NZ792179A - Pyrazolopyridine derivatives as hpk1 modulators and uses thereof for the treatment of cancer - Google Patents
Pyrazolopyridine derivatives as hpk1 modulators and uses thereof for the treatment of cancerInfo
- Publication number
- NZ792179A NZ792179A NZ792179A NZ79217917A NZ792179A NZ 792179 A NZ792179 A NZ 792179A NZ 792179 A NZ792179 A NZ 792179A NZ 79217917 A NZ79217917 A NZ 79217917A NZ 792179 A NZ792179 A NZ 792179A
- Authority
- NZ
- New Zealand
- Prior art keywords
- alkyl
- independently selected
- cycloalkyl
- alkenyl
- alkynyl
- Prior art date
Links
- 201000011510 cancer Diseases 0.000 title abstract 2
- 101710008905 hpk-1 Proteins 0.000 title 1
- 230000000051 modifying Effects 0.000 title 1
- 150000005229 pyrazolopyridines Chemical class 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract 5
- 125000002947 alkylene group Chemical group 0.000 claims 7
- 125000000041 C6-C10 aryl group Chemical group 0.000 claims 5
- 125000000753 cycloalkyl group Chemical group 0.000 claims 5
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims 5
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 4
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims 4
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims 4
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 claims 4
- 229910052799 carbon Inorganic materials 0.000 claims 4
- 125000001424 substituent group Chemical group 0.000 claims 3
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims 2
- 125000004432 carbon atoms Chemical group C* 0.000 claims 2
- 125000005843 halogen group Chemical group 0.000 claims 2
- 229910052717 sulfur Inorganic materials 0.000 claims 2
- 229910003667 SRa Inorganic materials 0.000 claims 1
- 125000003118 aryl group Chemical group 0.000 claims 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims 1
- 125000001072 heteroaryl group Chemical group 0.000 claims 1
- 125000005842 heteroatoms Chemical group 0.000 claims 1
- 125000004043 oxo group Chemical group O=* 0.000 claims 1
- 229910052760 oxygen Inorganic materials 0.000 claims 1
- 150000003839 salts Chemical class 0.000 claims 1
- 239000011780 sodium chloride Substances 0.000 claims 1
- 101700017591 sra-7 Proteins 0.000 claims 1
- 102100013144 MAP4K1 Human genes 0.000 abstract 2
- 101710038956 MAP4K1 Proteins 0.000 abstract 2
- 201000010099 disease Diseases 0.000 abstract 2
- 230000000694 effects Effects 0.000 abstract 2
- 230000002730 additional Effects 0.000 abstract 1
- 230000002401 inhibitory effect Effects 0.000 abstract 1
- 239000008194 pharmaceutical composition Substances 0.000 abstract 1
Abstract
Disclosed are compounds of Formula (I), methods of using the compounds for inhibiting HPK1 activity and pharmaceutical compositions comprising such compounds. The compounds are useful in treating, preventing or ameliorating diseases or disorders associated with HPK1 activity such as cancer.
Description
PYRAZOLOPYRIDINE COMPOUNDS AND USES THEREOF
This application is a onal application from New d patent application no. 752472. The
disclosures of New Zealand patent application no. 752472 and corresponding international patent
application no. , are orated herein by reference in their entirety.
FIELD OF THE INVENTION
The disclosure provides compounds as well as their compositions and methods of use. The
compounds modulate poietic progenitor kinase 1 (HPK1) ty and are useful in the
treatment of various diseases including cancer.
BACKGROUND OF THE INVENTION
Hematopoietic progenitor kinase 1 (HPK1) originally cloned from hematopoietic
progenitor cells is a member of MAP kinase kinase kinase kinases (MAP4Ks) family, which
includes MAP4K1/HPK1, MAP4K2/GCK, /GLK, MAP4K4/HGK, MAP4K5/KHS, and
/MINK (Hu, M.C., et al., Genes Dev, 1996. 10(18): p. 2251-64). HPK1 is of particular
interest because it is predominantly expressed in hematopoietic cells such as T cells, B cells,
macrophages, dendritic cells, neutrophils, and mast cells (Hu, M.C., et al., Genes Dev, 1996.
(18): p. 2251-64; Kiefer, F., et al., EMBO J, 1996. 15(24): p. 7013-25). HPK1 kinase activity
has been shown to be induced upon activation of T cell ors (TCR) (Liou, J., et al.,
Immunity, 2000. 12(4): p. 399-408), B cell receptors (BCR) (Liou, J., et al., ty, 2000.
12(4): p. 399-408), transforming growth factor receptor (TGF-βR) (Wang, W., et al., J Biol Chem,
1997. ): p. 22771-5; Zhou, G., et al., J Biol Chem, 1999. ): p. 13133-8), or Gscoupled
PGE2 receptors (EP2 and EP4) (Ikegami, R., et al., J Immunol, 2001. 166(7): p. 4689-96).
As such, HPK1 regulates diverse functions of various immune cells.
HPK1 is important in regulating the functions of various immune cells and it has been implicated
in autoimmune diseases and anti-tumor ty (Shui, J.W., et al., Nat Immunol, 2007. 8(1): p.
84-91; Wang, X., et al., J Biol Chem, 2012. 287(14): p. 11037-48). HPK1 knockout mice were
more susceptible to the induction of experimental autoimmune encephalomyelitis (EAE) (Shui,
J.W., et al., Nat Immunol, 2007. 8(1): p. 84-91). In human, HPK1 was downregulated in
peripheral blood mononuclear cells of psoriatic arthritis patients or T cells of systemic lupus
erythematosus (SLE) ts (Batliwalla, F.M., et al., Mol Med, 2005. 11(1-12): p. 21-9). Those
observations suggested that attenuation of HPK1 activity may contribute to autoimmunity in
patients. rmore, HPK1 may also control anti-tumor immunity via T cell-dependent
mechanisms. In the PGE2-producing Lewis lung carcinoma tumor model, the tumors developed
more slowly in HPK1 knockout mice as compared to
wild-type mice (see US 2007/0087988). In addition, it was shown that adoptive transfer of
HPKl deficient T cells was more effective in controlling tumor growth and metastasis than
wild-type T cells (Alzabin, S., et al., Cancer Immunol Immunother, 2010. 59(3): p. 419-29).
Similarly, BMDCs from HPKI knockout mice were more efficient to mount a T cell response
to eradicate Lewis lung carcinoma as compared to wild-type BMDCs in, S., et al., J
l, 2009. 182(10): p. 6187-94). These data, in conjunction with the restricted
expression of HPKl in poietic cells and lack of effect on the normal development of
immune cells, suggest that HPKI may be an excellent drug target for enhancing antitumor
immunity. Accordingly, there is a need for new compounds that modulate HPKl ty.
SUMMARY
The present disclosure provides, inter alia, a compound of Formula (I):
R2 R1
CyA /
l \
N ’N
or a pharmaceutically acceptable salt thereof, wherein constituent variables are defined
herein.
The present disclosure further provides a pharmaceutical composition comprising a
compound of the disclosure, or a pharmaceutically acceptable salt thereof, and at least one
pharmaceutically acceptable r or excipient.
The present disclosure further provides methods of inhibiting HPKI activity, which
comprises administering to an individual a compound of the sure, or a
pharmaceutically acceptable salt thereof.
The present disclosure further provides methods of ng a disease or disorder in a
t comprising administering to the t a therapeutically effective amount of a
compound of the disclosure, or a pharmaceutically acceptable salt thereof.
DETAILED DESCRIPTION
The present disclosure provides, a compound of Formula (I):
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R2 R1
CyA /
| \
N \ N/
or a pharmaceutically acceptable salt thereof, wherein:
R1 is selected from Cyl, C1-6 alkyl, C2—6 alkenyl, C2-6 alkynyl, Ci.6 haloalkyl, halo, CN,
N02, 0R3, SR3, C(O)Rb, C(O)NRCRd, C(O)OR"‘, b, OC(O)NRCRd, NRCR“,
NRCC(O)Rb, NR“C(O)ORa, )NRCRd, C(=NRe)Rb, C(=NORa)Rb, C(=NRe)NRcRd,
NRCC(=NR6)NRCRd, NRCS(O)Rb, NRCS(O)2R", NRCS(O)2NRCRd, , S(O)NR“Rd, and
S(O)2NRCRd; wherein said C1—6 alkyl, C2—6 alkenyl and C26 l are each optionally
substituted with l, 2, 3, or 4 substituents independently selected from R10,
Cy1 is selected from C340 lkyl, 4-10 membered heterocycloalkyl, C640 aryl and
-10 membered heteroaryl, wherein each 4-10 membered heterocycloalkyl and 5-10
membered heteroaryl has at least one orming carbon atom and 1, 2, 3, or 4 ring-forming
heteroatoms independently selected from N, O, and S; wherein the N and S are optionally
oxidized; wherein a ring-forming carbon atom of 5-10 membered heteroaryl and 4-10
membered heterocycloalkyl is optionally substituted by oxo to form a carbonyl group; and
wherein the C340 cycloalkyl, 4-10 membered heterocycloalkyl, C640 aryl and 5-10 membered
heteroaryl are each optionally substituted with l, 2, 3 or 4 substituents independently selected
from R10;
CyA is C640 aryl optionally substituted with l, 2, 3 or 4 substituents independently
ed from R20;
R2 is ed from H, C1—6 alkyl, C2—6 alkenyl, C2—6 alkynyl, Ci-6 haloalkyl, C340
cycloalkyl, 4-10 membered heterocycloalkyl, C640 aryl, 5-10 membered heteroaryl, C340
cycloalkyl-C1-3 alkylene, 4-10 membered heterocycloalkyl-Ci-3 alkylene, C640 aryl-Ci—3
alkylene, 5-10 membered heteroaryl-Ci.3 alkylene, halo, CN, ORa7, SRa7, C(O)Rb7,
C(O)NRC7Rd7, C(O)OR37, NRC7Rd7, NRC7C(O)R"7, NRC7C(O)ORa7, NRC7S(O)R"7,
NRC7S(O)2R"7, NRC7S(O)2NRC7Rd7, S(O)Rb7, S(O)NRC7Rd7, S(O)2Rb7, and S(O)2NRC7Rd7;
wherein said C1-6 alkyl, C2-6 alkenyl, C2—6 alkynyl, C340 cycloalkyl, 4-10 membered
cycloalkyl, C640 aryl, 5—10 ed heteroaryl, C340 cycloalkyl-C1—3 alkylene, 4—1 0
membered heterocycloalkyl-Cm alkylene, C640 aryl-C14 ne and 5-10 membered
heteroaryl-Cm alkylene are each optionally tuted with 1, 2, 3, or 4 substituents
independently selected from R30;
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each R10 is independently selected from C1—6 alkyl, C2—6 alkenyl, C2-6 alkynyl, C1-6
haloalkyl, C340 cycloalkyl, 4-10 membered heterocycloalkyl, C640 aryl, 5-10 membered
heteroaryl, C340 cycloalkyl-Cm ne, 4-10 membered cycloalkyl-Ga alkylene, C6-
aryl-C1—3 alkylene, 5-10 membered heteroaryl-C1-3 alkylene, halo, CN, N02, ORal, SR“,
C(O)Rbl, C(O)NR°1R‘“, C(O)0Ra1, OC(O)Rb1, OC(O)NRC1R‘“,NRC1RC”, NRC1C(O)Rb1,
NRC1C(O)OR31, NRC1C(O)NR“1R‘“, C(=NRel)Rb1, C(=N0Ra1)Rb1, C(=NR61)NRcle1,
NR“1C(=NR61)NR°1R‘“, NRc1S(0)Rb1, NRCIS(O)2R"1,NRC18(O)2NRC1Rd1, S(O)Rb1,
S(O)NRC1R‘“, S(O)2Rb1, and S(O)2NRC1R‘“; wherein said C1-6 alkyl, C2-6 alkenyl, C2-6
alkynyl, C340 cycloalkyl, 4-10 membered heterocycloalkyl, C640 aryl, 5-10 membered
heteroaryl, C340 cycloalkyl-Cm alkylene, 4-10 membered heterocycloalkyl-C13 alkylene, C6-
aryl-C1—3 ne and 5-10 membered heteroaryl-C1—3 alkylene are each optionally
substituted with 1, 2, 3, or 4 substituents independently ed from R“;
or two R10 substituents taken together with the carbon atom to which they are attached
form a spiro 3membered heterocycloalkyl ring, or a spiro C3-6 lkyl ring; wherein
each spiro 3-7—membered heterocycloalkyl ring has at least one ring-forming carbon atom
and 1, 2 or 3, ring—forming heteroatoms independently selected from N, O, and S; wherein a
ring-forming carbon atom of each spiro 3membered heterocycloalkyl ring is ally
substituted by oxo to form a carbonyl group; and n the spiro 3membered
cycloalkyl ring and spiro C3—6 cycloalkyl ring are each optionally substituted with 1, 2,
3 or 4 substituents independently selected from R“,
each R11 is independently selected from C1—6 alkyl, C2-6 alkenyl, C2-6 l, C1-6
haloalkyl, C340 cycloalkyl, 4-10 membered heterocycloalkyl, C640 aryl, 5-10 ed
heteroaryl, C340 cycloalkyl-Cm alkylene, 4-10 membered heterocycloalkyl-C13 alkylene, C6-
aryl-C1-3 alkylene, 5-10 ed heteroaryl-C1-3 alkylene, halo, CN, ORa3, SRa3, C(O)Rb3,
C(O)NRC3Rd3, C(O)0Ra3, NRc3Rd3, O)R"3, NRC3C(O)ORa3, NRC3S(O)Rb3,
NRC3S(O)2R"3, NRC3S(O)2NRC3Rd3, S(O)Rb3, S(O)NRC3Rd3, b3, and S(O)2NRC3Rd3,
wherein said C1-6 alkyl, C2—6 alkenyl, C2—6 alkynyl, C340 cycloalkyl, 4-10 membered
cycloalkyl, C640 aryl, 5-10 membered heteroaryl, C340 cycloalkyl-Cm alkylene, 4-10
membered heterocycloalkyl-C13 alkylene, C640 aryl-C1.3 alkylene and 5-10 membered
heteroaryl-C1-3 alkylene are each optionally substituted with 1, 2, 3, or 4 substituents
independently selected from R”;
each R12 is independently selected from C1-6 alkyl, C2-6 l, C2-6 alkynyl, C1-6
haloalkyl, C3-6 cycloalkyl, C640 aryl, 5-10 membered heteroaryl, 4—7 membered
cycloalkyl, halo, CN, ORaS, SRaS, C(O)Rb5, C(O)NRC5Rd5, C(O)OR35, NR°5Rd5,
W0 20183’049200
NRCSC(O)R"5, NRCSC(O)OR35, NRCSS(O)R"5, O)2Rb5, NRCSS(O)2NRC5Rd5, S(O)Rb5,
C5Rd5, S(O)2Rb5, and R95Rd5, n said C1-6 alkyl, C2-6 alkenyl, C2-6
alkynyl, C3.6 cycloalkyl, C640 aryl, 5-10 ed heteroaryl and 4-7 ed
heterocycloalkyl are each optionally substituted with 1, 2, 3, or 4 substituents independently
selected from Rg;
each R20 is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6
haloalkyl, C340 cycloalkyl, 4-10 membered heterocycloalkyl, C640 aryl, 5-10 membered
aryl, C340 cycloalkyl-C13 alkylene, 4-10 membered heterocycloalkyl-C1-3 alkylene, C6-
aryl-C1-3 alkylene, 5-10 membered heteroaryl-C1-3 alkylene, halo, CN, N02, ORaZ, SRaZ,
C(O)Rb2, C(O)NRC2Rd2, C(O)OR"‘2, OC(O)Rb2, OC(O)NRC2Rd2, NRCZR‘”, NRC2C(O)R'°2,
NRC2C(O)ORa2, NRCZC(O)NRC2Rd2, C(=NR62)Rb2, C(=N0Ra2)Rb2, C(=NR€2)NRc2Rd2,
NR62C(=NR62)NR62Rd2, NRCZS(O)R'32, NRCZS(O)2R"2, NRCZS(O)2NRC2Rd2, S(O)R"2,
S(O)NRCZRd2, S(O)2Rb2, and RC2Rd2; wherein said C1-6 alkyl, C2-6 alkenyl, C2-6
alkynyl, C340 cycloalkyl, 4-10 membered heterocycloalkyl, C640 aryl, 5-10 membered
heteroaryl, C340 cycloalkyl-C13 alkylene, 4-10 membered heterocycloalkyl-C1-3 alkylene, C6—
aryl-C1—3 alkylene and 5—10 membered heteroaryl-C1—3 alkylene are each optionally
substituted with 1, 2, 3, or 4 tuents independently selected from R“;
or two adjacent R20 substituents on the CyA ring, taken together with the atoms to
which they are attached, form a fused C3—7 cycloalkyl ring, wherein a ring-forming carbon
atom of the fused C3.7 cycloalkyl ring is optionally substituted by oxo to form a carbonyl
group; and wherein the fused C3.7 cycloalkyl ring is optionally substituted with 1, 2, 3 or 4
tuents independently selected from R21,
each R21 is independently ed from C1—6 alkyl, C2—6 l, C2—6 alkynyl, C1-6
haloalkyl, C340 cycloalkyl, 4-10 membered heterocycloalkyl, C640 aryl, 5-10 membered
heteroaryl, C340 cycloalkyl-C13 alkylene, 4-10 membered heterocycloalkyl-C1-3 alkylene, C6-
aryl-C1—3 alkylene, 5-10 ed heteroaryl-C1—3 ne, halo, CN, ORa4, SR“, C(O)Rb4,
C(0)NRc4Rd4, C(O)OR34, NRC4Rd4, NRc4C(0)Rb4, NRC4C(O)ORa4, NRC4S(O)R"4,
NRC4S(O)2R"4, NRC4S(O)2NRC4Rd4, S(O)Rb4, S(O)NRC4Rd4, S(O)2Rb4, and S(O)2NR“4Rd4;
wherein said C1-6 alkyl, C26 alkenyl, C2—6 alkynyl, C340 cycloalkyl, 4-10 membered
heterocycloalkyl, C640 aryl, 5-10 membered heteroaryl, C340 cycloalkyl-C13 alkylene, 4—10
membered heterocycloalkyl-C1-3 alkylene, C640 aryl-C1.3 alkylene and 5-10 membered
heteroaryl-C1.3 alkylene are each optionally substituted with 1, 2, 3, or 4 substituents
independently selected from R”,
W0 2018f049200
or two R21 tuents taken together with the carbon atom to which they are attached
form a spiro C3-7 lkyl ring; wherein a ring-forming carbon atom of the spiro C34
cycloalkyl ring is optionally tuted by 0x0 to form a carbonyl group; and wherein the
spiro C3—7 cycloalkyl ring is optionally substituted with 1, 2, 3 or 4 substituents independently
selected from R”;
each R22 is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6
haloalkyl, C3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl, 4-7 ed heterocycloalkyl,
halo, CN, OR“, SRa6, C(O)Rb6, C(O)NRC6Rd6, C(O)OR"‘6, NRCGRdG, O)Rb6,
NRCGC(O)OR36, NRCGS(0)Rb6, NRCGS(O)2R"6, NRCGS(O)2NRCGRd6, 6, S(O)NRC6Rd6,
S(O)2Rb6, and S(O)2NRC6Rd6, wherein said C1—6 alkyl, C2—6 alkenyl, C2—6 alkynyl, C3—6
cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-7 membered cycloalkyl are each
ally substituted with 1, 2, 3, or 4 substituents independently selected from Rg;
each R30 is independently selected from C1—6 alkyl, C2-6 alkenyl, C2—6 l, C16
haloalkyl, C3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl,
halo, CN, ORaS, SRaS, C(O)Rb8, C(O)NRC8Rd8, C(O)OR38, NRCSRdS, NRCSC(O)R"8,
NRCSC(O)OR33, NRCBS(O)RbS, NRcss(O)2Rb8, NRCSS(O)2NRC8R‘18, S(O)Rb8, S(O)NRCSRd3,
S(O)2Rb8, and S(O)2NR°SRdS; wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6
cycloalkyl, phenyl, 5-6 ed heteroaryl and 4-7 membered heterocycloalkyl are each
optionally substituted with 1, 2, 3, or 4 substituents independently selected from Rg;
each R3 and RC is independently selected from H, C16 alkyl, C2—6 alkenyl, C2-6 alkynyl,
C1-6 haloalkyl, C340 cycloalkyl, 4-10 ed heterocycloalkyl, C640 aryl and 5—10
membered heteroaryl; wherein said C1—6 alkyl, C2—6 alkenyl, C2-6 alkynyl, C340 cycloalkyl, 4-
membered heterocycloalkyl, C640 aryl and 5-10 membered heteroaryl are each optionally
substituted with 1, 2, 3, or 4 substituents independently ed from R”,
each Rd is independently selected from C1—6 alkyl, C2—6 alkenyl, C2—6 alkynyl, C1—6
haloalkyl, C340 cycloalkyl, 4-10 membered heterocycloalkyl, C640 aryl and 5-10 membered
heteroaryl; wherein said 06 alkyl, C2—6 alkenyl, C2—6 alkynyl, C340 cycloalkyl, 4-10
membered heterocycloalkyl, C640 aryl and 5-10 ed heteroaryl are each optionally
substituted with 1, 2, 3, or 4 substituents independently selected from R10;
or any Rc and Rd attached to the same N atom, together with the N atom to which they
are attached, form a 4-10 membered heterocycloalkyl group optionally substituted with 1, 2,
3 or 4 substituents independently selected from R10;
each Rb is independently selected from C1-6 alkyl, C2—6 alkenyl, C2-6 alkynyl, C1-6
haloalkyl, C340 lkyl, 4-10 ed heterocycloalkyl, C640 aryl, and 5-10 membered
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aryl; wherein said C1-6 alkyl, C2—6 alkenyl, C2—6 alkynyl, C340 cycloalkyl, 4-10
membered heterocycloalkyl, C640 aryl and 5-10 membered aryl are each optionally
tuted with 1, 2, 3, or 4 substituents independently selected from R10;
each R6 is independently selected from H, CN, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkylthio,
C1-6 alkylsulfonyl, C1.6 alkylcarbonyl, Ci-6 alkylaminosulfonyl, yl, C1-6 alkylcarbamyl,
6 alkyl)carbamyl, aminosulfonyl, Ci.6 alkylaminosulfonyl and di(C1—6
alkyl)aminosulfonyl;
each R31, RCl and Rdl is ndently selected from H, C16 alkyl, C2—6 alkenyl, C2-6
alkynyl, C1-6haloa1ky1, C340 lkyl, 4-10 membered heterocycloalkyl, C640 aryl and 5-10
membered heteroaryl; wherein said C1—6 alkyl, C2—6 alkenyl, C2—6 alkynyl, C340 cycloalkyl, 4-
membered heterocycloalkyl, C640 aryl and 5-10 membered heteroaryl are each optionally
substituted with 1, 2, 3, or 4 substituents independently selected from R“;
or any RCl and R(11 attached to the same N atom, together with the N atom to which
they are attached, form a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionally
substituted with 1, 2, 3 or 4 substituents independently selected from R“;
each Rbl is independently selected from C1—6 alkyl, C2—6 alkenyl, C2-6 alkynyl, C1-6
kyl, C340 cycloalkyl, 4-10 membered heterocycloalkyl, C640 aryl and 5-10 ed
heteroaryl; wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 l, C340 cycloalkyl, 4-10
membered heterocycloalkyl, C640 aryl and 5-10 membered heteroaryl are each optionally
tuted with 1, 2, 3, or 4 substituents independently selected from R“;
each R61 is independently ed from H, CN, C1-6 alkyl, Ci.6 haloalkyl, Cl-6
alkylthio, C1-6 alkylsulfonyl, Ci.6 alkylcarbonyl, Ci.6 alkylaminosulfonyl, carbamyl, C1—6
alkylcarbamyl, di(Ci-6 alkyl)carbamyl, aminosulfonyl, Ci.6 alkylaminosulfonyl and d1(C1-6
alky1)aminosulfony1;
each Raz, RC2 and Rdz, is independently selected from H, C16 alkyl, C2—6 alkenyl, C2—6
alkynyl, C1-6 haloalkyl, C340 cycloalkyl, 4-10 membered heterocycloalkyl, C640 aryl and 5-10
membered heteroaryl, wherein said C1—6 alkyl, C2—6 alkenyl, C2—6 alkynyl, C340 cycloalkyl, 4-
membered heterocycloalkyl, C640 aryl and 5-10 membered heteroaryl are each optionally
substituted with 1, 2, 3, or 4 substituents independently selected from R21;
or any Rcz and R£12 attached to the same N atom, together with the N atom to which
they are attached, form a 4-, 5-, 6- or 7-membered heterocycloalkyl group ally
substituted with 1, 2, 3 or 4 substituents independently selected from R“;
each R” is independently selected from C1-6 alkyl, C2-6 alkenyl, C2—6 alkynyl, C1-6
haloalkyl, C340 cycloalkyl, 4-10 membered heterocycloalkyl, C640 aryl and 5—10 membered
W0 2018f049200
heteroaryl; wherein said C1-6 alkyl, C2-6 l, C2-6 alkynyl, C3—1o cycloalkyl, 4-10
membered heterocycloalkyl, C6-10 aryl and 5-10 membered heteroaryl are each optionally
substituted with 1, 2, 3, or 4 substituents independently selected from R“;
each R"2 is ndently selected from H, CN, C1-6 alkyl, C1-6 haloalkyl, C1-6
alkylthio, Cl-6 alkylsulfonyl, C1-6 alkylcarbonyl, C1-6 alkylaminosulfonyl, carbamyl, C1-6
alkylcarbamyl, di(C1-6 alkyl)carbamyl, aminosulfonyl, C1-6 alkylaminosulfonyl and d1(C1-6
alkyl)aminosulfonyl;
each R33, RC3 and R“, is independently selected from H, C1-6 alkyl, C2—6 alkenyl, C2-6
l, C1-6 haloalkyl, C3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-7 membered
heterocycloalkyl; wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 l, C3-6 lkyl, phenyl,
-6 membered heteroaryl and 4-7 membered heterocycloalkyl are each optionally substituted
with 1, 2, 3, or 4 substituents independently selected from R”,
or any RC3 and R(13 attached to the same N atom, together with the N atom to which
they are attached, form a 4-, 5-, 6- or 7-membered heterocycloalkyl group ally
substituted with 1, 2 or 3 substituents independently selected from R”;
each R'33 is independently ed from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6
haloalkyl, C3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-7 membered
heterocycloalkyl; wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 lkyl, phenyl,
-6 membered heteroaryl and 4-7 membered heterocycloalkyl are each optionally tuted
with 1, 2, 3, or 4 substituents independently ed from R”;
each R34, RC4 and Rd“, is independently selected from H, C1-6 alkyl, Cz—e alkenyl, C2-6
alkynyl, C1-6 haloalkyl, C3-6 cycloalkyl, phenyl, 5-6 ed aryl and 4-7 membered
heterocycloalkyl; wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 l, C3-6 cycloalkyl, phenyl,
-6 membered heteroaryl and 4-7 membered cycloalkyl are each optionally substituted
with 1, 2, 3, or 4 substituents independently selected from R22,
or any R04 and RC14 attached to the same N atom, together with the N atom to which
they are attached, form a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionally
substituted with 1, 2 or 3 substituents independently selected from R";
each R'34 is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6
haloalkyl, C3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-7 membered
heterocycloalkyl; wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 lkyl, phenyl,
-6 membered heteroaryl and 4-7 membered heterocycloalkyl are each optionally substituted
with 1, 2, 3, or 4 substituents independently selected from R”;
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each R35, RCS and R“, is independently selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6
alkynyl and Cl-6 haloalkyl, wherein said C1-6 alkyl, C2-6 alkenyl and C24 alkynyl are each
optionally substituted with 1, 2, 3, or 4 substituents independently selected from Rg;
each R” is independently selected from C14 alkyl, C2-6 l, C2-6 alkynyl and C14
haloalkyl, wherein said C1-6 alkyl, C2-6 alkenyl and C2-6 alkynyl are each ally
substituted with 1, 2, 3, or 4 substituents independently ed from Rg;
each R36, RC6 and Rd6 is independently selected from H, C1-6 alkyl, C2—6 alkenyl, C2-6
alkynyl and C1-6haloalkyl; wherein said C1-6 alkyl, C2-6 alkenyl and C24 alkynyl are each
optionally substituted with 1, 2, 3, or 4 substituents independently selected from Rg;
each Rb6 is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6
haloalkyl, wherein said C1-6 alkyl, C2-6 l and C2-6 alkynyl are each optionally
substituted with 1, 2, 3, or 4 substituents independently selected from Rg;
each R37, RC7, and Rd7 is independently selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6
alkynyl, Cl-6 haloalkyl, C340 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl and 5-10
membered heteroaryl; wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C340 cycloalkyl, 4-
ed heterocy yl, C6-10 aryl and 5-10 membered heteroaryl are each optionally
substituted with 1, 2, 3, or 4 substituents ndently selected from R30;
or any RC7 and RC17 attached to the same N atom, together with the N atom to which
they are attached, form a 4-, 5-, 6- or 7-membered cycloalkyl group optionally
substituted with 1, 2 or 3 substituents independently selected from R30;
each Rb7 is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6
kyl, C340 cycloalkyl, 4-10 membered cycloalkyl, C6-10 aryl, 5-10 membered
heteroaryl; wherein said C1-6 alkyl, C2-6 l, C2-6 alkynyl, C340 cycloalkyl, 4—10
membered heterocycloalkyl, C6-10 aryl and 5-10 membered heteroaryl are each optionally
substituted with 1, 2, 3, or 4 tuents independently ed from R30,
each R38, RC8 and R“, is independently selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6
alkynyl, C1-6 haloalkyl, C3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl and 4—7 membered
heterocycloalkyl; wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, phenyl,
-6 membered aryl and 4-7 membered heterocycloalkyl are each optionally substituted
with 1, 2, 3, or 4 substituents independently selected from Rg,
or any RCS and Rds attached to the same N atom, together with the N atom to which
they are attached, form a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionally
substituted with 1, 2 or 3 substituents independently selected from Rg;
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each Rbg is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6
haloalkyl, C3-6 cycloalkyl, , 5-6 ed heteroaryl and 4-7 membered
heterocycloalkyl; wherein said C1-6 alkyl, C2-6 l, C2-6 l, C3-6 cycloalkyl, phenyl,
-6 membered heteroaryl and 4-7 membered heterocycloalkyl are each optionally substituted
with 1, 2, 3, or 4 substituents independently selected from Rg; and
each Rg is ndently selected from OH, N02, CN, halo, C1-6 alkyl, C2-6 alkenyl,
C2-6 alkynyl, Cl-6 haloalkyl, C3-6 cycloalkyl, C3-6 cycloalkyl-Cm alkylene, C1—6 alkoxy, C1-6
haloalkoxy, C1-3 alkoxy-Ci-3 alkyl, C1-3 alkoxy-C1-3 alkoxy, HO-C1—3 alkoxy, HO-C1—3 alkyl,
cyano-C1—3 alkyl, H2N-C1-3 alkyl, amino, C1-6 alkylamino, 6 alkyl)amino, thio, C1-6
alkylthio, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, carbamyl, C1-6 alkylcarbamyl, dl(Cl-6
alkyl)carbamyl, carboxy, C1-6 alkylcarbonyl, C1-6 alkoxycarbonyl, C1-6 alkylcarbonylamino,
C1-6 alkylsulfonylamino, aminosulfonyl, C1-6 alkylaminosulfonyl, dl(C1-6 alkyl)aminosulfonyl,
aminosulfonylamino, C1-6 alkylaminosulfonylamino, dl(C1-6 alkyl)aminosulfonylamino,
arninocarbonylamino, C1-6 alkylaminocarbonylamino, and dl(C1-6 alkyl)aminocarbonylamino;
provided that
1) R1 is other than CH3;
2) Rb is other than unsubstituted or substituted piperidine;
3) Rb is other than unsubstituted or substituted propyl;
4) when Rb is phenyl, then R10 is other than pyrrolidin-l-ylmethyl; and
5) when CyA is phenyl or halo-phenyl, then Rb is other than cyclopropyl and
cyclopentyl.
In some embodiments, CyA is C6-10 aryl optionally tuted with 1, 2, or 3
tuents independently selected from R20.
In some embodiments, CyA is phenyl optionally substituted with 1, 2, 3, or 4
substituents independently ed from R20. In some embodiments, CyA is phenyl ally
substituted with 1, 2, or 3 substituents independently ed from R20.
In some embodiments, CyA is phenyl ally substituted with 1, 2, 3, or 4
substituents independently selected from R20, wherein optionally two adjacent R20
substituents on the CyA ring, taken together with the atoms to which they are attached, form a
fused C3.7 cycloalkyl ring; wherein a ring-forming carbon atom of each fused C3.7 cycloalkyl
ring is optionally substituted by oxo to form a carbonyl group; and wherein the fused C3-7
cycloalkyl ring are each optionally substituted with 1, 2, 3 or 4 substituents independently
selected from R“.
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In some embodiments, each R20 is independently selected from C1-6 alkyl, C2-6
alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C340 cycloalkyl, 4-10 membered heterocycloalkyl, 4-10
membered heterocycloalkyl-Ci-3 alkylene, C6-10 aryl, 5-10 membered heteroaryl, halo, CN,
N02, ORaZ, SRaZ, C(O)Rb2, C(O)NR°2Rd2, C(O)0Ra2, b2, OC(O)NR°2R“2, NRCZRdz,
NRC2C(O)Rb2, NR°2C(O)OR"‘2, NR“2C(O)NRC2Rd2, NRCZS(O)Rb2, NRCZS(O)2R"2,
NRCZS(O)2NR°2Rd2, S(0)Rb2, S(O)NRC2Rd2, S(O)2Rb2, and S(O)2NRC2Rd2; wherein said C13
alkyl, C2-0 l, C2-6 alkynyl, C340 cycloalkyl, 4-10 membered heterocycloalkyl, 4-10
ed heterocycloalkyl-Ci.3 alkylene, C6-10 aryl, and 5-10 membered heteroaryl are each
optionally substituted with 1, 2, or 3 substituents independently ed from R21; or two
nt R20 substituents on the CyA ring, taken together with the atoms to which they are
attached, form a fused C3—7 lkyl ring, wherein a ring-forming carbon atom of each
fused C3-7 lkyl ring is optionally substituted by oxo to form a carbonyl group; and
n the fused C3-7 cycloalkyl ring are each optionally substituted with 1, 2, 3 or 4
tuents independently selected from R21.
In some ments, each R20 is independently selected from C1-6 alkyl, C2-6
alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C340 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10
aryl, 5-10 membered heteroaryl, halo, CN, N02, ORaZ, SRaz, C(O)Rb2, C(O)NRCZRd2,
C(O)OR32, OC(O)Rb2, OC(O)NRCZRd2, NRCZRdZ, NRC2C(O)Rb2, NRCZC(O)OR32,
NRC2S(O)R"2, NRC2S(O)2Rb2, NRCZS(O)2NR°2Rd2, S(O)Rb2, S(O)NRC2Rd2, S(O)2Rb2, and
S(O)2NR°2R“2; wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 l, C340 cycloalkyl, 4—10
membered heterocycloalkyl, C6-10 aryl, and 5-10 membered heteroaryl are each optionally
substituted with 1, 2, or 3 substituents ndently ed from R21, or two adjacent R20
substituents on the CyA ring, taken together with the atoms to which they are ed, form a
fused C3-7 cycloalkyl ring, wherein a ring-forming carbon atom of each fused C3.7 cycloalkyl
ring is optionally substituted by oxo to form a carbonyl group, and wherein the fused C3-7
cycloalkyl ling are each optionally substituted with 1, 2, 3 or 4 substituents independently
selected from R“.
In some embodiments, each R20 is independently selected from C1-6 alkyl, C2-6
alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C340 cycloalkyl, 4-10 membered heterocycloalkyl, 4-10
membered heterocycloalkyl-C1—3 alkylene, C6-10 aryl, 5-10 membered heteroaryl, halo, ORaZ,
C(O)Rb2, C(O)NRC2Rd2, C(O)OR32, OC(O)R'°2, OC(O)NRC2Rd2, NRCQR‘fl, NRCZC(O)Rb2,
NRCZC(O)OR32, and NRC2C(O)NRCZR‘12; wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl,
C340 cycloalkyl, 4—10 membered heterocycloalkyl, 4-10 membered heterocycloalkyl-C1—3
alkylene, C6-10 aryl, and 5-10 membered heteroaryl are each optionally substituted with 1, 2,
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or 3 substituents independently selected from R21, or two adjacent R20 substituents on the CyA
ring, taken together with the atoms to which they are attached, form a fused C3-7 lkyl
ring; wherein a ring-forming carbon atom of each fused C3-7 cycloalkyl ring is optionally
substituted by oxo to form a yl group; and wherein the fused C3—7 cycloalkyl ring are
each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R“.
In some ments, each R20 is independently selected from C1-6 alkyl, C2-6
alkenyl, C2—6 alkynyl, C1-6 haloalkyl, C3-1o lkyl, 4-10 membered heterocycloalkyl, C6-10
aryl, 5-10 membered heteroaryl, halo, ORaZ, C(O)Rb2, C(O)NRC2Rd2, C(O)OR32, NRCZRdZ,
NR92C(O)Rb2, and NRC2C(O)ORa2, wherein said C1-6 alkyl, C2-6 l, C2-6 alkynyl, C3—10
cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl, and 5-10 membered heteroaryl are
each optionally substituted with 1, 2, or 3 substituents independently selected from R“; or
two adjacent R20 substituents on the CyA ring, taken together with the atoms to which they are
attached, form a fused C3.7 lkyl ring, wherein a orming carbon atom of each
fused C3-7 cycloalkyl ring is optionally substituted by oxo to form a carbonyl group; and
wherein the fused C3: cycloalkyl ring are each optionally substituted with 1, 2, 3 or 4
substituents independently selected from R21.
In some embodiments, each R20 is independently selected from C1-6 alkyl, C1-6
haloalkyl, €3.10 cycloalkyl, halo, 4-10 membered heterocycloalkyl, 4-10 membered
heterocycloalkyl-C1—3 alkylene, ORaZ, C(O)Rb2, C(O)NRC2Rd2, OC(O)Rb2, OC(O)NRC2Rd2,
NRCszZ, NR°2C(O)Rb2, NR“2C(O)OR32, and NRC2C(O)NRC2Rd2; wherein said C1—6 alkyl, C340
cycloalkyl, 4—10 membered heterocycloalkyl, and 4-10 membered heterocycloalkyl-C1.3
ne are each ally substituted with 1 or 2 tuents independently selected from
R21; or two adj acent R20 substituents on the CyA ring, taken together with the atoms to which
they are attached, form a fused C3.7 cycloalkyl ring, and wherein the fused C3-7 cycloalkyl
ring is optionally tuted with 1, 2, 3 or 4 substituents independently selected from R21.
In some embodiments, each R20 is independently selected from C1-6 alkyl, C1-6
haloalkyl, C340 cycloalkyl, halo, and ORaZ, wherein said C1-6 alkyl and C340 lkyl are
each optionally substituted with 1 or 2 substituents ndently selected from R“; or two
adjacent R20 substituents on the CyA ring, taken together with the atoms to which they are
attached, form a fused C3.7 cycloalkyl ring, and wherein the fused C3.7 cycloalkyl ring is
optionally substituted with 1, 2, 3 or 4 substituents independently selected from R“.
In some embodiments, each R20 is independently selected from C1-6 alkyl, C1-6
kyl, 4—10 membered heterocycloalkyl, 4-10 membered heterocycloalkyl-C1—3 alkylene,
and halo; wherein said C1-6 alkyl, 4-10 membered heterocycloalkyl, and 4—10 membered
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heterocycloalkyl-C13 alkylene are each optionally tuted with 1 or 2 substituents
independently selected from R“; or two adjacent R20 substituents on the CyA ring, taken
together with the atoms to which they are attached, form a fused C3-7 cycloalkyl nng; and
wherein the fused C3-7 cycloalkyl ring is optionally substituted with 1, 2, 3 or 4 substituents
independently selected from R“.
In some embodiments, each R20 is independently selected from C1-6 alkyl optionally
substituted with 1 or 2 substituents independently selected from R21. In some embodiments,
each R21 is independently selected from 4-10 membered heterocycloalkyl or NR°4Rd4. In
some embodiments, each RC4 and RC”, is independently selected from H or C1-6 alkyl. In some
embodiments, R20 is (C1-6 alkyl), 4-6 membered heterocycloalkyl, CH2-(4-6
membered heterocycloalkyl). In some embodiments, R20 is H3, CH2NH(i-propyl),
CH2-azetidinyl, CH2NH(CH2)CH3, 0r CH(CH3)(NHCH3).
In some embodiments, R20 is halo, C1-6 alkyl, C1-6 haloalkyl, (Cl-6 alkyl), 4-6
membered heterocycloalkyl, or CH2-(4-6 membered heterocycloalkyl), In some
embodiments, R20 is fluoro, methyl, trifluoromethyl, CH2NHCH3, i-propyl), CH2-
azetidinyl, CH2NH(CH2)CH3, or CH(CH3)(NHCH3).
In some embodiments, each R20 is independently selected from methyl,
trifluoromethyl, cyclopropyl substituted with methanamine, fluoro, chloro, hydroxy, methoxy,
ethoxy, C(O)NH(CH2)2OCH3, CO-(3-methoxyazetidin-l-yl), NHC(O)—cyclobutyl, NHC(O)-
benzyl, amino, dimethylamino, NHC(O)CH2-(pyrrolidin-l-yl), NHC(O)—( l-methyllH-pyrazolyl
), CHz-(cyclopentyl), CH2-(pyridinyl), NHC(O)CH2-(7-
azabicyclo[2.2.1]heptanyl), NHC(O)-(7-oxa—2-azaspiro[3.5]nonanyl),
NHC(O)CH(CH3)—(pyrrolidinyl), NHC(O)NH(CH2)2OCH3, NHC(O)CHz-(azetidin-l-yl),
NHC(O)CH2—(3,3-dimethylazetidin-l-yl), NHC(O)C-(l-methylpiperidinyl), NHC(O)CH2-
(dimethylamino), NHC(O)CH2-((1R,4S)—2-azabicyclo[2.2.1]heptanyl), NHC(O)(CH2)2-
(dimethylamino), CHzCN, (methylamino)methyl, azetidin-l-ylmethyl, CH2NH-
(tetrahydro—2H—pyranyl), (isopropylamino)methyl, cyclobutyl-NHCH(CH3)2,
(methylamino)ethy1, (CH2)2NH-(tetrahydro-2H-pyranyl), (CH2)2NH-(l-isopropy1azetidin-
3-yl), OCHz-(azetidinyl), tetrahydro-2H-pyranyloxy, OCH2-(pyridinyl),
OC(O)N(CH3)2, (morpholinyl), CH2NH—(pyridinyl), CHzNH-(l-methyl-IH-
pyrazolyl), CH2NH(CH2)2OH, CH2NH—cyclopropyl, (3-methoxypiperidinyl)methyl,
amino)methyl, pyrrolidin-l-ylmethyl, oxyazetidinyl)methyl, pyrrolidinyl,
l-methylpyrrolidin—Z-yl, piperidin-Z-yl, CH2NHCH2CF3, CH2NH—(3—cyclobutanol), (1-
pyrrolidinol)methyl, H2C(CH3)2OH, CH2NHCH2-(1-methyl-lH-imidazolyl),
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CH2NHCH2-(oxazol—4—yl), H2CN, CH(CH3)NH(CH3), CH2NHC(O)CH3,
CH2NHC(O)O(CH3), difluoromethoxy, cyanomethyl, aminomethyl, (hydroxyl)methyl,
amino, CH2(3,3-dimethylazetidinyl), CH2NH-(3-methoxycyclobutyl), CHzNHCHz-(l-
cyclopropyl), and morpholinyl.
In some embodiments, each R20 is independently ed from methyl,
trifluoromethyl, cyclopropyl substituted with methanamine, fluoro, chloro, hydroxy, methoxy,
and . For example, each R20 is independently methoxy or fluoro.
In some embodiments, CyA is selected from 2-fluoromethoxyphenyl, 1-[1—(3-
fuorophenyl)cyclopropyl]methanamine, 2,6-difluorophenyl, 2,6-dimethylphenyl, 2,4,6-
trifluorophenyl, 2-chlorofluorophenyl, l-hydroxy-3,5-difluoro-phenyl, 2-fluoro
methylphenyl, 2-ethoxyfluorophenyl, 2-chloromethoxyphenyl, and 2-fluoro
(trifluoromethyl)phenyl.
In some embodiments, R1 is ed from Cyl, C1-6 alkyl, C2-6 alkenyl, C2-6 l,
C1-6 kyl, halo, CN, N02, ORa, SRa, C(O)Rb, C(O)NRCRd, C(O)ORa, OC(O)Rb,
OC(O)NRCRd, NRcRd, NRCC(O)Rb, NRCC(O)ORa, NRCS(O)Rb, NRCS(O)2Rb, S(O)Rb,
S(O)NRCRd, and S(O)2NRCRd; wherein said C1-6 alkyl, C2-6 alkenyl and C2-6 alkynyl are each
optionally substituted with l, 2, 3, or 4 substituents independently selected from R10.
In some ments, R1 is selected from Cyl, C1-6 alkyl, C2-6 alkenyl, Cz-e alkynyl,
C1—6 haloalkyl, halo, ORa, C(O)Rb, C(O)NRcRd, C(O)0Ra, NRCRd, NRCC(O)Rb, and
NRCC(O)OR3; n said C1-6 alkyl, C2-6 alkenyl and C2-6 alkynyl are each optionally
substituted with 1, 2, 3, or 4 substituents independently selected from R10.
In some embodiments, R1 is selected from Cyl, C2-6 alkenyl, C(O)NR°R“, NRcRd, and
NRCC(O)Rb; wherein said C2-6 alkenyl is optionally substituted with 1, 2, 3, or 4 substituents
independently selected from R10.
In some embodiments, R1 is ed from Cyl, C(O)NRCRd, NRCRd, and NRCC(O)Rb.
In some embodiments, R1 is ed from phenyl, pyridinyl, pyrazolyl, thiazolyl, C(O)NRCRd
and NRCC(O)R"; wherein the phenyl, pyridinyl, pyrazolyl, and thiazolyl are each optionally
substituted with 1, 2 or 3 substituents independently selected from R10.
In some embodiments:
each Rc is independently selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and
C1-6 haloalkyl;
each R‘l is independently selected from C1-6 alkyl, C2-6 alkenyl, Cz-e alkynyl, C1-6
haloalkyl, and C6-10 aryl; wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C6-10 aryl are
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each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R10;
each Rb is independently selected from 7-10 membered heterocycloalkyl, C640 aryl,
and 5-10 membered heteroaryl; wherein said 7-10 membered heterocycloalkyl, C640 aryl and
—10 membered heteroaryl are each ally substituted with 1, 2, 3, or 4 substituents
independently selected from R10.
In some embodiments:
each RC is H;
each R‘1 is independently selected from C1—6 alkyl and C640 aryl, wherein said C1-6
alkyl and C640 aryl are each ally substituted with 1 or 2 substituents independently
ed from R10; and
each Rb is independently selected from 7-10 membered heterocycloalkyl, C640 aryl,
and 5-10 membered heteroaryl; n said 7-10 membered heterocycloalkyl, C640 aryl and
-10 membered heteroaryl are each optionally substituted with 1 or 2 substituents
independently selected from R10.
In some embodiments, R1 is NRCC(O)Rb. For example, RC can be H, C1-6 alkyl, C2-6
alkenyl, C2-6 alkynyl, or 06 haloalkyl, wherein said C1-6 alkyl, C2-6 alkenyl, and C26 alkynyl
of Rc are each optionally substituted with 1, 2, 3, or 4 tuents independently selected
from R10; and Rh can be selected from C1—6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1—6 kyl, C3—
10 cycloalkyl, 4—10 membered heterocycloalkyl, C640 aryl, and 5-10 membered heteroaryl;
wherein said C1-6 alkyl, C2-6 alkenyl, C2—6 l, C340 cycloalkyl, 4-10 membered
heterocycloalkyl, C640 aryl and 5-10 ed heteroaryl of Rb are each optionally
substituted with 1, 2, 3, or 4 substituents independently selected from R”. In n
embodiments, Rc is H or C16 alkyl, and Rb is ed from C340 cycloalkyl, 4-10 membered
heterocycloalkyl, C640 aryl, and 5-10 membered heteroaryl, wherein said C340 cycloalkyl, 4-
membered heterocycloalkyl, C640 aryl and 5-10 membered heteroaryl are each optionally
substituted with 1, 2, 3, or 4 substituents independently selected from R10. In n
embodiments, Rc is H; and Rb is selected from 4-10 membered heterocycloalkyl, C640 aryl,
and 5-10 membered heteroaryl; wherein said 4-10 membered heterocycloalkyl, C640 aryl and
5-10 membered heteroaryl are each optionally substituted with 1, 2, or 3 substituents
independently selected from R10.
In n embodiments, R1 is Cyl. In certain embodiments, Cy1 is selected from 4-10
membered heterocycloalkyl, C640 aryl and 5-10 membered heteroaryl, wherein each 4-10
membered heterocycloalkyl and 5-10 membered heteroaryl has at least one ring-forming
W0 49200
carbon atom and 1, 2, 3, or 4 orming heteroatoms independently selected from N, O,
and S; n the N and S are optionally oxidized; n a ring-forming carbon atom of
-10 membered heteroaryl and 4-10 membered heterocycloalkyl is optionally substituted by
0x0 to form a carbonyl group; and wherein the 4-10 ed heterocycloalkyl, C640 aryl
and 5—10 membered heteroaryl are each optionally substituted with 1, 2, 3 or 4 substituents
independently selected from R10.
In some embodiments, Cy1 is thiazolyl, isoxazolyl, zinonyl, 1,2,3,4-
tetrahydroisoquinolinyl, piperazinyl, phenyl, lyl, pyridinyl, imidazolyl, or pyrimidinyl,
each is optionally with 1, 2, 3 or 4 substituents independently selected from R10.
In some embodiments, Cy1 is pyrazolyl optionally with 1, 2, or 3 substituents
independently selected from R10. In some embodiments, Cy1 is pyrazolyl optionally with 1
substituents independently selected from R10. In some embodiments, R10 is C16 alkyl. In
some embodiments, Cy1 is lyl optionally substituted with C16 alkyl (e.g., methyl or
ethyl), In some ments, Cy1 is 1-methy1-1H-pyrazoly1. In some ments, Cy1 is
1-ethyl-1H-pyrazoly1.
In certain embodiments, Cy1 is thiazolyl, isoxazolyl, piperazinonyl, 1,2,3,4—
tetrahydroisoquinolinyl, piperazinyl, or phenyl; each is optionally with 1, 2, 3 or 4
substituents independently selected from R”.
In certain embodiments, R1 is C(O)NRCRd. In certain embodiments, RC is selected
from H, 06 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1.6haloa1ky1; wherein said C1-6 alkyl, C2-6
alkenyl, and C2-6 alkynyl of Rc are each optionally substituted with 1, 2, 3, or 4 substituents
independently selected from R10, and RC1 is selected from C340 cycloalkyl, 4-10 membered
heterocycloalkyl, C640 aryl and 5-10 membered heteroaryl, n said C340 cycloalkyl, 4-
membered heterocycloalkyl, C640 aryl and 5-10 membered heteroaryl of R‘1 are each
optionally substituted with 1, 2, 3, or 4 substituents independently selected from R10. In
certain embodiments, RC is H, and RC1 is C640 aryl optionally substituted with 1, 2, or 3
substituents independently selected from R10.
In certain embodiments, R1 is NRCRd. In certain embodiments, RC is selected from H,
C1—6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C16 haloalkyl, wherein said C16 alkyl, C2-6 alkenyl,
and C2-6 alkynyl of Rc are each optionally tuted with 1, 2, 3, or 4 substituents
independently selected from R10; and Rd is selected from C1-6 alkyl, C2-6 l, C2-6 alkynyl,
and C16 haloalkyl; wherein said C1-6 alkyl, C2-6 alkenyl, and C26 alkynyl of RCl are each
optionally substituted with 1, 2, 3, or 4 substituents independently selected from R10. In
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certain embodiments, Rc is H; and Rd is C16 alkyl optionally substituted with 1, 2, or 3
substituents ndently selected from R10.
In n embodiments, each R10 is independently selected from 06 alkyl, C2-6
alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C340 cycloalkyl, 4-10 membered heterocycloalkyl, C640
aryl, 5-10 membered heteroaryl, halo, CN, ORal, SR“, C(O)Rb1, C(O)NRC1R‘”, C(O)ORa1,
OC(O)Rb1, OC(O)NRC1R‘“, NRclel, NRC1C(O)Rb1, NRC1C(O)OR"‘1, NRcls(0)Rbl,
NRcls(0)2Rbl, NRclS(0)2NRc1Rd1, 1, Cle1, S(O)2Rb1, and S(O)2NR°1R‘“;
wherein said C1-6 alkyl, C2-6 alkenyl, C2—6 alkynyl, C340 cycloalkyl, 4-10 membered
heterocycloalkyl, C640 aryl, and 5-10 membered heteroaryl are each optionally substituted
with 1, 2, 3, or 4 substituents independently selected from R“.
In certain embodiments, each R10 is independently selected from 06 alkyl, C2—6
alkenyl, C2—6 alkynyl, C1.6 haloalkyl, C340 cycloalkyl, 4-10 membered cycloalkyl, C640
aryl, 5-10 ed heteroaryl, halo, CN, ORal, SRal, C(O)Rb1, C(O)NRCIR‘“, C(O)OR31,
NRCIR‘“, and NRC1C(O)Rb1; wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C340
cycloalkyl, 4-10 membered heterocycloalkyl, C640 aryl, and 5-10 membered heteroaryl are
each optionally substituted with 1, 2, 3, or 4 tuents independently selected from R“.
In some embodiments, each R10 is independently selected from 06 alkyl, C340
cycloalkyl, 4-10 membered heterocycloalkyl, C640 aryl, 5-10 ed heteroaryl, halo, CN,
ORal, C(O)NRC1R‘“, and NRCIR‘“; wherein said C1—6 alkyl, C340 cycloalkyl, 4—10 membered
cycloalkyl, C640 aryl, and 5-10 membered heteroaryl are each optionally substituted
with I, 2, or 3 substituents independently selected from R“.
In certain embodiments, each R10 is independently selected from C1-6 alkyl, C340
cycloalkyl, 4—10 ed heterocycloalkyl, C640 aryl, 5-10 membered heteroaryl, halo, CN,
and OR“; wherein said C1—6 alkyl, C340 cycloalkyl, 4-10 membered heterocycloalkyl, C640
aryl, and 5-10 membered heteroaryl are each optionally tuted with 1, 2, or 3
substituents independently selected from R“.
In some embodiments, each R11 is independently selected from C1-6 alkyl, C2—6
alkenyl, C2.6 l, C1.6 haloalkyl, C340 cycloalkyl, 4-10 membered heterocycloalkyl, C640
aryl, 5-10 membered heteroaryl, C340 lkyl-C1.3 alkylene, 4-10 membered
heterocycloalkyl-C1-3 alkylene, C640 a1yl-C1—3 alkylene, 5-10 membered heteroaryl—C13
alkylene, halo, CN, OR“, SR”, C(O)Rb3, C(O)NRC3Rd3, C(O)ORa3, NRC3Rd3, NRC3C(O)Rb3,
and NRC3C(O)OR33; wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C340 cycloalkyl, 4-10
membered heterocycloalkyl, C640 aryl, 5-10 membered heteroaryl, C340 cycloalkyl-C1—3
alkylene, 4-10 membered heterocycloalkyl-C1.3 alkylene, C640 aryl-C1.3 alkylene and 5-10
W0 2018f049200
ed heteroaryl-C1.3 ne are each optionally substituted with 1, 2, 3, or 4
substituents independently selected from R”.
In some embodiments, each R11 is independently selected from 06 alkyl, C2-6
l, C2-6 alkynyl, C1-6 kyl, C340 cycloalkyl, 4-10 membered heterocycloalkyl, C640
aryl, 5-10 membered heteroaryl, halo, CN, ORa3, C(O)Rb3, C(O)NRC3Rd3, C(O)ORa3,
NRC3Rd3, and NRC3C(O)Rb3; wherein said C1—6 alkyl, C2-6 alkenyl, C2—6 alkynyl, C340
cycloalkyl, 4—10 membered heterocycloalkyl, C640 aryl, and 5-10 membered heteroaryl are
each optionally tuted with 1, 2, 3, or 4 substituents independently selected from R”.
In some embodiments, each R11 is independently selected from from C16 alkyl, C640
aryl, 5-10 membered heteroaryl, halo, CN, ORa3, a3, wherein said C16 alkyl, C640
aryl, and 5-10 membered aryl are each optionally substituted with 1, 2, or 3
substituents independently selected from R”.
In some embodiments, each R10 is independently selected from methyl, bromo, fluoro,
CN, ethyl, methoxy, 4-morpholinyl, 3-oxopiperazinyl, 4-methylpiperazin-l-yl, yl-
3-oxopiperazin-l-yl, 4-ethylpiperazinyl, 3-oxo(2,2,2-trifluoroethyl)piperazinyl, 4-
(methylsulfonyl)piperazinyl, piperazin-l-yl, ropylpiperazinyl, 4-cyclopropyl
oxopiperazin-l-yl, 4-(methy1sulfonyl)piperazinyl, 4-bromo-phenyl, 4-cyanophenyl, 4-
pyridyl, methylaminocarbonyl, isopropylaminocarbonyl, 3-hydroxypyrrolidinyl, 3-
methoxypiperidin-l-yl, 1-methylpiperidinyl, ethylmethylamino, cyclopropyl, ethyl, 2-
cyanophenyl, tetrahydro-2H-pyrany1, azetidinyl, hydroxyethyl, 4-methoxypiperidin
yl, 3-fluoropyrrolidinyl, 4-methylcarbonylpiperazinyl, and 4-hydroxypiperidin—1-yl, 4-
methoxycarbonylpiperazinyl, amino, 2-hydroxypropylamino, (1-methyl-1H—pyrazol
hylamino, and 3-cyanocyclopentylamino.
In certain embodiments, each R10 is independently selected from methyl, bromo,
fluoro, CN, ethyl, methoxy, 4-morpholinyl, 3-oxopiperazinyl, 4-methylpiperazinyl, 4-
methyloxopiperazinyl, 4-ethylpiperazinyl, 3 -oxo(2,2,2-trifluoroethyl)piperazin
yl, 4-(methylsulfonyl)piperazinyl, piperazin-l-yl, 4-isopropylpiperazin-1—yl, 4-
cyclopropyloxopiperazinyl, 4-(methylsulfonyl)piperazinyl, 4-bromo-phenyl, 4-
cyanophenyl, and 4-pyridy1.
In n embodiments, R2 is selected from H, C1—6 alkyl, C2-6 alkenyl, C2-6 alkynyl,
C1-6 haloalkyl, C340 cycloalkyl, 4-10 membered heterocycloalkyl, C640 aryl, 5-10 membered
heteroaryl, C340 lkyl-C1.3 alkylene, halo, ORa7, C(O)Rb7, C(O)NRC7RC'7, C(O)ORa7,
NRC7Rd7, NR°7C(O)R"7, and O)ORa7; wherein said C1-6 alkyl, C2-6 alkenyl, C2-6
alkynyl, C340 cycloalkyl, 4-10 membered cycloalkyl, C640 aryl, and 5-10 membered
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heteroaryl are each optionally substituted with 1, 2, 3, or 4 substituents independently
selected from R30.
In n embodiments, R2 is selected from H, C1-6 alkyl, C2-6 alkenyl, Cz-e alkynyl,
C1-6 haloalkyl, halo, ORa7, 7, C(O)NRC7Rd7, C(O)ORa7, NRC7Rd7, NR°7C(O)Rb7, and
NRC7C(O)ORa7; wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 l are each optionally
substituted with 1, 2, 3, or 4 substituents independently selected from R”.
In certain embodiments, R2 is selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl,
C1-6 haloalkyl, and halo.
In certain embodiments, R2 is selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 l,
C1-6 haloalkyl, halo, and OR”.
In certain embodiments, R2 is H.
In some embodiments, provided herein is a compound having Formula 11:
CyA /
l \
N\ N,N
wherein CyA and R1 are as described herein, or a pharmaceutically acceptable salt thereof.
In some embodiments, provided herein is a compound having Formula 111:
R2 R1
(R20>n l N
N\ N,
(111)
wherein n is 1, 2, 3, or 4, and R1, R2, and R20 are as described herein; or a pharmaceutically
acceptable salt thereof.
In some embodiments, provided herein is a compound having a IV:
l \
(R20>n N
N\ N,
wherein n is 1, 2, 3, or 4; and R1 and R20 are as described herein; or a pharmaceutically
acceptable salt thereof.
In some embodiments, provided herein is a compound having Formula Va, Formula
Vb, a Vc, or Formula Vd:
(R20>n l N
N\ N,
(Va),
RC\Ner
(R20>n l N
N\ N,
(Vc), or
wherein n is 1, 2, 3, or 4, and R20, Cyl, Rb, RC, and RC1 are as described herein; or a
ceutically acceptable salt thereof.
In some embodiments, provided herein is a compound having Formula Va:
(R20>n I N
N\ N,
wherein n is 1, 2, 3, or 4; and R20 and Cy1 are as described ; or a pharmaceutically
acceptable salt thereof.
In some embodiments, provided herein is a compound having Formula Vb:
(R2°>n | ,N
(Vb),
wherein n is 1, 2, 3, or 4; and R20, Rb and RC are as described herein, or a pharmaceutically
acceptable salt thereof.
In some ments, provided herein is a compound having Formula Vc:
RC\N’Rd
(R20>n l N
N\ N
wherein n is 1, 2, 3, or 4; and R20, Rc and Rd are as described ; or a pharmaceutically
able salt thereof.
In some ments, provided herein is a compound having Formula Vd:
wherein n is 1, 2, 3, or 4, and R20, RC, and RC1 are as described herein; or a pharmaceutically
acceptable salt f.
In some embodiments, provided herein is a compound having Formula Val:
\ —3
(R20)n I N
N\ N!
(Val)
wherein n is 1, 2, 3, or 4; and R20 and R10 are as described herein; or a pharmaceutically
acceptable salt thereof
In some embodiments, n of Formula III, Formula IV, Formula Va, Formula Vb,
Formula Vc, Formula Vd and Formula Val is 2. In some embodiments, n of Formula 111,
Formula IV, Formula Va, Formula Vb, Formula Vc and Formula Vd is 2.
In some embodiments, n of Formula III, a IV, Formula Va, Formula Vb,
Formula Vc, Formula Vd and Formula Val is 1. In some embodiments, n of Formula 111,
a IV, Formula Va, Formula Vb, Formula Vc and Formula Vd is 1.
In some embodiments, n of Formula III, Formula IV, Formula Va, Formula Vb,
Formula Vc, Formula Vd, and Formula Val is 3. In some embodiments, n of Formula 111,
Formula IV, Formula Va, Formula Vb, Formula Vc and Formula Vd is 3.
In some embodiments, n of Formula 111, Formula IV, Formula Va, a Vb,
Formula Vc, Formula Vd and Formula Val is 4.
In some embodiments, each R20 of Formula 111, Formula IV, a Va, Formula
Vb, Formula V0 and Formula Vd is independently methoxy or fluoro. In some embodiments,
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each R20 of Formula 111, Formula IV, Formula Va, Formula Vb, Formula Vc, Formula Vd and
Formula Val is independently methoxy or fluoro.
In some ments, one or more of the hydrogens of any of the formulae described
herein is replaced or substituted with deuterium.
