polycyclic compounds as allosteric inhibitors of shp2

专利摘要:
The present invention relates to SHP2 inhibitors and their use in the treatment of disease. Pharmaceutical compositions comprising the same are also disclosed.
公开号:BR112020009757A2
申请号:R112020009757-8
申请日:2018-12-14
公开日:2020-11-03
发明作者:Elena S. Koltun；Christos TZITZILONIS；Jie Jack Li；Adrian Liam Gill；James Joseph Cregg；Naing N. Aay；Andreas BUCKL；Kevin T. Mellem；Brian R. BLANK；Jennifer Pitzen；Gang Wang；Ashutosh S. Jogalekar；Walter S. Won
申请人:Revolution Medicines, Inc.；
IPC主号:

专利说明:

[0001] [0001] CROSS REFERENCE TO RELATED REQUESTS
[0002] [0002] This application claims the benefit of US Provisional Patent Application No. 62 / 599,583, filed on December 15, 2017 and US Provisional Patent Application No. 62 / 678,891, filed on May 31, 2018; whose content is incorporated in this document as a reference in its entirety.
[0003] [0003] FIELD OF DISSEMINATION
[0004] [0004] The present invention relates to inhibitors of the protein tyrosine phosphatase SHP2 useful in the treatment of diseases or disorders. Specifically, the present invention relates to compounds and compositions including SHP2, methods of treating diseases associated with SHP2, and methods of synthesizing these compounds.
[0005] [0005] BACKGROUND OF THE INVENTION
[0006] [0006] The tyrosine phosphatase-2 protein containing the SH2 domain is a non-receptor tyrosine phosphatase-2 protein encoded by the PTPNl 1 gene that contributes to multiple cellular functions including proliferation, differentiation, cell cycle maintenance and migration. SHP2 is involved in signaling through the protein kinase activated by the Ras mitogen, JAK-STAT or the phosphoinositol 3-kinase-AKT pathways.
[0007] [0007] SHP2 has two 2 N-terminal Src homology domains (N-SH2 and C-SH2), a catalytic domain (PTP), and a C-terminal tail. The two SH2 domains control the subcellular location and functional regulation of SHP2. The molecule exists in an inactive, self-inhibited conformation stabilized by a binding network involving residues from both the N-SH2 and PTP domains. Stimulation through, for example, cytokines or growth factors leads to exposure of the catalytic site resulting in enzymatic activation of SHP2.
[0008] [0008] Mutations in the PTPNl 1 gene and subsequently in SHP2 have been identified in several human diseases, such as Noonan syndrome, Leopard syndrome, juvenile myelomonocytic leukemias, neuroblastoma, melanoma, acute myeloid leukemia and cancers of the breast, lung and colon. SHP2, in this way, represents a highly attractive target for the development of new therapies for the treatment of various diseases. The compounds of the present invention fulfill the need for small molecules that inhibit SHP2 activity.
[0009] [0009] BRIEF SUMMARY
[0010] [0010] The present invention relates to compounds capable of inhibiting SHP2 activity. The present invention further provides a process for the preparation of compounds, pharmaceutical preparations comprising said compounds and methods of using said compounds and compositions in the management of diseases or disorders associated with the aberrant SHP2 activity.
[0011] [0011] One aspect of the present invention relates to compounds of formula I ':
[0012] [0012] and pharmaceutically acceptable salts thereof, prodrugs, solvates, hydrates, tautomers, and isomers thereof, in which:
[0013] [0013] R4 is H or;
[0014] [0014] A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl and heteroaryl are 5 to 12 monocyclic members or 5 to 12 polycyclic members;
[0015] [0015] R1 is independently, in each occurrence, –H, –C1- C6alkyl, –C2-C6alkenyl, –C4-C8cycloalkenyl, –C2-C6alkynyl, –C3- C8cycloalkyl, –OH, –OR6, halogen, –NO2, –CN, –NR5R6, –SR5, - S (O) 2NR5R6, –S (O) 2R5, –NR5S (O) 2NR5R6, –NR5S (O) 2R6, –S (O) NR5R6, –S (O) R5 , –NR5S (O) NR5R6, –NR5S (O) R6, –C (O) R5, –CO2R5, - C (O) NR5R6, –NR5C (O) R6, monocyclic or polycyclic heterocyclyl, spiroheterocyclic, heteroaryl, or oxo, where each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, heterocyclyl, spiroheterocyclyl, or heteroaryl is optionally substituted with one or more –OH, halogen, –NO2, oxo, = O, –CN, - R5, –OR5, –NR5R6, −SR5, –S (O) 2NR5R6, - S (O) 2R5, –NR5S (O) 2NR5R6, –NR5S (O) 2R6, –S (O) NR5R6, –S (O ) R5, - NR5S (O) NR5R6, –NR5S (O) R6, heterocycle, aryl or heteroaryl;
[0016] [0016] Y1 is –S–, a direct link, –NH-, –S (O) 2-, –S (O) 2-NH-, - C (= CH2) -, -CH2-, or -S (O)-;
[0017] [0017] X1 is N or CR2;
[0018] [0018] X2 is N or CH;
[0019] [0019] B, including the atoms at the points of attachment, is a 5 to 12 membered monocyclic or polycyclic heterocycle or a 5 to 12 membered monocyclic or polycyclic heteroaryl;
[0020] [0020] Y2 is –NRa–, - (CRa2) m–, –O–, –C (O) -, –C (Ra) 2NH–, - (CRa2) mO–, –C (O) N (Ra ) -, –N (Ra) C (O) -, –S (O) 2N (Ra) -, –N (Ra) S (O) 2–, - N (Ra) C (O) N (Ra) -, –N (Ra) C (S) N (Ra) -, –C (O) O–, –OC (O) -, - OC (O) N (Ra) -, –N (Ra) C ( O) O–, –C (O) N (Ra) O–, –N (Ra) C (S) -, - C (S) N (Ra) -, or –OC (O) O–; wherein the connection on the left side of Y2, as shown, is connected to the ring and the connection on the right side of the Y2 portion, as shown, is connected to R3;
[0021] [0021] Ra is independently, in each occurrence, –H, –OH, –C3- C8cycloalkyl, –C1-C6alkyl, 3- to 12-membered heterocyclyl, or - (CH2) n-aryl, where each alkyl or cycloalkyl is optionally substituted with one or more –NH2, or where 2 Ra, together with the carbon atom to which they are attached, can combine to form a 3- to 8-membered cycloalkyl;
[0022] [0022] Rb is independently, in each occurrence, –H, –OH, - C1-C6alkyl, –C3-C8cycloalkyl, –C2-C6alkenyl, - (CH2) n-aryl, heterocyclyl containing 1-5 heteroatoms selected a starting from the group consisting of N, S, P and O, or heteroaryl containing 1-5 heteroatoms selected from the group consisting of N, S, P and O; where each alkyl, cycloalkyl, alkenyl, heterocycle, heteroaryl, or - (CH2) n-aryl is optionally substituted with one or more –OH, halogen, –NO2, oxo, –CN, −R5, –OR5, –NR5R6, −SR5, –S (O) 2NR5R6, –S (O) 2R5, - NR5S (O) 2NR5R6, –NR5S (O) 2R6, –S (O) NR5R6, –S (O) R5, - NR5S (O) NR5R6, –NR5S (O) R6, –C (O) NR5R6, –NR5C (O) R6, heterocycle, aryl, heteroaryl, - (CH2) nOH, –C1-C6alkyl, –CF3, –CHF2 or –CH2F;
[0023] [0023] R2 is independently –H, –NH2, –ORb, –CN, –C1- C6alkyl, –C2-C6alkenyl, –C4-C8cycloalkenyl, –C2-C6alkynyl, halogen, –C (O) ORb, –C3- C8cycloalkyl, aryl, heterocyclyl containing 1-5 heteroatoms selected from the group consisting of N, S, P and O, or heteroaryl containing 1-5 heteroatoms selected from the group consisting of N, S, P and O; where each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more –OH, halogen, –NO2, oxo, −R5, –OR5, –NR5R6, - SR5, –S (O) 2NR5R6, –S (O) 2R5, –NR5S (O) 2NR5R6, –NR5S (O) 2R6, –S (O) NR5R6, –S (O) R5, –NR5S (O) NR5R6 , –NR5S (O) R6, heterocycle, aryl or heteroaryl;
[0024] [0024] R3 is independently –H, –C1-C6alkyl, a 3- to 12-membered monocyclic or polycyclic heterocycle, a 5- to 12-membered spiroheterocycle, C3-C8cycloalkyl, - (CH2) n-Rb, or - (CH2) nC (O) NR5R6, where each alkyl, spiroheterocycle, heterocycle, or cycloalkyl is optionally substituted with one or more –C1-C6alkyl, –OH, –NH2, –ORb, - NHRb, - (CH2) nOH, heterocyclyl , or spiroheterocyclyl; or
[0025] [0025] R3 can combine with Ra to form a 3 to 12 membered monocyclic or polycyclic heterocycle or a 5 to 12 membered spiroheterocycle, where each heterocycle or spiroheterocycle is optionally substituted with one or more –C1-C6alkyl, halogen, - OH, –ORb, - NH2, –NHRb, optionally substituted heteroaryl, optionally substituted heterocyclyl, - (CH2) nNH2, - (CH2) nOH, –COORb, –CONHRb, - CONH (CH2) nCOORb, –NHCOORb, - OC (O) -NR5R6, –CF3, –CHF2, - CH2F, or = O; wherein the heteroaryl and heterocyclyl are optionally substituted with –CN;
[0026] [0026] R5 and R6 are independently, in each occurrence, –H, - C1-C6alkyl, –C2-C6alkenyl, –C4-C8cycloalkenyl, –C2-C6alkynyl, - C3-C8cycloalkyl, a 3- to 12-membered monocyclic heterocycle polycyclic, –OR7, –SR7, halogen, –NR7R8, –NO2, –CF3, or –CN;
[0027] [0027] R7 and R8 are independently, in each occurrence, –H, - C1-C6alkyl, –C2-C6alkenyl, –C4-C8cycloalkenyl, –C2-C6alquinyl, - C3-C8cycloalkyl, –ORb, or a 3 to 3 heterocycle 12 monocyclic or polycyclic members, where each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, or heterocycle is optionally substituted with one or more –OH, –SH, –NH2, –NO2, or –CN;
[0028] [0028] m is independently 1, 2, 3, 4, 5 or 6; and
[0029] [0029] n is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;
[0030] [0030] as long as when X2 is N and ring B is a 5-membered monocyclic heteroaryl containing 3-4 nitrogen atoms, then don't be; and
[0031] [0031] as long as when X1 is N; X2 is CH and Y1 is NH; then R1 is not C3-C8cycloalkyl or heteroaryl.
[0032] [0032] One aspect of the present invention relates to compounds of formula I:
[0033] [0033] and pharmaceutically acceptable salts thereof, prodrugs, solvates, hydrates, tautomers, and isomers thereof, in which:
[0034] [0034] R4 is H or;
[0035] [0035] A is cycloalkyl, heterocycloalkyl, aryl or heteroaryl, in which cycloalkyl, heterocycloalkyl, aryl and heteroaryl are monocyclic from 5 to 12 members or polycyclic from 5 to 12 members;
[0036] [0036] R1 is independently, in each occurrence, –H, –C1- C6alkyl, –C2-C6alkenyl, –C4-C8cycloalkenyl, –C2-C6alkynyl, –C3- C8cycloalkyl, –OH, –OR6, halogen, –NO2, –CN, –NR5R6, –SR5, - S (O) 2NR5R6, –S (O) 2R5, –NR5S (O) 2NR5R6, –NR5S (O) 2R6, –S (O) NR5R6, –S (O) R5 , –NR5S (O) NR5R6, –NR5S (O) R6, –C (O) R5, –CO2R5, - C (O) NR5R6, –NR5C (O) R6, monocyclic or polycyclic heterocyclyl, spiroheterocyclic, heteroaryl, or oxo, where each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, heterocyclyl, spiroheterocyclyl, or heteroaryl is optionally substituted with one or more –OH, halogen, –NO2, oxo, = O, –CN, - R5, –OR5, –NR5R6, −SR5, –S (O) 2NR5R6, - S (O) 2R5, –NR5S (O) 2NR5R6, –NR5S (O) 2R6, –S (O) NR5R6, –S (O ) R5, - NR5S (O) NR5R6, –NR5S (O) R6, heterocycle, aryl or heteroaryl;
[0037] [0037] Y1 is –S–, a direct link, –NH-, –S (O) 2-, –S (O) 2-NH-, - C (= CH2) -, -CH2- or -S ( O)-;
[0038] [0038] X1 is N or CR2;
[0039] [0039] X2 is N or CH;
[0040] [0040] B, including atoms at the points of attachment, is a 5 to 12 membered monocyclic or polycyclic heterocycle or a 5 to 12 membered monocyclic or polycyclic heteroaryl;
[0041] [0041] Y2 is –NRa–, - (CRa2) m–, –C (O) -, –C (Ra) 2NH–, - (CRa2) mO–, - C (O) N (Ra) -, - N (Ra) C (O) -, –S (O) 2N (Ra) -, –N (Ra) S (O) 2–, –N (Ra) C (O) N (Ra) -, - N (Ra) C (S) N (Ra) -, –C (O) O–, –OC (O) -, –OC (O) N (Ra) -, –N (Ra) C (O) O– , –C (O) N (Ra) O–, –N (Ra) C (S) -, –C (S) N (Ra) -, or –OC (O) O–; wherein the connection on the left side of Y2, as shown, is connected to the ring and the connection on the right side of the Y2 portion, as shown, is connected to R3;
[0042] [0042] Ra is independently, in each occurrence, –H, –OH, –C3- C8cycloalkyl, –C1-C6alkyl, 3- to 12-membered heterocyclyl, or - (CH2) n-aryl, where each alkyl or cycloalkyl is optionally substituted with one or more –NH2, or where 2 Ra, together with the carbon atom to which they are attached, can combine to form a 3- to 8-membered cycloalkyl;
[0043] [0043] Rb is independently, in each occurrence, –H, –OH, - C1-C6alkyl, –C3-C8cycloalkyl, –C2-C6alkenyl, - (CH2) n-aryl, heterocyclyl containing 1-5 heteroatoms selected a starting from the group consisting of N, S, P and O, or heteroaryl containing 1-5 heteroatoms selected from the group consisting of N, S, P and O; where each alkyl, cycloalkyl, alkenyl, heterocycle, heteroaryl, or - (CH2) n-aryl is optionally substituted with one or more –OH, halogen, –NO2, oxo, –CN, −R5, –OR5, –NR5R6, −SR5, –S (O) 2NR5R6, –S (O) 2R5, - NR5S (O) 2NR5R6, –NR5S (O) 2R6, –S (O) NR5R6, –S (O) R5, - NR5S (O) NR5R6, –NR5S (O) R6, –C (O) NR5R6, –NR5C (O) R6, heterocycle, aryl, heteroaryl, - (CH2) nOH, –C1-C6alkyl, –CF3, –CHF2 or –CH2F;
[0044] [0044] R2 is independently –H, –NH2, –ORb, –CN, –C1- C6alkyl, –C2-C6alkenyl, –C4-C8cycloalkenyl, –C2-C6alkynyl, halogen, –C (O) ORb, –C3- C8cycloalkyl, aryl, heterocyclyl containing 1-5 heteroatoms selected from the group consisting of N, S, P and O, or heteroaryl containing 1-5 heteroatoms selected from the group consisting of N, S, P and O; where each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more –OH, halogen, –NO2, oxo, - CN, −R5, –OR5, –NR5R6 , −SR5, –S (O) 2NR5R6, –S (O) 2R5, - NR5S (O) 2NR5R6, –NR5S (O) 2R6, –S (O) NR5R6, –S (O) R5, - NR5S (O ) NR5R6, –NR5S (O) R6, heterocycle, aryl or heteroaryl;
[0045] [0045] R3 is independently –H, –C1-C6alkyl, a 3- to 12-membered monocyclic or polycyclic heterocycle, a 5- to 12-membered spiroheterocycle, C3-C8cycloalkyl, or - (CH2) n-Rb, where each alkyl , spiroheterocycle, heterocycle, or cycloalkyl is optionally substituted with one or more –C1-C6alkyl, –OH, –NH2, –ORb, –NHRb, - (CH2) nOH, heterocyclyl, or spiroheterocyclic; or
[0046] [0046] R3 can be combined with Ra to form a 3 to 12 membered monocyclic or polycyclic heterocycle or a 5 to 12 membered spiroheterocycle, where each heterocycle or spiroheterocycle is optionally substituted with one or more –C1-C6alkyl, halogen, –OH, - ORb, –NH2, –NHRb, heteroaryl, heterocyclyl, - (CH2) nNH2, - (CH2) nOH, - COORb, –CONHRb, –CONH (CH2) nCOORb, –NHCOORb, –CF3, - CHF2, –CH2F, or = O;
[0047] [0047] R5 and R6 are independently, at each occurrence, –H, - C1-C6alkyl, –C2-C6alkenyl, –C4-C8cycloalkenyl, –C2-C6alkynyl, - C3-C8cycloalkyl, a 3- to 12-membered monocyclic heterocycle polycyclic, –OR7, –SR7, halogen, –NR7R8, –NO2, –CF3 or –CN;
[0048] [0048] R7 and R8 are independently, in each occurrence, –H, - C1-C6alkyl, –C2-C6alkenyl, –C4-C8cycloalkenyl, –C2-C6alquinyl, - C3-C8cycloalkyl, –ORb, or a 3 to heterocycle 12 monocyclic or polycyclic members, where each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, or heterocycle is optionally substituted with one or more –OH, –SH, –NH2, –NO2 or –CN;
[0049] [0049] m is independently 1, 2, 3, 4, 5 or 6; and
[0050] [0050] n is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.
[0051] [0051] One aspect of the present invention relates to compounds of formula II ':
[0052] [0052] and pharmaceutically acceptable salts thereof, prodrugs, solvates, hydrates, tautomers, and isomers thereof, in which:
[0053] [0053] A is cycloalkyl, heterocycloalkyl, aryl or heteroaryl, in which cycloalkyl, heterocycloalkyl, aryl and heteroaryl are monocyclic from 5 to 12 members or polycyclic from 5 to 12 members;
[0054] [0054] R1 is independently, in each occurrence, –H, –C1- C6alkyl, –C2-C6alkenyl, –C4-C8cycloalkenyl, –C2-C6alkynyl, –C3- C8cycloalkyl, –OH, –OR6, halogen, –NO2, –CN, –NR5R6, –SR5, - S (O) 2NR5R6, –S (O) 2R5, –NR5S (O) 2NR5R6, –NR5S (O) 2R6, –S (O) NR5R6, –S (O) R5 , –NR5S (O) NR5R6, –NR5S (O) R6, –C (O) R5, –CO2R5, - C (O) NR5R6, –NR5C (O) R6, monocyclic or polycyclic heterocyclyl, spiroheterocycly, heteroaryl or oxo, where each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, heterocyclyl, spiroheterocyclyl or heteroaryl is optionally substituted with one or more –OH, halogen, –NO2, oxo, = O, –CN, −R5, –OR5, –NR5R6, −SR5, –S (O) 2NR5R6, - S (O) 2R5, –NR5S (O) 2NR5R6, –NR5S (O) 2R6, –S (O) NR5R6, –S (O) R5 , - NR5S (O) NR5R6, –NR5S (O) R6, heterocycle, aryl or heteroaryl;
[0055] [0055] Y1 is –S–, a direct link, –NH-, –S (O) 2-, –S (O) 2-NH-, - C (= CH2) -, -CH2- or -S ( O)-;
[0056] [0056] X1 is N or CR2;
[0057] [0057] X2 is N or CH;
[0058] [0058] B, including atoms at the points of attachment, is a 5 to 12 membered monocyclic or polycyclic heterocycle or a 5 to 12 membered monocyclic or polycyclic heteroaryl;
[0059] [0059] Y2 is –NRa–, - (CRa2) m–, –O–, –C (O) -, –C (Ra) 2NH–, - (CRa2) mO–, –C (O) N (Ra ) -, –N (Ra) C (O) -, –S (O) 2N (Ra) -, –N (Ra) S (O) 2–, - N (Ra) C (O) N (Ra) -, –N (Ra) C (S) N (Ra) -, –C (O) O–, –OC (O) -, - OC (O) N (Ra) -, –N (Ra) C ( O) O–, –C (O) N (Ra) O–, –N (Ra) C (S) -, - C (S) N (Ra) -, or –OC (O) O–; wherein the connection on the left side of Y2, as shown, is connected to the ring and the connection on the right side of the Y2 portion, as shown, is connected to R3;
[0060] [0060] Ra is independently, in each occurrence, –H, –OH, –C3- C8cycloalkyl, –C1-C6alkyl, 3- to 12-membered heterocyclyl, or - (CH2) n-aryl, where each alkyl or cycloalkyl is optionally substituted with one or more –NH2, or where 2 Ra, together with the carbon atom to which they are attached, can combine to form a 3- to 8-membered cycloalkyl;
[0061] [0061] Rb is independently, in each occurrence, –H, –OH, - C1-C6alkyl, –C3-C8cycloalkyl, –C2-C6alkenyl, - (CH2) n-aryl, heterocyclyl containing 1-5 heteroatoms selected a starting from the group consisting of N, S, P and O, or heteroaryl containing 1-5 heteroatoms selected from the group consisting of N, S, P and O; where each alkyl, cycloalkyl, alkenyl, heterocycle, heteroaryl, or - (CH2) n-aryl is optionally substituted with one or more –OH, halogen, –NO2, oxo, –CN, −R5, –OR5, –NR5R6, −SR5, –S (O) 2NR5R6, –S (O) 2R5, - NR5S (O) 2NR5R6, –NR5S (O) 2R6, –S (O) NR5R6, –S (O) R5, - NR5S (O) NR5R6, –NR5S (O) R6, –C (O) NR5R6, –NR5C (O) R6, heterocycle, aryl, heteroaryl, - (CH2) nOH, –C1-C6alkyl, –CF3, –CHF2 or –CH2F;
[0062] [0062] R2 is independently –H, –NH2, –ORb, –CN, –C1- C6alkyl, –C2-C6alkenyl, –C4-C8cycloalkenyl, –C2-C6alkynyl, halogen, –C (O) ORb, –C3- C8cycloalkyl, aryl, heterocyclyl containing 1-
[0063] [0063] R3 is independently –H, –C1-C6alkyl, a 3- to 12-membered monocyclic or polycyclic heterocycle, a 5- to 12-membered spiroheterocycle, C3-C8cycloalkyl, - (CH2) n-Rb, or - (CH2) nC (O) NR5R6, where each alkyl, spiroheterocycle, heterocycle, or cycloalkyl is optionally substituted with one or more –C1-C6alkyl, –OH, –NH2, –ORb, –NHRb, - (CH2) nOH, heterocyclyl or spiroheterocyclyl; or
[0064] [0064] R3 can combine with Ra to form a 3 to 12 membered monocyclic or polycyclic heterocycle or a 5 to 12 membered spiroheterocycle, where each heterocycle or spiroheterocycle is optionally substituted with one or more –C1-C6alkyl, halogen , –OH, - ORb, –NH2, –NHRb, optionally substituted heteroaryl, optionally substituted heterocyclyl, - (CH2) nNH2, - (CH2) nOH, –COORb, - CONHRb, –CONH (CH2) nCOORb, –NHCOORb, - OC (O) -NR5R6, –CF3, - CHF2, –CH2F ou = O; wherein the heteroaryl and heterocyclyl are optionally substituted with –CN;
[0065] [0065] R5 and R6 are independently, in each occurrence, –H, - C1-C6alkyl, –C2-C6alkenyl, –C4-C8cycloalkenyl, –C2-C6alkynyl, - C3-C8cycloalkyl, a 3- to 12-membered monocyclic heterocycle polycyclic, –OR7, –SR7, halogen, –NR7R8, –NO2, –CF3 or –CN;
[0066] [0066] R7 and R8 are independently, in each occurrence, –H, - C1-C6alkyl, –C2-C6alkenyl, –C4-C8cycloalkenyl, –C2-C6alkynyl, - C3-C8cycloalkyl, –ORb, or a 3 to heterocycle 12 monocyclic or polycyclic members, where each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl or heterocycle is optionally substituted with one or more –OH, –SH, –NH2, –NO2 or –CN;
[0067] [0067] m is independently 1, 2, 3, 4, 5 or 6; and
[0068] [0068] n is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;
[0069] [0069] as long as when X2 is N and ring B is a 5-membered monocyclic heteroaryl containing 3-4 nitrogen atoms, then don't be; and
[0070] [0070] as long as when X1 is N; X2 is CH and Y1 is NH; then R1 is not C3-C8cycloalkyl or heteroaryl.
[0071] [0071] One aspect of the present invention relates to compounds of formula II:
[0072] [0072] and pharmaceutically acceptable salts thereof, prodrugs, solvates, hydrates, tautomers, and isomers thereof, in which:
[0073] [0073] A is cycloalkyl, heterocycloalkyl, aryl or heteroaryl, in which cycloalkyl, heterocycloalkyl, aryl and heteroaryl are monocyclic from 5 to 12 members or polycyclic from 5 to 12 members;
[0074] [0074] R1 is independently, in each occurrence, –H, –C1- C6alkyl, –C2-C6alkenyl, –C4-C8cycloalkenyl, –C2-C6alkynyl, –C3- C8cycloalkyl, –OH, –OR6, halogen, –NO2, –CN, –NR5R6, –SR5, - S (O) 2NR5R6, –S (O) 2R5, –NR5S (O) 2NR5R6, –NR5S (O) 2R6, –S (O) NR5R6, –S (O) R5 , –NR5S (O) NR5R6, –NR5S (O) R6, –C (O) R5, –CO2R5, - C (O) NR5R6, –NR5C (O) R6, monocyclic or polycyclic heterocyclyl, spiro-
[0075] [0075] Y1 is –S–, a direct link, –NH-, –S (O) 2-, –S (O) 2-NH-, - C (= CH2) -, -CH2- or -S ( O)-;
[0076] [0076] X1 is N or CR2;
[0077] [0077] X2 is N or CH;
[0078] [0078] B, including atoms at the points of attachment, is a 5 to 12 membered monocyclic or polycyclic heterocycle or a 5 to 12 membered monocyclic or polycyclic heteroaryl;
[0079] [0079] Y2 is –NRa–, - (CRa2) m–, –C (O) -, –C (Ra) 2NH–, - (CRa2) mO–, - C (O) N (Ra) -, - N (Ra) C (O) -, –S (O) 2N (Ra) -, –N (Ra) S (O) 2–, - N (Ra) C (O) N (Ra) -, –N (Ra) C (S) N (Ra) -, –C (O) O–, –OC (O) -, - OC (O) N (Ra) -, –N (Ra) C (O) O– , –C (O) N (Ra) O–, –N (Ra) C (S) -, - C (S) N (Ra) -, or –OC (O) O–; wherein the connection on the left side of Y2, as shown, is connected to the ring and the connection on the right side of the Y2 portion, as shown, is connected to R3;
[0080] [0080] Ra is independently, at each occurrence, –H, –OH, –C3- C8cycloalkyl, –C1-C6alkyl, 3- to 12-membered heterocyclyl, or - (CH2) n-aryl, where each alkyl or cycloalkyl is optionally substituted with one or more –NH2, or where 2 Ra, together with the carbon atom to which they are attached, can combine to form a 3- to 8-membered cycloalkyl;
[0081] [0081] Rb is independently, in each occurrence, –H, –OH, - C1-C6alkyl, –C3-C8cycloalkyl, –C2-C6alkenyl, - (CH2) n-aryl, heterocyclyl containing 1-5 heteroatoms selected a from the con-
[0082] [0082] R2 is independently –H, –NH2, –ORb, –CN, –C1- C6alkyl, –C2-C6alkenyl, –C4-C8cycloalkenyl, –C2-C6alkynyl, halogen, –C (O) ORb, –C3- C8cycloalkyl, aryl, heterocyclyl containing 1-5 heteroatoms selected from the group consisting of N, S, P and O, or heteroaryl containing 1-5 heteroatoms selected from the group consisting of N, S, P and O; where each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more –OH, halogen, –NO2, oxo, - CN, −R5, –OR5, –NR5R6 , −SR5, –S (O) 2NR5R6, –S (O) 2R5, - NR5S (O) 2NR5R6, –NR5S (O) 2R6, –S (O) NR5R6, –S (O) R5, - NR5S (O ) NR5R6, –NR5S (O) R6, heterocycle, aryl or heteroaryl;
[0083] [0083] R3 is independently –H, –C1-C6alkyl, a 3- to 12-membered monocyclic or polycyclic heterocycle, a 5- to 12-membered spiroheterocycle, C3-C8cycloalkyl, or - (CH2) n-Rb, where each alkyl , spiroheterocycle, heterocycle, or cycloalkyl is optionally substituted with one or more –C1-C6alkyl, –OH, –NH2, –ORb, –NHRb, - (CH2) nOH, heterocyclyl or spiroheterocyclic; or
[0084] [0084] R3 can combine with Ra to form a 3 to 12 membered monocyclic or polycyclic heterocycle or a 5 to 12 membered spiroheterocycle, where each heterocycle or spiroheterocycle is optionally substituted with one or more –C1-C6alkyl, halogen , –OH, - ORb, –NH2, –NHRb, heteroaryl, heterocyclyl, - (CH2) nNH2, - (CH2) nOH, -
[0085] [0085] R5 and R6 are independently, in each occurrence, –H, - C1-C6alkyl, –C2-C6alkenyl, –C4-C8cycloalkenyl, –C2-C6alkynyl, - C3-C8cycloalkyl, a 3- to 12-membered monocyclic heterocycle polycyclic, –OR7, –SR7, halogen, –NR7R8, –NO2, –CF3 or –CN;
[0086] [0086] R7 and R8 are independently, in each occurrence, –H, - C1-C6alkyl, –C2-C6alkenyl, –C4-C8cycloalkenyl, –C2-C6alquinyl, - C3-C8cycloalkyl, –ORb, or a 3 to heterocycle 12 monocyclic or polycyclic members, where each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl or heterocycle is optionally substituted with one or more –OH, –SH, –NH2, –NO2 or –CN;
[0087] [0087] m is independently 1, 2, 3, 4, 5 or 6; and
[0088] [0088] n is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.
[0089] [0089] One aspect of the present invention relates to compounds of formula III ':
[0090] [0090] and pharmaceutically acceptable salts thereof, prodrugs, solvates, hydrates, tautomers, and isomers thereof, in which:
[0091] [0091] A is cycloalkyl, heterocycloalkyl, aryl or heteroaryl, in which cycloalkyl, heterocycloalkyl, aryl and heteroaryl are monocyclic from 5 to 12 members or polycyclic from 5 to 12 members;
[0092] [0092] R1 is independently, in each occurrence, –H, –C1- C6alkyl, –C2-C6alkenyl, –C4-C8cycloalkenyl, –C2-C6alkynyl, –C3- C8cycloalkyl, –OH, –OR6, halogen, –NO2, –CN, –NR5R6, –SR5, - S (O) 2NR5R6, –S (O) 2R5, –NR5S (O) 2NR5R6, –NR5S (O) 2R6, –S (O) NR5R6, –S (O) R5 , –NR5S (O) NR5R6, –NR5S (O) R6, –C (O) R5, –CO2R5, -
[0093] [0093] X1 is N or CR2;
[0094] [0094] X2 is N or CH;
[0095] [0095] B, including atoms at the points of attachment, is a 5 to 12 membered monocyclic or polycyclic heterocycle or a 5 to 12 membered monocyclic or polycyclic heteroaryl;
[0096] [0096] Y2 is –NRa–, - (CRa2) m–, –O–, –C (O) -, –C (Ra) 2NH–, - (CRa2) mO–, –C (O) N (Ra ) -, –N (Ra) C (O) -, –S (O) 2N (Ra) -, –N (Ra) S (O) 2–, - N (Ra) C (O) N (Ra) -, –N (Ra) C (S) N (Ra) -, –C (O) O–, –OC (O) -, - OC (O) N (Ra) -, –N (Ra) C ( O) O–, –C (O) N (Ra) O–, –N (Ra) C (S) -, - C (S) N (Ra) -, or –OC (O) O–; wherein the connection on the left side of Y2, as shown, is connected to the ring and the connection on the right side of the Y2 portion, as shown, is connected to R3;
[0097] [0097] Ra is independently, in each occurrence, –H, –OH, –C3- C8cycloalkyl, –C1-C6alkyl, 3- to 12-membered heterocyclyl, or - (CH2) n-aryl, where each alkyl or cycloalkyl is optionally substituted with one or more –NH2, or where 2 Ra, together with the carbon atom to which they are attached, can combine to form a 3- to 8-membered cycloalkyl;
[0098] [0098] Rb is independently, in each occurrence, –H, –OH, - C1-C6alkyl, –C3-C8cycloalkyl, –C2-C6alkenyl, - (CH2) n-aryl, heterocyclyl containing 1-5 heteroatoms selected a starting from the group consisting of N, S, P and O, or heteroaryl containing 1-5 heteroatoms selected from the group consisting of N, S, P and O; where each alkyl, cycloalkyl, alkenyl, heterocycle, heteroaryl, or - (CH2) n-aryl is optionally substituted with one or more –OH, halogen, –NO2, oxo, –CN, −R5, –OR5, –NR5R6, −SR5, –S (O) 2NR5R6, –S (O) 2R5, - NR5S (O) 2NR5R6, –NR5S (O) 2R6, –S (O) NR5R6, –S (O) R5, - NR5S (O) NR5R6, –NR5S (O) R6, –C (O) NR5R6, –NR5C (O) R6, heterocycle, aryl, heteroaryl, - (CH2) nOH, –C1-C6alkyl, –CF3, –CHF2 or –CH2F;
[0099] [0099] R2 is independently –H, –NH2, –ORb, –CN, –C1- C6alkyl, –C2-C6alkenyl, –C4-C8cycloalkenyl, –C2-C6alkynyl, halogen, –C (O) ORb, –C3- C8cycloalkyl, aryl, heterocyclyl containing 1-5 heteroatoms selected from the group consisting of N, S, P and O, or heteroaryl containing 1-5 heteroatoms selected from the group consisting of N, S, P and O; where each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more –OH, halogen, –NO2, oxo, −R5, –OR5, –NR5R6, −SR5 , –S (O) 2NR5R6, –S (O) 2R5, –NR5S (O) 2NR5R6, –NR5S (O) 2R6, –S (O) NR5R6, –S (O) R5, –NR5S (O) NR5R6, –NR5S (O) R6, heterocycle, aryl or heteroaryl;
[0100] [0100] R3 is independently –H, –C1-C6alkyl, a 3- to 12-membered monocyclic or polycyclic heterocycle, a 5- to 12-membered spiroheterocycle, C3-C8cycloalkyl, - (CH2) n-Rb, or - (CH2) nC (O) NR5R6, where each alkyl, spiroheterocycle, heterocycle, or cycloalkyl is optionally substituted with one or more –C1-C6alkyl, –OH, –NH2, –ORb, –NHRb, - (CH2) nOH, heterocyclyl or spiroheterocyclyl; or
[0101] [0101] R3 can combine with Ra to form a 3 to 12 membered monocyclic or polycyclic heterocycle, a 5 to 12 membered spiroheterocycle, in which each heterocycle or spiroheterocycle is optionally substituted with one or more –C1-C6alkyl, halogen, - OH, –ORb, - NH2, –NHRb, optionally substituted heteroaryl, optionally substituted heterocyclyl, - (CH2) nNH2, - (CH2) nOH, –COORb, –CONHRb, - CONH (CH2) nCOORb, –NHCOORb, - OC (O) -NR5R6, –CF3, –CHF2, -
[0102] [0102] R5 and R6 are independently, in each occurrence, –H, - C1-C6alkyl, –C2-C6alkenyl, –C4-C8cycloalkenyl, –C2-C6alkynyl, - C3-C8cycloalkyl, a 3- to 12-membered monocyclic heterocycle polycyclic, –OR7, –SR7, halogen, –NR7R8, –NO2, –CF3 or –CN;
[0103] [0103] R7 and R8 are independently, in each occurrence, –H, - C1-C6alkyl, –C2-C6alkenyl, –C4-C8cycloalkenyl, –C2-C6alquinyl, - C3-C8cycloalkyl, –ORb, or a 3 to 3 heterocycle 12 monocyclic or polycyclic members, where each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl or heterocycle is optionally substituted with one or more –OH, –SH, –NH2, –NO2 or –CN;
[0104] [0104] m is independently 1, 2, 3, 4, 5 or 6; and
[0105] [0105] n is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.
[0106] [0106] One aspect of the present invention relates to compounds of formula III:
[0107] [0107] and pharmaceutically acceptable salts thereof, prodrugs, solvates, hydrates, tautomers, and isomers thereof, in which:
[0108] [0108] A is cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl and heteroaryl are monocyclic from 5 to 12 members or polycyclic from 5 to 12 members;
[0109] [0109] R1 is independently, in each occurrence, –H, –C1- C6alkyl, –C2-C6alkenyl, –C4-C8cycloalkenyl, –C2-C6alkynyl, –C3- C8cycloalkyl, –OH, –OR6, halogen, –NO2, –CN, –NR5R6, –SR5, - S (O) 2NR5R6, –S (O) 2R5, –NR5S (O) 2NR5R6, –NR5S (O) 2R6, –S (O) NR5R6, –S (O) R5 , –NR5S (O) NR5R6, –NR5S (O) R6, –C (O) R5, –CO2R5, -
[0110] [0110] X1 is N or CR2;
[0111] [0111] X2 is N or CH;
[0112] [0112] B, including the atoms at the points of attachment, is a 5 to 12 membered monocyclic or polycyclic heterocycle or a 5 to 12 membered monocyclic or polycyclic heteroaryl;
[0113] [0113] Y2 is –NRa–, - (CRa2) m–, –C (O) -, –C (Ra) 2NH–, - (CRa2) mO–, - C (O) N (Ra) -, - N (Ra) C (O) -, –S (O) 2N (Ra) -, –N (Ra) S (O) 2–, - N (Ra) C (O) N (Ra) -, –N (Ra) C (S) N (Ra) -, –C (O) O–, –OC (O) -, - OC (O) N (Ra) -, –N (Ra) C (O) O– , –C (O) N (Ra) O–, –N (Ra) C (S) -, - C (S) N (Ra) -, or –OC (O) O–; wherein the connection on the left side of Y2, as shown, is connected to the ring and the connection on the right side of the Y2 portion, as shown, is connected to R3;
[0114] [0114] Ra is independently, at each occurrence, –H, –OH, –C3- C8cycloalkyl, –C1-C6alkyl, 3- to 12-membered heterocyclyl, or - (CH2) n-aryl, where each alkyl or cycloalkyl is optionally substituted with one or more –NH2, or where 2 Ra, together with the carbon atom to which they are attached, can combine to form a 3- to 8-membered cycloalkyl;
[0115] [0115] Rb is independently, in each occurrence, –H, –OH, - C1-C6alkyl, –C3-C8cycloalkyl, –C2-C6alkenyl, - (CH2) n-aryl, heterocyclyl containing 1-5 hetero atoms selected a starting from the group consisting of N, S, P and O, or heteroaryl containing 1-5 heteroatoms selected from the group consisting of N, S, P and O; where each alkyl, cycloalkyl, alkenyl, heterocycle, heteroaryl or - (CH2) n-aryl is optionally substituted with one or more –OH, halogen, –NO2, oxo, –CN, −R5, –OR5, –NR5R6, - SR5, –S (O) 2NR5R6, –S (O) 2R5, - NR5S (O) 2NR5R6, –NR5S (O) 2R6, –S (O) NR5R6, –S (O) R5, - NR5S (O) NR5R6 , –NR5S (O) R6, –C (O) NR5R6, –NR5C (O) R6, heterocycle, aryl, heteroaryl, - (CH2) nOH, –C1-C6alkyl, –CF3, –CHF2 or –CH2F;
[0116] [0116] R2 is independently –H, –NH2, –ORb, –CN, –C1- C6alkyl, –C2-C6alkenyl, –C4-C8cycloalkenyl, –C2-C6alkynyl, halogen, –C (O) ORb, –C3- C8cycloalkyl, aryl, heterocyclyl containing 1-5 heteroatoms selected from the group consisting of N, S, P and O, or heteroaryl containing 1-5 heteroatoms selected from the group consisting of N, S, P and O; where each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more –OH, halogen, –NO2, oxo, - CN, −R5, –OR5, –NR5R6 , −SR5, –S (O) 2NR5R6, –S (O) 2R5, - NR5S (O) 2NR5R6, –NR5S (O) 2R6, –S (O) NR5R6, –S (O) R5, - NR5S (O ) NR5R6, –NR5S (O) R6, heterocycle, aryl or heteroaryl;
[0117] [0117] R3 is independently –H, –C1-C6alkyl, a 3- to 12-membered monocyclic or polycyclic heterocycle, a 5- to 12-membered spiroheterocycle, C3-C8cycloalkyl or - (CH2) n-Rb, where each alkyl, spiroheterocycle, heterocycle or cycloalkyl is optionally substituted with one or more –C1-C6alkyl, –OH, –NH2, –ORb, –NHRb, - (CH2) nOH, heterocyclyl, or spiroheterocyclic; or
[0118] [0118] R3 can combine with Ra to form a 3 to 12 membered monocyclic or polycyclic heterocycle or a 5 to 12 membered spiroheterocycle, where each heterocycle or spiroheterocycle is optionally substituted with one or more –C1-C6alkyl, halogen , –OH, - ORb, –NH2, –NHRb, heteroaryl, heterocyclyl, - (CH2) nNH2, - (CH2) nOH, - COORb, –CONHRb, –CONH (CH2) nCOORb, –NHCOORb, –CF3, –CHF2 , –CH2F ou = O;
[0119] [0119] R5 and R6 are independently, in each occurrence, –H, - C1-C6alkyl, –C2-C6alkenyl, –C4-C8cycloalkenyl, –C2-C6alkynyl, - C3-C8cycloalkyl, a 3- to 12-membered monocyclic heterocycle polycyclic, –OR7, –SR7, halogen, –NR7R8, –NO2, –CF3 or –CN;
[0120] [0120] R7 and R8 are independently, in each occurrence, –H, - C1-C6alkyl, –C2-C6alkenyl, –C4-C8cycloalkenyl, –C2-C6alquinyl, - C3-C8cycloalkyl, –ORb, or a 3 to heterocycle 12 monocyclic or polycyclic members, where each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl or heterocycle is optionally substituted with one or more –OH, –SH, –NH2, –NO2 or –CN;
[0121] [0121] m is independently 1, 2, 3, 4, 5 or 6; and
[0122] [0122] n is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.
[0123] [0123] One aspect of the present invention relates to compounds of formula IV ':
[0124] [0124] and pharmaceutically acceptable salts thereof, prodrugs, solvates, hydrates, tautomers, and isomers thereof, where:
[0125] [0125] A is cycloalkyl, heterocycloalkyl, aryl or heteroaryl, where cycloalkyl, heterocycloalkyl, aryl and heteroaryl are monocyclic from 5 to 12 members or polycyclic from 5 to 12 members;
[0126] [0126] R1 is independently, in each occurrence, –H, –C1- C6alkyl, –C2-C6alkenyl, –C4-C8cycloalkenyl, –C2-C6alkynyl, –C3- C8cycloalkyl, –OH, –OR6, halogen, –NO2, –CN, –NR5R6, –SR5, - S (O) 2NR5R6, –S (O) 2R5, –NR5S (O) 2NR5R6, –NR5S (O) 2R6, –S (O) NR5R6, –S (O) R5 , –NR5S (O) NR5R6, –NR5S (O) R6, –C (O) R5, –CO2R5, -
[0127] [0127] X1 is N or CR2;
[0128] [0128] X2 is N or CH;
[0129] [0129] B, including atoms at the points of attachment, is a 5 to 12 membered monocyclic or polycyclic heterocycle or a 5 to 12 membered monocyclic or polycyclic heteroaryl;
[0130] [0130] Y2 is –NRa–, - (CRa2) m–, –O–, –C (O) -, –C (Ra) 2NH–, - (CRa2) mO–, –C (O) N (Ra ) -, –N (Ra) C (O) -, –S (O) 2N (Ra) -, –N (Ra) S (O) 2–, - N (Ra) C (O) N (Ra) -, –N (Ra) C (S) N (Ra) -, –C (O) O–, –OC (O) -, - OC (O) N (Ra) -, –N (Ra) C ( O) O–, –C (O) N (Ra) O–, –N (Ra) C (S) -, - C (S) N (Ra) -, or –OC (O) O–; wherein the connection on the left side of Y2, as shown, is connected to the ring and the connection on the right side of the Y2 portion, as shown, is connected to R3;
[0131] [0131] Ra is independently, at each occurrence, –H, –OH, –C3- C8cycloalkyl, –C1-C6alkyl, 3- to 12-membered heterocyclyl, or - (CH2) n-aryl, where each alkyl or cycloalkyl is optionally substituted with one or more –NH2, or where 2 Ra, together with the carbon atom to which they are attached, can combine to form a 3- to 8-membered cycloalkyl;
[0132] [0132] Rb is independently, in each occurrence, –H, –OH, - C1-C6alkyl, –C3-C8cycloalkyl, –C2-C6alkenyl, - (CH2) n-aryl, heterocyclyl containing 1-5 hetero atoms selected a starting from the group consisting of N, S, P and O, or heteroaryl containing 1-5 heteroatoms selected from the group consisting of N, S, P and O; where each alkyl, cycloalkyl, alkenyl, heterocycle, heteroaryl, or - (CH2) n-aryl is optionally substituted with one or more –OH, halogen, –NO2, oxo, –CN, −R5, –OR5, –NR5R6, −SR5, –S (O) 2NR5R6, –S (O) 2R5, - NR5S (O) 2NR5R6, –NR5S (O) 2R6, –S (O) NR5R6, –S (O) R5, - NR5S (O) NR5R6, –NR5S (O) R6, –C (O) NR5R6, –NR5C (O) R6, heterocycle, aryl, heteroaryl, - (CH2) nOH, –C1-C6alkyl, –CF3, –CHF2, or –CH2F;
[0133] [0133] R2 is independently –H, –NH2, –ORb, –CN, –C1- C6alkyl, –C2-C6alkenyl, –C4-C8cycloalkenyl, –C2-C6alkynyl, halogen, –C (O) ORb, –C3- C8cycloalkyl, aryl, heterocyclyl containing 1-5 heteroatoms selected from the group consisting of N, S, P and O, or heteroaryl containing 1-5 heteroatoms selected from the group consisting of N, S, P and O; where each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more –OH, halogen, –NO2, oxo, −R5, –OR5, –NR5R6, −SR5 , –S (O) 2NR5R6, –S (O) 2R5, –NR5S (O) 2NR5R6, –NR5S (O) 2R6, –S (O) NR5R6, –S (O) R5, –NR5S (O) NR5R6, –NR5S (O) R6, heterocycle, aryl or heteroaryl;
[0134] [0134] R3 is independently –H, –C1-C6alkyl, a 3- to 12-membered monocyclic or polycyclic heterocycle, a 5- to 12-membered spiroheterocycle, C3-C8cycloalkyl, - (CH2) n-Rb, or - (CH2) nC (O) NR5R6, where each alkyl, spiroheterocycle, heterocycle, or cycloalkyl is optionally substituted with one or more –C1-C6alkyl, –OH, –NH2, –ORb, –NHRb, - (CH2) nOH, heterocyclyl or spiroheterocyclyl; or
[0135] [0135] R3 can combine with Ra to form a 3 to 12 membered monocyclic or polycyclic heterocycle, a 5 to 12 membered spiroheterocycle, in which each heterocycle or spiroheterocycle is optionally substituted with one or more –C1-C6alkyl, halogen, - OH, –ORb, - NH2, –NHRb, optionally substituted heteroaryl, optionally substituted heterocyclyl, - (CH2) nNH2, - (CH2) nOH, –COORb, –CONHRb, - CONH (CH2) nCOORb, –NHCOORb, - OC (O) -NR5R6, –CF3, –CHF2, -
[0136] [0136] R5 and R6 are independently, in each occurrence, –H, - C1-C6alkyl, –C2-C6alkenyl, –C4-C8cycloalkenyl, –C2-C6alkynyl, - C3-C8cycloalkyl, a 3 to 12 membered monocyclic heterocycle polycyclic, –OR7, –SR7, halogen, –NR7R8, –NO2, –CF3 or –CN;
[0137] [0137] R7 and R8 are independently, in each occurrence, –H, - C1-C6alkyl, –C2-C6alkenyl, –C4-C8cycloalkenyl, –C2-C6alquinyl, - C3-C8cycloalkyl, –ORb, or a 3 to 3 heterocycle 12 monocyclic or polycyclic members, where each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl or heterocycle is optionally substituted with one or more –OH, –SH, –NH2, –NO2 or –CN;
[0138] [0138] m is independently 1, 2, 3, 4, 5 or 6; and
[0139] [0139] n is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;
[0140] [0140] as long as when X2 is N and ring B is a 5-membered monocyclic heteroaryl containing 3-4 nitrogen atoms, then don't be.
[0141] [0141] One aspect of the present invention relates to compounds of formula IV:
[0142] [0142] and pharmaceutically acceptable salts thereof, prodrugs, solvates, hydrates, tautomers, and isomers thereof, in which:
[0143] [0143] A is cycloalkyl, heterocycloalkyl, aryl or heteroaryl, where cycloalkyl, heterocycloalkyl, aryl and heteroaryl are monocyclic from 5 to 12 members or polycyclic from 5 to 12 members;
[0144] [0144] R1 is independently, in each occurrence, –H, –C1- C6alkyl, –C2-C6alkenyl, –C4-C8cycloalkenyl, –C2-C6alkynyl, –C3- C8cycloalkyl, –OH, –OR6, halogen, –NO2, –CN, –NR5R6, –SR5, - S (O) 2NR5R6, –S (O) 2R5, –NR5S (O) 2NR5R6, –NR5S (O) 2R6, –S (O) NR5R6, –S (O) R5 , –NR5S (O) NR5R6, –NR5S (O) R6, –C (O) R5, –CO2R5, - C (O) NR5R6, –NR5C (O) R6, monocyclic or polycyclic heterocyclyl, spiroheterocycly, heteroaryl or oxo, where each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, heterocyclyl, spiroheterocyclyl or heteroaryl is optionally substituted with one or more –OH, halogen, –NO2, oxo, = O, –CN, −R5, –OR5, –NR5R6, −SR5, –S (O) 2NR5R6, - S (O) 2R5, –NR5S (O) 2NR5R6, –NR5S (O) 2R6, –S (O) NR5R6, –S (O) R5 , - NR5S (O) NR5R6, –NR5S (O) R6, heterocycle, aryl or heteroaryl;
[0145] [0145] X1 is N or CR2;
[0146] [0146] X2 is N or CH;
[0147] [0147] B, including atoms at the points of attachment, is a 5 to 12 membered monocyclic or polycyclic heterocycle or a 5 to 12 membered monocyclic or polycyclic heteroaryl;
[0148] [0148] Y2 is –NRa–, - (CRa2) m–, –C (O) -, –C (Ra) 2NH–, - (CRa2) mO–, - C (O) N (Ra) -, - N (Ra) C (O) -, –S (O) 2N (Ra) -, –N (Ra) S (O) 2–, - N (Ra) C (O) N (Ra) -, –N (Ra) C (S) N (Ra) -, –C (O) O–, –OC (O) -, - OC (O) N (Ra) -, –N (Ra) C (O) O– , –C (O) N (Ra) O–, –N (Ra) C (S) -, - C (S) N (Ra) -, or –OC (O) O–; wherein the connection on the left side of Y2, as shown, is connected to the ring and the connection on the right side of the Y2 portion, as shown, is connected to R3;
[0149] [0149] Ra is independently, at each occurrence, –H, –OH, –C3- C8cycloalkyl, –C1-C6alkyl, 3- to 12-membered heterocyclyl, or - (CH2) n-aryl, where each alkyl or cycloalkyl is optionally substituted with one or more –NH2, or where 2 Ra, together with the carbon atom to which they are attached, can combine to form a 3- to 8-membered cycloalkyl;
[0150] [0150] Rb is independently, in each occurrence, –H, –OH, - C1-C6alkyl, –C3-C8cycloalkyl, –C2-C6alkenyl, - (CH2) n-aryl, heterocyclyl containing 1-5 hetero atoms selected a starting from the group consisting of N, S, P and O, or heteroaryl containing 1-5 heteroatoms selected from the group consisting of N, S, P and O; where each alkyl, cycloalkyl, alkenyl, heterocycle, heteroaryl, or - (CH2) n-aryl is optionally substituted with one or more –OH, halogen, –NO2, oxo, –CN, −R5, –OR5, –NR5R6, −SR5, –S (O) 2NR5R6, –S (O) 2R5, - NR5S (O) 2NR5R6, –NR5S (O) 2R6, –S (O) NR5R6, –S (O) R5, - NR5S (O) NR5R6, –NR5S (O) R6, –C (O) NR5R6, –NR5C (O) R6, heterocycle, aryl, heteroaryl, - (CH2) nOH, –C1-C6alkyl, –CF3, –CHF2 or –CH2F;
[0151] [0151] R2 is independently –H, –NH2, –ORb, –CN, –C1- C6alkyl, –C2-C6alkenyl, –C4-C8cycloalkenyl, –C2-C6alkynyl, halogen, –C (O) ORb, –C3- C8cycloalkyl, aryl, heterocyclyl containing 1-5 heteroatoms selected from the group consisting of N, S, P and O, or heteroaryl containing 1-5 heteroatoms selected from the group consisting of N, S, P and O; where each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more –OH, halogen, –NO2, oxo, - CN, −R5, –OR5, –NR5R6 , −SR5, –S (O) 2NR5R6, –S (O) 2R5, - NR5S (O) 2NR5R6, –NR5S (O) 2R6, –S (O) NR5R6, –S (O) R5, - NR5S (O ) NR5R6, –NR5S (O) R6, heterocycle, aryl or heteroaryl;
[0152] [0152] R3 is independently –H, –C1-C6alkyl, a 3- to 12-membered monocyclic or polycyclic heterocycle, a 5- to 12-membered spiroheterocycle, C3-C8cycloalkyl, or - (CH2) n-Rb, where each alkyl , spiroheterocycle, heterocycle or cycloalkyl is optionally substituted with one or more –C1-C6alkyl, –OH, –NH2, –ORb, –NHRb, - (CH2) nOH, heterocyclyl or spiroheterocyclic; or
[0153] [0153] R3 can combine with Ra to form a 3 to 12 membered monocyclic or polycyclic heterocycle or a 5 to 5-membered spiroheterocycle
[0154] [0154] R5 and R6 are independently, in each occurrence, –H, - C1-C6alkyl, –C2-C6alkenyl, –C4-C8cycloalkenyl, –C2-C6alkynyl, - C3-C8cycloalkyl, a 3- to 12-membered monocyclic heterocycle polycyclic, –OR7, –SR7, halogen, –NR7R8, –NO2, –CF3 or –CN;
[0155] [0155] R7 and R8 are independently, in each occurrence, –H, - C1-C6alkyl, –C2-C6alkenyl, –C4-C8cycloalkenyl, –C2-C6alquinyl, - C3-C8cycloalkyl, –ORb, or a 3 to 3 heterocycle 12 monocyclic or polycyclic members, where each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, or heterocycle is optionally substituted with one or more –OH, –SH, –NH2, –NO2, or –CN;
[0156] [0156] m is independently 1, 2, 3, 4, 5 or 6; and
[0157] [0157] n is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.
[0158] [0158] One aspect of the present invention relates to compounds of formula V:
[0159] [0159] and pharmaceutically acceptable salts thereof, prodrugs, solvates, hydrates, tautomers, and isomers thereof, in which:
[0160] [0160] A is aryl or heteroaryl, where aryl and heteroaryl are monocyclic from 5 to 12 members or polycyclic from 5 to 12 members;
[0161] [0161] R1 is independently, in each occurrence, –H, –C1- C6alkyl, –C2-C6alkenyl, –C4-C8cycloalkenyl, –C2-C6alkynyl, –C3- C8cycloalkyl, –OH, –OR6, halogen, –NO2, –CN, –NR5R6, –SR5, -
[0162] [0162] Y1 is –S–, -O-, –NH-, or –CH2-;
[0163] [0163] X1 is N or CR2;
[0164] [0164] X2 is N or CH;
[0165] [0165] B, including the atoms at the points of attachment, is a 5 to 12 membered monocyclic or polycyclic heterocycle or a 5 to 12 membered monocyclic or polycyclic heteroaryl;
[0166] [0166] Y2 is –NRa–, - (CRa2) mO–, –O–, or –C (O) N (Ra) -; wherein the connection on the left side of Y2, as shown, is connected to the ring and the connection on the right side of the Y2 portion, as shown, is connected to R3;
[0167] [0167] Ra is independently, in each occurrence, –H or –C1- C6alkyl;
[0168] [0168] Rb is independently, at each occurrence, –H, –OH, - C1-C6alkyl, –C3-C8cycloalkyl, –C2-C6alkenyl, - (CH2) n-aryl, heterocyclyl containing 1-5 heteroatoms selected a starting from the group consisting of N, S, P and O, or heteroaryl containing 1-5 heteroatoms selected from the group consisting of N, S, P and O; where each alkyl, cycloalkyl, alkenyl, heterocycle, heteroaryl, or - (CH2) n-aryl is optionally substituted with one or more –OH, halogen, –NO2, oxo, –CN, −R5, –OR5, –NR5R6, −SR5, –S (O) 2NR5R6, –S (O) 2R5, - NR5S (O) 2NR5R6, –NR5S (O) 2R6, –S (O) NR5R6, –S (O) R5, - NR5S (O) NR5R6, –NR5S (O) R6, –C (O) NR5R6, –NR5C (O) R6, heterocycle,
[0169] [0169] R2 is independently –H, –NH2, –ORb, –CN, –C1- C6alkyl, –C2-C6alkenyl, –C4-C8cycloalkenyl, –C2-C6alkynyl, halogen, –C (O) ORb, –C3- C8cycloalkyl, aryl, heterocyclyl containing 1-5 heteroatoms selected from the group consisting of N, S, P and O, or heteroaryl containing 1-5 heteroatoms selected from the group consisting of N, S, P and O; where each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more –OH, halogen, –NO2, oxo, −R5, –OR5, –NR5R6, - SR5, –S (O) 2NR5R6, –S (O) 2R5, –NR5S (O) 2NR5R6, –NR5S (O) 2R6, –S (O) NR5R6, –S (O) R5, –NR5S (O) NR5R6 , –NR5S (O) R6, heterocycle, aryl or heteroaryl;
