pyrazolopyrimidinone compounds and uses thereof

专利摘要:
  The present invention relates to pyrazolopyrimidinone compounds. The present invention also relates to pharmaceutical compositions containing such compounds and methods of treating autoimmune, inflammatory and neurodegenerative diseases by administering these compounds and pharmaceutical compositions to individuals in need thereof. The present invention also relates to the use of such compounds for research or other non-therapeutic purposes.
公开号:BR112020003676A2
申请号:R112020003676-5
申请日:2018-09-14
公开日:2020-09-01
发明作者:Chudi Obioma NDUBAKU；Mariam ZAKY；Laura GILLARD；Hossein ISMAILI；George Edwin Katibah；Tucker Curran Roberts；Leonard Sung；Stephane Ciblat；Franck Raeppel；Vu Linh Ly；Yeeman K. Ramtohul；Taras RYBAK
申请人:Aduro Biotech, Inc.；
IPC主号:

专利说明:

[001] [001] This application claims priority and benefit from U.S. Provisional Applications 62 / 559,482, filed on September 15, 2017; 62 / 633,248, filed on February 21, 2018; and 62 / 687,769, filed on June 20, 2018, the content of which is incorporated herein by reference in its entirety. BACKGROUND
[002] [002] The enzyme GMP-AMP cyclic synthase (CGAS) catalyzes the synthesis of cyclic GMP-AMP (CGAMP) from ATP and GTP in the presence of DNA. This cCGAMP then functions as a second messenger that binds and activates the interferon gene stimulator (STING). The activation of IRF3 and NF-KB signaling by this route results in the production of cytokines and interferons of type |, which trigger an innate immune response to bacterial or viral infection. Genetic mutations that alter the balance of this pathway can result in increased activation of the STING pathway, resulting in autoimmune and inflammatory diseases. For example, a loss-of-function mutation in the TREX1 exo-nuclease, which digests DNA, can result in an accumulation of auto-DNA in the cytosol, leading to excessive levels of CGAMP produced by cGAS and elevated expression of induced genes. interferon in this pathway. The mutations in TREX1 are associated with systemic inflammatory diseases, such as the Aicardi-Goutieres syndrome, familial lupus pernio and systemic lupus erythematosus. Trex ”mice have been shown to exhibit autoimmune and inflammatory phenotypes that are eliminated with the genetic exclusion of cGas in these mice (Gao et al., PNAS 112 (42): E5699-705, 2015; Gray et al., The Journal of Immunology 195: 1939-1943, 2015). Thus, inhibitors of the CGAS / STING pathway are needed to treat a variety of diseases. SUMMARY
[003] [003] The present invention provides the compounds of formula (1): o 1 YA R
[004] [004] Y is -CR = Or -N =;
[005] [005] R 'is Q-TI- (X') n;
[006] [006] Q 'is a bond or C1-3 alkylene, in which the C1-3 alkylene group is optionally substituted with one or more substituents independently selected from the group consisting of ha, C1-6 alkyl, C2.6 alkenyl, C2.6 alkynyl, cyano, C1-6 haloalkyl, - OR ” and -NRY2R *;
[007] [007] T 'is Ca.8 cycloalkyl, Ce-10 aryl, 3 to 12 membered heterocycloalkyl, 5 to 10 membered heteroaryl, -C (= O) Co-3 alkylene-C3-8 cycloalkyl, -C (= O) -Co-.3 alkylene-Ce-10 aryl, -C (= O0) -Co-3 alkylene-heterocycloalkyl from 3 to 12 members, -C (= O) -Co-3 alkylene-heteroaryl from 5 to 10 members, -NRºRº, -S (= O) 2Rº, -NRºC (= O) Rº, -NRºC (= 0O) NRºR , -NRºC (= O) ORº, -NRºS (= O) .Rº, -C ( = O) NRºS (= O) Rº, - NRºS (= O) aNRºRº, -C (= O) NRºRº or -S (= O) aNRºRº;
[008] [008] each X 'is independently selected from the group consisting of halo, cyano, oxo, Co.3 alkylene-C (= O) Rº, Thigh alkylene-ORº, Co.3 alkylene-C (= O0 ) OR "º, Co.3 alkylene-OC (= O) Rº, Co-3a alkylene-NRºR $, Co.3a alkylene-N * RºRIRº, Co.3 alkylene-S (= O) nRº, Co3 al - kilene-NRºC (= O) Rº, Co.3 alkylene-NRºC (= O) NRºR $, Co.3 alkylene-OC (= O) NRºR $ º, Co.3a alkylene-NRºC (= 0) ORº, Co .3 alkylene-NRºS (= O) 2Rº,
[009] [009] and each R $ * º is optionally substituted with one or more substituents independently selected from the group consisting of halo, cyano, nitro, oxo, C1-6 alkyl, C2.6 alkenyl, Ca.6 alkynyl , C1.6 haloalkyl, Co.3 alkylene-NRºRÍ, Co.3 alkylene-ORº, Co-3 alkylene-NRºC (= O) Rº, Co.3 alkylene-NRºC (= 0O) ORº, Cos alkylene-NRºC (= O) NRºRÍ, Co.3 alkylene-OC (= O) Rº, Co.3 alkylene-C (= 0) OR "º, Cos alkylene-C (= O) NRºR ', Cos alkylene-C (= O) Rº , Cos alkylene-S (= O) mRº, Co.3 alkylene-S (= O) 2aNRºRÍ, Co.3 Algylene-NRºS (= O) 2Rº, Co-3 alkylene-C (= O) NRºS (= O) 2Rº, Co.3 alkylene-NRºS (= O) NRºR 'and Rº , Where R $ Is Co3 alkylene-Ca.8 cycloalkyl, Co-3 alkylene-Ce-10 aryl, Co-3 alkylene-heterocycloalkyl of 3 to 12 members, or Co3 alkylene-heteroaryl of 5 to 10 members,
[0010] [0010] and each R * º is optionally substituted with one or more substituents independently selected from the group consisting of halo, oxo, C1-6 alkyl, C2.6 alkenyl, C2-6 alkynyl, cyano, C1-6 haloalkyl , -OR "and -NR“ R ';
[0011] [0011] R is Q2-T2- (X ) ,;
[0012] [0012] Q is a bond or C1-3 alkylene, where the C1-3 alkylene group is optionally substituted with one or more substituents independently selected from the group consisting of ha, C1-6 alkyl, C2.6 alkenyl, C2.6 alkynyl, cyano, C1-6 haloalkyl, - OR ”and -NR“ R;
[0013] [0013] T is H, halo, cyano, C1.6 alkyl, Ca.6 alkenyl, C2.6 alkynyl, C3-.8 cycloalkyl, Ce-10 aryl, 3 to 12 membered heterocycloalkyl, hetero-
[0014] [0014] every X is independently selected from the group consisting of halo, cyano, oxo, Co-3 alkylene-OR ", Co.3 alkylene-S (= O) MmR", Co.3 alkylene-NR "Rº, Co.3a alkylene -C (= O) NR "Rº, Thigh alkylene-C (= O0) OR" and R $, where R $ is C1.6 alkyl, C2.6 alkenyl, Ca.6 alkynyl, Co -3 alkylene-C3a.8 cycloalkyl, Co-3 alkylene-Ce-10 aryl, Co-3a alkylene-heterocycloalkyl of 3 to 12 members, or Co.3 alkylene-heteroaryl of 5 to 10 members;
[0015] [0015] and R $ is optionally substituted with one or more substituents independently selected from the group consisting of halo, oxo, cyano, Co.a alkylene-OR , Co-3 alkylene-S (= O ) mnRº, Co-3 alkylene-NRPR9, Co.3 alkylene-C (= O) NRPR9, Co.3a alkylene-Co-3 alkylene-C (= O0) ORP, C1-6 alkyl, C2.6 someone , C2.6 alkynyl, C1-.6 haloalkyl and R $, where R * º is Co. alkylene-Ca.8 cycloalkyl, Co.a alkylene-Ce-10 aryl, Co-.3 alkylene-heterocycloalkyl from 3 to 12 members, or Co-3 alkylene-heteroaryl of 5 to 10 members;
[0016] [0016] and each R * º is optionally substituted with one or more substituents independently selected from the group consisting of halo, oxo, C1-6 alkyl, C2.6 alkenyl, C2-6 alkynyl, cyano, C1-6 haloalkyl , -OR ”º and -NRYMRX;
[0017] [0017] Rº is C1.3 alkyl, C1.3 haloalkyl, C2.3 algenyl, C2.3 alkynyl, Ca6 cycloalkyl, -CN, -OR "', -C (= O) R', -S ( = O) mR ', NR'R' or - C (= 0) OR ", where C1-3 alkyl, C2.3 alkenyl and C2.3 alkynyl are optionally substituted with a cycloalkyl Ca;
[0018] [0018] Rº is C1.6 alkyl, C1-6 haloalkyl, S (= O) mR ", Co.3a alkylene-C3-68 cycloalkyl, Co-3 alkylene-Ce-10 aryl, Co.a alkylene-heterocycle
[0019] [0019] each of Rº and Rº, independently, is H or RS, where R $ is C1.6 alkyl, Ca.6 alkenyl, Ca.6 alkynyl, Co.3 alkylene-C3-8 cycloalkyl, Co-3 alkylene-CCE-10 aryl, Co-3 alkylene-heterocycloalkyl of 3 to 12 members, or Co.3 alkylene-heteroaryl of 5 to 10 members;
[0020] [0020] and R $ is optionally substituted with one or more substituents independently selected from the group consisting of halo, cyano, oxo, C1-.6 haloalkyl, Co-3 alkylene-ORº , Co.3 alkylene- C (= O) Rº , Co.3 alkylene-C (= 0) ORº , Co.3 alkylene-OC (= O) Rº , Co.3 alkylene-C (= O) NRºR% , Co.3 alkylene-S (= O) nR , Co.3 alkylene-S (= O) 2 NRº2R% º, Co3 alkylene-NRº2R , Co.3 alkylene-NRº2C (= O) Rº , Co. al - kilene-NRº2C (= 0) OR, Co.3a alkylene-NRº2C (= O) NRº2Rº, Co.a alkylene-NRºS (= O0) 2Rº, Co alkylene-C (= O) NRºPS (= 0) 2R , Co.3 alkylene-NRº2S (= O) toNRºº2R%, Co.3 alkylene-N (S (= O) 2Rº), and R $ 6, where R * $ º is C1-6 alkyl, C2. 6 alkenyl, C2.6 alkynyl, Co-3 alkylene-C3-8 cycloalkyl, Co-3 alkylene-Ce-10 aryl, Co.3 alkylene-heterocycloalkyl of 3 to 12 members, or Co.3 alkylene-heteroaryl of 5 to 10 members;
[0021] [0021] and each RS is optionally substituted with one or more substituents independently selected from the group consisting of halo, cyano, oxo, C1-6 alkyl, C2.6 alkenyl, C2.6 alkynyl, C1-6 haloalkyl, Co -a algylene-NRº2R , Co.3 alkylene-OR , Co.3 alkylene-NRº2C (= O) Rº, Co.3 alkylene-NRº2C (= 0) OR, Co.3 alkylene-NRºº * C (= O) NRºR , Co.3 alkylene-OC (= O) Rº, Co.a alkylene-C (= O) ORº, Co.3 alkylene-C (= O) NRºR , Co3 alkylene-C ( = O) R% º, Co.3 alkylene-
[0022] [0022] and each R $ ”is optionally substituted with one or more substituents independently selected from the group consisting of halo, oxo, C1-6 alkyl, C2.6 alkenyl, C2-6 alkynyl, cyano, C1-6 haloalkyl , -OR “6 and -NRY6R * 6:
[0023] [0023] each of Rº, Rº2, Ri, Rº and Rº, independently, is H or R $, where R $ is C1.6 alkyl, C2.6 alkenyl, C2.6 alkynyl, Co-3 alkylene-C3 -8 cycloalkyl, Co-3 alkylene-Ce-10 aryl, Cos alkylene-heterocycloalkyl of 3 to 12 members, or Thigh alkylene-heteroaryl of 10 members;
[0024] [0024] and each R $ is optionally substituted with one or more substituents independently selected from the group consisting of halo, cyano, oxo, C1-6 alkyl, C2.6 alkenyl, C2.6 alkynyl, C1-6 haloalkyl, Co-3 alkylene-NRºR8, Co.3 alkylene-OR, Co.3 alkylene-C (= 0) OR, Co.3 alkylene-C (= O) NRº% ºR8, Co.3 alkylene-C (= O) Rº, Co.3 alkylene-S (= O) nmRº%, Co.3a alkylene-S (= O) aNRººRº, Co.3 alkylene- NR $ EC (= O) R, Co.3 alkylene-NRES ( = O) nR% and R $ ºº, where R * º is Co3 alkylene-C3-8 cycloalkyl, Co-3 alkylene-Ce-10 aryl, Cos alkylene-heterocycloalkyl of 3 to 12 members, Co-3 alkylene-heteroaryl from 5 to members;
[0025] [0025] and each Rº is optionally substituted with one or more substituents independently selected from the group consisting of halo, oxo, C1-6 alkyl, C2.6 alkenyl, C2-6 alkynyl, cyano, C1-.6 haloalkyl, -OR “ and -NRYW / RY ";
[0026] [0026] each of Rº, Rº, Rº, R (, Rº and R $, independently, is H or R $ 'º, where R $ * º is C1.6 alkyl, C2.6 alkenyl, Ca .6 al-
[0027] [0027] and each R $ * º is optionally substituted with one or more substituents independently selected from the group consisting of halo, oxo, C1-6 alkyl, C2.6 alkenyl, C2-6 alkynyl, cyano, C1-6 haloalkyl, -OR "$ and -NRY6R *;
[0028] [0028] each of RK * and R "", is independently selected from the group consisting of R $, -ORK, and-NRKR ";
[0029] [0029] each of RK and R ", independently, is H or Rº , where R" is C1.6 alkyl, C2.6 alkenyl, C2.6 alkynyl, Co-3 alkylene-C3-8 cycloalkyl, Co -3 alkylene-CCE-10 aryl, Co-3 alkylene-heterocycloalkyl of 3 to 12 members, or Co.3 alkylene-heteroaryl of 5 to 10 members;
[0030] [0030] and each Rº is optionally substituted with one or more substituents independently selected from the group consisting of halo, cyano, oxo, C1-6 alkyl, C2.6 alkenyl, C2.6 alkynyl, C1-6 haloalkyl, Co -a algylene-NR "2Rº , Co.3 algylene-OR” , Co.3 alkylene-C (= 0) OR ”, Co.3 alkylene-C (= O) NR" 2Rº , Co. 3 C-alkylene (= O) R ”, Co3 alkylene-S (= O) nR", Co.3 alkylene-S (= O) aNR "2Rº and R $ *!, in which R $! is Co.3 alkylene-C3.6 cycloalkyl, Co-3 alkylene-Ce-10 aryl, Co.3 alkylene-heterocycloalkyl of 3 to 12 members, Co-3a alkylene-heteroaryl of 5 to 10 members;
[0031] [0031] and each R $ ** is optionally substituted with one or more substituents independently selected from the group consisting of halo, oxo, cyano, Co.3 alkylene-ORP , Co.3 alkylene-S (= O) mRP , Co-3 alkylene-NRP2R * , Co.3a alkylene-C (= O) NRP2R *, Co-3 alkylene-Co-3 alkylene-C (= 0) ORP , C1-6 alkyl, Ca. 6 alkenyl, C2.6 alkynyl, C1-.6 haloalkyl and R $ * , In which R $ is Co.3 alkylene-C3a.8 cycloalkyl, Co-3 alkylene-Ce-10 aryl, Co-3 alkylene-heterocycloalkyl of 3 to 12 members, or Co.3 alkylene-heteroaryl of 5 to 10 members;
[0032] [0032] each R $ '* is optionally substituted with one or more substituents independently selected from the group consisting of halo, oxo, C1-6 alkyl, C2.6 alkenyl, C2-6 alkynyl, cyano, C1-6 haloalkyl, -OR "“ º e - NRY9R *;
[0033] [0033] each of Rº, Rº, Rº and Rº, independently, is H or R $ * 3, in which R $ is C1.6 alkyl, Ca.6 alkenyl, Ca.6 alkynyl, Co-3 alkylene-C3.8 cycloalkyl, Co.3 alkylene-Ce-10 aryl, Co3 alkylene-heterocycloalkyl of 3 to 12 members, or Thigh alkylene- 10-membered heteroaryl;
[0034] [0034] each R $ * is optionally substituted with one or more substituents independently selected from the group consisting of halo, oxo, cyano, Co.3 alkylene-ORP, Co.3 alkylene-S (= O) mRP, Co.3 alkylene-NRPºR, Co .3 alkylene-C (= O) NRPºRB, Co3 alkylene-C (= 0) OR ", C1.6 alkyl, C2.6 alkenyl, C2.6 alkynyl, C1-6 haloalkyl and R $ * º, in that R $ ** is Co.3 alkylene-Ca.6 cycloalkyl, Co-3 alkylene-CCE-10 aryl, Co-3 alkylene-heterocycloalkyl from 3 to 12 members, or Co-3 alkylene-heteroaryl from 5 to 10 members;
[0035] [0035] each R $ ** is optionally substituted with one or more substituents independently selected from the group consisting of halo, oxo, C1-6 alkyl, C2.6 alkenyl, C2-6 alkynyl, cyano, C1-6 haloalkyl , -ORY1st and -NRW10RX10:
[0036] [0036] each of RP, RP , RPº, R9, Rº and R%, independently, is H or R5 $ '5, where R ** ** is C1.6 alkyl, C2.6 alkenyl, Ca .6 alkynyl, Co-3 alkylene-C3-38 cycloalkyl, Co-3 alkylene-Ce-10 aryl, Co-3 alkylene-heterocycloalkyl from 3 to 12 members, or Cos3 alkylene-heteroaryl from 5 to 10 members ;
[0037] [0037] each R $ '** is optionally substituted with one or more substituents independently selected from the group consisting of halo, oxo, C1-6 alkyl, C2.6 alkenyl, C2-6 alkynyl, cyano, C1-6 haloalkyl, -OR * !! and -NRW1IRX11;
[0038] [0038] each of R ', R' and Rº, independently, is H or R $ '6, where R $' 6 is C1.6 alkyl, C2.6 alkenyl, C2.6 alkynyl, Co-3 here - leno-C3-8 cycloalkyl, Co-3 alkylene-Ce-10 aryl, Co.3a alkylene-heterocycloalkyl of 3 to 12 members, or Co3 alkylene-heteroaryl of 5 to 10 members;
[0039] [0039] and each R $ 'º is optionally substituted with one or more substituents independently selected from the group consisting of halo, oxo, C1-6 alkyl, C2.6 alkenyl, C2-6 alkynyl, cyano, C1-6 haloalkyl, -C (= 0) ORY! 2, -OR "! and -NRW12RX12:
[0040] [0040] each Rº, R2, Rus, RW4, Rus, RW6, RW ", RW8, Ru9, Rwio Rw! 1, RW12, Rx, Rº, Re, RM, RS, RO, RO Re Rx Rx10 Rx11 is RX12 indepen - dentically, it is H, C1-6 alkyl, C2.6 alkenyl, C2.6 alkynyl or C1-6 haloalkyl;
[0041] [0041] each of n and p independently is O, 1, 2, 3,4, or 5, where when T 'is H, foot 0; and
[0042] [0042] is 0oO, 1, or2;
[0043] [0043] with the proviso that, for compounds where Y is -CRº =:
[0044] [0044] a) when R 'is unsubstituted phenyl, R is methyl and Rº is methyl, Rº is not ethyl, unsubstituted phenyl or unsubstituted pyridine;
[0045] [0045] b) when R 'is unsubstituted cyclohexyl, R is methyl and Rº is methyl, Rº is not unsubstituted pyridine;
[0046] [0046] c) when R is unsubstituted cyclopentyl, R is methyl and R3 is methyl, Rº is not ethyl or unsubstituted pyridine,
[0047] [0047] d) when R for methyl, R $ for methyl and Rº for 3,4-di-ethoxy-phenyl, R 'is not 1-substituted 1-pyrrolidine, 1-substituted 1-piperidine, 4-methyl-1-piperidine, 4- (phenylmethyl ) -1-piperidine, 2-1,2,3,4-tetrahydro-isoquinoline unsubstituted, unsubstituted morpholine, or NHCH2CH> 2-3-indole;
[0048] [0048] e) when R1 is CH> 2-unsubstituted phenyl, R for methyl and
[0049] [0049] f) when R for methyl, Rº for methyl and Rº for unsubstituted pyridine, R 'is not CH2-phenyl, where phenyl is substituted with 4-CN, 4-NO;>, 4-F or 2-F;
[0050] [0050] g) when R for methyl, Rº for methyl and Rº for ethyl, R 'is not CH2-phenyl, where phenyl is replaced with 4-CN or 4-NO;>;
[0051] [0051] h) when R for methyl, Rº for methyl and Rº for 4-methoxy-phenyl, R 'is not CH> -phenyl, where phenyl is substituted with 2-Cl, 3-Cl, 4-Br, 2-methyl or 4-methyl ;
[0052] [0052] i) when R for methyl, Rº for methyl and Rº for unsubstituted phenyl, R 'is not CH7z-phenyl, where phenyl is substituted with 2-Cl, 3-Cl, 4-CIl, 4-Br, 2-methyl, 3- methyl, 4-methyl, 4-isopropyl or 4-tert-butyl; or R 'is not unsubstituted CH2-1-naphthylene or unsubstituted CH2-pyridine;
[0053] [0053] j) when R for methyl, Rº for methyl and Rº for 4-Cl-phenyl, R 'is not CH7-phenyl, where phenyl is replaced with 2-Cl, 4-CI or 4-isopropyl;
[0054] [0054] k) when R 'is CH> -substituted phenyl, R for methyl and R3 for trifluoromethyl, Rº is not unsubstituted phenyl or phenyl substituted with 2-Cl or 4-Cl;
[0055] [0055] |) the compound is not in which R 'is CH2-4-Br-phenyl, Rº is methyl, Rô is ethyl and Rº is unsubstituted phenyl;
[0056] [0056] m) when R is methyl, Rº is methyl and Rº is unsubstituted phenyl, R 'is not CH2CH2C (= O) NH-phenyl, in which the phenyl ring is unsubstituted or is substituted in position 4 with CI, methyl or methoxy;
[0057] [0057] n) when R is methyl or ethyl, Rº is methyl and Rº is unsubstituted phenyl, R 'is unsubstituted pyrazolo [1,5-a] pyrimidin-7-yl;
[0058] [0058] o) when R for H, R $ for isopropyl and Rº for methyl, R 'is not unsubstituted pyrazole; and
[0059] [0059] p) the compound is not in which R 'is CH7-unsubstituted phenyl, R is H, Rô is methyl and Rº is unsubstituted phenyl; and
[0060] [0060] with the proviso that, for compounds where Y is -N =, the compound is not in which R 'is unsubstituted phenyl, Ré He Rº is 2-fluoro-phenyl.
[0061] [0061] For example, the compound can be of Formula (IA) or Formula (IA '): o o' NOR NOR RH (lJouj Rº (IA).
[0062] [0062] For example, Q 'is a bond or -CH2- and T' is Ca.8 cycloalkyl, Ce-10 aryl, 3 to 12 membered heterocycloalkyl, 5 to 10 membered heteroaryl or -C (= O ) NRºRº.
[0063] [0063] For example, Q 'is a bond and T' is C3a.8 cycloalkyl, Ce-10 aryl, 3 to 12 membered heterocycloalkyl, or 5 to 10 membered heteroaryl.
[0064] [0064] For example, Q 'is a link and T'! it is Ce-10 aryl, 3 to 12 membered heterocyclylalkyl, or 5 to 10 membered heteroaryl.
[0065] [0065] For example, Q 'is a bond and T' is phenyl, 5 or 6 membered monocyclic heteroaryl, or 9 or 10 membered bicyclic heteroaryl, preferably, where T 'is 9 or 10 membered bicyclic heteroaryl.
[0066] [0066] For example, Q 'is a bond or -CH2-, Tº is -C (= O) NRºRº and enéo.
[0067] [0067] For example, one of Rº and Rº is H or methyl and the other of Rº and Rº is not H or methyl.
[0068] [0068] For example, Rº is Q2-T2- (Xº) ,, O is a connection, Tº is H,
[0069] [0069] For example, Rº is Q2-T2- (Xº) ,, O is a bond, Tº is H, halo, cyano, C1-.6 alkyl, C1-6 haloalkyl, C2.6 alkenyl, or C2-6 alkynyl, and each X independently it is halo or OC1-: alkyl.
[0070] [0070] For example, R is H, cyano, methyl or methoxymethyl.
[0071] [0071] For example, R is H, methyl or methoxymethyl.
[0072] [0072] For example, Rº is C13 alkyl, C1.3 haloalkyl, -CN, - S (= O0) 2C1-3 alkyl or -C (= 0) OC1-3 alkyl.
[0073] [0073] For example, R is -CN, C1.3 alkyl, C1.3 haloalkyl or - C (= 0) OC1 + 3 alkyl.
[0074] [0074] For example, Rº is C13 alkyl, C1.3 haloalkyl or - C (= 0) OC1 + 3 alkyl.
[0075] [0075] For example, Rº is -CF3, methyl or -C (= 0) OC1-3 alkyl.
[0076] [0076] For example, Rô is -CF3 or -CN.
[0077] [0077] For example, Rº is -CF; 3
[0078] [0078] For example, R is -CN.
[0079] [0079] For example, Rº is C1.3 alkyl, C1-3 haloalkyl, -S (= O) 2C1-3 alkyl, C3-8 cycloalkyl, Ce-10 aryl, 3 to 12 membered heterocycloalkyl, or heteroaryl of 5 to 10 members, where C3.6 cycloalkyl, Ce-10 aryl, 3 to 12 membered heterocycloalkyl, or 5 to 10 membered heteroaryl are optionally substituted with 1-3 substituents selected from the group consisting of halo, oxo, C1-6 alkyl, C2-6 alkenyl, C2.6 alkynyl, cyano, C1-6 haloalkyl, -OR “and -NR“ R *,
[0080] [0080] For example, Rº is C3.8 cycloalkyl, Ce-10 aryl, heterocycloal-
[0081] [0081] For example, Rº is Ca.8 cycloalkyl or Ce-10 aryl, where C3-8 cycloalkyl and Ce-10 aryl are optionally substituted with 1-3 substitutes selected from the group consisting of halo, oxo , C1-6 alkyl, Ca.6 alkenyl, Ca.6 alkynyl, cyano, C1.6 haloalkyl, -OR "e - NR * R *, where R" º and R "are independently H, C1.6 alkyl or C1-6 haloalkyl.
[0082] [0082] For example, Rº is phenyl optionally substituted with 1-3 substituents selected from the group consisting of halo, oxo, C1-6 alkyl, Ca.6 alkenyl, C2.6 alkynyl, cyano, C1-.6 haloalkyl , -OR “* and -NR“ SR *, where R ”º and R * are independently H, C1-6 alkyl or C1-6 haloalkyl.
[0083] [0083] For example, Rº is Ca.8cycloalkyl.
[0084] [0084] For example, Rº is cyclopentyl.
[0085] [0085] For example, Rº is phenyl.
[0086] [0086] For example, the compound can be of Formula (la) or Formula (la '): o "1
[0087] [0087] For example, Q 'is a bond or -CH2- and T' is Ca.8 cycloalkyl, Ce-10 aryl, 3 to 12 membered heterocycloalkyl, 5 to 10 membered heteroaryl or -C (= O ) NRºRº.
[0088] [0088] For example, Q 'is a bond and T' is Ca.8 cycloalkyl, Ce-10 aryl, 3 to 12 membered heterocycloalkyl, or 5 to 10 membered heteroaryl.
[0089] [0089] For example, Q 'is a bond and T' is Ce-10 aryl, 3 to 12 membered heterocycloalkyl, or 5 to 10 membered heteroaryl.
[0090] [0090] For example, Q 'is a bond and T' is phenyl, 5 or 6 membered monocyclic heteroaryl, or 9 or 10 membered bicyclic heteroaryl, preferably where T 'is 9 or 10 membered bicyclic heteroaryl.
[0091] [0091] For example, Q 'is a bond or -CH2-, T is -C (= O) NRºRº and enéo.
[0092] [0092] For example, one of Rº and Rº is H or methyl and the other of Rº and Rb is not H or methyl.
[0093] [0093] For example, right, O.
[0094] [0094] For example, T 'is aryl or heteroaryl, preferably phenyl, monocyclic heteroaryl of 5 or 6 members, or bicyclic heteroaryl of 9 or 10 members.
[0095] [0095] For example, T 'is a 5 to 10 membered heteroaryl.
[0096] [0096] For example, T 'is pyridinyl, pyrazinyl, pyridazinyl, pyrimidine, indolyl, indolinyl, isoindolyl, isoindolinyl, indazolyl, pyrazolopyridine, pyrazolopyrimidinyl, oxazolopyrimidyl, oxazolopyrimidine, benzazidine, oxazol, pyridine, benzine , dihydrobenzofuranyl, isobenzofuranyl, dihydroisobenzofuranyl, triazolo-pyridinyl, benzothiazolyl, azabenzimidazolyl, azabenzoxazolyl, aza-benzothiazolyl, imidazopyridinyl, quinolinyl, isoquinyloxy, isoquinol, thylazol, zolazole -hydro-oxazoloazepinyl, tetrahydrobenzoxazolyl, oxadiazolyl, thiadiazolyl, pyrazolyl, triazolyl, imidazolyl, furanyl or thiophenyl.
[0097] [0097] For example, T 'is pyridinyl, pyrazinyl, pyridazinyl, pyrimidine-
[0098] [0098] For example, T 'is Co-1 alkylene-Ce-10 aryl.
[0099] [0099] For example, T 'is phenyl, benzyl, naphthyl, or CHonaftila.
[00100] For example, T 'is 3 to 12 membered heterocycloalkyl, preferably 4 to 10 membered heterocycloalkyl.
[00101] [00101] For example, T 'is piperazine, piperidine, quinuclidine or morpholine.
[00102] [00102] For example, the compound can be of Formula (lb) or Formula (Ib ”): the" R
[00103] [00103] - Subsets of Formula (1) compounds include those of Formula (lla) or Formula (lla '): oo - Ti Nº Sel Rô XX> A Nº x oem - = Pr Rº Y Rº RH (Ilajou Rº (a ).
[00104] [00104] - Subsets of compounds of Formula (1) include those of Formula (Ilb) or Formula (IIb "): Q 1 À 0X) - (MX Nº. 17 VA ns O NW OO = = es R Yo R RH (lbjou RH (lb). For example, T 'is C3.8 cycloalkyl, Ce-10 aryl, heterocycloalkyl from 3 to
[00105] [00105] - Subsets of Formula (1) compounds include those of Formula (llc) or Formula (Ile):
[00106] [00106] —Setsets of compounds of Formula (1) include those of Formula (lld) or Formula (11d "): a o 2 . In Nº“ eb es R2º. Nº RH (djou Rº HF (11d).
[00107] [00107] - Subsets of compounds of Formula (1) include those of Formula (Ile) or Formula (lle "):
[00108] [00108] —Setsets of compounds of Formula (1) include those of Formula (IIf) or Formula (IIf): o
[00109] [00109] For example, one between Rº and Rº independently is 5 to 10 membered heteroaryl and the other is hydrogen.
[00110] [00110] For example, one of Rº and Rº independently is pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, indolyl, indazolyl, benzimidazole, imidazopyridinyl, quinolinyl, isoquinolinyl, quinazolinyl, oxazolyl, isoxazolyl, iszazole, thiazole , oxadiazolyl, triazolyl, imidazolyl, furan or thiophenyl, and the other one between Rº and Rº is hydrogen.
[00111] [00111] For example, one of Rº and Rº is Co, alkylene-Ce-10 aryl.
[00112] [00112] For example, one between Rº and Rº independently is phenomenal
[00113] [00113] For example, one of Rº and Rº independently is 5 to 9 membered heterocycloalkyl.
[00114] [00114] For example, one of Rº and Rº independently is dihydrobenzofuran, tetrahydrobenzimidazole, morpholine, tetrahydrofuran, piperidine or piperazine.
[00115] [00115] - For example, each one between Rº and R independently it is Cs.6 cycloalkyl.
[00116] [00116] For example, each of Rº and Rº independently is cyclohexane or cyclopropane.
[00117] [00117] For example, X * is Co. alkylene-Ce-10 aryl.
[00118] [00118] For example, X 'is phenyl, benzyl, naphthyl, or CHonaphyl.
[00119] [00119] For example, X 'is 5 to 10 membered heteroaryl.
[00120] [00120] For example, X * is benzoxazolyl, benzimidazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, indolyl, indazolyl, imidazopyridinyl, quinolinyl, isoquinolinyl, quinazolinyl, oxazolyl, isoxazolyl, thiazolol, triazolol, iszazole, triazolol, iszazole, tris or thiophenyl.
[00121] [00121] For example, X 'is 5- to 9-membered heterocycloalkyl.
[00122] [00122] For example, X 'is tetrahydrobenzoxazole, tetrahydrobenzimidazole, morpholine, tetrahydrofuran, tetrahydropyran, piperidine, pyrrolidine or piperazine.
[00123] [00123] For example, X 'is Ca.ecycloalkyl.
[00124] [00124] For example, X ' is ORº or C (= 0) C1-6 alkyl.
[00125] [00125] For example, X * is C1.3alkyl.
[00126] [00126] For example, X * º is OCF3, C13 alkyl, NHo, CN, OH or halo.
[00127] [00127] For example, X 'is Co. alkylene-C (= NRº) NRºRº.
[00128] [00128] For example, X 'is Co: alkylene-NRºC (= NRº) NRºRº.
[00129] [00129] In an example, for a compound of Formula |, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate or pharmaceutically acceptable hydrate thereof:
[00130] [00130] In an example, for a compound of Formula |, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate or pharmaceutically acceptable hydrate thereof: R 'is - (CH2) S * U "I-C (= O) NRºRº; -CHCH2-NRºRºà; -CH2CH7- NRºC (= O) Rº; -C (= O) NRºS (= O) 2Rº; - (CH2) 0-1-Ce6-10 aryl; - (CH2) 0-1 5- to 6-membered monocyclic heteroaryl; - (CH> 2) 9 to 10 membered 0-1-bicyclic heteroaryl; a 4- to 6-membered monocyclic heterocycloalkyl; a 9 to 10 membered bicyclic heterocycloalkyl; -C (= O)-4- to 6-membered monocyclic heterocycloalkyl; -C (= O) -9 to 10-membered bicyclic heterocycloalkyl; wherein the aryl, 5 heteroaryl and heterocycloalkyl rings are optionally independently substituted with 1, 2,3,4, or 5 X '; each X 'is independently halo; cyan; oxo; C1-6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halo, Co3 alkylene-NRºRi, Co.3 alkylene-ORº, Co.3 alkylene-C (= 0) ORº, Co.3 alkylene-C3a6 cycloalkyl, Cos alkylene-Ce-10 aryl, and Cos3 alkylene-heterocycloalkyl of 4 to 6 members, where heterocycloalkyl is optionally independently substituted with one or more C1-6 alkyl; Co.3 alkylene-C3.6 cycloalkyl optionally substituted with one or more substituents independently selected from the group consisting of C1.6 alkyl, C1-6 haloalkyl, Co.3 alkylene-NRºRÍ, and Co-3 alkylene-ORº; Co-3 alkylene-Ce-10 aryl, where Ce-10 aryl is optionally substituted with one or more substituents selected from the group consisting of halo, cyano, nitro, C1-.6 alkyl, C1.6 ha - loalkyl, Co3 alkylene-NRºR ', Cos alkylene-ORº, Cosa alkylene-C (= O0) ORº, Co-3 alkylene-C (= O) Rº, Co-3 alkylene-S (= O) mRº, and Cos alkylene-NRºS (= O) 2Rº; Co3 alkylene-heterocycloalkyl monocyclic of
[00131] [00131] In another aspect, the present invention provides the compounds of Formula (Ill):
[00132] [00132] In a modality of compounds of Formula (Ill), D is the 9 or 10 membered bicyclic heteroaryl optionally substituted with 1, 2, 3, or 4 R.
[00133] [00133] In one embodiment, a subset of Formula (III) compounds includes those of Formula (Illa):
[00134] [00134] In a compound of Formula (lla) compounds, Rê is - CN or C13 alkyl optionally substituted with a -NH> 2, -NHC1-3 alkyl, -N (C1-3 alkyl) 2, -C (= 0) OH, -C (= 0) OC1 + 3 alkyl, -S (= O) nmC1-3 alkyl, -C (= O) C1.3 alkyl, -OR , or 5- or 6-membered monocyclic heteroaryl, where monocyclic heteroaryl is optionally substituted with 1 or 2 alkyl C1.3; and R 'is -CN or -CF3, where R is as defined for the compounds of Formula (Ill).
[00135] [00135] In another aspect, the present invention provides the compounds of Formula (IV):
[00136] [00136] In another aspect, conjugates are provided comprising compounds of the invention attached to a suitable linker. In one embodiment, compounds of Formula | may be modified by substituting or modifying the substituent Rº or R $, for example, in compounds of Formula IA, or substituting or modifying the substituent Rº in compounds of Formula IA ', to provide a suitable substituent comprising a reactive group capable of connect to a suitable binder. In some embodiments, the reactive group comprises a suitable hydroxy or amine group (for example, a R $ or Rº substitute or a modification thereof comprising an -OH, -NH2, C (= O) NH> and similar) that is able to react with a suitable binder. In one embodiment, compounds of Formula | can be modified by substituting or modifying the substituent Rº or R $, for example, in compounds of Formula IA, or substituting or modifying the substituent Rº in compounds of Formula IA ', to provide a suitable substituent attached to a linker moiety, in that said linker portion comprises a reactive group capable of binding to a suitable linker. In one embodiment, the compounds of Formula | can be modified by substituting or modifying the R3 or R $ substituent, for example, on Formula IA compounds, or by substituting or modifying the Rº substituent on Formula IA 'compounds, to provide a suitable substituent attached to a linker portion, wherein the said linker portion is attached to a suitable linker. In one embodiment, the ligand binds to an ubiquitin E3 ligase. In some embodiments, the E3 ubiquitin ligase is MDM2, clAP1, CRBN or VHL. In one embodiment, a modified compound of the invention is a compound of Formula (Va), Formula (Vb) or Formula (Vc): o o 1 FND R NO CR RH (Va), ALR NR (vp), or
[9] [9] Ad vo, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate or pharmaceutically acceptable hydrate thereof. In these formulas, A is an E3 ubiquitin ligase ligand; L1 is a suitable ligand, R º is a suitable R3 or modification or substitution of R3 (as defined in Formula 1) and R º is a suitable Rº or modification or substitution of Rº (as defined in Formula 1 ); and R ', R , R and Rº are as defined for the compounds of Formula (1).
[00137] [00137] Representative compounds of the present invention include compounds listed in Table 1 (by name in Table 1A and structure in Table 1B).
[00138] [00138] With reference to the present invention comprising a compound as described herein, the compound includes a compound of Formula | (including IA, IA ', la, la', lb and 1b '), Formula Il (i.e. including Ila, 1la', 1lb, 11b ', lc, Hc, Ud, 1d ", 1le, 1le', 11f and 11), Formula 11l (including Illa) or Formula IV and all of its modalities, including any pharmaceutically acceptable salt, pharmaceutically acceptable solvate or pharmaceutically acceptable hydrate thereof.
[00139] [00139] The present invention provides a pharmaceutical composition comprising a compound as described herein, including any pharmaceutically acceptable salt, pharmaceutically acceptable solvate or pharmaceutically acceptable hydrate thereof, together with a pharmaceutically acceptable diluent or carrier.
[00140] [00140] The present provides a kit comprising a compound as described herein, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate or pharmaceutically acceptable hydrate thereof, including any container, package or dispenser together with instructions for administration.
[00141] [00141] The present invention provides a compound as described herein, including any pharmaceutically acceptable salt, pharmaceutically acceptable solvate or pharmaceutically acceptable hydrate thereof, for use in the treatment of a condition mediated by the cCGAS / STING pathway.
[00142] [00142] The present invention provides a method for inhibiting the cGAS / STING pathway in a cell, comprising contacting the cell with one or more compounds or compositions of the present invention.
[00143] [00143] The present invention provides a method for inhibiting the production of cytokines in a cell, comprising contacting the cell with one or more compounds or compositions of the present invention, including any pharmaceutically acceptable salt, pharmaceutically acceptable solvate or hydrate pharmaceutically acceptable product.
[00144] [00144] The present invention provides a method of treating a condition mediated by the CGAS / STING pathway, comprising administering to an individual in need an effective amount of one or more compounds or compositions of the present invention, including any pharmaceutically acceptable salt, pharmaceutically acceptable solvate or pharmaceutically acceptable hydrate thereof.
[00145] [00145] For example, the condition mediated by the CGAS / STING pathway is an autoimmune, inflammatory or neurodegenerative condition. For example, where the disease is selected from the group consisting of systemic inflammatory response syndrome (SIRS), sepsis, septic shock, atherosclerosis, celiac disease, dermatomyositis, scleroderma, interstitial cystitis, transplant rejection (eg, en disease) - graft versus host), Aicardi-Goutieres syndrome, Hutchison Guilford progeria syndrome, Singleton-Merten syndrome, proteasome-associated autoinflammatory syndrome, SAVI (STING-associated vasculopathy with onset in childhood), CANDLE syndrome (Derma- chronic atypical neutrophilic tosis with elevated temperature and lipodystrophy), systemic lupus erythematosus, rheumatoid arthritis, juvenile rheumatoid arthritis, Wegener's disease, inflammatory bowel disease (eg, ulcerative colitis, Crohn's disease), idiopathic thrombocytopenic purpura, thrombotic thrombocytopenic purpura, autoimmune thrombocytopenia, multiple sclerosis, psoriasis, IgA nephropathy, IgM polyneuropathies, glomerulonef ritis, autoimmune myocarditis, severe myasthenia gravis, vasculitis, Type 1 diabetes, Type 2 diabetes, Sjorgen syndrome, X-linked reticulated pigment disorder, polymyositis, spondylo-chondrodysplasia, age-related macular degeneration, Alzheimer's disease and Parkinson's disease .
