U.S. patent application number 17/515758 was filed with the patent office on 2022-05-05 for ectonucleotide pyrophosphatase-phosphodiesterase-1 (enpp1) inhibitors and uses thereof.
The applicant listed for this patent is INTEGRAL BIOSCIENCES PRIVATE LIMITED. Invention is credited to Amantullah Ansari, Sarvajit Chakravarty, Abhinandan Danodia, Ashu Gupta, Pradeep S. Jadhavar, Farha Khan, Sagar Patni, Dhananjay Pendharkar, Brahmam Pujala, Sreekanth A. Ramachandran, Uzma Saeed, Shreya Sapra, Balaji Dashrath Sathe, Sanjeev Soni.
Application Number | 20220135598 17/515758 |
Document ID | / |
Family ID | 1000006003267 |
Filed Date | 2022-05-05 |
United States Patent
Application |
20220135598 |
Kind Code |
A1 |
Pujala; Brahmam ; et
al. |
May 5, 2022 |
ECTONUCLEOTIDE PYROPHOSPHATASE-PHOSPHODIESTERASE-1 (ENPP1)
INHIBITORS AND USES THEREOF
Abstract
The present invention discloses compounds useful in treatment of
conditions associated with dysfunction of ectonucleotide
pyrophosphatase/phosphodiesterase-1 (ENPP1) enzyme. Specifically,
the present invention discloses compound of formula (J) which
exhibit inhibitory activity against ENPP1. Method of treating
conditions associated with over-expression of ENPP1 gene with such
compound is disclosed. Uses thereof, pharmaceutical composition,
and kits are also disclosed. ##STR00001##
Inventors: |
Pujala; Brahmam; (Greater
Noida, IN) ; Ansari; Amantullah; (Great Noida,
IN) ; Sapra; Shreya; (Noida, IN) ; Jadhavar;
Pradeep S.; (Greater Noida, IN) ; Pendharkar;
Dhananjay; (Greater Noida, IN) ; Ramachandran;
Sreekanth A.; (Greater Noida, IN) ; Saeed; Uzma;
(Okhla, IN) ; Danodia; Abhinandan; (Greater Noida,
IN) ; Khan; Farha; (Noida, IN) ; Patni;
Sagar; (Greater Noida, IN) ; Soni; Sanjeev;
(Noida, IN) ; Gupta; Ashu; (Noida, IN) ;
Chakravarty; Sarvajit; (Edmond, OK) ; Sathe; Balaji
Dashrath; (Greater Noida, IN) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
INTEGRAL BIOSCIENCES PRIVATE LIMITED |
Noida |
|
IN |
|
|
Family ID: |
1000006003267 |
Appl. No.: |
17/515758 |
Filed: |
November 1, 2021 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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63192605 |
May 25, 2021 |
|
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|
63107818 |
Oct 30, 2020 |
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Current U.S.
Class: |
514/64 |
Current CPC
Class: |
C07F 9/65583 20130101;
C07D 487/04 20130101; C07D 403/04 20130101; C07D 471/04 20130101;
C07F 5/025 20130101; C07D 491/056 20130101; C07D 403/14 20130101;
C07D 401/14 20130101 |
International
Class: |
C07F 5/02 20060101
C07F005/02; C07D 403/04 20060101 C07D403/04; C07D 471/04 20060101
C07D471/04; C07D 487/04 20060101 C07D487/04; C07D 491/056 20060101
C07D491/056; C07F 9/6558 20060101 C07F009/6558; C07D 401/14
20060101 C07D401/14; C07D 403/14 20060101 C07D403/14 |
Claims
1. A compound of formula (J) ##STR00718## or a salt thereof,
wherein C is 5- to 6-membered heteroaryl optionally substituted
with R.sup.1; D is C.sub.6-aryl or 5- to 6-membered heteroaryl,
each of which is optionally substituted with R.sup.2, wherein D is
fused to C; A is hydrogen, C.sub.1-C.sub.6 alkyl, or C.sub.6-aryl,
each of which is optionally substituted with halogen; G is a bond,
--CH.sub.2-- or --CH.sub.2--CH.sub.2--; R.sup.a and R.sup.b are
independently hydrogen or C.sub.1-C.sub.6 alkyl; or R.sup.a and
R.sup.b are taken together with the atoms to which they are
attached to form a C.sub.3-C.sub.6 cycloalkyl ring; or any one of
R.sup.a and R.sup.b, and A are taken together along with the atoms
to which they are attached to form a C.sub.4-C.sub.6 cycloalkyl
ring; L is a bond, linear or branched C.sub.1-C.sub.6 alkylene or
linear or branched C.sub.2-C.sub.6 alkenylene; t is 0 or 1;
provided that when t is 0 then L is linear or branched
C.sub.2-C.sub.6 alkenylene; Z is --NR.sup.cS(O).sub.2NH.sub.2,
--NR.sup.cS(O).sub.2CH.sub.3, --SO.sub.2NH.sub.2,
--NR.sup.cC(O)CH.sub.3, --C(O)OH, --CONH.sub.2, NR.sup.cCONH.sub.2,
--CONH(OH), --B(OH).sub.2--P(O)(OH).sub.2, --SO.sub.2OH,
--NR.sup.cS(O).sub.2CF.sub.3, --NR.sup.cS(O).sub.2NHCH.sub.3, or
--NR.sup.1CH.sub.2C.sub.6-aryl-S(O).sub.2NH.sub.2. each R.sup.1 and
R.sup.2 are independently hydrogen, oxo, C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.3-C.sub.6
cycloalkyl, adamantly, 3- to 6-membered heterocyclyl, C.sub.6-aryl,
5- to 6-membered heteroaryl, --CN, halogen, C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.6haloalkoxy, --OR.sup.10, --SR.sup.10,
--S(O).sub.2R.sup.10, --S(O).sub.2NR.sup.11R.sup.12,
--NR.sup.10S(O).sub.2R.sup.11, --NR.sup.11R.sup.12, --C(O)R.sup.10,
--NR.sup.10C(O)R.sup.11, --NR.sup.10C(O)NR.sup.11R.sup.12,
--C(O)OR.sup.10, --C(O)ONR.sup.11R.sup.12, --C(O)NR.sup.11R.sup.12,
wherein each of which is optionally substituted by R.sup.9; or any
two of R.sup.2 are taken together with the atoms to which they
attached to form a C.sub.5-C.sub.6 cycloalkyl, 5- to 6-membered
heterocyclyl, C.sub.6-aryl or 5- to 6-membered heteroaryl, wherein
each of which is optionally substituted by R.sup.9; R.sup.9 is oxo,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.3-C.sub.6
cycloalkyl, 3- to 6-membered heterocyclyl, C.sub.6-aryl, 5- to
6-membered heteroaryl, --CN, halogen, C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.6 haloalkoxy, C.sub.1-C.sub.6 haloalkyl, --OR.sup.13,
--SR.sup.13, --S(O).sub.2R.sup.13, --S(O).sub.2NR.sup.14R.sup.15,
--NR.sup.13S(O).sub.2R.sup.14, --NR.sup.14R.sup.15, --C(O)R.sup.13,
--NR.sup.13C(O)R.sup.14, --NR.sup.13C(O)NR.sup.14R.sup.15,
--C(O)OR.sup.13, --C(O)ONR.sup.14R.sup.15, --C(O)NR.sup.14R.sup.15
or C.sub.1-C.sub.6 alkyl optionally substituted by oxo, OH or
halogen; R.sup.c is hydrogen, C.sub.1-C.sub.6 alkyl,
C.sub.3-C.sub.6 cycloalkyl, --(C.sub.1-C.sub.6
alkylene)C.sub.3-C.sub.6 cycloalkyl, 3- to 6-membered heterocyclyl,
--(C.sub.1-C.sub.6 alkylene).sub.3- to 6-membered heterocyclyl,
--(C.sub.1-C.sub.6 alkylene)C.sub.6-aryl, 5- to 6-membered
heteroaryl, --(C.sub.1-C.sub.6 alkylene).sub.5- to 6-membered
heteroaryl, C.sub.1-C.sub.6 haloalkyl, --(C.sub.1-C.sub.6
alkylene)OR.sup.13, --(C.sub.1-C.sub.6 alkylene)SR.sup.13,
--(C.sub.1-C.sub.6 alkylene)S(O).sub.2R.sup.13, --(C.sub.1-C.sub.6
alkylene)S(O).sub.2NR.sup.14R.sup.15, --(C.sub.1-C.sub.6
alkylene)NR.sup.13S(O).sub.2R.sup.14, --(C.sub.1-C.sub.6
alkylene)NR.sup.14R.sup.15, --(C.sub.1-C.sub.6
alkylene)C(O)R.sup.13, --(C.sub.1-C.sub.6
alkylene)NR.sup.13C(O)R.sup.14, --(C.sub.1-C.sub.6
alkylene)NR.sup.13C(O)NR.sup.14R.sup.15, --(C.sub.1-C.sub.6
alkylene)C(O)OR.sup.13, --(C.sub.1-C.sub.6 alkylene)
C(O)ONR.sup.14R.sup.15 or --(C.sub.1-C.sub.6
alkylene)-C(O)NR.sup.14R.sup.15, each of which is optionally
substituted with R.sup.d; R.sup.d is hydrogen, halogen, --OH, oxo,
--CN, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.6 haloalkoxy, --COOH or C.sub.1-C.sub.6 alkyl
optionally substituted with --OH, halogen, CN or oxo; each
R.sup.10, R.sup.11 and R.sup.12 is independently hydrogen,
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, C.sub.3-C.sub.6 cycloalkyl, --(C.sub.1-C.sub.6
alkylene)C.sub.3-C.sub.6 cycloalkyl-, 3- to 6-membered heterocyclyl
or, --(C.sub.1-C.sub.6 alkylene).sub.3- to 6-membered heterocyclyl,
wherein each of R.sup.10, R.sup.11 and R.sup.12 is independently
optionally substituted by oxo, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, --CN, halogen, C.sub.1-C.sub.6 alkoxy or
C.sub.1-C.sub.6 alkyl optionally substituted by oxo, OH, halogen;
or R.sup.11 and R.sup.12 are taken together with the atoms to which
they attached to form a 3-6 membered heterocyclyl optionally
substituted by oxo, OH, halogen or C.sub.1-C.sub.6 alkyl optionally
substituted by oxo, OH or halogen; each R.sup.13, R.sup.14 and
R.sup.15 is independently hydrogen, C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6
haloalkyl, C.sub.3-C.sub.6 cycloalkyl or 3- to 6-membered
heterocyclyl, wherein each of R.sup.10, R.sup.11 and R.sup.12 is
independently optionally substituted by oxo, --OH, C.sub.2-C.sub.6
alkenyl, C.sub.2-C.sub.6 alkynyl, --CN, halogen or C.sub.1-C.sub.6
alkyl optionally substituted by oxo, OH, halogen; or R.sup.14 and
R.sup.15 are taken together with the atoms to which they attached
to form a 3-6 membered heterocyclyl optionally substituted by oxo,
OH, halogen, or C.sub.1-C.sub.6 alkyl optionally substituted by
oxo, OH or halogen; m is 0, 1 or 2; and n is 0, 1, 2, 3 or 4;
provided that when Z is --NR.sup.cS(O).sub.2CH.sub.3, --CONH.sub.2
or --C(O)OH, G is a bond and t is 1 then L is not a bond; and the
compound is not:
1-[7-(4-Bromo-2,6-dimethylphenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-
-4-yl]-3-azetidinebutanoic acid;
1-[7-(4-Bromo-2,6-dimethylphenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-
-4-yl]-3-azetidinepentanoic acid; or Acetamide,
N-[[1-(6-fluoro-2-benzoxazolyl)-3-azetidinyl]methyl]-N-methyl.
2. The compound of claim 1, wherein A is selected from hydrogen,
C.sub.1-C.sub.6 alkyl or C.sub.6-aryl, each of which is optionally
substituted with halogen.
3. The compound of claim 2, wherein A is hydrogen.
4. The compound of claim 2, wherein A is methyl.
5. The compound of claim 2, wherein A is --CF.sub.3.
6. The compound of claim 2, wherein A is phenyl.
7. The compound of claim 1, wherein G is selected from a bond,
--CH.sub.2-- or --CH.sub.2--CH.sub.2--.
8. The compound of claim 7, wherein G is a bond.
9. The compound of claim 7, wherein G is --CH.sub.2--.
10. The compound of claim 7, wherein G is
--CH.sub.2--CH.sub.2--.
11. The compound of claim 1, wherein R.sup.a and R.sup.b are
independently selected from hydrogen or C.sub.1-C.sub.6 alkyl.
12. The compound of claim 11, wherein R.sup.a and R.sup.b both are
hydrogen.
13. The compound of claim 11, wherein any one of R.sup.a and
R.sup.b is hydrogen and other one is C.sub.1-C.sub.6 alkyl.
14. The compound of claim 11, wherein R.sup.a and R.sup.b both are
C.sub.1-C.sub.6 alkyl.
15. The compound of claim 13, wherein any one of R.sup.a and
R.sup.b is hydrogen and other one is methyl.
16. The compound of claim 13, wherein any one of R.sup.a and
R.sup.b is hydrogen and other one is ethyl.
17. The compound of claim 14, wherein R.sup.a and R.sup.b both are
methyl.
18. The compound of claim 1, wherein R.sup.a and R.sup.b are taken
together with the atoms to which they attached to form a
C.sub.3-C.sub.6 cycloalkyl ring.
19. The compound of claim 18, wherein R.sup.a and R.sup.b are taken
together with the atoms to which they attached to form a
cycloproplyl ring.
20. The compound of claim 1, wherein any one of R.sup.a and
R.sup.b, and A are taken together along with the atoms to which
they are attached to form a C.sub.4-C.sub.6 cycloalkyl.
21. The compound of claim 20, wherein any one of R.sup.a and
R.sup.b, and A are taken together along with the atoms to which
they are attached to form a cyclobutyl ring.
22. The compound of claim 20, wherein any one of R.sup.a and
R.sup.b, and A are taken together along with the atoms to which
they are attached to form a cyclopentyl ring.
23. The compound of claim 20, wherein any one of R.sup.a and
R.sup.b, and A are taken together along with the atoms to which
they are attached to form a cyclohexyl ring.
24. The compound of claim 1, wherein L is selected from a bond,
linear or branched C.sub.1-C.sub.6 alkylene, or linear or branched
C.sub.2-C.sub.6 alkenylene.
25. The compound of claim 24, wherein L is a bond.
26. The compound of claim 24, wherein L is --CH.sub.2--.
27. The compound of claim 24, wherein L is --C.sub.2H.sub.4--.
28. The compound of claim 24, wherein L is --C.sub.3H.sub.6--.
29. The compound of claim 24, wherein L is --CH(CH.sub.3)--.
30. The compound of claim 24, wherein L is
--C(CH.sub.3).sub.2--.
31. The compound of claim 24, wherein L is
--CH(CH.sub.3)--CH.sub.2--.
32. The compound of claim 24, wherein L is
--CH.sub.2CH(CH.sub.3)--.
33. The compound of claim 24, wherein L is
--C(CH.sub.3).sub.2--CH.sub.2--.
34. The compound of claim 24, wherein L is
--CH.sub.2C(CH.sub.3).sub.2--.
35. The compound of claim 24, wherein L is
--CH(C.sub.2H.sub.5)--CH.sub.2--.
36. The compound of claim 24, wherein L is --CH.dbd.CH--.
37. The compound of claim 1, wherein t is 0 or 1.
38. The compound of claim 37, wherein t is 0.
39. The compound of claim 37, wherein t is 1.
40. The compound of claim 1, wherein Z is selected from
--NR.sup.cSO.sub.2NH.sub.2, --NR.sup.cS(O).sub.2CH.sub.3,
--SO.sub.2NH.sub.2, --NR.sup.cC(O)CH.sub.3, --C(O)OH, --CONH.sub.2,
NR.sup.cCONH.sub.2, --CONH(OH), --B(OH).sub.2, --P(O)(OH).sub.2,
--SO.sub.2OH, --NR.sup.cS(O).sub.2CF.sub.3,
--NR.sup.cS(O).sub.2NHCH.sub.3 or
--NR.sup.cCH.sub.2C.sub.6-aryl-S(O).sub.2NH.sub.2.
41. The compound of claim 40, wherein Z is
NR.sup.cSO.sub.2NH.sub.2.
42. The compound of claim 40, wherein Z is
--NHS(O).sub.2CH.sub.3.
43. The compound of claim 40, wherein Z is --SO.sub.2NH.sub.2.
44. The compound of claim 40, wherein Z is --NHC(O)CH.sub.3.
45. The compound of claim 40, wherein Z is --C(O)OH.
46. The compound of claim 40, wherein Z is --CONH.sub.2.
47. The compound of claim 40, wherein Z is --NHCONH.sub.2.
48. The compound of claim 40, wherein Z is --CONH(OH).
49. The compound of claim 40, wherein Z is --B(OH).sub.2.
50. The compound of claim 40, wherein Z is --P(O)(OH).sub.2.
51. The compound of claim 40, wherein Z is --S(O).sub.20H.
52. The compound of claim 40, wherein Z is
--NR.sup.cS(O).sub.2CF.sub.3.
53. The compound of claim 40, wherein Z is
--NR.sup.cS(O).sub.2NHCH.sub.3.
54. The compound of claim 40, wherein Z is
--NR.sup.cCH.sub.2C.sub.6-aryl-S(O).sub.2NH.sub.2.
55. The compound of claim 1, wherein R.sup.c is hydrogen,
C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.6 cycloalkyl,
--(C.sub.1-C.sub.6 alkylene)C.sub.3-C.sub.6 cycloalkyl, 3- to
6-membered heterocyclyl, --(C.sub.1-C.sub.6 alkylene) 3- to
6-membered heterocyclyl, --(C.sub.1-C.sub.6 alkylene)C.sub.6-aryl,
5- to 6-membered heteroaryl, --(C.sub.1-C.sub.6 alkylene) 5- to
6-membered heteroaryl, C.sub.1-C.sub.6 haloalkyl,
--(C.sub.1-C.sub.6 alkylene)OR.sup.13, --(C.sub.1-C.sub.6
alkylene)SR.sup.13, --(C.sub.1-C.sub.6 alkylene)S(O).sub.2R.sup.13,
--(C.sub.1-C.sub.6 alkylene)S(O).sub.2NR.sup.14R.sup.15,
--(C.sub.1-C.sub.6 alkylene)NR.sup.13S(O).sub.2R.sup.14,
--(C.sub.1-C.sub.6 alkylene)NR.sup.14R.sup.15, --(C.sub.1-C.sub.6
alkylene)C(O)R.sup.13, --(C.sub.1-C.sub.6
alkylene)NR.sup.13C(O)R.sup.14, --(C.sub.1-C.sub.6
alkylene)NR.sup.13C(O)NR.sup.14R.sup.15, --(C.sub.1-C.sub.6
alkylene)C(O)OR.sup.13, --(C.sub.1-C.sub.6 alkylene)
C(O)ONR.sup.14R.sup.15 or --(C.sub.1-C.sub.6
alkylene)-C(O)NR.sup.14R.sup.15, each of which is optionally
substituted with R.sup.d.
56. The compound of claim 55, wherein R.sup.c is selected from the
group consisting of methyl, ethyl, isopropyl, n-propyl, n-butyl,
cyclopropyl, cyclobutyl, cyclopentyl, ##STR00719##
57. The compound of claim 1, wherein Z is selected from the group
consisting of ##STR00720## ##STR00721## ##STR00722##
58. The compound of claim 1, wherein G, R.sup.a, R.sup.b, L, t and
Z together is selected from the group consisting of ##STR00723##
##STR00724##
59. The compound of claim 20, wherein L and Z together is selected
from the group consisting of ##STR00725## ##STR00726##
60. The compound of claim 1, wherein C is 5- to 6-membered
heteroaryl optionally substituted with R.sup.1.
61. The compound of claim 60, wherein C is selected from the group
consisting of imidazole, pyrazzole, pyrrole, pyridine, pyrimidine,
pyridone, pyrimidone, pyridazine, pyridazinone and triazine,
wherein each of which is optionally substituted with oxo, methyl,
ethyl, ethylene, propynyl, cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, adamantly, oxetanyl, tetrahydropyranyl, pyrazolyl,
pyridyl, pyrimidyl, phenyl, --Cl, --CONH.sub.2, --NH.sub.2,
--CHF.sub.2, --CF.sub.3 and --CN; wherein each of which is
optionally further substituted with pyridyl, F, CF.sub.3 and
CHF.sub.2.
62. The compound of claim 1, wherein D is is C.sub.6-aryl or 5- to
6-membered heteroaryl, each of which is optionally substituted with
R.sup.2.
63. The compound of claim 62, wherein D is selected from the group
consisting of phenyl, pyrrole, pyrazole, imidazole, pyridine,
thiophene and pyrimidine; wherein each of which is optionally
substituted with fluorine, bromine, chloro, oxo, methyl, ethyl,
isopropyl, methoxy, ethoxy, propoxy, phenyl, 4-methoxypheyl, --CN,
--OCH.sub.2F, --OCH.sub.2OCH.sub.3,
--(OCH.sub.2CH.sub.2)morpholine, 4-hydroxycyclohexyl, --CF.sub.3,
cyclopropyl and phenyl.
64. The compound of claim 1, wherein any two of R.sup.2 are taken
together with the atoms to which they attached to form a
C.sub.5-C.sub.6 cycloalkyl, 5- to 6-membered heterocyclyl,
C.sub.6-aryl or 5- to 6-membered heteroaryl, wherein each of which
is optionally substituted by R.sup.9.
65. The compound of claim 64, wherein any two of R.sup.2 are taken
together with the atoms to which they attached to form imidazole,
dioxole and dihydro dioxine, wherein each of which is optionally
substituted with methyl.
66. The compound of any of the claim 1, wherein m is any of the 0
to 2.
67. The compound of any of the claim 1, wherein n is any of the 0
to 4.
68. The compound of any of the claim 1, wherein C, D, R.sup.1 and
R.sup.2 together is selected from the group consisting of
##STR00727## ##STR00728## ##STR00729##
69. The compound of claim 68, wherein C, D, R.sup.1 and R.sup.2
together is selected from the group consisting of ##STR00730##
##STR00731## ##STR00732## ##STR00733## ##STR00734## ##STR00735##
##STR00736## ##STR00737## ##STR00738## ##STR00739## ##STR00740##
##STR00741## ##STR00742## ##STR00743##
70. The compound of claim 1, wherein the compound is a compound of
formula (I): ##STR00744## or a salt thereof, wherein A, G, R.sup.a,
R.sup.b, L, Z, C, D, R.sup.1, R.sup.2, m and n are as detailed
herein.
71. The compound of claim 1, wherein the compound is a compound of
formula (II): ##STR00745## or a salt thereof, wherein A, R.sup.a,
R.sup.b, L, Z, C, D, R.sup.1, R.sup.2 m and n are as detailed
herein.
72. The compound of claim 1, wherein the compound is a compound of
formula (III): ##STR00746## or a salt thereof, wherein L, Z, C, D,
R.sup.1, R.sup.2, m and n are as detailed herein.
73. The compound of claim 1, wherein the compound is a compound of
formula (IV): ##STR00747## or a salt thereof, wherein X is N or
CR.sup.1; Y is N or CR.sup.1; provided that at same time both X and
Y are not N; and A, G, R.sup.a, R.sup.b, L, Z, D, R.sup.1, R.sup.2,
n and t are as detailed herein.
74. The compound of claim 71, wherein the compound is any of the
compound of formula (IV-1) to (IV-11): ##STR00748## ##STR00749##
##STR00750## or a salt thereof, wherein X.sub.1, X.sub.2 and
X.sub.3 are independently N, NR.sup.2 or CR.sup.2; provided that
any one of X.sub.1, X.sub.2 and X.sub.3 is NR.sup.2 and others are
N or CR.sup.2; and A, G, R.sup.a, R.sup.b, L, Z, R.sup.1, R.sup.2
and t are as detailed herein.
75. The compound of claim 1, wherein the compound is a compound of
formula (V): ##STR00751## or a salt thereof, wherein X is N or
CR.sup.1; Y is N or CR.sup.1; provided that at same time both X and
Y are not N; and L, Z, D, R.sup.1, R.sup.2 and n are as detailed
herein.
76. The compound of claim 73, wherein the compound is any of the
compound of formula (V-1) to (V-11): ##STR00752## ##STR00753##
##STR00754## or a salt thereof, wherein X.sub.1, X.sub.2 and
X.sub.3 are independently N, NR.sup.2 or CR.sup.2; provided that
any one of X.sub.1, X.sub.2 and X.sub.3 is NR.sup.2 and others are
N or CR.sup.2; and L, Z, R.sup.1 and R.sup.2 are as detailed
herein.
77. The compound of claim 1, wherein the compound is a compound of
formula (VI): ##STR00755## or a salt thereof, wherein Y.sub.1 is N
or NR.sup.1; Y.sub.2 is N, NR.sup.1 or CR.sup.1; provided that any
one of Y.sub.1 and Y.sub.2 is NR.sup.1 and other one is other than
NR.sup.1; and A, G, R.sup.a, R.sup.b, L, Z, R.sup.1, R.sup.2 and t
are as detailed herein.
78. The compound of claim 1, wherein the compound is a compound of
formula (VII): ##STR00756## or a salt thereof, wherein Z.sub.1 is N
or CR.sup.1; and A, G, R.sup.a, R.sup.b, L, Z, R.sup.1, R.sup.2 and
t are as detailed herein.
79. The compound of claim 1, wherein the compound is a compound of
formula (VIII): ##STR00757## or a salt thereof, wherein A, G,
R.sup.a, R.sup.b, L, Z, R.sup.1, R.sup.2 and t are as detailed
herein.
80. The compound of claim 1, wherein the compound is a compound of
formula (IX): ##STR00758## or a salt thereof, wherein Y.sub.1 is N
or NR.sup.1; Y.sub.2 is N, NR.sup.1 or CR.sup.1; provided that one
of Y.sub.1 and Y.sub.2 is NR.sup.1 and other one is other than
NR.sup.1; and L, Z, R.sup.1 and R.sup.2 are as detailed herein.
81. The compound of claim 1, wherein the compound is a compound of
formula (X): ##STR00759## or a salt thereof, wherein Z.sub.1 is N
or CR.sup.1; and L, Z, Rand R.sup.2 are as detailed herein.
82. The compound of claim 1, wherein the compound is a compound of
formula (XI): ##STR00760## or a salt thereof, wherein L, Z, Rand
R.sup.2 are as detailed herein.
83. The compound of claim 1, wherein the compound is a compound of
formula (XII): ##STR00761## or a salt thereof, wherein, X is N or
CR.sup.1; X.sub.4 and X.sub.5 is independently N or CR.sup.2;
provided that at same time both are not N; and A, G, R.sup.a,
R.sup.b, L, Z, R.sup.1, R.sup.2 and t are as detailed herein.
84. The compound of claim 81, wherein the compound is any of the
compound of formula (XII-1) to (XII-6): ##STR00762## ##STR00763##
or a salt thereof, wherein A, G, R.sup.a, R.sup.b, L, Z, R.sup.1,
R.sup.2, R.sup.c and t are as detailed herein.
85. The compound of claim 1, wherein the compound is a compound of
formula (XIII): ##STR00764## or a salt thereof, wherein, X is N or
CR.sup.1; X.sub.4 and X.sub.5 is independently N or CR.sup.2;
provided that at same time both are not N; and L, Z, R.sup.1 and
R.sup.2 are as detailed herein.
86. The compound of claim 83, wherein the compound is any of the
compound of formula (XIII-1) to (XIII-9): ##STR00765## or a salt
thereof, wherein L, Z, R.sup.1, R.sup.2 and R.sup.c are as detailed
herein.
87. The compound of claim 1, wherein the compound is selected from
the compound No. 1.1 to 1.135 as mentioned in table-1.
88. The compound of claim 1, wherein the compound is selected from
the compound No. 2.1 to 2.362 as mentioned in table-2.
89. A method of treating a disease or disorder associated with
ENPP1 enzyme in an individual in need thereof, wherein the method
comprises administering to the individual an effective amount of
the compound of claim 1.
90. A method of treating cancer in an individual in need thereof,
wherein the method comprises administering to the individual an
effective amount of the compound of claim 1.
91. A method of inhibiting ENPP1 enzyme in an individual in need
thereof, wherein the method comprises administering to the
individual an effective amount of the compound of claim 1.
92. A method of treating a disease or disorder associated with
ENPP1 enzyme in an individual in need thereof, wherein the method
comprises administering to the individual an effective amount of
the compound of claim 1 in combination with other therapeutic
agents.
93. A pharmaceutical composition, comprising the compound of claim
1, and atleast one pharmaceutically acceptable excipient.
94. A method of treating a disease or disorder associated with
ENPP1 enzyme in an individual in need thereof, wherein the method
comprises administering to the individual a pharmaceutical
composition comprising an effective amount of the compound of claim
1.
95. Use of the compound of claim 1 in the manufacture of the
medicament for treatment of a disease or disorder associated with
this ENPP1 gene.
Description
CROSS REFERENCE TO RELATED APPLICATION
[0001] This application claims the priority benefits of US
Provisional Sr. No. 63/107,818, filed on Oct. 30, 2020; and US
Provisional Sr. No. 63/192,605, filed on May 25, 2021, disclosures
of which are incorporated herein by reference in its
entireties.
FIELD OF THE INVENTION
[0002] The present invention generally relates to compounds
possessing anti-cancer activity useful in the treatment of
proliferative disorders. The invention also provides method of
synthesis of said compounds, method of using said compounds,
pharmaceutical compositions comprising said compounds and method of
using thereof.
BACKGROUND OF THE INVENTION
[0003] ENPP1, ectonucleotide pyrophosphatase/phosphodiesterase 1,
is a type II transmembrane glycoprotein with pyrophosphatase and
phosphodiesterase activity, expressed highly in bone and cartilage.
ATP is an identified substrate of ENPP1, which is hydrolyzed to AMP
and PPi. CD73 converts AMP to adenosine and inorganic phosphate
(Pi). ENPP1 hydrolysis of pyrophosphate bonds (such as in ATP) and
phosphodiester bonds (such as in oligonucleotides) to produce
nucleoside 5'-monophosphates, as part of the functions mediated by
nucleotide pyrophosphatases/phosphodiesterase (NPPs), which is
necessary in a wide range of cellular processes including
nucleotide recycling, purinergic receptor signaling and
ATP-mediated apoptosis.
[0004] Recently, ENPP1 has been found to play an important role in
the immunological responses to various stimuli through the cyclic
GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING)
pathway. Damage associated molecular patterns (DAMPs) as well as
pathogen associated molecular patterns (PAMPs) activate the immune
system via STING. cGAS senses cytosolic DNA and catalyzes the
conversion of GTP and ATP to cyclic GMP-AMP (cGAMP). Subsequently,
2,3'-cGAMP activates STING to initiate an inflammatory response via
the TANK-binding kinase 1 (TBK1)-Interferon Regulatory Factor (IRF)
3 pathway to produce type 1 interferons (IFNs) and other cytokines.
A link between the cGAS-STING pathway and ENPP1 has emerged whereby
the hydrolysis of cGAMP by ENPP1 attenuates cGAS-STING signaling.
ENPP1 plays a regulatory function in immune cells such as
neutrophils, macrophages, dendritic cells, natural killer cells,
and B lymphocytes. ENPP1 expression is heightened in M2 macrophages
in the presence of cancer and promotes tumor growth and spread. The
role of ENPP1 in cancer is exemplified by the observations of
enhanced tumor metastasis to the bone from breast cancer, for
example, by over-expression of ENPP1.
[0005] Recent reports suggest that the cyclic dinucleotides, a
substrate for ENPP1, stimulate innate immunity via STING-dependent
activation of interferon genes. ENPP1 inhibition of STING pathway
activation is critical for tumor control, similar to that of
checkpoint inhibitors such as anti PD-1 or PD-L1 which are
promising immunotherapeutics for various cancers.
[0006] Since STING activation is a promising therapeutic strategy
to cure cancer, more and more compounds that activate the STING
pathway have been reported. ENPP1, as a highly potent
cGAMP-degradation enzyme, makes the application of ENPP1 inhibitors
for anti-tumor therapy.
[0007] ADP-ribosylation is a conserved post-translational protein
modification that plays a role in all major cellular processes,
particularly DNA repair, transcription, translation, stress
response and cell death. Poly(ADP-ribosyl)ation (PARylation)
mediated by poly ADP-ribose polymerases (PARPs) plays a key role in
DNA damage repair. Suppression of PARylation by PARP inhibitors
impairs DNA damage repair and induces apoptosis of tumor cells with
repair defects. Thus, PARP inhibitors have been approved by the US
FDA for various types of cancer treatment. However, recent studies
suggest that dePARylation also plays a key role in DNA damage
repair. Instead of antagonizing PARylation, dePARylation acts as a
downstream step of PARylation in DNA damage repair. Protein
PARylation can be reversed by the macrodomain containing proteins
PARG, TARG1, MacroD1 and MacroD2, and ENPP1. Recently it is known
that ENPP1 play a role in dePARylation process by h hydrolysing the
ester bond known to link proteins to ADP-ribose as well as
consecutive ADP-ribose subunits. DePARylation inhibitors represent
a novel class of inhibitors alternative to PARP inhibition, and may
overcome chemo-resistance of PARPi. Thus, ENPP1 inhibitors can also
play an important role in DNA damage repair process.
[0008] Based on the above principles, there is an urgent and
growing need of a class of anti-tumor compounds which can inhibit
ENPP1 and treat various types of cancer.
SUMMARY OF THE INVENTION
[0009] In one aspect, the present invention provides a compound of
formula (IA):
##STR00002##
or a salt thereof, wherein A, G, R.sup.a, R.sup.b, L, Z, C, D,
R.sup.1, R.sup.2, m, n and t are as detailed herein.
[0010] In some aspects, the compound of formula (J) or a salt
thereof, is a compound of formula (IA) or a salt thereof, as
detailed herein.
[0011] In some aspects, the compound of formula (J) or a salt
thereof, is a compound of formula (I) or a salt thereof, as
detailed herein.
[0012] In some aspects, the compound of formula (J) or a salt
thereof, is a compound of formula (II) or a salt thereof, as
detailed herein.
[0013] In some aspects, the compound of formula (J) or a salt
thereof, is a compound of formula (III) or a salt thereof, as
detailed herein.
[0014] In some aspects, the compound of formula (J) or a salt
thereof, is a compound of formula (IV) or a salt thereof, as
detailed herein.
[0015] In some aspects, the compound of formula (J) or a salt
thereof, is any of the compounds of formula (IV-1) to (IV-11) or a
salt thereof, as detailed herein.
[0016] In some aspects, the compound of formula (J) or a salt
thereof, is a compound of formula (V) or a salt thereof, as
detailed herein.
[0017] In some aspects, the compound of formula (J) or a salt
thereof, any of the compounds of formula (V-1) to (V-11) or a salt
thereof, as detailed herein.
[0018] In some aspects, the compound of formula (J) or a salt
thereof, is a compound of formula (VI) or a salt thereof, as
detailed herein.
[0019] In some aspects, the compound of formula (J) or a salt
thereof, is a compound of formula (VII) or a salt thereof, as
detailed herein.
[0020] In some aspects, the compound of formula (J) or a salt
thereof, is a compound of formula (VIII) or a salt thereof, as
detailed herein.
[0021] In some aspects, the compound of formula (J) or a salt
thereof, is a compound of formula (IX) or a salt thereof, as
detailed herein.
[0022] In some aspects, the compound of formula (J) or a salt
thereof, is a compound of formula (X) or a salt thereof, as
detailed herein.
[0023] In some aspects, the compound of formula (J) or a salt
thereof, is a compound of formula (XI) or a salt thereof, as
detailed herein.
[0024] In some aspects, the compound of formula (J) or a salt
thereof, is a compound of formula (XII) or a salt thereof, as
detailed herein.
[0025] In some aspects, the compound of formula (J) or a salt
thereof, is any of compounds of formula (XII-1) to (XII-6) or a
salt thereof, as detailed herein.
[0026] In some aspects, the compound of formula (J) or a salt
thereof, is a compound of formula (XIII) or a salt thereof, as
detailed herein.
[0027] In some aspects, the compound of formula (J) or a salt
thereof, is any of compounds of formula (XIII-1) to (XIII-9) or a
salt thereof, as detailed herein.
[0028] In some aspects, the present invention provides method of
treating a disease or disorder associated with ENPP1 enzyme in an
individual in need thereof, wherein the method comprises
administering to the individual an effective amount of a compound
of the present invention (collectively, a compound of formula (J),
(IA), (I), (II), (III), (IV), (IV-1) to (IV-11), (V), (V-1) to
(V-11), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XII-1) to
(XII-6), (XIII) and (XIII-1) to (XIII-9)), or a salt thereof.
[0029] In some aspects, the present invention provides method of
treating cancer in an individual in need thereof, wherein the
method comprises administering to the individual an effective
amount of a compound of the present invention (collectively, a
compound of formula (J), (IA), (I), (II), (III), (IV), (IV-1) to
(IV-11), (V), (V-1) to (V-11), (VI), (VII), (VIII), (IX), (X),
(XI), (XII), (XII-1) to (XII-6), (XIII) and (XIII-1) to (XIII-9)),
or a salt thereof.
[0030] In some aspects, the present invention provides method of
inhibiting ENPP1 enzyme in an individual in need thereof, wherein
the method comprises administering to the individual an effective
amount of a compound of the present invention (collectively, a
compound of formula (J), (IA), (I), (II), (III), (IV), (IV-1) to
(IV-11), (V), (V-1) to (V-11), (VI), (VII), (VIII), (IX), (X),
(XI), (XII), (XII-1) to (XII-6), (XIII) and (XIII-1) to (XIII-9)),
or a salt thereof.
[0031] In some aspects, the present invention provides method of
treating a disease or disorder associated with ENPP1 enzyme in an
individual in need thereof, wherein the method comprises
administering to the individual an effective amount of a compound
of the present invention (collectively, a compound of formula (J),
(IA), (I), (II), (III), (IV), (IV-1) to (IV-11), (V), (V-1) to
(V-11), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XII-1) to
(XII-6), (XIII) and (XIII-1) to (XIII-9)), or a salt thereof in
combination with other therapeutic agents.
[0032] In some aspects, the present invention also provides
pharmaceutical compositions, comprising a compound of the present
invention (collectively, a compound of formula (J), (IA), (I),
(II), (III), (IV), (IV-1) to (IV-11), (V), (V-1) to (V-11), (VI),
(VII), (VIII), (IX), (X), (XI), (XII), (XII-1) to (XII-6), (XIII)
and (XIII-1) to (XIII-9)), or a salt thereof, and at least one
pharmaceutically acceptable excipient.
[0033] In some aspects, the present invention provides method of
treating a disease or disorder associated with ENPP1 enzyme in an
individual in need thereof, wherein the method comprises
administering to the individual a pharmaceutical composition
comprising an effective amount of a compound of the present
invention (collectively, a compound of formula (J), (IA), (I),
(II), (III), (IV), (IV-1) to (IV-11), (V), (V-1) to (V-11), (VI),
(VII), (VIII), (IX), (X), (XI), (XII), (XII-1) to (XII-6), (XIII)
and (XIII-1) to (XIII-9)), or a salt thereof.
[0034] In some aspects, the present invention provides uses of the
compound of the present invention (collectively, a compound of
formula (J), (IA), (I), (II), (III), (IV), (IV-1) to (IV-11), (V),
(V-1) to (V-11), (VI), (VII), (VIII), (IX), (X), (XI), (XII),
(XII-1) to (XII-6), (XIII) and (XIII-1) to (XIII-9)), or a salt
thereof in the manufacture of the medicament for treatment of a
disease or disorder associated with this ENPP1 gene.
[0035] In some aspects, the present invention provides processes
for synthesizing compounds disclosed herein and intermediates used
to synthesize the disclosed compounds.
BRIEF DESCRIPTION OF THE DRAWINGS
[0036] FIG. 1 is a bar-graph of the IP-10 release in THP-1 cell
lines for a compound of the present invention.
DETAILED DESCRIPTION OF THE INVENTION
Definitions
[0037] "Alkyl" refers to and includes saturated linear and branched
univalent hydrocarbon structures and combination thereof, having
the number of carbon atoms designated (i.e., C.sub.1-C.sub.10 means
one to ten carbons). Particular alkyl groups are those having 1 to
20 carbon atoms (a "C.sub.1-C.sub.20 alkyl"). More particular alkyl
groups are those having 1 to 8 carbon atoms (a "C.sub.1-C.sub.8
alkyl"), 3 to 8 carbon atoms (a "C.sub.3-C.sub.8 alkyl"), 1 to 6
carbon atoms (a "C.sub.1-C.sub.6 alkyl"), 1 to 5 carbon atoms (a
"C.sub.1-C.sub.5 alkyl"), or 1 to 4 carbon atoms (a
"C.sub.1-C.sub.4 alkyl"). Examples of alkyl include, but are not
limited to, groups such as methyl, ethyl, n-propyl, isopropyl,
n-butyl, t-butyl, isobutyl, sec-butyl, homologs and isomers of, for
example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like.
[0038] "Alkenyl" as used herein refers to an unsaturated linear or
branched univalent hydrocarbon chain or combination thereof, having
at least one site of olefinic unsaturation (i.e., having at least
one moiety of the formula C.dbd.C) and having the number of carbon
atoms designated (i.e., C.sub.2-C.sub.10 means two to ten carbon
atoms). The alkenyl group may be in "cis" or "trans"
configurations, or alternatively in "E" or "Z" configurations.
Particular alkenyl groups are those having 2 to 20 carbon atoms (a
"C.sub.2-C.sub.2M alkenyl"), having 2 to 8 carbon atoms (a
"C.sub.2-C.sub.8 alkenyl"), having 2 to 6 carbon atoms (a
"C.sub.2-C.sub.6 alkenyl"), or having 2 to 4 carbon atoms (a
"C.sub.2-C.sub.4 alkenyl"). Examples of alkenyl include, but are
not limited to, groups such as ethenyl (or vinyl), prop-1-enyl,
prop-2-enyl (or allyl), 2-methylprop-1-enyl, but-1-enyl,
but-2-enyl, but-3-enyl, buta-1,3-dienyl, 2-methylbuta-1,3-dienyl,
homologs and isomers thereof, and the like.
[0039] "Alkylene" as used herein refers to the same residues as
alkyl, but having bivalency. Particular alkylene groups are those
having 1 to 6 carbon atoms (a "C.sub.1-C.sub.6 alkylene"), 1 to 5
carbon atoms (a "C.sub.1-C.sub.5 alkylene"), 1 to 4 carbon atoms (a
"C.sub.1-C.sub.4 alkylene") or 1 to 3 carbon atoms (a
"C.sub.1-C.sub.3 alkylene"). Examples of alkylene include, but are
not limited to, groups such as methylene (--CH.sub.2--), ethylene
(--CH.sub.2CH.sub.2--), propylene (--CH.sub.2CH.sub.2CH.sub.2--),
butylene (--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--), and the like.
[0040] "Alkynyl" as used herein refers to an unsaturated linear or
branched univalent hydrocarbon chain or combination thereof, having
at least one site of acetylenic unsaturation (i.e., having at least
one moiety of the formula C.ident.C) and having the number of
carbon atoms designated (i.e., C.sub.2-C.sub.10 means two to ten
carbon atoms). Particular alkynyl groups are those having 2 to 20
carbon atoms (a "C.sub.2-C.sub.2M alkynyl"), having 2 to 8 carbon
atoms (a "C.sub.2-C.sub.8 alkynyl"), having 2 to 6 carbon atoms (a
"C.sub.2-C.sub.6 alkynyl"), or having 2 to 4 carbon atoms (a
"C.sub.2-C.sub.4 alkynyl"). Examples of alkynyl include, but are
not limited to, groups such as ethynyl (or acetylenyl),
prop-1-ynyl, prop-2-ynyl (or propargyl), but-1-ynyl, but-2-ynyl,
but-3-ynyl, homologs and isomers thereof, and the like.
[0041] "Aryl" refers to and includes polyunsaturated aromatic
hydrocarbon groups. Aryl may contain additional fused rings (e.g.,
from 1 to 3 rings), including additionally fused aryl, heteroaryl,
cycloalkyl, and/or heterocyclyl rings. In one variation, the aryl
group contains from 6 to 14 annular carbon atoms. Examples of aryl
groups include, but are not limited to, phenyl, naphthyl, biphenyl,
and the like.
[0042] "Carbonyl" refers to the group C.dbd.O.
[0043] "Cycloalkyl" refers to and includes cyclic univalent
hydrocarbon structures, which may be fully saturated, mono- or
polyunsaturated, but which are non-aromatic, having the number of
carbon atoms designated (e.g., C.sub.1-C.sub.10 means one to ten
carbons). Cycloalkyl can consist of one ring, such as cyclohexyl,
or multiple rings, such as adamantly, but excludes aryl groups. A
cycloalkyl comprising more than one ring may be fused, spiro or
bridged, or combinations thereof. A preferred cycloalkyl is a
cyclic hydrocarbon having from 3 to 13 annular carbon atoms. A more
preferred cycloalkyl is a cyclic hydrocarbon having from 3 to 8
annular carbon atoms (a "C.sub.3-C.sub.8 cycloalkyl"). Examples of
cycloalkyl include, but are not limited to, cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, 1-cyclohexenyl,
3-cyclohexenyl, cycloheptyl, norbomyl, and the like.
[0044] "Halo" or "halogen" refers to elements of the Group 17
series having atomic number 9 to 85. Preferred halo groups include
fluoro, chloro, bromo and iodo. Where a residue is substituted with
more than one halogen, it may be referred to by using a prefix
corresponding to the number of halogen moieties attached, e.g.,
dihaloaryl, dihaloalkyl, trihaloaryl etc. refer to aryl and alkyl
substituted with two ("di") or three ("tri") halo groups, which may
be but are not necessarily the same halo; thus
4-chloro-3-fluorophenyl is within the scope of dihaloaryl. An alkyl
group in which each hydrogen is replaced with a halo group is
referred to as a "perhaloalkyl." A preferred perhaloalkyl group is
trifluoroalkyl (--CF.sub.3). Similarly, "perhaloalkoxy" refers to
an alkoxy group in which a halogen takes the place of each H in the
hydrocarbon making up the alkyl moiety of the alkoxy group. An
example of a perhaloalkoxy group is trifluoromethoxy
(--OCF.sub.3).
[0045] "Heteroaryl" refers to and includes unsaturated aromatic
cyclic groups having from 1 to 10 annular carbon atoms and at least
one annular heteroatom, including but not limited to heteroatoms
such as nitrogen, oxygen and sulfur, wherein the nitrogen and
sulfur atoms are optionally oxidized, and the nitrogen atom(s) are
optionally quaternized. A heteroaryl group can be attached to the
remainder of the molecule at an annular carbon or at an annular
heteroatom. Heteroaryl may contain additional fused rings (e.g.,
from 1 to 3 rings), including additionally fused aryl, heteroaryl,
cycloalkyl, and/or heterocyclyl rings. Examples of heteroaryl
groups include, but are not limited to imidazolyl, pyrrolyl,
pyrazolyl, 1,2,4-triazolyl, thiophenyl, furanyl, thiazolyl,
isothiazolyl, 1,3,4-thiadiazolyl oxazolyl, isoxazolyl,
1,3,4-oxadiazolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl,
indolyl, indazolyl, benzoimidazolyl, pyrrolopyridinyl,
pyrrolopyridazinyl, pyrrolopyrimidinyl, pyrazolopyridinyl,
pyrazolopyrimidinyl, imidazopyridinyl, purinyl, benzofuranyl,
furopyridinyl, benzooxazolyl, benzothiophenyl, benzothiazolyl,
oxazolopyridinyl, thiazolopyridinyl, thienopyridinyl, quinolinyl,
quinolonyl, naphthyridinyl, quinazolinyl, pyridopyrimidinyl,
cinnolinyl or pyridopyridazinyl and the like.
[0046] "Heterocycle" or "heterocyclyl" refers to a saturated or an
unsaturated non-aromatic group having from 1 to 10 annular carbon
atoms and from 1 to 4 annular heteroatoms, such as nitrogen, sulfur
or oxygen, and the like, wherein the nitrogen and sulfur atoms are
optionally oxidized, and the nitrogen atom(s) are optionally
quaternized. A heterocyclyl group may have a single ring or
multiple condensed rings, but excludes heteroaryl groups. A
heterocycle comprising more than one ring may be fused, spiro or
bridged, or any combination thereof. In fused ring systems, one or
more of the fused rings can be aryl or heteroaryl. Examples of
heterocyclyl groups include, but are not limited to, aziridinyl,
azetidinyl, oxetanyl, morpholinyl, thiomorpholinyl, azepanyl
tetrahydropyranyl, dihydropyranyl, piperidinyl, piperazinyl,
pyrrolidinyl, thiazolinyl, thiazolidinyl, tetrahydrofuranyl,
tetrahydrothiophenyl, and the like.
[0047] "Oxo" refers to the moiety .dbd.O.
[0048] "ENPP1" refers to Ectonucleotide Pyrophosphatase
Phosphodiesterase 1.
[0049] "Optionally substituted" unless otherwise specified means
that a group may be unsubstituted or substituted by one or more
(e.g., 1, 2, 3, 4 or 5) of the substituents listed for that group
in which the substituents may be the same of different. In one
embodiment, an optionally substituted group has one substituent. In
another embodiment, an optionally substituted group has two
substituents. In another embodiment, an optionally substituted
group has three substituents. In another embodiment, an optionally
substituted group has four substituents. In some embodiments, an
optionally substituted group has 1 to 2, 2 to 5, 3 to 5, 2 to 3, 2
to 4, 3 to 4, 1 to 3, 1 to 4 or 1 to 5 substituents.
[0050] A "medicament" or "pharmaceutical composition" refers to an
pharmaceutical formulation in administrable form comprising atleast
one pharmaceutically active ingredient and one or more
pharmaceutically acceptable carrier.
[0051] A "pharmaceutically acceptable carrier" or "pharmaceutically
acceptable excipient" refers to an ingredient in a pharmaceutical
formulation, other than an active ingredient, which is nontoxic to
a subject. A pharmaceutically acceptable carrier includes, but is
not limited to, a buffer, excipient, stabilizer, or
preservative.
[0052] As used herein, "treatment" or "treating" is an approach for
obtaining beneficial or desired results including clinical results.
For example, beneficial or desired results include, but are not
limited to, one or more of the following: decreasing symptoms
resulting from the disease, increasing the quality of life of those
suffering from the disease, decreasing the dose of other
medications required to treat the disease, delaying the progression
of the disease, and/or prolonging survival of individuals. In
reference to cancers or other unwanted cell proliferation,
beneficial or desired results include shrinking a tumor (reducing
tumor size); decreasing the growth rate of the tumor (such as to
suppress tumor growth); reducing the number of cancer cells;
inhibiting, retarding or slowing to some extent and preferably
stopping cancer cell infiltration into peripheral organs;
inhibiting (slowing to some extent and preferably stopping) tumor
metastasis; inhibiting tumor growth; preventing or delaying
occurrence and/or recurrence of tumor; and/or relieving to some
extent one or more of the symptoms associated with the cancer. In
some embodiments, beneficial or desired results include preventing
or delaying occurrence and/or recurrence, such as of unwanted cell
proliferation.
[0053] As used herein, "delaying development of a disease" means to
defer, hinder, slow, retard, stabilize, and/or postpone development
of the disease (such as cancer). This delay can be of varying
lengths of time, depending on the history of the disease and/or
individual being treated. As is evident to one skilled in the art,
a sufficient or significant delay can, in effect, encompass
prevention, in that the individual does not develop the disease.
For example, a late-stage cancer, such as development of
metastasis, may be delayed.
[0054] As used herein, an "effective dosage" or "effective amount"
of compound or salt thereof or pharmaceutical composition is an
amount sufficient to effect beneficial or desired results. For
prophylactic use, beneficial or desired results include results
such as eliminating or reducing the risk, lessening the severity
of, or delaying the onset of the disease, including biochemical,
histological and/or behavioral symptoms of the disease, its
complications and intermediate pathological phenotypes presenting
during development of the disease. For therapeutic use, beneficial
or desired results include ameliorating, palliating, lessening,
delaying or decreasing one or more symptoms resulting from the
disease, increasing the quality of life of those suffering from the
disease, decreasing the dose of other medications required to treat
the disease, enhancing effect of another medication such as via
targeting, delaying the progression of the disease, and/or
prolonging survival. In reference to cancers or other unwanted cell
proliferation, an effective amount comprises an amount sufficient
to cause a tumor to shrink and/or to decrease the growth rate of
the tumor (such as to suppress tumor growth) or to prevent or delay
other unwanted cell proliferation. In some embodiments, an
effective amount is an amount sufficient to delay development. In
some embodiments, an effective amount is an amount sufficient to
prevent or delay occurrence and/or recurrence. An effective amount
can be administered in one or more administrations, in the case of
cancer, the effective amount of the drug or composition may: (i)
reduce the number of cancer cells; (ii) reduce tumor size; (iii)
inhibit, retard, slow to some extent and preferably stop cancer
cell infiltration into peripheral organs; (iv) inhibit (i.e., slow
to some extent and preferably stop) tumor metastasis; (v) inhibit
tumor growth; (vi) prevent or delay occurrence and/or recurrence of
tumor; and/or (vii) relieve to some extent one or more of the
symptoms associated with the cancer. An effective dosage can be
administered in one or more administrations. For purposes of this
disclosure, an effective dosage of compound or a salt thereof, or
pharmaceutical composition is an amount sufficient to accomplish
prophylactic or therapeutic treatment either directly or
indirectly. It is intended and understood that an effective dosage
of a compound or salt thereof, or pharmaceutical composition may or
may not be achieved in conjunction with another drug, compound, or
pharmaceutical composition. Thus, an "effective dosage" may be
considered in the context of administering one or more therapeutic
agents, and a single agent may be considered to be given in an
effective amount if, in conjunction with one or more other agents,
a desirable result may be or is achieved.
[0055] As used herein, the term "individual" is a mammal, including
humans. An individual includes, but is not limited to, human,
bovine, horse, feline, canine, rodent, or primate. In some
embodiments, the individual is human. The individual (such as a
human) may have advanced disease or lesser extent of disease, such
as low tumor burden. In some embodiments, the individual is at an
early stage of a proliferative disease (such as cancer). In some
embodiments, the individual is at an advanced stage of a
proliferative disease (such as an advanced cancer).
[0056] Reference to "about" a value or parameter herein includes
(and describes) embodiments that are directed to that value or
parameter per se. For example, description referring to "about X"
includes description of "X".
[0057] It is understood that aspects and variations described
herein also include "consisting" and/or "consisting essentially of"
aspects and variations.
Compounds
[0058] In one aspect, provided is a compound of the formula
(J):
##STR00003##
or a salt thereof, wherein
[0059] C is 5- to 6-membered heteroaryl optionally substituted with
R.sup.1;
[0060] D is C.sub.6-aryl or 5- to 6-membered heteroaryl, each of
which is optionally substituted with R.sup.2, wherein D is fused to
C;
[0061] A is hydrogen, C.sub.1-C.sub.6 alkyl, or C.sub.6-aryl, each
of which is optionally substituted with halogen;
[0062] G is a bond, --CH.sub.2-- or --CH.sub.2--CH.sub.2--;
[0063] R.sup.a and R.sup.b are independently hydrogen or
C.sub.1-C.sub.6 alkyl; [0064] or R.sup.a and R.sup.b are taken
together with the atoms to which they are attached to form a
C.sub.3-C.sub.6 cycloalkyl ring;
[0065] or any one of R.sup.a and R.sup.b, and A are taken together
along with the atoms to which they are attached to form a
C.sub.4-C.sub.6 cycloalkyl ring;
[0066] L is a bond, linear or branched C.sub.1-C.sub.6 alkylene or
linear or branched C.sub.2-C.sub.6 alkenylene;
[0067] t is 0 or 1;
[0068] provided that when t is 0 then L is linear or branched
C.sub.2-C.sub.6 alkenylene;
[0069] Z is --NR.sup.cS(O).sub.2NH.sub.2,
--NR.sup.cS(O).sub.2CH.sub.3, --SO.sub.2NH.sub.2,
--NR.sup.cC(O)CH.sub.3, --C(O)OH, --CONH.sub.2, NR.sup.cCONH.sub.2,
--CONH(OH), --B(OH).sub.2--P(O)(OH).sub.2, --SO.sub.2OH,
--NR.sup.cS(O).sub.2CF.sub.3, --NR.sup.cS(O).sub.2NHCH.sub.3, or
--NR.sup.cCH.sub.2C.sub.6-aryl-S(O).sub.2NH.sub.2.
[0070] each R.sup.1 and R.sup.2 are independently hydrogen, oxo,
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, C.sub.3-C.sub.6 cycloalkyl, adamantly, 3- to 6-membered
heterocyclyl, C.sub.6-aryl, 5- to 6-membered heteroaryl, --CN,
halogen, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 haloalkoxy,
--OR.sup.10, --SR.sup.10, --S(O).sub.2R.sup.10,
--S(O).sub.2NR.sup.11R.sup.12, --NR.sup.10S(O).sub.2R.sup.11,
--NR.sup.11R.sup.12, --C(O)R.sup.10, --NR.sup.10C(O)R.sup.11,
--NR.sup.10C(O)NR.sup.11R.sup.12, --C(O)OR.sup.10,
--C(O)ONR.sup.11R.sup.12, --C(O)NR.sup.11R.sup.12, wherein each of
which is optionally substituted by R.sup.9;
[0071] or any two of R.sup.2 are taken together with the atoms to
which they attached to form a C.sub.5-C.sub.6 cycloalkyl, 5- to
6-membered heterocyclyl, C.sub.6-aryl or 5- to 6-membered
heteroaryl, wherein each of which is optionally substituted by
R.sup.9;
[0072] R.sup.9 is oxo, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, C.sub.3-C.sub.6 cycloalkyl, 3- to 6-membered heterocyclyl,
C.sub.6-aryl, 5- to 6-membered heteroaryl, --CN, halogen,
C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 haloalkoxy, C.sub.1-C.sub.6
haloalkyl, --OR.sup.13, --SR.sup.13, --S(O).sub.2R.sup.13,
--S(O).sub.2NR.sup.14R.sup.15, --NR.sup.13S(O).sub.2R.sup.14,
--NR.sup.14R.sup.15, --C(O)R.sup.13, --NR.sup.13C(O)R.sup.14,
--NR.sup.13C(O)NR.sup.14R.sup.15, --C(O)OR.sup.13,
--C(O)ONR.sup.14R.sup.15, --C(O)NR.sup.14R.sup.15 or
C.sub.1-C.sub.6 alkyl optionally substituted by oxo, OH or
halogen;
[0073] R.sup.c is hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.6
cycloalkyl, --(C.sub.1-C.sub.6 alkylene)C.sub.3-C.sub.6 cycloalkyl,
3- to 6-membered heterocyclyl, --(C.sub.1-C.sub.6 alkylene).sub.3-
to 6-membered heterocyclyl, --(C.sub.1-C.sub.6
alkylene)C.sub.6-aryl, 5- to 6-membered heteroaryl,
--(C.sub.1-C.sub.6 alkylene).sub.5- to 6-membered heteroaryl,
C.sub.1-C.sub.6 haloalkyl, --(C.sub.1-C.sub.6 alkylene)OR.sup.13,
--(C.sub.1-C.sub.6 alkylene)SR.sup.13, --(C.sub.1-C.sub.6
alkylene)S(O).sub.2R.sup.13, --(C.sub.1-C.sub.6
alkylene)S(O).sub.2NR.sup.14R.sup.15, --(C.sub.1-C.sub.6
alkylene)NR.sup.13S(O).sub.2R.sup.14, --(C.sub.1-C.sub.6
alkylene)NR.sup.14R.sup.15, --(C.sub.1-C.sub.6
alkylene)C(O)R.sup.13, --(C.sub.1-C.sub.6
alkylene)NR.sup.13C(O)R.sup.14, --(C.sub.1-C.sub.6
alkylene)NR.sup.13C(O)NR.sup.14R.sup.15, --(C.sub.1-C.sub.6
alkylene)C(O)OR.sup.13, --(C.sub.1-C.sub.6 alkylene)
C(O)ONR.sup.14R.sup.15 or --(C.sub.1-C.sub.6
alkylene)-C(O)NR.sup.14R.sup.15, each of which is optionally
substituted with R.sup.d;
[0074] R.sup.d is hydrogen, halogen, --OH, oxo, --CN,
C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6
haloalkoxy, --COOH or C.sub.1-C.sub.6 alkyl optionally substituted
with --OH, halogen, CN or oxo;
[0075] each R.sup.10, R.sup.11 and R.sup.12 is independently
hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, C.sub.3-C.sub.6 cycloalkyl,
--(C.sub.1-C.sub.6 alkylene)C.sub.3-C.sub.6 cycloalkyl-, 3- to
6-membered heterocyclyl or, --(C.sub.1-C.sub.6 alkylene).sub.3- to
6-membered heterocyclyl, wherein each of R.sup.10, R.sup.11 and
R.sup.12 is independently optionally substituted by oxo,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, --CN, halogen,
C.sub.1-C.sub.6 alkoxy or C.sub.1-C.sub.6 alkyl optionally
substituted by oxo, OH, halogen;
[0076] or R.sup.11 and R.sup.12 are taken together with the atoms
to which they attached to form a 3-6 membered heterocyclyl
optionally substituted by oxo, OH, halogen or C.sub.1-C.sub.6 alkyl
optionally substituted by oxo, OH or halogen;
[0077] each R.sup.13, R.sup.14 and R.sup.15 is independently
hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6 haloalkyl, C.sub.3-C.sub.6
cycloalkyl or 3- to 6-membered heterocyclyl, wherein each of
R.sup.10, R.sup.11 and R.sup.12 is independently optionally
substituted by oxo, --OH, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, --CN, halogen or C.sub.1-C.sub.6 alkyl optionally
substituted by oxo, OH, halogen;
[0078] or R.sup.14 and R.sup.15 are taken together with the atoms
to which they attached to form a 3-6 membered heterocyclyl
optionally substituted by oxo, OH, halogen, or C.sub.1-C.sub.6
alkyl optionally substituted by oxo, OH or halogen;
[0079] m is 0, 1 or 2; and
[0080] n is 0, 1, 2, 3 or 4;
[0081] provided that when Z is --NR.sup.cS(O).sub.2CH.sub.3,
--CONH.sub.2 or --C(O)OH, G is a bond and t is 1 then L is not a
bond; and
[0082] the compound is not: [0083]
1-[7-(4-Bromo-2,6-dimethylphenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-
-4-yl]-3-azetidinebutanoic acid; [0084]
1-[7-(4-Bromo-2,6-dimethylphenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-
-4-yl]-3-azetidinepentanoic acid; or [0085] Acetamide,
N-[[1-(6-fluoro-2-benzoxazolyl)-3-azetidinyl]methyl]-N-methyl.
[0086] In one aspect, provided is a compound of the formula
(IA):
##STR00004##
or a salt thereof, wherein
[0087] C is 5- to 6-membered heteroaryl optionally substituted with
R.sup.1;
[0088] D is C.sub.6-aryl or 5- to 6-membered heteroaryl, each of
which is optionally substituted with R.sup.2, wherein D is fused to
C;
[0089] A is hydrogen, C.sub.1-C.sub.6 alkyl, or C.sub.6-aryl, each
of which is optionally substituted with halogen;
[0090] G is a bond, --CH.sub.2-- or --CH.sub.2--CH.sub.2--;
[0091] R.sup.a and R.sup.b are independently hydrogen or
C.sub.1-C.sub.6 alkyl; [0092] or R.sup.a and R.sup.b are taken
together with the atoms to which they are attached to form a
C.sub.3-C.sub.6 cycloalkyl ring;
[0093] or any one of R.sup.a and R.sup.b, and A are taken together
along with the atoms to which they are attached to form a
C.sub.4-C.sub.6 cycloalkyl ring;
[0094] L is a bond, linear or branched C.sub.1-C.sub.6 alkylene or
linear or branched C.sub.2-C.sub.6 alkenylene;
[0095] t is 0 or 1;
[0096] provided that when t is 0 then L is linear or branched
C.sub.2-C.sub.6 alkenylene;
[0097] Z is --NR.sup.cS(O).sub.2NH.sub.2,
--NR.sup.cS(O).sub.2CH.sub.3, --SO.sub.2NH.sub.2,
--NR.sup.cC(O)CH.sub.3, --C(O)OH, --CONH.sub.2, NR.sup.cCONH.sub.2,
--CONH(OH), --B(OH).sub.2--P(O)(OH).sub.2, --SO.sub.2OH,
--NR.sup.cS(O).sub.2CF.sub.3 or --NR.sup.cS(O).sub.2NHCH.sub.3,
[0098] R.sup.c is hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.6
cycloalkyl, or C.sub.1-C.sub.6 haloalkyl;
[0099] each R.sup.1 and R.sup.2 are independently hydrogen, oxo,
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, C.sub.3-C.sub.6 cycloalkyl, adamantly, 3- to 6-membered
heterocyclyl, C.sub.6-aryl, 5- to 6-membered heteroaryl, --CN,
halogen, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 haloalkoxy,
--OR.sup.10, --SR.sup.10, --S(O).sub.2R.sup.10,
--S(O).sub.2NR.sup.11R.sup.12, --NR.sup.10S(O).sub.2R.sup.11,
--NR.sup.11R.sup.12, --C(O)R.sup.10, --NR.sup.10C(O)R.sup.11,
--NR.sup.10C(O)NR.sup.11R.sup.12, --C(O)OR.sup.10,
--C(O)ONR.sup.11R.sup.12, --C(O)NR.sup.11R.sup.12, wherein each of
which is optionally substituted by R.sup.9;
[0100] or any two of R.sup.2 are taken together with the atoms to
which they attached to form a C.sub.5-C.sub.6 cycloalkyl, 5- to
6-membered heterocyclyl, C.sub.6-aryl or 5- to 6-membered
heteroaryl, wherein each of which is optionally substituted by
R.sup.9;
[0101] R.sup.9 is oxo, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, C.sub.3-C.sub.6 cycloalkyl, 3- to 6-membered heterocyclyl,
C.sub.6-aryl, 5- to 6-membered heteroaryl, --CN, halogen,
C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 haloalkoxy, C.sub.1-C.sub.6
haloalkyl, --OR.sup.13, --SR.sup.13, --S(O).sub.2R.sup.13,
--S(O).sub.2NR.sup.14R.sup.15, --NR.sup.13S(O).sub.2R.sup.14,
--NR.sup.14R.sup.15, --C(O)R.sup.13, --NR.sup.13C(O)R.sup.14,
--NR.sup.13C(O)NR.sup.14R.sup.15, --C(O)OR.sup.13,
--C(O)ONR.sup.14R.sup.15, --C(O)NR.sup.14R.sup.15 or
C.sub.1-C.sub.6 alkyl optionally substituted by oxo, OH or
halogen;
[0102] each R.sup.10, R.sup.11 and R.sup.12 is independently
hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, C.sub.3-C.sub.6 cycloalkyl or 3- to
6-membered heterocyclyl, wherein each of R.sup.10, R.sup.11 and
R.sup.12 is independently optionally substituted by oxo,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, --CN, halogen,
C.sub.1-C.sub.6 alkoxy or C.sub.1-C.sub.6 alkyl optionally
substituted by oxo, OH, halogen;
[0103] or R.sup.11 and R.sup.12 are taken together with the atoms
to which they attached to form a 3-6 membered heterocyclyl
optionally substituted by oxo, OH, halogen or C.sub.1-C.sub.6 alkyl
optionally substituted by oxo, OH or halogen;
[0104] each R.sup.13, R.sup.14 and R.sup.15 is independently
hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, C.sub.3-C.sub.6 cycloalkyl or 3- to
6-membered heterocyclyl, wherein each of R.sup.10, R.sup.11 and
R.sup.12 is independently optionally substituted by oxo,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, --CN, halogen or
C.sub.1-C.sub.6 alkyl optionally substituted by oxo, OH,
halogen;
[0105] or R.sup.14 and R.sup.15 are taken together with the atoms
to which they attached to form a 3-6 membered heterocyclyl
optionally substituted by oxo, OH, halogen, or C.sub.1-C.sub.6
alkyl optionally substituted by oxo, OH or halogen;
[0106] m is 0, 1 or 2; and
[0107] n is 0, 1, 2, 3 or 4.
[0108] In one aspect, provided is a compound of the formula
(I):
##STR00005##
or a salt thereof, wherein
[0109] C is 5- to 6-membered heteroaryl optionally substituted with
R.sup.1;
[0110] D is C.sub.6-aryl or 5- to 6-membered heteroaryl, each of
which is optionally substituted with R.sup.2, wherein D is fused to
C;
[0111] A is hydrogen or C.sub.1-C.sub.6 alkyl;
[0112] G is a bond, --CH.sub.2-- or --CH.sub.2--CH.sub.2--;
[0113] R.sup.a and R.sup.b are independently hydrogen or
C.sub.1-C.sub.6 alkyl; [0114] or R.sup.a and R.sup.b are taken
together with the atoms to which they are attached to form a
C.sub.3-C.sub.6 cycloalkyl ring;
[0115] or any one of R.sup.a and R.sup.b, and A are taken together
along with the atoms to which they are attached to form a
C.sub.4-C.sub.6 cycloalkyl ring; [0116] L is a bond or linear or
branched C.sub.1-C.sub.6 alkylene; [0117] Z is
--NR.sup.cS(O).sub.2NH.sub.2, --NR.sup.cS(O).sub.2CH.sub.3,
--SO.sub.2NH.sub.2, --NR.sup.cC(O)CH.sub.3, --C(O)OH, --CONH.sub.2,
NR.sup.cCONH.sub.2, --CONH(OH), --B(OH).sub.2 or --P(O)(OH).sub.2;
[0118] R.sup.c is hydrogen, C.sub.1-C.sub.6 alkyl or
C.sub.3-C.sub.6 cycloalkyl;
[0119] each R.sup.1 and R.sup.2 are independently hydrogen, oxo,
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, C.sub.3-C.sub.6 cycloalkyl, 3- to 6-membered heterocyclyl,
C.sub.6-aryl, 5- to 6-membered heteroaryl, --CN, halogen,
C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6haloalkoxy, --OR.sup.10,
--SR.sup.10, --S(O).sub.2R.sup.10, --S(O).sub.2NR.sup.11R.sup.12,
--NR.sup.10S(O).sub.2R.sup.11, --NR.sup.11R.sup.12, --C(O)R.sup.10,
--NR.sup.10C(O)R.sup.11, --NR.sup.10C(O)NR.sup.11R.sup.12,
--C(O)OR.sup.10, --C(O)ONR.sup.11R.sup.12, --C(O)NR.sup.11R.sup.12,
wherein each of which is optionally substituted by R.sup.9;
[0120] or any two of R.sup.2 are taken together with the atoms to
which they attached to form a C.sub.5-C.sub.6 cycloalkyl, 5- to
6-membered heterocyclyl, C.sub.6-aryl or 5- to 6-membered
heteroaryl, wherein each of which is optionally substituted by
R.sup.9;
[0121] R.sup.9 is oxo, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, C.sub.3-C.sub.6 cycloalkyl, 3- to 6-membered heterocyclyl,
C.sub.6-aryl, 5- to 6-membered heteroaryl, --CN, halogen,
C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 haloalkoxy, C.sub.1-C.sub.6
haloalkyl, --OR.sup.13, --SR.sup.13, --S(O).sub.2R.sup.13,
--S(O).sub.2NR.sup.14R.sup.15, --NR.sup.13S(O).sub.2R.sup.14,
--NR.sup.14R.sup.15, --C(O)R.sup.13, --NR.sup.13C(O)R.sup.14,
--NR.sup.13C(O)NR.sup.14R.sup.15, --C(O)OR.sup.13,
--C(O)ONR.sup.14R.sup.15, --C(O)NR.sup.14R.sup.15 or
C.sub.1-C.sub.6 alkyl optionally substituted by oxo, OH or
halogen;
[0122] each R.sup.10, R.sup.11 and R.sup.12 is independently
hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, C.sub.3-C.sub.6 cycloalkyl or 3- to
6-membered heterocyclyl, wherein each of R.sup.10, R.sup.11 and
R.sup.12 is independently optionally substituted by oxo,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, --CN, halogen,
C.sub.1-C.sub.6 alkoxy or C.sub.1-C.sub.6 alkyl optionally
substituted by oxo, OH, halogen;
[0123] or R.sup.11 and R.sup.12 are taken together with the atoms
to which they attached to form a 3-6 membered heterocyclyl
optionally substituted by oxo, OH, halogen or C.sub.1-C.sub.6 alkyl
optionally substituted by oxo, OH or halogen;
[0124] each R.sup.13, R.sup.14 and R.sup.15 is independently
hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, C.sub.3-C.sub.6 cycloalkyl or 3- to
6-membered heterocyclyl, wherein each of R.sup.10, R.sup.11 and
R.sup.12 is independently optionally substituted by oxo,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, --CN, halogen or
C.sub.1-C.sub.6 alkyl optionally substituted by oxo, OH,
halogen;
[0125] or R.sup.14 and R.sup.15 are taken together with the atoms
to which they attached to form a 3-6 membered heterocyclyl
optionally substituted by oxo, OH, halogen, or C.sub.1-C.sub.6
alkyl optionally substituted by oxo, OH or halogen;
[0126] m is 0, 1 or 2; and
[0127] n is 0, 1, 2, or 4.
[0128] In some embodiments of a compound of formula (J), A is
hydrogen. In some embodiments of a compound of formula (J), A is
C.sub.1-C.sub.6 alkyl. In some embodiments of a compound of formula
(J), A is methyl. In some embodiments of a compound of formula (J),
A is C.sub.1-C.sub.6 alkyl optionally substituted by halogen. In
some embodiments of a compound of formula (J), A is --CF.sub.3. In
some embodiments of a compound of formula (J), A is C.sub.6-aryl.
In some embodiments of a compound of formula (J), A is phenyl.
[0129] In some embodiments of a compound of formula (J), G is a
bond. In some embodiments of a compound of formula (J), G is
--CH.sub.2--. In some embodiments of a compound of formula (J), G
is --CH.sub.2--CH.sub.2--. In some embodiments of a compound of
formula (J), G is a bond, and the A, C, D, L, Z, R.sup.a, R.sup.b,
R.sup.1, R.sup.2, m, n and t are as detailed herein. In some
embodiments of a compound of formula (J), G is --CH.sub.2--, and
the A, C, D, L, Z, R.sup.a, R.sup.b, R.sup.1, R.sup.2, m, n and t
are as detailed herein. In some embodiments of a compound of
formula (J), G is --CH.sub.2--CH.sub.2--, and the A, C, D, L, Z,
R.sup.a, R.sup.b, R.sup.1, R.sup.2, m, n and t are as detailed
herein.
[0130] In some embodiments of a compound of formula (J), R.sup.a
and R.sup.b are independently hydrogen or C.sub.1-C.sub.6 alkyl. In
some embodiments of a compound of formula (J), R.sup.a and R.sup.b
both are hydrogen. In some embodiments of a compound of formula
(J), any one of R.sup.a and R.sup.b is hydrogen and other is
C.sub.1-C.sub.6 alkyl. In some embodiments of a compound of formula
(J), R.sup.a and R.sup.b both are C.sub.1-C.sub.6 alkyl. In some
embodiments of a compound of formula (J), any one of R.sup.a and
R.sup.b is hydrogen and other is methyl. In some embodiments of a
compound of formula (J), any one of R.sup.a and R.sup.b is hydrogen
and other is ethyl. In some embodiments of a compound of formula
(J), R.sup.a and R.sup.b both are methyl.
[0131] In some embodiments of a compound of formula (J), R.sup.a
and R.sup.b are taken together with the atoms to which they
attached to form a C.sub.3-C.sub.6 cycloalkyl ring. In some
embodiments of a compound of formula (J), R.sup.a and R.sup.b are
taken together with the atoms to which they attached to form a
cycloproplyl ring.
[0132] In some embodiments of a compound of formula (J), any one of
R.sup.a and R.sup.b, and A are taken together along with the atoms
to which they are attached to form a C.sub.4-C.sub.6 cycloalkyl. In
some embodiments of a compound of formula (J), any one of R.sup.a
and R.sup.b, and A are taken together along with the atoms to which
they are attached to form a cyclobutyl ring. In some embodiments of
a compound of formula (J), any one of R.sup.a and R.sup.b, and A
are taken together along with the atoms to which they are attached
to form a cyclopentyl ring. In some embodiments of a compound of
formula (J), any one of R.sup.a and R.sup.b, and A are taken
together along with the atoms to which they are attached to form a
cyclohexyl ring.
[0133] In some embodiments of a compound of formula (J), any one of
R.sup.a and R.sup.b, and A are taken together along with the atoms
to which they are attached to form a C.sub.4-C.sub.6 cycloalkyl
ring, in such case other one of R.sup.a or R.sup.b is hydrogen. In
some embodiments of a compound of formula (J), any one of R.sup.a
and R.sup.b, and A are taken together along with the atoms to which
they are attached to form a cyclobutyl ring, in such case other one
of R.sup.a or R.sup.b is hydrogen. In some embodiments of a
compound of formula (J), any one of R.sup.a and R.sup.b, and A are
taken together along with the atoms to which they are attached to
form a cyclopentyl ring, in such case other one of R.sup.a or
R.sup.b is hydrogen. In some embodiments of a compound of formula
(J), any one of R.sup.a and R.sup.b, and A are taken together along
with the atoms to which they are attached to form a cyclohexyl
ring, in such case other one of R.sup.a or R.sup.b is hydrogen.
[0134] In some embodiments of a compound of formula (J), G is a
bond, CH.sub.2 or --CH.sub.2--CH.sub.2--; and any one of R.sup.a
and R.sup.b, and A are taken together along with the atoms to which
they are attached to form a C.sub.4-C.sub.6 cycloalkyl ring. In
some embodiments of a compound of formula (J), G is CH.sub.2; and
any one of R.sup.a and R.sup.b, and A are taken together along with
the atoms to which they are attached to form a cyclobutyl ring. In
some embodiments of a compound of formula (J), G is CH.sub.2; and
any one of R.sup.a and R.sup.b, and A are taken together along with
the atoms to which they are attached to form a cyclopentyl ring. In
some embodiments of a compound of formula (J), G is
CH.sub.2--CH.sub.2--; and any one of R.sup.a and R.sup.b, and A are
taken together along with the atoms to which they are attached to
form a cyclohexyl ring.
[0135] In some embodiments of a compound of formula (J), L is a
bond, or C.sub.1-C.sub.6 alkylene or C.sub.2-C.sub.6 alkenylene.
The C.sub.1-C.sub.6 alkylene or C.sub.2-C.sub.6 alkenylene can be a
linear or branched. In some embodiments of a compound of formula
(J), L is a bond. In some embodiments of a compound of formula (J),
L is a C.sub.1-C.sub.6 alkylene. In some embodiments of a compound
of formula (J), L is --CH.sub.2--. In some embodiments of a
compound of formula (J), L is --C.sub.2H.sub.4--. In some
embodiments of a compound of formula (J), L is --C.sub.3H.sub.6--.
In some embodiments of a compound of formula (J), L is
--CH(CH.sub.3)--. In some embodiments of a compound of formula (J),
L is --C(CH.sub.3).sub.2--. In some embodiments of a compound of
formula (J), L is --CH(CH.sub.3)--CH.sub.2--. In some embodiments
of a compound of formula (J), L is --CH.sub.2--CH(CH.sub.3)--. In
some embodiments of a compound of formula (J), L is
--C(CH.sub.3).sub.2--CH.sub.2--. In some embodiments of a compound
of formula (J), L is --CH.sub.2--C(CH.sub.3).sub.2--. In some
embodiments of a compound of formula (J), L is
--CH(C.sub.2H.sub.5)--CH.sub.2--.
[0136] In some embodiments of a compound of formula (J), L is a
C.sub.2-C.sub.6 alkynelene. The C.sub.2-C.sub.6 alkenylene can be a
linear or branched. In some embodiments of a compound of formula
(J), L is a --CH.dbd.CH--. In some embodiments of a compound of
formula (J), L is a --CH.sub.2--CH.dbd.CH--.
[0137] In some embodiments of a compound of formula (J), t is 0 or
1. In some embodiments of a compound of formula (J), t is 0. In
some embodiments of a compound of formula (J), t is 1.
[0138] In some embodiments of a compound of formula (J), when t is
0 then R.sup.a and R.sup.b are absent and L is C.sub.2-C.sub.6
alkynelene. In some embodiments of a compound of formula (J), when
t is 0 then R.sup.a and R.sup.b are absent and L is
--CH.dbd.CH--.
[0139] In some embodiments of a compound of formula (J), when t is
1 then R.sup.a and R.sup.b are present and L is a bond or
C.sub.1-C.sub.6 alkylene. In some embodiments of a compound of
formula (J), when t is 1 then R.sup.a and R.sup.b are present and L
is a bond. In some embodiments of a compound of formula (J), when t
is 1 then R.sup.a and R.sup.b are present and L is C.sub.1-C.sub.6
alkylene. In some embodiments of a compound of formula (J), when t
is 1 then R.sup.a and R.sup.b are present and L is --CH.sub.2--. In
some embodiments of a compound of formula (J), when t is 1 then
R.sup.a and R.sup.b are present and L is --CH.sub.2--CH.sub.2--.
Wherein R.sup.a and R.sup.b are independently selected from
hydrogen or C.sub.1-C.sub.6 alkyl.
[0140] In some embodiments of a compound of formula (J), when t is
1 then R.sup.a and R.sup.b are present and any one of R.sup.a and
R.sup.b, and A are taken together along with the atoms to which
they are attached to form a C.sub.4-C.sub.6 cycloalkyl ring, in
such case other one of R.sup.a or R.sup.b is hydrogen. In some
embodiments of a compound of formula (J), when t is 1 then R.sup.a
and R.sup.b are present and any one of R.sup.a and R.sup.b, and A
are taken together along with the atoms to which they are attached
to form a cyclobutyl ring, in such case other one of R.sup.a or
R.sup.b is hydrogen.
[0141] In some embodiments of a compound of formula (J), Z is
selected from --NR.sup.cSO.sub.2NH.sub.2,
--NR.sup.cS(O).sub.2CH.sub.3, --SO.sub.2NH.sub.2,
--NR.sup.cC(O)CH.sub.3, --C(O)OH, --CONH.sub.2, NR.sup.cCONH.sub.2,
--CONH(OH), --B(OH).sub.2, --P(O)(OH).sub.2, --SO.sub.2OH,
--NR.sup.cS(O).sub.2CF.sub.3, --NR.sup.cS(O).sub.2NHCH.sub.3 or
--NR.sup.cCH.sub.2C.sub.6-aryl-S(O).sub.2NH.sub.2. In some
embodiments of a compound of formula (J), Z is
--NR.sup.cS(O).sub.2NH.sub.2. In some embodiments of a compound of
formula (J), Z is --NR.sup.cS(O).sub.2CH.sub.3. In some embodiments
of a compound of formula (J), Z is --SO.sub.2NH.sub.2. In some
embodiments of a compound of formula (J), Z is
--NR.sup.cC(O)CH.sub.3. In some embodiments of a compound of
formula (J), Z is --C(O)OH. In some embodiments of a compound of
formula (J), Z is --CONH.sub.2. In some embodiments of a compound
of formula (J), Z is --NR.sup.cCONH.sub.2. In some embodiments of a
compound of formula (J), Z is --CONH(OH). In some embodiments of a
compound of formula (J), Z is --B(OH).sub.2. In some embodiments of
a compound of formula (J), Z is --P(O)(OH).sub.2. In some
embodiments of a compound of formula (J), Z is-SO.sub.2OH. In some
embodiments of a compound of formula (J), Z
is-NR.sup.cS(O).sub.2CF.sub.3. In some embodiments of a compound of
formula (J), Z is --NR.sup.cS(O).sub.2NHCH.sub.3. In some
embodiments of a compound of formula (J), Z is
--NR.sup.cCH.sub.2C.sub.6-aryl-S(O).sub.2NH. In some embodiments of
a compound of formula (J), R.sup.c is selected from hydrogen,
C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.6 cycloalkyl or
C.sub.1-C.sub.6 haloalkyl. In some embodiments of a compound of
formula (J), R.sup.c is methyl. In some embodiments of a compound
of formula (J), R.sup.c is ethyl. In some embodiments of a compound
of formula (J), R.sup.c is isopropyl. In some embodiments of a
compound of formula (J), R.sup.c is n-propyl. In some embodiments
of a compound of formula (J), R.sup.c is cyclopropyl. In some
embodiments of a compound of formula (J), R.sup.c is
##STR00006##
In some embodiments of a compound of formula (J), R.sup.c is
##STR00007##
In some embodiments of a compound of formula (J), R.sup.c is
##STR00008##
[0142] In some embodiments of a compound of formula (J) R.sup.c is
--(C.sub.1-C.sub.6 alkylene)C.sub.3-C.sub.6 cycloalkyl optionally
substituted with R.sup.d. In some embodiments of a compound of
formula (J) R.sup.c is 3- to 6-membered heterocyclyl optionally
substituted with R.sup.d. In some embodiments of a compound of
formula (J) R.sup.c is --(C.sub.1-C.sub.6 alkylene).sub.3- to
6-membered heterocyclyl optionally substituted with R.sup.d. In
some embodiments of a compound of formula (J) R.sup.c is
--(C.sub.1-C.sub.6 alkylene)C.sub.6-aryl optionally substituted
with R.sup.d. In some embodiments of a compound of formula (J)
R.sup.c is 5- to 6-membered heteroaryl optionally substituted with
R.sup.d. In some embodiments of a compound of formula (J) R.sup.c
is --(C.sub.1-C.sub.6 alkylene) 5- to 6-membered heteroaryl
optionally substituted with R.sup.d. In some embodiments of a
compound of formula (J) R.sup.c is --(C.sub.1-C.sub.6
alkylene)OR.sup.13. In some embodiments of a compound of formula
(J) R.sup.c is --(C.sub.1-C.sub.6 alkylene)SR.sup.13. In some
embodiments of a compound of formula (J) R.sup.c is
--(C.sub.1-C.sub.6 alkylene)S(O).sub.2R.sup.13. In some embodiments
of a compound of formula (J) R.sup.c is --(C.sub.1-C.sub.6
alkylene)S(O).sub.2NR.sup.14R.sup.15. In some embodiments of a
compound of formula (J) R.sup.c is --(C.sub.1-C.sub.6
alkylene)NR.sup.13S(O).sub.2R.sup.14. In some embodiments of a
compound of formula (J) R.sup.c is --(C.sub.1-C.sub.6
alkylene)NR.sup.14R.sup.15. In some embodiments of a compound of
formula (J) R.sup.c is --(C.sub.1-C.sub.6 alkylene)C(O)R.sup.13. In
some embodiments of a compound of formula (J) R.sup.c is
--(C.sub.1-C.sub.6 alkylene)NR.sup.13C(O)R.sup.14. In some
embodiments of a compound of formula (J) R.sup.c is
--(C.sub.1-C.sub.6 alkylene)NR.sup.13C(O)NR.sup.14R.sup.15. In some
embodiments of a compound of formula (J) R.sup.c is
--(C.sub.1-C.sub.6 alkylene)C(O)OR.sup.13. In some embodiments of a
compound of formula (J) R.sup.c is --(C.sub.1-C.sub.6 alkylene)
C(O)ONR.sup.14R.sup.15. In some embodiments of a compound of
formula (J) R.sup.c is --(C.sub.1-C.sub.6
alkylene)-C(O)NR.sup.14R.sup.15.
[0143] In some embodiments of a compound of formula (J),
--C.sub.1-C.sub.6 alkylene of any R.sup.c group may be optionally
substituted with R.sup.d.
[0144] In some embodiments of a compound of formula (J),
--C.sub.1-C.sub.6 alkylene of any R.sup.c group is linear or
branched.
[0145] In some embodiments of a compound of formula (J) R.sup.c is
selected from the group consisting of methyl, ethyl, isopropyl,
n-propyl, n-butyl, cyclopropyl, cyclobutyl, cyclopentyl,
##STR00009##
wherein wavy lines denote the attachment points.
[0146] In some embodiments of a compound of formula (J), Z is
selected from the group consisting of
##STR00010## ##STR00011## ##STR00012## ##STR00013##
wherein wavy lines denote the attachment points.
[0147] In some embodiments of a compound of formula (J), Z is
--NR.sup.cSO.sub.2NH.sub.2.
[0148] In some embodiments of a compound of formula (J), Z is
--NHSO.sub.2NH.sub.2. In some embodiments of a compound of formula
(J), Z is
##STR00014##
In some embodiments of a compound of formula (J), Z is
##STR00015##
In some embodiments of a compound of formula (J), Z is
##STR00016##
In some embodiments of a compound of formula (J), Z is
##STR00017##
In some embodiments of a compound of formula (J), Z is
##STR00018##
In some embodiments of a compound of formula (J), Z is
##STR00019##
In some embodiments of a compound of formula (J), Z is
##STR00020##
In some embodiments of a compound of formula (J), Z is
##STR00021##
[0149] In some embodiments of a compound of formula (J), Z is
--NHS(O).sub.2CH.sub.3.
[0150] In some embodiments of a compound of formula (J), Z is
--SO.sub.2NH.sub.2.
[0151] In some embodiments of a compound of formula (J), Z is
--NHC(O)CH.sub.3.
[0152] In some embodiments of a compound of formula (J), Z is
--C(O)OH.
[0153] In some embodiments of a compound of formula (J), Z is
--CONH.sub.2.
[0154] In some embodiments of a compound of formula (J), Z is
--NHCONH.sub.2.
[0155] In some embodiments of a compound of formula (J), Z is
--CONH(OH).
[0156] In some embodiments of a compound of formula (J), Z is
--B(OH).sub.2.
[0157] In some embodiments of a compound of formula (J), Z is
--P(O)(OH).sub.2.
[0158] In some embodiments of a compound of formula (J), Z is
--S(O).sub.2OH.
[0159] In some embodiments of a compound of formula (J), Z is
--NR.sup.cS(O).sub.2CF.sub.3.
[0160] In some embodiments of a compound of formula (J), Z is
--NR.sup.cS(O).sub.2NHCH.sub.3.
[0161] In some embodiments of a compound of formula (J), Z is
--NR.sup.cCH.sub.2C.sub.6-aryl-S(O).sub.2NH.sub.2.
[0162] In some embodiments of a compound of formula (J), Z is
--NHCH.sub.2C.sub.6-aryl-S(O).sub.2NH.sub.2.
[0163] In some embodiments of a compound of formula (J), Z is
--N(CH.sub.3)CH.sub.2C.sub.6-aryl-S(O).sub.2NH.sub.2.
[0164] In some embodiments of a compound of formula (J), G,
R.sup.a, R.sup.b, L, t and Z together is selected from the group
consisting of
##STR00022## ##STR00023## ##STR00024##
wherein wavy lines denote the attachment points.
[0165] In some embodiments of a compound of formula (J), when any
one of R.sup.a and R.sup.b, and A are taken together along with the
atoms to which they are attached to form a C.sub.4-C.sub.6
cycloalkyl ring then L and Z together is selected from the group
consisting of
##STR00025##
wherein wavy lines denote the attachment points.
[0166] In some embodiments of a compound of formula (J), when any
one of R.sup.a and R.sup.b, and A are taken together along with the
atoms to which they are attached to form a C.sub.4-C.sub.6
cycloalkyl ring then L and Z together is selected from the group
consisting of
##STR00026## ##STR00027## ##STR00028##
wherein wavy lines denote the attachment points.
[0167] In some embodiments of a compound of formula (J), when any
one of R.sup.a and R.sup.b, and A are taken together along with the
atoms to which they are attached to form a cyclobutyl ring (which
forms with the azetidine an azaspiroheptane ring) then L and Z
together is selected from the group consisting of
##STR00029## ##STR00030## ##STR00031##
wherein wavy lines denote the attachment points.
[0168] In some embodiments of a compound of formula (J), C is 5- to
6-membered heteroaryl optionally substituted with R.sup.1. In
embodiments of a compound of formula (J), C is 5-membered
heteroaryl optionally substituted with R.sup.1. In embodiments of a
compound of formula (J), C is 6-membered heteroaryl optionally
substituted with R.sup.1. In embodiments of a compound of formula
(J), C is selected from the group consisting of imidazole,
pyrazzole, pyrrole, pyridine, pyrimidine, pyridone, pyrimidone,
pyridazine, pyridazinone and triazine, wherein each of which is
optionally substituted with R.sup.1. In some embodiments of the
compound of formula (J), the R.sup.1 is selected from hydrogen,
oxo, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, C.sub.3-C.sub.6 cycloalkyl, 3- to
6-membered heterocyclyl, C.sub.6-aryl, 5- to 6-membered heteroaryl,
--CN, --CONR.sup.11R.sup.12 or --NR.sup.11R.sup.12, wherein each of
which is optionally substituted by R.sup.9. In some embodiments of
the compound of formula (J), the R.sup.1 is selected from hydrogen,
oxo, methyl, ethyl, ethylene, propynyl, cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, adamantly, oxetanyl, tetrahydropyranyl,
pyrazolyl, pyridyl, pyrimidyl, phenyl, --CONH.sub.2, --NH.sub.2,
--CHF.sub.2, --CF.sub.3, Cl, and --CN; wherein each of which is
optionally further substituted with pyridyl, F, CF.sub.3 and
CHF.sub.2.
[0169] In some embodiments of the compound of formula (J), the D is
C.sub.6-aryl or 5- to 6-membered heteroaryl, each of which is
optionally substituted with R.sup.2; wherein D is fused to C. In
some embodiments of the compound of formula (J), the D is
C.sub.6-aryl optionally substituted with R.sup.2; wherein D is
fused to C. In some embodiments of the compound of formula (J), the
D is 5- to 6-membered heteroaryl optionally substituted with
R.sup.2; wherein D is fused to C. In some embodiments of the
compound of formula (J), the D is 5-membered heteroaryl optionally
substituted with R.sup.2; wherein D is fused to C. In some
embodiments of the compound of formula (J), the D is 6-membered
heteroaryl optionally substituted with R.sup.2; wherein D is fused
to C. In some embodiments of the compound of formula (J), the D is
selected from the group consisting of phenyl, pyrrole, pyrazole,
imidazole, pyridine, thiophene and pyrimidine optionally
substituted with R.sup.2; wherein each of which is fused to C. In
some embodiments of the compound of formula (J), R.sup.2 is
selected from hydrogen, halogen, oxo, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, C.sub.3-C.sub.6 cycloalkyl, --OR.sup.10,
--CN and C.sub.6-aryl; wherein each of which is optionally
substituted by R.sup.9. In some embodiments of the compound of
formula (J), R.sup.2 is selected from hydrogen, fluorine, bromine,
chloro, oxo, methyl, ethyl, isopropyl, methoxy, ethoxy, propoxy,
phenyl, 4-methoxypheyl, --CN, --OCH.sub.2F, --OCH.sub.2OCH.sub.3,
--(OCH.sub.2CH.sub.2)morpholine, 4-hydroxycyclohexyl, --CF.sub.3,
cyclopropyl and phenyl.
[0170] In some embodiments of the compound of formula (J), any two
of R.sup.2 are taken together with the atoms to which they attached
to form a C.sub.5-C.sub.6 cycloalkyl, 5- to 6-membered
heterocyclyl, C.sub.6-aryl or 5- to 6-membered heteroaryl, wherein
each of which is optionally substituted by R.sup.9. In some
embodiments of the compound of formula (J), any two of R.sup.2 are
taken together with the atoms to which they attached to form
imidazole, dioxole and dihydro dioxine, wherein each of which is
optionally substituted with methyl.
[0171] In some embodiments of a compound of formula (J), m is 0. In
some embodiments of a compound of formula (J), m is 1. In some
embodiments of a compound of formula (J), m is 2.
[0172] In some embodiments of a compound of formula (J), n is 0. In
some embodiments of a compound of formula (J), n is 1. In some
embodiments of a compound of formula (J), n is 2. In some
embodiments of a compound of formula (J), n is 3. In some
embodiments of a compound of formula (J), n is 4.
[0173] In some embodiments of a compound of formula (J), C, D,
R.sup.1 and R.sup.2 together is selected from the group consisting
of
##STR00032## ##STR00033## ##STR00034## ##STR00035##
wherein wave lines denote the attachment points.
[0174] In some embodiments of a compound of formula (J), C, D,
R.sup.1 and R.sup.2 together is selected from the group consisting
of
##STR00036## ##STR00037## ##STR00038## ##STR00039## ##STR00040##
##STR00041## ##STR00042## ##STR00043## ##STR00044## ##STR00045##
##STR00046## ##STR00047## ##STR00048## ##STR00049##
##STR00050##
wherein wavy lines denote the attachment points.
[0175] It is understood that each description of A, G, R.sup.a,
R.sup.b, L, Z, C, D, R.sup.1, R.sup.2, R.sup.c, m, n and t may be
independently combined with each description of A, G, R.sup.a,
R.sup.b, L, Z, C, D, R.sup.1, R.sup.2, R.sup.c, m, n and t the same
as if each and every combination were specifically and individually
listed.
[0176] In some embodiments, provided is a compound of formula
(II):
##STR00051##
or a salt thereof, wherein A, R.sup.a, R.sup.b, L, Z, C, D,
R.sup.1, R.sup.2 m and n are as detailed herein.
[0177] In some embodiments, provided is a compound of formula
(III):
##STR00052##
or a salt thereof, wherein L, Z, C, D, R.sup.1, R.sup.2, m and n
are as detailed herein.
