U.S. patent application number 17/557215 was filed with the patent office on 2022-06-16 for inhibiting ubiquitin specific peptidase 30.
The applicant listed for this patent is FORMA Therapeutics, Inc.. Invention is credited to Alexandre Joseph Buckmelter, Justin Caravella, Bingsong Han, Stephanos Ioannidis, Cuixian Liu, Matthew W. Martin, Scot Mente, Steven Mischke, David James Richard.
Application Number | 20220185806 17/557215 |
Document ID | / |
Family ID | |
Filed Date | 2022-06-16 |
United States Patent
Application |
20220185806 |
Kind Code |
A1 |
Caravella; Justin ; et
al. |
June 16, 2022 |
INHIBITING UBIQUITIN SPECIFIC PEPTIDASE 30
Abstract
The present disclosure relates to chemical entities useful as
inhibitors of Ubiquitin Specific Peptidase 30 (USP30),
pharmaceutical compositions comprising the chemical entities, and
methods of using the chemical entities. The chemical entities as
disclosed herein can be useful in the treatment of a disease,
disorder, or condition involving mitochondrial dysfunction,
including neurodegenerative diseases, motor neuron diseases,
metabolic disorders, and cancers, among other ailments.
Inventors: |
Caravella; Justin;
(Cambridge, MA) ; Han; Bingsong; (Westwood,
MA) ; Liu; Cuixian; (Madison, CT) ; Ioannidis;
Stephanos; (Natick, MA) ; Buckmelter; Alexandre
Joseph; (Acton, MA) ; Richard; David James;
(Littleton, MA) ; Martin; Matthew W.; (Arlington,
MA) ; Mischke; Steven; (Waltham, MA) ; Mente;
Scot; (Watertown, MA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
FORMA Therapeutics, Inc. |
Watertown |
MA |
US |
|
|
Appl. No.: |
17/557215 |
Filed: |
December 21, 2021 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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16753439 |
Apr 3, 2020 |
11247987 |
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PCT/US2018/054520 |
Oct 5, 2018 |
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17557215 |
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62569177 |
Oct 6, 2017 |
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International
Class: |
C07D 417/12 20060101
C07D417/12; C07C 261/04 20060101 C07C261/04; C07D 231/40 20060101
C07D231/40; C07D 241/04 20060101 C07D241/04; C07D 265/30 20060101
C07D265/30; C07D 277/46 20060101 C07D277/46; C07D 277/56 20060101
C07D277/56; C07D 417/04 20060101 C07D417/04 |
Claims
1. A compound of Formula (I): ##STR00456## or a pharmaceutically
acceptable salt thereof, wherein: R is independently chosen from
hydrogen, OH, CN, (C.sub.1-C.sub.6) alkyl, (C.sub.1-C.sub.6)
alkoxy, (C.sub.1-C.sub.6) haloalkyl, (C.sub.1-C.sub.6) haloalkoxy,
halogen, (C.sub.3-C.sub.6) cycloalkyl, and (C.sub.3-C.sub.6)
heterocycloalkyl; n is 0, 1, or 2; wherein, if n is 2, the R groups
can combine to form a fused ring system with R.sub.1; R.sub.1 is a
3-6 membered carbocyclic or heterocyclic ring; R.sub.2 is chosen
from amides, reverse amides, and ureas; X is independently chosen
from hydrogen, alkyl, and heteroalkyl, wherein the alkyl and
heteroalkyl can optionally cyclize with R, R.sub.1, or R.sub.3 or
with another X group when multiple X groups are present; R.sub.3 is
chosen from hydrogen, halogen, alkyl, heteroalkyl, haloalkyl,
alkoxy, heteroalkoxy, haloalkoxy, carbonylalkyl,
carbonylheteroalkyl, carbocyclic, heterocyclic, aryl, and
heteroaryl, wherein any rings are optionally substituted with 1 or
2 R; R.sub.4 is independently chosen from alkyl, heteroalkyl,
haloalkyl, alkoxy, cycloalkoxy, heteroalkoxy, haloalkoxy,
carboxyalkyl, heterocarboxyalkyl, carbocyclic, heterocyclic, aryl
and heteroaryl, wherein any rings are optionally substituted with 1
or 2 Y groups; Y is independently chosen from hydrogen, OH, CN,
N(X).sub.2, (C.sub.1-C.sub.6) alkyl, (C.sub.1-C.sub.6) heteroalkyl,
(C.sub.1-C.sub.6) alkoxy, (C.sub.1-C.sub.6) haloalkyl,
(C.sub.1-C.sub.6) haloalkoxy, halogen, (C.sub.3-C.sub.6)
cycloalkyl, (C.sub.3-C.sub.6) heterocycloalkyl, (C.sub.5-C.sub.8)
aryl, and (C.sub.4-C.sub.8) heteroaryl; and m is 0, 1, or 2.
2. The compound of claim 1, wherein R.sub.1 is a 4-membered
carbocyclic or heterocyclic ring.
3. (canceled)
4. The compound of claim 1, wherein R.sub.1 is chosen from
cyclobutane and cyclopentane.
5-6. (canceled)
7. The compound of claim 1, wherein R.sub.2 is an amide.
8. The compound of claim 1, wherein R.sub.3 is chosen from aryl and
heteroaryl rings.
9. The compound of claim 1, wherein R.sub.3 is chosen from
thiazole, indenyl, pyrazole, and phenyl rings.
10. The compound of claim 1, wherein R.sub.3 is chosen from
carbocyclic and heterocyclic rings.
11. The compound of claim 1, wherein m is 0.
12. The compound of claim 1, wherein R.sub.4 is chosen from
carbocyclic and heterocyclic rings optionally substituted with 1 or
2 Y.
13. The compound of claim 1, wherein R.sub.4 is chosen from alkyl,
heteroalkyl, and haloalkyl.
14. The compound of claim 1, wherein R.sub.4 is chosen from aryl
and heteroaryl rings optionally substituted with 1 or 2 Y.
15. The compound of claim 1, wherein R is halogen.
16. (canceled)
17. A pharmaceutical composition comprising the compound of claim 1
or a pharmaceutically acceptable salt thereof and a
pharmaceutically acceptable carrier.
18. A compound selected from: TABLE-US-00014 Compound 10-1
##STR00457## cis-4-(cyanoamino)-N-(5-cyclohexyl-1,3-
thiazol-2-yl)cyclohexane-1-carboxamide; Compound 10-2 ##STR00458##
trans-4-(cyanoamino)-N-(5-cyclohexyl-
1,3-thiazol-2-yl)cyclohexane-1- carboxamide; Compound 10-3
##STR00459## (1R,2R)-2-(cyanoamino)-N-(5- cyclohexyl-1,3-thiazol-2-
yl)cyclopentane-1-carboxamide; Compound 10-4 ##STR00460##
(1R,3S)-3-(cyanoamino)-N-(5-
cyclohexyl-1,3-thiazol-2-yl)cyclohexane- 1-carboxamide; Compound
10-5 ##STR00461## (1S,3S)-3-(cyanoamino)-N-(5-
cyclohexyl-1,3-thiazol-2-yl)cyclohexane- 1-carboxamide; Compound
10-6 ##STR00462## (1S,3R)-3-(cyanoamino)-N-(5-
cyclohexyl-1,3-thiazol-2-yl)cyclohexane- 1-carboxamide; Compound
10-7 ##STR00463## (1R,2S)-2-(cyanoamino)-N-(5-
cyclohexyl-1,3-thiazol-2- yl)cyclopentane-1-carboxamide; Compound
10-8 ##STR00464## (1S,2R)-2-(cyanoamino)-N-(5-
cyclohexyl-1,3-thiazol-2- yl)cyclopentane-1-carboxamide; Compound
10-9 ##STR00465## (1S,2S)-2-(cyanoamino)-N-(5-
cyclohexy1-1,3-thiazol-2- yl)cyclopentane-1-carboxamide; Compound
10-10 ##STR00466## (1S,3S)-3-(cyanoamino)-N-[5-(oxan-4-
yl)-1,3-thiazol-2-yl]cyclopentane-1- carboxamide; Compound 10-11
##STR00467## (1R,3R)-3-(cyanoamino)-N-[5-(oxan-4-
yl)-1,3-thiazol-2-yl]cyclopentane-1- carboxamide; Compound 11-1
##STR00468## trans-2-(cyanoamino)-N-(5-cyclohexyl-
1,3-thiazol-2-yl)cyclopropane-1- carboxamide; Compound 11-2
##STR00469## cis-2-(cyanoamino)-N-(5-cyclohexy1-1,3-
thiazol-2-yl)cyclopropane-1- carboxamide; Compound 2-2 ##STR00470##
(3S)-3-(cyanoamino)-N-(5-cyclohexyl-
1,3-thiazol-2-yl)pyrrolidine-1- carboxamide; Compound 2-3
##STR00471## (3R)-3-(cyanoamino)-N-(5-cyclohexyl-
1,3-thiazol-2-yl)pyrrolidine-1- carboxamide; Compound 12-1
##STR00472## (1R,3S)-3-(cyanoamino)-N-(5-phenyl-
1,3-thiazol-2-yl)cyclopentane-1- carboxamide; Compound 12-2
##STR00473## (1S,3S)-3-(cyanoamino)-N-(1-phenyl-
1H-pyrazol-3-yl)cyclopentane-1- carboxamide; Compound 12-3
##STR00474## (1S,3S)-3-(cyanoamino)-N-(5- cyclohexy1-1,3-thiazol-2-
yl)cyclopentane-1-carboxamide; Compound 12-4 ##STR00475##
(1S,3S)-3-(cyanoamino)-N-(5-phenyl-
1,3-thiazol-2-yl)cyclopentane-1- carboxamide; Compound 12-5
##STR00476## (1S,3S)-3-(cyanoamino)-N-(2,3-dihydro-
1H-inden-5-yl)cyclopentane-1- carboxamide; Compound 12-6
##STR00477## {[(1S,3S)-3-(4-phenylpiperazine-1-
carbonyl)cyclopentyl]amino}carbonitrile; Compound 12-7 ##STR00478##
(1S,3R)-N-(5-tert-buty1-1,3-thiazol-2-y1)-
3-(cyanoamino)cyclopentane-1- carboxamide; Compound 12-8
##STR00479## {[(3S)-1-[2-(2,3-dichlorophenyl)-1,3-
thiazole-4-carbonyl]pyrrolidin-3- yl]amino}carbonitrile; and
Compound 12-9 ##STR00480##
({1-[2-(2,4-dichlorophenyl)-1,3-thiazole- 4-carbonyl]piperidin-4-
yl}amino)carbonitrile
or a pharmaceutically acceptable salt thereof.
19. A pharmaceutical composition comprising the compound of claim
18 or a pharmaceutically acceptable salt thereof and a
pharmaceutically acceptable carrier.
20. The compound of claim 1, wherein R.sub.1 is chosen from
cyclopropane, cyclobutane, cyclopentane, cyclohexane, and
pyrrolidine.
21. The compound of claim 20, wherein R.sub.3 is chosen from aryl
and heteroaryl rings.
22. The compound of claim 21, wherein R.sub.4 is chosen from
carbocyclic and heterocyclic rings optionally substituted with 1 or
2 Y.
23. The compound of claim 8, wherein R.sub.4 is chosen from
carbocyclic and heterocyclic rings optionally substituted with 1 or
2 Y.
Description
[0001] The present patent application is a divisional application
of U.S. application Ser. No. 16/753,439, filed on Apr. 3, 2020,
which is a U.S. National Stage Application of PCT/US18/54520, filed
Oct. 5, 2018, which claims the benefit of U.S. Provisional Patent
Application No. 62/569,177, filed Oct. 6, 2017, which is
incorporated herein by reference in its entirety.
TECHNICAL FIELD
[0002] The present disclosure is directed to novel chemical
entities, methods for their preparation, synthesis and manufacture,
which can act as inhibitors of Ubiquitin Specific Peptidase 30
(USP30), a member of the deubiquitinating (DUB) enzyme family. The
present disclosure also describes the use of these USP30 inhibitors
in the treatment of diseases or disorders associated with USP30
enzymes, such as the treatment of mitochondrial dysfunction
diseases or disorders, neurodegenerative diseases, and in the
treatment of cancer. Specifically, the disclosure is concerned with
chemical entities and compositions inhibiting USP30, methods of
treating diseases or disorders associated with USP30, and methods
of synthesis of these compounds.
BACKGROUND
[0003] The ubiquitination system is a highly-regulated process
which affects a wide variety of cellular activities and
physiological processes. Dysregulation of this system is commonly
associated with several human diseases, including cancer,
neurodegenerative disorders, muscle dystrophies, and
cardiomyophaties, amongst others (Popovic, et al., Nature Medicine
2014, 20, 1242-1253). Ubiquitination is a reversible process,
facilitated by a group of proteins known as deubiquitinating
enzymes (DUBs), which deconjugate ubiquitin (Ub) from the
substrate. DUBs are encoded by approximately 100 human genes and
are divided into six families, with the largest family being the
ubiquitin-specific proteases (USPs) with more than 50 members.
[0004] Ubiquitin regulates mitochondrial dynamics and biogenesis,
affecting the abundance and function of these organelles. Many
age-related diseases, particularly neurodegenerative disorders,
have been linked to mitochondrial dysfunction and impairment of the
ubiquitination system (Ross, et al., Int J Mol Sci. 2015, 16(8),
19458-19476).
[0005] Parkinson's disease (PD) is a neurodegenerative disorder
that affects more than 10 million people worldwide, including
60,000 new diagnoses a year in the US alone (Parkinson's Disease
Foundation, www.pdf.org). PD is characterized by the loss of
dopaminergic neurons in the substantia nigra. Although the exact
mechanism of neuronal loss is not yet fully elucidated, an
increasing body of evidence links mitochondrial dysfunction with
dopaminergic neuron vulnerability.
[0006] Mitophagy, the clearance of dysfunctional mitochondria
through autophagy, appears to be specifically important in certain
genetically defined subsets of Parkinson's patients.
Loss-of-function mutations in PRKN (gene encoding the Parkin
protein) present as a form of autosomal recessive juvenile
Parkinsonism (AR-JP) (Shimura, et al., Nat Genet. 2000, 25(3),
302-305; Sriram, et al., Hum Mol Genet. 2005, 14(17), 2571-2586;
Ekholm-Reed, et al., Mol Cell Biol. 2013, 33(18), 3627-3643). In
the late 1990's genetic analysis of Japanese families revealed that
mutations in PARK2 (nPRKN) were responsible for AR-JP (Matsumine,
et al., Am J Hum Genet. 1997, 60(3), 588-596). Subsequent
investigation of different ethnic populations independently
replicated the association between PRKN mutations and early-onset
PD. Later genetic work identified mutations in PINK1 which result
in early-onset recessive PD (Valente, et al., Science. 2004,
304(5674), 1158-1160; Valente, et al., Ann Neurol. 2004, 56(3),
336-341).
[0007] Parkin (E3 ubiquitin ligase) and PINK1 (kinase) are key
regulators of mitophagy. In healthy mitochondria, PINK1
localization to the mitochondrial outer membrane (MOM) and exposure
to the cytosol is limited by rapid import to the mitochondrial
inner membrane (MIM). Once localized to the MIM, PINK1 is processed
by several proteases, such as presenilin associated rhomboid-like
protease (PARL), to yield a truncated version of PINK1 which is
subsequently degraded by the proteasome (Meissner et al.,
Autophagy. 2015, 11(9), 1484-1498). Upon mitochondrial
depolarization or dysfunction, PINK1 accumulates in the
mitochondrial outer membrane (MOM), recruiting and activating
Parkin via PINK1-dependent phosphorylation of both ubiquitin and
Parkin. Consequently, activated Parkin ubiquitinates MOM proteins
like TOMM20 to trigger mitophagy (Pickrell et al., Neuron. 2015,
85(2), 257-273).
[0008] USP30 is embedded in the MOM with its catalytic DUB domain
oriented towards the cytosol and has been shown to antagonize
Parkin-mediated ubiquitination of common substrates, consequently
opposing Parkin-mediated mitophagy. Genetic silencing of USP30
results in increased ubiquitination of several Parkin substrates
followed by increased mitophagy. In model organisms, USP30
depletion is able to rescue mitophagy defects caused by pathogenic
Parkin mutations, as well as restore mitochondria morphology and
function, and dopamine levels. (Nakamura, et al., Mol Biol Cell.
2008, 19(5), 1903-1911; Bingol, et al., Nature 2014,
510(7505):370-5). Therefore, inhibition of USP30 could present a
novel treatment paradigm for PD, by promoting mitochondrial
turnover.
[0009] USP30 inhibition could also benefit patients with other
indications which involve mitochondria function, including but not
limited to, neurodegenerative diseases, motor neuron diseases,
metabolic disorders, cardio-vascular diseases, psychiatric
diseases, osteoarthritis, and cancer. For example, mitochondria
play a central role in apoptotic cell death. The key event in this
process is BAX/BAK-dependent mitochondrial outer-membrane
permeabilization. USP30 regulates BAX/BAK-dependent apoptosis, and
its depletion sensitizes cancer cells to ABT-737, a BCL-2
inhibitor/BH3-mimetic (Liang, et al., EMBO reports 2015, 16,
618-627). These studies suggest a utility for a USP30 inhibitor in
anti-cancer therapy.
[0010] There remains a need for USP30 inhibitor compounds. Such
compounds would be useful, for example, in the development of new
therapies for Parkinson's disease.
SUMMARY
[0011] The present disclosure provides compounds of Formula
(Ia):
##STR00001##
and pharmaceutically acceptable salts, solvates, prodrugs,
stereoisomers, and tautomers thereof, wherein:
[0012] R is independently chosen from hydrogen, OH, CN,
(C.sub.1-C.sub.6) alkyl groups, (C.sub.1-C.sub.6) alkoxy groups,
(C.sub.1-C.sub.6) haloalkyl groups, (C.sub.1-C.sub.6) haloalkoxy
groups, halogen, (C.sub.3-C.sub.6) cycloalkyl groups, and
(C.sub.3-C.sub.6) heterocycloalkyl groups;
[0013] n is 0, 1, or 2;
wherein, if n is 2, the R groups can combine to form a fused ring
system with R.sub.1;
[0014] R.sub.1 is a 4-membered cyclic or heterocyclic group;
[0015] R.sub.2 is chosen from C(X).sub.n, S(O).sub.2, N(X),
heteroatom linkers, N(X)S(O).sub.2, N(X)S(O).sub.2N(X),
carbonylalkyl groups, and carbonylheteroalkyl groups, wherein the
alkyl portion of carbonylalkyl and carbonylheteroalkyl groups can
optionally cyclize with R, R.sub.1, or R.sub.3;
[0016] X is independently chosen from hydrogen, alkyl groups, and
heteroalkyl groups, wherein the alkyl and heteroalkyl groups can
optionally cyclize with R, R.sub.1, or R.sub.3 or with another X
group when multiple X groups are present;
[0017] R.sub.3 is chosen from hydrogen, halogens, alkyl groups,
heteroalkyl groups, haloalkyl groups, alkoxy groups, heteroalkoxy
groups, haloalkoxy groups, carbonylalkyl groups,
carbonylheteroalkyl groups, cyclic groups, heterocyclic groups,
aryl groups, and heteroaryl groups, wherein any rings are
optionally substituted with 1 or 2 R groups;
[0018] R.sub.4 is independently chosen from alkyl groups,
heteroalkyl groups, haloalkyl groups, alkoxy groups, cycloalkoxy
groups, heteroalkoxy groups, haloalkoxy groups, carboxyalkyl
groups, heterocarboxyalkyl groups, cyclic groups, heterocyclic
groups, aryl groups and heteroaryl groups, wherein any rings are
optionally substituted with 1 or 2 Y groups;
[0019] Y is independently chosen from hydrogen, OH, CN, N(X).sub.2,
(C.sub.1-C.sub.6) alkyl groups, (C.sub.1-C.sub.6) heteroalkyl
groups, (C.sub.1-C.sub.6) alkoxy groups, (C.sub.1-C.sub.6)
haloalkyl groups, (C.sub.1-C.sub.6) haloalkoxy groups, halogen,
(C.sub.3-C.sub.6) cycloalkyl groups, (C.sub.3-C.sub.6)
heterocycloalkyl groups, (C.sub.5-C.sub.8) aryl groups, and
(C.sub.4-C.sub.8) heteroaryl groups; and
[0020] m is 0, 1, or 2.
[0021] The present disclosure provides compounds of Formula
(Ib):
##STR00002##
and pharmaceutically acceptable salts, solvates, prodrugs,
stereoisomers, and tautomers thereof, wherein:
[0022] R is independently chosen from hydrogen, OH, CN,
(C.sub.1-C.sub.6) alkyl groups, (C.sub.1-C.sub.6) alkoxy groups,
(C.sub.1-C.sub.6) haloalkyl groups, (C.sub.1-C.sub.6) haloalkoxy
groups, halogen, (C.sub.3-C.sub.6) cycloalkyl groups, and
(C.sub.3-C.sub.6) heterocycloalkyl groups;
[0023] n is 0, 1, or 2; wherein, if n is 2, the R groups can
combine to form a fused ring system with R.sub.1;
[0024] R.sub.1 is chosen from 3-6 membered cyclic or heterocyclic
groups;
[0025] R.sub.2 is chosen from carbonylheteroalkyl groups, wherein
the alkyl portion of the carbonylheteroalkyl group can optionally
cyclize with R, R.sub.1, or R.sub.3;
[0026] X is independently chosen from hydrogen, alkyl groups, and
heteroalkyl groups, wherein the alkyl and heteroalkyl groups can
optionally cyclize with R, R.sub.1, or R.sub.3 or with another X
group when multiple X groups are present;
[0027] R.sub.3 is chosen from hydrogen, halogens, alkyl groups,
heteroalkyl groups, haloalkyl groups, alkoxy groups, heteroalkoxy
groups, haloalkoxy groups, carbonylalkyl groups,
carbonylheteroalkyl groups, cyclic groups, heterocyclic groups,
aryl groups, and heteroaryl groups, wherein any rings are
optionally substituted with 1 or 2 R groups;
[0028] R.sub.4 is independently chosen from alkyl groups,
heteroalkyl groups, haloalkyl groups, alkoxy groups, cycloalkoxy
groups, heteroalkoxy groups, haloalkoxy groups, carboxyalkyl
groups, heterocarboxyalkyl groups, cyclic groups, heterocyclic
groups, aryl groups and heteroaryl groups, wherein any rings are
optionally substituted with 1 or 2 Y groups;
[0029] Y is independently chosen from hydrogen, OH, CN, N(X).sub.2,
(C.sub.1-C.sub.6) alkyl groups, (C.sub.1-C.sub.6) heteroalkyl
groups, (C.sub.1-C.sub.6) alkoxy groups, (C.sub.1-C.sub.6)
haloalkyl groups, (C.sub.1-C.sub.6) haloalkoxy groups, halogen,
(C.sub.3-C.sub.6) cycloalkyl groups, (C.sub.3-C.sub.6)
heterocycloalkyl groups, (C.sub.5-C.sub.8) aryl groups, and
(C.sub.4-C.sub.8) heteroaryl groups; and
[0030] m is 0, 1, or 2.
[0031] The present disclosure provides compounds of Formula
(Ic):
##STR00003##
and pharmaceutically acceptable salts, solvates, prodrugs,
stereoisomers, and tautomers thereof, wherein:
[0032] R is independently chosen from hydrogen, OH, CN,
(C.sub.1-C.sub.6) alkyl groups, (C.sub.1-C.sub.6) alkoxy groups,
(C.sub.1-C.sub.6) haloalkyl groups, (C.sub.1-C.sub.6) haloalkoxy
groups, halogen, (C.sub.3-C.sub.6) cycloalkyl groups, and
(C.sub.3-C.sub.6) heterocycloalkyl groups;
[0033] n is 0, 1, or 2; wherein, if n is 2, the R groups can
combine to form a fused ring system with R.sub.1;
[0034] R.sub.1 is a 4-membered cyclic or heterocyclic group;
[0035] R.sub.2 is a carbonylheteroalkyl group, wherein the alkyl
portion of the carbonylheteroalkyl group can optionally cyclize
with R, R.sub.1, or R.sub.3;
[0036] X is independently chosen from hydrogen, alkyl groups, and
heteroalkyl groups, wherein the alkyl and heteroalkyl groups can
optionally cyclize with R, R.sub.1, or R.sub.3 or with another X
group when multiple X groups are present;
[0037] R.sub.3 is chosen from hydrogen, halogens, alkyl groups,
heteroalkyl groups, haloalkyl groups, alkoxy groups, heteroalkoxy
groups, haloalkoxy groups, carbonylalkyl groups,
carbonylheteroalkyl groups, cyclic groups, heterocyclic groups,
aryl groups, and heteroaryl groups, wherein any rings are
optionally substituted with 1 or 2 R groups;
[0038] R.sub.4 is independently chosen from alkyl groups,
heteroalkyl groups, haloalkyl groups, alkoxy groups, cycloalkoxy
groups, heteroalkoxy groups, haloalkoxy groups, carboxyalkyl
groups, heterocarboxyalkyl groups, cyclic groups, heterocyclic
groups, aryl groups and heteroaryl groups, wherein any rings are
optionally substituted with 1 or 2 Y groups;
[0039] Y is independently chosen from hydrogen, OH, CN, N(X).sub.2,
(C.sub.1-C.sub.6) alkyl groups, (C.sub.1-C.sub.6) heteroalkyl
groups, (C.sub.1-C.sub.6) alkoxy groups, (C.sub.1-C.sub.6)
haloalkyl groups, (C.sub.1-C.sub.6) haloalkoxy groups, halogen,
(C.sub.3-C.sub.6) cycloalkyl groups, (C.sub.3-C.sub.6)
heterocycloalkyl groups, (C.sub.5-C.sub.8) aryl groups, and
(C.sub.4-C.sub.8) heteroaryl groups; and
[0040] m is 0, 1, or 2.
[0041] The present disclosure provides compounds of Formula
(II):
##STR00004##
and pharmaceutically acceptable salts, solvates, prodrugs,
stereoisomers, and tautomers thereof, wherein:
[0042] A is N or CR.sub.b;
[0043] R.sub.a is selected from the group consisting of hydrogen
and (C.sub.1-C.sub.6) alkyl groups;
[0044] R.sub.b is selected from the group consisting of: hydrogen,
halogen, OH, (C.sub.1-C.sub.6) alkyl groups optionally substituted
with one or more R.sub.5 and (C.sub.1-C.sub.6) alkoxy groups
optionally substituted with one or more R.sub.5; or
[0045] R.sub.b and X together form a (C.sub.3-C.sub.6) spirocyclic
cycloalkyl or (C.sub.3-C.sub.6) spirocyclic heterocycloalkyl;
[0046] each of R.sub.c, R.sub.d, R.sub.e and R.sub.f is
independently selected from the group consisting of: hydrogen,
halogen, --OR.sub.5 and (C.sub.1-C.sub.6) alkyl groups optionally
substituted with one or more R.sub.5;
[0047] R.sub.2 is selected from the group consisting of: C(O)N(X),
N(X)C(O);
[0048] X is independently chosen from hydrogen, alkyl groups, and
heteroalkyl groups, wherein the alkyl and heteroalkyl groups can
optionally cyclize with R.sub.b, or R.sub.3;
[0049] R.sub.1 is selected from the group consisting of:
(C.sub.1-C.sub.6) alkyl (e.g., a linker to R.sub.4, or when X forms
a cycloalkyl together with R.sub.3), (C.sub.3-C.sub.6) cycloalkyl,
(C.sub.1-C.sub.6) heteroalkyl (e.g., when X forms a heterocyclyl
together with R.sub.3), aryl having 1 to 3 aromatic rings
(including aryl groups optionally substituted with 1 or 2 R groups)
and heteroaryl having 1 to 3 aromatic rings (including heteroaryl
groups optionally substituted with 1 or 2 R groups);
[0050] R.sub.4 (present when m is 1 or 2) is independently chosen
from alkyl groups, cycloalkyl groups, heteroalkyl groups, haloalkyl
groups, alkoxy groups, cycloalkoxy groups, heteroalkoxy groups,
haloalkoxy groups, carboxyalkyl groups, heterocarboxyalkyl groups,
cyclic groups, heterocyclic groups, aryl groups and heteroaryl
groups, wherein any rings are optionally substituted with 1 or 2 Y
groups;
[0051] R.sub.5 is selected from the group consisting of: hydrogen,
halogen, OH, (C.sub.1-C.sub.3) alkyl groups, and (C.sub.1-C.sub.3)
alkoxy groups;
[0052] R is independently chosen from hydrogen, OH, CN,
(C.sub.1-C.sub.6) alkyl groups, (C.sub.1-C.sub.6) alkoxy groups,
(C.sub.1-C.sub.6) haloalkyl groups, (C.sub.1-C.sub.6) haloalkoxy
groups, halogen, (C.sub.3-C.sub.6) cycloalkyl groups,
(C.sub.3-C.sub.6) heterocycloalkyl groups;
(C.sub.3-C.sub.6)cycloalkyloxy groups and (C.sub.1-C.sub.6)
alkoxyalkyl groups;
[0053] Y is independently chosen from hydrogen, OH, CN, N(X).sub.2,
(C.sub.1-C.sub.6) alkyl groups, (C.sub.1-C.sub.6) heteroalkyl
groups, (C.sub.1-C.sub.6) alkoxy groups, (C.sub.1-C.sub.6)
haloalkyl groups, (C.sub.1-C.sub.6) haloalkoxy groups, halogen,
(C.sub.3-C.sub.6) cycloalkyl groups, (C.sub.3-C.sub.6)
heterocycloalkyl groups, (C.sub.5-C.sub.8) aryl groups,
(C.sub.4-C.sub.8) heteroaryl groups, and (C.sub.4-C.sub.8)
heteroaryl groups substituted with C.sub.1-C.sub.3 alkyl; and
[0054] m is 0, 1, or 2.
[0055] The present disclosure provides compounds of Formula
(III):
##STR00005##
and pharmaceutically acceptable salts, solvates, prodrugs,
stereoisomers, and tautomers thereof, wherein:
[0056] R.sub.a is selected from the group consisting of hydrogen
and (C.sub.1-C.sub.6) alkyl groups;
[0057] R.sub.b is selected from the group consisting of: hydrogen,
halogen, OH, (C.sub.1-C.sub.6) alkyl groups optionally substituted
with one or more R.sub.5 and (C.sub.1-C.sub.6) alkoxy groups
optionally substituted with one or more R.sub.5; or
[0058] R.sub.b and X together form a (C.sub.3-C.sub.6) spirocyclic
cycloalkyl or (C.sub.3-C.sub.6) spirocyclic heterocycloalkyl;
[0059] each of R.sub.c, R.sub.d, R.sub.e and R.sub.f is
independently selected from the group consisting of: hydrogen,
halogen, --OR.sub.5 and (C.sub.1-C.sub.6) alkyl groups optionally
substituted with one or more R.sub.5;
[0060] X is independently chosen from hydrogen, alkyl groups, and
heteroalkyl groups, wherein the alkyl and heteroalkyl groups can
optionally cyclize with R.sub.b, or R.sub.3;
[0061] R.sub.3 is selected from the group consisting of:
(C.sub.1-C.sub.3) alkyl, (C.sub.1-C.sub.3) heteroalkyl, and 5-10
membered cyclic, heterocyclic, aryl, and heteroaryl groups, wherein
any of the rings can be optionally substituted with 1 or 2 R
groups;
[0062] R.sub.4 (present when m is 1 or 2) is independently chosen
from alkyl groups, cycloalkyl groups, heteroalkyl groups, haloalkyl
groups, alkoxy groups, cycloalkoxy groups, heteroalkoxy groups,
haloalkoxy groups, carboxyalkyl groups, heterocarboxyalkyl groups,
cyclic groups, heterocyclic groups, aryl groups and heteroaryl
groups, wherein any rings are optionally substituted with 1 or 2 Y
groups;
[0063] R.sub.5 is selected from the group consisting of: hydrogen,
halogen, OH, (C.sub.1-C.sub.3) alkyl groups, and (C.sub.1-C.sub.3)
alkoxy groups;
[0064] R is independently chosen from hydrogen, OH, CN,
(C.sub.1-C.sub.6) alkyl groups, (C.sub.1-C.sub.6) alkoxy groups,
(C.sub.1-C.sub.6) haloalkyl groups, (C.sub.1-C.sub.6) haloalkoxy
groups, halogen, (C.sub.3-C.sub.6) cycloalkyl groups,
(C.sub.3-C.sub.6) heterocycloalkyl groups;
(C.sub.3-C.sub.6)cycloalkyloxy groups and (C.sub.1-C.sub.6)
alkoxyalkyl groups;
[0065] Y is independently chosen from hydrogen, OH, CN, N(X).sub.2,
(C.sub.1-C.sub.6) alkyl groups, (C.sub.1-C.sub.6) heteroalkyl
groups, (C.sub.1-C.sub.6) alkoxy groups, (C.sub.1-C.sub.6)
haloalkyl groups, (C.sub.1-C.sub.6) haloalkoxy groups, halogen,
(C.sub.3-C.sub.6) cycloalkyl groups, (C.sub.3-C.sub.6)
heterocycloalkyl groups, (C.sub.5-C.sub.8) aryl groups, and
(C.sub.4-C.sub.8) heteroaryl groups, and (C.sub.4-C.sub.8)
heteroaryl groups substituted with C.sub.1-C.sub.3 alkyl; and
[0066] m is 0, 1, or 2.
[0067] The present disclosure also provides compounds of Formula
(I):
##STR00006##
and pharmaceutically acceptable salts, solvates, prodrugs,
stereoisomers, and tautomers thereof, wherein:
[0068] R is independently chosen from hydrogen, OH, CN,
(C.sub.1-C.sub.6) alkyl groups, (C.sub.1-C.sub.6) alkoxy groups,
(C.sub.1-C.sub.6) haloalkyl groups, (C.sub.1-C.sub.6) haloalkoxy
groups, halogen, (C.sub.3-C.sub.6) cycloalkyl groups, and
(C.sub.3-C.sub.6) heterocycloalkyl groups;
[0069] n is 0, 1, or 2; wherein, if n is 2, the R groups can
combine to form a fused ring system with R.sub.1;
[0070] R.sub.1 is chosen from 3-6 membered cyclic or heterocyclic
groups;
[0071] R.sub.2 is chosen from C(X).sub.n, S(O).sub.2, N(X),
heteroatom linkers, N(X)S(O).sub.2, N(X)S(O).sub.2N(X),
carbonylalkyl groups, and carbonylheteroalkyl groups, wherein the
alkyl portion of carbonylalkyl and carbonylheteroalkyl groups can
optionally cyclize with R, R.sub.1, or R.sub.3: X is independently
chosen from hydrogen, alkyl groups, and heteroalkyl groups, wherein
the alkyl and heteroalkyl groups can optionally cyclize with R,
R.sub.1, or R.sub.3 or with another X group when multiple X groups
are present;
[0072] R.sub.3 is chosen from hydrogen, halogens, alkyl groups,
heteroalkyl groups, haloalkyl groups, alkoxy groups, heteroalkoxy
groups, haloalkoxy groups, carbonylalkyl groups,
carbonylheteroalkyl groups, cyclic groups, heterocyclic groups,
aryl groups, and heteroaryl groups, wherein any rings are
optionally substituted with 1 or 2 R groups;
[0073] R4 is independently chosen from alkyl groups, heteroalkyl
groups, haloalkyl groups, alkoxy groups, cycloalkoxy groups,
heteroalkoxy groups, haloalkoxy groups, carboxyalkyl groups,
heterocarboxyalkyl groups, cyclic groups, heterocyclic groups, aryl
groups and heteroaryl groups, wherein any rings are optionally
substituted with 1 or 2 Y groups;
[0074] Y is independently chosen from hydrogen, OH, CN, N(X).sub.2,
(C.sub.1-C.sub.6) alkyl groups, (C.sub.1-C.sub.6) heteroalkyl
groups, (C.sub.1-C.sub.6) alkoxy groups, (C.sub.1-C.sub.6)
haloalkyl groups, (C.sub.1-C.sub.6) haloalkoxy groups, halogen,
(C.sub.3-C.sub.6) cycloalkyl groups, (C.sub.3-C.sub.6)
heterocycloalkyl groups, (C.sub.5-C.sub.8) aryl groups, and
(C.sub.4-C.sub.8) heteroaryl groups; and
[0075] m is 0, 1, or 2.
[0076] Another aspect of the present disclosure relates to a method
of treating a disease or disorder associated with inhibition of
Ubiquitin Specific Peptidase 30 (USP30). The method comprises
administering to a patient in need of a treatment for diseases or
disorders associated with inhibition of USP30 an effective amount
of at least one chemical entity chosen from compounds of Formula
(I), and pharmaceutically acceptable salts, solvates, prodrugs,
stereoisomers, and tautomers thereof.
[0077] Another aspect of the disclosure is directed to a method of
inhibiting USP30. The method involves administering to a patient in
need thereof an effective amount of at least one chemical entity
chosen from compounds of Formula (I), and pharmaceutically
acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and
tautomers thereof.
[0078] Another aspect of the disclosure relates to a method of
treating neurodegenerative diseases. The method comprises
administering to a patient in need thereof an effective amount of
at least one chemical entity chosen from compounds of Formula (I),
and pharmaceutically acceptable salts, solvates, prodrugs,
stereoisomers, and tautomers thereof.
[0079] Preferably the compounds of the disclosure are for use in a
method of treating Parkinson's disease, wherein the method
comprises administering to a patient in need thereof an effective
amount of at least one chemical entity of the disclosure or a
pharmaceutically acceptable salt, solvate, prodrug, stereoisomer,
or tautomer thereof.
[0080] Another aspect of the disclosure is directed to
pharmaceutical compositions comprising at least one chemical entity
chosen from compounds of Formula (I), and pharmaceutically
acceptable salts, solvates, prodrugs, stereoisomers, and tautomers
thereof, and a pharmaceutically acceptable carrier. The
pharmaceutical acceptable carrier may further include an excipient,
diluent, or surfactant.
[0081] Another aspect of the present disclosure relates to at least
one chemical entity chosen from compounds of Formula (I), and
pharmaceutically acceptable salts, solvates, prodrugs,
stereoisomers, and tautomers thereof, for use in the manufacture of
a medicament for treating a disease associated with inhibiting
USP30.
[0082] Another aspect of the present disclosure relates to the use
of at least one chemical entity chosen from compounds of Formula
(I), and pharmaceutically acceptable salts, solvates, prodrugs,
stereoisomers, and tautomers thereof, in the treatment of a disease
associated with inhibiting USP30.
[0083] As summarized above, and as set forth in detail below, the
present disclosure relates to chemical entities and compositions
that are capable of inhibiting the activity of USP30. The
disclosure also relates to methods of treating, preventing or
ameliorating a disease or disorder in which USP30 plays a role by
administering to a patient in need thereof a therapeutically
effective amount of at least one chemical entity chosen from
compounds of Formula (I), and pharmaceutically acceptable salts,
solvates, prodrugs, stereoisomers, and tautomers thereof. The
methods of the present disclosure can be used in the treatment of a
variety of USP30 dependent diseases and disorders by inhibiting the
activity of USP30. Inhibition of USP30 as disclosed herein provides
a novel approach to the treatment, prevention, or amelioration of
diseases including, but not limited to, cancer.
DETAILED DESCRIPTION
[0084] The present disclosure describes compounds that inhibit
USP30. Compounds that inhibit USP30 are useful in the development
of novel therapies for the treatment of diseases or disorders
associated with USP30 enzymes, such as the treatment of
mitochondrial dysfunction diseases or disorders, neurodegenerative
diseases, and in the treatment of cancer. Specifically, the present
disclosure is concerned with chemical entities and compositions
inhibiting USP30, methods of treating diseases or disorders
associated with USP30, and methods of synthesis of these compounds.
In some embodiments the compounds of the invention are USP30
inhibitors having an IC.sub.50 value of <10 .mu.M and >0.001
.mu.M when tested in the Biochemical Assay of Example A herein.
Preferably, the compounds of the invention are USP30 inhibitors
having an IC.sub.50 value of <1 .mu.M and >0.001 .mu.M when
tested in the Biochemical Assay of Example A herein.
[0085] In a first aspect of the disclosure, the chemical entities
chosen from compounds of Formula (I):
##STR00007##
[0086] and pharmaceutically acceptable salts, solvates, prodrugs,
stereoisomers, and tautomers thereof, are described wherein R,
R.sub.1, R.sub.2, R.sub.3, R.sub.4, n, and m are as described
herein above. In further aspects of the disclosure, compounds of
Formula (Ia), (Ib), and (Ic) and pharmaceutically acceptable salts,
solvates, prodrugs, stereoisomers, and tautomers thereof as
described herein above are provided.
[0087] In a further aspect of the disclosure, compounds of Formula
(II):
##STR00008##
[0088] and pharmaceutically acceptable salts, solvates, prodrugs,
stereoisomers, and tautomers thereof are provided, wherein A,
R.sub.a, R.sub.b, R.sub.c, R.sub.d, R.sub.e, R.sub.f, R, R.sub.2,
R.sub.3, R.sub.4, R.sub.5, X, Y, and m are as described herein
above.
[0089] In a further aspect of the disclosure, compounds of Formula
(III):
##STR00009##
and pharmaceutically acceptable salts, solvates, prodrugs,
stereoisomers, and tautomers thereof are provided, wherein R.sub.a,
R.sub.b, R.sub.c, R.sub.d, R.sub.e, R.sub.f, R, R.sub.3, R.sub.4,
R.sub.5, X, Y, and m are as described herein above.