[00146] [00146] For example, in which the disease is SIRS, sepsis, septic shock, atherosclerosis, celiac disease, interstitial cystitis, transplant rejection, Aicardi-Goutieres Syndrome, perioperous lupus erythematosus, systemic lupus erythematosus, idiopathic thrombocytopathic purpura, thrombotic thrombocytopenic purpura, autoimmune thrombocytopenia, spondyloenchondrodysplasia, psoriasis, Type 1 diabetes, Type 2 diabetes or Sjogren's syndrome.
[00147] [00147] A method of treating an inflammatory disease in an individual, comprising administering to the individual in need of a therapeutically effective amount of one or more compounds or compositions of the present invention, including any pharmaceutically acceptable salt, pharmaceutically acceptable solvate or pharmaceutically acceptable hydrate thereof.
[00148] [00148] For example, where the disease is rheumatoid arthritis, juvenile rheumatoid arthritis, inflammatory bowel disease (ulcerative colitis, Crohn's disease), age-related macular degeneration, IgA nephropathy, glomerulonephritis, vasculitis, polymyositis or disease We- gener.
[00149] [00149] Another aspect of the invention provides a method of treating neurodegenerative diseases in an individual, comprising administering to the individual in need a therapeutically effective amount of one or more compounds or compositions of the present invention, including any pharmaceutically salt. acceptable, pharmaceutically acceptable solvate or pharmaceutically acceptable hydrate thereof.
[00150] [00150] For example, where the disease is Alzheimer's disease, Parkinson's disease, multiple sclerosis, IgM polyneuropathies or myasthenia gravis.
[00151] [00151] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as is commonly understood by one versed in the technique to which this invention belongs. In the specification, singular forms also include the plural, unless the context clearly indicates otherwise. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. All publications, patent applications, patents and other references mentioned herein are incorporated by reference. The references cited here are not accepted as being prior art to the claimed invention. In the event of a conflict, this specification, including definitions, will prevail. In addition, the materials, methods and examples are illustrative only and are not intended to be limiting.
[00152] [00152] Other features and advantages of the invention will be evident from the description and detailed claims below. DRAWINGS
[00153] [00153] Figure 1 represents the expression of RANTES or MCP-1 cytokines together with cell viability as a function of the Log10 (UM) concentration of compound C1089 in bone marrow derived from Trex1-KO mice. DETAILED DESCRIPTION
[00154] [00154] STING (stimulator of interferon genes) is a central mediator of a cytosolic pathway that triggers interferon type | in response to the detection of cytosolic double-stranded DNA (ds) from infectious pathogens or aberrant host cells (Molecular Patterns Associated with Hazards, DAMPS) (Barber, Immunol. Rev 243: 99-108, 2011). Alternatively known as TMEM173, MITA, ERIS and MPYS, STING was discovered using cDNA expression cloning methods as a defense factor for MyD88 independent host cells, expressed in macrophages, dendritic cells (DCs) and fibroblasts that induce the expression of IFN-B and NF-kB-dependent pro-inflammatory cytokines in response to the detection of cytoplasmic DNA, in response to infection by the herpes simplex virus (Ishikawa and Barber, Nature 455: 674-79, 2008).
[00155] [00155] - Although STING was discovered to be the critical sensor to induce the production of IFN-B in response to infection by the herpes simplex virus, the mechanism for this detection function remained initially elusive. This puzzle was solved with the discovery of cyclic GMP-AMP synthase (CGAS), a nucleotide transferase from the host cell that binds directly to the dsDNA and, in response, synthesizes a second messenger, c [G (2 /, 5 ') DA
[00156] [00156] Given the role of cGAS on the STING route and the role of type | in several diseases, treatment with an inhibitor of the cCGAS / STING pathway can have therapeutic benefit in several inflammatory, autoimmune and neurodegenerative diseases, including, but not limited to, systemic inflammatory response syndrome (SIRS), sepsis, septic shock , atherosclerosis, celiac disease, dermatomyositis, scleroderma, interstitial cystitis, transplant rejection (eg, graft versus host disease), Aicardi-Goutieres syndrome, Hutchison Guilford progeria syndrome, Singleton-Merten syndrome, autoinflammatory syndrome associated with proteasome, SAVI (vasculopathy associated with STING beginning in childhood), CAN-DLE syndrome (chronic atypical neutrophilic dermatosis with lipodystrophy and high temperature), perioperous lupus erythematosus, systemic lupus erythematosus, rheumatoid arthritis, rheumatoid arthritis juvenile, inflammatory disease
[00157] [00157] The present invention provides new compounds of pyrazolopyrimidinone or triazolopyrimidinone, synthetic methods for producing the compounds, pharmaceutical compositions containing them and various uses of the compounds. Pyrazolopyrimidinone and Triazolopyrimidinone Compounds
[00158] [00158] The present invention provides the compounds of Formula (I), including Formula (IA) and Formula (IA): o 1
[00159] [00159] For example, the compound can be of Formula (IA) or Formula (IA '): o o' A NOORE rr R RH (IAjou Rº (IA).
[00160] [00160] For example, Q 'is a bond or -CH2- and T' is Ca.8 cycloalkyl, Ce-10 aryl, 3 to 12 membered heterocycloalkyl, 5 to 10 membered heteroaryl or -C (= O ) NRºRº.
[00161] [00161] For example, Q 'is a bond and T' is C3.8 cycloalkyl, Ce-10 aryl, 3 to 12 membered heterocycloalkyl, or 5 to 10 membered heteroaryl.
[00162] [00162] For example, Q 'is a bond and T' is Ce-10 aryl, 3 to 12 membered heterocycloalkyl, or 5 to 10 membered heteroaryl.
[00163] [00163] For example, Q 'is a bond and T' is phenyl, 5 or 6 membered monocyclic heteroaryl, or 9 or 10 membered bicyclic heteroaryl, preferably where T 'is 9 or 10 membered bicyclic heteroaryl.
[00164] [00164] For example, Q 'is a bond or -CH2-, T is -C (= O) NRºRº and enéo.
[00165] [00165] For example, one of Rº and Rº is H or methyl and the other of Rº and Rb is not H or methyl.
[00166] [00166] For example, R is Q2-T2- (Xº) ,, Q is a bond, Tº is H, halo, cyano, C1-6 alkyl, C1-6 haloalkyl, C2.6 alkenyl, C2.6 alkynyl, C3-8 cycloalkyl, Ce-10 aryl, 3 to 12 membered heterocycloalkyl, or heteroaryl of 5 to 10 members, each X independently it is halo, cyano, oxo, Co.3 alkylene-OR "”, Co.3 alkylene-S (= O) mR ", Co-3a alkylene-NR" Rº, Cos alkylene-C (= O) NR "Rº , Sew alkylene-Co3 alkylene-
[00167] [00167] For example, R is Q2-T2- (Xº) ,, Q is a bond, Tº is H, halo, cyano, C1-.6 alkyl, C1-6 haloalkyl, C2.6 alkenyl, or C2-6 alkynyl, and each X independently it is halo or -OC1-6 alkyl.
[00168] [00168] For example, R is H, cyano, methyl or methoxymethyl.
[00169] [00169] For example, R is H, methyl or methoxymethyl.
[00170] [00170] For example, Rº is C1.3 alkyl, C1.3 haloalkyl, -CN, -S (= O) C1-3 alkyl or -C (= 0) OC1-3 alkyl.
[00171] [00171] For example, Rº is -CN, C1.3 alkyl, C1.3 haloalkyl or - C (= 0) OC1 + 3 alkyl.
[00172] [00172] For example, Rº is C1.3 alkyl, C1.3 haloalkyl or -C (= O) OC1-3 alkyl.
[00173] [00173] For example, Rº is -CF3, methyl or -C (= 0) OC1-3 alkyl.
[00174] [00174] For example, Rº is -CF3or-CN.
[00175] [00175] - For example, Rô is -CF3
[00176] [00176] For example, Rº is -CN.
[00177] [00177] For example, Rº is C1.3 alkyl, C1.3 haloalkyl, -S (= O) 2C1-3 alkyl, Ca.8 cycloalkyl, Ce-10 aryl, 3 to 12 membered heterocycloalkyl, or heteroaryl of 5 to 10 members, where C3.6 cycloalkyl, Ce-10 aryl, 3 to 12 membered heterocycloalkyl, or 5 to 10 membered heteroaryl are optionally substituted with 1-3 substituents selected from the group consisting of halo, oxo, C1-6 alkyl, C2.6 alkenyl, C2.6 alkynyl, cyano, C1-6 haloalkyl, -ORYS and -NR $ 5R *,
[00178] [00178] For example, Rº is C3.8 cycloalkyl, Ce-10 aryl, 3 to 12 membered heterocycloalkyl, or 5 to 10 membered heteroaryl, where C3-8 cycloalkyl, Ce-10 aryl, 3-heterocycloalkyl to 12-membered, or 5 to 10-membered heteroaryl are optionally substituted with 1-3 substituents selected from the group consisting of halo, oxo, C1-6 alkyl, C2.6 alkenyl, C2.6 alkynyl, cyano, C1- 6 haloalkyl, -
[00179] [00179] For example, Rº is C3.8cycloalkyl or Ce-10 aryl, where C3-8 cycloalkyl and Ce-10 aryl are optionally substituted with 1-3 substitutes selected from the group consisting of halo, oxo, C1-6 alkyl, Ca.6 alkenyl, C2.6 alkynyl, cyano, C1-6 haloalkyl, -OR “S and - NR“ SR *, where R ”S and R“ * are independently H, C1.6 alkyl or C1-6 haloalkyl.
[00180] [00180] For example, Rº is phenyl optionally substituted with 1-3 substituents selected from the group consisting of halo, oxo, C1-6 alkyl, C2.6 alkenyl, C2.6 alkynyl, cyano, C1.6 haloalkyl, -OR “and -NR * SR *, where R" ”º and R * are independently H, C1.6 alkyl or C1-6 haloalkyl.
[00181] [00181] For example, Rº is Ca.gcicloalkyl.
[00182] [00182] For example, D is cyclopentyl.
[00183] [00183] For example, Rº is Ce-1oarila.
[00184] [00184] For example, Rº is phenyl.
[00185] [00185] - For example, the compound can be of Formula (la) or Formula (la '): o o x x F3CA | N | SE 8 (la) or (la).
[001868] [001868] For example, Q 'is a link or -CH> -.
[00187] [00187] For example, T 'is -C (= O) -C alkylene-Ce-10 aryl or - C (= O0) -Co-1 alkylene-heteroaryl of 5 to 10 members.
[00188] [00188] For example, Q 'is a bond or -CH2- and T' is Ca.8 cycloalkyl, Ce-10 aryl, 3 to 12 membered heterocycloalkyl, 5 to 10 membered heteroaryl or -C (= O ) NRºRº.
[00189] [00189] For example, Q 'is a bond and T' is C3.8 cycloalkyl, Ce-10 aryl, 3 to 12 membered heterocycloalkyl, or 5 to 10 membered heteroaryl.
[00190] [00190] For example, Q 'is a bond and T' is Ce-10 aryl, 3 to 12 membered heterocyclylalkyl, or 5 to 10 membered heteroaryl.
[00191] [00191] For example, Q 'is a bond and T' is phenyl, 5 or 6 membered monocyclic heteroaryl, or 9 or 10 membered bicyclic heteroaryl, preferably where T 'is 9 or 10 membered bicyclic heteroaryl.
[00192] [00192] For example, T 'is C (= O) NRºRbenéoO.
[00193] [00193] For example, one of Rº and Rº is H or methyl and the other of Rº and Rb is not H or methyl.
[00194] [00194] Porexample, right.
[00195] [00195] - For example, T 'is aryl or heteroaryl, preferably phenyl, monocyclic heteroaryl of 5 or 6 members, or bicyclic heteroaryl of 9 or 10 members.
[00196] [00196] For example, T 'is 5 to 10 membered heteroaryl.
[00197] [00197] For example, T 'is pyridinyl, pyrazinyl, pyridazinyl, pyrimidine, indolyl, indolinyl, isoindolyl, isoindolinyl, indazolyl, pyrazolopyridine, pyrazolopyrimidinyl, oxazolopyrimidine, oxazolopyrimidine, benzazolyridin, oxazolopyridin, oxazolopyridine , dihydrobenzofuranyl, isobenzofuranyl, dihydroisobenzofuranyl, triazolo-pyridinyl, benzothiazolyl, azabenzimidazolyl, azabenzoxazolyl, aza-benzothiazolyl, quinolinyl, isoquinolinyl, quinazolinyl, oxazolyl, isoazolyl, isoxyol, -oxazoloazepinyl, tetrahydrobenzoxazolyl, oxadiazolyl, thiadiazolyl, pyrazolyl, triazolyl, imidazolyl, furanyl or thiophenyl.
[00198] [00198] For example, T 'is pyridinyl, pyrazinyl, pyridazinyl, pyrimidine, indolyl, indazolyl, pyrazolopyridinyl, benzimidazolyl, benzothiazolyl, azabenzimidazolyl, azabenzoxazolyl, azabenzothiazylil, isoxazolin, quinidine -
[00199] [00199] For example, T 'is pyridinyl, pyrazinyl, pyridazinyl, pyrimidine, indolyl, indazolyl, pyrazolopyridinyl, benzimidazolyl, benzothiazolyl, azabenzimidazolyl, azabenzoxazolyl, azabenzothiazylyl, isoxazolin, quinine, imidazole - azolyl, isothiazolyl, benzoxazolyl, tetrahydrobenzoxazolyl, tetrahydro-benzimidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, imidazolyl, furanyl or thiophenyl, and X * is halo, Co. anyone-ORº, Co.3 someone or NRº, R $ ', where R $' is C1.6 alkyl or Co.3 alkylene-C3-8 cycloalkyl.
[00200] [00200] - For example, T 'is Co: alkylene-Ce-10 aryl.
[00201] [00201] For example, T 'is phenyl, benzyl, naphthyl, or CHonaftila.
[00202] [00202] For example, T 'is 3 to 12 membered heterocycloalkyl, preferably 4 to 10 membered heterocycloalkyl.
[00203] [00203] For example, T 'is piperazine, piperidine, quinuclidine, or morpholine.
[00204] [00204] For example, R is Qº-Tº- (Xº) ,, O is a bond, Tº is H, halo, cyano, C1-6 alkyl, C1-6 haloalkyl, C2.6 alkenyl, C2.6 alkynyl, C3-8 cycloalkyl, Ce-10 aryl, 3 to 12 membered heterocycloalkyl, or heteroaryl of 5 to 10 members, each X independently it is halo, cyano, oxo, Co.3 alkylene-OR "”, Co.3 alkylene-S (= O) mR ", Co-3a alkylene-NR" Rº, Cos alkylene-C (= O) NR "Rº , C alkylene-Co3 alkylene-C (= O0) OR ", and each Rº and Rº is independently H, C1.6 alkyl, C2.6 alkenyl, C2.6 alkynyl or C1-.6 haloalkyl.
[00205] [00205] For example, R is Qº-Tº- (Xº) ,, OQ is a bond, Tº is H, halo, cyano, C1-.6 alkyl, C1-6 haloalkyl, C2.6 alkenyl, or C2-6 alkynyl, and each X independently it is halo or OC1-6 alkyl.
[00206] [00206] For example, R is H, cyano, methyl or methoxymethyl.
[00207] [00207] For example, R is H, methyl or methoxymethyl.
[00208] [00208] The present invention provides the compounds of Formula (lb) or Formula (Ib '): o "1 N-n R No R FREX | | Ne)
[00209] [00209] In some modalities of Formula lb or Ib ', Q' is a bond or -CH2- and T is Ca.8 cycloalkyl, Ce-10 aryl, 3 to 12 membered heterocycloalkyl, 5 to 10 membered heteroaryl or -C (= O) NRºRº.
[00210] [00210] In some modalities of Formula lb or Ib ', Q' is a bond and T 'is Ca.8 cycloalkyl, Ce-10 aryl, 3 to 12 membered heterocycloalkyl, or 5 to 10 membered heteroaryl.
[00211] [00211] In some modalities of Formula lb or Ib ', Q' is a bond or -CH2- and T 'is -C (= ONRºRP and né O.
[00212] [00212] Another subset of the compounds of Formula (1) include those of Formula (1la), Formula (Ila '), Formula (Ilb) or Formula (IIb'): o o - Ti No. Sox! Rê XX SON XX om Pr R rx R RH (la), RP (a, (9) o 1 N 7X Ny 1170 RO NOT Né | = = Ps R2 Y. R2 RH (lb) or Rº AB (11),
[00213] [00213] R º, R% 3, Ri, T !, X'ension as defined for Formula |.
[00214] [00214] In some modalities of Formula lla, Ila ', Ilb, or IIb', T 'is Ca8 cycloalkyl, Ce-10 aryl, 3 to 12 membered heterocycloalkyl, 5 to 10 membered heteroaryl, or C (= O) NRºRº.
[00215] [00215] In some modalities of Formula lla, or Ila ', T is Cas cycloalkyl, Ce-10 aryl, 3 to 12 membered heterocycloalkyl, or hetero-
[00216] [00216] In some modalities of Formula 1, Ila ', Ilb, or IIb, T! is -C (= O) NRºRb and right O.
[00217] [00217] In some modalities of Formula lla, Ila ', Ilb or IlIb', R is Q2-T2- (Xº) ,, O is a bond, T º is H, halo, cyano, C1.6 alkyl, C1-6 haloalkyl, C2.6 alkenyl, C2-6 alkynyl, Ca-8 cycloalkyl, Ce-10 aryl, 3 to 3-heterocycloalkyl 12 members, or heteroaryl of 5 to 10 members, each X independently is halo, cyano, oxo, Co-3 alkylene-OR ", Co-3 alkylene-S (= O) mR", Co-alkylene-NR "Rº, Co.3 alkylene-C (= O) NR" Rº, Co-3 alkylene-Co-3 alkylene-C (= O0) OR ", and each R" and Rº is independently H, C1.6 alkyl, C2.6 alkenyl, C2.6 alkynyl or C1-6 haloalkyl.
[00218] [00218] In some modalities of Formula lla, lla ', Ilb, or IIb', R is Q2-T2- (X ) ,, O is a call, T is H, halo, cyano, C1-6 alkyl, C1-6 haloalkyl, C2.6 alkenyl, or C2.6 alkynyl, and each X independently it is halo or -OC1 alkyl.
[00219] [00219] In some modalities of Formula lla, lla ', Ilb, or IIb', R is H, cyano, methyl or methoxymethyl.
[00220] [00220] In some modalities of Formula lla, lla ', Ilb, or IIb', R is H, methyl or methoxymethyl.
[00221] [00221] In some modalities of Formula lla or Ilb, Rº is C13 alkyl, C1-3 haloalkyl,
[00222] [00222] —-CN, -S (= 0) 2C1-3 alkyl or -C (= 0) OC1-3 alkyl.
[00223] [00223] In some modalities of Formula lla or Ilb, Rº is C13 alkyl, C1-3 haloalkyl or -C (= 0) OC1-3 alkyl.
[00224] [00224] In some modalities of Formula lla or Ilb, Rº is -CN, - CF3, methyl or -C (= 0) OC1-3 alkyl.
[00225] [00225] In some modalities of Formula lla or Ilb, Rº is -CN or -CF3.
[00226] [00226] In some modalities of Formula lla, lla ', Ilb, or IIb', Rº is C1.3 alkyl, C1-3 haloalkyl, -S (= O) 2C1-3 alkyl, Ca-8 cycloalkyl,
[00227] [00227] In some modalities of Formula lla, Ila ', Ilb, or IIb, Rº is C38 cycloalkyl, Ce-10 aryl, 3 to 12 membered heterocycloalkyl, or 5 to 10 membered heteroaryl, where C3-68 cycloalkyl, Ce-10 aryl, 3 to 12 membered heterocycloalkyl, or 5 to 10 membered heteroaryl are optionally substituted with 1-3 substituents selected from the group consisting of halo, oxo, C1-6 alkyl, C2. 6 alkenyl, Ca.6 alkynyl, cyano, C1.6 haloalkyl, -OR “S and -NRºR *, where Rw5 and Rx5 are independently H, C1-6 alkyl or C1-6 haloalkyl.
[00228] [00228] In some modalities of Formula lla, Ila ', Ilb, or IIb, Rº is Ca.8 cycloalkyl or Ce-10 aryl, where Ca.8 cycloalkyl and Ce-10 aryl are optionally substituted with 1-3 selected substituents from the group consisting of halo, oxo, C1-.6 alkyl, C2.6 alkenyl, C2.6 alkynyl, cyano, C1-6 haloalkyl, -OR “S and -NR * R *, where R“ º and R * º are independently H, C1-6 alkyl or C1-6 haloalkyl.
[00229] [00229] In some modalities of Formula lla, lla ', Ilb, or IIb', Rº is Cagcycloalkyl.
[00230] [00230] In some modalities of Formula lla, lla ', Ilb, or IIb', Rº is cyclopentyl.
[00231] [00231] In some modalities of Formula lla, lla ', Ilb, or IIb', Rº is Ce-10arila.
[00232] [00232] In some modalities of Formula lla, lla ', Ilb, or IIb', Rº is phenyl.
[00233] [00233] In some modalities of Formula lla, lla ', Ilb, or IIb',
[00234] [00234] -C (= O0) -Co3 alkylene-heterocycloalkyl of 3 to 12 members, -C (= O) -Co.3 alkylene-heteroaryl of 5 to 10 members, -NRºRº, - S (= O) 2Rº, -NRºC (= O) Rº, -NRºC (= O) NRºRº,
[00235] [00235] -NRºC (= O) JORº, -NRºS (= O) .Rº, -C (= O) NRºS (= O) Rº, - NRºS (= O) aNRºRb, -C (= O) NRºRº or - S (= O0) NRºRº; each X 'independently is halo, cyano, oxo, Co.3 alkylene-C (= O) Rº, Co-3 alkylene-ORº, Co-3a alkylene-NRºR $, Co.3 alkylene-OC (= O) NRºR $, Co.38 alkylene-C (ENRº) NRºRº, Co.3 alkylene-NRºC (= NRº) NRºR $ º, or R $, where Rºº is C1-6 alkyl, C2.6 alkenyl, C2.6 alkynyl , C1-.6 haloalkyl, Co-3 alkylene-C38 cycloalkyl, Co-3 alkylene-Ce-10 aryl, Co.3 alkylene-heterocycloalkyl from 3 to 12 members, or Co3 alkylene-heteroaryl from 5 to 10 members and R $ * is optionally substituted with one or more substituents independently selected from the group consisting of halo, oxo, C1-.6 alkyl, C2-6 alkenyl, C2.6 alkynyl, C1-6 haloalkyl - la, Co.3 alkylene-NRºR5, Co.3 alkylene-ORº, Co.3 alkylene-NRºC (= O) Rº, Co3 alkylene-NRºC (= 0) ORº, Co.3 alkylene-NRºC (= O) NRºR , Co.3 alkylene-OC (= O) Rº, Co-38 alkylene-C (= O0) ORº, Co-a alkylene-C (= O) Rº, Co-3 alkylene-S (= O) nRº , Co3 alkylene-S (= O) NRºRÍ, Co.3 alkylene-NRºS (= O) 2Rº, Co3 alkylene-NRºS (= O) 2aNRºR 'and R $ ºº, in which R $ is Co.3 alkylene-C3-8 cycloalkyl, Co-3 alkylene-Ce-10 aryl, Co.3a alkylene-heterocycloalkyl of 3 to 12 members, Co.3 alkylene-heteroaryl of 5 to 10 members and R * º is optionally substituted with one or more substituents independently selected from the group consisting of halo, C1-6 alkyl, Ca.6 alkenyl, C2.6 alkynyl, cyano, C1-6 haloalkyl, - OR “and -NR“ R “.
[00236] [00236] Yet another subset of the compounds of Formula | including those of Formula (llc), Formula (llc '), Formula (Ild) or Formula
[00237] [00237] RR, RI, Rº and Rº are as defined for Formula |
[00238] [00238] In some modalities of Formula Ilc, IlC ', Ild, or Ild', R is Q2-T2- (Xº) ,, O is a call, T is H, halo, cyano, C1-.6 alkyl, C1-6 haloalkyl, C2.6 alkenyl, C2-6 alkynyl, Ca-8 cycloalkyl, Ce-10 aryl, 3 to 12-membered heterocycloalkyl, or heteroaryl of 5 to 10 members, each X independently is halo, cyano, oxo, Co-3 alkylene-OR ", Co-3 alkylene-S (= O) mR", Co-alkylene-NR "Rº, Co.3 alkylene-C (= O) NR" Rº, Co-3 alkylene-Co-3 alkylene-C (= O0) OR ", and each R" and Rº is independently H, C1.6 alkyl, C2.6 alkenyl, C2.6 alkynyl or C1-6 haloalkyl.
[00239] [00239] In some modalities of Formula llc, llc ', ld, or lId', R is Q2-T2- (Xº) ,, O is a call, T is H, halo, cyano, C1-6 alkyl, C1-6 haloalkyl, C2.6 alkenyl, or Ca.6 alkynyl, and each X independently it is halo or OC1-6 alkyl.
[00240] [00240] In some modalities of Formula llc, llc ', ld, or lld', R is H, cyano, methyl or methoxymethyl.
[00241] [00241] In some modalities of Formula llc, llc ', ld, or lld', R is H, methyl or methoxymethyl.
[00242] [00242] In some modalities of Formula llc or Ild, Rô is C13 alkyl, C1-3 haloalkyl,
[00243] [00243] —-CN, -S (= 0) 2C1-3 alkyl or -C (= 0) OC1-3 alkyl.
[00244] [00244] In some modalities of Formula llc or Ild, Rº is -ON, C1-3 alkyl, C1-3 haloalkyl or -C (= 0) OC1-3 alkyl.
[00245] [00245] “In some modalities of Formula Ilc or Ild, Rº is C1.3 alkyl, C1-3 haloalkyl or -C (= 0) OC1: 3 alkyl.
[00246] [00246] In some modalities of Formula llc or Ild, Rº is -ON, - CF3, methyl or -C (= 0) OC1-3 alkyl.
[00247] [00247] In some modalities of Formula llc or Ild, Rº is -CN or -CF3.
[00248] [00248] In some modalities of Formula Ilc, IlC ', Ild, or Ild', Rº is C1.3 alkyl, C1-3 haloalkyl, -S (= O) 2C1-3 alkyl, Ca.8 cycloalkyl, Cçe-10 aryl, 3 to 12 membered heterocycloalkyl, or 5 to membered heteroaryl, where Cs3.6 cycloalkyl, Ce-10 aryl, 3 to 12 membered heterocycloalkyl, or 5 to 10 membered heteroaryl are optionally substituted with 1-3 substituents selected from the group consisting of halo, oxo, C1-6 alkyl, C2.6 alkenyl, C2-6 alkynyl, cyano, C1-6 haloalkyl, -OR "S and -NRYR *,
[00249] [00249] In some modalities of Formula llc, llc ', ld, or lld', Rº is C3.8 cycloalkyl, Ce-10 aryl, 3 to 12 membered heterocycloalkyl, or 5 to 10 membered heteroaryl, where C3. 6 cycloalkyl, Ce-10 aryl, 3 to 12 membered heterocycloalkyl, or 5 to 10 membered heteroaryl are optionally substituted with 1-3 substituents selected from the group consisting of halo, oxo, C1-6 alkyl , C2.6 alkenyl, C2.6 alkynyl, cyano, C1.6 haloalkyl, -OR "* and -NRºR", where Rw5 and Rx5 are independently H, C1-6 alkyl or C1-6 haloalkyl.
[00250] [00250] In some modalities of Formula llc, llc ', ld, or lld', Rº is Ca.8 cycloalkyl or Ce-10 aryl, where Ca.8 cycloalkyl and Ce-10 aryl are optionally substituted with 1-3 substituents selected from the group consisting of halo, oxo, C1-.6 alkyl, C2.6 alkenyl, C2.6 alkynyl, cyano, C1.6 haloalkyl, -OR ”º and -NR * R, where R% and R * º are independently H, C1-6 alkyl or C1-6 haloalkyl.
[00251] [00251] In some modalities of Formula llc, llc ', ld, or lld',
[00252] [00252] In some modalities of Formula Ilc, IlC ', Ild, or Id, Rº is cyclopentyl.
[00253] [00253] In some modalities of Formula llc or Ildllc, llc ', Ild, or Ild', Rº is Ce-1narila.
[00254] [00254] In some modalities of Formula Ilc, IlC ', Ild, or Id, Rº is phenyl.
[00255] [00255] - Yet another subset of the compounds of Formula (1) include those of Formula (Ile), Formula (Ile '), Formula (IIf) or Formula (If): o NnNN o N — N Rº NOR (Ile), or “(Ile), oo Nº 2N No AN. RH X '(lif, or Rº À * (1)
[00256] [00256] where each X 'independently is halo, cyano, Co.3 alkylene-C (= O) Rº, Co-3 alkylene-ORº, Co-3 alkylene-C (= O0) OR "º, Cox3 alkylene-OC (= O) Rº, Co.3 alkylene-NRºR $, Co.3 alkylene-S (= O) mRº, Co-3 alkylene-NRºC (= O) Rº, Co.3a alkylene-NRºC ( = O) NRºR $ º, Co.3 alkylene-OC (= O) NRºR $ º, Co.3 alkylene-NRºC (= 0) ORº, Co3 alkylene-NRºS (= O), Rº, Co.a alkylene-C (= O) NRºS (= O) 2Rº, Co.3 alkylene-NRºS (= O) aNRºRº, Co-3 alkylene-C (= O) NRºR $, Co.3 alkylene-S (= O) aNRºRº, Co. 3 alkylene-C (ENRº) NRºRº, Co.3 alkylene-NRºC (= NRº) NRºR $ º, or R $, where Rº is C1-6 alkyl, C2.6 alkenyl, C2.6 alkynyl, Co-3 alkylene -C3-8 cycloalkyl, Co-3 alkylene-Ce-10 aryl, Co.3 alkylene-heterocycloalkyl of 3 to 12 members, or Co.3 alkylene-heteroaryl of 5 to 10 members, R , Rô, R $ , Rº, Rº and R $ are as defined for Formula |
[00257] [00257] In some modalities of Formula lle, Ile ', IIf or IIf, R is Q2-T2- (Xº) ,, O is a call, T is H, halo, cyano, C1-.6 alkyl, C1-6 haloalkyl, C2.6 alkenyl, C2-6 alkynyl, Ca-8 cycloalkyl, Ce-10 aryl, 3 to 12-membered heterocycloalkyl, or heteroaryl of 5 to 10 members, each X independently is halo, cyano, oxo, Co.3 alkylene-OR ", Co-3a alkylene-S (= O) mR", Co-alkylene-NR "Rº, Co.3 alkylene-C (= O) NR" Rº, Co-3 alkylene-Co-3 alkylene-C (= O0) OR ", and each R" and Rº is independently H, C1.6 alkyl, C2.6 alkenyl, C2.6 alkynyl or C1-6 haloalkyl.
[00258] [00258] “In some modalities of Formula Ile, Ile ', IIf or IIf, R is Q2-T2- (Xº) ,, O is a bond, T º is H, halo, cyano, C1.6 alkyl, C1-6 haloalkyl, C2.6 alkenyl, or Ca.6 alkynyl, and each X independently it is halo or -OC1 alkyl.
[00259] [00259] In some modalities of Formula lle, Ile ', IIf or IIf, R is H, cyano, methyl or methoxymethyl.
[00260] [00260] In some modalities of Formula Ile, Ile ”, IIf or IIf, R is H, methyl or methoxymethyl.
[00261] [00261] In some modalities of Formula lle or IIf, Rº is C1.3 alkyl, C1-3 haloalkyl, -CN, S (= O0) 2C1-3 alkyl or -C (= 0) OC1-3 alkyl.
[00262] [00262] In some modalities of Formula lle or If, Rº is -CN, C1-3 alkyl, C1-3 haloalkyl or -C (= 0) OC1-3 alkyl.
[00263] [00263] In some modalities of Formula lle or IIf, Rº is C1.3 alkyl, C1-3 haloalkyl or -C (= 0) OC1-3 alkyl.
[00264] [00264] In some modalities of Formula Ile or IIf, Rº is -ON, - CF3, methyl or -C (= 0) OC1-3 alkyl.
[00265] [00265] In some modalities of Formula lle or IIf, R $ is -CN or -CF3.
[00266] [00266] In some modalities of Formula lle, Ile ', IIf or IIf, Rº is C1-3 alkyl, C1-3 haloalkyl, S (= O0) 2C1-3 alkyl, Ca-8 cycloalkyl, Ce-10 aryl, heterocycloalkyl 3 to 12 membered, or 5 to 10 membered heteroaryl, where C3.68 cycloalkyl, Ce-10 aryl, 3 to 12 membered heterocycloalkyl, or 5 to 10 membered heteroaryl are optionally substituted with 1-3 selected substituents a from the group consisting of halo, oxo, C1-6 alkyl, C2.6 alkenyl, C2-6 alkynyl, cyano, C1-6 haloalkyl, -OR “S and -NR $ 5R *,
[00267] [00267] In some modalities of Formula lle, Ile ', IIf or IIf, Rº is C3.8 cycloalkyl, Ce-10 aryl, 3 to 12 membered heterocycloalkyl, or 5 to 10 membered heteroaryl, where C3.6 cycloalkyl , Ce-10 aryl, 3 to 12 membered heterocycloalkyl, or 5 to 10 membered heteroaryl are optionally substituted with 1-3 substituents selected from the group consisting of halo, oxo, C1-.6 alkyl, C2. 6 alkenyl, C2.6 alkynyl, cyano, C1.6 haloalkyl, -OR "S and -NR" SR, where Rw5 and Rx5 are independently H, C1-6 alkyl or C1-.6 haloalkyl.
[00268] [00268] In some modalities of Formula Ile, Ile ', IIf or IIf, Rº is C3a.8 cycloalkyl or Ce-10 aryl, in which Ca.6 cycloalkyl and Ce-10 aryl are optionally substituted with 1-3 substituents selected a from the group consisting of halo, oxo, C1-.6 alkyl, C2-.6 alkenyl, C2.6 alkynyl, cyano, C1-6 haloalkyl, OR “, and NR * R *, where R" S and R “* are independently H, C1-6 alkyl or C1-6 haloalkyl.
[00269] [00269] In some modalities of Formula lle, Ile ', IIf or IIf, Rº is Ca.gcicloalkyl.
[00270] [00270] In some modalities of Formula Ile, Ile ', IIf or IIf, Rº is cyclopentyl.
[00271] [00271] In some modalities of Formula Ile, Ile ', IIf or IIf, Rº is Ce-10arila.
[00272] [00272] In some modalities of Formula lle, Ile ', IIf or IIf, Rº is phenyl.
[00273] [00273] “Any of the substituents described herein for any one of R ', R , R% 3, R% º, Rº, Rb, Rº, Rº, Rº, Rí, R9, Rº, Ri, Ri, R4 R ”, Rº, Rº, R, R $, Rº, R”, RR, R “, Rz, Rº, R $ ', R & , RS, R $ º, Q, Q , TI, TP, X', and X can be combined with any of the substituents described here for one or more of the remainder within R ', R2 , Rºà, R $, Rº, Rº, Rº, R $, Rº, R1, R9, Rº, Ri, Ri, RK , Rm, R ", Re, R ', Ri, Re, R, R62, Rx, R2, Rº,
[00274] [00274] In one mode, R ', Q !, TI, X, Rº, R , Rº, R, Re, R5, R9, Rº, R $, R82º, R%, Rº2, R, D and Rº are each as defined, where applicable, in any of the Formula | (including IA, IA ', la, la', lb and I1b '), Formula II (i.e., including la, Ila', Ilb, IIb ', llc, lie ”, Id, Id', Ile, Nle ', If and 11f).
[00275] [00275] For example, T 'is C (= ONRºRt ené O.
[00276] [00276] For example, one between Rº and Rº independently is 5 to 10-membered heteroaryl and the other is hydrogen.
[00277] [00277] For example, one of Rº and Rº independently is pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, indolyl, indazolyl, benzimidazole, imidazopyridinyl, quinolinyl, isoquinolinyl, quinazolinyl, oxazolyl, isoxazolyl, iszazole, thiazole , oxadiazolyl, pyrazolyl, benzodioxolyl, dihydrobenzofuranyl, triazolyl, imidazolyl, furanila or thiophenyl, each of which is optionally substituted with one or more groups independently selected from cyano, C1-6 haloalkyl, Co.a someoneylene-S (= O) mR% , Co. alkylene-OR , Co.3 alkylene-NRº2R% and R $ 6, where R $ is C1.6 alkyl, Co.3 alkylene-Ca.8 cycloalkyl, or Co-3 alkylene-Ce-10 aryl.
[00278] [00278] For example, one of Rº and Rº independently is pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, indolyl, indazolyl, benzimidazole, imidazopyridinyl, quinolinyl, isoquinolinyl, quinazolinyl, oxazolyl, isoxazolyl, iszazole, thiazole , oxadiazolyl, pyrazolyl, benzodioxolyl, dihydrobenzofuranyl, triazolyl, imidazolyl, furanila or thiophenyl, each of which is optionally substituted with one or more groups independently selected from cyan, -CF3, -S (= O0 ) 2CHs3, -OCHsa, -NH2 and R $ 6, where R% * is CH; s, i-propyl, cyclopropyl, cyclopentyl, cyclohexyl, or phenyl.
[00279] [00279] For example, one of R and R is Cos alkylene-C-10 aryl.
[00280] [00280] For example, one between Rº and Rº independently is phenomenal
[00281] [00281] For example, one of Rº and Rº independently is phenyl, -CH2phenyl, naphthyl or -CHanaftila, each of which is optionally substituted with one or more groups independently selected from F, Cl, cyan, -CF3, -S (= O0) 2CHs3, -S (= O) 2i-propyl, - NHS (= O) 2CH3, -NHS (= O) 2phenyl, -N (S (= O) 2CH3) 2 , -NHC (= O) CH ;,
[00282] [00282] - “- NHC (= 0) OCH; 3, -OCH3, -OCF3, -Hi-propyl, -Ocyclopentyl, - OCH> phenyl, -NH2, -N (CH3) 2 and R $, where Rº is -CHs3, -CH20CHs, i- propyl, or R $ ”, where R $ 7 is cyclopropyl, cyclopentyl, cyclohexyl, phenyl, pyrrolidinyl, or piperidinyl.
[00283] [00283] For example, one between Rº and Rº independently is optionally substituted with 5- to 9-membered heterocycloalkyl.
[00284] [00284] For example, one of Rº and Rº independently is, tetrahydrobenzimidazole, morpholine, tetrahydrofuran, tetrahydropyran, pyrrolidine, piperidine or piperazine, each of which is optionally substituted with Co.3 alkylene -C (= O) R , Co. alkylene-C (= 0) ORºº , or R $, where R% $ º is Ci1.6 alkyl.
[00285] [00285] For example, one of Rº and Rº independently is, tetrahydrobenzimidazole, morpholine, tetrahydrofuran, tetrahydropyran, pyrrolidine, piperidine or piperazine, each of which is optionally substituted with -CH3, - C (= O) CHs3 or -C (= 0O) Ot-butyl.
[00286] [00286] For example, one of Rº and Rº independently is Cs-6 cycloalkyl and the other is hydrogen.
[00287] [00287] For example, each of Rº and Rº independently is cyclohexane or cyclopropane, each of which is optionally substituted with Co-3 algylene-ORº or Co-3 alkylene-NRºº2Rº,
[00288] [00288] For example, each of Rº and Rº independently is cyclohexane or cyclopropane, each of which is optionally substituted with -OH, -OCH3 or -NH>.
[00289] [00289] For example, X 'is optionally substituted with Co.1 alkylene-Ce-10 aryl.
[00290] [00290] For example, X 'is phenyl, benzyl, naphthyl, or CHonaftila.
[00291] [00291] For example, X 'is optionally substituted with 5 to 10 membered heteroaryl.
[00292] [00292] For example, X * is benzoxazolyl, benzimidazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, indolyl, indazolyl, imidazopyridinyl, quinolinyl, isoquinolinyl, quinazolinyl, oxazolyl, isoxazolyl, thiazolol, triazolol, iszazolyl, triazolol, iszolol, triazole, or thiophenyl, each of which can be optionally substituted with one or more substituents selected from oxo.
[00293] [00293] For example, X 'is optionally substituted with 5- to 9-membered heterocycloalkyl.
[00294] [00294] For example, X 'is tetrahydrobenzoxazole, tetrahydrobenzimidazole, morpholine, tetrahydrofuran, tetrahydropyran, piperidine, pyrrolidine or piperazine, each of which can be optionally substituted with one or more substituents independently selected from C1-.6 alkyl, C1-.6 haloalkyl, Co-3 alkylene-ORº, Co-3 alkylene-C (= 0) ORº, or R & ºº, in which R * is Co.3 alkylene-CCE-10 aryl.
[00295] [00295] For example, X * is optionally substituted with C3.6 cycloalkyl.
[00296] [00296] For example, X 'is -ORº or -C (= 0) C1-6 alkyl.
[00297] [00297] For example, X 'is Ci.3alkyl.
[00298] [00298] For example, X ' is -OCF3, -OC1-3 alkyl, -NH2, -CN, -OH or halo.
[00299] [00299] For example, X 'is Co, alkylene-C (= NRº) NRºRi. - For example, X 'is -C (= NH) NH>.
[00300] [00300] For example, X * is Co alkylene-NRºC (= NRº) NRºRº. For example, X * is -NHC (= NH) NH,>.
[00301] [00301] For example, R is Q2-T2- (Xº) ,, O is a bond, T º is H, halo, cyano, C1-6 alkyl, C1-6 haloalkyl, C2.6 alkenyl, C2.6 alkynyl, C3-8 cycloalkyl, Ce-10 aryl, 3 to 12 membered heterocycloalkyl , or 5 to 10 membered heteroaryl, each X independently is halo, cyano, oxo, Co.3 alkylene-OR "", Co.3 alkylene-S (= O) mR ", Co-3a alkylene-NR" Rº, Co3 alkylene-C (= O) NR "Rº , Co.3 alkylene-Co-3 alkylene-C (= O) OR ”, and each Rº and Rº is independently H, C1-6 alkyl, C2.6 alkenyl, Ca.6 alkynyl or C1-6 haloalkyl.
[00302] [00302] For example, Rº is Q2-T2- (Xº) ,, O is a bond, Tº is H, halo, cyano, C1-.6 alkyl, C1-6 haloalkyl, C2.6 alkenyl, or C2-6 alkynyl, and each X independently it is halo or -OC1-6 alkyl.
[00303] [00303] For example, R is H, cyano, methyl or methoxymethyl.
[00304] [00304] For example, R is H, methyl or methoxymethyl.
[00305] [00305] For example, Rº is C1.3 alkyl, C1.3 haloalkyl, -CN, -S (= O) C1-3 alkyl or C (= 0) OC1-3 alkyl.
[00306] [00306] For example, Rº is -CN, C1.3 alkyl, C1.3 haloalkyl or - C (= 0) OC1 + 3 alkyl.