[0170] [0170] R3 is independently –H, –C1-C6alkyl, a 3- to 12-membered monocyclic or polycyclic heterocycle, a 5- to 12-membered spiroheterocycle, C3-C8cycloalkyl, or - - (CH2) nC (O) NR5R6, where each alkyl, spiroheterocycle, heterocycle, or cycloalkyl is optionally substituted with one or more –C1-C6alkyl, –OH, –ORb, - (CH2) nOH, hetero-cyclocyte or spiro-heterocyclyl; or
[0171] [0171] R3 can combine with Ra to form a 3 to 12 membered monocyclic or polycyclic heterocycle or a 5 to 12 membered spiroheterocycle, where each heterocycle or spiroheterocycle is optionally substituted with one or more –C1-C6alkyl, halogen , –OH, - ORb, optionally substituted heteroaryl, optionally substituted heterocyclyl, - (CH2) nOH, –COORb, –CONHRb, –CONH (CH2) nCOORb, - NHCOORb, -OC (O) -NR5R6, –CF3, –CHF2 , –CH2F, or = O; wherein the heteroaryl and heterocyclyl are optionally substituted with –CN;
[0172] [0172] R5 and R6 are independently, in each occurrence, –H, - C1-C6alkyl, –C2-C6alkenyl, –C4-C8cycloalkenyl, –C2-C6alkynyl, - C3-C8cycloalkyl, a 3- to 12-membered monocyclic heterocycle polycyclic, –OR7, –SR7, halogen, –NR7R8, –NO2, –CF3 or –CN;
[0173] [0173] R7 and R8 are independently, in each occurrence, –H, - C1-C6alkyl, –C2-C6alkenyl, –C4-C8cycloalkenyl, –C2-C6alquinyl, - C3-C8cycloalkyl, –ORb, or a 3 to heterocycle 12 monocyclic or polycyclic members, where each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, or heterocycle is optionally substituted with one or more –OH, –SH, –NH2, –NO2 or –CN;
[0174] [0174] m is independently 1, 2, 3, 4, 5 or 6; and
[0175] [0175] n is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;
[0176] [0176] as long as when X2 is N and ring B is a 5-membered monocyclic heteroaryl containing 3-4 nitrogen atoms, then don't be; and
[0177] [0177] as long as when X1 is N; X2 is CH and Y1 is NH; then R1 is not C3-C8cycloalkyl or heteroaryl.
[0178] [0178] One aspect of the present invention relates to compounds of formula VI:
[0179] [0179] and pharmaceutically acceptable salts thereof, prodrugs, solvates, hydrates, tautomers, and isomers thereof, where:
[0180] [0180] A is cycloalkyl, heterocycloalkyl, aryl or heteroaryl, in which cycloalkyl, heterocycloalkyl, aryl and heteroaryl are monocyclic from 5 to 12 members or polycyclic from 5 to 12 members;
[0181] [0181] R1 is independently, in each occurrence, –H, –C1- C6alkyl, –C2-C6alkenyl, –C4-C8cycloalkenyl, –C2-C6alkynyl, –C3- C8cycloalkyl, –OH, –OR6, halogen, –NO2, –CN, –NR5R6, –SR5, -
[0182] [0182] Y1 is –S–, a direct link, –NH-, –S (O) 2-, –S (O) 2-NH-, - C (= CH2) -, -CH2- or -S ( O)-;
[0183] [0183] X1 is N or C;
[0184] [0184] X2 is N or CH;
[0185] [0185] X3 is N or C;
[0186] [0186] B, including the atoms at the points of attachment, is a 5 to 12 membered monocyclic or polycyclic heterocycle or a 5 to 12 membered monocyclic or polycyclic heteroaryl;
[0187] [0187] D, including the atoms at the points of attachment, is a 5- to 7-membered monocyclic heterocycle or a 5- to 7-membered monocyclic heteroaryl;
[0188] [0188] Y2 is –NRa–, - (CRa2) m–, –O–, –C (O) -, –C (Ra) 2NH–, - (CRa2) mO–, –C (O) N (Ra ) -, –N (Ra) C (O) -, –S (O) 2N (Ra) -, –N (Ra) S (O) 2–, - N (Ra) C (O) N (Ra) -, –N (Ra) C (S) N (Ra) -, –C (O) O–, –OC (O) -, - OC (O) N (Ra) -, –N (Ra) C ( O) O–, –C (O) N (Ra) O–, –N (Ra) C (S) -, - C (S) N (Ra) -, or –OC (O) O–; wherein the connection on the left side of Y2, as shown, is connected to the ring and the connection on the right side of the Y2 portion, as shown, is connected to R3;
[0189] [0189] Ra is independently, in each occurrence, –H, –OH, –C3- C8cycloalkyl, –C1-C6alkyl, 3 to 12 membered heterocyclyl, or -
[0190] [0190] Rb is independently, at each occurrence, –H, –OH, - C1-C6alkyl, –C3-C8cycloalkyl, –C2-C6alkenyl, - (CH2) n-aryl, heterocyclyl containing 1-5 hetero atoms selected a starting from the group consisting of N, S, P and O, or heteroaryl containing 1-5 heteroatoms selected from the group consisting of N, S, P and O; where each alkyl, cycloalkyl, alkenyl, heterocycle, heteroaryl, or - (CH2) n-aryl is optionally substituted with one or more –OH, halogen, –NO2, oxo, –CN, −R5, –OR5, –NR5R6, −SR5, –S (O) 2NR5R6, –S (O) 2R5, - NR5S (O) 2NR5R6, –NR5S (O) 2R6, –S (O) NR5R6, –S (O) R5, - NR5S (O) NR5R6, –NR5S (O) R6, –C (O) NR5R6, –NR5C (O) R6, heterocycle, aryl, heteroaryl, - (CH2) nOH, –C1-C6alkyl, –CF3, –CHF2, or –CH2F;
[0191] [0191] R2 is independently –H, –NH2, –ORb, –CN, –C1- C6alkyl, –C2-C6alkenyl, –C4-C8cycloalkenyl, –C2-C6alkynyl, halogen, –C (O) ORb, –C3- C8cycloalkyl, aryl, heterocyclyl containing 1-5 heteroatoms selected from the group consisting of N, S, P and O, or heteroaryl containing 1-5 heteroatoms selected from the group consisting of N, S, P and O; where each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more –OH, halogen, –NO2, oxo, - CN, −R5, –OR5, - NR5R6, −SR5, –S (O) 2NR5R6, –S (O) 2R5, - NR5S (O) 2NR5R6, –NR5S (O) 2R6, –S (O) NR5R6, –S (O) R5, - NR5S ( O) NR5R6, –NR5S (O) R6, heterocycle, aryl or heteroaryl;
[0192] [0192] R3 is independently –H, –C1-C6alkyl, a 3- to 12-membered monocyclic or polycyclic heterocycle, a 5- to 12-membered spiroheterocycle, C3-C8cycloalkyl or - (CH2) n-Rb, where each alkyl, spiroheterocycle, heterocycle or cycloalkyl is optionally substituted with one or more –C1-C6alkyl, –OH, –NH2, –ORb, –NHRb, - (CH2) nOH, - (CH2) nC (O) NR5R6, heterocyclyl or spiroheterocyclic; or
[0193] [0193] R3 can combine with Ra to form a 3 to 12 membered monocyclic or polycyclic heterocycle or a 5 to 12 membered spiroheterocycle, where each heterocycle or spiroheterocycle is optionally substituted with one or more –C1-C6alkyl, halogen , –OH, - ORb, –NH2, –NHRb, optionally substituted heteroaryl, optionally substituted heterocyclyl, - (CH2) nNH2, - (CH2) nOH, –COORb, - CONHRb, –CONH (CH2) nCOORb, –NHCOORb, - OC (O) -NR5R6, –CF3, - CHF2, –CH2F, or = O; wherein the heteroaryl and heterocyclyl are optionally substituted with –CN;
[0194] [0194] R5 and R6 are independently, in each occurrence, –H, - C1-C6alkyl, –C2-C6alkenyl, –C4-C8cycloalkenyl, –C2-C6alkynyl, - C3-C8cycloalkyl, a 3- to 12-membered monocyclic heterocycle polycyclic, –OR7, –SR7, halogen, –NR7R8, –NO2, –CF3 or –CN;
[0195] [0195] R7 and R8 are independently, in each occurrence, –H, - C1-C6alkyl, –C2-C6alkenyl, –C4-C8cycloalkenyl, –C2-C6alquinyl, - C3-C8cycloalkyl, –ORb, or a 3 to 3 heterocycle 12 monocyclic or polycyclic members, where each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl or heterocycle is optionally substituted with one or more –OH, –SH, –NH2, –NO2 or –CN;
[0196] [0196] m is independently 1, 2, 3, 4, 5 or 6; and
[0197] [0197] n is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.
[0198] [0198] Another aspect of the present invention relates to methods of treating a disease associated with SHP2 modulation in an individual who needs it, comprising administering to the individual an effective amount of a compound of formula I, I ', II , II ', III, III', IV, IV ', V, or VI and pharmaceutically acceptable salts of the same, prodrugs, solvates, hydrates, tautomers, and isomers of the same.
[0199] [0199] Another aspect of the present invention relates to methods of inhibiting SHP2. The method comprises administering to a patient in need thereof an effective amount of a compound of formula I, I ', II, II', III, III ', IV, IV', V or VI, and pharmaceutically acceptable salts thereof , prodrugs, solvates, hydrates, tautomers, and isomers thereof.
[0200] [0200] Another aspect of the present invention relates to pharmaceutical compositions comprising a compound of formula I, I ', II, II', III, III ', IV, IV', V or VI, and pharmaceutically acceptable salts of same, prodrugs, solvates, hydrates, tautomers, and isomers thereof and a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier may further comprise an excipient, diluent or surfactant. The pharmaceutical composition can be effective to treat a disease associated with SHP2 modulation in an individual who needs it.
[0201] [0201] Another aspect of the present invention relates to a compound of formula I, I ', II, II', III, III ', IV, IV', V or VI, and pharmaceutically acceptable salts thereof , prodrugs, solvates, hydrates, tautomers, and isomers thereof, for use in the treatment or prevention of a disease associated with SHP2 modulation.
[0202] [0202] Another aspect of the present invention relates to the use of a compound of formula I, I ', II, II', III, III ', IV, IV', V or VI, and pharmaceutically acceptable salts thereof , prodrugs, solvates, hydrates, tautomers, and isomers thereof, in the manufacture of a medication for the treatment or prevention of a disease associated with SHP2 modulation.
[0203] [0203] The present invention also provides compounds that are useful in inhibiting SHP2.
[0204] [0204] DETAILED DESCRIPTION OF THE DISCLOSURE
[0205] [0205] The details of the present invention are presented in the description attached below. Although methods and materials similar or equivalent to those described in this document can be used in the practice or testing of the present invention, illustrative methods and materials are now described. Other characteristics, objectives and advantages of the present invention will be apparent from the description and the claims. In the specification and the appended claims, singular forms also include the plural unless the context clearly indicates otherwise. Unless otherwise defined, all technical and scientific terms used in this document have the same meaning as commonly understood by a person skilled in the art to which the present invention belongs. All patents and publications cited in this specification are incorporated by reference in their entirety.
[0206] [0206] Terms
[0207] [0207] The articles “one” and “one” are used in this description to refer to one or more of one (that is, at least one) of the article's grammatical purpose. For example, “an element” means an element or more than one element.
[0208] [0208] The term "and / or" is used in this description to mean both "and" and "or" unless otherwise indicated.
[0209] [0209] By "optional" or "optionally" it is understood that the subsequently described event or circumstance may or may not occur, and that the description includes cases where it occurs and cases where it does not occur. For example, "optionally substituted aryl" encompasses both "aryl" and "substituted aryl" as defined in this document. It will be understood by those skilled in the art, with respect to any group containing one or more substituents, that said groups do not intend to introduce any substitution or substitution patterns that are sterically impracticable, synthetically unfeasible and / or inherently unstable.
[0210] [0210] It is understood that the term “optionally substituted” means that a given chemical moiety (for example, an alkyl group) may (but does not need to) be linked to other substituents (for example, heteroatoms). For example, an alkyl group that is optionally substituted may be a fully saturated alkyl chain (i.e., a pure hydrocarbon). Alternatively, the same optionally substituted alkyl group may have different substituents for hydrogen. For example, it may, at any point along the chain, be attached to a halogen atom, a hydroxyl group, or any other substituent described in this document. As such, the term “optionally substituted” means that a given chemical moiety has the potential to contain other functional groups, but it does not necessarily have any other functional groups.
[0211] [0211] The term "aryl" refers to cyclic, aromatic hydrocarbon groups that have 1 to 2 aromatic rings, including monocyclic or bicyclic groups such as phenyl, biphenyl or naphthyl. Where it contains two aromatic rings (bicyclic, etc.), the aromatic rings of the aryl group can be joined at the same point (for example, biphenyl) or fused (for example, naphthyl). The aryl group can be optionally substituted by one or more substituents, for example, 1 to 5 substituents, at any point of attachment. Exemplifying substituents include, but are not limited to, −H, −halogen, −O-C1-C6alkyl, −C1- C6alkyl, −OC2-C6alkenyl, −OC2-C6alquinyl, −C2-C6alkenyl, −C2- C6alquinyl , −OH, −OP (O) (OH) 2, −OC (O) C1-C6alkyl, −C (O) C1- C6alkyl, −OC (O) OC1-C6alkyl, −NH2, −NH (C1-C6alkyl) ), −N (C1- C6alkyl) 2, −S (O) 2-C1-C6alkyl, −S (O) NHC1-C6alkyl and −S (O) N (C1- C6alkyl) 2. The substituents can themselves be optionally substituted.
[0212] [0212] Unless specifically defined otherwise, "heteroaryl" means a monovalent or multivalent aromatic monocyclic radical or an aromatic polycyclic radical of 5 to 24 ring atoms, containing one or more ring heteroatoms selected from N , S, P and O, the remaining ring atoms being C.
[0213] [0213] "Alkyl" refers to a straight or branched chain hydrocarbon. C1-C6alkyl groups contain 1 to 6 carbon atoms. Examples of a C1-C6alkyl group include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, isopropyl, isobutyl, sec-butyl and tert-butyl, isopentyl and neopentyl.
[0214] [0214] The term "alkenyl" means an aliphatic hydrocarbon group containing a direct carbon - carbon bond and which can be direct or branched having about 2 to about 6 carbon atoms in the chain. Certain alkenyl groups have 2 to about 4 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl are attached to a linear alkenyl chain. Exemplary alkenyl groups include ethylene, propenyl, n-butenyl and i-butenyl. A C2-C6 alkenyl group is an alkenyl group containing between 2 and 6 carbon atoms.
[0215] [0215] The term "alkynyl" means an aliphatic hydrocarbon group containing a carbon-carbon triple bond and which can be straight or branched having about 2 to about 6 carbon atoms in the chain. Certain alkynyl groups have 2 to about 4 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl are attached to a linear alkynyl chain. Exemplifying alkynyl groups include ethynyl, propynyl, n-butynyl, 2-butynyl, 3-methylbutynyl and n-pentynyl. An alkynyl C2-C6 group is an alkynyl group containing between 2 and 6 carbon atoms.
[0216] [0216] The term "cycloalkyl" means monocyclic or polycyclic saturated carbon rings containing 3-18 carbon atoms. Examples of cycloalkyl groups include, without limitation, cyclopropyl, cyclo-butyl, cyclopentyl, cyclohexyl, cycloheptanyl, cyclooctanyl, norboranyl, norborenyl, bicycles [2.2.2] octanyl or bicycles [2.2.2] octenyl. A C3-C8 cycloalkyl group is a cycloalkyl group containing between 3 and 8 carbon atoms. A cycloalkyl group can be fused (for example, decalin) or branched (for example, norbornane).
[0217] [0217] The term “cycloalkenyl” means monocyclic, non-aromatic unsaturated carbon rings containing 4-18 carbon atoms.
[0218] [0218] The terms “heterocyclyl” or “heterocycloalkyl” or “heterocycle” refer to rings of 3 to 24 monocyclic or polycyclic members containing carbon and heteroatoms selected from oxygen, phosphorus, nitrogen and sulfur and in which they do not exist delocalized π electrons (aromaticity) shared between ring carbon or heteroatoms. Heterocyclyl rings include, but are not limited to, ox-ethanyl, azetadinyl, tetrahydrofuranyl, pyrrolidinyl, oxazolinyl, oxazolinyl, thiazolinyl, thiazolidinyl, pyranyl, thiopyranyl, tetrahydropyranyl, dioxalinyl, pfolidinyl, piperidinyl, morpholinyl, piperidinyl, piperidinyl, morphine, piperidinyl, piperidinyl, morphine, , thiomorpholinyl S-oxide, thio-morpholinyl S-dioxide, piperazinyl, azepinyl, oxepinyl, diazepinyl, tropanilla and homotropanil. A heterocyclyl or heterocycloalkyl ring can also be fused or branched, for example, it can be a bicyclic ring.
[0219] [0219] In some modalities “heterocyclyl” or “heterocycloalkyl” or “heterocycle” is a mono or bicyclic, saturated, partially unsaturated or unsaturated ring containing 3-24 atoms of which at least one atom is chosen from nitrogen, sulfur or oxygen, which can, unless otherwise specified, be attached to carbon or nitrogen, where a -CH2– group can optionally be replaced by a -C (O) - or a sulfur atom in the ring it can be optionally oxidized to form the S-oxides. “Heterocyclyl” can be a mono- or bicyclic, saturated, partially saturated or unsaturated ring containing 5 or 6 atoms of which at least one atom is chosen from nitrogen, sulfur or oxygen, which can, unless specified otherwise, be bonded to carbon or nitrogen, where a group -CH2– can optionally be replaced by a -
[0220] [0220] As used herein, the term "halo" or "halogen" means a fluorine, chlorine, bromine or iodine group.
[0221] [0221] The term "carbonyl" refers to a functional group comprising a double carbon atom attached to an oxygen atom. It can be abbreviated in this document as “oxo”, as C (O), or as C = O.
[0222] [0222] "Spirocycle" or "spirocyclic" means carbogenic bicyclic ring systems with both rings connected through a single atom. The ring can be different in size and nature, or identical in size and nature. Examples include spiropentane, spirohexane, spiroheptane, spirooctan, spirononian or spirodecane. One or both rings on a spirocycle can be fused to another carbocyclic, heterocyclic, aromatic or heteroaromatic ring. One or more of the carbon atoms in the spirocycle can be replaced with a hetero atom (for example, O, N, S or P). A C5-C12 spirocycle is a spirocycle containing between 5 and 12 carbon atoms. In some embodiments, a C5-C12 spirocycle is a spirocycle containing 5 to 12 carbon atoms. One or more of the carbon atoms can be replaced with a hetero atom.
[0223] [0223] It is understood that the term "spirocyclic heterocycle", "spirohetterocycline" or "spiroheterocycle" means a spirocycle in which at least one of the rings is a heterocycle (for example, at least one of the rings is furanyl, morpholinyl or piperadinyl). A spirocyclic heterocycle can contain between 5 and 12 atoms, at least one of which is a heteroatom selected from N, O, S and P. In some embodiments, a spirocyclic heterocycle can contain at least 5 to 12 atoms one of which is a heteroatom selected from N, O, S and P.
[0224] [0224] The description also includes pharmaceutical compositions comprising an effective amount of a disclosed compound and a pharmaceutically acceptable carrier. Representative "pharmaceutically acceptable salts" include, for example, water-soluble salts and non-water-soluble salts, such as acetate, amsonate (4,4-diaminostilbene-2,2-disulfonate), benzenesulfonate, benzonate, bicarbonate, bisulfate , bitartrate, borate, bromide, butyrate, calcium, calcium edetate, camsylate, carbonate, chloride, citrate, clavulariate, dihydrochloride, edetate, edisylate, stolate, esilate, fiunarate, gluceptate, gluconate, glutamate, glycolylsulfate, hexafluorohydrate, hexafluorosulfate , hydrabamine, hydrobromide, hydrochloride, hydroxinaftoate, iodate, setionate, lactate, lac Tobionate, laurate, magnesium, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, N-methyl saline ammonium, 3-hydroxy-oxy-2-naphthoate, oleate, oxalate, palmitate, pamoate (1,1-methylene-bis-2-hydroxy-oxy-3-naphthoate, einbonate), pantothenate, phosphate / diphosphate, picrate , polygalacturonate, propionate, p-toluenesulfonat o, salicylate, stearate, subacetate, succinate, sulfate, sulfosalicylate, suramate, tannate, tartrate, theoclate, tosylate, trietiodide, and valerate salts.
[0225] [0225] The term “tautomers” refers to a set of compounds that have the same number and type of atoms, but differ in the connectivity of the bond and are in balance with each other. A "tautomer" is a unique member of this set of compounds. Typically, a single tautomer is illustrated, but it is understood that this unique structure is intended to represent all possible tautomers that may exist. Examples include enol ketone tautomerism. When a ketone is illustrated, it is understood that both the enol and ketone forms are part of the present invention.
[0226] [0226] For example, the compounds of the present invention can exist in tautomeric form. In some modalities of formula I, I ', II, II', III, III ', IV, IV', V or VI, X1 can be CR2 and R2 can be oxygen and X2 can be nitrogen and the tautomers of the compounds can exist in balance:.
[0227] [0227] The compounds of the present invention can also include all isotopes of atoms that occur in the intermediates or final compounds. Isotopes include those atoms having the same atomic number but different mass numbers. For example, hydrogen isotopes include tritium and deuterium. One or more atoms constituting the compounds of the present invention can be exchanged or replaced with isotopes of the atoms in natural or unnatural abundance. In some embodiments, the compound comprises at least one deuterium atom. For example, one or more hydrogen atoms in a compound of the present invention can be exchanged or replaced with deuterium. In some embodiments, the compound comprises two or more deuterium atoms. In some embodiments, the compound comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 deuterium atoms. Synthetic methods for including isotopes in organic compounds are known in the art.
[0228] [0228] The term "prodrug" as used in this description, means a compound that is convertible in vivo by metabolic means (for example, through hydrolysis) into a disclosed compound. In addition, as used herein a prodrug is a drug that is inactive in the body, but is typically transformed in the body either during absorption or after absorption in the gastrointestinal tract of the active compound. The conversion of the prodrug into the active compound in the body can be done chemically or biologically (that is, using an enzyme).
[0229] [0229] The term "solvate" refers to a complex of variable stoichiometry formed by a solute and solvent. Said solvents for the purpose of the present invention may not interfere with the biological activity of the solute. Examples of suitable solvents include, but are not limited to, water, MeOH, EtOH and AcOH. Solvates in which water is the solvent molecule are typically referred to as hydrates. Hydrates include compositions containing stoichiometric amounts of water, as well as compositions containing varying amounts of water.
[0230] [0230] The term "isomer" refers to compounds that have the same composition and molecular weight but differ in physical and / or chemical properties. The structural difference can be in constitution (geometric isomers) or in the ability to rotate the plane of polarized light (stereoisomers). With respect to stereoisomers, the compounds of formula I can have one or more asymmetric carbon atoms and can occur as racemates, racemic mixtures and as individual enantiomers or diastereomers.
[0231] [0231] The term "stereoisomers" refers to the set of compounds that have the same number and type of atoms and share the same connecting connectivity between those atoms, but differ in the three-dimensional structure. The term "stereoisomer" refers to any member of this set of compounds. For example, a stereoisomer can be an enantiomer or a diastereomer.
[0232] [0232] The term "enantiomers" refers to a pair of stereoisomers that are mirror images superimposed on each other. The term "enantiomer" refers to a single member of this pair of stereoisomers. The term "racemic" refers to a 1: 1 mixture of a pair of enantiomers.
[0233] [0233] The term "diastereomers" refers to the set of stereoisomers that cannot be superimposed by praying around single bonds. For example, cis and trans double bonds, endo- and exo- substitution in bicyclic ring systems, and compounds containing multiple stereogenic centers with different relative configurations are considered to be diastereomers. The term "diastereomer" refers to any member of this set of compounds. In some examples presented, the synthetic route can produce a single diastereomer or a mixture of diastereomers.
[0234] [0234] An "effective amount" when used in connection with a compound is an amount effective to treat or prevent disease in an individual as described in this document.
[0235] [0235] The term "vehicle", as used in this description, encompasses excipients and diluents and means a material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in the loading or transport of a pharmaceutical agent from one organ, or body part, to another organ, or body part of an individual.
[0236] [0236] The term "treat" in relation to an individual, refers to improving at least one symptom of the individual's disorder. Treating includes healing, improving, or at least partially improving the disorder.
[0237] [0237] The term “prevent” or “preventing” in relation to an individual refers to maintaining a disease or disorder to afflict the individual. Prevention includes prophylactic treatment. For example, prevention may include administering to the individual a compound disclosed in the present document before an individual is afflicted with a disease and administration will keep the individual from being afflicted with the disease.
[0238] [0238] The term "disorder" is used in this description to mean, is used interchangeably with, the terms disease, condition, or illness, unless otherwise indicated.
[0239] [0239] The term "administer", "administering" or "administration" as used in this description refers to either directly administering a disclosed compound or pharmaceutically acceptable salt of the disclosed compound or composition to an individual, or administering a derivative of prodrug or analogue of the compound or pharmaceutically acceptable salt of the compound or composition to the individual, which can form an equivalent amount of active compound within the individual's body.
[0240] [0240] A "patient" or "individual" is a mammal, for example, a human, mouse, rat, guinea pig, dog, cat, horse, pig or non-human primate, such as an ape, chimpanzee, bear buíno or rhesus.
[0241] [0241] Compounds of the formulas disclosed
[0242] [0242] In a first aspect, the compounds of formula I 'are described:
[0243] [0243] and pharmaceutically acceptable salts thereof, prodrugs, solvates, hydrates, tautomers, or isomers thereof, wherein B, X1, X2, R3, R4 and Y2 are described as above.
[0244] [0244] In another aspect, the compounds of formula I are described:
[0245] [0245] and pharmaceutically acceptable salts thereof, prodrugs, solvates, hydrates, tautomers, or isomers thereof, wherein B, X1, X2, R3, R4 and Y2 are described as above.
[0246] [0246] In another aspect, the compounds of formula II 'are described:
[0247] [0247] and pharmaceutically acceptable salts thereof, prodrugs, solvates, hydrates, tautomers, or isomers thereof, wherein A, B, X1, X2, R1, R3, Y1, Y2 and n are described as above.
[0248] [0248] In another aspect, the compounds of formula II are described:
[0249] [0249] and pharmaceutically acceptable salts thereof, prodrugs, solvates, hydrates, tautomers, or isomers thereof, wherein A, B, X1, X2, R1, R3, Y1, Y2 and n are described as above.
[0250] [0250] In another aspect, the compounds of the formula III 'are described:
[0251] [0251] and pharmaceutically acceptable salts thereof, prodrugs, solvates, hydrates, tautomers, or isomers thereof, wherein A, B, X1, X2, R1, R3, Y2 and n are described as above.
[0252] [0252] In another aspect, the compounds of formula III are described:
[0253] [0253] and pharmaceutically acceptable salts thereof, prodrugs, solvates, hydrates, tautomers, or isomers thereof, wherein A, B, X1, X2, R1, R3, Y2 and n are described as above.
[0254] [0254] In another aspect, the compounds of formula IV 'are described:
[0255] [0255] and pharmaceutically acceptable salts thereof, prodrugs, solvates, hydrates, tautomers, or isomers thereof, wherein A, B, X1, X2, R1, R3, Y2 and n are described as above.
[0256] [0256] In another aspect, the compounds of formula IV are described:
[0257] [0257] and pharmaceutically acceptable salts thereof, prodrugs, solvates, hydrates, tautomers, or isomers thereof, wherein A, B, X1, X2, R1, R3, Y2 and n are described as above.
[0258] [0258] In another aspect, the compounds of formula V are described:
[0259] [0259] and pharmaceutically acceptable salts thereof, prodrugs, solvates, hydrates, tautomers, or isomers thereof, wherein A, B, X1, X2, R1, R3, Y1, Y2 and n are described as above.
[0260] [0260] In another aspect, the compounds of formula VI are described:
[0261] [0261] and pharmaceutically acceptable salts thereof, prodrugs, solvates, hydrates, tautomers, or isomers thereof, where A, B, D, X1, X2, X3, R1, R3, Y1, Y2 and n are described as above.
[0262] [0262] In certain modalities of formula I and I ', the compound is of formula I-A:
[0263] [0263] and pharmaceutically acceptable salts thereof, prodrugs, solvates, hydrates, tautomers, and isomers thereof, where XB1 is N, CH, S, or O; XB2 is N, CH, S, or O; and XB3 is N, CH, S, or O.
[0264] [0264] In certain modalities, XB1 is N. In certain modalities, XB1 is CH. In certain modalities, XB1 is S. In certain modalities, XB1 is O. In certain modalities, XB2 is N. In certain modalities, XB2 is CH. In certain modalities, XB2 is S. In certain modalities, XB2 is O. In certain modalities, XB3 is N. In certain modalities, XB3 is CH. In certain modalities, XB3 is S. In certain modalities, XB3 is O.
[0265] [0265] In certain modalities, XB1 is N or CH; XB2 is N or CH; and XB3 is N or CH. In certain embodiments, XB1 is N. In certain embodiments, XB1 is CH. In certain embodiments, XB2 is N. In certain embodiments, XB2 is CH. In certain embodiments, XB3 is N. In certain embodiments, XB3 is CH.
[0266] [0266] In certain modalities of formula I-A,, where it is a single bond or double bond to satisfy valence rules, it is,,,,,,, or.
[0267] [0267] In certain modalities of formula I and I ', the compound is of formula I-B:
[0268] [0268] and pharmaceutically acceptable salts thereof, prodrugs, solvates, hydrates, tautomers, and isomers thereof, where XB4 is N or CH; XB5 is N or CH; XB6 is N or CH; and XB7 is N or CH.
[0269] [0269] In certain modalities, XB4 is N. In certain modalities, XB4 is CH. In certain embodiments, XB5 is N. In certain embodiments, XB5 is CH. In certain embodiments, XB6 is N. In certain embodiments, XB6 is CH. In certain embodiments, XB7 is N. In certain embodiments, XB7 is CH.
[0270] [0270] In certain modalities of formula I and I ', the compound is of formula I-C:
[0271] [0271] and pharmaceutically acceptable salts thereof, prodrugs, solvates, hydrates, tautomers, and isomers thereof.
[0272] [0272] In certain modalities of formula I and I ', the compound is of formula I-D:
[0273] [0273] and pharmaceutically acceptable salts thereof, prodrugs, solvates, hydrates, tautomers, and isomers thereof, where:
[0274] [0274] C forms a 3 to 12 membered monocyclic heterocycle, a 3 to 12 membered polycyclic heterocycle, a 5 to 12 membered spiroheterocycle, together with the nitrogen atom to which it is attached, to which the heterocycle or spiroheterocycle is optionally substituted with –C1-C6alkyl, –OH, or –NH2.
[0275] [0275] In certain modalities of formula I-D, ring C, together with the nitrogen atom to which it is attached, is an optionally substituted 3 to 12 membered monocyclic heterocycle. In certain embodiments, ring C, together with the nitrogen atom to which it is attached, is an optionally substituted 3 to 12 membered polycyclic heterocycle. In certain embodiments, ring C, together with the nitrogen atom to which it is attached, is an optionally substituted 5 to 12 membered spiroheterocycle.
[0276] [0276] In certain modalities of formula ID, C forms a 3 to 12 membered monocyclic heterocycle, 3 to 12 membered polycyclic heterocycle, a 5 to 12 membered spiroheterocycle, together with the nitrogen atom to which it is attached , in which the heterocycle or spirohet-erocycle is replaced with –NH2.
[0277] [0277] In certain embodiments, ring C, together with the nitrogen atom to which it is attached, is an optionally sub-
[0278] [0278] In certain modalities of formula I and I ', the compound is of formula I-E:
[0279] [0279] and pharmaceutically acceptable salts thereof, prodrugs, solvates, hydrates, tautomers, and isomers thereof, where XB4 is N or CH; XB5 is N or CH; XB6 is N or CH; and XB7 is N or CH.
[0280] [0280] In certain modalities of formula I and I ', the compound is of formula I-F:
[0281] [0281] and pharmaceutically acceptable salts thereof, prodrugs, solvates, hydrates, tautomers, and isomers thereof, where XB4 is N or CH; XB5 is N or CH; XB6 is N or CH; and XB7 is N or CH.
[0282] [0282] In certain modalities of formula I and I ', R4 is H. In certain modalities, R4 is.
[0283] [0283] In certain modalities of formula II and II ', the compound is of formula II-A:
[0284] [0284] and pharmaceutically acceptable salts thereof, prodrugs, solvates, hydrates, tautomers, and isomers thereof, where XB1 is N, CH, S or O; XB2 is N, CH, S or O; and XB3 is N, CH, S or O.
[0285] [0285] In certain modalities, XB1 is N. In certain modalities, XB1 is CH. In certain modalities, XB1 is S. In certain modalities, XB1 is O. In certain modalities, XB2 is N. In certain modalities, XB2 is CH. In certain modalities, XB2 is S. In certain modalities, XB2 is O. In certain modalities, XB3 is N. In certain modalities, XB3 is CH. In certain modalities, XB3 is S. In certain modalities, XB3 is O.
[0286] [0286] In certain embodiments, XB1 is N or CH; XB2 is N or CH; and XB3 is N or CH. In certain embodiments, XB1 is N. In certain embodiments, XB1 is CH. In certain embodiments, XB2 is N. In certain embodiments, XB2 is CH. In certain embodiments, XB3 is N. In certain embodiments, XB3 is CH.
[0287] [0287] In certain modalities of formula II-A,, where it is a single bond or double bond to satisfy the rules of valence, it is,,,,,,, or.
[0288] [0288] In certain modalities of formula II and II ', the compound is of formula II-B:
[0289] [0289] and pharmaceutically acceptable salts thereof, prodrugs, solvates, hydrates, tautomers, and isomers thereof, where XB4 is N or CH; XB5 is N or CH; XB6 is N or CH; and XB7 is N or CH.
[0290] [0290] In certain modalities, XB4 is N. In certain modalities, XB4 is CH. In certain embodiments, XB5 is N. In certain embodiments, XB5 is CH. In certain embodiments, XB6 is N. In certain embodiments, XB6 is CH. In certain embodiments, XB7 is N. In certain embodiments, XB7 is CH.
[0291] [0291] In certain modalities of formula II and II ', the compound is of formula II-C:
[0292] [0292] and pharmaceutically acceptable salts thereof, prodrugs, solvates, hydrates, tautomers, and isomers thereof.
[0293] [0293] In certain modalities of formula II and II ', the compound is of formula II-D:
[0294] [0294] and pharmaceutically acceptable salts thereof, prodrugs, solvates, hydrates, tautomers, and isomers thereof, where:
[0295] [0295] C forms a 3 to 12 membered monocyclic heterocycle, 3 to 12 membered polycyclic heterocycle, a 5 to 12 membered spiroheterocycle, together with the nitrogen atom to which it is attached, to which the heterocycle or spiroheterocycle is optionally substituted with –C1-C6alkyl, –OH or –NH2.
[0296] [0296] In certain modalities of formula II-D, ring C, together with the nitrogen atom to which it is attached, is an optionally substituted 3 to 12 membered monocyclic heterocycle. In certain embodiments, ring C, together with the nitrogen atom to which it is attached, is an optionally substituted 3 to 12 membered polycyclic heterocycle. In certain embodiments, ring C, together with the nitrogen atom to which it is attached, is an optionally substituted 5 to 12 membered spiroheterocycle.
[0297] [0297] In certain modalities of formula II-D, C forms a 3 to 12 membered monocyclic heterocycle, 3 to 12 membered polycyclic heterocycle, a 5 to 12 membered spiroheterocycle, together with the nitrogen atom to which it is on, in which the heterocycle or spiroheterocycle is replaced with –NH2.
[0298] [0298] In certain modalities, ring C, together with the nitrogen atom to which it is attached, is an optionally substituted. In certain embodiments, ring C, together with the nitrogen atom to which it is attached, is an optionally substituted.
[0299] [0299] In certain modalities of formula II and II ', the compound is of formula II-E:
[0300] [0300] and pharmaceutically acceptable salts thereof, prodrugs, solvates, hydrates, tautomers, and isomers thereof, where XB4 is N or CH; XB5 is N or CH; XB6 is N or CH; and XB7 is N or CH.
[0301] [0301] In certain modalities of formula II and II ', the compound is of formula II-F:
[0302] [0302] and pharmaceutically acceptable salts thereof, prodrugs, solvates, hydrates, tautomers, and isomers thereof, where XB4 is N or CH; XB5 is N or CH; XB6 is N or CH; and XB7 is N or CH.
[0303] [0303] In certain embodiments of formula III and III ', the compound is of formula III-A:
[0304] [0304] and pharmaceutically acceptable salts thereof, prodrugs, solvates, hydrates, tautomers, and isomers thereof, where XB1 is N, CH, S or O; XB2 is N, CH, S or O; and XB3 is N, CH, S or O.
[0305] [0305] In certain modalities, XB1 is N. In certain modalities, XB1 is CH. In certain modalities, XB1 is S. In certain modalities, XB1 is O. In certain modalities, XB2 is N. In certain modalities, XB2 is CH. In certain modalities, XB2 is S. In certain modalities, XB2 is O. In certain modalities, XB3 is N. In certain modalities, XB3 is CH. In certain modalities, XB3 is S. In certain modalities, XB3 is O.
[0306] [0306] In certain embodiments, XB1 is N or CH; XB2 is N or CH; and XB3 is N or CH. In certain embodiments, XB1 is N. In certain embodiments, XB1 is CH. In certain embodiments, XB2 is N. In certain embodiments, XB2 is CH. In certain embodiments, XB3 is N. In certain embodiments, XB3 is CH.
[0307] [0307] In certain modalities of formula III-A,, where it is a single bond or double bond to satisfy the rules of valence, it is,,,,,,, or.
[0308] [0308] In certain embodiments of formula III and III ', the compound is of formula III-B:
[0309] [0309] and pharmaceutically acceptable salts thereof, prodrugs, solvates, hydrates, tautomers, and isomers thereof, where XB4 is N or CH; XB5 is N or CH; XB6 is N or CH; and XB7 is N or CH.
[0310] [0310] In certain modalities, XB4 is N. In certain modalities, XB4 is CH. In certain embodiments, XB5 is N. In certain embodiments, XB5 is CH. In certain embodiments, XB6 is N. In certain embodiments, XB6 is CH. In certain embodiments, XB7 is N. In certain embodiments, XB7 is CH.
[0311] [0311] In certain modalities of formula III and III ', the compound is of formula III-C:
[0312] [0312] and pharmaceutically acceptable salts thereof, prodrugs, solvates, hydrates, tautomers, and isomers thereof.
[0313] [0313] In certain modalities of formula III and III ', the compound is of formula III-D:
[0314] [0314] and pharmaceutically acceptable salts thereof, prodrugs, solvates, hydrates, tautomers, and isomers thereof, where:
[0315] [0315] C forms a 3 to 12 membered monocyclic heterocycle, 3 to 12 membered polycyclic heterocycle, a 5 to 12 membered spiroheterocycle, together with the nitrogen atom to which it is attached, to which the heterocycle or spiroheterocycle is optionally substituted with –C1-C6alkyl, –OH or –NH2.
[0316] [0316] In certain modalities of formula III-D, ring C, together with the nitrogen atom to which it is attached, is an optionally substituted 3 to 12 membered monocyclic heterocycle. In certain embodiments, ring C, together with the nitrogen atom to which it is attached, is an optionally substituted 3 to 12 membered polycyclic heterocycle. In certain embodiments, ring C, together with the nitrogen atom to which it is attached, is an optionally substituted 5 to 12 membered spiroheterocycle.
[0317] [0317] In certain modalities of formula III-D, C forms a 3 to 12 membered monocyclic heterocycle, 3 to 12 membered polycyclic heterocycle, a 5 to 12 membered spiroheterocycle, together with the nitrogen atom to which it is linked, in which the heterocycle or spirohet-erocycle is replaced with –NH2.
[0318] [0318] In certain modalities, ring C, together with the nitrogen atom to which it is attached, is an optionally substituted. In certain embodiments, ring C, together with the nitrogen atom to which it is attached, is an optionally substituted.
[0319] [0319] In certain modalities of formula III and III ', the compound is of formula III-E:
[0320] [0320] and pharmaceutically acceptable salts thereof, prodrugs, solvates, hydrates, tautomers, and isomers thereof, where XB4 is N or CH; XB5 is N or CH; XB6 is N or CH; and XB7 is N or CH.
[0321] [0321] In certain embodiments of formula III and III ', the compound is of formula III-F:
[0322] [0322] and pharmaceutically acceptable salts thereof, prodrugs, solvates, hydrates, tautomers, and isomers thereof, where
[0323] [0323] In certain modalities of formula IV and IV ', the compound is of formula IV-A:
[0324] [0324] and pharmaceutically acceptable salts thereof, prodrugs, solvates, hydrates, tautomers, and isomers thereof, where XB1 is N, CH, S or O; XB2 is N, CH, S or O; and XB3 is N, CH, S or O.
[0325] [0325] In certain modalities, XB1 is N. In certain modalities, XB1 is CH. In certain modalities, XB1 is S. In certain modalities, XB1 is O. In certain modalities, XB2 is N. In certain modalities, XB2 is CH. In certain modalities, XB2 is S. In certain modalities, XB2 is O. In certain modalities, XB3 is N. In certain modalities, XB3 is CH. In certain modalities, XB3 is S. In certain modalities, XB3 is O.
[0326] [0326] In certain embodiments, XB1 is N or CH; XB2 is N or CH; and XB3 is N or CH. In certain embodiments, XB1 is N. In certain embodiments, XB1 is CH. In certain embodiments, XB2 is N. In certain embodiments, XB2 is CH. In certain embodiments, XB3 is N. In certain embodiments, XB3 is CH.
[0327] [0327] In certain modalities of formula IV-A,, where it is a single or double bond to satisfy the rules of valência, it is,,,,
[0328] [0328] In certain modalities of formula IV and IV ', the compound is of formula IV-B:
[0329] [0329] and pharmaceutically acceptable salts thereof, prodrugs, solvates, hydrates, tautomers, and isomers thereof, where XB4 is N or CH; XB5 is N or CH; XB6 is N or CH; and XB7 is N or CH.
[0330] [0330] In certain modalities, XB4 is N. In certain modalities, XB4 is CH. In certain embodiments, XB5 is N. In certain embodiments, XB5 is CH. In certain embodiments, XB6 is N. In certain embodiments, XB6 is CH. In certain embodiments, XB7 is N. In certain embodiments, XB7 is CH.
[0331] [0331] In certain embodiments of formula IV and IV ', the compound is of formula IV-C:
[0332] [0332] and pharmaceutically acceptable salts thereof, prodrugs, solvates, hydrates, tautomers, and isomers thereof.
[0333] [0333] In certain modalities of formula IV and IV ', the compound is of formula IV-D:
[0334] [0334] and pharmaceutically acceptable salts thereof, prodrugs, solvates, hydrates, tautomers, and isomers thereof, in which:
[0335] [0335] C forms a 3 to 12 membered monocyclic heterocycle, 3 to 12 membered polycyclic heterocycle, a 5 to 12 membered spiroheterocycle, together with the nitrogen atom to which it is attached, to which the heterocycle or spiroheterocycle is optionally substituted with –C1-C6alkyl, –OH or –NH2.
[0336] [0336] In certain modalities of formula IV-D, ring C, together with the nitrogen atom to which it is attached, is an optionally substituted 3 to 12 membered monocyclic heterocycle. In certain embodiments, ring C, together with the nitrogen atom to which it is attached, is an optionally substituted 3 to 12 membered polycyclic heterocycle. In certain embodiments, ring C, together with the nitrogen atom to which it is attached, is an optionally substituted 5 to 12 membered spiroheterocycle.
[0337] [0337] In certain modalities of formula IV-D, C forms a 3 to 12 membered monocyclic heterocycle, 3 to 12 membered polycyclic heterocycle, a 5 to 12 membered spiroheterocycle, together with the nitrogen atom to which it is linked, in which the heterocycle or spirohet-erocycle is replaced with –NH2.
[0338] [0338] In certain embodiments, ring C, together with the nitrogen atom to which it is attached, is an optionally sub-
[0339] [0339] In certain modalities of formula IV and IV ', the compound is of formula IV-E:
[0340] [0340] and pharmaceutically acceptable salts thereof, prodrugs, solvates, hydrates, tautomers, and isomers thereof, where XB4 is N or CH; XB5 is N or CH; XB6 is N or CH; and XB7 is N or CH.
[0341] [0341] In certain modalities of formula IV and IV ', the compound is of formula IV-F:
[0342] [0342] and pharmaceutically acceptable salts thereof, prodrugs, solvates, hydrates, tautomers, and isomers thereof, where XB4 is N or CH; XB5 is N or CH; XB6 is N or CH; and XB7 is N or CH.
[0343] [0343] Certain modalities of formula I-IV and I'-IV 'and V-VI are described below.
[0344] [0344] In certain modalities, Y1 is –S–. In certain embodiments, Y1 is a direct link. In certain embodiments, Y1 is –NH-. In certain embodiments, Y1 is –C (= CH2) - or –CH2-. In certain modalities, Y1 is -
[0345] [0345] In certain modalities, X1 is N. In certain modalities, X1 is CR2. In certain embodiments, R2 is –H, –NH2, -ORb, or –C1-C6alkyl. In certain embodiments, R2 is –H, –NH2, -OH or –CH3.
[0346] [0346] In certain modalities, X2 is N. In certain modalities, X2 is CH.
[0347] [0347] In certain modalities, X1 is N and X2 is N. In certain modalities, X1 is N and X2 is CH. In certain embodiments, X1 is CR2 and X2 is N. In certain embodiments, X1 is C and X2 is CR2. In certain embodiments, R2 is –H, –NH2, -OH or –C1-C6alkyl.
