NZ786561A - Pyrrolotriazine compounds as tam inhibitors - Google Patents

Pyrrolotriazine compounds as tam inhibitors

Info

Publication number
NZ786561A
NZ786561A NZ786561A NZ78656117A NZ786561A NZ 786561 A NZ786561 A NZ 786561A NZ 786561 A NZ786561 A NZ 786561A NZ 78656117 A NZ78656117 A NZ 78656117A NZ 786561 A NZ786561 A NZ 786561A
Authority
NZ
New Zealand
Prior art keywords
alkyl
independently selected
cycloalkyl
alkylene
membered
Prior art date
Application number
NZ786561A
Inventor
Yun Long Li
xiaozhao Wang
Joseph Barbosa
David M Burns
Hao Feng
Joseph Glenn
Chunhong He
Taisheng Huang
Song Mei
Jincong Zhuo
Original Assignee
Incyte Corporation
Filing date
Publication date
Application filed by Incyte Corporation filed Critical Incyte Corporation
Publication of NZ786561A publication Critical patent/NZ786561A/en

Links

Abstract

This application relates to compounds of Formula I or pharmaceutically acceptable salts thereof, which are inhibitors of TAM kinases which are useful for the treatment of disorders such as cancer.

Description

PYRROLOTRIAZINE COMPOUNDS AS TAM INHIBITORS CROSS-REFERENCE TO RELATED APPLICATIONS The present ation is a onal application from New d Patent Application No. 747736. The entire disclosures of New Zealand Patent Application No. 747736 and its corresponding International Patent Application No. , are incorporated herein by nce.
This application claims priority to U.S. Provisional Patent Application Nos. 62/314,066, filed on March 28, 2016; 62/362,934, filed on July 15, 2016; 62/438,750, filed on December 23, 2016; the entireties of which are incorporated herein by reference.
TECHNICAL FIELD This application relates to pyrrolotriazine inhibitors of TAM kinases, and in one embodiment tors of AXL and MER kinases, which are useful in the treatment of disorders such as cancer, as well as pharmaceutical compositions related thereto.
BACKGROUND OF INVENTION Receptor tyrosine kinases (RTKs) are cell surface proteins that transmit signals from the ellular environment to the cell cytoplasm and nucleus to regulate cellular events such as survival, growth, proliferation, differentiation, adhesion and migration.
The TAM ily consists of three RTKs including Tyro3, AXL and Mer (Graham et al., 2014, Nature Reviews Cancer 14, 769-785; Linger et al., 2008, Advances in Cancer Research 100, 35-83). TAM kinases are characterized by an extracellular ligand binding domain consisting of two immunoglobulin-like domains and two fibronectin type III domains. Two ligands, growth arrest specific 6 (GAS6) and protein S (PROS1), have been identified for TAM kinases. GAS6 can bind to and activate all three TAM kinases, while PROS1 is a ligand for Mer and Tyro3 (Graham et al., 2014, Nature Reviews Cancer 14, 769-785).
AXL (also known as UFO, ARK, JTK11 and TYRO7) was originally identified as a transforming gene from DNA of patients with chronic myelogenous leukemia an et al., 1991, Mol Cell Biol 11, 5016-5031; Graham et al., 2014, Nature Reviews Cancer 14 , 5; Linger et al., 2008, Advances in Cancer Research 100, . GAS6 binds to AXL and induces subsequent auto- phosphorylation and activation of AXL tyrosine kinase. AXL activates several downstream signaling pathways including PI3K-Akt, PK, PLC-PKC (Feneyrolles et al., 2014, lar Cancer Therapeutics 13, 2141-2148; Linger et al., 2008, Advances in Cancer Research 100, 35-83).
MER (also known as MERTK, EYK, RYK, RP38, NYK and TYR012) was originally identified as a phospho-protein from a lymphoblastoid sion library (Graham et al., 1995, ne 10, 2349-2359; Graham et al., 2014, Nature Reviews Cancer 14, 769-785; Linger et al., 2008, Advances in Cancer Research 100, 35—83).
Both GAS6 and PROS1 can bind to Mer and induce the phosphorylation and 1O activation of Mer kinase (Lew et al., 2014). Like AXL, MER activation also s ream signaling pathways including PI3K-Akt and Raf-MAPK (Linger et al., 2008, Advances in Cancer ch 100, 35-83).
TYRO3 (also known as DTK, SKY, RSE, BRT, TIF, ETK2) was originally identified through a PCR—based cloning study (Lai et al., Neuron 6, 691-?0, 1991; Graham et al., 2014, Nature Reviews Cancer 14, 769-785; Linger et al., 2008, Advances in Cancer Research 100, 35-83). Both ligands, GAS6 and PROS], can bind to and activate TYRO3. Although the ing pathways downstream ofTYRO3 activation are the least studied among TAM RTKs, it appears that both PI3K-Akt and Raf-MAPK pathways are involved (Linger et al., 2008, Advances in Cancer Research 100, . AXL, MER and TYRO3 are found to be over-expressed in cancer cells.
Accordingly, there is a need for compounds and methods of use thereof for the modulation ofTAM kinases in the treatment of cancer.
SUMMARY OF INVENTION In one aspect, the present application relates to compounds having Formula I: or a pharmaceutically acceptable salt thereof, wherein variables R1, R2, R3, CyC and CyB are as described herein.
The present application further provides compositions comprising a compound bed , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
The present application also provides methods of ting TAM s, and in one embodiment methods of inhibiting AXL and MER kinases, comprising contacting one or more TAM kinase with a compound described herein, or a pharmaceutically acceptable salt thereof.
The present application also provides a nd bed herein, or a pharmaceutically acceptable salt f, for use in any of the methods described herein.
The present application further provides use of a compound described herein, or a pharmaceutically acceptable salt thereof, for manufacture of a medicament for use in any of the methods described herein.
DETAILED DESCRIPTION The application provides, inter alia, a compound of Formula I: I or a pharmaceutically acceptable salt thereof, wherein: R1 is Al-Az-A3-RA, R2 is H, halo, CN, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, cyano-C1-3 alkyl or C1-6 alkoxyalkyl, R3 is H, halo, CN, C1-6 alkyl, C1—6 haloalkyl, 0R3, SR3, C(O)NRCRd, NRcRd, NRCC(O)Rb, )2Rb or S(O)2Rb, wherein said C1-6 alkyl and C1-6 haloalkyl are optionally substituted with 1, 2 or 3 substituents independently selected from halo, W0 2017!]72596 CN, 0R3, SR3, C(O)NRCRd, NRCRd, NRCC(O)Rb, NRCS(O)2Rb, S(O)2Rb, )ORa, NRCC(O)NRCR‘1,NRCS(O)2NRCRd and CyR3; Al is selected from a bond, CyAl, —Y—, —C1.3 alkylene—, —C1-3 alkylene—Y—, — Y—C1-3 alkylene—, and —C1-2 alkylene—Y—C1-2 alkylene—; wherein said alkylene groups are each optionally substituted with 1, 2, or 3 substituents independently ed from halo, CN, OH, C1—3 alkyl, C1—3 alkoxy, C1.3 haloalkyl, C1-3 haloalkoxy, amino, C1—3 alkylamino, and di(C1-3 alkyl)arnino, A2 is selected from a bond, CyAz, —Y—, —C1.3 ne—, —C1-3 alkylene—Y—, — Y—C1.3 alkylene—, and —C1-2 alkylene—Y—C1.2 alkylene—, wherein said alkylene groups 1O are each optionally substituted with 1, 2, or 3 substituents independently selected from halo, CN, OH, C1—3 alkyl, C1—3 , C1.3 kyl, C1-3 haloalkoxy, amino, C1—3 alkylamino, and di(C1—3 alkyl)arnino, A3 is selected from a bond, CyA3, —Y—, —C1.3 alkylene—, —C1-3 alkylene—Y—, — Y—C1-3 alkylene—, and —C1-2 alkylene—Y—C1.2 alkylene—, wherein said alkylene groups are each optionally substituted with 1, 2, or 3 substituents independently selected from halo, CN, OH, C1-3 alkyl, C1-3 alkoxy, C1-3 haloalkyl, C1-3 haloalkoxy, amino, C1-3 alkylamino, and 3 amino; RA is H, C1-6 alkyl, C1-6 haloalkyl, halo, C3-6 cycloalkyl, CN, N02, OR", SR", C(O)Rb1, C(O)NRC1R‘", C(O)ORa1, OC(O)Rb1, OC(O)NRC1Rd1, NRCIRC", NRCIOR‘", NRC1C(O)Rb1, O)ORa1, NRC1C(O)NRC1R‘", C(=NR61)Rb1, C(=NR61)NRcle1, NRclc(=NRel)NRcle1, NRC1S(O)Rb1, NRCls(O)2Rb1, )2NRC1R‘", S(O)Rb1, S(O)NR°1R‘", S(O)2Rb1, or S(O)2NRC1R‘", n said C1-6 alkyl or C1-6 haloalkyl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from R"; Y is O, S, S(O), S(O)2, C(O), f, NRfC(O), NRfC(O)NRf, NRfS(O)2NRf, S(O)2NRf, NRfS(O)2, or NRf, each Rf is independently selected from H and C13 alkyl, CyAl is C3.7 cycloalkyl, phenyl, 5-6 membered heteroaryl, or 4-7 membered heterocycloalkyl; wherein each 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl 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 ring-forming carbon atom of C33 cycloalkyl and 4- 7 membered heterocycloalkyl is optionally substituted by 0x0 to form a carbonyl W0 2017!]72596 group; and wherein the C34 cycloalkyl, phenyl, 5-6 membered heteroaryl, and 4—7 membered heterocycloalkyl are each optionally substituted with 1, 2, 3 or 4 substituents independently ed from R"; each RA1 is independently selected from OH, N02, CN, halo, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, cyano-C1—3 alkyl, HO-C1—3 alkyl, H2N-C1—3 alkyl, amino, C1-6 mino, di(C1-6 amino, thio, C1-6 alkylthio, Cl—6 alkylsulfinyl, C1-6 alkylsulfonyl, carbamyl, C1-6 alkylcarbamyl, di(C1-6 alkyl)carbamyl, carboxy, Cl-G alkylcarbonyl, C1-6 alkoxycarbonyl, C1-6 alkylcarbonylarnino, Cl-G alkylsulfonylamino, aminosulfonyl, C1-6 alkylaminosulfonyl, di(Cl-G 1O alkyl)aminosulfonyl, aminosulfonylamino, C1-6 minosulfonylamino, di(Cl-G aminosulfonylamino, aminocarbonylamino, C1-6 minocarbonylamino, and di(C1—6 alkyl)aminocarbonylamino, CyA2 is C3.7 cycloalkyl, , 5-6 membered heteroaryl, or 4-? membered heterocycloalkyl; wherein each 5-6 membered heteroaryl and 4-7 ed heterocycloalkyl has at least one orming carbon atom and 1, 2, 3, or 4 ringforming heteroatoms independently selected from N, O, and S; wherein the N and S are optionally oxidized; wherein a ring-forming carbon atom of CM lkyl and 4- 7 membered heterocycloalkyl is optionally substituted by oxo to form a carbonyl group; and wherein the C34 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 R", each RA2 is independently selected from OH, N02, CN, halo, C1-6 alkyl, C1-6 haloalkyl, Cl-6 alkoxy, C1-6 haloalkoxy, cyano-C1—3 alkyl, HO-C1—3 alkyl, H2N—C1—3 alkyl, amino, C1-6 alkylamino, di(C1.6 alkyl)amino, thio, C1-6 alkylthio, C1-6 ulfinyl, C1-6 alkylsulfonyl, carbamyl, C1-6 alkylcarbamyl, di(C1-6 alkyl)carbamyl, carboxy, Cl-6 alkylcarbonyl, C1-6 alkoxycarbonyl, C1-6 alkylcarbonylamino, Cl-6 alkylsulfonylamino, ulfonyl, C1-6 alkylaminosulfonyl, di(Cl-G alkyl)aminosulfonyl, aminosulfonylamino, C1-6 alkylaminosulfonylamino, di(Cl-6 alkyl)aminosulfonylamino, aminocarbonylamino, C1-6 minocarbonylamino, and di(C 1-6 alkyl)aminocarbonylamino; CyA3 is C3-7 cycloalkyl, phenyl, 5-6 membered heteroaryl, or 4-? membered heterocycloalkyl; wherein each 5-6 membered heteroaryl and 4-7 membered W0 2017!]72596 heterocycloalkyl has at least one ring-forming carbon atom and 1, 2, 3, or 4 ring- forrning heteroatoms independently selected from N, O, and S, wherein the N and S are optionally oxidized; wherein a orming carbon atom of CM lkyl and 4- 7 membered heterocy yl is optionally substituted by oxo to form a yl group; and wherein the C34 cycloalkyl, phenyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl are each optionally substituted with 1, 2, 3 or 4 substituents independently ed from R", each RA3 is independently selected from OH, N02, CN, halo, C1-6 alkyl, C1-6 haloalkyl, Cl-6 alkoxy, C1-6 haloalkoxy, cyano-C1—3 alkyl, HO-C1—3 alkyl, H2N—C1—3 1O alkyl, amino, C1-6 mino, di(Cre alkyl)amino, thio, C1-6 alkylthio, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, carbamyl, C1-6 alkylcarbamyl, dl(C1-6 alkyl)carbamyl, carboxy, Cl-6 arbonyl, C1-6 alkoxycarbonyl, C1-6 alkylcarbonylamino, Cl-6 alkylsulfonylamino, aminosulfonyl, C1-6 alkylaminosulfonyl, di(Cl-G alkyl)aminosulfonyl, aminosulfonylamino, C1-6 alkylaminosulfonylamino, di(Cl-6 alkyl)aminosulfonylamino, aminocarbonylamino, C1—6 alkylaminocarbonylamino, and dl(C1-6 alkyl)aminocarbonylamino, CyR3 is C3-7 cycloalkyl, phenyl, 5-6 membered heteroaryl, or 4-? membered cycloalkyl; wherein each 5-6 membered aryl and 4-7 membered cycloalkyl has at least one ring-forming carbon atom and 1, 2, 3, or 4 ring- g heteroatoms independently selected from N, O, and S; wherein the N and S are optionally oxidized; wherein a ring-forming carbon atom of C30 cycloalkyl and 4- 7 membered heterocycloalkyl is optionally substituted by oxo to form a carbonyl group; and wherein the C34 cycloalkyl, phenyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl are each optionally substituted with 1, 2, 3 or 4 substituents ndently selected from Rg, CyC is phenylene or 5-6 membered heteroarylene, wherein the 5-6 membered heteroarylene has at least one ring-forming carbon atom and 1 or 2 ring-forming heteroatoms independently selected from N, O, and S, and wherein the phenylene and -6 membered heteroarylene are each optionally substituted by 1, 2, 3, or 4 substituents independently ed from RC, each RC is independently selected from OH, CN, halo, C1-4 alkyl, C1-3 haloalkyl, C14 alkoxy, C1-3 haloalkoxy, cyano-C1-3 alkyl, HO-C1-3 alkyl, amino, C1-4 W0 2017!]72596 alkylamino, 4 alkyl)amino, C1-4 alkylsulfinyl, C1-4 alkylsulfonyl, carbamyl, C1.4 alkylcarbamyl, di(C1-4 carbamyl, carboxy, C1-4 alkylcarbonyl, C1—4 alkoxycarbonyl, C1.4 alkylcarbonylamino, C1.4 alkylsulfonylamino, ulfonyl, C1- 4 alkylaminosulfonyl, and di(C1.4 alkyl)aminosulfonyl; CyB is C340 cycloalkyl or 4-10 membered heterocycloalkyl; wherein at least one ring-forming carbon atom of C340 cycloalkyl and 4-10 membered heterocycloalkyl is substituted by oxo to form a carbonyl group, wherein the 4-10 membered cycloalkyl 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, and wherein the C340 cycloalkyl and 4-10 membered heterocycloalkyl are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from RB, or CyB is 6-10 membered aryl or 5-10 membered heteroaryl, wherein the 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; n the N and S are ally oxidized; wherein: (a) at least one ring-forming carbon atom of the 5- membered heteroaryl is substituted by oxo to form a carbonyl group; or (b) the 6- membered aryl or 5-10 membered heteroaryl is substituted by halo, CN, N02, ORaz, SRaZ, C(O)Rb2, C(O)NR"2Rd2, C(O)OR32, OC(O)Rb2, OC(O)NR°2Rd2, NRCZRdZ, NRCZORdZ, NRc2C(0)Rb2, NR"2C(O)OR32, NRCZC(O)NRC2Rd2, NRCZS(O)R"Z, NRCZS(O)2R"2, NRCZS(O)2NRCZRd2, 2, S(O)NRC2Rd2, S(0)2Rb2, and S(O)2NR°2Rd2; and wherein the 6-10 membered aryl or 5-10 membered heteroaryl is further ally substituted with 1, 2, 3 or 4 substituents independently ed from RB; each RB is independently ed from halo, C1-6 alkyl, C2-6 alkynyl, Cl-6 haloalkyl, C3-6 cycloalkyl, phenyl, 5-6 ed heteroaryl, 4-7 membered heterocycloalkyl, CN, N02, ORaZ, SRaZ, C(O)Rb2, C(O)NRC2Rd2, C(O)OR32, 0C(O)Rb2, OC(O)NRCZRd2, NRCZRdZ, NRCZORdZ, NRC2C(O)Rb2, NRC2C(O)OR32, NRCZC(O)NRCZRd2, NRCZS(O)Rb2, NRCZS(O)2Rb2, NRCZS(O)2NRC2Rd2, S(O)Rb2, S(O)NR32Rd2, S(O)2Rb2, and S(O)2NRC2Rd2, wherein said C1-6 alkyl, C2-6 alkynyl, C3—6 lkyl, , 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, or 4 tuents independently selected from each R11 is independently selected from CN, N02, ORa3, SR", C(O)R"3, C(O)NR°3Rd3, C(O)ORa3, OC(O)Rb3, OC(O)NRC3Rd3, NRC3Rd3, NRC3ORd3, NRC3C(O)Rb3, NRC3C(O)ORa3, NRC3C(O)NRC3Rd3, NRC3S(O)Rb3, O)2Rb3, NRC3S(O)2NR°3Rd3, S(O)Rb3, S(O)NRC3Rd3, S(O)2Rb3, and Rc3Rd3; each R12 is independently selected from halo, CN, N02, C1-6 alkyl, Cl-6 haloalkyl, C3-6 cycloalkyl, , 5-6 membered aryl, 4-7 ed heterocycloalkyl, ORa", SR", C(O)Rb4, C(O)NRC4Rd4, C(O)0Ra4, OC(O)Rb4, 1O 0C(0)NRc4Rd4, NRC4Rd4, NRC4ORd4, NRC4C(O)Rb4, NRC4C(O)ORa4, NRc4C(0)NRc4Rd4, NRC4S(O)Rb4, NRC4S(O)2Rb4, NRC4S(O)2NRC4Rd4, S(O)Rb4, S(O)NRC4Rd4, S(O)2Rb4, and S(O)2NRC4Rd4, wherein said C1-6 alkyl, C3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl are each optionally tuted with 1, 2, 3, or 4 substituents independently selected from Rg; R3 is selected from H, C1-6 alkyl, and C1-6 haloalkyl, Rb is selected from C1-6 alkyl and C1-6 haloalkyl, Rc and Rd are each independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C3-6 lkyl, phenyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl, C3-6 cycloalkyl-Cm alkylene, phenyl-Ci-3 alkylene, 5-6 membered heteroaryl-C1—3 alkylene, and 4-6 membered heterocycloalkyl3 alkylene, wherein said C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl, C3-6 cycloalkyl-C1-3 alkylene, phenyl-C1-3 alkylene, 5-6 ed heteroaryl-C1-3 alkylene, and 4-6 membered cycloalkyl-Ci.3 alkylene are each optionally substituted with 1, 2 or 3 substituents independently selected from Rg; R31, RCl and Rdl are each ndently selected from H, C1-6 alkyl, and C1-6 haloalkyl, wherein said C1-6 alkyl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from Rg, or alternatively, RCl and Rdl 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 ndently selected from W0 2017!]72596 Rbl is selected from C1-6 alkyl and C1-6 haloalkyl, each of which is optionally substituted with 1, 2, 3, or 4 substituents ndently selected from Rg; R61 is selected from H, CN, C1-6 alkyl, C1-6 kyl, C1-6 alkylthio, Cl-6 alkylsulfonyl, C1-6 alkylcarbonyl, C1-6 alkylaminosulfonyl, carbamyl, C1-6 alkylcarbamyl, dl(C1-6 alkyl)carbamyl, aminosulfonyl, C1-6 alkylaminosulfonyl, and dl(C1-6 alkyl)aminosulfonyl; each R32, Rcz, and R‘12 is independently selected from H, C1-6 alkyl, Cl-6 haloalkyl, C3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl; wherein said C1-6 alkyl, C3-6 cycloalkyl, phenyl, 5-6 membered 1O aryl, and 4-7 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R12, or alternatively, any RC2 and Rdz attached to the same N atom, together with the N atom to which they are attached, form a 4-, 5-, 6- or ered heterocycloalkyl group optionally substituted with 1, 2 or 3 substituents independently ed from R12; each R132 is independently selected from C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, , 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R"; each R33, RC3 and Rd3 is independently selected from H, C1-6 alkyl, Cm haloalkyl, C3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, C3-6 cycloalkyl-C1.4 alkylene, phenyl-C1-4 alkylene, 5-6 membered heteroaryl-CM alkylene, and 4-7 membered heterocycloalkyl-C1-4 alkylene; n said C1-6 alkyl, C3-6 lkyl, phenyl, 5-6 membered aryl, 4-7 membered heterocycloalkyl, C3-6 cycloalkyl-C1.4 alkylene, -C1-4 alkylene, 5-6 membered heteroaryl-CM alkylene, and 4-7 membered heterocycloalkyl-C14 alkylene are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Rg, atively, 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 W0 2017!]72596 each R133 is independently selected from C1-6 alkyl, C1-6 kyl, C3-6 cycloalkyl, phenyl, 5-6 membered aryl, 4-7 membered heterocycloalkyl, C3-6 cycloalkyl-CM alkylene, phenyl-C1-4 alkylene, 5-6 membered heteroaryl-C 1.4 alkylene, and 4-? membered heterocycloalkyl-C1-4 ne, each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from Rg; each R34, RC4 and R", is independently ed from H, C1-6 alkyl, and C1-6 haloalkyl; wherein said C1-6 alkyl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from Rg, or alternatively, any RC4 and Rd4 attached to the same N atom, together with the N 1O atom to which they are attached, form a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionally tuted with 1, 2 or 3 substituents independently selected from each R134 is independently selected from C1-6 alkyl and C1-6 haloalkyl, each of which is optionally substituted with 1, 2, 3, or 4 substituents ndently selected from Rg; and each Rg is independently selected from OH, N02, CN, halo, C1-6 alkyl, C1-6 haloalkyl, Cl-6 alkoxy, C1-6 haloalkoxy, C1-3 alkyl, HO-C1-3 alkyl, H2N-C1-3 alkyl, amino, C1-6 alkylamino, di(Crs alky1)amino,thio, C1-6 alkylthio, C1-6 alkylsulfinyl, C1—6 alkylsulfonyl, carbamyl, C1-6 alkylcarbamyl, di(Cre alkyl)carbamyl, carboxy, Cl-6 alkylcarbonyl, C1-6 alkoxycarbonyl, C1-6 arbonylamino, Cl-6 alkylsulfonylamino, aminosulfonyl, C1-6 minosulfonyl, dl(C1-6 alkyl)aminosulfonyl, aminosulfonylamino, C1-6 alkylaminosulfonylamino, di(Cr—s alkyl)aminosulfony1amino, aminocarbonylamino, C1-6 alkylaminocarbonylarnino, and dl(C1-6 alkyl)aminocarbonylamino, provided that: 1) A3 is not Y-Y when one of A1, A2 or A3 is a bond, or Y—Y-Y; and 2) when A3 is —Y— or —C1-3 alkylene—Y— then RA is H, C1-6 alkyl, or Cl-6 haloalkyl, wherein said C1-6 alkyl or C1-6 haloalkyl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from R".
In some embodiments, provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein: W0 2017!]72596 R1 is Al-Az-A3-RA; R2 is H, halo, CN, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, cyano-C1.3 alkyl or Cm alkoxyalkyl; R3 is H, halo, CN, C1-6 alkyl, C1-6 haloalkyl, 0R3, SR3, C(O)NRCRd, NRcRd, NRCC(O)Rb, NRCS(O)2Rb or S(O)2Rb; wherein said C1-6 alkyl and C1-6 haloalkyl are ally substituted with 1, 2 or 3 substituents independently selected from halo, CN, 0R3, SR3, C(O)NRCRd, NRCRd, NRCC(O)Rb, NRCS(O)2Rb, b, )OR3, NR"C(O)NRCRd, NRCS(O)2NRCRd and CyR3; Al is selected from a bond, CyAl, —Y—, —C1.3 alkylene—, —C1-3 alkylene—Y—, — Y—C1.3 alkylene—, and —C1-2 alkylene—Y—C1.2 alkylene—, wherein said alkylene groups are each optionally substituted with 1, 2, or 3 substituents independently selected from halo, CN, OH, C1—3 alkyl, C1—3 alkoxy, C1—3 kyl, C1—3 haloalkoxy, amino, C1—3 alkylamino, and di(C1-3 alkyl)amino, A2 is selected from a bond, CyAz, —Y—, —C1.3 alkylene—, —C1-3 alkylene—Y—, — Y—C1-3 alkylene—, and —C1-2 alkylene—Y—C1.2 alkylene—; wherein said alkylene groups are each optionally substituted with 1, 2, or 3 substituents independently selected from halo, CN, OH, C1-3 alkyl, C1-3 alkoxy, C1-3 haloalkyl, C1-3 haloalkoxy, amino, C1-3 alkylamino, and di(C1-3 alkyl)amino; A3 is ed from a bond, CyA3, —Y—, —C1.3 alkylene—, —C1-3 alkylene—Y—, — Y—C1-3 alkylene—, and —C1-2 alkylene—Y—C1.2 alkylene—; wherein said alkylene groups are each optionally substituted with 1, 2, or 3 substituents ndently selected from halo, CN, OH, C1—3 alkyl, C1—3 alkoxy, C1.3 haloalkyl, C1-3 haloalkoxy, amino, C1—3 alkylamino, and 3 alkyl)amino, RA is H, C1-6 alkyl, C1-6 haloalkyl, halo, CN, N02, ORal, SR", C(O)R"1, C(O)NRC1R‘", C(O)ORa1, OC(O)Rb1, OC(O)NRC1R‘", NRCle1,NR61OR‘", NRC1C(O)Rbl,NR61C(O)ORa1, NRCIC(O)NRC1R‘", C(=NR61)Rb1, C(=NR‘>1)NRCIR‘", NRclc(=NRel)NR61Rd1, NRC18(O)Rb1, NRcls(0)2Rbl, NRcls(0)2NRcle1, S(O)Rb1, S(O)NRC1R‘", S(O)2Rb1, or RC1R‘", wherein said C1-6 alkyl or C1-6 haloalkyl is optionally tuted with 1, 2, 3 or 4 substituents ndently selected from R"; Y is O, S, S(O), S(O)2, C(O), C(O)NRf, NRfC(O), NRfC(O)NRf, NRfS(O)2NRf, Rf, NRfS(O)2, or NRf; each Rf is independently selected from H and C1-3 alkyl; W0 2017!]72596 CyAl is C3.7 cycloalkyl, phenyl, 5-6 membered heteroaryl, or 4-? membered heterocycloalkyl; wherein each 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl has at least one ring-forming carbon atom and 1, 2, 3, or 4 ringforming heteroatoms independently selected from N, O, and S; wherein the N and S are optionally oxidized; wherein a ring-forming carbon atom of C33 cycloalkyl and 4- 7 membered heterocycloalkyl is optionally substituted by oxo to form a carbonyl group; and wherein the C34 cycloalkyl, phenyl, 5-6 membered heteroaryl, and 4-7 ed heterocycloalkyl are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R", 1O each RA1 is independently selected from OH, N02, CN, halo, C1-6 alkyl, C1-6 haloalkyl, Cm alkoxy, C1-6 haloalkoxy, cyano-C1—3 alkyl, HO-C1—3 alkyl, —3 alkyl, amino, C1-6 alkylamino, di(C1—6 alkyl)amino, thio, C1-6 alkylthio, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, carbamyl, C1-6 alkylcarbamyl, di(C1-6 alkyl)carbamyl, carboxy, C145 alkylcarbonyl, C1-6 alkoxycarbonyl, C1-6 alkylcarbonylamino, Cl-6 alkylsulfonylamino, aminosulfonyl, C1-6 alkylaminosulfonyl, di(Cra alkyl)aminosulfonyl, aminosulfonylamino, C1-6 alkylaminosulfonylamino, di(Cl-6 alkyl)aminosulfonylamino, aminocarbonylamino, C1-6 alkylaminocarbonylamino, and di(C1-6 alkyl)aminocarbonylamino; CyA2 is C3.7 cycloalkyl, phenyl, 5-6 membered heteroaryl, or 4-? membered heterocycloalkyl; n each 5-6 ed heteroaryl and 4-7 membered heterocycloalkyl has at least one ring-forming carbon atom and 1, 2, 3, or 4 ring- forming atoms independently ed from N, O, and S; wherein the N and S are ally oxidized, wherein a orming carbon atom of C3.7 cycloalkyl and 4- 7 membered heterocycloalkyl is optionally tuted by oxo to form a carbonyl group; and wherein the C34 cycloalkyl, phenyl, 5-6 membered heteroaryl, and 4-7 membered cycloalkyl are each ally substituted with 1, 2, 3 or 4 tuents independently selected from R", each RA2 is independently selected from OH, N02, CN, halo, C1-6 alkyl, C1-6 haloalkyl, Cl-6 alkoxy, C1-6 haloalkoxy, cyano-C1—3 alkyl, HO-C1—3 alkyl, H2N-C1—3 alkyl, amino, C1-6 alkylamino, di(Cl-G alkyl)arnino, thio, C1-6 alkylthio, C1-6 alkylsulfinyl, Cm alkylsulfonyl, yl, C1-6 alkylcarbamyl, di(C1.6 alkyl)carbamyl, carboxy, Cl-6 alkylcarbonyl, C1-6 alkoxycarbonyl, C1-6 alkylcarbonylamino, C1-6 W0 2017!]72596 alkylsulfonylamino, aminosulfonyl, C1-6 alkylaminosulfonyl, di(C1-6 alkyl)aminosulfonyl, aminosulfonylamino, C1-6 alkylaminosulfonylamino, di(Cl-6 alkyl)aminosulfonylamino, aminocarbonylamino, C1-6 alkylaminocarbonylamino, and di(C1-6 alkyl)aminocarbonylamjno; CyA3 is C3.7 cycloalkyl, phenyl, 5-6 membered heteroaryl, or 4-? membered heterocycloalkyl; wherein each 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl has at least one ring-forming carbon atom and 1, 2, 3, or 4 ringforming heteroatoms ndently selected from N, O, and S; wherein the N and S are optionally oxidized, wherein a ring-forming carbon atom of C3.7 cycloalkyl and 4- 1O 7 membered heterocycloalkyl is optionally tuted by oxo to form a yl group; and wherein the C34 cycloalkyl, phenyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl are each optionally substituted with 1, 2, 3 or 4 tuents independently selected from R", each RA3 is independently selected from OH, N02, CN, halo, C1-6 alkyl, C1-6 haloalkyl, Cl-6 alkoxy, C1-6 koxy, C1—3 alkyl, HO-C1—3 alkyl, —3 alkyl, amino, C1-6 alkylamino, dl(C1-6 alkyl)amino, thio, C1-6 alkylthio, C1-6 alkylsulfinyl, Cm alkylsulfonyl, carbamyl, C1-6 alkylcarbamyl, di(Cl-G alkyl)carbamyl, carboxy, Cl-6 alkylcarbonyl, C14; alkoxycarbonyl, C1-6 alkylcarbonylamino, C1-6 alkylsulfonylamino, aminosulfonyl, C1-6 alkylaminosulfonyl, di(C1—6 alkyl)aminosulfonyl, aminosulfonylamino, C1-6 alkylaminosulfonylamino, di(Cl-6 alkyl)aminosulfonylamino, aminocarbonylarnino, C1-6 alkylaminocarbonylamino, and dl(C1-6 alkyl)aminocarbonylamino, CyR3 is C3.7 cycloalkyl, phenyl, 5-6 membered heteroaryl, or 4-? ed heterocycloalkyl; wherein each 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl has at least one ring-forming carbon atom and 1, 2, 3, or 4 ring- g heteroatoms independently selected from N, O, and S, wherein the N and S are optionally oxidized; wherein a orming carbon atom of C34 cycloalkyl and 4- 7 ed heterocycloalkyl is optionally substituted by oxo to form a carbonyl group; and wherein the C34 cycloalkyl, , 5-6 membered heteroaryl, and 4—7 membered heterocycloalkyl are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from Rg; W0 2017!]72596 CyC is phenylene or 5-6 membered heteroarylene; wherein the 5-6 membered heteroarylene has at least one ring-forming carbon atom and 1 or 2 ring-forming heteroatoms independently selected from N, O, and S; and wherein the phenylene and -6 membered heteroarylene are each optionally tuted by 1, 2, 3, or 4 substituents independently selected from RC; each RC is independently selected from OH, CN, halo, C1—4 alkyl, C1—3 haloalkyl, C14 alkoxy, C1.3 haloalkoxy, cyano-C1—3 alkyl, HO-C1-3 alkyl, amino, C1—4 alkylamino, di(C1-4 alkyl)amino, C1.4 alkylsulfinyl, C1.4 alkylsulfonyl, carbamyl, C1-4 alkylcarbamyl, di(C1-4 alkyl)carbamyl, y, C1.4 alkylcarbonyl, C1—4 1O alkoxycarbonyl, C1.4 alkylcarbonylamino, C1.4 alkylsulfonylamino, aminosulfonyl, C1- 4 minosulfonyl, and di(C1-4 aminosulfonyl, CyB is C3-10 cycloalkyl or 4-10 membered heterocycloalkyl; wherein at least one orming carbon atom of C340 lkyl and 4-10 membered heterocycloalkyl is substituted by oxo to form a carbonyl group; n the 4-10 membered heterocycloalkyl 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; and wherein the C340 cycloalkyl and 4-10 membered heterocycloalkyl are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from RB; or CyB is 6-10 membered aryl or 5-10 membered heteroaryl; wherein the 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 ed, wherein: (a) at least one ring-forming carbon atom of the 5- membered heteroaryl is tuted by oxo to form a carbonyl group; or (b) the 6- 10 membered aryl or 5-10 membered heteroaryl is substituted by halo, CN, N02, ORaZ, SRaz, 2, C(O)NRC2Rd2, C(O)0Ra2, OC(O)Rb2, OC(O)NRCZRd2, NRCZRdZ, NRCZORdZ, NRCZC(O)Rb2, NRC2C(O)ORa2, NRCZC(O)NRC2Rd2, NRCZS(O)R"2, NRCZS(O)2R'32, NRCZS(O)2NRCZRd2, 2, S(O)NRC2Rd2, S(O)2Rb2, and S(O)2NR62Rd2; and wherein the 6-10 membered aryl or 5-10 membered heteroaryl is further optionally substituted with 1, 2, 3 or 4 substituents independently selected from RB; W0 72596 each RB is independently selected from halo, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, , 5—6 ed heteroaryl, 4-7 membered cycloalkyl, CN, N02, ORaz, SR", C(O)Rb2, C(O)NRCZRd2, C(O)OR32, OC(O)Rb2, OC(O)NR°2Rd2, 'Z, NRCZORdz, NR°2C(O)R"2, NR°2C(O)OR32, NR92C(O)NR92Rd2, NRCZS(O)Rb2, NRCZS(O)2R"2, NRCZS(O)2NRCZRd2, S(O)Rb2, S(O)NRC2Rd2, S(O)2Rb2, and S(O)2NR°2Rd2; wherein said C1-6 alkyl, C3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl are each optionally substituted with l, 2, 3, or 4 substituents ndently selected from R", each R11 is independently ed from CN, N02, OR", SR", C(O)Rb3, 1O C(O)NRC3Rd3, C(O)0Ra3, OC(O)Rb3, RC3Rd3, NRC3Rd3, NRC3ORd3, NRC3C(O)R"3, NRC3C(O)ORa3, NRC3C(O)NRC3Rd3, NRC3S(O)Rb3, NRC3S(O)2R"3, NRC3S(O)2NRC3Rd3, S(O)Rb3, S(O)NRC3Rd3, S(O)2Rb3, and S(O)2NRC3Rd3; each R12 is independently selected from halo, CN, N02, C1-6 alkyl, Cl-6 haloalkyl, C3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, ORa", SR", C(O)Rb4, C(O)NRC4Rd4, C(O)ORa4, OC(O)R"4, RC4Rd4, NRC4Rd4, NRC4OR‘14, NR°4C(O)Rb4, NRC4C(O)OR34, NRC4C(O)NRC4Rd4, NR°4S(O)Rb4, NRC4S(O)2Rb4, NRC4S(O)2NRC4Rd4, S(O)Rb4, S(O)NR°4Rd4, S(O)2Rb4, and R°4Rd4; wherein said C1-6 alkyl, C3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl are each optionally substituted with l, 2, 3, or 4 substituents independently selected from Rg; R8 is ed from H, C1-6 alkyl, and C1-6 haloalkyl, Rb is selected from C1-6 alkyl and C1-6 haloalkyl, RC and Rd are each independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, phenyl, 5-6 ed heteroaryl, 4-6 membered heterocycloalkyl, C3-6 cycloalkyl-C1-3 ne, phenyl-C1-3 alkylene, 5-6 membered heteroaryl-C1—3 alkylene, and 4-6 membered cycloalkyl-C1-3 alkylene, wherein said C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl, C3-6 cycloalkyl-C1-3 alkylene, phenyl-C1-3 alkylene, 5-6 membered heteroaryl—C1-3 alkylene, and 4-6 membered heterocycloalkyl-C1.3 alkylene are each optionally substituted with 1, 2 or 3 substituents independently selected from Rg; W0 2017!]72596 R31, RCl and R‘11 are each independently ed from H, C1-6 alkyl, and C1-6 haloalkyl, wherein said C1-6 alkyl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from Rg; or alternatively, RC1 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 or 3 substituents independently selected from Rbl is selected from C1-6 alkyl and C1-6 kyl, each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from Rg; 1O R61 is ed from H, CN, C1-6 alkyl, C1-6 kyl, C1-6 alkylthio, Cl-6 alkylsulfonyl, Cl-G alkylcarbonyl, C1-6 alkylaminosulfonyl, carbamyl, C1-6 alkylcarbamyl, dl(C1-6 alkyl)carbamyl, aminosulfonyl, C1-6 minosulfonyl, and dl(C1-6 alkyl)aminosulfonyl, each R32, R62, and R‘12 is independently ed from H, C1-6 alkyl, Cl-6 haloalkyl, C345 cycloalkyl, phenyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl; wherein said C1-6 alkyl, C3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl, and 4-7 ed heterocycloalkyl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R"; or alternatively, any RCZ and Rdz 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 or 3 substituents independently selected from each sz is independently selected from C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl, and 4-7 ed heterocycloalkyl, each of which is optionally tuted with 1, 2, 3, or 4 substituents independently selected from R12; each R33, RC3 and Rd3 is independently selected from H, C1-6 alkyl, C145 haloalkyl, C3-6 cycloalkyl, , 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, C3-6 cycloalkyl-C1.4 alkylene, phenyl-C1-4 alkylene, 5-6 membered heteroaryl-CM alkylene, and 4-7 membered cycloalkyl-C14 alkylene; wherein said C1-6 alkyl, C3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, C3-6 cycloalkyl-C1-4 alkylene, phenyl-C1-4 alkylene, 5-6 membered W0 2017!]72596 heteroaryl-CM alkylene, and 4-7 membered heterocycloalkyl-C14 alkylene are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Rg; alternatively, any RC3 and R‘13 attached to the same N atom, er with the N atom to which they are attached, form a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionally substituted with l, 2 or 3 substituents independently ed from each Rb3 is independently selected from C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, C3-6 1O cycloalkyl-C1-4 alkylene, phenyl-C1-4 ne, 5-6 ed heteroaryl-C1-4 alkylene, and 4-7 membered heterocycloalkyl-Cm alkylene, each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from Rg; each R34, RC4 and Rd", is independently selected from H, C1-6 alkyl, and C1-6 kyl; wherein said C1-6 alkyl is optionally substituted with 1, 2, 3, or 4 substituents independently ed from Rg, or atively, any RC4 and R(14 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 each Rb4 is ndently selected from C1-6 alkyl and C1-6 haloalkyl, each of which is optionally tuted with 1, 2, 3, or 4 substituents independently selected from Rg; and each Rg is independently selected from OH, N02, CN, halo, C1-6 alkyl, C1-6 haloalkyl, Cm alkoxy, C1-6 haloalkoxy, cyano-C1—3 alkyl, HO-C1—3 alkyl, H2N-C1—3 alkyl, amino, C1-6 alkylamino, di(C1.6 amino, thio, C1-6 alkylthio, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, carbamyl, C1-6 alkylcarbamyl, di(C1-6 alkyl)carbamyl, carboxy, C143 alkylcarbonyl, C1-6 alkoxycarbonyl, C1-6 alkylcarbonylamino, Cl-G alkylsulfonylamino, aminosulfonyl, C1-6 alkylaminosulfonyl, di(C1—6 alkyl)aminosulfonyl, aminosulfonylamino, C1-6 alkylaminosulfonylamino, di(Cl-6 alkyl)aminosulfonylamino, aminocarbonylamino, C1-6 alkylaminocarbonylamino, and di(C1.6 alkyl)aminocarbonylamino; provided that: W0 2017!]72596 2017/024270 1) Al-AZ—A3 is not Y-Y when one of A1, A2 or A3 is a bond, or Y-Y-Y; and 2) when A3 is —Y— or —C1—3 alkylene—Y— then RA is H, C1-6 alkyl, or C1-6 haloalkyl, wherein said C14; alkyl or C1-6 kyl is optionally substituted with 1, 2, 3 or 4 tuents independently selected from R".
In some embodiments, A1 is a bond.
In some embodiments, A2 is a bond.
In some embodiments, A3 is a bond.
In some embodiments, RA is H, halo, C1-6 alkyl or C1-6 haloalkyl.
In some embodiments, RA is C1-6 alkyl. 1O In some embodiments, RA is methyl or ethyl.
In some embodiments, A1 is a bond. For example, R1 is A2-A3-RA.
In some embodiments, A1 is a bond, A2 is a bond, and A3 is CyA3. For example, R1 is CyA3-RA.
In some embodiments, one of A1, A2, and A3 is not a bond.
In some embodiments, one of A1, A2, and A3 is —C1.3 alkylene—, —Y—, —C1—3 alkylene—Y—, or —Y—C1-3 alkylene—. In some embodiments, one of A1, A2, and A3 is — C1-6 ne— or —Y—. In some ments, one of A1, A2, and A3 is —C1-6 alkylene— . In some embodiments, one of A1, A2, and A3 is methylene.
In some embodiments, R1 is H, halo, C1-6 alkyl or C1-6 haloalkyl.
In some embodiments, R1 is C1-6 alkyl. In some embodiments, R1 is methyl or ethyl.
In some embodiments, R1 is A2-A3-RA.
In some embodiments, R1 is CyA3-RA.
In some embodiments, CyA3 is C34 cycloalkyl, 5-6 membered heteroaryl, or 4- 7 membered heterocycloalkyl, each optionally substituted with 1, 2, 3 or 4 substituents independently ed from R".
In some embodiments, CyA3 is C3-6 cycloalkyl or 4-6 membered heterocycloalkyl, each optionally substituted with 1 or 2 substituents independently selected from RA3.
In some embodiments, CyA3 is piperidinyl, cyclohexyl, or tetrahydropyranyl; each optionally substituted with 1 or 2 substituents independently selected from RA3.
W0 2017/‘172596 In some embodiments, CyA3 is C3-6 cycloalkyl optionally substituted with 1, 2, 3 or 4 independently selected RA3 groups. In some embodiments, CyA3 is cyclohexyl and cyclopropyl optionally substituted with 1, 2, 3 or 4 independently selected RA3 groups.
In some embodiments, CyA3 is 4-6 membered heterocycloalkyl optionally substituted with 1, 2, 3 or 4 ndently selected RA3 groups. In some embodimets, CyA3 is piperidinyl or morpholinyl optionally substituted With 1, 2, 3 or 4 independently selected RA3 groups.
In some embodiments, CyA3 is 5-10 membered heteroaryl optionally 1O substituted with 1, 2, 3 or 4 ndently selected RA3 groups. In some embodiments, CyA3 is l optionally substituted with 1, 2, 3 or 4 independently ed RA3 groups.
In some embodiments, CyA3 is piperidinyl, cyclohexyl, tetrahydropyranyl, pyrazolyl, pyridinyl, inyl, cyclopropyl, or morpholinyl, each optionally substituted with 1 or 2 substituents independently selected from R".
In some embodiments, CyA3 is piperidinyl, pyridyl, morpholinyl, cyclohexyl, or tetrahydropyranyl, each ally substituted with 1, 2, 3 or 4 independently ed RA3 groups.
In some ments, CyA3 is piperidinyl optionally substituted with 1, 2, 3 or 4 ndently selected RA3 groups.
In some embodiments, CyA3 is cyclohexyl optionally substituted with 1, 2, 3 or 4 independently selected RA3 .
In some embodiments, CyA3 is morpholinyl optionally substituted with 1, 2, 3 or 4 independently selected RA3 groups.
In some embodiments, CyA3 is 0 H CyA3_1 CyA3_2 CyA3_3 wherein CyA3-1, CyA3-2 and CyA3-3 are each optionally substituted with 1, 2 or 3 substituents independently selected from RA3.
In some embodiments, A1 is a bond, A2 is a bond, A3 is a bond, and RA is methyl or ethyl; or A1 is a bond, A2 is a bond, and A3 is CyA3-RA selected from RA RA In some embodiments, RA is C1-6 alkyl, CN, OR", NR"R", C(O)Rb1, C(O)NRCIR", C(O)OR", S(O)Rb1, S(O)NR"R", S(O)2Rbl or S(O)2NRC1R"; wherein said C1-6 alkyl is optionally substituted with 1 or 2 substituents independently selected from R", provided that if RA is attached to a nitrogen atom, then RA is not CN, OR", or NRCIR‘".
In some embodiments, RA is C1-6 alkyl, CN, OR", C(O)Rb1, C(O)NRCIR", ", and S(O)2Rb1, wherein said C1-6 alkyl is ally substituted with l substituent selected from R", provided that if RA is attached to a nitrogen atom, then RA is not CN or OR". In some embodiments, R[)1 is isopropyl.
In some embodiments, each RA is independently selected from C1-3 alkyl, CN, OH, methylcarbonyl, methoxycarbonyl, methylaminocarbonyl, and methylsulfonyl, wherein said C1—3 alkyl is optionally substituted with a OH or OCH3 group, provided that if RA is attached to a en atom, then RA is not CN or OH.
In some embodiments, each RA is independently selected from CH3, CH2CH3, CN, OH, CH2CH20H, CH2CH20CH3, C(O)CH3, C(O)CH20H, C(O)CH(OH)CH3, S(O)2CH3, H3, C(O)N(CH3)2, C(O)NHCH3, CH2CH3)2, and C(O)N(CH3)(CH2CH3).
In some embodiments, each RA is independently selected from CH3, CH2CH3, CH(CH3)2, CN, OH, 0H, CH2CH20CH3, C(O)CH3, C(O)CH2CH3, C(O)CH(CH3)2, C(O)CH20H, C(O)CH(OH)CH3, S(O)2CH3, H3, C(O)N(CH3)2, C(O)N(CH2CH3)2, C(O)N(CH3)(CH2CH3), C(O)NHCH3, (CH2CH3) and C(O)[morpholinyl].
In some embodiments, each R11 is independently OR".
In some ments, each R11 is independently OH or OCH3.
In some embodiments, CyA3 is piperidinyl, exyl, tetrahydropyranyl, pyrazolyl, pyridinyl, azetidinyl, cyclopropyl, or morpholinyl, each optionally substituted with RA independently selected from CH3, CN, OH, CH2CH20H, CH2CH20CH3, C(O)CH3, C(O)CH2CH3, C(O)CH(CH3)2, C(O)CH20H, C(O)CH(CH3)OH, S(O)2CH3, C(O)OCH3, C(O)N(CH3)2, C(O)NH(CH3), W0 2017!]72596 C(O)N(CH2CH3)2, C(O)NH(CH2CH3), C(O)N(CH3)(CH2CH3), CH2C(O)N(CH3)2, 1— methyloxopyrrolidin—3—yl, C(O)(cyclopropyl), N(CH3)2, and C(O)(morpholiny1).
In some embodiments, CyA3 is piperidinyl, cyclohexyl, or ydropyranyl; each ally substituted with RA independently selected from CH3, CN, OH, CH2CHzOH, CH2CH20CH3, 3, C(O)CH20H, C(O)CH(CH3)OH, S(O)2CH3, C(O)OCH3, C(O)N(CH3)2, C(O)NH(CH3), CH2CH3)2, C(O)NH(CH2CH3) and C(O)N(CH3)(CH2CH3).
In some embodiments, CyA3 is piperidinyl, cyclohexyl, or tetrahydropyranyl; each optionally substituted with RA independently selected from CH3, , 1O CH(CH3)2, CN, OH, CH2CH20H, CH2CH20CH3, C(O)CH3, C(O)CH2CH3, C(O)CH(CH3)2, C(O)CH20H, C(O)CH(OH)CH3, S(O)2CH3, C(O)OCH3, C(O)N(CH3)2, C(O)N(CH2CH3)2, C(O)N(CH3)(CH2CH3), C(O)NHCH3, C(O)NH(CH2CH3) and C(O)(morpholinyl) In some embodiments, CyA3 is piperidinyl, pyIidyl, morpholinyl, cyclohexyl, or tetrahydropyranyl; each optionally substituted with 1, 2, 3 or 4 groups independently selected from CH3, CH2CH3, CN, OH, CH2CH2OH, CH2CH20CH3, C(O)CH3, C(O)CH20H, C(O)CH(OH)CH3, S(O)2CH3, C(O)OCH3, C(O)N(CH3)2, C(O)NHCH3, C(O)N(CH2CH3)2, and C(O)N(CH3)(CH2CH3).
In some embodiments, A1 is a bond, A2 is CyAZ, A3 is -Y—, RA is C3-6 lkyl (e.g., cyclopropyl), -Y- is C(O), and CyA2 is 4-7 membered cycloalkyl (e.g., piperidinyl).
W0 72596 In some embodiments R1 is\rK . In some embodimebts, R1 is VA0 In some embodiments R11s.In some embodiments, R1 is5/10 GAOIn some embodiments R1IS 0A0.
In some embodiments, R2 is H, halo, C1—4 alkyl, C1—4 haloalkyl, C1—4 alkoxy, or C14 haloalkoxy. In some embodiments, R2 is H or C14 alkyl. In some embodiments, R2 is H.
In some ments, R3 is H.
In preferred embodiments, CyB forms a hydrogen bond with the NH of the amide group. For example, if the CyB group has an oxo group, the CyB can form a hydrogen bond through the carbonyl group with the NH of the amide group.
Similarly, CyB can be substituted with an electron donating substituent capable of forming a hydrogen bond with the NH of the amide group. Below are illustrative examples wherein W is an electron ng group such as halo, CN, N02, ORaZ, SRaZ, C(0)Rb2, C(O)NRCZRd2, C(0)0Ra2, 0C(0)Rb2, OC(O)NRC2Rd2, , NRcloRdZ, NRC2C(O)Rb2, NRC2C(O)ORa2, NRCZC(O)NRC2Rd2, NRC28(O)R"2, NRCZS(O)2R"2, NRCZS(O)2NRCZRd2, S(O)Rb2, S(O)NRC2Rd2, S(O)2Rb2, and S(O)2NRC2Rd2: In some ments, CyB is C340 cycloalkyl or 4-10 ed heterocycloalkyl; wherein at least one ring-forming carbon atom of C3—10 cycloalkyl and 4-10 membered heterocycloalkyl is substituted by oxo to form a carbonyl group; wherein the 4-10 membered heterocycloalkyl 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; and wherein the C340 cycloalkyl and 4—10 membered heterocycloalkyl are each optionally substituted with 1, 2, 3 or 4 tuents independently selected from RB, or CyB is 5-10 membered heteroaryl; wherein the 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) at least one ring-forming carbon atom of the 5-10 membered aryl is substituted by oxo to form a carbonyl group; or (b) the 5-10 membered aryl is substituted by halo, CN, N02, ORaZ, SRaZ, C(0)Rb2, C(O)NRCZRd2, C(0)0Ra2, 0C(0)Rb2, OC(O)NRC2Rd2, NRCZR‘n, NRdOR‘fl, NRC2C(O)Rb2, NRCZC(O)ORa2, O)NRC2Rd2, NRCZS(O)R"2, NRc2S(0)2Rb2, NRCZS(O)2NRCZR‘12, S(O)Rb2, S(O)NRC2Rd2, S(O)2Rb2, and S(O)2NRcsz2; and n the 5-10 membered heteroaryl is further optionally substituted with 1, 2, 3 or 4 substituents independently selected from RB.
W0 2017!]72596 In some embodiments, CyB is C3—10 cycloalkyl or 4-10 ed heterocycloalkyl; wherein at least one ring-forming carbon atom of €3-10 cycloalkyl and 4-10 ed heterocycloalkyl is substituted by oxo to form a carbonyl group; wherein the 4-10 membered heterocycloalkyl 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, and wherein the C340 cycloalkyl and 4—10 membered heterocycloalkyl are each optionally substituted with 1, 2, 3 or 4 substituents ndently selected from RB.
In some ments, CyB is 5-10 membered heteroaryl, wherein the 5—10 1O 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, n: (a) at least one ring-forming carbon atom of the 5- membered heteroaryl is substituted by oxo to form a carbonyl group; or (b) the 5- membered heteroaryl is substituted by halo, CN, N02, ORaZ, SRaZ, C(O)Rb2, C(O)NR62R"2, C(O)OR32, OC(O)Rb2, OC(O)NRCZRd2, NRCZRdZ, NRdORdz, NRC2C(O)R"2, NRCZC(O)OR32, NRCZC(O)NRC2Rd2, NRCZS(O)Rb2, O)2R"2, NRCZS(O)2NRC2Rd2, 2, S(O)NRC2Rd2, S(O)2Rb2, and S(O)2NRC2Rd2; and wherein the 5-10 membered heteroaryl is further optionally substituted with 1, 2, 3 or 4 substituents independently selected from RB.
In some embodiments, CyB is 4-10 membered heterocycloalkyl; wherein at least one orming carbon atom of 4-10 membered heterocycloalkyl is substituted by oxo to form a carbonyl group, wherein the 4-10 membered heterocycloalkyl has at least one orming carbon atom and l, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O, and S, and wherein the 4-10 membered heterocycloalkyl is optionally substituted with l, 2 or 3 substituents independently selected from RB; or CyB is 5-6 ed heteroaryl, having at least one ring-forming carbon atom which is substituted by oxo to form a carbonyl group and l or 2 ring-forming heteroatoms independently selected from N, O, and S, wherein the N and S are optionally oxidized; wherein the 5-6 ed heteroaryl is further optionally substituted with 1, 2, or 3 substituents independently selected from RB‘ W0 72596 In some embodiments, CyB is 4-10 membered heterocycloalkyl; wherein at least one orming carbon atom of 4-10 membered heterocycloalkyl is substituted by oxo to form a carbonyl group; wherein the 4-10 membered heterocycloalkyl has at least one ring-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O, and S; and wherein the 4-10 membered heterocycloalkyl is optionally substituted with 1, 2 or 3 substituents independently selected from RB.
In some embodiments, CyB is 5-10 membered heteroaryl, having at least one ring-forming carbon atom which is substituted by oxo to form a carbonyl group and 1 1O or 2 ring-forming heteroatoms independently selected from N, O, and S; wherein the N and S are optionally oxidized, wherein the 5-6 membered heteroaryl is further ally substituted with 1, 2, or 3 substituents independently selected from RB.
In some embodiments, CyB is 4-10 membered heterocycloalkyl or 5-10 membered heteroaryl n one ring-forming carbon atom at the ortho position is substituted by oxo to form a yl group. The ortho position refers to the ring- forrning carbon atom directly adjacent to the ring-forming atom connecting the CyB group to the —C(=O)NH-CyC- linker.
In some embodiments, CyB is — HN-NH _ \ NH HNJLNH NH 0 o / \ 0 06f) ’ 0 , CyB-l CyB-2 CyB-3 CyB-4 CyB—S HN-N 0 HT \ 0% N\ CyB-6 CyB-7 n CyB-l, CyB-2, CyB-3, CyB-4, CyB-S, CyB-6, and CyB-7 are each optionally substituted with 1, 2 or 3 independently ed RB groups.
In some embodiments, CyB is _N HN N_ \ _\ NH HIN—< \ \ NH NH \ or \ , N\ , , CyB—8 CyB-9 CyB-IO CyB-ll wherein CyB-8, CyB-9, CyB-IO, CyB-4, and CyB-ll are each optionally substituted with 1, 2 or 3 independently ed RB groups.
In some embodiments, CyB is CyB—l CyB-2 CyB-3 _N\ HN HN S} \E N=\ \ NH N,\ NH or , flo , , I? SNH O O O CyB-8 CyB—9 CyB-lO CyB-ll wherein CyB-I, CyB-2, CyB-3, CyB-8, CyB-9, CyB-IO, CyB-4, and CyB-ll are each optionally substituted with l, 2 or 3 independently selected RB .
In some embodiments, CyB is CyB-l ally tuted with 1, 2 or 3 independently selected RB groups. In some embodiments, CyB is CyB—2 optionally substituted with 1, 2 or 3 independently selected RB groups. In some embodiments, CyB is CyB—3 optionally substituted with 1, 2 or 3 independently selected RB groups. 1O In some embodiments, CyB is CyB-4 optionally substituted with 1, 2 or 3 independently selected RB . In some embodiments, CyB is CyB-S ally substituted with 1, 2 or 3 independently selected RB groups. In some embodiments, CyB is CyB-6 optionally substituted with 1, 2 or 3 independently selected RB groups.
In some embodiments, CyB is CyB-7 optionally substituted with 1, 2 or 3 independently selected RB groups.
In some embodiments, CyB is W0 2017!]72596 O 0 _\RB REE JL ,RB RBx ,RB REK N-RB RQ=\ N N N-N N—N \ \ N—RB ,\J 0 x53 RB R 0 / 0 RB O O CyB-la CyB-2a CyB-3a CyB—4a CyB-Sa RB\N—N/jo RB \T \ OW RB CyB-6a CyB-7a.
In some ments, CyB is CyB-la. In some embodiments, CyB is CyB-2a.
In some embodiments, CyB is CyB-3a. In some embodiments, CyB is CyB—4a In some embodiments, CyB is CyB-Sa. In some embodiments, CyB is CyB-6a. In some embodiments, CyB is CyB-7a.
In some embodiments, CyB is C340 cycloalkyl optionally substituted with 1, 2 or 3 independently selected RB groups. In some embodiments, CyB is cyclopropyl.
In some embodiments, CyB is cyclopropyl, CyB-l CyB-2 wherein the cyclopropyl, CyB-l and CyB-2 are each optionally substituted with 1, 2 or 3 ndently selected RB groups.
In some embodiments, CyB is — HN HN \ NH "QM_ 01M" \ O O L5H. or O , 3 , CyB-I CyB-2 CyB-3 CyB-IO wherein CyB-l, CyB-2, CyB-3, and CyB-IO are each ally substituted with 1, 2 or 3 tuents independently selected from RB.
In some embodiments, CyB is \ NH :\_ NH , CyB-l CyB-2 wherein CyB-l and CyB-2 are each ally substituted with l, 2 or 3 independently selected RB groups.
In some embodiments, CyB is — Jok HN—NH —— \ NH HN NH \ NH 7 ’ ’ 0 Of 0 / a O / CyB-l CyB-2 CyB-3 CyB-4 CyB-S wherein CyB-l, CyB-2, CyB-3, CyB-4 and CyB-S are each optionally substituted with 1, 2 or 3 independently selected RB groups.
In some embodiments, CyB is \ NH :\— NH , CyB-l CyB-2 wherein CyB-l and CyB-2 are each optionally tuted with 1, 2 or 3 substituents ndently selected from RB.
In some embodiments, CyB is —— {—NH H )LNHN \ NH 0r , 3 O 0% CyB-l CyB-2 CyB-3 wherein CyB-l, CyB-2 and CyB-3 are each optionally substituted with 1, 2 or 3 independently selected RB groups.
In some embodiments, CyB is CyB-l wherein CyB-l is optionally substituted with l, 2 or 3 independently selected In some embodiments, CyB is QNHo , CyB-2 wherein CyB-2 is optionally substituted with l, 2 or 3 independently selected RB groups.
In some embodiments, CyB is HN NH CyB-3 wherein CyB-3 is optionally substituted with l, 2 or 3 independently selected RB groups.
In some embodiments, CyB is — \ NH NH or Q \ = CyB-l CyB-2 wherein CyB-l and CyB-2 are each optionally tuted with 1, 2 or 3 substituents independently selected from RB, each RB is independently methyl, ethyl, isopropyl, tyl, or phenyl, each of which is optionally substituted by 1 or 2 substituents independently selected from W0 2017!]72596 each R12 is independently selected from halo, phenyl, and OR"; wherein said phenyl is optionally substituted by 1 or 2 substituents independently selected from Rg group; each R34 is H or C1-3 alkyl; and each Rg is independently selected from halo.
In some embodiments, CyB is — JL — \ NH HN NH HN \ NH or 7 3 3 O / \ o o CyB-l CyB-2 CyB-3 CyB-10 wherein CyB-l, CyB-2, CyB-3, and CyB-10 are each optionally substituted with 1, 2 or 3 substituents independently selected from RB, each RB is independently methyl, ethyl, isopropyl, sec-butyl, 2-pyridinyl, or phenyl, each of which is optionally substituted by 1 or 2 substituents ndently selected from R"; each R12 is independently selected from C1-6 alkyl, halo, , and OR"; wherein said C1-6 alkyl and phenyl are each optionally substituted by 1 or 2 substituents independently ed from Rg group; each R84 is H or C1—3 alkyl, and each Rg is independently selected from halo.
In some embodiments, CyB is — \_ NH HNJLNH \ NH Or 3 3 O 02% CyB-l CyB-2 CyB-3 wherein CyB-l, CyB-2 and CyB-3 are each optionally substituted with 1, 2 or 3 substituents independently selected from RB, each RB is ndently methyl, ethyl, isopropyl, sec-butyl, or phenyl, each of which is optionally substituted by 1 or 2 substituents independently selected from each R12 is ndently selected from halo, phenyl, and OR"; wherein said phenyl is ally substituted by 1 or 2 substituents independently selected from Rg group; each R34 is H or C1—3 alkyl; and each Rg is independently selected from halo.
In some embodiments, CyB is CyB-l CyB-2 wherein CyB-l and CyB-2 are each optionally substituted with 1, 2 or 3 groups independently selected from unsubstituted phenyl, 4-fluoro-phenyl, CH2(phenyl), CH(CH20H)phenyl, CH3, CH2CH3, CH(CH20H)CH2CH3, 0H)CH3, CH2CH20H, OCH2CH3 and OCH3.
In some embodiments, CyB is CyB-l CyB-2 CyB-3 wherein CyB-l, CyB-2, and CyB-3 are each optionally substituted with 1, 2 or 3 groups independently selected from unsubstituted phenyl, 4-fluoro-phenyl, 3— fluorophenyl, 2-fluorophenyl, dinyl, CH2(phenyl), CH(CH20H)phenyl, CH3, CH2CH3, CH(CH3)2, CH(CH20H)CH2CH3, CH(CH20H)CH3, CH2CH20H, OCH2CH3 and OCH3 In some embodiments, CyB is — \_ NH HNANH \ NH , , o \ CyB-l CyB-2 CyB-3 wherein CyB-l, CyB-2 and CyB-3 are each optionally substituted with 1, 2 or 3 substituents independently selected from unsubstituted phenyl, 4-fluoro-phenyl, 3- fluoro-phenyl, 2-fluoro-phenyl, CH2(phenyl), CH(CH20H)phenyl, CH3, CH2CH3, CH(CH3)2, CH(CH20H)CH2CH3, CH(CH20H)CH3, CH2CH20H, OCH2CH3 and OCH3.
In some embodiments, CyB is HNANH \— NH O or 0% CyB-2 CyB-3, wherein CyB-2 and CyB-3 are each optionally substituted 1, 2 or 3 groups ndently ed from unsubstituted phenyl, CH(CH3)2, and 2-pyridinyl.
In some ments, CyB is CyB-2 wherein CyB-2 is optionally substituted 1, 2 or 3 groups independently selected from unsubstituted phenyl, CH(CH3)2, and 2-pyridinyl.
In some embodiments, CyB is CyB-3, wherein CyB—3 is optionally substituted 1, 2 or 3 groups independently selected from unsubstituted phenyl, CH(CH3)2, and 2-pyridinyl.
In some embodiments, CyB is W0 2017!]72596 HNJLNH CyB-3, wherein CyB-3 is substituted with unsubstituted phenyl and CH(CH3)2.
In some embodiments, CyB is HNJLNH CyB-3, n CyB-3 is substituted with pyridinyl (e.g., 2-pyridinyl, 3-pyridinyl, and 4-pyridiny1) and CH(CH3)2.
In some ments, each RB is independently selected from halo, C1-6 alkyl, C2-6 l, C145 haloalkyl, C3.5 cycloalkyl, phenyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, CN, ORaz, C(O)Rb2, C(O)NRC2Rd2, C(O)OR32, NRCZRdZ, NR°2C(O)Rb2, and O)ORa2; wherein said C1-6 alkyl, C2-6 alkynyl, C34 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 In some embodiments, each RB is independently unsubstituted phenyl, 4- fluoro-phenyl, 3-fluorophenyl, 2-fluorophenyl, CH2(phenyl), CH(CH20H)pheny1, Br, Cl, CN, CH3, CHF2, CH2CH3, CH20CH3, 2CH3, CH(CH3)2, CH(CH20H)CH2CH3, CH(CH20H)CH3, CH2CH20H, CH2CH(OH)(CH3), OCH3, OCH2CH3, C(O)NH2, C(O)CH3, 2,5-difluorophenyl, 3-pyridinyl, 2-pyridinyl, 1- methyl-lH-pyrazolyl, 1-methyl-lH-pyrazolyl, l-methyl-lH-pyrazolyl, 1,4- dimethyl-1H—pyrazolyl, 1,5-dimethyl-lH-pyrazolyl, 2-methylthiazolyl, cyclohexyl, 3-cyanophenyl, 5-methy1isoxazolyl, 5-fluoropyridinyl, 5- fluoropyridin-Z-yl, 3-cyanophenyl, CH2CN, thiazolyl, 6-methylpyridinyl, 2- W0 2017!]72596 methylpyridinyl, 6—methylpyridinyl, pyIimidin-Z-yl, morpholin—4-yl, cyclopropyl, oxazolyl, CCCH(OH)(CH3), or C(O)NH(4-fluoro-phenyl).
In some embodiments, each RE is independently unsubstituted phenyl, 4- phenyl, 3-fluoropheny1, 2-fluorophenyl, CH2(phenyl), CH(CH20H)phenyl, Br, CN, CH3, CH2CH3, CH(CH3)2, CH(CH20H)CH2CH3, CH(CH20H)CH3, CH2CH20H, CH2CH(OH)(CH3), OCH3, OCH2CH3, C(O)NH2, 3, 2,5-difluorophenyl, 3- pyridinyl, 2-pyridinyl, l-methyl-lH-pyrazolyl, l-methyl-lH—pyrazolyl, 1- methyl-IH—pyrazol-S-yl, 2-methylthiazolyl, cyclohexyl, 3-cyanophenyl, 5- methylisoxazolyl, 5-fluoropy1idinyl, 3-cyanophenyl, CH2CN, thiazol-4—yl, 6- 1O methylpyridinyl, pyIimidin-Z-yl, morpholinyl, cyclopropyl, oxazol-Z-yl, CCCH(OH)(CH3), or (4-fluoro-phenyl).
In some embodiments, each RB is independently unsubstituted phenyl, 4- fluoro-phenyl, ophenyl, 2-fluorophenyl, 2-pyridinyl, CH2(phenyl), CH(CH20H)phenyl, CH3, CH2CH3, CH(CH3)2, CH(CH20H)CH2CH3, CH(CH20H)CH3, CH2CH20H, OCH3, OCH2CH3, or (4-fluoro—phenyl).
In some embodiments, each RB is independently unsubstituted phenyl, 4- fluoro-phenyl, enyl), CH(CH20H)phenyl, CH3, CH2CH3, CH(CH20H)CH2CH3, CH(CH20H)CH3, CH2CH20H, OCH3, OCH2CH3, or C(O)NH(4—fluoro-phenyl), In some embodiments, each RB is independently unsubstituted phenyl, 4- fluoro-phenyl, 3-fluoro-phenyl, 2-fluoro-phenyl, CH2(phenyl), CH(CH20H)phenyl, CH3, CH2CH3, )2, CH(CH20H)CH2CH3, CH(CH20H)CH3, CH2CH20H, OCH3, OCH2CH3, or C(O)NH(4-fluoro-phenyl).
In some embodiments, each RB is independently unsubstituted phenyl or 4- fluoro-phenyl, 3-fluoro-phenyl, 2-fluoro-phenyl, dinyl, CH3, CH2CH3 or )2. In some embodiments, each RB is independently unsubstituted phenyl or 4-fluoro-phenyl, 3-fluoro-phenyl, o-phenyl, CH3, CH2CH3 or CH(CH3)2. In some embodiments, each RB is tituted phenyl, CH(CH3)2, or 2-pyridinyl. In some embodiments, each RB is ndently unsubstituted phenyl or 4-fluoro- phenyl. In some embodiments, each RB is unsubstituted phenyl. In some embodiments, each RB is 4-fluoro-phenyl. In some embodiments, each RB is pyridinyl (e.g., 2-pyridiny1). In some embodiments, each R13 is independently unsubstituted W0 2017!]72596 phenyl or CH(CH3)2. In some embodiments, each RB is ndently unsubstituted phenyl or CH2CH3. In some embodiments, each RB is independently 4-fluoro-pheny1 or CH(CH3)2. In some embodiments, each RE is ndently 4-fluoro-phenyl or CH2CH3. In some ments, each RE is independently 3-fluoro-phenyl or CH(CH3)2. In some embodiments, each RB is independently 3-fluoro-phenyl or CH2CH3. In some embodiments, each RB is independently 2-fluoro-phenyl or CH(CH3)2. In some ments, each RB is independently 2-fluoro-phenyl or CH2CH3.
In some embodiments, CyC is phenylene optionally substituted by 1, 2, 3, or 4 1O substituents independently selected from RC.
EQE or éflé In some embodiments, CyC is RC wherein the RC group on the phenylene ring is ortho to the pyrrolo[2,1-f][1,2,4]triazine ring in Formula I.
In some embodiments, each RC is independently selected from OH, halo, C1—4 alkyl, and CH haloalkyl. In some embodiments, each RC is independently halo or C1-4 alkyl. In some embodiments, each RC is independently F, C1, or methyl. In some embodiments, each RC is F, i®é or éflé . . c .
In some embodlments, CyC is R where1n RC is F, C1, or methyl, wherein the phenyl ring is attached to the pyrrolo[2,1— f] ]triazine ring at left site of attachment.
EQE or 3Q; In some embodiments, CyC is RC wherein RC is F, wherein the phenyl ring is ed to the pyrrolo[2,l-f] [1,2,4]triazine ring at left site of attachment.
In some embodiments, R1 is RA RA RA is CH3, CH2CH3, CN, OH, CH2CH20H, CH2CH20CH3, C(O)CH3, (CH3)2, C(O)(cyclopropy1), C(O)CH2CH3, C(O)CH20H, C(O)CH(OH)CH3, SOzCH3, C(O)OCH3, C(O)N(CH3)2, C(O)NHCH3, CH2CH3)2, C(O)N(CH3)(CH2CH3), or orpholinyl), CyB is CyB-lO CyB-2 CyB-3 wherein CyB-l, CyB-2, and CyB-3 are each ally substituted with l or 2 substituents independently selected from RB, each RB is independently unsubstituted phenyl, 4-F-phenyl, 3-F-phenyl, 2-F— phenyl, 2-pyridiny1, CH2(pheny1), CH(pheny1)CH20H, methyl, ethyl, isopropyl, CH(CH20H)CH2CH3, CH(CH20H)CH3, CH2CH20H or OCH2CH3; CyC is phenylene optionally substituted with 1 RC group; and RC is F, C1 or Br.
In some embodiments, R1 is RA is CH3, CH2CH3, CN, OH, CH2CH20H, CH2CH20CH3, C(O)CH3, C(O)CH20H, C(O)CH(OH)CH3, SOzCH3, C(O)OCH3, C(O)N(CH3)2, C(O)NHCH3, C(O)N(CH2CH3)2 or C(O)N(CH3)(CH2CH3), CyB is CyB-l CyB-2 wherein CyB-l and CyB-2 are each optionally substituted with l or 2 substituents independently selected from RB, each RB is independently tituted phenyl, 4-F-phenyl, CH2(phenyl), CH(phenyl)CH20H, methyl, ethyl, CH(CH20H)CH2CH3, CH(CH20H)CH3, CH2CH20H or 3; CyC is phenylene optionally substituted with 1 RC group; and RC is F, C1 or Br.
In some ments, R1 is Wm: Jam: (9 or o; RA RA RA is CH3, CH2CH3, CN, OH, CH2CH20H, CH2CH20CH3, C(O)CH3, C(O)CH(CH3)2, C(O)CH2CH3, C(O)CH20H, C(O)CH(OH)CH3, SOzCH3, C(O)OCH3, C(O)N(CH3)2, C(O)NHCH3, C(O)N(CH2CH3)2, CH3)(CH2CH3), or C(O)(morpholinyl), CyB is — —NH HNANH \ NH or ’ Q ’ O 02>? CyB-l CyB-2 CyB-3 wherein CyB-l, CyB-Z, and CyB-3 are each optionally substituted with l or 2 substituents independently selected from RB, W0 2017!]72596 each RB is independently unsubstituted , 4-F-phenyl, 3-F-phenyl, 2-F— phenyl, CH2(pheny1), CH(phenyl)CH20H, methyl, ethyl, isopropyl, CH(CH20H)CH2CH3, CH(CH20H)CH3, CH2CH20H or OCH2CH3; CyC is phenylene optionally substituted with 1 RC group; and RC is F, C1 or Br, In some embodiments, the heteroaryl group of e. g., CyA, and CyB is optionally substituted with an oxo to form a carbonyl. For example, the 5-10 membered heteroaryl group of CyB can be substituted with an oxo to form a carbonyl which includes groups such as 2-pyridone e.g.,QNH0 . Heteroaryl group can also include \ _ substituted pyridone (e.g., substituted done) such as $0 and In some embodiments: (1) A1, A2, and A3 are each a bond and RA is C1-6 alkyl or (2) Al and A2 are each a bond, A3 is CyA3, and each RA is independently selected from C1-6 alkyl, CN, OR", C(O)Rb1, C(O)NRC1R‘", C(O)OR31, and S(O)2R"1; wherein said C1-6 alkyl is ally substituted with a R11 group, provided that if RA is attached to a nitrogen atom, then RA is not CN or OR"; each R", R", and Rdl are independently H or 04 alkyl; each Rbl is independently C1—4 alkyl; each R11 is independently OR"; R2 is H; R3 is H; CyB is a 7,8-dihydroquinoline—2,5(lH,6H)-dione or 2-pyridone ring, which is ally tuted with 1 or 2 independently selected RB groups; each RB is independently methyl, ethyl, isopropyl, sec-butyl, or phenyl, each of which is optionally substituted by 1 or 2 independently selected R12 groups; each R12 is independently ed from halo, phenyl, and OR"; wherein said phenyl is optionally substituted by 1 or 2 ndently selected Rg group; and each Rg is independently halo; W0 2017!]72596 each R34 is independently H or C1—4 alkyl; CyC is phenylene optionally substituted by 1 RC group; and each RC is independently halo or C1-4 alkyl.
In some embodiments: (1) A1, A2, and A3 are each a bond and RA is methyl or (3 i ethyl; or (2) A1 and A2 are each a bond; A3-RA is selected from O RA and ; ; each RA is independently selected from C1.3 alkyl; CN; OH; methylcarbonyl, ycarbonyl, N,N-dimethylaminocarbonyl; and methylsulfonyl; wherein said C1. 3 alkyl is ally substituted with a OH or OCH3 group; provided that if RA is attached to a nitrogen atom, then RA is not CN or OH; R2 is H; R3 is H; CyB is a 7;8-dihydroquinoline—2;5(1H;6H)-dione or 2-py1idone ring; which is optionally substituted with a RB group; each RB is independently methyl; ethyl; isopropyl; sec-butyl; or ; each of which is optionally substituted by 1 or 2 independently selected R12 groups; each R12 is independently selected from halo; phenyl; and OH; wherein said phenyl is optionally substituted by 1 or 2 ndently selected Rg group; each Rg is F; and EQE or éflé CyC is RC wherein RC is F; wherein the phenyl ring is attached to the pyrrolo[2;l-f] [1,2,4]tn'azine ring at left site of attachment.
In some embodiments: A1 and A2 are each a bond, A3-RA is, RA; each RA is independently selected from C1.3 alkyl, methylcarbonyl, ethylcarbonyl, iso-propylcarbonyl, N,N—dimethylaminocarbonyl, N,N- diethylaminocarbonyl, N,N—(methyl)(ethyl)aminocarbonyl and orpholin R2 is H; R3 is H; CyB is a 7,8-dihydroquinoline—2,5(lH,6H)-dione or 2,4-dioxo-l,2,3,4— tetrahydropyrimidine ring, which is optionally substituted by l or 2 independently 1O selected RB groups; each RE is ndently methyl, ethyl, isopropyl, sec-butyl, or phenyl, each of which is optionally substituted by l or 2 independently selected R12 groups; each R12 is independently selected from halo; and CyC is unsubstituted phenylene.
In some ments, the present disclosure provides compounds having Formula (Ila): or a pharmaceutically acceptable salt thereof, wherein the variables of a (IIa) are as defined in Formula (I) or any embodiments of compounds of Formula (I) as described herein In some embodiments, the present disclosure es compounds having Formula (IIal) or Formula (IIaZ): H\N\«CyB H\N‘«CyB o o NH2 NH2 N/ / / R2 JN\/ / RZRC R3J\N\ / \ , N ,N R3 N R1 R1 Hal IIa2 or a pharmaceutically acceptable salt thereof, wherein the variables of Formula (Hal) and Formula (IIa2) are as defined in Formula (I) or any embodiments of compounds of Formula (I) as described herein In some embodiments, the present disclosure provides compounds having Formula (IIbl) or Formula (IIb2): H CyI3 H C B y N\\< N~< 0 O NH2 NH2 N / / N/ / kN’N\ / KN,N\ / R1 R1 IIbl IIb2 or a pharmaceutically able salt thereof, wherein the les of Formula (IIbl) and Formula (IIb2) are as defined in Formula (I) or any embodiments of compounds of a (I) as described herein In some embodiments, the present disclosure provides compounds having Formula (IIcl) or a (IIc2): NH2 NH2 N/ / N/ / kw\ / kw\ / R1 R1 IIcl IIc2 or a pharmaceutically acceptable salt thereof, wherein the variables of a (IIcl) and Formula (IIc2) are as defined in Formula (I) or any ments of compounds of Formula (I) as described herein In some embodiments, the present disclosure provides compounds having Formula (IIdl) or Formula (IId2): NH2 NH2 N/ / N/ / kw\ / kw\ / R1 R1 IIdl IId2 or a pharmaceutically acceptable salt thereof, wherein the variables of Formula (IIdl) and Formula (IId2) are as defined in Formula (I) or any embodiments of compounds of a (I) as described herein.
In some embodiments, the present disclosure provides nds having Formula (IIel): or a pharmaceutically acceptable salt thereof, wherein the les of a (IIel) are as defined in Formula (I) or any embodiments of compounds of Formula (I) as described herein In some embodiments, the present disclosure es compounds having Formula (Hf1) or Formula (IIf2): or a pharmaceutically acceptable salt thereof, wherein the variables of Formula (Hfl) are as defined in Formula (I) or any embodiments of compounds of Formula (I) as described herein.
In some embodiments, the t disclosure provides compounds having Formula (Ilgl) or Formula (Hg2): RB\ 0 RB\ o 0 N4 0 H" N-RB N-RB H ‘ H \ N N o o NH2 NH2 N/ / N/ RC K ,N / K ,N / N N R1 R1 IIgl IIg2 or a pharmaceutically acceptable salt thereof, wherein the variables of Formula (IIgl) and Formula (IIg2) are as defined in Formula (I) or any embodiments of compounds of Formula (I) as described herein.
In some embodiments, the present disclosure es compounds having Formula (Ilg3), Formula , a (IIgS): ($2)th\ (WM—Q\N O O N% O N\( N-F N-F H ‘ H \ N N NH2 NH2 N/ RC / N/ / KWN / K ,N / R1 R1 IIg3 IIg4 or a pharmaceutically acceptable salt thereof, n the variables of Formula (IIg3), Formula (Ilg4), and Formula (IIgS) are as defined in Formula (I) or any ments of compounds of Formula (I) as described herein, and t is 0, 1, 2, 3, or 4.
In some embodiments, the present disclosure provides compounds having Formula (IIh 1 ): R\B 0 0 N4 H \ N‘RB NH2 Cyc o N’ / K ,N / or a pharmaceutically acceptable salt thereof, wherein the variables of Formula (IIhl) are as defined in Formula (I) or any ments of compounds of Formula (I) as described .
In some embodiments, the present disclosure provides compounds having Formula (IIil): \N\ B H \ R NH2 CyC O N/ / kN\ ,N / or a pharmaceutically acceptable salt thereof, n the variables of Formula (IIil) are as defined in Formula (I) or any embodiments of compounds of Formula (I) as bed herein.
In some embodiments, the present disclosure provides compounds having Formula (Illa), Formula (IVa), Formula (Va), Formula (VIa), Formula (VIla), or Formula (VIIIa): H C' H C‘ N\\< ' N1 ' N N" \S O O o \S NH2 —N NH2 —N , , N’ / N’ / RAN, R2 R2 \ / W\ / R1 R1 VIa VIIIa or a pharmaceutically acceptable salt f, wherein the variables of Formula (IIIa), Formula (IVa), Formula (Va), Formula (VIa), a (VIIa), and Formula (VIIIa) are as defined in Formula (I) or any embodiments of compounds of Formula (I) as described herein.