[00307] [00307] For example, Rº is C1.3 alkyl, C1.3 haloalkyl or -C (= O) OC'1-3 alkyl.
[00308] [00308] For example, R is CN, CF3, methyl or -C (= 0) OC1-3 alkyl.
[00309] [00309] For example, Rº is -CN or -CF3.
[00310] [00310] For example, Rº is C1.3 alkyl, C1-3 haloalkyl, -S (= O) 2C1-3 alkyl, C3-8 cycloalkyl, Ce-10 aryl, heterocycloalkyl of 3 to 12 members, or heteroaryl of 5 to 10 members, where C3.6 cycloalkyl, Ce-10 aryl, 3 to 12 membered heterocycloalkyl, or 5 to 10 membered heteroaryl are optionally substituted with 1-3 substituents selected from the group consisting of halo, oxo, C1-6 alkyl, C2.6 alkenyl, C2.6 alkynyl, cyano, C1-6 haloalkyl, -ORYS and -NR $ 5R *,
[00311] [00311] For example, Rº is C3.8 cycloalkyl, Ce-10 aryl, 3 to 12 membered heterocycloalkyl, or 5 to 10 membered heteroaryl, where C3-8 cycloalkyl, Ce-10 aryl, 3-heterocycloalkyl to 12-membered, or 5 to 10-membered heteroaryl are optionally substituted with 1-3 substituents selected from the group consisting of halo, oxo, C1-6 alkyl, C2.6 alkenyl, C2.6 alkynyl, cyano, C1- 6 haloalkyl, - OR "and -NR“ R *, where R “º and R“ * are independently H, C1-6 alkyl or C1-.6 haloalkyl.
[00312] [00312] For example, Rº is Ca.8cycloalkyl or Ce-10 aryl, where Ca-8 cycloalkyl and Ce-10 aryl are optionally substituted with 1-3 substitutes selected from the group consisting of halo, oxo, C1-6 alkyl, Ca.6 alkenyl, C2.6 alkynyl, cyano, C1-.6 haloalkyl, -OR “and - NRY“ SR *, where R ”S and R“ * are independently H, C1-6 alkyl or C1-6 haloalkyl.
[00313] [00313] For example, Rº is Ca.gcicloalkyl.
[00314] [00314] For example, Rº is cyclopentyl.
[00315] [00315] For example, Rº is Ce-10arila.
[00316] [00316] For example, Rº is phenyl.
[00317] [00317] In some embodiments, for a compound of Formula |, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate or pharmaceutically acceptable hydrate thereof: Y is -CR = Or -N =; R 'is Q-TI- (0XI) n; Q 'is a bond, -CH2- or -CH2CH> a-; T 'is Ce-10 aryl, 3 to 12 membered heterocycloalkyl, 5 to 10 membered heteroaryl, -C (= O) -Co-3 3 to 12 membered alkylene-heterocycloalkyl, -NRºRº,
[00318] [00318] In one embodiment, for a compound of Formula |, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate or pharmaceutically acceptable hydrate thereof: R 'is - (CH2) S * U “I-C (= O) NRºRº; -CHCH2-NRºRºà; -CH2CH7- NRºC (= O) Rº; -C (= O) NRºS (= O) 2Rº; - (CH2) 0-1-Ce6-10 aryl; - (CH2) 0-1-hetero-
[00319] [00319] In another aspect, the present invention provides the compounds of Formula (Ill): the
[00320] [00320] or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate or pharmaceutically acceptable hydrate thereof. In this formula: Rº is selected from the group consisting of - C (= O) NRºR! º; -CH2C (= O) NR! IR ' ; -CHoCHaNRI3R4; -CH> -phenyl; -CH> -5-membered monocyclic heteroaryl optionally substituted with a C1-3 alkyl, C5-6 monocyclic cycloalkyl, or phenyl, wherein phenyl is optionally substituted with a -OC1-3 alkyl; phenyl optionally substituted with a halo or C1-3 alkyl; a 5- or 6-membered monocyclic heterocycloalkyl optionally substituted with 1, 2, or 3 R '$; a 5- or 6-membered monocyclic heteroaryl optionally substituted with 1, 2, or 3 R'8; and 9 or 10 membered bicyclic heteroaryl optionally substituted with 1, 2, 3, or 4 R '";
[00321] [00321] In a modality of compounds of Formula (Ill), D is the 9 or 10 membered bicyclic heteroaryl optionally substituted with 1, 2, 3, or 4 R.
[00322] [00322] In one embodiment, a subset of compounds of Formula (Il!) Include those of Formula (llla): Ya = Y, N Ka "4 FÊ) Rô Ro (Illa), or a pharmaceutically acceptable salt, pharmaceutically solvate acceptable or pharmaceutically acceptable hydrate thereof, where Y1 IS -O-, -NH-, -NR2- or -S-, and Y2, Ya, Ya, € Ys are -N = or -CR º =, goes down that 0.1 0u2 of Y2, Y3, Ya, and Ys are -N =; where Rº is selected from the group consisting of C1.3haloalkyl; Ca.6 cycloalkyl-
[00323] [00323] "-NHC1.3 alkyl or -N (C1-3 alkyl) 2; and phenyl optionally substituted with a halo, -CN, C13 alkyl, C1-.3 haloalkyl, -OC1-3 alkyl, -NH2, -NHC1-3 alkyl or -N (C1-3 alkyl) o; and where R º is H or R ”7, where R * is as defined for the compounds of Formula (Ill), descends that O, 1, 2 or 3 among Y2, Y3, Ya, and Y5 are -CR Ú =, where R ”is R'7; and in which R $, R and Rô are as defined for the compounds of Formula (Ill).
[00324] [00324] In a compound of Formula (Illa) compounds, Rº is - CN or C13 alkyl optionally substituted with a -NH> 2, -NHC1-3 alkyl, -N (C1-3 alkyl) 2, -C (= 0) OH, -C (= 0) OC'13 alkyl,
[00325] [00325] —-S (= O) mC1-3 alkyl, -C (= O0) C1-3 alkyl, -OR , or 5- or 6-membered monocyclic heteroaryl, where monocyclic heteroaryl is optionally substituted with 1 or 2 C1.3 alquila; and R 'is -CN or -CF3, where R is as defined for the compounds of Formula (III).
[00326] [00326] In another aspect, the present invention provides the compounds of Formula (IV): the
[00327] [00327] Representative compounds of the present invention are listed in Table 1A below followed by their compound number:
[00328] [00328] Representative compounds have the following structures, as shown in Table 1B below: Table 1B O, No No.
[00329] [00329] In one embodiment, the compound is selected from the group consisting of 5-methyl-7-0x0-N, 3-diphenyl-2- (trifluoromethyl) -4,7-dihydropyrazolo [1,5- a] pyrimidine-6-carboxamide (A1002); N- (2-aminophenyl) -5-methyl-7-0x0-3-phenyl-2- (trifluoromethyl) -4,7-dihydropyrazolo [1,5-a] pyrimidine-6-carboxamide (A1006); 5-methyl-7-0x0-3-phenyl-N- (pyridin-2-yl) -2- (trifluoromethyl) -4,7-dihydropyrazolo [1,5-a] pyrimidine-6-carboxamide (A1017) ; 5-methyl-N- (2- (methylsulfonamido) phenyl) -7-0x0-3-phenyl-2- (trifluoromethyl) -4,7-dihydropyrolo [1,5-a] pyrimidine-6-carboxamide (A1022);
[00330] [00330] In one embodiment, the compound is selected from the group consisting of N- (2- (5-methyl-7-0x0-3-phenyl-2- (trifluoromethyl) -4,7-dihydropyrazolo [ 1,5-a] pyrimidin-6- 6- (4-methoxybenzo [aJoxazol | -2-i1) -5-methyl-3-phenyl-2- (trifluoromethyl) pyrazolo [1,5- 6- (5-methoxy -1H-benzo [aimidazol | -2-yl) -5-methyl-3-phenyl-2- (trifluoromethyl) pyrazolo [1,5- 5-methyl-3-phenyl-6- (4,5,6,7 -tetrahydro-1H-benzo [alimidazo | -2-i1) -2-
[00331] [00331] "When used herein," alkyl "," C1, C2, Ca, Ca, C5 or Cs alkyl "or" C1-6 alkyl "is intended to include saturated aliphatic hydrocarbon groups of branched (linear) C1, C2 , Ca, Ca, C5 or Cs and branched saturated aliphatic hydrocarbon groups C3, Ca, Cs or Ce. For example, C1-Cs6 alkyl is intended to include C1, C2, Ca, Ca, Os and Cs alkyl groups. Examples of alkyl include, portions having one to six carbon atoms, but, however, not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n- pentyl, s-pentyl or n-hexyl. The term Cm-n means that the alkyl group has "m" to "n" carbon atoms. The term "alkylene" refers to an alkyl group having a substituent, that is, when used herein it is a divalent alkyl moiety. For example, Co.3 alkylene, when used herein as part of a substituent on another group includes a direct bond, a linear group - CH2-, -CH2CH2- or -CH2CH2CH2- or a branched -CH (CH3) -, - CH2CH (CH3) - or -CH (CH3) CH2-, where C> or C; 3 alkylene is preferably linear. For groups described as having more than one alkyl component, for example, -N (C1-3alkyl) 2, -C (= O) N (C1-3alkyl) ,, -P (= O) (C1-3alkyl) 2, or the like, the alkyl components can be the same or different. For example, dialkylamino represented as - N (C1-3alkyl) 2 includes N, N-dimethylamino, N, N-diethylamino, N-isopropyl-N-methyl-amino and the like.
[00332] [00332] In certain embodiments, a straight chain or branched alkyl has six or less carbon atoms (for example, C1-C6 for straight chain, C3-C6 for branched chain) and in another mode, a chain alkyl straight or branched has four or less carbon atoms.
[00333] [00333] “When used herein, the term" cycloalkyl "refers to a system of mono or multiple saturated or unsaturated non-aromatic hydrocarbon rings (e.g., fused, bridged or spiro rings) having 3 to 30 carbon atoms (eg, C3-10) For example, a C3.3 cycloalkyl is intended to include a monocyclic, bicyclic or tricyclic ring having 3, 4, 5, 6, 7 or 8 carbon atoms. Examples of cycloalkyl rings include, but are not limited to, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cycloheptenyl, cycloheptyl, cycloheptenyl, adamantyl, cyclooctyl, cyclooctenyl, cyclo -octadienyl, fluorenyl, phenyl, naphthyl, indanyl, adamantyl and tetrahydronaphthyl. Bridged rings are also included in the definition of cycloalkyl, including, for example, [3.3.0] bicyclooctane, [4.3.O] bicyclononane, [4.4.0] bicyclodecane and [2.2.2] bicyclooctane . A bridged ring occurs when one or more carbon atoms connect two non-adjacent carbon atoms. In one embodiment, the bridge rings are one or two carbon atoms. Note that a bridge always converts a monocyclic ring to a tri-cyclic ring. When a ring is bridged, the substituents cited for the ring may also be present on the bridge. Fused rings (eg, naphthyl, tetrahydronaftyl) and spiro are also included. In the case of multicyclic rings, none of them are aromatic.
[00334] [00334] The term "heterocycloalkyl" refers to a 3 to 8 membered monocyclic ring system, 7 to 12 membered bicyclic (fused, bridged or spiro rings) or 11 to 14 membered (fused, bridged or spiro rings), non-aromatic, saturated or unsaturated, having one or more heteroatoms (such as O, N, S or Se), unless otherwise specified. For example, a 3- to 12-membered heterocycloalkyl ring is intended to include a monocyclic, bicyclic or tricyclic ring having 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 atoms selected from among C, O, N, S and Se. In the case of multicyclic rings, none of the rings are aromatic. Examples of heterocycloalkyl groups include, however, are not limited to, piperidinyl, piperazinyl, pyrrolidinyl, dioxanyl, tetrahydrofuranyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, oxiranyl, azetidinyl, 1,2,3, -tetrahydropyridinyl, tetrahydropyranyl, dihydropyranyl, pyranyl, morpholinyl, 1,4-diazepanyl, 1,4-oxazepanyl, 2-0xa-5-azabicycle [2.2.1] heptanyl, 2,5-diazabicycle [2.2 .1] heptanil, 2-0xa- 6-azospiro [3.3] heptanyl, 2,6-diazaspiro [3.3] heptanyl, 1,4-dioxa-8-azospiro [4.5] decanil, decahydroquinolinyl, 2H , 6H-1,5,2-dithiazinyl, dihydrofuro [2,3-b] tetrahydrofuran, imidazolinyl, morpholinyl, octahydroisoquinolinyl, oxazolinyl (dihydro-oxazolyl), oxazolidinyl, piperidonyl, 4-piperidonyl, piperonyl, pyranyl, pyrazolidinyl, pyrazolinyl, pyrrolinyl, 2H-pyridinyl, quinuclidinyl, 6H-1,2,5-thiadiazinyl, and the like.
[00335] [00335] —Substituted alkyl is alkyl, where the designated substituents replace one or more hydrogen atoms in one or more carbons in the main hydrocarbon chain. Such substituents may include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, oxo, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, alkylcarbonyl, aminocarbonyl, aminocarbonyl, alkylcarbonyl, aminocarbonyl, aminocarbonyl, alkylcarbonyl, aminocarbonyl, aminocarbonyl, aminocarbonyl, alkylcarbonyl, aminocarbonyl, alkylcarbonyl, aminocarbonyl. alkylthiocarbonyl, alkoxy, phosphate, phosphonate, phosphinate, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino
[00336] [00336] An "arylalkyl" or "aralkyl" moiety is an alkyl substituted by an aryl (for example, phenylmethyl (benzyl)). An "alkylaryl" portion is an aryl substituted by an alkyl (for example, methylphenyl).
[00337] [00337] “When used herein," alkylene binder "must include divalent branched chain (linear) aliphatic hydrocarbon groups C1, C2, C3, Ca, C5 or Cs and branched saturated aliphatic hydrocarbon groups C2, C3 , Ca, Cs or Cs groups. For example, the C1.3 algylene ligand as used in the description of Q 'and Q Formula here is a C1-3 alkylene intended to include C1, C2 and C3 alkyl linking groups. These linking groups are linked to Formula | main and T 'or T . Examples of alkylene binder include portions having from one to six carbon atoms, such as, but not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, i-butyl , n-pentyl, s-pentyl or n-hexyl.
[00338] [00338] "" Alkenyl "includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, however, which contain at least one double bond. For example, the term "alkenyl" includes branched-chain alkenyl groups (for example, ethylene, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, renenyl, decenyl) and branched alkenyl groups. In certain modalities, a straight or branched alkenyl group has six or less carbon atoms in its main chain (for example, C2-C6 for linear chain, C3-C6 for branched chain). The term "C2.6" or "C2-C6" includes alkenyl groups containing two to six carbon atoms
[00339] [00339] —Substituted alkenyl is alkenyl, in which the designated substituents replace one or more hydrogen atoms in one or more carbon atoms in the main hydrocarbon chain. Such substituents may include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, alkylaminocarbonyl, alkylaminocarbonyl, alkylaminocarbonyl, alkylaminocarbonyl, alkylaminocarbonate, alkylaminocarbonate phosphinate, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio sulphate, sulphates, sulfates, sulphates, sulfates, , sulfonamido, nitro, trifluoromethyl, cyano, heterocyclyl, alkylaryl or an aromatic or heteroaromatic moiety.
[00340] [00340] - "" Alquinila "includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyl groups described above, however, which contain at least one triple bond. For example, "alkynyl" includes straight-chain alkynyl groups (for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptylnyl, octylnyl, ninylyl, decinyl) and branched alkynyl groups. In certain embodiments, a straight-chain or branched alkynyl group has six or less carbon atoms in its main chain (for example, C2-C6 for line-air chain, C3-C6 for ramified chain). The term "C2.6" or "C2-C6" includes alkynyl groups containing two to six carbon atoms. The term "C3.6" or "C3-Cs" includes alkynyl groups containing three to six carbon atoms.
[00341] [00341] - Substituted alkynyl is alkynyl, in which the designated substituents replace one or more hydrogen atoms in one or more carbon atoms in the main hydrocarbon chain. Such subsidies
[00342] [00342] “Other optionally substituted moieties (such as cycloalkyl, heterocycloalkyl, aryl or optionally substituted heteroaryl) include both unsubstituted moieties and the moieties that have one or more of the designated substituents. For example, substituted heterocycloalkyl includes those substituted by one or more alkyl groups, such as 2,2,6,6-tetramethyl-piperidinyl and 2,2,6,6-tetramethyl-1,2,3,6- tetrahydropyridinyl.
[00343] [00343] "" Arila "includes groups with aromaticity, including" conjugated "or multicyclic systems with at least one aromatic ring and without a heteroatom in the ring structure. For example, a C-10 aryl is intended to include a monocyclic, bicyclic or tricyclic ring having 6, 7, 8, 9 or 10 carbon atoms. Examples include phenyl, 1,2,3,4-tetrahydronaphthalenyl, naphthalene, etc.
[00344] [00344] "Heteroaryl" groups are aryl groups, as defined above, except having one to four heteroatoms in the ring structure, and may also be referred to as "agile heterocycles" or "heteroaromatics". For example, a 5- to 10-membered heteroaryl ring is intended to include a 5, 6, 7, 8, 9 or 10-membered, monocyclic, aromatic heterocyclic ring with 5, 6, 7, 8, 9, or 10 members, a stable in carbon atoms and one or more hetero atoms, for example, 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 hetero atoms, or for example, 1, 2, 3, 4, 5, or 6 heteroatoms, selected independently from the group consisting of nitrogen, oxygen, sulfur, selenium and boron. The nitrogen atom can be substituted or unsubstituted (that is, N or NR where R is H or other substituents, as defined). The nitrogen and sulfur heteroatoms can optionally be oxidized (ie, N% + O and S (= O) ,, where p = 1 or 2). It should be noted that the total number of S and O atoms in the aromatic heterocycle is not greater than 1. Preferred heteroaryl groups here include 5 or 6 membered monocyclic heteroaryl or 9 or 10 membered bicyclic heteroaryl.
[00345] [00345] “Examples of heteroaryl groups include pyrrolyl, furanyl, thiophenyl, thiazolyl, isothiazolyl, imidazolyl, triazolyl, tetrazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyridinyl, pyrazinyl, pyridazinyl, indimol, , isoquinolinyl, pyridazinyl, pyrido-oxazolyl, pyridoimidazolyl, pyridothiazoyl, pyridinyl, pyrimidinyl, oxadazolyl (e.g. 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-0xadazolyl, 1,3,4-oxadiazolyl), pyrazolopyridinyl, benzimidazolyl, tetrahydrobenzimidazolyl, benzothiazolyl, benzofuranyl, dihydrobenzofuranyl, pteridinyl, purinyl, pyrazinyl, benzothiofuranyl, benztriazolyl, benzthiazolyl, benzisetrazolol, benztetrazol , azabenzoxazolyl, azabenzothiazolyl, thiadiazolyl (e.g. 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thia-diazolyl, 1,2,3-thiadiazolyl), triazinyl, triazolyl (for example, 1,2,3-triazolyl a, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl), benzoxazolinyl, benzimidazolinyl, indolizinyl, quinazolinyl, 4H-quinolizinyl, quinoxalinyl, benzodioxolyl, benzoxazolyl, benzoxadiazolyl, tetra -hydrobenzo-xazolyl (eg 4,5,6,7-tetrahydrobenzo [alloxazolyl), tetrahydro-benzimidazolyl (eg 4,5,6,7-tetrahydro-1H-benzo [aimida-
[00346] [00346] In addition, the terms "aryl" and "heteroaryl" include multicyclic aryl and heteroaryl groups, for example, tricyclic or bicyclic rings.
[00347] [00347] In the case of multicyclic aromatic rings, only one of the rings needs to be aromatic (for example, 2,3-dihydroindole), although all rings can be aromatic (for example, quinoline). The second ring can also be cast or bridged.
[00348] [00348] The cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring can be substituted at one or more ring positions (for example, the carbon or ring-forming hetero atom, such as N), with such substitutes, as described above, for example , alkyl, alkenyl, alkynyl, halogen, hydroxyl, oxo, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminocarbonyl, aralkylaminocarbonyl, alkylalkylaminocarbonyl
[00349] [00349] The term "substituted", when used here, means that any one or more hydrogen atoms in the designated atom is replaced by a selection of the indicated groups, provided that the normal value of the designated atom is not exceeded and that the replacement results in a stable compound. When a moiety is indicated as substituted by one or more substituents, this usually indicates substitution by 1, 2, 3, 4, 5 or more, including 1a 5, 1a4,1a3,1a2 or 1 substituents selected independently from an individual group - cado. When a substituent is oxo or keto (ie, = O), then 2 hydrogen atoms in the atom are replaced. Keto substituents are not present in aromatic portions. Double ring bonds, when used here, are double bonds that are formed between two adjacent ring atoms (for example, C = C, C = N or N = N). "Stable compound" and "stable structure" means to indicate a compound that is strong enough to survive isolation with a useful degree of purity from a mixture of reaction and formulation into an effective therapeutic agent.
[00350] [00350] When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then that substituent can be attached to any atom in the ring. When a substituent is listed without indicating the atom through which that substituent is attached to the rest of the compound of a given formula, then that substituent can be attached through any atom in that formula. Combinations of substituents and / or variables are permitted, however, only if such combinations result in stable compounds.
[00351] [00351] - When any variable (for example, X *) occurs more than once in any constituent or formula of a compound, its definition in each occurrence is independent of its definition in all other occurrences. So, for example, if a group is shown to be replaced with 0-2 parts X ', then the group can optionally be replaced with up to two portions X' and X 'in each occurrence is selected regardless of the definition of X '. In addition, combinations of substituents and / or variables are permitted, however, only if such combinations result in stable compounds.
[00352] [00352] The term "hydroxy" or "hydroxyl" includes groups with an -OH Or -O-.
[00353] [00353] “When used here," halo "or" halogen "refers to fluorine, chlorine, bromine and iodine. The term "perhalogenated" generally refers to a portion in which all hydrogen atoms are replaced with halogen atoms. The term "haloalkyl" or "haloalkoxy" refers to an alkyl or alkoxy substituted with one or more halogen atoms. For example, C1-6 haloalkyl indicates an alkyl group of 1 to 6 carbons (linear or branched) where one or more hydrogens are replaced by a halogen.
[00354] [00354] The term "carbonyl" includes compounds and moieties that contain a carbon connected with a double bond to an oxygen atom. Examples of portions containing a carbonyl include, but are not limited to, aldehydes, ketones, carboxylic acids, amides,
[00355] [00355] The term "carboxyl" refers to -COOH or its C1-C; alkyl ester.
[00356] [00356] "" Acyl "includes portions containing the acyl radical (R-C (= O) -) or a carbonyl group. "Substituted acyl" includes acyl groups, where one or more hydrogen atoms are replaced by, for example, alkyl groups, alkynyl groups, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxy, phosphate, phosphonate, phosphinate, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylaminoaminoaminoaminoaminoaminoaminoaminoaminoaminoaminoaminoaminoaminoaminoaminoaminoaminoaminoaminoaminoaminoaminoaminoaminoaminoaminoaminoaminoaminoaminoaminoaminoaminoaminoaminoaminoaminoaminoaminoaminoaminoaminoaminoaminoaminoaminoaminoaminoaminoaminoaminoaminoaminoaminoaminoaminoaminoaminoaminoaminoaminoaminoaminoaminoaminoaminoaminoaminoaminoaminoaminoaminoaminoaminoaminoaminoamino. amidino, imino, sulfhydryl, alkyl- Itio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonate, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.
[00357] [00357] - "" Alkoxyalkyl "," alkylaminoalkyl "and" thioalkoxyalkyl "include in alkyl groups, as described above, in which oxygen, nitrogen or sulfur atoms replace one or more carbon atoms in the main hydrocarbon chain.
[00358] [00358] The term "alkoxy" or "alkoxy" includes covalently substituted and unsubstituted alkyl groups attached to an oxygen atom. Examples of alkoxy groups or alkoxy radicals include, but are not limited to, methoxy, ethoxy, isopropyloxy, propoxy, butoxy and pentoxy groups. Examples of substituted alkoxy groups include halogenated alkoxy groups. The alkoxy groups can be substituted by groups such as alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylcarbonyl, alkylcarbonyl, alkylcarbonyl, alkylcarbonyl, alkylcarbonyl, alkylcarbonyl, alkylcarbonyl, alkylcarbonyl, alkylcarbonyl, alkylcarbonyl, alkylcarbonyl, alkylcarbonyl, alkylcarbonyl, alkylcarbonyl, alkylcarbonyl, alkylcarbonyl, alkylcarbonyl, alkylcarbonyl. ,
[00359] [00359] The term "ester" includes compounds or moieties that contain a carbon or a heteroatom attached to an oxygen atom that is attached to the carbon of a carbonyl group. The term "ester" includes alkoxycarbonyl groups, such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, pentoxycarbonyl, etc.
[00360] [00360] "Tautomer" is one of two or more structural isomers that exist in equilibrium and is easily converted from one isomeric form to another. This conversion results in the formal migration of a hydrogen atom accompanied by an exchange of adjacent conjugated double bonds. Tautomers exist as a mixture of a tautomeric group in solution. In solutions where tautomerization is possible, a chemical balance of tautomers will be achieved. The exact ratio of tautomers depends on several factors, including temperature, solvent and pH. The concept of tautomers that are interconvertible by tautomerization is called tautomerism.
[00361] [00361] Of the various types of tautomerism that are possible, two are commonly observed. In keto-enol tautomerism there is a simultaneous exchange of electrons and a hydrogen atom. Ring chain tautomerism arises as a result of the aldehyde group (-CHO) in a sugar chain molecule that reacts with one of the hydroxy groups (-OH) in the same molecule to obtain a cyclic form
[00362] [00362] Common tautomeric pairs are: ketone-enol, amide-nitrile, lactam-lactim, tautomerism of amide-imidic acid in heterocyclic rings (for example, in nucleobases such as guanine, thymine and cytosine), imine-enamine and enamine- enamine. An example of keto-enol balance is between pyrazolo [1,5-a] pyrimidin-7 (4H) -onas and the corresponding pyrazolo [1,5-a] pyrimidin-7-o0l, as shown below .
[00363] [00363] It should be understood that the compounds of the present invention can be represented as different tautomers. It should also be understood that when the compounds have tautomeric forms, all tautomeric forms should be included in the scope of the present invention, and the naming of the compounds does not exclude any tautomeric form. It will be understood that certain tautomers may have a higher level of activity than others. Synthesis of pyrazolopyrimidinone and triazolopyrimidinone compounds
[00364] [00364] The present invention provides methods for the synthesis of compounds of any Formula described herein. The present invention also provides detailed methods for the synthesis of various described compounds of the present invention, according to the schemes to follow and further exemplified for specific compounds, as shown in the Examples.
[00365] [00365] - Throughout the description, where the compositions are described as having, including or comprising specific components, it is contemplated that the compositions also essentially consist of, or consist of the recited components. Similarly, where
[00366] [00366] The synthetic processes of the invention can tolerate a wide variety of functional groups, therefore, several substituted starting materials can be used. The processes generally provide the desired final compound at or near the end of the general process, although it may be desirable in certain cases to further convert the compound to a pharmaceutically acceptable salt, solvate, hydrate, ester or prodrug.
[00367] [00367] The compounds of the present invention can be prepared in several ways, using commercially available starting materials, compounds known in the literature or easily prepared intermediates, using standard synthetic methods and procedures, known to those skilled in the art, or which will be evident to the technician versed in the light of the teachings contained herein. Standard synthetic methods and procedures for the preparation of organic molecules and transformations and manipulations of functional groups can be obtained from the relevant scientific literature or from standard textbooks in the field. Although not limited to any one or several sources, classic texts such as Smith, M. B., March, J., March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th edition, John Wiley & Sons: New York, 2001; Greene, T.W., Wuts, P.G. M., Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons: New York, 1999; R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); L. Fieser and M. Fieser, Fieser and
[00368] [00368] “For example, the compounds of the present invention can be prepared according to the processes illustrated below in Schemes 1,2,3e4. Scheme 1 o N —— NH "'" N R NH, = - Rº R Y R R (A)
[00369] [00369] Scheme 1 shows the synthesis of a compound of Formula (A), which can be a compound of Formula (1), where Y can be CRº (Formula IA) or Y can be N (Formula IA), R is RN and RI, RA, R $ and Rº are within the definitions of the Formula | (see, for example, Example 5), or they can provide an intermediate that can also be reacted to provide the compounds of Formula | (for example, R 'can be - C (= O) OMe, -CH2C (= O) Me (see Example 1 or 2), hydrogen (see Example 3 or 12). R "is, for example, methyl Substituted aminopyrazoles, or aminotriazoles, many of which are commercially available or can be made by reacting a beta-keto amide with a properly substituted hydrazide, or using another chemical known to someone skilled in the art, can be condensed with a beta -keto ester suitably substituted to produce compounds of A, including compounds of Formula (1).
[00370] [00370] Scheme 2 shows the synthesis of pyrazolopyrimidinones of Formula (Ild) and triazolopyrimidinones of Formula (Ild '), where Y, R , R $, Rº and Rº are within the definitions of Formula (1). An aminopyrazole or amino triazole can be condensed with an appropriate beta-keto ester, for example, dimethyl 2-acetylsuccinate, to produce an ester (for example, R 'of scheme 1 above = CH2C (= O0) OMe, see Example 2) which is then saponified to produce an acid (compound B). The acid can then be coupled to an NRºRº group to produce the compounds of Formula (lld) or (Ild '). The compounds of Formulas (llc) or (llc ') can be synthesized using a similar routine, starting with a beta-keto ester such as dimethyl 2-acetylmalonate (for example, scheme 1 where R' = C (= 0) OMe, see o Example 1) Scheme 3 o NnH oo N s | Y A ”N no + pa one mmrA— FP) R2 Ro H c o Mm o XE TX), E XY |)" OX |, (lla, Y = CR ); (Va) OoR o o
[00371] [00371] Scheme 3 shows the synthesis of some pyrazolopyrimidinones of Formula (lla) or triazolopyrimidinones of Formula (lla '), where Y, R À, R $, T' and X 'are within the definitions of Formula (1). An aminopyrazole or aminotriazole can be condensed with an appropriate beta-keto ester to produce compound C (for example, scheme 1 where R 'is H) an ester that is subsequently brominated (for example, by Example 3, the corresponding iodine compound is prepared by Example 4). The T! -X 'group can then be introduced via a metal-catalyzed cross-coupling reaction with an M-T! -X' group to produce compounds of Formula (1la) or (1la '). Alternatively, the brominated intermediate can be converted into a metallized nucleophile, which can react with an electrophilic T! -X 'group to form compounds of Formula (1la) or (1la'). "M" refers to functional metal groups such as B (OH) 2, Sn (here!) 3, Si (alkyl) ;, MgBr, Li, CuLi, ZnCl and the like. Specific reactions where R 'is Br are found in Examples 3 and R' iodine in Examples 4, 10 and 12. Scheme 4 o Por Agam ES - = FI - = V Ê Ro Cs Re, 8 (If, Y = CR3); (If)
[00372] [00372] Scheme 4 shows the synthesis of compounds of formula
[00373] [00373] The compounds of the invention can also be used in the preparation of Proteolysis Targeting Chimeras (PRO-TACs), wherein the conjugates of the invention are conjugated to the linker that binds an ubiquitin ligase through a suitable linker. For example, a compound of Formula | it can be modified from the position of the Rº or Rº substituent to provide a binder, which can be reacted to bind to a suitable binder. Thus, in one embodiment, a conjugate is provided comprising a compound of the invention that binds cGAS bound to a ligand of an E3 ubiquitin ligase, wherein the resulting conjugate binds to E3 ubiquitin ligase and cGAS. This results in the binding of ubiquitin to the cCGAS protein by E3 ubiquitin binds. The resulting modified cGAS is then processed by the cell, resulting in protein degradation. Suitable ligands that inhibit E3 ubiquitin ligase, and suitable ligands, and methods for preparing such conjugates are well known to one skilled in the art. See, for example, Collins et al /., Biochemical Journal 2017, 474: 1127-1147; Bondeson et al., Nature Chemical Biology 2015, 11: 611-617; and Toure and Crews, Angew. Chem. Int. Ed. 2016, 55: 2-10.
[00374] [00374] Thus, the conjugates are provided comprising the compounds of the invention attached to a suitable linker. In a modality, compounds of Formula | can be modified
[00375] [00375] The phrase "condition mediated by the CGAS / STING pathway", when used here, comprises autoimmune, inflammatory and neurodegenerative conditions. For example, the autoimmune disorder selected from the disease may be an interferonopathy of the type | (for example, Aicardi-Goutieres syndrome, Sjogren's syndrome, Singleton-Merten syndrome, proteasome-associated autoinflammatory syndrome, SAVI (STING-associated vasculopathy with childhood onset), CANDLE syndrome, pernicious lupus erythematosus, lupus erythematosus systemic, spondyloenchondodysplasia), rheumatoid arthritis, juvenile rheumatoid arthritis, juvenile thrombocytopenic purpura, autoimmune myocarditis, thrombotic thrombocytopenic purpura, autoimmune thrombocytopenia, psoriasis, Type I diabetes or Type 2 diabetes is a Type 2 diabetes or Type 2 diabetes. atherosclerosis, dermatomyositis, SIS, sepsis, septic shock, celiac disease, interstitial cystitis, transplant rejection, inflammatory bowel disease (ulcerative colitis, Crohn's disease), age-related macular degeneration, IgA nephropathy, glomerulonephritis, vasculitis, polymyositis or disease of Wegener.
[00376] [00376] The compound of the invention, as described here, can be useful in the treatment of a variety of diseases, where modulation of the CGAS / STING pathway can provide therapeutic benefit. In some aspects, a compound of the invention inhibits the CGAS / STING pathway, and may be useful in the treatment of a disease selected from the group consisting of systemic inflammatory response syndrome (SIRS), sepsis, septic shock, atherosclerosis, celiac disease, dermatomyositis, scleroderma, interstitial cystitis, transplant rejection (for example, graft versus host disease), Aicardi-Goutieres syndrome, Hutchison Guilford progeria syndrome, Singleton-Merten syndrome, autoinflammatory syndrome associated with proteasome, SAVI (vasculopathy associated with STING with onset in childhood), CAN-DLE syndrome (Chronic Atypical Neutrophilic Dermatosis with Lipodystrophy and High Temperature), perioperous lupus erythematosus, systemic lupus erythematosus, rheumatoid arthritis, rheumatoid arthritis juvenile, Wegener disease, inflammatory bowel disease (eg, ulcerative colitis, Crohn's disease), idiopathic thrombocytopenic purpura, thrombo-cytopenic purpura tr ombotic, autoimmune thrombocytopenia, multiple sclerosis, psoriasis, IgA nephropathy, IgM polyneuropathies, glomerulonephritis, autoimmune myocarditis, myasthenia gravis, vasculitis, Type 1 diabetes, Type 2 diabetes, Sjorgen syndrome, reticulated pigment disorder linked to X , polymyositis, spondyloencondrodysplasia, age-related macular degeneration, Alzheimer's disease and Parkinson's disease. In some embodiments, the compounds of the invention are useful in the treatment of Aicardi-Goutieres Syndrome, X-linked reticulated pigmentary disorder, dermatomyositis, systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis or Type 1 diabetes | or type Il.