[0090] The details of the disclosure are set forth in the
accompanying description below. Although methods and materials
similar or equivalent to those described herein can be used in the
practice or testing of the present disclosure, illustrative methods
and materials are now described. Other features, objects, and
advantages of the disclosure will be apparent from the description
and from the claims. In the specification and the appended claims,
the singular forms also include the plural unless the context
clearly dictates otherwise. Unless defined otherwise, all technical
and scientific terms used herein have the same meaning as commonly
understood by one of ordinary skill in the art to which this
disclosure belongs. All patents and publications cited in this
specification are incorporated herein by reference in their
entireties.
[0091] The articles "a" and "an" are used in this disclosure to
refer to one or more than one (e.g., to at least one) of the
grammatical object of the article. By way of example, "an element"
means one element or more than one element.
[0092] The term "and/or" is used in this disclosure to mean either
"and" or "or" unless indicated otherwise.
[0093] The term "optionally substituted" is understood to mean that
a given chemical moiety (e.g., an alkyl group) can (but is not
required to) be bonded other substituents (e.g., heteroatoms). For
instance, an alkyl group that is optionally substituted can be a
fully saturated alkyl chain (e.g., a pure hydrocarbon).
Alternatively, the same optionally substituted alkyl group can have
substituents different from hydrogen. For instance, it can, at any
point along the chain be bounded to a halogen atom, a hydroxyl
group, or any other substituent described herein. Thus the term
"optionally substituted" means that a given chemical moiety has the
potential to contain other functional groups, but does not
necessarily have any further functional groups. Suitable
substituents used in the optional substitution of the described
groups include, without limitation, halogen, oxo, --OH, --CN,
--COOH, --CH.sub.2CN, --O--(C.sub.1-C.sub.6) alkyl,
(C.sub.1-C.sub.6) alkyl, (C.sub.1-C.sub.6) alkoxy,
(C.sub.1-C.sub.6) haloalkyl, (C.sub.1-C.sub.6) haloalkoxy,
--O--(C.sub.2-C.sub.6) alkenyl, --O--(C.sub.2-C.sub.6) alkynyl,
(C.sub.2-C.sub.6) alkenyl, (C.sub.2-C.sub.6) alkynyl, --OH,
--OP(O)(OH).sub.2, --OC(O)(C.sub.1-C.sub.6) alkyl,
--C(O)(C.sub.1-C.sub.6) alkyl, --OC(O)O(C.sub.1-C.sub.6) alkyl,
--NH.sub.2, --NH((C.sub.1-C.sub.6) alkyl), --N((C.sub.1-C.sub.6)
alkyl).sub.2, --NHC(O)(C.sub.1-C.sub.6) alkyl,
--C(O)NH(C.sub.1-C.sub.6) alkyl, --S(O).sub.2(C.sub.1-C.sub.6)
alkyl, --S(O)NH(C.sub.1-C.sub.6) alkyl, and S(O)N((C.sub.1-C.sub.6)
alkyl).sub.2. The substituents can themselves be optionally
substituted. "Optionally substituted" as used herein also refers to
substituted or unsubstituted whose meaning is described below.
[0094] As used herein, the term "substituted" means that the
specified group or moiety bears one or more suitable substituents
wherein the substituents may connect to the specified group or
moiety at one or more positions. For example, an aryl substituted
with a cycloalkyl may indicate that the cycloalkyl connects to one
atom of the aryl with a bond or by fusing with the aryl and sharing
two or more common atoms.
[0095] As used herein, the term "unsubstituted" means that the
specified group bears no substituents.
[0096] Unless otherwise specifically defined, the term "aryl"
refers to cyclic, aromatic hydrocarbon groups that have 1 to 3
aromatic rings, including monocyclic or bicyclic groups such as
phenyl, biphenyl or naphthyl. Where containing two aromatic rings
(bicyclic, etc.), the aromatic rings of the aryl group may be
joined at a single point (e.g., biphenyl), or fused (e.g.,
naphthyl). The aryl group may be optionally substituted by one or
more substituents, e.g., 1 to 5 substituents, at any point of
attachment. Exemplary substituents include, but are not limited to,
--H, -halogen, --O--(C.sub.1-C.sub.6) alkyl, (C.sub.1-C.sub.6)
alkyl, --O--(C.sub.2-C.sub.6) alkenyl, --O--(C.sub.2-C.sub.6)
alkynyl, (C.sub.2-C.sub.6) alkenyl, (C.sub.2-C.sub.6) alkynyl,
--OH, --OP(O)(OH).sub.2, --OC(O)(C.sub.1-C.sub.6) alkyl,
--C(O)(C.sub.1-C.sub.6) alkyl, --OC(O)O(C.sub.1-C.sub.6) alkyl,
--NH.sub.2, NH((C.sub.1-C.sub.6) alkyl), N((C.sub.1-C.sub.6)
alkyl).sub.2, --S(O).sub.2--(C.sub.1-C.sub.6) alkyl,
--S(O)NH(C.sub.1-C.sub.6) alkyl, and --S(O)N((C.sub.1-C.sub.6)
alkyl).sub.2. The substituents can themselves be optionally
substituted. Furthermore when containing two fused rings the aryl
groups herein defined may have an unsaturated or partially
saturated ring fused with a fully saturated ring. Exemplary ring
systems of these aryl groups include, but are not limited to,
phenyl, biphenyl, naphthyl, anthracenyl, phenalenyl, phenanthrenyl,
indanyl, indenyl, tetrahydronaphthalenyl, tetrahydrobenzoannulenyl,
and the like.
[0097] Unless otherwise specifically defined, "heteroaryl" means a
monovalent monocyclic aromatic radical of 5 to 24 ring atoms or a
polycyclic aromatic radical, containing one or more ring
heteroatoms selected from N, O, and S, the remaining ring atoms
being C. Heteroaryl as herein defined also means a bicyclic
heteroaromatic group wherein the heteroatom is selected from N, O,
and S. The aromatic radical is optionally substituted independently
with one or more substituents described herein. Examples include,
but are not limited to, furyl, thienyl, pyrrolyl, pyridyl,
pyrazolyl, pyrimidinyl, imidazolyl, isoxazolyl, oxazolyl,
oxadiazolyl, pyrazinyl, indolyl, thiophen-2-yl, quinolyl,
benzopyranyl, isothiazolyl, thiazolyl, thiadiazole, indazole,
benzimidazolyl, thieno[3,2-b]thiophene, triazolyl, triazinyl,
imidazo[1,2-b]pyrazolyl, furo[2,3-c]pyridinyl,
imidazo[1,2-a]pyridinyl, indazolyl, pyrrolo[2,3-c]pyridinyl,
pyrrolo[3,2-c]pyridinyl, pyrazolo[3,4-c]pyridinyl,
thieno[3,2-c]pyridinyl, thieno[2,3-c]pyridinyl,
thieno[2,3-b]pyridinyl, benzothiazolyl, indolyl, indolinyl,
indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuranyl,
benzofuran, chromanyl, thiochromanyl, tetrahydroquinolinyl,
dihydrobenzothiazine, dihydrobenzoxanyl, quinolinyl, isoquinolinyl,
1,6-naphthyridinyl, benzo[de]isoquinolinyl,
pyrido[4,3-b][1,6]naphthyridinyl, thieno[2,3-b]pyrazinyl,
quinazolinyl, tetrazolo[1,5-a]pyridinyl,
[1,2,4]triazolo[4,3-a]pyridinyl, isoindolyl,
pyrrolo[2,3-b]pyridinyl, pyrrolo[3,4-b]pyridinyl,
pyrrolo[3,2-b]pyridinyl, imidazo[5,4-b]pyridinyl,
pyrrolo[1,2-a]pyrimidinyl, tetrahydro pyrrolo[1,2-a]pyrimidinyl,
dibenzo[b,d] thiophene, pyridin-2-one, furo[3,2-c]pyridinyl,
furo[2,3-c]pyridinyl, 1H-pyrido[3,4-b][1,4] thiazinyl,
benzooxazolyl, benzoisoxazolyl, furo[2,3-b]pyridinyl,
benzothiophenyl, 1,5-naphthyridinyl, furo[3,2-b]pyridine,
[1,2,4]triazolo[1,5-a]pyridinyl, benzo [1,2,3]triazolyl,
imidazo[1,2-a]pyrimidinyl, [1,2,4]triazolo[4,3-b]pyridazinyl,
benzo[c][1,2,5]thiadiazolyl, benzo[c][1,2,5]oxadiazole,
1,3-dihydro-2H-benzo[d]imidazol-2-one, 3,4-dihydro-2H-pyrazolo
[1,5-b][1,2]oxazinyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridinyl,
thiazolo[5,4-d]thiazolyl, imidazo[2,1-b][1,3,4]thiadiazolyl,
thieno[2,3-b]pyrrolyl, thieno[2,3-d]thiazole,
1a,2,3,7b-tetrahydro-1H-cyclopropa[c][1,8]naphthyridine,
3H-indolyl, and derivatives thereof. Furthermore the terms
"heteroaryl" and "heteroar-", as used herein, also include groups
in which a heteroaromatic ring is fused to one or more aryl,
cycloaliphatic, or heterocyclyl rings, where the radical or point
of attachment is on the heteroaromatic ring. Nonlimiting examples
include indolinyl, indolinonyl, dihydrobenzothiophenyl,
dihydrobenzofuran, chromanyl, thiochromanyl, tetrahydroquinolinyl,
dihydrobenzothiazine, 3,4-dihydro-1H-isoquinolinyl,
2,3-dihydrobenzofuran, indolinyl, indolyl, isoindolyl and
dihydrobenzoxanyl.
[0098] Halogen or "halo" refers to fluorine, chlorine, bromine, or
iodine.
[0099] Alkyl refers to a straight or branched chain saturated
hydrocarbon containing 1-12 carbon atoms. Examples of a
(C.sub.1-C.sub.6) alkyl group include, but are not limited to,
methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl,
sec-butyl, tert-butyl, isopentyl, neopentyl, and isohexyl.
[0100] "Alkoxy" refers to a straight or branched chain saturated
hydrocarbon containing 1-12 carbon atoms containing a terminal "O"
in the chain, e.g., --O(alkyl). Examples of alkoxy groups include
without limitation, methoxy, ethoxy, propoxy, butoxy, t-butoxy, or
pentoxy groups.
[0101] The terms "alkylene" or "alkylenyl" refer to a divalent
alkyl radical. Any of the above mentioned monovalent alkyl groups
may be an alkylene by abstraction of a second hydrogen atom from
the alkyl. As herein defined, alkylene may also be a
C.sub.0-C.sub.6 alkylene. An alkylene may further be a
C.sub.0-C.sub.4 alkylene. Typical alkylene groups include, but are
not limited to, --CH.sub.2--, --CH(CH.sub.3)--,
--C(CH.sub.3).sub.2--, --CH.sub.2CH.sub.2--,
--CH.sub.2CH(CH.sub.3)--, --CH.sub.2C(CH.sub.3).sub.2--,
--CH.sub.2CH.sub.2CH.sub.2--, --CH.sub.2CH.sub.2CH.sub.2CH.sub.2--,
and the like.
[0102] The term "carbonylalkyl" means an alkyl group as defined
above, where the alkyl group is substituted with one or more C(O)
groups.
[0103] The term "carbonylheteroalkyl" is similar to the
carbonylalkyl group as defined above, in that an alkyl group
containing heteroatoms such as N, S, O ("heteroalkyl"), is
substituted with one or more C(O) groups. Non-limiting examples of
carbonylheteroalkyl groups include amide, reverse amide, and
alkylamide-type groups such as NXC(O), C(X).sub.2NXC(O), C(O)NX,
urea-type groups such as NXC(O)NX, wherein X is chosen from
hydrogen, alkyl, and heteroalkyl groups, wherein the alkyl and
heteroalkyl groups can optionally cyclize with other groups on the
compound, such as R, R1, R3, or with another X group when multiple
X groups are present.
[0104] "Cycloalkyl" or "carbocyclyl" means monocyclic or polycyclic
saturated carbon rings containing 3-18 carbon atoms. One or two
ring carbon atoms in the cycloalkyl ring can optionally be replaced
by a --C(O)-- group. Examples of cycloalkyl groups include, without
limitations, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
cycloheptanyl, cyclooctanyl, norboranyl, norborenyl,
bicyclo[2.2.2]octanyl, or bicyclo[2.2.2]octenyl and derivatives
thereof. A C.sub.3-C.sub.8 cycloalkyl is a cycloalkyl group
containing between 3 and 8 carbon atoms. A cycloalkyl group can be
fused (e.g., decalin) or bridged (e.g., norbornane).
[0105] "Heterocyclyl" or "heterocycloalkyl" monocyclic or
polycyclic rings containing carbon and heteroatoms taken from
oxygen, nitrogen, or sulfur and wherein there is not delocalized
.pi. electrons (aromaticity) shared among the entire ring carbon or
heteroatoms. One or two ring carbon atoms in the heterocycloalkyl
ring can optionally be replaced by a --C(O)-- group. The
heterocycloalkyl ring structure may be substituted by one or more
substituents. The substituents can themselves be optionally
substituted. Examples of heterocyclyl rings include, but are not
limited to, oxetanyl, azetadinyl, tetrahydrofuranyl,
tetrahydropyranyl, pyrrolidinyl, oxazolinyl, oxazolidinyl,
thiazolinyl, thiazolidinyl, pyranyl, thiopyranyl,
tetrahydropyranyl, dioxalinyl, piperidinyl, morpholinyl,
thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl
S-dioxide, piperazinyl, azepinyl, oxepinyl, diazepinyl, tropanyl,
oxazolidinonyl, and homotropanyl. As used herein, "heterocyclyl"
and "heterocycloalkyl" also includes bridged and spirocyclic ring
systems where at least one atom is a heteroatom. A heterocyclic
ring as a substituent may attach via a ring heteroatom (e.g.
"N-linked") or via a ring carbon (e.g. "C-linked").
[0106] The term "hydroxyalkyl" means an alkyl group as defined
above, where the alkyl group is substituted with one or more OH
groups. Examples of hydroxyalkyl groups include HO--CH.sub.2--,
HO--CH.sub.2--CH.sub.2-- and CH.sub.3--CH(OH)--.
[0107] The term "haloalkyl" as used herein refers to an alkyl
group, as defined herein, which is substituted one or more halogen.
Examples of haloalkyl groups include, but are not limited to,
trifluoromethyl, difluoromethyl, pentafluoroethyl, trichloromethyl,
etc.
[0108] The term "haloalkoxy" as used herein refers to an alkoxy
group, as defined herein, which is substituted one or more halogen.
Examples of haloalkyl groups include, but are not limited to,
trifluoromethoxy, difluoromethoxy, pentafluoroethoxy,
trichloromethoxy, etc.
[0109] The term "cyano" as used herein means a substituent having a
carbon atom joined to a nitrogen atom by a triple bond, e.g.,
C.ident.N.
[0110] The term "solvate" refers to a complex of variable
stoichiometry formed by a solute and solvent. Such solvents for the
purpose of the disclosure may not interfere with the biological
activity of the solute. Examples of suitable solvents include, but
are not limited to, water, MeOH, EtOH, and AcOH. Solvates wherein
water is the solvent molecule are typically referred to as
hydrates. Hydrates include compositions containing stoichiometric
amounts of water, as well as compositions containing variable
amounts of water.
[0111] The term "isomer" refers to compounds that have the same
composition and molecular weight but differ in physical and/or
chemical properties. The structural difference may be in
constitution (geometric isomers) or in the ability to rotate the
plane of polarized light (stereoisomers). With regard to
stereoisomers, the compounds of Formula (I) may have one or more
asymmetric carbon atom and may occur as racemates, racemic mixtures
and as individual enantiomers or diastereomers.
[0112] The disclosure also includes pharmaceutical compositions
comprising an effective amount of a disclosed compound and a
pharmaceutically acceptable carrier. Representative
"pharmaceutically acceptable salts" include, e.g., water-soluble
and water-insoluble salts, such as the acetate, amsonate
(4,4-diaminostilbene-2,2-disulfonate), benzenesulfonate, benzoate,
bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate,
calcium, calcium edetate, camsylate, carbonate, chloride, citrate,
clavulariate, dihydrochloride, edetate, edisylate, estolate,
esylate, fumerate, fiunarate, gluceptate, gluconate, glutamate,
glycollylarsanilate, hexafluorophosphate, hexylresorcinate,
hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate,
iodide, isothionate, lactate, lactobionate, laurate, magnesium,
malate, maleate, mandelate, mesylate, methylbromide, methylnitrate,
methylsulfate, mucate, napsylate, nitrate, N-methylglucamine
ammonium salt, 3-hydroxy-2-naphthoate, oleate, oxalate, palmitate,
pamoate (1,1-methene-bis-2-hydroxy-3-naphthoate, einbonate),
pantothenate, phosphate/diphosphate, picrate, polygalacturonate,
propionate, p-toluenesulfonate, salicylate, stearate, subacetate,
succinate, sulfate, sulfosalicylate, suramate, tannate, tartrate,
teoclate, tosylate, triethiodide, and valerate salts.
[0113] A "patient" or "subject" is a mammal, e.g., a human, mouse,
rat, guinea pig, dog, cat, horse, cow, pig, or non-human primate,
such as a monkey, chimpanzee, baboon or rhesus.
[0114] An "effective amount" when used in connection with a
compound is an amount effective for treating or preventing a
disease in a subject as described herein.
[0115] The term "carrier", as used in this disclosure, encompasses
carriers, excipients, and diluents and means a material,
composition or vehicle, such as a liquid or solid filler, diluent,
excipient, solvent or encapsulating material, involved in carrying
or transporting a pharmaceutical agent from one organ, or portion
of the body, to another organ, or portion of the body of a
subject.
[0116] The term "treating" with regard to a subject, refers to
improving at least one symptom of the subject's disorder. Treating
includes curing, improving, or at least partially ameliorating the
disorder.
[0117] The term "disorder" is used in this disclosure to mean, and
is used interchangeably with, the terms disease, condition, or
illness, unless otherwise indicated.
[0118] The terms "administer", "administering", or "administration"
as used in this disclosure refer to either directly administering a
disclosed compound or pharmaceutically acceptable salt of the
disclosed compound or a composition to a subject, or administering
a prodrug derivative or analog of the compound or pharmaceutically
acceptable salt of the compound or composition to the subject,
which can form an equivalent amount of active compound within the
subject's body.
[0119] The term "prodrug," as used in this disclosure, means a
compound which is convertible in vivo by metabolic means (e.g., by
hydrolysis) to a disclosed compound.
[0120] As used herein, the term "neurodegenerative disease"
includes, but is not limited to, Alzheimer's disease and other
dementias, Parkinson's disease and other synucleinopathies such as
Multiple System Atrophy, dementia with Lewy Bodies and PD-related
disorders, Prion disease, Corticobasal Degeneration, Frontotemporal
Dementia, Posterior Cortical Atrophy, Primary Progressive Aphasia,
Progressive Supranuclear Palsy, Pick's disease, Chronic Traumatic
Encephelopathy, Dementia Pugilistica, Traumatic Brain Injury,
Vascular Dementia, Peripheral Neuropathy and Multiple
Sclerosis.
Formula I (and Formulae (Ia), (Ib), and (Ic))
[0121] The present disclosure relates to chemical entities chosen
from compounds of Formula (I) and pharmaceutically acceptable
salts, solvates, prodrugs, stereoisomers, and tautomers thereof,
capable of inhibiting USP30, which are useful for the treatment of
diseases and disorders associated with inhibition of USP30. The
disclosure further relates to chemical entities chosen from
compounds of Formula (T) and pharmaceutically acceptable salts,
solvates, prodrugs, stereoisomers, and tautomers thereof, which are
useful for inhibiting USP30.
[0122] The chemical entities disclosed are chosen from compounds of
Formula (I):
##STR00010##
and pharmaceutically acceptable salts, solvates, prodrugs,
stereoisomers, and tautomers thereof, wherein:
[0123] R is independently chosen from hydrogen, OH, CN,
(C.sub.1-C.sub.6) alkyl groups, (C.sub.1-C.sub.6) alkoxy groups,
(C.sub.1-C.sub.6) haloalkyl groups, (C.sub.1-C.sub.6) haloalkoxy
groups, halogen, (C.sub.3-C.sub.6) cycloalkyl groups, and
(C.sub.3-C.sub.6) heterocycloalkyl groups;
[0124] n is 0, 1, or 2; wherein, if n is 2, the R groups can
combine to form a fused ring system with R.sub.1;
[0125] R.sub.1 is chosen from 3-6 membered cyclic or heterocyclic
groups;
[0126] R.sub.2 is chosen from C(X).sub.n, S(O).sub.2, N(X),
heteroatom linkers, N(X)S(O).sub.2, N(X)S(O).sub.2N(X),
carbonylalkyl groups, and carbonylheteroalkyl groups, wherein the
alkyl portion of carbonylalkyl and carbonylheteroalkyl groups can
optionally cyclize with R, R.sub.1, or R.sub.3:
[0127] X is independently chosen from hydrogen, alkyl groups, and
heteroalkyl groups, wherein the alkyl and heteroalkyl groups can
optionally cyclize with R, R.sub.1, or R.sub.3 or with another X
group when multiple X groups are present;
[0128] R.sub.3 is chosen from hydrogen, halogens, alkyl groups,
heteroalkyl groups, haloalkyl groups, alkoxy groups, heteroalkoxy
groups, haloalkoxy groups, carbonylalkyl groups,
carbonylheteroalkyl groups, cyclic groups, heterocyclic groups,
aryl groups, and heteroaryl groups, wherein any rings are
optionally substituted with 1 or 2 R groups;
[0129] R.sub.4 is independently chosen from alkyl groups,
heteroalkyl groups, haloalkyl groups, alkoxy groups, cycloalkoxy
groups, heteroalkoxy groups, haloalkoxy groups, carboxyalkyl
groups, heterocarboxyalkyl groups, cyclic groups, heterocyclic
groups, aryl groups and heteroaryl groups, wherein any rings are
optionally substituted with 1 or 2 Y groups;
[0130] Y is independently chosen from hydrogen, OH, CN, N(X).sub.2,
(C.sub.1-C.sub.6) alkyl groups, (C.sub.1-C.sub.6) heteroalkyl
groups, (C.sub.1-C.sub.6) alkoxy groups, (C.sub.1-C.sub.6)
haloalkyl groups, (C.sub.1-C.sub.6) haloalkoxy groups, halogen,
(C.sub.3-C.sub.6) cycloalkyl groups, (C.sub.3-C.sub.6)
heterocycloalkyl groups, (C.sub.5-C.sub.8) aryl groups, and
(C.sub.4-C.sub.8) heteroaryl groups; and
[0131] m is 0, 1, or 2.
[0132] In some embodiments of Formula (I) above, R is chosen from
halogens.
[0133] In some embodiments of Formula (I) above, R.sub.1 is chosen
from cyclopropane, cyclobutane, cyclopentane, and cyclohexane. In
some embodiments, R.sub.1 is chosen from cyclobutane and
cyclopentane. In some embodiments, R.sub.1 is chosen from
heterocyclic groups. In some embodiments, R.sub.1 is a pyrrolidine.
In some embodiments of Formula (I) above, R.sub.1 is a cyclic
group. In some embodiments of Formula (I) above, R.sub.1 is a
heterocyclic group. In some embodiments of Formula (I) above,
R.sub.1 is preferably cyclobutane.
[0134] In some embodiments of Formula (I) above, R.sub.2 is chosen
from carbonylalkyl and heterocarbonylalkyl groups. In some
embodiments, R.sub.2 is chosen from amides, reverse amides, and
ureas.
[0135] In some embodiments of Formula (I) above, R.sub.2 is chosen
from carbonylalkyl and heterocarbonylalkyl groups wherein the
groups optionally cyclize to adjacent groups. In some embodiments,
R.sub.2 is chosen from amides, reverse amides, and ureas, wherein
the amides and reverse amides are optionally cyclized to adjacent
groups.
[0136] In some embodiments of Formula (I) above, R.sub.2 is a
carbonylheteroalkyl group, wherein the alkyl portion of the
carbonylheteroalkyl group can optionally cyclize with R, R.sub.1,
or R.sub.3. In some embodiments of Formula (I) above, R.sub.2 is an
amide or reverse amide group. In some embodiments of Formula (I)
above, R.sub.2 is preferably an amide. In some embodiments of
Formula (I) above, R.sub.2 is a reverse amide. In some embodiments
of Formula (I) above, R.sub.2 is selected from C(O)N(X) and
N(X)C(O). In some embodiments of Formula (I) above, R.sub.2 is
preferably C(O)N(X). In some embodiments of Formula (I) above,
R.sub.2 is N(X)C(O).
[0137] In some embodiments of Formula (I) above, R.sub.3 is chosen
from aryl and heteroaryl rings. In some embodiments, R.sub.3 is
chosen from thiazole, indenyl, pyrazole, and phenyl rings. In some
embodiments, R.sub.3 is chosen from cyclic and heterocyclic
rings.
[0138] In some embodiments R.sub.3 is chosen from thiazole,
indenyl, pyrazole, phenyl, benzothiazole, and oxazole rings.
[0139] In some embodiments of Formula (I) above, R.sub.4 is chosen
from cyclic and heterocyclic rings optionally substituted with 1 or
2 R. In some embodiments, R.sub.4 is chosen from alkyl,
heteroalkyl, and haloalkyl groups. In some embodiments, R.sub.4 is
chosen from aryl and heteroaryl rings optionally substituted with 1
or 2 R.
[0140] In some embodiments of Formula (I) above, m is 0. In some
embodiments, m is 1. In some embodiments, m is 2.
[0141] In some embodiments of Formula (I) above, R.sub.1 is a
cyclobutane optionally substituted with 1 or 2 R; R is chosen from
(C.sub.1-C.sub.6) alkyl groups, (C.sub.1-C.sub.6) haloalkyl groups,
(C.sub.1-C.sub.6) alkoxy groups, and halogens; R.sub.2 is chosen
from amides or reverse amides; R.sub.3 is chosen from
C.sub.1-C.sub.3 alkyl linkers, thiazole, phenyl, benzothiazole,
oxazole groups optionally substituted with 1 or 2 R; R.sub.4 is
chosen from cyclic rings, alkyl groups, and heteroaryl groups
optionally substituted with 1 or 2 Y; Y is chosen from
(C.sub.1-C.sub.6) alkyl groups, (C.sub.3-C.sub.6) cycloalkyl
groups.
[0142] In some embodiments of Formula (I) above, R.sub.1 is a
cyclobutane optionally substituted with 1 or 2 R; R is chosen from
(C.sub.1-C.sub.6) alkyl groups, (C.sub.1-C.sub.6) haloalkyl groups,
(C.sub.1-C.sub.6) alkoxy groups, and halogens; R.sub.2 is chosen
from amides and reverse amides that form spirocyclic rings with
R.sub.1; R.sub.3 is chosen from thiazole, phenyl, and oxazole
groups optionally substituted with 1 or 2 R; R.sub.4 is chosen from
cyclic rings, alkyl groups, and heteroaryl groups optionally
substituted with 1 or 2 Y; Y is chosen from (C.sub.1-C.sub.6) alkyl
groups, and (C.sub.3-C.sub.6) cycloalkyl groups.
[0143] In some embodiments of Formula (I) above, R.sub.1 is a
cyclobutane, R.sub.2 is chosen from carbonylalkyl and
heterocarbonylalkyl groups (e.g. amides, reverse amides, and ureas,
preferably amides), R.sub.3 is chosen from aryl and heteroaryl
rings (e.g. thiazole, indenyl, pyrazole, and phenyl rings)
preferably heteroaryl rings, and R.sub.4 is chosen from aryl and
heteroaryl rings optionally substituted with 1 or 2 R.
[0144] In some embodiments of Formula (I) above, R.sub.1 is a
cyclobutane, R.sub.b is chosen from carbonylalkyl and
heterocarbonylalkyl groups (e.g. amides, reverse amides, and ureas,
preferably amides), R.sub.3 is chosen from aryl and heteroaryl
rings (e.g. thiazole, indenyl, pyrazole, and phenyl rings)
preferably heteroaryl rings, and R.sub.4 is chosen from cyclic and
heterocyclic rings optionally substituted with 1 or 2 R.
[0145] In some embodiments of Formula (I) above, R.sub.1 is a
cyclobutane, R.sub.2 is chosen from carbonylalkyl and
heterocarbonylalkyl groups (e.g. amides, reverse amides, and ureas,
preferably amides), R.sub.3 is chosen from aryl and heteroaryl
rings (e.g. thiazole, indenyl, pyrazole, and phenyl rings)
preferably heteroaryl rings, and R.sub.4 is chosen from alkyl,
heteroalkyl, and haloalkyl groups.
[0146] Non-limiting illustrative compounds of the disclosure
include:
TABLE-US-00001 Example No. Structure Chemical Name Compound 10-1
##STR00011## cis-4-(cyanoamino)-N-(5-cyclohexyl-
1,3-thiazol-2-yl)cyclohexane-1- carboxamide Compound 10-2
##STR00012## trans-4-(cyanoamino)-N-(5-cyclohexyl-
1,3-thiazol-2-yl)cyclohexane-1- carboxamide Compound 10-3
##STR00013## (1R,2R)-2-(cyanoamino)-N-(5- cyclohexyl-1,3-thiazol-2-
yl)cyclopentane-1-carboxamide Compound 10-4 ##STR00014##
(1R,3S)-3-(cyanoamino)-N-(5- cyclohexyl-1,3-thiazol-2-
yl)cyclohexane-1-carboxamide Compound 10-5 ##STR00015##
(1S,3S)-3-(cyanoamino)-N-(5- cyclohexyl-1,3-thiazol-2-
yl)cyclohexane-1-carboxamide Compound 10-6 ##STR00016##
(1S,3R)-3-(cyanoamino)-N-(5- cyclohexyl-1,3-thiazol-2-
yl)cyclohexane-1-carboxamide Compound 10-7 ##STR00017##
(1R,2S)-2-(cyanoamino)-N-(5- cyclohexyl-1,3-thiazol-2-
yl)cyclopentane-1-carboxamide Compound 10-8 ##STR00018##
(1S,2R)-2-(cyanoamino)-N-(5- cyclohexyl-1,3-thiazol-2-
yl)cyclopentane-1-carboxamide Compound 10-9 ##STR00019##
(1S,2S)-2-(cyanoamino)-N-(5- cyclohexyl-1,3-thiazol-2-
yl)cyclopentane-1-carboxamide Compound 1-1 ##STR00020##
trans-3-(cyanoamino)-N-[5-(oxan-4-yl)-
1,3-thiazol-2-yl]cyclobutane-1- carboxamide Compound 10-10
##STR00021## (1S,3S)-3-(cyanoamino)-N-[5-(oxan-4-
yl)-1,3-thiazol-2-yl]cyclopentane-1- carboxamide Compound 10-11
##STR00022## (1R,3R)-3-(cyanoamino)-N-[5-(oxan-4-
yl)-1,3-thiazol-2-yl]cyclopentane-1- carboxamide Compound 11-1
##STR00023## trans-2-(cyanoamino)-N-(5-cyclohexyl-
1,3-thiazol-2-yl)cyclopropane-1- carboxamide Compound 11-2
##STR00024## cis-2-(cyanoamino)-N-(5-cyclohexyl-
1,3-thiazol-2-yl)cyclopropane-1- carboxamide Compound 2-1
##STR00025## 3-(cyanoamino)-N-(5-cyclohexyl-1,3-
thiazol-2-yl)azetidine-1-carboxamide Compound 2-2 ##STR00026##
(3S)-3-(cyanoamino)-N-(5-cyclohexyl-
1,3-thiazol-2-yl)pyrrolidine-1- carboxamide Compound 2-3
##STR00027## (3R)-3-(cyanoamino)-N-(5-cyclohexyl-
1,3-thiazol-2-yl)pyrrolidine-1- carboxamide Compound 3-1
##STR00028## 5-phenyl-N-[(trans)-3-
(cyanoamino)cyclobutyl]-1,3-thiazole-2- carboxamide Compound 4-1
##STR00029## 5-phenyl-N-[(cis)-3-
(cyanoamino)cyclobutyl]-1,3-thiazole-2- carboxamide Compound 12-1
##STR00030## (1R,3S)-3-(cyanoamino)-N-(5-phenyl-
1,3-thiazol-2-yl)cyclopentane-1- carboxamide Compound 12-2
##STR00031## (1S,3S)-3-(cyanoamino)-N-(1-phenyl-
1H-pyrazol-3-yl)cyclopentane-1- carboxamide Compound 12-3
##STR00032## (1S,3S)-3-(cyanoamino)-N-(5- cyclohexyl-1,3-thiazol-2-
yl)cyclopentane-1-carboxamide Compound 12-4 ##STR00033##
(1S,3S)-3-(cyanoamino)-N-(5-phenyl-
1,3-thiazol-2-yl)cyclopentane-1- carboxamide Compound 5-1
##STR00034## cis-3-(cyanoamino)-N-(1-phenyl-1H-
pyrazol-4-yl)cyclobutane-1- carboxamide Compound 5-2 ##STR00035##
cis-3-(cyanoamino)-N-(1-phenyl-1H- pyrazol-3-yl)cyclobutane-1-
carboxamide Compound 5-3 ##STR00036##
cis-3-(cyanoamino)-N-(5-cyclohexyl- 1,3-thiazol-2-yl)cyclobutane-1-
carboxamide Compound 5-4 ##STR00037##
cis-3-(cyanoamino)-N-(5-phenyl-1,3-
thiazol-2-yl)cyclobutane-1-carboxamide Compound 5-5 ##STR00038##
trans-3-(cyanoamino)-N-(1-phenyl-1H- pyrazol-4-yl)cyclobutane-1-
carboxamide Compound 5-6 ##STR00039##
trans-3-(cyanoamino)-N-(1-phenyl-1H- pyrazol-3-yl)cyclobutane-1-
carboxamide Compound 5-7 ##STR00040##
trans-3-(cyanoamino)-N-(5-cyclohexyl-
1,3-thiazol-2-yl)cyclobutane-1- carboxamide Compound 5-8
##STR00041## trans-3-(cyanoamino)-N-(5-phenyl-1,3-
thiazol-2-yl)cyclobutane-1-carboxamide Compound 12-5 ##STR00042##
(1S,3S)-3-(cyanoamino)-N-(2,3-
dihydro-1H-inden-5-yl)cyclopentane-1- carboxamide Compound 12-6
##STR00043## {[(1S,3S)-3-(4-phenylpiperazine-1-
earbonyl)cyclopentyl]amino}carbonitrile Compound 12-7 ##STR00044##
(1S,3R)-N-(5-tert-butyl-1,3-thiazol-2-
yl)-3-(cyanoamino)cyclopentane-1- carboxamide Compound 5-9
##STR00045## cis-3-(cyanoamino)-N-(2,3-dihydro-1H-
inden-5-yl)cyclobutane-1-carboxamide Compound 5-10 ##STR00046##
cis-N-(5-tert-butyl-1,3-thiazol-2-yl)-3- (cyanoamino)cyclobutane-1-
carboxamide Compound 5-11 ##STR00047##
{[cis-3-(4-phenylpiperazine-1-
carbonyl)cyclobutyl]amino}carbonitrile Compound 5-12 ##STR00048##
trans-3-(cyanoamino)-N-(2,3-dihydro- 1H-inden-5-yl)cyclobutane-1-
carboxamide Compound 5-13 ##STR00049##
trans-N-(5-tert-butyl-1,3-thiazol-2-yl)-3-
(cyanoamino)cyclobutane-1- carboxamide Compound 5-14 ##STR00050##
trans-3-(cyanoamino)-N-[4-(morpholin-
4-yl)phenyl]cyclobutane-1-carboxamide Compound 12-8 ##STR00051##
{[(3S)-1-[2-(2,3-dichlorophenyl)-1,3-
thiazole-4-carbonyl]pyrrolidin-3- yl]amino}carbonitrile Compound
12-9 ##STR00052## ({1-[2-(2,4-dichlorophenyl)-1,3-
thiazole-4-carbonyl]piperidin-4- yl}amino)carbonitrile
[0147] Any of the features disclosed above in the context of the
compounds of Formula (I) may also be applied to any of the
compounds of Formulae (Ia), (Ib), (Ic), (II), and (III) disclosed
herein.
Formula (Ia)
[0148] In any of the embodiments of Formula (I) disclosed above,
the compound of Formula (I) may be a compound of Formula (Ia) as
described herein above. The compounds of Formula (Ia) correspond to
compounds of Formula (I) wherein R.sub.1 is a 4-membered cyclic or
heterocyclic group.
[0149] In some embodiments of Formula (Ia) above, R is chosen from
halogens
[0150] In some embodiments of Formula (Ia), R.sub.1 is a cyclic
group. In some embodiments of Formula (Ia), R.sub.1 is a
heterocyclic group. In some embodiments of Formula (Ia), R.sub.1 is
preferably cyclobutane.
[0151] In some embodiments of Formula (Ia), R.sub.2 is chosen from
carbonylalkyl and heterocarbonylalkyl groups. In some embodiments
of Formula (Ia), R.sub.2 is chosen from amides, reverse amides, and
ureas.
[0152] In some embodiments of Formula (Ia), R.sub.2 is chosen from
carbonylalkyl and heterocarbonylalkyl groups wherein the groups
optionally cyclize to adjacent groups. In some embodiments, R.sub.2
is chosen from amides, reverse amides, and ureas, wherein the
amides and reverse amides are optionally cyclized to adjacent
groups.
[0153] In some embodiments of Formula (I) above, R.sub.2 is a
carbonylheteroalkyl group, wherein the alkyl portion of the
carbonylheteroalkyl group can optionally cyclize with R, R.sub.1,
or R.sub.3. In some embodiments of Formula (Ia), R.sub.2 is an
amide or reverse amide group. In some embodiments of Formula (Ia),
R.sub.2 is preferably an amide. In some embodiments of Formula
(Ia), R.sub.2 is a reverse amide. In some embodiments of Formula
(Ia), R.sub.2 is selected from C(O)N(X) and N(X)C(O). In some
embodiments of Formula (Ia), R.sub.2 is preferably C(O)N(X). In
some embodiments of Formula (Ia), R.sub.2 is N(X)C(O).
[0154] In some embodiments of Formula (Ia), R.sub.3 is chosen from
aryl and heteroaryl rings. In some embodiments of Formula (Ia),
R.sub.3 is chosen from thiazole, indenyl, pyrazole, and phenyl
rings. In some embodiments of Formula (Ia), R.sub.3 is chosen from
cyclic and heterocyclic rings.
[0155] In some embodiments of Formula (Ia), R.sub.3 is chosen from
thiazole, indenyl, pyrazole, phenyl, benzothiazole, and oxazole
rings.
[0156] In some embodiments of Formula (Ia), R.sub.4 is chosen from
cyclic and heterocyclic rings optionally substituted with 1 or 2 R.
In some embodiments of Formula (Ia), R.sub.4 is chosen from alkyl,
heteroalkyl, and haloalkyl groups. In some embodiments of Formula
(Ia), R.sub.4 is chosen from aryl and heteroaryl rings optionally
substituted with 1 or 2 R.
[0157] In some embodiments of Formula (Ia), m is 0. In some
embodiments of Formula (Ia), m is 1. In some embodiments of Formula
(Ia), m is 2.
[0158] In some embodiments of Formula (Ia) above, R.sub.1 is a
cyclobutane optionally substituted with 1 or 2 R; R is chosen from
(C.sub.1-C.sub.6) alkyl groups, (C.sub.1-C.sub.6) haloalkyl groups,
(C.sub.1-C.sub.6) alkoxy groups, and halogens; R.sub.2 is chosen
from amides or reverse amides; R.sub.3 is chosen from
C.sub.1-C.sub.3 alkyl linkers, thiazole, phenyl, benzothiazole,
oxazole groups optionally substituted with 1 or 2 R; R.sub.4 is
chosen from cyclic rings, alkyl groups, and heteroaryl groups
optionally substituted with 1 or 2 Y; Y is chosen from
(C.sub.1-C.sub.6) alkyl groups, (C.sub.3-C.sub.6) cycloalkyl
groups.
[0159] In some embodiments of Formula (Ia) above, R.sub.1 is a
cyclobutane optionally substituted with 1 or 2 R; R is chosen from
(C.sub.1-C.sub.6) alkyl groups, (C.sub.1-C.sub.6) haloalkyl groups,
(C.sub.1-C.sub.6) alkoxy groups, and halogens: R.sub.2 is chosen
from amides and reverse amides that form spirocyclic rings with
R.sub.1; R.sub.3 is chosen from thiazole, phenyl, and oxazole
groups optionally substituted with 1 or 2 R; R.sub.4 is chosen from
cyclic rings, alkyl groups, and heteroaryl groups optionally
substituted with 1 or 2 Y; Y is chosen from (C.sub.1-C.sub.6) alkyl
groups, and (C.sub.3-C.sub.6) cycloalkyl groups.
[0160] In some embodiments of Formula (Ia) above, R.sub.1 is a
cyclobutane, R.sub.2 is chosen from carbonylalkyl and
heterocarbonylalkyl groups (e.g. amides, reverse amides, and ureas,
preferably amides), R.sub.3 is chosen from aryl and heteroaryl
rings (e.g. thiazole, indenyl, pyrazole, and phenyl rings)
preferably heteroaryl rings, and R.sub.4 is chosen from aryl and
heteroaryl rings optionally substituted with 1 or 2 R.
[0161] In some embodiments of Formula (Ia) above, R.sub.1 is a
cyclobutane, R.sub.2 is chosen from carbonylalkyl and
heterocarbonylalkyl groups (e.g. amides, reverse amides, and ureas,
preferably amides), R.sub.3 is chosen from aryl and heteroaryl
rings (e.g. thiazole, indenyl, pyrazole, and phenyl rings)
preferably heteroaryl rings, and R.sub.4 is chosen from cyclic and
heterocyclic rings optionally substituted with 1 or 2 R.