[0178] In some embodiments, provided is a compound of formula
(IV):
##STR00053##
or a salt thereof, wherein
[0179] X is N or CR.sup.1;
[0180] Y is N or CR.sup.1; provided that at same time X and Y both
are not N;
and A, G, R.sup.a, R.sup.b, L, Z, D, R.sup.1, R.sup.2, n and t are
as detailed herein.
[0181] In some embodiments, provided is a compound of any one of
formula (IV-1) to (IV-11):
##STR00054## ##STR00055## ##STR00056## ##STR00057##
or a salt thereof, wherein
[0182] X.sub.1, X.sub.2 and X.sub.3 are independently N, NR.sup.2
or CR.sup.2;
[0183] provided that any one of X.sub.1, X.sub.2 and X.sub.3 is
NR.sup.2 and others are N or CR.sup.2;
and A, G, R.sup.a, R.sup.b, L, Z, R.sup.1, R.sup.2 and t are as
detailed herein.
[0184] In some embodiments, provided is a compound of formula
(V):
##STR00058##
or a salt thereof, wherein
[0185] X is N or CR.sup.1;
[0186] Y is N or CR.sup.1; provided that at same time X and Y both
are not N;
and L, Z, D, R.sup.1, R.sup.2 and n are as detailed herein.
[0187] In some embodiments, provided is a compound of any one of
formula (V-1) to (V-11):
##STR00059## ##STR00060## ##STR00061## ##STR00062##
or a salt thereof, wherein
[0188] X.sub.1, X.sub.2 and X.sub.3 are independently N, NR.sup.2
or CR.sup.2;
[0189] provided that any one of X.sub.1, X.sub.2 and X.sub.3 is
NR.sup.2 and others are N or CR.sup.2;
and L, Z, R.sup.1 and R.sup.2 are as detailed herein.
[0190] In some embodiments, provided is a compound of formula
(VI):
##STR00063##
or a salt thereof, wherein [0191] Y.sub.1 is N or NR.sup.1; [0192]
Y.sub.2 is N, NR.sup.1 or CR.sup.1; provided that any one of
Y.sub.1 and Y.sub.2 is NR.sup.1 and other one is other than
NR.sup.1; and A, G, R.sup.a, R.sup.b, L, Z, R.sup.1, R.sup.2 and t
are as detailed herein.
[0193] In some embodiments, provided is a compound of formula
(VII):
##STR00064##
or a salt thereof, wherein
[0194] Z.sub.1 is N or CR.sup.1;
and A, G, R.sup.a, R.sup.b, L, Z, R.sup.1, R.sup.2 and t are as
detailed herein.
[0195] In some embodiments, provided is a compound of formula
(VIII):
##STR00065##
or a salt thereof, wherein, A, G, R.sup.a, R.sup.b, L, Z, R.sup.1,
R.sup.2 and t are as detailed herein.
[0196] In some embodiments, provided is a compound of formula
(IX):
##STR00066##
or a salt thereof, wherein [0197] Y.sub.1 is N or NR.sup.1; [0198]
Y.sub.2 is N, NR.sup.1 or CR.sup.1; provided that any one of
Y.sub.1 and Y.sub.2 is NR.sup.1 and other one is other than
NR.sup.1; and L, Z, Rand R.sup.2 are as detailed herein.
[0199] In some embodiments, provided is a compound of formula
(X):
##STR00067##
or a salt thereof, wherein
[0200] Z.sub.1 is N or CR.sup.1;
and L, Z, Rand R.sup.2 are as detailed herein.
[0201] In some embodiments, provided is a compound of formula
(XI):
##STR00068##
or a salt thereof, wherein L, Z, Rand R.sup.2 are as detailed
herein.
[0202] In some embodiments, provided is a compound of formula
(XII):
##STR00069##
or a salt thereof, wherein,
[0203] X is N or CR.sup.1;
[0204] X.sub.4 and X.sub.5 is independently N or CR.sup.2; provided
that at same time both are not N;
and A, G, R.sup.a, R.sup.b, L, Z, R.sup.1, R.sup.2 and t are as
detailed herein.
[0205] In some embodiments, provided is a compound of any one of
formula (XII-1) to (XII-6):
##STR00070## ##STR00071##
or a salt thereof, wherein A, G, R.sup.a, R.sup.b, L, Z, R.sup.1,
R.sup.2, R.sup.c and t are as detailed herein.
[0206] In some embodiments, provided is a compound of formula
(XIII):
##STR00072##
or a salt thereof, wherein
[0207] X is N or CR.sup.1;
[0208] X.sub.4 and X.sub.5 is independently N or CR.sup.2; provided
that at same time both are not N;
and L, Z, R.sup.1 and R.sup.2 are as detailed herein.
[0209] In some embodiments, provided is a compound of any one of
formula (XIII-1) to (XIII-9):
##STR00073## ##STR00074## ##STR00075##
or a salt thereof, wherein L, Z, R.sup.1, R.sup.2 and R.sup.1 are
as detailed herein.
[0210] Also provided are salts of compounds referred to herein,
such as pharmaceutically acceptable salts. The invention also
includes any or all of the stereochemical forms, including any
enantiomeric or diastereomeric forms, and any tautomers or other
forms of the compounds described.
[0211] A compound as detailed herein may in one aspect be in a
purified form and compositions comprising a compound in purified
forms are detailed herein. Compositions comprising a compound as
detailed herein or a salt thereof are provided, such as
compositions of substantially pure compounds. In some embodiments,
a composition containing a compound as detailed herein or a salt
thereof is in substantially pure form. Unless otherwise stated,
"substantially pure" intends a composition that contains no more
than 35% impurity, wherein the impurity denotes a compound other
than the compound comprising the majority of the composition or a
salt thereof. In some embodiments, a composition of substantially
pure compound or a salt thereof is provided wherein the composition
contains no more than 25%, 20%, 15%, 10%, or 5% impurity. In some
embodiments, a composition of substantially pure compound or a salt
thereof is provided wherein the composition contains or no more
than 3%, 2%, 1% or 0.5% impurity.
[0212] Representative compounds of the present invention
(collectively, a compound of formula (J), (IA), (I), (II), (III),
(IV), (IV-1) to (IV-11), (V), (V-1) to (V-11), (VI), (VII), (VIII),
(IX), (X), (XI), (XII), (XII-1) to (XII-6), (XIII) and (XIII-1) to
(XIII-9)) are listed in table-1 and table-2. It is understood that
individual enantiomers and diastereomers are included in the
generic compound structures shown in table-1 and table-2. Specific
synthetic methods for preparing compounds of table-1 are provided
examples herein.
TABLE-US-00001 TABLE 1 Compounds S.No. Compounds 1.1 ##STR00076##
1.2 ##STR00077## 1.3 ##STR00078## 1.4 ##STR00079## 1.5 ##STR00080##
1.6 ##STR00081## 1.7 ##STR00082## 1.8 ##STR00083## 1.9 ##STR00084##
1.10 ##STR00085## 1.11 ##STR00086## 1.12 ##STR00087## 1.13
##STR00088## 1.14 ##STR00089## 1.15 ##STR00090## 1.16 ##STR00091##
1.17 ##STR00092## 1.18 ##STR00093## 1.19 ##STR00094## 1.20
##STR00095## 1.21 ##STR00096## 1.22 ##STR00097## 1.23 ##STR00098##
1.24 ##STR00099## 1.25 ##STR00100## 1.26 ##STR00101## 1.27
##STR00102## 1.28 ##STR00103## 1.29 ##STR00104## 1.30 ##STR00105##
1.31 ##STR00106## 1.32 ##STR00107## 1.33 ##STR00108## 1.34
##STR00109## 1.35 ##STR00110## 1.36 ##STR00111## 1.37 ##STR00112##
1.38 ##STR00113## 1.39 ##STR00114## 1.40 ##STR00115## 1.41
##STR00116## 1.42 ##STR00117## 1.43 ##STR00118## 1.44 ##STR00119##
1.45 ##STR00120## 1.46 ##STR00121## 1.47 ##STR00122## 1.48
##STR00123## 1.49 ##STR00124## 1.50 ##STR00125## 1.51 ##STR00126##
1.52 ##STR00127## 1.53 ##STR00128## 1.54 ##STR00129## 1.55
##STR00130## 1.56 ##STR00131## 1.57 ##STR00132## 1.58 ##STR00133##
1.59 ##STR00134## 1.60 ##STR00135## 1.61 ##STR00136## 1.62
##STR00137## 1.63 ##STR00138## 1.64 ##STR00139## 1.65 ##STR00140##
1.66 ##STR00141## 1.67 ##STR00142## 1.68 ##STR00143## 1.69
##STR00144## 1.70 ##STR00145## 1.71 ##STR00146## 1.72 ##STR00147##
1.73 ##STR00148## 1.74 ##STR00149## 1.75 ##STR00150## 1.76
##STR00151## 1.77 ##STR00152## 1.78 ##STR00153## 1.79 ##STR00154##
1.80 ##STR00155## 1.81 ##STR00156## 1.82 ##STR00157## 1.83
##STR00158## 1.84 ##STR00159## 1.85 ##STR00160## 1.86 ##STR00161##
1.87 ##STR00162## 1.88 ##STR00163## 1.89 ##STR00164## 1.90
##STR00165## 1.91 ##STR00166## 1.92 ##STR00167## 1.93 ##STR00168##
1.94 ##STR00169## 1.95 ##STR00170## 1.96 ##STR00171## 1.97
##STR00172## 1.98 ##STR00173## 1.99 ##STR00174## 1.100 ##STR00175##
1.101 ##STR00176## 1.102 ##STR00177## 1.103 ##STR00178## 1.104
##STR00179## 1.105 ##STR00180## 1.106 ##STR00181## 1.107
##STR00182## 1.108 ##STR00183## 1.109 ##STR00184## 1.110
##STR00185## 1.111 ##STR00186## 1.112 ##STR00187## 1.113
##STR00188## 1.114 ##STR00189## 1.115 ##STR00190## 1.116
##STR00191## 1.117 ##STR00192## 1.118 ##STR00193## 1.119
##STR00194## 1.120 ##STR00195## 1.121 ##STR00196## 1.122
##STR00197## 1.123 ##STR00198##
1.124 ##STR00199## 1.125 ##STR00200## 1.126 ##STR00201## 1.127
##STR00202## 1.128 ##STR00203## 1.129 ##STR00204## 1.130
##STR00205## 1.131 ##STR00206## 1.132 ##STR00207## 1.133
##STR00208## 1.134 ##STR00209## 1.135 ##STR00210##
[0213] The compounds illustrated in table-2 are prepared in a
manner analogous to the techniques used in connection with the
preparation of the table-1 compounds and in accordance, using
appropriate, analogous starting materials and by utilizing the
general synthetic schemes illustrated below.
TABLE-US-00002 TABLE 2 Compounds S.No. Compounds 2.1 ##STR00211##
2.2 ##STR00212## 2.3 ##STR00213## 2.4 ##STR00214## 2.5 ##STR00215##
2.6 ##STR00216## 2.7 ##STR00217## 2.8 ##STR00218## 2.9 ##STR00219##
2.10 ##STR00220## 2.11 ##STR00221## 2.12 ##STR00222## 2.13
##STR00223## 2.14 ##STR00224## 2.15 ##STR00225## 2.16 ##STR00226##
2.17 ##STR00227## 2.18 ##STR00228## 2.19 ##STR00229## 2.20
##STR00230## 2.21 ##STR00231## 2.22 ##STR00232## 2.23 ##STR00233##
2.24 ##STR00234## 2.25 ##STR00235## 2.26 ##STR00236## 2.27
##STR00237## 2.28 ##STR00238## 2.29 ##STR00239## 2.30 ##STR00240##
2.31 ##STR00241## 2.32 ##STR00242## 2.33 ##STR00243## 2.34
##STR00244## 2.35 ##STR00245## 2.36 ##STR00246## 2.37 ##STR00247##
2.38 ##STR00248## 2.39 ##STR00249## 2.40 ##STR00250## 2.41
##STR00251## 2.42 ##STR00252## 2.43 ##STR00253## 2.44 ##STR00254##
2.45 ##STR00255## 2.46 ##STR00256## 2.47 ##STR00257## 2.48
##STR00258## 2.49 ##STR00259## 2.50 ##STR00260## 2.51 ##STR00261##
2.52 ##STR00262## 2.53 ##STR00263## 2.54 ##STR00264## 2.55
##STR00265## 2.56 ##STR00266## 2.57 ##STR00267## 2.58 ##STR00268##
2.59 ##STR00269## 2.60 ##STR00270## 2.61 ##STR00271## 2.62
##STR00272## 2.63 ##STR00273## 2.64 ##STR00274## 2.65 ##STR00275##
2.66 ##STR00276## 2.67 ##STR00277## 2.68 ##STR00278## 2.69
##STR00279## 2.70 ##STR00280## 2.71 ##STR00281## 2.72 ##STR00282##
2.73 ##STR00283## 2.74 ##STR00284## 2.75 ##STR00285## 2.76
##STR00286## 2.77 ##STR00287## 2.78 ##STR00288## 2.79 ##STR00289##
2.80 ##STR00290## 2.81 ##STR00291## 2.82 ##STR00292## 2.83
##STR00293## 2.84 ##STR00294## 2.85 ##STR00295## 2.86 ##STR00296##
2.87 ##STR00297## 2.88 ##STR00298## 2.89 ##STR00299## 2.90
##STR00300## 2.91 ##STR00301## 2.92 ##STR00302## 2.93 ##STR00303##
2.94 ##STR00304## 2.95 ##STR00305## 2.96 ##STR00306## 2.97
##STR00307## 2.98 ##STR00308## 2.99 ##STR00309## 2.100 ##STR00310##
2.101 ##STR00311## 2.102 ##STR00312## 2.103 ##STR00313## 2.104
##STR00314## 2.105 ##STR00315## 2.106 ##STR00316## 2.107
##STR00317## 2.108 ##STR00318## 2.109 ##STR00319## 2.110
##STR00320## 2.111 ##STR00321## 2.112 ##STR00322## 2.113
##STR00323## 2.114 ##STR00324## 2.115 ##STR00325## 2.116
##STR00326## 2.117 ##STR00327## 2.118 ##STR00328## 2.119
##STR00329## 2.120 ##STR00330## 2.121 ##STR00331## 2.122
##STR00332## 2.123 ##STR00333##
2.124 ##STR00334## 2.125 ##STR00335## 2.126 ##STR00336## 2.127
##STR00337## 2.128 ##STR00338## 2.129 ##STR00339## 2.130
##STR00340## 2.131 ##STR00341## 2.132 ##STR00342## 2.133
##STR00343## 2.134 ##STR00344## 2.135 ##STR00345## 2.136
##STR00346## 2.137 ##STR00347## 2.138 ##STR00348## 2.139
##STR00349## 2.140 ##STR00350## 2.141 ##STR00351## 2.142
##STR00352## 2.143 ##STR00353## 2.144 ##STR00354## 2.145
##STR00355## 2.146 ##STR00356## 2.147 ##STR00357## 2.148
##STR00358## 2.149 ##STR00359## 2.150 ##STR00360## 2.151
##STR00361## 2.152 ##STR00362## 2.153 ##STR00363## 2.154
##STR00364## 2.155 ##STR00365## 2.156 ##STR00366## 2.157
##STR00367## 2.158 ##STR00368## 2.159 ##STR00369## 2.160
##STR00370## 2.161 ##STR00371## 2.162 ##STR00372## 2.163
##STR00373## 2.164 ##STR00374## 2.165 ##STR00375## 2.166
##STR00376## 2.167 ##STR00377## 2.168 ##STR00378## 2.169
##STR00379## 2.170 ##STR00380## 2.171 ##STR00381## 2.172
##STR00382## 2.173 ##STR00383## 2.174 ##STR00384## 2.175
##STR00385## 2.176 ##STR00386## 2.177 ##STR00387## 2.178
##STR00388## 2.179 ##STR00389## 2.180 ##STR00390## 2.181
##STR00391## 2.182 ##STR00392## 2.183 ##STR00393## 2.184
##STR00394## 2.185 ##STR00395## 2.186 ##STR00396## 2.187
##STR00397## 2.188 ##STR00398## 2.189 ##STR00399## 2.190 Compound
No. 1.81 of table-1 2.191 Compound No. 1.98 of table-1 2.192
##STR00400## 2.193 ##STR00401## 2.194 ##STR00402## 2.195
##STR00403## 2.196 ##STR00404## 2.197 ##STR00405## 2.198
##STR00406## 2.199 ##STR00407## 2.200 ##STR00408## 2.201 Compound
No. 1.80 of table-1 2.202 Compound No. 1.77 of table-1 2.203
Compound No. 1.91 of table-1 2.204 ##STR00409## 2.205 ##STR00410##
2.206 Compound No. 1.84 of table-1 2.207 ##STR00411## 2.208
Compound No. 1.87 of table-1 2.209 ##STR00412## 2.210 ##STR00413##
2.211 ##STR00414## 2.212 ##STR00415## 2.213 ##STR00416## 2.214
##STR00417## 2.215 Compound No. 1.86 of table-1 2.216 ##STR00418##
2.217 ##STR00419## 2.218 ##STR00420## 2.219 ##STR00421## 2.220
##STR00422## 2.221 ##STR00423## 2.222 ##STR00424## 2.223
##STR00425## 2.224 ##STR00426## 2.225 ##STR00427## 2.226
##STR00428## 2.227 ##STR00429## 2.228 ##STR00430## 2.229
##STR00431## 2.230 ##STR00432## 2.231 ##STR00433## 2.232
##STR00434## 2.233 ##STR00435## 2.234 ##STR00436## 2.235
##STR00437## 2.236 ##STR00438## 2.237 Compound No. 1.99 of table-1
2.238 Compound No. 1.82 of table-1 2.239 Compound No. 1.97 of
table-1 2.240 ##STR00439## 2.241 ##STR00440## 2.242 ##STR00441##
2.243 ##STR00442## 2.244 ##STR00443## 2.245 ##STR00444## 2.246
Compound No. 1.93 of table-1 2.247 ##STR00445## 2.248 ##STR00446##
2.249 ##STR00447## 2.250 ##STR00448## 2.251 ##STR00449##
2.252 ##STR00450## 2.253 ##STR00451## 2.254 ##STR00452## 2.255
##STR00453## 2.256 ##STR00454## 2.257 ##STR00455## 2.258
##STR00456## 2.259 ##STR00457## 2.260 ##STR00458## 2.261
##STR00459## 2.262 ##STR00460## 2.263 ##STR00461## 2.264
##STR00462## 2.265 ##STR00463## 2.266 ##STR00464## 2.267
##STR00465## 2.268 ##STR00466## 2.269 ##STR00467## 2.270
##STR00468## 2.271 ##STR00469## 2.272 ##STR00470## 2.273
##STR00471## 2.274 ##STR00472## 2.275 ##STR00473## 2.276
##STR00474## 2.277 ##STR00475## 2.278 ##STR00476## 2.279
##STR00477## 2.280 ##STR00478## 2.281 ##STR00479## 2.282
##STR00480## 2.283 ##STR00481## 2.284 Compound No. 1.123 of table-1
2.285 ##STR00482## 2.286 ##STR00483## 2.287 ##STR00484## 2.288
##STR00485## 2.289 Compound No. 1.127 of table-1 2.290 ##STR00486##
2.291 ##STR00487## 2.292 ##STR00488## 2.293 ##STR00489## 2.294
##STR00490## 2.295 ##STR00491## 2.296 ##STR00492## 2.297
##STR00493## 2.298 ##STR00494## 2.299 ##STR00495## 2.300
##STR00496## 2.301 ##STR00497## 2.302 ##STR00498## 2.303
##STR00499## 2.304 ##STR00500## 2.305 ##STR00501## 2.306
##STR00502## 2.307 ##STR00503## 2.308 ##STR00504## 2.309
##STR00505## 2.310 ##STR00506## 2.311 ##STR00507## 2.312
##STR00508## 2.313 ##STR00509## 2.314 ##STR00510## 2.315
##STR00511## 2.316 ##STR00512## 2.317 ##STR00513## 2.318
##STR00514## 2.319 ##STR00515## 2.320 ##STR00516## 2.321
##STR00517## 2.322 ##STR00518## 2.323 ##STR00519## 2.324
##STR00520## 2.325 ##STR00521## 2.326 ##STR00522## 2.327
##STR00523## 2.328 ##STR00524## 2.329 ##STR00525## 2.330
##STR00526## 2.331 ##STR00527## 2.332 ##STR00528## 2.333
##STR00529## 2.334 ##STR00530## 2.335 ##STR00531## 2.336
##STR00532## 2.337 ##STR00533## 2.338 ##STR00534## 2.339
##STR00535## 2.340 ##STR00536## 2.341 ##STR00537## 2.342
##STR00538## 2.343 ##STR00539## 2.344 ##STR00540## 2.345
##STR00541## 2.346 ##STR00542## 2.347 ##STR00543## 2.348
##STR00544## 2.349 ##STR00545## 2.350 ##STR00546## 2.351
##STR00547## 2.352 ##STR00548## 2.353 ##STR00549## 2.354
##STR00550## 2.355 ##STR00551## 2.356 ##STR00552## 2.357
##STR00553## 2.358 ##STR00554## 2.359 ##STR00555## 2.360
##STR00556## 2.361 ##STR00557## 2.362 ##STR00558##
[0214] In some embodiments, provided herein are compounds described
in table-1 and table-2, or a salt, polymorph, solvate, enantiomer,
stereoisomer or tautomer thereof, and uses thereof.
[0215] The embodiments and variations described herein are suitable
for compounds of any formulae detailed herein, where
applicable.
[0216] Representative examples of compounds detailed herein,
including intermediates and final compounds according to the
present disclosure are depicted herein. It is understood that in
one aspect, any of the compounds described herein may be used in
the methods detailed herein, including, where applicable,
intermediate compounds that may be isolated and administered to an
individual.
[0217] The compounds depicted herein may be present as salts even
if salts are not depicted and it is understood that the present
disclosure embraces all salts and solvates of the compounds
depicted here, as well as the non-salt and non-solvate form of the
compound, as is well understood by the skilled artisan. In some
embodiments, the salts of the compounds provided herein are
pharmaceutically acceptable salts. Where one or more tertiary amine
moiety is present in the compound, the N-oxides are also provided
and described.
[0218] Where tautomeric forms may be present for any of the
compounds described herein, each and every tautomeric form is
intended even though only one or some of the tautomeric forms may
be explicitly depicted. The tautomeric forms specifically depicted
may or may not be the predominant forms in solution or when used
according to the methods described herein.
[0219] The present disclosure also includes any or all of the
stereochemical forms, including any enantiomeric or diastereomeric
forms of the compounds described. All forms of the compounds are
also embraced by the invention, such as crystalline or
non-crystalline forms of the compounds. Compositions comprising a
compound of the invention are also intended, such as a composition
of substantially pure compound, including a specific stereochemical
form thereof, or a composition comprising mixtures of compounds of
the invention in any ratio, including two or more stereochemical
forms, such as in a racemic or non-racemic mixture.
[0220] The invention also intends isotopically-labeled and/or
isotopically-enriched forms of compounds described herein. The
compounds herein may contain unnatural proportions of atomic
isotopes at one or more of the atoms that constitute such
compounds. In some embodiments, the compound is
isotopically-labeled, such as an isotopically-labeled compound of
the formula (J), or variations thereof described herein, where a
fraction of one or more atoms are replaced by an isotope of the
same element. Exemplary isotopes that can be incorporated into
compounds of the invention include isotopes of hydrogen, carbon,
nitrogen, oxygen, phosphorus, sulfur, chlorine, such as .sup.2H,
.sup.3H, .sup.11C, .sup.13C, .sup.14C .sup.13N, .sup.15O, .sup.17O,
.sup.32p .sup.35S, .sup.18F, .sup.36Cl. Certain isotope labeled
compounds (e.g. .sup.3H and .sup.14C) are useful in compound or
substrate tissue distribution studies. Incorporation of heavier
isotopes such as deuterium (.sup.2H) can afford certain therapeutic
advantages resulting from greater metabolic stability, for example,
increased in vivo half-life, or reduced dosage requirements and,
hence may be preferred in some instances.
[0221] Isotopically-labeled compounds of the present invention can
generally be prepared by standard methods and techniques known to
those skilled in the art or by procedures similar to those
described in the accompanying Examples substituting appropriate
isotopically-labeled reagents in place of the corresponding
non-labeled reagent.
[0222] The invention also includes any or all metabolites of any of
the compounds described. The metabolites may include any chemical
species generated by a biotransformation of any of the compounds
described, such as intermediates and products of metabolism of the
compound, such as would be generated in vivo following
administration to a human.
[0223] Articles of manufacture comprising a compound described
herein, or a salt or solvate thereof, in a suitable container are
provided. The container may be a vial, jar, ampoule, preloaded
syringe, i.v. bag, and the like.
[0224] Preferably, the compounds detailed herein are orally
bioavailable. However, the compounds may also be formulated for
parenteral (e.g., intravenous) administration.
[0225] One or several compounds described herein can be used in the
preparation of a medicament by combining the compound or compounds
as an active ingredient with a pharmacologically acceptable
carrier, which are known in the art. Depending on the therapeutic
form of the medication, the carrier may be in various forms. In one
variation, the manufacture of a medicament is for use in any of the
methods disclosed herein, e.g., for the treatment of cancer.
General Synthetic Methods
[0226] The compounds of the invention may be prepared by a number
of processes as generally described below and more specifically in
the Examples hereinafter (such as the schemes provided in the
Examples below). In the following process descriptions, the symbols
when used in the formulae depicted are to be understood to
represent those groups described above in relation to the formulae
herein.
[0227] Where it is desired to obtain a particular enantiomer of a
compound, this may be accomplished from a corresponding mixture of
enantiomers using any suitable conventional procedure for
separating or resolving enantiomers. Thus, for example,
diastereomeric derivatives may be produced by reaction of a mixture
of enantiomers, e.g., a racemate, and an appropriate chiral
compound. The diastereomers may then be separated by any convenient
means, for example by crystallization and the desired enantiomer
recovered. In another resolution process, a racemate may be
separated using chiral High Performance Liquid Chromatography.
Alternatively, if desired a particular enantiomer may be obtained
by using an appropriate chiral intermediate in one of the processes
described.
[0228] Chromatography, recrystallization and other conventional
separation procedures may also be used with intermediates or final
products where it is desired to obtain a particular isomer of a
compound or to otherwise purify a product of a reaction.
[0229] Solvates and/or polymorphs of a compound provided herein or
a pharmaceutically acceptable salt thereof are also contemplated.
Solvates contain either stoichiometric or non-stoichiometric
amounts of a solvent, and are often formed during the process of
crystallization. Hydrates are formed when the solvent is water, or
alcoholates are formed when the solvent is alcohol. Polymorphs
include the different crystal packing arrangements of the same
elemental composition of a compound. Polymorphs usually have
different X-ray diffraction patterns, infrared spectra, melting
points, density, hardness, crystal shape, optical and electrical
properties, stability, and/or solubility. Various factors such as
the recrystallization solvent, rate of crystallization, and storage
temperature may cause a single crystal form to dominate
[0230] In some embodiments, compounds of the present invention
(collectively, a compound of formula (J), (IA), (I), (II), (III),
(IV), (IV-1) to (IV-11), (V), (V-1) to (V-11), (VI), (VII), (VIII),
(IX), (X), (XI), (XII), (XII-1) to (XII-6), (XIII) and (XIII-1) to
(XIII-9)) are synthesized according to general Scheme 1 to 8.
General Synthetic Scheme:
##STR00559##
[0231] wherein A, G, R.sup.a, R.sup.b, L, Z, C, D, R.sup.1,
R.sup.2, m, n and t are as detailed herein.
##STR00560##
wherein A, G, R.sup.a, R.sup.b, L, Z, C, R.sup.1, R.sup.2 , n and t
are as detailed herein.
##STR00561##
wherein A, G, R.sup.a, R.sup.b, L, Z, R.sup.1, R.sup.2 and t are as
detailed herein.
##STR00562##
wherein A, G, R.sup.a, R.sup.b, L, Z, R.sup.1, R.sup.2 and t are as
detailed herein.
##STR00563##
wherein A, G, R.sup.a, R.sup.b, L, Z, R.sup.1, R.sup.2 and t are as
detailed herein.
##STR00564##
wherein A, G, R.sup.1, R.sup.b, L, Z, R.sup.1, R.sup.2 and t are as
detailed herein.
##STR00565## ##STR00566##
wherein R.sup.2 and R.sup.c are as detailed herein.
##STR00567## ##STR00568##
wherein R.sup.2 and R.sup.c are as detailed herein.
[0232] In some cases, enantiomers or diastereomers are synthesized
chirally pure. In some cases, stereoisomers are separated to give
single enantiomers or diastereomers as single, unknown
stereoisomers, and are arbitrarily drawn as single isomers. Where
appropriate, information is given on separation method and elution
time and order.
Pharmaceutical Compositions and Formulations
[0233] Pharmaceutical compositions of any of the compounds detailed
herein are embraced by this disclosure. Thus, the present
disclosure includes pharmaceutical compositions comprising a
compound as detailed herein or a salt thereof and a
pharmaceutically acceptable carrier or excipient. In one aspect,
the pharmaceutically acceptable salt is an acid addition salt, such
as a salt formed with an inorganic or organic acid. Pharmaceutical
compositions may take a form suitable for oral, buccal, parenteral,
nasal, topical or rectal administration or a form suitable for
administration by inhalation.
[0234] A compound as detailed herein may in one aspect be in a
purified form and compositions comprising a compound in purified
forms are detailed herein. Compositions comprising a compound as
detailed herein or a salt thereof are provided, such as
compositions of substantially pure compounds. In some embodiments,
a composition containing a compound as detailed herein or a salt
thereof is in substantially pure form.
[0235] In one variation, the compounds herein are synthetic
compounds prepared for administration to an individual. In another
variation, compositions are provided containing a compound in
substantially pure form. In another variation, the present
disclosure embraces pharmaceutical compositions comprising a
compound detailed herein and a pharmaceutically acceptable carrier.
In another variation, methods of administering a compound are
provided. The purified forms, pharmaceutical compositions and
methods of administering the compounds are suitable for any
compound or form thereof detailed herein.
[0236] A compound detailed herein or salt thereof may be formulated
for any available delivery route, including an oral, mucosal (e.g.,
nasal, sublingual, vaginal, buccal or rectal), parenteral (e.g.,
intramuscular, subcutaneous or intravenous), topical or transdermal
delivery form. A compound or salt thereof may be formulated with
suitable carriers to provide delivery forms that include, but are
not limited to, tablets, caplets, capsules (such as hard gelatin
capsules or soft elastic gelatin capsules), cachets, troches,
lozenges, gums, dispersions, suppositories, ointments, cataplasms
(poultices), pastes, powders, dressings, creams, solutions,
patches, aerosols (e.g., nasal spray or inhalers), gels,
suspensions (e.g., aqueous or non-aqueous liquid suspensions,
oil-in-water emulsions or water-in-oil liquid emulsions), solutions
and elixirs.
[0237] One or several compounds described herein or a salt thereof
can be used in the preparation of a formulation, such as a
pharmaceutical formulation, by combining the compound or compounds,
or a salt thereof, as an active ingredient with a pharmaceutically
acceptable carrier, such as those mentioned above. Depending on the
therapeutic form of the system (e.g., transdermal patch vs. oral
tablet), the carrier may be in various forms. In addition,
pharmaceutical formulations may contain preservatives,
solubilizers, stabilizers, re-wetting agents, emulgators,
sweeteners, dyes, adjusters, and salts for the adjustment of
osmotic pressure, buffers, coating agents or antioxidants.
Formulations comprising the compound may also contain other
substances which have valuable therapeutic properties.
Pharmaceutical formulations may be prepared by known pharmaceutical
methods. Suitable formulations can be found, e.g., in Remington's
Pharmaceutical Sciences, Mack Publishing Company, Philadelphia,
Pa., 20.sup.th ed. (2000), which is incorporated herein by
reference.
[0238] Compounds as described herein may be administered to
individuals in a form of generally accepted oral compositions, such
as tablets, coated tablets, and gel capsules in a hard or in soft
shell, emulsions or suspensions. Examples of carriers, which may be
used for the preparation of such compositions, are lactose, corn
starch or its derivatives, talc, stearate or its salts, etc.
Acceptable carriers for gel capsules with soft shell are, for
instance, plant oils, wax, fats, semisolid and liquid poly-ols, and
so on. In addition, pharmaceutical formulations may contain
preservatives, solubilizers, stabilizers, re-wetting agents,
emulgators, sweeteners, dyes, adjusters, and salts for the
adjustment of osmotic pressure, buffers, coating agents or
antioxidants.
[0239] Any of the compounds described herein can be formulated in a
tablet in any dosage form described, for example, a compound as
described herein or a salt thereof can be incorporated in tablet in
an amount ranging from about 1 mg to about 1000 mg.
[0240] Compositions comprising a compound provided herein are also
described. In one variation, the composition comprises a compound
or salt thereof and a pharmaceutically acceptable carrier or
excipient. In another variation, a composition of substantially
pure compound is provided.
Methods of Use
[0241] Compounds and compositions detailed herein, such as a
pharmaceutical composition containing a compound of any formula
provided herein or a salt thereof and a pharmaceutically acceptable
carrier or excipient, may be used in methods of administration and
treatment as provided herein. The compounds and compositions may
also be used in in vitro methods, such as in vitro methods of
administering a compound or composition to cells for screening
purposes and/or for conducting quality control assays.
[0242] Provided herein is a method of treating a disease in an
individual comprising administering an effective amount of a
compounds of the present invention (collectively, a compound of
formula (J), (IA), (I), (II), (III), (IV), (IV-1) to (IV-11), (V),
(V-1) to (V-11), (VI), (VII), (VIII), (IX), (X), (XI), (XII),
(XII-1) to (XII-6), (XIII) and (XIII-1) to (XIII-9)) or any
embodiment, variation or aspect thereof or the present compounds or
the compounds detailed or described herein) or a pharmaceutically
acceptable salt thereof, to the individual. Further provided herein
is a method of treating a proliferative disease in an individual,
comprising administering an effective amount of the compounds of
the present invention (collectively, a compound of formula (J),
(IA), (I), (II), (III), (IV), (IV-1) to (IV-11), (V), (V-1) to
(V-11), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XII-1) to
(XII-6), (XIII) and (XIII-1) to (XIII-9)) or a pharmaceutically
acceptable salt thereof, to the individual. Also provided herein is
a method of treating cancer in an individual comprising
administering an effective amount of the compounds of the present
invention (collectively, a compound of formula (J), (IA), (I),
(II), (III), (IV), (IV-1) to (IV-11), (V), (V-1) to (V-11), (VI),
(VII), (VIII), (IX), (X), (XI), (XII), (XII-1) to (XII-6), (XIII)
and (XIII-1) to (XIII-9)) or a pharmaceutically acceptable salt
thereof, to the individual. In some embodiments, the compound is
administered to the individual according to a dosage and/or method
of administration described herein.
[0243] Another aspect of the invention relates to a method of
treating a disease or disorder associated with ENPP1. The method
involves administering to a patient in need of a treatment for
diseases or disorders associated with ENPP1 an effective amount of
the compositions and compounds of the present invention
(collectively, a compound of formula (J), (IA), (I), (II), (III),
(IV), (IV-1) to (IV-11), (V), (V-1) to (V-11), (VI), (VII), (VIII),
(IX), (X), (XI), (XII), (XII-1) to (XII-6), (XIII) and (XIII-1) to
(XIII-9)) or a pharmaceutically acceptable salt thereof.
[0244] Another aspect of the invention is directed to a method
inhibiting ENPP1. The method involves administering to a patient in
need thereof an effective amount of the compositions or compounds
of formula (J), (IA), (I), (II), (III), (IV), (IV-1) to (IV-11),
(V), (V-1) to (V-11), (VI), (VII), (VIII), (IX), (X), (XI), (XII),
(XII-1) to (XII-6), (XIII) and (XIII-1) to (XIII-9) or a
pharmaceutically acceptable salt thereof.
[0245] Aspects of the present disclosure include methods for
inhibiting the hydrolase activity of ENPP1 against cGAMP provides
for increased levels of cGAMP and/or downstream modulation (e.g.,
activation) of the STING pathway. It is also known that cGAMP is
present in the extracellular space and that ENPP1 can control
extracellular levels of cGAMP. ENPP1 inhibition can modulate STING
activity, and thus it is used in the treatment of a variety of
diseases, e.g., as a target for cancer immunotherapy. As such, the
subject methods can provide for selective extracellular inhibition
of ENPP1 activity (e.g., hydrolase activity of cGAMP) to increase
extracellular levels of cGAMP and activate the stimulator of
interferon genes (STING) pathway. In some instances, the subject
method is a method for increasing a STING mediated response in a
subject. In some instances, the subject method is a method for
modulating an immune response in a subject.
[0246] A "STING mediated response" refers to any response that is
mediated by STING, including, but not limited to, immune responses,
e.g., to bacterial pathogens, viral pathogens, and eukaryotic
pathogens. STING also functions in certain autoimmune diseases
initiated by inappropriate recognition of self DNA as well as for
the induction of adaptive immunity in response to DNA vaccines. By
increasing a STING mediated response in a subject is meant an
increase in a STING mediated response in a subject as compared to a
control subject (e.g., a subject who is not administered a subject
compound). In some cases, the subject is human and the subject
compounds and methods provide for activation of human STING. In
some cases, the STING mediated response includes modulation of an
immune response. In some instances, the subject method is a method
of modulating an immune response in a subject.
[0247] In some cases, the STING mediated response includes
increasing the production of an interferon (e.g., a type I
interferon (IFN), type III interferon (IFN)) in a subject.
Interferons (IFNs) are proteins having a variety of biological
activities, e.g., antiviral, immunomodulating and
antiproliferative. IFNs are relatively small, species-specific,
single chain polypeptides, produced by mammalian cells in response
to exposure to a variety of inducers such as viruses, polypeptides,
mitogens and the like. Interferons protect animal tissues and cells
against viral attack and are an important host defense mechanism.
Interferons may be classified as Type-I, Type-II and Type-III
interferons. Mammalian Type-I interferons of interest include
IFN-.alpha., IFN-.beta., IFN-k, IFN-.delta., IFN-.epsilon.,
IFN-.tau., IFN-.omega., and IFN-.zeta..
[0248] Interferons find use in the treatment of a variety of
cancers since these molecules have anti-cancer activity that acts
at multiple levels. Interferon proteins can directly inhibit the
proliferation of human tumor cells. In some cases, the
anti-proliferative activity is also synergistic with a variety of
approved chemotherapeutic agents such as cisplatin, 5FU and
paclitaxel. The immunomodulatory activity of interferon proteins
can also lead to the induction of an anti-tumor immune response.
This response includes activation of NK cells, stimulation of
macrophage activity and induction of major histocompatibility
complex (MHC) class I surface expression, leading to the induction
of anti-tumor cytotoxic T lymphocyte activity. In addition,
interferons play a role in cross-presentation of antigens in the
immune system. Moreover, some studies further indicate that
IFN-.beta. protein may have anti-angiogenic activity. Angiogenesis,
new blood vessel formation, is critical for the growth of solid
tumors. IFN-.beta. may inhibit angiogenesis by inhibiting the
expression of pro-angiogenic factors such as bFGF and VEGF.
Interferon proteins may also inhibit tumor invasiveness by
modulating the expression of enzymes, such as collagenase and
elastase, which are important in tissue remodeling.
[0249] Another aspect of the invention relates to ENPP1 inhibitor,
inhibit the hydrolysis of cGAMP. The method comprises administering
to a patient in need thereof an effective amount of the
compositions or compounds of the present invention of formula (J),
(IA), (I), (II), (III), (IV), (IV-1) to (IV-11), (V), (V-1) to
(V-11), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XII-1) to
(XII-6), (XIII) and (XIII-1) to (XIII-9), or a pharmaceutically
acceptable salt thereof.
[0250] One therapeutic use of the compounds or compositions of the
present invention which inhibit ENPP1 is to provide treatment to
patients or subjects suffering from cell proliferative diseases and
cancers including, without limitation, glioma, glioblastoma
multiforme, paraganglioma, supratentorial primordial
neuroectodermal tumors, acute myeloid leukemia (AML), prostate
cancer, thyroid cancer, colon cancer, chondrosarcoma,
cholangiocarcinoma, peripheral T-cell lymphoma, melanoma,
intrahepatic cholangiocarcinoma (IHCC), myelodysplastic syndrome
(MDS), myeloproliferative disease (MPD), and other solid tumors.
Targeted treatments for these cancers and cell proliferative
diseases are not currently available to patients suffering from
these conditions. Therefore, there is a need for new therapeutic
agents selective to these conditions.
[0251] Another therapeutic use of the compounds or compositions of
the present invention which inhibit ENPP1 is to provide treatment
to patients or subjects suffering from cell proliferative diseases
and cancers including sarcomas and carcinomas. In some embodiments,
examples such as sarcomas and carcinomas are cancer that may be
treated as solid tumors. In some embodiments, examples such as
leukemia are the cancer that may be treated as liquid tumors.
Present invention may treat different types of cancers that
include, but are not limited to, adrenocortical cancer, bladder
cancer, brain tumors, breast cancer, prostate cancer, colorectal
cancer, colon cancer, endometrial cancer, gallbladder cancer,
gastric cancer, head and neck cancer, hematopoietic cancer, kidney
cancer, leukemia, oral cancer, uterine carcinoma, Hodgkin lymphoma,
liver cancer, lung cancer, pancreatic cancer, prostate cancer,
ovarian cancer, sarcoma, skin cancer and thyroid cancer. In some
embodiments, the breast cancer is classified as carcinoma of breast
(ER negative or ER positive), mammary adenocarcinoma, primary
breast ductal carcinoma, mammary ductal carcinoma (ER positive, ER
negative or HER2 positive), triple negative breast cancer (TNBC),
HER2 positive breast cancer or luminal breast cancer. In some
embodiments, the breast cancer is unclassified. In some
embodiments, a basal-like TNBC, an immunomodulatory TNBC,
mesenchymal TNBC (mesenchymal or mesenchymal stem-like) or a
luminal androgen receptor TNBC are triple negative breast. In some
embodiments, prostate adenocarcinoma is prostate cancer. In some
embodiments, the ovary adenocarcinoma is ovarian cancer. In some
embodiments, lung carcinoma, adenocarcinoma, non-small lung
carcinoma, mucoepidermoid, anaplastic large cell are lung cancer.
In some embodiments, the lung cancer is unclassified. In some
embodiments, the colon adenocarcinomas, colon carcinoma, metastatic
colorectal cancer, colon adenocarcinoma from a metastatic site
lymph node are colon cancer. In some embodiments astrocytoma,
glioblastoma, meduloblastoma, neuroblastoma or meningioma are brain
tumor. In some embodiments, stomach cancer is gastric cancer. In
some embodiments, cholangiocarcinoma or hepatoblastoma,
hepatocellular carcinoma are liver cancers. In some embodiments,
liver cancer is derived from hepatitis B virus. In some
embodiments, liver cancer is virus negative. In some embodiments,
medullary thyroid cancer or follicular thyroid cancer, papillary
thyroid carcinomas are classified as thyroid cancer. In some
embodiments, uterine papillary serous carcinoma or uterine clear
cell carcinoma, high grade endometroid cancer are endometrial
cancer. In some embodiments, gallbladder adenocarcinoma or squamous
cell gallbladder carcinoma are gallbladder cancer. In some
embodiments, renal cell carcinoma or urothelial cell carcinoma are
classified as kidney cancer. In some embodiments, adrenal cortical
carcinoma adrenocortical is cancer. In some embodiments,
fibrosarcoma or Ewing's sarcoma, osteosarcoma, rhabdomiosarcoma and
synovial sarcoma are classified as sarcoma. In some embodiments,
basal cell carcinoma, melanoma or squamous carcinoma are classified
as skin cancer. In some embodiments, cancer of the trachea,
laryngeal cancer, nasopharyngeal cancer and oropharyngeal cancer
are classified as head and neck cancer. In some embodiments, acute
lymphoblastic leukemia, acute promyelocytic leukemia, chronic
myelogenous leukemia, chronic lymphocytic leukemia, mantle cell
lymphoma or multiple myeloma are classified as leukemia.
[0252] The disclosed compounds of the invention can be administered
in effective amounts to treat or prevent a disorder and/or prevent
the development thereof in subjects.
Combination Therapy
[0253] The compound of the present invention may be administered
either simultaneously with, or before or after, one or more other
therapeutic agents. The compound of the present invention may be
administered separately, by the same or different route of
administration, or together in the same pharmaceutical composition
as the other agents.
[0254] In some embodiments, the methods described herein comprise
the additional step of co-administering to a subject in need
thereof a second therapy e.g., an additional cancer therapeutic
agent or an additional cancer treatment. In one embodiment, the
other therapeutic agent is selected from: vascular endothelial
growth factor (VEGF) receptor inhibitors, topoisomerase II
inhibitors, smoothened inhibitors, alkylating agents, chemotherapy
agents, anti-tumor antibiotics, anti-metabolites, retinoids,
immunomodulatory agents including but not limited to anti-cancer
vaccines, CTLA-4, LAG-3 and PD-1/PDL-1 antagonists, nitrosoureas,
antitumor antibiotics, plant (vinca) alkaloids, steroid hormones,
taxanes, nucleoside analogs, steroids, anthracyclines, thyroid
hormone replacement drugs, thymidylatetargeted drugs, Chimeric
Antigen Receptor/T cell therapies, Chimeric Antigen Receptor/NK
cell therapies, apoptosis regulator inhibitors (e.g., B cell
CLL/lymphoma 2 (BCL-2) BCL-2-like 1 (BCLXL) inhibitors),
CARP-1/CCAR1 (Cell division cycle and apoptosis regulator 1)
inhibitors, colonystimulating factor-1 receptor (CSF1R) inhibitors,
CD47 inhibitors, and other cell therapies.
[0255] In some embodiments, the additional cancer therapeutic agent
is alkylating agents. Examples of alkylating agents, include but
are not limited to, temozolomide, dactinomycin, melphalan,
altretamine, carmustine, bendamustine, busulfan, carboplatin,
lomustine, cisplatin, chlorambucil, cyclophosphamide, dacarbazine,
altretamine, ifosfamide, procarbazine, mechlorethamine,
streptozocin and thiotepa.
[0256] In some embodiments, the additional cancer therapeutic agent
is a chemotherapy agent. Examples of chemotherapeutic agents used
in cancer therapy include, for example, antimetabolites (e.g.,
folic acid, purine, and pyrimidine derivatives), alkylating agents
(e.g., nitrogen mustards, nitrosoureas, platinum, alkyl sulfonates,
hydrazines, triazenes, aziridines, spindle poison, cytotoxic
agents, topoisomerase inhibitors and others), and hypomethylating
agents (e.g., decitabine (5-aza-deoxycytidine), zebularine,
isothiocyanates, azacitidine (5-azacytidine),
5-flouro-2'-deoxycytidine, 5,6-dihydro-5-azacytidine and others).
Exemplary agents include Aclarubicin, Actinomycin, Alitretinoin,
Altretamine, Aminopterin, Aminolevulinic acid, Amrubicin,
Amsacrine, Anagrelide, Arsenic trioxide, Asparaginase, Atrasentan,
Belotecan, Bexarotene, bendamustine, Bleomycin, Bortezomib,
Busulfan, Camptothecin, Capecitabine, Carboplatin, Carboquone,
Carmofur, Carmustine, Celecoxib, Chlorambucil, Chlormethine,
Cisplatin, Cladribine, Clofarabine, Crisantaspase,
Cyclophosphamide, Cytarabine, Dacarbazine, Dactinomycin,
Daunorubicin, Decitabine, Demecolcine, Docetaxel, Doxorubicin,
Efaproxiral, Elesclomol, Elsamitrucin, Enocitabine, Epirubicin,
Estramustine, Etoglucid, Etoposide, Floxuridine, Fludarabine,
Fluorouracil (5FU), Fotemustine, Gemcitabine, Gliadel implants,
Hydroxycarbamide, Hydroxyurea, Idarubicin, Ifosfamide, Irinotecan,
Irofulven, Ixabepilone, Larotaxel, Leucovorin, Liposomal
doxorubicin, Liposomal daunorubicin, Lonidamine, Lomustine,
Lucanthone, Mannosulfan, Masoprocol, Melphalan, Mercaptopurine,
Mesna, Methotrexate, Methyl aminolevulinate, Mitobronitol,
Mitoguazone, Mitotane, Mitomycin, Mitoxantrone, Nedaplatin,
Nimustine, Oblimersen, Omacetaxine, Ortataxel, Oxaliplatin,
Paclitaxel, Pegaspargase, Pemetrexed, Pentostatin, Pirarubicin,
Pixantrone, Plicamycin, Porfimer sodium, Prednimustine,
Procarbazine, Raltitrexed, Ranimustine, Rubitecan, Sapacitabine,
Semustine, Sitimagene ceradenovec, Strataplatin, Streptozocin,
Talaporfin, Tegafur-uracil, Temoporfin, Temozolomide, Teniposide,
Tesetaxel, Testolactone, Tetranitrate, Thiotepa, Tiazofurine,
Tioguanine, Tipifarnib, Topotecan, Trabectedin, Triaziquone,
Triethylenemelamine, Triplatin, Tretinoin, Treosulfan,
Trofosfamide, Uramustine, Valrubicin, Verteporfin, Vinblastine,
Vincristine, Vindesine, Vinflunine, Vinorelbine, Vorinostat,
Zorubicin, and other cytostatic or cytotoxic agents described
herein.
[0257] In some embodiments, the additional cancer therapeutic agent
is a PARP inhibitors such as Olaparib, Rucaparib, Niraparib and
Talazoparib.
[0258] Other possible additional therapeutic modalities include
tyrosine kinase inhibitors, cyclin-dependent kinase inhibitors,
gene therapy, hormonal therapy, peptide and dendritic cell
vaccines, synthetic chlorotoxins, and radiolabeled drugs and
antibodies.
[0259] In some embodiments, the compound of the present invention
may be administered either simultaneously with, or before or after,
one or more other immunotherapeutic agents which modulate the
immune targets like TIM-3 (T-cell immunoglobulin and mucin
domain-3), LAG-3 (Lymphocyte-associated gene 3), TIGIT (T cell
immunoreceptor with Ig and ITIM domains), VISTA (V-domain Ig
suppressor of T cell activation), A2a (Adenosine A2a receptor), A2b
(Adenosine A2b receptor), IDO (Indoleamine-pyrrole
2,3-dioxygenase), TDO (tryptophan-2,3-dioxygenase), Arginase, CD73,
CD39, OX40, CD160, BTLA, TCR (T-cell receptor), CD28, GITR
(glucocorticoid-induced TNFR family related protein), HVEM, CD226,
CD96 and B7-H3.
Dosing and Method of Administration
[0260] The dose of a compound administered to an individual (such
as a human) may vary with the particular compound or salt thereof,
the method of administration, and the particular disease, such as
type and stage of cancer, being treated. In some embodiments, the
amount of the compound or salt thereof is a therapeutically
effective amount.
[0261] The effective amount of the compound may in one aspect be a
dose of between about 0.01 and about 100 mg/kg. Effective amounts
or doses of the compounds of the invention may be ascertained by
routine methods, such as modeling, dose escalation, or clinical
trials, taking into account routine factors, e.g., the mode or
route of administration or drug delivery, the pharmacokinetics of
the agent, the severity and course of the disease to be treated,
the subject's health status, condition, and weight. An exemplary
dose is in the range of about from about 0.7 mg to 7 g daily, or
about 7 mg to 350 mg daily, or about 350 mg to 1.75 g daily, or
about 1.75 to 7 g daily.
[0262] Any of the methods provided herein may in one aspect
comprise administering to an individual a pharmaceutical
composition that contains an effective amount of a compound
provided herein or a salt thereof and a pharmaceutically acceptable
excipient.
[0263] A compound or composition of the invention may be
administered to an individual in accordance with an effective
dosing regimen for a desired period of time or duration, such as at
least about one month, at least about 2 months, at least about 3
months, at least about 6 months, or at least about 12 months or
longer, which in some variations may be for the duration of the
individual's life. In one variation, the compound is administered
on a daily or intermittent schedule. The compound can be
administered to an individual continuously (for example, at least
once daily) over a period of time. The dosing frequency can also be
less than once daily, e.g., about a once weekly dosing. The dosing
frequency can be more than once daily, e.g., twice or three times
daily. The dosing frequency can also be intermittent, including a
`drug holiday` (e.g., once daily dosing for 7 days followed by no
doses for 7 days, repeated for any 14 day time period, such as
about 2 months, about 4 months, about 6 months or more). Any of the
dosing frequencies can employ any of the compounds described herein
together with any of the dosages described herein.
[0264] The compounds provided herein or a salt thereof may be
administered to an individual via various routes, including, e.g.,
intravenous, intramuscular, subcutaneous, oral and transdermal. A
compound provided herein can be administered frequently at low
doses, known as `metronomic therapy,` or as part of a maintenance
therapy using compound alone or in combination with one or more
additional drugs. Metronomic therapy or maintenance therapy can
comprise administration of a compound provided herein in cycles.
Metronomic therapy or maintenance therapy can comprise
intra-tumoral administration of a compound provided herein.
[0265] In one aspect, the invention provides a method of treating
cancer in an individual by parenterally administering to the
individual (e.g., a human) an effective amount of a compound or
salt thereof. In some embodiments, the route of administration is
intravenous, intra-arterial, intramuscular, or subcutaneous. In
some embodiments, the route of administration is oral. In still
other embodiments, the route of administration is transdermal.
[0266] The invention also provides compositions (including
pharmaceutical compositions) as described herein for the use in
treating, preventing, and/or delaying the onset and/or development
of cancer and other methods described herein. In certain
embodiments, the composition comprises a pharmaceutical formulation
which is present in a unit dosage form
[0267] Also provided are articles of manufacture comprising a
compound of the disclosure or a salt thereof, composition, and unit
dosages described herein in suitable packaging for use in the
methods described herein. Suitable packaging is known in the art
and includes, for example, vials, vessels, ampules, bottles, jars,
flexible packaging and the like. An article of manufacture may
further be sterilized and/or sealed.
Kits:
[0268] The present disclosure further provides kits for carrying
out the methods of the invention, which comprises one or more
compounds described herein or a composition comprising a compound
described herein. The kits may employ any of the compounds
disclosed herein. In one variation, the kit employs a compound
described herein or a pharmaceutically acceptable salt thereof. The
kits may be used for any one or more of the uses described herein,
and, accordingly, may contain instructions for the treatment of
cancer.
[0269] Kits generally comprise suitable packaging. The kits may
comprise one or more containers comprising any compound described
herein. Each component (if there is more than one component) can be
packaged in separate containers or some components can be combined
in one container where cross-reactivity and shelf-life permit.
[0270] The kits may be in unit dosage forms, bulk packages (e.g.,
multi-dose packages) or sub-unit doses. For example, kits may be
provided that contain sufficient dosages of a compound as disclosed
herein and/or a second pharmaceutically active compound useful for
a disease detailed herein to provide effective treatment of an
individual for an extended period, such as any of a week, 2 weeks,
3 weeks, 4 weeks, 6 weeks, 8 weeks, 3 months, 4 months, 5 months, 7
months, 8 months, 9 months, or more. Kits may also include multiple
unit doses of the compounds and instructions for use and be
packaged in quantities sufficient for storage and use in pharmacies
(e.g., hospital pharmacies and compounding pharmacies).
[0271] The kits may optionally include a set of instructions,
generally written instructions, although electronic storage media
(e.g., magnetic diskette or optical disk) containing instructions
are also acceptable, relating to the use of component(s) of the
methods of the present invention. The instructions included with
the kit generally include information as to the components and
their administration to an individual
[0272] The invention can be further understood by reference to the
following examples, which are provided by way of illustration and
are not meant to be limiting.
[0273] Although the invention has been described and illustrated
with a certain degree of particularity, it is understood that the
present disclosure has been made only by way of example, and that
numerous changes in the combination and arrangement of parts can be
resorted to by those skilled in the art without departing from the
spirit and scope of the invention, as defined by the claims.
[0274] The chemical reactions in the Examples described can be
readily adapted to prepare a number of other compounds disclosed
herein, and alternative methods for preparing the compounds of this
disclosure are deemed to be within the scope of this disclosure.
For example, the synthesis of non-exemplified compounds according
to the present disclosure can be successfully performed by
modifications apparent to those skilled in the art, e.g., by
appropriately protecting interfering groups, by utilizing other
suitable reagents known in the art other than those described, or
by making routine modifications of reaction conditions, reagents,
and starting materials. Alternatively, other reactions disclosed
herein or known in the art will be recognized as having
applicability for preparing other compounds of the present
disclosure.
UPLC-MS Standard Procedures
Method-1:
[0275] Instrument: Waters Acquity UPLC-MS SQD 3100; Column: Acquity
BEH Shield RP 18, 50.times.2.1 mm, 1.7 .mu.m; Eluent A: 0.05%
Trifluoroacetic acid in Water, Eluent B: Acetonitrile; Gradient:
10% B to 90% B in 4.5 min, hold for 3 min, 90% B to 10% B in 0.5
min (Run Time: 10.0 min); Flow rate: 0.35 mL/min; Temperature:
25.degree. C., PDA scan: 210 nm-400 nm.
EXAMPLES
Example-1: Synthesis of
(2-(1-(6,7-dimethoxyquinazolin-4-yl)azetidin-3-yl)ethyl)aminisulfonamide,
(Compound 1.1)
##STR00569##
[0277] Step-1: Synthesis of 4-chloro-6,7-dimethoxyquinazoline: A
mixture of 6,7-dimethoxyquinazolin-4 (3H)-one (1 g, 4.86 mol, 1 eq)
in POCl.sub.3 (2.5 mL) was allowed to stir at 120.degree. C. for 2
h. Progress of reaction was monitored by TLC. After completion
reaction mixture was cooled to RT, diluted with cold water (100 mL)
and allowed to stir for 5 minutes. Solid was filtered, washed with
water and dried under vacuum to afford
4-chloro-6,7-dimethoxyquinazoline (800 mg, 74%). LCMS: 225
[M+1].sup.+
[0278] Step-2: Synthesis of tert-butyl
2-(1-(6,7-dimethoxyquinazolin-4-yl)azetidin-3-yl) ethylcarbamate: A
suspension of 4-chloro-6,7-dimethoxyquinazoline (200 mg, 0.89 mmol,
1.0 eq), tert-butyl 2-(azetidin-3-yl)ethylcarbamate hydrochloride
(211 mg, 0.89 mmol, 1.0 eq) and triethylamine (0.25 mL, 1.78 mmol,
2.0 eq) in DMF (2.5 mL) was allowed to stir at 100.degree. C. for 1
h. Reaction mixture was cooled to RT, diluted with cold water (50
mL) and allowed to stir at RT for 10 minutes. Solid was filtered,
washed with water and dried under vacuum to afford tert-butyl
2-(1-(6,7-dimethoxyquinazolin-4-yl)azetidin-3-yl) ethylcarbamate
(240 mg, 69%). LCMS: 389 [M+1].sup.+
[0279] Step-3: Synthesis of
2-(1-(6,7-dimethoxyquinazolin-4-yl)azetidin-3-yl)ethanamine
2,2,2-trifluoroacetate: To a solution of tert-butyl
2-(1-(6,7-dimethoxyquinazolin-4-yl)azetidin-3-yl) ethylcarbamate
(240 mg, 0.61 mmol, 1 eq) in DCM (5 mL) was added TFA (5 mL) and
the mixture was allowed to stir at RT for 3 h. Progress of reaction
was monitored by TLC. After completion, reaction mixture was
concentrated under reduced pressure to get residue which was
triturated with diethylether (20 mL) to afford
2-(1-(6,7-dimethoxyquinazolin-4-yl)azetidin-3-yl)ethanamine
2,2,2-trifluoroacetate (200 mg, 81%). LCMS: 289 [M+1].sup.+
[0280] Step-4: Synthesis of tert-butyl
N-(2-(1-(6,7-dimethoxyquinazolin-4-yl)azetidin-3-yl)ethyl)sulfamoylcarbam-
ate: To a solution of
-(1-(6,7-dimethoxyquinazolin-4-yl)azetidin-3-yl)ethanamine
2,2,2-trifluoroacetate (200 mg, 0.49 mmol, 1 eq) in dichloromethane
(40 mL) were added
N-(tert-butoxycarbonyl)-N-[4-(dimethylazaniumylidene)-1,4-dihydropyridin--
1ylsulfonyl]azanide (149 mg. 0.49 mmol, 1 eq) and
N,N-diisopropylethylamine (0.17 mL, 0.99 mmol, 2 eq) and the
reaction mixture was allowed to stir at RT for 24 h. Progress of
reaction was monitored by LCMS. After completion, reaction mixture
was diluted with water (50 mL) and extracted with ethyl acetate
(3.times.100 mL). Combined organic layer was washed with brine (50
mL) and dried over anhydrous sodium sulfate. Removal of solvent
under reduced pressure afforded tert-butyl
N-(2-(1-(6,7-dimethoxyquinazolin-4-yl)azetidin-3-yl)ethyl)sulfamoylcarbam-
ate (200 mg, 86%) which was used in the next step without
purification. LCMS: 468[M+1].sup.+
[0281] Step-5: Synthesis of
(2-(1-(6,7-dimethoxyquinazolin-4-yl)azetidin-3-yl)ethyl)aminisulfonamide:
To a solution of tert-butyl
N-(2-(1-(6,7-dimethoxyquinazolin-4-yl)azetidin-3-yl)ethyl)sulfamoylcarbam-
ate (200 mg, 0.42 mmol, 1 eq) in DCM (5 mL) was added TFA (5 mL)
and the resulting mixture was allowed to stir at RT for 2 h.
Progress of reaction was monitored by TLC. After completion,
reaction mixture was concentrated under reduced pressure to afford
crude which was purified by reversed phase HPLC to afford
(2-(1-(6,7-dimethoxyquinazolin-4-yl)azetidin-3-yl)ethyl)aminisulfonamide
(50 mg, 32%). LCMS: 368 [M+1].sup.+; .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 8.31 (s, 1H), 7.19 (s, 1H), 7.10 (s, 1H),
6.56 (brs, 1H), 6.50 (s, 2H), 4.60-4.50 (m, 2H), 4.18-4.06 (m, 2H),
3.87 (s, 3H), 7.86 (s, 3H), 2.95-2.83 (m, 3H), 1.88-1.78 (m,
2H).
Example-2: Synthesis of
(2-(1-(6,7-dimethoxy-2-oxo-1,2-dihydroquinazolin-4-yl)azetidin-3-yl)ethyl-
)amiosulfonamide, (Compound 1.2)
##STR00570##
[0283] Step-1: Synthesis of 6,7-dimethoxyquinazoline-2,4
(1H,3H)-dione: A solid mixture of methyl
2-amino-4,5-dimethoxybenzoate (500 mg, 2.36 mmol, 1 eq) and urea
(300 mg) was fused at 180.degree. C. for 1 h. Progress of reaction
was monitored by TLC. After completion reaction mixture was cooled
to RT, diluted with cold water (100 mL) and allowed to stir for 5
minutes. Solid was filtered, washed with water and dried under
vacuum to afford 6,7-dimethoxyquinazoline-2,4 (1H,3H)-dione (360
mg, 68%). LCMS: 222[M+1].sup.+
[0284] Step-2: Synthesis of 2,4-dichloro-6,7-dimethoxyquinazoline:
A mixture of 6,7-dimethoxyquinazolin-4 (3H)-one (360 mg, 1.62 mmol,
1 eq) in POCl.sub.3 (0.5 mL) was allowed to stir at 120.degree. C.
for 12 h. Progress of reaction was monitored by TLC. After
completion, reaction mixture was cooled to RT, diluted with cold
water (100 mL) and allowed to stir for 5 minutes. Solid was
filtered, washed with water and dried under vacuum to afford
2,4-dichloro-6,7-dimethoxyquinazoline (300 mg, 72%). LCMS:
258[M+1].sup.+
[0285] Step-3: Synthesis of tert-butyl
2-(1-(2-chloro-6,7-dimethoxyquinazolin-4-yl)azetidin-3-yl)ethylcarbamate:
A suspension of to 2,4-dichloro-6,7-dimethoxyquinazoline (50 mg,
0.19 mmol, 1.0 eq), tert-butyl 2-(azetidin-3-yl)ethylcarbamate
hydrochloride (45.7 mg, 0.19 mmol, 1.0 eq) and N,N
diisopropylethylamine (50 mg, 0.38 mmol, 2.0 eq) in DMF (5 mL) was
allowed to stir at 80.degree. C. for 2 h. Progress of reaction was
monitored by TLC. Reaction mixture was cooled to RT, diluted with
cold water (10 mL) and extracted with ethyl acetate (3.times.20
mL). Combined organic layer was dried over anhydrous sodium
sulfate. Removal of solvent under reduced pressure gave crude which
was purified by Combi-Flash to afford tert-butyl
2-(1-(2-chloro-6,7-dimethoxyquinazolin-4-yl)azetidin-3-yl)ethylcarbamate
(38 mg, 47%). LCMS: 422 [M+1].sup.+
[0286] Step-4: Synthesis
2-(1-(2-chloro-6,7-dimethoxyquinazolin-4-yl)azetidin-3-yl)ethanamine
2,2,2-trifluoroacetate: To a solution of tert-butyl
2-(1-(2-chloro-6,7-dimethoxyquinazolin-4-yl)azetidin-3-yl)ethylcarbamate
(38 mg, 0.09 mmol, 1 eq) in DCM (5 mL) was added TFA (1 mL) and the
mixture was allowed to stir at RT for 2 h. Progress of reaction was
monitored by TLC. After completion, reaction mixture was
concentrated under reduced pressure to get residue which was
triturated with diethyl ether (5 mL) to afford
2-(1-(2-chloro-6,7-dimethoxyquinazolin-4-yl)azetidin-3-yl)ethanamine
2,2,2-trifluoroacetate (37 mg, 97%). LCMS: 322 [M+1].sup.+
[0287] Step-5: Synthesis of tert-butyl
N-(2-(1-(2-chloro-6,7-dimethoxyquinazolin-4-yl)azetidin-3-yl)ethyl)sulfam-
oylcarbamate: To a solution of
2-(1-(2-chloro-6,7-dimethoxyquinazolin-4-yl)azetidin-3-yl)ethanamine
2,2,2-trifluoroacetate (37 mg, 0.08 mmol, 1 eq) in dichloromethane
(5 mL) were added
N-(tert-butoxycarbonyl)-N-[4-(dimethylazaniumylidene)-1,4-dihydropyridin--
1ylsulfonyl]azanide (31.89 mg. 0.10 mmol, 1.2 eq) and
N,N-diisopropylethylamine (20.64 mg, 0.16 mmol, 2 eq) and the
reaction mixture was allowed to stir at RT for 24 h. Progress of
reaction was monitored by LCMS. After completion, reaction mixture
was diluted with water (50 mL) and extracted with ethyl acetate
(3.times.100 mL). Combined organic layer was washed with brine (50
mL) and dried over anhydrous sodium sulfate. Removal of solvent
under reduced pressure to obtain the crude which was purified by
Combi-Flash to afforded tert-butyl
N-(2-(1-(2-chloro-6,7-dimethoxyquinazolin-4-yl)azetidin-3-yl)ethyl)sulfam-
oylcarbamate (30 mg, 68%) LCMS: 501[M+1].sup.+
[0288] Step-6: Synthesis of
(2-(1-(6,7-dimethoxy-2-oxo-1,2-dihydroquinazolin-4-yl)azetidin-3-yl)ethyl-
)amiosulfonamide: To a solution of tert-butyl
N-(2-(1-(6,7-dimethoxyquinazolin-4-yl)azetidin-3-yl)ethyl)sulfamoylcarbam-
ate (30 mg, 0.05 mmol, 1 eq) in acetic acid (5 mL) was added water
(2 drops) and the resulting mixture was allowed to stir at
80.degree. C. for 2 h. Progress of reaction was monitored by LCMS.
After completion, reaction mixture was concentrated under reduced
pressure to afford crude which was purified by reversed phase HPLC
to afford
(2-(1-(6,7-dimethoxy-2-oxo-1,2-dihydroquinazolin-4-yl)azetidin-3-yl)ethyl-
)amiosulfonamide (50 mg, 32%). LCMS: 383 [M+1].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. ppm 10.45 (brs, 1H), 8.16 (brs,
1H), 7.52 (s, 1H), 6.76 (s, 2H), 6.67 (s, 1H), 3.80 (s, 6H),
3.70-3.60 (m, 3H), 3.4-3.1 (m, 2H), 2.98 (brs, 1H), 1.98 (brs, 2H),
1.65 (brs, 1H).
Example-3: Synthesis of
(2-(1-(6-methoxypyrido[3,4-d]pyrimidin-4-yl)azetidin-3-yl)ethyl)aminisulf-
onamide, (Compound 1.3)
##STR00571##
[0290] Step-1: Synthesis of 5-amino-2-methoxyisonicotinic acid: To
a solution of 5-(tert-butoxycarbonylamino)-2-methoxyisonicotinic
acid (2 g, 7.4 mmol, 1 eq) in DCM (15 mL) was added TFA (15 mL) and
the reaction mixture was allowed to stir at RT for 3 h. Progress of
reaction was monitored by TLC. After completion, reaction mixture
was concentrated under reduced pressure to get crude which was
triturated using diethyl ether to afford
5-amino-2-methoxyisonicotinic acid (1 g, 80%). LCMS:
169[M+1].sup.+
[0291] Step-2: Synthesis of 6-methoxypyrido[3,4-d]pyrimidin-4
(3H)-one: To a solution of 5-amino-2-methoxyisonicotinic acid (0.5
g, 2.9 mmol, 1 eq) in ethanol (5 mL) were added
triethylorthoformate (0.79 mL, 4.7 mmol, 1.6 eq) and ammonium
acetate (0.29 g, 3.7 mmol, 1.3 eq.) and the reaction mixture was
allowed to stir at 90.degree. C. for 16 h. After completion,
reaction mixture was filtered and washed with hexane to get
6-methoxypyrido[3,4-d]pyrimidin-4 (3H)-one as white solid (370 mg,
70%). LCMS: 178[M+1].sup.+
[0292] Step-3: Synthesis of
4-chloro-6-methoxypyrido[3,4-d]pyrimidine: To a solution of
6-methoxypyrido[3,4-d]pyrimidin-4 (3H)-one (0.28 g, 1.5 mmol, 1 eq)
in CHCl.sub.3 (10 mL) were added POCl.sub.3 (0.5 mL, 5.3 mmol, 3.5
eq) and triethylamine (0.8 mL, 5.6 mmol, 3.7 eq) and the reaction
mixture was allowed to stir at 80.degree. C. for 16 h. Progress of
reaction was monitored by TLC. After completion, reaction mixture
was cooled to RT, concentrated under reduced pressure to get
residue, to which saturated aq. NaHCO.sub.3 solution (50 mL) was
added and extracted with ethyl acetate (3.times.100 mL). Combined
organic layer was washed with brine (3.times.50 mL) and dried over
anhydrous sodium sulfate. Removal of solvent under reduced pressure
afforded crude which was purified using Combi-Flash to afford
4-chloro-6-methoxypyrido[3,4-d]pyrimidine (0.2 g, 65%). LCMS: 196
[M+1].sup.+
[0293] Step-4: Synthesis of tert-butyl
2-(1-(6-methoxypyrido[3,4-d]pyrimidin-4-yl)azetidin-3-yl)ethylcarbamate:
A suspension of -chloro-6-methoxypyrido[3,4-d]pyrimidine (40 mg,
0.20 mmol, 1 eq), tert-butyl 2-(azetidin-3-yl)ethylcarbamate
hydrochloride (50 mg, 0.20 mmol, 1.0 eq) and DIPEA (0.07 mL, 0.41
mmol, 2.0 eq) in DMF (2 mL) was allowed to stir at 80.degree. C.
for 2 h. Progress of reaction was monitored by TLC. After
completion, reaction mixture was diluted with cold water (50 mL)
and extracted with ethyl acetate (3.times.100 mL). Combined organic
layer was washed with brine (3.times.50 mL) and dried over
anhydrous sodium sulfate. Removal of solvent under reduced pressure
afforded tert-butyl
2-(1-(6-methoxypyrido[3,4-d]pyrimidin-4-yl)azetidin-3-yl)ethylcarbamate
(0.1 g) which was used in the next step without purification. LCMS:
360[M+1].sup.+
[0294] Step-5: Synthesis of
2-(1-(6-methoxypyrido[3,4-d]pyrimidin-4-yl)azetidin-3-yl)ethanamine
2,2,2-trifluoroacetate: To a solution of tert-butyl
2-(1-(6-methoxypyrido[3,4-d]pyrimidin-4-yl)azetidin-3-yl)ethylcarbamate
(200 mg, 0.05 mmol, 1 eq) in DCM (2 mL) was added TFA (2 mL) and
allowed to stir at RT for 2 h. Progress of reaction was monitored
by TLC. After completion, reaction mixture was concentrated under
reduced pressure to afford crude which was triturated with diethyl
ether to afford
2-(1-(6-methoxypyrido[3,4-d]pyrimidin-4-yl)azetidin-3-yl)ethanamine
2,2,2-trifluoroacetate (200 mg, 97%). LCMS: 260 [M+1].sup.+
[0295] Step-6: Synthesis of tert-butyl
N-(2-(1-(6-methoxypyrido[3,4-d]pyrimidin-4-yl)azetidin-3-yl)ethyl)sulfamo-
ylcarbamate: To a solution of
2-(1-(6-methoxypyrido[3,4-d]pyrimidin-4-yl)azetidin-3-yl)ethanamine
2,2,2-trifluoroacetate (200 mg, 0.53 mmol, 1 eq) in dichloromethane
(25 mL) were added
N-(tert-butoxycarbonyl)-N-[4-(dimethylazaniumylidene)-1,4-dihydropyridin--
1ylsulfonyl]azanide (161 mg. 0.53 mmol, 1 eq) and
N,N-diisopropylethylamine (0.18 mL, 0.6 mmol, 2 eq) and the
reaction mixture was allowed to stir at RT for 16 h. Progress of
reaction was monitored by LCMS. After completion, reaction mixture
was concentrated under reduced pressure to get residue which was
purified by reversed phase HPLC to afford tert-butyl
N-(2-(1-(6-methoxypyrido[3,4-d]pyrimidin-4-yl)azetidin-3-yl)ethyl)sulfamo-
ylcarbamate (60 mg, 26%). LCMS: 439[M+1].sup.+
[0296] Step-7: Synthesis of
(2-(1-(6-methoxypyrido[3,4-d]pyrimidin-4-yl)azetidin-3-yl)ethyl)aminisulf-
onamide: To a solution of tert-butyl
N-(2-(1-(6-methoxypyrido[3,4-d]pyrimidin-4-yl)azetidin-3-yl)ethyl)sulfamo-
ylcarbamate (30 mg, 0.06 mmol, 1 eq) in DCM (5 mL) was added TFA (1
mL) and allowed to stir at RT for 2 h. Progress of reaction was
monitored by TLC. After completion, reaction mixture was
concentrated under reduced pressure to afford crude which was
triturated with diethyl ether to afford desired product as TFA salt
which was basified with ammonia solution (0.2 mL, 7N in MeOH) and
lyophillized to afford
(2-(1-(6-methoxypyrido[3,4-d]pyrimidin-4-yl)azetidin-3-yl)ethyl)aminisulf-
onamide (19 mg, 82%). LCMS: 339 [M+1].sup.+; .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 8.84 (s, 1H), 8.43 (s, 1H), 7.09 (s, 1H),
6.98 (s, 1H), 6.59 (brs, 1H), 6.55 (s, 2H), 4.60-4.20 (brs, 4H),
3.97 (s, 3H), 2.98-2.82 (m, 3H), 1.90-1.78 (m, 2H).
Example-4: Synthesis of
(2-(1-(8-methoxyquinazolin-4-yl)azetidin-3-yl)ethyl)aminosulfonamide,
(Compound 1.4)
##STR00572##
[0298] Step-1: Synthesis of 8-methoxyquinazolin-4 (3H)-one: To a
solution of 2-amino-3-methoxybenzoic acid (1 g, 5.9 mmol, 1 eq) in
ethanol (10 mL) were added triethylorthoformate (2.58 mL, 15 mmol,
2.6 eq) and ammonium acetate (1.06 g, 13.7 mmol, 2.3 eq.) and the
reaction mixture was allowed to stir at 90.degree. C. for 32 h.
After completion, reaction mixture was filtered and washed with
hexane to get 8-methoxyquinazolin-4 (3H)-one as white solid (0.9 g,
86%) LCMS: 177 [M+1].sup.+
[0299] Step-2: Synthesis of 4-chloro-8-methoxyquinazoline: A
mixture of 8-methoxyquinazolin-4 (3H)-one (0.15 g, 0.85 mmol, 1 eq)
in POCl.sub.3 (1.63 mL) was allowed to stir at 120.degree. C. for 2
h. Progress of reaction was monitored by TLC. After completion,
reaction mixture was cooled to RT, diluted with cold water (100 mL)
and extracted with ethyl acetate (3.times.100 mL). Combined organic
layer was washed with brine (50 mL) and dried over anhydrous sodium
sulfate. Removal of solvent under reduced pressure afforded crude
4-chloro-8-methoxyquinazoline (0.1 g, 61%) which was used in the
next step without purification. LCMS: 195 [M+1].sup.+
[0300] Step-3: Synthesis of tert-butyl
2-(1-(8-methoxyquinazolin-4-yl)azetidin-3-yl)ethylcarbamate: A
suspension of 4-chloro-8-methoxyquinazoline (40 mg, 0.20 mmol, 1
eq), tert-butyl 2-(azetidin-3-yl)ethylcarbamate hydrochloride (50
mg, 0.20 mmol, 1.0 eq) and DIPEA (0.07 mL, 0.41 mmol, 2.0 eq) in
DMF (1 mL) was allowed to stir at 80.degree. C. for 2 h. Progress
of reaction was monitored by TLC. After completion, reaction
mixture was diluted with cold water (50 mL) and extracted with
ethyl acetate (3.times.100 mL). Combined organic layer was washed
with brine (3.times.50 mL) and dried over anhydrous sodium sulfate.
Removal of solvent under reduced pressure afforded tert-butyl
2-(1-(8-methoxyquinazolin-4-yl)azetidin-3-yl)ethylcarbamate (0.08
g) which was used in the next step without purification. LCMS: 359
[M+1].sup.+
[0301] Step-4: Synthesis of
2-(1-(8-methoxyquinazolin-4-yl)azetidin-3-yl)ethanamine
2,2,2-trifluoroacetate: To a solution of tert-butyl
2-(1-(8-methoxyquinazolin-4-yl)azetidin-3-yl)ethylcarbamate (80 mg,
0.22 mmol, 1 eq) in DCM (4 mL) was added TFA (4 mL) and the mixture
was allowed to stir at RT for 2 h. Progress of reaction was
monitored by TLC. After completion, reaction mixture was
concentrated under reduced pressure to get
2-(1-(8-methoxyquinazolin-4-yl)azetidin-3-yl)ethanamine
2,2,2-trifluoroacetate (0.1 g) which was used in the next step
without purification. LCMS: 259 [M+1].sup.+
[0302] Step-5: Synthesis of tert-butyl
N-(2-(1-(8-methoxyquinazolin-4-yl)azetidin-3-yl)ethyl)sulfamoylcarbamate:
To a solution of
2-(1-(8-methoxyquinazolin-4-yl)azetidin-3-yl)ethanamine
2,2,2-trifluoroacetate (100 mg, 0.26 mmol, 1 eq) in dichloromethane
(20 mL) were added
N-(tert-butoxycarbonyl)-N-[4-(dimethylazaniumylidene)-1,4-dihydropyridin--
1ylsulfonyl]azanide (161 mg. 0.53 mmol, 2 eq) and
N,N-diisopropylethylamine (0.18 mL, 1.07 mmol, 4 eq) and the
reaction mixture was allowed to stir at RT for 48 h. Progress of
reaction was monitored by LCMS. After completion, reaction mixture
was concentrated under reduced pressure to get residue which was
purified by reversed phase HPLC to afford tert-butyl
N-(2-(1-(8-methoxyquinazolin-4-yl)azetidin-3-yl)ethyl)sulfamoylcarbamate
(35 mg, 30%). LCMS: 438 [M+1].sup.+
[0303] Step-6: Synthesis of
(2-(1-(8-methoxyquinazolin-4-yl)azetidin-3-yl)ethyl)aminosulfonamide:
To a solution of tert-butyl
N-(2-(1-(8-methoxyquinazolin-4-yl)azetidin-3-yl)ethyl)sulfamoylcarbamate
(35 mg, 0.80 mmol, 1 eq) in DCM (3 mL) was added TFA (1.5 mL) and
allowed to stir at RT for 1 h. Progress of reaction was monitored
by TLC. After completion, reaction mixture was concentrated under
reduced pressure to afford crude which was triturated with diethyl
ether to afford
(2-(1-(8-methoxyquinazolin-4-yl)azetidin-3-yl)ethyl)aminosulfonamide
(10 mg, 38%) as TFA salt. LCMS: 338 [M+1].sup.+; .sup.1H NMR (400
MHz, DMSO-d.sub.6) (ppm 13.85 (brs, 1H), 8.62 (s, 1H), 7.70-7.58
(m, 3H), 6.60 (brs, 1H), 6.55 (s, 2H), 5.18-5.00 (m, 1H), 4.75-4.50
(m, 2H), 4.22-4.10 (m, 1H), 4.03 (s, 3H), 3.02-2.90 (m, 3H),
1.98-1.82 (m, 2H).
Example-5: Synthesis of
3-(1-(6,7-dimethoxyquinazolin-4-yl)azetidin-3-yl)propanoic acid,
(Compound 1.5)
##STR00573##
[0305] Step-1: Synthesis of (E)-tert-butyl
3-(3-ethoxy-3-oxoprop-1-enyl)azetidine-1-carboxylate: To a solution
of ethyl 2-(diethoxyphosphoryl)acetate (0.220 g, 1.188 mmol, 1 eq)
in THF (10 mL) was added sodium hydride (0.072 g, 1.782 mmol, 1.5
eq) at 0.degree. C. and the reaction mixture was allowed to stir at
0.degree. C. for 5 minutes, followed by addition of tert-butyl
3-formylazetidine-1-carboxylate (0.319 g, 1.426 mmol, 1.2 eq) and
then the reaction mixture was allowed to stir at 0.degree. C. for
30 minutes. After completion, reaction mixture was diluted with
water (50 mL) and extracted with ethyl acetate (3.times.50 mL).
Combined organic layer was washed with brine (50 mL) and dried over
anhydrous sodium sulfate. Removal of solvent under reduced pressure
afforded (E)-tert-butyl
3-(3-ethoxy-3-oxoprop-1-enyl)azetidine-1-carboxylate (0.3 g, 99%)
which was used in the next step without purification.
[0306] Step-2: Synthesis of tert-butyl
3-(3-ethoxy-3-oxopropyl)azetidine-1-carboxylate: To a solution of
(E)-tert-butyl 3-(3-ethoxy-3-oxoprop-1-enyl)azetidine-1-carboxylate
(0.3 g, 1.175 mmol, 1 eq) in ethanol (20 mL) was added Pd--C (0.1
g) and the reaction mixture was allowed to stir at RT under H.sub.2
atmosphere for 2 h. After completion, reaction mixture was filtered
through celite-bed and bed was washed with ethyl acetate (50 mL).
Removal of solvent under reduced pressure afforded tert-butyl
3-(3-ethoxy-3-oxopropyl)azetidine-1-carboxylate (0.3 g, 99%).
[0307] Step-3: Synthesis of ethyl 3-(azetidin-3-yl)propanoate: To a
solution of tert-butyl
3-(3-ethoxy-3-oxopropyl)azetidine-1-carboxylate (0.3 g, 1.17 mmol,
1 eq) in DCM (10 mL) was added trifluoroacetic acid (3 mL). The
reaction mixture was allowed to stir at RT for overnight. After
completion, removal of solvent under reduced pressure afforded
crude ethyl 3-(azetidin-3-yl)propanoate (0.350 g) which was used in
the next step without purification.
[0308] Step-4: Synthesis of ethyl
3-(1-(6,7-dimethoxyquinazolin-4-yl)azetidin-3-yl)propanoate: To a
solution of 4-chloro-6,7-dimethoxyquinazoline (0.120 g, 0.534 mmol,
1 eq) in DMF (2 mL) were added DIPEA (0.28 mL, 1.60 mmol, 3 eq) and
ethyl 3-(azetidin-3-yl)propanoate (0.100 g, 0.641 mmol, 1.2 eq) and
the mixture was allowed to stir at 80.degree. C. for 5 h. After
completion, reaction mixture was diluted with water (50 mL) and
extracted with ethyl acetate (3.times.80 mL). Combined organic
layer was washed with brine (2.times.50 mL) and dried over
anhydrous sodium sulfate. Removal of solvent under reduced pressure
afford crude which was purified by Combi-Flash on silica gel using
ethyl acetate-hexane system as eluent to afford ethyl
3-(1-(6,7-dimethoxyquinazolin-4-yl)azetidin-3-yl)propanoate (0.080
g, 43%).
[0309] Step-5: Synthesis of
3-(1-(6,7-dimethoxyquinazolin-4-yl)azetidin-3-yl)propanoic acid: To
a solution of
3-(1-(6,7-dimethoxyquinazolin-4-yl)azetidin-3-yl)propanoate (0.080
g, 0.232 mmol, 1 eq) in ethanol (10 mL) was added aq. NaOH (0.3 mL)
and the reaction mixture was allowed to stir at RT for 2 h.
Progress of reaction was monitored by TLC. After completion,
reaction mixture was concentrated under reduced pressure to get
residue which was purified by reversed phase HPLC to afford
3-(1-(6,7-dimethoxyquinazolin-4-yl)azetidin-3-yl)propanoic acid (02
mg, 3%). LCMS: 318[M+1].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. ppm 8.32 (s, 1H), 7.20 (m, 1H), 7.10 (s, 1H), 4.55 (brs,
2H), 4.07 (brs, 2H), 3.86 (s, 6H), 2.68 (brs, 1H), 2.05 (brs, 2H),
1.82 (brs, 2H).
Example-6: Synthesis of
N-{2-[1-(6,7-dimethoxyquinazolin-4-yl)azetidin-3-yl]ethyl}methanesulfonam-
ide, (Compound 1.6)
##STR00574##
[0311] To a solution of
2-(1-(6,7-dimethoxyquinazolin-4-yl)azetidin-3-yl)ethanamine
2,2,2-trifluoroacetate (87 mg, 0.22 mmol, 1 eq) in dichloromethane
(10 mL) were added methane sulphonyl chloride (27 mg. 0.24 mmol,
1.1 eq) and triethylamine (45 mg, 0.45 mmol, 2 eq) and the reaction
mixture was allowed to stir at RT for 2 h. Progress of reaction was
monitored by LCMS. After completion, reaction mixture was diluted
with water (20 mL) and extracted with ethyl acetate (3.times.25
mL). Combined organic layer was washed with brine (50 mL) and dried
over anhydrous sodium sulfate. Removal of solvent under reduced
pressure afforded crude which was purified by reversed phase HPLC
to afford
N-(2-(1-(6,7-dimethoxyquinazolin-4-yl)azetidin-3-yl)ethyl)methanesulfonam-
ide (9 mg, 11%). LCMS: 367 [M+1].sup.+; .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 8.46 (s, 1H), 7.22 (s, 1H), 7.19 (s, 1H),
7.06 (brs, 1H), 4.65 (brs, 2H), 4.25 (brs, 2H), 3.92 (s, 3H), 3.90
(s, 3H), 3.05-2.80 (m, 3H), 2.90 (s, 3H), 1.88-1.80 (m, 2H).
Example-7: Synthesis of
N-{2-[1-(6,7-dimethoxyquinazolin-4-yl)azetidin-3-yl]ethyl}acetamide,
(Compound 1.7)
##STR00575##
[0313] To a solution of
2-(1-(6,7-dimethoxyquinazolin-4-yl)azetidin-3-yl)ethanamine
2,2,2-trifluoroacetate (88 mg, 0.22 mmol, 1 eq) in dichloromethane
(10 mL) were added acetyl chloride (20 mg. 0.25 mmol, 1.1 eq) and
triethylamine (45 mg, 0.45 mmol, 2 eq) and the reaction mixture was
allowed to stir at RT for 2 h. Progress of reaction was monitored
by LCMS. After completion, reaction mixture was diluted with water
(20 mL) and extracted with ethyl acetate (3.times.25 mL). Combined
organic layer was washed with brine (50 mL) and dried over
anhydrous sodium sulfate. Removal of solvent under reduced pressure
afforded crude which was purified by reversed phase HPLC to afford
(N-{2-[1-(6,7-dimethoxyquinazolin-4-yl)azetidin-3-yl]ethyl}acetamide
(11 mg, 15%). LCMS: 331 [M+1].sup.+; .sup.1H NMR (400 MHz,
DMSO-d.sub.6) (ppm 8.31 (s, 1H), 7.83 (brs, 1H), 7.20 (s, 1H), 7.10
(s, 1H), 4.60-4.50 (m, 2H), 4.18-4.01 (m, 2H), 3.90 (s, 3H), 3.87
(s, 3H), 3.10-3.00 (m, 2H), 2.80-2.70 (m, 1H), 1.80-1.70 (m, 2H),
1.80 (s, 3H).
Example-8: Synthesis of
(2-(1-(7-methoxyquinazolin-4-yl)azetidin-3-yl)ethyl)aminisulfonamide,
(Compound 1.8)
##STR00576##
[0315] Step-1: Synthesis of 7-methoxyquinazolin-4 (3H)-one: To a
solution of 2-amino-4-methoxybenzoic acid (1 g, 5.9 mmol, 1 eq) in
ethanol (10 mL) were added triethylorthoformate (1.59 mL, 9.5 mmol,
1.6 eq) and ammonium acetate (0.59 g, 7.7 mmol, 1.3 eq.) and the
reaction mixture was allowed to stir at 90.degree. C. for 16 h.
Progress of reaction was monitored by LTC. After completion,
reaction mixture was cooled to RT, filtered, washed with hexane and
dried to afford 7-methoxyquinazolin-4 (3H)-one (700 mg, 67%). LCMS:
177 [M+1].sup.+
[0316] Step-2: Synthesis of 4-chloro-7-methoxyquinazoline: A
mixture of 7-methoxyquinazolin-4 (3H)-one (0.2 g, 1.1 mmol, 1 eq)
in POCl.sub.3 (2 mL) was allowed to stir at 120.degree. C. for 2 h.
Progress of reaction was monitored by TLC. After completion,
reaction mixture was cooled to RT, diluted with cold water (100 mL)
and extracted with ethyl acetate (3.times.100 mL). Combined organic
layer was washed with water (3.times.50 mL) followed by brine (50
mL) and dried over anhydrous sodium sulfate. Removal of solvent
under reduced pressure afforded 4-chloro-7-methoxyquinazoline (0.1
g, 45%) which was used in the next step without purification. LCMS:
195 [M+1].sup.+
[0317] Step-3: Synthesis of tert-butyl
2-(1-(7-methoxyquinazolin-4-yl)azetidin-3-yl)ethylcarbamate: A
suspension of 4-chloro-7-methoxyquinazoline (40 mg, 0.20 mmol, 1
eq), tert-butyl 2-(azetidin-3-yl)ethylcarbamate hydrochloride (50
mg, 0.20 mmol, 1.0 eq) and DIPEA (0.07 mL, 0.41 mmol, 2.0 eq) in
DMF (1 mL) was allowed to stir at 80.degree. C. for 2 h. Progress
of reaction was monitored by TLC. After completion, reaction
mixture was diluted with cold water (50 mL) and extracted with
ethyl acetate (3.times.100 mL). Combined organic layer was washed
with brine (3.times.50 mL) and dried over anhydrous sodium sulfate.
Removal of solvent under reduced pressure afforded tert-butyl
2-(1-(7-methoxyquinazolin-4-yl)azetidin-3-yl)ethylcarbamate (0.1 g)
crude which was used in the next step without purification. LCMS:
359 [M+1].sup.+
[0318] Step-4: Synthesis of
2-(1-(7-methoxyquinazolin-4-yl)azetidin-3-yl)ethanamine
2,2,2-trifluoroacetate: To a solution of tert-butyl
2-(1-(7-methoxyquinazolin-4-yl)azetidin-3-yl)ethylcarbamate (100
mg, 0.27 mmol, 1 eq) in DCM (5 mL) was added TFA (4 mL) and the
mixture was allowed to stir at RT for 1 h. Progress of reaction was
monitored by TLC. After completion, reaction mixture was
concentrated under reduced pressure to afford crude
2-(1-(7-methoxyquinazolin-4-yl)azetidin-3-yl)ethanamine
2,2,2-trifluoroacetate (200 mg) which was used in the next step
without purification. LCMS: 259 [M+1].sup.+
[0319] Step-5: Synthesis of tert-butyl
N-(2-(1-(7-methoxyquinazolin-4-yl)azetidin-3-yl)ethyl)sulfamoylcarbamate:
To a solution of
2-(1-(7-methoxyquinazolin-4-yl)azetidin-3-yl)ethanamine
2,2,2-trifluoroacetate (200 mg, 0.53 mmol, 1 eq) in dichloromethane
(50 mL) were added
N-(tert-butoxycarbonyl)-N-[4-(dimethylazaniumylidene)-1,4-dihydropyridin--
1ylsulfonyl]azanide (342 mg. 1.13 mmol, 2.1 eq) and
N,N-diisopropylethylamine (0.37 mL, 2.14 mmol, 4 eq) and the
reaction mixture was allowed to stir at RT for 48 h. Progress of
reaction was monitored by LCMS. After completion, reaction mixture
was concentrated under reduced pressure to get crude residue which
was purified by reversed phase HPLC to afford tert-butyl
N-(2-(1-(7-methoxyquinazolin-4-yl)azetidin-3-yl)ethyl)sulfamoylcarbamate
(16 mg, 7%). LCMS: 438 [M+1].sup.+
[0320] Step-6: Synthesis of
(2-(1-(7-methoxyquinazolin-4-yl)azetidin-3-yl)ethyl)aminisulfonamide:
To a solution of tert-butyl
N-(2-(1-(7-methoxyquinazolin-4-yl)azetidin-3-yl)ethyl)sulfamoylcarbamate
(16 mg, 0.036 mmol, 1 eq) in DCM (2 mL) was added TFA (1 mL) and
allowed to stir at RT for 2 h. Progress of reaction was monitored
by TLC. After completion, reaction mixture was concentrated under
reduced pressure to afford crude which was triturated with diethyl
ether to afford
(2-(1-(7-methoxyquinazolin-4-yl)azetidin-3-yl)ethyl)aminisulfonamide
(10 mg, 83%). LCMS: 338 [M+1].sup.+; .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 8.44 (s, 1H), 8.00 (d, 1H), 7.25 (d, 1H),
7.11 (s, 1H), 6.30 (brs, 1H), 6.31 (s, 2H), 4.75 (brs, 2H), 4.30
(brs, 2H), 3.94 (s, 3H), 3.00-3.82 (m, 3H), 1.90-1.80 (m, 2H).
Example-9: Synthesis of
(2-(1-(3-cyano-8-methoxyquinolin-4-yl)azetidin-3-yl)ethyl)aminisulfonamid-
e, (Compound 1.9)
##STR00577##
[0322] Step-1: Synthesis of 2-amino-3-methoxybenzoic acid: A
mixture of 2-amino-3-methoxybenzoic acid (2 g, 11.9 mmol, 1 eq) in
DMF-DMA (13.6 mL) was refluxed for 6 h. Reaction mixture was
concentrated under reduced pressure at 70.degree. C. to afford
crude product which was purified by trituration with hexane at
-78.degree. C. to afford (E)-methyl
2-((dimethylamino)methyleneamino)-3-methoxybenzoate (1.4 g, 50%).
LCMS: 237 [M+1].sup.+
[0323] Step-2: Synthesis of
8-methoxy-4-oxo-1,4-dihydroquinoline-3-carbonitrile: To a solution
of n-BuLi (2.5 M in hexane, 1.37 mL, 3.4 mmol, 2.71 eq) in THF (2
mL) at -78.degree. C. was added a solution of CH--CN (0.18 mL, 3.5
mmol, 2.77 eq) in THF (3.5 mL) drop wise over a time period of 10
minute and the resulting mixture was allowed to stir at the same
temperature for 15 minutes. To the reaction mixture was then added
a solution of (E)-methyl
2-((dimethylamino)methyleneamino)-3-methoxybenzoate (0.3 g, 1.2
mmol, 1 eq) in THF (2.5 mL) over a period of 30 minutes at
-78.degree. C., and then allowed to stir at the same temperature
for additional 30 minutes. Reaction mixture was treated with acetic
acid (0.43 mL) and warmed to room temperature. Solvent was
evaporated under reduced pressure; the residue was triturated with
cold water (20 mL), filtered and dried under vacuum to afford
8-methoxy-4-oxo-1,4-dihydroquinoline-3-carbonitrile (0.2 g, 79%) as
white solid. LCMS: 201 [M+1].sup.+
[0324] Step-3: Synthesis of
4-chloro-8-methoxyquinoline-3-carbonitrile: To stirred solution of
8-methoxy-4-oxo-1,4-dihydroquinoline-3-carbonitrile (0.1 g, 0.49
mmol, 1 eq) in POCl.sub.3 (1 mL) was added DMF (5 drops) and the
mixture was allowed to stir at 120.degree. C. for 1 h. Progress of
reaction was monitored by TLC. After completion, reaction mixture
was cooled to RT, diluted with cold water (100 mL) and triturated.