[00377] [00377] “When used here," treating "or" treating "describes the handling and care of a mammal (eg, human patient) for the purpose of combating a disease, condition or disorder and includes administration of a compound of the present invention, or a pharmaceutical
[00378] [00378] “A compound of the present invention, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate or pharmaceutically acceptable hydrate thereof, can also be used to prevent a disease, condition or disorder, or used to identify suitable candidates for these purposes . When used here, "preventing" or "preventing" describes the reduction or elimination of the appearance of symptoms or complications of the disease, condition or disorder.
[00379] [00379] “When used here, the term" relieve "is intended to describe a process by which the severity of a sign or symptom of a disorder is decreased. It is important to note that a sign or symptom can be relieved without being eliminated. In a preferred embodiment, administration of pharmaceutical compositions of the invention leads to the elimination of a sign or symptom, however, elimination is not necessary. Effective dosages are expected to decrease the severity of a sign or symptom. For example, a sign or symptom of a disorder such as an autoimmune, inflammatory or neurodegenerative disease, which can occur in several places, is relieved if the severity of the disease decreases in at least one of the several places.
[00380] [00380] The compounds of the present invention can inhibit the cCGAS / STING pathway and, consequently, in one aspect of the invention, certain compounds described herein are candidates for the treatment or prevention of certain conditions and diseases. The present invention provides methods for the treatment of conditions and diseases in which the course of the condition or disease can be influenced by the CGAS / STING pathway. The method includes administering to an individual in need of such treatment, a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt, metabolite, solvate, hydrate or stereoisomer thereof.
[00381] [00381] The present invention provides a method for inhibiting the cGAS / STING pathway in a cell, comprising contacting the cell with one or more compounds or compositions of the present invention.
[00382] [00382] The present invention also provides a method of treating a condition mediated by the CGAS / STING pathway, comprising administering to a patient in need of an effective amount of one or more compounds or compositions of the present invention . In some modalities, the condition mediated by the CcGAS / STING pathway is an autoimmune, inflammatory or neurodegenerative condition or cancer (see, Raiburn, ER et al., Mol Cell Pharma- col. 2009; 1 (1): 29-43 and Urbanska, AM et a /., Cell Biochem Biophys. 2015 Jul; 72 (3): 757-69).
[00383] [00383] The present invention also provides a method for inhibiting the production of type interferon | mediated by the CGAS / STING pathway, comprising: administering to the individual in need of him a therapeutically effective amount of one or more compounds or compositions of the present invention. The CGAS / STING pathway of cytosolic DNA perception as this phrase is used here comprises the following proteins: SAMHD1, DNase Il, STAT1I, STAT2, TREX1, ENPP1, cGAS, STING, IRF3, IRF7, TBK1, IKK and NF- «XB. Such a method can be practiced in vitro, in a cell or in an organism (for example, in a human being).
[00384] [00384] The present invention also provides a method of treating an interferon-mediated disease type | in an individual, comprising: administering to the individual in need thereof a therapeutically effective amount of one or more compounds or compositions of the present invention.
[00385] [00385] The present invention also provides a method of inhibiting cytokine production in a cell, comprising: contacting the cell with one or more compounds or compositions of the present invention.
[00386] [00386] The present invention also provides a method of treating a cytokine-mediated disease in an individual, comprising: administering to the individual in need thereof a therapeutically effective amount of one or more compounds or compositions of the present invention.
[00387] [00387] The present invention provides a method of treating an autoimmune disease in an individual, comprising administering to the individual in need thereof a therapeutically effective amount of one or more compounds or compositions of the present invention. In some embodiments, the autoimmune disease may be a type of interferonopathy | (for example, Aicardi-Goutieres Syndrome, Sjogren's Syndrome, Singleton-Merten Syndrome, proteasome-associated autoinflammatory syndrome, SAVI (STING-associated vasculopathy with childhood onset), CANDLE syndrome, perioperous lupus erythematosus, systemic lupus erythematosus, spondylo-chondrodysplasia), rheumatoid arthritis, juvenile rheumatoid arthritis, idiopathic thrombocytopenic purpura, autoimmune myocarditis, thrombotic thrombocytopenic purpura, autoimmune thrombocytopenia, type 2, type 2 diabetes, psoriasis.
[00388] [00388] The present invention provides a method of treating an inflammatory disease in an individual, comprising administering to the individual in need thereof a therapeutically effective amount of one or more compounds or compositions of the present invention. For example, the inflammatory disease can be atherosclerosis, dermatomyositis, SRIS, sepsis, septic shock, celiac disease, interstitial cystitis, transplant rejection, inflammatory bowel disease (ulcerative colitis, Crohn's disease), age-related macular degeneration, nephropathy by IgA, glomerulonetphyritis, vasculitis, polymyositis or Wegener's disease.
[00389] [00389] The present invention also provides a method of treating neurodegenerative diseases in an individual, comprising administering to the individual in need thereof a therapeutically effective amount of one or more compounds or compositions of the present invention. For example, neurodegenerative disease can be Alzheimer's disease, Parkinson's disease, multiple sclerosis, IgM polyneuropathies or myasthenia gravis.
[00390] [00390] The compounds of the invention can also be used in combination with additional agents for the treatment of autoimmune and inflammatory diseases. Janus Kinase inhibitors (Jak inhibitors), including a Jak1, Jak2, Jak3 or Tyk2 inhibitor, or compound that inhibits any combination thereof, including Jak1 / 2 inhibitors. Jak inhibitors can block cytokine-mediated signaling via the JAK-STAT pathway, and have been developed to treat a variety of inflammatory and autoimmune diseases. For example, tofacitinib is an approved Jak1i and Jak3 inhibitor used for the treatment of rheumatoid arthritis, psoriatic arthritis and ulcerative colitis; baricitinib is a Jak1 and Jak2 inhibitor approved in Europe and used to treat rheumatoid arthritis; filgotinib is a Jak1 inhibitor that is being developed for the treatment of rheumatoid arthritis and Crohn's disease.
[00391] [00391] The present invention provides a method of treating a disease in an individual, comprising administering to the individual in need thereof a therapeutically effective amount of a compound of the invention in combination with a Janus Kinase (Jak) inhibitor , including a Jak1, Jak2, Jak3 or Tyk2 inhibitor, or compound that inhibits any combination thereof. In some
[00392] [00392] The present invention also provides for the use of one or more compounds or compositions of the present invention to inhibit the cCGAS / STING pathway in a cell.
[00393] [00393] The present invention also provides for the use of one or more compounds or compositions of the present invention for the treatment of a condition mediated by the CGAS / STING pathway.
[00394] [00394] The present invention also provides for the use of one or more compounds or compositions of the present invention to inhibit the production of interferon type | mediated by the CcGAS / STING pathway in a cell.
[00395] [00395] The present invention also provides for the use of one or more compounds or compositions of the present invention for the treatment of an interferon-mediated disease |
[00396] [00396] The present invention also provides for the use of one or more compounds or compositions of the present invention to inhibit cytokine production in a cell.
[00397] [00397] The present invention also provides for the use of one or more compounds or compositions of the present invention for the treatment of a condition mediated by the CGAS / STING pathway.
[00398] [00398] The present invention also provides for the use of one or more compounds or compositions of the present invention for the treatment of an autoimmune disease. In some modalities, the autoimmune disease may be a type of interferonopathy | (for example, Aicardi-Goutieres syndrome, Sjogren's syndrome, Singleton-Merten syndrome, proteasome-associated autoinflammatory syndrome, SAVI (STING-associated vasculopathy with childhood onset), CANDLE syndrome, pernicious lupus erythematosus, systemic lupus erythematosus, spondyloenchondrodysplasia), rheumatoid arthritis, juvenile rheumatoid arthritis, idiopathic thrombocytopenic purpura, autoimmune myocarditis, thrombotic purpuric thrombocytopenia, autoimmune thrombocytopenia, psoriasis, Type 1 diabetes or Type 2 diabetes.
[00399] [00399] The present invention also provides for the use of one or more compounds or compositions of the present invention for the treatment of an inflammatory disease. For example, the inflammatory disease can be atherosclerosis, dermatomyositis, SIRS, sepsis, septic shock, celiac disease, interstitial cystitis, transplant rejection, inflammatory bowel disease (ulcerative colitis, Crohn's disease), age-related macular degeneration , IgA nephropathy, glomerulonephritis, vasculitis, polymyositis or Wegener's disease.
[00400] [00400] The present invention also provides the use of one or more compounds or compositions of the present invention for the treatment of a neurodegenerative disease. For example, neurodegenerative disease can be Alzheimer's disease, Parkinson's disease, multiple sclerosis, IgM polyneuropathies or myasthenia gravis.
[00401] [00401] The present invention also provides one or more compounds or compositions of the present invention for use in inhibiting the cCGAS / STING pathway in a cell.
[00402] [00402] The present invention also provides one or more compounds or compositions of the present invention for use in the treatment of a condition mediated by the CGAS / STING pathway.
[00403] [00403] The present invention also provides one or more compounds or compositions of the present invention for use in inhibiting the production of interferon type | mediated via CGAS / STING in a cell.
[00404] [00404] The present invention also provides one or more compounds or compositions of the present invention for use in the treatment of an | interferon-mediated disease.
[00405] [00405] The present invention also provides one or more compounds or compositions of the present invention for use in inhibiting cytokine production in a cell.
[00406] [00406] The present invention also provides one or more compounds or compositions of the present invention for use in the treatment of a condition mediated by the CGAS / STING pathway.
[00407] [00407] The present invention also provides one or more compounds or compositions of the present invention for use in the treatment of an autoimmune disease, such as those described herein.
[00408] [00408] The present invention also provides one or more compounds or compositions of the present invention for use in the treatment of an inflammatory disease, such as those described herein.
[00409] [00409] The present invention also provides one or more compounds or compositions of the present invention for use in the treatment of a neurodegenerative disease, such as those described herein.
[00410] [00410] “Any of the one or more compounds or compositions for use described above may be for use in combination with a Janus Kinase (Jak) inhibitor, such as those described herein.
[00411] [00411] The present invention also provides for the use of one or more compounds or compositions of the present invention in the manufacture of a medicament to inhibit the CGAS / STING pathway in a cell.
[00412] [00412] The present invention further provides the use of one or more compounds or compositions of the present invention in the manufacture of a medicament for the treatment of a condition mediated by the cCGAS / STING pathway.
[00413] [00413] The present invention further provides the use of one or more compounds or compositions of the present invention in the manufacture of a medicament to inhibit the production of interferon type | in a cell.
[00414] [00414] The present invention further provides for the use of one or more compounds or compositions of the present invention in the manufacture of a medicament for the treatment of an interferon-mediated disease of type |
[00415] [00415] The present invention further provides the use of one or more compounds or compositions of the present invention in the manufacture of a medicament to inhibit the production of cytokines in a cell.
[00416] [00416] The present invention further provides the use of one or more compounds or compositions of the present invention in the manufacture of a medicament for the treatment of a cytokine-mediated condition.
[00417] [00417] The present invention further provides the use of one or more compounds or compositions of the present invention in the manufacture of a medicament for the treatment of an autoimmune disease, such as those described herein.
[00418] [00418] The present invention further provides for the use of one or more compounds or compositions of the present invention in the manufacture of a medicament for the treatment of an inflammatory disease, such as those described herein.
[00419] [00419] The present invention further provides the use of one or more compounds or compositions of the present invention in the manufacture of a medicament for the treatment of a neurodegenerative disease, such as those described herein.
[00420] [00420] The present invention further provides the use of one or more compounds or compositions of the present invention in combination with a Janus Kinase (Jak) inhibitor, including an Jak1, Jak2, Jak3 or Tik2 inhibitor, or compound that inhibits any combination of them, in the manufacture of a medicine for the treatment of a disease selected from the group consisting of SIRS, sepsis, septic shock, atherosclerosis, celiac disease, dermatomyositis, scleroderma, interstitial cystitis, transplant rejection (for example, x versus host), Aicardi-Goutieres syndrome, Hutchison Guilford progeria syndrome, Singleton-Merten syndrome, proteasome-associated autoinflammation syndrome, SAVI, CANDLE syndrome, perioid lupus erythematosus, systemic lupus erythematosus, rheumatoid arthritis, rheumatoid arthritis , Wegener's disease, inflammatory bowel disease (for example, ulcerative colitis,
[00421] [00421] The cCGAS inhibitory activity of any of the compounds described here can be determined by the reaction of the compound in an environment adequately buffered with a DNA activated cGAS in the presence of ATP and GTP. The antagonistic activity can then be quantified by measuring the amount of ATP and / or GTP remaining after the reaction is stopped. The human CGAS sequence encoding amino acids 155-522 (DAAPGASKLRAVLEKLKLSRDDISTAAGMVKGVVDHLLLRLKCDSAF RGVGLLNTGSYYEHVKISAPNEFDVMFKLEVPRIQLEEYSNTRAYYFV KFKRNPKENPLSQFLEGEILSASKMLSKFRKIIKEEINDIKDTDVIMKRK RGGSPAVTLLISEKISVDITLALESKSSWPASTQEGLRIQNWLSAKVR KQLRLKPFYLVPKHAKEGNGFQEETWRLSFSHIEKEILNNHGKSKTC CENKEEKCCRKDCLKLMKYLLEQLKERFKDKKHLDKFSSYHVKTAFF
[00422] [00422] The inhibitory activity of the CGAS / STING pathway of any of the compounds described here can also be determined by measuring changes in the signature of the interferon type | resulting from the administration of the compound (s).
[00423] [00423] — Potential CGAS antagonists, for example, the pyrazolopyrimidinone compounds described here, can be made to interact, in a suitably buffered environment, with a DNA-activated cGAS in the presence of ATP and GTP. The antagonistic activity can then be quantified by measuring the amount of ATP and / or GTP remaining after the reaction is stopped.
[00424] [00424] A cell assay can be used to evaluate the compounds of the invention for their ability to inhibit the CGAS / STING pathway. Cells expressing a luciferase-based reporter that is linked to activation of IRF-3 are used to determine the response as a function of the concentration of the compound. Such an assay is described in Vincent et al., Nature Communications 2017, 8 (1): 750, doi: 10.1038 / s41467- 017-00833-9.
[00425] [00425] A cell assay can be used to evaluate the compounds of the invention for their ability to inhibit cytokine production. Bone marrow macrophages harvested from mice can be used to determine the response depending on the concentration of the compound. Pharmaceutical Compositions
[00426] [00426] The present invention also provides pharmaceutical compositions
[00427] [00427] A "pharmaceutical composition" is a formulation that contains the compounds of the present invention in a form suitable for administration to an individual. In one embodiment, the pharmaceutical composition is in bulk or in unit dosage form. The unit dosage form is one of several forms, including, for example, a capsule, an IV pouch, a pill, a single pump in an aerosol inhaler or a bottle. The amount of active ingredient (for example, a formulation of the described compound or salt, hydrate, solvate or isomer) in a unit dose of composition is an effective amount and is varied according to the particular treatment involved. Someone skilled in the art will understand that it is sometimes necessary to make routine dosage variations, depending on the age and condition of the patient. The dosage will also depend on the route of administration. A variety of pathways are considered, including oral, pulmonary, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, inhalation, buccal, sublingual, intra-pleural, intrathecal, intranasal and the like. Dosage forms for topical or transdermal administration of a compound of this invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, implants and inhalants. In one embodiment, the active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier and any necessary preservatives, buffers or propellants.
[00428] [00428] “When used herein, the phrase" pharmaceutically acceptable "refers to compounds, anions, cations, materials, compositions, vehicles and / or dosage forms that are, within the scope of an appropriate medical judgment, suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic response or other problem or complication, proportional to a reasonable benefit / risk ratio.
[00429] [00429] "" Pharmaceutically acceptable excipient "means an excipient that is useful in the preparation of a pharmaceutical composition that is generally safe, non-toxic and neither biological nor undesirable, and includes excipient acceptable for veterinary use, as well as pharmaceutical use. human. A "pharmaceutically acceptable excipient", as used in the specification and claims, includes one and more than one excipient.
[00430] [00430] A pharmaceutical composition of the invention is formulated to be compatible with the intended route of administration. Examples of routes of administration include parenteral administration, for example, intravenous, intradermal, subcutaneous, oral (e.g., inhalation), transdermal (topical) and transmucosal. Solutions or suspensions used for parenteral, intradermal or subcutaneous application may include the following components: a sterile diluent, such as water for injection, saline, fixed oils, polyethylene glycols, glycerin, propylene glycol or other synthetic solvents ; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylene diaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for adjusting tonicity such as sodium chloride or dextrose. The pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide. Parenteral preparation can be enclosed in ampoules, disposable syringes or vials for multiple doses of glass or plastic.
[00431] [00431] A compound or pharmaceutical composition of the invention can be administered to an individual in many of the well-known methods currently used for chemotherapeutic treatment. The chosen dose should be sufficient to constitute an effective treatment, but not so high as to cause unacceptable side effects. The state of the disease condition and the patient's health should preferably be closely monitored during and for a reasonable period after treatment.
[00432] [00432] The term "therapeutically effective amount", when used herein, refers to an amount of a pharmaceutical agent to treat, ameliorate or prevent an identified disease or condition, or exhibit a detectable therapeutic or inhibitory effect. The effect can be detected by any test method known in the art. The actual amount needed by an individual will depend on the individual's body weight, size and health; the nature and extent of the condition; and the therapy or combination of therapy selected for administration. Therapeutically effective amounts for a given situation can be determined by routine experimentation, within the clinician's experience and judgment.
[00433] [00433] For any compound, the therapeutically effective amount can be estimated initially in cell culture assays, for example, neoplastic cells or in animal models, usually rats, mice, rabbits, dogs or pigs. The animal model can also be used to determine the appropriate concentration range and route of administration. This information can then be used to determine doses and routes useful for administration in humans. Therapeutic / prophylactic efficacy and toxicity can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, for example, EDso (the therapeutically effective dose in 50% of the population) and LDso (the lethal dose for 50% of the population ). The dose ratio between toxic and therapeutic effects is the therapeutic index and can be expressed as the LDs5o / EDso ratio. Pharmaceutical compositions that exhibit high therapeutic indexes are preferred. Dosage can vary within this range, depending on the dosage form used, patient sensitivity and route of administration.
[00434] [00434] The dosage and administration are adjusted to provide sufficient levels of the active agent (s) or to maintain the desired effect. Factors that can be taken into account include the severity of the disease state, the individual's general health, the age, weight and sex of the individual, diet, time and frequency of administration, drug combination (s), reaction sensitivities and tolerance / response to therapy. Long-acting pharmaceutical compositions can be administered every 3 to 4 days, every week or once every two weeks, depending on the half-life and the purification rate of the particular formulation.
[00435] [00435] Pharmaceutical compositions containing active compounds of the present invention can be manufactured in a generally known manner, for example, by means of conventional mixing, dissolving, granulating, making pills, levigation, emulsification, encapsulation, entrapment or freeze-drying processes. Pharmaceutical compositions can be formulated in a conventional manner using one or more pharmaceutically acceptable carriers comprising excipients and / or auxiliaries that facilitate the processing of the active compounds in preparations that can be used pharmaceutically. Obviously, the appropriate formulation depends on the chosen route of administration.
[00436] [00436] Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (where soluble in water) or sterile dispersions and powders for the extemporaneous preparation of sterile injectable solutions or dispersions. For intravenous administration, suitable vehicles include physiological saline, bacterial water, cremophor EL) (BASF, Parsippany, N.J.) or phosphate buffered saline (PBS). In all cases, the composition must be sterile and must be fluid to the extent that it is easy to separate. It must be stable in the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The vehicle can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol and liquid polyethylene glycol, and the like) and their suitable mixtures. Adequate fluidity can be maintained, for example, by using a coating such as lecithin, by maintaining the required particle size in the case of dispersion and by using surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol and sorbitol and sodium chloride in the composition. Prolonged absorption of the injectable compositions can be achieved by including in the composition an agent that delays absorption, for example, aluminum monostearate and gelatin.
[00437] [00437] Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in an appropriate solvent with one or a combination of ingredients listed above, as needed, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the active compound in a sterile vehicle that contains a basic dispersion medium and the other necessary ingredients from those listed above. In the case of sterile powders for the preparation of sterile injectable solutions, the methods of preparation are vacuum drying and lyophilization which produce a powder of the active ingredient plus any additional desired ingredient from a previously filtered solution. sterilized.
[00438] [00438] In general, a compound of the application will be administered in therapeutically effective amounts through any of the usual and acceptable modes known in the art, alone or in combination with one or more therapeutic agents. A therapeutically effective amount can vary widely, depending on the severity of the disease, the age and relative health of the individual, the strength of the compound used and other factors. Therapeutic amounts or doses also vary depending on the route of administration, as well as the possibility of coupling with other agents.
[00439] [00439] - After improving the condition of an individual, a maintenance dose of a compound, composition or combination of this application can be administered, if necessary. Thereafter, the dosage or frequency of administration, or both, may be reduced, depending on the symptoms, to a level where the improved condition is maintained when the symptoms have been relieved to the desired level, treatment must cease. The individual may, however, require intermittent long-term treatment after any recurrence of the symptoms of the disease.
[00440] [00440] It will be understood, however, that the total daily use of the compounds and compositions of this application will be decided by the attending physician within the scope of the correct medical judgment. The specific starting dose for any particular patient will depend on a variety of factors, including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the patient's age, body weight, general health, sex and diet; the time of administration, route of administration and rate of excretion of the specific compound used; the duration of treatment; drugs used in combination or coinciding with the specific compound used; and similar factors well known in the medical arts.
[00441] [00441] The term "pharmaceutical combination", when used here, means a product that results from mixing or combining more than one active ingredient and includes fixed and non-fixed combinations of the active ingredients. The term "fixed combination" means that the active ingredients, for example, an application compound and a coagent, are both administered to a patient simultaneously in the form of a single entity or dosage. The term "non-fixed combination" means that the active ingredients, for example, an application compound and a coagent, are both administered to a patient as separate entities simultaneously, simultaneously or simultaneously or sequentially without time limits. where administration provides therapeutically effective levels of the two compounds in the patient's body. The latter also applies to cocktail therapy, for example, the administration of three or more active ingredients.
[00442] [00442] Oral compositions generally include an inert diluent or a pharmaceutically acceptable edible carrier. They can be packed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, troches or capsules. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, where the compound in the fluid carrier is applied orally and agitated and expectorated or swallowed. Pharmaceutically compatible binding agents and / or adjuvant materials can be included as part of the composition. Tablets, pills, capsules, troches and the like can contain any of the following ingredients or compounds of a similar nature: a binder such as microcrystalline cellulose, tragacanth gum or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel or corn starch; a lubricant like magnesium stearate or Sterotes; a glidant like colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent, such as peppermint, methyl salicylate or orange flavoring.
[00443] [00443] For administration by inhalation, the compounds are released in the form of an aerosol spray from a pressurized container or dispenser, which contains a suitable propellant, for example, a gas such as carbon dioxide or a nebulizer.
[00444] [00444] Systemic administration can also be by transmucosal or transdermal means. For transmucosal or transdermal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art and include, for example, transmucosal administration, detergents, bile salts and fusidic acid derivatives. Transmucosal administration can be performed through the use of nasal sprays or suppositories. For transdermal administration, the active compounds are formulated into ointments, ointments, gels or creams, as is generally known in the art.
[00445] [00445] The active compounds can be prepared with pharmaceutically acceptable vehicles that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including microencapsulated implants and delivery systems. Biodegradable and biocompatible polymers, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters and polylactic acid can be used. The methods for preparing such formulations will be apparent to those skilled in the art. Liposomal suspensions (including liposomes targeted to cells infected with monoclonal antibodies to viral antigens) can also be used as pharmaceutically acceptable vehicles.
[00446] [00446] “It may be advantageous to formulate oral or parenteral compositions in the form of a dosage unit to facilitate administration and uniformity of dosage. The dosage unit form When used herein refers to physically discrete units suitable as unitary dosages for the individual to be treated; each unit containing a predetermined amount of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for the dosage unit forms of the invention is dictated and directly dependent on the unique characteristics of the active compound and the particular therapeutic effect to be achieved.
[00447] [00447] In therapeutic applications, the dosages of the pharmaceutical compositions used according to the invention vary depending on the agent, age, weight and clinical condition of the recipient patient and the experience and judgment of the clinician or physician administering the therapy, among others factors affecting the selected dosage. In general, the dose should be sufficient to result in delay and, preferably, regression, in the progression of autoimmune, neurodegenerative or inflammatory disease. Doses can be in single, divided or continuous doses (the dose of which can be adjusted for the patient's weight in kg, body surface area in month and age in years). An effective amount of a pharmaceutical agent is one that provides an objectively identifiable improvement, as observed by the clinician or other qualified observer. As used here, the term "effective dosage" refers to the amount of an active compound to produce the desired biological effect on an individual or cell.
[00448] [00448] The pharmaceutical compositions can be included in a container, package or dispenser together with instructions for administration.
[00449] [00449] “The compounds of the present invention are capable of forming more salts. All of these forms are also considered within the scope of the claimed invention.
[00450] [00450] "When used herein," pharmaceutically acceptable salts "refers to derivatives of the compounds of the present invention in which the parent compound is modified through the production of acidic or basic salts. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues, such as amines, alkaline or organic salts of acid residues, such as carboxylic acids and the like. Pharmaceutically acceptable salts include conventional non-toxic salts or quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, these conventional non-toxic salts include, but are not limited to, those derived from organic and inorganic acids selected from 2-acetoxybenzoic, 2-hydroxyethanesulfonic, acetic, ascorbic, benzene sulfonic, benzoic, bicarbonate, bistrate, bitaryic, boric, boric, butyric, calcium, calcium edetic, cansilate, carbonic, chloric, citric, clavular, dihydrochloride, edetic, disulfonic ethane, 1,2-ethanesulfonic, stolate, esilate, fumaric, glyco-heptote - nico, glyconic, glutamic, glycolic, glycosilic hexafluorophosphoric, hexylresorcinic, hydrabamic, hydrobromic, hydrochloric, iodidic, hydroxy-maleic, hydroxinaftoic, iodic, isethionic, lactic, lactobionic, lauryl sulfonic, methanic, maleic, manic, manic, manic, manic, manic, manic, manic, manic, manic, manic, manic, manic, manic, manic, manic, manic, manic, manic, manic, manic, manic, manic, manic, manic, manic, manic, manic, manic, manic, manic, manic, manic, manic, manic, manic, manic, manic, manic, manic, manic, manic, manic, manic, manic, manic, manic, manic, manic, , napsyl, nitric, N-methylglycamine ammonium salt, 3-hydroxy-2-naphthoic, oleic, oxalic, pamoic, pantothenic, phenylacetic, phosphoric, polygalacturonic, propionic, salicylic, es theoretical, subaceti-