[0162] In some embodiments of Formula (Ia) above, R.sub.1 is a
cyclobutane, R.sub.2 is chosen from carbonylalkyl and
heterocarbonylalkyl groups (e.g. amides, reverse amides, and ureas,
preferably amides), R.sub.3 is chosen from aryl and heteroaryl
rings (e.g. thiazole, indenyl, pyrazole, and phenyl rings)
preferably heteroaryl rings, and R.sub.4 is chosen from alkyl,
heteroalkyl, and haloalkyl groups.
[0163] Any of the features disclosed above in the context of the
compounds of Formula (Ia) may also be applied to any of the
compounds of Formulae (I), (Ib), (Ic), (II), and (III) disclosed
herein.
Formula (Ib)
[0164] In any of the embodiments disclosed above, the compound of
Formula (I) may be a compound of Formula (Ib) as described herein
above. The compounds of Formula (Ib) correspond to compounds of
Formula (I) wherein R.sub.2 is carbonylheteroalkyl group, wherein
the alkyl portion of the carbonylheteroalkyl group can optionally
cyclize with R, R.sub.1, or R.sub.3.
[0165] In some embodiments of Formula (Ib) above, R is chosen from
halogens
[0166] In some embodiments of Formula (Ib), R.sub.1 is a 4-membered
cyclic or heterocyclic group. In some embodiments of Formula (Tb),
R.sub.1 is a cyclic group. In some embodiments of Formula (Ib),
R.sub.1 is a heterocyclic group. In some embodiments of Formula
(Ib), R.sub.1 is preferably cyclobutane.
[0167] In some embodiments of Formula (Ib), R.sub.2 is chosen from
amides, reverse amides, and ureas. In some embodiments of Formula
(Ib), R.sub.2 is chosen from heterocarbonylalkyl groups wherein the
group optionally cyclizes to adjacent groups. In some embodiments,
R.sub.2 is chosen from amides, reverse amides, and ureas, wherein
the amides and reverse amides are optionally cyclized to adjacent
groups.
[0168] In some embodiments of Formula (Ib) above, R.sub.2 is a
carbonylheteroalkyl group, wherein the alkyl portion of the
carbonylheteroalkyl group can optionally cyclize with R, R.sub.1,
or R.sub.3. In some embodiments of Formula (Tb), R.sub.2 is an
amide or reverse amide group. In some embodiments of Formula (Ib),
R.sub.2 is preferably an amide. In some embodiments of Formula
(Ib), R.sub.2 is a reverse amide. In some embodiments of Formula
(Ib), R.sub.2 is selected from C(O)N(X) and N(X)C(O). In some
embodiments of Formula (Ib), R.sub.2 is preferably C(O)N(X). In
some embodiments of Formula (Tb), R.sub.2 is N(X)C(O).
[0169] In some embodiments of Formula (Ib), R.sub.3 is chosen from
aryl and heteroaryl rings. In some embodiments of Formula (Ib),
R.sub.3 is chosen from thiazole, indenyl, pyrazole, and phenyl
rings. In some embodiments of Formula (Ib), R.sub.3 is chosen from
cyclic and heterocyclic rings.
[0170] In some embodiments of Formula (Ib), R.sub.3 is chosen from
thiazole, indenyl, pyrazole, phenyl, benzothiazole, and oxazole
rings.
[0171] In some embodiments of Formula (Ib), R.sub.4 is chosen from
cyclic and heterocyclic rings optionally substituted with 1 or 2 R.
In some embodiments of Formula (Ib), R.sub.4 is chosen from alkyl,
heteroalkyl, and haloalkyl groups. In some embodiments of Formula
(Ib), R.sub.4 is chosen from aryl and heteroaryl rings optionally
substituted with 1 or 2 R.
[0172] In some embodiments of Formula (Ib), m is 0. In some
embodiments of Formula (Ib), m is 1. In some embodiments of Formula
(Ib), m is 2.
[0173] In some embodiments of Formula (Ib) above, R.sub.1 is a
cyclobutane optionally substituted with 1 or 2 R; R is chosen from
(C.sub.1-C.sub.6) alkyl groups, (C.sub.1-C.sub.6) haloalkyl groups,
(C.sub.1-C.sub.6) alkoxy groups, and halogens; R.sub.2 is chosen
from amides or reverse amides; R.sub.3 is chosen from
C.sub.1-C.sub.3 alkyl linkers, thiazole, phenyl, benzothiazole,
oxazole groups optionally substituted with 1 or 2 R; R.sub.4 is
chosen from cyclic rings, alkyl groups, and heteroaryl groups
optionally substituted with 1 or 2 Y; Y is chosen from
(C.sub.1-C.sub.6) alkyl groups, (C.sub.3-C.sub.6) cycloalkyl
groups.
[0174] In some embodiments of Formula (Ib) above, R.sub.1 is a
cyclobutane optionally substituted with 1 or 2 R; R is chosen from
(C.sub.1-C.sub.6) alkyl groups, (C.sub.1-C.sub.6) haloalkyl groups,
(C.sub.1-C.sub.6) alkoxy groups, and halogens; R.sub.2 is chosen
from amides and reverse amides that form spirocyclic rings with
R.sub.1; R.sub.3 is chosen from thiazole, phenyl, and oxazole
groups optionally substituted with 1 or 2 R; R.sub.4 is chosen from
cyclic rings, alkyl groups, and heteroaryl groups optionally
substituted with 1 or 2 Y; Y is chosen from (C.sub.1-C.sub.6) alkyl
groups, and (C.sub.3-C.sub.6) cycloalkyl groups.
[0175] In some embodiments of Formula (Ib) above, R.sub.1 is a
cyclobutane, R.sub.2 is chosen from carbonylalkyl and
heterocarbonylalkyl groups (e.g. amides, reverse amides, and ureas,
preferably amides), R.sub.3 is chosen from aryl and heteroaryl
rings (e.g. thiazole, indenyl, pyrazole, and phenyl rings)
preferably heteroaryl rings, and R.sub.4 is chosen from aryl and
heteroaryl rings optionally substituted with 1 or 2 R.
[0176] In some embodiments of Formula (Ib) above, R.sub.1 is a
cyclobutane, R.sub.2 is chosen from carbonylalkyl and
heterocarbonylalkyl groups (e.g. amides, reverse amides, and ureas,
preferably amides), R.sub.3 is chosen from aryl and heteroaryl
rings (e.g. thiazole, indenyl, pyrazole, and phenyl rings)
preferably heteroaryl rings, and R.sub.4 is chosen from cyclic and
heterocyclic rings optionally substituted with 1 or 2 R.
[0177] In some embodiments of Formula (Ib) above, R.sub.1 is a
cyclobutane, R.sub.2 is chosen from carbonylalkyl and
heterocarbonylalkyl groups (e.g. amides, reverse amides, and ureas,
preferably amides), R.sub.3 is chosen from aryl and heteroaryl
rings (e.g. thiazole, indenyl, pyrazole, and phenyl rings)
preferably heteroaryl rings, and R.sub.4 is chosen from alkyl,
heteroalkyl, and haloalkyl groups.
[0178] Any of the features disclosed above in the context of the
compounds of Formula (Ib) may also be applied to any of the
compounds of Formulae (I), (Ia), (Ic), (II), and (Ill) disclosed
herein.
Formula (Ic)
[0179] In any of the embodiments disclosed above, the compound of
Formula (I) may be a compound of Formula (Ic) as described herein
above. The compounds of Formula (Ic) correspond to compounds of
Formula (I) wherein R.sub.1 is a 4-membered cyclic or heterocyclic
group; and R.sub.2 is carbonylheteroalkyl group, wherein the alkyl
portion of the carbonylheteroalkyl group can optionally cyclize
with R, R.sub.1, or R.sub.3.
[0180] In some embodiments of Formula (Ic) above, R is chosen from
halogens.
[0181] In some embodiments of Formula (Ic), R.sub.1 is a cyclic
group. In some embodiments of Formula (Ic), R.sub.1 is a
heterocyclic group. In some embodiments of Formula (Ic), R.sub.1 is
preferably cyclobutane.
[0182] In some embodiments of Formula (Ic), R.sub.2 is chosen from
amides, reverse amides, and ureas. In some embodiments of Formula
(Ic), R.sub.2 is chosen from heterocarbonylalkyl groups wherein the
group optionally cyclizes to adjacent groups. In some embodiments,
R.sub.2 is chosen from amides, reverse amides, and ureas, wherein
the amides and reverse amides are optionally cyclized to adjacent
groups.
[0183] In some embodiments of Formula (Ic), R.sub.2 is an amide or
reverse amide group. In some embodiments of Formula (Ic), R.sub.2
is preferably an amide. In some embodiments of Formula (Ic),
R.sub.2 is a reverse amide. In some embodiments of Formula (Ic),
R.sub.2 is selected from C(O)N(X) and N(X)C(O). In some embodiments
of Formula (Ic), R.sub.2 is preferably C(O)N(X). In some
embodiments of Formula (Ic), R.sub.2 is N(X)C(O).
[0184] In some embodiments of Formula (Ic), R.sub.3 is chosen from
aryl and heteroaryl rings. In some embodiments of Formula (Ic),
R.sub.3 is chosen from thiazole, indenyl, pyrazole, and phenyl
rings. In some embodiments of Formula (Ic), R.sub.3 is chosen from
cyclic and heterocyclic rings.
[0185] In some embodiments of Formula (Ic), R.sub.3 is chosen from
thiazole, indenyl, pyrazole, phenyl, benzothiazole, and oxazole
rings.
[0186] In some embodiments of Formula (Ic), R.sub.4 is chosen from
cyclic and heterocyclic rings optionally substituted with 1 or 2 R.
In some embodiments of Formula (Ic), R.sub.4 is chosen from alkyl,
heteroalkyl, and haloalkyl groups. In some embodiments of Formula
(Ic), R.sub.4 is chosen from aryl and heteroaryl rings optionally
substituted with 1 or 2 R.
[0187] In some embodiments of Formula (Ic), m is 0. In some
embodiments of Formula (Ic), m is 1. In some embodiments of Formula
(Ic), m is 2.
[0188] In some embodiments of Formula (Ic) above, R.sub.1 is a
cyclobutane optionally substituted with 1 or 2 R; R is chosen from
(C.sub.1-C.sub.6) alkyl groups, (C.sub.1-C.sub.6) haloalkyl groups,
(C.sub.1-C.sub.6) alkoxy groups, and halogens; R.sub.2 is chosen
from amides or reverse amides; R.sub.3 is chosen from
C.sub.1-C.sub.3 alkyl linkers, thiazole, phenyl, benzothiazole,
oxazole groups optionally substituted with 1 or 2 R; R.sub.4 is
chosen from cyclic rings, alkyl groups, and heteroaryl groups
optionally substituted with 1 or 2 Y; Y is chosen from
(C.sub.1-C.sub.6) alkyl groups, (C.sub.3-C.sub.6) cycloalkyl
groups.
[0189] In some embodiments of Formula (Ic) above, R.sub.1 is a
cyclobutane optionally substituted with 1 or 2 R; R is chosen from
(C.sub.1-C.sub.6) alkyl groups, (C.sub.1-C.sub.6) haloalkyl groups,
(C.sub.1-C.sub.6) alkoxy groups, and halogens; R.sub.2 is chosen
from amides and reverse amides that form spirocyclic rings with
R.sub.1; R.sub.3 is chosen from thiazole, phenyl, and oxazole
groups optionally substituted with 1 or 2 R; R.sub.4 is chosen from
cyclic rings, alkyl groups, and heteroaryl groups optionally
substituted with 1 or 2 Y; Y is chosen from (C.sub.1-C.sub.6) alkyl
groups, and (C.sub.3-C.sub.6) cycloalkyl groups.
[0190] In some embodiments of Formula (Ic) above, R.sub.1 is a
cyclobutane, R.sub.2 is chosen from carbonylalkyl and
heterocarbonylalkyl groups (e.g. amides, reverse amides, and ureas,
preferably amides), R.sub.3 is chosen from aryl and heteroaryl
rings (e.g. thiazole, indenyl, pyrazole, and phenyl rings)
preferably heteroaryl rings, and R.sub.4 is chosen from aryl and
heteroaryl rings optionally substituted with 1 or 2 R.
[0191] In some embodiments of Formula (Ic) above, R.sub.1 is a
cyclobutane, R.sub.2 is chosen from carbonylalkyl and
heterocarbonylalkyl groups (e.g. amides, reverse amides, and ureas,
preferably amides), R.sub.3 is chosen from aryl and heteroaryl
rings (e.g. thiazole, indenyl, pyrazole, and phenyl rings)
preferably heteroaryl rings, and R.sub.4 is chosen from cyclic and
heterocyclic rings optionally substituted with 1 or 2 R.
[0192] In some embodiments of Formula (Ic) above, R.sub.1 is a
cyclobutane, R.sub.2 is chosen from carbonylalkyl and
heterocarbonylalkyl groups (e.g. amides, reverse amides, and ureas,
preferably amides), R.sub.3 is chosen from aryl and heteroaryl
rings (e.g. thiazole, indenyl, pyrazole, and phenyl rings)
preferably heteroaryl rings, and R.sub.4 is chosen from alkyl,
heteroalkyl, and haloalkyl groups.
[0193] Any of the features disclosed above in the context of the
compounds of Formula (Ic) may also be applied to any of the
compounds of Formulae (I), (la), (Ib), (II), and (III) disclosed
herein.
[0194] Non-limiting illustrative compounds of the disclosure
include:
TABLE-US-00002 Example No. Structure Chemical Name Compound 1-1
##STR00053## trans-3-(cyanoamino)-N-[5-(oxan-4-
yl)-1,3-thiazol-2-yl]cyclobutane-1- carboxamide Compound 2-1
##STR00054## 3-(cyanoamino)-N-(5-cyclohexyl-1,3-
thiazol-2-yl)azetidine-1-carboxamide Compound 3-1 ##STR00055##
5-phenyl-N-[(trans)-3- (cyanoamino)cyclobutyl]-1,3-thiazole-
2-carboxamide Compound 4-1 ##STR00056## 5-phenyl-N-[(cis)-3-
(cyanoamino)cyclobutyl]-1,3-thiazole- 2-carboxamide Compound 5-1
##STR00057## cis-3-(cyanoamino)-N-(1-phenyl-1H-
pyrazol-4-yl)cyclobutane-1- carboxamide Compound 5-2 ##STR00058##
cis-3-(cyanoamino)-N-(1-phenyl-1H- pyrazol-3-yl)cyclobutane-1-
carboxamide Compound 5-3 ##STR00059##
cis-3-(cyanoamino)-N-(5-cyclohexyl- 1,3-thiazol-2-yl)cyclobutane-1-
carboxamide Compound 5-4 ##STR00060##
cis-3-(cyanoamino)-N-(5-phenyl-1,3- thiazol-2-yl)cyclobutane-3-
carboxamide Compound 5-5 ##STR00061##
trans-3-(cyanoamino)-N-(1-phenyl-1H- pyrazol-4-yl)cyclobutane-1-
carboxamide Compound 5-6 ##STR00062##
trans-3-(cyanoamino)-N-(1-phenyl-1H- pyrazol-3-yl)cyclobutane-1-
carboxamide Compound 5-7 ##STR00063##
trans-3-(cyanoamino)-N-(5-cyclohexyl-
1,3-thiazol-2-yl)cyclobutane-1- carboxamide Compound 5-8
##STR00064## trans-3-(cyanoamino)-N-(5-phenyl-1,3-
thiazol-2-yl)cyclobutane-1- carboxamide Compound 5-9 ##STR00065##
cis-3-(cyanoamino)-N-(2,3-dihydro- 1H-inden-5-yl)cyclobutane-1-
carboxamide Compound 5-10 ##STR00066##
cis-N-(5-tert-butyl-1,3-thiazol-2-yl)-3- (cyanoamino)cyclobutane-1-
carboxamide Compound 5-11 ##STR00067##
{[cis-3-(4-phenylpiperazine-1-
carbonyl)cyclobutyl]amino}carbonitrile Compound 5-12 ##STR00068##
trans-3-(cyanoamino)-N-(2,3-dihydro- 1H-inden-5-yl)cyclobutane-1-
carboxamide Compound 5-13 ##STR00069##
trans-N-(5-tert-butyl-1,3-thiazol-2-yl)-
3-(cyanoamino)cyclobutane-1- carboxamide Compound 5-14 ##STR00070##
trans-3-(cyanoamino)-N-[4- (morpholin-4-yl)phenyl]cyclobutane-1-
carboxamide
and pharmaceutically acceptable salts, solvates, prodrugs,
stereoisomers, and tautomers thereof.
[0195] Non-limiting illustrative compounds of the disclosure also
include:
TABLE-US-00003 Example No. Structure Chemical Name Compound 1-2
##STR00071## (1r,3r)-3-(cyanoamino)-N-(1-methyl-
3-phenyl-1H-pyrazol-5- yl)cyclobutane-1-carboxamide Compound 1-3
##STR00072## (1r,3r)-3-(cyanoamino)-N-(2- cyclohexyl-1,3-thiazol-5-
yl)cyclobutane-1-carboxamide Compound 1-4 ##STR00073##
(1r,3r)-3-(cyanoamino)-N-(2- cyclohexyl-1,3-thiazol-5-yl)-N-
methylcyclobutane-1-carboxamide Compound 1-5 ##STR00074##
(1r,3r)-N-(5-tert-butyl-1,3-thiazol-2- yl)-3-(cyanoamino)-N-
methylcyclobutane-1-carboxamide Compound 1-6 ##STR00075##
(1r,3r)-3-(cyanoamino)-N-(3- cyclohexyl-1-methyl-1H-pyrazol-5-
yl)cyclobutane-1-carboxamide Compound 1-7 ##STR00076##
(1r,3r)-3-(cyanoamino)-N-(2- cyclohexyl-4-methyl-1,3-thiazol-5-
yl)cyclobutane-1-carboxamide Compound 1-8 ##STR00077##
(1r,3r)-3-(cyanoamino)-N-{2-[2-
(propan-2-yloxy)phenyl]-1,3-thiazol- 5-yl}cyclobutane-1-carboxamide
Compound 1-9 ##STR00078## (1r,3r)-3-(cyanoamino)-N-[2-(3,3-
difluorocyclobutyl)-1,3-thiazol-5- yl]cyclobutane-1-carboxamide
Compound 1-10 ##STR00079## (1r,3r)-N-(4-chloro-5-cyclohexyl-
1,3-thiazol-2-yl)-3- (cyanoamino)cyclobutane-1- carboxamide
Compound 1-11 ##STR00080## (1r,3s)-3-(cyanoamino)-N-(2-
cyclohexyl-1,3-thiazol-5-yl)-1- methylcyclobutane-1-carboxamide
Compound 1-12 ##STR00081## (1r,3r)-3-(cyanoamino)-N-{2-[(1S)-
2,2-dimethylcyclohexyl]-1,3-thiazol- 5-yl}cyclobutane-1-carboxamide
Compound 1-13 ##STR00082## (1r,3r)-3-(cyanoamino)-N-{2-[(1R)-
2,2-dimethylcyclohexyl]-1,3-thiazol- 5-yl}cyclobutane-1-carboxamide
Compound 1-14 ##STR00083## (1r,3r)-N-(4-chloro-2-cyclohexyl-
1,3-thiazol-5-yl)-3- (cyanoamino)cyclobutane-1- carboxamide
Compound 1-15 ##STR00084## (1R,3R)-3-(cyanoamino)-N-(2-
cyclohexyl-1,3-thiazol-5-yl)-2,2- dimethylcyclobutane-1-carboxamide
Compound 1-16 ##STR00085## (1r,3r)-3-(cyanoamino)-N-[5-
cyclohexyl-4-(methoxymethyl)-1,3- thiazol-2-yl]cyclobutane-1-
carboxamide Compound 1-17 ##STR00086## (1r,3r)-3-(cyanoamino)-N-(2-
cyclohexyl-4-fluoro-1,3-thiazol-5- yl)cyclobutane-1-carboxamide
Compound 1-18 ##STR00087## (1s,3s)-N-(4-chloro-5-cyclohexyl-
1,3-thiazol-2-yl)-3- (cyanoamino)cyclobutane-1- carboxamide
Compound 1-19 ##STR00088## (1r,3r)-N-(5-tert-butyl-4-chloro-1,3-
thiazol-2-yl)-3- (cyanoamino)cyclobutane-1 carboxamide Compound
1-20 ##STR00089## (1r,3r)-N-[4-chloro-3-
(trifluoromethyl)phenyl]-3- (cyanoamino)cyclobutane-1- carboxamide
Compound 1-21 ##STR00090## (1r,3r)-3-(cyanoamino)-N-{5-
[(1S,2R)-2-methylcyclohexyl]-1,3- thiazol-2-yl}cyclobutane-1-
carboxamide Compound 1-22 ##STR00091## (1r,3r)-3-(cyanoamino)-N-{5-
[(1R,2S)-2-methylcyclohexyl]-1,3- thiazol-2-yl}cyclobutane-1-
carboxamide Compound 1-23 ##STR00092## (1r,3r)-3-(cyanoamino)-N-{5-
[(1S,2S)-2-methylcyclohexyl]-1,3- thiazol-2-yl}cyclobutane-1-
carboxamide Compound 1-24 ##STR00093## (1r,3r)-3-(cyanoamino)-N-{5-
[(1R,2R)-2-methylcyclohexyl]-1,3- thiazol-2-yl}cyclobutane-1-
carboxamide Compound 1-25 ##STR00094## (1r,3r)-3-(cyanoamino)-N-(5-
cyclohexyl-4-cyclopropyl-1,3- thiazol-2-yl)cyclobutane-1-
carboxamide Compound 1-26 ##STR00095## (1r,3r)-3-(cyanoamino)-N-[5-
cyclohexyl-4-(1-cyclopropyl-1H- pyrazol-4-yl)-1,3-thiazol-2-
yl]cyclobutane-1-carboxamide Compound 1-27 ##STR00096##
(1r,3r)-3-(cyanoamino)-N-[4- (trifluoromethyl)pyridin-2-
yl]cyclobutane-1-carboxamide Compound 1-28 ##STR00097##
(1r,3r)-3-(cyanoamino)-N-{5-[(2S}- oxan-2-yl]-1,3-thiazol-2-
yl}cyclobutane-1-carboxamide Compound 1-29 ##STR00098##
(1r,3r)-3-(cyanoamino)-N-(5- cyclohexyl-4-methyl-1,3-thiazol-2-
yl)cyclobutane-1-carboxamide Compound 1-30 ##STR00099##
(1r,3r)-3-(cyanoamino)-N-(5- cyclohexyl-1-methyl-1H-pyrazol-3-
yl)cyclobutane-1-carboxamide Compound 1-31 ##STR00100##
(1r,3r)-3-(cyanoamino)-N-[5- cyclohexyl-4-(trifluoromethyl)-1,3-
thiazol-2-yl]cyclobutane-1- carboxamide Compound 1-32 ##STR00101##
(1r,3r)-3-(cyanoamino)-N-{5- [(1S,2R)-2-
(trifluoromethyl)cyclohexyl]-1,3- thiazol-2-yl}cyclobutane-1-
carboxamide Compound 1-33 ##STR00102## (1r,3r)-3-(cyanoamino)-N-{5-
[(1R,2S)-2- (trifluoromethyl)cyclohexyl]-1,3-
thiazol-2-yl]cyclobutane-1- carboxamide Compound 1-34 ##STR00103##
(1r,3r)-3-(cyanoamino)-N-{5- [(1S,2S)-2-
(trifluoromethyl)cyclohexyl]-1,3- thiazol-2-yl}cyclobutane-1-
carboxamide Compound 1-35 ##STR00104## (1r,3r)-3-(cyanoamino)-N-{5-
[(1R,2R)-2- (trifluoromethyl)cyclohexyl]-1,3-
thiazol-2-yl}cyclobutane-1- carboxamide Compound 1-36 ##STR00105##
(1r,3r)-N-(4-chloro-5-cyclopropyl- 1,3-thiazol-2-yl)-3-
(cyanoamino)cyclobutane-1- carboxamide Compound 1-37 ##STR00106##
(1r,3r)-N-{5-[(2R)- bicyclo[2.2.2]octan-2-yl]-1,3- thiazol-2-yl}-3-
(cyanoamino)cyclobutane-1- carboxamide Compound 1-38 ##STR00107##
(1r,3r)-N-{5-[(2S)- bicyclo[2.2.2]octan-2-yl]-1,3- thiazol-2-yl}-3-
(cyanoamino)cyclobutane-1- carboxamide Compound 1-39 ##STR00108##
(1r,3r)-N-(5-chloro-1-cyclohexyl- 1H-pyrazol-3-yl)-3-
(cyanoamino)cyclobutane-1- carboxamide Compound 1-40 ##STR00109##
(1r,3r)-3-(cyanoamino)-N-[5-(3- cyanophenyl)-1,3-thiazol-2-
yl]cyclobutane-1-carboxamide Compound 1-41 ##STR00110##
(1r,3r)-N-[3-(3-chlorophenyl)-1,2- oxazol-5-yl]-3-
(cyanoamino)cyclobutane-1- carboxamide Compound 1-42 ##STR00111##
(1r,3s)-3-(cyanoamino)-N-(5- cyclohexyl-1,3-thiazol-2-yl)-1-
methylcyclobutane-1-carboxamide Compound 1-43 ##STR00112##
(1r,3r)-N-[5-(3-chlorophenyl)-1,2- oxazol-3-yl]-3-
(cyanoamino)cyclobutane-1- carboxamide Compound 1-44 ##STR00113##
(1r,3s)-N-(4-chloro-5-cyclohexyl-
1,3-thiazol-2-yl)-3-(cyanoamino)-1- methylcyclobutane-1-carboxamide
Compound 1-45 ##STR00114## (1r,3r)-N-[3-(3-chlorophenyl)-1,2-
oxazol-5-yl]-3-(cyanoamino)-N- methylcyclobutane-1-carboxamide
Compound 1-46 ##STR00115## (1r,3s)-3-(cyanoamino)-N-(2-
cyclohexyl-1,3-thiazol-5-yl)-1- ethylcyclobutane-1-carboxamide
Compound 1-47 ##STR00116## (1s,3s)-N-(4-chloro-5-cyclohexyl-
1,3-thiazol-2-yl)-3-(cyanoamino)-1- fluorocyclobutane-1-carboxamide
Compound 1-48 ##STR00117## (1r,3r)-N-(4-chloro-5-cyclohexyl-
1,3-thiazol-2-yl)-3-(cyanoamino)-1- fluorocyclobutane-1-carboxamide
Compound 1-49 ##STR00118## (1r,3r)-N-(4-chloro-5-cyclohexyl-
1,3-thiazol-2-yl)-3-(cyanoamino)-N- methylcyclobutane-1-carboxamide
Compound 1-50 ##STR00119## (1r,3r)-N-(5-tert-butyl-4-chloro-1,3-
thiazol-2-yl)-3-(cyanoamino)-N- methylcyclobutane-1-carboxamide
Compound 1-51 ##STR00120## (1r,3r)-3-(cyanoamino)-N-[3-(3-
cyanophenyl)-1,2-oxazol-5- yl]cyclobutane-1-carboxamide Compound
1-52 ##STR00121## (1r,3r)-N-[5-(3-chlorophenyl)-1,2-
oxazol-3-yl]-3-(cyanoamino)-N- methylcyclobutane-1-carboxamide
Compound 1-53 ##STR00122## (1r,3r)-3-(cyanoamino)-N-(5-
cyclohexyl-1,3-oxazol-2- yl)cyclobutane-1-carboxamide Compound 1-54
##STR00123## (1r,3r)-N-(5-tert-butyl-4-chloro-1,3-
thiazol-2-yl)-3-(cyanoamino)-1- fluoro-N-methylcyclobutane-1-
carboxamide Compound 1-55 ##STR00124##
(1r,3r)-N-(4-chloro-5-cyclohexyl-
1,3-thiazol-2-yl)-3-(cyanoamino)-1- fluoro-N-methylcyclobutane-1-
carboxamide Compound 1-56 ##STR00125##
(1s,3s)-3-(cyanoamino)-1-fluoro-N-
{3-[4-(trifluoromethyl)phenyl]-1H- pyrazol-5-yl}cyclobutane-1-
carboxamide Compound 1-57 ##STR00126##
(1r,3r)-3-(cyanoamino)-1-fluoro-N-
{3-[4-(trifluoromethyl)phenyl]-1H- pyrazol-5-yl}cyclobutane-1-
carboxamide Compound 1-58 ##STR00127##
(1s,3s)-N-(4-chloro-5-cyclohexyl-
1,3-thiazol-2-yl)-3-(cyanoamino)-1- fluoro-N-methylcyclobutane-1-
carboxamide Compound 1-59 ##STR00128##
(1s,3s)-N-(5-tert-butyl-4-chloro-1,3-
thiazol-2-yl)-3-(cyanoamino)-1- fluorocyclobutane-1-carboxamide
Compound 1-60 ##STR00129## (1r,3r)-N-(5-tert-butyl-4-chloro-1,3-
thiazol-2-yl)-3-(cyanoamino)-1- fluorocyclobutane-1-carboxamide
Compound 1-61 ##STR00130## (1r,3r)-3-(cyanoamino)-N-[3-(2-
fluorophenyl)-5- methylphenyl]cyclobutane-1- carboxamide Compound
1-62 ##STR00131## (1r,3r)-N-(3-chloro-5- cyclohexylphenyl)-3-
(cyanoamino)cyclobutane-1- carboxamide Compound 1-63 ##STR00132##
(1r,3r)-3-(cyanoamino)-N-[4-fluoro- 3-(piperidin-1-
yl)phenyl]cyclobutane-1- carboxamide Compound 1-64 ##STR00133##
(1r,3r)-3-(cyanoamino)-N-(7- cyclobutoxy-1,3-benzothiazol-2-
yl)cyclobutane-1-carboxamide Compound 1-65 ##STR00134##
(1r,3r)-3-(cyanoamino)-N-(7- cyclobutoxy-1,3-benzothiazol-2-yl)-
1-fluorocyclobutane-1-carboxamide Compound 1-66 ##STR00135##
(1s,3s)-3-(cyanoamino)-N-(7- cyclobutoxy-1,3-benzothiazol-2-yl)-
1-fluorocyclobutane-1-carboxamide Compound 1-67 ##STR00136##
(1r,3r)-3-(cyanoamino)-N- {[(1R,2R,5R)-6,6-
dimethylbicyclo[3.1.1]heptan-2- yl]methyl}cyclobutane-1-
carboxamide Compound 1-68 ##STR00137##
(1r,3r)-N-[4-(4-chlorophenyl)-1,3- thiazol-2-yl]-3-
(cyanoamino)cyclobutane-1- carboxamide Compound 1-69 ##STR00138##
(1r,3r)-3-(cyanoamino)-N-(3- phenylphenyl)cyclobutane-1-
carboxamide Compound 1-70 ##STR00139##
(1r,3r)-3-(cyanoamino)-N-{[4- (propan-2-
yl]phenyl]methyl}cyclobutane-1- carboxamide Compound 1-71
##STR00140## (1r,3r)-3-(cyanoamino)-N-[(1s,4s)-4-
tert-butylcyclohexyl]cyclobutane-1- carboxamide Compound 1-72
##STR00141## (1r,3r)-3-(cyanoamino)-N- {[(1R,2R,5R)-6,6-
dimethylbicyclo[3.1.1]heptan-2- yl]methyl}cyclobutane-1-
carboxamide Compound 1-73 ##STR00142## (1r,3r)-3-(cyanoamino)-N-[3-
(trifluoromethyl)phenyl]cyclobutane- 1-carboxamide Compound 3-2
##STR00143## {[1-(2-phenyl-1,3-thiazole-5-
carbonyl)-1-azaspiro[3.3]heptan-6- yl]amino}carbonitrile Compound
3-3 ##STR00144## 3-[4-(1-methyl-1H-pyrazol-4-
yl)phenyl]-N-[(1s,3s)-3- (cyanoamino)cyclobutyl]-1,2-
oxazole-5-carboxamide Compound 3-4 ##STR00145##
{[(2r,4s)-5-{3-[4-(1-methyl-1H- prazol-4-yl)phenyl]-1,2-oxazole-5-
carbonyl}-5-azaspiro[3.4]octan-2- yl]amino}carbonitrile Compound
3-5 ##STR00146## {[(4r,6s)-1-{3-[4-(1-methyl-1H-
pyrazol-4-yl)phenyl]-1,2-oxazole-5-
carbonyl}-1-azaspiro[3.3]heptan-6- yl]amino}carbonitrile Compound
3-6 ##STR00147## 3-(3-cyanophenyl)-N-methyl-N-
[(1r,3r)-3-(cyanoamino)cyclobutyl]- 1,2-oxazole-5-carboxamide
Compound 6-1 ##STR00148## {[(1r,3r)-3-[(4S)-4-[(5-cyclohexyl-
1,3-thiazol-2-yl)amino]-2- oxopyrrolidin-1-
yl]cyclobutyl]amino}carbonitrile Compound 7-1 ##STR00149##
{[(2r,4s)-6-(5-tert-butyl-4-chloro- 1,3-thiazol-2-yl)-5-oxo-6-
azaspiro[3.4]octan-2- yl]amino}carbonitrile Compound 7-2
##STR00150## {[(2s,4r)-6-(4-chloro-5-cyclohexyl-
1,3-thiazol-2-yl)-5-oxo-6- azaspiro[3.4]octan-2-
yl]amino}carbonitrile Compound 7-3 ##STR00151##
{[(2r,4s)-6-(4-chloro-5-cyclohexyl- 1,3-thiazol-2-yl)-5-oxo-6-
azaspiro[3.4]octan-2- yl]amino}carbonitrile Compound 8-1
##STR00152## (1r,3r)-N-(5-tert-butyl-4-chloro-1,3-
thiazol-2-yl)-3-(cyanoamino)-1- methoxycyclobutane-1-carboxamide
Compound 9-1 ##STR00153## (1s,3s)-N-(5-tert-butyl-4-chloro-1,3-
thiazol-2-yl)-1-chloro-3- (cyanoamino)cyclobutane-1- carboxamide
Compound 9-2 ##STR00154## (1r,3r)-N-(5-tert-butyl-4-chloro-1,3-
thiazol-2-yl)-1-chloro-3- (cyanoamino)cyclobutane-1-
carboxamide
and pharmaceutically acceptable salts, solvates, prodrugs,
stereoisomers, and tautomers thereof.
Formula II
[0196] The disclosure also provides compounds of Formula II:
##STR00155##
wherein A, R.sub.a, R.sub.b, R.sub.c, R.sub.d, R.sub.e, R.sub.f, R,
R.sub.2, R.sub.3, R.sub.4, R.sub.5, X, Y, and m are as described
herein above.
[0197] The disclosure provides compounds of Formula (II), wherein
preferably A is CR.sub.b.
[0198] The disclosure provides compounds of Formula (II), wherein
R.sub.a is hydrogen.
[0199] The disclosure provides compounds of Formula (H), wherein
R.sub.b is selected from hydrogen, halogen, (C.sub.1-C.sub.6) alkyl
groups optionally substituted with one or more R.sub.5, and
(C.sub.1-C.sub.6) alkoxy groups optionally substituted with one or
more R.sub.5.
[0200] The disclosure provides compounds of formula (II), wherein
both R.sub.a and R.sub.b are each hydrogen.
[0201] The disclosure provides compounds of Formula (II), wherein
each of R.sub.c, R.sub.d, R.sub.e, and R.sub.f is independently
selected from the group consisting of hydrogen and
(C.sub.1-C.sub.6) alkyl groups optionally substituted with one or
more R.sub.5. In some embodiments of Formula (II), each of R.sub.c,
R.sub.d, R.sub.e, and R.sub.f in the compounds of Formula (II) is
hydrogen.
[0202] The disclosure provides compounds of Formula (II) wherein
R.sub.2 is selected from amides and reverse amides. The disclosure
provides compounds of Formula (II) wherein R.sub.2 is an amide. The
disclosure provides compounds of Formula (II) wherein R.sub.2 is a
reverse amide. The disclosure provides compounds of Formula (II)
wherein R.sub.2 is selected from C(O)N(X) and N(X)C(O). The
disclosure provides compounds of Formula (II), wherein R.sub.2 is
preferably C(O)N(X). The disclosure provides compounds of Formula
(II), wherein R.sub.2 is N(X)C(O).
[0203] In a preferred embodiment of Formula (II), A is CR.sub.b and
R.sub.2 is selected from amides and reverse amides. In one
embodiment A is CR.sub.b and R.sub.2 is a reverse amide. More
preferably, A is CR.sub.b and R.sub.2 is an amide.
[0204] In a preferred embodiment of Formula (II), A is CR.sub.b and
R.sub.2 is selected from C(O)N(X) and N(X)C(O). In one embodiment A
is CR.sub.b and R.sub.2 is N(X)C(O). More preferably, A is CR.sub.b
and R.sub.2 is C(O)N(X).
[0205] The disclosure provides compounds of Formula (II), wherein X
is selected from hydrogen and alkyl groups. In some embodiments of
Formula (II) X is H.
[0206] The disclosure provides compounds of Formula (II), wherein X
is selected from alkyl groups and heteroalkyl groups, and the alkyl
and heteroalkyl groups cyclize with R.sub.b or R.sub.3.
[0207] The disclosure provides compounds of Formula (II) wherein
R.sub.3 is selected from the group consisting of aryl having 1 to 3
aromatic rings (including aryl groups optionally substituted with 1
or 2 R groups) and heteroaryl having 1 to 3 aromatic rings
(including heteroaryl groups optionally substituted with 1 or 2 R
groups). In some embodiments of Formula (II) R.sub.3 is a
heteroaryl group having 1 to 3 aromatic rings (including heteroaryl
groups optionally substituted with 1 or 2 R groups). In some
embodiments of Formula (II), R.sub.3 is a heteroaryl group having 1
aromatic ring optionally substituted with 1 or 2 R groups. In some
embodiments of Formula (II) R.sub.3 is a heteroaryl group having 1
aromatic ring optionally substituted with 1 or 2 R groups wherein
the aromatic ring features two heteroatoms, preferably one nitrogen
and one sulphur atom. In some embodiments of Formula (II) R.sub.3
is a heteroaryl group having 1 aromatic ring optionally substituted
with 1 or 2 R groups wherein the aromatic ring is a 5 membered ring
featuring one nitrogen and one sulphur atom, preferably a thiazole
ring. In some embodiments of Formula (II) R.sub.3 is chosen from
thiazole, indenyl, pyrazole, phenyl, benzothiazole, and oxazole
rings.
[0208] The disclosure provides compounds of Formula (II), wherein
R.sub.4 is a cyclic group, e.g. a cycloalkyl group optionally
substituted with 1 or 2 Y groups. The disclosure provides compounds
of Formula (II), wherein R.sub.4 is an aryl group optionally
substituted with 1 or 2 Y groups. The disclosure provides compounds
of Formula (II), wherein R.sub.4 is a cyclohexyl group or phenyl
group. The disclosure provides compounds of Formula (II) wherein
R.sub.4 is a cyclohexyl group. The disclosure provides compounds of
Formula (II), wherein R.sub.4 is a phenyl group.
[0209] The disclosure provides compounds of Formula (II) wherein, A
is CR.sub.b, R.sub.b is selected from hydrogen and
(C.sub.1-C.sub.6)alkyl groups, each of R.sub.a, R.sub.c, R.sub.d,
R.sub.e, and R.sub.f is hydrogen, R.sub.2 is C(O)N(X), X is
selected from hydrogen and alkyl groups, and R.sub.3 is a
heteroaryl group having 1 aromatic ring optionally substituted with
1 or 2 R groups wherein the aromatic ring features one nitrogen and
one sulphur atom; and R.sub.4 is a cyclic group or aryl group
optionally substituted with 1 or 2 Y groups.
[0210] The disclosure provides compounds of Formula (II) wherein, A
is CR.sub.b, R.sub.b is selected from hydrogen and
(C.sub.1-C.sub.6)alkyl groups, each of R.sub.a, R.sub.c, R.sub.d,
R.sub.e, and R.sub.f is hydrogen, R.sub.2 is C(O)N(X), X is
selected from hydrogen and alkyl groups, and R.sub.3 is a thiazole
ring optionally substituted with 1 or 2 R groups; and R.sub.4 is a
6-membered cyclic group or aryl group optionally substituted with 1
or 2 Y groups.
[0211] Any of the features disclosed above in the context of the
compounds of Formula (II) may also be applied to any of the
compounds of Formulae (I), (Ia), (Ib), (Ic), and (III) disclosed
herein.
Formula III
[0212] The disclosure also provides compounds of Formula (III):
##STR00156##
wherein R.sub.a, R.sub.b, R.sub.c, R.sub.d, R.sub.e, R.sub.f, R,
R.sub.3, R.sub.4, R.sub.5, X, Y, and m are as described herein
above.
[0213] The disclosure provides compounds of Formula (III), wherein
R.sub.a is hydrogen.
[0214] The disclosure provides compounds of Formula (III), wherein
R.sub.b is selected from hydrogen, halogen, (C.sub.1-C.sub.6) alkyl
groups optionally substituted with one or more R.sub.5, and
(C.sub.1-C.sub.6) alkoxy groups optionally substituted with one or
more R.sub.5.
[0215] The disclosure provides compounds of formula (III), wherein
both R.sub.a and R.sub.b are each hydrogen.
[0216] The disclosure provides compounds of Formula (III), wherein
each of R.sub.c, R.sub.d, R.sub.e, and R.sub.f is independently
selected from the group consisting of hydrogen and
(C.sub.1-C.sub.6) alkyl groups optionally substituted with one or
more R.sub.5. In some embodiments of the disclosure, each of
R.sub.c, R.sub.d, R.sub.e, and R.sub.f in the compounds of Formula
(III) is hydrogen.
[0217] The disclosure provides compounds of Formula (III), wherein
X is selected from hydrogen and alkyl groups. In some embodiments
of the compounds of Formula (III) X is H.
[0218] The disclosure provides compounds of Formula (III), wherein
X is selected from alkyl groups and heteroalkyl groups, and the
alkyl and heteroalkyl groups cyclize with R.sub.b or R.sub.3.