In some embodiments, the present disclosure provides compounds having Formula (IIIb), Formula (IVb), Formula (Vb), Formula (VIb), a (Vllb), or Formula (VIIIb): N\\(yH CB / \N o NH2 — N’ / K ,N / W0 72596 HNfiycE HN~ In some embodiments: R1 is Al-Az-A3-RA; R2 is H, halo, CN, C1-4 alkyl, C1-4 kyl, Ci-4 alkoxy, C1-4 haloalkoxy, cyano-C1-3 alkyl or C1-6 alkoxyalkyl; R3 is H, halo, CN, C1-6 alkyl, C1-6 kyl, 0R3, SR3, C(O)NRCRd, NRcRd, NR°C(O)R", NRCS(O)2Rb or S(O)2Rb; wherein said C1-6 alkyl and C1-6 haloalkyl are optionally tuted with 1, 2 or 3 substituents independently ed from halo, CN, 0R3, SR3, C(O)NRCRd, NRcRd, NRCC(O)Rb, NRCS(O)2Rb, S(O)2Rb, NRCC(O)OR3, NR"C(O)NRCRd, NRCS(O)2NRCRd and CyR3; Al is selected from a bond, CyAl, —Y—, —C1-3 alkylene—, —Ci-3 alkylene—Y—, — Y—C1-3 alkylene—, and —Ci-2 alkylene—Y—Ci.2 alkylene—, wherein said alkylene groups are each optionally substituted with l, 2, or 3 substituents independently selected from halo, CN, OH, C1-3 alkyl, C1-3 alkoxy, C1-3 haloalkyl, C1-3 koxy, amino, C1-3 alkylamino, and dl(C1-3 alkyl)amino, A2 is selected from a bond, CyAz, —Y—, —C1-3 alkylene—, —Ci-3 alkylene—Y—, — Y—Ci-3 alkylene—, and —Ci-2 alkylene—Y—Ci.2 alkylene—, wherein said alkylene groups are each ally substituted with l, 2, or 3 substituents independently selected from halo, CN, OH, C1-3 alkyl, C1-3 alkoxy, C1-3 kyl, C1-3 haloalkoxy, amino, C1-3 alkylamino, and di(C1-3 alkyl)amino, W0 2017!]72596 A3 is selected from a bond, CyA3, —Y—, —C1—3 alkylene—, —Ci-3 alkylene—Y—, — Y—C1-3 alkylene—, and —C1-2 alkylene—Y—Ci-2 alkylene—; wherein said alkylene groups are each optionally substituted with 1, 2, or 3 substituents ndently selected from halo, CN, OH, C1-3 alkyl, C1-3 alkoxy, Ci-3 haloalkyl, C1-3 haloalkoxy, amino, C1—3 alkylamino, and di(Ci-3 alkyl)amino; RA is H, C1-6 alkyl, C1-6 haloalkyl, halo, CN, N02, OR", SR", C(O)Rb1, C(O)NR°1R‘", C(O)OR31, OC(O)Rb1, OC(O)NRC1R‘", NRClR‘", NR°10R‘", NR°1C(O)R"1,NR"1C(O)ORa1,NR91C(O)NR91R‘", C(=NRel)Rb1, C(=NRel)NRC1Rd1, NR°1C(=NR61)NRCIR‘", NRC18(O)Rb1, NRcls(0)2Rbl, NRCIS(O)2NR°1R‘", S(O)Rb1, 1O S(O)NRC1R‘", S(O)2Rb1, or S(O)2NRC1R‘", n said C1-6 alkyl or C1-6 haloalkyl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from R"; Y is O, S, S(O), S(O)2, C(O), f, NRfC(O), )NRf, NRfS(O)2NRf, S(O)2NRf, NRfS(O)2, or NRf, each Rf is independently selected from H and C13 alkyl, CyAl is C3.7 cycloalkyl, phenyl, 5-6 membered heteroaryl, or 4-? membered heterocycloalkyl; n each 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl has at least one ring-forming carbon atom and 1, 2, 3, or 4 ringforming heteroatoms independently selected from N, O, and S; wherein the N and S are optionally oxidized; n a ring-forming carbon atom of C30 cycloalkyl and 4- 7 membered heterocycloalkyl is optionally substituted by oxo to form a carbonyl group; and wherein the C34 cycloalkyl, phenyl, 5-6 ed aryl, and 4-7 membered heterocycloalkyl are each ally substituted with 1, 2, 3 or 4 substituents independently selected from R", each RA1 is independently selected from OH, N02, CN, halo, C1-6 alkyl, C1-6 haloalkyl, Cl-6 alkoxy, C1-6 haloalkoxy, cyano-C1—3 alkyl, HO-C1—3 alkyl, H2N-C1—3 alkyl, amino, C1-6 alkylamino, 6 alkyl)amino, thio, C1-6 alkylthio, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, yl, C1-6 alkylcarbamyl, dl(C1-6 alkyl)carbamyl, carboxy, C145 alkylcarbonyl, C1-6 alkoxycarbonyl, C1-6 alkylcarbonylamino, Cl-6 alkylsulfonylamino, aminosulfonyl, C1-6 alkylaminosulfonyl, dl(C1-6 alkyl)aminosulfonyl, ulfonylamino, C1-6 alkylaminosulfonylamino, di(Cl-6 alkyl)aminosulfonylamino, arninocarbonylamino, C1-6 alkylaminocarbonylamino, and di(C1-6 alkyl)aminocarbonylamino; W0 2017!]72596 2017/024270 CyA2 is C3.7 cycloalkyl, phenyl, 5-6 membered heteroaryl, or 4-? membered heterocycloalkyl; wherein each 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl has at least one ring-forming carbon atom and 1, 2, 3, or 4 ringforming heteroatoms independently selected from N, O, and S; wherein the N and S are optionally oxidized; wherein a ring-forming carbon atom of C33 lkyl and 4- 7 membered heterocycloalkyl is optionally substituted by oxo to form a carbonyl group; and wherein the C34 cycloalkyl, phenyl, 5-6 ed aryl, and 4-7 membered heterocycloalkyl are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R", 1O each RA2 is independently selected from OH, N02, CN, halo, C1-6 alkyl, C1-6 haloalkyl, Cm alkoxy, C1-6 haloalkoxy, cyano-C1—3 alkyl, HO-C1—3 alkyl, H2N-C1—3 alkyl, amino, C1-6 alkylamino, di(C1—6 alkyl)amino, thio, C1-6 alkylthio, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, carbamyl, C1-6 alkylcarbamyl, di(C1-6 alkyl)carbamyl, carboxy, Cm alkylcarbonyl, C1-6 alkoxycarbonyl, C1-6 alkylcarbonylamino, Cl-6 alkylsulfonylamino, ulfonyl, C1-6 minosulfonyl, di(Cra alkyl)aminosulfonyl, aminosulfonylamino, C1-6 alkylaminosulfonylamino, di(Cl-6 alkyl)aminosulfonylamino, aminocarbonylamino, C1-6 minocarbonylamino, and di(C1-6 aminocarbonylamino; CyA3 is C3.7 cycloalkyl, , 5-6 membered heteroaryl, or 4-? membered heterocycloalkyl; wherein each 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl 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 C3.7 cycloalkyl and 4- 7 membered heterocycloalkyl is optionally substituted by oxo to form a carbonyl group; and wherein the C34 cycloalkyl, , 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from RA3, each RA3 is independently selected from OH, N02, CN, halo, C1-6 alkyl, C1-6 haloalkyl, Cl-6 alkoxy, C1-6 haloalkoxy, cyano-C1—3 alkyl, 3 alkyl, H2N-C1—3 alkyl, amino, C1-6 alkylamino, di(Cl-G alkyl)arnino, thio, C1-6 hio, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, carbamyl, C1-6 alkylcarbamyl, di(C1.6 alkyl)carbamyl, carboxy, Cl-6 alkylcarbonyl, C1-6 alkoxycarbonyl, C1-6 alkylcarbonylamino, C1-6 W0 2017!]72596 alkylsulfonylamino, aminosulfonyl, C1-6 alkylaminosulfonyl, di(C1-6 alkyl)aminosulfonyl, aminosulfonylamino, C1-6 alkylaminosulfonylamino, 6 alkyl)aminosulfonylamino, aminocarbonylamino, C1-6 alkylaminocarbonylamino, and di(C1-6 alkyl)aminocarbonylamjno; CyR3 is C3.7 cycloalkyl, phenyl, 5-6 membered heteroaryl, or 4-? membered heterocycloalkyl; wherein each 5-6 ed heteroaryl and 4-7 membered heterocycloalkyl has at least one ring-forming carbon atom and 1, 2, 3, or 4 ringforming heteroatoms independently selected from N, O, and S; wherein the N and S are optionally oxidized, wherein a ring-forming carbon atom of C3.7 lkyl and 4- 1O 7 membered heterocycloalkyl is optionally substituted by oxo to form a carbonyl group; and wherein the C34 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, CyC is ene or 5-6 membered heteroarylene; wherein the 5-6 membered heteroarylene has at least one ring-forming carbon atom and 1 or 2 ring-fonning heteroatoms independently selected from N, O, and S; and wherein the phenylene and -6 membered heteroarylene are each optionally substituted by 1, 2, 3, or 4 substituents independently selected from RC; each RC is independently selected from OH, CN, halo, C1—4 alkyl, C1—3 kyl, C14 alkoxy, C1.3 haloalkoxy, cyano-C1—3 alkyl, 3 alkyl, amino, C1—4 alkylamino, di(C1—4 alkyl)amino, C1—4 alkylsulfinyl, C1—4 alkylsulfonyl, carbamyl, C1—4 alkylcarbamyl, di(C1-4 alkyl)carbamyl, carboxy, C1.4 alkylcarbonyl, C1—4 carbonyl, C1.4 alkylcarbonylamino, C1.4 alkylsulfonylamino, aminosulfonyl, C1- 4 alkylaminosulfonyl, and di(C1-4 alkyl)aminosulfonyl, CyB is C340 cycloalkyl or 4-10 membered cycloalkyl, wherein at least one ring—forming carbon atom of C340 cycloalkyl and 4-10 membered heterocycloalkyl is substituted by oxo to form a carbonyl group, n the 4-10 membered heterocycloalkyl has at least one ring-forming 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; and wherein the C340 cycloalkyl and 4-10 ed heterocycloalkyl are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from RB; or W0 2017!]72596 CyB is 5-10 membered heteroaryl; n the 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) at least one ring-forming carbon atom of the 5-10 membered heteroaryl is substituted by oxo to form a carbonyl group; or (b) the 5—10 membered aryl is substituted by halo, CN, N02, ORaZ, SRaZ, C(O)Rb2, C(O)NR°2Rd2, C(O)OR"2, OC(O)Rb2, OC(O)NRCZRd2, NRCZRdZ, NRCZORdZ, NRC2C(O)Rb2, NRC2C(O)OR32, O)NRC2Rd2, NRCZS(O)Rb2, O)2Rb2, NRCZS(O)2NR"2Rd2, S(O)Rb2, S(O)NR"2Rd2, S(O)2Rb2, and S(O)2NRC2Rd2, and wherein the 5-10 membered 1O heteroaryl is further optionally substituted with 1, 2, 3 or 4 substituents independently selected from RB; each RB is independently selected from halo, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, CN, N02, OR‘Q, SR", C(O)Rb2, C(O)NRC2Rd2, C(O)0Ra2, OC(O)Rb2, OC(O)NR62Rd2, NRc2Rd2, NRczoRdz, NRCZC(O)Rb2, NRC2C(O)OR32, NRC2C(O)NRC2Rd2, NRCzs(O)Rb2, NRCQS(O)2R"2, NRCZS(O)2NRCZRd2, 2, S(O)NRC2Rd2, S(O)2Rb2, and S(O)2NR°2Rd2; wherein said C1-6 alkyl, C3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl, and 4-7 ed heterocycloalkyl are each ally substituted with 1, 2, 3, or 4 substituents independently selected from R"; each R11 is independently selected from CN, N02, OR", SR", C(O)Rb3, C(O)NR°3Rd3, C(O)0Ra3, OC(O)Rb3, OC(O)NRC3Rd3, 3, NR°3ORd3, NRC3C(O)R"3, NRC3C(O)OR33, NRC3C(O)NRC3Rd3, NRC3S(O)Rb3, O)2R"3, NR°3S(O)2NRC3Rd3, S(O)Rb3, S(O)NRC3Rd3, b3, and R°3Rd3; each R12 is independently selected from halo, CN, N02, C1-6 alkyl, Cl-6 kyl, C3-6 cycloalkyl, phenyl, 5-6 ed heteroaryl, 4-7 membered heterocycloalkyl, ORa", SR", C(O)Rb4, C(O)NRC4Rd4, C(O)0Ra4, OC(O)R"4, OC(O)NRC4Rd4, NRc4Rd4, NRC4ORd4, NRC4C(O)Rb4, NRC4C(O)OR34, NRc4C(0)NRc4Rd4, NRc4S(0)Rb4, NRC4S(O)2Rb4, NRc4S(0)2NRc4Rd4, S(0)Rb4, S(O)NRC4Rd4, S(O)2Rb4, and S(O)2NRC4Rd4, wherein said C1-6 alkyl, C3-6 cycloalkyl, phenyl, 5—6 membered heteroaryl, and 4-7 membered cycloalkyl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Rg; R3 is selected from H, C1-6 alkyl, and C1-6 haloalkyl; W0 2017!]72596 Rb is selected from C1-6 alkyl and C1-6 haloalkyl; RC and Rd are each independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, phenyl, 5-6 membered aryl, 4-6 membered heterocycloalkyl, C3-6 lkyl-Ci.3 alkylene, phenyl-Ci-3 alkylene, 5-6 membered heteroaryl-C1—3 alkylene, and 4-6 membered heterocycloalkyl-Cm alkylene, wherein said C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl, C3-6 cycloalkyl-C1-3 alkylene, phenyl-C1-3 alkylene, 5-6 membered heteroaryl-C1-3 alkylene, and 4-6 membered heterocycloalkyl-Ci.3 alkylene are each optionally substituted with 1, 2 or 3 substituents independently selected from Rg; 1O R31, RCl and Rdl are each independently selected from H, C1-6 alkyl, and C1-6 haloalkyl; wherein said C1-6 alkyl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from Rg, or alternatively, RCl and Rdl 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 Rbl is selected from C1-6 alkyl and C1-6 kyl, each of which is optionally substituted with 1, 2, 3, or 4 tuents ndently selected from Rg; R61 is ed from H, CN, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkylthio, C1-6 alkylsulfonyl, C1-6 alkylcarbonyl, C1-6 alkylarninosulfonyl, carbamyl, C1—6 arbamyl, dl(C1-6 alkyl)carbamyl, aminosulfonyl, C1-6 alkylaminosulfonyl, and dl(C1-6 alkyl)aminosulfonyl, each R32, Rcz, and Rdz is independently selected from H, C1-6 alkyl, Cl-6 haloalkyl, C34 cycloalkyl, , 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl; wherein said C1-6 alkyl, C3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl are each ally substituted with 1, 2, 3, or 4 substituents independently selected from R12, or alternatively, any RC2 and Rdz 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 W0 2017!]72596 each R132 is independently selected from C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, or 4 substituents independently ed from R"; each R33, RC3 and Rd3 is independently ed from H, C1-6 alkyl, Cm kyl, C3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, C3-6 cycloalkyl-C1.4 alkylene, phenyl-C1-4 alkylene, 5-6 membered heteroaryl-CM alkylene, and 4-7 membered heterocycloalkyl-C1-4 alkylene; wherein said C1-6 alkyl, C3-6 cycloalkyl, phenyl, 5-6 ed heteroaryl, 4-7 membered 1O heterocycloalkyl, C3-6 cycloalkyl-C1.4 alkylene, -C1-4 alkylene, 5-6 membered heteroaryl-CM ne, and 4-7 membered cycloalkyl-C14 alkylene are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Rg; alternatively, any RC3 and Rd3 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 or 3 substituents independently selected from each R[)3 is independently selected from C1-6 alkyl, C1-6 haloalkyl, C34 cycloalkyl, phenyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, C3-6 cycloalkyl-CM alkylene, phenyl-C1-4 alkylene, 5-6 membered heteroaryl-C1-4 ne, and 4-7 membered heterocycloalkyl-C14 ne, each of which is optionally substituted with 1, 2, 3, or 4 substituents independently ed from Rg; each R", RC4 and Rd", is independently selected from H, C1-6 alkyl, and C1-6 haloalkyl; wherein said C1-6 alkyl is optionally substituted with 1, 2, 3, or 4 substituents independently ed from Rg, or alternatively, any RC4 and Rd4 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 each R134 is independently selected from C1-6 alkyl and C1-6 haloalkyl, each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from Rg; and W0 2017!]72596 each Rg is independently selected from OH, N02, CN, halo, C1-6 alkyl, C1-6 kyl, Cl-6 alkoxy, C1-6 haloalkoxy, cyano-C1-3 alkyl, HO-C1-3 alkyl, H2N—C1—3 alkyl, amino, C1-6 alkylamino, dl(C1-6 alky1)amino, thio, C1-6 alkylthio, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, carbamyl, C1-6 alkylcarbamyl, 6 alkyl)carbamy1, carboxy, Cl-6 alkylcarbonyl, C1-6 carbonyl, C1-6 alkylcarbonylamino, Cl-6 alkylsulfonylamino, ulfonyl, C1-6 alkylaminosulfonyl, dl(C1-6 alkyl)aminosulfonyl, ulfonylamino, C1-6 alkylaminosulfonylamino, dl(Cl-6 alkyl)arninosulfonylamino, aminocarbonylamino, C1-6 alkylaminocarbonylamino, and dl(C1-6 alkyl)aminocarbonylamino, 1O provided that: 1) Al-AZ-A3 is not Y-Y when one of A1, A2 or A3 is a bond, or Y—Y-Y; and 2) when A3 is —Y— or —C1-3 alkylene—Y— then RA is H, C1-6 alkyl, or Cl-6 haloalkyl, wherein said C1-6 alkyl or C1-6 haloalkyl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from R".
In some embodiments: R1 is Al-Az-A3-RA; R2 is H, halo, CN, C1-4 alkyl, or C1-4 haloalkyl; R3 is H, halo, CN, C1-6 alkyl, or C1-6 haloalkyl; Al is selected from a bond, CyAl, —Y—, —C1.3 alkylene—, —C1-3 alkylene—Y—, and —Y—C1-3 ne—; A2 is selected from a bond, CyAz, —Y—, —C1—3 alkylene—, —C1—3 alkylene—Y—, and —Y—C1-3 alkylene—; A3 is selected from a bond, CyA3, —Y—, —C1.3 alkylene—, —C1-3 ne—Y—, and —Y—C1-3 alkylene—, RA is H, C1-6 alkyl, C1-6 haloalkyl, halo, CN, N02, ORE", SR", C(O)Rb1, C(O)NRCIR‘", C(O)0Ra1, OC(O)Rb1, OC(O)NRC1R‘", NRCle1,NRC1C(O)Rb1, NRC1C(O)OR31, S(O)Rb1, S(O)NRC1R‘", b1, or S(O)2NRC1R‘"; wherein said C1-6 alkyl or Cm haloalkyl is optionally substituted with 1, 2, 3 or 4 substituents independently ed from R", Y is O, S, S(O), S(O)2, or C(O), CyA1 is C3-7 cycloalkyl, phenyl, 5-6 membered heteroaryl, or 4-? membered heterocycloalkyl; wherein each 5-6 membered heteroaIyl and 4-7 membered W0 2017!]72596 cycloalkyl has at least one ring-forming carbon atom and 1, 2, 3, or 4 ring- forrning heteroatoms independently ed from N, O, and S, n the N and S are optionally oxidized; wherein a ring-forming carbon atom of CM cycloalkyl and 4- 7 membered heterocy cloalkyl is optionally substituted by oxo to form a carbonyl group; and wherein the C34 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 R", each RAl is independently selected from OH, N02, CN, halo, C1-6 alkyl, C1-6 haloalkyl, Cl-6 alkoxy, C1-6 koxy, cyano-C1—3 alkyl, HO-C1—3 alkyl, H2N—C1—3 1O alkyl, amino, C1-6 alkylamino, di(Cre alkyl)amino, thio, C1-6 alkylthio, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, carbamyl, C1-6 arbamyl, 6 alkyl)carbamyl, y, Cl-6 alkylcarbonyl, C1-6 alkoxycarbonyl, C1-6 alkylcarbonylamino, Cl-6 alkylsulfonylamino, aminosulfonyl, C1-6 alkylaminosulfonyl, di(Cl-G aminosulfonyl, aminosulfonylamino, C1-6 alkylaminosulfonylamino, 6 alkyl)aminosulfonylamino, aminocarbonylamino, C1—6 alkylaminocarbonylamino, and dl(C1-6 alkyl)aminocarbonylamino, CyA2 is C3-7 cycloalkyl, phenyl, 5-6 membered heteroaryl, or 4-? membered heterocycloalkyl; n each 5-6 membered heteroaryl and 4-7 ed heterocycloalkyl 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 C30 lkyl and 4- 7 membered heterocycloalkyl is optionally substituted by oxo to form a carbonyl group; and wherein the C34 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 R", each RA2 is independently selected from OH, N02, CN, halo, C1-6 alkyl, C1-6 haloalkyl, Cl-6 alkoxy, C1-6 haloalkoxy, cyano-C1—3 alkyl, HO-C1—3 alkyl, H2N-C1—3 alkyl, amino, C1-6 alkylamino, dl(C1-6 alkyl)amino, thio, C1-6 alkylthio, C1-6 alkylsulfinyl, C1—6 alkylsulfonyl, carbamyl, C1-6 alkylcarbamyl, di(Cra alkyl)carbamyl, carboxy, Cl-6 alkylcarbonyl, C1-6 alkoxycarbonyl, C1-6 alkylcarbonylamino, Cl-6 alkylsulfonylamino, aminosulfonyl, C1-6 alkylaminosulfonyl, di(Cl-G alky1)aminosulfonyl, aminosulfonylamino, C1-6 alkylaminosulfonylamino, di(Cl-6 W0 2017!]72596 alkyl)aminosulfonylamino, aminocarbonylamino, C1-6 alkylaminocarbonylamino, and 6 alkyl)aminocarbonylamino; CyA3 is C3-7 cycloalkyl, phenyl, 5-6 membered heteroaryl, or 4-? membered heterocycloalkyl; wherein each 5-6 membered aryl and 4-7 ed cycloalkyl has at least one ring-forming carbon atom and 1, 2, 3, or 4 ringforming heteroatoms independently selected from N, O, and S; wherein the N and S are optionally oxidized; wherein a ring-forming carbon atom of C3: cycloalkyl and 4- 7 membered heterocycloalkyl is optionally substituted by oxo to form a carbonyl group; and wherein the C34 cycloalkyl, phenyl, 5-6 membered heteroaryl, and 4-7 1O membered heterocycloalkyl are each optionally substituted with l, 2, 3 or 4 substituents independently selected from RA3, each RA3 is independently selected from OH, N02, CN, halo, C1-6 alkyl, Cl-G haloalkyl, Cl-6 alkoxy, C1-6 haloalkoxy, cyano-C1—3 alkyl, 3 alkyl, H2N-C1—3 alkyl, amino, C1-6 alkylamino, dl(C1-6 amino, thio, C1-6 alkylthio, Cl-6 alkylsulfinyl, Cm ulfonyl, carbamyl, C1-6 alkylcarbamyl, dl(C1-6 alkyl)carbamyl, y, Cl-6 alkylcarbonyl, C1-6 alkoxycarbonyl, C1-6 alkylcarbonylamino, C1-6 alkylsulfonylamino, aminosulfonyl, C1-5 alkylaminosulfonyl, di(Cl-G alkyl)aminosulfonyl, aminosulfonylamino, C1-6 alkylarrfinosdfonylamino, di(Cl-6 alkyl)aminosulfonylamino, aminocarbonylamino, C1-6 alkylaminocarbonylamino, and dl(C1-6 aminocarbonylamino; CyC is phenylene or 5-6 membered arylene; wherein the 5-6 membered heteroarylene has at least one ring-forming carbon atom and 1 or 2 ring-forming heteroatoms ndently selected from N, O, and S; and wherein the phenylene and -6 membered heteroarylene are each optionally substituted by l, 2, 3, or 4 substituents independently selected from RC, each RC is independently selected from OH, CN, halo, C1—4 alkyl, C1—3 haloalkyl, C14 alkoxy, C1.3 haloalkoxy, cyano-C1—3 alkyl, HO-C1-3 alkyl, amino, C1—4 alkylamino, di(C1-4 alkyl)amino, C1.4 alkylsulfinyl, C1.4 alkylsulfonyl, carbamyl, C1—4 alkylcarbamyl, di(C1-4 alkyl)carbamyl, carboxy, C1.4 alkylcarbonyl, C1—4 alkoxycarbonyl, C1-4 alkylcarbonylamino, C1-4 alkylsulfonylamino, ulfonyl, C1. 4 alkylaminosulfonyl, and di(C1.4 alkyl)aminosulfonyl; W0 2017!]72596 CyB is €3.10 cycloalkyl or 4-10 membered heterocycloalkyl; wherein at least one ring-forming carbon atom of C340 cycloalkyl and 4-10 membered heterocycloalkyl is substituted by oxo to form a carbonyl group; wherein the 4-10 ed heterocycloalkyl 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; and wherein the C340 cycloalkyl and 4-10 membered heterocycloalkyl are each optionally substituted with l, 2, 3 or 4 substituents independently selected from RB, or CyB is 6-10 membered aryl or 5-10 membered aryl, wherein the 5-10 1O membered heteroaryl has at least one ring-forming carbon atom and 1, 2, 3, or 4 ring- g heteroatoms independently selected from N, O, and S, wherein the N and S are optionally oxidized; wherein: (a) at least one ring-forming carbon atom of the 5- membered heteroaryl is substituted by oxo to form a carbonyl group; or (b) the 6- membered aryl or 5-10 ed heteroaryl is substituted by halo, CN, N02, 0Ra2, SR", 2, C(O)NRCZRd2, C(0)0Ra2, 0C(0)Rb2, OC(O)NRC2Rd2, NRCZRdZ, NRC20Rd2, NRC2C(O)Rb2, NRCZC(O)OR32, NRC2C(O)NRC2R‘12, NRdS(O)R"2, O)2R'°2, NR°ZS(O)2NR°2Rd2, S(O)Rb2, S(O)NR°2Rd2, S(O)2Rb2, and S(O)2NR°2Rd2; and wherein the 6-10 membered aryl or 5-10 membered heteroaryl is further ally substituted with l, 2, 3 or 4 substituents independently selected from RB; each RB is independently selected from halo, C1-6 alkyl, C1-6 kyl, C3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, CN, N02, ORaZ, SRaZ, C(O)Rb2, C2Rd2, a2, OC(O)Rb2, OC(O)NR°2Rd2, NRcleZ, NRC20Rd2, O)Rb2, NRC2C(O)ORa2, NRC2C(O)NRCZRd2, NRCZS(O)Rb2, NRCZS(O)2R"2, NRCZS(O)2NRCZRd2, S(O)Rb2, S(O)NRC2Rd2, S(O)2Rb2, and S(O)2NR62Rd2; wherein said C1-6 alkyl, C3-6 lkyl, phenyl, 5-6 ed heteroaryl, and 4-7 membered heterocycloalkyl are each optionally substituted with l, 2, 3, or 4 substituents independently selected from R", each R11 is independently selected from CN, N02, ORa3, SRa3, C(O)Rb3, C(O)NRC3Rd3, C(O)OR33, OC(O)Rb3, OC(O)NRC3Rd3, NRC3Rd3, NRC3ORd3, NRC3C(O)R"3, NRC3C(O)OR33, NRC3C(O)NRC3Rd3, NRC3S(O)Rb3, NRC3S(O)2Rb3, NRC3S(O)2NRC3Rd3, S(O)Rb3, S(O)NRC3Rd3, S(O)2Rb3, and S(O)2NR°3Rd3; W0 2017!]72596 each R12 is independently selected from halo, CN, N02, C1-6 alkyl, Cl-6 haloalkyl, C3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, ORa", SRa", 4, C(O)NRC4Rd4, C(O)OR34, OC(O)Rb4, OC(O)NR°4Rd4, NR°4Rd4, NRC4ORd4, NRC4C(O)Rb4, NRC4C(O)OR34, NRC4C(O)NR°4Rd4, NRC4S(O)Rb4, NRC4S(O)2R"4, NRC4S(O)2NRC4Rd4, S(O)Rb4, S(O)NR°4Rd4, S(O)2Rb4, and S(O)2NRC4Rd4, n said C1-6 alkyl, C34 lkyl, phenyl, 5-6 membered heteroaryl, and 4-7 ed heterocycloalkyl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Rg; R31, RCl and Rdl are each independently selected from H, C1-6 alkyl, and C1-6 1O haloalkyl, wherein said C1-6 alkyl is optionally tuted with 1, 2, 3, or 4 substituents independently selected from Rg, or alternatively, RC1 and Rdl 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 tuted with 1, 2 or 3 substituents independently selected from Rg; Rbl is selected from C1-6 alkyl and C1-6 kyl, each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from Rg; each R32, RC2, and R‘12 is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl, and 4—7 membered heterocycloalkyl; wherein said C1-6 alkyl, C3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl, and 4-7 membered cycloalkyl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R", or alternatively, any RC2 and Rdz ed 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 each R132 is independently selected from C1-6 alkyl, C1-6 haloalkyl, C345 cycloalkyl, phenyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, or 4 substituents independently ed from R"; each R33, RC3 and R‘13 is independently selected from H, C1-6 alkyl, Cl-6 kyl, C3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl, 4-7 membered W0 172596 heterocycloalkyl, C3-6 lkyl-C1-4 alkylene, phenyl-Ci-4 alkylene, 5-6 membered heteroaryl-CM alkylene, and 4-7 membered heterocycloalkyl-C14 alkylene, wherein said C1-6 alkyl, C3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl, 4-7 ed heterocycloalkyl, C3-6 cycloalkyl-Ci-4 alkylene, phenyl-C1-4 alkylene, 5-6 membered heteroaryl-CM alkylene, and 4-7 membered heterocycloalkyl-C14 alkylene are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Rg; alternatively, any RC3 and Rd3 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 1O group optionally substituted with 1, 2 or 3 substituents independently selected from each R133 is ndently selected from C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, C3-6 cycloalkyl-CH ne, phenyl-C1-4 alkylene, 5-6 membered aryl-C1-4 alkylene, and 4-? membered heterocycloalkyl-C14 alkylene, each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from Rg; each R34, RC4 and R", is independently ed from H, C1-6 alkyl, and C1-6 haloalkyl, wherein said C14; alkyl is ally substituted with 1, 2, 3, or 4 substituents independently selected from Rg, or alternatively, any RC4 and Rd4 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 each Rb4 is independently selected from C1-6 alkyl and C1-6 haloalkyl, each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from Rg; and each Rg is independently selected from OH, N02, CN, halo, C1-6 alkyl, C1-6 haloalkyl, Cl-6 alkoxy, C1-6 haloalkoxy, cyano-C1—3 alkyl, HO-C1—3 alkyl, H2N-C1—3 alkyl, amino, C1-6 alkylamino, d1(C1-6 alky1)amino, thio, C1-6 alkylthio, Cl-6 alkylsulfinyl, C1-6 alkylsulfonyl, carbamyl, C1-6 alkylcarbamyl, dl(C1-6 carbamyl, carboxy, Cl-6 alkylcarbonyl, C1-6 alkoxycarbonyl, C1-6 alkylcarbonylamino, C1-6 alkylsulfonylamino, aminosulfonyl, C1-6 minosulfonyl, dl(C1-6 W0 2017!]72596 alkyl)aminosulfonyl, aminosulfonylamino, C1-6 alkylaminosulfonylamino, di(Cl-6 alkyl)aminosulfonylamino, aminocarbonylamino, C1-6 alkylaminocarbonylamino, and dl(C1-6 alkyl)aminocarbony1amino; provided that: 1) Al-AZ-A3 is not Y-Y when one of A1, A2 or A3 is a bond, or Y-Y—Y; and 2) when A3 is —Y— or —C1-3 alkylene—Y— then RA is H, C1-6 alkyl, or Cl-6 haloalkyl, wherein said C1-6 alkyl or C1-6 kyl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from R". 1O In some embodiments: R1 is Al-AZ-A3-RA, R2 is H, halo or C1—4 alkyl, R3 is H, halo or C1-6 alkyl, Al is selected from a bond, —Y—, and —C1.3 alkylene—, A2 is selected from a bond, —Y—, and —C1.3 alkylene—, A3 is selected from a bond, CyA3, —Y—, and —C1—3 alkylene—; RA is H, C1-6 alkyl, C1-6 haloalkyl, halo, CN, ORal, SR", C(O)Rb1, C(O)NR°1R‘", C(O)OR31, NRCIR‘", NR91C(O)Rb1, 1, S(O)NRC1R‘", b1, or S(O)2NRC1R‘"; wherein said C1-6 alkyl or C1-6 haloalkyl is optionally substituted with 1, 2, 3 or 4 tuents independently selected from R", Y is O, S, S(O), S(O)2, or C(O), CyA3 is C3.7 cycloalkyl, phenyl, 5-6 membered heteroaryl, or 4-? membered heterocycloalkyl; wherein each 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl 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 ring-forming carbon atom of C34 cycloalkyl and 4- 7 ed heterocycloalkyl is ally substituted by oxo to form a carbonyl group; and wherein the C34 cycloalkyl, phenyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl are each optionally substituted with 1, 2, 3 or 4 substituents independently ed from RA3, each RA3 is independently ed from OH, CN, halo, C1-6 alkyl, C1-6 haloalkyl, Cl-6 alkoxy, C1-6 haloalkoxy, cyano-C1-3 alkyl, HO-C1-3 alkyl, H2N-C1-3 alkyl, amino, C1-6 alkylamino, di(C1-6 alky1)amino, thio, C1-6 alkylthio, Cl-6 W0 2017!]72596 alkylsulfinyl, C1-6 alkylsulfonyl, carbamyl, C1-6 alkylcarbamyl, dl(C1-6 alkyl)carbamyl, carboxy, C14 alkylcarbonyl, and C14 alkoxycarbonyl; CyC is phenylene, wherein the ene is optionally substituted by 1, 2, 3, or 4 substituents independently selected from RC; each RC is ndently selected from OH, CN, halo, C1—4 alkyl, C1—3 haloalkyl, C14 alkoxy, C1.3 haloalkoxy, cyano-C1—3 alkyl, HO-C1-3 alkyl, amino, C1—4 alkylamino, and di(C1-4 alkyl)amino, CyB is C340 cycloalkyl or 4-10 membered heterocycloalkyl; wherein at least one ring-forming carbon atom of C340 cycloalkyl and 4-10 membered 1O heterocycloalkyl is substituted by oxo to form a carbonyl group; wherein the 4-10 membered heterocycloalkyl 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, and wherein the C340 cycloalkyl and 4-10 ed heterocycloalkyl are each optionally substituted with 1, 2, 3 or 4 substituents independently ed from RB; or CyB is 6-10 membered aryl or 5-10 ed heteroaryl; wherein the 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; n the N and S are optionally oxidized; wherein at least one ring-forming carbon atom of the 5—10 membered heteroaryl is substituted by oxo to form a carbonyl group; and wherein the 6-10 membered aryl or 5-10 membered heteroaryl is further optionally substituted with 1, 2, 3 or 4 substituents independently ed from RB, each RB is independently selected from halo, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, phenyl, 5-6 ed heteroaryl, 4-7 membered heterocycloalkyl, CN, N02, ORaZ, SRaZ, C(0)Rb2, C(O)NRC2Rd2, C(0)0Ra2, NRCZRdZ, NRC2C(O)R"2, NRCZS(O)R"2, NRczs(0)2Rb2, NRCZS(O)2NRC2Rd2, S(O)Rb2, S(O)NRC2Rd2, S(0)2Rb2, and S(O)2NRCZRd2; wherein said C1-6 alkyl, 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 ed from R"; each R11 is independently selected from CN, OR", SRa3, C(O)Rb3, C(O)NRC3Rd3, C(O)OR33, NRC3R‘13, NRC3C(O)Rb3, NRC3C(O)OR33, NRC3S(O)R'33, W0 2017!]72596 NRC3S(O)2R'33, NRC3S(O)2NRC3Rd3, S(O)Rb3, S(O)NRC3Rd3, S(O)2Rb3, and S(O)2NRC3Rd3; each R12 is independently selected from halo, CN, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, , 5-6 membered heteroaryl, 4-7 ed heterocycloalkyl, OR", SR", C(O)Rb4, C(O)NRC4Rd4, C(O)OR34, NRC4Rd4, NRC4C(O)Rb4, NR°4C(O)OR34, NRC4S(O)Rb4, NRC4S(O)2Rb4, NRc4S(0)2NRc4Rd4, S(O)Rb4, S(O)NRC4Rd4, S(O)2Rb4, and S(O)2NRC4Rd4, wherein said C1-6 alkyl, C3-6 cycloalkyl, phenyl, 5-6 membered aryl, and 4-7 ed heterocycloalkyl are each optionally substituted with l, 2, 3, or 4 substituents independently selected from Rg; 1O R31, RCl and Rdl are each independently selected from H, C1-6 alkyl, and C1-6 haloalkyl; wherein said C1-6 alkyl is optionally substituted with l, 2, 3, or 4 substituents ndently selected from Rg, Rbl is selected from C1-6 alkyl and C1-6 haloalkyl, each of which is optionally substituted with l, 2, 3, or 4 substituents independently selected from Rg; each R32, R62, and R‘12 is independently selected from H, C1-6 alkyl, Cl-6 kyl, C3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl; wherein said C1-6 alkyl, C3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl are each optionally tuted with l, 2, 3, or 4 substituents independently selected from R"; each Rb2 is independently selected from C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl, each of which is optionally substituted with l, 2, 3, or 4 substituents independently selected from R12; each R33, RC3 and Rd3 is independently selected from H, C1-6 alkyl, Cl-6 haloalkyl, C3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, C3-6 lkyl-C1.4 alkylene, phenyl-C1-4 alkylene, 5-6 membered heteroaryl-CM alkylene, and 4-7 membered cycloalkyl-C1-4 alkylene; wherein said C1-6 alkyl, C3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, C3-6 cycloalkyl-C1.4 alkylene, -C1-4 alkylene, 5-6 membered heteroaryl-CM alkylene, and 4-7 membered heterocycloalkyl-C14 alkylene are each ally tuted with 1, 2, 3, or 4 substituents ndently selected from Rg; W0 2017/‘172596 each R133 is independently selected from C1-6 alkyl, C1-6 haloalkyl, C3-6 lkyl, phenyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, C3-6 cycloalkyl-CM alkylene, phenyl-C1-4 ne, 5-6 membered heteroaryl-C 1.4 alkylene, and 4-? membered heterocycloalkyl-C1-4 alkylene, each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from Rg; each R34, RC4 and R", is independently selected from H, C1-6 alkyl, and C1-6 haloalkyl, wherein said C1-6 alkyl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from Rg, each Rb4 is ndently selected from C1-6 alkyl and C1-6 haloalkyl, each of 1O which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from Rg; and each Rg is independently selected from OH, N02, CN, halo, C1-6 alkyl, C1-6 haloalkyl, Cl-6 alkoxy, C1-6 haloalkoxy, C1—3 alkyl, HO-C1—3 alkyl, H2N-C1—3 alkyl, amino, C1-6 alkylamino, dl(C1-6 alkyl)arnino, thio, C1-6 alkylthio, Cl-6 ulfinyl, C1—6 alkylsulfonyl, carbamyl, C1-6 alkylcarbamyl, dl(C1-6 alkyl)carbamyl, carboxy, Cl-6 alkylcarbonyl, C1-6 alkoxycarbonyl, C1-6 alkylcarbonylamino, C1-6 alkylsulfonylamino, ulfonyl, C1-6 alkylaminosulfonyl, di(Cl-G aminosulfony1, aminosulfonylamino, C1-6 alkylanfinosrflfonylamino, di(Cl-6 a1kyl)aminosulfony1arnino, arninocarbonylarnino, C1-6 alkylarninocarbonylamino, and di(C 1-6 alkyl)arninocarbony1arnino; provided that: 1) Al—AZ-A3 is not Y-Y when one of A1, A2 or A3 is a bond, or Y-Y-Y; and 2) when A3 is —Y— or —C1-3 alkylene—Y— then RA is H, C1-6 alkyl, or Cl-6 haloalkyl, wherein said C1-6 alkyl or C1-6 haloalkyl is optionally substituted with 1, 2, 3 or 4 substituents ndently selected from R".
In some embodiments: R1 is Al-Az-A3-RA; R2 is H or C14 alkyl; R3 is H or C1-6 alkyl; Al is selected from a bond and —C1—3 alkylene—; A2 is selected from a bond and —C1.3 alkylene—; A3 is selected from a bond, CyA3, and —C1.3 alkylene—; W0 2017!]72596 RA is H, C1-6 alkyl, CN, ORal, C(O)Rb1, C(O)NRC1R‘", C(O)OR31, NRCIR‘", NRC1C(O)Rb1, S(O)Rb1, S(O)NRCle1, S(O)2Rb1, or S(O)2NRCIR‘"; wherein said C1-6 alkyl is optionally tuted with 1, 2, 3 or 4 substituents independently selected from R"; CyA3 is C3.7 cycloalkyl, phenyl, 5-6 membered heteroaryl, or 4-? membered cycloalkyl; n each 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl has at least one ring-forming carbon atom and 1, 2, 3, or 4 ringforming heteroatoms independently ed from N, O, and S; wherein the N and S are optionally oxidized, n a orming carbon atom of C3.7 cycloalkyl and 4- 1O 7 membered heterocycloalkyl is ally substituted by oxo to form a carbonyl group, and wherein the C34 cycloalkyl, phenyl, 5-6 membered heteroaryl, and 4-7 membered cycloalkyl are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R", each RA3 is independently selected from OH, CN, halo, C1-6 alkyl, Cm kyl, and C1-6 alkoxy; CyC is phenylene, wherein the phenylene is optionally substituted by 1, 2, 3, or 4 substituents independently selected from RC; each RC is independently selected from OH, CN, halo, C1-4 alkyl, C1-3 kyl, C14 alkoxy, and C1-3 haloalkoxy, CyB is C340 cycloalkyl or 4-10 membered heterocycloalkyl; wherein at least one ring-forming carbon atom of C3—10 cycloalkyl and 4-10 membered heterocycloalkyl is substituted by oxo to form a carbonyl group; wherein the 4-10 membered heterocycloalkyl 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, and wherein the C340 cycloalkyl and 4-10 membered heterocycloalkyl are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from RB, or CyB is 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl has at least one ring-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatoms ndently selected from N, O, and S, wherein the N and S are optionally oxidized; wherein at least one ring-forming carbon atom of the 5-10 membered heteroaryl is substituted by oxo to form a carbonyl group; and wherein the 5-10 W0 2017!]72596 membered heteroaryl is further optionally substituted with 1, 2, 3 or 4 substituents independently selected from RB; each RB is independently selected from halo, C1-6 alkyl, C1-6 haloalkyl, phenyl, ORaZ, SR", C(O)Rb2, C(O)NRC2Rd2, and C(O)OR32; wherein said C1-6 alkyl and phenyl are each optionally substituted with l, 2, 3, or 4 substituents independently selected from R12; each R11 is independently selected from CN or ORa3; each R12 is independently ed from halo, CN, C1-6 alkyl, C1-6 kyl, phenyl, ORa", C(O)Rb4, C(O)NRC4Rd4, and C(O)ORa4, wherein said C1-6 alkyl, C3-6 1O cycloalkyl, phenyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, or 4 tuents independently selected from R31, RCl and R(11 are each independently ed from H, C1-6 alkyl, and C1-6 haloalkyl, wherein said C1-6 alkyl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from Rg, Rbl is selected from C1-6 alkyl and C1-6 haloalkyl, each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from Rg; each R32, RC2, and R‘12 is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, and phenyl; wherein said C1-6 alkyl and phenyl are each optionally substituted with l, 2, 3, or 4 substituents independently selected from R"; each sz is independently selected from C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, and phenyl, each of which is optionally tuted with 1, 2, 3, or 4 substituents independently selected from R12, each Ra3 is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, phenyl, phenyl-C14 alkylene, wherein said C1-6 alkyl, , and -C14 alkylene are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from each R34, RC4 and R", is independently selected from H, C1-6 alkyl, and C1-6 haloalkyl, wherein said C1-6 alkyl is optionally substituted with 1, 2, 3, or 4 substituents ndently selected from Rg, W0 2017!]72596 each R134 is independently selected from C1-6 alkyl and C1-6 haloalkyl, each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from Rg; and each Rg is independently selected from OH, N02, CN, halo, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, cyano-C1—3 alkyl, HO-C1—3 alkyl, H2N-C1—3 alkyl, amino, C1-6 alkylamino, and dl(C1-6 alkyl)amino.
In some embodiments: R1 is A3-RA, (1) wherein said A1, A2, and A3 are each a bond, and RA is C1-6 alkyl or C(O)NRC1R‘", (2) wherein said A1 is a bond, A2 is a bond or —C1—3 1O alkylene—, A3 is CyA3, and RA is C1—6 alkyl, CN, ORa1,NRC1Rd1, C(O)Rb1, C(O)NRCIR‘", a1, or S(O)2Rb1; wherein said C1-6 alkyl of RA is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R", or (3) n Al is CyAl, A2 is a bond or C(O), A3 is CyA3, and RA is H; R2 is H; R3 is H; CyAl is C3.7 lkyl or 4-7 membered heterocycloalkyl; wherein the 4-7 membered heterocycloalkyl 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 ring-forming carbon atom ofCM cycloalkyl and 4-? membered heterocycloalkyl is optionally tuted by oxo to form a carbonyl group; CyA3 is C3.7 cycloalkyl, 6 membered heteroaryl, or 4-7 membered heterocycloalkyl; wherein each 6 membered heteroaryl and 4-7 membered cycloalkyl 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 orming carbon atom of C34 cycloalkyl and 4- 7 ed heterocycloalkyl is optionally substituted by oxo to form a carbonyl group; and wherein the C34 cycloalkyl, 6 ed heteroaryl, and 4-? membered heterocycloalkyl are each optionally substituted with 1, 2, 3 or 4 C1-6 alkyl; CyB is €3.10 cycloalkyl or 4-10 membered heterocycloalkyl; wherein at least one ring-forming carbon atom of C340 cycloalkyl and 4-10 membered heterocycloalkyl is substituted by oxo to form a carbonyl group; wherein the 4-10 W0 2017!]72596 membered heterocycloalkyl has at least one ring-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O, and S; and wherein the C340 cycloalkyl and 4-10 membered heterocycloalkyl are each optionally tuted with 1 or 2 tuents independently selected from RB; or CyB is 5-10 membered heteroaryl, having one ring-forming carbon atom which is substituted with oxo to form a carbonyl group and 1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O, and S, n the N and S are optionally oxidized; wherein the 5-10 membered heteroaryl is further optionally tuted with l, 2, 3 or 4 substituents independently selected from RB; 1O each RE is independently selected from C1-6 alkyl, C2-6 alkynyl, CN, halo, phenyl, 5-6 membered heteroaryl, C34 cycloalkyl, 4-7 membered heterocycloalkyl, ORaZ, C(O)Rb2, and C(O)NRC2Rd2, wherein said C1-6 alkyl, C2-6 l, phenyl, 5-6 membered heteroaryl, C34 cycloalkyl, and 4-7 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R"; CyC is phenylene optionally substituted by 1, 2, 3, or 4 substituents independently selected from RC; each RC is independently selected from halo and C14 alkyl; each R11 is independently OR213 or C(O)NRC3Rd3; each R12 is independently selected from halo, C1-6 alkyl, CN, phenyl, and ORa4; each R", R", and Rdl is independently selected from H and C1-6 alkyl; each Rbl is independently selected from C1-6 alkyl, each R33, RC3, Rd3 and R214 is independently selected from H and C1-6 alkyl; and each Raz, R132, RC2, and Rdz is independently selected from H, C1-6 alkyl, and phenyl; n said C1-6 alkyl and phenyl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R12.
In some embodiments: R1 is Al-AZ-A3-RA, (1) wherein said A1, A2, and A3 are each a bond, and RA is C1-6 alkyl, or (2) wherein said A1 is a bond, A2 is a bond or — C1.3 alkylene—, A3 is CyA3, and RA is C1-6 alkyl, CN, OR", NRCIR‘", C(O)Rb1, "R‘", C(O)OR31, or S(O)2Rb1, n said C1-6 alkyl of RA is ally substituted with 1, 2, 3, or 4 substituents ndently selected from R"; R2 is H; W0 2017!]72596 R3 is H; CyA3 is C3-7 cycloalkyl, 6 ed heteroaryl, or 4-7 membered heterocycloalkyl; wherein each 6 membered heteroaryl and 4-7 membered heterocycloalkyl 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 C34 cycloalkyl and 4- 7 membered heterocycloalkyl is optionally tuted by oxo to form a carbonyl group; CyB is C340 cycloalkyl or 4-10 membered heterocycloalkyl, wherein at least 1O one ring-forming carbon atom of C340 cycloalkyl and 4-10 membered heterocycloalkyl is tuted by oxo to form a carbonyl group, wherein the 4-10 membered heterocycloalkyl has at least one ring-forming carbon atom and 1, 2, 3, or 4 ring—forming heteroatoms ndently ed from N, O, and S; and wherein the C340 cycloalkyl and 4-10 membered heterocycloalkyl are each optionally substituted with 1 or 2 substituents independently selected from RB, or CyB is 5-10 membered heteroaryl, having one ring-forming carbon atom which is substituted with oxo to form a carbonyl group 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 the 5-10 membered heteroaryl is further optionally substituted with l, 2, 3 or 4 substituents independently selected from RB; each RB is ndently selected from C1-6 alkyl, phenyl, OR", and C(O)NR°2Rd2; n said C1-6 alkyl and phenyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from R12, Cyc is phenylene optionally substituted by 1, 2, 3, or 4 tuents independently selected from RC, each RC is independently selected from halo and C14 alkyl, each R11 is independently ORa3, each R12 is independently selected from halo, phenyl, and OR"; each R31, R61, and R(11 is independently selected from H and C1-6 alkyl; each Rbl is independently selected from C1-6 alkyl, each Ra3 and Ra4 is independently selected from H and C1-6 alkyl; and W0 2017!]72596 each R32, R62, and R‘12 is independently selected from H, C1-6 alkyl, and phenyl; n said C1—6 alkyl and phenyl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R".
In some embodiments: R1 is Al-AZ-A3-RA, (1) wherein said A1, A2, and A3 are each a bond, and RA is C1-6 alkyl, or (2) wherein said A1 and A2 are each a bond, A3 is CyA3, and RA is C1-6 alkyl, CN, OR", C(O)Rb1, C(O)NRC1R‘", C(O)OR31, or S(O)2Rb1; wherein said C1-6 alkyl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R", R2 is H; 1O R3 is H; CyA3 is C3.7 cycloalkyl or 4-7 membered heterocycloalkyl, wherein the 4-7 membered cycloalkyl has at least one ring-forming carbon atom and 1, 2, 3, or 4 ring—forming heteroatoms ndently selected from N, O, and S; wherein a ring- forming carbon atom of C34 lkyl and 4-7 membered cycloalkyl is optionally substituted by oxo to form a yl group; CyB is 5-10 membered heterocycloalkyl; wherein the 5-10 membered heterocycloalkyl has at least one orming carbon atom and 1, 2, 3, or 4 ringforming heteroatoms independently selected from N, O, and S, wherein at least one ring-forming carbon atom of 5-10 membered heterocycloalkyl is substituted by oxo to form a carbonyl group; and wherein the 5-10 membered heterocycloalkyl is optionally substituted with l or 2 substituents independently selected from RB; or CyB is 5-10 membered heteroaryl, having one ring-forming carbon atom which is substituted with oxo to form a carbonyl group 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 the 5-10 membered heteroaryl is further ally substituted with 1, 2, 3 or 4 substituents independently ed from RB; each RB is independently selected from C1-6 alkyl and phenyl; wherein said C1— 6 alkyl and phenyl are ally substituted with 1, 2, 3, or 4 substituents independently selected from R12; CyC is phenylene optionally substituted by 1, 2, 3, or 4 substituents independently selected from RC; each RC is independently halo; W0 2017!]72596 each R11 is independently OR", each R12 is independently selected from halo, , and OR"; each R31, R", and R‘11 is independently selected from H and C1-6 alkyl; each R[)1 is independently selected from C1-6 alkyl; and each R33 and Ra4 is independently selected from H and C1-6 alkyl.
In some ments: R1 is Al-AZ-A3-RA, (1) wherein said A1, A2, and A3 are each a bond, and RA is C1-6 alkyl, or (2) wherein said A1 and A2 are each a bond, A3 is CyA3, and RA is C1-6 alkyl, CN, OR", C(O)Rb1, C(O)NRC1R‘", C(O)OR31, or S(O)2Rb1; wherein said C1-6 alkyl is optionally substituted with 1, 2, 3, or 4 substituents 1O independently ed from R", R2 is H; R3 is H; CyA3 is C3.7 cycloalkyl or 4-7 membered heterocycloalkyl; wherein the 4-7 membered heterocycloalkyl 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 a ring— forrning carbon atom of C34 cycloalkyl and 4-7 membered heterocycloalkyl is optionally substituted by oxo to form a carbonyl group; CyB is 5-6 membered aryl, having one ring-forming carbon atom which is substituted with oxo to form a carbonyl group and 1 or 2 ring—forming heteroatoms independently ed from N, O, and S; wherein the N and S are optionally oxidized; wherein the 5-6 membered heteroaryl is further optionally tuted with 1 or 2 substituents ndently ed from RB, each RB is independently selected from C1-6 alkyl and phenyl; wherein said C1— 6 alkyl and phenyl are optionally substituted with 1, 2, 3, or 4 substituents independently selected from R12, Cyc is phenylene optionally substituted by 1, 2, 3, or 4 substituents independently selected from RC, each RC is independently halo, each R11 is independently OR", each R12 is independently selected from halo, phenyl, and OR"; each R", R", and R‘11 is independently selected from H and C1-6 alkyl; each Rb1 is independently selected from C1-6 alkyl; and W0 2017!]72596 each R33 and R34 is independently selected from H and C1-6 alkyl.
In some embodiments: R1 is Al-A2-A3-RA, (1) wherein said A1, A2, and A3 are each a bond, and RA is Cm alkyl, or (2) wherein said A1 and A2 are each a bond, A3 is CyA3, and RA is C1-6 alkyl, CN, OR", 1, C(O)NRCIRC", C(O)OR31, or S(O)2Rb1, wherein said C1-6 alkyl is optionally substituted with l, 2, 3, or 4 substituents independently selected from R"; R2 is H; R3 is H; CyA3 is C3.7 cycloalkyl or 4-7 membered heterocycloalkyl; wherein the 4-7 1O ed heterocycloalkyl has at least one orming carbon atom and 1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O, and S; wherein a ring- forrning carbon atom of C34 cycloalkyl and 4-7 ed cycloalkyl is optionally substituted by oxo to form a carbonyl group, CyB is 5—10 membered cycloalkyl, wherein the 5-10 membered heterocycloalkyl has at least one ring-forming carbon atom and 1, 2, 3, or 4 ringforrning heteroatoms independently selected from N, O, and S; wherein at least one ring-forming carbon atom of 5-10 membered cycloalkyl is substituted by oxo to form a carbonyl group; and wherein the 5-10 membered heterocycloalkyl is optionally substituted with 1 or 2 substituents independently selected from RB; wherein each RB is independently selected from C1-6 alkyl and phenyl; wherein said C1—6 alkyl and phenyl are optionally substituted with 1, 2, 3, or 4 substituents independently selected from R"; CyC is phenylene ally substituted by 1, 2, 3, or 4 substituents independently selected from RC, each RC is independently halo, each R11 is independently ORa3, each R12 is independently selected from halo, phenyl, and OR"; each R31, R61, and Rd1 is independently selected from H and C1-6 alkyl; each Rbl is ndently selected from C1-6 alkyl; and each R33 and R34 is independently selected from H and C1-6 alkyl.
In some embodiments: R1 is Al-AZ-A3-RA, (1) wherein said A1, A2, and A3 are each a bond, and RA is C1-6 alkyl, or (2) wherein said A1 and A2 are each a bond, A3 is W0 2017!]72596 CyA3, and RA is C1-6 alkyl, CN, OR", C(O)Rb1, C(O)NRC1R‘", C(O)OR31, or S(O)2Rb1; wherein said Cm alkyl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R"; R2 is H; R3 is H; CyA3 is C3.7 cycloalkyl or 4-7 membered heterocycloalkyl; wherein the 4-7 membered heterocycloalkyl 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 a ring- forming carbon atom of C34 cycloalkyl and 4-7 membered heterocycloalkyl is 1O optionally substituted by oxo to form a carbonyl group; CyB is 5-10 membered heterocycloalkyl; wherein the 5-10 membered heterocycloalkyl has at least one ring-forming carbon atom and 1, 2, 3, or 4 ringforming heteroatoms independently selected from N, O, and S; wherein at least one ring-forming carbon atom of 5-10 membered heterocycloalkyl is substituted by oxo to form a yl group; and wherein the 5-10 membered heterocycloalkyl is optionally tuted with l or 2 tuents independently selected from RB; or CyB is 5-10 membered heteroaryl, having one ring-forming carbon atom which is substituted with oxo to form a carbonyl group and 1, 2, 3, or 4 orming heteroatoms independently selected from N, O, and S; n the N and S are optionally oxidized; wherein the 5-10 membered heteroaryl is further optionally substituted with l, 2, 3 or 4 substituents independently selected from RB; each RB is independently selected from C1-6 alkyl and phenyl; wherein said C1— 6 alkyl and phenyl are optionally substituted with l, 2, 3, or 4 substituents independently selected from R12; Cyc is phenylene optionally tuted by l, 2, 3, or 4 substituents independently selected from RC; each RC is independently halo, each R11 is ndently ORa3; each R12 is independently selected from halo, phenyl, and OR"; each R", R", and R(11 is independently selected from H and C1-6 alkyl; alternatively, RCl and R‘11 attached to the same N atom, together with the N atom to which they are attached, form a 6-membered heterocycloalkyl group; W0 2017!]72596 each Rbl is independently selected from C1-6 alkyl; and each Ra3 and Ra4 is independently selected from H and C1-6 alkyl.
In some embodiments: R1 is Al-AZ-A3-RA, (1) wherein said A1, A2, and A3 are each a bond, and RA is C14; alkyl, or (2) wherein said A1 and A2 are each a bond, A3 is CyA3, and RA is C1-6 alkyl, CN, OR", C(O)Rb1, C(O)NR"1RC", C(O)OR31, or S(O)2Rb1; n said C1-6 alkyl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R", R2 is H; R3 is H; 1O CyA3 is C3.7 cycloalkyl or 4-7 ed heterocycloalkyl, wherein the 4-7 membered heterocycloalkyl 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 a ring- forming carbon atom of C34 cycloalkyl and 4-7 membered heterocycloalkyl is optionally substituted by oxo to form a carbonyl group, CyB is 5-6 membered aryl, having one orming carbon atom which is substituted with 0x0 to form a carbonyl group and 1 or 2 orming heteroatoms independently selected from N, O, and S; wherein the N and S are optionally oxidized; wherein the 5-6 membered heteroaryl is further optionally substituted with 1 or 2 substituents independently selected from RB; each RB is independently selected from C1-6 alkyl and phenyl; wherein said C1— 6 alkyl and phenyl are optionally substituted with 1, 2, 3, or 4 substituents ndently selected from R12, CyC is phenylene optionally substituted by 1, 2, 3, or 4 substituents independently ed from RC, each RC is independently halo, each R11 is independently ORa3, each R12 is independently selected from halo, phenyl, and OR"; each R31, R61, and Rd1 is independently selected from H and C1-6 alkyl; alternatively, RCl and R‘11 attached to the same N atom, together with the N atom to which they are attached, form a 6-membered heterocycloalkyl group; each Rbl is independently selected from C1-6 alkyl; and each R33 and R84 is independently selected from H and C1-6 alkyl.
W0 2017!]72596 In some embodiments: R1 is A3-RA, (1) wherein said A1, A2, and A3 are each a bond, and RA is C1-6 alkyl, or (2) wherein said A1 and A2 are each a bond, A3 is CyA3, and RA is C1-6 alkyl, CN, OR", C(O)Rb1, C(O)NRC1Rd1, 31, or S(O)2Rb1; wherein said C1-6 alkyl is optionally substituted with l, 2, 3, or 4 substituents independently selected from R"; R2 is H; R3 is H; CyA3 is C3.7 cycloalkyl or 4-7 membered heterocycloalkyl, wherein the 4—7 membered heterocycloalkyl has at least one ring-forming carbon atom and 1, 2, 3, or 1O 4 ring-forming heteroatoms independently selected from N, O, and S, wherein a ring- forming carbon atom of C34 cycloalkyl and 4-7 membered heterocycloalkyl is optionally substituted by oxo to form a carbonyl group, CyB is 5-10 membered heterocycloalkyl, wherein the 5-10 membered heterocycloalkyl 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 at least one ring-forming carbon atom of 5-10 membered heterocycloalkyl is substituted by oxo to form a carbonyl group; and wherein the 5-10 membered heterocycloalkyl is ally substituted with 1 or 2 substituents independently ed from RB; wherein each RB is ndently selected from C1-6 alkyl and ; wherein said C1-6 alkyl and phenyl are optionally substituted with l, 2, 3, or 4 substituents independently selected from R"; CyC is phenylene optionally substituted by l, 2, 3, or 4 substituents ndently selected from RC, each RC is independently halo, each R11 is independently ORa3, each R12 is independently selected from halo, phenyl, and OR"; each R31, R61, and Rdl is independently selected from H and C1-6 alkyl; atively, RCl and Rdl attached to the same N atom, together with the N atom to which they are attached, form a 6-membered heterocycloalkyl group; each Rbl is independently selected from C1-6 alkyl; and each Ra3 and Ra4 is independently selected from H and C1-6 alkyl.
W0 2017!]72596 In some embodiments: R1 is Al-AZ-A3-RA, (1) wherein said A1, A2, and A3 are each a bond, and RA is C(O)NRCIR‘11 or C1-6 alkyl; or (2) wherein said A1 is a bond, A2 is a bond or —C1.3 alkylene—, A3 is CyA3, and RA is H, C1-6 alkyl, CN, ORE", C(O)Rb1, C(O)NR°1R‘", NRCIR‘", C(O)OR31, or S(O)2Rb1; wherein said C1-6 alkyl is optionally substituted with l, 2, 3, or 4 substituents ndently selected from R"; (3) n A1 is CyAl, A2 is Y, Y is C(O), A3 is CyA3, and RA is H; or (4) wherein Al is a bond, A2 is CyAz, A3 is CyA3, wherein RA is C1-6 alkyl, R2 is H; R3 is H; 1O CyA3 is 5-6 membered heteroaryl, C34 lkyl or 4-7 membered heterocycloalkyl; wherein the 4-7 membered heterocycloalkyl 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 a orming carbon atom of C34 cycloalkyl and 4-7 membered heterocycloalkyl is optionally substituted by oxo to form a carbonyl grOUp; CyB is 5-10 membered heterocycloalkyl, wherein the 5-10 membered heterocycloalkyl has at least one ring-forming carbon atom and l, 2, 3, or 4 ringforming heteroatoms independently selected from N, O, and S; wherein at least one orming carbon atom of 5-10 membered heterocycloalkyl is substituted by 0x0 to form a carbonyl group; and wherein the 5-10 membered heterocycloalkyl is optionally substituted with l or 2 substituents independently selected from RB, each RB is independently selected from halo, CN, C1-6 alkyl, C2-6 alkynyl, C3-6 cycloalkyl, 5—6 membered heteroaryl, 4-7 ed heterocycloalkyl, phenyl, ORaZ, C(O)Rb2, C(O)NRC2Rd2, wherein said C1-6 alkyl, C2-6 alkynyl, C3-6 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, and phenyl are optionally substituted with 1, 2, 3, or 4 substituents independently selected from R"; CyC is phenylene ally substituted by 1, 2, 3, or 4 substituents independently selected from RC, each RC is ndently halo, each R11 is independently OR33 or C(O)NRC3Rd3; each R12 is independently selected from halo, CN, C1-6 alkyl, and OR"; each R31, R", and R‘11 is independently selected from H and C1-6 alkyl; W0 2017I172596 2017/024270 alternatively, RCl and R(11 attached to the same N atom, together with the N atom to which they are attached, form a 6-membered heterocycloalkyl group; each Rb1 is independently selected from C1-6 alkyl; and each R33 and Ra4 is ndently selected from H and C1-6 alkyl.
In some embodiments, CyB is CyB—l CyB-2 CyB-3 _N‘ HN HN \ N=\ \ NH , Nl\ NH Ho , ’2\ E , ,2\ SNH 0 0 O CyB-8 CyB-9 CyB-IO CyB-ll wherein CyB-l, CyB-2, CyB-3, CyB-8, CyB-9, CyB-10, CyB-4, and CyB—ll are each optionally substituted with 1, 2 or 3 independently selected RB groups; R1 is Al-AZ-A3-RA, (1) wherein said A1, A2, and A3 are each a bond, and RA is C(O)NR°1Rdl or C1-6 alkyl; or (2) wherein said A1 is a bond, A2 is a bond or —C1—3 alkylene—, A3 is CyA3, and RA is H, C1-6 alkyl, CN, OR", C(O)Rb1, C(O)NR°1R‘", NRCIR‘", C(O)ORa1, or S(O)2Rb1, wherein said C1-6 alkyl is ally substituted with 1, 2, 3, or 4 substituents ndently selected from R", (3) wherein Al is CyAl, A2 is Y, Y is C(O), A3 is CyA3, and RA is H, or (4) wherein A1 is a bond, A2 is CyAZ, A3 is CyA3, n RA is C1-6 alkyl, R2 is H; R3 is H; CyA3 is 5-6 membered heteroaryl, C34 cycloalkyl or 4-7 membered heterocycloalkyl; wherein the 4-7 membered heterocycloalkyl 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 a ring-forming carbon atom of C34 cycloalkyl and 4-7 membered heterocycloalkyl is optionally substituted by oxo to form a carbonyl group; W0 2017!]72596 each RB is independently selected from halo, CN, C1-6 alkyl, C2-6 alkynyl, C3—6 cycloalkyl, 5-6 membered heteroaryl, 4-7 ed heterocycloalkyl, phenyl, ORaz, C(O)Rb2, C(O)NRC2Rd2, wherein said C1-6 alkyl, C2-6 l, C3-6 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, and phenyl are optionally substituted with 1, 2, 3, or 4 substituents independently selected from R"; CyC is ene optionally substituted by 1, 2, 3, or 4 tuents independently selected from RC, each RC is independently halo, each R11 is independently OR213 or C(O)NRC3Rd3, 1O each R12 is independently ed from halo, CN, C1-6 alkyl, and OR"; each R31, RC1, and Rdl is independently selected from H and C1-6 alkyl; alternatively, RC1 and Rdl attached to the same N atom, together with the N atom to which they are attached, form a 6-membered heterocycloalkyl group; each Rbl is independently ed from C1-6 alkyl; and each R33 and R34 is independently selected from H and C1-6 alkyl.
It is further appreciated that certain features of the invention, which are, for clarity, bed in the context of separate embodiments, can also be provided in combination in a single embodiment. Conversely, various features of the invention which are, for brevity, described in the context of a single embodiment, can also be provided separately or in any suitable bination.
At various places in the present specification, substituents of compounds provided herein are disclosed in groups or in ranges. It is specifically intended that the invention include each and every individual subcombination of the members of such groups and ranges. For example, the term "Ci—6 alkyl" is specifically intended to individually disclose methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl.
At n 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 any ring member provided that the valency of the atom is not exceeded. For example, an azetidine ring may be attached at any position of the ring, whereas an azetidinyl ring is attached at the 3-position.
W0 2017!]72596 2017/024270 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 heterocycloalkyl ring, pyrazolyl is an e of a 5-membered heteroaryl ring, pyridyl is an e of a 6- membered heteroaryl ring, and 1,2,3,4-tetrahydro-naphthalene is an example of a 10- membered cycloalkyl group.
For compounds ed herein in which a variable s more than once, each variable can be a ent moiety independently selected from the group defining the variable. For example, where a structure is described having two R 1O groups that are simultaneously present on the same compound, the two R groups can represent different moieties independently selected from the group defined for R. In another example, when an optionally multiple tuent is designated in the form: (f)(R), then it is to be understood that substituent R can occur p number of times on the ring, and R can be a different moiety at each occurrence. It is to be understood that each R group may replace any en atom attached to a ring atom, including one or both of the (CH2)n hydrogen atoms. Further, in the above example, should the variable Q be defined to include hydrogens, such as when Q is said to be CH2, NH, etc, any floating substituent such as R in the above example, can replace a hydrogen of the Q variable as well as a hydrogen in any other non-variable component of the ring.
As used herein, the phrase nally substituted" means unsubstituted or substituted. The substituents are independently selected, and substitution may be at any chemically accessible position. As used herein, 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 en atoms. It is to be understood that substitution at a given atom is limited by valency.
Throughout the definitions, the term "Cm—m" indicates a range which es the endpoints, wherein n and m are integers and indicate the number of carbons.
Examples include C1-4, C1-6, and the like.
As used herein, the term "Cu—m alkyl", employed alone or in combination with other terms, refers to a saturated arbon group that may be straight-chain or W0 2017!]72596 2017/024270 branched, having n to m carbons. 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 homologs such as ylbutyl, n-pentyl, 3- pentyl, n-hexyl, 1,2,2-trimethylpropyl, and the like. In some embodiments, 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.
As used herein, "Cu—m l" refers to an alkyl group having one or more double carbon—carbon bonds and having 11 to m carbons. Example alkenyl groups include, but are not d to, ethenyl, n-propenyl, isopropenyl, n-butenyl, sec— 1O butenyl, and the like. In some embodiments, the alkenyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms.
As used herein, "Cu—m alkynyl" refers to an alkyl group having one or more triple carbon-carbon bonds and having 11 to m carbons. Example alkynyl groups include, but are not limited to, l, 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.
As used herein, the term "Cn—m alkylene", employed alone or in combination with other terms, refers to a divalent alkyl g group having 11 to m carbons.
Examples of alkylene groups include, but are not limited to, ethan-1,1-diyl, ethan-l,2- diyl, propan-1,l,-diyl, propan-l,3-diyl, propan-l,2-diyl, butan—l,4—diyl, butan-1,3- diyl, butan-1,2-diyl, 2-methyl-propan-l,3-diyl, and the like. In some embodiments, the alkylene moiety contains 2 to 6, 2 to 4, 2 to 3, l to 6, l to 4, or 1 to 2 carbon atoms.
As used herein, the term "Cu—m alkoxy", employed alone or in ation with other terms, refers to a group of a -O-alkyl, wherein the alkyl group has n to m carbons. Example alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (e. g., n-propoxy and isopropoxy), butoxy (e. g., n-butoxy and tert- butoxy), and the like. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.
As used herein, the term "Cu—m alkylamino" refers to a group of formula -NH(alkyl), n the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. Examples of alkylamino groups include, but are not d to, N-methylamino, N-ethylamino, N- W0 2017!]72596 propylamino (e.g., N—(n-propyl)amino and N-isopropylamino), N—butylamino (e.g., N- (n-butyl)amino and N—(tert—butyl)amino), and the like.
As used herein, the term "Cm—m alkoxycarbonyl" refers to a group of formula -C(O)O-alkyl, wherein the alkyl group has n to m carbon atoms. In some ments, the alkyl group has I to 6, I to 4, or 1 to 3 carbon atoms. Examples of carbonyl groups include, but are not limited to, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl (e.g., n-propoxycarbonyl and poxycarbonyl), butoxycarbonyl (e.g., n-butoxycarbonyl and tert-butoxycarbonyl), and the like.
As used herein, the term "Cu—m alkylcarbonyl" refers to a group of 1O formula -C(O)-alkyl, wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, l to 4, or 1 to 3 carbon atoms. Examples of alkylcarbonyl groups include, but are not limited to, carbonyl, ethylcarbonyl, propylcarbonyl (e. g., n-propylcarbonyl and isopropylcarbonyl), butylcarbonyl (e.g., nbutylcarbonyl and tert—butylcarbonyl), and the like.
As used herein, the term "Cu—m alkylcarbonylarnino" refers to a group of formula -NHC(O)—alkyl, wherein the alkyl group has n to In carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.
As used herein, the term "Cu—m alkylsulfonylamino" refers to a group of formula -NHS(O)2-alkyl, wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, l to 4, or 1 to 3 carbon atoms.
As used herein, the term sulfonyl" refers to a group of formula -S(O)2NH2.
As used herein, the term "Cu—m alkylaminosulfonyl" refers to a group of formula -S(O)2NH(alkyl), wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, l to 4, or 1 to 3 carbon atoms.
As used herein, the term "di(Cn.m aminosulfonyl" refers to a group of a —S(O)2N(alkyl)2, wherein each alkyl group independently has n to m carbon atoms. In some embodiments, each alkyl group has, independently, 1 to 6, 1 to 4, or 1 to 3 carbon atoms.
As used herein, the term "aminosulfonylamino" refers to a group of formula - NHS(O)2NH2.
W0 2017!]72596 As used herein, the term "Cn—m minosulfonylarnino" refers to a group of formula -NHS(O)2NH(alkyl), wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.
As used herein, the term "di(Cn-m alkyl)aminosulfonylamino" refers to a group of formula -NHS(O)2N(a1ky1)2, wherein each alkyl group independently has n to m carbon atoms. In some ments, each alkyl group has, independently, 1 to 6, l to 4, or 1 to 3 carbon atoms.
As used herein, the term "aminocarbonylamino", employed alone or in combination with other terms, refers to a group of formula -NHC(O)NH2. 1O As used herein, the term "Cu—m alkylaminocarbonylamino" refers to a group of formula —NHC(O)NH(alkyl), wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.
As used herein, the term "di(Cn.m alkyl)aminocarbonylamino" refers to a group of formula )N(a1ky1)2, n each alkyl group independently has n to m carbon atoms. In some embodiments, each alkyl group has, independently, l to 6, 1 to 4, or 1 to 3 carbon atoms.
As used herein, the term "Cm—m arbamyl" refers to a group of formula -C(O)-NH(a1kyl), wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.
As used herein, the term "thio" refers to a group of formula —SH.
As used herein, the term "Cu—m alkylthio" refers to a group of formula —S-alkyl, wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, l to 4, or 1 to 3 carbon atoms.
As used herein, the term "Cu—m alkylsulfinyl" refers to a group of formula -S(O)-alkyl, wherein the alkyl group has n to m carbon atoms. In some ments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.
As used herein, the term "Cu—m alkylsulfonyl" refers to a group of a —S(O)2-a1ky1, wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.
As used herein, the term "amino" refers to a group of formula —NH2.
As used herein, the term "carbamyl" to a group of formula —C(O)NH2.
W0 2017!]72596 As used herein, the term "carbonyl", employed alone or in combination with other terms, refers to a —C(=O)— group, which may also be written as C(O).
As used herein, the term "carboxy" refers to a -C(O)OH group.
As used herein, the term "cyano-Ci-3 alkyl" refers to a group of formula -(C1-3 alkylene)—CN.
As used herein, the term "HO-C13 alkyl" refers to a group of formula —(C1—3 alkylene)—OH.
As used herein, the term "HO-C1-3 alkyl" refers to a group of a —(C1-3 alkylene)—OH. 1O As used herein, the term "di(Cn.m-alkyl)amino" refers to a group of formula - N(alky1)2, n the two alkyl groups each has, independently, n to m carbon atoms. In some embodiments, each alkyl group independently has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.
As used herein, the term "di(Cn-m-alkyl)carbamyl" refers to a group of formula —C(O)N(alkyl)2, wherein the two alkyl groups each has, independently, n to m carbon atoms. In some embodiments, each alkyl group independently has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.
As used herein, "halo" refers to F, Cl, Br, or I. In some embodiments, halo is F, C1, or Br. In some embodiments, halo is F or Cl.
As used herein, "Cu—m koxy" refers to a group of formula —O—haloalkyl having n to m carbon atoms. An example haloalkoxy group is OCF3. In some embodiments, the haloalkoxy group is ated only. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.
As used herein, the term "Cu—m haloalkyl", employed alone or in combination with other terms, refers to an alkyl group having from one halogen atom to 25+1 halogen atoms which may be the same or different, where "s" is the number of carbon atoms in the alkyl group, wherein the alkyl group has n to m carbon atoms. In some embodiments, the haloalkyl group is fluorinated only. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.
As used herein, "cycloalkyl" refers to non-aromatic cyclic hydrocarbons ing cyclized alkyl and/or alkenyl groups. Cycloalkyl groups can e mono- or polycyclic (e.g., having 2, 3 or 4 fused rings) groups and spirocycles. Ring- W0 2017!]72596 forming carbon atoms of a cycloalkyl group can be optionally substituted by oxo or sulfido (e.g., C(O) or C(S)). Also ed in the definition of cycloalkyl are moieties that have one or more aromatic rings fused (i.e., having a bond in common with) to the cycloalkyl ring, for example, 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 including a ring-forming atom of the fused aromatic ring. Cycloalkyl groups can have 3, 4, 5, 6, 7, 8, 9, or 10 ring-forming carbons (C340). In some embodiments, the cycloalkyl is a C340 monocyclic or ic cycloalkyl. In some embodiments, the cycloalkyl is a C34 monocyclic 1O cycloalkyl. In some embodiments, the cycloalkyl is a C340 monocyclic or ic non-aromatic carbocycle, which optionally has ring members which have oxo (=0) or sulfido (=S) substitution and which optionally has a phenyl or 5-6 membered aromatic heterocycle fused to the non-aromatic n of the ring structure, wherein the heterocycle has 1-3 ring members independently ed from N, S, or O. In some embodiments, the cycloalkyl is a C34 monocyclic non-aromatic carbocycle, which optionally has ring members which have oxo (=0) or sulfido (=S) substitution and which optionally has a phenyl or 5-6 membered aromatic heterocycle fused to the non-aromatic portion of the ring structure, wherein the heterocycle has 1-3 ring members independently selected from N, S, or O. In some embodiments, the cycloalkyl is a C34 clic lkyl. Example cycloalkyl groups e cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, eptatrienyl, norbomyl, norpinyl, norcamyl, and the like. In some embodiments, cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
As used herein, the term "aryl," employed alone or in combination with other terms, refers to an aromatic arbon group, which may be monocyclic or polycyclic (e.g., having 2, 3 or 4 fused rings). Examples of aryl rings include, but are not limited to, phenyl, l-naphthyl, 2-naphthyl, and the like. In some ments, aryl groups have from 6 to 10 carbon atoms or 6 carbon atoms. In some embodiments, the aryl group is a monocyclic or bicyclic group. In some embodiments, the aryl group is phenyl or naphthyl. In some embodiments, the aryl group is phenyl.
W0 72596 2017/024270 As used herein, the term "phenylene", refers to a divalent phenyl linking group. In some embodiments, the phenylene is optionally substituted as described herein.
As used herein, "heteroaryl" refers to a monocyclic or polycyclic aromatic heterocycle having at least one heteroatom ring member ed from sulfur, oxygen, and en. In some embodiments, the heteroaryl ring has 1, 2, 3, or 4 heteroatom ring members independently selected from nitrogen, sulfur and oxygen. In some embodiments, any ring-forming N in a heteroaryl moiety can be an N-oxide. In one embodiment the heteroaryl group is a 5 to 10 membered heteroaryl group. In another 1O embodiment the heteroaryl group is a 5 to 6 membered heteroaryl group. In certain embodiments, the heteroaryl group is a monocyclic or bicyclic ic ring system having 5 to 10 ring-forming atoms, wherein 1 to 4 ring-forming atoms are atoms independently selected from N, O, and S, wherein the N and S as ring members are each optionally oxidized, the carbon ring s may be optionally replaced by carbonyl. In another preferred embodiment, the heteroaryl group is a monocyclic aromatic ring system having 5 to 6 ring-forming atoms, n 1 to 4 ring-forming atoms are heteroatoms independently selected from N, O, and S, wherein the N and S as ring members are each optionally ed, the carbon ring members may be optionally replaced by carbonyl.
In some embodiments, the heteroaryl is a five-membered or six—membereted heteroaryl ring. A embered aryl ring is a heteroaryl with a ring 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 are thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, lyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 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 with a ring having six ring atoms wherein one or more (e.g., 1, 2, or 3) ring atoms are independently selected from N, O, and S. Exemplary six-membered ring heteroaryls are pyridyl, pyrazinyl, pyrimidinyl, triazinyl, pyridone, uracil and zinyl. In some embodiments, pyridone is substituted e.g., 1-methylpyridin-2(1H)-one and 1-phenylpyridin-2(1H)- one. In some embodiments, uracil is substituted with, e.g., phenyl, isopropyl, and W0 2017!]72596 pyridinyl. In some embodiments, uracil is substituted with phenyl and isopropyl, e.g., 1-isopropyl-2,4-dioxopheny1-1,2,3,4-tetrahydropyrimidine. In some ments, uracil is substituted with pyridinyl and isopropyl, e.g., ropyl-2,4-dioxo inyl)—1,2,3,4-tetrahydropyrimidine.
As used herein, the term "heteroarylene", refers to a divalent heteroaryl g group. In some embodiments, the heteroarylene is ally substituted as described herein.