Precipitate was filtered and dried under vacuum to afford
4-chloro-8-methoxyquinoline-3-carbonitrile (30 mg, 28%) as white
solid. LCMS: 219 [M+1].sup.+
[0325] Step-4: Synthesis of tert-butyl
2-(1-(3-cyano-8-methoxyquinolin-4-yl)azetidin-3-yl)ethylcarbamate:
A suspension of 4-chloro-8-methoxyquinoline-3-carbonitrile (30 mg,
0.13 mmol, 1 eq), tert-butyl 2-(azetidin-3-yl)ethylcarbamate
hydrochloride (35 mg, 0.13 mmol, 1.0 eq) and DIPEA (0.05 mL, 0.27
mmol, 2.0 eq) in DMF (1 mL) was allowed to stir at 80.degree. C.
for 2 h. Progress of reaction was monitored by TLC. After
completion, reaction mixture was diluted with cold water (50 mL)
and extracted with ethyl acetate (3.times.100 mL). Combined organic
layer was washed with brine (3.times.50 mL) and dried over
anhydrous sodium sulfate. Removal of solvent under reduced pressure
afforded tert-butyl
2-(1-(3-cyano-8-methoxyquinolin-4-yl)azetidin-3-yl)ethylcarbamate
(0.08 g) which was used in the next step without purification.
LCMS: 383 [M+1].sup.+
[0326] Step-5: Synthesis of
4-(3-(2-aminoethyl)azetidin-1-yl)-8-methoxyquinoline-3-carbonitrile
2,2,2-trifluoroacetate: To a solution of tert-butyl
2-(1-(3-cyano-8-methoxyquinolin-4-yl)azetidin-3-yl)ethylcarbamate
(80 mg, 0.2 mmol, 1 eq) in DCM (4 mL) was added TFA (3 mL) and the
mixture was allowed to stir at RT for 1 h. Progress of reaction was
monitored by TLC. After completion, reaction mixture was
concentrated under reduced pressure to afford
4-(3-(2-aminoethyl)azetidin-1-yl)-8-methoxyquinoline-3-carbonitrile
2,2,2-trifluoroacetate (0.15 g) which was used in the next step
without purification. LCMS: 283 [M+1].sup.+
[0327] Step-6: Synthesis of tert-butyl
N-(2-(1-(3-cyano-8-methoxyquinolin-4-yl)azetidin-3-yl)ethyl)sulfamoylcarb-
amate: To a solution of
4-(3-(2-aminoethyl)azetidin-1-yl)-8-methoxyquinoline-3-carbonitrile
2,2,2-trifluoroacetate (150 mg, 0.37 mmol, 1 eq) in dichloromethane
(25 mL) were added
N-(tert-butoxycarbonyl)-N-[4-(dimethylazaniumylidene)-1,4-dihydropyridin--
1ylsulfonyl]azanide (171 mg. 0.55 mmol, 1.5 eq) and
N,N-diisopropylethylamine (0.28 mL, 1.48 mmol, 4 eq) and the
reaction mixture was allowed to stir at RT for 48 h. Progress of
reaction was monitored by LCMS. After completion, reaction mixture
was concentrated under reduced pressure to get residue which was
purified by reversed phase HPLC to afford tert-butyl
N-(2-(1-(3-cyano-8-methoxyquinolin-4-yl)azetidin-3-yl)ethyl)sulfamoylcarb-
amate (30 mg, 17%). LCMS: 462 [M+1].sup.+
[0328] Step-7: Synthesis of
(2-(1-(3-cyano-8-methoxyquinolin-4-yl)azetidin-3-yl)ethyl)aminisulfonamid-
e: To a solution of tert-butyl
N-(2-(1-(3-cyano-8-methoxyquinolin-4-yl)azetidin-3-yl)ethyl)sulfamoylcarb-
amate (30 mg, 0.06 mmol, 1 eq) in DCM (2 mL) was added TFA (0.5 mL)
and allowed to stir at RT for 1 h. Progress of reaction was
monitored by TLC. After completion, reaction mixture was
concentrated under reduced pressure to afford crude which was
triturated using diethyl ether to afford desired compound as TFA
salt which was basified using 7 N NH.sub.3 in methanol to afford
(2-(1-(3-cyano-8-methoxyquinolin-4-yl)azetidin-3-yl)ethyl)aminisulfonamid-
e (27 mg). LCMS: 362 [M+1].sup.+; .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 8.39 (s, 1H), 7.71 (d, 1H), 7.39 (t, 1H),
7.24 (d, 1H), 6.58-6.47 (m, 3H), 4.90-4.80 (m, 2H), 4.46-4.38 (m,
2H), 3.88 (s, 3H), 2.90-2.88 (m, 3H), 1.88-1.78 (m, 2H).
Example-10: Synthesis of
N-((1-(6,7-dimethoxyquinazolin-4-yl)azetidin-3-yl)methyl)
aminisulfonamide, (Compound 1.10)
##STR00578##
[0330] Step-1: Synthesis of tert-butyl
(1-(6,7-dimethoxyquinazolin-4-yl)azetidin-3-yl)methylcarbamate: A
suspension of 4-chloro-6,7-dimethoxyquinazoline (50 mg, 0.22 mmol,
1.0 eq), tert-butyl azetidin-3-ylmethylcarbamate hydrochloride (50
mg, 0.22 mmol, 1.0 eq) and N, N-Diisopropylethylamine (57 mg, 0.44
mmol, 2.0 eq) in DMF (1 mL) was allowed to stir at 80.degree. C.
for 2 h. Progress of reaction was monitored by TLC. After
completion, reaction mixture was diluted with water (10 mL) and
extracted with ethyl acetate (3.times.25 mL). Combined organic
layer was washed with water (5.times.50 mL) followed by brine (50
mL) and dried over anhydrous sodium sulfate. Removal of solvent
under reduced pressure afforded tert-butyl
(1-(6,7-dimethoxyquinazolin-4-yl)azetidin-3-yl)methylcarbamate
which was used in the next step without purification (83 mg, 100%).
LCMS: 374 [M+1].sup.+
[0331] Step-2: Synthesis of
(1-(6,7-dimethoxyquinazolin-4-yl)azetidin-3-yl)methanamine
2,2,2-trifluoroacetate: To a solution of tert-butyl
(1-(6,7-dimethoxyquinazolin-4-yl)azetidin-3-yl)methylcarbamate (83
mg, 0.22 mmol, 1 eq) in DCM (5 mL) was added TFA (1 mL) and the
mixture was allowed to stir at RT for 2 h. Progress of reaction was
monitored by TLC. After completion, reaction mixture was
concentrated under reduced pressure to get crude which was
triturated with diethyl ether (10 mL) to afford
(1-(6,7-dimethoxyquinazolin-4-yl)azetidin-3-yl)methanamine
2,2,2-trifluoroacetate (80 mg, 93%). LCMS: 274[M+1].sup.+
[0332] Step-3: Synthesis of tert-butyl
N-((1-(6,7-dimethoxyquinazolin-4-yl)azetidin-3-yl)methyl)sulfamoylcarbama-
te: To a solution of
1-(6,7-dimethoxyquinazolin-4-yl)azetidin-3-yl)methanamine
2,2,2-trifluoroacetate (80 mg, 0.20 mmol, 1 eq) in dichloromethane
(5 mL) were added
N-(tert-butoxycarbonyl)-N-[4-(dimethylazaniumylidene)-1,4-dihydropyridin--
1ylsulfonyl]azanide (93 mg. 0.30 mmol, 1.5 eq) and
N,N-diisopropylethylamine (51.6 mg, 0.40 mmol, 2 eq) and the
reaction mixture was allowed to stir at RT for 24 h. Progress of
reaction was monitored by LCMS. After completion, solvent was
removed under reduced pressure to afford crude which was purified
by reversed phase HPLC to tert-butyl
N-((1-(6,7-dimethoxyquinazolin-4-yl)azetidin-3-yl)methyl)sulfamoylcarbama-
te (18 mg, 20%). LCMS: 454[M+1].sup.+
[0333] Step-4: Synthesis of
N-((1-(6,7-dimethoxyquinazolin-4-yl)azetidin-3-yl)methyl)
aminisulfonamide: To a solution of tert-butyl
N-((1-(6,7-dimethoxyquinazolin-4-yl)azetidin-3-yl)methyl)sulfamoylcarbama-
te (9 mg, 0.02 mmol, 1 eq) in DCM (3 mL) was added TFA (0.5 mL) and
the resulting mixture was allowed to stir at RT for 2 h. Progress
of reaction was monitored by TLC. After completion, reaction
mixture was concentrated under reduced pressure to afford crude
which was purified by trituration with ether and pentane to afford
(1-(6,7-dimethoxyquinazolin-4-yl)azetidin-3-yl)methylaminosulfonamide
(50 mg, 71%). LCMS: 354 [M+1].sup.+; .sup.1H NMR (400 MHz,
DMSO-d.sub.6) (ppm 14.00 (brs, 1H), 8.61 (s, 1H), 7.28 (s, 1H),
7.16 (s, 1H), 6.85 (brs, 1H), 6.62 (brs, 2H), 5.00-4.20 (m, 4H),
3.96 (s, 3H), 3.94 (s, 3H), 3.30-3.18 (m, 2H), 3.10-2.98 (m,
1H).
Example-11: Synthesis of
(2-(1-(6,7-dimethoxyquinolin-4-yl)azetidin-3-yl)ethyl)aminosulfonamide,
(Compound 1.11)
##STR00579##
[0335] Step-1: Synthesis of 4-chloro-6,7-dimethoxyquinoline: A
mixture of 6,7-dimethoxyquinolin-4 (1H)-one (1 g, 4.87 mmol, 1 eq)
in POCl.sub.3 (2 mL) was allowed to stir at 120.degree. C. for 12
h. Progress of reaction was monitored by TLC. After completion,
reaction mixture poured on crushed ice and extracted with ethyl
acetate (3.times.50 mL). Combined organic layer was washed with
brine (20 mL) and dried over anhydrous sodium sulfate. Solvent was
removed under reduced pressure to afford
4-chloro-6,7-dimethoxyquinoline (500 mg, 46%). LCMS: 224
[M+1].sup.+
[0336] Step-2: Synthesis of tert-butyl
2-(1-(6,7-dimethoxyquinolin-4-yl)azetidin-3-yl)ethylcarbamate: A
suspension of 4-chloro-6,7-dimethoxyquinoline (50 mg, 0.22 mmol,
1.0 eq), tert-butyl 2-(azetidin-3-yl)ethylcarbamate hydrochloride
(53 mg, 0.22 mmol, 1.0 eq) and N,N-diisopropylethylamine (56 mg,
0.44 mmol, 2.0 eq) in ethanol (1 mL) was allowed to stir at
70.degree. C. for 48 h. Progress of reaction was monitored by TLC
After completion, reaction mixture was removed under reduced
pressure to afford tert-butyl
2-(1-(6,7-dimethoxyquinolin-4-yl)azetidin-3-yl)ethylcarbamate which
is carried further without purification (50 mg, 58%). LCMS: 387
[M+1].sup.+
[0337] Step-3: Synthesis of
2-(1-(6,7-dimethoxyquinolin-4-yl)azetidin-3-yl)ethanamine
2,2,2-trifluoroacetate: To a solution of tert-butyl
2-(1-(6,7-dimethoxyquinolin-4-yl)azetidin-3-yl)ethylcarbamate (50
mg, 0.13 mmol, 1 eq) in DCM (2.5 mL) was added TFA (1 mL) and the
mixture was allowed to stir at RT for 2 h. Progress of reaction was
monitored by TLC. After completion, reaction mixture was
concentrated under reduced pressure to get residue which was
triturated with diethyl ether (10 mL) to afford
2-(1-(6,7-dimethoxyquinolin-4-yl)azetidin-3-yl)ethanamine
2,2,2-trifluoroacetate (50 mg, 96%). LCMS: 287[M+1].sup.+
[0338] Step-4: Synthesis of tert-butyl
N-(2-(1-(6,7-dimethoxyquinolin-4-yl)azetidin-3-yl)ethyl)sulfamoylcarbamat-
e: To a solution of
2-(1-(6,7-dimethoxyquinolin-4-yl)azetidin-3-yl)ethanamine
2,2,2-trifluoroacetate (50 mg, 0.12 mmol, 1 eq) in dichloromethane
(5 mL) were added
N-(tert-butoxycarbonyl)-N-[4-(dimethylazaniumylidene)-1,4-dihydropyridin--
1ylsulfonyl]azanide (37 mg. 0.12 mmol, 1.5 eq) and
N,N-diisopropylethylamine (31 mg, 0.24 mmol, 2 eq) and the reaction
mixture was allowed to stir at RT for 24 h. Progress of reaction
was monitored by LCMS. After completion, solvent was removed under
reduced pressure to afford crude which was purified by reversed
phase HPLC to afford tert-butyl
N-(2-(1-(6,7-dimethoxyquinolin-4-yl)azetidin-3-yl)ethyl)sulfamoylcarbamat-
e (18 mg, 32%). LCMS: 467[M+1].sup.+
[0339] Step-5: Synthesis of
(2-(1-(6,7-dimethoxyquinolin-4-yl)azetidin-3-yl)ethyl)aminosulfonamide:
To a solution of tert-butyl
N-(2-(1-(6,7-dimethoxyquinolin-4-yl)azetidin-3-yl)ethyl)sulfamoylcarbamat-
e (17 mg, 0.036 mmol, 1 eq) in DCM (3 mL) was added TFA (0.5 mL)
and the resulting mixture was allowed to stir at RT for 2 h.
Progress of reaction was monitored by TLC. After completion,
reaction mixture was concentrated under reduced pressure to afford
crude which was purified by reversed phase HPLC to afford
(2-(1-(6,7-dimethoxyquinolin-4-yl)azetidin-3-yl)ethyl)aminosulfonamide
as TFA salt (10 mg, 56%). LCMS: 367 [M+1].sup.+; .sup.1H NMR (400
MHz, DMSO-d.sub.6) (ppm 13.28 (brs, 1H), 8.27 (d, 1H), 7.39 (s,
1H), 7.25 (s, 1H), 6.60 (brs, 1H), 6.55 (s, 2H), 6.31 (d, 1H), 5.17
(brs, 1H), 4.74 (brs, 1H), 4.45 (brs, 1H), 4.02 (brs, 1H), 3.95 (s,
6H), 3.03-2.90 (m, 3H), 1.90-1.81 (m, 2H).
Example-12: Synthesis of
(2-(1-(3-cyano-6,7-dimethoxyquinolin-4-yl)azetidin-3-yl)ethyl)aminisulfon-
amide, (Compound 1.12)
##STR00580##
[0341] Step-1: Synthesis of (Z)-methyl
2-((dimethylamino)methyleneamino)-4,5-dimethoxybenzoate: A mixture
of 2-amino-4,5-dimethoxybenzoic acid (2 g, 100 mmol, 1 eq) in
DMF-DMA (12 mL) was allowed to stir at 120.degree. C. for 6 h.
Progress of reaction was monitored by TLC. After completion,
reaction mixture was cooled to RT, concentrated under reduced
pressure at 70.degree. C. to get crude residue which was purified
by trituration with pentane to afford (Z)-methyl
2-((dimethylamino)methyleneamino)-4,5-dimethoxybenzoate (1.8 g,
68%).
[0342] Step-2: Synthesis of
3-(2-amino-4,5-dimethoxyphenyl)-3-oxopropanenitrile: To a solution
of 2.5 M n-BuLi in THF (1.7 mL, 4.25 mmol, 2.2 eq) in THF (10 mL)
at -78.degree. C. was added a solution of MeCN (0.25 mL, 4.25 mmol,
2.2 eq) in THF (5 mL) drop wise and the resulting mixture was
allowed to stir at the same temperature for 10 minutes. To the
mixture was then added a solution of (Z)-methyl
2-((dimethylamino)methyleneamino)-4,5-dimethoxybenzoate (500 mg,
1.9 mmol, 1 eq) in THF (10 mL) and the mixture was allowed to stir
at -78.degree. C. for 2.5 h. To the reaction mixture was added
acetic acid (0.6 mL), the reaction mixture was gradually warmed to
RT and allowed to stir overnight. Reaction mixture was filtered,
solid was dried to get crude which was purified by Combi-Flash on
silica gel using ethyl acetate-hexane system as eluent to afford
3-(2-amino-4,5-dimethoxyphenyl)-3-oxopropanenitrile (200 mg,
48%).
[0343] Step-3: Synthesis of
6,7-dimethoxy-4-oxo-1,4-dihydroquinoline-3-carbonitrile: To a
solution of 3-(2-amino-4,5-dimethoxyphenyl)-3-oxopropanenitrile
(200 mg, 0.90 mmol, 1 eq) in dioxane (5 mL) was added DMF-DMA (0.25
mL, 1.8 mmol, 2 eq) and the resulting mixture was allowed to stir
at 100.degree. C. for 4 h. Progress of reaction was monitored by
TLC. After completion, reaction mixture was cooled to RT and
concentrated under reduced pressure at 70.degree. C. to afford
crude which was purified by trituration with diethyl ether to
afford 6,7-dimethoxy-4-oxo-1,4-dihydroquinoline-3-carbonitrile (100
mg, 48%). LCMS: 231[M+1].sup.+
[0344] Step-4: Synthesis of
4-chloro-6,7-dimethoxyquinoline-3-carbonitrile: A mixture of
6,7-dimethoxy-4-oxo-1,4-dihydroquinoline-3-carbonitrile (100 mg
0.43 mmol, 1 eq) in POCl.sub.3 (0.5 mL) was allowed to stir at
120.degree. C. for 12 h. Progress of reaction was monitored by TLC.
After completion, reaction mixture was diluted with ice-cold water
(100 mL) and extracted with ethyl acetate (3.times.20 mL). Combined
organic layer was washed with water (3.times.50 mL) followed by
brine (20 mL) and dried over anhydrous sodium sulfate. Solvent was
removed under reduced pressure afforded
4-chloro-6,7-dimethoxyquinoline-3-carbonitrile (80 mg, 74.76%).
LCMS: 248 [M+1].sup.+
[0345] Step-5: Synthesis of tert-butyl
2-(1-(3-cyano-6,7-dimethoxyquinolin-4-yl)azetidin-3-yl)ethylcarbamate:
A suspension of 4-chloro-6,7-dimethoxyquinoline-3-carbonitrile (50
mg, 0.20 mmol, 1.0 eq), tert-butyl 2-(azetidin-3-yl)ethylcarbamate
hydrochloride (47.5 mg, 0.20 mmol, 1.0 eq) and
N,N-diisopropylethylamine (51.6 mg, 0.40 mmol, 2.0 eq) in DMF (1
mL) was allowed to stir at 80.degree. C. for 2 h. Progress of
reaction was monitored by TLC. After completion, reaction mixture
was diluted with water (10 mL) and extracted with ethyl acetate
(3.times.25 mL). Combined organic layer was washed with brine (50
mL) and dried over anhydrous sodium sulfate. Removal of solvent
under reduced pressure gave tert-butyl
2-(1-(3-cyano-6,7-dimethoxyquinolin-4-yl)azetidin-3-yl)ethylcarbamate
(80 mg, 100%). LCMS: 374 [M+1].sup.+
[0346] Step-6: Synthesis of
4-(3-(2-aminoethyl)azetidin-1-yl)-6,7-dimethoxyquinoline-3-carbonitrile
2,2,2-trifluoroacetate: To a solution of tert-butyl
2-(1-(3-cyano-6,7-dimethoxyquinolin-4-yl)azetidin-3-yl)ethylcarbamate
(80 mg, 0.19 mmol, 1 eq) in DCM (5 mL) was added TFA (2 mL) and the
mixture was allowed to stir at RT for 2 h. Progress of reaction was
monitored by TLC. After completion, reaction mixture was
concentrated under reduced pressure to get crude, which was
triturated with diethyl ether (10 mL) to afford
4-(3-(2-aminoethyl)azetidin-1-yl)-6,7-dimethoxyquinoline-3-carboni-
trile 2,2,2-trifluoroacetate (80 mg, 97%). LCMS: 312[M+1].sup.+
[0347] Step-7: Synthesis of tert-butyl
N-(2-(1-(3-cyano-6,7-dimethoxyquinolin-4-yl)azetidin-3-yl)ethyl)sulfamoyl-
carbamate: To a solution of
4-(3-(2-aminoethyl)azetidin-1-yl)-6,7-dimethoxyquinoline-3-carbonitrile
2,2,2-trifluoroacetate (80 mg, 0.18 mmol, 1 eq) in dichloromethane
(5 mL) were added
N-(tert-butoxycarbonyl)-N-[4-(dimethylazaniumylidene)-1,4-dihydropyridin--
1ylsulfonyl]azanide (84 mg. 0.30 mmol, 1.5 eq) and
N,N-diisopropylethylamine (46 mg, 0.36 mmol, 2 eq) and the reaction
mixture was allowed to stir at RT for 24 h. Progress of reaction
was monitored by LCMS. After completion, solvent was removed under
reduced pressure to afford crude which was purified by reversed
phase HPLC to tert-butyl
N-(2-(1-(3-cyano-6,7-dimethoxyquinolin-4-yl)azetidin-3-yl)ethyl)sulfamoyl-
carbamate (10 mg, 10%). LCMS: 492[M+1].sup.+
[0348] Step-8: Synthesis of
(2-(1-(3-cyano-6,7-dimethoxyquinolin-4-yl)azetidin-3-yl)ethyl)aminisulfon-
amide: To a solution of tert-butyl
N-(2-(1-(3-cyano-6,7-dimethoxyquinolin-4-yl)azetidin-3-yl)ethyl)sulfamoyl-
carbamate (9 mg, 0.018 mmol, 1 eq) in DCM (3 mL) was added TFA (0.5
mL) and the resulting mixture was allowed to stir at RT for 2 h.
Progress of reaction was monitored by TLC. After completion,
reaction mixture was concentrated under reduced pressure to afford
crude which was triturated with diethyl ether to afford
(2-(1-(3-cyano-6,7-dimethoxyquinolin-4-yl)azetidin-3-yl)ethyl)aminisulfon-
amide (5 mg, 55%). LCMS: 392 [M+1].sup.+; .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 8.80 (s, 1H), 7.42 (s, 1H), 7.17 (s, 1H),
6.60 (brs, 1H), 6.55 (s, 2H), 5.20-5.02 (m, 2H), 4.78-4.42 (m, 2H),
3.99 (s, 3H), 3.98 (s, 3H), 3.00-2.83 (m, 3H), 1.96-1.83 (m,
2H).
Example-13: Synthesis of
4-(3-(2-sulfamoylaminoethyl)azetidine-1-yl)-7-methoxyquinoline-3-carbonit-
rile, (Compound 1.13)
##STR00581##
[0350] Step-1: Synthesis of (E)-methyl
2-((dimethylamino)methyleneamino)-4-methoxybenzoate: A mixture of
(E)-methyl 2-((dimethylamino)methyleneamino)-4-methoxybenzoate (2
g, 11.9 mmol, 1 eq) in DMF-DMA (13.6 mL) was refluxed for 6 h.
Progress of reaction was monitored by TLC. After completion,
reaction mixture was concentrated under reduced pressure at
70.degree. C. to afford oily crude which was purified by
trituration with hexane at -78.degree. C. to afford (E)-methyl
2-((dimethylamino)methyleneamino)-4-methoxybenzoate (1.4 g, 50%).
LCMS: 237 [M+1].sup.+
[0351] Step-2: Synthesis of
7-methoxy-4-oxo-1,4-dihydroquinoline-3-carbonitrile: To a solution
of a solution t-BuLi (2.5 M in hexane, 1.37 mL, 3.4 mmol, 2.71 eq)
in THF (2 mL) at -78.degree. C. was added a solution of CH.sub.3CN
(0.18 ml, 3.5 mmol, 2.77 eq) in THF (3.5 mL) drop wise over a
period of 10 minutes. The white suspension formed was then stirred
for 15 minutes. To the suspension w % as added a solution of
(E)-methyl 2-((dimethylamino)methyleneamino)-4-methoxybenzoate (0.3
g, 1.2 mmol, 1 eq) of THF (2.5 mL) over a period of 30 minutes. The
resulting mixture was then allowed to stir at -78.degree. C. for
additional 30 minutes. During this period, the mixture gradually
became clear. To the mixture was then added acetic acid (0.43 mL)
and the thick slurry formed was stirred and warmed to room
temperature Reaction mixture was concentrated under vacuum and
residue was diluted with cold water (50 mL). Solid was collected by
filtration, washed with water and dried under vacuum to afford
7-methoxy-4-oxo-1,4-dihydroquinoline-3-carbonitrile (0.08 g, 31%)
as white solid. LCMS: 201 [M+1].sup.+
[0352] Step-3: Synthesis of
4-chloro-7-methoxyquinoline-3-carbonitrile: To a solution of
7-methoxy-4-oxo-1,4-dihydroquinoline-3-carbonitrile (0.1 g, 0.49
mmol, 1 eq) in POCl.sub.3 (1 mL) was added DMF (5 drops) and the
mixture was allowed to stir at 120.degree. C. for 2 h. Progress of
reaction was monitored by TLC. After completion, reaction mixture
was cooled to RT, diluted with cold water (100 mL) and filtered.
Solid was dried under vacuum to afford
4-chloro-7-methoxyquinoline-3-carbonitrile (60 mg, 60%) as white
solid. LCMS: 219 [M+1].sup.+
[0353] Step-4: Synthesis of tert-butyl
2-(1-(3-cyano-7-methoxyquinolin-4-yl)azetidin-3-yl)ethylcarbamate:
A mixture of 4-chloro-7-methoxyquinoline-3-carbonitrile (46 mg,
0.21 mmol, 1 eq), tert-butyl 2-(azetidin-3-yl)ethylcarbamate
hydrochloride (50 mg, 0.21 mmol, 1.0 eq) and DIPEA (0.07 mL, 0.42
mmol, 2.0 eq) in DMF (2 mL) was allowed to stir at 80.degree. C.
for 2 h. Progress of reaction was monitored by TLC. After
completion, reaction mixture was diluted with cold water (50 mL)
and extracted with ethyl acetate (3.times.100 mL). Combined organic
layer was washed with brine (3.times.50 mL) and dried over
anhydrous sodium sulfate. Removal of solvent under reduced pressure
afforded tert-butyl
2-(1-(3-cyano-7-methoxyquinolin-4-yl)azetidin-3-yl)ethylcarbamate
(0.12 g, crude) which was used in the next step without
purification. LCMS: 383 [M+1].sup.+
[0354] Step-5: Synthesis
4-(3-(2-aminoethyl)azetidin-1-yl)-7-methoxyquinoline-3-carbonitrile
2,2,2-trifluoroacetate: To a solution of tert-butyl
2-(1-(3-cyano-7-methoxyquinolin-4-yl)azetidin-3-yl)ethylcarbamate
(120 mg, 0.3 mmol, 1 eq) in DCM (4 mL) was added TFA (3 mL) and the
resulting mixture was allowed to stir at RT for 1 h. Progress of
reaction was monitored by TLC. After completion, reaction mixture
was concentrated under reduced pressure to get
4-(3-(2-aminoethyl)azetidin-1-yl)-7-methoxyquinoline-3-carbonitrile
2,2,2-trifluoroacetate (0.15 g) which was used in the next step
without purification. LCMS: 283 [M+1].sup.+
[0355] Step-6: Synthesis of tert-butyl
N-(2-(1-(3-cyano-7-methoxyquinolin-4-yl)azetidin-3-yl)ethyl)sulfamoylcarb-
amate: To a solution of
4-(3-(2-aminoethyl)azetidin-1-yl)-7-methoxyquinoline-3-carbonitrile
2,2,2-trifluoroacetate (150 mg, 0.37 mmol, 1 eq) in dichloromethane
(25 mL) were added
N-(tert-butoxycarbonyl)-N-[4-(dimethylazaniumylidene)-1,4-dihydropyridin--
1ylsulfonyl]azanide (171 mg. 0.55 mmol, 1.5 eq) and
N,N-diisopropylethylamine (0.28 mL, 1.48 mmol, 4 eq) and the
reaction mixture was allowed to stir at RT for 48 h. Progress of
reaction was monitored by LCMS. After completion, reaction mixture
was concentrated under reduced pressure to get residue which was
purified by reversed phase HPLC to afford tert-butyl
N-(2-(1-(3-cyano-7-methoxyquinolin-4-yl)azetidin-3-yl)ethyl)sulfamoylcarb-
amate (25 mg, 14%). LCMS: 462 [M+1].sup.+
[0356] Step-7: Synthesis of
4-(3-(2-sulfamoylaminoethyl)azetidine-1-yl)-7-methoxyquinoline-3-carbonit-
rile: To a solution of tert-butyl
N-(2-(1-(3-cyano-7-methoxyquinolin-4-yl)azetidin-3-yl)ethyl)sulfamoylcarb-
amate (25 mg, 0.05 mmol, 1 eq) in DCM (2.5 mL) was added TFA (0.5
mL) and the resulting mixture allowed to stir at RT for 2 h.
Progress of reaction was monitored by TLC. After completion,
reaction mixture was concentrated under reduced pressure to afford
crude which was triturated using diethyl ether to afford
4-(3-(2-sulfamoylaminoethyl)azetidine-1-yl)-7-methoxyquinoline-3-carbonit-
rile (14 mg, 74%) as TFA salt. LCMS: 362 [M+1].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. ppm 8.46 (s, 1H), 8.02 (d, 1H),
7.22 (s, 1H), 7.10 (d, 2H), 6.60-6.50 (m, 3H), 4.95-4.86 (m, 2H),
4.50-4.40 (m, 2H), 3.90 (s, 3H), 2.95-2.80 (m, 3H), 1.90-1.80 (m,
2H).
Example-14: Synthesis of
4-(3-(2-sulfamoylaminoethyl)azetidine-1-yl)-5-methyl-5H-pyrrolo[3,2-d]pyr-
imidine, (Compound 1.14)
##STR00582##
[0358] Step-1: Synthesis of tert-butyl
3-(2-(methylsulfonyloxy)ethyl)azetidine-1-carboxylate: To a
solution of tert-butyl 3-(2-hydroxyethyl)azetidine-1-carboxylate (2
g, 9.93 mmol, 1 eq) in DCM (50 mL) was added triethylamine (3.4 mL,
24.83 mmol, 2.5 eq) and the reaction mixture was allowed to stir at
0.degree. C. for 5 minutes. To the mixture was added methane
sulfonyl chloride (2.27 g, 19.87 mmol, 2 eq) and the reaction
mixture to stir at 0.degree. C. for 10 minutes followed by stirring
at RT for 2 h. Progress of reaction is monitored by .sup.1H NMR.
After completion, reaction mixture was diluted with water (100 mL)
and extracted with ethyl acetate (3.times.100 mL). Combined organic
layer was washed with brine (150 mL) and dried over anhydrous
sodium sulfate. Removal of solvent under reduced pressure afforded
tert-butyl 3-(2-(methylsulfonyloxy)ethyl)azetidine-1-carboxylate
(3.8 g, Crude) which was used in the next step without
purification.
[0359] Step-2: Synthesis of tert-butyl
3-(2-azidoethyl)azetidine-1-carboxylate: To a solution of
tert-butyl 3-(2-(methylsulfonyloxy)ethyl)azetidine-1-carboxylate
(3.7 g, 13.25 mmol, 1 eq) in DMF (30 mL), was added sodium azide
(3.4 g, 52.98 mmol, 4 eq) and the reaction mixture was allowed to
stir at 60.degree. C. for 2 h. Progress of reaction is monitored by
.sup.1H NMR. After completion, reaction mixture was diluted with
water (100 mL) and extracted with diethyl ether (3.times.150 mL).
Combined organic layer was washed with water (2.times.100 mL)
followed by brine (150 mL) and dried over anhydrous sodium sulfate.
Removal of solvent under reduced pressure afforded tert-butyl
3-(2-azidoethyl)azetidine-1-carboxylate (2.9 g, Crude) which was
used in the next step without purification.
[0360] Step-3: Synthesis of tert-butyl
3-(2-aminoethyl)azetidine-1-carboxylate: To a solution of
tert-butyl 3-(2-azidoethyl)azetidine-1-carboxylate (2.9 g, 12.81
mmol, 1 eq) in ethanol (100 mL) was added Pd/C (1.2 g) and the
reaction mixture was allowed to stir at RT under H.sub.2 atmosphere
using balloon for 3 h. Progress of reaction was monitored by TLC.
After completion, reaction mixture was filtered through celite-bed.
Removal of solvent under reduced pressure afforded crude tert-butyl
3-(2-aminoethyl)azetidine-1-carboxylate (2.5 g, Crude) which was
used in the next step without purification.
[0361] Step-4: Synthesis of tert-butyl
3-(2-(N-(tert-butoxycarbonyl)sulfamoylamino)ethyl)azetidine-1-carboxylate-
: To a solution of tert-butyl
3-(2-aminoethyl)azetidine-1-carboxylate (1 g, 4.99 mmol, 1 eq) in
dichloromethane (50 mL) were added
N-(tert-butoxycarbonyl)-N-[4-(dimethylazaniumylidene)-1,4-dihydropyridin--
1ylsulfonyl]azanide (1.8 mg, 5.99 mmol, 1.2 eq) and
N,N-diisopropylethylamine (1.73 mL, 9.98 mmol, 2 eq) and the
reaction mixture was allowed to stir at RT for 48 h. Progress of
reaction was monitored by TLC. After completion, reaction mixture
was concentrated under reduced pressure to get crude which was
purified by Combi-Flash using ethyl acetate-hexane system as eluent
to afford tert-butyl
3-(2-(N-(tert-butoxycarbonyl)sulfamoylamino)ethyl)azetidine-1-carboxylate
(0.45 g, 24%).
[0362] Step-5: Synthesis of 3-(2-sulfamoylaminoethyl)azetidine: To
a solution of tert-butyl
3-(2-(N-(tert-butoxycarbonyl)sulfamoylamino)ethyl)azetidine-1-carboxylate
(0.420 g, 1.11 mmol, 1 eq) in DCM (10 mL) was added TFA (3 mL) and
the mixture was allowed to stir at RT for 1.5 h. Progress of
reaction was monitored by .sup.1H NMR. After completion, reaction
mixture was concentrated under reduced pressure to afford crude
which was triturated with diethyl ether to afford
3-(2-sulfamoylaminoethyl)azetidine (0.3 g, 98%) as TFA salt.
[0363] Step-6: Synthesis of
4-(3-(2-sulfamoylaminoethyl)azetidine-1-yl)-5-methyl-5H-pyrrolo[3,2-d]pyr-
imidine: A mixture of 4-chloro-5-methyl-5H-pyrrolo[3,2-d]pyrimidine
(60 mg, 0.34 mmol, 2 eq), 3-(2-sulfamoylaminoethyl)azetidine
trifluoroacetate (50 mg, 0.17 mmol, 1.0 eq) and DIPEA (0.05 mL,
0.34 mmol, 2.0 eq) in DMF (1.5 mL) was allowed to stir at
80.degree. C. for 5 h. Progress of reaction was monitored by TLC.
After completion, reaction mixture was concentrated under reduced
pressure to get crude which was triturated using diethylether,
ethylacetate and ethanol to afford
4-(3-(2-sulfamoylaminoethyl)azetidine-1-yl)-5-methyl-5H-pyrrolo[3,2-d]pyr-
imidine (7 mg, 13%). LCMS: 311 [M+1].sup.+; .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 8.57 (s, 1H), 8.00 (d, 1H), 6.61-6.45 (m,
4H), 4.70-4.58 (m, 2H), 4.25-4.17 (m, 2H), 4.00 (s, 3H), 3.00-2.80
(m, 3H), 1.90-1.80 (m, 2H).
Example-15: Synthesis of
4-(6-sulfamoylamino-2-azaspiro[3.3]heptan-2-yl)-6,7-dimethoxyquinazoline,
(Compound 1.15)
##STR00583## ##STR00584##
[0365] Step-1: Synthesis of tert-butyl
2-(6,7-dimethoxyquinazolin-4-yl)-2-azaspiro[3.3]heptan-6-ylcarbamate:
A suspension of 4-chloro-6,7-dimethoxyquinazoline (100 mg, 0.44
mmol, 1.0 eq), tert-butyl 2-azaspiro[3.3]heptan-6-ylcarbamate (90
mg, 0.44 mmol, 1.0 eq) and DIPEA (0.15 mL, 0.88 mmol, 2.0 eq) in
DMF (1.5 mL) was allowed to stir at 80.degree. C. for 2 h. Progress
of reaction was monitored by TLC. After completion, reaction
mixture was diluted with water (50 mL) and extracted with ethyl
acetate (3.times.100 mL). Combined organic layer was washed with
brine (3.times.50 mL) and dried over anhydrous sodium sulfate.
Removal of solvent under reduced pressure afforded tert-butyl
2-(6,7-dimethoxyquinazolin-4-yl)-2-azaspiro[3.3]heptan-6-ylcarbamate
(0.12 g, 67%) which was used in the next step without purification.
LCMS: 401 [M+1].sup.+
[0366] Step-2: Synthesis of
2-(6,7-dimethoxyquinazolin-4-yl)-2-azaspiro[3.3]heptan-6-amine
2,2,2-trifluoroacetate: To a solution of tert-butyl
2-(6,7-dimethoxyquinazolin-4-yl)-2-azaspiro[3.3]heptan-6-ylcarbamate
(120 mg, 0.29 mmol, 1 eq) in DCM (4 mL) was added TFA (2.5 mL) and
the resulting mixture was allowed to stir at RT for 1 h. Progress
of reaction was monitored by TLC. After completion, reaction
mixture was concentrated under reduced pressure to afford
2-(6,7-dimethoxyquinazolin-4-yl)-2-azaspiro[3.3]heptan-6-amine
2,2,2-trifluoroacetate (120 mg, 97%) which was used in the next
step without purification. LCMS: 301 [M+1].sup.+
[0367] Step-3: Synthesis of tert-butyl
N-(2-(6,7-dimethoxyquinazolin-4-yl)-2-azaspiro[3.3]heptan-6-yl)sulfamoylc-
arbamate: To a solution of
2-(6,7-dimethoxyquinazolin-4-yl)-2-azaspiro[3.3]heptan-6-amine
2,2,2-trifluoroacetate (150 mg, 0.36 mmol, 1 eq) in dichloromethane
(30 mL) were added
N-(tert-butoxycarbonyl)-N-[4-(dimethylazaniumylidene)-1,4-dihydropyridin--
1ylsulfonyl]azanide (163 mg. 0.54 mmol, 1.5 eq) and
N,N-diisopropylethylamine (0.12 mL, 0.72 mmol, 2 eq) and the
reaction mixture was allowed to stir at RT for 16 h. Progress of
reaction was monitored by LCMS. After completion, reaction mixture
was concentrated under reduced pressure to afford crude product
which was purified using reversed phase HPLC to afford tert-butyl
N-(2-(6,7-dimethoxyquinazolin-4-yl)-2-azaspiro[3.3]heptan-6-yl)sulfamoylc-
arbamate (55 mg, 32%). LCMS: 480 [M+1].sup.+
[0368] Step-4: Synthesis of
4-(6-sulfamoylamino-2-azaspiro[3.3]heptan-2-yl)-6,7-dimethoxyquinazoline:
To a solution of tert-butyl
N-(2-(6,7-dimethoxyquinazolin-4-yl)-2-azaspiro[3.3]heptan-6-yl)sulfamoylc-
arbamate (25 mg, 0.05 mmol, 1 eq) in DCM (3 mL) was added TFA (1
mL) and allowed to stir at RT for 1 h. Progress of reaction was
monitored by TLC. After completion, reaction mixture was
concentrated under reduced pressure to afford crude which was
triturated using diethyl ether and pentane to afford
4-(6-Sulfamoylamino-2-azaspiro[3.3]heptan-2-yl)-6,7-dimethoxyquinazoline
(20 mg, 80%) as TFA salt. LCMS: 380 [M+1].sup.+; .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. ppm 14.20 (brs, 1H), 8.65 (s, 1H), 7.29
(s, 1H), 7.21 (s, 1H), 6.92 (d, 1H), 6.55 (s, 2H), 4.70 (brs, 4H),
4.96 (s, 6H), 3.80-3.60 (m, 1H), 2.70-2.50 (m, 2H), 2.40-2.20 (m,
2H).
Example-16: Synthesis of
4-(3-(2-sulfamoylaminoethyl)azetidine-1-yl)-6-methoxyquinazoline,
(Compound 1.16)
##STR00585##
[0370] Step-1: Synthesis of 4-chloro-6-methoxyquinazoline: A
mixture of 6-methoxyquinazolin-4 (3H)-one (0.2 g, 1.1 mmol, 1 eq)
in POCl.sub.3 (2 mL) was allowed to stir at 120.degree. C. for 2 h.
Progress of reaction was monitored by TLC. After completion,
reaction mixture was cooled to RT, diluted with cold water (100 mL)
and extracted with ethyl acetate (3.times.100 mL). Combined organic
layer was washed with water (3.times.50 mL) and dried over
anhydrous sodium sulfate. Removal of solvent under reduced pressure
afforded 6-methoxyquinazolin-4 (3H)-one (0.15 g, 68%) which was
used in the next step without purification. LCMS: 195
[M+1].sup.+
[0371] Step-2: Synthesis of
4-(3-(2-sulfamoylaminoethyl)azetidine-1-yl)-6-methoxyquinazoline: A
suspension of 6-methoxyquinazolin-4 (3H)-one (70 mg, 0.34 mmol, 2
eq), 3-(2-sulfamoylaminoethyl)azetidine trifluoroacetate (50 mg,
0.17 mmol, 1.0 eq) and DIPEA (0.06 mL, 0.34 mmol, 2.0 eq) in DMF (1
mL) was allowed to stir at 80.degree. C. for 5 h. Progress of
reaction was monitored by TLC. After completion, reaction mixture
was concentrated under reduced pressure to afford residue which was
triturated with ether, ethyl acetate and then pentane to get crude
which was purified by reversed phase HPLC to afford
4-(3-(2-sulfamoylaminoethyl)azetidine-1-yl)-6-methoxyquinazolin- e
(7 mg, 12%). LCMS: 338[M+1].sup.+; .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 8.37 (s, 1H), 7.66 (d, 1H), 7.42 (d, 1H),
7.24 (s, 1H), 6.59 (brs, 1H), 6.52 (s, 2H), 4.60 (brs, 2H), 4.17
(brs, 2H), 3.87 (s, 3H), 2.96-2.80 (m, 3H), 1.90-1.80 (m, 2H).
Example-17: Synthesis of
4-(3-(2-sulfamoylaminoethyl)azetidine-1-yl)-6,7-dimethoxy-2-methylquinazo-
line, (Compound 1.17)
##STR00586##
[0373] Step-1: Synthesis of 6,7-dimethoxy-2-methylquinazolin-4
(3H)-one: A mixture of methyl 2-amino-4,5-dimethoxybenzoate (0.5 g,
2.5 mmol, 1 eq), acetamidine hydrochloride (0.48 g, 5 mmol, 2.0 eq)
and in anhydrous sodium acetate (0.416 g, 5 mmol, 2.0 eq)
2-methoxyethanol (6 mL) was allowed to stir at 90.degree. C. for 16
h. Progress of reaction was monitored by TLC. Reaction mixture was
cooled to RT, solid was filtered, washed with hexane and dried to
afford 6,7-dimethoxy-2-methylquinazolin-4 (3H)-one (247 mg, 43%) as
white solid. LCMS: 221 [M+1].sup.+
[0374] Step-2: Synthesis of
4-chloro-6,7-dimethoxy-2-methylquinazoline: A mixture of
6,7-dimethoxy-2-methylquinazolin-4 (3H)-one (0.25 g, 1.1 mmol, 1
eq) in POCl.sub.3 (2 mL) was allowed to stir at 120.degree. C. for
2 h. Progress of reaction was monitored by TLC. After completion,
reaction mixture was cooled to RT, diluted with cold water (100 mL)
and extracted with ethyl acetate (3.times.100 mL). Combined organic
layer was washed with water (3.times.50 mL) and dried over
anhydrous sodium sulfate. Removal of solvent under reduced pressure
afforded 4-chloro-6,7-dimethoxy-2-methylquinazoline (0.2 g, 74%)
which was used in the next step without purification. LCMS: 239
[M+1].sup.+
[0375] Step-3: Synthesis of
4-(3-(2-sulfamoylaminoethyl)azetidine-1-yl)-6,7-dimethoxy-2-methylquinazo-
line: A suspension of 4-chloro-6,7-dimethoxy-2-methylquinazoline
(80 mg, 0.34 mmol, 2 eq), 3-(2-sulfamoylaminoethyl)azetidine
trifluoroacetate (50 mg, 0.17 mmol, 1.0 eq) and DIPEA (0.06 mL,
0.34 mmol, 2.0 eq) in DMF (1 mL) was allowed to stir at 80.degree.
C. for 5 h. Progress of reaction was monitored by TLC. After 3 h,
reaction mixture was concentrated under reduced pressure to afford
crude which was purified using reversed phase HPLC to afford
4-(3-(2-sulfamoylaminoethyl)azetidine-1-yl)-6,7-dimethoxy-2-methylquinazo-
line (12 mg, 18%). LCMS: 382 [M+1].sup.+; .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 7.19 (s, 1H), 7.05 (s, 1H), 6.60-6.45 (m,
3H), 4.61-4.50 (m, 2H), 4.18-4.02 (m, 2H), 3.88 (s, 3H), 3.86 (s,
3H), 2.95-2.2.80 (m, 3H), 2.4 (s, 3H), 1.90-1.80 (m, 2H).
Example-18: Synthesis of
8-(3-(2-sulfamoylaminoethyl)azetidine-1-yl)-[1,3]dioxolo[4,5-g]quinazolin-
e, (Compound 1.18)
##STR00587##
[0377] Step-1: Synthesis of [1,3]dioxolo[4,5-g]quinazolin-8
(5H)-one: A mixture of 6-amino-1,3-benzodioxole-5-carboxylic acid
(300 mg, 1.65 mmol, 1 eq), triethylorthoformate (391 mg, 2.65 mmol,
1.6 eq) and ammonium acetate (165 mg, 2.14 mmol, 1.3 eq) in ethanol
(10 mL) was stirred at 80.degree. C. for 12 h. Progress of reaction
was monitored by TLC. After completion, reaction mixture was cooled
to RT. The solid obtained was filtered, washed with ether (10 mL)
and dried under vacuum to afford [1,3]dioxolo[4,5-g]quinazolin-8
(5H)-one (247 mg, 78%). LCMS: 190[M+1].sup.+
[0378] Step-2: Synthesis of 8-chloro[1,3]dioxolo[4,5-g]quinazoline:
To the stirred solution of [1,3]dioxolo[4,5-g]quinazolin-8 (5H)-one
(150 mg, 0.78 mmol, 1 eq) in triethylamine (3 mL) was added
POCl.sub.3 (0.8 mL, 7.89 mmol, 10 eq) and the reaction mixture was
heated at 80.degree. C. for 3 h. Progress of reaction was monitored
by TLC. After completion, reaction mixture was cooled to RT,
diluted with ice cold water (10 mL) and extracted with ethyl
acetate (3.times.10 mL). The organic layer was evaporated under
reduced pressure to obtain 8-chloro[1,3]dioxolo[4,5-g]quinazoline
(100 mg, 61%). LCMS: 208[M+1].sup.+
[0379] Step-3: Synthesis of
N-{2-[1-([1,3]dioxolo[4,5-g]quinazolin-8-yl)azetidin-3-yl]ethyl}sulfuric
diamide: A suspension of 8-chloro[1,3]dioxolo[4,5-g]quinazoline
(100 mg, 0.48 mmol, 1.0 eq), N-[2-(azetidin-3-yl)ethyl]sulfuric
diamide triflorocetic acid (132 mg, 0.48 mmol, 1.0 eq) and N,N
diisopropylethylamine (124 mg, 0.96 mmol, 2.0 eq) in DMF (2 mL) was
allowed to stir at 80.degree. C. for 2 h. Progress of reaction was
monitored by TLC. Reaction mixture was cooled to RT, DMF was
removed under reduced pressure, triturated with ether (10 mL) and
ethyl acetate (10 mL). Solid obtained was purified by reversed
phase HPLC to afford
N-{2-[1-([1,3]dioxolo[4,5-g]quinazolin-8-yl)azetidin-3-yl]ethyl}sulfuric
diamide (10 mg, 6%). LCMS: 350[M+1].sup.+; .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 8.31 (s, 1H), 7.27 (s, 1H), 7.10 (s, 1H),
6.60 (brs, 1H), 6.52 (s, 2H), 6.20 (s, 2H), 4.60-4.45 (m, 2H),
4.18-4.02 (m, 2H), 2.95-2.78 (m, 3H), 1.88-1.78 (m, 2H).
Example-19: Synthesis of
4-(3-(2-sulfamoylaminoethyl)azetidine-1-yl)-8-ethoxyquinazoline,
(Compound 1.19)
##STR00588## ##STR00589##
[0381] Step-1: Synthesis of ethyl 3-ethoxy-2-nitrobenzoate: To a
solution of 3-hydroxy-2-nitrobenzoic acid (1 g, 5.4 mmol, 1 eq) in
DMF (10 mL) were added K.sub.2CO.sub.3 (3.8 gm, 27 mmol, 5 eq) and
ethyl iodide (2.2 ml, 27 mmol, 5 eq.) and the reaction mixture was
allowed to stir at 60.degree. C. for 3 h. Progress of reaction was
monitored by TLC. After completion, reaction mixture was diluted
with cold water (100 mL) and stirred for 5 minutes. Solid was
filtered, washed with water and dried under vacuum to get ethyl
3-ethoxy-2-nitrobenzoate as white solid (0.8 g, 62%).
[0382] Step-2: Synthesis of ethyl 2-amino-3-ethoxybenzoate: To a
solution of ethyl 3-ethoxy-2-nitrobenzoate (0.8 g, 3.3 mmol, 1 eq)
in acetic acid (5 mL) was added iron powder (1.28 g, 23 mmol, 7 eq)
and the reaction mixture was allowed to stir at 70.degree. C. for 3
h. Progress of reaction was monitored by TLC. After completion,
reaction mixture was filtered, filtrate was diluted with water and
extracted with ethyl acetate (3.times.50 ml). Combined organic
layer was washed with brine (50 mL) and dried over anhydrous sodium
sulfate. Removal of solvent under reduced pressure afforded crude
which was purified by Combi-Flash using ethyl acetate-hexane system
as eluent to get ethyl 2-amino-3-ethoxybenzoate (0.4 g, 58%).
[0383] Step-3: Synthesis of 8-ethoxyquinazolin-4 (3H)-one: To a
solution of 2-amino-3-ethoxybenzoate (0.4 g, 1.9 mmol, 1 eq) in
ethanol (5 mL) were added triethyl orthoformate (0.45 mL, 3 mmol,
1.6 eq) and ammonium acetate (0.19 g, 2.4 mmol, 1.3 eq.) and the
reaction mixture was allowed to stir at 90.degree. C. for 32 h.
Progress of reaction was monitored by TLC. After completion,
reaction mixture was filtered, washed with hexane and dried under
vacuum to get 8-ethoxyquinazolin-4 (3H)-one as white solid (0.3 g,
83%). LCMS: 190 [M+1].sup.+
[0384] Step-4: Synthesis of 4-chloro-8-ethoxyquinazoline: A mixture
of 8-ethoxyquinazolin-4 (3H)-one (0.2 g, 1 mmol, 1 eq) in
POCl.sub.3 (2 mL) was allowed to stir at 120.degree. C. for 2 h.
Progress of reaction was monitored by TLC. After completion,
reaction mixture was cooled to RT, diluted with cold water (100 mL)
and extracted with ethyl acetate (3.times.100 mL). Combined organic
layer was washed with water (3.times.50 mL) followed by brine (50
mL) and dried over anhydrous sodium sulfate. Removal of solvent
under reduced pressure afforded 4-chloro-8-ethoxyquinazoline (0.1
g) which was used in the next step without purification.
[0385] Step-5: Synthesis of tert-butyl
2-(1-(8-ethoxyquinazolin-4-yl)azetidin-3-yl)ethylcarbamate: A
suspension of 4-chloro-8-ethoxyquinazoline (100 mg, 0.48 mmol, 1
eq), tert-butyl 2-(azetidin-3-yl)ethylcarbamate hydrochloride (96
mg, 0.48 mmol, 1.0 eq) and DIPEA (0.17 mL, 0.96 mmol, 2.0 eq) in
DMF (1 mL) was allowed to stir at 80.degree. C. for 2 h. Progress
of reaction was monitored by TLC. After completion, reaction
mixture was diluted with cold water (50 mL) and extracted with
ethyl acetate (3.times.100 mL). Combined organic layer was washed
with brine (3.times.50 mL) and dried over anhydrous sodium sulfate.
Removal of solvent under reduced pressure afforded tert-butyl
2-(1-(8-ethoxyquinazolin-4-yl)azetidin-3-yl)ethylcarbamate (80 mg,
45%) which was used in the next step without purification. LCMS:
373 [M+1].sup.+
[0386] Step-6: Synthesis of
2-(1-(8-ethoxyquinazolin-4-yl)azetidin-3-yl)ethanamine
2,2,2-trifluoroacetate: To a solution of tert-butyl
2-(1-(8-ethoxyquinazolin-4-yl)azetidin-3-yl)ethylcarbamate (100 mg,
0.22 mmol, 1 eq) in DCM (4 mL) was added TFA (2 mL) and the mixture
was allowed to stir at RT for 2 h. Progress of reaction was
monitored by TLC. After completion, reaction mixture was
concentrated under reduced pressure to get
2-(1-(8-ethoxyquinazolin-4-yl)azetidin-3-yl)ethanamine
2,2,2-trifluoroacetate (0.1 g) which was used in the next step
without purification. LCMS: 273 [M+1].sup.+
[0387] Step-7: Synthesis of tert-butyl
N-(2-(1-(8-ethoxyquinazolin-4-yl)azetidin-3-yl)ethyl)sulfamoylcarbamate:
To a solution of
2-(1-(8-methoxyquinazolin-4-yl)azetidin-3-yl)ethanamine
2,2,2-trifluoroacetate (100 mg, 0.24 mmol, 1 eq) in dichloromethane
(15 mL) were added
N-(tert-butoxycarbonyl)-N-[4-(dimethylazaniumylidene)-1,4-dihydropyridin--
1ylsulfonyl]azanide (132 mg. 0.43 mmol, 1.2 eq) and
N,N-diisopropylethylamine (0.12 mL, 0.48 mmol, 2 eq) and the
reaction mixture was allowed to stir at RT for 48 h. Progress of
reaction was monitored by LCMS. After completion, reaction mixture
was concentrated under reduced pressure to get residue which was
purified by reversed phase HPLC to afford tert-butyl
N-(2-(1-(8-ethoxyquinazolin-4-yl)azetidin-3-yl)ethyl)sulfamoylcarbamate
(15 mg, 14%). LCMS: 452 [M+1].sup.+
[0388] Step-8: Synthesis of Synthesis of
4-(3-(2-sulfamoylaminoethyl)azetidine-1-yl)-8-ethoxyquinazoline: To
a solution of tert-butyl
N-(2-(1-(8-ethoxyquinazolin-4-yl)azetidin-3-yl)ethyl)sulfamoylcarbamate
(15 mg, 0.033 mmol, 1 eq) in DCM (3 mL) was added TFA (1 mL) and
the resulting mixture was allowed to stir at RT for 1 h. Progress
of reaction was monitored by TLC. After completion, reaction
mixture was concentrated under reduced pressure to afford crude
which was triturated with diethyl ether to afford Synthesis of
4-(3-(2-sulfamoylaminoethyl)azetidine-1-yl)-8-ethoxyquinazoline (6
mg, 39%) as TFA salt. LCMS: 352 [M+1].sup.+; .sup.1H NMR (400 MHz,
DMSO-d.sub.6) (ppm 13.65 (brs, 1H), 8.64 (s, 1H), 7.62 (brs, 3H),
6.60 (brs, 1H), 6.55 (s, 2H), 5.02 (brs, 1H), 4.80-4.50 (m, 2H),
4.30 (q, 2H), 4.18 (brs, 1H), 3.00-2.83 (m, 3H), 1.93-1.83 (m, 2H),
1.45 (t, 3H)
Example-20: Synthesis of
4-(3-(2-sulfamoylaminoethyl)azetidine-1-yl)-5-methylpyrrolo[1,2-f][1,2,4]-
triazine, (Compound 1.20)
##STR00590## ##STR00591##
[0390] Step-1: Synthesis of ethyl
1-amino-3-methyl-1H-pyrrole-2-carboxylate: To a solution of sodium
hydride (0.372 g, 0.0093 mmol, 1.43 eq) in DMF (60 mL) was added a
solution of ethyl 3-methyl-1H-pyrrole-2-carboxylate (1 g, 0.0065
mmol, 1.0 eq) in DMF (20 mL) at 0.degree. C. and the reaction
mixture was allowed to stir at 0.degree. C. for 30 minutes,
followed by addition of O-(diphenylphosphoryl)hydroxylamine (2.68
g, 0.0115 mmol, 1.76 eq) portion wise. The reaction mixture was
allowed to stir at RT for overnight. Progress of reaction is
monitored using TLC. After completion, DMF was removed under
reduced pressure, residue was diluted with water (100 mL) and
extracted with ethyl acetate (3.times.100 mL). Combined organic
layer was washed with brine (150 mL) and dried over anhydrous
sodium sulfate. Removal of solvent under reduced pressure afforded
ethyl 1-amino-3-methyl-1H-pyrrole-2-carboxylate (0.6 g, 55%).
[0391] Step-2: Synthesis of
5-methylpyrrolo[1,2-f][1,2,4]triazin-4-ol: A solution of ethyl
1-amino-3-methyl-1H-pyrrole-2-carboxylate (0.2 g, 1.189 mmol, 1 eq)
in formamide (2 mL) was allowed to stir at 165.degree. C. for 6 h.
Progress of reaction is monitored by TLC. After completion,
reaction mixture was diluted with cold water (30 mL) and allowed to
stir for 10 minutes. Solid was filtered, washed with water followed
by hexane and dried under vacuum to afford
5-methylpyrrolo[1,2-f][1,2,4]triazin-4-ol (0.05 g, 28%).
[0392] Step-3: Synthesis of
4-chloro-5-methylpyrrolo[1,2-f][1,2,4]triazine: A mixture of
5-methylpyrrolo[1,2-f][1,2,4]triazin-4-ol (0.050 g, 0.335 mmol, 1
eq) in phosphoryl trichloride (2 mL) was allowed to stir at
110.degree. C. for 2 h. Progress of reaction is monitored by TLC.
After completion, reaction mixture was diluted with cold water (30
mL) and extracted with ethyl acetate (3.times.15 mL). Combined
organic layer was washed with brine (20 mL) and dried over
anhydrous sodium sulfate. Removal of solvent under reduced pressure
afforded 4-chloro-5-methylpyrrolo[1,2-f][1,2,4]triazine (0.050 g,
89%).
[0393] Step-4: Synthesis of tert-butyl
2-(1-(5-methylpyrrolo[1,2-f][1,2,4]triazin-4-yl)azetidin-3-yl)ethylcarbam-
ate: A suspension of 4-chloro-5-methylpyrrolo[1,2-f][1,2,4]triazine
(50 mg, 0.298 mmol, 1 eq), tert-butyl
2-(azetidin-3-yl)ethylcarbamate hydrochloride (70 mg, 0.298 mmol,
1.0 eq) and DIPEA (0.1 mL, 0.596 mmol, 2.0 eq) in DMF (1 mL) was
allowed to stir at 80.degree. C. for 2 h. Progress of reaction was
monitored by TLC. After completion, reaction mixture was diluted
with cold water (30 mL) and extracted with ethyl acetate
(3.times.70 mL). Combined organic layer was washed with brine
(3.times.50 mL) and dried over anhydrous sodium sulfate. Removal of
solvent under reduced pressure afforded tert-butyl
2-(1-(5-methylpyrrolo[1,2-f][1,2,4]triazin-4-yl)azetidin-3-yl)ethylcarbam-
ate (0.06 g) which was used in the next step without purification.
LCMS: 332[M+1].sup.+
[0394] Step-5: Synthesis of
2-(1-(5-methylpyrrolo[1,2-f][1,2,4]triazin-4-yl)azetidin-3-yl)ethanamine:
To a solution of tert-butyl
2-(1-(5-methylpyrrolo[1,2-f][1,2,4]triazin-4-yl)azetidin-3-yl)ethylcarbam-
ate (60 mg, 0.181 mmol, 1 eq) in DCM (10 mL) was added TFA (2 mL)
and the mixture was allowed to stir at RT for 2 h. Progress of
reaction was monitored by TLC. After completion, reaction mixture
was concentrated under reduced pressure to get
2-(1-(5-methylpyrrolo[1,2-f][1,2,4]triazin-4-yl)azetidin-3-yl)ethanamine
(0.05 g) which was used in the next step without purification.
[0395] Step-6: Synthesis of tert-butyl
N-(2-(1-(5-methylpyrrolo[1,2-f][1,2,4]triazin-4-yl)azetidin-3-yl)ethyl)su-
lfamoylcarbamate: To a solution of
2-(1-(5-methylpyrrolo[1,2-f][1,2,4]triazin-4-yl)azetidin-3-yl)ethanamine
(50 mg, 0.152 mmol, 1 eq) in dichloromethane (10 mL) were added
N-(tert-butoxycarbonyl)-N-[4-(dimethylazaniumylidene)-1,4-dihydropyridin--
1ylsulfonyl]azanide (68.84 mg. 0.228 mmol, 1.5 eq) and
N,N-diisopropylethylamine (0.3 mL, 0.304 mmol, 2 eq) and the
reaction mixture was allowed to stir at RT for 48 h. Progress of
reaction was monitored by LCMS. After completion, reaction mixture
was concentrated under reduced pressure to get residue which was
purified by reversed phase HPLC to afford
N-(2-(1-(5-methylpyrrolo[1,2-f][1,2,4]triazin-4-yl)azetidin-3-yl)ethyl)su-
lfamoylcarbamate (18 mg, 32%). LCMS: 411[M+1].sup.+
[0396] Step-7: Synthesis of
4-(3-(2-sulfamoylaminoethyl)azetidine-1-yl)-5-methylpyrrolo[1,2-f][1,2,4]-
triazine: To a solution of
N-(2-(1-(5-methylpyrrolo[1,2-f][1,2,4]triazin-4-yl)azetidin-3-yl)ethyl)su-
lfamoylcarbamate (18 mg, 0.044 mmol, 1 eq) in DCM (3 mL) was added
TFA (0.5 mL) and allowed to stir at RT for 1 h. Progress of
reaction was monitored by TLC. After completion, reaction mixture
was concentrated under reduced pressure to afford crude which was
triturated with diethyl ether to afford
4-(3-(2-sulfamoylaminoethyl)azetidine-1-yl)-5-methylpyrrolo[1,2-f][1,2,4]-
triazine (10 mg, 77%) as TFA salt. LCMS: 311[M+1].sup.+; .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 7.79 (s, 1H), 7.60 (s, 1H),
6.60-6.45 (m, 4H), 4.50-4.40 (m, 2H), 4.07-3.95 (m, 2H), 2.90-2.70
(m, 3H), 2.41 (s, 3H), 1.87-1.77 (m, 2H).
Example-21: Synthesis of
4-(3-(2-sulfamoylaminoethyl)azetidine-1-yl)-6,7-dimethoxy-2-phenylquinazo-
line, (Compound 1.21)
##STR00592##
[0398] Step-1: Synthesis of 6,7-dimethoxy-2-phenylquinazolin-4
(1H)-one: A mixture of methyl 2-amino-4,5-dimethoxybenzoate (500
mg, 1.65 mmol, 1 eq) and benzonitrile (244 mg, 2.65 mmol, 1.6 eq)
in 4M HCl in dioxane (10 mL) was sonicated for 30 minutes and then
heated at 100.degree. C. for 12 h. Progress of reaction was
monitored by TLC. After completion, reaction mixture was cooled to
RT, poured into ice-cold water and stirred for 15 minutes. The
solid obtained was filtered and dried under vacuum to afford
6,7-dimethoxy-2-phenylquinazolin-4 (1H)-one (250 mg, 37%). LCMS:
282[M+1].sup.+
[0399] Step-2: Synthesis of
4-chloro-6,7-dimethoxy-2-phenylquinazoline: To a stirred solution
of 6,7-dimethoxy-2-phenylquinazolin-4 (1H)-one (250 mg, 0.88 mmol,
1 eq) in POCl.sub.3 (2.5 mL) was stirred at 120.degree. C. for 2 h.
Progress of reaction was monitored by TLC. After completion,
reaction mixture was cooled to RT, poured into ice-cold water (20
mL) and stirred for 15 minutes. Solid was filtered and dried under
vacuum to afford 4-chloro-6,7-dimethoxy-2-phenylquinazoline (200
mg, 75%). LCMS: 300[M+1].sup.+
[0400] Step-3: Synthesis of
4-(3-(2-sulfamoylaminoethyl)azetidine-1-yl)-6,7-dimethoxy-2-phenylquinazo-
line: A suspension of 4-chloro-6,7-dimethoxy-2-phenylquinazoline
(54 mg, 0.18 mmol, 1.0 eq), N-[2-(azetidin-3-yl)ethyl]sulfuric
diamide triflorocetic acid (50 mg, 0.18 mmol, 1.0 eq) and N,N
diisopropylethylamine (46 mg, 0.36 mmol, 2.0 eq) in DMF (2 mL) was
allowed to stir at 80.degree. C. for 2 h. Progress of reaction was
monitored by TLC. Reaction mixture was cooled to RT, concentrated
under vacuum to get semi-solid residue which was triturated with
ether, ethyl acetate and then with pentane to afford crude solid
which was purified by reversed phase HPLC to afford
4-(3-(2-sulfamoylaminoethyl)azetidine-1-yl)-6,7-dimethoxy-2-phenylquinazo-
line (3 mg, 4%). LCMS: 350[M+1].sup.+; .sup.1H NMR (400 MHz,
DMSO-d.sub.6) (ppm 8.39 (d, 2H), 7.70-7.30 (m, 3H), 7.30 (s, 2H),
6.60 (brs, 1H), 6.53 (s, 2H), 4.80-4.55 (m, 2H), 4.40-4.20 (m, 2H),
3.97 (s, 3H), 3.93 (s, 3H), 3.00-2.90 (m, 3H), 1.94-1.84 (m,
2H).
Example-22: Synthesis of
4-(3-Methyl-3-(2-sulfamoylaminoethyl)azetidine-1-yl)-6,7-dimethoxyquinazo-
line, (Compound 1.22)
##STR00593## ##STR00594##
[0402] Step-1: Synthesis of tert-butyl
3-(hydroxymethyl)-3-methylazetidine-1-carboxylate: To a solution of
1-(tert-butoxycarbonyl)-3-methylazetidine-3-carboxylic acid (1.5 g,
6.97 mmol, 1 eq) in THF (20 mL) was added N-methylmorpholine (NMM)
(2.3 mL, 20.9 mmol, 3 eq) and isobutyl chloroformate (1.08 ml, 8.37
mmol, 1.2 eq) and the reaction mixture was allowed to stir at
0.degree. C. for 30 minutes. Progress of reaction is monitored by
TLC. After consumption of carboxylic acid, reaction mixture was
filtered through cotton plug, filtrate was cooled to 0.degree. C.
and to it was added a freshly prepared solution of NaBH.sub.4 (3 g,
81.08 mmol, 12 eq) in MeOH (50 ml) at 0.degree. C. in one portion.
Reaction mixture was then allowed to stir for 30 minutes. Progress
of reaction was monitored by .sup.1H NMR. After completion,
reaction mixture was diluted with aq. saturated NH.sub.4Cl solution
(100 mL) and extracted with ethyl acetate (3.times.100 mL).
Combined organic layer was washed with brine (150 mL) and dried
over anhydrous sodium sulfate. Removal of solvent under reduced
pressure gave crude oil which was purified by Combi-Flash on silica
gel using ethyl acetate-hexane system as eluent to afford
tert-butyl 3-(hydroxymethyl)-3-methylazetidine-1-carboxylate (1 g,
71%).
[0403] Step-2: Synthesis of tert-butyl
3-methyl-3-((methylsulfonyloxy)methyl)azetidine-1-carboxylate: To a
solution of tert-butyl
3-(hydroxymethyl)-3-methylazetidine-1-carboxylate (0.5 g, 2.48
mmol, 1 eq) in DCM (10 mL) was added triethylamine (0.67 mL, 4.97
mmol, 2 eq) and the reaction mixture was allowed to stir at
0.degree. C. for 5 minutes. To the mixture was added methane
sulfonyl chloride (0.42 g, 3.73 mmol, 1.5 eq) and the reaction
mixture to stir at 0.degree. C. for 10 minutes followed by stirring
at RT for 2 h. Progress of reaction is monitored by .sup.1H NMR.
After completion, reaction mixture was diluted with water (100 mL)
and extracted with ethyl acetate (3.times.100 mL). Combined organic
layer was washed with brine (150 mL) and dried over anhydrous
sodium sulfate. Removal of solvent under reduced pressure afforded
tert-butyl
3-methyl-3-((methylsulfonyloxy)methyl)azetidine-1-carboxylate (0.5
g, Crude) which was used in the next step without purification.
[0404] Step-3: Synthesis of tert-butyl
3-(cyanomethyl)-3-methylazetidine-1-carboxylate: To a solution of
tert-butyl
3-methyl-3-((methylsulfonyloxy)methyl)azetidine-1-carboxylate (0.5
g, 1.79 mmol, 1 eq) in DMSO (1 mL) was added sodium cyanide (0.22
g, 4.48 mmol, 2.5 eq) and the reaction mixture was allowed to stir
at 80.degree. C. for 16 h. Progress of reaction was monitored by
.sup.1H NMR. After completion, reaction mixture was diluted with
water (100 mL) and extracted with diethyl ether (3.times.150 mL).
Combined organic layer was washed with water (2.times.100 mL)
followed by brine (150 mL) and dried over anhydrous sodium sulfate.
Removal of solvent under reduced pressure afforded tert-butyl
3-(cyanomethyl)-3-methylazetidine-1-carboxylate (0.3 g) which was
used in the next step without purification.
[0405] Step-4: Synthesis of tert-butyl
3-(2-aminoethyl)-3-methylazetidine-1-carboxylate: To a solution of
tert-butyl 3-(cyanomethyl)-3-methylazetidine-1-carboxylate (0.3 g,
1.42 mmol, 1 eq) in ethanol (50 mL) was added Pd--C (0.3 g) and the
reaction mixture was allowed to stir at RT under H.sub.2 atmosphere
using balloon for 5 h. Progress of reaction was monitored by TLC.
After completion, reaction mixture was filtered through celite-bed.
Filtrate was concentrated under reduced pressure to afford
tert-butyl 3-(2-aminoethyl)-3-methylazetidine-1-carboxylate (0.25
g, Crude) which was used in the next step without purification.
[0406] Step-5: Synthesis of tert-butyl
3-(2-(N-(tert-butoxycarbonyl)sulfamoylamino)ethyl)-3-methylazetidine-1-ca-
rboxylate To a solution of tert-butyl
3-(2-aminoethyl)-3-methylazetidine-1-carboxylate (0.25 g, 1.16
mmol, 1 eq) in dichloromethane (10 mL) were added
N-(tert-butoxycarbonyl)-N-[4-(dimethylazaniumylidene)-1,4-dihydropyridin--
1ylsulfonyl]azanide (0.421 mg, 1.4 mmol, 1.2 eq) and
N,N-diisopropylethylamine (0.4 mL, 2.2 mmol, 2 eq) and the reaction
mixture was allowed to stir at RT for 48 h. Progress of reaction
was monitored by TLC. After completion, reaction mixture was
concentrated under reduced pressure to get crude which was purified
by Combi-Flash using ethyl acetate-hexane system as eluent to
afford tert-butyl
3-(2-(N-(tert-butoxycarbonyl)sulfamoylamino)ethyl)-3-methylazetidine-1-ca-
rboxylate (0.1 g, 22%).
[0407] Step-6: Synthesis of
3-methyl-3-(2-sulfamoylaminoethyl)azetidine trifluoroacetate: To a
solution of tert-butyl
3-(2-(N-(tert-butoxycarbonyl)sulfamoylamino)ethyl)-3-methylazetidine-1-ca-
rboxylate (0.1 g, 0.25 mmol, 1 eq) in DCM (5 mL) was added TFA (1
mL) and the mixture was allowed to stir at RT for 1.5 h. Progress
of reaction was monitored by .sup.1H NMR. After completion,
reaction mixture was concentrated under reduced pressure to afford
crude which was triturated with diethyl ether to afford
3-Methyl-3-(2-sulfamoylaminoethyl)azetidine trifluoroacetate (0.1
g).
[0408] Step-7: Synthesis of
4-(3-Methyl-3-(2-sulfamoylaminoethyl)azetidine-1-yl)-6,7-dimethoxyquinazo-
line: A mixture of 4-chloro-6,7-dimethoxyquinazoline (88 mg, 0.39
mmol, 1.2 eq), -Methyl-3-(2-sulfamoylaminoethyl)azetidine
trifluoroacetate (100 mg, 0.32 mmol, 1.0 eq) and DIPEA (0.11 mL,
0.65 mmol, 2.0 eq) in DMF (1 mL) was allowed to stir at 80.degree.
C. for 2 h. Progress of reaction was monitored by TLC. After
completion, reaction mixture was concentrated under reduced
pressure to get residue which was purified by reversed phase HPLC
to afford
4-(3-Methyl-3-(2-sulfamoylaminoethyl)azetidine-1-yl)-6,7-dimethoxyquinazo-
line (8 mg, 6%). LCMS: 382 [M+1].sup.+; .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 8.45 (s, 1H), 7.23 (s, 1H), 7.16 (s, 1H),
6.58 (s, 3H), 4.60-4.17 (m, 4H), 3.88 (s, 3H), 3.86 (s, 3H),
3.01-2.90 (m, 2H), 1.89-1.80 (m, 2H).
Example-23: Synthesis of
4-(3-(2-((sulfamoyl)(cyclopropyl)amino)ethyl)azetidine-1-yl)-6,7-dimethox-
yquinazoline, (Compound 1.23)
##STR00595## ##STR00596##
[0410] Step-1: Synthesis of tert-butyl
3-(2-oxoethyl)azetidine-1-carboxylate: To a solution of the
tert-butyl 3-(2-hydroxyethyl)azetidine-1-carboxylate (0.5 g, 2.48
mmol, 1 eq) in dichloromethane (18 mL) at 0.degree. C. was added
Dess-Martin peridionane (DMP) (3.1 g, 7.46 mmol 3.0 eq) and the
reaction mixture was stirred at RT for 2 h. Progress of reaction
was monitored by TLC. After completion, reaction mixture poured on
crushed ice and extracted with ethyl acetate (3.times.50 mL).
Combined organic layer was washed with brine (20 mL) and dried over
anhydrous sodium sulfate. Removal of solvent under reduced pressure
gave crude which was triturated with pentane (100 mL) at 0.degree.
C. and filtered. Filtrate was concentrated under vacuum to afford
tert-butyl 3-(2-oxoethyl)azetidine-1-carboxylate (0.350 g,
35%).
[0411] Step-2: Synthesis of tert-butyl
3-(2-(cyclopropylamino)ethyl)azetidine-1-carboxylate: To a stirred
solution of tert-butyl 3-(2-oxoethyl)azetidine-1-carboxylate (0.350
g, 1.76 mmol, 1.0 eq) in DCE (20 mL) were added cyclopropyl amine
(0.1 g, 1.76 mmol, 1.0 eq), acetic acid (0.3 mL, 5.27 mmol, 3.0 eq)
and the reaction mixture was allowed to stir at RT for 1 h. to the
mixture was then added NaCNBH.sub.3 (0.332 g, 5.27 mmol, 3.0 eq)
and the reaction mixture was stirred at room temperature for 1 h.
Progress of reaction was monitored by TLC. After completion,
reaction mixture was diluted with ice-cold water (50 mL) and
extracted with ethyl acetate (3.times.50 mL). Combined organic
layer was washed with brine (20 mL) and dried over anhydrous sodium
sulfate. Removal of solvent under reduced pressure afforded
tert-butyl 3-(2-(cyclopropylamino)ethyl)azetidine-1-carboxylate
(0.130 g, 36%) which was used in the next step without
purification.
[0412] Step-3: Synthesis of tert-butyl
3-(2-((N-(tert-butoxycarbonyl)sulfamoyl) (cyclopropyl)amino)
ethyl)azetidine-1-carboxylate: To a solution of tert-butyl
3-(2-(cyclopropylamino)ethyl)azetidine-1-carboxylate (130 mg, 0.541
mmol, 1 eq) in dichloromethane (5 mL) were added
N-(tert-butoxycarbonyl)-N-[4-(dimethylazaniumylidene)-1,4-dihydropyridin--
1ylsulfonyl]azanide (0.195 mg. 0.649 mmol, 1.5 eq) and
N,N-diisopropylethylamine (31 mg, 0.24 mmol, 2 eq) and the reaction
mixture was allowed to stir at RT for 24 h. Progress of reaction
was monitored by LCMS. After completion, solvent was removed under
reduced pressure to afford crude which was purified by reversed
phase HPLC to afford tert-butyl
3-(2-((N-(tert-butoxycarbonyl)sulfamoyl) (cyclopropyl)amino)
ethyl)azetidine-1-carboxylate (100 mg, 32%).
[0413] Step-4: Synthesis of
3-(2-((sulfamoyl)(cyclopropyl)amino)ethyl)azetidine
trifluoroacetate: To a solution of tert-butyl
3-(2-((N-(tert-butoxycarbonyl)sulfamoyl) (cyclopropyl)amino)
ethyl)azetidine-1-carboxylate (100 mg, 0.238 mmol, 1 eq) in DCM (5
mL) was added TFA (1 mL) and the mixture was allowed to stir at RT
for 2 h. Progress of reaction was monitored by TLC. After
completion, reaction mixture was concentrated under reduced
pressure to get oily residue which was triturated with diethyl
ether (10 mL) to afford
3-(2-((sulfamoyl)(cyclopropyl)amino)ethyl)azetidine
trifluoroacetate (70 mg, 93%).
[0414] Step-5: Synthesis of
4-(3-(2-((sulfamoyl)(cyclopropyl)amino)ethyl)azetidine-1-yl)-6,7-dimethox-
yquinazoline: A suspension of 4-chloro-6,7-dimethoxyquinazoline (70
mg, 0.22 mmol, 1.0 eq),
3-(2-((sulfamoyl)(cyclopropyl)amino)ethyl)azetidine
trifluoroacetate (54 mg, 0.24 mmol, 1.1 eq) and
N,N-diisopropylethylamine (56 mg, 0.26 mmol, 1.2 eq) in DMF (1 mL)
was allowed to stir at 80.degree. C. for 3 h. Progress of reaction
was monitored by LCMS. After completion, solvent was removed under
reduced pressure to afford crude which was purified by reversed
phase HPLC to afford
4-(3-(2-((sulfamoyl)(cyclopropyl)amino)ethyl)azetidine-1-yl)-6,7-dimethox-
yquinazoline (20 mg, 23%). LCMS: 408 [M+1].sup.+; .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. ppm 8.35 (s, 1H), 7.22 (s, 1H), 7.15 (s,
1H), 6.85 (s, 2H), 4.56 (brs., 2H), 4.13 (brs, 2H), 3.91 (s, 3H),
3.88 (s, 3H), 3.18-3.09 (m, 2H), 2.84-2.70 (m, 1H), 2.39-2.30 (m,
1H), 2.03-1.95 (m, 2H), 0.8 (brs, 4H).
Example-24: Synthesis of
4-(6-sulfamoylamino-2-azaspiro[3.3]heptan-2-yl)-6,7-dimethoxyquinoline-3--
carbonitrile, (Compound 1.24)
##STR00597## ##STR00598##
[0416] Step-1: Synthesis of tert-butyl
2-(3-cyano-6,7-dimethoxyquinolin-4-yl)-2-azaspiro[3.3]heptan-6-ylcarbamat-
e: A suspension of 4-chloro-6,7-dimethoxyquinoline-3-carbonitrile
(70 mg, 0.28 mmol, 1.2 eq), tert-butyl
2-azaspiro[3.3]heptan-6-ylcarbamate (50 mg, 0.23 mmol, 1.0 eq) and
DIPEA (0.08 mL, 0.47 mmol, 2.0 eq) in DMF (1 mL) was allowed to
stir at 80.degree. C. for 2 h. Progress of reaction was monitored
by TLC. After completion, reaction mixture was diluted with cold
water (50 mL) and extracted with ethyl acetate (3.times.100 mL).
Combined organic layer was washed with brine (3.times.50 mL) and
dried over anhydrous sodium sulfate. Removal of solvent under
reduced pressure afforded tert-butyl
2-(3-cyano-6,7-dimethoxyquinolin-4-yl)-2-azaspiro[3.3]heptan-6-ylcarbamat-
e (0.1 g, crude) which was used in the next step without
purification. LCMS: 425 [M+1].sup.+
[0417] Step-2: Synthesis of
4-(6-amino-2-azaspiro[3.3]heptan-2-yl)-6,7-dimethoxyquinoline-3-carbonitr-
ile 2,2,2-trifluoroacetate: To a solution of tert-butyl
2-(3-cyano-6,7-dimethoxyquinolin-4-yl)-2-azaspiro[3.3]heptan-6-ylcarbamat-
e (100 mg, 0.23 mmol, 1 eq) in DCM (5 mL) was added TFA (1 mL) and
the mixture was allowed to stir at RT for 2 h. Progress of reaction
was monitored by TLC. After completion, reaction mixture was
concentrated under reduced pressure to get
4-(6-amino-2-azaspiro[3.3]heptan-2-yl)-6,7-dimethoxyquinoline-3-carbonitr-
ile 2,2,2-trifluoroacetate (0.1 g, crude) which was used in the
next step without purification. LCMS: 325 [M+1].sup.+
[0418] Step-3: Synthesis of tert-butyl
N-(2-(3-cyano-6,7-dimethoxyquinolin-4-yl)-2-azaspiro[3.3]heptan-6-yl)sulf-
amoylcarbamate: To a solution of
4-(6-amino-2-azaspiro[3.3]heptan-2-yl)-6,7-dimethoxyquinoline-3-carbonitr-
ile 2,2,2-trifluoroacetate (100 mg, 0.30 mmol, 1 eq) in
dichloromethane (15 mL) were added
N-(tert-butoxycarbonyl)-N-[4-(dimethylazaniumylidene)-1,4-dihydropyridin--
1ylsulfonyl]azanide (111 mg. 0.37 mmol, 1.2 eq) and
N,N-diisopropylethylamine (0.1 mL, 0.61 mmol, 2 eq) and the
reaction mixture was allowed to stir at RT for 48 h. Progress of
reaction was monitored by LCMS. After completion, reaction mixture
was concentrated under reduced pressure to get residue which was
purified by reversed phase HPLC to afford tert-butyl
N-(2-(3-cyano-6,7-dimethoxyquinolin-4-yl)-2-azaspiro[3.3]heptan-6-yl)sulf-
amoylcarbamate (35 mg, 23%). LCMS: 504 [M+1].sup.+
[0419] Step-4: Synthesis of
4-(6-sulfamoylamino-2-azaspiro[3.3]heptan-2-yl)-6,7-dimethoxyquinoline-3--
carbonitrile: To a solution of tert-butyl
N-(2-(3-cyano-6,7-dimethoxyquinolin-4-yl)-2-azaspiro[3.3]heptan-6-yl)sulf-
amoylcarbamate (35 mg, 0.069 mmol, 1 eq) in DCM (4 mL) was added
TFA (0.8 mL) and allowed to stir at RT for 1 h. Progress of
reaction was monitored by TLC. After completion, reaction mixture
was concentrated under reduced pressure to afford crude which was
triturated with diethyl ether to afford
4-(6-sulfamoylamino-2-azaspiro[3.3]heptan-2-yl)-6,7-dimethoxyquino-
line-3-carbonitrile (20 mg, 56%) as TFA salt. LCMS: 404
[M+1].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 8.78
(s, 1H), 7.40 (s, 1H), 7.24 (s, 1H), 6.90 (d, 1H), 7.54 (s, 2H),
5.0.8 (s, 2H), 4.97 (s, 2H), 3.95 (s, 3H), 3.78-3.60 (m, 1H),
2.70-2.60 (m, 2H), 2.32-2.20 (m, 2H).
Example-25: Synthesis of
4-(3-(2-sulfamoylaminoethyl)azetidine-1-yl)-6,7-dimethoxy-2-phenylquinazo-
line, (Compound 1.25)
##STR00599##
[0421] Step-1: Synthesis of 2-cyclopropyl-6,7-dimethoxyquinazolin-4
(3H)-one: A mixture of methyl 2-amino-4,5-dimethoxybenzoate (1 g,
4.7 mmol, 1 eq) and cyclopropyl cyanide (1.04 mL, 14 mmol, 3 eq) in
4M HCl in dioxane (10 mL) was allowed to stir at 100.degree. C. for
16 h. Progress of reaction was monitored by TLC. After completion,
reaction mixture was poured to saturated aq. sodium carbonate
solution (50 mL) and allowed to stir for 5 minutes. Precipitate was
filtered and dried under vacuum to afford
2-cyclopropyl-6,7-dimethoxyquinazolin-4 (3H)-one (900 mg, 78%) as
white solid. LCMS: 247 [M+1].sup.+
[0422] Step-2: Synthesis of
4-chloro-2-cyclopropyl-6,7-dimethoxyquinazoline: A mixture of
2-cyclopropyl-6,7-dimethoxyquinazolin-4 (3H)-one (0.2 g, 0.81 mmol,
1 eq) in POCl.sub.3 (2 mL) was allowed to stir at 120.degree. C.
for 2 h. Progress of reaction was monitored by TLC. After
completion, reaction mixture was cooled to RT, diluted with cold
water (100 mL) and extracted with ethyl acetate (3.times.100 mL).
Combined organic layer was washed with water (3.times.50 mL) and
dried over anhydrous sodium sulfate. Removal of solvent under
reduced pressure afforded
4-chloro-2-cyclopropyl-6,7-dimethoxyquinazoline (0.15 g, 70%) which
was used in the next step without purification. LCMS: 265
[M+1].sup.+
[0423] Step-3: Synthesis of
4-(3-(2-sulfamoylaminoethyl)azetidine-1-yl)-2-cyclopropyl-6,7-dimethoxyqu-
inazoline: A suspension of
4-chloro-2-cyclopropyl-6,7-dimethoxyquinazoline (90 mg, 0.34 mmol,
2 eq), 3-(2-sulfamoylaminoethyl)azetidine trifluoroacetate (50 mg,
0.17 mmol, 1.0 eq) and DIPEA (0.06 mL, 0.34 mmol, 2.0 eq) in DMF (1
mL) was allowed to stir at 80.degree. C. for 3 h. Progress of
reaction was monitored by TLC. After 3 h, reaction mixture was
concentrated under reduced pressure to afford crude which was
purified using reversed phase HPLC to afford
4-(3-(2-sulfamoylaminoethyl)azetidine-1-yl)-2-cyclopropyl-6,7-dimethoxyqu-
inazoline (20 mg, 19%). LCMS: 408 [M+1].sup.+; .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. ppm 7.17 (s, 1H), 7.00 (s, 1H),
6.60-6.47 (m, 3H), 4.58-4.45 (m, 2H), 4.10-4.02 (m, 2H), 3.87 (s,
3H), 3.85 (s, 3H), 2.92-2.78 (m, 3H), 1.99-1.82 (m, 3H), 1.00-0.80
(m, 4H).
Example-26: Synthesis of
4-(6-sulfamoylamino-2-azaspiro[3.3]heptan-2-yl)-7-methoxyquinazoline,
(Compound 1.26)
##STR00600## ##STR00601##
[0425] Step-1: Synthesis of tert-butyl
2-(7-methoxyquinazolin-4-yl)-2-azaspiro[3.3]heptan-6-ylcarbamate: A
suspension of 4-chloro-7-methoxyquinazoline (55 mg, 0.28 mmol, 1
eq), tert-butyl 2-azaspiro[3.3]heptan-6-ylcarbamate (50 mg, 0.23
mmol, 1.0 eq) and DIPEA (0.1 mL, 0.47 mmol, 2.0 eq) in DMF (1 mL)
was allowed to stir at 80.degree. C. for 2 h. Progress of reaction
was monitored by TLC. After 2 h, reaction mixture was diluted with
cold water (50 mL) and extracted with ethyl acetate (3.times.100
mL). Combined organic layer was washed with brine (3.times.50 mL)
and dried over anhydrous sodium sulfate. Removal of solvent under
reduced pressure afforded tert-butyl
2-(7-methoxyquinazolin-4-yl)-2-azaspiro[3.3]heptan-6-ylcarbamate
(0.1 g) which was used in the next step without purification. LCMS:
371 [M+1].sup.+
[0426] Step-2: Synthesis of
2-(7-methoxyquinazolin-4-yl)-2-azaspiro[3.3]heptan-6-amine
2,2,2-trifluoroacetate: To a solution of tert-butyl
2-(7-methoxyquinazolin-4-yl)-2-azaspiro[3.3]heptan-6-ylcarbamate
(100 mg, 0.27 mmol, 1 eq) in DCM (4 mL) was added TFA (2 mL) and
the mixture was allowed to stir at RT for 1 h. Progress of reaction
was monitored by TLC. After completion, reaction mixture was
concentrated under reduced pressure to get
2-(7-methoxyquinazolin-4-yl)-2-azaspiro[3.3]heptan-6-amine
2,2,2-trifluoroacetate (0.15 g) which was used in the next step
without purification. LCMS: 271 [M+1].sup.+
[0427] Step-3: Synthesis of tert-butyl
N-(2-(7-methoxyquinazolin-4-yl)-2-azaspiro[3.3]heptan-6-yl)sulfamoylcarba-
mate: To a solution of
2-(7-methoxyquinazolin-4-yl)-2-azaspiro[3.3]heptan-6-amine
2,2,2-trifluoroacetate (150 mg, 0.39 mmol, 1 eq) in dichloromethane
(20 mL) were added
N-(tert-butoxycarbonyl)-N-[4-(dimethylazaniumylidene)-1,4-dihydropyridin--
1ylsulfonyl]azanide (176 mg. 0.58 mmol, 1.5 eq) and
N,N-diisopropylethylamine (0.13 mL, 0.78 mmol, 2 eq) and the
reaction mixture was allowed to stir at RT for 16 h. Progress of
reaction was monitored by LCMS. After completion, reaction mixture
was concentrated under reduced pressure to get residue which was
purified by reversed phase HPLC to afford tert-butyl
N-(2-(7-methoxyquinazolin-4-yl)-2-azaspiro[3.3]heptan-6-yl)sulfamoylcarba-
mate (30 mg, 17%). LCMS: 450 [M+1].sup.+
[0428] Step-4: Synthesis of
4-(6-sulfamoylamino-2-azaspiro[3.3]heptan-2-yl)-7-methoxyquinazoline:
To a solution of tert-butyl
N-(2-(7-methoxyquinazolin-4-yl)-2-azaspiro[3.3]heptan-6-yl)sulfamoylcarba-
mate (30 mg, 66 mmol, 1 eq) in DCM (3 mL) was added TFA (1 mL) and
allowed to stir at RT for 1 h. Progress of reaction was monitored
by TLC. After completion, reaction mixture was concentrated under
reduced pressure to afford crude which was triturated with diethyl
ether to afford
4-(6-sulfamoylamino-2-azaspiro[3.3]heptan-2-yl)-7-methoxyquinazoline
(15 mg, 50%) as TFA salt. LCMS: 350 [M+1].sup.+; .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. ppm 14.00 (brs, 1H), 8.67 (s, 1H), 7.98
(d, 1H), 7.08 (d, 1H), 7.18 (s, 1H), 6.90 (d, 1H), 6.53 (s, 2H),
4.65 (brs, 4H), 3.98 (s, 3H), 2.70-2.60 (m, 1H), 2.67-2.50 (m, 2H),
2.30-2.30 (m, 2H).
Example-27: Synthesis of
4-(3-(2-sulfamoylaminoethyl)azetidine-1-yl)-6,7-dimethoxycinnoline,
(Compound 1.27)
##STR00602## ##STR00603##
[0430] Step-1: Synthesis of 6,7-dimethoxycinnolin-4 (1H)-one: To a
solution of 1-(2-amino-4,5-dimethoxyphenyl)ethanone (1 g, 5.12
mmol, 1 eq) in a solution of Conc.HCl (36 mL) and water (5 mL) at
0.degree. C. was added a solution of sodium nitrite (0.353 g, 5.12
mmol, 1 eq) in water (2 mL) dropwise. The mixture was allowed to
stir at 0.degree. C. for 1 h followed by stirring at 75.degree. C.
for 4 h. Progress of reaction was monitored by .sup.1H NMR. After
completion, reaction mixture was cooled to RT, precipitates was
filtered, dissolved in water (150 mL) and basified with aq. NaOH up
to pH 12 and then neutralized with 2M HCl solution. Precipitate was
filtered, washed with hexane and dried under vacuum to afford
6,7-dimethoxycinnolin-4 (1H)-one (0.6 g, 57%). LCMS: 207
[M+1].sup.+
[0431] Step-2: Synthesis of 4-chloro-6,7-dimethoxycinnoline: A
mixture of 6,7-dimethoxycinnolin-4 (1H)-one (0.6 g, 2.90 mmol, 1
eq) in POCl.sub.3 (3 mL) was allowed to stir at 100.degree. C. for
2 h. Progress of reaction was monitored by TLC. After completion,
reaction mixture was cooled to RT, diluted with ice-cold water (20
mL) and extracted with ethyl acetate (3.times.30 mL). Combined
organic layer was washed with brine (50 mL) and dried over
anhydrous sodium sulfate. Removal of solvent under reduced pressure
afforded 4-chloro-6,7-dimethoxycinnoline (0.5 g, 77%).
[0432] Step-3: Synthesis of tert-butyl
2-(1-(6,7-dimethoxycinnolin-4-yl)azetidin-3-yl)ethylcarbamate: A
suspension of 4-chloro-6,7-dimethoxycinnoline (50 mg, 0.222 mmol, 1
eq), tert-butyl 2-(azetidin-3-yl)ethylcarbamate hydrochloride (52
mg, 0.222 mmol, 1.0 eq) and DIPEA (57 mg, 0.444 mmol, 2.0 eq) in
ethanol (5 mL) was allowed to stir at 70.degree. C. for 48 h.
Progress of reaction was monitored by TLC. After completion,
reaction mixture was concentrated under reduced pressure to afford
crude which was triturated with pentane to afford tert-butyl
2-(1-(6,7-dimethoxycinnolin-4-yl)azetidin-3-yl)ethylcarbamate (70
mg) which was used in the next step without purification. LCMS: 389
[M+1].sup.+
[0433] Step-4: Synthesis of
2-(1-(6,7-dimethoxycinnolin-4-yl)azetidin-3-yl)ethanamine: To a
solution of tert-butyl
2-(1-(6,7-dimethoxycinnolin-4-yl)azetidin-3-yl)ethylcarbamate (70
mg, 0.181 mmol, 1 eq) in DCM (5 mL) was added TFA (2 mL) and the
mixture was allowed to stir at RT for 2.5 h. Progress of reaction
was monitored by LCMS. After completion, reaction mixture was
concentrated under reduced pressure to get
2-(1-(6,7-dimethoxycinnolin-4-yl)azetidin-3-yl)ethanamine (70 mg)
which was used in the next step without purification.
[0434] Step-5: Synthesis of tert-butyl
N-(2-(1-(6,7-dimethoxycinnolin-4-yl)azetidin-3-yl)ethyl)sulfamoylcarbamat-
e: To a solution of
2-(1-(6,7-dimethoxycinnolin-4-yl)azetidin-3-yl)ethanamine (70 mg,
0.174 mmol, 1 eq) in dichloromethane (10 mL) were added
N-(tert-butoxycarbonyl)-N-[4-(dimethylazaniumylidene)-1,4-dihydropyridin--
1ylsulfonyl]azanide (104 mg. 0.348 mmol, 2 eq) and
N,N-diisopropylethylamine (44 mg, 0.348 mmol, 2 eq) and the
reaction mixture was allowed to stir at RT for 48 h. Progress of
reaction was monitored by LCMS. After completion, reaction mixture
was concentrated under reduced pressure to get crude residue which
was purified by reversed phase HPLC to afford tert-butyl
N-(2-(1-(6,7-dimethoxycinnolin-4-yl)azetidin-3-yl)ethyl)sulfamoylcarbamat-
e (20 mg, 18%). LCMS: 468[M+1].sup.+
[0435] Step-6 Synthesis of
4-(3-(2-sulfamoylaminoethyl)azetidine-1-yl)-6,7-dimethoxycinnoline:
To a solution of
N-(2-(1-(6,7-dimethoxycinnolin-4-yl)azetidin-3-yl)ethyl)sulfamoylcarbamat-
e (20 mg, 0.028 mmol, 1 eq) in DCM (5 mL) was added TFA (1 mL) and
allowed to stir at RT for 2 h. Progress of reaction was monitored
by TLC. After completion, reaction mixture was concentrated under
reduced pressure to afford crude which was triturated with diethyl
ether to afford
4-(3-(2-sulfamoylaminoethyl)azetidine-1-yl)-6,7-dimethoxycinnoline
(6 mg, 40%) as TFA salt. LCMS: 468[M+1].sup.+; .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. ppm 14.82 (brs, 1H), 8.11 (s, 1H), 7.30
(s, 1H), 7.20 (s, 1H), 6.63 (brs, 1H), 6.55 (s, 2H), 5.40-4.20
(brs, 4H), 4.00 (s, 3H), 3.99 (s, 3H), 3.18-2.90 (m, 3H), 1.96-1.85
(m, 2H).
