylNH2, WO 2017/216727 PCT/IB2017/053511 1253 chloro, bromo, iodo, oxo, -OH, -NH2 and -CN, C1-4alkoxy, C1-4a|koxy substituted with from 1 to 4 substituents independently selected from: fluoro, oxo, -OH, -COOH, -NH2, and -CN, -OP(O)(OH)2, -COOH, -CONH2, -N02, -NH2, -N(H)C1—5a|ky|, -N(H)C1-6alkyl substituted with from 1 to 9 substituents independently selected from: fluoro, chloro, bromo, iodo, C1-4alkoxy, oxo, phenyl, cycloalkyl, aminoC1-4alkoxy, heterocycloalkyl, methylheterocycloalkyl-, -OH, -NH2, -N(H)C1-4a|kyl, -N(C1—4aIky|)2, and -CN, -Ooxetanyl, -ONHC(NH)NH2, -NHcyclopropyl, -NHoxetanyl, -N(C1—5alky|)2, -S(O)2CH2CH3, S(O)2CH2CH2CH3, -3(0)2CH3, WO 2017/216727 provided that: X41 bbr X42bbr 1254 -SO2NH2, -S(O)2Dheny|, benzoyL benzylamino, -propylpyrrolidinyl, -methylcyclopropyl, cyclobutylamino, cyclobutyl-N(CH3)-, piperidinyl, imidazolyl, morpholinyl, morpholinylmethyl, methylpiperazinylmethyl, methylpiperazinyl, pyrrolidinyl, pyrrolidinylmethyl, (methoxypyridiny|methy|)amino, methylpyrrolidinyl, difluoropyrrolidinyl, dimethylpyrrolidinyl, (methylcyc|opropy|methy|)amino, hydroxymethylpyrrolidinyl, fluoropyrrolidinyl, fluorophenylmethylamino, piperazinlymethyl, oxazolidinyl, (methyloxetanmethy|)amino, (methylcyclobutylmethy|)amino, oxoimidazolidinyl, and 2-hydroxyethylpiperidinyl; are not both hydrogen, and R44bb' and R45bb' are not both hydrogen; PCT/IB2017/053511 WO 2017/216727 PCT/IB2017/053511 1255 or a pharmaceutically acceptable salt or prodrug thereof.
8. A compound according to Claim 7 represented by the following Formula (Vbbr): N R50bbr N \\\Cj=\/[C/// R51bbr R535)’; N/ Y5bbr/SrNH2 R54bbr (Vbbr) wherein: Y5bb' is selected from: S and NH; R5°bb' is selected from: C1—6a|ky|, C1-6alkyl substituted with from 1 to 9 substituents independently selected from: fluoro and chloro, -N(H)C1-4alkyl, -N(C1—4a|ky|)2, -SC1—4a|kyl, C1—4a|ky|oxy, aryl, alkyl substituted with from one to five substituents independently selected from: fluoro, chloro, -OH, C1-ealkyl, and C1-6alkyl substituted with from 1 to 9 substituents WO 2017/216727 PCT/IB2017/053511 1256 independently selected from: fluoro and chloro, heteroaryl, heteroalkyl substituted with from one to five substituents independently selected from: fluoro, chloro, -OH, C1-6a|ky|, and C1-6a|ky| substituted with from 1 to 9 substituents independently selected from: fluoro and chloro, cycloalkyl, cycloalkyl substituted with from one to five substituents independently selected from: fluoro, chloro, -OH, C1-6a|ky|, and C1-6a|kyl substituted with from 1 to 9 substituents independently selected from: fluoro and chloro; R51bb' is selected from: -CH3, phenyL phenyl substituted with 1 or 2 substituents independently selected from: fluoro, -CH3, -CF3, chloro, -C(O)pheny|, pyrrolidinyl, -C(O)NH2, -S(O)2NHCH3, -OCH2CH2N(CH3)2 and -CH2C(O)NH2, thienyl, piperidinyl, pyridine, and pyridine substituted with 1 or 2 substituents independently selected from: fluoro, -CH3, -CF3, and -OCH3; WO 2017/216727 R53bbr PCT/IB2017/053511 1257 R54bbr and are independently selected from: hydrogen, C1—6a|ky|, C1-6a|ky| substituted with from 1 to 9 substituents independently selected from: phenyl, morpholino, triazolyl, imidazolyl, -CH2CH2pyrro|idinyI, -OC(O)NH2, -OCH2CH2NH2, -ONHC(NH2)NH2, -NHCH2C(CH3)3. -NOCH3, -NHOH, -NHCH2CH2F, -N(CH3)CH2CH2OCH3, -N(CH2CH3)2, -NCH(CH2OH)2, -N(CH2CH2OH)2, -NHCH2CH2OH, -NHCH2CH2NH2, -N(CH3)CH2(CH3)2CH2OH, -NHCH2CH3, -NHCH2CH2OCH3, -N(CH3)CH2CH2OH, -NHC(O)C(O)NH2, -N(CH3)CH2CH2CH2OH, -N(CH3)CH2CH(OH)CH2OH, -N(CH3)CH2CH2NH2, oxo, -NHCH2C(CH3)2CH2OH, -OH, -NH2, -NHCH3, -NHCH2CH2CH2OH, -N(CH3)2, -N(CH3)CH2CH3, -NHOC(CH3)2NH2, -N(CH3)CH2cyc|opropy|, -NHCH2cyc|opropy|, -NHoxetany|, -NCH2CH2triazole, piperazinyl, piperidinyl, pyrazolyl, azepinyl, azetidinyl, methoxy, and cyclopropylamino, where said phenyl, morpholino, triazolyl, imidazolyl, azepinyl, azetidinyl, pyrrolidinyl piperazinyl, piperidinyl, oxetanyl, cyclopropyl, and pyrazolyl are optionally substituted with from 1 to 4 substituents independently selected from: methyl, fluoro, -NH2, -N(CH3)2, hydroxymethyl, oxo, -OH, and -CH2NH2, cycloalkyl, cycloalkyl substituted with from one to five substituents independently selected from: fluoro, chloro, WO 2017/216727 PCT/IB2017/053511 1258 -OH, C1-6alkyl, and C1-6alky| substituted with from 1 to 9 substituents independently selected from: fluoro and chloro; heterocycloalkyl, and heterocycloalkyl substituted with from 1 to 5 substituents independently selected from: fluoro, chloro, C1—6alky|, C1-6a|kyl substituted with from 1 to 9 substituents independently selected from: fluoro and chloro, C1-4alkoxy, and -OH, or R53bb' and R54bb' are taken together with the nitrogen to which they are attached, and optionally from 1 to 3 additional heteroatoms independenfly selected from O, N, and S, to form a heterocycloalkyl, to form a heterocycloalkyl, which is optionally substituted with from 1 to 5 substituents independently selected from: fluoro, chloro, C1—6aIkyI, C1-6alkyl substituted with from 1 to 9 substituents independently selected from: fluoro, chloro, C1-4a|koxy, oxo, phenyl, cycloalkyl, heterocycloalkyl, methylheterocycloalkyl, -OH, -NH2, -N(H)C1-5alkyl, aminoheterocycloalkyl, -N(C1-5alkyl)2, -CN, -N(C1—4a|kyl)(CH2OCH3), and -NHC1-4alkyl substituted by one ortwo substituents independently WO 2017/216727 PCT/IB2017/053511 1259 selected from oxo, NH2, and -OH, heterocycloalkyl, heterocycloalkyl substituted with from 1 to 9 substituents independently selected from: C1—6alky|, -C1-6a|kylOH, fluoro, -C1-5alkylNH2, chloro, 0x0 and -OH, C1-4alkoxy, C1-4alkoxy substituted with from 1 to 4 substituents Independently selected from: fluoro, oxo, -OH, -COOH, -NH2, and -CN, -OP(O)(OH)2, -COOH, -CONH2, -NH2, -N(H)C1-4alky|, -N(H)C1-6alkyl substituted with from 1 to 9 substituents independently selected from: fluoro, chloro, C1-4alkoxy, oxo, phenyl, cycloalkyl, aminoC1—4a|koxy, heterocycloalkyl, methylheterocycloalkyl, -OH, -NH2, -N(H)C1-4alky|, -N(C1—4alky|)2, and -CN, -Ooxetanyl, -ONHC(NH)NH2, -NHcyclopropyl, -NHoxetanyl, -N(C1—4alky|)2, WO 2017/216727 1260 -S(O)2CH2CH3, S(O)2CH2CH2CH3, -S(0)2CH3, -S(O)2pheny|, benzoyL benzylamino, -propylpyrrolidinyl, -methylcyclopropyl, cyclobutylamino, cyclobutyl-N(CH3)-, piperidinyl, imidazolyl, morpholinyl, morpholinylmethyl, methylpiperazinylmethyl, methylpiperazinlyl pyrrolidinyl, pyrrolidinylmethyl, (methoxypyridiny|methy|)amino, methylpyrrolidinyl, difluoropyrrolidinyl, dimethylpyrrolidinyl, (methylcyc|opropy|methy|)amin0, hydroxymethylpyrrolidinyl, fluoropyrrolidinyl, fluorophenylmethylamino, piperazinylmethyl, oxazolidinyl, (methyloxetanylmethy|)amino, (methylcyclobutylmethy|)amino, oxoimidazolidinyl, and 2-hydroxyethylpiperidinyl; PCT/IB2017/053511 WO 2017/216727 PCT/IB2017/053511 1261 provided that: R53bb' and R54bb' are not both hydrogen; or a pharmaceutically acceptable salt or prodrug thereof.
9. A compound according to claim 7 or claim 8 represented by the following Formula (Vlbbr): R6Obbr NSC \ C4; R61bbr 63bbr l NH2 R \N N/ A 64bb R ' (V|bbr) wherein: R6°bb' is selected from: C1—3aIkyI, C1-3a|ky| substituted with from 1 to 6 substituents independently selected from: fluoro and chloro, -N(H)C1-3alkyl, -N(C1—3a|ky|)2, -SC1—4a|kyl, C1-3a|ky|oxy, aryl, aryl substituted with from one to 3 substituents independently selected from: fluoro, chloro, -OH, and C1-3a|ky|, heteroaryl, heteroaryl substituted with from one to 3 substituents WO 2017/216727 PCT/IB2017/053511 1262 independently selected from: fluoro, chloro, -OH, and C1—3aIky|, cycloalkyl, cycloalkyl substituted with from one to three substituents independently selected from: fluoro, chloro, -OH, and C1—3a|ky|; Rmbbr is selected from: -CH3, phenyL phenyl substituted with 1 or 2 substituents independently selected from: fluoro, -CH3, -CF3, chloro, -C(O)pheny|, pyrrolidinyl, -C(O)NH2, -S(O)2NHCH3, -OCH2CH2N(CH3)2 and -CH2C(O)NH2, thienyl, piperidinyl, pyridine, and pyridine substituted with 1 or 2 substituents independently selected from: fluoro, -CH3, -CF3, and -OCH3; R63bbr R64bbr and are independently selected from: hydrogen, C1—4alky|, C1-4a|ky| substituted with from 1 to 4 substituents independently selected from: phenyl, morpholino, triazolyl, imidazolyl, -CH2CH2pyrrolidinyI, -OC(O)NH2, -OCH2CH2NH2, -ONHC(NH2)NH2, -NHCH2C(CH3)3, -NOCH3, -NHOH, WO 2017/216727 PCT/IB2017/053511 1263 -NHCH2CH2F, -N(CH3)CH2CH2OCH3, -N(CH2CH3)2, -NCH(CH2OH)2, -N(CH2CH2OH)2, -NHCH2CH2OH, -NHCH2CH2NH2, -N(CH3)CH2(CH3)2CH2OH, -NHCH2CH3, -NHCH2CH2OCH3, -N(CH3)CH2CH2OH, -NHC(O)C(O)NH2. -N(CH3)CH2CH2CH2OH, -N(CH3)CH2CH(OH)CH2OH, -N(CH3)CH2CH2NH2, oxo, -NHCH2C(CH3)2CH2OH, -OH, -NH2, -NHCH3, -NHCH2CH2CH2OH, -N(CH3)2, -N(CH3)CH2CH3, -NHOC(CH3)2NH2, -N(CH3)CH2cyclopropyl, -NHCH2cyc|opropy|, -NHoxetany|, -NCH2CH2triazo|e, piperazinyl, piperidinyl, pyrazolyl, azepinyl, azetidinyl, methoxy, and cyclopropylamino, where said phenyl, morpholino, triazolyl, imidazolyl, azepinyl, azetidinyl, pyrrolidinyl piperazinyl, piperidinyl, oxetanyl, cyclopropyl, and pyrazolyl are optionally substituted with from 1 to 4 substituents independently selected from: methyl, fluoro, -NH2, -N(CH3)2, hydroxymethyl, oxo, -OH, and -CH2NH2, cycloalkyl, cycloalkyl substituted with from 1 to 5 substituents independently selected from: fluoro, chloro, -OH, and C1-Salkyl, heterocycloalkyl, and heterocycloalkyl substituted with from 1 to 5 substituents independently selected from: fluoro, chloro, -OH, and C1_6alkyl, or WO 2017/216727 PCT/IB2017/053511 1264 R63bbr R64bbr and are taken together with the nitrogen to which they are attached, and optionally from 1 to 3 additional heteroatoms independenfly selected from O, N, and S, to form a heterocycloalkyl, to form a heterocycloalkyl, which is optionally substituted with from 1 to 5 substituents independently selected from: fluoro, chloro, -OH, -OP(O)(OH)2, -CN, C1—6alkyl, C1-6alkyl substituted with from 1 to 9 substituents independently selected from: fluoro, chloro, C1-4a|koxy, oxo, phenyl, cycloalkyl, heterocycloalkyl, methylheterocycloalkyl, -OH, -NH2, -N(H)C1-5alkyl, aminoheterocycloalkyl, -N(C1-5alky|)2, -CN, -N(C1—4alkyl)(CH2OCH3), and -NHC1—4alkyl substituted by one or two substituents independently selected from oxo, NH2, and -OH, heterocycloalkyl, heterocycloalkyl substituted with from 1 to 9 substituents independently selected from: C1-6alkyl, -C1-6a|ky|OH, fluoro, chloro, 0x0 and -OH, C1-4alkoxy, C1-4alkoxy substituted with from 1 to 4 substituents independently selected from: fluoro, oxo, -OH, -COOH, -NH2, and -CN, oxo, WO 2017/216727 PCT/IB2017/053511 1265 -NH2, -N(H)C1-6a|ky|, -N(H)C1-6a|ky| substituted with from 1 to 9 substituents independently selected from: fluoro, chloro, C1-4a|koxy, oxo, phenyl, cycloalkyl, aminoC1-4a|koxy, heterocycloalkyl, methylheterocycloalkyl, -OH, -NH2, -N(H)C1-4a|ky|, -N(C1-4aIky|)2, and -CN, -ONHC(NH)NH2. -Ooxetanyl, -ONHC(NH)NH2, -NHcyc|opropy|, -NHoxetany|, -N(C1—4a|ky|)2, -S(O)2CH2CH3, S(O)2CH2CH2CH3, -S(0)2CH3. -S(O)2pheny|, benzoyL benzylamino, -propylpyrrolidinyl, -methylcyclopropyl, cyclobutylamino, cyclobutyl-N(CH3)-, piperidinyl, imidazolyl, morpholinyl, morpholinylmethyl, methylpiperazinylmethyl, WO 2017/216727 provided that: R63bbr R64bbr PCT/IB2017/053511 1266 methylpiperazinyl, pyrrolidinyl, pyrrolidinylmethyl, (methoxypyridiny|methy|)amino, methylpyrrolidinyl, difluoropyrrolidinyl, dimethylpyrrolidinyl, (methylcyc|opropy|methy|)amino, hydroxymethylpyrrolidinyl, fluoropyrrolidinyl, (f|uoropheny|methy|)amino, piperazinylmethyl, oxazolidinyl, (methyloxetanylmethy|)amino, (methylcyclobutylmethyl)amino, oxoimidazolidinyl, and 2-hydroxyethylpiperidinyl; are not both hydrogen; or a pharmaceutically acceptable salt or prodrug thereof.