[0219] The disclosure provides compounds of Formula (III) wherein
R.sub.3 is selected from the group consisting of aryl having 1 to 3
aromatic rings (including aryl groups optionally substituted with 1
or 2 R groups) and heteroaryl having 1 to 3 aromatic rings
(including heteroaryl groups optionally substituted with 1 or 2 R
groups). In some embodiments of the disclosure R.sub.3 in the
compounds of Formula (III) is a heteroaryl group having 1 to 3
aromatic rings (including heteroaryl groups optionally substituted
with 1 or 2 R groups). In some embodiments, R.sub.3 is a heteroaryl
group having 1 aromatic ring optionally substituted with 1 or 2 R
groups. In some embodiments R.sub.3 is a heteroaryl group having 1
aromatic ring optionally substituted with 1 or 2 R groups wherein
the aromatic ring features two heteroatoms, preferably one nitrogen
and one sulphur atom. In some embodiments R.sub.3 is a heteroaryl
group having 1 aromatic ring optionally substituted with 1 or 2 R
groups wherein the aromatic ring is a 5 membered ring featuring one
nitrogen and one sulphur atom, preferably a thiazole ring. In some
embodiments of Formula (III) R.sub.3 is chosen from thiazole,
indenyl, pyrazole, phenyl, benzothiazole, and oxazole rings.
[0220] The disclosure provides compounds of Formula (III), wherein
R.sub.4 is a cyclic group, e.g. a cycloalkyl group optionally
substituted with 1 or 2 Y groups. The disclosure provides compounds
of Formula (III), wherein R.sub.4 is an aryl group optionally
substituted with 1 or 2 Y groups. The disclosure provides compounds
of Formula (III), wherein R.sub.4 is a cyclohexyl group or phenyl
group. The disclosure provides compounds of Formula (III) wherein
R.sub.4 is a cyclohexyl group.
[0221] The disclosure provides compounds of Formula (III) wherein,
R.sub.b is selected from hydrogen and (C.sub.1-C.sub.6)alkyl
groups, each of R.sub.a, R.sub.c, R.sub.d, R.sub.e, and R.sub.f is
hydrogen, X is selected from hydrogen and alkyl groups, and R.sub.3
is a heteroaryl group having 1 aromatic ring optionally substituted
with 1 or 2 R groups wherein the aromatic ring features one
nitrogen and one sulphur atom; and R.sub.4 is a cyclic group or
aryl group optionally substituted with 1 or 2 Y groups.
[0222] The disclosure provides compounds of Formula (III) wherein,
R.sub.b is selected from hydrogen and (C.sub.1-C.sub.6)alkyl
groups, each of R.sub.a, R.sub.c, R.sub.d, R.sub.e, and R.sub.f is
hydrogen, X is selected from hydrogen and alkyl groups, and R.sub.3
is a thiazole Ting optionally substituted with 1 or 2 R groups; and
R.sub.4 is a 6-membered cyclic group or aryl group optionally
substituted with 1 or 2 Y groups.
[0223] Any of the features disclosed above in the context of the
compounds of Formula (III) may also be applied to any of the
compounds of Formulae (I), (Ia), (Ib), (Ic), and (II) disclosed
herein.
[0224] In this disclosure, statements relating to compounds of
Formula (I) may also be applied to any of the compounds of Formula
(Ia), (Ib), (Ic), (II), and (III).
[0225] In another embodiment of the disclosure, the compounds of
Formula (I) are enantiomers. In some embodiments the compounds are
the (S)-enantiomer. In other embodiments the compounds are the
(R)-enantiomer. In yet other embodiments, the compounds of Formula
(I) may be (+) or (-) enantiomers.
[0226] It should be understood that all isomeric forms are included
within the present disclosure, including mixtures thereof. If the
compound contains a double bond, the substituent may be in the E or
Z configuration. If the compound contains a disubstituted
cycloalkyl, the cycloalkyl substituent may have a cis- or trans
configuration. All tautomeric forms are also intended to be
included.
[0227] Compounds of the disclosure, and pharmaceutically acceptable
salts, hydrates, solvates, stereoisomers and prodrugs thereof may
exist in their tautomeric form (for example, as an amide or imino
ether). All such tautomeric forms are contemplated herein as part
of the present disclosure.
[0228] The compounds of the disclosure may contain asymmetric or
chiral centers, and, therefore, exist in different stereoisomeric
forms. It is intended that all stereoisomeric forms of the
compounds of the disclosure as well as mixtures thereof, including
racemic mixtures, form part of the present disclosure. In addition,
the present disclosure embraces all geometric and positional
isomers. For example, if a compound of the disclosure incorporates
a double bond or a fused ring, both the cis- and trans-forms, as
well as mixtures, are embraced within the scope of the disclosure.
Each compound herein disclosed includes all the enantiomers that
conform to the general structure of the compound. The compounds may
be in a racemic or enantiomerically pure form, or any other form in
terms of stereochemistry. The assay results may reflect the data
collected for the racemic form, the enantiomerically pure form, or
any other form in terms of stereochemistry.
[0229] Diastereomeric mixtures can be separated into their
individual diastereomers on the basis of their physical chemical
differences by methods well known to those skilled in the art, such
as, for example, by chromatography and/or fractional
crystallization. Enantiomers can be separated by converting the
enantiomeric mixture into a diastereomeric mixture by reaction with
an appropriate optically active compound (e.g., chiral auxiliary
such as a chiral alcohol or Mosher's acid chloride), separating the
diastereomers and converting (e.g., hydrolyzing) the individual
diastereomers to the corresponding pure enantiomers. Also, some of
the compounds of the disclosure may be atropisomers (e.g.,
substituted biaryls) and are considered as part of this disclosure.
Enantiomers can also be separated by use of a chiral HPLC
column.
[0230] It is also possible that the compounds of the disclosure may
exist in different tautomeric forms, and all such forms are
embraced within the scope of the disclosure. Also, for example, all
keto-enol and imine-enamine forms of the compounds are included in
the disclosure.
[0231] All stereoisomers (for example, geometric isomers, optical
isomers and the like) of the present compounds (including those of
the salts, solvates, esters and prodrugs of the compounds as well
as the salts, solvates and esters of the prodrugs), such as those
which may exist due to asymmetric carbons on various substituents,
including enantiomeric forms (which may exist even in the absence
of asymmetric carbons), rotameric forms, atropisomers, and
diastereomeric forms, are contemplated within the scope of this
disclosure, as are positional isomers (such as, for example,
4-pyridyl and 3-pyridyl). (For example, if a compound of Formula
(I) incorporates a double bond or a fused ring, both the cis- and
trans-forms, as well as mixtures, are embraced within the scope of
the disclosure. Also, for example, all keto-enol and imine-enamine
forms of the compounds are included in the disclosure.) Individual
stereoisomers of the compounds of the disclosure may, for example,
be substantially free of other isomers, or may be admixed, for
example, as racemates or with all other, or other selected,
stereoisomers. The chiral centers of the present disclosure can
have the S or R configuration as defined by the IUPAC 1974
Recommendations. The use of the terms "salt", "solvate", "ester,"
"prodrug" and the like, is intended to equally apply to the salt,
solvate, ester and prodrug of enantiomers, stereoisomers, rotamers,
tautomers, positional isomers, racemates or prodrugs of the
compounds disclosed herein.
[0232] The compounds disclosed herein may form salts which are also
within the scope of this disclosure.
[0233] The present disclosure relates to compounds which can be
inhibitors of USP30.
[0234] The disclosure provides compounds having a USP30 IC.sub.50
(.mu.M) of 1 .mu.M or less. Non-limiting examples of compounds of
the disclosure having a USP30 IC.sub.50 (.mu.M) of 1 .mu.M or less
include those exemplified in tables A1 to A3 below having an
activity reported as "+++" or "++++".
[0235] The disclosure provides compounds having a USP30 IC.sub.50
(.mu.M) of less than 0.5 .mu.M.
[0236] The disclosure also provides compounds having a USP30
IC.sub.50 (.mu.M) of less than 0.1 .mu.M. Non-limiting examples of
compounds of the disclosure having a USP30 IC.sub.50 (.mu.M) of 1
.mu.M or less include those exemplified in tables A1 to A3 below
having an activity reported as "++++".
[0237] The present disclosure is directed to chemical entities
chosen from compounds as described herein and pharmaceutically
acceptable salts, solvates, prodrugs, stereoisomers, and tautomers
thereof, and pharmaceutical compositions comprising at least one
chemical entity chosen from compounds as described herein, and
pharmaceutically acceptable salts, solvates, prodrugs,
stereoisomers, and tautomers thereof.
[0238] In some embodiments of the methods described herein,
neurodegenerative disease is chosen from Alzheimer's disease and
other dementias, Parkinson's disease and other synucleinopathies
such as Multiple System Atrophy, dementia with Lewy Bodies and
PD-related disorders, Prion disease, Corticobasal Degeneration,
Frontotemporal Dementia, Posterior Cortical Atrophy, Primary
Progressive Aphasia, Progressive Supranuclear Palsy, Pick's
disease, Chronic Traumatic Encephelopathy, Dementia Pugilistica,
Traumatic Brain Injury, Vascular Dementia, Peripheral Neuropathy
and Multiple Sclerosis.
[0239] Another aspect of the disclosure is directed to
pharmaceutical compositions comprising a chemical entity chosen
from compounds of Formula (I), and pharmaceutically acceptable
salts, solvates, prodrugs, stereoisomers, and tautomers thereof and
a pharmaceutically acceptable carrier. The pharmaceutical
acceptable carrier may further include an excipient, diluent, or
surfactant.
[0240] The disclosed compounds of the disclosure can be
administered in effective amounts to treat or prevent a disorder
and/or prevent the development thereof in subjects.
[0241] Administration of the disclosed compounds can be
accomplished via any mode of administration for therapeutic agents.
These modes include systemic or local administration such as oral,
nasal, parenteral, transdermal, subcutaneous, vaginal, buccal,
rectal or topical administration modes.
[0242] Depending on the intended mode of administration, the
disclosed compositions can be in solid, semi-solid or liquid dosage
form, such as, for example, injectables, tablets, suppositories,
pills, time-release capsules, elixirs, tinctures, emulsions,
syrups, powders, liquids, suspensions, or the like, sometimes in
unit dosages and consistent with conventional pharmaceutical
practices. Likewise, they can also be administered in intravenous
(both bolus and infusion), intraperitoneal, subcutaneous or
intramuscular form, and all using forms well known to those skilled
in the pharmaceutical arts.
[0243] The present disclosure also relates to a pharmaceutical
composition comprising a compound disclosed herein and a
pharmaceutically acceptable carrier. The pharmaceutical acceptable
carrier may further include an excipient, diluent, additive, or
surfactant. The compounds or pharmaceutical compositions of the
disclosure may be administered via any mode of administration for
therapeutic agents. These modes include systemic or local
administration such as oral administration. Depending on the
intended mode of administration, the disclosed compounds or
compositions can be in solid dosage form, such as, for example,
tablets, or pills or the like, sometimes in unit dosages and
consistent with conventional pharmaceutical practices. Likewise,
they can also be administered using forms well known to those
skilled in the pharmaceutical arts.
[0244] The compounds of the disclosure can be administered in
effective amounts to treat or prevent a disorder and/or prevent the
development thereof in subjects.
[0245] In one embodiment, the present disclosure relates to a
method of preparing a pharmaceutical composition of the present
disclosure by mixing at least one pharmaceutically acceptable
compound of the present disclosure, and, optionally, one or more
pharmaceutically acceptable carriers, additives, or excipients.
Pharmaceutical compositions comprising a compound of the disclosure
can be prepared according to conventional mixing, granulating or
coating methods, respectively, and the present pharmaceutical
compositions can contain from about 0.1% to about 99%, from about
5% to about 90%, or from about 1% to about 20% of the disclosed
compound by weight or volume. The dosage forms of the present
disclosure, may contain a mixture of one or more compounds of this
disclosure, and may include additional materials known to those
skilled in the art as pharmaceutical excipients. Stabilizing
additives may be incorporated into the delivery agent solution.
With some drugs, the presence of such additives promotes the
stability and dispersibility of the agent in solution. The
stabilizing additives may be employed at a concentration ranging
from about 0.1 and 5% (W/V), preferably about 0.5% (W/V). Suitable,
but non-limiting, examples of stabilizing additives include gum
acacia, gelatin, methyl cellulose, polyethylene glycol, carboxylic
acids and salts thereof, and polylysine. In one embodiment, the
stabilizing additives are gum acacia, gelatin and methyl
cellulose.
[0246] The compounds of the disclosure provided herein are
preferably administered in a therapeutically effective amount
(e.g., an amount having a suitable favorable therapeutic index).
The amount and frequency of administration of the compounds of the
disclosure and/or the pharmaceutically acceptable salts thereof
will be regulated according to the judgment of the attending
clinician considering such factors as age, condition and size of
the patient as well as severity of the symptoms medical condition
being treated. The dosage regimen utilizing the disclosed compound
is selected in accordance with a variety of factors including type,
species, age, weight, sex and medical condition of the patient; the
severity of the condition to be treated; the route of
administration: the renal or hepatic function of the patient; and
the particular disclosed compound employed. A physician or
veterinarian of ordinary skill in the art can readily determine and
prescribe the effective amount of the drug required to prevent,
counter or arrest the progress of the condition.
[0247] The actual dosage employed may be varied depending upon the
requirements of the patient and the severity of the condition being
treated. Determination of the proper dosage regimen for a
particular situation is within the skill of the art. For
convenience, the total daily dosage may be divided and administered
in portions during the day as required.
[0248] Illustrative pharmaceutical compositions are tablets and
gelatin capsules comprising a Compound of the Disclosure and a
pharmaceutically acceptable carrier, such as a) a diluent, e.g.,
purified water, triglyceride oils, such as hydrogenated or
partially hydrogenated vegetable oil, or mixtures thereof, corn
oil, olive oil, sunflower oil, safflower oil, fish oils, such as
EPA or DHA, or their esters or triglycerides or mixtures thereof,
omega-3 fatty acids or derivatives thereof, lactose, dextrose,
sucrose, mannitol, sorbitol, cellulose, sodium, saccharin, glucose
and/or glycine; b) a lubricant, e.g., silica, talcum, stearic acid,
its magnesium or calcium salt, sodium oleate, sodium stearate,
magnesium stearate, sodium benzoate, sodium acetate, sodium
chloride and/or polyethylene glycol; for tablets also; c) a binder,
e.g., magnesium aluminum silicate, starch paste, gelatin,
tragacanth, methylcellulose, sodium carboxymethylcellulose,
magnesium carbonate, natural sugars such as glucose or
beta-lactose, corn sweeteners, natural and synthetic gums such as
acacia, tragacanth or sodium alginate, waxes and/or
polyvinylpyrrolidone, if desired; d) a disintegrant, e.g.,
starches, agar, methyl cellulose, bentonite, xanthan gum, algic
acid or its sodium salt, or effervescent mixtures; e) absorbent,
colorant, flavorant and sweetener; f) an emulsifier or dispersing
agent, such as Tween 80, Labrasol, HPMC, DOSS, caproyl 909,
labrafac, labrafil, peceol, transcutol, capmul MCM, capmul PG-12,
captex 355, gelucire, vitamin E TGPS or other acceptable
emulsifier; and/or g) an agent that enhances absorption of the
compound such as cyclodextrin, hydroxypropyl-cyclodextrin, PEG400,
PEG200.
[0249] Another aspect of the disclosure is directed to
pharmaceutical compositions comprising a chemical entity chosen
from compounds of Formula (I), and pharmaceutically acceptable
salts, solvates, prodrugs, stereoisomers, and tautomers thereof and
a pharmaceutically acceptable carrier. The pharmaceutical
acceptable carrier may further include an excipient, diluent, or
surfactant.
[0250] Compositions can be prepared according to conventional
mixing, granulating or coating methods, respectively, and the
present pharmaceutical compositions can contain from about 0.1% to
about 99%, from about 5% to about 90%, or from about 1% to about
20% of the disclosed compound by weight or volume.
[0251] The dosage regimen utilizing the disclosed compound is
selected in accordance with a variety of factors including type,
species, age, weight, sex and medical condition of the patient; the
severity of the condition to be treated; the route of
administration; the renal or hepatic function of the patient; and
the particular disclosed compound employed. A physician or
veterinarian of ordinary skill in the art can readily determine and
prescribe the effective amount of the drug required to prevent,
counter or arrest the progress of the condition.
[0252] Effective dosage amounts of the disclosed compounds, when
used for the indicated effects, range from about 0.5 mg to about
5000 mg of the disclosed compound as needed to treat the condition.
Compositions for in vivo or in vitro use can contain about 0.5, 5,
20, 50, 75, 100, 150, 250, 500, 750, 1000, 1250, 2500, 3500, or
5000 mg of the disclosed chemical entity, or, in a range of from
one amount to another amount in the list of doses. In one
embodiment, the compositions are in the form of a tablet that can
be scored.
Method of Synthesizing the Compounds
[0253] The compounds of the present disclosure may be made by a
variety of methods, including standard chemistry. Suitable
synthetic routes are depicted in the Schemes given below.
[0254] The compounds disclosed herein may be prepared by methods
known in the art of organic synthesis as set forth in part by the
following synthetic schemes. In the schemes described below, it is
well understood that protecting groups for sensitive or reactive
groups are employed where necessary in accordance with general
principles or chemistry. Protecting groups are manipulated
according to standard methods of organic synthesis (T. W. Greene
and P. G. M. Wuts, "Protective Groups in Organic Synthesis", Third
edition, Wiley, New York 1999). These groups are removed at a
convenient stage of the compound synthesis using methods that are
readily apparent to those skilled in the art. The selection
processes, as well as the reaction conditions and order of their
execution, shall be consistent with the preparation of compounds of
Formula (I).
[0255] Those skilled in the art will recognize if a stereocenter
exists in the compounds of Formula (I). Accordingly, the present
disclosure includes both possible stereoisomers (unless specified
in the synthesis) and includes not only racemic compounds but the
individual enantiomers and/or diastereomers as well. When a
compound is desired as a single enantiomer or diastereomer, it may
be obtained by stereospecific synthesis or by resolution of the
final product or any convenient intermediate. Resolution of the
final product, an intermediate, or a starting material may be
affected by any suitable method known in the art. See, for example,
"Stereochemistry of Organic Compounds" by E. L. Eliel, S. H. Wilen,
and L. N. Mander (Wiley-Interscience, 1994).
[0256] The compounds described herein may be made from commercially
available starting materials or synthesized using known organic,
inorganic, and/or enzymatic processes.
Preparation of Compounds
[0257] The compounds of the present disclosure can be prepared in a
number of ways known to those skilled in the art of organic
synthesis. By way of example, compounds of the present disclosure
can be synthesized using the methods described below, together with
synthetic methods known in the art of synthetic organic chemistry,
or variations thereof as appreciated by those skilled in the art.
Preferred methods include but are not limited to those methods
described below. General procedures to prepare compounds of the
instant invention are described in General Schemes 1 and 2.
##STR00157##
[0258] General Procedure: A Boc-protected amino acid can be coupled
to an amine (i.e., Z--NH.sub.2) using a standard coupling reagent
(i.e., HATU) and base (i.e., DIEA) in a suitable solvent (i.e.,
DMF). The Boc group can then be removed using either TFA or HCl in
a suitable solvent (i.e., DCM) to yield the corresponding crude
amine salt. Finally, the crude amine salt can be reacted with
cyanogen bromide in an appropriate solvent (i.e., THF) with excess
base (i.e., TEA or NaHCO.sub.3) at a range of temperatures (i.e.,
-20.degree. C. to 25.degree. C.) to afford the final product after
purification.
##STR00158##
[0259] General Procedure. A mono-Boc-protected diamine can be
treated with CDI and another amine (i.e., Z--NH.sub.2) in the
presence of a base (i.e., DIEA) in a suitable solvent (i.e., DCM)
to afford the corresponding urea intermediate. The Boc group can
then be removed using either TFA or HCl in a suitable solvent
(i.e., DCM) to yield the corresponding crude amine salt. Finally,
the crude amine salt can be reacted with cyanogen bromide in an
appropriate solvent (i.e., THF) with excess base (i.e., TEA or
NaHCO.sub.3) at a range of temperatures (i.e., -20.degree. C. to
25.degree. C.) to afford the final product after purification.
EXAMPLES
[0260] The disclosure is further illustrated by the following
examples and synthesis schemes, which are not to be construed as
limiting this disclosure in scope or spirit to the specific
procedures herein described. It is to be understood that the
examples are provided to illustrate certain embodiments and that no
limitation to the scope of the disclosure is intended thereby. It
is to be further understood that resort may be had to various other
embodiments, modifications, and equivalents thereof which may
suggest themselves to those skilled in the art without departing
from the spirit of the present disclosure and/or scope of the
appended claims.
Analytical Methods, Materials, and Instrumentation
[0261] Unless otherwise noted, reagents and solvents were used as
received from commercial suppliers. Unless otherwise noted,
reactions were conducted under an inert atmosphere of nitrogen.
Proton nuclear magnetic resonance (NMR) spectra were obtained on
either Bruker or Varian spectrometers at 300 or 400 MHz. Spectra
are given in ppm (S) and coupling constants, J, are reported in
Hertz. Tetramethylsilane (TMS) was used as an internal standard.
Mass spectra were collected using a Waters ZQ Single Quad Mass
Spectrometer (ion trap electrospray ionization (ESI)). Purity and
low resolution mass spectral data were measured using Waters
Acquity i-class ultra-performance liquid chromatography (UPLC)
system with Acquity Photo Diode Array Detector, Acquity Evaporative
Light Scattering Detector (ELSD) and Waters ZQ Mass Spectrometer.
Data was acquired using Waters MassLynx 4.1 software and purity
characterized by UV wavelength 220 nm, evaporative light scattering
detection (ELSD) and electrospray positive ion (ESI). (Column:
Acquity UPLC BEH C18 1.7 .mu.m 2.1.times.50 mm; Flow rate 0.6
mL/min; Solvent A (95/5/0.1%: 10 mM Ammonium
Formate/Acetonitrile/Formic Acid), Solvent B (95/5/0.09%:
Acetonitrile/Water/Formic Acid); gradient: 5-100/B from 0 to 2
mins, hold 100% B to 2.2 mins and 5% B at 2.21 mins. Preparatory
HPLC purifications were conducted as designated below. The absolute
configuration of the separated enantiomers of the compounds in the
examples described herein was occasionally determined. In all other
cases the absolute configuration of the separated enantiomers was
not determined and in those instances the configuration of the
resolved materials were arbitrarily assigned as R or S in each
case.
[0262] Abbreviations used in the following examples and elsewhere
herein are:
TABLE-US-00004 Abbreviation Name atm atmospheres AcOH acetic acid
Boc t-butoxycarbonyl CDI 1,1'-Carbonyldiimidazole CDCl.sub.3
deuterated chloroform Cs.sub.2CO.sub.3 cesium carbonate DAST
Diethylaminosulfur trifluoride DBU
1,8-Diazabicyclo[5.4.0]undec-7-ene DCM Dichloromethane, methylene
chloride DIEA diisopropylethylamine DMA N,N-dimethylacetamide DMF
N,N-dimethylformamide DMSO dimethylsulfoxide DPPA
Diphenylphosphoryl azide EDCI
1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide ES electrospray
Et.sub.3N triethylamine Et.sub.2O diethyl ether EtOAc ethyl acetate
EtOH ethanol h or hr hours H.sub.2O water HATU
1-[Bis(dimethylamino)methylene]-1H-1,2,3- triazolo[4,5-b]pyridinium
3-oxid hexafluorophosphate HBTU
N,N,N',N'-tetramethyl-O-(1H-benzotriazol-1-yl) uronium
hexafluorophosphate HCl hydrochloric acid HOBt Hydroxybenzotriazole
IPA isopropanol K.sub.2CO.sub.3 potassium carbonate LDA Lithium
diisopropylamide MeCN acetonitrile MeOH methanol MgSO.sub.4
magnesium sulfate min minutes MS mass spectrometry MTBE Methyl
tert-butyl ether Na.sub.2CO.sub.3 Sodium carbonate Na.sub.2SO.sub.4
sodium sulfate NaH sodium hydride NaHCO.sub.3 sodium bicarbonate
NaOH sodium hydroxide N.D. Not determined NH.sub.4HCO.sub.3
ammonium bicarbonate NH.sub.4OH ammonium hydroxide NMP
N-methyl-2-pyrrolidone Pd/C palladium on carbon Pd(dppf)Cl.sub.2
[1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium(II)
Pd(dppf)Cl.sub.2.cndot.CH.sub.2Cl.sub.2
[1,1'-bis(diphenylphosphino)ferrocene]
dichloropalladium(II)-dichloromethane adduct pet. ether petroleum
ether PhI(OAc).sub.2 (diacetoxyiodo)benzene prep-HPLC preparatory
high pressure liquid chromatography prep-TLC preparatory thin layer
chromatography rt Room temperature RT Retention time RuPhos
2-dicyclohexylphosphino-2',6'- diisopropoxybiphenyl RuPhos Pd G3
(2-Dicyclohexylphosphino-2',6'-diisopropoxy-
1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)] palladium(II)
methanesulfonate SFC Supercritical Fluid Chromatography t-BuOH
Tert-butanol TBS tert-butyl(dimethyl)silyl TEA triethylamine TFA
trifluoroacetic acid THF tetrahydrofuran
Synthetic Examples of Compounds of Formula (I)
Example 1.
trans-3-(cyanoamino)-N-[5-(oxan-4-yl)-1,3-thiazol-2-yl]cyclobut-
ane-1-carboxamide (Compound 1-1)
##STR00159##
[0263] Step 1. tert-butyl
(trans-(tetrahydro-2H-pyran-4-yl)thiazol-2-ylcarbamoyl)cyclobutylcarbamat-
e
[0264] A solution of
trans-3-(tert-butoxycarbonylamino)cyclobutanecarboxylic acid (169
mg, 0.786 mmol), HATU (298 mg, 0.790 mmol),
5-(tetrahydro-2H-pyran-4-yl)thiazol-2-amine (120 mg, 0.650 mmol)
and DIEA (0.320 mL, 1.96 mmol) in N,N-dimethylformamide (3 mL) was
stirred for 30 min at 25.degree. C. The reaction was then quenched
by the addition of water (10 mL). The resulting mixture was
extracted with ethyl acetate (3.times.10 mL). The organic layers
were combined, dried over anhydrous sodium sulfate, filtered and
concentrated under vacuum. The residue was purified by Prep-TLC
plate (developing solvent: 20:1 dichloromethane/methanol) to afford
tert-butyl
(trans-(tetrahydro-2H-pyran-4-yl)thiazol-2-ylcarbamoyl)cyclobutylcarbamat-
e as a yellow solid (80.0 mg). LCMS (ES, m/z) 382 [M+H].sup.+.
Step 2.
trans-3-amino-N-(5-(tetrahydro-2H-pyran-4-yl)thiazol-2-yl)cyclobut-
anecarboxamide 2,2,2-trifluoroacetate
[0265] A solution of tert-butyl
(trans-(tetrahydro-2H-pyran-4-yl)thiazol-2-ylcarbamoyl)cyclobutylcarbamat-
e (80.0 mg, 0.210 mmol) and trifluoroacetic acid (1 mL) in
dichloromethane (3 mL) was stirred for 2 h at 25.degree. C. The
resulting mixture was concentrated under vacuum to afford
trans-3-amino-N-(5-(tetrahydro-2H-pyran-4-yl)thiazol-2-yl)cyclobutanecarb-
oxamide 2,2,2-trifluoroacetate as yellow oil (90.0 mg). LCMS (ES,
m/z) 282 [M+H].sup.+.
Step 3.
trans-3-(cyanoamino)-N-[5-(oxan-4-yl)-1,3-thiazol-2-yl]cyclobutane-
-1-carboxamide
[0266] Cyanogen bromide (19.0 mg, 0.180 mmol) was added into a
stirring solution of
trans-3-amino-N-(5-(tetrahydro-2H-pyran-4-yl)thiazol-2-yl)cyclobutanecarb-
oxamide 2,2,2-trifluoroacetate (70.0 mg, 0.180 mmol) and TEA (0.074
mL, 0.530 mmol) in tetrahydrofuran (5 mL) at -20.degree. C. The
resulting solution was stirred for 30 min at -20.degree. C. The
reaction was then quenched by the addition of water (10 mL). The
resulting mixture was extracted with ethyl acetate (3.times.15 mL).
The organic layers were combined, dried over anhydrous sodium
sulfate, filtered and concentrated under vacuum. The residue was
purified by Prep-HPLC (Column: XBridge BEH130 RP18 OBD Column, 130
.ANG., 5 .mu.m, 19 mm*150 mm; Mobile phase, A: water (10 mM
NH.sub.4HCO.sub.3) and B: ACN (10% up to 40% over 7 min); Flow
rate: 20 mL/min; Detector: 254 & 220 nm) to afford
trans-3-(cyanoamino)-N-[5-(oxan-4-yl)-1,3-thiazol-2-yl]cyclobutane-1-carb-
oxamide as a white solid (5.40 mg). .sup.1H NMR (300 MHz,
DMSO-d.sub.6), S 11.92 (s, 1H), 7.22 (s, 1H), 7.19 (s, 1H),
3.92-3.79 (m, 3H), 3.46-3.42 (m, 2H), 3.28-3.19 (m, 1H), 3.07-2.98
(m, 1H), 2.47-2.42 (m, 2H), 2.27-2.17 (m, 2H), 1.88-1.83 (m, 2H),
1.68-1.55 (m, 2H). LC-MS (ESI) m/z 307.2 [M+H].sup.+
[0267] The following compounds were synthesized according to
General Scheme 1:
TABLE-US-00005 Example MS m/z No. Structure Chemical Name [M + H]+
1H NMR Compound 1-2 ##STR00160## (1r,3r)-3-(cyanoamino)-
N-(1-methyl-3-phenyl- 1H-pyrazol-5- yl)cyclobutane-1- carboxamide
296 10.01 (s, 1H), 7.75 (d, J = 8.0 Hz, 2H), 7.41-7.37 (m, 2H),
7.30-7.24 (m, 2H), 6.66 (s, 1H), 3.87-3.80 (m, 1H), 3.70 (s, 3H),
3.26-3.21 (m, 1H), 2.51-2.47 (m, 2H), 2.29-2.21 (m, 2H) Compound
1-3 ##STR00161## (1r,3r)-3-(cyanoamino)- N-(2-cyclohexyl-1,3-
thiazol-5- yl)cyclobutane-1- carboxamide 305 11.13 (br s, 1H), 7.31
(s, 1H), 7.22 (br s, 1H), 3.85-3.76 (m, 1H), 3.17-3.08 (m, 1H),
2.89-2.79 (m, 1H), 2.48-2.39 (m, 2H), 2.27-2.17 (m, 2H), 2.05-1.95
(m, 2H), 1.80-1.70 (m, 2H), 1.70-1.61 (m, 1H), 1.51-1.31 (m, 4H),
1.31-1.15 (m, 1H) Compound 1-4 ##STR00162##
(1r,3r)-3-(cyanoatnino)- N-(2-cyclohexyl-1,3- thiazol-5-yl)-N-
methylcyclobutane-1- carboxamide 319 7.56-7.38 (m, 1H), 7.28-7.05
(m, 1H), 3.72-3.53 (m, 2H), 3.32 (s, 2H), 3.17-3.05 (m, 1H),
2.97-2.80 (m, 1H), 2.46-2.35 (m, 1H), 2.35-2.25 (m, 2H), 2.08-1.87
(m, 3H), 1.80-1.62 (m, 3H), 1.51-1.29 (m, 4H), 1.29-1.19 (m, 1H)
Compound 1-5 ##STR00163## (1r,3r)-N-(5-tert-butyl-
1,3-thiazol-2-yl)-3- (cyanoamino)-N- methylcyclobutane-1-
carboxamide 293 7.33-7.20 (m, 2H), 3.71-3.61 (m, 2H), 347 (s, 3H),
2.60-2.51 (m, 2H), 2.35-2.28 (m, 2H), 1.33 (s, 9H) Compound 1-6
##STR00164## (1r,3r)-3-(cyanoamino)- N-(3-cyclohexyl-1-
methyl-1H-pyrazol-5- yl)cyclobutane-1- carboxamide 302 9.80 (br s,
1H), 7.22 (br s, 1H), 6.00 (s, 1H), 3.84-3.76 (m, 1H), 3.55 (s,
3H), 3.33-3.15 (m, 1H), 2.50-2.45 (m, 3H) 2.25-2.18 (m, 2H),
1.85-1.83 (m, 2H), 1.73-1.72 (m, 2H), 1.65 (d, J = 12.8 Hz, 1H),
1.37-1.26 (m, 4H), 1.25-1.15 (m, 1H) Compound 1-7 ##STR00165##
(1r,3r)-3-(cyanoamino)- N-(2-cyclohexyl-4- methyl-1,3-thiazol-5-
yl)cyclobutane-1- carboxamide 319 10.19 (br s, 1H), 7.22 (br s,
1H), 3.90-3.75 (m, 1H), 3.30-3.22 (m, 1H), 2.82-2.75 (m, 1H),
2.43-2.37 (m, 2H), 2.25-2.15 (m, 5H), 2.00-1.90 (m, 2H), 1.75-1.70
(m, 2H), 1.70-1.60 (m, 1H), 1.43-1.27 (m, 4H), 1.25-1.13 (m, 1H)
Compound 1-8 ##STR00166## (1r,3r)-3-(cyanoamino)-
N-{2-[2-(propan-2- yloxy)phenyl]-1,3- thiazol-5- yl}cyclobutane-1-
carboxamide 357 8.22 (d, J = 7.2 Hz, 1H), 7.60 (s, 1H), 7.37-7.33
(m, 1H), 7.22-7.20 (m, 1H), 4.93-4.91 (m, 1H), 3.88-3.84 (m, 1H),
3.28-3.12 (m, 1H), 2.51-2.43 (m, 2H), 2.33-2.08 (m, 2H), 1,43 (d, J
= 5.6 Hz, 6H) Compound 1-9 ##STR00167## (1r,3r)-3-(cyanoamino)-
N-[2-(3,3- difluomcyclobutyl)-1,3- thiazol-5- yl]cyclobutane-1-
carboxamide 313 11.28 (br s, 1H), 7.39 (s, 1H), 7.24 (br s, 1H),
3.82 (s, 1H), 3.73-3.64 (m, 1H), 3.20-3.10 (m, 1H), 3.09-2.97 (m,
1H), 2.95-2.77 (m, 1H), 2.86 (s, 2H), 2.45 (s, 2H), 2.29-2.19 (m,
2H Compound 1-10 ##STR00168## (1r,3r)-N-(4-chloro-5-
cyclohexyl-1,3-thiazol- 2-yl)-3-(cyanoamino) cyclobutane-1-
carboxamide 339, 341 12.10 (br s, 1H), 7.22 (d, J = 5.5 Hz, 1H),
3.85-3.74 (m, 1H), 3.27-3.16 (m, 1H), 2.86-2.76 (m, 1H), 2.48-2.41
(m, 2H), 2.28-2.16 (m, 2H), 1.92-1.82 (m, 2H), 1.82-1.72 (m, 2H),
1.71-1.63 (m, 1H), 1.42-1.17 (m, 5H) Compound 1-11 ##STR00169##
(1r,3s)-3-(cyanoamino)- N-(2-cyclohexyl-1,3- thiazol-5-yl)-1-
methylcyclobutane-1- carboxamide 319 11.83 (br s. 1H), 7.17 (s,
2H), 3.50-3.46 (m, 1H), 2.86-2.73 (m, 3H), 1.94-1.89 (m, 4H),
1.77-1.67 (m, 3H), 1.44 (s, 3H), 1.40-1.35 (m, 4H), 1.26-1.20 (m,
1H) Compound 1-12 ##STR00170## (1r,3s)-3-(cyanoamino)-
N-{2-[(1S)-2,2- dimethylcyclohexyl]- 1,3-thiazol-5-
yl}cyclobutane-1- carboxamide 333 11.15 (br s, 1H), 7.35 (s, 1H),
7.23 (br s, 1H), 3.90-3.78 (m, 1H), 3.19-3.09 (m, 1H), 2.77-2.69
(m, 1H), 2.49-2.40 (m, 2H), 2.29-2.17 (m, 2H), 1.87-1.72 (m, 2H),
1.70-1.61 (m, 1H), 1.55-1.43 (m, 3H), 1.36-1.21 (m, 2H), 0.87 (d, J
= 9.4 Hz, 6H) Compound 1-13 ##STR00171## (1r,3r)-3-(cyanoamino)-
N-{2-[(1R)-2,2- dimethylcyclohexyl]- 1,3-thiazol-5-
yl}cyclobutane-1- carboxamide 333 11.15 (br s, 1H), 7.35 (s, 1H),
7.23 (br s, 1H), 3.90-3.78 (m, 1H), 3.19-3.09 (m, 1H), 2.77-2.69
(m, 1H), 2.49-2.40 (m, 2H), 2.29-2.17 (m, 2H), 1.87-1.72 (m, 2H),
1.70-1.61 (m, 1H), 1.55-1.43 (m, 3H), 1.36-1.21 (m, 2H), 0.87 (d, J
= 9.4 Hz, 6H) Compound 1-14 ##STR00172## (1r,3r)-N-(4-chloro-2-
cyclohexyl-1,3-thiazol- 5-yl)-3-(cyanoamino) cyclobutane-1-
carboxamide 339, 341 10.7 (br s, 1H), 7.25 (br s, 1H), 3.62-3.58
(m, 1H), 3.09-3.04 (m, 1H), 2.88-2.83 (m, 1H), 2.45-2.39 (m, 2H),
2.18-2.10 (m, 2H), 2.00-1.87 (m, 2H), 1.77-1.74 (m, 2H), 1.68-1.65
(m, 1H), 1.47-1.31 (m, 4H), 1.26-1.21 (m, 1H). Compound 1-15
##STR00173## (1R,3R)-3- (cyanoamino)-N-(2- cyclohexyl-1,3-thiazol-
5-yl)-2,2- dimethylcyclobutane-1- carboxamide 333 1H-NMR (CD3OD,
400 MHz) .delta. (ppm): 7.11 (s, 1H), 3.46-3.42 (m, 1H), 2.83-2.79
(m, 2H), 2.49-2.41 (m, 1H), 2.34-2.27 (m, 1H), 2.05-2.00 (m, 2H),
1.86-1.85 (m, 2H), 1.77-1.74 (m, 1H), 1.52-1.40 (m, 4H), 1.38-1.28
(m, 4H), 1.02 (s, 3H). Compound 1-16 ##STR00174##
(1r,3r)-3-(cyanoamino)- N-[5-cyclohexyl-4- (methoxymethyl)-1,3-
thiazol-2- yl]cyclobutane-1- carboxamide 349 11.9 (br s, 1H), 7.23
(br s, 1H), 4.33 (s, 2H), 3.84-3.79 (m, 1H), 3.26-3.19 (m, 4H),
2.97-2.92 (m, 1H), 2.48-2.44 (m, 2H), 2.34-2.19 (m, 2H), 1.88-1.85
(m, 2H), 1.78-1.76 (m, 2H), 1.71-1.60 (m, 1H), 1.44-1.19 (m, 5H).