[00451] [00451] In addition to the pharmaceutically acceptable salts, the pharmaceutically acceptable compounds and salts, as described in this document, can be "pharmaceutically acceptable solvates" or, where the solvent is water, "pharmaceutically acceptable hydrates". For example, pharmaceutically acceptable solvates can be formed in which solvent molecules are incorporated into the crystalline network during crystallization. Solvates can involve non-aqueous solvents, such as ethanol, isopropanol, dimethylsulfoxide, acetic acid, ethanolamine and ethyl acetate, or they can involve water as a solvent that is incorporated into the crystalline structure. Solvates in which water is the solvent that is incorporated into the crystalline network are commonly referred to as "hydrates". Hydrates include stoichiometric hydrates, as well as compositions that contain varying amounts of water. The invention includes all such solvates or hydrates.
[00452] [00452] - When a described compound or its salt is named or represented by the structure, it must be understood that the compound or salt, including solvates or hydrates, can exist in crystalline forms, non-crystalline forms or a mixture thereof. The compound or salt, or solvates or hydrates thereof, may also exhibit polymorphism (that is, the ability to occur in different crystalline forms). These different crystalline forms are typically known as "polymorphs". It should be understood that, when named or represented by the structure, the described compound, or solvates or hydrates thereof, also includes all of their polymorphs. Polymorphs have the same chemical composition, but differ in
[00453] [00453] Other examples of pharmaceutically acceptable salts include hexanoic acid, propionic cyclopentane acid, pyruvic acid, malonic acid, 3- (4-hydroxybenzoyl) benzoic acid, cinnamic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4 - toluenesulfonic, camphorsulfonic acid, 4-methylbicyclo- [2.2.2] - oct-2-ene-1-carboxylic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, muconic acid and the like. The present invention also covers salts formed when an acidic proton present in the parent compound is replaced by a metal ion, for example, an alkali metal ion, an alkaline earth ion or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglycamine and the like. In the form of salt, it is understood that the ratio of the compound to the cation or anion of the salt can be 1: 1 or any different ratio of 1: 1, for example, 3: 1, 2: 1, 1: 2 or 1: 3.
[00454] [00454] It should be understood that all references to pharmaceutically acceptable salts include solvent addition forms (solves) or crystal forms (polymorphs), as defined herein, of the same salt.
[00455] [00455] The compounds of the present invention can also be prepared as esters, for example, pharmaceutically acceptable esters. For example, a functional group of carboxylic acid in a compound can be converted to its corresponding ester, for example, a methyl, ethyl or another ester. In addition, an alcohol group in a compound can be converted to its corresponding ester, for example, acetate, propionate or another ester.
[00456] The compounds of the present invention can also be prepared as prodrugs, for example, pharmaceutically acceptable prodrugs. The terms "prodrug" and "prodrug" are used interchangeably here and refer to any compound that releases a drug of active origin in vivo. Since prodrugs are known to improve numerous desirable qualities of pharmaceutical products (e.g., solubility, bioavailability, manufacture, etc.), the compounds of the present invention can be released in the form of a prodrug. Thus, the present invention is intended to cover prodrugs of the compounds currently claimed, methods of administering them and compositions containing them. "Prodrugs" are intended to include any covalently linked carriers that release an active parent drug of the present invention in vivo when that prodrug is administered to an individual. The prodrugs of the present invention are prepared by modifying the functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, in the original compound. Prodrugs include compounds of the present invention in which a hydroxy, amino, sulfhydryl, carboxy or carbonyl group is attached to any group that can be cleaved in vivo to form a free hydroxyl, free amino, free sulfhydryl, free carboxy or carbonyl group free, respectively.
[00457] [00457] “Examples of prodrugs include, among others, esters (for example, acetate, dialkylaminoacetates, formats, phosphates, derivatives
[00458] [00458] The compounds, or pharmaceutically acceptable salts, esters or prodrugs thereof, are administered via a route selected from the group consisting of enterally, orally, nasally, transdermally, pulmonary, inhalationally, buccally, sublingually, intraperitoneally, subcutaneously, intramuscu- larly, intravenously, rectally, intrapleurally, intrathecally and parenterally. In one embodiment, the compound is administered orally. Someone skilled in the art will recognize the advantages of certain administration routines.
[00459] [00459] The dosage regimen using the compounds 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 administration routine; the patient's renal and liver function; and the particular compound or its salt used. An ordinarily versed physician or veterinarian can easily determine and prescribe the effective amount of the drug needed to prevent, counter, or halt the progress of the condition.
[00460] [00460] Techniques for formulating and administering the described compounds of the invention can be found in Remington: Science and Practice of Pharmacy, 19 "edition, Mack Publishing Co., Easton, PA (1995). In one embodiment, the compounds described herein, and their pharmaceutically acceptable salts, are used in pharmaceutical preparations in combination with a pharmaceutically acceptable carrier or diluent. Suitable pharmaceutically acceptable vehicles include inert solid fillers or diluents and sterile aqueous or organic solutions. The compounds will be present in such pharmaceutical compositions in sufficient quantities to provide the desired dosage amount in the range described here.
[00461] [00461] All percentages and ratios used herein, unless otherwise indicated, are by weight. Other features and advantages of the present invention are evident from the different examples. The examples provided illustrate different components and methodology useful in the practice of the present invention. The examples do not limit the claimed invention. Based on the present description, the skilled technician can identify and employ other components and methodology useful for the practice of the present invention.
[00462] [00462] In the synthetic schemes described here, the compounds can be represented with a particular configuration for simplicity. Such particular configurations should not be construed as limiting the invention to either isomer, tautomer, regioisomer or stereoisomer, nor exclude mixtures of isomers, tautomers, regioisomers or stereoisomers; however, it will be understood that a given isomer, tautomer, regioisomer or stereoisomer may have a higher level of activity than another isomer, tautomer, regioisomer or stereoisomer.
[00463] [00463] Compounds designed, selected and / or optimized by the methods described above, once produced, can be characterized using a variety of assays known to those skilled in the art to determine whether the compounds have biological activity. For example, molecules can be characterized by conventional assays, including, but not limited to the assays described below, to determine whether they have predicted activity,
[00464] [00464] In addition, high throughput tracking can be used to speed up analysis using such assays. As a result, it may be possible to quickly trace the molecules described here for activity, using techniques known in the art. General methodologies for performing high throughput screening are described, for example, in Devlin (1998) High Throughput Screening, Marcell Dekker; and U.S. Patent No. 5,763,263. High-performance tests may use one or more different test techniques, including, but not limited to, those described below.
[00465] [00465] The present invention provides a kit comprising a compound capable of inhibiting the selected GAS / STING pathway of one or more compounds of the present invention, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate or pharmaceutically acceptable hydrate thereof, and instructions for use in the treatment of an autoimmune disease. In some modalities, autoimmune disease can be a type of interferonopathy | (for example, Ai- cardi-Goutieres syndrome, Sjogren's syndrome, Singleton-Merten syndrome, proteasome-associated autoinflammatory syndrome, SAVI (STING-associated vasculopathy with childhood onset), CAN-DLE syndrome, lupus erythematosus pernio, systemic lupus erythematosus, spondyloenchondodysplasia), rheumatoid arthritis, juvenile rheumatoid arthritis, idiopathic thrombocytopenic purpura, autoimmune myocarditis, thrombotic thrombocytopenic purpura, Type 1 diabetes, autoimmune thrombocytopenia, type 2 diabetes, autoimmune type 2
[00466] [00466] The present invention provides a kit comprising a compound capable of inhibiting the selected GAS / STING pathway of one or more compounds of the present invention, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate or pharmaceutically acceptable hydrate thereof, and instructions for use in the treatment of an inflammatory disease. In some modalities, the inflammatory disease may be atherosclerosis, dermatomyositis, SIRS, sepsis, septic shock, celiac disease, interstitial cystitis, transplant rejection, inflammatory bowel disease (ulcerative colitis, Crohn's disease), macular degeneration related to age, IgA nephropathy, glomerulonephritis, vasculitis, polymyositis or Wegener's disease.
[00467] [00467] The present invention provides a kit comprising a compound capable of inhibiting the selected GAS / STING pathway of one or more compounds of the present invention, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate or pharmaceutically acceptable hydrate thereof, and instructions for use in the treatment of a neurodegenerative disease. In some modalities, the neurodegenerative disease may be Alzheimer's disease, Parkinson's disease, multiple sclerosis, IgM polyneuropathies or myasthenia gravis.
[00468] [00468] The present invention provides a kit comprising a compound capable of inhibiting the production of type interferon | selected from one or more compounds of the present invention, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate or pharmaceutically acceptable hydrate thereof, and instructions for use in the treatment of an autoimmune disease. In some embodiments, the autoimmune disease may be a type of interferonopathy | (for example, Aicardi-Goutieres syndrome, Sjógren syndrome, Singleton-Merten syndrome, proteasome-associated autoinflammatory syndrome, SAVI (ST (childhood-onset vasculopathy), CANDLE syndrome, perioperous lupus erythematosus, systemic lupus erythematosus, spondyloenchondodysplasia), rheumatoid arthritis, juvenile rheumatoid arthritis, idiopathic thrombocytopenic purpura, autoimmune myocarditis, thrombotic thrombocytopenic purpura, autoimmune thrombocytopenia, type 2 diabetes, type 1, rheumatoid.
[00469] [00469] The present invention provides a kit comprising a compound capable of inhibiting the production of type interferon | selected from one or more compounds of the present invention, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate or pharmaceutically acceptable hydrate thereof, and instructions for use in the treatment of an inflammatory disease. In some modalities, the inflammatory disease may be atherosclerosis, dermatomyositis, SIRS, sepsis, septic shock, celiac disease, interstitial cystitis, transplant rejection, inflammatory bowel disease (ulcerative colitis, Crohn's disease), macular degeneration related to age, IgA nephropathy, glomerulonephritis, vasculitis, polymyositis or Wegener's disease.
[00470] [00470] The present invention provides a kit comprising a compound capable of inhibiting the production of type interferon | selected from one or more compounds of the present invention, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate or pharmaceutically acceptable hydrate thereof, and instructions for use in the treatment of a neurodegenerative disease. In some ways, neurodegenerative disease can be Alzheimer's disease, Parkinson's disease, multiple sclerosis, IgM polyneuropathies or myasthenia gravis.
[00471] [00471] The present invention provides a kit comprising a compound capable of inhibiting cytokine production selected from one or more compounds of the present invention, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate or pharmaceutically acceptable hydrate thereof, and instructions for use in the treatment of an autoimmune disease. In some modalities, the autoimmune disease may be an interferonopathy of the type | (for example, Aicardi-Goutieres syndrome, Sjógren's syndrome, Singleton-Merten syndrome, proteasome-associated autoinflammatory syndrome, SAVI (STING-associated vasculopathy with childhood onset), CANDLE syndrome, perioperous lupus erythematosus, lupus erythematosus systemic, spondyloenchondodysplasia), rheumatoid arthritis, juvenile rheumatoid arthritis, idiopathic thrombocytopenic purpura, autoimmune myocarditis, thrombotic thrombocytopenic purpura, autoimmune thrombocytopenia, psoriasis, Type 1 diabetes or Type 2 diabetes.
[00472] [00472] The present invention provides a kit comprising a compound capable of inhibiting cytokine production selected from one or more compounds of the present invention, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate or pharmaceutically acceptable hydrate thereof, and instructions for use in the treatment of an inflammatory disease. In some modalities, the inflammatory disease may be atherosclerosis, dermatomyositis, SIRS, sepsis, septic shock, celiac disease, interstitial cystitis, transplant rejection, inflammatory bowel disease (ulcerative colitis, Crohn's disease), age-related macular degeneration, IgA nephropathy, glomerulonephritis, vasculitis, polymyositis or Wegener's disease.
[00473] [00473] The present invention provides a kit comprising a compound capable of inhibiting cytokine production selected from one or more compounds of the present invention, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate or pharmaceutically acceptable hydrate thereof, and instructions for use in the treatment of a neurodegenerative disease. In some embodiments, the neurodegenerative disease may be Alzheimer's disease, Parkinson's disease, multiple sclerosis, IgM polyneuropathies or myasthenia gravis.
[00474] [00474] All publications and patent documents cited here are incorporated here by reference, as if each publication or document were specific and individually indicated to be incorporated here by reference. The citation of publications and patent documents is not intended to admit that any is pertinent to the prior art, nor to admit the content or the date of the same. The
[00475] [00475] NMR spectra were recorded on a Bruker Avance Il Ultra (500 MHz) shielding spectrometer. LCMS were purchased in a Waters Alliance 2695 with LC column heater system equipped with a Waters PDA 996 UV detector (210-300 nm) and an MS Waters ZQ 2000, ESI detector (ES +, 100-1200 amu). Mobile phases (Mobile phase A: Milli-Q H2O0 + 10mM Ammonium Formate pH: 3.8 (Am.F.) or Ammonium Bicarbonate pH: 10 (Am.B.), Mobile B: CH3CN). The LC conditions are: XBridge C18, 3.5 um, 4.6 x 30 mm; ISO 5% B for 0.5 min, 5% to 100% B in 5 minutes; maintaining 100% B for 2 minutes; flow rate: 3 mL / min. The methods described in the examples below can be easily modified by someone skilled in the art. Compounds made in a manner similar to the exemplified methods may include changes in reaction conditions, such as any or more of the concentrations of reagents, solvents, reaction times, temperatures, processing conditions, purification conditions, and similar to provide additional compounds of the invention as described herein.
[00476] [00476] —Abreviations and Acronyms. ACOH = acetic acid, Burgess reagent = 1-Methoxy-N-triethylammonesulfonyl-metanimidate, DOM = CH2Cl2 = dichloromethane, DIPEA = N, N-Diisopropylethylamine, DMEDA = N, N-Dimethylethylenediamine, DMF = Dimethylformamide, DMSO = oxide, EtOH = ethanol, EtOAc = ethyl acetate, FBS = Bovine Fetal Serum, HATU (Azabenzotriazole Hexafluorophosphate Tetramethyl Uronium) =
[00477] [00477] The synthesis of N- (4-methoxyphenyl) -5-methyl-7-0x0-3-phenyl-2- (trifluoro-methyl) -4,7-dihydropyrazolo [1,5-a] pyrimidine 6-carboxamide - (A1001) was performed in the following three steps: woooo FC A, | do emo te IO sm, H aa ADELINO S% NE EO, 3 4 Stage 3 o QD N DMF, HATU 8 ox É Õ 4 LOS Õ A1001 1-5
[00478] [00478] Step 1: Synthesis of methyl 5-methyl-7-0x0-3-phenyl-2- (trifluoromethyl) - 4,7-dihydropyrazolo [1,5-a] pyrimidine-6-carboxylate (1- 3). In a stirred solution of 4-phenyl-3- (trifluoromethyl) -1H-pyrazol-5-amine (1I-1, 2.00 g, 8.80 mmol) (WO 2012149157) in AcOH (10 mL) was added dimethyl 2-acetylmalonate (1-2, 1.3 eq, 1.99 g, 11.4 mmol) (JACS, 136 (34), 12137-12160, 2014). The reaction mixture was heated to 100 ºC for 30 min and concentrated in vacuo to dryness. The reaction mixture was triturated in EtOAc for 15 min. The solid was collected by filtration, washed with EtOAc, dried under high vacuum to produce compound 1-3 (1.60 g, 4.55 mmol, 52%) as a white solid that was used without further purification . * H NMR (500 MHz, DMSO) 5 12.69 (s, 1 H), 7.54 - 7.45 (m, 3 H), 7.45 - 7.42 (m, 2 H), 3, 81 (s, 3 H), 2.43 (s, 3H); MS (m / z): 325.0 [M + 1] *, 97.2%.
[00479] [00479] Step 2: Synthesis of 5-methyl-7-0x0-3-phenyl-2- (trifluoro-methyl) -4,7-dihydropyrazolo [1,5-a] pyrimidine-6-carboxylic acid (1 -4). In a stirred solution of compound 1-3 (1.60 g, 4.55 mmol) in a mixture of THF (25 ml) and MeOH (25 ml) a 2M sodium hydroxide solution (18.2 mL, 36.4 mmol). The reaction mixture was stirred at r.t. for 17 h, heated to reflux for 2 h and concentrated until dry. After adding water and 10% HCl, the white suspension was stirred at r.t. for 10 min. The solid was collected by filtration, washed with water, dried under high vacuum to provide compound 1-4 (1.42 9, 4.21 mmol, 92%) as a white solid that was used without further purification. * H NMR (500 MHz, DMSO) 13.07 (s, 1 H), 7.60 - 7.36 (m, H), 2.58 (s, 3 H); MS (m / z): 337.9 [M + 1] *, 96.3%.
[00480] [00480] Step 3: Synthesis of N- (4-methoxyphenyl) -5-methyl-7-0x0-3-phenyl- 2- (trifluoromethyl) -4,7-dihydropyrazolo [1,5-a] pyrimidine- 6-carboxamide (A1001): For a stirred solution of 5-methyl-7-0x0-3-phenyl-2- (trifluoromethyl) -4,7-dihydropyrazolo [1,5-a] pyrimidine-6-carboxylic acid (1-4, 50 mg, 0.15 mmol) in DMF (1 mL) HATU (85 mg, 0.22 mmol), p-anisidine (1-5, 27.7 mg, 0.22 mmol) was added and DIPEA (78 µL, 0.44 mmol). The reaction mixture was stirred at r.t. for 18h. After adding EtOAc, water and 10% HCl, the layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO. and concentrated in vacuo. The residue was purified by reverse flash chromatography (KP-C18-H5 (Biotage LLC, Charlotte, NC, USA), using a gradient of 0 to 100% MeCN in 10 mM aqueous ammonium formate buffer)
[00481] [00481] Table 2 below provides additional compounds that can be synthesized similarly to the methods described in Steps 1-3 above, optionally substituting the compound listed by 1-5 and / or by substituting 1-1 and / or 1- 2 where indicated. The data for the synthesized compounds are given in columns 3-5.
[00482] [00482] Synthesis of N- (2-aminophenyl) -2- (5-methyl-7-0x0-3-phenyl-2- (trifluoromethyl) -4,7-dihydropyrazolo [1,5-a] pyrimidin- 6-yl) acetamide (B1001) was carried out in three steps below: o Nº - o. Fed ti Step 1 Fe a Or Di Step 2 Fx, oMe - ”Are 9 E O + o AcOH, 100 * C H THF, MeOH, H 18 HW NaOH OMe o Step 3 o NH DMF, HATU RN Nx. OH Ny F5.AÁA OF TEA F.C <- | 3 = o N 8 + H 18 O B1001 1-9 No.
[00483] [00483] Step 1: Synthesis of 2- (5-methyl-7-0x0-3-phenyl-2- (trifluoromethyl) -4,7-dihydropyrazolo [1,5-a] pyrimidin-6-yl ) methyl acetate (1-7): a stirred solution of 4-phenyl-3- (trifluoromethyl) -1H-pyrazol-5-amine (1-1, 2.00 g, 8.80 mmol) (WO 2012149157) in AcCOH (15 ml) dimethyl 2-acetylsuccinate (1-6, 1.5 eq, 2.48 g, 13.2 mmol) was added. The reaction mixture was heated to 100 ºC for 5 h and concentrated to dryness. The reaction mixture was triturated in EtOAc for 15 min. The solid was collected by filtration, washed with EtOAc and dried in vacuo to provide compound 1-7 (2.38 g, 6.51 mmol, 74%) as a white solid that was used without further purification. * H NMR (500 MHz, DMSO) 5 12.27 (s, 1 H), 7.56 - 7.39 (m, 5 H), 3.63 (s, 3 H), 3.61 (s, 2H), 2.34 (s, 3H); MS (m / z): 365.9 [M + 1] *, 99.3%.
[00484] [00484] Step 2: Synthesis of 2- (5-methyl-7-0x0-3-phenyl-2- (trifluoromethyl) -4,7-dihydropyrazolo [1,5-a] pyrimidin-6- acid il) acetic (1-8): In a stirred solution of compound 1-7, 2.38 g, 6.51 mmol) in a mixture of THF (15 mL) and MeOH (15 mL) a solution of - 2M sodium oxide (15 mL, 30 mmol). The reaction mixture was stirred at r.t. for 1.5 h and concentrated to dryness. After adding water (15 ml) and 10% HCl (15 ml), the white suspension was stirred at r.t. for 15 min. The solid was collected by filtration, washed with water and dried in vacuo to provide compound 1-8 (2.27 g, 6.46 mmol, 99%) as a white solid which was used without further purification. MS (m / z): 352.1 [M + 1] *,> 99%.
[00485] [00485] Step 3: Synthesis of N- (2-aminophenyl) -2- (5-methyl-7-0x0-3-phenyl-2- (trifluoromethyl) -4,7-dihydropyrazolo [1,5 -a] pyrimidine-6-yl) acetamide (B1001): In a stirred solution of compound 1-8 (130 mg, 0.37 mmol) in DMF (1.8 ml) was added HATU (185 mg, 0.48 mmol), o-phenylenediamine (1-9, 161 mg, 1.48 mmol) and TEA (104 µl, 0.74 mmol). The reaction mixture was stirred at r.t. for 18h. After adding EtOAc, water and NaHCO ;, the layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO. and concentrated in vacuo. The residue was purified by reverse flash chromatography (KP-C18-H5, using a gradient of 0 to 100% MeCN in 10 mM aqueous ammonium formate buffer) to provide compound B1001 (122 mg, 0, 27 mmol, 75%) as a beige solid after lyophilization. * H NMR (500 MHz, DMSO) 5 12.24 (s, 1 H), 9.20 (s, 1 H), 7.53 - 7.50 (m, 2H), 7.47 - 7.43 (m, 3 H), 7.10 - 7.07 (m, 1 H), 6.93 - 6.88 (m, 1 H), 6.72 - 6.69 (m, 1H), 6, 52 (t, J = 7.0 Hz, 1 H), 4.86 (s, 2 H), 3.63 (s, 2H), 2.40 (s, 3H); MS (m / z): 442.1 [M + 1] *, 99.9%.
[00486] [00486] Table 3 below provides additional compounds that can be synthesized similarly to the methods described in Steps 1-3 above, replacing the compound listed by 1-9. The data for the synthesized compounds are given in columns 3-5.
[00487] [00487] Synthesis of 5-methyl-3-phenyl-6- (pyridin-4-i1) -2- (trifluoromethyl) pyrazolo [1,5-a] pyrimidin-7 (4H) -one (C1001) was performed on three steps to follow: N — NH oo Non Step 2 - - NH Ao o - = XxX - H 110 AcOH, 130 ºC and oºC 7 ErOR TPPIDCA 9 Ê V JN E Ny SS FAX AX Na, CO ,, 90 ºC FAN - The 12 PF Pain c1001 O
[00488] [00488] Step 1: Synthesis of 5-methyl-3-phenyl-2- (trifluoromethyl) pyrazolo [1,5-a] pyrimidin-7 (4H) -one (1-11): For a stirred solution of 4-phenyl-3- (trifluoromethyl) -1 H-pyrazol-5-amine (1-1, 1.43 g, 6.29 mmol) (WO 2012149157) in AcOH (31.5 mL) ethyl acetoacetate was added (1-10, 1 eq, 796 µL, 6.29 mmol). The reaction mixture was heated at 130 ºC for 1 h and concentrated to dryness. The reaction mixture was triturated in EtOAc for 15 min. The solid was collected by filtration, washed with EtOAc and dried in vacuo to provide compound 1-11 (1.04 g, 6.29 mmol, 56%) as a white solid which was used without further purification. * H NMR (500 MHz, DMSO) 5 12.27 (s, 1 H), 7.52 - 7.44 (m, 3 H), 7.43 - 6.7.40 (m, 2 H), 5.79 (d, J = 0.6 Hz, 1 H), 2.30 (s, 3H); MS (m / z): 294.1 [M + 1] *, 99.9%.
[00489] [00489] Step 2: Synthesis of 6-bromo-5-methyl-3-phenyl-2- (trifluoromethyl) pyrazolo [1,5-a] pyrimidin-7 (4H) -one (1-12): In a suspension Compound 1-11 (830 mg, 2.83 mmol) in DMF (9.4 mL) was added with N-bromosuccinimide (509 mg, 2.83 mmol) at 0 ° C. The reaction mixture was stirred at r.t. for 30 min. After adding water, the white suspension was stirred at r.t. for 10 min. The solid was collected by filtration, washed with water and dried in vacuo to provide compound 1-12 (921 mg, 2.47 mmol, 87%) as an off-white solid that was used without further purification. MS (m / z): 372.2-374.2 [M + 1J *, 98.1%.
[00490] [00490] Step 3: Synthesis of 5-methyl-3-phenyl-6- (pyridin-4-yl) -2- (trifluoromethyl) pyrazolo [1,5-a] pyrimidin-7 (4H) -one ( C1001): In a stirred solution of compound 1-12 (100 mg, 0.26 mmol) in a mixture of degassed EtOH (4 mL) and water (1 mL), pyridine-4-boronic acid (1- 13, 40 mg, 0.32 mmol), PA (PPh3) 2Cl2 (19 mg, 0.02 mmol) and Na2CO; 3 (117 mg, 1.10 mmol). The reaction mixture was heated at 90 ºC for 18 h. The reaction mixture was filtered through Celite, washed with MeOH and concentrated in vacuo. The residue was purified twice by reverse flash chromatography (KP-C18-H5, using a gradient of 0 to 100% MeCN in 10 mM aqueous ammonium formate buffer) to provide compound C1001 (7.4 mg, 0, 02 mmol, 7%) as a yellow solid after lyophilization. * H NMR (500 MHz, DMSO) 5 12.61 (bs, 1 H), 8.62 (s, 2 H), 7.52 - 7.48 (m, 4 H), 7.45 - 7, 39 (m, 3 H), 2.21 (s, 3H); MS (m / z): 371.2 [M + 1] *, 98.7%.
[00491] [00491] Table 4 below provides additional compounds that can be synthesized similarly to the methods described in Steps 1-3 above, replacing the compound listed by 1-13. The data for the synthesized compounds are given in columns 3-5.
[00492] [00492] Synthesis of 6- (4-methoxybenzo [alloxazol-2-i1) -5-methyl-3-phenyl-2- (trifluoromethyl) pyrazolo [1,5-a] pyrimidin-7 (4H) -one (C1014 ) was carried out in two stages as follows: o fe) 1 ra ra Stage 2 LTB, PAÇO AC), o DME oO ”EO
[00493] [00493] Step 1: Synthesis of 6-iodo-5-methyl-3-phenyl-2- (trifluoromethyl) pyrazolo [1,5-a] pyrimidin-7 (4H) -one (1-14): In a suspension of 5-methyl-3 = -phenyl-2- (trifluoromethyl) pyrazolo [1,5-a] pyrimidin-7 (4H) -one (1-11, 450 mg, 1.53 mmol) was added N-iodosuccinimide ( 363 mg, 1.53 mmol) at O ҼC. After 30 min, LCMS showed complete conversion. The reaction was poured into water. The precipitated solid was filtered, washed with dilute aqueous Na2S2O3 followed by water. The solid was dried under high vacuum to produce the desired 1-14. * H NMR (500 MHz, DMSO) 5 12.75 (bs, 1 H), 7.53 - 7.40 (m, 5 H), 2.58 (s, 3H). MS (m / z): 420.0 [M + 1] *.
[00494] [00494] Step 2: Synthesis of 6- (4-methoxybenzo [aJoxazol-2-yl) -5-methyl-3-phenyl-2- (trifluoromethyl) pyrazolo [1,5-a] pyrimidin-7 (4H) - one (C1014): A mixture of 6-iodo-5-methyl-3-phenyl-2- (trifluoromethyl) pyrazolo [1,5-a] pyrimidin -7 (4H) -one (1-14,100 mg, 239 umol) , 4-methoxybenzo [d] oxazole (1-15, 53.5 mg, 358 umol), lithium tert-Butoxide (133 µL, 1.43 mmol) and palladium (ll) acetate (5.36 mg , 23.9 umol) in DMF (1.50 mL) were degassed with nitrogen. The reaction mixture was heated to 110 ºC for 16 h. The crude reaction mixture was filtered through celite and washed with ethyl acetate. The filtrate was evaporated and the residue was purified by reverse phase column chromatography using a 20-70% MeCN / H2O gradient (0.1% ammonium formate buffer) to produce compound C1014 (96, 9% purity). * H NMR (500 MHz, DMSO) 5 12.95 (s, 1 H), 7.52 - 7.43 (m, 5 H), 7.35 (d, J = 4.6 Hz, 2H), 7.01 - 6.91 (m, 1 H), 4.00 (s, 3H), 2.48 (s, 3H). MS (m / z): 441.2 [M + 1] *.
[00495] [00495] Table 5 below provides additional compounds that can be synthesized similarly to the methods described in Steps 1-2 above, optionally replacing the compound listed as indicated by 1-15 and / or replacing 1-1 and / or 1-10 where indicated to provide the appropriate analog of 1-11 (by way of Example 3). The data for the synthesized compounds are given in columns 3-5.
[00496] [00496] The compounds in Table 5A below were synthesized similarly to the methods described in Steps 1-2 above, optionally replacing the compound listed as indicated by 1-15 and / or substituting 1-10 where indicated and No
[00497] [00497] Synthesis of 6- (8-methoxyimidazo [1,2-a] pyridin-2-yl) -5-methyl-3-phenyl-2- (trifluoromethyl) pyrazolo [1,5-a] pyrimidin-7 ( 4H) -one (C1044) was carried out in one step to follow: Rex 'Cox dioxane n 2112) A "RR NZ ST -> nc NA) HH 146 d TFA, 50 º C EN Ç 2 C1044
[00498] [00498] Step1: In a solution of 4-phenyl-3- (trifluoromethyl) -1H-pyrazol-5-amine (1-1, 55.0 mg, 242 umol) and ethyl 2- (8-methoxyimidazo [1, 2- alpiridin-2-i1) -3-oxobutanoate (1-16, 73.6 mg, 266 umol) in dioxane (807 µl) TFA (403 µl) was added and the reaction mixture was heated to 50 ° C for 6 h. LCMS shows that the reaction has been completed. The volatiles were removed in vacuo. The crude material was purified by reverse phase chromatography in a Companion Combiflash using 10g of C18 column with a gradient elution of 20-50% MeCN / H20 (0.1% ammonium formate buffer) for 15 minutes and a flow rate of 30 mL / min. Clean fractions were combined and lyophilized to provide compound C1044, * HNMR (500 MHz, DMSO) at 12.46 (s, 1 H), 8.31 (s, 1 H), 8.26 (d, J = 6.6 Hz, 1 H), 7.55 - 7.48 (m, 4 H), 7.46 (s, 1H), 6.85 (s, 1H), 6.70 (s, 1H), 3.97 (s, 3H), 2.71 - 2.60 (m, 3H). MS (m / z): 440.2 [M + 1] *, 98.1%.
[00499] [00499] Table 6 below provides additional compounds that can be synthesized similarly to the methods described in the step above, replacing the compound listed as indicated by 1-16, as well as replacing with 1-1 where indicated. The data for the synthesized compounds are given in columns 3-5.
[00500] [00500] Synthesis of 5-methyl-3-phenyl-6- (1-phenyl-1H-benzo [alimidazo | -2-yl) -2- (trifluoromethyl) pyrazolo [1,5-a] pyrimidin-7 (4H ) -one (C1229) was carried out in two steps below: Step 2 o o o 2) MeOH, 90 * C o 4) RA In AS AS Riad DOS mm mm. N C1229 "if
[00501] [00501] Step 1: Synthesis of 5-methyl-7-0x0-3-phenyl-2- (trifluoromethyl) - 4,7-dihydropyrazolo [1,5-a] pyrimidine-6-carbaldehyde (1-17) : A suspension of 5-methyl-3-phenyl-2- (trifluoromethyl) pyrazolo [1,5-a] pyrimidin-7 (4H) -one (1-11, 1.00 g, 3.41 mmol) in dry DMF (3.40 mL) it is pre-cooled to 0-4 ºC using an ice / water bath. In a separate flask, oxalyl chloride (383 uL, 4.43 mmol) is dissolved in DCM (3.41 mL) and cooled to 0-4 ºC using an ice / water bath. To this solution is added DMF (343 uL, 4.43 mmol) and the resulting mixture is added dropwise to the suspension of compound 1-11. The reaction mixture is stirred at 0-4 ºC and gradually heated to temperature environment. After overnight at room temperature, the reaction mixture is poured into a mixture of ice and 1M aqueous NaOH solution. EtOAc is then added and the layers are separated. The organic layer is washed with brine, dried over Na2SO4. anhydrous, filtered and concentrated in vacuo. The crude oil was purified by normal phase chromatography (SiO>, using a gradient of 0 to 20% MeOH in DCM) to provide the compound | -17, MS (m / z): 322.0 [ M + 1] *, 92.25%.
[00502] [00502] Step 2: Synthesis of 5-methyl-3-phenyl-6- (1-phenyl-1H-benzo [a] imidazol-2-yl1) -2- (trifluoromethyl) pyrazolo [1,5-a] pyrimidine -7 (4H) -one (01229): In a stirred solution of compound 1-17 (50 mg, 0.156 mmol) in MeOH (1 mL) was added N-phenylbenzene-1,2-diamine (I-
[00503] [00503] Table 7 below provides additional compounds that can be synthesized similarly to the methods described in steps 1-2 above, replacing the compound listed as indicated for 1-18, as well as substituting for 1-1 (via Example , 3) where indicated to produce the appropriate 1 | -11 analog. The data for the synthesized compounds are given in columns 3-5.
[00504] [00504] Synthesis of 5-chloro-6- (4-methoxybenzo [a] oxazol-2-i1) -3-phenyl-2- (trifluoromethyl) pyrazolo [1,5-a] pyrimidin-7 (4H) -one (C1071) and 5-methoxy-6- (4-methoxybenzo [aJoxazol-2-i1) -3-phenyl-2- (trifluoromethyl) pyrazolo [1,5-alpirimidin-7 (4H) -one (C1084) in two and three stages, respectively, as follows: FC qUNA qe NR oe: Stage1 E 2d + Co a) DCM, 120% Pe! oH S E H 119 O b) NaOMe, MeOH Ç Õ 1.20 o <<) the << Stage 2 Fe PO N P Stage ne AXO »POCL, 75%. 2 and MeOH, NaOMe o o K) c1071 120ºC &) Cc1084
[00505] [00505] Step 1: Synthesis of 5-hydroxy-6- (4-methoxybenzo [alloxazol-2- i1) -3-phenyl-2- (trifluoromethyl) pyrazolo [1,5-a] pyrimidin-7 (4H) - one / - (1-20): A mixture of 4-phenyl-3- (trifluoromethyl) -1 H-pyrazol-5-amine (1-1, 1.68 9, 7.40 mmol) and 2- (4 -methoxybenzo [d] oxazol-2-yl) malonate (1-19, 2.50 g, 8.14 mmol) were dissolved in DCM (5 ml). The reaction mixture was concentrated in vacuo and the residue was heated to 120 ºC for 2 h. LCMS showed complete reaction and the crude mixture was dissolved in MeOH (5 mL), and sodium methoxide in MeOH (30 mmol) was added and the reaction was stirred at r.t. for 3 h. The reaction was quenched with ACOH and concentrated in vacuo. The desired compound was broken after adding water. The resulting white solid was filtered and dried in vacuo to provide compound 1-20, MS (m / z): 443.0 [M + 1] *.
[00506] [00506] Step 2: Synthesis of 5-chloro-6- (4-methoxybenzo [alloxazol-2-yl) - 3-phenyl-2- (trifluoromethyl) pyrazolo [1,5-a] pyrimidin-7 (4H) - ona / (C1071): Compound 1-20 (2.0 g, 4.52 mmol) was dissolved in POCI3 (10 mL) and heated to 75 ° C for 4 h in a sealed tube. The excess POCI was removed in vacuo and the crude material was directly purified on normal phase flash chromatography (Hexanes: EtOAc, 100: 10 to 0: 100) to obtain compound C1071, MS (m / z): 460.8 [M + 1] *.