10. A compound according to anyone of claims 7 to 9 represented by the following Formula (Qb): wherein: 70a" N N~Q C/4 71a" _ \ R R723"-N |N/ SA}/NH2 R73a (Ob) R703" is selected from: WO 2017/216727 PCT/IB2017/053511 1267 ethyl, -OCH3, -CH2CF3, and cyclopropyl; R713" is selected from: phenyL phenyl substituted with 1 or 2 substituents independently selected from: fluoro, -CH3, -CF3, and chloro, pyridine, and pyridine substituted with 1 or 2 substituents independently selected from: fluoro, -CH3, -CF3, and -OCH3; and R723" and R733" are independently selected from: hydrogen, C1—4a|ky|, C1-4alkyl substituted with from 1 to 4 substituents independently selected from: phenyl, morpholino, triazolyl, imidazolyl, -CH2CH2pyrrolidinyl, -OC(O)NH2, -OCH2CH2NH2, -ONHC(NH2)NH2, -NHCH2C(CH3)3, -NOCH3, -NHOH, -NHCH2CH2F, -N(CH3)CH2CH2OCH3, -N(CH2CH3)2, -NCH(CH2OH)2, -N(CH2CH2OH)2, -NHCH2CH2OH, -NHCH2CH2NH2, -N(CH3)CH2(CH3)2CH2OH, -NHCH2CH3, -NHCH2CH2OCH3, -N(CH3)CH2CH2OH, -NHC(O)C(O)NH2, -N(CH3)CH2CH2CH2OH, -N(CH3)CH2CH(OH)CH2OH, -N(CH3)CH2CH2NH2, oxo, -NHCH2C(CH3)2CH2OH, -OH, -NH2, -NHCH3, -NHCH2CH2CH2OH, -N(CH3)2, -N(CH3)CH2CH3, -NHOC(CH3)2NH2, -N(CH3)CH2cyclopropy|, -NHCH2cyclopropy|, -NHoxetanyl, -NCH2CH2triazo|e, piperazinyl, piperidinyl, pyrazolyl, WO 2017/216727 PCT/IB2017/053511 1268 azepinyl, azetidinyl, methoxy, and cyclopropylamino, cyclobutyl, where said phenyl, morpholino, triazolyl, imidazolyl, azepinyl, azetidinyl, pyrrolidinyl piperazinyl, piperidinyl, oxetanyl, cyclopropyl, and pyrazolyl are optionally substituted with from 1 to 4 substituents independently selected from: methyl, fluoro, -NH2, -N(CH3)2, hydroxymethyl, oxo, -OH, and -CH2NH2, aminocyclobutyl, tetrahydrofu ran, 5-oxa-Zazaspiro[3.4]octan, and 8-azabicyc|o[3.2.1]octan, or R723" and R733” are taken together with the nitrogen to which they are attached, and optionally from 1 to 3 additional heteroatoms independenfly selected from O, N, and S, to form a heterocycloalkyl selected from: pyrrolidinyl, pyrro|o[3,4-c]pyrazo|y|, piperidinyl, 1,4diazepanyl, piperazinyl, 6,7-dihydro-triazo|o[4,5-c]pyridinyl, 2,9-diazaspiro[5.5]undecany|, 2,8-diazaspiro[4.5]decany|, octahydro-1H-pyrro|o[1,2a][1,4]diazepiny|, oxa-diazaspiro[4.5]decany|, oxazolyl, morpholinyl, 1-oxa-6-azaspiro[3.4]octany|, 2-oxa-6-azaspiro[3.4]octanyl, 1,7-diazaspiro[3.5]nonany|, 2,7-diazaspiro[3.5]nonany|, 2,6-diazaspiro[3.4]octany|, azetidinyl, WO 2017/216727 PCT/IB2017/053511 1269 hexahydropyrro|o[3,4-b]oxazinyl, dihydronaphthyridinyl, diazabicycloheptanyl, 1,8-diazaspiro[4.5]decany|, and 5-oxa-2-azaspiro[3.4]octanyl, all of which are optionally substituted with from 1 to 5 substituents independently selected from: fluoro, chloro, oxo, -OH, -OP(O)(OH)2, -CN, -CH3, -CH2OH, methoxy, -C(O)CH3, -C(O)NH2, -OCH2CH2OH, -OCH2CH2NH2, -ONHC(NH)NH2. -OC(O)NH2, -Ooxetanyl, -CH2CH2OH, -CH2CH2CH2OH, -CH2CH2CH3, -CH2CH2OCH3, -CH2CH(OH)CH3, WO 2017/216727 PCT/IB2017/053511 1270 -CH2CH(OH)CH2OH, -CH2C(O)OCH3. -CH2C(O)NH2, -C(O)CH(CH3)2, -CH2CH2N(CH3)2, -CH2CH2NHCH2CH3, -CH2CH2CH2N(CH3)2, -CH2CH2NHCH2C(CH3)3, -CH2CH2N(CH3)CH2OCH3, -C(CH3)2CH2OH, -CH2C(CH3)2OH, -CH2C(CH3)2OCH3, -C(O)CH2OH, -CH2isothiazo|yl, -CH2thiazo|y|, -CH2pyrazo|y|, -CH2imidazo|y|, -CH2Pyridiny|, -CH2oxazo|y|, -CH2pyrro|y|, -CH2isoxazo|y, -CH2furany|, -CH2CH2morpho|iny|, -CH2CH2pyrro|idiny|, WO 2017/216727 PCT/IB2017/053511 1271 -CH2CH2pyrro|idiny|CH3, -CH2CH2CH2pyrro|idiny|, -C(O)pheny|, -C(O)C(tetrahydropyrany|)NH2, -NH2, -NHCH3, -N(CH3)2, -NHC(O)CH3, -NHCH2CHF2. -NHCH2C(CH3)3, -NHCH2CH(CH3)2, -NHCH2CH2OCH3, -NHCH2CH2OH, -NHCH2CH2NH2, -NHCH2C(O)OH, -NHC(O)CH2NH2, -NHC(O)CH2CH2CH2NH2, -NHCH2C(O)NH2, -NHCH2C(OH)(CH3)2, -NHC(O)CH(CH3)NH2, -NHC(O)OCH(CH3)NH2, -NHC(O)CH(CH3)2, -NHC(O)C(CH3)2NH2, -NHC(O)CH2OH, -NHC(O)CH(CH2OH)NH2. WO 2017/216727 PCT/IB2017/053511 1272 -NHC(O)(0Xetany|)NH2, -NHC(O)OC(CH3)3, -NHC(CH3)2C(O)OCH3, -NHcyc|opropy|, -NHoxetany|, -CH2NH2, -CH2CH2NH2, -CH2CH2CH2NH2, -CH2NHCH2C(CH3)3. -CH2NHC(O)C(CH3)3, -CH2NHC(O)CH2NH2, -CH2NHC(O)CH2OH, -CH2N(CH3)2, -CH2NHCH3, -CH2N(CH2CH3)2, -CH2CH2N(CH3)2, -S(O)2CH2CH3, -S(O)2CH2CH2CH3, -S(O)2pheny|, -S(O)2CH3, benzoyL benzylamino, -propylpyrrolidinyl, -methylcyclopropyl, cyclobutylamino, cyclobutyl-N(CH3)-, piperidinyl, WO 2017/216727 provided that: PCT/IB2017/053511 1273 imidazolyl, morpholinyl, morpholinylmethyl, methylpiperazinylmethyl, methylpiperazinyl, pyrrolidinyl, pyrrolidinylmethyl, (methoxypyridiny|methy|)amino, methylpyrrolidinyl, difluoropyrrolidinyl, dimethylpyrrolidinyl, (methy|cyc|opropy|methyl)amino, hydroxymethylpyrrolidinyl, fluoropyrrolidinyl, (fluorophenylmethyl)amino, piperazinylmethyl, oxazolidinyl, (methyloxetanylmethyl)amino, (methylcyclobutylmethyl)amino, oxoimidazolidinyl, and 2-hydroxyethylpiperidinyl; R723" and R733” are not both hydrogen; or a pharmaceutically acceptable salt or prodrug thereof.
11. A compound of claim 7 selected from: 2-{[3,5-dicyano-6-(dimethylamino)-4-ethylpyridin-2-y|]sulfanyl}-2-phenylacetamide; 2-((3,5-dicyano-4-cyclopropyl-6-(1 ,4-diazepan-1-y|)pyridin-2-y|)thio)-2- phenylacetamide; 2-{[3,5-dicyano-4-cyclopropy|-6-(4-ethy|-1 ,4-diazepan-1-y|)pyridin-2-y|]su|fanyl}-2- phenylacetamide; WO 2017/216727 PCT/IB2017/053511 1274 2-((3,5-dicyano-4-ethyl-6-(4-propyl-1,4-diazepan-1-yl)pyridin-2-y|)thio)-2- phenylacetamide; 2-{[3,5-dicyano-4-ethyl-6-(4-ethyl-1 ,4-diazepan-1-y|)pyridin-2-y|]su|fany|}-2- phenylacetamide; 2-{[3,5-dicyano-4-ethyl-6-(5-oxo-1 ,4-diazepan-1-yl)pyridin-2-y|]su|fany|}-2- phenylacetamide; 2-((3,5-dicyano-4-cyclopropyl-6-morphoIinopyridin-2-y|)thio)-2-(pyridin-4- y|)acetamide; 2-{[3,5-dicyano-4-ethy|-6-(4-methyl-3-oxopiperazin-1-yl)pyridin-2-y|]su|fany|}-2- (pyridin-4-y|)acetamide; 2-[(3,5-dicyano-4-ethyl-6-{methy|[2-(morpholin-4-y|)ethy|]amino}pyridin-2- y|)suIfanyl]-2-phenylacetamide; 2-{[3,5-dicyano-4-ethy|-6-(4-propy|piperazin-1-y|)pyridin-2-y|]su|fany|}-2- phenylacetamide; 2-({3,5-dicyano-4-ethyl-6-[4-(piperidin-4-yl)piperazin-1-yl]pyridin-2-y|}su|fany|)-2- phenylacetamide; 2-({3,5-dicyano-4-cyclopropyl-6-[3-(hydroxymethy|)piperazin-1-y|]pyridin-2- y|}suIfanyl)-2-phenylacetamide; 2-{[3,5-dicyano-4-cyc|opropy|-6-(3-oxopiperazin-1-yl)pyridin-2-y|]su|fany|}-2- phenylacetamide; 2-({3,5-dicyano-4-cyclopropyl-6-[4-(morpholin-4-y|)piperidin-1-y|]pyridin-2- y|}suIfanyl)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-(2 ,8-d iazaspiro[4.5]decan-8-y|)pyridin-2-y|)th io)-2- phenylacetamide; 2-((3,5-Dicyano-4-cyclopropyl-6-(3-(dimethylamino)piperidin-1-y|)pyridin-2-y|)thio)- 2-phenylacetamide; 2-((3,5-Dicyano-4-cyclopropy|-6-(3-methylpiperazin-1-y|)pyridin-2-y|)thio)-2- phenylacetamide; 2-((3,5-Dicyano-4-cyclopropyl-6-(2-(hydroxymethyl)morpholino)pyridin-2-y|)thio)-2- phenylacetamide; WO 2017/216727 PCT/IB2017/053511 1275 2-((3,5-Dicyano-4-cyclopropyl-6-(2,6-dimethy|morpho|ino)pyridin-2-y|)thio)-2- phenylacetamide; 2-((3,5-Dicyano-4-cyclopropyl-6-(3-(dimethylamino)piperidin-1-y|)pyridin-2-y|)thio)- 2-phenylacetamide; 2-((6-(4-(Aminomethyl)-4-hydroxypiperidin-1-yl)-3,5-dicyano-4-cyc|opropy|pyridin- 2-y|)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-cyc|opropy|-6-(3-(methylamino)piperidin-1-yl)pyridin-2-y|)thio)-2- phenylacetamide; 2-((6-(3-aminopiperidin-1-yl)-3,5-dicyano-4-cyclopropylpyridin-2-y|)thio)-2- phenylacetamide; 2-((3,5-dicyano-4-cyclopropyl-6-(dimethylamino)pyridin-2-y|)thio)-2-(pyridin-4- y|)acetamide; 2-((3,5-dicyano-6-(dimethylamin0)-4-ethylpyridin-2-y|)thio)-2-(pyridin-4- y|)acetamide; 2-((6-(4-aminopiperidin-1-yl)-3,5-dicyano-4-cyclopropylpyridin-2-y|)thio)-2- phenylacetamide; 2-((3,5-dicyan0-4-cyclopropyl-6-(4-(dimethy|amino)piperidin-1-y|)pyridin-2-y|)thio)- 2-phenylacetamide; 2-((3,5-dicyano-4-cyclopropyl-6-(piperazin-1-y|)pyridin-2-y|)thio)-2-(pyridin-4- y|)acetamide; 2-((3,5-dicyano-4-cyclopropyl-6-(1 ,4-diazepan-1-y|)pyridin-2-y|)thio)-2-(pyridin-4- y|)acetamide; 2-((3,5-dicyano-4-cyclopropyl-6-((R)-3-hyd roxypiperidin-1-y|)pyridin-2-y|)thio)-2- phenylacetamide; 2-(3,5-dicyano-4-cyclopropyl-6-((S)-3-hydroxypiperidin-1-y|)pyridin-2-y|thio)-2- phenylacetamide; 2-((3,5-dicyan0-4-cyclopropyl-6-((S)-3-hydroxypyrro|idin-1-y|)pyridin-2-y|)thio)-2- (pyridin-4-y|)acetamide; 2-((3,5-dicyano-4-ethyl-6-(4-ethylpiperazin-1-y|)pyridin-2-y|)thio)-2- phenylacetamide; WO 2017/216727 PCT/IB2017/053511 1276 2-((3,5-Dicyano-4-ethyl-6-(1-oxa-6-azaspiro[3.4]octan-6-yl)pyridin-2-y|)thio)-2- phenylacetamide; 2-((6-(4-(3-aminopropy|)piperazin-1-yl)-3,5-dicyano-4-ethylpyridin-2-y|)thio)-2- phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-(1,7-diazaspiro[3.5]nonan-1-y|)pyridin-2-y|)thio)-2- phenylacetamide; 2-((3,5-Dicyano-4-cyclopropyl-6-(4-(pyrrolidin-1-y|methy|)piperidin-1-y|)pyridin-2- y|)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-cyclopropy|-6-(4-(4-methy|piperazin-1-y|)piperidin-1-y|)pyridin-2- y|)thio)-2-phenylacetamide; (R)-2-((3,5-dicyano-6-(1,4-diazepan-1-yl)-4-ethylpyridin-2-yl)amino)-2- phenylacetamide; 2-((3,5-Dicyano-4-cyclopropyl-6-(4-(pyrrolidin-1-y|)piperidin-1-y|)pyridin-2-y|)thio)- 2-phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-(2,7-diazaspiro[3.5]nonan-7-y|)pyridin-2-y|)thio)-2- phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-(2,6-d iazaspiro[3.4]octan-6-y|)pyrid in-2-y|)th io)-2- phenylacetamide; 2-((3,5-dicyano-4-cyclopropyl-6-(1,4-diazepan-1-yl)pyridin-2-y|)thio)propanamide; 2-((3,5-Dicyano-4-ethy|-6-(4-(2-oxoimidazolidin-1-y|)piperidin-1-y|)pyridin-2- y|)thio)-2-phenylacetamide; 2-((3,5-Dicya no-4-ethyl-6-(4-hydroxypiperidin-1-y|)pyridin-2-y|)thio)-2- phenylacetamide; 2-((3,5-Dicyano-4-ethy|-6-((S)-3-hydroxypyrrolidin-1-y|)pyridin-2-y|)thio)-2- phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-(3-oxopiperazin-1-y|)pyridin-2-y|)thio)-2- phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-((2-meth oxyethyl)(methy|)amino)pyridin-2-y|)thio)-2- phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-(3-methoxyazetidin-1-y|)pyridin-2-y|)thio)-2- phenylacetamide; WO 2017/216727 PCT/IB2017/053511 1277 2-((3,5-Dicyan0-4-ethyl-6-(piperazin-1-y|)pyridin-2-y|)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-(4-methyl-1 ,4-diazepan-1-y|)pyridin-2-y|)thio)-2- phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-morpholinopyridin-2-y|)thio)-2-phenylacetamide; 2-[[6-(azetidin-1-yl)-3,5-dicyano-4-ethyl-2-pyridy|]suIfanyl]-2-phenyl-acetamide; 2-((3,5-dicyano-4-ethyl-6-(4-oxopiperidin-1-y|)pyridin-2-y|)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-(1'-(2-hydroxyethyl)-[4,4'-bipiperidin]-1-y|)pyridin-2- y|)thio)-2-phenylacetamide; 