Compound 1-17 ##STR00175## (1r,3r)-3-(cyanoamino)-
N-(2-cyclohexyl-4- fluoro-1,3-thiazol-5- yl)cyclobutane-1-
carboxamide 323 10.9 (br s, 1H), 7.24 (br s, 1H), 3.84-3.80 (m,
1H), 3.27-3.02 (m, 1H), 2.84-2.77 (m, 1H), 2.47-2.42 (m, 2H),
2.25-2.20 (m, 2H), 1.99-1.96 (m, 2H), 1.76-1.74 (m, 2H), 1.67-1.64
(m, 1H), 1.47-1.31 (m, 4H), 1.27-1.18 (m, 1H). Compound 1-18
##STR00176## (1s,3s)-N-(4-chloro-5- cyclohexyl-1,3-thiazol-
2-yl)-3-(cyanoamino) cyclobutane-1- carboxamide 339, 341 11.50 (br
s, 1H), 7.22 (br s, 1H), 3.67-3.55 (m, 1H), 2.96-2.76 (m, 2H),
2.47-2.37 (m, 2H), 2.20-2.08 (m, 2H), 1.92-1.82 (m, 2H), 1.82-1.73
(m, 2H), 1.72-1.65 (m, 1H), 1.42-1.17 (m, 5H) Compound 1-19
##STR00177## (1r,3r)-N-(5-tert-butyl- 4-chloro-1,3-thiazol-2-
yl)-3-(cyanoamino) cyclobutane-1- carboxamide 313, 315 11.40 (br s,
1H), 7.27 (br s, 1H), 3.82-3.78 (m, 1H), 3.22-3.17 (m, 1H),
2.51-2.43 (m, 2H), 2.26-2.20 (m, 2H), 1.41 (s, 9H) Compound 1-20
##STR00178## (1r,3r)-N-[4-chloro-3- (trifluoromethyl) phenyl]-3-
(cyanoamino) cyclobutane-1- carboxamide 318, 320 10.40 (br s, 1H),
8.24 (s, 1H), 7.83 (d, J = 8.4 Hz, 1H), 7.66 (d, J = 8.8 Hz, 1H),
7.25 (br s, 1H), 3.86-3.79 (m, 1H), 3.18-3.13 (m, 1H), 2.51-2.47
(m, 2H), 2.27-2.20 (m, 2H) Compound 1-21 ##STR00179## (1r,3r)-3-
(cyanoarruno)-N-{5- [(1S,2R)-2- methylcyclohexyl]-1,3- thiazol-2-
yl}cyclobutane-1- carboxamide 319 11.87 (br s, 1H), 7.20 (d, J =
5.2. Hz, 1H), 7.14 (s, 1H), 3.86-3.75 (m, 1H), 3.27-3.17 (m, 1H),
2.48-2.34 (m, 3H), 2.27-2.16 (m, 2H), 1.88-1.64 (m, 4H), 1.47-1.21
(m, 4H), 1.12-0.96 (m, 1H), 0.73 (d, J = 6.4 Hz, 3H) Compound 1-22
##STR00180## (1r,3r)-3-(cycloamino)- N-{5-[(1R,2S)-2-
methylcyclohexyl]-1,3- thiazol-2- yl}cyclobutane-1- carboxamide 319
11.87 (br, 1H), 7.20 (d, J = 5.2 Hz, 1H), 7.14 (s, 1H), 3.86-3.75
(m, 1H), 3.27-3.17 (m, 1H). 2.48-2.34 (m, 3H), 2.27-2.16 (m, 2H),
1.88-1.64 (m, 4H), 1.47-1.21 (m, 4H), 1.12-0.96 (m, 1H), 0.73 (d, J
= 6.4 Hz, 3H) Compound 1-23 ##STR00181## (1r,3r)-3-(cyanoamino)-
N-{5-[(1S,2S)-2- methylcyclohexyl]-1,3- thiazol-2-
yl}cyclobutane-1- carboxamide 319 11.88 (br s, 1H), 7.23 (s, 1H),
7.11 (s, 1H), 3.88-3.76 (m, 1H), 3.29-3.18 (m, 1H), 3.15-3.03 (m,
1H), 2.49-2.41 (m, 2H), 2.27-2.17 (m, 2H), 2.04-1.94 (m, 1H),
1.77-1.46 (m, 6H), 1.46-1.34 (m, 2H), 0.75 (d, J = 6.8 Hz, 3H)
Compound 1-24 ##STR00182## (1r,3r)-3-(cyanoamino)- N-{5-[(1R,2R)-2-
methylcyclohexyl]-1,3- thiazol-2- yl}cyclobutane-1- carboxamide 319
11.88 (br s, 1H), 7.23 (s, 1H), 7.11 (s, 1H), 3.88-3.76 (m, 1H),
3.29-3.18 (m, 1H), 3.15-3.03 (m, 1H), 2.49-2.41 (m, 2H), 2.27-2.17
(m, 2H), 2.04-1.94 (m, 1H), 1.77-1.46 (m, 6H), 1.46-1.34 (m, 2H),
0.75 (d, J = 6.8 Hz, 3H) Compound 1-25 ##STR00183##
(1r,3r)-3-(cyanoamino)- N-(5-cyclohexyl-4- cyclopropyl-1,3-
thiazol-2- yl)cyclobutane-1- carboxamide 345 11.80 (s, 1H), 7.22
(d, J = 5.6 Hz, 1H), 3.80-3.77 (m, 1H), 3.20-3.16 (m, 1H),
3.00-2.91 (m, 1H), 2.45-2.35 (m, 2H), 2.25-2.12 (m, 2H), 1.96-1.89
(m, 2H), 1.79-1.68 (m, 3H), 1.21-1.41 (m, 5H), 1.79-1.68 (m, 3H),
0.85-0.73 (m, 4H Compound 1-26 ##STR00184## (1r,3r)-3-(cyanoamino)-
N-[5-cyclohexyl-4-(1- cyclopropyl-1H- pyrazol-4-yl)-1,3- thiazol-2-
yl]cyclobutane-1- carboxamide 411 11.90-12.05 (m, 1H), 7.91 (s,
1H), 7.63 (s, 1H), 7.24 (d, J = 4.8 Hz, 1H), 3.85-3.80 (m, 2H),
3.24-3.21 (m, 1H), 3.02-2.98 (m, 2H), 2.48-2.43 (m, 2H), 2.26-2.19
(m, 2H), 1.94-1.91 (m, 2H), 1.79-1.70 (m, 3H), 1.46-1.11 (m, 5H),
1.09-0.96 (m, 4H) Compound 1-27 ##STR00185##
(1r,3r)-3-(cyanoamino)- N-[4-(trifluoromethyl) pyridin-2-
yl]cyclobutane-1- carboxamide 285 11.99 (br s, 1H), 8.59 (d, J =
5.2 Hz, 1H), 8.46 (s, 1H), 7.46 (d, J = 5.2 Hz, 1H), 7.22 (d, J =
5.6 Hz, 1H), 3.84-3.78 (m, 1H), 3.29-3.26 (m, 1H), 2.48-2.46 (m,
2H), 2.27-2.20 (m, 2H) Compound 1-28 ##STR00186##
(1r,3r)-3-(cyanoamino)- N-{5-[(2S)-oxan-2-yl]- 1,3-thiazol-2-
yl]cyclobutane-1- carboxamide 307 11.97 (br s, 1H), 7.30 (s, 1H),
7.23 (br s, 1H), 4.57-4.55 (m, 1H), 3.96-3.93 (m, 1H), 3.84-3.81
(m, 1H), 3.56-3.46 (m, 1H), 3.27-3.22 (m, 1H), 2.51-2.44 (m, 2H),
2.33-2.19 (m, 2H), 1.90-1.84 (m, 2H), 1.70-1.50 (m, 4H) Compound
1-29 ##STR00187## (1r,3r)-3-(cyanoamino)- N-(5-cyclohexyl-4-
methyl-1,3-thiazol-2- yl)cyclobutane-1- carboxamide 319 7.26 (br s,
1H), 3.85-3.77 (m, 1H), 3.22-3.16 (m, 1H), 2.81-2.75 (m, 1H),
2.52-2.41 (m, 2H), 2.25-2.19 (m, 2H), 2.17 (s, 1H), 1.86-1.80 (m,
2H), 1.80-1.70 (m, 2H), 1.70-1.60 (m, 1H), 1.40-1.20 (m, 5H)
Compound 1-30 ##STR00188## (1r,3r)-3-(cyanoamino)-
N-(5-cyclohexyl-1- methyl-1H-pyrazol-3- yl)cyclobutane-1-
carboxamide 302 10.23 (br s, 1H), 7.30-6.80 (br s, 1H), 6.30 (s,
1H), 3.82-3.79 (m, H), 3.63 (s, 3H), 3.11-3.07 (m, 1H), 2.65-2.59
(m, 1H), 2.41-2.35 (m, 2H), 2.19-2.12 (m, 2H), 1.87-1.83 (m, 2H),
1.78-1.75 (m, 2H), 1.71-1.68 (m, 1H), 1.43-1.20 (m, 5H) Compound
1-31 ##STR00189## (1r,3r)-3-(cyanoamino)- N-[5-cyclohexyl-4-
(trifluoromethyl)-1,3- thiazol-2- yl]cyclobutane-1- carboxamide 373
7.24 (s, 1H), 3.84-3.76 (m, 1H), 3.27-3.14 (m, 1H), 3.13-3.00 (m,
1H), 2.48-2.45 (m, 2H), 2.28-2.17 (m, 2H), 1.97-1.87 (m, 2H),
1.83-1.73 (m, 2H), 1.73-1.64 (m, 1H), 1.44-1.29 (m, 4H) Compound
1-32 ##STR00190## (1r,3r)-3-(cyanoamino)- N-{5-[(1S,2R)-2-
(trifluoromethyl) cyclohexyl]-1,3-thiazol- 2-yl}cyclobutane-1-
carboxamide 373 11.57-11.08 (br s, 1H), 7.22-7.21 (br s, 1H),
4.90-4.85 (m, 1H), 4.36-4.31 (m, 1H), 3.79-3.70 (m, 1H), 3.39-3.33
(m, 1H), 3.16-3.11 (m, 1H), 2.43-2.37 (m, 2H), 2.21-2.17 (m, 4H),
2.08-1.95 (m, 1H), 1.80-1.70 (m, 1H), 1.59-1.42 (m, 3H), 1.29-1.24
(m, 1H) Compound 1-33 ##STR00191## (1r,3r)-3-(cyanoamino)-
N-{5-[(1R,2S)-2- (trifluoromethyl) cyclohexyl]-1,3-thiazol-
2-yl}cyclobutane-1- carboxamide 373 11.32 (br s. 1H), 7.22-7.21 (br
s, 1H), 4.76-4.71 (m, 1H), 4.53-4.48 (m, 1H), 3.79-3.70 (m, 1H),
3.15-3.10 (m, 1H), 3.04-2.97 (m, 1H), 2.40-2.37 (m, 3H), 2.40-2.37
(m, 3H), 2.22-2.14 (m, 2H), 2.02-1.90 (m, 2H), 1.77-1.74 (m, 1H),
1.68-1.52 (m, 2H), 1.49-1.43 (m, 1H), 1.30-1.24 (m, 1H) Compound
1-34 ##STR00192## (1r,3r)-3-(cyanoamino)- N-{5-[(1S,2S)-2-
(trifluoromethyl) cyclohexyl-1-1,3- thiazol-2- yl}cyclobutane-1-
carboxamide 373 11.28 (br s, 1H), 7.22 (br s, 1H), 4.91-4.85 (m,
1H), 4.36-4.31 (m, 1H), 3.79-3.70 (m, 1H), 3.41-3.35 (m, 1H),
3.16-3.11 (m, 1H), 2.40-2.37 (m, 2H), 2.21-2.08 (m, 4H), 1.99-1.95
(m, 1H), 1.77-1.73 (m, 1H), 1.59-1.42 (m, 3H), 1.33-1.24 (m, 1H)
Compound 1-35 ##STR00193## (1r,3r)-3-(cyanoamino)- N-{5-[(1R,2R)-2-
(trifluoromethyl) cyclohexyl]-1,3-thiazol- 2-yl}cyclobutane-1-
carboxamide 373 11.20 (br s, 1H), 7.22. (br s, 1H), 4.76-4.71 (m,
1H), 4.53-4.48 (m, 1H), 3.76-3.72 (m, 1H), 3.15-3.10 (m, 1H),
3.06-2.90 (m, 1H), 2.40-2.37 (m, 3H), 2.26-2.08 (m, 2H), 2.02-1.90
(m, 2H), 1.77-1.74 (m, 1H), 1.67-1.60 (m, 2H), 1.52-1.43 (m, 1H),
1.30-1.24 (m, 1H) Compound 1-36 ##STR00194## (1r,3r)-N-(4-chloro-5-
cyclopropyl-1,3- thiazol-2-yl)-3- (cyanoamino) cyclobutane-1-
carboxamide 297, 299 12.19 (br s, 1H), 7.24 (br s, 1H), 3.82-3.76
(m, 1H), 3.24-3.18 (m, 1H), 2.50-2.42 (m, 2H), 2.26-2.18 (m, 2H),
2.00-1.90 (m, 1H), 1.10-1.00 (m, 2H), 1.70-1.60 (m, 2H) Compound
1-37 ##STR00195## (1r,3r)-N-{5-[(2R)- bicyclo[2.2.2]octan-2-
yl]-1,3-thiazol-2-yl}-3- (cyanoamino) cyclobutane-1- carboxamide
331 7.25 (br s, 1H), 7.22 (s, 1H), 3.84-3.79 (m, 1H), 3.25-3.20 (m,
1H), 3.15-3.11 (m, 1H), 2.51-2.43 (m, 2H), 2.25-2.18 (m, 2H),
2.05-2.00 (m, 1H), 1.70-1.56 (m, 11H) Compound 1-38 ##STR00196##
(1r,3r)-N-{5-[(2S)- bicyclo[2.2.2]octan-2- yl]-1.3-thiazol-2-yl}-3-
(cyanoamino) cyclobutane-1- carboxamide 331 7.25 (br s, 1H), 7.22
(s, 1H), 3.86-3.77 (m, 1H), 3.25-3.21 (m, 1H), 3.15-3.11 (m, 1H),
2.51-2.43 (m, 2H), 2.25-2.18 (m, 2H), 2.05-2.00 (m, 1H), 1.70-1.61
(m, 11H) Compound 1-39 ##STR00197## (1r,3r)-N-(5-chloro-1-
cyclohexyl-1H-pyrazol- 3-yl)-3-(cyanoamino) cyclobutane-1-
carboxamide
322, 324 10.60 (br s, 1H), 7.20 (br s, 1H), 6.57 (s, 1H), 4.23-4.15
(m, 1H), 3.84-3.77 (m, 1H), 3.15-3.08 (m, 1H), 2.43-2.37 (m, 2H),
2.20-2.12 (m, 2H), 1.82-1.74 (m, 4H), 1.73-1.65 (m, 3H), 1.45-1.35
(m, 2H), 1.20-1.10 (m, 1H) Compound 1-40 ##STR00198##
(1r,3r-3-(cyanoamino)- N-[5-(3-cyanophenyl)- 1,3-thiazol-2-
yl]cyclobutane-1- carboxamide 324 12.27 (br s, 1H), 8.17 (s, 1H),
8.06 (s, 1H), 7.93 (d, J = 8.4 Hz, 1H), 7.76 (d, J = 7.6 Hz, 1H),
7.63 (t, J = 8.0 Hz, 1H), 7.28 (br s, 1H), 3.87-3.80 (m, 1H),
3.31-3.28 (m, 1H), 2.55-2.52 (m, 1H), 2.52-2.49 (m, 1H), 2.30-2.23
(m, 2H) Compound 1-41 ##STR00199## (1r,3r)-N-[3-(3-
chlomphenyl)-1,2- oxazol-5-yl]-3- (cyanoamino) cyclobutane-1-
carboxamide 317, 319 11.75 (br s, 1H), 7.92 (s, 1H), 7.83 (d, J =
7.2 Hz, 1H), 7.59-7.52 (m, 2H), 7.26 (br s, 1H), 6.85 (s, 1H),
3.85-3.77 (m, 1H), 3.26-3.19 (m, 1H), 2.53-2.49 (m, 1H), 2.49-2.47
(m, 1H), 2.29-2.21 (m, 2H) Compound 1-42 ##STR00200##
(1r,3s)-3-(cyanoamino)- N-(5-cyclohexyl-1,3- thiazol-2-yl)-1-
methylcyclobutane-1- carboxamide 305 12.06 (s, 1H), 7.24 (d, J = 6
Hz, 1H), 6.72 (s, 1H), 3.66-3.56 (m, 1H), 2.95-2.87 (m, 1H),
2.68-2.56 (m, 1H), 2.45-2.41 (m, 2H), 2.19-2.12 (m, 2H), 1.93-1.84
(m, 2H), 1.79-1.68 (m, 3H), 1.45-1.27 (m, 4H), 1.26-1.13 (m, 1H)
Compound 1-43 ##STR00201## (1r,3r)-N-1-5-(3- chlorophenyl)-1,2-
oxazol-3-yl]-3- (cyanoamino) cyclobutane-1- carboxamide 317, 319
11.09 (br s, 1H), 7.99 (s, 1H), 7.88-7.85 (m, 1H), 7.58-7.57 (m,
2H), 7.17-7.52 (m, 1H), 7.25-7.23 (br s, 1H), 3.83-3.79 (m, 1H),
3.23-3.21 (m, 1H), 2.48-2.45 (m, 2H), 2.27-2.20 (m, 2H) Compound
1-44 ##STR00202## (1r,3s)-N-(4-chloro-5- cyclohexyl-1,3-thiazol-
2-yl)-3-(cyanoamino)- 1-methylcyclobutane-1- carboxamide 353, 355
12.19 (br s, 1H)7.19-7.18 (br s, 1H), 3.52-3.44 (m, 1H), 2.85-2.80
(m, 3H), 1.94-1.89 (m, 4H), 1.79-1.70 (m, 2H), 1.70-1.67 (m, 1H),
1.43 (s, 3H), 1.39-1.30 (m, 4H), 1.30-1.20 (m, 1H) Compound 1-45
##STR00203## (1r,3r)-N-[3-(3- chlorophenyl)-1,2- oxazol-5-yl]-3-
(cyanoamino)-N- methylcyclobutane-1- carboxamide 331, 333 7.94 (s,
1H), 7.86 (d, J = 7.2 Hz, 1H), 7.60-7.57 (m, 2H), 7.23 (br s, 1H),
7.01 (s, 1H), 3.80-3.40 (m, 5H), 2.60-2.40 (m, 2H), 2.30-2.20 (m,
2H) Compound 1-46 ##STR00204## (1r,3s)-3-(cyanoamino)-
N-(2-cyclohexyl-1,3- thiazol-5-yl)-1- ethylcyclobutane-1-
carboxamide 333 10.92 (br s, 1H), 7.40 (s, 1H), 7.21 (br s 1H),
3.40-3.38 (m, 1H), 2.86-2.82 (m, 1H), 2.78-2.73 (m, 2H), 2.01-1.67
(m, 9H,1.52-1.36 (m, 4H), 1.32-1.22 (m, 1H), 0.71 (t, J = 7.2 Hz,
3H) Compound 1-47 ##STR00205## (1s,3s)-N-(4-chloro-5-
cyclohexyl-1,3-thiazol- 2-yl)-3-(cyanoamino)-
1-fluorocyclobutane-1- carboxamide 357, 359 12.63 (br s, 1H), 7.44
(br s, 1H), 4.07-4.00 (m, 1H), 2.87-2.82 (m, 1H), 2.76-2.59 (m,
4H), 1.95-1.89 (m, 2H), 1.79-1.77 (m, 2H), 1.73-1.67 (m, 1H),
1.42-1.17 (m, 5H) Compound 1-48 ##STR00206## (1r,3r)-N-(4-chloro-5-
cyclohexyl-1,3-thiazol- 2-yl)-3-(cyanoamino)-
1-fluorocyclobutane-1- carboxamide 357, 359 12.64 (br s, 1H), 7.47
(br s, 1H), 3.52-3.49 (m, 1H), 3.04-2.97 (m, 2H), 2.87-2.82 (m,
1H), 2.48-2.42 (m, 2H), 1.92-1.89 (m, 2H), 1.79-1.77 (m, 2H),
1.71-1.67 (m, 1H), 1.42-1.17 (m, 5H) Compound 1-49 ##STR00207##
(1r,3r)-N-(4-chloro-5- cyclohexyl-1,3-thiazol-
2-yl)-3-(cyanoamino)- N-methylcyclobutane- 1-carboxamide 353, 355
7.28 (br s, 1H), 3.71-3.63 (m, 2H), 3.43 (s, 3H), 2.82-2.77 (m,
1H), 2.58-2.51 (m, 2H), 2.35-2.28 (m, 2H), 1.90-1.88 (m, 2H),
1.77-1.72 (m, 2H), 1.70-1.67 (m, 1H), 1.42-1.22 (m, 5H) Compound
1-50 ##STR00208## (1r,3r)-N-(5-tert-butyl- 4-chloro-1,3-thiazol-2-
yl)-3-(cyanoamino)-N- methylcyclobutane-1- carboxamide 327, 329
7.28 (br s, 1H), 3.69-3.63 (m, 2H), 3.42 (s, 3H), 2.60-2.51 (m,
2H), 2.35-2.28 (m, 2H), 1.41 (s, 9H) Compound 1-51 ##STR00209##
(1r,3r-3-(cyanoamino)- N-[3-(3-cyanophenyl)- 1,2-oxazol-5-
yl]cyclobutane-1- carboxamide 308 11.80 (br s, 1H), 8.37 (s, 1H),
8.22 (d, J = 8.0 Hz, 1H), 7.99 (d, J = 7.6 Hz, 1H), 7.73 (t, J =
8.0 Hz, 1H), 7.27 (br s, 1H), 6.95 (s, 1H), 3.85-3.80 (m, 1H),
3.26-3.22 (m, 1H), 2.55-2.49 (m, 2H), 2.30-2.23 (m, 2H) Compound
1-52 ##STR00210## (1r 3r)-N-[5-(3- chlorophenyl)-l.2-
oxazol-3-yl]-3- (cyanoamino)-N- methylcyclobutane-1- carboxamide
331, 333 8.01 (s, 1H), 7.89-7.86 (m, 1H), 7.61-7.57 (m, 3H), 7.26
(br s, 1H), 3.74-3.69 (m, 1H), 3.59-3.55 (m, 1H), 3.32 (s, 3H),
2.52-2.51 (m, 2H), 2.34-2.27 (m, 2H) Compound 1-53 ##STR00211##
(1r,3r)-3-(cyanoamino)- N-(5-cyclohexyl-1,3- oxazol-2-
yl)cyclobutane-1- carboxamide 289 7.25 (br s, 2H), 6.91 (s, 1H),
3.78-3.75 (m, 1H), 3.22-3.17 (m, 1H), 2.68-2.62 (m, 1H), 2.47-2.40
(m, 2H), 2.34-2.15 (m, 2H), 1.92-1.86 (m, 2H), 1.78-1.71 (m, 2H),
1.70-1.64 (m, 1H), 1.40-1.15 (m, 5H) Compound 1-54 ##STR00212##
(1r,3r)-N-(5-tert-butyl- 4-chloro-1,3-thiazol-2-
yl)-3-(cyanoamino)-1- fluoro-N- methylcyclobutane-1- carboxamide
345, 347 7.40 (br s, 1H), 3.51 (s, 3H), 3.50-3.25 (m, 3H) 2.58-2.51
(m, 2H), 1.41 (s, 9H) Compound 1-55 ##STR00213##
(1r,3r)-N-(4-chloro-5- cyclohexyl-1,3-thiazol-
2-yl)-3-(cyanoamino)- 1-fluoro-N- methylcyclobutane-1- carboxamide
370, 373 7.51 (br s, 1H), 3.52 (s, 3H), 3.34-3.24 (m, 3H),
2.88-2.84 (m, 1H), 2.58-2.51 (m, 2H), 1.92-1.89 (m, 2H), 1.79-1.74
(m, 2H), 1.71-1.68 (m, 1H), 1.43-1.23 (m, 5H) Compound 1-56
##STR00214## (1s,3r)-3-(cyanoamino)- 1-fluoro-N-{3-[4-
(trifluoromethyl) phenyl]-1H-pyrazol-5- yl}cyclobutane-1-
carboxamide 368 13.3 (br s, 1H), 10.6 (br s, 1H), 7.97 (d, J = 8.0
Hz, 2H), 7.83 (d, J = 8.4 Hz, 2H), 7.45 (br s, 1H), 7.08 (s, 1H),
4.07-4.01 (m, 1H), 2.72-2.61 (m, 4H). Compound 1-57 ##STR00215##
(1r,3r)-3-(cyanoamino)- 1-fluoro-N-{3-[4- (trifluoromethyl)
phenyl]-1H-pyrazol-5- yl}cyclobutane-1- carboxamide 368 13.2 (br s,
1H), 10.6 (br s, 1H), 7.97 (d, J = 8.0 Hz, 2H), 7.83 (d, J = 8.4
Hz, 2H), 7.47 (br s, 1H), 7.07 (s, 1H), 4.05-3.98 (m, 1H),
3.02-2.97 (m, 2H), 2.51-2.42 (m, 2H). Compound 1-58 ##STR00216##
(1s,3s)-N-(4-chloro-5- cyclohexyl-1,3-thiazol-
2-yl)-3-(cyanoamino)- 1-fluoro-N- methylcyclobutane-1- carboxamide
371, 373 751 (br s, 1H), 3.52 (s, 3H), 3.34-3.24 (m, 3H), 2.88-2.84
(m, 1H), 2.58-2.51 (m, 2H), 1.92-1.89 (m, 2H), 1.79-1.74 (m, 2H),
1.71-1.68 (m, 1H), 1.43-1.23 (m, 5H) Compound 1-59 ##STR00217##
(1s,3s)-N-(5-tert-butyl- 4-chloro-1,3-thiazol-2-
yl)-3-(cyanoamino)-1- fluorocyclobutane-1- carboxamide 331, 333
12.57 (br s, 1H), 7.43 (br s, 1H), 4.07-3.98 (m, 1H), 2.72-2.61 (m,
4H), 1.41 (s, 9H) Compound 1-60 ##STR00218##
(1r,3r)-N-(5-tert-butyl- 4-chloro-1,3-thiazol-2-
yl)-3-(cyanoamino)-1- fluorocyclobutane-1- carboxamide 331, 333
12.57 (br s, 1H), 7.48 (br s, 1H), 3.51-3.48 (m, 1H), 3.00-2.97 (m,
2H), 2.50-2.41 (m, 2H), 1.41 (s, 9H). Compound 1-61 ##STR00219##
(1r,3r)-3-(cyanoamino)- N-[3-(2-fluorophenyl)- 5-methylphenyl]
cyclobutane-1- carboxamide 324 9.96 (br s, 1H), 7.63 (s, 1H),
7.50-7.,40 (m, 3H), 7.33-7.28 (m, 2H), 7.24 (br s, 1H), 7.04 (s,
1H), 3.85-3.80 (m, 1H), 3.17-3.12 (m, 1H), 2.49-2.43 (m, 2H), 2.34
(s, 3H), 2.25-2.18 (m, 2H). Compound 1-62 ##STR00220##
(1r,3r)-N-(3-chloro-5- cyclohexylphenyl)-3- (cyanoamino)
cyclobutane-1- carboxamide 332, 334 10.0 (br s, 1H), 7.62 (s, 1H),
7.35 (s, 1H), 7.24 (br s, 1H), 6.95 (s, 1H), 3.85-3.80 (m, 1H),
3.15-3.08 (m, 1H), 2.48-2.42 (m, 3H), 2.24-2.17 (m, 2H), 1.78-1.68
(m, 5H), 1.40-1.20 (m, 5H). Compound 1-63 ##STR00221##
(1r,3r)-3-(cyanoamino)- N-[4-fluoro-3- (piperidin-1-yl)phenyl]
cyclobutane-1- carboxamide 317 9.85 (br s, 1H), 7.37 (dd, J = 8.0,
2.4 Hz, 1H), 7.17--7.13 (m, 1H), 7.04--6.99 (m, 1H), 3.84-3.80 (m,
1H), 3.12-3.07 (m, 1H), 2.94-2.92 (m, 4H), 2.48-2.42 (m, 2H),
2.21-2.18 (m, 2H), 1.69-1.64 (m, 4H), 1.54-1.51 (m, 2H). Compound
1-64 ##STR00222## (1r,3r)-3-(cyanoamino)- N-(7-cyclobutoxy-1,3-
benzothiazol-2- yl)cyclobutane-1- carboxamide 343 7.35-7.30 (m,
2H), 6.74-6.72 (m, 1H), 4.89-4.82 (m, 1H), 3.84-3.70 (m, 1H),
3.32-3.25 (m, 1H), 2.49-2.45 (m, 4H), 2.30-2.22 (m, 2H), 2.14-2.09
(m, 1H), 0.86-0.79 (m, 1H), 0.74-0.65 (m, 1H). Compound 1-65
##STR00223## (1r,3r)-3-(cyanoamino)- N-(7-cyclobutoxy-1,3-
benzothiazol-2-yl)-1- fluorocyclobutane-1- carboxamide 361 7.45 (br
s, 1H), 7.34-7.32 (m, 2H), 6.75-6.74 (m, 1H), 4.90-4.87 (m, 1H),
3.62-3.57 (m, 1H), 3.08-2.98 (m, 2H), 2.47-2.42 (m, 4H), 2.15-2.08
(m, 2H), 1.85-1.82 (m, 1H), 1.72-1.65 (m, 2H). Compound I-66
##STR00224## (1s,3s)-3- (cyanoamino)-N-(7- cyclobutoxv-1,3-
benzothiazol-2-yl)-1- fluorocyclobutane-1- carboxamide 361
7.16-7.14 (m, 2H), 6.63-6.54 (m, 2H), 6.09 (br s, 1H), 4.83-4.80
(m., 1H), 3.95-3.92 (m, 1H), 2.70-2.58 (m, 4H), 2.47-2.33 (m, 2H),
2.14-2.09 (m, 2H), 1.83-1.81 (m, 1H), 1.70-1.63 (m, 2H). Compound
1-67 ##STR00225## (1r,3r)-3-(cyanoamino)- N-{[(1R,2R,5R)-6,6-
dimethylbicyclo[3.1.1] heptan-2-yl]methyl} cyclobutane-1-
carboxamide 276 Compound 1-68 ##STR00226## (1r,3r)-N-[4-(4-
chlorophenyl)-1,3- thiazol-2-yl]-3- (cyanoamino) cyclobutane-1-
carboxamide 333 Compound 1-69 ##STR00227## (1r,3r)-3-(cyanoamino)-
N-(3-phenylphenyl) cyclobutane-1- carboxamide 292 Compound 1-70
##STR00228## (1r,3r)-3-(cyanoamino)- N-{[4-(propan-2-
yl)phenyl]methyl} cyclobutane-1- carboxamide 272 Compound 1-71
##STR00229## (1r,3r)-3-(cyanoamino)- N-[(1s,4s)-tert-
butylcyclohexyl] cyclobutane-1- carboxamide 278 Compound 1-72
##STR00230## (1r,3r)-3-(cyanoamino)- N-(1R,2R,5R)-6,6-
dimethylbicyclo[3.1.1] heptan-2-yl]methyl} cyclobutane-1-
carboxamide 276 Compound 1-73 ##STR00231## (1r,3r)-3-(cyanoamino)-
N-[3-(trifluoromethyl) phenyl]cyclobutane-1- carboxamide 284
Example 2-1.
3-(cyanoamino)-N-(5-cyclohexyl-1,3-thiazol-2-yl)azetidine-1-carboxamide
(Compound 2-1)
##STR00232##
[0268] Step 1. tert-butyl
(1-((5-cyclohexylthiazol-2-yl)carbamoyl)azetidin-3-yl)carbamate
[0269] Into a 50 mL round-bottom flask was placed
5-cyclohexylthiazol-2-amine (300 mg, 1.65 mmol), dichloromethane (5
mL) and triethylamine (833 mg, 8.23 mmol). This was followed by the
addition of N,N'-carbonyldiimidazole (348 mg, 2.15 mmol). The
resulting solution was stirred for 2 h at room temperature. Then
tert-butyl azetidin-3-ylcarbamate (369 mg, 2.14 mmol) was added.
The resulting solution was stirred overnight at room temperature.
The reaction mixture was poured into water (5 mL) and then
extracted with ethyl acetate (3.times.10 mL). The organic layers
were combined, dried over anhydrous sodium sulfate, filtered and
concentrated under vacuum. The residue was purified by silica gel
chromatography (eluting with 1:1 ethyl acetate/petroleum ether) to
afford tert-butyl
(1-((5-cyclohexylthiazol-2-yl)carbamoyl)azetidin-3-yl)carbamate as
a yellow solid. LC-MS (ESI) m/z 381.2[M+H].sup.+
Step 2. 3-amino-N-(5-cyclohexylthiazol-2-yl)azetidine-1-carboxamide
TFA Salt
[0270] Into a 50 mL round-bottom flask was placed tert-butyl
(1-((5-cyclohexylthiazol-2-yl)carbamoyl)azetidin-3-yl)carbamate
(190 mg, 0.50 mmol), dichloromethane (3 mL) and trifluoroacetic
acid (1 mL). The resulting solution was stirred for 2 h at room
temperature. The reaction mixture was concentrated under vacuum.
The residue was treated with ethyl ether and dried under vacuum to
afford 3-amino-N-(5-cyclohexylthiazol-2-yl)azetidine-1-carboxamide
TFA salt as a yellow oil. LC-MS (ESI) m/z 281.2[M+H].sup.+
Step 3.
3-(cyanoamino)-N-(5-cyclohexyl-1,3-thiazol-2-yl)azetidine-1-carbox-
amide
[0271] Into a 50 mL round-bottom flask was placed
3-amino-N-(5-cyclohexylthiazol-2-yl)azetidine-1-carboxamide TFA
salt (160 mg, 0.41 mmol), dichloromethane (5 mL), potassium
carbonate (169 mg, 1.22 mmol) and cyanogen bromide (44 mg, 0.42
mmol). The resulting solution was stirred for 2 h at room
temperature. The reaction mixture was poured into water (5 mL) and
then extracted with ethyl acetate (3.times.10 mL). The organic
layers were combined, dried over anhydrous sodium sulfate, filtered
and concentrated under vacuum. The residue was purified by
prep-HPLC (Column: XBridge Shield RP18 OBD Column, 130 .ANG., 5
.mu.m, 19 mm.times.150 mm; Mobile phase: water (10 mM
NH.sub.4HCO.sub.3), MeCN (30% MeCN up to 50% over 10 min); Flow
rate: 20 mL/min; Detector: 254 & 220 nm) to afford
3-cyanamido-N-(5-cyclohexylthiazol-2-yl)azetidine-1-carboxamide as
a white solid. 1H NMR (300 MHz, DMSO-d.sub.6) .delta. 6.96 (s, 1H),
4.43-4.38 (m, 2H), 4.21-4.10 (m, 3H), 2.77-2.73 (m, 1H), 1.81 (s,
4H), 1.45-1.32 (m, 7H). LC-MS (ESI) m/z 306.2[M+H].sup.+
Example 3-1,
5-phenyl-N-[(trans)-3-(cyanoamino)cyclobutyl]-1,3-thiazole-2-carboxamide
(Compound 3-1)
##STR00233##
[0272] Step 1. tert-butyl
((trans)-3-(5-bromothiazole-2-carboxamido)cyclobutyl)carbamate
[0273] Into a 100 mL round-bottom flask was placed
5-bromothiazole-2-carboxylic acid (300 mg, 1.41 mmol),
N,N-dimethylformamide (5 mL), tert-butyl
N-[(trans)-3-aminocyclobutyl]carbamate (270 mg, 1.42 mmol),
N,N-diisopropylethylamine (560 mg, 4.33 mmol) and HATU (661 mg,
1.74 mmol). The resulting solution was stirred for 1 h at room
temperature. The reaction mixture was poured into water (5 mL) and
then extracted with ethyl acetate (3.times.10 mL). The organic
layers were combined, dried over anhydrous sodium sulfate, filtered
and concentrated under vacuum. The residue was purified by prep-TLC
(eluting with 1:1 ethyl acetate/petroleum ether) to afford
tert-butyl
((trans)-3-(5-bromothiazole-2-carboxamido)cyclobutyl)carbamate as a
yellow solid. LC-MS (ESI) m-z 320.0, 322.0 [M+H-tBu].sup.+
Step 2. tert-butyl
((trans)-3-(5-phenylthiazole-2-carboxamido)cyclobutyl)carbamate
[0274] Into a 100 mL round-bottom flask purged and maintained with
an inert atmosphere of nitrogen was placed tert-butyl
((trans)-3-(5-bromothiazole-2-carboxamido)cyclobutyl)carbamate (200
mg, 0.51 mmol), 1,4-dioxane (15 mL), water (5 mL), phenylboronic
acid (78 mg, 0.63 mmol, 1.23), potassium carbonate (219 mg, 1.58
mmol) and Pd(dppf)Cl.sub.2 (39 mg, 0.05 mmol). The resulting
mixture was stirred overnight at 80.degree. C. After cooling to
room temperature, the reaction mixture was poured into water (10
mL) and then extracted with ethyl acetate (3.times.10 mL). The
organic layers were combined, dried over anhydrous sodium sulfate,
filtered and concentrated under vacuum. The residue was purified by
silica gel chromatography (eluting with 1:1 ethyl acetate/petroleum
ether) to afford tert-butyl
((trans)-3-(5-phenylthiazole-2-carboxamido)cyclobutyl)carbamate as
a white solid. LC-MS (ESI) m/z 374.2 [M+H].sup.+
Step 3.
N-((trans)-3-aminocyclobutyl)-5-phenylthiazole-2-carboxamide TFA
Salt
[0275] Into a 50 mL round-bottom flask was placed tert-butyl
((trans)-3-(5-phenylthiazole-2-carboxamido)cyclobutyl)carbamate (60
mg, 0.15 mmol), dichloromethane (3 mL) and trifluoroacetic acid
(0.6 mL). The resulting solution was stirred for 1 h at room
temperature. The reaction mixture was concentrated under vacuum.
The residue was treated with ethyl ether and dried under vacuum to
afford N-((trans)-3-aminocyclobutyl)-5-phenylthiazole-2-carboxamide
TFA salt as a yellow oil. LC-MS (ESI) m/z 274.2 [M+H].sup.+
Step 4.
5-phenyl-N-[(trans)-3-(cyanoamino)cyclobutyl]-1,3-thiazole-2-carbo-
xamide
[0276] Into a 50 mL round-bottom flask was placed
N-((trans)-3-aminocyclobutyl)-5-phenylthiazole-2-carboxamide TFA
salt (50 mg, 0.12 mmol), tetrahydrofuran (5 mL) and triethylamine
(16 mg, 0.16 mmol). After cooling to -10.degree. C., to this
solution was added cyanogen bromide (17 mg, 0.16 mmol). The
resulting solution was stirred for 30 min at -10.degree. C. The
reaction mixture was poured into water (5 mL) and then extracted
with ethyl acetate (3.times.10 mL). The organic layers were
combined, dried over anhydrous sodium sulfate, filtered and
concentrated under vacuum. The residue was purified by prep-HPLC
(Column: XBridge Shield RP18 OBD Column, 130 .ANG., 5 .mu.m. 19
mm.times.150 mm; Mobile phase: water (10 mM NH.sub.4HCO.sub.3),
MeCN (25% MeCN up to 55% over 7 min); Flow rate: 20 mL/min;
Detector: 254 & 220 nm) to afford
N-((trans)-3-cyanamidocyclobutyl)-5-phenylthiazole-2-carboxamide as
a white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.9.31 (d,
J=7.60 Hz, 1H), 8.44 (s, 1H), 7.80-7.77 (m, 2H), 7.51-7.41 (m, 3H),
7.22 (s, 1H), 4.56-4.50 (m, 1H), 3.85 (d, J=3.20 Hz, 1H), 2.51-2.46
(m, 2H), 2.33-2.08 (m, 2H). LC-MS (ESI) m/z 299.2 [M+H]+
[0277] The following compounds were synthesized in a manner
analogous to Compound 3-1:
TABLE-US-00006 Example MS m/z No. Structure Chemical Name [M + H]+
1H NMR Compound 3-2 ##STR00234## {[1-(2-1,3- thiazolo-5-
carbonyl)-1- azaspiro[3.3] heptan-6- yl]amino} carbonitrile 325
8.25 (s, 1H), 8.03-7.98 (m, 2H), 7.57-7.52 (m, 3H), 6.52 (s, 1H),
4.43-4.39 (m, 2H), 3.47-3.41 (m, 1H), 3.06-3.01 (m, 2H), 2.55-2.42
(m, 4H) Compound 3-3 ##STR00235## 3-[4-(1-methyl- 1H-pyrazol-4-
yl)phenyl]-N- [(1s,3s)-3- (cyanoamino) cyclobutyl]-1.2- oxazole-5-
carboxamide 363 1H-NMR (CD3OD, 400 MHz) .delta. (ppm): 8.09 (s,
1H), 7.92-7.89 (m, 3H), 7.72 (dd, J = 6.8, 2.0 Hz, 2H), 7.40 (s,
1H), 4.21-4.17 (m, 1H), 3.97 (s, 3H), 3.56-3.48 (m, 1H), 2.81-2.75
(m, 2H), 2.26-2.18 (m, 2H). Compound 3-4 ##STR00236##
{[(2r,4s)-5-{3-[4- (1-methyl-1H- pyrazol-4- yl)phenyl]-1,2-
oxazole-5- carbonyl}-5- azaspiro[3.4] octan-2-yl]amino}
carbonitrile 403 1H-NMR (CDCl3, 400 MHz) .delta. (ppm): 7.85-7.83
(m, 3H), 7.71 (s, 1H), 7.61 (d, J = 8.0 Hz, 2H), 7.18 (s, 1H),
4.40-4.34 (m, 1H), 4.00 (s, 3H), 3.96-3.92 (m, 2H), 3.47-4.41 (m,
2H), 2.37-2.241 (m, 4H), 1.96-1.91 (m, 2H). Compound 3-5
##STR00237## {[(4r,6s)-1-{3-[4- (1-methyl-1H- pyrazol-4-
yl)phenyl]-1,2- oxazole-5- carbonyl}-1- azaspiro[3.3] heptan-6-
yl]amino} carbonitrile 389 8.27 (s, 1H), 7.98 (s, 1H), 7.93 (d, J =
8.4 Hz, 2H), 7.73 (d, J = 8.4 Hz, 2H), 7.60 (s, 1H), 7.30 (d. J =
6.0 Hz, 1H), 4.46-4.42 (m, 2H), 3.89 (s, 3H), 3.48-3.44 (m, 1H),
3.06-3.00 (m, 2H), 2.48-2.42 (m, 4H) Compound 3-6 ##STR00238##
3-(3-cyanophenyl)- N-methyl-N- [(1r,3r)-3- (cyanoamino)
cyclobutyl]-1,2- oxazole-5- carboxamide 322 8.45 (s, 1H), 8.31 (d,
J = 7.6 Hz, 1H), 8.04 (d, J = 7.6 Hz, 1H), 7.78 (t, J = 8.0 Hz,
1H), 7.71-7.59 (m, 1H), 7.24 (br s, 1H), 5.12-5.08 (m, 0.5H),
4.74-4.70 (m, 0.5H), 3.82-3.78 (m, 1H), 3.14-3.06 (m, 3H),
2.73-2.60 (m, 2H), 2.45-2.22 (m, 2H)
Example 4-1.