As used herein, "heterocycloalkyl" refers to non-aromatic monocyclic or polycyclic heterocycles having one or more ring-forming heteroatoms selected from 1O O, N, or S. Included in cycloalkyl are monocyclic 4-, 5-, 6-, 7 -, 8-, 9- or 10- membered heterocycloalkyl groups. Heterocycloalkyl groups can also include spirocycles. Example cycloalkyl groups include pyrrolidin-Z-one, 1,3- isoxazolidin-Z-one, pyranyl, tetrahydropuran, oxetanyl, azetidinyl, morpholino, thiomorpholino, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, azepanyl, benzazapene, and the like. Ring—forming carbon atoms and heteroatoms of a heterocycloalkyl group can be optionally substituted by oxo or sulfido (erg, C(O), S(O), C(S), or S(O)2, etc). The heterocycloalkyl group can be attached through a ring-forming carbon atom or a ring- forming heteroatom, In some embodiments, the heterocycloalkyl group contains 0 to 3 double bonds. In some embodiments, the heterocycloalkyl group contains 0 to 2 double bonds. Also included in the definition of heterocycloalkyl are moieties that have one or more aromatic rings fused (i.€., having a bond in common with) to the cycloalkyl ring, for example, benzo or thienyl tives of piperidine, morpholine, 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. In some ments, the heterocycloalkyl group is a morpholine ring, pyrrolidine ring, piperazine ring, piperidine ring, dihydropyran ring, tetrahydropyran ring, tetrahyropyridine, ine ring, or tetrahydrofuran ring. In certain embodiments, the heterocyloalkyl group is a monocyclic or bicyclic non- aromatic ring or ring system having 4 to 10 ring-forming atoms, n 1 to 4 ring- forming atoms are heteroatoms independently selected from N, O, and S, wherein the W0 2017!]72596 N and S as ring members are each optionally oxidized, the carbon ring s may be optionally replaced by carbonyl, and the heterocycloalkyl group can be optionally fused to a 5-6 membered aryl or phenyl ring, wherein the 5-6 membered heteroaryl ring may have 1-3 heteroatom ring members ndently selected from N, S, and O. In another embodiment, the heterocyloalkyl group is a clic non- aromatic ring or ring system having 4 to 6 ring-forming atoms, wherein 1 to 2 ring- forrning atoms are heteroatoms independently selected from N, O, and S, wherein the N and S as ring members are each optionally oxidized, the carbon ring members may be optionally replaced by carbonyl, and the heterocycloalkyl group can be optionally 1O fused to a 5-6 membered heteroaryl or phenyl ring, wherein the 5-6 membered heteroaryl ring may have 1-3 heteroatom ring members independently selected from N, S, and O. In some embodiments, a IO-membered heterocycloalkyl group is 7,8- dihydroquinoline—2,5(1H,6H)-dione. In some embodiments, a 6-membered heterocycloalkyl group is pipendinyl, piperazinyl, or tetrahydropyranyl.
In some embodiments, the aryl group (e.g., phenyl), aryl group, heterocycloalkyl group, or cycloalkyl group as used herein (e.g., in variables CyAl, CyAZ, CyA3, CyC etc.) can be a terminal group or an internal group (e.g., a divalent linker). In some embodiments, the terms aryl, heteroaryl, heterocycloalkyl, and cycloalkyl and their corresponding arylene, heteroarylene, hetercycloalkylene and cycloalkylene terms are used interchangeably. A skilled artisan would readily recognize whether such a group is a terminal substituent or a linker based on the ure, the substituents bed herein, and the context in which such a term appears. For example, even though the disclosure may list phenyl in the ion of es such as CyAZ, depending on the substitution pattern, the disclosure also covers ene .
As used herein, "Cu—m cycloalkyl-Co.p alkylene" refers to a group of formula — alkylene-cycloalkyl, wherein the cycloalkyl group has n to m ring members and the alkylene group has 0 to p carbon atoms.
As used herein, "Cm—m heterocycloalkyl-Co.p alkylene" refers to a group of formula —alkylene—heterocycloalkyl, n the heterocycloalkyl group has n to m ring members and the alkylene group has 0 to p carbon atoms.
W0 72596 As used , "phenyl-Co—p alkylene" refers to a group of formula —alkylene— phenyl, wherein the ne group has 0 to p carbon atoms.
As used herein, "Cm-m aryl-Co.p ne" refers to a group of formula — alkylene-aryl, wherein the aryl group has n to m ring members and the alkylene group has 0 to p carbon atoms, As used herein, "Cu—m heteroaryl-Cw alkylene" refers to a group of formula — alkylene-heteroaryl, wherein the heteroaryl group has n to m ring members and the alkylene group has 0 to p carbon atoms.
As used herein, the term "oxo" refers to an oxygen atom as a divalent 1O substituent, g a carbonyl group when attached to a carbon (e.g., C=O), or attached to a heteroatom forming a sulfoxide or sulfone group.
At certain places, the definitions or embodiments refer to specific rings (e.g., an azetidine ring, a pyridine ring, etc). Unless otherwise ted, these rings can be attached to any ring member provided that the valency of the atom is not ed.
For example, an azetidine ring may be attached at any position of the ring, whereas a pyridin—3—yl ring is attached at the 3-position.
The compounds described herein can be asymmetric (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise ted, Compounds of the present disclosure that contain asymmetrically substituted carbon atoms can be isolated in optically active or racerrric 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 es or by stereoselective synthesis. Many geometric isomers of olefins, C=N double bonds, and the like can also be present in the nds described herein, and all such stable isomers are contemplated in the present sure. Cis and trans geometric isomers of the compounds of the present disclosure are described and may be isolated as a mixture of isomers or as separated isomeric forms. In some ments, the compound has the (R)-confrguration. In some embodiments, the compound has the (SQ-configuration.
Resolution of racemic mixtures of compounds can be carried out by any of numerous methods known in the art. An example method includes fractional recrystallizaion using a chiral resolving acid which is an optically active, salt-forming W0 2017!]72596 organic acid. Suitable resolving agents for fractional recrystallization methods are, for example, 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 -camphorsulfonic acid.
Other resolving agents suitable for onal crystallization methods include stereoisomerically pure forms of OL-methylbenzylamine (e.g., S and R forms, or diastereomerically pure forms), 2-phenylglycinol, norephedn'ne, ine, N- methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane, and the like.
Resolution of racemic mixtures can also be carried out by elution on a column 1O packed with an optically active resolving agent (6. g., dinitrobenzoylphenylglycine).
Suitable elution solvent composition can be determined by one skilled in the art.
Compounds provided herein also include tautomeric forms. Tautomeric forms result from the swapping of a single bond with an adjacent double bond together with the itant migration of a proton. Tautomeric forms include prototropic tautomers which are isomeric protonation states having the same empirical formula and total charge. Example prototropic tautomers include ketone — enol pairs, amide - imidic acid pairs, lactam — lactim pairs, enamine — imine pairs, and annular forms where a proton can occupy two or more positions of a heterocyclic , for example, 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 riate substitution.
All compounds, and pharmaceutically acceptable salts thereof, can be found together with other substances such as water and solvents (e.g. hydrates and solvates) or can be isolated.
In some embodiments, ation of compounds can involve the addition of acids or bases to affect, for example, catalysis of a d on or ion of salt forms such as acid addition salts.
Example acids can be inorganic or organic acids and include, but are not limited to, strong and weak acids. Some example acids include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, p-toluenesulfonic acid, 4- nitrobenzoic acid, methanesulfonic acid, esulfonic acid, trifluoroacetic acid, and nitric acid. Some weak acids include, but are not d to acetic acid, propionic W0 2017!]72596 acid, butanoic acid, c acid, tartaric acid, pentanoic acid, hexanoic acid, heptanoic acid, octanoic acid, nonanoic acid, and decanoic acid.
Example bases include lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium ate, potassium carbonate, and sodium bicarbonate. Some example strong bases include, but are not limited to, ide, alkoxides, metal amides, metal hydrides, metal dialkylamides and ines, wherein; alkoxides e lithium, sodium and potassium salts of methyl, ethyl and t-butyl oxides; metal amides include sodium amide, potassium amide and lithium amide; metal hydrides include sodium e, ium hydride and lithium 1O hydride; and metal dialkylamides include lithium, sodium, and potassium salts of methyl, ethyl, n-propyl, iso-propyl, n-butyl, tert—butyl, trimethylsilyl and cyclohexyl substituted amides.
In some embodiments, the compounds provided herein, or salts thereof, are substantially isolated. By "substantially isolated" is meant that the compound is at least partially or substantially separated from the environment in which it was formed or detected. Partial separation can include, for example, a composition enriched in the compounds provided herein. Substantial separation can include compositions containing 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 provided herein, or salt thereof. Methods for isolating compounds and their salts are routine in the art.
Compounds of the invention can also include all es of atoms occurring in the intermediates or final compounds. Isotopes include those atoms having the same atomic number but different mass numbers. For e, isotopes of hydrogen include tritium and deuterium. One or more constituent atoms of the compounds of the invention can be replaced or substituted with isotopes of the atoms in natural or non-natural abundance. In some embodiments, the compound includes at least one deuterium atom. For example, one or more hydrogen atoms in a compound of the present sure can be replaced or substituted by deuterium. 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 ium atoms. tic methods for including es into organic compounds are known in the art.
W0 2017!]72596 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 ements, and hence may be red in some circumstances. (A. Kerekes etal. J. Med. Chem. 2011, 54, 201-210; R. Xu etal. J. Label Compd. Radiopharm. 2015, 58, 308-312).
The term "compound" as used herein is meant to e all stereoisomers, geometric isomers, tautomers, and isotopes of the structures depicted. Compounds herein identified by name or structure as one particular eric form are intended to include other tautomeric forms unless otherwise specified. 1O 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, ic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
The present application also includes pharmaceutically acceptable salts of the compounds described herein. The present disclosure also includes pharmaceutically acceptable salts of the compounds described herein As used herein, "pharmaceutically acceptable salts" refers to derivatives of the disclosed compounds wherein the parent compound is modified by converting an ng acid or base moiety to its salt form. Examples of pharmaceutically 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 ylic acids, and the like. The pharmaceutically acceptable salts of the present disclosure include the tional non-toxic salts of the parent compound formed, for e, from non-toxic nic or organic acids. The pharmaceutically acceptable salts of the present disclosure can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. lly, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the riate 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 (ACN) are preferred. Lists of le salts are found in Remington ’3 Pharmaceutical W0 2017!]72596 Sciences, 17th ed; Mack Publishing Company; Easton; Pa; 1985; p. 1418 and Jaumai ofPharmaceutical Science, 66; 2 (1977); each of which is orated herein by reference in its entirety.
The following abbreviations may be used herein: AcOH (acetic acid); AczO (acetic anhydride); aq. us); atm. (atmosphere(s)); Boc (i—butoxycarbonyl); br (broad); Cbz (carboxybenzyl); calc. (calculated); (1 (doublet); dd (doublet of doublets); DCM (dichloromethane); DEAD (diethyl azodicarboxylate); DIAD (N;N’- diisopropyl icarboxylate); DIPEA (N;N-diisopropylethylarnine); DMF (N;N- dimethylformamide); Et ); EtOAc (ethyl acetate); g (gram(s)); h (hour(s)); 1O HATU (N;N;N’;N'-tetramethyl-O-(7-azabenzotriazolyl)uronium hexafluorophosphate); HCl (hydrochloric acid); HPLC (high performance liquid tography); Hz (hertz); J (coupling constant); LCMS (liquid chromatography — mass spectrometry); m (multiplet); M (molar); mCPBA oroperoxybenzoic acid); MgSO4 sium sulfate); MS (Mass spectrometry); Me (methyl); MeCN (acetonitrile); MeOH (methanol); mg (milligram(s)); min. (minutes(s)); mL (milliliter(s)); mrnol (millimole(s)); N (normal); NaHCO3 (sodium bicarbonate); NaOH (sodium hydroxide); NazSO4 (sodium sulfate); NH4Cl (ammonium chloride); NH4OH (ammonium hydroxide); nM (nanomolar); NMR (nuclear magnetic resonance spectroscopy); OTf (trifluoromethanesulfonate); Pd (palladium); Ph (phenyl); pM (picomolar); PMB (para-methoxybenzyl); POCl3 (phosphoryl chloride); RP-HPLC (reverse phase high performance liquid chromatography); 5 (singlet); t (triplet or tertiary); TBS (tert-butyldimethylsilyl); tert (tertiary); tt (triplet of triplets); t-Bu (tertbutyl ); TFA (trifluoroacetic acid); THF (tetrahydrofuran); ug (microgram(s)); uL (microliter(s)); uM (micromolar); wt% (weight percent).
As used herein; the term "cell" is meant to refer to a cell that is in vitra; ex viva or in viva. In some embodiments; an ex viva cell can be part of a tissue sample excised from an organism such as a mammal. In some embodiments; an in vitra cell can be a cell in a cell culture. In some embodiments; an in viva cell is a cell living in an organism such as a mammal.
As used herein; the term "contacting" refers to the bringing together of ted moieties in an in vitra system or an in viva system. For e; "contacting" the TAM s with a compound of the sure includes the W0 2017!]72596 administration of a compound of the present disclosure to an individual or patient, such as a human, having TAM, as well as, for example, introducing a compound of the disclosure into a sample containing a cellular or purified preparation containing the TAM kinases.
As used herein, the term "individual" or "patient," used hangeably, refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, , sheep, horses, or es, and most preferably .
As used herein, the phrase "therapeutically ive amount" refers to the amount of active compound or pharmaceutical agent that elicits the biological or 1O medicinal response 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 1) inhibiting the e; for example, inhibiting a disease, condition or disorder in an individual who is encing or displaying the ogy or symptomatology of the disease, ion or disorder (116., arresting further development of the pathology and/or symptomatology), or 2) ameliorating the disease; for example, ameliorating a e, condition or er in an individual who is experiencing or displaying the ogy or matology of the disease, condition or disorder (126., reversing the pathology and/or symptomatology).
As used herein the term "preventing" or "prevention" refers to preventing the disease; for example, preventing a disease, condition or disorder in an individual who may be predisposed to the disease, condition or disorder but does not yet experience or display the pathology or symptomatology of the disease.
Synthesis Compounds provided herein, including salts thereof, can be prepared using known organic synthesis techniques and according to various possible synthetic The reactions for preparing compounds provided herein can be carried out in suitable solvents which can be readily selected by one of skill in the art of organic synthesis. Suitable solvents can be substantially nonreactive with the starting materials (reactants), the intermediates, or products at the temperatures at which the W0 2017!]72596 reactions are carried out, e.g., temperatures which can range from the solvent's freezing temperature to the solvent's boiling temperature. 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 provided herein can e the protection and deprotection of s 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 can be found, for example, in 1O T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 3rd. Ed., Wiley & Sons, Inc., New York (1999), which is incorporated herein by reference in its entirety.
Reactions can be monitored ing to any suitable method known in the art. For example, product ion can be monitored by spectroscopic means, such as r magnetic resonance spectroscopy (e.g., 1H or 13C), ed spectroscopy, spectrophotometry (e. g., UV-visible), or mass spectrometry, or by chromatography such as high performance liquid tography (HPLC) or thin layer chromatography.
The expressions, "ambient temperature", "room temperature", and "rt", 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, for example, a temperature from about 20 0C to about 30 0C.
Compounds as sed herein can be prepared by one skilled in the art ing to preparatory routes known in the literature and according to various possible synthetic routes. Example synthetic s for preparing compounds of the present application are provided in Scheme 1 below.
The reactions for preparing compounds provided herein can be carried out in suitable solvents which can be readily selected by one of skill in the art of organic synthesis. Suitable solvents can be substantially nonreactive with the starting materials (reactants), the intermediates, or products 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 g ature. A given reaction can be W0 2017!]72596 carried out in one solvent or a mixture of more than one t. ing on the particular reaction step, suitable solvents for a ular reaction step can be selected by the skilled artisan.
Preparation of compounds provided herein can involve the protection and deprotection of various chemical groups. The need for protection and ection, and the selection of appropriate protecting groups, can be readily determined by one skilled in the art. The chemistry of protecting groups can be found, for e, in T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 3rd Ed, Wiley & Sons, Inc, New York (1999), which is incorporated herein by reference in 1O its entirety.
Reactions can be monitored according to any le method known in the art. For example, product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g., 1H or 13C), infrared spectroscopy, ophotometry (e.g., UV-visible), or mass spectrometry, or by chromatography such as high performance liquid chromatography (HPLC) or thin layer chromatography.
The sions, "ambient temperature", "room temperature", and "rt", 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 on is carried out, for example, a temperature from about 20 °C to about 30 °C.
Compounds as disclosed herein can be prepared by one skilled in the art according to preparatory routes known in the literature. A compound of FormulaI can be prepared according to Scheme 1. Compounds (i) can be prepared by standard Suzuki coupling of bromides (i-a) with boronic esters or acids (i-b), wherein R1 contains the alkenylene functionality. Catalytic hydrogenation of the R1 functional group using Pd on carbon or another suitable catalyst can then provide nds (ii) wherein R1 contains the alkylene functionality. Selective bromination of compound (ii) using, e.g., NBS, yields bromides (iii) which are then directly treated with boronic esters or acids (iv) under, e.g., standard Suzuki coupling conditions, to afford nds of Formula 1. Alternatively, nds of FormulaI can be prepared through Suzuki coupling of bromides (iii) with boronic esters or acids (v) followed by reaction of the resultant amines (vi) with carboxylic acids (vii), and a le coupling reagent such as HATU or BOP.
Scheme 1 NH2 IB-Rl NH2 NH2 N/ / Pd/C. H2 R2 (i-b) N/ / 3J\\ / 3J\\ R2 R2 ’N IN / 31: \ ’N// R N Suzuki R N R3 N Br R1 R (i-a) (0 (ii) wherein R1 = alkenylene wherein R1 = alkylene DMF R3 N o R1 Suzukl (m) j: // R2 R3 N ’B-Cyc NHZ Formulal The ion will be described in greater detail by way of specific examples.
The following examples are offered for illustrative purposes, and are not intended to limit the invention in any manner. Those of skill in the art will readily recognize a variety of non-critical parameters which can be changed or modified to yield essentially the same results. The compounds of the Examples were found to be inhibitors ofTAM kinases as described below.
Preparatory LC-MS purifications of some of the compounds prepared were performed on Waters mass directed fractionation systems. The basic equipment setup, ols, and control re for the operation of these systems have been W0 2017!]72596 described in detail in the literature. See e. g. "Two-Pump At Column Dilution Configuration 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, J.
Combs". Chem, 5, 670 (2003), and "Preparative LC-MS Purification: Improved Compound Specific Method Optimization", K. Blom, B. Glass, R. Sparks, A. Combs, J. Combi. Chem, 6, 874-883 (2004). The compounds separated were typically ted to analytical liquid chromatography mass spectrometry (LCMS) for purity check under the following ions: ment, Agilent 1100 series, LC/MSD, 1O : Waters SunfireTM C18 5 um le size, 2.1 X 5.0 mm, Buffers: mobile phase A: 0.025% TFA in water and mobile phase B: acetonitnle; 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 ative scale by reverse-phase high performance liquid chromatography LC) with MS detector or flash chromatography (silica gel) as indicated in the Examples. Typical preparative reverse-phase high performance liquid chromatography (RP—HPLC) column conditions are as follows: pH = 2 purifications: Waters SunfireTM C18 5 um particle size, 19 x 100 mm column, eluting with mobile phase A: 0.1% TFA oroacetic acid) 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: Improved Compound c Method Optimization", K. Blom, B.
Glass, R. Sparks, A. Combs, J. Comb. Chem, 6, 874-883 (2004)]. lly, the flow rate used with the 30 X 100 mm column was 60 mL/minute. pH = 10 tions: Waters XBIidge C18 5 um particle size, 19 x 100 mm column, 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: Improved Compound Specific Method Optimization", K. Blom, B. Glass, R. Sparks, A. Combs,J. Comb.
W0 2017!]72596 Chem, 6, 874—883 (2004)]. Typically, the flow rate used with 30 x 100 mm column was 60 mL/minute.
TAMkinases Receptor tyrosine kinases (RTKs) are cell surface proteins that transmit signals from the extracellular environment to the cell cytoplasm and nucleus to regulate cellular events such as survival, growth, proliferation, differentiation, adhesion and migration. All RTKs contain an extracellular ligand binding domain and a cytoplasmic protein tyrosine kinase domain. Ligand binding leads to the 1O dimerization of RTKs, which rs the activation of the cytoplasmic kinase and initiates downstream signal transduction pathways. RTKs can be classified into distinct subfamilies based on their sequence rity. The TAM subfamily consists of three RTKs ing TYRO3, AXL and MER (Graham et al., 2014, Nature reviews Cancer 14, 769-785; and Linger et al., 2008, Oncogene 32, 3420-3431).
TAM kinases are characterized by an extracellular ligand binding domain consisting of two globulin-like domains and two fibronectin type 111 domains. Two ligands, growth arrest specific 6 (GAS6) and protein S (ProS), have been fied for TAM kinases. GAS6 can bind to and activate all three TAM kinases, while ProS is a ligand for MER and TYRO3 (Graham et al., 2014, Nature reviews Cancer 14, 769-785).
TAM kinases are over-expressed in many cancers and play ant roles in tumor initiation and maintenance, therefore, TAM inhibition represents an attractive approach for targeting another class of oncogenic RTKs (Graham et al., 2014, Nature reviews Cancer 14, 769-785, and Linger et al., 2008, Oncogene 32, 3420-3431).
Axl was originally identified as a transforming gene from DNA of patients with chronic myelogenous leukemia (O'Bryan et al., 1991, Molecular and ar biology 11, 5016-5031). GAS6 binds to Axl and induces subsequent auto— phosphorylation and activation of Axl tyrosine kinase. Axl activates l downstream signaling pathways including PI3K-Akt, PK, PLC-PKC (Feneyrolles et al., 2014, Molecular cancer therapeutics 13, 2141-2148; Linger et al., 2008, ne 32, 3420-3431). AXL is over-expressed or amplified in a variety of malignancies ing lung cancer, prostate cancer, colon , breast cancer, W0 2017!]72596 melanoma, and renal cell carcinoma (Linger et al., 2008, Oncogene 32, 3420-3431).
Over-expression of AXL is correlated with poor prognosis (Linger et al., 2008, Oncogene 32, 3420-3431). As a result, AXL activation promotes cancer cell survival, proliferation, angiogenesis, metastasis, and resistance to chemotherapy and targeted therapies. AXL knockdown or AXL antibody can inhibit the migration of breast cancer and NSCLC cancer in vitro, and blocked tumor growth in xenograft tumor models (Li etal., 2009, Oncogene 28, 3442-3455). In pancreatic cancer cells, inhibition of AXL decreased cell eration and survival (Koorstra et al., 2009, Cancer biology & therapy 8, 618-626). In prostate cancer, AXL inhibition decreased 1O cell migration, invasion, and eration (Tai et al., 2008, Oncogene 27, 4044-4055).
In addition, AXL over-expression or cation is a major mechanism for resistance to EGFR inhibitors by lung cancer cells, and AXL tion can reverse the resistance (Zhang et al., 2012, Nature genetics 44, 852-860).
Mer was originally identified as a o-protein from a lymphoblastoid expression library (Graham et al., 1995, Oncogene 10, 2349-2359). Both GAS6 and ProS can bind to Mer and induce the phosphorylation and activation of Mer kinase (Lew et al., 2014. eLife, 3:e03385). Like Axl, Mer activation also conveys downstream signaling pathways including PI3K-Akt and Raf-MAPK (Linger et al., 2008, Oncogene 32, 3420-3431). MER is over-expressed in many cancers including le myeloma, gastric, prostate, breast, melanoma and rhabdomyosarcoma (Linger et al., 2008, Oncogene 32, 3420-3431). MER own inhibits le myeloma cell growth in vitro and in aft models (Waizenegger et al., 2014, Leukemia, 1—9). In acute myeloid leukemia, MER knockdown induced apoptosis, decreased colony formation, and increased survival in a mouse model (Lee-Sherick et al., 2013, Oncogene 32, 5359-5368). MER inhibition increased apoptosis, decreased colony formation, increased chemo-sensitivity, and decreased tumor growth in NSCLC (Linger et al., 2013, Oncogene 32, 3420-3431). Similar effects are ed for MER own in melanoma gel et al., 2013) and glioblastoma (Wang et al., 2013, Oncogene 32, 872-882).
Tyro3 was ally identified through a PCR-based cloning study (Lai and Lemke, 1991, Neuron 6, 691-704). Both ligands, GAS6 and ProS, can bind to and activate Tyro3. TYRO3 also plays a role in cancer growth and proliferation. TYRO3 W0 2017!]72596 is over-expressed in melanoma cells, and knockdown of TYRO3 induces apoptosis in these cells (Demarest et a1., 2013, Biochemistry 52, 3102-3118).
In addition to their role as transforming oncogenes, TAM kinases have emerged as ial immune-oncology s. The durable al responses to immune checkpoint blockade observed in cancer patients clearly indicate that the immune system plays a critical role in tumor initiation and maintenance. Genetic mutations from cancer cells can provide a e set of antigens that the immune cells can use to distinguish tumor cells from their normal counterpart. However, cancer cells have evolved multiple mechanisms to evade host immune surveillance. 1O In fact, one hallmark of human cancer is its ability to avoid immune destruction.
Cancer cells can induce an immune-suppressive microenvironment by promoting the formation of M2 tumor associated macrophages, myeloid derived suppressor cells , and tory T cells. Cancer cells can also produce high levels of immune checkpoint proteins such as PD-Ll to induce T cell anergy or exhaustion. It is now clear that tumors co-opt certain immune-checkpoint pathways as a major mechanism of immune resistance (Pardoll, 2012, Cancer 12, 252-264). Antagonizing these negative regulators of T-cell function With antibodies has shown striking efficacy in clinical trials of a number of malignancies including advanced melanoma, non-small cell lung and bladder cancer. While these therapies have shown encouraging results, not all patients mount an anti-tumor response ting that other immune- suppressive ys may also be important.
TAM kinases have been shown to function as checkpoints for immune activation in the tumor milieu. All TAM kinases are expressed in NK cells, and TAM kinases inhibit the anti-tumor ty ofNK cells. LDC1267, a small molecule TAM inhibitor, activates NK cells, and blocks metastasis in tumor models with different histologies (Paolino et a1., 2014, Nature 507, 2). In addition, MER kinase promotes the activity of tumor ated macrophages through the increased secretion of immune suppressive cytokines such as ILIO and IL4, and decreased production of immune activating cytokines such as IL12(Cook et a1., 2013, The Journal of clinical igation 123, 242). MER inhibition has been shown to reverse this effect. As a result, MER knockout mice are resistant to PyVmT tumor formation (Cook et a1., 2013, The Journal of clinical investigation [23, 3231-3242).
W0 2017!]72596 The role of TAM kinases in the immune se is also supported by knockout mouse studies. TAM triple knockout mice (TKO) are . However, these mice displayed signs of autoimmune disease including ed spleen and lymph nodes, autoantibody production, n footpad and , skin lesions, and systemic lupus erythematosus (Lu and Lemke, 2001, Science 293, 306-311). This is consistent with the knockout ype for approved immune-oncology targets such as CTLA4 and PD-l. Both CTLA-4 and PD-1 knockout mice showed signs of autoimmune disease, and these mice die within a few weeks after birth (Chambers et al., 1997, Immunity 7, 885-895; and Nishimura et al., 2001, Science 291, 319-322). 1O TAM inhibition will have not only direct activity against neoplastic cells, but also activate the anti-cancer immune response. Thus TAM inhibitors represent an attractive approach for the ent of cancer as single agents. In addition, TAM inhibitors may be combined with other targeted therapies, chemotherapies, radiation, or immunotherapeutic agents to achieve l efficacy in the clinic.
Methods of Use Compounds of the present disclosure can modulate or inhibit the activity of TAM s. For example, the compounds of the disclosure can be used to t activity of a TAM kinase in a cell or in an individual or patient in need of inhibition of the s by administering an inhibiting amount of a compound of the disclosure to the cell, individual, or patient.
In some embodiments, the compounds of the disclosure are selective for the TAM kinases over one or more of other kinases. In some embodiments, the compounds of the disclosure are selective for the TAM kinases over other kinases. In some embodiments, the selectivity is 2-fold or more, 3-fold or more, 5-fold or more, -fold or more, 25-fold or more, 50-fold or more, or 100-fold or more.
The compounds of the invention can inhibit one or more of AXL, MER and TYRO3. In some embodiments the compounds are selective for one TAM kinase over another. "Selective" means that the compound binds to or inhibits a TAM kinase with greater affinity or potency, respectively, compared to a nce enzyme, such as another TAM . For example, the compounds can be selective for AXL over MER and TYRO3, selective for MER over AXL and TYRO3, or selective for AXL W0 2017!]72596 and MER over TYRO3. In some embodiments, the compounds inhibit all of the TAM family members (e.g, AXL, MER and TYRO3). In some embodiments, the compounds can be selective for AXL and MER over TYRO3 and other kinases. In some embodiments, provided herein is a method for inhibiting AXL and MER kinase, which comprises contacting the AXL and MER kinase with a compound provided , or a pharmaceutically acceptable salt thereof.
As TAM kinases inhibitors, the compounds of the disclosure are useful in the treatment of various diseases associated with abnormal expression or ty of the TAM kinases. Compounds which inhibit TAM kinases will be useful in providing a 1O means of preventing the growth or inducing apoptosis in tumors, particularly by inhibiting angiogenesis. It is therefore anticipated that the compounds will prove useful in treating or preventing proliferative disorders such as cancers. In particular, s with activating mutants of receptor tyrosine kinases or upregulation of receptor tyrosine kinases may be particularly sensitive to the inhibitors.
In certain embodiments, the disclosure provides a method for treating a disease or disorder mediated by TAM kinases in a patient in need thereof, comprising the step of administering to said patient a compound provided herein, or a pharmaceutically acceptable composition f.
For e, the compounds of the sure are useful in the treatment of cancer. Example cancers include bladder cancer, breast cancer, cervical cancer, ctal , cancer of the small intestine, colon cancer, rectal cancer, cancer of the anus, endometrial cancer, c cancer, head and neck cancer (e. g., cancers of the , hypopharynx, nasopharynx, oropharynx, lips, and mouth), kidney cancer, liver cancer (e.g., hepatocellular carcinoma, cholangiocellular carcinoma), lung cancer (e.g., adenocarcinoma, small cell lung cancer and non-small cell lung carcinomas, parvicellular and rvicellular carcinoma, bronchial carcinoma, bronchial adenoma, pleuropulmonary blastoma), ovarian cancer, prostate cancer, testicular cancer, uterine cancer, esophageal , gall bladder , pancreatic cancer (e.g. exocrine pancreatic carcinoma), stomach cancer, thyroid cancer, parathyroid cancer, skin cancer (e.g., squamous cell carcinoma, Kaposi sarcoma, Merkel cell skin cancer), and brain cancer (e. g., astrocytoma, oblastoma, ependymoma, neuro-ectodermal tumors, pineal tumors).
W0 72596 Other cancers treatable with the nds of the sure include bone cancer, intraocular cancers, gynecological cancers, cancer of the endocrine system, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, pituitary cancer, triple-negative breast cancer (TNBC) and environmentally induced cancers including those induced by asbestos.
Further example s include hematopoietic malignancies such as leukemia or lymphoma, multiple myeloma, chronic lymphocytic lymphoma, adult T cell leukemia, B—cell lymphoma, cutaneous T-cell lymphoma, acute myelogenous ia, Hodgkin’s or non-Hodgkin’s lymphoma, myeloproliferative neoplasms 1O (e.g., polycythemia vera, essential ocythemia, and primary myelofibrosis), Waldenstrom's Macroglubulinemia, hairy cell lymphoma, c myelogenic lymphoma, acute lymphoblastic lymphoma, AIDS-related lymphomas, and Burkitt's lymphoma.
Other s treatable with the compounds of the disclosure include tumors of the eye, glioblastoma, melanoma, rhabdosarcoma, lymphosarcoma, and osteosarcoma.
Compounds of the disclosure can also be useful in the inhibition of tumor metastisis.
In some embodiments, diseases 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 cancers, gynecological cancers, and skin ary hematological s include lymphomas and ias such as acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), c myelogenous leukemia (CML), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), Non-Hodgkin lymphoma (including relapsed or refractory NHL), follicular lymphoma (FL), Hodgkin ma, lymphoblastic lymphoma, myeloproliferative diseases (e.g., primary myelofibrosis (PMF), polycythemia vera (PV), essential thrombocytosis (ET)), myelodysplasia syndrome (MDS), T-cell acute lymphoblastic lymphoma (T—ALL), le myeloma, cutaneous T-cell lymphoma, peripheral T— cell lymphoma, Waldenstrom's Macroglubulinemia, hairy cell lymphoma, c myelogenic lymphoma and Burkitt’s lymphoma.
Exemplary as include chondrosarcoma, s sarcoma, osteosarcoma, rhabdomyosarcoma, angiosarcoma, fibrosarcoma, liposarcoma, myxoma, myoma, rhabdosarcoma, fibroma, lipoma, harmatoma, and teratoma, Exemplary lung cancers include non-small cell lung cancer (NSCLC), small cell lung cancer, bronchogenic carcinoma (squamous cell, undifferentiated small cell, erentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, 1O bronchial adenoma, chondromatous hamartoma, and mesothelioma. ary gastrointestinal cancers include cancers of the esophagus (squamous cell oma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, ma, leiomyosarcoma), pancreas l adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, Vipoma), small bowel carcinoma, lymphoma, carcinoid tumors, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, a), large bowel (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma), colorectal cancer and bile duct cancer. ary genitourinary tract cancers include cancers of the kidney (adenocarcinoma, Wilm's tumor [nephroblastoma], renal cell carcinoma), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma, lial carcinoma), prostate (adenocarcinoma, sarcoma), and testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma).
Exemplary liver cancers include hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, and hemangioma.
Exemplary bone cancers include, for example, osteogenic sarcoma (osteosarcoma), arcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma ulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochronfroma (osteocartilaginous W0 2017!]72596 exostoses), benign oma, chondroblastoma, chondromyxofibroma, osteoid osteoma, and giant cell tumors Exemplary nervous system cancers e cancers of the skull (osteoma, hemangioma, granuloma, xanthoma, is deformans), meninges (meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma, meduoblastoma, , ependymoma, germinoma (pinealoma), glioblastoma, glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), and spinal cord (neurofibroma, meningioma, glioma, sarcoma), as well as neuroblastoma, Lhermitte- Duclos disease, neoplasm of the central nervous system (CNS), primary CNS 1O ma and spinal axis tumor.
Exemplary gynecological cancers include cancers of the uterus (endometrial carcinoma), cervix (cervical oma, pre -tumor cervical dysplasia), ovaries (ovarian oma (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa—thecal cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial oma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), and fallopian tubes (carcinoma).
Exemplary skin cancers include melanoma, basal cell carcinoma, squamous cell carcinoma, 's sarcoma, Merkel cell skin , moles dysplastic nevi, lipoma, angioma, dermatofibroma, and keloids.
Exemplary head and neck cancers include glioblastoma, melanoma, rhabdosarcoma, lymphosarcoma, osteosarcoma, us cell omas, adenocarcinomas, oral cancer, laryngeal cancer, nasopharyngeal cancer, nasal and paranasal cancers, thyroid and parathyroid cancers.
In some embodiments, the present disclosure provides a method for treating cellular carcinoma in a patient in need f, comprising the step of administering to said patient a compound of Formula (I) or a compound as disclosed herein, or a pharmaceutically acceptable salt thereof, or a composition comprising a compound of Formula (I) or a nd as disclosed herein, In some ments, the present disclosure provides a method for treating Rhabdomyosarcoma, esophageal cancer, breast cancer, or cancer of a head or neck, in W0 2017!]72596 a t in need thereof, comprising the step of administering to said patient a compound Formula (I) or a compound as disclosed herein, or a pharmaceutically acceptable salt thereof, or a composition comprising a nd of Formula (I) or a compound as disclosed herein.
In some embodiments, the present disclosure provides a method of ng cancer, wherein the cancer is selected from hepatocellular cancer, breast cancer, r cancer, colorectal cancer, melanoma, mesothelioma, lung cancer, prostate cancer, pancreatic cancer, testicular cancer, thyroid cancer, squamous cell carcinoma, glioblastoma, neuroblastoma, e cancer, and rhabdosarcoma. 1O Targeting TAM receptor tyrosine kinases can provide a therapeutic approach to treat viral diseases (T Shibata, et.al. The Journal ofImmunology, 2014, 192, 3569- 3581). The present disclosure provides a method for treating ions such as viral infections. The method includes stering to a patient in need thereof, a therapeutically effective amount of a compound of a (I) or any of the formulas as described herein, a compound as recited in any of the claims and described herein, a salt thereof. Examples of viruses causing infections treatable by methods of the present disclosure include, but are not limit to, human immunodeficiency virus, human papillomavirus, influenza, hepatitis A, B, C or D viruses, adenovirus, poxvirus, herpes simplex Viruses, human galovirus, severe acute respiratory syndrome virus, ebola virus, Marburg virus and measles virus. In some embodiments, s causing infections treatable by methods of the t disclosure include, but are not limit to, hepatitis (A, B, or C), herpes virus (e.g., VZV, HSV-l, HAV—6, HSV- II, and CMV, Epstein Barr virus), adenovirus, influenza virus, flaviviruses (for example: West Nile, dengue, tick-bome encephalitis, yellow fever, Zika), echovirus, rhinovirus, kie virus, comovirus, respiratory syncytial virus, irus, rotavirus, s virus, rubella virus, parvovirus, vaccinia virus, HTLV virus, dengue virus, papillomavirus, molluscum virus, irus, rabies virus, JC virus and arboviral encephalitis virus.
In some embodiments, the present disclosure provides a method for treating thrombus formation (J.M.E.M. Cosemans etal. J. mbosis and Haemostasis 2010, 8, 179?-1808 and A. Angelillo-Scherrer et.al. J. Clin. Invest. 2008, 118, 583- 596).
W0 2017!]72596 Combination Therapy One or more additional pharmaceutical agents or treatment methods such as, for example, anti-viral agents, chemotherapeutics or other anti-cancer agents, immune enhancers, immunosuppressants, radiation, anti-tumor and anti—viral vaccines, cytokine therapy (e,g., 1L2, GM-CSF, etc), and/or tyrosine kinase inhibitors can be used in combination with the compounds of a (I) or a compound as described herein for treatment of TAM-associated diseases, disorders or conditions. The agents can be ed with the t compounds in a single dosage form, or the agents 1O can be stered simultaneously or sequentially as separate dosage forms.
Suitable antiviral agents contemplated for use in combination with the compounds of the present disclosure can comprise nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs), non-nucleoside e transcriptase tors (NNRTIs), protease inhibitors and other antiviral drugs.
Example suitable NRTIs include zidovudine (AZT); didanosine (ddl); zalcitabine (ddC); stavudine (d4T); lamivudine (3TC); ir (1592U89); ir xil [bis(POM)-PMEA]; lobucavir (EMS-180194); BCH-1065 2; emitricitabine [(-)-FTC]; beta-L-FD4 (also called beta-L-D4C and named beta-L-2', 3'-dicleoxy fluoro-cytidene); DAPD, ((-)-beta—D-2,6,-diamino-purine dioxolane); and lodenosine (FddA). l suitable NNRTIs include nevirapine (BI-RG—587); delaviradine (BHAP, U-90152); efavirenz 66); PNU-l42721; AG-1549; MKC-442 (l- (ethoxy-methyl)—5-(l-methylethyl)(phenylmethyl)-(2,4(lH,3H)-pyrimidinedione); and (+)-calanolide A (NSC-675451) and B. Typical suitable protease inhibitors include saquinavir (Ro 31-8959); ritonavir 38); indinavir (MK-639); nelfnavir (AG-1343); amprenavir (141W94); lasinavir (EMS-234475); DMP-450; BMS- 2322623; ABT-378; and AG—l 549. Other antiviral agents include hydroxyurea, ribavirin, IL-2, IL-12, pentafuside and Yissum Project No.11607.
Suitable agents for use in combination with the compounds of the present application for the treatment of cancer include chemotherapeutic , targeted cancer therapies, immunotherapies or radiation therapy. Compounds of this application may be effective in combination with anti-hormonal agents for treatment of breast cancer and other tumors. Suitable examples are anti-estrogen agents W0 2017!]72596 including but not limited to tamoxifen and toremifene, ase inhibitors including but not limited to letrozole, anastrozole, and exemestane, adrenocorticosteroids (e.g. prednisone), progestins (e. g. megastrol acetate), and estrogen receptor nists (e.g. fulvestrant). le anti-hormone agents used for treatment of prostate and other cancers may also be combined with compounds of the present disclosure. These e anti-androgens including but not limited to flutamide, bicalutamide, and nilutamide, luteinizing hormone-releasing hormone (LHRH) analogs including leuprolide, oserelin, triptorelin, and histrelin, LHRH antagonists (e. g. degarelix), androgen receptor blockers (e. g. enzalutamide) and agents that inhibit androgen 1O production (e. g. abiraterone).
Compounds of the present disclosure may be combined with or in sequence with other agents t membrane receptor kinases ally for patients who have ped primary or acquired resistance to the targeted therapy. These therapeutic agents include inhibitors or antibodies against EGFR, Her2, VEGFR, c—Met, Ret, IGFRl, PDGFR, FGFRl, FGFRZ, FGFR3, FGFR4, TrkA, TrkB, TrkC, ROS, c-Kit, or Flt—3 and against cancer-associated fusion protein kinases such as l and EML4-Alk. Inhibitors against EGFR e gefitinib and nib, and inhibitors against EGFR/I-Ier2 include but are not limited to dacomitinib, afatinib, lapitinib and nib. Antibodies against the EGFR e but are not limited to mab, panitumumab and necitumumab. Inhibitors of c-Met may be used in combination with TAM inhibitors. These include onartumzumab, tivantnib, and INC-280. Agents t FGFRs e but not limited to AZD4547, BAY1187982, ARQ087, BGJ398, BIBFl 120, TK1258, lucitanib, dovitinib, TAS-120, 756493, and Debiol347. Agents against Trks include but not limited to LOXO-IOI and RXDX- 101. Agents against Abl (or Bcr-Abl) include imatinib, dasatinib, nilotinib, and ponatinib and those against Alk (or EML4-ALK) include crizotinib.
Angiogenesis inhibitors may be efficacious in some tumors in combination with TAM inhibitors. These include antibodies against VEGF or VEGFR or kinase inhibitors of VEGFR. Antibodies or other therapeutic proteins against VEGF include bevacizumab and aflibercept. Inhibitors of VEGFR kinases and other anti- angiogenesis inhibitors include but are not limited to sunitinib, sorafenib, axitinib, cediranib, pazopanib, regorafenib, brivanib, and vandetanib W0 2017!]72596 Activation of intracellular signaling pathways is frequent in cancer, and agents targeting components of these pathways have been combined with receptor targeting agents to enhance efficacy and reduce resistance. Examples of agents that may be combined with compounds of the present sure include inhibitors of the PI3K- OR pathway, inhibitors of the Raf-MAPK pathway, inhibitors ofJAK-STAT y, inhibitors of Pim kinases, and inhibitors of protein chaperones and cell cycle progression.
Agents against the PI3 kinase include but are not limited to pilaralisib, idelalisib, buparlisib, and 9. In some embodiments, the PI3K inhibitor is 1O ive for PI3K alpha, PI3K beta, PI3K gamma or PI3K delta. Inhibitors of mTOR such as rapamycin, sirolimus, temsirolimus, and everolimus may be ed with TAM kinases inhibitors. Other suitable examples include but are not limited to vemurafenib and enib (Raf inhibitors) and trametinib, selumetinib and GDC- 0973 (MEK inhibitors). tors of one or more JAKs (e.g., ruxolitinib, baricitinib, tofacitinib), Hsp90 (e.g., tanespimycin), cyclin dependent kinases (e.g., palbociclib), PARP (e.g., olaparib), and proteasomes (e.g., bortezomib, carfilzomib) can also be combined with compounds of the present disclosure. In some ments, the JAK inhibitor is selective for JAKI over JAKZ and JAK3. Agents against Pim kinases include but not limited to , 3914, and SGI-1776.
Other suitable agents for use in combination with the compounds of the present disclosure include chemotherapy combinations such as um-based doublets used in lung cancer and other solid tumors (cisplatin or carboplatin plus gemcitabine; cisplatin or carboplatin plus docetaxel, cisplatin or carboplatin plus paclitaxel; cisplatin or carboplatin plus pemetrexed) or gemcitabine plus paclitaxel bound particles (Abraxane®).
Suitable chemotherapeutic or other anti-cancer agents include, for example, alkylating agents (including, without limitation, nitrogen mustards, ethylenimine derivatives, alkyl sulfonates, nitrosoureas and nes) such as uracil mustard, chlormethine, cyclophosphamide (CytoxanTM), ifosfamide, melphalan, chlorambucil, pipobroman, ylene-melamine, triethylenethiophosphoramine, busulfan, carmustine, lomustine, streptozocin, dacarbazine, and temozolomide.
W0 2017!]72596 Other le agents for use in ation with the compounds of the t sure include: azine (DTIC), optionally, along with other chemotherapy drugs such as carmustine (BCNU) and cisplatin; the "Dartmouth regimen," which consists of DTIC, BCNU, cisplatin and tamoxifen; a combination of cisplatin, vinblastine, and DTIC; or temozolomide. Compounds provided herein may also be combined with immunotherapy drugs, including cytokines such as interferon alpha, interleukin 2, and tumor necrosis factor (TNF) inhibitors.
Suitable chemotherapeutic or other anti-cancer agents include, for example, antimetabolites ding, without limitation, folic acid antagonists, pyrimidine 1O analogs, purine analogs and adenosine deaminase inhibitors) such as methotrexate, 5- fluorouracil, floxuridine, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine ate, pentostatine, and gemcitabine.
Suitable chemotherapeutic or other anti-cancer agents further include, for example, certain natural ts and their derivatives (for example, vinca alkaloids, antitumor antibiotics, enzymes, lymphokines and epipodophyllotoxins) such as vinblastine, vincristine, vindesine, bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, ara—C, paclitaxel (TAXOLTM), mithramycin, oformycin, cin-C, L-asparaginase, interferons (especially IFN-a), etoposide, and teniposide, Other cytotoxic agents include navelbene, CPT-l 1, anastrazole, letrazole, capecitabine, reloxafine, cyclophosphamide, ide, and droloxafine.
Also suitable are cytotoxic agents such as epidophyllotoxin; an antineoplastic enzyme; a topoisomerase inhibitor, procarbazine, mitoxantrone, platinum coordination complexes such as atin and carboplatin, ical response modifiers; growth inhibitors, antihormonal therapeutic agents, leucovorin; tegafur; and haematopoietic growth s.
Other anti-cancer agent(s) include antibody therapeutics such as trastuzumab (Herceptin), antibodies to costimulatory molecules such as CTLA-4, 4-1BB and PD- 1, or antibodies to cytokines (IL-10, TGF-B, etc).
Other anti-cancer agents include CSFlR inhibitors (PLX3397, LY3022855, etc.) and CSFlR antibodies (IMC-CS4, RG7155, etc), W0 72596 Other anti-cancer agents include BET inhibitors (INCB054329, OTXOlS, CPI- 0610, etc), LSDl inhibitors (GSK2979552, INCB059872, etc), HDAC inhibitors (panobinostat, vorinostat, etc), DNA methyl transferase inhibitors (azacitidine and bine), and other epigenetic modulators.
Other anti-cancer agents include Bcl2 inhibitor ABT-199, and other Bcl-2 family protein inhibitors.
Other anti-acner agents e TGF beta receptor kinase inhibitor such as LY2157299.
Other anti-cancer agents include BTK inhibitor such as ibrutinib. 1O Other anti-cancer agents include beta n pathway inhibitors, notch pathway inhibitors and hedgehog pathway inhibitors.
Other anti-cancer agents include inhibitors of s associated cell proliferative disorder. These s include but not limited to Aurora—A, CDKl, CDK2, CDK3, CDKS, CDK7, CDK8, CDK9, ephrin receptor kinases, CHKl, CHK2, SRC, Yes, Fyn, Lck, Fer, Fes, Syk, Itk, BmX, GSK3, JNK, PAKl, PAK2, PAK3, PAK4, PDKl, PKA, PKC, Rsk and SGK.
Other ancer agents also include those that block immune cell migration such as antagonists to chemokine receptors, including CCR2 and CCR4.
Other anti-cancer agents also include those that augment the immune system such as adj uvants or adoptive T cell transfer.
Anti-cancer vaccines include dendritic cells, synthetic peptides, DNA vaccines and inant Viruses.
One or more additional immune checkpoint inhibitors can be used in combination with a compound as described herein for treatment of sociated es, disorders or ions. Exemplary immune checkpoint inhibitors include inhibitors against immune checkpoint molecules such as CD27, CD28, CD40, CD122, CD96, CD73, CD47, 0X40, GITR, CSFlR, 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, CD96, TIGIT, PD-l, PD-Ll and PD-L2. In some embodiments, the immune checkpoint 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, , IDO, KIR, LAG3, PD-l, TIM3, CD96, TIGIT, 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, LAIRl inhibitors, CD160 inhibitors, 2B4 inhibitors and TGFR beta inhibitors.
In some embodiments, the inhibitor of an immune checkpoint molecule is anti- PDl antibody, anti-PD-Ll antibody, or anti-CTLA-4 antibody.
In some embodiments, the inhibitor of an immune checkpoint molecule is an tor of PD-l, e. g., an anti-PD-l monoclonal antibody. In some embodiments, the 1O D-l monoclonal antibody is nivolumab, pembrolizumab (also known as MK- 3475), pidilizumab, SHR-1210, , or 4. In some embodiments, the D—l monoclonal antibody is nivolumab, pembrolizumab, or PDROOI. In some embodiments, the anti-PDI antibody is pembrolizumab.
In some embodiments, the inhibitor of an immune oint molecule is an inhibitor of PD-LI, e.g., an anti-PD-Ll monoclonal antibody. In some embodiments, 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 (atezolizumab) or MEDI4736 (durvalumab).
In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of CTLA-4, e. g., an anti-CTLA-4 antibody. In some embodiments, the anti- CTLA-4 antibody is umab or tremelimumab.
In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of LAG3, e. g., an anti-LAG3 antibody. In some ments, the anti- LAG3 antibody is 6016 or LAG525.
In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of GITR, e. g, an anti-GITR antibody. In some embodiments, the anti-GITR antibody is TRX518, MK-4l66, INCAGN01876 or MK-1248.
In some embodiments, the inhibitor of an immune checkpoint le is an inhibitor of 0X40, e.g., an anti-0X40 antibody or OX40L fusion protein. In some embodiments, the X40 antibody is MED10562, INCAGN01949, GSK283I781, GSK-3174998, MOXR—0916, PF-04518600 or LAG525. In some embodiments, the OX40L fusion protein is MEDI6383.
In some embodiments, the inhibitor of an immune oint molecule is an inhibitor of CD20, e.g., an D20 dy. In some embodiments, the anti-CD20 antibody is obinutuzumab or mab.
The compounds of the present disclosure can be used in combination with bispecific dies. In some embodiments, one of the domains of the bispecific antibody s PD-l, 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 1O agent is an alkylating agent, a proteasome inhibitor, a corticosteroid, or an immunomodulatory agent. Examples of an ting agent include cyclophosphamide (CY), melphalan (MEL), and bendamustine. In some embodiments, the proteasome tor is carfilzomib. In some ments, the corticosteroid is dexamethasone (DEX). In some embodiments, the immunomodulatory agent is lenalidomide (LEN) or pomalidomide (POM).
The compounds of the present disclosure can be combined with r immunogenic agent, such as ous cells, purified tumor antigens (including recombinant proteins, peptides, and carbohydrate molecules), cells, and cells transfected with genes encoding immune stimulating 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 compounds of the present sure can be used in combination with a vaccination 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 implicated in human cancers such as Human Papilloma Viruses (HPV), Hepatitis Viruses (HBV and HCV) and Kaposi's Herpes Sarcoma Virus (KHSV). In some embodiments, the compounds of the present disclosure can be used in combination with tumor specific antigen such as heat shock ns isolated from tumor tissue itself. In some embodiments, the compounds of the present disclosure can be combined with dendritic cells immunization to activate potent anti-tumor responses.
W0 2017!]72596 The compounds of the present disclosure can be used in combination with bispecific macrocyclic peptides that target Fc alpha or Fc gamma receptor-expressing effectors cells to tumor cells. The nds of the present disclosure can also be combined with macrocyclic peptides that te host immune responsiveness.
The compounds of the present disclosure can be used in combination with arginase inhibitors, for example CB-1158.
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 origin. 1O The compounds of the present disclosure can be used as anticoagulant as single agent or in combination with other anticoagulants including but not limited to apixaban, dabigatran, edoxaban, fondaparinex, heparin, xaban, and warfarin.
Methods for the safe and effective administration of most of these chemotherapeutic agents are known to those d in the art. In addition, their stration is described in the standard literature. For e, the administration of many of the chemotherapeutic agents is described in the "Physicians" Desk Reference" (PDR, e.g., 1996 edition, Medical ics Company, Montvale, NJ), the disclosure of which is incorporated herein by reference as if set forth in its Pharmaceutical Formulations and Dosage Forms When employed as pharmaceuticals, the compounds provided herein can be administered in the form of pharmaceutical compositions which refers to a combination of a compound provided herein, or its pharmaceutically acceptable salt, and at least one pharmaceutically acceptable carrier. 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 r local or systemic treatment is desired and upon the area to be d. stration may be topical (including ophthalmic and to mucous membranes including intranasal, vaginal and rectal delivery), pulmonary (e.g., by inhalation or insufflation of powders or aerosols, ing by nebulizer; racheal, intranasal, epidermal and transdermal), ocular, oral or parenteral. Methods for ocular delivery can include topical administration (eye drops), W0 2017!]72596 subconj unctival, ular or intravitreal injection or introduction by balloon catheter or ophthalmic inserts surgically placed in the conjunctival sac. Parenteral administration includes intravenous, rten'al, subcutaneous, intraperitoneal, or intramuscular injection or on; or intracranial, e. g., intrathecal or intraventricular, stration. Parenteral administration can be in the form of a single bolus dose, or may be, for example, by a continuous perfusion pump. Pharmaceutical compositions and formulations for topical stration may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders.
Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and 1O the like may be necessary or desirable.
This application also includes pharmaceutical compositions which contain, as the active ient, one or more of the compounds provided herein in combination with one or more ceutically acceptable carriers. In making the compositions of the t disclosure, the active ingredient is typically mixed with an excipient, d by an excipient or enclosed within such a carrier in the form of, for e, a capsule, sachet, paper, or other container. When the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, , aerosols (as a solid or in a liquid medium), ointments ning, for example, up to 10 % by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile inj ectable solutions, and sterile packaged powders.
In preparing a formulation, the active compound 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 le size of less than 200 mesh. If the active compound is ntially water soluble, the particle size can be adjusted by milling to provide a substantially uniform distribution in the ation, eg, about 40 mesh.
Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, n, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. The formulations can additionally include: W0 2017!]72596 lubricating agents such as talc, ium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl- and propylhydroxy-benzoates; sweetening agents; and flavoring agents. The compositions of the present disclosure can be formulated so as to provide quick, sustained or d release of the active ingredient after stration to the patient by ing procedures known in the art.
The compositions can be formulated in a unit dosage form, each dosage ning from about 5 to about 100 mg, more y about 10 to about 30 mg, of the active ingredient. The term "unit dosage forms" refers to physically discrete units 1O suitable as unitary dosages for human subjects and other s, each unit containing a predetermined quantity of active material ated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.
The active compound can be effective over a wide dosage range and is generally administered in a pharmaceutically effective amount. It will be understood, however, that the amount of the 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 response of the individual patient, the severity of the patient’s ms, and the like.
For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical ent to form a solid rmulation composition containing a homogeneous mixture of a compound of the t disclosure. When referring to these pre—formulation compositions as homogeneous, the active ingredient is typically dispersed evenly throughout the composition so that the composition can be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. This solid pre-formulation is then subdivided into unit dosage forms of the type bed above containing from, for example, 0.1 to about 500 mg of the active ingredient of the present disclosure.
The tablets or pills of the present disclosure can be coated or otherwise 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 former. The two W0 2017!]72596 ents can be separated by an enteric layer which serves to resist disintegration in the stomach and permit the inner ent 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 polymeric acids with such materials as shellac, cetyl alcohol, and ose acetate.
The liquid forms in which the compounds and compositions of the present disclosure 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 1O oil, as well as elixirs and similar pharmaceutical vehicles.
The compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and s. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described supra. In some embodiments, the compositions are administered by the oral or nasal atory route for local or systemic effect. Compositions in can be nebulized by use of inert gases. Nebulized solutions may be breathed directly from the nebulizing device or the nebulizing device can be attached to a face masks tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions can be administered orally or nasally from s which deliver the formulation in an appropriate manner.
The amount of compound or ition 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 applications, compositions can be administered to a patient already ing from a disease in an amount sufficient to cure or at least partially arrest the symptoms of the disease 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 l condition of the patient, and the like.
The compositions stered to a t can be in the form of pharmaceutical compositions bed above. These compositions can be sterilized by tional sterilization techniques, or may be sterile filtered. Aqueous solutions W0 2017!]72596 can be packaged for use as is, or lyophilized, the lyophilized preparation being ed with a sterile aqueous r prior to administration. The pH of the compound 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 the compounds of the present disclosure can vary according to, for example, the ular use for which the treatment is made, the manner of administration of the compound, the health and condition of the patient, 1O and the judgment of the prescribing physician. The proportion or concentration of a compound provided herein in a pharmaceutical composition can vary depending upon a number of factors including dosage, chemical characteristics (e.g., hobicity), and the route of administration. For example, the compounds provided herein can be provided in an aqueous physiological buffer solution containing about 0.1 to about 10% w/v of the compound for parenteral administration. Some l dose ranges are from about 1 ug/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 selected, 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.
The compounds provided herein can also be formulated in combination with one or more onal active ingredients which can include any ceutical agent such as anti-viral , vaccines, antibodies, immune enhancers, immune ssants, anti-inflammatory agents and the like. d Compounds andAssay Methods r aspect of the present disclosure relates to fluorescent dye, spin label, heavy metal or radio-labeled compounds provided herein that would be useful not only in imaging but also in assays, both in vitro and in vivo, for localizing and quantitating the TAM kinases in tissue samples, including human, and for identifying W0 2017!]72596 2017/024270 TAM kinases ligands by inhibition binding of a labeled compound. Accordingly, the present disclosure includes TAM kinases assays that contain such labeled nds.
The t disclosure further includes isotopically-labeled compounds of the invention. An "isotopically" or "radio-labeled" compound is a compound provided herein where one or more atoms are replaced or substituted by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature (i.e., naturally occurring). Suitable radionuclides that may be incorporated in nds of the present disclosure include but are not limited to 2H (also written as D for deuterium), 3H (also written as T for m), 11C, 13C, 14C, 13N, 1O "N, 150, 170, 1803 18F, 35$, 36CL 82Br, 75Br, 76131.3 77Br, 1231, 12413 1251 and 1311. The radionuclide that is incorporated in the instant radio-labeled nds will depend on the specific application of that radio-labeled compound. For example, for in vitro TAM kinases labeling and competition assays, compounds that incorporate 3H, 14C, 82Br, 125I, 131I, or 358 will generally be most useful. For radio-imaging applications 11C, 18F, 125I, 123I, 1241, 1311, 75Br, 76Br or 77Br will generally be most useful.
It is understood that a -labeled" or "labeled compound" is a compound that has incorporated at least one radionuclide. In some embodiments the radionuclide is selected from the group ting of 3H, 14C, 125I, 358 and 82Br.
Synthetic methods for incorporating radio-isotopes into organic compounds are applicable to compounds ed herein and are well known in the art.
A radio—labeled compound provided herein can be used in a screening assay to identify/evaluate compounds. In general terms, a newly synthesized or identified compound (i.e., test compound) can be evaluated for its ability to reduce binding of the radio-labeled compound of the application to the TAM kinases. Accordingly, the ability of a test compound to compete with the radio-labeled nd for binding to the TAM kinases directly ates to its binding affinity. nds of the invention can also include all isotopes of atoms occurring in the intermediates or final compounds. Isotopes e those atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen e tritium and deuterium. One or more constituent atoms of the compounds of the invention can be replaced or substituted with isotopes of the atoms in natural or non-natural abundance. In some embodiments, the compound includes at least one W0 2017!]72596 deuterium atom. For example, one or more hydrogen atoms in a compound of the present disclosure can be ed or substituted by deuterium. In some embodiments, the compound includes two or more deuterium atoms. In some embodiments, the compound includes 1, 2, 3, 4, 5, 6, 7 or 8 deuterium atoms. Synthetic methods for including isotopes into organic compounds are known in the art.
The present disclosure also includes pharmaceutical kits useful, for example, in the treatment or prevention of TAM-associated diseases or disorders, y, 1O diabetes and other es referred to herein which include one or more containers containing a pharmaceutical composition comprising a eutically effective amount of a compound provided herein. Such kits can further include, if desired, one or more of various tional pharmaceutical kit components, such as, for example, containers with one or more pharmaceutically acceptable carriers, additional containers, etc, as will be readily nt to those skilled in the art. Instructions, either as inserts or as labels, indicating quantities of the ents to be administered, guidelines for administration, and/or guidelines for mixing the components, can also be included in the kit.
The invention will be described in greater detail by way of specific examples.
The following examples are offered for illustrative purposes, and are not intended to limit the invention in any manner. Those of skill in the at will readily recognize a variety of non—critical parameters which can be changed or modified to yield ially the same results. The nds of the Examples were found to be inhibitors of TAM kinases as described below.
Preparatory LC-MS purifications of some of the compounds prepared were performed on Waters mass directed fractionation s. The basic ent setup, protocols, and control software for the ion of these systems have been described in detail in the literature. See e. g. "Two-Pump At Column on Configuration for Preparative LC-MS", K. Blom, J. Combi. Chem, 4, 295 (2002); "Optimizing Preparative LC-MS rations and Methods for Parallel Synthesis Purification", K. Blom, R. Sparks, J. Doughty, G. Everlof, T. Haque, A. Combs, J.