2-((3,5-Dicyano-6-((3S,5R)-3,5-dimethylpiperazin-1-yl)-4-ethylpyridin-2-y|)thio)-2- phenylacetamide; 2-((6-(8-azabicyc|o[3.2.1]octan-3-y|(methy|)amino)-3,5-dicyano-4-ethylpyridin-2- y|)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-cyclopro pyl-6-(2-(hyd roxymethyl)morpholino)pyridin-2-y|)thio)-2- phenylacetamide; (R)-2-((3,5-dicyano-6-(dimethylamino)-4-ethylpyridin-2-y|)thio)-2-phenylacetamide; (R)-2-[(3,5-Dicyano-4-ethyl-6-morpholino-2-pyridy|)suIfanyl]-2-phenyl-acetamide; 2-{[3,5-dicyano-4-ethyl-6-(5-methyl-1,4-diazepan-1-y|)pyridin-2-y|]su|fany|}-2- phenylacetamide; 2-({3,5-Dicyano-4-ethy|-6-[4-(2-methoxyethyl)-1,4-diazepan-1-y|]pyridin-2- y|}suIfanyl)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-(4-(2-hydroxypropyl)-1 ,4-diazepan-1-y|)pyridin-2-y|)thio)- 2-phenylacetamide; Methyl 2-[4-(6-{[carbamoy|(pheny|)methy|]suIfanyl}-3,5-dicyano-4-ethylpyridin-2- yl)-1 ,4-diazepan-1-y|]acetate; 2-{[3,5-Dicyano-4-cyclopropy|-6-(4-methy|-5-oxo-1,4-diazepan-1-y|)pyridin-2- y|]sulfanyl}-2-phenylacetamide; 2-{[3,5-Dicyano-4-cyclopropyl-6-(5-oxo-1 ,4-diazepan-1-yl)pyridin-2-y|]su|fany|}-2- phenylacetamide; 2-{[3,5-Dicyano-4-ethy|-6-(4-methy|-5-oxo-1 ,4-diazepan-1-y|)pyridin-2-y|]su|fany|}- 2-phenylacetamide; WO 2017/216727 PCT/IB2017/053511 1278 2-{[3,5-Dicyano-6-(1,4-diazepan-1-yl)-4-ethylpyridin-2-y|]su|fany|}-2- phenylacetamide; 2-({3,5-Dicyano-6-[4-(2-hydroxyethyl)-1,4-diazepan-1-y|]-4-(2,2,2- trifluoroethyl)pyridin-2-y|}su|fany|)-2-phenylacetamide; (2R)-2-({3,5-Dicyano-4-ethyl-6-[4-(2-hyd roxyethyl)-1 ,4-diazepan-1-y|]pyridin-2- y|}amino)-2-phenylacetamide; 2-({6-[(38)-3-Aminopyrrolidin-1-yl]-3,5-dicyano-4-cyclopropylpyridin-2-y|}su|fany|)- 2-phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-(2,9-diazaspiro[5.5]undecan-9-yl)pyridin-2-y|)thio)-2- phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-(hexahydro-1H-pyrro|o[1,2-a][1,4]diazepin-2(3H)- y|)pyridin-2-y|)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-(2-methyl-2,9-diazaspiro[5.5]undecan-9-y|)pyridin-2- y|)thio)-2-phenylacetamide; 2-((3,5-Dicyano-6-(2-(cyclopropylmethyl)-2,9-diazaspiro[5.5]undecan-9-y|)-4- ethylpyridin-2-y|)thio)-2-phenylacetamide; 2-((3,5-Dicyano-6-(4-(3-(dimethylamin0)propy|)piperazin-1-y|)-4-ethy|pyridin-2- y|)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-(4-(pyrroIidin-3-y|)piperidin-1-y|)pyridin-2-y|)thio)-2- phenylacetamide; 2-((6-([4,4‘-Bipiperidin]-1-yl)-3,5-dicyano-4-ethylpyridin-2-y|)thio)-2- phenylacetamide; 2-((6-(4-(2-Aminoethyl)piperazin-1-yl)-3,5-dicyano-4-ethylpyridin-2-y|)thio)-2- phenylacetamide; 2-((6-(4-(3-Aminopropy|)piperazin-1-yl)-3,5-dicyano-4-cyclopropylpyridin-2-y|)thio)- 2-phenylacetamide; 2-((3,5-Dicyano-4-cyclopropy|-6-(4-((4-methy|piperazin-1-y|)methyl)piperidin-1- y|)pyridin-2-y|)thio)-2-phenylacetamide; 2-((6-(4-Acetylpiperazin-1-yl)-3,5-dicyano-4-ethylpyridin-2-y|)thio)-2- phenylacetamide; WO 2017/216727 PCT/IB2017/053511 1279 2-((3,5-Dicyano-4-cyclopropyl-6-(dimethy|amino)pyridin-2-y|)thio)-2- phenylacetamide; 2-(4-ChIorophenyl)-2-((3,5-dicyano-6-(dimethylamino)-4-ethy|pyridin-2- y|)thio)acetamide; 2-((3,5-Dicyano-4-ethyl-6-(4-(2-hydroxyethy|)piperazin-1-y|)pyridin-2-y|)thio)-2- phenylacetamide; 2-[(3,5-Dicyano-4-cyclopropyl-6-morpholino-2-pyridy|)su|fany|]-2-pheny|- acetamide; 2-((6-(4-Benzoylpiperazin-1-yl)-3,5-dicyano-4-ethylpyridin-2-y|)thio)-2- phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-((58,6S)-6-hydroxy-1-(methylsulfonyl)-1,8- diazaspiro[4.5]decan-8-y|)pyridin-2-y|)thio)-2-phenylacetamide; 2-((3,5-Dicyano-6-(4,4-difluoropiperidin-1-yl)-4-ethylpyridin-2-y|)thio)-2- phenylacetamide; (R)-2-((3,5-Dicyano-4-ethyl-6-((R)-3-hydroxypyrro|idin-1-y|)pyridin-2-y|)thio)-2- phenylacetamide; 2-((3,5-dicyano-4-(fu ran-2-yl)-6-(4-methyl-1 ,4-diazepan-1-y|)pyridin-2-y|)thio)-2- phenylacetamide; 2-((6-(4-Amino-4-methylpiperidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-y|)thio)-2- phenylacetamide; 2-Amino-N-(1-(6-((2-amino-2-oxo-1-pheny|ethy|)thio)-3,5-dicyano-4-ethy|pyridin-2- y|)piperidin-4-y|)acetamide; (28)-2-Amino-N-(1-(6-((2-amino-2-oxo-1-pheny|ethy|)thio)-3,5-dicyano-4- ethylpyridin-2-yl)piperidin-4-yl)propanamide; 2-((6-(4-(3-Aminooxetane-3-carbony|)piperazin-1-yl)-3,5-dicyano-4-ethy|pyridin-2- y|)thio)-2-phenylacetamide; 4-Amino-N-(1-(6-((2-amino-2-oxo-1-pheny|ethy|)thio)-3,5-dicyano-4-ethy|pyridin-2- y|)piperidin-4-y|)tetrahydro-2H-pyran-4-carboxamide; 2-((6-(4-(4-Aminotetrahydro-2H-pyran-4-carbony|)piperazin-1-y|)-3,5-dicyano-4- ethylpyridin-2-y|)thio)-2-phenylacetamide; WO 2017/216727 PCT/IB2017/053511 1280 2-((3,5-Dicyano-6-(4-(2-hydroxyethyl)-1,4-diazepan-1-y|)-4-methoxypyridin-2- y|)thio)-2-phenylacetamide; 2-((6-(4-Aminopiperidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-y|)thio)-2- phenylacetamide; 2-((6-((2-Aminoethy|)(methy|)amino)-3,5-dicyano-4-ethylpyridin-2-y|)thio)-2- phenylacetamide; 2-((6-((2-Amino-2-oxoethyl)(methy|)amino)-3,5-dicyano-4-ethylpyridin-2-y|)thio)-2- phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-(3-hydroxyazetidin-1-y|)pyridin-2-y|)thio)-2- phenylacetamide; 2-(3,5-Dicyano-4-ethyl-6-((2-hydroxyethy|)(methy|)amino)pyridin-2-y|thio)-2- phenylacetamide; 2-Amino-N-(1-(6-((2-amino-2-oxo-1-pheny|ethy|)thio)-3,5-dicyano-4-ethy|pyridin-2- y|)piperidin-4-yl)-2-methylpropanamide; 2-((6-(4-(2-Aminoethoxy)piperidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-y|)thio)-2- phenylacetamide; 1-(6-((2-Amino-2-oxo-1-pheny|ethy|)thio)-3,5-dicyano-4-ethylpyridin-2-y|)pyrro|idin- 3-yl dihydrogen phosphate; 2-((6-((2-Amino-2-oxo-1-pheny|ethy|)thio)-3,5-dicyano-4-ethy|pyridin-2- y|)(methy|)amino)ethyl dihydrogen phosphate; 1-(6-((2-Amino-2-oxo-1-pheny|ethy|)thio)-3,5-dicyano-4-ethylpyridin-2-y|)azetidin- 3-yl dihydrogen phosphate; (28)-2-((1-(6-((2-Amino-2-oxo-1-pheny|ethy|)thio)-3,5-dicyano-4-ethy|pyridin-2- y|)piperidin-4-y|)oxy)ethy| 2-amino-3-methylbutanoate; 2-((1-(6-((2-Amino-2-oxo-1-pheny|ethy|)thio)-3,5-dicyano-4-ethylpyridin-2- y|)piperidin-4-y|)oxy)ethy| dihydrogen phosphate; 1-(6-((2-Amino-2-oxo-1-pheny|ethy|)thio)-3,5-dicyano-4-ethylpyridin-2-y|)piperidin- 4-yl dihydrogen phosphate; 2-((3,5-Dicyano-6-(dimethylamino)-4-ethylpyridin-2-y|)thio)-2-(piperidin-4- y|)acetamide; WO 2017/216727 PCT/IB2017/053511 1281 2-((3,5-Dicyan0-4-ethyl-6-(4-(propylsu|fony|)piperazin-1-y|)pyridin-2-y|)thio)-2- phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-(4-(phenylsulfony|)piperazin-1-y|)pyridin-2-y|)thio)-2- phenylacetamide; 2-((3,5-Dicyano-4-ethy|-6-((R)-3-hydroxypyrrolidin-1-y|)pyridin-2-y|)thio)-2- phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-(2-oxa-6-azaspiro[3.4]octan-6-yl)pyridin-2-y|)thio)-2- phenylacetamide; (R)-2-((3,5-Dicyano-4-ethy|-6-(4-ethy|-1 ,4-diazepan-1-y|)pyridin-2-yl)amino)-2- phenylacetamide; (R)-2-((3,5-Dicyano-4-ethyl-6-(4-(3-(pyrrolidin-1-y|)propy|)-1,4-diazepan-1- y|)pyridin-2-y|)amino)-2-phenylacetamide; 2-(3,5-Dicyano-4-cyc|opropy|-6-(3-hydroxypiperidin-1-y|)pyridin-2-y|thio)-2- phenylacetamide; 2-((3,5-Dich|oro-4-ethy|-6-(4-methyl-1 ,4-diazepan-1-yl) pyridin-2-y|)thio)-2- phenylacetamide; 2-((3,5-Dicyano-6-(1,1-dioxidothiomorpholino)-4-ethylpyridin-2-y|)thio)-2- phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-(methy|(2-(piperazin-1-y|)ethy|)amino)pyridin-2-y|)thio)-2- phenylacetamide; (R)-2-((3,5-Dicyano-4-ethyl-6-((S)-3-hyd roxypyrrolidin-1-y|)pyridin-2-y|)thio)-2- phenylacetamide; 2-((6-((2-(4-(Aminomethyl)-4-hydroxypiperidin-1-y|)ethy|)(methy|)amino)-3,5- dicyano-4-ethylpyridin-2-y|)thio)-2-phenylacetamide; 2-((4-Cyano-3-(1 ,4-diazepan-1-yl)-6,7-dihydro-5H-cyc|openta[c]pyridin-1-y|)thio)-2- phenylacetamide; 2-((6-(4-(1H-Imidazol-1-y|)piperidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-y|)thio)-2- phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-(4-(pyridin-4-ylmethyl)piperazin-1-y|)pyridin-2-y|)thio)-2- phenylacetamide; WO 2017/216727 PCT/IB2017/053511 1282 2-((3,5-Dicyano-6-(2-(dimethylamin0)ethoxy)-4-ethylpyridin-2-y|)thio)-2- phenylacetamide; 2-((1-(6-((2-Amino-2-oxo-1-pheny|ethy|)thio)-3,5-dicyano-4-cyclopropy|pyridin-2- y|)piperidin-3-y|)amino)acetic acid; 2-((3,5-Dicyano-4-ethyl-6-(4-(oxazol-2-ylmethy|)piperazin-1-y|)pyridin-2-y|)thio)-2- phenylacetamide; 2-((6-(4-((1H-Pyrrol-2-yl) methyl) piperazin-1-yl)-3,5-dicyano-4-ethy|pyridin-2- y|)thio)-2-phenylacetamide; 2-((3,5-Dicyano-6-(3,4-dihydro-2,7-naphthyridin-2 (1H)-yl)-4-ethylpyridin-2-y|)thio) 2-phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-((8)-3-hyd roxypyrrolid in-1 -y|)pyrid in-2-y|)thio)-2-(pyrid in- 3-y|)aceta mide; 2-((6-(4-((1H-Pyrro|-3-y|)methy|)piperazin-1-yl)-3,5-dicyano-4-ethylpyridin-2- y|)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-(4-(isoxazoI-3-y|methy|)piperazin-1-y|)pyridin-2-y|)thio)- 2-phenylacetamide; 2-((3,5-Dicyan0-4-ethyl-6-(4-(oxazol-5-ylmethy|)piperazin-1-y|)pyridin-2-y|)thio)-2- phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-(4-(isoxazoI-4-y|methy|)piperazin-1-y|)pyridin-2-y|)thio)- 2-phenylacetamide; 3-Amino-N-(1-(6-((2-amino-2-oxo-1-pheny|ethy|)thio)-3,5-dicyano-4-ethylpyridin-2- y|)piperidin-4-y|)oxetane-3-carboxamide; 2-((6-(4-((1H-Pyrazol-4-y|)methy|)piperazin-1-yl)-3,5-dicyano-4-ethy|pyridin-2- y|)thio)-2-phenylacetamide; 2-((6-(4-((1H-Imidazol-5-yl)methy|)piperazin-1-yl)-3,5-dicyano-4-ethy|pyridin-2- y|)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-(4-(1-hydroxy-2-methylpropan-2-y|)piperazin-1- y|)pyridin-2-y|)thio)-2-phenylacetamide; 2-((6-(4-((1H-Imidazol-2-yl)methy|)piperazin-1-yl)-3,5-dicyano-4-ethy|pyridin-2- y|)thio)-2-phenylacetamide; 2-((3,5-Dicyano-6-(dimethylamino)-4-methoxypyridin-2-y|)thio)-2-phenylacetamide; WO 2017/216727 PCT/IB2017/053511 1283 2-((3,5-Dicyano-6-(dimethylamino)-4-ethoxypyridin-2-y|)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-ethoxy-6-(4-(2-hyd roxyethyl)-1 ,4-diazepan-1-yl) pyridin-2- y|)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-ethy|-6-(4-(2-hydroxy-2-methylpropyl)-1 ,4-diazepan-1-y|)pyridin- 2-y|)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-(4-(thiazol-5-ylmethyl)piperazin-1-y|)pyridin-2-y|)thio)-2- phenylacetamide; 2-((3,5-Dicya no-4-ethyl-6-(piperazin-1-y|)pyridin-2-y|)thio)-2-(4- fluorophenyl)acetamide; 2-((3,5-Dicyano-4-ethyl-6-(4-(isothiazol-4-ylmethy|)piperazin-1-y|)pyridin-2-y|)thio)- 2-phenylacetamide; 2-((3,5-Dicyano-6-(dimethylamino)-4-ethylpyridin-2-y|)thio)-2-(4- fluorophenyl)acetamide; 2-((3,5-Dicyano-6-(dimethylamino)-4-ethylpyridin-2-y|)thio)-2- (5-f|uoropyridin-2- y|)acetamide; 2-((3,5-Dicyano-4-ethyl-6-(4-(furan-3-y|methy|)piperazin-1-y|)pyridin-2-y|)thio)-2- phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-((2-morpho|inoethy|)thio)pyridin-2-y|)thio)-2- phenylacetamide; 