NLRP3 modifiers

Abstract

To provide modulator compounds of NLRP3, which may be used as medicaments for the treatment of proliferative disorders, such as cancer in a subject (e.g., a human).SOLUTION: The present invention provides a compound represented by formula (I).SELECTED DRAWING: None

Description

[Technical Field]

[0001] (Technical field) This application features chemical classes, e.g., compounds or pharmaceutically acceptable salts and / or hydrates and / or co-crystals of the compounds, and / or drug combinations that modulate (e.g., agonize or partially agonize) NLRP3, useful for treating conditions, diseases, or disorders (e.g., cancers exhibiting low T cell infiltration) that contribute to the pathology and / or symptoms and / or progression and / or treatment-refractory symptoms of the condition, disease, or disorder in a subject, e.g., a human, where increased NLRP3 signaling pathway activity can compensate for a deficiency in innate immune activity. This application also features compositions and other methods of using and making the compositions.

[0002] Background technology Nucleotide-binding oligomerization domain-like receptors ("NLRs") comprise a family of intracellular receptors that detect pathogen-associated molecular patterns ("PAMPs") and endogenous molecules (see, e.g., Ting, JPY et al., "The NLR gene family: a standard nomenclature," Immunity, vol. 28, no. 3, pp. 285-287, 2008).

[0003] NLRP refers to a subfamily of NLRs that contain pyrin domains and are composed of proteins such as NLRP1, NLRP3, NLRP4, NLRP6, NLRP7, and NLRP12. NLRPs are thought to be involved in the formation of multiprotein complexes called inflammasomes (see, for example, Chaput, C. et al., "NOD-like receptors in lung diseases," Frontiers in Immunology, 4:article 393, (2013)). These complexes typically contain one or two NLR proteins, the adaptor molecule CARD domain-containing apoptosis-associated speck-like protein (ASC), and the procaspase-1F family (see, for example, Bauernfeind, F. and Hornung, V. "Of inflammasomes and pathogens-sensing of microbes by the inflammasome," EMBO Molecular Medicine, 5(6):814-826, (2013)).

[0004] One such inflammasome is formed by the NLRP3 scaffold, the ASC adaptor, and pro-caspase-1 (see, e.g., Hirota, JA, et al., "The airway epithelium nucleotide-binding domain and leucine-rich repeat protein 3 inflammatory is activated by urban particulate matter," Journal of Allergy and Clinical Immunology, vol. 129, no. 4, pp. 1116.e6-1125.e6, 2012). Its expression is thought to be induced by inflammatory cytokines and TLR agonists in myeloid cells and human bronchial epithelial cells (Id.). The NLRP3 inflammasome is thought to mediate the caspase-1-dependent conversion of pro-IL-1β and pro-IL-18 to IL-1β and IL-18. Furthermore, IL-1β and IL-18 have been shown to play important roles in the treatment of various cancer types (see, e.g., Chen, L.C. et al., EMBO Mol Med., 4(12):1276-1293 (2012) and Tse, B. W.C. et al., PLoS One, 6(9):e24241 (2011)). IL-18 has been shown to reverse resistance to checkpoint inhibitors in an animal tumor model of colon cancer (see, Ma, Z. et al., Clin. Cancer Res. (2016) DOI:10.1158 / 1078-0432. CCR-15-1655).

[0005] (Summary of the Invention) The present invention relates to a compound of formula (I): [ka] wherein all variables are defined herein below. The present invention relates to the compound

[0006] Included within the scope of the present invention are pharmaceutically acceptable salts, stereoisomers, tautomers and solvates of compounds of formula (I).

[0007] The present invention also relates to pharmaceutical compositions comprising one or more compounds of the present invention.The present invention relates to methods of treating cancer using one or more compounds of the present invention.

[0008] The present invention also provides processes and intermediates for making compounds of formula (I) or pharmaceutically acceptable salts, stereoisomers, tautomers and solvates thereof.

[0009] The compounds of the present invention may be used in therapy.

[0010] The compounds of the invention may be used for the manufacture of a medicament for the treatment of cancer.

[0011] The compounds of the present invention may be used alone, in combination with other compounds of the present invention, or in combination with one or more other drugs.

[0012] Other features and advantages of the invention will be apparent from the following detailed description and claims.

[0013] (Compounds of the present invention) In a first aspect, the present invention relates in particular to compounds of formula (I): [ka] [In the formula, [ka] teeth, [ka] are independently selected from; R 1 are each independently the following group: (i)H; (ii) halo; (iii) XR 5 (Wherein X is C 1-6 alkylene, and R 5 H, OH, cyano, C 1-4 Alkoxy, C 1-4 Haloalkoxy, -C(O)OR a , -NR b R c or -C(O)NR b R k is); (iv) C substituted with 1 to 6 F 1-6 alkyl; (v) C substituted with 0 to 6 F 3-6 cycloalkyl; (vi)(C 1-3 alkylene)-aryl: wherein the aryl is selected from 0 to 3 R d is replaced by; or (vii)(C 1-3 alkylene)-heteroaryl containing 5 to 6 ring atoms, wherein the 1 to 4 ring atoms are each independently selected from N, N(R f ), O and S, wherein the heteroaryl is selected from 0 to 3 R d is replaced by; R 1a are independently H, C substituted with 0-6 F 1-6 C which is alkyl or substituted with 0-6 F 3-6 is cycloalkyl; R 2 are each independently the following group: (i)H; (ii)-YR 6 ; (iii) -C(O)-YR 6 : During the ceremony, Y is independently 0 to 4 R e C replaced with 1-8 alkylene; and ·R 6 are each independently one of the following groups: H, OH, CN, OR a , -C(O)Ra , -C(O)OR a , -NR b R c , -C(O)NR b R k , -SO 1-2 R h , [ka] or heteroaryl containing 5 to 10 ring atoms, wherein 1 to 4 ring atoms are each selected from N, N(R f ), O, and S, and the heteroaryl is selected independently from 0 to 3 R d is replaced by; (iv)-(Y 1 ) n -Y 2 -(Y 3 ) p -R 7 : During the ceremony, n is independently 0, 1, or 2; p is independently 0 or 1; Y 1 and Y 3 each independently represents 0 to 2 R e C replaced with 1-3 is alkylene; Y 2 are independently 0 to 4 R g C replaced with 3-6 cycloalkylene or heterocycloalkylene containing 3 to 8 ring atoms, wherein 1 to 2 of the ring atoms are each independently N, N(R f ) and O, wherein the heterocycloalkylene is selected from 0 to 4 R g is substituted with; and ·R 7 H, OH, -OR a , -C(O)OR a , -NR b R c , -C(O)NR b R kor heteroaryl containing 5 to 6 ring atoms, wherein the 1 to 4 ring atoms are each independently selected from N, N(R f ), O and S, wherein the heteroaryl is selected from 0 to 4 R g is replaced by; (v)-Z 1 -Z 2 -Z 3 -R 8 : During the ceremony, Z 1 is C substituted with 0-6 F 1-3 is alkylene; Z 2 is -N(R f )-, -O- or -S-; Z 3 is C substituted with 0-6 F 2-5 alkylene; and ·R 8 OH, OR a , -C(O)R a , -C(O)OR a , -NR b R c , -C(O)NR b R k or heteroaryl containing 5 to 6 ring atoms, wherein the 1 to 4 ring atoms are each independently selected from N, N(R f ), O and S, wherein the heteroaryl is selected from 0 to 3 R d is replaced by; R 3 are independently halo or -(C 0-3 alkylene)-(5-membered heteroaryl), wherein the heteroaryl has 1 to 4 ring carbon atoms and N, N(R f ), 1 to 4 ring heteroatoms each independently selected from O and S, and 0 to 3 R g substituted with; 3 is furanyl, R 2 is C 1-4 is other than alkyl; R 4H, halo, cyano, OH, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Haloalkoxy, -C(O)OH, -C(O)OR a , -NR j R k , -C(O)NR j R k , -SO 1-2 R h and 0 to 2 R e C replaced with 1-4 independently selected from alkyl; R a are each independently the following group: (i) 0 to 3 R e C replaced with 1-6 alkyl; (ii)-(C 0-3 Alkylene)-C 3-6 Cycloalkyl: wherein the cycloalkyl is selected from 0 to 4 R g is replaced by; (iii)-(C 0-3 alkylene)-heterocyclyl having 3 to 10 ring atoms, wherein the 1 to 3 ring atoms are each independently N(R f ), O and S(O) 0-2 and the heterocyclyl is selected from 0 to 4 R g is replaced by; (iv)-(C 0-3 alkylene)-(C 6-10 aryl): wherein the aryl is selected from 0 to 5 R d is replaced by; or (v)-(C 0-3 alkylene)-heteroaryl containing 5 to 10 ring atoms, wherein the 1 to 4 ring atoms are each independently selected from N, N(R f ), O and S, wherein the heteroaryl is selected from 0 to 3 R d is replaced by; R b are each independently H or R a and; Rc are each independently H, -C(O)R a , -C(O)OR a , -C(O)NR j R k , -S(O) 1-2 R h , 0 to 2 R e C replaced with 1-6 Alkyl-(C 0-3 alkylene)-(0 to 4 R n -substituted phenyl) and -(C 0-3 and N(R alkylene)-heteroaryl containing 5 to 6 ring atoms, wherein the 1 to 4 ring atoms are each independently selected from N, N(R f ), O and S, wherein the heteroaryl is selected from 0 to 3 R n is substituted with; or R b and R c together with the nitrogen atom to which each is attached form a heterocyclyl containing 3 to 10 ring atoms, wherein the 1 to 3 ring atoms are each independently selected from N(R f ), O and S, wherein the heterocyclyl is selected from 0 to 4 R g is replaced by; R d are each independently halo, OH, cyano, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Haloalkoxy, -C(O)(C 1-4 alkyl), -C(O)OH, -C(O)O(C 1-4 alkyl), -NR j R k , -N(R m )(C(O)(C 1-4 alkyl), -N(R m )(C(O)O(C 1-4 alkyl), -C(O)NR j R k , -S(O) 1-2 R h , -S(O) 1-2NR h R j , 0 to 2 R e C replaced with 1-6 Alkyl and -(C 0-3 alkylene)-R p Selected from; R e are each independently halo, OH, cyano, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Haloalkoxy, -C(O)OR a , -OC(O)R h , -NR b R c and -CONR b R k Selected from; R f are each independently H, OH, or C 1-4 Alkyl, C 1-4 Alkoxy, -C(O)(C 1-4 alkyl), -C(O)(C 1-4 haloalkyl), -C(O)O(C 1-4 alkyl), -C(O)NR j R k , -S(O) 1-2 R h and -(C 0-3 alkylene)-phenyl; R g are each independently oxo or R d and; R h are each independently 0 to 2 R n C replaced with 1-6 Alkyl, C 1-4 Haloalkyl and -(C 0-3 alkylene)-R p Selected from; R j and R m are each independently H or C 1-4 is alkyl; R kare each independently H, C 1-4 Alkyl and -(C 0-2 alkylene)-phenyl; R n are each independently halo, OH, C 1-6 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, cyano, -C(O)OH, -C(O)O(C 1-4 alkyl), -NR j R k and -CONR j R k Selected from: R p are each independently 0 to 4 C 1-4 Alkyl-substituted C 3-6 cycloalkyl; heterocyclyl containing 3 to 10 ring atoms, wherein 1 to 3 ring atoms are each independently NH, N(C 1-4 alkyl), O and S, wherein the heterocyclyl is selected from 0 to 4 independently selected C 1-4 substituted with alkyl); 0 to 3 R n and heteroaryl containing 5 to 10 ring atoms, wherein 1 to 4 ring atoms are each independently selected from N, NH, N(C 1-4 alkyl), O and S, wherein the heteroaryl is selected from 0 to 3 R n ) are selected from or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof.

[0014] In one embodiment, R 1a are independently C substituted with 0 to 6 F 1-6 C substituted with alkyl or 0-6 F 3-6 It is cycloalkyl.

[0015] In one embodiment, R 3 are independently halo or -(C 0-3alkylene)-(5-membered heteroaryl), wherein the heteroaryl has 1 to 4 ring carbon atoms and each independently N, N(R f ) and S, and 0 to 3 R g is replaced by .

[0016] In one embodiment, R 6 are independently OH, OR a , -C(O)R a , -C(O)OR a , -NR b R c , -C(O)NR b R k or heteroaryl containing 5 to 6 ring atoms, wherein 1 to 4 ring atoms are each independently selected from N, N(R f ), O and S, wherein the heteroaryl is selected from 0 to 3 R d is replaced by .

[0017] In one embodiment, R h is C 1-6 Alkyl, C 1-4 Haloalkyl and -(C 0-3 alkylene)-R p are independently selected from

[0018] In another aspect, the present invention provides a compound of formula (I): [In the formula, [ka] teeth, [ka] are independently selected from; R 1 are each independently the following group: (i)H; (ii) halo; (iii) XR 5 (wherein X is an unbranched C 1-6 alkylene, and R5 H, OH, cyano, C 1-4 Alkoxy, C 1-4 Haloalkoxy, -C(O)OR a , -NR b R c or -C(O)NR b R k is); (iv)(C 1-3 alkylene)-aryl: wherein the aryl is selected from 0 to 3 R d is replaced by; or (v)(C 1-3 alkylene)-heteroaryl containing 5 to 6 ring atoms, wherein the 1 to 4 ring atoms are each independently selected from N, N(R f ), O and S, wherein the heteroaryl is selected from 0 to 3 R d is replaced by; R 2 are each independently the following group: (i)H; (ii)-YR 6 ; (iii) -C(O)-YR 6 : During the ceremony, Y is independently 0 to 4 R e C replaced with 1-8 alkylene; and ·R 6 are each independently OH, OR a , -C(O)R a , -C(O)OR a , -NR b R c , -C(O)NR b R k or heteroaryl containing 5 to 6 ring atoms, wherein the 1 to 4 ring atoms are each selected from N, N(R f ), O, and S, and the heteroaryl is selected independently from 0 to 3 R d is replaced by; (iv)-(Y 1 ) n -Y 2 -(Y 3 ) p-R 7 : During the ceremony, each of n and p is independently 0 or 1; Y 1 and Y 3 are each independently 0 to 2 R e C replaced with 1-3 is alkylene; Y 2 are independently 0 to 4 R g C replaced with 3-6 cycloalkylene or heterocycloalkylene containing 3 to 8 ring atoms, wherein 1 to 2 ring atoms are each independently selected from N, N(R f ) and O, wherein the heterocycloalkylene is selected from 0 to 4 R g is substituted with; and ·R 7 H, OH, -C(O)OR a , -NR b R c , -C(O)NR b R k or heteroaryl containing 5 to 6 ring atoms, wherein the 1 to 4 ring atoms are each selected from N, N(R f ), O, and S, wherein the heteroaryl is selected from 0 to 4 R g is replaced by; or (v)-Z 1 -Z 2 -Z 3 -R 8 : During the ceremony, Z 1 is C substituted with 0-6 F 1-3 is alkylene; Z 2 is -N(R f )-, -O- or -S-; Z 3 is C substituted with 0-6 F 2-5 alkylene; and ·R 8 OH, OR a , -C(O)R a , -C(O)OR a, -NR b R c , -C(O)NR b R k or heteroaryl containing 5 to 6 ring atoms, wherein 1 to 4 ring atoms are N, N(R f ), O, and S, and the heteroaryl is selected independently from 0 to 3 R d is replaced by; R 3 are independently halo or -(C 0-3 alkylene)-(5-membered heteroaryl), wherein the heteroaryl has 1 to 4 ring carbon atoms and N, N(R f ), 1 to 4 ring heteroatoms each independently selected from O and S, and 0 to 3 R g substituted with; 3 is furanyl, R 2 is C 1-4 is other than alkyl; R 4 H, halo, cyano, OH, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Haloalkoxy, -C(O)OH, -C(O)OR a , -NR j R k , -C(O)NR j R k , -SO 1-2 R h and 0 to 2 R e C replaced with 1-4 independently selected from alkyl; R a are each independently the following group: (i) 0 to 2 R e C replaced with 1-6 alkyl; (ii)-(C 0-3 Alkylene)-C 3-6 Cycloalkyl: wherein the cycloalkyl is selected from 0 to 4 R g is replaced by; (iii)-(C 0-3alkylene)-heterocyclyl having 3 to 10 ring atoms, wherein the 1 to 3 ring atoms are each independently N(R f ), O and S, wherein the heterocyclyl is selected from 0 to 4 R g is replaced by; (iv)-(C 0-3 alkylene)-(C 6-10 aryl): wherein the aryl is selected from 0 to 5 R d is replaced with; or (v)-(C 0-3 alkylene)-heteroaryl containing 5 to 10 ring atoms, wherein the 1 to 4 ring atoms are each independently selected from N, N(R f ), O and S, wherein the heteroaryl is selected from 0 to 3 R d is replaced by; R b are each independently H or R a and; R c are each independently H, -C(O)R a , -C(O)OR a , -C(O)NR j R k , -S(O) 1-2 R h , 0 to 2 R e C replaced with 1-6 Alkyl, -(C 0-3 alkylene)-(0 to 4 R n phenyl substituted with -(C 0-3 and heteroaryl containing 5 to 6 ring atoms, wherein the 1 to 4 ring atoms are each selected from N, N(R alkylene)- f ), O, and S, and the heteroaryl is selected independently from 0 to 3 R n is substituted with; or R b and R c together with the nitrogen atom to which each is attached form a heterocyclyl containing 3 to 10 ring atoms, wherein the 1 to 3 ring atoms are each independently selected from N(R f), O and S, wherein the heterocyclyl is selected from 0 to 4 R g is replaced by; R d are each independently halo, OH, cyano, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Haloalkoxy, -C(O)(C 1-4 alkyl), -C(O)OH, -C(O)O(C 1-4 alkyl), -NR j R k , -N(R m )(C(O)(C 1-4 alkyl), -N(R m )(C(O)O(C 1-4 alkyl), -C(O)NR j R k , -S(O) 1-2 R h , -S(O) 1-2 NR h R j , 0 to 2 R e C replaced with 1-6 Alkyl and -(C 0-3 alkylene)-R p Selected from; R e are each independently halo, OH, cyano, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Haloalkoxy, -C(O)OR a , -OC(O)R h , -NR b R c and -CONR b R k Selected from; R f are each independently H, OH, or C 1-4 Alkyl, C 1-4 Alkoxy, -C(O)(C 1-4 alkyl), -C(O)O(C 1-4 alkyl), -C(O)NRj R k , -S(O) 1-2 R h and -(C 0-3 alkylene)-phenyl; R g are each independently oxo or R d and; R h are each independently C 1-6 Alkyl, C 1-4 Haloalkyl and -(C 0-3 alkylene)-R p Selected from; R j and R m are each independently H or C 1-4 is alkyl; R k are each independently H, C 1-4 Alkyl and -(C 0-2 alkylene)-phenyl; R n are each independently halo, OH, C 1-6 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, cyano, -C(O)OH, -C(O)O(C 1-4 alkyl), -NR j R k and -CONR j R k Selected from: R p are each independently 0 to 4 C 1-4 Alkyl-substituted C 3-6 cycloalkyl; heterocyclyl containing 3 to 10 ring atoms, wherein 1 to 3 ring atoms are each independently NH, N(C 1-4 alkyl), O and S, wherein the heterocyclyl is selected from 0 to 4 independently selected C 1-4 substituted with alkyl); 0 to 3 R nand heteroaryl containing 5 to 10 ring atoms, wherein 1 to 4 ring atoms are each independently selected from N, NH, N(C 1-4 alkyl), O and S, wherein the heteroaryl is selected from 0 to 3 R n ) are selected from or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof.

[0019] In a second aspect, the present invention provides a compound of formula (I) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, within the scope of the first aspect: R 3 are independently -(C 0-3 alkylene)-(5-membered heteroaryl), wherein the heteroaryl has 2 to 4 ring carbon atoms and N, N(R f ) and S, and 0 to 3 R g is substituted with; and R 6 are each independently OH, OR a , -C(O)R a , -C(O)OR a , -NR b R c , -C(O)NR b R k , -SO2(C 1-4 and heteroaryl containing 5 to 6 ring atoms, wherein the 1 to 4 ring atoms are each independently selected from N, N(R alkyl), and heteroaryl containing 5 to 6 ring atoms. f ), O and S, wherein the heteroaryl is selected from 0 to 3 R d is replaced by .

[0020] In another aspect, the present invention provides a compound of formula (I) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, within the scope of the first aspect: R 3 are independently -(C 0-3alkylene)-(5-membered heteroaryl), wherein the heteroaryl has 2 to 4 ring carbon atoms and N, N(R f ) and S, and 0 to 3 R g is substituted with; and R 6 are each independently OH, OR a , -C(O)R a , -C(O)OR a , -NR b R c , -C(O)NR b R k or heteroaryl containing 5 to 6 ring atoms, wherein 1 to 4 ring atoms are each independently selected from N, N(R f ), O and S, wherein the heteroaryl is selected from 0 to 3 R d is replaced by .

[0021] In a third aspect, the present invention provides a compound of formula (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh) or (IIi) within the scope of the first or second aspect: [ka] [ka] or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof.

[0022] In another aspect, the present invention provides a compound of formula (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg-1) or (IIh) within the scope of the first or second aspect: [ka] [ka] or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof.

[0023] In another aspect, the present invention provides a compound of formula (IIa), (IIb), (IIc), (IId) or (IIe) within the scope of the first or second aspect: [ka] or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof.

[0024] In a fourth aspect, the present invention provides a compound of formula (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh) or (IIi) within the scope of the first, second or third aspect: R 1 are each independently H, halo, and C 1-4 alkyl; R 2 each independently represents H, C substituted with 0 to 3 F; 1-4 Alkyl, -YR 6 , -(CH2) 1-3 O(CH2) 2-3 OR a , -(CH2) 0-2 -Y 2 -R 7 and [ka] Selected from; Y is independently 0 to 3 R e C replaced with 1-6 is alkylene; R 3 are each independently -(C 0-2 alkylene)-(5-membered heteroaryl), wherein the heteroaryl has 2 to 4 ring carbon atoms and each independently N, N(R f ) and S, and the heteroaryl contains 0 to 2 R g However, R 3 is furanyl, R 2 is C 1-4is other than alkyl; R 4 are each independently H, halo, and C 1-4 alkyl; R 6 OH, CN, OR a , -C(O)R a , N.R. b R c , -C(O)NR b R k , -SO2(C 1-4 alkyl), [ka] and heteroaryl containing 5 to 10 ring atoms, wherein the 1 to 4 ring atoms are each independently selected from N, N(R f ), O and S, wherein the heteroaryl is selected from 0 to 3 R d is replaced by; -Y 2 -R 7 is 0 to 2 R d C replaced with 3-6 cycloalkyl, [ka] are independently selected from; R a are each independently the following group: (i) 0 to 3 R e C replaced with 1-6 alkyl; (ii) 0 to 2 R g C replaced with 3-6 cycloalkyl; (iii)-(C 0-2 alkylene)-heterocyclyl containing 4 to 10 ring atoms, wherein the 1 to 3 ring atoms are each independently N(R f ), O and S, wherein the heterocyclyl is selected from 0 to 3 R g is replaced by; (iv)-(C 0-2 alkylene)-(C 6-10aryl): wherein the aryl is selected from 0 to 3 R d or (v)-(C 0-2 alkylene)-heteroaryl containing 5 to 10 ring atoms, wherein the 1 to 3 ring atoms are each independently selected from N, N(R f ), O and S, wherein the heteroaryl is selected from 0 to 3 R d is replaced by; R b are each independently H or R a and; R c are each independently H, -C(O)R a , -C(O)OR a , -C(O)NR j R k , -S(O)2R h , 0 to 2 R e C replaced with 1-6 Alkyl, -(C 0-3 alkylene)-(0 to 4 R n -substituted phenyl) and -(C 0-3 and N(R alkylene)-heteroaryl containing 5 to 6 ring atoms, wherein 1 to 4 ring atoms are selected from N, N(R f ), O, and S, and the heteroaryl is selected independently from 0 to 3 R n is substituted with; or R b and R c together with the nitrogen atom to which they are attached form a heterocyclyl containing 3 to 10 ring atoms, and the 1 to 3 ring atoms are each independently N(R f ), O and S, wherein the heterocyclyl is selected from 0 to 3 R g is replaced by; R d are each independently OH, halo, CN, or C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Haloalkoxy, -C(O)O(C 1-4 alkyl), NH2, N(C 1-4 alkyl)2, -CONH2, -CONH(C 1-4alkyl), -NHC(O)(C 1-4 alkyl), -NHC(O)O(C 1-4 alkyl), -S(O)2(C 1-4 alkyl), benzoxy, 0 to 2 R e C replaced with 1-4 alkyl, phenyl, and heteroaryl containing 5 to 6 ring atoms, wherein 1 to 4 ring atoms are each independently selected from N, N(R f ), O and S, wherein the heteroaryl is selected from 0 to 2 R n is replaced by; R e are each independently halo, OH, CN, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Haloalkoxy, -CONH2 and -CONH(C 1-4 alkyl); R f are each independently H, C 1-4 Alkyl, -C(O)C 1-4 Alkyl and -C(O)(C 1-4 haloalkyl); R g are each independently oxo or R d and; R h are independently 0 to 2 R n C replaced with 1-4 Alkyl, C 3-6 is cycloalkyl or phenyl; R j are independently H or C 1-4 is alkyl; R k is H, C 1-4 independently selected from alkyl and phenyl; and R n are each independently a halo, C 1-4 Alkyl and C 1-4 alkoxy, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof.

[0025] In one embodiment, R b is H, C 1-4 Alkyl and -(C 0-2 alkylene)-phenyl.

[0026] In one embodiment, R e Halo, OH, C 1-4 Alkoxy, C 1-4 Haloalkyl and C 1-4 haloalkoxy.

[0027] In one embodiment, R f is H, C 1-4 Alkyl and -C(O)C 1-4 alkyl.

[0028] In one embodiment, R g are independently OH or C 1-4 It is an alkoxy.

[0029] In one embodiment, R h independently, C 1-4 It is alkyl or phenyl.

[0030] In another aspect, the present invention provides a compound of formula (IIa), (IIb), (IIc), (IId) or (IIe) within the scope of the first, second or third aspect: During the ceremony, R 1 are each independently H, halo, and C 1-4 alkyl; R 2 are each independently H, -(CH2) 1-3 -R 6 , -(CH2) 1-3 O(CH2) 2-3 OR a and -(CH2) 1-2 -Y 2 -R 7 Selected from; R 3 are independently -(C 0-2alkylene)-(5-membered heteroaryl), wherein the heteroaryl has 2 to 4 ring carbon atoms and each independently N, N(R f ) and S, and the heteroaryl contains 0 to 2 R g is replaced by; R 4 are each independently H, halo, and C 1-4 alkyl; R 6 are each independently OH, OR a , -NR b R c , -C(O)NR b R k or heteroaryl containing 5 to 6 ring atoms, wherein the 1 to 4 ring atoms are each independently selected from N, N(R f ), O and S, wherein the heteroaryl is selected from 0 to 3 R d is replaced by; -Y 2 -R 7 teeth, [ka] are independently selected from; R a are each independently the following group: (i) 0 to 2 R e C replaced with 1-6 alkyl; (ii) 0 to 2 R g C replaced with 3-6 cycloalkyl; (iii)-(C 0-2 alkylene)-heterocyclyl containing 4 to 10 ring atoms, wherein the 1 to 3 ring atoms are each independently N(R f ), O and S, wherein the heterocyclyl is selected from 0 to 3 R g is replaced by; (iv)-(C 0-2 alkylene)-(C 6-10 aryl): wherein the aryl is selected from 0 to 3 R d is replaced by; or (v)-(C 0-2 alkylene)-heteroaryl containing 5 to 10 ring atoms, wherein the 1 to 3 ring atoms are each independently selected from N, N(R f ), O and S, wherein the heteroaryl is selected from 0 to 3 R d is replaced by; R b are each independently H, C 1-4 Alkyl and -(C 0-2 alkylene)-phenyl; R c are each independently H, -C(O)R a , -C(O)OR a , -C(O)NR j R k , -S(O)2R h , 0 to 2 R e C replaced with 1-6 Alkyl, -(C 0-3 alkylene)-(0 to 4 R n -substituted phenyl) and -(C 0-3 and N(R alkylene)-heteroaryl containing 5 to 6 ring atoms, wherein 1 to 4 ring atoms are selected from N, N(R f ), O, and S, and the heteroaryl is selected independently from 0 to 3 R n is substituted with; or R b and R c together with the nitrogen atom to which they are attached form a heterocyclyl containing 3 to 10 ring atoms, and the 1 to 3 ring atoms are each independently N(R f ), O and S, wherein the heterocyclyl is selected from 0 to 3 R g is replaced by; R d are each independently halo, CN, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Haloalkoxy, -C(O)O(C 1-4 alkyl), -NHC(O)(C 1-4 alkyl), -NHC(O)O(C 1-4 alkyl), -S(O)2(C1-4 alkyl), benzoxy, 0 to 2 R e C replaced with 1-4 alkyl and heteroaryl containing 5 to 6 ring atoms, wherein the 1 to 4 ring atoms are each independently selected from N, N(R f ), O and S, wherein the heteroaryl is selected from 0 to 2 R n may be substituted with; R e are each independently F, Cl, OH, C 1-4 Alkoxy, C 1-4 Haloalkyl and C 1-4 haloalkoxy; R f are each independently H or C 1-4 is alkyl; R h independently, C 1-4 is alkyl or phenyl; R j are independently H or C 1-4 alkyl; R k is H, C 1-4 independently selected from alkyl and phenyl; and R n are each independently F, Cl, or C 1-4 Alkyl and C 1-4 alkoxy, The present invention provides a compound, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0031] In a fifth aspect, the present invention provides a compound of formula (IIa) in the first to fourth aspects: [ka] [In the formula, R 1 are H, F and C 1-4 independently selected from alkyl; R 2 is C substituted with H, 0-3 F 1-4 Alkyl, -(CH2) 1-3 -R 6, -(CH2) 1-2 CH(CH3)OH, -(CH2) 1-2 C(CH3)2OH, -(CH2) 1-2 CH(OCH3)CH2OH, -CH(CH3)(CH2) 1-2 OH, -(CH2) 1-2 CH(OH)CH2F, -(CH2) 1-2 CH(CH3)O(C 1-4 alkyl), -(CH2) 1-3 O(CH2) 2-3 OR a , -CH2CH(CH3)NHC(O)R a and -(CH2) 1-2 -Y 2 -R 7 are independently selected from; R 3 is independently a 5-membered heteroaryl containing 3 to 4 ring carbon atoms and 1 to 2 ring heteroatoms each independently selected from N, NH, and S; provided that R 3 is furanyl, R 2 is C 1-4 is other than alkyl; R 4 H, halo and C 1-4 independently selected from alkyl; R 6 OH, OR a , N.R. b R c , -NR b C(O)R a , -C(O)NR b R k , -NHC(O)OR a , -NHC(O)NR j R k , -NHS(O)2R h , -SO2(C 1-4 alkyl), [ka] and heteroaryl containing 5 to 6 ring atoms, wherein the 1 to 4 ring atoms are each independently selected from N, N(R f), O and S, wherein the heteroaryl is selected from 0 to 3 R d is replaced by; -Y 2 -R 7 is 0 to 2 R d C replaced with 3-6 cycloalkyl, [ka] are independently selected from; R a are each independently 0 to 2 R e C replaced with 1-4 Alkyl, C 3-6 cycloalkyl, [ka] Phenyl, benzyl, oxazolyl, isoxazolyl, thiazolyl, N-(C 1-4 alkyl)-pyrazolyl, pyrazol-1-yl, N-(C 1-4 alkyl)-imidazolyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, N-(C 1-4 alkyl)-benzimidazolyl, pyrazolo[1,5-a]pyrimidinyl and [ka] (wherein each ring group is selected from 0 to 3 R d (substituted with); R b are each independently H, C 1-4 alkyl or phenyl substituted with 0-2 F; R c independently, C 1-4 Alkyl, -(C 0-3 alkylene)-(0 to 3 R n phenyl substituted with -(C 0-3 alkylene)-heteroaryl containing 5 to 6 ring atoms, wherein 1 to 4 ring atoms are each selected from N, N(R f ), O, and S, and the heteroaryl is selected independently from 0 to 3 Rn is replaced by; R d are each independently halo, CN, -CHOH, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Haloalkoxy, -C(O)O(C 1-4 alkyl), -CONH2, NH2, N(C 1-4 alkyl)2, -NHC(O)(C 1-4 alkyl), -NHC(O)O(C 1-4 alkyl), -S(O)2(C 1-4 and N, N(R alkyl), benzoxy, phenyl, and heteroaryl containing 5 to 6 ring atoms, wherein the 1 to 4 ring atoms are each independently selected from N, N(R f ), O and S, wherein the heteroaryl is selected from 0 to 2 R n is replaced by; R e are each independently halo, OH, C 1-4 Alkoxy, C 1-4 Haloalkyl and C 1-4 haloalkoxy; R f are each independently H or C 1-4 is alkyl; R h independently, C 1-4 is alkyl or phenyl; R j are independently H or C 1-4 is alkyl; R k is H, C 1-4 selected from alkyl and phenyl; and R n are each independently a halo, C 1-4 Alkyl and C 1-4 alkoxy] or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof.

[0032] In another aspect, in the first to fourth aspects, the present invention provides a compound of formula (IIa): During the ceremony, R 1 are H, F and C 1-4 alkyl; R 2 is C substituted with H, 0-3 F 1-4 Alkyl, -(CH2) 1-3 -R 6 , -(CH2) 1-3 O(CH2) 2-3 OR a and -(CH2) 1-2 -Y 2 -R 7 are independently selected from; R 3 is independently a 5-membered heteroaryl containing 3-4 ring carbon atoms and 1-2 ring heteroatoms selected from N, NH, and S; R 4 H, halo and C 1-4 independently selected from alkyl; R 6 OH, OR a , N.R. b R c , -NR b C(O)R a , -C(O)NHR k , -NHC(O)OR a , -NHC(O)NR j R k , -NHS(O)2R h , -SO2(C 1-4 alkyl), [ka] and heteroaryl containing 5 to 6 ring atoms, wherein the 1 to 4 ring atoms are each independently selected from N, N(R f ), O and S, wherein the heteroaryl is selected from 0 to 3 R d is replaced by; -Y 2 -R 7 teeth, [ka] are independently selected from; R a are each independently 0 to 1 R e C replaced with 1-4 Alkyl, C 3-6 cycloalkyl, [ka] , phenyl, benzyl, oxazolyl, isoxazolyl, thiazolyl, N-(C 1-4 alkyl)-pyrazolyl, pyrazol-1-yl, N-(C 1-4 alkyl)-imidazolyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, N-(C 1-4 alkyl)-benzimidazolyl, pyrazolo[1,5-a]pyrimidinyl and [ka] (wherein each ring group is selected from 0 to 3 R d (substituted with); R b are each independently H or C 1-4 is alkyl; R c independently, C 1-4 Alkyl, -(C 0-3 alkylene)-(0 to 3 R n phenyl substituted with -(C 0-3 alkylene)-heteroaryl containing 5 to 6 ring atoms, wherein the 1 to 4 ring atoms are each selected from N, N(R f ), O, and S, and the heteroaryl is selected independently from 0 to 3 R n is replaced by; R d are each independently halo, CN, -CHOH, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Haloalkoxy, -C(O)O(C 1-4 alkyl), -NHC(O)O(C1-4 alkyl), -S(O)2(C 1-4 and independently selected from N, N(R alkyl), benzoxy, phenyl, and heteroaryl containing 5 to 6 ring atoms, wherein the 1 to 4 ring atoms are each independently selected from N, N(R alkyl), benzoxy, phenyl, and heteroaryl containing 5 to 6 ring atoms. f ), O, and S, wherein the heteroaryl is selected from 0 to 2 R n is replaced by; R e are each independently halo, OH, C 1-4 Alkoxy, C 1-4 Haloalkyl and C 1-4 haloalkoxy; R f are each independently H or C 1-4 is alkyl; R h independently, C 1-4 is alkyl or phenyl; R j are independently H or C 1-4 is alkyl; R k is H, C 1-4 independently selected from alkyl and phenyl; and R n are each independently a halo, C 1-4 Alkyl and C 1-4 alkoxy] or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof.

[0033] In another aspect, the present invention provides a compound of formula (IIa) in the first to fourth aspects: During the ceremony, R 1 are H, F and C 1-4 independently selected from alkyl; R 2 is -(CH2) 1-3 -R 6 , -(CH2) 1-3 O(CH2) 2-3 OR a and -(CH2) 1-2 -Y 2-R 7 are independently selected from; R 3 is independently a 5-membered heteroaryl, said heteroaryl containing 3 to 4 ring carbon atoms and 1 to 2 ring heteroatoms each independently selected from N, NH, O, and S; R 4 are H, F and C 1-4 independently selected from alkyl; R 6 OH, OR a , N.R. b R c , -NR b C(O)R a , -C(O)NHR k , -NHC(O)OR a , -NHC(O)NR j R k , -NHS(O)2R h , [ka] and heteroaryl containing 5 to 6 ring atoms, wherein the 1 to 4 ring atoms are each independently selected from N, N(R f ), O and S, wherein the heteroaryl is selected from 0 to 3 R d is replaced by; -Y 2 -R 7 teeth, [ka] are independently selected from; R a each independently represents a C substituted with 0 to 1 OH; 1-4 Alkyl, tetrahydro-2H-pyranyl, phenyl, benzyl, oxazolyl, isoxazolyl, thiazolyl, N-(C 1-4 alkyl)-pyrazolyl, pyrazol-1-yl, N-(C 1-4 alkyl)-imidazolyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, N-(C 1-4alkyl)-benzimidazolyl, pyrazolo[1,5-a]pyrimidinyl and [ka] (wherein each ring group is selected from 0 to 3 R d (which has been replaced by are independently selected from; R b are each independently H or C 1-4 is alkyl; R c independently, C 1-4 Alkyl, -(C 0-3 alkylene)-(0 to 3 R n phenyl substituted with -(C 0-3 alkylene)-heteroaryl containing 5 to 6 ring atoms, wherein 1 to 4 ring atoms are each selected from N, N(R f ), O, and S, and the heteroaryl is selected independently from 0 to 3 R n is replaced by; R d are each independently F, Cl, CN, -CHOH, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Haloalkoxy, -C(O)O(C 1-4 alkyl), -NHC(O)O(C 1-4 alkyl), -S(O)2(C 1-4 alkyl), benzoxy, and heteroaryl containing 5 to 6 ring atoms, wherein the 1 to 4 ring atoms are each independently selected from N, N(R f ), O and S, wherein the heteroaryl is selected from 0 to 2 R n is replaced by; R f are each independently H or C 1-4 is alkyl; R h independently, C 1-4 is alkyl or phenyl; R j are independently H or C 1-4is alkyl; R k is H, C 1-4 independently selected from alkyl and phenyl; and R n are each independently F, Cl, or C 1-4 Alkyl and C 1-4 alkoxy, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof.

[0034] In a sixth aspect, the present invention provides a compound of formula (IIa) in the first to fifth aspects: During the ceremony, R 1 is H; R 2 is C substituted with H, 0-3 F 1-4 Alkyl, -(CH2) 1-3 -R 6 , -(CH2) 1-2 CH(CH3)OH, -(CH2) 1-2 C(CH3)2OH, -(CH2) 1-2 CH(OCH3)CH2OH, -CH(CH3)(CH2) 1-2 OH, -(CH2) 1-2 CH(OH)CH2F, -(CH2) 1-2 CH(CH3)O(C 1-4 alkyl), -(CH2) 1-3 O(CH2) 2-3 OR a , -CH2CH(CH3)NHC(O)R a and -(CH2) 1-2 -Y 2 -R 7 are independently selected from; R 3 teeth, [ka] are independently selected from; R 4 are independently H, F, or Cl; R 6 OH, OR a , N.R. bR c , -NR b C(O)R a , -C(O)NR b R k , -NHC(O)O(C 1-6 alkyl), -NHC(O)OPh, -NHC(O)N(C 1-4 alkyl)2, -NHC(O)N(C 1-4 alkyl)Ph, -NHS(O)2(C 1-4 alkyl), -SO2(C 1-4 alkyl), [ka] and heteroaryl containing 5 to 6 ring atoms, wherein the 1 to 4 ring atoms are each independently selected from N, N(R f ), O and S, wherein the heteroaryl is selected from 0 to 3 R d is replaced by; -Y 2 -R 7 is 0 to 2 R d C replaced with 3-6 cycloalkyl, [ka] are independently selected from; R a are each independently 0 to 2 R e C replaced with 1-4 Alkyl, C 3-6 cycloalkyl, [ka] , phenyl, benzyl, oxazolyl, isoxazolyl, thiazolyl, N-(C 1-4 alkyl)-pyrazolyl, pyrazol-1-yl, N-(C 1-4 alkyl)-imidazolyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, N-(C 1-4 alkyl)-benzimidazolyl, pyrazolo[1,5-a]pyrimidinyl and [ka] (wherein each ring group is selected from 0 to 3 R d (which has been replaced by are independently selected from; R b are each independently H, C 1-4 alkyl or phenyl substituted with 0-2 F; R c independently, C 1-4 Alkyl, -(C 0-3 alkylene)-(0 to 3 R n phenyl substituted with -(C 0-3 alkylene)-heteroaryl containing 5 to 6 ring atoms, wherein the 1 to 4 ring atoms are each selected from N, N(R f ), O, and S, and the heteroaryl is selected independently from 0 to 3 R n is replaced by; R d are each independently F, Cl, CN, -CHOH, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Haloalkoxy, -C(O)O(C 1-4 alkyl), -CONH2, NH2, N(C 1-4 alkyl)2, -NHC(O)(C 1-4 alkyl), -NHC(O)O(C 1-4 alkyl), -S(O)2(C 1-4 and N, N(R alkyl), benzoxy, phenyl, and heteroaryl containing 5 to 6 ring atoms, wherein the 1 to 4 ring atoms are each independently selected from N, N(R f ), O and S, wherein the heteroaryl is selected from 0 to 2 R n is replaced by; R e are each independently F, Cl, OH, C 1-4 Alkoxy, C 1-4 Haloalkyl and C 1-4 haloalkoxy; R f are each independently H or C 1-4 is alkyl; R k is H, C 1-4 independently selected from alkyl and phenyl; R n are each independently F, Cl, or C 1-4 Alkyl and C 1-4 alkoxy, or a stereoisomer, tautomer, or a pharmaceutically acceptable salt thereof.