Combz'. Chem, 5, 670 (2003), and "Preparative LC-MS Purification: Improved Compound Specific Method Optimization", K. Blom, B. Glass, R. Sparks, A. Combs, J. Combi. Chem, 6, 874-883 (2004). The compounds separated were typically subjected to analytical liquid tography mass spectrometry (LCMS) for purity check under the following conditions: Instrument; t 1100 series, LC/MSD, Column: Waters SunfireTM C18 5 pm 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 e—phase high performance liquid chromatography (RP-HPLC) with MS 1O detector or flash chromatography (silica gel) as indicated in the Examples. Typical preparative reverse-phase high performance liquid tography (RP-HPLC) column conditions are as follows: pH = 2 purifications: Waters SunfireTM C18 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: acetonitrile; the flow rate was 30 mL/minute, the separating gradient was optimized for each compound using the Compound c Method Optimization protocol as described in the literature [see "Preparative LCMS Purification: Improved Compound Specific Method Optimization", K. Blom, B.
Glass, R. Sparks, A. Combs, J. Comb. Chem, 6, 874-883 (2004)]. Typically, the flow rate used with the 30 X 100 mm column was 60 ute. pH = 10 purifications: Waters e C18 5 mm le size, 19 x 100 mm column, 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 nd using the Compound Specific Method Optimization protocol as described in the literature [See rative LCMS Purification: Improved Compound c Method Optimization", K. Blom, B. Glass, R. Sparks, A. Combs, J. Comb.
Chem, 6, 874-883 (2004)]. Typically, the flow rate used with 30 X 100 mm column was 60 mL/minute.
EXAMPLES Example 1. N-[4-(4-Aminoethylpyrrolo[2,1-f][1,2,4]triazin-S-yl)phenyl](4- fluorophenyl)-2,5-dioxo-1,2,5,6,7,8-hexahydroquinoline—3-carboxamide W0 2017I172596 \ N—< >—F HN O Step I : N—[(2, 6—Dl'0xocyclohexylidene)methyl]urea HZN—<\ To a mixture of 1,3-cyclohexanedione (from Aldrich, 500 mg, 4.46 mmol) and urea (268 mg, 4.46 mmol) dissolved in N,N-dimethylformamide (1.73 mL at 50 0C), was added ethyl orthoformate (1.11 mL, 6.69 mmol) and acetic acid (8.9 mL). The reaction e was heated in a sealed tube at 90 °C for 3 h. The reaction mixture was cooled, concentrated under vacuum, and left at rt for crystallization. The resulting precipitate was filtered by vacuum and the cake was washed with cold sec- 1O BuOH to give the desired product as off-white powders (536 mg, 66%). LCMS calcd for C3H11N203 (M+H)+: m/z = 183.1. Found: 183.1.
Step 2: Methyi1 2, 5-dl'0x0-5, 6, 7,8-2‘6trahydr0-2H—chr0menecarb0xylate N-[(2,6-Dioxocyclohexylidene)methyl]urea (50 mg, 0.27 mmol) was dissolved in dry NN—dimethylformamide (0.54 mL), followed by the addition of acetic acid, ethyl ester (35.4 mg, 0.36 mmol) and potassium utoxide (61.6 mg, 0.55 mmol) with stirring. The reaction mixture was heated at 100 °C for 1 h. After filtration and removal of the solvent, an oily residue was ed as the desired product (70 mg). The crude product was used directly in the next step without W0 2017!]72596 further purification. LCMS calcd for C11H1105 (M+H)+: m/z = 2231. Found: 2231.
Step 3: Methyl J-(4-flu0r0phenyD-2, 5-dz'0x0-1, 2, 5, 6, 7, 8-hexahydr0quz’n0lz’ne ylate To a solution of methyl 2,5-dioxo-5,6,7,8-tetrahydro-2H-chromene-3— ylate (30 mg, 0.14 mmol) in tetrahydrofuran (0.4 mL) and MN- dimethylformamide (0.1 mL) at It was added p-fluoroaniline (15 mg, 0.14 mmol). The reaction mixture was stirred at rt for 3 h, followed by the addition ofN—(3— 1O dimethylaminopropyl)-N’-ethylcarbodiimide hydrochloride (34 mg, 0.18 mmol) and 4-dimethylaminopyridine (4.1 mg, 0.034 mol) at rt. The reaction mixture was stirred at rt for additional 20 h. After ion, the crude was d by prep LC-MS (pH = 2 method; Waters SunFire PrepC18 5pm OBDTM column, 30x100 mm, 60 mL/min, eluting with a gradient of MeCN and water with 0.1% TFA) to give the desired product (12 mg, 28%). LCMS calcd for C17H15FNO4 (M+H)+: m/z = 316.1. Found: Step 4: 1—(4—FZu0r0phenyU-2, 5-dl'0x0-1, 2, 5, 6, 7, 8-hexahydr0quinoline-3—carb0xylz’c To a on of methyl 1-(4-fluorophenyl)-2,5-dioxo-1,2,5,6,7,8— hexahydroquinolinecarboxylate (5.0 mg, 0.016 mmol) in methanol (0.10 mL) was added 1.0 M sodium hydroxide in water (0.15 mL). The reaction mixture was stirred at rt for 30 min, and the crude was neutralized with HCl (1N), diluted with EtOAc.
The EtOAc layer was separated, and the aqueous layer was washed with EtOAc twice. The combined organic layers were dried, concentrated under vacuum to give the desired acid t as off-white powders. LCMS calcd for C16H13FNO4 (M+H)+: m/Z = 3021. Found: 302.2.
Step 5: 7- Vinylpyrr010[2, 1 -f][1 triazz'namz'ne , 2, 4] In a sealed flask a mixture of 5-tetramethylvinyl-1,3,2-dioxaborolane (from Aldrich, 1.52 g, 9.86 mmol), 7-bromopyrrolo[2,1-f][1,2,4]triazin-4—amine (from J & W Pharm Lab, 1.50 g, 7.04 mmol) and MN—diisopropylethylamine (3.7 mL, 21 mmol) in 1,4-dioxane (20 mL) and water (0.97 mL) was stirred and flushed with N2 for 5 min before bis(tri-t—butylphosphine)palladium (540 mg, 1.0 mmol) was 1O added. The reaction mixture was sealed and heated at 110 0C in an oil bath for 60 min, filtered through a pad of celite and concentrated. The crude was purified by Biotage silica gel column chromatography (40 g column, 0 to 100% EtOAc in hexanes) to give the desired product as white powders (541 mg, 48%). LCMS calcd for CsH9N4 (M+H)+: m/z= 161.1. Found: 161.1.
Step 6: 7—Ez‘hylpyrr010[2, 1-f][1, 2, 4]trz'azz'namme To a solution of 7-vinylpyrrolo[2,1-f][1,2,4]triazinamine (1.00 g, 6.24 mmol) in methanol (30 mL) was added a e of palladium (1.33 g) (5% Pd on carbon). The reaction mixture was placed on hydrogen Parr shaker at 25 psi for 2 h.
After ion through a celite pad, the filtrate was concentrated under vacuum to give the desired t as off-white powders. LCMS calcd for 4 (M+H)+: m/z = 1631. Found: 163.1.
Step 7: 5-Br0m0- 7—ethylpyrr010[2, 1fl[1, 2, 4]triazz'naml'ne W0 2017!]72596 NH2 Br kN'N\ / To a solution of lpyrrolo[2,1-f][1,2,4]triazinamine (600 mg, 3.7 mmol) in NN—dimethylformamide (16 mL) was added N—bromosuccinimide (395 mg, 2.22 mmol). The resulting mixture was stirred at rt for 30 min, d with EtOAc and filtered. The filtrate was washed with saturated NaHCO3, water, dried over Na2SO4, filtered and concentrated under vacuum to give the d product as tan solid. LCMS calcd for CsHioBrN4 (M+H)+: m/z = 241.0, 243.0. Found: 241.0, 243.0.
Step 8: 5-(4-Amin0pheny0ez‘hylpyrr010[2, 1fl[1, 2, zinamine In a sealed tube a mixture of 5-bromoethylpyrrolo[2,1-f] [1,2,4]triazin amine (200 mg, 0.83 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)aniline (from Aldrich, 236 mg, 1.08 mmol) and NN—diisopropylethylamine (0.43 mL, 2.5 mmol) in 1,4-dioxane (3.24 mL) and water (0.30 mL) was stirred and flushed with N2 for 5 min before bis(tri-t—butylphosphine)palladium (130 mg, 0.25 mmol) was added. The reaction mixture was sealed and heated at 110°C in an oil bath for 1 h.
After filtration, the crude was diluted with MeOH and purified by prep LC—MS (pH = method; XBridgeTM PrepC18 5pm OBDTM column, 30x100 mm, 60 mL/min, eluting with a gradient of MeCN and water with 0.15% NH4OH) to give the desired product as light brown powders (88 mg, 42%). LCMS calcd for C14H16N5 (M+H)+: m/z = 2541. Found: 254.1.
Step 9: N-[4-(4-Amz'n0ethylpyrr010[2,1-fl[1,2,4]triazinyl)phenyl](4— fluorophenyD-Z, x0-1, 2, 5, 6, 7, 8-hexahydr0quinoline-S-carboxamz’de -(4-Aminophenyl)ethylpyrrolo[2,1-f][1,2,4]triazinamine (3.2 mg, 0.013 mmol), 1-(4-fluorophenyl)-2,5-dioxo-1,2,5,6,7,8-hexahydroquinoline W0 72596 2017/024270 carboxylic acid (4.6 mg, 0.015 mmol) (prepared in Example 1, step 4), N,N,N’,N’- tetramethyl-O-(7-azabenzotriazolyl)uronium hexafluorophosphate (12 mg, 0.032 mmol) in NN-dimethylformamide (0.10 mL) and NN-diisopropylethylamine (5.0 mg, 0.04 mmol) were mixed together and stirred at It for 20 min. The mixture was filtered, concentrated and purified by prep LC-MS (pH = 10 method; XBridgeTM PrepC18 5pm OBDTM column, 30x100 mm, 60 mL/min, eluting with a gradient of MeCN and water with 0.15% NH4OH) to give the desired product as white powders (1.6 mg, %). LCMS calcd for C30H26FN603 (M+H)+: m/z = 537.2. Found: 5372 1O Example 2. N—[4-(4-Amin0-7—ethylpyrrolo[2,1-f] [1,2,4]triazin-S-yl)phenyl]-1— [(1R)hydroxyphenylethyl]ox0-1,2-dihydr0pyridine-3—carb0xamide HN O N/ .— QN—N / Step 1: )-2—Hydr0xyphenylethyZ]0x0-1,2—dz'hydr0pyridme—3—carb0xyz’z'c HO O 0 Dimethyl [(2E)methoxypropenylidene]malonate (from Acros Organics, 0.20 g, 1.00 mmol) was taken up in methanol (1.8 mL), combined with (2R)aminophenylethanol (0.14 g, 1.00 mmol) and MN—diisopropylethylamine (0.55 mL, 3.2 mmol). The on mixture was sealed and stirred for 2 h at 130 0C.
Then the reaction mixture was combined with 2.0 M sodium hydroxide in methanol (50 mL) and 2.0 M sodium hydroxide in water (5.0 mL) and continuously stirred at rt for 2 h. The crude was neutralized with HCl (3N), extracted with 3. The combined organic layers were dried, d and concentrated under vacuum to give the desired product as light brown gum. LCMS calcd for C14H14NO4 (M+H)+: m/z = W0 2017!]72596 2601. Found: 260.1.
Step 2: N—[4-(4-Amz'n0- lpyrr010[2, 1-fl[1, 2, 4]trz'azz'nyl)pheny1]-I-[(1R) y—I —phenylethyl]0x0-1, 2-dz'hydr0pyrz‘dz‘ne-S-carboxamz‘de -(4-aminophenyl)ethylpyrrolo[2,l-fl[1,2,4]triazinamine (3.0 mg, 0.012 mmol) (prepared in Example HF1, step 8), 1-[(1R)hydroxyphenylethyl]— 2-oxo-1,2—dihydropyridinecarboxylic acid (3.6 mg, 0.014 mmol), N,N,N’,N’— tetramethyl—O-(7-azabenzotriazolyl)uronium hexafluorophosphate (11.2 mg, 0.03 1O mmol) in N,N—dimethylformamide (0.10 mL) and MN—diisopropylethylamine (4.6 mg, 0.035 mmol) were mixed together and stirred at It for 60 min. The reaction mixture was filtered, concentrated and purified by prep LC-MS (pH = 10 method; XBridgeTM PrepC18 5pm OBDTM column, 30x100 mm, 60 mL/min, eluting with a gradient of MeCN and water with 0.15% NH4OH) to give the desired product as white powders (2.0 mg, 34%). LCMS calcd for N603 (M+H)+: m/z = 4952. Found: 4952.
Example 3. N-[4-(4-Aminoethylpyrrolo[2,1-f] [1,2,4]triazin-S-yl)phenyl] 2-hydroxy-l-methylethyl]oxo-1,2-dihydropyridinecarboxamide \ NJ; HN O N’ .— QN'N / Step 1: 1-[(1R)Hydr0xy—1-methylethyl]-2—0x0-1,2-dihydr0pyridinecarboxylz'c HO O Dimethyl [(2E)methoxypropenylidene]malonate (from Acros Organics, 200 mg, 1.00 mmol) was taken up in methanol (1.82 mL), combined with (R)-(-)aminopropanol (from Aldrich, 75.0 mg, 1.00 mmol) and MN- diisopropylethylamine (0.55 mL, 3.2 mmol). The reaction mixture was sealed and W0 2017!]72596 2017/024270 stirred for 2 h at 130 0C. Then the reaction mixture was ed with 2.0 M sodium hydroxide in methanol (50 mL) and 2.0 M sodium hydroxide in water (5.0 mL) and continuously stirred at rt for 2 h. The reaction mixture was acidified with 5.0 mL of HCl (3 N), concentrated under vacuum to remove solvents. The residue was washed with THF and EtOAc, dried, filtered and concentrated under vacuum to give the d product as off-white powders. LCMS calcd for C9H12NO4 (M+H)+: m/z = 198.1. Found: 198.1.
Step 2: N—[4-(4-Aml'n0- 7-ethylpyrr010[2, 1-fl[1, 2, 4]!riazinyl)phenyl][(1R) 1O hydroxy—I —methylethyl]-2—0x0-1, 2—dihydr0pyridinecarboxamide -(4-Aminopheny1)ethy1pyrrolo[2,l-f][1,2,4]triazinamine (5.0 mg, 0.020 mmol) (prepared in e HFl, step 8), 1-[(1R)hydroxymethylethy1]— 2-oxo-l,2-dihydropyridinecarboxy1ic acid (4.7 mg, 0.024 mmol), N,N,N’,N’- tetramethyl-O—(7—azabenzotriazolyl)uronium hexafluorophosphate (18.8 mg, 0.05 mmol) in NN—dimethylformamide (0.1 mL) and NN—diisopropylethylamine (7.7 mg, 0.06 mmol) were mixed together and stirred at rt for 30 min. The mixture was filtered, concentrated and purified by prep LC-MS (pH = 10 method; XBridgeTM PrepC18 Sum OBDTM column, 30x100 mm, 60 mL/min, eluting with a gradient of MeCN and water with 0.15% NH4OH) to give the desired t as white powders (2.0 mg, 23%). LCMS calcd for N603 (M+H)+: m/z = 433.2. Found: 4332.
Example 4. N-[4-(4-Aminoethylpyrrolo[2,1-f][1,2,4]triazin-S-yl)phenyl]-1— [(1R)(hydroxymethyl)propyl]oxo-1,2-dihydropyridine—3—carboxamide Step 1: 1-[(1R)-]-(Hydroxymethprropyl]0x0-1,2-dz'hydr0pyridmecarb0xylz‘c HOéQf’—OHO Dimethyl [(2E)methoxypropenylidene]malonate (from Acros Organics, 200 mg, 1.00 mmol) was taken up in methanol (1.82 mL), combined with (2R)aminobutan-l-ol (89.0 mg, 1.00 mmol) and MN-diisopropylethylamine (0.55 mL, 3.2 mmol). The reaction mixture was sealed and stirred for 2 h at 130 °C. Then the reaction mixture was combined with 2.0 M sodium ide in methanol (50 mL) and 2.0 M sodium hydroxide in water (5.0 mL) and continuously stirred at It for 1 h. The reaction mixture was acidified with 5.0 mL of HCl (3 N), concentrated under vacuum to remove solvents. The residue was washed with THF and EtOAc, 1O dried, filtered and concentrated under vacuum to give the desired product as off-white powders. LCMS calcd for C10H14NO4 (M+H)+: m/z = 212.1. Found: 2121 Step 2: N—[4-(4-Amz'n0ethylpyrr010[2,1-fl[1,2,4]lriazinyl)phenyl][(1R) (hydroxymethprropylj-Z-oxo-J, 2—dihydr0pyridine-S-carboxamz‘de 5-(4-Aminophenyl)ethy1pyrrolo[2,1-f][1,2,4]triazinamine (5.0 mg, 0.020 mmol) red in e HF1, step 8), 1-[(1R)(hydroxymethyl)propyl]- 2—oxo-1,2—dihydropyridinecarboxylic acid (5.0 mg, 0.024 mmol), N,N,N’,N’- tetramethyl-O-(7-azabenzotriazolyl)uronium hexafluorophosphate (18.8 mg, 0.049 mmol) in NN—dimethylformamide (0.1 mL) and sopropylethylamine (7.7 mg, 0.06 mmol) were mixed together and stirred at It for 30 min. The reaction mixture was filtered, trated and purified by prep LC-MS (pH = 10 method, XBridgeTM PrepC18 5pm OBDTM column, 30x100 mm, 60 mL/min, eluting with a gradient of MeCN and water with 0.15% NH4OH) to give the d product as white s (1.7 mg, 19%). LCMS calcd for C24H27N603 (M+H)+: m/z = 447.2. Found: 447.2.
Example 5. N-[4-(4-Amin0ethylpyrrolo[2,1-f][1,2,4]triazin-S-yl)phenyl]-1— benzyl—Z-oxo—1,2-dihydropyridine—3-carboxamide -(4—Aminophenyl)ethylpyrrolo[2,1-f][1,2,4]triazinamine(4.6 mg, 0.02 mmol) red in Example 1, step 8), 1-benzyloxo-1,2-dihydropyridine—3— carboxylic acid (from Aurum Pharmatech, 5 mg, 0.02 mmol), N,N,N’, ’-tetramethyl- 0-(7-azabenzotriazolyl)uronium hexafluorophosphate (17.3 mg, 0.05 mmol) in MN-dimethylformamide (0.1 mL) and MN—diisopropylethylamine (7 mg, 0.05 mmol) were mixed together and stirred at rt for 30 min. The reaction mixture was filtered, concentrated and purified by prep LC-MS (pH = 10 method; XBridgeTM PrepC18 5pm OBDTM column, 30x100 mm, 60 mL/min, eluting with a gradient of MeCN and water with 0.15% NH4OH) to give the desired product as white powders (2.4 mg, 28%). LCMS calcd for C27H25N602 (M+H)+: m/z = 465.2. Found: 4652.
Example 6. N-[4-(4-Amin0ethylpyrrolo[2,1-f] [1,2,4]triazin-S-yl)phenyl]-1— methyl-Z-oxo-l,2-dihydropyridine—3-carboxamide minophenyl)ethylpyrrolo[2,l-f][1,2,4]triazinamine (4 mg, 0.02 mmol) (prepared in Example 1, step 8), 1-methyloxo-1,2-dihydropyridine ylic acid (from Synthonix, 2.9 mg, 0.02 mmol), ,N’-tetramethyl-O-(7- azabenzotriazol-l—y1)uronium hexafluorophosphate (12 mg, 0.03 mmol) in MN- dimethylformamide (0.1 mL) and triethylamine (4.8 mg, 0.05 mmol) were mixed together and d at rt for 30 min. The reaction mixture was filtered, concentrated and purified by prep LC-MS (pH = 10 method; XBridgeTM PrepC18 5pm OBDTM column, 30x100 mm, 60 , eluting with a gradient of MeCN and water with 0.15% NH4OH) to give the desired product as white powders (1.6 mg, 26%). LCMS calcd for C21H21N602 (M+H)+: m/z = 389.2. Found: 389.2.
Example 7a. N-{4-[4-Amino—7—(cishydr0xycyclohexyl)pyrrolo[2,1- ]] [1,2,4] triazin-S-yl] }0xo- l-phenyl-1,2-dihydropyridine—3—carb0xamide Example 7b. N—{4—[4-Amin0(transhydroxycyclohexyl)pyrrolo[2,1- 1] [1,2,4] triazin-S-yl] phenyl}0x0phenyl-1,2-dihydropyridine-S-carboxamide go no HN O HN O 1 0 OH OH Step 1: Methyl 2—0x0phenyl-1,2-dz'hydr0pyrz‘dz'ne-S-carboxylate o o O A mixture of methyl 2-oxo-1,2-dihydropy1idinecarboxylate (from Aldrich, 1.50 g, 9.80 mmol), phenylboronic acid (3.6 g, 29 mmol), ted 4A molecular sieves (2.8 g, 12 mmol) and cupric e (3.6 g, 20.0 mmol) in methylene chloride (60 mL) was treated with pyridine (2.4 mL, 29 mmol). The reaction mixture was stirred at rt for 60 h, filtered h a celite pad. The filtrate was concentrated under vacuum. The crude product was purified by Biotage silica gel chromatography (0 to 100% ethyl acetate in hexanes) to afford the desired product as white powders (1.26 g, 56%). LCMS calcd for C13H12NO3 (M+H)+: m/z = 230.1. Found: 2301.
Step 2: 2—0x0phenyZ-1,2-a’z‘hydr0pyridinecarb0xyll'c acid HOYQI\I O 0 \© W0 2017/‘172596 Methyl 2—oxophenyl-1,2-dihydropyridine—3-carboxylate (800 mg, 3.49 mmol) was dissolved in tetrahydrofuran (7.4 mL) and methanol (37 mL). The mixture was then treated with 1.0 M sodium hydroxide in water (14.0 mL), and d at rt for 30 min. The reaction mixture was neutralized with HCl (12 M) to pH = 6-7.
The solvents were removed under vacuum and the product precipitated out. The solid was collected by vacuum filtration, and the cake was washed with water and dried ght to give the desired acid product as white powders (636 mg, 85%). LCMS calcd for NO3 (M+H)+: m/z = 216.1. Found: 216.1.
Step 3: 2—0x0phenyl—N-[4-(4, 4, 5, 5-z‘ez‘ramez‘hyl-I, 3, 2-dl'0xab0r0lan-Z—prhenyU- 1, 2-dihydr0pyridinecarboxamide Q5 0 O 0 To a mixture of ,5,5-tetramethyl-1,3,2-dioxaborolanyl)aniline (from Aldrich, 214 mg, 0.98 mmol) and 2-oxophenyl-1,2-dihydropyridinecarboxylic acid (200 mg, 0.93 mmol) in MN-dimethylformamide (4.5 mL) was added triethylamine (194 uL, 1.4 mmol) followed by N,N,N',N'—tetramethyl-O-(7- azabenzotriazol—1-y1)uronium hexafluorophosphate (424 mg, 1.12 mmol). The resulting reaction mixture, which became a mixture of solids quickly, was stirred at rt for 1 h. The solids were filtered and washed with water. Drying by vacuum suction gave the desired product as a white solid (306 mg, 79%). LCMS calcd for C24H26BN204 (M+H)+: m/z = 417.2. Found: 417.2.
Step 4: [tert—Bugzlflimethyysilyl]0xy}cyclohexenyl)pyrr0[0[2, 1- f][1, 2, 4]triazinamine W0 2017!]72596 A mixture of tert—butyl(dimethyl){[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)cyclohexeny1]oxy}silane (450 mg, 1.33 mol), 7-bromopyrrolo[2,1- ,4]triazinamine (283 mg, 1.33 mmol), sodium carbonate (470 mg, 4.4 mmol), and [1,1’—bis(di-cyc1ohexy1phosphino)ferrocene]dichloropalladium(II) (101 mg, 0.133 mmol) in Iert-butyl alcohol (4.0 mL) and water (1.5 mL) was degassed with nitrogen, then d and heated at 110 °C for 2 h, then 95 °C overnight. The mixture was diluted with ethyl acetate, washed with saturated NaHCO3, water, dried over NazSO4, filtered and concentrated. The product was purified by Biotage silica gel chromatography (0 to 50% EtOAc in hexanes) to give the desired product as off-white 1O powders (242.3 mg, 53%). LCMS calcd for C18H29N4OSl (M+H)+: m/z = 345.2.
Found: 345.2.
Step 5: 7—(4—{[z‘ert-Bug/Mdimethymilyljoxy}cyclohenypyrrolo[2, 1-f][1, 2, 4]triazz'n amine O'Si~ 7A To a solution of 7-(4- { buty1(dimethy1)si1y1]oxy}cyclohex-l-en-l- rolo[2,1-f][1,2,4]triazinamine (230 mg, 0.67 mmol) in methanol (2.8 mL) and tetrahydrofuran (1.4 mL) was added a mixture of palladium (4.6 mg) (10% Pd on carbon). The reaction mixture was vacuumed and placed under a hydrogen balloon for 1 h. After filtration through a celite pad, the filtrate was trated under vacuum to give the desired product (161.9 mg, 70%). LCMS calcd for N4OSl (M+H)+: m/z = 347.2. Found: 347.2.
Step 6: 5—Br0m0-7—(4-{[tert—butyl(dz'methyl)silyljoxy}cyclohexyljpyrrofop, 1- flfl, 2, 4jtriazinamine W0 2017!]72596 O'Si\ To a solution of 7-(4- { [tert-butyl(dimethyl)silyl]oxy}cyclohexyl)pyrrolo[2,1- f][1,2,4]triazin—4-amine (80.0 mg, 0.23 mmol) in methylformamide (1.0 mL) was added N—bromosuccinimide (39.0 mg, 0.22 mmol). The resulting mixture was stirred at It for 10 min. The reaction mixture was d with EtOAc, filtered.
The filtrate was washed with saturated NaHCO3, water, dried, filtered again and concentrated under vacuum to give the desired product as tan solid. LCMS calcd for C18H30BrN4OSi (M+H)+: m/z = 425.1,427.1. Found: 425.1, 427.1.
Step 7: N-{4—[4—Amin0-7—(4-{[tert—butyl(dimethyl)silyl]0xy}cyclohexyl)pyrr0[0[2, 1- f][1, 2, 4jtriazinyljphenyl}0x0phenyZ-1, 2-dz'hydr0pyrz'dz‘necarb0xamide A mixture of 2-oxophenyl-N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan nyl]-1,2-dihydropyridinecarboxamide (48.9 mg, 0.12 mmol) (prepared in Example 7, step 3), 5-bromo(4-{[tert— butyl(dimethyl)silyl]oxy}cyclohexyl)pyrrolo[2,1-f][1,2,4]triazinamine (50 mg, 0.12 mmol), sodium carbonate (42 mg, 0.39 mmol), and [1,1’-bis(di- exylphosphino)ferrocene]dichloropalladium (II) (13.4 mg, 0.018 mmol) in tert— butyl alcohol (035 mL) and water (0.13 mL) was degassed with nitrogen, then stirred and heated at 110 °C for 1 h. The mixture was diluted with ethyl acetate, washed with W0 2017!]72596 saturated NaHCO3, water, dried over NazSO4, filtered and concentrated. The crude product was purified by Biotage silica gel chromatography (0 to 100% EtOAc in hexanes) to give the desired product as white powders (34 mg, 46%). LCMS calcd for C36H43N6O3Si (M+H)+: m/z = 635.3. Found: 635.3.
Step 8: N—{4—[4—Amin0(4—hydr0xycyclohexy0pyrr010[2,1fl[1,2,4]z‘riazin—5— yljphenyl}—2—0x0phenyl-1, 2-dl'hydr0pyridinecarb0xamide A solution -[4-amino(4-{[tert- butyl(dimethyl)silyl] oxy } cyclohexyl)pyrrolo[2, l -f] [l ,2,4]triazinyl]phenyl}—2-oxo- 1O l-phenyl-1,2-dihydropyridine—3-carboxamide (34 mg, 0.05 mmol) in tetrahydrofuran (0.2 mL) was treated with 4.0 M hydrogen chloride in dioxane (0.9 mL, 3.6 mmol).
The reaction mixture was stirred at It for 30 min. The crude (trans and cis isomers with a ratio of 1:4) was concentrated under vacuum and d by prep LC-MS (pH = 10 method; XBridgeTM PrepC18 511m OBDTM column, 30X100 mm, 60 mL/min, eluting with a gradient of MeCN and water with 0.15% NH4OH) to give the desired cis isomer (9.2 mg, 33%). The minor trans isomer (3.5 mg, 12%) was also isolated. Retention time (RT) = RT = 1.189 min for minor trans isomer, first peak off the column; RT = 1.216 min for major cis isomer, second peak off the column. LCMS calcd for C30H29N603 (M+H)+: m/z = 521.2. Found: 521.2. 1H NMR (500 MHz, dmso)512.06(s, 1H), 8.62 (dd, .1: 7.3, 2.2 Hz, 1H), 8.14 (dd, J: 66,22 Hz, 1H), 7.90 (s, 1H), 7.82 (d, J: 8.6 Hz, 2H), 7.66 — 7.52 (m, 6H), 7.47 (d, J: 8.5 Hz, 2H), 6.78 — 6.72 (m, 2H), 6.55 (s, 1H), 4.38 (d, J: 2.9 Hz, 1H), 3.92 (s, 1H), 3.62 (d, J: 6.5 Hz, 1H), 3.16 (t, J: 11.4 Hz, 1H), 1.99 — 1.84 (m, 2H), 1.84 — 1.70 (m,4H), 1.62 (t, J: 12.2 Hz, 1H).
Example 8. 4—Amin0methylpyrrolo[2,1-j] [1,2,4]triazin-5—yl)phenyl] 0x0phenyl-1,2-dihydropyridine—3—carboxamide \_ "43 HN O W0 2017!]72596 Step 1: y1pyrr010[2,1fl[1,2,4]triazinamine kN'N\ / To a solution of 7-bromopyrrolo[2,1-f] [1,2,4]triazinamine (from J & W Pharm Lab, 150 mg, 0.70 mmol) in tetrahydrofuran (2.86 mL) under N2 at rt was added tetrakis(triphenylphosphine)palladium(0) (163 mg, 0.14 mmol). The mixture in a sealed flask was ted and refilled with N2 several times, followed by the addition of 2.0 M dimethylzinc in toluene (5.3 mL, 10 mol) at rt. The reaction mixture was heated at 90 0C for 4 h. The reaction mixture was quenched with ice- water, extracted with EtOAc. The combined organic layers were dried over NazSO4, 1O d, concentrated under vacuum to give the crude, which was purified by prep LC-MS (pH = 10 method, XBIidgeTM PrepC18 5um OBDTM column, 30x100 mm, 60 mL/min, eluting with a nt of MeCN and water with 0.15% NH4OH) to afford the d product as white powders (29.2 mg, 28%). LCMS calcd for C7H9N4 (M+H)+: m/z = 149.1. Found: 149.1.
Step 2: 5-Br0m0methylpyrr010[2,1fl[1,2,4]z‘rz‘azz‘n-4—amme N H2 Br NC / To a solution of 7-methylpyrrolo[2,1-f][1,2,4]triazinamine (29.2 mg, 0.20 mmol) in N,N—dimethylformamide (0.85 mL) was added N-bromosuccinimide (33.3 mg, 0.19 mmol). The resulting mixture was stirred at rt for 15 min and the reaction mixture was diluted with EtOAc, filtered, then washed with saturated NaHCO3, water, dried, filtered and concentrated under vacuum to give the desired product as off-white powders. LCMS calcd for C7HsBrN4 (M+H)+: m/z = 227.0, 229.0. Found: 2270, 229.0.
Step 3: N—[4-(4-Amin0- 7-methylpyrr010[2, 1-fl[1, 2, 4]triazinyUphenyfj0x0 phenyi-I,2-dz‘hydr0pyrz‘dz'necarboxamide In a sealed tube a mixture of 5-bromomethy1pyrrolo[2,1-f][1,2,4]tn'azin amine (5.6 mg, 0.02 mmol), 2-oxophenyl-N-[4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolany1)phenyl]-1,2-dihydropyridinecarboxarnide (8.0 mg, 0.02 mmol) (prepared in Example 7, step 3) and NN—diisopropylethylamine (0.01 mL, 006 mmol) in oxane (0.14 mL) and water (20 uL) was d together and flushed with N2 bubble for 5 min before bis(tri-t-butylphosphine)palladium (4.? mg, 0.01 mmol) was added. The reaction mixture was sealed and then heated at 110 °C for 1 h.
After separation and the aqueous layer extracted with EtOAc, the organic layer was dried, filtered and concentrated under vacuum. The crude was purified by prep LC- MS (pH = 10 ; XBridgeTM PrepC18 5um OBDTM column, 30x100 mm, 60 mL/min, eluting with a gradient of MeCN and water with 0.15% NH4OH) to give the 1O desired product (2.8 mg, 36%). LCMS calcd for C25H21N602 (M+H)+: m/z = 437.2.
Found: 4372.
Example 9. N—[4—(4—Amin0methylpyrrolo[2,1—j] [1,2,4]triazin-5—yl)phenyl] (4-fluorophenyl)—2-oxo-1,2—dihydropyridinecarboxamide Step I: Methyl 1-(4-flu0r0phenyU0x0-1, 2-dihydr0pyrl'dinecarb0xyiate A mixture of methyl 2-oxo-1,2-dihydropyridinecarboxylate (from Aldrich, 1.50 g, 9.8 mmol), 4-fluorophenylboronic acid (from Aldrich, 4.1 g, 29 mmol), activated 4A lar sieves (2.8 g, 12 mmol) and cupric acetate (3.6 g, 20 mmol) in methylene chloride (60 mL) was treated with pyridine (2.4 mL) and then stirred at rt for 18 h. The mixture was filtered through celite and the filtrate was concentrated under vacuum. The crude was purified by Biotage silica gel column tography (0 to 100% ethyl acetate in hexanes) to afford the desired product as off-white gum (1.33 g, 55%). LCMS calcd for C13H11FNO3 (M+H)+: m/z = 2481.
Found: 2481.
W0 2017!]72596 Step 2: 1—(4—Flu0r0phenyU0x0-1,2-dz'hydr0pyridz'necarboxylz'c acid HOYE:N o o 0, Methyl 1-(4-fluorophenyl)oxo-1,2-dihydropyridinecarboxylate (800 mg, 3.24 mmol) was dissolved in ydrofuran (6.82 mL) and methanol (3.41 mL). The mixture was then treated with 1.0 M sodium hydroxide in water (12.9 mL), and the reaction mixture was stirred at rt for 30 min. The reaction mixture was neutralized with HCl (12 M) to pH = 6-7. The solvents were removed under vacuum and the t precipitated out. The solid was collected by vacuum filtration, and the cake 1O was washed with water and dried ght to give the desired acid product as white powders (540 mg, 72%). LCMS calcd for C12H9FNO3 (M+H)+: m/z = 2341. Found: 2341.
Step 3: 1-(4-Flu0r0phenyl)-2—0x0-N-[4-(4, 4, 5, 5-tetramethyl-1, 3, 2-dz'0xab0rolan yl)phenyl]-1 , 2-dihydr0pyridinecarboxamz'de To a mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)aniline (from Aldrich, 197.3 mg, 0.90 mmol) and 1-(4-fluorophenyl)oxo-1,2-dihydropyridine carboxylic acid (from Aldrich, 200 mg, 0.86 mmol) in MN-dimethylformamide (4.0 mL) was added triethylamine (180 uL, 1.3 mmol) followed by N,N,N’, ’-tetramethyl- 0-(7-azabenzotriazolyl)uronium hexafluorophosphate (391 mg, 1.03 mmol). The ing mixture, which became a mixture of solids quickly, was d at rt for 1 h.
The solids were filtered and washed with water. Drying by vacuum suction gave the desired product as a white solid (343 mg, 92%). LCMS calcd for BFN204 (M+H)+: m/z = 435.2. Found: 435.2.
Step 4: N-[3-Flu0r0(4, 4, 5, 5-tetramethyl—1, 3, 2-dz'0xab0r0lany0phenylj0x0-J - phenyZ-I , 2-dz’hydr0pyrz’dz’necarboxamz'de To a mixture of 3-fluoro(4,4,5,5-tetramethyl-1,3,2-dioxaborolan yl)aniline (from Aldrich, 289.2 mg, 1.22 mmol) and 2-oxophenyl-l,2- dihydropyridinecarboxylic acid (250 mg, 1.16 mmol) (prepared in Example 7, step 2) in N,N-dimethylformamide (5.0 mL) was added triethylamine (243 uL, 1.74 mmol) followed by N,N,N',N'—tetramethyl(7-azabenzotriazolyl)uronium hexafluorophosphate (530 mg, 1.39 mmol). The resulting mixture, which became a mixture of solids quickly, was stirred at It for 1 h. The solids were d and washed with water. Drying by vacuum suction gave the desired product as a white solid (335 mg, 66%). LCMS calcd for C24H25BFN204 (M+H)+: m/z = 435.2. Found: 4352.
Step 5: 1-(4-Flu0r0phenyl)-N-[3-flu0r0(4, 4, 5, 5-tetramethyl-I, 3, 2-dioxab0r01an ylj-Z-oxo-J, 2—dihydr0pyrz'dinecarb0xaml'de 43 O 0 OF To a mixture of 3-fluoro(4,4,5,5-tetramethyl-1,3,2-dioxaborolan yl)aniline (from Aldrich, 213.5 mg, 0.90 mmol) and 1-(4-fluorophenyl)—2—oxo-1,2- dihydropyridinecarboxylic acid (200 mg, 0.86 mmol) (prepared in Example 9, step 2) in MN-dimethylformamide (4.7 mL) was added triethylamine (179 uL, 1.29 mmol) followed by N,N,N',N'—tetramethyl(7-azabenzotriazolyl)uronium hexafluorophosphate (391 mg, 1.03 mmol). The resulting mixture, which became a mixture of solids quickly, was stirred at It for 1 h. The solids were filtered and washed with water. Drying by vacuum suction gave the desired product as a white solid (305 mg, 29%). LCMS calcd for C24H24BF2N204 (M+H)+: m/Z = 4532. Found: 4532.
Step 6: 4-Amz'n0- 7-methylpyrrolo[2, 1-f][1, 2, 4]triaziny[)phenyZ]-I -(4- henyD-2—0x0-J, 2-dz'hydropyrz'dme-S-carboxamz'de In a sealed tube a mixture of 5-bromomethy1pyrrolo[2,l-f][1,2,4]triazin—4— amine (5 mg, 0.02 mmol) (prepared in Example 8, step 2), 1-(4-fluorophenyl)—2-oxo— N-[4-(4,4,5,5-tetramethy1-1,3 ,2-dioxaborolanyl)phenyl]-1,2-dihydropyridine carboxamide (8 mg, 0.02 mmol) red in Example 9, step 3) and MN- diisopropylethylamine (0.01 mL, 0.05 mmol) in 1,4-dioxane (0.13 mL) and water (20 uL) was stirred together and flushed with N2 for 5 min before i-z‘- butylphosphine)palladium (4.2 mg, 0.01 mmol) was added. The reaction mixture was sealed and then heated at 110 0C for 1 h. After separation and the aqueous layer extracted with EtOAc, the organic layer was dried, d and concentrated under 1O vacuum. The crude was purified by prep LC-MS (pH = 10 method, XBridgeTM PrepC18 5pm OBDTM column, 30x100 mm, 60 mL/min, eluting with a gradient of MeCN and water with 0.15% NH4OH) to give the desired product (2.4 mg, 32%).
LCMS calcd for FN602 (M+H)+: m/z = 455.2. Found: 455.2.
Example 10. N-[4-(4-Aminomethylpyrrolo[2,1-f] [1,2,4]triazinyl)—3— fluorophenyl]oxo-l-phenyl-1,2-dihydropyridinecarboxamide In a sealed tube a mixture of 5-bromomethy1pyrrolo[2,l-f] [1,2,4]triazin amine (5 mg, 0.016 mmol) (prepared in Example 8, step 2), N-[3-fluoro(4,4,5,5- tetramethyl- l ,3 xaborolanyl)phenyl]oxophenyl-1,2-dihydropyridine carboxamide (7.5 mg, 0.017 mmol) (prepared in Example 9, step 4) and MN- diisopropylethylamine (0.01 mL, 0.049 mmol) in oxane (0.128 mL) and water (20 uL) was stirred together and flushed with N2 for 5 min before bis(tri-t- butylphosphine)palladium (4.2 mg, 0.01 mmol) was added. The reaction mixture was sealed and then heated at 110 0C for 1 h. After separation and the aqueous layer extracted with EtOAc, the organic layer was dried, filtered and concentrated under vacuum. The crude was purified by prep LC-MS (pH = 10 method; XBridgeTM PrepC18 5um OBDTM column, 30x100 mm, 60 mL/min, eluting with a gradient of MeCN and water with 0.15% NH4OH) to give the desired product (1.7 mg, 23%).
LCMS calcd for C25H20FN602 : m/z = 455.2. Found: 455.2.
Example 11. N—[4-(4-Amin0methylpyrrolo[2,1-f] [1,2,4]triazin-5—yl)—3— fluorophenyl](4-flu0r0phenyl)—2—0x0-1,2-dihydropyridinecarb0xamide In a sealed tube a mixture of 5-bromomethylpyrrolo[2,1-f][1,2,4]triazin amine (3.2 mg, 0.01 mmol) (prepared in e 8, step 2), 1-(4-fluorophenyl)—N—[3- fluoro(4,4,5,5 -tetramethyl-1,3,2-dioxaborolanyl)phenyl]oxo-1,2- dihydropyridinecarboxamide (5 mg, 0.01 mmol) (prepared in Example 9, step 5) and MN-diisopropylethylamine (0.01 mL, 0.04 mmol) in 1,4-dioxane (0.15 mL) and water (20 uL) was stirred together and flushed with N2 for 5 min before bis(tri-z‘- butylphosphine)pa11adium (2.7 mg, 0.005 mmol) was added. The on mixture was sealed and then heated at 110 °C for l h. After separation and the aqueous layer extracted with EtOAc, the organic layer was dried, filtered and concentrated under vacuum. The crude was purified by prep LC-MS (pH = 10 method; XBridgeTM PrepC18 5pm OBDTM column, 30x100 mm, 60 mL/min, eluting with a gradient of MeCN and water with 0.15% NH4OH) to give the desired product (2.0 mg, 40%). LCMS calcd for C25H19F2N602 (M+H)+: m/z = 473.2. Found: 473.2.
Example 12. N— [4-(4-Aminoethylpyrrolo ] [1,2,4]triazinyl)—3— fluorophenyl]oxo-l-phenyl-1,2-dihydropyridinecarboxamide W0 2017!]72596 In a sealed tube a mixture of 5-bromoethy1pyrrolo[2,l-f][1,2,4]triazin-4— amine (6 mg, 0.018 mmol) (prepared in Example 1, step 7), N—[3-fluoro(4,4,5,5- ethyl-1,3,2-dioxaborolanyl)phenyl]oxophenyl-1,2-dihydropyridine carboxamide (8.3 mg, 0.02 mmol) (prepared in e 9, step 4) and MN- diisopropylethylamine (0.02 mL, 0.11 mmol) in 1,4-dioxane (0.14 mL) and water (20 uL) was stirred together and flushed with N2 for 5 min before bis(tri-tbutylphosphine dium (4.6 mg, 0.01 mmol) was added. The reaction mixture was sealed and then heated at 110 0C for 1 h. After separation and the aqueous layer extracted with EtOAc, the organic layer was dried, filtered and concentrated under 1O vacuum. The crude was purified by prep LC-MS (pH = 10 method, XBridgeTM PrepC18 5pm OBDTM column, 30x100 mm, 60 mL/min, eluting with a gradient of MeCN and water with 0.15% NH4OH) to give the desired product (2.4 mg, 28%).
LCMS calcd for FN602 : m/z = 469.2. Found: 469.2.
Example 13. N-{4-[4—Amino(tetrahydr0-2H-pyran-4—yl)pyrrolo[2,1- f] [1,2,4] triazin-S-yl] phenyl}oxo- l-phenyl-l,2-dihydropyridine-3—carboxamide N’ —— N‘N / Step 1: 7-(3,6-Dihydr0-2H—pyranyl)pyrr0[0[2,1-fl[1,2,4]triazinamine In a sealed flask a mixture of 4-(4,4,5,5-tetramethy1-1,3,2-dioxaborolan yl)-3,6-dihydro-2H-pyran (from Aldrich, 0.64 g, 3.01 mmol), 7-bromopyrrolo[2,1- f][1,2,4]triazinamine (from J & W Pharm Lab, 0.500 g, 2.35 mmol) and MN- W0 172596 2017/024270 diisopropylethylamine (1.2 mL, 7.0 mmol) in oxane (6 mL) and water (032 mL) was stirred together and flushed with N2 for 5 min before bis(tri-t— butylphosphine)palladium (100 mg, 0.24 mmol) was added. The reaction mixture was then sealed and heated at 120 °C for 4 h, filtered through a pad of celite and concentrated. The crude was purified by Biotage silica gel column chromatography (40 g column, 0 to 100% EtOAc in hexanes) to give the desired product as white powders (168.5 mg, 33%). LCMS calcd for C11H13N4O (M+H)+: m/z = 217.1. Found: 217.1.
Step 2: 7—(Tetrahydr0-2H—pyrany0pyrr010[2, 1fl[I , 2, 4jtriazinamine To a solution of 7-(3,6-dihydro-2H-pyranyl)pyrrolo[2,l-f] [1,2,4]triazin amine (120 mg, 0.55 mmol) in methanol (2.67 mL) and THF (1.3 mL) was added a mixture of palladium (120 mg) (10% Pd on ). The reaction mixture was placed under a hydrogen balloon for 2 hours. After filtration through a celite pad, the e was concentrated under vacuum to give the desired product as white powders (90.2 mg, 75%). LCMS calcd for C11H15N4O (M+H)+: m/z = 219.1. Found: 219.1.
Step 3: 5—Br0m0-7—(retrahydro-ZH—pyranyl)pyrr0[0[2, 1fl[1, 2, azin—4—amine NH: Br Nk/ / 0 To a solution of 7-(tetrahydro-2H-pyranyl)pyrrolo[2,l-f][1,2,4]triazin amine (50 mg, 0.23 mmol) in MN—dimethylformamide (0.99 mL) was added N- bromosuccinimide (41 mg, 0.23 mmol). The resulting mixture was stirred at rt for 15 min. The reaction mixture was diluted with EtOAc, filtered. The filtrate was washed with saturated NaHCO3, water, dried, filtered again and concentrated under vacuum to give the desired product as tan solid. LCMS calcd for C11H14BrN4O (M+H)+: m/z = W0 72596 297.0, 299.0. Found: 297.0, 299.0.
Step 4: N—{4-[4—Amz’n0- 7-(retrahydro-2H-pyranyl)pyrr0Zo[2, 1fl[1 , 2, 4]z‘riazz’n yljphenyl}—2—0x0-1 -phenyl-1, 2-dz'hydr0pyrz‘dz‘ne-S—carboxamz‘de In a sealed tube a mixture of 5-bromo(tetrahydro-2H—pyran yl)pyrrolo[2,1-f][1,2,4]triazinamine (6 mg, 0.02 mmol), 2-oxophenyl-N-[4- (4,4,5,5-tetramethyl-1,3 ,2-dioxaborolanyl)phenyl]-1,2-dihydropyridine carboxamide (8.8 mg, 0.02 mmol) (prepared in Example 7, step 3) and MN- diisopropylethylamine (0.01 mL, 0.06 mmol) in 1,4-dioxane (0.15 mL) and water (20 uL) was stirred er and flushed with N2 or 5 min before bis(tri-z‘- butylphosphine)palladium (5.2 mg, 0.01 mmol) was added. The reaction mixture was sealed and then heated at 110 0C for 1 h. After separation and the aqueous layer extracted with EtOAc, the organic layer was dried, filtered and concentrated under vacuum. The crude was purified by prep LC-MS (pH = 10 method; XBridgeTM PrepC18 Sum OBDTM column, 30x100 mm, 60 , eluting with a nt of MeCN and water with 0.15% NH4OH) to give the desired t (3.2 mg, 31%).
LCMS calcd for C29H27N603 (M+H)+: m/z = 507.2. Found: 5072.
Example 14. N-{4-[4-Amino(tetrahydr0-2H-pyranyl)pyrrolo[2,1- f] [1,2,4]triazinyl] phenyl}(4-fluorophenyl)oxo-1,2-dihydr0pyridine—3— carboxamide In a sealed tube a mixture of 5-bromo(tetrahydro-2H—pyran yl)pyrrolo[2,l-f][1,2,4]triazinamine (6 mg, 0.02 mmol) (prepared in Example 13, step 3), 1-(4-fluorophenyl)oxo-N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan yl)phenyl]-1,2-dihydropyridinecarboxamide (9.2 mg, 0.02 mmol) (prepared in Example 9, step 3) and NN—diisopropylethylamine (0.01 mL, 0.06 mmol) in 1,4- dioxane (0.15 mL) and water (20 uL) was stirred together and flushed with N2 for 5 min before bis(t1i-t-butylphosphine)palladium (5.2 mg, 0.01 mmol) was added. The reaction mixture was sealed and then heated at 110 °C for 1 h. After separation and the aqueous layer extracted with EtOAc, the organic layer was dried, filtered and concentrated under vacuum. The crude was purified by prep LC-MS (pH = 10 method; eTM PrepC18 5pm OBDTM column, 30x100 mm, 60 mL/min, eluting with a gradient of MeCN and water with 0.15% NH4OH) to give the desired product (4.8 mg, 45%). LCMS calcd for C29H26FN603 (M+H)+: m/z = 525.2. Found: 525.2.
Example 15. N-{4-[4-Amino(tetrahydr0-2H-pyran-4—yl)pyrrolo[2,1- ]] [1,2,4] triazin-S-yl] flu0r0phenyl}0x0- l-phenyl-1,2—dihydropyridine—3— carboxamide .8243 N’ —— Ax F N—N / In a sealed tube a mixture of 5-bromo(tetrahydro-2H-pyran yl)pyrrolo[2,1—f][1,2,4]triazinamine (5 mg, 0.02 mmol) red in e 13, step 3), N-[3—fluoro(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)phenyl]-2—oxo-l- phenyl-l,2—dihydropyridine—3-carboxamide (7.3 mg, 0.017 mmol) (prepared in Example 9, step 4) and MN—diisopropylethylamine (0.01 mL, 0.06 mmol) in 1,4- dioxane (0.15 mL) and water (20 uL) was d er and flushed with N2 for 5 min before bis(tri-t-butylphosphine)palladium (4.3 mg, 0.01 mmol) was added. The reaction mixture was sealed and then heated at 110 0C for 2 h. After separation and the aqueous layer extracted with EtOAc, the organic layer was dried, filtered and concentrated under vacuum. The crude was d by prep LC-MS (pH = 2 method; Waters SunFire PrepC18 Sum OBDTM column, 30x100 mm, 60 mL/min, eluting with a gradient of MeCN and water with 0.1% TFA) to give the desired product as white powders (6.4 mg, 72%). LCMS calcd for C29H26FN603 (M+H)+: m/z = 5252. Found: 5252.
Example 16. N-{4-[4-Amin0(tetrahydro—2H-pyran-4—yl)pyrrolo[2,1- f] [1,2,4]triazin-S-yl]fluorophenyl}(4-fluorophenyl)—2-0x0-1,2- dihydr0pyridine—3-carboxamide In a sealed tube a mixture of o(tetrahydro-2H—pyran yl)pyrrolo[2,1-f][1,2,4]triazinamine (6 mg, 0.02 mmol) (prepared in Example 13, step 3), 1-(4-fluorophenyl)—N—[3-fluoro(4,4,5,5-tetramethyl-1,3,2—dioxaborolan yl)phenyl]oxo-1,2-dihydropyridinecarboxamide (9.6 mg, 0.02 mmol) (prepared in Example 9, step 5) and NN-diisopropylethylamine (0.01 mL, 006 mmol) in 1,4- dioxane (0.15 mL) and water (20 uL) was stirred together and flushed with N2 for 5 min before bis(tri-t-butylphosphine)palladium (5.2 mg, 0.01 mmol) was added. The reaction e was sealed and then heated at 110 0C for 1 h. After separation and the aqueous layer extracted with EtOAc, the organic layer was dried, filtered and trated under vacuum. The crude was purified by prep LC-MS (pH = 10 method; XBridgeTM PrepC18 5pm OBDTM column, 30x100 mm, 60 mL/min, eluting with a gradient of MeCN and water with 0.15% NH4OH) to give the desired product (4.4 mg, 40%). LCMS calcd for C29H25F2N603 (M+H)+: m/Z = 543.2. Found: 543.2.
Example 17a. N-{4-[4-Amin0(cishydroxycyclohexyl)pyrrolo[2,1- f] ] triazin-S-yl] phenyl}(4-flu0rophenyl)oxo- 1,2-dihydropyridine carboxamide e 17b. N-{4-[4-Amino—7-(transhydroxycyclohexyl)pyrrolo[2,1- f] [1,2,4]triazinyl] phenyl}(4-fluorophenyl)oxo-1,2-dihydropyridine W0 72596 carboxamide \ @F \ "@F HN O HN O o O NH2 NH2 N/ g N/ _— Q‘N—N / QN—N / OH 25H Step 1: N—{4-[4-Amz'n0- 7-(4-{[tert—butyl(dimethyl)siZyljoxy}cyclohenypyrrolo[2, [- f][1,2,4]triazinyl]phenyl}(4-flu0r0phenyl)-2—0x0-1,2-dl'hydr0pyridine carboxamide \ N—< >—F HN O N’ —— QN—N / 0 SI\ In a sealed tube a mixture of 5-bromo(4-{[tert— butyl(dimethyl)silyl]oxy}cyclohexyl)pyrrolo[2,l-f][l,2,4]triazinamine (5 mg, 1O 0.012 mmol) (prepared in Example 7, step 6), l-(4-fluorophenyl)—2-oxo-N-[4-(4,4,5,5- ethyl- 1,3 xaborolanyl)phenyl]-1,2-dihydropyridine-3 -carboxamide (5.4 mg, 0.012 mmol) (prepared in Example 9, step 3) and MN—diisopropylethylamine (0012 mL, 007 mmol) in 1,4-dioxane (0.15 mL) and water (20 uL) was stirred together and flushed with N2 for 5 min before bis(tri-t-butylphosphine)palladium (3 mg, 0.006 mmol) was added. The reaction mixture was sealed and then heated at 110 °C for 1 h. After separation and the aqueous layer extracted with EtOAc, the organic layer was dried, filtered and concentrated under vacuum. The crude was used directly in the next step. LCMS calcd for C36H42FN603Sl (M+H)+: m/z = 6533. Found: 6533.
Step 2: 4-Amz‘n0(4-hydr0xycyclohexy0pyrr010[2,1-fl[1,2,4]triazin yl]phenyl}-1 -(4-flu0r0phenyl)0x0-1, 2-dz'hydr0pyrz‘dz‘necarb0xamz’de A on ofN—{4-[4-amino(4-{[z‘erz‘- butyl(dimethyl)silyl]oxy}cyclohexyl)pyrrolo[2, 1 -f] [1 ,2,4]triazin—5-yl]phenyl}(4- fluorophenyl)—2-oxo-l,2-dihydropyridinecarboxamide (7.7 mg, 0.012 mmol) in methanol (0.05 mL) was treated with 4.0 M hydrogen chloride in dioxane (0.20 mL) .
The reaction mixture was stirred at It for 20 min. The crude was concentrated under vacuum and purified by prep LC-MS (pH = 10 method; eTM PrepC18 5pm 1O OBDTM column, 30X100 mm, 60 mL/min, eluting with a gradient of MeCN and water with 0.15% NH4OH) to give the desired product (cis isomer) as white powders (2.8 mg, 44%). RT = 2.047 min for the major cis isomer, second peak off the column. The trans isomer is the minor product and is the first peak off the column. The trans isomer was not isolated. LCMS calcd for C30H28FN603 (M+H)+: m/z = 539.2. Found: 539.2.
Example 18a. N-{4-[4-Amino(cishydroxycyclohexyl)pyrrolo[2,1- ]] [1,2,4] triazin-S-yl] fluorophenyl}oxo- 1-phenyl-1,2-dihydropyridine carboxamide Example 18b. N-{4-[4-Amino(transhydroxycyclohexyl)pyrr0l0[2,1- ]] [1,2,4]triazinyl]flu0r0phenyl}ox0- l-phenyl-1,2—dihydr0pyridine—3— carboxamide Step 1: 4—Amz’n0- 7-(4-{[tert—butyl(dz'methyl)sz‘lyl]0xy}cyc[0hexyl)pyrr010[2, 1 - f][1 , 2, 4]triazin-5—yUfluorophenyl}-2—0x0-J-phenyZ-1, 2—dz'hydr0pyrz’dz’ne—3— W0 2017!]72596 carboxamide In a sealed tube a e of 5-bromo(4-{[tert— butyl(dimethyl)silyl]oxy}cyclohexyl)pyrrolo[2,1-f][1,2,4]triazinamine (6 mg, 0.014 mmol) (prepared in Example 7, step 6), N-[3-fluoro(4,4,5,5-tetramethyl- 1,3 ,2—dioxaborolanyl)phenyl]oxophenyl-1,2-dihydropyridine—3-carboxamide (6.1 mg, 0.014 mmol) (prepared in Example 9, step 4) and MN-diisopropylethylamine (0.014 mL, 008 mmol) in 1,4-dioxane (0.15 mL) and water (20 uL) was stirred together and flushed with N2 for 5 min before i-t-buty1phosphine)palladium (3.6 mg, 0.007 mmol) was added. The reaction mixture was sealed and then heated at 110 °C for 40 min. After separation and the aqueous layer extracted with EtOAc, the organic layer was dried, filtered and concentrated under vacuum. The crude was directly used in the next step. LCMS calcd for FN603Sl (M+H)+: m/z = 6533.
Found: 6533.
Step 2: N—{4—[4-Aml‘n0- 7-(4-hydr0xycyclohenypyrr010[2,1-fl[1,2,4]triazin—5—yl] fluorophenyl}-2—0x0phenyl-1,2-dihydr0pyridinecarboxamide A solution ofN-{4-[4-amino(4-{[tert— butyl(dimethyl)silyl] oxy } cyclohexyl)pyrrolo[2, 1 -f] [1 ,2,4]triazinyl]—3— fluorophenyl}oxophenyl-1,2-dihydropyridinecarboxamide (9.2 mg, 0.014 mmol) in l (0.06 mL) was treated with 4.0 M hydrogen chloride in dioxane (0.24 mL) . The reaction mixture was stirred at It for 30 min. The crude was concentrated under vacuum and purified by prep LC-MS (pH = 2 ; Waters SunFire PrepC18 Sum OBDTM column, 30x100 mm, 60 mL/min, eluting with a gradient of MeCN and water with 0.1% TFA) to give the desired product (cis isomer) as white powders. RT = 1.208 min for the cis isomer, second peak off the column.
LCMS calcd for C3OH28FN603 (M+H)+: m/z = 539.2. Found: 539.2.
Example 19a. N-{4-[4-Amino(cishydroxycyclohexyl)pyrrolo[2,1- f] [1,2,4]triazin-S-yl]fluorophenyl}(4-fluorophenyl)—2-0x0-1,2- dihydr0pyridine—3-carboxamide Example 19b. N-{4-[4-Amino(transhydroxycyclohexyl)pyrrolo[2,1- ]] ] triazin-S-yl] -3—fluorophenyl}- 1-(4-fluorophenyl)—2-oxo- 1,2- dihydropyridine—3-carb0xamide Step 1: 4-Amz'n0- 7-(4-{[tert—bugzl(dimez‘hyl)silyl]0xy}cyc[0hexyl)pyrr010[2, 1 - fl[1,2,4]triazinyl]—3-flu0r0phenyl}(4-flu0r0phenyl)-2—0x0-1,2—dihydr0pyridine- 3-carb0xamide In a sealed tube a mixture of 5-bromo(4-{[tert- butyl(dimethyl)silyl]oxy}cyclohexyl)pyrrolo[2,1-f][1,2,4]triazinamine (5 mg, 0.012 mmol) (prepared in Example 7, step 6), 1-(4-fluorophenyl)-N-[3-fluoro W0 2017!]72596 2017/024270 ,5—tetramethy1—1,3,2-dioxaborolany1)pheny1]oxo-1,2-dihydropyridine—3- carboxamide (5.6 mg, 0.012 mmol) red in Example 9, step 5) and MN- diisopropylethylamine (0.012 mL, 007 mmol) in 1,4-dioxane (0.15 mL) and water (20 nL) was d together and flushed with N2 for 5 min before bis(tri-t— butylphosphine)palladium (3 mg, 0.006 mmol) was added. The reaction mixture was sealed and then heated at 100 °C for 1 h. After separation and the aqueous layer extracted with EtOAc, the organic layer was dried, filtered and concentrated under vacuum. The crude was used directly in the next step. LCMS calcd for C36H41F2N603Sl (M+H)+: m/z = 671.3. Found: 671.3.
Step 2: N—{4-[4-Amz'n0(4-hydr0xycyclohenypyrr010[2,1fl[1,2,4]triazin—5—yl] fluorophenyl}(4-flu0r0phenyl)0x0-1, 2-dihydr0pyridine-S-carboxamide A solution ofN—{4-[4-amino(4-{[tert— butyl(dimethy1)silyl] oxy } cyclohexyl)pyrrolo[2, 1 -f] [1 ,2,4]triazinyl] fluorophenyl}(4-fluorophenyl)—2-oxo-l,2-dihydropyridinecarboxamide (7.9 mg, 0.012 mmol) in methanol (0.05 mL) was treated with 4.0 M hydrogen chloride in dioxane (0.2 mL) . The reaction mixture was stirred at rt for 30 min. The crude was concentrated under vacuum and purified by prep LC-MS (pH = 10 method; XBridgeTM PrepC18 Sum OBDTM column, 30x100 mm, 60 mL/min, eluting with a gradient of MeCN and water with 0.15% NH4OH) to give the d product (cis isomer) as white powders (1.8 mg, 27%). RT = 2.114 min for the major cis isomer, second peak off the column. The trans isomer was not isolated, which is the first peak off the column. LCMS calcd for C30H27F2N603 (M+H)+: m/z = 557.2. Found: 5572.
Example 20. N-{4-[4-Amino(1-methylpiperidinyl)pyrrolo[2,1- ]] ]triazin-S-yl] phenyl}0xo- 1-phenyl-1,2-dihydropyridine-3—carboxamide W0 2017!]72596 Step I: 7—(1—Methyl-1,2,3,6-tetrahydropyridinyl)pyrr0[0[2,1-fl[1,2,4]triazirz amine The mixture of 7-bromopyrrolo[2,l-f][1,2,4]triazinamine (from J & W Pharm Lab, 208 mg, 0.97 mmol), 1-methyl(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-Z-yl)—1,2,3,6-tetrahydropyridine (from Aldrich, 250 mg, 1.12 mmol), potassium phosphate (0.61 g, 2.9 mmol) in 1,4-dioxane (3.4 mL) and water (1.1 mL) was degassed, d with nitrogen, followed by addition of 1O dicyclohexyl(2',4’,6’-triisopropy1biphenyly1)phosphine - (2'-arninobiphenyl y1)(chloro)palladium (1:1) (110 mg, 0.14 mmol). The reaction mixture was degassed again, refilled with nitrogen and was then sealed and heated at 80 °C for 1 h. The reaction mixture was allowed to cool to It, diluted with ethyl acetate, washed with brine, dried over sodium sulfate, filtered, and trated under vacuum to give the crude product, which was used directly in the next step. LCMS calcd for C12H16N5 (M+H)+: m/z = 230.1. Found: 230.1.
Step 2: 7-(1-Methylpzperz'diny0pyrr0[0[2, 1fl[I , 2, 4jtrz'azz'namz'ne W0 2017I172596 To a solution of ethyl-1,2,3,6-tetrahydropyridinyl)pyrrolo[2,1- f][1,2,4]triazin-4—amine (134 mg, 0.26 mmol) in methanol (1.26 mL) and THF (0.5 mL) was added a mixture of palladium (150 mg, 0.14 mmol) (10% Pd on carbon).
The on mixture was placed under a hydrogen balloon for 4 hours. After filtration through a celite pad, the e was concentrated under vacuum to give the crude.
The crude was further purified by prep LC-MS (pH = 10 method; XBridgeTM PrepC18 5um OBDTM column, 30x100 mm, 60 mL/min, eluting with a nt of MeCN and water with 0.15% NH4OH) to give the desired product as white powders (22 mg, 36%). LCMS calcd for C12H18N5 (M+H)+: m/z = 232.2. Found: 1O 232.2.
Step 3: 5-Br0m0(1-methylpz'perl'diny0pyrr0[0[2,1-fl[1,2,4]triazin-4—amine NHz Br kN.N\ / To a solution of ethylpiperidinyl)pyrrolo[2,1-f][1,2,4]triazin amine (16.5 mg, 0.07 mmol) in ethylformamide (0.31 mL) and tetrahydrofuran (0.20 mL) was added N-bromosuccinimide (10.2 mg, 0.06 mmol).
The resulting mixture was stirred at It for 10 min. The reaction mixture was diluted with EtOAc, filtered. The filtrate was washed with saturated , water, dried, filtered and concentrated under vacuum to give the desired product as tan solid.
LCMS calcd for C12H17BrN5 (M+H)+: m/z = 310.1, 312.1. Found: 310.], 312.1.
Step 4: N-{4-[4-Amz'n0- 7-(I-methylpl'peridinyl)pyrr0[0[2, 1-fi[1, 2, 4]triazin yljphenyl}0x0phenyl-1, 2-dz'hydr0pyridine-S-carboxamide In a sealed tube a mixture of 5-bromo(1-methylpiperidinyl)pyrrolo[2,1- f][1,2,4]triazinamine (4 mg, 0.013 mmol), 2-oxophenyl-N-[4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolanyl)phenyl]-1 ,2-dihydropyridine-3 -carboxamide (5 . 6 mg, 0.014 mmol) (prepared in Example 7, step 3) and NN—diisopropylethylamine (0.012 mL, 0.078 mmol) in 1,4-dioxane (0.15 m) and water (20 pL) was stirred together and flushed with N2 for 5 min before bis(tri-t-butylphosphine)palladium (3.3 mg, 0.006 mmol) was added. The reaction mixture was sealed and then heated at 110 °C for 40 min. After separation and the s layer extracted with EtOAc, the organic layer was dried, filtered and concentrated under vacuum. The crude was purified by prep LC-MS (pH = 10 method; XBridgeTM PrepC18 5pm OBDTM , 30x100 mm, 60 mL/min, eluting with a gradient of MeCN and water with 0.15% NH4OH) to give the desired product (4.0 mg, 60%). LCMS calcd for C30H30N702 (M+H)+: m/z = 520.2. Found: 520.2.
Example 21. N-{4-[4-Amino(1-methylpiperidinyl)pyrrolo[2,1- 1O ]] [1,2,4]triazin-S-yl] phenyl}(4-flu0rophenyl)0xo- 1,2-dihydr0pyridine—3- carboxamide In a sealed tube a mixture of 5-bromo(1-methylpiperidinyl)pyrrolo[2,1- f][l,2,4]triazinamine (4 mg, 0.013 mmol) (prepared in Example 20, step 3), 1-(4- henyl)—2-oxo-N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)phenyl]-1,2- dihydropyridinecarboxamide (5.9 mg, 0.014 mmol) (prepared in Example 9, step 3) and MN—diisopropylethylamine (0.014 mL, 0.04 mmol) in oxane (0.15 mL) and water (20 uL) was stirred together and flushed with N2 for 5 min before bis(tri-t-butylphosphine)palladium (3.3 mg, 0.006 mmol) was added. The reaction mixture was sealed and then heated at 110 0C for 1 h. After separation and the aqueous layer extracted with EtOAc, the organic layer was dried, filtered and concentrated under vacuum. The crude was purified by prep LC-MS (pH = 10 method; eTM PrepC18 5pm OBDTM column, 30x100 mm, 60 mL/min, eluting with a gradient of MeCN and water with 0.15% NH4OH) to give the desired product (2.1 mg, 30%). LCMS calcd for C30H29FN702 (M+H)+: m/z = 5382. Found: 538.2.
Example 22. N-{4-[4-Amino(1-methylpiperidinyl)pyrrolo[2,1- f] [1,2,4] triazin-S-yl] fluorophenyl}ox0- l-phenyl-l,2-dihydropyridine-3— carboxamide In a sealed tube a mixture of o(1-methylpiperidinyl)pyrrolo[2,1- f][1,2,4]triazinamine (3 mg, 0.01 mmol) (prepared in Example 20, step 3), N—[3- fluoro(4,4,5,5 -tetramethyl-1,3,2-dioxaborolanyl)phenyl]oxophenyl-1,2- dihydropyridinecarboxamide (4.2 mg, 0.01 mmol) (prepared in Example 9, step 4) and MN-diisopropylethylamine (0.01 mL, 0.03 mmol) in 1,4-dioxane (0.15 mL) and water (20 uL) was stirred together and flushed with N2 for 5 min before bis(tri-t- butylphosphine)palladium (2.5 mg, 0.005 mmol) was added. The on mixture was sealed and then heated at 110 °C for 40 min. After separation and the aqueous layer extracted with EtOAc, the organic layer was dried, filtered and trated under vacuum. The crude was purified by prep LC-MS (pH = 2 method; Waters SunFire PrepC18 5pm OBDTM , 30x100 mm, 60 mL/min, g with a gradient of MeCN and water with 0.1% TFA) to give the desired product. LCMS calcd for C30H29FN702 (M+H)+: m/z = 538.2. Found: 538.2.
Example 23. N— {4- [4-Amino(1-methylpiperidinyl)pyrrolo[2,1- j][1,2,4]triazin-S-yl]fluorophenyl}(4-fluorophenyl)—2-ox0-1,2- dihydropyridine—3-carb0xamide In a sealed tube a e of 5-bromo(1-methylpiperidinyl)pyrrolo[2,1- f][1,2,4]triazinamine (4 mg, 0.013 mmol) (prepared in e 20, step 3), 1-(4- henyl)-N—[3-fluoro(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)phenyl] oxo-1,2—dihydropyridinecarboxamide (5.8 mg, 0.013 mmol) (prepared in Example 9, step 5) and N,N—diisopropylethylamine (0.014 mL, 0.08 mmol) in 1,4-dioxane (0.15 mL) and water (20 uL) was stirred together and flushed with N2 for 5 min before bis(tri-t—butylphosphine)palladium (3.3 mg, 0.006 mmol) was added. The reaction mixture was sealed and then heated at 110 0C for 40 min. After separation and the aqueous layer extracted with EtOAc, the organic layer was dried, filtered and trated under vacuum. The crude was purified by prep LC-MS (pH = 10 method; XBridgeTM PrepC18 5pm OBDTM column, 30x100 mm, 60 mL/min, eluting with a gradient of MeCN and water with 0.15% NH4OH) to give the desired product (2.5 mg, 35%). LCMS calcd for C30H28F2N702 (M+H)+: m/z = 556.3. Found: 5563.
Example 24. N-{4-[7-(l-Acetylpiperidinyl)—4-aminopyrrolo[2,1- ]] [1,2,4]triazin-S-yl] phenyl}-2—0xo- l-phenyl-1,2-dihydropyridine—S-carboxamide HN O Step 1: 7-(1-Acetyl-],2,3,6-tetrahydr0pyridinyl)pyrr0[0[2,1-fl[1,2,4]triazm amine A mixture of l-acetyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)— 1,2,3,6-tetrahydropyridine (from Combi-Blocks, 500 mg, 1.99 mmol), ?- bromopyrrolo[2,1-f][1,2,4]triazinamine (from J & W Pharm Lab, 424 mg, 1.99 mmol), sodium carbonate (700 mg, 6.6 mmol), and [1,1’-bis(di- cyclohexylphosphino)ferrocene]dichloropalladium (II) (199 mg, 0.26 mmol) in tertbutyl alcohol (6.0 mL) and water (2.2 mL) was ed with nitrogen, then stirred and heated at 110 °C for 2 h. The e was diluted with ethyl acetate, washed with saturated NaHCOs, water, dried over NazSO4, filtered and concentrated. The product was purified by Biotage silica gel chromatography (20 g column, 0 to 30% MeOH in EtOAc) to give the desired product as brown solid (317 mg, 62%). LCMS calcd for C13H16N50 (M+H)+: m/z = 258.1. Found: 258.1.
Step 2: 7—(1—Acetylpz'perz'dz'ny0pyrr0Zo[2,1fl[1,2,4]trz'azmamme To a cloudy solution of 7-(1-acetyl-1,2,3,6-tetrahydropyn'din rolo[2,l-f][1,2,4]tnazinamine (305 mg, 1.19 mmol) in methanol (49 mL) and tetrahydrofuran (2.4 mL) was added a e of palladium (610 mg) (10% Pd on carbon). The reaction mixture was placed under a hydrogen balloon for 18 h, and filtered through a celite pad. The filtrate was concentrated under vacuum to give the desired product as light brown s (187 mg, 61%). LCMS calcd for C13H18N50 (M+H)+: m/z = 260.1. Found: 260.1.
Step 3: 7-(1-Acetylpiperidinyl)-5—br0m0pyrr0[0[2,1fl[1,2,4]trz‘azmamine N H2 Br kN'N\ / To a solution of 7-(1-acetylpiperidinyl)pyrrolo[2,1-f][1,2,4]triazinamine (178 mg, 0.69 mmol) in N,N-dimethylformamide (3.0 mL) was added N- uccinimide (116 mg, 0.65 mmol). The resulting mixture was stirred at It for 15 min. The reaction mixture was diluted with EtOAc, and filtered. The e was washed with saturated NaHCO3, water, dried, filtered and trated under vacuum to give the desired product as tan solid. LCMS calcd for C13H17BrN50 (M+H)+: m/z = 338.1, 3401. Found: 338.1, 340.1.
Step 4: N-{4-[7—(1-Acetylpzperidinyl)amin0pyrr0[0[2, 1-f][1,2,4]triazin-5— yljphenyl}0x0-] -pheny[—], ydr0pyridine-S-carboxamide In a sealed tube a mixture of 7-(1-acety1pipendinyl)bromopyrrolo[2,1- f][1,2,4]triazinamine (6 mg, 0.02 mmol), 2-oxophenyl-N-[4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolanyl)phenyl]-1 ,2-dihydropyridine-3 -carboxamide (7. 8 mg, 0.019 mmol) (prepared in Example 7, step 3) and MN—diisopropylethylamine (0.018 mL, 0.11 mmol) in 1,4-dioxane (0.15 mL) and water (20 uL) was stirred together and flushed with N2 for 5 min before bis(tri-t-butylphosphine)palladium (4.5 mg, 0.009 mmol) was added. The reaction mixture was sealed and then heated at 110 0C for 1 h. After separation and the aqueous layer extracted with EtOAc, the organic layer was dried, filtered and concentrated under vacuum. The crude was purified by prep LC-MS (pH = 10 method, XBridgeTM PrepC18 5um OBDTM column, 30x100 mm, 60 mL/min, eluting with a gradient of MeCN and water with 0.15% NH4OH) to give the desired product (3.0 mg, 31%) as. LCMS calcd for C31H30N7O3 (M+H)+: m/z = 5482. Found: 548.2. e 25. N-{4-[7-(1-Acetylpiperidinyl)aminopyrrolo[2,1- f] [1,2,4] triazin-S-yl] phenyl}(4-flu0rophenyl)oxo- 1,2-dihydropyridine amide In a sealed tube a mixture of 7-(1-acetylpipe1idinyl)bromopyrrolo[2,1- f][1,2,4]triazinamine (6 mg, 0.02 mmol) (prepared in Example 24, step 3), 1-(4- fluorophenyl)oxo-N— 4,5 ,5-tetramethyl-1,3,2-dioxaborolanyl)phenyl]-1,2- dihydropyridinecarboxamide (8.1 mg, 0.019 mmol) (prepared in Example 9, step 3) and MN-diisopropylethylamine (0.018 mL, 0.11 mmol) in 1,4-dioxane (0.15 mL) and water (20 uL) was stirred together and flushed with N2 for 5 min before bis(tri-t-butylphosphine)palladium (4.5 mg, 0.009 mmol) was added. The reaction mixture was sealed and then heated at 110 °C for 1 h. After separation and the aqueous layer extracted with EtOAc, the organic layer was dried, d and concentrated under vacuum. The crude was purified by prep LC-MS (pH = 10 ; XBridgeTM PrepC18 5pm OBDTM column, 30x100 mm, 60 mL/min, eluting with a gradient of MeCN and water with 0.15% NH4OH) to give the desired product (2.9 mg, 29%) as. LCMS calcd for C31H29FN7O3 (M+H)+: m/z = 566.2. Found: 566.2.
Example 26. N-{4-[7-(1-Acetylpiperidinyl)—4-aminopyrrolo[2,1- ]] [1,2,4]triazin-S-yl] flu0r0phenyl}0x0- yl-1,2—dihydropyridine—3— carboxamide In a sealed tube a mixture of 7-(1-acetylpipe1idinyl)bromopyrrolo[2,1- f][1,2,4]triazinamine (6 mg, 0.02 mmol) (prepared in Example 24, step 3), N—[3- fluoro-4—(4,4,5 ,5 -tetramethyl-1,3,2-dioxaborolanyl)phenyl]oxophenyl-1,2- dihydropyridinecarboxamide (8.1 mg, 0.02 mmol) (prepared in Example 9, step 4) and sopropylethylamine (0.18 mL, 0.11 mmol) in oxane (0.15 mL) and water (20 uL) was stirred er and flushed with N2 for 5 min before bis(tri-t- butylphosphine)palladium (4.5 mg, 0.01 mmol) was added. The reaction mixture was sealed and then heated at 110 0C for 1 h. After separation and the aqueous layer ted with EtOAc, the organic layer was dried, filtered and concentrated under vacuum. The crude was purified by prep LC-MS (pH = 10 method; XBridgeTM PrepC18 5pm OBDTM column, 30x100 mm, 60 mL/min, eluting with a gradient of MeCN and water with 0.15% NH4OH) to give the desired product (2.4 mg, 24%) as.
LCMS calcd for C31H29FN7O3 (M+H)+: m/z = 566.2. Found: 566.2.
Example 27. N-{4-[7-(1-Acetylpiperidinyl)—4-aminopyrrolo[2,1- ]] [1,2,4]triazin-S-yl] fluorophenyl}- 1-(4-fluorophenyl)—2-ox0- 1,2- dihydropyridine—S-carboxamide In a sealed tube a mixture of 7-(1-acetylpiperidinyl)bromopyrrolo[2,1- f][1,2,4]triazinamine (6 mg, 0.02 mmol) (prepared in Example 24, step 3), 1-(4- fluorophenyl)-N—[3-fluoro(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)phenyl] oxo-1,2-dihydropyridinecarboxamide (8.4 mg, 0.02 mmol) (prepared in Example 9, step 5) and N,N—diisopropylethylamine (0.018 mL, 0.11 mmol) in 1,4-dioxane (0.15 mL) and water (20 uL) was stirred together and flushed with N2 for 5 min before bis(tri-t—butylphosphine)palladium (4.5 mg, 0.009 mmol) was added. The reaction mixture was sealed and then heated at 110 °C for 1 h. After separation and the aqueous layer ted with EtOAc, the organic layer was dried, filtered and concentrated under vacuum. The crude was purified by prep LC-MS (pH = 10 method; eTM PrepC18 5pm OBDTM column, 30x100 mm, 60 mL/min, eluting with a gradient of MeCN and water with 0.15% NH4OH) to give the desired product as ite powders (2.3 mg, 22%). LCMS calcd for C31H28F2N703 (M+H)+: m/z = 584.2. Found: 584.2.
Example 28a. N—{4—[4-Amino(ciscyanocyclohexyl)pyrrolo[2,1- ]] [1,2,4]triazin-S-yl] phenyl}-2—0xo- l-phenyl-1,2-dihydropyridine-3—carboxamide Example 28b. N— {4- [4-Amino—7-(trans—4-cyanocyclohexyl)pyrrolo [2,1- f] [1,2,4]triazin-5—yl] phenyl}-2—0xo- l-phenyl-1,2-dihydropyridine-3—carb0xamide W0 2017!]72596 O O NH2 NH2 N’ —— N’ ’ {\N—N / QN—N / \N \N Step 1: 4—(4-Amin0pyrr010[2,1-fl[1,2,4]triazinyl)cyclohexenecarbonitrile A mixture of 4—(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)cyclohexene— 1-carbonit1ile (from Pharma Block, 500 mg, 2.15 mmol), 7-bromopyrrolo[2,1- f][1,2,4]triazinamine (from J & W Pharm Lab, 457 mg, 2.14 mmol), sodium carbonate (760 mg, 7.1 mmol), and [1,1’-bis(di- cyclohexylphosphino)ferrocene]dichloropalladium (II) (211 mg, 0.279 mmol) in tert- butyl alcohol (6.4 mL) and water (2.4 mL) was degassed with nitrogen, then stirred and heated at 110 °C for 2 h. The mixture was diluted with ethyl acetate, washed with saturated NaHCO3, water, dried over NazSO4, d and concentrated. The product was purified by e silica gel chromatography (20 g column, 0 to 100% EtOAc in hexanes) to give the desired product as off-white s (238 mg, 46%). LCMS calcd for C13H14N5 (M+H)+: m/z = 240.1. Found: 240.1.
Step 2: 4—(4—Amin0pyrrolo[2,1-fl[1,2,4]trl'azinyl)cyclohexanecarbonitrile To a solution of 4-(4-aminopyrrolo[2,1-f] [1,2,4]triazinyl)cyclohexene- 1-carbonitrile (238 mg, 0.99 mmol) in methanol (4.1 mL) and tetrahydrofuran (2.0 mL) was added a mixture of palladium (512 mg) (10% Pd on carbon). The reaction mixture was placed under a hydrogen balloon for 18 h. After filtration through a celite pad, the filtrate was concentrated under vacuum to give the desired product as clear gum (147.2 mg, 61%). LCMS calcd for N5 (M+H)+: m/z = 242.1. Found: 242.1.
Step 3: min0br0m0pyrr010[2,1-fl[1,2,4]trz'azz'nyl)cyclohexanecarbom‘trile NHz Br "C / To a solution of 4-(4-aminopyrrolo[2,1-f] [1,2,4]triazin yl)cyclohexanecarbonitrile (137 mg, 0.57 mmol) in MN-dimethylformamide (2.4 mL) was added N—bromosuccinimide (96 mg, 0.54 mmol). The resulting mixture was stirred at rt for 15 min. The reaction e was diluted with EtOAc, and filtered.
The filtrate was washed with saturated NaHCO3, water, dried, filtered and concentrated under vacuum to give the desired product as off-white powders (182 mg, 100%). LCMS calcd for C13H15BrN5 (M+H)+: m/z = 320.0, 322.0. Found: 3200, 322.0.
Step 4: N-{4—[4—Amin0- 7-(4-cyanocyclohexy0pyrr0[0[2, 1-f][1, 2, 4]trl'azirz yljpherzyl}0x0-] -phenyl-1, ydr0pyridine-S-carboxamide In a sealed tube a e of 4-(4-aminobromopy1rolo[2,1-f][1,2,4]triazin- 7-yl)cyclohexanecarbonitrile (9 mg, 0.03 mmol), 2-oxophenyl-N-[4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolany1)phenyl]-1,2-dihydropyridinecarboxamide (11.? mg, 0.028 mmol) (prepared in Example 7, step 3) and MN- diisopropylethylamine (0.015 mL, 0.084 mmol) in 1,4-dioxane (0.11 mL) and water (20 uL) was stirred together and flushed with N2 or 5 min before bis(tri—t- butylphosphine)palladium (7.2 mg, 0.014 mmol) was added. The reaction mixture was sealed and then heated at 110 0C for 1 h. After tion and the aqueous layer extracted with EtOAc, the organic layer was dried, filtered and concentrated under . The crude was purified by prep LC-MS (pH = 10 method; eTM PrepC18 Sum OBDTM column, 30x100 mm, 60 mL/min, eluting with a gradient of MeCN and water with 0.15% NH4OH) to give the desired cis isomer as off-white powders. RT: 1.341 min for the cis isomer, first peak off the column. LCMS calcd for C31H28N702 (M+H)+: m/z = 530.2. Found: 5302.
Example 29a. 4-Amino(ciscyanocyclohexyl)pyrrolo[2,1- f] [1,2,4]triazinyl] phenyl}(4-fluorophenyl)oxo-1,2-dihydropyridine—3- carboxamide Example 29b. N-{4-[4-Amino(transcyanocyclohexyl)pyrrolo[2,1- f][1,2,4]triazinyl]phenyl}(4-fluoropheny1)oxo-1,2-dihydropyridine amide \ N—< >—F \ —< >—F HN O HN O O NHZ NHZ N/ .— N/ , (\N—N / (\N—N / \N :SN In a sealed tube a mixture of 4-(4-aminobromopyrrolo[2,1-f][1,2,4]triazin- 7-yl)cyclohexanecarbonitrile (9 mg, 0.028 mmol) (prepared in Example 28, step 3), 1- (4-fluoropheny1)oxo—N—[4-(4,4,5,5-tetramethy1-1,3,2-dioxaborolan-2—yl)pheny1]— 1,2-dihydropyridinecarboxamide (13 mg, 0.03 mmol) (prepared in Example 9, step 3) and NN-diisopropylethylamine (0015 mL, 0.08 mmol) in 1,4-dioxane (0.11 W0 72596 mL) and water (20 uL) was stirred together and flushed with N2 for 5 min before bis(tri—t—butylphosphine)palladium (7.2 mg, 0.014 mmol) was added. The on mixture was sealed and then heated at 110 °C for 1 h. After separation and the aqueous layer extracted with EtOAc, the organic layer was dried, d and concentrated under vacuum. The crude was purified by prep LC-MS (pH = 10 method; XBridgeTM PrepC18 5pm OBDTM column, 30x100 mm, 60 mL/min, eluting with a gradient of MeCN and water with 0.15% NH4OH) to give the desired cis isomer. RT = 1.352 min for the cis isomer, first peak off the column. LCMS (M+H)+: found m/z = 548.3. LCMS calcd for FN702 (M+H)+: m/z = 548.2. Found: 1O 548.2. e 30a. N—{4—[4—Amin0(ciscyanocyclohexyl)pyrrolo[2,1- ]] [1,2,4] triazin-S-yl] flu0r0phenyl}0x0- l-phenyl-1,2—dihydr0pyridine—3- carboxamide e 30b. N- {4- [4-Amino—7-(trans—4-cyanocyclohexyl)pyrrolo [2,1- f] [1,2,4] triazin-S-yl] fluorophenyl}ox0- l-phenyl-l,2-dihydropyridine carboxamide In a sealed tube a mixture of 4-(4-aminobromopyrrolo[2,1-f][1,2,4]triazin- 7-yl)cyclohexanecarbonitrile (9 mg, 0.028 mmol) (prepared in Example 28, step 3), N—[3-fluoro(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)phenyl]—2-oxo phenyl-l,2-dihydropyridine—3-carboxamide (13 mg, 0.03 mmol) (prepared in Example 9, step 4) and N,N—diisopropylethylamine (0.015 mL, 0.084 mmol) in 1,4-dioxane (0.11 mL) and water (20 uL) was stirred together and flushed with N2 for 5 min before bis(tri-t-butylphosphine)palladium (7.2 mg, 0.014 mmol) was added. The reaction mixture was sealed and then heated at 110 °C for 1 h. After separation and the aqueous layer extracted with EtOAc, the organic layer was dried, filtered and concentrated under vacuum. The crude was purified by prep LC-MS (pH = 10 ; XBridgeTM PrepC18 5pm OBDTM , 30x100 mm, 60 , eluting with a gradient of MeCN and water with 0.15% NH4OH) to give the desired cis isomer as white powders. RT = 1.332 min for the cis isomer, first peak off the column. LCMS calcd for C31H27FN702 (M+H)+: m/z = 548.2. Found: 548.2.
Example 31a. N—{4—[4—Amino(ciscyanocyclohexyl)pyrrolo[2,1- fl ]triazinyl] fluorophenyl}- 1-(4-fluorophenyl)—2-ox0- 1,2- 1O dihydropyridine—3-carb0xamide e 31b. N— {4- [4-Amino—7-(trans—4-cyanocyclohexyl)pyrrolo [2,1- 1] [1,2,4] triazin-S-yl] rophenyl}- 1-(4-fluorophenyl)—2-oxo- 1,2- dihydropyridine—3-carb0xamide N’ .—- N’ F .— F (\N'N / QN—N / \N \N In a sealed tube a mixture of 4-(4-aminobromopyrrolo[2,1-f][1,2,4]triazin- 7-yl)cyclohexanecarbonitrile (9 mg, 0.03 mmol) (prepared in Example 28, step 3), l- (4-fluorophenyl)-N-[3-fluoro(4,4,5,5-tetramethyl-l,3,2-dioxaborolanyl)phenyl]- 2-oxo-1,2-dihydropyridinecarboxamide (13 mg, 0.03 mmol) (prepared in Example 9, step 5) and N,N—diisopropylethylamine (0.015 mL, 0.084 mmol) in 1,4-dioxane (0.11 mL) and water (20 uL) was stirred together and flushed with N2 bubble for 5 min before bis(tri-t-butylphosphine)palladium (7.2 mg, 0.014 mmol) was added. The reaction mixture was sealed and then heated at 110 0C for 1 h. After separation and the aqueous layer extracted with EtOAc, the organic layer was dried, filtered and concentrated under vacuum. The crude was purified by prep LC-MS (pH = 10 method; XBridgeTM PrepC18 5pm OBDTM column, 30x100 mm, 60 mL/min, eluting with a gradient of MeCN and water with 0.15% NH4OH) to give the desired cis isomer as white powders. RT = 2.666 min for the cis isomer, first peak off the column. LCMS (M+H)+: found m/z = 566.3. LCMS calcd for F2N702 (M+H)+: m/z = 5662. Found: 566.2.
Example 32. N—[4-(4-Aminopiperidinylpyrrolo[2,1-f] [1,2,4]triazin-5— yl)phenyl]-2—0xo-l-phenyl-1,2-dihydropyridine—3-carboxamide Step I: tart-Bury] 4-(4-amin0pyrr010[2, 1fl[1,2,4]triazin-7—yl)-3, 6-dl'hydr0pyridine- 1(2H)—carb0xylate N NH2 A mixture of tert-butyl ,5,5-tetramethyl-1,3,2-dioxaborolanyl)—3,6- dihydropyridine-1(2H)-carboxylate (from Aldrich, 0.885 g, 2.86 mol), 7- bromopyrrolo[2,1-f][1,2,4]triazinamine (from J & W Pharm Lab, 610 mg, 2.86 mmol), sodium carbonate (1.0 g, 9.5 mmol), and [1,1’-bis(di- cyclohexylphosphino)ferrocene]dichloropalladium (II) (217 mg, 0.286 mmol) in tert- butyl alcohol (8.6 mL) and water (3.2 mL) was degassed with nitrogen, then stirred and heated at 110 °C for 2 h. The mixture was diluted with ethyl e, washed with saturated NaHCO3, water, dried over , filtered and concentrated. The crude was purified by Biotage silica gel chromatography (40 g column, 0 to 100% EtOAc in hexanes) to give the desired product as off-white powders (705 mg, 78%). LCMS calcd for C16H22N502 (M+H)+: m/z = 316.2. Found: 3162.
Step 2: tert—Butyl 4-(4-amin0pyrrolo[2,1-j][1,2,4]trl'azz'nyUpiperidine carboxylate To a slightly cloudy solution of tert—butyl minopyrrolo[2,1- f][1,2,4]triazinyl)-3,6-dihydropyridine-1(2H)-carboxylate (700 mg, 2.22 mmol) in methanol (9.2 mL) and tetrahydrofuran (4.6 mL) was added a mixture of palladium (2.20 g) (10% Pd on ). The reaction mixture was placed under a hydrogen balloon for 20 h, and filtered through a celite pad. The filtrate was concentrated under vacuum to give the desired product as light brown powders (455 mg, 65%). LCMS calcd for N502 : m/z = 3182. Found: 3182.
Step 3: tert—Butyl min0br0m0pyrrolo[2, 1fl[1 , 2, 4]triazz‘n- 7-y0piperidine-1 - carboxylate N NH2 To a solution of tert—butyl 4-(4-aminopyrrolo[2,1-f][1,2,4]triazin yl)piperidinecarboxylate (450 mg, 1.42 mmol) in N,N-dimethylformamide (6.1 mL) was added N—bromosuccinimide (240 mg, 1.35 mmol). The resulting mixture was stirred at rt for 10 min. The reaction mixture was diluted with EtOAc, filtered. The filtrate was washed with saturated NaHCO3, water, dried, filtered and concentrated under vacuum to give the desired product as tan solid. LCMS calcd for C16H23BrN502 (M+H)+: m/z= 396.1, 398.1. Found: 3961, 398.1.