5-phenyl-N-[(cis)-3-(cyanoamino)cyclobutyl]-1,3-thiazole-2-carboxamide
(Compound 4-1)
##STR00239##
[0278] Step 1. 5-phenylthiazole-2-carboxylic acid
[0279] Into a 100 mL round-bottom flask purged and maintained with
an inert atmosphere of nitrogen was placed
5-bromothiazole-2-carboxylic acid (1 g, 4.71 mmol), phenylboronic
acid (707 mg, 5.68 mmol), potassium carbonate (2 g, 14.47 mmol),
1,4-dioxane (20 mL), water (2 mL) and Pd(dppf)Cl.sub.2 (352 mg,
0.48 mmol). The resulting mixture was stirred for 16 h at
80.degree. C. After cooling to room temperature, the reaction
mixture was poured into water (5 mL) and then washed with ethyl
ether (2.times.5 mL). The aqueous layer was acidified to pH 5 with
hydrochloric acid (1N) and then extracted with ethyl acetate
(3.times.20 mL). The organic layers were combined, dried over
anhydrous sodium sulfate, filtered and concentrated under vacuum to
afford 5-phenylthiazole-2-carboxylic acid as a brown solid. LC-MS
(ESI) m/z 206.1 [M+H].sup.+
Step 2. tert-butyl
((cis)-3-(5-phenylthiazole-2-carboxamido)cyclobutyl)carbamate
[0280] Into a 100 mL round-bottom flask was placed
5-phenylthiazole-2-carboxylic acid (120 mg, 0.56 mmol),
N,N-dimethylformamide (20 mL), tert-butyl
N-[(cis)-3-aminocyclobutyl]carbamate (109 mg, 0.57 mmol),
N,N-diisopropylethylamine (227 mg, 1.76 mmol) and HATU (267 mg,
0.70 mmol). The resulting solution was stirred for 1 h at room
temperature. The reaction mixture was poured into water (10 mL) and
then extracted with ethyl acetate (3.times.20 mL). The organic
layers were combined, dried over anhydrous sodium sulfate, filtered
and concentrated under vacuum. The residue was purified by silica
gel chromatography (eluting with 1:3 ethyl acetate/petroleum ether)
to afford tert-butyl
((cis)-3-(5-phenylthiazole-2-carboxamido)cyclobutyl)carbamate as a
white solid. LC-MS (ESI) m/z 374.2 [M+H].sup.+
Step 3. N-(cis)-3-aminocyclobutyl)-5-phenylthiazole-2-carboxamide
TFA Salt
[0281] Into a 50 mL round-bottom flask was placed tert-butyl
(cis)-3-(5-phenylthiazole-2-carboxamido)cyclobutyl)carbamate (200
mg, 0.51 mmol), dichloromethane (5 mL) and trifluoroacetic acid (1
mL). The resulting solution was stirred for 1 h at room
temperature. The reaction mixture was concentrated under vacuum.
The residue was treated with ethyl ether and dried under vacuum to
afford N-(cis)-3-aminocyclobutyl)-5-phenylthiazole-2-carboxamide
TFA salt as a yellow oil. LC-MS (ESI) m/z 274.2 [M+H].sup.+
Step 4.
5-phenyl-N-[(cis)-3-(cyanoamino)cyclobutyl]-1,3-thiazole-2-carboxa-
mide
[0282] Into a 50 mL round-bottom flask was placed
N-(cis)-3-aminocyclobutyl)-5-phenylthiazole-2-carboxamide TFA salt
(120 mg, 0.29 mmol), tetrahydrofuran (10 mL) and triethylamine (54
mg, 0.53 mmol). After cooling to -10.degree. C., to this solution
was added cyanogen bromide (56 mg, 0.52 mmol). The resulting
solution was stirred for 30 min at -10.degree. C. The reaction
mixture was poured into water (5 mL) and then extracted with ethyl
acetate (3.times.10 mL). The organic layers were combined, dried
over anhydrous sodium sulfate, filtered and concentrated under
vacuum. The residue was purified by prep-HPLC (Column: XBridge
Shield RP18 OBD Column, 130 .ANG., 5 .mu.m, 19 mm.times.150 mm;
Mobile phase: water (10 mM NH.sub.4HCO.sub.3), MeCN (25% MeCN up to
55% over 7 min); Flow rate: 20 mL/min; Detector: 254 & 220 nm)
to afford
N-(cis)-3-cyanamidocyclobutyl)-5-phenylthiazole-2-carboxamide as a
white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 9.30 (d,
J=7.60 Hz, 1H), 8.43 (s, 1H), 7.78 (d, J=7.20 Hz, 2H), 7.51-7.43
(m, 3H), 7.17 (d, J=4.40 Hz, 1H), 4.06-4.04 (m, 1H), 3.39-3.33 (m,
1H), 2.56-2.50 (m, 2H), 2.23-2.16 (m, 2H). LC-MS (ESI) m/z 299.2
[M+H].sup.+
Example 5:
cis-3-(cyanoamino)-N-(5-cyclohexyl-1,3-thiazol-2-yl)cyclobutane-
-1-carboxamide (Compound 5-3)
##STR00240##
[0283] Step 1. tert-butyl
N-[cis-3-[(5-cyclohexyl-1,3-thiazol-2-yl)carbamoyl]cyclobutyl]carbamate
[0284] To a stirring mixture of
cis-3-[[(tert-butoxy)carbonyl]amino]cyclobutane-1-carboxylic acid
(100 mg, 0.465 mmol) in DMF (4 mL) was added HATU (212 mg, 0.560
mmol), DIEA (0.230 mL, 1.39 mmol) and
5-cyclohexyl-1,3-thiazol-2-amine (93.0 mg, 0.510 mmol) at
25.degree. C. The resulting solution was stirred for 1.5 h at
25.degree. C. The resulting mixture was diluted with water (10 mL)
and extracted with DCM (3.times.15 mL). The combined organic layer
was washed with brine (4.times.30 mL), dried over anhydrous sodium
sulfate, filtered and concentrated under reduced pressure. The
residue was purified by silica gel column chromatography (eluting
with 1/1 with ethyl acetate/petroleum ether) to afford tert-butyl
N-[cis-3-[(5-cyclohexyl-1,3-thiazol-2-yl)carbamoyl]cyclobutyl]carbamate
as a white solid (98.0 mg). LCMS (ES, m/z): 380 [M+H].sup.+.
Step 2.
cis-3-amino-N-(5-cyclohexyl-1,3-thiazol-2-yl)cyclobutane-1-carboxa-
mide 2,2,2-trifluoroacetate
[0285] A solution of tert-butyl
N-[(cis)-3-[(5-cyclohexyl-1,3-thiazol-2-yl)carbamoyl]cyclobutyl]carbamate
(98.0 mg, 0.258 mmol) and TFA (1 mL) in DCM (5 mL) was stirred for
1 h at 25.degree. C. The resulting mixture was concentrated under
reduced pressure to give
cis-3-amino-N-(5-cyclohexyl-1,3-thiazol-2-yl)cyclobutane-1-carboxamide
2,2,2-trifluoroacetate as yellow oil (102 mg). LCMS (ES, m/z): 280
[M+H].sup.+.
Step 3.
cis-3-(cyanoamino)-N-(5-cyclohexyl-1,3-thiazol-2-yl)cyclobutane-1--
carboxamide
[0286] To a stirring mixture of
cis-3-amino-N-(5-cyclohexyl-1,3-thiazol-2-yl)cyclobutane-1-carboxamide
2,2,2-trifluoroacetate (102 mg, 0.271 mmol) in DMF (2 mL) was added
Et.sub.3N (0.072 mL, 0.520 mmol) dropwise at 0.degree. C. Then BrCN
(28.0 mg, 0.260 mmol) was added. The mixture was stirred for 2 h at
25.degree. C. and then poured into ice/water (5 mL). The resulting
mixture was extracted with DCM (3.times.10 mL). The combined
organic layer was washed with brine (20 mL), dried over anhydrous
sodium sulfate, filtered and concentrated under reduced pressure.
The residue was purified by Prep-HPLC (Column, Kinetex EVO C18
Column, 21.2.times.150 mm, 5 .mu.m; Mobile phase, A: water (10
mmol/L NH.sub.4HCO.sub.3) and B: ACN (27% up to 46% in 10 min);
Detector, UV 254/220 nm). The collected fraction was lyophilized to
give
cis-3-(cyanoamino)-N-(5-cyclohexyl-1,3-thiazol-2-yl)cyclobutane-1-carboxa-
mide as a white solid (14.9 mg). .sup.1H-NMR (DMSO-da, 400 MHz)
.delta. (ppm): 11.88 (br s, 1H), 7.20 (br s, 1H), 7.14 (s, 1H),
3.67-3.55 (m, 1H), 2.97-2.85 (m, 1H), 2.83-2.71 (m, 1H), 2.47-2.36
(m, 2H), 2.20-2.10 (m, 2H), 2.00-1.88 (m, 2H), 1.81- 1.71 (m, 2H),
1.71-1.62 (m, 1H), 1.44-1.29 (m, 4H), 1.28-1.15 (m, 1H). LCMS (ES,
m/z): 305 [M+H].sup.+
[0287] The following compounds were synthesized according to
Example 5:
TABLE-US-00007 Example MS m/z No. Structure Chemical Name [M + H]+
Compound 5-1 ##STR00241## cis-3-(cyanoamino)-N-(1-phenyl-1H-
pyrazol-4-yl)cyclobutane-1- carboxamide LC-MS (ESI) m/z 282.2 [M +
H].sup.+ Compound 5-2 ##STR00242##
cis-3-(cyanoamino)-N-(1-phenyl-1H- pyrazol-3-yl)cyclobutane-1-
carboxamide LC-MS (ESI) m/z 282.2 [M + H].sup.+ Compound 5-4
##STR00243## cis-3-(cyanoamino)-N-(5-phenyl-1,3-
thiazol-2-yl)cyclobutane-1- carboxamide LC-MS (ESI) m/z 299.1 [M +
H].sup.+ Compound 5-5 ##STR00244##
trans-3-(cyanoamino)-N-(1-phenyl- 1H-pyrazol-4-yl)cyclobutane-1-
carboxamide LC-MS (ESI) m/z 282.2 [M + H].sup.+ Compound 5-6
##STR00245## trans-3-(cyanoamino)-N-(1-phenyl-
1H-pyrazol-3-yl)cyclobutane-1- carboxamide LC-MS (ESI) m/z 282.2 [M
+ H].sup.+ Compound 5-7 ##STR00246## trans-3-(cyanoamino)-N-(5-
cyclohexyl-1,3-thazol-2- yl)cyclobutane-1-carboxamide LC-MS (ESI)
m/z 305.2 [M + H].sup.+ Compound 5-8 ##STR00247##
trans-3-(cyanoamino)-N-(5-phenyl- 1,3-thiazol-2-yl)cyclobutane-1-
carboxamide LC-MS (ESI) m/z 299.2 [M + H].sup.+ Compound 5-9
##STR00248## cis-3-(cyanoamino)-N-(2,3-dihydro-
1H-inden-5-yl)cyclobutane-1- carboxamide LC-MS (ESI) m/z 256.2 [M +
H].sup.+ Compound 5-10 ##STR00249##
cis-N-(5-tert-butyl-1,3-thiazol-2-yl)-3- (cyanoamino)cyclobutane-1-
carboxamide LC-MS (ESI) m/z 279.2 [M + H].sup.+ Compound 5-11
##STR00250## {[cis-3-(4-phenylpiperazine-1-
carbonyl)cyclobutylamino}carbonitrile LC-MS (ESI) m/z 285.3 [M +
H].sup.+ Compound 5-12 ##STR00251##
trans-3-(cyanoamino)-N-(2,3-dihydro- 1H-inden-5-yl)cyclobutane-1-
carboxamide LC-MS (ESI) m/z 256.2 [M + H].sup.+ Compound 5-13
##STR00252## trans-N-(5-tert-butyl-1,3-thiazol-2-yl)-
3-(cyanoamino)cyclobutane-1- carboxamide LC-MS (ESI) m/z 279.2 [M +
H].sup.+ Compound 5-14 ##STR00253## trans-3-(cyanoamino)-N-[4-
(morpholin-4-yl)phenyl]cyclobutane- 1-carboxamide LC-MS (ESI) m/z
301.2 [M + H.sup.+
Example 6:
{[(1r,3r)-3-[(4S)-4-[(5-cyclohexyl-1,3-thiazol-2-yl)amino]-2-ox-
opyrrolidin-1-yl]cyclobutyl]amino}formonitrile (Compound 6-1)
##STR00254## ##STR00255##
[0288] Step 1. 1-(2-Amino-1,3-thiazol-5-yl)cyclohexan-1-ol
[0289] A solution of n-BuLi (2.5 M in hexane)(200 mL) was added to
a solution of 1,3-thiazol-2-amine (25.0 g, 0.250 mol) in THF (200
mL) at -78.degree. C. and then the mixture was stirred for 15 min
at -78.degree. C. Trimethylchlorosilane (54.5 g, 0.500 mol) was
added at -78.degree. C. The resulting mixture was stirred for 30
min at -25.degree. C. A solution of n-BuLi (2.5 M in hexane) (100
mL) was added at -78.degree. C. and the mixture was stirred for 15
min at -78.degree. C. Cyclohexanone (27.0 g, 0.275 mol) was added
and the resulting mixture was stirred for an additional 30 min at
-78.degree. C. The reaction was quenched with ammonium chloride
(200 mL sat.) at -78.degree. C. The resulting mixture was extracted
with ethyl acetate (3.times.200 mL). The combined organic layers
were washed with brine (200 mL), dried over anhydrous sodium
sulfate, filtered and concentrated under vacuum to afford
1-(2-amino-1,3-thiazol-5-yl)cyclohexan-1-ol as a brown solid (26.0
g). LCMS (ES, m/z) 199 [M+H].sup.+.
Step 2. 5-Cyclohexyl-1,3-thiazol-2-amine
[0290] Triethylsilane (122 g, 1.05 mol) and TFA (90 mL) were added
to a solution of 1-(2-amino-1,3-thiazol-5-yl)cyclohexan-1-ol (23.0
g, 115 mmol) in DCM (500 mL), and the reaction mixture stirred for
1 h at 25.degree. C. The resulting mixture was concentrated under
vacuum. The residue was re-crystallized from ethyl ether (50 mL).
The solids were collected by filtration to afford
5-cyclohexyl-1,3-thiazol-2-amine as an off-white solid (18.0 g).
LCMS (ES, m/z): 183 [M+H].sup.+.
Step 3. 2-Bromo-5-cyclohexyl-1,3-thiazole
[0291] tert-Butyl nitrite (8.83 mL, 81.4 mmol) was added into a
stirring mixture of 5-cyclohexyl-1,3-thiazol-2-amine (10.0 g, 54.9
mmol) and CuBr.sub.2 (24.5 g, 108 mmol) in ACN (200 mL) at
0.degree. C. The resulting mixture was stirred for 1.5 h at
25.degree. C. The reaction was quenched by the addition of water
(100 mL). The solvent was removed under vacuum. The residue was
extracted with dichloromethane (3.times.300 mL). The combined
organic layers were dried over anhydrous sodium sulfate. After
filtration, the filtrate was concentrated under reduced pressure.
The residue was purified by silica gel chromatography (eluting with
1:10 ethyl acetate/petroleum ether) to afford
2-bromo-5-cyclohexyl-1,3-thiazole as yellow oil (10.8 g). LCMS (ES,
m/z): 246,248 [M+H].sup.+.
Step 4. Methyl
(3S)-3-[[(benzyloxy)carbonyl]amino]-4-hydroxybutanoate
[0292] A solution of
(2S)-2-[[(benzyloxy)carbonyl]amino]-4-methoxy-4-oxobutanoic acid
(8.00 g, 27.1 mmol), NMM (2.88 g, 27.1 mmol), and ethyl
chloroformate (4.01 g, 35.1 mmol) in THF (50 mL) was stirred for 10
min at -10.degree. C. To the above mixture was added NaBH.sub.4
(5.38 g, 135 mmol) in one portion at -10.degree. C. Methanol (70
mL) was added dropwise at -10.degree. C., and the resulting mixture
was stirred for additional 30 min at 0.degree. C. The solvent was
removed under vacuum. The pH value of the residue was adjusted to 6
with hydrochloric acid (1 N) at 0.degree. C. The resulting mixture
was extracted with DCM (3.times.50 mL). The combined organic layers
were dried over anhydrous sodium sulfate, filtered, and
concentrated under vacuum. The residue was purified by reverse
phase chromatography (Column, C18 silica gel; Mobile phase, A:
water (containing 10 mM NH.sub.4HCO.sub.3) and B: ACN (10% to 50%
in 10 min); Detector, UV 254/220 nm) to afford methyl
(3S)-3-[[(benzyloxy)carbonyl]amino]-4-hydroxybutanoate as colorless
oil (3.00 g). LCMS (ES, m/z) 268 [M+H].sup.+.
Step 5. Methyl
(3S)-3-[[(benzyloxy)carbonyl]amino]-4-oxobutanoate
[0293] DMP (6.77 g, 15.2 mmol) was added in portions to a 0.degree.
C. solution of methyl
(3S)-3-[[(benzyloxy)carbonyl]amino]-4-hydroxybutanoate (3.00 g,
10.1 mmol) in DCM (40 mL). The mixture was stirred for 2 h at
25.degree. C. The reaction was quenched with saturated aqueous
sodium thiosulfate (10 mL). The solids were filtered out and the
filter cake was washed with DCM (3.times.10 mL). The filtrate was
washed with sodium bicarbonate (2.times.20 mL, sat.). The combined
organic layers were dried over anhydrous sodium sulfate. After
filtration, the filtrate was concentrated under reduced pressure.
The residue was purified by reverse phase chromatography (Column,
C18 silica gel; Mobile phase, A: water (containing 10 mM
NH.sub.4HCO.sub.3) and B: ACN (5% to 50% in 5 min); Detector, UV
254/220 nm) to afford methyl
(3S)-3-[[(benzyloxy)carbonyl]amino]-4-oxobutanoate as yellow oil
(2.00 g). LCMS (ES, m/z) 266 [M+H].sup.+.
Step 6. Benzyl
N-[(3S)-5-oxo-1-[(1r,3r)-3-[[(tert-butoxy)carbonyl]amino]cyclobutyl]pyrro-
lidin-3-yl]carbamate
[0294] A solution of tert-butyl
N-[(trans)-3-aminocyclobutyl]carbamate (545 mg, 2.78 mmol) and
methyl (35)-3-[[(benzyloxy)carbonyl]amino]-4-oxobutanoate (820 mg,
2.78 mmol) in DCM (30 mL) was stirred for 1 h at 25.degree. C.
Sodium triacetoxyborohydride (807 mg, 3.62 mmol) was added in two
portions, and the resulting mixture was stirred for additional 14 h
at 25.degree. C. The reaction was quenched by the addition of
water/ice (30 mL). The resulting mixture was extracted with DCM
(2.times.50 mL). The combined organic layers were washed with brine
(50 mL), dried over anhydrous sodium sulfate, filtered and
concentrated under vacuum. The residue was treated with DMF (5 mL).
The solids were collected by filtration, washed with MeOH
(3.times.10 mL) and dried in an oven to afford benzyl
N-[(3S)-5-oxo-1-[(trans)-3-[[(tert-butoxy)carbonyl]amino]cyclobutyl]pyrro-
lidin-3-yl]carbamate as a white solid (800 mg). LCMS (ES, m/z) 404
[M+H].sup.+.
Step 7. tert-butyl
N-[(1r,3r)-3-(4-amino-2-oxopyrrolidin-1-yl)cyclobutyl]carbamate
[0295] A mixture of benzyl
N-[(3S)-5-oxo-1-[(1r,3r)-3-[[(tert-butoxy)carbonyl]amino]cyclobutyl]pyrro-
lidin-3-yl]carbamate (800 mg, 1.99 mmol) and palladium on carbon
(500 mg, 10%) in methanol (30 mL) was stirred for 4 h at 25.degree.
C. under hydrogen atmosphere (balloon). The solids were filtered
out and the filter cake was washed with methanol (2.times.5 mL).
The filtrate was concentrated under reduced pressure to afford
tert-butyl
N-[(trans)-3-(4-amino-2-oxopyrrolidin-1-yl)cyclobutyl]carbamate as
colorless oil (480 mg). LCMS (ES, m/z) 270 [M+H].sup.+.
Step 8. tert-butyl
N-[(trans)-3-[4-[(5-cyclohexyl-1,3-thiazol-2-yl)amino]-2-oxopyrrolidin-1--
yl]cyclobutyl]carbamate
[0296] A mixture of tert-butyl
N-[(trans)-3-(4-amino-2-oxopyrrolidin-1-yl)cyclobutyl]carbamate
(300 mg, 1.12 mmol), 2-bromo-5-cyclohexyl-1,3-thiazole (360 mg,
1.32 mmol), BrettPhos (120 mg, 0.220 mmol), 3.sup.rd generation
BrettPhos precatalyst (100 mg, 0.100 mmol), and t-BuOK (180 mg,
1.52 mmol) in dioxane (20 mL) was stirred for 1 h at 100.degree. C.
After cooling to 25.degree. C., the reaction was quenched by the
addition of water (30 mL). The resulting mixture was extracted with
ethyl acetate (2.times.30 mL). The combined organic layers were
washed with brine (30 mL), dried over anhydrous sodium sulfate,
filtered and concentrated under vacuum. The residue was purified by
reverse phase chromatography (Column, C18 silica gel; Mobile phase,
A: water (containing 10 mM NH.sub.4HCO.sub.3) and B: ACN (30% to
70% in 10 min); Detector, UV 254/220 nm) to afford tert-butyl
N-[(trans)-3-[4-[(5-cyclohexyl-1,3-thiazol-2-yl)amino]-2-oxopyrrolidin-1--
yl]cyclobutyl]carbamate as a yellow solid (300 mg). LCMS (ES, m/z)
435 [M+H].sup.+.
Step 9.
4-[(5-cyclohexyl-1,3-thiazol-2-yl)amino]-1-[(trans)-3-aminocyclobu-
tyl]pyrrolidin-2-one 2,2,2-trifluroacetate
[0297] A solution of tert-butyl
N-[(trans)-3-[4-[(5-cyclohexyl-1,3-thiazol-2-yl)amino]-2-oxopyrrolidin-1--
yl]cyclobutyl]carbamate (180 mg, 0.331 mmol) and TFA (1 mL) in DCM
(5 mL) was stirred for 1 h at 25.degree. C. The resulting mixture
was concentrated under vacuum to afford
4-[(5-cyclohexyl-1,3-thiazol-2-yl)amino]-1-[(trans)-3-aminocyclobutyl]pyr-
rolidin-2-one 2,2,2-trifluoroacetate as yellow oil (200 mg). LCMS
(ES, m/z) 335 [M+H].sup.+.
Step 10.
[[(trans)-3-[4-[(5-cyclohexyl-1,3-thiazol-2-yl)amino]-2-oxopyrrol-
idin-1-yl]cyclobutyl]amino]formonitrile
[0298] A mixture of
4-[(5-cyclohexyl-1,3-thiazol-2-yl)amino]-1-[(trans)-3-aminocyclobutyl]pyr-
rolidin-2-one 2,2,2-trifluoroacetate (200 mg, 0.464 mmol) and
NaHCO.sub.3 (315 mg, 3.56 mmol) in DMF (4 mL) was stirred for 30
min at 0.degree. C. A solution of cyanogen bromide (40.0 mg, 0.360
mmol) in DMF (1 mL) was added dropwise at 0.degree. C. The
resulting mixture was stirred for 14 h at 25.degree. C. The
reaction was quenched by the addition of water/ice (10 mL). The
resulting mixture was extracted with ethyl acetate (2.times.20 mL).
The combined organic layers were washed with brine (20 mL), dried
over anhydrous sodium sulfate, filtered and concentrated under
vacuum. The residue was purified by Prep-HPLC (Column: XBridge
Shield RP18 OBD, 5 .mu.m, 19.times.150 mm; Mobile Phase, A: water
(containing 10 mM ammonium bicarbonate) and B: CH.sub.3CN (2% to
40% over 1 min); Detector: UV 254/220 nm). The product fractions
were lyophilized to afford
[[(1r,3r)-3-[4-[(5-cyclohexyl-1,3-thiazol-2-yl)amino]-2-oxopyrroli-
din-1-yl]cyclobutyl]amino]formonitrile as a white solid (70 mg).
LCMS (ES, m/z) 360 [M+H].sup.+.
Step 11.
(1r,3r)-3-[(4S)-4-[(5-cyclohexyl-1,3-thiazol-2-yl)aminol-2-oxopyr-
rolidin-1-yl]cyclobutyl]amino)formonitrile
[0299]
[[(1r,3r)-3-[4-[(5-Cyclohexyl-1,3-thiazol-2-yl)amino]-2-oxopyrrolid-
in-1-yl]cyclobutyl]amino]formonitrile (70.0 mg, 0.175 mmol) was
separated by Chiral-HPLC (Column: CHIRALPAK IE, 2.times.25 cm, 5
um; Mobile Phase A: MTBE (containing 0.2% IPA) and B: EtOH (hold
20% in 14 min); Flow rate. 17 mL/min; Detector: 220/254 nm;
RT.sub.1: 9.148 min; RT.sub.2:11.792 min). The first eluting isomer
(RT.sub.1=9.148 min) was collected and lyophilized to afford a
yellow oil arbitrarily assigned as
{[(1r,3r)-3-[(4S)-4-[(5-cyclohexyl-1,3-thiazol-2-yl)amino]-2-oxopyrrolidi-
n-1-yl]cyclobutyl]amino}formonitrile (28.3 mg). .sup.1H-NMR
(DMSO-46, 400 MHz) .delta. (ppm): 7.68 (br s, 1H), 7.24 (br s, 1H),
6.72 (s, 1H), 4.73-4.69 (m, 1H), 4.26-4.24 (m, 1H), 3.80-3.72 (m,
2H), 3.26-3.21 (m, 1H), 2.71-2.59 (m, 2H), 2.51-2.46 (m, 1H),
2.25-2.20 (m, 1H), 2.11-2.06 (m, 2H), 1.89-1.87 (m, 2H), 1.74-1.71
(m, 2H), 1.66-1.63 (m, 1H), 1.37-1.13 (m, 6H). LCMS (ES, m/z) 360
[M+H].sup.+. The second eluting isomer (RT=11.792 min) was
collected and lyophilized to afford a yellow oil arbitrarily
assigned as
{[(1r,3r)-3-[(4R)-4-[(5-cyclohexyl-1,3-thiazol-2-yl)amino]-2-oxopyrrolidi-
n-1-yl]cyclobutyl]amino}formonitrile (26.2 mg). LCMS (ES, m/z) 360
[M+H].sup.+.
Example 7.
{[(2r,4s)-6-(5-tert-butyl-4-chloro-1,3-thiazol-2-yl)-5-oxo-6-az-
aspiro[3.4]octan-2-yl]amino}carbonitrile (Compound 7-1)
##STR00256##
[0300] Step 1. tert-butyl
N-[5-oxo-6-azaspiro[3.4]octan-2-yl]carbamate
[0301] Di-tert-butyl dicarbonate (0.600 mL, 2.73 mmol) was added to
a solution of 2-amino-6-azaspiro[3.4]octan-5-one (300 mg, 2.14
mmol) and Na.sub.2CO.sub.3 (454 mg, 4.24 mmol) in dioxane (5 mL)
and water (0.5 mL) and the solution stirred for 4 h at 25.degree.
C. The resulting mixture was diluted with water (10 mL) and
extracted with ethyl acetate (3.times.50 mL). The combined organic
layers were dried over anhydrous sodium sulfate, filtered and
concentrated under vacuum. The residue was purified by reverse
phase chromatography (Column, C18 silica gel; Mobile phase, A:
water (containing 10 mM NH4HCO3) and B: ACN (5% to 50% in 5 min);
Detector, UV 254/220 nm) to afford tert-butyl
N-[5-oxo-6-azaspiro[3.4]octan-2-yl]carbamate as a white solid (400
mg). LCMS (ES, m/z) 241 [M+H].sup.+.
Step 2. tert-butyl
N-[6-(5-tert-butyl-1,3-thiazol-2-yl)-5-oxo-6-azaspiro[3.4]octan-2-yl]carb-
amate
[0302] A mixture of tert-butyl
N-[5-oxo-6-azaspiro[3.4]octan-2-yl]carbamate (654 mg, 2.59 mmol),
2-bromo-5-tert-butyl-1,3-thiazole (600 mg, 2.59 mmol),
K.sub.3PO.sub.4 (1.67 g, 7.79 mmol), CuI (99.6 mg, 0.518 mmol), and
methyl[2-(methylamino)ethyl]amine (115 mg, 1.30 mmol) in toluene
(12 mL) was stirred for 16 h at 100.degree. C. After cooling to
25.degree. C., the reaction was quenched by the addition of water
(50 mL). The resulting mixture was extracted with ethyl acetate
(3.times.100 mL). The combined organic layers were washed with
brine (100 mL), dried over anhydrous sodium sulfate. After
filtration, the filtrate was concentrated under reduced pressure.
The residue was purified by silica gel chromatography (eluting with
3:7 petroleum ether/ethyl acetate) to afford
N-[6-(5-tert-butyl-1,3-thiazol-2-yl)-5-oxo-6-azaspiro[3.4]octan-2-yl]carb-
amate as a yellow solid (690 mg). LCMS (ES, m/z): 380
[M+H].sup.+.
Step 3. tert-butyl
N-[6-(5-tert-butyl-4-chloro-1,3-thiazol-2-yl)-5-oxo-6-azaspiro[3.4]octan--
2-yl]carbamate
[0303] A solution of tert-butyl
N-[6-(5-tert-butyl-1,3-thiazol-2-yl)-5-oxo-6-azaspiro[3.4]octan-2-yl]carb-
amate (600 mg, 1.50 mmol) and NCS (300 mg, 2.25 mmol) in
acetonitrile (10 mL) was stirred for 16 h at 60.degree. C. The
mixture was allowed to cool down to 25.degree. C. The reaction was
quenched by the addition of water (20 mL). The resulting mixture
was extracted with ethyl acetate (3.times.50 mL). The combined
organic layers were dried over anhydrous sodium sulfate. After
filtration, the filtrate was concentrated under reduced pressure.
The residue was purified by silica gel chromatography (eluting with
1:1 petroleum ether/ethyl acetate) to afford tert-butyl
N-[6-(5-tert-butyl-4-chloro-1,3-thiazol-2-yl)-5-oxo-6-azaspiro[3.4]octan--
2-yl]carbamate as yellow oil (270 mg). LCMS (ES, m/z): 414, 416
[M+H].sup.+.
Step 4.
2-amino-6-(5-tert-butyl-4-chloro-1,3-thiazol-2-yl)-6-azaspiro[3.4]-
octan-5-one 2,2,2-trifluoroacetate
[0304] A solution of tert-butyl
N-[6-(5-tert-butyl-4-chloro-1,3-thiazol-2-yl)-5-oxo-6-azaspiro[3.4]octan--
2-yl]carbamate (200 mg, 0.460 mmol) and TFA (2 mL) in DCM (5 mL)
was stirred for 1 h at 25.degree. C. The resulting mixture was
concentrated under vacuum to afford
2-amino-6-(5-tert-butyl-4-chloro-1,3-thiazol-2-yl)-6-azaspiro[3.4]octan-5-
-one 2,2,2-trifluroracetate as yellow oil (210 mg). LCMS (ES, m/z):
314, 316 [M+H].sup.+.
Step 5.
[[6-(5-tert-butyl-4-chloro-1,3-thiazol-2-yl)-5-oxo-6-azaspiro[3.4]-
octan-2-yl]amino]formonitrile
[0305] A mixture of
2-amino-6-(5-tert-butyl-4-chloro-1,3-thiazol-2-yl)-6-azaspiro[3.4]octan-5-
-one 2,2,2-trifluroracetate (150 mg, 0.365 mmol), NaHCO.sub.3 (132
mg, 1.58 mmol) and BrCN (33.4 mg, 0.320 mmol) in DMF (3 mL) was
stirred for 4 h at 25.degree. C. The reaction was quenched by the
addition of water (10 mL). The resulting mixture was extracted with
ethyl acetate (3.times.30 mL). The combined organic layers were
washed with brine (30 mL), dried over anhydrous sodium sulfate.
After filtration, the filtrate was concentrated under reduced
pressure. The residue was purified by Prep-HPLC (Column: XBridge
Prep Phenyl OBD Column, 5 .mu.m, 19.times.150 mm; Mobile Phase, A:
water (containing 0.05% ammonium bicarbonate) and B: CH.sub.3CN
(13% to 37% in 7 min); Detector: UV 254 nm). The product fractions
were lyophilized to afford
[[6-(5-tert-butyl-4-chloro-1,3-thiazol-2-yl)-5-oxo-6-azaspiro[3.4]octan-2-
-yl]amino]formonitrile as a white solid (70.0 mg). LCMS (ES, m/z):
314, 316 [M+H].sup.+.
Step 6.
[[(2s,4r)-6-(5-tert-butyl-4-chloro-1,3-thiazol-2-yl)-5-oxo-6-azasp-
iro[3.4]octan-2-yl]amino]formonitrile and
[[(2r,4s)-6-(5-tert-butyl-4-chloro-1,3-thiazol-2-yl)-5-oxo-6-azaspiro[3.4-
]octan-2-yl]amino]formonitrile
[0306]
[[6-(5-tert-butyl-4-chloro-1,3-thiazol-2-yl)-5-oxo-6-azaspiro[3.4]o-
ctan-2-yl]amino]formonitrile (70.0 mg, 0.223 mmol) was separated by
Chiral-HPLC (Column, CHIRALPAK IA, 5 um, 2.times.25 cm; Mobile
phase, A: hexane and B: ethanol (hold 30% in 10 min); flow rate: 20
mL/min; Detector: 254 and 220 nm; RT.sub.1: 7.043 min; RT.sub.2:
8.368 min). The product fraction (RT: 7.043 min) was lyophilized to
afford a white solid arbitrarily assigned as
[[(2s,4r)-6-(5-tert-butyl-4-chloro-1,3-thiazol-2-yl)-5-oxo-6-azaspiro[3.4-
]octan-2-yl]amino]formonitrile (22.6 mg). .sup.1H-NMR
(DMSO-d.sub.6, 400 MHz) .delta. (ppm): 7.35 (br s, 1H), 3.89-3.86
(m, 2H), 3.83-3.82 (m, 1H), 2.34-2.23 (m, 6H), 1.41 (s, 9H). LCMS
(ES, m/z): 339, 341[M+H].sup.+.
The product fraction (RT: 8.368 min) was lyophilized to afford a
white solid arbitrarily assigned as
[[(2r,4s)-6-(5-tert-butyl-4-chloro-1,3-thiazol-2-yl)-5-oxo-6-azaspiro[3.4-
]octan-2-yl]amino]formonitrile (15.1 mg). .sup.1H-NMR
(DMSO-d.sub.6, 400 MHz) .delta. (ppm): 7.30 (br s, 1H), 3.88-3.85
(m, 2H), 3.81-3.80 (m, 1H), 2.63-2.62 (m, 2H), 2.28-2.24 (m, 2H),
2.16-2.12 (m, 2H), 1.42 (s, 9H). LCMS (ES, m/z): 339,
341[M+H].sup.+.
[0307] The following compounds were synthesized according to
Example 7:
TABLE-US-00008 Example MS m/z No. Structure Chemical Name [M + H]+
1H NMR Compound 7-2 ##STR00257## {[(2s,4r)-6-(4-chloro-
5-cyclohexyl-1,3- thiazol-2-yl)-5-oxo- 6-azaspiro[3.4]octan- 2-
yl]amino}carbonitrile 365, 367 7.35 (br s, 1H), 3.92-3.88 (m, 2H),
3.83-3.79 (m, 1H), 2.86-2.85 (m, 1H), 2.32-2.24 (m, 6H), 1.90-1.87
(m, 2H, 1.79-1.76 (m, 2H), 1.70-1.67 (m, 1H), 1.38-1.18 (m, 5H)
Compound 7-3 ##STR00258## {[(2r,4s)-6-(4-chloro- 5-cyclohexyl-1,3-
thiazol-2-yl)-5-oxo- 6-azaspiro[3.4]octan- 2- yl]amino}carbonitrile
365, 367 7.28 (br s, 1H), 3.90-3.87 (m, 2H), 3.84-3.78 (m, 1H),
2.86-2.85 (m, 1H), 2.66-2.61 (m, 2H), 2.28-2.25 (m, 2H), 2.15-2.08
(m, 2H), 1.90-1.87 (m, 2H), 1.79-1.76 (m, 2H), 1.70-1.67 (m, 1H),
1.41-1.18 (m, 5H)
Example 8.
N-(5-tert-butyl-4-chloro-1,3-thiazol-2-yl)-3-(cyanoamino)-1-met-
hoxycyclobutane-1-carboxamide (Compound 8-1)
##STR00259## ##STR00260##
[0308] Step 1. 5-tert-butyl-1,3-thiazol-2-amine
[0309] A solution of 3,3-dimethylbutanal (20.0 g, 0.200 mol),
pyrrolidine (17.5 mL, 0.214 mol) and TsOH (40.0 mg, 0.232 mol) in
cyclohexane (280 mL) was heated to reflux for 3 h. After cooling to
25.degree. C., the solvent was removed under reduced pressure. The
residue was dissolved in methanol (80 mL). The resulting solution
was added into a stirring mixture of sulfur (6.40 g, 194 mmol) and
cyanamide (8.39 g, 0.200 mol) in methanol (20 mL) at 0.degree. C.
The reaction mixture was stirred for 12 h at 25.degree. C. and then
concentrated under reduce pressure. The residue was purified by
silica gel chromatography (eluting with 1:1 ethyl acetate/petroleum
ether) to afford 5-tert-butyl-1,3-thiazol-2-amine as a light yellow
solid (8.10 g). LCMS (ES, m/z): 157 [M+H].sup.+.
Step 2. tert-butyl N-(5-tert-butyl-1,3-thiazol-2-yl)carbamate
[0310] A solution of 5-tert-butyl-1,3-thiazol-2-amine (500 mg, 3.21
mmol), di-tert-butyl dicarbonate (1.39 g, 6.38 mmol), and
Na.sub.2CO.sub.3 (680 mg, 6.42 mmol) in ethyl acetate (10 mL) and
water (10 mL) was stirred for 16 h at 25.degree. C. The reaction
solution was diluted with water (30 mL). The resulting mixture was
extracted with ethyl acetate (3.times.60 mL). The combined organic
layers were washed with brine (70 mL), dried over anhydrous sodium
sulfate, filtered and concentrated under vacuum. The residue was
purified by silica gel chromatography (eluting with 1:4 ethyl
acetate/petroleum ether) to afford tert-butyl
N-(5-tert-butyl-1,3-thiazol-2-yl)carbamate as a yellow solid (700
mg). LCMS (ES, m/z): 257 [M+H].sup.+.
Step 3. tert-butyl
N-(5-tert-butyl-4-chloro-1,3-thiazol-2-yl)carbamate
[0311] A solution of tert-butyl
N-(5-tert-butyl-1,3-thiazol-2-yl)carbamate (700 mg, 2.73 mmol) and
NCS (852 mg, 3.55 mmol) in MeCN was stirred for 2 h at 60.degree.
C. After cooling down to 25.degree. C., the solids were filtered
out and the filtrate was concentrated under reduced pressure. The
residue was diluted with water (50 mL) at 25.degree. C. The
resulting mixture was extracted with ethyl acetate (2.times.50 mL).
The organic layers were combined, washed with brine (40 mL), dried
over anhydrous sodium sulfate, filtered and concentrated under
vacuum. The residue was purified by silica gel chromatography
(eluting with 1:5 ethyl acetate/petroleum ether) to afford
tert-butyl N-(5-tert-butyl-4-chloro-1,3-thiazol-2-yl)carbamate as a
white solid (530 mg). LCMS (ES, m/z): 291, 293 [M+H].sup.+.
Step 4. 5-tert-butyl-4-chloro-1,3-thiazol-2-amine
[0312] A solution of tert-butyl
N-(5-tert-butyl-4-chloro-1,3-thiazol-2-yl)carbamate (525 mg, 1.80
mmol) and TFA (2 mL) in DCM (5 mL) was stirred for 14 h at
25.degree. C. The resulting mixture was concentrated under vacuum.
The residue was purified by reverse phase chromatography (Column,
C18 silica gel; Mobile phase, A: water (containing 10 Mm
NH.sub.4HCO.sub.3) and B: ACN (10% to 50% in 8 min); Detector, UV
254/220 nm) to afford 5-tert-butyl-4-chloro-1,3-thiazol-2-amine as
a yellow solid (310 mg). LCMS (ES, m/z): 191, 193 [M+H].sup.+.
Step 5.
2-(3-Hydroxycyclobutyl)-2,3,3a,7a-tetrahydro-1H-isoindole-1,3-dion-
e
[0313] Triethylamine (20.2 mL, 192 mmol) was added to a solution of
3-aminocyclobutan-1-ol hydrochloride (10.0 g, 76.8 mmol) and
1,3-dihydro-2-benzofuran-1,3-dione (15.5 g, 100 mmol) in toluene
(400 mL). The resulting mixture was stirred for 6 h at 120.degree.
C. After cooling to 25.degree. C., the resulting mixture was
concentrated under reduced pressure. The residue was purified by
silica gel chromatography (eluting with 1:1 ethyl acetate/petroleum
ether) to afford
2-(3-hydroxycyclobutyl)-2,3,3a,7a-tetrahydro-1H-isoindole-1,3-dione
as a white solid (8.00 g). LCMS (ES, m/z): 218 [M+H].sup.+.
Step 6. 2-(3-Oxocyclobutyl)-2,3-dihydro-1H-isoindole-1,3-dione
[0314] DMP (7.91 g, 18.6 mmol) was added in portions to a 0.degree.
C. solution of
2-(3-hydroxycyclobutyl)-2,3-dihydro-1H-isoindole-1,3-dione (3.00 g,
12.4 mmol) in DCM (60 mL). The resulting mixture was stirred for 2
h at 25.degree. C. The solids were filtered out and the filter cake
was washed with DCM (3.times.20 mL). The filtrate was concentrated
under reduced pressure. The residue was treated with ethyl acetate
(20 mL). The solids were collected by filtration and dried in an
oven to give 2-(3-oxocyclobutyl)-2,3-dihydro-1H-isoindole-1,3-dione
as a white solid (2.70 g). LCMS (ES, m/z): 216 [M+H].sup.+.
Step 7.