[0348] [0348] In certain embodiments, R2 is independently –H, –NH2, –ORb, –CN, –C1-C6alkyl, –C2-C6alkenyl, –C4-C8cycloalkenyl, - C2-C6alkynyl, halogen, –C (O) ORb , –C3-C8cycloalkyl, heterocyclyl containing 1-5 heteroatoms selected from the group consisting of N, S, P and O, or heteroaryl containing 1-5 heteroatoms selected from the group consisting of N, S, P and O; where each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, heterocyclyl or heteroaryl is optionally substituted with one or more –OH, halogen, –NO2, oxo, –CN, −R5, –OR5, –NR5R6, −SR5, –S (O) 2NR5R6, –S (O) 2R5, - NR5S (O) 2NR5R6, –NR5S (O) 2R6, –S (O) NR5R6, –S (O) R5, –NR5S (O) NR5R6, - NR5S (O) R6, heterocycle, aryl or heteroaryl.
[0349] [0349] In certain embodiments, R2 is independently –H, –NH2, –ORb, –CN, –C1-C6alkyl, –C2-C6alkenyl, –C4-C8cycloalkenyl, - C2-C6alkynyl, halogen, –C (O) ORb , –C3-C8cycloalkyl, aryl, heterocyclyl containing 1-5 heteroatoms selected from the group consisting of N, S, P and O, or heteroaryl containing 1-5 heteroatoms selected from the group consisting of N , S, P and O; where each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more –OH, halogen, –NO2, oxo, −R5, –OR5, –NR5R6, −SR5, –S ( O) 2NR5R6, -
[0350] [0350] In certain modalities, if R2 is aryl, then the aryl is optionally substituted with one or more –OH, halogen, –NO2, oxo, −R5, –OR5, –NR5R6, −SR5, –S (O ) 2NR5R6, –S (O) 2R5, –NR5S (O) 2NR5R6, –NR5S (O) 2R6, –S (O) NR5R6, –S (O) R5, –NR5S (O) NR5R6, –NR5S (O) R6, heterocycle, aryl or heteroaryl.
[0351] [0351] In certain embodiments, R2 is –H. In certain embodiments, R2 is –NH2. In certain embodiments, R2 is OH. In certain embodiments, R2 is CH3. In certain embodiments, R2 is ORb. In certain embodiments, R2 is –C1-C6alkyl. In certain embodiments, R2 is –CN. In certain modalities, R2 is –C2-C6alkenyl. In certain embodiments, R2 is –C4-C8cycloalkenyl. In certain embodiments, R2 is –C2-C6alkynyl. In certain embodiments, R2 is –C3-C8cycloalkyl. In certain embodiments, R2 is aryl. In certain embodiments, R2 is heterocyclyl containing 1-5 heteroatoms selected from the group consisting of N, S, P or O. In one or more modalities, R2 is either heteroaryl containing 1-5 heteroatoms selected from the group consisting of in N, S, P or O.
[0352] [0352] In certain embodiments, B, including the atoms at the points of attachment, is a 5- to 12-membered monocyclic or polycyclic heterocycle. In certain embodiments, B, including the atoms at the points of attachment, is a 5- to 6-membered monocyclic heterocycle. In certain embodiments, B, including the atoms at the points of attachment, is a 7 to 12-membered monocyclic heterocycle.
[0353] [0353] In certain embodiments, B, including the atoms at the points of attachment, is a 5- to 12-membered polycyclic heterocyclyl. In certain embodiments, the heterocyclyl ring is fused. In certain embodiments, the heterocyclyl ring is bridged.
[0354] [0354] In one or more modalities, B, including the atoms at the points of attachment, is a 5- to 12-membered monocyclic or polycyclic heteroaryl. In certain embodiments, B, including the atoms at the points of attachment, is a 5- to 6-membered monocyclic heteroaryl. In certain embodiments, B, including the atoms at the points of attachment, is a 7 to 12-membered monocyclic heteroaryl.
[0355] [0355] In certain embodiments, B, including atoms at the points of attachment, is a 5- to 12-membered polycyclic heteroaryl. In certain embodiments, polycyclic heteroaryl is a condensed multiple ring as described above. The rings of the multiple condensed ring system can be connected to each other via fused, spiro and bridged connections when permitted by valency requirements.
[0356] [0356] In certain embodiments, where B, including the atoms at the points of attachment, is, where XB1 is N, CH, S, or O; XB2 is N, CH, S, or O; XB3 is N, CH, S, or O; and where it is a single or double bond to satisfy the valence rules.
[0357] [0357] In certain modalities, XB1 is N. In certain modalities, XB1 is CH. In certain modalities, XB1 is S. In certain modalities, XB1 is O. In certain modalities, XB2 is N. In certain modalities, XB2 is CH. In certain modalities, XB2 is S. In certain modalities, XB2 is O. In certain modalities, XB3 is N. In certain modalities, XB3 is CH. In certain modalities, XB3 is S. In certain modalities, XB3 is O.
[0358] [0358] In certain embodiments, XB1 is N or CH; XB2 is N or CH; and XB3 is N or CH. In certain embodiments, XB1 is N. In certain embodiments, XB1 is CH. In certain embodiments, XB2 is N. In certain embodiments, XB2 is CH. In certain embodiments, XB3 is N. In certain embodiments, XB3 is CH.
[0359] [0359] In certain embodiments, where B, including the atoms at the points of attachment, is,,,,,,, or.
[0360] [0360] In certain embodiments, B, including the atoms at the points of attachment, is, where XB4 is N or CH; XB5 is N or CH; XB6 is N or CH; and XB7 is N or CH; and where it is a single or double bond to satisfy the valence rules.
[0361] [0361] In certain modalities, XB4 is N. In certain modalities, XB4 is CH. In certain embodiments, XB5 is N. In certain embodiments, XB5 is CH. In certain embodiments, XB6 is N. In certain embodiments, XB6 is CH. In certain embodiments, XB7 is N. In certain embodiments, XB7 is CH.
[0362] [0362] In certain modalities, where B, including atoms at the points of attachment, is, where it is a single bond or double bond to satisfy the valence rules.
[0363] [0363] In certain modalities of formula VI, D, including atoms at the points of attachment, is a monocyclic heterocycle of 5 to 7 members. In certain embodiments, D, including the atoms at the points of attachment, is a 5- to 6-membered monocyclic heterocycle.
[0364] [0364] In certain modalities of formula VI, D, including the atoms at the points of attachment, is a monocyclic heteroaryl of 5 to 7 members. In certain embodiments, D, including atoms at the points of attachment, is a 5- to 6-membered monocyclic heteroaryl.
[0365] [0365] In certain modalities of formula VI, X3 is N. In certain modalities of formula VI, X3 is C.
[0366] [0366] In certain modalities, A is a cycloalkyl. In certain embodiments, A is heterocycloalkyl. In certain embodiments, A is a monocyclic heterocycloalkyl. In certain embodiments, A is a bicyclic heterocycloalkyl. In certain embodiments, A is aryl. In certain embodiments, A is phenyl. In certain embodiments, A is heteroaryl. In certain embodiments, A is pyridyl.
[0367] [0367] In certain embodiments, A is a 5- to 12-membered monocyclic heteroaryl. In certain embodiments, A is a 5- to 12-membered polycyclic heteroaryl. In certain embodiments, A is a 5- to 12-membered monocyclic aryl. In certain modalities, A is polycyclic aryl of 5 to 12 members. In certain embodiments, A is a 5- to 12-membered monocyclic heterocycloalkyl. In certain embodiments, A is 5 to 12-membered polycyclic heterocycloalkyl. In certain embodiments, A is a 5- to 12-membered monocyclic cycloalkyl. In certain embodiments, A is 5 to 12-membered polycyclic cycloalkyl.
[0368] [0368] In certain embodiments, R1 is independently –OH, - NO2, –CN, halogen or –NR5R6. In certain modalities, n is 1. In certain modalities, n is 2. In certain modalities, n is 3. In certain modalities, n is 4.
[0369] [0369] In certain modalities, A, including R1, is selected from the group consisting of, and. In certain modalities, A, including R1, is selected from the con-
[0370] [0370] In certain embodiments, Y2 is –NRa–, - (CRa2) m -, - C (Ra) 2NH–, - (CRa2) mO–, –C (O) N (Ra) -, –N (Ra ) C (O) -, –S (O) 2N (Ra) -, –N (Ra) S (O) 2–, –N (Ra) C (O) N (Ra) -, –N (Ra) C (S) N (Ra) -, –C (O) O–, –OC (O) -, - OC (O) N (Ra) -, –N (Ra) C (O) O–, –C (O) N (Ra) O–, –N (Ra) C (S) -, - C (S) N (Ra) -, or –OC (O) O–; wherein the connection on the left side of Y2, as shown, is connected to the ring and the connection on the right side of the Y2 portion, as shown, is connected to R3.
[0371] [0371] In certain embodiments, Y2 is –NRa–, - (CRa2) m -, - C (Ra) 2NH–, - (CRa2) mO–, –S (O) 2N (Ra) -, –N (Ra ) S (O) 2 -, - N (Ra) C (S) N (Ra) -, - N (Ra) C (S) - or –C (S) N (Ra) -; wherein the connection on the left side of Y2, as shown, is connected to the ring and the connection on the right side of the Y2 portion, as shown, is connected to R3.
[0372] [0372] In certain embodiments, Y2 is –NRa -, - C (Ra) 2NH -, - C (O) N (Ra) -, –N (Ra) C (O) -, –S (O) 2N ( Ra) -, –N (Ra) S (O) 2–, - N (Ra) C (O) N (Ra) -, –N (Ra) C (S) N (Ra) -, - OC (O ) N (Ra) -, –N (Ra) C (O) O–, - C (O) N (Ra) O–, –N (Ra) C (S) - or –C (S) N (Ra ) -; wherein the connection on the left side of Y2, as shown, is connected to the ring and the connection on the right side of the Y2 portion, as shown, is connected to R3.
[0373] [0373] In certain modalities, Y2 is –NRa–. In certain modalities, Y2 is - (CRa2) m–. In certain embodiments, Y2 is –C (O) -. In certain embodiments, Y2 is –C (Ra) 2NH– or - (CRa2) mO–. In certain modalities,
[0374] [0374] In certain modalities, Ra is –H. In certain embodiments, Ra is –OH. In one or more modalities, Ra is –C3-C8cycloalkyl. In certain modalities, Ra is –C1-C6alkyl.
[0375] [0375] In certain embodiments, R3 is –C1-C6alkyl. In certain embodiments, R3 is a monocyclic or polycyclic heterocycle of 3 to 12 members. In certain embodiments, R3 is a 3- to 12-membered monocyclic heterocycle. In certain embodiments, R3 is a 5- to 12-membered polycyclic heterocycle. In certain embodiments, R3 is - (CH2) nC (O) NR5R6.
[0376] [0376] In certain embodiments, R3 and Ra together with the atom to which they are attached combine to form an optionally substituted 3- to 12-membered monocyclic heterocycle. In certain embodiments, R3 and Ra together with the atoms to which they are attached combine to form an optionally substituted 3- to 12-membered polycyclic heterocycle. In certain embodiments, R3 and Ra together with the atoms to which they are attached combine to form an optionally substituted 5- to 12-membered spiroheterocycle.
[0377] [0377] In certain modalities, R3 and Ra together with the atom to which they are attached combine to form an optionally substituted one. In certain embodiments, R3 and Ra together with the atom to which they are attached combine to form an optionally substituted. In certain embodiments, R3 and Ra together with the atom to which they are attached combine to form an optionally substituted one.
[0378] [0378] In certain embodiments, R3 and Ra together with the atom to which they are attached combine to form a 3 to 12 membered monocyclic or polycyclic heterocycle, a 5 to 12 membered spiroheterocycle, in which each heterocycle or spiroheterocycle it is optionally substituted with one or more selected from the group consisting of C1-C6alkyl, –OH, halogen, –NH2, –NHRb, –CF3, –CHF2 or –CH2F. In certain embodiments, one or more substituents are selected from the group consisting of –C1-C6alkyl, halogen, –OH, –ORb, - NH2, –NHRb, - (CH2) nNH2, - (CH2) nOH,, –CF3 , –CHF2, –CH2F and = O. In certain embodiments, one or more substituents are selected from the group consisting of –COORb, –CONHRb, –CONH (CH2) nCOORb and– NHCOORb. In certain embodiments, one or more substituents are -O- C (O) -NR5R6. In certain embodiments, one or more substituents are an optionally substituted heteroaryl or optionally substituted heterocyclyl, where the heteroaryl and heterocyclyl are optionally substituted with -CN.
[0379] [0379] In certain modalities, R3 and Ra together with the atom to which they are attached, and including the substituents, combine to form. In certain embodiments, R3 to Ra together with the atom to which they are attached, and including the substituents, combine to form. In certain embodiments, R3 and Ra together with the atom to which they are attached combine to form
[0380] [0380] In certain modalities, Rb is H. In one or more modalities, Rb is C1-C6 alkyl. In one or more modalities, Rb is –C1- C6cycloalkyl. In one or more modalities, Rb is –C2-C6alkenila. In one or more modalities, Rb is heterocyclyl containing 1-5 heteroatoms selected from the group consisting of N, S, P or O.
[0381] [0381] In certain modalities, R5 and R6 are independently, in each occurrence, –H, –C1-C6alkyl, –C2-C6alkenyl, –C4-C8cycloalkenyl, –C2-C6alkynyl, –C3-C8cycloalkyl, a heterocycle of 3 to 12 monocyclic or polycyclic members, –OR7, –SR7, halogen, –NR7R8, - NO2, –CF3 or –CN.
[0382] [0382] In certain embodiments, R5 and R6 are independently, in each occurrence, –H, –C1-C6alkyl, –C2-C6alkenyl, –C4-C8cycloalkenyl, –C2-C6alkynyl, –C3-C8cycloalkyl, a heterocycle of 3 to 12 monocyclic or polycyclic members, -OR7, –SR7, halogen, –NR7R8, - NO2, –CF3 or –CN.
[0383] [0383] As described above, R7 and R8 are independently, at each occurrence, –H, –C1-C6alkyl, –C2-C6alkenyl, –C4-C8cycloalkenyl, –C2-C6alkynyl, –C3-C8cycloalkyl, –ORb, or a 3 to 12 membered monocyclic or polycyclic heterocycle, where each alkyl,
[0384] [0384] As described above, m is independently 1, 2, 3, 4, 5 or 6. In certain examples, m is 1. In certain examples, m is 2. In certain examples, m is 3. In certain examples, m is 4. In certain examples, m is 5. In certain examples, m is 6.
[0385] [0385] As described above, n is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10. In certain examples, n is 0. In certain examples, n is 1. In certain examples examples, n is 2. In certain examples, n is 3. In certain examples, n is 4. In certain examples, n is 5. In certain examples, n is
[0386] [0386] In a variation of the formula I, I ', II, II', III, III ', IV, IV', V and VI, X1 is CR2; R2 is H, -NH2, -OH, or -C1-C6alkyl and B, including the atoms at the points of attachment, is a 5- to 6-membered monocyclic heteroaryl. In certain examples of formula I, I ', II, II', III, III ', IV, IV', V and VI, X1 is CR2; R2 is H, -NH2, -OH, or -C1-C6alkyl and B, including the atoms at the points of attachment, is a 5-membered monocyclic heteroaryl. In certain examples of formula I, I ', II, II', III, III ', IV, IV', V and VI, X1 is CR2; R2 is H, - NH2, -OH, or –C1-C6alkyl and B, including the atoms at the points of attachment, is a 6-membered monocyclic heteroaryl.
[0387] [0387] In a variation of the formula I, I ', II, II', III, III ', V and VI, Y1 is S and A is a cycloalkyl. In certain examples of formula I, I ', II, II', III, III ', V and VI, Y1 is S and A is heterocycloalkyl. In certain examples of formula I, I ', II, II', III, III ', V and VI, Y1 is S and A is aryl. In certain examples of formula I, I ', II, II', III, III ', V and VI, Y1 is S and A is heteroaryl.
[0388] [0388] In a variation of formula I, I ', II, II', IV, IV ', V and VI, Y1 is a direct bond and A is a cycloalkyl. In certain examples of formula I, I ', II, II', IV, IV ', V and VI, Y1 is a direct bond and A is heterocycloalkyl. In certain examples of formula I, I ', II, II', IV, IV ', V and VI, Y1 is a direct bond and A is aryl. In certain examples of formula I, I ', II, II', IV, IV ', V and VI, Y1 is a direct bond and A is heteroaryl.
[0389] [0389] In a variation of formula V, Y1 is –S- and ring A is heteroaryl (for example, pyridine). In certain examples, Y1 is –S- and ring A is aryl. In certain embodiments, Y1 is –S-; ring A is heteroaryl (for example, pyridine); and R1 is NH2 and Cl. In certain embodiments, Y1 is –S-; ring A is aryl; and R1 is NH2 and Cl.
[0390] [0390] In a variation of formula V, R3 can combine with Ra to form a 3- to 12-membered monocyclic or polycyclic heterocycle or a 5- to 12-membered spiroheterocycle, where each heterocycle or spiroheterocycle is optionally substituted with one or more– OH or - (CH2) nOH (for example, -CH2OH).
[0391] [0391] In a variation of formula V, Y2 is –NRa–; Ra is H; and R3 is independently –C1-C6alkyl, where the alkyl is optionally substituted with one or more –OH.
[0392] [0392] In some embodiments, the compound of formula I or I ', or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof, has one, two or three or more of the following characteristics:
[0393] [0393] a) X1 is CR2;
[0394] [0394] b) R2 is –H, –NH2, -OH or –CH3;
[0395] [0395] c) X2 is N;
[0396] [0396] d) B, including the atoms at the points of attachment, is a 5- to 6-membered monocyclic heterocycle;
[0397] [0397] e) Y1 is –S-;
[0398] [0398] f) A is aryl.
[0399] [0399] In some embodiments, the compound of formula I or I ', or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof, has one, two or three or more of the following characteristics:
[0400] [0400] a) X1 is CR2;
[0401] [0401] b) R2 is –H, –NH2, -OH or –CH3;
[0402] [0402] c) X2 is N;
[0403] [0403] d) B, including the atoms at the points of attachment, is a 5- to 6-membered monocyclic heterocycle;
[0404] [0404] e) Y1 is a direct link;
[0405] [0405] f) A is aryl.
[0406] [0406] In some embodiments, the compound of formula I or I ', or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof, has one, two or three or more of the following characteristics:
[0407] [0407] a) X1 is CR2;
[0408] [0408] b) R2 is –H, –NH2, -OH or –CH3;
[0409] [0409] c) X2 is N;
[0410] [0410] d) B, including the atoms at the points of attachment, is a 5- to 6-membered monocyclic heterocycle;
[0411] [0411] e) Y1 is –S-;
[0412] [0412] f) A is heteroaryl.
[0413] [0413] In some embodiments, the compound of formula I or I ', or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof, has one, two or three or more of the following characteristics:
[0414] [0414] a) X1 is CR2;
[0415] [0415] b) R2 is –H, –NH2, -OH or –CH3;
[0416] [0416] c) X2 is N;
[0417] [0417] d) B, including the atoms at the points of attachment, is a 5- to 6-membered monocyclic heterocycle;
[0418] [0418] e) Y1 is a direct link;
[0419] [0419] f) A is heteroaryl.
[0420] [0420] In some embodiments, the compound of formula I or I ', or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof, has one, two or three or more of the following characteristics:
[0421] [0421] a) X1 is CR2;
[0422] [0422] b) R2 is –H, –NH2, -OH or –CH3;
[0423] [0423] c) X2 is N;
[0424] [0424] d) B, including the atoms at the points of attachment, is a 5- to 6-membered monocyclic heterocycle;
[0425] [0425] e) Y2 is –NRa–;
[0426] [0426] f) R3 and Ra together with the atoms to which they are attached combine to form an optionally substituted 5 to 12 membered spiroheterocycle.
[0427] [0427] In some embodiments, the compound of formula I or I ', or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof, has one, two or three or more of the following characteristics:
[0428] [0428] a) X1 is CR2;
[0429] [0429] b) R2 is –H, –NH2, -OH or –CH3;
[0430] [0430] c) X2 is N;
[0431] [0431] d) B, including the atoms at the points of attachment, is a 5- to 6-membered monocyclic heterocycle;
[0432] [0432] e) Y2 is –NRa–;
[0433] [0433] f) R3 and Ra together with the atoms to which they are attached combine to form an optionally substituted 3- to 12-membered heterocycle.
[0434] [0434] The present invention provides a compound, and pharmaceutically acceptable salts, solvates, stereoisomers and tautomers of the same, selected from the group consisting of: Compound
[0435] [0435] The present invention provides a compound, and pharmaceutically acceptable salts, solvates, stereoisomers, and tautomers of the same, selected from the group consisting of:
[0436] [0436] Methods of synthesizing the disclosed compounds
[0437] [0437] The compounds of the present invention can be produced by a variety of methods, including standard chemistry. Various synthetic forms are shown in the diagrams given below.
[0438] [0438] The compounds of any of the formulas described in this document can be prepared by methods known in the art of organic synthesis as presented in part by the synthetic schemes and examples that follow. In the schemes described below, it will be well understood that protecting groups for sensitive or reactive groups are employed where necessary according to general principles or chemistry. Protective groups are handled according to standard methods of organic synthesis (T. W. Greene and P. G. M. Wuts, "Protective Groups in Organic Synthesis",
[0439] [0439] Those skilled in the art will recognize whether a stereocenter exists in any of the compounds of the present invention. Accordingly, the present invention includes both possible stereoisomers (unless specified in the synthesis) and includes not only racemic compounds but also individual enantiomers and / or diastereomers. When a compound is desired as a single enantiomer or diastereomer, it can be obtained by stereospecific synthesis or by resolving the final product or any convenient intermediary. The resolution of the final product, an intermediate or starting material can be affected by any suitable method known in the art. See, for example, "Stereochemistry of Organic Compounds" by E. L. Eliel, S. H. Wilen, and L. N. Mander (Wiley-Interterscience, 1994).
[0440] [0440] Preparation of compounds
[0441] [0441] The compounds described in this document can be produced from commercially available starting materials or synthesized using known organic, inorganic and / or enzymatic processes.
[0442] [0442] The compounds of the present invention can be prepared in various ways well known to those skilled in the art of organic synthesis. As an example, the compounds of the description can be synthesized using the methods described below, together with the synthetic methods known in the art of synthetic organic chemistry or variations thereon as appreciated by those skilled in the art. These methods include, but are not limited to, the methods described below.
[0443] [0443] Scheme 1. General synthesis of 8- (phenylthio) imidazo [1,2-c] pi-rimidin-5-amine (or an alternative bicyclic structure)
[0444] [0444] The general synthesis of 8- (phenylthio) imidazopyrimidin-5-amines is shown in scheme 1. In the scheme, the Z ring refers to an aryl or heteroaryl ring. 8-bromo-5-chloroimidazo [1,2-c] pyrimidine (or an alternative bicyclic structure) can be coupled to a substituted primary or secondary amine to give 8-bromoimidazo [1,2-c] pyrimidine-5-amine. The resulting intermediate can be coupled to a substituted aryl- or heteroaryl-thiol in the presence of a copper catalyst (for example, CuI) or under SNAr conditions. Alternatively, the resulting intermediate can be coupled to an appropriately substituted aryl or heteroaryl boronic acid in the presence of Pd catalyst. Additional deprotection and / or functionalization steps may be necessary to produce the final compound.
[0445] [0445] Methods of using the disclosed compounds
[0446] [0446] Another aspect of the present invention relates to a method of treating a disease associated with modulation of SHP2 in an individual who needs it. The method involves administering to a patient in need of treatment for diseases or disorders associated with modulating SHP2 from an effective amount of a compound of formula I, I ', II, II', III, III ', IV, IV', V or VI. In one embodiment, the disease can be, but it is not limited to Noonan's syndrome, Leopard's syndrome, juvenile myelomonocytic leukemias, neuroblastoma, melanoma, acute myeloid leukemia and breast, lung and colon cancers. SHP2 is an important downstream signaling molecule for a variety of receptor tyrosine kinases, including platelet-derived growth factor receptors (PDGF-R), fibroblast growth factor (FGF-R) and epidermal growth factor ( EGF-R). SHP2 is also an important downstream signaling molecule for the activation of the mitogen-activated protein (MAP) kinase pathway that can lead to cell transformation, a prerequisite for the development of cancer. SHP2 inactivation significantly inhibited cell growth of lung cancer cell lines with SHP2 mutation or EML4 / ALK translocations as well as EGFR amplified breast cancers and esophageal cancers. SHP2 is also activated downstream of oncogenes in gastric carcinoma, anaplastic large cell lymphoma and globlastoma.
[0447] [0447] In addition, SHP2 has a role in signal transduction originating from immunological checkpoint molecules, including but not limited to programmed cell death protein 1 (PD-1) and protein 4 associated with cytotoxic T lymphocyte (CTLA-4 ). In this context, modulation of the SHP2 function can lead to immune activation, specifically anti-cancer immune responses.
[0448] [0448] Another aspect of the present invention relates to a method of inhibiting SHP2. The method involves administering to a patient in need of an effective amount of formula I, I ', II, II', III, III ', IV, IV', V or VI.
[0449] [0449] The present invention relates to compositions capable of modulating SHP2 (e.g., inhibition) activity. The present invention also relates to the therapeutic use of said compounds.
[0450] [0450] The disclosed compound can be administered in amounts effective to treat or prevent a disorder and / or prevent its development in individuals.
[0451] [0451] Another aspect of the present invention relates to a compound of formula I, I ', II, II', III, III ', IV, IV', V or VI, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the treatment or prevention of a disease associated with SHP2 modulation. In some modalities, the disease is Noonan syndrome, Leopard syndrome, juvenile myelomonocytic leukemias, neuroblastoma, melanoma, acute myeloid leukemia and breast, lung and colon cancers. SHP2 is an important downstream signaling molecule for a variety of receptor tyrosine kinases, including platelet-derived growth factor receptors (PDGF-R), fibroblast growth factor (FGF-R) and epidermal growth (EGF-R). SHP2 is also an important downstream signaling molecule for the activation of the mitogen-activated protein (MAP) kinase pathway that can lead to cell transformation, a prerequisite for the development of cancer. SHP2 inactivation significantly inhibited cell growth of lung cancer cell lines with SHP2 mutation or EML4 / ALK translocations as well as EGFR amplified breast cancers and esophageal cancers. SHP2 is also activated downstream of oncogenes in gastric carcinoma, anaplastic large cell lymphoma and glioblastoma.
[0452] [0452] In another aspect, the present invention relates to the use of a compound of formula I, I ', II, II', III, III ', IV, IV', V or VI, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in the manufacture of a drug to treat or prevent a disease.
[0453] [0453] Administration of the disclosed compounds can be achieved through any mode of administration for therapeutic agents. These modes include systemic or local administration such as oral, nasal, parenteral, transdermal, subcutaneous, vaginal, buccal, rectal or topical administration.
[0454] [0454] Depending on the intended mode of administration, the disclosed compounds or pharmaceutical compositions may be in solid, semi-solid or liquid pharmaceutical form, such as, for example, injectables, tablets, suppositories, pills, release capsules delayed, elixirs, tinctures, emulsions, syrups, powders, liquids, suspensions or the like, sometimes in unit dosages and consistent with conventional pharmaceutical practices. Likewise, they can also be administered intravenously (both bolus and infusion), intraperitoneal, subcutaneous or intramuscular and all using ways well known to those skilled in the pharmaceutical art.
[0455] [0455] Illustrative pharmaceutical compositions are tablets and gelatin capsules comprising a compound of the description and a pharmaceutically acceptable carrier, such as one) a diluent, for example, purified water, triglyceride oils, such as hydrogenated vegetable oil or partially hydrogenated vegetable oil, or mixtures thereof, corn oil, olive oil, sunflower oil, safflower oil, fish oils, such as EPA or DHA, or their esters or triglycerides or mixtures thereof, omega-3 fatty acids or derivatives thereof, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, sodium, saccharin, glucose and / or glycine; b) a lubricant, for example, silica, talc, stearic acid, its magnesium or calcium salt, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and / or polyethylene glycol; for pills too; c) a binder, for example, magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, magnesium carbonate, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, waxes and / or polyvinylpyrrolidone, if desired; d) a disintegrant, for example, starches, agar, methyl cellulose, bentonite, xanthan gum, alginic acid or its sodium salt, or effervescent mixtures; e) absorbent, color, flavor and sweetener; f) an emulsifier or dispersing agent, such as Tween 80, Labrasol, HPMC, DOSS, caproyl 909, labrafac, labrafil, peceol, transcutol, capmul MCM, capmul PG-12, captex 355, gelucire, vitamin E TGPS or other acceptable emulsifier ; and / or g) an agent that increases the absorption of the compound such as cyclodextrin, hydroxypropyl-cyclodextrin, PEG400, PEG200.
[0456] [0456] Liquid compositions, particularly injectable, can, for example, be prepared by dissolving, dispersing, etc. For example, the disclosed compound is dissolved in u mixed with a pharmaceutically acceptable solvent such as, for example, water, saline, aqueous dextrose, glycerol, ethanol and the like, to thereby form an injectable isotonic solution or suspension. Proteins such as albumin, chylomicron particles or whey proteins can be used to solubilize the disclosed compounds.
[0457] [0457] The disclosed compounds can also be formulated as a suppository that can be prepared from emulsions or fatty suspensions, using polyalkylene glycols such as propylene glycol, as the carrier.
[0458] [0458] The disclosed compounds can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, containing cholesterol, stearylamine or phosphatidylcholine. In some embodiments, a film of lipid components is hydrated with an aqueous drug solution to a form of lipid layer encapsulating the drug, as described for example in US Patent No. 5,262,564, the content of which is incorporated herein by way of reference.
[0459] [0459] The disclosed compounds can also be released by using monoclonal antibodies as individual vehicles to which the disclosed compounds are coupled. The disclosed compounds can also be coupled with soluble polymers as targetable drug carriers. Said polymers may include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylspanamidephenol or polyethyleneoxidepolylysine substituted with palmitoyl residues. In addition, the disclosed compounds can be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyiepsilon caprolactone, polyhydroxy butyric acid, polyiorthesters, polyacetals, polyhydro-pyrines, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels. In one embodiment, the disclosed compounds are not covalently bound to a polymer, for example, a polycarboxylic acid polymer, or a polyacrylate.
[0460] [0460] Parenteral injectable administration is generally used for subcutaneous, intramuscular or intravenous injections and infusions. Injectables can be prepared in conventional forms, either as liquid solutions or suspensions or solid forms suitable for dissolving in liquid before injection.
[0461] [0461] Another aspect of the present invention relates to a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier may also include an excipient, diluent or surfactant.
[0462] [0462] The compositions can be prepared according to conventional mixing, granulating or coating methods, respectively, and the present pharmaceutical compositions can contain from about 0.1% to about 99%, from about 5% to about 90%, or about 1% to about 20% of the disclosed compound by weight or volume.
[0463] [0463] The dosage regimen using the disclosed compound is selected according to a variety of factors including the type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the patient's renal or liver function; and the specific compound disclosed employed. A physician or veterinarian skilled in the art can readily determine and prescribe the effective amount of the drug needed to prevent, contain or halt the progress of the condition.
[0464] [0464] The effective dosage amounts of the disclosed compounds, when used for the indicated effects, range from about 0.5 mg to about 5000 mg of the disclosed compound as needed to treat the condition. Compositions for use in vivo or in vitro can contain about 0.5; 5; 20; 50; 75; 100; 150; 250; 500; 750; 1000; 1250; 2500; 3500 or 5000 mg of the disclosed compound, or, in a range of one amount to another amount in the dose list. In one embodiment, the compositions are in the form of a tablet that can be marked.
[0465] [0465] Modalities
[0466] [0466] Some modalities of this description are Modality I, as follows:
[0467] [0467] Mode I-1. A compound of formula II:
[0468] [0468] or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer or isomer thereof, where:
[0469] [0469] A is cycloalkyl, heterocycloalkyl, aryl or heteroaryl, where cycloalkyl, heterocycloalkyl, aryl and heteroaryl are monocyclic from 5 to 12 members or polycyclic from 5 to 12 members;
[0470] [0470] R1 is independently, in each occurrence, –H, –C1- C6alkyl, –C2-C6alkenyl, –C4-C8cycloalkenyl, –C2-C6alkynyl, –C3- C8cycloalkyl, –OH, –OR6, halogen, –NO2, –CN, –NR5R6, –SR5, - S (O) 2NR5R6, –S (O) 2R5, –NR5S (O) 2NR5R6, –NR5S (O) 2R6, –S (O) NR5R6, –S (O) R5 , –NR5S (O) NR5R6, –NR5S (O) R6, –C (O) R5, –CO2R5, - C (O) NR5R6, –NR5C (O) R6, monocyclic or polycyclic heterocyclyl, spiroheterocyclic, heteroaryl, or oxo, where each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, heterocyclyl, spiroheterocyclyl, or heteroaryl is optionally substituted with one or more –OH, halogen, –NO2, oxo, = O, –CN, - R5, –OR5, –NR5R6, −SR5, –S (O) 2NR5R6, - S (O) 2R5, –NR5S (O) 2NR5R6, –NR5S (O) 2R6, –S (O) NR5R6, –S (O ) R5, - NR5S (O) NR5R6, –NR5S (O) R6, heterocycle, aryl or heteroaryl;
[0471] [0471] Y1 is –S–, a direct link, –NH-, –S (O) 2-, –S (O) 2-NH-, - C (= CH2) -, -CH2- or -S ( O)-;
[0472] [0472] X1 is N or CR2;
[0473] [0473] X2 is N or CH;
[0474] [0474] B, including the atoms at the points of attachment, is a 5 to 12 membered monocyclic or polycyclic heterocycle or a 5 to 12 membered monocyclic or polycyclic heteroaryl;
[0475] [0475] Y2 is –NRa–, - (CRa2) m–, –C (O) -, –C (Ra) 2NH–, - (CRa2) mO–, - C (O) N (Ra) -, - N (Ra) C (O) -, –S (O) 2N (Ra) -, –N (Ra) S (O) 2–, –N (Ra) C (O) N (Ra) -, - N (Ra) C (S) N (Ra) -, –C (O) O–, –OC (O) -, –OC (O) N (Ra) -, –N (Ra) C (O) O– , –C (O) N (Ra) O–, –N (Ra) C (S) -, –C (S) N (Ra) -, or –OC (O) O–; wherein the link on the left side of Y2, as shown, is linked to the ring and the link on the right side of the Y2 portion, as shown, is linked to R3;
[0476] [0476] Ra is independently, at each occurrence, –H, –OH, –C3- C8cycloalkyl, –C1-C6alkyl, 3- to 12-membered heterocyclyl, or - (CH2) n-aryl, where each alkyl or cycloalkyl is optionally substituted with one or more –NH2, or where 2 Ra, together with the carbon atom to which they are attached, can combine to form a 3- to 8-membered cycloalkyl;
[0477] [0477] Rb is independently, at each occurrence, –H, –OH, - C1-C6alkyl, –C3-C8cycloalkyl, –C2-C6alkenyl, - (CH2) n-aryl, heterocyclyl containing 1-5 heteroatoms selected a starting from the group consisting of N, S, P and O, or heteroaryl containing 1-5 heteroatoms selected from the group consisting of N, S, P and O; where each alkyl, cycloalkyl, alkenyl, heterocycle, heteroaryl or - (CH2) n-aryl is optionally substituted with one or more –OH, halogen, –NO2, oxo, –CN, −R5, –OR5, –NR5R6, - SR5, –S (O) 2NR5R6, –S (O) 2R5, - NR5S (O) 2NR5R6, –NR5S (O) 2R6, –S (O) NR5R6, –S (O) R5, - NR5S (O) NR5R6 , –NR5S (O) R6, –C (O) NR5R6, –NR5C (O) R6, heterocycle, aryl, heteroaryl, - (CH2) nOH, –C1-C6alkyl, –CF3, –CHF2 or –CH2F;
[0478] [0478] R2 is independently –H, –NH2, –ORb, –CN, –C1- C6alkyl, –C2-C6alkenyl, –C4-C8cycloalkenyl, –C2-C6alkynyl, halogen, –C (O) ORb, –C3- C8cycloalkyl, aryl, heterocyclyl containing 1-5 heteroatoms selected from the group consisting of N, S, P and O, or heteroaryl containing 1-5 heteroatoms selected from the group consisting of N, S, P and O; where each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more –OH, halogen, –NO2, oxo, - CN, −R5, –OR5, –NR5R6 , −SR5, –S (O) 2NR5R6, –S (O) 2R5, - NR5S (O) 2NR5R6, –NR5S (O) 2R6, –S (O) NR5R6, –S (O) R5, - NR5S (O ) NR5R6, –NR5S (O) R6, heterocycle, aryl or heteroaryl;
[0479] [0479] R3 is independently –H, –C1-C6alkyl, a 3- to 12-membered monocyclic or polycyclic heterocycle, a 5- to 12-membered spiroheterocycle, C3-C8cycloalkyl or - (CH2) n-Rb, where each alkyl, spiroheterocycle, heterocycle or cycloalkyl is optionally substituted with one or more –C1-C6alkyl, –OH, –NH2, –ORb, –NHRb, - (CH2) nOH, heterocyclyl or spiroheterocyclic; or
[0480] [0480] R3 can combine with Ra to form a 3 to 12 membered monocyclic or polycyclic heterocycle a 5 to 12 membered spiroheterocycle, where each heterocycle or spiroheterocycle is optionally substituted with one or more –C1-C6alkyl, halogen, –OH , –ORb, - NH2, –NHRb, heteroaryl, heterocyclyl, - (CH2) nNH2, - (CH2) nOH, - COORb, –CONHRb, –CONH (CH2) nCOORb, –NHCOORb, –CF3, –CHF2, –CH2F or = O;
[0481] [0481] R5 and R6 are independently, at each occurrence, –H, - C1-C6alkyl, –C2-C6alkenyl, –C4-C8cycloalkenyl, –C2-C6alkynyl, - C3-C8cycloalkyl, a 3- to 12-membered monocyclic heterocycle polycyclic, –OR7, –SR7, halogen, –NR7R8, –NO2, –CF3 or –CN;
[0482] [0482] R7 and R8 are independently, in each occurrence, –H, - C1-C6alkyl, –C2-C6alkenyl, –C4-C8cycloalkenyl, –C2-C6alquinyl, - C3-C8cycloalkyl, –ORb, or a 3 to heterocycle 12 monocyclic or polycyclic members, where each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, or heterocycle is optionally substituted with one or more –OH, –SH, –NH2, –NO2 or –CN;
[0483] [0483] m is independently 1, 2, 3, 4, 5 or 6; and
[0484] [0484] n is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.
[0485] [0485] Mode I-2. The compound of modality I-1, where Y1 is –S–.
[0486] [0486] Mode I-3. The compound of modality I-1, where Y1 is a direct bond.
[0487] [0487] Mode I-4. The compound of any of modalities I-1 to I-3, where X1 is N.
[0488] [0488] Mode I-5. The compound of any of modalities I-1 to I-3, where X1 is CR2.
[0489] [0489] Mode I-6. The compound of modality I-5, where R2 is –H, –NH2, -OH or –C1-C6alkyl.
[0490] [0490] Mode I-7. The compound of any of modalities I-1 to I-3, where X2 is N.
[0491] [0491] Mode I-8. The compound of any of modalities I-1 to I-3, where X2 is CH.
[0492] [0492] Mode I-9. The compound of any of modalities I-1 to I-3, where X1 is N and X2 is N.
[0493] [0493] Mode I-10. The compound of any of modalities I- to I-3, where X1 is N and X2 is CH.
[0494] [0494] Mode I-11. The compound of any of modalities I-1 to I-3, where X1 is CR2 and X2 is N.
[0495] [0495] Mode I-12. The compound of any of modalities I-1 to I-3, where X1 is CR2 and X2 is CH.
[0496] [0496] Mode I-13. The compound of any of the modalities I-11 to I-12, where R2 is –H, –NH2, -OH or –C1-C6alkyl.
[0497] [0497] Mode I-14. The compound of any of modalities I-1 to I-13, where B, including the atoms at the points of attachment, is a 5- to 12-membered monocyclic heteroaryl.
[0498] [0498] Mode I-15. The compound of any of modalities I-1 to I-14, where B, including the atoms at the points of attachment, is, where XB1 is N, CH, S, or O; XB2 is N, CH, S, or O; and XB3 is N, CH, S, or O.
[0499] [0499] Mode I-16. The compound of any of modalities I-1 to I-14, where B, including atoms at the points of attachment,
[0500] [0500] Mode I-17. The compound of any of modalities I-1 to I-16, where A is cycloalkyl.
[0501] [0501] Mode I-18. The compound of any of modalities I-1 to I-16, where A is heterocycloalkyl.
[0502] [0502] Mode I-19. The compound of any of modalities I-1 to I-16, where A is aryl.
[0503] [0503] Mode I-20. The compound of any of modalities I-1 to I-16, where A is phenyl.
[0504] [0504] Mode I-21. The compound of any of modalities I-1 to I-16, where A is heteroaryl.
[0505] [0505] Mode I-22. The compound of any of modalities I-1 to I-16, where A is pyridyl.
[0506] [0506] Mode I-23. The compound of any of modalities I-1 to I-22, where R1 is independently –OH, –NO2, –CN, halogen or –NR5R6.
[0507] [0507] Mode I-24. The compound of any of modalities I-1 to I-23, where Y2 is –NRa–.
[0508] [0508] Mode I-25. The compound of any of the modalities I-1 to I-23, where Y2 is - (CRa2) m–.
[0509] [0509] Mode I-26. The compound of any of the modalities I-1 to I-25, where Ra is –H.
[0510] [0510] Mode I-27. The compound of any of the modalities I-1 to I-25, where Ra is –C1-C6alkyl.
[0511] [0511] Mode I-28. The compound of any of the modalities I-1 to I-27, where R3 is –C1-C6alkyl.
[0512] [0512] Mode I-29. The compound of any of the modalities I-1 to I-27, where R3 is monocyclic or polycyclic heterocycle with 3 to 12 members.
[0513] [0513] Mode I-30. The compound of any of the modalities I-1 to I-27, where R3 is a 3- to 12-membered monocyclic heterocycle.
[0514] [0514] Mode I-31. The compound of any of the modalities I-1 to I-27, where R3 is a 5 to 12 membered polycyclic heterocycle.
[0515] [0515] Mode I-32. The compound of any of the modalities I-1 to I-25, in which R3 and Ra together with the atom to which they are attached, combine to form the 3- to 12-membered monocyclic heterocycle.
[0516] [0516] Mode I-33. The compound of any of the modalities I-1 to I-25, in which R3 and Ra together with the atoms to which they are attached, combine to form a 3- to 12-membered polycyclic heterocycle.
[0517] [0517] Mode I-34. The compound of any of the modalities I-1 to I-25, in which R3 and Ra together with the atoms to which they are attached, combine to form a 5- to 12-membered spiroheterocycle.
[0518] [0518] Mode I-35. The compound of any of the modalities I-32 to I-34, in which heterocycle or spirocycle formed by R3 and Ra is substituted with one or more substituents selected from the group consisting of C1-C6alkyl, –OH, halogen, - NH2, –NHRb, –CF3, –CHF2 or –CH2F.
[0519] [0519] Mode I-36. A compound, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, selected from the group consisting of:
[0520] [0520] Mode I-37. A pharmaceutical composition comprising a compound of any one of embodiments I-1 to I-36, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer or isomer thereof, and a pharmaceutically acceptable carrier.
[0521] [0521] Mode I-38. A method of treating a disease associated with modulation of SHP2 in an individual who needs it, comprising administering to the individual an effective amount of a compound of any of the modalities I-1 to I-36, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer or isomer thereof.
[0522] [0522] Mode I-39. The I-38 method, in which the disease is selected from Noonan syndrome, Leopard syndrome, juvenile myelomonocytic leukemias, neuroblastoma, melanoma, acute myeloid leukemia and cancers of the breast, lung and colon.
[0523] [0523] Mode I-40. A compound of any of modalities I-1 to I-36 for use in the treatment or prevention of a disease associated with SHP2 modulation.
[0524] [0524] Mode I-41. Use of a compound of any of modalities I-1 to I-36 in the manufacture of a drug for the treatment or prevention of a disease associated with SHP2 modulation.
[0525] [0525] Some modalities of this description are Modality II, as follows:
[0526] [0526] Mode II-1. A compound of formula II ':
[0527] [0527] or a pharmaceutically acceptable salt, prodrug, solvate,
[0528] [0528] A is cycloalkyl, heterocycloalkyl, aryl or heteroaryl, where cycloalkyl, heterocycloalkyl, aryl and heteroaryl are monocyclic from 5 to 12 members or polycyclic from 5 to 12 members;
[0529] [0529] R1 is independently, in each occurrence, –H, –C1- C6alkyl, –C2-C6alkenyl, –C4-C8cycloalkenyl, –C2-C6alkynyl, –C3- C8cycloalkyl, –OH, –OR6, halogen, –NO2, –CN, –NR5R6, –SR5, - S (O) 2NR5R6, –S (O) 2R5, –NR5S (O) 2NR5R6, –NR5S (O) 2R6, –S (O) NR5R6, –S (O) R5 , –NR5S (O) NR5R6, –NR5S (O) R6, –C (O) R5, –CO2R5, - C (O) NR5R6, –NR5C (O) R6, monocyclic or polycyclic heterocyclyl, spiroheterocycly, heteroaryl or oxo, where each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, heterocyclyl, spiroheterocyclyl or heteroaryl is optionally substituted with one or more –OH, halogen, –NO2, oxo, = O, –CN, −R5, –OR5, –NR5R6, −SR5, –S (O) 2NR5R6, - S (O) 2R5, –NR5S (O) 2NR5R6, –NR5S (O) 2R6, –S (O) NR5R6, –S (O) R5 , - NR5S (O) NR5R6, –NR5S (O) R6, heterocycle, aryl or heteroaryl;
[0530] [0530] Y1 is –S–, a direct link, –NH-, –S (O) 2-, –S (O) 2-NH-, - C (= CH2) -, -CH2- or -S ( O)-;
[0531] [0531] X1 is N or CR2;
[0532] [0532] X2 is N or CH;
[0533] [0533] B, including atoms at the points of attachment, is a 5 to 12 membered monocyclic or polycyclic heterocycle or a 5 to 12 membered monocyclic or polycyclic heteroaryl;
[0534] [0534] Y2 is –NRa–, - (CRa2) m–, –O–, –C (O) -, –C (Ra) 2NH–, - (CRa2) mO–, –C (O) N (Ra ) -, –N (Ra) C (O) -, –S (O) 2N (Ra) -, –N (Ra) S (O) 2–, - N (Ra) C (O) N (Ra) -, –N (Ra) C (S) N (Ra) -, –C (O) O–, –OC (O) -, - OC (O) N (Ra) -, –N (Ra) C ( O) O–, –C (O) N (Ra) O–, –N (Ra) C (S) -, - C (S) N (Ra) -, or –OC (O) O–; wherein the link on the left side of Y2, as shown, is linked to the ring and the link on the right side of the Y2 portion, as shown, is linked to R3;
[0535] [0535] Ra is independently, at each occurrence, –H, –OH, –C3- C8cycloalkyl, –C1-C6alkyl, 3- to 12-membered heterocyclyl, or - (CH2) n-aryl, where each alkyl or cycloalkyl is optionally substituted with one or more –NH2, or where 2 Ra, together with the carbon atom to which they are attached, can combine to form a 3- to 8-membered cycloalkyl;