[00507] [00507] Step3: Synthesis of 5-methoxy-6- (4-methoxybenzo [alloxazol-2- i1) -3-phenyl-2- (trifluoromethyl) pyrazolo [1,5-a] pyrimidin-7 (4H) -one - (C1084): Sodium methoxide (0.05 mL of 25% in MeOH, 0.217 mmol) was added to a solution of compound C1071 (10 mg, 0.0217 mmol) dissolved in MeOH (1.0 mL, alternatively, DMF can be used here depending on the desired compound) with stirring, and then heated to 120 ° C for 1 h. The reaction mixture was quenched with saturated NH.4Cl solution, diluted with EtOAc (5 mL), and the two phases were separated. The organic layer was washed with saturated NHLCI, then brine and dried over Na2SO2. The mixture was concentrated in vacuo and purified by reverse phase chromatography using MeCN / H2O (0.1% ammonium formate buffer) as the eluent to provide compound C1084. * H NMR (500 MHz, DMSO) 5 7.66 (d, J = 7.5 Hz, 2 H), 7.44 (t, JU = 7.8 Hz, 2 H), 7.29 (m, 3 H), 6.98 - 6.94 (m, 1 H), 4.00 (s, 3H), 3.83 (s, 3H). MS (m / z): 457.1 [M + 1] *, 96.0%.
[00508] [00508] Table 8 below provides additional compounds that can be synthesized similarly to the methods described in step 3 above, replacing the compound listed for NaOMe in Step 3. Data for the synthesized compounds are provided in columns 3-5.
[00509] [00509] Synthesis of N- (2-hydroxycyclohexyl) -5-methyl-7-0x0-3-phenyl-2- (trifluoromethyl) -4,7-dihydropyrazolo [1,5-a] pyrimidine-6 -carboxamide (A1141), 5-methyl-7-0x0-N- (2-oxocyclohexyl) -3-phenyl-2- (trifluoromethyl) -4,7- dihydropyrazolo [1,5-a] pyrimidine- 6-carboxamide (A1142), and 5-methyl-3-phenyl-6- (4,5,6,7-tetrahydrobenzo [d] oxazol-2-yl1) -2- (trifluoromethyl) pyrazole [1,5 -a] pyrimidin-7 (4H) -one (C1015) was performed in one, two and three steps, respectively, as follows: ooo LAO SS mM SÕ Memo Sd 4 A1141 oo O o O Step 2 e and O Step 3 te DIPEA, Pyr-SO, FÊ THF, complex FEA reagent, 0 º Õ 4 1142 - Burgess, 50% SS c1015
[00510] [00510] Step 1: Synthesis of N- (2-hydroxycyclohexyl) -5-methyl-7-0x0-3-phenyl-2- (trifluoromethyl) -4,7-dihydropyrazolo [1,5-a] pyrimidine-6-carboxamide (A1141): In a mixture of 5-methyl-7-0x0-3-phenyl-2- (trifluoro-methyl) -4,7-dihydropyrazolo [1,5-a] pyrimidine-6-carboxylic (1-4, 50.0 mg, 148 umol), trans-2-aminocyclohexanol hydrochloride (1-21, 45.0 mg, 297 umol), HATU (58.1 mg, 148 umol) in DMF (740 yuL) TEA (83.5 uL, 593 umol) was added and the solution was stirred at room temperature for 24 h. Subsequently, the reaction mixture was purified directly on a reverse flash chromatography (KP-C18-H5, using a gradient of 0 to 100% MeCN in 10 mM aqueous ammonium formate buffer) to provide compound A1141 as a white solid after lyophilization. * H NMR (MHz, DMSO) 5 12.53 (s, 1 H), 7.55 - 7.39 (m, 5 H), 4.65 (s, 1 H), 3.68 - 3.52 (m, 1 H), 3.37 - 3.31 (m,
[00511] [00511] Step 2: Synthesis of 5-methyl-7-oxo-N- (2-oxocyclohexyl) -3-phenyl-2- (trifluoromethyl) -4,7-dihydropyrazolo [1,5-a] pyrimidine-6-carboxamide (A1142): In a solution of compound A1141 (50.0 mg, 115 umol) in DIPEA (241 µL, 1.37 mmol), sulfur trioxide-pyridine complex (220 mg, 1, 38 mmol) followed by DIPEA (241 µL, 1.37 mmol) at 0 ° C. The reaction was gradually heated to r.t. during the night. After 18 h, the reaction mixture was diluted with IN HCI (10 ml) and extracted with EtOAc (3 x 10 ml). The organic fraction was washed with brine (10 mL), dried over Na> 2 SO, filtered and concentrated in vacuo. The crude reaction mixture was directly subjected to purification by reverse flash chromatography (KP-C18-H5, using a gradient of 0 to 100% MeCN in 10 mM aqueous ammonium formate buffer) to provide compound A1142 (22 , 5 mg, 45%) as a solid white after lyophilization. * H NMR (500 MHz, DMSO) 5 12.71 (s, 1H), 7.55 (d, J = 7.2 Hz, 2H), 7.43 (t, J = 7.6 Hz, 2H) , 7.381 (s, 1 H), 4.60 (dt, J = 12.3, 6.2 Hz, 1 H), 2.59 (s, 3 H), 2.47 - 2.38 (m, 2 H), 2.38 - 2.28 (m, 1 H), 2.08 - 1.99 (m, 1H), 1.87 - 1.73 (m, 2H), 1.62 (s, 1H), 1.50 - 1.39 (m, 1H). MS (m / z): 433.1 [M + 1] *, 96.9%.
[00512] [00512] Step3: Synthesis of 5-methyl-3-phenyl-6- (4,5,6,7-tetrahydrobenzo [a oxazo] -2-yl) -2- (trifluoromethyl) pyrazolo [1,5- a] pyrimidin-7 (4H) -one (C1015): In a 10 ml bottle containing compound A1142 (21.5 mg, 49.7 umol) in THF (2.50 ml), Burgess reagent (30 ml) was added , 6 mg, 124 umol). The resulting solution was stirred overnight at 50 ° C. Additional Burgess reagent (61.4 mg, 249 umol) was added and stirred until total consumption of the starting material. Subsequently, the crude solution was directly subjected to purification by reverse flash chromatography (KP-C18-H5, using a gradient of 0 to 100% MeCN in 10 mM aqueous ammonium formate buffer)
[00513] [00513] Table 9 below provides additional compounds that can be synthesized similarly to the methods described in steps 1-3 above, optionally substituting the compound listed by 1-21 and / or by substituting 1-1 and / or 1-2 (see Example 1) where indicated to provide the appropriate analogue for 1-4. The data for the synthesized compounds are given in columns 3-5.
[00514] [00514] Synthesis of (S) -N- (1-hydroxy-3-methoxypropan-2-yl) -5-methyl-7-ox0-3-phenyl-2- (trifluoromethyl) -4,7-dihydropyrazole [1,5-a] pyrimidine-6-carboxamide (A1143), and (R) -6- (4- (methoxymethyl) -4,5-dihydro-oxazol-2-yl) - 5-methyl-3 -phenyl-2- (trifluoromethyl) pyrazolo [1,5-a] pyrimidin-7 (4H) -one (C1184) was performed in one and two stages, respectively, as follows: oo N Hori AN o and DIPER To 4 1-22 / o
[00515] [00515] Step1: Synthesis of (S) -N- (1-hydroxy-3-methoxypropan-2-yl) - 5-methyl-7-0x0-3-phenyl-2- (trifluoromethyl) -4,7-di -hydropyrazolo [1,5-a] pyrimidine-6-carboxamide (A1143): A solution of 5-methyl-7-0x0-3-phenyl-2- (trifluoromethyl) -4,7-dihydropyrazole [ 1,5-a] pyrimidine-6-carboxylic (1-4, see Example 1, 1.00 g, 2.97 mmol), HATU (4.51 g, 11.9 mmol) and N, N-diisopropylethylamine ( 2.61 mL, 14.8 mmol) in DMF (319 µL) was stirred for 30 min. L-serine-methyl ether hydrochloride (1-22, 840 mg, 5.93 mmol) was added. The resulting solution was stirred at r.t. for 1h. 1 N HCI was added and the mixture was extracted with EtOAc (3 x 20 ml). The organic layer was washed with sat. (10 ml), then brine (10 ml) and dried over Na> 2SO:, filtered and concentrated to provide compound A1143, MS (m / z): 425.0 [M + 1] *.
[00516] [00516] Step 2: Synthesis of (R) -6- (4- (methoxymethyl) -4,5-dihydro-oxa-
[00517] [00517] Table 10 below provides additional compounds that can be synthesized similarly to the methods described in steps 1-2 above, replacing the compound listed by 1-22. The data for the synthesized compounds are given in columns 3-5.
[00518] [00518] Synthesis of 5-methyl-6- (1-oxoisoindolin-2-yl) -3-phenyl-2- (trifluoro-methyl) pyrazolo [1,5-a] pyrimidin-7 (4H) -one (C1214 ) was carried out in the following stage: O, NN Ã! . N-. TO YO PS 'O PO XX Cc1214 H DMEDA, Cs, CO ;, NS 114 as Cul, 1,4-dioxane, Sd 120ºC
[00519] [00519] Step1: In a sealed tube, 1-isoindolinone (1-23, 32.4 mg, 239 umol), N, N "-dimethylethylenediamine (27.0 ul, 239 umol), Cs2C0O; 3 (236 mg , 716 umol), copper iodide (22.7 mg, 119 umol) and was stimulated with nitrogen, then 1,4-dioxane (2.39 mL) and 6-iodine-5-methyl-3-phenyl-2 - (trifluoromethyl) pyrazolo [1,5-a] pyrimidin-7 (4H) -one (1-14, 100 mg, 239 umol) was added. The mixture was bubbled with nitrogen for 5 min. then heated to 120 ° C overnight The crude mixture was concentrated in vacuo, then subjected to purification by reverse flash chromatography (KP-C18-H5, using a gradient of 0 to 100% MeCN in ammonium formate buffer aqueous 10 mM) to provide compound C1214 as a white solid after lyophilization. * H NMR (500 MHz, DMSO) 5 12.69 (s, 1 H), 7.79 (d, J = 7.5 Hz, 1 H), 7.72 - 7.66 (m, 2H), 7.60 - 7.54 (m, 1 H), 7.54 - 7.47 (m, 4 H), 7.45 - 7, 39 (m, 1 H), 4.89 (d, J = 17.2 Hz, 1 H), 4.60 (d, J = 17.2 Hz, 1 H), 2.24 (s, 3H); MS (m / z): 425.1 [M + 1] *, 99.7%.
[00520] [00520] Table 11 below provides additional compounds that can be synthesized similarly to the methods described in the step above, replacing the compound listed by 1-23. The data for the synthesized compounds are given in columns 3-5.
[00521] [00521] Synthesis of 5 - ((2-hydroxyethoxy) methyl) -6- (4-methoxybenzo [a] oxazol-2-11) -7-0x0-3-phenyl-4,7-dihydropyrazolo [ 1,5-a] pyrimidine-2-carbonitrile (C1248) was performed in four stages, as follows: o NH Ne <1) | Step 2 feet and AcOR, fa, N and DMF, NIS NH 125 —following 100ºC A '1-24 A) 1-26 oo In the short term, NE DME, NaH 2 9 on A 4 + Ho = NL rar 28) r2o Step 4 Meo DMF, LiotBu, o O Pd (OAc) , 95 ºC Ny o OMe NE SK 2 C1248
[00522] [00522] Step 1: Synthesis of 5- (chloromethyl) -7-0x0-3-phenyl-4,7-dihydropyrazole [1,5-alpirimidine-2-carbonitrile (1-26): Ethyl 4- Chloroacetoacetate (1-25, 927 µl, 6.51 mmol) was added to a solution of 5-amine-4-phenyl-1H-pyrazol-3-carbonitrile (1-24, 1.00 g, 4 , 34 mmol) in AcOH (4.93 mL). The solution was stirred at r.t. for 15 min and then heated to 100 ºC for 1h. After cooling, the white suspension was filtered and the resulting solid was washed with Et2O (x3) to provide compound | - 26 as a beige solid. MS (m / z): [M + H] * 285.0.
[00523] [00523] Step 2: Synthesis of 5- (chloromethyl) -B6-iodine-7-0x0-3-phenyl-4,7-dihydropyrazolo [1,5-a] pyrimidine-2-carbonitrile (1-27) : In a 20 ml microwave vial, compound 1-26 (500 mg, 1.76 mmol) in DMF (11.7 ml) was added. N-iodosuccinimide (489 mg, 2.11 mmol) was then added in one portion. The reaction was stirred
[00524] [00524] Step 3: Synthesis of 5 - ((2-hydroxyethoxy) methyl) -6-iodo-7-0x0- 3-phenyl-4,7-dihydropyrazolo [1,5-a] pyrimidine-2-carbonitrile (1-29): In a 10 ml flame-dried microwave flask, sodium hydride (60% in mineral oil) (7.1 mg, 0.49 mmol) in dry DMF (0 , 7 mL). Then, ethylene glycol (1-28, 25.1 µL, 0.45 mmol) was added. The mixture was stirred at r.t. over 5 min and compound 1-27 (80.0 mg, 0.20 mmol) in DMF (0.7 mL) was added dropwise. The reaction was stirred at r.t. for 18 h, then quenched with ammonium chloride. The organic layers were separated and the aqueous layer was extracted (2x) with EtOAc. The organic layers were combined, washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to provide a brownish oil. This crude material was recrystallized from DCM / diethyl ether, filtered and washed with diethyl ether (3x) to provide compound 1-29 as a yellow solid. MS (m / z): [M + H] * 437.0,
[00525] [00525] Step 4: Synthesis of 5 - ((2-hydroxyethoxy) methyl) -6- (4-methoxy-benzo [alloxazol-2-i1) -7-0x0-3-phenyl-4,7-dihydropyrazole [1,5-a] pyrimidine-2-carbonitrile (C1248): In a 10 ml flame-dried microwave vial, compound 1-29 (50.0 mg, 0.12 mmol), 4 -methoxybenzo [alloxazole (1-15, 26.6 mg, 0.17 mmol), lithium tert-butoxide (47.3 mg, 0.57 mmol) and palladium (ll) acetate (2.63 mg, 10 mol%) in dry DMF (0.40 ml). Then, the
[00526] [00526] Table 12 below provides additional compounds that can be synthesized similarly to the methods described in steps 1-4 above, optionally substituting the compound listed by 1-15 and / or by substituting 1-24 and / or 1-28 Where indicated. The data for the synthesized compounds are given in columns 3-5.
[00527] [00527] Synthesis of 6- (4-methoxybenzo [aloxazol-2-yl) -7-0x0-3-phenyl-2- (trifluoromethyl) -4,7-dihydropyrazolo [1,5-a] pyrimidine- 5-carboxylic (01131) and 6- (4-methoxybenzo [a] oxazol-2-yl) -N- (2-methoxyethyl) -7-0x0-3-phenyl -2- (trifluoromethyl) -4,7-di -hydropyrazolo [1,5-a] pyrimidine-S-carboxamide (C1142) was performed in three and four stages, respectively, as follows: the Nx. F.C EX, o Step 1 in AN | NH AA to ACOH, 100 ºC ÊF N OS x o H r3o O 11 o Stage3 PN! DMF, LTB, Etapaz FOX) | , PdA (OAc), 110 ºC —— N E DMF, NIS, H oºcâàta oMe 132 + N
[00528] [00528] Step1: Synthesis of ethyl 7-0x0-3-phenyl-2- (trifluoromethyl) -4,7-dihydropyrazolo [1,5-a] pyrimidine-5-carboxylate (1-31): In a solution 4-phenyl-3- (trifluoromethyl) -1H-pyrazol-5-amine (1-1, 1.0 g, 4.48 mmol) in AcCOH (5 mL) was added with diethyl oxalacetate (1-30, 0.98 g, 5.2 mmol). The reaction mixture was heated to 100 º C for 120 min. Acetic acid was removed in vacuo. Et2O / Hex 1: 1 (5 mL) was added and stirred at r.t. for 5 min. The mixture was filtered, washed with
[00529] [00529] Step 2: Synthesis of ethyl 6-sludge-7-0x0-3-phenyl-2- (trifluoromethyl) -4,7-dihydropyrazolo [1,5-a] pyrimidine-S-carboxylate / ( 1-32): In a stirred solution of compound 1-31 (1.2 g, 3.36 mmol) in DMF (11.2 mL) cooled to 0 ºC (white suspension), N-iodosuccinimide (0 , 87 g, 3.52 mmol), then warmed to room temperature. After 1 h, LCMS showed complete conversion. The reaction mixture was poured over Na2S2O; 3 (30 ml). The precipitated solid was filtered, washed with NaHCO; diluted and dried in vacuo to produce compound 1-32 as a white solid. MS (m / z): 477.9 [M + 1] *.
[00530] [00530] Step 3: Synthesis of 6- (4-methoxybenzo [a] oxazol-2-yl) - 7-0x0-3-phenyl-2- (trifluoromethyl) -4,7-dihydropyrazole acid [1,5 -a] pyrimidine-5-carboxylic (C1131): Compound 1-32 (300 mg, 629 umol), 4-methoxy-benzo [d] oxazole (1-15, 1.5 eq, 141 mg, 943 umol), lithium tert-butoxide (292 µL, 3.14 mmol), palladium (II) acetate (14.3 mg, 62.9 umol) were added in DMF (2 ml). The reaction was degassed with nitrogen and then heated to 110 ºC for 4 h. The reaction was cooled to r.t. and the product precipitated with 1N HCI and, subsequently, filtered. The obtained solid was purified by reverse phase chromatography 0 - 100% MeCN / H2O (0.1% ammonium bicarbonate buffer) and lyophilized to produce compound C1131 as a white solid. * H NMR (500 MHz, DMSO) at 7.60 (d, J = 7.6 Hz, 2H), 7.42 (t, J = 7.7 Hz, 2H), 71.380 (t, J = 7, 4 Hz, 1 H), 7.24 - 7.21 (m, 2H), 6.89 - 6.84 (m, 1H), 3.98 (s, 3H); MS (m / z): 471.1 / 427.1 [M + 11 °, 100%.
[00531] [00531] Step 4: Synthesis of 6- (4-methoxybenzo [d] oxazol-2-yl) -N- (2-methoxyethyl) -7-0x0-3-phenyl-2- (trifluoromethyl) -4,7- dihydropyrazolo [1,5-a] pyridimine-5-carboxamide (C1142): A solution of compound C1131 (25.0 mg, 53.2 umol) in THF (500 µL) was cooled to 0 ° C. Oxalyl chloride (13.8 ul, 159 umol) was added followed by a drop of
[00532] [00532] Table 13 below provides additional compounds that can be synthesized similarly to the methods described in steps 1-4 above, replacing the compound listed by 1-33 or replacing I-24 with | -1, when indicated. The data for the synthesized compounds are given in columns 3-5.
[00533] [00533] Synthesis of 6- (4-methoxybenzo [alloxazol-2-yl) -7-0x0-3-phenyl-2- (trifluoromethyl) -4,7-dihydropyrazolo [1,5-a] pyrimidine-S -carbonitrile (C1089) was carried out in the following stage: —Oo —Oo oo EC JO Pd, Zn (CN); ”XI N Cl N CN NY; c1071 SS.
[00534] [00534] Step 1: Compound C1071 (see, Example 7, Step 2, 20.0 mg, 0.0434 mmol), Pd (TFA) 2 (1.44 mg, 0.00434 mmol), Zinc cyanide (5 , 20 mg, 0.0434 mmol), TrixPhos (3.53 mg, 0.00868 mmol), Zn (0.203 uL, 0.0217 mmol) were successively loaded into a glass tube equipped with a magnetic stir bar and cap threaded thread. The tube was evacuated and refilled with nitrogen. DMAC (anhydrous, 99.8%, 3 mL) was added via syringe and the resulting reaction mixture was degassed. The reaction mixture was then heated to 110 ºC for 14 hours. The reaction mixture was then cooled to room temperature, diluted with MeCN, filtered through Celite. The solvent was evaporated and the crude material was purified by semi-preparative HPLC-MS using MEeCN and 10 mM aqueous AmForm buffer as the eluent to provide compound C1089 (8.00 mg, 41%). H NMR (500 MHz, DMSO) 8.27 (s, 1 H), 7.57 (d, J = 7.3 Hz, 2H), 7.48 (t, | = 7.7 Hz, 2H) , 7.37 - 7.32 (m, 3 H), 6.94 (dd, J = 7.3, 1.7 Hz, 1 H), 4.04 (s, 3H). LCMS m / z: [M + H] * = 452.2; 5-100% MeCN / H2O (0.1% AMF buffer) for 7 min.
[00535] [00535] Synthesis of 5-amino-6- (4-methoxybenzo [alloxazol-2-i1) -3-phenyl-2- (trifluoromethyl) pyrazolo [1,5-a] pyrimidin-7 (4H) -one (C1085 ) was carried out in the following step: —Oo - Oo. oO N - o 4 | S A | NN O NH, z N — N Oo
[00536] [00536] Step1: A mixture of acetamide (51.8 mg, 868 umol), C1071 (see, Example 7, Step 2, 10.0 mg, 21.7 umol) and K2CO; 3 (51.8 mg, 109 umol) was heated to 200 ºC for 2 h. The reaction mixture was dissolved in 1 ml of DMSO and purified by reverse flash chromatography (KP-C18-H5 reverse phase column using MeCN and 10 mM aqueous AmForm buffer as eluent) to provide C1085 (2 mg, 21%) . H NMR (500 MHz, DMSO) 5 8.15 (s, 1 H), 7.58 (d, J = 7.3 Hz, 2 H), 7.37 (t, J = 7.8 Hz, 2 H), 7.27 - 7.19 (m, 2H), 7.15 (d, J = 8.1 Hz, 1 H), 6.86 (d, J = 7.6 Hz, 1 H) , 3.96 (s, 3H). LOCMS m / z: [M + H] "= 442.0; 5-100% MeCN / H2O (0.1% AMF buffer) for 7 min. Example 15
[00537] [00537] Synthesis of 6- (4-methoxybenzo [d] oxazol-2-yl) -5- (1-methyl-1H-pyrazol-4-i1) -3-phenyl-2- (trifluoromethyl) pyrazole [1, 5-a] pyrimidin-7 (4H) -one (C1255) was performed in the following step: d Box 2X) Ne (HO), B. . À Fe aaa + CT H3O, NazCO ;, AXIS at 134 PdldppfiCk, Ns AS = (CHzOMe), LN W / emo 100 ºC
[00538] [00538] Step1: A mixture of compound C1071 (see, Example 7, Step 2, 30.0 mg, 62.9 umol, see Example 7), boronic acid (1-methyl-1H-pyrazol-4-yl) ( 1-34, 12.5 mg, 94.4 umol), sodium carbonate (13.3 mg, 126 umol) and [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (II) (30.6 mg, 37.4 umol) in water (110 uL) and dimethoxyethane (220 uL) were degassed by bubbling under nitrogen for 5 min. The reaction was stirred overnight at 110 ° C. The crude mixture was concentrated in vacuo, then purified by reverse phase chromatography (KP-C18-H5, using a gradient of O to 100% MeCN in 10 mM aqueous AmForm buffer) to provide compound C1255 after lyophilization. * 'H NMR (500 MHz, DMSO- d6) 5 7.94 (s, 1 H), 7.56 (d J = 7.3 Hz, 2 H), 7.53 - 7.46 (m, 2 H), 7.45 - 7.35 (m, 2 H), 7.31 (d, J = 7.6 Hz, 1 H), 7.05 (s, 1 H), 6.98 (d, J = 7.7 Hz, 1 H), 3.98 (s, 3 H), 3.76 (s, 3H); MS (m / z): 507.3 [M + 1) ”.
[00539] [00539] “Compounds 6- (4-methoxybenzo [aloxazol-2-i1) -5- (3-methylisoxazol-4-i1) -3-phenyl-2- (trifluoromethyl) pyrazole [1,5-a] pyrimidine-7 (4H) -one (01253) and 6- (4-methoxybenzo [alloxazol-2-i1) -3-phenyl-5- (1H-pyrazol-4-i1) -2- (trifluoromethyl) pyrazole [1 , 5-a] pyrimidin-7 (4H) -one (C1254) —o - o
[00540] [00540] Synthesis of 5- (dimethylphosphoryl) -6- (4-methoxybenzo [alloxazol-2- i1) -3-phenyl-2- (trifluoromethyl) pyrazolo [1,5-a] pyrimidin-7 (4H) -one (C1284) was performed in a following step: d Fa S Cl HP (O) M , Pd (OAc) ,, Sº Px Xantphos, K; PO, ci1o71 DMA, 130 ºC C1284
[00541] [00541] Step 1: A mixture of compound C1071 (see, Example 7, Step 2, 20.0 mg, 0.043 mmol), dimethylphosphine oxide (10.0 mg, 0.130 mmol), PAd (OAc) 2 (1, 48 mg, 0.00651 mmol), Xantphos (7.69 mg, 0.013 mmol)) and K3POa (27.6 mg, 0.130 mmol) in DMF (500 yuL) was degassed with N>, The reaction mixture was, in then heated at 130 ºC for 3 h after which it was filtered over celite and washed with MeOH. The filtrate was evaporated in vacuo and the resulting material was purified by reverse phase HPLC (AmF / MeCN) to provide Compound C1284. * H NMR (500 MHz, DMSO) 5 7.69 (d, J = 7.5 Hz, 2 H), 7.44 (t, J = 7.7 Hz, 2H), 7.32 - 7.23 (m, 3 H), 6.89 (d, J = 7.4 Hz, 1 H), 4.00 (s, 3 H), 1.69 (s, 3 H), 1.67 (s, 3H); MS (m / z): 503.1 [M + 1] *, 100%.
[00542] [00542] Synthesis of 5-methyl-6- (5-methyl-1,3,4-0xadiazol-2-i1) -3-phenyl-2- (trifluoromethyl) pyrazolo [1,5-a] pyrimidin-7 ( 4H) -one (D1001) or 5-methyl-6- ((5-methyl-1,3,4-0xadiazol | -2-yl) methyl) -3-phenyl-2- (trifluoromethyl) pyrazole [1,5 - alpirimidin-7 (4H) -one (D1032) was carried out in the following stage: 7 n = 0o1 "ne ne OT o ne OE
[00543] [00543] Step 1: Preparation of 5-methyl-6 - (((5-methyl-1,3,4-0xadiazole-
[00544] [00544] Step 1: 5-methyl-6- (5-methyl-1,3,4-0xadiazol-2-yl) -3-phenyl-2- (trifluoromethyl) pyrazolo [1,5-a] pyrimidin -7 (4H) -one (D1001) was prepared following this method from compound 1-4 (see, Example 1). * H NMR (500 MHz, DMSO) 5 7.54 (d, J = 7.4 Hz, 2 H), 7.45 (t, JU = 7.7 Hz, 2H), 7.35 (t, J = 7.4 Hz, 1 H), 2.55 (s, 3H), 2.31 (s, 3H); MS (m / z): 376.1 [M + 1] *, 99.0%.
[00545] [00545] Table 14 below provides additional compounds that can be synthesized similarly to the methods described in step above | -4, unless otherwise indicated by replacing the compound listed with 1-35 and / or replacing 1-1 and / or 1-2 where indicated to provide the appropriate analogue of 1-4 (by way of Example 1). The data for the synthesized compounds are given in columns 3-5.
[00546] [00546] Synthesis of 6- (2-aminoethyl) -5-methyl-3-phenyl-2- (trifluoromethyl) pyrazolo [1,5-a] pyrimidin-7 (4H) -one (B1012) and N- (2- (5-methyl-7-0x0-3-phenyl- 2- (trifluoromethyl) -4,7-dihydropyrazolo [1,5-a] pyrimidin-6-yl) ethyl) acetamide (B1013) was performed in four and five stages, respectively, as follows: 9 o se een Stage 1 Lv OH Stage YA —— Fne << | - (H a) THF, LAH N THF, CH; S (O), CI, SD 1 b) NaoH dd TEA, 0ºC E cN / 36 oo A 9 s N. Fen Jo Step 3 and eMmpR AO º Ad - do MeOH, PdiC, H, SD rs7 A 18 oo H ss NH - N in Fm and N DIPEA, DMF FÊ N = H o AH) B1012 Ah Sd 139 '
[00547] [00547] Step1: Synthesis of 6- (2-hydroxyethyl) -5-methyl-3-phenyl-2- (trifluoromethyl) pyrazolo [1,5-a] pyrimidin-7 (4H) -one (1-36 ): Lithium aluminum hydride (457 µl, 12.4 mmol) was added to a white suspension of 2- (5-methyl-7-0x0-3-phenyl-2- (trifluoromethyl) -4,7-di- hydropyrazolo [1,5-a] pyrimidin-6-yl) methyl acetate (1-7, 2.27 g, 6.21 mmol, see Example 2) in THF (60 mL). The solution was stirred at r.t. for 1.5 h. 2M NaOH (12 mL) was added and stirred at r.t. for 30 min. The mixture was filtered, washed with THF (2 x 15 ml) and the filtrate was concentrated in vacuo. The crude material was purified by reverse phase chromatography (KP-C18-H5, 30 g, 0 to 100% MeCN in water, 10 mM ammonium formate in 20 column volumes) to provide compound 1-36. * H NMR (500 MHz, DMSO) 5 12.09 (s, 1 H), 7.55 - 7.20 (m, 5 H), 4.61 (t, J = 5.6 Hz, 1 H) , 3.50 (dd, J = 12.6, 6.8 Hz, 2 H), 2.67 (t, J = 6.9 Hz, 2 H), 2.37 (s,
[00548] [00548] Step 2: Synthesis of 2- (5-methyl-7-0x0- 3-phenyl-2- (trifluoromethyl) -4,7-dihydropyrazolo [1,5-a] pyrimidin-6-yl methanesulfonate ) ethyl - (1-37): Methanesulfonyl chloride (127 µl, 1.63 mmol) was added to a solution of 1-36 (500 mg, 1.48 mmol) and triethylamine (417 µL, 2.96 mmol) in THF (30 mL) at 0 ° C. The solution was stirred at 0 ºC for 1.5 h. EtOAc (75 ml), water (50 ml) and 10% HCl (3 ml) were added and the layers were separated. The aqueous layer was extracted with EtOAc (2 x 50 ml). The combined organic layers were washed with brine (50 ml), dried over Na2SO4. and concentrated in vacuo. The solid was triturated with DCM (20 ml) for 15 min, filtered, washed with DCM (2 x 5 ml) and dried in vacuo to provide compound 1-37, * H NMR (500 MHz, DMSO) 5 12.19 (s, 1 H), 7.53 - 7.44 (m, 3 H), 7.44 - 7.40 (m, 2 H), 4.32 (t, J = 6.7 Hz, 2 H ), 3.17 (s, 3 H), 2.94 (t, J = 6.7 Hz, 2H), 2.40 (s 3H). MS (m / z): 416.0 [M + 1) ”.
[00549] [00549] Step 3: Synthesis of 6- (2-azidoethyl) -5-methyl-3-phenyl-2- (trifluoromethyl) pyrazolo [1,5-a] pyrimidin-7 (4H) -one (1- 38): Sodium azide (37.7 µl, 578 µmol) was added to a solution of 1-37 (200 mg, 481 upumol) in DMF (3.00 ml). The solution was stirred at r.t. for 1h. EtOAc (25 ml), water (25 ml) and 10% HCl (1 ml) were added and the layers were separated. The aqueous layer was extracted with EtOAc (2 x 25 ml). The combined organic layers were washed with brine (25 ml), dried over Na2SO. and concentrated in vacuo to provide compound 1-38, * H NMR (400 MHz, DMSO) 5 12.19 (s, 1 H), 7.54 - 7.38 (m, 5 H), 3.47 ( t, J = 7.1 Hz, 2H), 2.79 (tl J = 7.1 Hz, 2 H), 2.41 (s, 3H). MS (m / z): 363.2 [M + 1) *.
[00550] [00550] Step 4: Synthesis of 6- (2-aminoethyl) -5-methyl-3-phenyl-2- (trifluoromethyl) pyrazolo [1,5-a] pyrimidin-7 (4H) -one (B1012) : A mixture of | - 38 (162 mg, 447 umol), loading palladium on coal 10% (200 mg, 188 umol) in MeOH (10 ml) was hydrogenated under an
[00551] [00551] Step 5: Synthesis of N- (2- (5-methyl-7-0x0-3-phenyl-2- (trifluoro-methyl) -4,7-dihydropyrazolo [1,5-a] pyrimidin- 6-yl) ethyl) acetamide - (B1013): Acetyl chloride (1-39,10.3 uL, 143 umol) was added to a solution of B1012 (40.0 mg, 119 umol) and N N-diisopropylethylamine ( 62.2 µl, 357 µmol) in DMF (2.00 ml). The yellow solution was stirred at r.t. by 17h. EtOAc (25 ml), water (25 ml) and 10% HCl (1 ml) were added and the layers were separated. The aqueous layer was extracted with EtOAc (2 x 25 ml). The combined organic layers were washed with brine (25 ml), dried over Na2SO. and concentrated in vacuo. Purification by reverse phase chromatography (KP-C18-H5, 12 g, 100% MeCN in water, 10 mM ammonium formate in 40 column volumes) provided compound B1013. * H NMR (500 MHz, DMSO) 5 12.08 (s, 1 H), 7.93 (t, J = 5.8 Hz, 1 H), 7.53 - 7.48 (m, 2H), 7.48 - 7.39 (m, 3 H), 3.17 (dd, J = 13.5 Hz, 6.5 Hz, 2 H), 2.62 (t, J = 7.1 Hz, 2 H), 2.34 (s, 3 H), 1.77 (s, 3H). MS (m / z): 379.1 [M + 1] *.
[00552] [00552] - N- (2- (5-methyl-7-0x0-3-phenyl-2- (trifluoromethyl) -4,7-dihydropyrazolo [1,5-a] pyrimidin-6-yl) ethyl) Denzamide (B1014) o N Õ f) o OO o N
[00553] [00553] - 6- (2 - ((3-methoxyphenyl) amino) ethyl) -5-methyl-3-phenyl-2- (trifluoro-methyl) pyrazolo [1,5-a] pyrimidin-7 (4H) - ona (B1015) o 'th i AXO N
[00554] [00554] Step 1: Sodium hydride (3.76 mg, 156 umol) was added to a solution of 1-37 (50.0 mg, 120 umol) and m-anisidine (1-40, 17.1 µL, 144 µmol) in DMF (1.00 ml). The solution was heated to 70 ºC for 45 min. EtOAc (25 ml), water (25 ml) and 10% HCl (1 ml) were added and the layers were separated. The aqueous layer was extracted with EtOAc (2 x 25 ml). The combined organic layers were washed with brine (25 ml), dried over Na2SO. and concentrated in vacuo. Purification by reverse phase chromatography (KP-C18-H5, 12.9, 100% MeCN in water, 10 mM ammonium formate in 20 column volumes) to provide Compound B1015, * H NMR (400 MHz , DMSO) 5 8.17 (s, 1 H), 7.54 (d, J = 7.6 Hz, 2 H), 7.40 (t, J = 7.6 Hz, 2 H), 7, 28 (t, J = 7.5 Hz, 1 H), 6.94 (t, J = 8.2 Hz, 1 H), 6.23 - 6.15 (m, 2 H), 6.10 - 6.03 (m, 1 H), 5.79 (s, 1 H), 3.67 (s, 3 H), 3.15 - 3.05 (m, 2H), 2.75 (t, J = 7.2 Hz, 2 H), 2.27 (s, 3H). MS (m / z): 443.1 [M + 1) ”. Example 19: Synthesis of Triazolopyrimidinone analogs.
[00555] [00555] —Triazolopyrimidinone analogs of the pyrazolopyrimidine compounds described in Examples 1-18 above, for example,
[00556] [00556] Step 1: Synthesis of 5-methyl-3-phenyl- [1,2,3] triazolo [1,5-a] pyrimidin-7 (4H) -one (1-42): 4-phenyl -1H -1,2,3-triazole-5-amine (1-41) was reacted with ethyl acetoacetate (I-10) according to the methods described in Step 1 of Example 3 to provide the compound 1-42 desired.
[00557] [00557] Step 2: Synthesis of 6-iodo-5-methyl-3-phenyl- [1,2,3] triazolo [1,5-a] pyrimidin-7 (4H) -one (1-43): Compound 1-42 was reacted according to the methods described in Step 1 of Example 4 to provide the desired compound 1-43.
[00558] [00558] Step3: Synthesis of 6- (4-methoxybenzo [a] oxazol-2-yl) -5-methyl-3-phenyl- [1,2,3] triazolo [1,5-a] pyrimidin-7 ( 4H) -one (E1001): Compound | - 43 was reacted with 4-methoxybenzo [d] oxazole (1-15) according to the methods described in Step 2 of Example 4 to provide the desired E1001 compound. * H NMR (500 MHz, DMSO) 6 8.40 - 8.33 (m, 3 H), 7.48 - 7.41 (m, 2 H), 7.30 - 7.26 (m, 2 H ), 7.23 (t, J = 7.4 Hz, 1 H), 6.94 - 6.89 (m, 1H), 4.02 (s, 3H), 2.49 (s, 3H). MS (m / z): 374.1 [M + 1) *, 94%. Example 20: Assay of biochemical activity of cCGAS
[00559] [00559] The human cCGAS sequence encoding amino acids 155-522 was cloned into a pET-based expression plasmid (EMD Millipore). The resulting construct contained a tandem N-terminal hexahistidine marker, maltose-binding protein fusion,
[00560] [00560] Construction sequence: Amino acids 155-522, human cGAS DAAPGASKLRAVLEKLKLSRDDISTAAGMVKGVVDHLLLRLKCDSAF RGVGLLNTGSYYEHVKISAPNEFDVMFKLEVPRIQLEEYSNTRAYYFV KFKRNPKENPLSQFLEGEILSASKMLSKFRKIIKEEINDIKDTDVIMKRK RGGSPAVTLLISEKISVDITLALESKSSWPASTQEGLRIQNWLSAKVR KQLRLKPFYLVPKHAKEGNGFQEETWRLSFSHIEKEILNNHGKSKTC CENKEEKCCRKDCLKLMKYLLEQLKERFKDKKHLDKFSSYHVKTAFF
[00561] [00561] The protein was expressed and purified from E. coli BL21 DE3 Rosetta 2 cells (EMD Millipore) using standard techniques. The cells were grown in 2x yeast extract tryptone medium and expression was initiated by the addition of isopropyl B-D-1-thiogalactopyranoside. The expression continued overnight at 18 ºC. The cells were harvested by centrifugation and subsequently lysed by sonication. The insoluble fraction was removed by centrifugation. The maltose-binding protein (MBP) fusion proteins were purified on a dextrin-sepharose column (GE Healtcare) and the MBP marker was removed using tobacco engraving virus protease overnight during dialysis. The protein was further purified on a heparin column (GE Healtcare) and eluted using a NaCl gradient. The column fraction was pooled and also purified on a Superdex 75 gel filtration column (GE Healtcare). The protein was quantified using absorbance at 280 nm. The protein was then quickly frozen in liquid nitrogen and stored at -80 ºC until use.
[00562] [00562] - Potential antagonists were diluted in 100% dimethyl sulfoxide and added to the reaction. The final concentration of dimethylsulfoxide was 5%. The compounds were tested at 1 µM with 3 or 4-fold serial dilutions up to 0.000051 or 0.000004 µM, respectively.
[00563] [00563] Two complementary DNA oligos (IDT DNA) were refreshed by slow cooling from 95 ºC. The resulting double-stranded DNA was used to activate cGAS.
[00564] [00564] —Tapes top link: 8 "-TACAGATCTACTAGTGATCTATGACTGATCTGTACATGATCTACA-3 'SEQ. ID No. 2
[00565] [00565] —Lower ribbon link: 3-TGTAGATCATGTACAGATCAGTCATAGATCACTAGTAGATCTGTA-3 'SEQ. ID No. 3
[00566] [00566] The reactions were carried out at 37 ºC for 1.25 hours. Reaction buffer: 20 mM Tris HCI pH 9, 100 mM NaCl, 5 mM MgCl2, bovine gamma globulin 0.1 g / ml, 250 UM adenosine triphosphate, 100 UM guanosine triphosphate, Tris hydrochloride (2 -carboxyethyl) 0.5 mM phosphine, 1 µM double-stranded DNA and purified 300 nM cGAS protein.
[00567] [00567] The reactions were stopped and the ATP levels in the reaction were measured using a luciferase-based assay. Promega Kinase-Glo Max Assay. Luminescence was measured on a plate reader (Molecular Devices). The values were normalized to control the cavities without compost.
[00568] [00568] Table 15 below provides ICs data for certain compounds of the invention in cGAS. "A" indicates an IC50 value between less than 20 µM, "B" indicates an IC50 value between 20 and 250 µM and "C" indicates an ICso above the upper limit of the assay (250 µM), or where a value of IC5o cannot be generated from the data. Table 15
[00569] [00569] A cell assay can be used to evaluate the compounds of the invention for their ability to inhibit the CGAS / STING pathway. Cells that express a luciferase-based reporter that is linked to the activation of IRF-3 are used to determine the response as a function of the concentration of the compound. Such an essay is described in Vincent et a /., Nature Communications 2017, 8 (1): 750, doi:
[00570] [00570] Inhibition of secreted cytokine was measured in bone marrow derived macrophages (BMMs) from diseased mice to assess the potency of the compounds of the invention as described herein. Mice that lack the gene for the Trex1 protein (trex1 - / - or Trex1-KO) exhibit autoimmune and autoinflammatory diseases dependent on the CGAS / STING pathway, including the secretion of cytokines highlighted by the cells. To derive macrophages from the bone marrow, the marrow extracted from the femurs and tibiae were harvested from Trex1-KO mice and cultured in growth medium supplemented with macrophage colony stimulating factor (M-CSF). Differentiated BMMs were harvested and frozen for subsequent experimentation. For treatment with compound C1089 (see, Example 13), a frozen BMM raw material from Trex1-KO was thawed and 1x10º cells were seeded in a 96-well format. BMMs were treated with a series of dilutions of C1089 and incubated overnight at 37 ºC, CO2> 5%, at which time the cell supernatants were collected and stored at -80 ºC for subsequent analyzes. The medium used for this dilution series was without FBS. The remaining cells were assessed for viability using The Cell Titer Glo 2.0 kit, according to the manufacturer's instructions. BMM supernatants were evaluated for normal secreted, expressed and secreted cytokine T cell (RANTES / CCL5) or for secreted cytokine monocyte chemoprotein protein 1 (MCP-1 / CCL2) using Flex Set mice from cytometric account (BD Biosciences). The cytokine concentration was calculated from a standard and normalized curve for vehicle treated cells (DMSO).
[00571] [00571] AFig. 1 shows that C1089 can significantly inhibit cytokine secretion by BMM from sick Trex1-KO (RANTES / CCL5 ICso = 1.251 µM, MCP-1 / CCL2 IC5so = 6.973 UM). In addition, BMM was 100% viable at these concentrations, indicating that the inhibition is not simply due to cell cytotoxicity. Additional compounds were evaluated by this assay.
[00572] [00572] Table 17 below provides IC 50 data for certain compounds of the invention for inhibiting RANTES expression. "A" indicates an ICso value less than 5 µM, "B" indicates an IC50 value between 5 and UM and "C" indicates where an ICso value cannot be calculated from the data. ND does not indicate data for this cytokine. In this table, column M refers to MCP-1 and column R refers to RANTES.
[00573] [00573] The description of each of the patent documents and scientific articles referred to herein is incorporated by reference for all purposes. EQUIVALENTS
[00574] [00574] The invention can be incorporated in other specific forms without departing from the spirit or its essential characteristics. The foregoing modalities must therefore be considered in all illustrative, rather than limiting, aspects of the invention described herein. The scope of the invention is therefore indicated by the appended claims, and not by the previous description, and any changes that fall within the meaning and equivalence range of the claims must be covered therein.