3-(1,3-Dioxo-2,3-dihydro-1H-isoindol-2-yl)-1-hydroxycyclobutane-1--
carbonitrile
[0315] ZnI.sub.2 (210 mg, 0.630 mmol) was added to a 0.degree. C.
solution of 2-(3-oxocyclobutyl)-2,3-dihydro-1H-isoindole-1,3-dione
(7.50 g, 31.4 mmol) and TMSCN (200 mL). The resulting mixture was
stirred for 20 h at 25.degree. C., and then concentrated under
vacuum. The residue was purified by silica gel chromatography
(eluting with 1:1 ethyl acetate/petroleum ether) to afford
3-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)-1-hydroxycyclobutane-1-carboni-
trile as a white solid (5.50 g). LCMS (ES, m/z): 315
[M+H].sup.+.
Step 8. Methyl
3-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)-1-hydroxycyclobutane-1-carboxy-
late
[0316] H.sub.2SO.sub.4 (25.0 mL, con.) was added to a 0.degree. C.
solution of
3-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)-1-[(trimethylsilyl)oxy]cyclobu-
tane-1-carbonitrile (6.00 g, 17.2 mmol) in MeOH (100 mL). The
reaction mixture stirred for 3 h at 90.degree. C. After cooling to
25.degree. C., the solvent was removed under vacuum. The pH value
of the residue was adjusted to 7-8 with saturated aqueous
Na.sub.2CO.sub.3 solution. The resulting mixture was extracted with
DCM (2.times.100 mL). The combined organic layers were dried over
anhydrous sodium sulfate. After filtration, the filtrate was
concentrated under reduced pressure. The residue was purified by
reverse phase chromatography (Column, C18 silica gel; Mobile phase,
A: water (containing 0.05% TFA) and B: ACN (10% to 50% in 10 min);
Detector, UV 254/220 nm) to afford methyl
3-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)-1-hydroxycyclobutane-1-carboxy-
late (2.10 g) as a yellow solid. LCMS (ES, m/z): 276
[M+H].sup.+.
Step 9. Methyl
3-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)-1-methoxycyclobutane-1-carboxy-
late
[0317] A mixture of methyl
3-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)-1-hydroxycyclobutane-1-carboxy-
late (500 mg, 1.64 mmol), CH.sub.3I (0.540 mL, 8.21 mmol) and
Ag.sub.2O (4.00 g, 16.4 mmol) in DCM (8 mL) was stirred for 20 h at
40.degree. C. The solids were filtered out and the filter cake was
washed with DCM (2.times.10 mL). The filtrate was concentrated
under reduced pressure. The residue was purified by reverse phase
chromatography (Column, C18 silica gel; Mobile phase, A: water
(containing 0.05% TFA) and B: ACN (40% to 80% in 10 min); Detector,
UV 254/220 nm) to afford methyl
3-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)-1-methoxycyclobutane-1-carboxy-
late (200 mg) as a white solid. LCMS (ES, m/z): 290
[M+H].sup.+.
Step 10.
3-(1,3-Dioxo-2,3-dihydro-1H-isoindol-2-yl)-1-methoxycyclobutane-1-
-carboxylic acid
[0318] A mixture of methyl
3-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)-1-methoxycyclobutane-1-carboxy-
late (400 mg, 1.38 mmol) and hydrochloric acid (8 mL, 4N) was
stirred for 4 h at 90.degree. C. After cooling to 25.degree. C.,
the resulting mixture was concentrated under reduced pressure. The
residue was purified by reverse phase chromatography (Column, C18
silica gel; Mobile Phase, A: water (containing 0.05% TFA) and B:
CH.sub.3CN (18% to 25% over 8 min); Detector: UV 220/254 nm) to
afford
3-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)-1-methoxycyclobutane-1-carboxy-
lic acid as a white solid (200 mg). LCMS (ES, m/z): 276
[M+H].sup.+.
Step 11.
N-(5-tert-butyl-4-chloro-1,3-thiazol-2-yl)-3-(1,3-dioxo-2,3-dihyd-
ro-1H-isoindol-2-yl)-1-methoxycyclobutane-1-carboxamide
[0319] A mixture of
3-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)-1-methoxycyclobutane-1-carboxy-
lic acid (290 mg, 0.948 mmol),
5-tert-butyl-4-chloro-1,3-thiazol-2-amine (301 mg, 1.42 mmol), DCC
(515 mg, 2.37 mmol) and DMAP (305 mg, 2.37 mmol) in DCM (10 mL) was
stirred for 30 h at 25.degree. C. The solids were filtered out and
the filtrate was diluted with water (40 mL). The resulting mixture
was extracted with DCM (2.times.40 mL). The combined organic layers
were dried over anhydrous sodium sulfate, filtered, and
concentrated under vacuum. The residue was purified by silica gel
chromatography (eluting with 1:1 ethyl acetate/petroleum ether) to
afford
N-(5-tert-butyl-4-chloro-1,3-thiazol-2-yl)-3-(1,3-dioxo-2,3-dihydro-1H-is-
oindol-2-yl)-1-methoxycyclobutane-1-carboxamide as a yellow solid
(150 mg). LCMS (ES, m/z): 448, 450 [M+H].sup.+.
Step 12.
3-amino-N-(5-tert-butyl-4-chloro-1,3-thiazol-2-yl)-1-methoxycyclo-
butane-1-carboxamide 2,2,2-trifluoroacetate
[0320] A solution of
N-(5-tert-butyl-4-chloro-1,3-thiazol-2-yl)-3-(1,3-dioxo-2,3-dihydro-1H-is-
oindol-2-yl)-1-methoxycyclobutane-1-carboxamide (140 mg, 0.281
mmol) and hydrazine hydrate solution (0.140 mL, 80% in water) in
EtOH (4 mL) stirred for 4 h at 50.degree. C. After cooling to
25.degree. C., the resulting mixture was concentrated under vacuum.
The residue was purified by reverse phase chromatography (Column,
C18 silica gel; Mobile phase, A: water (containing 0.05% TFA) and
B: ACN (10/% to 50% in 10 min); Detector, UV 254/220 nm) to afford
3-amino-N-(5-tert-butyl-4-chloro-1,3-thiazol-2-yl)-1-methoxycyclobutane-1-
-carboxamide 2,2,2-trifluoroacetate as a yellow solid (70.0 mg).
LCMS (ES, m/z): 318, 320 [M+H].sup.+.
Step 13.
N-(5-tert-butyl-4-chloro-1,3-thiazol-2-yl)-3-(cyanoamino)-1-metho-
xycyclobutane-1-carboxamide
[0321] A mixture of
3-amino-N-(5-tert-butyl-4-chloro-1,3-thiazol-2-yl)-1-methoxycyclobutane-1-
-carboxamide 2,2,2-trifluoroacetate (70.0 mg, 0.220 mmol),
NaHCO.sub.3 (185 mg, 2.20 mmol) and BrCN (23.3 mg, 0.220 mmol) in
DMF (2 mL) was stirred for 2 h at 25.degree. C. The reaction was
quenched by the addition of water/ice (5 mL). The resulting mixture
was extracted with ethyl acetate (3.times.10 mL). The combined
organic layers were washed with brine (5 mL), dried over anhydrous
sodium sulfate. After filtration, the filtrate was concentrated
under reduced pressure. The residue was purified by Prep-HPLC
(Column: XBridge Shield RP18 OBD Column, 5 .mu.m, 19.times.150 mm;
Mobile Phase, A: water (containing 10 mM ammonium bicarbonate) and
B: acetonitrile (65% to 75% in 7 min); Detector: UV 254 nm). The
product fractions were lyophilized to afford
N-(5-tert-butyl-4-chloro-1,3-thiazol-2-yl)-3-(cyanoamino)-1-methoxycyclob-
utane-1-carboxamide as a white solid (27.3 mg). .sup.1H-NMR
(DMSO-d.sub.6, 400 MHz) .delta. (ppm): 10.28 (br s, 1H), 7.30 (br
s, 1H), 3.10 (s, 3H), 2.77-2.76 (m, 2H), 2.51-2.50 (m, 2H), 1.41
(s, 9H). LCMS (ES, m/z): 343, 345 [M+H].sup.+.
Example 9.
(1s,3s)-N-(5-tert-butyl-4-chloro-1,3-thiazol-2-yl)-1-chloro-3-(-
cyanoamino)cyclobutane-1-carboxamide (Compound 9-1) and
(1r,3r)-N-(5-tert-butyl-4-chloro-1,3-thiazol-2-yl)-1-chloro-3-(cyanoamino-
)cyclobutane-1-carboxamide (Compound 9-2)
##STR00261##
[0322] Step 1. Methyl
1-chloro-3-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)cyclobutane-1-carboxyl-
ate
[0323] A solution of methyl
3-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)-1-hydroxycyclobutane-1-carboxy-
late (1.50 g, 4.90 mmol), DMF (3 mL) and SOCl.sub.2 (30 mL) in
CCl.sub.4 (30 mL) was stirred for 30 h at 100.degree. C. After
cooling to 25.degree. C., the resulting mixture was concentrated
under reduced pressure. The residue was purified by reverse phase
chromatography (Column, C18 silica gel; Mobile phase, A: water
(0.05% TFA) and B: ACN (10% to 50% in 10 min); Detector, UV 254/220
nm) to afford methyl
1-chloro-3-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)cyclobutane-1-carboxyl-
ate as a white solid (500 mg). LCMS (ES, m/z): 294, 296
[M+H].sup.+.
Step 2.
1-Chloro-3-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)cyclobutane-1-c-
arboxylic acid
[0324] A mixture of methyl
1-chloro-3-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)cyclobutane-1-carboxyl-
ate (500 mg, 1.70 mmol) and hydrochloric acid (3 mL, 4 N) was
stirred for 1 h at 90.degree. C. After cooling down to 25.degree.
C., the resulting mixture was concentrated under vacuum. The
residue was purified by reverse phase chromatography (Column, C18
silica gel; Mobile phase, A: water (containing 0.05% TFA) B: ACN
(10% to 80% in 10 min); Detector, UV 254/220 nm) to afford
1-chloro-3-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)cyclobutane-1-carboxyl-
ic acid as a white solid (360 mg). LCMS (ES, m/z): 280, 282
[M+H].sup.+.
Step 3.
N-(5-tert-butyl-4-chloro-1,3-thiazol-2-yl)-1-chloro-3-(1,3-dioxo-2-
,3-dihydro-1H-isoindol-2-yl)cyclobutane-1-carboxamide
[0325] A solution of
1-chloro-3-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)cyclobutane-1-carboxyl-
ic acid (360 mg, 1.28 mmol) and
5-tert-butyl-4-chloro-1,3-thiazol-2-amine (294 mg, 1.39 mmol) in
pyridine (10 mL) was stirred for 5 min at 0.degree. C. POCl.sub.3
(0.46 mL, 9.23 mmol) was added at 0.degree. C., and the resulting
mixture stirred for an additional 14 h at 0.degree. C. The reaction
was then quenched by the addition of ice/water (20 mL). The
resulting mixture was extracted with ethyl acetate (2.times.40 mL).
The combined organic layers were dried over anhydrous sodium
sulfate, filtered and concentrated under vacuum. The residue was
purified by silica gel chromatography (eluting with 1:1 ethyl
acetate/petroleum ether) to afford
N-(5-tert-butyl-4-chloro-1,3-thiazol-2-yl)-1-chloro-3-(1,3-dioxo-2,3-dihy-
dro-1H-isoindol-2-yl)cyclobutane-1-carboxamide as a yellow solid
(280 mg). LCMS (ES, m/z): 452, 454 [M+H].sup.+.
Step 4.
3-amino-N-(5-tert-butyl-4-chloro-1,3-thiazol-2-yl)-1-chlorocyclobu-
tane-1-carboxamide 2,2,2-trifluoroacetate
[0326] A solution of
N-(5-tert-butyl-4-chloro-1,3-thiazol-2-yl)-1-chloro-3-(1,3-dioxo-2,3-dihy-
dro-1H-isoindol-2-yl)cyclobutane-1-carboxamide (280 mg, 0.619 mmol)
and hydrazine hydrate solution (0.29 mL, 80% in water) in EtOH (5
mL) was stirred for 2 h at 50.degree. C. After cooling down to
25.degree. C., the resulting mixture was concentrated under vacuum.
The residue was purified by reverse phase chromatography (Column,
C18 silica gel; Mobile phase, A: water (containing 0.05% TFA) and
B: ACN (10% to 50% in 10 min); Detector, UV 254/220 nm) to afford
3-amino-N-(5-tert-butyl-4-chloro-1,3-thiazol-2-yl)-1-chlorocyclobutane-1--
carboxamide 2,2,2-trifluoroacetate as a white solid (100 mg). LCMS
(ES, m/z): 322, 324 [M+H].sup.+.
Step 5.
N-(5-tert-butyl-4-chloro-,3-thiazol-2-yl)-1-chloro-3-(cyanoamino)c-
yclobutane-1-carboxamide
[0327] Sodium bicarbonate (182 mg, 2.06 mmol) was added into a
stirring solution of
3-amino-N-(5-tert-butyl-4-chloro-1,3-thiazol-2-yl)-1-chlorocyclobutane-1--
carboxamide 2,2,2-trifluoroacetate (100 mg, 0.228 mmol) in DMF (3
mL). The resulting solution was stirred for 0.5 h at 25.degree. C.
A solution of BrCN (23.0 mg, 0.206 mmol) in DMF (0.5 mL) was added
at 0.degree. C., and the resulting solution stirred for 14 h at
25.degree. C. The reaction was then quenched by the addition of
ice/water (10 mL). The resulting mixture was extracted with ethyl
acetate (2.times.20 mL). The combined organic layers were dried
over anhydrous sodium sulfate, filtered and concentrated under
vacuum. The residue was purified by Prep-HPLC (Column: XBridge Prep
C18 OBD Column, 5 .mu.m, 19.times.150 mm; Mobile Phase, A: water
(containing 10 mM ammonium bicarbonate) and B: CH.sub.3CN (45% to
75% over 7 min); Detector: UV 254 nm). The product fractions were
lyophilized to afford
N-(5-tert-butyl-4-chloro-1,3-thiazol-2-yl)-1-chloro-3-(cyanoamino)cyclobu-
tane-1-carboxamide as a white solid (30.0 mg). LCMS (ES, m/z): 347,
349 [M+H].sup.+.
Step 6.
(1s,3s)-N-(5-tert-butyl-4-chloro-1,3-thiazol-2-yl)-1-chloro-3-(cya-
noamino)cyclobutane-1-carboxamide
[0328]
N-(5-tert-butyl-4-chloro-1,3-thiazol-2-yl)-1-chloro-3-(cyanoamino)c-
yclobutane-1-carboxamide (30.0 mg, 0.086 mmol) was separated by
Chiral-HPLC (Column: CHIRALPAK IG, 2.times.25 cm, 5 um; Mobile
Phase A: n-hexane and B: EtOH (hold 10% in 30 min); Flow rate: 20
mL/min; Detector: 220 and 254 nm; RT1:18.708 min; RT2:21.346 min).
The first product fractions (RT=18.708 min) were lyophilized to
afford a white solid arbitrarily assigned as
(1s,3s)-N-(5-tert-butyl-4-chloro-1,3-thiazol-2-yl)-1-chloro-3-(cyanoamino-
)cyclobutane-1-carboxamide (1.40 mg). .sup.1H-NMR (DMSO-d.sub.6,
400 MHz) .delta. (ppm): 12.78 (br s, 1H), 7.50 (br s, 1H),
3.48-3.38 (m, 1H), 2.60-2.52 (m, 4H), 1.42 (s, 9H). LCMS (ES, m/z):
347,349 [M+H].sup.+. The second product fractions (RT=21.346 min)
were lyophilized to afford a white solid arbitrarily assigned as
(1r,3r)-N-(5-tert-butyl-4-chloro-1,3-thiazol-2-yl)-1-chloro-3-(cyanoamino-
)cyclobutane-1-carboxamide (25.0 mg). .sup.1H-NMR (DMSO-dr, 400
MHz) .delta. (ppm): 12.77 (br s, 1H), 7.31 (br s, 1H), 4.04-3.99
(m, 1H), 2.85-2.75 (m, 4H), 1.42 (s, 9H). LCMS (ES, m/z): 347, 349
[M+H].sup.+.
Example 10-1.
cis-4-(cyanoamino)-N-(5-cyclohexyl-1,3-thiazol-2-yl)cyclohexane-1-carboxa-
mide (Compound 10-1)
##STR00262##
[0329] Step 1. cis-tert-butyl
N-[4-[(5-cyclohexyl-1,3-thiazol-2-yl)carbamoyl]cyclohexyl]carbamate
[0330] Into a 25 mL round-bottom flask was placed
cis-4-[(tert-butoxy)carbonyl]aminocyclohexane-1-carboxylic acid
(160 mg, 0.66 mmol), N,N-dimethylformamide (5 mL),
N,N-diisopropylethylamine (212 mg, 1.64 mmol), HATU (417 mg, 1.10
mmol) and 5-cyclohexylthiazol-2-amine (100 mg, 0.49 mmol). The
resulting solution was stirred for 18 h at 25.degree. C. The
resulting solution was poured into water (10 mL) and then extracted
with ethyl acetate (3.times.10 mL). The organic layers were
combined, dried over anhydrous sodium sulfate, filtered and
concentrated under vacuum. The residue was purified by silica gel
chromatography (eluting with 1:1 ethyl acetate/petroleum ether) to
afford cis-tert-butyl
N-[4-[(5-cyclohexyl-1,3-thiazol-2-yl)carbamoyl]cyclohexyl]carbamate
as a yellow oil. LC-MS (ESI) m/z 408.2 [M+H].sup.+
Step 2.
cis-4-amino-N-(5-cyclohexyl-1,3-thiazol-2-yl)cyclohexane-1-carboxa-
mide TFA salt
[0331] Into a 25 mL round-bottom flask was placed cis-tert-butyl
N-[4-[(5-cyclohexyl-1,3-thiazol-2-yl)carbamoyl]cyclohexyl]carbamate
(70 mg, 0.15 mmol), dichloromethane (4 mL) and trifluoroacetic acid
(1 mL). The resulting solution was stirred for 2 h at 25.degree. C.
The reaction mixture was concentrated under vacuum. The residue was
treated with ethyl ether and dried under vacuum to afford
cis-4-amino-N-(5-cyclohexyl-1,3-thiazol-2-yl)cyclohexane-1-carboxamide
TFA salt as a yellow oil. LC-MS (ESI) m/z 308.2 [M+H].sup.+
Step 3.
cis-4-(cyanoamino)-N-(5-cyclohexyl-1,3-thiazol-2-yl)cyclohexane-1--
carboxamide
[0332] Into a 25 mL round-bottom flask was placed
cis-4-amino-N-(5-cyclohexyl-1,3-thiazol-2-yl)cyclohexane-1-carboxamide
TFA salt (40 mg, 0.12 mmol), tetrahydrofuran (5 mL) and
triethylamine (26 mg, 0.26 mmol). Then cyanogen bromide (13 mg,
0.12 mmol) was added at -20.degree. C. The resulting solution was
stirred for 1 h at -20.degree. C. The reaction mixture was poured
into water (5 mL) and then extracted with ethyl acetate (3.times.5
mL). The residue was purified by prep-TLC (eluting with 10:1
dichloromethane/methanol), and further purified by prep-HPLC
(Column: XBridge Shield RP18 OBD Column, 130 .ANG., 5 .mu.m, 19
mm.times.150 mm; Mobile phase: water (10 mM NH.sub.4HCO.sub.3),
MeCN (40% MeCN up to 65% over 7 min); Flow rate: 20 mL/min;
Detector: 254 & 220 nm) to afford
cis-4-(cyanoamino)-N-(5-cyclohexyl-1,3-thiazol-2-yl)cyclohexane-
-1-carboxamide. .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta.11.83
(br s, 1H), 7.14 (s, 1H), 6.77 (s, 1H), 2.76-2.68 (m, 1H),
2.65-2.50 (m, 1H), 1.95-1.81 (m, 2H), 1.76-1.49 (m, 11H), 1.43-1.31
(m, 4H), 1.29-1.22 (m, 2H). LC-MS (ESI) m/z 333.2 [M+H].sup.+
[0333] The following compounds were prepared according to Example
10-1:
Compound 10-2.
trans-4-(cyanoamino)-N-(5-cyclohexyl-1,3-thiazol-2-yl)cyclohexane-1-carbo-
xamide
##STR00263##
[0335] .sup.1H NMR (300 MHz, DMSO-d.sub.6), .delta. 11.85 (s, 1H),
7.14 (s, 1H), 6.86 (d, J=4.80 Hz, 1H), 3.00-2.91 (m, 1H), 2.75 (s,
1H), 2.44-2.36 (m, 1H), 1.94-1.84 (m, 6H), 1.73-1.64 (m, 3H),
1.54-1.42 (m, 2H), 1.38-1.23 (m, 7H).
[0336] LC-MS (ESI) m/z 333.2 [M+H].sup.+
Compound 10-3.
(1R,2R)-2-(cyanoamino)-N-(5-cyclohexyl-1,3-thiazol-2-yl)cyclopentane-1-ca-
rboxamide
##STR00264##
[0338] H NMR (300 MHz, DMSO-d.sub.6) .delta. 7.15 (s, 1H),
3.77-3.70 (m, 1H), 2.90-2.76 (m, 2H), 2.27-1.92 (m, 4H), 1.74-1.60
(m, 7H), 1.43-1.01 (m, 5H).
[0339] LC-MS (ESI) m/z 319.2 [M+H].sup.+
Compound 10-4.
(1R,3S)-3-(cyanoamino)-N-(5-cyclohexyl-1,3-thiazol-2-yl)cyclohexane-1-car-
boxamide
##STR00265##
[0341] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 11.88 (s, 1H),
7.14 (d, J=0.60 Hz, 1H), 6.91 (d, J=4.80 Hz, 1H), 2.98-2.97 (m,
1H), 2.76-2.53 (m, 1H), 2.50-2.49 (m, 1H), 1.97-1.64 (m, 9H),
1.30-1.26 (m, 9H).
[0342] LC-MS (ESI) m/z 333.1 [M+H].sup.+
Compound 10-5.
(1S,3S)-3-(cyanoamino)-N-(5-cyclohexyl-1,3-thiazol-2-yl)cyclohexane-1-car-
boxamide
##STR00266##
[0344] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 11.88 (s, 1H),
7.14 (d, J=0.60 Hz, 1H), 6.91 (d, J=4.80 Hz, 1H), 2.98-2.97 (m,
1H), 2.76-2.53 (m, 1H), 2.50-2.49 (m, 1H), 1.97-1.64 (m, 9H),
1.30-1.26 (m, 9H).
[0345] LC-MS (ESI) m/z 333.1 [M+H].sup.+
Compound 10-6.
(1S,3R)-3-(cyanoamino)-N-(5-cyclohexyl-1,3-thiazol-2-yl)cyclohexane-1-car-
boxamide
##STR00267##
[0347] .sup.1H NMR (300 MHz, DMSO-d.sub.6), .delta. 11.88 (s, 1H),
7.14 (s, 1H), 6.92 (d, J=4.80 Hz, 1H), 3.03-2.93 (m, 1H), 2.76-2.74
(m, 1H), 2.58-2.54 (m, 1H), 2.01-1.64 (m, 9H), 1.42-1.39 (m,
9H).
[0348] LC-MS (ESI) m/z 333.1 [M+H].sup.+
Compound 10-7.
(1R,2S)-2-(cyanoamino)-N-(5-cyclohexyl-1,3-thiazol-2-yl)cyclopentane-1-ca-
rboxamide
##STR00268##
[0350] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 7.09 (s, 1H),
3.75-3.62 (m, 1H), 2.95-2.70 (m, 2H), 2.13-1.88 (m, 4H), 1.67-1.42
(m, 7H), 1.47-0.82 (m, 5H).
[0351] LC-MS (ESI) m/z 319.2 [M+H].sup.+
Compound 10-8.
(1S,2R)-2-(cyanoamino)-N-(5-cyclohexyl-1,3-thiazol-2-yl)cyclopentane-1-ca-
rboxamide
##STR00269##
[0353] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 7.09 (s, 1H),
3.72-3.68 (m, 1H), 2.87-2.78 (m, 2H), 2.00-1.80 (m, 4H), 1.68-1.39
(m, 7H), 1.36-0.96 (m, 5H).
[0354] LC-MS (ESI) m/z 319.2 [M+H].sup.+
Compound 10-9.
(1S,2S)-2-(cyanoamino)-N-(5-cyclohexyl-1,3-thiazol-2-yl)cyclopentane-1-ca-
rboxamide
##STR00270##
[0356] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 7.16 (s, 1H),
3.78-3.70 (m, 1H), 2.90-2.73 (m, 2H), 2.10-1.92 (m, 4H), 1.75-1.52
(m, 7H), 1.42-1.18 (m, 5H).
[0357] LC-MS (ESI) m/z 319.2 [M+H].sup.+
Compound 10-10.
(1S,3S)-3-(cyanoamino)-N-[5-(oxan-4-yl)-1,3-thiazol-2-yl]cyclopentane-1-c-
arboxamide
##STR00271##
[0359] .sup.1H NMR (300 MHz, DMSO-d.sub.6), .delta. 12.00 (s, 1H),
7.20 (s, 1H), 6.85 (s, 1H), 3.92-3.89 (m, 2H), 3.88 (s, 1H),
3.73-3.39 (m, 2H), 3.15-3.03 (m, 2H), 2.08-1.96 (m, 3H), 1.92-1.83
(m, 3H), 1.82-1.73 (m, 1H), 1.67-1.66 (m, 3H).
[0360] LC-MS (ESI) m/z 321.2 [M+H].sup.+
Compound 10-11.
(1R,3R)-3-(cyanoamino)-N-[5-(oxan-4-yl)-1,3-thiazol-2-yl]cyclopentane-1-c-
arboxamide
##STR00272##
[0362] .sup.1H NMR (300 MHz, DMSO-d.sub.6), .delta. 11.99 (s, 1H),
7.19 (s, 1H), 6.86 (s, 1H), 3.92-3.87 (m, 2H), 3.72 (s, 1H),
3.46-3.39 (m, 2H), 3.13-3.03 (m, 2H), 2.08-1.97 (m, 2H), 1.88-1.82
(m, 4H), 1.77-1.55 (m, 4H).
[0363] LC-MS (ESI) m/z 321.2 [M+H].sup.+
Example 11-1.
trans-2-(cyanoamino)-N-(5-cyclohexyl-1,3-thiazol-2-yl)cyclopropane-1-carb-
oxamide (Compound 11-1)
##STR00273##
[0364] Step 1. tert-butyl
N-[(trans)-2-[(5-cyclohexyl-1,3-thiazol-2-yl)carbamoyl]cyclopropyl]carbam-
ate
[0365] Into a 8 mL vial was placed
(trans)-2-[(tert-butoxy)carbonyl]aminocyclopropane-1-carboxylic
acid (132 mg, 0.62 mmol), N,N-dimethylformamide (1 mL),
N,N-diisopropylethylamine (212 mg, 1.64 mmol), HATU (417 mg, 1.10
mmol) and 5-cyclohexyl-1,3-thiazol-2-amine (100 mg, 0.55 mmol). The
resulting solution was stirred for 2 h at 25.degree. C. The
reaction mixture was poured into water (2 mL) and then extracted
with ethyl acetate (3.times.2 mL). The organic layers were
combined, dried over anhydrous sodium sulfate, filtered and
concentrated under vacuum. The residue was purified by silica gel
chromatography (eluting with 1:1 ethyl acetate/petroleum ether) to
afford tert-butyl
N-[(trans)-2-[(5-cyclohexyl-1,3-thiazol-2-yl)carbamoyl]cyclopropyl]carbam-
ate as a white solid. LC-MS (ESI) m/z 366.1 [M+H].sup.+
Step 2.
(trans)-2-amino-N-(5-cyclohexyl-1,3-thiazol-2-yl)cyclopropane-1-ca-
rboxamide HCl Salt
[0366] Into a 8 mL vial was placed tert-butyl
N-[(trans)-2-[(5-cyclohexyl-1,3-thiazol-2-yl)carbamoyl]cyclopropyl]carbam-
ate (100 mg, 0.25 mmol), dichloromethane (2.4 mL) and a solution of
HCl in 1,4-dioxane (4 M, 0.9 mL). The resulting solution was
stirred for 6 h at 0.degree. C. The resulting mixture was
concentrated under vacuum, washed with ethyl ether, filtered and
concentrated under vacuum to afford
(trans)-2-amino-N-(5-cyclohexyl-1,3-thiazol-2-yl)cyclopropane-1-carboxami-
de HCl salt as a white solid. LC-MS (ESI) m/z 266.1 [M+H].sup.+
Step 3.
trans-2-(cyanoamino)-N-(5-cyclohexyl-1,3-thiazol-2-yl)cyclopropane-
-1-carboxamide
[0367] Into a 8 mL vial was placed
(trans)-2-amino-N-(5-cyclohexyl-1,3-thiazol-2-yl)cyclopropane-1-carboxami-
de HCl salt (70 mg, 0.21 mmol), N,N-dimethylformamide (1 mL) and
sodium bicarbonate (35 mg, 0.42 mmol). After cooling to 0.degree.
C., cyanogen bromide (22 mg, 0.21 mmol) was added. The resulting
solution was stirred for 1 h at 0.degree. C. and 18 h at room
temperature. The reaction mixture was poured into water (2 mL) and
then extracted with ethyl acetate (3.times.2 mL). The organic
layers were combined, dried over anhydrous sodium sulfate, filtered
and concentrated under vacuum. The residue was purified by prep-TLC
(eluting with 1:1 ethyl acetate/petroleum ether), and further
purified by prep-HPLC (Column: XBridge Shield RP18 OBD Column, 130
.ANG., 5 .mu.m, 19 mm.times.150 mm; Mobile phase: water (10 mM
NH.sub.4HCO.sub.3), MeCN (35% MeCN up to 65% over 7 min); Flow
rate: 20 mL/min; Detector: 254 & 220 nm). This resulted in
(trans)-2-(cyanoamino)-N-(5-cyclohexyl-1,3-thiazol-2-yl)cyclopropane-1-
-carboxamide as a white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 8.15 (s, 1H), 7.29 (s, 1H), 5.67-5.64 (m, 1H), 2.82-2.71
(m, 2H), 2.68-2.53 (m, 2H), 2.16-2.06 (m, 1H), 1.97-1.92 (m, 2H),
1.77-1.75 (m, 2H), 1.69-1.66 (m, 1H), 1.47-1.33 (m, 4H), 1.32-1.24
(m, 1H). LC-MS (ESI) m/z 291.2[M+H].sup.+
[0368] The following compounds were prepared according to Example
11-1:
Compound 11-2.
cis-2-(cyanoamino)-N-(5-cyclohexyl-1,3-thiazol-2-yl)cyclopropane-1-carbox-
amide
##STR00274##
[0370] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 7.98 (br s, 1H),
7.29 (s, 1H), 5.67-5.64 (m, 1H), 2.83-2.80 (m, 2H), 2.68-2.53 (m,
2H), 2.13-2.06 (m, 1H), 1.97-1.90 (m, 2H), 1.77-1.74 (m, 2H),
1.69-1.61 (m, 1H), 1.47-1.33 (m, 4H), 1.27-1.24 (m, 1H).
[0371] LC-MS (ESI) m/z 291.2[M+H].sup.+
[0372] The following compounds were also prepared according to
previous Example 2-1 above:
Compound 2-2.
(3S)-3-(cyanoamino)-N-(5-cyclohexyl-1,3-thiazol-2-yl)pyrrolidine-1-carbox-
amide
##STR00275##
[0374] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 10.51 (br s,
1H), 7.13 (s, 1H), 7.01 (s, 1H), 3.92-3.89 (m, 1H), 3.51-3.39 (m,
4H), 2.72-2.70 (m, 1H), 2.08-2.06 (m, 1H), 1.95-1.92 (m, 3H),
1.74-1.72 (m, 3H), 1.34-1.31 ((m, 4H), 1.26-1.16 (m, 1H).
[0375] LC-MS (ESI) m/z 320.4 [M+H].sup.+
Compound 2-3.
(3R)-3-(cyanoamino)-N-(5-cyclohexyl-1,3-thiazol-2-yl)pyrrolidine-1-carbox-
amide
##STR00276##
[0377] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 10.51 (br s,
1H), 7.13 (s, 1H), 7.01 (s, 1H), 3.89 (s, 1H), 3.51-3.39 (m, 4H),
2.72-2.70 (m, 1H), 2.09-2.07 (m, 1H), 1.99-1.92 (m, 3H), 1.74-1.66
(m, 3H), 1.34-1.31 (m, 4H), 1.26-1.16 (m, 1H).
[0378] LC-MS (ESI) m/z 320.1 [M+H].sup.+
Example 12-1.
(1R,3S)-3-(cyanoamino)-N-(5-phenyl-1,3-thiazol-2-yl)cyclopentane-1-carbox-
amide (Compound 12-1)
##STR00277##
[0380] A half-dram vial was charged with
(1R,3S)-3-((tert-butoxycarbonyl)amino)cyclopentane-1-carboxylic
acid (0.2 M in 1,4-dioxane, 225 .mu.L, 45 .mu.mol),
5-phenylthiazol-2-amine (0.2 M in 1,4-dioxane, 225 .mu.L, 45
.mu.mol) and DIEA (30 .mu.L, neat, 172 .mu.mol), then a solution of
2-chloro-1,3-dimethylimidazolinium chloride (0.2 M in DCE, 275
.mu.L, 55 .mu.mol) was added. The vial was sealed and shaken at
room temperature for 16 h. The reaction mixture was diluted with
brine (500 .mu.L) and extracted with ethyl acetate (2.times.500
.mu.L). The combined organic layers were evaporated to dryness
under a stream of N.sub.2 and 1,4-dioxane (250 .mu.L) was added to
the residue. The vial was sealed and shaken at 50.degree. C. for 15
min to dissolve the residue, then cooled to room temperature. HCl
(4 M in 1,4-dioxane, 150 .mu.L, 600 .mu.mol) was added, the vial
was sealed and shaken at room temperature for 3 h. The solvent was
evaporated and DMA (200 .mu.L) and DIEA (50 .mu.L, neat, 287
.mu.mol) were added. The vial was sealed and shaken at 50.degree.
C. for 15 min to dissolve the residue, then cooled to room
temperature. Cyanogen bromide (0.4 M in DMA, 225 .mu.L, 90 .mu.mol)
was added, the vial was sealed and shaken at room temperature for 3
h. DMSO (300 .mu.L) and AcOH (45 .mu.L) were added and the mixture
was purified by mass triggered preparative HPLC. The
product-containing fractions were combined and concentrated in a
Genevac to afford
(1R,3S)-3-(cyanoamino)-N-(5-phenyl-1,3-thiazol-2-yl)cyclopentane-1-carbox-
amide as an off-white solid. LC-MS (ESI) m/z 313 [M+H].sup.+
[0381] The following compounds were synthesized according to
Example 12-1:
TABLE-US-00009 Compound 12-2 ##STR00278##
(1S,3S)-3-(cyanoamino)-N-(1-phenyl-
1H-pyrazol-3-yl)cyclopentane.-1- carboxamide LC-MS (ESI) m/z 296.2
[M + H].sup.+ Compound 12-3 ##STR00279##
(1S,3S)-3-(cyanoamino)-N-(5- cyclohexyl-1,3-thiazol-2-
yl)cyclopentane-1-carboxamide LC-MS (ESI) m/z 319.2 [M + H].sup.+
Compound 12-4 ##STR00280## (1S,3S)-3-(cyanoamino)-N-(5-phenyl-
1,3-thiazol-2-yl)cyclopentane-1- carboxamide LC-MS (ESI) m/z 313.2
[M + H].sup.+ Compound 12-5 ##STR00281##
(1S,3S)-3-(cyanoamino)-N-(2,3-
dihydro-1H-inden-5-yl)cyclopentane-1- carboxamide LC-MS (ESI) m/z
270.2 [M + H].sup.+ Compound 12-6 ##STR00282##
(1S,3S)-3-(4-phenylpiperizine-1-
carbonyl)cyclopentyl]amino}carbonitrile LC-MS (ESI) m/z 299.2 [M +
H].sup.+ Compound 12-7 ##STR00283##
(1S,3R)-N-(5-tcrt-butyl-1,3-thiazol-2-
yl)-3-(cyanoamino)cyclopentane-1- carboxamide LC-MS (ESI) m/z 793.2
[M + H].sup.+ Compound 12-8 ##STR00284##
{[(3S)-1-[2-(2,3-dichlorophenyl)-1,3-
thiazole-4-carbonyl]pyrrolidin-3- yl]amino}carbonitrile LC-MS (ESI)
m/z 367 [M + H].sup.+ Compound 12-9 ##STR00285##
({1-[2-(2,4-dichlorophenyl)-1,3- thiazole-4-carbonyl]piperidin-4-
yl}amino)carbonitrile LC-MS (ESI) m/z 381 [M + H].sup.+
Example A: Biochemical Assay: Ubiquitin-Rhodamine 110 Assay for
USP30 Activity (USP30 Inhibitor Biochemical Assay)
[0382] In some embodiments, the compounds of the invention are
USP30 inhibitor compounds having an IC.sub.50 value of 1 micromolar
or less (e.g., between 0.001 micromolar and 1 micromolar) as
determined by the following USP30 Inhibitor Biochemical Assay. In
some embodiments, the compounds of the invention are USP30
inhibitor compounds having an IC.sub.50 value of less than 0.5
micromolar (e.g., between 0.001 micromolar and 0.5 micromolar) as
determined by the following USP30 Inhibitor Biochemical Assay. In
some embodiments the compounds of the invention are preferably
USP30 inhibitor compounds having an IC.sub.50 value of less than
0.1 micromolar (e.g., between 0.001 micromolar and 0.1 micromolar)
as determined by the following USP30 Inhibitor Biochemical
Assay.
[0383] The assay was performed in a final volume of 9 .mu.L in
assay buffer containing 20 mM Tris-HCl (pH 8.0, (1M Tris-HCl, pH
8.0 solution; Corning 46-031-CM)), 1 mM GSH (L-glutathione reduced,
Sigma-Aldrich, G4251-100G), 0.03% BGG (0.22 .mu.M filtered, Sigma,
G7516-25G), and 0.01% Triton X-100 (Sigma, T9284-10L). Nanoliter
quantities of 10-point, 3-fold serial dilution in DMSO were
pre-dispensed into 1536 assay plates (Corning, #3724BC) for a final
test concentration of 25 .mu.M to 1.3 nM, top to lowest dose,
respectively. Concentration and incubation times were optimized for
the maximal signal-to-background while maintaining initial velocity
conditions at a fixed substrate concentration. The final
concentration of USP30 (human recombinant USP30, Boston Biochem,
cat. #E-582) in the assay was 0.2 nM. Final substrate (Ub-Rh110;
Ubiquitin-Rhodamine 110, UbiQ-126) concentration was 25 nM with
[Ub-Rh110]<<Km. 3 .mu.L of 2.times.USP30 was added to assay
plates (pre-stamped with compound), preincubated for 30 minutes and
then treated with 3 .mu.L of 2.times.Ub-Rh110. Plates were
incubated for 30 minutes at room temperature before addition of 3
.mu.L of stop solution (final concentration of 10 mM citric acid
(Sigma, 251275-500G)). Fluorescence was read on the Envision
(excitation at 485 nm and emission at 535 nm; Perkin Elmer) or on
the PheraSTAR (excitation at 485 nm and emission at 535 nm; BMG
Labtech).
[0384] For all assay formats data were reported as percent
inhibition compared with control wells based on the following
equation: % inh=1-((FLU-Ave.sub.Low)/(Ave.sub.High-Ave.sub.Low))
where FLU=measured Fluorescence, Ave.sub.Low=average Fluorescence
of no enzyme control (n=16), and Ave.sub.High=average Fluorescence
of DMSO control (n=16). IC.sub.50 values were determined by curve
fitting of the standard 4 parameter logistic fitting algorithm
included in the Activity Base software package: IDBS XE Designer
Model205. Data is fitted using the Levenburg Marquardt
algorithm.
[0385] The activity of compounds in the USP30 biochemical IC.sub.50
assay (IC.sub.50 ranges) according to the present disclosure are
reported in the tables A1 to A3 below according to the following:
"-": inactive, "+": 10-25 .mu.M, "++": 1-10 .mu.M, "+++": 0.1-1
.mu.M, "++++": <0.1 .mu.M.