In some embodiments:
R1 is selected from Cyl, C2-6 alkenyl, C2—6 alkynyl, C1.6 haloalkyl, halo, CN, N02, ORa,
SR“, C(O)Rb, C(O)NR“Rd, C(O)OR“‘, OC(O)Rb, OC(O)NRCRd, NRCR“, NRCC(O)Rb,
NRCC(O)ORa, NRCC(O)NRCRd, C(=NRe)Rb, C(=NORa)Rb, C(=NRe)NR°Rd,
NRCC(=NR6)NRCRd, NRCS(O)Rb, )2Rb, NRCS(O)2NRCRd, S(O)Rb, S(O)NRCRd, and
S(O)2NR“Rd; wherein said C2—6 alkenyl and C26 alkynyl are each optionally substituted with
1, 2, 3, or 4 substituents independently selected from R10,
Cy1 is selected from C340 cycloalkyl, 4-10 membered heterocycloalkyl, C640 aryl and
-10 ed heteroaryl, wherein each 4-10 ed heterocycloalkyl and 5-10
membered aryl has at least one ring-forming carbon atom and 1, 2, 3, or 4 ring-forming
heteroatoms independently selected from N, O, and S, wherein the N and S are optionally
ed; wherein a ring-forming carbon atom of 5-10 membered aryl and 4-10
membered heterocycloalkyl is optionally substituted by oxo to form a carbonyl group; and
wherein the C340 cycloalkyl, 4-10 membered heterocycloalkyl, C640 aryl and 5-10 membered
heteroaryl are each optionally substituted with 1, 2, 3 or 4 substituents independently selected
from R10;
CyA is C640 aryl ally substituted with 1, 2, 3 or 4 substituents independently
selected from R20;
R2 is ed from H, C1—6 alkyl, C2—6 alkenyl, C2—6 alkynyl, C1-6 haloalkyl, C340
cycloalkyl, 4-10 membered heterocycloalkyl, C640 aryl, 5-10 membered heteroaryl, C340
lkyl-C1—3 alkylene, 4-10 membered heterocycloalkyl-C14 alkylene, C640 aryl-C1—3
alkylene, 5-10 membered heteroaryl-Cm ne, halo, CN, ORa7, SRa7, C(O)Rb7,
C(O)NRC7Rd7, C(O)OR37, NRC7Rd7, NRC7C(O)R"7, NRC7C(O)ORa7, NRC7S(O)R"7,
NRC7S(O)2R"7, NRC7S(O)2NRC7Rd7, S(O)Rb7, S(O)NRC7Rd7, b7, and S(O)2NRC7Rd7;
wherein said C1-6 alkyl, C2-6 alkenyl, C2—6 alkynyl, C340 cycloalkyl, 4-10 membered
heterocycloalkyl, C640 aryl, 5—10 membered heteroaryl, C340 cycloalkyl-C1—3 alkylene, 4—1 0
membered heterocycloalkyl-Cm alkylene, C640 aryl-C14 alkylene and 5-10 membered
heteroaryl-Cm alkylene are each optionally substituted with 1, 2, 3, or 4 substituents
independently selected from R30;
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each R10 is independently selected from C1—6 alkyl, C2—6 alkenyl, C2-6 alkynyl, C1-6
haloalkyl, C340 cycloalkyl, 4-10 membered heterocycloalkyl, C640 aryl, 5-10 membered
heteroaryl, C340 cycloalkyl-C13 alkylene, 6-10 membered heterocycloalkyl-C13 alkylene, C6-
aryl-C1—3 alkylene, 5-10 membered aryl-C1-3 alkylene, halo, CN, N02, ORal, SR“,
C(O)Rbl, C(O)NR°1R‘“, C(O)0Ra1, OC(O)Rb1, RC1R‘“,NRC1RC”, NRC1C(O)Rb1,
NRC1C(O)OR31, NRC1C(O)NR“1R‘“, C(=NRel)Rb1, C(=N0Ra1)Rb1, C(=NR61)NRcle1,
NR“1C(=NR61)NR°1R‘“, NRc1S(0)Rb1, NRCIS(O)2R"1,NRC18(O)2NRC1Rd1, 1,
S(O)NRC1R‘“, S(O)2Rb1, and S(O)2NRC1R‘“; wherein said C2-6 alkenyl, C2-6 alkynyl, C340
cycloalkyl, 4-10 membered heterocycloalkyl, C640 aryl, 5-10 membered heteroaryl, C340
lkyl-Cm alkylene, 6-10 membered heterocycloalkyl-C13 alkylene, C640 aryl-C1—3
alkylene and 5-10 membered heteroaryl-C1—3 alkylene are each optionally tuted with 1,
2, 3, or 4 substituents independently selected from R“,
or two R10 substituents taken together with the carbon atom to which they are ed
form a spiro mbered heterocycloalkyl ring, or a spiro C3-6 cycloalkyl ring; wherein
each spiro 3-7—membered heterocycloalkyl ring has at least one ring-forming carbon atom
and 1, 2 or 3, ring—forming heteroatoms independently selected from N, O, and S; n a
ring-forming carbon atom of each spiro 3membered heterocycloalkyl ring is optionally
substituted by oxo to form a carbonyl group; and wherein the spiro 3membered
heterocycloalkyl ring and spiro C3—6 cycloalkyl ring are each optionally substituted with 1, 2,
3 or 4 substituents independently selected from R“,
each R11 is independently selected from C1—6 alkyl, C2-6 alkenyl, C2-6 l, C1-6
haloalkyl, C340 cycloalkyl, 4-10 membered heterocycloalkyl, C640 aryl, 5-10 membered
heteroaryl, C340 cycloalkyl-C13 alkylene, 4-10 membered heterocycloalkyl-C13 alkylene, C6-
aryl-C1-3 alkylene, 5-10 membered heteroaryl-C1-3 alkylene, halo, CN, ORa3, SRa3, 3,
C(O)NRC3Rd3, C(O)0Ra3, NRc3Rd3, NRC3C(O)R"3, NRC3C(O)ORa3, O)Rb3,
NRC3S(O)2R"3, O)2NRC3Rd3, S(O)Rb3, S(O)NRC3Rd3, S(O)2Rb3, and S(O)2NRC3Rd3,
wherein said C1-6 alkyl, C2—6 alkenyl, C2—6 alkynyl, C340 lkyl, 4-10 ed
heterocycloalkyl, C640 aryl, 5-10 membered heteroaryl, C340 lkyl-C13 alkylene, 4-10
membered heterocycloalkyl-C13 alkylene, C640 aryl-C1.3 alkylene and 5-10 membered
heteroaryl-C1-3 alkylene are each optionally substituted with 1, 2, 3, or 4 substituents
independently selected from R”;
each R12 is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6
haloalkyl, C3-6 cycloalkyl, C640 aryl, 5-10 membered heteroaryl, 4—7 membered
cycloalkyl, halo, CN, ORaS, SRaS, C(O)Rb5, C(O)NRC5Rd5, C(O)OR35, NR°5Rd5,
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O)R"5, NRCSC(O)OR35, NRCSS(O)R"5, NRCSS(O)2Rb5, NRCSS(O)2NRC5Rd5, S(O)Rb5,
S(O)NRC5Rd5, S(O)2Rb5, and S(O)2NR95Rd5, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6
alkynyl, C3.6 cycloalkyl, C640 aryl, 5-10 membered heteroaryl and 4-7 membered
heterocycloalkyl are each optionally substituted with 1, 2, 3, or 4 substituents independently
selected from Rg;
each R20 is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6
haloalkyl, C340 cycloalkyl, 4-10 membered heterocycloalkyl, C640 aryl, 5-10 membered
heteroaryl, C340 cycloalkyl-C13 alkylene, 4-10 membered heterocycloalkyl-C1-3 alkylene, C6-
1-3 alkylene, 5-10 membered heteroaryl-C1-3 alkylene, halo, CN, N02, ORaZ, SRaZ,
2, C(O)NRC2Rd2, C(O)OR"‘2, OC(O)Rb2, OC(O)NRC2Rd2, NRCZR‘”, NRC2C(O)R'°2,
NRC2C(O)ORa2, NRCZC(O)NRC2Rd2, 2)Rb2, C(=N0Ra2)Rb2, C(=NR€2)NRc2Rd2,
NR62C(=NR62)NR62Rd2, NRCZS(O)R'32, NRCZS(O)2R"2, O)2NRC2Rd2, S(O)R"2,
S(O)NRCZRd2, S(O)2Rb2, and S(O)2NRC2Rd2; n said C1-6 alkyl, C2-6 alkenyl, C2-6
alkynyl, C340 cycloalkyl, 4-10 membered heterocycloalkyl, C640 aryl, 5-10 membered
heteroaryl, C340 cycloalkyl-C13 alkylene, 4-10 membered heterocycloalkyl-C1-3 alkylene, C6—
aryl-C1—3 alkylene and 5—10 membered heteroaryl-C1—3 alkylene are each optionally
substituted with 1, 2, 3, or 4 substituents independently selected from R“;
or two nt R20 substituents on the CyA ring, taken together with the atoms to
which they are attached, form a fused C3—7 cycloalkyl ring, wherein a ring-forming carbon
atom of the fused C3.7 cycloalkyl ring is optionally substituted by oxo to form a carbonyl
group; and wherein the fused C3.7 cycloalkyl ring is optionally substituted with 1, 2, 3 or 4
substituents independently selected from R21,
each R21 is independently selected from C1—6 alkyl, C2—6 alkenyl, C2—6 alkynyl, C1-6
kyl, C340 cycloalkyl, 4-10 membered heterocycloalkyl, C640 aryl, 5-10 membered
heteroaryl, C340 cycloalkyl-C13 alkylene, 4-10 membered heterocycloalkyl-C1-3 alkylene, C6-
aryl-C1—3 ne, 5-10 membered heteroaryl-C1—3 alkylene, halo, CN, ORa4, SR“, C(O)Rb4,
C(0)NRc4Rd4, C(O)OR34, NRC4Rd4, NRc4C(0)Rb4, NRC4C(O)ORa4, NRC4S(O)R"4,
NRC4S(O)2R"4, NRC4S(O)2NRC4Rd4, 4, C4Rd4, S(O)2Rb4, and S(O)2NR“4Rd4;
wherein said C1-6 alkyl, C26 alkenyl, C2—6 alkynyl, C340 cycloalkyl, 4-10 membered
heterocycloalkyl, C640 aryl, 5-10 membered aryl, C340 cycloalkyl-C13 alkylene, 4—10
membered heterocycloalkyl-C1-3 alkylene, C640 aryl-C1.3 alkylene and 5-10 membered
heteroaryl-C1.3 alkylene are each optionally tuted with 1, 2, 3, or 4 substituents
independently selected from R”,
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or two R21 substituents taken together with the carbon atom to which they are attached
form a spiro C3-7 cycloalkyl ring; wherein a orming carbon atom of the spiro C34
cycloalkyl ring is optionally substituted by 0x0 to form a yl group; and wherein the
spiro C3—7 lkyl ring is optionally substituted with 1, 2, 3 or 4 substituents independently
selected from R”;
each R22 is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6
haloalkyl, C3-6 cycloalkyl, phenyl, 5-6 ed heteroaryl, 4-7 membered heterocycloalkyl,
halo, CN, OR“, SRa6, C(O)Rb6, C(O)NRC6Rd6, C(O)OR"‘6, G, NR°6C(O)Rb6,
NRCGC(O)OR36, NRCGS(0)Rb6, NRCGS(O)2R"6, NRCGS(O)2NRCGRd6, S(O)Rb6, S(O)NRC6Rd6,
S(O)2Rb6, and S(O)2NRC6Rd6, wherein said C1—6 alkyl, C2—6 alkenyl, C2—6 l, C3—6
cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl are each
optionally substituted with 1, 2, 3, or 4 substituents independently selected from Rg;
each R30 is independently selected from C1—6 alkyl, C2-6 alkenyl, C2—6 alkynyl, C16
haloalkyl, C3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl,
halo, CN, ORaS, SRaS, C(O)Rb8, C(O)NRC8Rd8, C(O)OR38, NRCSRdS, NRCSC(O)R"8,
NRCSC(O)OR33, NRCBS(O)Rb3, NRcss(O)2Rb3, NRCSS(O)2NRC8R‘18, S(O)Rb8, S(O)NRC3Rd3,
S(O)2Rb8, and S(O)2NR°SRdS; wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6
cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl are each
optionally substituted with 1, 2, 3, or 4 substituents independently selected from Rg;
each R3 and RC is independently selected from H, C16 alkyl, C2—6 alkenyl, C2-6 l,
C1-6 haloalkyl, C340 cycloalkyl, 4-10 membered heterocycloalkyl, C640 aryl and 5—10
membered heteroaryl; n said C1—6 alkyl, C2—6 alkenyl, C2-6 alkynyl, C340 cycloalkyl, 4-
membered heterocycloalkyl, C640 aryl and 5-10 membered heteroaryl are each optionally
substituted with 1, 2, 3, or 4 tuents independently selected from R”,
each Rd is independently selected from C1—6 alkyl, C2—6 alkenyl, C2—6 alkynyl, C1—6
haloalkyl, C340 cycloalkyl, 4-10 ed heterocycloalkyl, C640 aryl and 5-10 membered
heteroaryl; wherein said 06 alkyl, C2—6 alkenyl, C2—6 alkynyl, C340 cycloalkyl, 4-10
membered heterocycloalkyl, C640 aryl and 5-10 ed heteroaryl are each optionally
substituted with 1, 2, 3, or 4 substituents independently selected from R10;
or any Rc and Rd attached to the same N atom, er with the N atom to which they
are attached, form a 4-10 membered heterocycloalkyl group optionally tuted with 1, 2,
3 or 4 substituents independently ed from R10;
each Rb is independently selected from C2-6 alkenyl, C2-6 alkynyl, Cl-6 haloalkyl, 7-10
membered heterocycloalkyl, C640 aryl, and 5-10 membered heteroaryl, wherein said C2-6
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alkenyl, C2.6 alkynyl, 7-10 membered heterocycloalkyl, C640 aryl and 5-10 membered
heteroaryl are each optionally substituted with 1, 2, 3, or 4 substituents independently
selected from R10;
each R6 is independently ed from H, CN, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkylthio,
C1-6 alkylsulfonyl, C1.6 alkylcarbonyl, C1-6 minosulfonyl, carbamyl, C1-6 alkylcarbamyl,
di(C1-6 alkyl)carbamyl, aminosulfonyl, C1.6 alkylaminosulfonyl and di(C1—6
alkyl)aminosulfonyl;
each R31, RCl and Rdl is independently selected from H, C16 alkyl, C2—6 alkenyl, C2-6
alkynyl, C1-6haloa1ky1, C340 cycloalkyl, 4-10 membered cycloalkyl, C640 aryl and 5-10
membered heteroaryl, wherein said C1—6 alkyl, C2—6 alkenyl, C2—6 alkynyl, C340 cycloalkyl, 4-
membered heterocycloalkyl, C640 aryl and 5-10 membered aryl are each optionally
substituted with 1, 2, 3, or 4 substituents independently selected from R“,
or any RCl and R(11 ed to the same N atom, together with the N atom to which
they are ed, form a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionally
substituted with 1, 2, 3 or 4 substituents ndently selected from R“;
each Rbl is independently selected from C1—6 alkyl, C2—6 alkenyl, C2-6 alkynyl, C1-6
haloalkyl, C340 lkyl, 4-10 membered heterocycloalkyl, C640 aryl and 5-10 membered
heteroaryl; wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C340 cycloalkyl, 4-10
membered heterocycloalkyl, C640 aryl and 5-10 membered heteroaryl are each optionally
substituted with 1, 2, 3, or 4 substituents independently selected from R“;
each R61 is independently ed from H, CN, C1-6 alkyl, C1.6 haloalkyl, Cl-6
alkylthio, C1-6 alkylsulfonyl, C1.6 alkylcarbonyl, C1.6 alkylaminosulfonyl, carbamyl, C1—6
alkylcarbamyl, di(C1-6 alkyl)carbamyl, aminosulfonyl, C1.6 alkylaminosulfonyl and d1(C1-6
aminosulfonyl;
each Raz, RC2 and Rdz, is independently selected from H, C16 alkyl, C2—6 alkenyl, C2—6
alkynyl, C1-6 haloalkyl, C340 cycloalkyl, 4-10 membered heterocycloalkyl, C640 aryl and 5-10
membered heteroaryl, wherein said C1—6 alkyl, C2—6 alkenyl, C2—6 alkynyl, C340 cycloalkyl, 4-
membered heterocycloalkyl, C640 aryl and 5-10 ed heteroaryl are each optionally
substituted with 1, 2, 3, or 4 substituents independently selected from R21;
or any Rcz and R£12 attached to the same N atom, together with the N atom to which
they are ed, form a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionally
substituted with 1, 2, 3 or 4 substituents independently selected from R“;
each R” is independently selected from C1-6 alkyl, C2-6 alkenyl, C2—6 alkynyl, C1-6
haloalkyl, C340 lkyl, 4-10 membered heterocycloalkyl, C640 aryl and 5—10 membered
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heteroaryl; wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3—1o cycloalkyl, 4-10
membered cycloalkyl, C6-10 aryl and 5-10 membered heteroaryl are each optionally
tuted with 1, 2, 3, or 4 substituents independently selected from R“;
each R"2 is independently selected from H, CN, C1-6 alkyl, C1-6 haloalkyl, C1-6
alkylthio, Cl-6 alkylsulfonyl, C1-6 alkylcarbonyl, C1-6 minosulfonyl, carbamyl, C1-6
alkylcarbamyl, di(C1-6 alkyl)carbamyl, aminosulfonyl, C1-6 alkylaminosulfonyl and d1(C1-6
alkyl)aminosulfonyl;
each R33, RC3 and R“, is independently selected from H, C1-6 alkyl, C2—6 alkenyl, C2-6
alkynyl, C1-6 haloalkyl, C3-6 cycloalkyl, , 5-6 membered heteroaryl and 4-7 membered
heterocycloalkyl; wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, phenyl,
-6 membered heteroaryl and 4-7 membered heterocycloalkyl are each optionally substituted
with 1, 2, 3, or 4 substituents independently selected from R”,
or any RC3 and R(13 attached to the same N atom, together with the N atom to which
they are attached, form a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionally
substituted with 1, 2 or 3 substituents independently selected from R”;
each R'33 is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 l, C1-6
haloalkyl, C3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-7 membered
heterocycloalkyl; wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, ,
-6 membered heteroaryl and 4-7 ed heterocycloalkyl are each optionally tuted
with 1, 2, 3, or 4 substituents independently selected from R”;
each R34, RC4 and Rd“, is independently selected from H, C1-6 alkyl, Cz—e alkenyl, C2-6
alkynyl, C1-6 haloalkyl, C3-6 cycloalkyl, , 5-6 membered heteroaryl and 4-7 membered
heterocycloalkyl; wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, phenyl,
-6 membered heteroaryl and 4-7 membered heterocycloalkyl are each optionally substituted
with 1, 2, 3, or 4 substituents independently selected from R22,
or any R04 and RC14 attached to the same N atom, together with the N atom to which
they are attached, form a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionally
substituted with 1, 2 or 3 substituents independently ed from R";
each R'34 is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6
haloalkyl, C3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-7 membered
heterocycloalkyl; n said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, phenyl,
-6 membered heteroaryl and 4-7 membered heterocycloalkyl are each optionally substituted
with 1, 2, 3, or 4 substituents ndently selected from R”;
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each R35, RCS and R“, is independently selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6
alkynyl and Cl-6 haloalkyl, wherein said C1-6 alkyl, C2-6 alkenyl and C2-6 alkynyl are each
optionally substituted with 1, 2, 3, or 4 substituents independently selected from Rg;
each R” is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl and C1-6
haloalkyl, wherein said C1-6 alkyl, C2-6 alkenyl and C2-6 alkynyl are each optionally
tuted with 1, 2, 3, or 4 substituents ndently selected from Rg;
each R36, RC6 and Rd6 is independently selected from H, C1-6 alkyl, C2—6 l, C2-6
alkynyl and Cl-6 kyl, wherein said C1-6 alkyl, C2-6 alkenyl and C2-6 alkynyl are each
optionally substituted with 1, 2, 3, or 4 substituents independently selected from Rg;
each Rb6 is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6
haloalkyl, wherein said C1-6 alkyl, C2-6 alkenyl and C2-6 alkynyl are each optionally
substituted with 1, 2, 3, or 4 substituents ndently selected from Rg;
each R37, RC7, and Rd7 is independently selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6
alkynyl, Cl-6 haloalkyl, C340 cycloalkyl, 4-10 ed heterocycloalkyl, C6-10 aryl and 5-10
membered heteroaryl; wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 l, €3-10 cycloalkyl, 4-
membered heterocy cloalkyl, C6-10 aryl and 5-10 membered heteroaryl are each optionally
substituted with 1, 2, 3, or 4 substituents ndently selected from R30;
or any RC7 and RC17 attached to the same N atom, together with the N atom to which
they are attached, form a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionally
substituted with 1, 2 or 3 substituents independently selected from R30;
each Rb7 is independently selected from C1-6 alkyl, C2-6 l, C2-6 alkynyl, and C1-6
haloalkyl,
each R33, Rcg and R“, is independently selected from H, C1-6 alkyl, C2-6 l, C2-6
alkynyl, C1-6 haloalkyl, C3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-7 membered
heterocycloalkyl; wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, phenyl,
-6 membered heteroaryl and 4-7 membered heterocycloalkyl are each optionally substituted
with 1, 2, 3, or 4 substituents independently selected from Rg,
or any RCS and Rdg attached to the same N atom, together with the N atom to which
they are attached, form a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionally
substituted with 1, 2 or 3 substituents ndently ed from Rg;
each R'38 is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6
haloalkyl, C3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-7 membered
heterocycloalkyl; wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, phenyl,
W0 49200
-6 membered heteroaIyl and 4-7 membered heterocycloalkyl are each optionally substituted
with 1, 2, 3, or 4 substituents independently selected from Rg; and
each Rg is ndently selected from OH, N02, CN, halo, C1-6 alkyl, C2-6 alkenyl,
C2-6 alkynyl, Cl-6 haloalkyl, C3-6 cycloalkyl, C3-6 cycloalkyl-Ci—z alkylene, Cl—6 alkoxy, C1-6
haloalkoxy, C1-3 alkoxy-C1—3 alkyl, C1—3 alkoxy-C1—3 alkoxy, HO-C1—3 , HO-C1—3 alkyl,
cyano—C1-3 alkyl, H2N—C1.3 alkyl, amino, C1-6 alkylamino, dl(C1-6 alkyl)amino, thio, C1-6
alkylthio, Cl-6 alkylsulfinyl, C1-6 alkylsulfonyl, carbamyl, C1-6 alkylcarbamyl, dl(Cl-6
alkyl)carbamyl, carboxy, C1-6 alkylcarbonyl, C1-6 alkoxycarbonyl, C1-6 alkylcarbonylamino,
C1-6 alkylsulfonylamino, aminosulfonyl, C1-6 alkylaminosulfonyl, dl(C1-6 alkyl)aminosulfonyl,
aminosulfonylamino, C1-6 minosulfonylamino, dl(C1-6 alkyl)aminosulfonylamino,
aminocarbonylamino, C1-6 alkylaminocarbonylamino, and dl(C1-6 alkyl)aminocarbonylamino.
In some embodiments:
R1 is selected from Cyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, halo, CN, N02, 0R3,
SR3, , C(0)NRCRd, C(0)0Ra, 0C(0)Rb, OC(O)NRCRd, NRCRd, NRCC(O)R", and
NRCC(O)OR3; wherein said Cz—s l and Cz-e alkynyl are each optionally substituted with
1, 2, 3, or 4 tuents ndently selected from R10;
Cy1 is selected from C3-1o cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl and
-10 membered heteroaryl, wherein each 4-10 membered heterocycloalkyl and 5—10
membered heteroaryl has at least one ring-forming carbon atom and 1, 2, 3, or 4 ring-forming
atoms independently selected from N, O, and S, wherein the N and S are optionally
oxidized, wherein a ring-forming carbon atom of 5-10 membered heteroaryl and 4-10
membered heterocycloalkyl is optionally substituted by oxo to form a carbonyl group; and
wherein the C340 lkyl, 4-10 membered heterocycloalkyl, C6-10 aryl and 5-10 ed
heteroaryl are each optionally substituted with 1, 2, 3 or 4 substituents independently selected
from R10,
CyA is C6-10 aryl optionally substituted with 1, 2, 3 or 4 substituents independently
selected from R20;
R2 is ed from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, halo, CN,
OR”, SR37, C(O)Rb7, C(O)NRC7Rd7, C(O)ORa7, NRC7Rd7, NRC7C(O)Rb7, O)OR37,
NRC7S(O)Rb7, NRC7S(O)2Rb7, NRC7S(O)2NRC7Rd7, 7, S(O)NRC7Rd7, S(O)2R"7, and
S(O)2NRC7Rd7; wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally
substituted with 1, 2, 3, or 4 substituents independently selected from R30;
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each R10 is independently selected from C1—6 alkyl, C2—6 alkenyl, C2-6 alkynyl, C1-6
haloalkyl, C340 cycloalkyl, 4-10 membered heterocycloalkyl, C640 aryl, 5-10 membered
heteroaryl, halo, CN, N02, ORal, SR“, C(O)Rb1, C(O)NRC1RC”, C(O)OR31, OC(O)Rb1,
OC(O)NR°1R‘”, NRCIR‘“, NR°1C(O)Rb1, and NRC1C(O)OR31; wherein said C2-6 alkenyl, C2-6
alkynyl, C340 cycloalkyl, 4-10 membered heterocycloalkyl, C640 aryl, and 5-10 membered
heteroaryl are each optionally substituted with 1, 2, 3, or 4 substituents independently
ed from R“;
each R11 is independently ed from C1—6 alkyl, C2—6 alkenyl, C2—6 alkynyl, C1-6
haloalkyl, C340 lkyl, 4-10 membered heterocycloalkyl, C640 aryl, 5-10 membered
heteroaryl, halo, CN, ORa3, SRa3, C(O)Rb3, C(O)NRC3Rd3, C(O)ORa3, NRC3Rd3, NRC3C(O)Rb3,
NRC3C(O)ORa3, S(O)Rb3, S(O)NRC3Rd3, S(O)2Rb3, and S(O)2NRC3Rd3, wherein said 06 alkyl,
C2-6 alkenyl, C2-6 alkynyl, C340 cycloalkyl, 4-10 membered heterocycloalkyl, C640 aryl, and 5-
membered heteroaryl are each optionally substituted with 1, 2, 3, or 4 substituents
independently selected from R12;
each R12 is independently selected from C1-6 alkyl, C2—6 alkenyl, C2-6 alkynyl, C1-6
haloalkyl, halo, CN, OR”, SRaS, C(O)Rb5, C(O)NR95Rd5, C(O)OR35, NRCSR‘”, NRC5C(O)Rb5,
NR05C(O)OR35, NRCSS(O)Rb5, NRCSS(O)2R"5, NRC5S(O)2NRC5Rd5, S(O)Rb5, °5Rd5,
S(O)2Rb5, and S(O)2NR°5Rd5; wherein said C1-6 alkyl, C2-6 alkenyl, and C26 alkynyl are each
optionally substituted with 1, 2, 3, or 4 substituents independently selected from Rg;
each R20 is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6
haloalkyl, C340 cycloalkyl, 4-10 ed heterocycloalkyl, C640 aryl, 5-10 membered
heteroaryl, halo, CN, N02, ORaZ, SRaZ, C(O)Rb2, C(O)NRC2Rd2, C(O)0Ra2, OC(O)Rb2,
OC(O)NRC2R“2, NRCZRdz, NRC2C(O)Rb2, and O)OR"‘2, wherein said C1-6 alkyl, C2-6
alkenyl, C2—6 alkynyl, C340 cycloalkyl, 4-10 membered cycloalkyl, C640 aryl, and 5-10
membered aryl are each optionally substituted with 1, 2, 3, or 4 substituents
independently ed from R21,
each R21 is independently selected from C1—6 alkyl, C2—6 alkenyl, C2—6 alkynyl, C1—6
kyl, halo, CN, ORa“, SRa“, C(O)Rb4, C(O)NRC4Rd4, C(O)ORa4, NRC4Rd4, NRC4C(O)R"4,
and NRC4C(O)OR34; n said 06 alkyl, C2—6 alkenyl, and C26 l are each optionally
substituted with 1, 2, 3, or 4 substituents independently selected from R”;
each R22 is independently selected from C1-6 alkyl, C2-6 l, C2-6 alkynyl, C1-6
haloalkyl, phenyl, halo, CN, ORaG, SRaG, C(O)Rb6, C6Rd6, C(O)OR36, NR°6Rd6,
NRC6C(O)R"6, and NR°6C(O)OR"‘6;
W0 2018/‘049200
each R30 is independently selected from C1—6 alkyl, C2—6 alkenyl, C2-6 l, and C16
haloalkyl;
each R3 and Rc is independently selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl,
and C1-6 haloalkyl; wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally
substituted with 1, 2, 3, or 4 substituents independently selected from R10;
each Rd is independently selected from C1-6 alkyl, C2—6 alkenyl, C2—6 alkynyl, C1-6
haloalkyl, and C640 aryl; wherein said C1—6 alkyl, C2—6 alkenyl, C2-6 alkynyl, and C640 aryl are
each ally substituted with 1, 2, 3, or 4 substituents independently selected from R10;
each R1) is independently selected from C2—6 alkenyl, C2—6 alkynyl, C1.6haloalky1, 7-10
membered heterocycloalkyl, C640 aryl, and 5-10 membered heteroaryl, wherein said C2-6
alkenyl, C2.6 alkynyl, 7-10 membered heterocycloalkyl, C640 aryl and 5-10 membered
heteroaryl are each optionally substituted with 1, 2, 3, or 4 tuents independently
selected from R10;
each R“, RCl and R(11 is independently selected from H, C16 alkyl, C2-6 alkenyl, C2-6
alkynyl, and C16 haloalkyl;
each Rbl is ndently selected from C1—6 alkyl, C2—6 alkenyl, C2-6 alkynyl, C1-6
haloalkyl, C340 cycloalkyl, 4-10 membered heterocycloalkyl, C640 aryl and 5-10 ed
heteroaryl; wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C340 cycloalkyl, 4-10
ed heterocycloalkyl, C640 aryl and 5-10 membered heteroaryl are each optionally
substituted with 1, 2, 3, or 4 substituents independently selected from R“;
each R”, RC2 and R012, is independently selected from H, C16 alkyl, C2—6 l, C2-6
alkynyl, and C16 haloalkyl;
each R” is independently selected from C1—6 alkyl, C2—6 l, C2—6 alkynyl, and C1-6
haloalkyl;
each Ra3, RC3 and RC”, is independently selected from H, C16 alkyl, C2—6 alkenyl, C2—6
alkynyl, and C1—6haloalkyl,
each R'33 is independently selected from C1—6 alkyl, C2—6 alkenyl, C2—6 alkynyl, C1—6
haloalkyl, and phenyl;
each R34, RC4 and R“, is independently ed from H, C16 alkyl, C26 alkenyl, C2—6
alkynyl, C1-6 haloalkyl, and phenyl;
each R'34 is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6
haloalkyl, C3.6 cycloalkyl, and phenyl;
each R35, RCS and R“, is independently ed from H, C1-6 alkyl, C2-6 alkenyl, C2-6
alkynyl and C1-6haloalkyl;
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each R"5 is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl and C1—6
haloalkyl;
each R36, RC6 and RC16 is independently selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6
alkynyl and Cl-6 haloalkyl;
each R[)6 is independently selected from C1-6 alkyl, C2-6 l, C2-6 alkynyl, and C1-6
haloalkyl;
each R37, RC7, and Rd7 is independently ed from H, C1-6 alkyl, C2—6 alkenyl, C2-6
alkynyl, and Cl-6 haloalkyl; n said C1-6 alkyl, C2-6 l, and C2-6 alkynyl are each
optionally substituted with 1, 2, 3, or 4 tuents ndently selected from R30;
each Rb7 is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6
haloalkyl; n said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each ally
substituted with 1, 2, 3, or 4 substituents independently selected from R30;
each Rg is independently selected from OH, N02, CN, halo, C1-6 alkyl, C2-6 alkenyl,
C2-6 alkynyl, Cl-6 haloalkyl, C3-6 cycloalkyl, C3-6 lkyl-C1-2 alkylene, C1-6 alkoxy, C1-6
haloalkoxy, C1-3 alkoxy-C1—3 alkyl, 03 alkoxy-C1—3 alkoxy, HO-C1—3 alkoxy, HO-C1—3 alkyl,
cyano-C1-3 alkyl, H2N-C1-3 alkyl, amino, C1-6 alkylamino, d1(C1-6 alkyl)amino, thio, C1-6
alkylthio, Cl-6 alkylsulfinyl, C1-6 alkylsulfonyl, carbamyl, C1-6 alkylcarbamyl, dl(Cl-6
alkyl)carbamyl, carboxy, C1-s alkylcarbonyl, C1-6 alkoxycarbonyl, C1-6 alkylcarbonylamino,
C1-6 alkylsulfonylamino, aminosulfonyl, C1-6 alkylaminosulfonyl, dl(C1-6 alkyl)aminosulfony1,
aminosulfonylamino, C1-6 alkylaminosulfonylamino, d1(C1-6 alkyl)aminosulfonylamino,
arninocarbonylarnino, C1-6 alkylaminocarbonylamino, and dl(C1-6 alkyl)aminocarbonylamino.
In some ments:
R1 is selected from Cyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, halo, CN, ORa,
C(O)Rb, C(O)NR“Rd, C(O)ORa, NRCRd, NRCC(O)Rb, and NRCC(O)ORa; wherein said C2-6
alkenyl and C2-6 alkynyl are each optionally substituted with 1, 2, 3, or 4 substituents
independently selected from R10,
Cy1 is selected from 4-10 membered heterocycloalkyl, C6-10 aryl and 5-10 membered
heteroaryl, wherein each 4-10 membered heterocycloalkyl and 5-10 membered heteroaryl has
at least one ring—forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatoms
independently ed from N, O, and S; wherein the N and S are optionally oxidized;
wherein a ring-forming carbon atom of 5-10 membered heteroaryl and 4-10 ed
heterocycloalkyl is optionally substituted by oxo to form a carbonyl group; and wherein the
W0 49200
4-10 membered heterocycloalkyl, C640 aryl and 5-10 membered heteroaryl are each
optionally substituted with 1, 2, 3 or 4 substituents independently selected from R10;
CyA is C640 aryl optionally substituted with 1, 2, 3 or 4 substituents independently
selected from R20;
R2 is selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, and halo;
each R10 is ndently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6
haloalkyl, C340 cycloalkyl, 4-10 membered heterocycloalkyl, C640 aryl, 5-10 membered
heteroaryl, halo, CN, and ORal, wherein said C2—6 alkenyl, C2—6 l, C340 cycloalkyl, 4-10
membered cycloalkyl, C640 aryl, and 5-10 ed heteroaryl are each optionally
substituted with 1, 2, 3, or 4 substituents independently selected from R“,
each R11 is independently selected from 06 alkyl, C2—6 alkenyl, C2—6 alkynyl, C1—6
haloalkyl, C340 cycloalkyl, 4-10 membered heterocycloalkyl, C640 aryl, 5-10 membered
heteroaryl, halo, CN, 0Ra3, C3Rd3, NRC3Rd3, NRC3C(O)Rb3, S(O)2Rb3, and
S(O)2NRC3Rd3; wherein said 06 alkyl, C2—6 alkenyl, C2—6 alkynyl, C340 cycloalkyl, 4-10
membered heterocycloalkyl, C640 aryl, and 5-10 membered heteroaryl are each optionally
substituted with 1, 2, 3, or 4 substituents ndently selected from R”;
each R12 is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6
haloalkyl, and halo;
each R20 is independently selected from C1—6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6
haloalkyl, C340 cycloalkyl, 4-10 membered heterocycloalkyl, C640 aryl, 5-10 membered
heteroaryl, halo, and ORaZ; wherein said 06 alkyl, C2—6 alkenyl, C2-6 alkynyl, C340
cycloalkyl, 4—10 membered heterocycloalkyl, C640 aryl, and 5-10 membered heteroaryl are
each optionally substituted with 1, 2, 3, or 4 tuents ndently selected from R“;
each R21 is independently selected from C1—6 alkyl, C2—6 alkenyl, C2—6 l, C1-6
kyl, and halo; wherein said C1—6 alkyl, C2—6 alkenyl, and C26 alkynyl are each optionally
substituted with 1, 2, 3, or 4 substituents independently selected from R22,
each R22 is independently selected from C1—6 alkyl, C2—6 alkenyl, C2—6 alkynyl, C1—6
haloalkyl, phenyl, halo, NRCGRdG, and NRC6C(O)Rb6,
each R3 and Rc is independently selected from H and C16 alkyl,
each Rd is independently selected from C1—6 alkyl, C2—6 alkenyl, C2-6 alkynyl, C1-6
haloalkyl, and C640 aryl, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C640 aryl are
each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R10;
each Rb is ndently selected from C2-6 alkenyl, C2-6 alkynyl, Cl-6 haloalkyl, 7-10
membered heterocycloalkyl, C640 aryl, and 5-10 ed heteroaryl; wherein said C2-6
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alkenyl, C2-6 alkynyl, 7-10 membered heterocycloalkyl, C6-10 aryl and 5-10 membered
heteroaryl are each optionally substituted with 1, 2, 3, or 4 substituents independently
selected from R10;
each Rall is ndently selected from H and C1-6 alkyl;
each Ral2 is independently selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and
C1-6 haloalkyl;
each R33, RC3 and R“, is independently selected from H, C1-6 alkyl, C2—6 alkenyl, C2-6
alkynyl, and C1-6haloalkyl;
each Rb3 is independently ed from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6
haloalkyl, and phenyl;
each RCG and RC16 is independently selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6
alkynyl and Cl-6 haloalkyl, and
each R“ is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6
haloalkyl.
In some embodiments:
R1 is selected from Cyl, C(O)NRCR‘1, and NRCRd, NRCC(O)Rb;
Cy1 is selected from 4-10 membered heterocycloalkyl, C6-10 aryl and 5-10 membered
heteroaryl, wherein each 4-10 membered cycloalkyl and 5-10 membered heteroaryl has
at least one ring-forming carbon atom and l, 2, 3, or 4 ring-forming atoms
independently selected from N, O, and S, n the N and S are optionally oxidized;
n a ring-forming carbon atom of 5-10 membered heteroaryl and 4-10 membered
heterocycloalkyl is optionally substituted by oxo to form a carbonyl group; and wherein the
4-10 membered heterocycloalkyl, C6-10 aryl and 5-10 ed heteroaryl are each
optionally substituted with l or 2 substituents independently selected from R10;
CyA is C6-10 aryl optionally substituted with l or 2 substituents independently selected
from R20;
R2 is H;
each R10 is independently selected from C1-6 alkyl, C340 cycloalkyl, 4-10 membered
heterocycloalkyl, C6-10 aryl, 5-10 membered heteroaryl, halo, CN, and OR“; wherein said C3—
lkyl, 4-10 membered heterocycloalkyl, C6-10 aryl, and 5-10 membered heteroaryl are
each ally substituted with 1 or 2 substituents independently selected from R“;
each R11 is independently ed from C1-6 alkyl, C1-6 haloalkyl, 4—10 ed
heterocycloalkyl, halo, CN, and S(O)2Rb3; wherein said C1-6 alkyl and 4-10 membered
W0 2018f049200
heterocycloalkyl are each optionally substituted with 1 or 2 substituents independently
selected from R”;
each R12 is C1-6 alkyl;
each R20 is independently selected from C1-6 alkyl, C1-6 haloalkyl, C3—1o cycloalkyl,
halo, and OR”; wherein said C1-6 alkyl and C340 cycloalkyl are each ally substituted
with 1 or 2 substituents independently selected from R21;
each R21 is C1-6 alkyl optionally substituted with 1 or 2 substituents independently
selected from R”;
each R22 is ndently NRCGRdG;
each Ra and RC is H;
each Rd is independently selected from C1-6 alkyl and C6-10 aryl; wherein said C1-6
alkyl and C6-10 aryl are each optionally tuted with 1 or 2 substituents independently
selected from R10;
each Rb is independently selected from 7-10 membered heterocycloalkyl, C6-10 aryl,
and 5-10 membered heteroaryl; wherein said 7-10 ed heterocycloalkyl, C6-10 aryl and
-10 membered heteroaryl are each optionally tuted with 1 or 2 substituents
independently selected from R10;
each Rall is C1-6 alkyl;
each R“2 is independently selected from H and C1-6 alkyl;
each R[)3 is C1-6 alkyl; and
each RC6 and RC16 is H.
In some embodiments:
R1 is selected from Cyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, halo, CN; N02, ORa,
SRa, C(O)Rb, C(O)NRCRd, C(O)0Ra, OC(O)Rb, OC(O)NRCRd, NRCRd, NR°C(O)R", and
NRCC(O)ORa; wherein said C2-6 alkenyl and C2-6 alkynyl are each optionally substituted with
1, 2, 3, or 4 substituents independently selected from R10;
Cy1 is selected from C340 cycloalkyl, 4-10 membered cycloalkyl, C6-10 aryl and
-10 membered heteroaryl, wherein each 4-10 membered heterocycloalkyl and 5-10
membered heteroaryl has at least one orming carbon atom and 1, 2, 3, or 4 orming
heteroatoms independently selected from N, O, and S; wherein the N and S are optionally
oxidized; wherein a ring-forming carbon atom of 5-10 membered heteroaryl and 4-10
membered heterocycloalkyl is optionally substituted by oxo to form a yl group; and
wherein the €3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl and 5-10 membered
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heteroaryl are each optionally tuted with 1, 2, 3 or 4 substituents independently selected
from R10;
CyA is C640 aryl optionally substituted with 1, 2, 3 or 4 tuents independently
selected from R20;
R2 is selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, halo, CN,
0R3”, SR5”, C(O)Rb7, C(O)NR“7Rd7, C(O)OR"‘7, NRC7Rd7, NRC7C(O)Rb7, NRC7C(O)ORa7,
NRC7S(O)Rb7, NRC7S(O)2Rb7, NRC7S(O)2NRC7Rd7, S(O)Rb7, S(0)NRc7Rd7, S(O)2Rb7, and
S(O)2NR°7R“7; wherein said C1—6 alkyl, C2—6 alkenyl, and C26 l are each optionally
tuted with 1, 2, 3, or 4 substituents independently selected from R”;
each R10 is independently selected from C1—6 alkyl, C2—6 alkenyl, C2—6 alkynyl, C1-6
haloalkyl, C340 cycloalkyl, 4-10 membered heterocycloalkyl, C640 aryl, 5-10 membered
heteroaryl, halo, CN, N02, ORal, SR“, C(O)Rb1, C(O)NRC1R‘“, C(O)ORa1, OC(O)Rb1,
OC(O)NRCIR‘“, “, NRC1C(O)Rb1, and NRC1C(O)OR"‘1, wherein said C2-6 alkenyl, C2-6
alkynyl, C340 cycloalkyl, 4-10 membered heterocycloalkyl, C640 aryl, and 5-10 membered
heteroaryl are each optionally substituted with 1, 2, 3, or 4 substituents independently
selected from R“;
each R“ is independently selected from C1-6 alkyl, C2-6 l, C2-6 l, C1-6
haloalkyl, C340 cycloalkyl, 4-10 membered heterocycloalkyl, C640 aryl, 5-10 membered
heteroaryl, halo, CN, ORa3, SR”, C(O)Rb3, C(O)NRC3Rd3, C(O)0Ra3, NR°3Rd3, NR°3C(O)Rb3,
NRC3C(O)OR33, S(O)Rb3, S(O)NR“3Rd3, S(O)2Rb3, and S(O)2NRC3Rd3; wherein said C1-6 alkyl,
C2-6 alkenyl, C2-6 alkynyl, C340 cycloalkyl, 4-10 membered heterocycloalkyl, C640 aryl, and 5-
membered heteroaryl are each optionally substituted with 1, 2, 3, or 4 substituents
independently selected from R12,
each R12 is ndently selected from C1—6 alkyl, C2—6 alkenyl, C2—6 alkynyl, C1-6
haloalkyl, halo, CN, ORaS, SRaS, C(O)Rb5, C(O)NRC5Rd5, a5, S, NRC5C(O)R"5,
NRC5C(O)OR35, NRCSS(O)Rb5, NRCSS(O)2R"5, NRCSS(O)2NRC5Rd5, 5, S(O)NRCSRd5,
S(O)2Rb5, and S(O)2NR95Rd5, wherein said C1—6 alkyl, C2—6 alkenyl, and C26 alkynyl are each
ally tuted with 1, 2, 3, or 4 substituents independently selected from Rg;
each R20 is independently selected from C1—6 alkyl, C2—6 alkenyl, C2-6 l, C1-6
haloalkyl, C340 cycloalkyl, 4-10 membered heterocycloalkyl, C640 aryl, 5-10 membered
heteroaryl, 4-10 membered heterocycloalkyl-Ci-3 alkylene, halo, CN, N02, OR”, SRaz,
C(O)Rb2, C(O)NR°2Rd2, C(O)OR"‘2, OC(O)Rb2, OC(O)NRC2Rd2, NRCZRdZ, NR°2C(O)Rb2, and
NRC2C(O)OR32; wherein said C1-6 alkyl, C2-6 l, C2-6 alkynyl, C340 cycloalkyl, 4—10
membered heterocycloalkyl, C640 aryl, 5-10 membered heteroaryl, and 4—10 membered
W0 2018f049200 2017/050737
heterocycloalkyl-C1-3 alkylene are each optionally tuted with 1, 2, 3, or 4 substituents
independently selected from R“,
or two adjacent R20 substituents on the CyA ring, taken er with the atoms to
which they are attached, form a fused C3-7 cycloalkyl ring; wherein a ring-forming carbon
atom of the fused C34 lkyl ring is optionally substituted by oxo to form a carbonyl
group; and wherein the fused C34 cycloalkyl ring is optionally substituted with 1, 2, 3 or 4
substituents independently selected from R21,
each R21 is independently selected from C1—6 alkyl, C2—6 alkenyl, C2—6 alkynyl, C1-6
haloalkyl, C340 cycloalkyl, 4-10 membered heterocycloalkyl, C640 aryl, 5-10 membered
heteroaryl, halo, CN, ORa“, SRa“, C(O)Rb4, C(O)NRC4Rd4, C(O)ORa4, 4, NRC4C(O)Rb4,
and NRC4C(O)OR34; wherein said C1—6 alkyl, C2—6 alkenyl, C2—6 alkynyl, C340 cycloalkyl, 4-10
ed heterocycloalkyl, C640 aryl, and 5-10 membered heteroaryl are each optionally
substituted with 1, 2, 3, or 4 tuents independently selected from R”;
each R22 is independently selected from C1—6 alkyl, C2—6 alkenyl, C2-6 alkynyl, C1-6
haloalkyl, phenyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, halo, CN,
OR“, SR”, C(O)Rb6, C(O)NR66Rd6, C(O)OR36, NRCGRdG, NRC6C(O)Rb6, and NR66C(O)OR36;
wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and 5-6 membered heteroaryl are each
optionally substituted with 1 substituents independently ed from Rg;
each R30 is independently selected from C1—6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6
haloalkyl,
each R3 and Rc is independently selected from H, C16 alkyl, C2—6 alkenyl, C2-6 alkynyl,
and C16 haloalkyl, wherein said C1—6 alkyl, C2—6 alkenyl, and C26 alkynyl are each optionally
substituted with 1, 2, 3, or 4 substituents independently selected from R”;
each RC1 is independently selected from C1—6 alkyl, C2—6 l, C2—6 alkynyl, C1-6
haloalkyl, and C640 aryl, wherein said C1—6 alkyl, C2—6 alkenyl, C2—6 alkynyl, and C640 aryl are
each optionally substituted with 1, 2, 3, or 4 tuents independently selected from R10,
each Rb is independently selected from C2—6 alkenyl, C2—6 alkynyl, C1.6 haloalkyl, 7-10
membered heterocycloalkyl, C640 aryl, and 5-10 membered heteroaryl; wherein said C2—6
alkenyl, C2.6 alkynyl, 7-10 membered cycloalkyl, C640 aryl and 5-10 ed
heteroaryl are each optionally substituted with 1, 2, 3, or 4 substituents independently
selected from R10;
each R31, RC] and R‘” is independently selected from H, 06 alkyl, C2-6 alkenyl, C2-6
alkynyl, C1-6 haloalkyl, and C340 cycloalkyl; wherein said C1-6 alkyl, C2-6 alkenyl, C2-6
W0 2018f049200
alkynyl, and €3-10 cycloalkyl are each ally substituted with 1, 2, or 3 substituents
independently selected from R“;
each Rbl is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6
haloalkyl, C3—10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl and 5-10 membered
heteroaryl; wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3—10 cycloalkyl, 4-10
membered heterocycloalkyl, C6-10 aryl and 5-10 membered aryl are each optionally
substituted with 1, 2, 3, or 4 substituents ndently selected from R“;
each R”, RCZ and Rdz, is ndently selected from H, C1-6 alkyl, C2—6 alkenyl, C2-6
alkynyl, C1-6 haloalkyl, and 4-10 membered heterocycloalkyl, said C1-6 alkyl and 4—10
membered heterocycloalkyl are each optionally substituted with 1, 2, or 3 substituents
independently selected from R21,
or any RCZ and R£12 attached to the same N atom, together with the N atom to which
they are attached, form a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionally
substituted with 1, 2, 3 or 4 substituents independently selected from R21;
each R” is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6
haloalkyl, €3-10 cycloalkyl, 4-10 membered heterocycloalkyl, and 5-10 membered
heteroaryl;wherein said C1-6 alkyl, C340 cycloalkyl, 4-10 membered cycloalkyl, and 5-
membered heteroaryl are each optionally substituted with 1, 2, or 3 substituents
independently selected from R“,
each R33, RC3 and R“, is independently ed from H, C1-6 alkyl, Cz—e alkenyl, C2-6
alkynyl, and C1-6haloalkyl;
each Rb3 is ndently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6
haloalkyl, and phenyl,
each R“, RC4 and RC”, is independently selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6
alkynyl, C1-6 haloalkyl, phenyl, C3-6 lkyl, 5-6 membered heteroaryl and 4-7 membered
heterocycloalkyl; wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 l, phenyl, C3-6 cycloalkyl,
-6 membered heteroaryl and 4-7 membered cycloalkyl are each optionally substituted
with 1, 2, or 3 substituents independently selected from R”,
or any R“4 and R(14 attached to the same N atom, er with the N atom to which
they are attached, form a 4—, 5-, 6- or ered heterocycloalkyl group;
each R'34 is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6
haloalkyl, C3-6 cycloalkyl, and phenyl,
each R35, RCS and R“, is independently selected from H, C1-6 alkyl, Cz—e alkenyl, C2-6
alkynyl and C1-6haloalkyl;
W0 2018/‘049200
each R"5 is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl and C1—6
haloalkyl;
each R36, RC6 and RC16 is independently selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6
l and Cl-6 haloalkyl;
each R[)6 is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6
haloalkyl;
each R37, RC7, and Rd7 is independently selected from H, C1-6 alkyl, C2—6 alkenyl, C2-6
alkynyl, and Cl-6 haloalkyl; wherein said C1-6 alkyl, C2-6 l, and C2-6 alkynyl are each
optionally substituted with 1, 2, 3, or 4 tuents independently selected from R30;
each Rb7 is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6
haloalkyl; wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each ally
substituted with 1, 2, 3, or 4 substituents independently selected from R30;
each Rg is independently selected from OH, N02, CN, halo, C1-6 alkyl, C2-6 alkenyl,
C2-6 alkynyl, Cl-6 haloalkyl, C3-6 lkyl, C3-6 cycloalkyl-C1-2 alkylene, C1-6 alkoxy, C1-6
haloalkoxy, C1-3 alkoxy-C1—3 alkyl, 03 alkoxy-C1—3 alkoxy, HO-C1—3 alkoxy, 3 alkyl,
cyano-C1-3 alkyl, H2N-C1-3 alkyl, amino, C1-6 mino, d1(C1-6 alkyl)amino, thio, C1-6
alkylthio, Cl-6 alkylsulfinyl, C1-6 alkylsulfonyl, carbamyl, C1-6 alkylcarbamyl, dl(Cl-6
alkyl)carbamyl, carboxy, C1-s alkylcarbonyl, C1-6 alkoxycarbonyl, C1-6 alkylcarbonylamino,
C1-6 alkylsulfonylamino, aminosulfonyl, C1-6 alkylaminosulfonyl, dl(C1-6 alkyl)aminosulfony1,
aminosulfonylamino, C1-6 alkylaminosulfonylamino, d1(C1-6 alkyl)aminosulfonylamino,
arninocarbonylarnino, C1-6 alkylaminocarbonylamino, and dl(C1-6 alkyl)aminocarbonylamino.
In some embodiments:
R1 is ed from Cyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, halo, CN, ORa,
C(O)Rb, C(O)NR“Rd, C(O)ORa, NRCRd, NRCC(O)Rb, and NRCC(O)ORa; wherein said C2-6
alkenyl and C2-6 alkynyl are each optionally substituted with 1, 2, 3, or 4 substituents
independently selected from R10,
Cy1 is ed from 4-10 membered heterocycloalkyl, C6-10 aryl and 5-10 membered
heteroaryl, wherein each 4-10 membered heterocycloalkyl and 5-10 membered heteroaryl has
at least one ring—forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatoms
independently selected from N, O, and S; wherein the N and S are optionally oxidized;
wherein a orming carbon atom of 5-10 ed heteroaryl and 4-10 ed
heterocycloalkyl is optionally substituted by oxo to form a yl group; and wherein the
W0 2018f049200
4-10 ed heterocycloalkyl, C640 aryl and 5-10 membered heteroaryl are each
optionally substituted with 1, 2, 3 or 4 substituents independently selected from R10;
CyA is C640 aryl optionally substituted with 1, 2, 3 or 4 substituents independently
selected from R20;
R2 is selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, halo, and
each R10 is independently selected from C1—6 alkyl, C2-6 alkenyl, C2—6 alkynyl, C1-6
haloalkyl, C340 cycloalkyl, 4-10 membered heterocycloalkyl, C640 aryl, 5-10 membered
heteroaryl, halo, CN, ORal, C1R‘“, and NRClR‘“, wherein said C2.6 l, C2-6
alkynyl, C340 cycloalkyl, 4-10 membered heterocycloalkyl, C640 aryl, and 5-10 membered
heteroaryl are each optionally substituted with 1, 2, 3, or 4 tuents independently
selected from R“;
each R11 is independently selected from C1—6 alkyl, C2—6 alkenyl, C2—6 alkynyl, C1-6
haloalkyl, C340 cycloalkyl, 4-10 membered heterocycloalkyl, C640 aryl, 5-10 membered
heteroaryl, halo, CN, 0Ra3, C(O)ORa3, C(O)NRC3Rd3, NRC3Rd3, NRc3C(0)Rb3, S(O)2Rb3, and
S(O)2NRC3Rd3; wherein said C1—6 alkyl, C2-6 alkenyl, C2—6 alkynyl, C340 cycloalkyl, 4-10
ed heterocycloalkyl, C640 aryl, and 5-10 membered heteroaryl are each optionally
substituted with 1, 2, 3, or 4 substituents independently selected from R”;
each R12 is independently ed from C1—6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6
haloalkyl, halo, and CN;
each R20 is independently selected from C1—6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6
haloalkyl, C340 cycloalkyl, 4-10 membered heterocycloalkyl, C640 aryl, 5-10 membered
heteroaryl, 4-10 membered heterocycloalkyl-C1.3 alkylene, halo, ORaz, C(O)Rb2,
C(0)NR°2Rd2, 0C(0)Rb2, OC(O)NRC2Rd2, NRCZRdZ, NRC2C(O)Rb2, NR62C(0)0Ra2, and
O)NRCZRd2; wherein said C1—6 alkyl, C2—6 alkenyl, C2—6 alkynyl, C340 lkyl, 4-10
ed cycloalkyl, C640 aryl, 5-10 membered heteroaryl, and 4-10 membered
heterocycloalkyl-C1-3 alkylene are each optionally substituted with 1, 2, 3, or 4 substituents
independently selected from R21,
or two adjacent R20 substituents on the CyA ring, taken together with the atoms to
which they are attached, form a fused C3—7 cycloalkyl ring; wherein a ring-forming carbon
atom of the fused C34 cycloalkyl ring is ally substituted by oxo to form a carbonyl
group; and wherein the fused C34 cycloalkyl ring is optionally substituted with 1, 2, 3 or 4
tuents independently selected from R“,
W0 2018/‘049200
each R21 is independently selected from C1—6 alkyl, C2—6 alkenyl, C2-6 alkynyl, C1-6
haloalkyl, C340 lkyl, 4-10 membered heterocycloalkyl, C640 aryl, 5-10 membered
heteroaryl, halo, CN, ORa“, NR°4Rd4, NRC4C(O)Rb4, and NRC4C(O)OR34; wherein said 06
alkyl, C2-6 alkenyl, C2-6 alkynyl, and C340 lkyl, 4-10 membered heterocycloalkyl, C640
aryl, and 5—10 membered heteroaryl are each optionally substituted with 1, 2, 3, or 4
substituents independently selected from R22,
each R22 is independently selected from C1—6 alkyl, C2-6 alkenyl, C2—6 alkynyl, C1-6
haloalkyl, phenyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, halo, CN,
0R6a, NR°6Rd6, and O)R'°6; wherein said C1—6 alkyl, C2—6 l, C2-6 alkynyl, and 5-6
membered heteroaryl are each ally substituted with 1 or 2 substituents independently
selected from Rg;
each R3 and Rc is independently ed from H and C16 alkyl;
each Rd is independently selected from C1—6 alkyl, C2—6 alkenyl, C2—6 alkynyl, C1—6
haloalkyl, and C640 aryl, n said C1—6 alkyl, C2—6 l, C2—6 alkynyl, and C640 aryl are
each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R10;
each Rb is independently selected from C2—6 l, C2—6 alkynyl, C1.6 haloalkyl, 7-10
membered heterocycloalkyl, C640 aryl, and 5-10 membered heteroaryl; wherein said C2-6
alkenyl, C2-6 alkynyl, 7-10 membered heterocycloalkyl, C640 aryl and 5-10 membered
heteroaryl are each optionally substituted with 1, 2, 3, or 4 substituents ndently
selected from R10;
each R31, R“, and R011 is independently selected from H, C16 alkyl, and C340
lkyl, wherein said C1-6 alkyl and C340 cycloalkyl, are each optionally substituted with 1
or 2 substituents independently selected from R“,
each Raz, RCZ and RC12 is independently selected from H, C16 alkyl, C2—6 alkenyl, C2—6
alkynyl, C1-6 haloalkyl, and 4-10 membered heterocycloalkyl; wherein said C1—6 alkyl, C2—6
alkenyl, C2.6 alkynyl, and 4-10 membered heterocycloalkyl are each optionally substituted
with 1 or 2 substituents independently selected from R21;
or any Rcz and R‘12 attached to the same N atom, together with the N atom to which
they are attached, form a 4-, 5-, 6- or 7-membered cycloalkyl group optionally
substituted with 1, 2, 3 or 4 substituents independently selected from R21;
each R” is independently selected from C1-6 alkyl, C340 cycloalkyl, 4-10 membered
heterocycloalkyl, and 5-10 membered heteroaryl; wherein said 06 alkyl, C340 cycloalkyl, 4-
membered heterocycloalkyl, and 5-10 membered heteroaryl are each ally substituted
with 1 or 2 substituents independently selected from R21;
W0 2018f049200
each R33, RC3 and R“, is independently selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6
alkynyl, and C1-6 haloalkyl;
each Rb3 is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 l, C1-6
haloalkyl, and phenyl;
each R34, RC4 and R(14 is independently selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6
alkynyl, C1-6 haloalkyl, C3-6 cycloalkyl, 5-6 membered heteroaryl and 4—7 membered
heterocycloalkyl; wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 kyl, C3-6
cycloalkyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl are each optionally
substituted with 1 or 2 substituents independently selected from R22,
or any RC4 and RC14 attached to the same N atom, er with the N atom to which
they are attached, form a 4-, 5-, 6- or ered heterocycloalkyl group;
each R'34 is independently selected from C1-6 alkyl,
each R36 is independently ed from H and C1-6 alkyl,
each RCG and R‘16 is independently selected from H, C1-6 alkyl, Cz—e l, C2-6
alkynyl and Cl-6 haloalkyl;
each R“ is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6
haloalkyl;
each Ra7 is independently selected from H and C1-6 alkyl; and
each Rg is independently selected from C1-6 alkyl.
In some embodiments:
R1 is selected from Cyl, C2-6 alkenyl, C(O)NRCRd, and NRCRd, NRCC(O)Rb; n
said C2-6 alkenyl is optionally substituted with 1 independently selected from R10;
Cy1 is selected from 4-10 membered heterocycloalkyl, C6-10 aryl and 5-10 membered
heteroaryl, wherein each 4-10 ed heterocycloalkyl and 5-10 membered heteroaryl has
at least one ring-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatoms
independently ed from N, O, and S, wherein the N and S are optionally oxidized;
wherein a ring-forming carbon atom of 5-10 membered heteroaryl and 4-10 membered
heterocycloalkyl is optionally substituted by oxo to form a carbonyl group; and wherein the
4-10 membered cycloalkyl, C6-10 aryl and 5-10 membered heteroaryl are each
optionally substituted with 1 or 2 substituents independently ed from R10;
CyA is C6-10 aryl optionally substituted with 1, 2, 3, or 4 substituents independently
selected from R20;
R2 is H, halo, or OR”;
W0 2018f049200
each R10 is independently selected from C1—6 alkyl, C340 cycloalkyl, 4-10 membered
heterocycloalkyl, C640 aryl, 5—10 membered heteroaryl, halo, CN, OR“, C(O)NRCIR‘“, and
NRCIRC”; wherein said C340 cycloalkyl, 4-10 membered heterocycloalkyl, C640 aryl, and 5-10
membered aryl are each optionally substituted with 1 or 2 substituents independently
selected from R“;
each R11 is ndently selected from C1-6 alkyl, C1.6 haloalkyl, C640 aryl, 5-10
membered heteroaryl, 4-10 membered heterocycloalkyl, halo, CN, OR”, C(O)ORa3, and
S(O)2Rb3; wherein said C1-6 alkyl, C640 aryl, 5-10 membered heteroaryl, and 4-10 membered
heterocycloalkyl are each optionally substituted with 1 or 2 substituents independently
selected from R”;
each R12 is 06 alkyl, halo, or CN,
each R20 is independently selected from C1—6 alkyl, C1.6 haloalkyl, C340 lkyl, 4-
membered heterocycloalkyl, 4-10 membered heterocycloalkyl-C1.3 alkylene, halo, ORaz,
2, C(O)NRcsz2, 0C(0)Rb2, OC(O)NRC2Rd2, NRCZR‘”, NRC2C(O)Rb2, NRC2C(O)OR32,
and NRC2C(O)NRCZRd2; wherein said 06 alkyl, C340 cycloalkyl, 4-10 membered
heterocycloalkyl, and 4-10 membered heterocycloalkyl-C1—3 alkylene are each optionally
substituted with 1 or 2 substituents independently selected from R21;
or two adjacent R20 substituents on the CyA ring, taken er with the atoms to
which they are ed, form a fused C3—7 cycloalkyl ring; and wherein the fused C3—7
cycloalkyl ring is ally substituted with l or 2 substituents independently selected from
each R21 is C1-6 alkyl, C340 cycloalkyl, 4-10 ed heterocycloalkyl, C640 aryl, 5-
membered heteroaryl, halo, CN, ORa“, NRC4Rd4, NRC4C(O)Rb4, and NRC4C(O)ORa4;
wherein said C1-6 alkyl, C340 cycloalkyl, 4-10 membered cycloalkyl, C640 aryl, and 5-
10 membered heteroaryl are each optionally substituted with 1 or 2 substituents
independently selected from R22,
each R22 is independently ed from C1-6 alkyl, 5-6 membered aryl, 4-7
membered heterocycloalkyl, CN, OR316 and NRCGRdG, wherein said C16 alkyl and 5-6
membered heteroaryl are each optionally substituted with 1 or 2 substituents independently
selected from Rg;
each Ra and Rc is H;
each R‘l is independently selected from C1-6 alkyl, C640 aiyl, and 5-10 membered
heteroaryl; wherein said C1-6 alkyl, C640 aryl, and 5-10 membered heteroaryl are each
optionally tuted with 1 or 2 substituents independently selected from R10;
W0 49200
each Rb is independently selected from 7-10 membered heterocycloalkyl, C6-10 aIyl,
and 5-10 membered heteroaryl; n said 7-10 membered heterocycloalkyl, C6-10 aryl and
-10 membered heteroaryl are each optionally substituted with 1 or 2 substituents
independently selected from R10;
each R31, RC1 and R‘11 is independently selected from H, C1-6 alkyl, and C340
cycloalkyl, wherein said C1-6 alkyl and C340 cycloalkyl, are each optionally substituted with l
or 2 substituents independently selected from R“,
each R”, RCZ and Rdz is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, and
4-10 membered heterocycloalkyl, wherein said C1-6 alkyl and 4-10 membered
heterocycloalkyl are each optionally substituted with 1 or 2 substituents independently
selected from R“;
or any RCZ and R£12 attached to the same N atom, together with the N atom to which
they are attached, form a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionally
substituted with l or 2 tuents independently selected from R21,
each R” is independently selected from C1-6 alkyl, C340 lkyl, 4-10 membered
heterocycloalkyl, and 5—10 membered heteroaryl, wherein said C1-6 alkyl, C3—10 cycloalkyl, 4-
membered heterocy cloalkyl, and 5-10 membered heteroaryl are each optionally substituted
with 1 or 2 substituents ndently selected from R“;
each R213 is ndently selected from H and C1-6 alkyl;
each R[)3 is C1-6 alkyl;
each R34, RC4 and R014 is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C3-6
cycloalkyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl; n said C1-6
alkyl, C3-6 cycloalkyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl are each
optionally substituted with 1 or 2 substituents independently selected from R”;
or any RC4 and RC14 attached to the same N atom, together with the N atom to which
they are attached, form a 4-, 5-, 6- or 7-membered cycloalkyl group;
each R'34 is independently selected from C1-6 alkyl,
each R36 is independently selected from H and C1-6 alkyl,
each RC6 and R‘16 is H;
each R37 is ndently selected from H and C1-6 alkyl; and
each Rg is independently selected from C1-6 alkyl.
It is further appreciated that n features of the invention, which are, for y,
described in the context of separate embodiments, can also be provided in combination in a
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single embodiment (while the embodiments are intended to be combined as if written in
multiply dependent form). Conversely, s features of the invention which are, for
brevity, bed in the t of a single embodiment, can also be ed separately or
in any le subcombination. Thus, it is contemplated as features described as
embodiments of the compounds of a (I) can be combined in any suitable combination,
At various places in the present specification, certain features of the compounds are
disclosed in groups or in ranges. It is ically intended that such a disclosure include each
and every individual subcombination of the members of such groups and ranges. For
example, the term "Cl-6 alkyl" is specifically intended to individually disclose (without
limitation) methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl and C6 alkyl.
The term "n-membered," where n is an integer, typically describes the number of
ring-forming atoms in a moiety where the number of ring-forming atoms is n. For example,
piperidinyl is an example of a 6-membered cycloalkyl ring, pyrazolyl is an example of
a 5-membered heteroaryl ring, pyridyl is an example of a 6-membered aryl ring and
1,2,3,4-tetrahydro-naphthalene is an example of a lO-membered cycloalkyl group.
At s places in the present cation, variables defining divalent linking
groups may be described. It is specifically intended that each linking tuent include both
the forward and backward forms of the linking substituent. For example, -NR(CR'R")n-
includes both -NR(CR’R”)n- and -(CR'R")nNR- and is intended to disclose each of the forms
individually. Where the structure requires a linking group, the Markush variables listed for
that group are understood to be linking groups. For example, if the structure requires a
linking group and the Markush group definition for that variable lists "alkyl" or "aryl" then it
is understood that the "alkyl" or "aryl" represents a linking alkylene group or arylene group,
tively.
The term "substituted" means that an atom or group of atoms formally replaces
hydrogen as a "substituent" attached to another group. The term ituted", unless
otherwise indicated, refers to any level of substitution, e.g., mono-, di-, tri-, tetra— or
penta—substitution, where such substitution is permitted. The substituents are independently
selected, and tution may be at any chemically accessible position. It is to be understood
that substitution at a given atom is limited by valency. It is to be understood that tution
at a given atom results in a chemically stable molecule. The phrase "optionally substituted"
means unsubstituted or substituted. The term "substituted" means that a hydrogen atom is
removed and replaced by a substituent. A single divalent substituent, e.g., oxo, can replace
two hydrogen atoms.
W0 49200
The term "Cn—m" indicates a range which includes the endpoints, n n and m are
integers and te the number of s. Examples include Ci-4, C1-6 and the like.
The term "alkyl," employed alone or in combination with other terms, refers to a
saturated hydrocarbon group that may be straight-chained or branched. The term "Cu—m alkyl",
refers to an alkyl group having 11 to m carbon atoms. An alkyl group formally corresponds to
an alkane with one C-H bond replaced by the point of attachment of the alkyl group to the
remainder of the compound. In some ments, the alkyl group contains from 1 to 6
carbon atoms, from 1 to 4 carbon atoms, from 1 to 3 carbon atoms, or 1 to 2 carbon atoms.
Examples of alkyl moieties include, but are not limited to, chemical groups such as methyl,
ethyl, n-propyl, isopropyl, n-butyl, tert—butyl, isobutyl, sec-butyl, higher gs such as 2-
methyl-l-butyl, n-pentyl, yl, n-hexyl, 1,2,2-trimethylpropyl and the like.
The term "alkenyl," employed alone or in combination with other terms, refers to a
straight-chain or branched hydrocarbon group corresponding to an alkyl group having one or
more double carbon-carbon bonds. An alkenyl group formally corresponds to an alkene with
one C-H bond replaced by the point of attachment of the alkenyl group to the remainder of
the compound. The term "Cn—m l" refers to an alkenyl group having 11 to m carbons. In
some embodiments, the alkenyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms.
Example alkenyl groups include, but are not limited to, l, n-propenyl, isopropenyl, n-
butenyl, sec-butenyl and the like.
The term "alkynyl," employed alone or in combination with other terms, refers to a
straight—chain or branched hydrocarbon group corresponding to an alkyl group having one or
more triple carbon-carbon bonds. An l group formally corresponds to an alkyne with
one C-H bond replaced by the point of attachment of the alkyl group to the remainder of the
compound. The term "Ch-m alkynyl" refers to an alkynyl group having 11 to m carbons.
e alkynyl groups include, but are not limited to, ethynyl, propyn-l-yl, propynyl
and the like. In some embodiments, the alkynyl moiety contains 2 to 6, 2 to 4, or 2 to 3
carbon atoms.
The term "alkylene," employed alone or in combination with other terms, refers to a
divalent alkyl linking group. An alkylene group formally ponds to an alkane with two
C-H bond replaced by points of attachment of the alkylene group to the remainder of the
compound. The term "Cn-m alkylene" refers to an alkylene group having n to m carbon atoms.
Examples of alkylene groups include, but are not limited to, ethan-1,2-diyl, ethan-1,1-diy1,
propan-l,3-diyl, propan-1,2-diyl, propan-l,1-diyl, butan-l,4-diyl, butan—l,3—diyl, butan-l,2-
diyl, 2-methyl-propan-l,3-diyl and the like.
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The term "alkoxy," employed alone or in ation with other terms, refers to a
group of formula -O-a1ky1, wherein the alkyl group is as defined above. The term "Cn-m
alkoxy" refers to an alkoxy group, the alkyl group of which has n to m carbons. Example
alkoxy groups include methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), t—butoxy
and the like. In some embodiments, the alkyl group has I to 6, l to 4, or I to 3 carbon atoms,
The term "amino” refers to a group of formula —NH2.
The term "carbonyl," ed alone or in combination with other terms, refers to
a -C(=O)- group, which also may be written as C(O).
The term "cyano" or "nitrile" refers to a group of formula —CEN, which also may be
written as -CN.
The terms "halo" or "halogen", used alone or in combination with other terms, refers
to fluoro, chloro, bromo and iodo. In some embodiments, "halo" refers to a halogen atom
selected from F, C1, or Br. In some ments, halo groups are F.
The term "haloalkyl" as used herein refers to an alkyl group in which one or more of
the hydrogen atoms has been ed by a halogen atom. The term a10alkyl" refers to
a Cn-m alkyl group having n to m carbon atoms and from at least one up to {2(n to m)+1}
halogen atoms, which may either be the same or different. In some embodiments, the halogen
atoms are fluoro atoms. In some embodiments, the kyl group has 1 to 6 or 1 to 4 carbon
atoms. Example haloalkyl groups include CF3, C2F5, CHF2, CH2F, CC13, CHClz, C2Cls and
the like. In some embodiments, the haloalkyl group is a fluoroalkyl group.
The term "haloalkoxy," employed alone or in combination with other terms, refers to
a group of formula -O-haloalkyl, wherein the haloalkyl group is as defined above. The term
"Cn-m koxy" refers to a haloalkoxy group, the haloalkyl group of which has n to m
carbons. Example haloalkoxy groups include trifluoromethoxy and the like. In some
ments, the haloalkoxy group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.
The term "oxo" refers to an oxygen atom as a divalent substituent, forming a carbonyl
group when ed to carbon, or attached to a heteroatom forming a sulfoxide or sulfone
group, or an N—oxide group. In some embodiments, heterocyclic groups may be optionally
substituted by 1 or 2 oxo (=0) substituents.
The term "sulfido" refers to a sulfur atom as a divalent substituent, forming a
thiocarbonyl group (C=S) when attached to carbon.
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The term "aromatic" refers to a carbocycle or heterocycle having one or more
polyunsaturated rings having aromatic character (z'.e., having (4n + 2) delocalized 1!: (pi)
electrons where n is an integer).
The term " employed alone or in ation with other terms, refers to an
aromatic hydrocarbon group, which may be clic or polycyclic (e.g., having 2 fused
rings). The term "Cm-m aryl" refers to an aryl group having from n to m ring carbon atoms,
Aryl groups include, e.g., phenyl, naphthyl, and the like. In some embodiments, aryl groups
have from 6 to about 10 carbon atoms. In some ments aryl groups have 6 carbon
atoms. In some embodiments aryl groups have 10 carbon atoms. In some embodiments, the
aryl group is phenyl. In some embodiments, the aryl group is naphthyl.
The term "heteroaryl" or "heteroaromatic," employed alone or in combination with
other terms, refers to a monocyclic or polycyclic aromatic heterocycle having at least one
heteroatom ring member selected from sulfur, oxygen and nitrogen. In some embodiments,
the heteroaryl ring has 1, 2, 3 or 4 heteroatom ring members independently ed from
nitrogen, sulfur and oxygen. In some embodiments, any ring-forming N in a heteroaryl
moiety can be an N-oxide. In some embodiments, the heteroaryl has 5-14 ring atoms
including carbon atoms and l, 2, 3 or 4 heteroatom ring members independently ed
from nitrogen, sulfur and oxygen. In some embodiments, the heteroaryl has 5-10 ring atoms
including carbon atoms and l, 2, 3 or 4 heteroatom ring members ndently selected
from nitrogen, sulfur and oxygen. In some embodiments, the heteroaryl has 5-6 ring atoms
and l or 2 heteroatom ring members independently selected from nitrogen, sulfur and
oxygen. In some embodiments, the aryl is a five-membered or six-membered
heteroaryl ring. In other embodiments, the heteroaryl is an eight-membered, embered
or ten-membered fused bicyclic heteroaryl ring. Example heteroaryl groups include, but are
not limited to, pyridinyl (pyridyl), pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, lyl,
azolyl, oxazolyl, isoxazolyl, thiazolyl, imidazolyl, furanyl, thiophenyl, quinolinyl,
isoquinolinyl, naphthyridinyl (including l,2-, l,3-, 1,4-, 1,5-, 1,6-, l,7-, 1,8—, 2,3- and 2,6-
yridine), indolyl, benzothiophenyl, benzofuranyl, benzisoxazolyl, imidazo[l,2-
b]thiazolyl, l, and the like. In some embodiments, the aryl group is pyridone
(e.g., 2-pyridone).
A five-membered heteroaryl ring is a heteroaryl group having five ring atoms wherein
one or more (e.g., 1, 2 or 3) ring atoms are independently selected from N, O and S.
Exemplary five—membered ring heteroaryls include thienyl, furyl, pyrrolyl, imidazolyl,
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thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl, tetrazolyl, 1,2,3-
thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-triazolyl, 1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-
triazolyl, 1,3,4-thiadiazolyl and 1,3,4-oxadiazolyl.
A six-membered heteroaryl ring is a heteroaryl group having six ring atoms wherein
one or more (eg, 1, 2 or 3) ring atoms are independently selected from N, O and S.
Exemplary six-membered ring heteroaryls are pyridyl, pyrazinyl, pyrirnidinyl, triazinyl and
pyridazinyl.
The term "cycloalkyl," employed alone or in combination with other terms, refers to a
non-aromatic hydrocarbon ring system (monocyclic, ic or polycyclic), including
cyclized alkyl and alkenyl groups. The term "Cn-m cycloalkyl" refers to a cycloalkyl that has
n to m ring member carbon atoms. Cycloalkyl groups can include mono- or polycyclic (e. g.
having 2, 3 or 4 fused rings) groups and spirocycles. Cycloalkyl groups can have 3, 4, 5, 6 or
7 ring-forming s (C34). In some embodiments, the cycloalkyl group has 3 to 6 ring
members, 3 to 5 ring members, or 3 to 4 ring members. In some embodiments, the cycloalkyl
group is monocyclic. In some embodiments, the cycloalkyl group is monocyclic or bicyclic.
In some ments, the cycloalkyl group is a C3-6 monocyclic cycloalkyl group. Ring-
forming carbon atoms of a cycloalkyl group can be optionally oxidized to form an oxo or
sulfido group. Cycloalkyl groups also include cycloalkylidenes. In some embodiments,
cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. Also included in the
definition of cycloalkyl are es that have one or more aromatic rings fused (£16., having
a bond in common with) to the cycloalkyl ring, e.g., benzo or thienyl derivatives of
cyclopentane, cyclohexane and the like. A cycloalkyl group containing a fused aromatic ring
can be attached through any ring-forming atom ing a orming atom of the fused
aromatic ring. Examples of cycloalkyl groups e cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, eptatrienyl,
norbornyl, norpinyl, norcarnyl, bicyclo[l.l.l]pentanyl, bicyclo[2. l. nyl, and the like. In
some embodiments, the cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, or
exyl.
The term "heterocycloalkyl," employed alone or in combination with other terms,
refers to a non-aromatic ring or ring system, which may optionally contain one or more
alkenylene groups as part of the ring structure, which has at least one heteroatom ring
member independently ed from nitrogen, sulfur oxygen and orus, and which has
4-10 ring members, 4-7 ring s, or 4-6 ring members. Included Within the term
“heterocycloalkyl” are monocyclic 4-, 5-, 6- and ered heterocycloalkyl groups.
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cycloalkyl groups can include mono- or bicyclic (e.g., having two fused or bridged
rings) or spirocyclic ring systems. In some embodiments, the heterocycloalkyl group is a
monocyclic group having 1, 2 or 3 heteroatoms independently selected from nitrogen, sulfur
and oxygen. Ring-forming carbon atoms and heteroatoms of a heterocycloalkyl group can be
optionally oxidized to form an 0x0 or sulfido group or other oxidized linkage (eg, C(O),
S(O), C(S) or S(O)2, N—oxide etc.) or a nitrogen atom can be quaternized. The
heterocycloalkyl group can be attached through a ring-forming carbon atom or a ringforming
heteroatom. In some embodiments, the heterocycloalkyl group contains 0 to 3
double bonds. In some embodiments, the heterocycloalkyl group ns 0 to 2 double
bonds. Also included in the definition of heterocycloalkyl are moieties that have one or more
aromatic rings fused (Le. a bond in common with) to the heterocycloalkyl ring, e. g.
, having ,
benzo or thienyl derivatives of piperidine, line, azepine, etc. A heterocycloalkyl
group containing a fused aromatic ring can be attached through any ring-forming atom
including a ring-forming atom of the fused aromatic ring. es of heterocycloalkyl
groups include inyl, azepanyl, obenzofuranyl, dihydrofuranyl, dihydropyranyl,
morpholino, 3-oxopiperazinyl, 3-oxa—9-azaspiro[5.5]undecanyl, l-oxa
azaspiro[4.5]decany1, dinyl, piperazinyl, piperazinonyl, oxopiperazinyl, pyranyl,
pyrrolidinyl, quinuclidinyl, tetrahydrofuranyl, ydropyranyl,
1,2,3,4-tetrahydroquinoliny1, 1,2,3,4-tetrahydroisoquinolinyl, yl, benzodioxole, and
thiomorpholino.
At certain places, the definitions or embodiments refer to specific rings (e.g., an
azetidine ring, a pyridine ring, etc.). Unless otherwise indicated, these rings can be ed
to any ring member provided that the valency of the atom is not exceeded. For example, an
azetidine ring may be ed at any on of the ring, whereas an azetidinyl ring is
attached at the 3-position.
The compounds described herein can be asymmetric (e. g. one or more
, having
stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended unless
otherwise indicated. Compounds of the present invention that contain asymmetrically
substituted carbon atoms can be isolated in optically active or racemic forms. Methods on
how to prepare optically active forms from optically inactive starting materials are known in
the art, such as by resolution of racemic mixtures or by stereoselective sis. Many
geometric isomers of olefins, C=N double bonds and the like can also be present in the
compounds described herein, and all such stable isomers are contemplated in the present
W0 2018f049200
invention. Cis and trans geometric isomers of the compounds of the present invention are
described and may be isolated as a mixture of isomers or as separated isomeric forms.
Resolution of racemic mixtures of compounds can be carried out by any of numerous
methods known in the art. One method includes fractional recrystallization using a chiral
resolving acid which is an optically active, salt-forming organic acid. Suitable resolving
agents for fractional recrystallization methods are, e.g., optically active acids, such as the D
and L forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic
acid, lactic acid or the various optically active camphorsulfonic acids such as [3—
rsulfonic acid. Other resolving agents suitable for fractional crystallization methods
include stereoisomerically pure forms of oc-methylbenzylamine (e. g. S and R forms, or
reomerically pure forms), 2-pheny1glycinol, norephedrine, ephedrine, N—
methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane and the like.
Resolution of racemic mixtures can also be carried out by elution on a column packed
with an optically active resolving agent (e.g., dinitrobenzoylphenylglycine). Suitable elution
t composition can be ined by one skilled in the art.
In some embodiments, the compounds of the invention have the (R)-conf1guration. In
other ments, the compounds have the (S)-conf1guration. In compounds with more
than one chiral centers, each of the chiral centers in the compound may be ndently (R)
or (5), unless otherwise indicated.
Compounds of the ion also include tautomeric forms. Tautomeric forms result
from the swapping of a single bond with an adjacent double bond together with the
concomitant migration of a proton. Tautomeric forms include prototropic tautomers which
are isomeric protonation states having the same cal formula and total charge. Example
prototropic tautomers include ketone — enol pairs, amide - imidic acid pairs, lactam —1actim
pairs, enamine — imine pairs, and annular forms where a proton can occupy two or more
positions of a heterocyclic system, e.g., 1H- and 3H-imidazole, 1H-, 2H- and 4H- 1,2,4-
triazole, 1H- and 2H- isoindole and 1H- and 2H-pyrazole. Tautomeric forms can be in
equilibrium or sterically locked into one form by appropriate substitution.
Compounds of the invention can also e all es of atoms occurring in the
intermediates or final compounds. es include those atoms having the same atomic
number but different mass numbers. For example, es of hydrogen e tritium and
deuterium. One or more constituent atoms of the compounds of the invention can be replaced
or substituted with es of the atoms in natural or non-natural abundance. In some
W0 2018f049200
embodiments, the compound includes at least one deuterium atom For example, one or
more hydrogen atoms in a compound of the present disclosure can be replaced or substituted
by ium. In some embodiments, the compound includes two or more deuterium atoms.