Example-28: Synthesis of
2-(1-(6,7-dimethoxyquinazolin-4-yl)azetidin-3-yl)-N-hydroxyacetamide,
(Compound 1.28)
##STR00604##
[0437] Step-1: Synthesis of tert-butyl
3-(2-(benzyloxyamino)-2-oxoethyl)azetidine-1-carboxylate: To a
solution of 2-(1-(tert-butoxycarbonyl)azetidin-3-yl)acetic acid (1
g, 4.646 mmol, 1 eq) and O-benzylhydroxylamine (0.815 g, 5.110
mmol, 1.1 eq) in DCM (50 mL) were added
N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (1.06
g, 5.575 mmol, 1.2 eq), 4-(dimethylamino)pyridine (0.851 g, 6.969
mmol, 1.5 eq) and triethylamine (1.9 mL, 13.938 mmol, 3 eq) and the
reaction mixture was allowed to stir at RT overnight. Progress of
reaction is monitored using TLC. After completion, removal of
solvent is done under reduced pressure gave residue which was
diluted with water (100 mL) and extracted with ethyl acetate
(3.times.100 mL). Combined organic layer was washed with dil.HCl
(50 mL) followed by brine (150 mL) and dried over anhydrous sodium
sulfate. Removal of solvent under reduced pressure afforded
tert-butyl 3-(2-(benzyloxyamino)-2-oxoethyl)azetidine-1-carboxylate
(1.5 g, Crude) which was used in the next step without
purification.
[0438] Step-2: Synthesis of tert-butyl
3-(2-(hydroxyamino)-2-oxoethyl)azetidine-1-carboxylate: To a
solution of tert-butyl
3-(2-(benzyloxyamino)-2-oxoethyl)azetidine-1-carboxylate (0.5 g,
1.561 mmol, 1 eq) in methanol (20 mL) was added Pd--C (0.1 g) and
the reaction mixture was allowed to stir at RT under H.sub.2
atmosphere for 2 h. After completion, reaction mixture was filtered
through celite bed and bed was washed with methanol (20 mL).
Combined filtrate was concentrated under reduced pressure to afford
tert-butyl 3-(2-(hydroxyamino)-2-oxoethyl)azetidine-1-carboxylate
(0.360 g, Crude) which was used in the next step without
purification.
[0439] Step-3: Synthesis of 2-(azetidin-3-yl)-N-hydroxyacetamide:
To a solution of tert-butyl
3-(2-(hydroxyamino)-2-oxoethyl)azetidine-1-carboxylate (0.350 g,
1.520 mmol, 1 eq) in DCM (4 mL) was added TFA (1 mL) and mixture
was allowed to stir at RT for 2 h. Progress of reaction was
monitored by .sup.1H NMR. After completion, reaction mixture was
concentrated under reduced pressure to afford crude which was
triturated with diethyl ether to afford
2-(azetidin-3-yl)-N-hydroxyacetamide (0.350 g, crude) as TFA
salt.
[0440] Step-4: Synthesis of
2-(1-(6,7-dimethoxyquinazolin-4-yl)azetidin-3-yl)-N-hydroxyacetamide:
To a solution of 2-(azetidin-3-yl)-N-hydroxyacetamide (0.1 g, 0.440
mmol, 1 eq) in DMF (1.5 mL) were added N,N-diisopropylethylamine
(0.2 mL, 1.100 mmol, 2.5 eq) and 4-chloro-6,7-dimethoxyquinazoline
(1.73 mL, 9.986 mmol, 2 eq) and the reaction mixture was allowed to
stir at 85.degree. C. for 2 h. Progress of reaction was monitored
by LCMS. After completion, reaction mixture was concentrated under
reduced pressure, triturated with diethyl ether and ethyl acetate,
to get residue which was purified by reversed HPLC to afford
2-(1-(6,7-dimethoxyquinazolin-4-yl)azetidin-3-yl)-N-hydroxyacetamide
(2 mg, 2%). LCMS: 319 [M+1].sup.+; .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 10.6 (s, 1H), 8.61 (s, 1H), 7.32 (s, 2H),
4.8 (brs, 2H), 4.4 (brs, 2H), 3.98 (s, 6H), 3.6 (s, 1H), 3.15 (brs,
2H).
Example-29: Synthesis of
2-(1-(6,7-dimethoxyquinazolin-4-yl)azetidin-3-yl)ethylphosphonic
acid, (Compound 1.29)
##STR00605## ##STR00606##
[0442] Step-1: Synthesis of (E)-tert-butyl
3-(2-(diethoxyphosphoryl)vinyl)azetidine-1-carboxylate: To a
suspension of sodium hydride (60% in mineral oil, 0.052 g, 1.29
mmol, 1.2 eq) in THF (20 mL) was added tetraethyl
methylenediphosphonate (0.3 mL g, 1.189 mmol, 1.1 eq) dropwise at
0.degree. C. and the mixture was allowed to stir at the same
temperature for 30 minutes. To this mixture was added a solution of
tert-butyl 3-(2-oxoethyl)azetidine-1-carboxylate (0.2 g, 1.081
mmol, 1.0 eq) in THF (5 mL) and the resulting mixture was allowed
to stir at room temperature for 2 h. Progress of reaction was
monitored by TLC. After completion, reaction mixture was diluted
with saturated aq. NH.sub.4Cl (100 mL) and extracted with ethyl
acetate (3.times.30 ml). Combined organic layer was washed with
brine, dried over anhydrous Na.sub.2SO.sub.4 and evaporated to
dryness under vacuum to afford (E)-tert-butyl
3-(2-(diethoxyphosphoryl)vinyl)azetidine-1-carboxylate (0.3 g,
94%). LCMS: 320 [M+1].sup.+
[0443] Step-2: Synthesis of tert-butyl
3-(2-(diethoxyphosphoryl)ethyl)azetidine-1-carboxylate: To a
solution of (E)-tert-butyl
3-(2-(diethoxyphosphoryl)vinyl)azetidine-1-carboxylate (0.3 g,
0.940 mmol, 1.0 eq) in ethanol (50 mL) was added Pd/C (0.1 g) and
the reaction mixture was allowed to stir at RT under H.sub.2
atmosphere using balloon for 2 h. Progress of reaction was
monitored by TLC. After completion, reaction mixture was filtered
through celite-bed. Removal of solvent under reduced pressure
afforded tert-butyl
3-(2-(diethoxyphosphoryl)ethyl)azetidine-1-carboxylate (0.25 g,
83%). LCMS: 322[M+1].sup.+
[0444] Step-3: Synthesis of diethyl
2-(azetidin-3-yl)ethylphosphonate: To a solution of tert-butyl
3-(2-(diethoxyphosphoryl)ethyl)azetidine-1-carboxylate (0.250 g,
0.778 mmol, 1 eq) in DCM (5 mL) was added TFA (1 mL) and the
mixture was allowed to stir at RT for 2 h. Progress of reaction was
monitored by TLC. After completion, reaction mixture was
concentrated under reduced pressure to get oily residue which was
triturated with diethyl ether (10 mL) to afford diethyl
2-(azetidin-3-yl)ethylphosphonate (0.2 g, 81%). LCMS:
222[M+1].sup.+
[0445] Step-4: Synthesis of diethyl
2-(1-(6,7-dimethoxyquinazolin-4-yl)azetidin-3-yl)ethylphosphonate:
A suspension of 4-chloro-6,7-dimethoxyquinazoline (0.2 g, 0.8928
mmol, 1.0 eq), diethyl 2-(azetidin-3-yl)ethylphosphonate (0.215 mg,
0.9821 mmol, 1.1 eq) and N,N-diisopropylethylamine (0.185 mL, 1.071
mmol, 1.2 eq) in DMF (3 mL) was allowed to stir at 80.degree. C.
for 3 h. Progress of reaction was monitored by LCMS. After
completion, reaction mixture was cooled to RT and diluted with
ice-cold water (10 mL). Precipitate was filtered, washed with water
followed by pentane and dried under reduced pressure to afford
diethyl
2-(1-(6,7-dimethoxyquinazolin-4-yl)azetidin-3-yl)ethylphosphonate
(0.120 mg, 49%). LCMS: 410[M+1].sup.+
[0446] Step-5: Synthesis of
2-(1-(6,7-dimethoxyquinazolin-4-yl)azetidin-3-yl)ethylphosphonic
acid: A mixture of diethyl
2-(1-(6,7-dimethoxyquinazolin-4-yl)azetidin-3-yl)ethylphosphonate
(120 mg, 0.2933 mmol, 1.0 eq) in a solution of HBr in acetic acid
(3 mL) was stirred at 80.degree. C. for 3 h. Progress of reaction
was monitored by TLC. After completion, solvent was removed under
reduced pressure to afford crude which was purified by reversed
phase HPLC to afford
2-(1-(6,7-dimethoxyquinazolin-4-yl)azetidin-3-yl)ethylphosphonic
acid (7 mg, 6.79%). LCMS: 354[M+1].sup.+; .sup.1H NMR (400 MHz,
D.sub.2O:DMSO-d.sub.6) .delta. ppm 8.21 (s, 1H), 7.76 (s, 1H), 7.22
(s, 1H), 3.90 (s, 3H), 3.88 (s, 3H), 3.78-3.62 (m, 2H), 3.30-3.18
(m, 2H), 2.30-2.18 (m, 2H), 1.65-1.38 (m, 3H).
Example-30: Synthesis of
2-(1-(6,7-dimethoxyquinazolin-4-yl)azetidin-3-yl)ethylboronic acid,
(Compound 1.30)
##STR00607##
[0448] Step-1: Synthesis of tert-butyl
3-vinylazetidine-1-carboxylate: To a solution of
methyltriphenylphosphonium bromide (1 g, 2.85 mmol, 2.6 eq) in THF
(2 mL) was added n-butyllithium (2.5 mol/L solution in n-hexane,
1.3 mL, 3.24 mmol, 3 eq) at 0.degree. C. under a nitrogen
atmosphere, and the mixture was stirred at the same temperature for
10 minutes. To the reaction mixture a solution of tert-butyl
3-formylazetidine-1-carboxylate (200 mg, 1.08 mmol, 1.0 eq) in THF
(2 mL) was added at the same temperature, and the mixture was
stirred overnight at room temperature. To the reaction solution was
added an aqueous ammonium chloride solution (10 mL), and the
mixture was extracted with ethyl acetate (3.times.30 mL). The
combined organic layer was washed with water and brine, dried over
sodium sulfate, and concentrated. The residue was purified by
normal phase silica gel column chromatography (eluent: ethyl
acetate/n-hexane) to obtain tert-butyl
3-vinylazetidine-1-carboxylate (90 mg, 48%).
[0449] Step-2: Synthesis of 3-vinylazetidine
2,2,2-trifluoroacetate: To a solution of tert-butyl
3-ethenylazetidine-1-carboxylate (80 mg, 0.44 mmol, 1.0 eq) in
methylene chloride (4 mL) was added 0.4 mL TFA at 0.degree. C., and
the reaction mixture was stirred at RT for 48 h. The reaction
solution was concentrated and triturated with ether-hexane to get
the semisolid (60 mg, 69%) which was used as such for next step
without purification.
[0450] Step-3: Synthesis of
6,7-dimethoxy-4-(3-vinylazetidin-1-yl)quinazoline: To a solution of
3-vinylazetidine 2,2,2-trifluoroacetate (60 mg, 0.35 mmol, 1.0 eq)
in DMF (2 mL) were added 4-chloro-6,7-dimethoxyquinazoline (80 mg.
0.35 mmol, 1.0 eq) and N,N-diisopropylethylamine (0.135 g, 1.05
mmol, 3.0 eq) and the reaction mixture was allowed to stir at
80.degree. C. for 2 h. Progress of reaction was monitored by LCMS.
After completion, reaction mixture was diluted with water (20 mL)
and extracted with ethyl acetate (3.times.30 mL). Combined organic
layer was washed with brine (30 mL), dried over anhydrous sodium
sulfate and concentrated under vacuum to get the residue which was
purified by silica gel column chromatography (Eluent: ethyl
acetate/n-hexane) to obtain the title compound (50 mg, 52%). LCMS:
272[M+1].sup.+
[0451] Step-4: Synthesis of
6,7-dimethoxy-4-(3-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ethyl)-
azetidin-1-yl)quinazoline: To a solution of
6,7-dimethoxy-4-(3-vinylazetidin-1-yl)quinazoline (50 mg, 0.18
mmol, 1.0 eq) in DCM (4 mL) was added
bis(1,5-cyclooctadiene)diiridium(I) dichloride (3 mg, 4 mol %) and
1,2-bis(diphenylphosphino)ethane (4 mg, 8 mol %) and the reaction
mixture was allowed to stir at RT under nitrogen for 30 min. The
reaction was cooled to 0.degree. C. and pinacolborane (0.034 g,
0.27 mmol, 1.5 eq) was added dropwise. The reaction was allowed to
stir at RT for overnight. Progress of reaction was monitored by
LCMS. The reaction was quenched by addition of water (10 mL) and
extracted with DCM (3.times.25 mL). Combined organic layer was
washed with brine (30 mL), dried over anhydrous sodium sulfate and
concentrated under vacuum to get the residue which was purified by
normal phase silica gel column chromatography (eluent: ethyl
acetate/n-hexane) to obtain the title compound (30 mg, 41%). LCMS:
400[M+1].sup.+
[0452] Step-5: Synthesis of
2-(1-(6,7-dimethoxyquinazolin-4-yl)azetidin-3-yl)ethylboronic acid:
To a solution of
6,7-dimethoxy-4-(3-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ethyl)-
azetidin-1-yl)quinazoline (20 mg, 0.02 mmol, 1 eq) in MeOH:Hexane
(1:1, 2 mL) was added 2 M aqueous HCl (0.4 mL) and the resulting
reaction mixture was allowed to stir at RT for 24 h. The reaction
mixture was concentrated under reduced pressure to afford crude
product which was purified by RP-HPLC to afford
2-(1-(6,7-dimethoxyquinazolin-4-yl)azetidin-3-yl)ethylboronic acid
(1 mg, 6%). LCMS: 318 [M+1].sup.+; .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta. ppm 8.26 (s, 2H), 7.31 (s, 1H), 7.10 (s, 1H),
4.66 (brs, 2H), 4.18 (brs, 2H), 3.95 (s, 3H), 3.97 (s, 3H),
2.82-2.78 (m, 2H), 1.97-1.92 (m, 1H), 1.82-1.74 (m, 2H).
Example-31: Synthesis of
4-(3-(2-sulfamoylaminoethyl)azetidine-1-yl)-7,8-dimethoxyquinazoline,
(Compound 1.31)
##STR00608##
[0454] Step-1: Synthesis of 7,8-dimethoxyquinazolin-4 (3H)-one: To
a solution of 2-amino-3,4-dimethoxybenzoic acid (0.25 g, 1.26 mmol,
1 eq) in ethanol (3.5 mL) were added triethylorthoformate (0.43 mL,
2.6 mmol, 2.1 eq) and ammonium acetate (0.38 g, 4.9 mmol, 3.9 eq.)
and the reaction mixture was allowed to stir under reflux for 48 h.
Progress of reaction was monitored by TLC. After completion,
reaction mixture was cooled to RT, solid was filtered, washed with
hexane and dried under vacuum to afford 7,8-dimethoxyquinazolin-4
(3H)-one (0.19 g, 73%). LCMS: 207 [M+1].sup.+
[0455] Step-2: Synthesis of 4-chloro-7,8-dimethoxyquinazoline: A
mixture of 7,8-dimethoxyquinazolin-4 (3H)-one (0.1 g, 0.48 mmol, 1
eq) in POCl.sub.3 (1 mL) was allowed to stir at 120.degree. C. for
3 h. Progress of reaction was monitored by TLC. After completion
reaction mixture was cooled to RT, diluted with cold water (100 mL)
and extracted with ethyl acetate (3.times.100 mL). Combined organic
layer was washed with water (3.times.50 mL) followed by brine (50
mL) and dried over anhydrous sodium sulfate. Removal of solvent
under reduced pressure afforded 4-chloro-7,8-dimethoxyquinazoline
(0.1 g, 92%) which was used in the next step without purification.
LCMS: 225 [M+1].sup.+
[0456] Step-3: Synthesis of
4-(3-(2-sulfamoylaminoethyl)azetidine-1-yl)-7,8-dimethoxyquinazoline:
A suspension of 4-chloro-7,8-dimethoxyquinazoline (76 mg, 0.34
mmol, 2 eq), 3-(2-sulfamoylaminoethyl)azetidine trifluoroacetate
(50 mg, 0.17 mmol, 1.0 eq) and DIPEA (0.06 mL, 0.34 mmol, 2.0 eq)
in DMF (1.5 mL) was allowed to stir at 80.degree. C. for 3 h. After
3 h, reaction mixture was concentrated under reduced pressure to
afford crude product which was purified using reversed phase HPLC
to afford
4-(3-(2-sulfamoylaminoethyl)azetidine-1-yl)-7,8-dimethoxyquinazoline
(3.96 mg, 6%). LCMS: 368[M+1].sup.+; .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 8.38 (s, 1H), 7.69 (d, 1H), 7.28 (d, 1H),
6.57 (brs, 1H), 6.52 (s, 2H), 4.55 (brs, 2H), 4.08 (brs, 2H), 3.94
(s, 3H), 3.86 (s, 3H), 2.95-2.80 (m, 3H), 1.90-1.80 (m, 2H).
Example-32: Synthesis of
8-(3-(2-sulfamoylaminoethyl)azetidine-1-yl)-4-fluoro-1-methyl-1H-imidazo[-
4,5-g]quinazoline, (Compound 1.32)
##STR00609##
[0458] Step-1: Synthesis of
4-fluoro-1-methyl-1H-imidazo[4,5-g]quinazolin-8 (7H)-one: To a
solution of methyl
5-amino-4-fluoro-1-methyl-1H-benzo[d]imidazole-6-carboxylate (0.25
g, 1.1 mmol, 1 eq) in ethanol (3 mL) were added
triethylorthoformate (0.39 mL, 2.3 mmol, 2.1 eq) and ammonium
acetate (0.33 g, 4.3 mmol, 3.9 eq.) and the reaction mixture was
allowed to stir reflux for 48 h. Progress of reaction was monitored
by TLC. After completion, reaction mixture was cooled to RT, solid
was filtered to get residue which was triturated with diethyl the
and ethanol to afford
4-fluoro-1-methyl-1H-imidazo[4,5-g]quinazolin-8 (7H)-one (0.13 g,
53%). LCMS: 219[M+1].sup.+
[0459] Step-2: Synthesis of
8-chloro-4-fluoro-1-methyl-1H-imidazo[4,5-g]quinazoline: To a
solution of 4-fluoro-1-methyl-1H-imidazo[4,5-g]quinazolin-8
(7H)-one (50 mg, 0.22 mmol, 1 eq) in CHCl.sub.3 (2 mL) were added
POCl.sub.3 (0.06 mL, 0.72 mmol, 3.15 eq) and triethylamine (0.1 mL,
0.76 mmol, 3.35 eq) and reaction mixture was allowed to stir at
80.degree. C. for 16 h. Progress of reaction was monitored by TLC.
After completion, reaction mixture was cooled to RT, diluted with
cold water (100 mL) and extracted with ethyl acetate (3.times.100
mL). Combined organic layer was washed with brine (50 mL) and dried
over anhydrous sodium sulfate. Removal of solvent under reduced
pressure afforded
8-chloro-4-fluoro-1-methyl-1H-imidazo[4,5-g]quinazoline (40 mg,
54%) which was used in next step without purification. LCMS: 237
[M+1].sup.+
[0460] Step-3: Synthesis of
8-(3-(2-sulfamoylaminoethyl)azetidine-1-yl)-4-fluoro-1-methyl-1H-imidazo[-
4,5-g]quinazoline: A suspension of
8-chloro-4-fluoro-1-methyl-1H-imidazo[4,5-g]quinazoline (42 mg,
0.17 mmol, 1.5 eq), 3-(2-sulfamoylaminoethyl)azetidine
trifluoroacetate (35 mg, 0.11 mmol, 1.0 eq) and DIPEA (0.04 mL,
0.23 mmol, 2 eq) in DMF (1 mL) was allowed to stir at 80.degree. C.
for 3 h. Progress of reaction was monitored by TLC. After
completion, reaction mixture was concentrated under reduced
pressure to afford crude product which was purified by reversed
phase HPLC to afford
8-(3-(2-sulfamoylaminoethyl)azetidine-1-yl)-4-fluoro-1-methyl-1H-imidazo[-
4,5-g]quinazoline (1.6 mg, 3%). LCMS: 380[M+1].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. ppm 8.56 (s, 1H), 8.40 (s, 1H),
7.85 s, 1H), 6.59 (brs, 1H), 6.56 (s, 2H), 4.66 (brs, 2H), 4.25
(brs, 2H), 3.96 (s, 3H), 3.00-2.82 (m, 3H), 1.92-1.81 (m, 2H).
Example-33: Synthesis of
4-(3-(2-sulfamoylaminoethyl)azetidine-1-yl)-2-(4-fluorophenyl)-6,7-dimeth-
oxyquinazoline, (Compound 1.33)
##STR00610##
[0462] Step-1: Synthesis of
2-(4-fluorophenyl)-6,7-dimethoxyquinazolin-4 (1H)-one: A mixture of
methyl 2-amino-4,5-dimethoxybenzoate (500 mg, 2.36 mmol, 1 eq) and
4-fluorobenzonitrile (315 mg, 2.60 mmol, 1.1 eq) was suspended in
4M HCl in dioxane (10 mL) and the resulting mixture was sonicated
for 30 minutes. The reaction mixture was then allowed to stir at
100.degree. C. for 12 h. Progress of reaction was monitored by TLC.
After completion, reaction mixture was cooled to RT, diluted with
ice cold water and stirred for 15 minutes. Solid was filtered,
washed with water and dried under vacuum to afford
2-(4-fluorophenyl)-6,7-dimethoxyquinazolin-4 (1H)-one (250 mg,
35%). LCMS: 300[M+1].sup.+
[0463] Step-2: Synthesis of
4-chloro-2-(4-fluorophenyl)-6,7-dimethoxyquinazoline: A mixture of
2-(4-fluorophenyl)-6,7-dimethoxyquinazolin-4 (1H)-one (250 mg, 0.83
mmol, 1 eq) in POCl.sub.3 (2.5 mL) was allowed to stir at
120.degree. C. for 2 h. Progress of reaction was monitored by TLC.
After completion, reaction mixture was cooled to RT, diluted with
ice-cold water (50 mL) and stirred for 15 minutes. Solid was
filtered and dried under vacuum to afford
4-chloro-2-(4-fluorophenyl)-6,7-dimethoxyquinazoline (200 mg, 75%).
LCMS: 318[M+1].sup.+
[0464] Step-3: Synthesis of
4-(3-(2-sulfamoylaminoethyl)azetidine-1-yl)-2-(4-fluorophenyl)-6,7-dimeth-
oxyquinazoline: A suspension of
4-chloro-2-(4-fluorophenyl)-6,7-dimethoxyquinazoline (50 mg, 0.15
mmol, 1.0 eq), 3-(2-sulfamoylaminoethyl)azetidine trifluoroacetate
(43 mg, 0.15 mmol, 1.0 eq) and N,N diisopropylethylamine (38.7 mg,
0.30 mmol, 2.0 eq) in DMF (1 mL) was allowed to stir at 80.degree.
C. for 2 h. Progress of reaction was monitored by TLC. After
completion, reaction mixture was cooled to RT, DMF was removed
under reduced pressure to obtain crude which was purified by
reversed phase HPLC to afford
4-(3-(2-sulfamoylaminoethyl)azetidine-1-yl)-2-(4-fluorophenyl)-6,7-dimeth-
oxyquinazoline (13 mg, 18%). LCMS: 461 [M+1].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. ppm 8.42 (dd, 2H), 7.60-7.38 (m,
3H), 7.30 (s, 1H), 6.62 (brs, 1H), 6.58 (s, 2H), 5.20-4.20 (m, 4H),
3.98 (s, 3H), 7.95 (s, 3H), 3.02-2.85 (m, 3H), 1.92-1.83 (m,
2H).
Example-34: Synthesis of
4-(3-(2-sulfamoylaminoethyl)azetidine-1-yl)-7-methoxy-2-phenylquinazoline-
, (Compound 1.34)
##STR00611##
[0466] Step-1: Synthesis of 7-methoxy-2-phenylquinazolin-4
(1H)-one: A mixture of methyl 2-amino-4-methoxybenzoate (650 mg,
3.59 mmol, 1 eq) and benzonitrile (0.4 mL, 3.95 mmol, 1.1 eq) in 4M
HCl in dioxane (10 mL) was stirred at 100.degree. C. for 12 h.
Progress of reaction was monitored by TLC. After completion,
reaction mixture was cooled to RT, diluted with ice cold water and
stirred for 15 minutes. Solid obtained was filtered and dried under
vacuum to afford 7-methoxy-2-phenylquinazolin-4 (1H)-one (500 mg,
55%). LCMS: 252 [M+1].sup.+
[0467] Step-2: Synthesis of 4-chloro-7-methoxy-2-phenylquinazoline:
A mixture of 7-methoxy-2-phenylquinazolin-4 (1H)-one (165 mg, 0.65
mmol, 1 eq) in POCl.sub.3 (0.6 mL) was heated at 120.degree. C. for
2 h. Progress of reaction was monitored by TLC. After completion,
reaction mixture was cooled to RT, diluted with ice-cold water (10
mL) and stirred for 15 minutes. Solid was filtered and dried under
vacuum to 4-chloro-7-methoxy-2-phenylquinazoline (100 mg, 56%).
LCMS: 270[M+1].sup.+
[0468] Step-3: Synthesis of
4-(3-(2-sulfamoylaminoethyl)azetidine-1-yl)-7-methoxy-2-phenylquinazoline-
: A suspension of 4-chloro-7-methoxy-2-phenylquinazoline (50 mg,
0.18 mmol, 1.0 eq), N-[2-(azetidin-3-yl)ethyl]sulfuric diamide
triflorocetic acid (54 mg, 0.15 mmol, 1.0 eq) and N,N
diisopropylethylamine (47 mg, 0.30 mmol, 2.0 eq) in DMF (1 mL) was
allowed to stir at 80.degree. C. for 2 h. Progress of reaction was
monitored by TLC. Reaction mixture was cooled to RT, DMF was
removed under reduced pressure to give crude which was purified by
reversed phase HPLC to afford
4-(3-(2-sulfamoylaminoethyl)azetidine-1-yl)-7-methoxy-2-phenylquinazoline
(13 mg, 17%). LCMS: 413 [M+1].sup.+; 8.45 (d, 2H), 8.20 (s, 1H),
7.88 (d, 1H), 7.47 (brs, 3H), 7.20 (s, 1H), 7.04 (d, 1H), 6.01-6.50
(m, 3H), 4.65 (brs, 2H), 4.20 (brs, 2H), 3.91 (s, 3H), 3.00-2.82
(m, 3H), 1.92-1.80 (m, 2H).
Example-35: Synthesis of
4-(3-(2-sulfamoylaminoethyl)azetidine-1-yl)-6,7-dimethoxy-2-(pyridin-4-yl-
)quinazoline, (Compound 1.35)
##STR00612##
[0470] Step-1: Synthesis of
6,7-dimethoxy-2-(pyridin-4-yl)quinazolin-4 (1H)-one: A mixture of
methyl 2-amino-4,5-dimethoxybenzoate (1 g, 4.73 mmol, 1 eq) and
pyridine-4-carbonitrile (541 mg, 2.60 mmol, 1.1 eq) in 4M HCl in
dioxane (10 mL) was stirred at 100.degree. C. for 12 h. Progress of
reaction was monitored by TLC. After completion, reaction mixture
was cooled to RT, diluted with ice cold water and stirred for 15
minutes. Solid was filtered and dried under vacuum to afford
6,7-dimethoxy-2-(pyridin-4-yl)quinazolin-4 (1H)-one (410 mg, 30%).
LCMS: 283[M+1].sup.+
[0471] Step-2: Synthesis of
4-chloro-6,7-dimethoxy-2-(pyridin-4-yl)quinazoline: A mixture of
6,7-dimethoxy-2-(pyridin-4-yl)quinazolin-4 (1H)-one (200 mg, 0.90
mmol, 1 eq) in POCl.sub.3 (0.6 mL) was stirred at 120.degree. C.
for 2 h. Progress of reaction was monitored by TLC. After
completion, reaction mixture was cooled to RT, diluted with ice
cold water (10 mL) and stirred for 15 minutes. Solid was filtered
and dried under vacuum to afford
4-chloro-6,7-dimethoxy-2-(pyridin-4-yl)quinazoline (100 mg, 47%).
LCMS: 301[M+1].sup.+
[0472] Step-3: Synthesis of
4-(3-(2-sulfamoylaminoethyl)azetidine-1-yl)-6,7-dimethoxy-2-(pyridin-4-yl-
)quinazoline: A suspension of
4-chloro-6,7-dimethoxy-2-(pyridin-4-yl)quinazoline (50 mg, 0.16
mmol, 1.0 eq), 3-(2-sulfamoylaminoethyl)azetidine trifluoroacetate
(49 mg, 0.15 mmol, 1.0 eq) and N,N diisopropylethylamine (42 mg,
0.30 mmol, 2.0 eq) in DMF (1 mL) was allowed to stir at 80.degree.
C. for 2 h. Progress of reaction was monitored by TLC. Reaction
mixture was cooled to RT, DMF was removed under reduced pressure,
crude obtained was purified by reversed phase HPLC to afford
4-(3-(2-sulfamoylaminoethyl)azetidine-1-yl)-6,7-dimethoxy-2-(pyridin-4-yl-
)quinazoline (13 mg, 17%). LCMS: 461[M+1].sup.+; .sup.1H NMR (400
MHz, DMSO-d.sub.6) (ppm 8.70 (d, 2H), 8.29 (s, 1H), 8.28 (s, 1H),
7.24 (d, 2H), 6.60 (brs, 1H), 6.57 (s, 2H), 4.68 (brs, 2H), 4.25
(brs, 2H), 3.95 (s, 3H), 3.91 (s, 3H), 3.00-2.81 (m, 3H), 1.92-1.80
(m, 2H).
Example-36: Synthesis of
6,7-dimethoxy-2-(1-methylpyrazol-3-yl)-4-[3-[2-(sulfamoylamino)ethyl]azet-
idin-1-yl]quinazoline, (Compound 1.36)
##STR00613##
[0474] Step-1: Synthesis of
6,7-dimethoxy-2-(1-methylpyrazol-3-yl)quinazoline 4 (1H)-one: A
mixture of methyl 2-amino-4,5-dimethoxy-benzoate (500 mg, 2.36
mmol, 1 eq) and 1-methylpyrazole-3-carbonitrile (279 mg, 2.60 mmol,
1.1 eq) in 4M HCl in dioxane (5 mL) was sonicated for 30 minutes
and then stirred at 100.degree. C. for 12 h. Progress of reaction
was monitored by TLC. After completion, reaction mixture was cooled
to RT, poured into ice-cold water and stirred for 15 minutes. The
solid obtained was filtered and dried under vacuum to afford
6,7-dimethoxy-2-(1-methylpyrazol-3-yl)quinazoline 4 (1H)-one (415
mg, 56%). LCMS: 287 [M+1].sup.+
[0475] Step-2: Synthesis of
4-chloro-6,7-dimethoxy-2-(1-methylpyrazol-3-yl)quinazoline: To a
stirred solution of
6,7-dimethoxy-2-(1-methylpyrazol-3-yl)quinazoline 4 (1H)-one (200
mg, 0.69 mmol, 1 eq) in POCl.sub.3 (1 mL) was stirred at
120.degree. C. for 2 h. Progress of reaction was monitored by TLC.
After completion, reaction mixture was cooled to RT, poured into
ice-cold water (20 mL) and stirred for 15 minutes. Solid was
filtered and dried under vacuum to afford
4-chloro-6,7-dimethoxy-2-(1-methylpyrazol-3-yl)quinazoline (76 mg,
35%). LCMS: 305 [M+1].sup.+
[0476] Step-3: Synthesis of
6,7-dimethoxy-2-(1-methylpyrazol-3-yl)-4-[3-[2-(sulfamoylamino)ethyl]azet-
idin-1-yl]quinazoline: A suspension of
4-chloro-6,7-dimethoxy-2-(1-methylpyrazol-3-yl)quinazoline (50 mg,
0.164 mmol, 1.0 eq), N-[2-(azetidin-3-yl)ethyl]sulfuric diamide
triflorocetic acid (49 mg, 0.164 mmol, 1.0 eq) and N,N
diisopropylethylamine (60 mg, 0.32 mmol, 2.0 eq) in DMF (2 mL) was
allowed to stir at 80.degree. C. for 2 h. Progress of reaction was
monitored by TLC. Reaction mixture was cooled to RT, concentrated
under vacuum to get semi-solid residue which was triturated with
ether, ethyl acetate and then with pentane to afford crude solid
which was purified by reversed phase HPLC to afford
6,7-dimethoxy-2-(1-methylpyrazol-3-yl)-4-[3-[2-(sulfamoylamino)ethyl]azet-
idin-1-yl]quinazoline (3 mg, 4%). LCMS: 448 [M+1].sup.+; .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 13.90 (brs, 1H), 7.95 (s,
1H), 7.58 (s, 1H), 7.28 (s, 1H), 7.00 (s, 1H), 6.60 (s, 1H), 6.58
(s, 2H), 4.80 (brs, 2H), 4.42 (brs, 2H), 4.02 (s, 3H), 3.98 (s,
6H), 3.03-2.90 (m, 3H), 2.00-1.82 (m, 2H).
Example-37: Synthesis of
2-ethyl-7-methoxy-4-[3-[2-(sulfamoylamino)ethyl]azetidin-1-yl]quinazoline-
, (Compound 1.37)
##STR00614##
[0478] Step Step-1: Synthesis of methyl 2-amino-4-methoxy-benzoate:
To a mixture of 2-amino-4-methoxy-benzoic acid (5 g, 29.94 mmol, 1
eq) in methanol (100 mL) was added H.sub.2SO.sub.4 (6 mL) and then
allowed to reflux for 16 h. Progress of reaction was monitored by
TLC. After completion, reaction mixture was cooled to RT, and
concentrated under reduced pressure, neutralized with sodium
bicarbonate and diluted with water (100 mL), extracted with ethyl
acetate (300 mL). Organic layer was concentrated under reduced
pressure to afford the title compound (3.9 g, 78%). LCMS:
182[M+1].sup.+
[0479] Step-2: Synthesis of 2-ethyl-7-methoxy-1H-quinazolin-4-one:
A mixture of methyl 2-amino-4-methoxy-benzoate (800 mg, 4.41 mmol,
1 eq) and propanenitrile (330 mg, 4.48 mmol, 1.1 eq) in 4M HCl in
dioxane (09 mL) was sonicated for 30 minutes and followed by
heating at 100.degree. C. for 12 h. Progress of reaction was
monitored by TLC. After completion, reaction mixture was cooled to
RT, poured into ice-cold water and stirred for 15 minutes. The
solid obtained was filtered and dried under vacuum to afford the
title compound (350 mg, 38%). LCMS: 205[M+1].sup.+
[0480] Step-3: Synthesis of 4-chloro-2-ethyl-7-methoxy-quinazoline:
A stirred solution of 2-ethyl-7-methoxy-1H-quinazolin-4-one (200
mg, 0.98 mmol, 1 eq) in POCl.sub.3 (0.5 mL) was allowed to heat at
120.degree. C. for 2 h. Progress of reaction was monitored by TLC.
After completion, reaction mixture was cooled to RT, poured into
ice-cold water (20 mL) and stirred for 15 minutes. Solid was
filtered and dried under vacuum to afford the title compound (90
mg, 41%). LCMS: 223[M+1].sup.+
[0481] Step-4: Synthesis of
2-ethyl-7-methoxy-4-[3-[2-(sulfamoylamino)ethyl]azetidin-1-yl]quinazoline-
: A suspension of 4-chloro-2-ethyl-7-methoxy-quinazoline (90 mg,
0.40 mmol, 1.0 eq), N-[2-(azetidin-3-yl)ethyl]sulfuric diamide
triflorocetic acid (118 mg, 0.40 mmol, 1.0 eq) and N,N
diisopropylethylamine (150 mg, 0.81 mmol, 2.0 eq) in DMF (2 mL) was
allowed to stir at 80.degree. C. for 2 h. Progress of reaction was
monitored by TLC. Reaction mixture was cooled to RT, concentrated
under vacuum to get semi-solid residue which was triturated with
ether, ethyl acetate and then with pentane to afford crude solid
which was purified by RP-HPLC to afford the title compound (24 mg,
16%). LCMS: 366[M+1].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. ppm 7.85 (d, J=9.21 Hz, 1H), 7.11-6.99 (m, 2H), 6.61-6.47
(m, 3H), 4.59 (br. s., 2H), 4.15 (br. s., 2H), 3.88 (s, 3H),
2.98-2.81 (m, 3H), 2.70 (q, J=7.75 Hz, 2H), 1.91 (s, 1H), 1.85 (q,
J=6.72 Hz, 2H), 1.26 (t, J=7.45 Hz, 3H).
Example-38: Synthesis of
(2-(7-fluoro-6-methoxyquinazolin-4-yl)azetidin-3-yl))aminosulfonamide,
(Compound 1.38)
##STR00615##
[0483] Step-1: Synthesis of 6-fluoro-8-methoxyquinazolin-4
(3H)-one: To a stirred solution of
2-amino-5-fluoro-3-methoxybenzoic acid (0.5 g, 2.7 mmol, 1 eq) in
ethanol (6 mL) was added triethylorthoformate (0.8 mL, 4.8 mmol,
1.8 eq) and ammonium acetate (0.58 g, 7.5 mmol, 2.8 eq.). The
resulting reaction mixture was allowed to stir at 90.degree. C. for
48 h. After 48 h, reaction mixture was cooled to RT, filtered and
washed with hexane to afford the title compound (0.39 g, 74%).
LCMS: 195[M+1].sup.+
[0484] Step-2: Synthesis of 4-chloro-6-fluoro-8-methoxyquinazoline:
A mixture of 6-fluoro-8-methoxyquinazolin-4 (3H)-one in POCl.sub.3
(1.5 mL) was allowed to stir at 120.degree. C. for 2 h. Progress of
reaction of reaction was monitored by TLC. After completion,
reaction mixture was poured into cold water (100 mL), precipitates
so obtained were filtered, dried under vacuum to afford title
compound (0.11 g, 67%) which was used as such for next step without
purification. LCMS: 213[M+1].sup.+
[0485] Step-3: Synthesis of
(2-(7-fluoro-6-methoxyquinazolin-4-yl)azetidin-3-yl))aminosulfonamide:
A suspension of 4-chloro-6-fluoro-8-methoxyquinazoline (54 mg, 0.25
mmol, 1.5 eq), N-[2-(azetidin-3-yl)ethyl]sulfuric diamide
triflorocetic acid (50 mg, 0.17 mmol, 1.0 eq) and DIPEA (0.06 mL,
0.34 mmol, 2.0 eq) in DMF (1 mL) was allowed to stir at 80.degree.
C. for 3 h. After 3 h, reaction mixture was concentrated under
reduced pressure to afford crude which was purified using RP-HPLC
to afford the title compound (6 mg, 10%). LCMS: 356 [M+1];
.sup.1HNMR (400 MHz, DMSO-d.sub.6) .delta. ppm 8.39 (s, 1H), 7.23
(d, J=10.09 Hz, 1H), 7.17 (d, J=9.65 Hz, 1H), 6.48-6.60 (m, 3H),
4.56 (br. s., 2H), 4.13 (br. s., 2H), 3.92 (s, 3H), 2.92 (d, J=6.14
Hz, 2H), 2.84 (br. s., 1H), 1.84 (d, J=7.02 Hz, 2H).
Example-39: Synthesis of
3-(1-(6,7-dimethoxyquinazolin-4-yl)azetidin-3-yl)propane-1-sulfonamide,
(Compound 1.39)
##STR00616##
[0487] Step-1: Synthesis of N-(4-methoxybenzyl)methanesulfonamide:
To a solution of 4-methoxybenzylamine (2 g, 14 mmol, 1.0 eq) in DCM
(20 mL) was added triethylamine (3.96 mL, 29 mmol, 2 eq) and the
reaction mixture was allowed to stir at 0.degree. C. for 5 min. To
this mixture was added methane sulfonyl chloride (1.35 mL, 17 mmol,
1.2 eq) and the reaction mixture was stirred at 0.degree. C. for 10
min followed by stirring at RT for 2 h. Progress of reaction was
monitored by .sup.1H NMR. After completion, reaction mixture was
diluted with water (100 mL) and extracted with ethyl acetate
(3.times.100 mL). Combined organic layer was washed with brine (150
mL) and dried over anhydrous sodium sulfate. Removal of solvent
under reduced pressure afforded the title compound (2.5 g), which
was used for next step without purification.
[0488] Step-2: Synthesis of diethyl
(N-(4-methoxybenzyl)sulfamoyl)methylphosphonate:
N-(4-methoxybenzyl)methanesulfonamide (2 g, 9.2 mmol, 1 eq) was
dissolved in THF (20 ml) and cooled to -78.degree. C. To this
solution was added 2.5 M n-BuLi (7.6 mL, 18 mmol, 2 eq) dropwise
under nitrogen and the reaction was stirred at the same temperature
for 1 h. Diethyl chlorophosphate (0.8 mL, 4.6 mmol, 0.5 eq) in THF
(2 mL) was added dropwise to the reaction mixture at the same
temperature. The reaction was warmed to 0.degree. C. and stirred
for 1 h. The reaction mixture was quenched with NH.sub.4Cl solution
and extracted with EtOAc (3.times.100 mL). Combined organic layer
was washed with water (2.times.100 mL) followed by brine (150 mL)
and dried over anhydrous sodium sulfate. Removal of solvent under
reduced pressure provided crude product which was purified by
normal phase silica gel column chromatography using ethyl
acetate-hexane system as eluent to afford the title compound (0.8
g, 24%)
[0489] Step-3: Synthesis of diethyl
(N-(4-methoxybenzyl)sulfamoyl)methylphosphonate: Diethyl
(N-(4-methoxybenzyl)sulfamoyl)methylphosphonate (0.5 g, 1.4 mmol, 1
eq) was dissolved in THF (20 mL) and cooled the reaction mixture to
-78.degree. C. To this reaction mixture 2.5 M n-BuLi (1.2 mL, 2.9
mmol, 2.1 eq) was added dropwise under nitrogen atmosphere. The
reaction mixture was stirred at same temperature for 15 min. Then
added solution of tert-butyl 3-(2-oxoethyl)azetidine-1-carboxylate
(0.28 g, 1.4 mmol, 1 eq) in THF (2 mL) dropwise. Warmed the
reaction mixture to RT and stirred at RT for 16 h. Then quenched
the reaction mixture with saturated NH.sub.4Cl solution and
extracted with EtOAc (3.times.100 mL). Combined organic layer was
washed with water (2.times.100 mL) followed by brine (150 mL) and
dried over anhydrous sodium sulfate. Removal of solvent under
reduced pressure provided crude product which was purified by
normal phase silica gel column chromatography using ethyl
acetate-hexane system as eluent to afford the title compound (0.18
g, 32%)
[0490] Step-4: Synthesis of tert-butyl
3-(3-(N-(4-methoxybenzyl)sulfamoyl)propyl)azetidine-1-carboxylate:
To a solution of diethyl
(N-(4-methoxybenzyl)sulfamoyl)methylphosphonate (0.18 g, 0.45 mmol,
1 eq) in ethanol (10 mL) was added Pd/C (0.09 g) and the reaction
mixture was allowed to stir at RT under H.sub.2 atmosphere (using
balloon) for 3 h. Progress of reaction was monitored by TLC. After
completion, reaction mixture was filtered through celite-bed.
Removal of solvent under reduced pressure afforded crude (0.18 g)
which was used for next step without purification.
[0491] Step-5: Synthesis of 3-(azetidin-3-yl)propane-1-sulfonamide
trifluroacetate: To a solution of tert-butyl
3-(3-(N-(4-methoxybenzyl)sulfamoyl)propyl)azetidine-1-carboxylate
(0.05 g, 0.13 mmol, 1 eq) in DCM (2 mL) was added TFA (0.5 mL) and
the mixture was allowed to stir at RT for 16 h. Progress of
reaction was monitored by .sup.1H NMR. After completion, reaction
mixture was concentrated under reduced pressure to afford crude
which was triturated with diethyl ether to afford the title
compound (40 mg) which was used for next step without
purification.
[0492] Step 6: Synthesis of
3-(1-(6,7-dimethoxyquinazolin-4-yl)azetidin-3-yl)propane-1-sulfonamide:
A suspension of 6,7-dimethoxyquinazolin-4 (3H)-one (30 mg, 0.14
mmol, 2 eq), 3-(azetidin-3-yl)propane-1-sulfonamide trifluroacetate
(38 mg, 0.2 mmol, 1.0 eq) and DIPEA (0.04 mL, 0.3 mmol, 2.0 eq) in
DMF (1 mL) was allowed to stir at 80.degree. C. for 2 h. Progress
of reaction was monitored by TLC. After completion, reaction
mixture was concentrated under reduced pressure to afford residue
which was triturated with ether, ethyl acetate and then pentane to
get crude which was purified by RP-HPLC to afford the title
compound (5 mg, 10%). LCMS: 367[M+1].sup.+; .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 8.33 (s, 1H), 7.19 (s, 1H), 7.12 (s, 1H),
6.77 (s, 2H), 4.58 (br. s., 2H), 4.12 (br. s., 2H), 3.82-3.93 (m,
6H), 2.97-3.04 (m, 2H), 2.78 (br. s., 1H), 1.75 (s, 4H).
Example-40: Synthesis of
4-(3-(2-sulfamoylmethylaminoethyl)azetidine-1-yl)-7-methoxyquinazoline,
(Compound 1.40)
##STR00617## ##STR00618##
[0494] Step-1: Synthesis of tert-butyl
3-(2-(benzyloxycarbonylamino)ethyl)azetidine-1-carboxylate: To a
mixture of tert-butyl 3-(2-aminoethyl)azetidine-1-carboxylate (200
mg, 1 mmol, 1 eq) and NaHCO.sub.3 (168 mg, 2 mmol, 2 eq) in water
(5 mL) was added benzyl carbonochloridate (171 mg, 1 mmol, 1 eq)
and the resulting mixture was allowed to stir at RT for 2 h.
Progress of reaction was monitored by TLC. After completion,
reaction mixture was diluted with water (30 mL) and extracted with
ethyl acetate (3.times.50 mL). Combined organic layer was washed
with water (50 mL) followed brine (50 mL) and dried over anhydrous
sodium sulphate. Removal of solvent under reduced pressure afforded
tert-butyl
3-(2-(benzyloxycarbonylamino)ethyl)azetidine-1-carboxylate (250 mg,
64%).
[0495] Step-2: Synthesis of tert-butyl
3-(2-((benzyloxycarbonyl)(methyl)amino)ethyl)azetidine-1-carboxylate:
To a solution of tert-butyl
3-(2-(benzyloxycarbonylamino)ethyl)azetidine-1-carboxylate (250 mg,
0.75 mmol, 1 eq) in DMF (5 mL) at RT was added NaH (60 mg, 1.5
mmol, 2 eq) and the reaction mixture was stirred at RT for 10
minutes. To the mixture was then added methyl iodide (213 mg, 1.50
mmol, 2 eq) and the reaction mixture was stirred at RT for 2 h.
Progress of reaction was monitored by TLC. After completion,
reaction mixture was diluted with water (30 mL) and extracted with
diethyl ether (3.times.50 mL). Combined organic layer was washed
with water (2.times.50 mL) followed by brine (50 mL) and dried over
anhydrous sodium sulphate. Removal of solvent gave tert-butyl
3-(2-((benzyloxycarbonyl)(methyl)amino)ethyl)azetidine-1-carboxylate
(210 mg, 81%) which was used in the next step without
purification.
[0496] Step-3 Synthesis of tert-butyl
3-(2-(methylamino)ethyl)azetidine-1-carboxylate: To a solution of
tert-butyl
3-(2-((benzyloxycarbonyl)(methyl)amino)ethyl)azetidine-1-carboxylate
(210 mg) in ethanol (30 mL) was added 10% Pd--C (100 mg) and the
resulting mixture was hydrogenated at RT by nitrogen purging for 2
h. Progress of reaction was monitored by TLC. After completion,
reaction mixture was filtered through celite bed and bed was washed
with ethanol (10 mL). Combined filtrate was concentrated to afford
tert-butyl 3-(2-(methylamino)ethyl)azetidine-1-carboxylate (130 mg,
crude) which was used I the next step without purification.
[0497] Step-4: Synthesis of tert-butyl
3-(2-((N-(tert-butoxycarbonyl)sulfamoyl)
(methyl)amino)ethyl)azetidine-1-carboxylate: To a solution of
tert-butyl 3-(2-(methylamino)ethyl)azetidine-1-carboxylate (150 mg,
0.70 mmol, 1 eq) in dichloromethane (10 mL) were added
N-(tert-butoxycarbonyl)-N-[4-(dimethylazaniumylidene)-1,4-dihydropyridin--
1ylsulfonyl]azanide (317 mg 1.05 mmol, 1.5 eq) and
N,N-diisopropylethylamine (271 mg, 2.10 mmol, 3 eq) and the
reaction mixture was allowed to stir at RT for 2 days. Progress of
reaction was monitored by TLC. After completion, reaction mixture
was diluted with water (50 mL) and extracted with ethyl acetate
(3.times.100 mL). Combined organic layer was washed with brine (50
mL) and dried over anhydrous sodium sulfate. Removal of solvent
under reduced pressure afforded crude which was purified by
Combi-Flash on silica gel using ethyl acetate-hexane system as
eluent to afford tert-butyl
3-(2-((N-(tert-butoxycarbonyl)sulfamoyl)(methyl)amino)ethyl)azetidine-1-c-
arboxylatexylate (180 mg, 75%).
[0498] Step-5: Synthesis of
3-(2-sulfamoylmethylaminoethyl)azetidine trifluoroacetate: To a
solution of tert-butyl
3-(2-((N-(tert-butoxycarbonyl)sulfamoyl)(methyl)amino)ethyl)
azetidine-1-carboxylatexylate (180 mg, 0.46 mmol, 1 eq) in DCM (5
mL) was added TFA (1.5 mL) and the mixture was allowed to stir at
RT for 2 h. Progress of reaction was monitored by .sup.1H NMR.
After completion, reaction mixture was concentrated under reduced
pressure to afford crude which was triturated with diethyl ether to
afford 3-(2-sulfamoylmethylaminoethyl)azetidine trifluoroacetate
(160 mg, 86%).
[0499] Step-6: Synthesis of
4-(3-(2-sulfamoylmethylaminoethyl)azetidine-1-yl)-7-methoxyquinazoline:
A mixture of 4-chloro-7-methoxyquinazoline (50 mg, 0.256 mmol, 1.2
eq), 3-(2-sulfamoylmethylaminoethyl)azetidine trifluoroacetate (63
mg, 0.205 mmol, 1.0 eq) and DIPEA (0.138 mL, 0.768 mmol, 3.0 eq) in
DMF (1 mL) was allowed to stir at 80.degree. C. for 2 h. Progress
of reaction was monitored by TLC. After completion, reaction
mixture was concentrated under reduced pressure to get crude which
was triturated with diethyl ether, ethyl acetate and ether to
afford
4-(3-(2-sulfamoylmethylaminoethyl)azetidine-1-yl)-7-methoxyquinazoline
(20 mg, 27%). LCMS: 352 [M+1].sup.+; .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 8.38 (s, 1H), 7.83 (d, 1H), 7.10 (s, 1H),
7.06 (d, 1H), 6.72 (brs, 1H), 4.55 (brs, 2H), 4.12 (brs, 2H), 3.86
(s, 3H), 3.00-2.90 (m, 2H), 2.89-2.72 (m, 1H), 2.65 (s, 3H),
1.95-1.84 (m, 2H).
Example-41: Synthesis of
4-(3-(2-sulfamoylaminoethyl)azetidine-1-yl)-6-bromo-7-methoxyquinazoline,
(Compound 1.41)
##STR00619##
[0501] Step-1: Synthesis of 2-amino-5-bromo-4-methoxybenzoic acid:
To a solution of 2-amino-4-methoxybenzoic acid (1 g, 5.92 mmol, 1
eq) in DMF (30 mL) was added N-bromosuccinimide (1.17 g, 6.58 mmol,
1.1 eq) at 0.degree. C. and the reaction mixture was allowed to
stir at 0.degree. C. for 5 minutes followed by stirring at RT for 2
h. Progress of reaction was monitored by TLC. After completion,
reaction mixture was cooled to RT; solid was filtered to get
residue which was triturated with hexane to afford
2-amino-5-bromo-4-methoxybenzoic acid (0.950 g, 65%).
[0502] Step-2: Synthesis of 6-bromo-7-methoxyquinazolin-4 (1H)-one:
To a solution of 2-amino-5-bromo-4-methoxybenzoic acid (0.950 g,
3.86 mmol, 1 eq) in ethanol (15 mL) were added triethylorthoformate
(1.03 mL, 6.18 mmol, 1.6 eq) and ammonium acetate (0.386 g, 5.02
mmol, 1.3 eq.) and the reaction mixture was allowed to stir at
80.degree. C. for 12 h. Progress of reaction was monitored by TLC.
After completion, reaction mixture was cooled to RT, solid was
filtered to get residue which was triturated with diethyl ether and
ethanol to afford 6-bromo-7-methoxyquinazolin-4 (1H)-one (0.380 g,
39%).
[0503] Step-3: Synthesis of 6-bromo-4-chloro-7-methoxyquinazoline:
A suspension of 6-bromo-7-methoxyquinazolin-4 (1H)-one (0.180 g,
0.71 mmol, 1 eq) in POCl.sub.3 (1 mL) was allowed to stir at
120.degree. C. for 6 h. Progress of reaction was monitored by TLC.
After completion, reaction mixture was cooled to RT, diluted with
cold water (20 mL) and extracted with ethyl acetate (3.times.15
mL). Combined organic layer was washed with brine (50 mL) and dried
over anhydrous sodium sulfate. Removal of solvent under reduced
pressure afforded crude which was purified by Combi-Flash on silica
gel using ethyl acetate-hexane system as eluent to afford
6-bromo-4-chloro-7-methoxyquinazoline (80 mg, 42%).
[0504] Step-4: Synthesis of
4-(3-(2-sulfamoylaminoethyl)azetidine-1-yl)-6-bromo-7-methoxyquinazoline:
A suspension of 6-bromo-4-chloro-7-methoxyquinazoline (80 mg, 0.29
mmol, 1.0 eq), 3-(2-sulfamoylaminoethyl)azetidine trifluoroacetate
(80 mg, 0.292 mmol, 1.0 eq) and DIPEA (0.3 mL, 1.75 mmol, 6 eq) in
DMF (0.8 mL) was allowed to stir at 80.degree. C. for 3 h. Progress
of reaction was monitored by TLC. After completion, reaction
mixture was concentrated under reduced pressure to afford crude
product which was purified by reversed phase HPLC to afford
4-(3-(2-sulfamoylaminoethyl)azetidine-1-yl)-6-bromo-7-methoxyquinazoline
(10 mg, 8%). LCMS: 417 [M+1].sup.+; .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 8.56 (s, 1H), 8.40 (s, 1H), 8.05 s, 1H),
7.23 (s, 1H), 6.55 (t, 1H), 6.52 (s, 2H), 4.56 (brs, 2H), 4.14
(brs, 2H), 3.98 (s, 3H), 2.98-2.80 (m, 3H), 1.90-1.80 (m, 2H).
Example-42: Synthesis of
1-(cyclopropylmethyl)-7-methoxy-4-[3-[2-(sulfamoylamino)ethyl]azetidin-1--
yl]quinazoline, (Compound 1.42)
##STR00620##
[0506] Step-1: Synthesis of methyl 2-amino-4-methoxy-benzoate: A
mixture of 2-amino-4-methoxy-benzoic acid (5 g, 29.94 mmol, 1 eq)
in methanol (100 mL) was added H.sub.2SO.sub.4 (6 mL) and then
allowed to reflux for 16 h. Progress of reaction was monitored by
TLC. After completion, reaction mixture was cooled to RT,
concentrated under reduced pressure, neutralized with saturated aq.
sodium bicarbonate. Mixture was then diluted with water (100 mL)
and extracted with ethyl acetate (3.times.100 mL). Combined organic
layer was concentrated under reduced pressure to afford methyl
2-amino-4-methoxy-benzoate (3.9 g, 78%). LCMS: 182[M+1].sup.+
[0507] Step-2: Synthesis of
2-cyclopropyl-7-methoxy-1H-quinazolin-4-one: A mixture of methyl
2-amino-4-methoxy-benzoate (800 mg, 2.63 mmol, 1 eq) and
cyclopropanecarbonitrile (330 mL, 2.98 mmol, 1.1 eq) in 4M HCl in
dioxane (09 mL) was sonicated for 30 minutes and then heated at
100.degree. C. for 12 h. Progress of reaction was monitored by TLC.
After completion, reaction mixture was cooled to RT, poured into
ice-cold water and stirred for 15 minutes. The solid obtained was
filtered and dried under vacuum to afford
2-cyclopropyl-7-methoxy-1H-quinazolin-4-one (500 mg, 38%). LCMS:
217.2[M+1].sup.+.
[0508] Step-3: Synthesis of
4-chloro-1-(cyclopropylmethyl)-7-methoxy-quinazoline: A mixture of
2-cyclopropyl-7-methoxy-1H-quinazolin-4-one (200 mg, 0.92 mmol, 1
eq) in POCl.sub.3 (0.4 mL) was stirred at 120.degree. C. for 2 h.
Progress of reaction was monitored by TLC. After completion,
reaction mixture was cooled to RT, poured into ice-cold water (20
mL) and stirred for 15 minutes. Solid was filtered and dried under
vacuum to afford
4-chloro-1-(cyclopropylmethyl)-7-methoxy-quinazoline (100 mg, 41%).
LCMS: 235.2[M+1].sup.+
[0509] Step-4: Synthesis of
1-(cyclopropylmethyl)-7-methoxy-4-[3-[2-(sulfamoylamino)ethyl]
azetidin-1-yl]quinazoline: A suspension of
4-chloro-1-(cyclopropylmethyl)-7-methoxy-quinazoline (100 mg, 0.42
mmol, 1.0 eq), N-[2-(azetidin-3-yl)ethyl]sulfuric diamide
triflorocetic acid (124 mg, 0.42 mmol, 1.0 eq) and N,N
diisopropylethylamine (150 mg, 0.84 mmol, 2.0 eq) in DMF (2 mL) was
allowed to stir at 80.degree. C. for 2 h. Progress of reaction was
monitored by TLC. Reaction mixture was cooled to RT, concentrated
under vacuum to get semi-solid residue which was triturated with
ether, ethyl acetate and then with pentane to afford crude solid
which was purified by reversed phase HPLC to afford
1-(cyclopropylmethyl)-7-methoxy-4-[3-[2-(sulfamoylamino)ethyl]azetidin-1--
yl]quinazoline (10 mg, 6%). LCMS: 378[M+1].sup.+; .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. ppm 7.78 (d, 1H), 6.99 (s, 1H), 6.92 (d,
1H), 6.59-6.50 (m, 3H), 4.47 (brs, 2H), 4.05 (brs, 2H), 3.85 (s,
3H), 2.95-2.78 (m, 3H), 1.98 (brs, 1H), 1.91-1.77 (m, 2H),
1.02-0.95 (m, 2H), 0.90-0.80 (m, 2H).
Example-43: Synthesis of
1-(2,2-difluoroethyl)-6,7-dimethoxy-4-[3-[2-(sulfamoylamino)ethyl]azetidi-
n-1-yl]quinazoline, (Compound 1.43)
##STR00621##
[0511] Step-1: Synthesis of
2-(difluoromethyl)-6,7-dimethoxy-1H-quinazolin-4-one: A mixture of
methyl 2-amino-4,5-dimethoxy-benzoate (1 g, 4.72 mmol, 1 eq) and
2,2-difluoroacetonitrile (0.40 mL, 5.2 mmol, 1.1 eq) in 4M HCl in
dioxane (10 mL) was sonicated for 30 minutes and then heated at
100.degree. C. for 12 h. Progress of reaction was monitored by TLC.
After completion, reaction mixture was cooled to RT, poured into
ice-cold water and stirred for 15 minutes. The solid obtained was
filtered and dried under vacuum to afford
2-(difluoromethyl)-6,7-dimethoxy-1H-quinazolin-4-one (150 mg, 11%).
LCMS: 257[M+1].sup.+
[0512] Step-2: Synthesis of
4-chloro-1-(2,2-difluoroethyl)-6,7-dimethoxy-quinazoline: To a
stirred solution of
2-(difluoromethyl)-6,7-dimethoxy-1H-quinazolin-4-one (190 mg, 0.92
mmol, 1 eq) in POCl.sub.3 (0.4 mL) was stirred at 120.degree. C.
for 2 h. Progress of reaction was monitored by TLC. After
completion, reaction mixture was cooled to RT, poured into ice-cold
water (20 mL) and stirred for 15 minutes. Solid was filtered and
dried under vacuum to afford
4-chloro-1-(2,2-difluoroethyl)-6,7-dimethoxy-quinazoline (110 mg,
53%). LCMS: 275[M+1].sup.+
[0513] Step-3: Synthesis of
1-(2,2-difluoroethyl)-6,7-dimethoxy-4-[3-[2-(sulfamoylamino)ethyl]azetidi-
n-1-yl]quinazoline: A suspension of
4-chloro-1-(2,2-difluoroethyl)-6,7-dimethoxy-quinazoline (110 mg,
0.40 mmol, 1.0 eq), N-[2-(azetidin-3-yl)ethyl]sulfuric diamide
triflorocetic acid (117 mg, 0.40 mmol, 1.0 eq) and N,N
diisopropylethylamine (150 mg, 0.80 mmol, 2.0 eq) in DMF (2 mL) was
allowed to stir at 80.degree. C. for 2 h. Progress of reaction was
monitored by TLC. Reaction mixture was cooled to RT, concentrated
under vacuum to get semi-solid residue which was triturated with
ether, ethyl acetate and then with pentane to afford crude solid
which was purified by reversed phase HPLC to afford
1-(2,2-difluoroethyl)-6,7-dimethoxy-4-[3-[2-(sulfamoylamino)ethyl]azetidi-
n-1-yl]quinazoline (30 mg, 18%). LCMS: 418[M+1].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. ppm 7.23 (s, 2H), 6.62 (t, 1H),
6.70-6.40 (m, 3H), 4.65 (brs, 2H), 4.20 (brs, 2H), 3.95 (s, 6H),
3.00-2.80 (m, 3H), 1.90-1.80 (m, 2H).
Example-44: Synthesis of
4-(3-(2-sulfamoylaminoethyl)azetidine-1-yl)-7-methoxy-2-(pyridin-3-yl)qui-
nazoline, (Compound 1.44)
##STR00622##
[0515] Step-1: Synthesis of 7-methoxy-2-(pyridin-3-yl)quinazolin-4
(1H)-one: A mixture of methyl 2-amino-4-methoxybenzoate (800 mg,
4.47 mmol, 1 eq) and pyridine-3-carbonitrile (548 mg, 5.26 mmol,
1.1 eq) in 4M HCl in dioxane (10 mL) was heated at 100.degree. C.
for 12 h. Progress of reaction was monitored by TLC. After
completion reaction mixture was cooled to RT. It was poured into
ice cold water and stirred for 15 minutes. The solid obtained was
filtered and dried under vacuum to give
7-methoxy-2-(pyridin-3-yl)quinazolin-4 (1H)-one (550 mg, 30%).
LCMS: 253 [M+1].sup.+
[0516] Step-2: Synthesis of
4-chloro-7-methoxy-2-(pyridin-3-yl)quinazoline: A mixture of
7-methoxy-2-(pyridin-3-yl) quinazolin-4 (1H)-one (250 mg, 1.0 mmol,
1 eq) in POCl.sub.3 (0.3 mL) was stirred at 120.degree. C. for 2 h.
Progress of reaction was monitored by TLC. After completion
reaction mixture was cooled to RT, poured to ice (10 mL) and
stirred for 15 minutes. Solid was filtered and dried to afford
4-chloro-7-methoxy-2-(pyridin-3-yl)quinazoline (70 mg, 47%). LCMS:
271[M+1].sup.+
[0517] Step-3: Synthesis of
4-(3-(2-sulfamoylaminoethyl)azetidine-1-yl)-7-methoxy-2-(pyridin-3-yl)qui-
nazoline: A suspension of
4-chloro-7-methoxy-2-(pyridin-3-yl)quinazoline (70 mg, 0.258 mmol,
1.0 eq), 3-(2-sulfamoylaminoethyl)azetidine trifluoroacetate (75
mg, 0.258 mmol, 1.0 eq) and N,N diisopropylethylamine (42 mg, 0.51
mmol, 2.0 eq) in DMF (1 mL) was allowed to stir at 80.degree. C.
for 2 h. Progress of reaction was monitored by TLC. Reaction
mixture was cooled to RT, DMF was removed under reduced pressure,
crude obtained was purified by reversed phase HPLC to afford
4-(3-(2-sulfamoylaminoethyl)azetidine-1-yl)-7-methoxy-2-(pyridin-3-yl)qui-
nazoline (30 mg, 17%). LCMS: 415[M+1].sup.+; .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 9.58 (s, 1H), 8.70-8.62 (m, 2H), 7.90 (d,
1H), 7.53 (t, 1H), 7.22 (s, 1H), 7.06 (d, 1H), 6.62 (brs, 1H), 6.55
(s, 2H), 4.63 (brs, 2H), 4.22 (brs, 2H), 3.95 (s, 3H), 3.00-2.82
(m, 3H), 1.92-1.83 (m, 2H).
Example-45: Synthesis of
2-(1-adamantyl)-7-methoxy-4-[3-[2-(sulfamoylamino)ethyl]azetidin-1-yl]qui-
nazoline, (Compound 1.45)
##STR00623##
[0519] Step-1: Synthesis of methyl 2-amino-4-methoxy-benzoate: A
mixture of 2-amino-4-methoxy-benzoic acid (5 g, 29.94 mmol, 1 eq)
in methanol (100 mL) was added H.sub.2SO.sub.4 (6 mL) and then
allowed to reflux for 16 h. Progress of reaction was monitored by
TLC. After completion, reaction mixture was cooled to RT,
concentrated under reduced pressure, neutralized with sodium
bicarbonate, diluted with water (100 mL) and extracted with ethyl
acetate (3.times.100 mL). Combined organic layer was washed with
water (100 mL) and dried over anhydrous sodium. Removal of solvent
under reduced pressure afforded methyl 2-amino-4-methoxy-benzoate
(3.9 g, 78%). LCMS: 182 [M+1].sup.+
[0520] Step-2: Synthesis of
2-(1-adamantyl)-7-methoxy-1H-quinazolin-4-one: A mixture of methyl
2-amino-4-methoxy-benzoate (500 mg, 2.76 mmol, 1 eq) and
adamantane-1-carbonitrile (533 mL, 3.31 mmol, 1.1 eq) in 4M HCl in
dioxane (09 mL) was sonicated for 30 minutes and then heated at
100.degree. C. for 12 h. Progress of reaction was monitored by TLC.
After completion, reaction mixture was cooled to RT, poured into
ice-cold water and stirred for 15 minutes. The solid obtained was
filtered and dried under vacuum to afford
2-(1-adamantyl)-7-methoxy-1H-quinazolin-4-one (35 mg, 4%). LCMS:
311 [M+1].sup.+
[0521] Step-3: Synthesis of
2-(1-adamantyl)-4-chloro-7-methoxy-quinazoline: A mixture of
2-(1-adamantyl)-7-methoxy-1H-quinazolin-4-one (200 mg, 0.65 mmol, 1
eq) in POCl.sub.3 (0.2 mL) was stirred at 120.degree. C. for 2 h.
Progress of reaction was monitored by TLC. After completion,
reaction mixture was cooled to RT, poured into ice-cold water (20
mL) and stirred for 15 minutes. Solid was filtered and dried under
vacuum to afford 2-(1-adamantyl)-4-chloro-7-methoxy-quinazoline (40
mg, 19%). LCMS: 328 [M+1].sup.+
[0522] Step-4: Synthesis of
2-(1-adamantyl)-7-methoxy-4-[3-[2-(sulfamoylamino)ethyl]azetidin-1-yl]qui-
nazoline: A suspension of
2-(1-adamantyl)-4-chloro-7-methoxy-quinazoline (40 mg, 0.121 mmol,
1.0 eq), N-[2-(azetidin-3-yl)ethyl]sulfuric diamide triflorocetic
acid (24 mg, 0.121 mmol, 1.0 eq) and N,N-diisopropylethylamine (40
mg, 0.24 mmol, 2.0 eq) in DMF (2 mL) was allowed to stir at
80.degree. C. for 2 h. Progress of reaction was monitored by TLC.
Reaction mixture was cooled to RT, concentrated under vacuum to get
semi-solid residue which was triturated with ether, ethyl acetate
and then with pentane to afford crude solid which was purified by
reversed phase HPLC to afford
2-(1-adamantyl)-7-methoxy-4-[3-[2-(sulfamoylamino)ethyl]azetidin-1-yl]qui-
nazoline (5 mg, 9%). LCMS: 473 [M+1].sup.+; .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 7.79 (d, 1H), 7.03 (s, 1H), 7.97 (d, 1H),
6.60 (brs, 1H), 6.55 (brs, 2H), 4.52 (brs, 2H), 4.07 (brs, 2H),
3.86 (s, 3H), 2.95-2.78 (m, 3H), 2.10-1.97 (m, 6H), 1.92-1.80 (m,
2H), 1.79-1.61 (m, 9H).
Example-46: Synthesis of
N-[2-(6,7-di-methoxyquinazoline-4-yl)-2-azaspiro[3.3]hept-6-yl]-N-methyls-
ulfuric diamide, (Compound 1.46)
##STR00624##
[0524] Step-1: Synthesis of tert-butyl
6-(methylsulfonyloxy)-2-azaspiro[3.3]heptane-2-carboxylate To a
solution of tert-butyl 6-oxo-2-azaspiro[3.3]heptane-2-carboxylate
(1.2 g, 5.63 mmol, 1.0 eq) in dichloromethane (50 mL) at 0.degree.
C. was added triethylamine (1.7 g, 16.89 mmol, 3.0 eq) followed by
methanesulfonyl chloride (0.88 mL, 11.26 mmol, 2.0 eq) and the
resulting mixture was allowed to stir at RT for 2 h. Progress of
reaction was monitored by TLC. After completion, the reaction
mixture was concentrated under reduced pressure to obtain oily
residue which was suspended in water (100 mL) and extracted with
ethyl acetate (3.times.100 mL). The combined organic layer was
washed with 1N aq. HCl (50 mL) followed by brine (50 mL) and dried
over sodium sulphate. Removal of solvent under reduced pressure
afforded tert-butyl
6-(methylsulfonyloxy)-2-azaspiro[3.3]heptane-2-carboxylate (1.3 g,
79%) which was used in the next step without purification.
[0525] Step-2: Synthesis tert-butyl
6-azido-2-azaspiro[3.3]heptane-2-carboxylate To a solution of
tert-butyl
6-(methylsulfonyloxy)-2-azaspiro[3.3]heptane-2-carboxylate (2.7 g,
9.28 mmol, 1.0 eq) in DMF (10 mL) at RT was added sodium azide
(1.80 g, 27.84 mmol, 3.0 eq) and the reaction mixture was allowed
to stir at 70.degree. C. for 24 h. Progress of reaction was
monitored by TLC. After completion, the reaction mixture was cooled
to RT, diluted with water (100 mL) and extracted with ethyl acetate
(3.times.100 mL). The combined organic layer was washed with water
(2.times.100 mL) followed by brine and dried over anhydrous sodium
sulphate. Removal of solvent under reduced pressure afforded
tert-butyl 6-azido-2-azaspiro[3.3]heptane-2-carboxylate (2.1 g,
95%) which was used in the next step without purification.
[0526] Step-3: Synthesis of tert-butyl
6-amino-2-azaspiro[3.3]heptane-2-carboxylate To a stirred solution
of tert-butyl 6-azido-2-azaspiro[3.3]heptane-2-carboxylate (2.5 g,
0.01 mol, 1.0 eq) in 100 mL of ethanol was added Pd/C (1 g, 10% on
charcoal) and the reaction was allowed to stir at RT for 16 h.
After completion, reaction mixture was filtered through the bed of
celite and concentrated under reduced pressure to get tert-butyl
6-amino-2-azaspiro[3.3]heptane-2-carboxylate (2.3 g) which was used
as such for next step without further purification.
[0527] Step-4: Synthesis of tert-butyl
6-(benzyloxycarbonylamino)-2-azaspiro[3.3]heptane-2-carboxylate To
a stirred solution of tert-butyl
6-amino-2-azaspiro[3.3]heptane-2-carboxylate (0.24 g, 0.94 mmol,
1.0 eq) in 4 mL of water was added benzyl chloroformate (0.31 mL,
50% in toluene, 0.94 mmol, 1.0 eq) and sodium bicarbonate (0.15 g,
1.88 mmol, 2.0 eq). The resulting reaction mixture was allowed to
stir at RT for 3 h. After completion, reaction mixture was diluted
with water (50 mL) and extracted using ethyl acetate (3.times.30
mL). The combined organic layer was washed with brine (50 mL) dried
over anhydrous sodium sulphate filtered and concentrated under
vacuum to get the crude product which was purified by normal phase
silica gel column chromatography to get the desired tert-butyl
6-(benzyloxycarbonylamino)-2-azaspiro[3.3]heptane-2-carboxylate
(190 mg, 58%).
[0528] Step-5: Synthesis of tert-butyl
6-((benzyloxycarbonyl)(methyl)amino)-2-azaspiro[3.3]heptane-2-carboxylate
To a stirred solution of tert-butyl
6-(benzyloxycarbonylamino)-2-azaspiro[3.3]heptane-2-carboxylate
(0.19 g, 0.54 mmol, 1.0 eq) in 5 mL of DMF was added NaH (0.043 g,
60% in mineral oil, 1.09 mmol, 2.0 eq) and allowed the reaction
mixture to stir at RT. After 15 min Mel (0.1 mL, 1.64 mmol, 3.0 eq)
was added and reaction was allowed to stir at RT for 1 h. After
completion, reaction mixture was diluted with water (100 mL) and
extracted using diethyl ether (3.times.150 mL), dried (anhydrous
sodium sulphate), filtered and concentrated under reduced pressure
to get crude tert-butyl
6-((benzyloxycarbonyl)(methyl)amino)-2-azaspiro[3.3]heptane-2-carboxylate
(160 mg).
[0529] Step-6: Synthesis of tert-butyl
6-(methylamino)-2-azaspiro[3.3]heptane-2-carboxylate To a stirred
solution of tert-butyl
6-((benzyloxycarbonyl)(methyl)amino)-2-azaspiro[3.3]heptane-2-carboxylate
(0.16 g, 0.44 mmol, 1.0 eq) in 10 mL of ethanol was added Pd/C (0.1
g, 10% on charcoal) and allowed the reaction mixture to stir at RT
under hydrogen atmosphere. After completion, reaction mixture was
filtered through celite bed, filtrate was concentrated under
reduced pressure to get crude tert-butyl
6-(methylamino)-2-azaspiro[3.3]heptane-2-carboxylate (100 mg) which
was used as such for next step without further purification.
[0530] Step-7: Synthesis of tert-butyl
6-(methyl(sulfamoyl)amino)-2-azaspiro[3.3]heptane-2-carboxylate To
a solution of N-methyl-2-azaspiro[3.3]heptan-6-amine (100 mg, 0.44
mmol, 1.0 eq) in dichloromethane (5 mL) was added
N-(tert-butoxycarbonyl)-N-[4-(dimethylazaniumylidene)-1,4-dihydropyridin--
1ylsulfonyl]azanide (199 mg, 0.66 mmol, 1.5 eq) and
N,N-diisopropylethylamine (0.154 mL, 0.88 mmol, 2 eq) and the
reaction mixture was allowed to stir at RT for 48 h. After
completion, reaction mixture was concentrated under reduced
pressure to get crude which was purified by normal phase silica gel
column chromatography to afford tert-butyl
6-(methyl(sulfamoyl)amino)-2-azaspiro[3.3]heptane-2-carboxylate (70
mg, 52%).
[0531] Step-8: Synthesis of 2-azaspiro[3.3]heptan-6-methylamine
trifluoroacetate salt To a solution of tert-butyl
3-(2-((N-(tert-butoxycarbonyl)sulfamoyl)(methyl)amino)ethyl)azetidine-1-c-
arboxylate (180 mg, 0.46 mmol, 1 eq) in DCM (5 mL) was added TFA
(1.5 mL) and the mixture was allowed to stir at RT for 2 h. After
completion, reaction mixture was concentrated under reduced
pressure to afford crude which was triturated with diethyl ether to
afford 3-(2-sulfamoylmethylaminoethyl)azetidine trifluoroacetate
salt (120 mg, 85%).
[0532] Step-9: Synthesis of
N-[2-(6,7-di-methoxyquinazoline-4-yl)-2-azaspiro[3.3]hept-6-yl]-N-methyls-
ulfuric diamide A suspension of 2-azaspiro[3.3]heptan-6-methylamine
trifluoroacetate salt (50 mg, 0.15 mmol, 1 eq),
4-chloro-6,7-dimethoxyquinazoline (52 mg, 0.22 mmol, 1.5 eq) and
DIPEA (0.06 mL, 0.3 mmol, 2.0 eq) in DMF (1 mL) was allowed to stir
at 80.degree. C. for 3 h. Progress of the reaction was monitored by
TLC. After completion, reaction mixture was concentrated under
reduced pressure to get residue which was purified by RP-HPLC to
afford
N-[2-(6,7-di-methoxyquinazoline-4-yl)-2-azaspiro[3.3]hept-6-yl]-N-methyls-
ulfuric diamide (13 mg, 21% yield). LCMS: 394.4 [M+1].sup.+;
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 8.33 (s, 1H), 7.16
(s, 1H), 7.12 (s, 1H), 6.71 (br. s., 2H), 4.53 (br. s., 2H), 4.40
(br. s., 2H), 3.89 (d, J=3.07 Hz, 6H), 3.76-3.85 (m, 1H), 2.55 (s,
3H), 2.45-2.35 (m, 4H).
Example-47: Synthesis of
4-(3-(2-sulfamoylmethylaminoethyl)azetidine-1-yl)-6,7-di-methoxyquinazoli-
ne, (Compound 1.47)
##STR00625##
[0534] Step-1: Synthesis of tert-butyl
3-(2-(benzyloxycarbonylamino)ethyl)azetidine-1-carboxylate: To a
solution of tert-butyl 3-(2-aminoethyl)azetidine-1-carboxylate (0.2
g, 1.0 mmol, 1 eq) in H.sub.2O (5 mL), was added NaHCO.sub.3 (0.168
g, 2.0 mmol, 2.0 eq) and benzyl chloroformate (171 mg, 1.0 mmol, 1
eq). The reaction mixture was allowed to stir at RT for 3 h.
Progress of the reaction was monitored by .sup.1H NMR. After
completion, reaction mixture was diluted with water (100 mL) and
extracted with EtOAc (3.times.100 mL). Combined organic layer was
washed with brine (150 mL) and dried over anhydrous sodium sulfate.
Removal of solvent under reduced pressure afforded tert-butyl
3-(2-(benzyloxycarbonylamino)ethyl)azetidine-1-carboxylate (0.25 g,
74%) which was used in the next step without further
purification.
[0535] Step-2: Synthesis of tert-butyl
3-(2-((benzyloxycarbonyl)(methyl)amino)ethyl)azetidine-1-carboxylate:
To a solution of tert-butyl
3-(2-(benzyloxycarbonylamino)ethyl)azetidine-1-carboxylate (0.25 g,
0.75 mmol, 1 eq) in DMF (5 mL), was added NaH (60 mg, 1.5 mmol, 2.0
eq, .about.60% in paraffin oil) and the resulting mixture was
stirred at RT for 10 minutes. To the mixture was then added methyl
iodide (0.213 g, 1.5 mmol, 2 eq) and the reaction mixture was
allowed to stir at RT for 2 h. Progress of reaction is monitored by
.sup.1H NMR. After completion, reaction mixture was diluted with
water (100 mL) and extracted with EtOAc (3.times.100 mL). Combined
organic layer was washed with water (2.times.100 mL) followed by
brine (150 mL) and dried over anhydrous sodium sulfate. Removal of
solvent under reduced pressure afforded tert-butyl
3-(2-((benzyloxycarbonyl)(methyl)amino)ethyl)azetidine-1-carboxylate
(0.210 g, 80%) which was used in the next step without
purification.
[0536] Step-3: Synthesis of tert-butyl
3-(2-(methylamino)ethyl)azetidine-1-carboxylate: To a solution of
tert-butyl
3-(2-((benzyloxycarbonyl)(methyl)amino)ethyl)azetidine-1-carboxylate
(210 mg, 0.6 mmol, 1 eq) in ethanol (30 mL) was added Pd/C (100 mg)
and the reaction mixture was allowed to stir at RT under H.sub.2
atmosphere using balloon for 2 h. Progress of reaction was
monitored by TLC. After completion, reaction mixture was filtered
through celite-bed. Removal of solvent under reduced pressure
afforded crude tert-butyl
3-(2-(methylamino)ethyl)azetidine-1-carboxylate (130 mg, crude)
which was used in the next step without purification.
[0537] Step-4: Synthesis of tert-butyl
3-(2-((N-(tert-butoxycarbonyl)sulfamoyl)(methyl)amino)ethyl)azetidine-1-c-
arboxylate: To a solution of tert-butyl
3-(2-(methylamino)ethyl)azetidine-1-carboxylate (150 mg, 0.7 mmol,
1 eq) in dichloromethane (10 mL) were added
N-(tert-butoxycarbonyl)-N-[4-(dimethylazaniumylidene)-1,4-dihydropyridin--
1ylsulfonyl]azanide (317 mg, 1.05 mmol, 1.5 eq) and
N,N-diisopropylethylamine (271 mg, 2.1 mmol, 3 eq) and the reaction
mixture was allowed to stir at RT for 48 h. Progress of reaction
was monitored by TLC. After completion, reaction mixture was
concentrated under reduced pressure to get crude which was purified
by Combi-Flash using ethyl acetate-hexane system as eluent to
afford tert-butyl
3-(2-((N-(tert-butoxycarbonyl)sulfamoyl)(methyl)amino)ethyl)azetidine-1-c-
arboxylate (180 mg, 65%).
[0538] Step-5: Synthesis of
3-(2-sulfamoylmethylaminoethyl)azetidine trifluoroacetate: To a
solution of tert-butyl
3-(2-((N-(tert-butoxycarbonyl)sulfamoyl)(methyl)amino)ethyl)azetidine-1-c-
arboxylate (180 mg, 0.46 mmol, 1 eq) in DCM (5 mL) was added TFA
(1.5 mL) and the mixture was allowed to stir at RT for 2 h.
Progress of reaction was monitored by .sup.1H NMR. After
completion, reaction mixture was concentrated under reduced
pressure to afford crude which was triturated with diethyl ether to
afford 3-(2-sulfamoylmethylaminoethyl)azetidine trifluoroacetate
(120 mg, 85%).
[0539] Step-6: Synthesis of
4-(3-(2-sulfamoylmethylaminoethyl)azetidine-1-yl)-6,7-di-methoxyquinazoli-
ne: A suspension of 3-(2-sulfamoylmethylaminoethyl)azetidine
trifluoroacetate (54 mg, 0.24 mmol, 1.5 eq),
4-chloro-6,7-dimethoxyquinazoline (50 mg, 0.16 mmol, 1.0 eq) and
DIPEA (0.05 mL, 0.32 mmol, 2.0 eq) in DMF (1 mL) was allowed to
stir at 80.degree. C. for 3 h. Progress of reaction was monitored
by TLC. After 3 h, reaction mixture was concentrated under reduced
pressure to afford crude product which was purified using RP-HPLC
to afford
4-(3-(2-sulfamoylmethylaminoethyl)azetidine-1-yl)-6,7-di-methoxyquinazoli-
ne (18 mg, 29%). LCMS: 382 [M+1].sup.+; .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 8.33 (s, 1H), 7.19 (s, 1H), 7.12 (s, 1H),
6.71 (s, 2H), 4.57 (br. s., 3H), 4.14 (br. s., 2H), 3.90 (s, 3H),
3.87 (s, 3H), 2.96 (t, J=7.02 Hz, 2H), 2.83 (d, J=8.33 Hz, 2H),
2.62-2.67 (m, 3H), 1.85-1.95 (m, 3H).
Example-48: Synthesis of
N-[2-(6,7-di-methoxyquinazoline-4-yl)-2-azaspiro[3.3]hept-6-yl]-N-cyclopr-
opylsulfuric diamide, (Compound 1.48)
##STR00626##
[0541] Step-1: Synthesis of tert-butyl
6-(cyclopropylamino)-2-azaspiro[3.3]heptane-2-carboxylate: A
suspension of tert-butyl 6-oxo-2-azaspiro[3.3]heptane-2-carboxylate
(500 mg, 2.3 mmol, 1 eq), cyclopropyl amine (135 mg, 2.3 mmol, 1.0
eq) and acetic acid (0.4 mL, 6.9 mmol, 3 eq) in DCE (10 mL) was
stirred at 0.degree. C. for 30 minutes. After 30 minutes,
NaCNBH.sub.3 (0.44 g, 6.9 mmol, 3 eq) was added into above reaction
mixture and then resultant reaction mixture was allowed to stir at
RT for 4 h. Progress of reaction was monitored by TLC. After
completion, reaction mixture was concentrated under reduced
pressure to get residue which was diluted with saturated aqueous
NaHCO.sub.3 solution (100 mL) and extracted with ethyl acetate
(3.times.150 mL). Combined organic layer was washed with brine
(3.times.50 mL) and dried over anhydrous sodium sulfate. Removal of
solvent under reduced pressure to afford tert-butyl
6-(cyclopropylamino)-2-azaspiro[3.3]heptane-2-carboxylate (710 mg)
which was used in the next step without purification.
[0542] Step-2: Synthesis of tert-butyl
6-((N-(tert-butoxycarbonyl)sulfamoyl)(cyclopropyl)amino)-2-azaspiro[3.3]h-
eptane-2-carboxylate: To a solution of tert-butyl
6-(cyclopropylamino)-2-azaspiro[3.3]heptane-2-carboxylate (710 mg,
2.8 mmol, 1 eq) in DCM (50 mL) were added
N-(tert-butoxycarbonyl)-N-[4-(dimethylazaniumylidene)-1,4-dihydropyridin--
1ylsulfonyl]azanide (1.27 g, 4.2 mmol, 1.5 eq) and DIPEA (0.98 Ml,
5.6 mmol, 2 eq) and the mixture was allowed to stir at RT for 16 h.
Progress of reaction was monitored by TLC. After completion,
reaction mixture was concentrated under reduced pressure to get
crude product which was purified using combi flash column
chromatography to afford tert-butyl
6-((N-(tert-butoxycarbonyl)sulfamoyl)(cyclopropyl)amino)-2-azaspiro[3.3]h-
eptane-2-carboxylate (0.4 g, 33%).
[0543] Step-3: Synthesis of
(6-N-sulfamoylcyclopropylamino)-2-azaspiro[3.3]heptane
trifluoroacetate: To a solution of tert-butyl
6-((N-(tert-butoxycarbonyl)sulfamoyl)(cyclopropyl)amino)-2-azaspiro[3.3]h-
eptane-2-carboxylate (400 mg, 0.92 mmol, 1 eq) in DCM (10 mL) was
added TFA (3 mL) and was allowed to stir at RT for 2 h. Progress of
reaction was monitored by TLC. After completion, reaction mixture
was concentrated under reduced pressure to afford crude which was
triturated with diethyl ether to afford
(6-N-sulfamoylcyclopropylamino)-2-azaspiro[3.3]heptane
trifluoroacetate (300 mg, 94%) as TFA salt.
[0544] Step-4: Synthesis of
N-[2-(6,7-di-methoxyquinazoline-4-yl)-2-azaspiro[3.3]hept-6-yl]-N-cyclopr-
opylsulfuric diamide: A suspension of
(6-N-sulfamoylcyclopropylamino)-2-azaspiro[3.3]heptane
trifluoroacetate (100 mg, 0.28 mmol, 1 eq),
4-chloro-6,7-dimethoxyquinazoline (78 mg, 0.34 mmol, 1.2 eq) and
DIPEA (0.1 mL, 0.56 mmol, 2.0 eq) in DMF (1 mL) was allowed to stir
at 80.degree. C. for 3 h. Progress of reaction was monitored by
LCMS. After 3 h, reaction mixture was concentrated under reduced
pressure to get crude which was purified using reversed phase HPLC
to afford
N-[2-(6,7-di-methoxyquinazoline-4-yl)-2-azaspiro[3.3]hept-6-yl]-N-cyclopr-
opylsulfuric diamide (16 mg, 13%). LCMS: 420 [M+1].sup.+; .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 8.33 (s, 1H), 7.17 (s, 1H),
7.12 (s, 1H), 6.85 (br. s., 2H), 4.54 (br. s., 2H), 4.40 (br. s.,
2H), 3.89 (d, J=2.19 Hz, 6H), 2.07 (br. s., 1H), 1.65 (s, 4H), 1.23
(br. s., 1H), 0.70 (d, J=6.58 Hz, 4H)
Example-49: Synthesis of
N-(2-(6,7-dimethoxyquinazolin-4-yl)-2-azaspiro[3.3]heptan-6-yl)methanesul-
fonamide, (Compound 1.49)
##STR00627##
[0546] Step-1: Synthesis of tert-butyl
6-(methylsulfonyloxy)-2-azaspiro[3.3]heptane-2-carboxylate: To a
solution of tert-butyl
6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate (1.2 g, 5.63 mmol, 1
eq) in DCM (50 mL) were added triethylamine (1.7 g, 16.89 mmol, 3
eq) and mesyl chloride (1.3 g, 11.26 mmol, 2 eq) and reaction
mixture was allowed to stir at RT for 2 h. Progress of reaction was
monitored by .sup.1H NMR. After completion, reaction mixture was
concentrated, diluted with water (100 mL) and extracted with ethyl
acetate (3.times.100 mL). Combined organic layer was washed with
brine (150 mL) and dried over anhydrous sodium sulfate. Removal of
solvent under reduced pressure to afford tert-butyl
6-(methylsulfonyloxy)-2-azaspiro[3.3]heptane-2-carboxylate (1.3 g,
79%) which was used in the next step without purification.
[0547] Step-2: Synthesis of tert-butyl
6-azido-2-azaspiro[3.3]heptane-2-carboxylate: To a solution of
tert-butyl
6-(methylsulfonyloxy)-2-azaspiro[3.3]heptane-2-carboxylate (2.7 g,
9.28 mmol, 1 eq) in DMF (10 mL) was added sodium azide (1.8 g, 27.8
mmol, 3 eq) and the reaction mixture was allowed to stir at
70.degree. C. for 24 h. Progress of reaction is monitored by
.sup.1H NMR. After completion, reaction mixture was cooled, diluted
with water (100 mL) and extracted with diethyl ether (3.times.150
mL). Combined organic layer was washed with water (2.times.100 mL)
followed by brine (150 mL) and dried over anhydrous sodium sulfate.
Removal of solvent under reduced pressure to afford tert-butyl
6-azido-2-azaspiro[3.3]heptane-2-carboxylate (2.1 g, 95%) which was
used in the next step without purification.
[0548] Step-3: Synthesis of tert-butyl
6-amino-2-azaspiro[3.3]heptane-2-carboxylate: To a solution of
tert-butyl 6-azido-2-azaspiro[3.3]heptane-2-carboxylate (2.5 g, 10
mmol, 1 eq) in ethanol (100 mL) was added Pd/C (1 g, .about.10% on
charcoal) and the reaction mixture was allowed to stir at RT for 16
h under hydrogen atmosphere. Progress of reaction was monitored by
TLC. After completion, reaction mixture was filtered through celite
bed and filtrate so obtained was concentrated under reduced
pressure to afford tert-butyl
6-amino-2-azaspiro[3.3]heptane-2-carboxylate (2.3 g) which was used
in the next step without purification.
[0549] Step-4: Synthesis of tert-butyl
6-(methylsulfonamido)-2-azaspiro[3.3]heptane-2-carboxylate: To a
solution of Compound (D) (0.2 g, 0.94 mmol, 1 eq) in DCM (5 mL)
were added TEA (0.397 mL, 2.82 mmol, 3 eq) and mesyl chloride
(0.145 mL, 1.88 mmol, 2 eq) and then reaction mixture was allowed
to stir at RT for 2 h. Progress of reaction was monitored by TLC.
After 2 h, reaction mixture was cooled, diluted with aqueous
saturated NaHCO.sub.3 solution (100 mL) and extracted with DCM
(3.times.150 mL). Combined organic layer was washed with water
(2.times.100 mL) followed by brine (150 mL) and dried over
anhydrous sodium sulfate. Removal of solvent under reduced pressure
to afford tert-butyl
6-(methylsulfonamido)-2-azaspiro[3.3]heptane-2-carboxylate (0.23 g,
84%) which was used in the next step without purification.
[0550] Step-5: Synthesis of
N-(-2-azaspiro[3.3]heptan-6-yl)methanesulfonamide trifluoroacetate:
To a solution of tert-butyl
6-(methylsulfonamido)-2-azaspiro[3.3]heptane-2-carboxylate (230 mg,
0.79 mmol, 1 eq) in DCM (5 mL) was added TFA (2 mL) and was allowed
to stir at RT for 2 h. Progress of reaction was monitored by TLC.
After completion, reaction mixture was concentrated under reduced
pressure to afford crude which was triturated with diethyl ether to
afford N-(-2-azaspiro[3.3]heptan-6-yl)methanesulfonamide
trifluoroacetate (200 mg, 83%) as TFA salt.
[0551] Step-6: Synthesis of
N-(2-(6,7-dimethoxyquinazolin-4-yl)-2-azaspiro[3.3]heptan-6-yl)methanesul-
fonamide: A suspension of
N-(-2-azaspiro[3.3]heptan-6-yl)methanesulfonamide trifluoroacetate
(100 mg, 0.32 mmol, 1 eq), 4-chloro-6,7-dimethoxyquinazoline (88
mg, 0.39 mmol, 1.2 eq) and DIPEA (0.1 mL, 0.65 mmol, 2.0 eq) in DMF
(1 mL) was allowed to stir at 80.degree. C. for 3 h. Progress of
reaction was monitored by LCMS. After 3 h, reaction mixture was
concentrated under reduced pressure to get crude which was purified
using reversed phase HPLC to afford
N-(2-(6,7-dimethoxyquinazolin-4-yl)-2-azaspiro[3.3]heptan-6-yl)methanesul-
fonamide (18 mg, 14%). LCMS: 379 [M+1].sup.+; .sup.1H NMR (400 MHz,
DMSO-d.sub.6) (ppm 8.33 (s, 1H), 7.42 (d, J=7.45 Hz, 1H), 7.16 (s,
1H), 7.12 (s, 1H), 4.54 (br. s., 2H), 4.39 (br. s., 2H), 3.89 (d,
J=1.75 Hz, 6H), 3.73 (br. s., 1H), 2.86 (s, 3H), 2.65 (d, J=16.66
Hz, 4H).
Example-50: Synthesis of
4-(3-(2-sulfamoylaminoethyl)azetidine-1-yl)-6,8-di-methoxyquinazoline,
(Compound 1.50)
##STR00628##
[0553] Step-1: Synthesis of 6,8-dimethoxyquinazolin-4 (3H)-one: A
mixture of 2-amino-3,5-dimethoxybenzoic acid (0.25 g, 1.2 mmol, 1
eq), ammonium acetate (0.127 g, 1.5 mmol, 1.3 eq) and
triethylorthoformate (0.33 mL, 1.9 mmol, 1.6 eq) in ethanol (5 mL)
was allowed to stir at 90.degree. C. for 16 h. Progress of reaction
was monitored by TLC. Reaction mixture was cooled to RT, solid was
filtered, washed with hexane and dried to afford
6,8-dimethoxyquinazolin-4 (3H)-one (200 mg, 76%). LCMS: 207
[M+1].sup.+
[0554] Step-2: Synthesis of 4-chloro-6,8-dimethoxyquinazoline: The
stirred solution of 6,8-dimethoxyquinazolin-4 (3H)-one (0.2 g, 0.96
mmol, 1 eq) in 2 mL of POCl.sub.3 was heated at 120.degree. C. for
2 h. After completion reaction mixture was diluted with water (50
mL), precipitates so formed were filtered and dried under vacuum to
afford desired 4-chloro-6,8-dimethoxyquinazoline (100 mg, 46%).
LCMS: 225 [M+1].sup.+
[0555] Step-3: Synthesis of
4-(3-(2-sulfamoylaminoethyl)azetidine-1-yl)-6,8-di-methoxyquinazoline:
A suspension of 4-chloro-6,8-dimethoxyquinazoline (45 mg, 0.20
mmol, 1.2 eq), 3-(2-sulfamoylaminoethyl)azetidine trifluoroacetate
(50 mg, 0.17 mmol, 1.0 eq) and DIPEA (0.06 mL, 0.34 mmol, 2.0 eq)
in DMF (1 mL) was allowed to stir at 80.degree. C. for 3 h.