[0536] [0536] Rb is independently, in each occurrence, –H, –OH, - C1-C6alkyl, –C3-C8cycloalkyl, –C2-C6alkenyl, - (CH2) n-aryl, heterocyclyl containing 1-5 heteroatoms selected a starting from the group consisting of N, S, P and O, or heteroaryl containing 1-5 heteroatoms selected from the group consisting of N, S, P and O; where each alkyl, cycloalkyl, alkenyl, heterocycle, heteroaryl, or - (CH2) n-aryl is optionally substituted with one or more –OH, halogen, –NO2, oxo, –CN, −R5, –OR5, –NR5R6, −SR5, –S (O) 2NR5R6, –S (O) 2R5, - NR5S (O) 2NR5R6, –NR5S (O) 2R6, –S (O) NR5R6, –S (O) R5, - NR5S (O) NR5R6, –NR5S (O) R6, –C (O) NR5R6, –NR5C (O) R6, heterocycle, aryl, heteroaryl, - (CH2) nOH, –C1-C6alkyl, –CF3, –CHF2 or –CH2F;
[0537] [0537] R2 is independently –H, –NH2, –ORb, –CN, –C1- C6alkyl, –C2-C6alkenyl, –C4-C8cycloalkenyl, –C2-C6alkynyl, halogen, –C (O) ORb, –C3- C8cycloalkyl, aryl, heterocyclyl containing 1-5 heteroatoms selected from the group consisting of N, S, P and O, or heteroaryl containing 1-5 heteroatoms selected from the group consisting of N, S, P and O; where each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more –OH, halogen, –NO2, oxo, −R5, –OR5, –NR5R6, −SR5 , –S (O) 2NR5R6, –S (O) 2R5, –NR5S (O) 2NR5R6, –NR5S (O) 2R6, –S (O) NR5R6, –S (O) R5, –NR5S (O) NR5R6, –NR5S (O) R6, heterocycle, aryl or heteroaryl;
[0538] [0538] R3 is independently –H, –C1-C6alkyl, a 3- to 12-membered monocyclic or polycyclic heterocycle, a 5- to 12-membered spiroheterocycle, C3-C8cycloalkyl, - (CH2) n-Rb, or - (CH2) nC (O) NR5R6, where each alkyl, spiroheterocycle, heterocycle, or cycloalkyl is optionally substituted with one or more –C1-C6alkyl, –OH, –NH2, –ORb, –NHRb, - (CH2) nOH, heterocyclyl or spiroheterocyclyl; or
[0539] [0539] R3 can combine with Ra to form a 3 to 12 membered monocyclic or polycyclic heterocycle a 5 to 12 membered spiroheterocycle, where each heterocycle or spiroheterocycle is optionally substituted with one or more –C1-C6alkyl, halogen, –OH , –ORb, - NH2, –NHRb, optionally substituted heteroaryl, optionally substituted heterocyclyl, - (CH2) nNH2, - (CH2) nOH, –COORb, –CONHRb, - CONH (CH2) nCOORb, –NHCOORb, -OC (O) -NR5R6, –CF3, –CHF2, - CH2F or = O; wherein the heteroaryl and heterocyclyl are optionally substituted with –CN;
[0540] [0540] R5 and R6 are independently, in each occurrence, –H, - C1-C6alkyl, –C2-C6alkenyl, –C4-C8cycloalkenyl, –C2-C6alkynyl, - C3-C8cycloalkyl, a 3- to 12-membered monocyclic heterocycle polycyclic, –OR7, –SR7, halogen, –NR7R8, –NO2, –CF3 or –CN;
[0541] [0541] R7 and R8 are independently, in each occurrence, –H, - C1-C6alkyl, –C2-C6alkenyl, –C4-C8cycloalkenyl, –C2-C6alquinyl, - C3-C8cycloalkyl, –ORb, or a 3 to heterocycle 12 monocyclic or polycyclic members, where each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl or heterocycle is optionally substituted with one or more –OH, –SH, –NH2, –NO2 or –CN;
[0542] [0542] m is independently 1, 2, 3, 4, 5 or 6; and
[0543] [0543] n is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;
[0544] [0544] as long as when X2 is N and ring B is a 5-membered monocyclic heteroaryl containing 3-4 nitrogen atoms, then don't be; and
[0545] [0545] as long as when X1 is N; X2 is CH and Y1 is NH; then R1 is not C3-C8cycloalkyl or heteroaryl.
[0546] [0546] Mode II-2. The compound of modality II-1, where Y1 is –S–.
[0547] [0547] Mode II-3. The compound of mode II-1, where Y1 is a direct bond.
[0548] [0548] Mode II-4. The compound of any of the modalities II-1 to II-3, where X1 is N.
[0549] [0549] Mode II-5. The compound of any of the modalities II-1 to II-3, where X1 is CR2.
[0550] [0550] Mode II-6. The compound of modality II-5, where R2 is –H, –NH2, -OH or –C1-C6alkyl.
[0551] [0551] Mode II-7. The compound of any of the modalities II-1 to II-3, where X2 is N.
[0552] [0552] Mode II-8. The compound of any of the modalities II-1 to II-3, where X2 is CH.
[0553] [0553] Mode II-9. The compound of any of modalities II-1 to II-3, where X1 is N and X2 is N.
[0554] [0554] Mode II-10. The compound of any of the modalities II-1 to II-3, where X1 is N and X2 is CH.
[0555] [0555] Mode II-11. The compound of any of the modalities II-1 to II-3, where X1 is CR2 and X2 is N.
[0556] [0556] Mode II-12. The compound of any of the modalities II-1 to II-3, where X1 is CR2 and X2 is CH.
[0557] [0557] Mode II-13. The compound of any of the modalities II-11 to II-12, where R2 is –H, –NH2, -OH or –C1-C6alkyl.
[0558] [0558] Mode II-14. The compound of any of the modalities II-1 to II-13, where B, including the atoms at the points of attachment, is a 5- to 12-membered monocyclic heteroaryl.
[0559] [0559] Mode II-15. The compound of any of modalities II-1 to II-14, where B, including the atoms at the points of attachment,
[0560] [0560] Mode II-16. The compound of any of the modalities II-1 to II-14, where B, including the atoms at the points of attachment, is, where XB4 is N or CH; XB5 is N or CH; XB6 is N or CH; and XB7 is N or CH.
[0561] [0561] Mode II-17. The compound of any of modalities II-1 to II-16, where A is cycloalkyl.
[0562] [0562] Mode II-18. The compound of any of modalities II-1 to II-16, where A is heterocycloalkyl.
[0563] [0563] Mode II-19. The compound of any of modalities II-1 to II-16, where A is aryl.
[0564] [0564] Mode II-20. The compound of any of modalities II-1 to II-16, where A is phenyl.
[0565] [0565] Mode II-21. The compound of any of modalities II-1 to II-16, where A is heteroaryl.
[0566] [0566] Mode II-22. The compound of any of modalities II-1 to II-16, where A is pyridyl.
[0567] [0567] Mode II-23. The compound of any of modes II-1 to II-22, where R1 is independently –OH, –NO2, –CN, halogen or –NR5R6.
[0568] [0568] Mode II-24. The compound of any of the modalities II-1 to II-23, where Y2 is –NRa–.
[0569] [0569] Mode II-25. The compound of any of the modalities II-1 to II-23, where Y2 is - (CRa2) m–.
[0570] [0570] Mode II-26. The compound of any of the modalities II-1 to II-25, where Ra is –H.
[0571] [0571] Mode II-27. The compound of any of the modalities II-1 to II-25, where Ra is –C1-C6alkyl.
[0572] [0572] Mode II-28. The compound of any of the modalities II-1 to II-27, where R3 is –C1-C6alkyl.
[0573] [0573] Mode II-29. The compound of any of the modalities II-1 to II-27, where R3 is a monocyclic or polycyclic heterocycle with 3 to 12 members.
[0574] [0574] Mode II-30. The compound of any of the modalities II-1 to II-27, where R3 is a monocyclic heterocycle with 3 to 12 members.
[0575] [0575] Mode II-31. The compound of any of the modalities II-1 to II-27, where R3 is a polycyclic heterocycle of 5 to 12 members.
[0576] [0576] Mode II-32. The compound of any of the modalities II-1 to II-25, in which R3 and Ra together with the atom to which they are attached, combine to form a 3- to 12-membered monocyclic heterocycle.
[0577] [0577] Mode II-33. The compound of any of the modalities II-1 to II-25, in which R3 and Ra together with the atoms to which they are attached, combine to form a 3- to 12-membered polycyclic heterocycle.
[0578] [0578] Mode II-34. The compound of any of the modalities II-1 to II-25, in which R3 and Ra together with the atoms to which they are attached, combine to form a 5- to 12-membered spiroheterocycle.
[0579] [0579] Mode II-35. The compound of any of the modalities II-32 to II-34, in which heterocycle or spirocycle formed by R3 and Ra is substituted with one or more substituents selected from the group consisting of C1-C6alkyl, –OH, halogen, –NH2, –NHRb, –CF3, –CHF2 or –CH2F.
[0580] [0580] Mode II-36. A compound, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, selected from the group consisting of: Compound 1 2 3 4 5 6
[0581] [0581] Mode II-37. A compound, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, selected from the group consisting of:
[0582] [0582] Mode II-38. A pharmaceutical composition comprising a compound of any of the modalities II-1 to II-
[0583] [0583] Mode II-39. A method of treating a disease associated with SHP2 modulation in an individual who needs it, comprising administering to the individual an effective amount of a compound of any of the modalities II-1 to II-37, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer, or isomer thereof.
[0584] [0584] Mode II-40. The II-39 method, in which the disease is selected from Noonan syndrome, Leopard syndrome, juvenile myelomonocytic leukemias, neuroblastoma, melanoma, acute myeloid leukemia and cancers of the breast, lung and colon.
[0585] [0585] Mode II-41. A compound of any of modalities II-1 to II-37, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer, or isomer thereof, for use as a medicament.
[0586] [0586] Mode II-42. A compound of any of modalities II-1 to II-37, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer or isomer thereof, for use in the treatment or prevention of a disease associated with modulation of SHP2.
[0587] [0587] Mode II-43. Use of a compound of any of the modalities II-1 to II-37, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer or isomer thereof, in the manufacture of a medicament to treat or prevent a disease associated with modulation of SHP2.
[0588] [0588] Mode II-44. A method of treating a disease associated with SHP2 modulation in an individual who needs it, comprising administering to the individual an effective amount of a pharmaceutical composition of modality II-38.
[0589] [0589] Mode II-45. The II-44 method, in which the disease is selected from Noonan syndrome, Leopard syndrome, juvenile myelomonocytic leukemias, neuroblastoma, melanoma, acute myeloid leukemia and cancers of the breast, lung and colon.
[0590] [0590] Mode II-46. A pharmaceutical composition of mode II-38 for use as a medicine.
[0591] [0591] Mode II-47. A pharmaceutical composition of modality II-38 for use in the treatment or prevention of a disease associated with SHP2 modulation.
[0592] [0592] Mode II-48. Use of a pharmaceutical composition of modality II-38 in the manufacture of a medication to treat or prevent a disease associated with SHP2 modulation.
[0593] [0593] Some modes of this description are modality III, as follows:
[0594] [0594] Mode III-1. A compound of formula II ':
[0595] [0595] or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer or isomer thereof, where:
[0596] [0596] A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where cycloalkyl, heterocycloalkyl, aryl and heteroaryl are monocyclic from 5 to 12 members or polycyclic from 5 to 12 members;
[0597] [0597] R1 is independently, in each occurrence, –H, –C1- C6alkyl, –C2-C6alkenyl, –C4-C8cycloalkenyl, –C2-C6alkynyl, –C3- C8cycloalkyl, –OH, –OR6, halogen, –NO2, –CN, –NR5R6, –SR5, - S (O) 2NR5R6, –S (O) 2R5, –NR5S (O) 2NR5R6, –NR5S (O) 2R6, –S (O) NR5R6, –S (O) R5 , –NR5S (O) NR5R6, –NR5S (O) R6, –C (O) R5, –CO2R5, -
[0598] [0598] Y1 is –S–, a direct link, –NH-, –S (O) 2-, –S (O) 2-NH-, - C (= CH2) -, -CH2- or -S ( O)-;
[0599] [0599] X1 is N or CR2;
[0600] [0600] X2 is N or CH;
[0601] [0601] B, including atoms at the points of attachment, is a 5 to 12 membered monocyclic or polycyclic heterocycle or a 5 to 12 membered monocyclic or polycyclic heteroaryl;
[0602] [0602] Y2 is –NRa–, - (CRa2) m–, –O–, –C (O) -, –C (Ra) 2NH–, - (CRa2) mO–, –C (O) N (Ra ) -, –N (Ra) C (O) -, –S (O) 2N (Ra) -, –N (Ra) S (O) 2–, - N (Ra) C (O) N (Ra) -, –N (Ra) C (S) N (Ra) -, –C (O) O–, –OC (O) -, - OC (O) N (Ra) -, –N (Ra) C ( O) O–, –C (O) N (Ra) O–, –N (Ra) C (S) -, - C (S) N (Ra) -, or –OC (O) O–; wherein the link on the left side of Y2, as shown, is linked to the ring and the link on the right side of the Y2 portion, as shown, is linked to R3;
[0603] [0603] Ra is independently, at each occurrence, –H, –OH, –C3- C8cycloalkyl, –C1-C6alkyl, 3- to 12-membered heterocyclyl, or - (CH2) n-aryl, where each alkyl or cycloalkyl is optionally substituted with one or more –NH2, or where 2 Ra, together with the carbon atom to which they are attached, can combine to form a 3- to 8-membered cycloalkyl;
[0604] [0604] Rb is independently, in each occurrence, –H, –OH, - C1-C6alkyl, –C3-C8cycloalkyl, –C2-C6alkenyl, - (CH2) n-aryl, hetero-
[0605] [0605] R2 is independently –H, –NH2, –ORb, –CN, –C1- C6alkyl, –C2-C6alkenyl, –C4-C8cycloalkenyl, –C2-C6alkynyl, halogen, –C (O) ORb, –C3- C8cycloalkyl, aryl, heterocyclyl containing 1-5 heteroatoms selected from the group consisting of N, S, P and O, or heteroaryl containing 1-5 heteroatoms selected from the group consisting of N, S, P and O; where each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more –OH, halogen, –NO2, oxo, −R5, –OR5, –NR5R6, −SR5 , –S (O) 2NR5R6, –S (O) 2R5, –NR5S (O) 2NR5R6, –NR5S (O) 2R6, –S (O) NR5R6, –S (O) R5, –NR5S (O) NR5R6, –NR5S (O) R6, heterocycle, aryl or heteroaryl;
[0606] [0606] R3 is independently –H, –C1-C6alkyl, a 3- to 12-membered monocyclic or polycyclic heterocycle, a 5- to 12-membered spiroheterocycle, C3-C8cycloalkyl, - (CH2) n-Rb, or - (CH2) nC (O) NR5R6, where each alkyl, spiroheterocycle, heterocycle, or cycloalkyl is optionally substituted with one or more –C1-C6alkyl, –OH, –NH2, –ORb, –NHRb, - (CH2) nOH, heterocyclyl , or spiroheterocyclyl; or
[0607] [0607] R3 can combine with Ra to form a 3 to 12 membered monocyclic or polycyclic heterocycle or a 5 to 12 membered spiroheterocycle, where each heterocycle or spiroheterocycle is optionally substituted with one or more –C1-C6alkyl, halogen , –OH, -
[0608] [0608] R5 and R6 are independently, in each occurrence, –H, - C1-C6alkyl, –C2-C6alkenyl, –C4-C8cycloalkenyl, –C2-C6alkynyl, - C3-C8cycloalkyl, a 3- to 12-membered monocyclic heterocycle polycyclic, –OR7, –SR7, halogen, –NR7R8, –NO2, –CF3 or –CN;
[0609] [0609] R7 and R8 are independently, in each occurrence, –H, - C1-C6alkyl, –C2-C6alkenyl, –C4-C8cycloalkenyl, –C2-C6alquinyl, - C3-C8cycloalkyl, –ORb, or a 3 to 3 heterocycle 12 monocyclic or polycyclic members, where each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl or heterocycle is optionally substituted with one or more –OH, –SH, –NH2, –NO2, or –CN;
[0610] [0610] m is independently 1, 2, 3, 4, 5 or 6; and
[0611] [0611] n is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;
[0612] [0612] as long as when X2 is N and ring B is a 5-membered monocyclic heteroaryl containing 3-4 nitrogen atoms, then don't be; and
[0613] [0613] as long as when X1 is N; X2 is CH and Y1 is NH; then R1 is not C3-C8cycloalkyl or heteroaryl.
[0614] [0614] Mode III-2. A compound of formula VI:
[0615] [0615] or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer or isomer thereof, where:
[0616] [0616] A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, in which cycloalkyl, heterocycloalkyl, aryl and heteroaryl are monocyclic from 5 to 12 members or polycyclic from 5 to 12 members;
[0617] [0617] R1 is independently, in each occurrence, –H, –C1- C6alkyl, –C2-C6alkenyl, –C4-C8cycloalkenyl, –C2-C6alkynyl, –C3- C8cycloalkyl, –OH, –OR6, halogen, –NO2, –CN, –NR5R6, –SR5, - S (O) 2NR5R6, –S (O) 2R5, –NR5S (O) 2NR5R6, –NR5S (O) 2R6, –S (O) NR5R6, –S (O) R5 , –NR5S (O) NR5R6, –NR5S (O) R6, –C (O) R5, –CO2R5, - C (O) NR5R6, –NR5C (O) R6, monocyclic or polycyclic heterocyclyl, spiroheterocycly, heteroaryl or oxo, where each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, heterocyclyl, spiroheterocyclyl or heteroaryl is optionally substituted with one or more –OH, halogen, –NO2, oxo, = O, –CN, −R5, –OR5, –NR5R6, −SR5, –S (O) 2NR5R6, - S (O) 2R5, –NR5S (O) 2NR5R6, –NR5S (O) 2R6, –S (O) NR5R6, –S (O) R5 , - NR5S (O) NR5R6, –NR5S (O) R6, heterocycle, aryl or heteroaryl;
[0618] [0618] Y1 is –S–, a direct link, –NH-, –S (O) 2-, –S (O) 2-NH-, - C (= CH2) -, -CH2- or -S ( O)-;
[0619] [0619] X1 is N or C;
[0620] [0620] X2 is N or CH;
[0621] [0621] X3 is N or C;
[0622] [0622] B, including atoms at the points of attachment, is a 5 to 12 membered monocyclic or polycyclic heterocycle or a 5 to 12 membered monocyclic or polycyclic heteroaryl;
[0623] [0623] D, including the atoms at the points of attachment, is a 5- to 7-membered monocyclic heterocycle or a 5- to 7-membered monocyclic heteroaryl;
[0624] [0624] Y2 is –NRa–, - (CRa2) m–, –O–, –C (O) -, –C (Ra) 2NH–, - (CRa2) mO–, –C (O) N (Ra ) -, –N (Ra) C (O) -, –S (O) 2N (Ra) -, –N (Ra) S (O) 2–, -
[0625] [0625] Ra is independently, at each occurrence, –H, –OH, –C3- C8cycloalkyl, –C1-C6alkyl, 3- to 12-membered heterocyclyl, or - (CH2) n-aryl, where each alkyl or cycloalkyl is optionally substituted with one or more –NH2, or where 2 Ra, together with the carbon atom to which they are attached, can combine to form a 3- to 8-membered cycloalkyl;
[0626] [0626] Rb is independently, in each occurrence, –H, –OH, - C1-C6alkyl, –C3-C8cycloalkyl, –C2-C6alkenyl, - (CH2) n-aryl, heterocyclyl containing 1-5 heteroatoms selected a starting from the group consisting of N, S, P and O, or heteroaryl containing 1-5 heteroatoms selected from the group consisting of N, S, P and O; where each alkyl, cycloalkyl, alkenyl, heterocycle, heteroaryl, or - (CH2) n-aryl is optionally substituted with one or more –OH, halogen, –NO2, oxo, –CN, −R5, –OR5, –NR5R6, −SR5, –S (O) 2NR5R6, –S (O) 2R5, - NR5S (O) 2NR5R6, –NR5S (O) 2R6, –S (O) NR5R6, –S (O) R5, - NR5S (O) NR5R6, –NR5S (O) R6, –C (O) NR5R6, –NR5C (O) R6, heterocycle, aryl, heteroaryl, - (CH2) nOH, –C1-C6alkyl, –CF3, –CHF2 or –CH2F;
[0627] [0627] R2 is independently –H, –NH2, –ORb, –CN, –C1- C6alkyl, –C2-C6alkenyl, –C4-C8cycloalkenyl, –C2-C6alkynyl, halogen, –C (O) ORb, –C3- C8cycloalkyl, aryl, heterocyclyl containing 1-5 heteroatoms selected from the group consisting of N, S, P and O, or heteroaryl containing 1-5 heteroatoms selected from the group consisting of N, S, P and O; where each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more –OH, halogen, –NO2, oxo, -
[0628] [0628] R3 is independently –H, –C1-C6alkyl, a 3- to 12-membered monocyclic or polycyclic heterocycle, a 5- to 12-membered spiroheterocycle, C3-C8cycloalkyl, or - (CH2) n-Rb, where each alkyl , spiroheterocycle, heterocycle or cycloalkyl is optionally substituted with one or more –C1-C6alkyl, –OH, –NH2, –ORb, –NHRb, - (CH2) nOH, - (CH2) nC (O) NR5R6, heterocyclyl, or spiroheterocyclyl ; or
[0629] [0629] R3 can combine with Ra to form a 3 to 12 membered monocyclic or polycyclic heterocycle or a 5 to 12 membered spiroheterocycle, where each heterocycle or spiroheterocycle is optionally substituted with one or more –C1-C6alkyl, halogen , –OH, - ORb, –NH2, –NHRb, optionally substituted heteroaryl, optionally substituted heterocyclyl, - (CH2) nNH2, - (CH2) nOH, –COORb, - CONHRb, –CONH (CH2) nCOORb, –NHCOORb, - OC (O) -NR5R6, –CF3, - CHF2, –CH2F ou = O; wherein the heteroaryl and heterocyclyl are optionally substituted with –CN;
[0630] [0630] R5 and R6 are independently, at each occurrence, –H, - C1-C6alkyl, –C2-C6alkenyl, –C4-C8cycloalkenyl, –C2-C6alkynyl, - C3-C8cycloalkyl, a 3- to 12-membered monocyclic heterocycle or polycyclic, –OR7, –SR7, halogen, –NR7R8, –NO2, –CF3 or –CN;
[0631] [0631] R7 and R8 are independently, in each occurrence, –H, - C1-C6alkyl, –C2-C6alkenyl, –C4-C8cycloalkenyl, –C2-C6alquinyl, - C3-C8cycloalkyl, –ORb, or a 3 to heterocycle 12 monocyclic or polycyclic members, where each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl or heterocycle is optionally substituted with one or more –OH, –SH, –NH2, –NO2 or –CN;
[0632] [0632] m is independently 1, 2, 3, 4, 5 or 6; and
[0633] [0633] n is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.
[0634] [0634] Mode III-3. The compound of modality III-1 or III-2, where Y1 is –S–.
[0635] [0635] Mode III-4. The compound of the III-1 or III-2 modality, where Y1 is a direct bond.
[0636] [0636] Mode III-5. The compound of any of Modes III-1 to III-4, where X1 is N.
[0637] [0637] Mode III-6. The compound of any of Modes III-1 to III-4, where X1 is CR2.
[0638] [0638] Mode III-7. The compound of modality III-6, where R2 is –H, –NH2, -OH or –C1-C6alkyl.
[0639] [0639] Mode III-8. The compound of any of Modes III-1 to III-4, where X2 is N.
[0640] [0640] Mode III-9. The compound of any of Modes III-1 to III-4, where X2 is CH.
[0641] [0641] Mode III-10. The compound of any of Modes III-1 to III-4, where X1 is N and X2 is N.
[0642] [0642] Mode III-11. The compound of any of Modes III-1 to III-4, where X1 is N and X2 is CH.
[0643] [0643] Mode III-12. The compound of any of Modes III-1 to III-4, where X1 is CR2 and X2 is N.
[0644] [0644] Mode III-13. The compound of any of Modes III-1 to III-4, where X1 is CR2 and X2 is CH.
[0645] [0645] Mode III-14. The compound of any of Modes III-12 to III-13, wherein R2 is –H, –NH2, -OH or –C1- C6alkyl.
[0646] [0646] Mode III-15. The compound of any of Modes III-1 to III-14, wherein B, including the atoms at the points of attachment, is a 5- to 12-membered monocyclic heteroaryl.
[0647] [0647] Mode III-16. The compound of any of Modes III-1 to III-15, where B, including the atoms at the points of attachment, is, where XB1 is N, CH, S, or O; XB2 is N, CH, S, or O; and XB3 is N, CH, S, or O.
[0648] [0648] Mode III-17. The compound of any of Modes III-1 to III-15, where B, including the atoms at the points of attachment, is, where XB4 is N or CH; XB5 is N or CH; XB6 is N or CH; and XB7 is N or CH.
[0649] [0649] Mode III-18. The compound of any of the modalities III-1 to III-17, where A is cycloalkyl.
[0650] [0650] Mode III-19. The compound of any of the modalities III-1 to III-17, wherein A is heterocycloalkyl.
[0651] [0651] Mode III-20. The compound of any of the modalities III-1 to III-17, where A is aryl.
[0652] [0652] Mode III-21. The compound of any of the modalities III-1 to III-17, where A is phenyl.
[0653] [0653] Mode III-22. The compound of any of the modalities III-1 to III-17, where A is heteroaryl.
[0654] [0654] Mode III-23. The compound of any of the modalities III-1 to III-17, where A is pyridyl.
[0655] [0655] Mode III-24. The compound of any of Modalities III-1 to III-23, where R1 is independently –OH, –NO2, –CN, halogen or –NR5R6.
[0656] [0656] Mode III-25. The compound of any of the modalities III-1 to III-24, where Y2 is –NRa–.
[0657] [0657] Mode III-26. The compound of any of the modalities III-1 to III-24, where Y2 is - (CRa2) m–.
[0658] [0658] Mode III-27. The compound of any of the modalities III-1 to III-26, where Ra is –H.
[0659] [0659] Mode III-28. The compound of any of the modalities III-1 to III-26, where Ra is –C1-C6alkyl.
[0660] [0660] Mode III-29. The compound of any of the modalities III-1 to III-28, where R3 is –C1-C6alkyl.
[0661] [0661] Mode III-30. The compound of any of the modalities III-1 to III-28, wherein R3 is monocyclic or polycyclic heterocycle of 3 to 12 members.
[0662] [0662] Mode III-31. The compound of any of the modalities III-1 to III-28, wherein R3 is a 3- to 12-membered monocyclic heterocycle.
[0663] [0663] Mode III-32. The compound of any of the modalities III-1 to III-28, wherein R3 is a 5 to 12 membered polycyclic heterocycle.
[0664] [0664] Mode III-33. The compound of any of the modalities III-1 to III-26, in which R3 and Ra together with the atom to which they are attached, combine to form a 3- to 12-membered monocyclic heterocycle.
[0665] [0665] Mode III-34. The compound of any of the modalities III-1 to III-26, in which R3 and Ra together with the atoms to which they are attached, combine to form a 3- to 12-membered polycyclic heterocycle.
[0666] [0666] Mode III-35. The compound of any of the modalities III-1 to III-26, in which R3 and Ra together with the atoms to which they are attached, combine to form a 5- to 12-membered spiroheterocycle.
[0667] [0667] Mode III-36. The compound of any of the modalities III-33 to III-35, in which heterocycle or spirocycle formed by R3 and Ra is substituted with one or more substituents selected from the group consisting of C1-C6alkyl, –OH, halogen, –NH2 , –NHRb, –CF3, –CHF2 or –CH2F.
[0668] [0668] Mode III-37. A compound, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, selected from the group consisting of: Compound 1 2 3 4 5 6 7
[0669] [0669] Mode III-38. A compound, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, selected from the group consisting of:
[0670] [0670] Mode III-39. A pharmaceutical composition comprising a compound of any one of embodiments III-1 to III-38, or a pharmaceutically acceptable salt, prodrug, solvate, hydrosat, tautomer, or isomer thereof, and a pharmaceutically acceptable carrier.
[0671] [0671] Mode III-40. A method of treating a disease associated with SHP2 modulation in an individual who needs it, comprising administering to the individual an effective amount of a compound of any one of modalities III-1 to III-38, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer or isomer thereof.
[0672] [0672] Mode III-41. The III-40 method, in which the disease is selected from Noonan syndrome, Leopard syndrome, juvenile myelomonocytic leukemias, neuroblastoma, melanoma, acute myeloid leukemia and cancers of the breast, lung and colon.
[0673] [0673] Mode III-42. A compound of any one of embodiments III-1 to III-38, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer or isomer thereof, for use as a medicament.
[0674] [0674] Mode III-43. A compound of any of the modalities III-1 to III-38, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer or isomer thereof, for use in the treatment or prevention of a disease associated with SHP2 modulation .
[0675] [0675] Mode III-44. Use of a compound of any of the modalities III-1 to III-38, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer or isomer thereof, in the manufacture of a medicine to treat or prevent an associated disease associated with SHP2 modulation.
[0676] [0676] Mode III-45. A method of treating a disease associated with SHP2 modulation in an individual who needs it, comprising administering to the individual an effective amount of a pharmaceutical composition of modality III-39.
[0677] [0677] Mode III-46. The III-45 method, in which the disease is selected from Noonan syndrome, Leopard syndrome, juvenile myelomonocytic leukemias, neuroblastoma, melanoma, acute myeloid leukemia and cancers of the breast, lung and colon.
[0678] [0678] Mode III-47. A pharmaceutical composition of modality III-39 for use as a medicament.
[0679] [0679] Mode III-48. A pharmaceutical composition of modality III-39 for use in the treatment or prevention of a disease associated with modulation of SHP2.
[0680] [0680] Mode III-49. Use of a pharmaceutical composition of modality III-39 in the manufacture of a drug to treat or prevent a disease associated with SHP2 modulation.
[0681] [0681] Examples
[0682] [0682] The description is further illustrated by the examples and examples of synthesis that follow, which should not be interpreted as limiting this description in scope or spirit to the procedures described in this document. It should be understood that the examples are provided to illustrate certain modalities and that no limitation on the scope of the description is thus intended. It should be further understood that it may be necessary to resort to various other modalities, modifications and equivalents thereof that can be suggested to those skilled in the art without departing from the spirit of the present invention and / or the scope of the appended claims.
[0683] [0683] Definitions used in the examples that follow and throughout this document are: CH2Cl2, DCM Methylene chloride, dichloromethane CH3CN, MeCN Acetonitrile CuI Copper (I) DIPEA Diisopropylethyl amine DMF N, N-Dimethylformamide EtOAc Ethyl acetate hr Hour
[0684] [0684] Example 1. Synthesis of (3S, 4S) -8- {8 - [(2-amino-3-chloropyridin-4-yl) sulfanyl] imidazo [1,2-c] pyrimidin-5-yl } -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine (Compound 1)
[0685] [0685] Step 1. Synthesis of (3S, 4S) -8- {8-bromoimidazo [1,2-c] pi-rimidin-5-yl} -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine
[0686] [0686] To a solution of 8-bromo-5-chloroimidazo [1,2-c] pyrimidine (0.50 g; 2.15 mmol) in isopropanol (10 mL) were added (3S, 4S) - 3 -methyl-2-oxa-8-azaspiro [4.5] decan-4-amine (0.44 g; 2.1 mmol; HCl salt) and N, N-diisopropylethylamine (3.74 mL; 21.5 mmol) at room temperature. (Huang, Y et al. J. Med. Chem. 2017, 60, 2215.) The reaction was heated to 70 ° C for 3 h. Upon completion, the reaction mixture was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (0–20% MeOH / DCM) to yield (3S, 4S) -8- { 8-bromoimidazo [1,2-c] pyrimidin-5-yl} -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine (0.65 g, 83% yield). 1H NMR (500 MHz, Methanol-d4) δ 7.96 (s; 1H); 7.82 (d; J = 1.7 Hz; 1H); 7.66 (d; J = 1.6 Hz; 1H); 4.45 - 4.21 (m; 1H); 3.99 (dt; J = 9.2; 1.1 Hz; 1H); 3.88 (dd; J = 9.3; 0.8 Hz; 1H); 3.87 - 3.76 (m; 1H); 3.49 (t; J = 3.9 Hz; 1H); 3.28 - 3.10 (m; 3H); 2.06 (tdd; J = 11.1; 7.0; 3.9 Hz; 2H);
[0687] [0687] Step 2. Synthesis of (3S, 4S) -8- {8 - [(2-amino-3-chloropyridin-4-yl) sulfanyl] imidazo [1,2-c] pyrimidin-5-yl} - 3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine
[0688] [0688] (3S, 4S) -8- {8-bromoimidazo [1,2-c] pyrimidin-5-yl} -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine (100 mg, 273 µmol), 3-chloro-4- (potassiosulfanyl) pyridin-2-amine (81.2 mg; 409 µmol), [5- (diphenylphosphanyl) - 9,9-dimethyl-9H-xanten-4 -il] diphenylphosphane (known as XantPhos) (31.5 mg; 54.6 µmol), tris (dibenzylideneacetone) dipaladium (24.9 mg; 27.3 µmol) and a Teflon-coated magnetic rod were sequentially added to a 5 ml microwave vial. The bottle was capped and then sparged with nitrogen gas for 3 minutes. Dioxane (2.7 mL) was then added to this flask, which had been soaked with nitrogen gas for 45 minutes, followed by the addition of N, N-diisopropylethylamine (63.3 µL; 364 µmol). This heterogeneous mixture was then heated in a microwave at 120 ° C for 2 h. The reaction was filtered over a pad of celite, washed with 20% MeOH / DCM. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (0–20% MeOH / DCM). Purification by prep-HPLC (1-30% CH3CN / H2O with 0.1% formic acid) yielded (3S, 4S) -8- {8 - [(2-amino-3-chloropyridin-4-yl) sulfanyl] imidazo [1,2-c] pyrimidin-5-yl} -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine (45.2 mg; 37% yield) as a salt formic acid. 1H NMR (500 MHz, Methanol-d4) δ 8.47 (s; 1H); 8.05 (s; 1H); 7.82 (d; J = 1.6 Hz; 1H); 7.58 (d; J = 1.6 Hz; 1H); 7.49 (d; J = 5.6 Hz; 1H); 5.87 (d; J = 5.6 Hz; 1H); 4.32 (qd; J = 6.5; 4.2 Hz; 1H); 4.08 - 3.93 (m; 3H); 3.89 (d; J = 9.1 Hz; 1H); 3.45 (d; J = 4.2 Hz; 1H); 3.41 - 3.34 (m; 1H); 3.30 - 3.24 (m; 1H); 2.07 (ddt; J = 14.6; 11.0; 3.7 Hz; 2H);
[0689] [0689] Example 2. Synthesis of 4 - {[5- (4-amino-4-methylpiperidin-1-yl) imidazo [1,2-c] pyrimidin-8-yl] sulfanyl} -3-chloropyridin-2- amine (Compound 2)
[0690] [0690] 4 - {[5- (4-amino-4-methylpiperidin-1-yl) imidazo [1,2-c] pyrimidin-8-yl] sulfanyl} -3-chloropyridin-2-amine was synthesized from a similar to Example 1, except that (3S, 4S) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine was replaced with tert- (4-methylpiperidin-4-yl) carbamate butyl. 1H NMR (500 MHz, Methanol-d4) δ 8.51 (s; 1H); 8.07 (s; 1H); 7.84 (d; J = 1.6 Hz; 1H); 7.59 (d; J = 1.6 Hz; 1H); 7.49 (d; J = 5.5 Hz; 1H); 5.87 (d; J = 5.5 Hz; 1H); 3.96 (dt; J = 14.1; 4.6 Hz; 2H); 3.54 (ddd; J = 13.7; 10.1; 3.2 Hz; 2H); 2.13 - 2.04 (m; 2H); 2.03 - 1.95 (m; 2H); 1.53 (s; 3H). LC-MS (ESI): m / z: [M + H] calculated for C17H21ClN7S: 390.1; found 390.3.
[0691] [0691] Example 3. Synthesis of 1- [8- (2,3-dichlorophenyl) imidazo [1,2- c] pyrimidin-5-yl] -4-methylpiperidin-4-amine (Compound 3)
[0692] [0692]
[0693] [0693] Step 1. Synthesis of N- {1- [8- (2,3-dichlorophenyl) imidazo [1,2- c] pyrimidin-5-yl] -4-methylpiperidin-4-yl} tert-carbamate butyl
[0694] [0694] N- (1- {8-bromoimidazo [1,2-c] pyrimidin-5-yl} -4-methylpiperidin-4-
[0695] [0695] Step 2. Synthesis of 1- [8- (2,3-dichlorophenyl) imidazo [1,2-c] pyrimidin-5-yl] -4-methylpiperidin-4-amine
[0696] [0696] To a solution of tert N- {1- [8- (2,3-dichlorophenyl) imidazo [1,2-c] pyrimidin-5-yl] -4-methylpiperidin-4-yl} carbamate -butyl (52 mg, 109 µmol) in MeOH (2 ml) was added hydrogen chloride (4 M in dioxane, 1 ml) at room temperature. The reaction was allowed to stir for 4 h at room temperature. The solvent was removed under reduced pressure and purification by prep-HPLC yielded 1- [8- (2,3-dichlorophenyl) imidazo [1,2-c] pyrimidin-5-yl] -4-methylpiperidin-4 -amine (3.6 mg; 9% yield) as a formic acid salt. 1H NMR (500 MHz,
[0697] [0697] Example 4. Synthesis of (3S, 4S) -8- {8 - [(2-amino-3-chloropyridin-4-yl) sulfanyl] - [1,2,4] triazole [1,5 -c] pyrimidin-5-yl} -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine (Compound 4)
[0698] [0698] Step 1. Synthesis of (3S, 4S) -8 - ([1,2,4] triazolo [1,5-c] pyrimidin-5-yl) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine
[0699] [0699] To a solution of 5-chloro- [1,2,4] triazolo [1,5-c] pyrimidine (120 mg, 776 µmol) in DMA (3.88 mL) was added bis (3S, 4S) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine (277 mg; 1.16 mmol) and DIPEA (675 µL; 3.88 mmol). The reaction mixture was stirred in a capped flask at 90 ° C for 1 h. The resulting mixture was concentrated under reduced pressure and the crude residue was carried on to the next step without any further purification. LCMS (ESI): m / z: [Μ + H] calculated for C14H21N6O: 289.2; found 289.3.
[0700] [0700] Step 2. Synthesis of (3S, 4S) -8- (8-bromo- [1,2,4] triazolo [1,5-c] pyrimidin-5-yl) -3-methyl-2-oxa -8-azaspiro [4.5] decan-4-amine
[0701] [0701] To a solution of (3S, 4S) -8 - ([1,2,4] triazolo [1,5-c] pyrimidin-5-yl) -3-methyl-2-oxa-8-azaspiro [ 4.5] crude decan-4-amine (50 mg, 173 µmol) in CH3CN (865 µL) N-bromosuccinimide (61.5 mg; 346 µmol) was added. The reaction mixture was stirred at room temperature in a capped flask for 1 h. The resulting mixture was concentrated under reduced pressure and purified by column chromatography (10: 1 DCM: MeOH) to yield the desired product (3S, 4S) -8- (8-bromo- [1,2,4] triazole [1 , 5-c] pyrimidin-5-yl) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine (110 mg, 299 µmol, 79%). LCMS (ESI): m / z: [Μ + H] calculated for C14H20BrN6O: 367.1; found 367.0.
[0702] [0702] Step 3. Synthesis of (3S, 4S) -8- {8 - [(2-amino-3-chloropyridin-4-yl) sulfanyl] - [1,2,4] triazolo [1,5-c ] pyrimidin-5-yl} -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine.
[0703] [0703] To a microwave vial (3S, 4S) -8- (8-bromo- [1,2,4] triazolo [1,5-c] pyrimidin-5-yl) -3-methyl were added -2-oxa-8-azaspiro [4.5] decan-4-amine (110 mg, 299 µmol), 3-chloro-4- (potassiosulfanyl) pyridin-2-amine (89.0 mg; 448 µmol), Pd2 (dba) 3 (27.3 mg; 29.9 µmol), Xantphos (34.6 mg; 59.8 µmol) and DIPEA (154 µL, 897 µmol). The mixture was evacuated under vacuum for 15 min before adding degassed dioxane (1.49 ml). The reaction mixture was purged with N2 and evacuated three times before subjecting it to microwave conditions for 1.5 h at 130 ° C. The resulting reaction mixture was filtered through a pad of celite and the filtrate was concentrated under reduced pressure. The residue was purified by prep HPLC (5-30% ACN + 0.1% formic acid / H2O + 0.1% formic acid) to yield the desired product (3S, 4S) -8- {8 - [(2- amino-3-chloropyridin-4-yl) sulfanyl] - [1,2,4] triazolo [1,5-c] pyrimidin-5-yl} -3-methyl-2-oxa-8-azaspiro [4.5] decan -4-amine (30.0 mg; 84.9%) as the formic acid salt. 1H NMR (500 MHz, Methanol-d4) δ 8.53 (s; 1H); 8.36 (s; 1H); 8.21 (s; 1H); 7.54 (d; J = 5.5 Hz; 1H); 5.95 (d; J = 5.5 Hz; 1H); 4.87 (s; 2H); 4.30 (s; 1H); 3.98 (d; J = 8.8 Hz; 1H); 3.84 (d; J = 9.0 Hz; 2H); 3.78 - 3.63 (m; 2H); 1.97 (d; J = 20.5 Hz; 3H); 1.85 (d; J = 45.8 Hz; 1H); 1.30 (d; J = 7.3 Hz; 3H). LCMS (ESI): m / z: [M + H] calculated for C19H24ClN8OS: 447.1; found 447.4.
[0704] [0704] Example 5. Synthesis of (1R) -8- [8- (2,3-dichlorophenyl) imidazzo [1,5-a] pyridin-5-yl] -8-azaspiro [4.5] decan-1 -amine (Compound 5)
[0705] [0705]
[0706] [0706] Step 1. Synthesis of N - ((R) -8- (8-bromoimidazo [1,5-a] pyridin-5-yl) -8-azaspiro [4.5] decan-1-yl) -2- methylpropane-2-sulfinamide
[0707] [0707] To a reaction flask were added 8-bromo-5-chloroimidazo [1,5-a] pyridine (50.0 mg; 216 µmol), 2-methyl-N - ((R) -8-azaspiro [ 4.5] decan-1-yl) propane-2-sulfinamide (83.7 mg; 324 µmol), CuI (4.11 mg; 21.6 µmol), BTMPO (9.08 mg; 21.6 µmol) and K3PO4 (137 mg, 648 µmol). The flask was evacuated and filled with N2 three times before addition in DMSO (1 ml). The reaction was stirred in the vial capped flask overnight at 120 ° C. The resulting reaction mixture was diluted with EtOAc and H2O, and the aqueous layer was extracted three times with EtOAc. The combined organic layers were washed with brine. The resulting organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (0-10% MeOH / DCM) to yield the desired product N - ((R) -8- (8-bromoimidazo [1,5-a] pyridin-5-yl) -8-azaspiro [4.5] decan-1-yl) - 2-methylpropane-2-sulfinamide (68.0 mg; 149 µmol; 69.4%). LCMS (ESI): m / z: [M + H] calculated for C20H29BrN4OS: 453.1; found 452.9.
[0708] [0708] Step 2. Synthesis of N - ((R) -8- (8- (2,3-dichlorophenyl) imid-azo [1,5-a] pyridin-5-yl) -8-azaspiro [4.5] decan-1-yl) -2-methylpropane-2-sulfinamide
[0709] [0709] To a reaction flask were added N - ((R) -8- (8-bromimimazo [1,5-a] pyridin-5-yl) -8-azaspiro [4.5] decan-1-yl ) -2-methylpropane-2-sulfinamide (37 mg; 81.5 µmol), boronic acid (2,3-dichlorophenyl) (23.2 mg, 122 µmol), Pd (dppf) Cl2 · CH2Cl2 (13.3 mg ; 16.3 µmol) and K2CO3 (22.5 mg; 163 µmol). The mixture was evacuated and filled with N2 three times before addition in degassed CH3CN (815 µL). The reaction was stirred at 100 ° C for 2 h. The resulting mixture was filtered through a pad of celite. The filtrate was concentrated under reduced pressure and purified by column chromatography (0-100% EtOAc / Heptane followed by 0-10% MeOH / DCM) to yield the desired product. LCMS (ESI): m / z: [M + H] calculated for C26H33Cl2N4OS: 519.1; found 519.0.
[0710] [0710] Step 3. Synthesis of (1R) -8- [8- (2,3-dichlorophenyl) imidazo [1,5- a] pyridin-5-yl] -8-azaspiro [4.5] decan-1-amine
[0711] [0711] To a solution of N - ((R) -8- (8- (2,3-dichlorophenyl) imidazo [1,5- a] pyridin-5-yl) -8-azaspiro [4.5] decan-1 -yl) -2-methylpropane-2-sulfinamide (10 mg; 19.2 µmol) in methanol (1 ml) 4M HCl (14.4 µL; 57.6 µmol) in dioxane was added. The reaction mixture was stirred at 35 ° C for 1 h. The resulting reaction mixture was concentrated under reduced pressure and the residue was purified by prep HPLC (Biotage) using 5-35% ACN + 0.1% formic acid / H2O + 0.1% formic acid to yield the product desired (1R) -8- [8- (2,3-dichlorophenyl) imidazo [1,5-a] pyridin-5-yl] -8-azaspiro [4.5] decan-1-amine (3.00 mg; 7 , 22 µmol; 37.6%) as the formic acid salt. 1H NMR (500 MHz, Methanol-d4) δ 8.28 (s; 1H); 7.66 (dd; J = 6.5; 3.1 Hz; 1H); 7.45 - 7.37 (m; 2H); 7.07 (s; 1H); 6.86 (d; J = 7.2 Hz; 1H); 6.43 (d; J = 7.1 Hz; 1H); 4.59 (s; 1H); 3.46 (d; J = 29.9 Hz; 2H); 3.36 (d; J = 7.9 Hz; 1H); 3.06 (t; J = 12.1 Hz; 3H); 2.14 - 1.98 (m; 1H); 1.98 - 1.63 (m; 7H); 1.31 (s; 1H). LCMS (ESI): m / z: [M + H] calculated for C22H25Cl2N4: 415.1; found 415.3.
[0712] [0712] Example 6. Synthesis of (3S, 4S) -8- [8- (2,3-dichlorophenyl) -7-
[0713] [0713] Step 1. Synthesis of (2-chloro-6-methyl-pyrimidin-4-yl) hydrazine
[0714] [0714] To a solution of 2,4-dichloro-6-methyl-pyrimidine (10 g; 61.35 mmol) in EtOH (100 ml) was added TEA (9.4 ml; 67.5 mmol), followed by guided by NH2NH2 • H2O (4.21 ml; 85% purity, 73.6 mmol) at 0 ° C in drops. The mixture was stirred at 25 ° C for 8 h and then filtered. The filtrate was concentrated under reduced pressure and the crude residue was purified by a C18 reverse phase column to give (2-chloro-6-methyl-pyrimidin-4-yl) hydrazine (1.4 g; 8.83 mmol; 14.4% yield) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ 8.75 (br s, 1H), 6.59 (br s, 1H), 4.51 (br s, 1H), 2.20 (s, 3H).
[0715] [0715] Step 2. Synthesis of 7-methyl- [1,2,4] triazolo [4,3-c] pyrimidin-5-ol
[0716] [0716] To a solution of (2-chloro-6-methyl-pyrimidin-4-yl) hydrazine (1 g, 6.31 mmol) in trimethoxymethane (20 ml, 182 mmol) was added acetic acid (2 ml). The mixture was stirred at 120 ° C for 10 h and then filtered. The filtrate was concentrated under reduced pressure to give 7-methyl- [1,2,4] triazolo [4,3-c] pyrimidin-5-ol (0.7 g; 4.62 mmol; 73.2% yield - ment) as a gray solid. 1H NMR (400MHz, DMSO-d6) δ 12.01 (br s, 1H), 8.32 (s, 1H), 6.58 (s, 1H), 2.26 (s, 3H).
[0717] [0717] Step 3. Synthesis of 5-chloro-7-methyl- [1,2,4] triazolo [4,3-c] pyrimidine
[0718] [0718] To a solution of 7-methyl- [1,2,4] triazolo [4,3-c] pyrimidin-5-ol
[0719] [0719] Step 4. Synthesis of N - [(3S, 4S) -3-methyl-8- (7-methyl- [1,2,4] triazolo [4,3-c] pyrimidin-5-yl ) -2-oxa-8-azaspiro [4.5] decan-4-yl] tert-butyl carbamate
[0720] [0720] To a solution of 5-chloro-7-methyl- [1,2,4] triazolo [4,3-c] pyrimidine (315 mg; 1.87 mmol) and (3S, 4S) -3-methyl-2-oxa- 8-azaspiro [4.5] decan-4-amine (454 mg; 1.87 mmol) in i-PrOH (8 ml) DIPEA (2.6 ml; 15, 0 mmol). The mixture was stirred at 75 ° C for 2 h. The reaction was cooled to 25 ° C and tert-butyl carbonate (489 mg; 2.24 mmol) was added in drops. The mixture was stirred at room temperature for 1 h and then concentrated under reduced pressure. The crude residue was purified by column chromatography to give N- [(3S, 4S) -3-methyl-8- (7-methyl- [1,2,4] triazolo [4,3-c] pyrimidin-5- il) -2-oxa-8-azaspiro [4.5] decan-4-yl] tert-butyl carbamate (0.6 g; 1.49 mmol, 80% yield) as a white solid. LCMS (ESI): m / z [M + H] calculated for C20H31N6O3: 403.2; found 403.3; 1H NMR (400 MHz, DMSO-d6) δ 8.40 (s; 1H); 7.02 (t; J = 5.2 Hz; 2H); 4.2 - 4.1 (m; 2H); 3.98 - 3.87 (m; 2H); 3.7 - 3.68 (m; 1H); 3.54 (d; J = 8.4 Hz; 1H); 3.52 (d; J = 8.4 Hz; 1H); 2.36 (s; 3H); 1.78 - 1.67 (m; 3H); 1.62 - 1.54 (m; 1H); 1.39 (s; 9H); 1.02 (d; J = 6.0 Hz; 2H).
[0721] [0721] Step 5. Synthesis of N - [(3S, 4S) -8- (8-bromo-7-methyl- [1,2,4] tri-azolo [4,3-c] pyrimidin-5-yl ) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-yl] tert-butyl carbamate
[0722] [0722] To a solution of N - [(3S, 4S) -3-methyl-8- (7-methyl- [1,2,4] triazolo [4,3-c] pyrimidin-5-yl) -2-oxa-8-azaspiro [4.5] decan-4-yl] tert-butyl carbamate (0.6 g; 1.49 mmol) in DMF (6 ml) NBS (318 mg; 1.79 mmol) was added ). The reaction was stirred at 25 ° C for 1.5 h before Na2S2O3 aq. (50 ml) was added and the mixture was extracted with EtOAc. The combined organic layers were washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by column chromatography to give N - [(3S, 4S) -8- (8-bromo-7-methyl- [1,2,4] triazole [4,3 -c] pyrimidin-5-yl) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-yl] tert-butyl carbamate (480 mg; 0.94 mmol, 63% yield) as a white solid. LCMS (ESI): m / z [M + H] calculated for C20H30BrN6O3: 481.2; found 481.1; 1H NMR (400 MHz, DMSO-d6) δ 8.46 (s; 1H); 7.01 (d; J = 10.4 Hz; 1H); 4.20 - 4.14 (m; 2H); 4.04 - 4.01 (m; 2H); 3.89 (dd; J = 5.2; 10.4 Hz; 1H); 3.83 - 3.74 (m; 1H); 3.69 (d; J = 8.4 Hz; 1H); 3.53 (d; J = 8.4 Hz; 1H); 1.78 - 1.66 (m; 3H); 1.63 - 1.53 (m; 1H); 1.39 (s; 9H); 1.02 (d; J = 6.0 Hz; 3H).
[0723] [0723] Step 6. Synthesis of (3S, 4S) -8- [8- (2,3-dichlorophenyl) -7-methyl- [1,2,4] triazolo [4,3-c] pyrimidin-5- yl] -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine
[0724] [0724] To a solution of N - [(3S, 4S) -8- (8-bromo-7-methyl- [1,2,4] triazolo [4,3-c] pyrimidin-5-yl) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-yl] tert-butyl carbamate (80 mg; 0.17 mmol) and boronic acid (2,3-dichlorophenyl) (48 mg ; 0.25 mmol) in DME (0.8 ml) and H2O (0.13 ml) was added Na2CO3 (35 mg; 0.33 mmol), then Pd (PPh3) 4 (19 mg; 0.016 mmol) was added to a reaction mixture. The mixture was stirred at 100 ° C for 1 h and then diluted with EtOAc (5 ml) and the solvent was removed under reduced pressure. The crude residue was purified by chromatography on silica gel and the product was dissolved in MeOH (1.5 ml) and HCl (1.5 ml; 4 M in dioxane) was added. The mixture was stirred at 25 ° C for 1 h and then concentrated under reduced pressure to give (3S, 4S) -8- [8- (2,3-dichlorophenyl) -7-methyl- [1,2,4] triazolo [ 4,3-c] pyrimidin-5-yl] -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine (8.5 mg; 0.017 mmol, 10% yield). 1 H NMR (400 MHz, Methanol-d4) δ 10.66 (s; 1H); 9.71 (d; J = 8.30 Hz; 1H); 9.49 - 9.43 (m; 1H); 9.37 (d; J = 7.90 Hz; 1H); 6.96 (s; 2H); 6.32 (d; J = 4.40 Hz; 1H); 6.02 (d; J = 9.20 Hz; 1H); 5.91 (d; J = 9.60 Hz; 1H); 5.58 - 5.49 (m; 4H); 4.98 - 4.84 (m; 1H); 4.26 (s; 3H); 4.01 (d; J = 16.20 Hz; 3H); 3.80 (d; J = 12.30 Hz; 1H); 3.32 (d; J = 6.60 Hz; 3H). LCMS (ESI): m / z [M + H] calculated for C21H25Cl2N6O: 447.1; found 447.3.
[0725] [0725] Example 7. Synthesis of 4 - {[5- (4-amino-4-methylpiperidin-1-yl) - [1,2,4] triazolo [4,3-c] pyrimidin-8-yl] sulfanyl } -3-chloropyridin-2-amine (Compound 7)
[0726] [0726] Step 1. Synthesis of N- (1- {8-bromo- [1,2,4] triazolo [4,3-c] pi-rimidin-5-yl} -4-methylpiperidin-4-yl) tert-butyl carbamate
[0727] [0727] To a solution of 8-bromo-5- (methylsulfanyl) - [1,2,4] triazolo [4,3-c] pyrimidine (250 mg; 1.01 mmol) in dimethylacetamide (5.05 ml) tert-butyl N- (4-methylpiperidin-4-yl) carbamate (432 mg; 2.02 mmol) was added followed by N, N-diisopropylethylamine (878 µL; 5.05 mmol). This solution was heated to 40 ° C for 17 h, and the reaction was concentrated under reduced pressure. The resulting residue was purified by column chromatography to release N- (1- {8-bromo- [1,2,4] triazolo [4,3-c] pyrimidin-5-yl} -4- tert-butyl methylpiperidin-4-yl) carbamate (310 mg, 74% yield) as a solid. 1H NMR (500 MHz, Chloroform-d) δ 8.76 (s; 1H); 7.82 (s; 1H); 4.43 (s; 1H); 3.76 - 3.56 (m;
[0728] [0728] Step 2. Synthesis of N- (1- {8 - [(2-amino-3-chloropyridin-4-yl) sulpanyl] - [1,2,4] triazolo [4,3-c] pyrimidin-5-yl} -4-methylpiperidin-4-yl) tert-butyl carbamate