In some embodiments, the compound includes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 deuterium
atoms. Synthetic methods for ing isotopes into organic compounds are known in the art
(Deuterium ng in c Chemistry by Alan F. Thomas (New York, N.Y., Appleton-
Century-Crofts, 1971; The Renaissance of H/D ge by Jens Atzrodt, Volker Derdau,
Thorsten Fey and Jochen Zimmermann, Angew. Chem. Int. Ed. 2007, 7744-7765).
ically labeled nds can used in s studies such as NMR spectroscopy,
metabolism experiments, and/or assays.
Substitution with heavier isotopes such as deuterium, may 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 stances. (A.
Kerekes et.al. J. Med. Chem. 2011, 54, 201-210, R. Xu et.al. J. Label Compd. Radiopharm.
2015, 58, 308-312).The term, "compound," as used herein is meant to include all
stereoisomers, geometric isomers, tautomers and es of the structures depicted. The
term is also meant to refer to compounds of the ions, regardless of how they are
prepared, e. g., synthetically, through biological process (e. g., metabolism or enzyme
conversion), or a combination thereof.
All compounds, and pharmaceutically able salts thereof, can be found together
with other substances such as water and solvents (e. g., hydrates and solvates) or can be
isolated. When in the solid state, the compounds described herein and salts thereof may occur
in various forms and may, 6. g. take the form of solvates, including hydrates. The compounds
may be in any solid state form, such as a polymorph or solvate, so unless clearly indicated
ise, reference in the specification to compounds and salts thereof should be understood
as encompassing any solid state form of the compound.
In some embodiments, the compounds of the invention, or salts thereof, are
substantially isolated. By "substantially isolated" is meant that the compound is at least
lly or substantially separated from the environment in which it was formed or detected.
Partial separation can include, e.g., a composition enriched in the compounds of the
invention. Substantial separation can include compositions ning at least about 50%, at
least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about
95%, at least about 97%, or at least about 99% by weight of the compounds of the invention,
or salt thereof
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The phrase "pharmaceutically acceptable" is employed herein to refer to those
compounds, materials, compositions and/or dosage forms which are, within the scope of
sound medical judgment, suitable for use in contact with the tissues of human beings and
animals without excessive toxicity, irritation, allergic response, or other problem or
complication, surate with a reasonable benefit/risk ratio.
The expressions, "ambient temperature" and "room temperature," as used herein, are
understood in the art, and refer generally to a temperature, e. g. a reaction temperature, that is
about the temperature of the room in which the reaction is carried out, e. g., a temperature
from about 20 0C to about 30 0C.
The t invention also includes pharmaceutically acceptable salts of the
compounds described herein. The term "pharmaceutically able salts" refers to
derivatives of the disclosed compounds wherein the parent compound is modified by
converting an existing acid or base moiety to its salt form. Examples of ceutically
acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues
such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the
like. The pharmaceutically acceptable salts of the t ion include the xic
salts of the parent compound , e. g, from non-toxic inorganic or c acids. The
pharmaceutically acceptable salts of the present ion can be synthesized from the parent
compound which contains a basic or acidic moiety by conventional chemical methods.
Generally, such salts can be prepared by reacting the free acid or base forms of these
compounds with a stoichiometric amount of the appropriate base or acid in water or in an
organic solvent, or in a mixture of the two, generally, non-aqueous media like ether, ethyl
acetate, alcohols (e.g., methanol, ethanol, iso-propanol or butanol) or acetonitrile (MeCN) are
preferred. Lists of le salts are found in Remington 's Pharmaceutical Sciences, 17th Ed,
(Mack Publishing Company, Easton, 1985), p. 1418, Berge et al., J. Pharm. Sci., 1977,
66(1), 1-19 and in Stahl et al., Handbook ofPharmaceutical Salts: Properties, Selection, and
Use, (Wiley, 2002). In some embodiments, the compounds described herein e the N-
oxide forms.
Synthesis
Compounds of the invention, including salts thereof, can be prepared using known
organic synthesis techniques and can be synthesized ing to any of us possible
synthetic routes, such as those in the Schemes below.
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The reactions for preparing compounds of the invention can be carried out in suitable
solvents which can be readily selected by one of skill in the art of organic synthesis. le
solvents can be substantially non-reactive with the starting materials (reactants), the
intermediates or ts at the temperatures at which the reactions are carried out, e.g.,
temperatures which can range from the solvent's freezing temperature to the solvent’s boiling
ature. A given reaction can be carried out in one solvent or a mixture of more than one
solvent. Depending on the particular reaction step, suitable solvents for a particular reaction
step can be selected by the skilled artisan.
Preparation of nds of the invention can involve the protection and
deprotection of various chemical groups. The need for protection and deprotection, and the
selection of appropriate protecting groups, can be readily determined by one skilled in the art.
The chemistry of protecting groups is described, e. g., in Kocienski, Protecting Groups,
(Thieme, 2007); Robertson, Protecting Group Chemistry, (Oxford University Press, 2000),
Smith et ai, March’s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure,
6th Ed. (Wiley, 2007); Peturssion et al., "Protecting Groups in Carbohydrate Chemistry," J.
Chem. Educ, 1997, 74(11), 1297, and Wuts et al., Protective Groups in Organic sis,
4th Ed, (Wiley, 2006).
ons can be monitored according to any suitable method known in the art. For
example, product ion can be monitored by spectroscopic means, such as nuclear
magnetic resonance spectroscopy (e.g., 1H or 13C), infrared spectroscopy, spectrophotometry
(e. g., UV—visible), mass spectrometry or by tographic methods such as high
performance liquid chromatography (HPLC) or thin layer chromatography (TLC).
The Schemes below provide general guidance in connection with preparing the
compounds of the invention. One skilled in the art would tand that the preparations
shown in the Schemes can be modified or zed using general dge of organic
chemistry to prepare various nds of the invention.
nds of Formula (I) can be prepared, e.g., using a process as illustrated in the
schemes below.
Compounds of Formula (I) with various substitutions at on R1 such as those
described herein can be prepared using a process as illustrated in Scheme 1. In the process
depicted in Scheme 1, compounds of Formula 1-2 are formed after protection of the NH
group of the compounds of Formula 1-1 with a suitable protecting group (eg. SEM or Boc).
The chloro substituent in the compounds of Formula 1-2 can be converted into CyA via a
number of different coupling reactions, including Suzuki (e.g, in the presence of a
ium catalyst, such as Xphos Pd G2, and a base, such as potassium phosphate) or Stille
(e.g., in the presence of a palladium(0) catalyst, such as
tetrakis(triphenylphosphine)pa11adium(0)), and others, to give the compounds of Formula 1-3.
Deprotection of the protecting group (e.g., under acidic conditions, such as ent with
HCl or TFA) results in the formation of nds of a 1-4. These compounds can be
further halogenated with one of the halogenation agents (6. g., N18 or iodine) to form
compounds of Formula 1-5. The NH group of the pyrazole ring of the compounds of Formula
1-5 is protected with a suitable protecting group, such as Boc or SEM, to form compounds of
Formula 1-6. The halogen substituent in the compounds of Formula 1-6 can be converted into
R1 via anumber of ent cross-coupling reactions, including Stille (ACS Catalysis 2015,
, 3040-3053), Suzuki (Tetrahedron 2002, 58, 9633-9695), Sonogashira (Chem. Soc. Rev.
2011, 40, 5084-5121), i (ACS Catalysis 2016, 6, 1540-1552), Buchwald—Hartwig
amination (Chem. Sci. 2011, 2, 27-50), Cu—catalyzed amination (Org. React. 2014, 85, 1-688)
and , to give the compounds of Formula 1-7. Finally, deprotection of the protecting
group under acidic conditions (6. g. , treatment with HCl or TFA) results in the formation of
the desired compounds of Formula (I).
Scheme 1
Cl CI Suzuki or Stille
/ \N /
I NH Protection I \N coupling
, —> , —>
H .
H PG
1-1 1-2
R2 R2
_ CyA C A
\ NH Protectlon / \ le, DMF y / \
N ‘ ,N ‘— N
N \ N \
N N1
H H
H H
1-5 1 -4
Suzuki, Stille,
Negishi or
Cu cat. amination
R1 R2
CyA / Deprotection CyA /
| \
,N | ,N
N\ N
N \
PG 322/
H H
1 7 (|)
Alternatively, for the exploration of the substitution at on CyA, compounds of
Formula (I) can be prepared, using a process as illustrated in Scheme 2. Iodination of the
compounds of Formula 1-1 with one of the iodination agents, such as iodine or NIS, forms
compounds of a 2-2. The NH group of the pyrazole ring of the compounds of Formula
2-2 is protected with a suitable protecting group (6. g, Boc or SEM) to form compounds of
Formula 2-3. The iodo substituent in the compounds of Formula 2-3 can be converted into R1
Via a number of different cross-coupling ons, including Suzuki, Sonogashira, Negishi,
Buchwald—Hartwig amination, Cu—catalyzed amination and others, to give the compounds of
Formula 2-4. The chloro tuent in the compounds of Formula 2-4 can be further
converted into CyA via a number of different cross-coupling reactions, including Suzuki,
Stille, and others, to give the compounds of Formula 2-5. Finally, deprotection of the
ting group, 6. g. under acidic conditions, such as treatment with HCl or TFA, results in
the formation of the desired compounds of Formula (I).
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Scheme 2
R2 R2 R2
I I
/ CI / Cl /
| \ MS. DMF \ NH Protection \
,N —> | ,N —> | ,N
H H H PG
1-1 2-2 2.3
Suzuki, Stille,
Negishi or
Cu cat. amination
CyA / CAy / CI /
\N Deprotection Suzuki or Stille
I \
IN N
N N \ NN N \ NI
H lDG
- 2-4
Compounds of Formula (Ia) (compounds of aI n R1 is NRCC(O)Rb) can
be prepared, using a process as illustrated in Scheme 3. In the s depicted in Scheme 3,
compounds of Formula 3-1 react which hydroxylamine hydrochloride to form oxime
intermediates, which are further converted to compounds of Formula 3-2 under the standard
conditions (6. g. under treatment with cyanuric chloride). Cyclization upon treatment of the
compounds of Formula 3-2 with hydrazine e results in compounds of Formula 3-3. The
NH group of the pyrazole ring of the compounds of Formula 3-3 is protected with a suitable
ting group (6. g. , Boc) to form compounds of Formula 3-4. The halo tuent in the
compounds of a 3-4 can be further converted into CyA via a number of different crosscoupling
reactions, including Suzuki, Stille, and others, to give the compounds of Formula 3-
. Compounds of Formula 3-5 react with different acid chlorides in a presence of base, such
as triethylamine or DIPEA, to form compounds of Formula 3-6. Finally, deprotection of the
protecting group, 6. g. under acidic conditions, such as treatment with HCl or TFA, s in
the formation of the desired compounds of Formula (Ia). Alternatively compounds of
Formula 3-6 can be alkylated or arylated and then deprotected to prepare amides n RC
is other than hydrogen.
Scheme 3
R2 R2
1. Hydroxylamine Hal / CN Hal /
2. Cyanuric chloride l 20
—> I \N
N \ N \ N \
F N,
H H
343-2 3 3
2 HN/(Rb O
R 2 R2 )L R
NH2 NH2
A b Suzuki
Cy / CI R CyA Ha'
l \N / /
I \ orStille
‘— N ‘— l \N
N\ N’ N\ N N\ N
H PG H PG H PG
3-6 3-5 3-4
i ection
R2 HN/(Rb
CyA /
| \
Compounds of Formula (Ib) (compounds of Formula I wherein R1 is C(O)NRCRd) can
be prepared, using a process as illustrated in Scheme 4. In the process depicted in Scheme 4,
compounds of Formula 1-6 are converted into compounds of a 4-2 under Pd—catalyzed
carbonylation conditions, such as in a presence of Pd catalyst (e. g. , Pd(dppf)C12*DCM) and
base (6. g., triethylamine) under carbon monoxide here. Hydrolysis of the ester group
under basic conditions, such as LiOH or NaOH, forms the compounds of a 4-3.
Compounds of Formula 4-3 can be coupled to an amine, HNRCRd, using standard amide
coupling agents (e.g., HBTU, HATU or EDC) to give compounds of Formula 4-4. Finally,
deprotection of the protecting group, 6. g. under acidic conditions, such as treatment with HCl
or TFA, results in the formation of the desired compounds of Formula (lb).
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Scheme 4
R2 R2
I COOMe
CYA / Pd cat. LiOH
\ ylation THF/MeOH/HZO
I A —> //| \N —>
N \ N \
N N,’
H PG H PG
1-6 44
HI}! Amide
Rd coupling
R2 O N‘d
of R
| \ ection
,N <—
Compounds of a (Ic) (compounds of Formula I wherein R2 is F) can be
prepared, using a process as illustrated in Scheme 5. As ed in Scheme 5, the cross-
coupling reactions (6g, Suzuki and Stille) with 2-bromo-3,5-difluoropyridine afford the
compounds of Formula 5-2. Treating 5-2 with LDA at -78 °C followed by quenching with
methyl Forrnate gives 5-3 which is subsequently converted into 5-4 by treating with
hydrazine. Upon treating with NIS, 5-4 is converted into 5-5. The NH group of the pyrazole
ring of 5-5 is protected with a le protecting group (6. g. , Boc) to form compounds of
Formula 5-6. The iodo substituent in 5-6 can be further converted into R1 via a number of
cross-coupling reactions (e.g., Suzuki, Stille, Buchwald—Hartwig and others) to give
compounds of Formula 5-7. Finally, deprotection of the protecting group affords the desired
compounds of Formula (Ic).
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Schemes
CyA CyA
SuzukiorStille F 1)LDA F
NI \ NI \
/ /
2) O
F \ A F O
O H
-1 5-2 5-3
CyA CyA CYA
F Protection F NIS
N \ N \ NI \
I I /
/ /
| | /
/ /
,N‘N HN\N
-6 5_5 54
Suzuki,
Stille,
orBuchwald
\ Deprotection Q:/ R1
GN\[\1 HN‘N
-7 (Ic)
Alternatively, compounds of a (Ic) unds of FormulaI wherein R2 is F)
can be prepared, using a process as illustrated in Scheme 6. As depicted in Scheme 6,
treating o—3,S-difluoropyndine with LDA at -78 0C followed by quenching with
methyl formate gives 2-bromo-3,5-difluoroisonicotinaldehyde which is subsequently d
into (2-bromo-3,5-difluoropyndinyl)methanol by treating with NaBH4. (2—Bromo-3,5-
difluoropyridinyl)methanol is then converted into the compounds of Formula 6-3 via the
cross-coupling reactions (eg, Suzuki or Stille). Upon oxidation (e. g., with Dess-Martin
nane), 6-3 is converted into 5—3 which is subsequently ted into 5-4 by treating
with hydrazine. Treating 5—4 with NIS gives 5-5. The NH group of the pyrazole ring of 5-5 is
protected with a suitable protecting group (eg, Boo) to form compounds of Formula 5—6. The
iodo substituent in 5—6 can be further converted into R1 via a number of cross-coupling
reactions (e.g., Suzuki, Stille, Buchwald—Hartwig, and others) to give the compounds of
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Formula 5—7. Finally, deprotection of the protecting group affords the d compounds of
Formula (Ic).
Scheme 6
F 1) LDA
_Z \/
CyA Suzuki CyA
Stille
F F
F Protection \ orBuchwald N \
[\1 \ I
l / R1
HN\N GN\N ,N‘N
-5 5-6 5-7
Deprotection
/ R1
Compounds of Formula (I) with a variety of substitution at position R2 (rings, alkyl
and alkenyl chains and various functional groups) can be prepared, using a process as
illustrated in Scheme 7. In the process depicted in Scheme 7, bromination 5-chloro
methylpyridinamine 7-1 with brominating agents (e.g., bromine or NBS) forms
compounds of a 7-2, Acylation of the NH2 group in the compounds of Formula 7-2
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with acylating agents (e.g., AC2O or AcCl) followed by the treatment with amyl nitrite forms
compounds of Formula 7-3. These compounds can be further iodinated with one of the
iodinating agents (e.g., NIS or iodine) to form compounds of Formula 7-4. The NH group of
the pyrazole ring in the compounds of Formula 7-4 is protected with a suitable ting
group, such as Boc or SEM, to form compounds of a 7-5. The iodo substituent in the
compounds of Formula 7-5 can be ted into R1 via a number of different cross-coupling
reactions, including Suzuki, Stille, Negishi, Cu-catalyzed ion, and , to give the
compounds of a 7-6. The bromo substituent in the compounds of Formula 7—6 can be
further ted into CyA via a number of different cross-coupling reactions, including
Suzuki, Stille, Negishi, and others, to give the compounds of Formula 7-7. The chloro
substituent in the nds of Formula 7-7 can be further converted into R2 via a number of
different cross-coupling reactions, including Suzuki, Stille, Negishi, and , to give the
compounds of Formula 7-8. Finally, deprotection of the protecting group, 6.g. under acidic
conditions, such as treatment with HCl or TFA, results in the formation of the desired
compounds of Formula (I).
Scheme 7
Aczo then
l Bromination Amyl nitrite / \N Iodination
N \ N \ N \
NH2 N
J NH Protection
CI R1 I R1 Cl
Pd cat yA Suzuki or Suzuki or
Br Br
cross co uplingC / \ Stille / \ Stille /
l l 1 \
N ,N <— ,N
N N N N
JBPGDeprotection PG PG
7 7 7 6 7-5
R2 R1
HPK1 Kinase
Extensive studies have established that HPK1 is a negative regulator of T cell and B
cell activation (Hu, M.C., et a1, Genes Dev, 1996. 10(18): p. 2251-64; Kjefer, F., et a1.,
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EMBO J, 1996. 15(24): p. 7013-25). HPK1-deficient mouse T cells showed dramatically
increased activation ofTCR proximal signaling, enhanced IL-2 production, and hyper-
proliferation in vitro upon D3 stimulation (Shui, J.W., et al., Nat Immunol, 2007 . 8(1):
p. . Similar to T cells, HPK1 knockout B cells produced much higher levels of IgM
and IgG isoforms after KLH immunization and displayed hyper-proliferation potentially as a
result of ed BCR signaling. Wang, X, et al., J Biol Chem, 2012. 287(14): p. 11037-48.
Mechanistically, during TCR or BCR signaling, HPK1 is activated by LCK/ZAP70 (T cells)
or SYK/LYN (B cells) mediated-Tyr379 phosphorylation and its subsequent g to
adaptor protein SLP-76 (T cells) or BLNK (B cells) (Wang, X, et al., J Biol Chem, 2012.
287(14): p. 11037-48). Activated HPK1 phosphorylates SLP-76 on Ser376 or BLNK on
Thr152, g to the recruitment of signaling molecule 143 and ultimate ubiquitination-
mediated degradation of SLP-76 or BLNK (Liou, J et al., Immunity, 2000. 12(4): p. 399-
408; Di Bartolo, V., et al., J Exp Med, 2007. 204(3): p. 681-91). As SLP-76 and BLNK are
essential for TCR/BCR-mediated signaling activation (e.g. ERK, phospholipase Cy], calcium
flux, and NFAT activation), HPK1-mediated downregulation of these adaptor proteins
provide a negative feedback mechanism to attenuate signaling intensity during T cell or B
cell activation (Wang, K, et al., J Biol Chem, 2012. 287(14): p. 11037-48).
The bone marrow-derived tic cells (BDMCs) from HPK1 knockout mice
showed higher expression of co-stimulatory molecules (e.g. CD80/CD86) and enhanced
production of proinflammatory cytokines (IL-12, TNF-oc etc), and demonstrated superior
y to ate T cell eration in vitro and in vivo as compared to wild-type DCs
(Alzabin, S., et al., J Immunol, 2009. ): p. 6187-94). These data suggest that HPK1 is
also an important negative regulator of dendritic cell activation (Alzabin, S., et al., J
Immunol, 2009. 182(10): p. 6187-94). However, the signaling isms underlying HPK-
1 mediated negative regulation of DC activation remains to be elucidated.
In contrast, HPK1 appears to be a positive regulator of suppressive functions of
regulatory T cells (Treg) (Sawasdikosol, S. et al., The journal of immunology, 2012.
188(supplement l): p. 163). HPK1 deficient mouse Foxp3+ Tregs were defective in
ssing TCR-induced effector T cell proliferation, and paradoxically gained the ability to
produce IL—2 following TCR engagement (Sawasdikosol, S. et al., The Journal of
Immunology, 2012. pplement 1): p. 163). These data suggest that HPK1 is an
important regulator of Treg functions and peripheral self-tolerance.
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HPKl was also involved in PGE2-mediated inhibition of CD4+ T cell activation
(Ikegami, R., et al., J Immunol, 2001. : p. 4689-96). Studies published in US
08?988 indicated that HPKl kinase activity was increased by exposure to
physiological concentrations of PGE2 in CD4+ T cells and this effect was mediated by
PEGZ-induced PKA activation. The proliferation of HPKl deficient T cells was resistant to
the ssive effects of PGE2 (see US 2007/0087988). Therefore, PGE2-mediated
activation of HPKl may represent a novel regulatory pathway of modulating immune
response.
Uses offhe Compounds
The present disclosure provides methods of modulating (e.g., inhibiting) HPKl
activity, said method comprising administering to a patient a compound provided herein, or a
pharmaceutically acceptable salt thereof. In certain embodiments, the compounds of the
present disclosure, or pharmaceutically acceptable salts thereof, are useful for therapeutic
administration to e, stimulate and/or increase immunity in cancer. For example, a
method of treating a disease or disorder associated with inhibition of HPKl interaction can
include administering to a patient in need thereof a therapeutically effective amount of a
compound provided herein, or a pharmaceutically acceptable salt thereof The compounds of
the present disclosure can be used alone, in combination with other agents or therapies or as
an adjuvant or uvant for the treatment of diseases or disorders, including cancers. For
the uses described herein, any of the compounds of the disclosure, including any of the
embodiments thereof, may be used.
Examples of cancers that are treatable using the compounds of the present sure
include, but are not limited to, bone , atic cancer, skin cancer, cancer of the head
or neck, cutaneous or intraocular malignant melanoma, uterine cancer, ovarian cancer, rectal
cancer, cancer of the anal region, stomach cancer, testicular cancer, uterine ,
carcinoma of the fallopian tubes, carcinoma of the endometrium, endometrial cancer,
oma of the cervix, carcinoma of the , carcinoma of the vulva, Hodgkin's Disease,
dgkin's lymphoma, cancer of the esophagus, cancer of the small intestine, cancer of
the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of
the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, chronic or
acute leukernias ing acute myeloid leukemia, chronic myeloid leukemia, acute
lymphoblastic leukemia, chronic lymphocytic ia, solid tumors of childhood,
lymphocytic lymphoma, cancer of the r, cancer of the kidney or urethra, carcinoma of
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the renal pelvis, neoplasm of the central nervous system (CNS), primary CNS lymphoma,
tumor angiogenesis, spinal axis tumor, brain stem glioma, pituitary adenoma, Kaposi‘s
sarcoma, epidermoid cancer, squamous cell cancer, T -cell lymphoma, environmentally
induced cancers including those induced by asbestos, and combinations of said cancers.
In some embodiments, cancers ble with compounds of the present disclosure
include melanoma (e.g,, atic malignant melanoma), renal cancer (e.g. clear cell
carcinoma), prostate cancer (e. g. hormone refractory te adenocarcinoma), breast
, triple-negative breast cancer, colon cancer and lung cancer (e. g. non-small cell lung
cancer and small cell lung cancer). Additionally, the sure includes tory or
recurrent malignancies Whose growth may be inhibited using the compounds of the
disclosure.
In some embodiments, cancers that are treatable using the compounds of the present
disclosure e, but are not limited to, solid tumors (e.g., prostate cancer, colon cancer,
geal cancer, endometrial cancer, ovarian cancer, uterine cancer, renal , hepatic
cancer, pancreatic cancer, gastric cancer, breast cancer, lung cancer, cancers of the head and
neck, thyroid cancer, glioblastoma, sarcoma, bladder , etc.), hematological cancers
(e. g. , lymphoma, leukemia such as acute lymphoblastic leukemia (ALL), acute myelogenous
leukemia (AML), chronic lymphocytic ia (CLL), chronic myelogenous leukemia
(CML), DLBCL, mantle cell lymphoma, Non-Hodgkin lymphoma (including relapsed or
refractory NHL and recurrent follicular), Hodgkin lymphoma or multiple myeloma) and
combinations of said cancers.
In some embodiments, es and indications that are treatable using the
compounds of the present disclosure include, but are not limited to hematological cancers,
sarcomas, lung cancers, gastrointestinal cancers, genitourinary tract cancers, liver cancers,
bone cancers, nervous system s, gynecological cancers, and skin s.
Exemplary hematological cancers include lymphomas and leukemias such as acute
lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), acute promyelocytic
leukemia (APL), c lymphocytic leukemia (CLL), chronic myelogenous leukemia
(CML), diffuse large B-cell lymphoma ), mantle cell lymphoma, Non-Hodgkin
lymphoma (including relapsed or refractory NHL and recurrent follicular), n
lymphoma, myeloproliferative diseases (e.g., primary myelofibrosis (PMF), polycythernia
vera (PV), essential thrombocytosis (ET)), myelodysplasia syndrome (MDS), T-cell acute
lymphoblastic lymphoma (T-ALL), multiple myeloma, cutaneous T—cell lymphoma,
Waldenstrom's Macroglubulinernia, hairy cell lymphoma, chronic myelogenic lymphoma
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and Burkitt's lymphoma.
Exemplary sarcomas include chondrosarcoma, Ewing’s sarcoma, osteosarcoma,
rhabdomyosarcoma, angiosarcoma, fibrosarcoma, liposarcoma, myxoma, myoma,
rhabdosarcoma, fibroma, lipoma, harmatoma, and teratoma.
Exemplary lung cancers e non-small cell lung cancer (NSCLC), small cell lung
cancer, bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated
large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, ial adenoma,
chondromatous oma, and mesothelioma.
Exemplary gastrointestinal s include cancers of the esophagus (squamous cell
carcinoma, adenocarcinoma, osarcoma, lymphoma), stomach noma, lymphoma,
leiomyosarcoma), as (ductal adenocarcinoma, insulinoma, glucagonoma, noma,
carcinoid tumors, vipoma), small bowel (adenocarcinoma, lymphoma, carcinoid tumors,
Kaposi's sarcoma, leiomyoma, ioma, lipoma, neurofibroma, fibroma), large bowel
(adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma), and
colorectal cancer.
Exemplary urinary tract cancers include cancers of the kidney
(adenocarcinoma, Wilm’s tumor [nephroblastoma]), bladder and urethra (squamous cell
carcinoma, transitional cell carcinoma, arcinoma), prostate (adenocarcinoma,
sarcoma), and testis (seminoma, teratoma, embryonal carcinoma, carcinoma,
choriocarcinoma, sarcoma, interstitial cell oma, fibroma, fibroadenoma, adenomatoid
tumors, lipoma).
Exemplary liver cancers include hepatoma (hepatocellular carcinoma),
cholangiocarcinoma, hepatoblastoma, arcoma, hepatocellular adenoma, and
Exemplary bone cancers include, for example, osteogenic sarcoma (osteosarcoma),
fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's a, malignant
lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor
chordoma, osteochronfroma (osteocartilaginous exostoses), benign chondroma,
chondroblastoma, chondromyxofibroma, osteoid osteoma, and giant cell tumors
Exemplary nervous system cancers include cancers of the skull (osteoma,
hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma,
meningiosarcoma, gliomatosis), brain (astrocytoma, meduoblastoma, glioma, ependymoma,
gerrninoma (pinealoma), glioblastoma, glioblastoma multiform, oligodendroglioma,
W0 2018f049200
schwannoma, blastoma, congenital ), and spinal cord (neurofibroma,
meningioma, glioma, sarcoma), as well as neuroblastoma and Lhermitte—Duclos disease.
Exemplary gynecological s include cancers of the uterus (endometrial
carcinoma), cervix (cervical carcinoma, pre -tumor cervical dysplasia), ovaries (ovarian
carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified
carcinoma), granulosa—thecal cell tumors, Sertoli-Leydig cell tumors, dysgerrninoma,
malignant ma), vulva ous cell carcinoma, intraepithelial carcinoma,
arcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, us cell
carcinoma, botryoid sarcoma onal rhabdomyosarcoma), and fallopian tubes
noma).
Exemplary skin cancers include melanoma, basal cell oma, us cell
carcinoma, Kaposi's sarcoma, Merkel cell skin , moles dysplastic nevi, lipoma,
angioma, dermatofibroma, and keloids. In some embodiments, diseases and indications that
are treatable using the compounds of the present disclosure include, but are not limited to,
sickle cell disease (e.g., sickle cell anemia), triple-negative breast cancer (TNBC),
myelodysplastic syndromes, testicular cancer, bile duct cancer, esophageal cancer, and
urothelial carcinoma.
ary head and neck cancers include glioblastoma, melanoma, rhabdosarcoma,
lymphosarcoma, osteosarcoma, squamous cell carcinomas, arcinomas, oral cancer,
laryngeal cancer, nasopharyngeal cancer, nasal and paranasal cancers, thyroid and
parathyroid cancers.
In some embodiments, HPKl inhibitors may be used to treat tumors producing PGE2
(e. g. Cox-2 overexpressing tumors) and/or adenosine (CD73 and CD39 over-expressing
tumors). Overexpression of Cox-2 has been detected in a number of tumors, such as
colorectal, breast, pancreatic and lung cancers, where it ates with a poor prognosis.
Overexpression of COX-2 has been reported in hematological cancer models such as RAJI
(Burkitt’s lymphoma) and U937 (acute promonocytic leukemia) as well as in patient’s blast
cells. CD73 is up—regulated in various human carcinomas including those of colon, lung,
pancreas and ovary. Importantly, higher expression levels of CD73 are associated with tumor
neovascularization, invasiveness, and metastasis and with shorter patient survival time in
breast cancer.
The terms "individua " or "patient," used interchangeably, refer to any animal,
ing mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle,
sheep, horses, or primates, and most preferably humans.
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The phrase "therapeutically ive amount" refers to the amount of active compound
or pharmaceutical agent that elicits the biological or medicinal se in a tissue, system,
animal, individual or human that is being sought by a researcher, veterinarian, medical doctor
or other clinician.
As used herein, the term "treating" or "treatment" refers to one or more of (l)
inhibiting the disease; 6. g. a disease, condition or er in an individual who is
, inhibiting
experiencing or displaying the pathology or symptomatology of the disease, condition or
disorder (2.6., arresting further development of the pathology and/or symptomatology); and
(2) ameliorating the disease, e.g., ameliorating a disease, condition or disorder in an
individual who is experiencing or displaying the ogy or symptomatology of the
disease, condition or disorder (116., reversing the pathology and/or symptomatology) such as
decreasing the severity of disease.
In some embodiments, the compounds of the invention are useful in preventing or
reducing the risk of developing any of the diseases referred to herein; erg, preventing or
reducing the risk of developing a disease, condition or disorder in an individual who may be
predisposed to the e, condition or disorder but does not yet experience or y the
pathology or symptomatology of the disease.
Combination Therapies
Cancer cell growth and survival can be impacted by multiple signaling pathways.
Thus, it is useful to combine different enzyme/protein/receptor inhibitors, exhibiting different
preferences in the targets which they te the activities of, to treat such conditions.
Examples of agents that may be combined with compounds of the present disclosure include
inhibitors of the PI3K-AKT-mTOR pathway, inhibitors of the Raf-MAPK y,
inhibitors of AT pathway, inhibitors of beta catenin pathway, inhibitors of notch
pathway, inhibitors of hedgehog pathway, inhibitors of Pim kinases, and inhibitors of protein
chaperones and cell cycle progression. ing more than one signaling pathway (or more
than one biological molecule involved in a given signaling pathway) may reduce the
hood of drug-resistance arising in a cell population, and/or reduce the toxicity of
treatment.
The compounds of the t sure can be used in combination with one or
more other enzyme/protein/receptor inhibitors for the ent of diseases, such as cancer.
Examples of cancers e solid tumors and liquid tumors, such as blood cancers. For
example, the compounds of the present disclosure can be combined with one or more
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inhibitors of the following kinases for the treatment of cancer: Aktl, Akt2, Akt3, TGF—BR,
PKA, PKG, PKC, CaM-kinase, phosphorylase kinase, MEKK, ERK, MAPK, mTOR, EGFR,
HER2, HER3, HER4, INS-R, IGF-lR, IR-R, PDGFOLR, PDGFBR, CSFIR, KIT, FLK-II,
KDR/FLK-l, FLK-4, flt-l, FGFRI, FGFRZ, FGFR3, FGFR4, c-Met, Ron, Sea, TRKA,
TRKB, TRKC, FLT3, VEGFR/Fltz, Flt4, EphAl, EphA2, EphA3, EphBZ, EphB4, Tie2, Src,
Fyn, Lck, Fgr, Btk, Fak, SYK, FRK, JAK, ABL, ALK and B-Raf. In some embodiments, the
compounds of the present disclosure can be combined with one or more of the following
inhibitors for the treatment of cancer. Non-limiting examples of inhibitors that can be
combined with the compounds of the present disclosure for treatment of cancers include an
FGFR tor (FGFR1, FGFR2, FGFR3 or FGFR4, e.g., AZD4547, BAY1187982,
ARQ087, , BIBF1120, , nib, dovitinib, TAS-120, JNJ-42756493,
Debi01347, INCB54828, INCB62079 and INCB63904), a JAK inhibitor (JAKl and/or
JAK2, e.g., ruxolitinib, baricz‘tz‘m‘b 0r INCB39110), an IDO inhibitor (e.g., epacadostat and
NLG919), an LSDI inhibitor (e.g., GSK2979552, INCB59872 and INCB60003), a TDO
inhibitor, a PI3K-delta tor (e. g., INCB50797 and INCB50465), a amma
inhibitor such as a PI3K-gamma ive inhibitor, a CSFlR inhibitor (e.g., PLX3397 and
LY3022855), a TAM receptor tyrosine kinases (Tyro-3, Axl, and Mer), an angiogenesis
inhibitor, an interleukin receptor tor, bromo and extra terminal family members
inhibitors (for example, bromodomain tors or BET inhibitors such as OTX015, CPI-
0610, 329 and INCB57643) and an adenosine receptor antagonist or combinations
thereof. Inhibitors of HDAC such as panobinostat and vorinostat. Inhibitors of c-Met such as
onartumzumab, tivantnib, and 0. Inhibitors of BTK such as nib. Inhibitors of
mTOR such as rapamycin, sirolimus, olimus, and everolimus. Inhibitors of Raf, such
as vemurafenib and dabrafenib. Inhibitors of MEK such as trametinib, selumetinib and GDC-
0973. Inhibitors of Hsp90 (e. g., tanespimycin), cyclin dependent kinases (e.g., palbociclib),
PARP (e.g., olaparib) and Pim kinases (LGH447, INCB053914 and SGI-1776) can also be
combined with compounds of the present disclosure.
Compounds of the present disclosure can be used in combination with one or more
immune checkpoint inhibitors. Exemplary immune oint inhibitors include inhibitors
against immune checkpoint molecules such as CD20, CD27, CD28, CD39, CD40, CD122,
CD96, CD73, CD47, 0X40, GITR, CSFIR, JAK, PI3K delta, PI3K gamma, TAM, arginase,
CD137 (also known as 4-1BB), ICOS, A2AR, B7-H3, B7-H4, BTLA, CTLA-4, LAG3,
TIM3, VISTA, PD-l, PD-Ll and PD-L2. In some embodiments, the immune checkpoint
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molecule is a stimulatory checkpoint molecule selected from CD27, CD28, CD40, ICOS,
0X40, GITR and CD137. In some embodiments, the immune checkpoint molecule is an
inhibitory checkpoint molecule selected from A2AR, B7-H3, B7-H4, BTLA, CTLA-4, IDO,
KIR, LAG3, PD-l, TIM3, and VISTA. In some embodiments, the compounds provided
herein can be used in combination with one or more agents selected from KIR inhibitors,
TIGIT inhibitors, LAIRI inhibitors, CD160 inhibitors, 2B4 inhibitors and TGFR beta
inhibitors.
In some embodiments, the inhibitor of an immune checkpoint molecule is anti-PDI
antibody, anti—PD-Ll antibody, or anti-CTLA-4 antibody.
In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor
of PD-I, e.g., an anti-PD-I monoclonal antibody. In some embodiments, the anti-PD-l
onal antibody is nivolumab, pembrolizumab (also known as MK-34?5), pidilizumab,
SHR—1210, PDROOI, or AMP-224. In some embodiments, the anti-PD-l monoclonal
antibody is nivolumab or pembrolizumab. In some embodiments, the anti-PDI antibody is
pembrolizumab. In some embodiments, the anti PD-l antibody is SHR-1210.
In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor
of PD-Ll, e.g., an anti-PD-LI monoclonal antibody. In some ments, the anti-PD-LI
monoclonal antibody is EMS-935559, MEDI4736, MPDL3280A (also known as RG7446),
or MSB0010718C. In some embodiments, the anti-PD-Ll monoclonal antibody is
MPDL3280A or MEDI4736.
In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor
of CTLA-4, e.g., an anti-CTLA-4 dy. In some embodiments, the anti-CTLA—4
antibody is ipilimumab.
In some embodiments, the inhibitor of an immune checkpoint le is an inhibitor
of CSFIR, e.g., an anti- CSFIR dy. In some embodiments, the anti- CSFIR antibody
is 4 or RG7155.
In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor
of LAG3, e.g., an anti-LAG3 antibody. In some embodiments, the AG3 dy is
EMS-986016, LAG525, IMP321 or GSK2831781.
In some embodiments, the inhibitor of an immune oint molecule is an tor
of GITR, e.g., an anti-GITR antibody. In some embodiments, the ITR dy is
TRX518, MK-4166, MK1248, EMS-986156, MED11873 or GWN323.
In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor
of 0X40, e.g., an anti-0X40 antibody or OX40L fusion n. In some embodiments, the
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anti-0X40 antibody is MEDIOS62, MEDI6469, 16, PF-04518600 or GSK3174998.
In some embodiments, the OX40L fusion protein is MEDI63 83.
In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor
of TIM3, e.g., an anti-TIM3 antibody. In some embodiments, the anti-TIM3 antibody is
MBG—453.
In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor
of CD20, e.g., an D20 antibody. In some embodiments, the anti-CD20 antibody is
obinutuzumab or rituximab.
In some embodiments, the compounds of the invention can be used in combination
with one or more metabolic enzyme inhibitors. In some embodiments, the metabolic enzyme
inhibitor is an inhibitor of IDOl, TDO, or arginase. Examples of IDOl inhibitors include
epacadostat and NGL919. An example of an arginase inhibitor is CB-1158.
The compounds of the present disclosure can be used in combination with bispecific
antibodies. In some embodiments, one of the domains of the ific antibody targets PD-
1, PD-Ll, CTLA-4, GITR, 0X40, TIM3, LAG3, CD137, ICOS, CD3 or TGFB receptor.
Compounds of the present disclosure can be used in combination with one or more
agents for the treatment of diseases such as cancer. In some embodiments, the agent is an
alkylating agent, a proteasome inhibitor, a corticosteroid, or an immunomodulatory agent.
Examples of an alkylating agent include bendamustine, nitrogen ds, ethylenimine
derivatives, alkyl sulfonates, oureas and nes, uracil mustard, chlormethine,
cyclophosphamide (CytoxanTM), ifosfamide, melphalan, chlorambucil, pipobroman,
ylene-melamine, triethylenethiophosphoramine, busulfan, carmustine, lomustine,
streptozocin, dacarbazine, and temozolomide. In some embodiments, the proteasome
tor is carfilzomib. In some embodiments, the corticosteroid is thasone (DEX).
In some embodiments, the immunomodulatory agent is lenalidomide (LEN) or
pomalidomide (POM).
The nds of the present disclosure can further be used in combination with
other methods of ng cancers, for example by chemotherapy, irradiation therapy, tumor-
targeted therapy, nt therapy, immunotherapy or surgery. Examples of immunotherapy
include cytokine treatment (e. g., interferons, GM-CSF, G—CSF, IL-2), CRS—207
immunotherapy, cancer vaccine, monoclonal antibody, adoptive T cell transfer, oncolytic
virotherapy and immunomodulating small molecules, including thalidomide or JAK1/2
inhibitor and the like. The compounds can be administered in combination with one or more
anti—cancer drugs, such as a chemotherapeutics. Example chemotherapeutics include any of:
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abarelix, abiraterone, afatinib, aflibercept, aldesleukin, alemtuzumab, alitretinoin,
allopurinol, altretamine, ozole, arsenic trioxide, asparaginase, axitinib, azacitidine,
zumab, bexarotene, baricitinib, bicalutamide, bleomycin, bortezombi, bortezomib,
brivanib, buparlisib, busulfan intravenous, an oral, calusterone, capecitabine,
carboplatin, tine, cediranib, cetuXimab, chlorambucil, cisplatin, cladribine,
clofarabine, crizotinib, cyclophosphamide, cytarabine, dacarbazine, dacomitinib,
dactinomycin, dalteparin sodium, dasatinib, omycin, daunorubicin, decitabine,
degarelix, ukin, denileukin diftitox, oformycin, dexrazoxane, docetaxel,
doxorubicin, droloxafme, dromostanolone propionate, eculizumab, tamide,
epidophyllotoxin, epirubicin, erlotinib, estramustine, etoposide phosphate, etoposide,
tane, fentanyl citrate, filgrastim, floxuridine, fludarabine, fluorouracil, flutamide,
fulvestrant, gefitinib, gemcitabine, gemtuzumab ozogamicin, goserelin acetate, lin
acetate, ibritumomab tiuxetan, idarubicin, idelalisib, ifosfamide, imatinib mesylate, interferon
alfa 2a, irinotecan, nib ditosylate, lenalidomide, letrozole, leucovorin, leuprolide
e, levamisole, lomustine, meclorethamine, megestrol acetate, melphalan,
mercaptopurine, methotrexate, salen, mithramycin, mitomycin C, mitotane,
mitoxantrone, nandrolone phenpropionate, navelbene, necitumumab, nelarabine, neratinib,
nilotinib, nilutamide, nofetumomab, in, oxaliplatin, paclitaxel, pamidronate,
panitumumab, pazopanib, pegaspargase, pegfilgrastim, pemetrexed disodium, pentostatin,
pilaralisib, pipobroman, plicamycin, ponatinib, prednisone, procarbazine, quinacrine,
rasburicase, regorafenib, reloxafme, rituXimab, ruxolitinib, sorafenib, streptozocin, sunitinib,
sunitinib e, tamoxifen, tegafur, temozolomide, teniposide, testolactone, thalidomide,
thioguanine, thiotepa, topotecan, toremifene, tositumomab, trastuzumab, tretinoin, triptorelin,
uracil mustard, valrubicin, anib, Vinblastine, Vincristine, Vinorelbine, vorinostat and
zoledronate.
Other anti-cancer s) include antibody therapeutics such as trastuzumab
(Herceptin), antibodies to costimulatory molecules such as CTLA-4 (e.g., ipilimumab or
tremelimumab), 4—lBB, antibodies to PD-l and PD-Ll, or antibodies to cytokines (IL-10,
TGF-B, etc). Examples of antibodies to PD-l and/or PD-Ll that can be combined with
compounds of the t disclosure for the treatment of cancer or infections such as viral,
bacteria, fungus and parasite infections include, but are not limited to, nivolumab,
pembrolizumab, MPDL3280A, MEDI-4736 and SHR-1210.
Other anti—cancer agents include inhibitors of kinases associated cell proliferative
disorder. These kinases include but not d to Aurora-A, CDKl, CDKZ, CDK3, CDKS,
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CDK7, CDK8, CDK9, ephrin receptor s, CHKI, CHK2, SRC, Yes, Fyn, Lck, Fer, Fes,
Syk, Itk, Bmx, GSK3, JNK, PAK1, PAK2, PAK3, PAK4, PDKI, PKA, PKC, Rsk and SGK.
Other anti-cancer agents also include those that block immune cell migration such as
antagonists to chemokine receptors, including CCR2 and CCR4.
The compounds of the present disclosure can further be used in combination with one
or more anti-inflammatory agents, steroids, immunosuppressants or therapeutic antibodies.
The compounds of Formula (I) or any of the formulas as described herein, a
compound as recited in any of the claims and described herein, or salts f can be
combined with another immunogenic agent, such as ous cells, purified tumor antigens
(including inant proteins, peptides, and carbohydrate molecules), cells, and cells
transfected with genes encoding immune ating cytokines. Non-limiting examples of
tumor vaccines that can be used include peptides of melanoma antigens, such as peptides of
gp100, MAGE antigens, Trp-2, MARTI and/or tyrosinase, or tumor cells transfected to
express the cytokine GM-CSF.
The nds of Formula (I) or any of the formulas as described herein, a
compound as recited in any of the claims and described herein, or salts thereof can be used in
combination with a ation protocol for the treatment of cancer. In some embodiments,
the tumor cells are transduced to express GM-CSF. In some embodiments, tumor vaccines
include the proteins from Viruses ated in human cancers such as Human Papilloma
s (HPV), Hepatitis s (HBV and HCV) and Kaposi's Herpes Sarcoma Virus
(KHSV). In some ments, the compounds of the present disclosure can be used in
combination with tumor ic antigen such as heat shock proteins isolated from tumor
tissue itself. In some embodiments, the nds of Formula (I) or any of the formulas as
described herein, a compound as recited in any of the claims and described herein, or salts
thereof can be ed with dendritic cells immunization to activate potent anti-tumor
responses.
The compounds of the present sure can be used in combination with bispeciflc
macrocyclic peptides that target Fe alpha or Fe gamma receptor-expressing effectors cells to
tumor cells. The compounds of the present disclosure can also be combined with
macrocyclic peptides that activate host immune responsiveness
The compounds of the present disclosure can be used in combination with bone
marrow transplant for the treatment of a variety of tumors of hematopoietic .
Suitable antiviral agents contemplated for use in combination with the compounds of
the present disclosure can comprise nucleoside and nucleotide reverse transcriptase inhibitors
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(NRTIs), non-nucleoside reverse riptase inhibitors (NNRTIs), protease inhibitors and
other antiviral drugs.
Example suitable NRTIs include zidovudine (AZT); didanosine (ddl); zalcitabine
(ddC); stavudine (d4T); lamivudine (3TC); ir (1592U89); adefovir dipivoxil
[bis(POM)—PMEA]; lobucavir (EMS-180194); BCH-10652; emitricitabine [(-)—FTC]; beta-L-
FD4 (also called beta-L-D4C and named beta-L-2', 3'—dicleoxyfluoro—cytidene); DAPD,
((-)-beta—D-2,6,-diamino-purine dioxolane); and lodenosine (FddA). l suitable
NNRTIs include nevirapine —587), delaviradine (BHAP, U-90152); efavirenz (DMP-
266); PNU-142721; AG-1549, MKC-442 (l -(ethoxy-methyl)(l -methylethyl)—6—
(phenylmethyl)—(2,4(lH,3H)-pyrimidinedione); and (+)-calanolide A (NSC-675451) and B.
l suitable protease inhibitors include saquinavir (Ro 31-8959), ritonavir (ABT-538),
indinavir (MK-639); vir 43); amprenavir (141W94), lasinavir 34475);
DMP-450; EMS-2322623; ABT-378, and AG—l 549. Other antiviral agents e
hydroxyurea, ribavirin, IL-2, IL-12, pentafuside and Yissum Project No.1 1607.
When more than one pharmaceutical agent is administered to a patient, they can be
administered simultaneously, separately, tially, or in ation (e.g., for more than
two agents).
Formulation, Dosage Forms andAdministration
When employed as pharmaceuticals, the compounds of the present disclosure can be
administered in the form of ceutical compositions. Thus the present disclosure
provides a composition comprising a compound of Formula (I) or any of the formulas as
described herein, a compound as recited in any of the claims and described herein, or a
pharmaceutically able salt thereof, or any of the embodiments thereof, and at least one
pharmaceutically acceptable carrier or excipient. These compositions can be prepared in a
manner well known in the pharmaceutical art, and can be administered by a variety of routes,
depending upon whether local or systemic treatment is ted and upon the area to be
treated Administration may be topical (including transdermal, epidermal, ophthalmic and to
mucous membranes including intranasal, vaginal and rectal delivery), pulmonary (e.g., by
inhalation or insufflation of s or aerosols, including by nebulizer; intratracheal or
intranasal), oral or parenteral. Parenteral administration includes intravenous, intraarterial,
subcutaneous, intraperitoneal intramuscular or injection or on; or ranial, e.g,
intrathecal or intraventricular, administration. Parenteral administration can be in the form of
a single bolus dose, or may be, e.g., by a continuous perfusion pump. Pharmaceutical
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compositions and formulations for topical stration may include transdermal s,
ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders.
Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like
may be necessary or desirable.
This invention also includes pharmaceutical compositions which n, as the
active ingredient, the compound of the present disclosure or a pharmaceutically acceptable
salt thereof, in ation with one or more pharmaceutically acceptable carriers or
ents. In some embodiments, the composition is suitable for topical administration. In
making the compositions of the invention, the active ingredient is typically mixed with an
excipient, diluted by an excipient or enclosed within such a carrier in the form of, e. g. , a
capsule, sachet, paper, or other container. When the excipient serves as a diluent, it can be a
solid, serni—solid, or liquid material, which acts as a e, carrier or medium for the active
ingredient. Thus, the compositions can be in the form of tablets, pills, s, lozenges,
sachets, cachets, elixirs, suspensions, ons, solutions, syrups, aerosols (as a solid or in a
liquid medium), nts containing, e.g., up to 10% by weight of the active compound,
soft and hard gelatin capsules, suppositories, sterile inj ectable solutions and sterile packaged
In preparing a formulation, the active nd can be milled to provide the
appropriate particle size prior to combining with the other ingredients. If the active
compound is substantially insoluble, it can be milled to a particle size of less than 200 mesh.
If the active compound is substantially water soluble, the particle size can be adjusted by
milling to provide a substantially uniform bution in the formulation, e.g., about 40
mesh.
The compounds of the invention may be milled using known milling procedures such
as wet milling to obtain a particle size appropriate for tablet formation and for other
formulation types. Finely divided (nanoparticulate) preparations of the nds of the
invention can be prepared by processes known in the art see, e.g.,
Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol,
mannitol, es, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium
te, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup and methyl
cellulose. The formulations can additionally include: lubricating agents such as talc,
ium stearate and mineral oil; wetting agents; emulsifying and suspending agents;
preserving agents such as methyl- and hydroxy-benzoates; sweetening agents; and
flavoring agents. The compositions of the invention can be formulated so as to provide quick,
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sustained or delayed release of the active ingredient after administration to the patient by
employing procedures known in the art.
In some embodiments, the pharmaceutical composition comprises silicified
microcrystalline cellulose (SMCC) and at least one nd described herein, or a
pharmaceutically acceptable salt thereof. In some embodiments, the silicified
microcrystalline cellulose comprises about 98% microcrystalline cellulose and about 2%
silicon e w/W.
In some embodiments, the composition is a sustained release composition comprising
at least one nd described herein, or a pharmaceutically acceptable salt thereof, and at
least one pharmaceutically able carrier or excipient. In some embodiments, the
composition ses at least one compound described herein, or a pharmaceutically
acceptable salt thereof, and at least one component selected from microcrystalline cellulose,
lactose monohydrate, hydroxypropyl methylcellulose and polyethylene oxide. In some
embodiments, the composition comprises at least one compound described herein, or a
pharmaceutically acceptable salt thereof, and rystalline cellulose, lactose monohydrate
and ypropyl methylcellulose. In some embodiments, the composition comprises at
least one compound described herein, or a pharmaceutically acceptable salt thereof, and
rystalline cellulose, lactose monohydrate and polyethylene oxide. In some
embodiments, the composition further ses magnesium stearate or silicon dioxide. In
some ments, the rystalline cellulose is Avicel PH102TM. In some embodiments,
the lactose monohydrate is Fast-flo 316““. In some embodiments, the hydroxypropyl
methylcellulose is hydroxypropyl methylcellulose 2208 K4M (6g, Methocel K4 M
PremierTM) and/or hydroxypropyl methylcellulose 2208 K100LV (e.g., Methocel K00LVTM).
In some embodiments, the polyethylene oxide is polyethylene oxide WSR 1105 (e.g, Polyox
WSR 1105““).
In some ments, a wet granulation process is used to produce the composition.
In some embodiments, a dry granulation process is used to produce the composition.
The compositions can be formulated in a unit dosage form, each dosage containing
from about 5 to about 1,000 mg (1 g), more usually about 100 mg to about 500 mg, of the
active ingredient. In some embodiments, each dosage contains about 10 mg of the active
ient. In some embodiments, each dosage contains about 50 mg of the active ingredient.
In some embodiments, each dosage contains about 25 mg of the active ingredient. The term
"unit dosage forms" refers to physically discrete units suitable as unitary s for human
subjects and other mammals, each unit ning a predetermined quantity of active material
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calculated to produce the desired therapeutic effect, in association with a suitable
pharmaceutical excipient.
The components used to formulate the pharmaceutical itions are of high
purity and are ntially free of potentially harmful contaminants (e.g., at least National
Food grade, generally at least analytical grade, and more typically at least pharmaceutical
grade). Particularly for human ption, the composition is preferably manufactured or
formulated under Good Manufacturing Practice standards as defined in the able
tions of the US. Food and Drug Administration. For example, suitable formulations
may be e and/or ntially ic and/or in full compliance with all Good
Manufacturing Practice regulations of the US. Food and Drug Administration.
The active compound may be effective over a wide dosage range and is generally
administered in a therapeutically effective amount. It will be understood, however, that the
amount ofthe compound actually administered will usually be determined by a physician,
according to the relevant circumstances, including the condition to be treated, the chosen
route of administration, the actual compound administered, the age, weight, and se of
the individual t, the severity of the patient‘s symptoms and the like.
The therapeutic dosage of a compound of the present invention can vary according to,
e. g, the particular use for which the treatment is made, the manner of administration of the
compound, the health and condition of the patient, and the judgment of the prescribing
ian. The proportion or concentration of a compound of the invention in a
pharmaceutical composition can vary depending upon a number of factors including ,
chemical characteristics (6. g. and the route of administration. For example,
, hydrophobicity),
the compounds of the invention can be provided in an aqueous physiological buffer solution
containing about 0.1 to about 10% w/v of the compound for eral stration. Some
typical dose ranges are from about 1 pig/kg to about 1 g/kg of body weight per day. In some
embodiments, the dose range is from about 0.01 mg/kg to about 100 mg/kg of body weight
per day. The dosage is likely to depend on such variables as the type and extent of
progression of the disease or disorder, the overall health status of the particular patient, the
relative biological efficacy of the compound ed, formulation of the excipient, and its
route of administration. Effective doses can be extrapolated from dose-response curves
derived from in vitro or animal model test systems.
For preparing solid compositions such as tablets, the principal active ingredient is
mixed with a pharmaceutical excipient to form a solid preformulation composition
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containing a homogeneous mixture of a compound of the present invention. When referring
to these preforrnulation compositions as homogeneous, the active ingredient is typically
dispersed evenly hout the composition so that the composition can be readily
subdivided into equally effective unit dosage forms such as tablets, pills and capsules. This
solid preformulation is then subdivided into unit dosage forms of the type described above
containing from, e.g., about 0.1 to about 1000 mg of the active ingredient of the present
invention.
The tablets or pills of the present invention can be coated or ise compounded
to provide a dosage form affording the advantage of prolonged action. For example, the
tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in
the form of an envelope over the . The two components can be separated by an enteric
layer which serves to resist disintegration in the stomach and permit the inner component to
pass intact into the duodenum or to be delayed in release. A variety of materials can be used
for such c layers or coatings, such materials including a number of polymeric acids and
mixtures of ric acids with such materials as shellac, cetyl alcohol and cellulose
acetate.
The liquid forms in which the compounds and compositions of the present invention
can be incorporated for administration orally or by injection include aqueous solutions,
suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils
such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as s and similar
pharmaceutical vehicles.
Compositions for inhalation or insufflation include solutions and suspensions in
pharmaceutically acceptable, aqueous or organic solvents, or mixtures f, and powders.
The liquid or solid compositions may contain suitable pharmaceutically acceptable ents
as described supra. In some ments, the itions are administered by the oral or
nasal respiratory route for local or systemic . Compositions can be nebulized by use of
inert gases. Nebulized solutions may be ed ly from the nebulizing device or the
nebulizing device can be attached to a face mask, tent, or intermittent positive pressure
breathing machine. Solution, suspension, or powder itions can be administered orally
or nasally from devices which deliver the formulation in an appropriate manner.
Topical formulations can contain one or more conventional carriers. In some
embodiments, ointments can contain water and one or more hobic carriers selected
from, e.g., liquid paraffin, polyoxyethylene alkyl ether, propylene glycol, white Vaseline, and
the like. Carrier itions of creams can be based on water in combination with glycerol
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and one or more other components, 6. g, inemonostearate, PEG-glycerinemonostearate
and cetylstearyl l. Gels can be formulated using isopropyl alcohol and water, suitably
in combination with other ents such as, e. g., ol, hydroxyethyl cellulose, and the
like. In some ments, topical formulations contain at least about 0.1, at least about
0.25, at least about 0.5, at least about 1, at least about 2 or at least about 5 wt % of the
compound of the invention. The topical formulations can be suitably packaged in tubes of,
e. g., 100 g which are optionally associated with instructions for the treatment of the select
indication, e.g., psoriasis or other skin condition.
The amount of compound or composition administered to a patient will vary
depending upon what is being administered, the purpose of the administration, such as
prophylaxis or therapy, the state of the patient, the manner of administration and the like. In
therapeutic ations, compositions can be stered to a patient already suffering
from a disease in an amount sufficient to cure or at least partially arrest the ms of the
e and its complications. Effective doses will depend on the disease condition being
treated as well as by the judgment of the attending clinician depending upon factors such as
the severity of the disease, the age, weight and general ion of the patient and the like.
The compositions administered to a patient can be in the form of pharmaceutical
compositions described above. These compositions can be sterilized by tional
sterilization techniques, or may be sterile filtered. s solutions can be packaged for use
as is, or lyophilized, the lyophilized preparation being combined with a sterile aqueous
carrier prior to administration. The pH of the nd preparations typically will be
between 3 and 11, more preferably from 5 to 9 and most preferably from 7 to 8. It will be
understood that use of certain of the foregoing excipients, carriers or stabilizers will result in
the formation of pharmaceutical salts.
The therapeutic dosage of a compound of the present invention can vary according to,
e. g, the particular use for which the treatment is made, the manner of administration of the
compound, the health and condition of the patient, and the judgment of the prescribing
physician. The proportion or concentration of a compound of the invention in a
pharmaceutical composition can vary depending upon a number of factors including dosage,
chemical characteristics (6. g. and the route of administration. For e,
, hydrophobicity),
the compounds of the invention can be provided in an aqueous logical buffer solution
containing about 0.1 to about 10% w/v of the compound for parenteral administration. Some
typical dose ranges are from about 1 rig/kg to about 1 g/kg of body weight per day. In some
embodiments, the dose range is from about 0.01 mg/kg to about 100 mg/kg of body weight
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per day. The dosage is likely to depend on such variables as the type and extent of
progression of the disease or disorder, the overall health status of the particular patient, the
relative biological efficacy of the compound selected, formulation of the excipient, and its
route of stration. Effective doses can be extrapolated from dose-response curves
d from in vitro or animal model test s.
Labeled Compounds andAssay Methods
The compounds of the present disclosure can further be useful in investigations of
biological processes in normal and abnormal tissues. Thus, r aspect of the present
invention relates to fluorescent dye, spin label, heavy metal or radio-labeled compounds
provided herein that would be useful not only in imaging techniques but also in assays, both
in vitro and in viva, for localizing and quantitating HPKl protein in tissue samples, including
human, and for identifying HPKl s by inhibition binding of a labeled compound.
Accordingly, the present invention es HPKl binding assays that contain such labeled
compounds.
The present invention further includes isotopically-substituted nds of the
disclosure. An "isotopically-substituted" compound is a compound of the invention where
one or more atoms are replaced or substituted by an atom having the same atomic number but
a different atomic mass or mass . nds of the invention may contain isotopes
in a natural abundance as found in nature. Compounds of the invention may also have
isotopes in amounts r to that found in nature, e. g, synthetically incorporating low
natural abundance isotopes into the compounds of the invention so they are enriched in a
particularly useful isotope (e. g, 2H and 13C). It is to be tood that a "radio—labeled"
compound is a compound that has incorporated at least one isotope that is ctive (e. g,
uclide), e. g., 3H and 14C. Suitable radionuclides that may be incorporated in
compounds of the present invention include but are not limited to 3H (also written as T for
tritlum), 11C, 13C, 14C, 13Na UN, 1503 170, 180, 18F, 358, 36C1, SZBI', 75131.) 76131.) 77Br, 1231, 1241:
125I and 131I. The radionuclide that is incorporated in the t radio-labeled compounds will
depend on the specific application of that radio-labeled compound. In some embodiments the
radionuclide is selected from the group consisting of 3H, 14C, 125I, 358 and ”Br. For in vitro
HPKl labeling and competition assays, compounds that incorporate 3H, 14C, 82Br, 125I, 131I, or
358 will generally be most useful. For radio-imaging applications “C, 18F, 125I, 123I, 124I, 1311,
75Br, 76Br or 77Br will generally be most useful. Synthetic methods for incorporating radio-
isotopes into organic compounds are known in the art.
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Specifically, a labeled compound of the invention can be used in a screening assay to
identify and/or evaluate compounds. For example, a newly synthesized or identified
nd (21a, test compound) which is labeled can be ted for its ability to bind a
HPKl protein by monitoring its concentration variation when contacting with the HPKl,
through tracking of the ng. For example, a test compound (labeled) can be evaluated for
its ability to reduce binding of another nd which is known to bind to a HPKl protein
(116., standard compound). Accordingly, the ability of a test compound to compete with the
standard compound for binding to the HPKl protein directly correlates to its binding affinity.
Conversely, in some other screening assays, the standard compound is labeled and test
compounds are unlabeled. Accordingly, the concentration of the labeled standard compound
is monitored in order to te the competition between the standard compound and the test
compound, and the relative binding affinity of the test compound is thus ascertained.
The present disclosure also includes pharmaceutical kits useful, e.g., in the treatment
or prevention of diseases or disorders associated with the activity of HPKl, such as cancer or
infections, which include one or more ners ning a pharmaceutical composition
sing a therapeutically effective amount of a compound of Formula (I), or any of the
embodiments thereof. Such kits can further include one or more of various conventional
pharmaceutical kit ents, such as, e. g., containers with one or more pharmaceutically
able carriers, onal containers, etc, as will be readily apparent to those skilled in
the art. Instructions, either as inserts or as , indicating quantities of the components to
be administered, guidelines for administration, and/or guidelines for mixing the ents,
can also be included in the kit.
The invention will be described in greater detail by way of specific examples. The
following es are offered for illustrative purposes, and are not intended to limit the
invention in any manner. Those of skill in the art will readily ize a variety of non-
critical parameters which can be changed or modified to yield essentially the same results.
The compounds of the Examples have been found to inhibit the activity of HPKl according
to at least one assay described herein.
EXAMPLES
Experimental procedures for compounds of the invention are provided below.
Preparatory LC-MS purifications of some of the compounds prepared were performed on
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Waters mass directed fractionation systems. The basic equipment setup, protocols, and
control software for the operation of these s have been described in detail in the
literature. See e.g. “Two-Pump At Column Dilution ration for Preparative LC-MS”,
K. Blom, J. Combi. Chem, 4, 295 (2002); “Optimizing Preparative LC-MS Configurations
and Methods for Parallel Synthesis Purification”, K. Blom, R. Sparks, J. Doughty, G. Everlof,
T. Haque, A. Combs, .1 Combi. Chem, 5, 670 (2003), and rative LC-MS Purification:
Improved Compound Specific Method Optimization", K. Blom, B. Glass, R. Sparks, A.
Combs, J. Combi. Chem, 6, 874-883 (2004). The ted compounds were typically
subjected to ical liquid chromatography mass spectrometry (LCMS) for purity check
under the following conditions: Instrument, Agilent 1100 series, LC/MSD, Column: Waters
SunfireTM C18 5 mm particle size, 2.1 X 5.0 mm, Buffers: mobile phase A: 0.025% TFA in
water and mobile phase B: acetonitrile, gradient 2% to 80% of B in 3 minutes with flow rate
2.0 mL/minute.
Some of the compounds prepared were also separated on a preparative scale by
reverse-phase high performance liquid chromatography (RP-HPLC) with MS detector or
flash chromatography (silica gel) as indicated in the Examples Typical preparative e—
phase high performance liquid chromatography (RP-HPLC) column conditions are as
follows:
pH = 2 purifications: Waters SunfireTM C13 5 pm particle size, 19 x 100 mm column,
eluting with mobile phase A: 0.1% TFA (trifluoroacetic acid) in water and mobile phase B:
itrile; the flow rate was 30 mL/minute, the separating gradient was optimized for each
compound using the Compound Specific Method Optimization protocol as described in the
literature (see "Preparative LCMS Purification: Improved Compound c Method
Optimization", K. Blom, B. Glass, R. Sparks, A. Combs, J. Comb. Chem, 6, 3
(2004)). Typically, the flow rate used with the 30 X 100 mm column was 60 mL/minute.
pH = 10 ations: Waters XBridge C18 5 mm particle size, 19 X 100 mm ,
eluting with mobile phase A: 0.15% NH4OH in water and mobile phase B: acetonitrile; the
flow rate was 30 mL/minute, the separating gradient was optimized for each compound using
the Compound Specific Method Optimization protocol as described in the literature (See
"Preparative LCMS Purification: ed Compound Specific Method Optimization", K.
Blom, B. Glass, R. , A. Combs, J. Comb. Chem, 6, 874-883 (2004)). Typically, the
flow rate used with 30 x 100 mm column was 60 mL/rninute.
Degassed water refers to water where the ved oxygen has been displaced by
nitrogen through a procedure of bubbling nitrogen through the water for 15 minutes.
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Example 1. N—(S—(Z-Fluoro—6-methoxyphenyl)—1H-pyrazolo[3,4-c] pyridin
yl)benzamide
“Cy/Q|‘/
Step 1. 2-Br0m0flu0r0is0m'cotinom'z‘rl'le
Br ON
Hydroxylamine hydrochloride (2.73 g, 39.2 mmol) was added to a solution of 2-
bromofluoroisonicotinaldehyde (Combi-Blocks, 2.0 g, 9.80 mmol) in 2-propanol (19.61
mL). The reaction mixture was refluxed for 2h, and then the solvent was removed in vacuo.
The residue was redissolved in EtOAc. The c phase was washed with the saturated
NaHCO3 solution and brine, and was dried over sodium sulfate. The solvent was evaporated
in vacuo to give the oxime.
Cyanuric de (2.41 g, 13.04 mmol) was slowly add to DMF (1961 mL) at 0 °C.
After it was completely dissolved, obtained oxime was slowly added at 0 °C to this solution,
and the reaction was stirred at r.t. for 1h. Then the reaction was ed with water. The
product was extracted with ethyl acetate and the organic phase was washed with brine. The
organic phase was dried over sodium sulfate and the solvents were evaporated under reduced
pressure. Obtained crude product was used in the next step without r pufication (1 g,
51%).
Step 2. 5-Br0m0-1H-pyrazolo[3, 4-c]pyridinamine
I \
Water solution of hydrazine (0.6 mL, 10 mmol) was added to a on of o-
5-fluoroisonicotinonitrile (1.0 g, 4.98 mmol) in ethanol (15 mL). After stirring at reflux for
2h, the solvent was evaporated and the obtained crude product was used in the next step
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t further purification. LCMS calculated for CaHsBrN4 (M+H) + m/z = 2130; found
213. 1.
Step 3. utyl 3-amin0br0m0-1H-pyrazolo[3, 4—c]pyrz‘dz‘necarb0xyZate
[\1 \
/ NH2
B0 c/
t—butyl dicarbonate (1.127 g, 5.16 mmol) was added to a solution of 5-bromo-
azolo[3,4-c]pyridinamine (1.0 g, 4.69 mmol) and triethylamine (0.785 mL, 5.63
mmol) in CH2C12 (15 mL). After stirring at r.t. for 1h., water was added, and the mixture was
extracted with DCM. The organic phase was washed with brine and dried over sodium
sulfate. The solvent was evaporated under reduced pressure and obtained crude product was
ed by Biotage IsoleraTM (1.4 g, 87%). LCMS calculated for C11H14BrN402 (M+H) + m/z
= 313.0; found 313.0.
Step 4. tert—Butyl 3-amz'n0-5—(2-fluor0-6—meth0xyphenyl)-1H-pyra2010[3, 4-cjpyrz'dz'ne
carboxylaz‘e
F OMe
[\1 \
/ NHZ
tert—Butyl 3-aminobromo-1H-pyrazolo[3,4-c]pyridinecarboxy1ate (1.0 g, 3.19
mmol), (2-fluoromethoxyphenyl)boronic acid (0.814 g, 4.79 mmol), chloro(2-
dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-
biphenyl)]palladium(II) (Pd XPhos G2) (0.251 g, 0.319 mmol) and potassium phosphate
(1.356 g, 6.39 mmol) were placed in a flask, and the flask was evacuated and backfilled with
nitrogen three times. Then dioxane (20 mL) and degassed water (2 mL) were added, and
reaction was stirred at 90°C for 2h. After cooling to r.t., the on mixture was diluted with
ethyl acetate, and the resulting mixture was washed with brine. The separated organic phase
was dried over sodium sulfate. The solvents were evaporated under reduced pressure and
obtained crude product was purified by Biotage IsoleraTM (1.05 g, 92%). LCMS calculated
for C18H20FN403 (M+H) + m/z = 3592; found 359.2.
Step 5. N—(5-(2-Flu0r0meth0xyphenyU-1H-pyrazolo[3, 4-c]pyridin-S-ybbenzamz’de
Benzoyl chloride (6.47 mg, 0.046 mmol) was added to a solution of tert—butyl 3-
amino(2-fluoromethoxyphenyl)—1H-pyrazolo[3,4-c] pyridine-l -carboxylate (15 mg,
0.042 mmol) and DIPEA (10.97 ul, 0.063 mmol) in THF (1 mL). After stirring at 60 °C for
2h, reaction was quenched with methanol and solvents were evaporated in vacuo. DCM (1
mL) and trifluoroacetic acid (1 mL) were added to the obtained residue and the reaction was
stirred at r.t. for 1h. The reaction e was then d with acetonitrile and was purified
with prep-LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water
containing 0.1% TFA, at flow rate of 60 mL/min). LCMS calculated for C20H16FN402
(M+H)+: m/z = 3631; Found: 363.2.
e 2. N-(S-(Z-Fluoromethoxyphenyl)—1H-pyrazolo[3,4-c] pyridinyl)
methylbenzamide
This compound was prepared according to the procedures described in Example 1,
using 4-methylbenzoyl chloride instead of benzoyl chloride as starting material. LCMS
calculated for C21H18FN402 (M+H)+: m/z = 377.1, Found: 377.2.
Example 3. 4-Bromo-N—(5-(2-flu0r0meth0xyphenyl)—1H-pyrazolo[3,4—c]pyridin-3—
yl)benzamide
'/ OYQ/Br
This compound was ed according to the ures bed in Example 1,
using 4—bromobenzoyl chloride instead of benzoyl chloride as ng material. LCMS
calculated for C20H15BrFN402 (M+H)+: m/z = 441.0; Found: 441.1.
Example 4. 3-Bromo-N-(5-(2-fluoro—6-methoxyphenyl)-lH-pyrazolo[3,4-c]pyridin
yl)benzamide
F 0/ Br
N \ OVQ
HN‘N
This nd was prepared according to the procedures described in Example 1,
using 3-bromobenzoyl chloride instead of benzoyl chloride as starting material. LCMS
calculated for BrFN402 (M+H)+: m/z = 441.0; Found: 441.1.
Example 5. 4-Fluoro-N—(5-(2-flu0r0methoxyphenyl)—lH-pyrazolo[3,4-c]pyridin
yl)benzamide
|// OYQ/F
This compound was prepared according to the procedures described in Example 1,
using 4-fluorobenzoyl chloride instead of benzoyl chloride as starting material. LCMS
calculated for C20H15F2N402 (M+H)+: m/z = 381.1; Found: 381.2.
Example 6. 3-Fluoro-N—(5-(2-flu0r0methoxyphenyl)—1H-pyraz010[3,4—c]pyridin-S-
zamide
F 0/ F
N \ Q
This compound was prepared according to the procedures bed in Example 1,
using 3—fluorobenzoyl chloride d of benzoyl chloride as starting material. LCMS
calculated for C20H15F2N402 (M+H)+: m/z = 381.1; Found: 381.2.
Example 7. 3-Cyano-N-(S-(Z-fluoromethoxyphenyl)-1H-pyrazolo[3,4-c]pyridin
yl)benzamide
HN‘N
This compound was prepared according to the procedures described in e 1,
using 3-cyanobenzoy1 chloride instead of benzoyl de as starting material. LCMS
calculated for C21H15FN502 (M+H)+: m/z = 388.1; Found: 388.2.
Example 8. 4-Ethyl-N-(5-(2-fluoromethoxyphenyl)—1H-pyrazolo[3,4—c]pyridin-3—
yl)benzamide
This compound was ed according to the procedures described in Example 1,
using 4-ethylbenzoy1 chloride instead of benzoyl chloride as starting material. LCMS
calculated for C22H20FN402 (M+H)+: m/z = 391.2; Found: 391.3.
Example 9. N—(5-(2-Fluor0methoxyphenyl)—1H-pyrazolo[3,4-c] pyridin-3—yl)
methoxybenzamide
F 0/ 0"
N \ Q
This compound was ed according to the procedures described in Example 1,
using 3—methoxybenzoy1 chloride instead of benzoyl chloride as starting material. LCMS
calculated for C21H13FN4O3 (M+H)+: m/z = 393.1; Found: 393.2.