2-((3,5-Dicyano-6-(4-methyl-1 ,4-diazepan-1-yl)-4-(methylthio)pyridin-2-y|)thio)-2- phenylacetamide; 2-((3,5-DichIoro-4-ethyl-6-(4-(2-hydroxyethyl)-1,4-diazepan-1-y|)pyridin-2-y|)thio)- 2-phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-(hexahydropyrro|o[3,4-b][1,4]oxazin-6(2H)-y|)pyridin-2- y|)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-(4-methyl-1 ,4-diazepan-1-y|)pyridin-2-y|)thio)-2-(5- methylpyridin-2-y|)acetamide; 2-((3,5-Dicyano-4-ethyl-6-(4-methyl-1 ,4-diazepan-1-y|)pyridin-2-y|)thio)-2-(6- fluoropyridin-2-y|)acetamide; 2-((3,5-Dicyano-6-(4-(dimethy|amino)piperidin-1-yl)-4-ethylpyridin-2-y|)thio)-2-(4- fluorophenyl)acetamide; WO 2017/216727 PCT/IB2017/053511 1284 2-((3,5-Dicyano-4-ethyl-6-(4-methyl-1,4-diazepan-1-yl) pyridin-2-yl) thio)-2-(4- methylpyridin-2-yl) acetamide; 2-((3,5-Dicyano-4-ethyl-6-(4-methyl-1 ,4-diazepan-1-y|)pyridin-2-y|)thio)-2-(3- methoxypyridin-2-y|)acetamide; 2-((3,5-Dicyano-6-(4-(dimethy|amino)piperidin-1-yl)-4-ethylpyridin-2-y|)thio)-2-(2,4- difluoropheny|)acetamide; 2-((3,5-Dicyano-4-ethyl-6-(4-(pyrrolidin-1 -y|)pipe rid in-1 -y|)pyridin-2-y|)thio)-2-(5- fluoropyridin-2-y|)acetamide; 2-((3,5-Dicyano-4-ethoxy-6-(4-(2-hyd roxyethyl)-1 ,4-diazepan-1-y|)pyridin-2- y|)thio)propanamide; 2-((3,5-Dicyano-6-(4-(2-hyd roxyethyl)-1 ,4-diazepan-1-y|)-4-propoxypyridin-2- y|)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-(4-methyl-1 ,4-diazepan-1-y|)pyridin-2-y|)thio)-2-(4- methoxypyridin-2-y|)acetamide; 2-((3,5-Dicyano-4-ethyl-6-(2-methyl-2,8-diazaspiro[4.5]decan-8-y|)pyridin-2- y|)thio)-2-phenylacetamide; 2-((3,5-Dicyano-6-(4-(dimethy|amino)piperidin-1-yl)-4-ethylpyridin-2-y|)thio)-2-(3,4- difluoropheny|)acetamide; 1-(6-((2-Amino-2-oxo-1-pheny|ethy|)thio)-3,5-dicyano-4-ethylpyridin-2- y|)piperidine-4-carboxamide; 2-((3,5-Dicyano-6-((2-(dimethy|amino)ethy|)thio)-4-ethylpyridin-2-y|)thio)-2- phenylacetamide; 2-((3,5-Dicyano-6-((3S,4R)-3,4-dihydroxypyrrolidin-1-yl)-4-ethylpyridin-2-y|)thio)-2- phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-(4-methyl-1 ,4-diazepan-1-y|)pyridin-2-y|)thio)-2-(3- fluoropyridin-2-yl) acetamide; 2-((3,5-Dicyano-4-ethyl-6-(4-methyl-1 ,4-diazepan-1-y|)pyridin-2-y|)thio)-2-(5- methoxypyridin-2-y|)acetamide; 2-((3,5-Dicyano-4-ethyl-6-(4-(1-hydroxy-2-methylpropan-2-y|)piperazin-1- y|)pyridin-2-y|)thio)-2-(4-fluoropheny|)acetamide; WO 2017/216727 PCT/IB2017/053511 1285 2-((3,5-Dicyano-4-ethyl-6-(4-methyl-1 ,4-diazepan-1-y|)pyridin-2-y|)thio)-2-(3- (trifluoromethyl)pheny|)acetamide; 2-((3,5-Dicyano-4-ethyl-6-(4-(2-hydroxyethoxy)piperidin-1-y|)pyridin-2-y|)thio)-2- phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-(4-methyl-1 ,4-diazepan-1-yl) pyridin-2-y|)thio)-2-(2- fluoropyridin-3-y|)acetamide; 2-((3,5-Dicyano-4-ethyl-6-(4-methyl-1 ,4-diazepan-1-yl) pyridin-2-y|)thio)-2-(6- fluoropyridin-3-y|)acetamide; 3-((6-(2-Amino-2-oxo-1-phenylethylthio)-3,5-dicyano-4-ethylpyridin-2- y|)(methy|)amino)propanamide; 2-((3,5-Dicyano-4-ethyl-6-(4-(oxetan-3-y|oxy)piperidin-1-y|)pyridin-2-y|)thio)-2- phenylacetamide; 2-((3,5-Dicyano-6-(4-((2,2-difluoroethyl) amino)-4-methylpiperidin-1-y|)-4- ethylpyridin-2-yl) thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-(4-methyl-1 ,4-diazepan-1-y|)pyridin-2-y|)thio)-2-(4- (trifluoromethyl)pheny|)acetamide; 2-((6-(4-Aminopiperazin-1-yl)-3,5-dicyano-4-ethylpyridin-2-y|)thio)-2- phenylacetamide; 2-((6-((2-Amino-2-oxoethy|)thio)-3,5-dicyano-4-ethylpyridin-2-y|)thio)-2- phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-(pyrro|o[3,4-c]pyrazol-5(1H,4H,6H)-y|)pyridin-2-y|)thio)- 2-phenylacetamide; 2-((3,5-Dicyano-6-(dimethylamino)-4-ethylpyridin-2-y|)thio)-2-(5-methoxypyridin-2- y|)acetamide; 2-((3,5-Dicyano-6-(dimethylamin0)-4-ethylpyridin-2-y|)thio)-2-(5-methylpyridin-2- y|)acetamide; 2-((3,5-Dicyano-4-ethyl-6-(4-methyl-1 ,4-diazepan-1-y|)pyridin-2-y|)thio)-2-(2- fluoropyridin-4-y|)acetamide; 2-((3,5-Dicyano-4-ethyl-6-(4-hydroxy-4-(hydroxymethyl)piperidin-1-y|)pyridin-2- y|)thio)-2-phenylacetamide; WO 2017/216727 PCT/IB2017/053511 1286 2-((3,5-Dicyan0-4-ethy|-6-(2-oxo-3-oxa-1 ,8-diazaspiro[4.5]decan-8-y|)pyridin-2- y|)thio)-2-phenylacetamide; 2-((6-(4-Amino-4-(hydroxymethy|)piperidin-1-yl)-3,5-dicyano-4-ethylpyridin-2- y|)thio)-2-phenylacetamide; 2-((6-(4-(Aminomethyl)-4-hydroxypiperidin-1-yl)-3,5-dicyano-4-ethylpyridin-2- y|)thio)-2-phenylacetamide; 2-(3-Benzoylphenyl)-2-((3,5-dicyano-4-ethyl-6-(4-(2-hydroxyethyl)-1,4-diazepan-1- y|)pyridin-2-y|)thio)acetamide; 2-(4-Benzoylphenyl)-2-((3,5-dicyano-4-ethyl-6-(4-(2-hydroxyethyl)-1,4-diazepan-1- y|)pyridin-2-y|)thio)acetamide; 2-((3,5-Dicyano-4-ethyl-6-(4-methyl-1 ,4-diazepan-1-y|)pyridin-2-y|)thio)-2-(2- methylpyridin-4-y|)acetamide; 2-((3,5-Dicyano-4-ethyl-6-(4-methyl-1 ,4-diazepan-1-y|)pyridin-2-y|)thio)-2-(3- (pyrrolidin-1-y|)pheny|)acetamide; 2-((3,5-Dicyano-4-ethyl-6-(4-methyl-1 ,4-diazepan-1-y|)pyridin-2-y|)thio)-2-(3- fluoropyridin-4-y|)acetamide; 2-((3,5-Dicyano-4-ethyl-6-(4-methyl-1,4-diazepan-1-y|)pyridin-2-y|)thio)-2-(2,5- difluoropyridin-4-y|)acetamide; 2-((3,5-Dicyano-6-(4-(2,5-dioxoimidazolidin-1-y|)piperidin-1-y|)-4-ethy|pyridin-2- y|)thio)-2-phenylacetamide; 4-Amino-1-(6-((2-amino-2-oxo-1-phenylethyl) thio)-3, 5-dicyano-4-ethylpyridin-2-yl) piperidine-4-carboxamide; 2-((3,5-Dicyano-6-(4-(2,5-dioxopyrrolidin-1-y|)piperidin-1-y|)-4-ethy|pyridin-2- y|)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-(4-methyl-1,4-diazepan-1-y|)pyridin-2-y|)thio)-2- phenylacetamide (isomer 1); 2-((3,5-dicyano-4-ethy|-6-(4-methy|-1,4-diazepan-1-y|)pyridin-2-y|)thio)-2- phenylacetamide (lsomer 2) ; 2-((3,5-Dicyano-4-ethyl-6-(2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-8-y|)pyridin-2- y|)thio)-2-phenylacetamide; WO 2017/216727 PCT/IB2017/053511 1287 1-(6-((2-Amino-2-oxo-1-pheny|ethy|)thio)-3,5-dicyano-4-ethylpyridin-2-y|)-4- hydroxy piperidine-4-carboxamide; 1-(6-((2-Amino-2-oxo-1-pheny|ethy|)thio)-3,5-dicyano-4-ethylpyridin-2-y|)azetidin- 3-yl carbamate; 2-((3,5-Dicyano-6-(4-(2,4-dioxooxazolidin-3-y|)piperidin-1-y|)-4-ethy|pyridin-2- y|)thio)-2-phenylacetamide; 3-((6-((2-Amino-2-oxo-1-pheny|ethy|)thio)-3,5-dicyano-4-ethy|pyridin-2- y|)(methy|)amino)-2-hydroxy-2-methylpropanamide; 2-((3,5-Dicyano-4-ethyl-6-(3-(hyd roxymethy|)azetidin-1-y|)pyridin-2-y|)thio)-2- phenylacetamide; 2-(3,5-Dicyano-4-ethyl-6-(piperazin-1-y|)pyridin-2-ylthio)-2-(thiophen-3- y|)acetamide; 2-((3,5-Dicyano-4-ethyl-6-(4-methyl-1,4-diazepan-1-yl) pyridin-2-yl) thio)-2-(5- methylpyridin-3-yl) acetamide; 2-((6-(4-(3-Amino-2-oxopyrrolidin-1-y|)piperidin-1-yl)-3,5-dicyano-4-ethy|pyridin-2- y|)thio)-2-phenylacetamide; 1-(6-((2-Amino-2-oxo-1-pheny|ethy|)thio)-3,5-dicyano-4-ethylpyridin-2-y|)piperidin- 4-yl (28)-2-amino-3-methylbutanoate; 2-((6-((2-Amino-2-oxo-1-pheny|ethy|)thio)-3,5-dicyano-4-ethylpyridin-2-yl) (methyl) amino)ethy| (28)-2-amino-3-methylbutanoate; 2,2‘-((3,5-Dicyano-4-ethylpyridine-2,6-diy|)bis(suIfanediy|))bis(2-phenylacetamide) (28)-(1-(6-((2-Amino-2-oxo-1-pheny|ethy|)thio)-3,5-dicyano-4 —ethy| pyridin-2- y|)azetidin-3-y|)methy| 2-amino-3-methylbutanoate; 2-((6-(3-Aminoazetidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-y|)thio)-2- phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-methylpyridin-2-y|)thio)-2-phenylacetamide; N-(1-(6-((2-Amino-2-oxo-1-pheny|ethy|)thio)-3,5-dicyano-4-ethylpyridin-2- y|)piperidin-4-y|)-2-hydroxyacetamide; N-(1-(6-((2-Amino-2-oxo-1-pheny|ethy|)thio)-3,5-dicyano-4-ethylpyridin-2- y|)azetidin-3-yl)-2-hydroxyacetamide; WO 2017/216727 PCT/IB2017/053511 1288 2-((3-Cyano-4-ethy|-5-methyl-6-(piperazin-1-y|)pyridin-2-y|)thio)-2- phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-(5-methyl-2,5-diazabicyc|o[2.2.1]heptan-2-y|)pyridin-2- y|)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-(4-(2-(pyrrolidin-1-y|)ethy|)piperazin-1-y|)pyridin-2- y|)thio)-2-phenylacetamide; 2-((3,5-Dicyano-6-(dimethylamino)-4-ethylpyridin-2-y|)thio)-2-pheny|acetamide-2- (R)-2-((3,5-Dicyano-6-(dimethylamino)-4-ethylpyridin-2-y|)thio)-2- phenylacetamide-2-d; 2-((6-(4-(4-Bromobenzoy|)piperazin-1-yl)-3,5-dicyano-4-ethylpyridin-2-y|)thio)-2- phenylacetamide; 2-((3,5-Dicyano-4-ethy|-6-(4-(2-hydroxyethy|)-1,4-diazepan-1-y|)pyridin-2-y|)thio)- 2-phenylacetamide; 2-((3,5-Dicyano-6-(4-cyanopiperidin-1-yl)-4-ethylpyridin-2-y|)thio)-2- phenylacetamide; (S)-2-((3,5-Dicyano-4-ethyl-6-((S)-3-hyd roxypyrrolidin-1-y|)pyridin-2-y|)thio)-2- phenylacetamide; 2-((6-(4-Amino-4-methylpiperidin-1-yl)-3,5-dicyano-4-cyclopropy|pyridin-2-y|)thio)- 2-phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-((S)-3-hyd roxypyrrolid in-1 -y|)pyrid in-2-y|)thio)-2-(pyrid in- 2-y|)aceta mide; 2-((3,5-DichIoro-4-ethyl-6-(piperazin-1-yl)pyridin-2-y|)thio)-2-phenylacetamide; tert-Butyl (1-(6-((2-amino-2-oxo-1-pheny|ethy|)thio)-3,5-dicyano-4-ethylpyridin-2- y|)piperidin-4-y|)carbamate; 2-((6-(3-(2-Amino-2-oxoethy|)azetidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-y|)thio)-2- phenylacetamide; (2R)-1-(6-((2-Amino-2-oxo-1-pheny|ethy|)thio)-3,5-dicyano-4-ethylpyridin-2- y|)azetidin-3-yl 2-amino-3-methylbutanoate; 2-((3,5-Dicyano-4-ethyl-6-(methyl((5-oxo-4,5-dihydro-1H-1 ,2,4-triazo|-3- y|)methy|)amino)pyridin-2-y|)thio)-2-phenylacetamide; WO 2017/216727 PCT/IB2017/053511 1289 2-((6-(((4H-1 ,2,4-Triazol-3-yl)methy|)(methy|)amino)-3,5-dicyano-4-ethylpyridin-2- y|)thio)-2-phenylacetamide; 2-((3,5-Dicyan0-4-ethoxy-6-methylpyridin-2-y|)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4,6-diethylpyridin-2-y|)thio)-2-phenylacetamide; 2-((6-((2-(4H-1 ,2,4-Triazol-4-y|)ethy|)(methy|)amino)-3,5-dicyano-4-ethylpyridin-2-y|)thio)- phenylacetamide; 2-((6-(((1H-Pyrazol-3-y|)methy|)(methy|)amin0)-3,5-dicyano-4-ethylpyridin-2- y|)thio)-2-phenylacetamide; 2-((3,5-Dicyano-6-(6,7-dihydro-1H-[1,2,3]triazo|o[4,5-c]pyridin-5(4H)-y|)-4- ethylpyridin-2-y|)thio)-2-phenylacetamide; 2-((6-(((1H-Imidazol-2-y|)methy|)(methy|)amino)-3,5-dicyano-4-ethy|pyridin-2- y|)thio)-2-phenylacetamide; 2-((6-(((1H-Imidazol-5-y|)methy|)(methy|)amino)-3,5-dicyano-4-ethy|pyridin-2- y|)thio)-2-phenylacetamide; (2R)-2-Amino-N-(1-(6-((2-amino-2-oxo-1-pheny|ethy|)thio)-3,5-dicyano-4- ethylpyridin-2-yl)piperidin-4-yl)propanamide; 4-(2-Amino-1-((3,5-dicyano-4-ethy|-6-(4-methyl-1,4-diazepan-1-y|)pyridin-2- y|)thio)-2-oxoethy|)benzamide; 2-((3,5-Dicyano-4-cyclopropyl-6-(3-hydroxypyrrolidin-1-y|)pyridin-2-y|)thio)-2- phenylacetamide; 2-((3,5-Dicya no-4-ethyl-6-(3-hydroxypyrroIidin-1-y|)pyridin-2-y|)thio)-2- phenylacetamide; (2R)-2-Amino-N-(1-(6-((2-amino-2-oxo-1-pheny|ethy|)thio)-3,5-dicyano-4- cyclopropyl