[0729] [0729] To a 5 ml microwave flask were added N- (1- {8-bromo- [1,2,4] triazolo [4,3-c] pyrimidin-5-yl} -4-methylpiperidin -4-yl) tert-butyl carbamate (75 mg, 182 µmol), 3-chloro-4- (potassiosulfanyl) pyridin-2-amine (54.2 mg, 273 µmol), XantPhos (21.0 mg ; 36.4 µmol), tris (dibenzylidenoacetone) dipaladium (16.6 mg; 18.2 µmol) and a Teflon-coated magnetic rod. The flask was then capped and the free space was purged with nitrogen gas for 3 min. To a mixture of solids, dioxane (1.81 mL) was then added, which had been sparged with nitrogen gas for 45 minutes, followed by N, N-diisopropylethylamine (63.3 µL; 364 µmol). The heterogeneous solution was then placed in the microwave at 70 ° C for 90 mins. The resulting mixture was filtered through a pad of celite, washed with 20% MeOH / CH2Cl2 to elute the product. The filtrate was then concentrated under reduced pressure and the residue was purified by column chromatography to release N- (1- {8 - [(2-amino-3-chloropyridin-4-yl) sulfanyl] - [1,2, 4] triazolo [4,3-c] pyrimidin-5-yl} -4-methylpiperidin-4-yl) tert-butyl carbamate (40 mg, 44% yield). 1H NMR (500 MHz, Chloroform-d) δ 8.80 (s; 1H); 7.94 (s; 1H); 7.62 (d; J = 5.6 Hz; 1H); 6.01 (d; J = 5.6 Hz; 1H); 5.18 (s; 2H); 4.46 (s; 1H); 3.86 (dt; J = 13.7; 4.3 Hz; 2H); 3.60 (ddd; J = 13.6; 10.7; 2.9 Hz; 2H); 2.44 - 2.24 (m; 2H); 1.82 (ddd; J = 14.2; 10.6; 3.9 Hz; 2H); 1.46 (s; 12H). LC-MS (ESI): m / z: [M + H] + calculated for C21H28ClN8O2S: 491.2; found 491.1.
[0730] [0730] Step 3. Synthesis of 4 - {[5- (4-amino-4-methylpiperidin-1-yl) - [1,2,4] triazolo [4,3-c] pyrimidin-8-yl] sulfanyl } -3-chloropyridin-2-amine
[0731] [0731] To a solution of N- (1- {8 - [(2-amino-3-chloropyridin-4-yl) sulpanyl] - [1,2,4] triazolo [4,3-c] pyrimidin -5-yl} -4-methylpiperidin-4-yl) tert-butyl carbamate (40 mg; 81.4 µmol) in DCM (2 ml) trifluoroacetic acid (1 ml; 12.9 mmol) was added at room temperature . After stirring at room temperature for 30 minutes, the reaction was concentrated under reduced pressure. The residue was directly purified by preparative HPLC (1-10% CH3CN / H2O with 0.1% formic acid) to yield 4 - {[5- (4-amino-4-methylpiperidin-1-yl) - [1 , 2,4] triazolo [4,3-c] pyrimidin-8-yl] sulfanyl} -3-chloropyridin-2-amine (9.5 mg; 30% yield) as a formic acid salt. 1H NMR (500 MHz, Methanol-d4) δ 9.32 (s; 1H); 8.52 (s; 1H); 8.05 (s; 1H); 7.53 (d; J = 5.6 Hz; 1H); 6.03 (d; J = 5.6 Hz; 1H); 4.09 (dt; J = 14.9; 5.0 Hz; 2H); 3.68 (ddd; J = 13.7; 9.7; 3.6 Hz; 2H); 2.01 (dtd; J = 19.2; 14.6; 14.1; 7.0 Hz; 4H); 1.52 (s; 3H). LC-MS (ESI): m / z [M + H] + calculated for C16H20ClN8S: 391.1; found 391.2.
[0732] [0732] Example 8. Synthesis of (3S, 4S) -8- [8- (2,3-dichlorophenyl) -7-methylimidazo [1,2-c] pyrimidin-5-yl] -3-methyl-2- oxa-8-azaspiro [4.5] decan-4-amine.
[0733] [0733] (3S, 4S) -8- [8- (2,3-dichlorophenyl) -7-methylimidazo [1,2-c] pyrimidin-5-yl] -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine was synthesized in a similar manner to Example 15, except for 1H-indazol-6-ylboronic acid which was replaced with 2,3-dichlorophenylboronic acid. 1H NMR (500 MHz, Methanol-d4) δ 7.75 (d; J = 1.7 Hz; 1H); 7.68 (dd; J = 8.1; 1.6 Hz; 1H); 7.54 (d; J = 1.7 Hz; 1H); 7.45 (t; J = 7.9 Hz; 1H); 7.32 (dd; J = 7.6; 1.5 Hz; 1H); 4.33 (dtd; J = 7.0; 6.0; 3.9 Hz; 1H); 4.02 (d; J = 9.2 Hz; 1H); 3.99 - 3.87 (m; 3H); 3.53 (d; J = 4.1 Hz; 1H); 3.30 - 3.18 (m; 2H); 2.21 (s; 3H); 2.10 (tdd; J = 13.2; 6.9; 3.5 Hz; 2H); 1.99 (d; J = 13.7 Hz; 1H);
[0734] [0734] Example 9. Synthesis of (3S, 4S) -8- [8- (2-chloro-3-methoxy-phenyl) -7-methylimidazo [1,2-c] pyrimidin-5-yl] -3- methyl-2-oxa-8-azaspiro [4.5] decan-4-amine.
[0735] [0735] (3S, 4S) -8- [8- (2-chloro-3-methoxyphenyl) -7-methylimidazo [1,2-c] pyrimidin-5-yl] -3-methyl-2-oxa -8-azaspiro [4.5] decan-4-amine was synthesized in a similar manner to Example 15, except 1H-indazol-6-ylboronic acid which was replaced with 2-chloro-3-methoxyphenylboronic acid. 1 H NMR (500 MHz, Methanol-d4) δ 8.57 (s; 1H); 7.70 (d; J = 1.6 Hz; 1H); 7.45 (d; J = 1.5 Hz; 1H); 7.41 (dd; J = 8.3; 7.6 Hz; 1H); 7.20 (dd; J = 8.4; 1.4 Hz; 1H); 6.94 (dd; J = 7.6; 1.4 Hz; 1H); 4.35 - 4.20 (m; 1H); 3.97 (s; 3H); 3.95 (d; J = 9.1 Hz; 1H); 3.82 (d; J = 8.8 Hz; 1H); 3.81 - 3.74 (m; 2H); 3.32 - 3.17 (m; 2H); 2.19 (s; 3H); 2.07 (tdd; J = 14.2; 9.4; 5.1 Hz; 2H); 1.90 (d; J = 13.5 Hz; 1H); 1.83 (d; J = 13.6 Hz; 1H); 1.29 (d; J = 6.5 Hz; 3H). LC-MS (ESI): m / z: [M + H] + calculated for C23H29ClN5O2 442.2; found 442.4.
[0736] [0736] Example 10. 1- [4 - ({5 - [(3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl] imidazo [1, 2-c] pyrimidin-8-yl} sulfanyl) -3-chloropyridin-2-yl] azetidin-3-ol.
[0737] [0737] 1- [4 - ({5 - [(3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl] imidazo [1,2-c ] pyrimidin-8-yl} sulfanyl) -3-chloropyrididin-2-yl] azetidin-3-ol was synthesized in a similar manner to the Example
[0738] [0738] Example 11. Synthesis of (3S, 4S) -8- {8 - [(2,3-dichlorophenyl) sulfanyl] imidazo [1,2-c] pyrimidin-5-yl} -3-methyl- 2-oxa-8-azaspiro [4.5] decan-4-amine.
[0739] [0739] (3S, 4S) -8- {8 - [(2,3-dichlorophenyl) sulfanyl] imidazo [1,2-c] pi-rimidin-5-yl} -3-methyl-2-oxa-8 -azaspiro [4.5] decan-4-amine was synthesized in a similar manner to Example 1, except that 3-chloro-4- (potassium-sulfonyl) pyridin-2-amine was replaced with 2,3-dichlorobenzene-1- thiol. 1 H NMR (500 MHz, Methanol-d4) δ 8.55 (s; 1H); 8.03 (s; 1H); 7.84 (d; J = 1.6 Hz; 1H); 7.58 (d; J = 1.6 Hz; 1H); 7.32 (dd; J = 8.0; 1.4 Hz; 1H); 7.05 (t; J = 8.1 Hz; 1H); 6.69 (dd; J = 8.1; 1.4 Hz; 1H); 4.31 (qd; J = 6.5; 4.5 Hz; 1H); 4.01 - 3.87 (m; 3H); 3.84 (d; J = 8.9 Hz; 1H); 3.40 (ddd; J = 13.5; 10.5; 3.0 Hz; 1H); 3.29 (dd; J = 8.7; 3.7 Hz; 1H); 2.13 - 1.99 (m; 2H); 1.92 (d; J = 13.5 Hz; 1H); 1.82 (dd; J = 12.0; 3.2 Hz; 1H); 1.30 (d; J = 6.5 Hz; 3H). LCMS (ESI): m / z: [M + H] calculated for C21H25Cl2N5OS 464.1; found 464.0.
[0740] [0740] Example 12. Synthesis of (3S, 4S) -8- (8 - {[3-chloro-2- (3-midesulfonylazetidin-1-yl) pyridin-4-yl] sulfanyl} imidazo [1, 2-c] pyrimidin-5-yl) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine.
[0741] [0741] (3S, 4S) -8- (8 - {[3-chloro-2- (3-methanesulfonylazetidin-1-yl) pyridin-4-yl] sulfanyl} imidazo [1,2-c] pyrimidin -5-yl) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine was synthesized in a similar manner to Example 1, except that 3-chloro-4- (potassiosulfanyl) pyridin-2 -amine was replaced with 3-chloro-2- (3- (methylsulfonyl) azetidin-1-yl) pyridine-4-thiol. 1H NMR (400 MHz, Methanol-d4) δ 8.06 (s; 1 H) 7.83 (s; 1 H) 7.67 (d; J = 5.26 Hz; 1 H) 7.57 (s ; 1 H) 6.02 (d; J = 5.26 Hz; 1 H) 4.59 - 4.45 (m; 4 H) 4.35 - 4.26 (m; 2 H) 4.03 - 3.90 (m; 3 H) 3.86 (d; J = 9.21 Hz; 1 H) 3.48 (s; 3 H) 3.01 (s; 3 H) 2.13 - 1.75 (m; 4 H) 1.30 (d; J = 6.58 Hz; 3 H). LCMS (ESI): m / z: [M + H] calculated for C24H31ClN7O3S2: 564.2; found 564.1
[0742] [0742] Example 13. Synthesis of 1- [4 - ({5 - [(3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl] imidazo [ 1,2-c] pyrimidin-8-yl} sul-fanyl) -3-chloropyridin-2-yl] azetidine-3-carbonitrile.
[0743] [0743] 1- [4 - ({5 - [(3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl] imidazo [1,2-c ] pyrimidin-8-yl} sulfanyl) -3-chloropyridin-2-yl] azetidine-3-carbonitrile was synthesized in a similar manner to Example 1, except that 3-chloro-4- (potassiosulfanyl) pyridin-2 -amine was replaced with 1- (3-chloro-4-mercapto-2-pyridinyl) -3-azetidinecarbonitrile.1H NMR (400 MHz, Methanol-d4) δ 8.06 (s; 1 H) 7.83 (d; J = 1.75 Hz;
[0744] [0744] Example 14. Synthesis of 3 - ({5 - [(3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl] imidazo [1,2 -c] pyrimidin-8-yl} sulfanyl) - 2-chloro-N, N-dimethylbenzamide.
[0745] [0745] 3 - ({5 - [(3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl] imidazo [1,2-c] pyrimidin- 8-yl} sulfanyl) -2-chloro-N, N-dimethylbenzamide was synthesized in a similar manner to Example 1, except that 3-chloro-4- (potassiosulfanyl) pyridin-2-amine was replaced with 3-dimethyl- mide-2-chloro -1-thiol. 1H NMR (400 MHz, DMSO-d6) δ 8.34 (br s; 4 H) 8.00 (s; 1 H) 7.84 (d; J = 1.34 Hz; 1 H) 7.56 ( d; J = 1.47 Hz; 1 H) 7.14 - 7.19 (m; 1 H) 7.08 - 7.12 (m; 1 H) 6.76 (dd; J = 8.01; 1.65 Hz; 1 H) 4.05 - 4.14 (m; 1 H) 3.70 (br d; J = 8.31 Hz; 4 H) 3.53 (br d; J = 8.31 Hz; 1 H) 2.97 (d; J = 5.01 Hz; 1 H) 2.80 (s; 3 H) 2.61 - 2.65 (m; 1 H) 1.95 (br s; 1 H) 1.83 (br s; 1 H) 1.68 (br d; J = 19.32 Hz; 2 H) 1.10 (d; J = 6.36 Hz; 3 H). LCMS (ESI): m / z: [M + H] calculated for C24H30ClN6O2S: 501.2; found 501.1.
[0746] [0746] Example 15. Synthesis of (3S, 4S) -3-methyl-8- (8- {1H-pyrrolo [2,3-b] pyridin-4-ylsulfanyl} imidazo [1,2-c] pyrimidin-5-yl) -2-oxa-8-azaspiro [4.5] decan-4-amine.
[0747] [0747] (3S, 4S) -3-methyl-8- (8- {1H-pyrrolo [2,3-b] pyridin-4-ylsulfanyl} imid-azo [1,2-c] pyrimidin-5-yl ) -2-oxa-8-azaspiro [4.5] decan-4-amine was synthesized in a similar manner to Example 1, except that 3-chloro-4- (potassiosulfanyl) pyridin-2-amine was replaced with 4 -sulfanyl-1H-pyrrolo [2,3-b] pyridine. 1H NMR (400MHz, Methanol-d4) δ 8.06 (s; 1H); 7.88 (d; J = 5.5 Hz; 1H); 7.84 - 7.82 (m; 1H); 7.56 (s; 1H); 7.39 (d; J = 3.3 Hz; 1H); 6.57 (d; J = 3.5 Hz; 1H); 6.49 (d; J = 5.3 Hz; 1H); 4.30 - 4.24 (m; 1H); 3.94 - 3.82 (m; 3H); 3.77 (d; J = 9.0 Hz; 1H); 3.41 (br t; J = 10.7 Hz; 2H); 3.12 (br d; J = 5.1 Hz; 1H); 2.09 - 1.97 (m; 2H); 1.90 - 1.75 (m; 2H); 1.27 - 1.22 (m; 3H). LCMS (ESI): m / z: [M -H] calculated for C22H26N7OS: 436.2; found 436.1.
[0748] [0748] Example 16. Synthesis of (3S, 4S) -8- {8 - [(2-aminopyridin-4-yl) sulfanyl] imidazo [1,2-c] pyrimidin-5-yl} -3-methyl- 2-oxa-8-azaspiro [4.5] decan-4-amine.
[0749] [0749] (3S, 4S) -8- {8 - [(2-aminopyridin-4-yl) sulfanyl] imidazo [1,2-c] pi-rimidin-5-yl} -3-methyl-2-oxa -8-azaspiro [4.5] decan-4-amine was synthesized in a similar manner to Example 1, except that 3-chloro-4- (potassium-sulfonyl) pyridin-2-amine was replaced with 4- (potassiosulfanyl) pyridine -2- amine. 1H NMR (400MHz, Methanol-d4) δ 8.40 (br s; 1H); 8.06 (s; 1H); 7.82 (s; 1H); 7.64 (d; J = 5.7 Hz; 1H); 7.61 (s; 1H); 6.36 (br d; J = 4.4 Hz; 1H); 6.23 (s; 1H); 4.37 - 4.26 (m; 1H); 4.04 - 3.86 (m; 4H); 3.50 - 3.43 (m; 1H); 3.28 - 3.09 (m; 2H); 2.11 - 1.91 (m; 3H); 1.81 (br d; J = 14.8 Hz; 1H); 1.33 (d; J = 6.4 Hz; 3H). LCMS (ESI): m / z: [M -H] calculated for C20H26N7OS: 412.2; found 412.1.
[0750] [0750] Example 17. Synthesis of (3S, 4S) -8- (8- {1H-imidazo [4,5-b] pyridin-7-ylsulfanyl} imidazo [1,2-c] pyrimidin-5-yl) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine.
[0751] [0751] (3S, 4S) -8- (8- {1H-imidazo [4,5-b] pyridin-7-ylsulfanyl} imid-azo [1,2-c] pyrimidin-5-yl) -3- methyl-2-oxa-8-azaspiro [4.5] decan-4-amine was synthesized in a similar manner to Example 1, except that (3S, 4S) - 3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine was replaced with 7-sulfanyl-1H-imidazo [4,5-b] pyridine. 1H NMR (400MHz, Methanol-d4) δ 8.48 (br s; 1H); 8.38 (s; 1H); 8.13 (s; 1H); 8.02 (d; J = 5.3 Hz; 1H); 7.84 (d; J = 1.3 Hz; 1H); 7.57 (d; J = 1.5 Hz; 1H); 6.59 (br d; J = 4.4 Hz; 1H); 4.36 - 4.26 (m; 1H); 4.06 - 3.86 (m; 4H); 3.48 - 3.35 (m; 2H); 3.27 (br s; 1H); 2.15 - 2.02 (m; 2H); 1.99 - 1.92 (m; 1H); 1.82 (br d; J = 13.6 Hz; 1H); 1.32 (d; J = 6.5 Hz; 3H). LCMS (ESI): m / z: [M -H] calculated for C21H25N8OS: 437.2; found 437.1.
[0752] [0752] Example 18. Synthesis of (3S, 4S) -8- {8 - [(2-amino-6-methyl-pyridin-4-yl) sulfanyl] imidazo [1,2-c] pyrimidin-5-yl } -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine.
[0753] [0753] (3S, 4S) -8- {8 - [(2-amino-6-methylpyridin-4-yl) sulfanyl] imid-azo [1,2-c] pyrimidin-5-yl} -3-methyl -2-oxa-8-azaspiro [4.5] decan-4-amine was synthesized in a similar manner to Example 1, except that 3-chloro-4- (potassiosulfanyl) pyridin-2-amine was replaced with 2-amino- 6-methyl-pyridine-4-thiol. 1H NMR (400MHz, Methanol-d4) δ 8.48 (br d; J = 1.7 Hz; 1H); 8.06 (s; 1H); 7.83 (d; J = 1.3 Hz; 1H); 7.61 (d; J = 1.3 Hz; 1H); 6.34 (s; 1H); 6.08 (s; 1H); 4.32 (br dd; J = 4.4; 6.2 Hz; 1H); 4.04 - 3.85 (m; 4H); 3.49 - 3.41 (m; 1H); 3.36 (br s; 2H); 2.25 (s; 3H); 2.12 - 1.90 (m; 3H); 1.82 (br d; J = 13.1 Hz; 1H); 1.33 (d; J = 6.4 Hz; 3H). LCMS (ESI): m / z: [M -H] calculated for C21H28N7OS: 426.2; found 426.2.
[0754] [0754] Example 19. Synthesis of 2- {8 - [(2-amino-3-chloropyridin-4-
[0755] [0755] Step 1. Synthesis of tert-butyl N- [2- (8-bromoimidazo [1,2-c] pyrimidin-5-yl) -2-azaspiro [3.3] heptan-6-yl] carbamate
[0756] [0756] To a solution of 8-bromo-5-chloro-imidazo [1,2-c] pyrimidine (150 mg, 645 umol, 1 eq) in AcCN (3 ml) was added DIEA (416 mg; 3.23 mmol; 561 µL) and tert-butyl N- (2-azaspiro [3.3] heptan-6-yl) carbamate (205 mg, 967 µmol) The mixture was stirred at 50 ° C for 1 h. The reaction mixture was filtered and concentrated under reduced pressure and the remaining residue was purified by column chromatography to yield N- [2- (8-bromoimidazo [1,2-c] pyrimidin-5-yl) -2-azaspiro [ 3.3] heptan-6-yl] tert-butyl carbamate (210 mg, 514 µmol, 79% yield) as a yellow solid. 1H NMR (400 MHz, Methanol-d4) δ 7.81 (d; J = 1.54 Hz; 1 H) 7.77 (s; 1 H) 7.53 (d; J = 1.54 Hz; 1 H) 4.51 (s; 2 H) 4.37 (s; 2 H) 4.01 - 3.87 (m; 1 H) 2.64 - 2.59 (m; 3 H) 2.27 - 2.14 (m; 2 H) 1.43 (s; 9 H).
[0757] [0757] Step 2. Synthesis of N- [2- [8 - [(2-amino-3-chloro-4-pyridyl) sulpanyl] imidazo [1,2-c] pyrimidin-5-yl] -2 -azaspiro [3.3] heptan-6-yl] tert-butyl carbamate
[0758] [0758] To a solution of tert-butyl N- [2- (8-bromoimidazo [1,2-c] pyrimidin-5-yl) - 2-azaspiro [3.3] heptan-6-yl] carbamate (210 mg , 514 µmol) in dioxane (3 ml) were added 2-amino-3-chloro-pyridine-4-thiol (165 mg; 1.03 mmol), DIEA (199 mg; 1.54 mmol; 268 µL), Xantphos (178 mg, 308 µmol) and Pd2 (dba) 3 (141 mg, 154 µmol). The reaction mixture was stirred at 120 ° C for 1 h. The reaction mixture was filtered and concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography to yield N- [2- [8 - [(2-amino-3-chloro-4-pyridyl) ) sulfanyl] imidazo [1,2-c] pyrimidin-5-yl] -2-azaspiro [3.3] heptan-6-yl] tert-butyl carbamate (112 mg, 229 µmol, 44% yield) as a yellow solid. LCMS (ESI): m / z: [M + H] calculated for C22H27ClN7O2S: 488.2; found 488.1.
[0759] [0759] Step 3. 2- {8 - [(2-amino-3-chloropyridin-4-yl) sulfanyl] imidazzo [1,2-c] pyrimidin-5-yl} -2-azaspiro [3.3] heptan-6-amine.
[0760] [0760] A mixture of N- [2- [8 - [(2-amino-3-chloro-4-pyridyl) sul-fanyl] imidazo [1,2-c] pyrimidin-5-yl] -2-azaspiro [3.3] tert-butyl heptan-6-yl] carbamate (111 mg, 227 µmol) in HCl / MeOH (10 mL) was stirred at 25 ° C for 1 h. The reaction mixture was concentrated under reduced pressure and the remaining residue was purified by pre-HPLC to yield 2- {8 - [(2-amino-3-chloropyridin-4-yl) sulfanyl] imidazo [1,2-c] pyrimidin-5-yl} -2-azaspiro [3.3] heptan-6-amine (35 mg, 79 µmol, 34% yield) as a white solid. 1H NMR (400 MHz, Methanol-d4) δ 8.48 (s; 1 H) 7.93 (s; 1 H) 7.84 (d; J = 1.71 Hz; 1 H) 7.54 - 7 , 45 (m; 2 H) 5.89 (d; J = 5.50 Hz; 1 H) 4.69 (s; 2 H) 4.59 (s; 2 H) 3.85 -3.77 ( m; 1 H) 2.91 - 2.72 (m; 2 H) 2.59 - 2.42 (m; 2 H). LCMS (ESI): m / z: [M + H] calculated for chemical formula: C17H19ClN7S: 388.1; found 388.1.
[0761] [0761] Example 20. Synthesis of 3-chloro-4 - [(5- {2,7-diazaspiro [3.5] nonan-7-yl} imidazo [1,2-c] pyrimidin-8-yl) sulfanyl ] pyridin-2-amine.
[0762] [0762] 3-chloro-4 - [(5- {2,7-diazaspiro [3.5] nonan-7-yl} imidazo [1,2-c] pi-rimidin-8-yl) sulfanyl] pyridin-2- amine was synthesized in a similar manner to Example 19, except that tert-butyl N- (2-azaspiro [3.3] heptan-6-yl) carbamate was replaced with 2,7-diazaspiro [3.5] nonane-2-carboxy - tert-butyl broad. 1H NMR (400 MHz, Methanol-d4) δ 8.54 (s; 1 H) 8.04 (s; 1 H) 7.82 (d; J = 1.54 Hz; 1 H) 7.57 (s ; 1 H) 7.48 (d; J = 5.51 Hz; 1 H) 5.86 (d; J = 5.51 Hz; 1 H) 3.96 (s; 4 H) 3.62 - 3 , 54 (m; 4 H) 2.18 - 2.10 (m; 4 H). LCMS (ESI): m / z: [M + H] calculated for C18H21ClN7S: 402.1; found 402.1.
[0763] [0763] Example 21. Synthesis of 4 - ({5 - [(3S) -3-aminopyrrolidin-1-yl] imidazo [1,2-c] pyrimidin-8-yl} sulfanyl) -3-chloropyridin-2- the mine
[0764] [0764] 4 - ({5 - [(3S) -3-aminopyrrolidin-1-yl] imidazo [1,2-c] pyrimidin-8-yl} sulfanyl) -3-chloropyridin-2-amine was synthesized from a similar to Example 19, except that tert-butyl N- (2-azaspiro [3.3] heptan-6-yl) carbamate has been replaced with tert-butyl N - [(3S) -pyrrolidin-3-yl] carbamate . 1H NMR (400MHz, Methanol-d4) δ 8.16 (d; J = 1.7 Hz; 1 H); 7.92 (s; 1 H) 7.49 (d; J = 5.6 Hz; 1 H); 7.47 (d; J = 1.7 Hz; 1 H); 5.89 (d; J = 5.5 Hz; 1 H); 4.18-4.24 (m; 3 H); 3.90-3.96 (m; 2 H); 2.40-2.47 (m; 2 H); 2.13-2.18 (m; 2 H). LCMS (ESI): m / z: [M + H] calculated for C15H17SN7Cl: 362.1; found 362.0.
[0765] [0765] Example 22. Synthesis of 4 - ({5- [3- (2-aminoethyl) azetidin-1-yl] imidazo [1,2-c] pyrimidin-8-yl} sulfanyl) -3-chloropyridin-2 -the mine.
[0766] [0766] 4 - ({5- [3- (2-aminoethyl) azetidin-1-yl] imidazo [1,2-c] pyrimidin-8-yl} sulfanyl) -3-chloropyridin-2-amine was synthesized from in a similar manner to Example 19, except that tert-butyl N- (2-azaspiro [3.3] heptan-6-yl) carbamate has been replaced with 2- (azetidin-3-yl) ethanamine. 1H NMR (400MHz, Methanol-d4) δ 8.45 (br s; 1H); 7.94 (s; 1H); 7.86 (d; J = 1.7 Hz; 1H); 7.51 (d; J = 5.6 Hz; 1H); 7.48 (d; J = 1.6 Hz; 1H); 5.90 (d; J = 5.6 Hz;
[0767] [0767] Example 23. Synthesis of N1- {8 - [(2-amino-3-chloropyridin-4-yl) sulfanyl] imidazo [1,2-c] pyrimidin-5-yl} ethane-1,2-diamine .
[0768] [0768] N1- {8 - [(2-amino-3-chloropyridin-4-yl) sulfanyl] imidazo [1,2-c] pi-rimidin-5-yl} ethane-1,2-diamine was synthesized from in a similar manner to Example 19, except that tert-butyl N- (2-azaspiro [3.3] heptan-6-yl) carbamate has been replaced with N-Boc-ethylenediamine. 1H NMR (500 MHz, Methanol-d4) δ 8.47 (s; 2H); 8.02 (s; 1H); 7.93 (d; J = 1.6 Hz; 1H); 7.55 (d; J = 1.6 Hz; 1H); 7.51 (d; J = 5.6 Hz; 1H); 5.90 (d; J = 5.6 Hz; 1H); 3.99 (t; J = 5.7 Hz; 2H). LCMS (ESI): m / z: [M + H] calculated for C13H15ClN7S: 336.1; found 336.3.
[0769] [0769] Example 24. Synthesis of 4 - ({5 - [(3R) -3- (aminomethyl) pyrrolidin-1-yl] imidazo [1,2-c] pyrimidin-8-yl} sulfanyl) -3 -chloropyridin-2-amine.
[0770] [0770] 4 - ({5 - [(3R) -3- (aminomethyl) pyrrolidin-1-yl] imidazo [1,2-c] pi-rimidin-8-yl} sulfanyl) -3-chloropyridin-2- amine was synthesized in a similar manner to Example 19, except that N- (2-azaspiro [3.3] heptan-6-yl) carbamate was replaced with N - [(3S) -pyrrolidin-3-ylmethyl] (tert- butoxy) carboxymidic. 1H NMR (500 MHz, Methanol-d4) δ 8.19 (d; J = 1.9 Hz; 1H); 8.11 (d; J = 1.4 Hz; 1H); 7.95 (d; J = 2.8 Hz; 1H); 7.51 (d; J = 5.6 Hz; 1H); 7.48 (d; J = 1.6 Hz; 1H); 5.95 (dd; J = 9.4; 5.6 Hz; 1H); 4.25 - 4.15 (m; 2H); 4.11 (td; J = 10.2; 9.4; 7.1 Hz; 1H); 3.80 (dd; J = 10.8; 8.1 Hz; 1H); 3.23 - 3.09 (m; 2H); 2.76 - 2.66 (m; 1H); 2.38 (dq; J = 9.0; 5.0; 3.8 Hz; 1H); 2.01 - 1.80 (m; 1H). LCMS (ESI): m / z: [M + H] calculated for C16H19ClN7S: 376.9; found 376.4.
[0771] [0771] Example 25. Synthesis of (1R, 5S, 6R) -3- {8 - [(2-amino-3-chloropyridin-4-yl) sulfanyl] imidazo [1,2-c] pyrimidin-5 -il} -3-azabi- cycle [3.1.0] hexan-6-amine.
[0772] [0772] (1R, 5S, 6R) -3- {8 - [(2-amino-3-chloropyridin-4-yl) sulfanyl] imid-azo [1,2-c] pyrimidin-5-yl} -3 -azabicyclo [3.1.0] hexan-6-amine was synthesized in a similar manner to Example 19, except that tert-butyl N- (2-azaspiro [3.3] heptan-6-yl) carbamate was replaced with N acid - [(1R, 5S, 6S) -3-azabicyclo [3.1.0] hexan-6-yl] (tert-butoxy) carboxydimide. 1H NMR (500 MHz, Methanol-d4) δ 8.25 (d; J = 1.9 Hz; 1H); 8.03 (s; 1H); 7.57 - 7.47 (m; 2H); 6.18 (d; J = 6.6 Hz; 1H); 4.51 (d; J = 11.1 Hz; 2H); 4.16 (dt; J = 11.4; 2.0 Hz; 2H); 2.60 (t; J = 2.4 Hz; 1H); 2.29 (dt; J = 3.9; 1.8 Hz; 2H). LCMS (ESI): m / z: [M + H] calculated for C16H17ClN7S: 374.9; found 374.4.
[0773] [0773] Example 26. Synthesis of 4 - {[5- (3-amino-3-methylazetidin-1-yl) imidazo [1,2-c] pyrimidin-8-yl] sulfanyl} -3-chloropyridin-2- the mine.
[0774] [0774] 4 - {[5- (3-amino-3-methylazetidin-1-yl) imidazo [1,2-c] pyrimidin-8-yl] sulfanyl} -3-chloropyridin-2-amine was synthesized from a similar to Example 19, except that tert-butyl N- (2-azaspiro [3.3] heptan-6-yl) carbamate has been replaced with N- (3-methylazetidin-3-yl) hydrochloride (tert-butoxy ) carboxymidic. 1H NMR (500 MHz, Methanol-d4) δ 8.09 (s; 1H); 7.91 (d; J = 1.7 Hz; 1H); 7.59 (d; J = 1.7 Hz; 1H); 7.53 (d; J = 6.7 Hz; 1H); 6.21 (d; J = 6.7 Hz; 1H); 4.74 (d; J = 10.0 Hz; 2H); 4.67 (d; J = 10.0 Hz; 2H); 1.79 (s; 3H). LCMS (ESI): m / z: [M + H] calculated for C15H17ClN7S: 362.9; found 362.2.
[0775] [0775] Example 27. Synthesis of 3-chloro-4 - {[5- (piperazin-1-yl) imidazzo [1,2-c] pyrimidin-8-yl] sulfanyl} pyridin-2-amine.
[0776] [0776] 3-chloro-4 - {[5- (piperazin-1-yl) imidazo [1,2-c] pyrimidin-8-yl] sulpanyl] pyridin-2-amine was synthesized in a similar way to Example 19, except that tert-butyl N- (2-azaspiro [3.3] heptan-6-yl) carbamate was replaced with tert-butyl piperazine-1-carboxylate. 1H NMR (500 MHz, Methanol-d4) δ 8.19 (s; 1H); 8.01 (d; J = 1.7 Hz; 1H); 7.66 (d; J = 1.6 Hz; 1H); 7.52 (d; J = 6.4 Hz; 1H); 6.15 (d; J = 6.4 Hz; 1H); 3.92 (t; J = 5.1 Hz; 4H); 3.54 (t; J = 5.1 Hz; 5H). LCMS (ESI) m / z: [M + H]: calculated for C15H17ClN7S: 362.9; found 362.3.
[0777] [0777] Example 28. Synthesis of 4 - ({5 - [(3R) -3-aminopyrrolidin-1-yl] imidazo [1,2-c] pyrimidin-8-yl} sulfanyl) -3-chloropyridin-2- the mine.
[0778] [0778] 4 - ({5 - [(3R) -3-aminopyrrolidin-1-yl] imidazo [1,2-c] pyrimidin-8-yl} sulfanyl) -3-chloropyridin-2-amine was synthesized from a similar to Example 19, except that tert-butyl N- (2-azaspiro [3.3] heptan-6-yl) carbamate has been replaced with tert-butyl N - [(3R) -pyrrolidin-3-yl] carbamate . 1H NMR (400MHz, Methanol-d4) δ 8.52 - 8.38 (m; 2H); 8.17 (d; J = 1.5 Hz; 1H); 7.94 (s; 1H); 7.52 - 7.47 (m; 2H); 5.89 (d; J = 5.5 Hz; 1H); 4.31 - 4.17 (m; 3H); 4.08 - 3.95 (m; 2H); 2.51 (br dd; J = 5.7; 13.7 Hz; 1H); 2.23 (br d; J = 4.4 Hz; 1H). LCMS (ESI): m / z: [M + H] calculated for C15H17ClN7S: 362.1; found 362.2.
[0779] [0779] Example 29. Synthesis of (3S, 4S) -8- {8 - [(2-amino-3-chloropyridin-4-yl) sulfanyl] -7-methylimidazo [1,2-c] pyrimidin- 5-yl} -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine.
[0780] [0780] (3S, 4S) -8- {8 - [(2-amino-3-chloropyridin-4-yl) sulfanyl] -7-methylimidazo [1,2-c] pyrimidin-5-yl} - 3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine was synthesized in a similar manner to Example 1, except that (3S, 4S) -8- {8-bromoimidazo [1,2-c ] pyrimidin-5-yl} -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine has been replaced with (3S, 4S) -8- {8 - [(2-amino-3-chloropyridin -4-yl) sulfanyl] -7-methylimidazo [1,2-c] pyrimidin-5-yl} -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-yl. 1H NMR (500 MHz, Methanol-d4) δ 8.44 (s; 3H); 7.76 (d; J = 1.6 Hz; 1H); 7.52 (t; J = 1.2 Hz; 1H); 5.80 (d; J = 5.5 Hz; 1H); 4.38 - 4.31 (m; 1H); 4.02 (t; J = 11.5 Hz; 3H); 3.92 (d; J = 9.2 Hz; 1H); 3.50 (d; J = 4.2 Hz; 1H); 3.31 - 3.25 (m; 1H); 2.58 (s; 3H); 2.16 - 2.05 (m; 2H); 1.99 (d; J = 13.8 Hz; 1H); 1.84 (d; J = 13.2 Hz; 1H); 1.36 (d; J = 6.5 Hz; 3H). LCMS (ESI): m / z: [M + H] calculated for C21H27ClN7OS: 460.2; found 460.3.
[0781] [0781] Example 30. Synthesis of (3S, 4S) -8- [8- (2H-indazol-6-yl) -7-methylimidazo [1,2-c] pyrimidin-5-yl] -3-methyl- 2-oxa-8-azaspiro [4.5] decan-4-amine.
[0782] [0782] Step 1. Synthesis of 2-chloro-6-methyl-pyrimidin-4-amine.
[0783] [0783] A mixture of 2,4-dichloro-6-methyl-pyrimidine (40 g, 245 mmol) in NH3.H2O (500 mL) was stirred at 25 ° C for 44 h. The crude product was filtered and the resulting solution was concentrated under reduced pressure. The remaining residue was purified by chromatography on silica
[0784] [0784] Step 2. Synthesis of 5-bromo-2-chloro-6-methyl-pyrimidin-4-amine.
[0785] [0785] To a solution of 2-chloro-6-methyl-pyrimidin-4-amine (13 g, 91 mmol) in DMF (130 mL) was added NBS (24.2 g; 136 mmol) at 15 ° C, and the mixture was stirred at 15 ° C for 2 h. The mixture was quenched with the addition of a saturated Na2SO3 solution (130mL) and ice water (130mL). The resulting mixture was stirred for 5 min and the mixture was filtered to yield 5-bromo-2-chloro-6-methyl-pyrimidin-4-amine (16 g, 72 mmol, 79% yield) as a white solid LCMS ( ESI): m / z: [M + H] calculated for C5H6BrClN3: 223.9; found 223.8.
[0786] [0786] Step 3. Synthesis of 8-bromo-5-chloro-7-methyl-imidazo [1,2- c] pyrimidine
[0787] [0787] A mixture of 5-bromo-2-chloro-6-methyl-pyrimidin-4-amine (8 g, 36 mmol) in 2-chloroacetaldehyde (160 mL) was stirred at 100 ° C for 0.5 h. The resulting residue was purified by column chromatography to yield 8-bromo-5-chloro-7-methyl-imidazo [1,2-c] pyrimidine (3.5 g; 14.2 mmol, 40% yield) as a white solid. LCMS (ESI): m / z: [M + H] calculated for C7H6BrClN3: 247.9; found 248.1.
[0788] [0788] Step 4. Synthesis of (3S, 4S) -8- (8-bromo-7-methyl-imidazo [1,2-c] pyrimidin-5-yl) -3-methyl-2-oxa-8- azaspiro [4.5] decan-4-amine
[0789] [0789] A solution of 8-bromo-5-chloro-7-methyl-imidazo [1,2-c] pyrimidine (300 mg, 1.2 mmol), (3S, 4S) -3-methyl-2 -oxa-8-azaspiro [4.5] decan-4-amine (249 mg; 1.5 mmol) and DIPEA (1.6 g; 12.2 mmol; 2.1 mL) in i-PrOH (3 mL) was stirred at 70 ° C for 3 h. The mixture was cooled to 25 ° C and then concentrated under reduced pressure. The resulting residue was purified by column chromatography to yield (3S, 4S) -8- (8-bromo-7-methyl-imidazo [1,2-c] pyrimidin-5-yl) -3-methyl-2 -
[0790] [0790] Step 5. Synthesis of (3S, 4S) -8- [8- (2H-indazol-6-yl) -7-methylimidazo [1,2-c] pyrimidin-5-yl] -3- methyl-2-oxa-8-azaspiro [4.5] decan-4-amine.
[0791] [0791] To a solution of 1H-indazol-6-ylboronic acid (64 mg, 394 µmol) and (3S, 4S) -8- (8-bromo-7-methyl-imidazo [1,2-c] pyrimidin- 5-yl) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine (100 mg, 263 µmol) in DME (1 ml) and H2O (0.2 ml) Na2CO3 (56 mg, 526 µmol) and Pd (PPh3) 4 (30 mg, 26 µmol) under N2 at 25 ° C. The mixture was stirred at 100 ° C for 3 h. The mixture was cooled to 25 ° C and the mixture was filtered. The resulting solution was concentrated under reduced pressure and the resulting residue was purified by prep-HPLC to yield (3S, 4S) -8- [8- (2H-in-dazol-6-yl) -7-methylimidazo [1 , 2-c] pyrimidin-5-yl] -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine (8.5 mg; 20.2 µmol, 8% yield) as a solid White. 1H NMR (400MHz, Methanol-d4) δ 8.43 (s; 1H); 8.12 (s; 1H); 7.89 (d; J = 8.70 Hz; 1H); 7.70 (s; 1H); 7.58 (s; 1H); 7.48 (s; 1H); 7.17 (d; J = 7.60 Hz; 1H); 4.33 (s; 1H); 4.00 (d; J = 9.30 Hz; 1H); 3.92 - 3.82 (m; 3H); 3.48 (s; 1H); 3.23 - 3.17 (m; 2H); 2.33 (s; 3H); 2.13 - 2.07 (m; 2H); 1.99 - 1.96 (m; 1H); 1.82 (d; J = 12.80 Hz; 1H); 1.34 (d; J = 6.00 Hz; 3H). LCMS (ESI): m / z: [M + H] calculated for C23H28N7O: 418.2; found 418.4.
[0792] [0792] Example 31. Synthesis of 3- {5 - [(3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl] -7-methylimidazo [1 , 2-c] pyrimidin-8-yl} - 2-chloro-6-methoxybenzonitrile.
[0793] [0793] 3- {5 - [(3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl] -7-methylimidazo [1,2-c] pyrimidin-8-yl} -2-chloro-6-methoxybenzonitrile was synthesized in a similar manner to Example 15, except 1H-indazol-6-ylboronic acid which was replaced with 2-chloro-3-cyano-4-me - toxifenilborónico. 1H NMR (500 MHz, Methanol-d4) δ 8.50 (s; 1H); 7.70 (d; J = 1.6 Hz; 1H); 7.58 (d; J = 8.8 Hz; 1H); 7.47 (d; J = 1.6 Hz; 1H); 7.29 (d; J = 8.8 Hz; 1H); 4.34 - 4.28 (m; 1H); 4.06 (s; 3H); 3.98 (d; J = 9.0 Hz; 1H); 3.92 - 3.81 (m; 3H); 3.39 (d; J = 4.3 Hz; 1H); 3.28 - 3.16 (m; 2H); 2.20 (s; 3H); 2.13 - 2.02 (m; 2H); 1.94 (d; J = 13.9 Hz; 1H); 1.81 (d; J = 13.3 Hz; 1H); 1.31 (d; J = 6.5 Hz; 3H). LC-MS (ESI): m / z: [M + H] calculated for C24H28ClN6O2: 467.2; found 467.4.
[0794] [0794] Example 32. Synthesis of (3S, 4S) -8- [8- (1H-1,3-benzodiazol-4-yl) -7-methylimidazo [1,2-c] pyrimidin-5-yl] - 3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine.
[0795] [0795] (3S, 4S) -8- [8- (1H-1,3-benzodiazol-4-yl) -7-methylimidazo [1,2-c] pyrimidin-5-yl] -3-methyl-2 -oxa-8-azaspiro [4.5] decan-4-amine was synthesized in a similar manner to Example 15, except 1H-indazol-6-ylboronic acid which was replaced with 1H-benzimidazol-4-yl acid boronic. 1H NMR (500 MHz, Methanol-d4) δ 8.48 (s; 1H); 8.08 (s; 1H); 7.73 - 7.61 (m; 2H); 7.47 - 7.33 (m; 2H); 7.23 (dd; J = 7.4; 1.1 Hz; 1H); 4.38 - 4.20 (m; 1H); 3.95 (d; J = 9.0 Hz; 1H); 3.81 (dd; J = 23.1; 11.6 Hz; 3H); 3.33 (s; 1H); 3.26 - 3.12 (m; 2H); 2.19 (s; 3H); 2.05 (s; 2H); 1.91 (d; J = 13.7 Hz; 1H); 1.79 (d; J = 13.1 Hz; 1H); 1.28 (d; J = 6.5 Hz; 3H). LCMS (ESI): m / z: [Μ + H] calculated for C23H28N7O: 418.2; found 418.6.
[0796] [0796] Example 33. Synthesis of (3S, 4S) -8- [8- (1H-1,3-benzodiazol-6-yl) -7-methylimidazo [1,2-c] pyrimidin-5-yl] - 3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine.
[0797] [0797] (3S, 4S) -8- [8- (1H-1,3-benzodiazol-6-yl) -7-methylimidazo [1,2-c] pyrimidin-5-yl] -3-methyl-2 -oxa-8-azaspiro [4.5] decan-4-amine was synthesized in a similar manner to Example 5, except 1H-indazol-6-ylboronic acid which was replaced with 1H-benzimidazole-5-boronic acid . 1H NMR (500 MHz, Methanol-d4) δ 8.25 (s; 2H); 8.21 (s; 1H); 7.67 (dd; J = 8.3; 0.8 Hz; 1H); 7.63 (d; J = 1.6 Hz; 1H); 7.59 (t; J = 1.1 Hz; 1H); 7.41 (d; J = 1.5 Hz; 1H); 7.24 (dd; J = 8.3; 1.6 Hz; 1H); 4.36 - 4.20 (m; 1H); 3.94 (d; J = 9.1 Hz; 1H); 3.89 - 3.73 (m; 3H); 3.45 (d; J = 4.1 Hz; 1H); 3.12 (dt; J = 26.5; 12.0 Hz; 2H); 2.26 (s; 3H); 2.12 - 1.87 (m; 3H); 1.76 (d; J = 12.6 Hz; 1H); 1.28 (d; J = 6.5 Hz; 3H). LCMS (ESI): m / z: [Μ + H] calculated for C23H28N7O: 418.2; found 418.5.
[0798] [0798] Example 34. Synthesis of (3S, 4S) -3-methyl-8- [7-methyl-8- (1-methyl-1H-indazol-5-yl) imidazo [1,2-c] pyrimidin- 5-yl] -2-oxa-8-azaspiro [4.5] decan-4-amine.
[0799] [0799] (3S, 4S) -3-methyl-8- [7-methyl-8- (1-methyl-1H-indazol-5-yl) imid-azo [1,2-c] pyrimidin-5-yl ] -2-oxa-8-azaspiro [4.5] decan-4-amine was synthesized in a similar manner to Example 15, except 1H-indazol-6-ylboronic acid which was replaced with 1-methyl- 1H-indazole-5-boronic. 1H NMR (500 MHz, Methanol-d4) δ 8.43 (s; 1H); 8.03 (d; J = 1.0 Hz; 1H); 7.76 (dd; J = 1.6; 0.9 Hz; 1H); 7.66 (d; J = 1.6 Hz; 1H); 7.64 (dt; J = 8.7; 0.9 Hz; 1H); 7.45 (d; J = 1.5 Hz; 1H); 7.42 (dd; J = 8.7; 1.6 Hz; 1H); 4.36 - 4.25 (m; 1H); 4.10 (s; 3H); 3.97 (d; J = 9.1 Hz; 1H); 3.87 (d; J = 9.1 Hz; 1H); 3.81 (dd; J = 17.9; 13.3 Hz; 3H); 3.44 (d; J = 4.1 Hz;
[0800] [0800] Example 35. Synthesis of (3S, 4S) -8- [8- (1H-indol-7-yl) -7-methylimidazo [1,2-c] pyrimidin-5-yl] -3-methyl- 2-oxa-8-azaspiro [4.5] decan-4-amine.
[0801] [0801] (3S, 4S) -8- [8- (1H-indol-7-yl) -7-methylimidazo [1,2-c] pyrimidin-5-yl] -3-methyl-2-oxa-8 -azaspiro [4.5] decan-4-amine was synthesized in a similar manner to Example 15, except for 1H-indazol-6-ylboronic acid which was replaced with indole-7-boronic acid. 1H NMR (500 MHz, Methanol-d4) δ 8.38 (s; 1H); 7.67 (d; J = 1.6 Hz; 1H); 7.61 (dd; J = 7.9; 1.1 Hz; 1H); 7.39 (d; J = 1.5 Hz; 1H); 7.16 - 7.09 (m; 2H); 7.04 (dd; J = 7.2; 1.1 Hz; 1H); 6.48 (d; J = 3.1 Hz; 1H); 4.35 - 4.26 (m; 1H); 3.98 (d; J = 9.1 Hz; 1H); 3.88 (d; J = 9.1 Hz; 1H); 3.86 - 3.78 (m; 3H); 3.46 (d; J = 4.1 Hz; 1H); 3.20 (t; J = 12.4 Hz; 1H); 2.18 (s; 3H); 2.06 (d; J = 8.1 Hz; 2H); 1.97 (d; J = 13.6 Hz; 1H); 1.81 (d; J = 12.8 Hz; 1H); 1.31 (d; J = 6.5 Hz; 3H). LCMS (ESI): m / z: [Μ + H] calculated for C24H29N6O: 417.23; found 417.5.
[0802] [0802] Example 36. (3S, 4S) -8- [8- (2H-indazol-7-yl) -7-methylimid-azo [1,2-c] pyrimidin-5-yl] -3-methyl- 2-oxa-8-azaspiro [4.5] decan-4-amine.
[0803] [0803] (3S, 4S) -8- [8- (2H-indazol-7-yl) -7-methylimidazo [1,2-c] pyrimidin-
[0804] [0804] Example 37. Synthesis of (3S, 4S) -8- [8- (4-chloro-2H-indazol-6-yl) -7-methylimidazo [1,2-c] pyrimidin-5-yl] - 3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine.
[0805] [0805] (3S, 4S) -8- [8- (4-chloro-2H-indazol-6-yl) -7-methylimidazo [1,2- c] pyrimidin-5-yl] -3-methyl-2 -oxa-8-azaspiro [4.5] decan-4-amine was synthesized in a similar manner to Example 15, except for 1H-indazol-6-ylboronic acid which was replaced with (4-chloro-1H- indazol-6-il) boronic acid. 1H NMR (400 MHz, Methanol-d4) δ 8.53 (br s; 1 H) 8.16 (s; 1 H) 7.70 (s; 1 H) 7.50 (br d; J = 17, 73 Hz; 2 H) 7.19 (s; 1 H) 4.27 - 4.36 (m; 1 H) 3.98 (br d; J = 9.05 Hz; 1 H) 3.78 - 3 , 91 (m; 3 H) 3.41 (br d; J = 2.93 Hz; 1 H) 3.12 - 3.26 (m; 2 H) 3.12 - 3.26 (m; 1 H ) 2.34 (s; 3 H) 2.08 (br t; J = 11.86 Hz; 2 H) 1.94 (br d; J = 13.33 Hz; 1 H) 1.82 (br d ; J = 13.08 Hz; 1 H) 1.32 (br d; J = 6.36 Hz; 3 H). LCMS (ESI): m / z: [M + H] calculated for C23H27ClN7O: 452.2; found 452.1.
[0806] [0806] Synthesis of (4-chloro-1H-indazol-6-yl) boronic acid
[0807] [0807] A solution of n-BuLi (2.5 M; 423.37 µL) was added dropwise to a mixture of 6-bromo-4-chloro-1H-indazole (70 mg, 302 µmol) in THF (1 ml) at -70 ° C under N2. The mixture was stirred at -70 ° C for 0.5 h, after which a solution of B (OMe) 3 (63 mg, 605 µmol) in THF (1 ml) was added. The mixture was slowly allowed to warm to 20 ° C and stirred at 20 ° C for 12 h. The reaction mixture was then quenched with the addition of 1N HCl until pH = 2 was reached. The mixture was extracted with EtOAc (10 ml x 3) and the combined organic layers were washed with aqueous NaCl (10 ml x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to yield acid (4-chloro-1H-inda) - zol-6-yl) boronic (100 mg, crude) as a white solid. LCMS (ESI): m / z: [M -H] calculated for C7H5BClN2O2: 195.2; found 195.0.
[0808] [0808] Example 38. Synthesis of (3S, 4S) -8- [8- (5-chloro-2H-indazol-6-yl) -7-methylimidazo [1,2-c] pyrimidin-5-yl] - 3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine.
[0809] [0809] (3S, 4S) -8- [8- (5-chloro-2H-indazol-6-yl) -7-methylimidazo [1,2- c] pyrimidin-5-yl] -3-methyl-2 -oxa-8-azaspiro [4.5] decan-4-amine was synthesized in a similar manner to Example 15, except for 1H-indazol-6-ylboronic acid which was replaced with 5-chloro-6- (4 , 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-indazole. 1H NMR (400 MHz, Methanol-d4) δ 8.11 (s; 1 H) 8.02 (s; 1 H) 7.71 (s; 1 H) 7.54 (s; 1 H) 7.45 (d; J = 1.34 Hz; 1 H) 4.27 - 4.36 (m; 1 H) 3.98 (d; J = 9.05 Hz; 1 H) 3.87 (br d; J = 9.05 Hz; 3 H) 3.17 - 3.26 (m; 4 H) 2.21 (s; 3 H) 2.02 - 2.15 (m; 1 H) 2.02 - 2, 15 (m; 2 H) 1.94 (br d; J = 14.18 Hz; 1 H) 1.82 (br d; J = 13.33 Hz; 1 H) 1.31 (d; J = 6 , 48 Hz; 3 H). LCMS (ESI): m / z: [M + H] calculated for
[0810] [0810] Synthesis of 5-chloro-6- (4,4,5,5-tetramethyl-1,3,2-dioxaboro-lan-2-yl) -1H-indazole.
[0811] [0811] To a solution of 6-bromo-5-chloro-1H-indazole (100 mg, 432 µmol, 1 eq) in DMF (2 ml) was added 4,4,5,5-tetramethyl-2- (4 , 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1,3,2-dioxaborolane (187 mg, 734 µmol), Pd (dppf) Cl2.CH2Cl2 (35 mg, 43 µmol ) and KOAc (127 mg, 1.3 mmol, 3 eq). The mixture was stirred at 100 ° C for 15 h. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by column chromatography to yield 5-chloro-6- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-indazole (130 mg, crude) as yellow oil. LCMS (ESI): m / z: [M + H] calculated for C13H17BClN2O2: 279.1; found 278.9.
[0812] [0812] Example 39. Synthesis of (3S, 4S) -8- [8- (2H-indazol-5-yl) -7-methylimidazo [1,2-c] pyrimidin-5-yl] -3-methyl- 2-oxa-8-azaspiro [4.5] decan-4-amine.
[0813] [0813] (3S, 4S) -8- [8- (2H-indazol-5-yl) -7-methylimidazo [1,2-c] pi-rimidin-5-yl] -3-methyl-2-oxa -8-azaspiro [4.5] decan-4-amine was synthesized in a similar manner to Example 15, except for 1H-indazol-6-ylboronic acid which was replaced with 1H-indazol-5-boronic acid. 1H NMR (500 MHz, Methanol-d4) δ 8.41 (s; 2H); 8.06 (d; J = 1.0 Hz; 1H); 7.77 (t; J = 1.1 Hz; 1H); 7.67 - 7.58 (m; 2H); 7.42 (d; J = 1.1 Hz; 1H); 7.37 (dd; J = 8.6; 1.5 Hz; 1H); 4.28 (s; 1H); 3.95 (d; J = 9.1 Hz; 1H); 3.90 - 3.74 (m; 3H); 3.43 (s; 1H); 3.23 - 3.07 (m; 1H); 2.28 (s; 3H); 2.13 - 1.87 (m; 3H);
[0814] [0814] Example 40. Synthesis of (3S, 4S) -3-methyl-8- [7-methyl-8- (1-methyl-1H-indol-2-yl) imidazo [1,2-c] pyrimidin- 5-yl] -2-oxa-8-azaspiro [4.5] decan-4-amine.
[0815] [0815] (3S, 4S) -3-methyl-8- [7-methyl-8- (1-methyl-1H-indol-2-yl) imid-azo [1,2-c] pyrimidin-5-yl ] -2-oxa-8-azaspiro [4.5] decan-4-amine was synthesized in a similar way to Example 15, except for 1H-indazol-6-ylboronic acid which was replaced with N-methylindole- 2-boronic. 1 H NMR (500 MHz, Methanol-d4) δ 7.67 (d; J = 1.6 Hz; 1H); 7.54 (dt; J = 7.9; 1.0 Hz; 1H); 7.42 (d; J = 1.6 Hz; 1H); 7.38 (dt; J = 8.3; 1.0 Hz; 1H); 7.16 (ddd; J = 8.3; 7.1; 1.2 Hz; 1H); 7.03 (ddd; J = 8.0; 7.1; 1.0 Hz; 1H); 6.47 (d; J = 0.8 Hz; 1H); 4.32 - 4.19 (m; 1H); 3.92 (d; J = 8.9 Hz; 1H); 3.87 - 3.74 (m; 3H); 3.47 (s; 4H); 3.24 - 3.13 (m; 1H); 2.29 (s; 3H); 2.12 - 1.96 (m; 2H); 1.87 (d; J = 13.8 Hz; 1H); 1.77 (d; J = 13.5 Hz; 1H); 1.25 (d; J = 6.6 Hz; 4H). LCMS (ESI): m / z: [Μ + H] calculated for C25H31N6O: 431.2; found 431.1.
[0816] [0816] Example 41. Synthesis of (3S, 4S) -8- [8- (5-chloroquinoxalin-6-yl) -7-methylimidazo [1,2-c] pyrimidin-5-yl] -3-methyl- 2-oxa-8-azaspiro [4.5] decan-4-amine.
[0817] [0817] (3S, 4S) -8- [8- (5-chloroquinoxalin-6-yl) -7-methylimidazo [1,2-c] pi-rimidin-5-yl] -3-methyl-2-oxa -8-azaspiro [4.5] decan-4-amine was synthesized in a similar manner to Example 15, except 1H-indazol-6- acid
[0818] [0818] Example 42. Synthesis of (3S, 4S) -3-methyl-8- [7-methyl-8- (1-methyl-1H-indol-2-yl) imidazo [1,2-c] pyrimidin- 5-yl] -2-oxa-8-azaspiro [4.5] decan-4-amine.
[0819] [0819] (3S, 4S) -3-methyl-8- [7-methyl-8- (1-methyl-1H-indol-2-yl) imid-azo [1,2-c] pyrimidin-5-yl ] -2-oxa-8-azaspiro [4.5] decan-4-amine was synthesized in a similar manner to Example 15, except 1H-indazol-6-ylboronic acid which was replaced with quinoxaline-6- acid boronic. 1 H NMR (500 MHz, Methanol-d4) δ 8.98 (q; J = 2.0 Hz; 2H); 8.53 (s; 1H); 8.26 (d; J = 8.7 Hz; 1H); 8.20 (d; J = 1.9 Hz; 1H); 7.96 (dd; J = 8.6; 1.9 Hz; 1H); 7.77 (d; J = 1.6 Hz; 1H); 7.53 (d; J = 1.6 Hz; 1H); 4.41 - 4.26 (m; 1H); 4.02 (d; J = 9.0 Hz; 1H); 3.90 (t; J = 12.6 Hz; 3H); 3.43 (d; J = 4.2 Hz; 1H); 3.32 - 3.15 (m; 1H); 2.41 (s; 3H); 2.11 (t; J = 12.5 Hz; 2H); 1.98 (d; J = 13.5 Hz; 1H); 1.85 (d; J = 13.1 Hz; 1H); 1.34 (d; J = 6.4 Hz; 3H). LCMS (ESI): m / z: [Μ + H] calculated for C24H28N7O 430.5; found 430.1.
[0820] [0820] Example 43. Synthesis of (3S, 4S) -8- [8- (8-chloro-3,4-dihydro-2H-1-benzopyran-7-yl) -7-methylimidazo [1 , 2-c] pyrimidin-5-yl] -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine.
[0821] [0821] (3S, 4S) -8- [8- (8-chloro-3,4-dihydro-2H-1-benzopyran-7-yl) -7-methylimidazo [1,2-c] pyrimidin- 5-yl] -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine was synthesized in a similar manner to Example 15, except for 1H-indazol-6-ylboronic acid which was replaced with 2- (8-chlorochroman-7-yl) -4,4,5,5-tetramethyl-1,3,2-dioxaborolane. 1H NMR (500 MHz, Methanol-d4) δ 8.56 (s; 1H); 7.72 (d; J = 1.6 Hz; 1H); 7.50 (d; J = 1.5 Hz; 1H); 7.21 - 7.12 (m; 1H); 6.83 (d; J = 7.7 Hz; 1H); 4.38 (td; J = 6.6; 3.6 Hz; 3H); 4.05 (d; J = 9.1 Hz; 1H); 3.91 (dd; J = 30.8; 12.9 Hz; 3H); 3.50 (d; J = 4.2 Hz; 1H); 3.34 - 3.18 (m; 2H); 2.96 (t; J = 6.5 Hz; 2H); 2.25 (s; 3H); 2.22 - 2.08 (m; 4H); 2.01 (d; J = 13.9 Hz; 1H); 1.88 (d; J = 13.4 Hz; 1H); 1.39 (d; J = 6.5 Hz; 3H). LCMS (ESI): m / z: [Μ + H] calculated for C25H31ClN5O2: 468.21; found 468.4.
[0822] [0822] Example 44. Synthesis of (3S, 4S) -8- [8- (7-chloro-2,3-dihydro-1-benzofuran-6-yl) -7-methylimidazo [1,2-c] pyrimidin -5-yl] -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine.
[0823] [0823] (3S, 4S) -8- [8- (7-chloro-2,3-dihydro-1-benzofuran-6-yl) -7-methylimidazo [1,2-c] pyrimidin-5-yl] -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine was synthesized in a similar manner to Example 15, except 1H-indazol-6-ylboronic acid which was replaced with 2- (7-chlorine -2,3-di-1 hydrobenzofuran-6-yl) -4,4,5,5-tetramethyl-1,3,2-dioxaborolane. H NMR (500 MHz, Methanol-d4) δ 8.54 (s; 1H); 7.74 (d; J = 1.5 Hz; 1H); 7.52 (d; J = 1.6 Hz; 1H); 7.32 (dt; J = 7.3; 1.2 Hz; 1H); 6.87 (d; J = 7.5 Hz; 1H); 4.78 (t; J = 8.8 Hz; 2H); 4.39 (q; J = 6.4; 5.8 Hz; 1H); 4.06 (d; J = 9.1 Hz; 1H); 3.93 (dd; J = 27.7; 13.3 Hz; 3H); 3.55 - 3.41 (m; 3H); 3.30 (dd; J =
[0824] [0824] Example 45. Synthesis of 3- {5 - [(3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl] -7-methylimidazo [1 , 2-c] pyrimidin-8-yl} - 2-chlorobenzonitrile.
[0825] [0825] 3- {5 - [(3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl] -7-methylimidazo [1,2-c] pyrimidin-8-yl} -2-chlorobenzonitrile was synthesized in a similar manner to Example 15, except for 1H-indazol-6-ylboronic acid which was replaced with 2-chloro3-cyanophenylboronic acid. 1H NMR (500 MHz, Methanol-d4) δ 8.40 (s; 2H); 7.95 (dd; J = 7.7; 1.7 Hz; 1H); 7.73 (d; J = 1.6 Hz; 1H); 7.69 (dd; J = 7.8; 1.8 Hz; 1H); 7.64 (t; J = 7.7 Hz; 1H); 7.50 (d; J = 1.6 Hz; 1H); 4.41 - 4.29 (m; 1H); 4.06 - 3.85 (m; 5H); 3.50 (dd; J = 4.2; 1.4 Hz; 1H); 3.30 - 3.15 (m; 2H); 2.21 (s; 3H); 2.18 - 2.04 (m; 2H); 1.99 (d; J = 13.8 Hz; 1H); 1.83 (d; J = 13.0 Hz; 1H); 1.35 (d; J = 6.5 Hz; 3H). LCMS (ESI): m / z: [Μ + H] calculated for C23H26ClN6O: 437.2; found 437.4.
[0826] [0826] Example 46. Synthesis of 4- {5 - [(3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl] -7-methylimidazo [1 , 2-c] pyrimidin-8-yl} - 3-chloro-2-methoxybenzonitrile.
[0827] [0827] 4- {5 - [(3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan- 8-yl] -7-methylimidazo [1,2-c] pyrimidin-8-yl} -3-chloro-2-methoxybenzonitrile was synthesized in a similar manner to Example 15, except 1H-indazol-6-ylboronic acid which was replaced with (2-chloro-4-cyano-3-) methoxyphenyl) boronic acid. 1H NMR (500 MHz, Methanol-d4) δ 8.52 (s; 1H); 7.77 (d; J = 8.0 Hz; 1H); 7.73 (d; J = 1.6 Hz; 1H); 7.50 (d; J = 1.6 Hz; 1H); 7.30 (d; J = 8.0 Hz; 1H); 4.38 - 4.29 (m; 1H); 4.13 (s; 3H); 4.03 - 3.97 (m; 1H); 3.96 - 3.83 (m; 3H); 3.41 (d; J = 4.2 Hz; 1H); 3.31 - 3.17 (m; 2H); 2.22 (s; 3H); 2.16 - 2.03 (m; 2H); 1.96 (d; J = 13.9 Hz; 1H); 1.84 (d; J = 13.3 Hz; 1H); 1.34 (d; J = 6.5 Hz; 3H). LCMS (ESI): m / z: [Μ + H] calculated for C24H28ClN6O2 467.2; found 467.4.
[0828] [0828] Example 47. Synthesis of (3S, 4S) -8- [8- (3-chloro-2-methoxy-ridin-4-yl) -7-methylimidazo [1,2-c] pyrimidin-5-yl ] -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine.
[0829] [0829] (3S, 4S) -8- [8- (3-chloro-2-methoxypyridin-4-yl) -7-methylimid-azo [1,2-c] pyrimidin-5-yl] -3-methyl -2-oxa-8-azaspiro [4.5] decan-4-amine was synthesized in a similar manner to Example 15, except for 1H-indazol-6-ylboronic acid which was replaced with 3-chloro-2-methoxy-oxy acid - Boronic 4-pyridinyl. 1H NMR (500 MHz, Methanol-d4) δ 8.18 (d; J = 5.0 Hz; 1H); 7.73 (d; J = 1.6 Hz; 1H); 7.47 (d; J = 1.6 Hz; 1H); 6.97 (d; J = 5.1 Hz; 1H); 4.29 (qd; J = 6.4; 4.9 Hz; 1H); 3.93 (d; J = 8.7 Hz; 1H); 3.85 - 3.70 (m; 2H); 3.42 - 3.34 (m; 1H); 3.27 (dd; J = 13.3; 10.2 Hz; 1H); 3.12 (d; J = 4.9 Hz; 1H); 2.05 (dddd; J = 31.1; 14.2; 9.5; 4.0 Hz; 2H); 1.91 - 1.79 (m; 2H); 1.27 (d; J = 6.5 Hz; 3H). LCMS (ESI): m / z: [Μ + H] calculated for C22H28ClN6O2 443.2; found 443.3.
[0830] [0830] Example 48. Synthesis of (3S, 4S) -3-methyl-8- (7-methyl-8-pyrazolo [1,5-a] pyridin-6-yl-imidazo [1,2-c ] pyrimidin-5-yl) -2-oxa-8-azaspiro [4.5] decan-4-amine.
[0831] [0831] (3S, 4S) -3-methyl-8- (7-methyl-8-pyrazolo [1,5-a] pyridin-6-yl-imid-azo [1,2-c] pyrimidin-5- il) -2-oxa-8-azaspiro [4.5] decan-4-amine was synthesized in a similar manner to Example 15, except 1H-indazol-6-ylboronic acid which was replaced with 6- (4 , 4,5,5-tetramethyl-1,3,2-di-oxaborolan-2-yl) pyrazolo [1,5-a] pyridine. 1H NMR (400 MHz, Methanol-d4) δ 8.60 (s; 1 H) 8.50 (br s; 1 H) 8.02 (d; J = 2.32 Hz; 1 H) 7.78 ( d; J = 9.05 Hz; 1 H) 7.71 (d; J = 1.22 Hz; 1 H) 7.50 (d; J = 1.10 Hz; 1 H) 7.25 (d; J = 9.05 Hz; 1 H) 6.69 (d; J = 1.96 Hz; 1 H) 4.28 - 4.36 (m; 1 H) 3.99 (d; J = 9.05 Hz; 1 H) 3.80 - 3.91 (m; 3 H) 3.41 (d; J = 4.16 Hz; 1 H) 3.15 - 3.27 (m; 2 H) 2.40 (s; 3 H) 2.02 - 2.13 (m; 2 H) 1.91 - 1.99 (m; 1 H) 1.82 (br d; J = 13.45 Hz; 1 H) 1 , 32 (d; J = 6.60 Hz; 3 H). LCMS (ESI): m / z: [M + H] calculated for C23H28N7O: 418.2; found 418.2.
[0832] [0832] Example 49. Synthesis of (3S, 4S) -8- [8- (2,3-dichloro-5-me-toxiphenyl) -7-methylimidazo [1,2-c] pyrimidin-5-yl] - 3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine.
[0833] [0833] (3S, 4S) -8- [8- (2,3-dichloro-5-methoxyphenyl) -7-methylimidazo [1,2-c] pyrimidin-5-yl] -3-methyl-2-oxa -8-azaspiro [4.5] decan-4-amine was synthesized in a similar manner to Example 15, except 1H-indazol-6-ylboronic acid which was replaced with 2- (2,3-dichloro-5 -methoxy-oxy-phenyl) -4,4,5,5-tetramethyl-1,3,2-dioxaborolane. 1H NMR (400 MHz, DMSO- d6) δ 8.51 (s; 1 H) 7.68 (s; 1 H) 7.45 (d; J = 1.2 Hz; 1 H) 7.23 (d ; J = 3.2 Hz; 1 H) 6.88 (d; J = 2.8 Hz; 1 H) 4.31 - 4.28 (m; 1 H) 3.96 (d; J = 8, 8 Hz; 1 H) 3.86 - 3.82 (m; 5 H) 3.45 - 3.34 (m; 1 H) 3.30 - 3.19 (m; 3 H)
[0834] [0834] Example 50. Synthesis of (3S, 4S) -8- [8- (3-chloro-1H-indol-7-yl) -7-methylimidazo [1,2-c] pyrimidin-5-yl] - 3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine.
[0835] [0835] (3S, 4S) -8- [8- (3-chloro-1H-indol-7-yl) -7-methylimidazo [1,2-c] pi-rimidin-5-yl] -3-methyl -2-oxa-8-azaspiro [4.5] decan-4-amine amine was synthesized in a similar manner to Example 15, except 1H-indazol-6-ylboronic acid which was replaced with 3-chloro-7 - (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-indole. 1H NMR (500 MHz, Methanol-d4) δ 8.51 (s; 2H); 7.69 (d; J = 1.6 Hz; 1H); 7.63 - 7.57 (m; 1H); 7.40 (d; J = 1.6 Hz; 1H); 7.24 (t; J = 7.6 Hz; 1H); 7.19 - 7.12 (m; 2H); 4.60 (s; 1H); 4.36 - 4.25 (m; 1H); 3.96 (d; J = 8.9 Hz; 1H); 3.82 (dd; J = 24.3; 11.5 Hz; 3H); 3.44 (s; 1H); 3.16 (s; 1H); 2.19 (s; 3H); 2.07 (d; J = 12.0 Hz; 2H); 1.93 (d; J = 7.5 Hz; 1H); 1.82 (d; J = 12.6 Hz; 1H); 1.28 (d; J = 2.3 Hz; 5H). LCMS (ESI): m / z: [M + H] calculated for C24H28ClN6O 451.2 found 451.5.