Example 10. ro-N-(S-(2-quoro—6-meth0xyphenyl)—lH-pyrazolo[3,4-c]pyridin
yl)methylbenzamide
F o/
This compound was ed according to the procedures described in Example 1,
using 4-fluoro—3-methy1benzoy1 chloride d of benzoyl chloride as starting material.
LCMS calculated for C21H17F2N402 (M+H)+: m/z = 395.1; Found: 395.2.
Example 11. fluoro-N—(S-(Z-fluoro-G-methoxyphenyl)—1H-pyrazolo[3,4-c] pyridin-
3-yl)benzamide
F 0/, F
N\ WQ
// NH F
This compound was prepared according to the procedures described in Example 1,
using 3,5-difluorobenzoy1 chloride instead of benzoyl chloride as starting al. LCMS
calculated for C20H14F3N402 (M+H)+: m/z = 3991; Found: 399.2.
Example 12. 3,4-Difluoro-N—(S-(Z-fluoro-G-methoxyphenyl)—1H-pyrazolo[3,4—c] pyridin-
3-yl)benzamide
F o
N \\
// c§k/<::§r,F
This compound was ed according to the procedures described in Example 1,
using 3,4-difluorobenzoy1 chloride instead of benzoyl chloride as starting material. LCMS
calculated for C20H14F3N402 (M+H)+: m/z = 3991; Found: 3992.
e 13. N—(S-(Z-Fluoro—6—methoxyphenyl)—1H-pyrazolo[3,4-c] pyridin
yl)benzo[d] [l,3]dioxolecarboxamide
F o ‘1
This compound was prepared according to the procedures described in Example 1;
using benzo[d][1,3]dioxolecarbonyl de instead of benzoyl chloride as starting
material. LCMS calculated for C21H16FN404 (M+H)+: m/z = 407.1; Found: 407.2.
Example 14. N-(S-(Z-Fluor0methoxyphenyl)—1H-pyrazolo[3,4-c] pyridinyl)—1-
methyl-lH-pyrazolecarboxamide
F O
N\ O /N
l/ /N
This nd was prepared according to the procedures described in Example 1;
using 1-methyl-1H—pyrazolecarbonyl chloride instead of benzoyl chloride as starting
material. LCMS calculated for C18H16FN602 (M+H)+: m/z = 367.1; Found: 367.2.
e 15. N—(5-(2-Fluor0methoxyphenyl)—1H-pyrazolo[3,4-c] pyridin-S-yl)—1-
-1H-pyrazole—3-carboxamide
N \ /
This compound was prepared according to the procedures described in Example 1,
using 1-methyl-1H-pyrazolecarbony1 chloride instead of benzoyl chloride as starting
material. LCMS calculated for C18H16FN602 (M+H)+: m/z = 367.1; Found: 367.2.
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Example 16. N—(S-(Z-Fluoro—6—methoxyphenyl)—1H-pyrazolo[3,4-c] pyridinyl)
morpholinobenzamide
F o/ N
/ C’s/Q
Step 1. tert—Butyl 3-(3-br0m0benzamIda)-5—(2-fluor0methoxyphenyl)-1H-pyrazol0[3,4-
cjpyridme-I-carboxylaz‘e
3-Bromobenzoy1 chloride (206 mg, 0.939 mmol) was added to a on of tert-butyl
3-amino(2-fluoromethoxypheny1)-1H-pyrazolo[3,4-c]py1idinecarboxylate (Example
1, Step 4, 306 mg, 0.854 mmol) and DIPEA (224 uL, 1.281 mmol) in THF (6 mL). The
reaction mixture was stirred at 60 °C for 2h. Then methanol (1 mL) was added, and the
ts were evaporated in vacuo. Obtained crude product was purified by Biotage IsoleraTM
(360 mg, 87%). LCMS calculated for C25H23BrFN4O4 (M+H)+: m/z = 541.]; Found: 541.2.
Step 2. N-(5—(2—Flu0r0mez‘h0xyphenyl)-1H—pyra2010[3,4-c]pyrl'dmyl)
morpholinobenzamide
tert—Butyl 3-(3-bromobenzamido)(2-fluoromethoxypheny1)-1H—pyrazolo[3,4-
c]pyridine—1-carboxy1ate (15 mg, 0.028 mmol), morpholine (3.62 mg, 0.042 mmol), cesium
carbonate (18.1 mg, 0.055 mmol) and (2-dicyclohexylphosphino-2',6'-di-i-propoxy-
iphenyl)(2'-amino-1,1'-bipheny1y1)pa11adium(II) (RuPhos Pd G2, 2.2 mg, 2.77 umol)
were placed in a vial, and the vial was evacuated and backfilled with nitrgoen three times.
Then dioxane (2 mL) was added, and the reaction mixture was d at 100 °C for 2h. The
mixture was cooled to r.t. and solids were filtered off. The filtrate concentrated in vacuo.
DCM (1 mL) and trifluoroacetic acid (1 mL) were added to the obtained residue, and
the reaction was stirred at It, for 1h. The reaction mixture was then diluted with acetonitrile
and was purified with prep—LCMS (XBridge C18 column, eluting with a gradient of
acetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/rnin). LCMS calculated for
C24H23FN503 (M+H)+: m/z = 4482; Found: 448.3.
e 17. N—(S-(Z-Fluor0methoxyphenyl)—1H-pyrazolo[3,4-c] pyridin-3—yl)—3-(3-
oxopiperazin-l-yl)benzamide
/ N
F M‘s/Q'/ o
This compound was prepared according to the procedures described in e 16,
using piperazin-2—one instead of morpholine as starting al. LCMS calculated for
C24H22FN603 (M+H)+: m/z = 4612, Found: 461.2.
Example 18. N—(S-(Z-Fluoro—6—methoxyphenyl)—1H-pyrazolo[3,4-c] pyridinyl)-3—(4-
piperazinyl)benzamide
/ N)
F O
N \ O@
This compound was prepared according to the ures described in Example 16,
using 1-methylpiperazine instead of morpholine as starting material. LCMS calculated for
C25H26FN602 (M+H)+: m/z = 461.2, Found: 461.2.
Example 19. N-(S-(Z-Fluoromethoxyphenyl)—1H-pyrazolo[3,4-c] pyridinyl)(4-
methyloxopiperazinyl)benzamide
This compound was prepared according to the procedures described in e 16,
using l-methylpiperazin-Z-one instead of morpholine as ng material. LCMS calculated
for C25H24FN603 (M+H)+: m/z = 4752; Found: 475.3.
Example 20. 3-(4-Ethylpiperazinyl)-N-(5-(2-fluoromethoxyphenyl)—1H-
pyrazolo[3,4-c]pyridinyl)benzamide
F O
N ‘ Q
This compound was prepared according to the procedures described in Example 16,
using l-ethylpiperazine d of morpholine as starting material. LCMS calculated for
C26H28FN602 (M+H)+: m/z = 475.2; Found: 475.2.
Example 21. N—(S-(Z-Fluor0methoxyphenyl)—1H-pyrazolo[3,4-c] pyridin-3—yl)—3—(3-
oxo-4—(2,2,2-trifluoroethyl)piperazinyl)benzamide
/ N
F o
N\ on
HN\N
This nd was prepared according to the procedures described in Example 16,
using 1-(2,2,2-trifluoroethyl)piperazinone d of morpholine as starting material.
LCMS calculated for C26H23F4N603 (M+H)+: m/z = 543.2; Found: 543.3.
Example 22. N—(S-(Z-Fluoro—6-methoxyphenyl)—1H-pyrazolo[3,4-c] pyridinyl)-3—(4-
(methylsulfonyl)piperazinyl)benzamide
o\\,,/
/ N
F o
“1 \ OVQ
This compound was prepared according to the procedures described in Example 16,
using l-(methylsulfonyl)piperazine instead of morpholine as ng al. LCMS
calculated for C25H26FN604S (M+H)+: m/z = 525.2; Found: 525.1.
Example 23. N—(S-(2-fluoromethoxyphenyl)—1H-pyrazolo[3,4-c]pyridinyl)
(piperazin-l-yl)benzamide
/ N)
F o
This compound was prepared according to the procedures described in Example 16,
using tert—butyl piperazine-l-carboxylate instead of morpholine as starting material. LCMS
calculated for C24H24FN602 (M+H)+: m/z = 447.2; Found: 447.2.
e 24. N—(S-(2-Fluoromethoxyphenyl)—1H-pyrazolo[3,4-c] pyridinyl)—4-
morpholinobenzamide
F o //\O
N \ OYQKNQ
// NH
Step 1. tert—Buzyz’ 3-(4-br0m0benzamz‘d0)-5—(2flu0r0-6—mez‘h0xyphenyl)—1H—pyrazolo[3,4-
cjpyrl'dme-I -carb0xylate
This compound was prepared according to the procedures described in e 16,
Step 1, using 4—bromobenzoyl chloride instead of obenzoyl chloride as starting
material. LCMS ated for C25H23BrFN4O4 (M+H)+: m/z = 541.1, Found: 5412.
Step 2. N-(5—(2-Flu0r0mez‘h0xyphenyl)-1H—pyra2010[3,4-c]pyrl'dmyl)
morpholinobenzamide
tert—Butyl 3-(4-bromobenzamido)(2-fluoromethoxyphenyl)-1H—pyrazolo[3,4-
c]pyridinecarboxylate (15 mg, 0.028 mmol), morpholine (3.62 mg, 0.042 mmol), cesium
carbonate (18.1 mg, 0.055 mmol) and chloro(2-dicyclohexylphosphino-2',6'-di-i—propoxy—
iphenyl)(2'-amino-1,1'-biphenyly1)palladium(II) (RuPhos Pd G2, 2.2 mg, 2.77 umol)
were placed in a Vial, and the Vial was evacuated and backfilled with nitrgoen three times.
Then dioxane (2 mL) was added, and the reaction mixture was stirred at 100 °C for 2h. The
e was cooled to It. and the solids were filtered off. The filtrate was concentrated in
vacuo.
DCM (1 mL) and trifluoroacetic acid (1 mL) were added to the obtained residue, and
the on was stirred at r.t. for 1h. The reaction mixture was then diluted with acetonitrile
and was purified with prep-LCMS (XBridge C18 column, eluting with a gradient of
acetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min). LCMS calculated for
C24H23FN503 (M+H)+: m/z = 4482, Found: 448.2.
Example 25. N-(S-(Z-Fluor0methoxyphenyl)—1H-pyrazolo[3,4-c] pyridinyl)-4—(3-
oxopiperazinyl)benzamide
This compound was prepared according to the procedures described in Example 24,
using piperazinone instead of morpholine as starting material. LCMS calculated for
C24H22FN603 (M+H)+: m/z = 4612; Found: 461.3.
Example 26. N—(S-(Z-Fluor0methoxyphenyl)—1H-pyrazolo[3,4-c] pyridin-3—yl)(4-
methylpiperazinyl)benzamide
F o //\N/
N \ on/Ng
This compound was prepared according to the ures described in e 24,
using l-methylpiperazine instead of morpholine as starting material. LCMS calculated for
C25H26FN602 (M+H)+: m/z = 4612, Found: 461.3.
Example 27. N-(S-(2-quoromethoxyphenyl)—lH-pyrazolo[3,4-c] pyridinyl)(4-
methyl-3—oxopiperazinyl)benzamide
F 0 AN/
N \ OYQ/Nq
This compound was prepared ing to the procedures described in Example 24,
using ylpiperazinone instead of morpholine as starting material. LCMS calculated
for C25H24FN603 : m/z = 4752, Found: 475.3.
Example 28. 4-(4-Ethylpiperazinyl)-N-(5-(2-fluorometh0xyphenyl)—1H-
pyrazolo[3,4-c]pyridin-S-yl)benzamide
F 0 //\NJ
N \ O NV
This compound was prepared according to the procedures bed in Example 24,
using l-ethylpiperazine instead of morpholine as starting material. LCMS calculated for
C26H28FN602 (M+H)+: m/z = 4752; Found: 475.3.
Example 29. N—(S—(Z-Fluoromethoxyphenyl)—1H-pyraz010[3,4-c] n-3—yl)(3-
0x0-4—(2,2,2—triflu0roethyl)piperazinyl)benzamide
F 0/ A}0F F
N\ O Nd
This nd was prepared according to the procedures described in Example 24,
using 1-(2,2,2-trifluoroethy1)piperazinone instead of morpholine as starting material.
LCMS calculated for C26H23F4N603 (M+H)+: m/z = 543.2, Found: 543.2.
Example 30. N—(S-(2-Fluoro—6-methoxyphenyl)-1H-pyrazolo[3,4-c]pyridinyl)(4-
isop ropylpiperazin-l-yl)benzamide
F O //\N
N \ OYQ/NQ
This compound was prepared according to the procedures described in Example 24,
using 1-isopropylpiperazine instead of morpholine as starting material. LCMS ated for
C27H30FN602 (M+H)+: m/z = 489.2, Found: 489.3.
e 31. 4-(4-Cyclopropyl—3-ox0piperazinyl)-N-(5-(2-fluoromethoxyphenyl)—
1H-pyrazolo[3,4-c] pyridinyl)benzamide
“I: VG”
HN‘N
This compound was prepared ing to the ures described in Example 24,
using 1-cyclopropylpiperazin-Z-one instead of morpholine as starting material. LCMS
calculated for C27H26FN603 (M+H)+: m/z = 5012; Found: 501.3.
Example 32. N-(S-(2-Fluoro—6-methoxyphenyl)—1H-pyrazolo[3,4-c] pyridinyl)—4—(4-
(methylsulfonyl)piperazinyl)benzamide
F o/
l/\ 630
N \ Ofl/NW
This compound was prepared according to the procedures described in Example 24,
using 1-(methylsulfonyl)piperazine instead of morpholine as starting material. LCMS
calculated for C25H26FN604S (M+H)+: m/z = 5252; Found: 525.2.
Example 33. N-(S-(Z-Fluoromethoxyphenyl)—1H-pyrazolo[3,4-c] nyl)
(piperazin-l-yl)benzamide
F 0 /”\NH
N \\
// Q>/A<::7/N\/J
This compound was prepared according to the procedures described in e 24,
using tert-butyl piperazine-l-carboxylate instead of line as starting material. LCMS
calculated for C24H24FN602 (M+H)+: m/z = 4472; Found: 447.1.
e 34. 4-(5-(5-(2-Flu0r0methoxyphenyl)—1H-pyrazolo[3,4—c] pyridin
yl)thiazolyl)morpholine
Step 1. 5—Br0m0—1-((2—(trimethylsz‘lyl)ethoxy)mez‘hyl)-1H-pyra2010[3,4—c]pyridine
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o\/N N
NaH in mineral oil (510 mg, 13 mmol) was slowly added at 0 °C to a solution of 5-
bromo-lH-pyrazolo[3,4-c]pyridine (Astatech, 2.1 g, 11 mmol) and [B-
(trimethylsilyl)ethoxy]methyl chloride (2.30 mL, 13 mmol) in tetrahydrofuran (25 mL). After
ng at r.t. for 1h, the reaction mixture was quenched with water and extracted with ethyl
acetate. The organic phase was washed with brine and dried over sodium sulfate. The
solvents were evaporated under reduced pressure, and the obtained crude product was
purified by Biotage aTM (2.5 g, 70%). LCMS calculated for C12H19BrN3OSi (M+H) +
m/Z = 328.]; found 3281.
Step 2. 5-(2—Flu0r0meth0xyphenyl)((2—(trimethy]silyl)eth0xy)methyl)-1H—pyrazolo[3, 4-
cjpyrz'dme
-Bromo{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[3,4-c]pyridine (1.36 g,
4.16 mmol), (2-fluoromethoxyphenyl)boronic acid (0.85 g, 5.0 mmol), chloro(2-
dicyclohexylphosphino-2’,4’,6’-triisopropyl-1,1’-biphenyl)[2-(2’-amino-1,1 '-
biphenyl)]palladium(II) (Pd XPhos G2) (400 mg, 0.5 mmol), potassium phosphate (3.6 g, 17
mmol) and a magnet bar were placed in a flask. The flask was sealed with a rubber cap,
evacuated and led with nitrogen (this process was repeated a total of three times).
After dioxane (20 mL) and ed water (2 mL) were added, the mixture was heated at 90
°C for l h. The reaction mixture was then diluted with ethyl acetate, washed with brine and
the separated organic phase was dried over sodium sulfate. The ts were removed in
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vacuo and obtained crude product was purified by e IsoleraTM (0.7 g, 45%). LCMS
calculated for C19H25FN302Si (M+H) + m/z = 3742; found 3741.
Step 3. 5—(2—Flu0r0-6—meth0xyphenyU-1H-pyrazolo[3, 4—cjpyrz'dz'ne
F O
A solution of 5-(2-fluoromethoxyphenyl)—1-{[2-(trimethylsilyl)ethoxy]methyl}-
1H-pyrazolo[3,4-c]pyridine (0.70 g, 1.9 mmol) in a mixture of 1.0 M solution of hydrogen
chloride in water (8 mL, 8 mmol) and 4.0 M solution of hydrogen chloride in dioxane (8 mL,
33.6 mmol) was stirred at 80°C for 1h. Then methanol (8 mL) was added, and the reaction
e was further stirred at 80°C for 30 min. After g to r.t., the reaction was
neutralized to pH 7. The mixture was then extracted with ethyl acetate, and the organic phase
was washed with brine. The organic phase was dried over sodium sulfate and the solvents
were ated in vacuo. The obtained crude product was used in the next step without
further purification. LCMS calculated for C13H11FN3O (M+H) + m/z = 2441; found 244.0.
Step 4. luoro-6—methoxyphenyl)l'0d0-1H—pyrazolo[3, 4-c]pyridz'ne
Potassium hydroxide (0.39 g, 6.9 mmol) and iodine (0.88 g, 3.4 mmol) were added
to a solution of 5-(2-fluoromethoxyphenyl)-1H—pyrazolo[3,4-c]pyridine (from previous
step) in 1,4-dioxane (10 mL). The reaction mixture was stirred at 50 °C for 2 hours. After
cooling to r.t., water was added, and reaction was neutralized to pH 7, The mixture was then
extracted with ethyl e, and the organic phase was washed saturated solution of sodium
thiosulfate and brine. The organic phase was dried over sodium e, and the solvents were
evaporated in vacuo. The obtained crude product was used in the next step without further
purification. LCMS calculated for C13H10FIN3O (M+H) + m/z = 370.0; found 3700.
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Step 5. 5-(2—Flu0r0meth0xyphenyl)i0d0((2-(trimethylsilyl)ethoxy)methyl)—1H—
pyra2010[3, rz‘dme
NaH in mineral oil (95 mg, 2.4 mmol) was slowly added at 0°C to a solution of 5-(2-
fluoromethoxyphenyl)iodo-lH—pyrazolo[3,4-c]pyridine (0.80 g, 2.2 mmol) and [B-
(trimethylsilyl)ethoxy]methyl de (0.42 mL, 2.4 mmol) in ydrofuran (10 mL).
After stirring at r.t. for 1h, the reaction mixture was quenched with water, and the mixture
was extracted with ethyl e. The organic phase was washed with brine and dried over
sodium sulfate. The solvents were evaporated in vacuo and obtained crude product was
purified by Biotage IsoleraTM (650 mg, 59%). LCMS calculated for FIN3OzSi (M+H) +
m/z = 500.1; found 500.0.
Step 6. 4—(5—(5—(Z—Fluoro-6—meth0xyphenyl)-]H-pyrazolo[3, 4-cjpyrz'dm—3—yi)thiazol—Z—
hoZine
5-(2—Fluoromethoxyphenyl)iodo-l-((2-(trimethylsilyl)ethoxy)methyl)— 1H-
pyrazolo[3,4—c]pyridine (15 mg, 0.030 mmol), 4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-
2-yl)thiazol-2—yl)morpholine (13.3 mg, 0.045 mmol), chloro(2-dicyclohexylphosphino-
2’,4’,6’-triisopropyl-l,l’-biphenyl)[2-(2’-amino-l,l’-biphenyl)]palladium(II) (Pd XPhos G2)
(2.4 mg, 0.0030 mmol), potassium phosphate (13 mg, 0.062 mmol) and a magnet bar were
placed in a vial with septum, which was then evacuated and backfilled with nitrogen three
times. 1,4—Dioxane (1.5 mL) and degassed water (0.2 mL) were added and the reaction
mixture was stirred at 80 °C for 1 h. Then 1M solution of HCl in water (1 mL) and 4M
solution of HCl in dioxane (1 mL) were added, and reaction mixture was stirred at 80 °C for
1h. After this, ol (1 mL) was added and reaction was further stirred at 80°C for 30
min. The reaction mixture was then diluted with acetonitrile and was purified with prep-
LCMS (XBndge C18 column, eluting with a gradient of acetonitrile/water containing 0.1%
TFA, at flow rate of 60 mL/min). LCMS calculated for C20H19FN502S (M+H)“? m/z = 412.1;
Found: 4121.
Example 35. 5-(5-(2-Fluoro—6-methoxyphenyl)—lH-pyrazolo [3,4-c] pyridinyl)
methylisoxazole
This compound was prepared according to the procedures described in Example 34,
using 3-methyl—5-(4,4,5,5-tetramethy1-1,3,2-dioxaborolanyl)isoxazole instead of 4-(5-
(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)thiazolyl)morpholine as starting al.
LCMS calculated for C17H14FN402 (M+H)+: m/z = 325.1, Found: 325.1.
Example 36. 5-(5-(2-Fluoromethoxyphenyl)—1H-pyrazolo[3,4—c]pyridinyl)
methylthiazole
This compound was prepared ing to the procedures described in Example 34,
using 2-methyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)thiazole instead of 4-(5-
(4,4,5,5-tetramethy1-1,3,2-dioxaborolanyl)thiazolyl)morpholine as starting material.
LCMS calculated for C17H14FN4OS (M+H)+: m/z = 341.1, Found: 341.2.
Example 37. romophenyl)—4-(5—(2-fluoromethoxyphenyl)—1H-pyrazolo[3,4-
c] pyridinyl)piperazin-Z-one
/ N//\N
HNflxj %o
-(2-Fluoro—6-methoxypheny1)iodo((2-(trimethylsilyl)ethoxy)methyl)—1H-
lo[3,4—c]pyridine (Example 34, Step 5, 15 mg, 0.030 mmol), 1-(4-
bromophenyl)piperazinone (11 mg, 0.042 mmol), cesium carbonate (18.1 mg, 0.055
mmol) and chloro(2—dicy clohexylphosphino-Z',6'-di-i-propoxy-1,1'—biphenyl)(2'—amino—1 ,1 '—
biphenylyl)palladium(II) s Pd G2, 2.2 mg, 2.77 umol) were placed in a via,l and
the vial was evacuated and backfilled with nitrgoen three times. Then dioxane (2 mL) was
added, and the on mixture was stirred at 100°C for 2h. The mixture was cooled to It,
solids were filtered off, and the solvent of the filtrate was evaporated in vacuo.
Then 1M solution of HCl in water (1 mL) and 4M solution of HCl in dioxane (1 mL)
were added to the crude residue, and reaction mixture was d at 80 °C for 1h. Methanol
(1 mL) was added, and the resulting reaction mixture was further stirred at 80°C for 30 min.
The reaction mixture was then diluted with acetonitrile and was purified with prep-LCMS
(XBridge C18 column, eluting with a gradient of acetonitrile/water ning 0.1% TFA, at
flow rate of 60 mL/min). LCMS calculated for C23H20BrFN502 (M+H)+: m/z = 496.1; Found:
496.2.
Example 38. 2-(5-(2-Fluoro-G-methoxyphenyl)—1H-pyrazolo[3,4—c]pyridinyl)-1,2,3,4—
tetrahydroisoquinoline—7-carbonitrile
F o/
This nd was prepared according to the procedures described in Example 37,
using 1,2,3,4-tetrahydroisoquinolinecarbonitrile instead of 1-(4-bromophenyl)piperazin
one as ng material. LCMS calculated for C23H19FN50 (M+H)+: m/z = 400.2; Found:
400.1.
Example 39. 4-(4-(5-(2-Flu0r0methoxyphenyl)—1H-pyrazolo[3,4—c] pyridin-3—
yl)piperazinyl)benzonitrile
This compound was prepared according to the ures described in Example 37,
using 4-piperazin-1—y1benzonitrile instead of 1-(4-bromophenyl)piperazin-2—one as starting
material. LCMS calculated for C24H22FN60 (M+H)+: m/z = 4292; Found: 4292.
Example 40. 5-(2-Fluoromethoxyphenyl)—3-(4-(pyridinyl)piperazinyl)-1H-
pyrazolo[3,4—c]pyridine
F 0/
I/ N//\N\//N
/ \J
This compound was prepared according to the procedures described in Example 37,
using 1-(pyridinyl)piperazine d of 1-(4-bromophenyl)piperazin-2—one as starting
material. LCMS calculated for C22H22FN60 : m/z = 405.2; Found: 4052.
Example 41. 5-(2-Fluoromethoxyphenyl)—N—(4-(4-methylpiperazin-l-yl)benzyl)-1H-
pyrazolo[3,4-c]pyridinamine
[\1 \
H N//\N/
/ NVQ/ \J
This compound was prepared according to the procedures described in Example 37,
using (4-(4—methylpiperazin-l-yl)phenyl)methanamine instead of l-(4-
bromophenyl)piperazin-2—one as ng material. LCMS calculated for FNGO
(M+H)+: m/z = 447.2, Found: 447.2.
Example 42. 1-[1-(3—Fuoro{3—[4-(4-methylpiperazinyl)phenyl]-1H-pyrazolo[3,4-
c] pyridin-S-yl}phenyl)cyclopropyl]methanamine
W0 2018f049200
Step 1. 5-Ch10r0—3-i0d0-IH-pyrazolo[3, 4-c]pyridme
| \
To a solution of 5-chloro-1H-pyrazolo[3,4-c]pyridine (2.012 g, 13.10 mmol) in DMF
(40.0 mL) was added N—iodosuccinimide (4.47 g, 19.9 mmol). The mixture was then heated
to 80 °C for 1 h. After g to room temperatue, the mixture was concentrated in vacuo.
The resulting residue was purified on silica gel (120 g, 0-100% EtOAc in hexanes) to give the
desired product as a white solid (3.16 g, 86%). LCMS calculated for C6H4ClIN3 (M+H)+: m/z
= 2799; found 279.9.
Step 2. 5—Ck10r0—3—z'0d0{[2-(trimethylsilyl)ethoxyjmethyZ}-1H-pyrazolo[3,4—cjpyrz'dz'ne
I N Si\
N S
To a suspension ofNaH (60% in mineral oil, 348.2 mg, 8.706 mmol) in DMF (10.0
mL) at 0 °C was added a solution of 5-chloroiodo-1H-pyrazolo[3,4-c]pyridine (1.488 g,
.324 mmol) in DMF (10.0 mL) dropwise over a period of 10 min. The mixture was then
allowed to warm to room temperature and stirred for 20 min. After the reaction was cooled to
0 0C, a solution of [B-(trimethylsi1y1)ethoxy]methyl chloride (1184 mg, 7.102 mmol) in DMF
(5.0 mL) was added dropwise over a period of 10 min. The on was d to warm to
room temperature and stirred for 16 h. The reaction was quenched with sat. NH4C1 (aq), and
extracted with EtOAc. The separated organic layer was washed with brine, dried over
, filtered and concentrated. The residue was purified on silica gel (120 g, 0-50%
EtOAc in hexanes) to give the desired product as a pale yellow solid (1.429 g, 66%). LCMS
calculated for ClIN3OSi (M+H)+: m/z = 410.0; found 410.0.
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Step 3. 5—Ch10r0—3—[4—(4—methylpzperazz‘n—1—yl)phenyZ]{[2-(trz‘methyZSiZyOetl/zoxyjmethyl}—
1H-pyrazoZo[3, rz'dz'ne
To a screw-cap Vial equipped with a magnetic stir bar was added 5-chloro—3-iodo
{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[3,4-c]pyridine (1.429 g, 3.488 mmol), [4-(4-
methylpiperazinyl)phenyl]boronic acid (1.147 g, 5.212 mmol), [1,1'—
bis(diphenylphosphino)ferrocene]dichloropalladium(II) complexed with dichloromethane
(1:1) (310.2 mg, 0.3798 mmol) and K3PO4 (2.424 g, 11.42 mmol). The Vial was sealed with a
teflon-lined septum, evacuated and backfilled with nitrogen (this process was repeated a total
of three . 1,4—Dioxane (15.0 mL) was added ed by degassed water (5.00 mL).
The reaction was stirred at 100 °C for 3 h. After cooling to room temperature, the on
was diluted with EtOAc. The organic phase was washed with brine, dried over Na2S04,
filtered, and concentrated. The resulting residue was purified on silica gel (40 g, 0-100%
EtOAc in s, then 10% MeOH in CH2C12) to give the desired product as a dark solid
(1.379 g, 86%). LCMS calculated for C23H33CleOSi (M+H)+: m/z = 4582; found 4583.
Step 4. I-[1-(3—Br0m0-5—flu0r0phenyl)cyclopropyljmethanamme
F NH2
To 1—(3-bromofluorophenyl)cyclopropanecarbonitrile (1.005 g, 4.186 mmol) was
added a solution of 1.0 M borane in THF (13.0 mL, 13.0 mmol). The mixture was heated to
70 °C for 2 h. After cooling to room temperature, the mixture was treated with 6.0 M HCl
(aq) (14.0 mL, 840 mmol). The mixture was stirred at 60 °C for 5 h. The mixture was diluted
with EtOAc, and adjusted to pH 12 with 4 N NaOH(aq). The separated aqueous layer was
extracted with EtOAc (3 x). The ed organic layer was dried over Na2S04, filtered and
concentrated to give the crude product as a yellow oil, which was used directly in the next
step without further purification (2.11 g). LCMS calculated for CioHizBrFN (M+H)+: m/z =
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244.0; found 2440.
Step 5. tert—Butyl {[1 -(3-br0m0flu0r0phenyl)cyclopropyljmethyl}carbamate
F NHBoc
To a solution of 1-[1-(3-bromofluorophenyl)cyclopropy1]methanamine (1.022 g,
4.187 mmol) in CH2C12 (10.0 mL) was added di-tert-butyldicarbonate (1.531 g, 7.015 mmol).
The mixture was stirred at room temperature for 10 min, and then concentrated. The mixture
was d on silica gel (120 g, 0-100% EtOAc in hexanes) to give the d product as a
white solid (1.252 g, 87%). LCMS calculated for C15H20BrFN02 (M+H)+: m/z = 3441; found
344.0.
Step 6. tert—Butyl ({1-[3-flu0r0(4, 4,5, amethyl-1,3, 2—dl'0xab0rolan
y])phenyf]cyclopr0pyl}methy!)carbamate
To a screw—cap vial equipped with a magnetic stir bar was added tert-butyl {[1-(3-
bromofluorophenyl)cyclopropyl]methyl}carbamate (589.7 mg, 1.713 mmol),
4,4,5,5,4',4',5',5'—octamethyl-[2,2']bi[[1,3,2]dioxaborolanyl] (672.2 mg, 2.647 mmol), [1,1'—
bis(dipheny1phosphino)ferrocene]dichloropalladium(II) complexed with dichloromethane
(1:1) (389.8 mg, 0.4773 mmol), and KOAc (509.0 mg, 5.186 mmol). The vial was sealed
with a teflon-lined septum, evacuated and backfilled with nitrogen (this process was repeated
a total of three times). 1,4-Dioxane (10.0 mL) was added. The reaction was d at 100 °C
for 3 h. After cooling to room temperature, the reaction was diluted with CH2C12 and filtered.
The filtrate was concentrated. The resulting residue was purified on silica gel (40 g, 0-100%
EtOAc in hexanes) to give the desired product as a light yellow oil (571.4 mg, 85%). LCMS
ated for C21H31BFNNaO4 +: m/z = 4142; found 4143.
Step 7. 1 —[1—(3—FZu0r0-5—{3-[4—(4-methylpzperazmyZ)phenyZ]—1H-pyrazof0[3, 4—cjpyrz'dz'n-
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heny2)cyclopropyljmethanamme
To a screw-cap vial equipped with a magnetic stir bar was added 5—chloro[4-(4-
methylpiperazin-l-y1)pheny1]{[2-(trimethy1silyl)ethoxy]methyl}-1H-pyrazolo[3,4-
c] pyridine (30.0 mg, 0.0655 mmol), tert—butyl ({1-[3-fluoro(4,4,5,5-tetramethyl-1,3,2-
dioxaborolan—2—yl)phenyl]cyclopropyl}methy1)carbamate (49.5 mg, 0.126 mmol),
dicyclohexyl(2',4',6’-triisopropylbiphenylyl)phosphine-(2'-aminobiphenyl
yl)(chloro)palladium (1:1) (XPhos Pd G2, 5.0 mg, 0.0063 mmol), and K3PO4 (54.2 mg, 0.255
mmol). The vial was sealed with a teflon-lined septum, evacuated and backfilled with
nitrogen (this process was ed a total of three times). 1,4-Dioxane (1.50 mL) was added,
followed by water (150.0 uL). The reaction was stirred at 80 0C for 1 h. After cooling to room
temperature, the reaction mixture was diluted with CH2C12, filtered and concentrated. The
residue was dissolved in MeOH (3.00 mL) and treated with 4.0 M HCl in dioxane (2.00 mL,
8.00 mmol). The mixture was stirred at 65 0C for 2 h. After cooling to room temperature, the
mixture was purified using prep-LCMS (XBridge C18 column, eluting with a nt of
acetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min) to afford the desired
product as a yellow solid (17.9 mg). LCMS calculated for C27H30FN6 (M+H)+: m/z = 4573;
Found: 45?.3.
Example 43. 5—(2—Fluoro—6—methoxyphenyl)—3—(4-(4-methylpiperazin- l-yl)phenyl)—1H-
pyrazolo[3,4—c]pyridine
To a screw-cap vial equipped with a ic stir bar was added ro(4-(4-
piperazinyl)phenyl)((2-(trimethylsilyl)ethoxy)methyl)—1H—pyrazolo[3,4-
c]pyridine (Example 42, Step 3, 30.1 mg, 0.066 mmol), (2-fluoromethoxyphenyl)boronic
acid (229 mg, 0.135 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-
biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (XPhos Pd G2, 5.0 mg, 0.0063 mmol) and
K3PO4 (51.4 mg, 0.242 mmol). The vial was sealed with a teflon-lined septum, evacuated and
backfilled with nitrogen (this s was repeated a total of three times). 1,4-Dioxane (1.50
mL) was added, followed by water (150.0 uL). The reaction was stirred at 65 °C for 2 h.
After g to room temperature, the on mixture was diluted with CH2C12, filtered and
concentrated. The residue was dissolved in MeOH (3.00 mL) and treated with 4.0 M HCl in
dioxane (2.00 mL, 800 mmol). The mixture was stirred at 65 0C for 2 h. After cooling to
room temperature, the mixture was purified using prep-LCMS (XBridge C18 column, eluting
with a gradient of acetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min) to
afford the desired t as a yellow solid (19.4 mg). LCMS calculated for C24H25FN50
(M+H)+: m/z = 4182; Found: 418.3.
Example 44. -Diflu0rophenyl)(4-(4-methylpiperazin- 1-yl)phenyl)—1H-
pyrazolo[3,4-c]pyridine
This compound was prepared according to the procedures described in Example 43,
using ifluorophenyl)boronic acid instead of 2-fluoromethoxyphenylboronic acid as
starting material. LCMS ated for C23H22F2N5 : m/z = 4062; Found: 4062.
Example 45. 5-(2,6-Dimethylphenyl)—3-(4-(4-methylpiperazinyl)phenyl)—1H-
pyrazolo[3,4—c]pyridine
This compound was prepared ing to the procedures described in Example 43,
using (2,6—dimethylphenyl)boronic acid instead of 2-fluoromethoxypheny1boronic acid as
starting material. LCMS calculated for C25H28N5 (M+H)+: m/z = 398.2; Found: 3981.
Example 46. 3-(4-(4-Methylpiperazinyl)phenyl)—5-(2,4,6-trifluorophenyl)—1H-
pyrazolo[3,4-c]pyridine
WO 49200 2017/050737
This compound was prepared according to the procedures described in Example 43,
using (2,4,6-trifluorophenyl)boronic acid instead of 2-fluoromethoxyphenylboronic acid as
starting material. LCMS calculated for C23H21F3N5 (M+H)+: m/z = 424.2; Found: 4242.
Example 47. 5-(2-Chloroflu0r0phenyl)—3—(4-(4-methylpiperazin- 1-yl)phenyl)-1H-
pyrazolo[3,4-c] pyridine
This compound was prepared according to the procedures described in Example 43,
using (2-chlorofluorophenyl)boronic acid instead of 2-fluoro—6—methoxyphenylboronic
acid as starting material. LCMS calculated for C23H22ClFN5 (M+H)+: m/z = 422.2; Found:
422.2.
Example 48. 3,5—Difluor0-4—(3-(4-(4-methylpiperazinyl)phenyl)—1H-pyrazolo[3,4-
c]pyridinyl)phenol
This compound was prepared according to the procedures bed in e 43,
using (2,6-difluorohydroxyphenyl)boronic acid instead of 2-fluoro
methoxyphenylboronic acid as starting material. LCMS calculated for C23H22F2N50 (M+H)+:
m/z = 4222; Found: 4222.
Example 49. 5-(2-Fluoromethylphenyl)—3-(4—(4-methylpiperazinyl)phenyl)-1H-
pyrazolo[3,4-c]pyridine
This compound was prepared according to the procedures described in Example 43,
using (2-fluoro—6-methylphenyl)boronic acid instead of 2-fluoromethoxyphenylboronic
acid as starting material. LCMS calculated for FN5 (M+H)+: m/z = 402.2; Found:
402.2.
Example 50. 5-(2-Chloro(trifluoromethyl)phenyl)—3—(4-(4-methylpiperazin- 1-
yl)phenyl)—1H-pyrazolo [3,4—c]pyridine
This compound was prepared according to the procedures described in e 43,
using (2-chloro-6—(trifluoromethyl)phenyl)boronic acid instead of 2-fluoro
methoxyphenylboronic acid as starting material. LCMS calculated for C24H22C1F3Ns
(M+H)+: m/z = 472.2; Found: 472.2.
Example 51. 5-(2-Ethoxyfluor0phenyl)—3-(4-(4-methylpiperazinyl)phenyl)—1H-
pyrazolo[3,4-c]pyridine
This compound was ed ing to the procedures described in Example 43,
using (2-ethoxyfluorophenyl)boronic acid d of 2-fluoromethoxyphenylboronic
acid as starting material. LCMS calculated for FN50 (M+H)+: m/z = 4322; Found:
4322.
Example 52. 5-(2-Chloromethoxyphenyl)—3-(4-(4-methylpiperazinyl)phenyl)-1H-
pyrazolo[3,4—c]pyridine
This compound was prepared according to the procedures described in Example 43,
using (2-chloromethoxyphenyl)boronic acid instead of 2-fluoromethoxyphenylboronic
acid as starting al. LCMS calculated for C24H25C1N50 : m/z = 4342; Found:
4342.
Example 53. 5-(2-Fluoro(trifluoromethyl)phenyl)(4-(4-methylpiperazin- 1-
yl)phenyl)— lH-pyrazolo[3,4—c]pyridine
This compound was prepared according to the procedures described in Example 43,
using (2-fluoro(trifluoromethyl)phenyl)boronic acid instead of 2-fluoro
methoxyphenylboronic acid as starting material. LCMS calculated for C24H22F4Ns (M+H)+:
m/z = 4562; Found: 4562.
Example 54. 5-(2-Fuoromethoxyphenyl)-N-(4-(4-methylpiperazinyl)phenyl)-1H-
pyrazolo[3,4-c]pyridine-S-carboxamide
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Step 1. Methyl 5—(Z-fluorometh0xyphenyZ)((2-(trz'methylsz'lyl)ethoxy)methyl)—1H—
pyra2010[3, ridinecarboxylaz‘e
A mixture of 5-(2-fluoromethoxyphenyl)iodo((2-
(trimethylsilyl)ethoxy)methyl)-lH-pyrazolo[3,4-c]pyridine (Example 34, Step 5, 1.0 g, 2
mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complexed with
dichloromethane (1:1) (170 mg, 0.2 mmol, Combi-Blocks) was placed in a flask with a
septum. The flask was then evacuated and backfilled with nitrogen three times. After addition
of methanol (20 mL) and triethylamine (0.57 mL, 4 mmol), the flask was evacuated and
backfilled with carbon monoxide gas three times. Then balloon with carbon de gas
was connected to the reaction flask and reaction mixture was heated at 85°C overnight. After
cooling to r.t., the reaction mixture was filtered through Celite, and the e was
concentrated in vacuo. The crude material was purified by Biotage Isolera to give the desired
product (440 mg, 51%). LCMS calculated for C21H27FN3O4Si (M+H)+ m/z = 432.2; found:
432.2.
Step 2. 5-(2-Flu0r0meth0xyphenyl)((2—(trimethy]silyl)eth0xy)methyl)-]H—pyrazolo[3, 4-
cjpyrl'dl'ne-S-carboxyll'c acid
F o/
[\1 \
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1M Solution of sodium hydroxide in water (5 mL, 5 mmol) was added to a solution of
methyl 5-(2-fluoromethoxyphenyl)((2-(trimethylsilyl)ethoxy)methyl)-1H—pyrazolo[3,4-
c]pyridinecarboxylate (450 mg, 1 mmol) in tetrahydrofuran (5 mL) and methanol (3 mL).
After stirring at r.t. for 2 h, pH was adjusted to 5 by the addition of the 1M solution of HCl.
The mixture was then extracted with ethyl acetate, and the separated organic phase was
washed with brine. The organic phase was dried over sodium sulfate, and the solvents were
evaporated under reduced pressure. The obtained solid t was used in the next step
without further purification (396 mg, 95%). LCMS calculated for C20H25FN3O4Si (M+H)+
m/z = 4182; found 418.3.
Step 3. u0r0-6—meth0xyphenyl)-N-(4-(4-mez‘hylpiperazmyl)phenyZ)-1H-
pyrazolo[3, 4—c]pyridinecarboxamide
To a solution of 5-(2-fluoromethoxyphenyl)((2-(trimethylsilyl)ethoxy)methyl)—
1H—pyrazolo[3,4-c]pyridinecarboxylic acid (15 mg, 0.035 mmol) and 4-(4-
methylpiperazinyl)aniline (10 mg, 0.05 mmol) in ethylformamide (1.5 mL) were
added NN-diisopropylethylanfine (13 uL, 0.07 mmol) and N,N,N’,N’-tetramethyl-O-(7-
azabenzotriazol-l-yl)uronium orophosphate (15 mg, 0.04 mmol). After the reaction
mixture was stirred at r.t. for 2 hours, it was quenched with water. The mixture was extracted
with ethyl acetate. The organic phases were washed with brine and dried over sodium sulfate,
and the solvents were evaporated in vacuo. Then 1M solution of HCl in water (1 mL) and 4M
solution of HCl in dioxane (1 mL) were added to the crude residue, and reaction mixture was
stirred at 80 °C for 1h. Methanol (1 mL) was added, and reaction mixture was further stirred
at 80 °C for 30 min. The reaction e was then diluted with acetonitrile and was purified
with prep-LCMS (XBridge C18 column, g with a gradient of acetonitrile/water
containing 0.1% TFA, at flow rate of 60 mL/min). LCMS calculated for FN602
(M+H)+: m/z = 461.2; Found: 461.3.
Example 55. 5-(2-Fluoromethoxyphenyl)—N—(4-morpholinophenyl)—lH-pyrazolo[3,4-
c]pyridinecarboxamide
This compound was prepared according to the procedures described in Example 54,
using 4-morpholinoani1ine instead of 4-(4-methylpiperazinyl)aniline as starting material.
LCMS calculated for C24H23FN503 (M+H)+: m/z = 4482; Found: 448.3.
Example 56. N—(4—(4—Ethylpiperazin-l-yl)phenyl)—5-(2-fluor0meth0xyphenyl)—1H-
pyrazolo[3,4—c]pyridine-3—carboxamide
3 N
This compound was prepared ing to the procedures described in Example 54,
using 4-(4-ethylpiperazinyl)aniline instead of 4-(4-methylpiperazinyl)aniline as starting
material. LCMS calculated for FN602 (M+H)+: m/z = 4752; Found: 475.2.
Intermediate 1. tert-Butyl 5-chloro—3-(l-methyl-1H-pyrazolyl)-1H-pyrazolo[3,4—
c] pyridine-l-carboxylate
N Nx
\ / /
| \
NIS (10.57 g, 47.0 mmol) was added to a solution of 5-chloro-1H—pyrazolo[3,4-
c]pyridine (7.07 g, 46.0 mmol) in DMF (115 ml). After ng at 70 °C for 2h, reaction
mixture was cooled to r.t. and ylamine (9.63 ml, 69.1 mmol) was added followed by
boc-anhydride (15.07 g, 69.1 mmol). After stirring for an additional 2h at r.t., water was
added and precipitated product was collected by filtration, dried and was used in the next step
t further purification (17g, 97%). LCMS calculated for C11H12C11N302 (M+H)+: m/z =
3800; found 380.0.
Step 2. tart-Bury! 5-ch10r0(1-methyl-1H-pyrazolyl)-1H—pyrazolo[3, 4-cjpyridme
carboxylate
tert—Butyl 5-chloroiodo-1H-pyrazolo[3,4-c]pyridinecarboxylate (6.64 g, 17.49
mmol), PdC12(dppf)-CH2C12 adduct (1.429 g, 1.749 mmol), yl(4,4,5,5-tetramethyl-
1,3,2-dioxaborolanyl)-1H-pyrazole (3.64 g, 17.49 mmol) and ium phosphate (7.43 g,
.0 mmol) were placed in a flask and the flask was evacuated and backfilled with en
three times. Then dioxane (100 ml) and degassed water (10.0 ml) were added, and the
reaction mixture was stirred at 80 °C for 1 h. After cooling to r.t., water was added, and the
mixture was extracted with EtOAc. The combined organic phases were washed with brine,
dried over sodium sulfate and solvent evaporated. The crude product was purified by Biotage
IsoleraTM (4.7 g, 81%). LCMS calculated for C15H17C1N502 (M+H) + m/z = 3341; found
3342.
Intermediate 2. 5-Chlor0(1—methyl-1H-pyrazolyl)— 1-((2-
(trimethylsilyl)ethoxy)methyl)-lH-pyrazolo [3,4—c]pyridine
N Nx
\ / /
This compound was ed according to the procedures described in Example 42
(Steps 1-3), using 1-methyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)—lH-pyrazole
d of [4-(4-methylpiperazinyl)phenyl]boronic acid as starting material. LCMS
calculated for C16H23ClNSOSl (M+H)+: m/z = 364.1; Found: 364.1.
Example 57. 3,5-Difluoro-N-(2-methoxyethyl)(3-(1-methyl-1H-pyrazolyl)-1H-
pyrazolo[3,4-c]pyridin-S-yl)benzamide
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O NJ
F F
Nb /
/’ / N
/ /N
Step 1. Methyl 3, 5-dl'flu0r0(3-(1-methyl-1H—pyrazolyl)((2-
(trimethy]silyl)eth0xy)methyl)-1H-pyra2010[3, ridmyl)benzoate
COOMe
F F
N \ /
/’ / N
/ /N
-Chloro—3-(1—methy1—1H—pyrazolyl)—1-((2-(trirnethylsilyl)ethoxy)methyl)-1H—
pyrazolo[3,4-c]pyridine (348 mg, 0.956 mmol, Intermediate 2), methyl fluoro
(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)benzoate (342 mg, 1.148 mmol), chloro(2-
dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1“-
biphenyl)]palladium(II) (Pd XPhos G2) (75 mg, 0.096 mmol) and potassium phosphate (406
mg, 1.91 mmol) were placed in a flask and the flask was evacuated and backfilled with
nitrogen three times. Then dioxane (20 mL) and degassed water (2 mL) were added, and
reaction mixture was stirred at 90 °C for 2h. After cooling to r.t., the reaction mixture was
d with ethyl acetate, and the resulting mixture was washed with brine. The separated
organic phase was dried over sodium sulfate and concentrated under reduced pressure. The
obtained crude product was purified by Biotage IsoleraTM (440 mg, 92%). LCMS ated
for C24H28F2N503Sl (M+H) + m/z = 5002, found 5002.
Step 2. 3, 5-Diflu0r0(3-(1-methyl-1H—pyrazolyl)((2-(trl'methy]silyl)eth0xy)methyl)-
1H-pyrazoio[3, 4-cjpyridiny0benzoic acid
W0 2018f049200
F F
N \ /
/ / N
/ / N
1M Solution of sodium ide in water (5 mL, 5 mmol) was added to a solution of
methyl 3,5-difluoro(3-(l-methyl-lH-pyrazolyl)((2-(trimethylsilyl)ethoxy)methyl)-
lH-pyrazolo[3,4—c]pyridinyl)benzoate (440 mg, 0.881 mmol) in tetrahydrofuran (5 mL)
and methanol (3 mL). After stirring at r.t. for 2 h, the pH was adjusted to 5 by the addition of
an 1M solution of HCl. The resulting mixture was then extracted with ethyl acetate and
organic phase was washed with brine. The organic phase was dried over sodium sulfate and
the solvents were ated in vacuo. The obtained solid product was used in the next step
t further purification (403 mg, 94%). LCMS ated for C23H26F2N503S1 (M+H)+
m/z = 4862; found 486.3.
Step 3. 3,5-Diflu0r0-N-(2-meth0xyethyl)(3-(1-methyl-JH-pyrazoZyl)-1H—pyra2010[3, 4-
diny0benzamide
To a solution of 3,5-difluoro(3-(1-methyl-1H-pyrazolyl)((2-
(trimethylsilyl)ethoxy)methyl)-lH-pyrazolo[3,4-c]pyridinyl)benzoic acid (15 mg, 0.031
mmol) and 2-methoxyethanamine (4.64 mg, 0.062 mmol) in MN—dimethylformamide (1.5
mL) were added MN—diisopropylethylamine (13 uL, 0.07 mmol) and N,N,N’,N’-tetramethy1-
0-(7-azabenzotriazol-l-yl)uronium hexafluorophosphate (15 mg, 0.04 mmol). After the
reaction mixture was stirred at r.t. for 2 hours, it was quenched with water. The mixture was
extracted with ethyl acetate, and the ted organic phases were washed with brine, dried
over sodium sulfate. The solvents were evaporated in vacuo. Then 1M solution of HCl in
water (1 mL) and 4M solution of HCl in dioxane (1 mL) were added to the crude residue and
the reaction was stirred at 80 °C for 1 h. Then methanol (1 mL) was added, and reaction
mixture was further stirred at 80 °C for 30 min. The reaction mixture was then diluted with
acetonitrile and was purified with prep-LCMS (XBridge C18 column, eluting with a gradient
of acetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min). LCMS calculated for
F2N602 (M+H)+: m/z = 413.2; Found: 413.3.
WO 49200
Example 58. (3,5-Difluoro(3-(1-methyl-1H-pyrazolyl)—1H-pyrazolo[3,4-c] pyridin-
-yl)phenyl)(3-methoxyazetidin-l-yl)methanone
0 N7
F F
N|\ /
/ /'\‘
/ /N
This compound was prepared according to the procedures described in Example 57,
using 3-methoxyazetidine instead of 2-methoxyethanamine as starting material. LCMS
calculated for C21H19F2N602 (M+H)+: m/z = 4252; Found: 425.2.
Example 59. N-(2,4-Difluoro(3-(1-methyl-1H-pyrazolyl)—1H-pyrazolo[3,4—
c]pyridin-S-yl)phenyl)cyclobutanecarboxamide
F F
“l\ /
/ /'\‘
/ /N
HN\N
Step 1. 2, 4-Diflu0r0(4, 4, 5, 5-telmmethyl-1 , 3, 2-dl'0xaborolan-Z-yUaniZine
To a mixture of 4,4,5,5,4',4',5',5'-octamethyl-[2,2']bi[[1,3,2]dioxaborolanyl] (1.831 g,
7.21 mmol), potassium acetate (1.415 g, 14.42 mmol) and [1,1'-
bis(diphenylphosphino)ferrocene]dichloropalladium(II) complexed with dichloromethane
(1: 1) (0.785 g, 0.962 mmol) under nitrogen was added a solution of 3-bromo-2,4-
oaniline (1.0 g, 4.81 mmol) in 1,4-dioxane (20 mL). The e was stirred at 100 °C
overnight. After cooling to room temperature, the mixture was d with DCM and filtered
W0 2018/‘049200
through Celite. The filtrated was concentrated in vacuo. The residue was purified by e
IsoleraTM (740 mg, 60%). LCMS calculated for C12H17BF2NO2 (M+H) + m/z = 2561; found
2561.
Step 2. 2,4—Diflu0r0-3—(3-(1-methyl-IH-pyrazolyU((2-(trimethy]sz‘lyf)eth0xy)methyl)-
1H—pyrazof0[3, 4—cjpyridiny0anilme
F F
N \ /
/ / N
/ /N
—Chloro(1 -methyl- 1H-pyrazolyl)— 1 trimethylsilyl)ethoxy)methyl)-1H-
pyrazolo[3,4-c]pyridine (348 mg, 0.956 mmol, Intermediate 2), fluoro(4,4,5,5-
tetramethyl-l,3,2-dioxaborolanyl)aniline (293 mg, 1.148 mmol), chloro(2-
dicyclohexylphosphino—2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-
biphenyl)]palladium(II) (Pd XPhos G2) (75 mg, 0.096 mmol) and potassium phosphate (406
mg, 1.91 mmol) were placed in a flask and the flask was evacuated and backfilled with
nitrogen three times. Then dioxane (20 mL) and degassed water (2 mL) were added, and
reaction mixture was stirred at 90 °C for 2h. After cooling to r.t., the reaction mixture was
diluted with ethyl acetate, the resulting e was washed with brine, The separated
organic phase was dried over sodium sulfate. The solvents were ated in vacuo and
obtained crude t was purified by Biotage IsoleraTM (380 mg, 87%). LCMS calculated
for C22H27F2N60$i (M+H) + m/z = 4572, found 457.2.
Step 3. N-(Z,4-Diflu0r0(3-(1-mez‘hyl-1H—pyrazolyl)-1H—pyra2010[3, 4-c]pyridin
yUphenyDcyclobuz‘anecarboxamide
To a solution of fluoro(3-(1-methy1-1H-pyrazoly1)((2-
(trimethylsilyl)ethoxy)methy1)-1H-pyrazolo[3,4-c]pyridinyl)aniline (15 mg, 0.033 mmol)
and cyclobutanecarboxylic acid (3.29 mg, 0.033 mmol) in N,N—dimethylformamide (1.5 mL)
were added NN—diisopropylethylamine (13 uL, 0.07 mmol) and NNNCN'-tetramethyl—O-(7-
azabenzotriazol-l-y1)uronium hexafluorophosphate (15 mg, 0.04 mmol). After the reaction
mixture was stirred at r.t. for 2 hours, it was quenched with water. The mixture was extracted
with ethyl acetate, and the organic phases were washed with brine, dried over sodium sulfate
and solvents evaporated in vacuo. Then 1M solution of HCl in water (1 mL) and 4M solution
of HCl in dioxane (1 mL) were added to the crude residue, and reaction was d at 80 °C
for 1 h. After this methanol (1 mL) was added and reaction was further stirred at 80°C for 30
min. The reaction mixture was then d with acetonitrile and was purified with prep-
LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1%
TFA, at flow rate of 60 mL/min). LCMS calculated for C21H19F2N60 (M+H)+: m/z = 4092;
Found: 409.1.
Example 60. N—(2,4—Diflu0r0(3-(1-methyl-1H-pyrazolyl)-1H-pyrazolo[3,4-
c]pyridin-S—yl)phenyl)—2-phenylacetamide
F I:
N\ /
I/ /'\l
/ /N
This compound was ed according to the procedures described in Example 59,
using 2-phenylacetic acid instead of utanecarboxylic acid as starting material. LCMS
calculated for C24H19F2N6O (M+H)+: m/z = 445.2; Found: 445.3.
Example 61. 2,4-Difluoro-N—methyl-3—(3-(1-methyl-1H-pyrazol-4—yl)-lH-pyrazolo [3,4-
c] pyridin-S-yl)aniline
F F
ND /
/ /"l
/ /N
Example 62. 2,4-Difluoro-N,N—dimethyl-3—(3—(1—methyl-1H-pyrazolyl)-1H-
pyrazolo[3,4-c] pyridin-S-yl)aniline
Sodium hydride (2 mg, 0.049 mmol, 60% in mineral oil) was added to a solution of
2,4-difluoro(3—(1 l-1H-pyrazolyl)-1 -((2-(trimethylsilyl)ethoxy)methy l)—1H-
pyrazolo[3,4-c]pyridin-S-yl)aniline (15 mg, 0.033 mmol, Example 59, Step 2) and
iodomethane (13.99 mg, 0.099 mmol) in THF (2.0 mL). After the reaction mixture was
stirred at r.t. for 2 hours, it was quenched with water. The mixture was extracted with ethyl
acetate. The organic phases were washed with brine, dried over sodium sulfate and solvents
evaporated in vacuo. Then 1M solution of HCl in water (1 mL) and 4M solution of HCl in
e (1 mL) were added to the crude residue, and reaction was stirred at 80 °C for 1 h.
Then methanol (1 mL) was added, and reaction mixture was further d at 80 °C for 30
min. The reaction mixture was then diluted with acetonitrile and was purified with prep-
LCMS (XBIidge C18 column, eluting with a gradient of acetonitrile/water containing 0.1%
TFA, at flow rate of 60 mL/min) to give both products Example 61 and Example 62.
Example 61. LCMS calculated for C17H15F2N6 +: m/z = 341.1; Found: 3412.
Example 62. LCMS calculated for C18H17F2N6 (M--H)+: m/z = 355.2; Found: 3552.
Example 63. fluoro-N,N—dimethyl(3—(1—methyl-1H-pyrazolyl)—1H-
lo[3,4-c]pyridin-S-yl)aniline
F F
ND /
/ /"l
/ /N
HN\N
Step 1. 3, 5-Diflu0r0(4, 4, 5, 5-tetramethyl-1, 3, 2-di0xab0r01anyl)amZine
W0 2018f049200
To a mixture of 4,4,5,5,4',4',5',5'-octamethyl-[2,2']bi[[1,3,2]dioxaborolanyl] (2.75 g,
.8 mmol), potassium acetate (2.1 g, 21.6 mmol) and [1,1'—
bis(diphenylphosphino)ferrocene]dichloropalladium(II) complexed with dichloromethane
(1:1) (0.785 g, 0.962 mmol) under nitrogen was added a solution of 4-bromo-3,5—
difluoroaniline (1.5 g, 7.21 mmol) in 1,4-dioxane (20 mL). The mixture was stirred at 100 °C
overnight. After cooling to room temperature, the mixture was diluted with DCM and d
through Celite. The filtrated was concentrated in vacuo. The residue was d by Biotage
IsoleraTM (1.4 g, 76%). LCMS calculated for C12H17BF2N02 (M+H) + m/z = 256.]; found
256.2.
Step 2. 3, 5-Difluor0(3-(1-methyl-1H-pyrazolyl)((2-(trimethylsiZyDethoxy)mez‘hyl)-
1H-pyrazoZo[3, 4-cjpyridmyljam'lme
F F
“l \ /
/ / N
/ /N
5-Chloro-3 -(1 -methyl- 1H-pyrazolyl)— 1 trimethylsilyl)ethoxy)methyl)-1H-
pyrazolo[3,4—c]pyridine (348 mg, 0.956 mmol, Intermediate 2), 3,5-difluoro—4—(4,4,5,5-
tetramethyl—l,3,2-dioxaborolanyl)aniline (293 mg, 1.148 mmol), chloro(2-
dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'—
biphenyl)]palladium(II) (Pd XPhos G2) (75 mg, 0.096 mmol) and potassium phosphate (406
mg, 1.91 mmol) were placed in a flask and the flask was evacuated and backfilled with
en three times. Then dioxane (20 mL) and ed water (2 mL) were added and the
reaction was stirred at 90 °C for 2h. After cooling to rt, the reaction e was extracted
with ethyl acetate. The separate organic layer was washed with brine and dried over sodium
sulfate. The solvents were evaporated under reduced pressure and obtained crude product was
W0 2018f049200
purified by Biotage IsoleraTM (354 mg, 81%). LCMS calculated for C22H27F2NGOSl (M+H) +
m/z = 45?.2; found 457.2.
Step 3. 3,5—Diflu0r0-N,N—dz'methyl(3—(1-methyl—JH-pyrazoZyl)—1H—pyrazolo[3,4-
cjpyridin—5—y0aniline
Sodium hydride (2 mg, 0.049 mmol, 60% in mineral oil) was added to a solution of
3,5-difluoro(3-(1 -methyl-1H-pyrazolyl)-1 -((2-(trimethylsilyl)ethoxy)methyl)—1H-
pyrazolo[3,4-c]pyridinyl)aniline (15 mg, 0.033 mmol) and iodomethane (13.99 mg, 0.099
mmol) in THF (20 mL). After the reaction mixture was stirred at r.t. for 2 hours, it was
quenched with water. The mixture was extracted with ethyl acetate. The separated organic
phases were washed with brine, dried over sodium sulfate and solvents evaporated in vacuo.
Then 1M solution of HCl in water (1 mL) and 4M solution of HCl in dioxane (1 mL) were
added to the crude residue, and the resulting mixture was stirred at 80 °C for 1h. After this
methanol (1 mL) was added and reaction was further stirred at 80°C for 30 min. The reaction
mixture was then diluted with acetonitrile and was purified with prep-LCMS (XBridge C18
column, eluting with a nt of itrile/water containing 0.1% TFA, at flow rate of 60
). LCMS calculated for F2N6 (M+H)+: m/z = 3552; Found: 355.3.
Example 64. -Difluor0(3-(1-methyl-1H-pyrazolyl)—1H-pyraz0l0[3,4—
c] n-S—yl)phenyl)(pyrrolidinyl)acetamide
F F
ND /
/ /"l
/ /N
To a solution of 3,5-difluoro(3-(1-methyl-1H-pyrazolyl)((2-
(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridinyl)aniline (15 mg, 0.033 mmol,
Example 63, Step 2) and 2-(pyrrolidinyl)acetic acid (4.24 mg, 0.033 mmol) in MN-
dimethylformamide (1.5 mL) were added NN—diisopropylethylamine (13 uL, 0.07 mmol) and
, '-tetramethy1(7-azabenzotriazolyl)uronium hexafluorophosphate (15 mg, 0.04
mmol). After the reaction mixture was stirred at r.t. for 2 hours, it was quenched with water.
The mixture was extracted with ethyl acetate. The separated organic phases were washed
with brine, dried over sodium sulfate and solvents evaporated in vacuo. Then 1M solution of
HCl in water (1 mL) and 4M on of HCl in dioxane (1 mL) were added to the crude
residue, and resulting mixture was stirred at 80 °C for 1 h. Methanol (1 mL) was then added
and reaction was further d at 80 °C for 30 min. The reaction mixture was then diluted
with itrile and was purified with prep-LCMS (XBridge C18 column, eluting with a
gradient of acetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min). LCMS
ated for C22H22F2N7O (M+H)+: m/z = 438.2, Found: 438.2. 1H NMR (500 MHz,
DMSO-ds) 5 11.12 (s, 1H), 9.15 (s, 1H), 8.48 (s, 1H), 8.22 (s, 1H), 8.06 (s, 1H), 7.47 (d, J =
9.2 Hz, 2H), 4.34 (s, 2H), 3.93 (s, 3H), 3.66 (s, 2H), 3.17 (s, 2H), 1.99 (d, J = 50.3 Hz, 4H)
ppm.
Example 65. N-(3,S-Difluor0(3-(1-methyl-1H-pyrazolyl)—1H-pyrazolo[3,4—
c]pyridin-S-yl)phenyl)—l-methyl-1H-pyraz01e—4-carboxamide
This nd was prepared according to the procedures described in Example 64,
using 1-methyl-1H—pyrazolecarboxylic acid instead of 2-(pyrrolidinyl)acetic acid as
starting material. LCMS calculated for C21H17F2N80 (M+H)+: m/z = 435.2, Found: 435.1.
Example 66. 2-Cyclopentyl-N—(3,5-diflu0r0(3-(1-methyl-1H-pyrazol-4—yl)—1H-
pyrazolo[3,4-c]pyridin-S-yl)phenyl)acetamide
F F
ND /
/’ / N
/ /N
This compound was prepared according to the procedures described in Example 64,
using 2-cyclopentylacetic acid instead of 2-(pyrrolidinyl)acetic acid as starting material.
LCMS calculated for C23H23F2N60 (M+H)+: m/z = 4372; Found: 437 .2.
Example 67. N—(3,5-Difluoro—4-(3—(1-methyl-lH-pyrazolyl)-1H-pyraz0lo[3,4—
c]pyridin-S—yl)phenyl)—2-(pyridinyl)acetamide
O /|
F F
ND /
/ /'\‘
/ /N
This compound was prepared according to the procedures described in Example 64,
using 2-(pyridinyl)acetic acid d of 2-(pyrrolidinyl)acetic acid as starting material.
LCMS calculated for C23H18F2N7O (M+H)+: m/z = 446.2; Found: 446.2.
Example 68. 2-(7-Azabicyclo[2.2.1]heptan-7—yl)—N—(3,5-difluoro(3-(l-methyl-lH-
pyrazolyl)- lH-pyrazolo[3,4—c]pyridin-S-yl)phenyl)acetamide
HNJLD
F F
N. \ /
/ / N
/ /N
Step 1. tert—Butyl 5-(4-amin0-2, u0r0phenyl)(1-methyl-1H—pyrazolyl)—1H-
pyrazolo[3, 4-c]pyridinecarb0xylate
F F
N ‘ /
/ / "l
/ / N
This nd was prepared ing to the procedures described in Example 63
W0 2018/‘049200
(Steps 1—2), using Intermediate 1 instead of Intermediate 2 as starting material. LCMS
calculated for C21H21F2N602 (M+H)+: m/z = 427 .2; Found: 427 .2.
Step 2. tert—Butyl 2—ch10r0acetamid0)-2, 6-dz‘flu0r0phenyZ)(1—methyZ—1H—pyrazol-4—
yZ)-1H—pyrazolo[3, 4-c]pyrz'dmecarb0xylate
JK/CI
F F
N \ /
/ / "l
/ /N
To a solution of tert—butyl 5-(4-amino-2,6-difluorophenyl)(1-methyl-1H-pyrazol
yl)-1H-pyrazolo[3,4-c]pyridine—1-carboxylate (385 mg, 0.903 mmol) and 2—chloroacetic acid
(85 mg, 0.903 mmol) in ethylformamide (4 mL) were added MN-
diisopropylethylamine (315 uL, 1.8 mmol) and N,N,N’,N’-tetramethyl-O-(7-azabenzotriazol—
1-yl)uronium hexafluorophosphate (515 mg, 1.35 mmol). After stirring at r.t. for 2h, water
was added and the precipitated product was collected by filtration, dried and was used in the
next step without further purification (427 mg, 94%). LCMS ated for C23H22C1F2N603
: m/z = 5031; found 503.1.
Step 3. 2—(7—Azabicyclo[2.2.1]heptan-7—yU-N-(3,5-dlflu0r0(3-(1-methyl—1H—pyrazolyl)-
1H—pyrazolo[3, 4-c]pyridin-5—yl)phenyl)acez‘amide
7-Azabicyclo[2.2.1]heptane (4.4 mg, 0.045 mmol) was added to a solution of tert-
butyl 5-(4-(2-chloroacetamido)-2,6-difluorophenyl)(1-methyl-1H—pyrazolyl)—1H-
indazole—l—carboxylate (15 mg, 0.030 mmol) and DIPEA (0.01 mL, 0.06 mmol) in DMF (1
mL). After ng at 80 °C overnight, the reaction mixture was diluted with acetonitrile and
was purified with prep-LCMS (XBn'dge C18 column, eluting with a gradient of
acetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min). LCMS calculated for
C24H24F2N7O : m/z = 464.2; Found: 464.3. 1H NMR (500 MHz, DMSO-de) 8 11.12
(s, 1H), 9.14 (s, 1H), 8.48 (s, 1H), 8.22 (s, 1H), 8.12 — 800 (m, 1H), 7.48 (d, J = 9.3 Hz, 2H),
4.26 (s, 2H), 4.15 (d, J = 4.9 Hz, 2H), 3.93 (s, 3H), 2.05 (d, J = 7.5 Hz, 4H), 1.76 (dd, J =
19.6, 8.2 Hz, 4H) ppm.
Example 69. N-(3,5-Difluoro—4-(3—(l-methyl-1H-pyrazolyl)-lH-pyrazolo[3,4-
c] pyridin-S—yl)phenyl)—2-(7-oxa—Z-azaspiro[3.5]nonanyl)acetamide
HNJLNUO
This compound was prepared according to the procedures described in Example 68,
using 7-oxa—2—azaspiro[3.5]nonane instead of 7-azabicyclo[2.2. l]heptane as starting material.
LCMS calculated for C25H26F2N702 : m/z = 494.2; Found: 494.34
Example 70. N—(3,5-Difluoro—4-(3-(1-methyl-1H-pyrazolyl)-1H-pyrazolo[3,4-
c]pyridin-S-yl)phenyl)—2-(pyrrolidin-l-yl)pr0panamide
F F
ND /
/ /"l
/ /N
Step 1. utyl 5-(4-(2—ch10r0pr0panamid0)-2, 6—dl'flu0r0phenyU(1-methyl—1H—pyrazol-
4-yU-1H-pyrazolo[3, 4-c]pyridmecarb0xylate
HNjiT/m
“1 \ ’
// / N
/ / N
To a solution of utyl 5-(4-arnino-2,6-difluorophenyl)(l-methyl-lH—pyrazol
W0 2018f049200
yl)-1H—pyrazolo[3,4-c]pyridinecarboxylate (385 mg, 0.903 mmol, Example 68, Step 1)
and 2-chloropropanoic acid (98 mg, 0.903 mmol) in ethylformamide (4 mL) were
added NN-diisopropylethylamine (315 uL, 1.8 mmol) and NN,N’,N’-tetramethyl-O-(7-
azabenzotriazol-l-yl)uronium hexafluorophosphate (515 mg, 1.35 mmol). After stirring at r.t.
for 2h, water was added and the precipitated product was collected by filtration, dried and
was used in the next step without further purification (427 mg, 88%). LCMS calculated for
C24H24ClF2N603 (M+H)+: m/z = 517.2, found 517.2.
Step 3. N-(3,5—Diflu0r0-4—(3-(1-mez‘hyl-1H—pyrazolyl)-1H—pyra2010[3, ridin
yUphenyD-Z—(pyrrolz‘dm-I-yl)pr0panamide
Pyrrolidine (4 mg, 0.06 mmol) was added to a solution of tert—butyl 5—(4-(2-
chloropropanamido)—2,6-difluorophenyl)(1-methyl-1H-pyrazolyl)-1H-pyrazolo[3,4-
c]pyridine-l-carboxylate (15 mg, 0.029 mmol) and DIPEA (0.01 mL, 0.06 mmol) in DMF (1
mL). After stirring at 80 °C overnight, the on mixture was diluted with acetonitrile and
was purified with CMS (XBridge C18 column, eluting with a gradient of
acetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min). LCMS calculated for
C23H24F2N7O (M+H)+: m/z = 4522; Found: 452.3.
Example 71. l-(3,5-Difluor0-4—(3—(1-methyl-1H-pyrazolyl)—1H—pyraz0l0[3,4—
c]pyridin-S—yl)phenyl)(2-methoxyethyl)urea
Bis(trichloromethyl) carbonate (14.62 mg, 0.049 mmol) was added to a solution of
3,5-difluoro(3-(1 -methyl-1H-pyrazolyl)-1 -((2-(trimethylsilyl)ethoxy)methyl)-1H-
pyrazolo[3,4-c]pyridinyl)aniline (15 mg, 0.033 mmol, Example 63, Step 2) and
triethylamine (0018 mL, 0.131 mmol) in ydrofuran (1.5 mL). After ng at r.t. for 1
h, 2-methoxyethanamine (5 mg, 0.06 mmol) was added and the resulting mixture was
stirred for an additional 1 h. The reaction mixture was quenched with water and was ted
with ethyl acetate. The separated organic phases were washed with brine, dried over sodium
sulfate and solvents evaporated in vacuo. Then 1M solution of HCl in water (1 mL) and 4M
solution of HCl in dioxane (1 mL) were added to the crude residue, and the resulting mixture
was stirred at 80 °C for 1 h. Methanol (1 mL) was then added and reaction was r stirred
at 80 °C for 30 min. The reaction mixture was then diluted with acetonitrile and was purified
with prep-LCMS (XBridge C18 , eluting with a gradient of acetonitrile/water
containing 0.1% TFA, at flow rate of 60 mL/min). LCMS calculated for C20H20F2N702
(M+H)+: m/z = 4282; Found: 428.1.
Example 72. 2—(Azetidinyl)-N-(3-(difluoromethoxy)—5—fluor0(3-(l-methyl-1H-
lyl)—1H-pyrazolo[3,4—c]pyridin-S-yl)phenyl)acetamide
HNjL/N/j
F OCHF2
“l \ /
/ / "i
/ /N
Step 1. 1-(Dz’flu0r0methoxy)flu0r0-5—m‘tr0benzene
FOOCHFZ
To a e of sodium chlorodifluoroacetate (5.82 g, 38.2 mmol) and ium
carbonate (2.64 g, 19.10 mmol) in DMF (17 ml) and water (2 ml) was added 3-fluoro
nitrophenol (1.5 g, 9.55 mmol), and the mixture was stirred at 100 °C for 6 h (caution! a lot
of C02 is produced). After cooling down, the mixture was quenched with water and extracted
with EtOAc. The separated organic layer was then washed with water, brine and dried over
sodium sulfate, filtered and concentrated. The crude material was purified by Biotage
IsoleraTM (1.3 g, 66%).