[0035] In another aspect, the present invention provides, within the scope of any of the first to fifth aspects, R 1 But H; R 2 C substituted with H and 0-3 F 1-4 Alkyl, -(CH2) 1-3 -R 6 , -(CH2) 1-3 O(CH2) 2-3 OR a and -(CH2) 1-2 -Y 2 -R 7 are independently selected from; R 3 but, [ka] are independently selected from; R 4 is independently H, F, or Cl; R 6 But, OH, OR a , N.R. b R c , -NR b C(O)R a , -C(O)NHR k , -NHC(O)O(C 1-6 alkyl), -NHC(O)N(C 1-4 alkyl)2, -NHS(O)2(C 1-4 alkyl), -SO2(C 1-4 alkyl), [ka] and heteroaryl containing 5 to 6 ring atoms, wherein the 1 to 4 ring atoms are each independently selected from N, N(R f ), O and S, wherein the heteroaryl is selected from 0 to 3 R d is replaced by; -Y 2 -R 7 but, [ka] are independently selected from; R a are each independently 0 to 1 R e C replaced with 1-4 Alkyl, C 3-6 cycloalkyl, [ka] , phenyl, benzyl, oxazolyl, isoxazolyl, thiazolyl, N-(C 1-4 alkyl)-pyrazolyl, pyrazol-1-yl, N-(C 1-4 alkyl)-imidazolyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, N-(C 1-4 alkyl)-benzimidazolyl, pyrazolo[1,5-a]pyrimidinyl and [ka] wherein each ring group is selected from 0 to 3 R d is replaced by; R b are each independently H or C 1-4 is alkyl; R c But independently, C 1-4 Alkyl, -(C 0-3 alkylene)-(0 to 3 R n phenyl substituted with -(C 0-3 alkylene)-heteroaryl containing 5 to 6 ring atoms, wherein 1 to 4 ring atoms are each selected from N, N(R f), O, and S, and the heteroaryl is selected independently from 0 to 3 R n is replaced by; R d are each independently F, Cl, CN, -CHOH, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Haloalkoxy, -C(O)O(C 1-4 alkyl), -NHC(O)O(C 1-4 alkyl), -S(O)2(C 1-4 and N, N(R alkyl), benzoxy, phenyl, and heteroaryl containing 5 to 6 ring atoms, wherein the 1 to 4 ring atoms are each independently selected from N, N(R f ), O and S, wherein the heteroaryl is selected from 0 to 2 R n may be substituted with; R e are each independently F, Cl, OH, C 1-4 Alkoxy, C 1-4 Haloalkyl and C 1-4 haloalkoxy; R f are each independently H or C 1-4 is alkyl; R k But H, C 1-4 independently selected from alkyl and phenyl; and R n are each independently F, Cl, C 1-4 Alkyl and C 1-4 alkoxy, Provided is a compound of formula (IIa), or a stereoisomer, tautomer, or a pharmaceutically acceptable salt thereof:

[0036] In another aspect, the present invention provides, within the scope of any of the first to fifth aspects, R 1 But H; R 2 But -(CH2) 1-3 -R 6 , -(CH2) 1-3 O(CH2)2-3 OR a and -(CH2) 1-2 -Y 2 -R 7 selected from the group consisting of: R 3 but, [ka] are independently selected from; R 4 But H; R 6 But, OH, OR a , N.R. b R c , -NR b C(O)R a , -C(O)NH(C 1-4 alkyl), -C(O)NHPh, -NHC(O)O(C 1-6 alkyl), -NHC(O)N(C 1-4 alkyl)2, -NHS(O)2(C 1-4 alkyl), [ka] and heteroaryl containing 5 to 6 ring atoms, wherein the 1 to 4 ring atoms are each independently selected from N, N(R f ), O and S, wherein the heteroaryl is selected from 0 to 3 R d is replaced by; -Y 2 -R 7 but, [ka] are independently selected from; R a each independently represents a C substituted with 0 to 1 OH 1-4 Alkyl, tetrahydro-2H-pyranyl, phenyl, benzyl, oxazolyl, isoxazolyl, thiazolyl, N-(C 1-4 alkyl)-pyrazolyl, pyrazol-1-yl, N-(C 1-4alkyl)-imidazolyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, N-(C 1-4 alkyl)-benzimidazolyl, pyrazolo[1,5-a]pyrimidinyl and [ka] (wherein each ring group is selected from 0 to 3 R d (substituted with); R b are each independently H or C 1-4 is alkyl; R c But independently, C 1-4 Alkyl, -(C 0-3 alkylene)-(0 to 3 R n phenyl substituted with -(C 0-3 alkylene)-heteroaryl containing 5 to 6 ring atoms, wherein the 1 to 4 ring atoms are each N, N(R f ), O, and S, and the heteroaryl is selected independently from 0 to 3 R n is replaced by; R d are each independently F, Cl, CN, -CHOH, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Haloalkoxy, -C(O)O(C 1-4 alkyl), -NHC(O)O(C 1-4 alkyl), -S(O)2(C 1-4 and heteroaryl containing 5 to 6 ring atoms, wherein the 1 to 4 ring atoms are each independently selected from N, N(R alkyl), benzoxy, and heteroaryl containing 5 to 6 ring atoms. f ), O and S, wherein the heteroaryl is selected from 0 to 2 R n is replaced by; R f are each independently H or C 1-4 is alkyl; and R n are each independently F, Cl, C 1-4 Alkyl and C 1-4 alkoxy, Provided is a compound of formula (IIa), or a stereoisomer, tautomer, or a pharmaceutically acceptable salt thereof:

[0037] In a seventh aspect, the present invention provides a method for producing a composition comprising, within the scope of any one of the first to sixth aspects, R 1 But H; R 2 C substituted with H and 0-3 F 1-4 Alkyl, -(CH2) 1-3 -R 6 , -(CH2) 1-2 CH(CH3)OH, -(CH2) 1-2 C(CH3)2OH, -(CH2) 1-2 CH(OCH3)CH2OH, -CH(CH3)(CH2) 1-2 OH, -(CH2) 1-2 CH(OH)CH2F, -(CH2) 1-2 CH(CH3)O(C 1-4 alkyl), -CH2CH(CH3)NHC(O)R a and -(CH2) 1-2 -Y 2 -R 7 are independently selected from; R 3 But independently, [ka] and; R 4 is independently H, F, or Cl; R 6 But, OH, OR a , N(C 1-4 alkyl)2, -NH(C 1-4 alkyl), -NH(CH2) 1-2 (0 to 1 R d phenyl substituted with -N(C 1-2 Alkyl)Bn, -NH(pyridyl), -NR b C(O)R a , -NHC(O)O(C 1-6 alkyl), -NHC(O)OPh, -NHC(O)N(C 1-4alkyl)2, -NHC(O)CH2OCH2CF3, -NHC(O)N(C 1-4 alkyl) Ph, -C(O)NH2, -C(O)NH (0 to 2 R e C replaced with 1-4 alkyl), -C(O)N(CH3) (0 to 2 R e C replaced with 1-4 alkyl), -C(O)NH(C 3-6 -cycloalkyl), -C(O)NH(phenyl substituted with 0-1 F), -C(O)NH(pyridyl), -NHS(O)2(C 1-4 alkyl), -SO2(C 1-4 alkyl), [ka] and heteroaryl, which is selected from imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, oxadiazolyl, and pyridyl, wherein the heteroaryl is selected from 0 to 2 R d is replaced by; -Y 2 -R 7 However, 0 to 2 R d C replaced with 3-6 cycloalkyl, [ka] are independently selected from; R a each independently represents 0 to 2 R e C replaced with 1-4 Alkyl, C 3-6 cycloalkyl, [ka] , phenyl, oxazolyl, isoxazolyl, thiazolyl, N-(C 1-4 alkyl)-pyrazolyl, pyrazol-1-yl, N-(C 1-4 alkyl)-imidazolyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, N-(C 1-4wherein each ring group is independently selected from 0 to 3 R d is replaced by; R b are independently H or C 1-2 is alkyl; R d are each independently F, Cl, CN, -CHOH, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Haloalkoxy, -CONH2, NH2, N(C 1-4 alkyl)2, -C(O)O(C 1-4 alkyl), benzoxy, phenyl, and pyridyl; and R e But F, OH and C 1-4 independently selected from alkoxy; Provided is a compound of formula (IIa) or a tautomer or a pharmaceutically acceptable salt thereof:

[0038] In another aspect, the present invention provides, within the scope of any of the first to sixth aspects, R 1 But H; R 2 C substituted with H and 0-3 F 1-4 Alkyl or -(CH2) 2-3 -R 6 are independently selected from; R 3 But independently, [ka] and; R 4 is independently H, F, or Cl; R 6 But, OH, OR a , N(C 1-4 alkyl)2, -NR b C(O)R a , -NHC(O)O(C 1-6alkyl), -NHC(O)N(C 1-4 alkyl)2, -NHC(O)CH2OCH2CF3, -NHC(O)N(C 1-4 alkyl)Ph, C(O)NH2, -C(O)NHPh, -NHS(O)2(C 1-4 alkyl), -SO2(C 1-4 alkyl), [ka] , —NH(pyridyl), and heteroaryl, which is selected from imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, oxadiazolyl, and pyridyl, wherein the heteroaryl is selected from 0 to 2 R d is replaced by; R a However, each independently, C 1-4 Alkyl, C 3-6 cycloalkyl, [ka] , phenyl, oxazolyl, isoxazolyl, thiazolyl, N-(C 1-4 alkyl)-pyrazolyl, pyrazol-1-yl, N-(C 1-4 alkyl)-imidazolyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, N-(C 1-4 alkyl)-benzimidazolyl and pyrazolo[1,5-a]pyrimidinyl; wherein each ring group is selected from 0 to 3 R d is replaced by; R b are independently H or C 1-2 is alkyl; and R d are each independently F, Cl, CN, -CHOH, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 selected from haloalkoxy, benzoxy, phenyl and pyridyl; Provided is a compound of formula (IIa) or a tautomer or a pharmaceutically acceptable salt thereof:

[0039] In another aspect, the present invention provides, within the scope of any of the first to sixth aspects, R 1 But H; R 2 But -(CH2) 2-3 -R 6 and; R 3 But independently, [ka] and; R 4 But H; R 6 But, OH, OR a , N(C 1-4 alkyl)2, -NR b C(O)R a , -C(O)NHPh, -NHC(O)O(C 1-6 alkyl), -NHC(O)N(C 1-4 alkyl)2, -NHS(O)2(C 1-4 alkyl), [ka] and 0 to 2 R d independently selected from pyrazol-1-yl substituted with R a However, each independently, C 1-4 Alkyl, tetrahydro-2H-pyranyl, phenyl, oxazolyl, isoxazolyl, thiazolyl, N-(C 1-4 alkyl)-pyrazolyl, pyrazol-1-yl, N-(C 1-4 alkyl)-imidazolyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, N-(C 1-4 alkyl)-benzimidazolyl and pyrazolo[1,5-a]pyrimidinyl; wherein each ring group is selected from 0 to 3 R d is replaced by; R b are independently H or C 1-2 is alkyl; and R dare each independently F, Cl, CN, -CHOH, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 selected from haloalkoxy, benzoxy and pyridyl; Provided is a compound of formula (IIa) or a tautomer or a pharmaceutically acceptable salt thereof:

[0040] In an eighth aspect, the present invention provides a compound of formula (IIIa-1): [ka] [In the formula, R 2 is C substituted with H, 0-3 F 1-4 Alkyl, -(CH2) 1-2 OCHF2, -(CH2)2O(C 1-4 alkyl), -(CH2)2O(CH2)2(C 1-4 Alkoxy), -(CH2) 2-3 OH, -(CH2) 1-3 OR a , -(CH2) 1-2 CH(CH3)OH, -(CH2) 1-2 C(CH3)2OH, -(CH2) 1-2 CH(OCH3)CH2OH, -CH(CH3)(CH2) 1-2 OH, -(CH2) 1-2 CH(OH)CH2F, -(CH2) 1-2 CH(CH3)O(C 1-4 alkyl), -(CH2) 2-3 NHC(O)R a , -CH2CH(CH3)NHC(O)R a , -(CH2) 2-3 NHC(O)CH2OCH2CF3, -(CH2) 2-3 N(CH3)Bn, -(CH2) 2-3 N(CH3)C(O)Ph, -(CH2) 2-3 NHC(O)O(C 1-4 alkyl), -(CH2) 2-3 NHC(O)OPh, -(CH2)2C(O)NH2, -(CH2)2-3 SO2(C 1-4 alkyl), -(CH2) 1-2 NH(C 1-4 alkyl), -(CH2) 1-2 CONH(0 to 2 R e C replaced with 1-4 alkyl), -(CH2) 1-2 CON(CH3)(0 to 2 R e C replaced with 1-4 alkyl), -(CH2) 1-2 NH(CH2) 1-2 (0 to 1 R d phenyl substituted with -(CH2) 2-3 NH(pyridyl), -(CH2) 1-2 C(O)NH(pyridyl), -(CH2) 1-2 C(O)NH(phenyl substituted with 0-1 F), -(CH2) 1-2 CH(CH3)NHSO2(C 1-4 alkyl), [ka] and -(CH2) 1-3 -(heteroaryl), wherein the heteroaryl is selected from imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, oxadiazolyl, and pyridyl, and the heteroaryl is selected from 0 to 2 R d is replaced by; R 3 is, independently, [ka] and; R a is C 3-6 cycloalkyl, [ka] , phenyl, oxazolyl, thiazolyl, N-(C 1-4 alkyl)-pyrazolyl, N-(C 1-4 alkyl)-imidazolyl, pyridyl, pyrimidyl, pyrazinyl and N-(C1-4 and each ring group is independently selected from 0 to 2 R d is replaced by; R d are each independently F, Cl, CN, or C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Haloalkoxy, NH2, -C(O)O(C 1-4 alkyl), phenyl and benzoxy; and R e are F, OH and C 1-4 alkoxy] or a tautomer or a pharmaceutically acceptable salt thereof.

[0041] In another aspect, the present invention provides a compound of formula (IIIa-1): [ka] [In the formula, R 2 is C substituted with H, 0-3 F 1-4 Alkyl, -(CH2)2O(C 1-4 alkyl), -(CH2) 2-3 NHC(O)R a , -(CH2) 2-3 NHC(O)CH2OCH2CF3, -(CH2) 2-3 NHC(O)O(C 1-4 alkyl), -(CH2)2C(O)NH2, -(CH2) 2-3 SO2(C 1-4 alkyl), -(CH2) 2-3 NH(pyridyl), -(CH2) 1-2 C(O)NH(phenyl substituted with 0-1 F), [ka] and -(CH2) 1-3(heteroaryl), wherein the heteroaryl is selected from imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, oxadiazolyl, and pyridyl, and the heteroaryl is selected from 0 to 2 R d is replaced by; R 3 is, independently, [ka] and; R a is C 3-6 cycloalkyl, [ka] , phenyl, oxazolyl, thiazolyl, N-(C 1-4 alkyl)-pyrazolyl, N-(C 1-4 alkyl)-imidazolyl, pyridyl, pyrimidyl, pyrazinyl and N-(C 1-4 wherein each ring group is independently selected from 0 to 2 R d is substituted with; and R d are each independently F, Cl, CN, or C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 haloalkyl and phenyl] or a tautomer or a pharmaceutically acceptable salt thereof.

[0042] In another aspect, the present invention provides a compound of formula (IIIa-1): [ka] [In formula: R 2 is C substituted with H, 0-3 F 1-4 Alkyl, -(CH2)2O(C 1-4 alkyl), -(CH2) 2-3 NHC(O)R a , -(CH2) 2-3NHC(O)CH2OCH2CF3, -(CH2) 2-3 NHC(O)O(C 1-4 alkyl), -(CH2)2C(O)NH2, -(CH2) 2-3 SO2(C 1-4 alkyl), -(CH2) 2-3 NH(pyridyl), -(CH2) 1-2 C(O)NH(phenyl substituted with 0-1 F), [ka] and -(CH2) 1-3 (heteroaryl), wherein the heteroaryl is selected from imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, oxadiazolyl, and pyridyl, and the heteroaryl is selected from 0 to 2 R d is replaced by; R 3 is, independently, [ka] and; R a is C 3-6 Cycloalkyl, phenyl, oxazolyl, thiazolyl, N-(C 1-4 alkyl)-pyrazolyl, N-(C 1-4 alkyl)-imidazolyl, pyridyl, pyrimidyl, pyrazinyl and N-(C 1-4 wherein each ring group is independently selected from 0 to 2 R d is substituted with; and R d are each independently F, Cl, CN, or C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 haloalkyl and phenyl] or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof.

[0043] In another aspect, the present invention provides a compound of formula (IIIa): [ka] [In the formula, R 2 is -(CH2) 2- -NHC(O)R a , [ka] are independently selected from; R a is phenyl, oxazolyl, thiazolyl, N-(C 1-4 alkyl)-pyrazolyl, N-(C 1-4 alkyl)-imidazolyl, pyridyl, pyrimidyl, pyrazinyl and N-(C 1-4 alkyl)-benzimidazolyl, each ring group being independently selected from 0 to 2 R d is substituted with; and R d are each independently F, Cl, CN, or C 1-4 Alkyl, C 1-4 Alkoxy and C 1-4 haloalkyl] or a tautomer or a pharmaceutically acceptable salt thereof.

[0044] In a ninth aspect, the present invention provides, within the scope of the eighth aspect, R 2 C independently substituted with 0 to 3 F 1-4 Alkyl, -(CH2) 2-4 O(C 1-4 alkyl), -(CH2) 2-3 NHC(O)R a , -(CH2) 2-3 NHC(O)O(C 1-4 alkyl), -(CH2)2C(O)NH2, -(CH2) 1-2 C(O)NH(phenyl substituted with 0-1 F), -(CH2) 1-3(heteroaryl), wherein the heteroaryl is selected from imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, oxadiazolyl, and pyridyl, and the heteroaryl is selected from 0 to 2 R d is replaced by; R a is independently selected from oxazolyl, isoxazolyl, thiazolyl, N-methyl-imidazolyl, pyridyl, and pyrazinyl; wherein each ring group is selected from 0 to 2 R d is substituted with; and R d are each independently F, Cl, C 1-4 Alkyl, C 1-4 alkoxy and phenyl; Provided is a compound of formula (IIIa), or a tautomer or a pharmaceutically acceptable salt thereof:

[0045] In another aspect, the present invention provides, within the scope of the eighth aspect, R 2 But -(CH2) 2- -NHC(O)R a and; R a is independently selected from oxazolyl, thiazolyl, N-methyl-imidazolyl, pyridyl, and pyrazinyl; wherein each ring group is selected from 0 to 2 R d is substituted with; and R d are each independently F, Cl and C 1-4 selected from alkyl, Provided is a compound of formula (IIIa), or a tautomer or a pharmaceutically acceptable salt thereof:

[0046] In a tenth aspect, the present invention provides, within the scope of the ninth aspect, R d are each independently selected from F, Cl, CH3 and OCH3; Provided is a compound of formula (IIIa), or a tautomer or a pharmaceutically acceptable salt thereof:

[0047] In another embodiment, Rd are each independently selected from F, Cl, and CH3, or a tautomer or pharmaceutically acceptable salt thereof.

[0048] In an eleventh aspect, the present invention provides a compound of formula (IIIb-1): [ka] [In the formula, R 2 is C substituted with H, 0-3 F 1-4 Alkyl, -(CH2) 1-2 CH(OH)CH2F, -(CH2) 1-2 CH(OH)CF3, -(CH2) 1-2 CH(OH)CH2CF3, -(CH2) 1-2 OCHF2, -(CH2) 1-3 OCF3, -(CH2) 1-2 OCH2CF3, -(CH2) 2-5 OH, -(CH2) 2-5 CN, -(CH2) 1-2 CH(CH3)OH, -(CH2) 1-2 CH(CH3)CH2OH, -(CH2) 1-2 C(CH3)2OH, -C(CH3)2(CH2) 1-2 OH, -(CH2) 1-2 C(CH3)2CH2OH, -CH2CH(OH)CH2OH, -CH2CH(OH)(C 1-4 alkyl), -CH(CH3)(CH2) 1-2 OH, -CHCH(C 1-2 alkyl)(CH2) 1-2 OH, -CHCH(C 1-4 Alkoxy)(CH2) 1-2 OH, -(CH2) 2-4 O(0 to 2 R e C replaced with 1-4 alkyl), -(CH2) 1-2 CH(CH3)O(C 1-4 alkyl), -(CH2) 1-2 C(CH3)2O(C 1-4 alkyl), -CH(CH3)(CH2) 1-2 O(C1-4 alkyl), -CH2CH(OH)(CH2) 1-2 O(C 1-4 alkyl), -(CH2) 1-2 CH(CH3)NH2, -CH2C(CH3)2NH2, -(CH2) 2-3 NH(C 1-4 alkyl), -(CH2) 2-3 N(C 1-4 alkyl)2, -(CH2) 1-3 C(O)NH2, -(CH2) 1-2 C(CH3)2CONH2, -(CH2) 1-2 C(O)NH(0 to 2 R e C replaced with 1-4 alkyl), -(CH2) 1-2 C(O)N(CH3) (0-2 R e C replaced with 1-4 alkyl), -(CH2) 0-1 CH(CH3)(CH2) 0-1 C(O)NH(C 1-4 alkyl), -(CH2) 1-2 C(O)N(C 1-4 alkyl)2, -(CH2) 0-1 CH(CH3)C(O)N(C 1-4 alkyl)2, -(CH2) 1-2 C(O)N(C 1-2 alkyl)(CH2)2O(C 1-4 alkyl), -(CH2) 2-3 NHC(O)R a , -(CH2) 1-2 CH(CH3)NHC(O)R a , -CH2C(CH3)2NHC(O)R a , -(CH2) 2-3 N(CH3)C(O)R a , -(CH2) 2-3 S(O)2(C 1-4 alkyl), -CH2CH(CH3)S(O)2(C 1-4 alkyl), -(CH2) 2-3 NHS(O)2(C 1-4 alkyl), -CH2CH(CH3)NHS(O)2(C 1-4 alkyl), -(CH2) 2-3NHS(O)2(C 3-6 cycloalkyl), [ka] and -(CH2) 1-3 -(heteroaryl containing 5 to 10 ring atoms: the 1 to 4 ring atoms are each independently selected from N, N(R f ), O and S), wherein the heteroaryl is selected from 0 to 2 R d is replaced by; R 3 is, independently, [ka] and; R 4 are independently H or F; R a are independently 0 to 1 R e C replaced with 1-4 Alkyl, 0 to 2 R d C replaced with 3-6 cycloalkyl, [ka] , phenyl, or heteroaryl selected from oxazolyl, isoxazolyl, thiazolyl, pyridyl, and pyrazinyl, wherein the phenyl and heteroaryl are selected from 0 to 2 R d is replaced by; R d are each independently F, Cl, OH, CN, or C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, NH2, N(C 1-4 alkyl)2, -NHC(O)(C 1-4 alkyl) and phenyl; R e are F, OH and C 1-4 independently selected from alkoxy; and R f are each independently H, C1-4 Alkyl, -C(O)(C 1-4 alkyl) and -C(O)(C 1-4 haloalkyl). or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof.

[0049] In a twelfth aspect, the present invention provides, within the scope of the eleventh aspect, R 2 C substituted with H and 0-3 F 1-4 Alkyl, -(CH2) 1-2 CH(OH)CH2F, -(CH2) 1-2 CH(OH)CF3, -(CH2) 1-2 CH(OH)CH2CF3, -(CH2) 1-2 OCHF2, -(CH2) 1-3 OCF3, -(CH2) 1-2 OCH2CF3, -(CH2) 2-4 OH, -(CH2) 2-4 CN, -(CH2) 1-2 CH(CH3)OH, -(CH2) 1-2 CH(CH3)CH2OH, -(CH2) 1-2 C(CH3)2OH, -C(CH3)2(CH2) 1-2 OH, -(CH2) 1-2 C(CH3)2CH2OH, -CH2CH(OH)CH2OH, -CH2CH(OH)(C 1-4 alkyl), -CH(CH3)(CH2) 1-2 OH, -CHCH(C 1-2 alkyl)(CH2) 1-2 OH, -CHCH(C 1-4 Alkoxy)(CH2) 1-2 OH, -(CH2) 2-4 O(0 to 1 R e C replaced with 1-4 alkyl), -(CH2) 1-2 CH(CH3)O(C 1-4 alkyl), -(CH2) 1-2 C(CH3)2O(C 1-4 alkyl), -CH(CH3)(CH2) 1-2 O(C 1-4alkyl), -CH2CH(OH)(CH2) 1-2 O(C 1-4 alkyl), -(CH2) 1-2 CH(CH3)NH2, -CH2C(CH3)2NH2, -(CH2) 2-3 NH(C 1-4 alkyl), -(CH2) 2-3 N(C 1-4 alkyl)2, -(CH2) 1-3 C(O)NH2, -(CH2) 1-2 C(CH3)2CONH2, -(CH2) 1-2 C(O)NH(0 to 2 R e C replaced with 1-4 alkyl), -(CH2) 1-2 C(O)N(CH3) (0-2 R e C replaced with 1-4 alkyl), -(CH2) 0-1 CH(CH3)(CH2) 0-1 C(O)NH(C 1-4 alkyl), -(CH2) 1-2 C(O)N(C 1-4 alkyl)2, -(CH2) 0-1 CH(CH3)C(O)N(C 1-4 alkyl)2, -(CH2) 1-2 C(O)N(C 1-2 alkyl)(CH2)2O(C 1-4 alkyl), -(CH2) 2-3 NHC(O)R a , -CH2CH(CH3)NHC(O)R a , -CH2C(CH3)2NHC(O)R a , -(CH2) 2-3 S(O)2(C 1-4 alkyl), -CH2CH(CH3)S(O)2(C 1-4 alkyl), -(CH2) 2-3 NHS(O)2(C 1-4 alkyl), -CH2CH(CH3)NHS(O)2(C 1-4 alkyl), -(CH2) 2-3 NHS(O)2(C 3-6 cycloalkyl), [ka] [ka] and -(CH2) 1-2 (heteroaryl), wherein the heteroaryl is selected from imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, oxadiazolyl, pyridyl, and pyridazinyl, and the heteroaryl is selected from 0 to 2 R d is replaced by; R a are independently 0 to 1 R e C replaced with 1-4 Alkyl, [ka] , phenyl, or heteroaryl selected from oxazolyl, pyridyl, and pyrazinyl, wherein the phenyl and heteroaryl are selected from 0 to 2 R d is substituted with; and R d are each independently F, Cl, CN, C 1-4 Alkyl, C 1-4 Alkoxy and C 1-4 haloalkyl, Provided is a compound of formula (IIIb-1), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof:

[0050] In a thirteenth aspect, the present invention provides a compound according to any one of the eleventh or twelfth aspects, comprising R 3 But independently, [ka] or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof.

[0051] In a fourteenth aspect, the present invention provides a compound of formula (IIIb-2): [ka] [In the formula, R 2 is C substituted with H, 0-3 F 1-4 Alkyl, -(CH2) 2-4 OH, -(CH2) 2-4 CN, -(CH2) 1-2 CH(CH3)OH, -(CH2) 1-2 C(CH3)2OH, -CH2CH(OH)CH2OH, -CH2CH(OH)(C 1-4 alkyl), -CH(CH3)(CH2) 1-2 OH, -CHCH(C 1-2 alkyl)(CH2) 1-2 OH, -CHCH(C 1-2 Alkoxy)(CH2) 1-2 OH, -(CH2) 2-4 O(0 to 2 R e C replaced with 1-4 alkyl), -CH2C(CH3)2NH2, -(CH2) 1-3 C(O)NH2, -(CH2) 1-2 C(CH3)2CONH2, -(CH2) 1-2 C(O)NH(C 1-4 alkyl), -(CH2) 0-1 CH(CH3)(CH2) 0-1 C(O)NH(C 1-4 alkyl), -(CH2) 1-2 C(O)N(C 1-4 alkyl)2, -(CH2) 0-1 CH(CH3)C(O)N(C 1-4 alkyl)2, -(CH2) 1-2 C(O)NH(0 to 2 R e C replaced with 1-4 alkyl), -(CH2) 1-2 C(O)N(CH3) (0-2 R e C replaced with 1-4 alkyl), -CH2CH(CH3)NHC(O)(C 1-4 alkyl), -(CH2) 2-3 S(O)2(C 1-4 alkyl), -CH2CH(CH3)S(O)2(C 1-4alkyl), -(CH2) 2-3 NHS(O)2(C 1-4 alkyl), -CH2CH(CH3)NHS(O)2(C 1-4 alkyl), -(CH2) 2-3 NHS(O)2(C 3-6 cycloalkyl), [ka] are independently selected from R e are F, OH and C 1-4 alkoxy] or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof.

[0052] In a fifteenth aspect, the present invention provides a method for manufacturing a method of manufacturing a semiconductor device comprising: R 2 H, -CH2CHF2, -(CH2) 2-4 OH, -(CH2) 2-4 CN, -CH2CH(CH3)OH, -CH2C(CH3)2OH, -CH2CH(OH)CH2OH, -CH2CH(OH)CH2CH3, -CH(CH3)(CH2)2OH, -CH2C H(CH3)CH2OH, -CH2CH(OCH3)CH2OH, -(CH2)2O(CH2)2OH, -(CH2)2O(CH2)2OCH3, -CH2C(CH3)2NH2, -(CH2) 1-3 C(O)NH2, -CH2C(CH3)2CONH2, -(CH2) 1-2 C(O)NH(CH3), -(CH2) 1-2 C(O)NH(CH2CH3), -(CH2) 1-2 C(O)NH(CH(CH3)2), -(CH2) 0-1 CH(CH3)(CH2) 0-1 C(O)NH(CH3), -(CH2) 0-1 CH(CH3)C(O)NH(CH(CH3)2), -(CH2) 1-2 C(O)N(CH3)2, -(CH2) 0-1CH(CH3)C(O)N(CH3)2, -CH2C(O)NH(CH2CHF2), -CH(CH3)C(O)NH(CH2CHF2), -C(CH3)2C(O)NH(CH2CHF2), -(CH2) 1-2 C(O)NH(CH2)2OH, -CH(CH3)C(O)NH(CH2) 2-3 OH, -(CH2) 1-2 C(O)NH(C(CH3)2CH2OH), -(CH2) 1-2 C(O)NH(CH2)2OCH3, -(CH2) 1-2 C(O)N(CH3)(CH2)2OCH3, -CH2CH(CH3)NHC(O)(CH3), -(CH2) 2-3 S(O)2CH3, -(CH2) 2-3 S(O)2CH2CH3, -(CH2) 2-3 NHS(O)2CH3, -CH2CH(CH3)NHS(O)2CH3, -(CH2) 2-3 NHS(O)2(cyclopropyl), [ka] are independently selected from The present invention provides a compound of formula (IIIb-2), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof:

[0053] In another aspect, the present invention provides a compound of formula (IIIb): [ka] [In the formula, R 2 is C substituted with H, 0-3 F 1-4 Alkyl, -(CH2) 1-2 CH(OH)CF3, -CH2CH(CH3)NHC(O)(C 1-4 alkyl), -CH2C(CH3)2NHC(O)(C 1-4 alkyl), -(CH2) 2-3 NHC(O)R a , -(CH2) 2-3 NHC(O)CF(CH3)2, -(CH2) 2-3N(CH3)C(O)R a , -(CH2) 2-3 OH, -(CH2) 1-2 CH(CH3)OH, -(CH2) 1-2 C(CH3)2OH, -CH2CH(OH)CH2OH, -CH(CH3)(CH2) 1-2 OH, -(CH2) 2-4 O(C 1-4 alkyl), -CH2CH(CH3)NH2, -CH2C(CH3)2NH2, -(CH2) 2-3 NH(C 1-4 alkyl), -(CH2) 2-3 N(C 1-4 alkyl)2, -(CH2) 2-3 NHS(O)2(C 1-4 alkyl), -(CH2) 2-3 S(O)2(C 1-4 alkyl), [ka] and -(CH2) 1-3 (heteroaryl), wherein the heteroaryl is selected from imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, oxadiazolyl, and pyridyl, and the heteroaryl is selected from 0 to 2 R d is replaced by; R 3 is, independently, [ka] and; R a is C 1-4 Alkyl, C 3-6 cycloalkyl, [ka] , phenyl, or heteroaryl, which is selected from oxazolyl, isoxazolyl, thiazolyl, pyridyl, and pyrazinyl, wherein the phenyl and heteroaryl are selected from 0 to 2 R d is replaced by; R d are each independently F, Cl, CN, or C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 selected from haloalkyl and phenyl; and R f are each independently H, C 1-4 Alkyl, C(O)(C 1-4 alkyl) and C(O)(C 1-4 haloalkyl). or a tautomer or a pharmaceutically acceptable salt thereof.

[0054] In another aspect, within the scope of the above aspects, the present invention provides a method for producing a pharmaceutical composition comprising: R 2 But H, C 1-4 Alkyl, -(CH2) 1-2 CHF2, -(CH2) 1-2 CH(OH)CF3, -CH2C(CH3)2NHC(O)(C 1-4 alkyl), -(CH2) 2-3 NHC(O)R a , -(CH2) 2-3 OH, -(CH2) 1-2 CH(CH3)OH, -(CH2) 1-2 C(CH3)2OH, -CH2CH(OH)CH2OH, -CH(CH3)(CH2) 1-2 OH, -(CH2) 2-4 O(C 1-4 alkyl), -CH2CH(CH3)NH2, -CH2C(CH3)2NH2, -(CH2) 2-3 NH(C 1-4 alkyl), -(CH2) 2-3 N(C 1-4 alkyl)2, -(CH2) 2-3 NHS(O)2(C 1-4 alkyl), -(CH2) 2-3 S(O)2(C 1-4 alkyl), [ka] are independently selected from; and R aBut independently, C 1-4 Alkyl, [ka] , phenyl, or heteroaryl (which is selected from oxazolyl, pyridyl, and pyrazinyl), wherein the phenyl and heteroaryl are selected from 0 to 2 R d has been replaced by Provided is a compound of formula (IIIb), or a tautomer or a pharmaceutically acceptable salt thereof:

[0055] In another aspect, the present invention provides, within the scope of either of the above two aspects, R 3 But independently, [ka] or a tautomer or a pharmaceutically acceptable salt thereof.

[0056] In a sixteenth aspect, the present invention provides a compound of formula (IIIf): [ka] [In the formula, R 2 is -(CH2)2N(C 1-4 alkyl)2, -(CH2) 2- -OR a , -(CH2) 2- -NHC(O)R a and [ka] are independently selected from; R a is C substituted with 0-2 F 1-4 Alkyl, [ka] and heteroaryl, which is selected from thiazolyl and pyridyl, wherein the heteroaryl is selected from 0 to 2 Rd is substituted with; and R d are each independently F, Cl, CN, or C 1-4 Alkyl, C 1-4 Alkoxy and C 1-4 haloalkyl] or a tautomer or a pharmaceutically acceptable salt thereof.

[0057] In a seventeenth aspect, the present invention provides a compound of formula (IIIg-1): [ka] [In formula: R 1 are independently H, Cl or C 1-4 is alkyl; R 1a are independently H or C 1-4 is alkyl; R 2 is -(CH2) 1-4 -OH, -(CH2) 1-2 -OR a , -(CH2) 1-2 NH2, -(CH2) 1-2 NH(0 to 1 R e C replaced with 1-4 alkyl), -(CH2) 1-2 N(C 1-4 alkyl)2, -(CH2) 1-2- -NHC(O)R a , -(CH2) 2-3 NHS(O)2(C 1-4 alkyl), -(CH2) 2-3 NHS(O)2Ph, [ka] are independently selected from; R 3 is, independently, [ka] and; R ais C substituted with 0-2 F 1-4 Alkyl, [ka] and heteroaryl (which includes thiazolyl, oxazolyl, NC 1-4 alkyl-imidazolyl and pyridyl), wherein the heteroaryl is selected from 0 to 2 R d is replaced by; R d are each independently F, Cl, OH, CN, or C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl and -NHC(O)(C 1-4 alkyl); and R e is F, OH, C 1-4 Alkoxy and C 1-4 haloalkyl] or a tautomer or a pharmaceutically acceptable salt thereof.

[0058] In another aspect, the present invention provides a method for producing a pharmaceutical composition comprising: R 1a But H; R 2 But -(CH2) 1-4 -OH, [ka] are independently selected from; and R 3 But independently, [ka] That is, The present invention provides a compound of formula (IIIg-1), or a tautomer or a pharmaceutically acceptable salt thereof:

[0059] In an eighteenth aspect, the present invention provides a compound of formula (IIIg): [ka] [In the formula, R 2 is -(CH2) 1-2 NH2, -(CH2) 1-2 N(C 1-4 alkyl)2, -(CH2) 1-2 NH(0 to 1 R e C replaced with 1-4 alkyl), -(CH2) 1-2- -NHC(O)R a are independently selected from; R a is C substituted with 0-2 F 1-4 Alkyl, [ka] and heteroaryl, selected from thiazolyl and pyridyl, wherein the heteroaryl is selected from 0 to 2 R d is substituted with; and R d are each independently F, Cl, CN, or C 1-4 Alkyl, C 1-4 Alkoxy and C 1-4 haloalkyl; and R e are independently selected from F, OH, OCH3, CHF2 and CF3. or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof.

[0060] In another aspect, the present invention provides a method for producing a pharmaceutical composition comprising: R 2 But -(CH2)2N(C 1-4 alkyl)2, -(CH2) 2- -OR a , -(CH2) 2- -NHC(O)R a and [ka] are independently selected from; R aC substituted with 0-2 F 1-4 Alkyl, [ka] and heteroaryl, which is selected from thiazolyl and pyridyl, wherein the heteroaryl is selected from 0 to 2 R d is substituted with; and R d are each independently F, Cl, CN, C 1-4 Alkyl, C 1-4 Alkoxy and C 1-4 haloalkyl, Provided is a compound of formula (IIIg), or a tautomer or a pharmaceutically acceptable salt thereof:

[0061] In a nineteenth aspect, the present invention provides a compound of formula (IIIh): [ka] [In the formula, R 2 is C 1-4 Alkyl, -(CH2) 1-2 CHF2, -(CH2) 2-4 OH, -CH2CH(CH3)(CH2) 0-2 OH, -CH2CH(OH)CH2CH3, -(CH2) 1-2 C(CH3)2OH, -(CH2)2O(CH2) 1-2 OH, -(CH2) 2-4 O(C 1-4 alkyl), -CH2CH(OH)(CH2) 1-2 O(C 1-4 alkyl), -(CH2) 2-3 NH(C 1-4 alkyl), -(CH2) 2-3 N(C 1-4 alkyl), -(CH) (pyridyl), [ka] are independently selected from; and R 3is, independently, [ka] is] or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof.

[0062] In another aspect, the present invention provides a method for producing a pharmaceutical composition comprising: R 2 But -(CH2) 2-4 OH, -CH2CH(CH3)(CH2) 0-2 OH, -CH2CH(OH)CH2CH3, -(CH2) 1-2 C(CH3)2OH and -(CH2)2O(CH2) 1-2 are independently selected from OH; and R 3 But independently, [ka] That is, Provided is a compound of formula (IIIh), or a tautomer or a pharmaceutically acceptable salt thereof:

[0063] In another aspect, the present invention provides a compound of formula (IIIh): [ka] [In the formula, R 2 is C 1-4 Alkyl, -(CH2) 1-2 CHF2, -(CH2) 2-4 OH, -CH2CH(CH3)(CH2) 1-2 OH, -(CH2)2O(CH2) 1-2 OH, -(CH2) 2-4 O(C 1-4 alkyl), -CH2CH(OH)(CH2)2O(C 1-4 alkyl), -(CH2) 2-3 NH(C 1-4 alkyl), -(CH2) 2-3 N(C 1-4 alkyl), -(CH) (pyridyl), [ka] are independently selected from; and R 3 is, independently, [ka] is] or a tautomer or a pharmaceutically acceptable salt thereof.

[0064] In a twentieth aspect, the present invention provides a compound of formula (IIIi): [ka] [In the formula, R 2 is -(CH2) 2-4 OH, -(CH2) 2-4 O(C 1-4 alkyl), -(CH2) 2-3 N(C 1-4 alkyl)2 and -(CH2) 2-3 NHC(O)R a are independently selected from; R a independently, C 3-6 cycloalkyl, [ka] , phenyl, or heteroaryl selected from oxazolyl, isoxazolyl, thiazolyl, pyridyl, and pyrazinyl, wherein the phenyl and heteroaryl are selected from 0 to 2 R d is substituted with; and R d are each independently F, Cl, CN, or C 1-4 Alkyl, C 1-4 Alkoxy and C 1-4 haloalkyl] or a tautomer or a pharmaceutically acceptable salt thereof.

[0065] In another aspect, the present invention provides a method for producing a compound comprising:2 But independently, -(CH2) 2-4 OH or -(CH2) 2-4 O(C 1-4 alkyl), or a tautomer or a pharmaceutically acceptable salt thereof.

[0066] In another aspect, the present invention provides a compound selected from the exemplified examples, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0067] In another aspect, the present invention provides a compound selected from Examples 1-151, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0068] In another aspect, the present invention provides a compound selected from Examples 1-285, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0069] In another aspect, the present invention provides a compound selected from Examples 1-624, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0070] In another aspect, the present invention provides a method for producing a pharmaceutical composition comprising: [ka] [ka] [ka] [ka] or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0071] In another aspect, the present invention provides a method for producing a pharmaceutical composition comprising: [ka] [ka] or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0072] In another aspect, the present invention provides a method for producing a pharmaceutical composition comprising: [ka] or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0073] In another aspect, the present invention provides a method for producing a pharmaceutical composition comprising: [ka] [ka] or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0074] In another aspect, the present invention provides a method for producing a pharmaceutical composition comprising: [ka] or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0075] In yet another aspect, the present invention provides a method for producing a pharmaceutical composition comprising: [ka] [ka] or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0076] In yet another aspect, the present invention provides a method for producing a pharmaceutical composition comprising: [ka] or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0077] In yet another aspect, the present invention provides a method for producing a pharmaceutical composition comprising: [ka] or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0078] In yet another aspect, the present invention provides a method for producing a pharmaceutical composition comprising: [ka] or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0079] In yet another aspect, the present invention provides a method for producing a pharmaceutical composition comprising: [ka] or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0080] In yet another aspect, the present invention provides a method for producing a pharmaceutical composition comprising: [ka] or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0081] In another aspect, the invention provides a compound or a compound selected from any subset list of compounds selected from the exemplified examples within the scope of any of the above aspects.

[0082] In one embodiment, the present invention provides a compound of formula (IIa): [ka] or a tautomer or a pharmaceutically acceptable salt thereof.

[0083] In one embodiment, the present invention provides a compound of formula (IIb): [ka] or a tautomer or a pharmaceutically acceptable salt thereof.

[0084] In one embodiment, the present invention provides a compound of formula (IIc): [ka] or a tautomer or a pharmaceutically acceptable salt thereof.

[0085] In one embodiment, the present invention provides a compound of formula (IId): [ka] or a tautomer or a pharmaceutically acceptable salt thereof.

[0086] In one embodiment, the present invention provides a compound of formula (IIe): [ka] or a tautomer or a pharmaceutically acceptable salt thereof.

[0087] In one embodiment, the present invention provides a compound of formula (IIf): [ka] or a tautomer or a pharmaceutically acceptable salt thereof.

[0088] In one embodiment, the present invention provides a compound of formula (IIg): [ka] or a tautomer or a pharmaceutically acceptable salt thereof.

[0089] In one embodiment, the present invention provides a compound of formula (IIg-1): [ka] or a tautomer or a pharmaceutically acceptable salt thereof.

[0090] In one embodiment, the present invention provides a compound of formula (IIh): [ka] or a tautomer or a pharmaceutically acceptable salt thereof.

[0091] In one embodiment, the present invention provides a compound of formula (IIi): [ka] or a tautomer or a pharmaceutically acceptable salt thereof.

[0092] In some embodiments, R 1 is H or XR 5 where X is an unbranched C 1-6 alkylene, and R 5 H, OH, cyano, C 1-4 Alkoxy, C 1-4 Haloalkoxy, -C(O)OR a , -NR b R c or -C(O)NRb R k In another embodiment, R 1 is H or halo. In another embodiment, R 1 is H. In another embodiment, R 1 is H or XR 5 where X is an unbranched C 1-6 alkylene, and R 5 H, OH, cyano, C 1-4 Alkoxy, C 1-4 Haloalkoxy, -C(O)OR a , -NR b R c or -C(O)NR b R k In another embodiment, R 1 is (C 1-3 alkylene)-aryl, wherein the aryl is selected from 0 to 3 R d or (C 1-3 alkylene)-heteroaryl containing 5 to 6 ring atoms, wherein the 1 to 4 ring atoms are each independently selected from N, N(R f ), O and S, wherein the heteroaryl is selected from 0 to 3 R d In another embodiment, R 1 is (C 1-3 alkylene)-aryl, wherein the aryl is selected from 0 to 3 R d In another embodiment, R 1 is (C 1-3 alkylene)-heteroaryl containing 5 to 6 ring atoms, wherein the 1 to 4 ring atoms are each independently selected from N, N(R f ), O and S, wherein the heteroaryl is selected from 0 to 3 R d In another embodiment, R 1 is H, halo or C 1-4 In another embodiment, R 1 is H, F or C 1-4 It is alkyl.