Step 4: 5-Br0m0- 7-pz'perz'dz'nylpyrr010[2, 1fl[1, 2, 4]triazz‘namz‘ne dihydrochloride utyl 4-(4-amino-5 -bromopyrrolo[2, 1 -f] [1,2,4]triazinyl)piperidine carboxylate (562 mg, 1.42 mmol) was mixed with ol (3.5 mL) and 4.0 M hydrogen chloride in dioxane (7.1 mL). The mixture was stirred at It for 1 h. After concentration, the crude product was directly used in the next step as off-white powders. LCMS calcd for CiiHisBrNs (M+H)+: m/z = 296.0, 298.0. Found: 296.0, 298.0. 1O Step 5: 4-Amz'n0pzperl'dinylpyrr0[0[2, 1-fl[1,2,4]trl'azz'nyf)pheny1] oxo-I-phenyl—1, 2—dihydr0pyrz'dinecarboxamide In a sealed tube a mixture of 5-bromopiperidinylpyrrolo[2,1- f][l,2,4]triazin-4—amine dihydrochloride (6.7 mg, 0.013 mmol), 2-oxo-l-phenyl-N—[4- (4,4,5,5-tetramethyl-1,3 ,2-dioxaborolanyl)phenyl]-1,2-dihydropyridine carboxamide (5.4 mg, 0.013 mmol) (prepared in Example 7, step 3) and MN- diisopropylethylamine (0013 mL, 0.077 mmol) in 1,4-dioxane (0.15 mL) and water (20 uL) was stirred together and flushed with N2 for 5 min before bis(tri—t- butylphosphine)palladium (3.3 mg, 0.0064 mmol) was added. The reaction mixture was sealed and then heated at 110 0C for 60 min. After separation and the aqueous layer extracted with EtOAc, the organic layer was dried, filtered and concentrated under vacuum. The crude was purified by prep LC-MS (pH = 2 method; Waters SunFire PrepC18 5pm OBDTM column, 30x100 mm, 60 mL/min, eluting with a gradient of MeCN and water with 0.1% TFA) to give the d product as off- white powders (4 mg, 61%). LCMS calcd for C29H28N702 (M+H)+: m/z = 5062.
Found: 5062. e 33. N-[4-(4-Aminopiperidin-4—ylpyrrolo[2,1—f][1,2,4]triazin-5— yl)phenyl](4-fluorophenyl)oxo-1,2-dihydropyridinecarboxamide N/ _.
In a sealed tube a mixture of 5-bromopiperidinylpyrrolo[2,1- f][1,2,4]triazinamine dihydrochloride (6.7 mg, 0.013 mmol) (prepared in Example 32, step 4), 1-(4-fluorophenyl)oxo-N—[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan yl)phenyl]-1,2-dihydropyridinecarboxamide (5.6 mg, 0.013 mmol) (prepared in Example 9, step 3) and MN—diisopropylethylamine (0.013 mL, 0.08 mmol) in 1,4- dioxane (0.15 mL) and water (20 uL) was stirred er and flushed with N2 for 5 min before bis(tri-t-butylphosphine)palladium (3.3 mg, 0.006 mmol) was added. The reaction mixture was sealed and then heated at 110 0C for 60 min. After separation and the aqueous lay er extracted with EtOAc, the c layer was dried, filtered and concentrated under vacuum. The crude was purified by prep LC-MS (pH = 2 method; Waters SunFire PrepC18 5pm OBDTM column, 30x100 mm, 60 mL/min, g with a gradient of MeCN and water with 0.1% TFA) to give the desired product as white powders (4 mg, 59%). LCMS calcd for C29H27FN702 (M+H)+: m/z = 524.2. Found: 5242.
Example 34. N-[4-(4-Amin0piperidin-4—ylpyrrolo[2,1-f][1,2,4]triazin-5—yl)—3— phenyl]0x0-l-phenyl-1,2-dihydropyridinecarboxamide In a sealed tube a mixture of 5-bromopiperidinylpyrrolo[2,1- f][1,2,4]triazinamine dihydrochloride (6.7 mg, 0.013 mmol) (prepared in Example 32, step 4), N—[3-fluoro(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2—yl)phenyl]—2- oxo-l-phenyl-l,2-dihydropyridine—3-carboxamide (5.6 mg, 0.013 mmol) (prepared in Example 9, step 4) and MN-diisopropylethylamine (0.0067 mL, 0.039 mmol) in 1,4- dioxane (0.15 mL) and water (20 uL) was stirred together and flushed with N2 for 5 min before bis(tri-t—buty1phosphine)palladium(3.3 mg, 0.006 mmol) was added. The reaction mixture was sealed and then heated at 110 0C for 60 min. After tion and the aqueous layer ted with EtOAc, the organic layer was dried, filtered and concentrated under vacuum. The crude was purified by prep LC-MS (pH = 2 method; 1O Waters e PrepC18 5pm OBDTM , 30x100 mm, 60 mL/min, eluting with a gradient of MeCN and water with 0.1% TFA) to give the desired product as off- white powders (3.2 mg, 47%). LCMS calcd for C29H27FN702 (M+H)+: m/z = 524.2.
Found: 5242.
Example 35. N-[4-(4-Aminopiperidin-4—ylpyrrolo[2,1-f] [1,2,4]triazin-5—yl)—3— fluorophenyl]-l-(4-fluorophenyl)—2—oxo—1,2-dihydr0pyridinecarb0xamide In a sealed tube a mixture of opiperidinylpyrrolo[2,1- f][1,2,4]triazinamine dihydrochloride (6.7 mg, 0.013 mmol) (prepared in Example 32, step 4), 1-(4-fluorophenyl)-N-[3-fluoro(4,4,5,5-tetramethyl-1,3,2—dioxaborolan- 2-yl)phenyl]oxo-1,2-dihydropyridinecarboxamide (5.8 mg, 0.013 mmol) (prepared in Example 9, step 5) and MN—diisopropylethylamine (0.014 mL, 0.077 mmol) in 1,4-dioxane (0.15 mL) and water (20 uL) was stirred together and flushed with N2 for 5 min before bis(tri-t—butylphosphine)palladium (3.3 mg, 0.006 mmol) was added. The on mixture was sealed and then heated at 110 °C for 60 min. After separation and the aqueous layer extracted with EtOAc, the organic lay er W0 2017!]72596 was dried, filtered and concentrated under vacuum. The crude was d by prep LC-MS (pH = 2 method; Waters SunFire PrepC18 5pm OBDTM column, 30x100 mm, 60 mL/min, eluting with a gradient of MeCN and water with 0.1% TFA) to give the desired product as white powders (3.6 mg, 52%). LCMS calcd for F2N702 (M+H)+: m/z = 542.2. Found: 542.2.
Example 36. Methyl 4- [4-amino(4— { [(2-0xophenyl-1,2—dihydr0pyridin-3— yl)carb0nyl]amino}phenyl)pyrrolo [2,1-f] [1,2,4]triazinyl] piperidine—l- carboxylate Step 1: Methyl 4-(4-amin0-5—br0m0pyrrolo[2, 1fl[1 , 2, 4jtrz'azz'n- 7-yUpiperidifle-J - carboxylate To a mixture of 5-bromopiperidinylpyrrolo[2,1-f] [1,2,4]triazinamine dihydrochloride (56 mg, 0.11 mmol) (prepared in Example 32, step 4) in tetrahydrofuran (0.6 mL) was added 1.0 M sodium bicarbonate in water (065 mL, 0.65 mmol), ed by the slow addition of methyl chloroformate (42 "L, 0.54 mmol) at 0 °C. After stirred at rt for 10 min, the resultant mixture was filtered, ted with EtOAc, dried, filtered and concentrated to dryness under reduced pressure. The resulting crude was used ly in the next step as light yellow powders (52.6 mg). LCMS calcd for C13H17BrN502 (M+H)+: m/z = 354.0, 356.0.
Found: 3540, 356.0.
Step 2: Methyl 4-[4-amin0(4-{[(2-0x0phenyl-], 2-dz'hydr0pyrz‘dz‘n yl)carbonyljamz’no}phenyl)pyrr010[2, 1-f][1, 2, azmyljpz'perz'dz'ne—1—carb0xylate In a sealed tube a mixture of methyl minobromopyrrolo[2,1— f][1,2,4]triazin—7-yl)piperidinecarboxylate (6.8 mg, 0.014 mmol), 2-oxo-l-phenyl- N-[4-(4,4,5,5—tetramethyl-1,3 ,2-dioxaborolanyl)phenyl]-1,2-dihydropyridine—3 - carboxamide (6.2 mg, 0.015 mmol) (prepared in Example 7, step 3) and MN— diisopropylethylamine (0.0074 mL, 0.042 mmol) in 1,4-dioxane (0.11 mL) and water (20 uL) was stirred together and flushed with N2 for 5 min before bis(tri-t— butylphosphine)palladium (3.6 mg, 0.007 mmol) was added. The reaction mixture was sealed and then heated at 110 0C for 30 min. After separation and the aqueous layer extracted with EtOAc, the organic layer was dried, filtered and concentrated under vacuum. The crude was purified by prep LC-MS (pH = 2 method; Waters SunFire PrepC18 5pm OBDTM column, 30x100 mm, 60 mL/min, g with a nt of MeCN and water with 0.1% TFA) to give the desired product as off- white powders (6.5 mg, 82%). LCMS calcd for N7O4 (M+H)+: m/z = 564.2.
Found: 5642.
Example 37. Methyl 4-{4-amin0[4-({[1-(4-fluorophenyl)—2—ox0-1,2- dihydropyridinyl] carbonyl}amin0)phenyl] pyrrolo [2,1-f] [1,2,4]triazin-7— yl}piperidine—l-carboxylate \ N—< >—F HN O N’——- In a sealed tube a mixture of methyl 4-(4-aminobromopyrrolo[2,1- f][1,2,4]triazin-7—yl)piperidinecarboxylate (6.8 mg, 0.014 mmol) (prepared in Example 36, step 1), 1—(4-fluorophenyl)oxo-N—[4-(4,4,5,5-tetramethyl-1,3,2— dioxaborolan-Z-yl)phenyl]-1,2-dihydropyridinecarboxamide (6.4 mg, 0.015 mmol) (prepared in Example 9, step 3) and sopropylethylamine (0.0074 mL, 0.042 mmol) in oxane (011 mL) and water (20 uL) was stirred together and flushed with N2 for 5 min before bis(tri-t—butylphosphine)palladium (3.6 mg, 0.007 mmol) was added. The reaction mixture was sealed and then heated at 110 °C for 30 min. The crude was diluted with MeOH, filtered and purified by prep LC—MS (pH = 2 method; Waters SunFire PrepC18 5pm OBDTM column, 30x100 mm, 60 mL/min, 1O eluting with a gradient of MeCN and water with 0.1% TFA) to give the desired product as off-white powders (5.0 mg, 61%). LC-MS found m/z = 582.3. LCMS calcd for C31H29FN7O4 (M+H)+: m/z = 582.2. Found: 582.2.
Example 38. Methyl 4- [4-amino-5—(2—fluoro-4— { [(2-0xophenyl-1,2- dihydr0pyridinyl)carbonyl] amino}phenyl)pyrrolo [2,1-f] ] triazin yl] piperidine—l-carboxylate In a sealed tube a mixture of methyl 4-(4-aminobromopyrrolo[2,1- f][1,2,4]triazinyl)piperidinecarboxylate (6.8 mg, 0.014 mmol) (prepared in e 36, step 1), N-[3-fluoro(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2— yl)phenyl]oxophenyl-1,2-dihydropyridinecarboxamide (6.4 mg, 0.015 mmol) (prepared in Example 9, step 4) and sopropylethylamine (0.0074 mL, 004 mmol) in 1,4-dioxane (0.11 mL) and water (20 uL) was stirred together and flushed with N2 for 5 min before bis(tri—t-butylphosphine)palladium (3.6 mg, 0.007 mmol) was added. The reaction mixture was sealed and then heated at 110 °C for 30 min. The crude was diluted with MeOH, filtered and purified by prep LC-MS (pH = 2 method; Waters SunFire PrepC18 Sum OBDTM column, 30x100 mm, 60 mL/min, eluting with a gradient of MeCN and water with 0.1% TFA) to give the desired product as white powders (6.4 mg, 78%). LCMS calcd for C31H29FN7O4 (M+H)+: m/z = 582.2. Found: 5822.
Example 39. Methyl 4- {4-amin0-5— [2-fluoro({[1-(4-flu0r0phenyl)—2—0x0— 1,2- dihydropyridinyl] carbonyl}amin0)phenyl] pyrrolo [2,1-f] [1,2,4]triazin-7— yl}piperidine—l-carboxylate In a sealed tube a mixture of methyl minobromopyrrolo[2,1- f][l,2,4]triazinyl)piperidine-l-carboxylate (6.8 mg, 0.014 mmol) (prepared in Example 36, step 1), l-(4-fluorophenyl)-N—[3-fluoro(4,4,5,5-tetramethyl-l,3,2— orolanyl)phenyl]oxo-l,2-dihydropyridinecarboxamide (6.7 mg, 0.015 mmol) (prepared in Example 9, step 5) and MN—diisopropylethylamine (0.0074 mL, 0.042 mmol) in 1,4-dioxane (0.11 mL) and water (20 uL) was stirred together and flushed with N2 for 5 min before i-z‘-butylphosphine)palladium (3.6 mg, 0.007 mmol) was added. The reaction mixture was sealed and then heated at 110 °C for 30 min. The crude was diluted with MeOH, d and purified by prep LC-MS (pH = 2 method; Waters SunFire PrepC18 Sum OBDTM , 30x100 mm, 60 mL/min, g with a gradient of MeCN and water with 0.1% TFA) to give the desired product as white powders (4.9 mg, 58%). LCMS calcd for C31H28F2N704 (M+H)+: m/z = 6002. Found: 6002.
Example 40. N—(4-{4-Amino-7—[1-(methylsulfonyl)piperidinyl]pyrrolo[2,1- W0 2017!]72596 f] [1,2,4] triazin-S-yl}phenyl)oxo- l-phenyl- 1,2-dihydropyridinecarb0xamide Step 1: 5-Br0m0[1-(methylsulfonyUpl'peridinyl]pyrr0[0[2,1-fl[1,2,4]triazin amine NHz Br NC / To a e of 5-bromopiperidiny1pyrrolo[2,1-f][1,2,4]triazinamine ochloride (56 mg, 0.11 mmol) (prepared in Example 32, step 4) in tetrahydrofuran (0.6 mL) was added 1.0 M sodium bicarbonate in water (0.65 mL), followed by the slow addition of methanesulfonyl chloride (13 uL, 0.16 mmol) at 0 °C. After stirred at It for 10 min, the resultant mixture was filtered, extracted with EtOAc, dried, filtered and concentrated to dryness under reduced pressure. The resulting crude was used directly in the next step as light yellow s (36.5 mg, 90%). LCMS calcd for C12H17BrNstS (M+H)+: m/z = 374.0, 376.0. Found: 374.0, 376.0.
Step 2: N-(4-{4-Amin0[1-(methylsulfonyUpl'peridinyljpyrr0[0[2,1- fi[1, 2, 4]triazinyl}phenyl)0x0phenyl-1, 2-dz'hydr0pyrl'dz'necarboxamide In a sealed tube a mixture of o[1-(methylsulfonyl)piperidin-4— yl]pyrrolo[2,1-f][1,2,4]triazinamine (5 mg, 0.01 mmol), 2-oxophenyl-N-[4- (4,4,5,5-tetramethy1-1,3,2-dioxaborolan-Z-y1)phenyl]-1,2-dihydropyridine carboxamide (5.8 mg, 0.014 mmol) (prepared in Example 7, step 3) and MN- diisopropylethylamine (0.01 mL, 0.06 mmol) in oxane (0.15 mL) and water (20 uL) was stirred together and flushed with N2 for 5 min before bis(tri-t— butylphosphine)pa11adium (3.4 mg, 0.0067 mmol) was added. The reaction e was sealed and then heated at 110 °C for 30 min. The crude was diluted with MeOH, filtered and purified by prep LC-MS (pH = 2 method; Waters SunFire PrepC18 5um OBDTM column, 30x100 mm, 60 mL/min, eluting with a gradient of MeCN and water with 0.1% TFA) to give the d product as white powders (5.4 mg, 69%). LCMS calcd for C30H30N7O4S (M+H)+: m/z = 584.2. Found: 584.2. 1O e 41. N-(4-{4-Amino[1-(methylsulf0nyl)piperidin-4—yl]pyrrolo[2,1- f] [1,2,4]triazin-S-yl}phenyl)—1-(4-fluorophenyl)—2-0xo- 1,2-dihydr0pyridine carboxamide In a sealed tube a mixture of 5-bromo[1-(methylsulfonyl)piperidin-4— yl]pyrrolo[2,1—f][1,2,4]triazinamine (5 mg, 0.013 mmol) (prepared in Example 40, step 1), 1-(4—fluorophenyl)oxo-N-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan yl)pheny1]—1,2-dihydropyridinecarboxamide (6.1 mg, 0.014 mmol) (prepared in Example 9, step 3) and MN—diisopropylethylamine (0.01 mL, 0.06 mmol) in 1,4- dioxane (0.15 mL) and water (20 uL) was stirred together and flushed with N2 for 5 min before bis(tri-t-butylphosphine)palladium (3.4 mg, 0.0067 mmol) was added. The on mixture was sealed and then heated at 110 0C for 30 min. The crude was diluted with MeOH, filtered and purified by prep LC-MS (pH = 2 method; Waters SunFire PrepC18 5pm OBDTM column, 30x100 mm, 60 mL/min, eluting with a gradient of MeCN and water with 0.1% TFA) to give the desired product as white powders (6.2 mg, 77%). LCMS calcd for C30H29FN7O4S (M+H)+: m/z = 602.2.
Found: 6022.
Example 42. N—(4-{4-Amino-7—[1-(methylsulfonyl)piperidinyl]pyrrolo[2,1- f] [1,2,4] triazin-S-yl}fluorophenyl)—2-oxo- l-phenyl-1,2—dihydr0pyridine—3— amide In a sealed tube a mixture of 5-bromo[1-(methy1su1fonyl)piperidin y1]pyrrolo[2,1-f][1,2,4]triazinamine (5 mg, 0.013 mmol) (prepared in Example 40, step 1), N—[3-fluoro—4—(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)phenyl]oxo—1 - phenyl-l,2-dihydropyridine—3-carboxamide (6.1 mg, 0.014 mmol) (prepared in Example 9, step 4) and NN—diisopropylethylamine (0.01 mL, 006 mmol) in 1,4- dioxane (0.15 mL) and water (20 uL) was stirred together and flushed with N2 for 5 min before bis(tri-t-buty1phosphine)palladium (3.4 mg, 0.0067 mmol) was added. The reaction e was sealed and then heated at 110 0C for 30 min. The crude was d with MeOH, filtered and purified by prep LC-MS (pH = 2 method; Waters SunFire PrepC18 Sum OBDTM column, 30x100 mm, 60 mL/min, eluting with a gradient of MeCN and water with 0.1% TFA) to give the desired product as white powders (3.8 mg, 47%). LCMS calcd for C30H29FN7O4S (M+H)+: m/z = 602.2.
Found: 6022.
Example 43. 4-Amino-7—[1-(methylsulf0nyl)piperidin-4—yl]pyrrolo[2,l- f] [1,2,4]triazin-S-yl}fluorophenyl)—1-(4-fluorophenyl)—2-oxo-1,2- dihydropyridine—3-carboxamide In a sealed tube a mixture of 5-bromo[1-(methylsulfonyl)piperidin—4- yl]pyrrolo[2,l-f][1,2,4]triazinamine (5.3 mg, 0.014 mmol) (prepared in Example 40, step 1), 1-(4-fluorophenyl)-N-[3-fluoro(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)phenyl]oxo-1,2-dihydropyridinecarboxamide (6.7 mg, 0.015 mmol) (prepared in Example 9, step 5) and MN—diisopropylethylamine (0.01 mL, 005 mmol) in 1,4-dioxane (0.15 mL) and water (20 uL) was stirred together and flushed with N2 for 5 min before bis(tri-t-butylphosphine)palladium (3.6 mg, 0.007 mmol) was added. The reaction mixture was sealed and then heated at 110 °C for 30 min. The crude was diluted with MeOH, filtered and purified by prep LC-MS (pH = 2 method; Waters SunFire PrepC18 5pm OBDTM column, 30x100 mm, 60 mL/min, g with a gradient of MeCN and water with 0.1% TFA) to give the desired product as white powders (3.2 mg, 36%). LCMS calcd for C30H23F2N7O4S (M+H)+: m/z = 6202. Found: 620.2.
Example 44. N— [4-(4-Amino {1- [(dimethylamino)carbonyl]piperidin-4— yl }pyrrolo [2,1-j] [1,2,4] n-S-yl)phenyl] 0xo- yl-1,2—dihydropyridine— 3-carb0xamide W0 2017/‘172596 Step 1: 4-(4-Amin0br0m0pyrr010[2,1-fl[1,2,4]triazin-7—yZ)-N,N- dimethylpiperidz‘ne-I-carb0xamide NH2 Br kN.N\ / To a mixture of opiperidinylpyrrolo[2,1-f][1,2,4]triazinamine dihydrochloride (56 mg, 0.11 mmol) (prepared in e 32, step 4) in tetrahydrofuran (0.6 mL) was added 1.0 M sodium bicarbonate in water (065 mL, 065 mmol), ed by the slow addition of N,N—dimethylcarbamoyl chloride (140 mg, 1.3 mol) at 0 "C. After stirred at rt for 80 min, the ant mixture was filtered, extracted with EtOAc, dried, filtered and concentrated to dryness under reduced pressure. The resulting crude was used directly in the next step as light yellow powders (59.8 mg). LCMS calcd for C14H20BI'N60 (M+H)+: m/z = 367.1, 369.1.
Found: 367.1, 369.1.
Step 2: N-[4-(4-Amz'n0{I-[(dz'methylamino)carbonyljpz'peridinyl}pyrr010[2,1- f][1, 2, 4]triaziny0phenylj0x0phenyl-1, 2-dz'hydr0pyridine-S-carboxamide In a sealed tube a mixture of 4-(4-aminobromopyrrolo[2,1-f][1,2,4]triazin- 7-yl)—N,N—dimethylpiperidinecarboxamide (3.8 mg, 0.007 mmol), 2-oxo—1-phenyl- N-[4-(4,4,5,5-tetramethy1-1,3,Z-dioxaborolan-Z-yl)phenyl]-1,2-dihydropyridine carboxamide (3.1 mg, 0.0074 mmol) (prepared in Example 7, step 3) and MN- ropylethylamine (0.004 mL, 0.02 mmol) in 1,4-dioxane (0.1 mL) and water (15 uL) was stirred together and flushed with N2 for 5 min before bis(tri-t— butylphosphine)pa11adium (1.8 mg, 0.004 mmol) was added. The reaction mixture was sealed and then heated at 110 °C for 50 min. After separation and the aqueous layer extracted with EtOAc, the organic layer was dried, filtered and concentrated under . The crude was purified by prep LC-MS (pH = 2 method; Waters SunFire PrepC18 Sum OBDTM column, 30x100 mm, 60 mL/min, eluting with a nt of MeCN and water with 0.1% TFA) to give the desired product as white powders (2 mg, 49%). LCMS calcd for C32H33NsO3 (M+H)+: m/z = 577.3. Found: 1O 577.3.
Example 45. N— [4-(4-Amino {1- [(dimethylamino)carbonyl]piperidin yl}pyrrol0[2,1—f] [1,2,4]triazin-S-yl)phenyl](4-flu0r0phenyl)—2—oxo—1,2- dihydropyridine—3-carboxamide HN8N4 Ho N-N / In a sealed tube a mixture of 4-(4-aminobromopyrrolo[2,l-f][1,2,4]triazin- 7-yl)-N,N-dimethylpiperidine-l-carboxamide (3.8 mg, 0.007 mmol) (prepared in Example 44, step 1), l-(4-fluorophenyl)oxo-N-[4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan—Z-yl)phenyl]-l,2-dihydropyridinecarboxamide (3.2 mg, 0.0074 mmol) (prepared in Example 9, step 3) and MN—diisopropylethylamine (0006 mL, 0.03 mmol) in oxane (0.11 mL) and water (10 uL) was stirred together and flushed with N2 for 5 min before bis(tri-t—butylphosphine)palladium (1.8 mg, 0.004 mmol) was added. The reaction mixture was sealed and then heated at 110 0C for 50 min. The crude was diluted with MeOH, filtered and d by prep LC-MS (pH = 2 method; Waters SunFire PrepC18 Sum OBDTM column, 30x100 mm, 60 mL/min, eluting with a gradient of MeCN and water with 0.1% TFA) to give the desired product as white s (2.3 mg, 55%). LCMS calcd for C32H32FN303 (M+H)+: m/z = 5953. Found: 595.3.
Example 46. N-[4-(4-Amino—7—{1-[(dimethylamino)carb0nyl]piperidin-4— yl}pyrr0l0[2,l-f][1,2,4]triazin-S-yl)-3—fluorophenyl]0x0phenyl-1,2- dihydropyridine—3-carboxamide In a sealed tube a mixture of 4-(4-aminobromopyrrolo[2,1-f][1,2,4]triazin- 7-yl)-N,N—dimethylpiperidinecarboxamide (3.8 mg, 0.007 mmol) (prepared in e 44, step 1), N-[3-fluoro(4,4,5,5-tetramethy1-1,3,2-dioxaborolan yl)phenyl]—2-oxopheny1-1,2-dihydropyridinecarboxamide (3.2 mg, 0.0074 mmol) red in Example 9, step 4) and MN—diisopropylethylamine (0006 mL, 0.03 mmol) in 1,4-dioxane (0.11 mL) and water (10 uL) was stirred together and flushed with N2 for 5 min before bis(tri-t—buty1phosphine)pa11adium(1.8 mg, 0.004 mmol) was added. The reaction mixture was sealed and then heated at 110 °C for 50 min. The crude was diluted with MeOH, filtered and purified by prep LC-MS (pH = 2 method; Waters SunFire PrepC18 5pm OBDTM , 30x100 mm, 60 mL/min, eluting with a gradient of MeCN and water with 0.1% TFA) to give the desired product as white powders (3.8 mg, 91%). LCMS calcd for C32H32FNsO3 (M+H)+: m/z = 5953. Found: 595.3.
Example 47. N-[4-(4-Amino—7—{1-[(dimethylamino)carbonyl]piperidin-4— yl }pyrrolo[2,1-f] [1,2,4]triazin-S—yl)—3—fluorophenyl](4-flu0r0phenyl)oxo-1,2- dihydropyridine—3-carboxamide In a sealed tube a mixture of minobromopyrrolo[2,1-f][1,2,4]triazin- 7-yl)-N,N-dimethylpiperidinecarboxamide (3.8 mg, 0.007 mmol) (prepared in Example 44, step 1), 1-(4-fluorophenyl)-N-[3-fluoro(4,4,5,5-tetramethyl-1,3,2- dioxaborolanyl)phenyl]oxo-1,2-dihydropyridinecarboxamide (3.3 mg, 0.0074 mmol) (prepared in Example 9, step 5) and MN—diisopropylethylamine (0006 mL, 003 mmol) in oxane (0.11 mL) and water (15 uL) was stirred together and flushed with N2 for 5 min before bis(tri-t—butylphosphine)palladium (1.8 mg, 0.004 mmol) was added. The reaction mixture was sealed and then heated at 110 °C for 50 min. The crude was diluted with MeOH, filtered and purified by prep LC-MS (pH = 2 ; Waters SunFire PrepC18 Sum OBDTM column, 30x100 mm, 60 mL/min, eluting with a gradient of MeCN and water with 0.1% TFA) to give the desired product as white powders (2.4 mg, 56%). LCMS calcd for C32H31F2N803 (M+H)+: m/z = 6132. Found: 613.2.
Example 48. N—(4-{4-Amin0-7—[1-(2-meth0xyethyl)piperidin-4—yl]pyrr0l0[2,1- f] [1,2,4]triazin-S-yl}phenyl)—2—0xo- 1-phenyl- 1,2-dihydr0pyridine—3—carb0xamide 18:43 W0 2017!]72596 Step 1: 5-Br0m0- 2-methoxyethyUpiperz'dinyljpyrr0[0[2, 2, 4]triazin amine To a e of 5-bromopiperidinylpyrrolo[2,l-f][1,2,4]triazin-4—amine dihydrochloride (56 mg, 0.11 mmol) (prepared in Example 32, step 4) in ethanol (0.5 mL) was added potassium carbonate (90 mg, 0.65 mmol), triethylamine (91 uL, 0.65 mmol) and potassium iodide (27 mg, 0.16 mmol), followed by ethane, 1—bromo methoxy (75.4 mg, 0.54 mmol). The reaction e was sealed and refluxed in an oil bath at 110 0C for 1 h. After cooling, the mixture was filtered, and the cake was washed with EtOH. The filtrate was concentrated under reduced pressure to give the desired product as off-white powders. LCMS calcd for C14H21BrNsO (M+H)+: m/z = 354.1, 3561. Found: 354.1, 356.1.
Step 2: N-(4-{4-Amz'n0- 7-[1-(2-meth0xyethyl)pz‘perz‘dz'nyl]pyrr0[0[2, 1- fl[1, 2, 4]triazinyl}phenyl)0x0phenyZ-1, 2-dz'hydr0pyrz‘dme-3—carb0xamide In a sealed tube a mixture of 5-bromo[1-(2-methoxyethyl)piperidin—4— yl]pyrrolo[2,l-f][1,2,4]triazinamine (7.6 mg, 0.01 mmol), 2-oxophenyl-N—[4- (4,4,5,5-tetramethyl- l ,3 ,2-dioxaborolanyl)phenyl]-1,2-dihydropyridine carboxamide (3.7 mg, 0.01 mmol) (prepared in Example 7, step 3) and MN- diisopropylethylamine (0.006 mL, 0.03 mmol) in 1,4-dioxane (0.1 mL) and water (10 uL) was stirred together and flushed with N2 for 5 min before bis(tri-t- butylphosphine)pa11adium (2.2 mg, 0.004 mmol) was added. The reaction mixture was sealed and then heated at 110 0C for 40 min. After separation and the aqueous layer extracted with EtOAc, the organic layer was dried, filtered and concentrated under vacuum. The crude was purified by prep LC-MS (pH = 2 method; Waters SunFire 8 5pm OBDTM column, 30x100 mm, 60 mL/min, eluting with a gradient of MeCN and water with 0.1% TFA) to give the desired product as white powders (4 mg, 84%). LCMS calcd for C32H34N7O3 (M+H)+: m/z = 5643. Found: 5643.
Example 49. N—(4-{4-Amino—7—[1-(2-methoxyethyl)piperidinyl]pyrrolo[2,1- f] [1,2,4] triazin-S-yl } phenyl)—1-(4-fluorophenyl)—2-0x0- 1,2-dihyd r0pyridine carboxamide In a sealed tube a mixture of o[1-(2-methoxyethyl)piperidin yl]pyrrolo[2,1-f][1,2,4]triazinamine (7.6 mg, 0.0085 mmol) (prepared in Example 48, step 1), 1-(4-fluoropheny1)oxo-N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan yl)phenyl]-1,2-dihydropyridinecarboxamide (3.9 mg, 0.01 mmol) (prepared in e 9, step 3) and MN—diisopropylethylamine (0.007 mL, 0.04 mmol) in 1,4- dioxane (0.1 mL) and water (10 uL) was stirred er and flushed with N2 for 5 min before bis(tri-t-butylphosphine)palladium (2.2 mg, 0.004 mmol) was added. The reaction mixture was sealed and then heated at 110 0C for 40 min. After separation and the aqueous layer ted with EtOAc, the organic layer was dried, filtered and concentrated under vacuum. The crude was purified by prep LC-MS (pH = 2 method; Waters SunFire PrepC18 5pm OBDTM column, 30x100 mm, 60 mL/min, eluting with a gradient of MeCN and water with 0.1% TFA) to give the desired product as off- white powders (3.2 mg, 65%). LCMS calcd for C32H33FN703 (M+H)+: m/z = 582.3.
Found: 5823.
Example 50. N—(4-{4-Amino[1-(2-methoxyethyl)piperidinyl] pyrrolo[2,1- f] [1,2,4] triazin-S-yl }fluorophenyl)—2-ox0- yl-1,2-dihydropyridine-3— carboxamide In a sealed tube a mixture of 5-bromo[1-(2-methoxyethyl)piperidin—4- yl]pyrrolo[2,1-f][1,2,4]triazinamine (7.6 mg, 0.0085 mmol) (prepared in e 48, step 1), N-[3-fluoro(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)phenyl] oxophenyl-1,2-dihydropyridinecarboxamide (3.9 mg, 0.01 mmol) (prepared in Example 9, step 4) and NN—diisopropylethylamine (0.007 mL, 0.03 mmol) in 1,4- dioxane (0.12 mL) and water (15 uL) was stirred together and flushed with N2 for 5 min before bis(tri-t—butylphosphine)palladium (2.2 mg, 0.004 mmol) was added. The reaction mixture was sealed and then heated at 110 °C for 40 min. After separation and the aqueous lay er extracted with EtOAc, the organic layer was dried, filtered and concentrated under vacuum. The crude was purified by prep LC-MS (pH = 2 method; Waters SunFire PrepCl8 5pm OBDTM column, 30x100 mm, 60 , eluting with a gradient of MeCN and water with 0.1% TFA) to give the desired product as off- white powders (3.9 mg, 79%). LCMS calcd for C32H33FN7O3 (M+H)+: m/z = 5823.
Found: 5823.
Example 51. N—(4-{4-Amin0-7—[1-(2-meth0xyethyl)piperidin-4—yl]pyrrolo[2,1- f] ]triazin-S-yl}fluor0phenyl)— uorophenyl)—2-ox0- 1,2- dihydropyridine—3-carb0xamide In a sealed tube a mixture of 5-bromo[1-(2-methoxyethyl)piperidin—4- yl]pyrrolo[2,l-f][1,2,4]triazinamine (7.6 mg, 0.0085 mmol) (prepared in Example 48, step 1), 1-(4-fluorophenyl)-N-[3-fluoro(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)phenyl]oxo-1,2-dihydropyridinecarboxamide (4.0 mg, 0.01 mmol) (prepared in Example 9, step 5) and MN—diisopropylethylamine (0.007 mL, 004 mmol) in 1,4-dioxane (0.15 mL) and water (15 uL) was stirred together and flushed with N2 for 5 min before bis(tri-t-butylphosphine)palladium (2.2 mg, 0.004 mmol) was added. The reaction mixture was sealed and then heated at 110 °C for 40 min. After separation and the aqueous layer extracted with EtOAc, the organic lay er was dried, filtered and concentrated under . The crude was purified by prep LC—MS (pH = 2 method; Waters SunFire PrepC18 5um OBDTM column, 30x100 mm, 60 mL/min, eluting with a gradient of MeCN and water with 0.1% TFA) to give the desired t as white powders (3.5 mg, 69%). LCMS calcd for C32H32F2N7O3 (M+H)+: m/z = 600.3. Found: 600.3. e 52. N—(4-{4-Amin0-7— [1-(2-hydr0xyethyl)piperidinyl] pyrrolo[2,1— f] ]triazin-S-yl}phenyl)0xo- l-phenyl- 1,2-dihydr0pyridine—3—carboxamide W0 2017/‘172596 18:43 Step 1:2-[4—(4-Amin0br0m0pyrr010[2,1-fl[1,2,4]trl'azinyl)pz'peridin-1—yl]ethan0[ N H2 Br "i / To a mixture of 5-bromopiperidinylpyrrolo[2,l-f] [1,2,4]triazin-4—amine dihydrochloride (56 mg, 0.11 mmol) in ethanol (0.5 mL) red in Example 32, step 4) was added potassium ate (90 mg, 0.65 mmol), triethylamine (91 11L, 0.65 mmol) and potassium iodide (27 mg, 0.16 mmol), followed by 2-bromoethanol (67.8 mg, 0.54 mmol), The reaction mixture was sealed and refluxed in an oil bath at 110 °C for 1 h. After cooling, the mixture was filtered, and the cake was washed with 1O THF and EtOH. The filtrate was concentrated under reduced pressure to give the desired product as off-white powders. LCMS calcd for C12H19BrN50 : m/z = 340.1, 342.1. Found: 340.1, 342.1.
Step 2: N-(4-{4-Amz'n0[1-(2-hydr0xyethyUpiperidinyl]pyrr0[0[2,1- f][1, 2, 4]triazinyl}phenyl)0x0phenyl-1, 2-dz'hydr0pyrz'dz'necarb0xamide In a sealed tube a mixture of 2-[4-(4-aminobromopyrrolo[2,1- f][1,2,4]triazinyl)piperidinyl]ethanol (13 mg, 0.009 mmol), 2-oxo—1-phenyl-N— 4,5,5-tetramethyl-1,3,2-dioxaborolanyl)phenyl]-1,2-dihydropyridine—3- carboxamide (3.7 mg, 0.01 mmol) (prepared in Example 7, step 3) and MN- diisopropylethylamine (0.007 mL, 0.04 mmol) in 1,4-dioxane (0.15 mL) and water (15 pL) was stirred together and flushed with N2 for 5 min before bis(tri-t- butylphosphine)palladium (2.2 mg, 0.004 mmol) was added. The reaction mixture was sealed and then heated at 110 °C for 20 min. After separation and the aqueous layer ted with EtOAc, the organic layer was dried, filtered and concentrated under vacuum. The crude was purified by prep LC—MS (pH = 2 method; Waters SunFire PrepC18 5pm OBDTM column, 30x100 mm, 60 mL/min, eluting with a gradient of MeCN and water with 0.1% TFA) to give the desired product as off- white powders (2.3 mg, 49%). LCMS calcd for C31H32N703 (M+H)+: m/z = 5503.
Found: 5503. 1O Example 53. N—(4-{4-Amin0-7— hydr0xyethyl)piperidinyl] pyrrolo[2,1— f] [1,2,4]triazin-S-yl}phenyl)(4-fluorophenyl)—2-0xo- 1,2-dihydr0pyridine carboxamide In a sealed tube a mixture of 2-[4-(4-aminobromopyrrolo[2,1- f][1,2,4]triazinyl)piperidinyl]ethanol (13 mg, 0.009 mmol) red in Example 52, step 1), 1-(4-fluorophenyl)oxo-N-[4-(4,4,5,5-tetramethyl-1,3,2— dioxaborolan-Z-yl)phenyl]-1,2-dihydropyridinecarboxamide (3.9 mg, 0.01 mmol) (prepared in Example 9, step 3) and MN—diisopropylethylamine (0.007 mL, 004 mmol) in 1,4-dioxane (0.15 mL) and water (15 uL) was d together and flushed with N2 for 5 min before bis(tri-t—butylphosphine)palladium (2.2 mg, 0.0042 mmol) was added. The on mixture was sealed and then heated at 110 0C for 20 min. After separation and the aqueous layer extracted with EtOAc, the organic lay er was dried, filtered and concentrated under vacuum. The crude was d by prep LC-MS (pH = 2 method; Waters SunFire PrepC18 5um OBDTM column, 30x100 mm, 60 mL/min, eluting with a gradient of MeCN and water with 0.1% TFA) to give the W0 72596 desired product as ite powders (2.3 mg, 48%). LCMS calcd for C31H31FN7O3 (M+H)+: m/z = 568.2. Found: 568.2.
Example 54. N—(4-{4-Amino-7—[1-(2-hydroxyethyl)piperidinyl] pyrrol0[2,1- f] [1,2,4] triazin-S-yl}fluorophenyl)—2-oxo- l-phenyl-1,2—dihydr0pyridine—3— carboxamide In a sealed tube a e of 2-[4-(4-aminobromopyrrolo[2,1- f][1,2,4]triazin-7—y1)piperidinyl]ethanol (13 mg, 0.009 mmol) (prepared in Example 52, step 1), N-[3-fluoro(4,4,5,5-tetramethyl-1,3,2-dioxaborolan yl)phenyl]—2-oxophenyl-1,2-dihydropyridinecarboxamide (3.9 mg, 0.01 mmol) (prepared in Example 9, step 4) and NN—diisopropylethylamine (0.007 mL, 004 mmol) in 1,4-dioxane (0.15 mL) and water (15 uL) was stirred together and flushed with N2 for 5 min before bis(tri-t—butylphosphine)palladium (2.2 mg, 0.0042 mmol) was added. The reaction mixture was sealed and then heated at 110 °C for 20 min. After separation and the aqueous layer extracted with EtOAc, the organic layer was dried, d and concentrated under vacuum. The crude was purified by prep LC-MS (pH = 2 method, Waters SunFire PrepC18 5um OBDTM column, 30x100 mm, 60 mL/min, eluting with a gradient of MeCN and water with 0.1% TFA) to give the desired product as off-white powders (2.7 mg, 56%). LCMS calcd for C31H31FN7O3 (M+H)+: m/z = 568.2. Found: 568.2.
Example 55. N—(4-{4—Amino-7—[1-(2-hydroxyethyl)piperidinyl] pyrr0l0[2,l- f] ] triazin-S-yl}fluorophenyl)- 1-(4-fluorophenyl)oxo- 1,2- dihydropyridine—3-carboxamide In a sealed tube a mixture of 2-[4-(4-aminobromopyrrolo[2,1- f][1,2,4]triazinyl)piperidinyl]ethanol (13 mg, 0.009 mmol) (prepared in Example 52, step 1), 1-(4-fluorophenyl)-N—[3-fluoro(4,4,5,5-tetramethyl—1,3,2- dioxaborolanyl)phenyl]oxo-1,2-dihydropyridinecarboxamide (4.0 mg, 0.01 mmol) (prepared in Example 9, step 5) and MN-diisopropylethylamine (0007 mL, 0.04 mmol) in 1,4-dioxane (0.15 mL) and water (15 uL) was stirred together and flushed with N2 for 5 min before bis(tri-t—butylphosphine)palladium (2.2 mg, 0.004 mmol) was added. The reaction mixture was sealed and then heated at 110 °C for 20 min. After separation and the aqueous layer extracted with EtOAc, the c lay er was dried, filtered and concentrated under vacuum. The crude was purified by prep LC—MS (pH = 2 method; Waters SunFire PrepC18 5um OBDTM column, 30x100 mm, 60 mL/min, g with a gradient of MeCN and water with 0.1% TFA) to give the desired product as off-white s (2.2 mg, 44%). LCMS calcd for C31H30F2N7O3 (M+H)+: m/z = 586.2. Found: 586.2. e 56. N— {4-[4-Amino(1— { [ethyl(methyl)amino] carbonyl}piperidin yl)pyrrolo [2,1-f] [1,2,4] triazin-S-yl] phenyl}(4-flu0rophenyl)—2-0xo—1,2- dihydropyridine—3-carb0xamide W0 2017!]72596 HN O N’ ,— Step 1: 4-(4-Amin0br0m0pyrr010[2,1-fl[1,2,4]triazz'nyU-N-ethyZ-N- methylpiperidine-I-carboxamide To a mixture of opiperidinylpyrrolo[2,1-f][1,2,4]triazinamine dihydrochloride (20 mg, 0.04 mmol) (prepared in Example 32, step 4) in tetrahydrofuran (0.2 mL) was added 1.0 M sodium bicarbonate in water (0.23 mL, 0.23 mmol), followed by the slow addition of ethyl(methyl)carbamic chloride (56.5 mg, 0.46 mol) at 0 Celsius. After stirred at rt for 15 min, the resultant e was filtered, extracted with EtOAc, dried, filtered and concentrated to dryness under reduced pressure. The resulting crude was used directly in the next step as off-white powders (18.1 mg). LCMS calcd for C15H22BI'N60 : m/z = 381.1, 3831.
Found: 381.0, 383.0.
Step 2: N-{4-[4-Amz'n0(1-{[ethyl(methyl)aminojcarb0nyl}piperidin yUpyrr010[2, 1-fl[1,2,4]triazin-5—yl]phenyl}(4-flu0r0phenyl)0x0-],2- dihydropyridinecarb0xamide In a sealed tube a mixture of 4-(4-aminobromopyrrolo[2,1-f][1,2,4]triazin- 7-yl)-N—ethyl-N-methylpiperidinecarboxamide (3.3 mg, 0.007 mmol), 1-(4- fluorophenyl)oxo-N—[4-(4,4,5 ,5-tetramethyl-1,3,2-dioxaborolanyl)phenyl]-1,2- dihydropyridine—3-carboxamide (3.2 mg, 0.007 mmol) (prepared in Example 9, step 3) and N,N—diisopropylethylamine (0.004 mL, 0.02 mmol) in 1,4-dioxane (0.1 mL) and water (14 uL) was stirred er before bis(tri—z‘—butylphosphine)palladium (1.8 mg, 0.004 mmol) was added. The on mixture was sealed and then heated at 110 Celsius for 50 min. The crude was diluted with MeOH, filtered and purified by prep LC-MS (pH = 2 method; Waters SunFire 8 Sum OBDTM column, 30X100 mm, 60 mL/rnin, eluting with a gradient of MeCN and water with 0.1% TFA) to give the desired product as white powders (2.9 mg, 68%). LCMS calcd 1O for C33H34FN303 (M+H)+: m/z = 609.3. Found: 609.3.
Example 57. N— {4-[4-Amino(1— { [ethyl(methyl)amino] yl}piperidin yl)pyrrolo [2,1-f] [1,2,4] triazin-S-yl] phenyl}(4-flu0r0phenyl)—2,5-dioxo— 1,2,5,6,7,8-hexahydroquinoline—3—carboxamide \ N—< >—F HN O E" "\ N‘N / 0%N/\ Step 1: 1—(4-FluorophenyU-Z, 5-dl'0x0-N-[4-(4, 4, 5, 5-tez‘ramez‘hyl-1, 3, 2-di0xab0rolan- 2-yl)phenyl]-1, 2, 5, 6, 7, 8-hexahydr0quinoll‘ne-S-carboxaml'de To a mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)aniline (76.4 mg, 0.35 mmol) and 1-(4-fluorophenyl)-2,5-dioxo-1,2,5,6,7,8-hexahydroquinoline—3— carboxylic acid (100.0 mg, 0.33 mmol) (prepared in e 1, step 4) in N,N- dimethylformamide (1.5 mL) was added triethylamine (69 uL, 0.5 mmol) followed by N,N,N‘,N-tetramethyl-O-(7-azabenzotn'azolyl)uronium hexafluorophosphate (151 mg, 0.40 mmol). The resulting mixture, which became a mixture of solids quickly, was stirred at It for 60 min. The precipitate was filtered and washed with water and dry under vacuum to provide the desired product as white powders (186 mg). LCMS calcd for C28H29BFN205 (M+H)+: m/z = 5031. Found: 503.1.
Step 2: N—{4-[4-Amz‘n0-7—(I-{[ethyl(methyUamino]carb0nyl}piperidin-4— yl)pyrr010[2, 1-fl[1, 2, 4]triazinyl]phenyl}(4-flu0r0phenyl)-2, 5-dz'0x0-1, 2,5, 6, 7, 8- hexahydroquinoline-S-carboxamide In a sealed tube a mixture of 4-(4-aminobromopyrrolo[2,1-f][1,2,4]triazin- 7-yl)—N-ethyl-N—methylpiperidinecarboxamide (3.3 mg, 0.007 mmol) (prepared in Example 56, step 1), 1—(4-fluorophenyl)-2,5-dioxo-N—[4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-Z-yl)phenyl]-1,2,5,6,7,8-hexahydroquinolinecarboxamide (3.? mg, 0.00? mmol) and NJV-diisopropylethylamine (0.008 mL, 004 mmol) in 1,4-dioxane (0.10 mL) and water (14 uL) was stirred together before bis(tri—z‘— butylphosphine)palladium (1.8 mg, 0.004 mmol) was added. The reaction mixture was sealed and then heated at 110 Celsius for 50 min. The crude was diluted with MeOH, filtered and purified by prep LC-MS (pH = 2 ; Waters SunFire PrepC18 5pm OBDTM column, 30x100 mm, 60 mL/min, eluting with a gradient of MeCN and water with 0.1% TFA) to give the desired product as white s (3.8 mg, 80%). LCMS calcd for C37H3sFNsO4 : m/z = 677.3. Found: 677.3.
Example 58. N— {4-[4-Amino(1— { [ethyl(methyl)amino] carbonyl}piperidin yl)pyrrolo[2,l-f] [1,2,4]triazin-5—yl]flu0r0phenyl}(4-fluorophenyl)-2,5-dioxo- 1,2,5,6,7,8-hexahydroquinoline—3—carboxamide \ N—< >_F HN O 1 -— F N’N / Step 1: 1-(4-Flu0r0phenyl)-N-[3-flu0r0(4, 4, 5, 5-z‘ez‘ramez‘hyl-I, 3, 2-di0xab0rolan yUphenylj-Z 5-dz'0x0-1, 2, 5, 6, 7, 8-hexahydr0quinoline-S-carboxamide o o o \ [:L O\w F To a mixture of o(4,4,5,5-tetramethyl-1,3,2-dioxaborolan yl)aniline (82.6 mg, 0.35 mmol) (from Combi-Block) and 1-(4-fluorophenyl)—2,5- dioxo—1,2,5,6,7,8-hexahydroquinolinecarboxylic acid (100.0 mg, 0.33 mmol) (prepared in Example 1, step 4) in N,N-dimethylformamide (1.5 mL) was added ylamine (69 uL, 0.5 mmol) followed by N,N,N‘,N‘-tetramethy1-0—(7- 1O azabenzotriazolyl)uronium hexafluorophosphate (151 mg, 0.40 mmol). The resulting mixture was stirred at It for 2 h. The on mixture was concentrated under vacuum to remove most solvents, and precipitated out. The precipitate was d and washed with water. The cake was dried overnight by vacuum suction to give the desired product as off-white powders (156.5 mg, 91%). LCMS calcd for C28H28BF2N205 (M+H)+: m/z = 521.1. Found: 521.1.
Step 2: N—{4-[4—Amz'n0(1-{[ethyl(methy!)aminojcarb0nyl}pz‘peridz‘n yUpyrr0Z0[2, 1-f][1. 2, 4]triazin-5—yUj‘lu0r0phenyl}(4-flu0r0phenyZ)—2, 5—dz'0x0- 1,2,5, 6, 7, 8-hexahydr0quinoline-S-carboxamz‘de In a sealed tube a mixture of 4-(4-aminobromopyrrolo[2,1-f][1,2,4]triazin- 7-yl)-N—ethyl-N-methylpiperidinecarboxamide (3.3 mg, 0.007 mmol) (prepared in Example 56, step 1), 1-(4-fluorophenyl)-N—[3-fluoro(4,4,5,5-tetramethyl-1,3,2- dioxaborolanyl)phenyl]-2,5-dioxo-1,2,5,6,7,8-hexahydroquinoline—3—carboxamide (3.8 mg, 0.0074 mmol) and N,N-diisopropylethylamine (0.004 mL, 002 mmol) in 1,4-dioxane (0.1 mL) and water (14 uL) was d together before bis(tri—t- butylphosphine)palladium (1.8 mg, 0.004 mmol) was added. The on mixture was sealed and then heated at 110 Celsius for 50 min. The crude was diluted 1O with MeOH, filtered and purified by prep LC-MS (pH = 2 method; Waters SunFire PrepC18 5pm OBDTM , 30x100 mm, 60 mL/min, eluting with a gradient of MeCN and water with 0.1% TFA) to give the desired product as white powders (1.9 mg, 39%). LCMS calcd for C37H37F2N804 (M+H)+: m/z = 695.3. Found: 6953.
Example 59. N—(4-{4-Amino-7—[1-(2-hydroxyethyl)piperidinyl] pyrrolo[2,1- f] [1,2,4] triazin-S-yl }phenyl)— 1-(4-fluorophenyl)—2,5-dioxo- 1,2,5,6,7,8- hexahydroquinoline—S-carboxamide \ N_< >—F HN O N’ .— (N'N\ / In a sealed tube a mixture of 2-[4-(4-aminobromopyrrolo[2,1- ,4]triazinyl)piperidinyl]ethanol (10 mg, 0.007 mmol) (prepared in Example 52, step 1), 1—(4—fluorophenyl)-2,5-dioxo-N—[4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolanyl)phenyl]-1,2,5,6,7,8-hexahydroquinolinecarboxamide (3.? mg, 0.00% mmol) (prepared in Example 57, step 1) and N,N-diisopropylethylamine (0.004 mL, 002 mmol) in 1,4-dioxane (0.1 mL) and water (14 u) was stirred together before bis(tri-z‘-buty1phosphine)palladium (1.8 mg, 0.004 mmol) was added. The reaction mixture was sealed and then heated at 110 Celsius for 50 min. The crude was diluted with MeOH, filtered and purified by prep LC-MS (pH = 2 method; Waters SunFire PrepC18 Sum OBDTM column, 30x100 mm, 60 mL/min, eluting with a gradient of MeCN and water with 0.1% TFA) to give the desired product as white powders (2.1 mg, 47%). LCMS calcd for FN7O4 (M+H)+: m/z = 636.3. Found: 636.3. 1O Example 60. N—(4-{4-Amin0-7— hydr0xyethyl)piperidinyl] pyrrolo[2,1— f] [1,2,4]triazin-S-yl}fluor0phenyl)— 1-(4-flu0r0phenyl)—2,S-dioxo-1,2,5,6,7,8- droquinoline—3-carb0xamide \ N—< >—F HN o ’ T F \N—N/ In a sealed tube a mixture of 2-[4-(4-aminobromopyrrolo[2,l- f][l,2,4]triazinyl)piperidin-l-yl]ethanol (10 mg, 0.007 mmol) (prepared in Example 52, step 1), uorophenyl)-N-[3-fluoro(4,4,5,5-tetramethyl-l,3,2- dioxaborolan—2-yl)phenyl]-2,5-dioxo-1,2,5,6,7,8-hexahydroquinolinecarboxamide (3.8 mg, 0.0074 mmol) (prepared in Example 58, step 1) and MN- diisopropylethylamine (0.004 mL, 0.02 mmol) in 1,4-dioxane (0.1 mL) and water (14 uL) was stirred together before bis(tri-t—butylphosphine)pa11adium (1.8 mg, 0.004 mmol) was added. The reaction mixture was sealed and then heated at 110 Celsius for 50 min. The crude was d with MeOH, filtered and purified by prep LC—MS (pH = 2 method; Waters SunFire PrepC18 5um OBDTM column, 30x100 mm, 60 mL/min, eluting with a gradient of MeCN and water with 0.1% TFA) to give the desired product as white powders (2.4 mg, 52%). LCMS calcd for C35H34F2N7O4 (M+H)+: m/z = 654.3. Found: 6543.
Example 61. N-(4-(4-Amino(1-(dimethylcarbamoyl)piperidin-4— yl)pyrr0l0 [ 1,2-f] [1,2,4] n-S-yl)phenyl)—1-is0pr0pyl-2,4—di0x0phenyl- 1,2,3,4-tetrahydropyrimidine—S-carboxamide N N4 K ,N / 24 / N O \ O 0 To a mixuture of diethyl methylene)malonate (6.0 g, 32 mmol) and phenyl isocyanate (3.8 mL, 35 mmol) in l,2-dichloroethane (20 mL) at rt was added N,N-diisopropylethylamine (7.2 mL, 42 mmol). The reaction e was then stirred at 70 °C overnight, cooled to It, added Et20 (50 mL), and stirred for another 30 min.
The resulting solid was collected by filtration, washed with ether, and dried to give the product as a white solid (4.88 g, 50%). LCMS calcd for C15H19N205 (M+H)+: m/z = 307.]. Found: 307.2.
Step 2: Ethyl 2,4-di0x0phenyl-1,2,3,4-tetrahydropyrz'midinecarb0xyiate W0 2017/‘172596 2017/024270 EtOiEiN/QI N/go A mixture of diethyl 2-((3-phenylureido)methylene)malonate from previous step (4.88 g, 15.9 mmol) and 2.5 M NaOEt in EtOH (13 mL, 32 mmol) in EtOH (20 mL) was stired at rt for 1 h. The resulting mixture was diluted with EtOAc, washed/acidified with 1 N citric acid, washed with water, brine, dried over NazSO4, and concentrated to provide the crude product as a white solid, which was used directly in the next step (4.1 g, 99%). LCMS calcd for C13H13N204 (M+H)+: m/z = 261.1. Found: 261.1. 1O Step 3: ethyl I-is0pr0pyl-2, 4-di0x0phenyl-1,2, 3, ahydr0pyrimidz‘ne-5— carboxylate A e of ethyl 2,4-dioxophenyl-l,2,3,4-tetrahydropy1imidine carboxylate from previous step (1.50 g, 5.76 mmol), isopropyl iodide (1.2 mL, 12 mmol), and CszCO3 (5.6 g, 17 mmol) in DMF (20 mL) was stirred at 50 °C for 5 h.
The reaction mixture was then cooled to rt, diluted with EtOAc, washed with water, brine, dried over NazSO4, and concentrated to provide the crude t, which was used directly in the next step. LCMS calcd for C16H19N204 (M+H)+: m/z = 3031.
Found: 303.1.
Step 4: I-Isopropyl-Z, 4-dl'0x0phenyl-1, 2, 3, 4-tetrahydr0pyrimidine-5—carb03qylz‘c A mixture of ethyl 1-isopropy1-2,4-dioxophenyl-1,2,3,4- tetrahydropyrimidine-S-carboxylate from previous step (170 g, 5.62 mmol) in 4.0 M HCl in 1,4—dioxane (9.8 mL, 39 mmol) and water (2.1 mL) was stirred at 60 °C for 4 W0 2017/‘172596 h, cooled to rt, and added water. The resulting solid was then collected by filtration (washed with water) to give the product as a white solid (11 g, 71%). LCMS calcd for C14H15N204 (M+H)+: m/z = 275‘ 1. Found: 2751.
Step 5: 1—Isopr0pyl-2, 4-dz'0x0phenyl-N-(4-(4, 4, 5, 5-z‘ez‘ramez‘hyl-1, 3, 2—dioxab0rolan- enyU—1, 2, 3, 4-tetrahydr0pyrimidinecarb0xamide To a mixture of 1-isopropyl-2,4-dioxophenyl-1,2,3,4-tetrahydropyrimidine- oxylic acid from previous step (400 mg, 1 mmol) and 4-(4,4,5,5—tetramethyl-1, 3,2-dioxaborolanyl)aniline (320 mg, 1.46 mmol) in DMF (8 mL) at rt was added Et3N (305 uL, 2.19 mmol), followed by HATU (665 mg, 1.75 mmol). The resulting mixture was stirred at rt for 2 h and added water. The resulting solid was collected by filtration, washed with water, and dried to give the product as a slightly yellow solid (642 mg, 92%). LCMS calcd for C26H31BN305 (M+H)+: m/z = 4762. Found: 4762.
Step 6: {err—Bury! min0(4-{[(1-is0pr0pyl-2, 4-di0x0phenyl—I, 2, 3, 4— ahydropyrimidinyl)carbonyljamino}phenyl)pyrrolo[2, 1fl[1, 2, 4]triazin— 7- yljpiperidine—I-carb0xylate A mixture of 1-isopropyl-2,4-dioxophenyl-N-[4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-Z-yl)phenyl]-1,2,3,4-tetrahydropyrimidinecarboxamide from W0 2017!]72596 previous step (642 mg, 1.35 mmol), tert—butyl 4-(4-arninobrornopyrrolo[2,1-f][1,2, 4]triazinyl)piperidinecarboxylate (535 mg, 1.35 rnmol) (from example 32, step 3), XPhos Pd G2 (110 mg, 0.14 mmol), and Na2CO3 (290 mg, 2.7 mmol) in 1,4- Dioxane (10 mL) and water (2.5 mL) was purged with nitrogen, and stirred at 70 °C for 2 h. The reaction mixture was then cooled to It, diluted with EtOAc, washed with water, brine, dried over NazSO4, concentrated, and purified via column chromatrography (0% to 12% MeOH in DCM) to give the crude t as a yellow solid, which was used directly in the next step (898 mg, 100%). LCMS calcd for C36H41N805 (M+H)+: m/z = 665.3. Found: 665.3.
Step 7: N—(4-(4-Amino(pl'perl'dz'ny0pyrr0[0[1,2-fl[1,2,4]triazin-5—yl)phenyZ) isopropyl—2, 4-dz'0x0phenyl—1, 2, 3, 4-tetrahydr0pyrimidine-5—carb0xamEde kx, / To a solution of utyl 4-[4-amino(4-{[(1-isopropy1-2,4-dioxo phenyl-l ,2,3,4-tetrahydropynmidin-5 -y1)carbonyl]amino}phenyl)pyrrolo[2, l—f] [1,2, 4]triazinyl]piperidinecarboxylate from previous step (898 mg, 1.35 mmol) in CH2C12 (10 mL) at It was added 4.0 M HCl in 1,4-dioxane (3.4 mL, 14 mmol). The reaction mixture was stirred at rt for 2 h, diluted with Et20, and the resulting solid was ted by filtration to give the product as a yellow solid (~2HC1 salt) (702 mg, 81%). LCMS calcd for C31H33NsO3 : m/z = 565.3. Found: 5653.
Step 8: N—(4-(4-Amino(1-(a’z'methylcarbamoyUplperidiny0pyrr0£0[1, 2- f][1, 2, 4]triazmyl)phenyl)-J-z's0pr0pyl-2, 4-dz'0x0phenyl—1, 2, 3, 4- tetrahydropyrz’mz'dz'necarb0xamz'de To a solution -(4-aminopiperidinylpyrrolo[2,l-f][1,2,4]triazin yl)phenyl]—1—isopropy1—2,4-dioxophenyl-1,2,3,4-tetrahydropyrimidine—5- amide (~2 HCl salt) from previous step (150 mg, 0.24 mmol) in CH2C12 (5.0 mL) at rt was added Et3N (200 11L, 1.4 mrnol), followed by N,N—dimethylcarbamoyl chloride (65 uL, 0.70 mmol). The reaction mixture was stirred at rt for 3 h, diluted with CH2C12 (5.0 mL), washed with water, dried over NazSO4, and concentrated. The resulting residue was dissolved in MeCN (5% water, 0.5% TFA), and purified via pH 2 preparative LC/MS (MeCN/water with TFA) to give the product as a white solid (TFA salt). LCMS calcd for C34H38N904 : m/z = 636.3. Found: 636.3. 1H NMR (600 MHz, DMSO) 5 11.01 (s, 1H), 8.67 (s, 1H), 8.10 (s, 1H), 7.80 (d, J: 8.7 Hz, 2H), 7.52 (td, J: 6.9, 1.6 Hz, 2H), 7.49 — 7.43 (m, 3H), 7.40 — 7.33 (m, 2H), 6.75 (s, 1H), 4.78 (hept, J: 6.7 Hz, 1H), 3.66 (d, J: 13.1 Hz, 2H), 3.31 (tt, J=11.8,3.5 Hz, 1H), 2.86 (t, J: 11.7 Hz, 2H), 2.75 (s, 6H), 1.97 (d, J: 10.7 Hz, 2H), 1.67 (qd, J: 12.6, 3.8 Hz, 2H), 1.43 (d, J: 6.8 Hz, 6H).
Example 62. N—(4-(4-Amino—7—(1-(ethyl(methyl)carbamoyl)piperidin yl)pyrrol0 [ 1,2-f] [1 ,2,4] triazin-S-yl)phenyl)-l-isopropyl-2,4-dioxophenyl- 1,2,3,4-tetrahydropyrimidine—S-carboxamide To a solution ofN-[4-(4-aminopiperidinylpyrrolo[2,1-f][1,2,4]triazin yl)phenyl]isopropyl-2,4-dioxophenyl-1,2,3,4-tetrahydropyrimidine carboxamide (~2 HCl salt) (from example 61, step 7) (150 mg, 0.24 mmol) in CH2C12 (5.0 mL) at rt was added Et3N (200 11L, 1.4 mmol), followed by ethyl(methyl)carbamic chloride (86 mg, 0.70 mmol). The on mixture was stirred at rt overnight, d with CH2C12 (5.0 mL), washed with water, dried over NazSO4, and concentrated. The resulting residue was dissolved in MeCN (5% water, 0.5% TFA), and purified via pH 2 preparative LC/MS (MeCN/water with TFA) to give the product as a white solid (TFA salt). LCMS calcd for C35H40N9O4 (M+H)+: m/z = 650.3. Found: 650.3. 1H NMR (600 MHz, DMSO) 5 11.00 (s, 1H), 8.67 (s, 1H), 8.09 (s, 1H), 7.79 (d, J: 8.7 Hz, 2H), 7.56 — 7.50 (m, 2H), 7.50 — 7.43 (m, 3H), 7.40 — 7.34 (m, 2H), 6.74 (s, 1H), 4.78 (p, J: 6.8 Hz, 1H), 3.63 (d, J: 13.0 Hz, 2H), 3.30 (tt, J: 11.8, 3.5 Hz, 1H), 3.12 (q, J: 7.1 Hz, 2H), 2.85 (t, J: 11.8 Hz, 2H), 2.74 (s, 3H), 1.97 (d, J: 10.8 Hz, 2H), 1.67 (qd, J: 12.6, 3.7 Hz, 2H), 1.43 (d, J: 6.8 Hz, 1O 6H), 1.06 (t,J= 7.1 Hz, 3H).
Example 63. N-(4-(4-Amino(1-is0butyrylpiperidinyl)pyrrolo[1,2- f] [1,2,4] triazin-S-yl)phenyl)—1-isopr0pyl-2,4—diox0-3—phenyl— 1,2,3,4- tetrahydropyrimidine-S-carboxamide N N4 0 / K ,N / To a solution ofN-[4-(4-aminopiperidiny1pyrrolo[2,1-f][1,2,4]triazin yl)pheny1]—1-isopropy1-2,4-dioxopheny1-1,2,3,4-tetrahydropyrimidine—5— amide (~2HC1 salt) (from example 61, step 7) (150 mg, 0.24 mmol) in CH2C12 (5.0 mL) at rt was added Et3N (200 11L, 1.4 mmol), followed by isobutyryl chloride (30 11L, 0.28 mmol). The reaction mixture was d at rt for 15 min, d with CH2C12 (5.0 mL), washed with water, dried over NazSO4, and concentrated. The resulting residue was dissolved in MeCN (5% water, 0.5% TFA), and purified via pH 2 preparative LC/MS (MeCN/water with TFA) to give the product as a white solid (TFA salt). LCMS calcd for C35H39N804 (M+H)+: m/z = 635.3. Found: 635.3. 1H NMR (600 MHz, DMSO) 5 11.00 (s, 1H), 8.67 (s, 1H), 8.07 (s, 1H), 7.79 (d, J: 8.7 Hz, 2H), 7.54 — 7.50 (m, 2H), 7.49 — 7.43 (m, 3H), 7.39 — 7.34 (m, 2H), 6.72 (s, 1H), 4.78 (p, J= 6.8 Hz, 1H), 4.54 (d, J= 12.4 Hz, 1H), 4.06 (d, J= 12.6 Hz, 1H), 3.41 (n, J: 11.8, 3.6 Hz, 1H), 3.20 (t, J: 12.5 Hz, 1H), 2.90 (p, J: 6.7 Hz, 1H), 2.69 (t,J= 12.0 Hz, 1H), 2.03 (dd, J: 18 Hz, 2H), 1.67 — 1.59 (m, 1H), 1.55 — 1.47 (m, 1H), 1.43 (d, J: 6.8 Hz, 6H), 1.05 — 0.97 (m, 6H).
Example 64. N—(4-(4-Amino-7—(l-methylpiperidinyl)pyrrolo[1,2- ]] [1,2,4]triazin-S-yl)phenyl)—1-isopropyl-Z,4-diox0phenyl— 1,2,3,4- 1O tetrahydropyrimidine—S-carboxamide o / K ,N / To a mixture ofN-[4-(4-aminopiperidinylpyrrolo[2,1-f] [1,2,4]triazin yl)phenyl]—1-isopropyl-2,4-dioxophenyl-1,2,3,4-tetrahydropyrimidine carboxamide (~2HCl salt) (from example 61, step 7) (150 mg, 0.24 mmol) in CH2C12 (10 mL) at It was added NJV—diisopropylethylamine (82 uL, 0.47 mmol). The resulting e was stirred at It for 15 min, and formaldehyde in water (24 uL, 37wt%, 0.30 mmol) was added to the mixture. The resulting mixture was stirred for min and NaBH(OAc)3 (75 mg, 0.35 mmol) was added to the mixture. The reaction mixture was then stirred at rt for 15 min, added water (2.25 mL), trated, dissolved in MeCN (5% water, 0.5% TFA), and purified via pH 2 preparative LC/MS (MeCN/water with TFA) to give the product as a white solid (TFA salt). LCMS calcd for C32H35N803 (M+H)+: m/z = 579.3. Found: 579.3. 1H NMR (600 MHz, DMSO) 8 .99 (s, 1H), 8.67 (s, 1H), 7.99 (s, 1H), 7.79 (d, J: 8.7 Hz, 2H), 7.55 — 7.50 (m, 2H), 7.49 — 7.42 (m, 3H), 7.38 — 7.34 (m, 2H), 6.63 (s, 1H), 4.79 (p, J= 6.8 Hz, 1H), 3.54 (d, J: 11.3 Hz, 2H), 3.41 — 3.34 (m, 1H), 3.21 — 3.12 (m, 2H), 2.82 (d, J: 4.6 Hz, 3H), 2.27 (d, J: 13.9 Hz, 2H), 1.93 — 1.84 (m, 2H), 1.43 (d, J: 6.8 Hz, 6H).
Example 65. N-(4-(4-Amin0(1-(dimethylcarbamoyl)piperidin-4— yl)pyrr0l0 [ 1,2-f] [1,2,4] triazin-S-yl)phenyl)—3-(4-flu0rophenyl)— 1-is0pr0pyl-2,4- dioxo—1,2,3,4-tetrahydr0pyrimidine-S-carboxamide This compound was prepared following a synthetic sequence analogous to that for example 61. LCMS calcd for C34H37FN904 (M+H)+: m/z = 654.3. Found: 6543. 1O 1H NMR (600 MHz, DMSO) 5 10.98 (s, 1H), 8.67 (s, 1H), 8.08 (s, 1H), 7.83 — 7.75 (m, 2H), 7.48 — 7.45 (m, 2H), 7.45 — 7.41 (m, 2H), 7.38 — 7.32 (m, 2H), 6.73 (s, 1H), 4.81 — 4.75 (m, 1H), 3.66 (d, J: 13.1 Hz, 2H), 3.34 — 3.27 (m, 1H), 2.86 (t, J: 11.7 Hz, 2H), 2.75 (s, 6H), 1.97 (d, J: 10.7 Hz, 2H), 1.71 — 1.63 (m, 2H), 1.43 (d, J: 6.8 Hz, 6H).
Example 66. N-(4-(4-Amin0(1-(ethyl(methyl)carbamoyl)piperidin yl)pyrrolo[1,2-f] ] triazin-S-yl)phenyl)—3-(4-flu0r0phenyl)— 1-is0propyl-2,4— dioxo—1,2,3,4-tetrahydr0pyrimidine-S-carboxamide This compound was prepared following a synthetic sequence analogous to that for example 62. LCMS calcd for C35H39FN9O4 (M+H)+: m/z = 668.3. Found: 668.2. H NMR (600 MHz, DMSO) 5 10.98 (s, 1H), 8.67 (s, 1H), 8.07 (s, 1H), 7.83 — 7.76 (m, 2H), 7.50 — 7.41 (m, 4H), 7.39 — 7.33 (m, 2H), 6.73 (s, 1H), 4.82 — 4.73 (m, 1H), 3.63 (d, J: 13.1 Hz, 2H), 3.34 — 3.25 (m, 1H), 3.12 (q, J: 7.1 Hz, 2H), 2.85 (t, .1: 11.7 Hz, 2H), 2.74 (s, 3H), 1.98 (d, J: 10.6 Hz, 2H), 1.73 — 1.61 (m, 2H), 1.43 (d, J: 6.8 Hz, 6H), 1.06 (t, J= 7.1 Hz, 3H).
Example 67. N-(4-(4-Amino(1-(dimethylcarbamoyl)piperidin r0l0 [ 1,2-f] [1,2,4] triazin-S-yl)phenyl)— 1-ethyl(4-fluor0phenyl)—2,4-dioxo- 1,2,3,4-tetrahydropyrimidine—S-carboxamide This compound was prepared following a tic sequence analogous to that for example 61. LCMS calcd for C33H35FN9O4 (M+H)+: m/z = 6403. Found: 640.3. 1H NMR (600 MHz, DMSO) 8 10.97 (s, 1H), 8.87 (s, 1H), 8.09 (s, 1H), ?.82 — 7.76 (m, 2H), 7.48 — 7.40 (m, 4H), 7.38 — 7.33 (m, 2H), 6.74 (s, 1H), 4.02 (q, J: 7.1 Hz, 2H), 3.66 (d, J: 13.1 Hz, 2H), 3.34 — 3.27 (m, 1H), 2.86 (t, J: 11.7 Hz, 2H), 2.75 (s, 6H), 1.97 (d, J: 10.6 Hz, 2H), 1.71 — 1.62 (m, 2H), 1.30 (t, J: 7.1 Hz, 3H).
Example 68. N—(4-(4-Amino(1-(morpholinecarbonyl)piperidin-4— rol0[1,2—j] [1,2,4] triazin-S-yl)phenyl)— 1-ethyl(4-fluorophenyl)-2,4-dioxo- 4-tetrahydropyrimidine—S-carboxamide I=\Q o ofNHN This compound was prepared following a synthetic sequence analogous to that for example 61. LCMS calcd for C35H37FN905 (M+H)+: m/z = 682.3. Found: 682.3. 1H NMR (600 MHz, DMSO) 5 10.97 (s, 1H), 8.86 (s, 1H), 8.08 (s, 1H), 7.82 — 7.76 (m, 2H), 7.48 — 7.39 (m, 4H), 7.39 — 7.31 (m, 2H), 6.72 (s, 1H), 4.02 (q, J: 7.1 Hz, 2H), 3.72 (d, J: 13.1 Hz, 2H), 3.59 — 3.54 (m, 4H), 3.37 — 3.28 (m, 1H), 3.16 — 3.11 (m, 4H), 2.92 (t, J: 11.8 Hz, 2H), 1.98 (d, J: 10.7 Hz, 2H), 1.71 — 1.61 (m, 2H), 1.30 (t, J: 7.1 Hz, 3H).
Example 69. N-(4-(4-Amino(1-(ethyl(methyl)carbamoyl)piperidin yl)pyrrolo [ 1,2-f] [1 ,2,4] triazin-S-yl)phenyl)—3-(2-fluor0phenyl)- l-isopropyl-2,4- dioxo—1,2,3,4-tetrahydropyrimidine-S-carboxamide N/ / KN,N / 2,‘ /\ o N\ This compound was prepared following a synthetic sequence analogous to that for example 62. LCMS calcd for C35H39FN904 (M+H)+: m/z = 668.3. Found: 668.3. 1H NMR (600 MHz, DMSO) 5 10.83 (s, 1H), 8.72 (s, 1H), 8.07 (s, 1H), 7.82 — 7.77 (m, 2H), 7.59 — 7.51 (m, 2H), 7.49 — 7.35 (m, 4H), 6.73 (s, 1H), 4.81 — 4.73 (m, 1H), 3.63 (d, J: 13.1 Hz, 2H), 3.34 — 3.26 (m, 1H), 3.12 (q, J: 7.1 Hz, 2H), 2.85 (t, .1: 11.7 Hz, 2H), 2.74 (s, 3H), 1.98 (d, J: 10.6 Hz, 2H), 1.67 (qd, J: 12.6, 3.7 Hz, 2H), 1.44 (d, J: 6.8 Hz, 6H), 1.06 (t, J: 7.1 Hz, 3H).
Example 70. N-(4-(4-Amin0(1-(dimethylcarbamoyl)piperidin yl)pyrr0l0 [ 1,2-f] ] triazin-S-yl)phenyl)—3-(3-fluorophenyl)— 1-isopr0pyl-2,4- dioxo—1,2,3,4-tetrahydr0pyrimidine-S-carboxamide QNJENL This compound was prepared ing a synthetic sequence analogous to that for example 61. LCMS calcd for C34H37FN9O4 (M+H)+: m/z = 6543. Found: 654.2. 1H NMR (400 MHz, DMSO) 8 10.94 (s, 1H), 8.68 (s, 1H), 8.08 (s, 1H), 7.80 (d, J= 8.6 Hz, 2H), 7.63 — 7.52 (m, 1H), 7.47 (d, J: 8.6 Hz, 2H), 7.38 — 7.29 (m, 2H), 7.25 (d, J: 8.2 Hz, 1H), 6.74 (s, 1H), 4.78 (p, J: 6.8 Hz, 1H), 3.66 (d, J: 13.0 Hz, 2H), 3.37 — 3.20 (m, 1H), 2.87 (q, J: 11.3, 10.6 Hz, 2H), 2.75 (s, 6H), 1.97 (d, J: 10.8 Hz, 2H), 1.75 — 1.59 (m, 2H), 1.43 (d, J: 6.8 Hz, 6H).
Example 71. N—(4-(4-Amino-7—(1-is0butyrylpiperidinyl)pyrrolo[1,2- f] [1,2,4]triazin-S-yl)phenyl)—3-(3-flu0r0phenyl)— 1-is0propyl-2,4—dioxo-1,2,3,4— tetrahydropyrimidine—S-carboxamide This compound was prepared following a tic sequence analogous to that for example 63. LCMS calcd for C35H38FN804 (M+H)+: m/z = 653.3. Found: 653.3. 1H NMR (600 MHz, DMSO) 5 10.94 (s, 1H), 8.68 (s, 1H), 8.06 (s, 1H), 7.82 — 7.76 (m, 2H), 7.61 — 7.53 (m, 1H), 7.47 — 7.43 (m, 2H), 7.36 — 7.30 (m, 2H), 7.27 — 7.22 (m, 1H), 6.72 (s, 1H), 4.78 (p, J: 6.8 Hz, 1H), 4.54 (d, J: 12.2 Hz, 1H), 4.07 (d, J: 12.8 Hz, 1H), 3.45 — 3.37 (m, 1H), 3.20 (q, J: 10.7, 8.7 Hz, 1H), 2.90 (dq, .1: 13.5, 6.7 Hz, 1H), 2.69 (t, J: 12.1 Hz, 1H), 2.03 (dd, J: 313,119 Hz, 2H), 1.67 — 1.47 (m, 2H), 1.43 (d, J: 6.8 Hz, 6H), 1.04 — 0.98 (m, 6H).
Example 72. N-(4-(4-Amino(1-(dimethylcarbamoyl)piperidin yl)pyrr0l0 [ 1,2-f] [1 ,2,4] triazin-S-yl)phenyl)— 1-ethyl(3-fluorophenyl)-2,4-dioxo- 4-tetrahydropyrimidine—S-carboxamide o N\ This compound was prepared following a synthetic sequence analogous to that for e 61. LCMS calcd for C33H35FN9O4 (M+H)+: m/z = 640.3. Found: 6403. 1H NMR (600 MHz, DMSO) 8 10.94 (s, 1H), 8.88 (s, 1H), 8.07 (s, 1H), 7.83 — 7.75 (m, 2H), 7.57 (ddd, J= 9.0, 7.9, 6.4 Hz, 1H), 7.49 — 7.43 (m, 2H), 7.36 — 7.31 (m, 2H), 7.25 (ddd, J: 7.9, 1.7, 10 Hz, 1H), 6.73 (s, 1H), 4.02 (q, J: 7.1 Hz, 2H), 3.66 (d, J: 13.1 Hz, 2H), 3.34 — 3.26 (m, 1H), 2.86 (t, J: 11.7 Hz, 2H), 2.75 (s, 6H), 1.97 (d,J=10.7 Hz, 2H), 1.72 — 1.61 (m, 2H), 1.30 (t, J: 7.1 Hz, 3H).
Example 73. N-(4-(4-Amino(1-is0butyrylpiperidinyl)pyrrolo[1,2- f] [1,2,4] triazin-S-yl)phenyl)—1-ethyl-3—(3—flu0r0phenyl)—2,4-dioxo- 1,2,25,4- tetrahydropyrimidine—S-carboxamide W0 72596 This compound was ed following a synthetic sequence analogous to that for example 63. LCMS calcd for C34H36FN804 (M+H)+: m/z = 639.3. Found: 639.2. 1H NMR (600 MHz, DMSO) 5 10.94 (s, 1H), 8.88 (s, 1H), 8.10 (s, 1H), 7.84 — 7.73 (m, 2H), 7.60 — 7.52 (m, 1H), 7.49 — 7.43 (m, 2H), 7.38 — 7.30 (m, 2H), 7.25 (ddd, J: 7.9, 1.6, 1.0 Hz, 1H), 6.75 (s, 1H), 4.54 (d, J: 12.4 Hz, 1H), 4.11 — 3.97 (m, 3H), 3.41 (tt,J= 11.8, 3.6 Hz, 1H), 3.20 (t, J: 12.3 Hz, 1H), 2.94 — 2.85 (m, 1H), 2.69 (t, J=12.0 Hz, 1H), 2.03 (dd, J= 31.1,12.1Hz, 2H),1.69 —1.45(m, 2H), 1.30 (t, J= 7.1 Hz, 3H), 1.07 — 0.96 (m, 6H).
Example 74. N-(4-(4-Amino(l-is0butyrylpiperidinyl)pyrrolo[1,2- f] [1,2,4] triazin-S-yl)phenyl)—2,5-di0xophenyl- 1,2,5,6,7,8-hexahydroquinoline- 3-carboxamide This compound was prepared following a synthetic sequence analogous to that for example 57. LCMS calcd for C37H38N704 (M+H)+: m/z = 6443. Found: 6443. 1H NMR (600 MHz, DMSO)811.56(s, 1H), 8.95 (s, 1H), 7.99 (s, 1H), 7.8? — 7.77 (m, 2H), 7.69 — 7.61 (m, 2H), 7.60 — 7.56 (m, 1H), 7.50 — 7.39 (m, 4H), 6.66 (s, 1H), 4.54 (d, J: 11.9 Hz, 1H), 4.06 (d, J: 13.0 Hz, 1H), 3.44 — 3.36 (m, 1H), 3.25 — 3.14 (m, 1H), 2.95 — 2.86 (m, 1H), 2.73 — 2.65 (m, 1H), 2.57 — 2.48 (m, 4H), 2.11 — 1.94 (m, 4H), 1.62 (d, J: 8.8 Hz, 1H), 1.50 (d, J: 8.9 Hz, 1H), 1.01 (dd, J: 9.9, 6.9 Hz, 6H).
Example 75. N—(4—(4—Amin0(1-isobutyrylpiperidinyl)pyrrolo[1,2- 1O f] [1,2,4]triazin-S-yl)—3—fluorophenyl)—1-isopropyl—Z,4—diox0phenyl-1,2,3,4- tetrahydropyrimidine—S-carboxamide This compound was prepared ing a synthetic sequence analogous to that for e 63, using 3-fluoro(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)aniline instead of 4—(4,4,5,5-tetramethyl-l,3,2-dioxaborolanyl)aniline. This compound was purified via pH 2 preparative LC/MS (MeCN/water with TFA) to give the product as a white solid (TFA salt). LCMS calcd for C35H38FN804 : m/z = 653.3. Found: 653.3. 1H NMR (400 MHz, DMSO) 5 11.10 (s, 1H), 8.68 (s, 1H), 8.05 (s, 1H), 7.89 (dd, J=12.4, 2.0 Hz, 1H), 7.52 (dd, J: 8.1, 6.6 Hz, 2H), 7.49 — 7.43 (m, 2H), 7.41— 7.32 (m, 3H), 6.68 (s, 1H), 4.82 — 4.75 (m, 1H), 4.54 (d, J: 13.2 Hz, 1H), 4.06 (d, J: 13.0 Hz, 1H), 3.45 — 3.37 (m, 1H), 3.20 (t, J: 12.2 Hz, 1H), 2.90 (p, J: 6.7 Hz, 1H), 2.72 — 2.62 (m, 1H), 2.12 — 1.93 (m, 2H), 1.69 — 1.47 (m, 2H), 1.43 (d, J: 6.8 Hz, 6H), 1.01 (broad s, 6H).
Example 76. N—(4—(4—Amino—7-(1-isobutyrylpiperidinyl)pyrrolo[1,2- f] [1,2,4]triazin-S-yl)phenyl)—3-(2,5-diflu0r0phenyl)—l-isopropyl-2,4-dioxo-1,2,3,4- tetrahydropyrimidine—S-carboxamide EQNJM This compound was prepared following a synthetic sequence analogous to that for example 63, using fluoroisocyanatobenzene instead of isocyanatobenzene. This compound was purified Via pH 2 preparative LC/MS (MeCN/water with TFA) to give the product as TFA salt. LCMS calcd for C35H37F2N304 (M+H)+: m/z = 671.3. Found: 671.2. 1H NMR (400 MHz, DMSO) 5 10.76 (s, 1H), 8.73 (s, 1H), 8.04 (s, 1H), 7.81 (d, J: 8.6 Hz, 2H), 7.59 — 7.49 (m, 2H), 7.47 (d, J: 8.6 Hz, 3H), 6.71 (s, 1H), 4.79 (p, J: 6.8 Hz, 1H), 4.55 (d, J: 12.1 Hz, 1H), 4.08 (d, J: 12.4 Hz, 1H), 3.42 (t, J: 11.8 Hz, 1H), 3.26 — 3.15 (m, 1H), 2.91 (p, J: 6.7 Hz, 1H), 2.75 — 2.64 (m, 1H), 2.11 — 1.96 (m, 2H), 1.58 (m, J: 10.6 Hz, 2H), 1.45 (dd,J= 6.7, 3.1 Hz, 6H),1.03(d, J: 5.5 Hz, 6H). e 77. N—(4—(4—Amin0(1-isobutyrylpiperidinyl)pyrrolo[1,2- f] [1,2,4] triazin-S-yl)methylphenyl)—1-isopr0pyl-2,4-diox0-3—phenyl- 4- tetrahydropyrimidine-S-carboxamide This compound was prepared ing a synthetic sequence analogous to that for example 63, using 3-methyl(4,4,5,5-tetramethyl-l,3,2-dioxaborolan—2— yl)aniline instead of 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolanyl)aniline. This compound was purified via pH 2 preparative LC/MS (MeCN/water with TFA) to give the product as a white solid (TFA salt). LCMS calcd for C36H41N804 : m/z = 649.3. Found: 6493.
Example 78. N-(4-(4-Amino(1-isobutyrylpiperidinyl)pyrrolo[1,2- 1O f] [1,2,4] triazin-S-yl)phenyl)—1-isopropyl-2,4-di0xo-3—(pyridin-3—yl)— 1,2,3,4- tetrahydropyrimidine-S-carboxamide This compound was prepared following a tic sequence ous to that for example 63, using 3-isocyanatopyridine instead of isocyanatobenzene. This compound was purified via pH 2 preparative LC/MS (MeCN/water with TFA) to give the product as a white solid (TFA salt). LCMS calcd for C34H38N904 (M+H)+: m/z = 6363. Found: 636.3. 1H NMR (500 MHz, DMSO) 5 10.89 (s, 1H), 8.70 (s, 1H), 8.67 (dd, J= 4.8, 1.4 Hz, 1H), 8.60 (d, J= 2.2 Hz, 1H), 8.09 (s, 1H), 7.92 — 7.86 (m, 1H), 7.80 (d, J: 8.7 Hz, 2H), 7.61 (dd, J: 7.9, 4.6 Hz, 1H), 7.46 (d, J: 8.6 Hz, 2H), 6.75 (s, 1H), 4.83 — 4.76 (m, 1H), 4.54 (d, J: 11.9 Hz, 1H), 4.07 (d, J: 12.0 Hz, 1H), 3.46 — 3.36 (m, 1H), 3.20 (t, J: 12.6 Hz, 1H), 2.90 (p, J: 6.7 Hz, 1H), 2.69 (t, J: 11.7 Hz, 1H), 2.10 —1.95(m,2H), 1.69 — 1.48 (m, 2H), 1.44 (d, J: 6.8 Hz, 6H), 1.01 (t, J = 6.8 Hz, 6H).
Example 79. (R)-N-(4-(4-Amin0(1-(2-hydr0xypropanoyl)piperidin-4— rolo[1,2-f] [1,2,4] triazin-S-yl)phenyl)— 1-ethyl(4-fluorophenyl)—2,4-dioxo- 1,2,3,4-tetrahydropyrimidine—S-carboxamide Step 1: N—(4—(4—Amino-7—(pl‘peridinyl)pyrr0[0[1,2—fl[1,2,4]triazinyl)phenyl) ethyl(4—flu0r0phenyl)-2, 4-dl'0x0-1, 2, 3, 4-tetrahydr0pyrl'midinecarb0xamide W0 2017!]72596 This compound was prepared following a synthetic sequence analogous to that for example 61, from step 1 to step 7, using l-fluoroisocyanatobenzene instead of natobenzene, and using ethyl iodide instead of isopropyl iodide. LCMS calcd for FN803 (M+H)+: m/z = 569.2. Found: 569.3.
Step 2: (R)-N—(4-(4-Amin0-7—(1-(2-hydr0xypropanoybpiperidinyl)pyrr0[0[1,2- f][1, 2, 4]rriazin—5—yl)phenyl)—J—ethyl—3—(4—flu0r0phenyU-2, 4—dz'0x0—1, 2, 3, 4— tetrahydropyrz’mz'dz'necarb0xamz'de To a mixture of N—[4-(4-aminopiperidinylpyrrolo[2,l-f] [1,2,4]triazin yl)phenyl]—1-ethyl-3 -(4-fluorophenyl)-2,4-dioxo-l ,2,3 ,4-tetrahydropyrimidine—5- carboxamide (~2 HCl) (50.0 mg, 0.088 mmol) and (R)hydroxypropanoic acid (16 mg, 0.18 mmol) in DMF (3 mL) was added HATU (70 mg, 0.18 mmol), followed by Et3N (6] uM, 0.44 mmol). The on mixture was stirred at It for 1 h, diluted with MeCN (with 5% water, 0.5% TFA), and purified Via pH 2 preparative LC/MS (MeCN/water with TFA) to give the t as a white solid (TFA salt). LCMS calcd for C33H34FN805 (M+H)+: m/z = 641.3. Found: 641.3. 1H NMR (500 MHz, DMSO) 5 .95 (s, 1H), 8.85 (s, 1H), 8.05 (s, 1H), 7.78 (d, J: 8.6 Hz, 2H), 7.48 — 7.38 (m, 4H), 7.37 — 7.30 (m, 2H), 6.69 (d, J: 11.8 Hz, 1H), 4.53 — 4.40 (m, 1H), 4.10 (d, .1: 11.4 Hz, 1H), 4.01 (q, J: 7.1 Hz, 2H), 3.46 — 3.37 (m, 2H), 3.17 (m, 1H), 2.75 (m, 1H), 2.02 (d, J: 10.9 Hz, 2H), 1.50 (m, 2H), 1.29 (t, J: 7.1 Hz, 3H), 1.18 (d, J: 6.3 Hz, Example 80. 4-Amino(1-(cyclopropanecarbonyl)piperidin-4— yl)pyrr0l0 [ 1,2-j] [1 ,2,4] triazin-S-yl)phenyl)—1-(2-hydroxypropyl)-2,4—di0xo phenyl-1,2,3,4-tetrahydropyrimidine—S-carboxamide o / VOH |\\,N/ Step I: Ethyl 1-(2-(tert—butyldz'methylsilyloxy)pr0pyl)-2,4-dz'0x0phenyf—1,2,3,4- tetrahydropyrimidine-5—carb0xylate Q o N4N ED5fWe A mixture of ethyl 2,4-dioxophenyl-1,2,3,4-tetrahydropyrimidine—5- carboxylate (150 mg, 0.58 mmol) (from example 61, step 2), ((1-bromopropan-2— yl)oxy)(tert-butyl)dimethylsilane (292 mg, 1.15 mmol), and CsCO3 (563 mg, 1.73 mmol) in DMF (5 mL) was stirred at 100 0C for 5 h. The reaction mixture was then cooled to rt, diluted with EtOAc, washed with water, brine, dried over NazSO4, and concentrated to afford the crude product, which was used directly in the next step.
LCMS calcd for C22H33N205$i (M+H)+: m/z = 433.2. Found: 433.2.
Step 2: 1-(2—Hydr0xypr0pyD-2, x0phenyl-1, 2, 3, 4-telrahydr0pyrz’midine-5— carboxylic acid Q 0 N4 W0 172596 A mixture of ethyl 1-(2-((tert—butyldimethy1silyl)oxy)propyl)-2,4-dioxo phenyl-l,2,3,4-tetrahydropyrimidinecarboxylate (249 mg, 0.58 mmol) in 4 M HCl in 1,4-dioxane (1.44 mL, 5.76 mmol) and water (050 mL) was d at 70 °C for 3 h, cooled to rt, and concentrated. The resulting material was then purified via pH 2 preparative LC/MS (MeCN/water with TFA) to afford the product as a yellow oil, which was used directly in the next step. LCMS calcd for C14H15N205 (M+H)+: m/z = 291.1. Found: 291.0.
Step 3: N—(4—(4-Amino(pl'perl'dz'ny0pyrr0[0[1,2-fl[1,2,4]triazin-5—yl)phenyZ) (2-hydroxypr0pyl)-2, 4-dl'0x0phenyl-1, 2, 3, 4-tetrahydr0pyrimidz'necarboxamide 017/ VOH K ,N / This compound (~2 HCl salt) was prepared ing a synthetic ce analogous to that for example 61 from step 5 to step 7, using 1-(2-hydroxypropyl)- 2,4-dioxophenyl-1,2,3,4-tetrahydropynmidinecarboxylic acid instead of 1— isopropyl-2,4—dioxophenyl-1,2,3,4-tetrahydropyrimidinecarboxylic acid. LCMS calcd for C31H33NsO4 (M+H)+: m/z = 581.3. Found: 581.3.
Step 4: N-(4-(4-Amino(1-(cyclopropanecarbanyUplperidinyl)pyrrolo[1, 2- f][1 , 2, 4]triazinyl)phenyl)(2-hydr0xypr0pyl) -2, 4-dl'0x0phenyl-1, 2, 3, 4- tetrahydropyrimidine-5—carb0xamide To a mixture ofN—(4-(4-amino(piperidinyl)pyrrolo[2,1-f][1,2,4]triazin yl)phenyl)—1-(2-hydroxypropyl)-2,4-dioxo-3 -pheny1-1,2,3,4-tetrahydropyrimidine—S - carboxamide (~2 HCl salt) (25 mg, 0.038 mmol), cyclopropanecarboxylic acid (3.4 ul, 0.042 mmol), and HATU (29 mg, 0.077 mmol) in DMF (10 mL) at rt was added Et3N (0027 mL, 0.191 mmol). The reaction mixture was stirred at rt for 2 h, and the resulting e was directly purified via pH 2 preparative LC/MS water with TFA) to give the product as a white solid (a pair of enantiomers) (TFA salt). LCMS calcd for C35H37N805 : m/z = 649.3. Found: 6493.
Example 81. N—(4—(4—Amino(1-(2-(dimethylamino)—2—oxoethyl)piperidin-4— yl)pyrrolo [ 1,2-f] [1,2,4] triazin-S-yl)phenyl)—1-is0pr0pyl-2,4—dioxophenyl- 1,2,3,4-tetrahydropyrimidine—S-carboxamide N K HN 0?N K ,N / N\\(O 1O A mixture ofN-(4-(4-amino(piperidinyl)pyrrolo[2,l-f][1,2,4]triazin yl)phenyl)—1-isopropyl-2,4-dioxophenyl-1,2,3,4-tetrahydropyrimidine carboxamide (~2 HCl salt) (from example 61, step 7) (180 mg, 0.28 mmol), 2—bromo- N,N-dimethylacetamide (94 mg, 0.57 mmol), and Et3N (0.197 n11, 1.41 mmol) in DMF (2.5 ml) was stirred at It for 3 h. The reaction mixture was diluted with MeOH, and directly purified via pH 2 preparative LC/MS (MeCN/water with TFA) to give the product as a white solid (TFA salt). LCMS calcd for C35H40N9O4 (M+H)+: m/z = 650.3. Found: 650.3. 1H NMR (600 MHZ, DMSO) 5 11.00 (s, 1H), 8.67 (s, 1H), 8.03 (s, 1H), 7.80 (d, J: 8.5 Hz, 2H), 7.53 (t, J: 7.6 Hz, 2H), 7.49 — 7.39 (m, 3H), 7.37 (d, J: 7.3 Hz, 2H), 6.66 (s, 1H), 4.82 — 4.72 (m, 1H), 4.28 (s, 2H), 3.60 (d, J: 11.6 Hz, 2H), 3.47 — 3.34 (m, 1H), 3.26 — 3.12 (m, 2H), 2.96 (s, 3H), 2.92 (s, 3H), 2.31 — 2.22 (m, 2H), 2.12 — 2.01 (m, 2H), 1.43 (d, J: 6.8 Hz, 6H).
Example 82. N-(4-(4-Amino(1-(1-methyloxopyrrolidinyl)piperidin yl)pyrr0l0 [ 1,2-j] [1 ,2,4] triazin-S—yl)phenyl)—1-isopr0pyl-2,4—dioxophenyl- 1,2,3,4-tetrahydropyrimidine—S-carboxamide This compound was ed following a synthetic sequence analogous to that for example 81, using 3-bromo-l-methylpyrrolidinone instead of 2-bromo-N,N— ylacetamide, and the reaction mixture was heated at 75 °C for 1 h instead of being stirred at rt for 3 h. This compound was purified via pH 2 preparative LC/MS (MeCN/water with TFA) to give the product as a white solid (a pair of enantiomers) (TFA salt). LCMS calcd for C36H40N904 (M+H)+: m/z = 662.3. Found: 662.3.
Example 83. N—(4-(4-Amino(1-is0butyrylpiperidinyl)pyrrolo[1,2- f] [1,2,4] triazin-S-yl)phenyl)—1-isopropyl-2,4-di0xo—3—(pyridin-2—yl)—1,2,3,4— tetrahydropyrimidine-S-carboxamide 0H W0 2017!]72596 Step 1: 4-Am2710br0m0pyrr0[0[1 triazz'n- 7-przperidin-1 -yl)-2— , Z-fl[I , 2, 4] methyipropan-J-0ne To a mixture of 5-bromo(piperidinyl)pyrrolo[2,1-f][1,2,4]triazin—4— amine (N2 HCl) (939 mg, 2.54 mmol) (from example 32, step 4) in CH2C12 (25 ml) at rt was added EtsN (1.77 ml, 12.7 mmol). The reaction mixture was stirred at rt for 1 h, and added yryl chloride (0.29 ml, 2.80 mmol). The reaction mixture was then stirred at rt for 30 min, concentrated, and the resulting material was purified via column chromatography (0% to 10% MeOH in CH2C12) to give the t as a yellow solid (602 mg, 65%). LCMS calcd for C15H21BrN50 (M+H)+: m/z = 3661.
Found: 3661.
Step 2: 1-(4-(4-Amin0(4-amin0pheny0pyrrolofl, 2-fl[1, 2, 4]triazin-7—yl)piperz’dinyl)methylpr0pan0ne OH A mixture of 1-(4-(4-aminobromopyrrolo[2,1-f][1,2,4]triazin yl)piperidinyl)methylpropanone (400 mg, 1.09 mmol), 4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolanyl)aniline (251 mg, 1.15 mmol), XPhos Pd G2 (86 mg, 0.11 mmol), and NazCOs (232 mg, 2.18 mmol) in 1,4-dioxane (7.5 ml)/water (1.5 ml) was first purged with N2, and stirred at 85 0C for 3 h. The reaction mixture was then cooled to rt, filtered h a pad of Celite (washed with EtOAc), concentrated, and purified via column chromatography (0% to 10% MeOH in CH2C12) to give the W0 2017!]72596 t as a yellow solid (398 mg, 96%). LCMS calcd for C21H27N60 (M+H)+: m/z = 3792. Found: 379.2.
Step 3: Diez‘hyl 2-((S-pyridin-Z—ylureid0)methylene)malonate To a mixture of diethyl 2-(aminomethylene)malonate (3.0 g, 16.0 mmol) and 2-isocyanatopyridine (2.02 g, 16.8 mmol) in 1,2-dichloroethane (9.0 mL) at rt was added N,N—diisopropylethylamine (3.6 mL, 20.8 mmol). The reaction mixture was then stirred at 70 °C overnight, cooled to It, and directly purified via column 1O chromatography (0% to 15% MeOH in CH2C12) to give the product (3.18 g, 65%).
LCMS calcd for C14H18N305 (M+H)+: m/z = 308.1. Found: 308.1.
Step 4: I-Isopropyl-Z, 4-di0x009yridin-2—y0-1,2, 3, 4-tetrahydr0pyrz‘m{dine carboxylic acid O A mixture of diethyl 2-((3-(pyridinyl)ureido)methylene)malonate (3.18 g, .4 mmol) and 2.5 M NaOEt in EtOH (6.2 mL, 15.5 mmol) in EtOH (25 mL) was stired at rt for 3 h. The resulting mixture was diluted with EtOAc, and washed/acidified with 1 N citric acid solution (30 mL). The organic layer was separated, and the aqueous layer was further ted with 3:1 CHCl3/isopropyl alcohol (30 mL x 3). The combined organic layers were dried over Na2S04, and concentrated to provide the crude t, ethyl 2,4-dioxo(pyridinyl)—1,2,3,4- tetrahydropyrimidinecarboxylate, which was used directly in the next step. LCMS calcd for N3O4 (M+H)+: m/z = 262.1. Found: 262.2.