权利要求:
Claims (39)
[1]
1. Compound, characterized by the fact that it has the following Formula (1): o 1 o R RO, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate or pharmaceutically acceptable hydrate thereof, where Y is -CR '= or -N =; R 'is Q-TI- (0XI) n; Q 'is a C1.3 alkenylene bond, where the C13 alkylene group is optionally substituted with one or more substituents independently selected from the group consisting of halo, C1-6 alkyl, C2.6 alkenyl, C2.6 alkynyl, cyano, C1.6 haloalkyl, -OR “ and -NR $ 2R; T! is Ca.8 cycloalkyl, Ce-10 aryl, 3 to 12 membered heterocycloalkyl, 5 to 10 membered heteroaryl, -C (= O) Co-3 alkylene-C3a-8 cycloalkyl, -C (= O) - Co-3 alkylene-Ce-10 aryl, -C (= O) -Co-3 alkylene-hetero-cycloalkyl of 3 to 12 members, -C (= O) -Co-3 alkylene-heteroaryl of 5 to members, - NRºRº, -S (= O) 2Rº, -NRºC (= O) Rº, -NRºC (= O) NRºRL, - NRºC (= 0) ORº, -NRºS (= O) 2Rº, -C (= O) NRºS ( = O) 2R , -NRºS (= O) aNRºRº, -C (= O) NRºRº or -S (= O) -NRºRº; each X 'is independently selected from the group consisting of halo, cyano, oxo, Co-3 alkylene-C (= O) Rº, Co-3 alkylene-ORº, Co-3 alkylene-C (= 0) ORº, Co-3 alkylene-OC (= O) Rº, Co-3 alkylene-NRºRº, Co.3 alkylene-N * RºR9 $ Rº, Co.3 alkylene-S (= O) nRº, Co.3 alkylene-NRºC (= O) Rº, Co.3 alkylene-NRºC (= O) NRºR $, Co.3 alkylene-OC (= O) NRº R $, Co.3 alkylene-NRºC (= 0) OR ", Co.3 alkylene-NRºS (= O) 2Rº, Co.3 alkyl
leno-C (= O) NRºS (= O) 2Rº, Coa alkylene-NRºS (= O) 2NRºRº, Cos alkylene-C (= O) NRºRº, Co.3 alkylene-S (= O) aNRºRº, Co. 3 C-alkylene (= NRº) NRºRº, Co.3 alkylene-NRºC (= NRº) NRºRº and R $ ', where R $ is Ci alkyl, C2.6 alkenyl, C26 alkynyl, Co-3 alkylene-C3 -8 cycloalkyl, Co-3 alkylene-Ce-10 aryl, Co-3 alkylene-heterocycloalkyl of 3 to 12 members, or Co.3 alkylene-heteroaryl of 5 to 10 members;
and each R $ 'is optionally substituted with one or more substituents independently selected from the group consisting of halo, cyano, nitro, oxo, C1-6 alkyl, C2-.6 alkenyl, C2.6 alkynyl, C1- 6 haloalkyl, Co-3 alkylene-NRºRÍ, Co.3 alkylene-ORº, Co.3 alkylene-NRºC (= O) Rº, Co-3 alkylene-NRºC (= O0) ORº, Co-3 alkylene-NRºC ( = O) NRºR, Co.3 alkylene-OC (= O) Rº, Co.3 alkylene-C (= 0) ORº, Co.3 alkylene-C (= O) NRºR ', Co.3 alkylene-C (= O) Rº, Co.3 alkylene-S (= O) nRº, Co-3 alkylene-S (= O) aNRºRS, Co.3 alkylene-NRºS (= O) 2Rº, Co.3 alkylene-C (= O) NRºS (= O) 2Rº, Co.3 alkylene-NRºS (= O) .NRºR and R $ º, in which R $ is Co-3 alkylene-C3.8 cycloalkyl, Co-alkylene-Ce-10 aryl, Co-3 alkylene-heterocycloalkyl of 3 to 12 members, or Co.3 alkylene-heteroaryl of 5 to 10 members,
and each R * is optionally substituted with one or more substituents independently selected from the group consisting of halo, oxo, C1-6 alkyl, C2.6 alkenyl, C2.6 alkynyl, cyano, C1-6 haloalkyl, -OR " and -NR "R ';
R is Q2-T2- (Xº) p;
WHAT is a bond or C1-3 alkylene, where the C1-3 alkylene group is optionally substituted with one or more substituents independently selected from the group consisting of halo, C1-6 alkyl, Ca2.6 alkenyl, C2.6 alkynyl, cyano, C1-6 haloalkyl, -OR “3 and -NR $ R;
T is H, halo, cyano, C1-.6 alkyl, Ca.6 alkenyl, C2.6 alkynyl,
C3-8 cycloalkyl, Ce-10 aryl, 3 to 12 membered heterocycloalkyl, 5 to 10 membered heteroaryl, -C (= O) -Co.3 alkylene-Cz.8 cycloalkyl, - C (= O0) - Co-3 alkylene-Ce-10 aryl, -C (= O) -Co-3 alkylene-heterocycloalkyl of 3 to 12 members, -C (= O) -Co-3 alkylene-heteroaryl of 5 to 10 members, -OR , -S (= O) mRY, -P (= O) RKRmm, -NRKR ", -C (= 0) ORI or -C (= O) NRKR";
each X is independently selected from the group consisting of halo, cyano, oxo, Co-3 alkylene-OR "”, Co.3a alkylene-S (= O) mR ", Co-38 alkylene-NR" Rº, Co.3 C-alkylene (= O) NR "Rº, C-alkylene-thigh (= O0) OR" and R $ º, where R $ is C1.6 alkyl, C2.6 alkenyl, C2.6 alkynyl , Co-alkylene-Ca-8 cycloalkyl, Co-alkylene-Ce-10 aryl, Co-3 alkylene-heterocycloalkyl of 3 to 12 members, or Co-3 alkylene-heteroaryl of 5 to 10 members;
and R $ is optionally substituted with one or more substituents independently selected from the group consisting of halo, oxo, cyano, Co-3 alkylene-OR , Co.3 alkylene-S (= O) mnRº, Co- 3 alkylene-NRPR9, Co.3 alkylene-C (= O) NRPR9, Co.3 alkylene-Co-3 alkylene-C (= 0) ORP, C1-6 alkyl, C2.6 alkenyl, C2.6 alkynyl , C1-6 haloalkyl and R $, where R * º is Co3 alkylene-Ca.8 cycloalkyl, Co.a alkylene-Ce-10 aryl, Co.3 alkylene-heterocycloalkyl of 3 to 12 members, or Co.3 here - 5 to 10-membered lenoheteroaryl;
and each R * º is optionally substituted with one or more substituents independently selected from the group consisting of halo, oxo, C1-6 alkyl, C2.6 alkenyl, C2.6 alkynyl, cyano, C1-6 haloalkyl, -OR "º and -NRYMRX;
Rº is C1.3alkyl, C1.3 haloalkyl, C2.3 alkenyl, C2.3 alkynyl, C3-6 cycloalkyl, -CN, -OR "',
-C (= O) R ', -S (= O) mR', NR'R 'or -C (= 0) OR "', where C1-3 alkyl, C2.3 alkenyl and C2.3 alkynyl are optionally substituted with a C3-6 cycloalkyl;
Rº is C1-.6alkyl, C1-.6 haloalkyl, S (= O) mR ", Co.3 alkylene-C3a. 8 Cycloalkyl, Co-3 alkylene-Ce-10 aryl, Co.3 alkylene-heterocycloalkyl from 3 to 12 members, or Co.3 alkylene-heteroaryl of 5 to 10 members, where Co.3 alkylene-C3.8 cycloalkyl, Co-3 alkylene-Ce-10 aryl, Co-3 alkylene-heterocycloalkyl of 3 to 12 members, or Co-3 alkylene-heteroaryl of 5 to 10 members are optionally substituted with one or more substituents independently selected from the group consisting of halo, oxo, C1-6 alkyl, C2.6 alkenyl, C2.6 alkynyl, cyano, C1.6 haloalkyl, OR “and NRYR;
each between Rº and R , independently, is H or R $, where R $ is C1.6 alkyl, C2.6 alkenyl, C2.6 alkynyl, Co-3 alkylene-Ca6 cycloalkyl, Co-3 alkylene-Ce-10 aryl, Co-3 alkylene-heterocycloalkyl of 3 to 12 members, or Co.3 alkylene-heteroaryl of 5 to 10 members;
and R $ is optionally substituted with one or more substituents independently selected from the group consisting of halo, cyano, oxo, C1-.6 haloalkyl, Co-3 alkylene-ORº , Co.3 alkylene-C (= O) Rº , Co.3a alkylene-C (= 0) OR, Co.3 alkylene-OC (= O) Rº , Co.3 alkylene-C (= O) NRºR%, Co.3 alkylene- S (= O) nR , Co-3 alkylene-S (= O) NRº2R% º, Co.3 alkylene-NRº2R% , Co.3 alkylene-NRº2C (= O0) R , Co-3 alkylene-NRº2C (= 0) ORº, Co.3 alkylene-NRº2C (= O) NRºº2R%, Co.3 alkylene- NRº2S (= O) 2R , Cos alkylene-C (= O) NRº2S (= O) 2Rº , Cos alkylene- NRº2S (= O) aNRº2R% * , Co.3 alkylene- N (S (= O) 2R), and R $, where R is C1-6 alkyl, C2.6 alkenyl, C2.6 alkynyl, Co-3 alkylene-Ca-8 cycloalkyl, Co-3 alkylene-Ce- 10 aryl, Co-3 alkylene-heterocycloalkyl of 3 to 12 members, or Co-3 alkylene-heteroaryl of 5 to 10 members;
and each R% º is optionally substituted with one or more substituents independently selected from the group consisting of halo, cyano, oxo, C1-6 alkyl, C2.6 alkenyl, C2.6 alkynyl, C1-6 haloalkyl, Co- .3 alguylene-NRºRº , Co.3 alkylene-OR , Co3 alkylene-NRº2C (= O) Rº, Co.3 alkylene-NRº2C (= 0) OR, Co.3 alkylene-NRºº
C (= O) NRºRº, Co alkylene-OC (= O) Rº, Co3 alkylene-C (= 0) OR , Cos alkylene-C (= O) NRºR , Co.3 alkylene-C (= O) Rº , Co.3 alkylene-S (= O) m Rº , Co.3 alkylene-S (= O) aNRºR8, Co.3 alkylene-NRº2S (= O) 2Rº , Co.3 alkylene-C ( = O) NRººS (= O) 2Rº, Co.3 alkylene-NRº2S (= O) NRºR and R $, where R $ "is Co.3 alkylene-C3-6 cycloalkyl, Co-3 alkylene-Cce-10 aryl, Co-3 alkylene-heterocycloalkyl of 3 to 12 members, or Co-3 alkylene-he- teroaryl of 5 to 10 members;
and each R $ ”is optionally substituted with one or more substituents independently selected from the group consisting of halo, oxo, C1-6 alkyl, C2.6 alkenyl, C2.6 alkynyl, cyano, C1-6 haloalkyl, -OR “6 and -NR $ 6R * 6:
each of Rº, Rº, R $, Rº and Rºº, independently, is H or R $, where R $ is C1.6 alkyl, C2.6 alkenyl, C2.6 alkynyl, Co-3 alkylene-C3.8 cycloalkyl, Co-3 alkylene-Ce-10 aryl, Co.3 alkylene-heteroaryl of 3 to 12 members, or Co3 alkylene-heteroaryl of 5 to 10 members;
and each R $ º is optionally substituted with one or more substituents independently selected from the group consisting of halo, cyano, oxo, C1-6 alkyl, C2.6 alkenyl, C2.6 alkynyl, C1-6 haloalkyl, Co- alkylene-NRºR8, Co.3 alkylene-OR, Co. alkylene-C (= O0) ORº, Co.3a alkylene-C (= O) NRººR8, Co.3 alkylene-C (= O) Rº, Co3 alkylene-S (= O) mR%, Co3 alkylene-S (= O) aNRººR8, Co.3 alkylene-NREC (= O) R *, Co.3 alkylene-NRES (= O) nRº * and R $ ºº , where R * º is Co3 alkylene-C3.8 cycloalkyl, Co-3 alkylene-Ce-10 aryl, Co.3 alkylene-hetero-cycloalkyl of 3 to 12 members, Co3 alkylene-heteroaryl of 5 to 10 members;
and each R $ º is optionally substituted with one or more substituents independently selected from the group consisting of halo, oxo, C1-6 alkyl, C2.6 alkenyl, C2.6 alkynyl, cyano, C1-6 haloalkyl, -OR “ and -NRYWRY ";
each of Rº, Rº, Rº, R (, Rº and R $, independently, is H or R $ * º, where R $ * º is C1.6 alkyl, C2.6 alkenyl, C2.6 al - quinyl, Co-alkylene-Ca-8 cycloalkyl, Co-alkylene-Ce-10 aryl, Co-3 alkylene-heterocycloalkyl from 3 to 12 members, or Co-3 alkylene-hetero-aryl from 5 to 10 members;
and each R5 $ 'º is optionally substituted with one or more substituents independently selected from the group consisting of halo, oxo, C1-6 alkyl, C2.6 alkenyl, C2.6 alkynyl, cyano, C1-6 haloalkyl, - OR "S and -NRY6R *;
each of RK * and Rm ", is independently selected from the group consisting of RF, -ORK, and-NRKR";
each of RK and R ”, independently, is H or R , where R is C1.6 alkyl, C2.6 alkenyl, C2.6 alkynyl, Co-.3 alkylene-C3a.8 cycloalkyl, Co-3 alkylene-Ce-10 aryl, Co-3 alkylene-heterocycloalkyl of 3 to 12 members , or Co.3 alkylene-heteroaryl of 5 to 10 members;
and each R is optionally substituted with one or more substituents independently selected from the group consisting of halo, cyano, oxo, C1-6 alkyl, C2.6 alkenyl, C2.6 alkynyl, C1-6 haloalkyl, Co.3 alkylene-NR "2Rº , Co.3 alkylene-OR” , Co.3 alkylene-C (= 0) OR ” , Co.3 alkylene-C (= O) NR" 2Rº , Co.3 alkylene- C (= O) R " , Co-3 alkylene-S (= O) nR" , Co.3 alkylene-S (= O) aNR "2Rº And R $ * !, where R $"! is Co-3 alkylene-C3.8 cycloalkyl, Co-alkylene-Ce-10 aryl, Co-3 alkylene-heterocycloalkyl of 3 to 12 members, Co-3 alkylene-heteroaryl of 5 members;
and each R5 $ ** is optionally substituted with one or more substituents independently selected from the group consisting of halo, oxo, cyano, Cos alkylene-ORP , Co.3 alkylene-S (= O) mRP , Co- 3 alkylene-NRP2R%, Co.3 alkylene-C (= O) NRP2Rº, Co.3 alkylene-Co.3 alkylene-C (= 0) OR " , C1.6 alkyl, C2.6 alkenyl, Ca .6 al-
quinyl, C1.6 haloalkyl and R $ * , where R $ " is Co.3 alkylene-C3.8 cycloalkyl, Co-.3 alkylene-C-10 aryl, Co-.3 alkylene-heterocycloalkyl of 3 to 12 members, or Co.3 alkylene-heteroaryl of 5 to 10 members;
each R $ * is optionally substituted with one or more substituents independently selected from the group consisting of halo, oxo, C1-6 alkyl, C2.6 alkenyl, C2.6 alkynyl, cyano, C1-6 haloalkyl, -OR “and -NR * 9R *;
each among Rº, Rº, Rº and Rº, independently, is H or R $ '3, in which R $ * is C1.6 alkyl, Ca.6 alkenyl, C2.6 alkynyl, Co.3 alkylene-C3.3 cycloalkyl, Co-alkylene-C-10 aryl, Co-alkylene-heterocycloalkyl from 3 to 12 members, or Co-3 alkylene-heteroaryl of 5 to 10 members;
each R $ * is optionally substituted with one or more substituents independently selected from the group consisting of halo, oxo, cyano, Cos alkylene-ORP%, Co.3 alkylene-S (= O) mRP, Co.3 alkylene-NRPºR%, Co .3 alkylene-C (= O) NRPR%, Co.3 alkylene-C (= 0) OR ", C1.6 alkyl, C2.6 alkenyl, C2.6 alkynyl, C1-6 haloalkyl and R $ * º4, in which R $ " is Co.3 alkylene-Ca.8 cycloalkyl, Co-3 alkylene-Ce-10 aryl, Co-alkylene-heterocycloalkyl of 3 to 12 members, or Co-3 alkylene-heteroaryl of 5 to 10 members;
each R $ ** is optionally substituted with one or more substituents independently selected from the group consisting of halo, oxo, C1-6 alkyl, C2.6 alkenyl, C2.6 alkynyl, cyano, C1-6 haloalkyl, -ORY * 10 and -NRW10Rx10:
each of RP, RP , RP3, R9, R and R%, independently, is H or R $ * 5, where R $ ** is C1.6 alkyl, C2.6 alkenyl, C2.6 alkynyl, Co-alkylene-Ca-8 cycloalkyl, Co-alkylene-Ce-10 aryl, Co-3 alkylene-heterocycloalkyl of 3 to 12 members, or Co-3 alkylene-hetero-aryl of 5 to 10 members;
each R $ ** is optionally substituted with one or more substituents independently selected from the group consisting of halo, oxo, C1-6 alkyl, C2.6 alkenyl, C2.6 alkynyl, cyano, C1-6 haloalkyl, -OR * !! and -NRW1IRX11;
each of R ', R' and Rº, independently, is H or R $ '8, where R $' 6 is C1.6 alkyl, C2.6 alkenyl, C2.6 alkynyl, Co-3 alkylene-C3- 8 Cycloalkyl, Co-3 alkylene-Ce-10 aryl, Co.3 alkylene-heterocycloalkyl of 3 to 12 members, or Co.3 alkylene-heteroaryl of 5 to 10 members;
and each R $ 'º is optionally substituted with one or more substituents independently selected from the group consisting of halo, oxo, C1-6 alkyl, C2.6 alkenyl, C2.6 alkynyl, cyano, C1-6 haloalkyl, - C (= 0) ORY! 2, -OR "! 2 and -NRW12RX12;
each Rº, R2, R63, Rei, Rus, RW6, RW7, Ruw8 Rua Rwio Qwi1, R12, R “, Rº, RS, RX, RS, R *, RX, RS, Rº, Rx, Rx and RX, regardless dentically, it is H, C1-.6 alkyl, C2.6 alkenyl, C2.6 alkynyl or C1-6 haloalkyl;
each of n and p independently is O, 1, 2, 3, 4, or 5, where when T for H, p is 0; and m is 0, 1, or 2; with the proviso that, for compounds where Y is -CRº =:
a) when R 'is unsubstituted phenyl, R is methyl and Rº is methyl, Rº is not ethyl, unsubstituted phenyl or unsubstituted pyridine;
b) when R 'is unsubstituted cyclohexyl, R is methyl and R3 is methyl, Rº is not unsubstituted pyridine;
c) when R 'is unsubstituted cyclopentyl, R is methyl and R3 is methyl, Rº is not ethyl or unsubstituted pyridine,
d) when R for methyl, Rô for methyl and Rº for 3,4-di-ethoxy-phenyl, R 'is not unsubstituted 1-pyrrolidine, unsubstituted 1-piperidine, 4-methyl-1-piperidine, 4- (phenylmethyl) -1-piperidine, 2-1,2,3,4-tetrahydro-isoquinoline unsubstituted, unsubstituted morpholine, or NHCH2
CH2-3-indole;
e) when R 'is CH> - unsubstituted phenyl, R is methyl and R3 is methyl, Rº is not ethyl, trifluoromethyl, 1-methyl-piperidin-4-yl, unsubstituted pyridine, unsubstituted phenyl, monosubstituted phenyl with 4-F, 4-Cl, 2-methoxy or 4 -methoxy, or phenyl disubstituted with 3,4-methoxy;
f) when R for methyl, Rº for methyl and Rº for unsubstituted pyridine, R 'is not CH2-phenyl, where phenyl is substituted with 4-CN, 4-NO; ,, 4-F or 2-F;
g) when R for methyl, R $ for methyl and Rº for ethyl, R 'is not CH2-phenyl, where phenyl is replaced with 4-CN or 4-NO;>;
h) when R for methyl, Rº for methyl and Rº for 4-methoxy-phenyl, R 'is not CH> 2-phenyl, where phenyl is replaced with 2-Cl, 3-Cl, 4- Br, 2-methyl or 4- methyl;
i) when R for methyl, Rº for methyl and Rº for unsubstituted phenyl, R 'is not CH7> -phenyl, where phenyl is replaced with 2-Cl, 3-Cl, 4-CI, 4-Br, 2-methyl , 3-methyl, 4-methyl, 4-isopropyl or 4-tert-butyl; or R 'is not unsubstituted CH2-1-naphthylene or CH> 2-unsubstituted CH2;
j) when R for methyl, Rº for methyl and Rº for 4-Cl-phenyl, R 'is not CH7-phenyl, where phenyl is replaced with 2-Cl, 4-CI or 4-isopropyl;
k) when R 'is CH> -substituted phenyl, R for methyl and R3 for trifluoromethyl, Rº is not unsubstituted phenyl or phenyl substituted with 2-Cl or 4-CI;
1) the compound is not where R 'is CH7> -4-Br-phenyl, Rº is methyl, Rº is ethyl and Rº is unsubstituted phenyl;
m) when R for methyl, Rº for methyl and Rº for unsubstituted phenyl, R 'is not CHOCH2C (= O) NH-phenyl, in which the phenyl ring is unsubstituted or is substituted in position 4 with Cl, methyl or methoxy ; n) when R is methyl or ethyl, R3 is methyl and R4 is unsubstituted phenyl, R 'is unsubstituted pyrazolo [1,5-a] pyrimidin-7-yl; o) when R for H, Rô for isopropyl and Rº for methyl, R 'is not unsubstituted pyrazole; and p) the compound is not in which R 'is unsubstituted CH> -phenyl, R is H, Rô is methyl and Rº is unsubstituted phenyl; and with the proviso that, for compounds where Y is -N =, the compound is not in which R 'is unsubstituted phenyl, Ré He Rº is 2-fluoro-phenyl.
[2]
2. Compound according to claim 1, characterized by the fact that it has the following Formula (IA): the NÓTR RA (IA), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate or pharmaceutically acceptable hydrate thereof.
[3]
3. Composed according to claim 1 or 2, characterized by the fact that Q 'is a bond and T! is Ce-10 aryl, heterocycloalkyl of 3 to 12 members, or heteroaryl of 5 to 10 members, and ne 0, 1,2,3 or 4.
[4]
4. Compound according to claim 1 or 2, characterized by the fact that Q 'is a bond or -CH2- and T' is Ca.gcycloalkyl, Cçs-10 aryl, 3 to 12 membered heterocycloalkyl, heteroaryl of 5 to 10 members or -C (= O) NRºRº.
[5]
A compound according to claim 1 or 2, characterized by the fact that Q 'is a bond or -CH2-, T is -C (= O) NRºR! and no.
[6]
A compound according to any one of claims 1 to 4, characterized by the fact that T 'is 9 or 10 membered bicyclic heteroaryl.
[7]
7. Compound according to any one of claims 1,2,4 and 5, characterized by the fact that one of Rº and RéH or methyl.
[8]
8. Compound according to any one of claims 1,2,4 and 5, characterized by the fact that one of Rº and Rº independently is pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, indolyl, indazolyl, benzimidazolyl, imidazopyridinyl, quinolinyl, isoquinolinyl, quinazolinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, benzoxazolyl, oxadiazolyl, triazolyl, imidazolyl, furan, or thiophenyl, and the other is hydrogen or methyl.
[9]
9. Compound according to any one of claims 1 to 8, characterized by the fact that R is Q 2-T2- (X ) ,, Q is a bond, T º is H, halo, cyano, C1-6 alkyl, C1-6 haloalkyl, C2.6 alkenyl, or Ca.6 alkynyl, and each X independently it is halo or -OC1-6 alkyl.
[10]
10. Compound according to any one of claims 1 to 8, characterized by the fact that R is H, cyan, methyl or methoxymethyl.
[11]
11. Compound according to any one of claims 1 to 10, characterized by the fact that R $ is C1.3alkyl, C1-3haloalkyl, -CN, -S (= O0) 2C1-3 alkyl or -C (= 0) OC1: 3 alkyl.
[12]
12. Compound according to any one of claims 1 to 10, characterized in that Rº is -CN, C1.3 alkyl, C1-3 haloalkyl or -C (= 0) OC1: 3 alkyl.
[13]
13. Compound according to any one of claims 1 to 10, characterized by the fact that Rº is -CN or -CF3.
[14]
14. A compound according to any one of the claims
sections 1 to 13, characterized by the fact that Rº is C1.3alkyl, C1-3haloalkyl, -S (= O0) 2C1-3 alkyl, Ca-8 cycloalkyl, Ce-10 aryl, 3 to 12 membered heterocycloalkyl, or 5 to 10-membered heteroaryl, where C3-8 cycloalkyl, Ce-10-aryl, 3 to 12-membered heterocycloalkyl, or 5 to 10-membered heteroaryl are optionally substituted with 1-3 substitutes selected from the group consisting of halo, oxo, C1-6 alkyl, Ca.6 alkenyl, C2.6 alkynyl, cyano, C1-6 haloalkyl, -OR "and - NR * R *,
[15]
15. Compound according to any one of claims 1 to 13, characterized by the fact that Rº is Ca.8cycloalkyl or Ceylaryl, in which C3.8 cycloalkyl and Ce-10 aryl are optionally substituted with 1- 3 substituents selected from the group consisting of halo, oxo, C1-6 alkyl, C2-6 alkenyl, C2.6 alkynyl, cyano, C1-6 haloalkyl, -OR "S and -NR“ SR, where R ”º and R * are independently H, C1-6 alkyl or C1-6 haloalkyl.
[16]
16. A compound according to any one of claims 1 to 13, characterized in that Rº is phenyl optionally substituted with 1-3 substituents selected from the group consisting of halo, oxo, C1-6 alkyl, C2. 6 alkenyl, C2.6 alkynyl, cyano, C1-6 haloalkyl, -OR “S and -NR“ SR *, where R "” º and R “are independently H, C1-.6 alkyl or C1-6 haloalkyl.
[17]
17. Compound according to any one of claims 1 to 4 and 9 to 16, characterized in that T 'is aryl or heteroaryl.
[18]
18. A compound according to any one of claims 1 to 4 and 9a16, characterized by the fact that T 'is a 5- or 6-membered monocyclic heteroaryl or 9 or 10-membered bicyclic heteroaryl.
[19]
19. A compound according to any one of the claims
sections 1 to 4 and 9 to 16, characterized by the fact that T 'is pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, indolyl, indolinyl, isoindolyl, isoindolinyl, indazolyl, pyrazolopyridinyl, pyrazolopyrimidinyl, oxazolopyrimidinyl, imidazole, benzine -hydrobenzimi- dazolyl, benzofuranyl, dihydrobenzofuranyl, isobenzofuranyl, dihydroisobenzofuranyl, triazolopyridinyl, - benzothiazolyl, = azabenzimi- dazolyl, azabenzoxazolyl, azabenzotazolyl, quinazolazole, imidazinol, quinazole - azolyl, benzoxazolyl, benzodioxolyl, chromanyl, tetrahydro-oxazolazepinyl, tetrahydrobenzoxazolyl, oxadiazolyl, thiadiazolyl, pyrazolyl, triazolyl, imidazolyl, furanyl or thiophenyl.
[20]
20. Compound according to any one of claims 1 to 4 and 9 to 16, characterized by the fact that T 'is 3 to 12 membered heterocycloalkyl.
[21]
21. A compound according to claim 20, characterized by the fact that T 'is piperazine, piperidine, quinuclidine, or morpholine.
[22]
22. The compound according to claim 1 or 2, characterized by the fact that the compound has the following Formula (lb):
O Ri o (lb).
[23]
23. The compound according to claim 1 or 2, characterized by the fact that the compound has the following Formula (1la):
The Rº E and the “A, R RH (Ila).
[24]
24. Compound characterized by the fact that it has the following Formula (Ill):
O
Pe RO),
or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate or pharmaceutically acceptable hydrate thereof, wherein
Rº is selected from the group consisting of - C (= O) NRºR! º; -CH2C (= O) NR! R2; -CHCCHaNR! R * 4; -CH> -phenyl; -CH2- 5-membered monocyclic heteroaryl optionally substituted with a C1.3 alkyl, C5.6 monocyclic cycloalkyl, or phenyl, where phenyl is optionally substituted with a -OC1-3 alkyl; phenyl optionally substituted with a halo or C1-3 alkyl; a 5- or 6-membered monocyclic heterocycloalkyl optionally substituted with 1, 2, or 3 R '*; a 5- or 6-membered monocyclic heteroaryl optionally substituted with 1, 2, or 3 R'6; and 9 or 10 membered bicyclic heteroaryl optionally substituted with 1, 2, 3 or 4 R'7;
Rº and R'º are independently selected from the group consisting of H; C1.3 alkyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of -OH and -OC1-3 alkyl; -CH2phenyl; -S (= O) 2R'8; C5.6 cycloalkyl optionally substituted with an -NH> 2, oxo, -OH or -OC1-3 alkyl; phenyl optionally substituted with 1, 2, or 3 R '*; a 5- or 6-membered monocyclic hetero-cycloalkyl optionally substituted with a -C1-3 alkyl, -C (= O) C1-3 alkyl or -C (= 0) OC1-: alkyl; a 5- or 6-membered monocyclic heteroaryl optionally substituted with 1, 2, or 3 R2º; and a 9 or 10 membered bicyclic heteroaryl optionally substituted with 1 or 2 halo; or
Rº and R'º combine with the nitrogen to which they are attached to form a 5- or 6-membered monocyclic heterocycloalkyl | N-linked optionally substituted with a phenyl;
R '! and R ' they are independently selected from the group consisting of H; C1-3alkyl optionally substituted with an -OH or -OC1-3 alkyl; phenyl optionally substituted with an -NH2 or -OC1-3 alkyl; and a 5- or 6-membered monocyclic heteroaryl; or
R * 'and R ! combine with the nitrogen to which they are attached to form a 5- or 6-membered N-linked monocyclic heterocycloalkyl optionally substituted with a C1-3 alkyl, phenyl or - CH> 2-phenyl, where the phenyl phenyl ring or -CH2-phenyl is optionally substituted with a C1-3 alkyl;
R ' and R! * are independently selected from the group consisting of H; -C (= 0) C1-3 alkyl; -C (= O) phenyl; and phenyl optionally substituted with an -OC1-3 alkyl;
each R '* is independently selected from the group consisting of oxo; -C (= 0) OH; -C (= 0) OC1-3 alkyl; and C1-3 alkyl optionally substituted with an -OH or -OC1: 3 alkyl;
each R'º is independently selected from the group consisting of -CN; -C (= 0) OH; -C (= 0) OC'1-3 alkyl; -C (= O) NH> z; -C (= O) NHC1-3 alkyl; -C (= O) N (C1-3 alkyl) 2; -C (= NH) NH2; -NHC (= NH) NH>; -NH2; -NHC1-3 alkyl; -N (C1-3 alkyl); -NHC3.6 cycloalkyl; -N (C1-3 alkyl) C3.6 cycloalkyl; C1-3 alkyl optionally substituted with a -OH, -OC1-3 alkyl, or 5- or 6-membered monocyclic heterocycloalkyl, wherein monocyclic heterocycloalkyl is optionally substituted with -C1-3 alkyl; C1.3 haloalkyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of -OH and phenyl; -C3.6 cycloalkyl optionally substituted with -NH>, C1.3 alkyl, C1-3 haloalkyl or -OC1-3 alkyl; phenyl optionally substituted with -OH, -OC1-3 alkyl, -NO> 2, -NH2, -NHC1-3 alkyl or -N (C1-3 alkyl) 2; 5 or 6 membered monocyclic heterocycloalkyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of oxo, -OH, -NH ,,
-OC1-3 alkyl,
-C (= 0) C1-3 alkyl, -S (= 0) 2C1-3 alkyl, -C (= 0) OC1 + alkyl, - C (= 0) OCH2 phenyl, and C1.3 alkyl, where C1-. Alkyl is optionally substituted with -NH2, -NHS (= OO) 2C1-3 alkyl, -OH or -OC1-3 alkyl; and 5- or 6-membered monocyclic heteroaryl optionally substituted with an -OH or -OC1-3 alkyl;
each R * it is independently selected from the group consisting of oxo; halo; -OH; -CN; -NH> 2; -NHC1-3 alkyl; -N (C1-3 alkyl) 2; -N * (C1.3 alkyl) s; -NHC (= 0) C1-3 alkyl; -C (= 0) C1-.3 alkyl; -S (= O) mC1-3 alkyl; -C (= 0) OH; -C (= 0) OC1 + alkyl; -C (= O) NH> 2; -C (= O) NHC1-3 alkyl; -C (= O) N (C1-3 alkyl) .; -OC (= O) NH2; -OC (= O) NHC1 + 3 alkyl; -OC (= O) N (C 1-3 alkyl) o; -C (= NH) NH2; -C (= NH) NHC13 alkyl; - C (= NH) N (C 1-3 alkyl) 2; -OC1-3 haloalkyl; C1.3 haloalkyl; Ca.6 monocyclic cycloalkyl; C1-3 alkyl optionally substituted with a monocyclic C3-6 cycloalkyl, -OH, -OC1-3 alkyl, -C (= 0) OH, -C (= 0) OC1-3 alkyl, -NH2, -NHC1- 3 alkyl or -N (C1-3 alkyl) o; -OC1-3 alkyl optionally substituted with a monocyclic C3.6 cycloalkyl, phenyl, -OH, -OC1-3 alkyl, -C (= 0) OH, -C (= 0) OC1-3 alkyl, -C ( = O) NH>, -C (= O) NHC + .- 3 alkyl, -C (= O) N (C1-3 alkyl) 2, -NH2, -NHC1-3 alkyl, -N (C1-3 alkyl )>, - NHC (= 0O) C1-3 alkyl or -NHS (= 0) 2C1-3 alkyl; and phenyl optionally substituted with a halo, -CN, C1.3 alkyl, C1-3 haloalkyl, -OC1-3 alkyl, -NH2, -NHC1-3 alkyl or -N (C1-3 alkyl) 2;
R'º is selected from the group consisting of C1-3 alkyl; Ca.6 monocyclic cycloalkyl; the 5- or 6-membered monocyclic heteroaryl; phenyl; and -CH2phenyl; wherein the phenyl phenyl ring or -CH2 phenyl is optionally substituted with a halo, -CN or -OC1-3 alkyl; each R'º is independently selected from the group consisting of a halo; -CN; -NH2; -NHC1-3 alkyl; -N (C1-3 alkyl) 2; -NHC (= 0) C1-3 alkyl; -NHS (= O) 2C1-3 alkyl; -N (S (= O) 2C1-3 alkyl) 2a; -NHS (= O) 2C3x6 cycloalkyl; -NHS (= O) 2 phenyl; -NHC (= 0) OH; -NHC (= 0) OC'1-3 alkyl; -
S (= O0) 2C1-3 alkyl; -OC1-3 alkyl optionally substituted with a phenyl; C1.3 haloalkyl; -OC1-3 haloalkyl; Monocyclic C3a-.6 cycloalkyl; a 5- or 6-membered monocyclic heterocycloalkyl; and C1-3 alkyl optionally substituted with a monocyclic C3.6 cycloalkyl, -OH, -OC1-3 alkyl, -NH2, -NHC1-3 alkyl or -N (C1-3 alkyl) 2;
each R º is independently selected from the group consisting of -CN; -OC1-3 alkyl; -S (= O) 2C1-3 alkyl; C1-3 haloalkyl; and C1.3 alkyl optionally substituted with an -OH or -OC1-3 alkyl; and C3.6 monocyclic cycloalkyl;
R $ is selected from the group consisting of H; halo; -CN; -NH3z; -C (= O) JOH; -C (= 0) OC'1: 3 alkyl; -C (= 0) C1-3 alkyl; - S (= O) mC1-3 alkyl; -P (= O) (C1-3 alkyl) 2; -C (= O) NR2'Rº2; C1.3 haloalkyl; -OC1-3 alkyl optionally substituted with -OH, -OC1-3 alkyl, -NH> 2, -NHC1-3 alkyl or -N (C1-3 alkyl) 2; C1-3 alkyl optionally substituted with -NH2, -NHC1.3 alkyl, -N (C1-.3 alkyl) 2a, -C (= 0) OH, - C (= 0) OC1-3 alkyl, - S (= O) nC1-3 alkyl, -C (= 0) C1-3 alkyl, -OR , or 5- or 6-membered monocyclic heteroaryl, where monocyclic heteroaryl is optionally substituted with 1 or 2 C1 -3 alkyl; Ca.e monocyclic cycloalkyl optionally substituted with a -C (= O0) OH, - C (= 0) OC1: 3 alkyl or C1-3 alkyl, where C1-3 alkyl is optionally substituted with a -OH or - OC1-3 alkyl; a 5- or 6-membered mono-cyclic heterocycloalkyl optionally substituted with a -C (= 0) OH or -C (= 0) OC1: 3 alkyl; and a 5- or 6-membered heteroaryl optionally substituted with 1 or 2 C1-3alkyl;
R ' and Rº are independently selected from the group consisting of H; C1-.6 alkyl optionally substituted with -OH, -OC1-3 alkyl, -C (= 0) OH, -C (= 0) OC1-3 alkyl, -NH2, -NHC13 alkyl, -N (C1 -3 alkyl) 2, or 5- or 6-membered monocyclic heteroaryl; C + 7- 3 haloalkyl optionally substituted with an -OH or -OC1-3 alkyl;
a 5- or 6-membered monocyclic heteroaryl optionally substituted with 1 or 2 alkyl C1.3; and a 4- to 6-membered monocyclic heterocycloalkyl; or
R2 ' and R22 combine with the nitrogen to which they are attached to form a 5- or 6-membered N-linked monocyclic heterocycloalkyl optionally substituted with a -C (= 0) OH, -C (= 0) OC1-3 alkyl, or C1. Alkyl, wherein C1-3 alkyl is optionally substituted with an -OH or -OC1-3 alkyl;
R * Is selected from the group consisting of H; C1-3 haloalkyl; C1-.3 alkyl optionally substituted with -OH, -OC1-3 alkyl, -C (= 0) OH, -C (= 0) OC1: 3 alkyl, -C (= O) NH,>, -C ( = O) NHC1 + 3 alkyl, -C (= O) N (C1-3 alkyl) 2, phenyl, 5- or 6-membered monocyclic heteroaryl, or 5- or 6-membered monocyclic heterocycloalkyl, where monocyclic heterocycloalkyl is optionally substituted with 1 or 2 oxo or C1-3alkyl; a 4, 5 or 6 membered monocyclic heterocycloalkyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of oxo and C1.3 alkyl; and a 5- or 6-membered monocyclic heteroaryl;
R 'is selected from the group consisting of -CN; - OH; -C (= 0) OH; -C (= 0) OC1 + 3 alkyl;
-C (= 0) C1-3 alkyl; -S (= O) nC1-3 alkyl; -NH2; -NHC1-3 alkyl; -N (C1.3 alkyl) 2; C1-3 alkyl optionally substituted with a monocyclic cycloalkyl C3a.6; C1-3 haloalkyl; C2.3 alkenyl optionally substituted with a monocyclic cycloalkyl Cx; C2.3 alkyn optionally substituted with a monocyclic cycloalkyl C3.6; Monocyclic C3a-6 cycloalkyl; - 5- or 6-membered monocyclic O-heterocycloalkyl; and -OC1-3alkyl optionally substituted with an -OH, -OC1-3alkyl,
-C (= 0) OH or -C (= 0) OC1: 3 alkyl; and
R $ is selected from the group consisting of C1.3 alkyl; C1-.3 haloalkyl; monocyclic
C3.6 cycloalkyl; phenyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of -CN, halo, C1-3 alkyl, C1-3 haloalkyl, -OC1-3 alkyl and -OC1-3 haloalkyl ; and pyridinyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of - CN, halo, C1-3 alkyl, C1-3 haloalkyl, -OC1-3 alkyl and -OC1-3 haloalkyl, with the provided that:
a) when R $ is unsubstituted phenyl, R $ is methyl and R ”is methyl, R $ is not ethyl, unsubstituted phenyl or unsubstituted pyridine;
b) when R $ is unsubstituted cyclohexyl, R6 is methyl and R is methyl, R $ is not unsubstituted pyridine;
c) when R $ is unsubstituted cyclopentyl, R $ is methyl and R7 is methyl, Rô is not ethyl or unsubstituted pyridine,
d) when R $ is methyl, R 'is methyl and R8 is 3,4-di-ethoxy-phenyl, Rº is not unsubstituted 1-pyrrolidine, unsubstituted 1-piperidine, 4-methyl-1-piperidine, 2-1,2,3,4-unsubstituted tetrahydro-isoquinoline, or unsubstituted morpholine;
e) when R $ is CH> -substituted phenyl, R $ is methyl and R7 is methyl, Rº is not ethyl, trifluoromethyl, unsubstituted pyridine, unsubstituted phenyl, monosubstituted phenyl with 4-F, 4-CI, 2- methoxy or 4-methoxy, or phenyl disubstituted with 3,4-methoxy;
f) when R $ is CH> -substituted phenyl, R $ is methyl and R 'is trifluoromethyl, Rº is not unsubstituted phenyl or phenyl substituted with 2-Cl or 4-CI;
g) when R $ is methyl, R is methyl and Rº is unsubstituted phenyl, Rº is not CHXCH2C (= O) NH-phenyl, in which the phenyl ring is unsubstituted or is substituted in position 4 with Cl, methyl or methoxy;
h) when R $ is methyl or ethyl, R 'is methyl and Rº is unsubstituted phenyl, Rº is unsubstituted pyrazolo [1,5-a] pyrimidin-7-yl;
i) when R $ is H, R for isopropyl and Rô for methyl, Rº is not unsubstituted pyrazole; and j) the compound is not where Rº is CH> 2-unsubstituted phenyl, Rº is H, R 'is methyl and R8 is unsubstituted phenyl.
[25]
25. Compound according to claim 24, characterized by the fact that Rº is a 9 or 10 membered bicyclic heteroaryl optionally substituted with 1, 2, 3, or 4 R'7.
[26]
26. A compound according to claim 24, characterized by the fact that the compound has the following Formula (lla):
THE
Po Ro (la), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate or pharmaceutically acceptable hydrate thereof, where Y1 is -O-, -NH-, -NR2- or -S-, and Y2, Y3, Ya, and Ys are -N = or -CR * =, provided that 0.1 or 2 of Y2, Y3, Ya, and Ys are -N =; wherein R * is selected from the group consisting of C1-3 haloalkyl; Monocyclic C3a-6 cycloalkyl; C1-3 alkyl optionally substituted with a monocyclic C3a.6 cycloalkyl, -OH, -OC1-3 alkyl, -C (= O0) OH, -C (= 0) OC1-3 alkyl, - NH2, -NHC1: 3 alkyl or -N (C1-3 alkyl) 2; and phenyl optionally substituted with a halo, -CN, C1-3alkyl, C1-3 haloalkyl, -OC1-3 alkyl, -NH>, -NHC1-3 alkyl or -N (C1-3 alkyl) 2; and where R * º is H or R'7, provided that O, 1, 2 or 3 among Y> 2, Y3, Ya, and Y5 are -CR =, where RE is R7.
[27]
27. Compound according to claim 1, characterized by the fact that the compound is selected from the group consisting of a compound as recited in Table 1A or Table 1B.
[28]
28. Pharmaceutical composition, characterized in that it comprises the compound as defined in any one of claims 1 to 27, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate or pharmaceutically acceptable hydrate thereof, together with a diluent or carrier pharmaceutically acceptable.
[29]
29. Method for inhibiting the CGAS / STING pathway in a cell, characterized by the fact that it comprises contact of the cell with the compound as defined in any one of claims 1 to 27, or a pharmaceutically acceptable salt, pharmaceutically solvate acceptable or pharmaceutically acceptable hydrate thereof, or the composition as defined in claim 28.
[30]
30. Method for inhibiting cytokine production in a cell, characterized in that it comprises contact of the cell with the compound as defined in any of claims 1 to 27, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate or pharmaceutically acceptable hydrate, or the composition as defined in claim 28.
[31]
31. Use of a compound as defined in any one of claims 1 to 27, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvent or pharmaceutically acceptable hydrate thereof, or the composition as defined in claim 28, characterized by the fact that it is to prepare a medication or a Kkit for the treatment of a condition mediated by the CGAS / STING pathway.
[32]
32. Method, according to claim 31, characterized by the fact that the condition mediated by the CGAS / STING pathway is an autoimmune, inflammatory or neurodegenerative condition.
[33]
33. Use of the compound as defined in any of claims 1 to 27, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate or pharmaceutically acceptable hydrate thereof, or the composition as defined in claim 28, characterized in that it is to be prepared a medicine or kit for the treatment of a disease in an individual, in which the disease is selected from the group consisting of systemic inflammatory response syndrome (SIRS), sepsis, septic shock, atherosclerosis, celiac disease, dermatomyositis, scleroderma, interstitial cystitis, transplant rejection (for example, graft versus host disease), Aicardi-Goutieres syndrome, Hutchison Guilford progeria syndrome, Singleton-Merten syndrome, proteasome-associated autoinflammatory syndrome, SAVI (vasculopathy associated with STING beginning in childhood), CANDLE syndrome (chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature), lupus eritis matt pernium, systemic lupus erythematosus, rheumatoid arthritis, juvenile rheumatoid arthritis, Wegener's disease, inflammatory bowel disease (eg, ulcerative colitis, Crohn's disease), idiopathic thrombocytopenic purpura, thrombocytopenic thrombocytopenia, auto-thrombocytopenic thrombocytopenia - multiple clerosis, psoriasis, IgA nephropathy, IgM polyneuropathies, glomerulonephritis, autoimmune myocarditis, myasthenia gravis, vasculitis, Type 1 diabetes, Type 2 diabetes, Sjorgen's syndrome, X-linked reticular pigment disorder, polymyositis, spondylo-chondroplasty - age-related macular neration, Alzheimer's disease and Parkinson's disease.
[34]
34. Use of the compound as defined in any one of claims 1 to 27, including any pharmaceutically acceptable salt, pharmaceutically acceptable solvate or pharmaceutically acceptable hydrate thereof, or the composition as defined in claim 28, in combination with a Janus inhibitor Kinase (Jak), characterized by the fact that it is to prepare a medication or kit for the treatment of a disease in an individual, in which the disease is selected.
none of the group consisting of systemic inflammatory response syndrome (SIRS), sepsis, septic shock, atherosclerosis, celiac disease, dermatomyositis, scleroderma, interstitial cystitis, transplant rejection (for example, graft versus host disease), Ai- cardi-Goutieres syndrome, Hutchison Guilford progeria syndrome, Singleton-Merten syndrome, proteasome-associated autoinflammatory syndrome, SAVI (STING-associated vasculopathy with childhood onset), CANDLE syndrome (chronic atypical neutrophilic dermatosis with | i- podistrophy and elevated temperature), perioperous lupus erythematosus, systemic lupus erythematosus, rheumatoid arthritis, juvenile rheumatoid arthritis, Wegener's disease, inflammatory bowel disease (eg ulcerative colitis, Crohn's disease), idiopathic thrombocytopenic purpura , thrombotic thrombocytopenic purpura, autoimmune thrombocytopenia, multiple sclerosis, psoriasis, IgA nephropathy, IgM polyneuropathies, glomerulonephritis e, autoimmune myocarditis, myasthenia gravis, vasculitis, Type 1 diabetes, Type 2 diabetes, Sjorgen's syndrome, X-linked pigmented pigmentary disease, polymyositis, spondyloenchondodysplasia, age-related macular degeneration, Alzheimer's disease and disease Parkinson's.
[35]
35. Compound according to any one of claims 1 to 27, characterized in that it is for use in the treatment of a condition mediated by the CGAS / STING pathway.
[36]
36. A compound according to any one of claims 1 to 27, characterized in that it is for use in combination with a Janus Kinase inhibitor, for the treatment of a disease selected from the group consisting of inflammatory response syndrome. systemic disease (SIRS), sepsis, septic shock, atherosclerosis, celiac disease, dermatomyositis, scleroderma, interstitial cystitis, transplant rejection (for example, graft versus host disease), Aicardi-Goutieres syndrome, Hutchison syndrome Guilford progeria,
Singleton-Merten syndrome, proteasome-associated autoinflammatory syndrome, SAVI (vasculopathy associated with STING beginning in childhood), CANDLE syndrome (chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature), pernicious lupus erythematosus, systemic lupus erythematosus , rheumatoid arthritis, juvenile rheumatoid arthritis, Wegener's disease, inflammatory bowel disease (eg, ulcerative colitis, Crohn's disease), idiopathic thrombocytopenic purpura, thrombotic thrombocytopenic purpura, autoimmune thrombocytopenia, multiple sclerosis, nephropathy, multiple sclerosis IgA, IgM polyneuropathies, glomerulonephritis, autoimmune myocarditis, myasthenia gravis, vasculitis, Type 1 diabetes, Type 2 diabetes, Sjorgen syndrome, X-linked reticulated pigment disease, polymyositis, age-related macular degeneration, disease Alzheimer's disease and Parkinson's disease.
[37]
37. Composition, characterized by the fact that it comprises a compound as defined in any one of claims 1 to 27 and a Janus Kinase inhibitor.
[38]
38. Kit, characterized by the fact that it comprises a compound as defined in any one of claims 1 to 27 and a Janus Kinase inhibitor.
[39]
39. Invention, characterized by any of its embodiments or categories of claim encompassed by the material initially revealed in the patent application or in its examples presented here.