pyridin-2-y|)piperidin-4-y|)propanamide; 2-((6-((2-Aminoethy|)(methy|)amino)-3,5-dicyano-4-cyclopropylpyridin-2-y|)thio)-2- phenylacetamide; 2-Amino-N-(1-(6-((2-amino-2-oxo-1-phenylethyl) thio)-3,5-dicyano-4- cyclopropylpyrid in-2-yl)piperid in-4-yl)-2-methylpropa namide; 4-(2-Amino-1-((3,5-dicyano-6-(dimethylamino)-4-ethylpyridin-2-y|)thio)-2- oxoethy|)benzamide; WO 2017/216727 PCT/IB2017/053511 1290 2-(6-(4-Aminopiperidin-1-yl)-3-cyano-4-ethyl-5-methylpyridin-2-y|thio)-2- phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-(4-methyl-1,4-diazepan-1-y|)pyridin-2-y|)thio)-2-(4-(N- methylsulfamoy|)phenyl)acetamide; 2-((3,5-Dicyano-4-ethyl-6-(6-fluoro-1,4-diazepan-1-yl)pyridin-2-y|)thio)-2- phenylacetamide; 2-((6-(4-Amino-3,3-difluoropiperidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-y|)thio)-2- phenylacetamide; tert-Butyl (1-(6-((2-amino-2-oxo-1-phenylethyl) thio)-3,5-dicyano-4-ethy|pyridin-2- yl)-3,3-difluoropiperidin-4-yl) carbamate; 2-((3,5-Dicyano-4-cyclopropyl-6-((2-hydroxyethyl)(methy|)amino)pyridin-2-y|)thio)- 2-phenylacetamide; 2-((3,5-Dicyano-4-cyc|opropy|-6-(3-hydroxyazetidin-1-y|)pyridin-2-y|)thio)-2- phenylacetamide; 1-(6-((2-Amino-2-oxo-1-pheny|ethy|)thio)-3,5-dicyano-4-ethylpyridin-2- y|)pyrro|idine-3-carboxamide; 2-((6-((3-Aminopropyl) (methyl) amino)-3, 5-dicyano-4-cyclopropylpyridin-2-yl) thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-cyclopropyl-6-((2-(3-hydroxyazetidin-1-y|)-2- oxoethy|)(methy|)amino) pyridin-2-y|)thio)-2-phenylacetamide; 2-((6-(4-((2-Amino-2-oxoethy|)amino)piperidin-1-yl)-3,5-dicyano-4-ethylpyridin-2- y|)thio)-2-phenylacetamide; 2-((6-((2-Amino-2-oxoethyl)(methy|)amino)-3,5-dicyano-4-cyclopropylpyridin-2- y|)thio)-2-phenylacetamide; 2-((6-((2-Amino-2-oxo-1-phenylethyl) thio)-3, 5-dicyano-4-cyclopropylpyridin-2- y|)(methy|)amino)ethy| carbamate; (ZR)-2-Amino-N-(1-(6-((2-amino-2-oxo-1-pheny|ethy|)thio)-3,5-dicyano-4- ethylpyridin-2-y|)piperidin-4-yl)-3-hydroxypropanamide; (28)-2-Amino-N-(1-(6-((2-amino-2-oxo-1-phenylethyl) thio)-3, 5-dicyano-4- ethylpyridin-2-yl) piperidin-4-yl)-3-hydroxypropanamide; WO 2017/216727 PCT/IB2017/053511 1291 2-(4-(2-Amino-2-oxoethyl)phenyl)-2-(3,5-dicyano-4-ethyl-6-(4-methyl-1 ,4- diazepan-1-y|)pyridin-2-y|thio)acetamide; 2-(4-(2-Amino-2-oxoethyl)phenyl)-2-(3,5-dicyano-6-(dimethylamino)-4-ethylpyridin- 2-y|thio)acetamide; 2-((3,5-Dicyano-6-(dimethylamino)-4-ethylpyridin-2-y|)thio)-2-(4-(N- methylsulfamoy|)pheny|)acetamide; 2-((3,5-Dicyano-6-(dimethylamino-d6)-4-ethylpyridin-2-y|)thio)-2-phenylacetamide; (R)-2-((3,5-Dicyano-4-ethy|-6-(4-(pyrrolidin-1-yl)piperidin-1-y|)pyridin-2-y|)thio)-2- phenylacetamide; (R)-2-((3,5-Dicyano-6-(4-(dimethy|amino)piperidin-1-yl)-4-ethylpyridin-2-y|)thio)-2- phenylacetamide; 2-(3,5-dicyano-6-(dimethylamino)-4-ethylpyridin-2-ylthio)-2-(3-(2- (dimethylamino)ethoxy)pheny|)acetamide; 2-((3,5-Dicyano-4-ethyl-6-(4-(neopentylamino)piperidin-1-y|)pyridin-2-y|)thio)-2-(4- fluorophenyl)acetamide; 2-((3,5-dicyano-4-ethyl-6-(3-fluoro-4-A(neopenty|amino)piperidin-1-y|)pyridin-2- y|)thio)-2-phenylacetamide; 2-((6-(4-aminopiperidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-y|)thio)-2-(4- (trifluoromethyl)pheny|)acetamide; 2-((3,5-Dicyano-4-ethyl-6-(4-(pyrroIidin-1-y|)piperidin-1-y|)pyridin-2-y|)thio)-2- phenylacetamide; (R)-2-((6-(4-aminopiperidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-y|)thio)-2- phenylacetamide; 2-((6-((2-amino-2-oxoethyl)(methy|)amino)-3,5-dicyano-4-ethylpyridin-2-y|)thio)-2- phenylacetamide; (single enantiomer) (38)-1-(6-((2-amino-2-oxo-1-phenylethyl) thio)-3, 5-dicyano-4-ethylpyridin-2-yl) Pyrrolidin-3-yl dihydrogen phosphate; (3R)-1-(6-((2-amino-2-oxo-1-pheny|ethy|)thio)-3,5-dicyano-4-ethylpyridin-2- y|)pyrro|idin-3-yl dihydrogen phosphate; (S)-1-(6-(((S)-2-amino-2-oxo-1-pheny|ethy|)thio)-3,5-dicyano-4-ethylpyridin-2- y|)pyrro|idin-3-yl dihydrogen phosphate; WO 2017/216727 PCT/IB2017/053511 1292 (S)-1-(6-(((R)-2-amino-2-oxo-1-phenylethyl) thio)-3,5-dicyano-4-ethylpyridin-2-yl) pyrrolidin-3-yl dihydrogen phosphate; 2-((3,5-Dicyano-6-(dimethylamino)-4-ethylpyridin-2-y|)thio)-2-(3- (dimethylphosphory|)pheny|)acetamide; 2-((3,5-Dicyano-4-ethyl-6-((8)-3-hydroxypyrrolidin-1-y|)pyridin-2-y|)thio)-2-(3-( dimethy|phosphory|)pheny|)acetamide; (R)-2-((6-((2-amino-2-oxo-1-pheny|ethy|)thio)-3,5-dicyano-4-ethy|pyridin-2- y|)(methy|)amino)ethy| dihydrogen phosphate; (R)-2-((3,5-dicyano-4-ethyl-6-((S)-3-hydroxypyrro|idin-1-y|)pyridin-2-y|)thio)-2-(4- methoxypheny|)acetamide; (R)-2-(4-chIorophenyl)-2-((3,5-dicyano-4-ethyl-6-((S)-3-hydroxypyrrolidin-1- y|)pyridin-2-y|)thio)acetamide; (R)-2-((3,5-dicyano-4-ethyl-6-((S)-3-h yd roxypyrrolidin-1 -y|)pyridin-2-y|)th io)-2-(4- fluoro pheny|)acetamide; (S)-1-(6-(((R)-2-amino-1-(4-fluorophenyl)-2-oxoethy|)thio)-3,5-dicyano-4- ethylpyridin-2-y|)pyrro|idin-3-yl dihydrogen phosphate; 2-((3, 5-dicyano-4-ethyl-6-((S)-3-hydroxypyrro|idin-1-yl) pyridin-2-yl) thio)-2-(4- fluorophenyl) acetamide; 2-((3,5-dicyano-4-ethy|-6-((S)-3-hydroxypyrrolidin-1-yl) pyridin-2-yl) thio)-2-(2, 6- difluorophenyl) acetamide; 2-((3, 5-dicyano-4-ethyl-6-((S)-3-hydroxypyrrolidin-1-yl) pyridin-2-yl) thio)-2-(2, 3- difluorophenyl) acetamide; 2-((3, 5-dicyano-4-ethyl-6-((S)-3-hydroxypyrrolidin-1-yl) pyridin-2-yl) thio)-2-(2, 4- difluorophenyl) acetamide; 2-((3,5-d icyano-4-ethy|-6-(4-((S)-2-(hyd roxymethy|)pyrro|idin-1-y|)piperidin-1- y|)pyridin-2-y|)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-(4-((2-hydroxyethy|)(methy|)amino)piperidin-1-y|)pyridin- 2-y|)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-(4-((2-hydroxy-2-methylpropy|)(methy|)amino)piperidin-1- y|)pyridin-2-y|)thio)-2-phenylacetamide; WO 2017/216727 PCT/IB2017/053511 1293 2-((3,5-dicyano-4-ethyl-6-(4-(pyrroIidin-1-y|methy|)piperidin-1-y|)pyridin-2-y|)thio)- 2-phenylacetamide; 2-((3,5-dicyano-4-ethy|-6-(4-((2-methoxy-2-methylpropy|)amino)piperidin-1- y|)pyridin-2-y|)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethy|-6-(4-((2-hydroxy-2-methy|propy|)amino)piperidin-1- y|)pyridin-2-y|)thio)-2-phenylacetamide; 2-((3,5-dicyano-6-(4-(cyclobuty|amino)piperidin-1-yl)-4-ethylpyridin-2-y|)thio)-2- phenylacetamide; 2-((3,5-dicyano-4-ethy|-6-(4-(((3-methyloxetan-3-yl)methy|)amino)piperidin-1- y|)pyridin-2-y|)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-(4-(4-methylpiperazin-1-y|)piperidin-1-y|)pyridin-2- y|)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethy|-6-(4-((R)-2-methylpyrrolidin-1-y|)piperidin-1-y|)pyridin-2- y|)thio)-2-phenylacetamide; 2-((3,5-dicyano-6-(4-((2R,5S)-2,5-dimethylpyrrolidin-1-y|)piperidin-1-y|)-4- ethylpyridin-2-y|)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethy|-6-(4-((S)-2-methylpyrrolidin-1-y|)piperidin-1-y|)pyridin-2- y|)thio)-2-phenylacetamide; 2-((3,5-dicyan0-6-(4-(cyc|obuty|(methy|)amino)piperidin-1-y|)-4-ethy|pyridin-2- y|)thio)-2-phenylacetamide; 2-(6-(4-(benzylamino)piperidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-y|thio)-2- phenylacetamide; 2-((3,5-dicyano-4-ethy|-6-(4-(((6-methoxypyridin-2-yl)methy|)amino)piperidin-1- y|)pyridin-2-y|)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethy|-6-(4-((S)-3-fluoropyrrolidin-1-y|)piperidin-1-y|)pyridin-2- y|)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethy|-6-(methy|(2-((R)-2-methylpyrrolidin-1- y|)ethy|)amino)pyrid in-2-y|)th io)-2-phenylacetamide; 2-((3,5-dicyano-4-ethy|-6-(4-((R)-3-fluoropyrrolidin-1-y|)piperidin-1-y|)pyridin-2- y|)thio)-2-phenylacetamide; WO 2017/216727 PCT/IB2017/053511 1294 2-((3,5-dicyano-6-(4-((2S,5S)-2,5-dimethylpyrrolidin-1-y|)piperidin-1-y|)-4- ethylpyridin-2-y|)thio)-2-phenylacetamide; 2-((3,5-dicyan0-4-ethyl-6-(methy|(2-((S)-2-methylpyrrolidin-1- y|)ethy|)amino)pyrid in-2-y|)th io)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-(4-((R)-2-(hydroxymethy|)pyrro|idin-1-y|)piperidin-1- y|)pyridin-2-y|)thio)-2-phenylacetamide; 2-((3,5-dicyano-6-(4-(dimethy|amino)piperidin-1-yl)-4-ethylpyridin-2-y|)thio)-2-(4- fluorophenyl)acetamide; 2-((3,5-dicyano-4-ethyl-6-(4-(((1-methylcyclobutyl)methy|)amino)piperidin-1- y|)pyridin-2-y|)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethy|-6-(4-(((6-methoxypyridin-3-yl)methy|)amino)piperidin-1- y|)pyridin-2-y|)thio)-2-phenylacetamide; 2-(3,5-dicyano-4-ethy|-6-((2-(ethylamino)ethy|)(methy|)amino)pyridin-2-y|thio)-2- phenylacetamide; 2-((3,5-dicyano-4-ethy|-6-(4-((4-methy|piperazin-1 -y|)methy|) piperidin-1 -yl) pyridin- 2-y|)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-(methy|(2-(methylamino)ethy|)amino)pyridin-2-y|)thio)-2- phenylacetamide; 2-((3,5-dicyano-6-(4-((2R,5R)-2,5-dimethylpyrrolidin-1-y|)piperidin-1-y|)-4- ethylpyridin-2-y|)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-(4-(((1-methylcyclopropyl)methy|)amino)piperidin-1- y|)pyridin-2-y|)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethy|-6-(4-((4-fluorobenzy|)amino)piperidin-1-y|)pyridin-2-y|)thio)- 2-phenylacetamide; 2-((3,5-dicyano-4-ethy|-6-((2-((S)-2-(hyd roxymethy|)pyrro|idin-1- y|)ethy|)(methy|)amino)pyridin-2-y|)thio)-2-phenylacetamide; 2-(3,5-dicyano-6-((2-((2S,5R)-2,5-dimethylpyrrolidin-1-y|)ethy|)(methy|)amino)-4- ethylpyridin-2-ylthio)-2-phenylacetamide; 2-((6-((2-(azepan-1-y|)ethy|)(methy|)amino)-3,5-dicyano-4-ethylpyridin-2-y|)thio)-2- phenylacetamide; WO 2017/216727 PCT/IB2017/053511 1295 2-((3,5-dicyan0-4-ethyl-6-(methy|(2-(piperidin-1-y|)ethy|)amino)pyridin-2-y|)thio)-2- phenylacetamide; 2-((3,5-dicyano-4-ethy|-6-((2-((R)-2-(hydroxymethy|)pyrro|idin-1- y|)ethy|)(methy|)amino)pyridin-2-y|)thio)-2-phenylacetamide; 2-(3,5-dicyano-4-ethy|-6-((2-(ethy|(methy|)amino)ethy|)(methy|)amino)pyridin-2- ylth io)-2-phenylaceta mide; 2-((3,5-dicyano-6-((2-((2R,5R)-2,5-dimethylpyrrolidin-1-y|)ethy|)(methy|)amino)-4- ethylpyridin-2-y|)thio)-2-phenylacetamide; 2-(3,5-dicyano-4-ethy|-6-((2-((S)-3-hydroxypyrrolidin-1- y|)ethy|)(methy|)amino)pyridin-2-ylthio)-2-phenylacetamide; methyl 2-((1-(6-((2-amino-2-oxo-1-pheny|ethy|)thio)-3,5-dicyano-4-ethylpyridin-2- y|)piperidin-4-y|)amino)-2-methylpropanoate; 2-((3,5-dicyano-4-ethy|-6-(methy|(2-(neopentylamino)ethy|)amino)pyridin-2-yl)thio)- 2-phenylacetamide; 2-(3,5-dicyan0-4-ethyl-6-(methy|(2-(1-methylcyclopropylamino)ethyl)amino)pyridin- 2-ylthio)-2-phenylacetamide; 2-((3,5-dicyano-6-((2-((2S,5S)-2,5-dimethylpyrrolidin-1-y|)ethy|)(methy|)amino)-4- ethylpyridin-2-y|)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethy|-6-((2-((2-methoxyethy|)amino)ethy|)(methy|)amino)pyridin- 