A mixture of crude ethyl 2,4-dioxo(pyridinyl)-1,2,3,4- tetrahydropyrimidine-S-carboxylate from us step, propane (2.06 mL, 207 mmol), and CszCO3 (10.1 g, 31.0 mmol) in DMF (35 mL) was stirred at 3’0 W0 2017!]72596 °C for 3 h. The reaction mixture was then cooled to rt, diluted with 3:1 isopropy1 alcohol (75 mL), washed with water, brine, dried over Na2SO4, and concentrated to afford the crude product, ethyl 1-isopropyl-2,4-dioxo(pyridin y1)-1,2,3,4—tetrahydropyrimidinecarboxylate, which was used directly in the next step. LCMS calcd for C15H18N304 (M+H)+: rn/z = 304.1. Found: 3041.
A e of crude ethyl 1-isopropyl-2,4-dioxo(pyridinyl)-1,2,3,4— tetrahydropyrimidinecarboxylate from previous step in 4 M HCl in 1,4-dioxane (20 mL, 82 mmol) and water (5.0 mL) was stirred at 80 °C for 5 h, cooled to rt, and concentrated. The resulting al was then purified via column chromatography 1O (0% to 15% MeOH in CH2C12) to give the product as a slightly yellow solid (1.50 g, 47% three steps). LCMS calcd for C13H14N3O4 : m/z = 276.1. Found: 276.1.
Step 5: N-(4-(4-Amin0(1-z's0buWrylpiperidiny0pyrr0[0[1, 2—fi[1, 2, 4]triazin yUphenyU-I-isopr0pyl-2, 4-a’z'0x0(pyrz'din-2—yl)-1, 2, 3, 4-tetrahydropyrimidine carboxamide To a e of 1-isopropyl-2,4-dioxo(pyridinyl)-1,2,3,4- tetrahydropyrimidinecarboxylic acid (85 mg, 0.31 mmol), 1-(4-(4-amino(4- aminophenyl)pyrrolo[2,1-f][1,2,4]triaziny1)piperidinyl)methylpropanone (129 mg, 0.34 mmol), and HATU (141 mg, 0.37 mmol) in DMF (3.5 mL) at rt was added Et3N (0.13 mL, 093 mmol). The reaction mixture was stirred at rt for 1 h, diluted with CH2C12, and washed with water. The organic layer was separated, dried over Na2S04, concentrated, and purified via column chromatography (0% to 10% MeOH in CH2C12) to give the product, which was further purified via pH 2 preparative LC/MS (MeCN/water with TFA) to give the product as a white solid (TFA salt). LCMS calcd for C34H38N904 (M+H)+: m/z = 636.3. Found: 6363. 1H NMR (600 MHz, DMSO) 5 10.86 (s, 1H), 8.71 (s, 1H), 8.63 (ddd, J: 4.8, 1.8, 0.9 Hz, 1H), 8.10 (s, 1H), 8.06 (td, J: 7.7, 1.9 Hz, 1H), 7.80 (d, J: 8.7 Hz, 2H), 7.61 — 7.53 (m, 2H), 7.46 (d, J: 8.6 Hz, 2H), 6.76 (s, 1H), 4.77 (p, J: 6.8 Hz, 1H), 4.54 (d, J=12.2 Hz, 1H), 4.07 (d, J: 13.0 Hz,1H), 3.41 (tt, J: 11.8, 3.5 Hz,1H), 3.20 (t, J=12.4 Hz, 1H), 2.90 (p, J: 6.7 Hz, 1H), 2.69 (t, J: 12.1 Hz, 1H), 2.02 (dd, J: 30.5, 12.4 Hz, 2H), 1.70 — 1.48 (m, 2H), 1.44 (d, J: 6.8 Hz, 6H), 1.08 — 0.93 (m, Example 84. N-(4—(4-Amino—7-(1,3,5-trimethyl-1H-pyrazolyl)pyrrolo[1,2- f] [1,2,4]triazin-S-yl)phenyl)(3-fluorophenyl)isopropyl-2,4-dioxo-1,2,3,4- tetrahydropyrimidine-S-carboxamide Step I: 7-(3, 5-Dimethyl-1H—pyrazolyl)pyrr0[0[1 , Z-fl[I , 2, 4]triazz‘namine RNA / A mixture of 7-bromopyrrolo[2,1-f][1,2,4]triazinamine (0.32 g, 1.50mmol), 3,5-dimethy1(4,4,5,5-tetramethyl-1,3,2-dioxaborolan—2—yl)—1H- pyrazole (0.425 g, 1.80 mmol), Na2CO3 (0.318 g, 3.0 mmol), and XPhos Pd G2 (0.118 g, 0.150 mmol) in 1,4-dioxane (6.0 ml)/water (1.0 ml) was vacuumed and refilled with N2 twice and the on was stirred at 95 °C overnight. The reaction mixture was then cooled to rt, diluted with EtOAc, washed with water, brine, dried over NazSO4, trated, and purified via column chromatography (0% to 10% MeOH in CH2C12) to give the crude product as a yellow solid. LCMS calcd for C11H13N6 : m/z = 229.1. Found: 229.1.
Step 2: 5-Br0m0- 7-(3, 5-dz'methyl-1H—pyrazoly0pyrrolo[I , 2—f][1, 2, 4jtriazin amine W0 2017!]72596 NBS (0.18 g, 10 mmol) was added to a solution of 7-(3,5-dimethyl-1H- pyrazolyl)pyrrolo[2,17‘][l,2,4]triazinamine (0.23 g, 1.0 mmol) in DMSO (10 ml)/MeCN (1.0 ml)/water (20 uL) at 0 °C and the mixture was warmed to rt and stirred for 1 h. Water was added to the reaction mixture and the resulting solid was collected by ion, washed with water, and dried to e the product. LCMS calcd for CllHlZBI‘NG (M+H)+: m/z = 307.0. Found: 307.0.
Step 3: 4-Amz'n0-7—(3,5-dl'methyl-1H—pyrazoly0pyrr0[0[1,2-fi[1,2,4]trz‘azz'n- 1O 5-yl)phenyl)(3-flu0r0phenyl)l's0pr0pyl-2, 4-dl'0x0-1, 2, 3, 4-tetrahydr0pyrimidine- -carb0xamide QN’EN’A tMN\ / A mixture of 5-bromo(3,5-dimethyl-1H-pyrazolyl)pyrrolo[2,1- f][1,2,4]triazinamine (0.123 g, 0.40 mmol), uorophenyl)isopropyl-2,4- dioxo-N—(4—(4,4,5,5 -tetramethyl-1,3,2-dioxaborolanyl)phenyl)—1,2,3,4— tetrahydropyrimidine-S-carboxamide (0.217 g, 0.440 mmol) (prepared following a synthetic sequence analogous to that for example 61, from step 1 to step 5, using 1- fluoro-3—isocyanatobenzene instead of isocyanatobenzene), Na2CO3 (0.085 g, 0.80 mmol) and XPhos Pd G2 (0.031 g, 0.040 mmol) in 1,4-dioxane (2.0 ml)/water (0.4 ml) was vacuumed and refilled with N2 twice and the reaction mixture was stirred at 75 °C overnight. The resulting mixture was cooled to rt, diluted with MeCN (with 5% water, 0.5% TFA), d, and purified via pH 2 ative LC/MS (MeCN/water with TFA) to give the product as a white solid (TFA salt). LCMS calcd for C31H29FN9O3 (M+H)+: m/z = 594.2. Found: 594.2.
Step 4: N—(4—(4-Aml’n0(1, 3, 5-trz'methy!-1H-pyrazoly0pyrr0[0[1,2— fl[1, 2, 4]triazinyl)phenyl)(3-flu0r0phenyl)is0pr0pyl-2, 4-dz'0x0—I, 2, 3, 4— retrahydropyrimidine-5—carb0xamide Methyl iodide (3.2 ul, 0.051 mmol) was added to a mixture ofN-(4—(4—amino- 7-(3,5-dimethyl-lH-pyrazolyl)pyrrolo[2,1-f] [1,2,4]triazinyl)pheny1)-3—(3— 1O fluorophenyl)isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidinecarboxamide (30.0 mg, 0.051 mmol) and CszCO3 (32.9 mg, 0.10 mmol) in DMF (1.0 ml) at rt and the reaction mixture was stirred at rt for 1 h. The reaction mixture was then diluted with MeCN (with 5% water, 0.5% TFA), filtered, and purified via pH 2 preparative LC/MS (MeCN/water with TFA) to give the product as a white solid (TFA salt). LCMS calcd for C32H31FN903 : m/z = 608.3. Found: 608.3.
Example 85. N-(4-(4-amino(6-(dimethylcarbamoyl)methylpyridin-3— yl)pyrrol0 [ 1,2-f] [1 ,2,4] triazin-S-yl)phenyl)isopropyl-2,4-dioxophenyl- 1,2,3,4-tetrahydropyrimidine-S-carboxamide Step 1: 5-(4-Amin0br0m0pyrrolo[1,2-fl[1,2,4]trz'azinyl)-NN, 4- trimethylpicolz‘namz‘de This nd was prepared following a synthetic sequence analogous to that for example 84, from step 1 to step 2, using N,N,4-trimethyl(4,4,5,5-tetramethyl- 1,3,2—dioxaborolanyl)picolinamide instead of 3,5-dimethyl(4,4,5,5-tetramethyl- 1,3,2—dioxaborolanyl)—1H-pyrazole. LCMS calcd for C15H16BIN60 (M+H)+: m/z = 375.1. Found: 375.0.
Step 2: N-(4-(4-Amino(6—(dimethylcarbamoyl)methylpyridinyl)pyrr010[1,2- f][1, 2, 4]triazinyl)phenyl)is0pr0pyl—2, 4-di0x0phenyl-1, 2, 3, 4- tetrahydropyrimidine-5—carb0xamide A mixture of 1-isopropyl-2,4-dioxophenyl-N-(4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-Z-yl)phenyl)—1,2,3,4-tetrahydropyrimidine—5-carboxamide (30 mg, 0.063 mmol) (from e 61, step 5), 5-(4-aminobromopyrrolo[2,1- f][1,2,4]triazinyl)-N,N,4-t1imethylpicolinarrride (26 mg, 0.069 mmol), dicyclohexyl(2',4’,6’-triisopropylbiphenylyl)phosphine - (2'—aminobiphenyl yl)(chloro)palladium (1:1) (XPhos Pd G2) (5.0 mg, 6.3 umol), and Na2C03 (13.4 mg, 0.13 mmol) in 1,4-dioxane (1.5 mL)/water (0.3 mL) was purged with N2, and stirred at 70 °C for 2 h. The reaction e was cooled to rt, diluted with MeOH, filtered, and purified via pH 2 preparative LC/MS (MeCN/water with TFA) to give the product as a white solid (TFA salt). LCMS calcd for C35H34N9O4 (M+H)+: m/z = 644.3. Found: 644.3.
Example 86. o(4-(3-(3-flu0r0phenyl)—1-isopropyl-2,4-diox0-1,2,3,4- tetrahydropyrimidine-S-carboxamido)phenyl)-N,N-dimethylpyrrolo[2,1- 1] [1,2,4] triazinecarboxamide W0 172596 Step 1: 4-Amin0pyrr010[1, 2—fl[1, 2, 4]z‘riazine- 7-carb0m'z‘rl'le Na?/KN’N ,N’-Tetramethylethylenediamine (40 uL, 0.3 mmol), ZnCN (118 mg, 1.0 mmol), Tris(dibenzylideneacetone)dipalladium(0) (37 mg, 0.04 mmol) and (9,9- dimethyl-9H—xanthene—4,5-diyl)bis(diphenylphosphine) (46 mg, 0.080 mmol) was added successively to a solution of 7-bromopyrrolo[2,1-f][1,2,4]triazinamine (210 mg, 1.0 mmol) in DMF (2.0 mL) in a microwave vial. The vial was sealed, degassed three times, and stirred at 160 °C under microwave conditions for 8 min. The reaction mixture was cooled to rt, d (washed with CH2C12), and concentrated. The resulting material was washed with MeCN, and dried to provide the crude product, which was used directly in the next step. LCMS calcd for C7H6N5 (M+H)+: m/z = 160.1. Found: 160.0.
Step 2: 4-Amin0br0m0pyrr010[1,2—fl[1,2,4]triazinecarb0m'z‘rl'le NH2 Br N/ / NBS (0.117 g, 0.66 mmol) was added to a solution of 4-arninopyrrolo[2,1- f][1,2,4]triazine-7—carbonitrile (0.10 g, 0.63 mmol) in DMSO (1.0 mL)/MeCN (0.6 mL)/water (0.08 mL) at 0 OC and the reaction mixture was d at this temperature for 2 h. Water was added and the resulting solid was collected by filtration, washed W0 2017!]72596 with water, and dried to provide the product. LCMS calcd for C7H5BrNs (M+H)+: m/z = 2380. Found: 238.0.
Step 3: 4—Amz’n0-5—br0m0pyrr010[1,2—fl[1,2, 4]triazz'necarb0xylz‘c acid 12 M HCl in water (0.4 mL) was added to a mixture of 4-amino bromopyrrolo[2,1-f][1,2,4]triazinecarbonitrile (50 mg, 0.2 mmol) in 1,4—dioxane (0.4 mL). The reaction was stirred at 95 °C for 4 h, cooled to It, and concentrated to give the crude product, which was used directly in the next step. LCMS calcd for 1O C7H6BrN402 (M+H)+: m/Z = 257.0. Found: 257.0.
Step 4: 4-Amin0br0m0-N,N-dz'mez‘hylpyrr010[1, 2—fl[1, 2, 4]trl'azz'ne- 7-carb0xamide NH2 Br 2 M ylamine in THF (0.38 mL, 0.75 mmol) was added to a mixture of 4-amino—5-bromopyrrolo[2,l-f][l,2,4]triazinecarboxylic acid (25 mg, 0.097 mmol) and BOP (60 mg, 0.14 mmol) in DMF (1.0 mL), followed by Et3N (50 uL, 0.36 mmol). The reaction mixture was stirred at It for 3 h, diluted with EtOAc, washed with ted NaHCO3 on, water, brine, dried over Na2SO4, and concentrated to give the product, which was used ly in the next step. LCMS calcd for C9H11BrNsO (M+H)+: m/z = 284.0. Found: 284.0.
Step 5: 4-Amin0(4-(3-(3-flu0r0phenyl)is0pr0pyl-2, 4-dl'0x0-1,2, 3, 4- tetrahydropyrimidine-5—carb0xamido)phenyl)-N,N-dimethylpyrrolo[2, [- f][1, 2, 4]"iazine-7—carb0xamide A mixture of 3-(3-fluorophenyl)isopropyl-2,4-dioxo-N-[4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolanyl)phenyl]-1,2,3 ,4-tetrahydropyrimidine-S- carboxamide (0.020 g, 0.040 mmol) (prepared ing a synthetic sequence analogous to that for example 61, from step 1 to step 5, using o—3- isocyanatobenzene instead of isocyanatobenzene), 4-aminobromo-N,N— dimethylpyrrolo[2,1-f][1,2,4]triazinecarboxamide (0.016 g, 0.057 mmol), Na2C03 (9.0 mg, 0.085 mmol) and XPhos Pd G2 (3.3 mg, 0.0042 mmol) in 1,4-dioxane (1.0 mL)/water (0.1 mL) was ed and refilled with N2 and stirred at 75 °C for 5 h.
The resulting mixture was then cooled to rt, diluted with MeCN (with 5% water, 0.5% TFA), filtered, and purified via pH 2 preparative LC/MS (MeCN/water with TFA) to give the product as a white solid (TFA salt). LCMS calcd for C29H28FN804 : m/z = 571.2. Found: 571.1.
Example 87. N—(4-(4-Amin0(1-isobutyrylpiperidinyl)pyrrolo [2,1- ]] [1,2,4]triazin-S-yl)phenyl)—1-is0pr0pyl-3—(1—methyl- lH-pyrazolyl)-2,4-dioxo- 1,2,3,4-tetrahydropyrimidine—S-carboxamide A mixture of 1-methyl-1H-pyrazolamine (0.097 g, 1.0 mmol) and 1,1'- carbonyldiimidazole (0.178 g, 1.100 mmol) in DMSO (1 mL) was d at rt for 1 h, then diethyl 2-(aminomethylene)malonate (0.187 g, 1.00 mmol) was added to the solution. The reaction mixture was stirred at 80 °C overnight, cooled to rt, and directly purified via column chromatography (0% to 100% EtOAc in hexanes) to afford the product (0.204 g, 66%). LCMS calcd for C13H19N4Os (M+H)+: m/z = 311.1. Found: 311.2.
Step 2. Ethyl 3—(1-methyl-1H—pyrazoZyl)-2, 4-dz'0x0-1, 2, 3, 4-tetrahydropyrimidine yiate —N\l/N\/ Erick A mixture of 2.5 M NaOEt in EtOH (0.39 mL, 0.99 mmol) and diethyl 2-((3- (1-methyl-lH—pyrazolyl)ureido)methylene)malonate (0.204 g, 0.66 mmol) in EtOH (2 mL) was stirred at It for 3 h. The resulting mixture was diluted with CH2C12, and ed with 1 N HCl to pH ~7. The organic layer was separated, and the aqueous layer was further extracted with 10% MeOH in CH2C12. The combined organic layers were dried over NazSO4, and concentrated to provide the crude product (0.172 g, 1O 99%), which was used directly in the next step. LCMS calcd for C11H13N4O4 (M+H)+: m/z = 2651. Found: 265.2.
Step 3. Ethyl 1-isopr0pyl(1-methyl-1H—pyrazolyl)-2, 4-dl'0x0-1,2, 3, 4- tetrahydropyrz‘midinecarb0xylate _N\;LN/N\ CAN%iO/\ A A mixture of ethyl 3-(l-methyl-1H-pyrazolyl)-2,4-dioxo—l,2,3,4- tetrahydropyrimidine—5-carboxylate (0.172 g, 0.65 mmol), 2-iodopropane (0.13 mL, 1.30 mmol), and C52CO3 (0.636 g, 1.95 mmol) in DMF (2 mL) was d at 80 °C for 3 h. The reaction mixture was then cooled to rt, and filtered d with CH2C12). The filtrate was diluted with 10% MeOH in CH2C12, washed with water, brine, dried over NazSO4, and concentrated to afford the crude product (0.195 g, 98%), which was used directly in the next step. LCMS calcd for C14H19N4O4 (M+H)+: m/z = 3071 Found: 307.1.
Step 4. 1-Isopr0pyl(1-methyl-1H—pyrazolyl)-2, 4-dz'0x0-1, 2, 3, 4- tetrahydropyrz‘midinecarb0xylz'c acid —N\;N%j\OH;N\CAN A mixture of ethyl 1-isopropyl(1-methyl-1H-pyrazol-4—yl)-2,4—dioxo— 1,2,3,4-tetrahydropyrimidinecarboxylate (0.195 g, 0.64 mmol) in 4 M HCl in e (1.27 mL) and water (0.32 mL) was stirred at 80 oC overnight. The reaction mixture was then cooled to It, diluted with water (3 mL), and neutralized with 1N NaOH solution to pH ~5. The resulting mixture was extracted with 10% MeOH in CH2C12 (3 mL x 3), and the combined organic layers were dried over NazSO4, and concentrated to afford the crude product (0.172 g, 97%) which was used directly in the next step. LCMS calcd for C12H15N4O4 (M+H)+: m/z = 279.1. Found: 279. 1.
Step 5. N-(4—(4-Amin0-7—(1-z's0buWrylpiperidiny0pyrr0[0[2, 1fl[1, 2, 4]triazin yD-I-isopr0pyl(1-methyl-1H—pyrazolyl)-2, 4-dl'0x0-1, 2, 3, 4- tetrahydropyrimidine-5—carb0xamide To a mixture of 1—isopropyl(1-methyl-1H—pyrazolyl)—2,4-dioxo—1,2,3,4— tetrahydropyrimidine—5-carboxylic acid (0.014 g, 0.050 mmol) and HATU (0.021 g, 0.055 mmol) in DMF (1 mL) was added 1-(4-(4-amino-5—(4— aminophenyl)pyrrolo[2,1-j] ]triazinyl)piperidinyl)-2—methylpropanone (0.019 g, 0.050 mmol) (from example 83, step 2) and Et3N (0.021 n11, 0.15 mmol).
The mixture was stirred at It for 2 h., diluted with MeOH, adjusted with TFA to pH ~2, and purified via pH 2 preparative LC/MS water with TFA) to give the product as TFA salt. LCMS calcd for C33H39N1004 (M+H)+: m/z = 639.3. Found: 639.3. e 88. N—(4—(4—Amin0(1-isobutyrylpiperidinyl)pyrrolo[2,1- f][1,2,4]triazin-S-yl)phenyl)—1-is0pr0pyl-3—(1—methyl-lH-pyrazolyl)-2,4-dioxo- 1,2,3,4-tetrahydropyrimidine—S-carboxamide This compound was prepared following a synthetic sequence ous to that for example 87, using 1-methyl-1H—pyrazolarnine d of 1-methyl-1H—pyrazol- 4-amine. This compound was purified via pH 2 preparative LC/MS (MeCN/water with TFA) to give the product as TFA salt. LCMS calcd for C33H39N1004 : m/z= 639.3. Found: 6393.
Example 89. N—(4-(4-Amino(1-is0butyrylpiperidinyl)pyrrolo[1,2- 1] [1,2,4] triazin-S-yl)phenyl)—1-is0pr0pyl-3—(2-methylthiazol-5—yl)—2,4-dioxo- 1,2,3,4-tetrahydropyrimidine—S-carboxamide This compound was prepared following a synthetic sequence analogous to that for example 87, using 2-methylthiazolamine instead of l-methyl- lH-pyrazol amine. This compound was purified via pH 2 ative LC/MS (MeCN/water with TFA) to give the product as TFA salt. LCMS calcd for C33H33N9O4S (M+H)+: m/z = 656.3. Found: 656.3.
Example 90. N—(4—(4-Amino(1-is0butyrylpiperidinyl)pyrrolo[2,1- ]] [1,2,4] triazin-S-yl)phenyl)—3-cyclohexylisopropyl-2,4—dioxo— 1,2,3,4- tetrahydropyrimidine-S-carboxamide Step 1: 3-Cyclohexylis0pr0pyl-2, 4-dl'0x0-1, 2, 3, 4-2‘6trahydropyriml'dine carboxylic acid This compound was prepared following a synthetic sequence ous to that for example 61, step 1 to step 4, using isocyanatocyclohexane instead of natobenzene. LCMS calcd for C14H21N204 (M+H)+: m/z = 2812. Found: 281.].
Step 2: N—(4—(4-Amz'n0(1-z's0buWrylpz‘perz‘dz‘ny0pyrr0[0[2,1-fi[1,2,4]lriazin yl)—3—cyclohexylis0pr0pyl-2, 4-dl'0x0-1, 2, 3, 4-z‘etrahydropyrimidine—5— carboxamide To a mixture of 3-cyclohexylisopropyl-2,4-dioxo-1,2,3,4- ydropyrimidine—S-carboxylic acid (0.014 g, 0.050 mmol) and HATU (0.021 g, 1O 0.055 mmol) in DMF (1 mL) was added l-(4-(4-amino(4- aminophenyl)pyrrolo[2, l -f] [l,2,4]triazinyl)piperidin-l -yl)methylpropan—1-one (0.019 g, 0.050 mmol) (from example 83, step 2) and Et3N (0.021 H11, 015 mmol).
The mixture was stirred at rt for 2 h., diluted with MeOH, adjusted with TFA to pH N2, and purified via pH 2 preparative LC/MS (MeCN/water with TFA) to give the product as TFA salt. LCMS calcd for C35H45NsO4 (M+H)+: m/z = 6414. Found: 641.3.
Example 91. N-(4-(4-Amino(1-isobutyrylpiperidinyl)pyrrolo[2,1- ]] [1,2,4] triazin-S-yl)phenyl)—3-(3-cyanophenyl)—1-isopr0pyl-2,4—di0x0-l,2,3,4— tetrahydropyrimidine-S-carboxamide "’N\ > 0 N N / \ NHFg: )=oN /leN o Step 1: r0m0phenyl)is0pr0pyl—2, 4-dz'0x0-1,2, 3, 4-2‘6trahydropyrimidine carboxylic acid Br N OH CAN I This compound was prepared following a synthetic sequence analogous to that for example 61, from step 1 to step 4, using l-bromoisocyanatobenzene instead of W0 2017!]72596 isocyanatobenzene. LCMS calcd for BrN204 (M+H)+: m/z = 3530. Found: 353.1.
Step 2: N—(4—(4—Amz’n0(1-z'sobuQ/rylpz'perz'dz'ny0pyrr0[0[2,1—fl[1,2,4]triazin yUphenyl)—3—(3-br0m0phenyl)z's0pr0pyZ-2, 4-dz'0x0-1, 2, 3, 4-z‘etrahydropyrimidine-5— carboxamide To a mixture of 3-(3-bromophenyl)—1-isopropyl-2,4-dioxo-1,2,3,4— tetrahydropyrimidine-S-carboxylic acid (0.018 g, 0.050 mmol) and HATU (0.021 g, 0.055 mmol) in DMF (1 mL) was added 1-(4-(4-amino(4- aminophenyl)pyrrolo[2,1-f] [1,2,4]triazinyl)piperidinyl)methylpropanone (0.019 g, 0.050 mmol) (from example 83, step 2) and Et3N (0021 ml, 0.150 mmol).
The mixture was stirred at It for 2 h, and water (4 mL) was added. The resulting solid was collected by ion, washed with water, and dried to afford the product. LCMS calcd for BrNsO4 (M+H)+: m/z = 713.2. Found: 7132.
Step 3: N—(4—(4—Amz'n0-7—(I-l's0buWrylpiperidiny0pyrr0[0[2, 1fl[1, 2, 4]triazin yUphenyl)—3—(3-cyan0phenyl)is0pr0pyl-2, 4-dl'0x0-1, 2, 3, rahydropyrimidine carboxamide A mixture ofN—(4-(4-amino(1 -isobutyrylpiperidinyl)pyrrolo[2,1— ]] [1,2,4]triazinyl)phenyl)(3-bromophenyl)isopropyl-2,4-dioxo-1,2,3,4- tetrahydropyrimidine-S-carboxamide (0.036 g, 0.050 mmol), potassium hexacyanoferratefll) trihydrate (10.5 mg, 0.025 mmol), tBuXPhos Pd G3 (0.32 mg, 0.40 umol) and KOAc (0.61 mg, 6.3 umol) in a sealed screw Vial was de-gassed and recharged with -dioxane (0.50 mL) and water (0.50 mL) was then added. The mixture was re-degassed and charged with N2 for three cycles. The reaction mixture was then heated at 100 0C for 1 h, cooled to It, diluted with MeOH, adjusted with TFA to pH ~2, and purified Via pH 2 preparative LC/MS (MeCN/water with TFA) to give the t as TFA salt. LCMS calcd for C36H38N904 (M+H)+: m/z = 660.3.
Found: 660.3.
Example 92. N—(4—(4—Amino(1-isobutyrylpiperidinyl)pyrrolo[2,1- f] [1,2,4]triazin-S-yl)phenyl)—1-isopr0pyl(5-methylisoxazol-3—yl)—2,4—di0x0— 1,2,3,4-tetrahydropyrimidine-S-carboxamide o=( WC o N HZN \NJ This compound was prepared following a synthetic sequence analogous to that for example 87, using ylisoxazolamine instead of l-methyl-lH—pyrazol amine. This compound was purified via pH 2 preparative LC/MS (MeCN/water with TFA) to give the product as TFA salt. LCMS calcd for C33H38N905 (M+H)+: m/z = 640.3. Found: 6403. e 93. N-(4-(4-Amino(4-(dimethylamino)cyclohexyl)pyrrolo[2,1- f] [1,2,4]triazin-S-yl)phenyl)—1-isopropyl-2,4-dioxophenyl—1,2,3,4- tetrahydropyrimidine-S-carboxamide N NH l f‘ 2 O N\ H N\ \ NI};O O 7’ Step 1: tert-Butyl (4-(4-amin0pyrr010[2,1-fl[1,2,4]triazinyUcyclohex—3—en-I— yl)carbamate W0 2017!]72596 In a sealed vial, a mixture of 7-bromopyrrolo[2,1-f][1,2,4]tIiazinamine (300 mg, 1.41 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)cyclohex- 3-enylcarbamate (550 mg, 1.69 mmol), (2-dicyclohexylphosphino-2',4',6'-t1i-ipropyl-l ,1'-bipheny1)(2'-amino-1,1'-bipheny1y1) palladium(II) (55.4 mg, 0.070 mmol) and potassium phosphate tribasic (0.35 ml, 4.22 mmol) in 1,4-dioxane (10 ter (2.0 ml) was degassed and stirred at 90 °C under N2 for 2.5 h. The reaction mixture was cooled to It, diluted with EtOAc, and washed with brine. The organic layer was separated, dried over NazSO4, concentrated, and purified by column chromatography (0% to 10% MeOH in CH2C12) to give the product (400 mg, 86%). 1O LCMS calcd for N502 (M+H)+: m/z = 3302, Found: 330.1 Step 2: uz‘yl (4-(4-amin0pyrr010[2, 1-fl[1, 2, 4jtrz'azz'nyl)cyclohexyl)carbamate NHBoc To a mixture of tert-butyl (4-(4-aminopy1rolo[2,1-f][1,2,4]triazin-?- yl)cyclohex—3—enyl)carbamate (460 mg, 1.40 mmol) in MeOH (25 ml) was added % Pd/C (297 mg). The resulting mixture was stirred under 1 atm H2 (balloon).
After 22 h, more 10% Pd/C (160 mg) was added along with CH2C12 (5 mL). The reaction mixture was then stirred for another 23 h, filtered through Celite (washed with CH2C12), and concentrated to give the crude t (463 mg), which was used directly in the next step. LCMS calcd for C17H26N502 (M+H)+: m/z = 332.2; Found: 332.2 Step 3: tert-Butyl (4-(4-amin0br0m0pyrr010[2,1-fl[1,2,4]trz'azin yUcycfohexyDcarbamate W0 2017!]72596 To a solution of tert—butyl (4-(4-aminopyrrolo[2,1-f] [1,2,4]t1iazin—7- yl)cyclohexyl)carbamate (463 mg, 1.40 mmol) in DMF (15 ml) was added NBS (249 mg, 1.40 mmol). The resulting mixture was stirred at rt overnight. Water was then added to the reaction mixture, and the resulting solid was ted by filtration, washed with water, and dried to give the product as ayellow solid (443 mg), which was used directly in the next step. LCMS calcd for C17H25BrN502 (M+H)+: m/z = 4101; Found: 410.1.
Step 4: N—(4-(4-Amino(4-aminocyclohenypyrr010[2,1-fl[1,2,4]triazin-5— 1O yl)phenyD—I-is0pr0pyl-2, 4-di0x0phenyl-1, 2, 3, 4-tetrahydr0pyrimz‘dine-5— carboxamide N NH2 II/ \ 0 7 N\N \ \ NI};O O r A mixture of tert-butyl (4-(4-aminobromopyrrolo[2,1-f][1,2,4]triazin yl)cyclohexyl)carbamate (270 mg, 0.066 , 1-isopropyl-2,4-dioxophenyl-N- (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)phenyl)-1,2,3,4- tetrahydropyrirnidine-S-carboxamide (40.7 mg, 0.086 mmol) (from example 61, step ), chloro(2-dicyclohexylphosphino-2',4',6'-tIi-i-propyl-1,1'-biphenyl)(2'-arnino—1,1'- yl-2—yl) palladium(II) (2.6 mg, 3.3 umol) and potassium phosphate tribasic (41.9 mg, 0.197 mmol) in 1,4-dioxane (0.50 mL)/water (0.10 mL) was stirred at 90 °C under N2 for 2 h, cooled to rt, and partitioned between CH2C12 and water. The organic layer was separated and concentrated. To the crude residue was added CH2C12 (400 uL) and TFA (200 uL). The resulting on was d at rt for 1 h, and concentrated. The crude material was purified via pH 2 preparative LC/MS (MeCN/water with TFA) to give the t as TFA salt. LCMS calcd for C32H35N803 (M+H)+: m/z = 579.3; Found: 579.2.
Step 5: N-(4-(4-Amin0(4-(dz'methylamin0)cyclohenypyrr010[2, I-fl[1,2,4]triazin- -y[)phenyl)z‘sopr0pyZ-2, x0phenyZ-1, 2, 3, 4-tetrahydr0pyrz‘mrefine carboxamide To a mixture ofN-(4-(4-amino(4-aminocyclohexyl)pyrrolo[2,1- ,4]triazinyl)phenyl)—l-isopropyl-2,4-dioxophenyl-l,2,3,4— tetrahydropyrimidinecarboxamide (15 mg, 0.022 mmol), formaldehyde in water (37 wt%, 1.6 uL, 0.022 mmol) and Et3N (12 "L, 0.087 mmol) in THF (0.30 ml) was added sodium triacetoxyborohydride (50 mg, 2.05 mmol). The resulting mixture was stirred at rt overnight, filtered, and concentrated. The crude material was purified via pH 2 preparative LC/MS (MeCN/water with TFA) to give the product as TFA salt.
LCMS calculated for C34H39NsO3 (M+H)+: m/z = 607.3, Found: 607.3.
Example 94. N-(4—(4-amino(1-(cyclopr0panecarbonyl)azetidin-3— yl)pyrrolo[2,1-f] [1,2,4]triazin-S-yl)phenyl)—1-isopropyl-Z,4-dioxo-3—phenyl- 1,2,3,4-tetrahydropyrimidine—S-carboxamide N-Iodosuccinimide (2.5 g, 11 mmol) was added to a on of pyrrolo[1,2— f][1,2,4]triazinannne (1.5 g, 11 mmol) in DMF (10 mL) at rt and the on was stirred for 2 h. The reaction mixture was then diluted with EtOAc, washed with water W0 2017/‘172596 and concentrated. The resulting solid was washed with water, and dried to give the product. LCMS calcd for CsHsIN4 (M+H)+: m/z = 2610 Found: 2612.
Step 2: tert—Butyl 3-(4-amin0pyrr010[1,2—fl[1,2,4]z‘rz‘azz‘nyUazetidine—1—carb0xylate Zinc (0.690 g, 10.5 mmol) was suspended with 1,2-dibromoethane (60 uL, 0.70 mmol) in DMF (20 mL). The resulting mixture was stirred at 70 °C for 10 min and cooled to rt. Chlorotrimethylsilane (89 uL, 0.70 mmol) was added and stirring was continued for 1 h. A solution of tert—butyl 3-iodoazetidinecarboxylate (2.5 g, 8.8 mmol) in DMF (10 mL) was then added and the mixture was stirred at 40 °C for 1 h before a mixture of pyrrolo[2,1-f][1,2,4]triazinamine (2.4 g, 9.2 mmol), Tris(dibenzylideneacetone)dipalladium(0) (0.80 g, 0.88 mmol) and Tri-(2— fmy1)phosphine (0.41 g, 1.8 mmol) in DMF (12 mL) was added. The reaction mixture was then stirred at 75 °C overnight, cooled to rt, and partitioned between EtOAc and ted NH4Cl on. The organic layer was separated, washed with water, dried over MgSO4, trated and purified via column chromatography (0% to 100% EtOAc in hexanes) to give the product (1.0 g, 39%). LCMS calcd for C14H20N502 (M+H)+: m/z = 290.2. Found: 290.2.
Step 3: tert—Butyl 3-(4-amin0br0m0pyrr010[1,2—fl[1,2,4]z‘riazinyUazetidine carboxylate NBS (0.55 g, 3.1 mmol) was added to a on of tert—butyl 3-(4- aminopyrrolo[2,1-j][1,2,4]t1iazinyl)azetidine—1-carboxylate (0.94 g, 3.2 mmol) in DMSO/MeCN/water (7.0 mL/3.0 mL/0.2 mL) at 0 °C and the reaction mixture was W0 2017/‘172596 stirred at this temperature for 2 h. The resulting mixture was diluted with EtOAc, washed with water, concentrated, and purified via column tography (0% to 100% EtOAc in hexanes) to give the desire t (035 g, 29%). LCMS calcd for C14H19BrN502 (M+H)+: m/z = 368.1. Found: 368.0.
Step 4: {err—Bury] 3-(4-aml'n0(4-aminophenyUpyrr010[1, 2-fl[1,2, 4]triazin— 7— yUazetidine—I -carb0xylate H2N N\ H2N N A e of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)aniline (0.21 g, 0.95 mmol), tert—butyl minobromopyrrolo[2,l-f][1,2,4]triazin-?-yl)azetidine- l-carboxylate (0.35 g, 0.95 mmol), CszCO3 (0.62 g, 1.9 mmol) and dicyclohexyl(2',4',6'—triisopropylbipheny1yl)phosphine-(2'-arninobipheny1 yl)(chloro)palladium (1:1) (0.075 g, 0.095 mmol) in 1,4-dioxane/water was stirred at 85 °C for 2 h. The reaction mixture was then cooled to rt, and purified via column chromatography (0% to 100% EtOAc in hexanes) to give the product (0.28 g, 77%).
LCMS calcd for C20H25N602 (M+H)+: m/z = 381.2. Found: 381.3.
Step 5: tert—butyl 3-(4-aml'n0(4-(1-l's0pr0pyl-2, 4-di0x0phenyl-1,2, 3, 4— tez‘rahydropyrimidinecarb0xamid0)phenyl)pyrr010[2, 1fl[1 , 2, 4]triazin-7— yUazetidine-I-carb0xylate W0 2017/‘172596 To a mixture of tert—butyl 3-[4-amino(4-aminophenyl)pyrrolo[2,1- f][1,2,4]triazinyl]azetidinecarboxylate (140 mg, 0.37 mmol) and 1-isopropy1- 2,4-dioxophenyl-1,2,3,4-tetrahydropyrimidine-S-carboxylic acid (110 mg, 0.40 mmol) (from example 61, step 4) in DMF (3.0 mL) was added Et3N (0.10 mL, 0.74 mmol) followed by HATU (0.17 g, 0.44 mmol). The reaction mixture was stirred at rt for 1 h, quenched with water, and the resulting solid was collected by filtration, and dried to give the product. LCMS calcd for C34H37NsOs (M+H)+: m/z = 637.3. Found: 637.2.
Step 6: N-(4-(4-Amino(azetidiny0pyrr010[I,2-fl[1, 2, 4]triazinyl)phenyl)-1 - isopropyl—Z, 0phenyl—1, 2, 3, 4-tetrahydr0pyrimidinecarb0xamide tert-Butyl rnino(4-(1-isopropyl-2,4-dioxophenyl-1,2,3,4— tetrahydropyrirnidine—S-carboxamido)phenyl)pyrrolo[1,2-f] ]tn'azin yl)azetidine—1—carboxylate (0.25g, 0.39 mmol) was treated with 4 M HCl in 1,4— dioxane (0.098 mL, 0.39 mmol) in CH2C12 (1 mL) at rt for 1 h. The reaction mixture was then concentrated to give the product. LCMS calcd for C29H29N803 (M+H)+: m/z = 537.2. Found: 537.2.
Step 7: N-(4—(4-Amino(1-(cyclopr0panecarb0nyl)azetidin-S-yUpyrrofofl, 2- f][1, 2, 4]triazinyl)phenyl)is0pr0pyl—2, 4-dl'0x0phenyl-1, 2, 3, 4- tetrahydropyrimidinecarb0xamide To a mixture ofN—(4-(4-amino(azetidin-3 -yl)pyrrolo[2, 1 -f] [1,2,4]triazin yl)phenyl)isopropyl-2,4-dioxophenyl-1,2,3,4-tetrahydropyrimidine carboxamide (0.0055g, 10.3 umol) and Et3N (2.86 ul, 0.020 mmol) in CH2C12 (1 ml) was added cyclopropanecarbonyl chloride (1.3 mg, 0.012 mmol). The reaction e was stirred at rt for 1 h, trated, and purified via pH 2 preparative LC/MS (MeCN/water with TFA) to give the product as TFA salt. LCMS calcd for C33H33N804 (M+H)+: m/z = 605.3. Found: 605.2.
Example 95. N—(4-(4-Amin0(morpholinomethyl)pyrrolo [1,2-f] [1,2,4]triazin-5— yl)phenyl)— l-isopropyl-2,4—dioxo-3—phenyl-1,2,3,4-tetrahydropyrimidine—S- carboxamide o / kx ,N \\/O Step 1: 4-Amz’n0pyrr010[1,2-fl[1, 2, z‘ne-7—carbaldehyde To a solution of pyrrolo[2,1-f][1,2,4]triazinamine (1.0 g, 7.45 mmol) in DMF (15 mL) at 0 °C was added POCl3 (3.47 mL, 37.3 mmol). The reaction e was then stirred at 60 °C overnight, cooled to rt, quenched with saturated NaHCO3 solution, and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine, dried over NazSO4, concentrated, and purified via column chromatography (0% to 15% MeOH in CH2C12) to give the product (200 mg, 16%).
LCMS calcd for C7H7N4O (M+H)+: m/z = 163.1. Found: 163.1.
Step 2: 4-Amin0br0m0pyrrolofl, 2-fl[1, 2, 4]trz'azz'ne- 7-carbaldehyde To a solution of 4-aminopyrrolo[2,1-f][1,2,4]t1iazine—7-carbaldehyde (200 mg, 1.23 mmol) in THF (6.0 ml) at It was added 1,3-dibromo-5,5-dimethylhydantoin (212 mg, 0.74 mmol) portionwise. The reaction mixture was then stirred at rt for 1 h, and diluted with water (30 mL)/EtOAc (30 mL). The organic layer was ted, washed with brine, dried over NazSO4, and concentrated to give the t (127 mg, 43%), which was used directly in the next step. LCMS calcd for C7H6BI'N4O (M+H)+: m/z = 241.0. Found: 241.0. 1O Step 3: N-(4-(4-Amin0f0rmylpyrr010[1 , 2-fl[I , 2, 4]triazz'nyl)phenyl)-1 -isopr0pyl- 2, 4-diox0-3—phenyl-1, 2, 3, 4-2‘6trahydropyrimidinecarb0xamide o 34if A mixture of 4-aminobromopyrrolo[2,l-f] [1,2,4]triazinecarbaldehyde (126 mg, 0.52 mmol), 1-isopropyl-2,4-dioxophenyl-N-(4-(4,4,5,5-tetramethyl- 1,3,2—dioxaborolanyl)phenyl)—1,2,3,4-tetrahydropyrimidinecarboxamide (248 mg, 0.52 mmol) (from example 61, step 5), (2-dicyclohexylphosphino-2',4',6'- triisopropyl-l,1'-biphenyl)[2-(2'—amino-1,1'-biphenyl)]palladium(II) (XPhos Pd G2) (41 mg, 0.052 mmol), and Na2CO3 (111 mg, 1.04 mmol) in oxane (4.0 mL)/water (1.0 mL) was purged with N2, and stirred at 70 °C for 2 h. The reaction mixture was then cooled to rt, and diluted with water (30 mL)/EtOAc (30 mL). The organic layer was separated, washed with brine, dried over Na2SO4, concentrated, and purified via column chromatography (0% to 15% MeOH in CH2C12) to give the product (266 mg, 100%). LCMS calcd for C27H24N7O4 (M+H)+: m/z = 5102. Found: 10.2.
Step 4: N-(4-(4-Amino(morpholinomethyUpyrrolo[1, 2-fl[1 , 2, 4jtrz'azm yUphenyU-J -z’sopr0pyl—2. x0phenyl-1, 2, 3, 4-z‘etrahydr0pyrimidine carboxamide To a mixture ofN—(4-(4-aminoformylpyrrolo[2,l-f] [1,2,4]triazin yl)phenyl)—1-isopropyl-2,4-dioxophenyl-1,2,3,4-tetrahydropyrimidine carboxamide (20 mg, 0.039 mmol), morpholine (0.017 mL, 0.20 mmol), and acetic acid (0.01] mL, 0.20 mmol) in ClCH2CH2Cl (1.5 mL) at rt was added sodium triacetoxyborohydride (42 mg, 0.20 mmol). The on mixture was then stirred at 1O 50 °C for 15 min, cooled to rt, concentrated, diluted with MeOH, and purified via pH 2 preparative LC/MS (MeCN/water with TFA) to give the product as a white solid (TFA salt). LCMS calcd for NsO4 (M+H)+: m/z = 581.3. Found: 581.3.
Example 96. N-(4—(4—Amino—7-(1-isobutyrylpiperidinyl)pyrrolo[1,2- f] [1,2,4] triazin-S-yl)phenyl)—2-isopropyl-3,5-di0x0-4—phenyl-2,3,4,5-tetrahyd ro- 1,2,4-triazinecarboxamide ,N O H "1 Y E‘N \ O 0 o Step 1: ylhydrazinecarbothioamide 0%8 To a stirred solution of hydrazine e (1.7 g, 34 mmol) in isopropyl alcohol (300 mL) at It was added isothiocyanatobenzene (3.4 mL). The reaction mixture was stirred at It for 30 min, and the resulting solid was collected by filtration, washed with isopropanol, and dried to give the product (4.8 g). LCMS calcd for C7H10N3S (M+H)+: m/z = 168.1. Found: 168.1.
W0 2017/‘172596 Step 2: Ethyl 5-0x0phenylthz'0x0-2, 3, 4, 5-tetrahydr0-1, 2, 4-trz'azz'ne—6—carb0xylate ‘3inO\/ O TsN NH A mixture of propanedioic acid, oxo-, diethyl ester (5.0 mL, 33 mmol) and N- phenylhydrazinecarbothioamide (5.5 g, 33 mmol) in EtOH (100 mL) was refluxed for 3 days. The reaction e was cooled to It, and the resulting solid was collected by filtration, washed with cold EtOH, and dried to give the t (6 g, 66%). LCMS calcd for C12H12N303S (M+H)+: m/z = 278.1. Found: 278.2. 1O Step 3: Ethyl 3, 5-dz'0x0phenyl-2, 3, 4, 5-tetrahydr0-1,2, 4-trz'azz'ne-6—carb0xylate ‘3ino o\/ ONTNHo A mixture of ethyl 5-oxophenylthioxo-2,3,4,5-tetrahydro-1,2,4-triazine- 6-carboxylate (6.0 g, 22 mmol), H202 (30 wt% in water, 6.4 mL) and acetic acid (20 mL) in DMF (60 mL) was stirred at It overnight. The reaction mixture was then diluted with EtOAc, washed with water, brine, dried, and trated. The resulting solid was triturated with ether to give the product. LCMS calcd for C12H12N3O4 (M+H)+: m/z = 262.1. Found: 262.2.
Step 4: Ethyl 2-is0pr0pyl-3, 0phenyl-2, 3, 4, 5-tetrahydr0-1, 2, 4-triazine-6— carboxylate 0 NYC \/0 \ 'N N 7/ Isopropyl iodide (0.46 mL, 4.6 mmol) was added to a mixture of ethyl 3,5- dioxophenyl-2,3,4,5-tetrahydro-1,2,4-triazinecarboxylate (0.6 g, 2 mmol) and K2CO3 (0.95 g, 6.9 mmol) in DMF (7 mL). The reaction mixture was stirred at 65 W0 2017/‘172596 °C for 2 h, cooled to rt, diluted with EtOAc, and washed with saturated NaHCO3 solution, water, and brine. The organic layer was separated, dried over NazSO4, and concentrated to provide the product. LCMS calcd for C15H18N304 (M+H)+: m/z = 3041. Found: 3041.
Step 5: 2—Isopr0pyl-3, 5-dl'0x0phenyl-2, 3, 4, rahydr0-1, 2, 4-triazine—6—carb0xyll'c 0 NYC HO \ ,N A mixture of ethyl 2-isopropyl-3,5-dioxophenyl-2,3,4,5-tetrahydro-1,2,4- triazine—6-carboxylate (1.0 g, 3.4 mmol) and water (1.0 mL) in 4 M HCl in 1,4- dioxane (10 mL) was stirred at 70 °C overnight. The reaction mixture was cooled to rt, d with water, and extracted with EtOAc. The combined organic layers were dried over MgSO4 and trated to provide the desired product. LCMS calcd for C13H14N3O4 (M+H)+: m/z = 276.1. Found: 276.0 Step 6: tert—Butyl 4-[4-amino(4- { [(2-isopropyl-3,5-dioxophenyl-2,3,4,5- tetrahydro—1,2,4-triazinyl)carbonyl]amino}phenyl)pyrrolo[2, 1-f] [1 ,2,4]triazin yl]piperidine-l-carboxylate «N‘ W0 To a mixture of tert—butyl 4-[4-amino(4-aminophenyl)pyrrolo[2,1- fl ]triazinyl]piperidine—1-carboxylate (150 mg, 0.37 mmol) (from example 107, step 4) and 2-isopropyl-3,5-dioxophenyl-2,3,4,5-tetrahydro-1,2,4-triazine W0 2017/‘172596 carboxylic acid (101 mg, 0.37 mmol) in DMF (1.7 mL) was added Et3N (77 "L, 0.55 mmol) followed by HATU (0.168 g, 0.44 mmol). The reaction mixture was stirred at rt for 1 h, quenched with water, and the resulting solid was ted by filtration, and dried to give the product (0.2 g, 80%). LCMS calcd for C35H40N905 (M+H)+: m/z = 6663. Found: 6662.
Step 7: N—(4—(4-Amino(pl'perl'dz'ny0pyrr0[0[1,2—fl[1,2,4]triazin-5—y0phenyl) pyl—3, 5—di0x0phenyl—2, 3, 4, 5-tetrahydr0-1, 2, 4-z‘riazinecarb0xamide ,N O N\ NWNH < o o O 4 M HCl in 1,4-dioxane (0.71 mL, 2.8 mmol) was added to a mixture of tert— butyl 4-[4—amino—5—(4—{[(2-isopropyl-3,5-dioxopheny1-2,3,4,5-tetrahydro-1,2,4— triazinyl)carbony1]amino} pheny1)pyrrolo[2, 1 -f] [1 ,2,4]triazinyl]piperidine carboxylate (0.20 g, 0.30 mmol) in CH2C12 (0.47 mL). The mixture was stirred at rt for 1 h, and concentrated to give the product (0.17 g, 100%). LCMS calcd for C30H32N9O3 (M+H)+: m/z = 566.3. Found: 566.2.
Step 8: N—(4—(4-Aml'n0(1-l's0buWrylpiperidiny0pyrr0[0[1,2fl[1,2,4]triazin yl)phenyl)—2—is0pr0pyl-3, 0phenyl-2, 3, 4, 5—z‘etrahydr0-1, 2, 4-triazine—6— carboxamide Isobutyryl chloride (0.0044 g, 0.041 mmol) was added to a solution ofN—[4- (4-amino—7-piperidinylpyrrolo[2, 1 -f] [1,2,4]triazin-5 eny1] isopropyl-3,5- dioxo—4—pheny1-2,3,4,5-tetrahydro-1,2,4-triazinecarboxamide (20 mg, 0.03 mmol) and Et3N (24 "L, 0.17 mmol) in CH2C12 (1.1 mL). The reaction mixture was stirred at rt for 4 h, and directly purified via pH 2 preparative LC/MS (MeCN/water with TFA) to give the product as TFA salt. LCMS calcd for N904 (M+H)+: m/z = 6363.
Found: 6363.
W0 2017!]72596 Example 97. N-(4-(4-Amino(l-isobutyrylpiperidinyl)pyrrolo[2,1- f] [1,2,4] triazin-S-yl)phenyl)—l-isopropyl-G-methyl—5-(l-methyl- 1H-pyrazolyl)— 4-oxo-1,4-dihydropyridinecarboxamide N\#A I Step I: 3-((Dz'methylamin0)methylene)mez‘hyl—2H-pyran-2,4(3H)—di0ne o 0 To a solution of 6-methyl-2H-pyran-2,4(3H)-dione (13 g, 103 mmol) in toluene (30 mL) was added MN—dimethylformamide dimethyl acetal (15 ml, 113 mmol). The resulting solution was stirred at It for 36 h, and concentrated to give a red 1O solid, which was used directly in the next step. LCMS calcd for C9H12NO3 (M+H)+: m/z = 1821. Found: 182.1.
Step 2: 1-Isopr0pylmethyl0x0-1,4-dihydr0pyridinecarb0xyll'c acid To a 250 mL round-bottomed flask was added (E/Z)—3- thylamino)methylene)—6-methyl-2H-pyran-2,4(3H)-dione (2.0 g, 11.0 mmol), propanamine (1.41 mL, 16.6 mmol) and sodium tert—butoxide (1.57 g, 16.3 mmol) in EtOH (80 mL). The round bottom was equipped with an air ser and the resulting mixture was stirred at 90 °C for 18 h, cooled to rt, concentrated, and treated with water and CH2C12. The solution was acidified with 4 N HCl solution and upon W0 2017/‘172596 separation the aqueous layer was extracted with CH2C12. The combined organic layers were washed with water, brine, dried over NazSO4, and concentrated to give the crude product, which was used directly in the next step. LCMS calcd for C10H14NO3 (M+H)+: m/z = 196.1. Found: 196.1.
Step 3: 5—Br0m0is0pr0pyl-6—methyl0x0-1, 4-dz'hydr0pyridine-S-carboxylic acid Hoj\[R3r To a solution of 1-isopropylmethyloxo-1,4-dihydropyn'dine—3-carboxylic acid (219 mg, 1.12 mmol) in DCE (5 mL) was added NBS (295 mg, 1.66 mmol) and 1O the ing on was stirred at rt overnight, diluted with water, and upon separation the aqueous layer was extracted with CH2C12. The ed organic layers were washed with water, brine, dried over NazSO4, and concentrated to give the crude product, which was used directly in the next step. LCMS calcd for C10H13BrNO3 (M+H)+: m/z = 274.0. Found: 274.0.
Step 4: N-(4-(4—Amz'n0- 7-(1-z'sobutyrylpz'perz'dz‘nyUpyrr0Zo[2, 1-fl[1, 2, 4]triazz’n yUphenyl)—5—brom0z'sopr0pyZmethyZ0x0-1,4-dz'hydr0pyrz‘dme—3—carb0xamide 0 / To a solution of oisopropylmethyloxo-1,4-dihydropyridine carboxylic acid (154 mg, 0.56 mmol) and HATU (256 mg, 0.67 mmol) in DCE (5 mL) was added DIPEA (0.24 mL, 1.41 mmol) and 1-(4-(4-arnino(4- aminophenyl)pyrrolo[2,1-f] [1,2,4]triazinyl)piperidinyl)methylpropanone (213 mg, 0.56 mmol) (from example 83, step 2). The ing on was stirred at rt overnight, and purified via column chromatography (0% to 100% EtOAc in hexanes) to give the product. LCMS calcd for C31H37BrN7O3 (M+H)+: m/z = 6342.
Found: 6342.
Step 5: N—(4—(4—Amz'n0-7—(1-l's0buWrylpiperidiny0pyrr0[0[2,1-fi[1,2,4]triazin-5— yUphenyU—I—isopr0pyl-6—methyl(I-methyl—1H—pyrazolyl)0x0-1, 4— dihydropyridine-S-carboxamide A mixture ofN-(4-(4-amino(1-isobutyrylpiperidinyl)pyrrolo[2,1— f] [1,2,4]triazinyl)phenyl)bromoisopropylmethyloxo-1,4- dihydropyridinecarboxamide (62 mg, 0.098 mmol), (l-methyl-lH-pyrazol-S- onic acid (61.5 mg, 0.489 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-tri-ipropyl-l ,1'-biphenyl)(2'—amino-1,1'-biphenylyl) palladium(II) (Xphos Pd G2) (11.53 mg, 0.015 mmol), and ium phosphate tribasic (0.024 ml, 0.29 mmol) in 1,4-dioxane (2.0 ml) and water (0.40 ml) was degassed and purged with N2 several times prior to heating in a sealed vial at 90 °C overnight. After cooling to rt, the mixture was diluted with MeOH, filtered, and purified via pH 2 preparative LC/MS (MeCN/water with TFA) to give the product as TFA salt. LCMS calcd for C35H42N903 (M+H)+: m/z = 636.3. Found: 636.4. 1H NMR (600 MHz, DMSO) 8 12.87 (s, 1H), 8.73 (s, 1H), 8.06 (s, 1H), 7.82 (d, J: 8.7 Hz, 2H), 7.50 (d, J=1.8 Hz, 1H), 7.47 (d, J: 8.6 Hz, 2H), 6.73 (s, 1H), 6.21 (d, J: 1.8 Hz, 1H), 4.85 — 4.76 (m, 1H), 4.55 (d, J: 12.9 Hz, 1H), 4.08 (d, J: 13.1 Hz, 1H), 3.61 (s, 3H), 3.42 (dd, J: 11.9, 3.7 Hz, 1H), 3.28 — 3.16 (m, 1H), 2.98 — 2.86 (m, 1H), 2.77 — 2.64 (m, 1H), 2.33 (s, 3H), 2.13 — 1.96 (m, 2H), 1.71 — 1.58 (m, 1H), 1.58 — 1.47 (m, 7H),1.08 — 0.97 (m, 6H).
Example 98. N—(4-(4-Amino(1-is0butyrylpiperidinyl)pyrrolo[2,1- f] [1,2,4]triazin-S-yl)phenyl)—5'-fluoroisopropyl-Z-methyloxo-1,4-dihydro- [3,3'-bipyridine]-5—carboxamide This compound was ed following a synthetic sequence analogous to that for example 97, using (5-fluoropyridinyl)boronic acid d of (l-methyl—lH— pyrazol-S-yl)boronic acid. This compound was purified via pH 2 preparative LC/MS (MeCN/water with TFA) to give the product as TFA salt. LCMS calcd for C36H40FN803 (M+H)+: m/z = 651.3. Found: 651.3. 1H NMR (500 MHz, DMSO) 5 12.86 (s, 1H), 8.74 (s, 1H), 8.61 (d, J: 2.8 Hz, 1H), 8.34 (m, 1H), 8.08 (s, 1H), 7.82 (d, J: 8.7 Hz, 2H), 7.71 (m, 1H), 7.47 (d, J: 8.6 Hz, 2H), 6.75 (s, 1H), 4.83 (m, 1H), 4.56 (m, 1H), 4.09 (m, 1H), 3.42 (m, 1H), 3.21 (m, 1H), 2.91 (m, 1H), 2.70 (m, 1H), 2.34 (s, 3H), 2.02 (m, 2H), 1.64 (m, 1H), 1.53 (m, 7H), 1.02 (m, 6H).
Example 99. N-(4-(4-Amino(l-isobutyrylpiperidinyl)pyrrolo[2,1- f] [1,2,4] triazin-S-yl)phenyl)(3-cyanophenyl)-l-isopropylmethyloxo-1,4- dihydr0pyridine—3-carboxamide This compound was prepared following a synthetic sequence analogous to that for example 97, using (3-cyanophenyl)boronic acid instead of (l-methyl—lH-pyrazol- -yl)boronic acid. This compound was d via pH 2 preparative LC/MS (MeCN/water with TFA) to give the t as TFA salt. LCMS calculated for C38H41N803 (M+H)+: m/z = 657.3; Found: 657.3. 1H NMR (500 MHz, DMSO) 8 12.91 (s, 1H), 8.73 (s, 1H), 8.08 (s, 1H), 7.87 (m, 1H), 7.82 (d, J: 8.7 Hz, 2H), 7.74 (m, 1H), 7.69 (m, 1H), 7.61 (m, 1H), 7.46 (d, J= 8.6 Hz, 2H), 6.75 (s, 1H), 4.81 (m, 1H), 4.55 (m, 1H), 4.08 (m, 1H), 3.42 (m, 1H), 3.21 (m, 1H), 2.90 (m, 1H), 2.77 — 2.61 (m, 1H), 2.30 (s, 3H), 2.13 — 1.89 (m, 2H), 1.65 (m, 1H), 1.52 (m, 2H), 1.02 (m, Example 100. N—(4—(4-Amin0bromo(1-isobutyrylpiperidinyl)pyrrolo[1,2- f] [1,2,4]triazin-S-yl)phenyl)—4-methoxy—2—ox0phenyl-1,2-dihydr0pyridine—3- amide O / HN / K ,N / Br Step 1: 4-Mez‘h0xy-2—0x0-J-phenyl-1,2-dz'hydr0pyrz'dz'necarb0xylz‘c acid o / HO / A mixture of 4-methoxyoxo-1,2-dihydropyridinecarboxylic acid (1.40 g, 8.28 mmol) (from Enamine Ltd.), phenylboronic acid (4.04 g, 33.1 mmol), activated 4A molecular sieves (2.59 g) and copper (II) acetate (4.51 g, 24.8 mmol) in CH2C12 (50 mL) was treated with pyridine (2.68 mL) and stirred at rt for 3 days. The reaction e was then diluted with MeOH, filtered, concentrated, and purified via column chromatography (0% to 100% MeOH in EtOAc) to afford the product as a light greenish powder (244 mg, 12%). LCMS calcd for NO4 (M+H)+: m/z = 246.1.
Found: 246.1.
Step 2: N—(4—(4-Amino(1-z'sobugzrylpz'perz'dz'ny0pyrr0[0[1,2—f][1,2,4]triazin yl)phenyl)meth0xy0x0phenyl-1 , 2-dz'hydr0pyrz‘dz‘necarboxamz’de o / HN / K ,N / To a mixture of 4-methoxyoxophenyl-1,2-dihydropyridine-3—carboxylic acid (35 mg, 0.14 mmol) and 1-(4-(4-amino(4-aminophenyl)pyrrolo[2,1- f] [1,2,4]triazinyl)piperidinyl)methylpropanone (59.4 mg, 0.16 mmol) (from example 83, step 2) in DMF (571 uL) was added Et3N (60 uL), followed by HATU (109 mg, 0.29 mmol). The resulting mixture was stirred at rt for 30 min, filtered, and the crude material was d via column chromatography (0% to 30% MeOH in EtOAc) to give the desired product as a light yellow powder (?0 mg, 81%).
LCMS calcd for N704 (M+H)+: m/z = 606.3. Found: 6063.
Step 3: N—(4—(4-Amin0-6—br0m0- 7-(1-l's0bulyrylpiperidiny0pyrr010fl, 2— fl[1,2, 4]triazinyl)phenyl)meth0xy-2—0x0phenyl-1, 2-dihydr0pyridine—3— carboxamide To a solution ofN-(4-(4-amino(1-isobutyrylpipen'dinyl)pyrrolo[2,1- f] [1 ,2,4]triazinyl)phenyl)methoxyoxophenyl-1,2-dihydropyridine—3- carboxamide (61 mg, 0.10 mmol) in DMF (403 uL) was added NBS (19 mg, 0.11 mmol). The resulting mixture was stirred at It for 5 min, diluted with EtOAc/THF, filtered, washed with saturated NaHCO3 solution, water, brine, dried over NazSO4, and concentrated. The crude material was purified via pH 10 preparative LC/MS (MeCN/water with NH4OH) to give the product as an off-white powder. LCMS calcd for BrN7O4 : m/z = 684.2. Found: 684.2.
Example 101. 4-Amino(l-isobutyrylpiperidinyl)pyrrolo[1,2- f] [1,2,4] triazin-S-yl)phenyl)—5-bromo— 1-(S-fluor0pyridinyl)—6-methyl-2—oxo— W0 2017/‘172596 1,2-dihydropyridine-S-carboxamide N\ Br 0 / Step 1: 5-Br0m0-5’-flu0r0-6—methyl0x0-2H-[1,3’-blpyridinej-S-carboxylic acid F41,N O / Ethyl 5-bromo-5’-fluoromethyloxo-2H-[1,3'-bipyridine]carboxylate (1.0 g, 2.82 mmol) (from Affinity Research Chemicals) was ved in THF (10 mL) and ethanol (6.7 mL). The mixture was then treated with 1 M NaOH in water (11 mL), and the reaction mixture was d at 25 °C for 20 min. The resulting mixture was neutralized with 12 M HCl on to pH 6~7 and the organic solvents were removed under vacuum. The resulting e was extracted with EtOAc. The combined organic layers were dried, and concentrated to give the product as a light brown powder (975 mg). LCMS calcd for C12H9BrFN203 (M+H)+: m/z = 327.0.
Found: 3270.
Step 2: N-(4-(4-Amz'n0(1-l's0buWrylpiperidiny0pyrr0[0[2,1-fi[1,2,4]triazin yUphenyl)br0m0-5 ’-flu0r0methyl0x0-2H-[1, 3 ’-blpyridinej-S-carboxamide To a mixture of 5-bromo-5'-fluoromethyloxo-2H—[1,3'-bipyridine]—3- carboxylic acid (38 mg, 0.069 mmol) and 1-(4-(4-amino(4- aminophenyl)pyrrolo[2,1-f][1,2,4]tn'aziny1)piperidiny1)methylpropanone (25 mg, 0.066 mmol) (from example 83, step 2) in DMF (264 uL) was added Et3N (28 11L), followed by HATU (50 mg, 0.13 mmol). The resulting mixture was stirred at rt for 20 min, and the crude material was purified via pH 2 preparative LC/MS (MeCN/water with TFA) to give the t as an off-white powder (TFA salt).
LCMS calcd for C33H33BrFNsO3 (M+H)+: m/z = 687.2. Found: 687.2. 1H NMR (600 MHz, DMSO) 6 11.64 (s, 1H), 8.84 (d, J: 2.6 Hz, 1H), 8.62 (d, J: 12.6 Hz, 2H), 8.12 (dt, J: 92,23 Hz, 1H), 8.06 (s, 1H), 7.82 (d, J: 8.6 Hz, 2H), 7.47 (d, J: 8.5 Hz, 2H), 6.73 (s, 1H), 4.55 (d, J: 12.6 Hz, 1H), 4.07 (d, J: 14.0 Hz, 1H), 3.42 (tt, J = 12.0, 3.5 Hz, 1H), 3.21 (t, J: 12.9 Hz, 1H), 2.91 (dt, J: 13.5, 6.7 Hz, 1H), 2.75 — 2.66 (m, 2H), 2.25 (s, 3H), 2.04 (dd, J: 30.5, 13.5 Hz, 2H), 1.72 (m, 1H), 1.60 (m, 1O 1H), 1.52 (d,J= 12.1 Hz, 1H), 1.05 — 0.99 (m, 6H).
Example 102. N—(4—(4—Amino(1-isobutyrylpiperidinyl)pyrrolo[2,1- ]] [1,2,4] triazin-S-yl)phenyl)—5-(cyanomethyl)—5'-fluoromethyloxo-2H- [ 1,3'- bipyridine]carboxamide O —N K ,N / To a stirred mixture of N—(4-(4-amino(1-isobutyrylpiperidin-4— yl)pyrrolo[2, 1 -j] [1 riazinyl)phenyl)—5-bromo-5'-fluoromethyl-2—oxo-2H- [1,3'-bipyridine]carboxamide (8.0 mg, 0.012 mmol) (from example 101, step 2), isoxazol-4—ylboronic acid (2.0 mg, 0.02 mmol), 1,4-dioxane (200 11L), N-ethyl-N— isopropylpropanamine (4.5 mL) and water (40 11L) was added Pd(tBu3)2 (3.0 mg, .8 umol). The reaction mixture was then heated at 110 °C for 60 min, cooled to rt, diluted with DMF, and d via pH 10 preparative LC/MS (MeCN/water with NH4OH) to give the product as an off-white powder. LCMS calcd for C35H35FN903 (M+H)+: m/z = 648.3. Found: 648.3.
Example 103. N-(4-(4-Amin0(1-isobutyrylpiperidinyl)pyrrolo[2,l- f] [1,2,4] triazin-S-yl)phenyl)—5'-flu0r0methyl-2—oxo-S-(thiazolyl)—2H- [ 1,3'- bipyridine]carb0xamide O / To a mixture ofN—(4—(4-amino(l-isobutyrylpiperidinyl)pyrrolo[2,l- f] [1,2,4]triazin-5 -yl)phenyl)bromo-5'-fluoromethy1oxo-2H-[ 1 ,3'-bipy1idine] - 3-carboxamide (8.0 mg, 0.012 mmol) and Pd(Ph3P)4 (2.7 mg, 2.3 umol) in toluene (0.30 mL) was added 4-(tributylstannyl)thiazole (8.7 mg, 0.023 mmol). The reaction mixture was sealed in a microwave vial, vacuumed and backfilled with N2 several times, and heated at 120 °C for 20 h. The reaction mixture was cooled to rt, and the crude al was purified via pH 10 preparative LC/MS (MeCN/water with NH4OH) to give the t as an off-white powder. LCMS calcd for C36H35FN903S (M+H)+: m/z = 692.3. Found: 692.3.
Example 104. 4-Amino(1-isobutyrylpiperidinyl)pyrrolo[2,1- ]] [1,2,4] triazin-S-yl)phenyl)—6-oxo- l-phenyl- hydr0- [2,2'-bipyridine] carboxamide W0 2017!]72596 A mixture of 2-cyano-N—phenylacetamide (1.60 g, 10.0 mol), 3- (dimethylamino)(pyridinyl)propenone (1.94 g, 11.0 mmol) and 1,4- diazabicyclo[2.2.2]octane (0.98 mL, 10.0 mmol) in EtOH (20 mL) was heated at 90 °C overnight. After cooling to rt, the on mixture was concentrated, and ioned between CH2C12 (60 mL) and 2 M HCl solution (20 mL). The organic layer was ted, washed with water, dried over MgSO4, concentrated, and purified via column chromatography (20% to 100% EtOAc in hexanes) to afford the product (1.25 g, 46%). LCMS calcd for C17H12N3O (M+H)+: m/z = 274.1. Found: 2742.
Step 2: 6—0x0phenyl—1,6-dihydr0-[2,2'-bipyridinejcarb0xylic acid 6-Oxophenyl-1,6-dihydro-[2,2'-bipyridine]carbonitrile (0.20 g, 0.73 mmol) in concentrated sulfuric acid (1.5 mL) and water (1.5 mL) was heated at 120 °C for 3 h. After cooling to It, the reaction mixture was carefully neutralized at 0 °C with 10% NaOH solution to pH ~7. The resulting mixture was extracted with 9:1 CH2C12/MeOH (5 mL x 3), and the combined organic layers were dried over NazSO4, and concentrated to give the crude product (0.19 g, 89%), which was used directly in the next step. LCMS calcd for C17H13N203 (M+H)+: m/z = 293.1. Found: 293.1.
W0 2017!]72596 Step 3: N—(4-(4-Amin0-7—(J-z's0buWrylpiperidz‘ny0pyrr0[0[2, 1fl[1, 2, 4jtriazin yUphenyU—tfi—oxo—J -phenyl-1 , 6-dz'hydr0-[2, 2 ’-bzpyridz'nejcarb0xamide To a mixture of 6-oxophenyl-1,6-dihydro-[2,2'-bipyridine]carboxylic acid (0.015 g, 0.050 mmol) and HATU (0.021 g, 0.055 mmol) in DMF (3 mL) was added 1-(4-(4-amino(4-aminophenyl)pyrrolo[2,1-f] [1,2,4]triazinyl)piperidin yl)—2—methylpropanone (0.019 g, 0.0500 mmol) (from example 83, step 2) and Et3N (0.021 ml, 0.15 mmol). The mixture was stirred at rt until completion, diluted with MeOH, adjusted with TFA to pH ~2, and purified Via pH 2 preparative LC/MS (MeCN/water with TFA) to give the product as TFA salt. LCMS calcd for C38H37N803 : m/Z = 653.3. Found: 653.3.
Example 105. 4-Amino(1-is0butyrylpiperidin-4—yl)pyrrolo[2,1- ]] ] triazin-S-yl)phenyl)—6'-methyl0xophenyl- 1,6-dihydro— [2,3'- bipyridine]carboxamide 150 A mixture of 1-(6-methylpyridinyl)ethanone (2.50 g, 18.5 mmol) and 1,1-dimethoxy-N,N-dimethylmethanamine (4.41 g, 37.0 mmol) was heated at 100 °C for 8 h, cooled to rt, and trated. The resulting residue was triturated with ether.
The solid was then collected by filtration and washed with ether to afford the crude product (275 g, 78%). LCMS calcd for C11H15N20 (M+H)+: m/z = 1911 Found: Step 2: N-(4-(4—Amz’n0- 7-(1-z'sobuWrylpz'perz’dz‘ny0pyrroZo[2, 1-fl[1, 2, 4]triazz’n yUphenyU-6’-methyl—6-0x0phenyl-1, 6-dz‘hydr0-[2, 3 ’-bzpyridinejcarb0xamz'de W0 2017!]72596 This compound was prepared following a synthetic sequence ous to those for e 104, from step 1 to step 3, using 3-(dimethylamino)(6- methylpyridinyl)propenone instead of 3-(dimethylamino)(pyridin yl)prop—2-enone. This compound was purified via pH 2 preparative LC/MS (MeCN/water with TFA) to give the t as TFA salt. LCMS calcd for C39H39N303 (M+H)+: m/z = 667.3. Found: 667.3. e 106. N—(4-(4-Amino(1-is0butyrylpiperidin-4—yl)pyrrolo[2,1- ]] [1,2,4]triazin-S-yl)phenyl)methylox0- 1-phenyl- 1,6-dihydro- [2,3'- 1O bipyridine]carb0xamide /\ \/ This compound was prepared following a synthetic sequence analogous to those for example 105, step 1, using l-(pyridinyl)propan-l-one d of 1-(6- methylpyridin—3-yl)ethanone. LCMS calcd for C11H15N20 (M+H)+: m/z = 191.1.
Found: 191.1.
Step 2: N—(4-(4-Aml'n0(1-z's0buWrylpiperidiny0pyrr0[0[2,1-fi[1,2,4]triazin yUphenyl)methyl0x0phenyl-1, 6—dihydr0-[2, 3 ’-blpyridz'nejcarb0xamide This compound was prepared following a synthetic sequence analogous to those for e 104, from step 1 to step 3, using 3-(dimethylamino)methyl (pyridinyl)propen-l-one instead of 3-(dimethylamino)(pyridinyl)prop en-l-one. This compound was purified via pH 2 preparative LC/MS (MeCN/water with TFA) to give the product as TFA salt. LCMS calcd for C39H39N303 (M+H)+: m/z = 6623. Found: 667.3.
Example 107. N—{4—[4-Amino—7-(l-is0butyrylpiperidinyl)pyrrolo[2,1- f] [1,2,4] n-S-yl] phenyl}methyl(1-methyl- 1H-pyrazolyl)oxo phenyl-1,2-dihydropyridine—3-carboxamide To a mixture of 2-cyano-N-pheny1acetamide (5.0 g, 31.2 mmol) and 4- methoxybuteneone (6.2 g, 62 mmol) in 2-(2-methoxyethoxy)ethanol (75 mL) was added DABCO (3.50 g, 31.2 mmol). The resulting mixture was stirred at 120 °C overnight, cooled to It, concentrated, and the resulting material was partitioned between CH2C12 (300 mL) and 2 M HCl solution (100 mL). The organic layer was separated, washed with water, dried over MgS O4, concentrated, and added EtOAc. The mixture was stirred for 30 min, and the ing solid was ted by filtration and dried to give the t (3.17 g). The filtrate was concentrated and purified via column chromatography (20% to 90% EtOAc in hexanes) to give an additional 158 g of the product as a brown solid (72% combined). LCMS calcd for C13H11N20 (M+H)+: rn/z = 211.1. Found: 211.1.
Step 2: 6-Methyl—2-0x0phenyl-1,2—dihydr0pyridinecarboxylz'c acid o N A mixture of yloxo-l-phenyl-l,2-dihydropyridine—3-carbonitrile (3.17 g, 15.1 mmol) and KOH (3.47 g, 61.8 mmol) in EtOH (34 mL)/water (8.0 mL) was stirred at 90 °C for 46 h. EtOH was evaporated and the resulting mixture was d with water and washed with CH2C12. The aqueous layer was then acidified with 2 N HCl solution, and extracted with CH2C12. The combined organic layers were dried over MgS O4, and concentrated to give the product (2.2 g, 64%).
LCMS calcd for C13H12NO3 (M+H)+: m/z = 230.1. Found: 230.1.
Step 3: 5-Br0m0-6—methyl-2—0x0phenyl-1, 2-dl'hydr0pyridine-S-carboxylic acid 0 N To a solution of 6-methyloxophenyl-1,2-dihydropyridine—3-carboxylic acid (2.20 g, 9.6 mmol) in DMF (30 mL) was added NBS (1.70 g, 9.55 mmol). The reaction mixture was stirred at It for 4 h, added more NBS (300 mg), and stirred overnight. Water (100 mL) was then added to the reaction mixture at 0 OC, and stirring ued for 20 min. The resulting solid was collected by ion, washed with water, and dried to give the product as a tan solid (2.4 g, 81%). LCMS calcd for C13H11BrN03 (M+H)+: m/z = 308.0. Found: 308.0.
Step 4: tert-Butyl 4-[4-aml‘n0(4-amin0pheny0pyrr010[2, 1fl[1,2,4]triazin-7— yljpz'peridine-J-carb0xylate W0 2017!]72596 N’ / K ,N / A e of tert—butyl 4-(4-aminobromopyrrolo[2,l-f] [1,2,4]triazin—7- yl)piperidine—l-carboxylate (400 mg, 1 mmol) (from example 32, step 3), 4-(4,4,5,5- tetramethyl—l,3,2-dioxaborolanyl)aniline (265 mg, 1.21 mmol), dicyclohexyl(2',4',6'-triisopropylbiphenylyl)phosphine-(2'-aminobiphenyl yl)(chloro)palladium (1:1) (39.7 mg, 0.051 mmol), and potassium ate (643 mg, 3.03 mmol) in 1,4-dioxane (9 mL)/water (1.6 mL) was degassed with N2 and then stirred at 90 °C overnight. The reaction mixture was cooled to rt, diluted with EtOAc, filtered through Celite, concentrated, and purified via column tography (10% to 100% EtOAc in hexanes, then 10% MeOH in EtOAc) to give the product (200 mg, 50%). LCMS calcd for C22H29N602 (M+H)+: m/z = 4092. Found: 4092.
Step 5: tert—Butyl 4-[4-amin0(4-{[(5—br0m0mez‘hyl—2—0x0-I-phenyi—I, 2— dihydropyridinyl)carb0nyl]amino}phenyl)pyrr0[0[2, 1-fl[1, 2, 4]triazin— 7— yljpl'peridine—J xylate To a mixture of tert—butyl 4-[4-amino(4-aminophenyl)pyrrolo[2,1- f][1,2,4]triazinyl]piperidinecarboxylate (100 mg, 0.25 mmol) and 5-bromo methyloxophenyl-1,2-dihydropyridinecarboxylic acid (75 mg, 0.25 mmol) in DMF (15 mL) was added Et3N (51 uL, 0.37 mmol), followed by HATU (112 mg, 0.29 mmol). The resulting mixture was stirred at rt overnight, added water, and extracted with EtOAc. The ed organic layers were dried over NazSO4, W0 2017/‘172596 concentrated, and purified via column chromatography (10% to 80% EtOAc in hexanes, then 10% MeOH in EtOAc) to give the product (95 mg, 56%). LCMS calcd for C35H37BrN7O4 (M+H)+: m/z = 698.2. Found: 6983.
Step 6: {err—Bury! 4-{4-amz'n0[4-({[6-mez‘hyl-5—(1-mez‘hyl-1H-pyrazoi—4—yl)—2—0x0 phenyZ—I, Z—dihydropyridinyljcarb0nyl}amin0)phenyl]pyrrolo[2, 1-f][1, 2, 4]zriazin- 7—yl}pz‘peridinecarboxylate A mixture of tert—butyl 4-[4-amino(4-{[(5-bromomethyloxo—1— -1,2-dihydropyridinyl)carbonyl]amino}phenyl)pyrrolo[2,1-f][1,2,4]triazin- 7-yl]piperidinecarboxylate (95 mg, 0.14 mmol), 1-methy1(4,4,5,5-tetramethy1- 1,3,2—dioxaborolanyl)— 1H-pyrazole (34.0 mg, 0.16 mmol), dicyclohexyl(2',4',6’- triisopropylbiphenylyl)phosphine-(2'-aminobiphenylyl)(chloro)palladium (l: l) (5.3 mg, 0.0068 mmol), and potassium phosphate (87 mg, 0.41 mmol) in 1,4-dioxane (1.3 mL)/water (0.30 mL) was degassed with N2 and stirred at 90 °C for 3 h. The resulting mixture was cooled to rt, diluted with CH2C12/water, and filtered through Celite. The organic layer was separated, and concentrated to give the crude product (88 mg), which was used ly in the next step. LCMS calcd for C39H42N9O4 (M+H)+: m/z = 700.3. Found: 700.4.
Step 7: N-(4-(4-Amz'n0-7—(pzperidz'ny0pyrr010[1,2-fi[1,2,4]"iaziny0phenyD -5%]-mez‘hyl-1H—pyrazolyD0x0phenyl-1,2—dihydr0pyrz‘dine-3— carboxamide To a solution of utyl 4- {4-amino[4-({[6-methyl(1-methyl-1H— pyrazol-4—yl)—2-oxophenyl-1,2-dihydropyridin yl] carbonyl}amino)phenyl]pyrrolo[2, 1 -f] [1 ,2,4]triazinyl} piperidine— 1 -carboxylate (87 mg, 0.12 mmol) in CH2C12 (2 mL) was added TFA (1 mL). The resulting mixture was stirred at rt for 1 h, concentrated, and dried to give the product (90 mg) as TFA salt. LCMS calculated for C34H34N902 (M+H)+: m/z = 600.3, Found: 6002.
Step 8: N-{4—[4-Amz‘n0-7—(1-is0butyrylpzperidiny0pyrrolo[2, 1-f][1, 2, 4]triazin yljphenyl}-6—methyl(1-methyZ-]H-pyrazolyZ)0x0phenyl-1,2- dihydropyrz‘dz‘necarb0xamide To a mixture ofN-[4-(4-aminopiperidiny1pyrrolo[2,1-f] [1,2,4]triazin yl)phenyl]—6-methyl(1-methyl-1H-pyrazolyl)—2-oxo-1—phenyl—1,2- dihydropyridinecarboxamide (60 mg, 0.084 mmol) and Et3N (59 uL, 0.42 mmol) in CH2C12 (1 mL) was added isobutyryl de (12 uL, 0.11 mmol). The resulting mixture was d at It for 90 min, and directly d via pH 2 preparative LC/MS (MeCN/water with TFA) to give the product as TFA salt. LCMS calculated for C3sH4oN9O3 (M+H)+: m/z = 670.3, Found: 670.2. 1H NMR (600 MHz, DMSO) 6 12.05 (s, 1H), 8.46 (s, 1H), 8.01 (s, 1H), 7.97 (s, 1H), 7.81 (d, J: 8.7 Hz, 2H), 7.64 — 7.59 (m, 3H), 7.57 — 7.52 (m, 1H), 7.45 — 7.41 (m, 4H), 6.69 (s, 1H), 4.53 (d, J: 12.3 Hz, 1H), 4.05 (d, J: 12.9 Hz, 1H), 3.89 (s, 3H), 3.43 — 3.34 (m, 1H), 3.24 — 3.15 (m, 1H), 2.89 (hept, J: 6.7 Hz, 1H), 2.68 (t, J: 12.0 Hz, 1H), 2.09 (s, 3H), 2.02 (dd, J: 32.4, 13.2 Hz, 2H), 1.56 (dd, J: 72.6, 9.9 Hz, 2H), 1.03 — 0.97 (m, 6H).
Example 108. N—{4—[4-Amino—7-(l-is0butyrylpiperidinyl)pyrrolo[2,1- f] [1,2,4] triazin-S-yl] phenyl}methyloxo-l-phenyl-S-pyrimidin-Z-yl- 1,2- dihydr0pyridine—3-carboxamide W0 2017/‘172596 H I (N\NH2 N \ o 0 \ N\© Step 1: Ethyl 5-br0m0-6—methyl-2—0x0-I-phenyl-1, 2-dl'hydr0pyridinecarb0xylate A mixture of 5-bromomethyloxophenyl-1,2-dihydropyridine—3- carboxylic acid (1.0 g, 3.24 mmol) (example 107, step 3) and ic acid (180 uL, 3.4 mmol) in EtOH (60 mL) was refluxed for 3 days, cooled to rt, and concentrated.
The resulting residue was dissolved in CH2Cl2, washed with saturated NaHCO3 solution, dried over MgSO4, and concentrated to give the product as a brown solid (1 g). LCMS calcd for C15H15BrNO3 (M+H)+: m/z = 3360; Found: 3361.
Step 2: Ethyl yl-Z-oxophenyl-5—(4, 4, 5, 5-z‘ez‘ramez‘hyl-1, 3, 2-di0xab0roz’an yl)-1,2—dihydr0pyridine-S-carboxylare O\ /O \/O COON A mixture of ethyl omethyloxophenyl-1,2-dihydropyridine carboxylate (520 mg, 1.5 mmol), 5,4',4',5',5'-octamethyl- [2,2']bi[[1,3,2]dioxaborolanyl] (786 mg, 3.09 mmol), [1,1'- bis(diphenylphosphino)ferrocene] dichloropalladium (II) (57 mg, 0.07? mmol), and potassium acetate (455 mg, 4.64 mmol) in 1,4-dioxane (13 mL) was degassed with N2 for 5 min, and then stirred at 90 °C for 17 h, cooled to rt, and filtered through a plug of Celite (washed with EtOAc). The filtrate was washed with brine, dried over W0 2017/‘172596 Na2S04, and concentrated. The crude material was purified via column chromatography (15% to 65% EtOAc in hexanes) to give the product (168 mg, 28%).
LCMS calcd for C21H27BN05 (M+H)+: m/z = 384.2; Found: 3842.
Step 3: Ethyz7 6-methyl-Z-oxo-I-phenyl-5—pyrimidz'n-Z—yl-I,2—dz‘hydr0pyridine—3— carboxylate In a sealed microwave vial, a mixture of ethyl 6-methyloxophenyl (4,4,5,5—tetramethyl-1,3,2-dioxaborolanyl)—1,2-dihydropyridinecarboxylate (168 mg, 0.44 mmol), 2-bromopyrimidine (83.6 mg, 0.53 mmol), dicyclohexyl(2',4',6‘- triisopropylbiphenylyl)phosphine-(2'-aminobiphenylyl)(chloro)palladium (1: 1) (17 mg, 0.022 mmol) and potassium phosphate (279 mg, 1.32 mmol) in 1,4-dioxane (5 mL)/water (1 mL) was stirred at 90 °C for 2.5 h. The reaction mixture was then cooled to rt, diluted with CH2C12/water, and filtered through Celite. The organic layer was separated and concentrated to give the crude product (127 mg, 86%), which was used directly in the next step. LCMS calcd for C19H18N303 (M+H)+: m/z = 3361; Found: 3361.
Step 4: 6—Methyl—2-0x0phenyl—5-pyrimidin-Z—yl-I,2—dihydr0pyridine-S-carboxylic acid HO N o o 0 To a on of ethyl yloxophenylpyrimidin-2—yl-1,2- dihydropyridinecarboxylate (127 mg, 0.38 mmol) in MeOH (2 mL)/water (0.4 mL) was added Lithium hydroxide, monohydrate (79 mg, 1.89 mmol). The resulting mixture was d at 40 °C for 3 h, and MeOH was ated. This mixture was acidified with 1N HCl on, and the resulting solid was collected by filtration, W0 2017!]72596 washed with water, and dried to give the product (80 mg, 70%). LCMS calcd for C17H14N3O3 (M+H)+: m/z = 308.1, Found: 308.0.
Step 5: 6—Mez‘hyl—2—0x0phenylpyrz‘mz‘dz‘n-2—yl—N—[4—(4, 4, 5, 5—tetramethyl—1,3,2- orolan—2—yl)phenyl]-1,2-dz'hydr0pyrz‘dmecarboxamz'de o,IBQNH O Q o \ / To a mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)aniline (57 mg, 0.26 mmol) and 6-methyloxophenylpyrimidinyl-1,2-dihydropyridine—3- ylic acid (80 mg, 0.3 mmol) in DMF (1.6 mL) was added Et3N (54 uL, 0.390 mmol), followed by HATU (119 mg, 0.31 mmol). The resulting mixture was stirred at rt overnight, added water, and the resulting solid was collected by filtration, washed with water, and dried to give the product as a white solid (103 mg, 78%). LCMS calcd for C29H30BN4O4 (M+H)+: m/z = 509.2, Found: 5092.
Step 6: N—(4—(4—AminoQ71peridiny0pyrr0l0[1, 2—fl[1, 2, 4]triazin—5—yl)phenyl)-6— methyi—Z—oxo—1-phenyl(pyrimidin-Z—yU-I, 2-dihydr0pyridinecarb0xamide N].l/ \ NH2 N\ N HN "Q A mixture of tert—butyl 4-(4-aminobromopyrrolo[2,1-f] [1,2,4]triazin eridine-l-carboxylate (21 mg, 0.053 mmol) (from example 32, step 3), 6- methyl—2-oxophenyl-5 idinyl-N—[4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolanyl)phenyl]-1,2-dihydropyridinecarboxamide (32 mg, 0.064 rnrnol), dicyclohexyl(2',4',6'-triisopropylbiphenylyl)phosphine-(2'-aminobiphenyl yl)(chloro)palladium (1:1) (2.0 mg, 0.0027 mmol), and potassium phosphate (34 mg, 0.16 mmol) in 1,4-dioxane (0.65 mL)/water (0.1 mL) was degassed with N2, and then stirred at 90 °C for 2 h. The reaction mixture was cooled to rt, diluted with W0 2017!]72596 CHzClz/water, and filtered through Celite. The organic layer was separated, concentrated, and added CH2C12 (0.4 mL) and 4 M HCl in 1,4-dioxane (120 uL, 0.48 mmol). The resulting mixture was stirred at rt overnight, and trated to give the crude product (30 mg), which was used directly in the next step. LCMS calcd for C34H32N902 : m/z = 5983; Found: 598.2.
Step 7: N—{4—[4-Aml'n0- 7-(1-l's0buWrylplperidiny0pyrr010[2, 1fl[1, 2, 4]triazin nyl}—6—methyl-2—0x0phenylpyrimidin-Z—yl-1, 2-dihydr0pyridine—3— carboxamide This compound was prepared following a synthetic sequence analogous to those for example 107, step 8, using 4-amino(piperidinyl)pyrrolo[1,2- f] [1 riazinyl)phenyl)methyloxophenyl(pyrimidin-2—yl)—1 ,2- dihydropyridinecarboxamide instead ofN-[4-(4-aminopiperidinylpyrrolo[2,1- f] [1 ,2,4]triazinyl)phenyl] methyl(1-methyl- 1H-pyrazolyl)oxophenyl- 1,2-dihydropyridinecarboxamide. This compound was purified via pH 2 preparative LC/MS (MeCN/water with TFA) to give the product as TFA salt. LCMS calculated for C3sH3sN9O3 (M+H)+: m/z = 668.3; Found: 6682. 1H NMR (600 MHz, DMSO) 5 11.89 (s, 1H), 9.16 (s, 1H), 8.96 (d, J= 4.9 Hz, 2H), 8.08 (s, 1H), 7.83 (d, J = 8.7 Hz, 2H), 7.63 (t, J: 7.7 Hz, 2H), 7.59 — 7.53 (m, 1H), 7.51 — 7.44 (m, 5H), 6.74 (s, 1H), 4.53 (d, J: 12.3 Hz, 1H), 4.06 (d, J: 12.7 Hz, 1H), 3.48 — 3.33 (m, 1H), 3.19 (t, J: 12.4 Hz, 1H), 2.89 (hept, J: 6.7 Hz, 1H), 2.68 (t, J: 11.9 Hz, 1H), 2.40 (s, 3H), 2.01 (dd, J: 30.0, 12.2 Hz, 2H), 1.56 (dd, J: 74.3, 9.4 Hz, 2H), 1.00 (d, J: 3.9 Hz, 6H).
Example 109. N—{4—[4-Amino(l-methylpiperidinyl)pyrrolo[2,1- ]] [1,2,4]triazin-S-yl] phenyl}methylox0phenyl-S-pyrimidin-Z—yl- 1,2- dihydropyridine—3-carb0xamide To a mixture of 5-bromo(1-methylpipe11dinyl)pyrrolo[2,1- f][1,2,4]triazin-4—amine (from example 20, step 3) (31 mg, 0.10 mmol), 6-methy1-2— oxo-l-phenylpyrimidinyl-N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan yl)phenyl]—1,2-dihydropyridinecarboxamide (61 mg, 0.12 mmol), dicyclohexyl(2’,4',6'-triisopropylbiphenylyl)phosphine-(2'-arninobipheny1 yl)(chloro)palladium (1:1) (3.9 mg, 0.0050 mmol), and potassium phosphate (64 mg, 0.30 mmol) in 1,4-dioxane (1.2 mL)/water (0.2 mL) was degassed with N2 and then stirred at 90 0C for 3 h. The reaction mixture was cooled to It, diluted with MeOH, filtered, and purified Via pH 2 ative LC/MS (MeCN/water with TFA) to give the product as TFA salt. LCMS calcd for C35H34N902 (M+H)+: m/z = 612.3; Found: 612.2. 1H NMR (600 MHz, DMSO) 5 11.87 (s, 1H), 9.17 (s, 1H), 8.96 (d, .1: 4.9 Hz, 2H), 7.97 (s, 1H), 7.83 (d, J: 8.7 Hz, 2H), 7.63 (t, J: 7.7 Hz, 2H), 7.59 — 7.53 (m, 1H), 7.51 — 7.47 (m, 3H), 7.44 (d, J: 8.6 Hz, 2H), 6.62 (s, 1H), 3.61 — 3.43 (m, 2H), 3.42 — 3.32 (m, 1H), 3.16 (q, J: 10.4 Hz, 2H), 2.81 (d, J: 4.5 Hz, 3H), 2.41 (s, 3H), 2.26 (d, .1: 14.3 Hz, 2H), 1.93 — 1.85 (m, 2H).
Example 110. N-{4-[4-Amino—7-(l-isobutyrylpiperidinyl)pyrrolo[2,1- f] [1,2,4] triazin-S-yl] phenyl}methylmorpholinyloxo- l-phenyl- 1,2- dihydr0pyridine—3-carboxamide Step 1: 4-Amz'n0- 7—plperidinylpyrr010[2, 1fl[I , 2, 4]triaziny0phenyl]-6— methyfm0rph0linyl-2—0x0phenyl-1,2—dihydr0pyridinecarb0mmide r\/1//\2 O Q ‘N \ N HN {’3 W0 2017!]72596 A mixture of tert—butyl 4-[4-amino(4-{[(5-bromomethyloxo—l— phenyl- 1 ,2-dihydropyridin-3 -y1)carbony1] amino } phenyl)pyrrolo[2, 1 -f] [ 1 ,2,4]triazin- 7-yl]pipe1idinecarboxylate (52 mg, 0.074 mmol) (from example 10?, step 5) and morpholine (0.10 mL, 1.1 mmol) in DMF (1 mL) was heated at 180 °C under microwave conditions for 60 min, cooled to It, purified via pH 2 preparative LC/MS (MeCN/water with TFA), and concentrated (de-Boc occurred during this s) to give the product as TFA salt. LCMS calculated for C34H37NsO3 (M+H)+: m/z = 605.3; Found: 6054.
Step 2: N—{4-[4-Amin0(1-l's0bulyrylplperidiny0pyrr010[2,1-fl[1,2,4]triazin-5— yljphenyl}-6—methylm0rph01inyl0x0-I-phenyl-1 , 2-dihydr0pyridine—3- carboxamide This nd was prepared following a synthetic ce analogous to those for example 107, step 8, using N-[4-(4-aminopiperidinylpyrrolo[2,1- f] [1,2,4]triazinyl)phenyl]methylmorpholinyloxophenyl-1,2- dihydropyridine—3-carboxamide instead -(4-amino(piperidin—4— yl)pyrrolo[1,2-j] [1 ,2,4]triazinyl)phenyl)methyl(1-methyl-1H-pyrazolyl) oxo-l-phenyl-1,2-dihydropyndinecarboxamide. This compound was purified via pH 2 preparative LC/MS (MeCN/water with TFA) to give the product as TFA salt.
LCMS calculated for C3sH43NsO4 (M+H)+: m/z = 6753; Found: 6753.
Example 1 1 1. N—(4-(4-Amin0(1-isobutyrylpiperidinyl)pyrrolo[2,1- ]] ]triazin-S-yl)phenyl)—5-cyanomethyl0xo- l-phenyl- 1,2- dihydropyridine—3-carb0xamide Step 1: Ethyl 5-cyan0methyZ0x0-J-phenyl-1,2-dihydr0pyrz‘dz‘necarb0xylate A mixture of ethyl 5-bromomethyloxophenyl-1,2-dihydropyridine carboxylate (300 mg, 0.89 mmol) (from example 108, step 1), Pd2(dba)3 (32.7 mg, 0.036 mmol), Xantphos (41 mg, 0.071 mmol), Zinc cyanide (105 mg, 0.89 mmol) and TMEDA (0.040 ml, 0.27 mmol) in DMF (2.5 ml) was degassed with N2, and then stirred at 160 °C under microwave conditions for 10 min. After cooling to rt, the reaction mixture was filtered h Celite (washed with CH2C12), and concentrated to give the crude product (0.32 g), which was used directly in the next step. LCMS calcd for N203 (M+H)+: m/z = 2831, Found: 283.1.
Step 2: 5-Cyan0-6—methyl-2—0x0phenyl-1, ydr0pyridine-S-carboxylic acid A mixture of ethyl 5-cyanomethyloxophenyl-1,2-dihydropyridine carboxylate (250 mg, 0.89 mmol) and m hydroxide monohydrate (186 mg, 4.43 mmol) in MeOH (7.0ml)/water (0.70ml) was stirred at rt for 5 h, and MeOH was evaporated. Water was added and the resulting e was acidified with 1N HCl solution, stirred for another 10 min, filtered, and extracted with CH2C12. The combined organic layers were dried over MgSO4, and concentrated to give the product (147 mg, 65%). LCMS calculated for C14H11N203 (M+H)+: m/z = 2551; Found: 2550.
Step 3: ten-bury] 4-(4-aminc(4-(5-cyan0mez‘hyl0x0phenyl-I,2- dihya’ropyridinecarb0xamid0)phenyl)pyrrolo[2, 1fl[1, 2, 4]triazz‘n- 7-yi)piperidinecarb0xylaz‘e To a solution of tert—butyl mino(4-aminophenyl)pyrrolo[2,1- ]] [1,2,4]triazinyl)piperidine—1-carboxylate (200 mg, 0.49 mmol) (from example 107, step 4), 5-cyanomethyloxophenyl-1,2-dihydropyridinecarboxylic acid (124 mg, 0.49 mmol), and Et3N (0.102 mL, 0.73 mmol) in DMF (4 mL) was added HATU (223 mg, 0.59 mmol). The resulting mixture was stirred at rt overnight, added water, and the resulting solid was collected by filtration, washed with water, and dried to give a light yellow solid (307 mg). LCMS calcd for C36H37N804 (M+H)+: m/z = 6453; Found: 6454.
Step 4: N—(4-(4-Amino(pz'perz'dz'ny0pyrr0Zo[2,1-fi[1,2,4]triazin-5—yl)phenyl) cyano-é—mez‘hyl-2—0x0-J-phenyl-1, 2-dz'hydr0pyrz‘dz‘necarboxamz'de To a solution of tert—butyl 4-(4-amino(4-(5-cyanomethyl-2—oxo—1- phenyl-l ,2-dihydropyridine—3 -carboxamido)phenyl)pyrrolo[1,2-f] [1,2,4]triazin yl)piperidine—1-carboxylate (300 mg, 0.47 mmol) in CH2C12 (4.5 ml) was added 4 M HCl in 1,4—dioxane (0.93 mL, 3.72 mmol). The resulting mixture was stirred at rt for 4 h, added EtOAc, and the resulting solid was collected by ion, washed with EtOAc, and dried to give the product as a HCl salt (286 mg). LCMS calculated for N802 (M+H)+: m/z = 5452; Found: 5452.