Step 2. 3-(Diflu0r0meth0xy)flu0r0anilme
N H 2
FQOCHF2
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A mixture of 1-(difluoromethoxy)fluoronitrobenzene (1.3 g, 6.28 mmol), iron
(2.454 g, 43.9 mmol) and ammonium chloride (2.02 g, 37.7 mmol) in tetrahydrofuran (5 ml),
water (7‘ ml) and methanol (5 ml) was refluxed for 3h. After cooling to r.t., the solids were
filtered off and the solvents were evaporated in vacuo. The crude product concentrate was
d by Biotage IsoleraTM (1.27 g, 99%). LCMS calculated for C7H7F3NO (M+H)+: m/z =
178.1; Found: 178.1.
Step 3. 4-Br0m0(diflu0r0methoxy)-5—flu0r0anilme
N H 2
F OCHF2
NBS (1.3 g, 7.3 mmol) was added to a solution of 3-(difluoromethoxy)—5-
fluoroaniline (1.27 g, 7.17 mmol) in DMF (15 mL) at 0°C. After stirring at r.t. for 1 h, water
was added and the reaction mixture was ted with EtOAc. The separate organic layer
was washed with brine and purified by Biotage IsoleraTM (0.91 g, 50%). LCMS calculated for
C7H6BrF3NO (M+H)+: m/z = 2560; Found: 256.0.
Step 4. 3—(Diflu0r0methoxy)flu0r0(4, 4, 5, 5-z‘ez‘ramez‘hyZ-1, 3, 2-dz'0xab0r0Zan—2—y0anilz’ne
To a mixture of 5,4',4',5',5'-octamethyl-[2,2']bi[[l,3,2]dioxaborolanyl] (1.35 g,
.33 mmol), potassium acetate (1.05 g, 10.6 mmol) and [1,1'-
bis(diphenylphosphino)ferrocene]dichloropalladium(II) complexed with dichloromethane
(1:1) (029 g, 0.36 mmol) under nitrogen was added a solution of 4-bromo
(difluoromethoxy)fluoroaniline (0.909 g, 3.55 mmol) in 1,4-dioxane (20 mL). The
mixture was d at 100 °C overnight. After cooling to room ature, the mixture was
d with DCM and filtered h Celite. The filtrate was concentrated in vacuo. The
residue was purified by Biotage IsoleraTM (540 mg, 50%). LCMS calculated for
C13H18BF3NO3 (M+H) + m/z = 304.1; found 304.2.
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Step 5. tart-Bury! 5-(4-amz'n0-2—(difluoromethoxy)flu0r0phenyZ)(I-met}2yl—1H—pyrazol
yZ) —1H—pyrazolo[3, ridine—]—carb0xylate
F OCHF2
Ni \ /
/ / N
/ / N
tert—Butyl 5-chloro(1-methyl-1H-pyrazolyl)—1H-pyrazolo[3,4-c]pyridine
carboxylate (330 mg, 0.989 mmol, Intermediate 1), 3-(difluoromethoxy)fluoro(4,4,5,5-
tetramethyl—l,3,2-dioxaborolanyl)aniline (360 mg, 1.186 mmol), chloro(2-
dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'—
biphenyl)]palladium(II) (Pd XPhos G2) (75 mg, 0.096 mmol) and potassium phosphate (406
mg, 1.91 mmol) were placed in a flask and the flask was evacuated and backfilled with
nitrogen three times. Then e (20 mL) and degassed water (2 mL) were added, and the
reaction mixture was stirred at 90 °C for 2h. After cooling to r.t., the reaction mixture was
diluted with ethyl acetate, and the resulting mixture was washed with brine. The separated
organic phase was dried over sodium sulfate. The solvents were evaporated in vacuo and the
ed crude product was purified by Biotage IsoleraTM (291 mg, 62%). LCMS calculated
for C22H22F3N603 (M+H) + m/z = 475.2, found 475.2.
Step 6. tert—Butyl 5-(4-(2-ch10r0acez‘amid0)(dl'flu0r0methoxy)-6—flu0r0phenyl)—3-(1-
methyl-1H-pyrazolyD-1H—pyrazolo[3, 4-c]pyridinecarb0xylate
F OCHFZ
“1 \ /
/ / "l
/ /N
To a on of tert-butyl 5-(4-amino(difluoromethoxy)fluorophenyl)(1-
methyl-1H-pyrazolyl)-1H-pyrazolo[3,4-c]pyridinecarboxylate (188 mg, 0.396 mmol)
and 2-chloroacetic acid (37 mg, 0.39 mmol) in NN-dimethylformamide (3 mL) were added
W0 2018f049200
NN-diisopropylethylamine (138 uL, 0.79 mmol) and N,N,N’,N’-tetramethyl-O-(7-
zotriazol-l-y1)uronium hexafluorophosphate (226 mg, 0.59 mmol). After stirring at r.t.
for 2h, water was added and the itated product was collected by filtration, dried and
was used in the next step without further purification (209 mg, 96%). LCMS calculated for
C24H23ClF3N604 (M+H)+: m/z = 551.1; found 551.2.
Step 7. 2-(Azetidinyl)-N-(3-(diflu0r0meth0xy)flu0r0(3-(1-mez‘hyZ-1H—pyrazolyl)-
1H—pyrazolo[3, 4-c]pyridin-5—yl)phenyl)acetamide
Azetidine (3 mg, 0.05 mmol) was added to a solution of tert—butyl 5-(4-(2—
chloroacetamido)(difluoromethoxy)fluorophenyl)(1-methyl-lH-pyrazolyl)-1H-
pyrazolo[3,4—c]pyridine-l-carboxylate (15 mg, 0.027 mmol) and DIPEA (0.01 mL, 0.06
mmol) in DMF (1 mL). After stirring at 80 °C overnight, the reaction mixture was diluted
with acetonitrile and was purified with prep-LCMS (XBridge C18 , eluting with a
gradient of acetonitrile/water ning 0.1% TFA, at flow rate of 60 mL/min). LCMS
calculated for F3N702 (M+H)+: m/z = 4722, Found: 472.2.
Example 73. N-(3-Chlorofluoro(3-(1-methyl-1H-pyrazolyl)- lH-pyrazolo[3,4-
c] pyridin-S-yl)phenyl)—2-(pyrrolidin- 1-yl)acetamide
HNJLD
F CI
“1\ /
/ /"l
/ /N
Step 1. tert—Butyl 5-(2-ch10r0(2-ch10r0acetamido)-6—flu0r0phenyl)(1-methyl-1H-
pyrazolyl)-1H—pyrazolo[3, 4-c]pyridmecarb0xylate
F CI
“1 \ /
/ / N
/ /N
This compound was prepared according to the procedures described in Example 72
(Steps 3-6), using 3—chloro—5—fluoroaniline instead of 3-(difluoromethoxy)—5-fluoroani1ine as
starting material. LCMS calculated for C23H22C12FN603 (M+H)+: m/z = 519.1; Found: 519.1.
Step 2. N—(3—Chl0r0-5—flu0r0(3-(1-methyl-IH-pyrazolyl)-1H-pyrazofo[3,4—cjpyrz'dz'n
yUphenyQ—Z—(pyrrolz’din-I-yl)acetamide
Pyrrolidine (4 mg, 0.06 mmol) was added to a solution of tert—butyl hloro(2-
chloroacetamido)—6-fluorophenyl)(1-methyl-1H-pyrazolyl)—1H-pyrazolo[3,4—
c]pyridinecarboxylate (15 mg, 0.029 mmol) and DIPEA (0.01 mL, 0.06 mmol) in DMF (1
mL). After stirring at 80 °C overnight, the reaction mixture was diluted with acetonitrile and
was purified with prep-LCMS (XBridge C18 column, g with a gradient of
itrile/water containing 0.1% TFA, at flow rate of 60 mL/min). LCMS calculated for
C22H22C1FN7O (M+H)+: m/z = 454.2, Found: 454.2.
e 74. N-(3-Fluoro—S-methoxy(3—(1-methyl-1H-pyrazolyl)-lH-pyrazolo[3,4-
c]pyridin-S—yl)phenyl)—2-(pyrrolidin- l-yl)acetamide
HNJLD
F OMe
“l\ /
/ / "l
/ /N
Step 1. tert—Butyl 5-(4-(2—ch10r0acez‘amid0)flu0r0meth0xyphenyU(1-methyl-1H—
pyrazolyl)—1H—pyrazolo[3, 4-c]pyridmecarb0xylate
F OMe
“l \ /
/ / "l
/ /N
B00
This nd was prepared according to the procedures described in Example 72
(Steps 3-6), using 3-fluoromethoxyaniline instead of 3-(difluoromethoxy)fluoroaniline
as ng material. LCMS calculated for C24H25ClFNeO4 (M+H)+: m/z = 5152; Found:
515.2.
Step 2. N—(3—FZu0r0-5—methoxy-4—(3-(1-methyl—JH-pyrazoZyl)-1H—pyrazofo[3,4—cjpyrz'dz'n-
-yl)phenyi)—2—(pyrrolidin-I-yUacetamide
Pyrrolidine (4 mg, 0.06 mmol) was added to a solution of tert—butyl 5-(4—(2—
chloroacetamido)fluoromethoxyphenyl)—3-(1 -methyl-1H-pyrazolyl)- 1H-
pyrazolo[3,4—c]pyridinecarboxylate (15 mg, 0.029 mmol) and DIPEA (0.01 mL, 0.06
mmol) in DMF (1 mL). After stirring at 80 °C overnight, the reaction mixture was diluted
with itrile and was purified with prep-LCMS (XBridge C18 column, eluting with a
gradient of acetonitrile/water ning 0.1% TFA, at flow rate of 60 mL/min). LCMS
calculated for C23H25FN702 (M+H)+: m/z = 450.2, Found: 450.3.
e 75. 2-(3,3-Dimethylazetidinyl)-N-(3-fluoro-S-methoxy(3-(l-methyl-lH-
pyrazolyl)-1H-pyrazolo [3,4—c]pyridin-S-yl)phenyl)acetamide
F OMe
“l\ /
/ /'\l
/ /N
This compound was prepared according to the procedures described in Example 74,
using 3,3-dimethylazetidine instead of pyrrolidine as starting material. LCMS ated for
C24H27FN702 (M+H)+: m/z = 464.2, Found: 464.3.
Example 76. l-Methylpiperidinyl 3—flu0r0-5—meth0xy-4—(3—(1-methyl-1H-pyrazol
yl)-1H-pyrazolo[3,4-c] pyridin-S-yl)phenylcarbamate
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F OMe
ND /
/ / "l
/ /N
Step ]. tert—Butyl 5-(4-amin0flu0r0meth0xyphenyl)(1-methyl-1H—pyrazol—4-yl)-1H—
pyrazolo[3, 4—c]pyridinecarb0xylate
/ /'\l
This compound was ed according to the procedures described in Example 72
(Steps 3-5), using 3-fluoromethoxyaniline instead of 3-(difluoromethoxy)fluoroaniline
as ng material. LCMS calculated for FN603 (M+H)+: m/z = 439.2; Found: 439.2.
Step 2. I—Methylpiperidinyl 3-flu0r0-5—meth0xy(3-(I-methyZ-IH-pyrazol—4—yl)-1H-
pyra2010[3, 4—c]pyridl'n-5—yUphenylcarbamate
Bis(trichloromethyl) ate (15.23 mg, 0.051 mmol) was added to a solution of
tert—butyl 5-(4—aminofluoromethoxyphenyl)(1-methyl-1H-pyrazolyl)— 1H-
pyrazolo[3,4—c]pyridinecarboxylate (15 mg, 0.034 mmol) and triethylamine (0.019 mL,
0.137 mmol) in ydrofuran (1.0 mL). After stirring at r.t. for 30min, 1-methylpiperidin-
4-01 (3.94 mg, 0.034 mmol) was added and the reaction e was stirred for 1 h more.
After quenching with methanol, the solvents were evaporated and TFA (1 mL) added. After
stirring at r.t. for 30min, the reaction mixture was diluted with acetonitrile and was purified
with prep-LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water
containing 0.1% TFA, at flow rate of 60 mL/min). LCMS calculated for C24H27FN7O3
(M+H)+: m/z = 4802; Found: 480.1.
Example 77. 2-(Azetidinyl)-N-(2,3,5-triflu0r0-4—(3—(1-methyl-1H-pyrazol—4-yl)—1H-
pyrazolo[3,4-c]pyridin-S-yl)phenyl)acetamide
F F
ND /
/ /'\‘
/ /N
Step 1. utyl 5-(4-(2—ch10r0acetamid0)-2, 3, flu0r0phenyl)(1-methyl—1H—pyrazol
yU-IH—pyrazolo[3, 4-c]pyridmecarb0xylate
F F
“l \ /
/ / N
/ /N
Boc/
This nd was prepared according to the procedures described in e 72
(Steps 3-6), using 2,3,5-trifluoroaniline d of 3-(difluoromethoxy)—5—fluoroaniline as
starting material. LCMS calculated for C23H21C1F3N603 (M+H)+: m/z = 5212; Found: 5212.
Step 2. 2-(AzetidinyU-N-(2, 3, 5-2‘rz‘flu0r0(3-(1-mez‘hyl-1H—pyrazolyl)-1H—
pyra2010[3, 4—c]pyridinyl)phenyl)acetamide
Azetidine (2.2 mg, 0.04 mmol) was added to a solution of tert—butyl 5-(4—(2-
chloroacetamido)-2,3,6-trifluorophenyl)(1-methyl-1H-pyrazolyl)—1H—pyrazolo[3,4-
c]pyridine—1—carboxylate (10 mg, 0.019 mmol) and DIPEA (0.01 mL, 0.06 mmol) in DMF (1
mL). After stirring at 80 °C overnight, the reaction mixture was diluted with acetonitrile and
was purified with prep-LCMS (XBridge C18 column, eluting with a gradient of
acetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min) LCMS calculated for
C21H19F3N7O (M+H)+: m/z = 442.2; Found: 442.1.
Example 78. N-(3-Chloro-S-methyl(3-(1-methyl-1H-pyrazolyl)- lH-pyrazolo[3,4-
c] pyridin-S—yl)phenyl)—2-(dimethylamino)acetamide
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O |
Ni \ /
/ / “l
/ /N
Step 1. tert—Butyl 5-(2-ch10r0(2-ch10r0acetamido)-6—methylphenyl)(1-methyl—1H—
Zyl)—1H—pyrazolo[3, 4-c]pyridmecarb0xylate
HNJL/CI
“1 \ /
/ / "l
/ /N
This compound was prepared according to the procedures described in Example 72
(Steps 3-6), using 3-chloromethylaniline instead of 3-(difluoromethoxy)fluoroaniline as
starting material. LCMS calculated for C24H25C12N603 : m/z = 515.1; Found: 515.2.
Step 2. N-(3—Chl0r0methyl(3-(1-methyl—1H—pyrazolyl)-1H—pyrazo§0[3,4—cjpyrl'dl'n
yUphenyD-Z—(dimethylamin0)acetamide
Dimethylamine HCl salt (2 mg, 0.04 mmol) was added to a solution of tert—butyl 5-(2-
chloro-4—(2-chloroacetamido)—6-methylphenyl)(1-methyl-1H-pyrazol-4—yl)—1H—
pyrazolo[3,4—c]pyridinecarboxylate (10 mg, 0.019 mmol) and DIPEA (0.01 mL, 0.06
mmol) in DMF (1 mL). After stirring at 80 °C overnight, the reaction mixture was diluted
with acetonitrile and was d with prep-LCMS ge C18 column, eluting with a
gradient of acetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min). LCMS
calculated for C21H23ClN7O (M+H)+: m/z = 4242, Found: 424.2.
Example 79. 2-((1R,4S)Azabicyclo[2.2.1]heptan-Z-yl)-N-(3-methyl(3—(1-methyl-1H-
pyrazolyl)-lH-pyrazolo[3,4—c]pyridin-S-yl)phenyl)acetamide
W0 49200 2017/050737
“l\ /
/ /'\‘
/ /N
Step 1. tert—Butyl 5-(4-(2—ch10r0acetamtd0)-2—methylphenyl)(1-methyl-1H-pyrazolyl)—
1H—pyrazolo[3,4-c]pyrtdtnecarboxylate
“1 \ /
/ / "l
/ /N
This compound was prepared according to the procedures described in Example 72
(Steps 4-6), using 4-bromomethylaniline instead of 4-bromo(difluoromethoxy)
fluoroaniline as starting material. LCMS calculated for C24H26C1N603 (M+H)+: m/z = 4812;
Found: 4812.
Step 2. (1R, 459—2-Azabtcyclo[2. 2. Ijheptan0ne
Pd/C (0.583 g, 5wt%) was added to a solution of (1S,4R)azabicyclo[2.2. 1]hept
enone (2.39 g, 21.90 mmol) in MeOH (15.0 mL). After stirring under hydrogen for 2h at
r.t., the catalyst was filtered-off and the solvent was evaporated in vacuo. Obtained crude
product was used in the next step without further ation. LCMS calculated for CeroNO
: m/z = 112.1; Found: 112.1.
Step 3. (1R,4S)-2—azabicyclo[2.2.1]heptane, HCZ salt
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LAH (25.4 mL, 25.4 mmol) solution (1.0M in THF) was added to a solution of
(lR,4S)—2—azabicyclo[2.2.1]heptanone (2.35 g, 21.14 mmol) in THF (15.0 mL). Reaction
was refluxed for 3h. Then reaction was carefully quenched with water and NaOH solution.
Solids were filtered off, and 4M HCl on in dioxane was added to the obtained solution.
After t evaporation in vacuo, obtained crude HCl salt of the desired product was used
in the next step without further purification. LCMS calculated for C6H12N (M+H)+: m/z =
981, Found: 98.1.
Step 4. 2-((1R,4S)Azabicyc10[2.2.Ijhepz‘an-Z-yl)-N-(3-methyl(3-(1-methyl—IH-pyrazol-
H-pyrazolo[3, 4-c]pyridmyl)phenyl)acetamide
(1R,4S)—2—Azabicyclo[2.2.1]heptane (4 mg, 0.04 mmol) was added to a solution of
tert—butyl 5-(4-(2-chloroacetamido)methylphenyl)(1 -methyl-1H—pyrazolyl)-1H-
pyrazolo[3,4—c]pyridinecarboxylate (10 mg, 0.021 mmol) and DIPEA (0.01 mL, 006
mmol) in DMF (1 mL). After stirring at 80 °C overnight, the reaction mixture was d
with acetonitrile and was d with prep-LCMS (XBridge C18 column, eluting with a
gradient of acetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min). LCMS
calculated for C25H28N7O (M+H)+: m/z = 4422, Found: 442.2. 1H NMR (500 MHz, DMSO-
d6) 5 10.69 — 10.58 (m, 1H), 9.55 (s, 1H), 9.22 (s, 1H), 8.53 (s, 1H), 8.18 (s, 1H), 8.09 (s,
1H), 7.63 — 7.53 (m, 2H), 7.54 — 7.45 (m, 1H), 4.36 — 4.04 (m, 3H), 3.93 (s, 3H), 3.63 — 2.58
(m, 3H), 2.35 (s, 3H), 2.09 — 1.36 (m, 6H) ppm.
Example 80. N—(3-Fluoro-S-methyl(3-(l-methyl-1H-pyrazolyl)—1H-pyrazolo[3,4-
c] pyridin-S—yl)phenyl)—2-(pyrrolidinyl)acetamide
HNjDJ\/'\/‘3
“l\ /
/ /'\‘
/ /N
HN\N
Step 1. tert—Butyz’ 5-(4-(2—ch10r0acetamz'd0)-2—flu0r0-6—methylphenyl)—3—(1—methyZ—1H-
pyrazolyf)-1H-pyra2010[3, 4-c]pyridinecarb0xylate
“l \ /
/ / [‘1‘
/ /N
This compound was prepared ing to the procedures described in Example 72
(Steps 3-6), using 3-fluoromethylaniline instead of 3-(difluoromethoxy)—5-fluoroaniline as
starting material. LCMS calculated for C1FN603 (M+H)+: m/z = 499.2; Found: 499.2.
Step 2. N-(3-Flu0r0methyl(3-(1-methyl-1H—pyrazol—4-yl)-1H—pyrazolo[3,4—cjpyrl'din
yl)phenyU09yrrolidinyl)acetamide
Pyrrolidine (5 111, 0.06 mmol) was added to a solution of tert—butyl 5-(4-(2-
chloroacetamido)fluoro—6-methylphenyl)—3-(1-methyl-1H—pyrazolyl)—1H—pyrazolo[3,4-
dinecarboxylate (15 mg, 0.03 mmol) and DIPEA (0.01 mL, 006 mmol) in DMF (1
mL). After stirring at 80 °C overnight, the reaction mixture was diluted with acetonitrile and
was purified with prep-LCMS (XBn'dge C18 column, eluting with a gradient of
acetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min). LCMS calculated for
C23H25FN7O (M+H)+: m/z = 434.2; Found: 434.2. 1H NMR (600 MHZ, DMSO-dé) 5 10.78 (s,
1H), 9.15 (s, 1H), 8.49 (s, 1H), 8.08 (s, 1H), 8.07 — 8.01 (m, 1H), 7.54 (dd, J =11.4, 1.6 Hz,
1H), 7.27 (s, 1H), 4.30 (d, J = 3.8 Hz, 2H), 3.92 (s, 3H), 3.66 (br, 2H), 3.17 (br, 2H), 2.17 (s,
3H), 2.04 (br, 2H), 1.94 (br, 2H) ppm.
Example 81. ethylamino)-N-(3-fluoro-S-methyl(3—(l-methyl-1H-pyrazolyl)—
1H-pyrazolo[3,4—c]pyridin-S-yl)phenyl)acetamide
“l\ /
/ / N
/ /N
This compound was prepared according to the procedures described in Example 80,
using ylamine instead of pyrrolidine as starting material. LCMS calculated for
FN7O (M+H)+: m/z = 4082; Found: 408.2. 1H NMR (500 MHz, s) 8 10.84 (s,
1H), 9.20 (s, 1H), 8.51 (s, 1H), 8.14 (s, 1H), 8.06 (s, 1H), 7.61 — 7.49 (m, 1H), 7.28 (s, 1H),
4.20 (s, 2H), 3.92 (s, 3H), 2.92 (s, 6H), 2.18 (s, 3H) ppm.
Example 82. 2—(7—Azabicyclo[2.2.1]heptan-7—yl)—N—(3-fluoro—5-methyl-4—(3—(l-methyl-
1H-pyrazol-4—yl)—1H-pyrazolo[3,4-c] pyridin-S-yl)phenyl)acetamide
HNJ(JD\\/r\€i’>\>
N. \ /
/ / "l
/ / N
This compound was prepared according to the procedures described in Example 80,
using 7-azabicyclo[2.2. 1]heptane instead of pyrrolidine as starting material. LCMS calculated
for C25H27FN7O (M+H)+: m/z = 4602; Found: 460.2. 1H NMR (500 MHz, DMSO-ds) 5
.90 (s, 1H), 9.23 (s, 1H), 8.52 (s, 1H), 8.18 (s, 1H), 8.07 (s, 1H), 7.57 (d, J : 11.3 Hz, 1H),
7.31 (s, 1H), 4.25 (s, 2H), 4.13 (d, J = 4.3 Hz, 2H), 3.92 (s, 3H), 2.18 (s, 3H), 2.05 (s, 4H),
1.76 (dd, J = 20.9, 8.2 Hz, 4H) ppm.
Example 83. 2—((1R,4S)Azabicyclo[2.2.1]heptanyl)-N-(3-fluoro-S-methyl—4-(3—(1-
methyl-1H-pyrazol-4—yl)—1H-pyrazolo [3,4—c]pyridin-S-yl)phenyl)acetamide
HNi/N<\'l>'.
“l \ /
/ / "l
/ / N
This compound was prepared ing to the procedures described in Example 80,
using 7—(1R,4S)—2—azabicyclo[2.2,1]heptane le 79, Step 3) instead of pyrrolidine as
starting material. LCMS calculated for C25H27FN7O (M+H)+: m/z = 460.2; Found: 460.2. 1H
W0 2018f049200
NMR (500 MHz, DMSO-ds) 5 10.84 — 10.71 (m, 1H), 9.15 (s, 1H), 8.49 (s, 1H), 8.09 (s, 1H),
8.05 (s, 1H), 7.53 (d, J =11.5 Hz, 1H), 7.28 (s, 1H), 4.40 — 4.04 (m, 3H), 3.92 (s, 3H), 3.65 —
2.84 (m, 2H), 2.70 — 2.59 (m, 1H), 2.17 (s, 3H), 2.06 — 1.37 (m, 6H) ppm.
Example 84. 3-(Dimethylamino)-N-(3-fluoro—S-methyl(3—(1-methyl-lH-pyrazolyl)-
1H-pyraz0l0[3,4—c]pyridin-S-yl)phenyl)propanamide
HNMT/
N|\ /
/ /"l
/ /N
Step 1. tert—Butyl 5-(4-am1'n0flu0r0methylphenyl)(1-methyl-1H-pyrazol—4—y0-1H—
pyra2010[3, 4—c]pyridinecarb0xylate
"1\ /
/ / "1‘
/ /N
Boc/
This compound was prepared according to the procedures described in Example 72
(Steps 3-5), using 3-fluoromethylaniline instead of 3-(difluoromethoxy)—5-fluoroaniline as
starting material. LCMS calculated for C22H24FN602 (M+H)+: m/z = 4232; Found: 423.2.
Step 2. 3-(Dimethylamin0)-N-(3-fluor0methyl(3-(1-methyl-1H-pyrazol—4—yl)-1H—
pyrazolo[3, 4—c]pyridinyl)phenyl)pr0panamide
To a on of tert—butyl 5-(4-aminofluoromethylphenyl)(1-methyl- 1H-
pyrazolyl)-lH-pyrazolo[3,4-c]pyridine—1-carboxylate (10 mg, 0.024 mmol) and 3-
(dimethylamino)propanoic acid (2.77 mg, 0.024 mmol) in MN—dimethylformamide (1.5 mL)
were added NN-diisopropylethylamine (13 11L, 0.07 mmol) and N,N,N’, amethy1-O-(7-
zotriazol-l-y1)uronium hexafluorophosphate (15 mg, 0.04 mmol). After the reaction
e was stirred at H. for 2 hours, it was quenched with water. The resulting mixture was
extracted with ethyl acetate. The separated organic phases were washed with brine, dried over
sodium sulfate and solvents evaporated in vacuo. Then TFA (1 mL) was added and the
mixture was stirred at r.t. for 30min. The reaction mixture was then diluted with itnle
and was purified with prep-LCMS (XBridge C18 column, eluting with a gradient of
acetonitrile/water containing 0.1% TFA, at flow rate of 60 ). LCMS calculated for
C22H25FN7O (M+H)+: m/z = 4222; Found: 422.3.
Example 85. 2-Cyano-N—(3-fluoromethyl(3-(1-methyl-1H-pyrazol-4—yl)—1H-
lo[3,4-c]pyridin-S-yl)phenyl)acetamide
HNJK/CN
ND /
/ /'\l
/ /N
HN\N
This compound was prepared according to the procedures bed in Example 84,
using 2-cyanoacetic acid instead of 3-(dimethylamino)propanoic acid as starting material.
LCMS calculated for C20H17FN7O (M+H)+: m/z = 390.2; Found: 390.3.
Example 86. N—Methyl(2-methyl(3-(1-methyl-1H-pyrazolyl)—lH-pyrazolo[3,4-
c] pyridin-S-yl)phenyl)methanamine
Step 1. (2-Metl/zyZ(4, 4, 5, 5-tetramethyl-1, 3, 2-dl'0xaborolan-Z-yUpl/zenyl)methanol
M
W0 2018f049200
To a mixture of 4,4,5,5,4',4',5',5'-octamethyl-[2,2']bi[[1,3,2]dioxaborolanyl] (2.05 g,
8.1 mmol), potassium acetate (1.05 g, 10.7 mmol) and [1,1'-
bis(diphenylphosphino)ferrocene]dichloropalladium(II) complexed with dichloromethane
(1: 1) (0.44 g, 0.54 mmol) under nitrogen was added a solution of (3-bromo-2—
methylphenyl)methanol (1.08 g, 5.37 mmol) in 1,4-dioxane (20 mL). The mixture was stirred
at 100 °C overnight. After cooling to room temperature, the mixture was diluted with DCM
and filtered through Celite. The filtrate was concentrated in vacuo. The residue was purified
by Biotage IsoleraTM (446 mg, 36%). LCMS calculated for C14H20B02 20) + m/z =
2312, found 231.2.
Step 2. tert—Butyl 5-(3-(hydr0xymethyl)methylphenyl)(1-methyl-1H-pyrazolyl)-1H—
pyrazolo[3, 4—c]pyridinecarb0xylate
“1 \ /
/ / "l
/ /N
tert-Butyl 5-chloro(1-methyl-1H-pyrazolyl)-lH-pyrazolo[3,4-c]py1idine
carboxylate (500 mg, 1.498 mmol, Intermediate 1), (2-methyl(4,4,5,5-tetramethyl-1,3,2-
dioxaborolanyl)phenyl)methanol (446 mg, 1.798 mrnol), chloro(2-dicyclohexylphosphino-
2',4',6'-triisopropyl—1,1'-biphenyl)[2-(2'—amino-1,1'-biphenyl)]palladium(II) (Pd XPhos G2)
(118 mg, 0.15 mmol) and potassium phosphate (636 mg, 3 mmol) were placed in a flask and
the flask was evacuated and backfilled with nitrogen three times. Then dioxane (15 mL) and
degassed water (1.5 mL) were added. The mixture was stirred at 90 °C for 2h. After cooling
to r.t., the on mixture was diluted with ethyl acetate, and the resulting e was
washed with brine. The separated c phase was dried over sodium e. The solvents
were evaporated in vacuo and the obtained crude product was purified by Biotage IsoleraTM
(190 mg, 30%). LCMS calculated for N503 (M+H) + m/z = 4202, found 420.3.
Step 3. tert—Butyl 5-(3-f0rmyl-2—methylphenyl)(1-methyl-1H—pyrazoZy0-1H-
pyra2010[3, 4-cjpyrz’dme-J-carb0xylate
Dess—Martin periodinane (231 mg, 0.544 mmol) was added to a solution of tert—butyl
-(3-(hydroxymethyl)methylphenyl)(1-methyl-1H-pyrazolyl)-1H-pyrazolo[3,4-
c]pyridinecarboxylate (190 mg, 0.453 mmol) and pyridine (44.0 ul, 0.544 mmol) in DCM
(5 ml). After stirring at r.t. for 1 h, solvent was evaporated in vacuo and the obtained crude
product was purified by e aTM (170 mg, 90%). LCMS calculated for C23H24N503
(M+H) + m/z = 4182; found 418.2.
Step 4. N-MethyZ-J-(2-methyl(3-(1-methyl-1H—pyrazolyl)-1H—pyra2020[3, 4-cjpyridl'n
yUphenmeet/aanamme
Sodium triacetoxyborohydride (10.15 mg, 0.048 mmol) was added to a solution of
methanamine (2M in THF, 12 ul, 0.024 mmol), acetic acid (274 ul, 0.048 mmol) and tert-
butyl 5-(3-formyl-2—methylphenyl)(1-methyl-JH-pyrazol—4—yl)-1H-pyrazolo[3,4-
c]pyridine—1-carboxylate (10 mg, 0.024 mmol) in DCE (1 ml). After the reaction mixture was
d at r.t. for 2 hours, it was quenched with water. The mixture was extracted with ethyl
e. The separated organic phases washed with brine, dried over sodium sulfate and
solvents evaporated in vacuo. Then TFA (1 mL) was added and the reaction was stirred at r.t.
for 30min. The reaction mixture was then diluted with acetonitrile and was purified with
prep-LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing
0.1% TFA, at flow rate of 60 mL/min). LCMS calculated for C19H21N6 (M+H)? m/z = 3332,
Found: 333.2.
Example 87. N-Methyl(4-methyl(3-(l-methyl-1H-pyrazolyl)—lH-pyrazolo[3,4-
c] pyridin-S—yl)phenyl)methanamine
Ni \ /
/ / "l
/ / N
This compound was prepared according to the procedures described in Example 86,
using (3 -bromomethylphenyl)methanol instead of (3-bromomethylphenyl)methanol as
starting material. LCMS calculated for N6 (M+H)+: m/z = 3332; Found: 333.2.
Intermediate 3. (3-Bromo-Z-(trifluoromethyl)phenyl)methanol
To a mixture of 3-bromo(trifluoromethyl)benzoic acid (0.97 g, 3.61 mmol) and
triethylamine (0528 mL, 3.79 mmol) in ydrofuran (20 mL) was added isobutyl
carbonochloridate (0.491 mL, 3.79 mmol). After stirring for 30 min at r.t., the solids were
filtered-off, and a solution of sodium tetrahydroborate (0.273 g, 7.21 mmol) in water (1.300
mL) was slowly added to the filtrate. After stirring at r.t. for 30 min, the on mixture was
diluted with ethyl acetate, and the resulting mixture was washed with brine.The separated
organic phase was dried over sodium sulfate. The solvents were evaporated in vacuo and the
obtained crude product was purified by Biotage IsoleraTM (550 mg, 64%).
e 88. N—Methyl(3-(3-(1-methyl-1H-pyrazolyl)—lH-pyrazolo[3,4-c]pyridin
yl)(trifluoromethyl)phenyl)methanamine
This compound was prepared according to the procedures bed in Example 86,
using (3 -bromo(trifluoromethyl)phenyl)methanol (Intermediate 3) instead of (3-bromo—2—
methylphenyl)methanol as ng material. LCMS calculated for C19H18F3N6 (M+H)+: m/z =
387.2; Found: 387.1.
1H NMR (600 MHz, DMSO-de) 5 9.10 — 9.00 (m, 2H), 8.48 (s, 1H), 8.10 (d, J : 1.2 Hz, 1H),
8.06 (d, J = 0.6 Hz, 1H), 7.86 (t, J = 7.7 Hz, 1H), 7.81 (d, J = 7.7 Hz, 1H), 7.67 (d, J = 7.5 Hz,
1H), 4.41 (s, 2H), 3.92 (s, 3H), 2.75 (t, J = 5.2 Hz, 3H) ppm.
Example 89. 5-(3-(Azetidinylmethyl)(trifluoromethyl)phenyl)—3-(l-methyl-1H-
pyrazol-4—yl)—lH—pyrazolo [3,4—c]pyridine
This compound was prepared according to the procedures described in Example 86
and 88, using azetidine instead of methanamine as ng material. LCMS ated for
C21H20F3N6 (M+H)+: m/z = 413.2, Found: 413.2.
Example 90. N—(3-(3-(1-Methyl-1H-pyrazol—4-yl)—1H-pyrazolo[3,4-c] pyridin-S-yl)
(trifluoromethyl)benzyl)tetrahydro—2H-pyranamine
NI : N/
/ \
/ / N
This nd was prepared according to the procedures bed in Example 86
and 88, using tetrahydro-ZH—pyranamine instead of methanamine as starting material.
LCMS calculated for C23H24F3N60 (M+H)+: m/z = 457.2, Found: 457.1.
Example 91. N-(3-(3-(1-Methyl-1H-pyrazol—4-yl)—1H-pyrazolo[3,4-c] pyridin-S—yl)—2—
(trifluoromethyl)benzyl)propanamine
This compound was prepared according to the procedures described in Example 86
and 88, using —2—amine instead of methanamine as starting material. LCMS ated
for C21H22F3N6 (M+H)+: m/z = 4152; Found: 415.3. 1H NMR (500 MHz, DMSO-ds) 8 9.06
(d, J = 1.0 Hz, 1H), 8.91 (br, 1H), 8.46 (s, 1H), 8.14 — 8.04 (m, 2H), 7.92 — 7.81 (m, 2H), 7.68
(t, J = 4.4 Hz, 1H), 4.39 (br, 2H), 3.93 (s, 3H), 3.52 (dq, J = 11.9, 5.9 Hz, 1H), 1.35 (d, J = 6.5
Hz, 6H) ppm.
Intermediate 4. (3-Bromofluoromethylphenyl)methanol
LAH solution (5.75 mL, 5.75 mmol, 1.0M in THF) was added to a solution of ethyl 3-
bromofluoromethylbenzoate (Enamine, 1.25 g, 4.79 mmol) in THF (15.0 mL). The
reaction mixture was stirred at r.t. for 2h. Then reaction was carefully quenched with water
and NaOH solution. After solids were filtered off, the solvent of the filtrate was evaporated in
vacuo. ed crude product was used in the next step without further purification. LCMS
calculated for CsH7BrF (M+H—H20)+: m/z = 201.0; Found: 2010.
Example 92. luoro-Z-methyl-S-(3-(l-methyl-lH-pyrazolyl)-1H-pyraz010 [3,4-
c] n-S—yl)phenyl)-N-methylmethanamine
Ni \ /
/ / "l
/ / N
This compound was prepared according to the procedures described in Example 86,
using (3 -bromofluoromethylphenyl)methanol (Intermediate 4) instead of (3-bromo
methylphenyl)methanol as starting material. LCMS calculated for C19H20FN6 (M+H)+: m/z =
3512, Found: 3512.
Example 93. N-(4—Fluoro-2—methyl(3-(l-methyl-1H-pyrazolyl)-lH-pyrazolo[3,4-
c] pyridin-S-yl)benzyl)propan-Z-amine
“l\ /
/ /"l
/ /N
This compound was prepared according to the procedures described in Example 86
and 92, using propanamine instead of methanamine as starting material. LCMS calculated
for C21H24FN6 (M+H)+: m/z = 3792, Found: 379.3.
1H NMR (600 MHz, DMSO-d6) 5 9.16 (s, 1H), 8.67 (br, 1H), 8.48 (s, 1H), 8.04 (s, 2H), 7.58
(dd, J = 8.5, 5.7 Hz, 1H), 7.30 (t, J = 8.7 Hz, 1H), 4.30 — 4.16 (m, 2H), 3.92 (s, 3H), 3.48 (dp,
J = 12.4, 6.3 Hz, 1H), 2.15 (s, 3H), 1.34 (d, J = 6.5 Hz, 6H) ppm.
Example 94. 5—(3-(Azetidinylmethyl)fluoromethylphenyl)—3-(1-methyl-1H-
pyrazolyl)-lH-pyrazolo ]pyridine
ND /
/ /"l
/ /N
This compound was prepared according to the procedures described in Example 86
and 92, using azetidine instead of methanamine as ng material. LCMS calculated for
C21H22FN6 (M+H)+: m/z = 377.2, Found: 377.3.
e 95. 3—(3,5-Diflu0r0-4—(3—(1-methyl-1H-pyrazolyl)—1H-pyrazolo[3,4-
c]pyridin-5—yl)phenyl)—N—isopropylcyclobutanamine
F F
“l \ ’
/ / N
/ /N
Step 1. tart-Bury! 3-(3,5-dz'flu0r0phenyl)cyclobutylcarbamate
NH Boc
F F
Di—tert—butyl dicarbonate (4.77 g, 21.83 mmol) was added to a solution of 3—(3,5-
difluorophenyl)cyclobutanamine (2.5 g, 13.65 mmol) and tnethylamine (4.14 g, 40.9
mmol) in THF (25 ml). After stirring at r.t. for 1 h, solvent was evaporated in vacuo and the
obtained crude product was purified by Biotage IsoleraTM (3.2 g, 90%). LCMS calculated for
C11H12F2N02 (M+H-C4Hs) + m/z = 228.1; found 228.1.
Step 2. tert—Butyl 3-(3, 5-dl'flu0r0(4, 4, 5, 5-z‘ez‘ramethyl-I, 3, 2-dl'0xab0rolan
yUphenyDcyclobuz‘ylcarbamate
NHBoc
To a solution of tert—butyl 3-(3,5-difluorophenyl)cyclobutylcarbamate (3.2 g, 11.29
mmol) in THF (35 mL) at -78 0C was added llithium, 2.5 M in hexane (1355 mL, 33.9
mmol). The reaction mixture was stirred at -78°C for 1 hour before 2-isopropoxy-4,4,5,5-
tetramethyl—l,3,2-dioxaborolane (6.3 g, 33.9 mmol) was added dropwise. The ing
on was stirred at -78°C for another 1 hour, then warmed up to r.t. and quenched with
saturated NH4Cl solution in water (50 mL). The reaction mixture was diluted with ethyl
acetate, and the resulting mixture was washed with brine. The ted organic phase was
dried over sodium sulfate. The solvents were evaporated in vacuo and obtained crude product
was purified by Biotage aTM (2.7 g, 65%). LCMS calculated for BF2NO4 (M+H—
C4H8) + m/z = 354.2; found 354.2.
Step 3. rem—Bury! 5-(4-(3-(tert—butoxycarbonylammo)cyclobutyU-Z, 6—dz'flu0r0pheny0(1-
W0 2018/‘049200
methyl-1H-pyrazol—4-yl)-1H-pyrazolo[3, 4-0[pyridinecarb0xylate
NHBoc
F F
N \ /
/ / N
/ / N
-Chloro(1 -methyl- 1H-pyrazolyl)— 1 -((2-(trimethylsilyl)ethoxy)methyl)-1H-
pyrazolo[3,4—c]pyridine (600 mg, 1.8 mmol, Intermediate 1), tert—butyl (3-(3,5-difluoro
(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)phenyl)cyclobutyl)carbamate (1.177 g, 2.88
mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-
biphenyl)]palladium(II) (Pd XPhos G2) (280 mg, 0.36 mmol) and potassium phosphate (626
mg, 2.9 mmol) were placed in a flask and the flask was evacuated and backfilled with
nitrogen three times. Then dioxane (20 mL) and ed water (2 mL) were added. The
on mixture was stirred at 90 °C for 2h. After cooling to r.t., the reaction mixture was
diluted with ethyl acetate, and the resulting e was washed with brine. The separated
organic phase was dried over sodium e. The solvents were evaporated under reduced
pressure and obtained crude product was purified by Biotage IsoleraTM (753 mg, 72%).
LCMS calculated for C30H35F2N604 (M+H) + m/z = 5813, found 581.3.
Step 4. 3-(3,5—Diflu0r0(3-(1-mez‘hyl-1H—pyrazolyl)-1H—pyra2010[3,4-c]pyridirz
yDcyclobutanamme
F F
N.\ /
/ / N
/ /N
4M HCl solution in dioxane (2 mL, 8 mmol) was added to tert-butyl 5-(4-(3-((tert-
butoxycarbonyl)amino)cyclobutyl)—2,6-difluorophenyl)-3 -(1 -methyl- 1H-pyrazolyl)-1H-
W0 2018f049200
pyrazolo[3,4—c]pyridine—1-carboxylate (550 mg, 0.9 mmol), and the reaction mixture was
stirred at r.t. for 1 h. Then solvent was evaporated in vacuo, the obtained crude t was
dried and was used in the next step without further purification. LCMS calculated for
C20H19F2N6 (M+H)Jr m/z = 3812; found 381.1.
Step 5. 3-(3,5—Diflu0r0-4—(3-(1-methyl-1H-pyrazolyl)-1H—pyrazolo[3,4-c]pyridin
yUphenyD-N—isopropylcyclobutanamme
Sodium triacetoxyborohydride (16.7 mg, 0.08 mmol) was added to a solution of
propan-2—one (2.290 mg, 0.039 mmol), acetic acid (2.74 ul, 0.048 mmol) and 3-(3,5-difluoro-
1-methyl-lH-pyrazolyl)—1H—pyrazolo[3,4-c]pyridinyl)phenyl)cyclobutanamine
(15.0 mg, 0.039 mmol) in DCE (1 ml). After the reaction mixture was stirred at r.t. for 2
hours, it was diluted with acetonitrile and was purified with prep-LCMS (XBridge C18
column, g with a gradient of acetonitrile/water containing 0.1% TFA, at flow rate of 60
mL/min). LCMS calculated for C23H25F2N6 (M+H)+: m/z = 423.2, Found: 4233.
Example 96. 2-(3,5-Difluoro—4—(3—(1-methyl-1H-pyrazolyl)-1H-pyrazolo[3,4-
c] pyridin-S-yl)phenyl)—N—methylethanamine
Step 1. tert—Butyl 5-(2,6-dl'flu0r0(Z-hydroxyethyyphenyl)(1-methyl-1H-pyrazolyl)-
1H—pyrazolo[3,4-c]pyridinecarboxylate
F F
Ni \ /
/ / "i‘
/ / N
This nd was prepared ing to the procedures described in Example 95
W0 2018/‘049200
(Steps 2-3), using 2-(3,5—difluorophenyl)ethanol instead of tert—butyl 3-(3,5-
difluorophenyl)cyclobutylcarbamate as starting material. LCMS calculated for C23H24F2N503
(M+H)+: m/z = 4562; Found: 456.2.
Step 2. tert—Butyl 5-(2, 6-dz'flu0r0(2-0xoethy0phenyl)(1-methyZ-1H-pyrazol—4—yl)-1H-
pyra2010[3, 4—c]pyridinecarb0xylate
Dess-Martin periodinane (870 mg, 2.05 mmol) was added to a solution of tert—butyl 5-
(2,6-difluoro(2-hydroxyethyl)phenyl)—3-(1-methyl-1H-pyrazolyl)—1H—pyrazolo[3,4-
c]pyridinecarboxylate (0.78 g, 1.713 mmol) and ne (166.0 pl, 205 mmol) in DCM
(15 ml). After ng at r.t. for 1 h, solvent was evaporated in vacuo and the obtained crude
t was purified by Biotage IsoleraTM (653 mg, 84%). LCMS calculated for
C23H22F2N503 (M+H) + m/z = 454.2; found 454.2.
Step 3. 2-(3,5—Diflu0r0-4—(3-(1-methyl-1H-pyrazolyl)-1H—pyrazolo[3,4-c]pyridin
yUphenyD-N—methylethanamz'ne
Sodium triacetoxyborohydride (10.15 mg, 0.048 mmol) was added to a solution of
methanamine (2M in THF, 12 ul, 0.024 mmol), acetic acid (2.74 ul, 0.048 mmol) and tert-
butyl 5-(2,6-difluoro(2-oxoethyl)phenyl)—3-(1-methyl-IH-pyrazolyl)-IH-pyrazolo[3,4-
c]pyridine—1-carboxylate (11.0 mg, 0.024 mmol) in DCE (1 ml). After the reaction mixture
was stirred at r.t. for 2 hours, it was quenched with water. The reaction mixture was extracted
with ethyl acetate. The separated organic phases were washed with brine, dried over sodium
sulfate and solvents ated in vacuo. Then TFA (1 mL) was added, and the mixture was
stirred at r.t. for 30min. The on mixture was then diluted with itrile and was
purified with prep-LCMS (XBridge C18 column, g with a gradient of acetonitrile/water
containing 0.1% TFA, at flow rate of 60 mL/min). LCMS calculated for C19H19F2N6 (M+H)+:
m/z = 3692; Found: 369.2.
Example 97. 2-(2,4-Difluoro-3—(3—(1-methyl-1H-pyrazolyl)—1H-pyrazol0[3,4-
c] pyridin-S—yl)phenyl)—N—methylethanamine
F F
ND /
/ /"l
/ /N
This compound was prepared according to the procedures described in Example 96,
using 2-(2,4-difluorophenyl)ethanol instead of 2-(3,5-difluorophenyl)ethanol as starting
material. LCMS calculated for C19H19F2N6 : m/z = 3692, Found: 369.1.
Example 98. -Diflu0r0(3-(1-methyl-1H-pyrazolyl)—1H-pyrazolo[3,4-
c] pyridin-S-yl)phenethyl)tetrahydro-2H-pyranamine
F F
Nb /
/ /N
/ /N
HN\N
This compound was ed according to the procedures described in Example 97,
using tetrahydro-ZH—pyranamine instead of methanamine as starting material. LCMS
calculated for C23H25F2N60 (M+H)+: m/z = 4392, Found: 439.2.
Example 99. N-(3,S-Difluor0(3-(1-methyl-1H-pyrazolyl)—1H-pyrazolo[3,4-
c] pyridin-S—yl)phenethyl)—1-isopropylazetidin-S-amine
F F
ND /
/ /N
/ /N
This compound was prepared according to the procedures described in Example 96,
using 1-isopropylazetidinamine instead of methanamine as starting material. LCMS
calculated for C24H28F2N7 (M+H)+: m/z = 452.2; Found: 452.2.
ediate 5. tert-Butyl 5-(2-flu0romethoxyphenyl)—3—i0d0-1H-pyraz0l0[3,4—
c]pyridine—1-carb0xylate
F OMe
This compound was prepared according to the procedures described in Example 34
(Steps 1-5), using BOC2O instead of SEM-Cl as t. LCMS calculated for CisHisFIN3O3
(M+H)+: m/z = 4700; Found: 470.0.
Example 100. ro(5-(2-fluoromethoxyphenyl)—lH-pyrazolo[3,4-c]pyridin
yl)-N-methylbenzamide
Step 1. tert—Butyl 3-(3-flu0r0(methaxycarbonyUphenyl)(2-fluor0-6—methoxyphenyl)-1H—
pyra2010[3, 4—c]pyridinecarb0xylate
F OMe
/ O COOMe
tert-Butyl 5-(2-fluoromethoxyphenyl)—3-iodo-1H-pyrazolo[3,4-c]pyridine-1 -
carboxylate (1.00 g, 2.131 mmol, Intermediate 5), (3-fluoro
(methoxycarbonyl)phenyl)boronic acid (0.506 g, 2.56 mmol), chloro(2—
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dicyclohexylphosphino—2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-
biphenyl)]palladium(II) (Pd XPhos G2) (280 mg, 0.36 mmol) and potassium phosphate (626
mg, 2.9 mmol) were placed in a flask and the flask was evacuated and backfilled with
nitrogen three times. Then dioxane (20 mL) and degassed water (2 mL) were added and
reaction was stirred at 90 °C for 2h. After g to r.t., the reaction mixture was diluted
with ethyl acetate, and the resulting mixture was washed with brine. The ted organic
phase was dried over sodium sulfate. The solvents were evaporated in vacuo and the obtained
crude t was purified by Biotage IsoleraTM (835 mg, 79%). LCMS calculated for
C26H24F2N305 (M+H) + m/z = 496.2, found 496.1.
Step 2. 2-Flu0r0(5-(2-flu0r0meth0xyphenyU-1H-pyra2010[3, 4-c]pyridm-3—yl)benzoic
Lithium hydroxide (0.149 g, 6.23 mmol) was added to a solution of tert-butyl 3-(3-
fluoro—4—(methoxycarbonyl)phenyl)(2-fluoromethoxyphenyl)-1H-pyrazolo[3,4-
c]pyridine-l-carboxylate (618 mg, 1.246 mmol) in methanol (4 ml), THF (6.00 ml) and water
(2.0 ml). After stirring at 45 °C for 3h, the reaction mixture was neutralized with an HCl
solution and the solvents were evaporated in vacuo. Obtained crude product was dried and
used in the next step without further purification. LCMS calculated for C20H14F2N3O3 (M+H)
+ m/Z
= 382.1; found 382.1.
Step 3. 2-Flu0r0(5-(2-flu0r0meth0xyphenyl)-1H—pyra2010[3, 4-c]pyridinyl)-N-
methylbenzamide
To a on of 2-fluoro(5-(2-fluoromethoxyphenyl)-1H—pyrazolo[3,4-
c]pyridinyl)benzoic acid (10 mg, 0.026 mmol) and methanamine (2M in THF, 24 ul, 0.048
mmol) in NN-dimethylformamide (1.5 mL) were added sopropylethylamine (13 uL,
0.07 mmol) and ,N’—tetramethy1—O-(7-azabenzotriazoly1)uronium
hexafluorophosphate (15 mg, 0.04 mmol). After the reaction mixture was stirred at r.t. for 2
hours, it was then d with acetonitrile and was purified with prep—LCMS (XBridge C18
WO 49200
column, eluting with a gradient of acetonitrile/water containing 0.1% TFA, at flow rate of 60
mL/min). LCMS calculated for C21H17F2N402 (M+H)+: m/z = 395.1; Found: 395.2.
Example 101. 5-(5-(2-Fluor0methoxyphenyl)-1H-pyraz010[3,4-c]pyridin-3—yl)-N-
methylpicolinamide
This compound was prepared according to the procedures bed in Example 100;
using methyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)picolinate instead of (3-fluoro
(methoxycarbonyl)phenyl)boronic acid as starting material. LCMS calculated for
C20H17FN502 (M+H)+: m/z = 378.1; Found: 378.1.
e 102. 4-(5-(2-Fluoro—6-methoxyphenyl)—1H-pyrazolo[3,4-c] pyridinyl)
methoxy-N—methylbenzamide
This nd was prepared according to the procedures described in Example 100;
using 3-methoxy(methoxycarbonyl)phenylboronic acid instead of (3 -fluoro-4—
(methoxycarbonyl)phenyl)boronic acid as starting material. LCMS calculated for
C22H20FN4O3 : m/z = 407.2; Found: 407.2.
Example 103. 4-(5-(2-Fluor0methoxyphenyl)—1H-pyrazolo[3,4-c]pyridinyl)-N,2-
dimethylbenzamide
F OMe
N \ HN’
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This compound was prepared according to the procedures described in e 100,
using 4-(methoxycarbony1)methylphenylboronic acid instead of (3-fluoro
(methoxycarbonyl)phenyl)boronic acid as starting material. LCMS calculated for
C22H20FN402 (M+H)+: m/z = 3912; Found: 391.2.
Example 104. 1-(5-(2-Fluoromethoxyphenyl)—1H-pyrazolo[3,4-c] pyridin-3—yl)—N—
isopropyl-1H-imidazole-4—carboxamide
F OMe
O >\
| ~ H
/ #N
/ NvN
Step 1. Methyl I-(5-(2—flu0r0meth0xyphenyU((2-(trimez‘hylsilyl)ethoxy)methy1)-1H—
pyrazolo[3, 4-c]pyridinyl)-1H—imidazoZecarb0xylate
F OMe
NI \ #OMe~ /
/ NVN
-(2-Fluoromethoxyphenyl)iodo((2-(trimethylsilyl)ethoxy)methyl)-1H-
pyrazolo[3,4-c]pyridine (200 mg, 0.400 mmol, Example 34, Step 5), 8-hydroxyquinoline
(11.63 mg, 0.080 mmol), potassium carbonate (111 mg, 0.801 mmol) and copper(I) iodide
(15.2 mg, 0.080 mmol) were placed in a vial with septum. The vial was evacuated and
backfilled with nitrogen 3 times. After a solution of methyl 1H-imidazole-4—carboxylate (76
mg, 0.601 mmol) in DMSO (2 ml) was added, the reaction e was d at 100 °C
overnight. After cooling to r.t. water was added, the mixture was extracted with EtOAc. The
separated organic layer was washed with brine, dried over sodium sulfate and the t was
evaporated. The crude product was d by Biotage IsoleraTM. LCMS calculated for
C24H29FN504Si (M+H) + m/z = 498.2; found 498.3.
Step 2. I -(5-(2-Flu0r0meth0xyphenyl)((2-(trimez‘hylsz‘lyl)ethoxy)methy[)-1H-
pyra2010[3,4—cjpyridinyD-1H-imidazole-4—carb0xylz‘c acid
F OMe
t \ MW-
/ NvN
1M on of sodium hydroxide in water (1 mL, 1 mmol) was added to a solution of
methyl 1 -(5-(2-fluoromethoxyphenyl)((2-(trimethylsilyl)ethoxy)methyl)-1H-
pyrazolo[3,4—c]pyridinyl)-lH-imidazolecarboxylate (25 mg, 0.049 mmol) in
ydrofuran (2 mL) and methanol (1 mL). After stirring at r.t. for 2 h, the pH was adjusted
to 5 by the addition of a 1M HCl solution. The e was then extracted with ethyl acetate
and organic phase was washed with brine. The organic phase was dried over sodium sulfate
and the solvents were evaporated under reduced pressure. The obtained solid product was
used in the next step without r purification. LCMS calculated for C23H27FN504Si
(M+H)+ m/z = 4842; found 484.1.
Step 3. 1-(5-(2—Flu0r0meth0xyphenyl)-1H-pyrazolo[3, 4-c]pyrz‘dz‘nyZ)-N-isopr0pyl-1H-
imidazoZecarb0xamide
To a solution of 1-(5-(2-fluoromethoxypheny1)((2-
(trimethylsilyl)ethoxy)methyl)-lH-pyrazolo[3,4-c]pyridinyl)-1H—imidazolecarboxylic
acid (0.01 g, 0.02 mmol) and isopropylamine (4.43 ul, 0.052 mmol) in MN-
dimethylformamide (1.5 mL) were added MN—diisopropylethylamine (13 uL, 0.07 mmol) and
N,N,N', ’-tetramethyl(7-azabenzotriazolyl)uronium hexafluorophosphate (15 mg, 0.04
mmol). After the reaction mixture was stirred at r.t. for 2 hours, it was quenched with water.
The mixture was extracted with ethyl acetate. The separated organic phases were washed
with brine and dried over sodium sulfate, and solvents were evaporated in vacuo. Then 1M
solution of HCl in water (1 mL) and 4M solution of HCl in dioxane (1 mL) were added to the
crude residue, and reaction mixture was d at 80 °C for 1 h. Then methanol (1 mL) was
added, and the reaction mixture was further stirred at 80 °C for 30 min. The on mixture
was then diluted with acetonitrile and was purified with prep-LCMS (XBridge C18 column,
eluting with a gradient of acetonitrile/water containing 0.1% TFA, at flow rate of 60
mL/min). LCMS ated for C20H20FN602 (M+H)+: m/z = 3952; Found: 3952.
e 105. 1-(5-(2-Fluoromethoxyphenyl)—1H-pyrazolo[3,4-c]pyridin-3—yl)-N-
methyl- dazolecarboxamide
F OMe
/ W‘QLN~ H
/ NWN
This compound was prepared according to the procedures described in Example 104,
using methanamine instead of isopropylamine as starting material. LCMS calculated for
C18H16FN602 (M+H)+: m/z = 367.1; Found: 367.1.
Example 106. 5-(4-(Azetidinylmethoxy)—2,6-difluorophenyl)—3—(l-methyl-lH-pyrazol-
4-yl)-1H-pyrazolo[3,4-c] pyridine
F F
“l\ /
/ /"l
/ /N
Step 1. 3,5—Diflu0r0(3-(1-methyl-1H-pyrazol—4—yU((2-(trimethylsiZyUethoxy)methyl)-
1H—pyrazof0[3, 4—c]pyridinyl)phenol
F F
N \ /
/ / N
/ / N
This compound was prepared according to the procedures described in Example 57
(Step 1), using (2,6—difluorohydroxyphenyl)boronic acid instead of methyl 3,5-difluoro
(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-Z-yl)benzoate as starting material. LCMS calculated
for F2NSOZSl (M+H)+: m/z = 458.2; Found: 458.2.
Step 2. 5-(4-(Azez‘z'dmylmethoxy)-2,6-dz'flu0r0phenyl)(1-methyl-1H-pyrazolyD-1H-
[3, 4—0jpyrz'dz’ne
To a solution of 3,5-difluoro(3-(1-methyl-1H—pyrazolyl)((2-
(trimethylsilyl)ethoxy)methyl)-lH-pyrazolo[3,4-c]pyridinyl)phenol (30 mg, 0.066 mmol)
in DMF (1 ml) was added tert-butyl momethyl)azetidinecarboxylate (24.60 mg,
0.098 mmol) and cesium carbonate (32.0 mg, 0.098 mmol). After the reaction mixture was
stirred at 90 °C overnight, it was quenched with water. The mixture was extracted with ethyl
acetate. The separated organic phases were washed with brine and dried over sodium sulfate.
The solvents were evaporated in vacuo. Then 1M solution of HCl in water (1 mL) and 4M
solution ofHCl in dioxane (1 mL) were added to the crude residue, and reaction mixture was
stirred at 80 °C for l h. Methanol (1 mL) was added, and the reaction mixture was further
stirred at 80 °C for 30 min. The reaction mixture was then d with acetonitrile and was
purified with prep-LCMS (XBridge C18 column, g with a gradient of acetonitrile/water
containing 0.1% TFA, at flow rate of 60 mL/min). LCMS calculated for C20H19F2N60
(M+H)+: m/z = 397.2; Found: 397.2.
Example 107. 5-(2,6-Difluoro(tetrahydro-ZH-pyranyloxy)phenyl)—3—(l-methyl-lH-
pyrazolyl)-1H-pyrazolo[3,4—c]pyridine
F F
N.\ /
/ /"l
/ /N
This compound was ed according to the procedures described in e 106,
using 4-chlorotetrahydro-2H-pyran instead of utyl 2-(bromomethyl)azetidine
carboxylate as starting material. LCMS ated for C21H20F2N502 (M+H)+: m/z = 4122;
Found: 4122.
Example 108. 5-(2,6-Difluoro(pyr'idinylmethoxy)phenyl)(l-methyl-lH-pyrazol-
4-yl)- 1H-pyrazolo[3,4-c] pyridine
This nd was prepared according to the procedures described in Example 106,
using 4-(bromomethyl)pyridine instead of utyl 2-(bromomethyl)azetidine-1—carboxylate
as starting material. LCMS calculated for C22H17F2N60 (M+H)+: m/z = 4191; Found: 419.1.
Example 109. 3,5-Difluoro(3-(1-methyl-1H-pyrazolyl)—1H-pyrazolo[3,4-c]pyridin-
-yl)phenyl dimethylcarbamate
F F
ND /
/ /"l
/ /N
To a solution of 3,5-difluoro(3-(1-methyl-1H-pyrazolyl)((2-
(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridinyl)phenol (30 mg, 0.066 mmol,
Example 106, Step 1) in THF (1 ml) was added dimethylcarbamic chloride (10.58 mg, 0.098
mmol) and triethylamine (0.018 ml, 0.131 mmol). After stirring at r.t. for 30 min, 1-
methylpiperidin—4-ol (3.94 mg, 0.034 mmol) was added, and the reaction mixture was stirred
for 1 h. After the reaction mixture was d at r.t. for 1 h, it was quenched with water. The
mixture was ted with ethyl acetate. The separated organic phases were washed with
brine and dried over sodium sulfate. The solvents were evaporated in vacuo. Then 1M
solution of HCl in water (1 mL) and 4M solution of HCl in dioxane (1 mL) were added to the
crude residue, and on mixture was stirred at 80 °C for 1 h. Methanol (1 mL) was added,
and reaction mixture was further stirred at 80 °C for 30 min. The reaction mixture was then
diluted with acetonitrile and was purified with prep-LCMS (XBridge C18 , eluting
with a gradient of acetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min).
LCMS calculated for C19H17F2N602 (M+H)+: m/z = 399.1; Found: 399.1.
Example 110. 3,5-Difluoro(3-(1-methyl-1H-pyrazolyl)—1H-pyrazolo[3,4-c]pyridin-
-yl)phenyl line—4—carboxylate
This compound was prepared according to the procedures bed in Example 109,
using morpholinecarbonyl chloride instead of dimethylcarbamic chloride as starting
material. LCMS calculated for C21H19F2N603 (M+H)+: m/z = 4412; Found: 441.].
Example 1 1 1. N—Methyl- 1-(3-methyl(3-(l-methyl- 1H-pyrazolyl)-lH-pyrazolo [3,4-
c] pyridin-S—yl)phenyl)methanamine
“l\ /
/ /"i
/ /N
HN\N
This compound was ed according to the procedures described in Example 86,
using (4-bromo—3-methylphenyl)methanol instead of (3-bromomethylphenyl)methanol as
starting material. LCMS ated for C19H21N6 (M+H)+: m/z = 3332; Found: 333.1.
Example 112. N-Methyl(4-(3-(l-methyl-1H-pyrazolyl)—1H-pyrazolo[3,4-c] pyridin-
-yl)(trifluoromethyl)phenyl)methanamine
“l\ /
/ /'\I
/ /N
This compound was prepared according to the procedures described in Example 86,
using (4-bromo(trifluoromethyl)phenyl)methanol d of (3-bromo-2—
methylphenyl)methanol as starting material. LCMS calculated for C19H18F3N6 (M+H)+: m/z =
3872; Found: 387.1.
Example 113. 1-(5-(5-(2-Fluoromethyl((methylamino)methyl)phenyl)—1H-
pyrazolo[3,4-c]pyridinyl)pyridin-Z-yl)pyrrolidin-S-ol
1 \ /~ 0
/ /
/ \
Step 1. 4-Br0m0flu0r0methylam'lme
F Me
N—Bromosuccinimide (15.8 g, 89 mmol) was added to a on of 3—fluoro—5-
methylaniline (Combi-Blocks, 11 g, 88 mmol) in DMF (80 mL) cooled to 0 °C in an ice bath.
The reaction e was stirred at 0 °C for 30 minutes. After warming to r.t., the reaction
was stirred for an additional 1 hour. Water and EtOAc were then added, and the c
phase was washed with saturated aqueous NaHCO3 and brine. The organic phase was then
dried over magnesium sulfate and the solvents were evaporated under reduced pressure. The
crude product was purified by e IsoleraTM (17.2 g, 96%). LCMS calculated for
C7HsBrFN (M+H)+ m/z = 203.9; found 204.0.
Step 2. 2-Br0m0fluor0z‘0d0methylbenzene
F Me
To a solution of 4-bromofluoromethylaniline (7.28 g, 36 mmol) in acetonitrile
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(190 mL) cooled to 0 0C in an ice bath was added sulfuric acid (475 mL, 89 mmol) dissolved
in H20 (10 mL). After stirring for 5 minutes, a solution of sodium nitrite (4.92 g, 71.4 mmol)
in water (10 mL) was added dropwise and the reaction mixture was stirred for an additional
minutes at 0 °C. Potassium iodide (23.7 g, 143 mmol) in water (20 mL) was then added,
and the ice-bath was removed. After warming to It. the reaction mixture was stirred for an
additional 20 minutes before the reaction was quenched Via the addition of aqueous Na2S203.
The mixture was then extracted with ethyl acetate and the combined organic phases were
washed with brine, dried over magnesium sulfate, and concentrated under d re.
The crude product was purified by Biotage IsoleraTM (10.3 g, 94%). 1H NMR (400 MHz,
CDCl3) 5 7.39 (br s, 1H), 7.29 (m, 1H), 2.38 (s, 3H) ppm.
Step 3. 2-Br0m0-1fluoro-S-methyl-Zi-vz‘nylbenzene
F Me
To a solution of 2-bromofluoroiodomethylbenzene (10.3 g, 32.8 mmol) in
1,4-dioxane (80 mL) and water (13.3 mL) was added 4,4,5,5-tetramethylvinyl-1,3,2-
dioxaborolane (Aldrich, 6.16 mL, 34.5 mmol), [1,1’-
phenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)C12) (2.40 g, 3.3 mmol),
and potassium phosphate tribasic (13.9 g, 65.7 mmol). The reaction mixture was degassed,
backfilled with nitrogen, and heated to 70 °C for 1 h. After cooling to r.t. the reaction e
was filtered over a pad of Celite. The filtrate was d with water and extracted with ethyl
acetate. The ed organic phases were washed with brine, dried over magnesium e,
and concentrated under reduced pressure. The crude product was purified by Biotage
IsoleraTM (5.46 g, 77%). 1H NMR (400 MHz, CDC13) 5 7.05 (br s, 1H), 7.01 (dd, J: 2.0, 9.4
Hz, 1H), 6.60 (dd, J: 10.9, 17.5 Hz, 1H), 5.75 (d, J: 17.5 Hz, 1H), 5.31 (d, J: 10.9 Hz,
1H), 2.42 (s, 3H) ppm.
Step 4. 4-Br0m0flu0r0methylbenzaldehyde
H 0
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To a solution of 2—bromofluoromethylVinylbenzene (5.46 g, 25.4 mmol) in
acetone (46 mL) and water (4.6 mL) was sequentially added sodium periodate (21.7 g, 102
mmol) and a 4% aqueous solution of osmium tetroxide (8.07 mL, 127 mmol). The reaction
e was stirred at r.t. for 2 h, The reaction mixture was then filtered over a pad of Celite.
The filtrate was d with water and extracted with ethyl acetate. The combined organic
phases were washed with brine, dried over magnesium sulfate, and concentrated under
reduced pressure. The crude product was purified by Biotage IsoleraTM (3.22 g, 58%). 1H
NMR (400 MHZ, CDCl3) 5 9.93 (d, J: 1.8 Hz, 1H), 7.55 (d, J: 1.8 Hz, 1H), 7.44 (dd, J:
1.8, 7.8 Hz, 1H), 2.52 (s, 3H) ppm.
Step 5. 1-(4-Br0m0flu0r0-5—mez‘hylphenyl)-N-methylmethanamme
F Me
In a 20 mL scintillation Vial equipped with a magnetic stir bar, ofluoro
methylbenzaldehyde (1.46 g, 6.70 mmol) was dissolved in MeOH (6.70 mL), and the on
mixture was placed under a nitrogen environment. Following this, a 33% solution of
methanamine (3.15 g, 33.5 mmol) in ethanol and titanium(IV) isopropoxide (0.982 mL, 3.35
mmol) were added, and the on e was stirred at r.t. for 3 hours. Sodium
dride (1.01 g, 26.8 mmol) was then added to the reaction mixture n wise, and
stirring was continued at r.t. for an additional 1.5 hours. NH4OH (30% aqueous solution) was
added to the reaction mixture and stirring continued for another 15 minutes. The reaction
mixture was then acidified with 1 N HCl and extracted with ethyl e. The water layer
was then made basic and extracted with ethyl acetate. The combined organic phases were
washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure to
afford 1-(4-bromofluoromethylphenyl)—N—methylmethanamine (1.32 g, 85%) as a light
yellow oil. The crude product was used in the next step without further purification. LCMS
calculated for C9H12BrFN (M+H)+ m/z = 2320, found 231.9.
Step 6. tert—Butyl 4-br0m0flu0r0methylbenzyl(methyl)carbamaz‘e
To a solution of 1-(4-bromofluoromethylphenyl)-N—methylmethanamine (1.32
g, 5.67 mmol) and triethylamine (1.58 mL, 11.34 mmol) in THF (18.9 mL) was added di-tert—
butyl dicarbonate (1.58 mL, 6.80 mmol). The reaction e was then stirred at ambient
temperature for 1 hour. The reaction mixture was then diluted with water and extracted with
ethyl acetate. The combined organic layers were dried with magnesium e and
trated under reduced pressure. The crude product was purified by e IsoleraTM
(1.42 g, 78%). LCMS calculated for C10H12BrFNO2 (M+H-C4Hs)+ m/z = 276.0; found 276.0.
Step 7. tert-Butyz’ 3-flu0r0methyl(4, 4,5, 5—tetramethyl—1,3,2-dl'0xab0r02an
yl)benzyl(methyl)carbamate
In an oven—dried 20 mL scintillation Vial with a stir bar, tert—butyl (4—bromofluoro-
-methylbenzyl)(methyl)carbamate (573 mg, 1.73 mmol) was dissolved in THF (11.5 mL).
The reaction mixture was cooled to -78 °C in a dry ice/acetone bath and BuLi (1.6 M solution
in hexanes, 1.19 mL, 1.90 mmol) was added dropwise. The reaction mixture was then
allowed to stir for 3 minutes before ropyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (427
uL, 2.25 mmol) was added dropwise. The mixture was warmed to r.t and stirred for an
additional 5 hours. The reaction mixture was then quenched by the addition of water,
acidified to pH 5-6 using 1 N HCl, and extracted with ethyl e. The combined organic
layers were then washed with brine, dried over magnesium e, and concentrated to afford
tert—butyl 3—fluoromethy1—4—(4,4,5,5-tetramethyl-1,3,2-dioxaborolan
yl)benzyl(methyl)carbamate (679 mg, quantitative yield). The crude product was used in the
next step without further purification. LCMS calculated for C16H24BrFNO4 (M+H-C4Hs)Jr
m/z = 3242; found 324.1.
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Step 8. utyl 5—(4—((tert—butoxycarb0nyl(methyl)amin0)methyl)—2—flu0r0—6—mez‘hylphenyl)—
1H-pyrazoZo[3, 4-cjpyrz'dmecarb0xylate
In a 20 mL scintillation Vial equipped with a ic stir bar, utyl 5-chloro-1H-
pyrazolo[3,4-c]pyridinecarboxylate (0.649 g, 2.56 mmol) and tert—butyl (3—fluoro
methyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)benzyl)(methyl)carbamate (970 mg,
2.56 mmol) were ved in 1,4-dioxane (8.0 mL) and water (2.0 mL). To this mixture was
added chloro(2—dicyclohexylphosphino-2’,4’,6’-triisopropyl-1,1’-biphenyl)[2-(2’-amino-1,1 ’-
biphenyl)]palladium(II) (Pd XPhos G2) (400 mg, 0.51 mmol) and potassium phosphate
tribasic (1.6 g, 7.67 mmol). The reaction mixture was degassed (by bubbling nitrogen through
it), sealed and heated to 75 °C for 1 h. After cooling to r.t., the reaction mixture was diluted
with water and extracted with ethyl acetate. The combined organic layers were washed with
brine, dried over magnesium sulfate, and concentrated under reduced pressure. The crude
product was purified by Biotage aTM (300 mg, 25%). LCMS calculated for
C25H32FN4O4 (M+H)Jr m/z = 471.2; found 471.2.
Step 9. tert—Butyl 5-(4-((tert-butoxycarb0nyl(methyl)amm0)methyl)-2—flu0r0-6—methylphenyl)-
3-i0d0-1H—pyrazolo[3, 4-c]pyridmecarb0xylate
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In a 20 mL scintillation vial with a stir bar, tert—butyl 5-(4-(((tert-
butoxycarbonyl)(methy1)amino)methyl)fluoromethy1pheny1)-1H-pyrazolo[3,4-
c]pyridinecarboxy1ate (0.30 g, 0.638 mmol) and potassium carbonate (0.441 g, 3.19 mmol)
were ved in 1,4-dioxane (5 mL) and water (5 mL). The reaction mixture was heated to
80 0C for 2 hours. The reaction mixture was diluted with water and extracted with ethyl
e. The combined organic phases were washed with brine, dried over magnesium sulfate,
and concentrated under reduced pressure. The crude intermediate was dissolved in DMF (10
mL) and N-iodosuccinimide (0.15 g, 0.7 mmol) was added, and the reaction mixture heated to
60 0C for 1 hour. Triethylamine (0.15 ml, 1 mmol) and di-tert—butyl dicarbonate (0.168 ml,
0.72 mmol) were added to the reaction mixture, which was d at r.t for an additional 1 h.