2-y|)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethy|-6-(4-((2-methoxy-2-methylpropy|)(methy|)amino)piperidin- 1-y|)pyrid in-2-y|)th io)-2-phenylacetamide; 2-((3,5-dicyano-6-((2-(dimethylamino)ethy|)(methy|)amino)-4-ethylpyridin-2- y|)thio)-2-phenylacetamide; 2-(3,5-dicyano-4-ethy|-6-((2-((R)-3-hyd roxypyrro|idin-1- y|)ethy|)(methy|)amino)pyridin-2-ylthio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-((2-((2-fluoroethy|)amino)ethy|)(methy|)amino)pyridin-2- y|)thio)-2-phenylacetamide; 2-((3,5-dicyano-6-(4-(3,3-difluoropyrrolidin-1-y|)piperidin-1-y|)-4-ethy|pyridin-2- y|)thio)-2-phenylacetamide; WO 2017/216727 PCT/IB2017/053511 1296 2-((1-(6-((2-amino-2-oxo-1-pheny|ethy|)thio)-3,5-dicyano-4-ethy|pyridin-2- y|)piperidin-4-y|)amino)acetic acid; 2-((6-((3-aminocyclobuty|)(methy|)amino)-3,5-dicyano-4-ethylpyridin-2-y|)thio)-2- phenylacetamide; (R)-2-(3,5-dicyano-4-ethy|-6-(methy|((R)-tetrahyd rofuran-3-y|)amino)pyridin-2- ylth io)-2-phenylaceta mide; (S)-2-(3,5-dicyano-4-ethy|-6-(methy|((R)-tetrahydrofu ran-3-y|)amino)pyridin-2- ylthio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-(4-morpholinopiperidin-1-yl)pyridin-2-y|)thio)-2- phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-(4-(2-hyd roxyethyl)-3-oxopiperazin-1-y|)pyridin-2-y|)thio)- 2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-(4-(pyrroIidin-1-y|)piperidin-1-y|)pyridin-2-y|)thio)-2-(4- fluoropheny|)acetamide; (R)-2-((6-((38,4R)-4-amino-3-fluoropiperidin-1-yl)-3,5-dicyano-4-ethylpyridin-2- y|)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-(3-fluoro-4-(methylamino)piperidin-1-y|)pyridin-2-y|)thio)- 2-phenylacetamide; rel-2-((6-(trans)-4-amino-3-fluoropiperidin-1-yl)-3,5-dicyano-4-ethylpyridin-2- y|)thio)-2-phenylacetamide; (R)-2-((6-((3R,4S)-4-amino-3-fluoropipe rid in-1 -yl)-3 ,5-dicyano-4-ethylpyrid in-2- y|)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-(3-fluoro-4-((2-methoxyethy|)amino)piperidin-1-y|)pyridin- 2-y|)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-(methyl(2-(pyrrolidin-1-y|)ethy|)amino)pyridin-2-y|)thio)-2- phenylacetamide; 2-((3,5-dicyano-6-(3-((dimethy|amino)methy|)pyrrolidin-1-y|)-4-ethy|pyridin-2- y|)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethy|-6-(4-((2-hydroxy-2-methy|propy|)amino)piperidin-1- y|)pyrid in-2-y|)th io)-2-(4-fluoropheny|)acetamide; WO 2017/216727 PCT/IB2017/053511 1297 (R)-2-((6-((38,4R)-4-amino-3-hydroxypiperidin-1-yl)-3,5-dicyano-4-ethy|pyridin-2- y|)thio)-2-phenylacetamide; 2-((3,5-dicyano-6-((2-(diethy|amino)ethy|)(methy|)amino)-4-ethylpyridin-2-y|)thio)- 2-phenylacetamide; 2-((3,5-dicyano-6-((2-((R)-3-(dimethy|amino)pyrro|idin-1-y|)ethy|)(methy|)amino)-4- ethylpyridin-2-y|)thio)-2-phenylacetamide; 2-((3,5-dicyano-6-((2-((S)-3-(dimethylamino)pyrrolidin-1-y|)ethy|)(methy|)amino)-4- ethylpyridin-2-y|)thio)-2-phenylacetamide; (R)-2-((6-((3R,4R)-4-amino-3-fluoropiperidin-1-yl)-3,5-dicyano-4-ethylpyridin-2- y|)thio)-2-phenylacetamide; (R)-2-((6-((38,4S)-4-amino-3-fluoropipe rid in-1 -yl)-3,5-dicyano-4-ethylpyrid in-2- y|)thio)-2-phenylacetamide; 2-((3,5-dicyan0-4-ethyl-6-(3-(methylamino)pyrro|idin-1-yl)pyridin-2-y|)thio)-2- phenylacetamide; 2-((6-(4-aminopiperidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-y|)thio)-2-(4- fluorophenyl)acetamide; (R)-2-((6-((3R,4R)-4-amino-3-hydroxypiperidin-1-yl)-3,5-dicyano-4-ethy|pyridin-2- y|)thio)-2-phenylacetamide; 2-((6-((R)-3-aminopyrrolidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-y|)thio)-2- phenylacetamide; 2-((6-(3-(aminomethyl)pyrrolidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-y|)thio)-2- phenylacetamide; 2-((3,5-dicyano-4-ethy|-6-(4-(methylamino)piperidin-1-y|)pyridin-2-y|)thio)-2-(4- fluorophenyl)acetamide; 2-((3,5-dicyano-6-(4-(cyclopropylamino)-3-fluoropiperidin-1-y|)-4-ethy|pyridin-2- y|)thio)-2-phenylacetamide; 2-((6-((S)-3-aminopyrrolidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-y|)thio)-2- phenylacetamide; 2-((6-((2-((R)-3-aminopyrrolidin-1-y|)ethy|)(methy|)amino)-3,5-dicyano-4- ethylpyridin-2-y|)thio)-2-phenylacetamide; WO 2017/216727 PCT/IB2017/053511 1298 3,5-dicyano-6-((R)-3-(dimethylamino)pyrrolidin-1-yl)-4-ethylpyridin-2-y|)thio)-2-(4- fluorophenyl)acetamide; (S)-2-((6-((38,4R)-4-amino-3-fluoropipe rid in-1 -yl)-3,5-dicyano-4-ethylpyrid in-2- y|)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-(4-(neopenty|amino)piperidin-1-y|)pyridin-2-y|)thio)-2-(4- (trifluoromethyl)phenyl)acetamide; tert-butyl ((3S,4R)-1-(6-(((R)-2-amino-2-oxo-1-pheny|ethy|)thio)-3,5-dicyano-4- ethylpyrid in-2-yl)-3-hyd roxypiperid in-4-y|)ca rba mate; rel-ten-butyl (cis)-1-(6-((2-amino-2-oxo-1-pheny|ethy|)thio)-3,5-dicyano-4- ethylpyridin-2-yl)-3-fluoropiperidin-4-y|)carbamate; 2-((6-((2-((S)-3-aminopyrrolidin-1-y|)ethy|)(methy|)amino)-3,5-dicyano-4- ethylpyridin-2-y|)thio)-2-phenylacetamide; 2-((3,5-dicyano-6-((R)-3-(dimethy|amino)pyrro|idin-1-yl)-4-ethylpyridin-2-y|)thio)-2- phenylacetamide; tert-butyl ((3R,4S)-1-(6-(((R)-2-amino-2-oxo-1-pheny|ethy|)thio)-3,5-dicyano-4- ethylpyrid in-2-yl)-3-hyd roxypiperid in-4-y|)ca rba mate; rel-tert-butyl (cis)-1-(6-((2-amino-2-oxo-1-pheny|ethy|)thio)-3,5-dicyano-4- ethylpyridin-2-yl)-3-fluoropiperidin-4-y|)carbamate; 2-((3,5-dicyano-6-((S)-3-(dimethylamino)pyrrolidin-1-yl)-4-ethylpyridin-2-y|)thio)-2- phenylacetamide; (S)-2-((6-((3R,4S)-4-amino-3-fluoropipe rid in-1 -yl)-3,5-dicyano-4-ethylpyrid in-2- y|)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethy|-6-((S)-3-((2-hydroxy-2-methylpropy|)amino)pyrro|idin-1- y|)pyridin-2-y|)thio)-2-phenylacetamide; tert-butyl ((3R,4R)-1-(6-(((R)-2-amino-2-oxo-1-pheny|ethy|)thio)-3,5-dicyano-4- ethylpyrid in-2-yl)-3-hyd roxypiperid in-4-y|)ca rba mate; 2-((3,5-dicyano-6-((S)-3-(dimethylamino)pyrro|idin-1-yl)-4-ethylpyridin-2-y|)thio)-2- (4-fluoropheny|)acetamide; rel-2-((6-cis-4-amino-3-fluoropiperidin-1-yl)-3,5-dicyan0-4-ethylpyridin-2-y|)thio)-2- phenylacetamide; WO 2017/216727 PCT/IB2017/053511 1299 2-((3,5-dicyan0-4-ethyl-6-(4-(methylamino)piperidin-1-y|)pyridin-2-y|)thio)-2- phenylacetamide; 2-((3,5-dicyano-6-(4-(dimethy|amino)piperidin-1-yl)-4-ethylpyridin-2-y|)thio)-2- phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-(4-(ethy|(methy|)amino)piperidin-1-y|)pyridin-2-y|)thio)-2- phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-(4-(neopenty|amino)piperidin-1-y|)pyridin-2-y|)thio)-2- phenylacetamide; 2-((3,5-dicyano-4-ethy|-6-(4-(methyl(neopenty|)amino)piperidin-1-y|)pyridin-2- y|)thio)-2-phenylacetamide; 2-((3,5-dicyano-6-(4-(cyclopropy|amino)piperidin-1-yl)-4-ethylpyridin-2-y|)thio)-2- phenylacetamide; 2-((3,5-dicyano-4-ethy|-6-(4-((2-methoxyethy|)amino)piperidin-1-y|)pyridin-2- y|)thio)-2-phenylacetamide; 2-((3,5-dicyano-6-(4-((2,2-difluoroethy|)amino)piperidin-1-y|)-4-ethy|pyridin-2- y|)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethy|-6-((R)-2-((neopentylamino)methy|)morpho|ino)pyridin-2- y|)thio)-2-phenylacetamide; 2-((3,5-dicyano-6-(2-((dimethy|amino)methy|)morpholino)-4-ethylpyridin-2-y|)thio)- 2-phenylacetamide; 2-((3,5-dicyano-6-(2-((diethy|amino)methy|)morpholin0)-4-ethylpyridin-2-y|)thio)-2- phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-(2-(pyrrolidin-1-ylmethyl)morpholino)pyridin-2-y|)thio)-2- phenylacetamide; (R)-2-((6-((R)-2-(aminomethyl)morpholino)-3,5-dicyano-4-ethylpyridin-2-y|)thio)-2- phenylacetamide; 2-((6-(2-(aminomethyl)morpholino)-3,5-dicyano-4-ethylpyridin-2-y|)thio)-2- phenylacetamide; 2-((3,5-dicyano-4-ethy|-6-(2-((methy|amino)methy|)morpholino)pyridin-2-y|)thio)-2- phenylacetamide; WO 2017/216727 PCT/IB2017/053511 1300 2-((6-((R)-2-(a minomethy|)morpho|ino)-3 ,5-dicyano-4-ethylpyrid in-2-y|)th io)-2- phenylacetamide; 2-((3,5-dicyano-6-(3-((dimethylamino)methy|)piperidin-1-y|)-4-ethy|pyridin-2- y|)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethy|-6-(3-((methy|amino)methyl)piperidin-1-y|)pyridin-2-y|)thio)- 2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-((S)-2-((neopentylamino)methy|)morpho|ino)pyridin-2- y|)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-((8)-3-((neopenty|amino)methy|)piperidin-1-y|)pyridin-2- y|)thio)-2-phenylacetamide; 2-amino-N-(((2S)-4-(6-((2-amino-2-oxo-1-pheny|ethy|)thio)-3,5-dicyano-4- ethylpyridin-2-y|)morpho|in-2-yl)methyl)-2-methylpropanamide; 2-((6-((S)-3-(aminomethy|)piperidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-y|)thio)-2- phenylacetamide; 2-((3,5-dicyano-6-((R)-2-((diethylamino)methy|)morpholino)-4-ethylpyridin-2- y|)thio)-2-phenylacetamide; 2-amino-N-(((2R)-4-(6-((2-amino-2-oxo-1-pheny|ethy|)thio)-3,5-dicyano-4- ethylpyridin-2-y|)morpho|in-2-yl)methyl)-2-methylpropanamide; 2-((6-(4-aminopiperidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-y|)thio)-2-(3- fluoropyridin-2-y|)acetamide; 2-((6-((S)-2-(aminomethy|)morpho|ino)-3,5-dicyano-4-ethylpyridin-2-y|)thio)-2- phenylacetamide; 2-amino-N-(((3S)-1-(6-((2-amino-2-oxo-1-pheny|ethy|)thio)-3,5-dicyano-4- ethylpyridin-2-y|)piperidin-3-yl)methyl)-2-methylpropanamide; 2-amino-N-(((3S)-1-(6-((2-amino-2-oxo-1-pheny|ethy|)thio)-3,5-dicyano-4- ethylpyridin-2-y|)piperidin-3-y|)methy|)acetamide; 2-amino-N-(((2R)-4-(6-((2-amino-2-oxo-1-pheny|ethy|)thio)-3,5-dicyano-4- ethylpyridin-2-yl)morpholin-2-yl)methy|)acetamide; 2-((6-((R)-3-(a minomethy|)piperidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-y|)thio)-2-(4- fluorophenyl)acetamide; WO 2017/216727 PCT/IB2017/053511 1301 2-((3,5-dicyano-4-ethy|-6-((R)-3-((neopenty|amino)methyl)piperidin-1-y|)pyridin-2- y|)thio)-2-(4-fluoropheny|)acetamide; 2-amino-N-(((2S)-4-(6-((2-amino-2-oxo-1-pheny|ethy|)thio)-3,5-dicyano-4- ethylpyridin-2-y|)morpho|in-2-yl)methy|)acetamide; N-(((R)-4-(6-(((R)-2-amino-2-oxo-1-pheny|ethy|)thio)-3,5-dicyano-4-ethy|pyridin-2- y|)morphoIin-2-y|)methy|)-2-hydroxyacetamide; (S)-2-((6-(4-aminopiperidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-y|)thio)-2- phenylacetamide; 2-((6-((2-amino-2-oxo-1-pheny|ethy|)thio)-3,5-dicyano-4-ethy|pyridin-2- y|)(methy|)amino)-N-(2-hyd roxyethy|)-N-methylacetamide; 2-((3,5-dicyano-4-ethyl-6-((8)-3-(methylamino)piperidin-1-yl)pyridin-2-y|)thio)-2- phenylacetamide; 2-((6-(4-amino-4-methylpiperidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-y|)thio)-2- phenylacetamide; 2-((6-((2-amino-2-oxo-1-pheny|ethy|)thio)-3,5-dicyano-4-ethy|pyridin-2- y|)(methy|)amino)-N-((1-(hydroxymethy|)cyc|opropyl)methyl)-N-methylacetamide; 2-amino-N-(1-(6-((2-amino-2-oxo-1-pheny|ethy|)thio)-3,5-dicyano-4- cyclopropylpyridin-2-yl)azetidin-3-y|)acetamide; (28)-2-amino-N-(1-(6-((2-amino-2-oxo-1-pheny|ethy|)thio)-3,5-dicyano-4- cyclopropylpyridin-2-yl)azetidin-3-yl)-3-hydroxypropanamide; 