[0093] In some embodiments, R 2H, -YR 6 or -C(O)-YR 6 where Y is independently 0 to 4 R e C replaced with 1-8 alkylene; and R 6 are each independently H, OH, OR a , -C(O)R a , -C(O)OR a , -NR b R c , -C(O)NR b R k or heteroaryl containing 5 to 6 ring atoms, wherein 1 to 4 ring atoms are each selected from N, N(R f ), O, and S, and the heteroaryl is selected independently from 0 to 3 R d In another embodiment, R 2 is -YR 6 or -C(O)-YR 6 In another embodiment, R 2 is -YR 6 In another embodiment, R 2 is -(Y 1 ) n -Y 2 -(Y 3 ) p -R 7 wherein n and p are each independently 0 or 1; Y 1 and Y 3 are each independently 0 to 2 R e C replaced with 1-3 alkylene; Y 2 are independently 0 to 4 R g C replaced with 3-6 cycloalkylene or heterocycloalkylene containing 3 to 8 ring atoms, wherein 1 to 2 ring atoms are each independently N, N(R f ) and O, wherein the heterocycloalkylene is selected from 0 to 4 R g and R 7 H, OH, -C(O)OR a , -NR b R c, -C(O)NR b R k or heteroaryl containing 5 to 6 ring atoms, wherein 1 to 4 ring atoms are each selected from N, N(R f ), O, and S, wherein the heteroaryl is selected from 0 to 4 R g In another embodiment, R 2 -Z 1 -Z 2 -Z 3 -R 8 where Z 1 is C substituted with 0-6 F 1-3 alkylene; Z 2 is -N(R f )-, -O- or -S-; Z 3 is C substituted with 0-6 F 2-5 alkylene; and R 8 OH, OR a , -C(O)R a , -C(O)OR a , -NR b R c , -C(O)NR b R k or heteroaryl containing 5 to 6 ring atoms, wherein 1 to 4 ring atoms are each selected from N, N(R f ), O, and S, and the heteroaryl is selected independently from 0 to 3 R d is replaced by .

[0094] In some embodiments, R 2 is H, -(CH2) 1-3 -R 6 , -(CH2) 1-3 O(CH2) 2-3 OR a or -(CH2) 1-2 -Y 2 -R 7 In another embodiment, R 2 is -(CH2) 1-3 -R 6 , -(CH2) 1-3 O(CH2) 2-3 OR a or -(CH2) 1-2-Y 2 -R 7 In another embodiment, R 2 is -(CH2) 2-3 -R 6 In another embodiment, R 2 is -(CH2) 2- -NHC(O)R a , [ka] In another embodiment, R 2 is -(CH2) 2- -NHC(O)R a is.

[0095] In some embodiments, R 3 is -(C 0-3 alkylene)-(5-membered heteroaryl), wherein the heteroaryl has 2 to 4 ring carbon atoms and each independently N, N(R f ), 1 to 3 ring heteroatoms selected from O and S, and 0 to 3 R g In another embodiment, R 3 is -(C 0-2 alkylene)-(5-membered heteroaryl), wherein the heteroaryl has 2 to 4 ring carbon atoms and each independently N, N(R f ), O, and S, and the heteroaryl contains 0 to 2 R g In another embodiment, R 3 is a 5-membered heteroaryl containing 3 to 4 ring carbon atoms and 1 to 2 ring heteroatoms each independently selected from N, NH, O, and S. In another embodiment, R 3 teeth, [ka] In another embodiment, R 3 teeth, [ka] In another embodiment, R 3 teeth, [ka] is.

[0096] In some embodiments, R 4 is H, halo or C 1-4 In another embodiment, R 4 is H, F or C 1-4 It is alkyl.

[0097] In some embodiments, R 6 OH, OR a , -NR b R c , -C(O)NR b R k or heteroaryl containing 5 to 6 ring atoms, wherein the 1 to 4 ring atoms are each independently selected from N, N(R f ), O and S, wherein the heteroaryl is selected from 0 to 3 R d In another embodiment, R 6 OH, OR a , N.R. b R c , -NR b C(O)R a , -C(O)NHR k , -NHC(O)OR a , -NHC(O)NR j R k , -NHS(O)2R h , [ka] or heteroaryl containing 5 to 6 ring atoms, wherein the 1 to 4 ring atoms are each independently selected from N, N(R f ), O and S, wherein the heteroaryl is selected from 0 to 3 R d In another embodiment, R 6 OH, OR a , N.R. b Rc , -NR b C(O)R a , -C(O)NH(C 1-4 alkyl), -C(O)NHPh, -NHC(O)O(C 1-6 alkyl), -NHC(O)N(C 1-4 alkyl)2, -NHS(O)2(C 1-4 alkyl), [ka] or heteroaryl containing 5 to 6 ring atoms, wherein the 1 to 4 ring atoms are each independently selected from N, N(R f ), O and S, wherein the heteroaryl is selected from 0 to 3 R d In another embodiment, R 6 OH, OR a , N(C 1-4 alkyl)2, -NR b C(O)R a , -C(O)NHPh, -NHC(O)O(C 1-6 alkyl), -NHC(O)N(C 1-4 alkyl)2, -NHS(O)2(C 1-4 alkyl) [ka] and pyrazol-1-yl (0 to 2 R d In another embodiment, R 6 OH, OR a , -NR b R c or -C(O)NR b R k In another embodiment, R 6 is -NR b R c or -C(O)NR b R k is.

[0098] Those skilled in the art will recognize that some chemical structures described herein may be represented on paper in one or more alternative resonance forms, or may exist in one or more alternative tautomeric forms, even if kinetically such tautomers represent only a small fraction of a sample of the compound. Although such resonance forms or tautomers are not explicitly stated herein, such compounds will be expressly understood to be within the scope of this disclosure.

[0099] Other Aspects and Embodiments of the Invention In one embodiment, the method for regulating NLRP3 activity (agonizing and partially agonizing) is characterized by contacting NLRP3 with a group of chemicals specifically described herein (e.g., a compound generally or specifically described herein, or a pharmaceutically acceptable salt thereof, or a composition comprising them). In a preferred embodiment, the method for regulating NLRP3 activity is agonizing and partially agonizing. In certain embodiments, the method for regulating NLRP3 activity is agonizing. In certain embodiments, the method for regulating NLRP3 activity is partially agonizing. The method can include an in vitro method, for example, contacting a sample containing one or more cells containing NLRP3 (e.g., THP-1 cells) with a group of chemicals. The method can also include an in vivo method, for example, administering a group of chemicals to a subject (e.g., a human) with a disease in which increased NLRP3 signaling can compensate for the lack of innate immune activity involved in the pathology and / or symptoms and / or progression of the disease (e.g., cancer, such as refractory cancer).

[0100] In certain embodiments, the compounds of the invention are useful for treating a condition, disease, or disorder in which decreased NLRP3 activity is involved in the pathology and / or symptoms and / or progression of the condition, disease, or disorder (e.g., cancer) in a subject (e.g., a human) (e.g., a condition, disease, or disorder associated with inhibitory or impaired NLRP3 signaling).

[0101] A cancer may be said to be refractory when the cancer does not respond (or is resistant) to cancer treatment. Refractory cancers are also known as resistant cancers.

[0102] In another aspect, a method for treating cancer is characterized in that it comprises administering an effective amount of a chemical compound described herein (e.g., a compound described generally or specifically herein, or a pharmaceutically acceptable salt thereof, or a composition containing the compound) to a subject in need of such treatment. In some embodiments, the cancer may be a refractory cancer.

[0103] In a further aspect, a method for treating a disease in which increased NLRP3 signaling can compensate for a deficiency in innate immune activity involved in the pathology and / or symptoms and / or progression of the disease is characterized by comprising administering to a subject in need of such treatment an effective amount of a chemical entity described herein (e.g., a compound described generally or specifically herein, or a pharmaceutically acceptable salt thereof, or a composition containing said compound).

[0104] In another aspect, the method of treatment is characterized by comprising administering an effective amount of a chemical entity described herein (e.g., a compound described generally or specifically herein, or a pharmaceutically acceptable salt thereof, or a composition comprising thereof) to a subject having a disease in which an increase in the NLRP3 signaling pathway contributes to the pathology and / or symptoms and / or disease progression in which a deficiency in innate immune activity can be compensated for.

[0105] In a further aspect, the invention features a method of treatment that includes administering to a subject a chemical compound described herein (e.g., a compound described generally or specifically herein, or a pharmaceutically acceptable salt thereof, and compositions containing the same), wherein the chemical compound is administered in an amount effective to treat a disease in which increased NLRP3 signaling contributes to the pathology and / or symptoms and / or progression of the disease, thereby treating the disease.

[0106] Implementations may include one or more of the following aspects.

[0107] The chemical groups described herein may be administered in combination with one or more additional cancer treatment methods (e.g., surgery, radiation therapy, chemotherapy, toxin therapy, immunotherapy, cryotherapy, or gene therapy, or a combination thereof); for example, a cancer treatment method comprising administering one or more (e.g., 2, 3, 4, 5, 6, or more) additional anti-cancer agents. Non-limiting examples of additional anti-cancer agents (chemotherapeutic agents) include alkylating agents (e.g., cisplatin, carboplatin, mechlorethamine, cyclophosphamide, chlorambucil, ifosfamide, and / or oxaliplatin); and antimetabolites (e.g., azathioprine and / or mercaptopurine); terpenoids (e.g., vinca alkaloids and / or taxanes; e.g., vincristine, vinblastine, vinorelbine, and / or vindesine, taxanes, etc.). topoisomerases (e.g., type I topoisomerases and / or type II topoisomerases; e.g., camptothecins, e.g., irinotecan and / or topotecan; amsacrine, etoposide, etoposide phosphate and / or teniposide); antitumor antibiotics (e.g., actinomycin, anthracyclines, doxorubicin, daunorubicin, valrubicin, idarubicin, epirubicin, bromide, leomycin, plicamycin, and / or mitomycin; hormones (e.g., luteinizing hormone-releasing hormone agonists; e.g., leuprolidine, goserelin, triptorelin, histrelin, bicalutamide, flutamide, and / or nilutamide); antibodies (e.g., abciximab, adalimumab, alemtuzumab, atlitumab, basiliximab, belimumab, bevacizumab, brentuximab vedotin, canakinumab, cetuximab, certolizumab pegol, daclizumab, denosumab, eculizumab, efalizumab, gemtuzumab, golimumab, ibritumomab tiuxetan, infliximab, ipilimumab, muromonab-CD3, natalizumab, ofatumumab, omalizumab, palivizumab, panitumumab, ranibizumab, rituximab, tocilizumab, tositumomab, and / or trastuzumab); angiogenesis inhibitors; cytokines; thrombotic agents; growth inhibitors; antiparasitic agents;and immune checkpoint inhibitors targeting immune checkpoint receptors selected from CTLA-4, PD-1, PD-L1, PD-1-PD-L1, PD-1-PD-L2, T-cell immunoglobulin and mucin 3 (TIM3 or HAVCR2), galectin 9-TIM3, phosphatidylserine-TIM3, lymphocyte activation gene 3 protein (LAG3), MHC class II-LAG3, 4-1BB-4-1BB ligand, and OX40-OX40 ligand. Gand, GITR, GITR ligand-GITR, CD27, CD70-CD27, TNFRSF25, TNFRSF25-TL1A, CD40L, CD40-CD40 ligand, HVEM-LIGHT-LTA, HVEM, HVEM-BTLA, HVEM-CD160, HVEM-LIGHT, HVEM-BTLA-CD160, CD80, CD80-PDL-1, PDL2-CD80, CD244, CD48-CD244, CD244, ICOS, ICOS- ICOS ligand, B7-H3, B7-H4, VISTA, TMIGD2, HHLA2-TMIGD2, butyrophilin (including BTNL2), Siglec family, TIGIT and PVR family members, KIR, ILT and LIR, NKG2D and NKG2A, MICA and MICB, CD244, CD28, CD86-CD28, CD86-CTLA, CD80-CD28, phosphatidylserine, TIM3, phosphatidylserine Selected from TIM3, SIRPA-CD47, VEGF, neuropilin, CD160, CD30 and CD155 (e.g., CTLA-4 or PD1 or PD-L1) and other immunomodulators, such as interleukin-2 (IL-2), indoleamine 2,3-dioxygenase (IDO), IL-10, transforming growth factor-β (TGFβ), CD39, CD73 adenosine-CD39-CD73 and CXCR4-CXCL12;

[0108] The subject may have cancer; for example, the subject has undergone, and / or is undergoing, and / or will undergo one or more cancer treatments.

[0109] Non-limiting examples of cancers include acute myeloid leukemia, adrenocortical carcinoma, Kaposi's sarcoma, lymphoma, anal cancer, appendix cancer, teratocarcinoma / rhabdoid tumor, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, brain tumor, breast cancer, bronchial tumor, carcinoid tumor, cardiac tumor, cervical cancer, chordoma, chronic lymphocytic leukemia, chronic myeloproliferative neoplasm, colon cancer, colorectal cancer, craniopharynx cancer, bile duct cancer, endometrial cancer, ependymoma, esophageal cancer, nasal neuroblastoma, Ewing's sarcoma, eye cancer, fallopian tube cancer, biliary tract cancer, and urinary tract cancer. These include bladder cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor, germ cell tumor, hairy cell leukemia, head and neck cancer, heart cancer, liver cancer, hypopharyngeal cancer, pancreatic cancer, kidney cancer, laryngeal cancer, chronic myeloid leukemia, lip and oral cavity cancer, lung cancer, melanoma, Merkel cell carcinoma, mesothelioma, oral cancer, lip cancer, osteosarcoma, ovarian cancer, penile cancer, pharyngeal cancer, prostate cancer, rectal cancer, salivary gland cancer, skin cancer, small intestine cancer, soft tissue sarcoma, testicular cancer, throat cancer, thyroid cancer, urethral cancer, uterine cancer, vaginal cancer, and vulvar cancer.

[0110] In another embodiment, the mammal is identified as suffering from cancer or an infectious disease, such as Acinetobacter infection, actinomycosis, African sleeping sickness, acquired immune deficiency syndrome, amebiasis, anaplasmosis, anthrax, hemolytic alkanobacterial infection, Argentine hemorrhagic fever, ascariasis, aspergillosis, astrovirus infection, babesiosis, Bacillus cereus infection, bacterial pneumonia, bacterial vaginosis, Bacteroides infection, balantidiosis, raccoon roundworm infection, BK virus infection, black sand worm infection, Blastocystis hominis infection, blastomycosis, Bolivian hemorrhagic fever, Botulism, Brazilian hemorrhagic fever, brucellosis, bubonic plague, Burkholderia infection, Buruli ulcer, Calicivirus infection, Campylobacter infection, candidiasis, cat scratch disease, cellulitis, Chagas disease, chancroid, chickenpox, chikungunya fever, chlamydia infection, Chlamydia pneumoniae infection, cholera, chromoblastomycosis, Clonorchiasis, Clostridium difficile infection, coccidioidomycosis, Colorado tick fever, common cold, Creutzfeldt-Jakob disease, Crimean-Congo hemorrhagic fever, cryptococcosis, crypto Sporidiosis, cutaneous larva migrans, Cyclospora infection, cysticercosis, cytomegalovirus infection, dengue fever, desmodesmus infection, dienteramebiasis, diphtheria, diphyllobothriasis, dracunculiasis, Ebola hemorrhagic fever, echinococcosis, ehrlichiosis, pinworm infection, enterococcal infection, enterovirus infection, typhus, erythroderma infection, exanthema subitum, fascioliasis, fascioliasis, fatal familial insomnia, filariasis, food poisoning due to Clostridium myonecrosis, free-living amebic infection, Fusobacterium infection, gastroenteritis Gangrene, Geotrichum, Gerstmann-Straussler-Scheinker syndrome, Giardiasis, Glanders, Gnathostomiasis, Gonorrhea, Inguinal granuloma, Group A Streptococcus infection, Group B Streptococcus infection, Haemophilus influenzae infection, Hand, Foot and Mouth Disease, Hantavirus pulmonary syndrome, Heartland virus disease, Helicobacter pylori infection, Hemolytic uremic syndrome, Hemorrhagic fever with renal syndrome, Hepatitis A, Hepatitis B, Hepatitis C, Hepatitis D, Hepatitis E, Herpes simplex, Histoplasmosis, Hookworm infection, Human bocavirus infection, Human ehrlichiosis (E.ewingii infection), human granulocytic anaplasmosis, human metapneumovirus infection, human monocytic ehrlichiosis, human papillomavirus infection, human parainfluenza virus infection, membranous tapeworm disease, Epstein-Barr virus mononucleosis, influenza, isosporosis, Kawasaki disease, keratitis, Kingella kingae infection, kuru, Lassa fever, Legionnaires' disease, Pontiac fever, leishmaniasis, leprosy, leptospirosis, listeriosis, Lyme disease, lymphatic filariasis, Lymphocytic choriomeningitis virus, malaria, Marburg hemorrhagic fever, measles, Middle East respiratory syndrome, melioidosis, meningitis, meningococcal infection, fluke sympathomimesis, microsporidiosis, molluscum contagiosum, monkeypox, mumps, typhus, mycoplasma pneumonia, mycetoma, myiasis, neonatal conjunctivitis, variant Creutzfeldt-Jakob disease, nocardiosis, filariasis, paracoccidioidomycosis, paragonimiasis, pasteurellosis, head lice infestation, body lice infestation, pubic lice infestation, pelvic inflammatory disease, whooping cough, plague, pneumonia, acute polio Meningitis, Prevotella infection, primary amebic meningoencephalitis, progressive multifocal leukoencephalopathy, psittacosis, Q fever, rabies, relapsing fever, respiratory syncytial virus infection, rhinosporidiosis, rhinovirus infection, rickettsial infection, rickettsialpox, Rift Valley fever, Rocky Mountain spotted fever, rotavirus infection, rubella, salmonellosis, severe acute respiratory syndrome, scabies, schistosomiasis, septicemia, shigellosis, shingles, smallpox, sporotrichosis, staphylococcal food poisoning, staphylococcal infection, strongyloidiasis, subacute sclerosing panencephalitis, plum These include, but are not limited to, venom, tapeworm, tetanus, tinea barbae, tinea capitis, tinea corporis, tinea cruris, tinea manus, nematode palmar vera, tinea pedis, tinea unguium, tinea versicolor, toxocariasis, trachoma, toxoplasmosis, trichinosis, trichomoniasis, trichuriasis, tuberculosis, tularemia, typhoid fever, Ureaplasma urealyticum infection, valley fever, Venezuelan hemorrhagic fever, viral pneumonia, West Nile fever, white sand cricket, Yersinia pseudotuberculosis infection, Yersinia infection, yellow fever, and zygomycosis.

[0111] The chemical groups described herein can be administered intratumorally.

[0112] Chemical groups can be administered systemically (orally, subcutaneously, intramuscularly, intravenously).

[0113] The method can further include identifying the subject.

[0114] Other embodiments include those described in the detailed description and / or claims.

[0115] (definition) To facilitate understanding of the disclosure herein, additional definitions of terms are provided below. Generally, the nomenclature and laboratory methods used herein in organic chemistry, medicinal chemistry, and pharmacology are well known and commonly used in the art. Unless otherwise defined, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains.

[0116] Unless otherwise specified, the singular references include the plural references. For example, "a" and "an" can refer to one or more than one.

[0117] Unless otherwise specified, any heteroatom with unsatisfied valences is assumed to have sufficient hydrogen atoms to satisfy the valences.

[0118] For purposes of clarity, and in accordance with convention used in the art, the symbols: [ka] is used in the structural formulas and tables herein to represent the bond that is the site of attachment of a group or substituent to the structural center / nucleus.

[0119] Additionally, for purposes of clarity, when a substituent has a dash "-" that is not between two letters or symbols, this is used to indicate the point of attachment of the substituent. For example, -OCH is attached through the oxygen atom.

[0120] As used herein, the term "NLRP3" is meant to encompass, but is not limited to, nucleic acids, polynucleotides, oligonucleotides, sense and antisense polynucleotide strands, complementary sequences, peptides, polypeptides, proteins, homolog and / or ortholog NLRP3 molecules, isoforms, precursors, mutants, variants, derivatives, splice variants, alleles, different species, and active fragments thereof.

[0121] An "agonist" of NLRP3 includes a compound that directly binds to or modulates (e.g., activates, stabilizes, changes distribution, etc.) NLRP3 so as to increase the activity of NLRP3 at the protein level.

[0122] Certain compounds described herein that agonize NLRP3 to a lesser extent than NLRP3 full agonists can function as antagonists and agonists in assays.These compounds antagonize the activation of NLRP3 by NLRP3 full agonists.This is because they prevent all effects of NLRP3 interaction.However, these compounds themselves activate NLRP3 activity to some extent, but usually less than the corresponding amount of NLRP3 full agonists.Such compounds can be called "NLRP3 partial agonists".

[0123] In some embodiments, the compounds described herein are agonists (e.g., full agonists) of NLRP3. In other embodiments, the compounds described herein are partial agonists of NLRP3.

[0124] Generally, receptors exist in an activated form (Ra) and an inactivated form (Ri). Certain compounds that affect receptors can alter the ratio of Ra to Ri (Ra / Ri). For example, a full agonist can increase the Ra / Ri ratio, resulting in a "maximal" saturation effect. A partial agonist provides a lower response than that evoked by a full agonist (e.g., an endogenous agonist) when bound to its receptor. Therefore, the Ra / Ri for this partial agonist is lower than that of a full agonist. However, the potency of a partial agonist may be higher or lower than that of a full agonist.

[0125] As used herein, the term "acceptable" with respect to a formulation, composition, or ingredient means having no lasting adverse effects on the general health of the subject being treated.

[0126] "API" refers to active pharmaceutical ingredient.

[0127] As used herein, the term "effective amount" or "therapeutically effective amount" refers to a sufficient quantity of an administered chemical group (e.g., a compound active as a mitochondrial uncoupling agent, or a pharmaceutically acceptable salt and / or hydrate and / or cocrystal thereof; e.g., a compound such as niclosamide, or a pharmaceutically acceptable salt and / or hydrate and / or cocrystal thereof; e.g., a compound such as a niclosamide analog, or a pharmaceutically acceptable salt and / or hydrate and / or cocrystal thereof) to alleviate to some extent one or more symptoms of the disease or condition being treated. This can result in a reduction and / or alleviation of the symptoms, symptoms, or pathogenesis of the disease, or other desired changes in a biochemical system. For example, an "effective amount" for therapeutic use is the amount of a composition containing a compound disclosed herein required to produce a clinically significant reduction in the signs of the disease. In any individual case, an appropriate "effective" amount can be determined using any suitable technique, such as a dose escalation study.

[0128] The term "excipient" or "pharmaceutically acceptable excipient" means a pharmaceutically acceptable substance, composition, or vehicle, such as a liquid or solid filler, diluent, carrier, solvent, or encapsulant. In one embodiment, each component is "pharmaceutically acceptable" in the sense of being compatible with the other components of the pharmaceutical formulation, suitable for use in contact with the tissues or organs of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, and commensurate with a reasonable benefit / risk ratio. For example, Remington: The Science and Practice of Pharmacy, 22nd Edition, Pharmaceutical Press, London, UK (2012); Handbook of Pharmaceutical Excipients, 6th ed.; Rowe et al., Eds.; The Pharmaceutical Press and the American Excipients: (2009); Handbook of Pharmaceutical Additives, 3rd ed.; Ash and Ash Eds.; Gower Publishing Company:(2007);Pharmaceutical Preformulation and Formulation, 2nd ed.;Gibson Ed.;CRC Press LLC:Boca Raton, FL, (2009).

[0129] The term "pharmaceutically acceptable salt" refers to a formulation of a compound that does not cause significant irritation to an organism to which it is administered and does not impair the biological activity and properties of the compound. In some instances, pharmaceutically acceptable salts can be obtained by reacting a compound described herein with an acid (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, etc.). In some instances, pharmaceutically acceptable salts can be obtained by reacting a compound having an acidic group described herein with a base to form a salt (e.g., ammonium salt, alkali metal salt, e.g., sodium salt or potassium salt, alkaline earth metal salt, e.g., calcium salt or magnesium salt, salt of an organic base, e.g., dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, and amino acids, e.g., arginine, lysine, etc.), or by other predetermined methods. Pharmacologically acceptable salts are not particularly limited, as long as they can be used in medicines. Examples of salts that the compounds described herein may form with bases include: salts with inorganic bases such as sodium, potassium, magnesium, calcium, and aluminum; salts with organic bases such as methylamine, ethylamine, and ethanolamine; salts with basic amino acids such as lysine and ornithine; and ammonium salts. The salt may also be an acid addition salt, specifically exemplified by the acid addition salts with the following acids: inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid; organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, and ethanesulfonic acid; and acidic amino acids such as aspartic acid and glutamic acid.

[0130] The term "pharmaceutical composition" refers to a mixture of a compound described herein with other chemical components (collectively referred to herein as "excipients"), such as carriers, stabilizers, diluents, dispersing agents, suspending agents, and / or thickening agents. A pharmaceutical composition facilitates administration of a compound to an organism. Multiple techniques for administering a compound exist in the art, including, but not limited to, rectal, oral, intravenous, aerosol, parenteral, ocular, pulmonary, and topical administration.

[0131] The term "subject" refers to an animal, including, but not limited to, a primate (e.g., a human), monkey, cow, pig, sheep, goat, horse, dog, cat, rabbit, rat, or mouse. The terms "subject" and "patient" are used interchangeably herein, e.g., to refer to a mammalian subject, e.g., a human.

[0132] The terms "treat," "treating," and "treatment," in the sense of treating a disease or disorder, mean alleviating or eliminating the disorder, disease, or condition, or one or more symptoms associated with said disorder, disease, or condition; or the progression, spread, or worsening of the disease, disorder, or condition, or one or more symptoms thereof. "Treating cancer" refers to one or more of the following effects: (1) inhibiting tumor growth to some extent, e.g., (i) slowing down growth and (ii) completely halting growth; (2) reducing tumor cell number; (3) maintaining tumor size; (4) reducing tumor size; (5) inhibiting, e.g., (i) reducing, (ii) slowing down, or (iii) completely preventing tumor cell infiltration into peripheral tissues; (6) inhibiting, e.g., (i) reducing, (ii) slowing down, or (iii) completely preventing metastasis; (7) enhancing the anti-tumor immune response, which may result in (i) maintaining tumor size, (ii) reducing tumor size, (iii) slowing down tumor growth, (iv) reducing, slowing down, or preventing infiltration, and / or (8) alleviating to some extent the severity or number of one or more symptoms associated with the disorder.

[0133] The term "halo" refers to fluoro (F), chloro (Cl), bromo (Br) or iodo (I).

[0134] The term "alkyl" refers to a hydrocarbon chain that may be straight or branched containing the number of carbon atoms indicated. For example, C 1-10 indicates that the chain may contain 1 to 10 carbon atoms. Non-limiting examples include methyl, ethyl, iso-propyl, tert-butyl, and n-hexyl.

[0135] The term "alkylene" refers to a branched or unbranched divalent alkyl (eg, -CH2-).

[0136] The term "haloalkyl" refers to an alkyl in which one or more hydrogen atoms are replaced with an independently selected halo.

[0137] The term "alkoxy" refers to an -O-alkyl group (e.g., -OCH3).

[0138] The term "haloalkoxy" refers to an -O-haloalkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge. For example, "C 1-6 "Haloalkoxy" is intended to include C, C, C, C, C, C, and C haloalkoxy groups. Examples of haloalkoxy include, but are not limited to, trifluoromethoxy, 2,2,2-trifluoroethoxy, and pentafluoroethoxy.

[0139] The term "alkenyl" refers to a hydrocarbon chain that may be straight or branched and has one or more carbon-carbon double bonds. The alkenyl group portion contains the indicated number of carbon atoms. For example, C 2-6 indicates that the group may have from 2 to 6 carbon atoms in the group.

[0140] The term "alkynyl" refers to a hydrocarbon chain that may be straight or branched and has one or more carbon-carbon triple bonds. The alkynyl group portion contains the indicated number of carbon atoms. For example, C 2-6 indicates that the group may have 2 to 6 carbon atoms in the group.

[0141] The term "aromatic" generally refers to a ring that includes a resonance-stabilized ring arrangement of 4n+2 pi electrons, where n is an integer such as 1 or 2. Aromatic groups include aryl and heteroaryl groups. The term "non-aromatic group" refers to any group that does not fall within the definition of "aromatic group."

[0142] The term "aryl" refers to a 6-carbon monocyclic, 10-carbon bicyclic, or 14-carbon tricyclic aromatic ring system, in which 0, 1, 2, 3, or 4 atoms of each ring are optionally substituted, and in which the ring comprising the monocyclic group is aromatic, and at least one of the fused rings comprising the bicyclic or tricyclic group is aromatic, e.g., tetrahydronaphthyl. Examples of aryl groups include phenyl, naphthyl, and the like.

[0143] The term "cycloalkyl," as used herein, includes saturated cyclic hydrocarbon groups having 3 to 10 carbons, preferably 3 to 8 carbons, and more preferably 3 to 6 carbons, wherein the cycloalkyl group is optionally substituted. Preferred cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl. As used herein, the term "cycloalkylene" refers to a divalent cycloalkyl.

[0144] The term "heteroaryl" refers to an aromatic 5- to 8-membered monocyclic, 7- to 12-membered bicyclic or bridged, or 11- to 14-membered tricyclic ring system having 1 to 3 heteroatoms if monocyclic, 1 to 6 heteroatoms if bicyclic, spiro, or bridged, or 1 to 9 heteroatoms if tricyclic, wherein the heteroatoms are selected from O, N, or S (e.g., carbon atoms and 1 to 3, 1 to 6, or 1 to 9 N, O, or S heteroatoms if monocyclic, bicyclic, or tricyclic, respectively), wherein 0, 1, 2, 3, or 4 atoms of each ring are optionally substituted, and wherein the ring, including the monocyclic group, is aromatic, and at least one of the fused rings, including the bicyclic or tricyclic group, is aromatic (however, aromatic need not be the ring containing the heteroatoms, e.g., tetrahydroisoquinolinyl). Examples of heteroaryl groups also include pyridyl, furyl or furanyl, imidazolyl, benzimidazolyl, pyrimidinyl, thiophenyl or thienyl, quinolinyl, indolyl, thiazolyl, and the like.

[0145] The term "heterocyclyl" refers to a non-aromatic 5- to 8-membered monocyclic, 8- to 12-membered bicyclic, or 11- to 14-membered tricyclic ring system having 1 to 3 heteroatoms if monocyclic, 1 to 6 heteroatoms if bicyclic, or 1 to 9 heteroatoms if tricyclic, where the heteroatoms are selected from O, N, or S (e.g., carbon atoms and 1 to 3, 1 to 6, or 1 to 9 heteroatoms among N, O, or S, respectively, if monocyclic, bicyclic, or tricyclic), where 0, 1, 2, or 3 atoms of each ring are optionally substituted. Exemplary heterocyclyl groups include piperazinyl, pyrrolidinyl, dioxanyl, morpholinyl, tetrahydrofuranyl, and the like. The term "heterocycloalkylene" refers to a divalent heterocyclyl.

[0146] Furthermore, atoms constituting the compounds of the present embodiments are intended to encompass all isotopic forms of such atoms. As used herein, isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium, and isotopes of carbon include . 13 C and 14 C is one example.

[0147] The details of one or more embodiments of the invention are set forth in the accompanying drawings and the description below. Other features and advantages of the invention will be apparent from the description and claims.

[0148] This application features chemical compounds (e.g., pharmaceutically acceptable salts and / or hydrates and / or co-crystals and / or drug combinations) that modulate (e.g., agonize or partially agonize) NLRP3, which are useful for treating conditions, diseases, or disorders in a subject (e.g., a human) in which a deficiency in innate immune activity can be compensated for by increased NLRP3 signaling pathway activity, which is involved in the pathology and / or symptoms and / or progression of the condition, disease, or disorder (e.g., cancer). This application also features compositions and other methods of using and preparing the compositions.

[0149] Pharmaceutical Compositions and Administration In some embodiments, the chemical compound (e.g., a compound that modulates, e.g., agonizes or partially agonizes, NLRP3, or a pharmaceutically acceptable salt and / or hydrate and / or cocrystal and / or pharmaceutical combination thereof) is administered as a pharmaceutical composition including the chemical compound and one or more pharmaceutically acceptable excipients, and optionally one or more additional therapeutic agents, as described herein.

[0150] In some embodiments, the pharmaceutical composition comprises the compound of the present invention or its salt, and one or more pharmaceutically acceptable excipients.In some embodiments, the pharmaceutical composition comprises the compound of the present invention or its pharmaceutically acceptable salt, and one or more pharmaceutically acceptable excipients.In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of the compound of the present invention or its pharmaceutically acceptable salt, and one or more pharmaceutically acceptable excipients.

[0151] In some embodiments, chemical group can be administered in combination with one or more conventional pharmaceutical excipients.Pharmaceutically acceptable excipients include but are not limited to ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery system (SEDDS) (for example, d-α-tocopherol polyethylene glycol 1000 succinate), surfactants used in pharmaceutical dosage forms (for example, Tween, poloxamer or other similar polymer-based delivery matrices), serum proteins (for example, human serum albumin), buffer substances (for example, phosphate, Tris, glycine, sorbic acid, potassium sorbate), saturated vegetable fatty acid partial glyceride mixture, water, salt or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salt, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylate, wax, polyethylene-polyoxypropylene-block polymer and mutton fat. Cyclodextrins, e.g., α-, β-, and γ-cyclodextrin, or chemically modified derivatives, e.g., hydroxyalkyl cyclodextrins, e.g., 2- and 3-hydroxypropyl-β-cyclodextrin, or other solubilizing derivatives, can also be used to enhance delivery of the compounds described herein. Dosage forms or compositions can be prepared containing 0.005% to 100% of the chemical groups described herein, with the balance consisting of non-toxic excipients. Contemplated compositions contain 0.001% to 100%, in one embodiment 0.1 to 95%, in another embodiment 75 to 85%, and in a further embodiment 20 to 80%, of the chemical groups provided herein. Actual methods for preparing such dosage forms are known or will be apparent to those skilled in the art; see, for example, Remington: The Science and Practice of Pharmacy, 22 nd Edition (Pharmaceutical Press, London, UK. 2012).

[0152] Route of Administration and Composition Components In some embodiments, the chemical entities described herein or pharmaceutical compositions thereof may be administered to a subject in need thereof by any acceptable route of administration. Acceptable routes of administration include, but are not limited to, sublingual, cutaneous, intracervical, intranasal, intratracheal, intraintestinal, epidural, intrainterstitial, intraperitoneal, intra-arterial, intrabronchial, intrabursal, intracerebral, intrabursal, intracoronary, intradermal, intraductal, intraduodenal, intradural, intraepidermal, intraesophageal, intragastric, intragingival, intraileal, intralymphatic, intramedullary, intrameningeal, intramuscular, intraovarian, intraperitoneal, intraprostatic, intrapulmonary, intrathecal, intrathecal, intrasynovial, intratesticular, subarachnoid, intravascular, intratumoral, intrauterine, intraarterial, intravenous, nasal, nasogastric, oral, parenteral, transdermal, epidural, rectal, respiratory (inhalation), subcutaneous, sublingual, submucosal, topical, transdermal, transmucosal, transtracheal, ureteral, urethral, ​​and vaginal. In certain embodiments, the preferred route of administration is systemic administration.

[0153] The composition can be formulated for parenteral administration, for example, by intravenous, intramuscular, subcutaneous or intraperitoneal injection.Usually, such compositions can be prepared as injections, liquid solutions or suspensions; solid forms suitable for preparing solutions or suspensions by adding liquid before injection can also be prepared; the preparations can also be emulsified.The preparation of such preparations is understood by those skilled in the art from the present invention.

[0154] Suitable pharmaceutical forms for injection use include sterile aqueous solutions or powders; formulations including sesame oil, peanut oil, or aqueous propylene glycol; and sterile powders for the extemporaneous preparation of sterile injectable solutions or powders. In all cases, the pharmaceutical form must be sterile and fluid to the extent that it is easily syringable. It must be stable under the conditions of manufacture and storage and preserved against the contaminating action of microorganisms (e.g., bacteria and fungi).

[0155] The carrier may be a solvent or dispersion medium, containing, for example, water, ethanol, polyol (e.g., glycerin, propylene glycol, and liquid polyethylene glycol, etc.), suitable mixtures thereof, and vegetable oils. Proper fluidity can be maintained, for example, by using a coating agent such as lecithin, by maintaining a desired particle size in the case of powders, and by using surfactants. Prevention of microbial action can be achieved by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, thimerosal, etc. In many cases, it is preferable to include an isotonic agent, such as sugar or sodium chloride. Prolonged absorption of injectable compositions can be achieved by using absorption-delaying agents, such as aluminum stearate and gelatin, in the composition.

[0156] Sterile injectable solution can be prepared by incorporating the active compound in the required amount in a suitable solvent with various other ingredients as listed above, and then optionally performing sterile filtration.Generally, powders are prepared by incorporating various sterilized active ingredients into a sterile vehicle (containing the basic dispersion medium and other desired ingredients from those listed above).For sterile powders for preparing sterile injectable solution, the preferred preparation method is vacuum drying and freeze-drying technology, which obtains a powder containing the active ingredient plus any additional desired ingredients from the sterile filtered solution described above.

[0157] Intratumoral injections are discussed, for example, in Lammers, et al., "Effect of Intratumoral Injection on the Biodistribution and the Therapeutic Potential of HPMA Copolymer-Based Drug Deliver Systems," Neoplasia. 10:788-795 (2006).

[0158] Pharmaceutically acceptable excipients that can be used in rectal compositions as gels, creams, enemas, or rectal suppositories include cocoa butter glycerides, synthetic polymers such as polyvinylpyrrolidone, PEG (PEG ointments), glycerin, glycerinated gelatin, hydrogenated vegetable oils, poloxamer, polyethylene glycol mixtures of various molecular weights and fatty acid esters of polyethylene glycol, petrolatum, anhydrous lanolin, shark liver oil, sodium saccharin, menthol, sweet almond oil, sorbitol, sodium benzoate, anoxide SBN, vanilla essential oil, aerosols, parabens / phenoxyethanol, sodium methyl p-oxybenzoate, sodium propyl methyl paraben, sodium propyl paraben, sodium ... p-oxybenzoate, diethylamine, carbomer, carbopol, methyloxybenzoate, macrogol, cetostearyl ether, cocoyl caprylocaprate, isopropyl alcohol, propylene glycol, liquid paraffin, xanthan gum, carboxy-metabisulfite, sodium edetate, sodium benzoate, potassium metabisulfite, grapefruit seed extract, methylsulfonylmethane (MSM), lactic acid, glycine, vitamins such as vitamins A and E, and potassium acetate.

[0159] In some embodiments, suppositories can be prepared by mixing the chemical groups described herein with suitable non-irritating excipients or carriers, such as cocoa butter, polyethylene glycol, or suppository waxes, which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum to release the active compound. In other embodiments, compositions for rectal administration are in the form of enemas.

[0160] In other embodiments, the compounds described herein or pharmaceutical compositions thereof are suitable for local delivery to the digestive or GI tract by oral administration (eg, solid or liquid dosage form).

[0161] Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such solid dosage forms, the chemical group comprises one or more pharmaceutically acceptable excipients, such as sodium citrate or dicalcium phosphate salts, and / or: a) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol and silicic acid; b) binders, such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose and acacia; c) humectants, such as glycerin; d) disintegrants, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate; e) disintegrants, such as PEG-100, PEG-10 ... The composition may be mixed with a solution retarder, such as paraffin, f) absorption accelerators, such as quaternary ammonium compounds, g) wetting agents, such as cetyl alcohol and glycerin monostearate, h) absorbents, such as kaolin and bentonite clay, and i) lubricants, such as talc, potassium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may also contain buffering agents. Solid compositions of a similar type may also be used as fillers in soft and hard gelatin capsules, using the above-mentioned excipients such as lactose or milk sugar and high molecular weight polyethylene glycols.

[0162] In one embodiment, the composition is in the form of a unit dosage form, for example, a pill or tablet, so that the composition may contain, together with the chemical groups provided herein, diluents such as lactose, sucrose, dicalcium phosphate salts, etc.; lubricants such as magnesium stearate, etc.; and binders such as starch, gum acacia, polyvinylpyrrolidine, gelatin, cellulose, cellulose derivatives, etc. In another solid dosage form, powder, quince, solution or suspension (for example, propylene carbonate, vegetable oil, PEG, poloxamer 124 or triglyceride) is encapsulated in a capsule (gelatin or cellulose-based capsule). Unit dosage forms in which one or more chemical groups provided herein or additional active agents are physically separated include, for example, capsules (or tablets in capsules) containing granules of each agent; two-layer tablets; two-compartment gel capsules, etc. Enteric-coated or delayed-release oral dosage forms are also contemplated.

[0163] Other physiologically acceptable compounds include wetting agents, emulsifying agents, dispersing agents or preservatives which are particularly useful for preventing the growth or action of microorganisms. Various preservatives are well known and include, for example, phenol and ascorbic acid.

[0164] In some embodiments, the excipients are sterile and generally free of undesirable substances. These compositions can be sterilized by conventional, well-known sterilization techniques. Sterility is not required for various oral dosage form excipients, such as tablets and capsules. USP / NF standards are generally valid.

[0165] In certain embodiments, solid oral dosage form can further comprise one or more components that chemically and / or structurally facilitate the delivery of composition to stomach or lower GI; for example, ascending colon and / or transverse colon and / or distal colon and / or small intestine.Examples of formulation techniques are described in, for example, Filipski, KJ, et al., Current Topics in Medicinal Chemistry, 2013, 13, 776-802, all of which are incorporated herein by reference.

[0166] Examples include upper GI targeting technologies such as the Accordion Pill (Intec Pharma), floating capsules and substances capable of binding to mucosal walls.

[0167] Other examples include lower GI targeting technologies. Several enteric / pH-dependent coatings and excipients are available to target various regions of the intestinal tract. These materials are typically polymers designed to dissolve or erode within a specific pH range and are selected based on the GI region of the desired drug release. These materials function to protect acid-labile drugs from gastric fluids or, if the active ingredient is irritating, to limit exposure to the upper GI (e.g., hydroxypropyl methylcellulose phthalate-based, Coateric (polyvinyl acetate phthalate), cellulose acetate phthalate, hydroxypropyl methylcellulose acetate succinate, Eudragit (methacrylic acid-methyl methacrylate copolymer), and Marcoat). Other technologies include dosage forms that respond to local flora in the gastrointestinal tract, namely, pressure-regulated colonic delivery capsules and Pulsincap.

[0168] Ophthalmic compositions may include, but are not limited to, one or more of: viscogens (e.g., carboxymethylcellulose, glycerin, polyvinylpyrrolidone, polyethylene glycol); stabilizers (e.g., Pluronic (triblock copolymer), cyclodextrin); preservatives (e.g., benzalkonium chloride, ETDA, Sofzia (boric acid, propylene glycol, sorbitol, and zinc chloride; Alcon Laboratories, Inc.), Purite (stabilized oxychloro complex; Allergan, Inc.)).

[0169] Topical compositions can include ointments and creams. Ointments are semi-solid preparations, usually based on petrolatum or other petrolatum derivatives. Creams containing selected active substances are usually viscous liquids or semi-solid emulsions, often either water-in-oil or oil-in-water. Cream bases are usually water-soluble and contain an oil phase, an emulsifier, and an aqueous phase. The oil phase, sometimes called the "internal" phase, generally comprises mineral oil and a fatty alcohol, such as cetyl or stearyl alcohol; the aqueous phase usually, although not necessarily, exceeds the volume of the oil phase and generally contains a humectant. Emulsifiers in cream formulations are typically nonionic, anionic, cationic, or amphoteric surfactants. Like other carriers or vehicles, ointment bases must be inert, stable, non-irritating, and non-sensitizing.

[0170] In any of the above embodiments, the pharmaceutical compositions described herein may include one or more of the following: lipids, internal bilayered crosslinked multilamellar vesicles, biodegradable poly(D,L-lacto-co-glycolic acid) [PLGA] or polyanhydride-based nanoparticles or microparticles, and nanoporous particle-supported lipid bilayers.

[0171] Dosage Dosage amounts may vary depending on the requirements of the patient, the severity of the condition being treated, and the particular compound being used. Determination of the proper dosage for a particular situation can be determined by one of ordinary skill in the pharmaceutical arts. The total daily dosage may be administered in divided or smaller amounts throughout the day, or by means providing continuous delivery.