[0836] [0836] Example 51. (3S, 4S) -8- (8-imidazo [1,2-a] pyridin-7-yl-7-methyl-imidazo [1,2-c] pyrimidin-5-yl) - 3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine.
[0837] [0837] (3S, 4S) -8- (8-imidazo [1,2-a] pyridin-7-yl-7-methyl-imidazo [1,2-c] pyrimidin-5-yl) -3-methyl -2-oxa-8-azaspiro [4.5] decan-4-amine except 1H-indazol-6-ylboronic acid which has been replaced with 7- (4,4,5,5-tetra-methyl-1,3,2- dioxaborolan-2-yl) imidazo [1,2-a] pyridine. 1H NMR (400 MHz, Mehtanol-d4) δ 8.53 (d; J = 7.06 Hz; 1 H) 7.92 (s; 1 H) 7.71 (s; 1 H) 7.63 (d ; J = 1.10 Hz; 1 H) 7.60 (s; 1 H) 7.48 (d; J = 1.32 Hz; 1 H) 7.02 - 6.96 (m; 1 H) 4 , 32 - 4.21 (m; 1 H) 3.90 (d; J = 8.82 Hz; 1 H) 3.77 (br d; J = 8.82 Hz; 3 H) 3.22 (br t; J = 10.91 Hz; 1 H) 3.11 (d; J = 4.63 Hz; 1 H) 2.39 (s; 3 H) 2.13 - 1.96 (m; 2 H) 1.82 (br t; J = 15.88 Hz; 2 H) 1.24 (d; J = 6.39 Hz; 3 H). LCMS (ESI): m / z: [M + H] calculated for C23H28N7O: 418.2; found 418.2.
[0838] [0838] Example 52. Synthesis of (3S, 4S) -8- [8- (5-chloro-1H-indol-7-yl) -7-methylimidazo [1,2-c] pyrimidin-5-yl] - 3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine.
[0839] [0839] (3S, 4S) -8- [8- (5-chloro-1H-indol-7-yl) -7-methylimidazo [1,2-c] pi-rimidin-5-yl] -3-methyl -2-oxa-8-azaspiro [4.5] decan-4-amine was synthesized in a similar manner to Example 15, except for 1H-indazol-6-ylboronic acid which was replaced with 5-chloro-7- (4.4 , 5,5-tetramethyl-1,3,2-di-oxaborolan-2-yl) -1H-indole. 1H NMR (500 MHz, Methanol-d4) δ 8.50 (s; 1H); 7.69 (d; J = 1.6 Hz; 1H); 7.61 (d; J = 2.0 Hz; 1H); 7.40 (d; J = 1.5 Hz; 1H); 7.19 (d; J = 3.2 Hz; 1H); 7.05 (d; J = 2.0 Hz; 1H); 6.48 (d; J = 3.2 Hz; 1H); 4.35 - 4.23 (m; 1H); 3.95 (d; J = 9.0 Hz; 1H); 3.82 (dd; J = 20.8; 11.6 Hz; 3H); 3.21 (dd; J = 36.2; 12.1 Hz; 2H); 2.20 (s; 3H); 2.04 (d; J = 22.7 Hz; 2H); 1.93 (d; J = 10.0 Hz; 1H); 1.81 (d; J = 13.3 Hz; 1H); 1.29 (d; J = 6.5 Hz; 3H). LCMS (ESI): m / z: [M + H] calculated for C24H28ClN6O 451.2 found 451.4.
[0840] [0840] Example 53. Synthesis of (3S, 4S) -3-methyl-8- (7-methyl-8- {1H-pyrrolo [3,2-b] pyridin-7-yl} imidazo [1,2- c] pyrimidin-5-yl) -2-oxa-8-
[0841] [0841] (3S, 4S) -3-methyl-8- (7-methyl-8- {1H-pyrrolo [3,2-b] pyridin-7-yl} im-idazo [1,2-c] pyrimidin -5-yl) -2-oxa-8-azaspiro [4.5] decan-4-amine was synthesized in a similar manner to Example 15, except 1H-indazol-6-ylboronic acid which was replaced with pinacol 4-azaindol-7-boronic acid ester. 1H NMR (500 MHz, Methanol-d4) δ 8.41 (d; J = 3.0 Hz; 2H); 7.71 (d; J = 1.6 Hz; 1H); 7.53 (d; J = 3.3 Hz; 1H); 7.42 (d; J = 1.6 Hz; 1H); 7.18 (d; J = 5.0 Hz; 1H); 6.67 (d; J = 3.3 Hz; 1H); 4.37 - 4.24 (m; 1H); 3.99 (d; J = 9.1 Hz; 1H); 3.96 - 3.81 (m; 3H); 3.46 (d; J = 4.1 Hz; 1H); 3.19 (dd; J = 27.9; 14.8 Hz; 2H); 2.23 (s; 3H); 2.08 (tt; J = 11.1; 5.0 Hz; 2H); 1.98 (t; J = 14.7 Hz; 1H); 1.81 (d; J = 13.0 Hz; 1H); 1.31 (d; J = 6.5 Hz; 3H). LCMS (ESI): m / z: [M + H] calculated for C23H28N7O 418.5 found 418.5.
[0842] [0842] Example 54. Synthesis of 4- {5 - [(3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl] -7-methylimidazo [1 , 2-c] pyrimidin-8-yl} - 2,3-dichlorophenol.
[0843] [0843] 4- {5 - [(3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan- 8-yl] -7-methylimidazo [1,2-c] pyrimidin-8-yl} -2,3-dichlorophenol was synthesized in a similar manner to Example 15, except for 1H-indazol-6-ylboronic acid which was replaced with (2,3-dichloro-4-hydroxy-oxy- boronic). 1H NMR (400MHz, deuterium oxide) δ 7.82 (d; J = 1.8 Hz; 1 H); 7.70 (d; J = 1.6 Hz; 1 H); 7.21 (d; J = 8.6 Hz; 1 H); 7.11 (d; J = 8.4 Hz; 1 H); 4.43 (m; 1 H); 3.88-4.02 (m; 4 H); 3.63 (br d; J = 3.8 Hz; 1 H); 3.25-3.32 (m; 2 H); 2.28 (s; 3 H); 1.97-2.07 (m; 4 H); 1.83-1.86 (m; 1
[0844] [0844] Example 55. Synthesis of (3S, 4S) -8- [8- (3-fluoro-1H-indol-7-yl) -7-methylimidazo [1,2-c] pyrimidin-5-yl] - 3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine.
[0845] [0845] (3S, 4S) -8- [8- (3-fluoro-1H-indol-7-yl) -7-methylimidazo [1,2-c] pi-rimidin-5-yl] -3-methyl -2-oxa-8-azaspiro [4.5] decan-4-amine was synthesized in a similar manner to Example 15, except for 1H-indazol-6-ylboronic acid which was replaced with [1- (diethylcarbamoyl) -3- fluoro-2- (trimethylsilyl) -1H-indol-7-yl] boronic. 1H NMR (500 MHz, Methanol-d4) δ 8.45 (s; 3H); 7.67 (d; J = 1.6 Hz; 1H); 7.59 (d; J = 7.9 Hz; 1H); 7.39 (d; J = 1.5 Hz; 1H); 7.17 (t; J = 7.6 Hz; 1H); 7.10 (d; J = 7.1 Hz; 1H); 6.94 (d; J = 2.8 Hz; 1H); 4.60 (s; 1H); 4.36 - 4.24 (m; 1H); 3.97 (d; J = 9.1 Hz; 1H); 3.84 (dd; J = 29.1; 12.6 Hz; 3H); 3.61 (s; 1H); 3.41 (d; J = 4.7 Hz; 1H); 2.17 (s; 3H); 2.07 (s; 2H); 1.95 (d; J = 13.1 Hz; 1H); 1.81 (d; J = 13.4 Hz; 1H); 1.30 (d; J = 6.5 Hz; 3H). LCMS (ESI): m / z: [M + H] calculated for C24H28FN6O: 435.2; found 435.6.
[0846] [0846] Synthesis of [1- (diethylcarbamoyl) -3-fluoro-2- (trimethylsilyl) -1H-indol-7-yl] boronic acid.
[0847] [0847] Step 1. Synthesis of N, N-diethyl-3-fluoro-1H-indole-1-carboxamide
[0848] [0848] A solution of 3-chloro-1H-indole (250 mg; 1.6 mmol) in 2 ml THF was added to a suspension of sodium hydride (49 mg, 2 mmol) in 1 ml of THF at 0 ° C and the mixture stirred for 1hr at room temperature. After re-cooling to 0 ° C, N, N-diethylcarbamoyl chloride (5.58 ml; 44 mmol) was added and the reaction mixture was at room temperature for 18 h. The resulting reaction mixture was diluted with aq. (sat.) and EtOAc. The organic layer was separated, dried over MgSO4, filtered, and concentrated under reduced pressure. The resulting residue was carried on to the next step without any further purification. LCMS (ESI): m / z: [Μ + H] calculated for C13H16FN2O: 235.3; found 235.3.
[0849] [0849] Step 2. Synthesis of N, N-diethyl-3-fluoro-2- (trimethylsilyl) -1H-ind-dol-1-carboxamide
[0850] [0850] To a solution of N, N-diethyl-3-fluoro-1H-indole-1-carboxamide (200 mg, 853 µmol) in tetrahydrofuran (5.3 ml) was added chlorotrimethylsilane (225 µL; 1.78 mmol). The mixture was cooled to -78 ° C before addition in t-butyl (1.04 ml; 1.78 mmol) in drops. The reaction mixture was stirred in a capped flask at -78 ° C for 3 h. The resulting reaction mixture was quenched with sat. NH4Cl. (aq.) and then diluted with EtOAc. The organic layer was separated, dried over MgSO4, filtered, and concentrated under reduced pressure. The resulting residue was carried on to the next step without any further purification. LCMS (ESI): m / z: [Μ + H] calculated for C16H24FN2OSi: 307.5; found 307.4.
[0851] [0851] Step 3. Synthesis of [1- (diethylcarbamoyl) -3-fluoro-2- (trimethylsilyl) -1H-indol-7-yl] boronic acid
[0852] [0852] To a solution of N, N-diethyl-3-fluoro-2- (trimethylsilyl) -1H-indole-1-carboxamide (440 mg; 1.43 mmol) in tetrahydrofuran (4.29 mL) TMEDA (320 µL; 2.14 mmol) is added and then cooled to -78 ° C. Then, sec-butyl lithium group (1.52 mL, 2.14 mmol) was added in gums. The mixture was stirred in a capped flask at -78 ° C for 3 h. After,
[0853] [0853] Example 56. Synthesis of (3S, 4S) -8- [8- (2,3-dichlorophenyl) im-idazo [1,2-c] pyrimidin-5-yl] -3-methyl-2-oxa -8-azaspiro [4.5] decan-4-amine.
[0854] [0854] To a microwave vial (3S, 4S) -8- {8-bromoimidazo [1,2-c] pyrimidin-5-yl} -3-methyl-2-oxa-8-azaspiro [ 4.5] decan- 4-amine (80 mg, 218 µmol), boronic acid (2,3-dichlorophenyl) (62 mg, 327 µmol), tetracis (triphenylphosphine) palladium (25 mg, 22 µmol) and sodium carbonate (46 , 2 mg; 436 µmol). The flask was evacuated under vacuum for 10 minutes before addition in 1,2-dimethoxyethane (0.8 ml) and water (0.13 ml). The reaction flask was evacuated and purged with N2 three times before stirring under microwave conditions at 120 ° C for 1.5 h. The resulting reaction mixture was filtered through a pad of celite, washing with DCM and MeOH. The filtrate was concentrated and the resulting residue was purified by reverse phase HPLC to yield (3S, 4S) -8- [8- (2,3-dichlorophenyl) imidazo [1,2-c] pyrimidin-5-yl ] -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine (21 mg, 49 µmol, 22%) as the formic acid salt. 1H NMR (500 MHz, Methanol-d4) δ 7.81 (d; J = 1.6 Hz; 1H); 7.75 (s; 1H); 7.69 - 7.64 (m; 1H); 7.59 (d; J = 1.6 Hz; 1H); 7.45 - 7.40
[0855] [0855] Example 57: Synthesis of (3S, 4S) -8- [8- (2-chloro-3-methoxy-phenyl) imidazo [1,2-c] pyrimidin-5-yl] -3-methyl-2 -oxa-8-azaspiro [4.5] decan-4-amine.
[0856] [0856] (3S, 4S) -8- [8- (2-chloro-3-methoxyphenyl) imidazo [1,2-c] pyrimidin-5-yl] -3-methyl-2-oxa-8-azaspiro [ 4.5] decan-4-amine was synthesized in a similar manner to Example 56, except that boron (2,3-dichlorophenyl) acid was replaced with 2-chloro-3-methoxyphenylboronic acid. 1H NMR (500 MHz, Methanol-d4) δ 7.79 (s; 1H); 7.70 (s; 1H); 7.58 (s; 1H); 7.38 (t; J = 7.9 Hz; 1H); 7.19 (d; J = 8.3 Hz; 1H); 7.04 (d; J = 7.6 Hz; 1H); 4.33 (d; J = 7.1 Hz; 1H); 3.99 (d; J = 9.1 Hz; 1H); 3.94 (s; 3H); 3.86 (dd; J = 18.7; 12.2 Hz; 3H); 3.22 (dt; J = 27.6; 11.8 Hz; 2H); 2.15 - 2.03 (m; 2H); 1.95 (d; J = 13.6 Hz; 1H); 1.82 (d; J = 12.8 Hz; 1H); 1.38 - 1.28 (m; 3H). LCMS (ESI): m / z: [M + H] calculated for C22H27ClN5O2 428.2; found 428.4.
[0857] [0857] Example 58. Synthesis of (3S, 4S) -8- [8- (2-aminopyridin-4-yl) imidazo [1,2-c] pyrimidin-5-yl] -3-methyl-2-oxa -8-azaspiro [4.5] decan-4-amine.
[0858] [0858] (3S, 4S) -8- [8- (2-aminopyridin-4-yl) imidazo [1,2-c] pyrimidin-5-yl] - 3-methyl-2-oxa-8-azaspiro [ 4.5] decan-4-amine was synthesized in a similar manner to Example 56, except for (2,3-dichlorophenyl) boronic acid 1 which was replaced with (2-amino-4-pyridyl) boronic acid. H NMR (400MHz, Methanol-d4) δ 8.36 (br s; 1H); 8.06 (s; 1H); 7.96 (d; J = 6.0 Hz; 1H); 7.79 (d; J = 1.5 Hz; 1H); 7.66 (d; J = 1.3 Hz; 1H); 7.34 (s; 1H); 7.16 (dd; J = 1.5; 6.0 Hz; 1H); 4.35 - 4.28 (m; 1H); 4.35 - 4.28 (m; 1H); 4.01 - 3.85 (m; 4H); 3.47 (d; J = 4.2 Hz; 1H); 3.28 - 3.16 (m; 2H); 2.13 - 2.01 (m; 2H); 1.99 - 1.93 (m; 1H); 1.81 (br d; J = 12.3 Hz; 1H); 1.33 (d; J = 6.4 Hz; 3H). LCMS (ESI): m / z: [M + H] calculated for C20H26N7O: 380.2; found 380.2.
[0859] [0859] Example 59. Synthesis of (3S, 4S) -3-methyl-8- (8- {1H-pyrrolo [2,3-b] pyridin-4-yl} imidazo [1,2-c] pyrimidin-5-yl) -2-oxa-8-azaspiro [4.5] decan-4-amine.
[0860] [0860] (3S, 4S) -3-methyl-8- (8- {1H-pyrrolo [2,3-b] pyridin-4-yl} imid-azo [1,2-c] pyrimidin-5-yl ) -2-oxa-8-azaspiro [4.5] decan-4-amine was synthesized in a similar manner to Example 56, except for the boronic acid (2,3-dichlorophenyl) which was replaced with 4- (4.4 , 5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrrolo [2,3-b] pyridine. 1H NMR (400 MHz, Methanol-d4) δ 8.30 (d; J = 5.07 Hz; 1 H) 8.11 (s; 1 H) 7.84 (d; J = 1.54 Hz; 1 H) 7.63 (d; J = 1.54 Hz; 1 H) 7.54 (d; J = 5.07 Hz; 1 H) 7.45 (d; J = 3.53 Hz; 1 H) 6.54 (d; J = 3.53 Hz; 1 H) 4.24 - 4.31 (m; 1 H) 3.92 (d; J = 8.60 Hz; 1 H) 3.75 - 3 , 85 (m; 3 H) 3.38 (br t; J = 10.25 Hz; 1 H) 3.27 (br s; 1 H) 3.10 (d; J = 4.85 Hz; 1 H ) 1.98 - 2.12 (m; 2 H) 1.84 (br t; J = 13.45 Hz; 2 H) 1.25 (d; J = 6.39 Hz; 3 H). LCMS (ESI): m / z: [M + H] calculated for C22H26N7O: 404.2; found 404.1.
[0861] [0861] Example 60. (3S, 4S) -8- [8- (2-amino-3-chloropyridin-4-yl) im-idazo [1,2-c] pyrimidin-5-yl] -3-methyl -2-oxa-8-azaspiro [4.5] decan-4-amine.
[0862] [0862] (3S, 4S) -8- [8- (2-amino-3-chloropyridin-4-yl) imidazo [1,2-c] pi-rimidin-5-yl] -3-methyl-2- oxa-8-azaspiro [4.5] decan-4-amine was synthesized in a similar manner to Example 56, except (2,3-dichlorophenyl) boronic acid which was replaced with (2-amino-3-chloro-acid) 4-pi-ridil) boronic. 1H NMR (400MHz, Methanol-d4) δ 8.47 (br s; 1H); 7.97 (d; J = 5.1 Hz; 1H); 7.81 - 7.79 (m; 2H); 7.60 (d; J = 1.3 Hz; 1H); 6.75 (d; J = 5.3 Hz; 1H); 4.36 - 4.29 (m; 1H); 4.03 - 3.98 (m; 1H); 3.94 - 3.86 (m; 3H); 3.46 (d; J = 4.0 Hz; 1H); 3.29 - 3.15 (m; 2H); 2.13 - 2.02 (m; 2H); 2.00 - 1.93 (m; 1H); 1.82 (br d; J = 13.2 Hz; 1H); 1.33 (d; J = 6.4 Hz; 3H). LCMS (ESI): m / z: [M + H] calculated for C20H25ClN7O: 414.2; found 414.1.
[0863] [0863] Example 61. Synthesis of (3S, 4S) -8- {8 - [(2-amino-3-chloropyridin-4-yl) sulfanyl] -7-methyl- [1,2,4] triazole [4,3-c] pyrimidin-5-yl} -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine.
[0864] [0864] Step 1. Synthesis of N - [(3S, 4S) -8- [8 - [(2-amino-3-chloro-4-pyridyl) sulfanyl] -7-methyl- [1,2, 4] triazolo [4,3-c] pyrimidin-5-yl] -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-yl] tert-butyl carbamate
[0865] [0865] To a solution of N - [(3S, 4S) -8- (8-bromo-7-methyl- [1,2,4] triazolo [4,3-c] piramidin-5-yl) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-yl] tert-butyl carbamate (100 mg, 208 µmol) in dioxane (0.5 ml) were added 1.10 -phenanthroline (7.49 mg; 41.55 µmol), K3PO4 (88 mg, 415 µmol) and CuI (4 mg, 21 µmol) at 25 ° C. The mixture was stirred at 120 ° C for
[0866] [0866] Step 2. Synthesis of (3S, 4S) -8- [8 - [(2-amino-3-chloro-4-pyridyl) sulfanyl] -7-methyl- [1,2,4] triazole [4,3-c] pyrimidin-5-yl] -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine
[0867] [0867] A mixture of N - [(3S, 4S) -8- [8 - [(2-amino-3-chloro-4-pyridyl) sulfanyl] -7-methyl- [1,2,4] triazolo [4,3-c] pyrimidin-5-yl] -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-yl] tert-butyl carbamate (35 mg, 62 umol) in HCl / MeOH (3 mL) was stirred at 25 ° C for 0.5 h. The reaction mixture was diluted with EtOAc (5mL) and the solvent was removed under reduced pressure. The resulting residue was purified by prep-HPLC to yield (3S, 4S) -8- {8 - [(2-amino-3-chloropyridin-4-yl) sulfanyl] -7-methyl- [1,2,4 ] triazolo [4,3-c] pyrimidin-5-yl} -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine (5 mg, 11 µmol, 17% yield) as a solid White. 1H NMR (400MHz, Methanol-d4) δ 8.25 (s; 1H); 7.52 (d; J = 5.30 Hz; 1H); 5.86 (d; J = 5.30 Hz; 1H); 4.84 - 4.77 (m; 2H); 4.28 4.25 (m; 1H); 3.93 (d; J = 8.80Hz; 1H); 3.84 - 3.73 (m; 3H); 3.10 (d; J = 4.80 Hz; 1H); 2.54 (s; 3H); 2.01- 1.91 (m; 2H); 1.83 - 1.74 (m; 2H); 1.24 (d; J = 6.60 Hz; 3H). LCMS (ESI): m / z: [M + H] calculated for C20H26ClN8OS: 461.2; found 461.1.
[0868] [0868] Example 62. Synthesis of 1 - [(4R) -4-amino-8- [8- (2,3-dichlorophenyl) -7-methylimidazo [1,2-c] pyrimidin-5-yl] Azaspiro [4.5] decan-2-yl] azetidine-3-carbonitrile.
[0869] [0869] Step 1. Synthesis of N - [(1R, 3R) -8- {8-bromo-7-methylimid-azo [1,2-c] pyrimidin-5-yl} -3-hydroxy-oxy-8 -azaspiro [4.5] decan-1-yl] -2- methylpropane-2-sulfinamide
[0870] [0870] A solution of tert-butyl (1R, 3R) -3-hydroxy-oxy-1 - [(2-methylpropane-2-sulfinyl) amino] -8-azaspiro [4.5] decane-8-carboxylate (2g ; 5.3 mmol) was dissolved in TFA: DCM (1: 4) (6.6 mL) and stirred at room temperature for 30 minutes. The reaction was quenched with aq. saturated and diluted with EtOAc. The aqueous layer was removed and evaporated under reduced pressure. The remaining residue was dissolved in CH3CN (5.3 ml) and N, N-diisopropylethylamine (680 mg; 5.3 mmol) and 8-bromo-5-chloro-7-methylimidazo [1,2-c] pyrimidine (655 mg; 3.55 mmol) were subsequently added. The solution was heated at 60 ° C for 1 h after which the solution was cooled to room temperature and purified by chromatography on silica gel to yield N - [(1R, 3R) -8- {8-bromine -7-methylimidazo [1,2-c] pyrimidin-5-yl} -3-hydroxy-oxy-8-azaspiro [4.5] decan-1-yl] -2-methylpropane-2-sulfinamide as a white solid (750 mg, 59% yield). LCMS (ESI): m / z: [M + H] calculated for C20H31BrN5O2S 486.1; found 486.1
[0871] [0871] Step 2. Synthesis of N - [(1R, 3R) -8- [8- (2,3-dichlorophenyl) -7-methylimidazo [1,2-c] pyrimidin-5-yl] -3-hydroxy -oxy-8-azaspiro [4.5] decan-1-yl] -2-methylpropane-2-sulfinamide
[0872] [0872] To a solution of 2,3-dichlorophenylboronic acid (406 mg;
[0873] [0873] Step 3. Synthesis of N - [(1R) -8- [8- (2,3-dichlorophenyl) -7-methylimidazo [1,2-c] pyrimidin-5-yl] -3-oxo -8-azaspiro [4.5] decan-1-yl] -2-methylpro-pano-2-sulfinamide
[0874] [0874] To a solution of N - [(1R, 3R) -8- [8- (2,3-dichlorophenyl) -7-methylimidazo [1,2-c] pyrimidin-5-yl] -3-hydroxy- oxy-8-azaspiro [4.5] decan-1-yl] -2-methylpropane-2-sulfinamide (60 mg, 108 µmol) in DCM (1 ml) DMP (50 mg, 118 µmol) was added. The reaction was stirred at room temperature for 2.5 h. The mixture was then directly purified by silica gel column chromatography to yield N - [(1R) -8- [8- (2,3-dichlorophenyl) -7-methylimidazo [1,2-c] pyrimidin- 5-yl] -3-oxo-8-azaspiro [4.5] decan-1-yl] -2-methylpropane-2-sulfinamide (40 mg, 68% yield). LCMS (ESI): m / z: [M + H] calculated for C26H32Cl2N5O2S 548.2; found 548.4.
[0875] [0875] Step 4. Synthesis of 1 - [(4R) -4-amino-8- [8- (2,3-dichlorophenyl) - 7-methylimidazo [1,2-c] pyrimidin-5-yl] -8 -azaspiro [4.5] decan-2-yl] azetidine-3-carbonitrile.
[0876] [0876] To a solution of N - [(1R) -8- [8- (2,3-dichlorophenyl) -7-methylimid-
[0877] [0877] Example 63. Synthesis of (2R, 4R) -4-amino-8- [8- (2,3-dichlorophenyl) -7-methylimidazo [1,2-c] pyrimidin-5-yl N-methylcarbamate ] -8- azaspiro [4.5] decan-2-yl.
[0878] [0878] Carbonyldiimidazole (7 mg) was added to a solution of N - [(1R, 3R) -8- [8- (2,3-dichlorophenyl) -7-methylimidazo [1,2-c] pyrimidin-5- il] - 3-hydroxy-oxy-8-azaspiro [4.5] decan-1-yl] -2-methylpropane-2-sulfinamide (Example 62) in DCM (0.15 ml) and the reaction mixture was stirred at temperature room for 1 h. After 1 h, the reaction was passed through a small plug of silica and the filtrate was concentrated under reduced pressure. The resulting crude residue was dissolved in DCM and a solution of methyl amine (2M in THF; 0.15 ml) was added. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure and the resulting crude residue was dissolved in MeOH (0.2 ml) and a solution of HCL in dioxane (4M) (0.1 ml) was then added. The reaction was stirred for 30 mins. The solution was then concentrated under reduced pressure and the remaining residue was purified by reverse phase HPLC to yield (2R, 4R) -4-amino-8- [8- (2,3-dichlorophenyl) -7- N -methylcarbamate methylimid-azo [1,2-c] pyrimidin-5-yl] -8-azaspiro [4.5] decan-2-yl as a white solid (1.2 mg, 16% yield over 3 steps). 1H NMR (500 MHz, Methanol-d4) δ 8.56 (s; 1H); 7.73 - 7.59 (m; 2H); 7.50 - 7.39 (m; 2H); 7.32 (dt; J = 7.7; 1.5 Hz; 1H); 5.15 (s; 1H); 3.93 (d; J = 19.8 Hz; 2H); 3.31 - 3.11 (m; 3H); 2.73 (s; 3H); 2.67 (q; J = 7.2 Hz; 1H); 2.21 (s; 3H); 2.16 (td; J = 15.1; 14.5; 5.3 Hz; 1H); 2.10 - 1.75 (m; 4H); 1.59 (d; J = 13.4 Hz; 1H). LC-MS (ESI): m / z [M + H] + calculated for C24H29Cl2N6O2 503.2; found 503.4.
[0879] [0879] Example 64. Synthesis of (2R, 4R) -8- [8- (2-chloro-3-methoxy-phenyl) -7-methyl-imidazo [1,2-c] pyrimidin-5-yl ] - 2- (oxetan-3-yloxy) -8-azaspiro [4.5] decan-4-amine.
[0880] [0880] Step 1. Synthesis of (2R, 4R) -4-amino-8-azaspiro [4.5] decan-2-ol.
[0881] [0881] A mixture of tert-butyl (2R, 4R) -4- (tert-butylsulfinylamino) -2-hydroxy-oxy-8-azaspiro [4.5] decane-8-carboxylate (1 g, 2.7 mmol) in HCl / MeOH (20 mL) was stirred at 25 ° C for 0.5 h. The mixture was concentrated under reduced pressure to yield (2R, 4R) -4-amino-8-azaspiro [4.5] decan-2-ol (660 mg, crude) as a white solid.
[0882] [0882] Step 2. Synthesis of (2R, 4R) -4- (tert-butoxycarbonylamino) -2-hydroxy-oxy-8-azaspiro [4.5] tert-butyl decano-8-carboxylate
[0883] [0883] To a solution of (2R, 4R) -4-amino-8-azaspiro [4.5] decan-2-ol (650 mg; 3.8 mmol) in THF (10 mL) was added TEA (1.4 g; 13.3 mmol; 1.9 mL) and Boc2O (2.1 g; 9.5 mmol; 2.2 mL). The reaction mixture was stirred at 25 ° C for 16 h. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography to yield (2R, 4R) -4- (tert-butoxycarbonyl-mino) -2-hydroxy-oxy-8-azaspiro [4.5] tert-butyl decano-8-carboxylate (0.6 g; 1.62 mmol, 42% yield) as a white solid. 1H NMR (400 MHz, Chloroform-d) δ 5.18 (s; 1 H) 4.48 - 4.35 (m; 1 H) 3.92 - 3.64 (m; 4 H) 3.00 ( t; J = 10.69 Hz; 2 H) 2.24 - 2.15 (m; 1 H) 1.87 (d; J = 7.72 Hz; 1 H) 1.75 (s; 1 H) 1.69 - 1.48 (m; 7 H) 1.47 - 1.42 (m; 18 H) 1.32 -
[0884] [0884] Step 3. Synthesis of dimethyl-2 - [[(2R, 4R) -8-tert-butoxycarbonyl-4- (tert-butoxycarbonylamino) -8-azaspiro [4.5] decan-2-yl] oxide] pro panodioate.
[0885] [0885] To a solution of dimethyl 2-diazopropanedioate (281 mg; 1.8 mmol) in toluene (30 mL) were added (2R, 4R) -4- (tert-butoxycarbonylamino) -2-hydroxy-oxy-8 -azaspiro [4.5] tert-butyl decano-8-carboxylate (0.6 g; 1.6 mmol), and diacetoxyrodium (7.2 mg; 32 µmol). The reaction mixture was stirred at 65 ° C for 2 h. The reaction was quenched by the slow addition of H2O (40 ml) and then extracted with EtOAc (20 ml x 3). The combined organic phase was washed with brine (20 ml), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography to yield dimethyl2 - [[(2R, 4R) -8-tert-butoxycarbonyl-4- (tert-butoxycarbonylamino) - 8-azaspiro [4.5] decan-2-yl ] oxy] propanedioate (600 mg; 1.2 mmol; 74% yield) as a colorless oil. 1H NMR (400 MHz, Chloroform-d) δ 5.34 (d; J = 9.92 Hz; 1 H) 4.17 - 4.05 (m; 1 H) 3.90 (td; J = 6.56; 3.42 Hz; 1 H) 3.82 (d; J = 1.54 Hz; 6 H) 3.81 - 3.71 (m; 2 H) 3.06 - 2.90 (m ; 2 H) 2.22 - 2.11 (m; 1 H) 1.96 - 1.70 (m; 2 H) 1.68 - 1.49 (m; 4 H) 1.44 (d; J = 1.98 Hz; 18 H) 1.32 - 1.21 (m; 1 H). LCMS (ELSD): m / z: [M + Na] calculated for C24H40N2O9Na: 523.3; found 523.1.
[0886] [0886] Step 4. Synthesis of (2R, 4R) -4- (tert-butoxycarbonylamino) -2- [2-hydroxy-oxy-1- (hydroxymethyl) ethoxy] -8-azaspiro [4.5] decane-8-carboxylate tert-butyl.
[0887] [0887] To a solution of 2 - [[(2R, 4R) -8-tert-butoxycarbonyl-4- (tert-butoxycarbonylamino) -8-azaspiro [4.5] decan-2-yl] oxide] dimethyl propanedioate (400 mg, 799 µmol) in THF (6 ml) LiBH4 (61 mg; 2.8 mmol) was added at -20 ° C. The reaction mixture was stirred at -20 ° C for 1 h. The reaction was quenched by the slow addition of H2O (0.1 ml), extracted with EtOAc (15 ml), dried over Na2SO4, filtered and concentrated under reduced pressure. The remaining residue was purified by column chromatography to yield (2R, 4R) -4- (tert-butoxycarbonylamino) -2- [2-hydroxy-oxy-1- (hydroxymethyl) ethoxy] -8-azaspiro [4.5] tert-butyl decane-8-carboxylate (350 mg, 787 µmol, 98% yield) as a colorless oil. 1H NMR (400 MHz, Methanol-d4) δ 6.70 (d; J = 9.70 Hz; 1 H) 4.21 (s; 1 H) 3.88 - 3.74 (m; 2 H) 3 , 72 - 3.36 (m; 5 H) 2.99 (s; 2 H) 2.25 (dt; J = 13.89; 6.95 Hz; 1 H) 1.92 - 1.65 (m ; 3 H) 1.63 - 1.47 (m; 2 H) 1.44 (d; J = 5.29 Hz; 13 H).
[0888] [0888] Step 5. Synthesis of (2R, 4R) -4- (tert-butoxycarbonylamino) -2- [1 - [[tert-butyl (dimethyl) -sulfanyl] oxymethyl] -2-hydroxy-oxy-ethoxy] - 8-azaspiro [4.5] tert-butyl decano-8-carboxylate.
[0889] [0889] To a stirred solution of (2R, 4R) -4- (tert-butoxycarbonylamino) -2- [2-hydroxy-oxy-1- (hydroxymethyl) ethoxy] -8-azaspiro [4.5] decane-8 - tert-butyl carboxylate (0.28 g; 629 µmol) in THF (1.5 ml) at 0 ° C NaH (25.1 mg; 629 µmol, 60% purity) was added. After the solution was stirred at 20 ° C for 40 min, TBSCl (95 mg, 629 µmol, 77 µL) was added, and the reaction mixture was stirred at 20 ° C for 2 h. The reaction was quenched with the slow addition of H2O (20 ml), extracted with EtOAc (15 ml x 3), washed with brine (20 ml), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The remaining residue was purified by chromatography on silica gel to yield (2R, 4R) -4- (tert-butoxycarbonylamino) -2- [1 - [[tert-butyl (dimethyl) -sulfanyl] oxymethyl] -2- hydroxy-oxy-ethoxy] -8-azaspiro [4.5] tert-butyl decane-8-carboxylate (210 mg, 373 µmol, 59% yield) as a colorless oil. 1H NMR (400 MHz, Methanol-d4) δ 6.57 - 6.33 (m; 2 H) 4.13 (s; 2 H) 3.70 (dd; J = 8.82; 4.41 Hz; 3 H) 3.64 - 3.49 (m; 5 H) 3.45 - 3.29 (m; 3 H) 3.21 - 3.10 (m; 1 H) 2.90 (s; 4 H ) 2.25 - 2.07 (m; 2 H) 1.84 - 1.55 (m; 5 H) 1.50 - 1.39 (m; 3 H) 1.37 - 1.11 (m; 24 H) 0.90 - 0.72 (m; 12 H) 0.00 (d; J = 1.54 Hz; 6 H). LCMS (ESI): m / z: [M + Na] calculated for C28H54N2O7SiNa: 581.4; found 581.1
[0890] [0890] Step 6. Synthesis of (2R, 4R) -4- (tert-butoxycarbonylamino) -2-
[0891] [0891] To a solution of (2R, 4R) -4- (tert-butoxycarbonylamino) -2- [1- [[tert-butyl (dimethyl) -sulfanyl] oxymethyl] -2-hydroxy-oxy-ethoxy] -8 - azaspiro [4.5] tert-butyl decane-8-carboxylate (200 mg, 355 µmol) in THF (5 ml) NaH (21.32 mg; 533 µmol; 60% purity) was added at 0 ° C. The mixture was stirred at 0 ° C for 10 min, after which TosCl (101 mg, 533 µmol) was added. The reaction mixture was stirred at 25 ° C for 1 h. The reaction was quenched by the slow addition of H2O (20 ml) and then extracted with EtOAc (15 ml x 3). The combined organic phase was washed with brine (20 ml), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The remaining residue was purified by chromatography on silica gel to yield (2R, 4R) -4- (tert-butoxycarbonyl-mino) -2- [1 - [[tert-butyl (dimethyl) -sulfanyl] oxymethyl] -2- (p-tolylsulfonyloxy) ethoxy] - 8-azaspiro [4.5] tert-butyl decano-8-carboxylate (150 mg, 209 µmol, 58% yield) as a colorless oil. LCMS (ESI): m / z: [M + Na] calculated for C35H60N2O9SSiNa: 735.4; found 735.2.
[0892] [0892] Step 7. Synthesis of (2R, 4R) -4- (tert-butoxycarbonylamino) -2- [1- (hydroxymethyl) -2- (p-tolylsulfonyloxy) ethoxy] -8-azaspiro [4.5] decane-8 -car- tert-butyl boxylate.
[0893] [0893] To a solution of (2R, 4R) -4- (tert-butoxycarbonylamino) -2- [1- [[tert-butyl (dimethyl) -sulfanyl] oxymethyl] -2- (p-tolylsulfonyloxy) ethoxy] - 8-azaspiro [4.5] tert-butyl decano-8-carboxylate (150 mg, 209 umol) in HOAc (2.6 ml) H2O (1.4 ml) and THF (0.6 ml) were added. The reaction mixture was stirred at 20 ° C for 16 h. The reaction was quenched with H2O (20 ml) and extracted with EtOAc (15 ml x 3). The combined organic phases were washed with brine (20 ml), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The remaining residue was purified by chromatography on silica gel to yield (2R, 4R) -4- (tert-butoxycarbonylamino) -2- [1- (hydroxymethyl) -2- (p-
[0894] [0894] Step 8. Synthesis of tert-butyl (2R, 4R) -4- (tert-butoxycarbonylamino) -2- (oxetan-3-yloxy) -8-azaspiro [4.5] decane-8-carboxylate.
[0895] [0895] To a solution of (2R, 4R) -4- (tert-butoxycarbonylamino) -2- [1- (hydroxymethyl) -2 - (p-tolylsulfonyloxy) ethoxy] -8-azaspiro [4.5] decane-8- tert-butyl carboxylate (100 mg, 167 µmol) in DMF (5 ml) NaH (8 mg, 200 µmol, 60% purity) was added at 0 ° C. The reaction mixture was stirred at 25 ° C for 1 h. The reaction was quenched with H2O (20 mL) and extracted with EtOAc (15 mLx3). The combined organic phases were washed with brine (20 ml), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to yield (2R, 4R) -4- (tert-butoxycarbonylamino) -2- (oxetan-3-yloxy ) Tert -butyl-8-azaspiro [4.5] decan-8-carboxylate (70 mg, 164 umol, 98% yield) as a color oil. 1H NMR (400 MHz, Methanol-d4) δ 4.70 - 4.65 (m; 2 H) 4.56 - 4.50 (m; 1 H) 4.48 - 4.41 (m; 2 H) 3.88 - 3.68 (m; 4 H) 3.62 - 3.35 (m; 4 H) 2.84 (s; 2 H) 2.15 (dt; J = 13.39; 6.88 Hz; 2 H) 1.70 (d; J = 5.87 Hz; 3 H) 1.35 (s; 18 H) 1.20 (s; 2 H) 0.79 (s; 3 H); LCMS (ESI): m / z: [M + Na] calculated for C22H38N2O6Na: 449.3; found 449.1.
[0896] [0896] Step 9. Synthesis of (2R, 4R) -2- (oxetan-3-yloxy) -8-azaspiro [4.5] decan-4-amine.
[0897] [0897] To a solution of (2R, 4R) -4- (tert-butoxycarbonylamino) -2- (oxetan-3-yloxy) -8- azaspiro [4.5] tert-butyl decane-8-carboxylate (35 mg, 82 µmol, 1 eq) in DCM (0.5 ml) was added TFA (0.5 ml). The reaction mixture was stirred at 25 ° C for 1 h. The reaction mixture was concentrated under reduced pressure to yield (2R, 4R) -2- (oxetan-3-yloxy) -8-azaspiro [4.5] decan-4-amine (77 mg, crude) as a white solid. LCMS (ESI): m / z: [M + H] calculated for C12H23N2O2 227.2; found 227.2.
[0898] [0898] Step 10. Synthesis of (2R, 4R) -8- (8-bromo-7-methyl-imid-azo [1,2-c] pyrimidin-5-yl) -2- (oxetan-3-yloxy ) -8-azaspiro [4.5] decan-4-amine
[0899] [0899] To a solution of 8-bromo-5-chloro-7-methyl-imidazo [1,2-c] pyrimidine (19 mg, 77 µmol) in i-PrOH (1 ml) was added (2R, 4R) - 2- (oxetan-3-yloxy) -8-azaspiro [4.5] decan-4-amine (38 mg, 84 µmol, 2TFA) and DIEA (49.8 mg; 385 µmol, 67 µL). The reaction mixture was stirred at 80 ° C for 1 h, concentrated under reduced pressure and the resulting residue was purified by column chromatography to yield (2R, 4R) -8- (8-bromo-7-methyl-imidazo [1 , 2-c] pyrimidin-5-yl) -2- (oxetan-3-yloxy) -8-azaspiro [4.5] decan-4-amine (30 mg, 68 µmol, 44% yield) as a solid White. LCMS (ESI): m / z: [M + H] calculated for C19H27BrN5O2: 436.1; found 436.3. 1H NMR (400 MHz, Methanol-d4) δ 7.61 (d; J = 1.59 Hz; 1 H) 7.46 (d; J = 1.47 Hz; 1 H) 4.70 (q; J = 6.07 Hz; 2 H) 4.59 (dt; J = 11.28; 5.55 Hz; 1 H) 4.53 - 4.45 (m; 2 H) 4.00 (dt; J = 6.72; 3.12 Hz; 1 H) 3.83 - 3.66 (m; 2 H) 3.15 - 3.00 (m; 3 H) 2.46 (s; 3 H) 2.39 (dt; J = 14.21; 6.89 Hz; 1 H) 2.05 - 1.67 (m; 7 H) 1.46 (d; J = 12.35 Hz; 1 H)
[0900] [0900] Step 11. Synthesis of (2R, 4R) -8- [8- (2-chloro-3-methoxy-oxy-phenyl) -7-methyl-imidazo [1,2-c] pyrimidin-5-yl ] - 2- (oxetan-3-yloxy) -8-azaspiro [4.5] decan-4-amine
[0901] [0901] To a solution of (2R, 4R) -8- (8-bromo-7-methyl-imidazo [1,2-c] pyrimidin-5-yl) - 2- (oxetan-3-yloxy) -8 -azaspiro [4.5] decan-4-amine (25 mg, 57 µmol) in DME (1 ml) and H2O (0.2 ml) boronic acid (2-chloro-3-methoxy-oxy-phenyl) (21 mg, 114 µmol), Na2CO3 (12 mg, 114 umol) and Pd (PPh3) 4 (6.6 mg; 5.73 µmol). The mixture was stirred at 80 ° C for 1 h. The reaction was filtered and concentrated under reduced pressure. The resulting residue was purified by prep-HPLC to yield (2R, 4R) -8- [8- (2-chloro-3-methoxy-oxy-phenyl) -7-methyl-imidazo [1,2-c] pyrimidin- 5-yl] - 2- (ox-ethan-3-yloxy) -8-azaspiro [4.5] decan-4-amine (2 mg, 3.9 µmol, 7% yield) as a white solid. LCMS (ESI): m / z: [M + H] calculated for C26H33ClN5O3 498.2; found 498.0. 1H NMR (500 MHz, Methanol-d4) δ 8.52 (s; 1 H) 7.65 (s; 1 H) 7.43 (d; J = 1.54 Hz; 1 H) 7.39 (t; J = 8.05 Hz; 1 H) 7.18 (d; J = 7.06 Hz; 1 H) 6.91 (dd; J = 7.50; 1.32 Hz; 1 H) 4 , 82 - 4.76 (m; 3 H) 4.69 (dt; J = 11.30; 5.71 Hz; 1 H) 4.60 (dd; J = 6.06; 3.20 Hz; 3 H) 4.14 - 4.05 (m; 1 H) 3.94 (s; 3 H) 3.85 (d; J = 9.70 Hz; 1 H) 3.24 - 3.09 (m; 2 H) 2.49 (dt; J = 14.22; 7.00 Hz; 1 H) 2.17 (s; 3 H) 2.13 - 1.79 (m; 6 H) 1.58 (d ; J = 14.11 Hz; 1 H).
[0902] [0902] Example 65. Synthesis of (3S, 4S) -8- {8 - [(2-amino-3-chloro-pyridin-4-yl) sulfanyl] imidazo [1,2-a] pyrazin-5-yl } -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine.
[0903] [0903] Step 1. Synthesis of 4 - ({5-bromoimidazo [1,2-a] pyrazin-8-yl} sulfanyl) -3-chloropyridin-2-amine
[0904] [0904] 3-chloro-4- (potassiosulfanyl) pyridin-2-amine (78.8 mg; 397 µmol) and pyridinium p-toluenesulfonate (108 mg, 433 µmol) were dissolved in DMA (1.8 ml ). The resulting solution was stirred at room temperature for 5 minutes, then 5,8-dibromoimidazo [1,2-a] pyrazine (100 mg, 361 µmol) was added. The reaction was stirred for 5.5 h, then purified directly by column chromatography to yield 4 - ({5-bromoimidazo [1,2-a] pyrazin-8-yl} sulfanyl) -3-chloropyridin-2-amine (112 mg, 317 µmol, 88% yield). LCMS (ESI): m / z: [M + H] calculated for C11H8BrClN5S: 355.94; found 356.1.
[0905] [0905] Step 2. Synthesis of (3S, 4S) -8- {8 - [(2-amino-3-chloropyridin-4-
[0906] [0906] To a mixture of 4 - ({5-bromoimidazo [1,2-a] pyrazin-8-yl} sul-fanyl) -3-chloropyridin-2-amine (112.1 mg; 314 µmol) and N - [(3S, 4S) -8-chloro-3-methyl-2-oxa-8-azaspiro [4.5] decan-4-yl] chloranamine (89.9 mg; 376 µmol) in DMA (1.56 mL) N, N-diisopropylethylamine (545 µL; 3.14 mmol) was added. The reaction was sparged with N2 for 5 minutes, sealed, and heated to 100 ° C. After 14 h, the resulting mixture was purified by HPLC prep to yield (3S, 4S) -8- {8 - [(2-amino-3-chloropyridin-4-yl) sulfanyl] imidazo [1,2-a] pyrazin-5-yl} -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine as the formic acid salt (15 mg, 31 µmol, 10% yield). 1H NMR (500 MHz, Methanol-d4) δ 8.55 (s; 1H); 7.99 (d; J = 1.3 Hz; 1H); 7.83 (d; J = 1.2 Hz; 1H); 7.72 (d; J = 5.5 Hz; 1H); 7.55 (s; 1H); 6.49 (d; J = 5.5 Hz; 1H); 4.36 - 4.27 (m; 1H); 3.96 (d; J = 8.9 Hz; 1H); 3.84 (d; J = 8.9 Hz; 1H); 3.53 - 3.42 (m; 3H); 3.31 (d; J = 4.6 Hz; 1H); 3.16 - 3.01 (m; 2H); 2.14 - 2.03 (m; 2H); 1.99 - 1.91 (m; 1H); 1.89 - 1.81 (m; 1H); 1.31 (d; J = 6.5 Hz; 3H). LC-MS (ESI): m / z: [M + H] calculated for C20H25ClN7OS: 446.15; found 446.2.
[0907] [0907] Example 66. 2 - ({8 - [(2-amino-3-chloropyridin-4-yl) sulpanyl] imidazo [1,2-c] pyrimidin-5-yl} amino) acetamide.
[0908] [0908] Step 1. Synthesis of 2 - [(8-bromoimidazo [1,2-c] pyrimidin-5-yl) amino] acetamide
[0909] [0909] To a solution of 8-bromo-5-chloro-imidazo [1,2-c] pyrimidine (200 mg, 860 µmol) and 2-aminoacetamide (95.6 mg; 1.29 mmol) in CH3CN (3 mL) DIEA (556 mg; 4.3 mmol, 749 µL) was added. The mixture was stirred at 50 ° C for 0.5 h. The reaction mixture was filtered yielding 2 - [(8-bromoimidazo [1,2-c] pyrimidin-5-yl) amino] acetamide (210 mg, 778 µmol, 90% yield) as a white solid. LCMS
[0910] [0910] Step 2. Synthesis of 2 - ({8 - [(2-amino-3-chloropyridin-4-yl) sulpanyl] imidazo [1,2-c] pyrimidin-5-yl} amino) acetamide
[0911] [0911] To a solution of 2-amino-3-chloro-pyridine-4-thiol (187 mg; 1.2 mmol) and 2 - [(8-bromoimidazo [1,2-c] pyrimidin-5-yl) amino] acetamide (210 mg; 777.53 µmol) in DMSO (2 ml) Xantphos (269.94 mg; 466.52 µmol), DIEA (301.46 mg; 2.33 mmol; 406.29 µL) were added and Pd2 (dba) 3 (142 mg, 156 umol). The mixture was stirred at 125 ° C for 0.5 h. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure. The remaining residue was purified by prep-HPLC to yield 2 - ({8 - [(2-amino-3-chloropyridin-4-yl) sulfanyl] imidazo [1,2-c] pyrimidin-5-yl} amino) acetamide (9.6 mg; 27 µmol, 4% yield) as a white solid. 1H NMR (500MHz, DMSO-d6) δ 8.62 (s; 1H); 8.10 (d; J = 1.5 Hz; 1H); 7.90 (s; 1H); 7.60 (s; 1H); 7.55 (d; J = 5.4 Hz; 1H); 7.51 (d; J = 1.5 Hz; 1H); 7.13 (s; 1H); 6.29 (s; 2H); 5.76 (d; J = 5.4 Hz; 1H); 4.10 (d; J = 5.9 Hz; 2H). LCMS (ESI): m / z: [M + H] calculated for C13H13ClN7OS: 350.1; found 350.0.
[0912] [0912] Examples 67-80 were prepared in the same way as Example 66. Example M +1 Found 67 377.0 68 363.0
[0913] [0913] Example 81. 4 - [(5 - {[(1S, 3R) -3-aminocyclopentyl] oxy} imidazo [1,2-c] pyrimidin-8-yl) sulfanyl] -3-chloropyridin-2 -the mine.
[0914] [0914] Step 1. Synthesis of N - [(1R, 3S) -3- (8-bromoimidazo [1,2-c] pyrimidin-5-yl) oxycyclopentyl] tert-butyl carbamate
[0915] [0915] To a mixture of 8-bromo-5-chloro-imidazo [1,2-c] pyrimidine (200 mg, 860 µmol) and N - [(1R, 3S) -3-hydroxycyclopentyl] tert-butyl carbamate (190 mg, 946 µmol) in DMSO (2 ml) Cs2CO3 (561 mg; 1.7 mmol) was added in one portion at 25 ° C under N2. The mixture was stirred at 25 ° C for 4 h. H2O (10 mL) was added dropwise to the reaction mixture and the aqueous phase was extracted with EtOAc. The combined organic phase was washed with brine (5 ml x 2), dried with anhydrous Na2SO4, concentrated under reduced pressure. The residue was purified by column chromatography to yield N - [(1R, 3S) -3- (8-bromoimidazo [1,2-c] pyrimidin-5-yl) oxycyclopentyl] tert-butyl carbamate ( 187 mg, 471 µmol, 55% yield) as a white solid. 1H NMR (500 MHz, Chloroform-d) δ 7.79 (s; 1 H) 7.63 (dd; J = 9.48; 1.10 Hz; 2 H) 5.63 (br s; 1 H) 4.69 (br s; 1 H) 2.49 - 2.60 (m; 1 H) 2.09 - 2.19 (m; 3 H) 1.85 - 1.94 (m; 1 H) 1 , 73 - 1.80 (m; 1 H) 1.45 (d; J = 2.21 Hz; 8 H) 1.42 - 1.48 (m; 1 H).
[0916] [0916] Step 2. Synthesis of N - [(1R, 3S) -3- [8 - [(2-amino-3-chloro-4-pyridyl) sulfanyl] imidazo [1,2-c] pyrimidin- 5-yl] oxycyclopentyl] tert-butyl carbamate
[0917] [0917] To a mixture of N - [(1R, 3S) -3- (8-bromoimidazo [1,2-c] pyrimidin-5-yl) oxycyclopentyl]-tert-butyl carbamate (187 mg, 470 umol) and 2-amino-3-chloro-pyridine-4-thiol (151 mg, 941 µmol) in m-xylene (5 ml) Xantphos (109 mg, 188 µmol) DIEA (304 mg; 2.4 mmol , 410 µL) and Pd2 (dba) 3 (86.21 mg; 94.14 µmol) in a portion at 25 ° C under N2. The mixture was stirred at 140 ° C for 3 h. The reaction was filtered and purified by HPLC to yield N - [(1R, 3S) -3- [8 - [(2-amino-3-chloro-4-pyridyl) sulfanyl] imidazo [1,2-c] pyrimidin- 5-yl] oxycyclopentyl] tert-butyl carbamate (60 mg, 124 µmol, 26% yield) as a white solid. LCMS (ESI): m / z: [M + H] calculated for C21H26ClN6O3S: 477.1; found 477.2.
[0918] [0918] Step 3. 4 - [(5 - {[(1R, 3S) -3-aminocyclopentyl] oxy} imidazo [1,2-c] pyrimidin-8-yl) sulfanyl] -3-chloropyridin-2-amine .
[0919] [0919] To a solution of TMSCl (26 mg, 236 µmol, 30 µL) in
[0920] [0920] Example 82. (3S, 4S) -8- {8 - [(2-amino-3-chloropyridin-4-yl) sulfanyl] imidazo [1,2-a] pyrazin-5-yl} -3- methyl-2-oxa-8-azaspiro [4.5] decan-4-amine.
[0921] [0921] Step 1. Synthesis of 4 - ({5-bromoimidazo [1,2-a] pyrazin-8-yl} sulfanyl) -3-chloropyridin-2-amine
[0922] [0922] 3-chloro-4- (potassiosulfanyl) pyridin-2-amine (78.8 mg; 397 µmol) and pyridinium p-toluenesulfonate (108 mg, 433 µmol) were dissolved in DMA (1.8 ml ). The resulting solution was stirred at room temperature for 5 minutes, then 5,8-dibromoimidazo [1,2-a] pyrazine (100 mg, 361 µmol) was added. The reaction was stirred for 5.5 h, then purified by column chromatography to yield 4 - ({5-bromimimazo [1,2-a] pyrazin-8-yl} sulfanyl) -3-chloropyridin-2-amine (112 mg, 317 µmol, 88% yield). LC-MS (ESI): m / z: [M + H] calculated for C11H8BrClN5S: 355.9; found 356.1.
[0923] [0923] Step 2. (3S, 4S) -8- {8 - [(2-amino-3-chloropyridin-4-yl) sulpanyl] imidazo [1,2-a] pyrazin-5-yl} - 3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine.
[0924] [0924] To a mixture of 4 - ({5-bromoimidazo [1,2-a] pyrazin-8-yl} sul-fanyl) -3-chloropyridin-2-amine (112.1 mg; 314 µmol) and N - [(3S, 4S) -8-chloro-3-methyl-2-oxa-8-azaspiro [4.5] decan-4-yl] chloranamine (89.9 mg; 376 µmol) in DMA (1.56 mL) N, N-diisopropylethylamine (545 µL; 3.14 mmol) was added. The reaction was sparged with N2 for 5 minutes, sealed and heated to 100 ° C. After 14 h, the resulting mixture was purified by HPLC prep to yield (3S, 4S) -8- {8 - [(2-amino-3-chloropyridin-4-yl) sulfanyl] imidazo [1,2-a] pyrazin-5-yl} -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine as the formic acid salt (15 mg, 31 µmol, 10% yield). 1H NMR (500 MHz, Methanol-d4) δ 8.55 (s; 1H); 7.99 (d; J = 1.3 Hz; 1H); 7.83 (d; J = 1.2 Hz; 1H); 7.72 (d; J = 5.5 Hz; 1H); 7.55 (s; 1H); 6.49 (d; J = 5.5 Hz; 1H); 4.36 - 4.27 (m; 1H); 3.96 (d; J = 8.9 Hz; 1H); 3.84 (d; J = 8.9 Hz; 1H); 3.53 - 3.42 (m; 3H); 3.31 (d; J = 4.6 Hz; 1H); 3.16 - 3.01 (m; 2H); 2.14 - 2.03 (m; 2H); 1.99 - 1.91 (m; 1H); 1.89 - 1.81 (m; 1H); 1.31 (d; J = 6.5 Hz; 3H). LC-MS (ESI): m / z: [M + H] calculated for C20H25ClN7OS: 446.2; found 446.2.
[0925] [0925] Example 83. Synthesis of (3S, 4S) -8- [12- (2,3-dichlorophenyl) - 3,6,8,10,11-pentaazatriciclo [7.3.0.0², ⁶] dodeca-1 ( 12), 2,4,7,9-pentaen-7-yl] -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine.
[0926] [0926] Step 1. Synthesis of 6-chloro-1H-pyrazolo [3,4-d] pyrimidin-4-
[0927] [0927] A mixture of 4,6-dichloro-1H-pyrazolo [3,4-d] pyrimidine (5 g; 26.4 mmol) in aqueous ammonia (100 mL, 25%) was stirred at room temperature for 12h. The reaction mixture was then filtered and the filter cake was purified by prep-HPLC to yield 6-chloro-1H-pyrazolo [3,4-d] pyrimidin-4-amine (3.4 g; 75% yield) as a white solid. LCMS (ELSD): m / z: [M + H] calculated for C5H5ClN5: 170.0; found 170.1; 1H NMR (400 MHz, DMSO-d6) δ 13.4 (s; 1 H) 8.19 (s; 1 H) 8.08 (s; 1 H) 8.04 (s; 1 H).
[0928] [0928] Step 2. Synthesis of 3-bromo-6-chloro-1H-pyrazolo [3,4-d] pi-rimidin-4-amine
[0929] [0929] To a solution of 6-chloro-1H-pyrazolo [3,4-d] pyrimidin-4-amine (1 g; 5.9 mmol) in DMF (40 ml) was added NBS (2.1 g; 11.8 mmol). The reaction was stirred at room temperature for 16 h, after which Na2S2O3 sat. (20 ml) and water (20 ml) were added. A white precipitate formed and filtered to yield 3-bromo-6-chloro-1H-pyrazolo [3,4-d] pyrimidin-4-amine (1.2 g; 82% yield).
[0930] [0930] Step 3. Synthesis of 9-bromo-5-chloro-7H-imidazo [1,2-c] pyrazolo [4,3-e] pyrimidine.
[0931] [0931] A mixture of 3-bromo-6-chloro-1H-pyrazolo [3,4-d] pyrimidin-4-amine (1.2 g, 4.83 mmol) and 2-chloroacetaldehyde (12 mL) was stirred at 100 ° C for 2 h. After cooling to room temperature and removing the excess reagent under reduced pressure, the crude residue was purified by reverse phase column chromatography to yield 9-bromo-5-chloro-7H-imidazo [1,2-c] pyrazole [ 4,3-e] pyrimidine (0.7 g; 53% yield). 1H NMR (500 MHz, DMSO-d6) δ 14.51 (s; 1 H) 8.06 (d; J = 1.6 Hz; 1 H) 7.60 (d; J = 1.6 Hz; 1 H).
[0932] [0932] Step 4. Synthesis of (3S, 4S) -8- (9-bromo-7H-imidazo [1,2-c] pyrazolo [4,3-e] pyrimidin-5-yl) -3-methyl- 2-oxa-8-azaspiro [4.5] decan-4-amine.
[0933] [0933] To a solution of 9-bromo-5-chloro-7H-imidazo [1,2-c] pyrazolo [4,3-e] pyrimidine (0.7 g, 2.6 mmol) in i- PrOH (28 mL) was added (3S, 4S) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine (749 mg; 3.1 mmol) bis-hydrochloride and DIEA (4, 5 ml; 25.6 mmol). The reaction was stirred at 110 ° C for 3 h, cooled to room temperature and concentrated under reduced pressure. The crude product was purified by prep-HPLC to yield (3S, 4S) -8- (9-bromo-7H-imidazo [1,2-c] pyrazolo [4,3-e] pyrimidin-5-yl) -3 -methyl-2-oxa-8-azaspiro [4.5] decan-4-amine (0.42 g; 40% yield). 1H NMR (500 MHz, Methanol-d4) δ 8.46 (s; 1H) 7.71 (d; J = 2.0 Hz; 1 H) 7.48 (d; J = 1.6 Hz; 1 H ) 4.32 - 4.29 (m; 1 H) 3.98 (d; J = 8.8 Hz; 1 H) 3.87 - 3.85 (m; 3 H) 3.46 (d; J = 4.0 Hz; 1 H) 3.24 - 3.16 (m; 2 H) 2.09 - 2.04 (m; 3 H) 1.96 - 1.93 (m; 1 H) 1, 82 - 1.79 (m; 1 H) 1.32 (d; J = 6.4 Hz; 13 H).
[0934] [0934] Step 5. Synthesis of (3S, 4S) -8- [12- (2,3-dichlorophenyl) - 3,6,8,10,11-pentaazatriciclo [7.3.0.0², ⁶] dodeca-1 ( 12), 2,4,7,9-pentaen-7-yl] -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine.
[0935] [0935] To a solution of (3S, 4S) -8- (9-bromo-7H-imidazo [1,2-c] pyrazolo [4,3-e] pyrimidin-5-yl) -3-methyl -2-oxa-8-azaspiro [4.5] decan-4-amine (0.25 g; 0.62 mmol) in DMSO (7.5 mL) boronic acid (2,3-dichlorophenyl) (1.53) g; 8.0 mmol), Na2CO3 (652 mg, 6.2 mmol) and Pd (PPh3) 4 (142 mg, 120 µmol). The reaction was heated to 110 ° C for 5 h, cooled to room temperature and filtered. The solvent was removed under reduced pressure and the crude residue was purified by prep-HPLC to yield (3S, 4S) -8- [12- (2,3-dichlorophenyl) -3,6,8,10,11-pen- taazatriciclo [7.3.0.0², ⁶] dodeca-1 (12), 2,4,7,9-pentaen-7-yl] -3-methyl-2-oxa- 8-azaspiro [4.5] decan-4-amine (6 mg, 2% yield). 1H NMR (500 MHz, Methanol-d4) δ 8.50 (s; 1 H) 7.71 - 7.67 (m; 2 H) 7.55 (d; J = 6.4 Hz; 1 H) 7 , 44 - 7.42 (m; 1 H) 7.35 (d; J = 1.6 Hz; 1 H) 4.33 - 4.28 (m; 1 H) 3.97 - 3.95 (m ; 1 H) 3.86 - 3.79 (m; 3 H) 3.36 -3.34 (m; 1 H) 3.30 - 3.22 (m; 1 H) 2.10 - 2.04 (m; 2 H) 1.95 - 1.91 (m; 1 H) 1.83 - 1.80 (m; 1 H)
[0936] [0936] Biological examples - SHP2 allosteric inhibition assay
[0937] [0937] Without sticking to the theory, SHP2 is allosterically activated by binding bis-tyrosyl phosphorylated peptides to its 2 Src 2 (SH2) homology domains. The last activation step leads to the release of the SHP2 self-inhibiting interface, which in turn makes the SHP2 protein tyrosine phosphatase (PTP) active and available for substrate recognition and reaction catalysis. The catalytic activity of SHP2 was monitored using the DiFMUP substitute substrate in an immediate fluorescence assay format.
[0938] [0938] Phosphatase reactions were carried out at room temperature on a 96-well black polystyrene plate, smooth bottom, unbound surface (Corning, Cat # 3650) using a final reaction volume of 100 µL and the following conditions of assay buffer: 50 mM HEPES, pH 7.2, 100 mM NaCl, 0.5 mM EDTA, 0.05% P-20, 1 mM DTT.
[0939] [0939] Inhibition of SHP2 by the compounds of the invention (concentrations ranging from 0.00005-10 µM) was monitored using an assay in which 0.2 nM SHP2 was incubated with 0.5 µM of activation peptide vation 1 (sequence: H2N-LN (pY) IDLDLV (dPEG8) LST (pY) ASINFQK-amide) or activation peptide 2 (sequence: H2N-LN (pY) AQLWHA (dPEG8) LTI (pY) ATIRRF-amide). After a 30-60- minute incubation at 25 ° C, the replacement substrate DiFMUP (Invitogen, Cat # D6567) was added to a reaction and the activity was determined by a kinetic reading using a microplate reader (En - vision, Perkin-Elmer or Spectramax M5, Molecular Devices). The excitation and emission wave lengths were 340 nm and 450 nm, respectively. The initial rates were determined from a linear fit of the data, and the dose-response curves of the inhibitor were analyzed using adjustment of the IC50 regression curve normalized with control-based normalization.
[0940] [0940] Using the above protocol, the SHP2 inhibition measured as shown in Table 1.
[0941] [0941] Table-1: SHP2 inhibition of tested compounds Compound SHP2 IC50, nM Compound 1 (Example 1) 1 Compound 6 (Example 6) 10 Compound 4 (Example 4) 29 Compound 2 (Example 2) 120
[0942] [0942] Using the above protocol, the SHP2 inhibition measured as shown in Table 2. In the table below: “+++” refers to <= 50nM; "++ 'refers to> 50nM to <= 500nM; and “+” refers to> 500nM.
[0943] [0943] Table-2: SHP2 inhibition of tested compounds. SHP2 IC50 compound, nM 1 +++ 2 ++ 3 + 4 +++
[0944] [0944] Equivalents
[0945] [0945] While the present invention has been described in conjunction with the specific modalities presented above, many alternatives, modifications and other variations thereof will be apparent to those skilled in the art.
All these alternatives, modifications and variations are intended to fall within the spirit and scope of the present invention.