2-((6-((S)-3-aminopiperidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-y|)thio)-2- phenylacetamide; 2-((3,5-dicyano-4-ethy|-6-((2-((R)-3-hydroxypyrrolidin-1-y|)-2- oxoethy|)(methy|)amino)pyridin-2-y|)thio)-2-phenylacetamide; (ZR)-2-amino-N-(1-(6-((2-amino-2-oxo-1-pheny|ethy|)thio)-3,5-dicyano-4- cyclopropylpyridin-2-y|)azetidin-3-yl)-3-hydroxypropanamide; 2-((6-((2-amino-2-oxo-1-pheny|ethy|)thio)-3,5-dicyano-4-ethy|pyridin-2- yl)(methy|)amino)-N-(3-hyd roxy-2,2-dimethylpropyl)-N-methylacetamide; 2-((3,5-dicyan0-4-ethyl-6-((2-((S)-3-hydroxypyrrolidin-1-y|)-2- oxoethy|)(methy|)amino)pyridin-2-y|)thio)-2-phenylacetamide; WO 2017/216727 PCT/IB2017/053511 1302 2-((6-(4-amino-4-methylpiperidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-y|)thio)-2- phenylacetamide; 2-((6-(4-(aminomethyl)-4-fluoropiperidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-y|)thio)- 2-phenylacetamide hydrochloride; 2-((6-((2-amino-2-oxo-1-pheny|ethy|)thio)-3,5-dicyano-4-cyclopropylpyridin-2- y|)(methy|)amino)-N-(2-aminoethy|)acetamide hydrochloride; 2-((3,5-dicyano-4-ethyl-6-(methy|(2-oxo-2-(pyrrolidin-1-y|)ethy|)amino)pyridin-2- y|)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-((2-(4-hydroxypiperidin-1-y|)-2- oxoethyl)(methy|)amino)pyridin-2-y|)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-(methy|(2-oxo-2-(piperazin-1-y|)ethy|)amino)pyridin-2- y|)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethy|-6-(methy|(2-morpholino-2-oxoethy|)amino)pyridin-2- y|)thio)-2-phenylacetamide; (R)-2-((6-((8)-3-(aminomethyl)-3-hydroxypyrrolidin-1-y|)-3,5-dicyano-4- ethylpyridin-2-y|)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-((8)-3-(guanidinooxy)pyrro|idin-1-y|)pyridin-2-y|)thio)-2- phenylacetamide; 2-amino-N-(2-((6-((2-amino-2-oxo-1-pheny|ethy|)thio)-3,5-dicyano-4-ethy|pyridin-2- y|)(methy|)amino)ethyl)-2-methylpropanamide; 2-((6-((2-(2-aminoethoxy)ethy|)(methy|)amino)-3,5-dicyano-4-ethy|pyridin-2- y|)thio)-2-phenylacetamide; 4-amino-N-(1-(6-((2-amino-2-oxo-1-pheny|ethy|)thio)-3,5-dicyano-4-ethy|pyridin-2- y|)piperidin-4-y|)butanamide; 2-((6-((2-amino-2-oxo-1-pheny|ethy|)thio)-3,5-dicyano-4-ethy|pyridin-2- y|)(methy|)amino)-N-(2-aminoethyl)acetamide; 2-((6-((2-(azetidin-1-yl)-2-oxoethyl)(methy|)amino)-3,5-dicyano-4-ethylpyridin-2- y|)thio)-2-phenylacetamide; 2-((6-((R)-3-(aminomethyl)-3-fluoropyrrolidin-1-yl)-3,5-dicyano-4-ethy|pyridin-2- y|)thio)-2-phenylacetamide; WO 2017/216727 PCT/IB2017/053511 1303 2-((3,5-dicyano-4-ethy|-6-((2-(3-hydroxyazetidin-1-y|)-2- oxoethy|)(methy|)amino)pyridin-2-y|)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-(4-(guanidinooxy)piperidin-1-y|)pyridin-2-y|)thio)-2- phenylacetamide; 2-((6-(3-aminoazetidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-y|)thio)-2- phenylacetamide; (single stereoisomer) 2-((3,5-dicyano-4-ethy|-6-((R)-3-(methylamino)piperidin-1-y|)pyridin-2-y|)thio)-2- phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-((2-((3R,4S)-3-hyd roxy-4-(hydroxymethy|)pyrro|idin-1-y|)- 2-oxoethyl)(methy|)amino)pyridin-2-y|)thio)-2-phenylacetamide; (R)-2-((6-((S)-3-(aminomethyl)-3-fluoropyrrolidin-1-yl)-3,5-dicyano-4-ethylpyridin-2- y|)thio)-2-phenylacetamide; 2-((6-((2-amino-2-oxo-1-pheny|ethy|)thio)-3,5-dicyano-4-cyclopropylpyridin-2- y|)(methy|)amino)-N-(1,3-dihydroxypropan-2-y|)acetamide; 2-((3,5-dicyan0-4-ethy|-6-((S)-3-(oxetan-3-ylamino)piperidin-1-y|)pyridin-2-y|)thio)- 2-phenylacetamide; 2-((6-((2-amino-2-oxo-1-pheny|ethy|)thio)-3,5-dicyano-4-cyclopropylpyridin-2- y|)(methy|)amino)-N,N-bis(2-hydroxyethy|)acetamide; 2-amino-N-(1-(6-((2-amino-2-oxo-1-pheny|ethy|)thio)-3,5-dicyano-4- cyclopropylpyridin-2-yl)piperidin-4-y|)acetamide; 2-((3,5-dicyano-4-ethyl-6-(4-((2-hydroxyethy|)amino)-4-methylpiperidin-1- y|)pyridin-2-y|)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-((2-(guanidinooxy)ethy|)(methy|)amino)pyridin-2-y|)thio)- 2-phenylacetamide; 2-((6-(4-((2-aminoethy|)amino)piperidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-y|)thio)- 2-phenylacetamide; 2-((3,5-dicyano-4-ethy|-6-((2-((S)-2-(hyd roxymethyl)morpho|ino)-2- oxoethy|)(methy|)amino)pyridin-2-y|)thio)-2-phenylacetamide; 2-((3,5-dicyano-6-((2-((cis)-3,4-dihydroxypyrrolidin-1-y|)-2- oxoethyl)(methy|)amino)-4-ethylpyridin-2-y|)thio)-2-phenylacetamide; WO 2017/216727 PCT/IB2017/053511 1304 2-((3,5-dicyan0-4-ethyl-6-((2-((S)-3-(hydroxymethy|)pyrro|idin-1-y|)-2- oxoethy|)(methy|)amino)pyridin-2-y|)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-((2-((38,4S)-3-hydroxy-4-(hydroxymethy|)pyrro|idin-1-y|)- 2-oxoethyl)(methy|)amino)pyridin-2-y|)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-((S)-3-(neopentylamino)piperidin-1-yl)pyridin-2-y|)thio)-2- phenylacetamide; 2-((3,5-dicyano-4-ethy|-6-((2-((R)-3-(hydroxymethyl)pyrrolidin-1-y|)-2- oxoethy|)(methy|)amino)pyridin-2-y|)thio)-2-phenylacetamide; 2-((3,5-dicyano-6-((2-((3R,4R)-3,4-dihydroxypyrrolidin-1-y|)-2- oxoethyl)(methy|)amino)-4-ethylpyridin-2-y|)thio)-2-phenylacetamide; (R)-2-((3,5-dicyano-4-ethyl-6-((8)-3-h yd roxy-3-(hyd roxymethy|)pyrro|idin-1- y|)pyridin-2-y|)thio)-2-phenylacetamide; (28)-2-amino-N-(1-(6-((2-amino-2-oxo-1-pheny|ethy|)thio)-3,5-dicyano-4- cyclopropylpyridin-2-y|)piperidin-4-y|)propanamide; 2-((6-(4-(2-aminoethoxy)piperidin-1-yl)-3,5-dicyano-4-cyclopropylpyridin-2-y|)thio)- 2-phenylacetamide; 2-((3,5-dicyan0-4-cyclopropyl-6-(4-((2-hydroxyethy|)amino)piperidin-1-y|)pyridin-2- y|)thio)-2-phenylacetamide; 2-((6-((2-amino-2-oxo-1-pheny|ethy|)thio)-3,5-dicyano-4-ethy|pyridin-2- y|)(methy|)amino)-N-(1,3-dihydroxypropan-2-y|)acetamide; 2-((3,5-dicyano-6-((2-((3R,5S)-3 ,5-dihyd roxypiperidin-1-y|)-2- oxoethyl)(methy|)amino)-4-ethylpyridin-2-y|)thio)-2-phenylacetamide; 2-((3,5-dicyano-6-((2-((3S,4S)-3,4-dihydroxypyrrolidin-1-y|)-2- oxoethyl)(methy|)amino)-4-ethylpyridin-2-y|)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-(4-((2-hydroxyethy|)amino)-4-(hydroxymethy|)piperidin-1- y|)pyridin-2-y|)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethy|-6-((2-((R)-2-(hyd roxymethyl)morpho|ino)-2- oxoethy|)(methy|)amino)pyridin-2-y|)thio)-2-phenylacetamide; 2-((6-((2-amino-2-oxo-1-pheny|ethy|)thio)-3,5-dicyano-4-ethy|pyridin-2- y|)(methy|)amino)-N-methoxyacetamide; WO 2017/216727 PCT/IB2017/053511 1305 2-((3,5-dicyano-4-ethy|-6-((2-((3R,4R)-3-hydroxy-4-(hydroxymethyl)pyrro|idin-1-y|)- 2-oxoethyl)(methy|)amino)pyridin-2-y|)thio)-2-phenylacetamide; 2-((6-((2-amino-2-oxo-1-pheny|ethy|)thio)-3,5-dicyano-4-ethy|pyridin-2- y|)(methy|)amino)-N-(3-hyd roxypropyl)-N-methylacetamide; 2-((6-((2-amino-2-oxo-1-pheny|ethy|)thio)-3,5-dicyano-4-ethy|pyridin-2- y|)(methy|)amino)-N-((R)-2,3-dihyd roxypropy|)acetamide; 2-((6-(4-((2-amino-2-oxoethy|)amino)piperidin-1-y|)-3,5-dicyano-4- cyclopropylpyridin-2-y|)thio)-2-phenylacetamide; 2-((6-((2-amino-2-oxo-1-pheny|ethy|)thio)-3,5-dicyano-4-ethy|pyridin-2- y|)(methy|)amino)-N,N-bis(2-hydroxyethy|)acetamide; 2-((6-((2-amino-2-oxo-1-pheny|ethy|)thio)-3,5-dicyano-4-ethy|pyridin-2- y|)(methy|)amino)-N-(2-hydroxyethy|)acetamide; 2-((6-((3-aminopropyl)(methy|)amino)-3,5-dicyano-4-ethylpyridin-2-y|)thio)-2- phenylacetamide; 2-((6-(3-(aminomethy|)azetidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-y|)thio)-2- phenylacetamide; 2-((6-((2-amino-2-oxo-1-pheny|ethy|)thio)-3,5-dicyano-4-ethy|pyridin-2- y|)(methy|)amino)-N-((1-(hydroxymethy|)cyclopropy|)methy|)acetamide; (R)-2-((3,5-dicyano-4-ethyl-6-((S)-3-hydroxypyrro|idin-1-y|)pyridin-2-y|)thio)-2-(2,4- difluoropheny|)acetamide; 2-((6-((2-amino-2-oxo-1-pheny|ethy|)thio)-3,5-dicyano-4-ethy|pyridin-2- y|)(methy|)amino)-N-(3-(hydroxymethyl)oxetan-3-y|)acetamide; 2-((3,5-dicyano-4-ethyl-6-(3-(guanidinooxy)azetidin-1-y|)pyridin-2-y|)thio)-2- phenylacetamide; 2-((6-((2-amino-2-oxo-1-pheny|ethy|)thio)-3,5-dicyano-4-ethy|pyridin-2- yl)(methy|)amino)-N-(3-hyd roxypropy|)acetamide; 2-((3,5-dicyano-6-(4-(2,3-dihydroxypropyl)-1 ,4-diazepan-1-y|)-4-ethy|pyridin-2- y|)thio)-2-phenylacetamide; 2-((6-((2-amino-2-oxo-1-pheny|ethy|)thio)-3,5-dicyano-4-ethy|pyridin-2- y|)(methy|)amino)-N-hydroxyacetamide; WO 2017/216727 PCT/IB2017/053511 1306 3-amino-N-(1-(6-((2-amino-2-oxo-1-pheny|ethy|)thio)-3,5-dicyano-4- cyclopropylpyridin-2-y|)azetidin-3-y|)oxetane-3-carboxamide; 2-((3,5-dicyano-4-ethy|-6-((S)-3-hydroxypyrrolidin-1-y|)pyridin-2-y|)thio)-2-(2- fluorophenyl)acetamide; 2-((3,5-dicyano-6-((S)-3-(cyclopropylamino)piperidin-1-yl)-4-ethylpyridin-2-y|)thio)- 2-phenylacetamide; 2-((6-((2-amino-2-oxo-1-pheny|ethy|)thio)-3,5-dicyano-4-ethy|pyridin-2- y|)(methy|)amino)-N-(3-hydroxy-2,2-dimethy|propy|)acetamide; N-(2-(4H-1,2,4-triazoI-4-yl)ethy|)-2-((6-((2-amino-2-oxo-1-pheny|ethy|)thio)-3,5- dicyano-4-ethylpyridin-2-y|)(methy|)amino)acetamide; N1 -(2-((6-((2-amino-2-oxo-1 -pheny|ethy|)thio)-3,5-dicyano-4-ethylpyrid in-2- y|)(methy|)amino)ethy|)oxa|amide; 2-((6-(3-(aminomethyl)-3-fluoroazetidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-y|)thio)- 2-phenylacetamide; (R)-2-((3,5-dicyano-4-ethyl-6-((R)-3-hyd roxy-3-(hyd roxymethy|)pyrro|idin-1- y|)pyridin-2-y|)thio)-2-phenylacetamide; 2-((3,5-dicyano-6-((S)-3-((2,2-difluoroethy|)amino)piperidin-1-yl)-4-ethylpyridin-2- y|)thio)-2-phenylacetamide; 2-((6-((R)-3-aminopiperidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-y|)thio)-2- phenylacetamide; 2-((6-(4-aminopiperidin-1-yl)-3,5-dicyano-4-methoxypyridin-2-y|)thio)-2- phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-((S)-4-hydroxyisoxazolidin-2-y|)pyridin-2-y|)thio)-2- phenylacetamide; (R)-2-((3,5-dicyano-4-ethyl-6-((3-hydroxypro pyl)(methy|)amino)pyridin-2-y|)thio)-2- phenylacetamide; 2-((3,5-dicyano-6-((S)-3-hydroxypyrrolidin-1-yl)-4-methoxypyridin-2-y|)thio)-2- phenylacetamide; 2-((3,5-dicyano-4-ethy|-6-(4-(3-methoxyazetidin-1-y|)piperidin-1-y|)pyridin-2- y|)thio)-2-phenylacetamide; WO 2017/216727 PCT/IB2017/053511 1307 2-((3,5-dicyano-4-ethyl-6-(4-(3-methoxyazetidin-1-yl)piperidin-1-y|)pyridin-2- y|)thio)-2-(4-fluoropheny|)acetamide; (R)-2-((3,5-dicyano-4-ethyl-6-((2-hydroxyethyl)(methyl)amino) pyridin-2-y|)thio)-2- phenylacetamide; (R)-2-((3,5-dicyano-4-ethyl-6-((S)-3-hydroxypyrrolidin-1-y|)pyridin-2-y|)thio)-2-(4- fluorophenyl)acetamide; (R)-2-((6-((R)-3-(aminomethyl)-3-hydroxypyrrolidin-1-yl)-3,5-dicyano-4- ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-6-(4-(cyclobutyl(methyl)amino)piperidin-1-yl)-4-ethy|pyridin-2- yl)thio)-2-(4-fluorophenyl)acetamide; and 2-((3,5-dicyano-4-ethyl-6-(methy|(1-methylpyrrolidin-3-yl)amino)pyridin-2-yl)thio)-2- phenylacetamide; or a pharmaceutically acceptable salt or prodrug thereof.