The reaction e was then concentrated under reduced pressure and the crude product
was purified by Biotage aTM. LCMS calculated for C25H31FIN4O4 (M+H)+ m/z = 597.1,
found 597.].
Step 10. tart-Bury! 5-(4-((tert—butoxycarb0nyl(methyl)amm0)methyl)-2—flu0r0-6—
methylphenyl)-3—(6—ch10r0pyridmyl)-]H-pyrazolo[3, 4-c]pyrl'dl'ne-I -carb0xylaz‘e
F Me
| /N
\ CI
/ \/
tert—Butyl 5-(4-(((tert—butoxycarbonyl)(methyl)amino)methyl)fluoro
methylphenyl)—3-iodo-1H-pyrazolo[3,4-c]pyridinecarboxylate (0.3 g, 0.503 mmol),
PdC12(dppf)—CH2C12 adduct (0.082 g, 0.101 mmol), (6-chloropyridinyl)boronic acid (0.103
g, 0.654 mmol) and potassium phosphate (320 mg, 1.51 mmol) were placed in a flask and the
flask was evacuated and backfilled with nitrogen three times. Dioxane (5 m1) and ed
water (0.5 ml) were added, and the reaction mixture was d at 80 °C for 1 h. After
cooloing to H. water was added, and the mixture was extracted with EtOAc. The separated
organic layer was washed with brine and dried over sodium sulfate. The solvent was
evaporated under reduced re. The crude product was purified by Biotage IsoleraTM.
LCMS calculated for C30H34C1FN504 (M+H) + m/z = 582.2, found 582.2.
Step 11. 1—(5-(5-(2-Flu0r0methyl((methylamin0)methyl)phenyl)—1H—pyrazoz’0[3,4-
cjpyridinyl)pyrz’dmyl)pyrr01idmol
Pyrrolidinol (8.98 mg, 0.103 mmol) was added to a solution of tert-butyl 5-(4-
(((z‘ert—butoxycarbonyl)(methyl)amino)methyl)fluoromethylphenyl)(6-chloropyridin-
3-yl)—1H-pyrazolo[3,4-c]pyridinecarboxylate (0.020 g, 0.034 mmol) in 2-methoxyethan
01 (0.5 mL). After stirring at 120 °C overnight, the reaction mixture was d with
itrile and was purified with prep-LCMS (XBndge C18 column, eluting with a gradient
of acetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min). LCMS calculated for
C24H26FN6O (M+H)+: m/z = 4332, Found: 433.2.
e 114. 1-(3-Fluoro(3-(6-(3-meth0xypiperidinyl)pyridinyl)-1H-
pyrazolo[3,4-c]pyridinyl)methylphenyl)—N—methylmethanamine
1 \ /~ 0
/ \ /
This compound was prepared according to the procedures described in Example 113,
using oxypiperidine instead of pyrrolidinol as starting material. LCMS calculated
for C26H30FN60 (M+H)+: m/z = 4612, Found: 461.2.
Example 115. 5-(2-Flu0r0meth0xyphenyl)—3—(6-(1-methylpiperidinyl)pyridinyl)—
1H-pyrazolo[3,4-c] pyridine
Step 1. 3-(6-Br0m0pyridinyl)(2-flu0r0mez‘h0xyphenyl)((2-
(trimethyfsiiyl)ethoxy)methyl)-1H-pyrazolo[3, 4-c]pyridine
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luoromethoxyphenyl)iodo-l-((2-(trimethylsilyl)ethoxy)methyl)— 1H-
lo[3,4—c]pyridine (0.3 g, 0.6 mmol, Example 34, Step 5), triphenylphosphine palladium
de (50 mg, 0.07 mmol) and 2-bromo(tributylstannyl)pyridine (0.6 g, 1.34 mmol)
were placed in a flask and the flask was evacuated and backfilled with nitrogen three times.
Then DMF (4 ml) was added, and reaction mixture was stirred at 110 °C for 5h. After cooling
to r.t. water was added, the mixture was extracted with EtOAc. The separated organic layer
was washed with brine and dried over sodium sulfate. The solvent was evaporated. The crude
product was purified by Biotage IsoleraTM. LCMS calculated for C24H27BrFN4OzSi (M+H) +
m/Z = 529.]; found 529.1.
Step 2. 5—(2-Fluorometh0xyphenyl)(6-(1-methyl-1, 2, 3, 6-tetrahydropyridmy0pyrz'dm-
2-3/1)((2-(trimez‘hylsilyl)ethoxy)methyU-JH-pyrazolo[3, 4-cjpyrz'dz'ne
3-(6-Bromopyridinyl)(2-fluoromethoxyphenyl)-l-((2-
(trimethylsilyl)ethoxy)methyl)-lH-pyrazolo[3,4-c]pyridine (50 mg, 0.09 mmol), (l-methyll
,2,3,6-tetrahydropyridinyl)boronic acid (20 mg, 0.14 mmol), chloro(2-
dicyclohexylphosphino-2',4',6'-triisopropyl-l,l'-biphenyl)[2-(2'-amino-1,1'-
biphenyl)]palladium(II) (Pd XPhos G2) (5 mg, 0.006 mmol) and potassium phosphate (40
mg, 0.18 mmol) were placed in a flask and the flask was ted and lled with
nitrogen three times. Dioxane (1 mL) and degassed water (0.1 mL) were added, and reaction
mixture was stirred at 90 °C for 2h. After g to r.t., the reaction mixture was diluted with
ethyl acetate, and the resulting mixture was washed with brine. The separated organic phase
was dried over sodium e. The solvents were evaporated under reduced pressure and the
obtained crude product was purified by Biotage IsoleraTM. LCMS calculated for
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C30H37FN5028i (M+H) + m/z = 5463; found 5462.
Step 3. 5-(2-Flu0r0meth0xyphenyl)(6-(1-methylpz'perz'dz'nyl)pyrz'dz’nyl)-1H-
pyra2010[3, 4—0jpyrz'dz’ne
Pd/C (20 mg, 5wt%) was added to a solution of 5-(2-fluoromethoxyphenyl)(6-
(1 -methyl-1,2,3,6-tetrahydropyridinyl)pyridinyl)((2-(trimethylsilyl)ethoxy)methyl)—
1H-pyrazolo[3,4-c]pyridine (16 mg, 0.03 mmol) in MeOH (2 mL). After stirring under
hydrogen for 2h at r.t., the catalyst was filtered-off. The solvent of the filtrate was evaporated
in vacuo. Then 1M solution of HCl in water (1 mL) and 4M solution of HCl in dioxane (1
mL) were added to obtained crude product, and the reaction mixture was stirred at 80 ”C for 1
h. Methanol (1 mL) was added, and the reaction mixture was further stirred at 80 °C for 30
min. The reaction mixture was then diluted with acetonitrile and was purified with prep-
LCMS ge C18 column, eluting with a gradient of acetonitrile/water containing 0.1%
TFA, at flow rate of 60 mL/min). LCMS calculated for C24H25FN50 (M+H)? m/z = 418.2;
Found: 418.2.
Example 1 16. 3-(4-Bromostyryl)(2-fluoromethoxyphenyl)- 1H-pyrazolo[3,4-
c] pyridine
5-(2-Fluoromethoxyphenyl)iodo((2-(trimethylsilyl)ethoxy)methyl)- 1H-
pyrazolo[3,4-c]pyridine (50 mg, 0.1 mmol), 1-bromovinylbenzene (55 mg, 0.3 mmol),
chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-
biphenyl)]palladium(II) (Pd XPhos G2) (5 mg, 0.006 mmol) and ium ate (20
mg, 0.1 mmol) were placed in a vial, and the vial was ted and backfilled with nitrogen
three times. Then dioxane (1 mL) and degassed water (0.1 mL) were added, and reaction
mixture was stirred at 80 °C overnight. After cooling to r.t., the reaction mixture was diluted
with ethyl acetate, and the resulting e was washed with brine. The separated c
phase was dried over sodium sulfate. The solvents were evaporated in vacuo. Then 1M
solution of HCl in water (1 mL) and 4M solution of HCl in dioxane (1 mL) were added to the
crude residue, and the reaction e was stirred at 80 °C for l h. Methanol (1 mL) was
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added> and the reaction mixture was further stirred at 80 °C for 30 min. The reaction mixture
was then diluted with acetonitrile and was purified with prep-LCMS (XBridge C18 column,
eluting with a nt of acetonitrile/water containing 0.1% TFA, at flow rate of 60
). LCMS calculated for C21H16BrFN3O (M+H)+: m/z = 4241; Found: 4241.
e 117. l-(3-Flu0ro-5—methyl(3-(6-m0rpholinopyridin-Z-yl)—lH-pyrazolo[3,4-
clpyridin-S-yl)phenyl)-N-methylmethanamine
F (j
Step 1. tart-Bury! 4-(3-(6-chlor0pyridin-2—yl)((2-(trimethylsilyl)ethoxy)methyl)—1H—
10[3, ridinyUflMoromethylbenzyl(methyl)carbamate
/ \ /
This compound was prepared according to the procedures described in Example 115
(Step 1), using tert—butyl 3-fluoromethy1(4,4,5,5-tetramethy1-1,3,2-dioxaborolan
yl)benzyl(methyl)carbamate instead of (2-fluoromethoxyphenyl)boronic acid and 2-
chloro(tributylstanny1)pyridine instead of 2-bromo(tributylstannyl)pyridine as starting
material. LCMS calculated for C31H40C1FN503Si (M+H)+: m/z = 6122; Found: 6122.
Step 2. 1-(3-Flu0r0methyl(3-(6-m0rpholmopyrl'dl'n-Z-yl)-1H-pyra2030[3,4-cjpyridin
yUphenyi)-N-mez‘i/zylmethanamme
tert-Butyl (4-(3-(6-chloropyridiny1)((2-(t1imethylsilyl)ethoxy)methyl)-1H-
pyrazolo[3,4-c]pyridinyl)fluoro-5 -methylbenzyl)(methyl)carbamate (10 mg, 0.016
mmol), morpholine (14 mg, 0.163 mmol), cesium carbonate (5.3 mg, 0.016 mmol) and
chloro(2-dicyclohexy1phosphino-2',6'-di-i-propoxy-1,1'-biphenyl)(2'-amino-1,1'-biphenyl
yl)palladium(II) (RuPhos Pd G2, 5 mg, 6.3 umol) were placed in a vial, and the vial was
evacuated and backfilled with nitrgoen three times. Dioxane (2 mL) was added and the
reaction mixture was stirred at 100°C overnight. After cooling down to r.t., the solids were
filtered off, and the solvent of the filtrate was evaporated in vacuo. Then 1M on of HCl
in water (1 mL) and 4M solution of HCl in dioxane (1 mL) were added to the crude residue,
and the reaction mixture was stirred at 80°C for 1 h. ol (1 mL) was added, and the
reaction mixture was further stirred at 80 °C for 30 min. The reaction e was then
diluted with acetonitrile and was purified with prep-LCMS (XBndge C18 column, eluting
with a gradient of acetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min).
LCMS calculated for C24H26FN60 (M+H)+: m/z = 4332, Found: 433.3.
Example 118. N—Ethyl-G-(5-(2-flu0r0methyl-4—((methylamino)methyl)phenyl)—1H-
pyrazolo[3,4-c]pyridinyl)-N-methylpyridin-2—amine
This compound was prepared according to the ures described in Example 117,
using N—methylethanamine instead of morpholine as starting material. LCMS calculated for
FN6 (M+H)+: m/z = 405.2, Found: 4053.
e 119. 1-(3-Flu0r0-4—(3-(6-(4-methylpiperazinyl)pyridin-3—yl)—1H-
pyrazolo[3,4-c]pyridin-S-yl)—5-(trifluoromethyl)phenyl)—N—methylmethanamine
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Step 1. tert—Butyl 3-flu0r0-5—(trifluoromethyUbenzylfinez‘hyl)carbamaz‘e
F E
To a on of 3-fluoro(trifluoromethyl)benzaldehyde (20.0 g, 104 mmol) in
MeOH (500 ml) was added methylamine solution (104 ml, 208 mmol, 2M in THF) and the
on was stirred at rt. for 1 hour. After this time, sodium borohydride (188 g, 208 mmol)
was added, and the reaction mixture was stirred for additional 30 mins. The reaction mixture
was concentrated to dryness, and 300 mL of DCM was added. An aqueous solution of
sodium bicarbonate was added, and the on mixture was d at r.t. for another 1 hour.
The organic layer was separated, dried over MgSO4, filtered, and concentrated to dryness. To
a solution of the resulting residue in DCM (521 ml) was added triethylamine (14.5 ml, 104
mmol) and di-tert—butyl dicarbonate (22.7 g, 104 mmol). The resulting solution was stirred at
r.t. for 1 hour. The solution was concentrated to dryness, and the residue was purified by
silica gel chromatography using 0-70% ethyl acetate in hexanes to afford desired product as
colorless oil (15.1 g, 47.0%). LC-MS calculated for F4N02 (M+H-C4Hs) +: 2521;
found 2522.
Step 2. tert—Butyz’ 5-(4-((tert-butoxycarbonyl(methyUamin0)methyZ)flu0r0-6—
(trifluoromethybphenyl)-1H-pyrazolo[3, 4-c]pyrz'dmecarb0xylate
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To a solution of tert—butyl (3-fluoro(trifluoromethyl)benzyl)(methy1)carbamate (2.3
g, 7.5 mmol) in THF (33.3 ml) was added llithium (8.98 n11, 22.5 mmol) dropwise at -
78 °C, and the reaction mixture was stirred at -78°C for 1 hour. 2-Isopropoxy-4,4,5,5-
tetramethyl-l,3,2—dioxaborolane (5.57 g, 29.9 mmol) was added, and the mixture was
allowed to warm up to r.t. over 1 hour. The resulting solution was ed with water,
neutralized to pH=6, and the mixture was extracted with ethyl acetate. The organic lay er was
washed with brine, dried over MgSO4, filtered, and then concentrated to dryness. To a
solution of the resulting residue in dioxane (33.3 ml) and water (832 ml) was added
potassium phosphate (1.30 g, 7.48 mmol) and tert—butyl 5-chloro-1H-pyrazolo[3,4-
c]pyridine-l-carboxylate (1.0 g, 3.94 mmol). The e was degassed with N2, chloro(2-
dicyclohexylphosphino-2',4',6'-tri-i-propyl- l , l '-biphenyl)(2'-amino- l , l '-biphenyl-2—yl)
palladium(II) (0.118 g, 0.150 mmol) was added, and the reaction mixture was stirred at 60 °C
for 1 hour. The mixture was concentrated to dryness. The residue was purified by silica gel
chromatography using 0-100% ethyl acetate in hexanes to afford d product as yellowish
oil. LC-MS calculated for C25H29F4N4O4 : m/z =525.2, Found 525.2.
Step 3. tert—Butyl 5-(4-((tert-butoxycarbonyl(methyUamin0)methyZ)flu0r0-6—
(trif'luoromethybphenyl)i0d0-1H—pyra2010[3, 4-c]pyridmecarb0xylate
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To a solution of tert—butyl 5-(4-(((terz‘-butoxycarbonyl)(methyl)amino)methyl)
fluoro(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-c]pyridinecarboxylate (0.30 g, 0.572
mmol) in dioxane (5 ml) and water (5 ml) was added potassium carbonate (0.395 g, 2.86
mmol), and the reaction mixture was stirred at 80 °C for 2 hours. The mixture was cooled to
r.t., diluted with DCM, and washed with water, sodium onate and brine. The organic
layer was dried over MgSO4, filtered, and then concentrated to dryness.
NIS (0.143 g, 0.636 mmol) was added to a solution of the obtained residue in DMF (6
ml). After stirring at 70 °C for 2h, the on mixture was cooled to r.t. and triethylamine
(0.089 ml, 0.636 mmol) was added followed by di-tert—butyl dicarbonate (0.148 ml, 0.636
mmol). After ng for an addition 2h at r.t., water was added. The mixture was extracted
with EtOAc. The separated organic layer was washed with brine, dried over sodium e,
and the solvent was evaporated. The crude product was purified by Biotage IsoleraTM. LCMS
calculated for C25H23F4IN4O4 (M+H) + m/z = 651.1, found 651.1.
Step 4. 1-(3—Flu0r0(3-(6—(4-methylpiperazmyl)pyridinyl)-1H—pyrazolo[3,4-c]pyridl'n-
—yl)-5—(trifluoromethyUphenyU-N-methylmethanamme
To a screw-cap Vial equipped with a magnetic stir bar was added tert—butyl 5-(4-
(((z‘ert—butoxycarbonyl)(methyl)amino)methyl)fluoro(trifluoromethyl)phenyl)-3 -iodo-
azolo[3,4-c]pyridinecarboxylate (38.4 mg, 0.059 mmol), 1-methyl—4—(5-(4,4,5,5-
tetramethyl-l,3,2—dioxaborolanyl)pyridinyl)piperazine (18 mg, 0.059 mmol), chloro(2-
dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-
biphenyl)]palladium(II) (XPhos Pd G2, 7.0 mg, 8.90 umol) and cesium carbonate (59.7 mg,
0.183 mmol). The vial was sealed with a Teflon-lined septum, evacuated and backfilled with
nitrogen (this process was repeated a total of three times). Then 1,4-dioxane (2.00 ml) was
added via e, followed by water (200.0 ul). The reaction mixture was heated to 60 °C for
16 h. The reaction mixture was concentrated. To the residue was added CH2C12 (2.0 mL)
ed by TFA (2.0 mL), The mixture was stirred at room temperature for 15 min, and then
concentrated. The residue was purified using prep-LCMS (XBridge C18 column, eluting with
a gradient of acetonitrile/water containing 0.1% TFA, at flow rate of 60 ) to afford
the desired product. LCMS calculated F4N7 (M+H)+: m/z = 5002; found: 5002 1H
NMR (500 MHz, DMSO-ds) 5 9.17 (d, J = 1.2 Hz, 1H), 9.05 (br, 1H), 8.82 (d, J = 2.3 Hz,
1H), 8.24 (dd, J = 8.9, 2.4 Hz, 1H), 8.20 (s, 1H), 7.92 (s, 1H), 7.82 (d, J = 9.0 Hz, 1H), 7.11
(d, J = 8.9 Hz, 1H), 4.50 (d, J = 13.0 Hz, 2H), 4.35 (t, J = 5.6 Hz, 2H), 3.54 (d, J = 11.8 Hz,
2H), 3.27 — 3.15 (m, 2H), 3.12 (s, 2H), 2.87 (s, 3H), 2.66 (t, J = 5.2 Hz, 3H) ppm.
Example 120. 1—(4-(3-(6-Cyclopropylpyridin-S-yl)—1H-pyrazolo[3,4—c]pyridinyl)—3-
fluoro—S-(trifluoromethyl)phenyl)—N—methylmethanamine
This compound was prepared according to the procedures described in Example 119,
using 2-cyclopropyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2—yl)pyridine instead of 1-
methyl(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)py1idinyl)piperazine as starting
material. LCMS calculated for C23H20F4N5 : m/z = 4422; Found: 4422.
Example 121. 1-(3-Fluoro-4—(3-(6-morpholinopyridin-S-yl)—1H-pyrazolo[3,4—c]pyridin-S-
(trifluoromethyl)phenyl)—N—methylmethanamine
This compound was prepared according to the procedures described in Example 119,
using 4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)pyridinyl)morpholine instead of
l-methyl(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)pyridinyl)piperazine as
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starting material. LCMS calculated for C24H23F4N60 (M+H)+: m/z = 4872; Found: 487.2. 1H
NMR (500 MHz, DMSO-ds) 8 9.16 (d, J = 1.2 Hz, 1H), 8.98 (br, 1H), 8.77 (d, J = 2.1 Hz,
1H), 8.24 — 8.15 (m, 2H), 7.92 (s, 1H), 7.82 (d, J = 9.5 Hz, 1H), 7.01 (d, J = 8.9 Hz, 1H), 4.35
(t, J = 5.8 Hz, 2H), 3.77 — 3.69 (m, 4H), 3.58 — 3.50 (m, 4H), 2.66 (t, J = 5.3 Hz, 3H) ppm.
Example 122. -Difluoro(3-(l-methyl-1H-pyrazolyl)—lH-pyrazolo[3,4-
c] pyridin-S—yl)phenyl)—N—methylmethanamine
Step 1. (3, 5-Difluor0(4, 4, 5, 5-tetramethyl-1, 3, 2—di0xab0rolan-Z-yUphenyflmet/aanol
ff
To a solution of 3,5-difluoro(4,4,5,5-tetramethyl-1,3,2-dioxaborolan—2—
yl)benzaldehyde (4.0 g, 14.92 mmol) in tetrahydrofuran (149 ml) was added sodium
borohydride (0.677 g, 17.91 mmol). After 2 h, the reaction was quenched with sat. sodium
bicarbonate and extracted with ethyl acetate. The separated organic layer was washed with
brine, dried over sodium sulfate and concentrated. The crude product was used in the next
step without further purification.
Step 2. 1-(3,5-Diflu0r0(3-(1-mez‘hyl-1H—pyrazolyl)-1H—pyrazolo[3,4-c]pyridin
yUphenyE)-N—meti/zylmethanamine
This compound was ed ing to the ures described in Example 86
(Step 2-4), using (3,5-difluoro(4,4,5,5-tetramethyl-1,3,2-dioxaborolan
yl)phenyl)methanol instead of (2-methyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolan
yl)phenyl)methanol as starting material. LCMS calculated for F2N6 (M+H)+: m/z =
3552; Found: 3552. 1H NMR (600 MHz, DMSO-ds) 5 9.16 (d, J = 1.2 Hz, 1H), 9.09 (br,
1H), 8.49 (s, 1H), 8.24 (s, 1H), 8.07 (d, J = 0.6 Hz, 1H), 7.43 — 7.35 (m, 2H), 4.27 (t, J = 5.5
Hz, 2H), 3.93 (s, 3H), 2.64 (t, J = 5.1 Hz, 3H) ppm.
e 123. N—(3,5-Difluoro(3-(l-methyl-1H-pyraz01—4—yl)—1H-pyrazol0[3,4—
c]pyridin-S—yl)benzyl)propan-Z-amine
This compound was prepared according to the procedures described in Example 86
(Step 2-4) and Example 122, using amine instead of methanamine as ng
material. LCMS calculated for C20H21F2N6 (M+H)+: m/z = 383.2, Found: 383.3. 1H NMR
(600 MHz, DMSO-ds) 8 9.17 (d, J = 1.2 Hz, 1H), 9.02 (br, 1H), 8.48 (s, 1H), 8.23 (s, 1H),
8.07 (d, J = 0.6 Hz, 1H), 7.46 (d, J = 8.0 Hz, 2H), 4.38 — 4.19 (m, 2H), 3.93 (s, 3H), 3.37 (dt,
J = 12.3, 6.0 Hz, 1H), 1.33 (d, J = 6.5 Hz, 6H) ppm.
Example 124. N—(3,5-Difluoro(3-(l-methyl-1H-pyrazol-4—yl)—1H-pyraz0l0[3,4—
c]pyridin-S—yl)benzyl)pyridinamine
This compound was prepared according to the procedures described in Example 86
(Step 2-4) and Example 122, using pyridinamine instead of methanamine as starting
material. LCMS calculated for C22H18F2N7 (M+H)+: m/z = 4182; Found: 418.2.
Example 125. N-(3,5-Difluoro(3-(1-methyl-1H-pyrazolyl)-1H-pyrazolo[3,4-
c] pyridin-S—yl)benzyl)— l-methyl-lH-pyrazol-S-amine
This compound was prepared according to the procedures bed in Example 86
(Step 2-4) and Example 122, using 1-methyl-1H-pyrazolamine instead of methanamine as
starting material. LCMS calculated for C21H19F2Ns : m/z = 4212; Found: 421.2.
Example 126. 2-(3,5-Diflu0r0(3-(l-methyl-1H-pyrazolyl)—1H-pyraz0lo[3,4-
c] pyridin-S-yl)benzylamin0)ethanol
This compound was prepared according to the procedures described in Example 86
(Step 2-4) and Example 122, using 2-aminoethanol instead of methanamine as starting
material. LCMS calculated for C19H19F2N60 : m/z = 3852; Found: 3852.
Example 127. 1-(2,4-Difluoro(3-(1-methyl-1H-pyrazolyl)—1H-pyrazolo[3,4-
c] pyridin-S—yl)phenyl)—N—methylmethanamine
HN\N
Step 1. (2, 4-Diflu0r0(4, 4, 5, 5-tetramethyl-1, 3, 2-dz'0xab0rolany0pheny0methanol
WO 49200
This compound was ed according to the procedures described in Example 122
(Step 1), using 2,4-difluoro(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2—yl)benzaldehyde
instead of 3,5-difluoro(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)benzaldehyde.
Step 2. 1-(2,4—Diflu0r0(3-(1-mez‘hyl-1H—pyrazolyl)-1H—pyrazolo[3,4-c]pyridin
yUphenyU-N—methylmethanamme
This compound was prepared according to the procedures described in e 86
(Step 2-4), using (2,4-difluoro(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2—
nyl)methanol instead of (2-methyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolan
yl)phenyl)methanol as starting material. LCMS calculated for C18H17F2N6 (M+H)+: m/z =
355.2; Found: 355.1.
Example 128. N-(2,4-Difluoro(3-(1-methyl-1H-pyrazolyl)-1H-pyrazolo[3,4-
c]pyridin-S—yl)benzyl)propan-Z-amine
This nd was prepared according to the procedures described in Example 86
(Step 2-4) and Example 127, using propanamine instead of methanamine as starting
material. LCMS calculated for C20H21F2N6 (M+H)+: m/z = 383.2; Found: 3832.
Example 129. N—(2,4—Difluoro(3-(1-methyl-1H-pyrazolyl)—1H-pyrazolo[3,4-
c]pyridin-S-yl)benzyl)cyclopropanamine
This compound was ed according to the procedures described in Example 86
(Step 2-4) and Example 127, using cyclopropanamine instead of methanamine as starting
material. LCMS calculated for C20H19F2N6 (M+H)+: m/z = 3812; Found: 3812
Example 130. 5-(2,6-Diflu0r0((3-methoxypiperidinyl)methyl)phenyl)—3-(1-methyl-
1H-pyrazolyl)-1H-pyraz010[3,4-c] pyridine
This nd was prepared according to the procedures described in Example 86
(Step 2-4) and e 127, using 3-methoxypiperidine instead of methanamine as starting
material. LCMS calculated for C23H25F2N60 (M+H)+: m/z = 439.2; Found: 439.2.
Example 131. 1-(3-Fluoro(3—(1-methyl-1H-pyrazolyl)—1H-pyrazolo[3,4-c] pyridin-S-
yl)(triflu0r0methyl)phenyl)—N—methylmethanamine
F CF3
I /
\ / N
/ /N
|"IN‘N
This nd was prepared according to the procedures described in e 119,
using 1-methyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-lH-pyrazole instead of 1-
methyl(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)pyn'dinyl)piperazine as starting
material. LCMS calculated for C19H17F4N6 (M+H)+: m/z = 4052; Found: 4052. 1H NMR
(600 MHz, DMSO-ds) 8 9.22 — 9.03 (m, 2H), 8.46 (s, 1H), 8.21 — 8.14 (m, 1H), 8.04 (d, J =
0.7 Hz, 1H), 7.93 (s, 1H), 7.83 (d, J = 9.5 Hz, 1H), 4.36 (t, J = 5.5 Hz, 2H), 3.92 (s, 3H), 2.66
(t, J = 5.0 Hz, 3H) ppm.
Example 132. 1-(3-Flu0r0-4—(3—(4-(4-methylpiperazinyl)phenyl)—1H-pyraz0l0[3,4-
c] pyridin-S—yl)—5—(trifluoromethyl)phenyl)—N—methylmethanamine
This compound was prepared according to the procedures described in Example 119,
using 4-(4-methylpiperazin-l-yl)phenylboronic acid instead of yl(5-(4,4,5,5-
tetramethyl—l,3,2—dioxaborolanyl)pyridinyl)piperazine as starting material. LCMS
calculated for C26H27F4N6 (M+H)+: m/z = 4992; Found: 4992. 1H NMR (500 MHz, DMSO—
(16) 5 9.20 (br, 1H), 9.16 (s, 1H), 8.14 (s, 1H), 8.02 — 7.91 (m, 3H), 7.83 (d, J = 9.1Hz, 1H),
7.15 (d, J = 9.0 Hz, 2H), 4.36 (s, 2H), 4.01 — 3.87 (m, 2H), 3.66 — 3.45 (m, 2H), 3.28 — 3.14
(m, 2H), 3.12 — 2.98 (m, 2H), 2.88 (s, 3H), 2.66 (s, 3H) ppm.
Example 133. 1-(4-(3-(1-Ethyl-1H-pyrazolyl)—1H—pyrazolo[3,4-c] pyridin-S—yl)—3—
fluoro-S-methylphenyl)—N—methylmethanamine
To a screw-cap vial equipped with a magnetic stir bar was added tert—butyl 5-(4-
(((z‘ert-butoxycarbony1)(methyl)amino)methy1)fluoromethy1phenyl)iodo-1H-
lo[3,4-c]pyridine-l-carboxylate (300.0 mg, 0.503 mmol, Example 113, Step 9), (1-
1H—pyrazolyl)boronic acid (106 mg, 0.754 mmol), chloro(2-dicyclohexylphosphino-
2',4',6'-triisopropy1-1,1'-bipheny1)[2-(2'-amino-1,1'-bipheny1)]palladium(II) (XPhos Pd G2, 40
mg, 50 umol) and potassium phosphate (213 mg, 1.006 mmol). The vial was sealed with a
Teflon-lined septum, evacuated and backfilled with nitrogen (this process was ed a
total of three times). Then 1,4-dioxane (5.00 ml) was added Via syringe, followed by water
(500.0 ul). The reaction mixture was heated to 80 0C for 2 h. The reaction mixture was
concentrated. To the residue was added CH2C12 (2.0 mL) followed by TFA (2.0 mL). The
mixture was stirred at room temperature for 15 min, and then concentrated. The residue was
purified using prep-LCMS (XBridge C18 column, eluting with a nt of
acetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min) to afford the desired
product. LCMS calculated C20H22FN6 (M+H)+: m/z = 3652, found: 365.3. 1H NMR (500
MHz, DMSO-d6) 5 9.17 (s, 1H), 8.99 (br, 1H), 8.53 (s, 1H), 8.13 (s, 1H), 8.07 (d, J = 0.6 Hz,
1H), 7.38 — 7.17 (m, 2H), 4.28 — 4.08 (m, 4H), 2.63 (t, J = 5.3 Hz, 3H), 2.18 (s, 3H), 1.44 (t, J
= 7.3 Hz, 3H) ppm.
Example 134. 1-(4-(3-(1-Cyclopropyl-1H-pyrazolyl)-1H-pyrazolo[3,4-c] pyridin-S-yl)—
3-fluoro—S-methylphenyl)—N—methylmethanamine
N/ P
\l /"l
/ /N
This compound was prepared according to the procedures described in Example 133,
using opropy1(4,4,5,5-tetramethy1-1,3,2-dioxaborolany1)-1H-pyrazole instead of
(1-ethy1-1H—pyrazoly1)boronic acid as starting material. LCMS calculated for FN6
(M+H)+; rn/z = 3772; Found: 377.2. 1H NMR (500 MHz, DMSO-ds) 5 9.17 (s, 1H), 9.02 (br,
1H), 8.54 (s, 1H), 8.18 (s, 1H), 8.05 (s, 1H), 7.36 — 7.14 (m, 2H), 4.21 (t, J = 5.6 Hz, 2H),
3.80 (ft, J = 7.5, 3.8 Hz, 1H), 2.63 (t, J = 5.2 Hz, 3H), 2.18 (s, 3H), 1.19 — 1.12 (m, 2H), 1.06
— 0.94 (m, 2H) ppm.
Example 135. 2-(4-(5-(2-Fluoromethyl((methylamino)methyl)phenyl)-1H-
pyrazolo[3,4-c]pyridinyl)-1H-pyrazol- 1-yl)benzonitrile
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This compound was prepared according to the ures described in Example 133,
using 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1H-pyrazolyl)benzonitrile
instead of (1 -ethyl-1H-pyrazolyl)boronic acid as ng material. LCMS calculated for
C25H21FN7 (M+H)+: m/z = 4382; Found: 438.1.
Example 136. 1-(3-Fluoro-5—methyl(3-(1-(tetrahydro-2H-pyranyl)-1H-pyrazol
yl)-1H-pyrazolo[3,4-c] pyridin-S-yl)phenyl)—N—methylmethanamine
F O
\l / N
/ /N
This compound was prepared according to the procedures described in Example 133,
using 1 -(tetrahydro-2H-pyranyl)(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolanyl)- 1H-
pyrazole instead of (1-ethyl-1H—pyrazolyl)boronic acid as starting material. LCMS
calculated for C23H26FN60 (M+H)+: m/z = 421.2; Found: 421.2.
Example 137. 1-(3,5-Difluoro(3-(1-methyl-1H-pyrazolyl)—1H-pyrazolo[3,4-
clpyridin-S-yl)phenyl)—N—methylcyclopropanamine
F F
“1\ /
/ /r\‘
/ /N
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This nd was prepared according to the procedures bed in Example 95,
using 1-(3,5-difluoropheny1)cyclopropanamine instead of 3-(3,5-difluorophenyl)cyclobutan-
1-amine and formaldehyde instead of propanone as starting material. LCMS calculated for
C20H19F2N6 (M+H)+: m/z = 3812; Found: 381.2.
Example 138. l-(4-Fluoro-2—methoxy-3—(3—(1-methyl-1H-pyrazol—4-yl)—lH-pyrazolo[3,4-
c] pyridin-S—yl)phenyl)-N-methylmethanamine
Step 1. tert—ButylM—fluoro-Z—methoxybenzyloxy)dimethylsilane
F 0
To a solution of (4—fluoromethoxyphenyl)methanol (1.21 g, 7 .75 mmol) in DCM
(38.7 ml) were added imidazole (0.791 g, 11.62 mmol) and TBS-Cl (9.30 ml, 9.30 mmol).
After 1 h at r.t., the reaction was quenched with water and the layers separated. The aqueous
layer was extracted withi DCM, and the combined organic layers were washed with brine,
dried over sodium sulfate and concentrated. The residue was purified by Biotage IsoleraTM
(flash purification system with ethyl acetate/hexanes at a ratio from 0 to 20%) to provide the
desired product as a brown solid. LC-MS ated for C14H24F02Si [M+H]+ m/z: 2712,
found 271.2.
Step 2. 1-(4-Flu0r0-2—methoxy-S-(S-(I-methyl-1H—pyrazolyl)-1H—pyrazolo[3,4-c]pyridin-
-yl)phenyl)—N-mez‘hylmethanamme.
This compound was prepared according to the ures described in Example 96,
using tert-buty1(4-fluoromethoxybenzyloxy)dimethylsilane instead of 2-(3,5-
difluorophenyl)ethanol as starting al. LC-MS calculated for C19H20FN60 [M+H]+ m/z:
3672, found 3672.
e 139. N-(4-Fluoro-Z-methoxy-S-(3-(l-methyl-1H-pyrazolyl)-II-I-pyrazolo[3,4-
c]pyridin-S-yl)benzyl)ethanamine
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This compound was prepared using procedures analogous to those for e 138,
with ethylamine replacing methylamine. LCMS calculated for CZOHZZFNGO [M+H]+ m/z:
381.1; Found: 381.2.
Example 140. N-(5-(2,6-Diflu0r0((isopropylamino)methyl)phenyl)-1H-pyrazolo[3,4-
c] pyridin-3—yl)—4—(4-methylpiperazinyl)benzamide
Step 1. N—(5—Br0m0-1H—pyrazolo[3, 4-c]pyrz'dmyl)(4-methylpiperazin—1—yl)benzamz'de
@NH //\N/
\ O: f 7/Nq
HN\N
To a suspension of 4-(4-methylpiperazinyl)benzoic acid (528 mg, 2.395 mmol) in
DCM (8 ml) was added DMF (12.36 ul, 0.160 mmol) and oxalyl chloride (419 pl, 4.79
mmol), and the reaction mixture was stirred until a fine white suspension replaced the
original orange one (~2 h). The mixture was then concentrated and dried under vaccum to
remove excess oxalyl chloride. THF (8 ml) was added followed by hunig's base (837 pl, 4.79
mmol). After stirring for 5 mins, tert-butyl 3-aminobromo-1H-pyrazolo[3,4-c]pyridine
carboxylate (500 mg, 1.597 mmol) was added in one portion as a solid, and the on
mixture was heated to 85 0C for 3 h. After cooling to rt, the mixture was quenched with sat.
sodium bicarbonate solution and extracted with ethyl acetate. The separated organic lay er
was dried over sodium suflate and concentrated. The residue was purified by Biotage
aTM (flash purification system with methanol/dichloromethane at a ratio from 0 to 10%)
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to provide the desired product as a brown solid (342 mg, 46%). LC-MS calculated for
C18H20BrN60 [M+H]+ m/z: 4152/4172, found 4152/4172
Step 2. utyl 3, 5-dz'flu0r0(4, 4, 5, 5-tetramez‘hyZ-1 , 3, 0xab0r01an—2—
yZ)benzyfflsopropyl)carbamate.
To a solution of 3,5-difluoro(4,4,5,5-tetramethyl-1,3,2-dioxaborolan
yl)benzaldehyde (2.5 g, 9.33 mmol) in DCE (46.6 ml) was added propan-2—amine (1.621 ml,
18.65 mmol) and acetic acid (1.602 ml, 28.0 mmol). After ng at r.t. for 30 mins, sodium
triacetoxyborohydride (3.95 g, 18.65 mmol) was added, and the reaction was stirred an
additional 1 h at r.t. The on mixture was then concentrated and redissolved in DCM (37
mL), washed with saturated sodium bicarbonate, dried over sodium sulfate and filtered.
Triethylamine (2.60 ml, 18.65 mmol) and boc-anhydride (3.25 ml, 13.99 mmol) were added
to the filtrate, and the resulting mixture was stirred at r.t. for 2 h. The mixture was ed
with water and extracted with DCM. The organic layer was dried over sodium sulfate and
concentrated. The crude product was used in the next step without further purification.
Step 3. tert—Butyl 5-(4-((tert-butoxycarb0nylfis0pr0py0amin0)methy!)-2,6-diflu0r0phenyl)
(4-(4-methylpiperazmyl)benzamido)-1H—pyra2010[3,4-c]pyridinecarb0xylate
N \ Ofl/Nq
B00
To a mixture of tert—butyl 5-bromo(4-(4-methy1piperazinyl)benzamido)-1H—
pyrazolo[3,4-c]pyridinecarboxylate (239 mg, 0.464 mmol), tert-butyl (3,5-difluoro
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(4,4,5,5-tetramethyl-1,3,2—dioxaborolanyl)benzyl)(isopropyl)carbamate (763 mg, 1.855
mmol), XPhos Pd G2 (36.5 mg, 0.046 mmol) and potassium phosphate (246 mg, 1.159
mmol) were added oxane (2 ml) and water (500 111), and the reaction flask was
evacuated, back filled with nitrogen, then stirred at 80 °C for 1 h. The reaction was then
quenched with water and extracted with ethyl acetate. The organic layer was dried over
sodium , concentrated and purified by Biotage IsoleraTM (flash purification system
with methanol/dichloromethane at a ratio from 2 to 10%) to provide the desired product as a
brown solid. LC—MS calculated for F2N7Os [M+H]+ m/z: 720.3, found 720.3.
Step 4. N-(5—(2, 6-Dl'flu0r0(fis0pr0pylamm0)methyUphenyZ)-1H—pyrazolo[3,4—c]pyridm
yl)(4-methylpiperazmyl)benzaml'de
A solution of tert-butyl 5-(4-(((z‘erz‘-butoxycarbonyl)(isopropyl)amino)methyl)-2,6-
difluorophenyl)(4-(4-methylpiperazinyl)benzamido)—1H—pyrazolo[3,4-c]pyridine
carboxylate (253 mg, 0.351 mmol) in DCM (900 111) and TFA (900 111) was stirred at r.t. for
30 mins, then concentrated and purified directly on prep-LCMS (XBridge C18 column,
eluting with a gradient of acetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min)
to provide the desired product. LC-MS ated for C23H32F2N7O [M+H]+ m/z: 520.2,
found 5202. 1H NMR (500 MHz, DMSO-ds) 5 13.57 (s, 1H), 10.94 (s, 1H), 10.10 (s, 1H),
9.12 (d, J: 1.2 Hz, 1H), 8.94 (s, 2H), 8.03 (d, J: 9.0 Hz, 2H), 7.97 (s, 1H), 7.44 (d,J= 8.2
Hz, 2H), 7.12 (d, J: 9.1 Hz, 2H), 4.32 — 4.23 (m, 2H), 4.08 (d, J: 11.4 Hz, 2H), 3.54 (s,
2H), 3.37 (dt,J= 12.2, 5.9 Hz, 1H), 3.12 (m, 2H), 2.88 (s, 3H), 1.32 (s, 3H), 1.30 (s, 3H).
e 141. N—(S-(2,6-Diflu0r0(pyrrolidinylmethyl)phenyl)—lH-pyrazolo[3,4-
c] pyridin-S—yl)—4—(4-methylpiperazinyl)benzamide
[\1\ OQNQ
HN\N
Step 1. tert—Butyl 5-(2,6-dz'flu0r0f0rmylphenyl)(4-(4-methylpz‘perazz‘nyl)benzamid0)-
azoZ0[3, 4—cjpyrz'dz'necarb0xylate
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To a e of tert—butyl 5-bromo(4-(4-methylpiperazinyl)benzamido)— 1H-
pyrazolo[3,4-c]pyridinecarboxylate (319 mg, 0.619 mmol, Example 140, Step 1), (3,5-
difluoro-4—(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)phenyl)methanol (585 mg, 2.166
mmol, Example 122, Step 1), XPhos Pd G2 (48.7 mg, 0.062 mmol) and potassium phosphate,
tribasic (263 mg, 1.238 mmol) were added 1,4-dioxane (5 ml) and water (1 ml), and the
reaction flask was evacuated and back filled with nitrogen. The reaction e was stirred
at 80 °C for 1 h. The mixture was then cooled to r.t., diluted with DCM and filtered through a
plug of Celite. The filtrate was concentrated and redissolved in DCM (4 mL). Manganese
dioxide (538 mg, 6.19 mmol) was added, and the reaction mixture was heated to 60 OC
overnight. The mixture was then filtered through a plug of Celite, and the solid washed with a
large amount of DCM. The filtrate was concentrated, and the residue was d by Biotage
IsoleraTM (flash purification system with ethyl acetate/hexanes at a ratio from 20 to 100%,
then ol/dichloromethane at a ratio from 0 to 10%) to provide the desired product as a
brown solid. LC-MS calculated for C30H31F2N604 [M+H]+ m/z: 577.2, found 5772.
Step 2. 2,6-Dl'flu0r0(pyrr01idmylmez‘hyl)phenyl)-1H—pyrazolo[3,4-c]pyridinyl)-
4-(4-methylpiperazmyl)benzamide
To a solution of tert—butyl 5-(2,6-difluoroformylphenyl)(4-(4-methylpiperazin-
1-yl)benzamido)—1H-pyrazolo[3,4-c]pyridinecarboxylate (53 mg, 0.092 mmol) and
pyrrolidine (13.07 mg, 0.184 mmol) in DCE (919 pl) were added acetic acid (15.79 ul, 0.276
mmol) and sodium triacetoxyborohydride (48.7 mg, 0.230 mmol). After stirring at r.t. for 2 h,
the mixture was ed with sat. sodium bicarbonate and extracted with DCM. The
organic layer was dried over sodium sulfate and concentrated. The residue was dissolved in a
1:1 mixture of M (1 mL) and stirred at r.t. for 30 mins, then diluted with methanol
and d directly on prep-LCMS (XBridge C18 column, eluting with a gradient of
acetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min) to provide the desired
product. LC-MS calculated for C29H32F2N7O [M+H]Jr m/z: 532.2, found 5322. 1H NMR (500
MHz, DMSO-de) 8 13.59 (s, 1H), 10.95 (s, 1H), 10.32 (s, 1H), 10.17 (s, 1H), 9.12 (d, J: 1.2
Hz, 1H), 8.04 (d, J: 9.0 Hz, 2H), 7.98 (s, 1H), 7.44 (d, J: 8.0 Hz, 2H), 7.12 (d, J: 9.1 Hz,
2H), 4.45 (d, J= 4.3 Hz, 2H), 4.08 (d, J= 10.6 Hz, 2H), 3.54 (s, 2H), 3.48 (s, 2H), 3.14 (s,
4H), 2.88 (s, 3H), 2.07 (s, 2H), 1.90 (d, J: 5.8 Hz, 2H).
Example 142. N—(S-(4-(Azetidinylmethyl)-2,6-difluorophenyl)—1H-pyraz0l0[3,4—
c] pyridin-3—yl)—4—(4—methylpiperazinyl)benzamide
F F //\N/
N \ OQNW
This compound was prepared using procedures analogous to those for example 141,
with azetadine hydrochloride replacing pyrrolidine. LCMS ated for F2N7O
[M+H]+ m/z: 5182; Found: 518.2
Example 143. N—(S-(2,6-Difluoro((3-methoxyazetidinyl)methyl)phenyl)—1H-
pyrazolo[3,4—c]pyridinyl)(4-methylpiperazinyl)benzamide
F F //\N/
“1 \ OYQ/NQ
HN\N
This compound was prepared using procedures analogous to those for example 141,
with 4-methoxy azetadine ing pyrrolidine. LCMS calculated for C29H32F2N702 [M+H]+
m/z: 5482; Found: 548.2
Example 144. N-(S-(2,6-Difluoro((methylamino)methyl)phenyl)-lH-pyrazolo[3,4-
c]pyridin-3—yl)—l-methyl-1H-pyrazole—4—carboxamide
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F F
N\ O /|\i
|/ /N
Step 1. tert—Butyl 3,5-dl'flu0r0benzyl(methyUcarbamaz‘e.
F F
To a solution of 3,5-difluorobenzaldehyde (5.0 g, 35.2 mmol) in MeOH (176 ml) was
added methanamine (21.11 ml, 42.2 mmol, 2M solution in THF) and the on mixture
was stirred for 30 mins, then sodium borohydride (1.730 g, 45.7 mmol) was added. Stirring
was continued until the bubbling subsided (~15 mins). The mixture was then concentrated,
redissolved in DCM and washed with sat. sodium bicarbonate. The organic layer was dried
over sodium sulfate and filtered. ylamine (7.36 ml, 528 mmol) and boc-anhydride
(9.80 ml, 422 mmol) were added, and the reaction mixture stirred at r.t. for 2 h. The reaction
mixture was then quenched with water and extracted with DCM. The organic layer was dried
over sodium sulfate and concentrated. The residue purified by e IsoleraTM (flash
purification system with ethyl acetate/hexanes at a ratio from 0 to 40%) to provide the d
product as a solid (9.0 g, 99%). LC-MS calculated for C13H18F2N02 [M+H]+ m/z: 258.2,
found 258.2.
Step 2. tert—Butyl 0(4-((tert-butoxycarb0nyl(methyl)amm0)methyD-Z, 6-
difluorophenyU-IH—pyrazolo[3, 4-c]pyridmecarb0xylate
/ NH2
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To a solution of tert—butyl (3,5-difluorobenzyl)(methyl)carbamate (1849 mg, 7.18
mmol) in THF (16 ml) at -78 0C was added n-BuLi (5.75 ml, 14.37 mmol, 2.5M in hexane)
dropwise. The reaction mixture stirred at -78 °C for 45 mins, and 2-isopropoxy-4,4,5,5-
tetramethyl-l,3,2-dioxaborolane (2.204 ml, 10.78 mmol) was added dropwise. The reaction
mixture was stirred at -78 °C for 30 mins, and then warmed up to r.t.. The mixture was then
quenched with water and extracted with ethyl acetate. The organic layer was dried over
sodium sulfate and trated. To the residue was added 1,4-dioxane (10 ml), followed by
a solid e of tert—butyl 3-aminobromo-1H-pyrazolo[3,4-c]py1idine—1-carboxylate
(750 mg, 2.395 mmol, Example 1, Step 3), potassium phosphate (1271 mg, 5.99 mmol) and
XPhos Pd G2 (188 mg, 0.239 mmol). Water (2.0 ml) was added, and the reaction flask was
evacuated, back filled with nitrogen. The mixture was stirred at 80 °C for 1 h. After cooling,
the mixture was diluted with water and ethyl acetate, and the layers were separated. The
aqueous layer was extracted with ethyl acetate, and the combined organic layers dried over
sodium sulfate and concentrated. The residue was purified by Biotage IsoleraTM (flash
purification system with ethyl acetate/hexanes at a ratio from 0 to 100%) to provide the
desired product as a solid (280 mg, 24%). LC-MS calculated for C24H30F2N504 [M+H]+ m/z:
4902, found 490.2.
Step 3. N—(5—(2, 6—Dz’flu0r0-4—((methylammo)methyUphenyZ)-1H-pyrazolo[3,4—c]pyridinyl)-
I-mez‘hyf—IH—pyrazolecarb0xamz'de
To a suspension of 1-methyl-1H-pyrazolecarboxylic acid (19.36 mg, 0.154 mmol)
in DCM (0.5 ml) were added DMF (0.396 ul, 5.12 umol) and oxalyl de (0.013 ml,
0.154 mmol). The reaction mixture d at r.t. for 1 h. A solution of tert-butyl o
(4-(((terz‘-butoxycarbonyl)(methyl)amino)methyl)-2,6-difluorophenyl)-1H-indazole
carboxylate (25 mg, 0.051 mmol) and Hunig's base (0.045 ml, 0.256 mmol) in THF (0.500
ml) were added. The reaction mixture was heated to 80 OCfor 3 h. The mixture was then
cooled down and concentrated. The residue was ved in a 1:1 mixture of TFA/DCM.
The resulting mixture was d at r.t. for 30 mins, diluted with methanol, and purified
directly on prep-LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water
containing 0.1% TFA, at flow rate of 60 mL/min) to provide the desired product. LC-MS
ated for C19H18F2N7O [M+H]+ m/z: 398.2, found 3982
Example 145. N—(S-(2,6-Diflu0r0((methylamino)methyl)phenyl)—1H-pyrazol0[3,4—
c] pyridin-3—yl)—3-(4-methylpiperazinyl)benzamide
\ /
F F
N\ cm
This compound was prepared using procedures analogous to those for example 144,
with ethylpiperazinyl)benzoic acid replacing 1-methyl-1H-pyrazole-4—carboxylic
acid. The reaction was med at 90 °C. LCMS calculated for C26H28F2N7O [M+H]+ m/z:
4922; Found: 492.2
Example 146. N-(5-(2,6-Diflu0r0((isopropylamino)methyl)phenyl)-1H-pyrazolo[3,4—
c]pyridin-3—yl)—3-methoxybenzamide
Step 1. tert—Butyl 3-amin0(4-((tert—butoxycarbonylfis0pr0pyl)amin0)met}2yZ)—2,6-
difluorophenyD—IH—pyrazola[3, 4-c]pyridmecarb0xylate
This compound was prepared using procedures analogous to those for example 144,
steps 1-2, with isopropyl amine replacing methyl amine. LC-MS calculated for C26H34F2NSO4
[M+H]Jr m/z: 5182, found 518.2
Step 2. N-(5-(2, 6—Dz'flu0r0(fis0pr0pylamm0)methyUphenyl)-1H-pyra2030[3,4-cjpyridm
meth0xybenzamide
To a solution of tert—butyl 3-amino(4-(((tert-
butoxycarbonyl)(isopropyl)amino)methyl)-2,6-difluorophenyl)-lH-pyrazolo[3,4-c]pyridine-
1—carboxylate (25 mg, 0.048 mmol) and Hunig's base (42.2 ul, 0.242 mmol) in THF (966 pl)
was added 3-methoxybenzoyl chloride (24.72 mg, 0.145 mmol). The resulting mixture d
at 60 °C for 2 h, and then concentrated. The e was dissolved in a 1:1 mixture of
TFA/DCM. The resulting solution was stirred at for 1 h at r.t., d with methanol, and
purified on prep—LCMS (XBridge C18 column, eluting with a gradient of itrile/water
containing 0.1% TFA, at flow rate of 60 mL/min) to provide the desired product. LC-MS
calculated for C24H24F2N502 [M+H]+ m/z: 452.2, found 452.2
Example 147. Methyl 4-(4-(5-(2,6-diflu0r0((isopr0pylamino)methyl)phenyl)—1H-
pyrazolo[3,4-c]pyridin-S-ylcarbamoyl)phenyl)piperazinecarb0xylate
F F //\N’[<
N \ o/
/ O>/©/N\J I
HN\N
Step 1. 4-(4—(BenzyloxycarbonyUpl'perazmyl)benzoic acid
To a mixture of methyl 4-bromobenzoate (1.0 g, 4.65 mmol), benzyl piperazine-l-
carboxylate (1.348 ml, 6.98 mmol), Ruphos Pd G2 (0.181 g, 0.233 mmol) and cesium
carbonate (4.55 g, 13.95 mmol) was added 1,4-dioxane (15 ml), and the reaction flask was
evacuated, back filled with nitrogen. The reaction mixture wasstirred at 80 °C overnight. The
mixture was then diluted with water and ethyl e and the layers separated. The aqueous
layer was extracted with ethyl acetate, and the combined organic layers were dried over
sodium sulfate and concentrated. The residue was purified by e IsoleraTM (flash
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purification system with ethyl acetate/hexanes at a ratio from 0 to 100%) to provide the
desired product.
The obained product was dissolved in a 1:1 mixture of THF/water (20 mL), and
lithium hydroxide (0.334 g, 13.95 mmol) was added. The resulting mixture stirred at 60 °C
overnight. The mixture was diluted with ethyl acetate and washed with 1N HCl and brine,
and then the organic phase was dried over sodium sulfate and trated. The crude solid
was used in the next step without further purification. LC-MS calculated for C19H21N204
[M+H]+ rn/z: 341.2, found 341.2.
Step 2. tert—Butyl 5-(4-((tert-butoxycarbonylfisopropyyammo)methyl)-2, 6-dz'flu0r0phenyl)
(4-09iperazin—1-yl)benzamid0)-1H—pyra2010[3,4-c]pyridinecarb0xylate
F F //\NH
N \ onNJ
B0 c/
To a solution of 4-(4-((benzyloxy)carbonyl)piperazinyl)benzoic acid (165 mg,
0.484 mmol) in DCM (968 pl) were added DMF (1.5 ul, 0.019 mmol) and oxalyl de
(85 ul, 0.968 mmol). The on mixture was d for 15 minutes, and then concentrated.
Toluene was added, and the ing mixture concentrated. The resulting foam was dried
under high vacuum for 2 h. The resulting solid was then dissolved in THF (968 ill), and
Hunig's base (169 pl, 0.968 mmol) was added. A on of tert—butyl o-5—(4-(((tert—
butoxycarbonyl)(isopropyl)amino)methyl)—2,6-difluorophenyl)-1H-indazole—1 -carboxylate
(100 mg, 0.194 mmol, Example 122, Step 1) in THF was added, and the resulting mixture
was stirred at 85 °C overnight. The reaction mixture was quenched with water and extracted
with ethyl acetate. The organic layer was dried over sodium sulfate, concentrated and purified
by Biotage IsoleraTM (flash purification system with ethyl acetate/hexanes at a ratio from 0 to
100%) to provide the desired product as a solid.
The obtained solid was dissolved in methanol (2 mL), and palladium on carbon (41.2
mg, 0.039 mmol) was addded. The reaction flask was evacuated and back filled with
hydrogen gas from a balloon. After stirring at r.t. for 1h, the mixture was d through a
plug of Celite, and the filtrate was concentrated. The crude product (71 mg, 52%) was used in
the next step without further purification. LC-MS calculated for C37H46F2N705 [M+H]+ m/z:
7063, found 706.3.
Step 3. Methyl 4—(4-(5—(2, 6-dl'fluor0((isopropylamino)methyUphenyZ)—IH—pyrazol0[3, 4-
cjpyrz'dm—3—ylcarbamoyyphenybpiperazinecarboxylare.
To a solution of tert—butyl 5-(4-(((tert—butoxycarbonyl)(isopropyl)amino)methyl)-2,6-
difluorophenyl)—3—(4-(piperazinyl)benzamido)- 1H-pyrazolo [3 ,4-c]pyridinecarboxy1ate
(14 mg, 0.020 mmol) and Hunig's base (17.32 ul, 0.099 mmol) in DCM (400 pl) was added
methyl chloroformate (4.61 ul, 0.060 mmol). The reaction mixture was stirred at r.t. for 30
mins, TFA was added, and the stirring was continued for an onal 30 mins. The mixture
was then diluited with methanol and purified on prep-LCMS (XBridge C18 column, eluting
with a gradient of itrile/water containing 0.1% TFA, at flow rate of 60 ) to
provide the desired product. LC-MS calculated for C29H32F2N7O3 [M+H]+ m/z: 5642, found
5642.
Example 148. Methyl 4-(4-(5-(2,6-difluoro((isopropylamino)methyl)phenyl)-1H-
pyrazolo[3,4-c]pyridinylcarbamoyl)—3-fluorophenyl)piperazine- oxylate
This compound was prepared in an analogous n to Example 147, with methyl 4-
bromo-2—fluorobenzoate replacing methyl 4-bromobenzoate in Step 1. LC-MS calculated for
C29H31F3N7O3 [M+H]+ m/z: 582.2, found 582.2.
Example 149. N-(S-(2,6-Difluoro—4-((isopropylamino)methyl)phenyl)- lH-pyrazolo [3,4-
c]pyridin-3—yl)—2-methoxy(4-methylpiperazinyl)benzamide
/’/ NuNH O
HN\N \
Step 1. tert—Butyl 5-(4-((tert-butoxycarb0nylfis0pr0py0amin0)methyl)-2, 6-diflu0r0phenyl)
(2-mez‘h0xy—4—(piperazmyl)benzamido)-1H—pyrazolo[3, 4-c]pyridmecarb0xylate
/N\N 0\
S This compound was prepared using the procedure outlined in Example 147, steps 1-2,
with methyl 4-bromomethoxybenzoate replacing methyl obenzoate. LC-MS
calculated for C38H48F2N706 [M+H]Jr m/z: 736.3, found 736.3.
Step 2. N—(5—(2,6—Diflu0r0(fis0pr0pylamin0)methyUphenyl)-1H—pyrazoi0[3,4—cjpyridl'n
yl)-2—met}20xy—4—(4-methylpl'perazmyl)benzamide
To a solution of tert—butyl 5-(4-(((tert—butoxycarbony1)(isopropyl)amino)methy1)-2,6-
difluorophenyl)—3-(2-methoxy(piperaziny1)benzamido)-1H-pyrazolo[3,4-c]pyridine
carboxylate (17 mg, 0.023 mmol), paraformaldehyde (10.51 ul, 0.116 mmol) and acetic acid
(3.97 ul, 0.069 mmol) was added sodium triacetoxyborohydride (14.69 mg, 0.069 mmol).
The reaction mixture was stirred at r.t. for 1 h. TFA (0.5 mL) was added, and the stirring was
continued for 30 mins at r.t. The mixture was diluted with methanol and purified on prep-
LCMS (XBridge C18 column, eluting with a gradient of itrile/water containing 0.1%
TFA, at flow rate of 60 mL/min) to provide the desired product. LC-MS ated for
C29H34F2N702 [M+H]+ m/z: 5502, found 550.2.
Example 150. 2,6-Difluoro((isopropylamino)methyl)phenyl)-lH-pyrazolo[3,4-
c]pyridin-3—yl)—2—fluoro-3—(4-methylpiperazinyl)benzamide
F F F
N\ Oyé
This compound was prepared in an analogous fashion to Example 149, with methyl 3-
2—fluorobenzoate replacing methyl o benzoate in Step 1. LC-MS calculated for
C28H31F3N7O r m/z: 538.2, found 538.2.
e 151. N—(S-(2,6-Diflu0r0((isopropylamino)methyl)phenyl)-1H-pyrazolo[3,4—
c] pyridinyl)fluoro-3—(4-methylpiperazinyl)benzamide
This compound was prepared in an analogous fashion to Example 149, with methyl 3-
bromofluorobenzoate replacing methyl 4-bromo benzoate in Step 1. LC—MS calculated for
C28H31F3N7O [M+H]+ m/z: 538.2, found 538.2.
Example 152. N-(S-(2-Flu0r0methylphenyl)-1H-pyrazolo [3,4-c] pyridin-S-yl)(4-
methylpiperazin—1-yl)benzamide
F //\N/
[\1 \ OYQ/Nu
HN\N
To a mixture of tert—butyl 5-bromo(4-(4-methylpiperazinyl)benzamjdo)-1H—
pyrazolo[3,4-c]py1idinecarboxylate (20 mg, 0.039 mmol, Example 140, Step 1), (2-fluoro-
6-methylphenyl)boronic acid (9 mg, 0.058 mmol), XPhos Pd G2 (3.05 mg, 3.88 umol) and
potassium phosphate (16.47 mg, 0.078 mmol) were added 1,4-dioxane (323 pl) and water (64
ul). The reaction flask was evacuated and backfilled with nitrogen. The reaction mixture was
stirred at 80 °C for 1 h. The mixture was cooled to r.t. and quenched with water. The mixture
was extracted with ethyl acetate, and the organic layer was dried over sodium sulfate and
concentrated. The residue was dissolved in a 1:1 mixture of DCM/TFA. The resulting
mixture was stirred at r.t. for 30 mins, diluted with methanol, and purified on prep-LCMS
(XBridge C18 column, eluting with a gradient of itrile/water containing 0.1% TFA, at
flow rate of 60 mL/min) to provide the desired product. LC-MS calculated for C25H26FN6O
[M+H]+ m/z: 445.2, found 445.2. 1H NMR (600 MHz, DMSO-ds) 5 13.50 (s, 1H), 10.89 (s,
1H), 9.87 (s, 1H), 9.12 (d, J: 1.1 Hz, 1H), 8.03 (d, J: 9.0 Hz, 2H), 7.81 (s, 1H), 7.36 (td, J:
8.0, 6.0 Hz, 1H), 7.15 (dd, J = 24.4, 8.3 Hz, 2H), 7.11 (d, J: 9.0 Hz, 2H), 4.08 (d, J: 12.6
Hz, 2H), 3.54 (d, J: 11.1 Hz, 2H), 3.12 (dt, J: 24.9, 10.5 Hz, 4H), 2.87 (s, 3H), 2.15 (s,
Example 153. Z-Fluoro-G-(trifluoromethyl)phenyl)—1H-pyraz010[3,4-c]pyridin-S-
yl)(4-methylpiperazinyl)benzamide
F CF3 r/\N’_
v.19\\ o N\’J
This compound was ed in an analogous fashion to e 152, with (2-fluoro-
fluoromethyl)phenyl)boronic acid replacing (2-fluoromethylphenyl)boronic acid. LC-
MS calculated for C25H23F4N60 [M+H]+ m/z: 499.2, found 499.2
Example 154. N-(S-(4-((Ethylamino)methyl)—2—fluor0(trifluoromethyl)phenyl)—1H-
pyrazolo[3,4-c]pyridinyl)(4-methylpiperazinyl)benzamide
F CF3 //\N/
Nb 0%”
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Step 1. tert—Butyl ez‘hyl(3-flu0r0(4, 4, 5, 5—tetramez‘hyl-1, 3, ab0r01an-2—yD
(trifluoromethybbenzyl)carbamate
This compound was prepared in an analogous fashion to e 144 (Steps 1-2),
with 3-fluoro(trifluoromethyl)benzaldehyde replacing 3,5-difluorobenzaldehyde and
ethanamine replacing methanamine. LC-MS calculated for C21H31BF4NO4 [M+H]+ m/z:
448.2, found 448.2.
Step 2. N-(5-(4-((Ethylamin0)methyU-Z—fluoro(trl'flu0r0methy0phenyl)-]H—pyra2010[3, 4-
cjpyrl'dmyl)-4—(4-methylpiperazz‘nyl)benzaml'de
This compound was prepared in an analogous fashion to e 152, with z‘ert-butyl
ethyl(3-fluoro(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)
(trifluoromethyl)benzyl)carbamate replacing (2-fluoromethylphenyl)boronic acid. LC-MS
calculated for C23H30F4N7O [M+H]Jr m/z: 556.2, found 556.2.
Example 155. 5—(2,6-Difluoro—4-((isopr0pylamino)methyl)phenyl)—N—(4—(4—
methylpiperazin—1-yl)phenyl)—1H-pyrazolo[3,4-c] pyridine-S-carboxamide
F F
I o
/ N//\N/
HN\N N/Q/ \J
Step 1. Ethyl 5-ch10r0((2-(trimethylsilyl)ethow)methyl)-1H—pyra2010[3, ridme
carboxylate
W0 2018f049200
,N~N O’\
-Chloroiodo((2-(trimethylsilyl)ethoxy)methyl)-1H—pyrazolo[3,4-c]pyridine
(3.157 g, 7.71 mmol, Example 42, Step 2) was dissolved in DMF (11.56 ml) and l
(7.71 ml). Triethylamine (3.22 ml, 23.12 mmol) was added, followed by dppf—PdClz (0.629 g,
0.771 mmol). The reaction flask was evacuated and back filled with CO gas from a balloon.
The resulting solution was stirred at 80 °C overnight. The reaction mixture was quenched
with water and extracted with ethyl acetate. The organic layer was washed with water and
brine, dried over sodium suflate, and concentrated. The residue was d by Biotage
IsoleraTM (flash purification system with ethyl acetate/hexanes at a ratio from 0 to 75%) to
provide the desired product. LC-MS calculated for C15H23C1N3O3Si [M+H]+ m/z: 3562,
found 3562
Step 2. 5—Ch10r0-N-(4-(4-methylpzperazm-I-yUphenyZ)((2-(trimethylsiiy0ethoxy)methyl)-
1H-pyrazoZo[3, 4-cjpyridinecarboxamz'de
MM ”QC
To a mixture of ethyl 5S-chloro((2-(trimethylsilyl)ethoxy)methyl)-1H—pyrazolo[3,4-
c]pyridinecarboxylate (82 mg, 0.230 mmol) and 4-(4-methylpiperazinyl)aniline (88 mg,
0.461 mmol) in THF (1152 ul) was added ium tert-butoxide (922 pl, 0.922 mmol), and
the reaction mixture stirred at r.t. for 30 mins. The reaction was then quenched with water
and extracted with ethyl acetate. The organic layer was dried over sodium e and
concentrated. The residue was purified by Biotage IsoleraTM (flash purification system with
ol/dichlromethane at a ratio from 2 to 10%) to provide the desired t. LC-MS
calculated for C24H34ClN602Sl [M+H]+ m/z: 501.2, found 501.2.
Step 3. 5-(2, 6-Diflu0r0-4—f0rmylphenyl)-N-(4-(4-methy4pz‘perazz‘nyZ)phenyZ)-1 -((2-
(trimethyZSiZyl)ethoxy)methyl)-1H-pyraz010[3, 4-c]pyrz‘dz‘necarboxamz'de
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To a mixture of 5-chloro-N—(4-(4-methylpiperazinyl)phenyl)((2-
(trimethylsilyl)ethoxy)methyl)-IH-pyrazolo[3,4-c]pyridinecarboxamide (250 mg, 0.499
mmol), (3,5-difluoro(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)phenyl)methanol (202
mg, 0.748 mmol), Xphos Pd G2 (39.3 mg, 0.050 mmol) and potassium phosphate (212 mg,
0.998 mmol) were added 1,4-dioxane (2079 ul) and water (416 pl), and the reaction flask was
evacuated and back filled with nitrogen. The reaction mixture was stirred at 80 °C for 1 h.
The mixture was cooled to r.t., quenched with water and extracted with ethyl acetate. The
separated organic layer was dried over sodium sulfate and concentrated. The e was
dissolved in DCM (4 mL), and ese dioxide (434 mg, 4.99 mmol) was added. The
reaction e was heated to 60 °C for 1 h then filtered through a plug of Celite. The
filtrate was concentrated, and the residue was purified by Biotage IsoleraTM (flash
purification system with methanol/dichlromethane at a ratio from 2 to 10%) to provide the
desired product. LC—MS ated for C31H37F2N603Sl [M+H]Jr m/z: 6072, found 6072.
Step 4. 5-(2, 6—Diflu0r0((l'sapropylamin0)methyl)phenyZ)-N-(4-(4-methygaiperazin-I-
yUphenyU-IH—pyrazoloB, 4-c]pyridmecarboxamide
To a on of 5-(2,6-difluoroformylphenyl)-N-(4-(4-methylpiperazin—l-
yl)phenyl)((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridinecarboxamide
(50 mg, 0.082 mmol) and amine (13.49 ul, 0.165 mmol) in toluene (824 pl) was
added acetic acid (14 ul, 0.247 mmol), and the mixture was heated to 80 °C. After 1 h, it was
cooled to r.t. and methanol (1 mL) was added. Sodium borohydride (6.24 mg, 0.165 mmol)
was then added at r.t. After 5 mins, 4N HCl in dioxane (1 mL) was added, and the reaction
mixture heated to 80 0C for 1h. The mixture was then cooled to r.ti, diluted with ol
and purified on prep—LCMS (XBridge C18 column, eluting with a gradient of
acetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min) to provide the desired
product. LC-MS calculated for C28H32F2N7O [M+H]Jr m/z: 5202, found 5202
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Example 156. N—(S-(2,6—Difluoro(2-(pyrrolidinyl)acetamido)phenyl)—1H-
pyrazolo[3,4-c]pyridinyl)(4-methylpiperazinyl)benzamide
HNjL/D
N \ OQNQ
Step 1. utyl min0-2, 6—dl'flu0r0phenyl)(4-(4-mez‘hylpiperazm-I-yl)benzamid0)-
1H—pyrazolo[3,4-c]pyridinecarboxylate
F F //\N/
"1 \ OYQ/NQ
To a mixture of tert—butyl 5-bromo(4-(4-methy1piperazinyl)benzamido)-1H-
pyrazolo[3,4-c]pyridinecarboxylate (200 mg, 0.388 mmol, Example 140, Step 1), 3,5-
difluoro-4—(4,4,5,5-tetramethyl-1,3,2-dioxaborolany1)aniline (198 mg, 0.776 mmol,
Example 63, Step 1), XPhos Pd G2 (28.0 mg, 0.039 mmol) and potassium phosphate (206
mg, 0.970 mmol) were added 1,4-dioxane (3234 ul) and water (647 pl), and the reaction flask
was evacuated, back filled with nitrogen. The reaction mixture was stirred at 80 0C for 2 h.
The e was cooled to r.t., diluted with DCM and filtered through a plug of Celite. The
filtrate was concentrated and used in the next step without further purification. LC-MS
calculated for C29H32F2N7O3 [M+H]+ m/z: 564.2, found 564.2.
Step 2. 2,6—Dz‘flu0ro(2—(pyrroll'dmyl)acetamid0)phenyl)-1H-pyra2010[3,4-
cjpyrl'dmyl)-4—(4-methylplperazmyl)benzamide
To a solution of tert—butyl 5-(4-amino-2,6-difluorophenyl)(4-(4—methylpiperazin—1-
yl)benzamido)-lH-pyrazolo[3,4-c]pyridinecarboxy1ate (21 mg, 0.037 mmol) and Hunig's
base (19.52 ul, 0.112 mmol) in DCM (745 pl) at 0 °C was added 2-chloroacetyl chloride
(4.45 ul, 0.056 mmol), and the reaction mixture was warmed up to r.t. and stirred for 1 h. The
W0 2018f049200 2017/050737
reaction mixture was then ed with water and ted with DCM. The organic layer
was dried over sodium sulfate and concentrated.
The residue was dissolved in DMF (745 gal), and pyrrolidine (15.41 ul, 0.186 mmol)
was added. The mixture was stirred at 50 °C for 1 h, then cooled to r.t., quenched with water
and extracted with ethyl acetate. The organic layer was washed with water and brine, dried
over sodium sulfate and concentrated. The residue was dissolved in a 1:1 mixture of
DCMzTFA and stirred at It. for 1 h. The mixture was diluted with methanol and purified on
prep-LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing
0.1% TFA, at flow rate of 60 mL/min) to provide the desired product. LC-MS calculated for
C30H33F2N802 [M+H]+ m/z: 575.2, found 575.2
Example 157. 2-Amino-N-(5-(2-fluoromethylphenyl)-lH-pyrazolo[3,4-c]pyridinyl)—
4-(4-methylpiperazinyl)benzamide
F H N2 flN’
N/ O Nd
Step 1. tert—Butyz’ 3-amz'n0-5—(Z-fluoromethylphenyl)-1H-pyrazolo[3,4—c]pyridine
yfate
To a mixture of tert—butyl 3-aminobromo-1H-pyrazolo[3,4-c]pyridine
carboxylate (1.79 g, 5.72 mmol), (2-fluoromethylphenyl)boronic acid (1.320 g, 8.57
mmol), XPhos Pd G2 (0.225 g, 0.286 mmol) and potassium phosphate (2.427 g, 11.43 mmol)
were added 1,4-dioxane (15.24 ml) and water (3.81 ml), and the reaction flask was evacuated
and back filled with nitrogen. The reaction mixture was stirred at 80 °C for 1 h. The mixture
was then diluted with ethyl e and water, and the layers were separated. The organic
layer was dried over sodium e and concentrated. The e was purified by Biotage
IsoleraTM (flash purification system with ethyl acetate/hexanes at a ratio from 0 to 100%) to
W0 2018/‘049200
e the desired product as a brown powder (1.7 g, 87%). LC-MS calculated for
C18H20FN402 [M+H]+ m/z: 343.2, found 343.2.