Progress of reaction was monitored by TLC. After 3 h, reaction
mixture was concentrated under reduced pressure to afford crude
which was purified using RP-HPLC to afford
4-(3-(2-sulfamoylaminoethyl)azetidine-1-yl)-6,8-di-methoxyquinazol-
ine (29 mg, 46%). LCMS: 368 [M+1].sup.+; 1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 8.31 (s, 1H), 6.88 (d, J=2.63 Hz, 1H), 6.79
(d, J=2.19 Hz, 1H), 6.60 (br. s., 1H), 6.54 (br. s., 2H), 4.58 (br.
s., 2H), 4.14 (br. s., 2H), 3.74-3.96 (m, 6H), 2.91 (d, J=6.14 Hz,
2H), 2.83 (d, J=5.70 Hz, 1H), 1.80-1.91 (m, 2H),
Example-51: Synthesis of
3-(1-(6,7-dimethoxyquinazolin-4-yl)azetidin-3-yl)-N-hydroxypropanamide,
(Compound 1.51)
##STR00629##
[0557] To a solution of 3-(azetidin-3-yl)-N-hydroxypropanamide (0.1
g, 0.445 mmol, 1 eq) in DMF (1 mL) were added
N,N-diisopropylethylamine (0.3 mL, 1.34 mmol, 3 eq) and
4-chloro-6,7-dimethoxyquinazoline (0.1 g, 0.445 mmol, 1 eq) and the
reaction mixture was allowed to stir at 80.degree. C. for 2 h.
Progress of reaction was monitored by LCMS. After completion,
reaction mixture was concentrated under reduced pressure,
triturated with ethyl acetate and diethyl ether to get residue
which was purified by reversed phase chromatography to afford
3-(1-(6,7-dimethoxyquinazolin-4-yl)azetidin-3-yl)-N-hydroxypropanamide
(04 mg, 2.71%). LCMS: 333 [M+1].sup.+; .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 10.0 (s, 1H), 8.75 (s, 1H), 8.62 (s, 1H),
7.30 (s, 1H), 7.20 (s, 1H), 5.00-4.20 (m, 2H), 3.99 (s, 3H), 3.98
(s, 3H), 2.90-2.80 (m, 1H), 2.08-2.00 (m, 2H), 1.95-1.85 (m,
2H).
Example-52: Synthesis of
2-(1-(6,7-dimethoxyquinazolin-4-yl)azetidin-3-yl)ethanesulfonamide,
(Compound 1.52)
##STR00630##
[0559] Step-1: Synthesis of (E)-tert-butyl
3-(2-(N-(4-methoxybenzyl)sulfamoyl)vinyl)azetidine-1-carboxylate:
To a solution of diethyl
(N-(4-methoxybenzyl)sulfamoyl)methylphosphonate (0.5 g, 1.4 mmol, 1
eq) in THF (20 ml) at -78.degree. C. was added 2.5M n-BuLi in
hexane (1.2 ml, 2.9 mmol, 2.1 eq) dropwise under nitrogen and the
resulting mixture was stirred at the same temperature for 15 min.
To the mixture was then added a solution of tert-butyl
3-formylazetidine-1-carboxylate (0.26 g, 1.4 mmol, 1 eq) in THF (2
ml) dropwise. Reaction mixture was warmed to RT and stirred for 16
h. Reaction mixture was diluted with saturated aq. NH.sub.4Cl
solution (100 mL) and extracted with ethyl acetate (3.times.100
mL). Combined organic layer was washed with water (2.times.100 mL)
followed by brine (150 mL) and dried over anhydrous sodium sulfate.
Removal of solvent under reduced pressure gave crude which was
purified by Combi-Flash using ethyl acetate-hexane system as eluent
to afford (E)-tert-butyl
3-(2-(N-(4-methoxybenzyl)sulfamoyl)vinyl)azetidine-1-carboxylate
(0.3 g, 55%).
[0560] Step-2: Synthesis of tert-butyl
3-(2-(N-(4-methoxybenzyl)sulfamoyl)ethyl)azetidine-1-carboxylate:
To a solution of (E)-tert-butyl
3-(2-(N-(4-methoxybenzyl)sulfamoyl)vinyl)azetidine-1-carboxylate
(0.3 g, 0.78 mmol, 1 eq) in ethanol (20 mL) was added Pd/C (0.15 g)
and the reaction mixture was allowed to stir at RT under H.sub.2
atmosphere using balloon for 3 h. Progress of reaction was
monitored by TLC. After completion, reaction mixture was filtered
through celite-bed. Removal of solvent under reduced pressure
afforded crude tert-butyl
3-(2-(N-(4-methoxybenzyl)sulfamoyl)ethyl)azetidine-1-carboxylate
(0.3 g, Crude) which was used in the next step without
purification.
[0561] Step-3: Synthesis of 2-(azetidin-3-yl)ethanesulfonamide
trifluoroacetate: To a solution of tert-butyl
3-(2-(N-(4-methoxybenzyl)sulfamoyl)ethyl)azetidine-1-carboxylate
(0.1 g, 0.26 mmol, 1 eq) in DCM (4 mL) was added TFA (1 mL) and the
mixture was allowed to stir at RT for 16 h. Progress of reaction
was monitored by .sup.1H NMR. After completion, reaction mixture
was concentrated under reduced pressure to afford crude which was
triturated with diethyl ether to afford
2-(azetidin-3-yl)ethanesulfonamide trifluoroacetate (0.08 g,
Crude).
[0562] Step-4: Synthesis of
2-(1-(6,7-dimethoxyquinazolin-4-yl)azetidin-3-yl)ethanesulfonamide:
A suspension of 2-(azetidin-3-yl)ethanesulfonamide trifluoroacetate
(80 mg, 0.28 mmol, 1 eq), 4-chloro-6,7-dimethoxyquinazoline (77 mg,
0.34 mmol, 1.2 eq) and DIPEA (0.1 mL, 0.57 mmol, 2.0 eq) in DMF (1
mL) was allowed to stir at 80.degree. C. for 2 h. Progress of
reaction was monitored by TLC. After completion, reaction mixture
was concentrated under reduced pressure to get residue which was
purified by reversed phase HPLC to afford
2-(1-(6,7-dimethoxyquinazolin-4-yl)azetidin-3-yl)ethanesulfonamide
(0.024 g, 24%). LCMS: 353 [M+1].sup.+8.33 (s, 1H), 7.21 (s, 1H),
7.15 (s, 1H), 6.81 (s, 2H), 4.60-4.50 (m, 2H), 4.20-4.09 (m, 2H),
3.90 (s, 3H), 3.89 (s, 3H), 3.10-3.00 (m, 2H), 2.97-2.83 (m, 1H),
2.11-2.00 (m, 2H).
Example-53: Synthesis of
(2-(6,7-dimethoxyquinazolin-4-yl)-2-azaspiro[3.3]heptan-6-yl)methylboroni-
c acid, (Compound 1.53)
##STR00631##
[0564] Step-1: Synthesis of tert-butyl
6-methylene-2-azaspiro[3.3]heptane-2-carboxylate: To a solution
methyltriphenylphosphonium bromide (5.07 g, 14.22 mmol, 3 eq) in
THF (80 mL) was added n-butyllithium (5.7 mL, 14.22 mmol, 3 eq) at
0.degree. C. and the reaction mixture was allowed to stir at
0.degree. C. for 1 h. To the mixture was then added a solution of
tert-butyl 6-oxo-2-azaspiro[3.3]heptane-2-carboxylate (1 g, 4.74
mmol, 1 eq) in THF (10 mL) and the reaction mixture to stir at RT
for overnight. Progress of reaction was monitored by TLC. After
completion, reaction mixture was diluted with saturated ammonium
chloride solution (100 mL) and extracted with ethyl acetate
(3.times.100 mL). Combined organic layer was washed with brine (150
mL) and dried over anhydrous sodium sulfate. Removal of solvent
under reduced pressure gave crude which was purified by normal
phase silica-gel column chromatography to afford tert-butyl
6-methylene-2-azaspiro[3.3]heptane-2-carboxylate (0.680 g,
69%).
[0565] Step-2: Synthesis of tert-butyl
6-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl)-2-azaspiro[3.3]he-
ptane-2-carboxylate: A solution of
bis(1,5-cyclooctadiene)diiridium(I) dichloride (13 mg, 0.019 mmol,
0.04 eq) and ethylenebis(diphenylphosphine) (15 mg, 0.038 mmol,
0.08 eq) in DCM (5 mL) was deoxygenated by purging nitrogen for 30
minutes. To the mixture was then added a solution of tert-butyl
6-methylene-2-azaspiro[3.3]heptane-2-carboxylate (100 mg, 0.478
mmol, 1 eq) and 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (91 mg,
0.717 mmol, 1.5 eq) in DCM (2 mL). Reaction mixture was allowed to
stir at RT for 24 h. Progress of reaction is monitored by TLC.
After completion, reaction mixture was diluted with water (20 mL)
and extracted with ethyl acetate (3.times.15 mL). Combined organic
layer was washed with brine (30 mL) and dried over anhydrous sodium
sulfate. Removal of solvent under reduced pressure afforded crude
which was purified using Combi-Flash to afford tert-butyl
6-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl)-2-azaspiro[3.3]he-
ptane-2-carboxylate (0.1 g)
[0566] Step-3: Synthesis of
6-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl)-2-azaspiro[3.3]he-
ptane: To a solution of tert-butyl
6-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl)-2-azaspiro[3.3]he-
ptane-2-carboxylate (0.1 g, 0.297 mmol, 1 eq) in DCM (1 mL) was
added TFA (0.5 mL) and the mixture was allowed to stir at RT for 1
h. Progress of reaction was monitored by .sup.1H NMR. After
completion, reaction mixture was concentrated under reduced
pressure to afford crude which was triturated with diethyl ether to
afford
6-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl)-2-azaspiro[3.3]he-
ptane (0.1 g) as TFA salt.
[0567] Step-4: Synthesis of
(2-(6,7-dimethoxyquinazolin-4-yl)-2-azaspiro[3.3]heptan-6-yl)methylboroni-
c acid: A suspension of 4-chloro-6,7-dimethoxyquinazoline (67 mg,
0.297 mmol, 1.0 eq),
6-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl)-2-azaspiro[3.3]he-
ptane (0.1 g, 0.297 mmol, 1.0 eq) and DIPEA (0.1 mL, 0.594 mmol, 2
eq) in DMF (1 mL) was allowed to stir at 80.degree. C. for 2 h.
Progress of reaction was monitored by TLC. After completion,
reaction mixture was concentrated under reduced pressure to afford
crude product which was purified by reversed phase HPLC to afford
(2-(6,7-dimethoxyquinazolin-4-yl)-2-azaspiro[3.3]heptan-6-yl)methylboroni-
c acid (5 mg, 3%). LCMS: 344 [M+1].sup.+; .sup.1H NMR (400 MHz,
DMSO-d.sub.6) (ppm 8.38 (s, 1H), 7.42 (s, 2H), 7.20 (s, 1H), 7.10
(s, 1H), 4.50 (brs, 2H), 4.39 (brs, 2H), 3.90 (s, 6H), 2.50-2.20
(m, 5H), 1.85-1.75 (m, 2H).
Example-54: Synthesis of
N-{2-[1-(7-methoxy-6-methylquinazolin-4-yl)azetidin-3-yl]ethyl}sulfuric
diamide, (Compound 1.54)
##STR00632##
[0569] Step-1: Synthesis of methyl
2-amino-4-methoxy-5-methylbenzoate: To a solution of methyl
2-amino-5-bromo-4-methoxybenzoate (1 g, 3.84 mmol, 1 eq) in
1,4-dioxane (10 mL) was added boroxine (482 mg, 3.84 mmol, 1.0 eq)
and K.sub.2CO.sub.3 (1.5 g, 11.52 mmol, 3.0 eq) The reaction
mixture was deoxygenated with N.sub.2 for 5 min followed by the
addition of Pd(PPh.sub.3) (443 mg, 0.38 mmol, 0.1 eq). The reaction
mixture was again deoxygenated with N.sub.2 and the reaction
mixture was allowed to heat at 100.degree. C. for 12 h. Reaction
mixture was cooled to RT, diluted with water (10 mL) and extracted
with ethylacetate (3.times.10 mL). The organic layer was evaporated
under reduced pressure to obtain the crude which was purified by
normal phase column chromatography to give methyl
2-amino-4-methoxy-5-methylbenzoate (400 mg, 53%). LCMS:
195[M+1].+-.
[0570] Step-2: Synthesis of 7-methoxy-6-methylquinazolin-4
(1H)-one: To a solution of methyl
2-amino-4-methoxy-5-methylbenzoate (400 mg, 2.04 mmol, 1.0 eq) in
ethanol (10 mL) was added triethylorthoformate (485 mg, 3.27 mmol.
1.6 eq) and ammonium acetate (204 mg, 2.65 mmol, 1.3 eq), the
reaction mixture was allowed to stir at 100.degree. C. for 12 h.
Progress of reaction was monitored by TLC. After completion,
reaction mixture was cooled; the precipitated solid was filtered
and washed with pentane (10 mL) to afford
7-methoxy-6-methylquinazolin-4 (1H)-one (252 mg, 64%) which was
carried further without purification. LCMS: 190[M+1].sup.+
[0571] Step-3: Synthesis of 4-chloro-7-methoxy-6-methylquinazoline:
A mixture of 7-methoxy-6-methylquinazolin-4 (1H)-one (252 mg, 4.86
mol, 1 eq) in POCl.sub.3 (0.5 mL) was allowed to stir at
120.degree. C. for 2 h. Progress of reaction was monitored by TLC.
After completion reaction mixture was cooled to RT, diluted with
cold water (100 mL) and allowed to stir for 5 minutes. Solid
obtained was filtered, washed with water and dried under vacuum to
afford 4-chloro-7-methoxy-6-methylquinazoline (100 mg, 36%). LCMS:
208[M+1].sup.+
[0572] Step-4: Synthesis of
N-{2-[1-(7-methoxy-6-methylquinazolin-4-yl)azetidin-3-yl]ethyl}sulfuric
diamide: A suspension of 4-chloro-7-methoxy-6-methylquinazoline
(100 mg, 0.48 mmol, 1.0 eq), N-[2-(azetidin-3-yl)ethyl]sulfuric
diamide trifloroaceticacid (132 mg, 0.48 mmol, 1.0 eq) and
diisopropylethylenediamine (0.2 mL, 0.96 mmol, 2.0 eq) in DMF (2.5
mL) was allowed to stir at 80.degree. C. for 2 h. Reaction mixture
was cooled to RT. The solvent was removed under reduced pressure to
obtain the crude product which was purified by RP-chromatography to
afford
N-{2-[1-(7-methoxy-6-methylquinazolin-4-yl)azetidin-3-yl]ethyl}sulfuric
diamide (30 mg, 18%). LCMS: 351[M+1].sup.+; .sup.1H NMR (400 MHz,
DMSO-d.sub.6) ppm 8.35 (s, 1H), 7.68 (s, 1H), 7.08 (s, 1H),
6.38-6.64 (m, 3H), 4.55 (br. s., 2H), 4.11 (br. s., 2H), 3.75-3.99
(m, 3H), 2.73-3.02 (m, 3H), 2.28 (s, 3H), 1.85 (q, J=7.16 Hz,
2H).
Example-55: Synthesis of
(E)-2-(1-(6,7-dimethoxyquinazolin-4-yl)azetidin-3-yl)ethenesulfonamide,
(Compound 1.55)
##STR00633##
[0574] Step-1: Synthesis of (E)-2-(azetidin-3-yl)ethenesulfonamide:
To a solution of (E)-tert-butyl
3-(2-(N-(4-methoxybenzyl)sulfamoyl)vinyl)azetidine-1-carboxylate
(0.15 g, 0.39 mmol, 1 eq) in DCM (10 mL) was added TFA (1.5 mL) and
the mixture was allowed to stir at RT for 16 h. Progress of
reaction was monitored by .sup.1H NMR. After completion, reaction
mixture was concentrated under reduced pressure to afford crude
which was triturated with diethyl ether to afford
(E)-2-(azetidin-3-yl)ethenesulfonamide trifluoroacetate (0.1 g,
crude).
[0575] Step-2: Synthesis of
(E)-2-(1-(6,7-dimethoxyquinazolin-4-yl)azetidin-3-yl)ethenesulfonamide:
A suspension of (E)-2-(azetidin-3-yl)ethenesulfonamide
trifluoroacetate (100 mg, 0.36 mmol, 1 eq),
4-chloro-6,7-dimethoxyquinazoline (98 mg, 0.43 mmol, 1.2 eq) and
DIPEA (0.12 mL, 0.72 mmol, 2.0 eq) in DMF (1 mL) was allowed to
stir at 80.degree. C. for 2 h. Progress of reaction was monitored
by TLC. After completion, reaction mixture was concentrated under
reduced pressure to get residue which was purified by reversed
phase HPLC to afford
(E)-2-(1-(6,7-dimethoxyquinazolin-4-yl)azetidin-3-yl)ethenesulfonamide
(0.24 g, 19%). LCMS: 351 [M+1].sup.+; .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 8.39 (s, 1H), 7.19 (s, 1H), 7.16 (s, 1H),
7.02 (brs, 2H), 6.85 (dd, 1H), 6.72 (d, 1H), 4.75-4.63 (m, 2H),
4.42-4.30 (m, 2H), 3.89 (s, 3H), 3.88 (s, 3H), 3.78-3.65 (m,
1H).
Example-56: Synthesis of
3-(1-(7-methoxyquinazolin-4-yl)azetidin-3-yl)propane-1-sulfonamide,
(Compound 1.56)
##STR00634##
[0577] Step-1: Synthesis of (E)-tert-butyl
3-(3-(N-(4-methoxybenzyl)sulfamoyl)allyl)azetidine-1-carboxylate
(0.18 g, 32.14%): To a solution of diethyl
(N-(4-methoxybenzyl)sulfamoyl)methylphosphonate (0.5 g, 1.4 mmol, 1
eq) in THF (20 ml) at -78.degree. C. was added 2.5M n-BuLi (1.2 ml,
2.9 mmol, 2.1 eq) in hexane dropwise under nitrogen and the
reaction mixture was stirred at the same temperature for 15
minutes. To the mixture was then added solution of tert-butyl
3-(2-oxoethyl)azetidine-1-carboxylate (0.28 g, 1.4 mmol, 1 eq) in
THF (2 mL) dropwise. Reaction mixture was gradually warmed to RT
and stirred for 16 h. Progress of reaction was monitored by TLC.
After completion, reaction mixture was diluted with saturated aq.
NH.sub.4Cl solution and extracted with ethyl acetate (3.times.100
mL). Combined organic layer was washed with water (2.times.100 mL)
followed by brine (150 mL) and dried over anhydrous sodium sulfate.
Removal of solvent under reduced gave crude which was purified by
Combi-Flash using ethyl acetate-hexane system as eluent to afford
(E)-tert-butyl
3-(3-(N-(4-methoxybenzyl)sulfamoyl)allyl)azetidine-1-carboxylate
(0.18 g, 32.14%).
[0578] Step-2: Synthesis of tert-butyl
3-(3-(N-(4-methoxybenzyl)sulfamoyl)propyl)azetidine-1-carboxylate:
To a solution of (E)-tert-butyl
3-(3-(N-(4-methoxybenzyl)sulfamoyl)allyl)azetidine-1-carboxylate
(0.18 g, 0.45 mmol, 1 eq) in ethanol (10 mL) was added Pd/C (0.09
g) and the reaction mixture was allowed to stir at RT under H.sub.2
atmosphere using balloon for 3 h. Progress of reaction was
monitored by .sup.1H NMR. After completion, reaction mixture was
filtered through celite-bed. Removal of solvent under reduced
pressure afforded tert-butyl
3-(3-(N-(4-methoxybenzyl)sulfamoyl)propyl)azetidine-1-carboxylate
(0.18 g, crude) which was used in the next step without
purification.
[0579] Step-3: Synthesis of 3-(azetidin-3-yl)propane-1-sulfonamide
2,2,2-trifluoroacetate: To a solution of tert-butyl
3-(3-(N-(4-methoxybenzyl)sulfamoyl)propyl)azetidine-1-carboxylate
(0.12 g, 0.39 mmol, 1 eq) in DCM (2 mL) was added TFA (1 mL) and
the mixture was allowed to stir at RT for 16 h. Progress of
reaction was monitored by .sup.1H NMR. After completion, reaction
mixture was concentrated under reduced pressure to afford crude
which was triturated with diethyl ether to afford
3-(azetidin-3-yl)propane-1-sulfonamide 2,2,2-trifluoroacetate (0.1
g, crude) which was used in the next step without purification.
[0580] Step-4: Synthesis of
3-(1-(7-methoxyquinazolin-4-yl)azetidin-3-yl)propane-1-sulfonamide:
A suspension of 3-(azetidin-3-yl)propane-1-sulfonamide
2,2,2-trifluoroacetate (100 mg, 0.34 mmol, 1 eq),
4-chloro-7-methoxyquinazoline (67 mg, 0.34 mmol, 1 eq) and DIPEA
(0.119 mL, 0.68 mmol, 2.0 eq) in DMF (1 mL) was allowed to stir at
80.degree. C. for 2 h. Progress of reaction was monitored by TLC.
After completion, reaction mixture was concentrated under reduced
pressure to get residue which was purified by RP-HPLC to afford
3-(1-(7-methoxyquinazolin-4-yl)azetidin-3-yl)propane-1-sulfonamide
(0.014 g, 12%). LCMS: 337 [M+1].sup.+; .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 8.40 (s, 1H), 7.85 (d, 1H), 7.10 (s, 1H),
7.06 (d, 1H), 6.78 (s, 2H), 4.55 (brs, 2H), 4.07 (brs, 2H), 3.87
(s, 3H), 3.00 (t, 2H), 2.87-2.75 (m, 1H), 1.85-1.62 (m, 4H).
Example-57: Synthesis of
(2-(6,7-dimethoxyquinazolin-4-yl)-2-azaspiro[3.3]heptan-6-yl)methanesulfo-
namide, (Compound 1.57)
##STR00635##
[0582] Step-1: Synthesis of tert-butyl
6-((N-(4-methoxybenzyl)sulfamoyl)methylene)-2-azaspiro[3.3]
heptane-2-carboxylate: To a solution of diethyl
(N-(4-methoxybenzyl)sulfamoyl)methylphosphonate (0.3 g, 0.85 mmol,
1 eq) in THF (20 mL) at -78.degree. C. was added 2.5 M n-BuLi (0.71
mL, 1.79 mmol, 2.1 eq) dropwise under nitrogen and the resulting
mixture was stirred at the same temperature for 15 minutes. To the
mixture was then added a solution of tert-butyl
6-oxo-2-azaspiro[3.3]heptane-2-carboxylate (0.18 g, 0.85 mmol, 1
eq) in THF (2 mL) dropwise. Reaction mixture was warmed to RT and
stirred for 16 h. Reaction mixture was diluted with saturated aq.
NH.sub.4Cl solution and extracted with ethyl acetate (3.times.100
mL). Combined organic layer was washed with water (2.times.100 mL)
followed by brine (150 mL) and dried over anhydrous sodium sulfate.
Removal of solvent under reduced pressure gave crude which was
purified by Combi-Flash using ethyl acetate-hexane system as eluent
to afford tert-butyl
6-((N-(4-methoxybenzyl)sulfamoyl)methylene)-2-azaspiro[3.3]heptane-2-carb-
oxylate (0.12 g, 34%).
[0583] Step-2: Synthesis of tert-butyl
6-((N-(4-methoxybenzyl)sulfamoyl)methyl)-2-azaspiro[3.3]heptane-2-carboxy-
late: To a solution of tert-butyl
6-((N-(4-methoxybenzyl)sulfamoyl)methylene)-2-azaspiro[3.3]heptane-2-carb-
oxylate (0.12 g, 0.29 mmol, 1 eq) in ethanol (10 mL) was added Pd/C
(0.06 g) and the reaction mixture was allowed to stir at RT under
H.sub.2 atmosphere using balloon for 3 h. Progress of reaction was
monitored by TLC. After completion, reaction mixture was filtered
through celite-bed. Removal of solvent under reduced pressure
afforded crude tert-butyl
6-((N-(4-methoxybenzyl)sulfamoyl)methyl)-2-azaspiro[3.3]heptane-2-carboxy-
late (0.1 g, crude) which was used in the next step without
purification.
[0584] Step-3: Synthesis of diethyl ether to afford
2-azaspiro[3.3]heptan-6-ylmethanesulfonamide
2,2,2-trifluoroacetate: To a solution of tert-butyl
6-((N-(4-methoxybenzyl)sulfamoyl)methyl)-2-azaspiro[3.3]heptane-2-carboxy-
late (0.1 g, 0.24 mmol, 1 eq) in DCM (4 mL) was added TFA (1 mL)
and the mixture was allowed to stir at RT for 16 h. Progress of
reaction was monitored by .sup.1H NMR. After completion, reaction
mixture was concentrated under reduced pressure to afford crude
which was triturated with diethyl ether to afford
2-azaspiro[3.3]heptan-6-ylmethanesulfonamide 2,2,2-trifluoroacetate
(0.1 g, crude).
[0585] Step-4: Synthesis of
(2-(6,7-dimethoxyquinazolin-4-yl)-2-azaspiro[3.3]heptan-6-yl)methanesulfo-
namide: A suspension of
2-azaspiro[3.3]heptan-6-ylmethanesulfonamide 2,2,2-trifluoroacetate
(100 mg, 0.33 mmol, 1 eq), 4-chloro-6,7-dimethoxyquinazoline (89
mg, 0.39 mmol, 1.2 eq) and DIPEA (0.115 mL, 0.66 mmol, 2.0 eq) in
DMF (1 mL) was allowed to stir at 80.degree. C. for 2 h. Progress
of reaction was monitored by TLC. After completion, reaction
mixture was concentrated under reduced pressure to get residue
which was purified by RP-HPLC to afford
(2-(6,7-dimethoxyquinazolin-4-yl)-2-azaspiro[3.3]heptan-6-yl)methanesulfo-
namide (0.023 g, 18%). LCMS: 379 [M+1].sup.+; .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 8.31 (s, 1H), 7.19 (s, 1H), 7.09 (s, 1H),
6.75 (brs, 2H), 4.55 (brs, 2H), 4.39 (brs, 2H), 3.87 (s, 6H), 3.09
(d, 2H), 2.70-2.40 (m, 3H), 2.18-2.05 (m, 2H).
Example-58: Synthesis of
4-3-(2-(sulfamoylamino)ethyl)-3-phenylazetidin-1-yl-6,7-dimethoxyquinazol-
ine, (Compound 1.58)
##STR00636##
[0587] Step-1: Synthesis of tert-butyl
3-(2-ethoxy-2-oxoethylidene)azetidine-1-carboxylate: To a solution
of ethyl 2-(diethoxyphosphoryl)acetate tert-butyl
3-oxoazetidine-1-carboxylate (2.75 g, 12.29 mmol, 1.05 eq) in THF
(50 mL) at 0.degree. C. was added NaH (0.7 g, 17.55 mmol, 1.5 eq)
and reaction mixture was allowed to stir at 0.degree. C. for 10
minutes. To the mixture was then added tert-butyl
3-oxoazetidine-1-carboxylate (2 g, 11.7 mmol, 1 eq) and resultant
reaction mixture was allowed to stir at 0.degree. C. for 2 h. After
2 h, reaction mixture was diluted with water (100 mL) and extracted
with EtOAc (3.times.100 mL). Combined organic layer was washed with
brine (150 mL) and dried over anhydrous sodium sulfate. Removal of
solvent under reduced pressure afforded tert-butyl
3-(2-ethoxy-2-oxoethylidene)azetidine-1-carboxylate (2.8 g, crude)
which was used in the next step without purification.
[0588] Step-2: Synthesis of tert-butyl
3-(2-ethoxy-2-oxoethyl)-3-phenylazetidine-1-carboxylate: To a
suspension of
di-.mu.-chlorobis[(1,2,5,6-.eta.)-1,5-cyclooctadiene]dirhodium (12
mg, 0.024 mmol, 0.03 eq) in dioxane (2 mL) was added 1.5 M aq. KOH
solution (0.093 g, 1.65 mmol, 2 eq) mixture was allowed to stir at
RT for 5 minutes. To the mixture was then added phenylboronic acid
(0.2 g, 1.65 mmol, 2 eq) and a solution of tert-butyl
3-(2-ethoxy-2-oxoethylidene)azetidine-1-carboxylate (0.2 g, 0.82
mmol, 1 eq) in THF (3 mL). The reaction mixture was stirred at RT
for 16 h. Progress of reaction was monitored by TLC. After
completion, reaction mixture was diluted with water (100 mL) and
extracted with EtOAc (3.times.100 mL). Combined organic layer was
washed with brine (150 mL) and dried over anhydrous sodium sulfate.
Removal of solvent under reduced pressure gave crude which was
purified by Combi-Flash to afford tert-butyl
3-(2-ethoxy-2-oxoethyl)-3-phenylazetidine-1-carboxylate (0.15 g,
56%).
[0589] Step-3: Synthesis of
2-(1-(tert-butoxycarbonyl)-3-phenylazetidin-3-yl)acetic acid: To a
solution of tert-butyl
3-(2-ethoxy-2-oxoethyl)-3-phenylazetidine-1-carboxylate (1.31 g,
4.1 mmol, 1 eq) in a solution of THF-MeOH--H.sub.2O (8:2:1, 50 mL))
was added LiOH.H.sub.2O (0.86 g, 20 mmol, 5 eq) and mixture was
allowed to stir at RT for 16 h. Progress of reaction was monitored
by TLC. After completion, reaction mixture was concentrated under
reduced pressure to get residue which was diluted with saturated
aq. ammonium chloride solution (200 mL) and extracted with EtOAc
(4.times.150 mL). Combined organic layer was washed with brine (150
mL) and dried over anhydrous sodium sulfate. Removal of solvent
under reduced pressure afforded
2-(1-(tert-butoxycarbonyl)-3-phenylazetidin-3-yl)acetic acid (1.07
g, 89%) which was used in the next step without purification.
[0590] Step-4: Synthesis of tert-butyl
3-(2-hydroxyethyl)-3-phenylazetidine-1-carboxylate: To a solution
of 2-(1-(tert-butoxycarbonyl)-3-phenylazetidin-3-yl)acetic acid
(0.37 g, 1.26 mmol, 1 eq) in THF (10 mL) were added NMM (0.41 mL,
3.8 mmol, 3 eq) and isobutyl chloroformate (0.4 ml, 3.04 mmol, 2.4
eq) and reaction mixture was allowed to stir at 0.degree. C. for 2
h. To the mixture was then added a solution of NaBH.sub.4 (800 mg)
in methanol (10 mL) and mixture was allowed to stir at RT for 16 h.
Progress of reaction was monitored by TLC. After completion,
reaction mixture was concentrated under reduced pressure to get
residue and was diluted with sat. NH.sub.4Cl solution (100 mL) and
extracted with ethyl acetate (3.times.100 mL). Combined organic
layer was washed with brine (150 mL) and dried over anhydrous
sodium sulfate. Removal of solvent under reduced pressure to get
crude which was purified by Combi-Flash using ethyl acetate-hexane
system as eluent to afford tert-butyl
3-(2-hydroxyethyl)-3-phenylazetidine-1-carboxylate (240 mg,
68%).
[0591] Step-5: Synthesis of tert-butyl
3-(2-(methylsulfonyloxy)ethyl)-3-phenylazetidine-1-carboxylate: To
a solution of tert-butyl
3-(2-hydroxyethyl)-3-phenylazetidine-1-carboxylate (0.7 g, 2.5
mmol, 1 eq) in DCM (50 mL) were added triethylamine (1.06 mL, 7.5
mmol, 3 eq) and mesyl chloride (0.39 mL, 5 mmol, 2 eq) and reaction
mixture was allowed to stir at RT for 2 h. Progress of reaction was
monitored by TLC. After completion, reaction mixture was
concentrated under reduced pressure to get residue which was
diluted with water (100 mL) and extracted with ethyl acetate
(3.times.100 mL). Combined organic layer was washed with brine (150
mL) and dried over anhydrous sodium sulfate. Removal of solvent
under reduced pressure afforded tert-butyl
3-(2-(methylsulfonyloxy)ethyl)-3-phenylazetidine-1-carboxylate (0.9
g, crude) which was used in the next step without purification.
[0592] Step-6: Synthesis of tert-butyl
3-(2-azidoethyl)-3-phenylazetidine-1-carboxylate: To a solution of
tert-butyl
3-(2-(methylsulfonyloxy)ethyl)-3-phenylazetidine-1-carboxylate
(0.26 g, 0.73 mmol, 1 eq) in DMF (4 mL) was added sodium azide
(0.19 g, 2.9 mmol, 4 eq) and the reaction mixture was allowed to
stir at 60.degree. C. for 2 h. Progress of reaction is monitored by
TLC. After completion, reaction mixture was diluted with water (100
mL) and extracted with ethylacetate (3.times.50 mL). Combined
organic layer was washed with water (2.times.50 mL) followed by
brine (50 mL) and dried over anhydrous sodium sulfate. Removal of
solvent under reduced pressure afforded tert-butyl
3-(2-azidoethyl)-3-phenylazetidine-1-carboxylate (0.2 g, 90%) which
was used in the next step without purification.
[0593] Step-7: Synthesis of tert-butyl
3-(2-aminoethyl)-3-phenylazetidine-1-carboxylate: To a solution of
tert-butyl 3-(2-azidoethyl)-3-phenylazetidine-1-carboxylate (0.2 g,
0.66 mmol, 1 eq) in ethanol (6 mL) was added Pd--C (0.1 g,
.about.10% on charcoal) and reaction mixture was allowed to stir at
RT under H.sub.2 atmosphere using balloon for 2 h. Progress of
reaction was monitored by TLC. After completion, reaction mixture
was filtered through celite-bed. Removal of solvent under reduced
pressure afforded crude tert-butyl
3-(2-aminoethyl)-3-phenylazetidine-1-carboxylate (0.14 g, 76%)
which was used in the next step without purification.
[0594] Step-8: Synthesis of tert-butyl
3-(2-(N-(tert-butoxycarbonyl)sulfamoylamino)ethyl)-3-phenylazetidine-1-ca-
rboxylate: To a solution of tert-butyl
3-(2-aminoethyl)-3-phenylazetidine-1-carboxylate (0.6 g, 2.67 mmol,
1 eq) in dichloromethane (50 mL) were added
N-(tert-butoxycarbonyl)-N-[4-(dimethylazaniumylidene)-1,4-dihydropyridin--
1ylsulfonyl]azanide (0.98 g, 4 mmol, 1.5 eq) and
N,N-diisopropylethylamine (0.76 mL, 5.34 mmol, 2 eq) and the
reaction mixture was allowed to stir at RT for 16 h. After 16 h,
reaction mixture was concentrated under reduced pressure to get
crude which was purified by Combi-Flash using ethyl acetate-hexane
system as eluent to afford tert-butyl
3-(2-(N-(tert-butoxycarbonyl)sulfamoylamino)ethyl)-3-phenylazetidine-1-ca-
rboxylate (0.4 g, 40%).
[0595] Step-9: Synthesis of
3-(2-(sulfamoylamino)ethyl)-3-phenylazetidine trifluoroacetate: To
a solution of tert-butyl
3-(2-(N-(tert-butoxycarbonyl)sulfamoylamino)ethyl)-3-phenylazetidine-1-ca-
rboxylate (0.4 g, 0.87 mmol, 1 eq) in DCM (10 mL) was added TFA (4
mL) and the mixture was allowed to stir at RT for 1 h. Progress of
reaction was monitored by TLC. After completion, reaction mixture
was concentrated under reduced pressure to afford crude which was
triturated with diethyl ether to afford
3-(2-(sulfamoylamino)ethyl)-3-phenylazetidine trifluoroacetate (0.3
g, 92%).
[0596] Step-10: Synthesis of
4-3-(2-(sulfamoylamino)ethyl)-3-phenylazetidin-1-yl-6,7-dimethoxyquinazol-
ine: A mixture of 4-chloro-6,7-dimethoxyquinazoline (36 mg, 0.16
mmol, 1.2 eq), 3-(2-(sulfamoylamino)ethyl)-3-phenylazetidine
trifluoroacetate (50 mg, 0.13 mmol, 1.0 eq) and DIPEA (0.05 mL,
0.27 mmol, 2.0 eq) in DMF (1 mL) was allowed to stir at 80.degree.
C. for 3 h. Progress of reaction was monitored by TLC. After
completion, reaction mixture was concentrated under reduced
pressure to get residue which was purified by reversed phase HPLC
to afford
4-3-(2-(sulfamoylamino)ethyl)-3-phenylazetidin-1-yl-6,7-dimethoxyquinazol-
ine (18 mg, 30%). LCMS: 444 [M+1].sup.+; .sup.1HNMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 8.61 (s, 1H), 7.45-7.25 (m, 6H), 7.19 (s,
1H), 6.45 (brs, 3H), 4.85 (brs, 4H), 3.99 (s, 3H), 3.97 (s, 3H),
2.80-2.60 (m, 2H), 2.30-2.20 (m, 2H).
Example-59: Synthesis of
2-(1-(5-methylpyrrolo[1,2-f][1,2,4]triazin-4-yl)azetidin-3-yl)ethylboroni-
c acid, (Compound 1.59)
##STR00637##
[0598] Step 1: Synthesis of tert-butyl
3-ethynylazetidine-1-carboxylate: To a solution of tert-butyl
3-formylazetidine-1-carboxylate (0.6 g, 3.24 mmol, 1 eq) in
methanol (15 mL) were added potassium carbonate (0.9 g, 6.478 mmol,
2 eq) and dimethyl 1-diazo-2-oxopropylphosphonate (0.684 g, 3.564
mmol, 1.1 eq) and the reaction mixture to stir at RT for 2 h.
Progress of reaction is monitored by .sup.1H NMR. After completion,
reaction mixture was diluted with water (100 mL) and extracted with
ethyl acetate (3.times.100 mL). Combined organic layer was washed
with brine (150 mL) and dried over anhydrous sodium sulfate.
Removal of solvent under reduced pressure afforded tert-butyl
3-ethynylazetidine-1-carboxylate (0.5 g, crude) which was used in
the next step without purification.
[0599] Step 2: Synthesis of (E)-tert-butyl
3-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl)azetidine-1-carbo-
xylate: A solution of tert-butyl 3-ethynylazetidine-1-carboxylate
(0.45 g, 2.483 mmol, 1 eq) in toluene (10 mL) was oxygenated by
purging nitrogen for 10 minutes. To the mixture was then added
carbonylchlorohydrotris(triphenylphosphine)ruthenium (0.14 g, 0.149
mmol, 0.06 eq) and 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.9 mL,
6.208 mmol, 2.5 eq). Reaction mixture was allowed to stir at
50.degree. C. overnight. Progress of reaction is monitored by TLC.
After completion, reaction mixture was diluted with water (30 mL)
and extracted with ethyl acetate (3.times.20 mL). Combined organic
layer was washed with brine (150 mL) and dried over anhydrous
sodium sulfate. Removal of solvent under reduced pressure afforded
crude which was purified by Combi-Flash to afford (E)-tert-butyl
3-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl)azetidine-1-carbo-
xylate (0.6 g, 78%).
[0600] Step-3: Synthesis of tert-butyl
3-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ethyl)azetidine-1-carbo-
xylate: To a solution of (E)-tert-butyl
3-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl)azetidine-1-carbo-
xylate (0.5 g, 1.62 mmol, 1 eq) in methanol (25 mL) was added Pd--C
(0.225 g) and the reaction mixture was allowed to stir at RT under
H.sub.2 atmosphere using balloon for 2 h. Progress of reaction was
monitored by .sup.1H NMR. After completion, reaction mixture was
filtered through celite-bed. Removal of solvent under reduced
pressure afforded tert-butyl
3-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ethyl)azetidine-1-carbo-
xylate (0.45 g, crude) which was used in the next step without
purification.
[0601] Step-4: Synthesis of
3-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ethyl)azetidine:
To a solution of tert-butyl
3-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ethyl)azetidine-1-carbo-
xylate (0.185 g, 0.595 mmol, 1 eq) in DCM (5 mL) was added TFA (1.5
mL) and the mixture was allowed to stir at RT for 1 h. Progress of
reaction was monitored by .sup.1H NMR. After completion, reaction
mixture was concentrated under reduced pressure to afford crude
which was triturated with diethyl ether to afford
3-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ethyl)azetidine
(0.183 g) as TFA salt.
[0602] Step-5: Synthesis of
2-(1-(5-methylpyrrolo[1,2-f][1,2,4]triazin-4-yl)azetidin-3-yl)ethylboroni-
c acid: A suspension of
4-chloro-5-methylpyrrolo[1,2-f][1,2,4]triazine (0.1 g, 0.597 mmol,
1.0 eq),
3-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ethyl)azetidine
(0.183 g, 0.97 mmol, 1.0 eq) and DIPEA (0.2 mL, 1.194 mmol, 2 eq)
in DMF (1 mL) was allowed to stir at 80.degree. C. for 2 h.
Progress of reaction was monitored by TLC. After completion,
reaction mixture was concentrated under reduced pressure to afford
crude product which was purified by reversed phase HPLC to afford
2-(1-(5-methylpyrrolo[1,2-f][1,2,4]triazin-4-yl)azetidin-3-yl)ethylboroni-
c acid (5 mg, 3%). LCMS: 261 [M+1].sup.+; .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 7.76 (s, 1H), 7.59 (s, 1H), 7.48 s, 2H),
6.45 (s, 1H), 4.43-4.35 (m, 2H), 3.96-3.85 (s, 2H), 2.50-2.45 (m,
1H), 2.41 (s, 3H), 1.70-1.56 (m, 2H), 0.60-0.50 (m, 2H).
Example-60: Synthesis of
3-(1-(6,7-dimethoxyquinazolin-4-yl)azetidin-3-yl)propylboronic
acid, (Compound 1.60)
##STR00638##
[0604] Step-1: Synthesis of tert-butyl
3-allylazetidine-1-carboxylate: To a solution of
methyltriphenylphosphonium bromide (1.6 g, 4.4 mmol, 3.0 eq) in THF
(2 mL) was added n-butyllithium (2.5 mol/L solution in n-hexane, 3
mL, 5 eq) at 0.degree. C. under a nitrogen atmosphere, and the
mixture was stirred at the same temperature for 10 minutes. To the
reaction mixture a solution of tert-butyl
3-(2-oxoethyl)azetidine-1-carboxylate (200 mg, 1.00 mmol, 1.0 eq)
in THF (3 mL) was added at the same temperature, and the mixture
was stirred overnight at room temperature. To the reaction solution
was added an aqueous ammonium chloride solution (10 mL), and the
mixture was extracted with ethyl acetate (3.times.30 mL). The
combined organic layer was washed with water and brine, dried over
sodium sulfate, and concentrated. The residue was purified by
normal phase silica gel column chromatography (eluent: ethyl
acetate/n-hexane) to obtain tert-butyl
3-allylazetidine-1-carboxylate (80 mg, 41%).
[0605] Step-2: Synthesis of 3-allylazetidine
2,2,2-trifluoroacetate: To a solution of tert-butyl
3-ethenylazetidine-1-carboxylate (70 mg, 0.36 mmol, 1.0 eq) in
methylene chloride (4 mL) was added 0.5 mL TFA at 0.degree. C., and
the reaction mixture was stirred at RT for 48 h. The reaction
solution was concentrated and triturated with ether-hexane to get
the semisolid (65 mg, 86%) which was used as such for next step
without purification. .sup.1H-NMR (CDCl.sub.3): .delta. ppm 9.56
(2H, d), 5.65-5.68 (1H, m), 5.15-5.20 (2H, m), 4.1 (2H, s), 3.75
(2H, s), 3.05-3.15 (1H, m), 2.2 (2H, d)
[0606] Step-3: Synthesis of
4-(3-allylazetidin-1-yl)-6,7-dimethoxyquinazoline: To a solution of
3-allylazetidine 2,2,2-trifluoroacetate (60 mg, 0.31 mmol, 1.0 eq)
in DMF (2 mL) were added 4-chloro-6,7-dimethoxyquinazoline (70 mg.
0.31 mmol, 1.0 eq) and N,N-diisopropylethylamine (0.120 g, 0.93
mmol, 3.0 eq) and the reaction mixture was allowed to stir at
80.degree. C. for 2 h. Reaction mixture was diluted with water (10
mL) and extracted with ethyl acetate (3.times.30 mL). Combined
organic layer was washed with brine (20 mL), dried over anhydrous
sodium sulfate and concentrated under vacuum to get the residue
which was purified by silica gel column chromatography (Eluent:
ethyl acetate/n-hexane) to obtain the
4-(3-allylazetidin-1-yl)-6,7-dimethoxyquinazoline (80 mg, 90%).
LCMS: 286[M+1].sup.+
[0607] Step-4: Synthesis of
6,7-dimethoxy-4-(3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propyl-
)azetidin-1-yl)quinazoline: To a mixture of
bis(1,5-cyclooctadiene)diiridium(I) dichloride (6 mg, 4 mol %) and
1,2-bis(diphenylphosphino)ethane (6 mg, 8 mol %) was added DCM (2
mL) under nitrogen. The mixture was allowed to stir at RT for 1 h.
To this reaction mixture was cooled to 0.degree. C. and added
solution of 4-(3-allylazetidin-1-yl)-6,7-dimethoxyquinazoline
(0.060 g, 0.21 mmol, 1.0 eq) dissolved in DCM (1 mL) and
pinacolborane (0.040 g, 0.31 mmol, 1.5 eq). The reaction was
allowed to stir at RT for overnight. Progress of reaction was
monitored by LCMS. The reaction was quenched by addition of water
(10 mL) and extracted with DCM (3.times.25 mL). Combined organic
layer was washed with brine (30 mL), dried over anhydrous sodium
sulfate and concentrated under vacuum to get the residue which was
purified by RP-column chromatography to obtain the
6,7-dimethoxy-4-(3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propyl-
)azetidin-1-yl)quinazoline (10 mg, 12%). LCMS: 414[M+1].sup.+;
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 8.37 (s, 2H), 7.20
(br. s., 1H), 7.12 (br. s., 1H), 6.54 (br. s., 1H), 4.60 (s, 2H),
4.44 (br. s., 1H), 4.12 (s, 2H), 3.42 (d, J=5.70 Hz, 1H), 1.67 (br.
s., 2H), 1.46 (d, J=8.33 Hz, 2H).
Example-61: Synthesis
2-ethyl-6,7-dimethoxy-4-[3-[2-(sulfamoylamino)ethyl]azetidin-1-yl]quinazo-
line, (Compound 1.61)
##STR00639##
[0609] Step-1: Synthesis of
2-ethyl-6,7-dimethoxy-1H-quinazolin-4-one: A mixture of methyl
2-amino-4,5-dimethoxybenzoate (800 mg, 3.79 mmol, 1 eq) and
propanenitrile (229 mg, 4.17 mmol, 1.1 eq) in 4M HCl in dioxane (10
mL) was sonicated for 30 minutes and then heated at 100.degree. C.
for 12 h. Progress of reaction was monitored by TLC. After
completion, reaction mixture was cooled to RT, poured into ice-cold
water and stirred for 15 minutes. The solid obtained was filtered
and dried under vacuum to afford
2-ethyl-6,7-dimethoxy-1H-quinazolin-4-one (200 mg, 37%). LCMS:
234.2 [M+1].sup.+
[0610] Step-2: Synthesis of
4-chloro-2-ethyl-6,7-dimethoxy-quinazolin: A mixture of
2-ethyl-6,7-dimethoxy-1H-quinazolin-4-one (200 mg, 0.85 mmol, 1 eq)
in POCl.sub.3 (0.4 mL) was stirred at 120.degree. C. for 2 h.
Progress of reaction was monitored by TLC. After completion,
reaction mixture was cooled to RT, poured into ice-cold water (20
mL) and stirred for 15 minutes. Solid was filtered and dried under
vacuum to afford 4-chloro-2-ethyl-6,7-dimethoxy-quinazolin (52 mg,
23%). LCMS: 253.2 M+1].sup.+
[0611] Step-3: Synthesis of
2-ethyl-6,7-dimethoxy-4-[3-[2-(sulfamoylamino)ethyl]azetidin-1-yl]quinazo-
line: A suspension of 4-chloro-2-ethyl-6,7-dimethoxy-quinazolin (50
mg, 0.197 mmol, 1.0 eq), N-[2-(azetidin-3-yl)ethyl]sulfuric diamide
triflorocetic acid (57 mg, 0.197 mmol, 1.0 eq) and N,N
diisopropylethylamine (60 mg, 0.39 mmol, 2.0 eq) in DMF (2 mL) was
allowed to stir at 80.degree. C. for 2 h. Progress of reaction was
monitored by TLC. Reaction mixture was cooled to RT, concentrated
under vacuum to get semi-solid residue which was triturated with
ether, ethyl acetate and then with pentane to afford crude solid
which was purified by RP-HPLC to afford
2-ethyl-6,7-dimethoxy-4-[3-[2-(sulfamoylamino)ethyl]azetidin-1-yl]quinazo-
line (33 mg, 41%). LCMS: 397 [M+1].sup.+; .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 7.19 (s, 1H), 7.12 (s, 1H), 6.56 (brs,
1H), 6.53 (s, 2H), 4.67-4.52 (m, 2H), 4.23-4.11 (m, 2H), 3.87 (s,
3H), 3.85 (s, 3H), 2.99-2.80 (m, 3H), 2.67 (t, 2H), 2.90-2.83 (m,
2H), 1.22 (t, 3H).
Example-62: Synthesis
4-(6-N-sulfamoylamino)-2-azaspiro[3.3]heptan-2-yl)-5-methylpyrrolo[1,2-f]-
[1,2,4]triazine, (Compound 1.62)
##STR00640##
[0613] Step 1: Synthesis of tert-butyl
6-(methylsulfonyloxy)-2-azaspiro[3.3]heptane-2-carboxylate: To a
solution of tert-butyl
6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate (1.2 g, 5.63 mmol, 1
eq) in DCM (50 mL) was added triethylamine (1.7 g, 16.89 mmol, 3
eq) and the reaction mixture was allowed to stir at 0.degree. C.
for 5 minutes. To the mixture was added methane sulfonyl chloride
(1.3 g, 11.26 mmol, 2 eq) and the reaction mixture to stir at
0.degree. C. for 10 minutes followed by stirring at RT for 2 h.
Progress of reaction is monitored by .sup.1H NMR. After completion,
reaction mixture was diluted with water (100 mL) and extracted with
ethyl acetate (3.times.100 mL). Combined organic layer was washed
with brine (150 mL) and dried over anhydrous sodium sulfate.
Removal of solvent under reduced pressure afforded tert-butyl
6-(methylsulfonyloxy)-2-azaspiro[3.3]heptane-2-carboxylate (1.3 g,
Crude) which was used in the next step without purification.
[0614] Step-2: Synthesis of tert-butyl
6-azido-2-azaspiro[3.3]heptane-2-carboxylate: To a solution of
tert-butyl
6-(methylsulfonyloxy)-2-azaspiro[3.3]heptane-2-carboxylate (1.5 g,
5.15 mmol, 1 eq) in DMF (10 mL), was added NaN.sub.3 (1 g, 15.46
mmol, 3 eq) and the reaction mixture was allowed to stir at
70.degree. C. for 16 h. Progress of reaction is monitored by
.sup.1H NMR. After completion, reaction mixture was diluted with
water (100 mL) and extracted with diethyl ether (3.times.150 mL).
Combined organic layer was washed with water (2.times.100 mL)
followed by brine (150 mL) and dried over anhydrous sodium sulfate.
Removal of solvent under reduced pressure afforded tert-butyl
6-azido-2-azaspiro[3.3]heptane-2-carboxylate (1.2 g, Crude) which
was used in the next step without purification.
[0615] Step-3: Synthesis of tert-butyl
6-amino-2-azaspiro[3.3]heptane-2-carboxylate: To a solution of
tert-butyl 6-azido-2-azaspiro[3.3]heptane-2-carboxylate (1.2 g,
5.04 mmol, 1 eq) in ethanol (50 mL) was added Pd--C (0.6 g) and the
reaction mixture was allowed to stir at RT under H.sub.2 atmosphere
using balloon for 3 h. Progress of reaction was monitored by TLC.
After completion, reaction mixture was filtered through celite-bed.
Removal of solvent under reduced pressure afforded crude tert-butyl
6-amino-2-azaspiro[3.3]heptane-2-carboxylate (1 g, Crude) which was
used in the next step without purification.
[0616] Step-4: Synthesis of tert-butyl
6-(N-(tert-butoxycarbonyl)sulfamoylamino)-2-azaspiro[3.3]heptane-2-carbox-
ylate: To a solution of tert-butyl
6-amino-2-azaspiro[3.3]heptane-2-carboxylate (1 g, 4.71 mmol, 1 eq)
in dichloromethane (30 mL) were added
N-(tert-butoxycarbonyl)-N-[4-(dimethylazaniumylidene)-1,4-dihydropyridin--
1ylsulfonyl]azanide (2.12 g, 7.07 mmol, 1.5 eq) and
N,N-diisopropylethylamine (1.64 mL, 9.4 mmol, 2 eq) and the
reaction mixture was allowed to stir at RT for 48 h. Progress of
reaction was monitored by TLC. After completion, reaction mixture
was concentrated under reduced pressure to get crude which was
purified by Combi-Flash using ethyl acetate-hexane system as eluent
to afford tert-butyl
6-(N-(tert-butoxycarbonyl)sulfamoylamino)-2-azaspiro[3.3]heptane-2-carbox-
ylate (0.6 g, 32.5%).
[0617] Step-5: Synthesis of
(6-N-sulfamoylamino)-2-azaspiro[3.3]heptane: To a solution of
tert-butyl
6-(N-(tert-butoxycarbonyl)sulfamoylamino)-2-azaspiro[3.3]heptane-2-carbox-
ylate (0.6 g, 1.5 mmol, 1 eq) in DCM (10 mL) was added TFA (2 mL)
and the mixture was allowed to stir at RT for 1 h. Progress of
reaction was monitored by .sup.1H NMR. After completion, reaction
mixture was concentrated under reduced pressure to afford crude
which was triturated with diethyl ether to afford
(6-N-sulfamoylamino)-2-azaspiro[3.3]heptane (0.5 g) as TFA
salt.
[0618] Step-6: Synthesis of
4-(6-N-sulfamoylamino)-2-azaspiro[3.3]heptan-2-yl)-5-methylpyrrolo[1,2-f]-
[1,2,4]triazine: A suspension of
4-chloro-5-methylpyrrolo[1,2-f][1,2,4]triazine (90 mg, 0.54 mmol,
1.0 eq), (6-N-sulfamoylamino)-2-azaspiro[3.3]heptane (162 mg, 0.54
mmol, 1.0 eq) and DIPEA (0.18 mL, 1.07 mmol, 2 eq) in DMF (0.9 mL)
was allowed to stir at 80.degree. C. for 2 h. Progress of reaction
was monitored by TLC. After completion, reaction mixture was
concentrated under reduced pressure to afford crude product which
was purified by reversed phase HPLC to afford
4-(6-N-sulfamoylamino)-2-azaspiro[3.3]heptan-2-yl)-5-methylpyrrolo[1,2-f]-
[1,2,4]triazine (43 mg, 28.66%). LCMS: 323 [M+1].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. ppm 7.76 (s, 1H), 7.59 (d, 1H),
6.85 (d, 1H), 6.59 (brs, 1H), 6.52 (s, 2H), 4.42 (brs, 2H), 4.25
(brs, 2H), 3.67-3.60 (m, 1H), 2.60-2.42 (m, 2H), 2.40 (s, 3H),
2.23-2.14 (m, 2H).
Example-63: Synthesis
2-(6,7-dimethoxyquinazolin-4-yl)-N-hydroxy-2-azaspiro[3.3]heptane-6-carbo-
xamide, (Compound 1.63)
##STR00641##
[0620] Step-1: Synthesis tert-butyl
6-(benzyloxycarbamoyl)-2-azaspiro[3.3]heptane-2-carboxylate: To a
suspension of
2-(tert-butoxycarbonyl)-2-azaspiro[3.3]heptane-6-carboxylic acid
(250 mg, 1.03 mmol, 1 eq), O-benzylhydroxylamine hydrochloride (180
mg, 1.13 mmol, 1.1 eq) in DCM (15 mL) were added EDC.HCl (0.23 g,
1.23 mmol, 1.2 eq), DMAP (0.19 g, 1.54 mmol, 1.5 eq) and
triethylamine (0.43 mL, 3 mmol, 3 eq) and the resulting mixture was
allowed to stir at RT for 24 h. Progress of reaction was monitored
by TLC. After completion, reaction mixture was concentrated under
reduced pressure to get residue which was diluted with cold water
(50 mL) and extracted with ethyl acetate (3.times.100 mL). Combined
organic layer was washed with brine (3.times.50 mL) and dried over
anhydrous sodium sulfate. Removal of solvent under reduced pressure
to afforded tert-butyl
6-(benzyloxycarbamoyl)-2-azaspiro[3.3]heptane-2-carboxylate (245
mg, 68%) which was used in the next step without purification.
[0621] Step-2: Synthesis of tert-butyl
6-(hydroxycarbamoyl)-2-azaspiro[3.3]heptane-2-carboxylate: To a
solution of tert-butyl
6-(benzyloxycarbamoyl)-2-azaspiro[3.3]heptane-2-carboxylate (245
mg, 0.7 mmol, 1 eq) in MeOH (10 mL) was added Pd--C (70 mg, 10% on
charcoal) and the mixture was allowed to stir at RT for 4 h under
hydrogen atmosphere. Progress of reaction was monitored by TLC.
After completion, reaction mixture was filtered through celite-bed
and bed was washed with MeOH (10 mL). Filtrate was concentrated
under reduced pressure to afford tert-butyl
6-(hydroxycarbamoyl)-2-azaspiro[3.3]heptane-2-carboxylate (0.15 g,
85%) which was used in the next step without purification.
[0622] Step-3: Synthesis of
N-hydroxy-2-azaspiro[3.3]heptane-6-carboxamide trifluoroacetate: To
a solution of tert-butyl
6-(hydroxycarbamoyl)-2-azaspiro[3.3]heptane-2-carboxylate (150 mg,
0.58 mmol, 1 eq) in DCM (4 mL) was added TFA (1 mL) and the
resulting mixture was allowed to stir at RT for 2 h. Progress of
reaction was monitored by TLC. After completion, reaction mixture
was concentrated under reduced pressure to afford crude which was
triturated with diethyl ether to afford
N-hydroxy-2-azaspiro[3.3]heptane-6-carboxamide trifluoroacetate
(100 mg, 63%).
[0623] Step-4: Synthesis of
2-(6,7-dimethoxyquinazolin-4-yl)-N-hydroxy-2-azaspiro[3.3]heptane-6-carbo-
xamide: A suspension of
N-hydroxy-2-azaspiro[3.3]heptane-6-carboxamide trifluoroacetate
(100 mg, 0.37 mmol, 1 eq), 4-chloro-6,7-dimethoxyquinazoline (100
mg, 0.44 mmol, 1.2 eq) and DIPEA (0.13 mL, 0.74 mmol, 2.0 eq) in
DMF (1 mL) was allowed to stir at 80.degree. C. for 3 h. Progress
of reaction was monitored by TLC. After 3 h, reaction mixture was
concentrated under reduced pressure to afford crude which was
purified using RP-HPLC to afford
2-(6,7-dimethoxyquinazolin-4-yl)-N-hydroxy-2-azaspiro[3.3]heptane-6-carbo-
xamide (9 mg, 7%). LCMS: 345 [M+1].sup.+; .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 10.42 (brs, 1H), 8.82 (brs, 1H), 8.33 (s,
1H), 7.20 (s, 1H), 7.11 (s, 1H), 4.50 (brs, 2H), 4.41 (brs, 2H),
3.89 (s, 6H), 2.62-2.50 (m, 1H), 2.50-2.30 (m, 4H).
Example-64: Synthesis of
4-(3-(2-sulfamoylaminoethyl)azetidine-1-yl) quinazoline, (Compound
1.64)
##STR00642##
[0625] Step-1: Synthesis of quinazolin-4 (3H)-one: A mixture of
1H-benzo[d][1,3]oxazine-2,4-dione (1 g, 6.1 mmol, 1 eq), ammonium
acetate (0.614 g, 7.9 mmol, 1.3 eq) and triethylorthoformate (1.63
mL, 9.7 mmol, 1.6 eq) in ethanol (10 mL) was allowed to stir at
90.degree. C. for 48 h. Progress of reaction was monitored by TLC.
Reaction mixture was cooled to RT; solid was filtered, washed with
hexane and dried to quinazolin-4 (3H)-one (400 mg, 44%). LCMS: 147
[M+1].sup.+.
[0626] Step-2: Synthesis of 4-chloroquinazoline: The stirred
solution of quinazolin-4 (3H)-one (0.15 g, 1.02 mmol, 1 eq) in 1 mL
of POCl.sub.3 was heated at 120.degree. C. for 2 h. After
completion reaction mixture was diluted with water (150 mL) and
extracted using ethyl acetate (3.times.50 mL). Combined organic
layer was washed with water (3.times.30 mL), dried over anhydrous
sodium sulphate. Removal of solvent under reduced pressure afforded
4-chloroquinazoline (100 mg, 59%). LCMS: 165 [M+1].sup.+.
[0627] Step-3: Synthesis of
4-(3-(2-sulfamoylaminoethyl)azetidine-1-yl) quinazoline: A
suspension of 4-chloroquinazoline (70 mg, 0.40 mmol, 1.2 eq),
3-(2-sulfamoylaminoethyl) azetidine trifluoroacetate (100 mg, 0.34
mmol, 1.0 eq) and DIPEA (0.12 mL, 0.68 mmol, 2.0 eq) in DMF (1 mL)
was allowed to stir at 80.degree. C. for 3 h. Progress of reaction
was monitored by TLC. After 3 h, reaction mixture was concentrated
under reduced pressure to afford crude which was purified using
reversed phase HPLC to afford
4-(3-(2-sulfamoylaminoethyl)azetidine-1-yl) quinazoline (33 mg,
31%). LCMS: 308 [M+1].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. ppm 8.44 (s, 1H), 7.95 (d, 1H), 7.76 (t, 1H), 7.68 (d, 1H),
7.46 (t, 1H), 6.58 (brs, 1H), 6.55 (brs, 2H), 4.55 (brs, 2H), 4.18
(brs, 2H), 3.00-2.80 (m, 3H), 1.90-1.80 (m, 2H).
Example-65: Synthesis
3-(1-(6,7-dimethoxyquinazolin-4-yl)azetidin-3-yl)propane-1-sulfonic
acid, (Compound 1.65)
##STR00643##
[0629] Step-1: Synthesis of methyl methanesulfonate: To a solution
of methanol (5 g, 156 mmol, 1 eq) in DCM (100 mL) was added
triethylamine (42.5 mL, 312 mmol, 2 eq) and the reaction mixture
was allowed to stir at -30.degree. C. for 5 minutes. To the mixture
was added methane sulfonyl chloride (13.2 mL, 171 mmol, 1.1 eq) and
the reaction mixture allowed to stir at 0.degree. C. for 1 h.
Progress of reaction is monitored by .sup.1H NMR. After completion,
reaction mixture was diluted with water (100 mL) and extracted with
ethyl acetate (3.times.100 mL). Combined organic layer was washed
with aq. NaHCO.sub.3 (150 mL) followed by brine (150 mL) and dried
over anhydrous sodium sulfate. Removal of solvent under reduced
pressure afforded methyl methanesulfonate (5.5 g, Crude) which was
used in the next step without purification.
[0630] Step-2: Synthesis of methyl
(diethoxyphosphoryl)methanesulfonate): To a solution of methyl
methanesulfonate (2 g, 18.18 mmol, 1 eq) in THF (20 ml) at
-78.degree. C. was added 2.5M n-BuLi (14.5 ml, 36.36 mmol, 2 eq)
dropwise under nitrogen and the reaction mixture was stirred at the
same temperature for 1 h. To the mixture was added a solution of
diethyl chlorophosphate (1.4 ml, 9 mmol, 0.5 eq) in THF (2 ml)
dropwise. Reaction mixture was warmed to 0.degree. C. and stirred
at the same temperature for 1 h. Progress of reaction was monitored
by TLC. After completion, reaction mixture was diluted with
saturated aq. NH.sub.4Cl (100 mL) and extracted with ethyl acetate
(3.times.100 mL). Combined organic layer was washed with water
(2.times.100 mL) followed by brine (150 mL) and dried over
anhydrous sodium sulfate. Removal of solvent under reduced pressure
gave crude which was purified by Combi-Flash using ethyl
acetate-hexane system as eluent to afford methyl
(diethoxyphosphoryl)methanesulfonate) (1 g, 22%).
[0631] Step-3: Synthesis of (E)-tert-butyl
3-(3-(methoxysulfonyl)allyl)azetidine-1-carboxylate: To a solution
of methyl (diethoxyphosphoryl)methanesulfonate) (0.5 g, 2.03 mmol,
1 eq) in THF (10 ml) at -78.degree. C. was added 2.5M n-BuLi (1.7
ml, 4.2 mmol, 2.1 eq) dropwise under nitrogen and the reaction
mixture was stirred at the same temperature for 15 minutes. To the
reaction mixture was then added a solution of tert-butyl
3-(2-oxoethyl)azetidine-1-carboxylate (0.404 g, 2.03 mmol, 1 eq) in
THF (2 ml) dropwise. Reaction mixture was warmed to RT and stirred
for 16 h. Progress of reaction was monitored by TLC. After
completion, reaction mixture was diluted with saturated aq.
NH.sub.4Cl (100 mL) and extracted with ethyl acetate (3.times.100
mL). Combined organic layer was washed with water (2.times.100 mL)
followed by brine (150 mL) and dried over anhydrous sodium sulfate.
Removal of solvent under reduced pressure gave crude which was
purified by Combi-Flash using ethyl acetate-hexane system as eluent
to afford (E)-tert-butyl
3-(3-(methoxysulfonyl)allyl)azetidine-1-carboxylate (0.1 g,
17%).
[0632] Step-4: Synthesis of tert-butyl
3-(3-(methoxysulfonyl)propyl)azetidine-1-carboxylate: To a solution
of (E)-tert-butyl
3-(3-(methoxysulfonyl)allyl)azetidine-1-carboxylate (0.1 g, 0.34
mmol, 1 eq) in ethanol (10 mL) was added Pd/C (0.05 g) and the
reaction mixture was allowed to stir at RT under H.sub.2 atmosphere
using balloon for 3 h. Progress of reaction was monitored by TLC.
After completion, reaction mixture was filtered through celite-bed.
Removal of solvent under reduced pressure afforded crude tert-butyl
3-(3-(methoxysulfonyl)propyl)azetidine-1-carboxylate (0.09 g,
Crude) which was used in the next step without purification.
[0633] Step-5: Synthesis of methyl
3-(azetidin-3-yl)propane-1-sulfonate: To a solution of tert-butyl
3-(3-(methoxysulfonyl)propyl)azetidine-1-carboxylate (0.09 g, 0.306
mmol, 1 eq) in DCM (2 mL) was added TFA (1 mL) and the mixture was
allowed to stir at RT for 1 h. Progress of reaction was monitored
by .sup.1H NMR. After completion, reaction mixture was concentrated
under reduced pressure to afford crude which was triturated with
diethyl ether to afford methyl 3-(azetidin-3-yl)propane-1-sulfonate
(0.09 g, Crude) as TFA salt.
[0634] Step-6: Synthesis
3-(1-(6,7-dimethoxyquinazolin-4-yl)azetidin-3-yl)propane-1-sulfonic
acid: A suspension of methyl 3-(azetidin-3-yl)propane-1-sulfonate
(90 mg, 0.29 mmol, 1 eq), 4-chloro-6,7-dimethoxyquinazoline (80 mg,
0.35 mmol, 1.2 eq) and DIPEA (0.1 mL, 0.59 mmol, 2.0 eq) in DMF (1
mL) was allowed to stir at 80.degree. C. for 2 h. Progress of
reaction was monitored by TLC. After completion, reaction mixture
was concentrated under reduced pressure to get residue which was
purified by RP-HPLC to afford
3-(1-(6,7-dimethoxyquinazolin-4-yl)azetidin-3-yl)propane-1-sulfonic
acid (0.022 g, 21%). LCMS: 368 [M+1].sup.+; .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 8.31 (s, 1H), 7.22 (s, 1H), 7.11 (s, 1H),
4.62-4.48 (m, 2H), 4.12-4.02 (m, 2H), 3.90 (s, 3H), 3.89 (s, 3H),
2.82-2.70 (m, 1H), 2.50-2.40 (m, 2H), 1.80-1.58 (m, 4H).
Example-66: Synthesis
4-(3-(2-sulfamoylaminoethyl)azetidine-1-yl)-6-fluoro-7-methoxy
quinazoline, (Compound 1.66)
##STR00644##
[0636] Step-1: Synthesis of 2-amino-5-fluoro-4-methoxybenzoic acid:
A mixture of 2-amino-4-methoxybenzoic acid (1 g, 5.9 mmol, 1 eq)
and selectfluor (2 g, 5.9 mmol, 1 eq) in acetonitrile (50 mL) was
allowed to stir at 80.degree. C. for 4 h. Progress of reaction was
monitored by TLC. After 4 h, water (200 mL) was added into reaction
mixture and was extracted using ethyl acetate (3.times.50 mL). The
combined organic layer was washed with brine (50 mL) and dried over
anhydrous sodium sulphate. Removal of solvent under reduced
pressure gave crude which was purified by Combi-Flash to afford
2-amino-5-fluoro-4-methoxybenzoic acid (150 mg, 13%). LCMS: 186
[M+1].sup.+.
[0637] Step-2: Synthesis of 6-fluoro-7-methoxyquinazolin-4
(3H)-one: A mixture of 2-amino-5-fluoro-4-methoxybenzoic acid (0.17
g, 0.91 mmol, 1 eq), ammonium acetate (0.1 g, 1.19 mmol, 1.3 eq)
and triethylorthoformate (0.24 mL, 1.45 mmol, 1.6 eq) in ethanol (4
mL) was allowed to stir at 90.degree. C. for 16 h. Progress of
reaction was monitored by TLC. Reaction mixture was cooled to RT,
solid was filtered, washed with hexane and dried under vacuum to
afford 6-fluoro-7-methoxyquinazolin-4 (3H)-one (56 mg, 31%). LCMS:
195 [M+1].sup.+.
[0638] Step-3: Synthesis of 4-chloro-6-fluoro-7-methoxyquinazoline:
A mixture of 6-fluoro-7-methoxyquinazolin-4 (3H)-one (0.05 g, 0.28
mmol, 1 eq) in POCl.sub.3 (1 mL) was stirred at 120.degree. C. for
2 h. After completion, reaction mixture was diluted with water (150
mL) and extracted with ethyl acetate (3.times.50 mL). Combined
organic layer was washed with water (3.times.30 mL) and dried over
anhydrous sodium sulphate. Removal of solvent under reduced
pressure afforded 4-chloro-6-fluoro-7-methoxyquinazoline (50 mg,
81%). LCMS: 213 [M+1].sup.+.
[0639] Step-4: Synthesis
4-(3-(2-sulfamoylaminoethyl)azetidine-1-yl)-6-fluoro-7-methoxy
quinazoline: A suspension of 4-chloro-6-fluoro-7-methoxyquinazoline
(43 mg, 0.20 mmol, 1.2 eq), 3-(2-sulfamoylaminoethyl) azetidine
trifluoroacetate (50 mg, 0.17 mmol, 1.0 eq) and DIPEA (0.06 mL,
0.34 mmol, 2.0 eq) in DMF (1 mL) was allowed to stir at 80.degree.
C. for 3 h. Progress of reaction was monitored by TLC. After 3 h,
reaction mixture was concentrated under reduced pressure to afford
crude which was purified using reversed phase HPLC to afford
4-(3-(2-sulfamoylaminoethyl)azetidine-1-yl)-6-fluoro-7-methoxy
quinazoline (7 mg, 11%). LCMS: 356 [M+1].sup.+; .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. ppm 8.40 (s, 1H), 7.63 (d, 1H), 7.30 (d,
1H), 6.58 (brs, 1H), 6.56 (s, 2H), 4.55 (brs, 2H), 4.10 (brs, 2H),
3.98 (s, 3H), 2.96-2.80 (m, 3H), 1.95-1.79 (m, 2H).
Example-67: Synthesis
N-(2-(1-(6,7-dimethoxyquinazolin-4-yl)azetidin-3-yl)ethyl)-1,1,1-trifluor-
omethanesulfonamide, (Compound 1.67)
##STR00645##
[0641] Step-1: Synthesis of tert-butyl
3-(2-(trifluoromethylsulfonamido)ethyl)azetidine-1-carboxylate: To
a solution of tert-butyl 3-(2-aminoethyl)azetidine-1-carboxylate
(0.1 g, 0.49 mmol, 1 eq) in DCM (3 mL) was added triflic anhydride
(0.14 g, 0.49 mmol, 1 eq) and the reaction mixture was allowed to
stir at 0.degree. C. for 2 h. Progress of reaction was monitored by
.sup.1H NMR. After completion, reaction mixture was concentrated
under reduced pressure to afford
3-(2-(trifluoromethylsulfonamido)ethyl)azetidine-1-carboxylate
(0.15 g, 90%) which was used in the next step without
purification.
[0642] Step-2: Synthesis of
N-(2-(azetidin-3-yl)ethyl)-1,1,1-trifluoromethanesulfonamide
trifluoroacetate: To a solution of
3-(2-(trifluoromethylsulfonamido)ethyl)azetidine-1-carboxylate (150
mg, 0.45 mmol, 1 eq) in DCM (4 mL) was added TFA (1 mL) and the
reaction mixture was allowed to stir at RT for 1 h. Progress of
reaction was monitored by NMR. After completion, reaction mixture
was concentrated under reduced pressure to afford crude which was
triturated with diethyl ether to afford
N-(2-(azetidin-3-yl)ethyl)-1,1,1-trifluoromethanesulfonamide
trifluoroacetate (100 mg, 64%).
[0643] Step-3: Synthesis of
N-(2-(1-(6,7-dimethoxyquinazolin-4-yl)azetidin-3-yl)ethyl)-1,1,1-trifluor-
omethanesulfonamide: A suspension of
4-chloro-6,7-dimethoxyquinazoline (40 mg, 0.17 mmol, 1.2 eq),
N-(2-(azetidin-3-yl)ethyl)-1,1,1-trifluoromethanesulfonamide
trifluoroacetate (50 mg, 0.14 mmol, 1.0 eq) and DIPEA (0.05 mL,
0.28 mmol, 2.0 eq) in DMF (1 mL) was allowed to stir at 80.degree.
C. for 2 h. Progress of reaction was monitored by TLC. After 2 h,
reaction mixture was concentrated under reduced pressure to afford
crude which was purified using RP-HPLC to afford
N-(2-(1-(6,7-dimethoxyquinazolin-4-yl)azetidin-3-yl)ethyl)-1,1,1-trifluor-
omethanesulfonamide (2.7 mg, 5%). LCMS: 421 [M+1].sup.+; .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 8.31 (s, 1H), 7.21 (s, 1H),
7.10 (s, 1H), 4.60-4.46 (m, 2H), 4.18-4.02 (m, 2H), 3.88 (s, 3H),
3.86 (s, 3H), 2.96-2.78 (m, 3H), 1.80-1.62 (m, 2H).
Example-68: Synthesis 4
(6-N-methylsulfamoylamino)-2-azaspiro[3.3]heptan-2-yl-6,7-dimethoxycinnol-
ine, (Compound 1.68)
##STR00646##
[0645] Step-1: Synthesis of tert-butyl
6-(benzyloxycarbonylamino)-2-azaspiro[3.3]heptane-2-carboxylate: To
a solution of tert-butyl
6-amino-2-azaspiro[3.3]heptane-2-carboxylate (1 g, 4.7 mmol, 1 eq)
in H.sub.2O (50 mL), was added NaHCO.sub.3 (0.791 g, 9.4 mmol, 2.0
eq) and benzyl chloroformate (1.6 mL, 4.7 mmol, 1 eq). The reaction
mixture was allowed to stir at RT for 2 h. Progress of reaction is
monitored by .sup.1H NMR. After completion, reaction mixture was
diluted with water (100 mL) and extracted with EtOAc (3.times.100
mL). Combined organic layer was washed with brine (150 mL) and
dried over anhydrous sodium sulfate. Removal of solvent under
reduced pressure afforded tert-butyl
6-(benzyloxycarbonylamino)-2-azaspiro[3.3]heptane-2-carboxylate
(0.7 g, Crude) which was used in the next step without
purification.
[0646] Step-2: Synthesis of tert-butyl
6-((benzyloxycarbonyl)(methyl)amino)-2-azaspiro[3.3]heptane-2-carboxylate-
: To a solution of tert-butyl
3-(2-(benzyloxycarbonylamino)ethyl)azetidine-1-carboxylate (0.7 g,
2.0 mmol, 1 eq) in DMF (10 mL), was added NaH (0.161 g, 4.0 mmol,
2.0 eq) and the resulting mixture was stirred at RT for 10 minutes.
To the mixture was then added methyl iodide (0.37 mL, 6.0 mmol, 3
eq) and the reaction mixture was allowed to stir at RT for 2.
Progress of reaction is monitored by .sup.1H NMR. After completion,
reaction mixture was diluted with water (100 mL) and extracted with
EtOAc (3.times.100 mL). Combined organic layer was washed with
water (2.times.100 mL) followed by brine (150 mL) and dried over
anhydrous sodium sulfate. Removal of solvent under reduced pressure
afforded tert-butyl
6-((benzyloxycarbonyl)(methyl)amino)-2-azaspiro[3.3]heptane-2-carboxylate
(0.63 g, Crude) which was used in the next step without
purification.
[0647] Step-3: Synthesis of tert-butyl
6-(methylamino)-2-azaspiro[3.3]heptane-2-carboxylate: To a solution
of tert-butyl
6-((benzyloxycarbonyl)(methyl)amino)-2-azaspiro[3.3]heptane-2-carboxylate
(0.6 g, 1.6 mmol, 1 eq) in ethanol (20 mL) was added Pd/C (0.3 g)
and the reaction mixture was allowed to stir at RT under H.sub.2
atmosphere using balloon for 5 h. Progress of reaction was
monitored by TLC. After completion, reaction mixture was filtered
through celite-bed. Removal of solvent under reduced pressure
afforded crude tert-butyl
6-(methylamino)-2-azaspiro[3.3]heptane-2-carboxylate (0.4 g, Crude)
which was used in the next step without purification.
[0648] Step-4: Synthesis of tert-butyl
6-((N-(tert-butoxycarbonyl)sulfamoyl)(methyl)amino)-2-azaspiro[3.3]heptan-
e-2-carboxylate: To a solution of tert-butyl
6-(methylamino)-2-azaspiro[3.3]heptane-2-carboxylate (0.4 g, 1.7
mmol, 1 eq) in dichloromethane (15 mL) were added
N-(tert-butoxycarbonyl)-N-[4-(dimethylazaniumylidene)-1,4-dihydropyridin--
1ylsulfonyl]azanide (0.798 g, 2.6 mmol, 1.5 eq) and
N,N-diisopropylethylamine (0.6 mL, 3.5 mmol, 2 eq) and the reaction
mixture was allowed to stir at RT for 48 h. Progress of reaction
was monitored by TLC. After completion, reaction mixture was
concentrated under reduced pressure to get crude which was purified
by Combi-Flash using ethyl acetate-hexane system as eluent to
afford tert-butyl
6-((N-(tert-butoxycarbonyl)sulfamoyl)(methyl)amino)-2-azaspiro[3.3]heptan-
e-2-carboxylate (0.4 g, 56%).
[0649] Step-5: Synthesis of
(6-N-methylsulfamoylamino)-2-azaspiro[3.3]heptane: To a solution of
tert-butyl
6-((N-(tert-butoxycarbonyl)sulfamoyl)(methyl)amino)-2-azaspiro[3.3]heptan-
e-2-carboxylate (0.4 g, 0.98 mmol, 1 eq) in DCM (5 mL) was added
TFA (1 mL) and the mixture was allowed to stir at RT for 1 h.
Progress of reaction was monitored by .sup.1H NMR. After
completion, reaction mixture was concentrated under reduced
pressure to afford crude which was triturated with diethyl ether to
afford (6-N-methylsulfamoylamino)-2-azaspiro[3.3]heptane (0.35 g)
as TFA salt.
[0650] Step-6: Synthesis of 4
(6-N-methylsulfamoylamino)-2-azaspiro[3.3]heptan-2-yl-6,7-dimethoxycinnol-
ine: A suspension of
(6-N-methylsulfamoylamino)-2-azaspiro[3.3]heptane (100 mg, 0.31
mmol, 1 eq), 4-chloro-6,7-dimethoxycinnoline (85 mg, 0.37 mmol, 1.2
eq) and DIPEA (0.11 mL, 0.6 mmol, 2.0 eq) in DMF (1 mL) was allowed
to stir at 80.degree. C. for 2 h. Progress of reaction was
monitored by TLC. After completion, reaction mixture was
concentrated under reduced pressure to get residue which was
purified by reversed phase HPLC to afford 4
(6-N-methylsulfamoylamino)-2-azaspiro[3.3]heptan-2-yl-6,7-dimethoxycinnol-
ine (9 mg, 7% yield). LCMS: 394.4 [M+1].sup.+; .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. ppm 8.19 (s, 1H), 7.45 (s, 1H) 7.11 (s,
1H), 6.75 (s, 1H), 4.50 (s, 2H), 4.38 (s, 2H), 3.96 (s, 6H), 3.80
(m, 1H), 2.48 (s, 3H), 2.43 (s, 4H).
Example-69: Synthesis
4-3-(3-sulfamoylaminopropyl)azetidin-1-yl-6,7-dimethoxyquinazoline,
(Compound 1.69)
##STR00647##
[0652] Step-1: Synthesis of tert-butyl
3-(2-(methylsulfonyloxy)ethyl)azetidine-1-carboxylate: To a
solution of tert-butyl 3-(2-hydroxyethyl)azetidine-1-carboxylate
(1.8 g, 8.9 mmol, 1 eq) in DCM (20 mL) was added triethylamine (2.4
mL, 17.9 mmol, 2 eq) and the reaction mixture was allowed to stir
at 0.degree. C. for 5 minutes. To the mixture was added methane
sulfonyl chloride (1.1 mL, 13.4 mmol, 1.5 eq) and the reaction
mixture to stir at 0.degree. C. for 10 minutes followed by stirring
at RT for 2 h. Progress of reaction was monitored by .sup.1H NMR.
After completion, reaction mixture was diluted with water (100 mL)
and extracted with ethyl acetate (3.times.100 mL). Combined organic
layer was washed with brine (150 mL) and dried over anhydrous
sodium sulfate. Removal of solvent under reduced pressure afforded
tert-butyl 3-(2-(methylsulfonyloxy)ethyl)azetidine-1-carboxylate
(2.6 g, Crude) which was used in the next step without
purification.
[0653] Step-2: Synthesis of tert-butyl
3-(2-cyanoethyl)azetidine-1-carboxylate: To a solution of
tert-butyl 3-(2-(methylsulfonyloxy)ethyl)azetidine-1-carboxylate
(2.6 g, 9.3 mmol, 1 eq) in DMSO (10 mL), was added sodium cyanide
(1.16 g, 23.29 mmol, 2.5 eq) and the reaction mixture was allowed
to stir at 80.degree. C. for 16 h. Progress of reaction is
monitored by .sup.1H NMR. After completion, reaction mixture was
diluted with water (100 mL) and extracted with diethyl ether
(3.times.150 mL). Combined organic layer was washed with water
(2.times.100 mL) followed by brine (150 mL) and dried over
anhydrous sodium sulfate. Removal of solvent under reduced pressure
afforded tert-butyl 3-(2-cyanoethyl)azetidine-1-carboxylate (1.5 g,
Crude) which was used in the next step without purification.
[0654] Step-3: Synthesis of tert-butyl
3-(3-aminopropyl)azetidine-1-carboxylate: To a solution of
tert-butyl 3-(2-cyanoethyl)azetidine-1-carboxylate (1.5 g, 7.1
mmol, 1 eq) in ethanol (50 mL) was added Pd/C (0.75 g) and the
reaction mixture was allowed to stir at RT under H.sub.2 atmosphere
using balloon for 5 h. Progress of reaction was monitored by TLC.
After completion, reaction mixture was filtered through celite-bed.
Removal of solvent under reduced pressure afforded crude tert-butyl
3-(3-aminopropyl)azetidine-1-carboxylate (1.3 g, Crude) which was
used in the next step without purification.
[0655] Step-4: Synthesis of tert-butyl
3-(3-(N-(tert-butoxycarbonyl)sulfamoylamino)propyl)azetidine-1-carboxylat-
e: To a solution of tert-butyl
3-(3-aminopropyl)azetidine-1-carboxylate (0.2 g, 0.9 mmol, 1 eq) in
dichloromethane (15 mL) were added
N-(tert-butoxycarbonyl)-N-[4-(dimethylazaniumylidene)-1,4-dihydropyridin--
1ylsulfonyl]azanide (0.421 mg, 1.4 mmol, 1.5 eq) and
N,N-diisopropylethylamine (0.3 mL, 1.8 mmol, 2 eq) and the reaction
mixture was allowed to stir at RT for 48 h. Progress of reaction
was monitored by TLC. After completion, reaction mixture was
concentrated under reduced pressure to get crude which was purified
by Combi-Flash using ethyl acetate-hexane system as eluent to
afford tert-butyl
3-(3-(N-(tert-butoxycarbonyl)sulfamoylamino)propyl)azetidine-1-carboxylat-
e (0.15 g, 55.5%).
[0656] Step-5: Synthesis of 3-(3-sulfamoylaminopropyl)azetidine
trifluoroacetate: To a solution of tert-butyl
3-(3-(N-(tert-butoxycarbonyl)sulfamoylamino)propyl)azetidine-1-carboxylat-
e (0.15 g, 0.38 mmol, 1 eq) in DCM (5 mL) was added TFA (1 mL) and
the mixture was allowed to stir at RT for 1.5 h. Progress of
reaction was monitored by .sup.1H NMR. After completion, reaction
mixture was concentrated under reduced pressure to afford crude
which was triturated with diethyl ether to afford
3-(3-sulfamoylaminopropyl)azetidine trifluoroacetate (0.15 g).
[0657] Step-6: Synthesis of
4-3-(3-sulfamoylaminopropyl)azetidin-1-yl-6,7-dimethoxyquinazoline:
A mixture of 4-chloro-5-methyl-5H-pyrrolo[3,2-d]pyrimidine (38 mg,
0.17 mmol, 1 eq), 3-(3-sulfamoylaminopropyl)azetidine
trifluoroacetate (50 mg, 0.17 mmol, 1.0 eq) and DIPEA (0.029 mL,
0.34 mmol, 2.0 eq) in DMF (1 mL) was allowed to stir at 80.degree.
C. for 2 h. Progress of reaction was monitored by TLC. After
completion, reaction mixture was concentrated under reduced
pressure to get residue which was purified by RP-HPLC to afford
4-3-(3-sulfamoylaminopropyl)azetidin-1-yl-6,7-dimethoxyquinazoline
(2.1 mg, 3%). LCMS: 382.4 [M+1].sup.+; .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 8.35 (s, 1H), 7.20 (s, 1H), 7.12 (s, 1H),
6.50-6.42 (m, 3H), 4.62-4.50 (m, 2H), 4.17-4.02 (m, 2H), 3.88 (s,
3H), 3.87 (s, 3H), 2.92-2.81 (m, 2H), 2.60-2.68 (m, 1H)
Example-70: Synthesis
4-3-(3-sulfamoylaminopropan-2-yl)azetidin-1-yl-6,7-dimethoxyquinazoline,
(Compound 1.70)
##STR00648##
[0659] A mixture of 4-chloro-6,7-dimethoxyquinazoline (50 mg, 0.221
mmol, 1 eq), N-[2-(azetidin-3-yl)propyl]sulfuric diamide
trifluoroacetate (64 mg, 0.221 mmol, 1.0 eq) and DIPEA (0.078 mL,
0.442 mmol, 2.0 eq) in DMF (2 mL) was allowed to stir at 80.degree.
C. for 2 h. Progress of reaction was monitored by TLC. After
completion, reaction mixture was concentrated under reduced
pressure to get residue which was purified by RP-HPLC to afford the
title compound (20 mg, 23%). LCMS: 382 [M+1].sup.+; .sup.1H NMR
(400 MHz, METHANOL-d.sub.4) .delta. ppm 8.28 (s, 1H), 7.28 (s, 1H),
7.08 (s, 1H), 4.71 (br. s., 1H), 4.63 (br. s., 1H), 4.44 (br. s.,
1H), 3.97 (s, 3H), 3.94 (s, 3H), 2.99 (m, 2H), 2.78 (m, 1H), 2.05
(m, 1H), 1.97 (s, 1H), 1.01 (d, 2H).
Example-71: Synthesis
4-(3-(2-sulfamoylaminoethyl)azetidine-1-yl)-2,5-di-methylpyrrolo[1,2-f][1-
,2,4]triazine, (Compound 1.71)
##STR00649##
[0661] Step-1: Synthesis of
4-chloro-5-methylpyrrolo[1,2-f][1,2,4]triazine: A mixture of
2,5-dimethylpyrrolo[1,2-f][1,2,4]triazin-4-ol (100 mg, 0.613 mmol,
1 eq) in POCl.sub.3 (0.3 mL) was stirred at 120.degree. C. for 2 h.
Progress of reaction was monitored by TLC. After completion
reaction mixture was cooled to RT, poured to ice (10 mL) and
stirred for 15 minutes. Solid was filtered and dried to afford
4-chloro-2,5-dimethylpyrrolo[1,2-f][1,2,4]triazine (70 mg, 63%).
LCMS: 182 [M+1].sup.+
[0662] Step-2: Synthesis of
4-(3-(2-sulfamoylaminoethyl)azetidine-1-yl)-2,5-di-methylpyrrolo[1,2-f][1-
,2,4]triazine: A suspension of
4-chloro-2,5-dimethylpyrrolo[1,2-f][1,2,4]triazine (70 mg, 0.285
mmol, 1.0 eq), 3-(2-sulfamoylaminoethyl)azetidine trifluoroacetate
(80 mg, 0.285 mmol, 1.0 eq) and N,N diisopropylethylamine (74 mg,
0.772 mmol, 2.0 eq) in DMF (2 mL) was allowed to stir at 80.degree.
C. for 2 h. Progress of reaction was monitored by TLC. Reaction
mixture was cooled to RT, DMF was removed under reduced pressure,
crude obtained was purified by RP-HPLC to afford
4-(3-(2-sulfamoylaminoethyl)azetidine-1-yl)-2,5-di-methylpyrrolo[1,2-f][1-
,2,4]triazine (6 mg, 20.8%). LCMS: 325.2 [M+1].sup.+; .sup.1H NMR
(400 MHz, METHANOL-d.sub.4) .delta. ppm 7.38 (d, 1H), 6.41 (d, 1H),
4.55 (t, 2H), 4.09 (dd, 2H), 3.08 (t, 2H), 2.90 (m, 1H), 2.44 (s,
3H), 2.27 (s, 3H), 1.93 (q, 2H).
Example-72: Synthesis of
4-(3-(2-sulfamoylaminoethyl)azetidine-1-yl)-6-bromo-5-methylpyrrolo[1,2-f-
][1,2,4]triazine, (Compound 1.72)
##STR00650##
[0664] Step-1: Synthesis of
6-bromo-4-chloro-5-methylpyrrolo[1,2-f][1,2,4]triazine: A mixture
of 6-bromo-5-methylpyrrolo[1,2-f][1,2,4]triazin-4-ol (100 mg, 0.440
mmol, 1 eq) in POCl.sub.3 (0.3 mL) was stirred at 120.degree. C.
for 2 h. Progress of the reaction was monitored by TLC. After
completion reaction mixture was cooled to RT, poured to ice (10 mL)
and stirred for 15 minutes. Solid was filtered and dried to afford
6-bromo-4-chloro-5-methylpyrrolo[1,2-f][1,2,4]triazine (70 mg,
65%). LCMS: 182 [M+1].sup.+
[0665] Step-2: Synthesis of
4-(3-(2-sulfamoylaminoethyl)azetidine-1-yl)-6-bromo-5-methylpyrrolo[1,2-f-
][1,2,4]triazine: A suspension of
6-bromo-4-chloro-5-methylpyrrolo[1,2-f][1,2,4]triazine (70 mg,
0.285 mmol, 1.0 eq), 3-(2-sulfamoylaminoethyl)azetidine
trifluoroacetate (79 mg, 0.285 mmol, 1.0 eq) and N,N
diisopropylethylamine (74 mg, 0.570 mmol, 2.0 eq) in DMF (2 mL) was
allowed to stir at 80.degree. C. for 2 h. Progress of reaction was
monitored by TLC. Reaction mixture was cooled to RT, DMF was
removed under reduced pressure, crude obtained was purified by
reversed phase HPLC to afford
4-(3-(2-sulfamoylaminoethyl)azetidine-1-yl)-6-bromo-5-methylpyrrolo[1,2-f-
][1,2,4]triazine (6 mg, 4%). LCMS: 389 [M+1].sup.+; .sup.1H NMR
(400 MHz, METHANOL-d.sub.4) .delta. ppm 7.72 (s, 1H), 7.63 (s, 1H),
4.58 (d, 3H), 4.12 (dd, 3H), 3.48 (br. s., 1H), 3.08 (t, 2H), 2.93
(d, 2H), 2.42 (s, 3H), 1.93 (q, 3H).
Example-73: Synthesis of
4-(6-N-methylsulfamoylamino)-2-azaspiro[3.3]heptan-2-yl)-5-methylpyrrolo[-
1,2-f][1,2,4]triazine, (Compound 1.73)
##STR00651##
[0667] A suspension of
(6-N-methylsulfamoylamino)-2-azaspiro[3.3]heptane (80 mg, 0.25
mmol, 1 eq), 4-chloro-5-methylpyrrolo[1,2-f][1,2,4]triazine (50 mg,
0.30 mmol, 1.2 eq) and DIPEA (0.08 mL, 0.50 mmol, 2.0 eq) in DMF (1
mL) was allowed to stir at 80.degree. C. for 2 h. Progress of
reaction was monitored by TLC. After completion, reaction mixture
was concentrated under reduced pressure to get residue which was
purified by reversed phase HPLC to afford
4-(6-N-methylsulfamoylamino)-2-azaspiro[3.3]heptan-2-yl)-5-methylpyrrolo[-
1,2-f][1,2,4]triazine (20 mg, 24% yield). LCMS: 337.4 [M+1].sup.+;
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 7.78 (s, 1H), 7.59
(s, 1H), 6.72 (s, 2H), 6.48 (s, 1H), 4.39 (brs, 2H), 4.26 (brs,
2H), 3.81-3.70 (m, 1H), 2.55 (s, 3H), 2.40 (s, 3H), 2.40-2.20 (m,
4H).
Example-74: Synthesis of
N-hydroxy-3-(1-(5-methylpyrrolo[1,2-f][1,2,4]triazin-4-yl)azetidin-3-yl)p-
ropanamide, (Compound 1.74)
##STR00652##
[0669] Step-1: Synthesis of tert-butyl
3-(3-ethoxy-3-oxopropyl)azetidine-1-carboxylate: To a solution of
(E)-tert-butyl 3-(3-ethoxy-3-oxoprop-1-enyl)azetidine-1-carboxylate
(0.6 g, 2.35 mmol, 1 eq) in ethanol (10 mL) was added Pd/C (0.2 g)
and the reaction mixture was allowed to stir at RT under H.sub.2
balloon for 2 h. After completion, reaction mixture was filtered
using celite bed. Filtrate was concentrated under reduced pressure
afforded tert-butyl 3-(3-ethoxy-3-oxopropyl)azetidine-1-carboxylate
(0.600 g, crude) which was used in the next step without
purification.
[0670] Step-2: Synthesis of
3-(1-(tert-butoxycarbonyl)azetidin-3-yl)propanoic acid: To a
solution of tert-butyl
3-(3-ethoxy-3-oxopropyl)azetidine-1-carboxylate (0.6 g, 2.33 mmol,
1 eq) in EtOH (10 mL) was added a solution of NaOH (0.466 g, 11.65
mmol, 5 eq) in water (2 mL) and the reaction mixture was allowed to
stir at RT overnight. Progress of reaction is monitored by
.sup.1H-NMR. After completion, solvent was removed under reduced
pressure, residue was acidified with 1N HCl and extracted with
ethyl acetate (3.times.100 mL). Combined organic layer was washed
with brine (150 mL) and dried over anhydrous sodium sulfate.
Removal of solvent under reduced pressure afforded
3-(1-(tert-butoxycarbonyl)azetidin-3-yl)propanoic acid (0.48 g,
crude) which was used in the next step without purification.
[0671] Step-3: Synthesis of tert-butyl
3-(3-(benzyloxyamino)-3-oxopropyl)azetidine-1-carboxylate: To a
solution of 3-(1-(tert-butoxycarbonyl)azetidin-3-yl)propanoic acid
(0.48 g, 2.094 mmol, 1 eq) and O-benzylhydroxylamine (0.367 g,
2.301 mmol, 1.1 eq) in DCM (30 mL) were added
N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (0.48
g, 2.513 mmol, 1.2 eq), 4-(Dimethylamino)pyridine (0.383 g, 3.141
mmol, 1.5 eq) and triethylamine (0.9 mL, 6.282 mmol, 3 eq), the
reaction mixture was allowed to stir at RT overnight. Progress of
reaction is monitored by TLC. After completion, removal of solvent
under reduced pressure gave residue which was diluted with water
(100 mL) and extracted with ethyl acetate (3.times.100 mL).