TABLE-US-00010 TABLE A1 Example USP30 No. Structure Chemical Name
potency range Compound 1-1 ##STR00286##
trans-3-(cyanoamino)-N-[5-(oxan-4-yl)-
1,3-thiazol-2-yl]cyclobutane-1- carboxamide ++ Compound 2-1
##STR00287## 3-(cyanoamino)-N-(5-cyclohexyl-1,3-
thiazol-2-yl)azetidine-1-carboxamide ++ Compound 3-1 ##STR00288##
5-phenyl-N-[(trans)-3- cyanoamino)cyclobutyl]-1,3-thiazole-2-
carboxamide ++ Compound 4-1 ##STR00289## 5-phenyl-N-[(cis)-3-
(cyanoamino)cyclobutyl]-1,3-thiazole- 2-carboxamide ++ Compound 5-1
##STR00290## cis-3-(cyanoamino)-N-(1-phenyl-1H-
pyrazol-4-yl)cyclobutane-1- carboxamide ++ Compound 5-2
##STR00291## cis-3-(cyanoamino)-N-(1-phenyl-1H-
pyrazol-3-yl)cyclobutane-1- carboxamide + Compound 5-3 ##STR00292##
cis-3-(cyanoamino)-N-(5-cyclohexyl- 1,3-thiazol-2-yl)cyclobutane-1-
carboxamide ++ Compound 5-4 ##STR00293##
cis-3-(cyanoamino)-N-(5-phenyl-1,3-
thiazol-2-yl)cyclobutane-1-carboxamide ++ Compound 5-5 ##STR00294##
trans-3-(cyanoamino)-N-(1-phenyl-1H- pyrazol-4-yl)cyclobutane-1-
carboxamide ++ Compound 5-6 ##STR00295##
trans-3-(cyanoamino)-N-(1-phenyl-1H- pyrazol-3-yl)cyclobutane-1-
carboxamide ++ Compound 5-7 ##STR00296##
trans-3-(cyanoamino)-N-(5-cyclohexyl-
1,3-thiazol-2-yl)cyclobutane-1- carboxamide +++ Compound 5-8
##STR00297## trans-3-(cyanoamino)-N-(5-phenyl-1,3-
thiazol-2-yl)cyclobutane-1-carboxamide ++ Compound 5-9 ##STR00298##
cis-3-(cyanoamino)-N-(2,3-dihydro-1H-
inden-5-yl)cyclobutane-1-carboxamide ++ Compound 5-10 ##STR00299##
cis-N-(5-tert-butyl-1,3-thiazol-2-yl)-3- (cyanoamino)cyclobutane-1-
carboxamide + Compound 5-11 ##STR00300##
{[cis-3-(4-phenylpiperazine-1-
carbonyl)cyclobutyl]amino}carbonitirile - Compound 5-12
##STR00301## trans-3-(cyanoamino)-N-(2,3-dihydro-
1H-inden-5-yl)cyclobutane-1- carboxamide ++ Compound 5-13
##STR00302## trans-N-(5-tert-butyl-1,3-thiazol-2-yl)-
3-(cyanoamino)cyclobutane-1- carboxamide +++ Compound 5-14
##STR00303## trans-3-(cyanoamino)-N-[4-(morpholin-
4-yl)phenyl]cyclobutane-1-carboxamide +
TABLE-US-00011 TABLE A2 USP30 Example potentcy No. Structure
Chemical Name range Compound 1-2 ##STR00304##
(1r,3r)-3-(cyanoamino)-N-(1- methyl-3-phenyl-1H-pyrazol-5-
yl)cyclobutane-1-carboxamide +++ Compound 1-3 ##STR00305##
(1r,3r)-3-(cyanoamino)-N-(2- cyclohexyl-1,3-thiazol-5-
yl)cyclobutane-1-carboxamide ++++ Compound 1-4 ##STR00306##
(1r,3r)-3-(cyanoamino)-N-(2- cyclohexyl-1,3-thiazol-5-yl)-N-
methylcyclobutane-1- carboxamide +++ Compound 1-5 ##STR00307##
(1r,3r)-N-(5-tert-butyl-1,3- thiazol-2-yl)-3-(cyanoamino)-
N-methylcyclobutane-1- carboxamide +++ Compound 1-6 ##STR00308##
(1r,3r)-3-(cyanoamino)-N-(3- cyclohexyl-1-methyl-1H-
pyrazol-5-yl)cyclobutane-1- carboxamide +++ Compound 1-7
##STR00309## (1r,3r)-3-(cyanoamino)-N-(2- cyclohexyl-4-methyl-1,3-
thiazol-5-yl)cyclobutane-1- carboxamide +++ Compound 1-8
##STR00310## (1r,3r)-3-(cyanoamino)-N-{2-
[2-(propan-2-yloxy)phenyl]- 1,3-thiazol-5-yl}cyclobutane-1-
carboxamide +++ Compound 1-9 ##STR00311##
(1r,3r)-3-(cyanoamino)-N-[2- (3,3-difluorocyclobutyl)-1,3-
thiazol-5-yl]cyclobutane-1- carboxamide +++ Compound 1-10
##STR00312## (1r,3r)-N-(4-chloro-5- cyclohexyl-1,3-thiazol-2-yl)-3-
(cyanoamino)cyclobutane-1- carboxamide ++++ Compound 1-11
##STR00313## (1r,3s)-3-(cyanoamino)-N-(2-
cyclohexyl-1,3-thiazol-5-yl)-1- methylcyclobutane-1- carboxamide
++++ Compound 1-12 ##STR00314## (1r,3r)-3-(cyanoamino)-N-{2-
[(1S)-2,2-dimethylcyclohexyl]- 1,3-thiazol-5-yl}cyclobutane-1-
carboxamide ++++ Compound 1-13 ##STR00315##
(1r,3r)-3-(cyanoamino)-N-{2- [(1R)-2,2-dimethylcyclohexyl]-
1,3-thiazol-5-yl}cyclobutane-1- carboxamide +++ Compound 1-14
##STR00316## (1r,3r)-N-(4-chloro-2- cyclohexyl-1,3-thiazol-5-yl)-3-
(cyanoamino)cyclobutane-1- carboxamide +++ Compound 1-15
##STR00317## (1R,3R)-3-(cyanoamino)-N-(2-
cyclohexyl-1,3-thiazol-5-yl)- 2,2-dimethylcyclobutane-1-
carboxamide +++ Compound 1-16 ##STR00318##
(1r,3r)-3-(cyanoamino)-N-[5- cyclohexyl-4-
(methoxymethyl)-1,3-thiazol-2- yl]cyclobutane-1-carboxamide ++++
Compound 1-17 ##STR00319## (1r,3r)-3-(cyanoamino)-N-(2-
cyclohexyl-4-fluoro-1,3- thiazol-5-yl)cyclobutane-1- carboxamide
+++ Compound 1-18 ##STR00320## (1s,3s)-N-(4-chloro-5-
cyclohexyl-1,3-thiazol-2-yl)-3- (cyanoamino)cyclobutane-1-
carboxamide +++ Compound 1-19 ##STR00321##
(1r,3r)-N-(5-tert-butyl)-4- chloro-1,3-thiazol-2-yl)-3-
(cyanoamino)cyclobutane-1- carboxamide ++++ Compound 1-20
##STR00322## (1r,3r)-N-[4-chloro-3- (trifluoromethyl)phenyl]-3-
(cyanoamino)cyclobutane-1- carboxamide ++ Compound 1-21
##STR00323## (1r,3r)-3-(cyanoamino)-N-{5-
[(1S,2R)-2-methylcyclohexyl]- 1,3-thiazol-2-yl}cyclobutane-1-
carboxamide +++ Compound 1-22 ##STR00324##
(1r,3r)-3-(cyanoamino)-N-{5- [(1R,2S)-2-methylcyclohexyl]-
1,3-thiazol-2-yl}cyclobutane-1- carboxamide +++ Compond 1-23
##STR00325## (1r,3r)-3-(cyanoamino)-N-{5-
[(1S,2S)-2-methylcyclohexyl]- 1,3-thiazol-2-yl}cyclobutane-1-
carboxamide ++++ Compound 1-24 ##STR00326##
(1r,3r)-3-(cyanoamino)-N-{5- [(1R,2R)-2-methylcyclohexyl]-
1,3-thiazol-2-yl}cyclobutane-1- carboxamide ++++ Compound 1-25
##STR00327## (1r,3r)-3-(cyanoamino)-N-(5-
cyclohexyl-4-cyclopropyl-1,3- thiazol-2-yl)cyclobutane-1-
carboxamide ++++ Compound 1-26 ##STR00328##
(1r,3r)-3-(cyanoamino)-N-[5- cyclohexyl-4-(1-cyclopropyl-
1H-pyrazol-4-yl)-1,3-thiazol-2- yl]cyclobutane-1-carboxamide ++++
Compound 1-27 ##STR00329## (1r,3r)-3-(cyanoamino)-N-[4-
(trifluoromethyl)pyridin-2- yl]cyclobutane-1-carboxamide +++
Compound 1-28 ##STR00330## (1r,3r)-3-(cyanoamino)-N-{5-
[(2S)-oxa-2-yl]-1,3-thiazol-2- yl}cyclobutane-1-carboxamide ++
Compound 1-29 ##STR00331## (1r,3r)-3-(cyanoamino)-N-(5-
cyclohexyl-4-methyl-1,3- thiazol-2-yl)cyclobutane-1- carboxamide
++++ Compound 1-30 ##STR00332## (1r,3r)-3-(cyanoamino)-N-(5-
cyclohexyl-1-methyl-1H- pyrazol-3-yl)cyclobutane-1- carboxamide +++
Compound 1-31 ##STR00333## (1r,3r)-3-(cyanoamino)-N-[5-
cyclohexyl-4-(trifluoromethyl)- 1,3-thiazol-2-yl]cyclobutane-1-
carboxamide ++++ Compound 1-32 ##STR00334##
(1r,3r)-3-(cyanoamino)-N-{5- [(1S,2R)-2-
(trifluoromethyl)cyclohexyl]- 1,3-thiazol-2-yl}cyclobutane-1-
carboxamide +++ Compound 1-33 ##STR00335##
(1r,3r)-3-(cyanoamino)-N-{5- [(1R,2S)-2-
(trifluoromethyl)cyclohexyl]- 1,3-thiazol-2-yl}cyclobutane-1-
carboxamide +++ Compound 1-34 ##STR00336##
(1r,3r)-3-(cyanoamino)-N-{5- [(1S,2S)-2-
(trifluoromethyl)cyclohexyl]- 1,3-thiazol-2-yl}cyclobutane-1-
carboxamide +++ Compound 1-35 ##STR00337##
(1r,3r)-3-(cyanoamino)-N-{5- [(1R,2R)-2-
(trifluoromethyl)cyclohexyl]- 1,3-thiazol-2-yl}cyclobutane-1-
carboxamide +++ Compound 1-36 ##STR00338## (1r,3r)-N-(4-chloro-5-
cyclopropyl-1,3-thiazol-2-yl)- 3-(cyanoamino)cyclobutane-1-
carboxamide ++++ Compound 1-37 ##STR00339## (1r,3r)-N-{5-[(2R)-
bicyclo[2.2.2]octan-2-yl]-1,3- thiazol-2-yl}-3-
(cyanoamino)cyclobutane-1- carboxamide ++++ Compound 1-38
##STR00340## (1r,3r)-N-{5-[(2S)- bicyclo[2.2.2]octan-2-yl]-1,3-
thiazol-2-yl}-3- (cyanoamino)cyclobutane-1- carboxamide +++
Compound 1-39 ##STR00341## (1r,3r)-N-(5-chloro-1-
cyclohexyl-1H-pyrazol-3-yl)-3- (cyanoamino)cyclobutane-1-
carboxamide +++ Compound 1-40 ##STR00342##
(1r,3r)-3-(cyanoamino)-N-[5- (3-cyanophenyl)-1,3-thiazol-2-
yl]cyclobutane-1-carboxamide +++ Compound 1-41 ##STR00343##
(1r,3r)-N-[3-(3-chlorophenyl)- 1,2-oxazol-5-yl]-3-
(cyanoamino)cyclobutane-1- carboxamide +++ Compound 1-42
##STR00344## (1r,3s)-3-(cyanoamino)-N-(5-
cyclohexyl-1,3-thiazol-2-yl)-1- methylcyclobutane-1- carboxamide
+++ Compound 1-43 ##STR00345## (1r,3r)-N-[5-(3-chlorophenyl)-
1,2-oxazol-3-yl]-3- (cyanoamino)cyclobutane-1- carboxamide +++
Compound 1-44 ##STR00346## (1r,3s)-N-(4-chloro-5-
cyclohexyl-1,3-thiazol-2-yl)-3- (cyanoamino)-1-
methylcyclobutane-1- carboxamide ++++ Compound 1-45 ##STR00347##
(1r,3r)-N-[3-(3-chlorophenyl)- 1,2-oxazol-5-yl]-3- (cyanoamino)-N-
methylcyclobutane-1- carboxamide +++ Compound 1-46 ##STR00348##
(1r,3s)-3-(cyanoamino)-N-(2- cyclohexyl-1,3-thiazol-5-yl)-1-
ethylcyclobutane-1- carboxamide +++ Compound 1-47 ##STR00349##
(1s,3s)-N-(4-chloro-5- cyclohexyl-1,3-thiazol-2-yl)-3-
(cyanoamino)-1- fluorocyclobutane-1- carboxamide +++ Compound 1-48
##STR00350## (1r,3r)-N-(4-chloro-5- cyclohexyl-1,3-thiazol-2-yl)-3-
(cyanoamino)-1- fluorocyclobutane-1- carboxamide ++++ Compound 1-49
##STR00351## (1r,3r)-N-(4-chloro-5- cyclohexyl-1,3-thiazol-2-yl)-3-
(cyanoamino)-N- methylcyclobutane-1- carboxamide ++++ Compound 1-50
##STR00352## (1r,3r)-N-(5-tert-butyl-4- chloro-1,3-thiazol-2-yl)-3-
(cyanoamino)-N- methylcyclobutane-1- carboxamide ++++ Compound 1-51
##STR00353## (1r,3r)-3-(cyanoamino)-N-[3-
(3-cyanophenyl)-1,2-oxazol-4- yl]cyclobutane-1-carboxamide +++
Compound 1-52 ##STR00354## (1r,3r)-N-[5-(3-chlorophenyl)-
1,2-oxazol-3-yl]-3- (cyanoamino)-N- methylcyclobutane-1-
carboxamide +++ Compound 1-53 ##STR00355##
(1r,3r)-3-(cyanoamino)-N-(5- cyclohexyl-1,3-oxazol-2-
yl)cyclobutane-1-carboxamide +++ Compound 1-54 ##STR00356##
(1r,3r)-N-(5-tert-butyl-4- chloro-1,3-thiazol-2-yl)-3-
(cyanoamino)-1-fluoro-N- methylcyclobutane-1- carboxamide ++++
Compound 1-55 ##STR00357## (1r,3r)-N-(4-chloro-5-
cyclohexyl-1,3-thiazol-2-yl)-3- (cyanoamino)-1-fluoro-N-
methylcyclobutane-1- carboxamide ++++ Compound 1-56 ##STR00358##
(1s,3s)-3-(cyanoamino)-1- fluoro-N-{3-[4-
(trifluoromethyl)phenyl]-1H- pyrazol-5-yl}cyclobutane-1-
carboxamide +++ Compound 1-57 ##STR00359##
(1r,3r)-3-(cyanoamino)-1- fluoro-N-{3-[4-
(trifluoromethyl)phenyl]-1H- pyrazol-5-yl}cyclobutane-1-
carboxamide +++ Compound 1-58 ##STR00360## (1s,3s)-N-(4-chloro-5-
cyclohexyl-1,3-thiazol-2-yl)-3- (cyanoamino)-1-fluoro-N-
methylcyclobutane-1- carboxamide +++ Compound 1-59 ##STR00361##
(1s,3s)-N-(5-tert-butyl-4- chloro-1,3-thiazol-2-yl)-3-
(cyanoamino)-1- fluorocyclobutane-1- carboxamide +++ Compound 1-60
##STR00362## (1r,3r)-N-(5-tert-butyl-4- chloro-1,3-thiazol-2-yl)-3-
(cyanoamino)-1- fluorocyclobutane-1- carboxamide ++++ Compound 1-61
##STR00363## (1r,3r)-3-(cyanoamino)-N-[3- (2-fluorophenyl)-5-
methylphenyl]cyclobutane-1- carboxamide +++ Compound 1-62
##STR00364## (1r,3r)-N-(3-chloro-5- cyclohexylphenyl)-3-
(cyanoamino)cyclobutane-1- carboxamide ++++ Compound 1-63
##STR00365## (1r,3r)-3-(cyanoamino)-N-[4- fluoro-3-(piperidin-1-
yl)phenyl]cyclobutane-1- carboxamide +++ Compound 1-64 ##STR00366##
(1r,3r)-3-(cyanoamino)-N-(7- cyclobutoxy-1,3-benzothiazol-
2-yl)cyclobutane-1- carboxamide +++ Compound 1-65 ##STR00367##
(1r,3r)-3-(cyanoamino)-N-(7- cyclobutoxy-1,3-benzothiazol-
2-yl)-1-fluorocyclobutane-1- carboxamide ++++ Compound 1-66
##STR00368## (1s,3s)-3-(cyanoamino)-N-(7-
cyclobutoxy-1,3-benzothiazol- 2-yl)-1-fluorocyclobutane-1-
carboxamide +++ Compound 1-67 ##STR00369##
(1r,3r)-3-(cyanoamino)-N- {[(1R,2R,5R)-6,6-
dimethylbicyclo[3.1.1]heptan- 2-yl]methyl}cyclobutane-1-
carboxamide +++ Compound 1-68 ##STR00370##
(1r,3r)-N-[4-(4-chlorophenyl)- 1,3-thiazol-2-yl]-3-
(cyanoamino)cyclobutane-1- carboxamide +++ Compound 1-69
##STR00371## (1r,3r)-3-(cyanoamino)-N-(3-
phenylphenyl)cyclobutane-1- carboxamide +++ Compound 1-70
##STR00372## (1r,3r)-3-(cyanoamino)-N-{[4- (propan-2-
yl)phenyl]methyl}cyclobutane- 1-carboxamide ++++ Compound 1-71
##STR00373## (1r,3r)-3-(cyanoamino)-N- [(1s,4s)-4-tert-
butylcyclohexyl]cyclobutane- 1-carboxamide +++
Compound 1-72 ##STR00374## (1r,3r)-3-(cyanoamino)-N-
{[(1R,2R,5R)-6,6- dimethylbicyclo[3.1.1]heptan-
2-yl]methyl}cyclobutane-1- carboxamide +++ Compound 1-73
##STR00375## (1r,3r)-3-(cyanoamino)-N-[3-
(trifluoromethyl)phenyl]cyclobu- tane-1-carboxamide +++ Compound
3-2 ##STR00376## {[1-(2-phenyl-1,3-thiazol-5- carbonyl)-1-
azaspiro[3.3]heptan-6- yl]amino}carbonitrile +++ Compound 3-3
##STR00377## 3-[4-(1-methyl-1H-pyrazol-4- yl)phenyl]-N-[(1s,3s)-3-
(cyanoamino)cyclobutyl]-1,2- oxazol-5-carboxamide +++ Compound 3-4
##STR00378## {[(2r,4s)-5-{3-[4-(1-methyl-
1H-pyrazol-4-yl)phenyl]-1,2- oxazole-5-carbonyl}-5-
azaspiro[3.4]octan-2- yl]amino}carbonitrile +++ Compound 3-5
##STR00379## {[(4r,6s)-1-{3-[4-(1-methyl-
1H-pyrazol-4-yl)phenyl]-1,2- oxazole-5-carbonyl}-1-
azaspiro[3.3]heptan-6- yl]amino}carbonitrile +++ Compound 3-6
##STR00380## 3-(3-cyanophenyl)-N-methyl- N-[(1r,3r)-3-
(cyanoamino)cyclobutyl]-1,2- oxazole-5-carboxamide ++ Compound 6-1
##STR00381## {[(1r,3r)-3-[(4S)-4-[(5- cyclohexyl-1,3-thiazol-2-
yl)amino]-2-oxopyrrolidin-1- yl]cyclobutyl]amino}carbonitrile +++
Compound 7-1 ##STR00382## {[(2r,4s)-6-(5-tert-butyl-4-
chloro-1,3-thiazol-2-yl)-5-oxo- 6-azaspiro[3.4]octan-2-
yl]amino}carbonitrile ++++ Compound 7-2 ##STR00383##
{[(2s,4r)-6-(4-chloro- cyclohexyl-1,3-thiazol-2-yl)-5-
oxo-6-azaspiro[3.4]octan-2- yl]amino}carbonitrile +++ Compound 7-3
##STR00384## {[(2r,4s)-6-(4-chloro-5-
cyclohexyl-1,3-thiazol-2-yl)-5- oxo-6-azaspiro[3.4]octan-2-
yl]amino}carbonitrile ++++ Compound 8-1 ##STR00385##
(1r,3r)-N-(5-tert-butyl-4- chloro-1,3-thiazol-2-yl)-3-
(cyanoamino)-1- methoxycyclobutane-1- carboxamide ++++ Compound 9-1
##STR00386## (1s,3s)-N-(5-tert-butyl-4- chloro-1,3-thiazol-2-yl)-1-
chloro-3- (cyanoamino)cyclobutane-1- carboxamide ++++ Compound 9-2
##STR00387## (1r,3r)-N-(5-tert-butyl-4- chloro-1,3-thiazol-2-yl)-1-
chloro-3- (cyanoamino)cyclobutane-1- carboxamide +++
TABLE-US-00012 TABLE A3 USP30 Example potency no. Molecule Chemical
Name range Compound 10-1 ##STR00388## cis-4-(cyanoamino)-N-(5-
cyclohexyl-1,3-thiazol-2- yl)cyclohexane-1- carboxamide +++
Compound 10-2 ##STR00389## trans-4-(cyanoamino)-N-
(5-cyclohexyl-1,3-thiazol- 2-yl)cyclohexane-1- carboxamide ++
Compound 10-3 ##STR00390## (1r,2R)-2-(cyanoamino)-
N-(5-cyclohexyl-1,3- thiazol-2-yl)cyclopentane- 1-carboxamide ++
Compound 10-4 ##STR00391## (1R,3S)-3-(cyanoamino)-
N-(5-cyclohexyl-1,3- thiazol-2-yl)cyclohexane- 1-carboxamide -
Compound 10-5 ##STR00392## (1S,3S)-3-(cyanoamino)-
N-(5-cyclohexyl-1,3- thiazol-2-yl)cyclohexane- 1-carboxamide -
Compound 10-6 ##STR00393## (1S,3R)-3-(cyanoamino)-
N-(5-cyclohexyl-1,3- thiazol-2-yl)cyclohexane- 1-carboxamide ++
Compund 10-7 ##STR00394## (1R,2S)-2-(cyanoamino)-
N-(5-cyclohexyl-1,3- thiazol-2-yl)cyclopentane- 1-carboxamide ++
Compound 10-8 ##STR00395## (1S,2R)-2-(cyanoamino)-
N-(5-cyclohexyl-1,3- thiazol-2-yl)cyclopentane- 1-carboxamide ++
Compound 10-9 ##STR00396## (1S,2S)-2-(cyanoamino)-
N-(5-cyclohexyl-1,3- thiazol-2-yl)cyclopentane- 1-carboxamide ++
Compound 1-10 ##STR00397## trans-3-(cyanoamino)-N-
[5-(oxan-4-yl)-1,3-thiazol- 2-yl]cyclobutane-1- carboxamide ++
Compound 10-10 ##STR00398## (1S,3S)-3-(cyanoamino)-
N-[5-(oxan-4-yl)-1,3- thiazol-2-yl]cyclopentane- 1-carboxamide ++
Compound 10-11 ##STR00399## (1R,3R)-3-(cyanoamino)-
N-[5-(oxan-4-yl)-1,3- thiazol-2-yl]cyclopentane- 1-carboxamide +
Compound 11-1 ##STR00400## trans-2-(cyanoamino)-N-
(5-cyclohexyl-1,3-thiazol- 2-yl)cyclopropane-1- carboxamide ++
Compound 11-2 ##STR00401## cis-2-(cyanoamino)-N-(5-
cyclohexyl-1,3-thiazol-2- yl)cyclopropae-1- carboxamide ++ Compound
2-2 ##STR00402## (3S)-3-(cyanoamino)-N- (5-cyclohexyl-1,3-thiazol-
2-yl)pyrrolidine-1- carboxamide ++ Compound 2-3 ##STR00403##
(3R)-3-(cyanoamino)-N- (5-cyclohexyl-1,3-thiazol-
2-yl)pyrrolidine-1- carboxamide Compound 12-1 ##STR00404##
(1R,3S)-3-(cyanoamino)- N-(5-phenyl-1,3-thiazol-
2-yl)cyclopentane-1- carboxamide ++ Compund 12-2 ##STR00405##
(1S,3S)-3-(cyanoamino)- N-(1-phenyl-1H-pyrazol-
3-yl)cyclopentane-1- carboxamide + Compound 12-3 ##STR00406##
(1S,3S)-3-(cyanoamino)- N-(5-cyclohexyl-1,3-
thiazol-2-yl)cyclopentane- 1-carboxamide +++ Compound 12-4
##STR00407## (1S,3S)-3-(cyanoamino)- N-(5-phenyl-1,3-thiazol-
2-yl)cyclopentane-1- carboxamide ++ Compound 12-5 ##STR00408##
(1S,3S)-3-(cyanoamino)- N-(2,3-dihydro-1H-inden-
5-yl)cyclopentane-1- carboxamide + Compound 12-6 ##STR00409##
{[(1S,3S)-3-(4- phenylpiperazine-1- carbonyl)cyclopentyl]ami-
no}carbonitrile - Compound 12-7 ##STR00410##
(1S,3R)-N-(5-tert-butyl- 1,3-thiazol-2-yl)-3-
(cyanoamino)cyclopentane- 1-carboxamide ++ Compound 12-8
##STR00411## {[(3S)-1-[2-(2,3- dichlorophenyl)-1,3- thiazole-4-
carbonyl]pyrrolidin-3- yl]amino}carbonitrile ++ Compound 12-9
##STR00412## ({1-[2-(2,4- dichlorophenyl)-1,3- thiazole-4-
carobnyl]piperidin-4- yl}amino)carbonitrile +
EQUIVALENTS
[0386] Those skilled in the art will recognize, or be able to
ascertain, using no more than routine experimentation, numerous
equivalents to the specific embodiments described specifically
herein. Such equivalents are intended to be encompassed in the
scope of the following claims. Embodiments of the disclosure are
set out in the following numbered clauses: [0387] 1. At least one
chemical entity chosen from compounds of Formula (I):
##STR00413##
[0387] and pharmaceutically acceptable salts, solvates, prodrugs,
stereoisomers, and tautomers thereof, wherein:
[0388] R is independently chosen from hydrogen, OH, CN,
(C.sub.1-C.sub.6) alkyl groups, (C.sub.1-C.sub.6) alkoxy groups,
(C.sub.1-C.sub.6) haloalkyl groups, (C.sub.1-C.sub.6) haloalkoxy
groups, halogen, (C.sub.3-C.sub.6) cycloalkyl groups, and
(C.sub.3-C.sub.6) heterocycloalkyl groups;
[0389] n is 0, 1, or 2;
wherein, if n is 2, the R groups can combine to form a fused ring
system with R.sub.1;
[0390] R.sub.1 is chosen from 3-6 membered cyclic or heterocyclic
groups;
[0391] R.sub.2 is chosen from C(X).sub.n, S(O).sub.2, N(X),
heteroatom linkers, N(X)S(O).sub.2, N(X)S(O).sub.2N(X),
carbonylalkyl groups, and carbonylheteroalkyl groups, wherein the
alkyl portion of carbonylalkyl and carbonylheteroalkyl groups can
optionally cyclize with R, R.sub.1, or R.sub.3:
[0392] X is independently chosen from hydrogen, alkyl groups, and
heteroalkyl groups, wherein the alkyl and heteroalkyl groups can
optionally cyclize with R, R.sub.1, or R.sub.3 or with another X
group when multiple X groups are present;
[0393] R.sub.3 is chosen from hydrogen, halogens, alkyl groups,
heteroalkyl groups, haloalkyl groups, alkoxy groups, heteroalkoxy
groups, haloalkoxy groups, carbonylalkyl groups,
carbonylheteroalkyl groups, cyclic groups, heterocyclic groups,
aryl groups, and heteroaryl groups, wherein any rings are
optionally substituted with 1 or 2 R groups;
[0394] R4 is independently chosen from alkyl groups, heteroalkyl
groups, haloalkyl groups, alkoxy groups, cycloalkoxy groups,
heteroalkoxy groups, haloalkoxy groups, carboxyalkyl groups,
heterocarboxyalkyl groups, cyclic groups, heterocyclic groups, aryl
groups and heteroaryl groups, wherein any rings are optionally
substituted with 1 or 2 Y groups;
[0395] Y is independently chosen from hydrogen, OH, CN, N(X).sub.2,
(C.sub.1-C.sub.6) alkyl groups, (C.sub.1-C.sub.6) heteroalkyl
groups, (C.sub.1-C.sub.6) alkoxy groups, (C.sub.1-C.sub.6)
haloalkyl groups, (C.sub.1-C.sub.6) haloalkoxy groups, halogen,
(C.sub.3-C.sub.6) cycloalkyl groups, (C.sub.3-C.sub.6)
heterocycloalkyl groups, (C.sub.5-C.sub.8) aryl groups, and
(C.sub.4-C.sub.8) heteroaryl groups; and
[0396] m is 0, 1, or 2. [0397] 2. The chemical entity of clause 1,
wherein R.sub.1 is chosen from cyclopropane, cyclobutane,
cyclopentane, and cyclohexane. [0398] 3. The chemical entity of
clause 1, wherein R.sub.1 is chosen from cyclobutane and
cyclopentane. [0399] 4. The chemical entity of clause 1, wherein
R.sub.1 is chosen from heterocyclic groups. [0400] 5. The chemical
entity of clause 1, wherein R.sub.1 is a pyrrolidine. [0401] 6. The
chemical entity of clause 1, wherein R.sub.2 is chosen from
carbonylalkyl and heterocarbonylalkyl groups. [0402] 7. The
chemical entity of clause 1, wherein R.sub.2 is chosen from amides,
reversed amides, and ureas. [0403] 8. The chemical entity of clause
1, wherein R.sub.2 is an amide. [0404] 9. The chemical entity of
clause 1, wherein R.sub.3 is chosen from aryl and heteroaryl rings.
[0405] 10. The chemical entity of clause 1, wherein R.sub.3 is
chosen from thiazole, indenyl, pyrazole, and phenyl rings. [0406]
11. The chemical entity of clause 1, wherein R.sub.3 is chosen from
cyclic and heterocyclic rings. [0407] 12. The chemical entity of
clause 1, wherein m is 0. [0408] 13. The chemical entity of clause
1, wherein R.sub.4 is chosen from cyclic and heterocyclic rings
optionally substituted with 1 or 2 R. [0409] 14. The chemical
entity of clause 1, wherein R.sub.4 is chosen from alkyl,
heteroalkyl, and haloalkyl groups. [0410] 15. The chemical entity
of clause 1, wherein R.sub.4 is chosen from aryl and heteroaryl
rings optionally substituted with 1 or 2 R. [0411] 16. The chemical
entity of clause 1 wherein R is chosen from halogens. [0412] 17.
The chemical entity of clause 1, chosen from the following
compounds:
TABLE-US-00013 [0412] Example No. Structure Chemical Name Compound
10-1 ##STR00414## cis-4-(cyanoamino)-N-(5-
cyclohexyl-1,3-thiazol-2- yl)cyclohexane-1- carboxamide Compound
10-2 ##STR00415## trans-4-(cyanoamino)-N-(5-
cyclohexyl-1,3-thiazol-2- yl)cyclohexane-1- carboxamide Compound
10-3 ##STR00416## (1R,2R)-2-(cyanoamino)-N-
(5-cyclohexyl-1,3-thiazol-2- yl)cyclopentane-1- carboxamide
Compound 10-4 ##STR00417## (1R,3S)-3-(cyanoamino)-N-
(5-cyclohexyl-1,3-thiazol-2- yl)cyclohexane-1- carboxamide Compound
10-5 ##STR00418## (1S,3S)-3-(cyanoamino)-N-
(5-cyclohexyl-1,3-thiazol-2- yl)cyclohexane-1- carboxamide Compound
10-6 ##STR00419## (1S,3R)-3-(cyanoamino)-N-
(5-cyclohexyl-1,3-thiazol-2- yl)cyclohexane-1- carboxamide Compound
10-7 ##STR00420## (1R,2S)-2-(cyanoamino)-N-
(5-cyclohexyl-1,3-thiazol-2- yl)cyclopentane-1- carboxamide
Compound 10-8 ##STR00421## (1S,2R)-2-(cyanoamino)-N-
(5-cyclohexyl-1,3-thiazol-2- yl)cyclopentane-1- carboxamide Compund
10-9 ##STR00422## (1S,2S)-2-(cyanoamino)-N-
(5-cyclohexyl-1,3-thiazol-2- yl)cyclopentane-1- carboxamide
Compound 1-1 ##STR00423## trans-3-(cyanoamino)-N-[5-
(oxan-4-yl)-1,3-thiazol-2- yl]cyclobutane-1- carboxamide Compound
10-10 ##STR00424## (1S,3S)-3-(cyanoamino)-N-
[5-(oxan-4-yl)-1,3-thiazol-2- yl]cyclopentane-1- carboxamide
Compound 10-11 ##STR00425## (1R,3R)-3-(cyanoamino)-N-
[5-(oxan-4-yl)-1,3-thiazol-2- yl]cyclopentane-1- carboxamide
Compound 11-1 ##STR00426## trans-2-(cyanoamino)-N-(5-
cyclohexyl-1,3-thiazol-2- yl)cyclopropane-1- carboxamide Compound
11-2 ##STR00427## cis-2-(cyanoamino)-N-(5-
cyclohexyl-1,3-thiazol-2- yl)cyclopropane-1- carboxamide Compound
2-1 ##STR00428## 3-(cyanoamino)-N-(5- cyclohexyl-1,3-thiazol-2-
yl)azetidine-1-carboxamide Compound 2-2 ##STR00429##
(3S)-3-(cyanoamino)-N-(5- cyclohexyl-1,3-thiazol-2-
yl)pyrrolidine-1- carboxamide Compound 2-3 ##STR00430##
(3R)-3-(cyanoamino)-N-(5- cyclohexyl-1,3-thiazol-2-
yl)pyrrolidine-1- carboxamide Compound 3-1 ##STR00431##
5-phenyl-N-[(trans)-3- (cyanoamino)cyclobutyl]-
1,3-thiazole-2-carboxamide Compound 4-1 ##STR00432##
5-phenyl-N-[(cis)-3- (cyanoamino)cyclobutyl]-
1,3-thiazole-2-carboxamide Compound 12-1 ##STR00433##
(1R,3S)-3-(cyanoamino)-N- (5-phenyl-1,3-thiazol-2-
yl)cyclopentane-1- carboxamide Compound 12-2 ##STR00434##
(1S,3S)-3-(cyanoamino)-N- (1-phenyl-1H-pyrazol-3-
yl)cyclopentane-1- carboxamide Compound 12-3 ##STR00435##
(1S,3S)-3-(cyanoamino)-N- (5-cyclohexyl-1,3-thiazol-2-
yl)cyclopentane-1- carboxamide Compound 12-4 ##STR00436##
(1S,3S)-3-(cyanoamino)-N- (5-phenyl-1,3-thiazol-2-
yl)cyclopentane-1- carboxamide Compound 5-1 ##STR00437##
cis-3-(cyanoamino)-N-(1- phenyl-1H-pyrazol-4- yl)cyclobutane-1-
carboxamide Compound 5-2 ##STR00438## cis-3-(cyanoamino)-N-(1-
phenyl-1H-pyrazol-3- yl)cyclobutane-1- carboxamide Compound 5-3
##STR00439## cis-3-(cyanoamino)-N-(5- cyclohexyl-1,3-thiazol-2-
y)cyclobutane-1- carboxamide Compound 5-4 ##STR00440##
cis-3-(cyanoamino)-N-(5- phenyl-1,3-thiazol-2- yl)cyclobutane-1-
carboxamide Compound 5-5 ##STR00441## trans-3-(cyanoamino)-N-(1-
phenyl-1H-pyrazol-4- yl)cyclobutane-1- carboxamide Compound 5-6
##STR00442## trans-3-(cyanoamino)-N-(1- phenyl-1H-pyrazol-3-
yl)cyclobutane-1- carboxamide Compound 5-7 ##STR00443##
trans-3-(cyanoamino)-N-(5- cyclohexyl-1,3-thiazol-2-
yl)cyclobutane-1- carboxamide Compound 5-8 ##STR00444##
trans-3-(cyanoamino)-N-(5- phenyl-1,3-thiazol-2- yl)cyclobutane-1-
carboxamide Compound 12-5 ##STR00445## (1S,3S)-3-(cyanoamino)-N-
(2,3-dihydro-1H-inden-5- yl)cyclopentane-1- carboxamide Compound
12-6 ##STR00446## {[(1S,3S)-3-(4- phenylpiperazine-1-
carbonyl)cyclopentyl]amino} carbonitrile Compound 12-7 ##STR00447##
(1S,3R)-N-(5-tert-butyl-1,3- thiazol-2-yl)-3-
(cyanoamino)cyclopentane- 1-carboxamide Compound 5-9 ##STR00448##
cis-3-(cyanoamino)-N-(2,3- dihydro-1H-inden-5- yl)cyclobutane-1-
carboxamide Compound 5-10 ##STR00449## cis-N-(5-tert-butyl-1,3-
thiazol-2-yl)-3- (cyanoamino)cyclobutane- 1-carboxamide Compound
5-11 ##STR00450## {[cis-3-(4-phenylpiperazine- 1-
carbonyl)cyclobutyl]amino} carbonitrile Compound 5-12 ##STR00451##
trans-3-(cyanoamino)-N- (2,3-dihydro-1H-inden-5- yl)cyclobutane-1-
carboxamide Compound 5-13 ##STR00452## trans-N-(5-tert-butyl-1,3-
thiazol-2-yl)-3- (cyanoamino)cyclobutane- 1-carboxamide Compound
5-14 ##STR00453## trans-3-(cyanoamino)-N-[4- (morpholin-4-
yl)phenyl]cyclobutane-1- carboxamide Compound 12-8 ##STR00454##
{[(3S)-1-[2-(2,3- dichlorophenyl)-1,3- thiazole-4-
carbonyl]pyrrolidine-3- yl]amino}carbonitrile Compound 12-9
##STR00455## ({1-[2-(2,4-dichlorophenyl)- 1,3-thiazole-4-
carbonyl]piperidine-4- yl}amino)carbonitrile
[0413] and pharmaceutically acceptable salts, solvates, prodrugs,
stereoisomers, and tautomers thereof. [0414] 18. A composition
comprising at least one chemical entity of any one of clauses 1-17,
and a pharmaceutically acceptable carrier. [0415] 19. A method of
inhibiting USP30 in vitro comprising administering to a
Ubiquitin-Rhodamine 110 assay for USP30 activity an effective
amount of at least one chemical entity of any one of clauses 1-17.
[0416] 20. A method for treating at least one disease, disorder, or
condition associated with mitochondrial dysfunction comprising
administering to a patient in need thereof an effective amount of
at least one chemical entity of any one of clauses 1-17. [0417] 21.
The method of clause 20, wherein the at least one disease,
disorder, or condition is chosen from neurodegenerative diseases,
motor neuron diseases, metabolic disorders, cardio-vascular
diseases, psychiatric diseases, osteoarthritis, and cancer. [0418]
22. The method of clause 21, wherein the neurodegenerative disease
is chosen from Alzheimer's disease, Parkinson's disease, dementia,
Prion disease, corticobasal degeneration, Posterior Cortical
Atrophy, Primary Progressive Aphasia, Progressive Supranuclear
Palsy, Pick's disease, Chronic Traumatic Encephelopathy, Traumatic
Brain Injury, peripheral neuropathy, and multiple sclerosis. [0419]
23. The method of clause 21, wherein the motor neuron disease is
chosen from Amyltrophic Lateral Sclerosis (ALS), Huntington's
disease, Spinocerebellar Ataxia, Ataxia, and Spinal Muscular
Atrophy. [0420] 24. The method of clause 21 wherein the metabolic
disorder is chosen from diabetes, mitochondrial encephalomyopathy,
Stroke-Like Episodes (MELAS), mitochondrial myopathy,
encephalopathy, lactic acidosis, Leber's hereditary optic
neuropathy (LHON), neuropathy, ataxia, retinitis
pigmentosa-maternally inherited Leigh syndrome (NARP-MILS), Danon
disease, diabetic nephropathy, retinitis pigmentosa-maternally
inherited Leigh syndrome (NARP-MILS), multiple sulfatase deficiency
(MSD), mucolipidosis II (ML II), mucolipidosis III (ML III),
mucolipidosis IV (ML IV), GM1-gangliosidosis (GM1), neuronal
ceroid-lipofuscinoses (NCLl), Alpers disease, Barth syndrome,
Beta-oxidation defects, camitine-acyl-camitine deficiency, camitine
deficiency, creatine deficiency syndrome, co-enzyme Q 10
deficiency, complex I deficiency, complex II deficiency, CPT I
deficiency, CPT II deficiency, glutaric aciduria type II,
Keams-Sayre syndrome, lactic acidosis, long-chain acyl-CoA
dehydrogenase deficiency (LCHAD), Leigh disease complex III
deficiency, complex IV deficiency, complex V deficiency, COX
deficiency, chronic progressive external syndrome, lethal infantile
cardiomyopathy (LIC), Luft disease, glutaric aciduria type II,
medium-chain acyl-CoA dehydrogenase deficiency (MCAD), myoclonic
epilepsy and ragged-red fiber (MERRF) syndrome, mitochondrial
cytopathy, mitochondrial recessive ataxia syndrome, mitochondrial
DNA depletion syndrome, myoneurogastrointestinal disorder and
encephalopathy, Pearson syndrome, pyruvate dehydrogenase
deficiency, pyruvate carboxylase deficiency, POLG ophthalmoplegia
syndrome mutations, medium/short-chain 3-hydroxyacyl-CoA
dehydrogenase (M/SCHAD) deficiency, and very long-chain acyl-CoA
dehydrogenase (VLCAD) deficiency. [0421] 25. The method of clause
21 wherein the cardiovascular disorder is chosen from transthyretin
amyloidosis, heart failure, ischemic heart disease leading to
cardiac infarction, and cardiac amyloidosis. [0422] 26. The method
of clause 21 wherein the psychiatric disease is chosen from
schizophrenia, depression, and general anxiety disorder. [0423] 27.
The method of clause 21, wherein the cancer is chosen from bladder
cancer, breast cancer, cervical cancer, colorectal cancer,
esophageal cancer, gastric cancer, head and neck cancer,
hematologic cancer, lung cancer, liver cancer, lymphoma,
neurological cancer, ovarian, pancreatic cancer, prostate cancer,
renal cancer, sarcoma, skin cancer, thyroid cancer, and uterine
cancer.
* * * * *
References