Step 2. tert—Butyl 3-(4-fluor0m'trobenzamz‘do)(2-fluor0methylphenyb—1H—
pyrazolo[3, 4—c]pyridinecarb0xylate
To a suspension of 4-fluoronitrobenzoic acid (595 mg, 3.21 mmol) in DCM (7 mL)
was added DMF (11.31 ul, 0.146 mmol) and oxalyl chloride (281 ul, 3.21 mmol), and the
reaction mixture was stirred at r.t. until homogeneous (~1 h). To the mixture was added a
on of tert-butyl 3-amino(2-fluoromethylphenyl)—1H—pyrazolo[3,4-c]pyridine
carboxylate (500 mg, 1.460 mmol) and Hunig's base (765 ul, 4.38 mmol) in THF (7 mL). The
mixture was stirred at r.t. overnight. 1-Methylpiperazine (488 ul, 4.38 mmol) was added, and
the on mixture was stirred for an additional 1 h at r.t. The mixture was filtered h a
plug of Celite, and the filtrate was trated. The residue was purified by Biotage
IsoleraTM (flash purification system with ethyl acetate/hexanes at a ratio from 0 to 100%) to
provide the desired product as a pale yellow solid (524 mg, 70%). LC-MS calculated for
C25H22F2N505 [M+H]Jr m/z: 510.2, found 510.2.
Step 3. 2-Amin0—N-(5-(2flu0r0-6—methylphenyl)-1H—pyra2010[3,4-c]pyridin-3—yl)—4-(4-
methylpiperazin-I-yl)benzamide
To solution of utyl 3-(4-fluoronitrobenzamido)(2-fluoro-6—methylphenyl)-
azolo[3,4-c]pyridinecarboxylate (524 mg, 1.029 mmol) and Hunig's base (539 pl,
3.09 mmol) in DMSO (10 mL) was added 1-methylpiperazine (229 ul, 2.057 mmol), and the
reaction mixture was heated to 90 °C for 3 h. The mixture was quenched with water and
extracted with ethyl acetate. The organic layer was washed with water and brine, dried over
sodium sulfate and concentrated to provide the desired product. The crude product was
ved in methanol (10 mL), and palladium on carbon (386 mg, 0.363 mmol) was added.
The reaction flask was evacuated and back filled with hydrogen gas from a balloon. The
reaction mixture was stirred at 55 °C for 1 h. The mixture was filtered through a plug of
, and the filtrate was purified on prep-LCMS (XBridge C18 column, eluting with a
nt of acetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min) to provide the
desired product. LC-MS calculated for C25H27FN7O [M+H]‘r m/z: 4602, found 460.2.
Example 158. N—(S-(2-Fluoro—6—methylphenyl)—lH-pyrazolo [3,4-c] pyridin-3—yl)—2-(2-
hydroxypropylamino)—4—(4—methylpiperazinyl)benzamide
r/<bH
F HN //\N/
To a on of 2-amino-N—(5-(2-fluoromethylphenyl)-1H—pyrazolo[3,4—c]pyridin-
3-yl)(4-methylpiperazinyl)benzamide (15 mg, 0.033 mmol, Example 157),
tetramethylammonium triacetoxyborohydride (42.9 mg, 0.163 mmol) and TFA (12.57 ul,
0.163 mmol) in DCE (653 pl) was added 2-((z‘ert-butyldimethylsilyl)oxy)propanal (18.4 mg,
0.098 mmol). The reaction mixture was stirred at r.t. for 5 mins, ed with TFA (0.5
mL), and allowed to stir overnight. The reaction mixture was diluted with ol and
purified on prep-LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water
containing 0.1% TFA, at flow rate of 60 mL/min) to provide the desired product. LC-MS
calculated for C23H33FN702 [M+H]+ m/z: 518.2, found 518.2.
Example 159. N—(S-(2-Flu0r0-6—methylphenyl)—1H-pyrazolo ] pyridin-3—yl)—2—((1-
methyl-lH-pyrazol-S-yl)methylamin0)(4-methylpipcrazinyl)benzamide
F HN //\N/
N’I OYUNV
HN\N
This compound was prepared in an analogous n to Example 158, with l-methyl-
1H—pyrazole—4—carbaldehyde replacing 2-((tert—butyldimethylsilyl)oxy)propanal. LC-MS
calculated for C30H33FN90 [M+H]Jr m/z: 554.2, found 5542.
Example 160. 2-(3-Cyanocyclopentylamino)—N—(5-(2-flu0r0methylphenyl)—1H-
pyrazolo[3,4-c]pyridinyl)(4-methylpiperazinyl)benzamide
F HN //\N/
N/ 0 Nu
This compound was prepared in an analogous fashion to Example 158, with 3-
oxocyclopentane-l-carbonitrile ing 2-((z‘ert-butyldimethylsilyl)oxy)propanal. LC-MS
calculated for C31H34FNsO [M+H]+ m/z: 5532, found 553.2.
Example 161. 2-(4-(5-(2,6-Diflu0r0((methylamino)methyl)phenyl)—lH-pyrazolo[3,4-
c] pyridin-3—yl)-1H-pyrazolyl)benz0nitrile
Step 1. utyl (tert-butoxycarbonylfinethyUamin0)methyl)-2,6-dz'fluor0phenyU
i0d0-1H—pyrazolo[3, 4-c]pyridmecarb0xylate
This compound was prepared according to the procedures described in Example 119,
step 1-3 using 3,5-difluorobenzaldehyde instead of 3-fluoro(trifluoromethyl)benzaldehyde
as starting material. LCMS calculated for C24H28FZIN404 (M+H)+: m/z = 601.1; Found:
601.0.
Step 2. 2-(4-(5-(2, 6-Dz'flu0r0((methylamin0)methyl)phenyl)-1H-pyra2010[3, 4-cjpyrz'dm
yl)—1H—pyrazol—I-yDbenzonitrile
A mixture of tert—butyl 5-(4-(((terz‘-butoxycarbonyl)(methyl)amino)methyl)—2,6-
ophenyl)—3-iodo-1H-pyrazolo[3,4-c]pyridinecarboxylate (20 mg, 0.033 mmol), 2-
(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1H-pyrazolyl)benzonitrile (29.5 mg,
0.100 mmol), (1,1'-bis(diphenylphosphino)ferrocene)-dichloropalladium(II) complexed with
dichloromethane (1:1) (2.72 mg, 3.33 umol) and potassium ate (13.81 mg, 0.100
mmol) in dioxane (2 mL) and water (0.4 mL) was d at 70 °C for 2 h. After cooling to
room temperature, the mixture was concentrated in vacuo. The crude mixture was then
dissolved in DCM (2.0 mL), and TFA (2.0 mL) was added se at room temperature.
After stirring for 2 h, the mixture was concentrated in vacuo. The crude mixture was
dissolved in MeOH (3.5 mL) and 10% s NH4OH (1.5 mL). The mixture was purified
with prep-LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water
containing 0.1% TFA, at flow rate of 60 mL/min) to give the desired t. LCMS
calculated for C24H18F2N7 (M+H)+: m/z = 442.2; Found: 4422.
Example 162. 1-(4-(3-(1-(Azetidinyl)—1H-pyrazolyl)—1H-pyrazolo[3,4-c]pyridin-S-
yl)—3,5—difluor0phenyl)-N-methylmethanamine
This compound was prepared according to the procedures described in Example 161,
step 7 using tert-butyl 3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-lH-pyrazol-l-
yl)azetidine—1-carboxylate instead of 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1H-
pyrazol-l-yl)benzonitrile as starting material. LC-MS calculated for C20H20F2N7 (M+H)+ :
m/z = 396.2; found 396.2.
Example 163. 1-(3,5-Difluoro(3-(2-(4-methylpiperazinyl)pyridinyl)-1H-
pyrazolo[3,4-c]pyridinyl)phenyl)—N—methylmethanamine
This nd was prepared according to the procedures described in Example 161,
step 7 using l-methyl(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)pyridin
yl)piperazine instead of 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-lH-pyrazol-lyl
)benzonitrile as starting material. LC-MS calculated for C24H26F2N7 (M+H)+: m/z = 450.2;
found 4502.
Example 164. 2-(4-(5-(2,6-Difluoro—4—((methylamino)methyl)phenyl)-lH—pyrazolo[3,4-
c] pyridin-3—yl)- lH-pyrazol- 1-yl)ethanol
This nd was prepared according to the procedures described in Example 161,
step 7 using 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-lH-pyrazol-l-yl)ethanol
instead of 4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-lH-pyrazol-l-yl)benzonitrile as
starting material. LC—MS calculated for C19H19F2N60 (M+H)+: m/z = 3852; found 385.2.
e 165. l-(3,5-Difluoro—4-(3-(4-methoxyphenyl)—1H-pyrazolo[3,4-c] pyridin-S-
yl)phenyl)—N—methylmethanamine
This nd was prepared according to the procedures described in Example 161,
step 7 using (4—methoxyphenyl)boronic acid instead of 2-(4-(4,4,5,5-tetramethyl—1,3,2-
dioxaborolanyl)-1H-pyrazolyl)benzonitrile as starting material. LC-MS calculated for
C21H19F2N4O (M+H)+: m/z = 3812; found 381.1.
Example 166. 1-(5-(5-(2,6-Diflu0r0-4—((methylamino)methyl)phenyl)—lH-pyrazolo[3,4-
c]pyridinyl)pyridin-2—yl)piperidin-4—ol
Step 1. tert—Butyl 3, 5-dl'flu0r0(3-l'0d0((2—(trimethylsilyl)ethoxy)methyZ)-1H—
pyrazolo[3, 4—0]pyridinyl)benzyl(methyl)carbamaz‘e
To a solution of tert-butyl ifluoro(3-iodo-1H-pyrazolo[3,4-c]pyridin-S-
yl)benzyl)(methyl)carbamate (380 g, 7.60 mmol, Example 161, Step 5) in THF (38 mL) was
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added N,N-diisopropylethylamine (1.99 mL, 11.4 mmol) and 2-(trimethylsilyl)ethoxymethyl
chloride (1.42 mL, 7.98 mol) at r.t. After stirring for 18 h, the mixture was quenched with
water (60 mL) and extracted with ethyl acetate. The solvents of the ted organic layers
were evaporated under reduced pressure to give the crude t. The obtained crude
t was purified by Biotage IsoleraTM to give the desired product. LCMS calculated for
C25H34F21N4O3Si (M+H)+: m/z = 631.1, Found: 631.2.
Step 2. tert—Butyl 4-(3-(6-ch10r0pyridmyl)((2-(trimethylsilyl)ethoxy)methyl)—1H—
lo[3, 4-c]pyridinyl) -3, 5-dl'flu0r0benzyl(methyl)carbamate
A mixture of tert-butyl (3,5-difluoro(3-iodo-l-((2-(trimethylsilyl)ethoxy)methyl)-
lH-pyrazolo[3,4-c]pyridinyl)benzyl)(methyl)carbamate (176 mg, 0.279 mol), (6-
chloropyridinyl)boronic acid (48.3 mg, 0.307 mmol), (1,l'-
bis(diphenylphosphino)ferrocene)-dichloropalladium(II) complexed with dichloromethane
(1:1) (22.80 mg, 0.028 mmol) and potassium carbonate (77 mg, 0.558 mmol) in dioxane (20
mL) and water (4 mL) was stirred at 70 °C for 2 h. After cooling to r.t., the mixture was
trated in vacuo. The obtained crude t was purified by Biotage IsoleraTM to give
the desired product. LCMS calculated for C30H37C1F2N503Si (M+H)+: m/z = 616.2; Found:
616.3.
Step 3. 1-(5-(5-(2, 6—Diflu0r0((methylamin0)methyl)phenyl)-1H-pyrazo[0[3, 4-cjpyridl'n
yUpyrl'dm-2—yl)piperidinol
A mixture of tert—butyl (4-(3-(6-chloropyridinyl)((2-
(trimethylsilyl)ethoxy)methyl)-lH-pyrazolo[3,4-c]pyridiny1)-3,5-
difluorobenzyl)(methyl)carbamate (15 mg, 0.024 mmol), piperidinol (4.92 mg, 0.049
mmol), RuPhos Pd G3 (2.0 mg, 2.43 umol) and cesium carbonate (23.8 mg, 0.073 mmol) in
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dioxane (1 ml) was stirred at 90 °C for 3 h. After cooling to room temperature, the mixture
was concentrated in vacuo. The crude e was ved in DCM (2.0 mL), and TFA (2.0
mL) was added dropwise at room temperature. After stirring for 2 h, the mixture was
concentrated in vacuo. The crude mixture was dissolved in MeOH (3.5 mL) and 10%
aqueous NH4OH (1.5 mL), The ing e was purified with prep-LCMS (XBridge
C18 column, eluting with a gradient of acetonitrile/water containing 0.1% TFA, at flow rate
of 60 mL/min) to give the desired product. LCMS calculated for C24H25F2N6O (M+H)+: m/z
= 451.2, Found: 451.2.
Example 167. 1-(3,S-Diflu0r0(3-(5—(3—fluoropyrrolidinyl)pyridinyl)—1H-
pyrazolo[3,4—c]pyridin-S-yl)phenyl)—N—methylmethanamine
Step 1. tert—Butyl 4-(3-(5-ch10r0pyridinyl)((2—(z‘rz‘mez‘hylsz‘lyl)ethoxy)methyl)—1H—
pyra2010[3, rz'dz'nyl) -3, 5-dz'flu0r0benzyl(methyl)carbamate
A mixture of tert—butyl (3,5-difluoro(3-iodo((2-(trimethylsilyl)ethoxy)methyl)—
1H—pyrazolo[3,4-c]pyridinyl)benzyl)(methyl)carbamate (874 mg, 1.39 mmol, Example
166, Step 1), 5-chloro(tributylstannyl)pyridine (614 mg, 1.53 mmol),
tetrakis(triphenylphosphine)palladium(0) (160 mg, 0.139 mmol) and CuI (52.8 mg, 0.277
mmol) in dioxane (30 mL) was stirred at 100 °C for 2 h. After cooling to room temperature,
the mixture was concentrated in vacuo. The obtained crude product was purified by Biotage
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IsoleraTM to give the desired product. LCMS calculated for C30H37C1F2N503Si (M+H)+: m/z
= 6162; Found: 6161.
Step 2. 1—(3,5—Diflu0r0-4—(3-(5-(3-flu0r0pyrrolz'dz‘nyZ)pyrz‘dz'n-2—yl)—1H—pyrazolo[3,4-
cjpyridin—5—y0phenyl)-N-methylmethanamine
A mixture of tert—butyl (4-(3-(5-chloropyridinyl)((2-
(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridinyl)-3,5-
difluorobenzyl)(methyl)carbamate (22 mg, 0.036 mmol), 3-fluoropyrrolidine (6.36 mg, 0.071
mmol), RuPhos Pd G3 (2.98 mg, 3.57 umol) and cesium carbonate (34.9 mg, 0.107 mmol) in
dioxane (1 ml) was stirred at 90 °C for 3 h. After cooling to room temperature, the mixture
was concentrated in vacuo. The crude mixture was then dissolved in DCM (2.0 mL), and
TFA (2.0 mL) was added dropwise at room temperature. After stirring for 2 h, the mixture
was concentrated in vacuo. The crude mixture was dissolved in MeOH (3.5 mL) and 10%
aqueous NH4OH (1.5 mL). The e was d with prep-LCMS (XBridge C18
column, eluting with a gradient of acetonitrile/water ning 0.1% TFA, at flow rate of 60
mL/min) to give the desired product. LCMS calculated for C23H22F3N6 (M+H)+: m/z = 439.2;
Found: 4392.
Example 168. 1-(3-Flu0r0-5—methyl(3-(l-methyl-lH-pyrazolyl)-1H-pyrazolo[3,4-
din-S—yl)phenyl)-N-methylmethanamine
N.\ /
/ /'\l
/ /N
A mixture of tert—butyl (4-bromofluoromethylbenzyl)(methyl)carbamate (60
mg, 0.181 mmol, Example 113, Steps 1-6), ,4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-
dioxaborolane) (68.8 mg, 0.271 mmol), potassium acetate (53.2 mg, 0.542 mmol) and (1,1'-
bis(diphenylphosphino)ferrocene)—dichloropalladium(II) complexed with dichloromethane
(1:1) (295 mg, 0.036 mmol) in dioxane (10 mL) was stirred at 110 °C for 24 h. After cooling
to room ature, the mixture was concentrated in vacuo. A mixture of this crude
material, 5-chloro(1 -methyl- azolyl)((2-(trimethylsilyl)ethoxy)methyl)- 1H-
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pyrazolo[3,4—c]pyridine (21.8 mg, 0.060 mmol, Intermediate 2), XPhos Pd G2 (4.42 mg, 600
pmol) and cesium carbonate (58.6 mg, 0.180 mmol) in dioxane (10 mL) and water (2 mL)
was stirred at 70 °C for 18 h. After cooling to room temperature, the e was
concentrated in vacuo. The crude mixture was then dissolved in DCM (2.0 mL), and TFA
(2.0 mL) was added dropwise at room temperature. After stirring for 2 h, the mixture was
concentrated in vacuo, The crude e was dissolved in MeOH (3.5 mL) and 10%
aqueous NH4OH (1.5 mL). The mixture was purified with prep-LCMS (XBridge C18
column, eluting with a gradient of acetonitrile/water containing 0.1% TFA, at flow rate of 60
mL/min) to give the desired product. LCMS calculated for C19H20FN6 (M+H)+: m/z = 351.2,
Found: 351.1. 1H NMR (TFA salt, 600 MHz, (CD3)2SO) 5 9.16 (d, J: 1.3 Hz, 1H), 9.01 (br
s, 2H), 8.49 (d, J: 0.8 Hz, 1H), 8.10 (t, J: 1.1 Hz, 1H), 8.05 (d, J: 0.8 Hz, 1H), 7.34 — 7.27
(m, 2H), 4.19 (t, .1: 5.7 Hz, 2H), 3.91 (s, 3H), 2.62 (t, J: 5.2 Hz, 3H), 2.17 (s, 3H).
Example 169. 2-Fluoromethyl((methylamino)methyl)phenyl)—1H-
pyrazolo[3,4-c]pyridinyl)-N-methylbenzamide
Step 1. hlor0((2—(trimethylsilyl)ethoxy)methyl)-1H—pyra2010[3,4-c]pyridinyl)-N-
methylbenzamide
/NH
A solution of 5—chloroiodo((2-(trimethylsilyl)ethoxy)methyl)-1H—pyrazolo[3,4-
c]pyridine (215 mg, 0.525 mmol, e 42, Step 2), (4-(methy1carbamoyl)phenyl)boronic
acid (94 mg, 0.525 mmol), (1,1'-bis(diphenylphosphino)ferrocene)-dichloropalladium(II)
complexed with dichloromethane (1:1) (42.9 mg, 0.052 mmol) and potassium carbonate (145
mg, 1.05 mmol) in dioxane (3.0 mL) and water (0.5 mL) was stirred at 70 °C for 5 h. After
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cooling to room temperature, the mixture was concentrated in vacuo. The obtained crude
product was purified by Biotage aTM to give the desired product. LCMS calculated for
C20H26ClN4OZSl (M+H)+: m/z = 4172; Found: 417.2.
Step 2. 4—(5—(2—FZu0r0-6—methyl((methylamm0)methyUphenyU-1H-pyrazoio[3,4—c]pyrz'dz'n-
3-yZ)-N-methylbenzamide
This compound was prepared according to the procedures bed in Example 168,
using 4-(5-chloro—1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridin—3-y1)-N—
methylbenzamide instead of 5-chloro(1-methy1-1H-pyrazoly1)—1-((2-
thylsilyl)ethoxy)methy1)-1H-pyrazolo[3,4-c]pyridine as starting material. LC-MS
calculated for C23H23FN50 (M+H)+: m/z = 4042; found 404.1.
e 170. 4-(5-(2-Fluoromethyl-4—(pyrrolidin-2—yl)phenyl)—1H-pyrazolo[3,4-
c] pyridin-3—yl)—N-methylbenzamide
N\ O
l/ /O
HN\N
Step 1. utyl 4-(4-br0m0flu0r0methylphenyl)0x0bulylcarbamate
A<04:
To a solution of 2—bromofluoroiodomethylbenzene (1.34 g, 4.25 mmol,
Example 168, Step 2) in THF (30 mL) was added a solution of isopropylmagnesium chloride
in THF (2.13 mL, 425 mmol, 2 M) dropwise at -40 °C. After stirring at -40 °C for 1 h, the
mixture was cooled to —78 °C, and tert—butyl 2-oxopyrrolidine-l-carboxylate (0.726 mL, 425
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mmol) was added. The resulting mixture was slowly warmed to rt. over 1.5 h. The mixture
was quenched with 1 M HCl and extracted with ethyl acetate. The separated organic layers
wered concentrated in vacuo. The obtained crude product was purified by Biotage IsoleraTM
to give the desired product. LCMS calculated for C11H14BrFNO (M-C5H302+H)+: m/z =
2740; Found: 2740.
Step 2. tert—Butyl 2-(4-br0m0flu0r0methylphenyUpyrrolidinecarboxylate
A solution of tert—butyl 4-(4-bromofluoromethylphenyl)oxobutylcarbamate
(1.30 g, 3.47 mmol) in DCM (15 mL) was added 15 mL TFA, and the e was stirred at
RT for 30 min. The mixture was concentrated in vacuo and dissolved in 30 mL THF. To this
solution was added triethylamine (0.593 mL, 4.25 mmol) and sodium triacetoxyborohydride
(1.80 g, 8.51 mmol). The mixture was stirred at r.t. for 18 h and then quenched with 1 M
NaOH. The mixture was extracted with ethyl acetate. The separated organic layers were
concentrated in vacuo. The obtained crude product was ved in THF (20 mL). To this
solution was added di-tert—butyl dicarbonate (1.86 g, 8.51 mmol) and triethylamine (0513
mL, 3.68 mol) at r.t. After stirring for 1 h, the ts were evaporated under reduced
pressure and the obtained crude product was purified by e IsoleraTM to give the desired
product. LCMS ated for C12H14BrFN02 (M—C4Hs+H)+: m/z = 3020; Found: 302.0.
Step 3. 4-(5-(2-Flu0r0methyl(pyrrolz'din-Z—yyphenyl)-1H—pyra2010[3,4—c]pyridinyl)-
N-methylbenzamide
A mixture of tert—butyl 2-(4-bromofluoromethylphenyl)pyrrolidine
carboxylate (65 mg, 0.181 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2—dioxaborolane)
(69.1 mg, 0.272 mmol), potassium acetate (53.4 mg, 0.544 mmol) and (1,1'-
phenylphosphino)ferrocene)—dichloropalladium(II) xed with dichloromethane
(1: 1) (29.6 mg, 0.036 mmol) in dioxane (10 mL) was stirred at 110 °C for 24 h. After cooling
to room temperature, the mixture was concentrated in vacuo. A mixture of this crude
al, 4-(5-chloro((2-(trimethylsilyl)ethoxy)methyl)— 1H-pyrazolo [3 ,4—c]pyridinyl)—
N—methylbenzamide (23.41 mg, 0.056 mmol, Example 169, Step 1), XPhos Pd G2 (4.14 mg,
.61 umol) and cesium carbonate (54.9 mg, 0.168 mmol) in dioxane (10 mL) and water (2
mL) was stirred at 3’0 °C for 18 h. After cooling to room temperature, the mixture was
concentrated in vacuo. The crude mixture was then dissolved in DCM (2.0 mL), and TFA
(2.0 mL) was added dropwise at room temperature. After stirring for 2 h, the mixture was
concentrated in vacuo, The crude mixture was dissolved in MeOH (3.5 mL) and 10%
aqueous NH4OH (1.5 mL). The mixture was purified with prep-LCMS (XBridge C18
, eluting with a gradient of acetonitrile/water containing 0.1% TFA, at flow rate of 60
mL/min) to give the desired product. LCMS calculated for C25H25FN50 (M+H)+: m/z =
430.2; Found: 430.2.
Example 171. 5-(2-Fluoromethyl(pyrrolidin-Z-yl)phenyl)—3-(l-methyl-lH-pyrazol-
1H-pyrazolo[3,4-c] ne
N. \ /
/ / "l
/ / N
peak 1
Step 1. tert—Butyl 2-(3-flu0r0methyl(3-(1-methyl-1H—pyrazolyl)((2—
(trimethylsilyl)eth0xy)methyl)-1H—pyra2010[3, ridmyl)phenyUpyrrolidine
carboxylate
N \ /
/ / "l
/ / N
,N‘N ,
SEM SEM
peak1 peak2
To a solution of tert—butyl 2-(4-bromofluoromethylphenyl)pyrrolidine-l-
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ylate (850 mg, 2.37 mmol, Example 170, Step 2) in THF (10 mL) was added nBuLi
(1.56 mL, 2.491 mmol, 1.6 M) at —78 °C. After ng for 1 h, 2-isopropoxy-4,4,5,5-
tetramethyl-l,3,2-dioxaborolane (629 uL, 3.08 mmol) was added dropwise, and the mixture
was slowly warmed to RT over 6 h. The mixture was quenched with water (10 mL) and
extracted with ethyl acetate. The solvents of the separated c layers were evaporated
under reduced pressure to give the crude al. A mixture of the crude al, 5-chloro-
3-(1-methyl-1H—pyrazolyl)((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4—
c]pyridine (691 mg, 1.90 mmol, Intermediate 2), XPhos Pd G2 (93 mg, 0.119 mmol), cesium
carbonate (1.55 g, 4.75 mmol) in dioxane (20 mL) and water (4 mL) was stirred at 60 °C for
18 h. After cooling to room temperature, the mixture was concentrated in vacuo. The
obtained crude product was purified by Biotage IsoleraTM to give the desired product. The
two enantiomers were separated with chiral prep-HPLC (Phenomenex Lux Amylose-l
50mm, 5 micron, eluting with 15% EtOH in hexanes, at flow rate of 18 mL/min, tR, peak
1 = 8.67 min, tR,peakz = 12.75 min). Peak 1: LCMS calculated for C32H44FN603Sl (M+H)+:
m/z = 6073; Found: 607.3. Peak 2: LCMS calculated for C32H44FN603Sl (M+H)+: m/z =
607.3; Found: 6073.
Step 2. 5-(2-Flu0r0methyl(pyrrolz'dm-Z-ybphenyl)(1-methyZ-1H-pyrazolyl)-]H-
pyra2010[3, 4—cjpyrz'dz'ne
tert—Butyl 2-(3-fluoromethyl(3-(1-methyl-1H-pyrazolyl)—1-((2—
(trimethylsilyl)ethoxy)methyl)-1H—pyrazolo[3,4-c]pyridinyl)phenyl)pyrrolidine
carboxylate (peak 1, 200 mg) was dissolved in DCM (2.0 mL), and TFA (2.0 mL) was added
se at room temperature. After stirring for 2 h, the mixture was concentrated in vacuo.
The crude e was dissolved in MeOH (3.5 mL) and 10% aqueous NH4OH (1.5 mL).
The mixture was purified with prep-LCMS (XBIidge C18 column, eluting with a gradient of
acetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min) to give the desired
product. LCMS calculated for C21H22FN6 (M+H)+: m/z = 377.2, Found: 3773 1H NMR
(TFA salt, 500 MHz, SO) 5 9.50 (br s, 1H), 9.14 (d, J: 1.3 Hz, 1H), 8.79 (br s, 1H),
8.48 (s, 1H), 8.11 — 8.01 (m, 2H), 7.37 — 7.29 (m, 2H), 4.63 (m, 1H), 3.92 (s, 3H), 3.44 (m,
1H), 3.36 (m, 1H), 2.44 (m, 1H), 2.20 (s, 3H), 2.20 — 1.98 (m, 3H).
Example 172. 5-(2-Fluoro—6-methyl(pyrrolidin-Z-yl)phenyl)(l-methyl-lH-pyrazol-
4—yl)— 1H-pyrazolo[3,4-c] pyridine
NI \ /
/ / “1'
/ /N
peak2
This compound was prepared according to the procedures described in Example 171,
using tert—butyl 2-(3-fluoromethyl(3-(1-methyl-1H—pyrazolyl)((2-
thylsilyl)ethoxy)methyl)-1H—pyrazolo[3,4-c]pyridinyl)phenyl)pyrrolidine
carboxylate (peak 2, Example 171, Step 1) instead of tert—butyl 2-(3-fluoromethyl(3-(1-
methyl-1H—pyrazolyl)((2-(trimethylsilyl)ethoxy)methyl)—1H—pyrazolo[3,4-c]pyridin-S-
yl)phenyl)pyrrolidinecarboxylate (peak 1) as starting material. LCMS calculated for
C21H22FN6 (M+H)+: m/z = 3772, Found: 377.3. 1H NMR (TFA salt, 500 MHz, (CD3)2SO) 5
9.50 (br s, 1H), 9.14 (d, J: 1.3 Hz, 1H), 8.79 (br s, 1H), 8.48 (s, 1H), 8.11 — 8.01 (m, 2H),
7.37 — 7.29 (m, 2H), 4.63 (m, 1H), 3.92 (s, 3H), 3.44 (m, 1H), 3.36 (m, 1H), 2.44 (m, 1H),
2.20 (s, 3H), 2.20 — 1.98 (m, 3H).
Example 173. 5-(2-Fluoromethyl-4—(l-methylpyrrolidin-2—yl)phenyl)—3—(l-methyl-1H-
pyrazol-4—yl)—1H—pyrazolo ]pyridine
N.\ /
/ /'\‘
/ /N
HN\N
To a solution of 5-(2-fluoromethyl(pyrrolidinyl)phenyl)(1-methyl-1H—
pyrazolyl)-1H—pyrazolo[3,4-c]pyridine (10 mg, 0.027 mmol, peak 1, Example 171, Step 2)
in THF was added formaldehyde solution (37% in water, 20 uL) and sodium
toxyborohydride (22.5 mg, 0.106 mol) at RT. After stirring for l h, the solvents were
evaporated under reduced pressure and the obtained crude product was d with prep-
LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1%
TFA, at flow rate of 60 mL/min) to give the desired product. LCMS calculated for C22H24FN6
(M+H)+: m/z = 391.2; Found: 391.3.
Example 174. 5-(2-Fluoromethyl(piperidinyl)phenyl)(l-methyl-1H-pyrazol
yl)— 1H-pyrazol0[3,4-c] pyridine
ND /
/ / N
/ /N
peak1
Step 1. tert—Butyz’ 6-(4-br0m0flu0r0-5—methylphenyl)-3,4-dihydr0pyridine-1(2H)-
carboxyfate
\ NYC
A solution of 2-bromofluoroiodomethy1benzene (526 mg, 1.67 mmol,
Example 168, Step 2), utyl 6-(4,4,5,5-tetramethy1-1,3,2-dioxaborolanyl)—3,4-
dihydropyridine—l(2H)-carboxy1ate (516 mg, 1.67 mmol), (1,1'—
bis(dipheny1phosphino)ferrocene)—dichloropa11adium(II) complexed with dichloromethane
(1:1) (136 mg, 0.167 mmol) and potassium carbonate (461 mg, 3.34 mmol) in dioxane (10
mL) and water (2mL) was stirred at 65 °C for 18 h. After cooling to room temperature, the
mixture was concentrated in vacuo. The obtained crude product was purified by Biotage
IsoleraTM to give the desired product. LCMS calculated for BrFN02 (M—C4Hs+H)+:
m/z = 314.0; Found: 313.9.
Step 2. tert-Butyl 2-(4-br0m0flu0r0methy]phenyl)piperidine-I-carb0xyiate
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A solution of utyl 6-(4-bromofluoromethylphenyl)-3,4-dihydropyridine—
1(2H)—carboxylate (530 mg, 1.42 mmol) in DCM (10 mL) was added 10 mL TFA, and the
mixture was stirred at RT for 30 min. The mixture was trated in vacuo and then
ved in 20 mL THF. To this solution was added tnethylamine (0.233 mL, 1.67 mmol)
and sodium toxyborohydride (707 mg, 3.34 mmol). The mixture was stirred at r.t. for 18
h and then quenched with 1 M NaOH. The mixture was extracted with ethyl acetate. The
separated organic layers were concentrated in vacuo. The obtained crude product was
dissolved in THF (20 mL). To this solution was added di-z‘ert—butyl dicarbonate (364 mg,
1.67 mol) at r.t.. After stirring for 3 h, the solvents were evaporated under d pressure
and the obtained crude product was purified by Biotage IsoleraTM to give the desired product.
LCMS calculated for C13H16BrFN02 (M—C4Hs+H)+: m/z = 316.0; Found: 315.9.
Step 3. tert—Butyl 2—(3-fluor0methyl(3-(1-mez‘hyZ-JH-pyrazolyl)((2-
(trimethyisiiyl)eth0xy)methyl)-1H-pyra2010[3, 4-0jpyridmyl)phenyUpz‘peridine—1 —
carboxyfate
peak 1 peak 2
To a solution of tert—butyl 2-(4-bromofluoromethylphenyl)piperidine—1-
carboxylate (258 mg, 0.693 mmol) in THF (10 mL) was added nBuLi (0.48 mL, 0.762 mmol,
1.6 M) at -78 °C. After stirring for 1 h, 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane
(184 uL, 0.901 mmol) was added dropwise, and the resulting e was slowly warmed to
RT over 6 h. The mixture was quenched with water (10 mL) and extracted with ethyl acetate.
W0 2018f049200 2017/050737
The separated organic layers were evaporated under reduced pressure to give the crude
material. A e of the crude material, 5-chloro(1-methyl-1H—pyrazoly1)((2-
(trimethylsilyl)ethoxy)methy1)-1H—pyrazolo[3,4-c]pyridine (202 mg, 0.554 mmol,
Intermediate 2), XPhos Pd G2 (27.3 mg, 0.035 mmol), cesium carbonate (452 mg, 1.39
mmol) in e (20 mL) and water (4 mL) was stirred at 60 °C for 18 h. After cooling to
room temperature, the mixture was concentrated in vacuo. The obtained crude product was
purified by Biotage IsoleraTM to give the desired product. The two enantiomers were
separated with chiral prep-HPLC (Phenomenex Amylose-2 21.1x250mm, 5 micron, eluting
with 45% EtOH in hexanes, at flow rate of 18 mL/min, tR,peak1 = 6.33 min, k2 = 9.98
min). Peak 1: LCMS calculated for C33H46FN603Sl (M+H)+: m/z = 621.3, Found: 621.3.
Peak 2: LCMS calculated for C33H46FN603Sl : m/z = 621.3, Found: 621.3.
Step 4. 5-(2—Fluoro-6—methyl(191peridin-2—y0pheny0(I-methyl-1H-pyrazoIy0-1H—
pyrazolo[3, 4—c]pyridine
tert—Butyl 2-(3 -fluoromethyl(3-(1-methyl-1H-pyrazolyl)((2-
(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo [3 ,4-c]pyridin-5 -y1)pheny1)piperidine—1 -
carboxylate (peak 1, 100 mg) was dissolved in DCM (2.0 mL), and TFA (2.0 mL) was added
dropwise at room temperature. After stirring for 2 h, the mixture was concentrated in vacuo.
The crude mixture was dissolved in MeOH (3.5 mL) and 10% aqueous NH4OH (1.5 mL).
The mixture was d with prep-LCMS (XBridge C18 column, eluting with a gradient of
acetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min) to give the desired
product. LCMS calculated for C22H24FN6 : m/z = 3912, Found: 3912. 1H NMR
(TFA salt, 500 MHz, (CD3)2SO) 5 9.14 (d, J: 1.3 Hz, 1H), 9.05 (m, 1H), 8.76 (m, 1H), 8.49
(s, 1H), 8.14 — 8.01 (m, 2H), 7.37 — 7.26 (m, 2H), 4.31 (t, J = 11.4 Hz, 1H), 3.92 (s, 3H), 3.42
(m, 1H), 3.09 (m, 1H), 2.53 (m, 1H), 2.19 (s, 3H), 2.02 (m, 1H), 1.96 — 1.80 (m, 2H), 1.80 —
1.58 (m, 2H).
Example 175. 5-(2-Fluor0methyl(piperidin-2—yl)phenyl)(l-methyl-1H-pyrazol
-pyrazolo[3,4-c] pyridine
N \ /
/ / N
/ /N
peak2
This compound was prepared according to the procedures described in Example 174,
using utyl 2-(3-fluoromethyl(3-(1-methyl-1H-pyrazolyl)((2-
(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridinyl)phenyl)piperidine—l-
carboxylate (peak 2, e 174, Step 3) instead of tert—butyl 2-(3-fluoromethyl(3-(1-
methyl-1H—pyrazolyl)((2-(trimethylsilyl)ethoxy)methyl)—1H—pyrazolo[3,4-c]pyridin-S-
yl)phenyl)piperidinecarboxylate (peak 1) as starting material. LCMS calculated for
C22H24FN6 (M+H)+: m/z = 3912, Found: 391.2.
Example 176. N-(3-Fluoromethyl(3-(1-methyl-1H-pyrazolyl)- lH-pyrazolo[3,4-
c] pyridin-S-yl)benzyl)ethanamine
ND /
/ /"l
/ /N
Step 1. 5-(Z—Fluoromethylvmylphenyl)(1-methyl-1H—pyrazolyl)((2—
(trimethy]silyl)eth0xy)methyl)-1H—pyrazolo[3, 4-c]pyridme
N \ /
/ / "l
/ / N
W0 2018f049200
To a solution of ofluoromethylvinylbenzene (1.03g, 4.79 mmol,
Example 168, Step 3) in THF (40 mL) was added nBuLi (3.14 mL, 503 mmol, 16 M) at -7 8
°C. After stirring for 1 h, 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.27 mL,
6.23 mmol) was added dropwise, and the resulting mixture was slowly warmed to RT over 6
h. The mixture was quenched with water (10 mL) and extracted with ethyl acetate. The
separated organic layers were concentrated under reduced pressure to give the crude material.
A mixture of the crude material, 5-chloro(1-methyl-1H-pyrazolyl)((2-
(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine (1.39 g, 3.83 mmol, ediate
2), XPhos Pd G2 (188 mg, 0.239 mmol), cesium carbonate (3.12 g, 9.58 mmol) in dioxane
(20 mL) and water (4 mL) was d at 60 °C for 18 h. After g to room temperature,
the mixture was concentrated in vacuo. The obtained crude t was purified by Biotage
aTM to give the desired product. LCMS calculated for C25H31FN50Si (M+H)+: m/z =
4642, Found: 464.2.
Step 2. 3-FEu0r0methyl(3-(1-methyl-1H—pyrazolyl)((2-
(trimethyfsiiyl)ethoxy)methyl)-1H-pyrazolo[3, 4-c]pyridinyl)benzaldehyde
N \ /
/ / "l
/ / N
To a mixture of 5-(2-fluoromethylvinylphenyl)—3-(1-methyl-1H-pyrazolyl)
((2-(trimethylsilyl)ethoxy)methyl)—1H-pyrazolo[3,4-c]pyridine (1.82 g, 3.93 mmol), sodium
periodate (3.36 g, 15.7 mmol) in acetone (20 mL) and water (2 mL) was added osmium
tetroxide solution (4% in water, 2.49 g, 0.393 mmol). After stirring at r.t. for 5 h, the mixture
was quenched with water (10 mL) and extracted with ethyl acetate. The separated organic
layers were concentrated under reduced pressure, and the obtained crude product was purified
by e IsoleraTM to give the desired product. LCMS calculated for C24H29FN502$i
(M+H)+: m/z = 466.2; Found: 466.3.
Step 3. N-(3-Flu0r0-5—methyl(3—(1-methyl-1H-pyrazoZyl)-1H-pyrazo[0[3,4-cjpyridz'n
yUbenzyDethanamine
W0 2018/‘049200
To a solution of 3—fluoromethyl(3-(1-methy1-1H—pyrazolyl)—1-((2-
(trimethylsilyl)ethoxy)methyl)—lH-pyrazolo[3,4-c]pyridinyl)benzaldehyde (80 mg, 0.172
mmol), ethylamine on (2 M in THF, 0.258 mL, 0.515 mmol) and acetic acid (0030 mL,
0.515 mmol) in THF (10 mL) was added sodium triacetoxyborohydride (109 mg, 0.515
mmol). After stirring for 18 h, the mixture was concentrated in vacuo. The crude mixture was
then dissolved in DCM (2.0 mL), and TFA (2.0 mL) was added dropwise at room
temperature. After ng for 2 h, the mixture was concentrated in vacuo. The crude mixture
was ved in MeOH (3.5 mL) and 10% aqueous NH4OH (1.5 mL). The mixture was
d with prep-LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water
containing 0.1% TFA, at flow rate of 60 mL/min) to give the desired t. LCMS
calculated for C20H22FN6 (M+H)+: m/z = 365.2, Found: 365.3. 1H NMR (TFA salt, 600 MHz,
SO) 8 13.64 (br s, 1H), 9.13 (d, .1: 1.4 Hz, 1H), 8.82 (br s, 2H), 8.47 (s, 1H), 8.14 —
7.94 (m, 2H), 7.38 — 7.24 (m, 2H), 4.21 (m, 2H), 3.91 (s, 3H), 3.02 (m, 2H), 2.18 (s, 3H),
1.25 (t,J= 7.2 Hz, 3H).
Examples 177—188 were prepared according to the procedures described in Example
176 using indicated s.m. instead of ethylamine.
Sm Anal tical data
N—(3-Fluoro cyclopropana LC-MS found 377.1
methyl(3-(1- mine
methyl-1H-
pyrazolyl)— 1H-
pyrazolo[3,4-
c]pyridin
yl)benzyl)cyclopro
panamine
N—(3-Fluoro LC-MS found 379.1
methyl(3-(1- 1H NMR (TFA salt, 500
methyl-1H- MHz, (CD3)2SO) 8 9.15 (d,
pyrazolyl)— 1H- J: 1.3 Hz,1H), 8.82 (br s,
pyrazolo[3,4- 2H), 8.47 (s, 1H), 8.09 —
c]pyridin 8.02 (m, 2H), 7.38 — 7.32
yl)benzyl)propan- (m, 2H), 4.22 (t, J = 6.3 Hz,
2-amine 2H), 3.94 (s, 3H), 3.36 (m,
1H), 2.19 (s, 3H), 1.32 (d, J
= 6.5 Hz, 6H).
2,2,2-Trifluoro-N— 2,2,2- LC—MS found 419.1
(3-fluoromethyl- trifluoroethan
4-(3-(1-methy1- 1H- amine
ly1)-1H-
pyrazolo[3,4-
c]pyridin
yl)benzyl)ethanami
2-(3-F1uoro 2- LC-MS found 381.2
methyl(3-(1- aminoethanol 1H NMR (TFA salt, 500
methyl-1H- MHz, (CD3)2SO) 5 9.14 (d,
pyrazoly1)— 1H- J: 1.3 Hz, 1H), 8.96 (br s,
pyrazolo[3,4- 2H), 8.48 (s, 1H), 8.11 —
c]pyridin 8.01 (m, 2H), 7.39 — 7.29
yl)benzy1amino)eth (m, 2H), 4.24 (t, J = 5.5 Hz,
anol 2H), 3.92 (s, 3H), 3.71 (m,
2H), 3.03 (m, 2H), 2.19 (s,
3-(3-F1uoro 3- LC-MS found 407.2
methyl(3-(1- aminocyclobu
methyl-1H- tanol
pyrazoly1)—1H—
pyrazolo[3,4-
c]pyridin
zy1amino)cy
clobutanol
-(4-(Azetidin azetidine LC—MS found 3772
ylmethyl)fluoro- 1H NMR (TFA salt, 400
y1pheny1) MHZ, (CD3)2SO) 5 10.10
(l-methyl-IH- (br s, 2H), 9.13 (d, J: 1.3
pyrazoly1)— 1H- Hz, 1H), 8.49 (s, 1H), 8.11
pyrazolo[3,4- — 8.03 (m, 2H), 7.37 — 7.26
c]pyridine (m, 2H), 4.41 (d, J: 6.1
Hz, 2H), 4.23 — 4.02 (m,
4H), 3.89 (s, 3H), 2.47 —
2.35 (m, 2H), 2.18 (s, 3H).
1uoro pyrrolidin LC-MS found 407.2
methyl(3-(1- ol
methyl-1H-
pyrazoly1)— 1H-
pyrazolo[3,4-
c]pyridin
y1)benzy1)pyrrolidi
nol
WO 49200
1-(3-Fluoro l-amino-Z- LC—MS found 4092
methyl(3-(1- methylpropan
methyl-1H- ol
ly1)-1H-
pyrazolo[3,4-
c]pyridin
y1)benzy1amino)
methylpropanol
-(2-F1uoro((3- 3- LC-MS found 407.2
methoxyazetidin methoxyazeti
y1)methy1) dine
methylpheny1)
(1-methy1-1H-
pyrazoly1)— 1H-
pyrazolo[3,4-
c]pyridine
luoro (1 -methy1-1H— LC-MS found 4312
methyl(3-(1- imidazol
-1H- hanami
pyrazoly1)— 1H- ne
pyrazolo[3,4-
c]pyridin
y1)benzy1)(1-
methyl-1H-
imidazol
y1)methanamine
N—(3-Fluoro oxazol LC—MS found 418.2
methyl(3-(1- ylmethanamin
methyl-1H- e
pyrazoly1)— 1H-
pyrazolo[3,4-
c]pyridin
y1)benzy1)
(oxazol
y1)methanamine
2-(3-F1uoro 2- LC-MS found 3762
methyl(3-(1- aminoacetonit
methyl-1H- nle
pyrazoly1)— 1H-
pyrazolo[3,4-
c]pyridin
yl)benzy1amino)ac
etonitrile
Example 189. 1-(3-Fluoro-S-methyl(3-(l-methyl-1H-pyrazolyl)—1H-pyrazolo[3,4-
c] pyridin-S-yl)phenyl)—N—methylethanamine
peak 2
Step 1. 1-(3—Flu0r0methyl(3-(1-methyl-1H—pyrazolyl)((2—
(trimethyfsilyl)ethoxy)methyl)-1H—pyra2010[3, 4-c]pyridmyl)phenyl)ethanone
This compound was prepared according to the procedures described in Example 176,
using 4,4,5,5-tetramethyl(prop-l-enyl)-l,3,2-dioxaborolane instead of 4,4,55-
tetramethyl-Z-vinyl-l,3,2-dioxaborolane as starting al. LC-MS calculated for
C25H31FN5028i : m/z = 480.2; found 480.3.
Step 2. tert—Butyl 1-(3-flu0r0methyl(3-(1-methyl-1H—pyrazolyl)((2—
(trimethylsilyUethoxy)methyl)-1H—pyrazolo[3, 4-c]pyridin
yUphenyDethyl(methyl)carbamate
W0 2018f049200
peak 1 peak 2
To a solution of 1-(3-fluoromethyl(3-(1-methyl-1H-pyrazol-4—y1)((2-
(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridinyl)phenyl)ethanone (1.06 g,
2.21 mmol), methylamine hydrochloride (0.448 g, 6.63 mmol) and titanium(IV) poxide
(1.94 mL, 6.63 mmol) in MeOH (20 mL) was added sodium borohydride (0.167 g, 4.42
mol) at r.t.. After stirring for 1 h, the mixture was quenched with 1 M NaOH, extracted with
ethyl acetate and concentrated in vacuo. Then the crude product was dissolved in THF (20
mL) and di-tert—butyl dicarbonate (965 mg, 4.42 mmol) was added. After stirring for 2 h, the
mixture was concentrated in vacuo. The obtained crude product was purified by Biotage
IsoleraTM to give the desired product. Then, the two enantiomers were ted with chiral
PLC (Phenomenex Lux Cellulose-1, 21.2x250mm, 5 micron, eluting with 3% EtOH in
hexanes, at flow rate of 18 mL/min, tR, peakl = 22.02 min, k2 = 24.22 min). Peak 1:
LCMS calculated for C31H44FN603Sl : m/z = 595.3; Found: 5954. Peak 2: LCMS
calculated for C31H44FN603Sl (M+H)+: m/z = 5953, Found: 595.4.
Step 3. 1-(3-Flu0r0-5—methyl(3-(1-methyl-1H—pyrazolyl)-1H—pyrazolo[3,4—cjpyrl'din
yl)phenyD-N-methylethanamme
tert—Butyl 1-(3-fluoromethyl(3-(1-methyl-1H-pyrazolyl)((2-
(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridin
yl)phenyl)ethyl(methyl)carbamate (peak 2, 100 mg) was dissolved in DCM (2.0 mL) and
TFA (2.0 mL) was added dropwise at room temperature. After stirring for 2 h, the mixture
was concentrated in vacuo. The crude mixture was dissolved in MeOH (3.5 mL) and 10%
aqueous NH4OH (1.5 mL). The mixture was purified with prep-LCMS (XBridge C18
column, eluting with a gradient of itrile/water containing 0.1% TFA, at flow rate of 60
mL/min) to give the desired product. LCMS calculated for C20H22FN6 : m/z = 3652;
Found: 3651. 1H NMR (TFA salt, 500 MHz, (CD3)2SO) 5 9.20 — 9.04 (m, 2H), 8.92 (br s,
1H), 8.50 (s, 1H), 8.09 (d, J = 1.5 Hz, 1H), 8.05 (s, 1H), 7.38 — 7.25 (m, 2H), 4.38 (m, 1H),
W0 2018f049200
3.92 (s, 3H), 2.52 (m, 3H), 2.19 (s, 3H), 1.59 (d, J: 6.8 Hz, 3H).
Example 190. 1-(3-Fluoro-S-methyl(3-(l-methyl-1H-pyrazolyl)-lH-pyrazolo[3,4-
c] pyridinyl)phenyl)—N—methylethanamine
peak1
This compound was prepared ing to the procedures described in Example 189,
using tert—butyl 1-(3-fluoromethyl(3-(1-methyl-1H-pyrazolyl)((2-
(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridin
yl)phenyl)ethyl(methyl)carbamate (peak 1, Example 189, Step 2) instead of tert-butyl 1-(3-
fluoro-S-methyl—4—(3-(1 -methyl- 1H-pyrazolyl)— 1 -((2-(trimethylsilyl)ethoxy)methy1)-1H—
pyrazolo[3,4-c]pyridin-S-y1)phenyl)ethyl(methyl)carbamate (peak 2) as starting material.
LCMS calculated for C22H24FN6 : m/z = 391.2; Found: 3912.
e 191. N—(3—Fluoromethyl(3-(l-methyl-1H-pyrazol—4-yl)—lH-pyrazolo[3,4-
c]pyridin-S—yl)benzyl)acetamide
Nb /
/ /N
/ /N
Step 1. (3-FZu0r0methyl(3-(1-methyl-1H-pyrazolyl)((2-
(trimethyZSiZyDez‘hoxy)methyl)-1H-pyrazolo[3, 4-c]pyridz'nyl)phenyl)methanamz’ne
N. \ /
/ / "l
/ /N
To a solution of 3-fluoromethyl(3-(1-methyl-1H-pyrazolyl)((2—
(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridinyl)benzaldehyde (100 mg, 0.215
mmol, Example 176, Step 2), ammonium e (331 mg, 4.30 mmol) in MeOH (10 mL)
was added sodium cyanoborohydride (27.0 mg, 0.430 mmol). After stirring for 18 h, the
mixture was concentrated in vacuo. The crude mixture was purified with prep-LCMS
(XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% TFA, at
flow rate of 60 mL/min) to give the desired product. LCMS calculated for C24H32FN6081
(M+H)+: m/z = 4672; Found: 467.2.
Step 2. N—(3—Flu0r0—5—methyl—4—(3—(I—methyl—1H—pyrazoZyl)—1H—pyrazo[0[3,4—cjpyridz'n—5—
yl)benzyl)acetamide
To a solution of (3-fluoromethyl(3-(1-methy1-1H-pyrazolyl)((2-
(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridinyl)phenyl)methanamine (10 mg,
0.021 mmol) in THF (2 mL) was added pyridine (0.017 mL, 0.214 mmol) and acetic
anhydride (10.9 mg, 0.107 mol) at r.t.. After ng for 18 h, the mixture was concentrated
in vacuo. The crude product was dissolved in DCM (2.0 mL), and TFA (2.0 mL) was added
dropwise at room ature. After stirring for 2 h, the mixture was concentrated in vacuo.
The crude mixture was dissolved in MeOH (3.5 mL) and 10% aqueous NH4OH (1.5 mL).
The mixture was ed with prep-LCMS (XBridge C18 column, eluting with a gradient of
acetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min) to give the desired
product. LCMS ated for C20H20FN60 (M+H)+: m/z = 379.2, Found: 3792.
Example 192. Methyl o—5—methyl(3—(1-methyl-1H-pyrazolyl)-1H-
pyrazolo[3,4-c]pyridin-S-yl)benzylcarbamate
N/l /
\ / "l
/ /N
This compound was prepared ing to the procedures described in e 191,
using methyl carbonochloridate instead of acetic anhydride as starting material. LC-MS
calculated for C20H20FN602 (M+H)+: m/z = 3952, found 3952.
Example 193. 1-(4-(6-(5-(2-(Difluoromethoxy)—6-fluoro—4—
((methylamino)methyl)phenyl)—1H-pyrazolo [3,4-c] pyridinyl)pyridinyl)piperazin
yl)ethanone
Step 1. tert—Butyl 4-br0m0(difluoromez‘hoxy)flu0r0benzyl(methyUcarbamate
This compound was prepared according to the ures described in Example 168,
using 3-(difluoromethoxy)fluoroaniline (Example 72, Step 3) instead of 3-fluoro-5—
methylaniline as starting material. LC-MS calculated for C10H10BrF3NO3 (M—C4Hs+H)+: m/z
= 3280; found 32?.9.
Step 2. ry! 4-(3-(5-ch10r0pyridmy1)((2—(trimethylsilyl)ethoxy)methyl)—1H-
pyra2010[3, 4-0jpyridinyl)(dl'fluoromethoxy)fluorobenzyl(methyl)carbamaz‘e
This compound was prepared ing to the procedures described in Example 167,
using tert—butyl 4-bromo(difluoromethoxy)—5-fluorobenzyl(methyl)carbamate instead of
utyl 3,5-difluorobenzyl(methyl)carbamate as starting material. LC-MS calculated for
C31H38C1F3N504Si (M+H)+: m/z = 664.2; found 664.3.
Step 34 1-(4-(6-(5-(2—(Difluoromethoxy)flu0r0((methylamin0)methyUphenyD-1H-
pyrazolo[3, 4-cjpyridinyl)pyridiny0piperazinyl)ethan0ne
This compound was prepared according to the procedures bed in Example 167
using 1-(piperazinyl)ethanone instead of 3-fluoropyrrolidine as starting material. LC-
MS calculated for C26H27F3N702 (M+H)+: m/z = 5262; found 5260.
e 194. 2-(3-Fluoro-2—(3-(4-(4-methylpiperazinyl)phenyl)—1H-pyraz0l0[3,4-
c]pyridin-S—yl)phenyl)acetonitrile
Step 1. tert—Butyl 5-ch10r0(4-(4-methylpiperazmyl)phenyl)-1H-pyrazof0[3, 4-cjpyridine-
I-carboxyfate
W0 2018/‘049200
CI\ 0
This compound was ed according to the procedures described in Intermediate 1,
using (4—(4—methylpiperazinyl)phenyl)boronic acid d of 1-methyl-4—(4,4,5,5-
tetramethyl—l,3,2—dioxaborolanyl)-1H-pyrazole as starting material. LCMS calculated for
C22H27ClN502 (M+H)Jr m/z = 4282, found 428.2.
Step 2. 2-(2-Br0m0flu0r0pheny0acetoniz‘rl'le
To a e of 2-bromo(bromomethyl)fluorobenzene (1.755 g, 6.55 mmol) and
KCN (6?4.5 mg, 1036 mmol) was added EtOH (100.0 ml) followed by water (3000 ml).
The resulting homogeneous solution was stirred at 70 °C for 16 h. After cooling to room
temperature, the mixture was diluted with EtOAc, and washed with sat. NaHCO3 (aq). The
separated organic layer was dried over NazSO4, filtered and concentrated. The residue was
purified on silica gel (40 g, 0-50% EtOAc in hexanes) to give the desired product as a white
solid (726.8 mg, 52%).
Step 3. 2-(3-Flu0r0(4, 4, 5, 5—telmmethyl-1 , 3, 2-dl'oxaborolan-Z-yUphenyUacetonitri16
To a cap vial equipped with a magnetic stir bar was added 5,4',4',5',5'-
thyl-[2,2']bi[[1,3,2]dioxaborolanyl] (997.2 mg, 3.93 mmol), potassium acetate (1138
mg, 1160 mmol) and [1,1'—bis(dipheny1phosphino)ferrocene]dichloropalladiumfll)
complexed with dichloromethane (1:1) (416.3 mg, 0.510 mmol). The vial was sealed with a
Teflon-lined septum, evacuated and backfilled with nitrogen (this process was repeated a
total of three times). A solution of 2-(2-bromofluorophenyl)acetonitrile (726.9 mg, 3.40
W0 2018f049200
mmol) in 1,4-dioxane (15.0 mL) was added. The reaction mixture was stirred at 100 °C for 16
h. After cooling to room temperature, the mixture was diluted with , and washed with
brine. The organic layer was dried over ous NazSO4, filtered and concentrated. The
residue was purified on silica gel (40 g, 0-100% EtOAc in hexanes) to give the desired
product product (622.9 mg, 70%). LCMS calculated for C14H18BFN02 (M+H)’r m/z = 262.1;
found 2622.
Step 4. 2-(3-Flu0r0-2—(3-(4-(4-mez‘hylplperazmyl)phenyl)-1H—pyrazolo[3,4—c]pyridin
yl)phenyl)acet0nitrile
To a screw-cap Vial equipped with a magnetic stir bar was added tert—butyl 5-chloro-
3-(4-(4-methylpiperazinyl)phenyl)-lH-pyrazolo[3,4-c]pyridinecarboxylate (34.4 mg,
0.080 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2—(2'-
amino-1,1'-biphenyl)]palladium(II) (XPhos Pd G2, 9.5 mg, 0.012 mmol) and cesium
carbonate (88.2 mg, 0.271 mmol). The Vial was sealed with a Teflon-lined septum, evacuated
and backfilled with nitrogen (this process was repeated a total of three times). A solution of
uoro-2—(4,4,5,5—tetramethyl-1,3,2-dioxaborolanyl)phenyl)acetonitrile (35.5 mg,
0.136 mmol) in 1,4-dioxane (2.00 ml) was added, followed by water (2000 uL). The reaction
was heated to 50 °C for 16 h. The reaction mixture was concentrated. To the residue was
added CHzClz (2.0 mL) followed by TFA (2.0 mL). The resulting mixture was stirred at room
temperature for 15 min, and then trated. The residue was purified using prep-LCMS
(XBridge C18 column, eluting with a gradient of itrile/water containing 0.1% TFA, at
flow rate of 60 ) to afford the desired product. LCMS calculated for C25H24FN6
(M+H)+: m/z = 427.2; found: 427.2.
Example 195. (3-Flu0r0(3-(4-(4-methylpiperazinyl)phenyl)-1H-pyrazolo[3,4-
c] pyridin-S-yl)phenyl)methanamine
Step 1. tert—Butyl 2-br0m0flu0r0benzylcarbamaz‘e
W0 49200
FQVHTOK
Br 0
To a solution of 2-bromofluorobenzonitrile (2.460 g, 12.30 mmol) in THF (50.0
ml) at room temperature was added 1.0 M solution of borane—THF complex in THF (52.0 ml,
52.0 mmol). The mixture was stirred at 70 0C for 2 h. After cooling to room temperature, the
reaction mixture was quenched with 4.0 M HCl in water (50.0 ml, 200 mmol). The mixture
was d at 50 °C for 3 h and then cooled to 0 0C. The mixture was treated with 2 M K2CO3
(aq) until pH reached 10. The e was extracted with Et20. The organic layer was dried
over anhydrous NazSO4, filtered and concentrated. The resulting residue was dissolved in
CH2C12 (100 n11). Di-tert—butyldicarbonate (4.07 g, 18.65 mmol) was added. The mixture was
stirred at room temperature for 10 min, and then trated. The residue was purified on
silica gel (120 g, 0-50% EtOAc in hexanes) to give the desired product as a white solid
(2.497 g, 62%). LCMS calculated for CsHsBrFNOz (M+H-C4Hg)+ m/z = 2480; found 248.0.
Step 2. (3-FZuoro-Z-(3-(4-(4-methylpz'perazmyl)phenyZ)-1H-pyra2010[3, 4-0]pyridm
yUphenyUmethanamme
This compound was prepared according to the ures described in Example 194,
using tert-butyl 2—bromofluorobenzylcarbamate instead of 2—(2—bromo—3-
fluorophenyl)acetonitrile as starting material. LCMS calculated for C24H26FN6 (M+H)+: m/z
= 417.2; found: 417.2.
Example 196. (3—Fluor0-2—(3—(4-(4-methylpiperazinyl)phenyl)-1H-pyrazolo[3,4-
c] pyridin-5—yl)phenyl)methanol
\ Nd
N\/ O
This compound was ed according to the procedure described in Example 195,
using 2-fluoro—6-(hydroxymethyl)phenylboronic acid instead of tert—butyl (3-fluoro
,5-tetramethyl-1,3,2-dioxaborolanyl)benzyl)carbamate as the starting material.
LCMS ated for C24H25FN50 (M+H)+: m/z = 4182; found: 418.2.
Example 197. 4,6-Difluoro-N-methyl-S-(S-(4—(4-methylpiperazinyl)phenyl)-1H-
lo[3,4-c] pyridin-5—yl)—2,3-dihydro—lH-inden-l-amine
To a solution of fluoro-2,3-dihydro-1H—indenone (Ark Pharm, 4015 g, 23.88
mmol) in 2-propanol (90.0 ml) was added methylamine (2.0 M in methanol) (60.0 ml, 120
mmol) followed by titanium(IV) isopropoxide (15.31 ml, 51.7 mmol). The mixture was
stirred at 35 °C for 16 h before it was cooled to room temperature. Sodium borohydride
(1.312 g, 34.7 mmol) was added. The reaction was stirred at room temperature for 1 h, and
was ed with HCl (6.0 N in water) (60.0 ml, 360 mmol). The mixture was stirred at
room temperature for 2 h, and was treated with NaOH (4.0 N in water) until pH reached 10.
The mixture was extracted with Et20. The organic layer was dried over anhydrous NazS O4,
filtered and concentrated. The e was dissolved in CH2C12 (100 mL), and d with
Boc-anhydride (5.21 g, 23.88 mmol). After stirring at room temperature for 30 min, the
reaction was concentrated. The residue was purified on silica gel (120g, 0-100% EtOAc in
hexanes) to give the desired product as an oil (527 g, 78%). LCMS calculated for
C11H12F2N02 (M+H-C4Hs)+: m/z = 2281; found: 228.1.
Step 2. tert—Butyl 4, 6-dl'flu0r0(4,4,5,5-tetramethyl-1,3,2—di0xab0r01any0-2,3—dihydr0-
IH—z'nden—I—yl(mez‘hyl)carbamate
W0 2018f049200
To a on of tert-butyl (4,6-difluoro-2,3-dihydro-1H-inden
yl)(methy1)carbamate (5.27 g, 18.60 mmol) in THF (100.0 ml) at -78 °C under N2 was added
a solution of n-BuLi (2.5 M in hexanes) (15.00 ml, 37.5 mmol) slowly over a period of 20
min. The reaction was allowed to warm to -60 0C and stirred for 90 min. The reaction was
then cooled back to -78 0C. 2-Isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (10.79 g,
58.0 mmol) was added slowly over a period of 20 min. After stirring at -78 °C for another 10
min, the reaction mixture was allowed to warm to room temperature and stirred for 1 h. The
reaction was quenched with sat. NaHCO3, and extracted with Et20. The organic layer was
dried over Na2SO4, filtered and concentrated. The e was purified on silica gel (120 g, 0-
100% EtOAc in hexanes) to give the desired product as an oil (1.74 g, 23%). LCMS
calculated for C17H23BF2NO4 (M+H—C4Hs)+: m/z = 3542; found: 3541.
Step 3. 4, 6—Diflu0r0-N—methyl(3-(4-(4-methylpz'perazinyZ)phenyZ)-1H—pyrazoz’0[3, 4-
c]pyrz'din-5—yl)—2, 3-dihydr0-1H—indenamine
To a screw-cap Vial ed with a ic stir bar was added tert-butyl 5-chloro-
3-(4-(4-methylpiperazinyl)phenyl)-1H-pyrazolo[3,4-c]pyridinecarboxy1ate (31.4 mg,
0.073 mmol, Example 194, Step 1), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-
biphenyl)[2—(2'—amino-1,1'-biphenyl)]palladium(II) (XPhos Pd G2, 8.3 mg, 10.55 umol) and
cesium carbonate (76.3 mg, 0.234 mmol). The Vial was sealed with a Teflon-lined septum,
ted and backfilled with nitrogen (this process was repeated a total of three . A
solution of tert-butyl (4,6-difluoro(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-2,3-
dihydro-lH—inden-l-yl)(methyl)carbamate (28.8 mg, 0.070 mmol) in 1,4-dioxane (2.00 ml)
was added, followed by water (200.0 ul). The reaction mixture was heated to 50 °C for 16 h.
and thenconcentrated. To the residue was added CH2C12 (20 mL) followed by TFA (2.0 mL).
The mixture was stirred at room temperature for 15 min, and then concentrated. The residue
was purified using prep-LCMS (XBIidge C18 column, eluting with a gradient of
acetonitrile/water containing 0.1% TFA, at flow rate of 60 ) to afford the desired
product. LCMS calculated for C27H29F2N6 (M+H)+: m/z = 4752; found: 4753.
e 198. 4,6-Difluoro-N-methyl-S-(3-(l-methyl-lH-pyrazolyl)-lH-pyrazolo[3,4-
c]pyridin-S—yl)—2,3—dihydro-lH-inden-l-amine
This compound was prepared according to the procedure described in Example 197,
using tert-butyl 5-chloro(1-methyl-1H-pyrazolyl)-1H-pyrazolo[3,4-c]pyridine
carboxylate (Intermediate 1) instead of tert—butyl 5-chloro(4-(4-methylpiperazin
yl)phenyl)—1H—pyrazolo[3,4-c]pyridinecarboxy1ate as the starting material. LCMS
ated for C20H19F2N6 (M+H)+: m/z = 381.2; found: 38112. 1H NMR (TFA salt, 500 MHZ,
DMSO-de) 5 9.14 (d, J= 1.2 Hz, 1H), 9.09 (br, 2H), 8.46 (s, 1H), 8.19 (s, 1H), 8.04 (s, 1H),
7.46 (d, J= 8.8 Hz, 1H), 4.88 (m, 1H), 3.91 (s, 3H), 3.13 (m, 1H), 3.05 — 2.90 (m, 1H), 2.66
(t, J: 5.3 Hz, 3H), 2.62 — 2.52 (m, 1H), 2.27 (m, 1H).
Example 199. 6,8-Difluoro-N—methyl(3-(4-(4-methylpiperazinyl)phenyl)—1H-
pyrazolo[3,4—c]pyridin-S-yl)—1,2,3,4-tetrahydronaphthalen-Z-amine
This nd was prepared according to the procedure described in Example 197
using 6,8—difluoro-3,4—dihydronaphthalen-2(1H)—one (Ark Pharm) instead of 4,6—difluoro—2,3—
dihydro-lH-inden-l-one as the starting material. LCMS ated for C28H31F2N6 (M+H)+:
m/z = 4893; found: 489.3.
Example 200. fluoro-N—methyl(3-(1-methyl-1H-pyrazolyl)-lH-pyrazolo[3,4-
c] pyridin-S-yl)- 1,2,3,4-tetrahydronaphthalen-Z-amine
F /
N\ IN‘
\/ /N
This compound was prepared according to the procedure described in Example 199,
using tert—butyl 5-chloro(l-methyl-lH-pyrazolyl)-lH-pyrazolo[3,4-c]pyridine-lcarboxylate
instead of tert—butyl 5 -chloro(4-(4-methylpiperazinyl)phenyl)—1H-
pyrazolo[3,4-c]pyridine-l-carboxylate as the starting material. LCMS ated for
C21H21F2N6 (M+H)+: m/z = 3952; found: 3952.
Example 201. 4-(5-(1,3-Difluoro-S-(methylamino)—5,6,7,8-tetrahydronaphthalen-Z-yl)—
1H-pyrazolo[3,4-c]pyridin-3—yl)—N—methylbenzamide
Step 1. tert—Butyl 5, 7-dl'flu0r0(4, 4, 5, 5-tetramethyl-1,3, 2—di0xab0rolanyU—1, 2, 3, 4-
tetrahydronaphthalen-I-yl(methyl)carbamate
This compound was prepared according to the procedure bed in Example 197,
W0 2018/‘049200 2017/050737
using 5,7—difluoro-3,4—dihydronaphthalen-1(2H)—one (Ark Pharm) instead of 4,6—difluoro—2,3-
dihydro-lH—inden-l -one as the starting material. LCMS calculated for C22H32BF2NNaO4
(M+Na)+: m/z = 4462; found: 446.2.
Step 2. tert—Butyl 5-ch10r0(4-(methylcarbamoyUphenyl)-1H-pyrazolo[3,4—c]pyridine—1-
carboxyfate
2 I2
This compound was prepared according to the procedures described in Intermediate 1,
using N-methyl(4,4,5,5-tetramethy1-1,3,2-dioxaborolany1)benzamide instead of 1-
methy1(4,4,5,5-tetramethy1-1,3,2-dioxaborolanyl)-1H-pyrazole as starting material.
LCMS calculated for C19H20C1N4O3 (M+H)+ m/z = 387.1; found 387.1.
Step 3. 4-(5-(1,3-Dz'flu0r0(met‘hylamz'n0)-5, 6, 7,8-z‘etrahydronaphthalen-Z-yl)-1H-
pyra2010[3, ridz'nyl)-N-methylbenzamide
To a cap Vial equipped with a ic stir bar was added tert-butyl 5-chloro-
3-(4-(methylcarbamoyl)phenyl)-1H-pyrazolo[3,4-c]pyridinecarboxy1ate (30.3 mg, 0.078
mmol), chloro(2—dicyclohexylphosphino-2',4',6'-triisopropy1-1,1'-bipheny1)[2—(2'—amino-1,1'-
bipheny1)]palladium(II) (XPhos Pd G2, 8.5 mg, 10.80 umol) and cesium carbonate (77.7 mg,
0.238 mmol). The vial was sealed with a Teflon-lined septum, evacuated and backfilled with
nitrogen (this process was repeated a total of three . A solution of tert—butyl (5,7-
difluoro(4,4,5,5-tetramethy1-1,3,2-dioxaborolany1)-1,2,3,4-tetrahydronaphthalen
y1)(methy1)carbamate (29.7 mg, 0.070 mmol) in 1,4-dioxane (2.00 ml) was added, followed
by water (2000 pl). The reaction mixture was heated to 50 0C for 16 h, and ncentrated.
To the residue was added CH2C12 (2.0 mL) followed by TFA (2.0 mL). The mixture was
stirred at room ature for 15 min, and then concentrated. The residue was purified using
prep-LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing
0.1% TFA, at flow rate of 60 mL/min) to afford the desired product. LCMS calculated
C25H24F2N50 (M+H)+: m/z = 448.2; found: 448.3.
Example 202. 5,7-Difluoro—N—methyl-G-(3-(1-methyl-1H-pyrazolyl)-lH—pyrazolo[3,4-
c] pyridin-S—yl)- 1,2,3,4-tetrahydronaphthalen-l-amine
This compound was prepared according to the procedure described in Example 201,
using tert—butyl 5-chloro(l-methy1-lH-pyrazolyl)-lH-pyrazolo[3,4-c]pyridine-lcarboxylate
instead of tert—butyl ro(4-(methy1carbamoyl)pheny1)—lI-I-pyrazolo[3,4-
c]pyridine-l-carboxylate as the starting al. LCMS calculated for C21H21F2N6 (M+H)+:
m/z = 3952; found: 395.2.
Example 203. 5,7-Difluoro(3-(6-(4-methylpiperazin-l-yl)pyridinyl)-1H-
pyrazolo[3,4-c]pyridin-S-yl)—1,2,3,4-tetrahydronaphthalen-l-amine
Step 1. tert—Butyl 5, 7-dl'flu0r0(4,4,5,5-tetramethyl-1,3,2—di0xab0rolanyU—1,2,3,4-
tetrahydronaphthalen-I-ylcarbama2‘6
W0 2018f049200 2017/050737
This compound was prepared according to the procedure described in Example 201,
using ammonium acetate instead of methylamine as the starting material. LCMS ated
for C21H30BF2NNaO4 (M+Na)+: m/z = 432.2; found: 4322.
Step 2. terr—Butyl 5-ch10r0(6-(4-methylpiperazmyUpyridinyl)-1H—pyrazol0[3,4-
cjpyridme—I xylate
This compound was prepared according to the procedures described in Intermediate 1,
using 1-methyl(5-(4,4,5,5 -tetramethyl-1,3,2-dioxaborolanyl)pyridin-2—yl)piperazine
instead of l-methyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1H—pyrazole as starting
material. LCMS calculated for C211‘126Cll\1602(lVI‘l'HYr m/z = 4292; found 4291.
Step 3. 5, 7-Diflu0r0(3-(6-(4-methylpzperazz‘nyZ)pyrz‘dz‘nyl)-1H—pyrazoZo[3,4-
cjpyridin—5—yD—1,2,3,4-tetrahydr0naphthalen-J-amz‘ne
To a screw-cap Vial equipped with a magnetic stir bar was added tert-butyl 5-chloro-
3-(6-(4-methylpiperazin-l-yl)pyridinyl)-lH-pyrazolo[3,4-c]py1idinecarboxylate (28.9
mg, 0.06? mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'—
amino-1,1'-biphenyl)]palladium(II) (XPhos Pd G2, 7.5 mg, 9.53 umol) and cesium carbonate
(72.7 mg, 0.223 mmol). The Vial was sealed with a Teflon-lined septum, evacuated and
backfilled with nitrogen (this process was repeated a total of three times). A solution of tert-
butyl (5,7-difluoro(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)—1,2,3,4-
tetrahydronaphthalenyl)carbamate (26.0 mg, 0.064 mmol) in 1,4-dioxane (2.00 ml) was
added, followed by water (200.0 ul). The on mixture was heated to 50 °C for 16 h, and
then concentrated. To the residue was added CH2C12 (2.0 mL) ed by TFA (2.0 mL).