[0172] In some embodiments, the compounds described herein are administered in a dose range of about 0.001 mg / Kg to about 500 mg / Kg (e.g., about 0.001 mg / Kg to about 200 mg / Kg; about 0.01 mg / Kg to about 200 mg / Kg; about 0.01 mg / Kg to about 150 mg / Kg; about 0.01 mg / Kg to about 100 mg / Kg; about 0.01 mg / Kg to about 50 mg / Kg; about 0.01 mg / Kg to about 10 mg / Kg; about 0.01 mg / Kg to about 5 mg / Kg; about 0.01 mg / Kg to about 1 mg / Kg). g / Kg; about 0.01 mg / Kg to about 0.5 mg / Kg; about 0.01 mg / Kg to about 0.1 mg / Kg; about 0.1 mg / Kg to about 200 mg / Kg; about 0.1 mg / Kg to about 150 mg / Kg; about 0.1 mg / Kg to about 100 mg / Kg; about 0.1 mg / Kg to about 50 mg / Kg; about 0.1 mg / Kg to about 10 mg / Kg; about 0.1 mg / Kg to about 5 mg / Kg; about 0.1 mg / Kg to about 1 mg / Kg; about 0.1 mg / Kg to about 0.5 mg / Kg).

[0173] Treatment method The dosage can be administered on a daily basis (e.g., as a single dose or as two or more divided doses) or on a non-daily basis (e.g., every other day, every two days, once a week or two weeks, once every two weeks, once a month).

[0174] In some embodiments, the administration period of the compounds described herein is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months or more. In further embodiments, the period of time during which administration is discontinued is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months or more. In embodiments, the therapeutic compound is administered to an individual at intervals after a certain period of time. In another embodiment, the therapeutic compound is administered for a first period, a second period after the first period (administration is discontinued during the second period), a third period after the first period (administration of the therapeutic compound is initiated), and a fourth period after the third period (administration is discontinued). In aspects of this embodiment, the period of administration of the therapeutic compound followed by the period of discontinuation of administration is repeated for a predetermined period or any period of time. In further embodiments, the administration period is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months or more. In further embodiments, the period during which administration is discontinued is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months or more.

[0175] Treatment method In some embodiments, methods are provided for treating a subject having a condition, disease, or disorder (e.g., a condition, disease, or disorder associated with an inadequate immune response) in which a deficiency in innate immune activity can be corrected by increased NLRP3 signaling, which is involved in the pathology and / or symptoms and / or progression of the condition, disease, or disorder (e.g., cancer).

[0176] Indications In any of the methods described herein, the subject may have cancer. In some examples of any of the methods described herein, the mammal has been identified as having cancer or diagnosed as having cancer.

[0177] Non-limiting examples of cancers include acute myeloid leukemia, adrenocortical carcinoma, Kaposi's sarcoma, lymphoma, anal cancer, appendix cancer, teratocarcinoma / rhabdoid tumor, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, brain tumor, breast cancer, bronchial tumor, carcinoid tumor, cardiac tumor, cervical cancer, chordoma, chronic lymphocytic leukemia, chronic myeloproliferative neoplasm, colon cancer, colorectal cancer, craniopharynx cancer, bile duct cancer, endometrial cancer, ependymoma, esophageal cancer, nasal neuroblastoma, Ewing's sarcoma, eye cancer, fallopian tube cancer, biliary tract cancer, and urinary tract cancer. These include bladder cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor, germ cell tumor, hairy cell leukemia, head and neck cancer, heart cancer, liver cancer, hypopharyngeal cancer, pancreatic cancer, kidney cancer, laryngeal cancer, chronic myeloid leukemia, lip and oral cavity cancer, lung cancer, melanoma, Merkel cell carcinoma, mesothelioma, oral cancer, lip cancer, osteosarcoma, ovarian cancer, penile cancer, pharyngeal cancer, prostate cancer, rectal cancer, salivary gland cancer, skin cancer, small intestine cancer, soft tissue sarcoma, testicular cancer, throat cancer, thyroid cancer, urethral cancer, uterine cancer, vaginal cancer, and vulvar cancer.

[0178] In certain embodiments, non-limiting examples of cancer include breast cancer, colon cancer, rectal cancer, colorectal cancer, pancreatic cancer, and prostate cancer.

[0179] Methods for diagnosing a subject having cancer or identifying a mammal as having cancer are well known in the art. For example, a medical professional (e.g., a doctor, physician's assistant, or technician) may diagnose cancer in a mammal by observing one or more symptoms of cancer in the mammal. Non-limiting examples of symptoms of cancer include fatigue, thickened, felt-like lumps or areas under the skin, weight change, jaundice, dark or red skin, non-healing sores, changes to existing lentigines, changes in bowel or bladder function, persistent cough or difficulty breathing, difficulty swallowing, hoarseness, persistent indigestion or discomfort after eating, persistent and unexplained muscle or joint pain, persistent and unexplained fever or night sweats, and unexplained bleeding or bruising. Methods for diagnosing a subject having cancer or identifying a subject as having cancer may further include performing one or more diagnostic tests (e.g., performing one or more diagnostic tests on a biopsy or blood sample).

[0180] In some examples of any of the methods described herein, the subject may be a subject with cancer, a subject diagnosed with cancer, or a subject identified as having cancer who has been unresponsive to a prior history of cancer treatment. Diagnostic tests for diagnosing or identifying a mammal as having cancer are known to those of skill in the art.

[0181] In certain embodiments, methods are provided for treating a subject having a condition, disease, or disorder (e.g., a condition, disease, or disorder associated with an inadequate immune response) in which increased NLRP3 signaling, which is involved in the pathology and / or symptoms and / or progression of the condition, disease, or disorder (e.g., cancer), can correct a deficiency in innate immune activity.

[0182] In one embodiment, the present invention provides a method of treating cancer, which can be any cancer that does not elicit an optimal innate immune system response.

[0183] The innate immune system is the part of the immune system that consists of cells that respond to biological threats, such as infection or cancer, in an antigen-nonspecific manner and stimulate the acquired antigen-specific immune system. In general, complete elimination of the threat and sustained protection (= immunity) require the activity of the acquired antigen-specific immune system, which is dependent on stimulation by the innate immune system.

[0184] In certain embodiments, the invention provides methods of treating cancer, wherein the cancer is selected based on resistance to T-cell checkpoint inhibition, or, independent of cancer type, selected based on a failure to respond to prior T-cell checkpoint inhibitor treatment, or selected based on cancer types that are generally resistant to T-cell checkpoint inhibitor treatment (e.g., hormone receptor-positive breast cancer, microsatellite-stable colon or rectal cancer, pancreatic cancer, and prostate cancer).

[0185] In certain other embodiments, the present invention provides a method for treating cancer, comprising the NLPR3 agonist of the present invention, to treat non-inflammatory tumors with low CD8+ T-cell infiltration, enhance tumor immunogenicity, and promote inflammatory responses. For example, this combination can be used to treat solid tumors based on biopsy results that show low CD8+ T-cell infiltration or low gene expression produced by CD8+ T-cells.

[0186] Resistance to T-cell checkpoint inhibition refers to progression of the cancer on treatment or failure to respond within 6 months of treatment according to response criteria for the individual cancer (e.g., RECIST 1.1 for most solid tumors).

[0187] T-cell infiltration refers to the percentage of T-cells among all nucleated cells by immunohistochemistry of tumor biopsy specimens.

[0188] CD8+ T cell infiltration refers to the percentage of CD8+ cells among all nucleated cells by immunohistochemistry of tumor biopsy specimens.

[0189] In addition to immunohistochemistry to quantify CD8+ T-cells in biopsy specimens, expression of interferon-γ-like genes produced by CD8+ T cells can be measured by quantifying mRNA, for example, using next-generation genetic assays, and can provide information about CD8+ T-cell infiltration. Thresholds for low and high CD8+ T-cell infiltration by immunohistochemistry, an mRNA quantification technique, have been developed by various groups, taking into account the range of cancers and CD8+ T-cell infiltration for specific cancers.

[0190] In any of the methods described herein, the subject may have an infectious disease. In some examples of any of the methods described herein, the subject is identified as having an infectious disease or diagnosed as having an infectious disease. For example, the infectious disease may be caused by bacteria, viruses, fungi, parasites, or mycobacteria.

[0191] In any of the methods described herein, the subject may have an infectious disease. In some examples of all of the methods described herein, the subject may be identified as having an infectious disease or diagnosed as having an infectious disease. For example, the infectious disease may be caused by bacteria, viruses, fungi, parasites, or mycobacteria.

[0192] Non-limiting examples of infectious diseases include Acinetobacter infection, actinomycosis, African sleeping sickness, acquired immunodeficiency syndrome, amebiasis, anaplasmosis, anthrax, hemolytic alkanobacterial infection, Argentine hemorrhagic fever, ascariasis, aspergillosis, astrovirus infection, babesiosis, Bacillus cereus infection, bacterial pneumonia, bacterial vaginosis, Bacteroides infection, balantidiosis, raccoon roundworm infection, BK virus infection, black sand worm infection, Blastocystis hominis infection, blastomycosis, Bolivian hemorrhagic fever, Clostridium botulinum, Brazilian hemorrhagic fever, and Brucella. plague, bubonic plague, Burkholderia infection, Buruli ulcer, Calicivirus infection, Campylobacter infection, candidiasis, cat scratch disease, cellulitis, Chagas disease, chancroid, chickenpox, chikungunya fever, chlamydia infection, chlamydia pneumonia infection, cholera, chromoblastomycosis, clonorchiasis, Clostridium difficile infection, coccidioidomycosis, Colorado tick fever, common cold, Creutzfeldt-Jakob disease, Crimean-Congo hemorrhagic fever, cryptococcosis, cryptosporidiosis, cutaneous larva migrans, Cyclospora infection, cysticercosis, cytomegalovirus Viral infections, dengue fever, desmodesmus infection, dienteric amebiasis, diphtheria, diphyllobothriasis, dracunculiasis, Ebola hemorrhagic fever, echinococcosis, ehrlichiosis, pinworm infection, enterococcal infection, enterovirus infection, typhus, erythema maculata infection, exanthema subitum, fascioliasis, fascioliasis, fatal familial insomnia, filariasis, food poisoning due to Clostridium myonecrosis, free-living amebiasis, Fusobacterium infection, gas gangrene, geotrichosis, Gerstmann-Straussler-Scheinker syndrome, giardiasis, glanders, gnathostomiasis, gonorrhea, groin Granuloma, Group A Streptococcus infection, Group B Streptococcus infection, Haemophilus influenzae infection, Hand, foot and mouth disease, Hantavirus pulmonary syndrome, Heartland virus disease, Helicobacter pylori infection, Hemolytic uremic syndrome, Hemorrhagic fever with renal syndrome, Hepatitis A, Hepatitis B, Hepatitis C, Hepatitis D, Hepatitis E, Herpes simplex, Histoplasmosis, Hookworm infection, Human bocavirus infection, Human ehrlichiosis, Human granulocytic anaplasmosis, Human metapneumovirus infection, Human monocytic ehrlichiosis, Human papillomavirus infection, Human parainfluenza virus infection, Membranous tapeworm disease,Epstein-Barr virus infection, mononucleosis, influenza, isosporosis, Kawasaki disease, keratitis, Kingella kingae infection, kuru, Lassa fever, Legionnaires' disease, Pontiac fever, leishmaniasis, leprosy, leptospirosis, listeriosis, Lyme disease, lymphatic filariasis, lymphocytic choriomeningitis virus, malaria, Marburg hemorrhagic fever, measles, Middle East respiratory syndrome, melioidosis, meningitis, meningococcal infection, fluke mitosis, microsporidiosis , molluscum contagiosum, monkeypox, mumps, typhus, mycoplasma pneumonia, mycetoma, myiasis, neonatal conjunctivitis, variant Creutzfeldt-Jakob disease, nocardiosis, filariasis, paracoccidioidomycosis, paragonimiasis, pasteurellosis, head lice infestation, body lice infestation, pubic lice infestation, pelvic inflammatory disease, whooping cough, plague, pneumonia, acute poliomyelitis, Prevotella infection, primary amebic meningoencephalitis, progressive multifocal leukoencephalopathy, psittacosis, Q fever, rabies , relapsing fever, respiratory syncytial virus infection, rhinosporidiosis, rhinovirus infection, rickettsial infection, rickettsialpox, Rift Valley fever, Rocky Mountain spotted fever, rotavirus infection, rubella, salmonellosis, severe acute respiratory syndrome, scabies, schistosomiasis, septicemia, shigellosis, shingles, smallpox, sporotrichosis, staphylococcal food poisoning, staphylococcal infection, strongyloidiasis, subacute sclerosing panencephalitis, syphilis, taeniasis, tetanus, tinea barbae, tinea capitis, tinea pedis ... These include, but are not limited to, ringworm, tinea cruris, tinea manus, necrotic tinea palmaris, tinea pedis, tinea unguium, tinea versicolor, toxocariasis, trachoma, toxoplasmosis, trichinosis, trichomoniasis, trichuriasis, tuberculosis, tularemia, typhoid fever, Ureaplasma urealyticum infection, valley fever, Venezuelan hemorrhagic fever, viral pneumonia, West Nile fever, white sand cricket, Yersinia pseudotuberculosis infection, Yersinia infection, yellow fever, and zygomycosis.

[0193] Methods for diagnosing or identifying a subject with an infectious disease are well known in the art. For example, a medical professional (e.g., a doctor, physician's assistant, or technician) can diagnose an infectious disease in a subject by observing one or more symptoms of the disease in the subject. Non-limiting examples of symptoms of the disease include fever, diarrhea, fatigue, and muscle pain. A method for diagnosing a mammal with an infectious disease or identifying a subject with an infectious disease may further include performing one or more diagnostic tests (e.g., performing one or more diagnostic tests on a biopsy or blood sample). Diagnostic tests for diagnosing or identifying a subject with an infectious disease are known in the art.

[0194] Combination therapy The present disclosure contemplates both monotherapy as well as combination therapy. In some embodiments, the methods described herein further include administering one or more additional therapeutic agents (e.g., one or more additional therapeutic agents and / or one or more therapies) in combination with the administration of the compounds described herein.

[0195] In certain embodiments, the methods described herein can further comprise administering one or more additional cancer therapeutic agents.

[0196] The one or more additional cancer treatments may include, but are not limited to, surgery, radiation therapy, chemotherapy, toxin therapy, immunotherapy, cryotherapy, cancer vaccines (e.g., HPV vaccine, Hepatitis B vaccine, Oncophage, Provenge), and gene therapy, and combinations thereof. Immunotherapy includes, but is not limited to, adoptive cell therapy, hepatocyte and / or dendritic cell induction, blood transfusion, lavage, and / or other treatments, such as tumor freezing.

[0197] In some embodiments, the one or more other cancer treatments is chemotherapy, which can include administering one or more other chemotherapeutic agents.

[0198] In some embodiments, the other cancer therapy includes a (chemotherapeutic) immune modifier, e.g., an immune checkpoint inhibitor. In some of these embodiments, the immune checkpoint inhibitor is selected from the group consisting of CTLA-4, PD-1, PD-L1, PD-1-PD-L1, PD-1-PD-L2, T-cell immunoglobulin and mucin 3 (TIM3 or HAVCR2), galectin 9-TIM3, phosphatidylserine-TIM3, lymphocyte activation gene 3 protein (LAG3), MHC class II-LAG3, 4-1BB-4-1BB ligand, OX40-OX40 ligand, GITR, and GITR. Ligand-GITR, CD27, CD70-CD27, TNFRSF25, TNFRSF25-TL1A, CD40L, CD40-CD40 ligand, HVEM-LIGHT-LTA, HVEM, HVEM-BTLA, HVEM-CD160, HVEM-LIGHT, HVEM-BTLA-CD160, CD80, CD80-PDL-1, PDL2-CD80, CD244, CD48-CD244, CD244, ICOS, ICOS-ICOS ligand, B7-H3, B7- H4, VISTA, TMIGD2, HHLA2-TMIGD2, butyrophilin, e.g., BTNL2, Siglec family, TIGIT and PVR family members, KIR, ILT and LIR, NKG2D and NKG2A, MICA and MICB, CD244, CD28, CD86-CD28, CD86-CTLA, CD80-CD28, phosphatidylserine, TIM3, phosphatidylserine-TIM3, SIRPA-CD47, VEGF, The therapeutic agent targets immune checkpoint receptors selected from the group consisting of neuropilin, CD160, CD30, and CD155; e.g., CTLA-4 or PD1 or PD-L1), as well as other immunomodulators, such as interleukin-2 (IL-2), indoleamine 2,3-dioxygenase (IDO), IL-10, transforming growth factor-β (TGFβ), CD39, CD73, adenosine-CD93-CD73, and CXCR4-CXCL12. See, e.g., Postow, MJ Clin. Oncol. 2015, 33, 1.

[0199] In certain embodiments, the immune checkpoint inhibitor targets an immune checkpoint receptor selected from CTLA-4, PD-1, PD-L1, PD-1-PD-L1, and PD-1-PD-L2.

[0200] In certain embodiments, the immune checkpoint inhibitor is selected from: nivolumab (also known as "OPDIVO"; formally designated 5C4, BMS-936558, MDX-1106 or ONO-4538), pembrolizumab (also known as "KEYTRUDA", lambrolizumab and MK-3475; see WO2008 / 156712), PDR001 (Novartis; see WO2015 / 112900), MEDI-0680 (AstraZeneca; AMP-514; see WO 2012 / 145493), cemiplimab (REGN-2810) (Regeneron; see WO2015 / 112800), JS001 (TAIZHOU JUNSHI PHARMA; Si-Yang Liu et al., J. Hematol. Oncol. 10:136 (2017)), BGB-A317 (Beigene; see WO2015 / 35606 and US2015 / 0079109), INCSHR1210 (SHR-1210; Jiangsu Hengrui Medicine; see WO2015 / 085847; Si-Yang Liu et al., J. Hematol. Oncol. 10:136 (2017)), TSR-042 (ANB011; Tesaro Biopharmaceutical; see WO2014 / 179664), GLS-010 (WBP3055; Wuxi / Harbin Gloria pharmaceuticals; Si-Yang Liu et al., J. Hematol. Oncol.10:136 (2017)), AM-0001 (Armo), STI-1110 (Sorrento Therapeutics; see WO 2014 / 194302), AGEN2034 (Agenus; see WO 2017 / 040790), MGD013 (Macrogenics); IBI308 (Innovent; see WO 2017 / 024465, WO 2017 / 025016, WO 2017 / 132825, WO2017 / 133540); BMS-936559 (formerly 12A4 or MDX-1105; see, e.g., U.S. Pat. No. 7,943,743 and WO 2013 / 173223), MPDL3280A (RG7446, also known as atezolizumab and TECENTRIQ; US 8,217,149; see also Herbst et al. (2013) J Clin Oncol 31(suppl):3000), durvalumab (IMFINZI; MEDI-4736; AstraZeneca; see WO 2011 / 066389), avelumab (Pfizer; MSB-0010718C; BAVENCIO; WO 2013 / 079174), STI-1014 (Sorrento; see WO2013 / 181634), CX-072 (Cytomx; see WO2016 / 149201), KN035 (3D Med / Alphamab; see Zhang et al., Cell Discov. 7:3 (March 2017), LY3300054 (Eli Lilly Co.; see, e.g., WO 2017 / 034916), CK-301 (Checkpoint Therapeutics; Gorelik et al., AACR:Abstract 4606 (Apr 2016); urelumab, PF-05082566, MEDI6469, TRX518, varlilumab, CP870893, BMS986016, MGA271, lirilumab, IPH2201, emactuzumab, INCB024360, galunisertib, urocuplumab, BKT140, bavituximab, CC-90002, bevacizumab, MNRP1685A, ipilimumab (YERVOY; U.S. Pat. No. 6,984,720), MK-1308 (Merck), AGEN-1884 (Agenus Inc.; WO2016 / 196237) and tremelimumab (formerly ticilimumab, CP-675,206; AstraZeneca; see, e.g., WO 2000 / 037504 and Ribas, Update Cancer Ther. 2(3):133-39 (2007)).

[0201] In certain embodiments, the immune checkpoint inhibitor is selected from nivolumab, pembrolizumab, JS001, BGB-A317, INCSHR1210, TSR-042, GLS-010, STI-1110, MGD013, IBI308, BMS-936559, atezolizumab, durvalumab, avelumab, STI-1014, CX-072, KN035, LY3300054, CK-301, urelumab, PF-05082566, MEDI6469, TRX518, varlilumab, BMS-986016, ipilimumab, AGEN-1884, and tremelimumab.

[0202] In these embodiments, the immune checkpoint inhibitor is selected from the group consisting of urelumab, PF-05082566, MEDI6469, TRX518, varlilumab, CP-870893, pembrolizumab (PD1), nivolumab (PD1), atezolizumab (formerly MPDL3280A) (PDL1), MEDI4736 (PD-L1), abet Selected from Avelumab (PD-L1), PDR001 (PD1), BMS-986016, MGA271, Lirilumab 7, IPH2201, Emactuzumab, INCB024360, Galunisertib, Ulocuplumab, BKT140, Bavituximab, CC-90002, Bevacizumab, and MNRP1685A.

[0203] In certain embodiments, the immune checkpoint inhibitor is selected from nivolumab, ipilimumab, pembrolizumab, atezolizumab, durvalumab, and avelumab.

[0204] In certain embodiments, the immune checkpoint inhibitor is selected from nivolumab and ipilimumab.

[0205] In certain embodiments, the additional anticancer agent (chemotherapeutic agent) is a STING agonist.For example, STING agonist can comprise cyclic dinucleotide, for example, cAMP, cGMP and cGAMP, and the modified cyclic dinucleotide that comprises one or more of the following modified forms (2'-O / 3'-O bond, phosphorothioate bond, adenine and / or guanine analog, 2'-OH modified (for example, -OCH3 or substitution, for example, -F or N3).For example, see WO2014 / 189805.

[0206] In some embodiments, the other chemotherapeutic agent is an alkylating agent. Alkylating agents are so named because of their ability to alkylate many nucleophilic functional groups under conditions present in cells (including, but not limited to, cancer cells). In further embodiments, alkylating agents include, but are not limited to, cisplatin, carboplatin, mechlorethamine, cyclophosphamide, chlorambucil, ifosfamide, and / or oxaliplatin. In embodiments, alkylating agents can function by forming covalent bonds with amino, carboxyl, sulfhydryl, and phosphate groups in biologically important molecules, thereby rendering cells dysfunctional, or they can function by modifying cellular DNA. In further embodiments, alkylating agents are synthetic, semi-synthetic, or derivatives.

[0207] In some embodiments, the other chemotherapeutic agent is an antimetabolite.Antimetabolites disguise themselves as purines or pyrimidines, which are the building blocks of DNA, and generally prevent these substances from being incorporated into DNA during the "S" phase (of the cell cycle), thereby halting normal growth and division.Antimetabolites can also affect RNA synthesis.In some embodiments, antimetabolites include, but are not limited to, azathioprine and / or mercaptopurine.In further embodiments, antimetabolites are synthetic, semi-synthetic, or derivatives.

[0208] In some embodiments, the other chemotherapeutic agent is a plant alkaloid and / or terpenoid. These alkaloids are derived from plants and interfere with cell division, generally inhibiting the function of microtubules. In some embodiments, the plant alkaloid and / or terpenoid is a vinca alkaloid, podophyllotoxin, and / or taxane. Vinca alkaloids generally bind to specific sites on tubulin and inhibit the assembly of tubulin into microtubules during the M phase of the cell cycle. In some embodiments, the vinca alkaloid is obtained from Madagascar periwinkle, Catharanthus roseus (formerly known as Vinca rosea). In some embodiments, the vinca alkaloid includes, but is not limited to, vincristine, vinblastine, vinorelbine, and / or vindesine. In an embodiment, the taxane includes, but is not limited to, taxol, paclitaxel, and / or docetaxel. In a further embodiment, the plant alkaloid or terpenoid is synthetic, semi-synthetic, or a derivative. In a further embodiment, the podophyllotoxin includes, but is not limited to, etoposide and / or teniposide. In an embodiment, the taxane is, but is not limited to, docetaxel and / or ortataxel. In an embodiment, the cancer therapeutic agent is a topoisomerase. Topoisomerase is a key enzyme that maintains DNA topology. Inhibition of type I or type II topoisomerase disrupts proper DNA supercoiling, thereby disrupting both DNA transcription and replication. In a further embodiment, the topoisomerase is, but is not limited to, a type I topoisomerase inhibitor or a type II topoisomerase inhibitor. In an embodiment, the type I topoisomerase inhibitor is, but is not limited to, camptothecin.In another embodiment, the camptothecin is, but is not limited to, exatecan, irinotecan, lutotecan, topotecan, BNP1350, CKD602, DB67 (AR67), and / or ST1481. In an embodiment, the type II topoisomerase inhibitor is, but is not limited to, epipodophyllotoxin. In another embodiment, the epipodophyllotoxin is, but is not limited to, amsacrine, etoposide, etoposide phosphate, and / or teniposide. In another embodiment, the topoisomerase inhibitor is synthetic, semi-synthetic, or a derivative, including those found in nature, such as epipodophyllotoxin, a natural substance derived from the roots of American mayapple (Podophyllum petratum).

[0209] In some embodiments, the other chemotherapeutic agent is a stilbenoid. In further embodiments, stilbenoids include, but are not limited to, resveratrol, piceatannol, pinosylvin, pterostilbene, α-viniferin, ampelosin A, ampelosin E, diptoindonesin C, diptoindonesin F, ε-viniferin, flexosol A, gnetin H, hemsleyanol D, hopeaphenol, trans-diptoindonesin B, astringin, piceid, and diptoindonesin A. In further embodiments, the stilbenoid is synthetic, semi-synthetic, or derivative.

[0210] In certain embodiments, the other chemotherapeutic agent is an antitumor antibiotic. In certain embodiments, the antitumor antibiotic is, but is not limited to, actinomycin, an anthracenedione, an anthracycline, thalidomide, dichloroacetic acid, nicotinic acid, 2-deoxyglucose, and / or clofazimine. In certain embodiments, the actinomycin is, but is not limited to, actinomycin D, bacitracin, colistin (polymyxin E), and / or polymyxin B. In other embodiments, the anthracenedione is, but is not limited to, mitoxantrone and / or pixantrone. In further embodiments, the anthracycline is, but is not limited to, bleomycin, doxorubicin (adriamycin), daunorubicin (daunomycin), epirubicin, idarubicin, mitomycin, plicamycin, and / or valrubicin. In further embodiments, the antitumor antibiotic is a synthetic, semi-synthetic, or derivative.

[0211] In certain embodiments, the other chemotherapeutic agent is endostatin, angiogenin, angiostatin, chemokine, angiorestin, angiostatin (plasminogen fragment), basement membrane collagen-derived anti-angiogenic factor (tumstatin, canstatin, or arrestin), anti-angiogenic antithrombin III, signal transduction inhibitor, cartilage-derived inhibitor (CDI), CD59 complement fragment, fibronectin fragment, glob beta, heparinase, heparin hexasaccharide fragment, human chorionic gonadotropin (hCG), interferon alpha / beta / gamma, interferon-inducible protein (IP-10), ... The inhibitors are selected from leukin-12, kringle 5 (plasminogen fragment), metalloproteinase inhibitor (TIMP), 2-methoxyestradiol, fetal ribonuclease inhibitor, plasminogen activator inhibitor, platelet factor-4 (PF4), prolactin 16kD fragment, proliferin-related protein (PRP), various retinoids, tetrahydrocortisol-S, thrombospondin-1 (TSP-1), transforming growth factor-β (TGF-β), vasculostatin, vasostatin (calreticulin fragment), and the like.

[0212] In certain embodiments, the other chemotherapeutic agent is abiraterone acetate, altretamine, hydrovinblastine, auristatin, bexarotene, bicalutamide, BMS184476, 2,3,4,5,6-pentafluoro-N-(3-fluoro-4-methoxyphenyl)benzenesulfonamide, bleomycin, N,N-dimethyl-L-valyl-L-valyl-N-methyl-L-valyl-L-prolyl-1-Lproline-t-butylamide, cachectin, cemadotin, chlorambucil, cyclophosphamide, 3',4'-didehydro-4'-deoxy-8'-norvincaleukoblastine, docetaxel, doxetaxel, cyclophosphamide, carboplatin, carmustine, cisplatin, cryptophycin, cyclophosphamide, cytarabine, dacarbazine (DTIC), dactylic acid, cyclo ... and selected from cyclophosphite, daunorubicin, decitabine, dolastatins, doxorubicin (adriamycin), etoposide, 5-fluorouracil, finasteride, flutamide, hydroxyurea and hydroxyurea taxanes, ifosfamide, liarozol, lonidamine, lomustine (CCNU), MDV3100, mechlorethamine (nitrogen mustard), melphalan, mivobuline isethionate, rhizoxin, sertenef, streptozocin, mitomycin, methotrexate, taxanes, nilutamide, onapristone, paclitaxel, prednimustine, procarbazine, RPR109881, stramstine phosphate, tamoxifen, tasonermin, taxol, tretinoin, vinblastine, vincristine, vindesine sulfate, and vinflunine.

[0213] In some embodiments, the other chemotherapeutic agent is platinum, cisplatin, carboplatin, oxaliplatin, mechlorethamine, cyclophosphamide, chlorambucil, azathioprine, mercaptopurine, vincristine, vinblastine, vinorelbine, vindesine, etoposide and teniposide, paclitaxel, docetaxel, irinotecan, topotecan, amsacrine, etoposide, etoposide phosphate, teniposide, 5-fluorouracil, leucovorin, methotrexate, gemcitabine, taxane, leucovorin, mitomycin C, tegafur-uracil, idarubicin, fludarabine, mitoxantrone, ifosfamide and doxorubicin.Additional drugs include but are not limited to mTOR inhibitors (mammalian target of rapamycin), such as deforolimus.

[0214] In yet another embodiment, the additional chemotherapeutic agent may be selected from those detailed in US Pat. No. 7,927,613.

[0215] In yet another embodiment, the method further comprises (i) one or more antifungal agents (e.g., bifonazole, butoconazole, clotrimazole, econazole, ketoconazole, luliconazole, miconazole, omoconazole, oxiconazole, sertaconazole, sulconazole, tioconazole, albaconazole, efinaconazole, epoxiconazole, fluconazole, isavuconazole, itraconazole, posaconazole, propiconazole, ravuconazole, terconazole, voriconazole, abafungin, amorolfine, bromide, bupropion ... tenafine, naftifine, terbinafine, anidulafungin, caspofungin, micafungin, benzoic acid, ciclopirox, flucytosine, 5-fluorocytosine, griseofulvin, haloprogin, tolnaftate, undecylenic acid, and balsam of Peru) and (ii) one or more antibiotics (e.g., amikacin, gentamicin, kanamycin, neomycin, netilmicin, tobramycin, paromomycin, streptomycin, spectinomycin, geldanamycin, herbimycin, rifaximin, Methylparaben, loracarbef, ertapenem, doripenem, imipenem, cilastatin, meropenem, cefadroxil, cefazolin, cephalothin, cephalosin, cephalexin, cefaclor, cefamandole, cefoxitin, cefprozil, cefuroxime, cefixime, cefdinir, cefditoren, cefoperazone, cefotaxime, cefpodoxime, ceftazidime, ceftibuten, ceftizoxime, ceftriaxone, cefepime, ceftaroline fosamil, ceftobiprole, teicoplanin, vancomycin, telavancin, dalbavancin , oritavancin, clindamycin, lincomycin, daptomycin, azithromycin, clarithromycin, dirithromycin, erythromycin, roxithromycin, troleandomycin, telithromycin, spiramycin, aztreonam, furazolidone, nitrofurantoin, linezolid, pocizolid, radezolid, torezolid, amoxicillin, ampicillin, azlocillin, carbenicillin, cloxacillin, dicloxacillin, flucloxacillin, mezlocillin, methicillin, nafcillin, oxacillin, penicillin G,Penicillin V, piperacillin, penicillin G, temocillin, ticarcillin, amoxicillin, carburate, ampicillin, sulbactam, piperacillin, tazobactam, ticarcillin, clavulanate, bacitracin, colistin, polymyxin B, ciprofloxacin, enoxacin, gatifloxacin, gemifloxacin, levofloxacin, lomefloxacin, moxifloxacin, nalidixic acid, norfloxacin, ofloxacin, trovafloxacin, grepafloxacin, sparfloxacin, temafloxacin, mafenide, sulfacetamide, sulfadiazine, silver sulfadiazine, sulfadimethoxine, sulfamethoxazole, sulfanilamide, sulfasalazine, The treatment may include administering one or both of the following: sulfisoxazole, trimethoprim-sulfamethoxazole, sulfonamide chrysoidine, demeclocycline, minocycline, oxytetracycline, tetracycline, clofazimine, dapsone, capreomycin, cycloserine, ethambutol, ethionamide, isoniazid, pyrazinamide, rifampicin, rifabutin, rifapentine, streptomycin, arsphenamine, chloramphenicol, fosfomycin, fusidic acid, metronidazole, mupirocin, platensimycin, quinupristin, dalfopristin, thiamphenicol, tigecycline, tinidazole, trimethoprim, and teixobactin.

[0216] In some embodiments, the second therapeutic agent or therapy is administered to the subject prior to contacting or administering (e.g., about 1 hour, or about 6 hours, or about 12 hours, or about 24 hours, or about 48 hours, or about 1 week, or about 1 month) the group of chemicals.

[0217] In other embodiments, the second therapeutic agent or therapy is administered to the subject at about the same time as the contacting or administration of the group of chemicals. For example, the second therapeutic agent or therapy and the group of chemicals are provided to the subject simultaneously in the same dosage form. For another example, the second therapeutic agent or therapy and the group of chemicals are provided to the subject simultaneously in separate dosage forms.

[0218] In yet another embodiment, the second therapeutic agent or therapy is administered to the subject after contacting or administering the group of chemicals (e.g., about 1 hour, or about 6 hours, or about 12 hours, or about 24 hours, or about 48 hours, or about 1 week, or about 1 month).

[0219] Patient selection In some embodiments, the methods described herein further comprise identifying a subject (e.g., a patient) in need of said treatment (e.g., by biopsy, endoscopy, or other conventional methods known to those skilled in the art). In some embodiments, NLRP3 protein can function as a biomarker for certain cancer types.

[0220] In some embodiments, the chemical entities, methods and compositions described herein can be administered to certain treatment-resistant patient populations (e.g., patients resistant to checkpoint inhibitors).

[0221] In certain embodiments, the compounds of the present invention can be used in therapy. In certain embodiments, the present invention provides a combined preparation of a compound of the present invention or a pharmaceutically acceptable salt thereof and another therapeutic agent(s) for simultaneous, separate, or sequential use in therapy.

[0222] In some embodiments, the compound of the present invention or its pharmaceutically acceptable salt, or the pharmaceutical composition comprising them, can be used as medicine.In certain embodiments, the compound of the present invention is used for the manufacture of medicine for cancer treatment.In some embodiments, the compound of the present invention can be used for the manufacture of medicine for regulating NLRP3 activity.In some embodiments, this regulation includes agonizing NLRP3.

[0223] Manufacturing method As will be appreciated by those skilled in the art, methods for synthesizing compounds of the formulae herein will be apparent to those skilled in the art. For example, the compounds described herein can be synthesized, for example, using one or more of the methods described herein and / or using methods described in US 2015 / 0056224, the contents of each of which are incorporated herein by reference in their entirety. Synthetic chemical transformations and protection methods (protection and deprotection) useful in synthesizing the compounds described herein are known in the art and include, for example, those described in R. Larock, Comprehensive Organic Transforms, VCH Publishers (1989); T.W. Greene and R.G.M. Wuts, Protective Groups in Organic Synthesis, 2d. Ed., John Wiley and Sons (1991); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995), and revised editions thereof. The starting materials used in preparing the compounds of the present application are well known and may be prepared by known methods or commercially available. Those skilled in the art will also recognize and may vary the conditions and reagents described herein with art-recognized alternatives. For example, in many reactions, triethylamine can be exchanged for other bases, such as non-nucleophilic bases (eg, diisopropylamine, 1,8-diazabicycloundec-7-ene, 2,6-di-tert-butylpyridine, or tetrabutylphosphazene).

[0224] Those skilled in the art will be familiar with the various analytical methods that may be used to characterize the compounds described herein, such as: 1H NMR, heteronuclear NMR, mass spectroscopy, liquid chromatography, and infrared spectroscopy are recognized and are not intended to be limiting, but are a partial list of characterization methods available to those skilled in the art.

[0225] The following abbreviations have the indicated meanings: [Table 1] TIFF0007660634000141.tif170153 [Example]

[0226] The compounds of the present invention can be prepared by many methods well known to those skilled in the art of organic synthesis. The compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of organic synthetic chemistry, or variations thereof as would be understood by those skilled in the art. Preferred methods include, but are not limited to, the methods described below.

[0227] The compounds of the invention can be prepared using the reactions and techniques described in this section (eg, Schemes 1-11).

[0228] Compound 10 can be prepared by the synthetic procedure outlined in Scheme 1. Indole 1 (where the Hal group is a halide such as bromide) can be converted to intermediate 2 using a reagent such as ethyl 2-chloro-2-oxoacetate. Intermediate 2 can be converted to intermediate 2 by the addition of an appropriately functionalized hydrazine (NH-NH-PG) in the presence of an acid such as acetic acid. 1 ) to give intermediate 3, which is then converted to intermediate 4 using a chlorinating reagent (e.g., POCl). Intermediate 4 can be converted to intermediate 4 using ammonia or an appropriately functionalized amine (NH-PG 2 ) to give intermediate 5. Deprotection of intermediate 5 can be achieved in several ways known to those skilled in the art. For example, 1 =PG2 When = PMB, intermediate d5 can be treated with a reagent such as TFA to give intermediate 6. Intermediate 6 and coupling reagent 7 can be coupled via a suitable catalytic reaction to give intermediate 8. For example, this step can be achieved by treating intermediate 6 with a suitable brominated ester, such as 3-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole, in the presence of a catalyst (e.g., Pd(dppf)Cl2). Alternatively, this step can be achieved by treating intermediate 6 with a suitable heterocycle, such as pyrazole, in the presence of a copper catalyst (e.g., copper(I) iodide) and a ligand (e.g., N,N'-dimethyl-ethylenediamine), to give intermediate 8. In the final step of Scheme 1, compound 10 can be prepared by reacting intermediate 8 with a suitably functionalized alkylating reagent (R 2 -X) where X is a leaving group such as a halide. 3 If R contains a protecting group, it may be removed at this stage under appropriate conditions. 3 When -M is 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole, the tetrahydropyran group can be removed by treatment with a reagent such as TFA.

[0229] [ka] Alternatively, intermediate 6 can be reacted with an alkylating agent (R 2 -X) to give compound 10a, which is then catalytically coupled to a suitable coupling partner: R 3 -M can be used to convert to compound 10.

[0230] [ka] An alternative synthesis of intermediate 8 can be achieved by a two-step procedure as shown in Scheme 3. In the first step, intermediate 5 (prepared as in Scheme 1) is reacted with a suitable coupling reagent (R 3 -M) to give intermediate 11, which can then be deprotected using an acid such as TFA to give intermediate 8. [ka] Analogs such as compounds 13a and 13b can be prepared according to the synthetic route illustrated in Scheme 4. Using appropriate conditions, the protecting group can be removed from 12 (prepared as per Scheme 1 or 2) to provide compound 13a. For example, when PG=Boc, this can be achieved by treatment with a reagent such as TFA. R 3 If R contains a protecting group, the protecting group may be removed in this step. 3If 13a contains a tetrahydropyran-protected pyrazole, the protecting group can be removed by treatment with a reagent such as TFA. Compound 13a can then be converted to the desired final product by treatment with an appropriate reagent. For example, 13a can be converted to an amide by treatment with an appropriately substituted carboxylic acid in the presence of a suitable coupling reagent (e.g., HATU) and a base (e.g., N,N-diisopropylethylamine). Alternatively, compound 13a can be converted to an isoindolinone by treatment with a reagent such as methyl 2-(bromomethyl)benzoate or an appropriately substituted analog thereof in the presence of a base (e.g., N,N-diisopropylethylamine). Alternatively, compound 13a can be alkylated by treatment with an appropriately substituted aldehyde or ketone in the presence of a suitable reducing agent (e.g., sodium triacetoxyborohydride). Alternatively, compound 13a can be converted to a sulfonamide by treatment with an appropriately substituted sulfonyl chloride in the presence of a base (e.g., triethylamine). Alternatively, compound 13a can be converted to a urea by treatment with an appropriately substituted isocyanate or carbamoyl chloride in the presence of a base (e.g., triethylamine). Alternatively, compound 13a can be converted to a carbamate by treatment with an appropriately substituted chloroformate in the presence of a base (e.g., triethylamine). [ka] Analogs such as compounds 15a and 15b can be prepared according to the synthetic route illustrated in Scheme 5. Using appropriate conditions, the protecting group can be removed from intermediate 14 (prepared as per Scheme 1 or 2) to give compound 15a. For example, when PG=TBS, this can be achieved by treatment with a reagent such as TBAF. Compound 15a can then be converted to compound 15b by treatment with an appropriate reagent. For example, compound 15a can be converted to an aryl or heteroaryl ether by treatment with an appropriately substituted phenol in the presence of a suitable reagent, such as DIAD and triphenylphosphine. In the final step, R 3 If R contains a protecting group, it can be removed using appropriate conditions. For example, 3 If X contains a tetrahydropyran protected pyrazole, this group can be removed by treatment with a reagent such as TFA.

[0231] [ka] Compound 22 can be prepared by the synthetic procedure outlined in Scheme 6. Intermediate 17 can be prepared by treating quinoline 16 with a suitable halogenating reagent (e.g., iodine) in the presence of a base, such as sodium hydroxide. Intermediate 17 can then be coupled with a suitably substituted alkyne 18 under the influence of a suitable catalyst, such as Pd(Ph3)4, to give cyclized product 19. Furthermore, compound 21 can be achieved in a two-step procedure by first treating intermediate 19 with a suitable oxidizing agent (e.g., m-CPBA) to give oxide 20, which can then be converted to compound 21 using a reagent (e.g., tosyl chloride) and an amine (e.g., ammonia). Subsequent catalytic cross-coupling of compound 21 with a suitable coupling partner can then give compound 22.

[0232] [ka] Analogs such as compound 29 can be prepared according to the synthetic route illustrated in Scheme 7. In Scheme 7, intermediate 25 can be obtained by amide bond formation between intermediate 23 and acid 24 in the presence of a suitable coupling reagent (e.g., HATU). Intermediate 25 can undergo a cyclization reaction in the presence of a suitable reagent, such as C2Cl6 and PPh3, to obtain intermediate 26. Further, intermediate 26 can be treated with a suitable oxidizing agent, such as m-CPBA, to obtain oxide 27, which can be converted to compound 28 in a two-step procedure using a reagent (e.g., tosyl chloride) and an amine (e.g., ammonia). Compound 29 can be obtained after a catalytic cross-coupling reaction of compound 28 with a suitable coupling partner.

[0233] [ka] Analogs such as compound 33 can be prepared according to the synthetic route illustrated in Scheme 8. In Scheme 8, intermediate 25 (prepared as shown in Scheme 7) can be converted to intermediate 30 using an appropriate reagent, such as Lawesson's reagent, in the presence of a base (e.g., pyridine). Furthermore, compound 33 can be obtained in a two-step procedure by first treating compound 30 with an appropriate oxidizing agent, such as m-CPBA, to give oxide 31, which can be converted to compound 32 using a reagent (e.g., tosyl chloride) and an amine (e.g., ammonia). Compound 33 can be obtained after a catalytic cross-coupling reaction of compound 32 with an appropriate coupling partner.

[0234] [ka] Analogs such as compound 40 can be prepared according to the synthetic route illustrated in Scheme 9. In Scheme 9, compound 34 (prepared according to WO2013 / 045400) can be protected with a suitable protecting group (e.g., PMB) to give intermediate 35. Intermediate 35 can then be converted to intermediate 36 using a chlorinating reagent (e.g., POCl). Ammonia or an appropriately functionalized amine (NH-PG 2 ) to intermediate 36 to give intermediate 37. Deprotection of intermediate 37 can be achieved in several ways known to those skilled in the art. For example, PG 1 =PG 2 When = PMB, compound 5 can be treated with a reagent such as TFA to give intermediate 38. Intermediate 38 can be reacted with an appropriately functionalized alkylating reagent (R 2 Compound 39 can be prepared by treatment with a suitable catalyzed coupling reagent with R 3 If R contains a protecting group, it may be removed at this stage using appropriate conditions. 3 If -M is 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole, the tetrahydropyran group can be removed by treatment with a reagent such as TFA.