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EP3681888A1|2020-07-22|

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CO2020002107A2|2020-05-29|

---

MA50256A|2020-07-22|

---

CN111212839A|2020-05-29|

---

ECSP20018586A|2020-06-30|

---

PH12020500500A1|2021-03-01|

---

JOP20200055A1|2019-03-15|

---

EP3681888A4|2021-07-07|

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DOP2020000051A|2020-08-15|

引用文献:

---

公开号 | 申请日 | 公开日 | 申请人 | 专利标题

---

---

US4522811A|1982-07-08|1985-06-11|Syntex Inc.|Serial injection of muramyldipeptides and liposomes enhances the anti-infective activity of muramyldipeptides|

---

JPH0241977B2|1985-06-30|1990-09-20|

---

JPH02131235A|1988-11-12|1990-05-21|Fuji Photo Film Co Ltd|Silver halide photographic sensitive material containing novel coupler|

---

EP0503099A4|1990-10-09|1993-12-01|Otsuka Pharmaceutical Co., Ltd.|Pyrimidine derivative, production thereof, and androgen inhibitor|

---

US5688949A|1991-04-22|1997-11-18|Otsuka Pharmaceutical Factory, Inc.|Pyrazolo 1,5-A!pyrimidine derivatives and anti-inflammatory agent containing the same|

---

US5763263A|1995-11-27|1998-06-09|Dehlinger; Peter J.|Method and apparatus for producing position addressable combinatorial libraries|

---

CN1169149A|1995-09-28|1997-12-31|株式会社大制药工场|Analgesics composition|

---

FR2746309B1|1996-03-22|1998-04-17|Oreal|KERATINIC FIBER DYEING COMPOSITION CONTAINING PYRAZOLOPYRIMIDINEOXO; THEIR USE FOR DYEING AS COUPLERS, DYEING METHODS|

---

US6060478A|1996-07-24|2000-05-09|Dupont Pharmaceuticals|Azolo triazines and pyrimidines|

---

CN1092659C|1997-03-14|2002-10-16|大塚制药株式会社|Novel pyrimidine derivative|

---

JP3625362B2|1997-09-08|2005-03-02|コニカミノルタホールディングス株式会社|Thermal transfer recording material and thermal transfer recording method|

---

US6245759B1|1999-03-11|2001-06-12|Merck & Co., Inc.|Tyrosine kinase inhibitors|

---

AU2002367953C1|2001-05-04|2009-02-19|Paratek Pharmaceuticals, Inc|Transcription factor modulating compounds and methods of use thereof|

---

US7405235B2|2001-05-04|2008-07-29|Paratek Pharmaceuticals, Inc.|Transcription factor modulating compounds and methods of use thereof|

---

US7449488B2|2002-06-04|2008-11-11|Schering Corporation|Pyrazolopyrimidines as protein kinase inhibitors|

---

CN1671710A|2002-06-04|2005-09-21|新创世纪药品公司|Pyrazolo[1,5a]pyrimidine compounds as antiviral agents|

---

AU2003291226B2|2002-11-01|2009-06-04|Paratek Pharmaceuticals, Inc.|Transcription factor modulating compounds and methods of use thereof|

---

JP2005008581A|2003-06-20|2005-01-13|Kissei Pharmaceut Co Ltd|NEW PYRAZOLO[1,5-a]PYRIMIDINE DERIVATIVE, MEDICINAL COMPOSITION CONTAINING THE SAME AND APPLICATION THEREOF|

---

DE10356579A1|2003-12-04|2005-07-07|Merck Patent Gmbh|amine derivatives|

---

US20060160799A1|2004-04-23|2006-07-20|Alekshun Michael N|Transcription factor modulating compounds and methods of use thereof|

---

KR20100053556A|2007-08-14|2010-05-20|바이엘 쉐링 파마 악티엔게젤샤프트|Fused bicyclic pyrimidines|

---

WO2009039323A1|2007-09-19|2009-03-26|Smithkline Beecham Corporation|Prolyl hydroxylase inhibitors|

---

WO2009071705A1|2007-12-07|2009-06-11|Galapagos Nv|Pyrazolepyrimidine compounds useful for the treatment of degenerative & inflammatory diseases|

---

CA2708300A1|2007-12-11|2009-06-18|Schering Corporation|Gamma secretase modulators|

---

WO2009076593A1|2007-12-13|2009-06-18|Vertex Pharmaceuticals Incorporated|Modulators of cystic fibrosis transmembrane conductance regulator|

---

CA2709784A1|2007-12-21|2009-07-09|University Of Rochester|Method for altering the lifespan of eukaryotic organisms|

---

CN101906105B|2009-06-08|2013-01-16|河北医科大学|Pyrazolo pyrimidone derivative as well as drug combination thereof and application thereof|

---

CN101671336B|2009-09-23|2013-11-13|辽宁利锋科技开发有限公司|Aromatic heterocyclic pyridine derivatives and analogs and preparation method and application thereof|

---

UA110347C2|2010-08-12|2015-12-25|Бьорінгер Інгельхайм Інтернаціональ Гмбх|Derivative 6-cycloalkanes 1.5 dyhidropirazol [3,4-d] pyrimidine-4-one and their use as inhibitors pde9a|

---

CN103328479A|2010-09-27|2013-09-25|普罗克斯马根有限公司|7-hydroxy-pyrazolo[1,5-A] pyrimidine compounds and their use as CCR2 receptor antagonists|

---

US10953012B2|2011-04-26|2021-03-23|Bioenergenix Llc|Heterocyclic compounds for the inhibition of pask|

---

EP2518070A1|2011-04-29|2012-10-31|Almirall, S.A.|Pyrrolotriazinone derivatives as PI3K inhibitors|

---

KR20150014506A|2012-05-23|2015-02-06|사피라 파르마슈티칼즈 게엠베하|7-Oxo-4,7-Dihydro-Pyrazolo[1,5-A]Pyrimidine Derivatives Which Are Useful in the Treatment, Amelioration or Prevention of a Viral Disease|

---

ES2617861T3|2012-05-23|2017-06-20|Savira Pharmaceuticals Gmbh|7-Oxo-thiazolopyridine-carbonic acid derivatives and their use in the treatment, improvement or prevention of a viral disease|

---

CN104619699A|2012-08-06|2015-05-13|萨维拉制药有限公司|Dihydroxypyrimidine carbonic acid derivatives and their use in the treatment, amelioration or prevention of a viral disease|

---

CA2904760A1|2013-03-13|2014-09-18|Genentech, Inc.|Pyrazolo compounds and uses thereof|

---

WO2015035062A1|2013-09-05|2015-03-12|Genentech, Inc.|Antiproliferative compounds|

---

WO2015135094A1|2014-03-13|2015-09-17|Genentech, Inc.|Therapeutic compounds and uses thereof|

---

WO2015183989A1|2014-05-27|2015-12-03|Navigen, Inc.|Arf6 inhibitors and methods of synthesis and use thereof|

---

CN106146508A|2015-03-19|2016-11-23|浙江导明医药科技有限公司|The drug combination optimized and treatment cancer and the purposes of autoimmune disease thereof|

---

JP6754772B2|2015-10-23|2020-09-16|武田薬品工業株式会社|Heterocyclic compound|

---

EP3394032A4|2015-12-21|2019-09-18|The University of Chicago|Compounds and methods for treating, detecting, and identifying compounds to treat apicomplexan parasitic diseases|

---

AU2017251155B2|2016-04-15|2021-08-05|Bayer Animal Health Gmbh|Pyrazolopyrimidine derivatives|

---

US20200317674A1|2016-06-03|2020-10-08|An2H Discovery Limited|Pyrazolopyrimidine derivatives and the compositions and methods of treatment regarding the same|

---

WO2018039972A1|2016-08-31|2018-03-08|Agios Pharmaceuticals, Inc.|Inhibitors of cellular metabolic processes|

---

WO2018045071A1|2016-08-31|2018-03-08|Agios Pharmaceuticals, Inc.|Inhibitors of cellular metabolic processes|

---

WO2018229683A1|2017-06-15|2018-12-20|Novartis Ag|5,6-fused-bicyclic compounds and compositions for the treatment of parasitic diseases|

---

WO2019040499A2|2017-08-21|2019-02-28|Navigen, Inc.|Arf6 inhibitors and related methods|WO2018045071A1|2016-08-31|2018-03-08|Agios Pharmaceuticals, Inc.|Inhibitors of cellular metabolic processes|

---

JOP20170192A1|2016-12-01|2019-01-30|Takeda Pharmaceuticals Co|Cyclic dinucleotide|

---

US11203610B2|2017-12-20|2021-12-21|Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I.|2′3′ cyclic dinucleotides with phosphonate bond activating the sting adaptor protein|

---

US10966999B2|2017-12-20|2021-04-06|Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I.|3′3′ cyclic dinucleotides with phosphonate bond activating the sting adaptor protein|

---

TW202005655A|2018-04-06|2020-02-01|捷克科學院有機化學與生物化學研究所|2'3'-cyclic dinucleotides|

---

WO2020227159A2|2019-05-03|2020-11-12|Flagship Pioneering Innovations V, Inc.|Methods of modulating immune activity|

---

CN110724143B|2019-10-09|2021-03-23|清华大学|Preparation of target BTK protein degradation compound and application of target BTK protein degradation compound in treatment of autoimmune system diseases and tumors|

---

CN113248491B|2020-02-11|2022-02-25|中国科学院上海药物研究所|Substituted indole urea derivatives, synthesis method and application thereof|

---

WO2021233854A1|2020-05-20|2021-11-25|F. Hoffmann-La Roche Ag|New malonitrile derivatives|

---

WO2021233851A1|2020-05-20|2021-11-25|F. Hoffmann-La Roche Ag|New malonitrile derivatives|

---

WO2021233852A1|2020-05-20|2021-11-25|F. Hoffmann-La Roche Ag|Cgas inhibiting triazolopyrimidone derivatives|

法律状态:
2021-11-23| B350| Update of information on the portal [chapter 15.35 patent gazette]|

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2021-12-28| B11A| Dismissal acc. art.33 of ipl - examination not requested within 36 months of filing|

优先权:

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申请号 | 申请日 | 专利标题

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US201762559482P| true| 2017-09-15|2017-09-15|

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US62/559,482|2017-09-15|

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US201862633248P| true| 2018-02-21|2018-02-21|

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US62/633,248|2018-02-21|

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US201862687769P| true| 2018-06-20|2018-06-20|

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US62/687,769|2018-06-20|

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PCT/US2018/051014|WO2019055750A1|2017-09-15|2018-09-14|Pyrazolopyrimidinone compounds and uses thereof|

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