Combined organic layer was washed with dil. HCl and brine (150 mL)
and dried over anhydrous sodium sulfate. Removal of solvent under
reduced pressure afforded tert-butyl
3-(3-(benzyloxyamino)-3-oxopropyl)azetidine-1-carboxylate (0.6 g,
crude) which was used in the next step without purification.
[0672] Step-4: Synthesis of tert-butyl
3-(3-(hydroxyamino)-3-oxopropyl)azetidine-1-carboxylate: To a
solution of tert-butyl
3-(3-(benzyloxyamino)-3-oxopropyl)azetidine-1-carboxylate (0.6 g,
1.794 mmol, 1 eq) in methanol (25 mL) was added Pd/C (0.125 g) and
the reaction mixture was allowed to stir at RT under H.sub.2
atmosphere using hydrogen balloon for 2 h. After completion,
reaction mixture was filtered using celite bed. Removal of solvent
under reduced pressure afforded tert-butyl
3-(3-(hydroxyamino)-3-oxopropyl)azetidine-1-carboxylate (0.4 g,
crude) which was used in the next step without purification.
[0673] Step-5: Synthesis of 3-(azetidin-3-yl)-N-hydroxypropanamide
trifluoroacetate: To a solution of tert-butyl
3-(3-(hydroxyamino)-3-oxopropyl)azetidine-1-carboxylate (0.4 g,
1.637 mmol, 1 eq) in DCM (5 mL) was added TFA (1 mL) and the
mixture was allowed to stir at RT for 2 h. Progress of reaction was
monitored by .sup.1H NMR. After completion, reaction mixture was
concentrated under reduced pressure to afford crude which was
triturated with diethyl ether to afford
3-(azetidin-3-yl)-N-hydroxypropanamide trifluoroacetate (0.250 g,
crude) which was used in the next step without purification.
[0674] Step-6: Synthesis of
N-hydroxy-3-(1-(5-methylpyrrolo[1,2-f][1,2,4]triazin-4-yl)azetidin-3-yl)p-
ropanamide: A suspension of 3-(azetidin-3-yl)-N-hydroxypropanamide
trifluoroacetate (80 mg, 0.31 mmol, 1 eq),
4-chloro-5-methylpyrrolo[1,2-f][1,2,4]triazine (62 mg, 0.37 mmol,
1.2 eq) and DIPEA (0.1 mL, 0.62 mmol, 2.0 eq) in DMF (1 mL) was
allowed to stir at 80.degree. C. for 2 h. Progress of reaction was
monitored by TLC. After completion, reaction mixture was
concentrated under reduced pressure to get residue which was
purified by RP-HPLC to afford
N-hydroxy-3-(1-(5-methylpyrrolo[1,2-f][1,2,4]triazin-4-yl)azetidin-3-yl)p-
ropanamide (6.5 mg, 8% yield). LCMS: 276.3 [M+1].sup.+1H NMR (400
MHz, DMSO-d.sub.6) .delta. ppm 8.75 (brs, 1H), 7.78 (s, 1H), 7.58
(s, 1H, 6.46 (s, 1H), 4.45-4.37 (m, 2H), 4.02-3.90 (m, 2H), 2.65
(brs, 1H), 2.40 (s, 3H), 2.02-1.92 (m, 2H), 1.90-1.80 (m, 2H).
Example-75: Synthesis of
N-[2-(6-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-azaspiro[3.3]-
hept-6-yl]-N-methylsulfuric diamide, (Compound 1.75)
##STR00653##
[0676] Step-1: Synthesis of ethyl
4-chloro-3-methyl-1H-pyrrole-2-carboxylate: To a solution of ethyl
3-methyl-1H-pyrrole-2-carboxylate (1 g, 6.53 mmol, 1.0 eq) in DMF
(10 mL) was added a N-chlorosuccinamide (872 mg, 6.53 mmol) portion
wise. The reaction mixture was allowed to stir at RT for 12 h.
Progress of reaction is monitored using TLC. After completion,
reaction mixture was diluted with water (100 mL) and extracted with
ethyl acetate (3.times.100 mL). Combined organic layer was washed
with brine (150 mL) and dried over anhydrous sodium sulfate.
Removal of solvent under reduced pressure afforded the crude which
was purified by Combi-Flash to obtain the ethyl
4-chloro-3-methyl-1H-pyrrole-2-carboxylate (600 mg, 57%). LCMS:
187[M+1].sup.+
[0677] Step-2: Synthesis of ethyl
1-amino-4-chloro-3-methyl-1H-pyrrole-2-carboxylate: To a solution
of sodium hydride (0.183 g, 5.64 mmol, 1.43 eq) in DMF (50 mL) was
added a solution of ethyl
4-chloro-3-methyl-1H-pyrrole-2-carboxylate. ((0.600 g, 3.20 mmol, 1
eq) in DMF (10 mL) at 0.degree. C. and the reaction mixture was
allowed to stir at 0.degree. C. for 30 minutes, followed by
addition of O-(diphenylphosphoryl)hydroxylamine (1.3 g, 5.64 mmol,
1.76 eq) portion wise. The reaction mixture was allowed to stir at
RT for 12 h. Progress of reaction is monitored using TLC. After
completion, DMF was removed under reduced pressure; residue was
diluted with water (100 mL) and extracted with ethyl acetate
(3.times.100 mL). Combined organic layer was washed with brine (150
mL) and dried over anhydrous sodium sulfate. Removal of solvent
under reduced pressure afforded ethyl
1-amino-4-chloro-3-methyl-1H-pyrrole-2-carboxylate (0.4 g, 61%).
LCMS: 202[M+1].sup.+
[0678] Step-3: Synthesis of
6-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-ol: A solution of
ethyl 1-amino-4-chloro-3-methyl-1H-pyrrole-2-carboxylate (0.3 g,
1.48 mmol, 1 eq) in formamide (5 mL) was allowed to stir at
165.degree. C. for 6 h. Progress of reaction is monitored by TLC.
After completion, reaction mixture was diluted with cold water (30
mL) and allowed to stir for 10 minutes. Solid was filtered, washed
with water followed by hexane and dried under vacuum to afford
7-chloro-5-methylpyrrolo [2,1-f][1,2,4]triazin-4-ol (0.242 g, 83%).
LCMS: 183[M+1].sup.+.
[0679] Step-4: Synthesis of
4,6-dichloro-5-methylpyrrolo[2,1-f][1,2,4]triazine: A mixture of
7-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-ol (0.242 g, 1.32
mmol, 1 eq) in phosphoryl trichloride (5 mL) was allowed to stir at
110.degree. C. for 2 h. Progress of reaction is monitored by TLC.
After completion, reaction mixture was diluted with cold water (30
mL) and extracted with ethyl acetate (3.times.15 mL). Combined
organic layer was washed with brine (20 mL) and dried over
anhydrous sodium sulfate. Solvent was removed under reduced
pressure to give 4,6-dichloro-5-methylpyrrolo[2,1-f][1,2,4]triazine
(0.163 g, 61%). LCMS: 201[M+1].sup.+.
[0680] Step-5: Synthesis of
N-[2-(6-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-azaspiro[3.3]-
hept-6-yl]-N-methylsulfuric diamide: A suspension of
4,6-dichloro-5-methylpyrrolo[2,1-f][1,2,4]triazine (50 mg, 0.24
mmol, 1 eq), N-2-azaspiro[3.3]hept-6-yl-N-methylsulfuric diamide
trifloroacetic acid (75 mg, 0.24 mmol, 1.0 eq) and DIPEA (0.1 mL,
0.48 mmol, 2.0 eq) in DMF (1 mL) was allowed to stir at 80.degree.
C. for 2 h. Progress of reaction was monitored by TLC. After
completion, reaction mixture was diluted with cold water (30 mL)
and extracted with ethyl acetate (3.times.70 mL). Combined organic
layer was washed with brine (3.times.50 mL) and dried over
anhydrous sodium sulfate. Removal of solvent under reduced pressure
to obtain the crude which was purified by reversed phase to afford
N-[2-(6-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-aza-
spiro[3.3]hept-6-yl]-N-methylsulfuric diamide (0.06 g). LCMS:
371[M+1].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm
7.90 (s, 1H), 7.85 (s, 1H), 6.71 (s, 2H), 4.42 (brs, 2H) 4.29 (s,
2H), 3.80-3.70 (s, 1H), 2.52 (s, 3H), 2.50-2.28 (m, 4H), 2.37 (s,
3H).
Example-76: Synthesis of
N-[2-(7-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-azaspiro[3.3]-
hept-6-yl]-N-methylsulfuric diamide, (Compound 1.76)
##STR00654##
[0682] Step-1: Synthesis of ethyl
5-chloro-3-methyl-1H-pyrrole-2-carboxylate: To a solution of ethyl
3-methyl-1H-pyrrole-2-carboxylate (1 g, 6.53 mmol, 1.0 eq) in DMF
(10 mL) was added a N-chlorosuccinamide (872 mg, 6.53 mmol) portion
wise. The reaction mixture was allowed to stir at RT for 12 h.
Progress of reaction is monitored using TLC. After completion, it
was diluted with water (100 mL) and extracted with ethyl acetate
(3.times.100 mL). Combined organic layer was washed with brine (150
mL) and dried over anhydrous sodium sulfate. Removal of solvent
under reduced pressure afforded the crude which was purified by
Combi-Flash to obtain the ethyl
5-chloro-3-methyl-1H-pyrrole-2-carboxylate (481 mg, 40%). LCMS:
187[M+1].sup.+
[0683] Step-2: Synthesis of ethyl
1-amino-5-chloro-3-methyl-1H-pyrrole-2-carboxylate: To a suspension
of sodium hydride (0.147 g, 3.67 mmol, 1.43 eq) in DMF (25 mL) was
added a solution of ethyl
5-chloro-3-methyl-1H-pyrrole-2-carboxylate (0.481 g, 2.57 mmol, 1
eq) in DMF (10 mL) at 0.degree. C. and the reaction mixture was
allowed to stir at 0.degree. C. for 30 minutes, followed by
addition of O-(diphenylphosphoryl)hydroxylamine (1.0 g, 4.52 mmol,
1.76 eq) portion wise. The reaction mixture was allowed to stir at
RT for 12 h. Progress of reaction is monitored using TLC. After
completion, DMF was removed under reduced pressure; residue was
diluted with water (100 mL) and extracted with ethyl acetate
(3.times.100 mL). Combined organic layer was washed with brine (150
mL) and dried over anhydrous sodium sulfate. Removal of solvent
under reduced pressure afforded ethyl
1-amino-5-chloro-3-methyl-1H-pyrrole-2-carboxylate (0.3 g, 57%).
LCMS: 202[M+1].sup.+
[0684] Step-3: Synthesis of
7-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-ol: A solution of
ethyl 1-amino-5-chloro-3-methyl-1H-pyrrole-2-carboxylate (0.3 g,
1.48 mmol, 1 eq) in formamide (5 mL) was allowed to stir at
165.degree. C. for 6 h. Progress of reaction is monitored by TLC.
After completion, reaction mixture was diluted with cold water (30
mL) and allowed to stir for 10 minutes. Solid was filtered, washed
with water followed by hexane and dried under vacuum to afford
7-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-ol (0.225 g, 83%).
LCMS: 183[M+1].sup.+
[0685] Step-4: Synthesis of
4,7-dichloro-5-methylpyrrolo[2,1-f][1,2,4]triazine: A mixture of
7-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-ol (0.225 g, 1.22
mmol, 1 eq) in phosphoryl trichloride (5 mL) was allowed to stir at
110.degree. C. for 2 h. Progress of reaction is monitored by TLC.
After completion, reaction mixture was diluted with cold water (30
mL) and extracted with ethyl acetate (3.times.15 mL). Combined
organic layer was washed with brine (20 mL) and dried over
anhydrous sodium sulfate. Solvent was removed under reduced
pressure to give 4,7-dichloro-5-methylpyrrolo[2,1-f][1,2,4]triazine
0.2 g, 87%). LCMS: 201M+1].sup.+
[0686] Step-5: Synthesis of
N-[2-(7-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-azaspiro[3.3]-
hept-6-yl]-N-methylsulfuric diamide: A suspension of
4,7-dichloro-5-methylpyrrolo[2,1-f][1,2,4]triazine (50 mg, 0.24
mmol, 1 eq), N-2-azaspiro[3.3]hept-6-yl-N-methylsulfuric diamide
trifloroacetic acid (75 mg, 0.24 mmol, 1.0 eq) and DIPEA (0.1 mL,
0.48 mmol, 2.0 eq) in DMF (1 mL) was allowed to stir at 80.degree.
C. for 2 h. Progress of reaction was monitored by TLC. After
completion, reaction mixture was diluted with cold water (30 mL)
and extracted with ethyl acetate (3.times.70 mL). Combined organic
layer was washed with brine (3.times.50 mL) and dried over
anhydrous sodium sulfate. Removal of solvent under reduced pressure
to obtain the crude which was purified by reversed phase to afford
N-[2-(7-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-aza-
spiro[3.3]hept-6-yl]-N-methylsulfuric diamide (6 mg, 7%). LCMS:
371[M+1].sup.+, .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm
7.90 (s, 1H), 6.71 (s, 2H), 6.62 (s, 1H), 4.42 (brs, 2H) 4.29 (brs,
2H), 3.80-3.70 (s, 1H), 2.52 (s, 3H), 2.50-2.28 (m, 4H), 2.37 (s,
3H).
Example-77: Synthesis of
N-(2-(5,7-dimethylpyrrolo[1,2-f][1,2,4]triazin-4-yl)-2-azaspiro[3.3]
heptan-6-yl)-N-methylsulfamide, (Compound 1.77)
##STR00655##
[0688] Step-1: Synthesis of ethyl
1-amino-3,5-dimethyl-1H-pyrrole-2-carboxylate: To a suspension of
sodium hydride (0.720 g, 17.95 mmol, 1.5 eq) in DMF (25 mL) was
added a solution of ethyl
5-chloro-3-methyl-1H-pyrrole-2-carboxylate (2.0 g, 11.97 mmol, 1
eq) in DMF (60 mL) at 0.degree. C. and the reaction mixture was
allowed to stir at 0.degree. C. for 30 minutes, was added of
O-(diphenylphosphoryl)hydroxylamine (4.45 g, 19.16 mmol, 1 eq)
portion wise. The reaction mixture was allowed to stir at RT for 12
h. Progress of reaction is monitored using TLC. After completion,
residue was diluted with cold water (100 mL) and extracted with
ethyl acetate (3.times.100 mL). Combined organic layer was washed
with brine (150 mL) and dried over anhydrous sodium sulfate.
Removal of solvent under reduced pressure afforded ethyl
1-amino-3,5-dimethyl-1H-pyrrole-2-carboxylate (1.5 g, 69.12%).
LCMS: 182 [M+1].sup.+
[0689] Step-2: Synthesis of
5,7-dimethylpyrrolo[1,2-f][1,2,4]triazin-4-ol: To a solution of
ethyl 1-amino-3,5-dimethyl-1H-pyrrole-2-carboxylate (1.5 g, 8.24
mmol, 1 eq) in formamide (15 mL) was allowed to stir at 165.degree.
C. for 16 h. Progress of reaction is monitored by TLC. After
completion, reaction mixture was diluted with cold water (100 mL)
and allowed to stir for 10 minutes. Solid was filtered, washed with
water followed by hexane and dried under vacuum to afford
5,7-dimethylpyrrolo[1,2-f][1,2,4]triazin-4-ol (0.7 g, 53.84%).
LCMS: 164 [M+1].sup.+
[0690] Step-3: Synthesis of
4-chloro-5,7-dimethylpyrrolo[1,2-f][1,2,4]triazine: To a mixture of
5,7-dimethylpyrrolo[1,2-f][1,2,4]triazin-4-ol (0.5 g, 3.048 mmol, 1
eq) in phosphoryl oxychloride (3 mL) was allowed to stir at
130.degree. C. for 2 h. Progress of reaction is monitored by TLC.
After completion, reaction mixture was diluted with cold water (30
mL) and extracted with ethyl acetate (3.times.20 mL). Combined
organic layer was washed with brine (20 mL) and dried over
anhydrous sodium sulfate. Solvent was removed under reduced
pressure to give 4-chloro-5,7-dimethylpyrrolo[1,2-f][1,2,4]triazine
(0.3 g, 55%). LCMS: 182 [M+1].sup.+
[0691] Step-4: Synthesis of
N--(N-(2-(5,7-dimethylpyrrolo[1,2-f][1,2,4]triazin-4-yl)-2-azaspiro[3.3]h-
eptan-6-yl)-N-methylsulfamamide: The mixture of
4-chloro-5,7-dimethylpyrrolo[1,2-f][1,2,4]triazine (200 mg, 0.828
mmol, 1 eq), N-methyl-N-(2-azaspiro[3.3]heptan-6-yl)sulfamamide,
2,2,2-trifluoroacetate salt (0.370 mg, 1.215 mmol, 1.1 eq) and
DIPEA (0.26 mL, 1.542 mmol, 1.5 eq) in DMF (5 mL) was allowed to
stir at 85.degree. C. for 3 h. Progress of reaction was monitored
by TLC. After completion, reaction mixture was diluted with cold
water (30 mL) and extracted with ethyl acetate (3.times.70 mL).
Combined organic layer was washed with brine (3.times.50 mL) and
dried over anhydrous sodium sulfate. Removal of solvent under
reduced pressure to obtain the crude, which was purified by
reversed phase to afford
N--(N-(2-(5,7-dimethylpyrrolo[1,2-f][1,2,4]triazin-4-yl)-2-azaspiro[3.3]h-
eptan-6-yl)-N-methylsulfamamide (15 mg, 3.88%). LCMS: 351
[M+1].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 7.81
(s, 1H), 6.69 (s, 2H), 6.33 (s, 1H), 4.37 (s, 2H), 4.25 (s, 2H),
3.81-3.75 (m, 1H), 2.60-2.20 (m, 13H).
Example-78: Synthesis of
N-(2-(6-cyano-5-methylpyrrolo[1,2-f][1,2,4]triazin-4-yl)-2-azaspiro[3.3]
heptan-6-yl)-N-methylsulfamamide, (Compound 1.78)
##STR00656##
[0693] Step-1: Synthesis of ethyl
4-cyano-3-methyl-1H-pyrrole-2-carboxylate: To a solution of ethyl
3-methyl-1H-pyrrole-2-carboxylate (1.0 g, 6.535 mmol, 1.0 eq) in
CH.sub.3CN (5 mL) at -10.degree. C. was added a solution of
Chlorosulfonyl isocyanate (0.924 g, 6.535 mmol, 1.0 eq) in
CH.sub.3CN (5 mL) over 5 min. The solution rapidly became yellow
and solid precipitate was deposited. N,N-dimethylformamide (1 mL)
was added in reaction mixture and solution became colorless. To
this reaction mixture was then added TEA (1.8 mL, 13.07 mmol, 2.0
eq) then white precipitate was formed. The reaction mixture was
allowed to stir at RT for 2 h. Progress of reaction is monitored
using TLC. After completion, reaction mixture poured onto ice water
and extracted with ethyl acetate (3.times.100 mL). Combined organic
layer was washed with brine (100 mL) and dried over anhydrous
sodium sulfate. Removal of solvent under reduced pressure afforded
ethyl 4-cyano-3-methyl-1H-pyrrole-2-carboxylate (0.9 g, 81.81%).
LCMS: 179 [M+1].sup.+
[0694] Step-2: Synthesis of ethyl
1-amino-4-cyano-3-methyl-1H-pyrrole-2-carboxylate: To a suspension
of sodium hydride (0.286 g, 7.162 mmol, 1.5 eq) in DMF (25 mL) was
added a solution of ethyl 4-cyano-3-methyl-1H-pyrrole-2-carboxylate
(0.850 g, 4.775 mmol, 1 eq) in DMF (25 mL) at 0.degree. C. The
reaction mixture was allowed to stir at 0.degree. C. for 30 minutes
and added O-(diphenylphosphoryl) hydroxylamine (1.6 g, 7.162 mmol,
1.5 eq) portion wise. The reaction mixture was allowed to stir at
RT for 12 h. Progress of reaction is monitored using TLC. After
completion, DMF was removed under reduced pressure; residue was
diluted with water (300 mL) and extracted with ethyl acetate
(3.times.200 mL). Combined organic layer was washed with brine (250
mL) and dried over anhydrous sodium sulfate. Removal of solvent
under reduced pressure afforded ethyl
1-amino-4-cyano-3-methyl-1H-pyrrole-2-carboxylate (4.0 g, 60.60%).
LCMS: 194 [M+1].sup.+
[0695] Step-3: Synthesis of
4-hydroxy-5-methylpyrrolo[1,2-f][1,2,4]triazine-6-carbonitrile: To
a solution of ethyl
1-amino-4-cyano-3-methyl-1H-pyrrole-2-carboxylate (0.5 g, 2.590
mmol, 1 eq) in formamide (10 mL) was allowed to stir at 165.degree.
C. for 16 h. Progress of reaction is monitored by TLC. After
completion, reaction mixture was diluted with cold water (100 mL)
and allowed to stir for 10 minutes. Solid was filtered, washed with
water followed by hexane and dried under vacuum to afford
4-hydroxy-5-methylpyrrolo[1,2-f][1,2,4]triazine-6-carbonitrile (0.3
g, 77.72%). LCMS: 175 [M+1].sup.+
[0696] Step-4: Synthesis of
4-chloro-5-methylpyrrolo[1,2-f][1,2,4]triazine-6-carbonitrile: To a
solution of
4-hydroxy-5-methylpyrrolo[1,2-f][1,2,4]triazine-6-carbonitrile (0.3
g, 2.013 mmol, 1 eq) in N,N-Diisopropylethylamine was added a
solution of phosphoryl oxychloride (0.188 mL, 2.013 mmol, 1 eq) at
0.degree. C. and the reaction mixture was allowed to stir at
0.degree. C. for 10 minutes. The reaction mixture was allowed to
stir at 130.degree. C. for 2 h. Progress of reaction is monitored
by TLC. After completion, reaction mixture was diluted with cold
water (30 mL) and extracted with ethyl acetate (3.times.20 mL).
Combined organic layer was washed with brine (20 mL) and dried over
anhydrous sodium sulfate. Solvent was removed under reduced
pressure to give
4-chloro-5-methylpyrrolo[1,2-f][1,2,4]triazine-6-carbonitrile (0.22
g, 57%). LCMS: 193 [M+1].sup.+
[0697] Step-5: Synthesis of
N-(2-(6-cyano-5-methylpyrrolo[1,2-f][1,2,4]triazin-4-yl)-2-azaspiro[3.3]h-
eptan-6-yl)-N-methylsulfamamide: A mixture of
4-chloro-5-methylpyrrolo[1,2-f][1,2,4]triazine-6-carbonitrile (0.2
g, 1.04 mmol, 1 eq),
N-methyl-N-(2-azaspiro[3.3]heptan-6-yl)sulfamamide,
2,2,2-trifluoroacetate salt (0.350 g, 1.14 mmol, 1.1 eq) and DIPEA
(0.272 mL, 1.562 mmol, 1.5 eq) in DMF (10 mL) was allowed to stir
at 85.degree. C. for 3 h. Progress of reaction was monitored by
TLC. After completion, reaction mixture was diluted with cold water
(30 mL) and extracted with ethyl acetate (3.times.50 mL). Combined
organic layer was washed with brine (3.times.30 mL) and dried over
anhydrous sodium sulfate. Removal of solvent under reduced pressure
to obtain the crude which was purified by reversed phase to afford
N-(2-(6-cyano-5-methylpyrrolo[1,2-f][1,2,4]triazin-4-yl)-2-azaspiro[3.3]h-
eptan-6-yl)-N-methylsulfamamide (10 mg, 2.65%). LCMS:
362[M+1].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm
8.37 (s, 1H), 7.92 (s, 1H), 6.70 (s, 2H), 4.48 (s, 2H), 4.35 (s,
2H), 3.74-3.79 (m, 1H), 2.6-2.22 (m, 10H).
Example-79: Synthesis of
N-(2-(7-bromo-5-methylpyrrolo[1,2-f][1,2,4]triazin-4-yl)-2-azaspiro
[3.3]heptan-6-yl)-N-methylsulfamamide, (Compound 1.79)
##STR00657##
[0699] Step-1: Synthesis of ethyl
1-amino-3-methyl-1H-pyrrole-2-carboxylate: To a suspension of
sodium hydride (2.352 g, 58.82 mmol, 1.5 eq) in DMF (25 mL) was
added a solution of ethyl 3-methyl-1H-pyrrole-2-carboxylate (6.0 g,
39.21 mmol, 1 eq) in DMF (120 mL) at 0.degree. C. The reaction
mixture was allowed to stir at 0.degree. C. for 30 minutes and was
added O-(diphenylphosphoryl)hydroxylamine (15.53 g, 65.65 mmol, 1.7
eq) portion wise. The reaction mixture was allowed to stir at RT
for 12 h. Progress of reaction was monitored by TLC. After
completion, THF was removed under reduced pressure; residue was
diluted with water (300 mL) and extracted with ethyl acetate
(3.times.200 mL). Combined organic layer was washed with brine (250
mL) and dried over anhydrous sodium sulfate. Removal of solvent
under reduced pressure afforded ethyl
1-amino-3-methyl-1H-pyrrole-2-carboxylate (4.0 g, 60.60%). LCMS:
169 [M+1].sup.+
[0700] Step-2: Synthesis of
5-methylpyrrolo[1,2-f][1,2,4]triazin-4-ol: A solution of ethyl
1-amino-3-methyl-1H-pyrrole-2-carboxylate (4 g, 23.95 mmol, 1 eq)
in formamide (40 mL) was allowed to stir at 165.degree. C. for 16
h. Progress of reaction is monitored by TLC. After completion,
reaction mixture was cooled to RT, diluted with cold water (100 mL)
under stirring. The formed precipitate was filtered and dried under
vacuum to afford 5-methylpyrrolo[1,2-f][1,2,4]triazin-4-ol (3.0 g,
85.71%). LCMS: 150 [M+1].sup.+
[0701] Step-3: Synthesis of
7-bromo-5-methylpyrrolo[1,2-f][1,2,4]triazin-4-ol: To a solution of
5-methylpyrrolo[1,2-f][1,2,4]triazin-4-ol (1.0 g, 6.71 mmol, 1.0
eq) in DMF (20 mL) was added N-Bromosuccinimide (1.20 g, 6.71 mmol,
1.0 eq) portion wise. The reaction mixture was allowed to stir at
RT for 72 h. Progress of reaction is monitored using TLC. After
completion, reaction mixture was diluted with water (30 mL) and
extracted with ethyl acetate (3.times.20 mL). Combined organic
layer was washed with brine (3.times.10 mL) and dried over
anhydrous sodium sulfate. Removal of solvent under reduced pressure
afforded the crude which was purified by Combi-Flash to obtain
7-bromo-5-methylpyrrolo[1,2-f][1,2,4]triazin-4-ol (0.8 g, 52.63%).
LCMS: 228 [M+1].sup.+
[0702] Step-4: Synthesis of
7-bromo-4-chloro-5-methylpyrrolo[1,2-f][1,2,4]triazine: A mixture
of 7-bromo-5-methylpyrrolo[1,2-f][1,2,4]triazin-4-ol (0.2 g, 0.877
mmol, 1 eq) in phosphoryl oxychloride (5 mL) was allowed to stir at
130.degree. C. for 2 h. Progress of reaction is monitored by TLC.
After completion, reaction mixture was diluted with cold water (30
mL) and extracted with ethyl acetate (3.times.20 mL). Combined
organic layer was washed with brine (20 mL) and dried over
anhydrous sodium sulfate. Solvent was removed under reduced
pressure to give
7-bromo-4-chloro-5-methylpyrrolo[1,2-f][1,2,4]triazine (0.15 g,
70%). LCMS: 246 [M+1].sup.+
[0703] Step-5: Synthesis of
N-(2-(7-bromo-5-methylpyrrolo[1,2-f][1,2,4]triazin-4-yl)-2-azaspiro[3.3]h-
eptan-6-yl)-N-methylsulfamamide: A mixture of
7-bromo-4-chloro-5-methylpyrrolo[1,2-f][1,2,4]triazine (0.15 g,
0.612 mmol, 1 eq), N-2-azaspiro[3.3]hept-6-yl-N-methylsulfuric
diamide trifloroacetic acid (0.207 g, 0.673 mmol, 1.1 eq) and DIPEA
(0.213 mL, 1.224 mmol, 2.0 eq) in DMF (10 mL) was allowed to stir
at 85.degree. C. for 3 h. Progress of reaction was monitored by
TLC. After completion, reaction mixture was diluted with cold water
(30 mL) and extracted with ethyl acetate (3.times.50 mL). Combined
organic layer was washed with brine (3.times.30 mL) and dried over
anhydrous sodium sulfate. Removal of solvent under reduced pressure
to obtain the crude which was purified by reversed phase to afford
N-(2-(7-bromo-5-methylpyrrolo[1,2-f][1,2,4]triazin-4-yl)-2-azaspiro[3.3]h-
eptan-6-yl)-N-methylsulfamamide (15 mg, 6.05%). LCMS:
415[M+1].sup.+, .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm
7.91 (s, 1H), 6.72-6.69 (m, 3H), 4.42 (s, 2H), 4.29 (s, 2H),
3.80-3.76 (m, 1H), 2.54-2.38 (m, 10H).
Example-80: Synthesis of
N-(2-(7-fluoro-5-methylpyrrolo[1,2-f][1,2,4]triazin-4-yl)-2-azaspiro[3.3]-
heptan-6-yl)-N-methylsulfamamide, (Compound 1.80)
##STR00658##
[0705] Step-1: Synthesis of ethyl
1-amino-3-methyl-1H-pyrrole-2-carboxylate: To a suspension of
sodium hydride (2.352 g, 58.82 mmol, 1.5 eq) in DMF (25 mL) was
added a solution of ethyl 3-methyl-1H-pyrrole-2-carboxylate (6.0 g,
39.21 mmol, 1 eq) in DMF (120 mL) at 0.degree. C. and the reaction
mixture was allowed to stir at 0.degree. C. for 30 minutes,
followed by addition of O-(diphenylphosphoryl)hydroxylamine (15.53
g, 65.65 mmol, 1.7 eq) portion wise. The reaction mixture was
allowed to stir at RT for 12 h. Progress of reaction is monitored
using TLC. After completion, reaction mixture was diluted with
ice-cold water (300 mL) and extracted with ethyl acetate
(3.times.200 mL). Combined organic layer was washed with brine (250
mL) and dried over anhydrous sodium sulfate. Removal of solvent
under reduced pressure afforded ethyl
1-amino-3-methyl-1H-pyrrole-2-carboxylate (4.0 g, 60.60%). LCMS:
169 [M+1].sup.+
[0706] Step-2: Synthesis of
5-methylpyrrolo[1,2-f][1,2,4]triazin-4-ol: A solution of ethyl
1-amino-3-methyl-1H-pyrrole-2-carboxylate (4 g, 23.95 mmol, 1 eq)
in formamide (40 mL) was allowed to stir at 165.degree. C. for 16
h. Progress of reaction is monitored by TLC. After completion,
reaction mixture was diluted with cold water (600 mL) and allowed
to stir for 10 minutes. Solid was filtered, washed with water
followed by hexane and dried under vacuum to afford
5-methylpyrrolo[1,2-f][1,2,4]triazin-4-ol (3.0 g, 85.71%). LCMS:
150 [M+1].sup.+
[0707] Step-3: Synthesis of
7-fluoro-5-methylpyrrolo[1,2-f][1,2,4]triazin-4-ol: To a solution
of ethyl 5-methylpyrrolo[1,2-f][1,2,4]triazin-4-ol (0.1 g, 0.666
mmol, 1.0 eq) in DMF (10 mL) was added Selectfluor (0.235 g, 0.666
mmol, 1.0 eq) portion wise. The reaction mixture was allowed to
stir at RT for 72 h. Progress of reaction is monitored using TLC.
After completion, it was diluted with water (30 mL) and extracted
with ethyl acetate (3.times.20 mL). Combined organic layer was
washed with brine (3.times.10 mL) and dried over anhydrous sodium
sulfate. Removal of solvent under reduced pressure afforded the
crude which was purified by Combi-Flash to obtain the
7-fluoro-5-methylpyrrolo[1,2-f][1,2,4]triazin-4-ol (0.12 g,
54.05%). LCMS: 168 [M+1].sup.+
[0708] Step-4: Synthesis of
4-chloro-7-fluoro-5-methylpyrrolo[1,2-f][1,2,4]triazine: A mixture
of 7-fluoro-5-methylpyrrolo[1,2-f][1,2,4]triazin-4-ol (0.12 g,
0.718 mmol, 1 eq) in phosphoryl oxychloride (2 mL) was allowed to
stir at 130.degree. C. for 2 h. Progress of reaction is monitored
by TLC. After completion, reaction mixture was diluted with cold
water (30 mL) and extracted with ethyl acetate (3.times.20 mL).
Combined organic layer was washed with brine (20 mL) and dried over
anhydrous sodium sulfate. Solvent was removed under reduced
pressure to give
4-chloro-7-fluoro-5-methylpyrrolo[1,2-f][1,2,4]triazine (0.12 g,
90%). LCMS: 186 [M+1].sup.+
[0709] Step-5: Synthesis of
N-(2-(7-fluoro-5-methylpyrrolo[1,2-f][1,2,4]triazin-4-yl)-2-azaspiro[3.3]-
heptan-6-yl)-N-methylsulfamamide: A mixture of
4-chloro-7-fluoro-5-methylpyrrolo[1,2-f][1,2,4]triazine (120 mg,
0.648 mmol, 1 eq),
N-methyl-N-(2-azaspiro[3.3]heptan-6-yl)sulfamamide
2,2,2-trifluoroacetaldehyde (237 mg, 0.778 mmol, 1.1 eq) and DIPEA
(0.169 mL, 0.972 mmol, 1.5 eq) in DMF (10 mL) was allowed to stir
at 85.degree. C. for 3 h. Progress of reaction was monitored by
TLC. After completion, reaction mixture was diluted with cold water
(30 mL) and extracted with ethyl acetate (3.times.50 mL). Combined
organic layer was washed with brine (3.times.30 mL) and dried over
anhydrous sodium sulfate. Removal of solvent under reduced pressure
to obtain the crude, which was purified by reversed phase to afford
N-(2-(7-fluoro-5-methylpyrrolo[1,2-f][1,2,4]triazin-4-yl)-2-azaspiro[3.3]-
heptan-6-yl)-N-methylsulfamamide (7 mg, 3.05%). LCMS:
355[M+1].sup.+, .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm
7.80 (s, 1H), 6.70 (s, 2H), 6.27 (m, 1H), 4.41 (s, 2H), 4.29 (s,
2H), 3.74-3.79 (m, 1H), 2.53 (s, 3H), 2.29-2.43 (m, 7H)
Example-81: Synthesis of
N-(2-(7-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-azaspiro[3.3]-
heptan-6-yl)-N-cyclopropylsulfamamide, (Compound 1.81)
##STR00659##
[0711] Step-1: Synthesis of tert-butyl
6-(cyclopropylamino)-2-azaspiro[3.3]heptane-2-carboxylate: A
suspension of tert-butyl 6-oxo-2-azaspiro[3.3]heptane-2-carboxylate
(250 mg, 1.18 mmol, 1.0 eq), cyclopropylamine (81 mg, 1.41 mmol,
1.2 eq) in methanol (3 mL) was stirred at RT for overnight. After
overnight stirring, NaBH.sub.4 (67 mg, 1.77 mmol, 1.5 eq) was added
into above reaction mixture portion wise at 0.degree. C. and
allowed to stir for 1 h at 0.degree. C. Progress of reaction was
monitored by TLC. After completion, reaction mixture was
concentrated under reduced pressure to get residue which was
diluted with water (30 mL) and extracted with DCM (2.times.50 mL).
Combined organic layer was washed with brine (1.times.20 mL) and
dried over anhydrous sodium sulfate. Removal of solvent under
reduced pressure to afford tert-butyl
6-(cyclopropylamino)-2-azaspiro[3.3]heptane-2-carboxylate (255 mg,
85%) which was used in the next step without purification.
[0712] Step-2: Synthesis of tert-butyl
6-((N-(tert-butoxycarbonyl)sulfamoyl)(cyclopropyl)amino)-2-azaspiro[3.3]h-
eptane-2-carboxylate: To a solution of tert-butyl
6-(cyclopropylamino)-2-azaspiro[3.3]heptane-2-carboxylate (250 mg,
0.99 mmol, 1.0 eq) in DCM (8 mL) were added
N-(tert-butoxycarbonyl)-N-[4-(dimethylazaniumylidene)-1,4-dihydropyridin--
1ylsulfonyl]azanide (359 mg, 1.11 mmol, 1.2 eq) and DIPEA (191 mg,
1.48 mmol, 1.5 eq) and the mixture was allowed to stir at RT for
overnight. Progress of reaction was monitored by TLC. After
completion, reaction mixture was diluted with water (25 mL) and
extracted with DCM (2.times.50 mL). Combined organic layer was
washed with brine (1.times.20 mL), dried over anhydrous sodium
sulfate and concentrated under reduced pressure to afford
tert-butyl
6-((N-(tert-butoxycarbonyl)sulfamoyl)(cyclopropyl)amino)-2-azaspiro[3.3]h-
eptane-2-carboxylate (300 mg, 70%).
[0713] Step-3: Synthesis of
N-cyclopropyl-N-(2-azaspiro[3.3]heptan-6-yl)sulfamamide
trifluoroacetate: To a solution of tert-butyl
6-((N-(tert-butoxycarbonyl)sulfamoyl)(cyclopropyl)amino)-2-azaspiro[3.3]h-
eptane-2-carboxylate (300 mg, 0.69 mmol, 1.0 eq) in DCM (5 mL) was
added TFA (2 mL) and was allowed to stir at RT for 2 h. Progress of
reaction was monitored by TLC. After completion, reaction mixture
was concentrated under reduced pressure to afford crude which was
triturated with diethyl ether to afford
N-cyclopropyl-N-(2-azaspiro[3.3]heptan-6-yl)sulfamamide
trifluoroacetate (210 mg, 88%).
[0714] Step-4: Synthesis of
N-(2-(7-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-azaspiro[3.3]-
heptan-6-yl)-N-cyclopropylsulfamamide: A suspension of
N-cyclopropyl-N-(2-azaspiro[3.3]heptan-6-yl)sulfamamide
trifluoroacetate (162 mg, 0.49 mmol, 1.0 eq),
4,7-dichloro-5-methylpyrrolo[2,1-f][1,2,4]triazine (100 mg, 0.49
mmol, 1.0 eq) and DIPEA (128 mg, 0.99 mmol, 2.0 eq) in DMF (1.5 mL)
was allowed to stir at 80.degree. C. for 2 h. Progress of reaction
was monitored by TLC and LCMS. After completion of reaction,
reaction mixture was diluted with water (30 mL) and extracted with
ethyl acetate (2.times.50 mL). Combined organic layer was washed
with brine (1.times.20 mL), dried over anhydrous sodium sulfate and
concentrated under reduced pressure to get crude which was purified
by using reversed phase chromatography to afford
N-(2-(7-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-azaspiro[3.3]-
heptan-6-yl)-N-cyclopropylsulfamamide (2.56 mg, 1.3%). LCMS: 397
[M+1].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 7.91
(s, 1H), 6.83 (br. s., 2H), 6.64 (s, 1H), 4.43 (br. s., 2H), 4.29
(br. s., 2H), 3.92-3.80 (m, 1H), 3.17 (d, J=5.3 Hz, 1H), 2.40 (s,
3H), 2.05 (br. s., 2H), 1.99 (br. s., 1H), 1.65 (s, 1H), 0.69 (br.
s., 4H)
Example-82: Synthesis of
N-(2-(7-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-azaspiro[3.3]-
heptan-6-yl)-N-isopropylsulfamamide, (Compound 1.82)
##STR00660##
[0716] Step-1: Synthesis of tert-butyl
6-(isopropylamino)-2-azaspiro[3.3]heptane-2-carboxylate: A
suspension of tert-butyl 6-oxo-2-azaspiro[3.3]heptane-2-carboxylate
(250 mg, 1.18 mmol, 1.0 eq), isopropylamine (84 mg, 1.42 mmol, 1.2
eq) in methanol (3 mL) was stirred at RT for overnight. After
overnight stirring, NaBH.sub.4 (67 mg, 1.77 mmol, 1.5 eq) was added
into above reaction mixture portion wise at 0.degree. C. and
allowed to stir the reaction mixture for 1 h at 0.degree. C.
Progress of reaction was monitored by TLC. After completion,
reaction mixture was concentrated under reduced pressure to get
residue which was diluted with water (20 mL) and extracted with DCM
(2.times.50 mL). Combined organic layer was washed with brine
(1.times.20 mL), dried over anhydrous sodium sulfate and
concentrated under reduced pressure to afford tert-butyl
6-(isopropylamino)-2-azaspiro[3.3]heptane-2-carboxylate (252 mg,
84%) which was used into the next step without purification.
[0717] Step-2: Synthesis of tert-butyl
6-((N-(tert-butoxycarbonyl)sulfamoyl)(isopropyl)amino)-2-azaspiro[3.3]hep-
tane-2-carboxylate: To a solution of tert-butyl
6-(isopropylamino)-2-azaspiro[3.3]heptane-2-carboxylate (240 mg,
0.94 mmol, 1.0 eq) in DCM (8 mL) were added
N-(tert-butoxycarbonyl)-N-[4-(dimethylazaniumylidene)-1,4-dihydropyridinl-
ylsulfonyl]azanide (342 mg, 1.13 mmol, 1.2 eq) and DIPEA (182 mg,
1.41 mmol, 1.5 eq) and the mixture was allowed to stir at RT for
overnight. Progress of reaction was monitored by TLC. After
completion, reaction mixture was diluted with water (25 mL) and
extracted with DCM (2.times.150 mL). Combined organic layer was
washed with brine (1.times.20 mL), dried over anhydrous sodium
sulfate and concentrated under reduced pressure to afford
tert-butyl
6-((N-(tert-butoxycarbonyl)sulfamoyl)(isopropyl)amino)-2-azaspiro[3.3]hep-
tane-2-carboxylate (300 mg, 73%).
[0718] Step-3: Synthesis of
N-isopropyl-N-(2-azaspiro[3.3]heptan-6-yl)sulfamamide
trifluoroacetate: To a solution of tert-butyl
6-((N-(tert-butoxycarbonyl)sulfamoyl)(isopropyl)amino)-2-azaspiro[3.3]hep-
tane-2-carboxylate (300 mg, 0.692 mmol, 1.0 eq) in DCM (5 mL) was
added TFA (2 mL) and was allowed to stir at RT for 2 h. Progress of
reaction was monitored by TLC. After completion, reaction mixture
was concentrated under reduced pressure to afford crude which was
triturated with diethyl ether to afford
N-isopropyl-N-(2-azaspiro[3.3]heptan-6-yl)sulfamamide
trifluoroacetate (250 mg, 95.8%).
[0719] Step-4: Synthesis of
N-(2-(7-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-azaspiro[3.3]-
heptan-6-yl)-N-isopropylsulfamamide: A suspension of
N-isopropyl-N-(2-azaspiro[3.3]heptan-6-yl)sulfamamide
trifluoroacetate (155 mg, 0.448 mmol, 1.0 eq),
4,7-dichloro-5-methylpyrrolo[2,1-f][1,2,4]triazine (90 mg, 0.448
mmol, 1.0 eq) and DIPEA (115 mg, 0.896 mmol, 2.0 eq) in DMF (1.5
mL) was allowed to stir at 80.degree. C. for 2 h. Progress of
reaction was monitored by TLC and LCMS. After completion, reaction
mixture was diluted with water (20 mL) and extracted with ethyl
acetate (1.times.50 mL). Combined organic layer was washed with
brine (1.times.20 mL), dried over anhydrous sodium sulfate and
concentrated under reduced pressure to get crude which was purified
using reversed phase chromatography to afford
N-(2-(7-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-azaspiro[3.3]-
heptan-6-yl)-N-isopropylsulfamamide (9.5 mg, 5.3%). LCMS: 399
[M+1].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 7.90
(s, 1H), 6.69-6.61 (m, 3H), 4.43 (s, 2H), 4.28 (s, 2H), 3.85-3.75
(m, 2H), 2.67 (t, J=10.7 Hz, 3H), 2.43-2.33 (m, 4H), 1.14 (d, J=7.0
Hz, 6H).
Example-83: Synthesis of
N-(2-(1-(7-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)azetidin-3-yl-
)ethyl)-N-isopropylsulfamamide, (Compound 1.83)
##STR00661##
[0721] Step-1: Synthesis of tert-butyl
3-(2-oxoethyl)azetidine-1-carboxylate: A suspension of (1.0 g, 4.95
mmol, 1.0 eq) in DCM (40 mL) at 0.degree. C. was added DMP (6.29 g,
14.8 mmol, 3.0 eq) was added portion wise at 0.degree. C. into
above reaction mixture. After addition, reaction mixture was
stirred at RT for 2 h. Progress of reaction was monitored by TLC.
After completion, reaction mixture was concentrated under reduced
pressure to get residue which was diluted with water (150 mL) and
extracted with DCM (3.times.250 mL). Combined organic layer was
washed with brine (3.times.50 mL), dried over anhydrous sodium
sulfate and concentrated under reduced pressure to afford
tert-butyl 3-(2-oxoethyl)azetidine-1-carboxylate (1.1 g, 92%) which
was used in the next step without purification.
[0722] Step-2: Synthesis of tert-butyl
3-(2-(isopropylamino)ethyl)azetidine-1-carboxylate: A suspension of
(500 mg, 2.5 mmol, 1 eq), isopropylamine (177 mg, 3.01 mmol, 1.2
eq) in methanol (10 mL) was stirred at RT for overnight. After
overnight stirring, NaBH.sub.4 (142 mg, 3.75 mmol, 1.5 eq) was
added to reaction mixture portion wise at 0.degree. C. and allowed
to stir the reaction mixture for 1 h at 0.degree. C. Progress of
reaction was monitored by TLC. After completion, reaction mixture
was concentrated under reduced pressure to get residue which was
diluted with water (150 mL) and extracted with ethyl acetate
(3.times.150 mL). Combined organic layer was washed with brine
(3.times.50 mL), dried over anhydrous sodium sulfate and
concentrated under reduced pressure to afford tert-butyl
3-(2-(isopropylamino)ethyl)azetidine-1-carboxylate (470 mg, 77.5%)
which was used in the next step without purification.
[0723] Step-3: Synthesis of tert-butyl
3-(2-((N-(tert-butoxycarbonyl)sulfamoyl)(isopropyl)amino)ethyl)azetidine--
1-carboxylate: To a solution of tert-butyl
3-(2-(isopropylamino)ethyl)azetidine-1-carboxylate (470 mg, 1.94
mmol, 1.0 eq) in DCM (6 mL) were added
N-(tert-butoxycarbonyl)-N-[4-(dimethylazaniumylidene)-1,4-dihydropyridinl-
ylsulfonyl]azanide (703 mg, 2.32 mmol, 1.2 eq) and DIPEA (650 mg,
5.02 mmol, 2.5 eq) and the mixture was allowed to stir at RT for
overnight. Progress of reaction was monitored by TLC. After
completion, reaction mixture was diluted with water (50 mL) and
extracted with DCM (2.times.150 mL). Combined organic layer was
washed with brine (1.times.50 mL), dried over anhydrous sodium
sulfate and concentrated under reduced pressure to afford
tert-butyl tert-butyl
3-(2-((N-(tert-butoxycarbonyl)sulfamoyl)(isopropyl)amino)ethyl)azetidine--
1-carboxylate (400 mg, 51%).
[0724] Step-4: Synthesis of
N-(2-(azetidin-3-yl)ethyl)-N-isopropylsulfamamide trifluoroacetate:
To a solution of tert-butyl
3-(2-((N-(tert-butoxycarbonyl)sulfamoyl)(isopropyl)amino)ethyl)azetidine--
1-carboxylate (400 mg, 0.922 mmol, 1 eq) in DCM (5 mL) was added
TFA (1.6 mL) and was allowed to stir at RT for 2 h. Progress of
reaction was monitored by TLC. After completion, reaction mixture
was concentrated under reduced pressure to afford crude which was
triturated with diethyl ether to afford
N-(2-(azetidin-3-yl)ethyl)-N-isopropylsulfamamide trifluoroacetate
(300 mg, 97%).
[0725] Step-5: Synthesis of
N-(2-(1-(7-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)azetidin-3-yl-
)ethyl)-N-isopropylsulfamamide: A suspension of
N-(2-(azetidin-3-yl)ethyl)-N-isopropylsulfamamide trifluoroacetate
(95 mg, 0.298 mmol, 1.0 eq),
4,7-dichloro-5-methylpyrrolo[2,1-f][1,2,4]triazine (60 mg, 0.298
mmol, 1.0 eq) and DIPEA (77 mg, 0.596 mmol, 2.0 eq) in DMF (1.5 mL)
was allowed to stir at 80.degree. C. for 2 h. Progress of reaction
was monitored by TLC and LCMS. After completion, reaction mixture
was diluted with water (10 mL) and extracted with ethyl acetate
(1.times.50 mL). Combined organic layer was washed with brine
(1.times.10 mL), dried over anhydrous sodium sulfate and
concentrated under reduced pressure to under reduced pressure to
get crude which was purified using reversed phase chromatography to
afford
N-(2-(1-(7-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)azetidin-3-yl-
)ethyl)-N-isopropylsulfamamide (21.47 mg, 18.6%). LCMS: 387
[M+1].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 7.90
(s, 1H), 6.63 (s, 3H), 4.46 (t, J=8.8 Hz, 2H), 4.02 (dd, J=5.7, 8.8
Hz, 2H), 3.93-3.87 (m, 1H), 2.96 (t, J=7.2 Hz, 2H), 2.77-2.68 (m,
1H), 2.39 (s, 3H), 1.94-1.87 (m, 2H), 1.11 (d, J=7.0 Hz, 6H)
Example-84: Synthesis of
N-(2-(1-(7-chloro-5-methylpyrrolo[1,2-f][1,2,4]triazin-4-yl)azetidin-3-yl-
)ethyl)-N-methylsulfamide, (Compound 1.84)
##STR00662##
[0727] Step-1: Synthesis of tert-butyl 3-(2-oxoethyl)
azetidine-1-carboxylate: To a solution of the tert-butyl
3-(2-hydroxyethyl)azetidine-1-carboxylate (0.5 g, 2.48 mmol, 1 eq)
in dichloromethane (18 mL) at 0.degree. C. was added Dess-Martin
peridionane (DMP) (3.1 g, 7.46 mmol 3.0 eq) and the reaction
mixture was stirred at RT for 2 h. Progress of reaction was
monitored by TLC. After completion, reaction mixture poured on
crushed ice and extracted with ethyl acetate (3.times.50 mL).
Combined organic layer was washed with brine (20 mL) and dried over
anhydrous sodium sulfate. Removal of solvent under reduced pressure
gave crude which was triturated with pentane (100 mL) at 0.degree.
C. and filtered. Filtrate was concentrated under vacuum to afford
tert-butyl 3-(2-(methylamino)ethyl)azetidine-1-carboxylate (400 mg,
80.8%). .sup.1H NMR (400 MHz, CDCl.sub.3-d) .delta. ppm 9.77 (s,
1H), 4.13-4.08 (m, 2H), 3.67-3.52 (m, 2H), 2.87-2.77 (m, 1H),
2.66-2.61 (m, 2H), 1.56 (s, 3H), 1.43 (s, 9H).
[0728] Step-2: Synthesis of tert-butyl
3-(2-((N-(tert-butoxycarbonyl)
sulfamoyl)(methyl)amino)ethyl)azetidine-1-carboxylate: To a stirred
solution of tert-butyl 3-(2-oxoethyl) azetidine-1-carboxylate (400
mg, 2.00 mmol, 1.0 eq) in MeOH (15.0 mL) was added Methylamine (1.5
mL, 3.011 mmol, 1.5 eq) at 0.degree. C. The resulting mixture was
stirred at room temperature for overnight. The reaction mixture was
then cooled to 0.degree. C. followed by addition of NaBH.sub.4 (136
mg, 4.00 mmol, 3.0 eq) at 0.degree. C. The reaction mixture was
stirred at room temperature for 2 h. The progress of reaction was
monitored by TLC. The reaction mixture was concentrated, basified
with NaHCO.sub.3 solution (20 mL), extracted with EtOAc
(2.times.150 mL). The combined organic layer was washed with water
(50 mL), with brine (50 mL), dried over Na.sub.2SO.sub.4
concentrated to get crude product. The crude product was triturated
in pentane to afford tert-butyl 3-(2-(methylamino) ethyl)
azetidine-1-carboxylate (500 mg, 116.27%) as liquid, which was
further used further next step without purification.
[0729] Step-3: Synthesis of tert-butyl
3-(2-((N-(tert-butoxycarbonyl)
sulfamoyl)(methyl)amino)ethyl)azetidine-1-carboxylate: To a
solution of tert-butyl 3-((methylamino) methyl)
azetidine-1-carboxylate (500 mg, 2.33 mmol, 1 eq) and
N-(1-(N-(tert-butoxycarbonyl)sulfamoyl)pyridin-4
(1H)-ylidene)-N-methylmethanaminium (846 mg. 2.779 mmol, 1.2 eq) in
dichloromethane (10 mL) N,N-diisopropylethylamine (1.23 ml, 6.99
mmol, 3 eq) was added and the reaction mixture was allowed to stir
at RT for overnight. Progress of reaction was monitored by NMR.
After completion, the reaction mixture was diluted with water (50
mL) and extracted with DCM (150 ml.times.2). Combined organic layer
was washed with brine (50 mL), dried over anhydrous sodium sulfate
and concentrated to get crude product. The crude product was
triturated in pentane to afford tert-butyl
3-(2-((N-(tert-butoxycarbonyl) sulfamoyl) (methyl) amino) ethyl)
azetidine-1-carboxylate (700 mg, 76.24%) as liquid which was used
in the next step without purification.
[0730] Step-4: Synthesis of
3-(2-((N-sulfamoyl)(methyl)amino)ethyl)azetidine trifluoroacetate:
To a solution of tert-butyl 3-(2-((N-(tert-butoxycarbonyl)
sulfamoyl)(methyl)amino)ethyl)azetidine-1-carboxylate (700 mg,
1.719 mmol, 1 eq) in DCM (10 mL) was added TFA (2 mL) and the
mixture was allowed to stir at RT for 2 h. Progress of reaction was
monitored by NMR. After completion, reaction mixture was
concentrated under reduced pressure to get of
3-(2-((N-sulfamoyl)(methyl)amino)ethyl)azetidine trifluoroacetate
(500 mg) which was used in the next step without purification.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 8.70 (brs., 2H),
6.69 (brs., 1H), 3.88-3.93 (m, 2H), 3.61-3.65 (m, 2H), 2.91-2.74
(m, 3H), 2.59 (s, 3H), 1.73-1.79 (m, 2H).
[0731] Step-4: Synthesis
N-(2-(1-(7-chloro-5-methylpyrrolo[1,2-f][1,2,4]triazin-4-yl)azetidin-3-yl-
)ethyl)-N-methylsulfamide: To a solution of
3-(2-((N-sulfamoyl)(methyl)amino) ethyl)azetidine trifluoroacetate
(191 mg, 0.989 mmol, 1 eq) and
4,7-dichloro-5-methylpyrrolo[1,2-f][1,2,4]triazine (100 mg, 0.494
mmol, 1 eq) in DMF (2 ml) was added N,N-diisopropylethylamine (0.12
mL, 0.741 mmol, 2 eq). The reaction mixture was allowed to stir at
90.degree. C. for overnight. Progress of reaction was monitored by
LCMS. After completion of reaction, reaction mixture was diluted
with water (30 ml) extracted with ethyl acetate (150 ml.times.2).
Combined organic layer was washed with brine (50 mL) and dried over
anhydrous sodium sulfate concentrated to get crude product. which
was purified by reversed phase chromatography to afford
N-(2-(1-(7-chloro-5-methylpyrrolo[1,2-f][1,2,4]triazin-4-yl)azetidin-3-yl-
)ethyl)-N-methylsulfamide (18 mg, 5.07%). LCMS: 359.8 [M+1].sup.+;
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 7.90 (s, 1H), 6.69
(s, 2H), 6.63 (s, 1H), 4.46-4.41 (m, 2H), 4.03-3.98 (m, 2H),
2.95-2.90 (m, 2H), 2.81-2.74 (m, 1H), 2.64 (s, 3H), 2.39 (s, 3H),
1.91-1.85 (m, 2H).
Example-85: Synthesis of
N--(N-(2-(7-chloro-2-cyclopropyl-5-methylpyrrolo[1,2-f][1,2,4]triazin-4-y-
l)-2-azaspiro[3.3]heptan-6-yl)-N-methylsulfamoyl)acetamide,
(Compound 1.85)
##STR00663## ##STR00664##
[0733] Step-1: Synthesis of ethyl
5-chloro-3-methyl-1H-pyrrole-2-carboxylate: To a solution of ethyl
3-methyl-1H-pyrrole-2-carboxylate (4 g, 26.14 mmol, 1 eq) in DMF
(30 mL) was added N-chlorosuccinimide (3.47 g, 26.14 mmol, 1.1 eq)
at 0.degree. C. and the reaction mixture was allowed to stir at
0.degree. C. for 5 minutes followed by stirring at room temperature
for overnight. Progress of reaction was monitored by TLC. After
completion, reaction mixture was cooled to room temperature; solid
was filtered to get residue which was triturated with pentane to
afford ethyl 5-chloro-3-methyl-1H-pyrrole-2-carboxylate (2.8 g,
57.25%). LCMS: 188 [M+1].sup.+
[0734] Step-2: Synthesis of ethyl
1-amino-5-chloro-3-methyl-1H-pyrrole-2-carboxylate: To a solution
of ethyl 5-chloro-3-methyl-1H-pyrrole-2-carboxylate (2.8 g, 14.97
mmol, 1 eq) in DMF (120 mL) was added Sodium hydride (0.9 g, 22.42
mmol, 1.1 eq) at 0.degree. C. and the reaction mixture was allowed
to stir at 0.degree. C. for 15 minutes. To this reaction mixture,
was added O-(diphenylphosphoryl)hydroxylamine (4.53 g, 19.46 mmol,
1.3 eq) at 0.degree. C. portion wise and allowed to stir at room
temperature for overnight. Progress of reaction was monitored by
TLC. After completion of reaction, the reaction mixture was diluted
with water (250 mL) and extracted with MTEB (250 ml.times.2). The
combined organic layer was washed with brine (50 mL) and dried over
anhydrous sodium sulfate concentrated to get product to afford
ethyl 1-amino-5-chloro-3-methyl-1H-pyrrole-2-carboxylate (3.0 g,
99.20%). LCMS: 203 [M+1].sup.+
[0735] Step-3: Synthesis of ethyl
5-chloro-1-(cyclopropanecarboximidamido)-3-methyl-1H-pyrrole-2-carboxylat-
e: A mixture of ethyl
1-amino-5-chloro-3-methyl-1H-pyrrole-2-carboxylate (400 mg, 2.37
mmol, 1 eq) and cyclopropanecarbonitrile (191 mg, 2.85 mmol, 1.2
eq) in 4M HCl in dioxane (4 mL) was allowed to stir at 100.degree.
C. for 16 h. Progress of reaction was monitored by TLC. After
completion of reaction, reaction mixture was cooled to room
temperature, quenched with NaHCO.sub.3 and extracted with ethyl
acetate (150 ml.times.2). Combined organic layer was washed with
brine (50 mL) and dried over anhydrous sodium sulfate concentrated
to get crude product. The crude product was purified by combi flash
chromatography [silica gel 100-200 mesh, elution 0-40% Ethyl
acetate in hexane] to afford ethyl
5-chloro-1-(cyclopropanecarboximidamido)-3-methyl-1H-pyrrole-2-carboxylat-
e (350 mg, 65.73%). LCMS: 270 [M+1].sup.+
[0736] Step-4: Synthesis of
7-chloro-2-cyclopropyl-5-methylpyrrolo[1,2-f][1,2,4]triazin-4-ol:
To a solution of ethyl
5-chloro-1-(cyclopropanecarboximidamido)-3-methyl-1H-pyrrole-2-carboxylat-
e (300 mg, 1.114 room temperature and the reaction mixture was
allowed to stir at 85.degree. C. for 30 min. Progress of reaction
was monitored by TLC. After completion, the reaction mixture was
diluted with water (150 mL) and extracted with ethyl acetate (250
ml.times.2), Combined organic layer was washed with brine (50 mL)
and dried over anhydrous sodium sulfate concentrated to get crude
which was purified by combiflash elution (0-30% ETOAc/Hexane) to
afford
7-chloro-2-cyclopropyl-5-methylpyrrolo[1,2-f][1,2,4]triazin-4-ol
(190 mg, 76.38%). LCMS: 224 [M+1].sup.+
[0737] Step-5: Synthesis of
4,7-dichloro-2-cyclopropyl-5-methylpyrrolo[1,2-f][1,2,4]triazine:
The mixture of
7-chloro-2-cyclopropyl-5-methylpyrrolo[1,2-f][1,2,4]triazin-4-ol
(190 mg, 0.849 mmol, 1 eq) in POCl.sub.3 (2 mL) was allowed to stir
at 120.degree. C. for 2 h. Progress of reaction was monitored by
TLC. After completion reaction mixture was cooled to room
temperature, quenched with NaHCO.sub.3 to maintain pH-7 and
extracted with ethyl acetate (150 ml.times.2). Combined organic
layer was washed with brine (50 mL) and dried over anhydrous sodium
sulfate concentrated to get crude product. The crude product was
purified by combi-flash chromatography [silica gel 100-200 mesh,
elution 0-10% Ethyl acetate in hexane] to afford
4,7-dichloro-2-cyclopropyl-5-methylpyrrolo[1,2-f][1,2,4]triazine as
yellow solid (110 mg, 53.64%). LCMS: 242 [M+1].sup.+
[0738] Step-6: Synthesis of
N--(N-(2-(7-chloro-2-cyclopropyl-5-methylpyrrolo[1,2-f][1,2,4]triazin-4-y-
l)-2-azaspiro[3.3]heptan-6-yl)-N-methylsulfamoyl)acetamide: To a
solution of,
7-dichloro-2-cyclopropyl-5-methylpyrrolo[1,2-f][1,2,4]triazine (110
mg, 0.454 mmol, 1 eq) and
N-methyl-N-(2-azaspiro[3.3]heptan-6-yl)sulfamamide trifluoroacetate
(186 mg, 0.908 mmol, 1 eq) in DMF (2 ml) was added
N,N-diisopropylethylamine (0.09 mL, 0.544 mmol, 1.5 eq). The
reaction mixture was allowed to stir at 90.degree. C. for
overnight. Progress of reaction was monitored by LCMS. After
completion, reaction mixture was diluted with water (30 ml)
extracted with ethyl acetate (150 ml.times.2). Combined organic
layer was washed with brine (50 mL) and dried over anhydrous sodium
sulfate concentrated to get crude product. which was purified by
combiflash (elution 0-70% EtoAc/Hexane) to afford
N--(N-(2-(7-chloro-2-cyclopropyl-5-methylpyrrolo[1,2-f][1,2,4]triazin-4-y-
l)-2-azaspiro[3.3]heptan-6-yl)-N-methylsulfamoyl)acetamide (90 mg,
48.20%). LCMS: 411 [M+1].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. ppm 6.68 (s, 2H), 6.52 (s, 1H), 4.36 (s, 2H), 4.23 (s, 2H),
3.76-3.70 (m, 1H), 2.53 (s, 3H), 2.43-2.28 (m, 7H), 1.81-1.89 (m,
1H), 0.96-0.90 (m, 2H), 0.86-0.79 (m, 2H)
Example-86: Synthesis of
N-((1-(7-chloro-5-methylpyrrolo[1,2-f][1,2,4]triazin-4-yl)azetidin-3-yl)m-
ethyl) sulfamamide, (Compound 1.86)
##STR00665##
[0740] Step-1: Synthesis of tert-butyl 3-((methylamino) methyl)
azetidine-1-carboxylate: To a stirred solution of tert-butyl
3-formylazetidine-1-carboxylate (500 mg, 2.69 mmol, 1.0 eq) in MeOH
(10.0 mL) was added methylamine (0.38 mL, 4.04 mmol, 1.5 eq) at
0.degree. C. The resulting mixture was stirred at room temperature
for overnight. The reaction mixture was then cooled to 0.degree. C.
followed by addition of NaBH.sub.4 (204 mg, 5.398 mmol, 3.0 eq) at
0.degree. C. The reaction mixture was stirred at room temperature
for 1 h. The progress of reaction was monitored by TLC & NMR.
The reaction mixture was concentrated, basified with NaHCO.sub.3
solution (20 mL), extracted with EtOAc (2.times.150 mL). The
combined organic layer was washed with water (50 mL), with brine
(50 mL), dried over Na.sub.2SO.sub.4 and concentrated to get crude
product. The crude product was triturated in pentane to afford
tert-butyl 3-((methylamino) methyl) azetidine-1-carboxylate (500
mg, 92.48%) as liquid. .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta.
ppm 4.01-3.96 (m, 2H), 3.60-3.55 (m, 2H), 2.79-2.73 (m, 2H),
2.65-2.60 (m, 1H), 2.44 (s, 3H), 1.43 (s, 9H).
[0741] Step-2: Synthesis of tert-butyl
3-(((N-(tert-butoxycarbonyl)sulfamoyl)(methyl)
amino)methyl)azetidine-1-carboxylate: To a solution of tert-butyl
3-((methylamino) methyl) azetidine-1-carboxylate (500 mg, 2.49
mmol, 1 eq) and N-(1-(N-(tert-butoxycarbonyl)sulfamoyl)pyridin-4
(1H)-ylidene)-N-methylmethanaminium (827 mg. 2.74 mmol, 1.1 eq) in
dichloromethane (10 mL) was added N,N-diisopropylethylamine (1 ml,
6.22 mmol, 2.5 eq). The reaction mixture was then allowed to stir
at RT for overnight. Progress of reaction was monitored by TLC
& NMR. After completion, the reaction mixture was diluted with
water (50 mL) and extracted with DCM (150 ml.times.2), Combined
organic layer was washed with brine (50 mL) and dried over
anhydrous sodium sulfate concentrated to get crude product. The
crude product was triturated in pentane to afford tert-butyl
3-(((N-(tert-butoxycarbonyl) sulfamoyl) (methyl) amino) methyl)
azetidine-1-carboxylate (500 mg, 52.77%) as liquid. .sup.1H NMR
(400 MHz, CHLOROFORM-d) .delta. ppm 4.01-3.96 (m, 2H), 3.64-3.72
(m, 2H), 3.53 (brs., 1H), 2.92 (s, 2H), 2.78-2.86 (m, 1H), 2.44 (s,
3H), 1.49-1.40 (m, 18H).
[0742] Step-3: Synthesis of 3-(N-sulfamoyl) (methyl) amino) methyl)
azetidine trifluoroacetate: To a solution of tert-butyl
3-(((N-(tert-butoxycarbonyl) sulfamoyl) (methyl) amino) methyl)
azetidine-1-carboxylate (500 mg, 1.318 mmol, 1 eq) in DCM (5 mL)
was added TFA (1.5 mL) and the mixture was allowed to stir at RT
for 2 h. Progress of reaction was monitored by TLC. After
completion, reaction mixture was concentrated under reduced
pressure to get of 3-(N-sulfamoyl) (methyl) amino) methyl)
azetidine trifluoroacetate (500 mg) which was used in the next step
without purification. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
ppm 8.69-8.57 (brs., 2H), 6.83 (brs., 1H), 4.05-3.89 (m, 2H),
3.74-3.63 (m, 2H), 3.21-3.10 (m, 2H), 3.05-3.01 (m, 1H), 2.61 (s,
3H).
[0743] Step-4: Synthesis
N-((1-(7-chloro-5-methylpyrrolo[1,2-f][1,2,4]triazin-4-yl)azetidin-3-yl)m-
ethyl) sulfamamide: To a solution of 3-(N-sulfamoyl) (methyl)
amino) methyl) azetidine trifluoroacetate (378 mg, 0.995 mmol, 1
eq) and 4,7-dichloro-5-methylpyrrolo[1,2-f][1,2,4]triazine (200 mg,
0.995 mmol, 1 eq) in DMF (3 ml), N,N-diisopropylethylamine (0.3 mL,
0.304 mmol, 2 eq) was added. The reaction mixture was allowed to
stir at 90.degree. C. for overnight. Progress of reaction was
monitored by LCMS. After completion, reaction mixture was diluted
with water (30 ml) extracted with ethyl acetate (150 ml.times.2).).
Combined organic layer was washed with brine (50 mL) and dried over
anhydrous sodium sulfate concentrated to get crude product. which
was purified by reversed phase chromatography to afford
N-((1-(7-chloro-5-methylpyrrolo[1,2-f][1,2,4]triazin-4-yl)azetidin-3-yl)m-
ethyl) sulfamamide (41 mg, 20.86%). LCMS: 345.08[M+1].sup.+;
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 7.92 (s, 1H), 6.80
(s, 2H), 6.64 (s, 1H), 4.44-4.39 (m, 2H), 4.06-4.01 (m, 2H),
3.21-3.16 (m, 2H), 3.01-2.96 (m, 1H), 2.66 (s, 3H), 2.39 (s,
3H).
Example-87: Synthesis of
N-(2-(7-methoxycinnolin-4-yl)-2-azaspiro[3.3]heptan-6-yl)-N-methylsulfami-
de, (Compound 1.87)
##STR00666##
[0745] Step-1: Synthesis of 4-chloro-7-methoxycinnoline: A mixture
of 7-methoxycinnolin-4-ol (200 mg, 1.135 mol, 1 eq) in POCl.sub.3
(2.0 mL) was allowed to stir at 120.degree. C. for 2 h. Progress of
reaction was monitored by TLC. After completion reaction mixture
was cooled to RT, quenched with NaHCO.sub.3 to maintain pH-7 and
extracted with ethyl acetate (150 ml.times.2). Combined organic
layer was washed with brine (50 mL) and dried over anhydrous sodium
sulfate concentrated to get crude product. The crude product was
purified by combi-flash chromatography [silica gel 100-200 mesh,
elution 0-10% Ethyl acetate in hexane] to
4-chloro-7-methoxycinnoline (150 mg, 67.89%) as white solid. LCMS:
195 [M+1].sup.+
[0746] Step-2: Synthesis
N-(2-(7-methoxycinnolin-4-yl)-2-azaspiro[3.3]heptan-6-yl)-N-methylsulfami-
de: To a solution of 4-chloro-7-methoxycinnoline (150 mg, 0.770
mmol, 1 eq) and N-methyl-N-(2-azaspiro[3.3]heptan-6-yl)sulfamamide
(245 mg, 0.770 mmol, 1 eq) in Ethanol (10 ml) was added
N,N-diisopropylethylamine (0.2 mL, 1.155 mmol, 1.5 eq). The
reaction mixture was allowed to stir at 90.degree. C. for
overnight. Progress of reaction was monitored by LCMS. After
completion, reaction mixture was concentrated under reduced
pressure to get residue and diluted with water (30 ml) and
extracted with ethyl acetate (150 ml.times.2). Combined organic
layer was washed with brine (50 mL) and dried over anhydrous sodium
sulfate concentrated to get crude product, which was purified by
reversed phase chromatography to afford
N-(2-(7-methoxycinnolin-4-yl)-2-azaspiro[3.3]heptan-6-yl)-N-methyl-
sulfamide (41 mg, 14.63%). LCMS: 364.1 [M+1].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. ppm 8.21 (s, 1H), 7.86 (d, J=9.65
Hz, 1H), 7.43 (d, J=2.63 Hz, 1H), 7.18 (dd, J=9.65, 2.63 Hz, 1H),
6.73 (s, 2H), 4.49 (s, 2H), 4.39 (s, 2H), 3.93 (s, 3H), 3.75-3.71
(m, 1H), 2.60-2.22 (s, 7H).
Example-88: Synthesis of
N-((1-(7-chloro-5-methylpyrrolo[1,2-f][1,2,4]triazin-4-yl)azetidin-3-yl)m-
ethyl)-N-cyclopropylsulfamamide, (Compound 1.88)
##STR00667##
[0748] Step-1: Synthesis of tert-butyl
3-((cyclopropylamino)methyl)azetidine-1-carboxylate: To a stirred
solution of tert-butyl 3-formylazetidine-1-carboxylate (500 mg,
2.69 mmol, 1.0 eq) in MeOH (10.0 mL) was added cyclopropanamine
(231 mg, 4.04 mmol, 1.5 eq) at 0.degree. C. The resulting mixture
was stirred at room temperature for overnight. The reaction mixture
was then cooled to 0.degree. C. followed by addition of NaBH.sub.4
(204 mg, 5.398 mmol, 3.0 eq) at 0.degree. C. The reaction mixture
was stirred at room temperature for 1 h. The progress of reaction
was monitored by TLC & NMR. The reaction mixture was
concentrated, basified with NaHCO.sub.3 solution (20 mL), extracted
with EtOAc (2.times.150 mL). The combined organic layer was washed
with water (50 mL), with brine (50 mL), dried over Na.sub.2SO.sub.4
and concentrated to get crude product. The crude product was
triturated in pentane to afford tert-butyl
3-((cyclopropylamino)methyl)azetidine-1-carboxylate (500 mg,
81.84%) as liquid. .sup.1H NMR (400 MHz, CDCl.sub.3-d) .delta. ppm
3.99-3.93 (m, 2H), 3.61-3.55 (m, 2H), 2.85-2.90 (m, 1H), 2.65-2.60
(m, 1H), 2.08-2.02 (m, 2H), 1.43 (s, 9H), 0.43-0.38 (m, 2H),
0.25-0.30 (m, 2H).
[0749] Step-2: Synthesis of tert-butyl
3-((cyclopropylamino)methyl)azetidine-1-carboxylate: To a solution
of tert-butyl 3-((methylamino) methyl) azetidine-1-carboxylate (500
mg, 2.20 mmol, 1.0 eq) and
N-(1-(N-(tert-butoxycarbonyl)sulfamoyl)pyridin-4
(1H)-ylidene)-N-methylmethanaminium (732.4 mg. 2.43 mmol, 1.1 eq)
in dichloromethane (10 mL) was added N,N-diisopropylethylamine
(1.05 ml, 6.075 mmol, 2.5 eq) and the reaction mixture was allowed
to stir at RT for overnight. Progress of reaction was monitored by
NMR. After completion, the reaction mixture was diluted with water
(50 mL) and extracted with DCM (150 ml.times.2), combined organic
layer was washed with brine (50 mL) and dried over anhydrous sodium
sulfate and concentrated to get crude product. The crude product
was triturated in pentane (50 ml) to afford tert-butyl
3-(((N-(tert-butoxycarbonyl)sulfamoyl)(cyclopropyl)amino)methyl)azetidine-
-1-carboxylate (500 mg, 55.81%) as liquid which was used in the
next step without purification.
[0750] Step-3: Synthesis of 3-(N-sulfamoyl) (cyclopropyl) amino)
methyl) azetidine trifluoroacetate: To a solution of tert-butyl
3-(((N-(tert-butoxycarbonyl) sulfamoyl) (cyclopropyl) amino)
methyl) azetidine-1-carboxylate (500 mg, 1.318 mmol, 1 eq) in DCM
(10 mL) was added TFA (4 mL) and the mixture was allowed to stir at
RT for 2 h. Progress of reaction was monitored by TLC. After
completion, reaction mixture was concentrated under reduced
pressure to get of 3-(N-sulfamoyl) (cyclopropyl) amino) methyl)
azetidine trifluoroacetate (250 mg) which was used in the next step
without purification.
[0751] Step-4: Synthesis of
N-((1-(7-chloro-5-methylpyrrolo[1,2-f][1,2,4]triazin-4-yl)azetidin-3-yl)m-
ethyl)-N-cyclopropylsulfamamide: To a solution of 3-(N-sulfamoyl)
(cyclopropyl) amino) methyl) azetidine trifluoroacetate (203.20 mg,
0.989 mmol, 2 eq) and
4,7-dichloro-5-methylpyrrolo[1,2-f][1,2,4]triazine (100 mg, 0.494
mmol, 1 eq) in DMF (2 ml) was added N,N-diisopropylethylamine (0.12
mL, 0.304 mmol, 2 eq). The reaction mixture was allowed to stir at
90.degree. C. for overnight. Progress of reaction was monitored by
LCMS. After completion, reaction mixture was diluted with water (30
ml) extracted with ethyl acetate (150 ml.times.2). Combined organic
layer was washed with brine (50 mL) and dried over anhydrous sodium
sulfate concentrated to get crude product, which was purified by
reversed phase chromatography to afford
N-((1-(7-chloro-5-methylpyrrolo[1,2-f][1,2,4]triazin-4-yl)azetidin-3-yl)m-
ethyl)-N-cyclopropyl sulfamamide (19 mg, 5.17%). LCMS:
371.10[M+1].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm
7.50 (s, 1H) 6.92 (s, 2H), 6.22 (s, 1H), 3.85-3.80 (m, 1H),
3.58-3.49 (m, 2H), 3.20-3.15-(m, 2H), 3.07-3.01 (m, 1H), 3.01-2.95
(m, 1H), 2.32 (s, 3H), 0.76-0.66 (m, 5H).
Example-89: Synthesis
N-((1-(7-chloro-5-methylpyrrolo[1,2-f][1,2,4]triazin-4-yl)azetidin-3-yl)m-
ethyl)-N-isopropylsulfamide, (Compound 1.89)
##STR00668##
[0753] Step-1: Synthesis of tert-butyl
3-((isopropylamino)methyl)azetidine-1-carboxylate: To a stirred
solution of tert-butyl 3-formylazetidine-1-carboxylate (500 mg,
2.69 mmol, 1.0 eq) in MeOH (10.0 mL) was added isopropanamine (238
mg, 4.04 mmol, 1.5 eq) at 0.degree. C. The resulting mixture was
stirred at room temperature for overnight. The reaction mixture was
then cooled to 0.degree. C. followed by addition of NaBH.sub.4 (204
mg, 5.398 mmol, 3.0 eq) at 0.degree. C. The reaction mixture was
stirred at room temperature for 1 h. The progress of reaction was
monitored by TLC. The reaction mixture was concentrated, basified
with NaHCO.sub.3 solution (20 mL), extracted with EtOAc
(2.times.150 mL). The combined organic layer was washed with water
(50 mL), with brine (50 mL), dried over Na.sub.2SO.sub.4 and
concentrated to get crude product. The crude product was triturated
using pentane (50 ml) to afford tert-butyl 3-((isopropylamino)
methyl) azetidine-1-carboxylate (500 mg, 81.07%) as liquid. LCMS:
229.1 [M+1].sup.+
[0754] Step-2: Synthesis of tert-butyl
3-(((N-(tert-butoxycarbonyl)sulfamoyl)(isopropyl)amino)
methyl)azetidine-1-carboxylate: To a solution of tert-butyl
3-((isopropylamino) methyl) azetidine-1-carboxylate (500 mg, 2.20
mmol, 1 eq) and N-(1-(N-(tert-butoxycarbonyl)sulfamoyl)pyridin-4
(1H)-ylidene)-N-methylmethanaminium (732.4 mg. 2.43 mmol, 1.1 eq)
in dichloromethane (10 mL) was added N,N-diisopropylethylamine
(1.05 ml, 6.075 mmol, 2.5 eq) and the reaction mixture was allowed
to stir at RT for overnight. Progress of reaction was monitored by
NMR. After completion, the reaction mixture was diluted with water
(50 mL) and extracted with DCM (150 ml.times.2). The combined
organic layer was washed with brine (50 mL) and dried over
anhydrous sodium sulfate concentrated to get crude product. The
crude product was triturated in pentane to afford tert-butyl
3-(((N-(tert-butoxycarbonyl)sulfamoyl)(isopropyl)amino)
methyl)azetidine-1-carboxylate (500 mg, 56.02%) as liquid. LCMS:
408.2 [M+1].sup.+
[0755] Step-3: Synthesis of 3-(N-sulfamoyl) (isopropyl) amino)
methyl) azetidine trifluoroacetate: To a solution of tert-butyl
3-(((N-(tert-butoxycarbonyl) sulfamoyl) (isopropyl) amino) methyl)
azetidine-1-carboxylate (500 mg, 1.226 mmol, 1 eq) in DCM (10 mL)
was added TFA (4 mL) and the mixture was allowed to stir at RT for
2 h. Progress of reaction was monitored by TLC. After completion,
reaction mixture was concentrated under reduced pressure to get of
3-(N-sulfamoyl) (isopropyl) amino) methyl) azetidine
trifluoroacetate (250 mg) which was used in the next step without
purification. LCMS: 208.1 [M+1].sup.+
[0756] Step-4: Synthesis of
N-((1-(7-chloro-5-methylpyrrolo[1,2-f][1,2,4]triazin-4-yl)azetidin-3-yl)m-
ethyl)-N-isopropylsulfamide: To a solution of 3-(N-sulfamoyl)
(isopropyl) amino) methyl) azetidine trifluoroacetate (205 mg,
0.989 mmol, 2 eq) and
4,7-dichloro-5-methylpyrrolo[1,2-f][1,2,4]triazine (100 mg, 0.494
mmol, 1 eq) in DMF (2 ml) was added N,N-diisopropylethylamine (0.12
mL, 0.304 mmol, 2 eq). The reaction mixture was allowed to stir at
90.degree. C. for overnight. Progress of reaction was monitored by
LCMS. After completion of reaction, reaction mixture was diluted
with water (30 ml) and extracted with ethyl acetate (150
ml.times.2). Combined organic layer was washed with brine (50 mL)
and dried over anhydrous sodium sulfate concentrated to get crude
product. which was purified by reversed phase chromatography to
afford
N-((1-(7-chloro-5-methylpyrrolo[1,2-f][1,2,4]triazin-4-yl)azetidin-3-yl)m-
ethyl)-N-isopropylsulfamide (13 mg, 3.52%). LCMS: 373.1
[M+1].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 7.91
(s, 1H), 6.71 (s, 2H), 6.63 (s, 1H), 4.39-4.34 (m, 2H), 4.11-4.06
(m, 2H), 3.93-3.88 (m, 1H), 3.27-3.22 (m, 2H), 3.05-2.99 (m, 1H),
2.39 (s, 3H), 1.19-1.03 (m, 6H).
Example-90: Synthesis of
N-(2-(7-chloro-2-(difluoromethyl)-5-methyl-7aH-cyclopenta[d]pyrimidin-4-y-
l)-2-azaspiro[3.3]heptan-6-yl)-N-methylsulfamamide, (Compound
1.90)
##STR00669##
[0758] Step-1: Synthesis of
7-chloro-2-(difluoromethyl)-5-methylpyrrolo[1,2-f][1,2,4]triazin-4-ol:
A mixture of ethyl
1-amino-5-chloro-3-methyl-1H-pyrrole-2-carboxylate (400 mg, 1.97
mmol, 1 eq) and 2,2-difluoroacetonitrile (182 mg, 2.36 mmol, 1.2
eq) in 4M HCl in dioxane (4 mL) was allowed to stir at 100.degree.
C. for 16 h. Progress of reaction was monitored by TLC. After
completion of reaction, reaction mixture was cooled to RT, quenched
with NaHCO.sub.3 solution and extracted with ethyl acetate (50
ml.times.2). Combined organic layer was washed with brine (50 mL)
and dried over anhydrous sodium sulfate concentrated to get crude
product (440 mg). The crude product (440 mg) was dissolved in
dioxane (4.0 ml) and was added CS.sub.2CO.sub.3 (1.28 g, 3.94 mmol,
2.0 eq). The reaction mixture was then allowed to stir at
85.degree. C. for 30 min. The progress of reaction was monitor by
LCMS. The LCMS showed the formation of desired product. The
reaction mixture was diluted with DM water (150 ml) and extracted
using ethyl acetate (250 ml.times.2). The combined organic layer
was concentrated to get crude product. The crude product was
purified by combi flash chromatography [silica gel 100-200 mesh,
elution 0-40% Ethyl acetate in hexane] to
7-chloro-2-(difluoromethyl)-5-methylpyrrolo[1,2-f][1,2,4]triazin-4-ol
(300 mg, 65.02%) LCMS: 234.2 [M+1].sup.+
[0759] Step-2: Synthesis of
4,7-dichloro-2-isopropyl-5-methylpyrrolo[1,2-f][1,2,4]triazine: A
mixture of
7-chloro-2-(difluoromethyl)-5-methylpyrrolo[1,2-f][1,2,4]triazin-4-ol
(300 mg, 1.19 mmol, 1.0 eq) in POCl.sub.3 (3 mL) was allowed to
stir at 120.degree. C. for 2 h. Progress of reaction was monitored
by TLC. After completion reaction mixture was cooled to RT,
quenched with NaHCO.sub.3 to maintain pH-7 and extracted with ethyl
acetate (50 ml.times.2). Combined organic layer was washed with
brine (40 mL) and dried over anhydrous sodium sulfate concentrated
to get crude product. The crude product was purified by combi-flash
chromatography [silica gel 100-200 mesh, elution 0-30% Ethyl
acetate in hexane] to get
4,7-dichloro-2-(difluoromethyl)-5-methylpyrrolo[1,2-f][1,2,4]triazine
as viscous oil. (280 mg, 86.41%) LCMS: 252.1 [M+1].sup.+
[0760] Step-3: Synthesis of
N-(2-(7-chloro-2-(difluoromethyl)-5-methyl-7aH-cyclopenta[d]pyrimidin-4-y-
l)-2-azaspiro[3.3]heptan-6-yl)-N-methylsulfamamide: To a solution
of,
4,7-dichloro-2-(difluoromethyl)-5-methylpyrrolo[1,2-f][1,2,4]triazine
(80 mg, 0.312 mmol, 1 eq) and
N-methyl-N-(2-azaspiro[3.3]heptan-6-yl)sulfamamide trifluoroacetate
(98 mg, 0.476 mmol, 1.5 eq) in DMF (2 ml) was added
N,N-diisopropylethylamine (0.08 mL, 0.475 mmol, 1.5 eq) was added.
The reaction mixture was allowed to stir at 90.degree. C. for 4 h.
Progress of reaction was monitored by LCMS. After completion,
reaction mixture was diluted with water (30 ml) extracted with
ethyl acetate (150 ml.times.2). Combined organic layer was washed
with brine (50 ml) and dried over anhydrous sodium sulfate
concentrated to get crude product, which was purified by reverse
phase chromatography to afford
N-(2-(7-chloro-2-(difluoromethyl)-5-methyl-7aH-cyclopenta[d]pyrimidin-4-y-
l)-2-azaspiro[3.3]heptan-6-yl)-N-methylsulfamamide (26 mg, 15.03%)
as white solid. LCMS: 421.4 [M+1].sup.+; .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 6.81-6.64 (m, 4H), 4.49 (s, 2H), 4.35 (s,
2H), 3.77-3.72 (m, 1H), 2.54-2.29 (m, 10H).
Example-91: Synthesis of
N-(2-(6-cyano-5-methylpyrrolo[1,2-f][1,2,4]triazin-4-yl)-2-azaspiro[3.3]
heptan-6-yl)-N-methylsulfamamide, (Compound 1.91)
##STR00670##
[0762] Step-1: Synthesis of
4-hydroxy-5-methylpyrrolo[1,2-f][1,2,4]triazine-7-carbonitrile: To
a solution of 5-methylpyrrolo[1,2-f][1,2,4]triazin-4-ol (0.250 g,
1.67 mmol, 1.0 eq) was dissolved in CH.sub.3CN (5 mL) and cooled to
-10.degree. C. was added a solution of Chlorosulfonyl isocyanate
(0.235 g, 1.67 mmol, 1.0 eq) in CH.sub.3CN (5 mL) was added to the
reaction mixture over 5 min. The solution rapidly became yellow and
solid precipitate was deposited. N,N-dimethylformamide (1 mL) was
added in reaction mixture and The solution became colorless then
TEA (0.455 mL, 3.333 mmol, 2.0 eq) was added to the reaction
mixture turned white precipitate was formed. The reaction mixture
was allowed to stir at RT for 2 h. Progress of reaction is
monitored using TLC. After completion, reaction mixture poured onto
ice water and extracted with ethyl acetate (3.times.50 mL).
Combined organic layer was washed with brine (50 mL) and dried over
anhydrous sodium sulfate. Removal of solvent under reduced pressure
afforded
4-hydroxy-5-methylpyrrolo[1,2-f][1,2,4]triazine-7-carbonitrile
(0.160 g, 55.17%). LCMS: 179 [M+1].sup.+
[0763] Step-2: Synthesis of
4-chloro-5-methylpyrrolo[1,2-f][1,2,4]triazine-6-carbonitrile: To a
solution of
4-hydroxy-5-methylpyrrolo[1,2-f][1,2,4]triazine-7-carbonitrile (0.3
g, 2.013 mmol, 1 eq) in N,N-Diisopropylethylamine was added a
solution of phosphoryl oxychloride (0.188 mL, 2.013 mmol, 1 eq) at
0.degree. C. and the reaction mixture was allowed to stir at
0.degree. C. for 10 minutes. The reaction mixture was allowed to
stir at 130.degree. C. for 2 h. Progress of reaction is monitored
by TLC. After completion, reaction mixture was diluted with cold
water (30 mL) and extracted with ethyl acetate (3.times.20 mL).
Combined organic layer was washed with brine (20 mL) and dried over
anhydrous sodium sulfate. Solvent was removed under reduced
pressure to give
4-chloro-5-methylpyrrolo[1,2-f][1,2,4]triazine-6-carbonitrile (0.22
g, 57%). LCMS: 193 [M+1].sup.+
[0764] Step-3: Synthesis of
N-(2-(6-cyano-5-methylpyrrolo[1,2-f][1,2,4]triazin-4-yl)-2-azaspiro[3.3]h-
eptan-6-yl)-N-methylsulfamamide: A mixture of
4-chloro-5-methylpyrrolo[1,2-f][1,2,4]triazine-6-carbonitrile (0.2
g, 1.04 mmol, 1 eq),
N-methyl-N-(2-azaspiro[3.3]heptan-6-yl)sulfamamide
2,2,2-trifluoroacetaldehyde (0.350 g, 1.14 mmol, 1.1 eq) and DIPEA
(0.272 mL, 1.562 mmol, 1.5 eq) in DMF (10 mL) was allowed to stir
at 85.degree. C. for 3 h. Progress of reaction was monitored by
TLC. After completion, reaction mixture was diluted with cold water
(30 mL) and extracted with ethyl acetate (3.times.50 mL). Combined
organic layer was washed with brine (3.times.30 mL) and dried over
anhydrous sodium sulfate. Removal of solvent under reduced pressure
to obtain the crude which was purified by reversed phase to afford
N-(2-(6-cyano-5-methylpyrrolo[1,2-f][1,2,4]triazin-4-yl)-2-azaspiro[3.3]h-
eptan-6-yl)-N-methylsulfamamide (10 mg, 2.65%). LCMS: 362
[M+1].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 8.06
(s, 1H), 7.24 (s, 1H), 6.70 (s, 2H), 4.48 (s, 2H), 4.35 (s, 2H),
3.82-3.74 (m, 1H), 2.58-2.22 (m, 10H).
Example-92: Synthesis of
N-(2-(1-(7-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)azetidin-3-yl-
)ethyl)-N-cyclopropylsulfamamide, (Compound 1.92)
##STR00671##
[0766] Step-1: Synthesis of tert-butyl
3-(2-oxoethyl)azetidine-1-carboxylate: A suspension of (1.0 g, 4.95
mmol, 1.0 eq) in DCM (40 mL) at 0.degree. C. was added DMP (6.29 g,
14.8 mmol, 3.0 eq) was added portion wise at 0.degree. C. into
above reaction mixture. After addition, reaction mixture was
stirred at RT for 2 h. Progress of reaction was monitored by TLC.
After completion, reaction mixture was concentrated under reduced
pressure to get residue which was diluted with water (150 mL) and
extracted with DCM (3.times.250 mL). Combined organic layer was
washed with brine (3.times.50 mL), dried over anhydrous sodium
sulfate and concentrated under reduced pressure to afford
tert-butyl 3-(2-oxoethyl)azetidine-1-carboxylate (1.1 g, 92.3%)
which was used into the next step without purification.
[0767] Step-2: Synthesis of tert-butyl
3-(2-(cyclopropylamino)ethyl)azetidine-1-carboxylate: A suspension
of (500 mg, 2.5 mmol, 1 eq), cyclopropylamine (172 mg, 3.01 mmol,
1.2 eq) in methanol (10 mL) was stirred at RT for overnight. After
overnight stirring, NaBH.sub.4 (142 mg, 3.75 mmol, 1.5 eq) was
added portion wise at 0.degree. C. and allowed to stir the reaction
mixture for 1 h at 0.degree. C. Progress of reaction was monitored
by TLC. After completion, reaction mixture was concentrated under
reduced pressure to get residue which was diluted with water (100
mL) and extracted with ethyl acetate (3.times.150 mL). Combined
organic layer was washed with brine (3.times.50 mL), dried over
anhydrous sodium sulfate and concentrated under reduced pressure to
afford tert-butyl
3-(2-(cyclopropylamino)ethyl)azetidine-1-carboxylate (470 mg) which
was used in the next step without purification (460 mg, 76.5%).
[0768] Step-3: Synthesis of tert-butyl
3-(2-((N-(tert-butoxycarbonyl)sulfamoyl)(cyclopropyl)amino)ethyl)azetidin-
e-1-carboxylate: To a solution of tert-butyl
3-(2-(cyclopropylamino)ethyl)azetidine-1-carboxylate (460 mg, 1.91
mmol, 1.0 eq) in DCM (10 mL) was added
N-(tert-butoxycarbonyl)-N-[4-(dimethylazaniumylidene)-1,4-dihydropyridinl-
ylsulfonyl]azanide (694 mg, 2.29 mmol, 1.2 eq) and DIPEA (370 mg,
2.86 mmol, 1.5 eq) and the mixture was allowed to stir at RT for
overnight. Progress of reaction was monitored by TLC. After
completion, reaction mixture was diluted with water (50 mL) and
extracted with DCM (2.times.150 mL). Combined organic layer was
washed with brine (1.times.50 mL), dried over anhydrous sodium
sulfate and concentrated under reduced pressure to afford
tert-butyl3-(2-((N-(tert-butoxycarbonyl)sulfamoyl)(cyclopropyl)amino)ethy-
l)azetidine-1-carboxylate (420 mg, 52%).
[0769] Step-4: Synthesis of
N-(2-(azetidin-3-yl)ethyl)-N-cyclopropylsulfamamide
2,2,2-trifluoroacetate: To a solution of
tert-butyl3-(2-((N-(tert-butoxycarbonyl)sulfamoyl)(cyclopropyl)amino)ethy-
l)azetidine-1-carboxylate (420 mg, 1.0 mmol, 1 eq) in DCM (4 mL)
was added TFA (1.2 mL) and was allowed to stir at RT for 2 h.
Progress of reaction was monitored by TLC. After completion,
reaction mixture was concentrated under reduced pressure to afford
crude which was triturated with diethyl ether to afford
N-(2-(azetidin-3-yl)ethyl)-N-cyclopropylsulfamamide
2,2,2-trifluoroacetate (320 mg, 96%).
[0770] Step-5: Synthesis of
N-(2-(1-(7-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)azetidin-3-yl-
)ethyl)-N-cyclopropylsulfamamide: A suspension of
N-(2-(azetidin-3-yl)ethyl)-N-cyclopropylsulfamamide
2,2,2-trifluoroacetate (94 mg, 0.298 mmol, 1.0 eq),
4,7-dichloro-5-methylpyrrolo[2,1-f][1,2,4]triazine (60 mg, 0.298
mmol, 1.0 eq) and DIPEA (77 mg, 0.596 mmol, 2.0 eq) in DMF (1.5 mL)
was allowed to stir at 80.degree. C. for 2 h. Progress of reaction
was monitored by TLC and LCMS. After completion of reaction,
reaction mixture was diluted with water (10 mL) and extracted with
ethyl acetate (1.times.50 mL). Combined organic layer was washed
with brine (1.times.10 mL), dried over anhydrous sodium sulfate and
concentrated under reduced pressure to obtain crude product which
was purified by using reversed phase chromatography to afford
N-(2-(1-(7-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)azetidin-3-yl-
)ethyl)-N-cyclopropylsulfamamide (26 mg, 22.6%). LCMS: 385
[M+1].sup.+; NMR: .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm
7.90 (s, 1H), 6.85 (s, 2H), 6.63 (s, 1H), 4.45 (t, J=8.8 Hz, 2H),
4.07-3.93 (m, 2H), 3.09 (t, J=7.0 Hz, 2H), 2.72 (br. s., 1H), 2.39
(s, 3H), 2.32 (br. s., 1H), 1.96 (d, J=7.0 Hz, 2H), 0.67 (br. s.,
4H)
Example-93: Synthesis of
N-(2-(7-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-azaspiro[3.3]-
heptan-6-yl)-N-(3,3,3-trifluoropropyl)sulfamamide, (Compound
1.93)
##STR00672##
[0772] Step-1: Synthesis of tert-butyl
6-(3,3,3-trifluoropropylamino)-2-azaspiro[3.3]heptane-2-carboxylate:
A suspension of tert-butyl
6-oxo-2-azaspiro[3.3]heptane-2-carboxylate (200 mg, 0.946 mmol, 1.0
eq), 3,3,3-trifluoropropan-1-amine hydrochloride (169 mg, 1.13
mmol, 1.2 eq) in methanol (5 mL) was stirred at RT for overnight.