[0235] [ka] [ka]

[0236] Compound 52 can be prepared by the synthetic procedure outlined in Scheme 10. In Scheme 10, quinoline 41 (wherein Hal 1 The R group is a halide such as bromide) is reacted with a substituted amine 42 (wherein R 1bis H), a protecting group (e.g., PMB or R 1a ) to give compound 43. Treatment of compound 43 with an iodination reagent (e.g., NIS) gives compound 44, which can be coupled with an appropriately substituted alkyne 45 under the action of a suitable catalyst (e.g., Pd(Ph3)2Cl2 and CuI) to give compound 46. Cyclization of compound 46 can be achieved under the action of a base (e.g., NaOH) to give compound 47. Conversion to compound 48 can be achieved by treating compound 47 with a suitable oxidizing agent, such as m-CPBA. Treatment of compound 48 with a reagent (e.g., tosyl chloride) and an amine (e.g., ammonia) gives compound 49. Coupling of compound 49 with a coupling reagent 50 under the action of a suitable catalyst gives compound 51. For example, this step can be achieved by treating compound 49 with an appropriate boronated ester, such as 3-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole, in the presence of a catalyst (e.g., Pd(dppf)Cl) to give compound 51. Alternatively, this step can be achieved by treating compound 49 with an appropriate heterocycle (e.g., pyrazole) in the presence of a copper catalyst (e.g., copper(I) iodide) and a ligand (e.g., N,N'-dimethyl-ethylenediamine) to give compound 51. In the final step of Scheme 10, compound 52 can be prepared by deprotecting compound 51 with a suitable reagent, such as TFA.

[0237] [ka] Compound 61 can be prepared by the synthetic procedure outlined in Scheme 11. In Scheme 11, quinoline 53 (wherein Hal) can be prepared by the synthesis of quinoline 53 using an appropriately substituted hydrazine such as (4-methoxybenzyl)hydrazine. 1The group is a halide, such as chloride, to give compound 54. Treatment of compound 54 with a suitable reagent, such as PCl3, in a suitable solvent, such as toluene, gives compound 55. Conversion to compound 56 can be achieved by treating compound 55 with a suitable oxidizing agent, such as MTO. Compound 56 can then be further converted to compound 57 using a suitable reagent, such as POCl3. Treatment of compound 57 with an amine, such as ammonia, gives compound 58. Deprotection of compound 58 can be achieved by the action of an acid, such as TFA, to give compound 59. Coupling of compound 59 with a suitable coupling reagent under the influence of a suitable catalyst can give compound 60. For example, this step can be achieved by treating compound 59 with a suitable boronic acid ester, such as 3-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole in the presence of a catalyst, such as Pd(dppf)Cl2, to give compound 60. Compound 61 can be prepared by reacting compound 60 with an appropriately functionalized alkylating reagent (R 2 -X), where X is a leaving group such as a halide. 2 or R 3 If R contains a protecting group, the protecting group may be removed at this stage using appropriate conditions. 3 When -M is 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole, the tetrahydropyran group can be removed by treatment with a reagent such as TFA.

[0238] To further illustrate the foregoing, the following non-limiting exemplary synthetic schemes are included. Variations of these examples in the claims are within the understanding of one of ordinary skill in the art and are considered to be within the scope of the invention described herein. Given this disclosure, one skilled in the art and those skilled in the art will recognize that they can make and use the compounds of the present invention even without all of the examples.

[0239] Example 1. Preparation of 3-[4-amino-7-(1H-pyrazol-3-yl)-2H-pyrazolo[3,4-c]quinolin-2-yl]propan-1-ol [ka] Step 1. Ethyl 2-(6-bromo-1H-indol-3-yl)-2-oxoacetate In a 150 mL round-bottom flask was placed 6-bromo-1H-indole (1.15 g, 5.89 mmol, 1.00 equiv) in EtO (30 mL). Ethyl 2-chloro-2-oxoacetate (922 mg, 6.78 mmol, 1.15 equiv) and pyridine (3 mL) were then added. The resulting solution was stirred at room temperature overnight. The reaction solution was then quenched by the addition of water. The resulting solution was extracted with ethyl acetate, and the organic layers were combined and concentrated in vacuo. The residue was purified on a silica gel column eluted with ethyl acetate / petroleum ether (1:3) to give ethyl 2-(6-bromo-1H-indol-3-yl)-2-oxoacetate (900 mg, 60%) as a solid. LC-MS m / z 296.1 [M+H] + .

[0240] Step 2. 7-Bromo-2-[(4-methoxyphenyl)methyl]-2H,4H,5H-pyrazolo[3,4-c]quinolin-4-one A solution of ethyl 2-(6-bromo-1H-indol-3-yl)-2-oxoacetate (1.7 g, 5.74 mmol, 1.00 equiv.) and [(4-methoxyphenyl)methyl]hydrazine (1.007 g, 6.62 mmol, 1.15 equiv.) in ethanol (25 mL) and acetic acid (3 mL) was placed in a 250 mL round-bottom flask. The resulting solution was stirred at 80 °C overnight. The reaction solution was then quenched by the addition of water. The resulting solution was extracted with ethyl acetate, and the organic layers were combined. The solution was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified on a silica gel column using ethyl acetate / petroleum ether (4:1) to give 7-bromo-2-[(4-methoxyphenyl)methyl]-2H,4H,5H-pyrazolo[3,4-c]quinolin-4-one (1.5 g, 68%) as a solid. LC-MS m / z 384.1[M+H] + .

[0241] Step 3. 7-Bromo-4-chloro-2-[(4-methoxyphenyl)methyl]-2H-pyrazolo[3,4-c]quinoline A 250 mL round-bottom flask was charged with a solution of 7-bromo-2-[(4-methoxyphenyl)methyl]-2H,4H,5H-pyrazolo[3,4-c]quinolin-4-one (1.3 g, 3.38 mmol, 1.00 equiv) in dichloromethane (10 mL). To the solution was added DMF (0.5 mL) and POCl (1.031 g, 6.72 mmol, 2.00 equiv). The resulting solution was stirred at 25 °C for 6 hours. The reaction solution was then quenched by the addition of aqueous KHPO. The resulting solution was extracted with dichloromethane, and the combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to give 7-bromo-4-chloro-2-[(4-methoxyphenyl)methyl]-2H-pyrazolo[3,4-c]quinoline (1.17 g, 86%) as an off-white solid. LC-MS m / z 402.3[M+H] + .

[0242] Step 4. 7-Bromo-2-[(4-methoxyphenyl)methyl]-2H,6H,7H-pyrazolo[3,4-c]quinolin-4-amine A solution of 7-bromo-4-chloro-2-[(4-methoxyphenyl)methyl]-2H-pyrazolo[3,4-c]quinoline (180 mg, 0.45 mmol, 1.00 equiv) and ammonia (3 mL, 5.00 equiv) in dioxane (3 mL) was placed in a 50 mL sealed tube. The resulting solution was stirred at 80 °C overnight. The reaction solution was then quenched by the addition of water, and the resulting solution was extracted with dichloromethane:CHOH (5:1). The organic layers were combined and concentrated in vacuo. The residue was purified on a silica gel column using dichloromethane / methanol (10:1) to give 7-bromo-2-[(4-methoxyphenyl)methyl]-2H,6H,7H-pyrazolo[3,4-c]quinolin-4-amine (140 mg, 81%) as a solid. LC-MS m / z 383.2 [M+H] + .

[0243] Step 5. 7-Bromo-2H-pyrazolo[3,4-c]quinolin-4-amine A solution of 7-bromo-2-[(4-methoxyphenyl)methyl]-2H,6H,7H-pyrazolo[3,4-c]quinolin-4-amine (400 mg, 1.04 mmol, 1.00 equiv) in trifluoroacetic acid (5 mL) was placed in a 30 mL sealed tube. The resulting solution was stirred at 80° C. overnight. The resulting mixture was concentrated in vacuo. The residue was purified on a silica gel column using dichloromethane / methanol (12:1) to give 7-bromo-2H-pyrazolo[3,4-c]quinolin-4-amine (250 mg, 92%) as an off-white solid. LC-MS m / z 263.1 [M+H] + .

[0244] Step 6. 2-[3-(benzyloxy)propyl]-7-bromo-2H-pyrazolo[3,4-c]quinolin-4-amine A solution of 7-bromo-2H-pyrazolo[3,4-c]quinolin-4-amine (688 mg, 2.62 mmol, 1.00 equiv) in DMF (8 mL) was placed in a 100 mL sealed tube. To the solution, CsCO (1.029 g, 3.16 mmol, 1.20 equiv) and [(3-bromopropoxy)methyl]benzene (624.24 mg, 2.72 mmol, 1.10 equiv) were added. The resulting solution was stirred overnight at 25 °C. The reaction solution was then quenched by the addition of water, and the resulting solution was extracted with dichloromethane:CHOH (5:1). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified on a silica gel column with dichloromethane / methanol (20:1) to give 2-[3-(benzyloxy)propyl]-7-bromo-2H-pyrazolo[3,4-c]quinolin-4-amine (500 mg, 46%) as a dark red solid. LC-MS m / z 411.3 [M+H] + .

[0245] Step 7. 2-[3-(benzyloxy)propyl]-7-(1H-pyrazol-3-yl)-[1,3]oxazole[5,4-c]quinolin-4-amine A solution of 2-[3-(benzyloxy)propyl]-7-bromo-[1,3]oxazole[5,4-c]quinolin-4-amine (500 mg, 1.21 mmol, 1.00 equiv.), 3-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (472 mg, 2.43 mmol, 2.00 equiv.), and CsCO (1.193 mg, 3.00 equiv.) in dioxane / water (10:1, 11 mL) was placed in a 50 mL sealed tube. Pd(dppf)Cl DCM (199.3 mg, 0.20 equiv.) was added to the solution under nitrogen. The resulting solution was stirred at 100 °C overnight. The reaction solution was then quenched by the addition of water. The resulting solution was extracted with dichloromethane:CHOH (5:1), and the organic layers were combined. The solution was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified on a silica gel column with dichloromethane / methanol (15:1) to give 2-[3-(benzyloxy)propyl]-7-(1H-pyrazol-3-yl)-[1,3]oxazole[5,4-c]quinolin-4-amine (300 mg, 62%) as a solid. LC-MS m / z 399.2 [M+H] + .

[0246] Step 8. 3-[4-amino-7-(1H-pyrazol-3-yl)-2H-pyrazolo[3,4-c]quinolin-2-yl]propan-1-ol A solution of 2-[3-(benzyloxy)propyl]-7-(1H-pyrazol-3-yl)-2H-pyrazolo[3,4-c]quinolin-4-amine (100 mg, 0.25 mmol, 1.00 equiv.) in trifluoroacetic acid (5 mL) was placed in a 50 mL sealed tube. The resulting solution was stirred overnight at 70 °C. The reaction solution was then quenched by the addition of water. The resulting mixture was concentrated in vacuo. The crude product was purified by Prep-HPLC using the following conditions: column, XBridge Shield RP18 OBD column, 19 x 250 mm, 10 μm; mobile phase, water (10 mM NH4HCO3) and ACN (20.0% ACN to 55.0% within 9 minutes); detector, UV 254 / 210 nm. This gave 3-[4-amino-7-(1H-pyrazol-3-yl)-2H-pyrazolo[3,4-c]quinolin-2-yl]propan-1-ol (11.6 mg, 15%) as a white solid. 1 H NMR (400 MHz, CD3OD-d4) δ 8.55 (s, 1H), 7.97-7.92 (m, 2H), 7.68 (br s, 2H), 6.72 (s, 1H), 4.60 (t, J = 6.8 Hz, 2H), 3.60 (t, J = 6.4 Hz, 2H), 2.26-2.21 (m, 2H). LC-MS m / z 309.1 [M+H] + .

[0247] Example 2. Preparation of 2-(3-phenoxypropyl)-7-(1H-pyrazol-3-yl)-2H-pyrazolo[3,4-c]quinolin-4-amine [ka] Step 1. 7-Bromo-2-(3-phenoxypropyl)-2H-pyrazolo[3,4-c]quinolin-4-amine To a solution of 7-bromo-2H-pyrazolo[3,4-c]quinolin-4-amine (16.9 mg, 0.064 mmol) in DMF (214 μL) at room temperature, cesium carbonate (25.1 mg, 0.077 mmol) was added, followed by (3-bromopropoxy)benzene (15.2 mg, 0.071 mmol). The reaction solution was stirred at room temperature for 3 hours. The reaction solution was diluted with EtOAc (20 mL), washed with HO (20 mL) and saturated aqueous NaCl (20 mL), dried over NaSO, filtered, and concentrated in vacuo. The crude material was purified by flash chromatography (12 g silica gel; linear gradient 0-10% MeOH-CH2Cl2) to give 7-bromo-2-(3-phenoxypropyl)-2H-pyrazolo[3,4-c]quinolin-4-amine (17.1 mg, 67%). LC-MS m / z 397 / 399 [M+H] + .

[0248] Step 2. 2-(3-phenoxypropyl)-7-(1H-pyrazol-3-yl)-2H-pyrazolo[3,4-c]quinolin-4-amine A solution of 7-bromo-2-(3-phenoxypropyl)-2H-pyrazolo[3,4-c]quinolin-4-amine (17.1 mg, 0.043 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (16.7 mg, 0.086 mmol), and cesium carbonate (42.1 mg, 0.129 mmol) in a mixture of dioxane (387 μL) and HO (43.0 μL) was sparged with N for 5 minutes, and then [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (6.3 mg, 8.6 μmol) was added. The reaction mixture was sealed and stirred at 100 °C for 21 hours. The reaction solution was cooled to room temperature, diluted with EtOAc (20 mL), washed with HO (20 mL) and saturated aqueous NaCl (20 mL), dried over NaSO, filtered, and concentrated in vacuo. The crude material was dissolved in DMF (2 mL), filtered (syringe filter), and purified by preparative LC / MS using the following conditions: Column: XBridge C18, 200 mm x 19 mm, 5 μm particles; Mobile Phase A: 5:95 acetonitrile:water (with 10 mM ammonium acetate); Mobile Phase B: 95:5 acetonitrile:water (with 10 mM ammonium acetate); Gradient: 16% B hold for 0 min, 16–56% B over 20 min, then 100% B hold for 4 min; Flow Rate: 20 mL / min; Column Temperature: 25 °C. Fraction collection was initiated by MS signal. Fractions containing the desired product were combined and dried by centrifugal evaporation to give 2-(3-phenoxypropyl)-7-(1H-pyrazol-3-yl)-2H-pyrazolo[3,4-c]quinolin-4-amine (3.6 mg, 22%). 1H NMR (500 MHz, DMSO-d6) δ 8.71 - 8.66 (m, 1H), 7.92 - 7.88 (m, 2H), 7.66 (s, 1H), 7.61 (dd, J=8.0, 1.5 Hz, 1H), 7.29 - 7.23 (m, 2H), 6.94 - 6.90 (m, 3H), 6.70 (d, J=2.1 Hz, 1H), 6.66 - 6.42 (m, 2H), 4.62 (t, J=7.0 Hz, 2H), 4.06 - 4.02 (m, 2H), 2.41 (quin, J=6.4 Hz, 2H). Analytical LC / MS conditions: Column: Waters XBridge C18, 2.1 mm x 50 mm, 1.7 μm particles; Mobile phase A: 5:95 acetonitrile:water (with 0.1% trifluoroacetic acid); Mobile phase B: 95:5 acetonitrile:water (with 0.1% trifluoroacetic acid); Temperature: 50 °C; Gradient: 0% B to 100% B over 3 min, then hold at 100% B for 0.75 min; Flow rate: 1 mL / min; Detection: MS and UV (220 nm). m / z 385.3 [M+H] + ;RT:1.39 minutes.

[0249] Examples 3 and 4. Preparation of 7-(1H-pyrazol-3-yl)-2-[3-(pyridin-2-yloxy)propyl]-2H-pyrazolo[3,4-c]quinolin-4-amine and 1-{3-[4-amino-7-(1H-pyrazol-3-yl)-2H-pyrazolo[3,4-c]quinolin-2-yl]propyl}-1,2-dihydropyridin-2-one [ka] Step 1. 7-Bromo-2-(3-((tert-butyldimethylsilyl)oxy)propyl)-2H-pyrazolo[3,4-c]quinolin-4-amine To a room temperature solution of 7-bromo-2H-pyrazolo[3,4-c]quinolin-4-amine, TFA (240 mg, 0.636 mmol) in DMF (2121 μL) was added cesium carbonate (622 mg, 1.91 mmol), followed by (3-bromopropoxy)(tert-butyl)dimethylsilane (162 μL, 0.700 mmol). The suspension was stirred at room temperature for 16 hours. The reaction solution was diluted with EtOAc (50 mL) and HO (50 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (50 mL). The combined organic layers were washed with saturated aqueous NaCl (50 mL), dried over NaSO, filtered, and concentrated in vacuo. The crude material was purified by flash chromatography (24 g silica gel; linear gradient 0 to 10% MeOH—CH2Cl2) to give 7-bromo-2-(3-((tert-butyldimethylsilyl)oxy)propyl)-2H-pyrazolo[3,4-c]quinolin-4-amine (214 mg, 77%) as a white solid, contaminated with ∼5% of the regioisomeric product. 1 H NMR (400 MHz, DMSO-d6) δ 8.73 (s, 1H), 7.85 (d, J=8.4 Hz, 1H), 7.58 (d, J=2.0 Hz, 1H), 7.31 (dd, J=8.4, 2.0 Hz, 1H), 6.96 (br s, 2H), 4.49 (t, J=7.1 Hz, 2H), 3.63 (t, J=6.0 Hz, 2H), 2.14 (quin, J=6.6 Hz, 2H), 0.86 (s, 9H), 0.02 (s, 6H);LC-MS m / z 435 [M+H] + .

[0250] Step 2. 2-(3-((tert-butyldimethylsilyl)oxy)propyl)-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-2H-pyrazolo[3,4-c]quinolin-4-amine A mixture of 7-bromo-2-(3-((tert-butyldimethylsilyl)oxy)propyl)-2H-pyrazolo[3,4-c]quinolin-4-amine (214 mg, 0.491 mmol), 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (205 mg, 0.737 mmol) and cesium carbonate (480 mg, 1.474 mmol) was evacuated and backfilled with N, then 1,4-dioxane (4423 μL) and HO (491 μL) were added. The resulting mixture was sparged with N for 10 minutes, then [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (17.98 mg, 0.025 mmol) was added. The mixture was sparged with N for 1 minute, then it was sealed and stirred at 100 °C for 30 minutes. The reaction solution was cooled to room temperature, diluted with EtOAc (50 mL), washed with HO (50 mL) and saturated aqueous NaCl (50 mL), dried over NaSO, filtered, and concentrated in vacuo. The crude material was purified by flash chromatography (12 g silica gel; linear gradient 0 to 10% MeOH—CH2Cl2) to afford 2-(3-((tert-butyldimethylsilyl)oxy)propyl)-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-2H-pyrazolo[3,4-c]quinolin-4-amine (242 mg, 97%) as a brown foam. 1H NMR (400 MHz, DMSO-d6) δ 8.76 (s, 1H), 8.01 (d, J=8.0 Hz, 1H), 7.62 (d, J=1.7 Hz, 1H), 7.58 (d, J=1.7 Hz, 1H), 7.32 (dd, J=8.0, 1.7 Hz, 1H), 6.86 (br s, 2H), 6.48 (d, J=1.7 Hz, 1H), 5.30 (dd, J=9.9, 2.0 Hz, 1H), 4.51 (t, J=7.1 Hz, 2H), 4.09 - 4.00 (m, 1H), 3.64 (t, J=6.0Hz, 2H), 3.62 - 3.53 (m, 1H), 2.48 - 2.37 (m, 1H), 2.21 - 2.12 (m, 2H), 2.00 - 1.90 (m, 1H), 1.79 (br d, J=12.5 Hz, 1H), 1.63 - 1.48 (m, 3H), 0.88 (s, 9H), 0.06 - 0.01 (m, 6H);LC-MS m / z 507 [M+H] + .

[0251] Step 3. 3-(4-amino-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-2H-pyrazolo[3,4-c]quinolin-2-yl)propan-1-ol To a solution of 2-(3-((tert-butyldimethylsilyl)oxy)propyl)-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-2H-pyrazolo[3,4-c]quinolin-4-amine (182 mg, 0.359 mmol) in THF (1796 μL) at room temperature was added tetrabutylammonium fluoride (1 M solution in THF) (431 μL, 0.431 mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo. The crude material was purified by flash chromatography (24 g silica gel; linear gradient 0-100% EtOAc-CH2Cl2, then 0-10% MeOH-CH2Cl2) to give 3-(4-amino-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-2H-pyrazolo[3,4-c]quinolin-2-yl)propan-1-ol (128 mg, 91%). 1 H NMR (400 MHz, DMSO-d6) δ 8.78 (s, 1H), 8.01 (d, J=8.0 Hz, 1H), 7.62 (d, J=1.6 Hz, 1H), 7.58 (d, J=1.7 Hz, 1H), 7.32 (dd, J=8.0, 1.8 Hz, 1H), 6.90 (br s, 2H), 6.48 (d, J=1.8 Hz, 1H), 5.30 (dd, J=10.0, 2.0 Hz, 1H), 4.69 (t, J=5.0 Hz, 1H), 4.52 (t, J=7.1 Hz, 2H), 4.07 - 4.00 (m, 1H), 3.62 - 3.54 (m, 1H), 3.45 (q, J=6.0 Hz, 2H), 2.47 - 2.37 (m, 1H), 2.10 (quin, J=6.6 Hz, 2H), 1.94 (br s, 1H), 1.79 (br d, J=12.6 Hz, 1H), 1.64 - 1.47 (m, 3H);LC-MS m / z 393[M+H] + .

[0252] Step 4. 7-(1H-pyrazol-3-yl)-2-[3-(pyridin-2-yloxy)propyl]-2H-pyrazolo[3,4-c]quinolin-4-amine and 1-{3-[4-amino-7-(1H-pyrazol-3-yl)-2H-pyrazolo[3,4-c]quinolin-2-yl]propyl}-1,2-dihydropyridin-2-one To a solution of 3-(4-amino-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-2H-pyrazolo[3,4-c]quinolin-2-yl)propan-1-ol (40 mg, 0.102 mmol), pyridin-2(1H)-one (10.7 mg, 0.112 mmol) and triphenylphosphine (32.1 mg, 0.122 mmol) in THF (1019 μL) at 0° C. was added diisopropyl azodicarboxylate (24.1 μL, 0.122 mmol) dropwise. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo.

[0253] The crude material was dissolved in CHCl (250 μL) and TFA (250 μL) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under vacuum. The crude material was transferred to CHCl and concentrated again. The crude material was dissolved in DMF (2 mL), filtered (syringe filter), and purified by preparative LC / MS using the following conditions: Column: XBridge C18, 200 mm x 19 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water (with 0.1% trifluoroacetic acid); Mobile phase B: 95:5 acetonitrile:water (with 0.1% trifluoroacetic acid); Gradient: 3% B hold for 0 min, 3–43% B over 20 min, then 100% B hold for 4 min; Flow rate: 20 mL / min; Column temperature: 25°C. Fraction collection was triggered by MS signal. Fractions containing the desired product were combined and dried by centrifugal evaporation to give 7-(1H-pyrazol-3-yl)-2-(3-(pyridin-2-yloxy)propyl)-2H-pyrazolo[3,4-c]quinolin-4-amine, TFA (28.5 mg, 56%) and 1-(3-(4-amino-7-(1H-pyrazol-3-yl)-2H-pyrazolo[3,4-c]quinolin-2-yl)propyl)pyridin-2(1H)-one, TFA (11.6 mg, 23%).

[0254] Characterization data for 7-(1H-pyrazol-3-yl)-2-(3-(pyridin-2-yloxy)propyl)-2H-pyrazolo[3,4-c]quinolin-4-amine, TFA: 1H NMR (500 MHz, DMSO-d6) δ 9.03 (s, 1H), 8.86 (s, 1H), 8.15 - 8.07 (m, 2H), 7.90 (br d, J=7.7 Hz, 1H), 7.87 - 7.78 (m, 1H), 7.72 - 7.65 (m, 1H), 6.99 - 6.92 (m, 1H), 6.79 (s, 1H), 6.75 (d, J=8.3 Hz, 1H), 4.70 (t, J=6.7 Hz, 2H), 4.33 (t, J=6.1 Hz, 2H), 2.49 - 2.42 (m, 2H). Analytical LC / MS conditions: Column: Waters XBridge C18, 2.1 mm x 50 mm, 1.7 μm particles; Mobile phase A: 5:95 acetonitrile:water (with 0.1% trifluoroacetic acid); Mobile phase B: 95:5 acetonitrile:water (with 0.1% trifluoroacetic acid); Temperature: 50°C; Gradient: 0% B to 100% B over 3 min, then hold at 100% B for 0.75 min; Flow rate: 1 mL / min; Detection: MS and UV (220 nm). m / z 386.3 [M+H] + ;RT:1.18 minutes. Characterization data for 1-(3-(4-amino-7-(1H-pyrazol-3-yl)-2H-pyrazolo[3,4-c]quinolin-2-yl)propyl)pyridin-2(1H)-one, TFA: 0.78 (br s, 1H), 6.39 (d, J=9.1 Hz, 1H), 6.24 (t, J=6.2 Hz, 1H), 4.55 (br t, J=6.9 Hz, 2H), 4.01 (br t, J=6.9 Hz, 2H), 2.40 - 2.32 (m, 2H). Analytical LC / MS conditions: Column: Waters XBridge C18, 2.1 mm x 50 mm, 1.7 μm particles; Mobile phase A: 5:95 Acetonitrile:water (with 0.1% trifluoroacetic acid); Mobile phase B: 95:5 acetonitrile:water (with 0.1% trifluoroacetic acid); Temperature: 50°C; Gradient: 0% B to 100% B over 3 min, then hold at 100% B for 0.75 min; Flow rate: 1 mL / min; Detection: MS and UV (220 nm). m / z 386.3 [M+H] + ;RT1.03 min.

[0255] Examples 5-9 were prepared from the appropriate starting materials following synthetic methods similar to those described in Example 3. Analytical LC / MS conditions: Column: Waters XBridge C18, 2.1 mm x 50 mm, 1.7 μm particles; Mobile phase A: 5:95 acetonitrile:water (with 0.1% trifluoroacetic acid); Mobile phase B: 95:5 acetonitrile:water (with 0.1% trifluoroacetic acid); Temperature: 50°C; Gradient: 0% B to 100% B over 3 minutes, then hold at 100% B for 0.75 minutes; Flow rate: 1 mL / min; Detection: MS and UV (220 nm).

[0256] [Table 2]

[0257] Example 10. Preparation of 2-(2-ethoxyethyl)-7-(1H-pyrazol-1-yl)-2H-pyrazolo[3,4-c]quinolin-4-amine [ka] Step 1. 7-Bromo-N,2-bis(4-methoxybenzyl)-2H-pyrazolo[3,4-c]quinolin-4-amine To a room temperature solution of 7-bromo-4-chloro-2-(4-methoxybenzyl)-2H-pyrazolo[3,4-c]quinoline (2.428 g, 6.03 mmol) in DMSO (20.10 mL) was added (4-methoxyphenyl)methanamine (1.576 mL, 12.06 mmol) followed by N,N-diisopropylethylamine (3.15 mL, 18.09 mmol). The reaction was stirred at 70 °C for 18 hours. The reaction was cooled to room temperature, diluted with EtOAc (500 mL), washed with HO (2 × 250 mL) and saturated aqueous NaCl (250 mL), dried over NaSO, filtered, and concentrated in vacuo to give a brown oil. The crude material was purified by flash chromatography (40 g silica gel; linear gradient 0 to 100% EtOAc-hexanes) to afford 7-bromo-N,2-bis(4-methoxybenzyl)-2H-pyrazolo[3,4-c]quinolin-4-amine (2.880 g, 95%) as a white foam. 1 H NMR (400 MHz, DMSO-d6) δ 8.79 (s, 1H), 7.96 (t, J=6.2 Hz, 1H), 7.85 (d, J=8.3 Hz, 1H), 7.63 (d, J=2.0 Hz, 1H), 7.37 (d, J=8.7 Hz, 2H), 7.32 - 7.27 (m, 3H), 6.95 - 6.90 (m, 2H), 6.87 - 6.82 (m, 2H), 5.58 (s, 2H), 4.66 (d, J=6.0 Hz, 2H), 3.72 (s, 3H), 3.69 (s, 3H); LC-MS m / z 503 / 505 [M+H] + .

[0258] Step 2. N,2-bis(4-methoxybenzyl)-7-(1H-pyrazol-1-yl)-2H-pyrazolo[3,4-c]quinolin-4-amine To a solution of pyrazole (97 mg, 1.43 mmol), 7-bromo-N,2-bis(4-methoxybenzyl)-2H-pyrazolo[3,4-c]quinolin-4-amine (600 mg, 1.19 mmol), copper(I) iodide (11.35 mg, 0.060 mmol), and (1S,2S)-N,N-dimethylcyclohexane-1,2-diamine (33.9 mg, 0.238 mmol) in toluene (2.5 mL) was added potassium carbonate (362 mg, 2.62 mmol). The reaction solution was purged with N and stirred at 120 °C for 24 h. The reaction solution was then cooled to room temperature, diluted with EtOAc, and filtered through a Celite pad. The filtrate was concentrated and purified by flash chromatography (40 g silica gel; linear gradient 0 to 100% EtOAc-hexanes) to give N,2-bis(4-methoxybenzyl)-7-(1H-pyrazol-1-yl)-2H-pyrazolo[3,4-c]quinolin-4-amine (495 mg, 85%). LC-MS m / z 491.4 [M+H] + .

[0259] Step 3. 7-(1H-pyrazol-1-yl)-2H-pyrazolo[3,4-c]quinolin-4-amine To a solution of N,2-bis(4-methoxybenzyl)-7-(1H-pyrazol-1-yl)-2H-pyrazolo[3,4-c]quinolin-4-amine (501 mg, 1.02 mmol) in TFA (3934 μL, 51.1 mmol) was added anisole (1116 μL, 10.2 mmol). The reaction mixture was stirred at 80° C. overnight. The reaction mixture was cooled to room temperature and concentrated in vacuo. The crude material was triturated with EtO and then filtered to give 7-(1H-pyrazol-1-yl)-2H-pyrazolo[3,4-c]quinolin-4-amine, TFA salt (350 mg, 94%). 1H NMR (400 MHz, methanol-d4) δ 8.81 (s, 1H), 8.39 (d, J=2.3 Hz, 1H), 8.26 (d, J=8.6 Hz, 1H), 8.11 (d, J=1.9 Hz, 1H), 7.92 (dd, J=8.6, 1.9 Hz, 1H), 7.83 (d, J=1.2 Hz, 1H), 6.63 (d, J=1.8 Hz, 1H); LC-MS m / z 251.1 [M+H] + .

[0260] Step 4. 2-(2-ethoxyethyl)-7-(1H-pyrazol-1-yl)-2H-pyrazolo[3,4-c]quinolin-4-amine A solution of 1-bromo-2-ethoxyethane (9.17 mg, 0.060 mmol) and 7-(1H-pyrazol-1-yl)-2H-pyrazolo[3,4-c]quinolin-4-amine (15 mg, 0.060 mmol) in DMF (0.3 mL) gave CsCO (78 mg, 0.240 mmol). The reaction solution was stirred at room temperature for 12 hours, and then filtered. The crude product was purified by preparative LC / MS using the following conditions: Column: XBridge C18, 200 mm x 19 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water (with 0.1% trifluoroacetic acid); Mobile phase B: 95:5 acetonitrile:water (with 0.1% trifluoroacetic acid); Gradient: 6% B held for 0 min, 6–46% B over 25 min, then 100% B held for 4 min; Flow rate: 20 mL / min; Column temperature: 25 °C. Fraction collection was initiated by MS and UV signals. Fractions containing the desired product were combined and dried by centrifugal evaporation to give 2-(2-ethoxyethyl)-7-(1H-pyrazol-1-yl)-2H-pyrazolo[3,4-c]quinolin-4-amine (6.9 mg, 26%). 1H NMR (500 MHz, DMSO-d6) δ 8.70 (s, 1H), 8.49 (d, J=2.0 Hz, 1H), 8.03 (d, J=8.4 Hz, 1H), 7.88 (d, J=2.0 Hz, 1H), 7.75 (s, 1H), 7.68 (dd, J=8.4, 2.1 Hz, 1H), 6.54 (s, 1H), 4.60 (t, J=5.3 Hz, 2H), 3.92 (t, J=5.3 Hz, 2H), 3.48 (q, J=6.9 Hz, 2H), 1.08 (t, J=6.9 Hz, 3H). Analytical LC / MS conditions: Column: Waters XBridge C18, 2.1 mm x 50 mm, 1.7 μm particles; Mobile phase A: 5:95 acetonitrile:water (with 0.1% trifluoroacetic acid); Mobile phase B: 95:5 acetonitrile:water (with 0.1% trifluoroacetic acid); Temperature: 50 °C; Gradient: 0% B to 100% B over 3 min, then hold at 100% B for 0.75 min; Flow rate: 1 mL / min; Detection: MS and UV (220 nm). m / z 323.2 [M+H] + ;RT:1.03 minutes.

[0261] Examples 11-19 were prepared from the appropriate starting materials according to the synthetic method described in Example 10. LC / MS Method: Column: Waters XBridge C18, 2.1 mm x 50 mm, 1.7 μm particles; Mobile Phase A: 5:95 acetonitrile:water (with 0.1% trifluoroacetic acid); Mobile Phase B: 95:5 acetonitrile:water (with 0.1% trifluoroacetic acid); Temperature: 50°C; Gradient: 0% B to 100% B over 3 minutes, then hold at 100% B for 0.75 minutes; Flow Rate: 1 mL / min; Detection: MS and UV (220 nm).

[0262] [Table 3] [Table 4]

[0263] Example 20. Preparation of 2-[2-(morpholin-4-yl)ethyl]-7-(1H-pyrazol-3-yl)-2H-pyrazolo[3,4-c]quinolin-4-amine [ka] Step 1. 7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-2H-pyrazolo[3,4-c]quinolin-4-amine A mixture of 7-bromo-2H-pyrazolo[3,4-c]quinolin-4-amine, TFA (2.988 g, 7.92 mmol), 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (3.31 g, 11.9 mmol) and potassium phosphate(III) (5.05 g, 23.8 mmol) was evacuated and backfilled with N, then mixed with dioxane (33.0 ml) and HO (6.60 ml). The resulting suspension was sparged with N for 15 minutes, then chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (0.312 g, 0.396 mmol) was added. The reaction solution was stirred at 100 °C for 2 hours. The reaction solution was cooled to room temperature and diluted with EtOAc (400 mL) and HO (400 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (2 x 200 mL). The combined organic layers were washed with saturated aqueous NaCl (400 mL), dried over NaSO, filtered, and concentrated in vacuo. The crude material was mixed with CH2Cl2 (10 mL), filtered, and washed with CH2Cl2 (3 x 10 mL) to give 7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-2H-pyrazolo[3,4-c]quinolin-4-amine (1.865 g, 70%). 1H NMR (400 MHz, DMSO-d6) δ 13.59 - 13.20 (m, 1H), 8.82 - 8.51 (m, 1H), 8.21 - 8.03 (m, 1H), 7.77 - 7.65 (m, 1H), 7.58 (d, J=1.7 Hz, 1H), 7.44 - 7.30 (m, 1H), 6.93 (br s, 2H), 6.49 (d, J=1.3 Hz, 1H), 5.30 (dd, J=10.0, 2.0 Hz, 1H), 4.08 - 4.02 (m, 1H), 3.62 - 3.55 (m, 1H), 2.47 - 2.37 (m, 1H), 1.97 - 1.91 (m, 1H), 1.79 (br d, J=13.1 Hz, 1H), 1.62 - 1.49 (m, 3H);LC-MS m / z 335 [M+H] + .

[0264] Step 2. 2-[2-(morpholin-4-yl)ethyl]-7-(1H-pyrazol-3-yl)-2H-pyrazolo[3,4-c]quinolin-4-amine To a solution of 7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-2H-pyrazolo[3,4-c]quinolin-4-amine (16.3 mg, 0.049 mmol) in DMF (162 μL) at room temperature was added cesium carbonate (47.6 mg, 0.146 mmol) followed by 4-(2-bromoethyl)morpholine hydrobromide (14.7 mg, 0.054 mmol). The suspension was stirred at room temperature for 16 h. The reaction solution was diluted with HO (2 mL) and extracted with EtOAc (3×2 mL). The organic layers were combined and concentrated.

[0265] The crude material was mixed with CHCl (200 μL) and TFA (200 μL) and stirred at room temperature for 1.5 hours. The reaction solution was concentrated under vacuum. The crude material was dissolved in DMF (2 mL), filtered (syringe filter), and purified by preparative LC / MS using the following conditions: Column: XBridge C18, 200 mm x 19 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water (with 10 mM ammonium acetate); Mobile phase B: 95:5 acetonitrile:water (with 10 mM ammonium acetate); Gradient: 6% B hold for 0 minutes, 6–46% B over 20 minutes, then 100% B hold for 4 minutes; Flow rate: 20 mL / min; Column temperature: 25°C. Fraction collection was triggered by MS signal. Fractions containing the desired product (the more polar of the two observed regioisomeric products) were combined and dried by centrifugal evaporation to give 2-(2-morpholinoethyl)-7-(1H-pyrazol-3-yl)-2H-pyrazolo[3,4-c]quinolin-4-amine (10.8 mg, 59%). 1 H NMR (500 MHz, DMSO-d6) δ 8.73 (s, 1H), 7.93 (d, J=8.0 Hz, 1H), 7.90 (s, 1H), 7.70 (br s, 1H), 7.64 (br d, J=7.4 Hz, 1H), 6.97 - 6.80 (m, 2H), 6.73 (d, J=1.9 Hz, 1H), 4.56 (t, J=6.3 Hz, 2H), 3.57 - 3.53 (m, 4H), 2.88 (br t, J=6.5 Hz, 2H), 2.48 - 2.43 (m, 4H). Analytical LC / MS conditions: Column: Waters XBridge C18, 2.1 mm x 50 mm, 1.7 μm particles; Mobile phase A: 5:95 acetonitrile:water (with 0.1% trifluoroacetic acid); Mobile phase B: 95:5 acetonitrile:water (with 0.1% trifluoroacetic acid); Temperature: 50 °C; Gradient: 0% B to 100% B over 3 min, then hold at 100% B for 0.75 min; Flow rate: 1 mL / min; Detection: MS and UV (220 nm). m / z 363.9 [M+H] + ;RT:0.84 minutes.

[0266] Examples 21-28 were prepared from the appropriate starting materials following a synthetic method similar to that described for Example 20. For Example 27, the reaction solution was stirred at 50°C for 4 hours. For this reaction, when two regioisomeric peaks were observed by HPLC, the product was usually the major peak and the more polar of the two peaks observed under the HPLC conditions used. Analytical LC / MS conditions: Column: Waters XBridge C18, 2.1 mm x 50 mm, 1.7 μm particles; Mobile phase A: 5:95 acetonitrile:water (with 0.1% trifluoroacetic acid); Mobile phase B: 95:5 acetonitrile:water (with 0.1% trifluoroacetic acid); Temperature: 50°C; Gradient: 0% B to 100% B over 3 minutes, then hold at 100% B for 0.75 minutes; Flow rate: 1 mL / min; Detection: MS and UV (220 nm).

[0267] [Table 5] [Table 6]

[0268] Example 29. Preparation of N-[2-[4-amino-7-(1H-pyrazol-3-yl)-2H-pyrazolo[3,4-c]quinolin-2-yl]ethyl]-N-ethylacetamide [ka] Step 1. 7-Bromo-2-(2-bromoethyl)-2H-pyrazolo[3,4-c]quinolin-4-amine In a 250 mL round-bottom flask was placed 7-bromo-2H-pyrazolo[3,4-c]quinolin-4-amine (2 g, 7.60 mmol, 1 equiv.), DMF (70 mL, 957.67 mmol), CsCO (5.0 g, 15.20 mmol, 2 equiv.), and 1,2-dibromoethane (2.1 g, 11.40 mmol, 1.5 equiv.). The resulting solution was stirred at room temperature for 5 h and then diluted with EtOAc (350 mL). The resulting mixture was washed with HO (2 x 100 mL) and brine (2 x 100 mL). The mixture was then concentrated and the residue was purified on a silica gel column with ethyl acetate / petroleum ether (0-70%) to give 7-bromo-2-(2-bromoethyl)-2H-pyrazolo[3,4-c]quinolin-4-amine (1.5 g, 53%) as a solid. LC-MS m / z [M+H] + =368.9.

[0269] Step 2. 7-Bromo-2-[2-(ethylamino)ethyl]-2H-pyrazolo[3,4-c]quinolin-4-amine In a 30 mL sealed tube, 7-bromo-2-(2-bromoethyl)-2H-pyrazolo[3,4-c]quinolin-4-amine (500 mg, 1.35 mmol, 1 equiv.), ACN (10 mL, 0.24 mmol), KCO (373.5 mg, 2.70 mmol, 2 equiv.), KI (22.4 mg, 0.14 mmol, 0.1 equiv.), and ethanamine (609.2 mg, 13.51 mmol, 10 equiv.) were placed. The resulting solution was stirred at 65 °C for 16 h. The reaction solution was filtered, and the filtrate was concentrated in vacuo. The residue was purified on a silica gel column with dichloromethane / methanol (0-10%) to give 7-bromo-2-[2-(ethylamino)ethyl]-2H-pyrazolo[3,4-c]quinolin-4-amine (250 mg, 55%) as a solid. LC-MS m / z [M+H] + =334.1.

[0270] Step 3. N-(2-[4-amino-7-bromo-2H-pyrazolo[3,4-c]quinolin-2-yl]ethyl)-N-ethylacetamide In a 25 mL three-necked round-bottom flask purged with and maintained under inert nitrogen, 7-bromo-2-[2-(ethylamino)ethyl]-2H-pyrazolo[3,4-c]quinolin-4-amine (250 mg, 0.75 mmol, 1 equiv.), DCM (10 mL, 157.30 mmol), TEA (227.1 mg, 2.24 mmol, 3 equiv.), and AcO (91.6 mg, 0.90 mmol, 1.2 equiv.) were added. The resulting solution was stirred at room temperature for 5 h. The resulting mixture was concentrated in vacuo, and the residue was purified on a silica gel column using dichloromethane / methanol (0–10%) to give N-(2-[4-amino-7-bromo-2H-pyrazolo[3,4-c]quinolin-2-yl]ethyl)-N-ethylacetamide (200 mg, 71%) as a solid. LC-MS m / z [M+H] + =376.1.