12. A pharmaceutical composition comprising a compound according to any one of claims 7 to 11 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.
13. A method of treating a disease selected from: cancer, pre-cancerous syndromes, beta haemoglobinopathy disorders, sickle cell disease, sickle cell anemia, and beta thalassemia, in a mammal in need thereof, which comprises administering to such mammal a therapeutically effective amount of a compound as described in any one of claims 7 to 11 or a pharmaceutically acceptable salt thereof.
14. The method of claim 13 wherein the mammal is a human.
15. A method of treating a disease selected from: cancer, pre-cancerous syndromes, beta haemoglobinopathy disordes, sickle cell disease, sickle cell anemia, and beta thalassemia, in a mammal in need thereof, which comprises administering to such mammal a therapeutically effective amount of a compound of claim 11 or a pharmaceutically acceptable salt thereof.
16. The method of claim 15 wherein the mammal is a human. WO 2017/216727 PCT/IB2017/053511 1308
17. The method according to claim 14 wherein said cancer is selected from: brain (gliomas), glioblastomas, astrocytomas, glioblastoma multiforme, Bannayan-Zonana syndrome, Cowden disease, Lhermitte-Duclos disease, breast, colon, head and neck, kidney, lung, liver, melanoma, ovarian, pancreatic, adenocarcinoma, ductal adenocarcinoma, adenosquamous carcinoma, acinar cell carcinoma, glucagonoma, insulinoma, prostate, sarcoma and thyroid.
18. The method according to claim 16 wherein: said cancer is selected from brain (gliomas), glioblastomas, astrocytomas, glioblastoma multiforme, Bannayan-Zonana syndrome, Cowden disease, Lhermitte-Duclos disease, breast, colon, head and neck, kidney, lung, liver, melanoma, ovarian, pancreatic, adenocarcinoma, ductal adenocarcinoma, adenosquamous carcinoma, acinar cell carcinoma, glucagonoma, insulinoma, prostate, sarcoma and thyroid.
19. Use of a compound as described in any one of claims 7 to 11 or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in treating or lessening the severity of cancer.
20. The method of inhibiting DNMT1 activity in a mammal in need thereof, which comprises administering to such mammal a therapeutically effective amount ofa compound as described in any one of claims 7 to 11 or a pharmaceutically acceptable salt thereof.
21. The method of claim 20 wherein the mammal is a human.
22. A method oftreating cancer in a mammal in need thereof, which comprises: administering to such mammal a therapeutically effective amount of a) a compound of as described in any one of claims 7 to 11 or a pharmaceutically acceptable salt thereof; and b) at least one anti-neoplastic agent.
23. The method claim 22, wherein the at least one anti-neoplastic agent is selected from the group consisting of: anti-microtubule agents, platinum coordination complexes, alkylating agents, antibiotic agents, topoisomerase II inhibitors, antimetabolites, topoisomerase I inhibitors, hormones and hormonal analogues, signal transduction pathway inhibitors, non-receptor tyrosine kinase angiogenesis, inhibitors, immunotherapeutic agents, proapoptotic agents, cell cycle signaling inhibitors, proteasome WO 2017/216727 PCT/IB2017/053511 1309 inhibitors, inhibitors of cancer metabolism, anti-PD-L1 agents, PD-1 antagonist, immuno- modulators, STING modulating compounds, CD39 inhibitors, A2a and A2a adenosine antagonists, TLR4 antagonists, antibodies to ICOS, and antibodies to OX40.
24. A pharmaceutical combination comprising: a) a compound as described in any one of claims 7 to 11 or a pharmaceutically acceptable salt thereof; and b) at least one anti-neoplastic agent.
25. A pharmaceutical combination as claimed in claim 24 for use in the treatment of cancer.
26. The method according to claim 13 wherein said cancer is selected from: breast cancer, inflammatory breast cancer, ductal carcinoma, lobular carcinoma, colon cancer, pancreatic cancer, insulinomas, adenocarcinoma, ductal adenocarcinoma, adenosquamous carcinoma, acinar cell carcinoma, glucagonoma, skin cancer, melanoma, metastatic melanoma, lung cancer, small cell lung cancer, non-small cell lung cancer, squamous cell carcinoma, adenocarcinoma, large cell carcinoma, brain (gliomas), glioblastomas, astrocytomas, glioblastoma multiforme, Bannayan-Zonana syndrome, Cowden disease, Lhermitte-Duclos disease, V\film's tumor, Ewing's sarcoma, Rhabdomyosarcoma, ependymoma, medulloblastoma, head and neck, kidney, liver, melanoma, ovarian, pancreatic, adenocarcinoma, ductal adenocarcinoma, adenosquamous carcinoma, acinar cell carcinoma, glucagonoma, insulinoma, prostate, sarcoma, osteosarcoma, giant cell tumor of bone, thyroid, lymphoblastic T cell leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, hairy-cell leukemia, acute lymphoblastic leukemia, acute myelogenous leukemia, chronic neutrophilic leukemia, acute lymphoblastic T cell leukemia, plasmacytoma, lmmunoblastic large cell leukemia, mantle cell leukemia, multiple myeloma, megakaryoblastic leukemia, multiple myeloma, acute megakaryocytic leukemia, promyelocytic leukemia, erythroleukemia, malignant lymphoma, hodgkins lymphoma, non-hodgkins lymphoma, lymphoblastic T cell lymphoma, Burkitt‘s lymphoma, follicular lymphoma, neuroblastoma, bladder cancer, urothelial cancer, vulval cancer, cervical cancer, endometrial cancer, renal cancer, mesothelioma, esophageal cancer, salivary gland cancer, hepatocellular cancer, gastric cancer, nasopharangeal cancer, buccal cancer, WO 2017/216727 PCT/IB2017/053511 1310 cancer of the mouth, GIST (gastrointestinal stromal tumor), neuroendocrine cancers and testicular cancer.
27. The method of claim 26 wherein the mammal is a human.
28. A process for preparing a pharmaceutical composition containing a pharmaceutically acceptable excipient and a compound of Formula (|Vbbr), (Vbbr), (V|bbr), or (Qb) as described in any one of claims 7 to 11 or a pharmaceutically acceptable salt thereof, which process comprises bringing the compound of Formula (|Vbbr), (Vbbr), (Vlbbr), or (Qb) or a pharmaceutically acceptable salt thereof into association with a pharmaceutically acceptable excipient.
29. The method according to claim 14 wherein said pre-cancerous syndrome is selected from: cervical intraepithelial neoplasia, monoclonal gammapathy of unknown significance (MGUS), myelodysplastic syndrome, aplastic anemia, cervical lesions, skin nevi (pre-melanoma), prostatic intraepithleial (intraductal) neoplasia (PIN), Ductal Carcinoma in situ (DCIS), colon polyps and severe hepatitis or cirrhosis.
30. A pharmaceutical combination comprising: a) a compound as described in any one of claims 7 to 11 or a pharmaceutically acceptable salt thereof; and b) at least one agent useful fortreating beta haemoglobinopathies.
31. A pharmaceutical combination as claimed in claim 30 for use in treating sickle cell disease.
32. A pharmaceutical combination as claimed in claim 30 for use in treating sickle cell anemia.
33. A pharmaceutical combination as claimed in claim 30 for use in treating beta- thalassemia.
34. The method of claim 1 wherein the compound is selected from: 1-(6-((2-amino-2-oxo-1-pheny|ethy|)thio)-3,5-dicyano-4-ethylpyridin-2-y|)pyrro|idin- 3-yl dihydrogen phosphate; WO 2017/216727 PCT/IB2017/053511 1311 1-(6-((2-amino-1-(4-fluorophenyl)-2-oxoethy|)thio)-3,5-dicyano-4-ethy|pyridin-2- yl)pyrrolidin-3-yl dihydrogen phosphate; 2-((6-((2-amino-2-oxo-1-phenylethy|)thio)-3,5-dicyano-4-ethylpyridin-2- y|)(methyl)amino)ethyl dihydrogen phosphate; 1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)azetidin-3- yl dihydrogen phosphate; (28)-2-((1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2- y|)piperidin-4-yl)oxy)ethy| 2-amino-3-methylbutanoate; 2-((1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2- y|)piperidin-4-yl)oxy)ethyl dihydrogen phosphate; and 1-(6-((2-amino-2-oxo-1-phenylethy|)thio)-3,5-dicyano-4-ethylpyridin-2-yl)piperidin- 4-yl dihydrogen phosphate; or a pharmaceutically acceptable salt thereof.
35. A prodrug ofa compound of claim 11 selected from: 1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)pyrrolidin- 3-yl dihydrogen phosphate; 1-(6-((2-amino-1-(4-fluorophenyl)-2-oxoethyl)thio)-3,5-dicyano-4-ethylpyridin-2- yl)pyrrolidin-3-yl dihydrogen phosphate; 2-((6-((2-amino-2-oxo-1-phenylethy|)thio)-3,5-dicyano-4-ethylpyridin-2- y|)(methy|)amino)ethy| dihydrogen phosphate; 1-(6-((2-amino-2-oxo-1-phenylethy|)thio)-3,5-dicyano-4-ethylpyridin-2-yl)azetidin-3- yl dihydrogen phosphate; (28)-2-((1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2- y|)piperidin-4-yl)oxy)ethyl 2-amino-3-methylbutanoate; 2-((1-(6-((2-amino-2-oxo-1-pheny|ethy|)thio)-3,5-dicyano-4-ethylpyridin-2- yl)piperidin-4-yl)oxy)ethyl dihydrogen phosphate; and 1-(6-((2-amino-2-oxo-1-pheny|ethy|)thio)-3,5-dicyano-4-ethylpyridin-2-y|)piperidin- 4-yl dihydrogen phosphate; WO 2017/216727 PCT/IB2017/053511 1312 or a pharmaceutically acceptable salt thereof.
36. The method of claim 1 wherein the compound is: 2-((3,5-dicyano-4-(furan-2-yl)- 6-(4-methyl-1,4-diazepan-1-yl)pyridin-2-y|)thio)-2-phenylacetamide; or a pharmaceutically acceptable salt or prodrug thereof.
37. The compound of claim 7 which is: 2-((3,5-dicyano-4-(furan-2-yl)-6-(4-methyl- 1 ,4-diazepan-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; or a pharmaceutically acceptable salt or prodrug thereof.
38. A method of treating a disease selected from: diabetic nephropathy, diabetes, poclocyte injury, atherosclerosis, psoriasis, idiopathic pulmonary fibrosis, scieroderma, liver cirrhosis, rheumatoid arthritis, and Alzheimers disease, in a mammal in need thereof, which comprises administering to such mammal a therapeutically effective amount ofa compound as described in any one of claims 7 to 11 or a pharmaceutically acceptable salt thereof.
39. The method of claim 38 wherein the mammal is a human.
40. A pharmaceutical composition comprising from 0.5 to 1,000 mg of a compound or pharmaceutically acceptable salt thereof as defined in any one of claims 1, 2 or 6, and from 0.5 to 1,000 mg ofa pharmaceutically acceptable excipient.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US62/349,227 | 2016-06-13 | ||
| US62/393,256 | 2016-09-12 | ||
| US62/412,343 | 2016-10-25 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| NZ747748A true NZ747748A (en) |
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