The mixture was d at room ature for 15 min, and then concentrated. The residue
was purified using prep—LCMS (XBridge C18 column, eluting with a gradient of
acetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min) to afford the desired
product. LCMS calculated for F2N7 (M+H)+: m/z = 4762; found: 4763.
e 204. 4-(5-(4,6-Difluoro(methylamino)—2,3—dihydro-1H-indenyl)-1H-
pyrazolo[3,4-c]pyridinyl)-N-methylbenzamide
This compound was prepared according to the procedure described in Example 201,
using 5,7-difluoro-2,3-dihydro- lH-inden-l-amine, HCl salt (AstaTech) instead of 5,7-
difluoro-3,4—dihydronaphthalen-l(2H)—one as the starting material. LCMS ated for
C24H22F2N50 (M+H)+: m/z = 434.2; found: 434.3.
e 205. fluoro—N—methyl-G-(S-(4—(4-methylpiperazinyl)phenyl)-1H-
pyrazolo[3,4-c]pyridin-S-yl)—2,3-dihydr0-lH-inden-l-amine
This compound was prepared according to the procedure described in Example 204,
using tert—butyl 5—chloro(4-(4-methylpiperazin-l-yl)phenyl)-lH-pyrazolo[3,4-c]pyridine-
l-carboxylate instead of tert—butyl 5-chloro(4-(methylcarbamoyl)phenyl)-1H-
pyrazolo[3,4—c]pyridinecarboxylate as the starting material. LCMS calculated for
C27H29F2N6 (M+H)+: m/z = 475.2; found: 4753.
Example 206. 5-Fluorometh0xy(3-(4—(4-methylpiperazinyl)phenyl)-1H-
pyrazolo[3,4-c]pyridin-S-yl)—2,3-dihydro-lH-inden-l-amine
This compound was prepared according to the procedure described in Example 197
using 5-fluoro—7-methoxy-2,3—dihydro- 1H—indenone (NetChem) instead of fluoro—
2,3-dihydro-1H-indenone as the starting material. LCMS calculated for C27H30FN6O
(M+H)+: m/z = 4732; found: 4733.
Example 207. S-Fluoromethoxy(3-(l-methyl-1H-pyrazolyl)—lH-pyrazolo[3,4-
c]pyridin-S—yl)—2,3-dihydro-lH-inden-l-amine
This compound was prepared according to the procedure described in Example 206,
using tert—butyl 5-chloro(l-methyl-lH-pyrazolyl)-1H—pyrazolo[3,4-c]pyridine-lcarboxylate
instead of tert—butyl 5 -chloro(4-(4-methylpiperazinyl)phenyl)—1H—
pyrazolo[3,4-c]pyridinecarboxylate as the starting material. LCMS calculated for
C20H20FN60 (M+H)+: m/z = 3792; found: 379.2.
Example 208. 2-Fluoro-S-(methylamin0)-5,6,7,8-tetrahydr0naphthalen- l-yl)—1H-
lo[3,4—c]pyridinyl)—N—methylpicolinamide
Step 1. ten-Bury! 5-br0m0-6—flu0r0-1,2,3,4-z‘ez‘rahydr0naphthalen-I-yl(methyf)carbamate
Br
W0 2018f049200
To a solution of 5—bromofluoro-3,4-dihydronaphthalen-1(2H)-one (Ark Pharm,
352.6 mg, 1.451 mmol) in 2-propanol (10.0 ml) was added methylamine (2.0 M in methanol)
(2.50 ml, 5.00 mmol) followed by titanium(IV) isopropoxide (596.0 mg, 2.097 mmol). The
mixture was stirred at 35 °C for 16 h before it was cooled to room temperature. Sodium
borohydride (53.4 mg, 1.412 mmol) was added. The reaction mixture was stirred at room
temperature for 1 h, and was ed with HCl (1.0 N in water) (30.0 ml, 30 mmol). The
mixture was stirred at room temperature for 2 h, and was d with NaOH (4.0 N in water)
until pH reached 10. The mixture was extracted with Et20. The organic layer was dried over
anhydrous NazSO4, filtered and concentrated. The e was dissolved in CH2C12 (10 ml),
and treated with Boc-anhydride (426.4 mg, 1.954 mmol). After stirring at room temperature
for 30 min, the reaction mixture was concentrated. The residue was purified on silica gel
(40g, 0-100% EtOAc in hexanes) to give the desired product (461.0 mg, 89%). LCMS
calculated for C12H14BrFN02 (M+H-C4Hs)+: m/z = 3020, found: 302.1.
Step 2. tert—Butyz’ 6-flu0r0(4, 4,5,5-tetramethyl-1,3,2-di0xab0rolanyD-1,2,3,4-
z‘ez‘rahydronaphz‘halen-J-yl(methyl)carbamate
\NJkok0
To a cap vial equipped with a magnetic stir bar was added 4,4,5,5,4',4',5',5'—
octamethyl-[2,2']bi[[1,3,2]dioxaborolanyl] (517.4 mg, 2.037 mmol), ium acetate (416.8
mg, 4.25 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II),
complexed with dichloromethane (1:1) (210.2 mg, 0.257 mmol). The vial was sealed with a
Teflon-lined septum, evacuated and backfilled with nitrogen (this process was repeated a
total of three times). A solution of tert—butyl (5-bromofluoro-1,2,3,4-tetrahydronaphthalen-
1-yl)(methyl)carbamate (461.0 mg, 1.287 mmol) in 1,4-dioxane (6.0 ml) was added via
syringe. The e was heated at 100 °C for 16 h. After cooling to room temperature, the
on mixture was diluted with CH2C12 and filtered. The filtrate was trated. The
residue was purified on silica gel (40 g, 0-100% EtOAc in hexanes) to give the desired
t (337.4 mg, 65%). LCMS calculated for C22H33BFNNaO4 (M+Na)+ m/z = 428.2,
found 428.2.
Step 3. utyl r0(6-(methylcarbamoyUpyrz‘dz‘n-S-yl)-1H-pyra2010[3.4-cjpyrz'dme-
1—carb0xyZaz‘e
This compound was prepared according to the procedures described in Intermediate 1,
using N—methyl-S-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)picolinamide instead of 1-
methyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1H-pyrazole as starting material.
LCMS calculated for C18H19ClNSO3 (M+H)+ m/z = 3881, found 388.1.
Step 4. 5-(5-(2—Fz’u0r0(methylamino)-5, 6, 7, 8-tetrahydr0naphthalen-I-yE)-1H-
pyra2010[3, 4-cjpyridmyl)-N-methylpicolmamide
To a screw-cap Vial equipped with a magnetic stir bar was added tert-butyl 5-chloro-
3-(6-(methylcarbamoyl)pyridinyl)-1H-pyrazolo[3,4-c]py1idinecarboxylate (30.3 mg,
0.078 mmol), chloro(2-dicyclohexylphosphino-2‘,4',6'-triisopropyl-1,1'—biphenyl)[2-(2'-
amino-1,1'-biphenyl)]palladium(II) (XPhos Pd G2, 8.5 mg, 10.80 umol) and cesium
carbonate (77.2 mg, 0.237 mmol). The Vial was sealed with a Teflon-lined septum, evacuated
and lled with nitrogen (this process was repeated a total of three times). A solution of
tert—butyl (6-fluoro(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1,2,3,4-
tetrahydronaphthalen-l-yl)(methyl)carbamate (28.1 mg, 0.069 mmol) in 1,4-dioxane (2.00
ml) was added, followed by water (200.0 ul). The reaction mixture was heated to 50 °C for
16 h, and then trated. To the residue was added CH2C12 (2.0 mL) ed by TFA
(2.0 mL). The mixture was stirred at room temperature for 15 min, and then concentrated.
The residue was purified using prep-LCMS (XBridge C18 column, eluting with a gradient of
acetonitrile/water ning 0.1% TFA, at flow rate of 60 mL/min) to afford the desired
product. LCMS calculated C24H24FN60 (M+H)+: m/z = 4312; found: 431.3.
Example 209. 6-Fluoro-N-methyl(3-(4-(4-methylpiperazinyl)phenyl)-1H-
pyrazol0[3,4-c]pyridin-S-yl)—1,2,3,4-tetrahydronaphthalen-l-amine
This compound was prepared according to the procedure described in Example 208,
using tert-butyl 5—chloro(4-(4-methylpiperazin-l-yl)phenyl)-lH-pyrazolo[3,4-c]pyridine-
l-carboxylate instead of tert—butyl 5-chloro(6-(methylcarbamoyl)pyridinyl)—1H-
pyrazolo[3,4—c]pyridine-l-carboxylate as the starting material. LCMS calculated for
FN6 (M+H)+: m/z = 4713; found: 471.3.
Example 210. 6-Fluoro(3—(1—methyl—1H-pyrazolyl)-lH-pyrazolo [3,4-c]pyridin
yl)-1,2,3,4-tetrahydronaphthalen-l-amine
F /
\ N\
\ / N
HN’N
Step 1. tert—Butyl 0(4, 4, 5, 5-tetramethyl-1,3, 2-di0xab0rolanyU-I, 2,3, 4-
tetrahydronaphthalenylcarbamate
HNiOJ<
This compound was ed according to the procedure described in Example 208,
using ammonium acetate instead of methylamine as the starting material. LCMS calculated
for C17H24BFNO4 (M+H-C4Hs)+: m/z = 336.2; found: 336.3.
Step 2. 6—FZu0r0—5-(3—(I-methyl-1H-pyrazolyl)-1H-pyrazolo[3, 4-c]pyridin—5—yl)-1,2, 3, 4-
W0 2018f049200
tetrahydronaphthalen-J-amine
To a screw-cap Vial equipped with a ic stir bar was added tert—butyl 5-chloro—
3-(1-methyl-1H-pyrazolyl)-1H-pyrazolo[3,4-c]pyridinecarboxylate (24.9 mg, 0.075
mmol, Intermediate 1), chloro(2-dicyclohexylphosphino-2',4',6'-t1iisopropyl-1,1'-biphenyl)[2-
(2'-amino—1,1'-biphenyl)]palladium(II) (XPhos Pd G2, 7.5 mg, 9.53 umol) and cesium
carbonate (72.4 mg, 0.222 mmol). The Vial was sealed with a Teflon-lined septum, evacuated
and backfilled with en (this process was repeated a total of three . A solution of
tert—butyl (6-fluoro(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1,2,3,4-
tetrahydronaphthalenyl)carbamate (25.0 mg, 0.064 mmol) in 1,4-dioxane (2.00 ml) was
added Via syringe, followed by water (200.0 ul). The reaction mixture was heated to 60 0C for
16 h. The reaction mixture was concentrated. To the residue was added CH2C12 (2.0 mL)
followed by TFA (2.0 mL). The mixture was stirred at room temperature for 15 min, and then
concentrated. The residue was purified using prep-LCMS (XBIidge C18 column, eluting with
a gradient of acetonitrile/water containing 0.1% TFA, at flow rate of 60 ) to afford
the desired product. LCMS ated for C27H30FN6 (M+H)+: m/z = 4572; found: 457.2.
Example 211. 2-(3,5-Difluoro(3-(2-(4-methylpiperazinyl)pyrimidinyl)-1H-
pyrazolo[3,4-c]pyridinyl)phenyl)acetonitrile
To a screw-cap Vial equipped with a magnetic stir bar was added 2-bromo-1,3-
difluoroiodobenzene (1360.8 mg, 4.27 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-
W0 2018/‘049200 2017/050737
2-yl)isoxazole (828.0 mg, 4.25 mmol), dichloro[1,1'—
bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct (”E210 mg, 0.890
mmol) and cesium carbonate (2843 mg, 8.73 mmol). The vial was sealed with a lined
septum, ted and backfilled with nitrogen (this process was repeated a total of three
times). 1,4—Dioxane (12.0 ml) was added Via syringe followed by water (2.0 ml). The reaction
was heated to 50 0C for 16 h. After cooling to room temperature, the organic layer was
separated and concentrated. The residue was purified on silica gel (40g, 0-100% EtOAc in
hexanes) to give the desired product as a pale yellow solid (502.9 mg, 46%).
Step 2. 2-(4-Br0m0-3,5-dl'flu0r0phenyl)acetonitrile
To a mixture of 4—(4-bromo-3,5-difluorophenyl)isoxazole (489.4 mg, 1.882 mmol)
and potassium e (5 84.8 mg, 10.07 mmol) was added DMF (50 ml) followed by water
(5.0 ml). The reaction was heated to 90 °C for 3 h. After cooling to room temperature, the
mixture was diluted with CH2C12, and washed with brine. The organic layer was dried over
anhydrous NazSO4, filtered and concentrated. The e was purified on silica gel (40g, 0-
100% EtOAc in hexanes) to give the desired product as an off-white solid (363.4 mg, 83%).
Step 3. 2-(3, 5—Diflu0r0-4—(4, 4, 5, 5-tez‘ramethyZ-1 , 3, 2-dl'oxaborolan-Z-yUphenyDacez‘om'trile
This compound was prepared ing to the procedure described in Example 194,
using 2-(4-bromo-3,5-difluorophenyl)acetonitrile instead of 2-(2-bromo
fluorophenyl)acetonitri1e as starting material. LCMS calculated for C14H17BF2N02 (M+H)+:
m/z = 280.1; found: 280.0.
Step 4. tert—Butyz’ 5-ch10r0(2-(4-methylpl'perazmyl)pyrl'ml'dinyl)-IH-pyra2010[3, 4-
cjpyrl'dme-I -carb0xylate
/N \Ir N0 \
\ / \ N
0=<O+
This compound was prepared according to the procedures described in Intermediate 1,
using 2-(4-methylpiperaziny1)(4,4,5,5-tetramethy1-1,3,2-dioxaborolanyl)pyrimidine
instead of y1(4,4,5,5-tetramethy1-1,3,2-dioxaborolany1)-1H-pyrazole as starting
al. LCMS calculated for C20H25C1N702 (M+H)+ m/z = 4302, found 430.2.
Step 5. 2-(3, 5-Diflu0r0(3-(2-(4-methylpl'perazmyUpyrimidinyl)-1H-pyra2010[3, 4-
cjpyrl'dmyl)phenyl)acet0nitrile
To a screw-cap vial equipped with a magnetic stir bar was added tert—butyl 5-chloro—
3-(2-(4-methylpiperazin—1—yl)pyrimidin-5 -y1)-1H—pyrazolo[3,4-c]pyridinecarboxy1ate
(40.9 mg, 0.095 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-
biphenyl)[2—(2'—amino-1,1’-bipheny1)]palladium(II) (XPhos Pd G2, 112 mg, 0.014 mmol) and
cesium carbonate (95.2 mg, 0.292 mmol). The Vial was sealed with a Teflon-lined septum,
evacuated and backfilled with nitrogen (this process was repeated a total of three times), A
solution of 2-(3,5-difluoro(4,4,5,5-tetramethy1-1,3,2-dioxaborolany1)phenyl)acetonitri1e
(66.8 mg, 0.239 mmol) in 1,4-dioxane (2.0 ml) was added Via syringe, followed by water
(200.0 ul). The reaction mixture was heated to 50 0C for 16 h. The reaction mixture was
concentrated. To the residue was added CH2C12 (2.0 mL) followed by TFA (2.0 mL). The
mixture was d at room temperature for 15 min, and then trated. The residue was
purified using CMS (XBridge C18 column, eluting with a gradient of
itrile/water containing 0.1% TFA, at flow rate of 60 mL/min) to afford the desired
product. LCMS calculated for C23H21F2Ns (M+H)+: m/z = 4472, found: 4422.
Example 212. 5,7-Difluoro(3-(1-methyl-1H-pyrazolyl)—1H-pyrazolo[3,4-c]pyridin-
-yl)-2,3-dihydro-1H-inden-l-ol
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F /
\ N‘
N I /N
Step 1. 5, 7-Diflu0r0-2, 3-dl'hydr0-1H-mden01
F F
To a solution of 5,7-difluoro-2,3-dihydro-1H-indenone (1.134 g, 6.74 mmol) in
MeOH (24.0 ml) was added NaBH4 (773.2 mg, 20.44 mmol). After ng room temperature
for 10 min, the mixture was diluted with CH2C12 and washed with sat. NaHCO3(aq). The
organic layer was dried over anhydrous NazSO4, filtered and concentrated. The residue was
purified on silica gel (40g, 0-100% EtOAc in hexanes) to give the desired product as a
colorless oil (981.4 mg, 86%).
Step 2 5, 7—Dz’flu0r0-6—(4, 4,5,5-tetramethyl—1,3,2—di0xab0r01an-2—yU—2, ydr0—1H—z’nden
To a solution of 5,7-difluoro-2,3-dihydro-1H-indenol (981.4 mg, 5.77 mmol) in
THF (40.0 ml) at -78 °C under N2 was added a solution of n-BuLi (2.5 M in s) (7.00
ml, 17.50 mmol) slowly via syringe over a period of 20 min. The reaction mixture was
allowed to warm to —60 °C and stirred for 60 min. The reaction was then cooled back to -7 8
0C. 2-Isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (4.64 ml, 22.73 mmol) was added
slowly via syringe over a period of 20 min. After stirring at -78 0C for 20 min, the reaction
mixture was allowed to warm to room temperature and d for 1 h. The reaction was
quenched with sat. NaHCO3, and extracted with Et20. The organic layer was dried over
W0 2018f049200
anhydrous , d and concentrated. The residue was purified on silica gel (40 g, 0-
100% EtOAc in hexanes) to give the desired product as a colorless oil (1.085 g, 64%).
Step 3. 5, 7—Difluor0-6—(3—(1-methy]-1H-pyrazol—4—yl)-1H-pyra2010[3,4—cjpyridin—5—yD-2,3-
dihydro—IH—inden-J -01
To a screw-cap Vial equipped with a magnetic stir bar was added tert-butyl 5-chloro-
3-(1-methyl-lH—pyrazolyl)—lH-pyrazolo[3,4-c]pyridinecarboxylate (26.4 mg, 0.079
mmol, ediate 1), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'—biphenyl)[2-
(2'-amino-1,1'—biphenyl)]palladium(II) (XPhos Pd G2, 10.0 mg, 0.013 mmol) and cesium
carbonate (86.3 mg, 0.265 mmol). The Vial was sealed with a Teflon-lined septum, evacuated
and lled with nitrogen (this process was repeated a total of three . A solution of
,7-difluoro(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)—2,3-dihydro-1H—indenol (25.0
mg, 0.084 mmol) in 1,4-dioxane (2.00 ml) was added, followed by water (2000 pl). The
reaction mixture was heated to 50 0C for 16 h. The reaction mixture was concentrated. To the
residue was added CH2C12 (2.0 mL) followed by TFA (2.0 mL). The mixture was stirred at
room temperature for 15 min, and then concentrated. The residue was purified using prep-
LCMS (XBIidge C18 column, eluting with a gradient of acetonitrile/water containing 0.1%
TFA, at flow rate of 60 ) to afford the desired product. LCMS calculated for
C19H16F2N50 (M+H)+: m/z = 368.1; found: 368.2.
Example 213. 5,7-Difluoro(3-(6-(4-methylpiperazinyl)pyridinyl)—1H-
pyrazolo[3,4-c]pyridin-S-yl)—2,3-dihydro-lH-inden- 1-ol
N\ / \ N
This compound was prepared according to the procedure bed in Example 212,
using tert—butyl 5-chloro(6-(4-methylpiperazinyl)pyridinyl)-1H-pyrazolo[3,4-
c]pyridine-1 -carboxy1ate instead of tert—butyl 5-chloro(1-methyl-1H-pyrazolyl)—1H—
pyrazolo[3,4-c]pyridinecarboxylate as the starting material. LCMS calculated for
C25H25F2N60 (M+H)+: m/z = 4632; found: 463.2.
Example 214. 6,8-Difluoro(4-methoxy(1-methyl-1H-pyrazolyl)-1H—pyrazolo[3,4-
c]pyridin-S-yl)—N-methyl-1,2,3,4-tetrahydronaphthalen-Z-amine
o /
\ \IN‘
\/ /N
Step 1. tert—Butyl 6—ch10r0methoxypyrl'dmylcarbamate
\~ O\~
HN \fl/Oj<
To a solution of 6—chloromethoxypyridinamine (1.992 g, 12.56 mmol) in THF
(1000 mL) at 0 °C was added a solution of KHMDS (1.0 M in THF) (28.0 mL, 280 mmol)
slowly via syringe over a period of 10 min. The e was stirred at 0 0C for 30 min. A
solution of Boc—anhydride (3.28 g, 15.03 mmol) in THF (10.0 mL) was added slowly Via
syringe over a period of 20 min. The mixture was allowed to warm to room temperature.
After stirring for 2 h, the reaction mixture was quenched with sat. NaHCO3(aq) and ted
with Et20. The c layer was dried over ous NazSO4, filtered and concentrated.
The residue was purified on silica gel (120 g, 0-100% EtOAc in hexanes) to give the desired
product as ayellow foamy solid (2.162 g, 67%). LCMS calculated for C11H16C1N203
(M+H)+: m/z = 2591; found: 259.1.
Step 2. tert—Butyl 6—chlor0-5—methoxymethylpyrl'dm-S-ylcarbamare
N \\ O\\
HN \g/OK
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To a solution of tert—butyl (6-chloromethoxypyridinyl)carbamate (2.102 g, 8.13
mmol) in THF (80.0 ml) at -78 °C under N2 was added TMEDA (3.81 n11, 25.3 mmol). A
solution of n-BuLi (2.5 M in hexanes) (9.00 ml, 22.50 mmol) was added slowly via syringe
over a period of 30 min. The reaction was allowed to warm to -30 °C and stirred for 2 h. The
reaction e was then cooled back to -78 0C. MeI (2.0 M in MTBE) (7.00 ml, 14.00
mmol) was added dropwise via syringe over a period of 30 min. After stirring at -78 °C for 1
h, the white suspension was allowed to warm to -20 0C and stirred for 2 h. The on was
quenched with water. The mixture was extracted with Et20. The organic layer was dried over
anhydrous Na2S04, filtered and concentrated. The ressidue was purified on silica gel (120 g,
0-100% EtOAc in hexanes) to give the desired product as a white solid (2.055 g, 93%).
LCMS ated for CrzHrsClN203 (M+H)+: m/z = 2731, found: 273.1.
Step 3. r0-5—methoxymethylpyrl'dm-S-amme
To a solution of tert-butyl (6-chloromethoxymethylpyridinyl)carbamate
(2.055 g, 7‘53 mmol) in CH2C12 (20.0 ml) was added TFA (20.0 ml). The mixture was stirred
at room temperature for 50 min, and then concentrated. The residue was ved in CH2C12,
washed with sat. NaHCO3 (aq). The organic layer was dried over anhydrous , filtered
and concentrated. The residue was purified on silica gel (40 g, 0-100% EtOAc in hexanes) to
give the desired product as a white solid (1.110 g, 85%). LCMS calculated for C7H10ClN20
(M+H)+: m/z = 173.0; found: 173.1.
Step 4. 5-Chlor0meth0xy—1H-pyra2010[3, ridme
To a solution of 6-chloromethoxymethy1pyridinamine (1.104 g, 6.40 mmol)
in acetic acid (220 mL) was added amyl nitrite (1.096 mL, 8.16 mmol). After stirring at
room temperature for 5 min, the mixture was heated to 80 °C for 1 h. The reaction mixture
was cooled to room temperature and concentrated in vacuo. The crude product was used
W0 2018f049200
directly in the next step without further purification. LCMS calculated for C7H7C1N3O
(M+H)+: m/z = 184.0; found: 184.1.
Step 5. tert—Butyl r0meth0xy(1-methyl—JH-pyrazoZyl)—1H—pyrazolo[3, 4-
cjpyridine—I xylate
\ N/
N \
\ / I
This compound was prepared according to the procedure bed in Intermediate
1, using 5-chloromethoxy-1H-pyrazolo[3,4-c]pyridine instead of 5-chloro—1H—
pyrazolo[3,4—c]pyridine as the starting material. LCMS calculated for C16H19C1N503 (M+H)+
m/Z = 364.]; found 364.1.
Step 6. 6,8-Diflu0r0- 7-(4-methoxy—3-(1-methyl-1H—pyrazoZyl)-1H-pyrazoio[3,4-cjpyrz'dm-
-yZ)-N-methyl-1
, 2, 3, 4-tetrahydronaphthalen-Z-amz‘ne
To a screw-cap Vial equipped with a magnetic stir bar was added tert-butyl 5-chloro-
4-methoxy(1-methy1-1H-pyrazolyl)-1H-pyrazolo[3,4-c]pyridine-1—carboxylate (31.5
mg, 0.087 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropy1-1,1'-bipheny1)[2-(2'—
amino-1,1'-bipheny1)]palladium(II) (XPhos Pd G2, 9.6 mg, 0.012 mmol) and cesium
carbonate (99.2 mg, 0.304 mmol). The Vial was sealed with a Teflon-lined septum, evacuated
and led with nitrogen (this s was repeated a total of three times). A on of
tert—butyl (6,8-difluoro(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)—1,2,3,4—
tetrahydronaphthaleny1)(methy1)carbamate (34.4 mg, 0.081 mmol, Example 199, Step 2)
in 1,4-dioxane (2.00 ml) was added, followed by water (200.0 ul). The reaction e was
heated to 50 °C for 16 h. The reaction mixture was concentrated. To the residue was added
CH2C12 (2.0 mL) followed by TFA (2.0 mL). The mixture was stirred at room temperature for
15 min, and then concentrated. The residue was purified using prep-LCMS ge C18
column, eluting with a gradient of acetonitrile/water containing 0.1% TFA, at flow rate of 60
mL/min) to afford the desired product. LCMS calculated for C22H23F2N60 (M+H)+: m/z =
4252; found: 425.2.
Example 215. 1-(3,5-Difluoro(4-methoxy(1-methyl-1H-pyrazolyl)-1H-
pyrazol0[3,4-c]pyridinyl)phenyl)—N—methylmethanamine
O /
N\ \IN\
\/ /N
This compound was prepared according to the procedure described in Example 214,
using tert—butyl 3,5-difluoro(4,4,5,5-tetramethyl-1,3,2-dioxaborolan
yl)benzyl(methyl)carbamate instead of tert—butyl (6,8-difluoro(4,4,5,5-tetramethyl-1,3,2-
orolanyl)-1,2,3,4-tetrahydronaphthalenyl)(methyl)carbamate as the starting
material. LCMS calculated for F2N60 (M+H)+: m/z = 3852, found: 3852.
Example 216. 5,7-Difluoro(4-fluoro-3—(l-methyl-1H-pyrazolyl)- azolo[3,4-
c] pyridin-S—yl)-2,3-dihydro-lH-inden-l-amine
Step 1. tert—Butyl rofluor0pyridinylcarbamate
N \\
HNTOK
0
To a flask equipped with a magnetic stir bar was added 5-bromochloro
fluoropyridine (5.237 g, 24.89 mmol), chloro[(4,5-bis(diphenylphosphino)—9,9—
dimethylxanthene)(2'-arnino-1,1'-biphenyl)]palladium(II) (XantPhos Pd G2, 2.254 g, 2.54
mmol), tert-butyl carbamate (3.191 g, 27.2 mmol) and cesium carbonate (20.06 g, 61.6
mmol). The flask was sealed with a septum, evacuated and backfilled with nitrogen (this
W0 2018/‘049200
process was repeated a total of three . 1,4-Dioxane (90.0 ml) was added. The reaction
mixture was stirred at 100 °C for 16 h. After cooling to room temperature, the reaction
mixture was diluted with CH2C12 and filtered. The filtrate was concentrated. The residue was
purified on silica gel (120 g, 0-50% EtOAc in hexanes) to give the desired product as a pale
yellow oil (2.745 g, 45%). LCMS calculated for C10H13ClFN202 : m/z = 247.1;
found: 247.1.
Step 2. tert—Butyl r0flu0r0methylpyridin-S-ylcarbamare
HNTO7<
To a solution of tert—butyl (6-chlorofluoropyn'dinyl)carbamate (2.745 g, 11.13
mmol) in THF (30.0 ml) at -78 °C under N2 was added a solution of n-BuLi (2.5 M in
hexanes) (12.0 ml, 300 mmol) slowly via syringe over a period of 30 min. The reaction
mixture was allowed to warm to -30 °C and d for 2 h. The reaction mixture was then
cooled back to -78 °C. Mel (2.0 M in MTBE) (9.00 ml, 18.00 mmol) was added dropwise via
syringe over a period of 30 min. After stirring at -78 °C for 1 h, the white sion was
allowed to warm to -20 0C and stirred for 2 h. The reaction mixture was quenched with water.
The mixture was extracted with Et20. The organic layer was dried over anhydrous NazS O4,
filtered and concentrated. The ressidue was d on silica gel (120 g, 0-50% EtOAc in
hexanes) to give the d product as a pale yellow solid (2.512 g, 87%). LCMS calculated
for C11H15ClFN202 (M+H)+: m/z = 261.1; found: 261.1.
Step 3. 6-Chlor0-5—flu0r0methylpyridm-S-amme
To a solution of tert—butyl (6-chlorofluoromethylpyridinyl)carbamate (2.512
g, 9.64 mmol) CH2C12 (30.0 ml) was added TFA (30.0 ml). The mixture was stirred at room
temperature for 50 min, and then concentrated. The residue was dissolved in CH2C12 and
washed with sat. NaHCO3 (aq). The organic layer was dried over anhydrous NazSO4, filtered
W0 2018f049200
and trated. The residue was purified on silica gel (40 g, 0-100% EtOAc in hexanes) to
give the desired product as a white solid (1.420 g, 92%). LCMS ated for C6H7C1FN2
: m/z = 161.0; found: 161.1.
Step 4. tert—Butyl 5-chlor0flu0r0(I-methyl-1H-pyrazoZyl)-1H-pyrazoio[3,4-
cjpyrz'dme—I —carb0xylate
This compound was prepared ing to the procedure described in Example 214,
using 6-chlorofluoromethylpyridinamine instead of 6-chloromethoxy
methylpyridinamine as the starting material. LCMS calculated for C15H16C1FN502 (M+H)+
m/z = 352.]; found 352.2.
Step 5. 5, 7-Difluor0(4-fluor0(1-methyl-1H-pyrazoZyl)-1H-pyrazolo[3,4-cjpyrz'dz'n
yl) -2, 3-dz’hydr0-1H-z’ndenamz'ne
To a screw-cap Vial equipped with a magnetic stir bar was added tert-butyl 5-chloro-
4-fluoro(1-methyl-1H—pyrazolyl)— lH-pyrazolo[3,4-c]pyridinecarboxylate (28.2 mg,
0.080 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'—
amino-1,1'-biphenyl)]palladium(II) (XPhos Pd G2, 8.5 mg, 10.80 umol) and cesium
carbonate (72.4 mg, 0.222 mmol). The Vial was sealed with a Teflon-lined septum, evacuated
and backfilled with nitrogen (this process was repeated a total of three times). A solution of
tert—butyl (5,7-difluoro(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)—2,3-dihydro-1H-
inden-l-yl)carbamate (27.6 mg, 0.070 mmol, Example 204, Step 2) in 1,4-dioxane (2.00 ml)
was added, followed by water (200.0 ul). The reaction e was heated to 50 °C for 16 h.
The reaction mixture was concentrated. To the residue was added CH2C12 (2.0 mL) followed
by TFA (2.0 mL). The mixture was stirred at room temperature for 15 min, and then
concentrated. The residue was purified using CMS ge C18 , eluting with
a gradient of acetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min) to afford
the desired product. LCMS calculated for C19H16F3N6 (M+H)+: m/z = 385.1; found: 3852.
Example 217. 1-(3,5-Difluoro(3-(2-(4-methylpiperazinyl)pyrimidinyl)—1H-
pyrazol0[3,4-c]pyridinyl)phenyl)—N—methylmethanamine
This compound was prepared according to the procedure described in Example 161,
using 2-(4-methylpiperazinyl)(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)pyrimidine
instead of 2—(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1H—pyrazolyl)benzonitrile as
the starting material. LCMS calculated for C23H25F2Ns (M+H)+: m/z = 451.2; found: 451.3.
1H NMR (TFA salt, 600 MHz, DMSO-ds) 5 10.18 (br, 1H), 9.21 (d, J: 1.1 Hz, 1H), 9.10 (br,
2H), 9.07 (s, 2H), 8.32 (s, 1H), 7.38 (d, J: 8.0 Hz, 2H), 4.79 (m, 2H), 4.24 (t, J: 4.5 Hz,
2H), 3.54 (m, 2H), 3.34 (m, 2H), 3.10 (m, 2H), 2.85 (s, 3H), 2.62 (t, J: 4.5 Hz, 3H).
e 218. 1-(5-(5-(2,6-Difluoro((methylamino)methyl)phenyl)-lH—pyrazolo[3,4-
c] pyridin-3—yl)pyrimidinyl)piperidinol
\ /N UOH
N‘ / \ I
This compound was prepared according to the procedure described in Example 161,
using 1-(5—(4,4,5,5-tetramethyl-1,3 ,2-dioxaborolanyl)pyrimidinyl)piperidinol instead
of 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)—1H—pyrazolyl)benzonitrile as the
starting al. LCMS calculated for C23H24F2N7O : m/z = 452.2; found: 452.2.
Example 219. 1-(3,5-Difluoro(3-(5-(4-methylpiperazin-l-yl)pyridinyl)—1H-
pyrazolo[3,4-c]pyridinyl)phenyl)—N—methylmethanamine
This compound was ed according to the ure described in Example 161,
using 5-(4-methylpiperazinyl)pyridinylboronic acid instead of 2-(4-(4,4,5,5—
tetramethyl-l,3,2-dioxaborolanyl)-1H-pyrazolyl)benzonitrile as the starting material.
LCMS calculated for C24H26F2N7 : m/z = 4502; found: 450.3.
Example 220. 4-Fluoro-N,6-dimethyl-S-(S-(l-methyl-1H-pyrazolyl)-1H-pyrazolo[3,4-
c]pyridin-S-yl)-2,3-dihydro-1H-indenamine
F /
\ N‘
N I
\ / /N
Step 1. 5-(Benzyz’0xy)flu0r0-6—i0d0-2, 3-dihydr0-1H—inden0ne
To a mixture of 4-fluorohydroxy-2,3-dihydro-1H-indenone (2.017 g, 12.14
mmol) and NIS (2.742 g, 12.19 mmol) was added DMF (30.0 ml). The mixture was stirred at
room temperature for 24 h. Benzyl bromide (2.820 g, 16.49 mmol) was added followed by
K2CO3 (5.088 g, 36.8 mmol). The reaction was stirred at 80 °C for 16 h. After g to
room temperature, the mixture was diluted with Et20 and washed with brine. The organic
layer was dried over anhydrous Na2S04, filtered and concentrated. The residue was purified
on silica gel (120g, 0-100% EtOAc in hexanes) to give the desired product as a yellow solid
(2.36 g, 51%). LCMS calculated for C16H13F102 (M+H)+: m/z = 383.0; found: 3830.
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Step 2. tert—Butyl 5—(benzyloxy)—4—flu0r0—6—z‘0d0—2, 3—dl'hydr0-1H—z'nden—1 —
yZ(methyZ)carbamaz‘e
To a solution of 5-(benzyloxy)fluoroiodo-2,3-dihydro-1H-indenone (2.36 g,
6.18 mmol) in 2-propanol (40.0 ml) was added methylamine (2.0 M in methanol) (16.0 ml,
32.0 mmol) followed by titanium(IV) poxide (3.962 g, 13.94 mmol). The mixture was
stirred at 35 °C for 16 h, and then cooled to r.t. Sodium borohydride (351.3 mg, 9.29 mmol)
was added. After stirring at room temperature for 30 min, the reaction was quenched with
HCl (6.0 N in water) (20.0 ml, 120 mmol). The resulting mixture was stirred at 40 °C for 2 h,
and cooled to room temperature. The mixture was treated with 4N NaOH until pH reached 10
and extracted with EtzO. The organic layer was dried over anhydrous Na2SO4, filtered and
concentrated. The e was dissolved in CH2C12. Boc-anhydride (1.505 g, 6.90 mmol) was
added. After g at room temperature for 30 min, the reaction e was quenched with
MeOH and concentrated. The residue was purified on silica gel (120g, 0-100% EtOAc in
hexanes) to give the desired product as a solid (2.60 g, 85%).
Step 3. utyl 5-(benzyloxy)flu0r0-6—methyl-2,3-dihydr0-1H—inden-I-
yl(methyl)carbamate
0%014
OBn
To a screw-cap vial equipped with a magnetic stir bar was added tert—butyl (5-
(benzyloxy)fluoroiodo-2,3-dihydro-1H-indenyl)(methyl)carbamate (1001.4 mg,
2.013 mmol), dicyclohexyl(2',4’,6'-triisopropylbiphenylyl)phosphine-(2'-aminobipheny1
yl)(chloro)palladium (1 :1) (XPhos Pd G2, 317.1 mg, 0.403 mmol), and potassium ate
(1783 mg, 8.40 mmol). The vial was sealed with a Teflon-lined septum, evacuated and
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backfilled with nitrogen (this process was repeated a total of three times). A solution of 2,4,6-
trimethyl-1,3,5,2,4,6—trioxatriborinane (830.6 mg, 6.62 mmol) in 1,4-dioxane (10.0 ml) was
added followed by water (2.00 ml). The on was stirred at 60 °C for 16 h. After cooling
to room temperature, the mixture was diluted with CH2C12, and washed with brine. The
organic layer was dried over anhydrous NazSO4, filtered and concentrated. The residue was
purified on silica gel (40 g, 0-100% EtOAc in hexanes) to give the d product. LCMS
calculated for C23H28FNNaO3 (M+Na)+: m/z = 4082, found: 408.2.
Step 4. tert—Butyl 4-flu0r0hydr0xy-6—methyl-2,3-dl'hydr0-1H—indenyl(methyl)carbamate
oii‘é
OH
To tert—butyl (5-(benzyloxy)fluoromethyl-2,3-dihydro-lH-inden—1—
yl)(methyl)carbamate (776.0 mg, 2.013 mmol) was added MeOH (25.0 mL) followed by
THF (5.00 mL). ium hydroxide on carbon (20 wt%) (566.2 mg, 0.806 mmol) was
added. The mixture was purged with H2 and stirred under H2 atmosphere (1 atm) for 16 h.
The mixture was filtered through a pad of Celite. The filtrate was concentrated in vacuo, and
the residue was d on silica gel (40%, 0-100% EtOAc in hexanes) to give the desired
product as a yellow foamy solid (234.1 mg, 39%).
Step 5. 1-(tert—Butoxycarb0nyl(methyl)amm0)flu0r0-6—methyl-2, 3-dihydr0-1H—irzdenyl
trifluoromethanesulfonate
0%(3‘é
To a solution of tert-butyl (4-fluorohydroxymethy1-2,3-dihydro-lH-inden-1 -
yl)(methyl)carbamate (234.1 mg, 0.793 mmol) in CH2C12 (5.0 ml) at 0 °C was added pyridine
(1001.7 mg, 12.66 mmol). A solution of romethanesulfonic anhydride (671.2 mg, 2.379
mmol) in CHzClz (5.0 mL) was added slowly. The reaction e was allowed to warm to
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room temperature and stirred for 6 h. The reaction mixture was quenched with 2 M K2CO3
(aq) and extraced with CH2C12. The organic layer was dried over anhydrous Na2SO4, filtered
and concentrated. The residue was d on silica gel (40g, 0-100% EtOAc in hexanes) to
give the desired product (284.9 mg, 84%). LCMS calculated for C13H14F4N05S (M+HC4Hs
)+: m/z = 372.1; found: 372.1.
Step 6. tert—Butyl 4-flu0r0-6—methyl(4, 4, 5, 5-tetramethyZ-1,3, 2-di0xab0r02an—2—yD-2, 3-
dihydro-IH-inden-I-yl(methyl)carbamaz‘e
To a screw-cap vial equipped with a magnetic stir bar was added 4,4,4',4',5,5,5',5'-
octamethyl-2,2'-bi(1,3,2—dioxaborolane) (231.6 mg, 0.912 mmol), potassium e (227.4
mg, 2.31? mmol) and [1,l'-bis(diphenylphosphino)ferrocene]dichloropalladiumfll),
xed with dichloromethane (1:1) (109.8 mg, 0.134 mmol). The vial was sealed with a
Teflon-lined septum, ted and backfilled with nitrogen (this process was repeated a
total of three times). A solution of 1-((terz‘-butoxycarbonyl)(methyl)amino)—4—fluoro—6-
methyl-2,3-dihydro- en-S-yl trifluoromethanesulfonate (284.9 mg, 0.667 mmol) in 1,4-
dioxane (5.0 mL) was added Via syringe. The mixture was stirred at 100 °C for 16 h. After
cooling to room temperature, the mixture was filtered. The filtrate was used ly in the
next step.
Step 7. 4-Flu0r0-N, 6-dl'methyl(3-(1-methyl-1H—pyrazolyl)-1H-pyrazolo[3,4-c]pyridin-
-yZ)-2, dr0-1H—inden-1amine
This compound was prepared according to the procedure bed in Example 198,
using tert—butyl 4-fluoromethyl(4,4,5,5-tetramethyl-l,3,2-dioxaborolanyl)-2,3-
dihydro— 1H-indeny1(methyl)carbamate instead of tert—butyl 4,6-difluoro(4,4,5,5-
tetramethyl-l ,3,2-dioxaborolanyl)-2,3-dihydro-lH-indeny1(methyl)carbamate as the
starting material. LCMS calculated for C21H22FN6 (M+H)+: m/z = 377 .2; found: 377.2. 1H
NMR (TFA salt, 600 MHz, DMSO-ds) 6 9.13 (d, J: 1.0 Hz, 1H), 9.05 — 8.87 (m, 2H), 8.47
(s, 1H), 8.03 (s, 1H), 8.03 (d, J: 0.6 Hz, 1H), 7.38 (s, 1H), 4.80 (m, 1H), 3.90 (s, 3H), 3.10
(m, 1H), 2.99 — 2.89 (m, 1H), 2.65 (t, J: 5.4 Hz, 3H), 2.57 — 2.50 (m, 1H), 2.24 (m, 1H),
2.14 (s, 3H).
e 221. 5-(3-((3,3-Dimethylazetidinyl)methyl)fluor0—2-methylphenyl)—3-(1-
methyl- 1H—pyraz01—4—yl)—1H—pyrazolo[3,4—c]pyridine
N.\ /
/ /'\‘
/ /N
This compound was prepared according to the procedures bed in Example 86
and 92, using 3,3-dimethylazetidine instead of methanamine as starting material. LCMS
calculated for C23H26FN6 (M+H)+: m/z = 4052, Found: 405.3.
1H NMR (500 MHz, DMSO-d6) 5 9.21 (s, 1H), 8.49 (s, 1H), 8.11 (s, 1H), 8.08 — 8.03 (m,
1H), 7.60 (dd, J = 8.6, 5.7 Hz, 1H), 7.29 (t, J = 8.7 Hz, 1H), 4.52 (d, J = 5.7 Hz, 2H), 4.09 —
3.94 (m, 4H), 3.92 (s, 3H), 2.14 (s, 3H), 1.35 (s, 3H), 1.30 (s, 3H) ppm.
Example 222. trans-N-(4-Fluoromethyl-3—(3—(l-methyl-1H—pyrazolyl)-1H-
pyrazolo[3,4—c]pyridin-S-yl)benzyl)meth0xycyclobutanamine
_.\OMe
N \ /
/ / N
/ /N
This compound was prepared according to the procedures bed in Example 86
and 92, using 3-methoxycyclobutanamine instead of methanamine as starting material.
LCMS calculated for C23H26FN6O (M+H)+: m/z = 421.2, Found: 4212.
Example 223. N—(4—Fluoromethyl-3—(3—(l-methyl-1H-pyrazolyl)-1H-pyrazolo[3,4-
c] pyridin-S-yl)benzyl)—3,3-dimethylcyclobutanamine
N \ /
/ / N
/ / N
This nd was prepared according to the procedures described in Example 86
and 92, using 3,3—dimethylcyclobutanamine instead of methanamine as starting material.
LCMS calculated for C24H28FN6 (M+H)+: m/z = 4192; Found: 419.2.
Example 224. N-(4-Fluoromethyl-3—(3-(1-methyl-1H-pyrazol—4-yl)—1H-pyrazolo[3,4-
c] pyridin-S—yl)benzyl)—1-(1-methylcyclopropyl)methanamine
“V /
/ /"l
/ /N
This compound was prepared according to the procedures described in Example 86
and 92, using (1-methylcyclopropyl)methanamine instead of methanamine as starting
material. LCMS ated for C23H26FN6 (M+H)+: m/z = 4052; Found: 4052.
Example 225. l-(4-Fuoro-3—(3—(1-methyl-1H-pyrazolyl)—1H-pyrazolo[3,4—c]pyridin-S-
yl)(triflu0r0methyl)phenyl)—N—methylmethanamine
F CF3
“1 \ /
/ / "l
/ / N
HN‘N
This nd was prepared according to the procedures described in e 131,
using 4-fluoro—2-(trifluoromethyl)benzaldehyde instead of 3-fluoro
(trifluoromethyl)benza1dehyde as starting al. LCMS calculated for C19H17F4N6
(M+H)+: m/z = 405.2; Found: 405.2.
1H NMR (500 MHz, DMSO-d6) 5 9.14 (br, 1H), 9.10 (s, 1H), 8.46 (s, 1H), 8.14 (s, 1H), 8.04
(s, 1H), 19? — 7.82 (m, 2H), 4.39 (br, 2H), 3.91 (s, 3H), 2.73 (s, 3H) ppm.
Example 226 and 227. 5-(2-Flu0ro-4—(pyrrolidin-Z-yl)—6-(trifluor0methyl)phenyl)—3—(1-
methyl- 1H-pyraz0]-4—yl)—lH-pyrazolo [3,4—c] pyridine
HN HN
F CF3 F CF3
N/ / N/
| | /
\ / N \ / N
/ /N
/ /N
HN\N HN\N
peak1 peak2
This compound was prepared according to the procedures bed in Example 171,
using 1-bromo—3-fluoro(trifluoromethyl)benzene instead of ofluoroiodo
methylbenzene as starting material. Peak 1: LCMS calculated for C21H19F4N6 (M+H)+: m/z =
431.2; Found: 431.2. 1H NMR (TFA salt, 500 MHz, (CD3)2SO) 5 13.70 (br s, 1H), 9.52 (br s,
1H), 9.11 (d, J=1.3 Hz, 1H), 8.95 (br s, 1H), 8.45 (s, 1H), 8.16 (d, J= 1.3 Hz,1H), 8.04 (d, J
= 0.8 Hz, 1H), 7.92
— 7.86 (m, 2H), 4.79 (m, 1H), 3.91 (s, 3H), 3.48 (m, 1H), 3.38 (m, 1H),
2.23 — 2.03 (m, 4H). Peak 2: LCMS calculated for F4N6 (M+H)+: m/z = 431.2; Found:
431.2.
Example 228 and 229. 1-(4-(3-(1-Cyclopropyl-1H-pyrazol-4—yl)—1H-pyraz0l0[3,4-
c]pyridin-S—yl)—3—fluoro-S-methylphenyl)—N—methylethanamine
| |
NH NH
F F
\ / "l \ / N
/N / /N
HN\N HN\N
peak1 peak2
This compound was prepared according to the procedures described in Example 189,
using 1-cyclopropyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-lH-pyrazole instead of
yl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-lH-pyrazole as starting material.
Peak 1: LCMS calculated for C22H24FN6 (M+H)+: m/z = 391.2; Found: 3912. Peak 2: LCMS
calculated for C22H24FN6 (M+H)+: m/z = 391.2; Found: 391.2.
Example 230 and 231. 3-(1-Ethyl-1H-pyrazolyl)—5—(2-flu0r0methyl(piperidin
nyl)—1H-pyrazolo[3,4-c]pyridine
HN HN
F F
N/ > N/ >
I I
\ / N \ / N
/ /N
/ /N
HN‘N HN\N
peak1 peak2
This compound was prepared ing to the procedures described in Example 174,
using 1-ethyl-4—(4,4;5,5-tetramethyl-1,3;2-dioxaborolanyl)-1H—pyrazole instead of 1—
methyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1H—pyrazole as starting material.
Peak 1: LCMS calculated for C23H26FN6 (M+H)+: m/z = 4052; Found: 4052. Peak 2: LCMS
calculated for C23H26FN6 (M+H)+: m/z = 405.2; Found: 4052.
Example 232 and 233. 3-(1-Cyclopropyl-1H-pyrazolyl)—5-(2-flu0r0methyl
(piperidin-Z-yl)phenyl)—lH-pyrazolo[3,4-c]pyridine
HN HN
F F
N/ P N/ P
I I
\ / "l \ / N
/ /N / /N
peak 1 peak 2
This compound was prepared according to the procedures described in Example 174;
using 1-cyclopropyl—4—(4;4;5,5-tetramethyl-1,3,2-dioxaborolanyl)-1H-pyrazole instead of
1-methy1(4,4,5,5-tetramethy1-1,3;2-dioxaborolanyl)-1H-pyrazole as starting material.
Peak 1: LCMS calculated for FN6 (M+H)+: m/z = 4172; Found: 4172. Peak 2: LCMS
calculated for C24H26FN6 (M+H)+: m/z = 417.2; Found: 417.2.
e 234. 3-(3-Fluoro-S-methyl(3-(l-methyl-1H-pyrazolyl)-1H-pyrazolo[3,4-
c] n-S-yl)phenyl)morpholine
A solution of 3-fluoromethyl(3-(1-methyl-1H-pyrazolyl)((2—
(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridinyl)benza1dehyde (40 mg, 0.086
mmol, Example 176, Step 2) and SnAP M reagent (31.3 mg, 0.086 mmol) in toluene (1 mL)
was refluxed at 120 °C for 1h. The mixture was concentrated under reduced pressure to afford
the imine intermediate. Separately, a solution of Cu(OTf)2 (31.1 mg, 0.086 mmol) in HFIP
(0.7 mL) was treated with 2,6-lutidine (10.01 ul, 0.086 mol) at RT. After stirring for 1 h, a
solution of the imine intermediate in DCM (1 mL) was added and the resulting mixture was
stirred at RT for 16 h. The, mixture was treated with NH4OH (aq) and extracted with ethyl
acetate. The combined organic phases were concentrated under reduced pressure to give the
crude product. The crude product was dissolved in DCM (2.0 mL), and TFA (2.0 mL) was
added dropwise at room temperature. After stirring for 2 h, the mixture was concentrated in
vacuo. The crude mixture was ved in MeOH (3.5 mL) and 10% aqueous NH4OH (1.5
mL) and ed with prep-LCMS (XBridge C18 column, eluting with a gradient of
acetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min) to give the desired
t. LCMS calculated for C21H22FN60 (M+H)+: m/z = 393.2, Found: 393.2.
Example 235. 1-(3-(Difluoromethyl)flu0r0-4—(3-(1-methyl-1H-pyrazolyl)-1H-
pyrazolo[3,4-c] pyridin-S-yl)phenyl)—N—methylmethanamine
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Step 1. tert—Butyl 3-(dl'flu0r0mez‘hyl)flu0r0benzyl(methyl)carbamate
This compound was prepared according to the ures described in Example 113
(Steps 3-6), using o(difluoromethyl)fluorobenzene instead of 2-bromofluoro-
-iodomethylbenzeneas starting material. LCMS calculated for C10H11F3N02 (M+H-
C4Hs)Jr m/z = 2342; found 234.1.
Step 2. tert—Butyl 3-(dz'fluoromethyl)flu0r0(4, 4, 5, ‘ramethyZ-1 , 3, Z—dioxaborolan-Z-
yUbenzyE(met/zyz’)carbamate
To a solution of tert-butyl (3-(difluoromethyl)—5-fluorobenzyl)(methyl)carbamate
(256.5 mg, 0.887 mmol) in THF (8.0 ml) at -78 0C was added LDA (240 M in THF) (600.0
ul, 1.200 mmol) dropwise. The mixture was stirred at -78 °C for 30 min. A solution of 2-
isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (336.0 mg, 1.806 mmol) in THF (50 ml)
was added dropwise. The reaction was stirred at -78 °C for 15 min and then allowed to warm
to room temperature. After stirring at room temperature for 20 min, the reaction was treated
with sat. NaHCO3 (aq) and ted with CH2C12. The combined organic phases were dried
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over anhydrous NazSO4, filtered and concentrated. The residue was purified on silica gel (20
g, 0-100% EtOAc in hexanes) to give the desired product (626 mg, 17%). LCMS ated
for C16H22BF3NO4 (M+H-C4H8)+ m/z = 360.2; found 3602.
Step 3. 1 —(3—(Difluoromethyl)flu0r0(3-(1-methyl-1H-pyrazolyl)—IH—pyrazolo[3, 4-
cjpyridin—5—y0phenyl)-N-methylmethanamine
A vial was charged with tert—butyl 5-chloro(1-methyl-1H—pyrazolyl)- 1H-
pyrazolo[3,4—c]pyridinecarboxylate (50.5 mg, 0.151 mmol, ediate 1) chloro(2-
dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'—arnino-1,1'-
biphenyl)]palladium(II) (XPhos Pd G2, 11.9 mg, 0.015 mmol) and cesium carbonate (156.2
mg, 0.479 mmol). The vial was sealed, evacuated and backfilled with nitrogen (this process
was repeated a total of three times). A solution of tert-butyl (3-(difluoromethyl)—5-fluoro
(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)benzyl)(methyl)carbamate (62.6 mg, 0.151
mmol) in 1,4-dioxane (3.0 ml) was added via syringe, followed by water (3000 1,11). The
reaction mixture was heated to 50 °C for 16 h. The reaction e cooled and concentrated.
The residue was dissolved in CH2C12 (5.0 mL) and treated with TFA (5.0 mL). The reaction
mixture was d at room temperature for 15 min, and then concentrated. The crude
on residue was purified using prep-LCMS (XBridge C18 , eluting with a
gradient of acetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min) to afford the
desired product. LCMS ated for C19H18F3N6 (M+H)+: rn/z = 3872; found: 3871 1H
NMR (TFA salt, 500 MHz, DMSO) 5 13.72 (br, 1H), 9.14 (d, J = 1.2 Hz, 1H), 8.96 (br, 2H),
8.46 (s, 1H), 8.22 (s, 1H), 8.04 (d, J: 0.6 Hz, 1H), 7.79 (s, 1H), 7.68 (d, J: 10.2 Hz, 1H),
7.01 (t, J: 54.7 Hz, 1H), 4.31 (t, J: 5.8 Hz, 2H), 3.91 (s, 3H), 2.63 (t, J: 5.2 Hz, 3H).
Example 236. N-(4-Fluoromethyl-3—(3—(l-methyl-1H-pyrazol—4-yl)—1H-pyrazolo[3,4-
c]pyridin-S-yl)benzyl)ethanamine
hl\ /
/ /"l
/ /N
This compound was prepared according to the procedures described in Example 86
and 92, using ethanamine instead of amine as starting material. LCMS calculated for
C20H22FN6 (M+H)+: m/z = 365.2; Found: 365.2.
e 237. N—(3—(3-(1-Methyl-1H-pyrazol-4—yl)—lH-pyrazolo[3,4-c]pyridin-S-yl)—2-
(trifluoromethyl)benzyl)ethanamine
“1 \ /
/ / "1
/ / N
This compound was prepared ing to the procedures described in Example 86
and 88, using ethanamine instead of methanamine as starting material. LCMS calculated for
F3N6 (M+H)+: m/z = 4012; Found: 401.2.
Example 238. 4-Fluoro-N,6-dimethyl-S-(S-(l-methyl-1H-pyrazol—4-yl)—lH-pyrazolo[3,4-
c]pyridin-S—yl)-2,3-dihydro-1H-indenamine (Peakl)
F /
\ N\
N I /N
Peak1
Two enantiomers of the e 220 were separated with chiral prep-HPLC
(Phenomenex Lux Cellulose-4, 21,1x250mm, 5 micron, eluting with 45% EtOH in hexanes,
at flow rate of 18 mL/min, tR,peak1 = 9.5 min, tR,peak2 = 12.8 min). Peak 1: LCMS calculated
for C21H22FN6 (M+H)+: m/z = 3772; found: 377.2.
Example 239. 4-Fluoro-N,6-dimethyl-S-(S-(l-methyl-1H-pyrazol—4-yl)—1H-pyrazolo[3,4-
c] pyridin-S—yl)-2,3-dihydro-1H-indenamine (Peak2)
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Peak2
The two omers of exmaple 220 were separated with chiral prep-HPLC
(Phenomenex Lux Cellulose-4, 21,1x250mm, 5 micron, eluting with 45% EtOH in hexanes,
at flow rate of 18 mL/mjn, tR,peak1 = 9.5 min, tR,peak2 = 12.8 min). Peak 2: LCMS calculated
for C21H22FN6 (M+H)+: m/z = 377.2; found: 377.2.
Example 240. 6-Fluoro-N—methyl-S-(3—(6—(4-methylpiperazin- 1-yl)pyridin-3—yl)—1H-
pyrazolo[3,4—c]pyridin-S-yl)—1,2,3,4-tetrahydronaphthalen-l-amine
Step 1. ury! 0—6—flu0r0—1,2,3,4—tetrahydr0naphthalen—1—yZ(methyZ)carbamate
\NJLOJ<O
To a solution of 5-bromofluoro-3,4-dihydronaphthalen-1(2H)-one (Ark Pharm,
312.6 mg, 1.286 mmol) in 2-propanol (10.0 ml) was added methylamine (2.0 M in methanol)
(2.50 n11, 5.00 mmol) followed by um(IV) isopropoxide (596.0 mg, 2.097 mmol). The
mixture was stirred at 35 0C for 16 h before it was cooled to room temperature. Sodium
borohydride (53.4 mg, 1.412 mmol) was added. The reaction was stirred at room temperature
for 1 h, and was quenched with HCl (1.0 N in water) (30.0 ml, 30 mmol). The mixture was
stirred at room temperature for 2 h, and was treated with NaOH (4.0 N in water) until pH
reached 10. The mixture was extracted with Et20. The organic layer was dried over
anhydrous Na2S04, filtered and concentrated. The residue was dissolved in CH2C12 (10 ml),
and treated with boc-anhydride (426.4 mg, 1.954 mmol). After stirring at room temperature
for 30 min, the reaction was concentrated. The residue was ed on silica gel (40g, 0-
100% EtOAc in hexanes) to give the desired product (461.0 mg, 89%). LCMS calculated for
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BrFN02 (M+H-C4Hs)+: m/z = 3020, found: 302.1.
Step 2. tert—Butyl 6-fluor0(4,4,5,5—tetramethyZ-1,3,2-di0xab0r01anyD-1,2,3,4-
z‘etrahydronaphz‘halen-I thyl)carbamate
\Niok
To a cap vial equipped with a magnetic stir bar was added 5,4',4',5',5'—
octamethyl—[2,2']bi[[1,3,2]dioxaborolanyl] (517.4 mg, 2.037 mmol), potassium acetate (416.8
mg, 4.25 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II),
complexed with dichloromethane (1:1) (210.2 mg, 0.257 mmol). The Vial was sealed with a
Teflon-lined septum, evacuated and backfilled with nitrogen (this process was repeated a
total of three times). A solution of utyl (5-bromofluoro-1,2,3,4-tetrahydronaphthalen—
1-yl)(methyl)carbamate (461.0 mg, 1.287 mmol) in 1,4-dioxane (6.0 ml) was added Via
syringe. The e was heated at 100 0C for 16 h. After cooling to room temperature, the
reaction mixture was diluted with CH2C12 and filtered. The filtrate was concentrated. The
residue was purified on silica gel (40 g, 0-100% EtOAc in hexanes) to give the desired
product (337.4 mg, 65%). LCMS calculated for C22H33BFNNaO4 (M+Na)+ m/z = 4282;
found 428.2.
Step 3. 6-Fluoro-N-methyl-5—(3-(6-(4-methylpiperazinyl)pyridmyl)-1H-pyrazolo[3, 4-
cjpyrl'dl'nyl)-1 -amme
, 2, 3, 4-tetrahydr0naphthalen-I
To a screw-cap vial equipped with a magnetic stir bar was added tert—butyl 5-chloro-
3-(6-(4-methylpiperazinyl)pyridinyl)-1H-pyrazolo[3,4-c] pyridine-l-carboxylate (34.0
mg, 0.079 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-l,l'-biphenyl)[2-(2'-
amino-l,l'-bipheny1)]palladium(II) (XPhos Pd G2, 8.0 mg, 10.17 umol) and cesium
carbonate (81.4 mg, 0.250 mmol). The Vial was sealed with a Teflon-lined septum, evacuated
and backfilled with nitrogen (this process was repeated a total of three times). A solution of
tert-butyl (6-fluoro(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1,2,3,4-
tetrahydronaphthalen-l-y1)(methyl)carbamate (28.1 mg, 0.069 mmol) in 1,4-dioxane (2.0 ml)
W0 2018f049200
was added via syringe, followed by water (200.0 pl). The on was heated to 50 °C for 16
h. The reaction was concentrated. To the residue was added CH2C12 (2.0 mL) followed by
TFA (2.0 mL). The mixture was stirred at room temperature for 15 mins, and then
concentrated. The residue was purified using prep-LCMS (XBn'dge C18 column, eluting with
a gradient of acetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min) to afford
the desired product. LCMS calculated C27H31FN7 (M+H)+: m/z = 4723, found: 472.3.
Example 241. 6-Fluoro(3—(4-(4-methylpiperazinyl)phenyl)-1H-pyrazolo[3,4-
c] pyridin-S—yl)—1,2,3,4-tetrahydronaphthalen-l-amine
Step 1. tert-Butyl 5-br0m0-6—flu0r0-1,2,3,4-tetrahydr0naphthalen-I-ylcarbamate
O NH
To a mixture of 5-bromofluoro-3,4-dihydronaphtha1en-1(2H)—one (Ark Pharm,
309.5 mg, 1.273 mmol), sodium cyanoborohydride (824.0 mg, 13.11 mmol) and ammonium
acetate (2.184 g, 28.3 mmol) was added 2-propanol (10.0 ml). The reaction was stirred at 70
0C for 16 h. After cooling to room temperature, the mixture was d with 2 M K2CO3 (aq)
and extracted with Et20. The organic layer was dried over ous , filtered and
concentrated. The residue was ved in CH2C12 (20 ml), and was treated with Boc—
anhydride (425.9 mg, 1.951 mmol). After stirring at room temperature for 30 min, the
reaction was concentrated. The residue was d on silica gel (40g, 0-100% EtOAc in
hexanes) to give the desired product as a white solid (316.3 mg, 72%). LCMS calculated for
C11H12BrFN02 (M+H-C4Hs)+: m/z = 2880; found: 288.0.
W0 2018f049200 2017/050737
Step 2. tert—Butyl 6-flu0r0(4,4,5,5-tetramethyl-1,3,2-di0xab0r01anyD-I,2,3,4-
tetrahydronaphz‘halen—1—ylcarbamare
HNkok
To a screw-cap vial equipped with a magnetic stir bar was added 4 4 5 5
, , , ,4',4',5',5'—
octamethyl-[2,2']bi[[1,3,2]dioxaborolanyl] (319.0 mg, 1.256 mmol), potassium e (272.1
mg, 2.77 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complexed
with dichloromethane (1:1) (150.1 mg, 0.184 mmol). The vial was sealed with a Teflon-lined
septum, evacuated and lled with nitrogen (this process was repeated a total of three
times). A solution of tert—butyl (5-bromofluoro-1,2,3,4-tetrahydronaphthalen
yl)carbamate (316.3 mg, 0.919 mmol) in 1,4-dioxane (6.0 ml) was added via syringe. The
mixture was heated at 100 °C for 16 h. After cooling to room temperature, the reaction
mixture was diluted with CH2C12 and ed. The filtrate was concentrated. The residue was
purified on silica gel (40 g, 0-100% EtOAc in hexanes) to give the desired product (200.0
mg, 56%). LCMS calculated for C17H24BFNO4 (M+H—C4Hs)+: m/z = 3362; found: 336.3.
Step 3. 6-FZu0ro—5-(3-(4-(4-mez‘hylpiperazmyl)phenyl)-1H—pyrazolo[3, 4-c]pyridinyl)-
1,2, 3, 4-z‘etrahydr0naphthalen-I-amine
To a screw-cap vial equipped with a magnetic stir bar was added tert—butyl 5-chloro-
3-(4-(4-methylpiperazinyl)phenyl)-1H-pyrazolo[3,4-c]pyridinecarboxylate (30.0 mg,
0.070 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-
amino-1,1'-biphenyl)]palladium(II) (XPhos Pd G2, 8.0 mg, 10.17 umol) and cesium
carbonate (72.8 mg, 0.223 mmol). The vial was sealed with a Teflon-lined septum, evacuated
and lled with nitrogen (this process was ed a total of three times). A solution of
tert—butyl (6-fluoro(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1,2,3,4-
tetrahydronaphthalen-l-yl)carbamate (25.0 mg, 0.064 mmol) in 1,4-dioxane (2.00 ml) was
added via syringe, followed by water (200.0 ul). The reaction was heated to 50 °C for 16 h.
The reaction was trated. To the residue was added CH2C12 (2.0 mL) followed by TFA
(2.0 mL). The e was stirred at room temperature for 15 min, and then concentrated.
W0 2018f049200 2017/050737
The residue was purified using prep-LCMS ge C18 column, eluting with a gradient of
itrile/water containing 0.1% TFA, at flow rate of 60 mL/min) to afford the desired
product. LCMS calculated for C27H30FN6 (M+H)+: m/z = 457.3; found: 457.3.
Example A. HPKl Kinase Binding Assay
A stock solution of 1 mM test compoundwas prepared in DMSO. The compound
plate was prepared by 3-fold and 11-point serial dilutions. 0.1 uL of the compound in
DMSO was transferred from the compound plate to the white 384 well polystyrene plates.
The assay buffer contained 50 mM HEPES, pH 7.5, 0.01% Tween-20, 5 mM MgC12, 0.01%
BSA, and 5 mM DTT. 5 ul of 4 nM active HPKl (SignalChem M23-11G) prepared in the
buffer was added to the plate. The enzyme concentration given was based on the given stock
concentration reported by the vender. 5 ul of 18 nM tracer 222 (ThermoFisher PV6121) and
4 nM LanthaScreen Eu—Anti GST antibody (ThermoFisher ) were added. After one
hour incubation at 25 °C, the plates were read on a PHERAstar FS plate reader (BMG
Labtech). Ki values were determined.
Compounds of the present disclosure, as exemplified in Examples, showed the Ki
values in the ing ranges: + = Ki 5 100 nM; ++ = 100 nM < Ki 5 500 nM; +++ = 500
nM < Ki S 2000 nM.
Table 1
whoop).— __
D—|D—|)—|D—iD—iD—iD—iD—i \DOONJQUIfiWNl—‘O _++ +
+ +
+ +
NO +
W0 2018/‘049200 2017/050737
WWNNNNNNNNN HOGOONQUIAWN)‘
b.) L»)
b.) 4;
—bwwwww OOOOQQU}
_Ul-Ié-Ié-Ié-lk-lk-lk O\OOO\JO\UI-l> +
U1 [\J
U1 0.)
UIUIUIUIUIUI \OOOQONUl-b
O\O\O\ JRWN
O\ U1
W0 2018/‘049200 PCT/U82017/050737
\] ._|
\l\]\l\l\l\l\l \OOONOUIAL»
0° .—
_000000 Ul-h-UJ
—0000 OO\)
I_ +|+
OKO Ul-IRUJN
_\O\l
E- +
+++++
+++++++ +
W0 2018f049200
e B. p—SLP76S376 HTRF Assay
One or more compounds of the invention can be tested using the p-SLP76S376 HTRF
assay described as follows. Jurkat cells (cultured in RPM11640 media with 10% FBS) are
collected and fuged, followed by resuspension in riate media at 3 x106 cells / ml.
The Jurkat cells (35ul) are sed into each well in a 384 well plate. Test compounds are
diluted with cell culture media for 40-fold dilution (adding 39 ul cell culture media into 1 ul
compound). The Jurkat cells in the well plate are treated with the test compounds at s
concentrations (adding 5 ul diluted compound into 35 ul Jurkat cells and starting from 3 uM
with 1:3 dilution) for 1 hour at 37 OC, 5% C02), followed by ent with anti-CD3
(5 ug/ml, OKT3 clone) for 30 min. A 1:25 dilution of 100x blocking reagent (from p-SLP76
ser376HTRF kit) with 4xLysis Buffer(LB) is ed and 15 ul of the 4xLB buffer with
ng reagent is added into each well and ted at room temperature for 45 mins with
gentle shaking. The cell lysate (16ul) is added into a Greiner white plate, treated with p-
SLP76 ser376HTRF reagents (2ul donor, 2ul acceptor) and incubated at 4 °C for overnight.
The homogeneous time resolved fluorescence (HTRF) is measured on a PHERAstar plate
reader the next day. ICso determination is performed by fitting the curve of percent inhibition
versus the log of the inhibitor concentration using the GraphPad Prism 5.0 software.
e C. Isolation of CD4+ or CD8+ T Cells and Cytokine Measurement
Blood samples are collected from healthy donors. CD4+ or CD8+ T cells are isolated
by negative ion using CD4+ or CD8+ enrichment kits (lifetech, USA). The purity of the
isolated CD4+ or CD8+ T cells is determined by flow cytometry and is routinely >80%. Cells
are cultured in RPMI 1640 supplemented with 10% FCS, glutamine and antibiotics
(Invitrogen Life Technologies, USA). For cytokine measurement, Jurkat cells or primary
CD4+ or CD8+ T cells are plated at 200 k cells/well and are stimulated for 24 h with anti—
CD3/anti-CD28 beads in the presence or absence of testing compounds at various
concentrations. 16 uL of supematants are then transferred to a white detection plate and
analyzed using the human IL2 or IFNy assay kits (Cisbio).
W0 2018/‘049200
Example D. Treg Assay
One or more compounds can be tested using the Regulatory T-cell proliferation assay
bed as following. Pn'mary D25- T-cells and CD4+/CD25+ regulatory T-cells
are isolated from human donated Peripheral Blood Mononuclear Cells, using an isolated kit
from Thermo Fisher Scientific (11363D). CD4+/CD25- T-cells are labeled with CFSE
(Thermo Fisher Scientific, C34554) following the protocol provided by the vendor. CFSE
labeled T—cells and CD4+/CD25+ regulatory T-cells are pended at the concentration of
IX 106 cells/ml in RPMI-l640 medium. 100ul of CFSE-labeled T-cells are mixed with or
without 50 pl of CD4+/CD25+ regulatory T-cells, treated with Sul of anti-CD3/CD28 beads
(Thermo Fisher Scientific, 11132D) and various concentrations of compounds diluted in SOul
of RPMI-l640 medium. Mixed populations of cells are cultured for 5 days (37 °C, 5% C02)
and proliferation of CFSE-labeled T-cells is analyzed by BD LSRFortessa X—20 using FITC
channel on the 5th day.
Various modifications of the ion, in addition to those bed herein, will be
apparent to those skilled in the art from the foregoing description. Such modifications are
also ed to fall within the scope of the appended claims. Each reference, including
t limitation all patent, patent applications, and publications, cited in the present
ation is incorporated herein by nce in its entirety.
W0 2018f049200
Claims (1)
1. A compound of Formula I: R2 R1 N ’N or a pharmaceutically acceptable salt f, wherein: R1 is selected from Cyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, halo, CN, N02, 0R3, SRa, C(O)Rb, C(O)NRCRd, C(O)OR“‘, OC(O)Rb, OC(O)NRCRd, NRCRd, NRCC(O)Rb, NR“C(O)OR"‘, NRCC(O)NRCRd, C(=NRe)Rb, C(=NOR"‘)R", C(=NRC)NRCRd, NRCC(=NRC)NRCR‘1, NRCS(O)Rb, NRCS(O)2Rb, NRCS(O)2NRCRd, S(O)Rb, S(O)NRCRd, and S(O)2NR°Rd; wherein said C1-6 alkyl, C2-6 alkenyl and C2-6 alkynyl are each optionally substituted with l, 2, 3, or 4 substituents independently selected from R10; Cyl is selected from C340 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl and 5-10 membered heteroaryl, wherein each 4-10 membered heterocycloalkyl and 5-10 membered heteroaryl has at least one ring-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O, and S; wherein the N and S are optionally oxidized; n a ring-forming carbon atom of 5-10 membered aryl and 4—10 membered heterocycloalkyl is optionally substituted by oxo to form a carbonyl group; and n the C340 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl and 5-10 ed heteroaryl are each optionally tuted with l, 2, 3 or 4 substituents independently selected from R10; CyA is C6-10 aryl optionally substituted with l, 2, 3 or 4 substituents ndently ed from R20; R2 is selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C340 cycloalkyl, 4-10 membered cycloalkyl, C6-10 aryl, 5-10 membered heteroaryl, C340 cycloalkyl-C1-3 alkylene, 4-10 membered heterocycloalkyl-C14 alkylene, C6-10 aryl-C1—3 alkylene, 5-10 membered heteroaryl-Cm alkylene, halo, CN, ORa7, SRa7, C(O)Rb7, C(O)NRC7Rd7, C(O)OR37, 7, NRC7C(O)Rb7, NRC7C(O)OR37, O)R"7, NRC7S(O)2R"7, O)2NRC7R‘17, S(O)Rb7, S(O)NRC7Rd7, S(O)2Rb7, and S(O)2NRC7Rd7; wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C340 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl, 5-10 membered heteroaryl, C340 cycloalkyl-C1.3 alkylene, 4-10 membered heterocycloalkyl-C14 alkylene, C6-10 aryl-C14 alkylene and 5—10 membered W0 2018f049200
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US62/385,584 | 2016-09-09 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| NZ792179A true NZ792179A (en) | 2022-09-30 |
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