[0271] Step 4. N-[2-[4-amino-7-(1H-pyrazol-3-yl)-2H-pyrazolo[3,4-c]quinolin-2-yl]ethyl]-N-ethylacetamide A 25 mL round-bottom flask was charged with N-(2-[4-amino-7-bromo-2H-pyrazolo[3,4-c]quinolin-2-yl]ethyl)-N-ethylacetamide (200 mg, 0.53 mmol, 1 equiv.), NaCO (112.7 mg, 1.06 mmol, 2 equiv.), 3-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (206.3 mg, 1.06 mmol, 2 equiv.), and Pd(PPh) (61.4 mg, 0.05 mmol, 0.1 equiv.) in dioxane (5 mL, 0.06 mmol) and HO (1.25 mL, 620.08 mmol). The resulting solution was stirred in a water bath at 80 °C for 16 h. The resulting mixture was concentrated, and the residue was purified on a silica gel column using dichloromethane / methanol (10:1). The crude product was purified by Prep-HPLC using the following conditions: Column: XBridge Shield RP18 OBD column 19*250 mm, 10 μm; Mobile phase A: Water (10 mM NH4HCO3), Mobile phase B: ACN; Flow rate: 25 mL / min; Gradient: 13% B to 40% B in 7 min; 254 / 210 nm; RT: 6.55 min. This gave N-[2-[4-amino-7-(1H-pyrazol-3-yl)-2H-pyrazolo[3,4-c]quinolin-2-yl]ethyl]-N-ethylacetamide (82.6 mg, 43%) as a white solid. 1 H-NMR:(300 MHz, DMSO-d6, ppm):δ 13.33-12.84 (m, 1H), 8.72 (s, 1H), 7.94-7.64 (m, 4H), 6.80-6.74 (m, 3H), 4.65-4.54 (m, 2H), 3.85-3.73 (m, 2H), 3.34-3.06 (m, 2H), 2.01 (s, 2H), 1.70 (s, 1H), 1.02-0.94 (m, 3H). LC method: Column: Kinetex EVO 3.0mm x 50 mm, 2.6 μm particles; Mobile phase A: water (containing 0.03% NH3H2O); Mobile phase B: acetonitrile; Temperature: 40 °C; Gradient: 10% B to 95% B over 2 min, then hold at 95% B for 0.60 min; Flow rate: 1.2 mL / min. m / z [M+H] +=336.3.LC RT:1.030min.

[0272] Example 30. Preparation of 2-(2-{hexahydro-1H-furo[3,4-c]pyrrol-5-yl}ethyl)-7-(1H-pyrazol-3-yl)-2H-pyrazolo[3,4-c]quinolin-4-amine [ka] Step 1. 7-Bromo-2-(2-[hexahydro-1H-furo[3,4-c]pyrrol-5-yl]ethyl)-2H-pyrazolo[3,4-c]quinolin-4-amine In a 30 mL sealed tube, 7-bromo-2-(2-bromoethyl)-2H-pyrazolo[3,4-c]quinolin-4-amine (400 mg, 1.08 mmol, 1 equiv.), K2CO3 (298.8 mg, 2.16 mmol, 2 equiv.), KI (17.9 mg, 0.11 mmol, 0.1 equiv.), and hexahydro-1H-furo[3,4-c]pyrrole (611.6 mg, 5.40 mmol, 5 equiv.) were placed in ACN (10 mg, 0.24 mmol, 0.225 equiv.). The resulting solution was stirred at 65 °C for 16 h. The reaction solution was filtered, and the filtrate was concentrated in vacuo. The residue was purified on a silica gel column with dichloromethane / methanol (0-10%) to give 7-bromo-2-(2-[hexahydro-1H-furo[3,4-c]pyrrol-5-yl]ethyl)-2H-pyrazolo[3,4-c]quinolin-4-amine (120 mg, 28%) as a solid. LC-MS: (ES, m / z): [M+H] + =402.1.

[0273] Step 2. 2-(2-[hexahydro-1H-furo[3,4-c]pyrrol-5-yl]ethyl)-7-(1H-pyrazol-3-yl)-2H-pyrazolo[3,4-c]quinolin-4-amine In a 30 mL sealed tube, 7-bromo-2-(2-[hexahydro-1H-furo[3,4-c]pyrrol-5-yl]ethyl)-2H-pyrazolo[3,4-c]quinolin-4-amine (120 mg, 0.30 mmol, 1 equiv.), NaCO (63.2 mg, 0.60 mmol, 2 equiv.), 3-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (115.8 mg, 0.60 mmol, 2 equiv.), and Pd(PPh) (34.5 mg, 0.03 mmol, 0.1 equiv.) were placed in dioxane (4 mL) and HO (1 mL). The resulting solution was stirred at 80 °C for 16 h. The resulting mixture was cooled to room temperature and concentrated. The residue was purified on a silica gel column with dichloromethane / methanol (0-10%). The crude product was purified again by Prep-HPLC using the following conditions: Column: XBridge Shield RP18 OBD column 19*250 mm, 10 μm; Mobile phase A: Water (10 mM NH4HCO3), Mobile phase B: ACN; Flow rate: 25 mL / min; Gradient: 15% B to 40% B over 7.5 min; 210 / 254 nm; RT: 6.90 min. This gave 2-(2-[hexahydro-1H-furo[3,4-c]pyrrol-5-yl]ethyl)-7-(1H-pyrazol-3-yl)-2H-pyrazolo[3,4-c]quinolin-4-amine (27.9 mg, 24%) as a solid. 1 H-NMR:(300 MHz, DMSO-d6, ppm):δ 13.28-12.85 (m, 1H), 8.74 (s, 1H),7.91-7.63 (m, 4H), 6.77-6.74 (m, 3H), 4.56-4.51 (m, 2H), 3.72-3.67 (m, 2H), 3.35-3.31 (m, 2H), 2.95-2.91 (m, 2H), 2.67-2.55 (m, 4H), 2.40-2.36 (m, 2H). LC method: Column: Kinetex EVO 3.0 mm x 50 mm, 2.6 μm Particles; Mobile phase A: Water (containing 0.03% NH3H2O); Mobile phase B: Acetonitrile; Temperature: 40°C; Gradient: 10% B to 95% B over 2 min, then hold at 95% B for 0.60 min; Flow rate: 1.2 mL / min. m / z [M+H]+ =390.2.LC RT:1.030min.

[0274] Example 31. Preparation of N-{2-[4-amino-7-(1H-pyrazol-3-yl)-2H-pyrazolo[3,4-c]quinolin-2-yl]ethyl}-5-fluoropyridine-2-carboxamide [ka] Step 1. tert-Butyl (2-(4-amino-7-bromo-2H-pyrazolo[3,4-c]quinolin-2-yl)ethyl)carbamate To a room temperature solution of 7-bromo-2H-pyrazolo[3,4-c]quinolin-4-amine, TFA (3.00 g, 7.96 mmol) in DMF (22.73 mL) was added cesium carbonate (7.78 g, 23.87 mmol) followed by tert-butyl (2-bromoethyl)carbamate (1.961 g, 8.75 mmol). The suspension was stirred at rt for 20 h. The reaction solution was diluted with EtOAc (300 mL) and H2O (300 mL). The layers were separated and the aqueous layer was extracted with EtOAc (100 mL). The combined organic layers were washed with saturated aqueous NaCl (300 mL), dried over Na2SO4, and filtered. Celite was added and the mixture was concentrated in vacuo. This material was dry loaded onto a column and purified by flash chromatography (80 g silica gel with a 25 g solid load cartridge; linear gradient 0 to 10% MeOH—CH2Cl2) to give tert-butyl (2-(4-amino-7-bromo-2H-pyrazolo[3,4-c]quinolin-2-yl)ethyl)carbamate (2.06 g, 64%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.67 (s, 1H), 7.85 (d, J=8.3 Hz, 1H), 7.58 (d, J=2.0 Hz, 1H), 7.30 (dd, J=8.3, 2.0 Hz, 1H), 7.05 (br t, J=5.4 Hz, 1H), 6.98 (br s, 2H), 4.45 (br t, J=6.1 Hz, 2H), 3.48 (q, J=6.0 Hz, 2H), 1.33 (s, 9H);LC-MS m / z 406 / 408 [M+H] + .

[0275] Step 2. tert-Butyl (2-(4-amino-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-2H-pyrazolo[3,4-c]quinolin-2-yl)ethyl)carbamate A mixture of tert-butyl (2-(4-amino-7-bromo-2H-pyrazolo[3,4-c]quinolin-2-yl)ethyl)carbamate (1.01 g, 2.49 mmol), 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.037 g, 3.73 mmol) and cesium carbonate (2.430 g, 7.46 mmol) was evacuated and backfilled with N, then 1,4-dioxane (22.37 ml) and HO (2.486 ml) were added. The resulting mixture was sparged with N for 15 minutes, then [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.091 g, 0.124 mmol) was added. The mixture was sparged with N for 1 minute, then it was stirred at 100 °C for 30 minutes. The reaction solution was cooled to room temperature, diluted with EtOAc (300 mL), washed with HO (150 mL) and saturated aqueous NaCl (150 mL), dried over NaSO, filtered, and concentrated in vacuo. The crude material was purified by flash chromatography (80 g silica gel; linear gradient 0-10% MeOH—CH2Cl2) to give tert-butyl (2-(4-amino-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-2H-pyrazolo[3,4-c]quinolin-2-yl)ethyl)carbamate (1.2 g, quant.) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 8.71 (s, 1H), 8.01 (d, J=8.1 Hz, 1H), 7.62 (d, J=1.6 Hz, 1H), 7.57 (d, J=1.7 Hz, 1H), 7.32 (dd, J=8.0, 1.8 Hz, 1H), 7.07 (br t, J=5.7 Hz, 1H), 6.89 (br s, 2H), 6.48 (d, J=1.7 Hz, 1H), 5.30 (dd, J=10.0, 2.0 Hz, 1H), 4.48 (br t, J=6.1 Hz, 2H), 4.07 - 4.01 (m, 1H), 3.61 - 3.54 (m, 1H), 3.50 (q, J=6.0 Hz, 2H), 2.47 - 2.36 (m, 1H), 1.99 - 1.90 (m, 1H), 1.79 (br d, J=13.4 Hz, 1H), 1.64 - 1.48 (m, 3H), 1.35 (s, 9H);LC-MS m / z 478 [M+H] + .

[0276] Step 3. 2-(2-aminoethyl)-7-(1H-pyrazol-3-yl)-2H-pyrazolo[3,4-c]quinolin-4-amine, 2TFA To a room temperature solution of tert-butyl (2-(4-amino-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-2H-pyrazolo[3,4-c]quinolin-2-yl)ethyl)carbamate (1.2 g, 2.5 mmol) in CHCl (6.17 mL) was added TFA (6.17 mL). The reaction was stirred at room temperature for 2 hours. The reaction was concentrated to approximately half its volume and then added dropwise to EtO (75 mL). The resulting solid was collected by vacuum filtration and washed with EtO (3 × 10 mL) to give 2-(2-aminoethyl)-7-(1H-pyrazol-3-yl)-2H-pyrazolo[3,4-c]quinolin-4-amine, 2TFA (1.121 g, 87%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 13.69 - 12.94 (m, 1H), 9.85 - 9.68 (m, 1H), 9.38 - 9.22 (m, 1H), 9.02 (s, 1H), 8.17 - 8.13 (m, 2H), 8.09 (br s, 2H), 7.94 (d, J=7.2 Hz, 1H), 7.85 (br s, 1H), 6.80 (d, J=2.1 Hz, 1H), 4.77 (t, J=5.7 Hz, 2H), 3.55 - 3.49 (m, 2H);LC-MS m / z 294 [M+H] + .

[0277] Step 4. N-{2-[4-amino-7-(1H-pyrazol-3-yl)-2H-pyrazolo[3,4-c]quinolin-2-yl]ethyl}-5-fluoropyridine-2-carboxamide To a solution of 2-(2-aminoethyl)-7-(1H-pyrazol-3-yl)-2H-pyrazolo[3,4-c]quinolin-4-amine, 2TFA (40 mg, 0.077 mmol) and 5-fluoropicolinic acid (10.8 mg, 0.077 mmol) in DMF (384 μL) at room temperature, N,N-diisopropylethylamine (53.5 μL, 0.307 mmol) was added, followed by HATU (29.2 mg, 0.077 mmol). The reaction solution was stirred at room temperature for 30 minutes. The reaction solution was diluted with HO (0.2 mL) and DMF (to a total volume of 2 mL), filtered (syringe filter), and purified by preparative LC / MS using the following conditions: Column: XBridge C18, 200 mm x 19 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water (with 0.1% trifluoroacetic acid); Mobile phase B: 95:5 acetonitrile:water (with 0.1% trifluoroacetic acid); Gradient: 2% B hold for 0 min, 2–42% B over 20 min, then 100% B hold for 4 min; Flow rate: 20 mL / min; Column temperature: 25 °C. Fraction collection was triggered by MS and UV signals. Fractions containing the desired product were combined and dried by centrifugal evaporation to give N-(2-(4-amino-7-(1H-pyrazol-3-yl)-2H-pyrazolo[3,4-c]quinolin-2-yl)ethyl)-5-fluoropicolinamide, 2TFA (15.8 mg, 31%). 1H NMR (500 MHz, DMSO-d6) δ 9.06 (br t, J=5.8 Hz, 1H), 8.93 (s, 1H), 8.61 (d, J=2.5 Hz, 1H), 8.12 - 8.02 (m, 3H), 7.90 - 7.77 (m, 3H), 6.78 (s, 1H), 4.71 (br t, J=5.9 Hz, 2H), 3.94 - 3.86 (m, 2H). Analytical LC / MS conditions: Column: Waters XBridge C18, 2.1mm×50mm, 1.7 μm particles; Mobile phase A: 5:95 acetonitrile:water (with 0.1% trifluoroacetic acid); Mobile phase B: 95:5 acetonitrile:water (with 0.1% trifluoroacetic acid); Temperature: 50°C; Gradient: 0% B to 100% B over 3 min, then hold at 100% B for 0.50 min; Flow rate: 1 mL / min; Detection: MS and UV (220 nm). m / z 417.3 [M+H] + ;RT:1.13 minutes.

[0278] Alternative method for the preparation of N-{2-[4-amino-7-(1H-pyrazol-3-yl)-2H-pyrazolo[3,4-c]quinolin-2-yl]ethyl}-5-fluoropyridine-2-carboxamide To a solution of 5-fluoropicolinic acid (29.8 mg, 0.211 mmol) in DMF (479 μL) at room temperature, N,N-diisopropylethylamine (66.8 μL, 0.384 mmol) was added, followed by HATU (72.9 mg, 0.192 mmol). This solution was stirred at room temperature for 5 minutes, and then added dropwise to a solution of 2-(2-aminoethyl)-7-(1H-pyrazol-3-yl)-2H-pyrazolo[3,4-c]quinolin-4-amine, 2TFA (100 mg, 0.192 mmol) and N,N-diisopropylethylamine (100 μL, 0.575 mmol) in DMF (479 μL). The reaction solution was stirred at room temperature for 30 minutes. The reaction solution was diluted with EtOAc (50 mL) and HO (50 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (50 mL). The combined organic layers were washed with 10% aqueous LiCl (2 x 50 mL) and saturated aqueous NaCl (50 mL), dried over NaSO, filtered, and concentrated in vacuo. The crude material was transferred to MeOH-CHCl, Celite was added, and the mixture was concentrated in vacuo. The material was dry-loaded onto a column and purified by flash chromatography (24 g RediSep Gold silica gel with a 5 g solid load cartridge; linear gradient 0 to 20% MeOH-CHCl) to afford N-(2-(4-amino-7-(1H-pyrazol-3-yl)-2H-pyrazolo[3,4-c]quinolin-2-yl)ethyl)-5-fluoropicolinamide (33.7 mg, 42%) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 13.33 - 12.77 (m, 1H), 9.04 (t, J=5.9 Hz, 1H), 8.69 (br s, 1H), 8.62 (d, J=2.7 Hz, 1H), 8.09 (dd, J=8.7, 4.7 Hz, 1H), 7.93 - 7.84 (m, 3H), 7.82 - 7.64 (m, 1H), 7.64 - 7.51 (m, 1H), 6.84 - 6.76 (m, 1H), 6.74 (br s, 2H), 4.65 (t, J=6.2 Hz, 2H), 3.88 (q, J=6.2 Hz, 2H); LC-MS m / z 417 [M+H]+ .

[0279] Examples 32-101 were prepared from the appropriate starting materials following synthetic methods similar to those described for Example 31. Analytical LC / MS conditions: Column: Waters XBridge C18, 2.1 mm x 50 mm, 1.7 μm particles; Mobile phase A: 5:95 acetonitrile:water (with 0.1% trifluoroacetic acid); Mobile phase B: 95:5 acetonitrile:water (with 0.1% trifluoroacetic acid); Temperature: 50°C; Gradient: 0% B to 100% B over 3 minutes, then hold at 100% B for 0.75 minutes; Flow rate: 1 mL / min; Detection: MS and UV (220 nm).

[0280] [Table 7] [Table 8] [Table 9] [Table 10] [Table 11] [Table 12] [Table 13] [Table 14] [Table 15] [Table 16] [Table 17] [Table 18] [Table 19] [Table 20] [Table 21]

[0281] Example 102. Preparation of 2-{2-[4-amino-7-(1H-pyrazol-3-yl)-2H-pyrazolo[3,4-c]quinolin-2-yl]ethyl}-2,3-dihydro-1H-isoindol-1-one [ka] To a solution of 2-(2-aminoethyl)-7-(1H-pyrazol-3-yl)-2H-pyrazolo[3,4-c]quinolin-4-amine, 2TFA (50 mg, 0.096 mmol) in DMF (479 μL) at room temperature, N,N-diisopropylethylamine (84 μL, 0.48 mmol) and methyl 2-(bromomethyl)benzoate (22.0 mg, 0.096 mmol) were added. The reaction solution was stirred at room temperature for 17 hours. The reaction solution was diluted with HO (0.1 mL) and DMF (to a total volume of 2 mL), filtered (syringe filter), and purified by preparative LC / MS using the following conditions: Column: XBridge C18, 200 mm x 19 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water (with 10 mM ammonium acetate); Mobile phase B: 95:5 acetonitrile:water (with 10 mM ammonium acetate); Gradient: 0% B hold for 0 min, 0–40% B over 20 min, then 100% B hold for 4 min; Flow rate: 20 mL / min; Column temperature: 25 °C. Fraction collection was triggered by MS and UV signals. Fractions containing the desired product were combined and dried by centrifugal evaporation to give 2-(2-(4-amino-7-(1H-pyrazol-3-yl)-2H-pyrazolo[3,4-c]quinolin-2-yl)ethyl)isoindolin-1-one (6.5 mg, 16%). 1H NMR (500 MHz, DMSO-d6) δ 8.73 (s, 1H), 7.88 (br s, 1H), 7.86 (br d, J=7.7 Hz, 1H), 7.76 - 7.52 (m, 5H), 7.48 - 7.43 (m, 1H), 6.72 (br Analytical LC / MS conditions Column: Waters XBridge C18, 2.1mm x 50mm, 1.7μm particles; Mobile phase A:5:95 Acetonitrile:water (with 0.1% trifluoroacetic acid); Mobile phase B: 95:5 acetonitrile:water (with 0.1% trifluoroacetic acid); Temperature: 50°C; Gradient: 0% B to 100% B over 3 min, then hold at 100% B for 0.50 min; Flow rate: 1 mL / min; Detection: MS and UV (220 nm). m / z 410.0 [M+H] + ;RT:1.11 minutes.

[0282] Example 103. Preparation of 2-{2-[4-amino-7-(1H-pyrazol-3-yl)-2H-pyrazolo[3,4-c]quinolin-2-yl]ethyl}-6-fluoro-2,3-dihydro-1H-isoindol-1-one [ka] To a solution of 2-(2-aminoethyl)-7-(1H-pyrazol-3-yl)-2H-pyrazolo[3,4-c]quinolin-4-amine, 2TFA (50 mg, 0.096 mmol) in DMF (479 μL) at room temperature, N,N-diisopropylethylamine (84 μL, 0.48 mmol) and methyl 2-(bromomethyl)-5-fluorobenzoate (23.7 mg, 0.096 mmol) were added. The reaction solution was stirred at room temperature for 2 hours. The reaction solution was diluted with HO (0.1 mL) and DMF (to a total volume of 2 mL), filtered (syringe filter), and purified by preparative LC / MS using the following conditions: Column: XBridge C18, 200 mm x 19 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water (with 0.1% trifluoroacetic acid); Mobile phase B: 95:5 acetonitrile:water (with 0.1% trifluoroacetic acid); Gradient: 4% B held for 0 min, 4–44% B over 20 min, then 100% B held for 4 min; Flow rate: 20 mL / min; Column temperature: 25 °C. Fraction collection was triggered by the MS signal. Fractions containing the desired product were combined and dried by centrifugal evaporation to give 2-(2-(4-amino-7-(1H-pyrazol-3-yl)-2H-pyrazolo[3,4-c]quinolin-2-yl)ethyl)-6-fluoroisoindolin-1-one, TFA (16.1 mg, 30%). 1H NMR (500 MHz, DMSO-d6) δ 8.96 (s, 1H), 8.14 - 8.05 (m, 1H), 8.02 (br d, J=8.3 Hz, 1H), 7.89 - 7.76 (m, 2H), 7.61 (dd, J=8.3, 4.4 Hz, Analytical LC / MS conditions: Column: Waters XBridge C18, 2.1mmx50mm, 1.7μm particles; Mobile phase A: 5:95 Acetonitrile:water (with 10 mM ammonium acetate); Mobile phase B: 95:5 acetonitrile:water (with 10 mM ammonium acetate); Temperature: 50°C; Gradient: 0% B to 100% B over 3 min, then hold at 100% B for 0.50 min; Flow rate: 1 mL / min; Detection: MS and UV (220 nm). m / z 428.3 [M+H] + ;RT:1.35 minutes.

[0283] Example 104. Preparation of 2-{2-[4-amino-7-(1H-pyrazol-3-yl)-2H-pyrazolo[3,4-c]quinolin-2-yl]ethyl}-5-chloro-2,3-dihydro-1H-isoindol-1-one [ka] To a solution of 2-(2-aminoethyl)-7-(1H-pyrazol-3-yl)-2H-pyrazolo[3,4-c]quinolin-4-amine, 2TFA (50 mg, 0.096 mmol) in DMF (479 μL) at room temperature, N,N-diisopropylethylamine (84 μL, 0.479 mmol) and methyl 2-(bromomethyl)-4-chlorobenzoate (25.3 mg, 0.096 mmol) were added. The reaction solution was stirred at room temperature for 2 hours. The reaction solution was diluted with HO (0.1 mL) and DMF (to a total volume of 2 mL), filtered (syringe filter), and purified by preparative LC / MS using the following conditions: Column: XBridge C18, 200 mm x 19 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water (with 10 mM ammonium acetate); Mobile phase B: 95:5 acetonitrile:water (with 10 mM ammonium acetate); Gradient: 11% B, hold for 0 min, 11–51% B over 20 min, then 100% B, hold for 4 min; Flow rate: 20 mL / min; Column temperature: 25 °C. Fraction collection was triggered by the MS signal. Fractions containing the desired product were combined and dried by centrifugal evaporation to give 2-(2-(4-amino-7-(1H-pyrazol-3-yl)-2H-pyrazolo[3,4-c]quinolin-2-yl)ethyl)-5-chloroisoindolin-1-one (11.9 mg, 28%). 1H NMR (500 MHz, DMSO-d6) δ 8.77 (s, 1H), 7.93 (br s, 1H), 7.89 (br d, J=8.3 Hz, 1H), 7.77 - 7.59 (m, 4H), 7.50 (br d, J=8.0 Hz, 1H), 6.74 (s, 1H), 4.74 (br t, J=5.5 Hz, 2H), 4.35 (s, 2H), 4.10 (br t, J=5.4 Hz, 2H). Analytical LC / MS conditions: Column: Waters XBridge C18, 2.1 mm × 50 mm, 1.7 μm particles; Mobile phase A: 5:95 acetonitrile:water (with 0.1% trifluoroacetic acid); Mobile phase B: 95:5 Acetonitrile:water (containing 0.1% trifluoroacetic acid); Temperature: 50°C; Gradient: 0% B to 100% B over 3 min, then hold at 100% B for 0.50 min; Flow rate: 1 mL / min; Detection: MS and UV (220 nm). m / z 444.1 [M+H] + ;RT:1.37 minutes.

[0284] Example 105. Preparation of 2-(2-{[(2-methylphenyl)methyl]amino}ethyl)-7-(1H-pyrazol-3-yl)-2H-pyrazolo[3,4-c]quinolin-4-amine [ka] To a solution of 2-(2-aminoethyl)-7-(1H-pyrazol-3-yl)-2H-pyrazolo[3,4-c]quinolin-4-amine, 2TFA (35 mg, 0.067 mmol) in DMF (336 μL) at room temperature, 2-methylbenzaldehyde (10.1 μL, 0.087 mmol) was added, followed by sodium triacetoxyborohydride (42.7 mg, 0.201 mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction solution was diluted with HO (100 μL) and DMF (to a total volume of 2 mL), filtered (syringe filter), and purified by preparative LC / MS using the following conditions: Column: XBridge C18, 200 mm x 19 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water (with 0.1% trifluoroacetic acid); Mobile phase B: 95:5 acetonitrile:water (with 0.1% trifluoroacetic acid); Gradient: 0% B hold for 0 min, 0–60% B over 25 min, then 100% B hold for 4 min; Flow rate: 20 mL / min; Column temperature: 25 °C. Fraction collection was triggered by MS and UV signals. Fractions containing the desired product were combined and dried by centrifugal evaporation to give 2-(2-((2-methylbenzyl)amino)ethyl)-7-(1H-pyrazol-3-yl)-2H-pyrazolo[3,4-c]quinolin-4-amine, 2TFA (17.5 mg, 40%). 1H NMR (500 MHz, DMSO-d6) δ 9.02 (s, 1H), 8.16 - 8.10 (m, 2H), 7.92 (br d, J=8.3 Hz, 1H), 7.83 (br s, 1H), 7.44 (br d, J=7.2 Hz, 1H), 7.34 - 7.29 (m, 1H), 7.29 - 7.24 (m, 2H), 6.80 (s, 1H), 4.91 (br t, J=5.6 Hz, 2H), 4.28 (s, 2H), 3.76 - 3.69 (m, 2H), 2.36 (s, 3H). Analytical LC / MS conditions: Column: Waters XBridge C18, 2.1 mm x 50 mm, 1.7 μm particles; Mobile phase A: 5:95 acetonitrile:water (with 0.1% trifluoroacetic acid); Mobile phase B: 95:5 acetonitrile:water (with 0.1% trifluoroacetic acid); Temperature: 50°C; Gradient: 0% B to 100% B over 3 min, then hold at 100% B for 0.75 min; Flow rate: 1 mL / min; Detection: MS and UV (220 nm). m / z 398.1 [M+H] + ;RT:1.08 minutes.

[0285] Examples 106-112 were prepared from the appropriate starting materials following synthetic methods similar to those described for Example 105. For Examples 106 and 108, triethylamine (2.5 equivalents) was added to the starting materials before the addition of other reagents. Analytical LC / MS conditions: Column: Waters XBridge C18, 2.1 mm x 50 mm, 1.7 μm particles; Mobile phase A: 5:95 acetonitrile:water (with 0.1% trifluoroacetic acid); Mobile phase B: 95:5 acetonitrile:water (with 0.1% trifluoroacetic acid); Temperature: 50°C; Gradient: 0% B to 100% B over 3 minutes, then hold at 100% B for 0.75 minutes; Flow rate: 1 mL / min; Detection: MS and UV (220 nm).

[0286] [Table 22] [Table 23]

[0287] Example 113. Preparation of N-{2-[4-amino-7-(1H-pyrazol-3-yl)-2H-pyrazolo[3,4-c]quinolin-2-yl]ethyl}methanesulfonamide [ka] To a solution of 2-(2-aminoethyl)-7-(1H-pyrazol-3-yl)-2H-pyrazolo[3,4-c]quinolin-4-amine, 2TFA (35 mg, 0.067 mmol) in DMF (224 μL) at room temperature was added triethylamine (37.4 μL, 0.269 mmol) followed by methanesulfonyl chloride (8.1 mg, 0.070 mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with HO (0.1 mL) and DMF (to a total volume of 2 mL), filtered (syringe filter), and purified by preparative LC / MS using the following conditions: Column: XBridge C18, 200 mm x 19 mm, 5 μm particles; Mobile Phase A: 5:95 acetonitrile:water (with 10 mM ammonium acetate); Mobile Phase B: 95:5 acetonitrile:water (with 10 mM ammonium acetate); Gradient: 0% B hold at 0 min, 0–40% B over 20 min, then 100% B hold for 4 min; Flow Rate: 20 mL / min; Column Temperature: 25 °C. Fraction collection was triggered by MS and UV signals. Fractions containing the desired product were combined and dried by centrifugal evaporation. This material was further purified by preparative LC / MS using the following conditions: Column: XBridge C18, 200 mm x 19 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water (with 0.1% trifluoroacetic acid); Mobile phase B: 95:5 acetonitrile:water (with 0.1% trifluoroacetic acid); Gradient: 13% B hold at 0 min, 13–36% B over 25 min, then 100% B hold for 2 min; Flow rate: 20 mL / min; Column temperature: 25 °C. Fraction collection was initiated by UV signal. Fractions containing the desired product were combined and dried by centrifugal evaporation to give N-(2-(4-amino-7-(1H-pyrazol-3-yl)-2H-pyrazolo[3,4-c]quinolin-2-yl)ethyl)methanesulfonamide, TFA (6.1 mg, 19%). 1H NMR (500 MHz, DMSO-d6) δ 8.97 (s, 1H), 8.16 - 8.09 (m, 2H), 7.90 (br d, J = 8.5 Hz, 1H), 7.82 (br s, 1H), 7.33 (br t, J = 5.8 Hz, 1H), 6.80 (s, 1H), 4.62 (br t, J = 5.6 Hz, 2H), 3.60 - 3.56 (m, 2H), 2.90 (s, 3H). Analytical LC / MS conditions: Column: Waters XBridge C18, 2.1 mm x 50 mm, 1.7 μm particles; Mobile phase A: 5:95 acetonitrile:water (with 0.1% trifluoroacetic acid); Mobile phase B: 95:5 Acetonitrile:water (containing 0.1% trifluoroacetic acid); Temperature: 50°C; Gradient: 0% B to 100% B over 3 min, then hold at 100% B for 0.75 min; Flow rate: 1 mL / min; Detection: MS and UV (220 nm). m / z 372 [M+H] + ;RT:0.94 minutes.

[0288] Example 114. Preparation of N-{2-[4-amino-7-(1H-pyrazol-3-yl)-2H-pyrazolo[3,4-c]quinolin-2-yl]ethyl}benzenesulfonamide [ka] To a solution of 2-(2-aminoethyl)-7-(1H-pyrazol-3-yl)-2H-pyrazolo[3,4-c]quinolin-4-amine, 2TFA (51 mg, 0.098 mmol) in DMF (326 μL) at 0°C, triethylamine (54.5 μL, 0.391 mmol) was added dropwise, followed by benzenesulfonyl chloride (13.1 μL, 0.103 mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction solution was diluted with HO (0.1 mL) and DMF (to a total volume of 2 mL), filtered (syringe filter), and purified by preparative LC / MS using the following conditions: Column: XBridge C18, 200 mm x 19 mm, 5 μm particles; Mobile Phase A: 5:95 acetonitrile:water (with 10 mM ammonium acetate); Mobile Phase B: 95:5 Acetonitrile:water (containing 10 mM ammonium acetate); gradient: 11% B held at 0 min, 11 to 51% B over 20 min, then 100% B held at 4 min; flow rate: 20 mL / min; column temperature: 25 °C. Fraction collection was triggered by the MS signal. Fractions containing the desired product were combined and dried by centrifugal evaporation to give N-(2-(4-amino-7-(1H-pyrazol-3-yl)-2H-pyrazolo[3,4-c]quinolin-2-yl)ethyl)benzenesulfonamide (34.3 mg, 80%). 1H NMR (500 MHz, DMSO-d6) δ 8.59 (s, 1H), 7.92 - 7.88 (m, 2H), 7.87 - 7.80 (m, 1H), 7.78 - 7.74 (m, 2H), 7.71 - 7.60 (m, 2H), 7.58 - 7.48 (m, 3H), 6.72 (d, J=2.0 Hz, 1H), 6.68 - 6.52 (m, 2H), 4.49 (t, J=6.1 Hz, 2H), 3.40 (br t, J=6.1 Hz, 2H). Analytical LC / MS conditions: Column: Waters XBridge C18, 2.1mm×50mm, 1.7μm particles; Mobile phase A:5:95 Acetonitrile:water (with 0.1% trifluoroacetic acid); Mobile phase B: 95:5 acetonitrile:water (with 0.1% trifluoroacetic acid); Temperature: 50°C; Gradient: 0% B to 100% B over 3 min, then hold at 100% B for 0.75 min; Flow rate: 1 mL / min; Detection: MS and UV (220 nm). m / z 434.3 [M+H] + ;RT: 1 minute.

[0289] Example 115. Preparation of 3-{2-[4-amino-7-(1H-pyrazol-3-yl)-2H-pyrazolo[3,4-c]quinolin-2-yl]ethyl}-1-phenylurea [ka] To a solution of 2-(2-aminoethyl)-7-(1H-pyrazol-3-yl)-2H-pyrazolo[3,4-c]quinolin-4-amine, 2TFA (40 mg, 0.077 mmol) in DMF (384 μL) at 0° C., triethylamine (42.8 μL, 0.307 mmol) was added, followed by phenyl isocyanate (8.3 μL, 0.077 mmol). The reaction solution was stirred at 0° C. for 1 hour. The reaction solution was diluted with HO (0.2 mL) and DMF (to a total volume of 2 mL), filtered (syringe filter), and purified by preparative LC / MS using the following conditions: Column: XBridge C18, 200 mm x 19 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water (with 10 mM ammonium acetate); Mobile phase B: 95:5 acetonitrile:water (with 10 mM ammonium acetate); Gradient: 8% B held for 0 min, 8–48% B over 20 min, then 100% B held for 4 min; Flow rate: 20 mL / min; Column temperature: 25 °C. Fraction collection was triggered by MS and UV signals. Fractions containing the desired product were combined and dried by centrifugal evaporation to give 1-(2-(4-amino-7-(1H-pyrazol-3-yl)-2H-pyrazolo[3,4-c]quinolin-2-yl)ethyl)-3-phenylurea (16.5 mg, 52%). 1H NMR (500 MHz, DMSO-d6) δ 8.73 (s, 1H), 8.55 (s, 1H), 7.93 (br d, J=8.0 Hz, 1H), 7.89 (s, 1H), 7.72 - 7.66 (m, 1H), 7.62 (br d, J=8.0 Hz, 1H), 7.37 (br d, J=7.7 Hz, 2H), 7.21 (t, J=8.0 Hz, 2H), 6.89 (t, J=7.3 Hz, 1H), 6.83 - 6.75 (m, 2H), 6.73 (d, J=1.7 Hz, 1H), 6.33 - 6.29 (m, 1H), 4.53 (br t, J = 5.5 Hz, 2H), 3.72 - 3.66 (m, 2H). Column: Waters XBridge C18, 2.1 mm x 50 mm, 1.7 μm particles; Mobile phase A: 5:95 acetonitrile:water (with 0.1% trifluoroacetic acid); Mobile phase B: 95:5 acetonitrile:water (with 0.1% trifluoroacetic acid); Temperature: 50 °C; Gradient: 0% B to 100% B over 3 min, then hold at 100% B for 0.50 min; Flow rate: 1 mL / min; Detection: MS and UV (220 nm). m / z 413.1 [M+H] + ;RT:1.14 minutes.

[0290] Example 116. Preparation of 1-{2-[4-amino-7-(1H-pyrazol-3-yl)-2H-pyrazolo[3,4-c]quinolin-2-yl]ethyl}-3,3-dimethylurea [ka] To a solution of 2-(2-aminoethyl)-7-(1H-pyrazol-3-yl)-2H-pyrazolo[3,4-c]quinolin-4-amine, 2TFA (40 mg, 0.077 mmol) in DMF (384 μL) at 0° C., triethylamine (42.8 μL, 0.307 mmol) was added, followed by dimethylcarbamyl chloride (7.1 μL, 0.077 mmol). The reaction solution was stirred at 0° C. for 30 minutes and then at room temperature for 1.5 hours. The reaction solution was diluted with HO (0.2 mL) and DMF (to a total volume of 2 mL), filtered (syringe filter), and purified by preparative LC / MS using the following conditions: Column: XBridge C18, 200 mm x 19 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water (with 10 mM ammonium acetate); Mobile phase B: 95:5 acetonitrile:water (with 10 mM ammonium acetate); Gradient: 1% B hold for 0 min, 1–41% B over 20 min, then 100% B hold for 4 min; Flow rate: 20 mL / min; Column temperature: 25 °C. Fraction collection was triggered by MS and UV signals. Fractions containing the desired product were combined and dried by centrifugal evaporation to give 3-(2-(4-amino-7-(1H-pyrazol-3-yl)-2H-pyrazolo[3,4-c]quinolin-2-yl)ethyl)-1,1-dimethylurea (20.5 mg, 73%). 1H NMR (500 MHz, DMSO-d6) δ 8.64 (s, 1H), 7.94 (br d, J = 8.3 Hz, 1H), 7.88 (s, 1H), 7.76 - 7.54 (m, 2H), 6.73 (br s, 3H), 6.50 (br t, J = 5.4 Hz, 1H), 4.47 (br t, J = 5.9 Hz, 2H), 3.57 - 3.52 (m, 2H), 2.75 (s, 6H). Analytical LC / MS conditions: Column: Waters XBridge C18, 2.1 mm x 50 mm, 1.7 μm particles; Mobile phase A: 5:95 acetonitrile:water (with 0.1% trifluoroacetic acid); Mobile phase B: 95:5 Acetonitrile:water (containing 0.1% trifluoroacetic acid); Temperature: 50°C; Gradient: 0% B to 100% B over 3 min, then hold at 100% B for 0.50 min; Flow rate: 1 mL / min; Detection: MS and UV (220 nm). m / z 365.3 [M+H] + ;RT:0.89min.

[0291] Example 117. Preparation of phenyl N-{2-[4-amino-7-(1H-pyrazol-3-yl)-2H-pyrazolo[3,4-c]quinolin-2-yl]ethyl}carbamate [ka] To a solution of 2-(2-aminoethyl)-7-(1H-pyrazol-3-yl)-2H-pyrazolo[3,4-c]quinolin-4-amine, 2TFA (40 mg, 0.077 mmol) in DMF (384 μL) at 0° C., triethylamine (42.8 μL, 0.307 mmol) was added, followed by phenyl chloroformate (9.6 μL, 0.077 mmol). The reaction solution was stirred at 0° C. for 30 minutes. The reaction solution was diluted with HO (0.2 mL) and DMF (to a total volume of 2 mL), filtered (syringe filter), and purified by preparative LC / MS using the following conditions: Column: XBridge C18, 200 mm x 19 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water (with 0.1% trifluoroacetic acid); Mobile phase B: 95:5 acetonitrile:water (with 0.1% trifluoroacetic acid); Gradient: 5% B hold for 0 min, 5–45% B over 20 min, then 100% B hold for 4 min; Flow rate: 20 mL / min; Column temperature: 25 °C. Fraction collection was initiated by MS and UV signals. Fractions containing the desired product were combined and dried by centrifugal evaporation to give phenyl(2-(4-amino-7-(1H-pyrazol-3-yl)-2H-pyrazolo[3,4-c]quinolin-2-yl)ethyl)carbamate, TFA (4.9 mg, 12%). 1H NMR (500 MHz, DMSO-d6) δ 9.95 - 9.67 (m, 1H), 9.34 - 9.20 (m, 1H), 9.01 (s, 1H), 8.15 (br d, J=8.5 Hz, 1H), 8.12 (br s, 1H), 7.96 (br t, J=5.9 Hz, 1H), 7.92 (br d, J=8.0 Hz, 1H), 7.82 (br s, 1H), 7.30 (br t, J=7.6 Hz, 2H), 7.19 - 7.14 (m, 1H), 7.02 (br d, J=7.7 Hz, 2H), 6.80 (s, 1H), 4.64 (br t, J = 5.4 Hz, 2H), 3.70 - 3.65 (m, 2H). Analytical LC / MS conditions: Column: Waters Acquity UPLC BEH C18, 2.1x50 mm, 1.7 μm particles; Mobile phase A: 5:95 acetonitrile:water (with 0.1% trifluoroacetic acid); Mobile phase B: 95:5 acetonitrile:water (with 0.1% trifluoroacetic acid); Temperature: 50 °C; Gradient: 0 to 100% B over 3 min, then hold at 100% B for 0.75 min; Flow rate: 1.0 mL / min; Detection: UV: 220 nm. m / z 414.4 [M+H] + ;RT:1.26 minutes.

[0292] Example 118. Preparation of tert-butyl N-{2-[4-amino-7-(1H-pyrazol-3-yl)-2H-pyrazolo[3,4-c]quinolin-2-yl]ethyl}carbamate [ka] A mixture of tert-butyl (2-(4-amino-7-bromo-2H-pyrazolo[3,4-c]quinolin-2-yl)ethyl)carbamate (39 mg, 0.096 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (37.3 mg, 0.192 mmol), and cesium carbonate (94 mg, 0.29 mmol) was evacuated and backfilled with N, followed by the addition of 1,4-dioxane (864 μL) and HO (96 μL). The resulting mixture was sparged with N for 10 minutes, followed by the addition of 1,1′-bis(di-tert-butylphosphino)ferrocenepalladium dichloride (6.26 mg, 9.60 μmol). The mixture was sparged with N for 1 minute, then it was sealed and stirred at 100° C. for 1 hour. The reaction solution was cooled to room temperature, diluted with EtOAc (30 mL), and washed with H O (30 mL). The aqueous layer was extracted with EtOAc, and the combined organic layers were washed with saturated aqueous NaCl (30 mL), dried over Na SO , filtered, and concentrated in vacuo. The crude material was dissolved in DMF (2 mL), filtered (syringe filter), and purified by preparative LC / MS using the following conditions: Column: XBridge C18, 200 mm x 19 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water (with 10 mM ammonium acetate); Mobile phase B: 95:5 acetonitrile:water (with 10 mM ammonium acetate); Gradient: 7% B hold at 0 min, 7-45% B over 25 min, then 100% B hold at 7 min; Flow rate: 20 mL / min; Column temperature: 25 °C. Fraction collection was triggered by the MS signal. Fractions containing the desired product were combined and dried by centrifugal evaporation. This material was further purified by preparative LC / MS using the following conditions: Column: XBridge Phenyl, 200 mm x 19 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water (with 10 mM ammonium acetate); Mobile phase B: 95:5 acetonitrile:water (with 10 mM ammonium acetate); Gradient: 9% B hold for 0 min, 9-49% B over 20 min, then 100% B hold for 4 min; Flow rate: 20 mL / min; Column temperature: 25°C. Fraction collection was triggered by MS and UV signals.Fractions containing the desired product were combined and dried by centrifugal evaporation to give tert-butyl (2-(4-amino-7-(1H-pyrazol-3-yl)-2H-pyrazolo[3,4-c]quinolin-2-yl)ethyl)carbamate (5.7 mg, 15%). 1 H NMR (500 MHz, DMSO-d6) δ 8.66 (s, 1H), 7.97 - 7.88 (m, 2H), 7.73 - 7.67 (m, 1H), 7.64 (br d, J=6.6 Hz, 1H), 7.05 (br d, J=4.7 Hz, 1H), 7.02 - 6.83 (m, 2H), 6.74 (s, 1H), 4.47 (br t, J=5.0 Hz, 2H), 3.53 - 3.46 (m, 2H), 1.34 (s, 9H). Analytical LC / MS conditions: Column: Waters XBridge C18, 2.1mm x 50mm, 1.7μm particles; Mobile phase A:5:95 Acetonitrile:water (with 0.1% trifluoroacetic acid); Mobile phase B: 95:5 acetonitrile:water (with 0.1% trifluoroacetic acid); Temperature: 50°C; Gradient: 0% B to 100% B over 3 min, then hold at 100% B for 0.50 min; Flow rate: 1 mL / min; Detection: MS and UV (220 nm). m / z 394.1 [M+H] + ;RT:1.18 minutes.