权利要求:
Claims (49)
[1]
1. Compound characterized by the fact that it has Formula II ': or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer or isomer thereof, in which: A is cycloalkyl, heterocycloalkyl, aryl or heteroaryl, in which cycloalkyl - kyl, heterocycloalkyl, aryl and heteroaryl are monocyclic from 5 to 12 members or polycyclic from 5 to 12 members; R1 is independently, in each occurrence, –H, –C1-C6alkyl, –C2- C6alkenyl, –C4-C8cycloalkenyl, –C2-C6alquinyl, –C3-C8cycloalkyl, - OH, –OR6, halogen, –NO2, –CN, –NR5R6, –SR5, –S (O) 2NR5R6, - S (O) 2R5, –NR5S (O) 2NR5R6, –NR5S (O) 2R6, –S (O) NR5R6, –S (O) R5, - NR5S (O) NR5R6, –NR5S (O) R6, –C (O) R5, –CO2R5, –C (O) NR5R6, - NR5C (O) R6, monocyclic or polycyclic heterocyclyl, spiroheterocyclyl, heteroaryl, or oxo, where each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, heterocyclyl, spiroheterocyclyl or heteroaryl is optionally substituted with one or more –OH, halogen, –NO2, oxo, = O, –CN, −R5, –OR5, –NR5R6, −SR5, –S (O) 2NR5R6, –S (O) 2R5, - NR5S (O) 2NR5R6, –NR5S (O) 2R6, –S (O) NR5R6, –S (O) R5, - NR5S (O) NR5R6, –NR5S (O) R6, heterocycle, aryl or heteroaryl; Y1 is –S–, a direct link, –NH-, –S (O) 2-, –S (O) 2-NH-, –C (= CH2) -, - CH2-, or -S (O) -; X1 is N or CR2; X2 is N or CH; B, including the atoms at the points of attachment, is a 5 to 12 membered monocyclic or polycyclic heterocycle or a 5 to 12 membered monocyclic or polycyclic heteroaryl;
Y2 is –NRa–, - (CRa2) m–, –O–, –C (O) -, –C (Ra) 2NH–, - (CRa2) mO–, - C (O) N (Ra) -, –N (Ra) C (O) -, –S (O) 2N (Ra) -, –N (Ra) S (O) 2–, - N (Ra) C (O) N (Ra) -, - N (Ra) C (S) N (Ra) -, –C (O) O–, –OC (O) -, - OC (O) N (Ra) -, –N (Ra) C (O) O -, –C (O) N (Ra) O–, –N (Ra) C (S) -, - C (S) N (Ra) -, or –OC (O) O–; wherein the link on the left side of Y2, as shown, is attached to the ring and the link on the right side of the Y2 portion, as shown, is attached to R3; Ra is independently, at each occurrence, –H, –OH, –C3-C8cycloalkyl, –C1-C6alkyl, 3- to 12-membered heterocyclyl, or - (CH2) n-aryl, where each alkyl or cycloalkyl is optionally substituted with one or more –NH2, or where 2 Ra, together with the carbon atom to which they are attached, can combine to form a 3- to 8-membered cycloalkyl; Rb is independently, at each occurrence, –H, –OH, –C1-C6alkyl, –C3-C8cycloalkyl, –C2-C6alkenyl, - (CH2) n-aryl, heterocyclyl containing 1-5 heteroatoms selected from the group consisting of N, S, P and O, or heteroaryl containing 1-5 heteroatoms selected from the group consisting of N, S, P and O; where each alkyl, cycloalkyl, alkenyl, heterocycle, heteroaryl, or - (CH2) n-aryl is optionally substituted with one or more –OH, halogen, –NO2, oxo, –CN, −R5, –OR5, –NR5R6, −SR5, - S (O) 2NR5R6, –S (O) 2R5, –NR5S (O) 2NR5R6, –NR5S (O) 2R6, –S (O) NR5R6, –S (O) R5, –NR5S (O) NR5R6, –NR5S (O) R6, –C (O) NR5R6, –NR5C (O) R6, heterocycle, aryl, heteroaryl, - (CH2) nOH, –C1-C6alkyl, –CF3, –CHF2 or –CH2F; R2 is independently –H, –NH2, –ORb, –CN, –C1-C6alkyl, –C2- C6alkenyl, –C4-C8cycloalkenyl, –C2-C6alkynyl, halogen, - C (O) ORb, –C3-C8cycloalkyl, aryl , heterocyclyl containing 1-5 heteroatoms selected from the group consisting of N, S, P and O, or
eroaryl containing 1-5 heteroatoms selected from the group consisting of N, S, P and O; where each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more –OH, halogen, –NO2, oxo, −R5, –OR5, - NR5R6, −SR5, –S ( O) 2NR5R6, –S (O) 2R5, –NR5S (O) 2NR5R6, - NR5S (O) 2R6, –S (O) NR5R6, –S (O) R5, –NR5S (O) NR5R6, –NR5S (O ) R6, heterocycle, aryl or heteroaryl; R3 is independently –H, –C1-C6alkyl, a 3- to 12-membered monocyclic or polycyclic heterocycle, a 5- to 12-membered spiroheterocycle, C3-C8cycloalkyl, - (CH2) n-Rb, or - (CH2) nC (O) NR5R6, where each alkyl, spiroheterocycle, heterocycle, or cycloalkyl is optionally substituted with one or more –C1-C6alkyl, –OH, –NH2, –ORb, –NHRb, - (CH2) nOH, heterocyclyl, or spiroheterocyclyl ; or R3 can combine with Ra to form a 3 to 12 membered monocyclic or polycyclic heterocycle or a 5 to 12 membered spiroheterocycle, where each heterocycle or spiroheterocycle is optionally substituted with one or more –C1-C6alkyl, halogen, –OH, –ORb, –NH2, - NHRb, optionally substituted heteroaryl, optionally substituted heterocyclyl, - (CH2) nNH2, - (CH2) nOH, –COORb, –CONHRb, - CONH (CH2) nCOORb, - NHCOORb, -OC (O) -NR5R6, –CF3, –CHF2, - CH2F ou = O; wherein the heteroaryl and heterocyclyl are optionally substituted with –CN; R5 and R6 are independently, in each occurrence, –H, –C1- C6alkyl, –C2-C6alkenyl, –C4-C8cycloalkenyl, –C2-C6alkynyl, –C3- C8cycloalkyl, a monocyclic or polycyclic heterocycle of 3 to 12 members , –OR7, –SR7, halogen, –NR7R8, –NO2, –CF3, or –CN; R7 and R8 are independently, in each occurrence, –H, –C1- C6alkyl, –C2-C6alkenyl, –C4-C8cycloalkenyl, –C2-C6alkynyl, –C3- C8cycloalkyl, –ORb, or a monocyclic or polycyclic heterocycle from 3 to 3 12 members, where each alkyl, alkenyl, cycloalkenyl, alkynyl,
cycloalkyl, or heterocycle is optionally substituted with one or more –OH, –SH, –NH2, –NO2 or –CN; m is independently 1, 2, 3, 4, 5 or 6; and n is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; as long as when X2 is N and ring B is a 5-membered monocyclic heteroaryl containing 3-4 nitrogen atoms, then don't be, and as long as when X1 is N; X2 is CH and Y1 is NH; then R1 is not C3-C8cycloalkyl or heteroaryl.
[2]
2. A compound characterized by the fact that it has Formula VI: or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer or isomer thereof, in which: A is cycloalkyl, heterocycloalkyl, aryl or heteroaryl, in which cycloalkyl chyl, heterocycloalkyl, aryl and heteroaryl are monocyclic from 5 to 12 members or polycyclic from 5 to 12 members; R1 is independently, in each occurrence, –H, –C1-C6alkyl, –C2- C6alkenyl, –C4-C8cycloalkenyl, –C2-C6alquinyl, –C3-C8cycloalkyl, - OH, –OR6, halogen, –NO2, –CN, –NR5R6, –SR5, –S (O) 2NR5R6, - S (O) 2R5, –NR5S (O) 2NR5R6, –NR5S (O) 2R6, –S (O) NR5R6, –S (O) R5, - NR5S (O) NR5R6, –NR5S (O) R6, –C (O) R5, –CO2R5, –C (O) NR5R6, - NR5C (O) R6, monocyclic or polycyclic heterocyclyl, spiroheterocyclyl, heteroaryl or oxo, where each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, heterocyclyl, spiroheterocyclyl or heteroaryl is optionally substituted with one or more –OH, halogen, –NO2, oxo,
= O, –CN, −R5, –OR5, –NR5R6, −SR5, –S (O) 2NR5R6, –S (O) 2R5, - NR5S (O) 2NR5R6, –NR5S (O) 2R6, –S (O ) NR5R6, –S (O) R5, - NR5S (O) NR5R6, –NR5S (O) R6, heterocycle, aryl or heteroaryl; Y1 is –S–, a direct link, –NH-, –S (O) 2-, –S (O) 2-NH-, –C (= CH2) -, - CH2- or -S (O) - ; X1 is N or C; X2 is N or CH; X3 is N or C; B, including the atoms at the points of attachment, is a 5 to 12 membered monocyclic or polycyclic heterocycle or a 5 to 12 membered monocyclic or polycyclic heteroaryl; D, including the atoms at the points of attachment, is a 5- to 7-membered monocyclic heterocycle or a 5- to 7-membered monocyclic heteroaryl; Y2 is –NRa–, - (CRa2) m–, –O–, –C (O) -, –C (Ra) 2NH–, - (CRa2) mO–, - C (O) N (Ra) -, –N (Ra) C (O) -, –S (O) 2N (Ra) -, –N (Ra) S (O) 2–, - N (Ra) C (O) N (Ra) -, - N (Ra) C (S) N (Ra) -, –C (O) O–, –OC (O) -, - OC (O) N (Ra) -, –N (Ra) C (O) O -, –C (O) N (Ra) O–, –N (Ra) C (S) -, - C (S) N (Ra) -, or –OC (O) O–; wherein the link on the left side of Y2, as shown, is attached to the ring and the link on the right side of the portion of the Y2 portion, as shown, is attached to R3; Ra is independently, at each occurrence, –H, –OH, –C3-C8cycloalkyl, –C1-C6alkyl, 3- to 12-membered heterocyclyl, or - (CH2) n-aryl, where each alkyl or cycloalkyl is optionally substituted with one or more –NH2, or where 2 Ra, together with the carbon atom to which they are attached, can combine to form a 3- to 8-membered cycloalkyl; Rb is independently, in each occurrence, –H, –OH, –C1-C6alkyl, –C3-C8cycloalkyl, –C2-C6alkenyl, - (CH2) n-aryl, heterocyclyl containing 1-5 heteroatoms selected from the group consisting of
N, S, P and O, or heteroaryl containing 1-5 heteroatoms selected from the group consisting of N, S, P and O; where each alkyl, cycloalkyl, alkenyl, heterocycle, heteroaryl, or - (CH2) n-aryl is optionally substituted with one or more –OH, halogen, –NO2, oxo, –CN, −R5, –OR5 , –NR5R6, −SR5, –S (O) 2NR5R6, –S (O) 2R5, –NR5S (O) 2NR5R6, –NR5S (O) 2R6, –S (O) NR5R6, –S (O) R5, - NR5S (O) NR5R6, –NR5S (O) R6, - C (O) NR5R6, –NR5C (O) R6, heterocycle, aryl, heteroaryl, - (CH2) nOH, - C1-C6alkyl, –CF3, –CHF2 or –CH2F; R2 is independently –H, –NH2, –ORb, –CN, –C1-C6alkyl, –C2- C6alkenyl, –C4-C8cycloalkenyl, –C2-C6alkynyl, halogen, - C (O) ORb, –C3-C8cycloalkyl, aryl , heterocyclyl containing 1-5 heteroatoms selected from the group consisting of N, S, P and O, or heteroaryl containing 1-5 heteroatoms selected from the group consisting of N, S, P and O; where each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more –OH, halogen, –NO2, oxo, –CN, −R5, - OR5, –NR5R6, −SR5, –S (O) 2NR5R6, –S (O) 2R5, –NR5S (O) 2NR5R6, - NR5S (O) 2R6, –S (O) NR5R6, –S (O) R5, –NR5S (O) NR5R6, - NR5S (O) R6, heterocycle, aryl or heteroaryl; R3 is independently –H, –C1-C6alkyl, a 3- to 12-membered monocyclic or polycyclic heterocycle, a 5- to 12-membered spiroheterocycle, C3-C8cycloalkyl, or - (CH2) n-Rb, where each alkyl, spiroheter- cyclo, heterocycle, or cycloalkyl is optionally substituted with one or more –C1-C6alkyl, –OH, –NH2, –ORb, –NHRb, - (CH2) nOH, - (CH2) nC (O) NR5R6, heterocyclyl or spiroheterocyclyl; or R3 can combine with Ra to form a 3 to 12 membered monocyclic or polycyclic heterocycle or a 5 to 12 membered spiroheterocycle, where each heterocycle or spiroheterocycle is optionally substituted with one or more –C1-C6alkyl, halogen, –OH, –ORb, –NH2, -
NHRb, optionally substituted heteroaryl, optionally substituted heterocyclyl, - (CH2) nNH2, - (CH2) nOH, –COORb, –CONHRb, - CONH (CH2) nCOORb, –NHCOORb, -OC (O) -NR5R6, –CF3 , –CHF2, - CH2F ou = O; wherein the heteroaryl and heterocyclyl are optionally substituted with –CN; R5 and R6 are independently, in each occurrence, –H, –C1- C6alkyl, –C2-C6alkenyl, –C4-C8cycloalkenyl, –C2-C6alkynyl, –C3- C8cycloalkyl, a monocyclic or polycyclic heterocycle of 3 to 12 members , –OR7, –SR7, halogen, –NR7R8, –NO2, –CF3, or –CN; R7 and R8 are independently, in each occurrence, –H, –C1- C6alkyl, –C2-C6alkenyl, –C4-C8cycloalkenyl, –C2-C6alkynyl, –C3- C8cycloalkyl, –ORb, or a monocyclic or polycyclic heterocycle from 3 to 3 12 members, where each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl or heterocycle is optionally substituted with one or more –OH, –SH, –NH2, –NO2 or –CN; m is independently 1, 2, 3, 4, 5 or 6; and n is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.
[3]
3. Compound according to claim 1 or 2, characterized by the fact that Y1 is –S–.
[4]
4. Compound according to claim 1 or 2, characterized by the fact that Y1 is a direct bond.
[5]
5. Compound according to any one of claims 1 to 4, characterized by the fact that X1 is N.
[6]
6. Compound according to any one of claims 1 to 4, characterized by the fact that X1 is CR2.
[7]
7. A compound according to claim 6, characterized by the fact that R2 is –H, –NH2, -OH or –C1-C6alkyl.
[8]
8. Compound according to any one of claims 1 to 4, characterized by the fact that X2 is N.
[9]
9. Compound according to any one of claims 1 to 4, characterized by the fact that X2 is CH.
[10]
10. Compound according to any one of claims 1 to 4, characterized in that X1 is N and X2 is N.
[11]
11. Compound according to any one of claims 1 to 4, characterized by the fact that X1 is N and X2 is CH.
[12]
12. Compound according to any one of claims 1 to 4, characterized in that X1 is CR2 and X2 is N.
[13]
13. Compound according to any one of claims 1 to 4, characterized in that X1 is CR2 and X2 is CH.
[14]
A compound according to claim 12 or 13, characterized by the fact that R2 is -H, -NH2, -OH or -C1-C6alkyl.
[15]
15. A compound according to any one of claims 1 to 14, characterized by the fact that B, including the atoms at the connection points, is a monocyclic heteroaryl of 5 to 12 members.
[16]
16. Compound according to any one of claims 1 to 15, characterized by the fact that B, including the atoms at the points of attachment, is, where XB1 is N, CH, S or O; XB2 is N, CH, S or O; and XB3 is N, CH, S or O.
[17]
17. A compound according to any one of claims 1 to 15, characterized by the fact that B, including the atoms at the points of attachment, is, where XB4 is N or CH; XB5 is N or CH; XB6 is N or CH; and XB7 is N or CH.
[18]
18. A compound according to any one of claims 1 to 17, characterized by the fact that A is cycloalkyl.
[19]
19. A compound according to any one of claims 1 to 17, characterized by the fact that A is heterocycloalkyl.
[20]
20. Compound according to any one of claims 1 to 17, characterized in that A is aryl.
[21]
21. Compound according to any one of claims 1 to 17, characterized by the fact that A is phenyl.
[22]
22. A compound according to any one of claims 1 to 17, characterized by the fact that A is heteroaryl.
[23]
23. Compound according to any one of claims 1 to 17, characterized by the fact that A is pyridyl.
[24]
24. Compound according to any one of claims 1 to 23, characterized by the fact that R1 is independently –OH, –NO2, –CN, halogen or –NR5R6.
[25]
25. Compound according to any one of claims 1 to 24, characterized by the fact that Y2 is –NRa–.
[26]
26. Compound according to any one of claims 1 to 24, characterized by the fact that Y2 is - (CRa2) m–.
[27]
27. Compound according to any one of claims 1 to 26, characterized by the fact that Ra is –H.
[28]
28. Compound according to any one of claims 1 to 26, characterized by the fact that Ra is –C1-C6alkyl.
[29]
29. Compound according to any one of claims 1 to 28, characterized by the fact that R3 is –C1-C6alkyl.
[30]
30. A compound according to any one of claims 1 to 28, characterized by the fact that R3 is a 3 to 12 membered monocyclic or polycyclic heterocycle.
[31]
31. A compound according to any one of claims 1 to 28, characterized by the fact that R3 is a 3 to 12 membered monocyclic heterocycle.
[32]
32. A compound according to any one of claims 1 to 28, characterized by the fact that R3 is a 5 to 12 membered polycyclic heterocycle.
[33]
33. A compound according to any one of claims 1 to 26, characterized in that R3 and Ra together with the atom to which they are attached combine to form a 3- to 12-membered monocyclic heterocycle.
[34]
34. Compound according to any one of claims 1 to 26, characterized by the fact that R3 and Ra together with the atoms to which they are attached combine to form a 3- to 12-membered polycyclic heterocycle.
[35]
35. Compound according to any one of claims 1 to 26, characterized by the fact that R3 and Ra together with the atoms to which they are attached combine to form a 5- to 12-membered spiroheterocycle.
[36]
36. A compound according to any one of claims 33 to 35, characterized in that the heterocycle or spirocycle formed by R3 and Ra is substituted with one or more substituents selected from the group consisting of C1-C6alkyl, - OH, halogen, - NH2, –NHRb, –CF3, –CHF2 or –CH2F.
[37]
37. Compound, or a pharmaceutically acceptable salt, solvent, stereoisomer, or tautomer thereof, selected from the group characterized by the fact that it consists of: Compound 1 2
[38]
38. A compound, or a pharmaceutically acceptable salt, solvent, stereoisomer, or tautomer thereof, selected from the group characterized by the fact that it consists of:
(2), (1), (3),
(5), (4), (6),
(7), (9), (8),
(10), (11), (12),
(13), (14), (15),
(16), (17), (18),
(19), (20), (21),
(22), (23), (24),
(25), (26), (27),
(28), (29), (30),
(31), (32), (33),
(34), (35), (36),
(37), (38), (39),
(40), (41), (42),
(43), (44), (45),
(46), (47), (48),
(49), (50), (51),
(52), (53), (54),
(55), (56), (57),
(58), (59), (60),
(61), (62), (63),
(64), (65), (66),
(67), (68), (69),
(70), (71), (72),
(73), (74), (75), (76), (77), (78), (79), (81) (80), (82), and (83).
[39]
39. Pharmaceutical composition characterized by the fact that it comprises a compound as defined in any one of claims 1 to 38, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer or isomer thereof, and a pharmaceutically acceptable carrier .
[40]
40. Method of treating a disease associated with SHP2 modulation in an individual who needs it, characterized in that it comprises administering to the individual an effective amount of a compound as defined in any of claims 1 to 38, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer or isomer thereof.
[41]
41. Method according to claim 40, characterized by the fact that the disease is selected from Noonan syndrome, Leopard syndrome, juvenile myelomonocytic leukemias, neuroblastoma, melanoma, acute myeloid leukemia and cancers of the breast, lung and colon.
[42]
42. A compound according to any one of claims 1 to 38, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer or isomer thereof, characterized in that it is for use as a medicament.
[43]
43. A compound according to any one of claims 1 to 38, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer or isomer thereof, characterized in that it is for use in the treatment or prevention of a disease. - associated with SHP2 modulation.
[44]
44. Use of a compound as defined in any one of claims 1 to 38, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer or isomer thereof, in the manufacture of a medicament characterized by the fact that it is to treat or prevent a disease associated with SHP2 modulation.
[45]
45. Method of treating a disease associated with SHP2 modulation in an individual who needs it, characterized by the fact that it comprises administering to the individual an effective amount of a pharmaceutical composition as defined in claim 39.
[46]
46. Method according to claim 45, characterized by the fact that the disease is selected from Noonan syndrome, Leopard syndrome, juvenile myelomonocytic leukemias, neuroblastoma, melanoma, acute myeloid leukemia and cancers of the breast, lung and colon.
[47]
47. Pharmaceutical composition according to claim 39, characterized in that it is for use as a medicine.
[48]
48. Pharmaceutical composition according to claim 39, characterized in that it is for use in the treatment or prevention of a disease associated with SHP2 modulation.
[49]
49. Use of the pharmaceutical composition as defined in claim 39 in the manufacture of a medicament characterized by the fact that it is for treating or preventing a disease associated with SHP2 modulation.