Step 5: N-(4-(4-Amin0-7—(1-z's0buWrylpiperz'dz‘n-ZI-yUpyrro[0[2, 1fl[1, 2, 4jtriazin y!)cyan0methyl-2—0x0phenyZ-1, 2—dz'hydr0pyrz‘dz‘ne-3—carb0xamide This compound was prepared ing a synthetic sequence analogous to those for example 107, step 8, using N-(4-(4-amino(piperidinyl)pyrrolo[2,1- f] [1 ,2,4]triazin-S-yl)phenyl)cyanomethyloxo-1 l-1,2—dihydropyridine- 3—carboxamide instead of N-(4-(4-amino(piperidinyl)pyrrolo[1,2— f] [1 ,2,4]triazin—5-yl)phenyl)methyl(1-methyl-1H-pyrazolyl)-2—oxo-l -phenyl- 1,2-dihydropyridinecarboxamide. This compound was d via pH 2 preparative LC/MS (MeCN/water with TFA) to give the product as TFA salt. LCMS calculated for C35H3stO3 (M+H)+: m/z = 6153; Found: 6153.
Example 111a. N3-(4-(4-Amin0(1-isobutyrylpiperidinyl)pyrrolo[2,1- ]] [1,2,4] triazin-S-yl)phenyl)methyl-2—ox0- 1-phenyl- 1,2-dihydropyridine—3,5— dicarboxamide This compound was generated as a by-product from the tic sequence bed in example 111, due to hydrolysis of the cyano group. This compound was purified via pH 2 preparative LC/MS (MeCN/water with TFA) to give the product as TFA salt. LCMS calculated for C35H37NsO4 (M+H)+: m/z = 6333; Found: 633.3.
Example 112. 5-Acetyl-N—(4—(4—amin0-7—(1-isobutyrylpiperidinyl)pyrrolo[1,2- ]] [1,2,4] triazin-S-yl)phenyl)methyl-2—ox0- 1-phenyl- 1,2-dihydropyridine—3— carboxamide W0 2017!]72596 A e of ethyl 5-bromomethyloxophenyl-1,2-dihydropyridine—3— carboxylate (0.46 g, 1.37 mmol) (from example 108, step 1), Palladium(II) acetate (7.7 mg, 0.034 mmol) in 1-buty1methy1imidazolium tetrafluoroborate (2.81 mL, .1 mmol) was vacuumed and backfilled with N2 three times. To the e was added 1-(vinyloxy)butane (0.90 mL, 6.84 mmol) and Et3N (0.23 mL, 1.64 mmol) and the reaction mixture was stirred at 115 °C overnight. The resulting mixture was then 1O cooled to rt, treated with HCl solution (7.07 ml, 11.63 mmol), stirred at rt for 30 min, and extracted with CH2C12. The combined organic layers were trated, and purified via column chromatography (0% to 100% EtOAc in hexanes) to give the product (0.22 g, 54 %). LCMS calcd for C17H18NO4 (M+H)+: m/z = 300.1. Found: 300.2.
Step 2: 5-AcetyZmethyl0x0phenyl-1,2-dl'hydr0pyridine-S-carboxylic acid W0 2017!]72596 A mixture of ethyl 5-acetylmethyloxopheny1-1,2-dihydropyridine—3— ylate (0.070 g, 0.23 mmol) in 1 M NaOH solution (1.0 mL) and MeOH (2.0 mL) was stirred at rt for 1 h, and then neutralized with 1 N HCl solution to pH ~5.
The resulting solid was collected by filtration, and dried to give the product (0.052g, 82 %). LCMS calcd for C15H14NO4 (M+H)+: m/z = 272.1. Found: 2721.
Step 3: 5—Acetyl-N-(4-(4-amino-7—(1-l's0buWrylpiperidiny0pyrr0[0[1,2— ]?[1 , 2, 4]triazinyl)phenyl)-6—methyl-2—0x0-I-phenyl-1 , 2-dihydr0pyridine—3— carboxamide 1O This compound was prepared following a tic sequence analogous to that for example 83, step 5, using ylmethyloxophenyl-1,2-dihydropyridine- 3-carboxylic acid instead of 1-isopropyl-2,4-dioxo(pyridinyl)-1,2,3,4— tetrahydropyrimidine—5-carboxylic acid. This compound was d via pH 2 preparative LC/MS (MeCN/water with TFA) to give the product as TFA salt. LCMS calcd for C36H38N704 (M+H)+: m/Z = 632.3. Found: 632.4. 1H NMR (500 MHz, DMSO) 8 11.67 (s, 1H), 8.95 (s, 1H), 8.00 (s, 1H), 7.86 — 7.78 (m, 2H), 7.66 — 7.59 (m, 2H), 7.59 — 7.53 (m, 1H), 7.50 — 7.37 (m, 4H), 6.67 (s, 1H), 4.57 — 4.51 (m, 1H), 4.09 — 4.01 (m,1H), 3.47 — 3.36 (m, 1H), 3.27 — 3.15 (m, 1H), 2.97 — 2.83 (m, 1H), 2.73 — 2.66 (m, 1H), 2.63 (s, 3H), 2.31 (s, 3H), 2.09 — 1.96 (m, 2H), 1.68 — 1.45 (m, 2H), 1.01 (t, J: 6.8 Hz, 6H).
Example 113. N—(4-(4-Amino(1-is0butyrylpiperidin-4—yl)pyrrolo[1,2- ]] [1,2,4]triazin-S-yl)phenyl)— 1-(5-fluoropyridin-3—yl)—2,5—diox0- 1,2,5,6,7,8— hexahydroquinoline—3-carboxamide W0 2017I172596 To a mixture of cyclohexane-1,3-dione (1.0 g, 8.9 mmol) in DMF (10 mL) was added 1 M t—BuOK in THF (8.9 mL, 8.9 mrnol) at 0 °C. The resulting mixture was d for 20 min and added ethyl (E)—2-cyanoethoxyacrylate (1.51 g, 8.9 mmol). The reaction mixture was warmed to rt, stirred for 2 h, quenched with 1N HCl solution, and extracted with EtOAc. The combined organic layers were concentrated and purified Via column chromatography (0% to 100% EtOAc in 1O hexanes) to give the product. LCMS calcd for C12H1305 : m/z = 237.1. Found: 237.2.
Step 2: 1-(5—Flu0r0pyrl'dinyl)-2, 5-dl'0x0-1,2, 5, 6, xahydr0quinoline—3— carboxylic acid A mixture of ethyl 2,5-dioxo-5,6,7,8-tetrahydro-2H-chrornene—3-carboxy1ate (0.28 g, 1.185 mmol) and 5-fluoropy1idinamine (0.133 g, 1.19 mrnol) in EtOH (3 mL) was stirred at rt overnight, treated with 1 M NaOH solution (2 mL), stirred at rt for 1 h, and purified via pH 2 preparative LC/MS (MeCN/water with TFA) to give the product (0.065 g, 18 %). LCMS calcd for C15H12FN204 (M+H)+: m/z = 303.1. Found: 303.2.
Step 3: N—(4—(4—Am1770(1-z'sobuWrylpz‘perz‘dz‘n-4—y0pyrr0[0[1, 2—fl[1, 2, 4]triazz’n yUphenyO—I—(5-flu0r0pyridinyl)-2, 5-dz'0x0-1, 2, 5, 6, 7, 8-hexahydr0quin0!1716—3- carboxamide This compound was prepared following a synthetic sequence analogous to that for example 83, step 5, using 1-(5-fluoropyridinyl)-2,5-dioxo-1,2,5,6,7,8- hexahydroquinolinecarboxylic acid instead of 1-isopropyl-2,4—dioxo-3—(pyridin-2— 2,3,4-tetrahydropyrimidine-S-carboxylic acid. This compound was purified via pH 2 preparative LC/MS (MeCN/water with TFA) to give the product as TFA salt.
LCMS calcd for C36H36FN804 (M+H)+: m/z = 663.3. Found: 663.4. 1H NMR (600 MHz, DMSO) 5 11.38 (s, 1H), 8.96 (s, 1H), 8.86 (d, J: 2.6 Hz, 1H), 8.68 — 8.62 (m, 1H), 8.16 — 8.12 (m, 1H), 8.09 (s, 1H), 7.84 (d, J: 8.7 Hz, 2H), 7.47 (d, J: 8.6 Hz, 2H),6.75(s,1H),4.58 — 4.51(m, 1H), 4.12 — 4.03 (m, 1H), 3.46 — 3.36 (m, 1H), 3.26 — 3.16 (m, 1H), 2.94 — 2.85 (m, 1H), 2.75 — 2.63 (m, 1H), 2.63 — 2.52 (m, 4H), 2.09 — 1.95 (m, 4H), 1.69 — 1.47 (m, 2H), 1.06 — 0.93 (m, 6H).
Example 114. 4-Amino(l-isobutyrylpiperidin-4—yl)pyrrolo[1,2- f][1,2,4]triazin-S-yl)phenyl)—7,7-dimethyl-2,5-dioxo—1-(pyridin-3—yl)—1,2,5,6,7,8- hexahydr0quinoline—3—carboxamide Step 1: Ethyl 7, 7-dz'methyl-2, 5-dz'0x0-5, 6, 7, 8-tetrahydr0-2H-chr0mene-3—carb0xylate W0 172596 o 0 To a mixture of 5,5-dimethylcyclohexane-1,3-dione (2.0 g, 14.3 mmol) in DMF (20 mL) was added 1M t—BuOK in THF (14.3 mL, 14.3 mmol) at 0 °C. The resulting mixture was stirred for 20 min, added ethyl (E)cyano-3—ethoxyacrylate (2.41 g, 14.3 mmol), warmed to It, and stirred overnight. The reaction mixture was quenched with 1 N HCl solution, extracted with EtOAc, and the ed organic layers were concentrated and purified via column chromatography (0% to 100% EtOAc in hexanes) to give the product (2.8 g, 74%). LCMS calcd for C14H17Os (M+H)+: m/z = 265.1. Found: 2652.
Step 2: 7, 7—Dimethyl-2, 5-dl'0x0(pyrz'dinyZ)-1, 2,5, 6, 7, 8-hexahydr0quinoline carboxylic acid O N A mixture of ethyl 7,7-dimethyl-2,5-dioxo-5,6,7,8-tetrahydro—2H—chromene carboxylate (244 mg, 0.92 mmol) and pyridinamine (87 mg, 0.92 mmol) in EtOH (3 mL) was stirred at 60 °C overnight, cooled to rt, and the resulting solid was collected by filtration, and dried to give the product (170 mg, 59 %). LCMS calcd for C17H17N204 (M+H)+: m/z = 313.1. Found: 313.2.
Step 3: N—(4-(4-Amin0-7—(1-is0buWrylpl'peridiny0pyrr0[0[1,2—fi[1, 2, zin yUphenyD-Z 7—dimethyl-2, 5-dl'0x0(pyrl'dinyl)-1, 2, 5, 6, 7, 8-hexahydr0quinoline carboxamide This compound was prepared following a synthetic sequence analogous to that for example 83, step 5, using 7,7-dimethyl-2,5-dioxo(pyridinyl)-1,2,5,6,7,8- droquinoline—3—carboxylic acid instead of 1-isopropy1-2,4-dioxo(pyridin—2— y1)-1,2,3,4—tetrahydropyrimidine-S-carboxylic acid. This compound was purified via pH 2 preparative LC/MS (MeCN/water with TFA) to give the t as TFA salt.
LCMS calcd for C38H41N804 (M+H)+: m/z = 673.3. Found: 673.4. 1H NMR (500 MHz, DMSO) 8 11.44 (s, 1H), 8.95 (s, 1H), 8.80 (dd, J: 4.8, 1.4 Hz, 1H), 8.70 (d, J = 2.4 Hz, 1H), 8.09 (s, 1H), 8.01 (dt, J: 8.1, 1.9 Hz, 1H), 7.84 (d, J: 8.6 Hz, 2H), 7.73 (dd, J= 8.1, 4.8 Hz, 1H), 7.47 (d, J= 8.6 Hz, 2H), 6.76 (s, 1H), 4.59 — 4.49 (m, 1H), 4.12 — 4.03 (m, 1H), 3.46 — 3.37 (m, 1H), 3.26 — 3.15 (m, 1H), 2.96 — 2.84 (m, 1H), 2.74 — 2.65 (m, 1H), 2.49 — 2.42 (m, 4H), 2.11 — 1.96 (m, 2H), 1.69 — 1.46 (m, 2H), 1.10— 0.89 (m, 12H).
Example 115. N—(4-(4-Amino(1-is0butyrylpiperidin-4—yl)pyrrolo[1,2- ]] [1,2,4]triazin-S-yl)phenyl)— 1-(5-fluor0pyridinyl)—6,6-dimethyl-2,5-dioxo- 1O 1,2,5,6,7,8-hexahydroquinoline—3—carboxamide .42,N Step I: Ethyl 6, 6-d1'methyl-2, 5-d1'0x0-5, 6, 7, 8—tetrahydr0-2H—chr0mene-3—carb0xylate £11.03o 0 0 0 To a mixture of 4,4-dimethylcyclohexane-1,3-dione (1.8 g, 12.8 mmol) in DMF (10 mL) was added 1 M t—BuOK in THF (12.8 mL, 12.8 mol) at 0 °C. The resulting mixture was stirred for 20 min, added ethyl (E)cyanoethoxyacrylate (2.17 g, 12.8 mmol), warmed to It, and stirred overnight. The reaction mixture was ed with 1 N HCl solution, ted with EtOAc, and the combined organic layers were trated and purified Via column chromatography (0% to 100% EtOAc in hexanes) to give the product (2.7 g, 80%). LCMS calcd for C14H17Os (M+H)+: m/z = 265.1. Found: 265.2.
Step 2: 1-(5-FZu0r0pyridinyl)-d 6—dz'methyl-2, 5-dl'0x0-1,2, 5, 6, 7, 8- droquinolmecarb0xylz'c acid HO /| O N A mixture of ethyl 6,6-dimethyl-2,5-dioxo-5,6,7,8-tetrahydro-2H—chromene carboxylate (200 mg, 0.76 mmol) and 5-fluoropyridinamine (85 mg, 0.76 mmol) in EtOH (3 mL) was stirred at 60 °C overnight, cooled to rt, and purified via pH 2 preparative LC/MS (MeCN/water with TFA) to give the product (75 mg, 30%).
LCMS calcd for C17H16FN204 (M+H)+: m/z = 331.1. Found: 331.2.
Step 3: N-(4—(4-Amin0-7—(1-is0buWrylpl'peridiny0pyrr0[0[1,Z-fi[1, 2, 4]triazin yUphenyD-I-(5-flu0r0pyridinyl)-6, 6—dimez‘hyl-2, 5-dz'0x0-1, 2, 5, 6, 7, 8- hexahydroquinoZine-S-carboxamide This compound was prepared following a synthetic sequence analogous to that for example 83, step 5, using uoropyridiny1)-6,6-dimethyl-2,5-dioxo- 6,7,8-hexahydroquinolinecarboxylic acid instead of 1-isopropyl-2,4-dioxo (pyridinyl)—1,2,3,4-tetrahydropyrimidinecarboxylic acid. This compound was purified via pH 2 preparative LC/MS water with TFA) to give the product as TFA salt. LCMS calcd for C3sH4oFNsO4 : m/z = 691.3. Found: 6914.
Example 116. N—{4—[4-Amino(1-isobutyrylpiperidinyl)pyrrolo[2,1- ]] [1,2,4]triazin-S-yl] phenyl}0xo- 1-phenylpyridin-3—yl-1,6- dihydropyrimidine—S-carboxamide Step 1: Sodium [immo(pyridinyl)methyl](phenyl)azam‘de LJYNH’ | Aniline (931 mg, 10.0 mmol) was added to 1.0 M sodium hexamethyldisilazane in THF (10 mL, 10.0 mmol). The resulting mixture was stirred at rt for 10 min, added 3-pyridinecarbonitrile (1.04 g, 10.0 mmol), stirred at rt for 1 h, and concentrated. The residue was d with ether, and the resulting solid was collected by filtration, washed with ether and dried to afford the product (2.10 g, 100%), which was used directly in the next step. LCMS calcd for C12H12N3 (M+2H- Na)+: m/z= 198.1. Found: 198.1. 1O Step 2: Ethyl 6-0x0phenyl-2—pyridinyldl'hydr0pyrz'midine-5—carb0xylate To a solution of [[imino(pyridinyl)methyl](phenyl)azanide (0.219 g, 1.00 mmol)in MeCN (5 mL) was added ammonium chloride (0.054 g, 1.00 mmol), ed by (ethoxymethylene)propanedioic acid, diethyl ester (0.20 mL, 1.00 mmol). The reaction mixture was stirred at 80°C for 2 h, cooled to rt, and concentrated. The resulting residue was dissolved in EtOAc, and washed with water and brine. The organic layer was separated, dried over MgSO4, concentrated, and purified via column tography (0% to 50% EtOAc in hexanes) to afford the product (0.167 g, 52%). LCMS calcd for C18H16N303 (M+H)+: m/z = 322.1. Found: 322.2.
Step 3: 6-0x0phenyl-2—pyridinyl-1,6-dl'hydr0pyrimidinecarb0xyfic acid W0 2017!]72596 A mixture of ethyl 6-oxophenylpyridiny1-1,6-dihydropyrimidine-5— carboxylate (133 mg, 0.41 mmol) and lithium iodide (138 mg, 1.03 mmol) in pyridine (2.5 mL) was stirred at 115°C overnight, cooled to rt, and concentrated. The resulting residue was dissolved in water (2 mL) and extracted with EtOAc (3 mL x 2). The aqueous layer was slowly acidified to pH ~4 with 1 N HCl on, and extracted with 5% MeOH in CH2C12 (3 mL x 3). The combined organic layers were washed with brine, dried over MgSO4, and concentrated to give the product (0.103 g, 85%), which was used directly in the next step. LCMS calcd for C16H12N303 (M+H)+: m/z = 294.1. Found: 294.1.
Step 4: N—{4-[4-Amin0(1-l's0bulyrylplperidiny0pyrr010[2,1-fl[1,2,4]triazin-5— nyl}0x0phenylpyridinyl-1, 6—dihydr0pyrimidine-5—carb0xamide This nd was prepared following a synthetic sequence analogous to that for example 83, step 5, using 6-oxophenylpyridinyl-1,6-dihydropyrimidine- 5-carboxylic acid instead of 1-isopropyl-2,4-dioxo(pyridinyl)-1,2,3,4- tetrahydropyrimidine—5-carboxylic acid. This compound was d via pH 2 preparative LC/MS (MeCN/water with TFA) to give the product as TFA salt. LCMS calcd for N903 (M+H)+: m/z = 654.3. Found: 654.3.
Example 117. N—{4—[4-Amino(1-isobutyrylpiperidin-4—yl)pyrrolo[2,1- ]] [1,2,4]triazin-S-yl]phenyl}cyclopropylox0phenyl-2,3- dihydropyridazinecarboxamide Step 1. (Z-CyclopropyZ0x0ethy!) (triphenybphosphonium bromide W0 2017/‘172596 A solution of 2-bromocyclopropylethanone (2.44 g, 15.0 mmol) and PPh3 (3.93 g, 15.0 mmol) in THF (60 mL) was stirred at reflux for 1 h, and cooled to rt.
The resulting solid was collected by filtration, and washed with ether to afford the product (3.91 g, 61%), which was used directly in the next step. LCMS calcd for C23H220P (M-Br)+: m/z = 345.1. Found: 345.2.
Step 2: I-Cyclopropyl-Z-(triphenylphosphoranylidene)ethanone A mixture of (2-Cyclopropyloxoethyl)(triphenyl)phosphonium bromide (3.91 g, from previous step) in 1N NaOH solution (40 mL) was stirred overnight, and extracted with . The combined organic layers were washed with brine, dried over MgSO4, and concentrated to afford the product (2.60 g, 50%). LCMS calcd for C23H220P (M+H)+: m/z = 345.1. Found: 345.2.
Step 3: 6—Cyclopropyl-S-0x0phenyl-2,3-dl'hydr0pyridazinecarboxylic acid N l OH To a solution of 1-cyclopropyl(triphenylphosphoranylidene)ethanone (1.72 g, 5.0 mmol) in THF (25 mL) was added diethyl 2-oxomalonate (1.3 g, ?.5 mmol).
The resulting mixture was stirred at rt for 30 min, trated, and the e was added to phenylhydrazine hydrochloride (1.08 g, 7.50 mmol) in EtOH/HzO (1:1, 50 mL). The reaction mixture was d at 80 °C overnight. After cooling to rt, the organic solvents were evaporated, and the e was diluted with CH2C12 (30 mL), and ted with 1N NaOH solution (5 mL x 3). The combined aqueous layers were adjusted with 6 N HCl to pH ~4, and extracted with EtOAc (5 mL x 3). The combined c layers were washed with water and brine, dried over MgSO4, and concentrated to give the product (0.562 g, 44%), which was used directly in the next step. LCMS calcd for C14H13N203 (M+H)+: m/z = 257.1. Found: 257.1.
Step 4: N—{4—[4-Aml'n0- 7-(1-l's0buWrylplperidiny0pyrr010[2, 1fl[1, 2, 4]triazin yljphenyl}—6—cyclopr0pyl0x0phenyl-2, 3-dl'hydr0pyridazinecarb0xamide This compound was prepared following a synthetic sequence analogous to that 1O for example 83, step 5, using 6-cyclopropyloxophenyl-2,3-dihydropyridazine carboxylic acid instead of 1-isopropyl-2,4-dioxo(py1idinyl)—1,2,3,4- tetrahydropyrimidine—5-carboxylic acid. This compound was purified Via pH 2 preparative LC/MS (MeCN/water with TFA) to give the product as TFA salt. LCMS calcd for C35H37NsO3 (M+H)+: m/z = 617.3. Found: 617.3 Example 118. N—(4—(4—Amino(l-isobutyrylpiperidinyl)pyrrolo[2,1- f] ]triazin-S-yl)phenyl)bromo—6-methyloxo-2H-[1,2'-bipyridine] carboxamide Step I: 5-Br0m0-6—methyl-2—0x0-2H—[1,2'-bipyridinej-S-carboxylic acid W0 2017!]72596 A mixture of ethyl 5-bromomethyl-2—oxo-2H—[1,2'-bipyridine]—3— ylate (800 mg, 2.37 mmol) (from Affinity Research Chemicals) in THF (7.9 mL)/MeOH (5.3 mL)/water (2.6 mL) was treated with lithium hydroxide monohydrate (0.33 mL, 11.9 mmol) at 0 °C. The reaction mixture was stirred at rt for 60 min, concentrated, and added water. The resulting e was neutralized with 12 M HCl solution to pH 6N7, and the resulting solid was collected by filtration, washed with water, and dried to give the product as a light yellow powder (784 mg, 100%).
LCMS calcd for C12H10BrN203 (M+H)+: m/z = 309.0. Found: 309.0. 1O Step 2: N—(4-(4-Aml'n0-7—(1-z's0buWrylpiperidiny0pyrr0[0[2,1-fl[1,2,4]triazin yUphenyl)br0m0-6—mez‘hyl-2—0x0-2H—[1,2’-blpyridine]carb0xamide To a mixture of 5-bromomethyloxo-2H—[1,2'-bipyridine]carboxylic acid (9.0 mg, 0.03 mmol) and 1-(4-(4-amino(4-aminophenyl)pyrrolo[2,1- f][1,2,4]triazinyl)piperidinyl)methylpropanone (10 mg, 0.03 mmol) (from example 83, step 2) in DMF (528 pl) was added Et3N (11 pl, 008 mmol), followed by HATU (20 mg, 0.053 mmol). The resulting e was stirred at rt for 20 min, filtered, and the crude was d via pH 2 preparative LC/MS (MeCN/water with TFA) to give the product as TFA salt. LCMS calcd for C33H34BrNsO3 (M+H)+: m/z = 669.2. Found: 669.2. 1H NMR (500 MHZ, DMSO) 5 11.69 (s, 1H), 8.75 — 8.67 (m, 2H), 8.60 (s, 1H), 8.17 (td, J: 7.8, 1.9 Hz,1H), 8.05 (s, 1H), 7.81 (d, J: 8.7 Hz,1H), 7.73 — 7.62 (m, 3H), 7.46 (d, J: 8.6 Hz, 1H), 6.72 (s, 1H), 4.55 (d, J: 13.6 Hz, 1H), 4.07 (d, J: 12.2 Hz, 1H), 3.42 (s, 1H), 3.27 — 3.16 (m, 1H), 2.91 (p, J: 6.7 Hz, 1H), 2.78 — 2.61 (m, 2H), 2.16 (s, 2H), 2.12 — 1.95 (m, 2H), 1.58 (dd, J: 59.5, , 2H), 1.02 (t, J: 6.6 Hz, 6H).
Example 119. N—(4-(4-Amino(1-isobutyrylpiperidinyl)pyrrolo[2,1- f] [1,2,4] triazin-S-yl)phenyl)— 1-cyclopr0pylmethyl(oxazolyl)oxo- 1,4- dihydropyridine—3—carboxamide W0 2017I172596 O / Step 1: I-Cyclopropylmez‘hyl0x0-1,4-dl'hydr0pyridinecarb0xylic acid A microwave vial was charged with (E/Z)((dimethylamino)methylene) methyl-2H—pyran-2,4(3H)-dione (1.92 g, 7.95 mmol) (from example 9?, step 1), cyclopropanamine (0.83 mL, 11.92 mmol) and t-BuONa (1.13 g, 11.76 mmol) in EtOH (5.0 mL). The resulting mixture was stirred at 90 °C for 18 h, cooled to rt, concentrated, and partitioned between water and CH2C12. The aqueous layer was acidified with 4 N HCl on and ted with CH2C12. The combined organic 1O layers were washed with water, brine, dried over NazSO4, and concentrated to give the product (1.1 g, 42%). LCMS calcd for C10H12NO3 (M+H)+: m/z = 194.1. Found: 194. 1.
Step 2: 5-Br0m0cyclopr0pylmez‘hyl0x0-1,4-dl'hydr0pyridz'necarb0xylic acid HoififrO A suspension of 1—cyclopropylmethyloxo-1,4-dihydropyridine—3- carboxylic acid (0.83 g, 4.30 mmol) in glacial acetic acid (6.0 mL) was treated with Brz (0.29 mL, 5.58 mmol) and the reaction mixture was stirred at rt for 4 days.
W0 2017/‘172596 Additional Br2 (100 uL) was added and the reaction mixture was stirred overnight, diluted with water, and the resulting solid was collected by filtration, washed with water, and dried to give the product as a beige solid (10 g, 86%). LCMS calcd for C10H11BrNOz (M+H)+: m/z = 272.0. Found: 272.0.
Step 3: N—(4—(4—Aml'n0(1-l's0buWrylpiperidiny0pyrr0[0[2,1-fl[1,2,4]triazin-5— yUphenyl)—5—br0m0cyclopr0pyl-6—methyl0x0-1,4-dihydr0pyridine-3— carboxamide O / A mixture of 4-amino(4-aminophenyl)pyrrolo[2,1-f][1,2,4]triazin yl)piperidinyl)methylpropanone (278 mg, 0.74 mmol) (from example 83, step 2), 5—bromocyclopropylmethyloxo-1,4-dihydropyridine—3-carboxylic acid (200 mg, 0.74 mmol), HATU (335 mg, 0.88 mmol) and Et3N (0.21 mL, 147 mmol) in DMF (5.0 mL) was stirred at rt for 2h, and then directly purified via column chromatography to afford the product (252 mg, 54%). LCMS calcd for C31H35BrN7O3 (M+H)+: m/z = 632.2. Found: 632.1.
Step 4: N-(4-(4-Amz'n0(1-z's0buWrylpiperidiny0pyrr0[0[2,1fl[1,2,4]triazin yl)cyclopr0pyl-6—mez‘hyl(0xazol-2—yl)0x0-1, 4-dl'hydr0pyridine amide To a solution ofN—(4-(4-amino(1-isobuty1ylpiperidinyl)pyrrolo[2,l- ]] [1,2,4]triazinyl)phenyl)bromocyclopropy1methyloxo-1,4- dihydropyridinecarboxamide (20 mg, 0.032 mmol) and 2-(tributylstannyl)oxazole (11 mg, 0.032 mmol) in 1,4-dioxane (2.0 mL) was added Pd(Ph3P)4 (7.3 mg, 6.3 W0 2017!]72596 umol). The reaction mixture was stirred at reflux overnight, cooled to rt, and the resulting e was purified via pH 2 preparative LC/MS (MeCN/water with TFA) to give the t as TFA salt. LCMS calcd for C34H37N304 (M+H)+: m/z = 621.3.
Found: 621.3.
Example 120. (S)-N-(4-(4-Amino(1-isobutyrylpiperidinyl)pyrr0lo[2,1- ]] [1,2,4] triazin-S-yl)phenyl)—5-(3-hydroxybut-l-yn- 1-yl)oxo- yl- 1,2- dihydropyridine—3-carb0xamide O N H | NH2 N \ N‘N Rm0 Step 1: N—(4-(4-Amz’n0(1-z'sobutyrylpz'perz’dz’ny0pyrr0[0[2,1-fl[1,2,4]triazz’n yUphenyl)br0m0-2—0x0phenyl—1,2-dz'hydr0pyrz‘dz‘necarboxamz'de A mixture of l-(4-(4-amino(4-aminophenyl)pyrrolo[2,l-f][1,2,4]triazin yl)piperidin-l-y1)methylpropan-l-one (257 mg, 0.68 mmol) (from example 83, step 2), 5-bromooxo-l-phenyl-l,2-dihydropyridinecarboxylic acid (200 mg, 0.68 mmol), HATU (310 mg, 0.82 mmol) and Et3N (0.19 mL, 1.36 mmol) in DMF (50 mL) was stirred at rt for 2 h. The reaction mixture was then purified via column W0 2017!]72596 chromatography to afford the product (310 mg, 70%). LCMS calcd for BrN7O3 (M+H)+: m/z = 654.2. Found: 654.3.
Step 2: (SQ—N—(4-(4-Amz'n0(1-z's0butyrylpzperz‘dz‘n-4—yl)pyrr0[0[2,1—f][1,2,4]z‘rz’azin- 5-yUphenyl)—5—(3-hydroxybut—I—yn-I—yl)-2—0x0phenyl-1,2-dz'hydr0pyridine—3— carboxamide N—(4—(4—amino(1-isobutyrylpiperidinyl)pyrrolo[2,1-f][1,2,4]triazin nyl)—5—bromooxophenyl-1,2-dihydropyridinecarboxamide (20 mg, 0.031 mmol) was dissolved in MeCN (10 mL), followed by the addition of (S)—but yn-2—ol (4.7 mg, 0.067 mmol), tris(tert—butyl)phosphine (1.0 mL), Pd(Ph3P)4 (3.5 mg, 3.1 umol), (I) iodide (0.36 mg, 1.9 umol), and Et3N (0.019 mL, 0.14 mmol).
The resulting mixture was d at 70 °C for 16 h, cooled to It, and purified via pH 2 preparative LC/MS (MeCN/water with TFA) to give the product as TFA salt. LCMS calcd for C37H33N7O4 (M+H)+: m/z = 644.3. Found: 644.5.
Example 121. N—(4—(4—Amino(l-isobutyrylpiperidinyl)pyrrolo[2,1- f] [1,2,4]triazin-S-yl)phenyl)-5'-fluoro—S,6-dimethyloxo-2H-[1,3'-bipyridine] carboxamide F \ / O / K ,N / A mixture of N—(4-(4-amino(1-isobutyrylpiperidinyl)pyrrolo[2,1- f] [1 ,2,4]triazin-5—yl)phenyl)bromo-5'-fluoromethyloxo-2H-[ 1,3'-bipyridine]— 3-carboxamide (8.0 mg, 0.012 mmol) (example 101, step 2) and PdC12(dppf)-CH2C12 adduct (10 mg, 1.2 umol) in 1,4-dioxane (0.50 mL) was sealed in a microwave vial, evacuated and refilled with N2 several times, followed by the addition of 2.0 M dimethylzinc in toluene (0.023 mL, 0.047 mmol). The reaction mixture was heated and d at 90 0C for 1 h, cooled to rt, and quenched with ice-water. The crude material was diluted with DMF and purified via pH 10 preparative LC/MS (MeCN/water with NH4OH) to give the desired product as a white solid. LCMS calcd for C34H36FNSO3 (M+H)+: m/z = 623.3. Found: 623.3.
Example 122. N—(4-(4-Amino(1-is0butyrylpiperidin-4—yl)pyrrolo[1,2- ]] [1,2,4] triazin-S-yl)phenyl)—5—(cyan0methyl)methyl-2—ox0- 1-(pyridin-2—yl)— 1,2- dihydropyridine—3-carb0xamide o / K ,N / In a sealed tube a mixture of N—(4-(4-amino(1-isobutyrylpiperidin-4— yl)pyrrolo[2,1-f] [l,2,4]triazinyl)phenyl)bromomethyloxo-2H—[1,2'- bipyridine]—3-carboxamide (10 mg, 0.02 mmol) (example 118, step 2), isoxazol—4- ylboronic acid (2.5 mg, 0.02 mmol) in oxane (0.30 mL), N-ethyl-N- isopropylpropanamine (7.7 uL 0.05 mmol) and water (60 uL) was stirred together before Pd(tBu3)2 (3.8 mg, 7.5 umol) was added. The reaction mixture was sealed and then heated and stirred at 110 °C for 1 h, cooled to rt, diluted with DMF, and purified via pH 10 preparative LC/MS water with NH4OH) to give the d product as awhite solid. LCMS calcd for N903 (M+H)+: m/z = 630.3. Found: 6303.
Example 123. N-(4-(4-Amino(1-isobutyrylpiperidinyl)pyrrolo[2,1- f] [1,2,4] triazin-S-yl)phenyl)—6-methyl(1-methyl- 1H-pyrazol-5—yl)-2—0x0—2H- [1,2'-bipyridine]carboxamide N / \ \ ,N o N K ,N / In a sealed tube a mixture of N-(4-(4-amino(1-isobutyrylpiperidin rolo[2,1-f] [1,2,4]triazinyl)phenyl)bromomethyloxo-2H—[1,2'- bipyridine]carboxamide (8.0 mg, 0.012 mmol) (example 118, step 2), (1-methyl- 1H—pyrazolyl)boronic acid (2.3 mg, 0.02 mmol), and DIPEA (4.6 mg, 0.036 mmol) in 1,4—dioxane (200 uL) and water (40 uL) was stirred together before Pd(tBu3)2 (3.1 mg, 6 umol) was added. The reaction mixture was sealed and then heated and d at 110 °C for 50 min, cooled to rt, diluted with DMF, and purified via pH 10 ative LC/MS (MeCN/water with NH4OH) to give the desired product as a white solid. LCMS calcd for C37H39N1003 (M+H)+: m/z = 671.3. Found: 671.3. 1H NMR (500 MHz, DMSO) 5 11.74 (s, 1H), 8.74 (dd, J: 4.9, 1.1 Hz, 1H), 8.38 (s, 1H), 8.18 (td, J: 7.8,1.9 Hz, 1H), 7.91 (s, 1H), 7.80 (d, J: 8.6 Hz, 2H), 7.76 (d, J: 7.9 Hz, 1H), 7.70 — 7.63 (m, 1H), 7.56 (d, J: 1.8 Hz, 1H), 7.43 (d, J: 8.6 Hz, 2H), 6.58 (s, 1H), 6.42 (d, J: 1.9 Hz, 1H), 4.54 (d, J: 11.9 Hz, 1H), 3.74 (s, 3H), 3.61 (s, 1H), 3.40 (t,J= 11.9 Hz,1H), 3.25 — 3.12 (m, 1H), 2.91 (p, J: 6.8 Hz,1H), 2.75 — 2.60 (m, 1H), 2.16 — 1.97 (m, 1H), 1.87 (s, 3H), 1.81 — 1.73 (m, 1H), 1.51 (d, J: 13.9 Hz, 2H), 1.02 (t, J: 6.6 Hz, 6H).
Example 124. N—(4—(4—Amino(1-isobutyrylpiperidinyl)pyrrolo[2,1- f] [1,2,4]triazin-S-yl)phenyl)—5-ch10r0-6—methyloxo-2H-[1,2'-bipyridine] carboxamide N\ Cl 0 / To a microwave vial was added 4-amino(1-isobutyrylpiperidin yl)pyrrolo[2,1-j] [1,2,4]triazinyl)phenyl)bromomethyloxo-2H—[1,2'- bipyridine]carboxamide (8.0 mg, 0.01 mmol) (example 118, step 2) and nickel(II) de (1.4 mg, 0.02 mmol) in DMF (0.40 mL). The vial was sealed and the reaction mixture was stirred at 180 °C under microwave conditions for 30 min, cooled to rt, and purified via pH 10 preparative LC/MS (MeCN/water with NH4OH) to give the desired product as a white solid. LCMS calcd for C33H34CleO3 (M+H)+: m/z = 6252. Found: 625.2.
Example 125. N—(4-(4-Amino(1-isobutyrylpiperidinyl)pyrrolo[2,1- ]] [1,2,4] triazinyl)phenyl)—6-methyl(1-methyl- 1H-pyrazol-3—yl)—2—0x0—2H- [1,2'-bipyridine]carb0xamide This compound was prepared following a tic sequence analogous to that for example 123, using 1—methyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2—yl)-1H— pyrazole instead of (1-methyl-1H-pyrazolyl)boronic acid. This compound was d via pH 10 preparative LC/MS (MeCN/water with NH4OH) to give the desired t as a white solid, LCMS calcd for C37H39N1003 (M+H)+: m/z = 671.3. Found: 671.3.
Example 126. N—(4-(4-Amino(1-isobutyrylpiperidinyl)pyrrolo[2,1- ]] [1,2,4] triazin-S-yl)phenyl)—6-methyl(oxazolyl)0xo-2H- [1,2‘-bipyridine] - 3-carboxamide K ,N / To a mixture -(4-amino(1-isobutyrylpiperidinyl)pyrrolo[2,1- ]] [1 ,2,4]triazin—5 -yl)phenyl)-5 -bromomethyloxo-2H-[1,2'-bipyridine]—3- carboxamide (10 mg, 0.02 mmol) (example 118, step 2), and Pd(Ph3P)4 (3.5 mg, 3.0 umol) in toluene (0.30 mL) was added 2-(tributylstannyl)oxazole (10.7 mg, 0.03 mmol). The reaction mixture was sealed in a microwave Vial, vacuumed and backfilled with N2 several times, and then heated and stirred at 120 0C for 22 h. The reaction e was cooled to rt, concentrated, and purified Via pH 2 preparative LC/MS (MeCN/water with TFA) to give the product as TFA salt. LCMS calcd for C36H36N904 (M+H)+: m/z = 658.3. Found: 658.3.
Example 127. N—(4—(4—Amino(l-isobutyrylpiperidinyl)pyrrolo[2,1- f] [1,2,4]triaziny1)phenyl)—5-(difluoromethyl)methyloxo-2H-[1,2'- bipyridine]carboxamide K ,N / Step 1: N—(4-(4-Aml'n0(1-l's0butyrylplperidl‘ny0pyrr0[0[2,1-fl[1,2,4]triazin-5— yUphenyl)-6—methyl0x0vinyl-2H-[1,2’-blpyridinej-S-carboxaml‘de K ,N / A e ofN—(4-(4-amino(1 -isobutyrylpiperidinyl)pyrrolo[2, 1 - f] [1 ,2,4]triazin-5 -yl)phenyl)-5 -bromomethyloxo-2H-[1,2'-bipyridine]—3— carboxamide (40 mg, 0.06 mmol) (example 118, step 2), 4,4,5,5-tetramethylvinyl- dioxaborolane (13.8 mg, 0.09 mmol), Na2CO3 (20.9 mg, 0.20 mmol), and [1,1’- Bis(di—cyclohexylphosphino)ferrocene] ropalladium (II) (4.5 mg, 6.0 umol) in tert—butyl alcohol (0.19 mL) and water (0.07 mL) was degassed with nitrogen, and then stirred and heated at 115 °C for 2 h. The resulting mixture was cooled to rt, diluted with EtOAc, washed with saturated NaHCO3 solution, water, and brine, dried over NazSO4, concentrated, and purified via column chromatography (0 to 15% MeOH in EtOAc) to give the desired product as an off-white solid (27.9 mg, 76%).
LCMS calcd for C35H37NsO3 (M+H)+: m/z = 617.3. Found: 617.3.
W0 2017/‘172596 Step 2: N—(4—(4-Amz'n0(1-z'sobutyrylpz'perz'dz'nyl)pyrr0[0[2, 1-f][1, 2, 4]triazin yUphenyDf0rmyl-6—methyl—2-0x0-2H-[1,2’-bz'pyrz'dz‘nej-S-carboxamide O O To a solution ofN—(4-(4-amino(1-isobutyrylpiperidinyl)pyrrolo[2,1- ]] [1,2,4]triazinyl)phenyl)methyloxovinyl-2H—[1,2'-bipyridine] carboxamide (20.0 mg, 0.032 mmol) in THF (0.37 mL) was added 0304 in water (4 wt.%) (0.06 mL, 9.7 umol) and sodium periodate (32.6 mg, 0.15 mmol) in water (003 mL). The reaction mixture was stirred at 70 °C for 1 h, cooled to rt, d h a plug of Celite, rinsed with THF, concentrated, and purified via pH 10 preparative LC/MS (MeCN/water with NH4OH) to give the desired product as a light yellow solid (6.5 mg, 31%). LCMS calcd for C34H35NsO4 (M+H)+: m/z = 619.3. Found: 6193.
Step 3: N—(4-(4-Aml'n0(1-l's0bulyrylpiperidinyl)pyrr0[0[2,1fl[1,2,4]triazin yUphenyl)—5-(diflu0r0methyl)-6—methyl0x0-2H—[1,2’-bl'pyrz'dl'nej-S-carboxamide To a solution ofN—(4-(4-amino(1-isobutyry1pipe1idinyl)pyrrolo[2,1- f] [1 ,2,4]triazin-5 -yl)phenyl)-5 -formylmethyloxo-2H-[1,2'-bipyridine]—3- carboxamide (8.0 mg, 0.01 mmol) in THF ( 0.16 mL) at 0 °C was slowly added (diethylamino)sulfur trifluoride (DAST) (0.034 mL, 0.259 mmol). The resulting reaction mixture was warmed to rt and d at rt for 21 h, diluted with DMF, and purified via pH 2 preparative LC/MS (MeCN/water with TFA) to give the product as TFA salt. LCMS calcd for C34H35F2NsO3 : m/z =641.3. Found: 641.3.
Example 128. N—(4-(4-Amino(1-isobutyrylpiperidinyl)pyrrolo[1,2- f] [1,2,4] triazin-S-yl)phenyl)—l-isopropyloxo—S-(pyridinyl)— 1,4- dihydropyridine—3-carboxamide Step I: Methyl 5-br0m0isopr0pyl0x0-1, 4-dl'hydropyridine-S-carboxylate A e of methyl 5-bromooxo-l,4-dihydropyridinecarboxylate (151 mg, 0.65 mmol) and C52CO3 (420 mg, 1.3 mmol) in DMF (3 mL) was stirred at rt for min and then isopropyl iodide (0.16 mL,1.6 mmol) was added. The reaction 1O mixture was d at It for 11 days, diluted with EtOAc, filtered through Celite trated, and purified Via column chromatography (0% to 100% EtOAc in hexanes then 0% to 10% methanol in CH2C12) to give the product as an off-white solid (103 mg, 58%). LCMS calcd for C10H13BrNO3 (M+H)+: m/z = 274.0. Found: 274.1.
Step 2: 5-Br0m0z's0pr0pyl0x0-1, 4-dl'hydr0pyridinecarb0xyll'c acid Ho%8r W0 2017!]72596 To a solution of methyl 5-bromoisopropyloxo-1,4-dihydropyridine carboxylate (103 mg, 0.376 mmol) in MeOH (2 mL) was added 3 M NaOH (0.2 mL) and the reaction mixture was stirred at rt for 4 h, acidified with 1 N HCl, diluted with brine, and extracted with EtOAc. The ed organic layers were dried over Na2S04, and concentrated to afford the crude product as an off—white solid, which was used directly in the next step (97 mg, 99%). LCMS calcd for C9H11BrNO3 (M+H)+: m/z = 2600. Found: 260.0.
Step 3: tert—Butyl 4-(4-amin0(4-(5-br0m0is0pr0pyl0x0-1,4-dz'hydr0pyridine- 3-carb0xamid0)phenyUpyrro[0[1, 2—fl[1, 2, zz'n- 7-yUpiperidinecarboxylate A solution of 5-bromo-l-isopropyloxo-1,4-dihydropyridine—3-carboxylic acid (83 mg, 0.319 mmol) and HATU (146 mg, 0.383 mmol) in DMF (2 mL) was treated with DIPEA (0.11 mL, 0.638 mmol). This mixture was then added via a cannula to a solution of tert-butyl 4-(4-amino(4-aminophenyl)pyrrolo[1,2— ,4]triazinyl)piperidinecarboxylate (130 mg, 0.319 mmol) (example 107, step 4) in DMF (1 mL). The on mixture was stirred at It for 40 min, diluted with water and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over NazSO4, concentrated, and d Via column chromatography (0% to 100% EtOAc in hexanes then 0% to 10% MeOH in CH2C12) to give the product as a yellow solid (208 mg, 100%). LCMS calcd for C31H37BrN7O4 (M+H)+: m/z = 6502. Found: 6502.
W0 2017/‘172596 Step 4: [err-Bury] 4-(4-amin0(4-(1-z'sopr0pyl0x0(pyrz'dl'nyl)-1,4- dihydropyridine-S-carb0xamid0)phenyl)pyrr0[0[1,2-f][1, 2, 4]triazz‘n— piperidinecarb0xylaz‘e 02-0)? A mixture of tert—butyl 4-(4-amino(4-(5-bromoisopropyloxo-1,4— dihydropyridinecarboxamido)phenyl)pyrrolo[1,2-f][1,2,4]triazinyl)piperidine carboxylate (76 mg, 0.117 mmol), pyridinylboronic acid (172 mg, 0.140 mmol), XPhos-Pd-G2 (9.2 mg, 0.012 mmol) and ium phosphate tribasic (62 mg, 0.292 mmol), in 1,4-dioxane/water (5:1, 2.4 mL) was degassed with nitrogen, and then heated and stirred at 90 °C for 2 h. The reaction mixture was cooled to rt, diluted with EtOAc, dried over NazSO4, d through Celite, concentrated, and purified via column chromatography (0% to 100% EtOAc in hexanes then 0% to 10% MeOH in CH2C12) to give the product as an off-white solid (60 mg, 79%). LCMS calcd for C36H41N804 (M+H)+: m/z = 649.3. Found: 649.3.
Step 5: N-(4-(4-Amino-7—(pl'perl'dl'ny0pyrr010[I, Z-fl[I , 2, 4]triazinyl)phenyZ)-1 - isopropyl—4-0x0(pyridinyl)-1,4-dihydr0pyridinecarboxamz'de A suspension of tert—butyl 4-(4-amino(4-(1-isopropyloxo(pyridin yl)-1,4-dihydropyridine-3 -carboxamido)phenyl)pyrrolo[1,2-f] [1,2,4]triazin yl)piperidine—1-carboxylate (60 mg, 0.092 mmol) in CH2C12 (1 mL) was treated with 4 M HCl in 1,4-dioxane (1 mL). The reaction e was stirred at rt for 2 h, and concentrated to afford a light yellow solid which was directly used in the next step.
LCMS calcd for C31H33N802 (M+H)+: m/z = 5493. Found: 5493.
Step 6: 4-Amz'n0(1-z'sobutyrylpz'perz’dz’ny0pyrr0[0[1,2fl[1,2,4]triazin yUphenyU-J -z’sopr0pyl—4-0x009yridz'nyl)-], ydr0pyrz‘dz‘necarb0xamz’de A mixture of N-(4-(4-amino(piperidinyl)pyrrolo[l,2—f][1,2,4]triazin yl)phenyl)—1-isopropyloxo(pyridinyl)-1,4-dihydropyridine—3—carboxamide (20 mg, 0.036 mmol) and Et3N (0.030 ml, 0.215 mmol) in CH2C12 (1 mL) was treated dropwise with 60 uL of a 10% (V/V) solution of isobutyryl chloride in CH2C12. The reaction mixture was stirred at rt for 40 min, quenched with saturated NaHCO3 solution, and extracted three times with EtOAc. The combined c layers were dried over NazSO4, concentrated, and purified Via pH 2 preparative LC/MS (MeCN/water with TFA) to afford the product as an off-white solid (15 mg as TFA salt). LCMS calcd for C35H39NsO3 : m/z = 619.3. Found: 619.3.
Example 129. N—(4-(4-amino(1-isobutyrylpiperidinyl)pyrrolo[1,2- f] [1,2,4] triazin-S-yl)phenyl)(5-fluoropyridin-3—yl)— 1-isopropyloxo- 1,4- dihydropyridine—3-carboxamide o / '\\,N/ This compound was prepared following a synthetic sequence analogous to that for example 128, using 3-fluoro(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2— yl)pyridine d of pyridinylboronic acid in step 4. This nd was purified Via pH 2 preparative LC/MS (MeCN/water with TFA) to give the product as the TFA salt. LCMS calcd for C35H33FNsO3 (M+H)+: m/z = 637.3. Found: 637.3.
Example 130. N-(4-(4-Amino(1-isobutyrylpiperidinyl)pyrrolo[2,l- f] [1,2,4]triazin-S-yl)phenyl)bromo—6-methyloxo-2H-[1,3'-bipyridine]-3— carboxamide 0 / K ,N / Step I: 5-Br0m0-6—methyl-2—0x0-2H—[1,3'-bz'pyridinej-S-carboxylz'c acid W0 2017!]72596 A mixture of ethyl 5-bromomethyloxo-2H-[1,3'-bipyridine]—3- carboxylate (570 mg, 1.69 mmol) (from Affinity Research Chemicals) and LiOH monohydrate (355 mg, 8.45 mmol) in MeOH (12 mL) and water (2.0 mL) was stirred at It for 2 h, and MeOH was evaporated. To the residue was added water and the resulting mixture was made slightly acidic by on of 1 N HCl, which caused a solid to form. The solids were collected by ion, washed with water, and dried to give the product as a pink solid (333 mg, 64%). LCMS calcd for C12H1oBrN203 (M+H)+: m/z = 309.0. Found: 309.0.
Step 2: N-(4—(4-Amz'n0-7—(1-z'sobuWrylpiperidiny0pyrr0[0[2,1-f][1,2,4]triazin yUphenyl)br0m0-6—methyl0x0-2H—[1, 3 ’-blpyridinej-S-carboxamide To a mixture of 1-(4-(4-amino(4-aminophenyl)pyrrolo[2,1-f][1,2,4]triazin— 7-yl)piperidinyl)methylpropanone (150 mg, 0.396 mmol) (Example 83, step 2) and 5-bromomethy1oxo-2H-[1,3'-bipyridine]carboxylic acid (123 mg, 0.396 mmol) in DMF (30 mL) was added Et3N (0.083 mL, 0.594 mmol), followed by HATU (181 mg, 0.476 mmol). The resulting mixture was stirred at rt for 3 h, added water, and d for another 15 min. The resulting solid was collected by ion, washed with water, and dried to give the product (250 mg, 94%). A portion of this material was further purified via pH 2 preparative LC/MS (MeCN/water with TFA) to give the product as TFA salt. LCMS calcd for BrN803 (M+H)+: m/z = 669.2.
Found: 669.2. 1H NMR (500 MHZ, DMSO) 5 11.70 (s, 1H), 8.75 (dd, J: 4.8, 1.5 Hz, 1H), 8.67 (d, J: 2.2 Hz, 1H), 8.58 (s, 1H), 8.09 (s, 1H), 7.97 (ddd, J: 8.1, 2.4, 1.6 Hz, 1H), 7.81 (d, J: 8.7 Hz, 2H), 7.68 (dd, J: 7.9, 4.6 Hz, 1H), 7.45 (d, .1: 8.6 Hz, 2H), 6.75 (s, 1H), 4.53 (d, J: 12.8 Hz, 1H), 4.06 (d, J: 13.3 Hz, 1H), 3.49 — 3.32 (m, 1H), 3.19 (t, .1: 11.8 Hz, 1H), 2.98 — 2.79 (m, 1H), 2.68 (t, J: 11.5 Hz, 1H), 2.19 (s, 3H), 2.11 — 1.93 (m, 2H), 1.56 (dd, J: 59.6, 10.9 Hz,2H),1.00(t,J= 6.8 Hz, 6H).
Example 131. N-(4-(4-amino(l-isobutyrylpiperidinyl)pyrrolo[2,1- W0 72596 f] ] triazin-S-yl)phenyl)—5-chloromethyloxo-2H- [ 1,3'-bipyridine]-3— carboxamide N\ / 0 / K ,N / A mixture ofN—(4-(4-amino(l-isobutyrylpiperidinyl)pyrrolo[2,1- f] [l ,2,4]triazin-5 enyl)-5 -bromomethyloxo-2H—[ l ,3'-bipyridine] carboxamide (30 mg, 0.045 mmol) (Example 130, step 2) and copper(I) chloride (13.3 mg, 0.134 mmol) in DMF (0.5 mL) was heated and stirred at 170 °C under microwave conditions for 12 min. The reaction mixture was cooled to rt, filtered, and purified via pH 2 preparative LC/MS (MeCN/water with TFA) to give the product as TFA salt. LCMS calcd for C33H34CleO3 (M+H)+: m/z = 6252. Found: 6253. 1H NMR (600 MHz, DMSO) 5 11.73 (s, 1H), 8.76 (s, 1H), 8.68 (s, 1H), 8.50 (s, 1H), 8.12 (s, 1H), 7.98 (ddd, J: 8.1, 2.4, 1.5 Hz, 1H), 7.82 (d, J: 8.7 Hz, 2H), 7.69 (dd, J = 8.0, 4.8 Hz, 1H), 7.47 (d, J: 8.6 Hz, 2H), 6.77 (s, 1H), 4.53 (d, J: 11.8 Hz, 1H), 4.06 (d, J: 12.9 Hz, 1H), 3.41 (tt, J: 11.8, 3.5 Hz, 1H), 3.20 (t, J: 12.7 Hz, 1H), 2.89 (hept, J: 6.8 Hz, 1H), 2.68 (t, J: 11.9 Hz, 1H), 2.16 (s, 3H), 2.01 (dd, J: 29.4, 12.3 Hz, 2H), 1.57 (dd, J: 73.5, 9.4 Hz, 2H), 1.01 (d, J: 6.9 Hz, 6H).
Example 132. N—(4-(4-Amino(1-isobutyrylpiperidinyl)pyrrolo[2,1- ]] [1,2,4] triazin-S-yl)phenyl)—5,6-dimethyl0xo-2H— [ 1,3'-bipyridine]-3— carboxamide o / '\\,N/ To a mixture of N—(4-(4-amino(1-isobutyrylpiperidinyl)pyrrolo[2,1- ]] [1 riazin-5 -yl)phenyl)-5 -bromomethyloxo-2H-[1,3'-bipyridine] carboxamjde (30 mg, 0.045 mmol) (Example 130, step 2) and PdClz(dppf)—CH2C12 adduct (09 mg, 1.1 umol) in 1,4-dioxane (0.50 mL) was added 2.0 M dimethyl zinc in toluene (0086 mL, 0.172 mmol) dropwise under an atmosphere of N2. The resulting mixture was stirred at 90 °C overnight, cooled to rt, filtered, and purified via pH 2 preparative LC/MS (MeCN/water with TFA) to give the product as TFA salt.
LCMS calcd for NsO3 : m/z = 605.3. Found: 6053.
Example 133. N—(4-(4-Amino(l-isobutyrylpiperidinyl)pyrrolo[2,1- ]] [1,2,4] triazin-S-yl)phenyl)—6-methyl(l-methyl- 1H-pyrazolyl)—2—0x0—2H- [1,3'-bipyridine]carb0xamide \ / / N \ / /N‘N O / K ,N / In a sealed vial, a mixture ofN-(4-(4-amino(1-isobuty1ylpiperidin W0 72596 rolo[2,1-f] [1 ,2,4]triazinyl)phenyl)bromomethyloxo-2H—[1,3'- bipyridine]—3-carboxamide (20 mg, 0.030 mmol) (Example 130, step 2), 1-methy1—4— (4,4,5,5-tetramethy1-1,3,2-dioxaborolany1)— 1H-pyrazole (12.4 mg, 0.060 mmol), XPhos Pd G2 (2.4 mg, 3.0 umol) and potassium phosphate tribasic (19.0 mg, 0.090 mmol) in 1,4-dioxane (0,40 mL)/water (0.07 mL) was stirred at 90 0C under N2 overnight. The on mixture was then cooled to rt, filtered, and purified via pH 2 preparative LC/MS (MeCN/water with TFA) to give the product as TFA salt. LCMS calcd for C37H39N1003 (M+H)+: m/z = 671.3. Found: 671.4. 1O Example 134. N—(4-(4-Amino(1-isobutyrylpiperidin-4—yl)pyrrolo[2,1- ]] [1,2,4]triazin-S-yl)phenyl)—6-methyl(1-methyl- 1H-pyraz01—5—yl)—2—0xo—2H— [1,3'-bipyridine]carb0xamide This compound was prepared following a synthetic sequence analogous to that for example 133, using 1-methyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2—yl)-1H- le instead of 1-methyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2—yl)— 1H- pyrazole. This compound was purified via pH 2 preparative LC/MS (MeCN/water with TFA) to give the product as TFA salt. LCMS calcd for C37H39N1003 (M+H)+: m/z = 6713. Found: 671.4.
Example 135. N—(4-(4-Amino(1-isobutyrylpiperidin-4—yl)pyrrolo[2,1- f] [1,2,4] n-S-yl)phenyl)—6-methyl(1-methyl- 1H-pyrazol-3—yl)-2—0x0—2H- [1,3'-bipyridine]carboxamide This compound was prepared ing a synthetic sequence analogous to that for example 133, using l-methyl(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2—yl)-1H- pyrazole instead of 1-methyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolan—2—yl)—1H- pyrazole. This compound was purified Via pH 2 preparative LC/MS (MeCN/water with TFA) to give the product as TFA salt. LCMS calcd for C37H39N1003 (M+H)+: m/z = 6?].3. Found: 671.4.
Example 136. N-(4-(4-Amino(1-isobutyrylpiperidinyl)pyrrolo[2,1- f] ]triazin-S-yl)phenyl)—5-bromo(methoxymethyl)—2-0x0phenyl-1,2— dihydr0pyridine—3-carboxamide N\ Br 0 / Step 1: Ethyl 5-br0m0-6—(br0m0methyl)-2—0x0phenyZ-1,2-dz'hydr0pyrz‘dine carboxylate To a mixture of ethyl 5-bromomethyloxophenyl-1,2—dihydropyridine- 3-carboxylate (310 mg, 0.92 mmol) (from Affinity Research Chemicals) and NBS (197 mg, 1.11 mmol) in carbon hloride (6.0 mL)/chloroform (2.5 mL) was added 2,2'—Azo-bis-isobutyronitrile (15.1 mg, 0.092 mmol). The resulting mixture was stirred at reflux for 6 h, cooled to rt, and concentrated. The resulting material was purified via column chromatography (20% to 70% EtOAc in hexanes) to give the product as a yellow solid (234 mg, 61%). LCMS calcd for Br2NO3 (M+H)+: m/z = 4139. Found: 414.0.
Step 2: 5-Br0m0-6—(meth0xymethyl)0x0phenyl-1, 2-dz'hydr0pyrl'dme carboxylic acid A mixture of ethyl 5-bromo(bromomethyl)oxophenyl-1,2- dihydropyridinecarboxylate (100 mg, 0.24 mmol) and LiOH drate (50.5 mg, 1.21 mmol) in MeOH (4 mL) and water (0.7 mL) was stirred at It for 1 h, and MeOH was evaporated. To the residue was added water and the resulting mixture was made slightly acidic by addition of 1 N HCl, which caused a solid to form. The solids were collected by filtration, washed with water, and dried to give the t as a yellow solid (79 mg, 97%). LCMS calcd for C14H13BrNO4 (M+H)+: m/z = 3380.
Found: 338.0.
Step 3: [err-Bury] 4-(4-amin0(4-(5-br0m0-6—(meth0xymethyl)0x0phenyZ-],2- dihydropyridine-S-carb0xamid0)phenyl)pyrrolo[1,2-f][1, 2, 4]triazz‘n- 7-y0pzperidine- 1 -carb0xylaz‘e W0 2017/‘172596 N \ Br 0 / kw\ / To a solution of tert—butyl 4-(4-amino(4-aminophenyl)pyrrolo[2,1- f][1,2,4]triazinyl)piperidinecarboxylate (95.0 mg, 0.23 mmol) (Example 107, step 4), 5-bromo(methoxymethy1)oxopheny1-1,2-dihydropyridine—3- ylic acid (79 mg, 0.23 mmol), and Et3N (0.049 mL, 0.349 mmol) in DMF (1.2 mL) was added HATU (106 mg, 0.28 mmol). The resulting mixture was stirred at rt for 2 h, added water, and stirred for another 10 min. The resulting solid was collected by filtration, washed with water, and dried to give the product as a light yellow solid (156 mg, 92%). LCMS calcd for C36H39BI‘N705 (M+H)+: m/z = 7282. Found: 728.4.
Step 4: 4-Amin0(piperidinyl)pyrr0[0[2,1-fl[1,2,4jfiiazin—5—y0phenyD br0m0—6—(mezh0xymethyl)-2—0x0phenyl-1,2-dihydr0pyridinecarb0xamide dihydrochloride Q l o N \ Br 0 / NH2 HCI K ,N / To a solution of tert—butyl 4-(4-amino(4-(5-bromo(methoxymethyl) oxo-l-phenyl-l,2-dihydropyridinecarboxamido)pheny1)pyrrolo[2,1-f][1,2,4]triazin- W0 2017!]72596 7-yl)piperidine-1—carboxylate (54 mg, 0.074 mmol) in CH2C12 (400 uL) was added 4 N HCl in oxane (148 uL, 0.59 mmol). The resulting mixture was stirred at It for 2 h, concentrated, and dried to give the product, which was used ly in the next step (50 mg, 96%). LCMS calcd for C31H31BrN7O3 (M+H)+: m/z = 628.2. Found: 6283.
Step 5: N—(4—(4-Aml'n0-7—(1-is0buWrylpzperidiny0pyrr0[0[2,1fl[1,2,4]triazin yUphenyl)—5—br0m0-6—(meth0xymez‘hyl)0x0phenyl-1, 2-dihydr0pyridine—3— carboxamide To a mixture ofN-(4-(4-amino(piperidinyl)pyrrolo[2,l-f] ]triazin yl)phenyl)bromo(methoxymethyl)—2-oxophenyl-1,2-dihydropyridine carboxamide dihydrochloride (20.0 mg, 0.029 mmol) and Et3N (0.020 mL, 014 mmol) in CH2C12 (0.40 mL) was added isobutyryl chloride (3.1 uL, 0.030 mmol). The resulting mixture was stirred at It overnight, concentrated, and purified via pH 2 preparative LC/MS (MeCN/water with TFA) to give the product as TFA salt. LCMS calcd for BrN7O4 (M+H)+: m/z = 698.2. Found: 698.2. 1H NMR (500 MHz, DMSO) 5 11.82 (s, 1H), 8.58 (s, 1H), 8.03 (s, 1H), 7.80 (d, J= 8.7 Hz, 2H), 7.63 — 7.53 (m, 3H), 7.45 (d, J= 8.6 Hz, 2H), 7.40 (d, J= 6.8 Hz, 2H), 6.69 (s, 1H), 4.53 (d, J=12.7 Hz, 1H), 4.14 (s, 2H), 4.05 (d, J: 13.8 Hz, 1H), 3.40 (t, J=11.8 Hz, 1H), 3.18 (d, J=12.9 Hz,1H), 2.99 (s, 3H), 2.94 — 2.81 (m,1H), 2.68 (t,J= 12.7 Hz, 1H), 2.10 — 1.95 (m, 2H), 1.56 (dd, J: 60.6, 9.7 Hz, 2H), 1.01 (d, J: 6.6 Hz, 6H).
Example 137. N—(4-(4-Amino(1-is0butyrylpiperidin-4—yl)pyrrolo[2,1- ]] [1,2,4]triazin-S-yl)phenyl)—5-cyano(ethoxymethyl)—2-0xo- 1-phenyl— 1,2- dihydropyridine—3-carb0xamide W0 2017/‘172596 2017/024270 N\ CN 0 / '\\,N/ Step 1: 0-6—(ez‘h0xymethyl)0x0phenyl-1,2-dz'hydr0pyrz'dz'necarb0xylz'c A mixture of ethyl 5-bromo(bromomethy1)oxophenyl-1,2- dihydropyridinecarboxylate (40 mg, 0.10 mmol) (Example 136, step 1) and LiOH monohydrate (22 mg, 0.52 mrnol) in EtOH (1.2 mL) and water (0.2 mL) was stirred at rt for 2 h, and EtOH was evaporated. To the residue was added water and the resulting mixture was made slightly acidic by addition of 1 N HCl, which caused a solid to form. The solid was collected by filtration, washed with water, and dried to give the product as a yellow solid (25 mg, 69%). LCMS calcd for C15H15BrNO4 (M+H)+: rn/z = 352.0. Found: 352.0.
Step 2: N-(4-(4-Amz'n0(1-l's0buWrylpzperidiny0pyrr0[0[2,1-f][1,2,4]triazin yUphenyl)br0m0-6—(eth0xymethyl)0x0phenyl—1,2-dihydr0pyridine—3- carboxamide W0 2017!]72596 N\ Br 0 / To a mixture of 1-(4-(4-amino(4-aminophenyl)pyrrolo[2,l-f][1,2,4]triazin- 7-yl)piperidinyl)methylpropanone (26 mg, 0.069 mmol) (Example 83, step 2) and o(ethoxymethyl)oxophenyl-1,2-dihydropyridinecarboxylic acid (24 mg, 0.069 mmol) in DMF (0.40 mL) was added Et3N (0.014 mL, 010 mmol), followed by HATU (31 mg, 0.082 mmol). The resulting mixture was stirred at rt for 90 min, added water, and stirred for r 10 min. The resulting solid was collected by filtration, washed with water, and dried to give the product as a light yellow solid (47 mg, 96%). LCMS calcd for C36H39BrN7O4 (M+H)+: m/z = 7122. 1O Found: 7122.
Step 3: N—(4—(4-Aml'n0(1-l's0buWrylpzperidiny0pyrr0[0[2,1fl[1,2,4]triazin yUphenyl)—5—cyan0-6—(eth0xymethyl)-2—0x0phenyl-1,2-dihydr0pyridine—3— carboxamide A e ofN—(4-(4-amino(1 -isobutyrylpiperidinyl)pyrrolo[2,l— f] ]triazinyl)phenyl)bromo(ethoxymethyl)oxophenyl-1,2- dihydropyridinecarboxamide (18.0 mg, 0.025 mmol), Pd(OAc)2 (0.23 mg, 1.0 umol), XantPhos (1.2 mg, 2.02 umol), Zinc cyanide (3.0 mg, 0.025 mmol) and TMEDA (1.1 11L, 7.6 umol) in DMF (0.50 mL) was degassed with N2, and then heated and stirred at 160 °C for 10 min under microwave conditions. The reaction mixture was cooled to rt, filtered, and purified via pH 2 preparative LC/MS (MeCN/water with TFA) to give the product as TFA salt. LCMS calcd for C37H39N804 (M+H)+: m/z = 659.3. Found: 659.3. 1H NMR (500 MHz, DMSO) 8 11.40 (s, 1H), 8.65 (s, 1H), 8,01 (s, 1H), 7.81 (d, J: 8.6 Hz, 2H), 7.68 — 152 (m, 3H), 7.50 — 3.38 (m, 4H), 6.67 (s, 1H), 4.51 (s, 1H), 4.22 (s, 2H), 4.04 (s, 1H), 3.40 (t, J: 11.7 Hz, 1H), 3.31 — 3.12 (m, 3H), 2.95 — 2.82 (m, 1H), 2.65 (d, J: 26.? Hz, 1H), 2.12 —1.94(m,2H), 1.76 — 1.38 (m,2H), 1.13 — 0.88 (m, 9H).
Example 138. N-(4-(4-Amino(1-is0butyrylpiperidinyl)pyrr0l0[2,1- ]] [1,2,4] triazin-S-yl)phenyl)—3-(1,4-dimethyl-1H-pyrazol-3—yl)— 1-isopr0pyl-2,4- dioxo—1,2,3,4-tetrahydr0pyrimidine-S-carboxamide This compound was prepared following a synthetic sequence analogous to that for example 87, using l,4-dimethyl-lH-pyrazolamine d of l-methyl-lH- pyrazol-4—amine. This compound was purified via pH 2 preparative LC/MS (MeCN/water with TFA) to give the product as TFA salt. LCMS calcd for C34H41N1004 (M+H)+: m/Z = 653.3. Found: 653.5.
Example 139. N-(4-(4-Amino(1-isobutyrylpiperidinyl)pyrrolo[2,1- ]] [1,2,4] triazin-S-yl)phenyl)— l-cyclopr0pyl-2,4-dioxophenyl- 1,2,3,4- tetrahydropyrimidine-S-carboxamide o=( ;\\>\(0 C} HN H2N \NJ/ Step]: l 2-((cyclopropylamin0)methylene)malonate X To a solution of diethyl oxymethylene)malonate (2.16 g, 10.0 mmol) in MeCN (20 mL) was added cyclopropylamine (0.70 mL, 101 mmol). The reaction mixture was stirred at rt overnight, then at 80 °C for l h, cooled to rt, and W0 2017!]72596 trated to give the crude product, which was used directly in the next step.
LCMS calcd for C11H13NO4 (M+H)+: m/z = 228.1. Found: 228.1.
Step 2: Ethyl 1-cyclopr0pyl-2, x0-3—phenyl—1, 2, 3, 4—z‘etrahydr0pyrimMine—5- carboxylate 2011(in A mixture of diethyl 2-((cyclopropylamino)methylene)malonate (0.45 g, 2.00 mmol) and isocyanatobenzene (0.476 g, 4.00 mmol) in pyridine (0.97 mL) was heated and stirred at 170 °C for 3 h, cooled to It, and purified Via column chromatography 1O (0% to 10% MeOH in CH2C12) to give the product (0.336 g, 56%). LCMS calcd for C16H17N204 (M+H)+: m/z = 301.1. Found: 301.2.
Step 3: 1-Cycl0pr0pyl-2, 4-dz'0x0phenyl-1, 2, 3, 4-tetrahydr0pyrz‘midmecarb0xylz'c A A mixture of ethyl 1-cyclopropyl-2,4-dioxophenyl-1,2,3,4- tetrahydropyrimidinecarboxylate (0.336 g, 1.12 mmol) in 4.0 M HCl in 1,4— dioxane (2.24 mL, 8.95 mmol) and water (0.56 mL) was stirred at 80 °C for 3 h, cooled to rt, and concentrated to afford the crude product, which was used directly in the next step. LCMS calcd for C14H13N204 (M+H)+: m/z = 273.1. Found: 273.1.
Step 4: N-(4-(4-Amz'n0(1-l's0buWrylpiperidiny0pyrr0[0[2,1-fi[1,2,4]triazin yU-I-cyclopr0pyl-2, 4-a’z'0x0phenyl-1, 2, 3, 4-z‘etrahydropyrimicfine-i carboxamide To a e of 1—cyclopropyl-2,4-dioxophenyl-1,2,3,4- tetrahydropyrimidinecarboxy1ic acid (0.014 g, 0.050 mmol) and HATU (0.021 g, 0.055 mmol) in DMF (1 mL) was added 1-(4-(4-amino(4- aminophenyl)pyrrolo[2,1-f] [1,2,4]triazinyl)piperidin-l-yl)methylpropan-l-one (0.019 g, 0.050 mmol) (Example 83, step 2) and Et3N (0021 mL, 0.150 mmol). The reaction mixture was d at rt for 2 h, diluted with MeOH, adjusted with TFA to pH 2, and purified via pH 2 preparative LC/MS (MeCN/water with TFA) to give the product as TFA salt. LCMS calcd for C35H37NsO4 (M+H)+: m/z = 633.3. Found: 633.3.
Example 140. N—(4-(4-Amin0-7—(1-isobutyrylpiperidinyl)pyrrolo[2,1- ]] [1,2,4]triazin-S-yl)phenyl)— 1-cyclopropyl-2,4-diox0(pyridinyl)-1,2,3,4- 1O tetrahydropyrimidine—S-carboxamide This compound was prepared following a synthetic sequence analogous to that for example 139, using 3-isocyanatopyridine instead of isocyanatobenzene in step 2.
This compound was purified via pH 2 ative LC/MS (MeCN/water with TFA) to give the product as TFA salt. LCMS calcd for C34H36N904 (M+H)+: m/z = 6343.
Found: 6343. e 141. N—(4-(4-Amin0-7—(1-isobutyrylpiperidinyl)pyrrolo[2,1- ]] [1,2,4]triazin-S-yl)phenyl)—1'-cyclopropyl-2'-methyl-4'-0x0-1',4'-dihydr0—[2,3'- bipyridine]-5'-carb0xamide W0 2017!]72596 Step 1: 3—((Dimethylamin0)methylene)-6—methyl-2H—pyran-2,4(3H)-dz'0ne O 0 To a solution of 6-methyl-2H-pyran-2,4(3H)—dione (11.5 g, 91 mmol) in toluene (30 mL) was added N,N—dimethylformarnide dimethyl acetal (13.1 mL, 98 mmol). The reaction mixture was then stirred overnight, and concentrated to give the crude product, which was used directly in the next step. LCMS calcd for C9H12NO3 (M+H)+: m/z = 182.1. Found: 182.3. 1O Step 2: 1—Cycz’0pr0pylmethyl0x0-1,4-dl'hydr0pyridine-S-carboxyfic acid 0 o A e of 3-((dimethylamino)methylene)—6-methyl-2H-pyran-2,4(3H)— dione (1.92 g, 7.95 mmol), cyclopropanamine (0.83 mL, 11.9 mmol) and sodium tert- butoxide (1.13 g, 11.8 mmol) in EtOH (5.0 mL) was heated and stirred at 90 °C for 18 h, cooled to rt, concentrated, and treated with water and CH2C12. The aqueous solution was acidified with 4 N HCl and extracted with CH2C12. The combined organic layers were washed with water, brine, dried over Na2SO4, and trated to give the desired compound (1.1 g, 42%). LCMS calcd for C10H12N03 (M+H)+: m/z = 194.1.
Found: 1943.
W0 2017!]72596 Step 3: 5-Br0m0cyclopr0pyl-6—methyl0x0-1,4-dl'hydr0pyridz'necarb0xylic HO IIBr A suspension of l-cyclopropylmethyloxo-1,4-dihydropyridine—3— carboxylic acid (0.83 g, 4.30 mmol) in glacial acetic acid (6.0 mL) was treated with Br2 (0.29 mL, 5.58 mmol). The reaction mixture was stirred at It for 4 days, added additional Br2 (100 uL), and stirred overnight. The reaction mixture was diluted with water, and the ing solid was collected by filtration, washed with water, and dried to give the product as a beige solid (1.0 g, 86% yield). LCMS calcd for C10H11BrNO3 1O : m/z = 272.0. Found: 272.2.
Step 4: N-(4—(4-Amz'n0-7—(1-z's0buWrylpiperidiny0pyrr0[0[2,1-f][1,2,4]triazin yUphenyl)br0m0cyclopr0pyl-6—methyl0x0-1,4-dihydr0pyrz‘dme carboxamide OB?/N’4/ A mixture of 1-(4-(4-amino(4-aminophenyl)pyrrolo[2,1-f][1,2,4]triazin yl)piperidin-l-yl)methylpropanone (278 mg, 0.735 mmol) (Example 83, step 2), -bromocyclopropylmethyloxo-1,4-dihydropyridinecarboxylic acid (200 mg, 0.735 mmol), HATU (335 mg, 0.882 mmol) and Et3N (0.21 mL, 1.4? mmol) in DMF (50 mL) was stirred at rt for 2h, and then purified via column chromatography to give the product (252 mg, 54 %). LCMS calcd for BrN7O3 (M+H)+: m/z = 632.2. Found: 632.3.
Step 5: N-(4-(4-Amz'n0-7—(J-z'sobuWrylpz'perz'dz'ny0pyrr0[0[2, , 2, 4jtriazin yUphenyU-J ’-cyclopr0pyl—2 ’-methyl-4 ’-0x0-1 ’, 4 ’-dz'hydr0-[2, 3 ’-bz‘pyridz'ne]-5 ’- carboxamide To a solution -(4-amino(1-isobutyrylpipendinyl)pyrrolo[2,1- f] [1,2,4]triazinyl)phenyl)bromocyclopropylmethyloxo-1,4- dihydropyridinecarboxamide (20.0 mg, 0.032 mmol) and 2- (tributylstannyl)pyridine (11.3 mg, 0.032 mmol) in 1,4-dioxane (2.0 mL) was added Pd(Ph3P)4 (7.3 mg, 6.3 umol). The reaction mixture was heated and stirred at reflux overnight, cooled to rt, and purified via pH 2 preparative LC/MS (MeCN/water with TFA) to give the product as TFA salt. LCMS calcd for N803 (M+H)+: m/z = 631.3. Found: 631.1. 1H NMR (500 MHz, DMSO) 5 13.0-11.8 (n1, 1H); 8.95 (m, 1H), 8.71 (s, 1H); 8.45 (m, 1H), 8.25 (s, 1H), 7.95-7.80 (m, 4H), 7.50 (m, 2H); 6.85 (m, 1H); 4.60 (m, 1H); 4.10 (m, 1H), 3.81 (m, 1H), 3.41 (m, 1H), 3.25 (m, 1H); 2.85 (m, 1H); 2.65 (m, 1H); 2.41 (s, 3H); 2.1-1.9 (m, 2H), 1.7-1.4 (m, 2H); 1.3-1.1 (m, 4H); 1.0 (m, 6H).
Example 142. N-(4-(4-Amino(l-isobutyrylpiperidinyl)pyrrolo[2,1- f][1,2,4]triazin-S-yl)phenyl)cyclopr0pyl-2,2'-dimethyl0x0-1,4-dihydr0-[3,3'- bipyridine]carboxamide To a solution of (2-methylpyridinyl)boronic acid (4.3 mg, 0.032 mmol) and 4-amino(1-isobutyrylpiperidinyl)pyrrolo[1,2-f] [1,2,4]triazin-S-yl)phenyl)- o-l-cyclopropylmethyloxo-1,4-dihydropyridinecarboxamide (20.0 mg, 0.032 mmol) (Example 141, step 4) in 1,4-dioxane (2.0 mL) and water (0.2 mL) were added K2CO3 (26.0 mg, 0.188 mmol) and Pd(Ph3P)4 (10.1 mg, 8.? umol). The reaction mixture was heated at reflux and stirred for 12 h, cooled to rt, and purified Via pH 2 preparative LC/MS (MeCN/water with TFA) to give the product as TFA salt. LCMS calcd for C37H41N803 (M+H)+: m/z = 6453. Found: 645.1.
Example 143. N—(4-(4-Amino(1-is0butyrylpiperidin-4—yl)pyrrolo[1,2- ]] [1,2,4] triazin-S-yl)phenyl)—1-isopropyl-2,4-di0xo-3—(pyrimidin-Z-yl)—1,2,3,4- 1O tetrahydropyrimidine—S-carboxamide NAN44N4 HN017/ K ,N / This compound was prepared following a tic sequence analogous to that for example 87, using pyrimidinamine instead of 1-methyl-1H—pyrazol-4—amine in step 1. This compound was purified Via pH 2 preparative LC/MS (MeCN/water with TFA) to give the product as TFA salt. LCMS calcd for C33H37N1004 : m/z = 637.3. Found: 637.3. 1H NMR (400 MHZ, DMSO) 5 10.68 (s, 1H), 9.08 (d, J: 4.9 Hz, 2H), 8.73 (s, 1H), 8.08 (s, 1H), 7.84 — 7.72 (m, 3H), 7.46 (d, J: 8.6 Hz, 2H), 6.75 (s, 1H), 4.76 (p, J: 6.7 Hz, 1H), 4.59 — 4.49 (m, 1H), 4.12 — 4.01 (m, 1H), 3.49 — 3.34 (m, 1H), 3.27 — 3.14 (m, 1H), 2.90 (p, J: 6.7 Hz, 1H), 2.76 — 2.61 (m, 1H), 2.11 — 1.94 (m, 2H), 1.72 — 1.49 (m, 2H), 1.45 (d, J: 6.8 Hz, 6H), 1.01 (s, 6H).
Example 144. N—(4-(4-Amin0-7—(l-is0butyrylpiperidinyl)pyrrolo[1,2- f] [1,2,4]triazin-S-yl)phenyl)-l-cyclopropyl-2,4-dioxo(pyridin-Z-yl)—1,2,23,4- tetrahydropyrimidine-S-carboxamide W0 72596 This compound was prepared following a synthetic sequence analogous to that for example 139, using 2-isocyanatopyridine instead of natobenzene in step 2.
This compound was purified Via pH 2 preparative LC/MS (MeCN/water with TFA) to give the product as TFA salt. LCMS calcd for C34H36N904 (M+H)+: m/z = 6343.
Found: 6343. 1H NMR (600 MHz, DMSO) 5 10.81 (s, 1H), 8.64 (ddd, J = 4.9, 1.9, 0.8 Hz, 1H), 8.53 (s, 1H), 8.13 — 8.00 (m, 2H), 7.83 — 7.74 (m, 2H), 7.56 (ddd,J= 7.5, 4.9, 1.0 Hz, 1H), 7.52 (dt, J: 8.0, 0.9 Hz, 1H), 7.49 — 7.41 (m, 2H), 6.73 (s, 1H), 4.54 (d, J=12.2 Hz, 1H), 4.07 (d, J= 12.8 Hz, 1H), 3.41 (tt, J= 11.8, 3.6 Hz, 1H), 3.34 — 3.28 (m, 1H), 3.20 (t, J: 12.3 Hz, 1H), 2.90 (p, J: 6.7 Hz, 1H), 2.69 (t, J: 12.0 Hz, 1H), 2.02 (dd, J: 30.8, 12.2 Hz, 2H), 1.67 — 1.47 (m, 2H), 1.1? — 0.84 (m, 10H).
Example 145. N—(4-(4-Amino(1-is0butyrylpiperidin-4—yl)pyrrolo[1,2- f] [1,2,4]triazin-S-yl)phenyl)—3-(5-fluor0pyridin-2—yl)— 1-is0pr0pyl-2,4—dioxo— 1,2,3,4-tetrahydropyrimidine—S-carboxamide This compound was prepared ing a synthetic sequence analogous to that for example 87, using 5-fluoropy1idinamine instead of l-methyl-lH—pyrazol amine in step 1. This compound was purified Via pH 2 preparative LC/MS (MeCN/water with TFA) to give the product as TFA salt. LCMS calcd for C34H37FN9O4 : m/z = 654.3. Found: 6543.
Example 146. N-(4-(4-Amino(1-isobutyrylpiperidinyl)pyrrolo[1,2- ]] [1,2,4] triazin-S-yl)phenyl)isopropyloxo-S-(pyridin-Z-yl)- 1,4- dihydr0pyridine—3-carboxamide Step 1: N-(4-(4-Amino(1-z's0buWryQJiperidiny0pyrr0[0[1,2-fl[1,2,4]triazin yUphenyl)br0m0-] -isopr0pyl0x0-1, 4-dz'hydr0pyridine-S-carboxamide o / K ,N / To a e of 1-(4-(4-amino(4-aminophenyl)pyrrolo[2,l-f][1,2,4]triazin- 7-yl)piperidinyl)methylpropanone (200 mg, 0.53 mmol) (example 83, step 2) and 5-bromoisopropyloxo-1,4-dihydropyridinecarboxylic acid (137 mg, 0.53 mmol) (example 128, step 2) in DMF (4.0 mL) was added Et3N (0.11 mL, 079 mmol), followed by HATU (241 mg, 0.63 mmol). The resulting mixture was stirred at rt for 3 h, added water, and d for another 15 min. The resulting solid was collected by filtration, washed with water, and dried to give the product. LCMS calcd for C30H35BrN703 : m/z = 620.2. Found: 620.2.
Step 2: N—(4—(4-Am1720(1-z'sobuWryépz‘perz‘dz‘nyl)pyrr0[0[1, Z-flfl, 2, 4]triazin yUphenyU—I—isopr0pyl0x0-5—(pyridin-Z—yl)-1, 4-dihydr0pyridine-3—carb0xamide To a mixture of N—(4-(4-amino(1-isobutyrylpiperidinyl)pyrrolo[2,l- f] [1,2,4]triazinyl)phenyl)bromoisopropyloxo-1,4-dihydropyridine—3- carboxarnide (40.0 mg, 0.064 mmol), Pd(PPh3)4 (14.9 mg, 0.013 mmol) in toluene (1.2 mL) was added butylstannyl)pyridine (0.042 mL, 0.129 mmol). The mixture was purged with N2, and heated and stirred at 120 °C overnight. The reaction mixture was then cooled to rt, diluted with MeOH, filtered and purified via pH 2 preparative LC/MS water with TFA) to give the product as TFA salt. LCMS calcd for C35H39NsO3 (M+H)+: m/z = 619.3. Found: 619.3.
Example 147. N—(4-(4-Amino(1-isobutyr'ylpiperidin-4—yl)pyrrolo[1,2- f] [1,2,4] triazin-S-yl)phenyl)— l-cyclopropylmethyloxo-S-(pyridin-3—yl)— 1,4- dihydropyridine—3-carboxamide A mixture ofN-(4-(4-amino(1-isobutyrylpiperidinyl)pyrrolo[2,1- f] [1,2,4]triazinyl)phenyl)bromocyclopropylmethyloxo-1,4- dihydropyridinecarboxamide (12.0 mg, 0.019 mmol) le 141 step 4), pyridinylboronic acid (2.8 mg, 0.023 mmol), Chloro(2-dicyclohexylphosphino- 2',4',6'-tri-i-propyl-1,1'-biphenyl)(2'-amino-1,1'-biphenylyl) palladium(II) (Xphos Pd G2) (1.5 mg, 1.90 umol), and potassium phosphate ic (8.9 mg, 0.042 mmol) in 1,4-dioxane (0.50 mL) and water (0.10 mL) were degassed with N2, and then heated and stirred at 80 °C for 2 h. The reaction mixture was then cooled to rt, diluted with MeOH, d, and purified Via pH 2 preparative LC/MS (MeCN/water with TFA) to give the product as TFA salt. LCMS calcd for C36H39N803 (M+H)+: m/z = 6313. Found: 6313.
Example 148. N—(4-(4-Amino(1-is0butyrylpiperidin-4—yl)pyrrolo[1,2- f] [1,2,4]triazin-S-yl)phenyl)—3-(1,5-dimethyl-1H-pyrazolyl)- 1-isopropyl—2,4- dioxo—1,2,3,4-tetrahydr0pyrimidine-S-carboxamide This compound was prepared following a synthetic sequence analogous to that for example 87, using l,5-dimethyl-lH-pyrazolamine instead of l-methyl-lH- pyrazol-4—amine in step 1. This compound was purified via pH 2 preparative LC/MS (MeCN/water with TFA) to give the product as TFA salt. LCMS calcd for C34H41N1004 (M+H)+: m/z = 6533. Found: 6533. e 149. N—(4-(4—Amino(1-isobutyrylpiperidinyl)pyrrolo[1,2- ]] [1,2,4] triazin-S-yl)phenyl)isopr0pyl(6-methylpyridinyl)-2,4-dioxo- 4-tetrahydropyrimidine-S-carboxamide This compound was prepared following a synthetic sequence analogous to that for example 87, using 6-methylpyridinamine instead of yl-lH-pyrazol amine in step 1. This compound was purified via pH 2 preparative LC/MS W0 2017!]72596 (MeCN/water with TFA) to give the product as TFA salt. LCMS calcd for C35H40N9O4 (M+H)+: m/z = 6503. Found: 650.3.
Example A Axl Autophosphorylation Assay Autophosphorylation of AXl was carried out by incubating the recombinant Axl protein (Life Technologies, PV4275) in buffer containing 50 mM Tris, pH7.5, 0.2 mg/ml Axl, 5 mM ATP, 20 mM MgC12 and 2 mM DTT at room temperature for 1 TAM tic Assay The kinase assay buffer contained 50 mM HEPES, pH7.5, 10 mM MgC12, 1 mM EGTA, 0.01% NP-40 and 2 mM DTT. 0.1 ul test nds dissolved in DMSO were transferred from compound plates to white 384-well assay plates (Greiner LUMITRAC plates). The final concentration of DMSO was 1.25%. Enzyme solutions of 5.1 nM phosphor—Axl, or 0.0625 nM c-Mer (Carna Biosciences, 08-108), or 0.366 nM Tyro3 (Life Technologies, PR7480A) were prepared in assay buffer. A 1 mM stock solution of peptide substrate Biotin-EQEDEPEGDYFEWLE-amide SEQ ID NO: 1 (Quality Controlled Biochemicals, MA) dissolved in DMSO was diluted to 1 uM in assay buffer containing 2000 uM ATP. 4 ul enzyme solution (or assay buffer for the enzyme blank) was added to the appropriate wells in each plate, and then 4 l substrate on was added to initiate the reaction. The plate was protected from light and incubated at room temperature for 60 min. The on was stopped by adding 4 ul detection solution containing 50 mM Tris-HCl, pH7 .8, 150 mM NaCl, 0.05%BSA, 45 mM EDTA, 180 nM SA-APC n Elmer, CR130-100) and 3 nM Eu—W1024 anti-phosphotyrosine PY20 (Perkin Elmer, AD0067). The plate was incubated for 1h at room temperature, and HTRF (homogenous time resolved fluorescence) signal was measured on a tar FS plate reader (BMG labtech).
Percentage of inhibition was calculated for each concentration and IC50 value was generated from curve fitting with GraphPad Prism software The nds ed herein were found to be inhibitors ofTAM according to the TAM Enzymatic Assay. All the compounds as described herein have been tested. The compounds shown in Table 1 below exhibit an IC50 of less than 1 uM t at least one kinase selected from Tyro3, Axl and Mer.
The compounds provided herein were found to be inhibitors of one or more of AXL, MER, and TYRO3. IC50 data is ed below in Table 1. The symbol "T" indicates an IC50 of S 5 nM, "TT" indicates an IC50 of > 5 nM but S 10 nM. "TTT" indicates an IC50 of > 10 nM but S 100 nM; "TTTT" indicates an IC50 of greater than 100 nM; and na indicates not available.
Table 1 Axl Mer Tyro3 IC50 IC50 IC50 Exam nle (nM) (nM) (nM) TTTT TTTT TTTT 7 (cis isomer) TT T TTTT 7 (trans isomer) 23 T T TTT Axl Mer Tyro3 ICso IC50 ICso Exam le (nM) (11M) (11M) 38 T TTT 39 T W" 40 H 4+«X‘«+«x« TTTT 64 +ax< TTT 65 +ax< TTT AK] Mer Tyro3 ICso ICso ICso Exam nle (11M) (11M) (RM) 81 111 82 +ax BAF3, BAF3-AXL, BAF3-MER or BAF3-TYRO3 cells lines were maintained in RPM11640 with 10% FBS (Gibco/Life Technologies, Carlsbad, CA).
To measure the effect of test compounds on cell viability, 1000 cells/well were plated into 384 well tissue culture plates in growth medium with a serial dilution of 1O compound or DMSO alone for 48 hours at 37°C with 5% C02, cell viability was measured by ATP assay (CellTiter-Glo Assay, Promega) according to the manufacturer's procedure. The data were converted to percent inhibition relative to DMSO control and ICso curves were fitted using GraphPad Prism software.
Example C. BaF3—AXL ELISA and BaF3—MER ELISA BaF3-AXL or BaF3-MER cells were maintained in culture medium RPMI with 10% FBS and puromycin (1 ug/ml, Gibco/Life Technologies, Carlsbad, CA). To measure the effect of test compounds on or-AXL or phosphor-MER, the cells were plated (5x104 cells/well) in a om polypropylene plate (Greiner e) in the presence or absence of test compounds diluted in culture medium, and incubated for 1 hour at 37 °C with 5% C02. The cells were harvested by fugation, and lysed in 110 pl of ice cold lysis buffer (Cell Signaling) with protease and phosphatase inhibitors (Halts PI, Thermo ) for 30 min on ice. The cell lysate was stored at - 80 0C for ELISA. ELISA plates were prepared by incubating Costar plate with anti- HA antibody (1 ug/ml) for 1 hour at room temperature. The plates were washed and blocked with PBS with 3% BSA. Cell lysate were loaded onto ELISA plate and incubated at 4 °C overnight. The plates were washed and ted with LANCE Eu- W1024 anti-phospho-tyrosine dy (PY-20) (Perkin Elmer) in DELFIA assay buffer (Perkin Elmer) for 1 hour, and read on the Pherastar (BMG Labtech). The data was converted to percent inhibition relative to DMSO control and ICso determination was performed by fitting the curve of t inhibition versus the log of the inhibitor concentration using GraphPad Prism.
W0 2017!]72596 Example D. H1299 Phospho-AXL ELISA H1299 cells (ATCC), human non-small cell lung carcinoma cell line with Axl expression, are maintained in culture medium RPMI with 10% FBS (Gibco/Life Technologies, Carlsbad, CA). To measure the effect of test compounds on phosphor- AXL, the cells were plated (30000 cells/well) in 96 well tissue culture plates (Costar) and incubated overnight at 37 0C with 5% C02. nds at an appropriate concentration were added and incubated for 1 hour at 37°C with 5% CO2. rhGas6 (R&D s, 6 ug/ml) were added to each well. Plates were incubated at 37 °C 1O with 5% CO2 for 15 min. Cells were harvested and lysed in 110 uL of ice cold lysis buffer (Cell Signaling) with protease and phosphatase inhibitors (Halts PI, Thermo ). The lysate was ted for 1 hour on ice and stored at -80 0C for ELISA.
ELISA plates were prepared by incubating Costar plate with anti-HA antibody (1 ug/ml) for 1 hour at room temperature. The plates were washed and blocked with PBS with 3% BSA. Cell lysate was loaded onto ELISA plates and ted at 4°C overnight. The plates were washed and incubated with LANCE Eu—W1024 anti- phospho-tyrosine antibody (PY-ZO) (Perkin Elmer) in DELFIA assay buffer (Perkin Elmer) for 1 hour, and read on the Pherastar (BMG Labtech). The data was converted to percent inhibition relative to DMSO control and ICso determination was performed by fitting the curve of percent inhibition versus the log of the inhibitor concentration using GraphPad Prism.
Example E. Whole Blood H1299 Phospho-AXL ELISA H1299 Cells (ATCC) are maintained in culture medium RPMI with 10% FBS (Gibco/Life Technologies, Carlsbad, CA). To e the effect of test compounds on phospho—AXL in whole blood, the cells are plated (30000 cells/well) in 96 well tissue e plates (Costar) and incubated overnight at 37 0C with 5% CO2. Blood obtained from normal donors was mixed test compounds for 1 hour. Culture medium was removed from H1299 cells, and blood with compound was added to each well.
After 1 hour incubation at 37 °C with 5% C02, rh-Gas6 (4 ug/ml, R&D Systems) was added to each well. The plate was incubated at 37 °C with 5% CO2 for 15 min. The cells were washed with PBS, and lysed in 110 uL of ice cold lysis buffer (Cell W0 2017!]72596 Signaling) with se and phosphatase inhibitors (Halts PI, Thermo Fisher) for 1 hour on ice. The plate was stored at -80 0C for ELISA‘ ELISA plates were prepared by incubating Costar plate with anti -HA antibody (lug/ml) for 1 hour at room temperature. The plates were washed and d with PBS with 3% BSA. Cell lysate were loaded onto ELISA plate and incubated at 4°C overnight. The plates were washed and incubated with LANCE 24 anti-phospho-tyrosine antibody (PY- ) (Perkin Elmer) in DELFIA assay buffer (Perkin Elmer) for 1 hour, and read on the Pherastar (BMG Labtech). The data was converted to percent tion relative to DMSO control and ICso determination was performed by fitting the curve of percent 1O inhibition versus the log of the inhibitor concentration using GraphPad Prism.
Example F. G361 o-Akt Cell Insight ELISA G361 cells , human malignant melanoma cell line expressing Mer, are ined in culture medium RPMI with 10% FBS (Gibco/Life logies, Carlsbad, CA). To measure the effect of test compounds on MER signaling pathway, the cells were plated at 2 x 104 cells/well in IOOuL volume in 96 well CellBind surface plates (Coming), and incubated overnight at 37 °C with 5% C02. 20 uL of test compounds at appropriate concentrations were added to the cells and incubated for 1 hour. rhGas6 (4 ug/ml, R&D s) was added to each well, and incubated for 20 min. The cells were fixed by adding 50 uL 4% rmaldehyde (Electron Microscopy Sciences) in PBS (Coming) for 30 min at room temperature. Plates were washed and incubated with 50 uL 0.2% triton X-IOO (Sigma) in PBS for 10 minutes at room temperature. Plates were washed and incubated with 100 uL blocking buffer (0.1% BSA in PBS) for 30 min. Plates are washed and incubated with Phospho-AKT (Ser473) (D9E) rabbit mAb (Cell Signaling) diluted in 0.1% BSA (1:300 dilution) at 4°C overnight. Plates were washed and incubated with 50 uL Alexaflour 488 F(ab')2 fragment of goat anti-rabbit IgG (H+L) (Molecular Probes, 1:1000 dilution) and Hoechst 33342 (Thermo Fisher, 1:2000 dilution) in PBS at room temperature for 2 hours. Plates were washed with PBS, and read on Cell Insight CX5 (Thermo Fisher).
Various modifications of the invention, in addition to those described herein, will be apparent to those skilled in the art from the foregoing description. Such W0 2017/‘172596 PCT/U82017/024270 modifications are also intended to fall within the scope of the appended claims. Each reference, including all patent, patent applications, and publications, cited in the present ation is incorporated herein by reference in its entirety.
W0 72596