[0293] Example 119. Preparation of N-{2-[4-amino-7-(1H-pyrazol-3-yl)-2H-pyrazolo[3,4-c]quinolin-2-yl]ethyl}-N-methylacetamide [ka] Step 1. tert-Butyl (2-(4-amino-7-bromo-2H-pyrazolo[3,4-c]quinolin-2-yl)ethyl)(methyl)carbamate To a room temperature solution of 7-bromo-2H-pyrazolo[3,4-c]quinolin-4-amine, TFA (513 mg, 1.36 mmol) in DMF (4534 μL) was added cesium carbonate (1330 mg, 4.08 mmol), followed by tert-butyl(2-chloroethyl)(methyl)carbamate (290 mg, 1.50 mmol) and lithium bromide (11.8 mg, 0.136 mmol). The suspension was stirred at room temperature for 19 hours and then at 50°C for 16 hours. The reaction solution was diluted with EtOAc (100 mL), washed with 10% aq. LiCl (2 x 50 mL), saturated aqueous NaCl (50 mL), dried over NaSO, and filtered. Celite was added, and the mixture was concentrated in vacuo. This material was dry loaded onto a column and purified by flash chromatography (40 g silica gel with a 25 g solid load cartridge; linear gradient 0 to 10% MeOH—CHCl) to give tert-butyl (2-(4-amino-7-bromo-2H-pyrazolo[3,4-c]quinolin-2-yl)ethyl)(methyl)carbamate (321 mg, 56%) as a yellow foam. NMR is consistent with a ∼2:1 ratio of rotamers. 1 H NMR (400 MHz, DMSO-d6) δ 8.70 - 8.64 (m, 1H), 7.85 (br d, J=8.3 Hz, 1H), 7.58 (d, J=2.0 Hz, 1H), 7.30 (dd, J=8.4, 2.0 Hz, 1H), 6.95 (br s, 2H), 4.54 (t, J=5.5 Hz, 2H), 3.70 (br d, J=3.0 Hz, 2H), 2.79 - 2.71 (m, 3H), 1.29 (br s, 3H), 1.01 (s, 6H). LC-MS m / z 420 / 422 [M+H] + .

[0294] Step 2. tert-Butyl (2-(4-amino-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-2H-pyrazolo[3,4-c]quinolin-2-yl)ethyl)(methyl)carbamate A mixture of tert-butyl (2-(4-amino-7-bromo-2H-pyrazolo[3,4-c]quinolin-2-yl)ethyl)(methyl)carbamate (320 mg, 0.761 mmol), 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (318 mg, 1.14 mmol) and cesium carbonate (744 mg, 2.28 mmol) was evacuated and backfilled with N, then 1,4-dioxane (6852 μL) and HO (761 μL) were added. The resulting mixture was sparged with N for 10 minutes, then [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (27.9 mg, 0.038 mmol) was added. The mixture was sparged with N for 1 minute, then it was sealed and stirred at 100 °C for 30 minutes. The reaction solution was cooled to room temperature, diluted with EtOAc (100 mL), washed with HO (100 mL) and saturated aqueous NaCl (100 mL), dried over NaSO, filtered, and concentrated in vacuo. The crude material was purified by flash chromatography (40 g silica gel; linear gradient 0 to 10% MeOH—CH2Cl2) to give tert-butyl (2-(4-amino-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-2H-pyrazolo[3,4-c]quinolin-2-yl)ethyl)(methyl)carbamate (305 mg, 81%) as a yellow foam. NMR was consistent with a ∼2:1 ratio of rotamers. 1H NMR (400 MHz, DMSO-d6) δ 8.74 - 8.66 (m, 1H), 8.01 (br d, J=7.9 Hz, 1H), 7.62 (d, J=1.6 Hz, 1H), 7.57 (d, J=1.8 Hz, 1H), 7.31 (dd, J=8.0, 1.8 Hz, 1H), 6.85 (br s, 2H), 6.48 (s, 1H), 5.30 (dd, J=9.9, 2.0 Hz, 1H), 4.57 (br t, J=5.5 Hz, 2H), 4.08 - 4.00 (m, 1H), 3.73 (br s, 2H), 3.63 - 3.53 (m, 1H), 2.77 - 2.69 (m, 3H), 2.46 - 2.37 (m, 1H), 2.01 - 1.89 (m, 1H), 1.79 (br d, J=12.3 Hz, 1H), 1.63 - 1.48 (m, 3H), 1.32 (br s, 3H), 1.13 - 1.02 (m, 6H). LC-MS m / z 492 [M+H] + .

[0295] Step 3. 2-(2-(methylamino)ethyl)-7-(1H-pyrazol-3-yl)-2H-pyrazolo[3,4-c]quinolin-4-amine To a solution of tert-butyl (2-(4-amino-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-2H-pyrazolo[3,4-c]quinolin-2-yl)ethyl)(methyl)carbamate (304 mg, 0.618 mmol) in CHCl (1546 μL) at room temperature was added TFA (1546 μL). The reaction solution was stirred at room temperature for 2 hours. The reaction solution was concentrated to approximately half its volume under a stream of N, and it was added dropwise to EtO (20 mL). The resulting solid was collected by vacuum filtration and washed with EtO (3 x 2 mL) to give 2-(2-(methylamino)ethyl)-7-(1H-pyrazol-3-yl)-2H-pyrazolo[3,4-c]quinolin-4-amine, 2TFA (272 mg, 82%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 13.70 - 12.93 (m, 1H), 9.84 - 9.66 (m, 1H), 9.45 - 9.26 (m, 1H), 9.03 (s, 1H), 8.79 - 8.65 (m, 2H), 8.19 - 8.10 (m, 2H), 7.93 (br d, J=8.0 Hz, 1H), 7.85 (br s, 1H), 6.80 (d, J=2.0 Hz, 1H), 4.85 (br t, J=5.6 Hz, 2H), 3.61 (br s, 2H), 2.70 (br s, 3H). LC-MS m / z 308 [M+H] + .

[0296] Step 4. N-{2-[4-amino-7-(1H-pyrazol-3-yl)-2H-pyrazolo[3,4-c]quinolin-2-yl]ethyl}-N-methylacetamide To a solution of 2-(2-(methylamino)ethyl)-7-(1H-pyrazol-3-yl)-2H-pyrazolo[3,4-c]quinolin-4-amine, 2TFA (20 mg, 0.037 mmol) in DMF (208 μL) at room temperature, was added acetic acid (2.136 μL, 0.037 mmol), followed by N,N-diisopropylethylamine (26.0 μL, 0.149 mmol) and HATU (14.20 mg, 0.037 mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction solution was diluted with HO (0.1 mL) and DMF (to a total volume of 2 mL), filtered (syringe filter), and purified by preparative LC / MS using the following conditions: Column: XBridge C18, 200 mm x 19 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water (with 0.1% trifluoroacetic acid); Mobile phase B: 95:5 Acetonitrile:water (with 0.1% trifluoroacetic acid); gradient: 0% B hold at 0 min, 0-40% B over 20 min, then 100% B hold at 4 min; flow rate: 20 mL / min; column temperature: 25 °C. Fraction collection was initiated by UV signal. Fractions containing the desired product were combined and dried by centrifugal evaporation to give N-(2-(4-amino-7-(1H-pyrazol-3-yl)-2H-pyrazolo[3,4-c]quinolin-2-yl)ethyl)-N-methylacetamide, TFA (14.1 mg, 80%). NMR is consistent with a ∼2:1 ratio of rotamers. 1H NMR (500 MHz, DMSO-d6) δ 8.86 (s, 1H), 8.07 - 7.99 (m, 2H), 7.80 (br dd, J=8.1, 6.6 Hz, 1H), 7.75 (br d, J=1.5 Hz, 1H), 6.74 (s, 1H), 4.70 (br t, J=5.9 Hz, 0.67H), 4.61 (br t, J=6.1 Hz, 1.33H), 3.92 - 3.86 (m, 0.67H), 3.83 (br t, J=6.1 Hz, 1.33H), 2.87 (s, 2H), 2.79 (s, 1H), 1.96 (s, 2H), 1.91 (s, 1H). Analytical LC / MS conditions: Column: Waters Acquity UPLC BEH C18, 2.1x50mm, 1.7μm particles; Mobile phase A: 5:95 acetonitrile:water (with 0.1% trifluoroacetic acid); Mobile phase B: 95:5 acetonitrile:water (with 0.1% trifluoroacetic acid); Temperature: 50°C; Gradient: 0 to 100% B over 3 min, then hold at 100% B for 0.75 min; Flow rate: 1.0 mL / min; Detection: UV: 220 nm. m / z 350.3 [M+H] + ;RT:0.87 minutes.

[0297] Example 120. Preparation of N-{2-[4-amino-7-(1H-pyrazol-3-yl)-2H-pyrazolo[3,4-c]quinolin-2-yl]ethyl}-N-methylbenzamide [ka] To benzoic acid (12.6 mg, 0.103 mmol) was added N,N-diisopropylethylamine (0.5 M solution in DMF) (0.374 mL, 0.187 mmol), followed by HATU (0.4 M solution in DMF) (0.233 mL, 0.093 mmol). The reaction solution was stirred at room temperature for 5 minutes, and then it was added dropwise to a solution of 2-(2-(methylamino)ethyl)-7-(1H-pyrazol-3-yl)-2H-pyrazolo[3,4-c]quinolin-4-amine, 2TFA (0.75 M N-diisopropylethylamine, 0.25 M solution in DMF) (0.374 mL, 0.093 mmol). The clear orange solution was stirred at room temperature for 1 hour. The reaction solution was diluted with HO (0.1 mL) and DMF (to a total volume of 2 mL), filtered (syringe filter), and purified by preparative LC / MS using the following conditions: Column: XBridge C18, 200 mm x 19 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water (with 10 mM ammonium acetate); Mobile phase B: 95:5 Acetonitrile:water (with 10 mM ammonium acetate); gradient: 7% B hold for 0 min, 7-47% B over 20 min, then 100% B hold for 4 min; flow rate: 20 mL / min; column temperature: 25 °C. Fraction collection was initiated by MS and UV signals. Fractions containing the desired product were combined and dried by centrifugal evaporation to give N-(2-(4-amino-7-(1H-pyrazol-3-yl)-2H-pyrazolo[3,4-c]quinolin-2-yl)ethyl)-N-methylbenzamide (30.5 mg, 79%). NMR is consistent with a ∼2:1 ratio of rotamers. 1H NMR (500 MHz, DMSO-d6) δ 8.81 (br s, 0.67H), 8.63 - 8.54 (m, 0.33H), 7.98 - 7.85 (m, 2H), 7.72 - 7.67 (m, 1H), 7.64 (br d, J=7.4 Hz, 1H), 7.46 - 7.12 (m, 4H), 6.94 - 6.56 (m, 4H), 4.74 - 4.68 (m, 1.33H), 4.60 - 4.54 (m, 067H), 4.01 - 3.95 (m, 1.33H), 3.82 - 3.75 (m, 0.67H), 3.02 (br s, 1H), 2.74 (br s, 2H). Analytical LC / MS conditions: Column: Waters XBridge C18, 2.1 mm x 50 mm, 1.7 μm particles; Mobile phase A: 5:95 acetonitrile:water (with 0.1% trifluoroacetic acid); Mobile phase B: 95:5 acetonitrile:water (with 0.1% trifluoroacetic acid); Temperature: 50 °C; Gradient: 0% B to 100% B over 3 min, then hold at 100% B for 0.50 min; Flow rate: 1 mL / min; Detection: MS and UV (220 nm). m / z 412.1 [M+H] + ;RT:1.21 minutes.

[0298] Example 121. Preparation of 2-{2-[benzyl(methyl)amino]ethyl}-7-(1H-pyrazol-3-yl)-2H-pyrazolo[3,4-c]quinolin-4-amine [ka] To a solution of 2-(2-(methylamino)ethyl)-7-(1H-pyrazol-3-yl)-2H-pyrazolo[3,4-c]quinolin-4-amine, 2TFA (20 mg, 0.037 mmol) in DMF (187 μL) at room temperature, benzaldehyde (5.0 μL, 0.049 mmol) was added, followed by sodium triacetoxyborohydride (23.8 mg, 0.112 mmol). The reaction solution was stirred at room temperature for 1 hour. The reaction solution was diluted with HO (100 μL) and DMF (to a total volume of 2 mL), filtered (syringe filter), and purified by preparative LC / MS using the following conditions: Column: XBridge C18, 200 mm x 19 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water (with 0.1% trifluoroacetic acid); Mobile phase B: 95:5 acetonitrile:water (with 0.1% trifluoroacetic acid); Gradient: 12% B held for 0 min, 12–37% B over 25 min, then 100% B held for 2 min; Flow rate: 20 mL / min; Column temperature: 25 °C. Fraction collection was initiated by MS and UV signals. Fractions containing the desired product were combined and dried by centrifugal evaporation to give 2-(2-(benzyl(methyl)amino)ethyl)-7-(1H-pyrazol-3-yl)-2H-pyrazolo[3,4-c]quinolin-4-amine, TFA (10.0 mg, 50%). 1H NMR (500 MHz, DMSO-d6) δ 8.98 (s, 1H), 8.14 (s, 1H), 8.12 (d, J=8.3 Hz, 1H), 7.93 (dd, J=8.2, 1.4 Hz, 1H), 7.81 (d, J=1.9 Hz, 1H), 7.38 - 7.29 (m, 5H), 6.78 (d, J=2.3 Hz, 1H), 4.91 - 4.81 (m, 2H), 4.23 - 3.97 (m, 2H). Analytical LC / MS conditions: Column: Waters Acquity UPLC BEH C18, 2.1x50mm, 1.7μm particles; Mobile phase A: 5:95 Acetonitrile:water (with 0.1% trifluoroacetic acid); Mobile phase B: 95:5 acetonitrile:water (with 0.1% trifluoroacetic acid); Temperature: 50°C; Gradient: 0 to 100% B over 3 min, then hold at 100% B for 0.75 min; Flow rate: 1.0 mL / min; Detection: UV: 220 nm. m / z 398 [M+H] + ;RT:1.03 minutes.

[0299] Example 122. Preparation of 1-{2-[4-amino-7-(1H-pyrazol-3-yl)-2H-pyrazolo[3,4-c]quinolin-2-yl]ethyl}pyrrolidin-2-one [ka] Step 1. N-(2-[7-bromo-2H-pyrazolo[3,4-c]quinolin-2-yl]ethyl)-4-chlorobutanamide In a 100 mL three-neck round-bottom flask were placed 2-(2-aminoethyl)-7-bromo-2H-pyrazolo[3,4-c]quinolin-4-amine (900 mg, 2.94 mmol, 1 equiv.), DCM (30 mL), pyridine (697.6 mg, 8.82 mmol, 3 equiv.), and 4-chlorobutanoyl chloride (829.0 mg, 5.88 mmol, 2 equiv.). The resulting solution was stirred at room temperature for 16 hours. The reaction solution was then quenched by the addition of MeOH. The resulting mixture was concentrated. The residue was loaded onto a silica gel column using dichloromethane / methanol (10:1) to afford N-(2-[7-bromo-2H-pyrazolo[3,4-c]quinolin-2-yl]ethyl)-4-chlorobutanamide (240 mg, 21%) as a pale yellow solid. LC-MS m / z [M+H] + =390.1.

[0300] Step 2. 1-(2-[4-amino-7-bromo-2H-pyrazolo[3,4-c]quinolin-2-yl]ethyl)pyrrolidin-2-one A 25 mL round-bottom flask was charged with N-(2-[4-amino-7-bromo-2H-pyrazolo[3,4-c]quinolin-2-yl]ethyl)-4-chlorobutanamide (300 mg, 0.73 mmol, 1 equiv.) in THF (7 mL). t-BuOK (163.9 mg, 1.46 mmol, 2 equiv.) was then added. The resulting solution was stirred at room temperature for 16 hours. The reaction solution was quenched by the addition of HO (20 mL). The resulting solution was extracted with ethyl acetate (3×20 mL). The resulting mixture was concentrated. The residue was loaded onto a silica gel column with dichloromethane / methanol (10:1) to afford 1-(2-[4-amino-7-bromo-2H-pyrazolo[3,4-c]quinolin-2-yl]ethyl)pyrrolidin-2-one (200 mg, 73%) as a pale yellow solid. LC-MS: (ES, m / z): [M+H] + =374.1.

[0301] Step 3. 1-[2-[4-amino-7-(1H-pyrazol-3-yl)-2H-pyrazolo[3,4-c]quinolin-2-yl]ethyl]pyrrolidin-2-one In a 20 mL sealed tube, purged with an inert atmosphere of nitrogen and maintained under an inert atmosphere, was placed 1-(2-[4-amino-7-bromo-2H-pyrazolo[3,4-c]quinolin-2-yl]ethyl)pyrrolidin-2-one (200 mg, 0.53 mmol, 1 equiv.), CsCO (348.3 mg, 1.07 mmol, 2 equiv.), 3-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (207.4 mg, 1.07 mmol, 2 equiv.), Pd(dppf)Cl (39.1 mg, 0.05 mmol, 0.1 equiv.) in dioxane (5 mL), and HO (1.25 mL). The resulting solution was stirred at 80 °C for 16 h. The resulting mixture was cooled to room temperature and concentrated. The residue was loaded onto a silica gel column using dichloromethane / methanol (10:1). The crude product was purified by Prep-HPLC using the following conditions: column, XBridge Shield RP18 OBD column, 19*250 mm, 10 μm; mobile phase, water (10 mM NH4HCO3) and ACN (15% Phase B to 40% in 7 min); detector: UV. This gave 1-[2-[4-amino-7-(1H-pyrazol-3-yl)-2H-pyrazolo[3,4-c]quinolin-2-yl]ethyl]pyrrolidin-2-one (35.4 mg, 18%) as a white solid. 1 H-NMR:(300 MHz, DMSO-d6, ppm):δ 13.32-12.85 (m br, 1H), 8.72 (s, 1H), 7.90-7.52 (m, 4H), 6.86 (s, 1H), 6.76 (s, 2H), 4.58-4.56 (m, LC method: Column: Kinetex EVO 3.0 mm x 50 mm, 2.6 μm particles; Mobile phase A: water (containing 0.03% NH3H2O); Mobile phase B: acetonitrile; Temperature: 40 °C; Gradient: 10% B to 95% B over 2 min, then hold at 95% B for 0.60 min; Flow rate: 1.2 mL / min. m / z 362.2 [M+H] + . RT: 0.939 minutes.

[0302] Example 123. Preparation of N-{3-[4-amino-7-(1H-pyrazol-3-yl)-2H-pyrazolo[3,4-c]quinolin-2-yl]propyl}benzamide [ka] Step 1. tert-Butyl (3-(4-amino-7-bromo-2H-pyrazolo[3,4-c]quinolin-2-yl)propyl)carbamate To a room temperature solution of 7-bromo-2H-pyrazolo[3,4-c]quinolin-4-amine, TFA (0.40 g, 1.06 mmol) in DMF (3.54 mL) was added cesium carbonate (1.037 g, 3.18 mmol) followed by tert-butyl (3-bromopropyl)carbamate (0.278 g, 1.17 mmol). The suspension was stirred at room temperature for 40 hours. The reaction solution was diluted with EtOAc (50 mL) and H2O (50 mL). The layers were separated and the aqueous layer was extracted with EtOAc (50 mL). The combined organic layers were washed with saturated aqueous NaCl (50 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The crude material was purified by flash chromatography (24 g silica gel; linear gradient 0 to 10% MeOH—CH2Cl2) to afford tert-butyl (3-(4-amino-7-bromo-2H-pyrazolo[3,4-c]quinolin-2-yl)propyl)carbamate (379 mg, 85%) as a white foam. 1 H NMR (400 MHz, DMSO-d6) δ 8.74 (s, 1H), 7.83 (d, J=8.3 Hz, 1H), 7.59 (d, J=2.0 Hz, 1H), 7.31 (dd, J=8.3, 2.1 Hz, 1H), 7.02 - 6.92 (m, LC-MS m / z 420 / 422 [M+H] + .

[0303] Step 2. tert-Butyl (3-(4-amino-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-2H-pyrazolo[3,4-c]quinolin-2-yl)propyl)carbamate A mixture of tert-butyl (3-(4-amino-7-bromo-2H-pyrazolo[3,4-c]quinolin-2-yl)propyl)carbamate (378 mg, 0.899 mmol), 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (375 mg, 1.35 mmol), and cesium carbonate (879 mg, 2.70 mmol) was evacuated and backfilled with N, followed by the addition of 1,4-dioxane (8094 μL) and HO (899 μL). The resulting mixture was sparged with N for 10 minutes, followed by the addition of [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (32.9 mg, 0.045 mmol). The mixture was sparged with N for 1 minute, and then it was stirred at 100 °C for 30 minutes. The reaction solution was cooled to room temperature, diluted with EtOAc (200 mL), washed with HO (100 mL) and saturated aqueous NaCl (100 mL), dried over NaSO, filtered, and concentrated in vacuo. The crude material was purified by flash chromatography (40 g silica gel; linear gradient 0 to 10% MeOH—CHCl) to afford tert-butyl (3-(4-amino-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-2H-pyrazolo[3,4-c]quinolin-2-yl)propyl)carbamate (474 ​​mg, quant.) as a brown foam. 1H NMR (400 MHz, DMSO-d6) δ 8.77 (s, 1H), 7.99 (d, J=8.0 Hz, 1H), 7.62 (d, J=1.7 Hz, 1H), 7.58 (d, J=1.7 Hz, 1H), 7.32 (dd, J=8.0, 1.7 Hz, 1H), 6.98 (br t, J=5.4 Hz, 1H), 6.89 (s, 2H), 6.48 (d, J=1.8 Hz, 1H), 5.30 (dd, J=9.9, 2.0 Hz, 1H), 4.46 (t, J=6.9 Hz, 2H), 4.04 (br d, J=9.3 Hz, 1H), 3.62 - 3.53 (m, 1H), 2.97 (q, J=6.5 Hz, 2H), 2.46 - 2.36 (m, 1H), 2.11 - 2.01 (m, 2H), 1.99 - 1.89 (m, 1H), 1.79 (br d, J=12.5 Hz, 1H), 1.64 - 1.48 (m, 3H), 1.38 (s, 9H). LC-MS m / z 492 [M+H] + .

[0304] Step 3. 2-(3-aminopropyl)-7-(1H-pyrazol-3-yl)-2H-pyrazolo[3,4-c]quinolin-4-amine, 2TFA To a room temperature solution of tert-butyl (3-(4-amino-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-2H-pyrazolo[3,4-c]quinolin-2-yl)propyl)carbamate (442 mg, 0.899 mmol) in CHCl (2248 μL) was added TFA (2248 μL). The reaction was stirred at room temperature for 2 hours. The reaction was concentrated to approximately half its volume and then added dropwise to EtO (50 mL). The resulting solid was collected by vacuum filtration and washed with EtO (3 × 2 mL) to give 2-(3-aminopropyl)-7-(1H-pyrazol-3-yl)-2H-pyrazolo[3,4-c]quinolin-4-amine, 2TFA (423 mg, 88%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 13.51 (br s, 1H), 9.86 - 9.70 (m, 1H), 9.29 - 9.17 (m, 1H), 9.01 (s, 1H), 8.15 (br s, 1H), 8.13 (d, J=8.3 Hz, 1H), 7.92 (dd, J=8.3, 1.1 Hz, 1H), 7.83 (br d, J=9.2 Hz, 4H), 6.80 (d, J=2.2 Hz, 1H), 4.63 (t, J=6.7 Hz, 2H), 2.94 - 2.84 (m, 2H), 2.29 - 2.19 (m, 2H). LC-MS m / z 308 [M+H] + .

[0305] Step 4. N-{3-[4-amino-7-(1H-pyrazol-3-yl)-2H-pyrazolo[3,4-c]quinolin-2-yl]propyl}benzamide To a solution of 2-(3-aminopropyl)-7-(1H-pyrazol-3-yl)-2H-pyrazolo[3,4-c]quinolin-4-amine, 2TFA (40 mg, 0.075 mmol), and benzoic acid (9.1 mg, 0.075 mmol) in DMF (374 μL) at room temperature, N,N-diisopropylethylamine (52.1 μL, 0.299 mmol) was added, followed by HATU (28.4 mg, 0.075 mmol). The reaction mixture was stirred at room temperature for 30 minutes. The reaction solution was diluted with HO (0.2 mL) and DMF (to a total volume of 2 mL), filtered (syringe filter), and purified by preparative LC / MS using the following conditions: Column: XBridge C18, 200 mm x 19 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water (with 10 mM ammonium acetate); Mobile phase B: 95:5 acetonitrile:water (with 10 mM ammonium acetate); Gradient: 7% B hold for 0 min, 7–47% B over 20 min, then 100% B hold for 4 min; Flow rate: 20 mL / min; Column temperature: 25 °C. Fraction collection was triggered by MS and UV signals. Fractions containing the desired product were combined and dried by centrifugal evaporation to give N-(3-(4-amino-7-(1H-pyrazol-3-yl)-2H-pyrazolo[3,4-c]quinolin-2-yl)propyl)benzamide (10.4 mg, 34%). 1H NMR (500 MHz, DMSO-d6) δ 8.76 (s, 1H), 8.58 (br t, J=5.2 Hz, 1H), 7.92 (d, J=8.3 Hz, 1H), 7.90 (s, 1H), 7.83 (br d, J=7.4 Hz, 2H), 7.69 (br s, 1H), 7.64 (br d, J=7.7 Hz, 1H), 7.54 - 7.49 (m, 1H), 7.47 - 7.43 (m, 2H), 6.99 - 6.76 (m, 2H), 6.73 (s, 1H), 4.51 (br t, J=6.7 Hz, 2H), 3.38 - 3.31 (m, 2H), 2.26 - 2.17 (m, 2H). Analytical LC / MS conditions: Column: Waters XBridge C18, 2.1 mm x 50 mm, 1.7 μm particles; Mobile phase A: 5:95 acetonitrile:water (with 0.1% trifluoroacetic acid); Mobile phase B: 95:5 acetonitrile:water (with 0.1% trifluoroacetic acid); Temperature: 50 °C; Gradient: 0% B to 100% B over 3 min, then hold at 100% B for 0.50 min; Flow rate: 1 mL / min; Detection: MS and UV (220 nm). m / z 412.1 [M+H] + ;RT:1.17 minutes.

[0306] Examples 124-126 were prepared from the appropriate starting materials following synthetic methods similar to those described for Example 123. Analytical LC / MS conditions: Column: Waters XBridge C18, 2.1 mm x 50 mm, 1.7 μm particles; Mobile phase A: 5:95 acetonitrile:water (with 0.1% trifluoroacetic acid); Mobile phase B: 95:5 acetonitrile:water (with 0.1% trifluoroacetic acid); Temperature: 50°C; Gradient: 0% B to 100% B over 3 minutes, then hold at 100% B for 0.75 minutes; Flow rate: 1 mL / min; Detection: MS and UV (220 nm).

[0307] [Table 24]

[0308] Example 127. Preparation of tert-butyl N-{2-[4-amino-7-(thiophen-2-yl)-2H-pyrazolo[3,4-c]quinolin-2-yl]ethyl}carbamate [ka] A mixture of tert-butyl (2-(4-amino-7-bromo-2H-pyrazolo[3,4-c]quinolin-2-yl)ethyl)carbamate (400 mg, 0.985 mmol), 4,4,5,5-tetramethyl-2-(thiophen-2-yl)-1,3,2-dioxaborolane (310 mg, 1.48 mmol), and cesium carbonate (962 mg, 2.95 mmol) was evacuated and backfilled with N, followed by the addition of 1,4-dioxane (8861 μL) and HO (985 μL). The resulting mixture was sparged with N for 10 minutes, followed by the addition of [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (36.0 mg, 0.049 mmol). The mixture was sparged with N for 1 minute, then it was sealed and stirred at 100 °C for 1 hour. The reaction solution was cooled to room temperature, diluted with EtOAc (100 mL), washed with HO (100 mL) and saturated aqueous NaCl (100 mL), dried over NaSO, filtered, and concentrated in vacuo. The crude material was purified by flash chromatography (40 g silica gel; linear gradient 0 to 10% MeOH-CHCl) to afford tert-butyl (2-(4-amino-7-(thiophen-2-yl)-2H-pyrazolo[3,4-c]quinolin-2-yl)ethyl)carbamate (396 mg, 98%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.66 (s, 1H), 7.92 (d, J=8.1 Hz, 1H), 7.70 (d, J=1.8 Hz, 1H), 7.55 (dd, J=3.6, 1.0 Hz, 1H), 7.53 (dd, J=5.1, 1.0 Hz, 1H), 7.49 (dd, J=8.1, 1.9 Hz, 1H), 7.15 (dd, J=5.0, 3.6 Hz, 1H), 7.07 (br t, J=5.7 Hz, 1H), 6.82 (br s, 2H), 4.46 (br t, J=6.1 Hz, 2H), 3.49 (q, J=6.0 Hz, 2H), 1.34 (s, 9H); LC-MS m / z 410 [M+H] + .

[0309] Example 128. Preparation of N-{2-[4-amino-7-(thiophen-2-yl)-2H-pyrazolo[3,4-c]quinolin-2-yl]ethyl}-2-methyl-1,3-oxazole-4-carboxamide [ka] Step 1. 2-(2-aminoethyl)-7-(thiophen-2-yl)-2H-pyrazolo[3,4-c]quinolin-4-amine, 2TFA To a room temperature suspension of tert-butyl (2-(4-amino-7-(thiophen-2-yl)-2H-pyrazolo[3,4-c]quinolin-2-yl)ethyl)carbamate (376 mg, 0.918 mmol) in CHCl (2295 μL) was added TFA (2295 μL), resulting in an orange solution (note rapid gas evolution). The reaction was stirred at room temperature for 30 min. The reaction was concentrated to approximately half its volume and then added dropwise to EtO (25 mL). The resulting solid was collected by vacuum filtration and washed with EtO (3 × 10 mL) to give 2-(2-aminoethyl)-7-(thiophen-2-yl)-2H-pyrazolo[3,4-c]quinolin-4-amine, 2TFA (428.6 mg, 87%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 9.95 - 9.10 (m, 2H), 9.02 (s, 1H), 8.13 (d, J=8.2 Hz, 1H), 8.17 - 8.05 (m, 2H), 7.93 (d, J=1.3 Hz, 1H), 7.83 (br d, J=8.1 Hz, 1H), 7.65 (dd, J=5.1, 1.0 Hz, 1H), 7.63 (dd, J=3.6, 1.1 Hz, 1H), 7.21 (dd, J=5.1, 3.7 Hz, 1H), 4.76 (t, J=5.7 Hz, 2H), 3.55 - 3.48 (m, 2H); LC-MS m / z 310 [M+H] + .

[0310] Step 2. N-{2-[4-amino-7-(thiophen-2-yl)-2H-pyrazolo[3,4-c]quinolin-2-yl]ethyl}-2-methyl-1,3-oxazole-4-carboxamide To 2-methyloxazole-4-carboxylic acid (13.0 mg, 0.092 mmol), N,N-diisopropylethylamine (0.5 M solution in DMF) (0.335 mL, 0.167 mmol) was added, followed by HATU (0.4 M solution in DMF) (0.209 mL, 0.084 mmol). The reaction solution was stirred at room temperature for 5 minutes and then added dropwise to a suspension of 2-(2-aminoethyl)-7-(thiophen-2-yl)-2H-pyrazolo[3,4-c]quinolin-4-amine, 2TFA (0.75 M N, 0.25 M in DMF containing N-diisopropylethylamine) (0.335 mL, 0.084 mmol). The reaction solution was stirred at room temperature for 2 hours. The reaction solution was diluted with HO (0.1 mL) and DMF (to a total volume of 2 mL), filtered (syringe filter), and purified by preparative LC / MS using the following conditions: Column: XBridge C18, 200 mm x 19 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water (with 10 mM ammonium acetate); Mobile phase B: 95:5 acetonitrile:water (with 10 mM ammonium acetate); Gradient: 16% B hold for 0 min, 16–56% B over 20 min, then 100% B hold for 4 min; Flow rate: 20 mL / min; Column temperature: 25 °C. Fraction collection was triggered by MS and UV signals. Fractions containing the desired product were combined and dried by centrifugal evaporation to give N-(2-(4-amino-7-(thiophen-2-yl)-2H-pyrazolo[3,4-c]quinolin-2-yl)ethyl)-2-methyloxazole-4-carboxamide (22.9 mg, 59%). 1H NMR (500 MHz, DMSO-d6) δ 8.74 (s, 1H), 8.49 (br t, J=5.6 Hz, 1H), 8.41 (s, 1H), 7.95 (d, J=8.0 Hz, 1H), 7.74 (d, J=1.4 Hz, 1H), 7.57 - 7.50 (m, 3H), 7.40 - 7.24 (m, 2H), 7.15 (dd, J=5.0, 3.9 Hz, 1H), 4.61 (br t, J=6.1 Hz, 2H), 3.80 (q, J=5.8 Hz, 2H), 2.42 (s, 3H). Analytical LC / MS conditions: Column: Waters XBridge C18, 2.1 mm x 50 mm, 1.7 μm particles; Mobile phase A: 5:95 acetonitrile:water (with 0.1% trifluoroacetic acid); Mobile phase B: 95:5 acetonitrile:water (with 0.1% trifluoroacetic acid); Temperature: 50 °C; Gradient: 0% B to 100% B over 3 min, then hold at 100% B for 0.50 min; Flow rate: 1 mL / min; Detection: MS and UV (220 nm). m / z 419 [M+H] + ;RT:1.34 minutes.

[0311] Examples 129-131 were prepared from the appropriate starting materials following synthetic methods similar to those described for Example 128. Analytical LC / MS conditions: Column: Waters XBridge C18, 2.1 mm x 50 mm, 1.7 μm particles; Mobile phase A: 5:95 acetonitrile:water (with 0.1% trifluoroacetic acid); Mobile phase B: 95:5 acetonitrile:water (with 0.1% trifluoroacetic acid); Temperature: 50°C; Gradient: 0% B to 100% B over 3 minutes, then hold at 100% B for 0.75 minutes; Flow rate: 1 mL / min; Detection: MS and UV (220 nm).

[0312] [Table 25]

[0313] Example 132. Preparation of N-{2-[4-amino-7-(1H-pyrazol-1-yl)-2H-pyrazolo[3,4-c]quinolin-2-yl]ethyl}benzamide [ka] Step 1. tert-Butyl (2-(4-amino-7-(1H-pyrazol-1-yl)-2H-pyrazolo[3,4-c]quinolin-2-yl)ethyl)carbamate A mixture of tert-butyl (2-(4-amino-7-bromo-2H-pyrazolo[3,4-c]quinolin-2-yl)ethyl)carbamate (0.498 g, 1.23 mmol), 1H-pyrazole (0.125 g, 1.84 mmol), and sodium carbonate (0.520 g, 4.90 mmol) was evacuated and backfilled with N, and then DMSO (12.26 mL) was added. The resulting mixture was sparged with N for 10 minutes, and then N,N'-dimethylethylenediamine (0.396 mL, 3.68 mmol) and copper(I) iodide (0.350 g, 1.84 mmol) were added. The mixture was sparged with N for 1 minute, then it was sealed and stirred at 120 °C for 1 hour. The reaction solution was cooled to room temperature. The reaction solution was diluted with EtOAc (200 mL), washed with HO (200 mL), 1:1 HO aqueous NHOH (200 mL), and saturated aqueous NaCl (200 mL), dried over NaSO, filtered, and concentrated in vacuo. The crude material was purified by flash chromatography (80 g silica gel; linear gradient 0 to 10% MeOH-CHCl) to give tert-butyl (2-(4-amino-7-(1H-pyrazol-1-yl)-2H-pyrazolo[3,4-c]quinolin-2-yl)ethyl)carbamate (395 mg, 82%). 1H NMR (400 MHz, DMSO-d6) δ 8.66 (s, 1H), 8.55 (d, J=2.2 Hz, 1H), 7.99 (d, J=8.4 Hz, 1H), 7.87 (d, J=2.1 Hz, 1H), 7.75 (d, J=1.5 Hz, 1H), 7.67 (dd, J=8.4, 2.3 Hz, 1H), 7.07 (br t, J=5.5 Hz, 1H), 6.89 (br s, 2H), 6.55 - 6.53 (m, 1H), 4.46 (br t, J=6.0 Hz, 2H), 3.49 (q, J=6.0 Hz, 2H), 1.34 (s, 9H); LC-MS m / z 394 [M+H] + .

[0314] Step 2. 2-(2-aminoethyl)-7-(1H-pyrazol-1-yl)-2H-pyrazolo[3,4-c]quinolin-4-amine, 2TFA To a room temperature solution of tert-butyl (2-(4-amino-7-(1H-pyrazol-1-yl)-2H-pyrazolo[3,4-c]quinolin-2-yl)ethyl)carbamate (396 mg, 1.01 mmol) in CHCl (2516 μL) was added TFA (2516 μL) (note gas evolution). The reaction was stirred at room temperature for 30 minutes. The reaction was concentrated to approximately half its volume and then added dropwise to EtO (25 mL). The resulting solid was collected by vacuum filtration and washed with EtO (3 × 10 mL) to give 2-(2-aminoethyl)-7-(1H-pyrazol-1-yl)-2H-pyrazolo[3,4-c]quinolin-4-amine, 2TFA (464 mg, 88%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 9.94 - 9.69 (m, 1H), 9.52 - 9.28 (m, 1H), 9.02 (s, 1H), 8.62 (d, J=2.5 Hz, 1H), 8.27 - 8.21 (m, 2H), 8.16 - 8.06 (m, 3H), 8.01 - 7.97 (m, 1H), 7.85 (d, J=1.4 Hz, 1H), 6.67 - 6.60 (m, 1H), 4.77 (t, J=5.6 Hz, 2H), 3.51 (br d, J=3.8 Hz, 2H);LC-MS m / z 294 [M+H] + .

[0315] Step 3. N-{2-[4-amino-7-(1H-pyrazol-1-yl)-2H-pyrazolo[3,4-c]quinolin-2-yl]ethyl}benzamide To benzoic acid (11.6 mg, 0.095 mmol) was added N,N-diisopropylethylamine (0.5 M solution in DMF) (0.345 mL, 0.173 mmol), followed by HATU (0.4 M solution in DMF) (0.216 mL, 0.086 mmol). The reaction solution was stirred at room temperature for 5 minutes, and then added to a suspension of 2-(2-aminoethyl)-7-(1H-pyrazol-1-yl)-2H-pyrazolo[3,4-c]quinolin-4-amine, 2TFA (0.75 M N, 0.25 M in DMF containing N-diisopropylethylamine) (0.345 mL, 0.086 mmol). The reaction solution was stirred at room temperature for 2 hours. The reaction solution was diluted with HO (0.1 mL) and DMF (to a total volume of 2 mL), filtered (syringe filter), and purified by preparative LC / MS using the following conditions: Column: XBridge C18, 200 mm x 19 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water (with 10 mM ammonium acetate); Mobile phase B: 95:5 Acetonitrile:water (containing 10 mM ammonium acetate); gradient: 8% B held at 0 min, 8–48% B over 25 min, then 100% B held at 7 min; flow rate: 20 mL / min; column temperature: 25°C. Fraction collection was triggered by MS signal. Fractions containing the desired product were combined and dried by centrifugal evaporation to give N-(2-(4-amino-7-(1H-pyrazol-1-yl)-2H-pyrazolo[3,4-c]quinolin-2-yl)ethyl)benzamide (23.1 mg, 67%). 1H NMR (500 MHz, DMSO-d6) δ 8.72 (s, 1H), 8.70 - 8.66 (m, 1H), 8.54 (br d, J=1.9 Hz, 1H), 8.01 - 7.95 (m, 1H), 7.87 (br s, 1H), 7.84 - 7.78 (m, 2H), 7.74 (s, 1H), 7.68 - 7.64 (m, 1H), 7.54 - 7.49 (m, 1H), 7.48 - 7.42 (m, 2H), 6.89 (br s, 2H), 6.54 (br s, 1H), 4.66 - 4.60 (m, 2H), 3.85 - 3.80 (m, 2H). Analytical LC / MS conditions: Column: Waters XBridge C18, 2.1 mm x 50 mm, 1.7 μm particles; Mobile phase A: 5:95 acetonitrile:water (with 0.1% trifluoroacetic acid); Mobile phase B: 95:5 acetonitrile:water (with 0.1% trifluoroacetic acid); Temperature: 50 °C; Gradient: 0% B to 100% B over 3 min, then hold at 100% B for 0.50 min; Flow rate: 1 mL / min; Detection: MS and UV (220 nm). m / z 398.1 [M+H] + ;RT:1.24 minutes.

[0316] Example 133. Preparation of N-{2-[4-amino-7-(1H-pyrazol-1-yl)-2H-pyrazolo[3,4-c]quinolin-2-yl]ethyl}pyridine-2-carboxamide [ka] To picolinic acid (11.7 mg, 0.095 mmol) was added N,N-diisopropylethylamine (0.5 M solution in DMF) (0.345 mL, 0.173 mmol), followed by HATU (0.4 M solution in DMF) (0.216 mL, 0.086 mmol). The reaction solution was stirred at room temperature for 5 minutes, and then added to a suspension of 2-(2-aminoethyl)-7-(1H-pyrazol-1-yl)-2H-pyrazolo[3,4-c]quinolin-4-amine, 2TFA (0.75 M N, 0.25 M in DMF containing N-diisopropylethylamine) (0.345 mL, 0.086 mmol). The reaction solution was stirred at room temperature for 2 hours. The reaction solution was diluted with HO (0.1 mL) and DMF (to a total volume of 2 mL), filtered (syringe filter), and purified by preparative LC / MS using the following conditions: Column: XBridge C18, 200 mm x 19 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water (with 10 mM ammonium acetate); Mobile phase B: 95:5 acetonitrile:water (with 10 mM ammonium acetate); Gradient: 8% B hold for 0 min, 8–48% B over 23 min, then 100% B hold for 6 min; Flow rate: 20 mL / min; Column temperature: 25 °C. Fraction collection was triggered by the MS signal. Fractions containing the desired product were combined and dried by centrifugal evaporation to give N-(2-(4-amino-7-(1H-pyrazol-1-yl)-2H-pyrazolo[3,4-c]quinolin-2-yl)ethyl)picolinamide (11.4 mg, 33%). 1H NMR (500 MHz, DMSO-d6) δ 9.07 (br t, J=6.1 Hz, 1H), 8.71 (s, 1H), 8.61 (d, J=4.7 Hz, 1H), 8.52 (d, J=2.2 Hz, 1H), 8.02 - 7.94 (m, 3H), 7.85 (d, J=1.9 Hz, 1H), 7.74 (s, 1H), 7.65 (dd, J=8.5, 1.9 Hz, 1H), 7.59 (br t, J=5.5 Hz, 1H), 6.86 (br s, 2H), 6.54 (s, 1H), 4.67 - 4.63 (m, 2H), 3.90 (q, J = 5.9 Hz, 2H). Analytical LC / MS conditions: Column: Waters XBridge C18, 2.1 mm x 50 mm, 1.7 μm particles; Mobile phase A: 5:95 acetonitrile:water (with 0.1% trifluoroacetic acid); Mobile phase B: 95:5 acetonitrile:water (with 0.1% trifluoroacetic acid); Temperature: 50 °C; Gradient: 0% B to 100% B over 3 min, then hold at 100% B for 0.50 min; Flow rate: 1 mL / min; Detection: MS and UV (220 nm). m / z 399.0 [M+H] + ;RT:0.98 minutes.

[0317] Example 134. Preparation of methyl N-[[4-amino-7-(1H-pyrazol-5-yl)-[1,3]thiazolo[4,5-c]quinolin-2-yl]methyl]carbamate [ka] Step 1. tert-Butyl N-[[(7-bromo-4-hydroxyquinolin-3-yl)carbamoyl]methyl]carbamate A 500 mL round-bottom flask was charged with 3-amino-7-bromoquinolin-4-ol (10 g, 41.83 mmol, 1 equiv.), HATU (23.9 g, 62.74 mmol, 1.5 equiv.), 2-[[(tert-butoxy)carbonyl]amino]acetic acid (7.3 g, 41.83 mmol, 1 equiv.), DCM (100 mL), and DIEA (16.2 g, 125.35 mmol, 3.0 equiv.). The resulting solution was stirred at room temperature for 1 h. The resulting solution was washed with EtOAc (30 mL) and filtered. The filtrate was concentrated in vacuo. This afforded 15 g (90.5%) of tert-butyl N-[[(7-bromo-4-hydroxyquinolin-3-yl)carbamoyl]methyl]carbamate as a pink solid.