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引用文献:

---

公开号 | 申请日 | 公开日 | 申请人 | 专利标题

---

---

US5262564A|1992-10-30|1993-11-16|Octamer, Inc.|Sulfinic acid adducts of organo nitroso compounds useful as retroviral inactivating agents anti-retroviral agents and anti-tumor agents|

---

EA201792205A1|2015-04-03|2018-02-28|Инсайт Корпорейшн|HETEROCYCLIC COMPOUNDS AS LSD1 INHIBITORS|

---

JP2020506178A|2017-01-23|2020-02-27|レヴォリューション・メディスンズ，インコーポレイテッド|Bicyclic compounds as allosteric SHP2 inhibitors|EP3463343A4|2016-05-31|2019-10-23|Board of Regents, University of Texas System|Heterocyclic inhibitors of ptpn11|

---

EA036446B1|2016-06-14|2020-11-11|Новартис Аг|Compounds and compositions for inhibiting the activity of shp2|

---

PE20190624A1|2016-07-12|2019-04-26|Revolution Medicines Inc|3-METIL PIRAZINAS 2,5-DISUSTITUIDAS AND 3-METIL PIRAZINAS 2,5,6-TRISUSTITUIDAS AS ALOSTERIC INHIBITORS OF SHP2|

---

CN110156786A|2018-02-13|2019-08-23|上海青煜医药科技有限公司|Pyrimido cycle compound and its preparation method and application|

---

CN112166110A|2018-03-21|2021-01-01|传达治疗有限公司|SHP2 phosphatase inhibitors and methods of use thereof|

---

BR112020022224A2|2018-05-02|2021-06-08|Navire Pharma, Inc.|ptpn11 substituted heterocyclic inhibitors|

---

CN112513050A|2018-07-24|2021-03-16|大鹏药品工业株式会社|Heterocyclic compounds inhibiting SHP2 activity|

---

SG11202100199UA|2018-08-10|2021-02-25|Navire Pharma Inc|6--3--2-methylpyrimidin-4-one derivatives and related compounds as ptpn11inhibitors for treating cancer|

---

EP3853233A1|2018-09-18|2021-07-28|Nikang Therapeutics, Inc.|Tri-substituted heteroaryl derivatives as src homology-2 phosphatase inhibitors|

---

EP3860717A1|2018-10-03|2021-08-11|Gilead Sciences, Inc.|Imidozopyrimidine derivatives|

---

CN111138412A|2018-11-06|2020-05-12|上海奕拓医药科技有限责任公司|Spiro aromatic ring compound and application thereof|

---

EP3878853A1|2018-11-07|2021-09-15|Shanghai Ringene BioPharma Co., Ltd.|Nitrogen-containing fused heterocyclic shp2 inhibitor compound, preparation method, and use|

---

JP2022509149A|2018-11-30|2022-01-20|上海拓界生物医薬科技有限公司|Derivatives of pyrimidines and 5-membered nitrogen heterocycles, their production methods, and their medical uses|

---

CN113795483A|2019-03-07|2021-12-14|默克专利有限公司|Carboxamide-pyrimidine derivatives as SHP2 antagonists|

---

TW202104194A|2019-04-08|2021-02-01|德商馬克專利公司|Pyrimidinone derivatives as shp2 antagonists|

---

CN111704611B|2019-07-25|2022-01-14|上海凌达生物医药有限公司|Aryl spiro SHP2 inhibitor compound, preparation method and application|

---

CN112300160A|2019-08-01|2021-02-02|上海奕拓医药科技有限责任公司|Spiro aromatic ring compound, preparation and application thereof|

---

EP3772513A1|2019-08-09|2021-02-10|C.N.C.C.S. S.c.a.r.l. Collezione Nazionale Dei Composti Chimici e Centro Screening|Shp2 inhibitors|

---

CN112574212A|2019-09-30|2021-03-30|上海拓界生物医药科技有限公司|Pyrimido five-membered nitrogen heterocyclic derivative, preparation method and medical application thereof|

---

CN110790711A|2019-11-29|2020-02-14|都创医药科技有限公司|Preparation method of 2-chloro-4-amino-6-methylpyrimidine compound|

---

WO2021121397A1|2019-12-19|2021-06-24|首药控股股份有限公司|Substituted alkynyl heterocyclic compound|

---

WO2021171261A1|2020-02-28|2021-09-02|Novartis Ag|A triple pharmaceutical combination comprising dabrafenib, an erk inhibitor and a shp2 inhibitor|

---

WO2021249449A1|2020-06-11|2021-12-16|Betta Pharmaceuticals Co., Ltd|Shp2 inhibitors, compositions and uses thereof|

---

WO2022017444A1|2020-07-24|2022-01-27|贝达药业股份有限公司|Shp2 inhibitor and composition and application thereof|

---

WO2022033430A1|2020-08-10|2022-02-17|深圳微芯生物科技股份有限公司|Heterotricyclic compound, preparation method therefor and use thereof|

法律状态:
2021-12-07| B350| Update of information on the portal [chapter 15.35 patent gazette]|

优先权:

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申请号 | 申请日 | 专利标题

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US201762599583P| true| 2017-12-15|2017-12-15|

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US62/599,583|2017-12-15|

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US201862678891P| true| 2018-05-31|2018-05-31|

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US62/678,891|2018-05-31|

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PCT/US2018/065817|WO2019118909A1|2017-12-15|2018-12-14|Polycyclic compounds as allosteric shp2 inhibitors|

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