After overnight stirring, NaBH.sub.4 (57 mg, 1.42 mmol, 1.5 eq) was
added into above reaction mixture portion wise at 0.degree. C. and
allowed to stir the reaction mixture for 1 h at 0.degree. C.
Progress of reaction was monitored by TLC. After completion,
reaction mixture was concentrated under reduced pressure to get
residue which was diluted with water (30 mL) and extracted with DCM
(2.times.50 mL). Combined organic layer was washed with brine
(1.times.20 mL), dried over anhydrous sodium sulfate and
concentrated under reduced pressure to afford tert-butyl
6-(3,3,3-trifluoropropylamino)-2-azaspiro[3.3]heptane-2-carboxylate
(220 mg, 75%) which was used into the next step without
purification.
[0773] Step-2: Synthesis of tert-butyl
6-((N-(tert-butoxycarbonyl)sulfamoyl)(3,3,3-trifluoropropyl)amino)-2-azas-
piro[3.3]heptane-2-carboxylate: To a solution of tert-butyl
6-(cyclopropylamino)-2-azaspiro[3.3]heptane-2-carboxylate (200 mg,
0.648 mmol, 1.0 eq) in DCM (5 mL) were added
N-(tert-butoxycarbonyl)-N-[4-(dimethylazaniumylidene)-1,4-dihydropyridin--
1ylsulfonyl]azanide (235 mg, 0.778 mmol, 1.2 eq) and DIPEA (125 mg,
0.972 mmol, 1.5 eq) and the mixture was allowed to stir at RT for
overnight. Progress of reaction was monitored by TLC. After
completion, reaction mixture was diluted with water (25 mL) and
extracted with DCM (2.times.50 mL). Combined organic layer was
washed with brine (1.times.20 mL), dried over anhydrous sodium
sulfate and concentrated under reduced pressure to obtain crude
product was purified by combiflash chromatography to afford
tert-butyl
6-((N-(tert-butoxycarbonyl)sulfamoyl)(3,3,3-trifluoropropyl)amino)-2-azas-
piro[3.3]heptane-2-carboxylate (90 mg, 29%).
[0774] Step-3: Synthesis of
N-(2-azaspiro[3.3]heptan-6-yl)-N-(3,3,3-trifluoropropyl)sulfamamide
2,2,2-trifluoroacetate: To a solution of tert-butyl
6-((N-(tert-butoxycarbonyl)sulfamoyl)(3,3,3-trifluoropropyl)amino)-2-azas-
piro[3.3]heptane-2-carboxylate (90 mg, 0.184 mmol, 1.0 eq) in DCM
(3 mL) was added TFA (0.2 mL) and was allowed to stir at RT for 2
h. Progress of reaction was monitored by TLC. After completion,
reaction mixture was concentrated under reduced pressure to afford
crude which was triturated with diethyl ether to afford
N-(2-azaspiro[3.3]heptan-6-yl)-N-(3,3,3-trifluoropropyl)sulfamamide
2,2,2-trifluoroacetate (70 mg, 94.5%).
[0775] Step-4: Synthesis of
N-(2-(7-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-azaspiro[3.3]-
heptan-6-yl)-N-(3,3,3-trifluoropropyl)sulfamamide:
[0776] A suspension of
N-(2-azaspiro[3.3]heptan-6-yl)-N-(3,3,3-trifluoropropyl)sulfamamide
2,2,2-trifluoroacetate (76 mg, 0.199 mmol, 1.0 eq),
4,7-dichloro-5-methylpyrrolo[2,1-f][1,2,4]triazine (40 mg, 0.199
mmol, 1.0 eq) and DIPEA (51 mg, 0.398 mmol, 2.0 eq) in DMF (1.0 mL)
was allowed to stir at 80.degree. C. for 2 h. Progress of reaction
was monitored by TLC and LCMS. After completion, reaction mixture
was diluted with water (30 mL) and extracted with ethyl acetate
(2.times.50 mL). Combined organic layer was washed with brine
(1.times.20 mL), dried over anhydrous sodium sulfate and
concentrated under reduced pressure to obtain crude which was
purified by combiflash chromatography to afford
N-(2-(7-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-azaspiro[3.3]-
heptan-6-yl)-N-(3,3,3-trifluoropropyl)sulfamamide (6 mg, 6.6%).
LCMS: 453 [M+1].sup.+; NMR: .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. ppm 7.91 (s, 1H), 6.91 (br. s., 2H), 6.64 (s, 1H), 4.42
(br. s., 2H), 4.31 (br. s., 2H), 3.86 (br. s., 1H), 3.22 (br. s.,
3H), 2.67 (br. s., 1H), 2.40 (s, 4H), 2.32 (br. s., 3H).
Example-94: Synthesis of
N-(2-(1-(7-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)azetidin-3-yl-
)ethyl)-N-cyclobutylsulfamamide, (Compound 1.94)
##STR00673##
[0778] Step-1: Synthesis of tert-butyl
3-(2-oxoethyl)azetidine-1-carboxylate: A suspension of tert-butyl
3-(2-hydroxyethyl)azetidine-1-carboxylate (2.0 g, 9.93 mmol, 1.0
eq) in DCM (50 mL) at 0.degree. C. was added DMAP (12.6 g, 29.8
mmol, 3.0 eq) was added portion wise at 0.degree. C. into above
reaction mixture. After addition, the reaction mixture was stirred
at RT for 3 h. Progress of reaction was monitored by TLC. After
completion, the reaction mixture was concentrated under reduced
pressure to get residue which was diluted with water (150 mL) and
extracted with DCM (3.times.250 mL). Combined organic layer was
washed with brine (3.times.50 mL), dried over anhydrous sodium
sulfate and concentrated under reduced pressure to afford
tert-butyl 3-(2-oxoethyl)azetidine-1-carboxylate (1.5 g, 76%) which
was used in the next step without purification.
[0779] Step-2: Synthesis of tert-butyl
3-(2-(cyclobutylamino)ethyl)azetidine-1-carboxylate: A suspension
of tert-butyl 3-(2-oxoethyl)azetidine-1-carboxylate (250 mg, 1.25
mmol, 1.0 eq), cyclobutylamine (107 mg, 1.50 mmol, 1.2 eq) in
methanol (5 mL) was stirred at RT for overnight. After overnight
stirring, NaBH.sub.4 (71 mg, 1.87 mmol, 1.5 eq) was added into
above reaction mixture portion wise at 0.degree. C. and allowed to
stir the reaction mixture for 1 h at 0.degree. C. Progress of
reaction was monitored by TLC. After completion, the reaction
mixture was concentrated under reduced pressure to get residue
which was diluted with water (100 mL) and extracted with ethyl
acetate (3.times.150 mL). Combined organic layer was washed with
brine (3.times.50 mL), dried over anhydrous sodium sulfate and
concentrated under reduced pressure to afford tert-butyl
3-(2-(cyclobutylamino)ethyl)azetidine-1-carboxylate (270 mg, 84.9%)
which was used in the next step without purification.
[0780] Step-3: Synthesis of
tert-butyl3-(2-((N-(tert-butoxycarbonyl)sulfamoyl)(cyclobut
yl)amino)ethyl)azetidine-1-carboxylate: To a solution of
tert-butyl3-(2-(cyclobutylamino)ethyl)azetidine-1-carboxylate (270
mg, 1.06 mmol, 1.0 eq) in DCM (5 mL) were added
N-(tert-butoxycarbonyl)-N-[4-(dimethylazaniumylidene)-1,4-dihydropyridinl-
ylsulfonyl]azanide (384 mg, 1.27 mmol, 1.2 eq) and DIPEA (205 mg,
1.59 mmol, 1.5 eq) and the mixture was allowed to stir at RT for
overnight. Progress of reaction was monitored by TLC. After
completion, reaction mixture was diluted with water (50 mL) and
extracted with DCM (2.times.100 mL). Combined organic layer was
washed with brine (1.times.50 mL), dried over anhydrous sodium
sulfate and concentrated under reduced pressure to afford
tert-butyl3-(2-((N-(tert-butoxycarbonyl)sulfamoyl)(cyclobutyl)amino)ethyl-
)azetidine-1-carboxylate (350 mg, 76%).
[0781] Step-4: Synthesis of
N-(2-(azetidin-3-yl)ethyl)-N-cyclobutylsulfamamide2,2,2-trifluoroacetate:
To a solution of
tert-butyl3-(2-((N-(tert-butoxycarbonyl)sulfamoyl)(cyclobutyl)amino)ethyl-
)azetidine-1-carboxylate (350 mg, 0.785 mmol, 1.0 eq) in DCM (4 mL)
was added TFA (1.0 mL) and was allowed to stir at RT for 2 h.
Progress of reaction was monitored by TLC. After completion, the
reaction mixture was concentrated under reduced pressure to afford
crude which was triturated with diethyl ether to afford
N-(2-(azetidin-3-yl)ethyl)-N-cyclobutylsulfamamide
2,2,2-trifluoroacetate (250 mg, 96.5%).
[0782] Step-5: Synthesis of
N-(2-(1-(7-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)azetidin-3-yl-
)ethyl)-N-cyclobutylsulfamamide: A suspension of
N-(2-(azetidin-3-yl)ethyl)-N-cyclobutylsulfamamide
2,2,2-trifluoroacetate (74 mg, 0.223 mmol, 1.0 eq),
4,7-dichloro-5-methylpyrrolo[2,1-f][1,2,4]triazine (45 mg, 0.223
mmol, 1.0 eq) and DIPEA (57.5 mg, 0.446 mmol, 2.0 eq) in DMF (1.0
mL) was allowed to stir at 80.degree. C. for 2 h. Progress of
reaction was monitored by TLC and LCMS. After completion, reaction
mixture was diluted with water (10 mL) and extracted with ethyl
acetate (1.times.50 mL). Combined organic layer was washed with
brine (1.times.10 mL), dried over anhydrous sodium sulfate and
concentrated under reduced pressure to obtain crude which was
purified using reversed phase chromatography to afford
N-(2-(1-(7-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)azetid-
in-3-yl)ethyl)-N-cyclobutylsulfamamide (13 mg, 14.6%). LCMS: 399
[M+1].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 7.90
(s, 1H), 6.63 (s, 1H), 6.66 (s, 2H), 4.45 (t, J=8.3 Hz, 2H), 4.02
(br. s., 2H), 3.96-3.87 (m, 1H), 3.01 (d, J=5.7 Hz, 2H), 2.76 (br.
s., 1H), 2.39 (s, 3H), 2.06 (d, J=9.6 Hz, 4H), 1.88 (d, J=6.6 Hz,
2H), 1.63-1.48 (m, 2H).
Example-95: Synthesis of
N-(2-(1-(7-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)azetidin-3-yl-
)ethyl)-N-propylsulfamamide, (Compound 1.95)
##STR00674##
[0784] Step-1: Synthesis of tert-butyl
3-(2-oxoethyl)azetidine-1-carboxylate: A suspension of (2.0 g, 9.93
mmol, 1.0 eq) in DCM (50 mL) at 0.degree. C. was added DMP (12.6 g,
29.8 mmol, 3.0 eq) was added portion wise at 0.degree. C. After
addition, the reaction mixture was stirred at RT for 3 h. Progress
of reaction was monitored by TLC. After completion, the reaction
mixture was concentrated under reduced pressure to get residue
which was diluted with water (150 mL) and extracted with DCM
(3.times.250 mL). Combined organic layer was washed with brine
(3.times.50 mL), dried over anhydrous sodium sulfate and
concentrated under reduced pressure to afford tert-butyl
3-(2-oxoethyl)azetidine-1-carboxylate (1.5 g, 76%) which was used
in the next step without purification.
[0785] Step-2: Synthesis of tert-butyl
3-(2-(propylamino)ethyl)azetidine-1-carboxylate: A suspension of
tert-butyl 3-(2-oxoethyl)azetidine-1-carboxylate (250 mg, 1.25
mmol, 1 eq), propylamine (89 mg, 1.50 mmol, 1.2 eq) in methanol (5
mL) was stirred at RT for overnight. After overnight stirring,
NaBH.sub.4 (71 mg, 1.875 mmol, 1.5 eq) was added into above
reaction mixture portion wise at 0.degree. C. and allowed to stir
the reaction mixture for 1 h at 0.degree. C. Progress of reaction
was monitored by TLC. After completion, the reaction mixture was
concentrated under reduced pressure to get residue which was
diluted with water (100 mL) and extracted with ethyl acetate
(3.times.100 mL). Combined organic layer was washed with brine
(3.times.50 mL), dried over anhydrous sodium sulfate and
concentrated under reduced pressure to afford tert-butyl
3-(2-(propylamino)ethyl)azetidine-1-carboxylate (200 mg, 66%) which
was used in the next step without purification.
[0786] Step-3: Synthesis of
tert-butyl3-(2-((N-(tert-butoxycarbonyl)sulfamoyl)(propyl)amino)ethyl)aze-
tidine-1-carboxylate: To a solution of tert-butyl
3-(2-(propylamino)ethyl)azetidine-1-carboxylate (200 mg, 0.825
mmol, 1.0 eq) in DCM (5 mL) were added
N-(tert-butoxycarbonyl)-N-[4-(dimethylazaniumylidene)-1,4-dihydropyridinl-
ylsulfonyl]azanide (299 mg, 0.990 mmol, 1.2 eq) and DIPEA (160 mg,
1.23 mmol, 1.5 eq) and the mixture was allowed to stir at RT for
overnight. Progress of reaction was monitored by TLC. After
completion, reaction mixture was diluted with water (50 mL) and
extracted with DCM (2.times.150 mL). Combined organic layer was
washed with brine (1.times.50 mL), dried over anhydrous sodium
sulfate and concentrated under reduced pressure to afford
tert-butyl3-(2-((N-(tert-butoxycarbonyl)sulfamoyl)(propyl)amino)ethyl)aze-
tidine-1-carboxylate (270 mg, 77.58%).
[0787] Step-4: Synthesis of
N-(2-(azetidin-3-yl)ethyl)-N-propylsulfamamide
2,2,2-trifluoroacetate: To a solution of
tert-butyl3-(2-((N-(tert-butoxycarbonyl)sulfamoyl)(propyl)amino)ethyl)aze-
tidine-1-carboxylate (270 mg, 0.623 mmol, 1 eq) in DCM (4 mL) was
added TFA (0.7 mL) and was allowed to stir at RT for 2 h. Progress
of reaction was monitored by TLC. After completion, reaction
mixture was concentrated under reduced pressure to afford crude
which was triturated with diethyl ether to afford
N-(2-(azetidin-3-yl)ethyl)-N-propylsulfamamide
2,2,2-trifluoroacetate (170 mg, 85.85%)).
[0788] Step-5: Synthesis of
N-(2-(1-(7-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)azetidin-3-yl-
)ethyl)-N-propylsulfamamide: A suspension of
N-(2-(azetidin-3-yl)ethyl)-N-propylsulfamamide
2,2,2-trifluoroacetate (71 mg, 0.223 mmol, 1.0 eq),
4,7-dichloro-5-methylpyrrolo[1,2-f][1,2,4]triazine (45 mg, 0.223
mmol, 1.0 eq) and DIPEA (57.5 mg, 0.446 mmol, 2.0 eq) in DMF (1.0
mL) was allowed to stir at 80.degree. C. for 2 h. Progress of
reaction was monitored by TLC and LCMS. After completion, reaction
mixture was diluted with water (10 mL) and extracted with ethyl
acetate (1.times.50 mL). Combined organic layer was washed with
brine (1.times.10 mL), dried over anhydrous sodium sulfate and
concentrated under reduced pressure to obtain crude product which
was purified using reversed phase chromatography to afford
N-(2-(1-(7-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)azetidin-3-yl-
)ethyl)-N-propylsulfamamide (6.8 mg, 7.8%). LCMS: 387 [M+1].sup.+;
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 7.90 (s, 1H),
6.69-6.59 (m, 3H), 4.45 (t, J=8.8 Hz, 2H), 4.07-3.99 (m, 2H),
3.03-2.93 (m, 4H), 2.76 (br. s., 1H), 2.39 (s, 3H), 1.88 (d, J=7.0
Hz, 2H), 1.58-1.51 (m, 2H), 0.84 (t, J=7.2 Hz, 3H).
Example-96: Synthesis of
N-(2-(6-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-2-azaspiro[3.3]-
heptan-6-yl)-N-methylsulfamamide, (Compound 1.96)
##STR00675##
[0790] A suspension of
N-methyl-N-(2-azaspiro[3.3]heptan-6-yl)sulfamamide
2,2,2-trifluoroacetate (149 mg, 0.492 mmol, 1.0 eq),
4,6-dichloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidine (100 mg, 0.492
mmol, 1.0 eq) and DIPEA (127 mg, 0.984 mmol, 2.0 eq) in DMF (1 mL)
was allowed to stir at 80.degree. C. for 2 h. Progress of reaction
was monitored by TLC and LCMS. After 2 h, reaction mixture was
diluted with water (20 mL) and extracted with ethyl acetate
(1.times.50 mL). Combined organic layer was washed with brine (10
mL), dried over anhydrous sodium sulfate and concentrated under
reduced pressure to get crude which was purified using combiflash
chromatography to afford
N-(2-(6-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-2-azaspiro[3.3]-
heptan-6-yl)-N-methylsulfamamide (24 mg, 13.11%) LCMS: 372
[M+1].sup.+; NMR: .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm
8.03-7.99 (s, 1H), 6.73 (s, 2H), 4.52 (s, 1H), 4.40 (s, 1H), 4.28
(s, 1H), 4.16 (s, 1H), 3.85 (s, 3H), 3.76 (br. s., 1H), 2.54 (s,
3H), 2.37 (br. s., 2H), 2.33 (br. s., 2H)
Example-97: Synthesis of
N-(2-(7-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-azaspiro[3.3]-
heptan-6-yl)-N-propylsulfamamide, (Compound 1.97)
##STR00676##
[0792] Step-1: Synthesis of tert-butyl
6-(propylamino)-2-azaspiro[3.3]heptane-2-carboxylate: To a stirred
solution of tert-butyl 6-oxo-2-azaspiro[3.3]heptane-2-carboxylate
(250 mg, 1.18 mmol, 1 eq) in methanol (5 ml) was added
n-propylamine (84 mg, 1.42 mmol, 1.2 eq) and the reaction mixture
was stirred at RT for overnight. To the reaction mixture,
NaBH.sub.4 (67 mg, 1.77 mmol, 1.5 eq) was added at 0.degree. C. and
then resultant reaction mixture was allowed to stir at 0.degree. C.
for 1 h. Progress of reaction was monitored by TLC and 1H-NMR.
After completion, the reaction mixture was concentrated under
reduced pressure to get residue which was diluted with water (100
mL) and extracted with dichloromethane (2.times.100 mL). Combined
organic layer was dried over anhydrous sodium sulfate and
concentrated under reduced pressure to afford tert-butyl
6-(propylamino)-2-azaspiro[3.3]heptane-2-carboxylate (290 mg, 96%)
which was used in the next step without purification.
[0793] Step-2: Synthesis of tert-butyl
6-((N-(tert-butoxycarbonyl)sulfamoyl)(propyl)amino)-2-azaspiro[3.3]heptan-
e-2-carboxylate: To a solution of tert-butyl
6-(propylamino)-2-azaspiro[3.3]heptane-2-carboxylate (290 mg, 1.14
mmol, 1 eq) in DCM (10 mL) were added
N-(tert-butoxycarbonyl)-N-[4-(dimethylazaniumylidene)-1,4-dihydropyridin--
1ylsulfonyl]azanide (413 mg, 1.36 mmol, 1.2 eq) and DIPEA (0.29 mL,
1.71 mmol, 1.5 eq) and the mixture was allowed to stir at RT for 16
h. Progress of reaction was monitored by TLC and 1H-NMR. After
completion, reaction mixture was concentrated under reduced
pressure to get residue which was washed with TN HCl solution (100
mL) and extracted with ethyl acetate (2.times.100 mL). Combined
organic layer was dried over anhydrous sodium sulfate and
concentrated under reduced pressure to afford tert-butyl
6-((N-(tert-butoxycarbonyl)sulfamoyl)(propyl)amino)-2-azaspiro[3.3]heptan-
e-2-carboxylate (380 mg, 77%).
[0794] Step-3: Synthesis of
N-propyl-N-(2-azaspiro[3.3]heptan-6-yl)sulfamamide
trifluoroacetate: To a solution of tert-butyl
6-((N-(tert-butoxycarbonyl)sulfamoyl)(propyl)amino)-2-azaspiro[3.3]heptan-
e-2-carboxylate (380 mg, 0.87 mmol, 1 eq) in DCM (10 mL) was added
TFA (3 mL) and was allowed to stir at RT for 2 h. Progress of
reaction was monitored by TLC. After completion, the reaction
mixture was concentrated under reduced pressure to afford crude
which was triturated with diethyl ether to afford
N-propyl-N-(2-azaspiro[3.3]heptan-6-yl)sulfamamide trifluoroacetate
(340 mg, 100%).
[0795] Step-4: Synthesis of
N-(2-(7-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-azaspiro[3.3]-
heptan-6-yl)-N-propylsulfamamide: A suspension of
N-propyl-N-(2-azaspiro[3.3]heptan-6-yl)sulfamamide trifluoroacetate
(172 mg, 0.49 mmol, 1 eq),
4,7-dichloro-5-methylpyrrolo[2,1-f][1,2,4]triazine (100 mg, 0.49
mmol, 1 eq) and DIPEA (0.12 mL, 0.74 mmol, 1.5 eq) in DMF (1 mL)
was allowed to stir at 80.degree. C. for 2 h. Progress of reaction
was monitored by LCMS and TLC. After completion, reaction mixture
was poured onto ice cold water (100 mL) and extracted with ethyl
acetate (100 mL). Organic layer was concentrated under reduced
pressure to get crude which was purified using reverse phase column
chromatography to afford
N-(2-(7-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-azaspiro[3.3]-
heptan-6-yl)-N-propylsulfamamide (8 mg, 7%). LCMS: 399 [M+1].sup.+;
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 0.83 (t, J=7.45 Hz,
3H) 1.51 (d, J=7.02 Hz, 2H) 2.32 (d, J=7.89 Hz, 2H) 2.39 (s, 5H)
2.84-2.97 (m, 2H) 3.80-3.94 (m, 1H) 4.30 (br. s., 2H) 4.41 (br. s.,
2H) 6.64 (d, J=9.65 Hz, 3H) 7.90 (s, 1H).
Example-98: Synthesis of
N-(2-(7-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-azaspiro[3.3]-
heptan-6-yl)-N-ethylsulfamamide, (Compound 1.98)
##STR00677##
[0797] Step-1: Synthesis of tert-butyl
6-(ethylamino)-2-azaspiro[3.3]heptane-2-carboxylate: To a stirred
solution of tert-butyl 6-oxo-2-azaspiro[3.3]heptane-2-carboxylate
(250 mg, 1.18 mmol, 1 eq) in methanol (5 mL) was added n-ethylamine
(64 mg, 1.42 mmol, 1.2 eq) and the reaction mixture was stirred at
RT for overnight. To the reaction mixture, NaBH.sub.4 (67 mg, 1.77
mmol, 1.5 eq) was added at 0.degree. C. and then resultant reaction
mixture was allowed to stir at 0.degree. C. for 1 h. Progress of
reaction was monitored by TLC and 1H-NMR. After completion,
reaction mixture was concentrated under reduced pressure to get
residue which was diluted with water (100 mL) and extracted with
dichloromethane (2.times.100 mL). Combined organic layer was dried
over anhydrous sodium sulfate and concentrated under reduced
pressure to afford tert-butyl
6-(ethylamino)-2-azaspiro[3.3]heptane-2-carboxylate (250 mg, 88%)
which was used in the next step without purification.
[0798] Step-2: Synthesis of tert-butyl
6-((N-(tert-butoxycarbonyl)sulfamoyl)(ethyl)amino)-2-azaspiro[3.3]heptane-
-2-carboxylate: To a solution of tert-butyl
6-(ethylamino)-2-azaspiro[3.3]heptane-2-carboxylate (250 mg, 1.04
mmol, 1 eq) in DCM (10 mL) were added
N-(tert-butoxycarbonyl)-N-[4-(dimethylazaniumylidene)-1,4-dihydropyridin--
1ylsulfonyl]azanide (377 mg, 1.24 mmol, 1.2 eq) and DIPEA (0.27 mL,
1.56 mmol, 1.5 eq) and the mixture was allowed to stir at RT for 16
h. Progress of reaction was monitored by TLC and 1H-NMR. After
completion, the reaction mixture was concentrated under reduced
pressure to get residue which was washed with 1N HCl solution (100
mL) and extracted with ethyl acetate (2.times.100 mL). Combined
organic layer was dried over anhydrous sodium sulfate and
concentrated it. The crude was purified by combiflash
chromatography to afford tert-butyl
6-((N-(tert-butoxycarbonyl)sulfamoyl)(ethyl)amino)-2-azaspiro[3.3]heptane-
-2-carboxylate (190 mg, 43%).
[0799] Step-3: Synthesis of
N-ethyl-N-(2-azaspiro[3.3]heptan-6-yl)sulfamamide trifluoroacetate:
To a solution of tert-butyl
6-((N-(tert-butoxycarbonyl)sulfamoyl)(ethyl)amino)-2-azaspiro[3.3]heptane-
-2-carboxylate (190 mg, 0.45 mmol, 1 eq) in DCM (10 mL) was added
TFA (2 mL) and was allowed to stir at RT for 2 h. Progress of
reaction was monitored by TLC. After completion, reaction mixture
was concentrated under reduced pressure to afford crude which was
triturated with diethyl ether to afford
N-ethyl-N-(2-azaspiro[3.3]heptan-6-yl)sulfamamide trifluoroacetate
(109 mg, 72.6%).
[0800] Step-4: Synthesis of
N-(2-(7-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-azaspiro[3.3]-
heptan-6-yl)-N-ethylsulfamamide: A suspension of
N-ethyl-N-(2-azaspiro[3.3]heptan-6-yl)sulfamamide trifluoroacetate
(109 mg, 0.49 mmol, 1 eq),
4,7-dichloro-5-methylpyrrolo[2,1-f][1,2,4]triazine (100 mg, 0.49
mmol, 1 eq) and DIPEA (0.17 mL, 0.99 mmol, 2 eq) in DMF (1 mL) was
allowed to stir at 80.degree. C. for 2 h. Progress of reaction was
monitored by LCMS and TLC. After completion, reaction mixture was
poured onto ice cold water (100 mL) and extracted with ethyl
acetate (100 mL). Combined organic layer was concentrated under
reduced pressure to get crude which was purified using reverse
phase column chromatography to afford
N-(2-(7-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-azaspi-
ro[3.3]heptan-6-yl)-N-ethylsulfamamide (1 mg, 0.8%). LCMS: 385
[M+1].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm
1.01-1.14 (m, 3H) 2.24-2.36 (m, 2H) 2.40 (s, 3H) 2.54 (m, 2H) 3.11
(m, 2H) 3.80-3.94 (m, 1H) 4.30 (s, 2H) 4.42 (s, 2H) 6.64 (d, J=9.21
Hz, 3H) 7.90 (s, 1H).
Example-99: Synthesis of
N-(2-(7-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-azaspiro[3.3]-
heptan-6-yl)-N-(2,2-difluoroethyl)sulfamamide, (Compound 1.99)
##STR00678##
[0802] Step-1: Synthesis of tert-butyl
6-((2,2-difluoroethyl)amino)-2-azaspiro[3.3]heptane-2-carboxylate:
To a stirred solution of tert-butyl
6-oxo-2-azaspiro[3.3]heptane-2-carboxylate (200 mg, 0.94 mmol, 1
eq) in methanol (5 mL) was added 2,2-difluoroethylamine (92 mg,
1.13 mmol, 1.2 eq) and the reaction mixture was stirred at RT for
overnight. To the reaction mixture, NaBH.sub.4 (179 mg, 4.73 mmol,
5 eq) was added at 0.degree. C. and then resultant reaction mixture
was allowed to stir at 0.degree. C. for 1 h. Progress of reaction
was monitored by TLC. After completion, reaction mixture was
concentrated under reduced pressure to get residue which was
diluted with water (100 mL) and extracted with dichloromethane
(2.times.100 mL). Combined organic layer was dried over anhydrous
sodium sulfate and concentrated under reduced pressure to afford
tert-butyl
6-((2,2-difluoroethyl)amino)-2-azaspiro[3.3]heptane-2-carboxylate
(290 mg, 100%) which was used in the next step without
purification.
[0803] Step-2: Synthesis of tert-butyl
6-((N-(tert-butoxycarbonyl)sulfamoyl)(2,2-difluoroethyl)amino)-2-azaspiro-
[3.3]heptane-2-carboxylate: To a solution of tert-butyl
6-((2,2-difluoroethyl)amino)-2-azaspiro[3.3]heptane-2-carboxylate
(290 mg, 1.04 mmol, 1 eq) in DCM (10 mL) were added
N-(tert-butoxycarbonyl)-N-[4-(dimethylazaniumylidene)-1,4-dihydropyridin--
1ylsulfonyl]azanide (380 mg, 1.25 mmol, 1.2 eq) and DIPEA (0.27 mL,
1.57 mmol, 1.5 eq) and the mixture was allowed to stir at RT for 16
h. Progress of reaction was monitored by TLC. After completion,
reaction mixture was concentrated under reduced pressure to get
residue which was washed with 1N HCl solution (100 mL) and
extracted with ethyl acetate (2.times.100 mL). Combined organic
layer was dried over anhydrous sodium sulfate and concentrated it.
The crude was purified by combiflash chromatography to afford
tert-butyl
6-((N-(tert-butoxycarbonyl)sulfamoyl)(2,2-difluoroethyl)amino)-2-azaspiro-
[3.3]heptane-2-carboxylate (190 mg, 38%).
[0804] Step-3: Synthesis of
N-(2,2-difluoroethyl)-N-(2-azaspiro[3.3]heptan-6-yl)sulfamamide
trifluoroacetate: To a solution of tert-butyl
6-((N-(tert-butoxycarbonyl)sulfamoyl)(2,2-difluoroethyl)amino)-2-azaspiro-
[3.3]heptane-2-carboxylate (190 mg, 0.41 mmol, 1 eq) in DCM (10 mL)
was added TFA (2 mL) and was allowed to stir at RT for 2 h.
Progress of reaction was monitored by TLC. After completion,
reaction mixture was concentrated under reduced pressure to afford
crude which was triturated with diethyl ether to afford
N-(2,2-difluoroethyl)-N-(2-azaspiro[3.3]heptan-6-yl)sulfamamide
trifluoroacetate (88 mg, 100%).
[0805] Step-4: Synthesis of
N-(2-(7-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-azaspiro[3.3]-
heptan-6-yl)-N-(2,2-difluoroethyl)sulfamamide: A suspension of
N-(2,2-difluoroethyl)-N-(2-azaspiro[3.3]heptan-6-yl)sulfamamide
trifluoroacetate (88 mg, 0.34 mmol, 1 eq),
4,7-dichloropyrrolo[2,1-f][1,2,4]triazine (70 mg, 0.34 mmol, 1 eq)
and DIPEA (0.12 mL, 0.69 mmol, 2 eq) in DMF (1 mL) was allowed to
stir at 80.degree. C. for 2 h. Progress of reaction was monitored
by LCMS and TLC. After completion, reaction mixture was poured onto
ice cold water (100 mL) and extracted with ethyl acetate (100 mL).
Combined organic layer was dried over anhydrous sodium sulfate and
concentrated under reduced pressure to get crude which was purified
using reverse phase column chromatography to afford
N-(2-(7-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-azaspiro[3.3]-
heptan-6-yl)-N-(2,2-difluoroethyl)sulfamamide (6 mg, 3.8%). LCMS:
421 [M+1].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm
2.25-2.36 (m, 4H) 2.40 (s, 5H) 3.88-4.05 (m, 1H) 4.31 (br. s., 2H)
4.40 (br. s., 2H) 6.01 (t, 1H) 6.63 (s, 1H) 7.01 (br. s., 2H) 7.90
(s, 1H).
Example-100: Synthesis of
N-methyl-N-(2-(5-phenylthieno[2,3-d]pyrimidin-4-yl)-2-azaspiro[3.3]heptan-
-6-yl)sulfamamide, (Compound 1.100)
##STR00679##
[0807] A suspension of
N-methyl-N-(2-azaspiro[3.3]heptan-6-yl)sulfamamide
2,2,2-trifluoroacetate (67 mg, 0.222 mmol, 1.10 eq),
4-chloro-5-phenylthieno[2,3-d]pyrimidine (50 mg, 0.202 mmol, 1.0
eq) and DIPEA (52 mg, 0.404 mmol, 2.0 eq) in DMF (1 mL) was allowed
to stir at 80.degree. C. for 2 h. Progress of reaction was
monitored by TLC and LCMS. After completion, reaction mixture was
diluted with water (20 mL) and extracted with ethyl acetate
(2.times.50 mL). Combined organic layer was washed with brine (10
mL), dried over anhydrous sodium sulfate and concentrated under
reduced pressure to obtain crude product which was purified using
combiflash chromatography to afford
N-methyl-N-(2-(5-phenylthieno[2,3-d]pyrimidin-4-yl)-2-azaspiro[3.3]heptan-
-6-yl)sulfamamide (30 mg, 35.7%) LCMS: 416 [M+1].sup.+; NMR:
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 8.46 (s, 1H), 7.54
(s, 1H), 7.54-7.46 (m, 3H), 7.45-7.38 (m, 2H), 6.62 (s, 2H),
3.64-3.36 (m, 5H), 2.40 (s, 3H), 2.14-1.95 (m, 4H).
Example-101: Synthesis of
N-(2-(7-chloro-2-isopropyl-5-methylpyrrolo[1,2-f][1,2,4]triazin-4-yl)-2-a-
zaspiro[3.3]heptan-6-yl)-N-methylsulfamide, (Compound 1.101)
##STR00680##
[0809] Step-1: Synthesis of ethyl
5-chloro-1-isobutyrimidamido-3-methyl-1H-pyrrole-2-carboxylate: A
mixture of ethyl 1-amino-5-chloro-3-methyl-1H-pyrrole-2-carboxylate
(500 mg, 2.97 mmol, 1 eq) and isobutyronitrile (246.5 mg, 3.56
mmol, 1.2 eq) in 4M HCl in dioxane (4 mL) was allowed to stir at
100.degree. C. for 16 h. Progress of reaction was monitored by TLC.
After completion of reaction, reaction mixture was cooled to RT,
quenched with NaHCO.sub.3 extracted with ethyl acetate (150
ml.times.2). Combined organic layer was washed with brine (50 mL)
and dried over anhydrous sodium sulfate concentrated to get crude
product. The crude product was purified by combi flash
chromatography [silica gel 100-200 mesh, elution 0-40% Ethyl
acetate in hexane] to ethyl
5-chloro-1-isobutyrimidamido-3-methyl-1H-pyrrole-2-carboxylate (470
mg, 70.09%) LCMS: 272.1 [M+1].sup.+
[0810] Step-2: Synthesis of
7-chloro-2-isopropyl-5-methylpyrrolo[1,2-f][1,2,4]triazin-4-ol: To
a solution of ethyl
5-chloro-1-isobutyrimidamido-3-methyl-1H-pyrrole-2-carboxylate (470
mg, 2.08 mmol, 1 eq) in Dioxane (8 mL) was added Cesium carbonate
(1.3 g, 4.165 mmol, 2 eq) at RT and the reaction mixture was
allowed to stir at 85.degree. C. for 30 min. Progress of reaction
was monitored by TLC. After completion, the reaction mixture was
diluted with water (150 mL) and extracted with ethyl acetate (250
ml.times.2). Combined organic layer was washed with brine (50 mL)
and dried over anhydrous sodium sulfate concentrated to get crude,
which was purified by combiflash elution (0-30% ETOAc/Hexane) to
afford
7-chloro-2-isopropyl-5-methylpyrrolo[1,2-f][1,2,4]triazin-4-ol (140
g, 35.86%). LCMS: 226 [M+1].sup.+
[0811] Step-3: Synthesis of
4,7-dichloro-2-isopropyl-5-methylpyrrolo[1,2-f][1,2,4]triazine: A
mixture of
7-chloro-2-cyclopropyl-5-methylpyrrolo[1,2-f][1,2,4]triazin-4-ol
(140 m g, 0.62 mmol, 1 eq) in POCl.sub.3 (3 mL) was allowed to stir
at 120.degree. C. for 2 h. Progress of reaction was monitored by
TLC. After completion reaction mixture was cooled to RT, quenched
with NaHCO.sub.3 to maintain pH-7 and extracted with ethyl acetate
(150 ml.times.2). Combined organic layer was washed with brine (50
mL) and dried over anhydrous sodium sulfate concentrated to get
crude product. The crude product was purified by combi flash
chromatography [silica gel 100-200 mesh, elution 0-10% Ethyl
acetate in hexane] to
4,7-dichloro-2-isopropyl-5-methylpyrrolo[1,2-f][1,2,4]triazine as
yellow solid. (100 mg, 66.03%) LCMS: 244 [M+1].sup.+
[0812] Step-4: Synthesis of
N-(2-(7-chloro-2-isopropyl-5-methylpyrrolo[1,2-f][1,2,4]triazin-4-yl)-2-a-
zaspiro[3.3]heptan-6-yl)-N-methylsulfamide: To a solution of,
4,7-dichloro-2-isopropyl-5-methylpyrrolo[1,2-f][1,2,4]triazine (100
mg, 0.411 mmol, 1.0 eq) and
N-methyl-N-(2-azaspiro[3.3]heptan-6-yl)sulfamamide trifluoroacetate
(126 mg, 0.617 mmol, 1 eq) in DMF (2 ml) was added
N,N-diisopropylethylamine (0.1 mL, 0.616 mmol, 1.5 eq). The
reaction mixture was allowed to stir at 90.degree. C. for
overnight. Progress of reaction was monitored by LCMS. After
completion, reaction mixture was diluted with water (30 ml)
extracted with ethyl acetate (150 ml.times.2). Combined organic
layer was washed with brine (50 mL) and dried over anhydrous sodium
sulfate concentrated to get crude product, which was purified by
reverse phase chromatography to afford
N-(2-(7-chloro-2-isopropyl-5-methylpyrrolo[1,2-f][1,2,4]triazin-4-yl)-2-a-
zaspiro[3.3]heptan-6-yl)-N-methylsulfamide (5 mg, 2.93%). LCMS:
413.1 [M+1].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm
6.69 (s, 2H), 6.56 (s, 1H), 4.41 (s, 2H), 4.28 (s, 2H), 3.76-3.71
(m, 1H), 2.81-2.76 (m, 1H), 2.53-2.33 (m, 10H), 1.22 (d, J=6.58 Hz,
6H).
Example-102: Synthesis of
N-(2-(7-chloro-5,6-dimethylpyrrolo[1,2-f][1,2,4]triazin-4-yl)-2-azaspiro[-
3.3]heptan-6-yl)-N-methylsulfamamide, (Compound 1.102)
##STR00681##
[0814] Step-1: Synthesis of ethyl
5-chloro-3,4-dimethyl-1H-pyrrole-2-carboxylate: To a solution of
ethyl 3,4-dimethyl-1H-pyrrole-2-carboxylate (500 mg, 2.99 mmol, 1
eq) in DMF (5 mL) was added N-chlorosuccinimide (439 mg, 3.28 mmol,
1.1 eq) at 0.degree. C. and the reaction mixture was allowed to
stir at RT for overnight. Progress of reaction was monitored by
TLC. After completion, to this reaction mixture was added ice-cold
water under stirring, the formed suspension was filtered to get
ethyl 5-chloro-3,4-dimethyl-1H-pyrrole-2-carboxylate (400 mg,
66.33%). LCMS: 202 [M+1].sup.+
[0815] Step-2: Synthesis of ethyl
1-amino-5-chloro-3,4-dimethyl-1H-pyrrole-2-carboxylate: To a
solution of ethyl 5-chloro-3,4-dimethyl-1H-pyrrole-2-carboxylate
(300 mg, 1.48 mmol, 1 eq) in DMF (20 mL) was added Sodium hydride
(0.9 mg, 2.23 mmol, 1.5 eq) at 0.degree. C. and the reaction
mixture was allowed to stir at 0.degree. C. for 15 minutes. To this
reaction mixture was added O-(diphenylphosphoryl)hydroxylamine (520
mg, 2.23 mmol, 1.5 eq) at 0.degree. C. portion wise and allowed to
stir at RT for overnight. Progress of reaction was monitored by
TLC. After completion, the reaction mixture was diluted with water
(250 mL) and extracted with MTEB (250 ml.times.2). Combined organic
layer was washed with brine (50 mL) and dried over anhydrous sodium
sulfate concentrated to get product to afford ethyl
1-amino-5-chloro-3,4-dimethyl-1H-pyrrole-2-carboxylate (200 mg,
62.04%). LCMS: 217 [M+1].sup.+
[0816] Step-3 Synthesis of
7-chloro-5,6-dimethylpyrrolo[1,2-f][1,2,4]triazin-4-ol: A solution
of ethyl 1-amino-5-chloro-3,4-dimethyl-1H-pyrrole-2-carboxylate
(200 mg, 0.92 mmol, 1 eq) in formamide (2 mL) was allowed to stir
at 165.degree. C. for overnight. Progress of reaction is monitored
by TLC. After completion, reaction mixture was diluted with cold
water (30 mL) and allowed to stir for 10 minutes. Solid was
filtered, washed with water followed by hexane and dried under
vacuum to afford 5-methylpyrrolo[1,2-f][1,2,4]triazin-4-ol (70 mg,
38.37%). LCMS: 198 [M+1].sup.+
[0817] Step-4: Synthesis of
4,7-dichloro-5,6-dimethylpyrrolo[1,2-f][1,2,4]triazine: A mixture
of 7-chloro-5,6-dimethylpyrrolo[1,2-f][1,2,4]triazin-4-ol (70 mg,
0.354 mmol, 1 eq) in POCl.sub.3 (1 mL) was allowed to stir at
120.degree. C. for 2 h. Progress of reaction was monitored by TLC.
After completion of reaction, reaction mixture was cooled to RT,
quenched with NaHCO.sub.3 to maintain pH-7 and extracted with ethyl
acetate (150 ml.times.2). Combined organic layer was washed with
brine (50 mL) and dried over anhydrous sodium sulfate concentrated
to get crude product used in next step without purification
4,7-dichloro-5,6-dimethylpyrrolo[1,2-f][1,2,4]triazine as off white
solid. (80 mg, LCMS: 216 [M+1].sup.+
[0818] Step-6: Synthesis of
N-(2-(7-chloro-5,6-dimethylpyrrolo[1,2-f][1,2,4]triazin-4-yl)-2-azaspiro[-
3.3]heptan-6-yl)-N-methylsulfamamide: To a solution of,
4,7-dichloro-5,6-dimethylpyrrolo[1,2-f][1,2,4]triazine (80 mg,
0.370 mmol, 1.0 eq) and
N-methyl-N-(2-azaspiro[3.3]heptan-6-yl)sulfamamide trifluoroacetate
(113 mg, 0.555 mmol, 1.5 eq) in DMF (2 ml) was added
N,N-diisopropylethylamine (0.09 mL, 0.555 mmol, 1.5 eq). The
reaction mixture was allowed to stir at 90.degree. C. for
overnight. Progress of reaction was monitored by LCMS. After
completion, reaction mixture was diluted with water (30 ml)
extracted with ethyl acetate (150 ml.times.2). Combined organic
layer was washed with brine (50 mL) and dried over anhydrous sodium
sulfate and concentrated to get crude product. The crude was
purified by reverse phase chromatography to get
N-(2-(7-chloro-5,6-dimethylpyrrolo[1,2-f][1,2,4]triazin-4-yl)-2-azaspiro[-
3.3]heptan-6-yl)-N-methylsulfamamide (90 mg, 63.15%). LCMS: 385.1
[M+1].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 7.87
(s, 1H), 6.67 (brs., 2H), 4.41 (s, 2H), 4.28 (s, 2H), 3.81-3.71 (m,
1H), 2.53-2.48 (m, 3H), 2.41-2.29 (m, 7H), 2.13 (s, 3H).
Example-103: Synthesis of
N-(2-(7-chloro-2,5-dimethylpyrrolo[1,2-f][1,2,4]triazin-4-yl)-2-azaspiro[-
3.3]heptan-6-yl)-N-propylsulfatamide, (Compound 1.103)
##STR00682##
[0820] Step-1: Synthesis ethyl
1-acetimidamido-5-chloro-3-methyl-1H-pyrrole-2-carboxylate: The
mixture of ethyl 1-amino-5-chloro-3-methyl-1H-pyrrole-2-carboxylate
(500 mg, 2.97 mmol, 1 eq) and Acetonitrile (145.8 mg, 3.55 mmol,
1.2 eq) in 4M HCl in dioxane (4 mL) was allowed to stir at
100.degree. C. for 16 h. Progress of reaction was monitored by TLC.
After completion of reaction, reaction mixture was cooled to RT,
quenched with NaHCO.sub.3 extracted with ethyl acetate (150
ml.times.2).). Combined organic layer was washed with brine (50 mL)
and dried over anhydrous sodium sulfate concentrated to get crude
product which was used in next step without purification ethyl
1-acetimidamido-5-chloro-3-methyl-1H-pyrrole-2-carboxylate (800 mg,
133.04%) LCMS: 244 [M+1].sup.+
[0821] Step-2: Synthesis of
7-chloro-2,5-dimethylpyrrolo[1,2-f][1,2,4]triazin-4-ol: To a
solution of ethyl
1-acetimidamido-5-chloro-3-methyl-1H-pyrrole-2-carboxylate (800 mg,
3.28 mmol, 1 eq) in Dioxane (15 mL) was added Cesium carbonate
(2.13 mg, 6.56 mmol, 2 eq) at RT and the reaction mixture was
allowed to stir at 85.degree. C. for 30 min. Progress of reaction
was monitored by TLC. After completion, the reaction mixture was
diluted with water (150 mL) and extracted with ethyl acetate (250
ml.times.2), Combined organic layer was washed with brine (50 mL)
and dried over anhydrous sodium sulfate concentrated to get crude
was purified by combiflash elution (0-30% ETOAc/Hexane) to afford
7-chloro-2,5-dimethylpyrrolo[1,2-f][1,2,4]triazin-4-ol (385 mg,
59.34%). LCMS: 198 [M+1].sup.+
[0822] Step-3: Synthesis of
4,7-dichloro-2,5-dimethylpyrrolo[1,2-f][1,2,4]triazine: The mixture
of 7-chloro-2,5-dimethylpyrrolo[1,2-f][1,2,4]triazin-4-ol (385 m g,
1.94 mmol, 1 eq) in POCl.sub.3 (5 mL) was allowed to stir at
120.degree. C. for 2 h. Progress of reaction was monitored by TLC.
After completion reaction mixture was cooled to RT, quenched with
NaHCO.sub.3 to maintain pH-7 and extracted with ethyl acetate (150
ml.times.2). Combined organic layer was washed with brine (50 mL)
and dried over anhydrous sodium sulfate concentrated to get crude
product. The crude product was purified by combi flash
chromatography [silica gel 100-200 mesh, elution 0-10% Ethyl
acetate in hexane] to
4,7-dichloro-2,5-dimethylpyrrolo[1,2-f][1,2,4]triazine (300 mg,
71.26%) as yellow solid. LCMS: 216 [M+1].sup.+
[0823] Step-4: Synthesis of
N-(2-(7-chloro-2,5-dimethylpyrrolo[1,2-f][1,2,4]triazin-4-yl)-2-azaspiro[-
3.3]heptan-6-yl)-N-propylsulfatamide: To a solution of
4,7-dichloro-2,5-dimethylpyrrolo[1,2-f][1,2,4]triazine (150 mg,
0.694 mmol, 1 eq) and
N-butyl-N-(2-azaspiro[3.3]heptan-6-yl)sulfamamide trifluoroacetate
(242 mg, 1.04 mmol, 1 eq) in DMF (3 ml), N,N-diisopropylethylamine
(0.18 mL, 1.04 mmol, 1.5 eq) was added. The reaction mixture was
allowed to stir at 90.degree. C. for overnight. Progress of
reaction was monitored by LCMS. After completion, reaction mixture
was diluted with water (30 ml) extracted with ethyl acetate (150
ml.times.2). Combined organic layer was washed with brine (50 mL)
and dried over anhydrous sodium sulfate concentrated to get crude
product. which was purified by reverse phase chromatography to
afford
N-(2-(7-chloro-2,5-dimethylpyrrolo[1,2-f][1,2,4]triazin-4-yl)-2-azaspiro[-
3.3]heptan-6-yl)-N-propylsulfatamide (50 mg, 17.44%). LCMS:
413[M+1].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm
6.65 (s, 2H), 6.55 (s, 1H), 4.40 (s, 2H), 4.28 (s, 2H), 3.87-3.82
(m, 1H), 2.94-2.87 (m, 2H), 2.49-2.23 (m, 10H), 1.51-1.46 (m, 2H),
0.83-0.78 (m, 3H).
Example-104: Synthesis of
N-(2-(1-(7-chloro-5-methylpyrrolo[1,2-f][1,2,4]triazin-4-yl)azetidin-3-yl-
)ethyl)sulfamamide, (Compound 1.104)
##STR00683##
[0825] To a solution of 3-(N-sulfamoyl) (ethyl) amino) azetidine
(177 mg, 0.989 mmol, 2.0 eq) and
4,7-dichloro-5-methylpyrrolo[1,2-f][1,2,4]triazine (100 mg, 0.494
mmol, 1 eq) in DMF (2 ml) was added N,N-diisopropylethylamine (0.12
mL, 0.741 mmol, 1.5 eq). The reaction mixture was allowed to stir
at 90.degree. C. for 4 h. Progress of reaction was monitored by
LCMS. After completion, reaction mixture was diluted with water (30
ml) extracted with ethyl acetate (50 ml.times.3). Combined organic
layer was washed with brine (50 mL) and dried over anhydrous sodium
sulfate concentrated to get crude product. which was purified by
reversed phase chromatography to afford
N-(2-(1-(7-chloro-5-methylpyrrolo[1,2-f][1,2,4]triazin-4-yl)azetidin-3-yl-
)ethyl)sulfamamide (12 mg, 7.05%). LCMS: 345.4 [M+1].sup.+; .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 7.90 (s, 1H), 6.63 (s, 1H),
6.53-6.48 (m, 2H), 4.46-4.41 (m, 2H), 4.02-3.97 (m, 2H), 2.91-2.85
(m, 2H), 2.84-2.77 (m, 1H), 2.39 (s, 3H), 1.85-1.78 (m, 2H).
Example-105: Synthesis of
N-methyl-N-(2-(1-methyl-JH-pyrazolo[3,4-d]pyrimidin-4-yl)-2-azaspiro[3.3]-
heptan-6-yl)sulfamamide, (Compound 1.105)
##STR00684##
[0827] A suspension of
N-methyl-N-(2-azaspiro[3.3]heptan-6-yl)sulfamamide
2,2,2-trifluoroacetate (179 mg, 0.593 mmol, 1.0 eq),
4-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidine (100 mg, 0.593 mmol,
1.0 eq) and DIPEA (153 mg, 1.186 mmol, 2.0 eq) in DMF (1 mL) was
allowed to stir at 80.degree. C. for 2 h. Progress of reaction was
monitored by TLC and LCMS. After completion, reaction mixture was
diluted with water (20 mL) and extracted with ethyl acetate
(2.times.50 mL). Combined organic layer was washed with brine (10
mL), dried over anhydrous sodium sulfate and concentrated under
reduced pressure to get crude which was purified using reverse
phase chromatography to afford
N-methyl-N-(2-(1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-2-azaspiro[3.3]-
heptan-6-yl)sulfamamide (18 mg, 9%). LCMS: 338 [M+1].sup.+; NMR:
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 8.22 (s, 1H), 7.99
(br. s., 1H), 6.72 (s, 2H), 4.61-4.05 (m, 4H) 3.89 (s, 3H),
3.82-3.61 (m, 1H), 2.55 (s, 3H), 2.45-2.30 (m, 4H).
Example-106: Synthesis of
N-(2-(7-chloro-2-(4-fluorophenyl)-5-methylpyrrolo[2,1-f][1,2,4]triazin-4--
yl)-2-azaspiro[3.3]heptan-6-yl)-N-methylsulfamamide, (Compound
1.106)
##STR00685##
[0829] Step-1: Synthesis of ethyl
5-chloro-1-(4-fluorobenzimidamido)-3-methyl-1H-pyrrole-2-carboxylate:
A mixture of ethyl
1-amino-5-chloro-3-methyl-1H-pyrrole-2-carboxylate (400 mg, 1.97
mmol, 1.0 eq), 4-fluorobenzonitrile (286 mg, 2.37 mmol, 1.2 eq) in
HCl in dioxane (4.0 M) (8 mL) was allowed to stir at 100.degree. C.
for 2 h. Progress of reaction is monitored by TLC. After
completion, the reaction mixture was neutralized with aqueous
NaHCO.sub.3 solution (10 mL) and extracted with ethyl acetate
(2.times.100 mL). Combined organic layer was washed with brine (50
mL), dried over anhydrous sodium sulfate and concentrated under
reduced pressure to obtain crude product which was purified by
combi flash chromatography to afford ethyl
5-chloro-1-(4-fluorobenzimidamido)-3-methyl-1H-pyrrole-2-carboxylate
(70 mg, 11%). LCMS: 324 [M+1].sup.+
[0830] Step-2: Synthesis of
7-chloro-2-(4-fluorophenyl)-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-ol:
A suspension of ethyl
5-chloro-1-(4-fluorobenzimidamido)-3-methyl-1H-pyrrole-2-carboxylate
(70 mg, 0.216 mmol, 1.0 eq) Cs.sub.2CO.sub.3 (106 mg, 0.324 mmol,
1.5 eq) in Dioxane (3 mL) was allowed to stir at 100.degree. C. for
2 h. Progress of reaction was monitored by TLC. After completion,
reaction mixture was diluted with cold water (20 mL) and extracted
with ethyl acetate (2.times.50 mL). Combined organic layer was
washed with brine (10 mL), dried over anhydrous sodium sulfate and
concentrated under reduced pressure to give
7-chloro-2-(4-fluorophenyl)-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-ol
(52 mg, 86.66%). LCMS: 278 [M+1].sup.+
[0831] Step-3: Synthesis of
4,7-dichloro-2-(4-fluorophenyl)-5-methylpyrrolo[2,1-f][1,2,4]triazine:
A mixture of
7-chloro-2-(4-fluorophenyl)-5-methylpyrrolo[1,2-f][1,2,4]triazin-4-ol
(50 mg, 0.179 mmol, 1.0 eq) in phosphoryl trichloride (0.3 mL) was
allowed to stir at 130.degree. C. for 2 h. Progress of reaction is
monitored by TLC. After completion, reaction mixture was diluted
with cold water (30 mL) and extracted with ethyl acetate
(3.times.15 mL). Combined organic layer was washed with brine (20
mL), dried over anhydrous sodium sulfate and concentrated under
reduced pressure to give
4,7-dichloro-2-(4-fluorophenyl)-5-methylpyrrolo[2,1-f][1,2,4]triazine
(47 mg, 88.67%). LCMS: 298 [M+1].sup.+
[0832] Step-4: Synthesis of
N-(2-(7-chloro-2-(4-fluorophenyl)-5-methylpyrrolo[2,1-f][1,2,4]triazin-4--
yl)-2-azaspiro[3.3]heptan-6-yl)-N-methylsulfamamide: A suspension
of
4,7-dichloro-2-(4-fluorophenyl)-5-methylpyrrolo[2,1-f][1,2,4]triazine
(45 mg, 0.151 mmol, 1.0 eq),
N-methyl-N-(2-azaspiro[3.3]heptan-6-yl)sulfamamide
2,2,2-trifluoroacetate (50 mg, 0.166 mmol, 1.1 eq) and DIPEA (40
mg, 0.302 mmol, 2.0 eq) in DMF (1 mL) was allowed to stir at
80.degree. C. for 2 h. Progress of reaction was monitored by TLC
and LCMS. After completion, reaction mixture was diluted with water
(20 mL) and extracted with ethyl acetate (1.times.50 mL). Combined
organic layer was washed with brine (10 mL), dried over anhydrous
sodium sulfate and concentrated under reduced pressure to get crude
product which was purified by using combi flash chromatography to
afford
N-(2-(7-chloro-2-(4-fluorophenyl)-5-methylpyrrolo[2,1-f][1,2,4]tri-
azin-4-yl)-2-azaspiro[3.3]heptan-6-yl)-N-methylsulfamamide (11 mg,
15.71%). LCMS: 465 [M+1].sup.+; NMR: 1H NMR (400 MHz, DMSO-d.sub.6)
.delta. ppm 8.38-8.23 (m, 2H), 7.32 (t, J=8.8 Hz, 2H), 6.80-6.62
(m, 3H), 4.53 (s, 2H), 4.41 (s, 2H), 3.84-3.75 (m, 1H), 2.55 (s,
3H), 2.43 (s, 3H), 2.39-2.27 (m, 4H).
Example-107: Synthesis of
N-(3-(1-(7-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)azetidin-3-yl-
)propyl)-N-methylsulfamamide, (Compound 1.107)
##STR00686## ##STR00687##
[0834] Step-1: Synthesis of tert-butyl
3-(3-oxopropyl)azetidine-1-carboxylate: A suspension of tert-butyl
3-(3-hydroxypropyl)azetidine-1-carboxylate (500 mg, 2.32 mmol, 1.0
eq) in DCM (15 mL) at 0.degree. C. was added DMP (1.48 g, 3.48
mmol, 1.5 eq) was added portion wise at 0.degree. C. After
addition, the reaction mixture was stirred at RT for overnight.
Progress of reaction was monitored by TLC. After completion, the
reaction mixture was diluted with water (50 mL) and extracted with
DCM (3.times.50 mL). Combined organic layer was washed with brine
(1.times.50 mL), dried over anhydrous sodium sulfate and
concentrated under reduced pressure to afford tert-butyl
3-(3-oxopropyl)azetidine-1-carboxylate (520 mg, 85%) which was used
in the next step without purification.
[0835] Step-2: Synthesis of tert-butyl
3-(3-(methylamino)propyl)azetidine-1-carboxylate: A suspension of
tert-butyl 3-(3-oxopropyl)azetidine-1-carboxylate (500 mg, 2.33
mmol, 1.0 eq), Methylamine (1.4 mL, 2.79 mmol, 1.2 eq) in methanol
(10 mL) was stirred at RT for overnight. After overnight stirring,
NaBH.sub.4 (132 mg, 3.49 mmol, 1.5 eq) was added into above
reaction mixture portion wise at 0.degree. C. and allowed to stir
the reaction mixture for 1 hr at 0.degree. C. Progress of reaction
was monitored by TLC. After completion, the reaction mixture was
concentrated under reduced pressure to get residue which was
diluted with water (50 mL) and extracted with ethyl acetate
(3.times.50 mL). Combined organic layer was washed with brine
(1.times.50 mL), dried over anhydrous sodium sulfate and
concentrated under reduced pressure to afford tert-butyl
3-(3-(methylamino)propyl)azetidine-1-carboxylate (420 mg, 78.9%)
which was used in the next step without purification.
[0836] Step-3: Synthesis of tert-butyl
3-(3-((N-(tert-butoxycarbonyl)sulfamoyl)(methyl)amino)propyl)azetidine-1--
carboxylate: To a solution of tert-butyl
3-(3-(methylamino)propyl)azetidine-1-carboxylate (420 mg, 1.84
mmol, 1.0 eq) in DCM (10 mL) were added
N-(tert-butoxycarbonyl)-N-[4-(dimethylazaniumylidene)-1,4-dihydropyridinl-
ylsulfonyl]azanide (669 mg, 2.20 mmol, 1.2 eq) and DIPEA (356 mg,
2.76 mmol, 1.5 eq) and the mixture was allowed to stir at RT for
overnight. Progress of reaction was monitored by TLC. After
completion, reaction mixture was diluted with water (50 mL) and
extracted with DCM (2.times.150 mL). Combined organic layer was
washed with brine (1.times.50 mL), dried over anhydrous sodium
sulfate and concentrated under reduced pressure. Crude was purified
by combi flash chromatography to afford tert-butyl
3-(3-((N-(tert-butoxycarbonyl)sulfamoyl)(methyl)amino)propyl)azetidine-1--
carboxylate (150 mg, 20%).
[0837] Step-4: Synthesis of
N-(3-(azetidin-3-yl)propyl)-N-methylsulfamamide
2,2,2-trifluoroacetate: To a solution of tert-butyl
3-(3-((N-(tert-butoxycarbonyl)sulfamoyl)(methyl)amino)propyl)azetidine-1--
carboxylate (150 mg, 0.368 mmol, 1 eq) in DCM (4 mL) was added TFA
(1 mL) and was allowed to stir at RT for 2 h. Progress of reaction
was monitored by TLC. After completion, reaction mixture was
concentrated under reduced pressure which was triturated with
diethyl ether to afford
N-(3-(azetidin-3-yl)propyl)-N-methylsulfamamide
2,2,2-trifluoroacetate (130 mg, 89%).
[0838] Step-5: Synthesis of
N-(3-(1-(7-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)azetidin-3-yl-
)propyl)-N-methylsulfamamide: A suspension of
N-(3-(azetidin-3-yl)propyl)-N-methylsulfamamide
2,2,2-trifluoroacetate (64 mg, 0.199 mmol, 1.0 eq),
4,7-dichloro-5-methylpyrrolo[2,1-f][1,2,4]triazine (40 mg, 0.199
mmol, 1.0 eq) and DIPEA (51.3 mg, 0.398 mmol, 2.0 eq) in DMF (1.0
mL) was allowed to stir at 80.degree. C. for 2 h. Progress of
reaction was monitored by TLC and LCMS. After completion, reaction
mixture was diluted with water (10 mL) and extracted with ethyl
acetate (2.times.50 mL). Combined organic layer was washed with
brine (1.times.10 mL), dried over anhydrous sodium sulfate and
concentrated under reduced pressure to obtain crude product which
was purified by reversed phase chromatography to afford
N-(3-(1-(7-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)aze-
tidin-3-yl)propyl)-N-methylsulfamamide (12 mg, 16.2%). LCMS:
373[M+1].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm
7.90 (s, 1H), 6.66 (m, 3H), 4.45 (t, J=8.8 Hz, 2H), 3.99 (dd,
J=5.7, 8.8 Hz, 2H), 2.91 (t, J=6.8 Hz, 2H), 2.79-2.69 (m, 1H) 2.61
(s, 3H), 2.39 (s, 3H), 1.61 (t, J=7.7 Hz, 2H), 1.52 (d, J=7.0 Hz,
2H)
Example-108: Synthesis of
N-(2-(2-amino-9H-purin-6-yl)-2-azaspiro[3.3]heptan-6-yl)-N-methylsulfamam-
ide, (Compound 1.108)
##STR00688##
[0840] A suspension of
N-methyl-N-(2-azaspiro[3.3]heptan-6-yl)sulfamamide
2,2,2-trifluoroacetate (100 mg, 0.589 mmol, 1.0 eq),
6-chloro-9H-purin-2-amine (214 mg, 0.707 mmol, 1.2 eq) and DIPEA
(152 mg, 1.17 mmol, 2.0 eq) in Ethanol (4 mL) was allowed to stir
at 90.degree. C. for overnight. Progress of reaction was monitored
by TLC and LCMS. After completion, solvent was removed under
reduced pressure. Residue was diluted in 50 mL of water and
extracted with DCM (2.times.50 mL). Aqueous layer was lyophilized
and solid product was washed with methanol and filtered through
Buchner funnel to afford
N-(2-(2-amino-9H-purin-6-yl)-2-azaspiro[3.3]heptan-6-yl)-N-methylsulfamam-
ide (48 mg, 24.12%) LCMS: 339 [M+1].sup.+; NMR: .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. ppm 12.20 (br. s., 1H), 7.71 (br. s.,
1H), 6.70 (s, 2H), 5.95 (br. s., 2H), 4.31 (br. s., 2H), 4.20 (br.
s., 2H), 3.73 (td, J=8.2, 16.6 Hz, 1H), 2.53 (s, 3H), 2.46-2.37 (m,
2H), 2.37-2.24 (m, 2H)
Example-109: Synthesis of
N-(2-(7-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-azaspiro[3.3]-
heptan-6-yl)-N-(4-(trifluoromethyl)benzyl)sulfamamide, (Compound
1.109)
##STR00689## ##STR00690##
[0842] Step-1: Synthesis of tert-butyl
6-(4-(trifluoromethyl)benzylamino)-2-azaspiro[3.3]heptane-2-carboxylate:
To a stirred solution of tert-butyl
6-oxo-2-azaspiro[3.3]heptane-2-carboxylate (200 mg, 0.946 mmol, 1
eq) in methanol (5 mL) was added
(4-(trifluoromethyl)phenyl)methanamine (199 mg, 1.13 mmol, 1.2 eq)
and the reaction mixture was stirred at RT for overnight. To the
reaction mixture, NaBH.sub.4 (54 mg, 1.41 mmol, 1.5 eq) was added
at 0.degree. C. and then resultant reaction mixture was allowed to
stir at 0.degree. C. for 1 h. Progress of reaction was monitored by
TLC. After completion, reaction mixture was concentrated under
reduced pressure to get residue which was diluted with water (50
mL) and extracted with dichloromethane (2.times.50 mL). Combined
organic layer was dried over anhydrous sodium sulfate and
concentrated under reduced pressure to afford tert-butyl
6-(4-(trifluoromethyl)benzylamino)-2-azaspiro[3.3]heptane-2-carboxylate
(210 mg, 60%) which was used in the next step without
purification.
[0843] Step-2: Synthesis of tert-butyl
6-((N-(tert-butoxycarbonyl)sulfamoyl)(4-(trifluoromethyl)benzyl)amino)-2--
azaspiro[3.3]heptane-2-carboxylate: To a solution of tert-butyl
6-(4-(trifluoromethyl)benzylamino)-2-azaspiro[3.3]heptane-2-carboxylate
(200 mg, 0.539 mmol, 1 eq) in DCM (10 mL) were added
N-(tert-butoxycarbonyl)-N-[4-(dimethylazaniumylidene)-1,4-dihydropyridin--
1ylsulfonyl]azanide (195 mg, 0.647 mmol, 1.2 eq) and DIPEA (104 mg,
0.808 mmol, 1.5 eq) and the mixture was allowed to stir at RT for
overnight. Progress of reaction was monitored by TLC. After
completion, the reaction mixture was concentrated under reduced
pressure to get residue which was washed with 1N HCl solution (50
mL) and extracted with ethyl acetate (2.times.50 mL). Combined
organic layer was dried over anhydrous sodium sulfate and
concentrated under reduced pressure to afford tert-butyl
6-((N-(tert-butoxycarbonyl)sulfamoyl)(4-(trifluoromethyl)benzyl)amino)-2--
azaspiro[3.3]heptane-2-carboxylate (260 mg, 87.8%).
[0844] Step-3: Synthesis of
N-(2-azaspiro[3.3]heptan-6-yl)-N-(4-(trifluoromethyl)benzyl)sulfamamide
2,2,2-trifluoroacetate: To a solution of tert-butyl
6-((N-(tert-butoxycarbonyl)sulfamoyl)(4-(trifluoromethyl)benzyl)amino)-2--
azaspiro[3.3]heptane-2-carboxylate (260 mg, 0.578 mmol, 1 eq) in
DCM (5 mL) was added TFA (1.5 mL) and was allowed to stir at RT for
2 h. Progress of reaction was monitored by TLC. After completion,
reaction mixture was concentrated under reduced pressure to afford
crude which was triturated with diethyl ether to afford
N-(2-azaspiro[3.3]heptan-6-yl)-N-(4-(trifluoromethyl)benzyl)sulfamamide
2,2,2-trifluoroacetate (180 mg, 70%).
[0845] Step-4: Synthesis of
N-(2-(7-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-azaspiro[3.3]-
heptan-6-yl)-N-(4-(trifluoromethyl)benzyl)sulfamamide: A suspension
of
N-(2-azaspiro[3.3]heptan-6-yl)-N-(4-(trifluoromethyl)benzyl)sulfamamide
2,2,2-trifluoroacetate (138 mg, 0.298 mmol, 1.0 eq),
4,7-dichloro-5-methylpyrrolo[2,1-f][1,2,4]triazine (60 mg, 0.298
mmol, 1.0 eq) and DIPEA (77 mg, 0.596 mmol, 2.0 eq) in DMF (1.0 mL)
was allowed to stir at 80.degree. C. for 2 h. Progress of reaction
was monitored by LCMS and TLC. After 2 h, reaction mixture was
diluted with water (10 mL) and extracted with ethyl acetate
(1.times.50 mL). Combined organic layer was washed with brine
(1.times.10 mL) and dried over anhydrous sodium sulfate,
Concentrated under reduced pressure to obtain crude product which
was purified using reversed phase chromatography to afford
N-(2-(7-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-azaspiro[3.3]-
heptan-6-yl)-N-(4-(trifluoromethyl)benzyl)sulfamamide (10 mg,
6.53%). LCMS: 515 [M+1].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. ppm 7.92 (br. s., 1H) 7.71 (m, 2H), 7.61 (m, 2H), 6.96 (br.
s., 2H), 6.73 (s, 1H), 4.31 (s, 2H), 4.28 (s, 2H), 4.22 (s, 2H),
4.12 (in, 1H), 2.43 (m, 2H), 2.42 (s, 3H), 2.37-2.24 (m, 2H).
Example-110: Synthesis of
N-(2-(7-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-azaspiro[3.3]-
heptan-6-yl)-N-cyclopentylsulfamamide, (Compound 1.110)
##STR00691##
[0847] Step-1: Synthesis of tert-butyl
6-(cyclopentylamino)-2-azaspiro[3.3]heptane-2-carboxylate: To a
stirred solution of tert-butyl
6-oxo-2-azaspiro[3.3]heptane-2-carboxylate (500 mg, 2.36 mmol, 1
eq) in methanol (5 mL) was added cyclopentylamine (241 mg, 2.84
mmol, 1.2 eq) and the reaction mixture was stirred at RT for
overnight. To the reaction mixture, NaBH.sub.4 (134 mg, 3.55 mmol,
1.5 eq) was added at 0.degree. C. and then resultant reaction
mixture was allowed to stir at 0.degree. C. for 1 h. Progress of
reaction was monitored by TLC and 1H-NMR. After completion,
reaction mixture was concentrated under reduced pressure to get
residue which was diluted with water (100 mL) and extracted with
dichloromethane (2.times.100 mL). Combined organic layer was dried
over anhydrous sodium sulfate, concentrated under reduced pressure
to afford tert-butyl
6-(cyclopentylamino)-2-azaspiro[3.3]heptane-2-carboxylate (650 mg,
98%) which was used in the next step without purification.
[0848] Step-2: Synthesis of tert-butyl
6-((N-(tert-butoxycarbonyl)sulfamoyl)(cyclopentyl)amino)-2-azaspiro[3.3]h-
eptane-2-carboxylate: To a solution of tert-butyl
6-(cyclopentylamino)-2-azaspiro[3.3]heptane-2-carboxylate (650 mg,
2.31 mmol, 1 eq) in DCM (10 mL) were added
N-(tert-butoxycarbonyl)-N-[4-(dimethylazaniumylidene)-1,4-dihydropyridin--
1ylsulfonyl]azanide (840 mg, 2.78 mmol, 1.2 eq) and DIPEA (0.6 mL,
3.47 mmol, 1.5 eq) and the mixture was allowed to stir at RT for 16
h. Progress of reaction was monitored by TLC and 1H-NMR. After
completion, the reaction mixture was concentrated under reduced
pressure to get residue which was washed with 1N HCl solution (100
mL) and extracted with ethyl acetate (2.times.100 mL). Combined
organic layer was dried over anhydrous sodium sulfate and
concentrated it. The crude was purified by combiflash
chromatography to afford tert-butyl
6-((N-(tert-butoxycarbonyl)sulfamoyl)(cyclopentyl)amino)-2-azaspiro[3.3]h-
eptane-2-carboxylate (750 mg, 70%).
[0849] Step-3: Synthesis of
N-cyclopentyl-N-(2-azaspiro[3.3]heptan-6-yl)sulfamamide
trifluoroacetate: To a solution of tert-butyl
6-((N-(tert-butoxycarbonyl)sulfamoyl)(cyclopentyl)amino)-2-azaspiro[3.3]h-
eptane-2-carboxylate (750 mg, 1.63 mmol, 1 eq) in DCM (10 mL) was
added TFA (4 mL) and was allowed to stir at RT for 2 h. Progress of
reaction was monitored by TLC. After completion, the reaction
mixture was concentrated under reduced pressure to afford crude
which was triturated with diethyl ether to afford
N-cyclopentyl-N-(2-azaspiro[3.3]heptan-6-yl)sulfamamide
trifluoroacetate (600 mg, 98%).
[0850] Step-4: Synthesis of
N-(2-(7-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-azaspiro[3.3]-
heptan-6-yl)-N-cyclopentylsulfamamide: A suspension of
N-cyclopentyl-N-(2-azaspiro[3.3]heptan-6-yl)sulfamamide
trifluoroacetate (180 mg, 0.48 mmol, 1 eq),
4,7-dichloro-5-methylpyrrolo[2,1-f][1,2,4]triazine (67 mg, 0.33
mmol, 0.7 eq) in IPA (2.5 mL) was allowed to stir at 80.degree. C.
for 2 h. Progress of reaction was monitored by LCMS and TLC. After
2 h, the reaction mixture was concentrated under reduced pressure
to obtain crude was added Water (100 mL) and extracted with ethyl
acetate (100 mL). Combined organic layer was concentrated under
reduced pressure to get crude which was purified using reverse
phase column chromatography to afford
N-(2-(7-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-azaspi-
ro[3.3]heptan-6-yl)-N-cyclopentylsulfamamide (9 mg, 6.3%). LCMS:
425 [M+1].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm
1.42 (br. s., 2H) 1.60 (br. s., 4H) 1.76 (d, J=8.77 Hz, 2H)
2.31-2.44 (br. s., 5H) 2.64-2.70 (m, 2H) 3.71-3.75 (m, 1H)
3.81-3.90 (m, 1H) 4.26 (br. s., 2H) 4.41 (br. s., 2H) 6.61-6.67
(br. s., 3H) 7.88 (s, 1H).
Example-111: Synthesis of
N-(2-(7-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-azaspiro[3.3]-
heptan-6-yl)-N-cyclobutylsulfamamide, (Compound 1.111)
##STR00692##
[0852] Step-1: Synthesis of tert-butyl
6-(cyclobutylamino)-2-azaspiro[3.3]heptane-2-carboxylate: To a
stirred solution of tert-butyl
6-oxo-2-azaspiro[3.3]heptane-2-carboxylate (250 mg, 1.18 mmol, 1
eq) in methanol (5 mL) was added cyclobutylamine (100 mg, 1.42
mmol, 1.2 eq) and the reaction mixture was stirred at RT for
overnight. To the reaction mixture, NaBH.sub.4 (67 mg, 1.77 mmol,
1.5 eq) was added at 0.degree. C. and then resultant reaction
mixture was allowed to stir at 0.degree. C. for 1 h. Progress of
reaction was monitored by TLC and 1H-NMR. After completion, the
reaction mixture was concentrated under reduced pressure to get
residue which was diluted with water (100 mL) and extracted with
dichloromethane (2.times.100 mL). Combined organic layer was dried
over anhydrous sodium sulfate, concentrated under reduced pressure
to afford tert-butyl
6-(cyclobutylamino)-2-azaspiro[3.3]heptane-2-carboxylate (200 mg,
63.4%) which was used in the next step without purification.
[0853] Step-2: Synthesis of tert-butyl
6-((N-(tert-butoxycarbonyl)sulfamoyl)(cyclobutyl)amino)-2-azaspiro[3.3]he-
ptane-2-carboxylate: To a solution of tert-butyl
6-(cyclobutylamino)-2-azaspiro[3.3]heptane-2-carboxylate (200 mg,
0.75 mmol, 1 eq) in DCM (10 mL) were added
N-(tert-butoxycarbonyl)-N-[4-(dimethylazaniumylidene)-1,4-dihydropyridin--
1ylsulfonyl]azanide (272 mg, 0.90 mmol, 1.2 eq) and DIPEA (0.19 mL,
1.12 mmol, 1.5 eq) and the mixture was allowed to stir at RT for 16
h. Progress of reaction was monitored by TLC and 1H-NMR. After
completion, reaction mixture was concentrated under reduced
pressure to get residue which was washed with 1N HCl solution (100
mL) and extracted with ethyl acetate (2.times.100 mL). Combined
organic layer was dried over anhydrous sodium sulfate and
concentrated under reduced pressure to afford tert-butyl
6-((N-(tert-butoxycarbonyl)sulfamoyl)(cyclobutyl)amino)-2-azaspiro[3.3]he-
ptane-2-carboxylate (320 mg, 95.8%).
[0854] Step-3: Synthesis of
N-cyclobutyl-N-(2-azaspiro[3.3]heptan-6-yl)sulfamamide
trifluoroacetic acid: To a solution of tert-butyl
6-((N-(tert-butoxycarbonyl)sulfamoyl)(cyclobutyl)amino)-2-azaspiro[3.3]he-
ptane-2-carboxylate (320 mg, 0.72 mmol, 1 eq) in DCM (5 mL) was
added TFA (2 mL) and was allowed to stir at RT for 2 h. Progress of
reaction was monitored by TLC. After completion, reaction mixture
was concentrated under reduced pressure to afford crude which was
triturated with diethyl ether to afford
N-cyclobutyl-N-(2-azaspiro[3.3]heptan-6-yl)sulfamamide
trifluoroacetic acid (225 mg, 87%) as TFA salt.
[0855] Step-4: Synthesis of
N-(2-(7-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-azaspiro[3.3]-
heptan-6-yl)-N-cyclobutylsulfamamide: A suspension of
N-cyclobutyl-N-(2-azaspiro[3.3]heptan-6-yl)sulfamamide
trifluoroacetic acid (178 mg, 0.49 mmol, 1 eq),
4,7-dichloro-5-methylpyrrolo[1,2-f][1,2,4]triazine (70 mg, 0.34
mmol, 0.7 eq) in IPA (5 mL) was allowed to stir at 80.degree. C.
for 2 h. Progress of reaction was monitored by LCMS and TLC. After
2 h, the reaction mixture was concentrated under reduced pressure.
Water (100 mL) was added into the reaction mixture and extracted
with ethyl acetate (100 mL). Combined organic layer was
concentrated under reduced pressure to get crude which was purified
using reverse phase column chromatography to afford
N-(2-(7-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-azaspi-
ro[3.3]heptan-6-yl)-N-cyclobutylsulfamamide (7 mg, 3.4%). LCMS: 411
[M+1].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.35
(s, 1H) 1.44-1.67 (m, 2H) 1.99-2.13 (m, 2H) 2.18-2.31 (m, 2H)
2.35-2.48 (m, 6H) 3.68-3.81 (m, 2H) 4.28 (s, 2H) 4.42 (s, 2H) 6.63
(s, 1H) 6.70 (s, 2H) 7.90 (s, 1H).
Example-112: Synthesis of
N-benzyl-N-(2-(7-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-azas-
piro[3.3]heptan-6-yl)sulfamamide, (Compound 1.112)
##STR00693##
[0857] Step-1: Synthesis of tert-butyl
6-(benzylamino)-2-azaspiro[3.3]heptane-2-carboxylate: To a stirred
solution of tert-butyl 6-oxo-2-azaspiro[3.3]heptane-2-carboxylate
(300 mg, 1.42 mmol, 1 eq) in methanol (5 mL) was added benzylamine
(182 mg, 1.70 mmol, 1.2 eq) and the reaction mixture was stirred at
RT for overnight. To the reaction mixture, NaBH.sub.4 (80 mg, 2.13
mmol, 1.5 eq) was added at 0.degree. C. and then resultant reaction
mixture was allowed to stir at 0.degree. C. for 1 h. Progress of
reaction was monitored by TLC and 1H-NMR. After completion,
reaction mixture was concentrated under reduced pressure to get
residue which was diluted with water (100 mL) and extracted with
dichloromethane (2.times.100 mL). Combined organic layer was dried
over anhydrous sodium sulfate. Removal of solvent under reduced
pressure to afford tert-butyl
6-(benzylamino)-2-azaspiro[3.3]heptane-2-carboxylate (550 mg, 100%)
which was used in the next step without purification.
[0858] Step-2: Synthesis of tert-butyl
6-(benzyl(N-(tert-butoxycarbonyl)sulfamoyl)amino)-2-azaspiro[3.3]heptane--
2-carboxylate: To a solution of tert-butyl
6-(benzylamino)-2-azaspiro[3.3]heptane-2-carboxylate (550 mg, 1.81
mmol, 1 eq) in DCM (10 mL) were added
N-(tert-butoxycarbonyl)-N-[4-(dimethylazaniumylidene)-1,4-dihydropyridin--
1ylsulfonyl]azanide (659 mg, 2.18 mmol, 1.2 eq) and DIPEA (0.47 mL,
2.72 mmol, 1.5 eq) and the mixture was allowed to stir at RT for 16
h. Progress of reaction was monitored by TLC and 1H-NMR. After
completion, the reaction mixture was concentrated under reduced
pressure to get residue which was washed with 1N HCl solution (100
mL) and extracted with ethyl acetate (2.times.100 mL). Combined
organic layer was dried over anhydrous sodium sulfate and
concentrated under reduced pressure to afford tert-butyl
6-(benzyl(N-(tert-butoxycarbonyl)sulfamoyl)amino)-2-azaspiro[3.3]heptane--
2-carboxylate (700 mg, 80%).
[0859] Step-3: Synthesis of
N-benzyl-N-(2-azaspiro[3.3]heptan-6-yl)sulfamamide
trifluoroacetate: To a solution of tert-butyl
6-((N-(tert-butoxycarbonyl)sulfamoyl)benzylamino)-2-azaspiro[3.3]heptane--
2-carboxylate (700 mg, 1.45 mmol, 1 eq) in DCM (5 mL) was added TFA
(2 mL) and was allowed to stir at RT for 2 h. Progress of reaction
was monitored by TLC. After completion, reaction mixture was
concentrated under reduced pressure to afford crude which was
triturated with diethyl ether to afford
N-benzyl-N-(2-azaspiro[3.3]heptan-6-yl)sulfamamide trifluoroacetate
(400 mg, 48.7%).
[0860] Step-4: Synthesis of
N-benzyl-N-(2-(7-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-azas-
piro[3.3]heptan-6-yl)sulfamamide: A suspension of
(6-N-sulfamoylbenzylamino)-2-azaspiro[3.3]heptane trifluoroacetate
(400 mg, 1.01 mmol, 1 eq),
4,7-dichloro-5-methylpyrrolo[2,1-f][1,2,4]triazine (142 mg, 0.70
mmol, 0.7 eq) in IPA (5 mL) was allowed to stir at 80.degree. C.
for 2 h. Progress of reaction was monitored by LCMS and TLC. After
2 h, the reaction mixture was concentrated under reduced pressure
to obtain crude was added water (100 mL) and extracted with ethyl
acetate (2.times.100 mL). Combined organic layer was concentrated
under reduced pressure to get crude which was purified using
reverse phase column chromatography to afford
N-benzyl-N-(2-(7-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-azas-
piro[3.3]heptan-6-yl)sulfamamide (10 mg, 3.17%). LCMS: 447
[M+1].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm
2.20-2.30 (m, 2H) 2.30-2.45 (m, 5H) 4.04 (dt, J=16.77, 8.50 Hz, 1H)
4.24 (d, J=14.91 Hz, 4H) 4.38 (s, 2H) 6.61 (s, 1H) 6.86 (s, 2H)
7.18-7.27 (m, 1H) 7.33 (q, J=7.60 Hz, 4H) 7.88 (s, 1H).
Example-113: Synthesis of
N-(2-(7-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-azaspiro[3.3]-
heptan-6-yl)-N-neopentylsulfamamide, (Compound 1.113)
##STR00694##
[0862] Step-1: Synthesis of tert-butyl
6-(neopentylamino)-2-azaspiro[3.3]heptane-2-carboxylate: To a
stirred solution of tert-butyl
6-oxo-2-azaspiro[3.3]heptane-2-carboxylate (300 mg, 1.42 mmol, 1
eq) in methanol (5 mL) was added 2,2-dimethylpropan-1-amine (148
mg, 1.70 mmol, 1.2 eq) and the reaction mixture was stirred at RT
for overnight. To the reaction mixture, NaBH.sub.4 (80 mg, 2.13
mmol, 1.5 eq) was added at 0.degree. C. and then resultant reaction
mixture was allowed to stir at 0.degree. C. for 1 h. Progress of
reaction was monitored by TLC and 1H-NMR. After completion,
reaction mixture was concentrated under reduced pressure to get
residue which was diluted with water (100 mL) and extracted with
dichloromethane (2.times.100 mL). Combined organic layer was dried
over anhydrous sodium sulfate, concentrated under reduced pressure
to afford tert-butyl
6-(neopentylamino)-2-azaspiro[3.3]heptane-2-carboxylate (380 mg,
94.7%) which was used in the next step without purification.
[0863] Step-2: Synthesis of tert-butyl
6-((N-(tert-butoxycarbonyl)sulfamoyl)(neopentyl)amino)-2-azaspiro[3.3]hep-
tane-2-carboxylate: To a solution of tert-butyl
6-(ethylamino)-2-azaspiro[3.3]heptane-2-carboxylate (380 mg, 1.34
mmol, 1 eq) in DCM (10 mL) were added
N-(tert-butoxycarbonyl)-N-[4-(dimethylazaniumylidene)-1,4-dihydropyridin--
1ylsulfonyl]azanide (488 mg, 1.61 mmol, 1.2 eq) and DIPEA (0.35 mL,
2.01 mmol, 1.5 eq) and the Reaction mixture was allowed to stir at
RT for 16 h. Progress of reaction was monitored by TLC and 1H-NMR.
After completion, the reaction mixture was concentrated under
reduced pressure to get residue which was washed with 1N HCl
solution (100 mL) and extracted with ethyl acetate (2.times.100
mL). Combined organic layer was dried over anhydrous sodium sulfate
and concentrated it under the reduced pressure to afford tert-butyl
6-((N-(tert-butoxycarbonyl)sulfamoyl)(neopentyl)amino)-2-azaspiro[3.3]hep-
tane-2-carboxylate (400 mg, 64%).
[0864] Step-3: Synthesis of
N-neopentyl-N-(2-azaspiro[3.3]heptan-6-yl)sulfamamide
trifluoroacetate: To a solution of tert-butyl
6-((N-(tert-butoxycarbonyl)sulfamoyl)(neopentyl)amino)-2-azaspiro[3.3]hep-
tane-2-carboxylate (400 mg, 0.86 mmol, 1 eq) in DCM (10 mL) was
added TFA (2 mL) and was allowed to stir at RT for 2 h. Progress of
reaction was monitored by TLC. After completion, reaction mixture
was concentrated under reduced pressure to afford crude which was
triturated with diethyl ether to afford
N-neopentyl-N-(2-azaspiro[3.3]heptan-6-yl)sulfamamide
trifluoroacetate (210 mg, 64%).
[0865] Step-4: Synthesis of
N-(2-(7-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-azaspiro[3.3]-
heptan-6-yl)-N-neopentylsulfamamide: A suspension of
N-neopentyl-N-(2-azaspiro[3.3]heptan-6-yl)sulfamamide
trifluoroacetate (196 mg, 0.52 mmol, 1 eq),
4,7-dichloro-5-methylpyrrolo[2,1-f][1,2,4]triazine (73 mg, 0.36
mmol, 0.7 eq) and DIPEA (0.18 mL, 1.04 mmol, 2 eq) in DMF (1 mL)
was allowed to stir at 80.degree. C. for 2 h. Progress of reaction
was monitored by LCMS and TLC. After 2 h, reaction mixture was
poured onto ice cold water (100 mL) and extracted with ethyl
acetate (100 mL). Combined organic layer was concentrated under
reduced pressure to get crude which was purified using reverse
phase column chromatography to afford
N-(2-(7-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-azaspiro[3.3]-
heptan-6-yl)-N-neopentylsulfamamide (17 mg, 7.6%). LCMS: 427
[M+1].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 0.87
(s, 9H) 2.07 (s, 1H) 2.39 (s, 3H) 2.45 (br. s., 3H) 2.80 (s, 2H)
3.72-3.86 (m, 2H) 4.29 (s, 2H) 4.40 (s, 2H) 6.64 (d, J=6.14 Hz, 2H)
7.90 (s, 1H).
Example-114: Synthesis of
N-butyl-N-(2-(7-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-azasp-
iro[3.3]heptan-6-yl)sulfamamide, (Compound 1.114)
##STR00695##
[0867] Step-1: Synthesis of tert-butyl
6-(butylamino)-2-azaspiro[3.3]heptane-2-carboxylate: To a stirred
solution of tert-butyl 6-oxo-2-azaspiro[3.3]heptane-2-carboxylate
(300 mg, 1.42 mmol, 1 eq) in methanol (5 mL) was added n-butylamine
(124 mg, 1.70 mmol, 1.2 eq) and the reaction mixture was stirred at
RT for overnight. To the reaction mixture, NaBH.sub.4 (80 mg, 2.13
mmol, 1.5 eq) was added at 0.degree. C. and then resultant reaction
mixture was allowed to stir at 0.degree. C. for 1 h. Progress of
reaction was monitored by TLC and 1H-NMR. After completion,
reaction mixture was concentrated under reduced pressure to get
residue which was diluted with water (100 mL) and extracted with
dichloromethane (2.times.100 mL), Combined organic layer was dried
over anhydrous sodium sulfate, concentrated under reduced pressure
to afford tert-butyl
6-(butylamino)-2-azaspiro[3.3]heptane-2-carboxylate (378 mg, 99%)
which was used in the next step without purification.
[0868] Step-2: Synthesis of tert-butyl
6-((N-(tert-butoxycarbonyl)sulfamoyl)(butyl)amino)-2-azaspiro[3.3]heptane-
-2-carboxylate: To a solution of tert-butyl
6-(butylamino)-2-azaspiro[3.3]heptane-2-carboxylate (378 mg, 1.40
mmol, 1 eq) in DCM (10 mL) were added
N-(tert-butoxycarbonyl)-N-[4-(dimethylazaniumylidene)-1,4-dihydropyridin--
1ylsulfonyl]azanide (510 mg, 1.69 mmol, 1.2 eq) and DIPEA (0.36 mL,
2.11 mmol, 1.5 eq) and the mixture was allowed to stir at RT for 16
h. Progress of reaction was monitored by TLC and 1H-NMR. After
completion, the reaction mixture was concentrated under reduced
pressure to get residue which was washed with 1N HCl solution (100
mL) and extracted with ethyl acetate (2.times.100 mL). Combined
organic layer was dried over anhydrous sodium sulfate. Removal of
solvent under reduced pressure to afford tert-butyl
6-((N-(tert-butoxycarbonyl)sulfamoyl)(butyl)amino)-2-azaspiro[3.3]heptane-
-2-carboxylate (600 mg, 95%).
[0869] Step-3: Synthesis of
N-butyl-N-(2-azaspiro[3.3]heptan-6-yl)sulfamamide trifluoroacetate:
To a solution of tert-butyl
6-((N-(tert-butoxycarbonyl)sulfamoyl)(butyl)amino)-2-azaspiro[3.3]heptane-
-2-carboxylate (600 mg, 1.34 mmol, 1 eq) in DCM (10 mL) was added
TFA (3 mL) and was allowed to stir at RT for 2 h. Progress of
reaction was monitored by TLC. After completion, reaction mixture
was concentrated under reduced pressure to afford crude which was
triturated with diethyl ether to afford
N-butyl-N-(2-azaspiro[3.3]heptan-6-yl)sulfamamide trifluoroacetate
(340 mg, 73%).
[0870] Step-4: Synthesis of
N-butyl-N-(2-(7-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-azasp-
iro[3.3]heptan-6-yl)sulfamamide: A suspension of
N-butyl-N-(2-azaspiro[3.3]heptan-6-yl)sulfamamide trifluoroacetate
(180 mg, 0.49 mmol, 1 eq),
4,7-dichloro-5-methylpyrrolo[2,1-f][1,2,4]triazine (70 mg, 0.34
mmol, 0.7 eq) and DIPEA (0.17 mL, 0.99 mmol, 2 eq) in DMF (1 mL)
was allowed to stir at 80.degree. C. for 2 h. Progress of reaction
was monitored by LCMS and TLC. After 2 h, the reaction mixture was
poured onto ice cold water (100 mL) and extracted with ethyl
acetate (100 mL). Combined organic layer was concentrated under
reduced pressure to get crude which was purified using reverse
phase column chromatography to afford
N-butyl-N-(2-(7-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)--
2-azaspiro[3.3]heptan-6-yl)sulfamamide (55 mg, 26%). LCMS: 413
[M+1].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 0.88
(t, J=7.24 Hz, 3H) 1.26 (dq, J=15.02, 7.42 Hz, 2H) 1.49 (dt,
J=14.91, 7.45 Hz, 2H) 2.24-2.36 (m, 2H) 2.36-2.42 (m, 3H) 2.42-2.47
(m, 2H) 2.89-3.00 (m, 2H) 3.86 (t, J=7.67 Hz, 1H) 4.30 (s, 2H) 4.41
(s, 2H) 6.64 (d, J=6.14 Hz, 3H) 7.90 (s, 1H).
Example-115: Synthesis of
N-(2-(7-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-azaspiro[3.3]-
heptan-6-yl)-N-(cyclopropylmethyl)sulfamamide, (Compounds
1.115)
##STR00696##
[0872] Step-1: Synthesis of tert-butyl
6-((cyclopropylmethyl)amino)-2-azaspiro[3.3]heptane-2-carboxylate:
To a stirred solution of tert-butyl
6-oxo-2-azaspiro[3.3]heptane-2-carboxylate (300 mg, 1.42 mmol, 1
eq) in methanol (5 mL) was added cyclopropylmethanamine (121 mg,
1.70 mmol, 1.2 eq) and the reaction mixture was stirred at RT for
overnight. To the reaction mixture, NaBH.sub.4 (80 mg, 2.13 mmol,
1.5 eq) was added at 0.degree. C. and then resultant reaction
mixture was allowed to stir at 0.degree. C. for 1 h. Progress of
reaction was monitored by TLC After completion, reaction mixture
was concentrated under reduced pressure to get residue which was
diluted with water (100 mL) and extracted with dichloromethane
(2.times.100 mL). Combined organic layer was dried over anhydrous
sodium sulfate. Removal of solvent under reduced pressure to afford
tert-butyl
6-((cyclopropylmethyl)amino)-2-azaspiro[3.3]heptane-2-carboxylate
(350 mg, 92.5%) which was used in the next step without
purification.
[0873] Step-2: Synthesis of tert-butyl
6-((N-(tert-butoxycarbonyl)sulfamoyl)(cyclopropylmethyl)amino)-2-azaspiro-
[3.3]heptane-2-carboxylate: To a solution of tert-butyl
6-((cyclopropylmethyl)amino)-2-azaspiro[3.3]heptane-2-carboxylate
(350 mg, 1.31 mmol, 1 eq) in DCM (10 mL) were added
N-(tert-butoxycarbonyl)-N-[4-(dimethylazaniumylidene)-1,4-dihydropyridin--
1ylsulfonyl]azanide (476 mg, 1.57 mmol, 1.2 eq) and DIPEA (0.34 mL,
1.97 mmol, 1.5 eq) and the mixture was allowed to stir at RT for 16
h. Progress of reaction was monitored by TLC. After completion,
reaction mixture was concentrated under reduced pressure to get
residue which was washed with 1N HCl solution (100 mL) and
extracted with ethyl acetate (2.times.100 mL). Combined organic
layer was dried over anhydrous sodium sulfate and concentrated
under reduced pressure to afford tert-butyl
6-((N-(tert-butoxycarbonyl)sulfamoyl)(cyclopropylmethyl)amino)-2-azaspiro-
[3.3]heptane-2-carboxylate (500 mg, 85.4%).
[0874] Step-3: Synthesis of
N-(cyclopropylmethyl)-N-(2-azaspiro[3.3]heptan-6-yl)sulfamidetrifluoroace-
tic acid: To a solution of tert-butyl
6-((N-(tert-butoxycarbonyl)sulfamoyl)(cyclopropylmethyl)amino)-2-azaspiro-
[3.3]heptane-2-carboxylate (500 mg, 1.12 mmol, 1 eq) in DCM (5 mL)
was added TFA (2 mL) and was allowed to stir at RT for 2 h.
Progress of reaction was monitored by TLC. After completion,
reaction mixture was concentrated under reduced pressure to afford
crude which was triturated with diethyl ether to afford
N-(cyclopropylmethyl)-N-(2-azaspiro[3.3]heptan-6-yl)sulfamide
trifluoroacetic acid (225 mg, 55.8%).