[0318] Step 2. tert-Butyl N-([7-bromo-[1,3]thiazolo[4,5-c]quinolin-2-yl]methyl)carbamate In a 500 mL round-bottom flask were placed tert-butyl N-[[(7-bromo-4-hydroxyquinolin-3-yl)carbamoyl]methyl]carbamate (20 g, 50.47 mmol, 1 equiv.), THF (250 mL), and Lawesson's reagent (16.3 g, 40.38 mmol, 0.8 equiv.). The resulting solution was stirred at 70 °C for 3 h. The reaction solution was then quenched by the addition of NaHCO (200 mL). The mixture was extracted with EtOAc (500 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. This afforded 9 g (45.2%) of tert-butyl N-([7-bromo-[1,3]thiazolo[4,5-c]quinolin-2-yl]methyl)carbamate as a pale yellow solid. LC-MS: (ES, m / z): [M+H] + =386.1.

[0319] Step 3. 7-Bromo-2-(((tert-butoxycarbonyl)amino)methyl)thiazolo[4,5-c]quinoline 5-oxide In a 100 mL round-bottom flask were placed tert-butyl N-([7-bromo-[1,3]thiazolo[4,5-c]quinolin-2-yl]methyl)carbamate (1.3 g, 3.30 mmol, 1 equiv.), DCM (20 mL), and m-CPBA (3.3 g, 13.19 mmol, 4 equiv., 70%). The resulting solution was stirred at room temperature for 5 h. The residue was loaded onto a silica gel column using dichloromethane / methanol (70:1). This afforded 1 g (73.92%) of 7-bromo-2-([[(tert-butoxy)carbonyl]amino]methyl)-[1,3]thiazolo[4,5-c]quinolin-5-ium-5-olate as a pale yellow solid. LC-MS: (ES, m / z): [M+H] + =412.1.

[0320] Step 4. tert-Butyl N-[[7-bromo-4-(tert-butylamino)-[1,3]thiazolo[4,5-c]quinolin-2-yl]methyl]carbamate In a 100 mL round-bottom flask were placed 7-bromo-2-([[(tert-butoxy)carbonyl]amino]methyl)-[1,3]thiazolo[4,5-c]quinolin-5-ium-5-olate (700 mg, 1.71 mmol, 1 equiv.), DCM (20 mL), 2-methylpropan-2-amine (623.9 mg, 8.53 mmol, 5 equiv.), and (4-methylbenzene)sulfonyl 4-methylbenzene-1-sulfonate (1.1 g, 3.41 mmol, 2 equiv.). The resulting solution was stirred at room temperature for 1 hour. The resulting mixture was concentrated. The crude product was purified by prep-TLC (PE / EA=2:1). This gave 680 mg (85.6%) of tert-butyl N-[[7-bromo-4-(tert-butylamino)-[1,3]thiazolo[4,5-c]quinolin-2-yl]methyl]carbamate as a pale yellow solid. LC-MS: (ES, m / z): [M+H] + =466.2.

[0321] Step 5. tert-Butyl N-[[4-(tert-butylamino)-7-(1H-pyrazol-5-yl)-[1,3]thiazolo[4,5-c]quinolin-2-yl]methyl]carbamate In a 30 mL sealed tube purged with and maintained under inert nitrogen was placed tert-butyl N-[[7-bromo-4-(tert-butylamino)-[1,3]thiazolo[4,5-c]quinolin-2-yl]methyl]carbamate (680 mg, 1.46 mmol, 1 equiv.), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (567.0 mg, 2.92 mmol, 2 equiv.), CsCO (1.4 g, 4.38 mmol, 3 equiv.), dioxane (10 mL), HO (1 mL), and Pd(dppf)Cl (213.8 mg, 0.29 mmol, 0.2 equiv.). The resulting solution was stirred at 100 °C for 16 h. The resulting solution was extracted with EtOAc, and the combined organic layers were concentrated in vacuo. The crude product was purified by prep-TLC (PE / EA=1:2). This afforded 420 mg (63.52%) of tert-butyl N-[[4-(tert-butylamino)-7-(1H-pyrazol-5-yl)-[1,3]thiazolo[4,5-c]quinolin-2-yl]methyl]carbamate as a pale yellow solid. LC-MS: (ES, m / z): [M+H] + =453.2.

[0322] Step 6. Methyl N-[[4-(tert-butylamino)-7-(1H-pyrazol-5-yl)-[1,3]thiazolo[4,5-c]quinolin-2-yl]methyl]carbamate A solution of tert-butyl N-[[4-(tert-butylamino)-7-(1H-pyrazol-5-yl)-[1,3]thiazolo[4,5-c]quinolin-2-yl]methyl]carbamate (150 mg, 0.33 mmol, 1 equiv.) in THF (10 mL) was placed in a 50 mL round-bottom flask. NaH (26.5 mg, 0.66 mmol, 2 equiv., 60%) was added, followed by methyl chlorocarbonate (62.6 mg, 0.66 mmol, 2 equiv.). The resulting solution was stirred at room temperature for 1 hour. The reaction solution was then quenched by the addition of MeOH. The resulting mixture was concentrated and heated to reflux in MeOH for 2 hours. The reaction solution was then cooled to room temperature and purified by prep-TLC (EA:PE=1:2). This gave 80 mg (58.80%) of methyl N-[[4-(tert-butylamino)-7-(1H-pyrazol-5-yl)-[1,3]thiazolo[4,5-c]quinolin-2-yl]methyl]carbamate as a pale yellow solid. LC-MS: (ES, m / z): [M+H] += 411.1.

[0323] Step 7. Methyl N-[[4-amino-7-(1H-pyrazol-5-yl)-[1,3]thiazolo[4,5-c]quinolin-2-yl]methyl]carbamate In a 25 mL round-bottom flask was placed methyl N-[[4-(tert-butylamino)-7-(1H-pyrazol-5-yl)-[1,3]thiazolo[4,5-c]quinolin-2-yl]methyl]carbamate (80 mg, 0.19 mmol, 1 equiv.) and TFA (5 mL). The resulting solution was stirred at 70 °C for 16 hours. The resulting mixture was concentrated in vacuo and purified by Prep-HPLC using the following conditions: column, XBridge Shield RP18 OBD column, 19 × 250 mm, 10 μm; mobile phase, water (10 mM NH4HCO3) and ACN (10% phase B to 60% in 7 min); detector, UV 254 nm. This yielded 25.9 mg (37.50%) of methyl N-[[4-amino-7-(1H-pyrazol-5-yl)-[1,3]thiazolo[4,5-c]quinolin-2-yl]methyl]carbamate as a white solid. LC Method: Column: Kinetex 2.6um EVO C18 100A 3.0mm x 50mm, 2.6µm particles; Mobile Phase A: Water-5mM NH4HCO3; Mobile Phase B: Acetonitrile; Temperature: 40°C; Gradient: 10% B to 95% B over 2.1 min, then hold at 95% B for 0.7 min; Flow Rate: 1.2 mL / min. LC RT: 1.073 min. LC-MS: (ES, m / z): [M+H] + =355.1.1H-NMR:(300 MHz, DMSO-d6, ppm) δ 13.45-12.97 (m, 1H), 8.31 (s, 1H), 8.01 (s, 1H), 7.89-7.57 (m, 3H), 7.02-6.93 (m, 2H), 6.84 (s, 1H), 4.67 (d, J = 5.9 Hz, 2H), 3.64 (s, 3H).

[0324] Example 135. Preparation of N-(2-(4-amino-7-(1H-pyrazol-5-yl)thiazolo[4,5-c]quinolin-2-yl)ethyl)benzamide [ka] Step 1. tert-Butyl N-[2-[(7-bromo-4-hydroxyquinolin-3-yl)carbamoyl]ethyl]carbamate A mixture of 3-amino-7-bromoquinolin-4-ol hydrochloride (25 g, 90.73 mmol, 1 equiv.), 3-[[(tert-butoxy)carbonyl]amino]propanoic acid (20.6 g, 108.87 mmol, 1.20 equiv.), HATU (51.7 g, 136.10 mmol, 1.5 equiv.), and DIEA (35.2 g, 272.20 mmol, 3 equiv.) in DCM (200 mL) was stirred at 25 °C for 3 h. The resulting mixture was diluted with water (200 mL). The resulting mixture was extracted with CHCl (2 × 200 mL). The combined organic layers were washed with brine (1 × 200 mL), dried over anhydrous NaSO, and concentrated in vacuo. The residue was washed with EtOAc (3x100 mL) to give tert-butyl N-[2-[(7-bromo-4-hydroxyquinolin-3-yl)carbamoyl]ethyl]carbamate (35 g, 94.02%) as a red solid. LC-MS: (ES, m / z): [M+H] + =410.1.

[0325] Step 2. tert-Butyl N-(2-[7-bromo-[1,3]thiazolo[4,5-c]quinolin-2-yl]ethyl)carbamate A solution of tert-butyl N-[2-[(7-bromo-4-hydroxyquinolin-3-yl)carbamoyl]ethyl]carbamate (3.7 g, 9.02 mmol, 1 equiv) and Lawesson's reagent (3.6 g, 8.90 mmol, 0.99 equiv) in methylbenzene (30 mL) was stirred at 100 °C for 1 h. The resulting mixture was diluted with water (100 mL). The mixture was basified to pH 8 with saturated aqueous NaHCO3. The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (1 x 100 mL), dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (5:1) to give tert-butyl N-(2-[7-bromo-[1,3]thiazolo[4,5-c]quinolin-2-yl]ethyl)carbamate (830 mg, 22.54%) as a yellow solid. LC-MS: (ES, m / z): [M+H] + =408.0. 1H-NMR: 1 H NMR (400 MHz, methanol-d4) δ 9.35 (s, 1H), 8.36 (d, J = 2.0 Hz, 1H), 8.05 (d, J = 8.7 Hz, 1H), 7.86 (m, 1H), 3.65 (t, J = 6.5 Hz, 2H), 3.45 (t, J = 6.5 Hz, 2H), 1.42 (s, 9H).

[0326] Step 3. 7-Bromo-2-(2-[[(tert-butoxy)carbonyl]amino]ethyl)-[1,3]thiazolo[4,5-c]quinolin-5-ium-5-olate A solution of tert-butyl N-(2-[7-bromo-[1,3]thiazolo[4,5-c]quinolin-2-yl]ethyl)carbamate (800 mg, 1.96 mmol, 1 equiv.) and m-CPBA (676.2 mg, 3.92 mmol, 2 equiv.) in DCM (20 mL) was stirred at room temperature for 4 hours. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with CHCl / MeOH (50:1) to give 7-bromo-2-(2-[[(tert-butoxy)carbonyl]amino]ethyl)-[1,3]thiazolo[4,5-c]quinolin-5-ium-5-olate (432 mg, 51.96%) as a yellow solid. LC-MS: (ES, m / z): [M+H] + =424.0.

[0327] Step 4. tert-Butyl N-(2-[4-amino-7-bromo-[1,3]thiazolo[4,5-c]quinolin-2-yl]ethyl)carbamate To a stirred solution of 7-bromo-2-(2-[[(tert-butoxy)carbonyl]amino]ethyl)-[1,3]thiazolo[4,5-c]quinolin-5-ium-5-olate (2 g, 4.71 mmol, 1 equiv.) and NHOH (10 mL) in DCM (30 mL) was added TsCl (1.8 g, 9.44 mmol, 2.00 equiv.). The resulting mixture was stirred at room temperature for 5 hours. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (1:1) to afford tert-butyl N-(2-[4-amino-7-bromo-[1,3]thiazolo[4,5-c]quinolin-2-yl]ethyl)carbamate (1.2 g, 60.14%) as a yellow solid. LC-MS: (ES, m / z): [M+H] + =423.0. H-NMR: 1 H NMR (400 MHz, DMSO-d6) δ 7.76 - 7.74 (m, 2H), 7.39 (m, 1H), 7.17 (d, J = 14.8 Hz, 3H), 3.46 (m, 2H), 3.32 (m, 2H), 1.37 (s, 9H).

[0328] Step 5. tert-Butyl N-[2-[4-amino-7-(1H-pyrazol-5-yl)-[1,3]thiazolo[4,5-c]quinolin-2-yl]ethyl]carbamate To a stirred solution of tert-butyl N-(2-[4-amino-7-bromo-[1,3]thiazolo[4,5-c]quinolin-2-yl]ethyl)carbamate (1.1 g, 2.60 mmol, 1 equiv.), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.1 g, 5.67 mmol, 2.18 equiv.), and CsCO (2.5 g, 7.80 mmol, 3 equiv.) in dioxane (15 mL) and HO (1.5 mL) under a nitrogen atmosphere, Pd(dppf)Cl (0.4 g, 0.52 mmol, 0.2 equiv.) was added at room temperature. The resulting mixture was stirred at 90 °C under a nitrogen atmosphere for 16 hours. The resulting mixture was concentrated in vacuo. The residue was purified by prep-TLC (CHCl / MeOH 10:1) to give tert-butyl N-[2-[4-amino-7-(1H-pyrazol-5-yl)-[1,3]thiazolo[4,5-c]quinolin-2-yl]ethyl]carbamate (690 mg, 64.69%) as a pale yellow solid. LC-MS: (ES, m / z): [M+H] + =411.2.

[0329] Step 6. 2-(2-aminoethyl)-7-(1H-pyrazol-5-yl)-[1,3]thiazolo[4,5-c]quinolin-4-amine In a 25 mL round-bottom flask was placed tert-butyl N-[2-[4-amino-7-(1H-pyrazol-5-yl)-[1,3]thiazolo[4,5-c]quinolin-2-yl]ethyl]carbamate (80 mg, 0.19 mmol, 1 equiv.), DCM (4 mL), and HCl / dioxane (4 mL). The resulting solution was stirred at room temperature for 6 hours. The resulting mixture was concentrated. The crude product was purified by Prep-HPLC using the following conditions: column, XBridge Shield RP18 OBD column, 5 μm, 19 × 150 mm; mobile phase, water (10 mM NH₄HCO₃) and ACN (20% Phase B to 45% in 8 min); detector, UV 210 / 254 nm. This gave 2-(2-aminoethyl)-7-(1H-pyrazol-5-yl)-[1,3]thiazolo[4,5-c]quinolin-4-amine (15 mg, 24.80%) as a pale yellow solid. LC-MS: (ES, m / z): [M+H] + =311.0. H-NMR: 1 H NMR (400 MHz, DMSO-d6) δ 13.04 - 12.91 (m, 1H), 8.05 (s, 1H), 7.96 - 7.62 (m, 3H), 6.94 - 6.82 (m, 3H), 3.29 (t, J = 6.6 Hz, 2H), 3.07 (t, J = 6.6 Hz, 2H), 1.86 (s, 2H).

[0330] Step 7. N-(2-(4-amino-7-(1H-pyrazol-5-yl)thiazolo[4,5-c]quinolin-2-yl)ethyl)benzamide In a 25 mL round-bottom flask were placed 2-(2-aminoethyl)-7-(1H-pyrazol-5-yl)-[1,3]thiazolo[4,5-c]quinolin-4-amine (80 mg, 0.26 mmol, 1 equiv.), DCM (5 mL), TEA (78.2 mg, 0.77 mmol, 3 equiv.), and benzoyl chloride (43.5 mg, 0.31 mmol, 1.2 equiv.). The resulting solution was stirred at room temperature for 16 hours. The resulting mixture was concentrated. The crude product was purified by Prep-HPLC using the following conditions: Column, Sunfire Prep C18 OBD column, 10 µm, 19 x 250 mm; mobile phase, water (0.05% TFA) and CAN (10% Phase B in 7 min to 60%); detector, UV 210 / 254 nm. This gave 15.5 mg (11.38%) of N-(2-(4-amino-7-(1H-pyrazol-5-yl)thiazolo[4,5-c]quinolin-2-yl)ethyl)benzamide 2,2,2-trifluoroacetate as a pale pink solid. LC Method: Column: Agilent Poroshell HPH-C 18 3.0 mm x 50 mm, 2.7 μm particles; Mobile phase A: water / 5 mmol NH4HCO3; Mobile phase B: acetonitrile; Temperature: 40 °C; Gradient: 10% B to 95% B over 2.1 min, then hold at 95% B for 0.6 min; Flow rate: 1.0 mL / min. LC RT: 1.236 min. LC-MS: (ES, m / z): [M+H] + =415.2. 1 H-NMR:(400 MHz, DMSO-d6, ppm) δ 9.29-9.08 (m, 1H), 8.78 (t, J = 5.8 Hz, 1H), 8.26 (s, 1H), 8.09-8.07 (m, 2H), 8.00-7.98 (m, 3H), 7.56-7.45 (m, 3H), 6.87 (d, J = 2.4 Hz, 1H), 3.83 (t, J = 6.3 Hz, 2H), 3.55 (t, J = 6.6 Hz, 2H).

[0331] Examples 136-141 were prepared from the appropriate starting materials following synthetic methods analogous to those described for Example 135.

[0332] Example 136. N-[2-[4-amino-7-(1H-pyrazol-5-yl)-[1,3]thiazolo[4,5-c]quinolin-2-yl]ethyl]pyridine-2-carboxamide [ka] LC Method: Column: Kinetex EVO 3.0 mm x 50 mm, 2.6 μm particles; Mobile Phase A: Water / 5 mmol NH4HCO3; Mobile Phase B: Acetonitrile; Temperature: 40 °C; Gradient: 10% B to 95% B over 2 min, then hold at 95% B for 0.6 min; Flow Rate: 1.2 mL / min. LC RT: 1.207 min. LC-MS: (ES, m / z): [M+H] + =416.0. 1 H-NMR:(400 MHz, DMSO-d6, ppm) δ 13.42-12.94 (m, 1H), 9.20 (t, J = 6.0 Hz, 1H), 8.66 (d, J = 5.0 Hz, 1H), 8.10-8.00 (m, 3H), 7.98-7.56 (m, 4H), 6.98-6.81 (m, 3H), 3.91 (m, 2H), 3.51 (t, J = 6.9 Hz, 2H).

[0333] Example 137. N-[2-[4-amino-7-(1H-pyrazol-5-yl)-[1,3]thiazolo[4,5-c]quinolin-2-yl]ethyl]oxetane-2-carboxamide [ka] LC Method: Column: Express C18 2.1 mm x 50 mm, 2.7 μm particles; Mobile Phase A: Water + 0.05% TFA; Mobile Phase B: Acetonitrile + 0.05% TFA; Temperature: 40 °C; Gradient: 5% B to 100% B over 2 min, then hold at 100% B for 0.7 min; Flow Rate: 1.0 mL / min. LC RT: 0.829 min. LC-MS: (ES, m / z): [M+H] + =395.1. 1H-NMR:(400 MHz, DMSO-d6, ppm) δ 13.34 (s, 1H), 8.39 (d, J = 6.2 Hz, 1H), 8.01 (s, 1H), 7.83-7.75 (m, 3H), 6.98-6.82 (m, 3H), 4.92 (m, 1H), 4.65-4.51 (m, 2H), 3.70 (m, 2H), 3.41 (t, J = 6.7 Hz, 2H), 2.94 - 2.85 (m, 1H), 2.45 (m, 1H).

[0334] Example 138. 2-(3-aminopropyl)-7-(1H-pyrazol-5-yl)-1,3]thiazolo[4,5-c]quinolin-4-amine [ka] LC Method: Column: Shim-pack XR-ODS, 3.0 mm x 50 mm, 2.2 μm particles; Mobile Phase A: Water (with 0.05% TFA); Mobile Phase B: Acetonitrile (with 0.05% TFA); Temperature: 40 °C; Gradient: 5% B to 95% B over 2 min, then hold at 95% B for 0.7 min; Flow Rate: 1.5 mL / min. LC RT: 0.776 min. LC-MS: (ES, m / z): [M+H] + =325.3. 1 H NMR:(400 MHz, methanol-d4, ppm) δ 8.01 (d, J = 1.6 Hz, 1H), 7.83-7.69 (m, 3H), 6.77 (d, J = 2.3 Hz, 1H), 3.26 (t, J = 7.5 Hz, 2H), 2.97-2.89 (m, 2H), 2.18-2.11 (m, 2H).

[0335] Example 139. N-[3-[4-amino-7-(1H-pyrazol-5-yl)-[1,3]thiazolo[4,5-c]quinolin-2-yl]propyl]acetamide [ka] LC Method: Column: Kinetex EVO, 3.0 mm x 50 mm, 2.6 μm particles; Mobile Phase A: Water (with 10 mM NH4HCO3); Mobile Phase B: Acetonitrile; Temperature: 40 °C; Gradient: 10% B to 95% B over 2 min, then hold at 95% B for 0.6 min; Flow Rate: 1.2 mL / min. LC RT: 1.020 min. LC-MS: (ES, m / z): [M+H] + =366.95. 1 H NMR (400 MHz, DMSO-d6, ppm) δ 13.45-12.96 (m, 1H), 8.02-7.96 (m, 2H), 7.83-7.79 (m, 3H), 6.98-6.85 (m, 3H), 3.22-3.17 (m, 4H), 2.08-1.95 (m, 2H), 1.83 (s, 3H).

[0336] Example 140. N-{[4-amino-7-(1H-pyrazol-3-yl)-[1,3]thiazolo[4,5-c]quinolin-2-yl]methyl}-N-ethylacetamide [ka] LC Method: Column: Shim-pack XR-ODS, 3.0 mm x 50 mm, 2.2 μm particles; Mobile Phase A: Water (with 0.05% TFA); Mobile Phase B: Acetonitrile (with 0.05% TFA); Temperature: 40 °C; Gradient: 5% B to 50% B over 2 min, 50% B to 100% B over 0.3 min, then hold at 100% B for 0.4 min; Flow Rate: 1.2 mL / min. LC RT: 1.679 min. LC-MS: (ES, m / z): [M+H]+ = 367.1. H-NMR:(CD3OD, ppm):δ 8.061(s, 1H), 7.848-7.741(m, 3H), 6.785(s, 1H), 5.091-4.990(m, 2H), 3.654-3.572(m, 2H), 2.252(s, 3H), 1.301-1.166(m, 3H).

[0337] Example 141. 2-[3-(benzyloxy)propyl]-7-(1H-pyrazol-3-yl)-[1,3]thiazolo[4,5-c]quinolin-4-amine [ka] 1 H NMR (400 MHz, methanol-d4) δ 8.07 (br s, 1H), 7.81 (br s, 3H), 7.37 - 7.14 (m, 5H), 6.80 (br s, 1H), 4.53 (s, 2H), 3.66 (t, J=6.0 Hz, 2H), 2.37 - 2.14 (m, 2H). LC-MS:(ES,m / z):[M+H] + =416.1.

[0338] Example 142. Preparation of 3-[4-amino-7-(1H-pyrazol-3-yl)-[1,3]thiazolo[4,5-c]quinolin-2-yl]propan-1-ol [ka] A solution of 2-[3-(benzyloxy)propyl]-7-(1H-pyrazol-3-yl)-[1,3]thiazolo[4,5-c]quinolin-4-amine (290 mg, 0.70 mmol, 1.00 equiv) in ethanol (30 mL) was placed in a 25 mL round-bottom flask. Pd(OH) (29 mg) was added to the solution. The resulting solution was degassed and refilled with hydrogen. The resulting solution was stirred in a water bath at 80° C. for 2 hours. The solid was collected by filtration. The resulting mixture was concentrated in vacuo. The crude product was purified by Prep-HPLC (HPLC-10) using the following conditions: column, XBridge Shield RP18 OBD column, 19*250 mm, 10 μm; mobile phase, water (10 mM NH4HCO3) and ACN (10.0% ACN to 36.0% in 8 min); detector, 254 / 210 nm. This gave 35.7 mg (16%) of 3-[4-amino-7-(1H-pyrazol-3-yl)-[1,3]thiazolo[4,5-c]quinolin-2-yl]propan-1-ol as a white solid. LC-MS: (ES, m / z): [M+H] + =326.0. H-NMR:(DMSO-d6, 300 MHz, ppm):δ 8.02 (s, 1H), 7.82-7.58 (m, 3H), 6.89-6.83 (m, 3H), 4.65 (t, J = 5.1 Hz, 1H), 3.58-3.52 (m, 2H), 3.23 (t, J = 5.1 Hz, 2H), 2.05-1.96 (m, 2H).

[0339] Example 143. Preparation of 2-[(dimethylamino)methyl]-7-(1H-pyrazol-5-yl)-[1,3]thiazolo[4,5-c]quinolin-4-amine [ka] In a 50 mL round-bottom flask, 2-(aminomethyl)-7-(1H-pyrazol-5-yl)-[1,3]thiazolo[4,5-c]quinolin-4-amine (50 mg, 0.17 mmol, 1 equiv.), MeOH (5 mL), AcOH (0.1 mL), HCHO (41.1 mg, 0.51 mmol, 3.00 equiv., 37%), and NaBH (19.1 mg, 0.51 mmol, 3.00 equiv.) were added. The resulting solution was stirred at room temperature for 2 hours. The resulting mixture was concentrated. The crude product was purified by Prep-HPLC using the following conditions: Column, XBridge Shield RP18 OBD column, 19 x 250 mm, 10 μm; Mobile phase, water (10 mM NHHCO) and ACN (20% Phase B to 60% in 8 min); Detector, UV 254 nm. This gave 10.1 mg (18.45%) of 2-[(dimethylamino)methyl]-7-(1H-pyrazol-5-yl)-[1,3]thiazolo[4,5-c]quinolin-4-amine as a white solid. LC Method: Column: Kinetex EVO C18 3.0 mm x 50 mm, 2.6 μm particles; Mobile Phase A: Water / 5 mmol NH4HCO3; Mobile Phase B: Acetonitrile; Temperature: 40 °C; Gradient: 10% B to 95% B over 2 min, then hold at 95% B for 0.6 min; Flow Rate: 1.2 mL / min. LC RT: 0.81 min. LC-MS: (ES, m / z): [M+H] + =325.0. 1 H-NMR:(400 MHz, DMSO-d6, ppm) δ 12.96 (s, 1H), 8.01 (s, 1H), 7.83-7.57 (m, 3H), 6.98 (s, 2H), 6.84 (s, 1H), 3.94 (s, 2H), 2.37 (s, 6H).

[0340] Example 144. Preparation of 2-[3-(diethylamino)propyl]-7-(1H-pyrazol-5-yl)-[1,3]thiazolo[4,5-c]quinolin-4-amine [ka] A solution of 2-(3-aminopropyl)-7-(1H-pyrazol-5-yl)-[1,3]thiazolo[4,5-c]quinolin-4-amine (70 mg, 0.22 mmol, 1 equiv.), acetaldehyde (14.3 mg, 0.32 mmol, 1.5 equiv.), and NaBHCN (27.1 mg, 0.43 mmol, 2 equiv.) in CHCOOH (0.5 mL) and MeOH (10 mL) was stirred overnight at room temperature. The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC using the following conditions (Column: XBridge Prep OBD C18 column 30x150 mm 5 um; Mobile phase A: water (10 mM NH4HCO3), Mobile phase B: ACN; Flow rate: 25 mL / min; Gradient: 25% B to 45% B over 10 min; 254 / 210 nm; RT: 8 min) to give 2-[3-(diethylamino)propyl]-7-(1H-pyrazol-5-yl)-[1,3]thiazolo[4,5-c]quinolin-4-amine (9.8 mg, 11.94%) as an off-white solid. LC Method: Column: Shim-pack XR-ODS 3.0 mm x 50 mm, 2.2 μm particles; Mobile Phase A: Water (with 0.05% TFA); Mobile Phase B: Acetonitrile (with 0.05% TFA); Temperature: 40 °C; Gradient: 5% B to 95% B over 1.7 min, then hold at 95% B for 1.0 min; Flow Rate: 1.5 mL / min. LC RT: 0.753 min. LC-MS: (ES, m / z): [M+H] + =381.4. 1 H-NMR:(300 MHz, CD3OD, ppm) δ 8.03 (s, 1H), 7.83 (d, J = 8.2 Hz, 1H), 7.77-7.70 (m, 2H), 6.78 (d, J = 2.3 Hz, 1H), 3.23 (t, J = 7.4 Hz, 2H), 2.67-2.60 (m, 6H), 2.16-2.08 (m, 2H), 1.09-1.05 (m, 6H).

[0341] Example 145. Preparation of 2-[(dimethylamino)methyl]-7-(1H-pyrazol-5-yl)-[1,3]oxazolo[4,5-c]quinolin-4-amine [ka] Step 1. tert-Butyl N-([7-bromo-[1,3]oxazolo[4,5-c]quinolin-2-yl]methyl)carbamate In a 500 mL round-bottom flask was placed tert-butyl N-[[(7-bromo-4-hydroxyquinolin-3-yl)carbamoyl]methyl]carbamate (10 g, 25.24 mmol, 1 equiv.), DCM (250 mL), CClCCl (9.0 g, 37.86 mmol, 1.50 equiv.), TEA (10.2 g, 100.80 mmol, 3.99 equiv.), and PPh (9.9 g, 37.75 mmol, 1.50 equiv.). The resulting solution was stirred at room temperature for 1 hour. The resulting mixture was diluted with water (200 mL). The resulting solution was extracted with dichloromethane (3 × 200 mL), and the combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was loaded onto a silica gel column with ethyl acetate / petroleum ether (1:4) to give 5 g (52.38%) of tert-butyl N-([7-bromo-[1,3]oxazolo[4,5-c]quinolin-2-yl]methyl)carbamate as a pink solid. LC-MS: (ES, m / z): [M+H] + =378.0.

[0342] Step 2. 7-Bromo-2-([[(tert-butoxy)carbonyl]amino]methyl)-[1,3]oxazolo[4,5-c]quinolin-5-ium-5-olate In a 100 mL round-bottom flask were placed tert-butyl N-([7-bromo-[1,3]oxazolo[4,5-c]quinolin-2-yl]methyl)carbamate (4.2 g, 11.10 mmol, 1 equiv.), DCM (50 mL), and m-CPBA (9.6 g, 55.63 mmol, 5.01 equiv.). The resulting solution was stirred at room temperature for 2 hours. The resulting mixture was concentrated in vacuo. The residue was loaded onto a silica gel column with dichloromethane / methanol (50:1). The resulting mixture was concentrated to give 1.8 g (41.12%) of 7-bromo-2-([[(tert-butoxy)carbonyl]amino]methyl)-[1,3]oxazolo[4,5-c]quinolin-5-ium-5-olate as a yellow solid. LC-MS: (ES, m / z): [M+H] += 394.0.

[0343] Step 3. tert-Butyl N-([4-amino-7-bromo-[1,3]oxazolo[4,5-c]quinolin-2-yl]methyl)carbamate A 100 mL round-bottom flask was charged with 7-bromo-2-([[(tert-butoxy)carbonyl]amino]methyl)-[1,3]oxazolo[4,5-c]quinolin-5-ium-5-olate (1.8 g, 4.57 mmol, 1 equiv.) in DCM (5 mL) and NH₃H₂O (5 mL). TsCl (1.8 g, 9.44 mmol, 2.07 equiv.) was then added. The resulting solution was stirred at room temperature for 1 hour. The resulting mixture was concentrated in vacuo. The residue was loaded onto a silica gel column using dichloromethane / methanol (50:1). The resulting mixture was concentrated in vacuo. This afforded 950 mg (52.91%) of tert-butyl N-([4-amino-7-bromo-[1,3]oxazolo[4,5-c]quinolin-2-yl]methyl)carbamate as an orange solid. LC-MS: (ES, m / z): [M+H] + =393.0.

[0344] Step 4. tert-Butyl N-[[4-amino-7-(1H-pyrazol-5-yl)-[1,3]oxazolo[4,5-c]quinolin-2-yl]methyl]carbamate In a 50 mL round-bottom flask under N2, tert-butyl N-([4-amino-7-bromo-[1,3]oxazolo[4,5-c]quinolin-2-yl]methyl)carbamate (900 mg, 2.29 mmol, 1 equiv.), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.9 g, 4.58 mmol, 2.00 equiv.), Cs2CO3 (2.2 g, 6.87 mmol, 3.00 equiv.), and Pd(dppf)Cl2 (334.9 mg, 0.46 mmol, 0.20 equiv.) in dioxane (5 mL) and HO (0.5 mL) were placed. The resulting mixture was stirred under a nitrogen atmosphere at 105 °C overnight. The resulting mixture was concentrated in vacuo. The residue was purified on a silica gel column with ethyl acetate / petroleum ether (1:4) to give 680 mg (78.10%) of tert-butyl N-[[4-amino-7-(1H-pyrazol-5-yl)-[1,3]oxazolo[4,5-c]quinolin-2-yl]methyl]carbamate as a brown solid. LC-MS: (ES, m / z): [M+H] + =381.2.

[0345] Step 5. 2-(Aminomethyl)-7-(1H-pyrazol-5-yl)-[1,3]oxazolo[4,5-c]quinolin-4-amine In a 25 mL round-bottom flask was placed tert-butyl N-[[4-amino-7-(1H-pyrazol-5-yl)-[1,3]oxazolo[4,5-c]quinolin-2-yl]methyl]carbamate (100 mg, 0.26 mmol, 1 equiv.) in DCM (5 mL) and HCl (4N) in dioxane (2 mL). The resulting solution was stirred at room temperature for 1.5 hours. The resulting mixture was concentrated in vacuo. The crude product was purified by Prep-HPLC using the following conditions: Column: XBridge Shield RP18 OBD column, 5 μm, 19 × 150 mm; Mobile phase: water (10 mM NH4HCO3) and ACN (15% Phase B to 33% in 8 minutes); Detector: UV 254 nm. This gave 8.9 mg (12.08%) of 2-(aminomethyl)-7-(1H-pyrazol-5-yl)-[1,3]oxazolo[4,5-c]quinolin-4-amine as a yellow solid. LC-MS: (ES, m / z): [M+H] + =281.1. H-NMR: 1 H NMR (400 MHz, DMSO-d6) δ 12.96 (s, 1H), 8.35 (m, 4H), 6.88 (d, J = 34.5 Hz, 3H), 4.16 (s, 2H), 1.24 (s, 1H).

[0346] Step 6. 2-[(Dimethylamino)methyl]-7-(1H-pyrazol-5-yl)-[1,3]oxazolo[4,5-c]quinolin-4-amine In a 50 mL round-bottom flask, 2-(aminomethyl)-7-(1H-pyrazol-5-yl)-[1,3]oxazolo[4,5-c]quinolin-4-amine (40 mg, 0.14 mmol, 1 equiv.), HCHO (12.9 mg, 0.43 mmol, 3.0 equiv.) in MeOH (2 mL), and CH3COOH (0.2 mL) were placed. NaBH3CN (26.9 mg, 0.43 mmol, 3.0 equiv.) was then added. The resulting solution was stirred at room temperature for 1 hour. The resulting mixture was concentrated. The crude product was purified by Prep-HPLC using the following conditions: Column: XBridge Prep OBD C18 column 30x150 mm 5 μm; Mob...

Claims

1. Formula (IIg): 【Chemistry 1】 [In the formula, R 1 is selected from H, halo, and C 1-4 alkyl; R 1a is H, C 1-6 alkyl substituted with 0-6 F or C 3-6 cycloalkyl substituted with 0-6 F; R 2 is -Y-R 6 ; Y is C 1-6 alkylene substituted with 0-3 R e ; R 3 is pyrazolyl; R 4 is selected from H and halo; R 6 is OH, CN, OR a , —C(O)R a , NR b R c , —C(O)NR b R k , —SO 2 (C 1-4 alkyl); 【Chemistry 2】 and heteroaryl containing 5-10 ring atoms, where the 1-4 ring atoms are each independently selected from N, N(R f ), O and S, and the heteroaryl is substituted with 0-3 R d ; Each R a is independently one of the following groups: (i) C 1-6 alkyl substituted with 0 to 3 R e ; (ii) C 3-6 cycloalkyl substituted with 0 to 2 R g ; (iii) -(C 0-2 alkylene)-heterocyclyl containing 4 to 10 ring atoms, wherein the 1 to 3 ring atoms are each independently selected from N(R f ), O and S, and the heterocyclyl is substituted with 0 to 3 R g ; (iv) -(C 0-2 alkylene)-(C 6-10 aryl), wherein the aryl is substituted with 0 to 3 R d ; or (v) -(C 0-2 alkylene)-heteroaryl containing 5 to 10 ring atoms, wherein the 1 to 3 ring atoms are each independently selected from N, N(R f ), O and S, and the heteroaryl is substituted with 0 to 3 R d ; Each R b is independently H or R a ; each R c is independently selected from H, —C(O)R a , —C(O)OR a , —C(O)NR j R k , —S(O) 2 R h , C 1-6 alkyl substituted with 0-2 R e , —(C 0-3 alkylene)-(phenyl substituted with 0-4 R n ), and —(C 0-3 alkylene)-heteroaryl containing 5-6 ring atoms, wherein the 1-4 ring atoms are each independently selected from N, N(R f ), O, and S, and the heteroaryl is substituted with 0-3 R n ; or R b and R c together with the nitrogen atom to which they are each bonded form a heterocyclyl containing 3 to 10 ring atoms, 1 to 3 ring atoms of which are each independently selected from N(R f ), O and S, and the heterocyclyl is substituted with 0 to 3 R g ; R d are each independently selected from OH, halo, CN, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, -C(O)O(C 1-4 alkyl), NH 2 , N(C 1-4 alkyl) 2 , -CONH 2 , -CONH(C 1-4 alkyl), -NHC(O)(C 1-4 alkyl), -NHC(O)O(C 1-4 alkyl), -S(O) 2 (C 1-4 alkyl), benzoxy, C 1-4 alkyl substituted with 0-2 R e , phenyl, and heteroaryl containing 5 to 6 ring atoms, said 1 to 4 ring atoms being each independently selected from N, N(R f ), O and S, and said heteroaryl being substituted with 0-2 R n ; R e are independently selected from halo, OH, CN, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, -CONH 2 and -CONH(C 1-4 alkyl); R f is independently selected from H, C 1-4 alkyl, —C(O)C 1-4 alkyl, and —C(O)(C 1-4 haloalkyl); Each R g is independently oxo or R d ; R h is independently C 1-4 alkyl, C 3-6 cycloalkyl or phenyl substituted with 0-2 R n ; R j is independently H or C 1-4 alkyl; R k is independently selected from H, C 1-4 alkyl and phenyl; and R n are independently selected from halo, C 1-4 alkyl and C 1-4 alkoxy. or a stereoisomer, tautomer, or pharma- ceutically acceptable salt thereof.

2. R １ is H, Cl or C １－４ is alkyl; R １ａ is H or C １－４ is alkyl; R ２ But -(CH ２ ) １－４ -OH, -(CH ２ ) １－２ -OR ａ , -(CH ２ ) １－２ N.H. ２ , -(CH ２ ) １－２ NH(0 to 1 R ｅ C substituted with １－４ alkyl), -(CH ２ ) １－２ N(C １－４ Alkyl) ２ , -(CH ２ ) １－２ -NHC(O)R ａ , -(CH ２ ) ２－３ NHS(O) ２ (C １－４ alkyl), -(CH ２ ) ２－３ NHS(O) ２ Ph, 【Chemistry 3】 Selected from: R ３ but, 【Chemistry 4】 and R ４ is H; R ａ is C substituted with 0 to 2 F １－４ Alkyl, 【Chemistry 5】 and heteroaryl, which includes thiazolyl, oxazolyl, N-C １－４ alkyl-imidazolyl and pyridyl, wherein the heteroaryl is selected from 0 to 2 R ｄ is substituted with; R ｄ each independently represents F, Cl, OH, CN, C １－４ Alkyl, C １－４ Alkoxy, C １－４ Haloalkyl and -NHC(O)(C １－４ alkyl); and R ｅ But, F, OH, C １－４ Alkoxy and C １－４ haloalkyl, 2. A compound according to claim 1, or a stereoisomer, tautomer or pharma- ceutically acceptable salt thereof.

3. R ２ But -(CH ２ ) １－２ N.H. ２ , -(CH ２ ) １－２ N(C １－４ Alkyl) ２ , -(CH ２ ) １－２ NH(0 to 1 R ｅ C substituted with １－４ alkyl), -(CH ２ ) １－２ -NHC(O)R ａ Selected from: R ３ but, 【Chemistry 6】 and R ａ is C substituted with 0 to 2 F １－４ Alkyl, 【Chemistry 7】 and heteroaryl, which is selected from thiazolyl and pyridyl, wherein the heteroaryl is selected from 0 to 2 R ｄ is substituted with; R ｄ Each independently represents F, Cl, CN, C １－４ Alkyl, C １－４ Alkoxy and C １－４ haloalkyl; and R ｅ But F, OH, OCH ３ , C.H.F. ２ and C.F. ３ Selected from:

3. A compound according to claim 2, or a stereoisomer, tautomer or pharma- ceutically acceptable salt thereof.

4. below: 【Chemistry 8】 【Chemistry 9】 【Chemistry 10】 【Chemistry 11】 【Chemistry 12】 2. The compound of claim 1, selected from: or a pharma- ceutically acceptable salt thereof.

5. A pharmaceutical composition comprising a compound according to any one of claims 1 to 4, or a pharma- ceutically acceptable salt thereof, and one or more pharma- ceutically acceptable excipients.

6. A medicament comprising the compound according to any one of claims 1 to 4 or a pharma- ceutically acceptable salt thereof, or the pharmaceutical composition according to claim 5.

7. 6. The pharmaceutical composition according to claim 5 for use in the treatment of cancer.

8. Cancers include acute myeloid leukemia, adrenal cortical carcinoma, Kaposi's sarcoma, lymphoma, anal cancer, appendix cancer, teratocarcinoma / rhabdoid tumor, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, brain tumor, breast cancer, bronchial tumor, carcinoid tumor, cardiac tumor, cervical cancer, chordoma, chronic lymphocytic leukemia, chronic myeloproliferative neoplasm, colon cancer, colorectal cancer, craniopharynx cancer, bile duct cancer, endometrial cancer, ependymoma, esophageal cancer, nasal neuroblastoma, Ewing's sarcoma, eye cancer, fallopian tube cancer, gallbladder cancer, and gastrointestinal carcinoid 8. The pharmaceutical composition of claim 7, wherein the cancer is selected from tumors, gastrointestinal stromal tumors, germ cell tumors, hairy cell leukemia, head and neck cancer, heart cancer, liver cancer, hypopharyngeal cancer, pancreatic cancer, kidney cancer, laryngeal cancer, chronic myeloid leukemia, lip and oral cavity cancer, lung cancer, melanoma, Merkel cell carcinoma, mesothelioma, oral cancer, lip cancer, osteosarcoma, ovarian cancer, penile cancer, pharyngeal cancer, prostate cancer, rectal cancer, salivary gland cancer, skin cancer, small intestine cancer, soft tissue sarcoma, testicular cancer, throat cancer, thyroid cancer, urethral cancer, uterine cancer, vaginal cancer and vulvar cancer.

9. 8. The pharmaceutical composition of claim 7, wherein the cancer is selected from breast cancer, colon cancer, rectal cancer, colorectal cancer, pancreatic cancer and prostate cancer.

10. 8. The pharmaceutical composition of claim 7, wherein the cancer is selected from hormone receptor positive breast cancer, macrosatellite stable colon or rectal cancer, pancreatic cancer and prostate cancer.

11. The pharmaceutical composition of any one of claims 5 and 7 to 10, which is administered in combination with one or more additional cancer therapies.

12. 12. The pharmaceutical composition of claim 11, wherein the one or more additional cancer treatments comprise surgery, radiation therapy, chemotherapy, toxin therapy, immunotherapy, cryotherapy or gene therapy, or a combination thereof.

13. Other cancer treatments include nivolumab, pembrolizumab, PDR001, MEDI-0680, cemiplimab, JS001, BGB-A317, INCSHR1210, TSR-042, GLS-010, AM-0001, STI-1110, AGEN2034 , MGD013, IBI308, BMS-936559, atezolizumab, durvalumab, avelumab, STI-1014, CX-072, LY3300054, CK-301, urelumab, PF-05082566, MEDI64 69, TRX518, varlilumab, CP-870893, BMS-986016, MGA271, lirilumab, IPH2201, emactuzumab, INCB024360, galunisertib, ulocuplumab umab, BKT140, Bavituximab, CC-90002, bevacizumab, MNRP1685A, ipilimumab, MK-1308, AGEN-1884 and tremelimumab. The pharmaceutical composition of claim 11, comprising one or more agents selected from the group consisting of tremelimumab, ...

14. 12. The pharmaceutical composition of claim 11, wherein the additional cancer treatment comprises one or more agents selected from nivolumab, ipilimumab, pembrolizumab, atezolizumab, durvalumab, and avelumab.

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