Claims (7)

WHAT IS CLAIMED IS:
1. A compound of Formula I: / CyB NH2 Cyc \n/ N / / J\\ R2 ,N / R3 N or a pharmaceutically acceptable salt thereof, wherein: R1 is Al-AZ-A3-RA, R2 is H, halo, CN, C1-4 alkyl, Ci-4 haloalkyl, C1-4 alkoxy, Ci-4 haloalkoxy, cyano-C1-3 alkyl or C1-6 alkoxyalkyl, R3 is H, halo, CN, C1-6 alkyl, C1-6 haloalkyl, 0R3, SRa, C(O)NRCRd, NRCRd, NRCC(O)R", NRCS(O)2Rb or S(O)2Rb, wherein said C1-6 alkyl and C1-6 haloalkyl are optionally substituted with 1, 2 or 3 tuents independently selected from halo, CN, 0R3, SR3, C(O)NRCRd, NRCRd, )R", NRCS(O)2Rb, S(O)2Rb, NR°C(O)OR3, NRCC(O)NRCR‘1,NRCS(O)2NRCRd and CyR3; Al is selected from a bond, CyAl, —Y—, —C1.3 ne—, —C1-3 alkylene—Y—, — Y—C1—3 alkylene—, and —C1-2 alkylene—Y—Ci—z alkylene—; wherein said ne groups are each optionally substituted with l, 2, or 3 substituents independently selected from halo, CN, OH, C1-3 alkyl, C1-3 alkoxy, C1-3 haloalkyl, C1-3 haloalkoxy, amino, C1—3 alkylamino, and dI(C1-3 alkyl)amino, A2 is selected from a bond, CyAz, —Y—, —C1-3 alkylene—, —Ci-3 alkylene—Y—, — Y—Ci.3 a1kylene—, and —Ci-2 alkylene—Y—Ci.2 alkylene—, n said alkylene groups are each optionally substituted with l, 2, or 3 substituents independently selected from halo, CN, OH, C13 alkyl, C1-3 alkoxy, C1-3 haloalkyl, C1-3 haloalkoxy, amino, C1—3 alkylamino, and dI(C1-3 alkyl)amino, A3 is ed from a bond, CyA3, —Y—, —C1-3 alkylene—, —Ci-3 alkylene—Y—, — Y—Ci-3 alkylene—, and —Ci-2 alkylene—Y—Ci.2 alkylene—, wherein said alkylene groups are each optionally tuted with l, 2, or 3 tuents independently selected from halo, CN, OH, C1-3 alkyl, C1-3 alkoxy, C1-3 haloalkyl, C1-3 haloalkoxy, amino, C1-3 alkylamino, and di(C1-3 alky1)amino; W0 2017!]72596 RA is H, C1-6 alkyl, C1-6 haloalkyl, halo, C3-6 cycloalkyl, CN, N02, OR‘“, SR“, C(O)Rb1, C(O)NR“R‘“, C(O)OR31, OC(O)Rb1, OC(O)NRC1R‘“,NRC1R‘“, NRCIOR‘“, NRC1C(O)R'°1, NRCIC(O)OR‘“, NRC1C(O)NRCIR‘“, C(=NRel)Rb1, C(=NRel)NR°1Rd1, NR°1C(=NR61)NR°1R‘“, NR°1S(O)Rb1, NR°1S(O)2Rb1, NRdS(O)2NR°1R‘”, S(O)Rb1, S(O)NRC1R‘“, S(O)2Rb1, or S(O)2NRCle1, wherein said C1-6 alkyl or C1-6 haloalkyl is optionally substituted with 1, 2, 3 or 4 substituents ndently selected from R“; Y is O, S, S(O), S(O)2, C(O), f, NRfC(O), NRfC(O)NRf, NRfS(O)2NRf, S(O)2NRf, NRfS(O)2, or NRf, each Rf is independently ed from H and C13 alkyl, CyAl is C3.7 cycloalkyl, phenyl, 5-6 membered heteroaryl, or 4-7 membered heterocycloalkyl; wherein each 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl has at least one ring-forming carbon atom and 1, 2, 3, or 4 ringforming heteroatoms independently selected from N, O, and S; wherein the N and S are optionally oxidized; wherein a ring-forming carbon atom of C34 cycloalkyl and 4- 7 membered heterocycloalkyl is optionally substituted by oxo to form a carbonyl group; and wherein the C34 cycloalkyl, phenyl, 5-6 membered heteroaryl, and 4—7 membered heterocycloalkyl are each optionally substituted with 1, 2, 3 or 4 substituents ndently selected from R“; each RAl is independently selected from OH, N02, CN, halo, C1-6 alkyl, C1-6 kyl, Cl-6 alkoxy, C1-6 haloalkoxy, cyano-C1—3 alkyl, HO-C1—3 alkyl, H2N-C1—3 alkyl, amino, C1-6 alkylamino, 6 a1ky1)amino, thio, C1-6 alkylthio, Cl—6 alkylsulfinyl, C1-6 alkylsulfonyl, carbamyl, C1-6 arbamyl, di(C1-6 alkyl)carbamy1, carboxy, Cl-6 alkylcarbonyl, C1-6 alkoxycarbonyl, C1-6 alkylcarbonylamino, Cl-6 alkylsulfonylamino, aminosulfonyl, C1-6 alkylaminosulfonyl, G a1ky1)aminosulfony1, aminosulfonylamino, C1-6 alkylaminosulfonylamino, G alky1)aminosulfony1amino, aminocarbonylarnino, C1-6 alkylaminocarbonylamino, and di(C1-6 aminocarbony1amino, CyA2 is C3.7 cycloalkyl, phenyl, 5-6 membered heteroaryl, or 4-? membered heterocycloalkyl; wherein each 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl 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 CM cycloalkyl and 4- W0 2017!]72596 7 membered cycloalkyl is optionally substituted by oxo to form a carbonyl group; and wherein the C34 cycloalkyl, phenyl, 5-6 membered heteroaryl, and 4-7 membered cycloalkyl are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from RM; each RA2 is ndently selected from OH, N02, CN, halo, C1-6 alkyl, C1-6 haloalkyl, Cl-6 alkoxy, C1-6 haloalkoxy, cyano-C1—3 alkyl, HO-C1—3 alkyl, H2N-C1—3 alkyl, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, thio, C1-6 alkylthio, C1—6 alkylsulfinyl, C1-6 alkylsulfonyl, carbamyl, C1-6 alkylcarbamyl, dl(C1-6 alkyl)carbamyl, carboxy, Cl-6 alkylcarbonyl, C1-6 alkoxycarbonyl, C1-6 alkylcarbonylamino, Cl-6 alkylsulfonylamino, aminosulfonyl, C1-6 alkylaminosulfonyl, di(C1—6 alkyl)aminosulfonyl, aminosulfonylamino, C1-6 alkylaminosulfonylamino, di(Cl-G alkyl)aminosulfonylamino, aminocarbonylamino, C1-6 alkylaminocarbonylamino, and di(C 1-6 aminocarbonylamino, CyA3 is C3.7 cycloalkyl, phenyl, 5-6 membered heteroaryl, or 4-? membered heterocycloalkyl; wherein each 5-6 ed heteroaryl and 4-7 membered heterocycloalkyl 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 ring-forming carbon atom of CM cycloalkyl and 4- 7 membered heterocycloalkyl is optionally substituted by oxo to form a yl group; and n the C34 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 R“, each RA3 is independently selected from OH, N02, CN, halo, C1-6 alkyl, C1-6 kyl, Cm alkoxy, C1-6 haloalkoxy, cyano-C1—3 alkyl, HO-C1—3 alkyl, H2N-C1—3 alkyl, amino, C1-6 alkylamino, di(Cl-G alkyl)amino, thio, C1-6 alkylthio, C1-6 alkylsulfinyl, C1-6 ulfonyl, carbamyl, C1-6 alkylcarbamyl, di(Ci-6 alkyl)carbamyl, carboxy, C143 alkylcarbonyl, C1-6 alkoxycarbonyl, C1-6 alkylcarbonylamino, Cl-G alkylsulfonylamino, aminosulfonyl, C1-6 alkylaminosulfonyl, di(C1—6 alkyl)aminosulfonyl, ulfonylamino, C1-6 alkylaminosulfonylamino, di(Cl-6 alkyl)aminosulfonylamino, arbonylamino, C1-6 alkylaminocarbonylamino, and dl(C1-6 alkyl)aminocarbonylamino; W0 2017!]72596 CyR3 is C3.7 cycloalkyl, phenyl, 5-6 membered heteroaryl, or 4—? membered heterocycloalkyl; wherein each 5-6 membered heteroaryl and 4-7 ed heterocycloalkyl has at least one ring-forming carbon atom and 1, 2, 3, or 4 ringforming heteroatoms independently selected from N, O, and S; wherein the N and S are optionally oxidized; wherein a ring-forming carbon atom of C33 cycloalkyl and 4- 7 membered heterocycloalkyl is optionally substituted by oxo to form a carbonyl group; and wherein the C34 cycloalkyl, phenyl, 5-6 membered aryl, and 4-7 membered heterocycloalkyl are each optionally substituted with 1, 2, 3 or 4 substituents independently ed from Rg, Cyc is phenylene or 5-6 membered heteroarylene, wherein the 5-6 membered heteroarylene has at least one ring-forming carbon atom and 1 or 2 ring-forming heteroatoms independently selected from N, O, and S, and wherein the phenylene and 5-6 membered arylene are each optionally substituted by 1, 2, 3, or 4 substituents independently selected from RC, each RC is independently selected from OH, CN, halo, C14 alkyl, C1—3 haloalkyl, C14 alkoxy, C1-3 haloalkoxy, cyano-C1-3 alkyl, HO-C1-3 alkyl, amino, C1—4 alkylamino, di(C1-4 alkyl)amino, C1.4 ulfinyl, C1.4 ulfonyl, carbamyl, C1-4 alkylcarbamyl, 4 alkyl)carbamyl, carboxy, C1-4 arbonyl, C1-4 alkoxycarbonyl, C1.4 alkylcarbonylamino, C1.4 alkylsulfonylamino, aminosulfonyl, C1— 4 alkylaminosulfonyl, and di(C1-4 alkyl)aminosulfonyl, CyB is C3—10 cycloalkyl or 4-10 membered heterocycloalkyl; wherein at least one ring-forming carbon atom of C3-1o cycloalkyl and 4-10 membered heterocycloalkyl is substituted by oxo to form a carbonyl group, wherein the 4—10 membered heterocycloalkyl 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, and wherein the C310 lkyl and 4-10 membered heterocycloalkyl are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from RB, or CyB is 6-10 ed aryl or 5-10 membered aryl, wherein the 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 oxidized; wherein: (a) at least one ring-forming carbon atom of the 5- 10 membered heteroaryl is substituted by oxo to form a carbonyl group; or (b) the 6— 10 membered aryl or 5—10 membered heteroaryl is substituted by halo, CN, N02, ORaZ, SR”, C(O)Rb2, C(O)NRCZRd2, C(O)OR32, OC(O)Rb2, OC(O)NRC2Rd2, NRCszZ, NRCZORdZ, NR°2C(O)Rb2, NR°2C(O)OR32, NRC2C(O)NR°2Rd2, NRCQS(O)R"2, NRCZS(O)2Rb2, O)2NRCZRd2, S(O)Rb2, S(O)NRC2Rd2, S(O)2Rb2, and S(O)2NRC2Rd2; and n the 6-10 membered aryl or 5-10 membered heteroaryl is further optionally substituted with 1, 2, 3 or 4 substituents independently selected from RB; each RB is independently selected from halo, C1-6 alkyl, C2-6 alkynyl, Cl-6 kyl, C3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, CN, N02, ORaZ, SRaZ, 2, C(O)NRC2Rd2, a2, OC(O)R"2, OC(O)NRC2Rd2, Z, dZ, NRC2C(O)Rb2, NRC2C(O)OR32, NRCZC(O)NRCZRd2, NRCZS(O)Rb2, NRCZS(O)2Rb2, NRCZS(O)2NRC2Rd2, S(O)Rb2, S(O)NRC2Rd2, S(O)2Rb2, and S(O)2NRC2Rd2; wherein said C1-6 alkyl, 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 ed from each R11 is independently selected from CN, N02, OR”, SR”, C(O)Rb3, C(O)NRC3Rd3, C(O)ORa3, OC(O)Rb3, OC(O)NRC3Rd3, 3, NRC3ORd3, NR°3C(O)Rb3, NRC3C(O)ORa3, NRC3C(O)NRC3Rd3, NRC3S(O)Rb3, NRC3S(O)2Rb3, O)2NRC3Rd3, S(O)Rb3, S(O)NRC3Rd3, S(O)2Rb3, and S(O)2NRC3Rd3; each R12 is independently selected from halo, CN, N02, C1-6 alkyl, Cl-6 haloalkyl, C3-6 cycloalkyl, , 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, ORa“, SR“, C(O)Rb4, C(O)NRC4Rd4, C(O)0Ra4, OC(O)Rb4, 0C(0)NRc4Rd4, NRC4Rd4, NRC4ORd4, NRC4C(O)Rb4, NRc4C(0)0Ra4, NRc4C(0)NRc4Rd4, NRC4S(O)Rb4, NRC4S(O)2Rb4, NRc4S(0)2NRc4Rd4, S(O)Rb4, S(O)NRC4Rd4, S(O)2Rb4, and S(O)2NRC4Rd4, wherein said C1-6 alkyl, C3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl are each optionally tuted with 1, 2, 3, or 4 substituents independently selected from Rg; R3 is selected from H, C1-6 alkyl, and C1-6 haloalkyl, Rb is selected from C1-6 alkyl and C1-6 haloalkyl, W0 2017!]72596 Rc and Rd are each independently ed from H, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl, C3-6 cycloalkyl-C1.3 alkylene, phenyl-C1-3 ne, 5-6 membered heteroaryl-C1-3 alkylene, and 4-6 membered heterocycloalkyl-C13 ne; wherein said C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl, 4—6 membered heterocycloalkyl, C3-6 cycloalkyl-C1-3 alkylene, phenyl-C1-3 alkylene, 5-6 membered heteroaryl-Cm alkylene, and 4-6 ed heterocycloalkyl-Cm alkylene are each optionally substituted with 1, 2 or 3 substituents independently selected from Rg; R31, RCl and Rdl are each independently ed from H, C1-6 alkyl, and C1-6 haloalkyl, wherein said C1-6 alkyl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from Rg, or alternatively, RC1 and Rdl 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 Rbl is selected from C1-6 alkyl and C1-6 haloalkyl, each of which is ally substituted with 1, 2, 3, or 4 substituents independently selected from Rg; R61 is selected from H, CN, C1-6 alkyl, C1-6 haloalkyl, C 1-6 alkylthio, Cl-6 alkylsulfonyl, C1-6 alkylcarbonyl, C1-6 alkylaminosulfonyl, carbamyl, C1-6 arbamyl, 6 alkyl)carbamyl, aminosulfonyl, C1-6 alkylaminosulfonyl, and dl(C1-6 alkyl)aminosulfonyl; each R32, Rcz, and Rdz is ndently selected from H, C1-6 alkyl, Cl-6 haloalkyl, C3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl, and 4-7 ed heterocycloalkyl; wherein said C1-6 alkyl, 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 R12, or alternatively, any RC2 and Rdz attached to the same N atom, together with the N atom to which they are attached, form a 4-, 5-, 6- or ered heterocycloalkyl group optionally substituted with 1, 2 or 3 substituents ndently selected from each R132 is independently selected from C1-6 alkyl, C1-6 haloalkyl, C34 cycloalkyl, phenyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl, W0 2017!]72596 each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R”; each R33, RC3 and R‘13 is independently selected from H, C1-6 alkyl, Cl-6 haloalkyl, C3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, C3-6 cycloalkyl-C1.4 alkylene, phenyl-C1-4 alkylene, 5-6 membered heteroaryl-CM alkylene, and 4-7 membered heterocycloalkyl-C1-4 alkylene; wherein said C1—6 alkyl, C3-6 cycloalkyl, phenyl, 5-6 ed heteroaryl, 4-7 membered heterocycloalkyl, C3-6 cycloalkyl-C1.4 alkylene, phenyl-C1-4 alkylene, 5-6 membered heteroaryl—C1-4 alkylene, and 4-7 membered heterocycloalkyl-C1-4 alkylene are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Rg; alternatively, any RC3 and Rd3 ed 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 each R133 is independently ed from C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, , 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, C3-6 cycloalkyl-CM ne, phenyl-C1-4 alkylene, 5-6 membered heteroaryl-C 1.4 alkylene, and 4-? membered heterocycloalkyl-C14 alkylene, each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from Rg; each R34, RC4 and R“, is independently ed from H, C1-6 alkyl, and C1-6 haloalkyl; wherein said C1-6 alkyl is optionally substituted with 1, 2, 3, or 4 tuents ndently selected from Rg, or alternatively, any RC4 and Rd4 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 each R134 is independently ed from C1-6 alkyl and C1-6 haloalkyl, each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from Rg; and each Rg is independently selected from OH, N02, CN, halo, C1-6 alkyl, C1-6 kyl, Cl-6 alkoxy, C1-6 koxy, cyano-C1-3 alkyl, HO-C1-3 alkyl, H2N-C1-3 W0 2017!]72596 alkyl, amino, C1-6 alkylamino, dl(C1-6 alkyl)arnino, thio, C1-6 alkylthio, C1-6 alkylsulfinyl, Cm alkylsulfonyl, carbamyl, C1-6 alkylcarbamyl, dl(C1-6 carbamyl, carboxy, Cl-6 alkylcarbonyl, C14; alkoxycarbonyl, C1-6 alkylcarbonylamino, C1-6 alkylsulfonylamino, aminosulfonyl, C1-6 alkylaminosulfonyl, dl(C1-6 alkyl)aminosulfonyl, ulfonylarnino, C1-6 alkylarninosulfonylamino, dl(Cl-6 alkyl)aminosulfonylarnino, carbonylamino, C1-6 alkylaminocarbonylarnino, and dl(C1-6 arninocarbonylarnino, provided that: 1) A3 is not Y-Y when one of A1, A2 or A3 is a bond, or Y-Y-Y; and 2) when A3 is —Y— or —C1-3 alkylene—Y— then RA is H, C1-6 alkyl, or Cl-6 haloalkyl, wherein said C1-6 alkyl or C1-6 haloalkyl is optionally tuted with 1, 2, 3 or 4 substituents independently selected from R“. 2, The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein: R1 is Al-Az-A3-RA; R2 is H, halo, CN, C1-4 alkyl, C1-4 haloalkyl, Ci-4 , C1-4 haloalkoxy, C1.3 alkyl or C1-6 alkoxyalkyl; R3 is H, halo, CN, C1-6 alkyl, C1.5 haloalkyl, 0R3, SR3, C(O)NRCRd, NRCRd, NRCC(O)Rb, NRCS(O)2Rb or S(O)2Rb, wherein said C1-6 alkyl and C1-6 haloalkyl are optionally substituted with 1, 2 or 3 substituents independently selected from halo, CN, 0R3, SR3, C(O)NRCRd, NRCRd, NRCC(O)Rb, NRCS(O)2Rb, S(O)2Rb, NR°C(O)ORa, NR“C(O)NRCRd, )2NRCRd and CyR3; Al is selected from a bond, CyAl, —Y—, —C1.3 alkylene—, —C1-3 alkylene—Y—, — Y—C1.3 alkylene—, and —C1-2 alkylene—Y—C1.2 alkylene—, wherein said alkylene groups are each optionally substituted with 1, 2, or 3 tuents independently selected from halo, CN, OH, C1—3 alkyl, C1—3 alkoxy, C1.3 haloalkyl, C1-3 haloalkoxy, amino, C1—3 alkylamino, and di(C1-3 alkyl)amino, A2 is selected from a bond, CyAz, —Y—, —C1.3 alkylene—, —C1-3 alkylene—Y—, — Y—C1-3 alkylene—, and —C1-2 alkylene—Y—C1-2 alkylene—; wherein said alkylene groups are each optionally substituted with 1, 2, or 3 substituents independently selected from W0 2017!]72596 halo, CN, OH, C1-3 alkyl, C1-3 alkoxy, C1-3 haloalkyl, C1-3 haloalkoxy, amino, C1-3 alkylamino, and di(C1-3 alky1)amino; A3 is selected from a bond, CyA3, —Y—, —C1.3 alkylene—, —C1-3 alkylene—Y—, — Y—C1-3 ne—, and —C1-2 alkylene—Y—C1-2 alkylene—; wherein said alkylene groups are each optionally substituted with 1, 2, or 3 substituents independently selected from halo, CN, OH, C1—3 alkyl, C1—3 alkoxy, C1.3 haloalkyl, C1-3 haloalkoxy, amino, C1—3 alkylamino, and di(C1-3 alkyl)arnino, RA is H, C1-6 alkyl, C1-6 haloalkyl, halo, CN, N02, OR“, SR“, C(O)Rbl, C(O)NRC1R‘“, C(O)0Ra1, OC(O)Rb1, OC(O)NRCle1, NRCle1,NR°10R‘“, NRClC(O)Rb1, NRC1C(O)ORa1, NRCIC(O)NRC1R‘“, C(=NRel)Rb1, 1)NRc1Rd1, NRClC(=NRel)NRC1Rd1, NRC18(O)Rb1, NRcls(0)2Rbl, 0)2NRcle1, 1, C1R‘“, S(O)2Rb1, or S(O)2NRC1R‘“, n said C1-6 alkyl or C1-6 haloalkyl is optionally substituted with 1, 2, 3 or 4 substituents independently ed from R“; Y is O, S, S(O), S(O)2, C(O), C(O)NRf, NRfC(O), NRfC(O)NRf, NRfS(O)2NRf, S(O)2NRf, NRfS(O)2, or NRf, each Rf is independently selected from H and C13 alkyl, CyA1 is C3-7 cycloalkyl, phenyl, 5-6 membered aryl, or 4-? membered heterocycloalkyl; wherein each 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl has at least one ring-forming carbon atom and 1, 2, 3, or 4 ringforrning heteroatoms independently selected from N, O, and S; wherein the N and S are optionally oxidized; wherein a ring-forming carbon atom of C33 cycloalkyl and 4- 7 membered heterocycloalkyl is optionally substituted by oxo to form a carbonyl group; and wherein the C34 cycloalkyl, phenyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl are each ally substituted with 1, 2, 3 or 4 substituents independently ed from R“, each RAl is ndently selected from OH, N02, CN, halo, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, cyano-C1—3 alkyl, HO-C1—3 alkyl, H2N-C1—3 alkyl, amino, C1-6 alkylamino, dl(C1-6 alkyl)arnino, thio, Cl-6 alkylthio, C1-6 alkylsulfinyl, Cm alkylsulfonyl, yl, C1-6 alkylcarbamyl, dl(C1-6 alkyl)carbamyl, carboxy, Cl-6 alkylcarbonyl, C1-6 alkoxycarbonyl, C1-6 alkylcarbonylamino, Cl-6 alkylsulfonylamino, aminosulfonyl, C1-6 minosulfonyl, dl(C1-6 alky1)aminosulfonyl, aminosulfonylamino, C1-6 alkylaminosulfonylamino, dl(Cl-6 W0 2017!]72596 alkyl)aminosulfonylamino, arbonylamino, C1-6 alkylaminocarbonylamino, and dl(C1-6 alkyl)aminocarbonylamino; CyA2 is C3-7 cycloalkyl, phenyl, 5-6 membered heteroaryl, or 4-? membered heterocycloalkyl; wherein each 5-6 membered heteroaryl and 4-7 membered cycloalkyl has at least one ring-forming carbon atom and 1, 2, 3, or 4 ringforming heteroatoms independently selected from N, O, and S; wherein the N and S are optionally oxidized; wherein a ring-forming carbon atom of C3: cycloalkyl and 4- 7 membered heterocycloalkyl is optionally substituted by oxo to form a carbonyl group; and wherein the C34 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 R“, each RA2 is independently selected from OH, N02, CN, halo, C1-6 alkyl, Cl-G haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, cyano-C1—3 alkyl, HO-C1—3 alkyl, H2N-C1—3 alkyl, amino, C1-6 alkylamino, dl(C1-6 amino, thio, C1-6 alkylthio, Cl-6 alkylsulfinyl, Cm alkylsulfonyl, yl, C1-6 arbamyl, dl(C1-6 alkyl)carbamyl, carboxy, Cl-6 alkylcarbonyl, C1-6 alkoxycarbonyl, C1-6 arbonylamino, C1-6 alkylsulfonylamino, aminosulfonyl, C1-5 alkylaminosulfonyl, di(Cl-G alkyl)aminosulfonyl, aminosulfonylamino, C1-6 alkylarrfinosdfonylamino, di(Cl-6 aminosulfonylamino, aminocarbonylamino, C1-6 minocarbonylamino, and dl(C1-6 alkyl)aminocarbonylamino; CyA3 is C3—7 cycloalkyl, phenyl, 5-6 membered heteroaryl, or 4-7 membered heterocycloalkyl; wherein each 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl has at least one ring-forming carbon atom and 1, 2, 3, or 4 ringforming heteroatoms independently ed from N, O, and S; wherein the N and S are optionally oxidized, wherein a ring-forming carbon atom of C34 cycloalkyl and 4- 7 membered heterocycloalkyl is optionally substituted by oxo to form a carbonyl group; and n the C34 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 R“, each RA3 is independently selected from OH, N02, CN, halo, C1-6 alkyl, C1-6 haloalkyl, Cl-6 alkoxy, C1-6 haloalkoxy, C1-3 alkyl, HO-C1-3 alkyl, H2N-C1-3 alkyl, amino, C1-6 alkylamino, di(Crs alkyl)amino, thio, C1-6 alkylthio, C1-6 W0 2017!]72596 alkylsulfinyl, C1-6 alkylsulfonyl, yl, C1-6 alkylcarbamyl, dl(C1-6 alkyl)carbamyl, carboxy, Cl-6 alkylcarbonyl, C1-6 alkoxycarbonyl, C1-6 alkylcarbonylamino, C1-6 alkylsulfonylamino, aminosulfonyl, C1-6 alkylaminosulfonyl, dl(C1-6 alkyl)aminosulfonyl, aminosulfonylamino, C14, alkylanfinosdfonylamino, dl(Cl-6 alkyl)aminosulfonylamino, aminocarbonylamino, C1-6 alkylarninocarbonylarnino, and dl(C1-6 alkyl)aminocarbonylamino, CyR3 is C3.7 cycloalkyl, phenyl, 5-6 membered aryl, or 4-? ed heterocycloalkyl; n each 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl has at least one ring-forming carbon atom and 1, 2, 3, or 4 ringforming heteroatoms independently selected from N, O, and S, wherein the N and S are optionally oxidized, wherein a ring-forming carbon atom of C34 cycloalkyl and 4- 7 membered heterocycloalkyl is optionally substituted by oxo to form a carbonyl group; and wherein the C34 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, CyC is phenylene or 5-6 membered heteroarylene; wherein the 5-6 membered arylene has at least one ring-forming carbon atom and 1 or 2 ring-forming heteroatoms ndently selected from N, O, and S; and wherein the ene and 5—6 membered heteroarylene are each optionally substituted by 1, 2, 3, or 4 substituents independently selected from RC, each RC is independently selected from OH, CN, halo, C1—4 alkyl, C1—3 kyl, C14 , C1.3 haloalkoxy, cyano-C1—3 alkyl, HO-C1-3 alkyl, amino, C1—4 alkylamino, di(C1-4 alkyl)amino, C1.4 alkylsulfinyl, C1.4 alkylsulfonyl, carbamyl, C1-4 alkylcarbamyl, di(C1-4 alkyl)carbamyl, carboxy, C1.4 arbonyl, C1—4 alkoxycarbonyl, C1.4 alkylcarbonylamino, C1.4 alkylsulfonylamino, aminosulfonyl, C1- 4 alkylaminosulfonyl, and di(C1-4 alkyl)aminosulfonyl, CyB is €3.10 cycloalkyl or 4-10 membered heterocycloalkyl, wherein at least one ring-forming carbon atom of C340 lkyl and 4-10 ed heterocycloalkyl is substituted by oxo to form a carbonyl group, wherein the 4-10 ed heterocycloalkyl 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; and wherein the C340 cycloalkyl and 4-10 membered W0 2017!]72596 heterocycloalkyl are each optionally substituted with 1, 2, 3 or 4 tuents ndently selected from RB; or CyB is 6-10 membered aryl or 5-10 membered heteroaryl; wherein the 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; n the N and S are optionally oxidized; wherein: (a) at least one ring-forming carbon atom of the 5- 10 membered heteroaryl is substituted by oxo to form a carbonyl group; or (b) the 6- 10 membered aryl or 5-10 membered heteroaryl is substituted by halo, CN, N02, ORaZ, SRaZ, C(O)Rb2, C(O)NRCZRd2, C(0)0Ra2, 0C(0)Rb2, OC(O)NR°2Rd2, NRCZRdZ, NRCZOR‘”, NR“2C(O)Rb2, NRC2C(O)ORa2, NRCZC(O)NRC2Rd2, NRCZS(O)R"2, NRCZS(O)2R"2, NRCZS(O)2NRC2Rd2, S(O)Rb2, C2Rd2, S(O)2Rb2, and S(O)2NR62Rd2; and wherein the 6-10 membered aryl or 5-10 membered heteroaryl is further optionally substituted with 1, 2, 3 or 4 substituents independently selected from RB; each RB is independently selected from halo, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, phenyl, 5—6 membered heteroaryl, 4-7 ed heterocycloalkyl, CN, N02, ORaz, SR”, C(O)Rb2, CZRd2, C(O)OR82, OC(O)Rb2, OC(O)NR°2Rd2, NRCZRC'Z, NRCZORdZ, NRC2C(O)Rb2, NR02C(O)OR32, NR92C(O)NRCZRd2, NRCZS(O)Rb2, NRCZS(O)2Rb2, NRCZS(O)2NRCZRd2, S(O)Rb2, S(O)NRC2Rd2, S(O)2Rb2, and S(O)2NRC2Rd2; n said C1-6 alkyl, 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 R”, each R11 is independently selected from CN, N02, OR“, SR”, C(O)Rb3, C(O)NR“3Rd3, C(O)0Ra3, OC(O)Rb3, OC(O)NRC3Rd3, NRC3Rd3, NRC3ORd3, O)Rb3, NRC3C(O)ORa3, NRC3C(O)NRC3Rd3, NRC3S(O)Rb3, NRC3S(O)2R"3, O)2NRC3Rd3, S(O)Rb3, S(O)NRC3Rd3, S(O)2Rb3, and S(O)2NRC3Rd3; each R12 is independently selected from halo, CN, N02, C1-6 alkyl, Cl-6 haloalkyl, C3-6 cycloalkyl, phenyl, 5-6 ed heteroaryl, 4-7 membered heterocycloalkyl, ORa“, SR“, C(O)Rb4, C(O)NRC4Rd4, C(O)ORa4, OC(O)R"4, OC(O)NRC4Rd4, 4, NRC4ORd4, NRC4C(O)Rb4, NRC4C(O)OR34, NRC4C(O)NRC4Rd4, O)Rb4, NRC4S(O)2Rb4, NRC4S(O)2NRC4R‘“, 4, S(O)NR°4Rd4, S(O)2Rb4, and S(O)2NRC4Rd4; wherein said C1-6 alkyl, C3-6 cycloalkyl, W0 2017!]72596 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; R3 is selected from H, C1-6 alkyl, and C1-6 haloalkyl, Rb is selected from C14; alkyl and C1.6haloalky1; Rc and Rd are each independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, , 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl, C3-6 cycloalkyl—C1-3 alkylene, phenyl-C1-3 alkylene, 5-6 membered heteroaryl-C1—3 alkylene, and 4-6 membered heterocycloalkyl3 alkylene, n said C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl, C3-6 cycloalkyl-C1-3 alkylene, phenyl-C1-3 alkylene, 5-6 membered heteroaryl-C1.3 alkylene, and 4-6 membered heterocycloalkyl-Ga alkylene are each optionally substituted with 1, 2 or 3 substituents independently selected from Rg; R31, RCl and R(11 are each independently selected from H, C1-6 alkyl, and C1-6 haloalkyl, wherein said C1-6 alkyl is ally substituted with 1, 2, 3, or 4 substituents independently selected from Rg, or alternatively, 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 or 3 substituents independently ed from Rbl is ed from C1-6 alkyl and C1-6 haloalkyl, each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from Rg; R61 is ed from H, CN, C1-6 alkyl, C1-6 haloalkyl, C1-6 hio, Cm alkylsulfonyl, C1-6 alkylcarbonyl, C1-6 alkylarninosulfonyl, carbamyl, C1-6 alkylcarbamyl, 6 alkyl)carbamyl, arninosulfonyl, C1-6 alkylaminosulfonyl, and d1(C1-6 alkyl)aminosulfonyl, each R32, R92, and Rdz is independently selected from H, C1-6 alkyl, Cl-6 haloalkyl, C3-6 cycloalkyl, phenyl, 5-6 ed heteroaryl, and 4-7 membered heterocycloalkyl; wherein said C1-6 alkyl, C3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl, and 4—7 membered heterocycloalkyl are each ally substituted with 1, 2, 3, or 4 substituents ndently selected from R”; or alternatively, 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 W0 2017!]72596 group optionally substituted with 1, 2 or 3 substituents independently selected from each R” is independently selected from C1-6 alkyl, C1-6 haloalkyl, C34 cycloalkyl, phenyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl, each of which is ally substituted with 1, 2, 3, or 4 substituents independently selected from R12; each R33, RC3 and R‘13 is independently selected from H, C1-6 alkyl, Cm haloalkyl, C3-6 cycloalkyl, , 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, C3-6 cycloalkyl-Ci.4 alkylene, phenyl-C1-4 alkylene, 5-6 membered heteroaryl-CM alkylene, and 4-7 membered heterocycloalkyl-Ci-4 alkylene; wherein said C1-6 alkyl, C3-6 cycloalkyl, , 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, C3-6 cycloalkyl-C1—4 alkylene, -C1—4 ne, 5-6 membered heteroaryl-CM alkylene, and 4-7 membered heterocycloalkyl-C14 alkylene are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Rg; alternatively, any RC3 and R(13 attached to the same N atom, er 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 tuents independently selected from each Rb3 is independently selected from C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, C3-6 cycloalkyl-CM alkylene, phenyl-C1-4 alkylene, 5-6 membered heteroaryl-C1-4 alkylene, and 4-7 membered heterocycloalkyl-Cm alkylene, each of which is optionally substituted with 1, 2, 3, or 4 substituents ndently selected from Rg; each R34, RC4 and Rd“, is independently selected from H, C1-6 alkyl, and C1-6 kyl, wherein said C1-6 alkyl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from Rg, or atively, any RC4 and Rd4 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 W0 2017/‘172596 each R134 is ndently ed from C1-6 alkyl and C1-6 haloalkyl, each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from Rg; and each Rg is independently selected from OH, N02, CN, halo, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, cyano-C1—3 alkyl, HO-C1—3 alkyl, H2N-C1—3 alkyl, amino, C1-6 alkylamino, dl(C1-6 alkyl)amino, thio, C1-6 alkylthio, Cl—6 alkylsulflnyl, C1-6 alkylsulfonyl, carbamyl, C1-6 alkylcarbamyl, dl(C1-6 alkyl)carbamy1, carboxy, Cl-6 alkylcarbonyl, C1-6 alkoxycarbonyl, C1-6 alkylcarbonylamino, Cl-6 alkylsulfonylamino, aminosulfonyl, C1-6 alkylaminosulfonyl, di(Cl-G alkyl)aminosulfonyl, aminosulfonylamino, C1-6 alkylaminosulfonylamino, di(Cl-6 alkyl)aminosulfonylamino, aminocarbonylamino, C1-6 alkylaminocarbonylamino, and dl(C1-6 alkyl)aminocarbonylamino, ed that: 1) Al-Az-A3 is not Y-Y when one of A1, A2 or A3 is a bond, or Y—Y-Y; and
2.) when A3 is —Y— or —C1-3 alkylene—Y— then RA is H, C1-6 alkyl, or Cl-6 haloalkyl, wherein said C1-6 alkyl or C1-6 haloalkyl is optionally substituted with 1, 2, 3 or 4 substituents independently ed from R“.
3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R1 is H, halo, C1-6 alkyl or C1-6 kyl.
4. The compound of claim 1 or 2, or a pharmaceutically acceptable salt f, wherein R1 is C1-6 alkyl.
5. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R1 is A2-A3-RA.
6. The compound of any one of claims 1, 2, and 5, or a ceutically acceptable salt thereof, wherein R1 is CyA3-RA.
7. The compound of any one of claims 1, 2, 5, and 6, or a pharmaceutically acceptable salt thereof, wherein CyA3 is C3-7 cycloalkyl, 5-6 membered heteroaryl, or W0 2017!]72596
NZ786561A 2017-03-27 Pyrrolotriazine compounds as tam inhibitors NZ786561A (en)

Publications (1)

Publication Number Publication Date
NZ786561A true NZ786561A (en) 2022-04-29

Family

ID=

Similar Documents

Publication Publication Date Title
AU2021245220B2 (en) Pyrrolotriazine compounds as tam inhibitors
TWI649318B (en) Bicyclic heterocycle as an FGFR inhibitor
AU2023270198A1 (en) Salts of pyrrolotriazine derivatives useful as tam inhibitors
NZ786561A (en) Pyrrolotriazine compounds as tam inhibitors
BR112018069612B1 (en) PYROLOTRIAZINE COMPOUNDS, USE THEREOF, PHARMACEUTICAL COMPOSITION COMPRISING THEM AND METHODS FOR INHIBITING A TAM KINASE, AND AXL AND MER KINASE IN VITRO