[0875] Step-4: Synthesis of
N-(2-(7-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-azaspiro[3.3]-
heptan-6-yl)-N-(cyclopropylmethyl)sulfamamide: A suspension of
N-(cyclopropylmethyl)-N-(2-azaspiro[3.3]heptan-6-yl)sulfamide
trifluoroacetic acid (200 mg, 0.55 mmol, 1 eq),
4,7-dichloro-5-methylpyrrolo[2,1-f][1,2,4]triazine (78 mg, 0.38
mmol, 0.7 eq) in IPA (5 mL) was added DIPEA (143 mg, 1.11 mmol, 2
eq.) and the reaction mixture was allowed to stir at 80.degree. C.
for 2 h. Progress of reaction was monitored by LCMS and TLC. After
2 h, the reaction mixture was concentrated under reduced pressure.
Water (100 mL) was added into the reaction mixture and extracted
with ethyl acetate (100 mL.times.2). Combined organic layer was
concentrated under reduced pressure to get crude which was purified
using reverse phase column chromatography to afford
N-(2-(7-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-azaspiro[3.3]-
heptan-6-yl)-N-(cyclopropylmethyl)sulfamamide (72 mg, 31.5%). LCMS:
411 [M+1].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm
0.14-0.27 (m, 2H) 0.39-0.50 (m, 2H) 0.96-1.08 (m, 1H) 2.25-2.42 (m,
8H) 2.86 (d, J=6.58 Hz, 2H) 3.77-3.94 (m, 1H) 4.29 (s, 2H) 4.41 (s,
2H) 6.63 (d, J=5.26 Hz, 2H) 7.90 (s, 1H).
Example-116: Synthesis of
N-(2-(7-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-azaspiro[3.3]-
heptan-6-yl)-N-(cyclobutylmethyl)sulfamide, (Compounds 1.116)
##STR00697##
[0877] Step-1: Synthesis of tert-butyl
6-((cyclobutylmethyl)amino)-2-azaspiro[3.3]heptane-2-carboxylate:
To a stirred solution of tert-butyl
6-oxo-2-azaspiro[3.3]heptane-2-carboxylate (300 mg, 1.42 mmol, 1
eq) in methanol (5 mL) was added cyclobutylmethanamine (145 mg,
1.70 mmol, 1.2 eq) and the reaction mixture was stirred at RT for
overnight. To the reaction mixture, NaBH.sub.4 (80 mg, 2.13 mmol,
1.5 eq) was added at 0.degree. C. and then resultant reaction
mixture was allowed to stir at 0.degree. C. for 1 h. Progress of
reaction was monitored by TLC. After completion, reaction mixture
was concentrated under reduced pressure to get residue which was
diluted with water (100 mL) and extracted with dichloromethane
(2.times.100 mL). Combined organic layer was dried over anhydrous
sodium sulfate. Removal of solvent under reduced pressure to afford
tert-butyl
6-((cyclobutylmethyl)amino)-2-azaspiro[3.3]heptane-2-carboxylate
(350 mg, 88%) which was used in the next step without
purification.
[0878] Step-2: Synthesis of tert-butyl
6-((N-(tert-butoxycarbonyl)sulfamoyl)(cyclobutylmethyl)amino)-2-azaspiro[-
3.3]heptane-2-carboxylate: To a solution of tert-butyl
6-((cyclobutylmethyl)amino)-2-azaspiro[3.3]heptane-2-carboxylate
(350 mg, 1.24 mmol, 1 eq) in DCM (10 mL) were added
N-(tert-butoxycarbonyl)-N-[4-(dimethylazaniumylidene)-1,4-dihydropyridin--
1ylsulfonyl]azanide (452 mg, 1.49 mmol, 1.2 eq) and DIPEA (0.32 mL,
1.87 mmol, 1.5 eq) and the mixture was allowed to stir at RT for 16
h. Progress of reaction was monitored by TLC and 1H-NMR. After
completion, reaction mixture was concentrated under reduced
pressure to get residue which was washed with 1N HCl solution (100
mL) and extracted with ethyl acetate (2.times.100 mL). Combined
organic layer was dried over anhydrous sodium sulfate and
concentrated under reduced pressure to afford tert-butyl
6-((N-(tert-butoxycarbonyl)sulfamoyl)(cyclobutylmethyl)amino)-2-azaspiro[-
3.3]heptane-2-carboxylate (550 mg, 95.9%).
[0879] Step-3: Synthesis of
N-(cyclobutylmethyl)-N-(2-azaspiro[3.3]heptan-6-yl)sulfamide
trifluoroacetic acid: To a solution of tert-butyl
6-((N-(tert-butoxycarbonyl)sulfamoyl)(cyclobutylmethyl)amino)-2-azaspiro[-
3.3]heptane-2-carboxylate (550 mg, 1.19 mmol, 1 eq) in DCM (5 mL)
was added TFA (2 mL) and was allowed to stir at RT for 2 h.
Progress of reaction was monitored by TLC. After completion,
reaction mixture was concentrated under reduced pressure to afford
crude which was triturated with diethyl ether to afford
N-(cyclobutylmethyl)-N-(2-azaspiro[3.3]heptan-6-yl)sulfamamide
trifluoroacetic acid (250 mg, 56%).
[0880] Step-4: Synthesis of
N-(2-(7-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-azaspiro[3.3]-
heptan-6-yl)-N-(cyclobutylmethyl)sulfamide: A suspension of
N-(cyclobutylmethyl)-N-(2-azaspiro[3.3]heptan-6-yl)sulfamide
trifluoroacetic acid (200 mg, 0.53 mmol, 1 eq),
4,7-dichloro-5-methylpyrrolo[2,1-f][1,2,4]triazine (75 mg, 0.37
mmol, 0.7 eq) in DMF (2 mL) was added DIPEA (0.13 mL, 0.80 mmol,
1.5 eq.) and the reaction mixture was allowed to stir at 80.degree.
C. for 2 h. Progress of reaction was monitored by LCMS and TLC.
After 2 h, the reaction mixture was concentrated under reduced
pressure. Water (100 mL) was added into the reaction mixture and
extracted with ethyl acetate (100 mL). Combined organic layer was
concentrated under reduced pressure to get crude which was purified
using reverse phase column chromatography to afford
N-(2-(7-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-azaspi-
ro[3.3]heptan-6-yl)-N-(cyclobutylmethyl)sulfamide (47 mg, 20.7%).
LCMS: 424 [M+1].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
ppm 1.61-1.72 (m, 2H) 1.72-1.84 (m, 2H) 1.94 (d, J=5.70 Hz, 2H)
2.24-2.37 (m, 3H) 2.40 (s, 3H) 2.67 (br. s., 1H) 2.96 (d, J=7.45
Hz, 2H) 2.95 (m, 2H) 3.76-3.90 (m, 1H) 4.31 (s, 2H) 4.41 (s, 2H)
6.64 (s, 2H) 7.91 (s, 1H).
Example-117: Synthesis of
N-(2-(7-chloro-5-methylpyrrolo[2,1-j][1,2,4]triazin-4-yl)-2-azaspiro[3.3]-
heptan-6-yl)-N-(cyclohexylmethyl)sulfamide, (Compounds 1.117)
##STR00698##
[0882] Step-1: Synthesis of tert-butyl
6-((cyclohexylmethyl)amino)-2-azaspiro[3.3]heptane-2-carboxylate:
To a stirred solution of tert-butyl
6-oxo-2-azaspiro[3.3]heptane-2-carboxylate (300 mg, 1.42 mmol, 1
eq) in methanol (5 mL) was added cyclohexylmethanamine (169 mg,
1.70 mmol, 1.2 eq) and the reaction mixture was stirred at RT for
overnight. To the reaction mixture, NaBH.sub.4 (80 mg, 2.13 mmol,
1.5 eq) was added at 0.degree. C. and then resultant reaction
mixture was allowed to stir at 0.degree. C. for 1 h. Progress of
reaction was monitored by TLC. After completion, reaction mixture
was concentrated under reduced pressure to get residue which was
diluted with water (100 mL) and extracted with dichloromethane
(2.times.100 mL). Combined organic layer was dried over anhydrous
sodium sulfate. Removal of solvent under reduced pressure to afford
tert-butyl
6-((cyclohexylmethyl)amino)-2-azaspiro[3.3]heptane-2-carboxylate
(400 mg, 91.2%) which was used in the next step without
purification.
[0883] Step-2: Synthesis of tert-butyl
6-((N-(tert-butoxycarbonyl)sulfamoyl)(cyclohexylmethyl)amino)-2-azaspiro[-
3.3]heptane-2-carboxylate: To a solution of tert-butyl
6-((cyclohexylmethyl)amino)-2-azaspiro[3.3]heptane-2-carboxylate
(400 mg, 1.29 mmol, 1 eq) in DCM (10 mL) were added
N-(tert-butoxycarbonyl)-N-[4-(dimethylazaniumylidene)-1,4-dihydropyridin--
1ylsulfonyl]azanide (470 mg, 1.55 mmol, 1.2 eq) and DIPEA (0.33 mL,
1.94 mmol, 1.5 eq) and the mixture was allowed to stir at RT for 16
h. Progress of reaction was monitored by TLC and 1H-NMR. After
completion, reaction mixture was concentrated under reduced
pressure to get residue which was washed with 1N HCl solution (100
mL) and extracted with ethyl acetate (2.times.100 mL). Combined
organic layer was dried over anhydrous sodium sulfate and
concentrated under reduced pressure to afford tert-butyl
6-((N-(tert-butoxycarbonyl)sulfamoyl)(cyclohexylmethyl)amino)-2-azaspiro[-
3.3]heptane-2-carboxylate (600 mg, 95%).
[0884] Step-3: Synthesis of
N-(cyclohexylmethyl)-N-(2-azaspiro[3.3]heptan-6-yl)sulfamide
trifluoroacetic acid: To a solution of tert-butyl
6-((N-(tert-butoxycarbonyl)sulfamoyl)(cyclohexylmethyl)amino)-2-azaspiro[-
3.3]heptane-2-carboxylate (600 mg, 1.23 mmol, 1 eq) in DCM (5 mL)
was added TFA (3 mL) and was allowed to stir at RT for 2 h.
Progress of reaction was monitored by TLC. After completion,
reaction mixture was concentrated under reduced pressure to afford
crude which was triturated with diethyl ether to afford
N-(cyclohexylmethyl)-N-(2-azaspiro[3.3]heptan-6-yl)sulfamide
trifluoroacetic acid (200 mg, 40.5%).
[0885] Step-4: Synthesis of
N-(2-(7-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-azaspiro[3.3]-
heptan-6-yl)-N-(cyclohexylmethyl)sulfamide: A suspension of
N-(cyclohexylmethyl)-N-(2-azaspiro[3.3]heptan-6-yl)sulfamide
trifluoroacetic acid (150 mg, 0.37 mmol, 1 eq),
4,7-dichloro-5-methylpyrrolo[2,1-f][1,2,4]triazine (52 mg, 0.26
mmol, 0.7 eq) in DMF (2 mL) was added DIPEA (0.1 mL, 0.56 mmol, 1.5
eq.) and the reaction mixture was allowed to stir at 80.degree. C.
for 2 h. Progress of reaction was monitored by LCMS and TLC. After
2 h, the reaction mixture was concentrated under reduced pressure.
Water (100 mL) was added into the reaction mixture and extracted
with ethyl acetate (100 mL). Combined organic layer was
concentrated under reduced pressure to get crude which was purified
using reverse phase column chromatography to afford
N-(2-(7-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-azaspi-
ro[3.3]heptan-6-yl)-N-(cyclohexylmethyl)sulfamide (56 mg, 33.13%).
LCMS: 453 [M+1].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
ppm 0.75-0.90 (m, 2H) 1.10-1.25 (m, 3H) 1.70 (br. s., 6H) 2.25-2.30
(m, 3H) 2.40 (s, 5H) 2.73 (d, J=7.02 Hz, 2H) 3.90 (s, 1H) 4.30 (s,
2H) 4.40 (s, 2H) 6.63 (s, 2H) 7.90 (s, 1H).
Example-118: Synthesis of
N-(2-(7-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-azaspiro[3.3]-
heptan-6-yl)-N-((4,4-difluorocyclohexyl)methyl)sulfamamide,
(Compounds 1.118)
##STR00699## ##STR00700##
[0887] Step-1: Synthesis of tert-butyl
6-(((4,4-difluorocyclohexyl)methyl)amino)-2-azaspiro[3.3]heptane-2-carbox-
ylate: To a stirred solution of tert-butyl
6-oxo-2-azaspiro[3.3]heptane-2-carboxylate (250 mg, 1.18 mmol, 1
eq) in methanol (8 mL) was added
(4,4-difluorocyclohexyl)methanamine (211 mg, 1.42 mmol, 1.2 eq) and
the reaction mixture was stirred at RT for overnight. To the
reaction mixture, NaBH.sub.4 (67 mg, 1.77 mmol, 1.5 eq) was added
at 0.degree. C. and then resultant reaction mixture was allowed to
stir at 0.degree. C. for 1 h. Progress of reaction was monitored by
TLC. After completion, reaction mixture was concentrated under
reduced pressure to get residue which was diluted with water (50
mL) and extracted with dichloromethane (2.times.50 mL). Combined
organic layer was dried over anhydrous sodium sulfate. Removal of
solvent under reduced pressure to afford tert-butyl
6-(((4,4-difluorocyclohexyl)methyl)amino)-2-azaspiro[3.3]heptane-2-carbox-
ylate which was used in the next step without purification (370 mg,
91.13%).
[0888] Step-2: Synthesis of tert-butyl
6-((N-(tert-butoxycarbonyl)sulfamoyl)((4,4-difluorocyclohexyl)methyl)amin-
o)-2-azaspiro[3.3]heptane-2-carboxylate: To a solution of
tert-butyl
6-(((4,4-difluorocyclohexyl)methyl)amino)-2-azaspiro[3.3]heptane-2-carbox-
ylate (370 mg, 1.07 mmol, 1 eq) in DCM (10 mL) were added
N-(tert-butoxycarbonyl)-N-[4-(dimethylazaniumylidene)-1,4-dihydropyridin--
1ylsulfonyl]azanide (389 mg, 1.29 mmol, 1.2 eq) and DIPEA (207 mg,
1.60 mmol, 1.5 eq) and the mixture was allowed to stir at RT for
overnight. Progress of reaction was monitored by TLC. After
completion, the reaction mixture was concentrated under reduced
pressure to get residue which was washed with 1N HCl solution (50
mL) and extracted with ethyl acetate (2.times.150 mL). Combined
organic layer was dried over anhydrous sodium sulfate and
concentrated under reduced pressure to obtain tert-butyl
6-((N-(tert-butoxycarbonyl)sulfamoyl)((4,4-difluorocyclohexyl)methyl)amin-
o)-2-azaspiro[3.3]heptane-2-carboxylate as desired product (550 mg,
98%).
[0889] Step-3: Synthesis of
N-((4,4-difluorocyclohexyl)methyl)-N-(2-azaspiro[3.3]heptan-6-yl)sulfamam-
ide 2,2,2-trifluoroacetate: To a solution of tert-butyl
6-((N-(tert-butoxycarbonyl)sulfamoyl)((4,4-difluorocyclohexyl)methyl)amin-
o)-2-azaspiro[3.3]heptane-2-carboxylate (550 mg, 1.05 mmol, 1 eq)
in DCM (6 mL) was added TFA (2.5 mL) and was allowed to stir at RT
for 2 h. Progress of reaction was monitored by TLC. After
completion, reaction mixture was concentrated under reduced
pressure to afford crude which was triturated with diethyl ether to
afford
N-((4,4-difluorocyclohexyl)methyl)-N-(2-azaspiro[3.3]heptan-6-yl)sulfamam-
ide 2,2,2-trifluoroacetate (390 mg, 84.9%).
[0890] Step-4: Synthesis of
N-(2-(7-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-azaspiro[3.3]-
heptan-6-yl)-N-((4,4-difluorocyclohexyl)methyl)sulfamamide: A
suspension of
N-((4,4-difluorocyclohexyl)methyl)-N-(2-azaspiro[3.3]heptan-6-yl)sulfa-
mamide 2,2,2-trifluoroacetate (131 mg, 0.298 mmol, 1.0 eq),
4,7-dichloro-5-methylpyrrolo[2,1-f][1,2,4]triazine (60 mg, 0.298
mmol, 1.0 eq) and DIPEA (77 mg, 0.596 mmol, 2.0 eq) in DMF (1.0 mL)
was allowed to stir at 80.degree. C. for 1 h. Progress of reaction
was monitored by LCMS and TLC. After 2 h, reaction mixture was
diluted with water (10 mL) and extracted with ethyl acetate
(1.times.50 mL). Combined organic layer was washed with brine
(1.times.10 mL) and dried over anhydrous sodium sulfate,
Concentrated under reduced pressure to obtain crude product which
was purified using reversed phase HPLC chromatography to afford
N-(2-(7-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-azaspiro[3.3]-
heptan-6-yl)-N-((4,4-difluorocyclohexyl)methyl)sulfamamide (13 mg,
9%). LCMS: 489 [M+1].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. ppm 7.91 (s, 1H), 6.70 (s, 2H), 6.63 (s, 1H), 4.40 (s, 2H),
4.31 (s, 2H), 3.88 (d, J=8.8 Hz, 1H), 2.82 (d, J=7.0 Hz, 2H), 2.40
(s, 3H), 2.32 (br. s., 3H), 1.99 (br. s., 2H), 1.79 (br. s., 4H),
1.70 (br. s., 2H), 1.20-1.06 (m, 2H).
Example-119: Synthesis of
N-(2-(7-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-azaspiro[3.3]-
heptan-6-yl)-N-((4-(trifluoromethyl)cyclohexyl)methyl)sulfamamide,
(Compounds 1.119)
##STR00701## ##STR00702##
[0892] Step-1: Synthesis of tert-butyl
6-(((4-(trifluoromethyl)cyclohexyl)methyl)amino)-2-azaspiro[3.3]heptane-2-
-carboxylate: To a stirred solution of tert-butyl
6-oxo-2-azaspiro[3.3]heptane-2-carboxylate (250 mg, 1.18 mmol, 1
eq) in methanol (8 mL) was added
(4-(trifluoromethyl)cyclohexyl)methanamine (257 mg, 1.42 mmol, 1.2
eq) and the reaction mixture was stirred at RT for overnight. To
the reaction mixture, NaBH.sub.4 (67 mg, 1.77 mmol, 1.5 eq) was
added at 0.degree. C. and then resultant reaction mixture was
allowed to stir at 0.degree. C. for 1 h. Progress of reaction was
monitored by TLC. After completion, reaction mixture was
concentrated under reduced pressure to get residue which was
diluted with water (50 mL) and extracted with dichloromethane
(2.times.150 mL). Combined organic layer was dried over anhydrous
sodium sulfate. Removal of solvent under reduced pressure to afford
tert-butyl
6-(((4-(trifluoromethyl)cyclohexyl)methyl)amino)-2-azaspiro[3.3]heptane-2-
-carboxylate (410 mg, 92.34%) which was used in the next step
without purification.
[0893] Step-2: Synthesis of tert-butyl
6-((N-(tert-butoxycarbonyl)sulfamoyl)((4-(trifluoromethyl)cyclohexyl)meth-
yl)amino)-2-azaspiro[3.3]heptane-2-carboxylate: To a solution of
tert-butyl
6-(((4-(trifluoromethyl)cyclohexyl)methyl)amino)-2-azaspiro[3.3]heptane-2-
-carboxylate (200 mg, 0.539 mmol, 1 eq) in DCM (10 mL) were added
N-(tert-butoxycarbonyl)-N-[4-(dimethylazaniumylidene)-1,4-dihydropyridin--
1ylsulfonyl]azanide (195 mg, 0.647 mmol, 1.2 eq) and DIPEA (104 mg,
0.808 mmol, 1.5 eq) and the mixture was allowed to stir at RT for
overnight. Progress of reaction was monitored by TLC After
completion, the reaction mixture was concentrated under reduced
pressure to get residue which was washed with 1N HCl solution (50
mL) and extracted with ethyl acetate (2.times.150 mL). Combined
organic layer was dried over anhydrous sodium sulfate and
concentrated under reduced pressure to obtain tert-butyl
6-((N-(tert-butoxycarbonyl)sulfamoyl)((4-(trifluoromethyl)cyclohexyl)meth-
yl)amino)-2-azaspiro[3.3]heptane-2-carboxylate as desired product
(560 mg, 92.56%).
[0894] Step-3: Synthesis of
N--(N-((4-trifluorocyclohexyl)methyl)-N-(2-azaspiro[3.3]heptan-6-yl)sulfa-
mamide 2,2,2-trifluoroacetate: To a solution of tert-butyl
6-((N-(tert-butoxycarbonyl)sulfamoyl)((4-(trifluoromethyl)cyclohexyl)meth-
yl)amino)-2-azaspiro[3.3]heptane-2-carboxylate (560 mg, 0.100 mmol,
1 eq) in DCM (4 mL) was added TFA (3 mL) and was allowed to stir at
RT for 2 h. Progress of reaction was monitored by TLC. After
completion, reaction mixture was concentrated under reduced
pressure to afford crude which was triturated with diethyl ether to
afford
N-(2-azaspiro[3.3]heptan-6-yl)-N-((4-(trifluoromethyl)cyclohexyl)methyl)s-
ulfamamide 2,2,2-trifluoroacetate (410 mg, 86.68%).
[0895] Step-4: Synthesis of
N-(2-(7-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-azaspiro[3.3]-
heptan-6-yl)-N-((4-(trifluoromethyl)cyclohexyl)methyl)sulfamamide:
A suspension of
N-(2-azaspiro[3.3]heptan-6-yl)-N-((4-(trifluoromethyl)cyclohexyl)methyl)s-
ulfamamide 2,2,2-trifluoroacetate (140 mg, 0.298 mmol, 1.0 eq),
4,7-dichloro-5-methylpyrrolo[2,1-f][1,2,4]triazine (60 mg, 0.298
mmol, 1.0 eq) and DIPEA (77 mg, 0.596 mmol, 2.0 eq) in DMF (1.0 mL)
was allowed to stir at 80.degree. C. for 1 h. Progress of reaction
was monitored by LCMS and TLC. After 2 h, reaction mixture was
diluted with water (10 mL) and extracted with ethyl acetate
(1.times.50 mL). Combined organic layer was washed with brine
(1.times.10 mL) and dried over anhydrous sodium sulfate,
Concentrated under reduced pressure to obtain crude product which
was purified using reversed phase HPLC chromatography to afford
N-(2-(7-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-azaspiro[3.3]-
heptan-6-yl)-N-((4-(trifluoromethyl)cyclohexyl)methyl)sulfamamide
(40 mg, 25.8% mg). LCMS: 521 [M+1].sup.+; .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 7.91 (s, 1H), 6.73-6.67 (m, 2H), 6.64 (s,
1H), 4.41 (s, 2H), 4.31 (s, 2H), 3.83 (dd, J=7.0, 14.5 Hz, 1H),
2.90-2.76 (d, J=7.5 Hz, 2H), 2.47-2.27 (m, 7H), 1.92-1.71 (m, 3H),
1.59-1.46 (d, J=7.5 Hz, 5H), 1.20 (d, J=11.4 Hz, 1H), 0.91 (d,
J=11.8 Hz, 1H).
Example-120: Synthesis of
N-(2-(7-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-azaspiro[3.3]-
heptan-6-yl)-N-(3,3,3-trifluoro-2-hydroxypropyl)sulfamamide,
(Compounds 1.120)
##STR00703##
[0897] Step-1: Synthesis of tert-butyl
6-((3,3,3-trifluoro-2-hydroxypropyl)amino)-2-azaspiro[3.3]heptane-2-carbo-
xylate: To a stirred solution of tert-butyl
6-oxo-2-azaspiro[3.3]heptane-2-carboxylate (100 mg, 0.473 mmol, 1
eq) in methanol (5 mL) was added 3-amino-1,1,1-trifluoropropan-2-ol
hydrochloride (94 mg, 0.568 mmol, 1.2 eq) and the reaction mixture
was stirred at RT for overnight. To the reaction mixture,
NaBH.sub.4 (27 mg, 0.7095 mmol, 1.5 eq) was added at 0.degree. C.
and then resultant reaction mixture was allowed to stir at
0.degree. C. for 1 h. Progress of reaction was monitored by TLC.
After completion, reaction mixture was concentrated under reduced
pressure to get residue which was diluted with water (50 mL) and
extracted with dichloromethane (2.times.50 mL). Combined organic
layer was dried over anhydrous sodium sulfate. Removal of solvent
under reduced pressure to afford tert-butyl
6-((3,3,3-trifluoro-2-hydroxypropyl)amino)-2-azaspiro[3.3]heptane-2-carbo-
xylate which was used in the next step without purification. (140
mg, 91.5%)
[0898] Step-2: Synthesis of tert-butyl
6-((N-(tert-butoxycarbonyl)sulfamoyl)(3,3,3-trifluoro-2-hydroxypropyl)ami-
no)-2-azaspiro[3.3]heptane-2-carboxylate: To a solution of
tert-butyl
6-((3,3,3-trifluoro-2-hydroxypropyl)amino)-2-azaspiro[3.3]heptane-2-carbo-
xylate (140 mg, 0.430 mmol, 1 eq) in DCM (5 mL) were added
N-(tert-butoxycarbonyl)-N-[4-(dimethylazaniumylidene)-1,4-dihydropyridin--
1ylsulfonyl]azanide (150 mg, 0.51 mmol, 1.2 eq) and DIPEA (83 mg,
0.695 mmol, 1.5 eq) and the mixture was allowed to stir at RT for
overnight. Progress of reaction was monitored by TLC. After
completion, the reaction mixture was concentrated under reduced
pressure to get residue which was washed with 1N HCl solution (50
mL) and extracted with ethyl acetate (2.times.50 mL). Combined
organic layer was dried over anhydrous sodium sulfate and
concentrated under reduced pressure to tert-butyl
6-((N-(tert-butoxycarbonyl)sulfamoyl)(3,3,3-trifluoro-2-hydroxypropyl)ami-
no)-2-azaspiro[3.3]heptane-2-carboxylate as desired product (160
mg, 74%).
[0899] Step-3: Synthesis of
N-(2-azaspiro[3.3]heptan-6-yl)-N-(3,3,3-trifluoro-2-hydroxypropyl)sulfama-
mide: To a solution of tert-butyl
6-((N-(tert-butoxycarbonyl)sulfamoyl)(3,3,3-trifluoro-2-hydroxypropyl)ami-
no)-2-azaspiro[3.3]heptane-2-carboxylate (160 mg, 0.317 mmol, 1 eq)
in DCM (4 mL) was added TFA (1.0 mL) and was allowed to stir at RT
for 2 h. Progress of reaction was monitored by TLC. After
completion, reaction mixture was concentrated under reduced
pressure to afford crude which was triturated with diethyl ether to
afford
N-(2-azaspiro[3.3]heptan-6-yl)-N-(3,3,3-trifluoro-2-hydroxypropyl)sulfama-
mide as a TFA salt (125 mg, 93%).
[0900] Step-4: Synthesis of
N-(2-(7-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-azaspiro[3.3]-
heptan-6-yl)-N-(3,3,3-trifluoro-2-hydroxypropyl)sulfamamide: A
suspension of
N-(2-azaspiro[3.3]heptan-6-yl)-N-(3,3,3-trifluoro-2-hydroxypropyl)sulf-
amamide as a TFA salt (124 mg, 0.298 mmol, 1.0 eq),
4,7-dichloro-5-methylpyrrolo[2,1-f][1,2,4]triazine (60 mg, 0.298
mmol, 1.0 eq) and DIPEA (77 mg, 0.596 mmol, 2.0 eq) in DMF (1.0 mL)
was allowed to stir at 80.degree. C. for 2 h. Progress of reaction
was monitored by LCMS and TLC. After 2 h, reaction mixture was
diluted with water (10 mL) and extracted with ethyl acetate
(1.times.50 mL). Combined organic layer was washed with brine
(1.times.10 mL) and dried over anhydrous sodium sulfate,
Concentrated under reduced pressure to obtain crude product which
was purified using reversed phase HPLC chromatography to afford
N-(2-(7-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-azaspiro[3.3]-
heptan-6-yl)-N-(3,3,3-trifluoro-2-hydroxypropyl)sulfamamide (7 mg,
5%). LCMS: 469 [M+1].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. ppm 7.91 (s, 1H), 6.88 (br. s., 2H), 6.63 (s, 1H), 6.50
(br. s., 1H), 4.46-4.35 (m, 2H), 4.31 (s, 2H), 4.16 (br. s., 1H),
3.96-3.87 (m, 1H), 3.20-3.10 (m, 1H), 2.90 (d, J=15.3 Hz, 1H),
2.46-2.22 (m, 6H), 2.08 (s, 1H).
Example-121: Synthesis of
N-(2,2-difluoroethyl)-N-(2-(I-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-2--
azaspiro[3.3]heptan-6-yl)sulfamamide, (Compounds 1.121)
##STR00704##
[0902] A suspension of
N-(2,2-difluoroethyl)-N-(2-azaspiro[3.3]heptan-6-yl)sulfamamide
2,2,2-trifluoroacetate (119 mg, 0.3235 mmol, 1.1 eq),
4-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidine (50 mg, 0.294 mmol,
1.0 eq) and DIPEA (0.1 mL, 0.588 mmol, 2.0 eq) in DMF (0.6 mL) was
allowed to stir at 80.degree. C. for 2 h. Progress of reaction was
monitored by LCMS and TLC. After 2 h, reaction mixture was diluted
with water (10 mL) and extracted with ethyl acetate (2.times.20
mL). Combined organic layer was washed with brine (1.times.10 mL)
and dried over anhydrous sodium sulfate, Concentrated under reduced
pressure to obtain crude product which was purified using reversed
phase HPLC chromatography to afford
N-(2,2-difluoroethyl)-N-(2-(1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-2--
azaspiro[3.3]heptan-6-yl)sulfamamide as desired product (16 mg,
14%). LCMS: 388 [M+1].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. ppm 8.23 (s, 1H), 8.00 (br. s., 1H), 7.13-6.84 (m, 2H),
6.17 (br. s., 1H), 6.03 (t, J=4.2 Hz, 1H), 4.47 (br. s., 1H), 4.37
(br. s., 1H), 4.25 (br. s., 1H), 4.13 (br. s., 1H), 4.05-3.95 (m,
1H), 3.95-3.77 (m, 3H), 3.55-3.36 (m, 2H), 2.44-2.17 (m, 3H).
Example-122: Synthesis of
N-(2-(7-chloro-5-methylpyrrolo[1,2-f][1,2,4]triazin-4-yl)-2-azaspiro[3.3]-
heptan-6-yl)-N-(2-methoxyethyl)sulfamamide, (Compound 1.122)
##STR00705##
[0904] Step-1: Synthesis of
2-(7-chloro-5-methylpyrrolo[1,2-f][1,2,4]triazin-4-yl)-2-azaspiro[3.3]hep-
tan-6-one: The mixture of
4,7-dichloro-5-methylpyrrolo[1,2-f][1,2,4]triazine (1.0 g, 4.95
mmol, 1 eq), N-methyl-N-(2-azaspiro[3.3]heptan-6-yl)sulfamamide,
2,2,2-trifluoroacetate salt (1.21 g, 5.44 mmol, 1.1 eq) and DIPEA
(1.3 mL, 7.42 mmol, 1.5 eq) in DMF (10 mL) was allowed to stir at
85.degree. C. for 3 h. Progress of reaction was monitored by TLC.
After completion, reaction mixture was diluted with cold water (30
mL) and extracted with ethyl acetate (3.times.70 mL). Combined
organic layer was washed with brine (3.times.50 mL) and dried over
anhydrous sodium sulfate. Removal of solvent under reduced pressure
to obtain the crude, which was purified by reversed phase to afford
2-(7-chloro-5-methylpyrrolo[1,2-f][1,2,4]triazin-4-yl)-2-azaspiro[3.3]hep-
tan-6-one (1.1 g, 80.30%). LCMS: 277.8 [M+1].sup.+
[0905] Step-2: Synthesis of
2-(7-chloro-5-methylpyrrolo[1,2-f][1,2,4]triazin-4-yl)-N-(2-methoxyethyl)-
-2-azaspiro[3.3]heptan-6-amine: To a stirred solution of
2-(7-chloro-5-methylpyrrolo[1,2-f][1,2,4]triazin-4-yl)-2-azaspiro[3.3]hep-
tan-6-one (0.160 g, 0.577 mmol, 1.0 eq) in MeOH (15.0 mL) was added
2-methoxyethanamine (0.043 g, 0.577 mmol, 1.0 eq) at 0.degree. C.
The resulting mixture was stirred at room temperature for
overnight. The reaction mixture was then cooled to 0.degree. C.
followed by addition of NaBH.sub.4 (0.043 mg, 1.154 mmol, 2.0 eq)
at 0.degree. C. The reaction mixture was stirred at room
temperature for 2 h. The progress of reaction was monitored by TLC.
The reaction mixture was concentrated, basified with NaHCO.sub.3
solution (20 mL), extracted with EtOAc (2.times.150 mL). The
combined organic layer was washed with water (50 mL), with brine
(50 mL), dried over Na.sub.2SO.sub.4 concentrated to get crude
product. The crude product was triturated in pentane to afford
2-(7-chloro-5-methylpyrrolo[1,2-f][1,2,4]triazin-4-yl)-N-(2-methoxyethyl)-
-2-azaspiro[3.3]heptan-6-amine (500 mg, 78.90%) as liquid, which
was further used further next step without purification. LCMS:
336.8 [M+1].sup.+
[0906] Step-3: Synthesis of tert-butyl
N-(2-(7-chloro-5-methylpyrrolo[1,2-f][1,2,4]triazin-4-yl)-2-azaspiro[3.3]-
heptan-6-yl)-N-(2-methoxyethyl)sulfamoylcarbamate: To a solution of
2-(7-chloro-5-methylpyrrolo[1,2-f][1,2,4]triazin-4-yl)-N-(2-methoxyethyl)-
-2-azaspiro[3.3]heptan-6-amine (0.150 g, 0.447 mmol, 1 eq) and
N-(1-(N-(tert-butoxycarbonyl)sulfamoyl)pyridin-4
(1H)-ylidene)-N-methylmethanaminium (0.161 g, 0.537 mmol, 1.2 eq)
in dichloromethane (10 mL) N,N-diisopropylethylamine (0.156 ml,
0.895 mmol, 2.0 eq) was added and the reaction mixture was allowed
to stir at RT for overnight. Progress of reaction was monitored by
NMR. After completion, the reaction mixture was diluted with water
(50 mL) and extracted with DCM (150 ml.times.2), combined organic
layer was washed with brine (50 mL) and dried over anhydrous sodium
sulfate concentrated to get crude product. The crude product was
triturated in pentane to afford tert-butyl
N-(2-(7-chloro-5-methylpyrrolo[1,2-f][1,2,4]triazin-4-yl)-2-azaspiro[3.3]-
heptan-6-yl)-N-(2-methoxyethyl)sulfamoylcarbamate (140 g, 60.85%)
as liquid which was used in the next step without purification.
LCMS: 516 [M+1].sup.+
[0907] Step-4: Synthesis of
N-(2-(7-chloro-5-methylpyrrolo[1,2-f][1,2,4]triazin-4-yl)-2-azaspiro[3.3]-
heptan-6-yl)-N-(2-methoxyethyl)sulfamamide: To a solution of
tert-butyl
N-(2-(7-chloro-5-methylpyrrolo[1,2-f][1,2,4]triazin-4-yl)-2-azaspiro[3.3]-
heptan-6-yl)-N-(2-methoxyethyl)sulfamoylcarbamate (0.1 g, 0.194
mmol, 1 eq) in DCM (10 mL) was added TFA (2 mL) and the mixture was
allowed to stir at RT for 2 h. Progress of reaction was monitored
by NMR. After completion, reaction mixture was diluted with cold
water (30 mL) and extracted with ethyl acetate (3.times.70 mL).
Combined organic layer was washed with brine (3.times.50 mL) and
dried over anhydrous sodium sulfate. Removal of solvent under
reduced pressure to obtain the crude, which was purified by
reversed phase to afford
N-(2-(7-chloro-5-methylpyrrolo[1,2-f][1,2,4]triazin-4-yl)-2-azaspiro[3.3]-
heptan-6-yl)-N-(2-methoxyethyl)sulfamamide (15 mg, 18.7%). LCMS:
415.9 [M+1].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm
7.90 (s, 1H), 6.73 (s, 2H), 6.63 (s, 1H), 4.41 (s, 2H), 4.30 (s,
2H), 3.93-3.87 (m, 1H), 3.42-3.39 (m, 2H), 3.26 (s, 3H), 3.17-3.12
(m, 2H), 2.40-2.26 (m, 7H).
Example-123: Synthesis of
N-(2-(7-chloro-5-methyl-5H-pyrrolo[3,2-d]pyrimidin-4-yl)-2-azaspiro[3.3]h-
eptan-6-yl)-N-methylsulfamamide, (Compound 1.123)
##STR00706##
[0909] Step-1: Synthesis of
4,7-dichloro-5-methyl-5H-pyrrolo[3,2-d]pyrimidine: To a solution of
4-chloro-5-methyl-5H-pyrrolo[3,2-d]pyrimidine (0.3 g, 1.796 mmol,
1.0 eq) in DMF (100 mL) was added a N-chlorosuccinamide (0.238 g,
1.796 mmol, 1.1 eq) portion wise. The reaction mixture was allowed
to stir at RT for 12 h. Progress of reaction is monitored using
TLC. After completion, it was diluted with water (50 mL) and
extracted with ethyl acetate (3.times.30 mL). Combined organic
layer was washed with brine (50 mL) and dried over anhydrous sodium
sulfate. Removal of solvent under reduced pressure afforded the
crude which was purified by Combi-Flash to obtain the
4,7-dichloro-5-methyl-5H-pyrrolo[3,2-d]pyrimidine (0.26 g, 72.2%).
LCMS: 203 [M+1].sup.+
[0910] Step-2: Synthesis of
N-(2-(7-chloro-5-methyl-5H-pyrrolo[3,2-d]pyrimidin-4-yl)-2-azaspiro[3.3]h-
eptan-6-yl)-N-methylsulfamamide: To a solution of
4,7-dichloro-5-methyl-5H-pyrrolo[3,2-d]pyrimidine (0.1 g, 0.492
mmol, 1 eq), N-2-azaspiro[3.3]hept-6-yl-N-methylsulfuric diamide
trifloroacetic acid (0.163 g, 0.541 mmol, 1.1 eq) and DIPEA (0.130
mL, 0.738 mmol, 1.5 eq) in DMF (10 mL) was allowed to stir at
85.degree. C. for 3 h. Progress of reaction was monitored by TLC.
After completion, reaction mixture was diluted with cold water (30
mL) and extracted with ethyl acetate (3.times.30 mL). Combined
organic layer was washed with brine (50 mL) and dried over
anhydrous sodium sulfate. Removal of solvent under reduced pressure
to obtain the crude, which was purified by reversed phase to afford
N-(2-(7-chloro-5-methyl-5H-pyrrolo[3,2-d]pyrimidin-4-yl)-2-azaspir-
o[3.3]heptan-6-yl)-N-methylsulfamamide (0.010 g, 5.55%). LCMS:
371.8 [M+1].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm
8.48 (s, 1H), 7.95 (s, 1H), 6.72 (s, 2H), 4.55 (s, 2H), 4.43 (s,
2H), 3.95 (s, 3H), 3.80-3.75 (m, 1H), 2.55 (s, 3H), 2.45-2.34 (m,
4H).
Example-124: Synthesis of
N-(2-(5-chloro-7,7a-dihydro-4aH-pyrrolo[2,3-d]pyrimidin-4-yl)-2-azaspiro[-
3.3]heptan-6-yl)-N-methylsulfamamide, (Compound 1.124)
##STR00707##
[0912] Step-1: Synthesis of
4,5-dichloro-7,7a-dihydro-4aH-pyrrolo[2,3-d]pyrimidine: To a
solution of 4-chloro-7,7a-dihydro-4aH-pyrrolo[2,3-d]pyrimidine (0.5
g, 3.26 mmol, 1.0 eq) in DMF (20 mL) was added N-chlorosuccinimide
(0.435 g, 3.26 mmol, 1.0 eq) portion wise. The reaction mixture was
allowed to stir at RT for 24 h. Progress of reaction is monitored
using TLC. After completion, reaction mixture was diluted with
water (30 mL) and extracted with ethyl acetate (3.times.15 mL).
Combined organic layer was washed with brine (3.times.10 mL) and
dried over anhydrous sodium sulfate. Removal of solvent under
reduced pressure afforded the crude which was purified by
Combi-Flash to obtain
4,5-dichloro-7,7a-dihydro-4aH-pyrrolo[2,3-d]pyrimidine (0.37 g,
56.37%). LCMS: 191 [M+1].sup.+
[0913] Step-2: Synthesis of
N-(2-(5-chloro-7,7a-dihydro-4aH-pyrrolo[2,3-d]pyrimidin-4-yl)-2-azaspiro[-
3.3]heptan-6-yl)-N-methylsulfamamide: A mixture of
4,5-dichloro-7,7a-dihydro-4aH-pyrrolo[2,3-d]pyrimidine (0.15 g,
0.806 mmol, 1 eq), N-2-azaspiro[3.3]hept-6-yl-N-methylsulfuric
diamide trifloroacetic acid (0.180 g, 0.887 mmol, 1.1 eq) and DIPEA
(0.213 mL, 1.209 mmol, 2.0 eq) in DMF (10 mL) was allowed to stir
at 85.degree. C. for 3 h. Progress of reaction was monitored by
TLC. After completion, reaction mixture was diluted with cold water
(30 mL) and extracted with ethyl acetate (3.times.20 mL). Combined
organic layer was washed with brine (3.times.15 mL) and dried over
anhydrous sodium sulfate. Removal of solvent under reduced pressure
to obtain the crude which was purified by reversed phase to afford
N-(2-(5-chloro-7,7a-dihydro-4aH-pyrrolo[2,3-d]pyrimidin-4-yl)-2-azaspiro[-
3.3]heptan-6-yl)-N-methylsulfamamide (10 mg, 3.57%). LCMS: 360
[M+1].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 8.48
(brs., 1H), 8.15 (s, 1H), 7.35 (s, 1H), 4.36 (s, 2H), 4.24 (s, 2H),
3.76-3.71 (m, 1H), 2.54 (s, 3H), 2.43-2.31 (m, 4H).
Example-125: Chiral Separation of
N-(2-(7-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-azaspiro[3.3]-
heptan-6-yl)-N-(3,3,3-trifluoro-2-hydroxypropyl)sulfamide (Compound
1.125 & 1.126)
##STR00708##
[0915] Enantiomers of
N-(2-(7-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-azaspiro[3.3]-
heptan-6-yl)-N-(3,3,3-trifluoro-2-hydroxypropyl)sulfamide (30 mg)
were separated by chiral chromatography to afford Isomer 1 (13 mg,
86.66%) and Isomer 2 (14 mg, 93.33%).
Isomer 1: UPLC-MS (Method 1): Rt 4.735; LCMS: 469.1 [M+1]; .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 7.90 (s, 1H), 6.89 (br. s.,
2H), 6.63 (s, 1H), 6.51 (d, J=4.8 Hz, 1H), 4.40 (br. s., 2H), 4.31
(s, 2H), 4.16 (br. s., 1H), 3.92 (td, J=8.5, 16.8 Hz, 1H),
2.97-2.80 (m, 2H), 2.54 (s, 1H), 2.46-2.28 (m, 6H). Isomer 2:
UPLC-MS (Method 1): Rt 4.746; LCMS: 469.1 [M+1].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. ppm 7.90 (s, 1H), 6.89 (br. s.,
2H), 6.63 (s, 1H), 6.52 (br. s., 1H), 4.40 (br. s., 2H), 4.30 (s,
2H), 4.15 (br. s., 1H), 3.96-3.87 (m, 1H), 2.97-2.86 (m, 2H), 2.54
(s, 1H), 2.43-2.26 (m, 6H).
Example-126: Synthesis of
N-[2-(7-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-azaspiro[3.3]-
hept-6-yl]-2-fluoroethylsulfuric diamide, (Compound 1.127)
##STR00709##
[0917] Step-1: Synthesis of tert-butyl
6-((2-fluoroethyl)amino)-2-azaspiro[3.3]heptane-2-carboxylate: To a
stirred solution of tert-butyl
6-oxo-2-azaspiro[3.3]heptane-2-carboxylate (150 mg, 0.710 mmol, 1
eq) in methanol (6 ml) was added 2-fluoroethylamine.HCl (77 mg,
0.781 mmol, 1.1 eq) and molecular sieves and the reaction mixture
was stirred at RT for 30 minutes. Then, NaCNBH.sub.3 (89 mg, 1.420
mmol, 2.0 eq) was added at 0.degree. C. followed by acetic acid
(0.15 mL) drop wise until the pH become slightly acidic. Then,
allowed the reaction mixture to stir at RT for overnight. Progress
of reaction was monitored by TLC. After completion, reaction
mixture was concentrated under reduced pressure to get residue
which was diluted with water (40 mL) and extracted with ethyl
acetate (3.times.30 mL). Combined organic layers were dried over
anhydrous sodium sulfate. Removal of solvent under reduced pressure
to afford tert-butyl
6-((2-fluoroethyl)amino)-2-azaspiro[3.3]heptane-2-carboxylate which
was used in the next step without purification (180 mg, 98%).
[0918] Step-2: Synthesis of tert-butyl
6-((N-(tert-butoxycarbonyl)sulfamoyl)(2-fluoroethyl)amino)-2-azaspiro[3.3-
]heptane-2-carboxylate: To a solution of tert-butyl
6-((2-fluoroethyl)amino)-2-azaspiro[3.3]heptane-2-carboxylate (180
mg, 0.697 mmol, 1 eq) in DCM (5 mL) was added
(tert-butoxycarbonyl)((4-(dimethyliminio)pyridin-1
(4H)-yl)sulfonyl)amide (252 mg, 0.837 mmol, 1.2 eq) and DIPEA (0.2
mL, 1.046 mmol, 1.5 eq) and the mixture was allowed to stir at RT
for overnight. Progress of reaction was monitored by TLC. After
completion, reaction mixture was washed with 1N HCl solution (100
mL) and extracted with DCM (2.times.60 mL). Combined organic layer
was dried over anhydrous sodium sulfate and concentrated to afford
tert-butyl
6-((N-(tert-butoxycarbonyl)sulfamoyl)(2-fluoroethyl)amino)-2-azaspiro[3.3-
]heptane-2-carboxylate which was used for next step without
purification (180 mg, 60%).
[0919] Step-3: Synthesis of
N-(2-fluoroethyl)-N-(2-azaspiro[3.3]heptan-6-yl)sulfamide
2,2,2-trifluoroacetate: To a solution of tert-butyl
6-((N-(tert-butoxycarbonyl)sulfamoyl)(2-flouroethyl)amino)-2-azaspiro[3.3-
]heptane-2-carboxylate (180 mg, 0.411 mmol, 1 eq) in DCM (4 mL) was
added TFA (1 mL) and was allowed to stir at RT for 2 h. Progress of
reaction was monitored by TLC. After completion, reaction mixture
was concentrated under reduced pressure to afford crude which was
triturated with diethyl ether to afford
N-(2-fluoroethyl)-N-(2-azaspiro[3.3]heptan-6-yl)sulfamide
2,2,2-trifluoroacetate (175 mg, 82%).
[0920] Step-4: Synthesis of
N-[2-(7-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-azaspiro[3.3]-
hept-6-yl]-2-fluoroethylsulfuric diamide: A suspension of
N-(2-fluoroethyl)-N-(2-azaspiro[3.3]heptan-6-yl)sulfamide
2,2,2-trifluoroacetate (175 mg, 0.5 mmol, 1 eq),
4,7-dichloro-5-methylpyrrolo[2,1-f][1,2,4]triazine (100 mg, 0.5
mmol, 1 eq) and DIPEA (0.14 mL, 0.75 mmol, 1.5 eq) in DMF (2 mL)
was allowed to stir at 80.degree. C. for 2.5 h. Progress of
reaction was monitored by LCMS and TLC. After 2.5 h, reaction
mixture was poured onto ice cold water (100 ml) and extracted with
ethyl acetate (100 ml). Combined organic layer was concentrated
under reduced pressure to get crude which was purified by combi
flash and then with trituration to afford
N-[2-(7-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-azaspiro[3.3]-
hept-6-yl]-2-fluoroethylsulfuric diamide (14 mg, 7%). LCMS: 403
[M+1].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 7.91
(s, 1H), 6.84 (s, 2H), 6.63 (s, 1H), 4.54 (t, J=5.5 Hz, 1H),
4.49-4.38 (m, 3H), 4.34-4.27 (m, 2H), 4.03-3.84 (m, 1H), 3.26 (t,
J=5.3 Hz, 2H), 2.43-2.23 (m, 7H).
Example-127: Synthesis of
N-(2-(7-chloro-5-methylpyrrolo[1,2-f][1,2,4]triazin-4-yl)-2-azaspiro[3.3]-
heptan-6-yl)-N-(2-methoxyethyl)sulfamamide, (Compound 1.128)
##STR00710##
[0922] Step-1: Synthesis of
2-(7-chloro-5-methylpyrrolo[1,2-f][1,2,4]triazin-4-yl)-2-azaspiro[3.3]hep-
tan-6-one: The mixture of
4,7-dichloro-5-methylpyrrolo[1,2-f][1,2,4]triazine (1.0 g, 4.95
mmol, 1 eq), N-methyl-N-(2-azaspiro[3.3]heptan-6-yl)sulfamamide,
2,2,2-trifluoroacetate salt (1.21 g, 5.44 mmol, 1.1 eq) and DIPEA
(1.3 mL, 7.42 mmol, 1.5 eq) in DMF (10 mL) was allowed to stir at
85.degree. C. for 3 h. Progress of reaction was monitored by TLC.
After completion, reaction mixture was diluted with cold water (30
mL) and extracted with ethyl acetate (3.times.70 mL). Combined
organic layer was washed with brine (3.times.50 mL) and dried over
anhydrous sodium sulfate. Removal of solvent under reduced pressure
to obtain the crude, which was purified by reversed phase to afford
2-(7-chloro-5-methylpyrrolo[1,2-f][1,2,4]triazin-4-yl)-2-azaspiro[3.3]hep-
tan-6-one (1.1 g, 80.30%). LCMS: 277.8 [M+1].sup.+
[0923] Step-2: Synthesis of
2-(7-chloro-5-methylpyrrolo[1,2-f][1,2,4]triazin-4-yl)-N-(2,2-difluoropro-
pyl)-2-azaspiro[3.3]heptan-6-amine: To a stirred solution of
2-(7-chloro-5-methylpyrrolo[1,2-f][1,2,4]triazin-4-yl)-2-azaspiro[3.3]hep-
tan-6-one (0.160 g, 0.578 mmol, 1.0 eq) in MeOH (15.0 mL) was added
2,2-difluoropropan-1-amine (0.055 g, 0.578 mmol, 1.0 eq) at
0.degree. C. The resulting mixture was stirred at room temperature
for overnight. The reaction mixture was then cooled to 0.degree. C.
followed by addition of NaBH.sub.4 (0.043 mg, 1.159 mmol, 2.0 eq)
at 0.degree. C. The reaction mixture was stirred at room
temperature for 2 h. The progress of reaction was monitored by TLC.
The reaction mixture was concentrated, basified with NaHCO.sub.3
solution (20 mL), extracted with EtOAc (3.times.50 mL). The
combined organic layer was washed with water (50 mL), with brine
(50 mL), dried over Na.sub.2SO.sub.4 concentrated to get crude
product. The crude product was triturated in pentane to afford
2-(7-chloro-5-methylpyrrolo[1,2-f][1,2,4]triazin-4-yl)-N-(2,2-difluoropro-
pyl)-2-azaspiro[3.3]heptan-6-amine (0.150 mg, 753.17%) as liquid,
which was further used further next step without purification.
LCMS: 356.1 [M+1].sup.+
[0924] Step-3: Synthesis of tert-butyl
N-(2-(7-chloro-5-methylpyrrolo[1,2-f][1,2,4]triazin-4-yl)-2-azaspiro[3.3]-
heptan-6-yl)-N-(2-methoxyethyl)sulfamoylcarbamate: To a solution of
2-(7-chloro-5-methylpyrrolo[1,2-f][1,2,4]triazin-4-yl)-N-(2-methoxyethyl)-
-2-azaspiro[3.3]heptan-6-amine (0.150 g, 0.422 mmol, 1 eq) and
N-(1-(N-(tert-butoxycarbonyl)sulfamoyl)pyridin-4
(1H)-ylidene)-N-methylmethanaminium (0.153 g, 0.507 mmol, 1.2 eq)
in dichloromethane (10 mL) N,N-diisopropylethylamine (0.15 ml,
0.845 mmol, 2.0 eq) was added and the reaction mixture was allowed
to stir at RT for overnight. Progress of reaction was monitored by
NMR. After completion, the reaction mixture was diluted with water
(50 mL) and extracted with DCM (3.times.50 mL), combined organic
layer was washed with brine (50 mL) and dried over anhydrous sodium
sulfate concentrated to get crude product. The crude product was
triturated in pentane to afford tert-butyl
N-(2-(7-chloro-5-methylpyrrolo[1,2-f][1,2,4]triazin-4-yl)-2-azaspiro[3.3]-
heptan-6-yl)-N-(2-methoxyethyl)sulfamoylcarbamate (0.130 g, 57.77%)
as liquid which was used in the next step without purification.
LCMS: 535.1 [M+1].sup.+
[0925] Step-4: Synthesis of
N-(2-(7-chloro-5-methylpyrrolo[1,2-f][1,2,4]triazin-4-yl)-2-azaspiro[3.3]-
heptan-6-yl)-N-(2-methoxyethyl)sulfamamide: To a solution of
tert-butyl
N-(2-(7-chloro-5-methylpyrrolo[1,2-f][1,2,4]triazin-4-yl)-2-azaspiro[3.3]-
heptan-6-yl)-N-(2-methoxyethyl)sulfamoylcarbamate (0.130 g, 0.243
mmol, 1 eq) in DCM (10 mL) was added TFA (2 mL) and the mixture was
allowed to stir at RT for 2 h. Progress of reaction was monitored
by NMR. After completion, reaction mixture was diluted with cold
water (30 mL) and extracted with ethyl acetate (3.times.70 mL).
Combined organic layer was washed with brine (3.times.50 mL) and
dried over anhydrous sodium sulfate. Removal of solvent under
reduced pressure to obtain the crude, which was purified by
reversed phase to afford
N-(2-(7-chloro-5-methylpyrrolo[1,2-f][1,2,4]triazin-4-yl)-2-azaspiro[3.3]-
heptan-6-yl)-N-(2-methoxyethyl)sulfamamide (10 mg, 9.52%). LCMS:
435.1 [M+1].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm
7.90 (s, 1H), 6.91 (s, 2H), 6.63 (s, 1H), 4.41 (s, 2H), 4.30 (s,
2H), 4.00-3.94 (m, 1H), 3.46-3.41 (m, 4H), 2.43-2.31 (m, 7H),
1.59-1.54 (m, 3H).
Example-128: Synthesis of
N-(2-(7-chloro-5-methylpyrrolo[1,2-f][1,2,4]triazin-4-yl)-2-azaspiro[3.3]-
heptan-6-yl)-N-(2,2,2-trifluoroethyl)sulfamamide, (Compound
1.129)
##STR00711##
[0927] Step-1: Synthesis of
2-(7-chloro-5-methylpyrrolo[1,2-f][1,2,4]triazin-4-yl)-2-azaspiro[3.3]hep-
tan-6-one: The mixture of
4,7-dichloro-5-methylpyrrolo[1,2-f][1,2,4]triazine (1.0 g, 4.95
mmol, 1 eq), N-methyl-N-(2-azaspiro[3.3]heptan-6-yl)sulfamamide,
2,2,2-trifluoroacetate salt (1.21 g, 5.44 mmol, 1.1 eq) and DIPEA
(1.3 mL, 7.42 mmol, 1.5 eq) in DMF (10 mL) was allowed to stir at
85.degree. C. for 3 h. Progress of reaction was monitored by TLC.
After completion, reaction mixture was diluted with cold water (30
mL) and extracted with ethyl acetate (3.times.70 mL). Combined
organic layer was washed with brine (3.times.50 mL) and dried over
anhydrous sodium sulfate. Removal of solvent under reduced pressure
to obtain the crude, which was purified by reversed phase to afford
2-(7-chloro-5-methylpyrrolo[1,2-f][1,2,4]triazin-4-yl)-2-azaspiro[3.3]hep-
tan-6-one (1.1 g, 80.30%). LCMS: 277.8 [M+1].sup.+
[0928] Step-2: Synthesis of
2-(7-chloro-5-methylpyrrolo[1,2-f][1,2,4]triazin-4-yl)-N-(2,2,2-trifluoro-
ethyl)-2-azaspiro[3.3]heptan-6-amine: To a stirred solution of
2-(7-chloro-5-methylpyrrolo[1,2-f][1,2,4]triazin-4-yl)-2-azaspiro[3.3]hep-
tan-6-one (0.160 g, 0.579 mmol, 1.0 eq) in MeOH (15.0 mL) was added
2-methoxyethanamine (0.057 g, 0.579 mmol, 1.0 eq) at 0.degree. C.
The resulting mixture was stirred at room temperature for
overnight. The reaction mixture was then cooled to 0.degree. C.
followed by addition of NaBH.sub.4 (0.043 g, 1.154 mmol, 2.0 eq) at
0.degree. C. The reaction mixture was stirred at room temperature
for 2 h. The progress of reaction was monitored by TLC. The
reaction mixture was concentrated, basified with NaHCO.sub.3
solution (20 mL), extracted with EtOAc (2.times.150 mL). The
combined organic layer was washed with water (50 mL), with brine
(50 mL), dried over Na.sub.2SO.sub.4 concentrated to get crude
product. The crude product was triturated in pentane to afford
2-(7-chloro-5-methylpyrrolo[1,2-f][1,2,4]triazin-4-yl)-N-(2,2,2-trifluoro-
ethyl)-2-azaspiro[3.3]heptan-6-amine (150 mg, 72.11%) as liquid,
which was further used further next step without purification.
LCMS: 360.1 [M+1].sup.+
[0929] Step-3: Synthesis of tert-butyl
N-(2-(7-chloro-5-methylpyrrolo[1,2-f][1,2,4]triazin-4-yl)-2-azaspiro[3.3]-
heptan-6-yl)-N-(2-methoxyethyl)sulfamoylcarbamate: To a solution of
2-(7-chloro-5-methylpyrrolo[1,2-f][1,2,4]triazin-4-yl)-N-(2-methoxyethyl)-
-2-azaspiro[3.3]heptan-6-amine (0.150 g, 0.417 mmol, 1 eq) and
N-(1-(N-(tert-butoxycarbonyl)sulfamoyl)pyridin-4
(1H)-ylidene)-N-methylmethanaminium (0.150 g, 0.501 mmol, 1.2 eq)
in dichloromethane (10 mL) N,N-diisopropylethylamine (0.153 ml,
0.835 mmol, 2.0 eq) was added and the reaction mixture was allowed
to stir at RT for overnight. Progress of reaction was monitored by
NMR. After completion, the reaction mixture was diluted with water
(50 mL) and extracted with DCM (150 ml.times.2), combined organic
layer was washed with brine (50 mL) and dried over anhydrous sodium
sulfate concentrated to get crude product. The crude product was
triturated in pentane to afford tert-butyl
N-(2-(7-chloro-5-methylpyrrolo[1,2-f][1,2,4]triazin-4-yl)-2-azaspiro[3.3]-
heptan-6-yl)-N-(2-methoxyethyl)sulfamoylcarbamate (130 mg, 51.38%)
as liquid which was used in the next step without purification.
LCMS: 539.1 [M+1].sup.+
[0930] Step-4: Synthesis of
N-(2-(7-chloro-5-methylpyrrolo[1,2-f][1,2,4]triazin-4-yl)-2-azaspiro[3.3]-
heptan-6-yl)-N-(2,2,2-trifluoroethyl)sulfamamide: To a solution of
tert-butyl
N-(2-(7-chloro-5-methylpyrrolo[1,2-f][1,2,4]triazin-4-yl)-2-azaspiro[3.3]-
heptan-6-yl)-N-(2,2,2-trifluoroethyl)sulfamoylcarbamate (0.130 g,
0.222 mmol, 1 eq) in DCM (10 mL) was added TFA (2 mL) and the
mixture was allowed to stir at RT for 2 h. Progress of reaction was
monitored by NMR. After completion, reaction mixture was diluted
with cold water (30 mL) and extracted with ethyl acetate
(3.times.70 mL). Combined organic layer was washed with brine
(3.times.50 mL) and dried over anhydrous sodium sulfate. Removal of
solvent under reduced pressure to obtain the crude, which was
purified by reversed phase to afford
N-(2-(7-chloro-5-methylpyrrolo[1,2-f][1,2,4]triazin-4-yl)-2-azaspiro[3.3]-
heptan-6-yl)-N-(2,2,2-trifluoroethyl)sulfamamide (10 mg, 10.3%).
LCMS: 439.1 [M+1].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. ppm 7.91 (s, 1H), 7.01 (m, 2H), 6.64 (s, 1H), 5.75 (s, 2H),
4.41 (s, 2H), 4.30 (s, 2H), 4.06-4.00 (m, 1H), 2.47-2.24 (m,
7H)
Example-129: Synthesis of
N-(2-(7-chloro-5-methylpyrrolo[1,2-f][1,2,4]triazin-4-yl)-2-azaspiro[3.3]-
heptan-6-yl)-N-(4,4,4-trifluorobutyl)sulfamamide, (Compound
1.130)
##STR00712##
[0932] Step-1: Synthesis of
2-(7-chloro-5-methylpyrrolo[1,2-f][1,2,4]triazin-4-yl)-2-azaspiro[3.3]hep-
tan-6-one: The mixture of
4,7-dichloro-5-methylpyrrolo[1,2-f][1,2,4]triazine (1.0 g, 4.95
mmol, 1 eq), N-methyl-N-(2-azaspiro[3.3]heptan-6-yl)sulfamamide,
2,2,2-trifluoroacetate salt (1.21 g, 5.44 mmol, 1.1 eq) and DIPEA
(1.3 mL, 7.42 mmol, 1.5 eq) in DMF (10 mL) was allowed to stir at
85.degree. C. for 3 h. Progress of reaction was monitored by TLC.
After completion, reaction mixture was diluted with cold water (30
mL) and extracted with ethyl acetate (3.times.70 mL). Combined
organic layer was washed with brine (3.times.50 mL) and dried over
anhydrous sodium sulfate. Removal of solvent under reduced pressure
to obtain the crude, which was purified by reversed phase to afford
2-(7-chloro-5-methylpyrrolo[1,2-f][1,2,4]triazin-4-yl)-2-azaspiro[3.3]hep-
tan-6-one (1.1 g, 80.30%). LCMS: 277.0 [M+1].sup.+
[0933] Step-2: Synthesis of
2-(7-chloro-5-methylpyrrolo[1,2-f][1,2,4]triazin-4-yl)-N-(4,4,4-trifluoro-
butyl)-2-azaspiro[3.3]heptan-6-amine: To a stirred solution of
2-(7-chloro-5-methylpyrrolo[1,2-f][1,2,4]triazin-4-yl)-2-azaspiro[3.3]hep-
tan-6-one (0.160 g, 0.579 mmol, 1.0 eq) in MeOH (15.0 mL) was added
2-methoxyethanamine (0.073.5 g, 0.579 mmol, 1.0 eq) at 0.degree. C.
The resulting mixture was stirred at room temperature for
overnight. The reaction mixture was then cooled to 0.degree. C.
followed by addition of NaBH.sub.4 (0.043 g, 1.159 mmol, 2.0 eq) at
0.degree. C. The reaction mixture was stirred at room temperature
for 2 h. The progress of reaction was monitored by TLC. The
reaction mixture was concentrated, basified with NaHCO.sub.3
solution (20 mL), extracted with EtOAc (2.times.150 mL). The
combined organic layer was washed with water (50 mL), with brine
(50 mL), dried over Na.sub.2SO.sub.4 concentrated to get crude
product. The crude product was triturated in pentane to afford
2-(7-chloro-5-methylpyrrolo[1,2-f][1,2,4]triazin-4-yl)-N-(4,4,4-trifluoro-
butyl)-2-azaspiro[3.3]heptan-6-amine (150 mg, 66.96%) as liquid,
which was further used further next step without purification.
LCMS: 388.1 [M+1].sup.+
[0934] Step-3: Synthesis of tert-butyl
N-(2-(7-chloro-5-methylpyrrolo[1,2-f][1,2,4]triazin-4-yl)-2-azaspiro[3.3]-
heptan-6-yl)-N-(4,4,4-trifluorobutyl)sulfamoylcarbamate: To a
solution of
2-(7-chloro-5-methylpyrrolo[1,2-f][1,2,4]triazin-4-yl)-N-(4,4,4-trifluoro-
butyl)-2-azaspiro[3.3]heptan-6-amine (0.150 g, 0.387 mmol, 1 eq)
and N-(1-(N-(tert-butoxycarbonyl)sulfamoyl)pyridin-4
(1H)-ylidene)-N-methylmethanaminium (0.139 g, 0.465 mmol, 1.2 eq)
in dichloromethane (10 mL) N,N-diisopropylethylamine (0.142 ml,
0.775 mmol, 2.0 eq) was added and the reaction mixture was allowed
to stir at RT for overnight. Progress of reaction was monitored by
NMR. After completion, the reaction mixture was diluted with water
(50 mL) and extracted with DCM (150 ml.times.2), combined organic
layer was washed with brine (50 mL) and dried over anhydrous sodium
sulfate concentrated to get crude product. The crude product was
triturated in pentane to afford tert-butyl
N-(2-(7-chloro-5-methylpyrrolo[1,2-f][1,2,4]triazin-4-yl)-2-azaspiro[3.3]-
heptan-6-yl)-N-(4,4,4-trifluorobutyl)sulfamoylcarbamate (130 g,
59.36%) as liquid which was used in the next step without
purification. LCMS: 567.1 [M+1].sup.+
[0935] Step-4: Synthesis of
N-(2-(7-chloro-5-methylpyrrolo[1,2-f][1,2,4]triazin-4-yl)-2-azaspiro[3.3]-
heptan-6-yl)-N-(4,4,4-trifluorobutyl)sulfamamide: To a solution of
tert-butyl
N-(2-(7-chloro-5-methylpyrrolo[1,2-f][1,2,4]triazin-4-yl)-2-azaspiro[3.3]-
heptan-6-yl)-N-(4,4,4-trifluorobutyl)sulfamoylcarbamate (0.130 g,
0.229 mmol, 1 eq) in DCM (10 mL) was added TFA (2 mL) and the
mixture was allowed to stir at RT for 2 h. Progress of reaction was
monitored by NMR. After completion, reaction mixture was diluted
with cold water (30 mL) and extracted with ethyl acetate
(3.times.70 mL). Combined organic layer was washed with brine
(3.times.50 mL) and dried over anhydrous sodium sulfate. Removal of
solvent under reduced pressure to obtain the crude, which was
purified by reversed phase to afford
N-(2-(7-chloro-5-methylpyrrolo[1,2-f][1,2,4]triazin-4-yl)-2-azaspiro[3.3]-
heptan-6-yl)-N-(4,4,4-trifluorobutyl)sulfamamide (10 mg, 9.3%).
LCMS: 467.1 [M+1].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. ppm 7.90 (s, 1H), 6.77 (s, 2H), 6.63 (s, 1H), 4.42 (m 2H),
4.30 (m, 2H), 3.83-3.94 (m, 1H), 3.05-3.01 (m, 2H), 2.39 (s, 3H),
2.37-2.19 (m, 5H), 1.78-1.73 (m, 2H).
Example-130: Synthesis of
N-(2,2-difluoroethyl)-N-(2-(7-methoxyquinazolin-4-yl)-2-azaspiro[3.3]hept-
an-6-yl) sulfamamide, (Compound 1.131)
##STR00713##
[0937] The mixture of
N-(2,2-difluoroethyl)-N-(2-azaspiro[3.3]heptan-6-yl)sulfamamide
(104 mg, 0.283 mmoles, 1.1 eq), 4-chloro-7-methoxyquinazoline (50
mg, 0.257 mmoles. 1.0 eq) and DIPEA (0.1 ml, 0.515 mmoles, 2.0 eq)
in DMF (1.2 mL) was allowed to stir at 85.degree. C. for 3 h.
Progress of reaction was monitored by TLC. After completion,
reaction mixture was diluted with cold water (10 mL) and extracted
with ethyl acetate (3.times.10 mL). Combined organic layer was
washed with cold water (2.times.10 mL) and dried over anhydrous
sodium sulfate. Removal of solvent under reduced pressure to obtain
the crude, which was purified by reversed phase chromatography to
afford
N-(2,2-difluoroethyl)-N-(2-(7-methoxyquinazolin-4-yl)-2-azaspiro[3.3]hept-
an-6-yl) sulfamamide (10 mg, 9.3%). LCMS: 414.1 [M+1].sup.+;
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 8.37 (s, 1H), 7.82
(m, 1H), 7.12-7.01 (m, 4H), 6.23-6.17 (m, 1H), 6.03-5.97 (m, 1H),
5.88-5.82 (m, 1H), 4.48-4.41 (m, 2H), 4.39 (m, 2H), 4.00-3.92 (m,
1H), 3.88 (s, 3H), 3.48-3.37 (m, 3H), 2.39-2.29 (m, 3H).
Example-131: Synthesis of
4-(((2-(7-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-azaspiro[3.-
3]heptan-6-yl)amino)methyl)benzenesulfonamide, (Compound 1.132)
##STR00714##
[0939] Step-1: Synthesis of tert-butyl
6-(4-sulfamoylbenzylamino)-2-azaspiro[3.3]heptane-2-carboxylate: To
a stirred solution of tert-butyl
6-oxo-2-azaspiro[3.3]heptane-2-carboxylate (200 mg, 0.946 mmol, 1
eq) in methanol (5 ml) was added 4-(aminomethyl)benzenesulfonamide
acetate (282 mg, 1.13 mmol, 1.2 eq) and the reaction mixture was
stirred at RT for overnight. To the reaction mixture, NaBH.sub.4
(54 mg, 1.41 mmol, 1.5 eq) was added at 0.degree. C. and then
resultant reaction mixture was allowed to stir at 0.degree. C. for
1 h. Progress of reaction was monitored by TLC. After completion,
reaction mixture was concentrated under reduced pressure to get
residue which was diluted with water (50 mL) and extracted with
dichloromethane (2.times.50 mL). Combined organic layer was dried
over anhydrous sodium sulfate. Removal of solvent under reduced
pressure to afford tert-butyl
6-(4-sulfamoylbenzylamino)-2-azaspiro[3.3]heptane-2-carboxylate
(310 mg, 85.87%) which was used in the next step without
purification.
[0940] Step-2: Synthesis of
4-((2-azaspiro[3.3]heptan-6-ylamino)methyl)benzenesulfonamide
2,2,2-trifluoroacetate: To a solution of tert-butyl
6-(4-sulfamoylbenzylamino)-2-azaspiro[3.3]heptane-2-carboxylate
(300 mg, 0.786 mmol, 1.0 eq) in DCM (5 mL) was added TFA (1.5 mL)
and was allowed to stir at RT for 2 h. Progress of reaction was
monitored by TLC. After completion, reaction mixture was
concentrated under reduced pressure to afford crude which was
triturated with diethyl ether to afford
4-((2-azaspiro[3.3]heptan-6-ylamino)methyl)benzenesulfonamide
2,2,2-trifluoroacetate (230 mg, 74.19%).
[0941] Step-3: Synthesis of
4-(((2-(7-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-azaspiro[3.-
3]heptan-6-yl)amino)methyl)benzenesulfonamide: A suspension of
4-((2-azaspiro[3.3]heptan-6-ylamino)methyl)benzenesulfonamide
2,2,2-trifluoroacetate (137 mg, 0.348 mmol, 1.0 eq),
4,7-dichloro-5-methylpyrrolo[2,1-f][1,2,4]triazine (70 mg, 0.348
mmol, 1.0 eq) and DIPEA (90 mg, 0.696 mmol, 2.0 eq) in DMF (1.0 mL)
was allowed to stir at 80.degree. C. for 2 h. Progress of reaction
was monitored by LCMS and TLC. After 2 h, reaction mixture was
diluted with water (10 mL) and extracted with ethyl acetate
(1.times.50 mL). Combined organic layer was washed with brine
(1.times.10 mL) and dried over anhydrous sodium sulfate,
Concentrated under reduced pressure to obtain crude product which
was purified using reversed phase HPLC chromatography to afford
4-(((2-(7-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-azaspiro[3.-
3]heptan-6-yl)amino)methyl)benzenesulfonamide (7 mg, 4.5%). LCMS:
447 [M+1].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm
8.25 (br. s., 1H), 7.89 (s, 1H), 7.75 (d, J=8.3 Hz, 2H), 7.49 (d,
J=7.9 Hz, 2H), 7.29 (s, 2H), 6.62 (s, 1H), 4.36 (s, 2H), 4.28 (br.
s., 2H), 3.67 (s, 2H), 3.13-3.00 (m, 2H), 2.38 (s, 3H), 2.02-1.90
(m, 3H).
Example-132: Synthesis of
4-(((2-(7-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-azaspiro[3.-
3]heptan-6-yl)(methyl)amino)methyl)benzenesulfonamide, (Compound
1.133)
##STR00715##
[0943] Step-1: Synthesis of 2-azaspiro[3.3]heptan-6-one
2,2,2-trifluoroacetate: To a solution of tert-butyl
6-oxo-2-azaspiro[3.3]heptane-2-carboxylate (200 mg, 0.946 mmol, 1.0
eq) in DCM (5 mL) was added TFA (1.0 mL) and was allowed to stir at
RT for 2 h. Progress of reaction was monitored by TLC. After
completion, reaction mixture was concentrated under reduced
pressure to obtain crude which was triturated with diethyl ether to
afford 2-azaspiro[3.3]heptan-6-one 2,2,2-trifluoroacetate as
desired product (160 mg, 75.11%).
[0944] Step-2: Synthesis of
2-(7-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-azaspiro[3.3]hep-
tan-6-one: A suspension of 2-azaspiro[3.3]heptan-6-one
2,2,2-trifluoroacetate (112 mg, 0.497 mmol, 1.0 eq),
4,7-dichloro-5-methylpyrrolo[2,1-f][1,2,4]triazine (100 mg, 0.298
mmol, 1.0 eq) and DIPEA (128 mg, 0.994 mmol, 2.0 eq) in DMF (1.0
mL) was allowed to stir at 80.degree. C. for 2 h. Progress of
reaction was monitored by LCMS and TLC. After 2 h, reaction mixture
was diluted with water (10 mL) and extracted with ethyl acetate
(1.times.50 mL). Combined organic layer was washed with brine
(1.times.10 mL) and dried over anhydrous sodium sulfate and
concentrated under reduced pressure to obtain
2-(7-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-azaspiro[-
3.3]heptan-6-one as crude product which was used in next step
without further purification (150 mg, 87.59%). LCMS: 277
[M+1].sup.+
[0945] Step-3: Synthesis of
4-(((2-(7-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-azaspiro[3.-
3]heptan-6-yl)amino)methyl)benzenesulfonamide: To a stirred
solution of
2-(7-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-azaspiro[3.3]hep-
tan-6-one (120 mg, 0.433 mmol, 1 eq) in methanol (5 ml) was added
4-(aminomethyl)benzenesulfonamide acetate (129 mg, 0.519 mmol, 1.2
eq) and the reaction mixture was stirred at RT for overnight. To
the reaction mixture, NaBH.sub.4 (25 mg, 0.649 mmol, 1.5 eq) was
added at 0.degree. C. and then resultant reaction mixture was
allowed to stir at 0.degree. C. for 1 h. Progress of reaction was
monitored by TLC. After completion, reaction mixture was
concentrated under reduced pressure to get residue which was
diluted with water (50 mL) and extracted with dichloromethane
(2.times.50 mL). Combined organic layer was dried over anhydrous
sodium sulfate. Removal of solvent under reduced pressure to afford
4-(((2-(7-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-azaspiro[3.-
3]heptan-6-yl)amino)methyl)benzenesulfonamide which was used in the
next step without purification (70 mg, 36.26%). LCMS: 447
[M+1].sup.+
[0946] Step-4: Synthesis of
4-(((2-(7-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-azaspiro[3.-
3]heptan-6-yl)(methyl)amino)methyl)benzenesulfonamide: To a stirred
solution of
4-(((2-(7-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-azaspiro[3.-
3]heptan-6-yl)amino)methyl)benzenesulfonamide (70 mg, 0.156 mmol, 1
eq) in formaldehyde (2 ml) was added formic acid (2 ml) and the
reaction mixture was stirred at 90.degree. C. for overnight.
Progress of reaction was monitored by TLC. After completion,
reaction mixture was concentrated under reduced pressure to get
residue which was diluted with water (10 mL) and extracted with
dichloromethane (1.times.50 mL). Combined organic layer was dried
over anhydrous sodium sulfate. Removal of solvent under reduced
pressure which was purified by reverse phase HPLC chromatography to
afford
4-(((2-(7-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-a-
zaspiro[3.3]heptan-6-yl)(methyl)amino)methyl)benzenesulfonamide (8
mg, 11.11%). LCMS: 461 [M+1].sup.+; .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 7.90 (s, 1H), 7.77 (d, J=7.9 Hz, 2H),
7.47 (d, J=7.9 Hz, 2H), 7.31 (s, 2H), 6.63 (s, 1H), 4.42 (s, 2H),
4.31 (s, 2H), 3.40 (br. s., 2H), 2.83 (br. s., 1H), 2.40 (s, 3H),
2.33 (br. s., 1H), 2.09 (br. s., 2H), 1.98-1.82 (m, 3H), 1.24 (br.
s., 1H).
Example-133: Synthesis of
N-(2-(7-chloro-5-methyl-5H-pyrrolo[3,2-d]pyrimidin-4-yl)-2-azaspiro[3.3]h-
eptan-6-yl)-N-(2,2-difluoroethyl)sulfamamide, (Compound 1.134)
##STR00716##
[0948] The mixture of
N-(2,2-difluoroethyl)-N-(2-azaspiro[3.3]heptan-6-yl)sulfamamide
2,2,2-trifluoroacetate salt (202 mg, 0.55 mmol, 1.1 eq),
4,7-dichloro-5-methyl-5H-pyrrolo[3,2-d]pyrimidine (100 mg, 0.5
mmol, 1.0 eq) and DIPEA (0.2 ml, 1.0 mmol, 2.0 eq) in DMF (1.5 mL)
was allowed to stir at 80.degree. C. for 3 h. Progress of reaction
was monitored by TLC. After completion, reaction mixture was
diluted with cold water (10 mL) and extracted with ethyl acetate
(3.times.20 mL). Combined organic layer was washed with cold water
(2.times.10 mL) and dried over anhydrous sodium sulfate. Removal of
solvent was done under reduced pressure to obtain the crude, which
was purified by reverse phase chromatography to afford
N-(2-(7-chloro-5-methyl-5H-pyrrolo[3,2-d]pyrimidin-4-yl)-2-azaspir-
o[3.3]heptan-6-yl)-N-(2,2-difluoroethyl)sulfamamide (5 mg, 23%).
LCMS: 421 [M+1].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
ppm 8.26 (s, 1H), 8.14 (s, 2H), 7.72 (s, 1H), 7.02 (s, 2H),
6.16-6.11 (m, 1H), 6.02 (m, 2H), 5.88-5.81 (br. s., 2H), 4.36 (s,
2H), 4.26 (s, 2H), 4.01-3.93 (m, 1H), 3.89 (s, 3H), 3.48-3.39 (m,
2H), 2.28-2.22 (m, 2H).
Example-134: Synthesis of
N-(2-(7-methoxyquinazolin-4-yl)-2-azaspiro[3.3]heptan-6-yl)-N-(3,3,3-trif-
luoro-2-hydroxypropyl)sulfamamide, (Compound 1.135)
##STR00717##
[0950] The mixture of
N--(N-(2-azaspiro[3.3]heptan-6-yl)-N-(3,3,3-trifluoro-2-hydroxypropyl)sul-
famamide 2,2,2-trifluoroacetate salt (261 mg, 0.567 mmol, 1.1 eq),
4-chloro-7-methoxyquinazoline (100 mg, 0.515 mmol, 1.0 eq) and
DIPEA (0.2 mL, 1.030 mmol, 2.0 eq) in DMF (1 mL) was allowed to
stir at 80.degree. C. for 2 h. Progress of reaction was monitored
by TLC. After completion, reaction mixture was diluted with ice
cold water (15 mL) and extracted with ethyl acetate (3.times.15
mL). Combined organic layer was washed with cold water (2.times.10
mL) and dried over anhydrous sodium sulfate. Removal of solvent was
done under reduced pressure to obtain the crude, which was purified
by reverse phase chromatography to afford
N-(2-(7-methoxyquinazolin-4-yl)-2-azaspiro[3.3]heptan-6-yl)-N-(3,3,3-trif-
luoro-2-hydroxypropyl)sulfamamide (20 mg, 8.4%). LCMS: 462
[M+1].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 8.37
(s, 1H), 7.83-7.78 (m, 1H), 7.11-7.01 (m, 2H), 6.91-6.87 (m, 2H),
6.52-6.57 (m, 1H), 4.48-4.40 (m, 4H), 4.18-4.12 (m, 1H), 3.88 (s,
3H), 2.86-2.96 (m, 2H), 2.33-2.28 (m 3H), 1.91 (s, 2H).
BIOLOGICAL EXAMPLES
Example-B1: ENPP1 Inhibition Assay
[0951] IC.sub.50 values of compounds against ENPP-1 (Ectonucleotide
Pyrophosphatase/Phosphodiesterase 1) were determined at Integral
BioSciences (India) using AMP Glo (Promega, Cat #V5011). Assay was
performed in a 30 .mu.L final volume in a white 96-well Half Area
plate (Costar, Cat #3693). Dose response curve for the compounds
were prepared in duplicates with starting conc. at 5 .mu.M and a
three-fold titration was performed. The reaction buffer consisted
of 50 mM Tris (pH 8.0), 0.5 mM CaCl.sub.2), 1 .mu.M ZnCl.sub.2, 250
mM NaCl and 0.1 mg/ml BSA. To the compound dilution, 15 uL of ENPP1
enzyme (R&D Systems; Cat #6136-EN-010) was added to each well
(final conc. 1 nM) and the mix was pre-incubated for 15 min at RT.
An equal volume (15 .mu.L) containing cGAMP (Sigma, Cat #SML-1229)
(final conc. 20 .mu.M) was added to initiate the enzyme reaction
and the reaction was incubated for 30 min at RT. The reaction was
then stopped by heating at 90.degree. C. for 3 minutes. 10 .mu.l of
reaction was then transferred to 384 well white, medium binding
plates (Grenier, Cat #781075) to which 10 .mu.l of AMP-Glo Reagent
1 was added and mixed well and incubated for 1 hour at 25.degree.
C. Following 60 min incubation, 20 .mu.L of detection mixture was
added to the enzyme reaction bringing the final volume to 40 .mu.L.
The reaction was further incubated for 60 min at RT after which the
plates were read using BioTek Plate reader.
[0952] Analysis was done using the standard curve by non-linear
regression, variable slope inhibitor curve fits (Graph-Pad Prism)
and IC.sub.50's of compounds were determined wherever possible.
[0953] The results of the ENPP1 inhibition assay are shown in
tables B1.
TABLE-US-00003 TABLE B1 ENPP1 Inhibition Assay Compound No. ENPP-1
IC.sub.50 (cGAMP; uM) 1.1 0.008 1.2 >5.0 1.3 0.220 1.4 0.072 1.5
0.160 1.6 0.090 1.7 0.120 1.8 0.008 1.9 0.032 1.10 0.028 1.11 0.090
1.12 0.004 1.13 0.011 1.14 0.120 1.15 0.005 1.16 0.076 1.17 0.057
1.18 >3.0 1.19 0.084 1.20 0.070 1.21 0.092 1.22 0.009 1.23 0.029
1.24 0.002 1.25 0.660 1.26 0.006 1.27 0.043 1.28 0.026 1.29 0.892
1.30 0.019 1.31 >3.0 1.32 >3.0 1.33 0.248 1.34 >3.0 1.35
0.099 1.36 0.464 1.37 >3.0 1.38 >3.0 1.39 0.056 1.40 0.793
1.41 0.737 1.42 >3.0 1.43 0.892 1.44 >3.0 1.45 >3.0 1.46
0.019 1.47 0.855 1.48 0.144 1.49 >1.980 1.50 1.476 1.51 0.015
1.52 0.043 1.53 0.122 1.54 1.681 1.55 0.036 1.56 0.085 1.57 0.011
1.58 0.660 1.59 >3.0 1.60 0.347 1.61 0.097 1.62 0.067 1.63 0.012
1.64 0.145 1.65 0.078 1.66 0.006 1.67 ND 1.68 0.003 1.69 0.003 1.70
0.024 1.71 >3.0 1.72 >3.0 1.73 0.247 1.74 ND 1.75 0.391 1.76
0.084 1.77 0.295 1.78 0.964 1.79 0.053 1.80 0.616 1.81 0.245 1.82
1.894 1.83 >3.0 1.84 >2.252 1.85 >2.385 1.86 0.106 1.87
0.024 1.88 ND 1.89 >3.0 1.90 >3.0 1.91 >3.0 1.92 1.505
1.93 0.019 1.94 >3.0 1.95 1.884 1.96 >3.0 1.97 0.036 1.98
0.055 1.99 0.010 1.100 >3.0 1.101 >3.0 1.102 0.812 1.103
0.590 1.104 >2.71 1.105 0.091 1.106 >3.0 1.107 0.061 1.108
>3.0 1.109 0.189 1.110 0.395 1.111 0.398 1.112 0.141 1.113 0.169
1.114 0.039 1.115 0.051 1.116 0.069 1.117 0.239 1.118 0.072 1.119
0.218 1.120 0.018 1.121 0.565 1.122 0.062 1.123 0.039 1.124 1.86
1.125 0.050 1.126 0.023 1.127 0.043 1.128 0.030 1.129 0.047 1.130
0.081 1.131 0.055 1.132 0.181 1.133 0.270 1.134 ND 1.135 ND *ND =
Not Done
Example-B2: IP-10 Cytokine Release Assay in THP-1 Cell Lines
[0954] Percent release of Interferon gamma-induced protein 10
(IP-10) was determined in acute monocytic leukemia (THP-1;
ATCC.RTM. TIB-202.TM.) cell line. THP-1 cells (0.2.times.10.sup.6
cells/well) were differentiated using phorbol 12-myristate
13-acetate (PMA, 10 nM (final concentration); Cat #P8139, Sigma)
and incubated for 24 h at 37.degree. C., 5% CO2 in an incubator
(cell culture conditions) prior to treating with serial dilutions
of compounds (3 fold, 6 point dose response starting at 10 .mu.M).
After treatment with the compounds cells were further incubated for
2 h under cell culture conditions and then exposed to 2',3'-cGAMP
(c-GAMP, 1 .mu.M (final concentration); Cat #SML 1229, Sigma).
Differentiated THP-1 cells were further cultured for 24 h after
which the supernatant was harvested, and ELISA was performed as per
the manufacturer's protocol (BD optEIA Human IP-10 ELISA Set; Cat
#550926 & 550534, BD Biosciences). Plates were read in Biotek
plate reader by measuring absorbance at 450 nm.
[0955] The release of absolute IP-10 in differentiated THP-1 by
compounds in the presence of cGAMP was quantified with reference to
standard after subtracting blank (negative) reading from the test
readings. The absolute release of IP-10 in the presence of cGAMP (1
.mu.M) is given in the bar-graph (FIG. 1) and in the table-B2a.
TABLE-US-00004 TABLE B2a Absolute percent release of IP-10 in THP-1
cell lines Percent release Compound/cGAMP IP-10 (Absolute) CGAMP (1
.mu.M) 5.6 CGAMP (1 .mu.M) + Compound 1.1 (10 .mu.M) 18.3 CGAMP (1
.mu.M) + Compound 1.1 (3.33 .mu.M) 13.1 CGAMP (1 .mu.M) + Compound
1.1 (1.11 .mu.M) 11.4 CGAMP (1 .mu.M) + Compound 1.1 (0.37 .mu.M)
8.9 CGAMP (1 .mu.M) + Compound 1.1 (0.12 .mu.M) 7.0 No drug/No
cGAMP 3.4
[0956] The release of IP-1 in differentiated THP-1 by compounds
over cGAMP induced release at four different concentrations of
cGAMP (1, 5, 10 & 30 .mu.M) was quantified with reference to
standard by normalizing the blank (negative) subtracted test
readings from average of cGAMP activated cells at that particular
concentration. The EC.sub.50's, was calculated by fitting the curve
to the "four-parameter variable slope logistic model" using Prism
Graph Pad.
[0957] The results are given in the table B2b.
TABLE-US-00005 TABLE B2b EC.sub.50 of compounds at different
concentration of cGAMP in THP-1 cell lines EC.sub.50 EC.sub.50
EC.sub.50 EC.sub.50 (.mu.M)@ (.mu.M)@ (.mu.M)@ (.mu.M)@ Compound 1
.mu.M of 5 .mu.M of 10 .mu.M of 30 .mu.M of No. cGAMP cGAMP cGAMP
cGAMP 1.1 0.308 <0.12 0.471 0.624 1.6 7.78 ND ND ND 1.7 >30
ND ND ND 1.17 0.129 ND ND ND 1.19 <0.120 ND ND ND 1.20 5.73 ND
ND ND 1.21 1.884 ND ND ND 1.22 0.490 ND ND ND 1.23 7.872 ND ND ND
1.26 <0.120 ND ND ND 1.27 <0.100 ND ND ND 1.28 9.559 ND ND ND
1.30 <0.120 ND ND ND 1.35 >30 ND ND ND 1.39 3.26 ND ND ND
1.46 0.912 ND ND ND 1.47 19.92 ND ND ND 1.48 >30 ND ND ND 1.49
>30 ND ND ND 1.50 >30 ND ND ND 1.51 >30 ND ND ND 1.52
>18.6 ND ND ND 1.63 <0.120 ND ND ND 1.66 <0.120 ND ND ND
1.69 0.724 ND ND ND 1.70 0.304 ND ND ND 1.76 0.071 ND ND ND *ND =
Not Done
Example-B3: IFN-.beta. Cytokine Release Assay in THP-1
[0958] Percent release of Interferon Beta (IFN-.beta.) was
determined in acute monocytic leukemia (THP-1; ATCC.RTM.
TIB-202.TM.) cell line. THP-1 cells (0.3.times.10.sup.6 cells/well)
were differentiated using phorbol 12-myristate 13-acetate (PMA, 50
ng/mL; Cat #P8139, Sigma) and incubated for 24 h at 37.degree. C.,
500 CO.sub.2 in an incubator (cell culture conditions) prior to
treating with serial dilutions of compounds (3 fold, 5 point dose
response starting at 30 .mu.M). After treatment with the compounds
cells were further incubated for 2 h under cell culture conditions
and then exposed to 2',3'-cGAMP (c-GAMP, 1 .mu.M; Cat #SML 1229,
Sigma). Differentiated THP-1 cells were further cultured for 6 h
after which the supernatant was harvested, and ELISA was performed
as per the manufacturer's protocol (Human IFN-beta Quantikine ELISA
Kit; Cat #DIFNB0, R&D systems). Plates were read in Biotek
plate reader by measuring absorbance at 450 nm.
[0959] The release of IFN-.beta. in differentiated THP-1 by
compounds over cGAMP induced release, was quantified with reference
to standard by normalizing the blank (negative) subtracted test
readings from average of c-GAMP activated cells and the IC.sub.50
was calculated by fitting the curve to the "four-parameter variable
slope logistic model" using Prism Graph Pad.
[0960] The results are presented in the table B3.
TABLE-US-00006 TABLE B3 EC.sub.50 of compounds at 1 .mu.M
concentration of cGAMP in THP-1 cell lines Compound No. EC.sub.50
(.mu.M) @ 1 .mu.M of cGAMP 1.1 <3.35 1.6 >30 1.20 >30 1.21
>30 1.23 >30 1.28 >30 1.30 >30 1.39 >30 1.70 2.82
1.71 >30 1.76 <0.120
Example-B4: IFN-.beta. in Mouse Splenocyte Assay
[0961] Percent release of Interferon Beta (IFN-.beta.) is
determined in mouse splenocytes isolated from Balb/c mice. Mouse
splenocytes (2.5*10.sup.5 cells/well) were activated with
Anti-mouse CD3e (3 .mu.g/ml, coated overnight at 4.degree. C.; Cat
#14-0032-82, eBioscience) and then incubated with Anti-mouse CD28
(3 .mu.g/ml soluble; Cat #16-0289-81, eBiosciences) for 24 h at
37.degree. C., 5% CO.sub.2 in an incubator (cell culture
conditions) prior to treating them with serial dilutions of
compounds (3 fold, 6 point dose response starting at 30 .mu.M).
After treatment with the compounds cells are further incubated for
2 h under cell culture conditions and then treated with 2',3'-cGAMP
(c-GAMP, 1 .mu.M; Cat #SML 1229, Sigma). Splenocytes were further
incubated under cell culture conditions for 24 hr after which the
supernatant was harvested, and ELISA was performed as per the
manufacturer's protocol (mIFN-.beta. kit; Cat #MIFNB0 & DY008,
R&D Systems). Plates were read in Biotek plate reader by
measuring absorbance at 450 nm.
[0962] The release of IFN-.beta. in mouse splenocytes by compounds
was quantified with reference to standard by normalizing the blank
(negative) subtracted test readings from average of c-GAMP
activated cells and the IC.sub.50 was calculated by fitting the
curve to the "four-parameter variable slope logistic model" using
Prism Graph Pad. The results are given in the table B4.
TABLE-US-00007 TABLE B4 IC.sub.50 for IFN-.beta. in mouse
splenocyte assay IFN-.beta. in mouse splenocyte Compound No.
IC.sub.50 (.mu.M) 1.1 3.088 1.76 3.258
Example-B5: IP-10 in Mouse Splenocyte Assay
[0963] Percent release of Interferon gamma-induced protein 10
(IP-10) was determined in mouse splenocytes isolated from Balb/c
mice. Mouse splenocytes (2.5*10.sup.5 cells/well) were activated
with Anti-mouse CD3e (3 .mu.g/ml, coated overnight at 4.degree. C.;
Cat #14-0032-82, eBioscience) and then incubated with Anti-mouse
CD28 (3 .mu.g/ml soluble; Cat #16-0289-81, eBiosciences) for 24 h
at 37.degree. C., 5% CO.sub.2 in an incubator (cell culture
conditions) prior to treating them with serial dilutions of
compounds (3 fold, 6 point dose response starting at 30 .mu.M).
After treatment with the compounds cells were further incubated for
2 h under cell culture conditions and then treated with 2',3'-cGAMP
(c-GAMP, 1 .mu.M; Cat #SML 1229, Sigma). Splenocytes were further
incubated under cell culture conditions for 48 hr after which the
supernatant was harvested, and ELISA was performed as per the
manufacturer's protocol (mIP-10 kit; Cat #DY466-05 & DY008,
R&D Systems). Plates were read in Biotek plate reader by
measuring absorbance at 450 nm.
[0964] The release of IP-10 in mouse splenocytes by compounds was
quantified with reference to standard by normalizing the blank
(negative) subtracted test readings from average of c-GAMP
activated cells and the IC.sub.50 was calculated by fitting the
curve to the "four-parameter variable slope logistic model" using
Prism Graph Pad. The results are shown in the table B5.
TABLE-US-00008 TABLE B5 IC.sub.50 for IP-10 in mouse splenocyte
assay IP-10 in mouse splenocyte Compound No. IC.sub.50 (.mu.M) 1.1
1.722 1.76 1.776
Example-B6: Determination of TBK1, IRF3 and NF-kB-p65
(Phosphorylated & Total) in THP-1 Assay
[0965] Determination of phosphorylated and total TBK1, IRF3 and
NF-kB-p65 is done in acute monocytic leukemia (THP-1; ATCC.RTM.
TIB-202.TM.) cell line. THP-1 cells (2*10{circumflex over ( )}6
cells/well) are activated with PMA (50 ng/ml; Cat #P8139, Sigma)
for 24 hour following which compound treatment for the induction of
TBK1 and its phoshorylation (Ser172) expression is done. After 24
hour of incubation, the differentiated THP-1 cells are treated with
30 .mu.M of compound for 2 hour and then exposed to cGAMP (10
.mu.g/mL; SML 1229, Sigma) for 90 min in cell culture conditions.
The cells are harvested, lysed and sonicated using 1.times.RIPA
buffer (Cat #9806; Cell Signaling Technologies) with protease
inhibitor (1.times.) and phosphatase inhibitor (1.times.). Protein
estimation is done using Bradford and sample is prepared in
5.times. Sample loading buffer. The samples are run by SDS PAGE
Electrophoresis and the protein bands are transferred onto PVDF
membrane by wet transfer. The membrane is blocked in 5% nonfat dry
milk and incubated with primary antibody (TBK; 1:1000, Cat #3504S;
Cell Signaling Technologies) and (phoshoTBK1; 1:1000, Cat #5483S;
Cell Signaling Technologies), (IRF3-1:1000, Cat #4302S; Cell
Signaling Technologies) and (phoshoIRF3-1:1000, Cat #4947S; Cell
Signaling Technologies), (NF-kB p65; 1:1000, Cat #8242S; Cell
Signaling Technologies) and (phosho NF-kB p65; 1:1000, Cat #3033S;
Cell Signaling Technologies) and secondary antibody (Anti rabbit
IgG; 1:2000; Cell Signaling Technologies). The membrane is then
developed using ECL reagent in a gel doc system. The expression of
protein is quantified by densitometry analysis.
* * * * *